One-Pot Synthesis of Chiral Organometallic Complexes

*Mei Luo*

## **Abstract**

Currently, organometallic complexes involving ligand oxazolines are typically obtained in two sequential steps, where the free ligand is given firstly from a functionalized nitrile by condensation reaction with an amino alcohol in the presence of a Lewis or Bronsted acid catalyst, followed by a further coordination with metal salts to obtain the corresponding oxazolinyl metal complexes. Usually, the yield of the two-step procedure is relatively low; considering that metal oxazoline complexes often contain Lewis acidic metals, it is possible that the two steps may be telescoped. A series of novel chiral organometallic complexes (**1–23**) were assembled in a single step from nitriles, chiral D/L amino alcohols, and a stoichiometric amount of metal salts (MCl2·nH2O/M(OAc)2·nH2O), with moderate to high yields (20–95%). All the crystalline compounds were fully characterized by NMR, IR, MS, and X-ray analyses.

**Keywords:** chiral organometallic complexes, nitriles, amino alcohols, metal salts, crystalline compounds

## **1. Introduction**

Chiral oxazolines constitute an important class of "privileged" ligands in asymmetric catalysis [1–8]. Organometallic complexes involving oxazoline ligands are typically obtained in two steps, where the free ligand is given firstly from a functionalized nitrile through condensation reaction with an amino alcohol in the presence of a Lewis or Bronsted acid catalyst, followed by further complexed coordination with metal salts to obtain the corresponding oxazolinyl metal complexes (**Figure 1**) [9, 10]. Usually, the yield of the two-step procedure is relatively low, and certain oxazolinyl organometallic complexes are difficult to obtain due to the poor coordination ability of the imine group from the oxazoline. It is conceivable that the two steps may be telescoped by using the requisite Lewis acid precursor. Herein, through the assembly of three reaction components (a nitrile, an amino alcohol, and metal salts), we first report a simple, one-step procedure for the preparation of N-containing heterocyclic zinc complexes (**1–15**), with the yield of certain products reaching 90% in the presence of a large amount of ZnCl2 (0.4–2.6 eq.) and certain chiral salicyloxazoline metal complexes (**16–23**) with yields ranging from 65 to 95% using 1.0 eq. of copper, cobalt, nickel, manganese, palladium, and platinum salts as the third component. In all the cases, the complexes were isolated, purified, and characterized. All the structures reported in this paper were confirmed by X-ray crystallography.

**Figure 1.** *Common method for the preparation of oxazolinyl metal complexes.*

## **2. One-step multicomponent synthesis of chiral oxazolinyl-zinc complexes**

The one-pot procedure was initially tested from the reaction of different 1-piperidine propionitrile derivatives with 2–3 eq. of amino alcohol refluxed in chlorobenzene for 72 h in the presence of 1–2.6 eq. of ZnCl2. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in H2O and extracted with CH2Cl2. The combined organic extracts were evaporated to give a crude red oil, which was purified by column chromatography (petroleum ether/CH2Cl2, 4/1) to afford the title compound as crystals. During the preliminary work, it quickly became apparent that the reaction results are controlled by the amount of ZnCl2 used (**Figure 2**); for example, employing 1.1 eq. or 2.6 eq. of ZnCl2, the desired crystal structures of the amino-oxazolidinyl zinc complex **1** and bis-oxazolidinyl zinc complex **2** containing two monodentate ligands can be obtained from the reaction of L-leucinol or L-valinol with 3-piperidin-1-yl-propionitrile, respectively, followed by evaporation of different ratios of petroleum and dichloromethane from the mixture after column separation but with only a low yield (25%) for complex **1** and moderate yield (65%) for complex **2**.

The nature of the side chain (R1 ) influenced the reaction outcome. Using L-phenylalaninol with 1.6 eq. of ZnCl2 or 1.5 eq. of ZnCl2 with 1-morpholinepropionitrile (X = O) and D-phenylglycinol, both led to the cleavage of the propionitrile, providing asymmetric diamine complexes **3** and **4** at very good yields of 86% and 90%, respectively. Interestingly, using 1-(2-cyanoethyl)-4-methylpiperazine (Z = NMe) as a precursor with 2.5 eq. of ZnCl2 led only to the formation of the zwitterionic piperazine complex **5**, irrespective of the amino alcohol used. The results again prove the effects of different amounts of metal salts on the reaction.

From the crystal structures of complexes **2–5**, we conclude that the propionitrile precursors are unstable and decompose into acetonitrile or the parent cyclic amines to afford complexes **2** and **3–5,** respectively, in the presence of a large amount of zinc chloride. For this reason, a number of nitrile precursors with additional N-donor were selected to be more robust against degradation under the reaction conditions. Consequently, a number of aromatic nitrile precursors containing additional N-donors were applied widely in these three-component reactions. In the process of selecting these reactions, the appropriate amount of ZnCl2 was carefully optimized to ensure specific results. Complex **6**, listed in **Figure 3**, contains two monodentate ligands coordinated via the oxazoline nitrogen and was afforded from the use of 3-aminobenzonitrile and D-leucinol in the presence of 0.44 eq.

**27**

1.2 eq. of ZnCl2.

**Figure 2.**

*One-Pot Synthesis of Chiral Organometallic Complexes DOI: http://dx.doi.org/10.5772/intechopen.89865*

of ZnCl2. Similarly, the bis-chelated complex **7** and the mono-chelated complex **8** were afforded to the corresponding yields of 80 and 78% from the use of 2-cyanopyridine with L-phenylalaninol and D-valinol, respectively, in the presence of

*Effect of the reaction stoichiometry of (metal precursor) ZnCl2.*

The formation of complexes **9** and **10** were studied using different amino alcohols, as seen in **Figure 4**. C2-symmetrical bis-oxazolines formed seven-membered chelate rings which derived from 1,2-dicyanobenzene, affording a 1:1 adduct with zinc dichloride. Indeed, the addition of isophthalonitrile with D-phenylglycinol (0.56 eq.) provided the predicted mono-chelated complex **9** [11] at a good yield (68%). However, a combination of a slight excess of L-valinol (0.72 eq.) caused the

Surprisingly, the combination of L-leucinol and L-phenylglycinol with tetracyanoethylene in the presence of 0.42 eq. of ZnCl2, respectively, provided neutral bis[bis(oxazoline)]zinc (II) complexes **11** and **12** with corresponding yields of 88 and 86% (**Figure 5**). The crystal structures of these methylene-bis(oxazoline) indicate that the tricyanomethane was formed as an intermediate from a disproportionation-rearrangement of the tetracyanoethylene precursor, although the precise mechanism of this pathway is unclear. In 2016, Kögel et al. reported the synthesis of complex **12** by a different route [12]. Interestingly, complex **12** was reported to exhibit an intense cotton effect as a result of exciton coupling. Indeed, the X-ray

addition of three amino alcohols to give complex **10** with a yield of 66%.

*One-Pot Synthesis of Chiral Organometallic Complexes DOI: http://dx.doi.org/10.5772/intechopen.89865*

#### **Figure 2.**

*Synthesis Methods and Crystallization*

**complexes**

**Figure 1.**

**2. One-step multicomponent synthesis of chiral oxazolinyl-zinc** 

for complex **1** and moderate yield (65%) for complex **2**.

*Common method for the preparation of oxazolinyl metal complexes.*

The nature of the side chain (R1

The one-pot procedure was initially tested from the reaction of different 1-piperidine propionitrile derivatives with 2–3 eq. of amino alcohol refluxed in chlorobenzene for 72 h in the presence of 1–2.6 eq. of ZnCl2. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in H2O and extracted with CH2Cl2. The combined organic extracts were evaporated to give a crude red oil, which was purified by column chromatography (petroleum ether/CH2Cl2, 4/1) to afford the title compound as crystals. During the preliminary work, it quickly became apparent that the reaction results are controlled by the amount of ZnCl2 used (**Figure 2**); for example, employing 1.1 eq. or 2.6 eq. of ZnCl2, the desired crystal structures of the amino-oxazolidinyl zinc complex **1** and bis-oxazolidinyl zinc complex **2** containing two monodentate ligands can be obtained from the reaction of L-leucinol or L-valinol with 3-piperidin-1-yl-propionitrile, respectively, followed by evaporation of different ratios of petroleum and dichloromethane from the mixture after column separation but with only a low yield (25%)

L-phenylalaninol with 1.6 eq. of ZnCl2 or 1.5 eq. of ZnCl2 with 1-morpholinepropionitrile (X = O) and D-phenylglycinol, both led to the cleavage of the propionitrile, providing asymmetric diamine complexes **3** and **4** at very good yields of 86% and 90%, respectively. Interestingly, using 1-(2-cyanoethyl)-4-methylpiperazine (Z = NMe) as a precursor with 2.5 eq. of ZnCl2 led only to the formation of the zwitterionic piperazine complex **5**, irrespective of the amino alcohol used. The results

From the crystal structures of complexes **2–5**, we conclude that the propionitrile precursors are unstable and decompose into acetonitrile or the parent cyclic amines to afford complexes **2** and **3–5,** respectively, in the presence of a large amount of zinc chloride. For this reason, a number of nitrile precursors with additional N-donor were selected to be more robust against degradation under the reaction conditions. Consequently, a number of aromatic nitrile precursors containing additional N-donors were applied widely in these three-component reactions. In the process of selecting these reactions, the appropriate amount of ZnCl2 was carefully optimized to ensure specific results. Complex **6**, listed in **Figure 3**, contains two monodentate ligands coordinated via the oxazoline nitrogen and was afforded from the use of 3-aminobenzonitrile and D-leucinol in the presence of 0.44 eq.

again prove the effects of different amounts of metal salts on the reaction.

) influenced the reaction outcome. Using

**26**

*Effect of the reaction stoichiometry of (metal precursor) ZnCl2.*

of ZnCl2. Similarly, the bis-chelated complex **7** and the mono-chelated complex **8** were afforded to the corresponding yields of 80 and 78% from the use of 2-cyanopyridine with L-phenylalaninol and D-valinol, respectively, in the presence of 1.2 eq. of ZnCl2.

The formation of complexes **9** and **10** were studied using different amino alcohols, as seen in **Figure 4**. C2-symmetrical bis-oxazolines formed seven-membered chelate rings which derived from 1,2-dicyanobenzene, affording a 1:1 adduct with zinc dichloride. Indeed, the addition of isophthalonitrile with D-phenylglycinol (0.56 eq.) provided the predicted mono-chelated complex **9** [11] at a good yield (68%). However, a combination of a slight excess of L-valinol (0.72 eq.) caused the addition of three amino alcohols to give complex **10** with a yield of 66%.

Surprisingly, the combination of L-leucinol and L-phenylglycinol with tetracyanoethylene in the presence of 0.42 eq. of ZnCl2, respectively, provided neutral bis[bis(oxazoline)]zinc (II) complexes **11** and **12** with corresponding yields of 88 and 86% (**Figure 5**). The crystal structures of these methylene-bis(oxazoline) indicate that the tricyanomethane was formed as an intermediate from a disproportionation-rearrangement of the tetracyanoethylene precursor, although the precise mechanism of this pathway is unclear. In 2016, Kögel et al. reported the synthesis of complex **12** by a different route [12]. Interestingly, complex **12** was reported to exhibit an intense cotton effect as a result of exciton coupling. Indeed, the X-ray

#### **Figure 3.** *Zinc complexes 6–8 derived from 3-aminobenzonitrile and 2-cyanopyridine.*

**Figure 4.** *Complexes 9–10 derived from isophthalonitrile.*

crystal structures of complexes **11** and **12** have been proven that due to the their coordination environments, isobutyl-substituted complex **11** has shown a fairly symmetrical tetrahedral comformation, while complex **12** is in highly distorted. This maybe the result of the favorable intramolecular π-interaction between one of the phenyl groups with the semicorrin structure of the adjacent ligand within 3.5 Å, effectively leading to the two chiral chromophores' close proximity to convenience exciton coupling [13].

In further study, 2-hydroxy-6-methylnicotinonitrile was employed as a precursor to test the applicability of the one-pot methodology in assembling complex multinuclear structures. In the presence of different amounts of ZnCl2 (1.72, 1.31,

**29**

**Figure 6.**

*Multinuclear zinc complexes 13–15.*

**Figure 5.**

*One-Pot Synthesis of Chiral Organometallic Complexes DOI: http://dx.doi.org/10.5772/intechopen.89865*

*Neutral zinc complexes derived from tetracyanoethylene.*

*One-Pot Synthesis of Chiral Organometallic Complexes DOI: http://dx.doi.org/10.5772/intechopen.89865*

*Synthesis Methods and Crystallization*

**28**

**Figure 3.**

**Figure 4.**

exciton coupling [13].

*Complexes 9–10 derived from isophthalonitrile.*

crystal structures of complexes **11** and **12** have been proven that due to the their coordination environments, isobutyl-substituted complex **11** has shown a fairly symmetrical tetrahedral comformation, while complex **12** is in highly distorted. This maybe the result of the favorable intramolecular π-interaction between one of the phenyl groups with the semicorrin structure of the adjacent ligand within 3.5 Å, effectively leading to the two chiral chromophores' close proximity to convenience

*Zinc complexes 6–8 derived from 3-aminobenzonitrile and 2-cyanopyridine.*

In further study, 2-hydroxy-6-methylnicotinonitrile was employed as a precursor to test the applicability of the one-pot methodology in assembling complex multinuclear structures. In the presence of different amounts of ZnCl2 (1.72, 1.31,

**Figure 5.** *Neutral zinc complexes derived from tetracyanoethylene.*

**Figure 6.** *Multinuclear zinc complexes 13–15.*

**Figure 7.** *The crystal structure of complex 1.*

**Figure 8.** *The crystal structure of complex 2.*

and 1.54 eq.), the corresponding condensation products with valinol, leucinol, or phenylalaninol furnished the binuclear zwitterionic complex **13** and highly symmetrical tetramers **14** and **15** at yields of 86, 80, and 82%, accordingly (**Figure 6**). Presumably, the formation of higher aggregates is prevented by the sterically demanding isopropyl substituents. A six-membered N,O-chelate ligand is complexed at each zinc metal center and connected to another metal center with a bridging donor ligand from the pendant pyridine. With each zinc atom located at a corner of a square grid, the planar N,O,N-ligands are oriented perpendicularly to one another with diagonal Zn···Zn distances of ca. 6 Å.

**31**

**Figure 12.**

*One-Pot Synthesis of Chiral Organometallic Complexes DOI: http://dx.doi.org/10.5772/intechopen.89865*

(**Table 1**).

**Figure 10.**

**Figure 11.**

*The crystal structure of complex 4.*

*The crystal structure of complex 5.*

*The crystal structure of complex 6.*

The crystal structures of all the complexes (**Figures 7**–**21**) are determined and reported by X-ray diffraction, elemental analysis, and IR. In all the cases, a distorted tetrahedral geometry is found at zinc(II), and the C〓N double-bond character of the oxazolinyl ligand is largely retained in the metal complexes

*One-Pot Synthesis of Chiral Organometallic Complexes DOI: http://dx.doi.org/10.5772/intechopen.89865*

The crystal structures of all the complexes (**Figures 7**–**21**) are determined and reported by X-ray diffraction, elemental analysis, and IR. In all the cases, a distorted tetrahedral geometry is found at zinc(II), and the C〓N double-bond character of the oxazolinyl ligand is largely retained in the metal complexes (**Table 1**).

#### **Figure 10.**

*Synthesis Methods and Crystallization*

**30**

**Figure 8.**

**Figure 7.**

**Figure 9.**

*The crystal structure of complex 2.*

*The crystal structure of complex 1.*

*The crystal structure of complex 3.*

and 1.54 eq.), the corresponding condensation products with valinol, leucinol, or phenylalaninol furnished the binuclear zwitterionic complex **13** and highly symmetrical tetramers **14** and **15** at yields of 86, 80, and 82%, accordingly (**Figure 6**). Presumably, the formation of higher aggregates is prevented by the sterically demanding isopropyl substituents. A six-membered N,O-chelate ligand is complexed at each zinc metal center and connected to another metal center with a bridging donor ligand from the pendant pyridine. With each zinc atom located at a corner of a square grid, the planar N,O,N-ligands are oriented perpendicularly to

one another with diagonal Zn···Zn distances of ca. 6 Å.

*The crystal structure of complex 4.*

**Figure 11.** *The crystal structure of complex 5.*

**Figure 12.** *The crystal structure of complex 6.*

**Figure 13.** *The crystal structure of complex 7.*

**Figure 14.** *The crystal structure of complex 8.*

**33**

**Figure 17.**

*The crystal structure of complex 11.*

**Figure 16.**

*The crystal structure of complex 10.*

*One-Pot Synthesis of Chiral Organometallic Complexes DOI: http://dx.doi.org/10.5772/intechopen.89865*

**Figure 15.** *The crystal structure of complex 9.*

*One-Pot Synthesis of Chiral Organometallic Complexes DOI: http://dx.doi.org/10.5772/intechopen.89865*

*Synthesis Methods and Crystallization*

**Figure 13.**

**Figure 14.**

*The crystal structure of complex 7.*

*The crystal structure of complex 8.*

**32**

**Figure 15.**

*The crystal structure of complex 9.*

**Figure 16.** *The crystal structure of complex 10.*

**Figure 17.** *The crystal structure of complex 11.*

**Figure 19.** *The crystal structure of complex 13.*

**35**

*a*

**Table 1.**

*Isolated yield from silica gel.*

**Figure 21.**

*The crystal structure of complex 15.*

*One-Pot Synthesis of Chiral Organometallic Complexes DOI: http://dx.doi.org/10.5772/intechopen.89865*

**3. One-step templated synthesis of chiral organometallic** 

Chiral oxazolinyl organometallic complexes are very important catalysts in organic chemistry [14–22]. Several organometallic complexes containing

**ZnCl2 (%) Products Yield (%)a** 114.2 1 25 259.8 2 65 152.8 3 86 144.6 4 90 245.8–256.0 5 56 44.1 6 90 121.8 7 80 122.9 8 85 56.1 9 86 72.6 10 90 42.2 11 88 42.2 12 86 172.1 13 86 130.7 14 80 153.6 15 82`

2-(2′-hydroxyphenyl) oxazolines are reported in the literature [23–42]. The general approach to the synthesis of metal complexes begins with ligand synthesis, followed by ligand reaction with metal salts to afford organometallic complexes [43].

**salicyloxazoline complexes**

*One-pot synthesis of zinc complexes (1–15).*

**Figure 20.** *The crystal structure of complex 14.*

*One-Pot Synthesis of Chiral Organometallic Complexes DOI: http://dx.doi.org/10.5772/intechopen.89865*

#### **Figure 21.**

*Synthesis Methods and Crystallization*

**34**

**Figure 20.**

**Figure 18.**

**Figure 19.**

*The crystal structure of complex 13.*

*The crystal structure of complex 14.*

*The crystal structure of complex 12.*

*The crystal structure of complex 15.*


#### **Table 1.**

*One-pot synthesis of zinc complexes (1–15).*
