In DMSO-d6; ##Related to TMS; a Experimental; b GIAO 6-31G\*\*; c CSGT 6-31G\*\*; d GIAO 6-311++G\*\*

Table 6. The experimental and calculated 1H chemical shifts in ppm


Structural and Vibrational Properties and NMR Characterization of (2'-furyl)-Imidazole Compounds 177

a B3LYP/6-311++G\*\*, average values; b In CDCl3; c Related to TMS

176 Magnetic Resonance Spectroscopy

N–H peak results. The most intense peak of this spectrum belongs to the C atom of the reference, while the following four peaks belong to the C atoms of the furyl group. The calculated chemical shifts are in agreement with the experimental ones, with RMSD values of 2.53 and 0.32 ppm for the 13C and 1H atoms, respectively. The agreement with our experimental data in these solvents is good, except for the H atom of the H–N bond in chloroform. This is because the calculations are for the gas phase, while the experimental values are for the CDCl3 solution, where the molecular interactions are important. It is important to mention that the registered NMR spectra at room temperature and low temperature were not sufficient to identify the tautomeric mixture of 1, because the speed of

Chem. Shift C(10) C(11) C(5) C(12) C(2) C(4) C(7) Exp.a 106.4 111.6 122.5 122.5 138.0 142.5 146.2 *syn* b 93.9 100.7 102.8 119.7 126.4 129.6 135.5 c 99.2 104.1 107.9 123.6 132.0 135.3 141.3 d 103.8 111.4 113.4 132.6 141.0 143.8 135.9 *anti* b 97.5 102.5 102.6 119.6 126.7 127.9 136.4 c 102.3 105.7 107.9 123.7 132.3 134.1 142.4 d 107.8 113.6 113.5 132.9 141.3 142.1 151.5 **AVERAGEb** 98.7 101.6 102.7 119.7 126.6 128.7 135.9 c 100.8 104.9 107.9 123.9 132.1 134.7 141.8 d 105.8 112.5 113.5 138.8 141.1 142.9 151.0 # In DMSO-d6; ##Related to TMS; a Experimental; b GIAO 6-31G\*\*; c CSGT 6-31G\*\*; d GIAO 6-311++G\*\*

Chem. shifts H C(10) H C(11) H C(12) H C(4) H C(5) Exp.a 6.57 6.82 6.82 7.10 7.71 *syn* b 6.02 6.09 7.16 6.50 6.87 c 3.60 3.79 4.74 4.10 4.38 d 6.26 6.70 7.37 6.70 7.05 *anti* b 6.70 6.16 7.05 6.47 6.85 c 3.88 4.30 4.66 4.12 4.33 d 3.92 6.38 7.25 6.70 7.03 **AVERAGE**B 6.36 6.12 7.10 6.49 6.86 c 3.74 4.04 7.70 4.11 4.35 d 5.09 6.32 7.31 6.70 7.04 # In DMSO-d6; ##Related to TMS; a Experimental; b GIAO 6-31G\*\*; c CSGT 6-31G\*\*; d GIAO 6-311++G\*\*

exchange of protons is higher than the response time of NMR.

Table 5. Experimental# and calculated## 13C chemical shifts in ppm

Table 6. The experimental and calculated 1H chemical shifts in ppm

Table 7. Experimental and calculated Chemical shifts (in ppm) for 4(5)-(2'-furyl)-imidazole

A comparison between the experimental and calculated chemical shifts for the C and H atoms for N-(2'-furyl)-imidazole are given in Tables 8 and 9, respectively. The calculation results show that the GIAO method reproduces quite well the 13C and 1H experimental chemical shifts values as shown by the calculated root mean square deviations (RMSD) values for each conformer. Furthermore, the shifts of the H atoms for both structures are similar in both conformers and practically equal to the average values. As expected, the latter values have a better agreement with the experimental data, probably because both conformers are present in the solution.


a Related to DCCl3; b GIAO, B3LYP/6-311++G\*

Table 8. 13C Experimental and calculated Chemical shifts (in ppm) for N-(2'-furyl)-imidazole


a Related to DCCl3; b GIAO, B3LYP/6-311++G\*

Table 9. 1H Experimental and calculated Chemical shifts (in ppm) for N-(2'-furyl)-imidazole

Structural and Vibrational Properties and NMR Characterization of (2'-furyl)-Imidazole Compounds 179

A notable difference between the frequencies of the C-H stretching modes is observed. The rotating of the imidazole ring with the furan ring increase or decrease the frequencies

> 2-(2'-furyl) imidazole

1300,1260 1229,1222 1106,1102 1084 1010

> 883,862 843,835 810,797 748,733 719

All compounds studied in this chapter were synthesized and only, the 2-(2'-furyl)-1Himidazole compound was isolated as a crystalline solid, which allowed the molecular structure's determination by means of the ray X diffraction. In all cases, the theoretical method that better reproduces the experimental data is the B3LYP/6-311++G\*\* combination, for this, the calculated molecular geometries and vibrational spectra were performed at this theory level. Each molecule presents two stable conformations, anti and syn, according to the orientations of the furan and imidazole rings. The calculations predicted that the conformation syn is the most stable, with exception of the isomer one, for which the anti conformer was the most stable. The distances among both rings only present appreciable changes for the isomer one which because the union in this case is by means of the C-N instead C-C like in the remaining ones. In the 4(5)-(2'-Furyl) Imidazole isomers, the infrared spectra at low temperature allowed the complete assignment of the both member's series. The PEM analysis shows that when the -electron delocalizated surface is longer, the hydrogen atoms are less retained by the carbon atoms and, for this reason, an increasing in

*anti, syn anti, syn* 

4-(2'-furyl) imidazole

5-(2'-furyl) imidazole

assigned to the alilic hydrogen.

N-(2'-furyl) imidazole

Table 11. Experimental vibrational frequencies for C-H groups

Description

C-H

Β C-H

C-H

**4. Conclusions** 

#### **3. Vibrational analysis**

For this analysis the vibrational frequencies were separated in two groups, the first group corresponds to the skeletal vibrations ring and the second ones to those vibrations related to the C-H groups, both are show in Tables 10 and 11, respectively. The analysis shows that the frequencies values for the C=C stretching of the imidazole ring is according to the respective length bonds. Furthermore, the frequencies values for the C=N stretching mode are longer for the N-(2'-furyl)-Imidazole, due to the highest p character of bound, which impedes the resonance effects between two rings. Changes in the frequencies values related to the C-O stretching modes are not observed, in accordance with the corresponding length bonds, where the variations were only observed for the imidazole ring. The vibrational ring modes are practically observed in the same region for all series molecules, while the corresponding torsions are in agreement with the imidazole ring in all series members and they are next to the reported values for the imidazole compound.


Table 10. Experimental Vibrational Frequencies for all modes of imidazole and furan rings of the series.


A notable difference between the frequencies of the C-H stretching modes is observed. The rotating of the imidazole ring with the furan ring increase or decrease the frequencies assigned to the alilic hydrogen.

Table 11. Experimental vibrational frequencies for C-H groups

#### **4. Conclusions**

178 Magnetic Resonance Spectroscopy

For this analysis the vibrational frequencies were separated in two groups, the first group corresponds to the skeletal vibrations ring and the second ones to those vibrations related to the C-H groups, both are show in Tables 10 and 11, respectively. The analysis shows that the frequencies values for the C=C stretching of the imidazole ring is according to the respective length bonds. Furthermore, the frequencies values for the C=N stretching mode are longer for the N-(2'-furyl)-Imidazole, due to the highest p character of bound, which impedes the resonance effects between two rings. Changes in the frequencies values related to the C-O stretching modes are not observed, in accordance with the corresponding length bonds, where the variations were only observed for the imidazole ring. The vibrational ring modes are practically observed in the same region for all series molecules, while the corresponding torsions are in agreement with the imidazole ring in all series members and they are next to

> 2-(2'-furyl)- Imidazole

> > 1625 1504

1428, 1393 1365, 1358 1159, 1133

> 1181 1075

> > 897 894

965,952 927,911

> 665 650

624,622 593,591

(C, N-C)int 409 402 404 404

Table 10. Experimental Vibrational Frequencies for all modes of imidazole and furan rings

*anti, syn anti, syn* 

 (C=C)imidazol 1521 1547, 1538 1516 1518 (C=N) 1493 1462,1453 1484 1484

(C-C) 1374 1380 1378 1342

4-(2'-furyl)- Imidazole

> 1638 1467

> 1304 1275 1120

> 1162 1067

> > 885 868

> > 942 916

> > 685 655

> > 621 591

5-(2'-furyl)- Imidazole

> 1638 1491

> 1307 1342 1119

> 1162 1067

> > 885 868

> > 964 918

> > 655 634

> > 624 591

**3. Vibrational analysis** 

Description

(C=C)furano

(C-N)

βRf

βRi

Ri

Rf

of the series.

(C-O) <sup>1162</sup>

the reported values for the imidazole compound.

N-(2'-furyl)- Imidazole

> 1625 1511

1305, 1285 1224 1104

1065

904 892

984 910

656 650

615 594 All compounds studied in this chapter were synthesized and only, the 2-(2'-furyl)-1Himidazole compound was isolated as a crystalline solid, which allowed the molecular structure's determination by means of the ray X diffraction. In all cases, the theoretical method that better reproduces the experimental data is the B3LYP/6-311++G\*\* combination, for this, the calculated molecular geometries and vibrational spectra were performed at this theory level. Each molecule presents two stable conformations, anti and syn, according to the orientations of the furan and imidazole rings. The calculations predicted that the conformation syn is the most stable, with exception of the isomer one, for which the anti conformer was the most stable. The distances among both rings only present appreciable changes for the isomer one which because the union in this case is by means of the C-N instead C-C like in the remaining ones. In the 4(5)-(2'-Furyl) Imidazole isomers, the infrared spectra at low temperature allowed the complete assignment of the both member's series. The PEM analysis shows that when the -electron delocalizated surface is longer, the hydrogen atoms are less retained by the carbon atoms and, for this reason, an increasing in

Structural and Vibrational Properties and NMR Characterization of (2'-furyl)-Imidazole Compounds 181

[12] Sztanke, K.; Fidecka, S.; dzierska, E. K; Karczmarzyk, Z.; Pihlaja, K.; Matosiuk, D., 2005,

[13] Ledesma, A. E.; Brandán, S. A.; Zinczuk, J.; Piro, O. E.; López González, J. J.; Ben

[15] Ledesma A. E.; Zinczuk, J.; López González, J. J.; Ben Altabef, A.; Brandán, S. A.,

[16] Ledesma, A. E.; Zinczuk, J.; López González, J. J. ; Ben Altabef, A.; Brandán, S. A*.,*

[18] Jones, R. A.; Civcir, P. U. Extended Heterocyclic Systems 2. The Synthesis and

[19] Rauhut, G.; Pulay, P., Transferable Scaling Factors for Density Functional Derived

[20] Rauhut, G.; Pulay, P., Transferable Scaling Factors for Density Functional Derived

[22] Sadlej-Sosnowska, N*.,* Molecular Similarity Based on Atomic Electrostatic Potential, *J.* 

[23] Vektariene, A. ; Vektaris, G.; Svoboda, J., 11th *International Electronic Conference on* 

[24] Ditchfield, R., Self-consistent perturbation theory of diamagnetism, *Mol. Phys.*, 1974,

[25] Cheeseman, J.; Trucks, G. ; Keith, T.; Frisch, M., A comparison of models for

*Chem.* 1995, Vol 99, N 39 (September 1995), pp 14572. ISSN: 1089-5639 [21] Kalincsak, F.; Pongor, G., Extension of the density functional derived scaled quantum

*Structure*, 2009, Vol 924–926 (April 2009), pp 322–331, ISSN: 0022-2860 [17] Zinczuk, J.; Ledesma, A. E.; Brandán, S. A.; Piro, O. E.; López-González, J. J.; Ben

2009, Vol 40, N°8 (August 2009), pp. 1004–1010, ISSN: 1097-4555

*Eur. J.Med. Chem., Vol* 40, N° 2, pp 127. ISSN: 0223- 5234

ISSN: 0022-2860

587–597, ISSN: 1097-4555

pp 11529- 11540. ISSN: 0040- 4020

2002), pp 999- 1011(13), ISSN: 1386-1425

Vol 27, N4 pp 789- 807. ISSN: 00268976

*Synthetic Organic Chemistry* (ECSOC-11), 2007.

104, N14 (April 1996), pp 5497–5509. ISSN: 1089-5639

31100. ISSN: 1089-5639

1099-1395.

Hydroxy-2-imidazolines, 2004, *J.Mol. Struct.,* Vol 697, N° 1–3 (April 2004), pp 49-60.

Altabef, A., 2008, Structural and vibrational study of 2-(2'-furyl)-1H- imidazole, *J. Phys. Org. Chem.*, Vol 21, N° 12 (December 2008), pp 1086–1097, ISSN: 1099-1395 [14] Ledesma, A. E.; Zinczuk, J.; López González, J. J.; Ben Altabef, A.; Brandán, S. A.,

Structural, vibrational spectra and normal coordinate analysis for two tautomers of 4(5)-(2'-furyl)-imidazole, *J. Raman Spectrosc*., 2010, Vol 41, N°5 (Mayo 2010), pp

Synthesis and vibrational analysis of N-(2'-Furyl)-Imidazole, *J. Raman Spectrosc*.,

Structural and vibrational study of 4-(2'-furyl)-1-methylimidazole *J. of Molecular* 

Altabef, A., Structural and vibrational study of 2-(2'- furyl)-4,5-1Hdihydroimidazole, *J. Phys. Org. Chem.*, 2009, Vol 21 (April 2010), pp 1–12, ISSN:

Characterisation of (2-Furyl)pyridines, (2-Thienyl)pyridines, and Furan-Pyridine and Thiophene-Pyridine Oligomers, Tetrahedron 1997, Vol 53, N 34 (August 1997),

Vibrational Force Fields, *J. Phys. Chem*. 1995, Vol 99, N10 (March 1995), pp 3093-

Vibrational Force Fields. [Erratum to document cited in CA122:199802], *J. Phys.* 

mechanical force field procedure, *Spectrochim. Acta A* 2002, Vol 58, N 5 (March

*Phys. Chem. A*, 2007, Vol 111, N 43 (October 2007), pp 11134–11140. ISSN: 1089-5639

calculating nuclear magnetic resonance shielding tensors, *J. Chem. Phys.,* 1996, Vol

the respective length bonds is observed. Due to this, the H atom is very labile in consequence can be easily substituted. The later behavior is observed when the frequencies of the C-H groups in the N-(2'-Furyl)-imidazole are analyzed in reference to the other compounds of this series. Finally, the N-(2'-Furyl)-imidazole compound is the most stable member of the series.

#### **5. References**


the respective length bonds is observed. Due to this, the H atom is very labile in consequence can be easily substituted. The later behavior is observed when the frequencies of the C-H groups in the N-(2'-Furyl)-imidazole are analyzed in reference to the other compounds of this series. Finally, the N-(2'-Furyl)-imidazole compound is the most stable

[1] Salerno, A. ; Perillo, I. A., 1H- and 13C-NMR Analysis of a Series of 1,2-Diaryl-1H-4,5-

[2] Szabo, B., Imidazoline antihypertensive drugs: a critical review on their mechanism of

[3] Gould, S. L.; Kodis, G.; Liddell, P. A.; Palacios, R. E.; Brune, A.; Gust, D.; Moore, T. A;

[5] Monterrey I. G.; Campiglia, P.; Lama, T.; La Colla, P.; Diurno, M. V.; Grieco, P.;

[6] Ooyama, Y.; Mamura, T.; Yoshida, K., A facile synthesis of solid-emissive fluorescent

[7] Rohwerder, M.; Michalik, A., Conducting polymers for corrosion protection: What

[8] Stroganova, T. A.; Butin, A. V.; Sorotskaya, J. N.; Kul'nevich, V. G., (Aryl)(2-furyl)alkanes

[10] Bellina, F.; Cauteruccio, S.; Rossi, R., Efficient and Practical Synthesis of 4(5)-Aryl-1H-

[11] Popov, S. A.; Andreev, R. V.; Romanenko, G. V.; Ovcharenko, V. I.; Reznikov, V. A.,

*Arkivoc 2000* (iv), 1, (September 2000), pp 641 – 659. ISSN 1551-7012. [9] Nevin K.; Dilek E.; Pervin U. C., Synthesis and characterization of novel

dihydroimidazoles, 2005, *Molecules*, Vol 10, N 2 (Febrary 2005), pp 435–443, ISSN:

action, 2002, *Pharmacol. Therapeut*. Vol 93, N 1 (January 2002) , pp. 1-35(35). ISSN:

Moore, A. L., Artificial photosynthetic reaction centers with carotenoid antennas, *Tetrahedron* 2006, Vol 62, N 9 (February 2006), pp 2074-2096. ISSN: 0040-4020 [4] Higashio, Y.; Shoji, T.; Erratum to "Heterocyclic compounds such as pyrrole, pyridines,

piperidine, indole, imidazol and pyrazines" [Appl. Catal. A: Gen. 221 (2001) 197– 207], *Applied Catalysis A: General* 2004, Vol 260, N 2 (March 2004), pp 249-251. ISSN:

Novellino, Synthesis of new pyrido [4,3- g and 3,4- g]quinoline-9,10-dione and dihydrothieno [2,3-g and 3,2-g]quinoline-4,9-dione derivatives and preliminary evaluation of cytotoxic activity, *E. Arkivoc* 2004 (v) 85 (February 2004), pp 85 – 96.

dyes: dialkylbenzo[b]naphtho[2,1-d]furan-6-one-type fluorophores with strong blue and green fluorescence emission properties, *Tetrahedron Lett.* 2007, Vol 48 (June

makes the difference between failure and success?, *Electrochimica Acta*. 2007, Vol 53,

and their derivatives, 20. Synthesis of symmetric bis- and tris(2-furyl)methanes, *E.*

heterosubstituted pyrroles, thiophenes, and furans, *E.* A*rkivoc 2008* (xii) (March

imidazoles and 2,4(5)-Diaryl-1H-imidazoles via Highly Selective Palladium-Catalyzed Arylation Reactions, 2007, *J. Org. Chem*., Vol 72, N° 22 (October 2007), pp

Aminonitrone-N-hydroxyaminoimine Tautomeric Equilibrium in the Series of 1-

member of the series.

1420-3049

0163 -7258

0926-860X

ISSN: 1551-7004

2007), pp 5791–5793. ISSN: 0040-4039

2008), pp 17-29. ISSN 1551-7012.

8543–8546. ISSN: 0022- 3263

N20 (December 2007), pp 1300-1313. ISSN: 0013-4686

**5. References** 

Hydroxy-2-imidazolines, 2004, *J.Mol. Struct.,* Vol 697, N° 1–3 (April 2004), pp 49-60. ISSN: 0022-2860


**10** 

*France* 

**NMR Spectroscopy: A Useful Tool in the** 

**Determination of the Electrophilic Character** 

M. Sebban, P. Sepulcri, C. Jovene, D. Vichard, F. Terrier and R. Goumont\*

2,1,3-Benzoxadiazoles **1** and related 1-oxides **2**, commonly referred to as benzofurazans and benzofuroxans, respectively are heteroaromatic 10-electron ring systems whose carbocyclic ring is intrinsically very susceptible to nucleophilic attack.1-9 Most importantly, the introduction of a NO2 group at C-4 enhances the electrophilic reactivity of this ring by several orders of magnitude, making it comparable to that of a trinitro substituted benzene ring. This property has raised considerable interest in the 1970-1980's, mostly in connection with the recognition that the ease of covalent nucleophilic addition to the carbocyclic ring is responsible for the inhibitory effect exerted by some mononitrobenzofurazans and – benzofuroxans on the biosynthesis of nucleic acid and protein in leucocytes, and the observed activity against leukaemia. Also much attention was directed to the SNAr reactivity of compounds like 4-chloro- and 4-fluoro-7-nitrobenzofurazans (**3**-**4**) which have become commonly used as fluorogenic reagents for detection and quantification of amino and thiol

In the last decades, we have been engaged in an effort to investigate the reactivity of strongly electrophilic aromatic and heteroaromatic substitutions and related -complex processes. In this context, we discovered that some appropriate substitutions of the carbocyclic ring of benzofurazan and benzofuroxan structures enhance so much the electron-deficiency of this ring that the resulting compounds can be reasonably ranked as superelectrophilic heteroaromatics. Referring meanly to the readily accessible prototype substrates, namely 4,6-dinitrobenzofuroxan (DNBF, **A**), this review will highlight this behaviour which has proved to be very useful to assess the nucleophilic reactivity of extremely weak carbon base. In the same context, some remarkable reactivity sequences deriving from an aza substitution of the carbocyclic ring or a change in the nature of the annelated ring will be also emphasized with a particular focus on the behaviour of this extremely electrophilic substrates, namely 6-nitro [2,1,3] oxadiazolo [4, 5-b] pyridine 1-oxide,

residues on proteins, drugs and biologically active molecules.

**1. Introduction** 

 \*

Corresponding Author

 **of Benzofuroxans - Case Examples of the** 

**Reactions of Nitrobenzofuroxans** 

*University of Versailles, ILV (Institut lavoisier de Versailles)* 

**with Dienes and Nucleophiles** 

[26] Keith, T. A.; Bader, R. F. W., Calculation of magnetic response properties using a continuous set of gauge transformations, *Chem. Phys.*, 1993, Vol 210, N1-3 (May 1993), pp 223–231. ISSN: 0301-0104

### **NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes and Nucleophiles**

M. Sebban, P. Sepulcri, C. Jovene, D. Vichard, F. Terrier and R. Goumont\* *University of Versailles, ILV (Institut lavoisier de Versailles) France* 

#### **1. Introduction**

182 Magnetic Resonance Spectroscopy

[26] Keith, T. A.; Bader, R. F. W., Calculation of magnetic response properties using a

1993), pp 223–231. ISSN: 0301-0104

continuous set of gauge transformations, *Chem. Phys.*, 1993, Vol 210, N1-3 (May

2,1,3-Benzoxadiazoles **1** and related 1-oxides **2**, commonly referred to as benzofurazans and benzofuroxans, respectively are heteroaromatic 10-electron ring systems whose carbocyclic ring is intrinsically very susceptible to nucleophilic attack.1-9 Most importantly, the introduction of a NO2 group at C-4 enhances the electrophilic reactivity of this ring by several orders of magnitude, making it comparable to that of a trinitro substituted benzene ring. This property has raised considerable interest in the 1970-1980's, mostly in connection with the recognition that the ease of covalent nucleophilic addition to the carbocyclic ring is responsible for the inhibitory effect exerted by some mononitrobenzofurazans and – benzofuroxans on the biosynthesis of nucleic acid and protein in leucocytes, and the observed activity against leukaemia. Also much attention was directed to the SNAr reactivity of compounds like 4-chloro- and 4-fluoro-7-nitrobenzofurazans (**3**-**4**) which have become commonly used as fluorogenic reagents for detection and quantification of amino and thiol residues on proteins, drugs and biologically active molecules.

In the last decades, we have been engaged in an effort to investigate the reactivity of strongly electrophilic aromatic and heteroaromatic substitutions and related -complex processes. In this context, we discovered that some appropriate substitutions of the carbocyclic ring of benzofurazan and benzofuroxan structures enhance so much the electron-deficiency of this ring that the resulting compounds can be reasonably ranked as superelectrophilic heteroaromatics. Referring meanly to the readily accessible prototype substrates, namely 4,6-dinitrobenzofuroxan (DNBF, **A**), this review will highlight this behaviour which has proved to be very useful to assess the nucleophilic reactivity of extremely weak carbon base. In the same context, some remarkable reactivity sequences deriving from an aza substitution of the carbocyclic ring or a change in the nature of the annelated ring will be also emphasized with a particular focus on the behaviour of this extremely electrophilic substrates, namely 6-nitro [2,1,3] oxadiazolo [4, 5-b] pyridine 1-oxide,

<sup>\*</sup> Corresponding Author

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

O2N

O2 N

Scheme 1. Diels-Alder Trapping of the o-dinitroso intermediate **6**.

double bond of **H**.

N

3 4

9

N

**7**

O2N

N O N

O

<sup>1</sup> <sup>2</sup>

+ -

N O N

O

unambiguously chemical assignments.

+ -

O2N <sup>N</sup> <sup>N</sup>

**<sup>H</sup>**, ANBF **<sup>6</sup>**

Scheme 1

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 185

*o*-dinitroso intermediate,15 diadducts **5** resulting from normal electron-demand Diels-Alder (NEDDA) processes involving the N=O double bonds of such intermediates as the dienophile contributors have also been isolated. Treatment of ANBF with cyclohexadiene in CHCl3 affords a 2:1 mixture of two products which were readily separated by column chromatography and isolated as pale yellow solids. The ORTEP view in Scheme 1 leaves no doubt that the major product is the diadduct **5** whose formation can only be accounted for in terms of two NEDDA processes in which the N=O double bonds of the *o*-dinitroso intermediate **6** play the role of the dienophiles contributors (Scheme 1). In view of the 1H and 13C NMR spectra, the minor product can be formulated as the cycloadducts **7**, which results from a regioselective and diastereoselective NEDDA process involving the C6-C7

N N

N

O

N

O

Some selected interactions will be presented in the first part of this review to illustrate that versatile and synthetically very promising Diels-Alder reactivity. It will be shown that NMR is a useful tool to determine the regioselectivity and the stereochemistry of the pericyclic processes. In many cases, the finding of characteristic couplings and/or signals with typical chemical shifts allows a fast determination of the regioselectivity of the Diels-Alder reactions. A short discussion of the NMR chemical shifts of the starting neutral materials (**A**-**H**) will show the influence of the substituent and of the position of this substituent on the chemical shifts. In some cases, 15N labelling of nitro group has been used to determine

The considerable interest in the study of the high susceptibility of nitrobenzofuroxans to undergo covalent addition or substitution processes has led to a numerous synthetic, analytical and biological applications. A prototype example of this behaviour are the facile carbon-carbon coupling reactions of 4,6-dinitrobenzofuroxan (DNBF, **A**) – the reference compound in the series – with a number of benzenoid aromatics (phenols, anilines) or excessive heteroaromatics (pyrroles, indoles, thiophenes…) whose carbon basicities are associated with large negative pka values. In all of these reactions, covalent addition takes

**5**

O

O

N N

<sup>9</sup> + -

O2N

4 5 6

> 7 8

O N

2 3

1

O

O


O

+

i.e. the 4-aza-6-nitro analogue of DNBF (ANBF, **H**). We demonstrated that highly electrophilic benzofuroxans, benzofurazans and related heteroaromatic substrates have also the potential to react in a variety of pericyclic patterns being able to contribute as dienophiles, heterodienes or carbodienes depending upon the experimental conditions and the reaction patterns at hand. Recently, it has been convincingly recognized that the exceptional electrophilic character of nitrobenzofuroxans is closely related to the low aromaticity of the carbocyclic ring. Crucial evidence for this relationship has been the discovery that the nitro-activated double bonds of this ring behave similarly to nitroalkene fragments in a variety of Diels-Alder processes, acting as dienophiles or heterodienes depending upon the reaction partner and the experimental conditions at hand.10-16 A first illustrative sequence refers to the reaction of ANBF with cyclohexadiene. Reflecting the potential 1-oxide/3-oxide interconversion of benzofuroxans through the intermediacy of an

N O N

N O N

N O N

N

**H**

N O N

+

O


N O N

+ -

NO2

O R

**2**

Cl

**4**

O2 N

i.e. the 4-aza-6-nitro analogue of DNBF (ANBF, **H**). We demonstrated that highly electrophilic benzofuroxans, benzofurazans and related heteroaromatic substrates have also the potential to react in a variety of pericyclic patterns being able to contribute as dienophiles, heterodienes or carbodienes depending upon the experimental conditions and the reaction patterns at hand. Recently, it has been convincingly recognized that the exceptional electrophilic character of nitrobenzofuroxans is closely related to the low aromaticity of the carbocyclic ring. Crucial evidence for this relationship has been the discovery that the nitro-activated double bonds of this ring behave similarly to nitroalkene fragments in a variety of Diels-Alder processes, acting as dienophiles or heterodienes depending upon the reaction partner and the experimental conditions at hand.10-16 A first illustrative sequence refers to the reaction of ANBF with cyclohexadiene. Reflecting the potential 1-oxide/3-oxide interconversion of benzofuroxans through the intermediacy of an

NO2

**1**

R

F

**3**

X

**A** X = Y = NO2 (DNBF) **B** X = NO2, Y = CF3 **C** X = NO2, Y = CN **D** X = NO2, Y = SO2CF3 **E** X = CF3, Y = NO2 **F** X = CN, Y = NO2 **G** X = SO2CF3, Y = NO2

Y

N O N

O

+ - *o*-dinitroso intermediate,15 diadducts **5** resulting from normal electron-demand Diels-Alder (NEDDA) processes involving the N=O double bonds of such intermediates as the dienophile contributors have also been isolated. Treatment of ANBF with cyclohexadiene in CHCl3 affords a 2:1 mixture of two products which were readily separated by column chromatography and isolated as pale yellow solids. The ORTEP view in Scheme 1 leaves no doubt that the major product is the diadduct **5** whose formation can only be accounted for in terms of two NEDDA processes in which the N=O double bonds of the *o*-dinitroso intermediate **6** play the role of the dienophiles contributors (Scheme 1). In view of the 1H and 13C NMR spectra, the minor product can be formulated as the cycloadducts **7**, which results from a regioselective and diastereoselective NEDDA process involving the C6-C7 double bond of **H**.

Scheme 1. Diels-Alder Trapping of the o-dinitroso intermediate **6**.

Some selected interactions will be presented in the first part of this review to illustrate that versatile and synthetically very promising Diels-Alder reactivity. It will be shown that NMR is a useful tool to determine the regioselectivity and the stereochemistry of the pericyclic processes. In many cases, the finding of characteristic couplings and/or signals with typical chemical shifts allows a fast determination of the regioselectivity of the Diels-Alder reactions. A short discussion of the NMR chemical shifts of the starting neutral materials (**A**-**H**) will show the influence of the substituent and of the position of this substituent on the chemical shifts. In some cases, 15N labelling of nitro group has been used to determine unambiguously chemical assignments.

The considerable interest in the study of the high susceptibility of nitrobenzofuroxans to undergo covalent addition or substitution processes has led to a numerous synthetic, analytical and biological applications. A prototype example of this behaviour are the facile carbon-carbon coupling reactions of 4,6-dinitrobenzofuroxan (DNBF, **A**) – the reference compound in the series – with a number of benzenoid aromatics (phenols, anilines) or excessive heteroaromatics (pyrroles, indoles, thiophenes…) whose carbon basicities are associated with large negative pka values. In all of these reactions, covalent addition takes

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

N O N

+

R

protons have quite identical chemical shifts.

\*Internal reference: CFCl3

R'

O

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 187

<sup>H</sup> Nu -

N O N


R

R'

O


(3)

Nu-

R, R' = EWG

The 1H NMR spectra of these heterocycles are characterized by two deshielded protons at around 9 ppm. The signals of these two protons are, in the most cases, doublets with a coupling constant from 1Hz to 2 Hz, depending of the position and of the nature of the substituent (see Table 1). Interestingly, the signal of H7 is at lower field than that of H5. But it has to be noticed that the position of these signals are largely dependent of the solvent and unambiguous attributions can be performed using 15N labelling of nitro groups as it was the case for DNBF (**A**).17 The 1H spectrum of DNBF (**A**) shows the HA and HX doublets of the AX system at 9.27 and 8.94 ppm, respectively, in dimethylsulfoxide (DMSO, JAX = 1.9 Hz). On 15N labelling of the 6-NO2 group, the HA and HX resonances show coupling with the nitrogen atom and coupling constant may be readily determined from the spectra (JN6HA = 2.4 Hz and JN6HX = 1.6Hz). On further 15N labelling at the 4-NO2 group, the HA resonance remains unaffected while that of HX undergoes an additional splitting: JN4HX = 2.9 Hz. These observations show unambiguously that HA is H7 and HX is H5 in DMSO. Similar experiments have been carried out in various solvents (Table 2). In THF and acetone, it is the high field resonance of the observed AX or AB patterns, respectively, that is split on the 15Nlabelling of the 4-NO2 group. That indicates a sequence of the H5 and H7 resonances in these solvents that is the same as that found in DMSO. In contrast, it is the HA resonances that is affected by labelling the 4-NO2 group in nitromethane, methylene chloride, chloroform, benzene and acetonitrile. This shows that the low field doublet of the AX (or AB) system is ascribable to H5 in these solvents. A particular situation is found in methanol where the two

**Compounds H5 H7 CF3\* Coupling constants (Hz)** 

**B** 8.74 8.87 -61.4 4J5/7 = 4J5/F 1.2

**A (DNBF)** 8.94 9.27 - 4J5/7 = 1.9

**C** 8.92 9.10 - **- D** 8.60 9.40 -76.2 - **E** 8.70 9.07 -61.7 4J5/F = 1.1 **F** 9.03 9.11 - 4J5/7 = 1.5 **G** 8.70 9.21 -76.9 4J5/7 = 1.8

Table 1. 1H NMR data for the Benzofuroxans **A-G** (DMSO-d6)

**2. NMR investigation of substituted benzofuroxans and benzofurazans** 

place at C-7 of the carbocyclic ring of DNBF to give stable -adducts of type **8** or **9**. Quantitative evaluation of thermodynamic reactivity is afforded from a comparison of p*K*<sup>a</sup> values for H2O addition to yield the respective -complexes, for example **C-A,OH**.

Thus the pK H O2 <sup>a</sup> value for hydration of 4,6-dinitrobenzofuroxan (DNBF) according to (eq. 1) is equal to 3.75 in water, as compared with a pK H O2 <sup>a</sup> value of 13.43 for hydration of TNB (eq. 2). It is this large difference in the thermodynamic ease of -complexation of DNBF and TNB, which has been the starting point for the discovery of a superelectrophilic dimension in the field of -complexation processes. On this basis, DNBF **A** and some related derivatives (**B**-**H**) have been termed superelectrophiles.1,2

The second part of this review will be closely related to the structure of -complexes and to the role of the various substituents in the stabilization of the negative charge. Interestingly, their inductive or mesomeric effect will be discussed in terms of NMR chemical shifts. Indeed, the variation of the chemical shift on going from the starting neutral materials (**A**-**H**) to the complexes is a nice reflection of the electron-withdrawing effect of the substituent (eq. 3, EWG = electron-withdrawing group). The special case of the trifluoromethanesulfonyl (SO2CF3) group will be extensively discussed.

#### **2. NMR investigation of substituted benzofuroxans and benzofurazans**

The 1H NMR spectra of these heterocycles are characterized by two deshielded protons at around 9 ppm. The signals of these two protons are, in the most cases, doublets with a coupling constant from 1Hz to 2 Hz, depending of the position and of the nature of the substituent (see Table 1). Interestingly, the signal of H7 is at lower field than that of H5. But it has to be noticed that the position of these signals are largely dependent of the solvent and unambiguous attributions can be performed using 15N labelling of nitro groups as it was the case for DNBF (**A**).17 The 1H spectrum of DNBF (**A**) shows the HA and HX doublets of the AX system at 9.27 and 8.94 ppm, respectively, in dimethylsulfoxide (DMSO, JAX = 1.9 Hz). On 15N labelling of the 6-NO2 group, the HA and HX resonances show coupling with the nitrogen atom and coupling constant may be readily determined from the spectra (JN6HA = 2.4 Hz and JN6HX = 1.6Hz). On further 15N labelling at the 4-NO2 group, the HA resonance remains unaffected while that of HX undergoes an additional splitting: JN4HX = 2.9 Hz. These observations show unambiguously that HA is H7 and HX is H5 in DMSO. Similar experiments have been carried out in various solvents (Table 2). In THF and acetone, it is the high field resonance of the observed AX or AB patterns, respectively, that is split on the 15Nlabelling of the 4-NO2 group. That indicates a sequence of the H5 and H7 resonances in these solvents that is the same as that found in DMSO. In contrast, it is the HA resonances that is affected by labelling the 4-NO2 group in nitromethane, methylene chloride, chloroform, benzene and acetonitrile. This shows that the low field doublet of the AX (or AB) system is ascribable to H5 in these solvents. A particular situation is found in methanol where the two protons have quite identical chemical shifts.


\*Internal reference: CFCl3

186 Magnetic Resonance Spectroscopy

place at C-7 of the carbocyclic ring of DNBF to give stable -adducts of type **8** or **9**. Quantitative evaluation of thermodynamic reactivity is afforded from a comparison of p*K*<sup>a</sup>

values for H2O addition to yield the respective -complexes, for example **C-A,OH**.

O N


O2 N

Thus the pK H O2 <sup>a</sup> value for hydration of 4,6-dinitrobenzofuroxan (DNBF) according to (eq. 1) is equal to 3.75 in water, as compared with a pK H O2 <sup>a</sup> value of 13.43 for hydration of TNB (eq. 2). It is this large difference in the thermodynamic ease of -complexation of DNBF and TNB, which has been the starting point for the discovery of a superelectrophilic dimension in the field of -complexation processes. On this basis, DNBF **A** and some related

Nu-

<sup>H</sup> Nu -

R, R' = EWG

**TNB TNB,OH**

The second part of this review will be closely related to the structure of -complexes and to the role of the various substituents in the stabilization of the negative charge. Interestingly, their inductive or mesomeric effect will be discussed in terms of NMR chemical shifts. Indeed, the variation of the chemical shift on going from the starting neutral materials (**A**-**H**) to the complexes is a nice reflection of the electron-withdrawing effect of the substituent (eq. 3, EWG = electron-withdrawing group). The special case of the trifluoromethanesulfonyl (SO2CF3)

MeO

N O N

+


(1)

N Me

H O

**9**

NO2

7


O2N

N O N


NO2

H OH

O


NO2


N O N

+


OMe

R

R'

O2 N

**8**

H O

NO2

7


N O N

+

O- <sup>N</sup>

derivatives (**B**-**H**) have been termed superelectrophiles.1,2

R

R'

O2

group will be extensively discussed.

N O N

NO2

N NO2

+

O

+ HO-

O2 N NO2


<sup>H</sup> <sup>O</sup> OH

**C-A,OH**

<sup>7</sup> +

NO2

7

DNBF, **A**

O2 N

Table 1. 1H NMR data for the Benzofuroxans **A-G** (DMSO-d6)

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

X

4 5

Y

Scheme 2. Resonance forms of substituted benzofuroxans.

Table 3. 13C NMR data for the Benzofuroxans **A-G** (DMSO-d6)

disappearance of its electron-releasing effect and has two major effects:

8.94 and H7 = 9.27 for **A**, H5 = 9.04 and H7 = 9.80 for **I**, in DMSO).

position are very broad due to long relaxation time.

C9 = 143.3 and C8 = 150.0 for **I**, in DMSO).

Table 4. 1H NMR data for the Benzofurazans **I-N** (DMSO-d6)

\*Internal reference: CFCl3

6 7 8

N O N

9

O

+ -

X

4 5

Y

6 7 8 N O N

<sup>+</sup> -

9

O

**Compounds C4 C5 C6 C7 C8 C9 CN CF3 A (DNBF)** 136.7 126.5 144.8 120.8 116.6 145.02 - - **B** 137.9 128.1 127.1 122.5 116.8 145.2 - 121.9 **C** 137.0 133.1 110.0 130.8 117.1 147.7 115.6 - **D** 138.1 128.4 127.6 132.1 118.0 145.2 - 119.0 **E** 118.8 127.2 145.6 118.5 114.9 147.68 - 121.3 **F** 102.5 135.9 146.0 119.0 114.6 150.2 112.5 - **G** 124.3 135.3 144.7 121.5 114.4 146.2 - 119.4

HMBC spectra recorded for these compounds exhibited characteristic correlations. For example, two correlations between C9 ( = 145 ppm) and H7 (JC9H7 = 5 Hz) and H5 (JC9H5 = 7-9 Hz), respectively, can be observed while C8 ( = 115 ppm) is only correlated with H7 (JC8H7 = 2-3 Hz). In the particular case of **B** and **E**, the couplings between the fluorine atoms of the CF3 moiety and the various carbons are helpful to assign unambiguously the chemical shifts. In most cases, the signals of the carbon atoms substituted by a NO2 group at the 4 or 6

To remove the N-oxide functionality of benzofuroxans, in order to obtain the benzofurazan analogues **I-N** may be easily achieved using triphenylphosphine in boiling toluene. Benzofurazans are obtained in fair to moderate yields and NMR spectra have been recorded (Table 4 and 5). The removal of the N-oxide functionality is going along with the

the resonances of H5 and H7 pertaining to **I-N** are at lower field than those of **A-F** (H5 =

the C8 resonance is now at lower field than that of C9 (C9 = 145.0 and C8 = 116.6 for **A**,

**Compounds H5 H7 CF3\* Coupling constants (Hz) I (DNBZ)** 9.04 9.80 - 4J5/7 = 1.9 **J** 8.83 9.38 -62.1 4J5/7 = 4J5/F 1.2 **K** 9.04 9.55 - **- L** 8.84 9.24 -76.7 4J5/7 = 1.3 **M** 8.62 9.63 -61.8 4J5/7 = 4J5/F 1.0 **N** 9.15 9.65 - 4J5/7 = 1.8

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 189

N O N

O

+

X


9

Y

6 7 8

N O N

<sup>+</sup> -

9

O

X

4 5

Y

6 7 8


Table 2. Solvent effect on 1H NMR data for 15N labelled DNBF

$$\begin{array}{ll} \mathbf{E} & \mathbf{X} = \mathbf{C} \mathbf{F}\_3, \text{ Y} = \mathbf{NO}\_2\\ \mathbf{F} & \mathbf{X} = \mathbf{CN}, \text{ Y} = \mathbf{NO}\_2 \end{array}$$

$$\mathbf{G} \cdot \mathbf{X} = \mathbf{SO}\_2 \mathbf{CF}\_3, \text{ Y} = \mathbf{NO}\_2.$$

**I** X = Y = NO2 (DNBZ) **J** X = NO2, Y = CF3 **K** X = NO2, Y = CN **L** X = NO2, Y = SO2CF3 **M** X = CF3, Y = NO2 **N** X = CN, Y = NO2

The 13C NMR spectra of benzofuroxans **A-F** show some characteristic features. The complete 13C NMR assignment of these compounds has been obtained using one- and twodimensional NMR techniques including HMQC and HMBC experiments. So, the two resonances pertaining to C5 and C7 are readily determined while the resonances of the C9 and C8 appear to be the key features of the 13C NMR spectra of benzofuroxans. With chemical shift of 145 and 115 ppm, respectively, the signals of C9 and C8 are quite independent of the position and of the nature of the substituent (see Table 3). The position of the signal pertaining to C8 with compare to that of C9 could be explained by the mesomeric effect of the N-oxide functionality.17-18

This substituent effect has been attributed to the presence of a partial negative charge on C8 resulting from a significant contribution of the second resonance form described in Scheme 2, while C9, more distant from the N-oxide function, remains unaffected or only slightly affected.

Scheme 2. Resonance forms of substituted benzofuroxans.

N Y

The 13C NMR spectra of benzofuroxans **A-F** show some characteristic features. The complete 13C NMR assignment of these compounds has been obtained using one- and twodimensional NMR techniques including HMQC and HMBC experiments. So, the two resonances pertaining to C5 and C7 are readily determined while the resonances of the C9 and C8 appear to be the key features of the 13C NMR spectra of benzofuroxans. With chemical shift of 145 and 115 ppm, respectively, the signals of C9 and C8 are quite independent of the position and of the nature of the substituent (see Table 3). The position of the signal pertaining to C8 with compare to that of C9 could be explained by the mesomeric

This substituent effect has been attributed to the presence of a partial negative charge on C8 resulting from a significant contribution of the second resonance form described in Scheme 2, while C9, more distant from the N-oxide function, remains unaffected or only slightly affected.

Table 2. Solvent effect on 1H NMR data for 15N labelled DNBF

X

4 3

9

**A** X = Y = NO2 (DNBF) **B** X = NO2, Y = CF3 **C** X = NO2, Y = CN **D** X = NO2, Y = SO2CF3 **E** X = CF3, Y = NO2 **F** X = CN, Y = NO2 **G** X = SO2CF3, Y = NO2

Y

effect of the N-oxide functionality.17-18

5

6 7 8

O N

2

O

+ -

1

**solvent H5 H7 DMSO** 8.94 9.27 **THF** 9.04 9.16 **Acetone** 9.11 9.14 **Methanol** 9.07 9.07 **Nitromethane** 9.14 8.96 **Acetonitrile** 8.98 8.90 **Methylene chloride** 9.13 8.86 **chloroform** 9.12 8.82 **benzene** 8.08 7.29

> N O N

1

2

X

5

6 7

4 3

9

8

**I** X = Y = NO2 (DNBZ) **J** X = NO2, Y = CF3 **K** X = NO2, Y = CN **L** X = NO2, Y = SO2CF3 **M** X = CF3, Y = NO2 **N** X = CN, Y = NO2


Table 3. 13C NMR data for the Benzofuroxans **A-G** (DMSO-d6)

HMBC spectra recorded for these compounds exhibited characteristic correlations. For example, two correlations between C9 ( = 145 ppm) and H7 (JC9H7 = 5 Hz) and H5 (JC9H5 = 7-9 Hz), respectively, can be observed while C8 ( = 115 ppm) is only correlated with H7 (JC8H7 = 2-3 Hz). In the particular case of **B** and **E**, the couplings between the fluorine atoms of the CF3 moiety and the various carbons are helpful to assign unambiguously the chemical shifts.

In most cases, the signals of the carbon atoms substituted by a NO2 group at the 4 or 6 position are very broad due to long relaxation time.

To remove the N-oxide functionality of benzofuroxans, in order to obtain the benzofurazan analogues **I-N** may be easily achieved using triphenylphosphine in boiling toluene. Benzofurazans are obtained in fair to moderate yields and NMR spectra have been recorded (Table 4 and 5). The removal of the N-oxide functionality is going along with the disappearance of its electron-releasing effect and has two major effects:



\*Internal reference: CFCl3

Table 4. 1H NMR data for the Benzofurazans **I-N** (DMSO-d6)

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

N O N

NO2

O2N

H

**10**

O


N O N

NO2

H

**11**

N O N

N O N

O

+ -

NO2

H

NO2

**10**

H

**11**

H

O

+ -

> N O N

NO2

H

**12**

N O

H

+ -

H

<sup>H</sup> <sup>O</sup>

O

+ -

H

N O

H

O

<sup>+</sup> - <sup>+</sup>

This implies that we are dealing with two highly regioselective and diastereoselective normal and inverse electron-demand Diels-Alder condensations. The regioselectivity at the C6-C7 double bond was readily demonstrated through 15N labelling of the 4-NO2 group of DNBF. In this instance, the only low filed proton observed in the 1H NMR spectra of **11** and **10** is coupled with the 15N atom indicating that this proton is H5. In addition, the observed 3JN4H5 coupling constants of 3.3 and 2.6 Hz, respectively, for **10** and **11** compare well with those previously reported for the parent DNBF molecule (3JN4H5 = 2.9 Hz).17 Regarding the adduct **11**, the first strong, though indirect, evidence for the proposed stereochemistry is that this structure is the only one which can be viewed as a precursor of the diadduct **12**.

O2N

N O

H

O

Scheme 3. Mechanism of the reaction of DNBF, A with cyclopentadiene.

<sup>+</sup> -

O

+ -

and **11**, respectively.

N O N

DNBF, **A**

NO2

O2N

O

+ - +

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 191

In this instance, the spectra recorded immediately after the mixing showed the formation of two new products, **X** and **Y**, in a 9:1 ratio. Raising the temperature to -10°C favors the formation of **Y** at the expense of **X**, both species being present in similar quantities after 30 minutes at this temperature, when the formation of **12** at the expense of **X** end **Y** begins to be detectable. Warming the solution to 0°C accelerated the appearance of **12**, which was the only product eventually present at the completion of the reaction process. On the basis of the collected 1H NMR information, there is little doubt that **X** and **Y** are the monoadducts **10**


Table 5. 13C NMR data for the Benzofurazans **I-N** (DMSO-d6)

#### **3. NMR as a tool in the elucidation of Diels-Alder processes**

In the introduction, we have mentioned that benzofuroxans are involved in a variety of Diels-Alder processes, acting as dienophiles or heterodienes depending upon the reaction partner, the position and the nature of the substituent of the carbocyclic ring and of the experimental conditions at hand (solvent and temperature). *In situ* NMR studies are very informative to understand the regioselectivity of the Diels-Alder process and to collect informations on the global reaction sequence. For example, does the Diels-Alder interaction involve the formation of any detectable short-live intermediates? Many studies have been carried out at low temperature (from -50°C to -20°C), using various amounts of dienes to investigate the formation of transient species which can only be characterized by NMR.

#### **3.1 Elucidation of the reaction of DNBF, a with cyclopentadiene13**

As it was mentioned below, the reaction of DNBF with cyclopentadiene leads to the stereoselective formation of the diadduct **12**. Informations on the reaction sequence leading to **12** was obtained by carrying out a series of experiments at -30°C, using lower concentrations of the reagents to overcome solubility problems.

ORTEP view of **12**

**Compounds C4 C5 C6 C7 C8 C9 CN CF3 I (DNBZ)** 136.8 125.1 148.7 122.5 150.0 143.3 - - **J** 138.1 126.6 131.3 124.9 150.1 143.2 - 122.0 **K** 137.2 133.3 115.8 131.3 149.9 142.9 114.7 - **L** 135.5 132.1 138.5 126.3 149.8 143.2 - 119.4 **M** 118.1 126.5 149.1 120.4 149.3 145.8 - 121.4 **N** 101.6 135.2 149.5 121.9 148.5 148.3 113.2 -

In the introduction, we have mentioned that benzofuroxans are involved in a variety of Diels-Alder processes, acting as dienophiles or heterodienes depending upon the reaction partner, the position and the nature of the substituent of the carbocyclic ring and of the experimental conditions at hand (solvent and temperature). *In situ* NMR studies are very informative to understand the regioselectivity of the Diels-Alder process and to collect informations on the global reaction sequence. For example, does the Diels-Alder interaction involve the formation of any detectable short-live intermediates? Many studies have been carried out at low temperature (from -50°C to -20°C), using various amounts of dienes to investigate the formation of transient species which can only be characterized by NMR.

As it was mentioned below, the reaction of DNBF with cyclopentadiene leads to the stereoselective formation of the diadduct **12**. Informations on the reaction sequence leading to **12** was obtained by carrying out a series of experiments at -30°C, using lower

> N O N

+ -

H

H H

**12**

12 13 14

6 7 8 9

18 19

<sup>10</sup> <sup>11</sup>

NO2

N O

H

O

H

15 16

<sup>+</sup> - <sup>4</sup> <sup>5</sup>

17

O

Table 5. 13C NMR data for the Benzofurazans **I-N** (DMSO-d6)

**3. NMR as a tool in the elucidation of Diels-Alder processes** 

**3.1 Elucidation of the reaction of DNBF, a with cyclopentadiene13**

concentrations of the reagents to overcome solubility problems.

ORTEP view of **12**

In this instance, the spectra recorded immediately after the mixing showed the formation of two new products, **X** and **Y**, in a 9:1 ratio. Raising the temperature to -10°C favors the formation of **Y** at the expense of **X**, both species being present in similar quantities after 30 minutes at this temperature, when the formation of **12** at the expense of **X** end **Y** begins to be detectable. Warming the solution to 0°C accelerated the appearance of **12**, which was the only product eventually present at the completion of the reaction process. On the basis of the collected 1H NMR information, there is little doubt that **X** and **Y** are the monoadducts **10** and **11**, respectively.

This implies that we are dealing with two highly regioselective and diastereoselective normal and inverse electron-demand Diels-Alder condensations. The regioselectivity at the C6-C7 double bond was readily demonstrated through 15N labelling of the 4-NO2 group of DNBF. In this instance, the only low filed proton observed in the 1H NMR spectra of **11** and **10** is coupled with the 15N atom indicating that this proton is H5. In addition, the observed 3JN4H5 coupling constants of 3.3 and 2.6 Hz, respectively, for **10** and **11** compare well with those previously reported for the parent DNBF molecule (3JN4H5 = 2.9 Hz).17 Regarding the adduct **11**, the first strong, though indirect, evidence for the proposed stereochemistry is that this structure is the only one which can be viewed as a precursor of the diadduct **12**.

Scheme 3. Mechanism of the reaction of DNBF, A with cyclopentadiene.

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

exerted by a NO2 group and a O-N+-O-

N O

+

10

H H O2N

17 16

H H

H

14 15

ORTEP view of **15**

12 13

11

<sup>3</sup>CH

a b

H H

a b

CH3

Fig. 1. Structures of Diels-Alder adducts **15** and **16**.

**15**

O


H H H

a b

N O N

3

O

<sup>1</sup> <sup>2</sup>

+ -

proximity of the protons H5 and H14b as well as of H7 and H10b.

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 193

shown by the ORTEP views of Figure 1, these two compounds correspond to diadducts which are only formed as the diastereomers **15** and **16**. The stereochemistry of **15** in the crystal agrees well with the structural information provided by a detailed analysis of the 1H and 13C NMR spectra recorded in CDCl3 via COSY and HETCOR, as well as J-modulation experiments. Among other notable diagnostic features for **15**, there is the observation that the disappearance of the low field proton and carbon resonances associated with the C4C5C6C7 fragment of the DNBF structure goes along with a strong deshielding of the two sp3 carbons C6 and C15. Both benefit from the strong electron-withdrawing inductive effect

typical is the presence of the three vinylic protons H16, H17a and H17b at 5.97, 5.45 and 5.35 ppm, respectively, in the 1H spectra. NOE experiments have revealed the close space

fragment of a dihydrooxazine N-oxide ring. Also

N O N

3

H H H

a b

NO2

CH3

**16**

ORTEP view of **16**

10

O2N H

> 12 13

11

<sup>3</sup>CH

H H

a b

Despite its remarkable stability in the solid state, the diadduct **15** is not the thermodynamically stable product of the reaction of DNBF with isoprene. Major changes in

H H

O

<sup>1</sup> <sup>2</sup>

+ -

NOE experiments have been carried out which have confirmed experimentally that the H7 and H10 protons of **11** are in a cis arrangement, as found in **12**. The details of this mechanism are summarized in Scheme 3.

In as much as the C6-C7 double bond of DNBF is involved in the two initial normal and inverse electron-demand Diels-Alder processes, the formation of the NEDDA and IEDDA adducts **10** and **11** is a clear-cut example of the potentially ambident nitroalkene Diels-Alder reactivity of DNBF. On the other hand, the preferred formation of the unsymmetrical IEDDA-NEDDA adduct **12** implies a greater dienophilic reactivity of the remaining nitroolefinic moiety in the IEDDA adduct **11** than in the NEDDA adduct **10**.10-16

#### **3.2 Elucidation of the reaction of DNBF with 2,3-dimethylbutadiene.10,15**

Information on the reaction sequences leading to **14** was also obtained by recording a series of 1H and 13C spectra within a few minutes after mixing equimolar amounts of DNBF and 2,3-dimethylbutadiene. At this stage, the spectra showed the partial disappearance of the signals due to the starting materials and the concomitant appearance of a new set of resonances indicating the formation of a new product. The evidence is that this product can be formulated as the monoadduct **13** resulting from a regioselective NEDDA process involving the C6C7 double bond of the DNBF as the dienophile contributor.

Scheme 4. Reaction of DNBF, A with 2,3-dimethylbutadiene.

The regioselectivity of the addition was demonstrated through 15N labelling of the 4-NO2 group of DNBF. In this instance, the only low-field proton H5 = 7.54 ppm observed in the 1H spectra of **13** is coupled with the 15N atom (3JN4H5 = 3 Hz), confirming that this proton is H5. In contrast, the *cis* configuration of **13** could not be unambiguously confirmed from the collected NMR data. However it is clear that structure **13** with the 6-NO2 group and H7 being on the same side of the two rings is the only one which can be viewed as a precursor of the diadduct **14** (Scheme 4).

#### **3.3 Time dependence of the 1 H NMR spectra of the adduct 15 obtained from the interaction of DNBF with isoprene10,15-16**

Treatment of DNBF with a large excess of isoprene (10 equiv.) in dichloromethane at room temperature for 2 days afforded two compounds in a 1/1 ratio (overall yield 90%) which were readily separated by taking advantage of their different solubilities in pentane (Scheme 3). As

NOE experiments have been carried out which have confirmed experimentally that the H7 and H10 protons of **11** are in a cis arrangement, as found in **12**. The details of this mechanism

In as much as the C6-C7 double bond of DNBF is involved in the two initial normal and inverse electron-demand Diels-Alder processes, the formation of the NEDDA and IEDDA adducts **10** and **11** is a clear-cut example of the potentially ambident nitroalkene Diels-Alder reactivity of DNBF. On the other hand, the preferred formation of the unsymmetrical IEDDA-NEDDA adduct **12** implies a greater dienophilic reactivity of the remaining

Information on the reaction sequences leading to **14** was also obtained by recording a series of 1H and 13C spectra within a few minutes after mixing equimolar amounts of DNBF and 2,3-dimethylbutadiene. At this stage, the spectra showed the partial disappearance of the signals due to the starting materials and the concomitant appearance of a new set of resonances indicating the formation of a new product. The evidence is that this product can be formulated as the monoadduct **13** resulting from a regioselective NEDDA process

> N O N

+ - <sup>1</sup> <sup>2</sup> N O N

H

10 <sup>11</sup> <sup>12</sup>

> <sup>3</sup> <sup>4</sup> <sup>5</sup> 6 <sup>7</sup> <sup>8</sup> 9

NO2

H

13

O2 N

**<sup>13</sup> <sup>14</sup>**

**H NMR spectra of the adduct 15 obtained from the** 

13 +

O


H O

The regioselectivity of the addition was demonstrated through 15N labelling of the 4-NO2 group of DNBF. In this instance, the only low-field proton H5 = 7.54 ppm observed in the 1H spectra of **13** is coupled with the 15N atom (3JN4H5 = 3 Hz), confirming that this proton is H5. In contrast, the *cis* configuration of **13** could not be unambiguously confirmed from the collected NMR data. However it is clear that structure **13** with the 6-NO2 group and H7 being on the same side of the two rings is the only one which can be viewed as a precursor

Treatment of DNBF with a large excess of isoprene (10 equiv.) in dichloromethane at room temperature for 2 days afforded two compounds in a 1/1 ratio (overall yield 90%) which were readily separated by taking advantage of their different solubilities in pentane (Scheme 3). As

NO2

<sup>3</sup> <sup>4</sup>

9

nitroolefinic moiety in the IEDDA adduct **11** than in the NEDDA adduct **10**.10-16

**3.2 Elucidation of the reaction of DNBF with 2,3-dimethylbutadiene.10,15**

involving the C6C7 double bond of the DNBF as the dienophile contributor.

O2 N

Scheme 4. Reaction of DNBF, A with 2,3-dimethylbutadiene.

5 6 <sup>7</sup> <sup>8</sup>

10 <sup>11</sup> <sup>12</sup>

are summarized in Scheme 3.

N O N

of the diadduct **14** (Scheme 4).

**3.3 Time dependence of the 1**

**interaction of DNBF with isoprene10,15-16** 

NO2

**A**

O2N

O

+ - shown by the ORTEP views of Figure 1, these two compounds correspond to diadducts which are only formed as the diastereomers **15** and **16**. The stereochemistry of **15** in the crystal agrees well with the structural information provided by a detailed analysis of the 1H and 13C NMR spectra recorded in CDCl3 via COSY and HETCOR, as well as J-modulation experiments. Among other notable diagnostic features for **15**, there is the observation that the disappearance of the low field proton and carbon resonances associated with the C4C5C6C7 fragment of the DNBF structure goes along with a strong deshielding of the two sp3 carbons C6 and C15. Both benefit from the strong electron-withdrawing inductive effect exerted by a NO2 group and a O-N+-O fragment of a dihydrooxazine N-oxide ring. Also typical is the presence of the three vinylic protons H16, H17a and H17b at 5.97, 5.45 and 5.35 ppm, respectively, in the 1H spectra. NOE experiments have revealed the close space proximity of the protons H5 and H14b as well as of H7 and H10b.

Fig. 1. Structures of Diels-Alder adducts **15** and **16**.

Despite its remarkable stability in the solid state, the diadduct **15** is not the thermodynamically stable product of the reaction of DNBF with isoprene. Major changes in

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

**15**, respectively, is an unprecedented finding in the chemistry of DNBF.

N O

+

10

CH3

O


H H H

b

N O

+

10

H

H H H17b <sup>a</sup>

H H O2N

H

14 15

12 13

11

**15**

H H

17 16

<sup>3</sup>CH

a b

H

a b

CH3

CH3

14 <sup>15</sup> <sup>16</sup> 17

10

H

H

<sup>H</sup> **<sup>16</sup>** <sup>15</sup> H12

<sup>3</sup>CH

H H

a b

t = one month

H H

O2N H

> 12 13

11

H

H H

H H O2N

H

14 15

t = 10 days +

12 13

11

H H

17 16

<sup>3</sup>CH

a b

H

a b

H16

t = 5 minutes

H17a

H12

O


H H H

a b

N O N

3

N O N

3

H H H

a b

NO2

O

H7

Fig. 2. Time dependence of the 1H NMR spectra of a pure sample of **15** in CDCl3.

+ - <sup>1</sup> <sup>2</sup>

O

<sup>1</sup> <sup>2</sup>

+ -

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 195

pathways to give a mixture of the NEDDA-NEDDA and NEDDA-IEDDA diadducts **16** and

N O N

3

O

<sup>1</sup> <sup>2</sup>

+ -

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5

**<sup>15</sup> <sup>16</sup>**

N O N

3

H10b H14a

CH3 11

CH3 15

H H H

a b

NO2

CH3

14 <sup>15</sup> <sup>16</sup> 17

CH2 13 H10 a H14b

10

H

H

<sup>3</sup>CH

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5

H7 H5

H H

a b

> H H

O2N H

> 12 13

CH2 14

H10a H13a H10b H13b

CH2 17

CH3 11,16

11

O

+ - <sup>1</sup> <sup>2</sup>

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5

H5

the 1H and 13C spectra occurred with time when a CDCl3 solution of **15** is kept at room temperature, with in about a month, an essentially complete disappearance of the resonances due to **15** and a concomitant development of new sets of proton or carbon signals ascribable to **16**. At completion of the interconversion, the recorded 1H and 13C spectra were in fact totally identical to those obtained after dissolution of a few crystals of **16** in the same solvent.15-16

In accordance with its greater olefinic character, the C6-C7 double bond of DNBF has been found to be more reactive than its C4-C5 counterpart in all Diels-Alder condensation pathways so far studied. Based on this, one could anticipate that the diadducts **15** and **16** are the result of competitive inverse and normal electron-demand reactions involving the remaining nitroalkene-like C4-C5 fragment of an initially formed NEDDA monoadduct of type **17** (Scheme 5 and Figure 2).

Scheme 5. Reaction of DNBF, A with isoprene.

Because of a more favorable thermodynamic driving force for formation of **16** than **15**, the complete equilibrium system of Scheme 5 is progressively shifted towards the obtention of the NEDDA-NEDDA diadducts **16**. There is little doubt that these species correspond to the products isolated in 1973 by Kresze and Bathelt.10 At this time, however, no attempt was made to elucidate the stereochemistry and the mechanistic course of the reactions.

That the addition of the second molecule of isoprene and 2,3-dimethylbutadiene to the monoadducts **17** occurs through competitive normal and inverse electron-demand

the 1H and 13C spectra occurred with time when a CDCl3 solution of **15** is kept at room temperature, with in about a month, an essentially complete disappearance of the resonances due to **15** and a concomitant development of new sets of proton or carbon signals ascribable to **16**. At completion of the interconversion, the recorded 1H and 13C spectra were in fact totally identical to those obtained after dissolution of a few crystals of **16**

In accordance with its greater olefinic character, the C6-C7 double bond of DNBF has been found to be more reactive than its C4-C5 counterpart in all Diels-Alder condensation pathways so far studied. Based on this, one could anticipate that the diadducts **15** and **16** are the result of competitive inverse and normal electron-demand reactions involving the remaining nitroalkene-like C4-C5 fragment of an initially formed NEDDA monoadduct of

> N O N

+ -

NO2

H

CH3

**17**

10 11

Scheme 5

Because of a more favorable thermodynamic driving force for formation of **16** than **15**, the complete equilibrium system of Scheme 5 is progressively shifted towards the obtention of the NEDDA-NEDDA diadducts **16**. There is little doubt that these species correspond to the products isolated in 1973 by Kresze and Bathelt.10 At this time, however, no attempt was

That the addition of the second molecule of isoprene and 2,3-dimethylbutadiene to the monoadducts **17** occurs through competitive normal and inverse electron-demand

made to elucidate the stereochemistry and the mechanistic course of the reactions.

O2N

12 13

H

R

O

N O N

3

N O

+

10

CH3

**15**

O


H H H

a b

N O N

3

O

<sup>1</sup> <sup>2</sup>

+ -

H H H

a b

NO2

CH3

**16**

11

10 12 13

> H H O2N

17 16

a b

H H

H

14 15

12 13

11

<sup>3</sup>CH

H H

a b O2 N H

<sup>3</sup>CH

H H

a b

> H H

O

<sup>1</sup> <sup>2</sup>

+ -

in the same solvent.15-16

type **17** (Scheme 5 and Figure 2).

N O N

NO2

DNBF

O2N

O

+ - <sup>3</sup>CH

Scheme 5. Reaction of DNBF, A with isoprene.

pathways to give a mixture of the NEDDA-NEDDA and NEDDA-IEDDA diadducts **16** and **15**, respectively, is an unprecedented finding in the chemistry of DNBF.

Fig. 2. Time dependence of the 1H NMR spectra of a pure sample of **15** in CDCl3.

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

**4. NMR in the study of the stability of -complexes** 

weak carbon nucleophiles, e.g. anilines, 3-aminothiophenes….

out to determine accurately the structure of this salt.19-21

NO2

<sup>7</sup> <sup>8</sup>

**18a**

5 6

**4.1 Regioselectivity of the covalent nucleophilic addition to DNBF, A** 

N

assignments of the chemical shifts for all protons (structures **19** and **20**).

H OH O

9


N

O


<sup>4</sup> OH

O2N N

1H nmr spectra exhibit three signals at = 8.93, 6.20 (doublet, J = 7Hz) and 6.55 (doublet, J = 7 Hz) ppm. When the salt is prepared with deuterium oxide, only two signals at 8.93 and 6.20 ppm (doublets, J = 1 Hz) are obtained. The use of the deuterated salts permits

Unfortunately structures **18a** and **18b** are both consistent with the NMR data and it's not possible to discriminate between the two structures on this basis. Moreover, interconversion between **18a** and **18b** may exist in solution and is possible by two different pathways. One

O2N

H

6

O


O

+

N

NO2

9


<sup>7</sup> <sup>8</sup>

**18b**

4 5

other hand.

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 197

Besides the potentiality of the versatile behaviour of DNBF in terms of new synthetic approaches to heterocyclic chemistry, the results obtained are in themselves evidence that the carbocyclic ring of this superelectrophilic heterocycle has a poor aromatic character relative to TNB. This suggests the existence of a significant relationship between aromaticity on the one hand, electrophilicity in -complex formation and pericyclic reactivity on the

Benzofuroxans **A-H** represent a class of neutral 10--electron deficient heteroaromatic substrates which exhibit an extremely high electrophilic character in many covalent nucleophilic addition and substitution processes.13-18 More importantly, **DNBF, A** reacts quantitatively at room temperature with such weak carbon -nucleophiles, as benzenoid aromatics (phenols, anilines) or -excessive heteroaromatics (indoles, pyrroles, thiophenes) to afford stable anionic C-bonded -adducts which are formally the products of SEAr substitution on the benzene or hetarene ring. Coupling to weakly activated enolic double bonds is also a process that is readily achieved with **DNBF, A**. Based on these findings, **DNBF, A** can be used as a convenient probe to assess the C-basicity of a number of very

The addition of sodium hydroxide solution to a solution of DNBF, **A** resulted in the immediate and quantitative formation of a -complex **18**, which can be seen as the two regio-isomeric Meisenheimer complexes **18a** or **18b**. Many NMR studies have been carried

The comprehensive and extensive study of the interactions between benzofuroxans and various dienes (cyclic or linear) highlights characteristic NMR data allowing to quickly determine if an adduct is the result of a Normal Electronic Demand Diels-Alder (NEDDA) reaction or of an Inverse Electronic Demand Diels-Alder (IEDDA) reaction. For example, for an IEDDA adducts, the 1H NMR spectra show a deshielded signal at 6 ppm typical of H11 and a multicoupled signal at 4 ppm typical of H10 (see Figure 3) while 13C NMR spectra show that the signals pertaining to carbon 7, 10, 14 are found to be at higher field in the case of IEDDA adducts than in the case of NEDDA adducts. For these latter adducts, the 1H NMR spectra exhibited broad signals at 3.5 ppm pertaining to H10 and H13 (Figure 3).

Fig. 3. Characteristic signals of Diels-Alder Adducts.

#### **4. NMR in the study of the stability of -complexes**

196 Magnetic Resonance Spectroscopy

The comprehensive and extensive study of the interactions between benzofuroxans and various dienes (cyclic or linear) highlights characteristic NMR data allowing to quickly determine if an adduct is the result of a Normal Electronic Demand Diels-Alder (NEDDA) reaction or of an Inverse Electronic Demand Diels-Alder (IEDDA) reaction. For example, for an IEDDA adducts, the 1H NMR spectra show a deshielded signal at 6 ppm typical of H11 and a multicoupled signal at 4 ppm typical of H10 (see Figure 3) while 13C NMR spectra show that the signals pertaining to carbon 7, 10, 14 are found to be at higher field in the case of IEDDA adducts than in the case of NEDDA adducts. For these latter adducts, the 1H

NMR spectra exhibited broad signals at 3.5 ppm pertaining to H10 and H13 (Figure 3).

5.81

5.79

H11

5.8

3.92 3.91

H7

4.15 4.10 4.05 4.00

H10 H13

3.58

3.69

3.95 3.90 3.85 3.80 3.75 3.70 3.65 3.60 3.55 3.50

4.08 4.05

H10

N

H

<sup>6</sup> +

8 9

7

11

12

X

6 7 8 9

11

14

5

4

10

IEDDA Adduct

14

13

N

+

H

NEDDA Adduct

10

N

O

O

Fig. 3. Characteristic signals of Diels-Alder Adducts.


X

4

H

H

N

+

5

O

O2 N

13

12


O

H

N

O

O


Besides the potentiality of the versatile behaviour of DNBF in terms of new synthetic approaches to heterocyclic chemistry, the results obtained are in themselves evidence that the carbocyclic ring of this superelectrophilic heterocycle has a poor aromatic character relative to TNB. This suggests the existence of a significant relationship between aromaticity on the one hand, electrophilicity in -complex formation and pericyclic reactivity on the other hand.

Benzofuroxans **A-H** represent a class of neutral 10--electron deficient heteroaromatic substrates which exhibit an extremely high electrophilic character in many covalent nucleophilic addition and substitution processes.13-18 More importantly, **DNBF, A** reacts quantitatively at room temperature with such weak carbon -nucleophiles, as benzenoid aromatics (phenols, anilines) or -excessive heteroaromatics (indoles, pyrroles, thiophenes) to afford stable anionic C-bonded -adducts which are formally the products of SEAr substitution on the benzene or hetarene ring. Coupling to weakly activated enolic double bonds is also a process that is readily achieved with **DNBF, A**. Based on these findings, **DNBF, A** can be used as a convenient probe to assess the C-basicity of a number of very weak carbon nucleophiles, e.g. anilines, 3-aminothiophenes….

#### **4.1 Regioselectivity of the covalent nucleophilic addition to DNBF, A**

The addition of sodium hydroxide solution to a solution of DNBF, **A** resulted in the immediate and quantitative formation of a -complex **18**, which can be seen as the two regio-isomeric Meisenheimer complexes **18a** or **18b**. Many NMR studies have been carried out to determine accurately the structure of this salt.19-21

1H nmr spectra exhibit three signals at = 8.93, 6.20 (doublet, J = 7Hz) and 6.55 (doublet, J = 7 Hz) ppm. When the salt is prepared with deuterium oxide, only two signals at 8.93 and 6.20 ppm (doublets, J = 1 Hz) are obtained. The use of the deuterated salts permits assignments of the chemical shifts for all protons (structures **19** and **20**).

Unfortunately structures **18a** and **18b** are both consistent with the NMR data and it's not possible to discriminate between the two structures on this basis. Moreover, interconversion between **18a** and **18b** may exist in solution and is possible by two different pathways. One

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

according to scheme 7 in this solvent.

N

+

O

+ MeO-

Scheme 7. Addition of methoxide ion to 4-nitrobenzofuroxan **21**.

O

N

Scheme 7

NO2

4

7

5

**21**

In these systems, rapid MeO-

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 199

The NMR spectra indicate only one product. If a second substance is present, its NMR spectrum is identical with the other or is present in too small amount to be detectable or the two are exchanging at a rapid state. However, consideration of resonance forms indicates that **18a** (delocalization of the negative charge into the two nitro groups) should be more stable than **18b** (delocalization of the negative charge into only one nitro group). The correct structure for the Meisenheimer complex formed by the reaction of DNBF, **A** with aqueous base is considered to be **18a**. Confirmation of this result has been further confirmed by the study of the case of nitrobenzofuroxan **21**, which react very similarly with water and OH- to afford hydroxy -adducts in aqueous solution. An analogous situation holds in methanol when there is a remarkable analogy between the rate and equilibrium parameters governing the ambident reactivity of 4-nitrobenzofuroxan **21**

N

+

O

O

N

**21'-OMe**

NO2

4

7

N

+

<sup>H</sup> <sup>O</sup> OMe

O

N

NO2

attack at the C-5 position of **21** to give **21'-OMe** is followed by

7

4

5

a slow and a nearly complete isomerization of these adducts to the thermodynamically more stable 7-complexes **21-OMe**. These isomers benefit from the greater efficiency of a para- than an ortho- NO2 group in delocalizing electron by resonance interaction. The formation of **21'- OMe** preceded the formation of the thermodynamically more stable **21-OMe** adduct. Only the C-7 adduct could be observed by room temperature NMR spectroscopy, it was necessary to cool the system at low temperature prior to start of the reaction in order to detect and characterize the C-5 adduct as the product of kinetic control. In as much as it occurs with

**21-OMe**

H

5

MeO

path is by a reversible hydroxylation at the 5- and 7-position (path a, scheme 6) and the other path involves a Boulton-Katritzky rearrangement (path b, Scheme 6).

Scheme 6. Interconversion between **18a** and **18b**.

path is by a reversible hydroxylation at the 5- and 7-position (path a, scheme 6) and the

O2 N

Ha

6

N

O

N

NO2

path a

9

<sup>7</sup> <sup>8</sup>

**A**

4 5

6

path b

O2 N


O


O2

+ OH-

Hb OD

**20**

Ha = 8.97 ppm (J = 1 Hz) Hb = 6.20 ppm (J = 1Hz)

O

8


6

7

H OH

**18b**


N NO2

<sup>4</sup> <sup>5</sup>

N O

+

N

9


<sup>7</sup> <sup>8</sup>

NO2


9

4 5

other path involves a Boulton-Katritzky rearrangement (path b, Scheme 6).

Hb OHc

**19**

Ha = 8.97 ppm

NO2

<sup>7</sup> <sup>8</sup>

**18a**

4

5 6

Hb = 6.20 ppm (J = 7Hz) Hc = 6.55 ppm (J = 7Hz)

N

+ OH-

H OH O

Scheme 6. Interconversion between **18a** and **18b**.

9


N

O


<sup>7</sup> <sup>8</sup>

O2 N

O2N

Ha

6

NO2


9

4 5

The NMR spectra indicate only one product. If a second substance is present, its NMR spectrum is identical with the other or is present in too small amount to be detectable or the two are exchanging at a rapid state. However, consideration of resonance forms indicates that **18a** (delocalization of the negative charge into the two nitro groups) should be more stable than **18b** (delocalization of the negative charge into only one nitro group). The correct structure for the Meisenheimer complex formed by the reaction of DNBF, **A** with aqueous base is considered to be **18a**. Confirmation of this result has been further confirmed by the study of the case of nitrobenzofuroxan **21**, which react very similarly with water and OH- to afford hydroxy -adducts in aqueous solution. An analogous situation holds in methanol when there is a remarkable analogy between the rate and equilibrium parameters governing the ambident reactivity of 4-nitrobenzofuroxan **21** according to scheme 7 in this solvent.

Scheme 7. Addition of methoxide ion to 4-nitrobenzofuroxan **21**.

In these systems, rapid MeO attack at the C-5 position of **21** to give **21'-OMe** is followed by a slow and a nearly complete isomerization of these adducts to the thermodynamically more stable 7-complexes **21-OMe**. These isomers benefit from the greater efficiency of a para- than an ortho- NO2 group in delocalizing electron by resonance interaction. The formation of **21'- OMe** preceded the formation of the thermodynamically more stable **21-OMe** adduct. Only the C-7 adduct could be observed by room temperature NMR spectroscopy, it was necessary to cool the system at low temperature prior to start of the reaction in order to detect and characterize the C-5 adduct as the product of kinetic control. In as much as it occurs with

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

of the carbocyclic ring of DNBF (Table 7).24

Compoun

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 201

Regarding 13C data, there are two noteworthy results: a) in accord with the sp2 → sp3 rehybridization resulting from the complexation of the DNBF moiety, there is a strong upfield shift of the C7 resonance (from 120.80 for DNBF to ~ 32 ppm for **22**); b) the substitution of 2-nitropropane (C = 79.10 ppm) by DNBF induces a significant low-field shift of the resonance of the C carbon of the nitroalkane moiety (C = 92.0 ppm for **22**, ~ 13 ppm). This latter result is mainly the reflection of the fact that a negatively charged DNBF structure exerts a notable – I effect. HMBC spectra recorded for these salts exhibited characteristic correlations. For example, one correlation between C9 ( = 150 ppm) and H5 (JC9H5 = 6 Hz) while C8 ( = 110 ppm) is only correlated with H7 (JC8H7 = 9 Hz). This latter correlation is a nice support that the covalent addition of the nucleophile takes place at C-7

Compounds **H5 H7 CH CF3\*** 

1.49 -

1.44 -57.3

1.56 -

1.52 -78.7

1.46 -58.8

1.46 -

23.2

21.3

22.9

22.8

23.2

22.9

**<sup>22</sup>**8.69 5.27 1.51

**<sup>25</sup>**7.68 4.73 1.54

**<sup>26</sup>**7.73 4.58 1.61

27 8.22 4.56 1.54

28 7.97 5.30 1.51

29 8.09 5.30 1.49

ds C4 C5 C6 C7 C8 C9 CN CF3 <sup>C</sup> Me 22 110.6 133.3 121.0 41.3 110.1 149.8 - - 92.1 23.3

25 106.4 132.7 99.7 40.2 110.0 150.8 - 124.5 92.6 24.9

26 108.7 140.4 80.5 42.5 109.3 150.0 121.1 - 92.6 23.5

27 113.3 144.2 90.4 41.3 109.1 149.8 - 120.2 92.5 23.0

28 91.0 134.2 110.9 41.5 109.6 151.4 - 123.9 92.7 23.8

29 73.8 141.1 115.1 41.3 109.2 153.6 117.8 - 92.5 23.5

Table 6. 1H NMR data for the adducts **22** and **25-29** (DMSO-d6)

Table 7. 13C NMR data for the adducts **22** and **25-29** (DMSO-d6)

other nucleophiles but is restricted to **21**, the ambident electrophilic behaviour depicted in scheme 7 is a typical feature of the chemistry of nitrobenzoxadiazoles. Because of a very fast interconversion between the C-5 and the C-7 adduct or because of a very high thermodynamic stability of the C-7 adduct, it has not been possible to detect and to characterize **18b,** the C-5 hydroxy--adduct of DNBF, even at low temperature.22-23

#### **4.2 NMR characterization of the C-7 adducts of DNBF, A and its derivatives B-H24**

We have succeeded in obtaining new spectroscopic data on the Meisenheimer complexes of DNBF, **A** in looking at the interaction of this compound with 2-nitropropane anion. As a major diagnostic feature in the 1H NMR spectra of **22** is the H7 resonance which appears at 5.27 ppm, being in the range commonly found for many C-bonded DNBF adducts, e.g. = 5.40 ppm for **23**.3,8 The shielding of the H7 resonance (H7 = 9.27 ppm for DNBF, H7 = 4 ppm) is due to the sp2 → sp3 rehybridization of the carbon 7 (Table 6). Also in accord with previous observations showing that the chemical shift of the H5 proton located between the two NO2 groups of the negatively charged DNBF moiety depends very little on the nature of the C-bonded structure, the H5 resonance for **22** is = 8.69 ppm and close to those found for related adducts, e.g. = 8.62 ppm for **24**.4 This slight shielding may be interpreted in terms of loss of the aromatic character and of appearance of a negative charge on the DNBF moiety.

other nucleophiles but is restricted to **21**, the ambident electrophilic behaviour depicted in scheme 7 is a typical feature of the chemistry of nitrobenzoxadiazoles. Because of a very fast interconversion between the C-5 and the C-7 adduct or because of a very high thermodynamic stability of the C-7 adduct, it has not been possible to detect and to

characterize **18b,** the C-5 hydroxy--adduct of DNBF, even at low temperature.22-23

character and of appearance of a negative charge on the DNBF moiety.

O2N

N

+

N

NO2


H

**23**

O2 N O

O


NH3

+

**4.2 NMR characterization of the C-7 adducts of DNBF, A and its derivatives B-H24**

We have succeeded in obtaining new spectroscopic data on the Meisenheimer complexes of DNBF, **A** in looking at the interaction of this compound with 2-nitropropane anion. As a major diagnostic feature in the 1H NMR spectra of **22** is the H7 resonance which appears at 5.27 ppm, being in the range commonly found for many C-bonded DNBF adducts, e.g. = 5.40 ppm for **23**.3,8 The shielding of the H7 resonance (H7 = 9.27 ppm for DNBF, H7 = 4 ppm) is due to the sp2 → sp3 rehybridization of the carbon 7 (Table 6). Also in accord with previous observations showing that the chemical shift of the H5 proton located between the two NO2 groups of the negatively charged DNBF moiety depends very little on the nature of the C-bonded structure, the H5 resonance for **22** is = 8.69 ppm and close to those found for related adducts, e.g. = 8.62 ppm for **24**.4 This slight shielding may be interpreted in terms of loss of the aromatic

N

H O

9


NO2

O2 N

MeO

NO2

<sup>7</sup> <sup>8</sup>

**22**

4

5 6 N

O


N

+

N

NO2


H S

**24**

O

O


Regarding 13C data, there are two noteworthy results: a) in accord with the sp2 → sp3 rehybridization resulting from the complexation of the DNBF moiety, there is a strong upfield shift of the C7 resonance (from 120.80 for DNBF to ~ 32 ppm for **22**); b) the substitution of 2-nitropropane (C = 79.10 ppm) by DNBF induces a significant low-field shift of the resonance of the C carbon of the nitroalkane moiety (C = 92.0 ppm for **22**, ~ 13 ppm). This latter result is mainly the reflection of the fact that a negatively charged DNBF structure exerts a notable – I effect. HMBC spectra recorded for these salts exhibited characteristic correlations. For example, one correlation between C9 ( = 150 ppm) and H5 (JC9H5 = 6 Hz) while C8 ( = 110 ppm) is only correlated with H7 (JC8H7 = 9 Hz). This latter correlation is a nice support that the covalent addition of the nucleophile takes place at C-7 of the carbocyclic ring of DNBF (Table 7).24


Table 6. 1H NMR data for the adducts **22** and **25-29** (DMSO-d6)


Table 7. 13C NMR data for the adducts **22** and **25-29** (DMSO-d6)

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

Y

N O N

+


Scheme 8. Resonance forms of sigma-complexes **25-29**.

equilibrium process to completion in acetonitrile solution.

H O

9

N O N

+


H O

9


NO2

NO2

<sup>7</sup> <sup>8</sup>

**C-NO2**

4 5 6

Y

NO2

according to the sequence O < N < C.

X


<sup>7</sup> <sup>8</sup>

4 5 6

O2 N

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 203

NO2

<sup>7</sup> <sup>8</sup>

4 5 6


N O N

+


H O

**- C-4 C-Y - -**

9

NO2

N O N


N O N

N O N


H O


9

NO2

NO2

<sup>7</sup> <sup>8</sup>

4 5 6

Y


H O

9

NO2

X

<sup>7</sup> <sup>8</sup>

4 5 6


O2N

H O

X = CF3, **28** X = CN, **29**

**4.3 15N NMR characterization of the N-adduct of DNBF, A with 4,5-dimethylthiazole** 

Treatment of DNBF, **A** with a two-fold excess of **30** in acetonitrile solution, followed by addition of diethylether, resulted in the precipitation of an orange solid corresponding to the 4,5-dimethylthiazolium salt of the adduct **N-30** (Scheme 9). Because of the strong acidifying effect exerted by a negatively charged DNBF moiety,24 the deprotonation of the NH2+ group of the initially formed zwitterion **N-30** by **30** acting as a base reagent is a facile process, accounting for the adduct salt **N-30;30,H+** being the thermodynamically stable product of the interaction and therefore for the need of two moles of **30** to drive the overall

The bonding of DNBF at a nitrogen center is supported by the presence of a relatively lowfield H7' resonance (H7' = 6.00 ppm) in the 1H nmr spectra. The evidence, however, is that this resonance is very sensitive to the nature of the atom or group bonded to that position, the shielding increasing with decreasing the electronegativity of the attached atom, i.e.


9

NO2

**C-X C-6 C-NO2 - - -**

X

Y= CF3, **25** Y = CN, **26** Y= SO2CF3, **27**

<sup>7</sup> <sup>8</sup>

4 5 6

O2 N

All the NMR data pertaining to **22** are summarized in Tables 6 and 7 together with the NMR data of the Meisenheimer complexes deriving from benzofuroxans **B-H**.

The delocalization of this negative charge over the DNBF moiety and over the two nitro groups is the main factor governing the outstanding stability of these Meisenheimer complexes. What will be the effect of the replacement of a nitro group by another electronwithdrawing group on the stability of the Meisenheimer complexes?

The first message emerging from the data, recorded for -adducts **25-29** and collected in Tables 6 and 7, is that the resonances of C7 (from 40.2 to 42.5 ppm), C8 (from 109.2 to 110.1 ppm), C9 (from 149.8 to 153.6 ppm) and C (from 92.1 to 92.7 ppm) are independent of the position and of the nature of the substituent and are consistent with those reported for the adduct **22**. It could be through evaluation of the chemical shift variations brought about by the complex formation that reliable information on the structural reorganization which accompanies the formation of the -adduct may be obtained. Such variations () are the result of a high field shift caused by the presence of the negative charge. On the basis of the above reasoning, a comparison in Table 8 of the H5, C4 and C6 associated with the complexes formation is very informative regarding the structure of the -adducts. As can be seen, large upfield shifts of H5 (H5 ~ 0.2-1.2 ppm), of C6 (C6 ~ 25-32 ppm) and of C4 (C4 ~ 24-38 ppm) occur upon -complex formation (see Table 8). Such agree well with the presence of the negative charge, with the loss of the aromatic character and with a sp2 → sp3 rehybridization. The large upfield shifts of C6 for salts **25-27** and of C4 for salts **28-29** is a large reflection that the resonance forms C-Y- and C-X-, respectively, play a major role in the stabilization of the negative charge (Scheme 8). Because of a large inductive effect of the cyano and trifluoromethyl groups, the negative charge is retained on the C4 or on the C6 carbon. In the case of the trifluoromethanesulfonyl group, the inductive effect is larger than for the two latter groups and is going along with the smallest H5 (0.38ppm) and the largest C6 (37 ppm) leaving no doubt that the SO2CF3 group is capable to stabilize a negative charge by a strong polarization effect. The negative charge is largely retained on the C6 carbon and is less delocalized through the carbocyclic ring.


Table 8. Changes in chemical Shifts (H5, C6 and C4 ) upon -complex formation in DMSO-d6

All the NMR data pertaining to **22** are summarized in Tables 6 and 7 together with the NMR

The delocalization of this negative charge over the DNBF moiety and over the two nitro groups is the main factor governing the outstanding stability of these Meisenheimer complexes. What will be the effect of the replacement of a nitro group by another electron-

The first message emerging from the data, recorded for -adducts **25-29** and collected in Tables 6 and 7, is that the resonances of C7 (from 40.2 to 42.5 ppm), C8 (from 109.2 to 110.1 ppm), C9 (from 149.8 to 153.6 ppm) and C (from 92.1 to 92.7 ppm) are independent of the position and of the nature of the substituent and are consistent with those reported for the adduct **22**. It could be through evaluation of the chemical shift variations brought about by the complex formation that reliable information on the structural reorganization which accompanies the formation of the -adduct may be obtained. Such variations () are the result of a high field shift caused by the presence of the negative charge. On the basis of the above reasoning, a comparison in Table 8 of the H5, C4 and C6 associated with the complexes formation is very informative regarding the structure of the -adducts. As can be seen, large upfield shifts of H5 (H5 ~ 0.2-1.2 ppm), of C6 (C6 ~ 25-32 ppm) and of C4 (C4 ~ 24-38 ppm) occur upon -complex formation (see Table 8). Such agree well with the presence of the negative charge, with the loss of the aromatic character and with a sp2 → sp3 rehybridization. The large upfield shifts of C6 for salts **25-27** and of C4 for salts **28-29** is a large reflection that the resonance forms C-Y- and C-X-, respectively, play a major role in the stabilization of the negative charge (Scheme 8). Because of a large inductive effect of the cyano and trifluoromethyl groups, the negative charge is retained on the C4 or on the C6 carbon. In the case of the trifluoromethanesulfonyl group, the inductive effect is larger than for the two latter groups and is going along with the smallest H5 (0.38ppm) and the largest C6 (37 ppm) leaving no doubt that the SO2CF3 group is capable to stabilize a negative charge by a strong polarization effect. The negative charge is largely retained on the C6 carbon and is less delocalized through the

**Compounds H5 C4 C6**

Table 8. Changes in chemical Shifts (H5, C6 and C4 ) upon -complex formation in

0.25 26.1 23.8 1.06 31.5 27.4 1.19 28.3 29.5 0.38 24.8 37.2 0.73 27.8 34.7 0.94 29.7 31.6

data of the Meisenheimer complexes deriving from benzofuroxans **B-H**.

withdrawing group on the stability of the Meisenheimer complexes?

carbocyclic ring.

DMSO-d6

Scheme 8. Resonance forms of sigma-complexes **25-29**.

#### **4.3 15N NMR characterization of the N-adduct of DNBF, A with 4,5-dimethylthiazole**

Treatment of DNBF, **A** with a two-fold excess of **30** in acetonitrile solution, followed by addition of diethylether, resulted in the precipitation of an orange solid corresponding to the 4,5-dimethylthiazolium salt of the adduct **N-30** (Scheme 9). Because of the strong acidifying effect exerted by a negatively charged DNBF moiety,24 the deprotonation of the NH2+ group of the initially formed zwitterion **N-30** by **30** acting as a base reagent is a facile process, accounting for the adduct salt **N-30;30,H+** being the thermodynamically stable product of the interaction and therefore for the need of two moles of **30** to drive the overall equilibrium process to completion in acetonitrile solution.

The bonding of DNBF at a nitrogen center is supported by the presence of a relatively lowfield H7' resonance (H7' = 6.00 ppm) in the 1H nmr spectra. The evidence, however, is that this resonance is very sensitive to the nature of the atom or group bonded to that position, the shielding increasing with decreasing the electronegativity of the attached atom, i.e. according to the sequence O < N < C.

NMR Spectroscopy: A Useful Tool in the Determination of the Electrophilic Character

N3 ''

N3

CH3

H5' H7'

furoxan ring, NO2

**N-30;30,H+**

**5. Conclusion** 

**6. References** 

*95*, 2261.

Fig. 4a. 1H-15N correlation for the adduct

short-live species involved in complicated mechanisms.

N1

of Benzofuroxans - Case Examples of the Reactions of Nitrobenzofuroxans with Dienes... 205

NH3 +

N S NH3

, Br - <sup>+</sup> 1" 2" 3" 4" 5"

Fig. 4b. 1H-15N correlation for

4,5-dimethylaminothiazolium bromide

3 CH

In this article we have highlighted some of the most significant examples where NMR spectroscopy brought important informations in the domain of the reactivity of benzofuroxans in synthetic applications (Diels-Alder, Meisenheimer Complexes formation). NMR strongly supports the structure of -complexes and informations on the capability of electron withdrawing groups to stabilize these complexes have been obtained. When complexes are stabilized by electron-withdrawing inductive effect (CF3, CN, SO2CF3), a large part of the negative charge is retained on the C4 or C6 carbon and is less delocalized through the carbocyclic ring. Moreover, the regioselectivity of the covalent nucleophilic addition can be unambiguously determined. The H7 resonance is a key feature to see if DNBF is bonded at a nitrogen (H7 ~ 6 ppm) or carbon (H7 ~ 4 ppm) center. In the case of Diels-Alder reactions, NMR appears to be a useful tool, and especially using 15N labelling, to highlight

[1] Terrier, F. In *Nucleophilic Aromatic Displacement*; Feuer, H, Ed.; VCH: New York, 1991.

Terrier, F *Chem. Rev.* 1982, *82*, 77. Buncel, E.; Dust, J. M.; Terrier, F *Chem. Rev.* 1995,

<sup>3</sup>CH

CH3

N3 ''

```
N-31
```
On this ground, the finding of a H7' resonance at 6.00 ppm and a C7' resonance at 46.1 ppm leaves little doubt regarding the N-bonded structure of the DNBF adduct of 4,5-dimethyl-2 aminothiazole **30**. As a matter of fact, the H7' resonance of **N-30** is very similar to that of the anionic aniline complex N-**31** (H7' = 6.08 ppm).3 1H-15N correlations based on long-range coupling are clearly in favour of structure **N-30**. In the spectra, correlations can be observed between the exocyclic nitrogen N1 ( = 87.1 ppm) and H7' ( = 6.00 ppm), between the endocyclic nitrogen N3 ( = 245.0 ppm) and the methyl group at C-4 ( = 2.05 ppm); concomitantly, the correlation between the endocyclic nitrogen N3" ( = 180.5 ppm) and the methyl group at C-4" ( = 2.08 ppm) of the thiazolium counterpart is observed (Figure 4a). This latter correlation is similar to that observed with the 4,5-dimethylaminothiazolium bromide (Figure 4b). To be noted is that all the 15N nmr data collected from the various correlations are in full agreement with a recent review on the use of long-range 1H-15N correlations in the structural determination of organic compounds.25-26

The formation of the nitrogen adduct of DNBF is strongly supported by the 15N NMR and especially through the 1H -15N correlations.

Fig. 4a. 1H-15N correlation for the adduct **N-30;30,H+**

Fig. 4b. 1H-15N correlation for 4,5-dimethylaminothiazolium bromide

#### **5. Conclusion**

204 Magnetic Resonance Spectroscopy

3 CH

<sup>3</sup>CH

NO2


NH <sup>H</sup>

**N-31**

On this ground, the finding of a H7' resonance at 6.00 ppm and a C7' resonance at 46.1 ppm leaves little doubt regarding the N-bonded structure of the DNBF adduct of 4,5-dimethyl-2 aminothiazole **30**. As a matter of fact, the H7' resonance of **N-30** is very similar to that of the anionic aniline complex N-**31** (H7' = 6.08 ppm).3 1H-15N correlations based on long-range coupling are clearly in favour of structure **N-30**. In the spectra, correlations can be observed between the exocyclic nitrogen N1 ( = 87.1 ppm) and H7' ( = 6.00 ppm), between the endocyclic nitrogen N3 ( = 245.0 ppm) and the methyl group at C-4 ( = 2.05 ppm); concomitantly, the correlation between the endocyclic nitrogen N3" ( = 180.5 ppm) and the methyl group at C-4" ( = 2.08 ppm) of the thiazolium counterpart is observed (Figure 4a). This latter correlation is similar to that observed with the 4,5-dimethylaminothiazolium bromide (Figure 4b). To be noted is that all the 15N nmr data collected from the various correlations are in full agreement with a recent review on the use of long-range 1H-15N

The formation of the nitrogen adduct of DNBF is strongly supported by the 15N NMR and

N O N

+

O


3 CH

3CH

N

fast **30**

N

2 3 4

S

N H

1

**N-30**

DNBF


,

<sup>3</sup>CH

<sup>3</sup>CH

N

3" 4"

**30,H+**

NH3

+ 1" 2"

S

Scheme 9

5"

NH2

+

**N-30**

DNBF


S

N

**30**

O2 N

<sup>3</sup>CH

**A**

DNBF +

3 CH

NH2

N O N

+

NO2


<sup>5</sup> with DNBF - :

H

4' 5' 6' 7' 8' 9' O


O2N

correlations in the structural determination of organic compounds.25-26

especially through the 1H -15N correlations.

k-1

k1 DNBF

S

In this article we have highlighted some of the most significant examples where NMR spectroscopy brought important informations in the domain of the reactivity of benzofuroxans in synthetic applications (Diels-Alder, Meisenheimer Complexes formation). NMR strongly supports the structure of -complexes and informations on the capability of electron withdrawing groups to stabilize these complexes have been obtained. When complexes are stabilized by electron-withdrawing inductive effect (CF3, CN, SO2CF3), a large part of the negative charge is retained on the C4 or C6 carbon and is less delocalized through the carbocyclic ring. Moreover, the regioselectivity of the covalent nucleophilic addition can be unambiguously determined. The H7 resonance is a key feature to see if DNBF is bonded at a nitrogen (H7 ~ 6 ppm) or carbon (H7 ~ 4 ppm) center. In the case of Diels-Alder reactions, NMR appears to be a useful tool, and especially using 15N labelling, to highlight short-live species involved in complicated mechanisms.

#### **6. References**

[1] Terrier, F. In *Nucleophilic Aromatic Displacement*; Feuer, H, Ed.; VCH: New York, 1991. Terrier, F *Chem. Rev.* 1982, *82*, 77. Buncel, E.; Dust, J. M.; Terrier, F *Chem. Rev.* 1995, *95*, 2261.

**11** 

*Japan* 

**NMR Spectroscopy for Studying** 

*2Department of Molecular Pathobiology and Cell Adhesion Biology,* 

The expansion of the modern pharmacopeia is driven by advances in structural genomics that enable the detailed understanding of drug – protein interactions necessary for the identification of novel compounds as well as improved variants of existing drugs. Our research has centered on understanding the mechanism by which a critical class of transmembrane receptor proteins, the integrins, become activated in healthy and disease states. An important component of this research has been in identifying novel inhibitors of integrin function and their mechanism of action. As we describe in the following sections, nuclear magnetic resonance spectroscopy (NMR) has been an essential tool in advances in

Integrins are a family of cell surface receptor proteins that mediate cell-matrix and cell-cell adhesion (Hynes, 2002). Integrin mediated adhesion is critical in multiple phases of development and maintenance of tissue physiology. Conversely, aberrant integrin function that can arise due to inappropriate increase or decrease in expression levels as well as inappropriate levels of activation is implicated in many diseases including cancer, neurological and immunological disorders (Shimaoka and Springer, 2003). The critical role of integrins in maintenance of healthy physiology has stimulated intense efforts to understand the mechanism of integrin mediated adhesion and identify pharmacological agents that can alter integrin function and thus restore the appropriate levels of cellular adhesion. Although the focus of this review is on NMR spectroscopy, as opposed to the related technique of magnetic resonance imaging (MRI), many of the compounds identified as integrin antagonists are also of interest as probes for MRI, particularly in the area of cancer imaging (Dijkgraaf et al., 2009). Thus, although we confine ourselves to understanding the interactions between antagonists and integrins by NMR in vitro, many of these results are directly applicable to the study of

Nuclear magnetic resonance (NMR) spectroscopy has played a central role in understanding the mechanism of integrin activation and providing insight into the nature and dynamic

**1. Introduction** 

this area, and is the major focus of this review.

integrin expression and function by MRI *in vivo*.

 \*

Corresponding Author

Nathan S. Astrof1 and Motomu Shimaoka2\*

*Mie University Graduate School of Medicine* 

**Integrin Antagonists** 

*1Mount Sinai School of Medicine* 

