**2.3 Conventional synthesis of 1, 5-Pyrazoles**

Pyrazoles are conventionally formed by (i) cycloadditions between 1,3 dipolar compounds and alkenes/alkynes and (ii) cyclocondensations of hydrazines and dicarbonyls (first reported in 1883 using dicarbonyls) as shown in **Figure 3** [2]. Additionally, multi-component or one-pot reactions utilizing a combination of consisting of at least three of the afore-mentioned compounds can also generate various substituted pyrazoles. Disadvantages of these methods include the use of unstable

**Figure 1.** *Tautomeric structures of an unsubstituted pyrazole.*

**Figure 2 .**

*Examples of drugs containing the pyrazole moiety.*

*Synthetic Strategies and Biological Activities of 1,5-Disubstituted Pyrazoles and 2,5-Disubstituted… DOI: http://dx.doi.org/10.5772/intechopen.108923*

**Figure 3.**

*Conventional reactions to form pyrazoles. A) Cycloadditions B) Cyclocondensations.*

reagents such as the diazo compounds in cycloadditions and product obtained as a mixture of regioisomers when substituted starting materials are used.

### **2.4 Recent synthetic routes towards 1, 5-Pyrazoles**

#### *2.4.1 Ruthenium-catalyzed Cyclocondensations of Propargyl alcohols and Hydrazines*

Metal catalysts have proved to be quite efficient in organic chemistry as means of carrying out various and sometimes difficult transformations. In the synthesis of pyrazoles, the bifunctional ruthenium cyclopentadienone complex (Ru Catalyst) catalyzes the reaction between secondary propargyl alcohols and nucleophiles such as hydrazine giving 1,5-disubstituted pyrazoles along with byproducts [3]. This cascade conversion likely proceeds via cycloisomerization, Michael addition, cyclocondensation and dehydrogenation/oxidation) steps [3]. The reaction proceeds via microwave irradiation in toluene and when the nucleophile is phenyl hydrazine (**2**), both the 1,5- and 1,3-disubstituted regioisomers (**a** and **b**) are formed along with the 3-phenylbutene byproduct **c** (**Figure 4**) [3]. The trends in the yields indicates that when the R group of the propargyl alcohol **1** is bulky or has unsaturated side chains, the reaction favors the 1,5-disubstituted pyrazoles leading to higher yield of this regioisomer.

From a mechanistic perspective as shown in **Figure 5**, Kaufmann *et al* [3] reported that the propargyl alcohol is activated by the Ru catalyst to form the by the chelated π-complex **I**, which is then converted to the alkynyl species **II**. A 1,2-hydrogen shift forms the alkenyl complex **III** which then undergoes a regioselective nucleophilic attack by phenyl hydrazine to give complex **IV**. Cyclocondensation of complex **IV** gives the alkyl complex **V** which subsequently undergoes a β-hydride elimination to give the 1,5-pyrazole. The active catalyst is regenerated by the elimination of hydrogen from the hydride complex **VI**. The 1,3- regioisomer is formed from the hydrazone of intermediate **III** while the byproduct is formed when the internal carbon of the alkynyl complex **II** undergoes a nucleophilic attack, when non-bulky propargyl alcohols are used.

#### *2.4.2 Ruthenium-catalyzed Cyclocondensation of Diazonium salts and Cyclopropanols*

Another Ruthenium-catalyzed reaction to synthesize pyrazoles was reported by Cardinale *et al* [4]. The photocatalysis of arenediazoniums (**10** and **12**) and

#### **Figure 4.**

*Regioisomeric pyrazoles produced by the ruthenium catalyzed cascade conversions between secondary propargyl alcohols and phenyl hydrazine [3].*

**Figure 5.** *Proposed mechanisms for the ruthenium catalyzed cascade conversions [3].*

arylcyclopropanols (**12** and **13**) using [Ru(bpy)3]2+ under blue light irradiation in acetonitrile yielded 1, 5 -disubstituted pyrazoles **14**–**21** (**Figure 6**). This photocatalysis provides several advantages such mild reaction conditions (20 mins at room temperature), compatibility with functional groups such as I, SF5, SO2NH2, N3, CN and high regioselectivity and yields.

The proposed mechanism of the photocatalysis is seen in **Figure 7** [4]. The reaction is proposed to be initiated when the [Ru2+]\* is the oxidatively quenched by the arenediazonium salt **10** (or **12**) to give [Ru3+] which oxidizes the cyclopropanol

*Synthetic Strategies and Biological Activities of 1,5-Disubstituted Pyrazoles and 2,5-Disubstituted… DOI: http://dx.doi.org/10.5772/intechopen.108923*

#### **Figure 6.**

*Ruthenium-catalyzed synthesis of pyrazoles under blue light. Synthetic scope of (a) diazonium salts and (B) cyclopropanols [4].*

**Figure 7.** *Proposed mechanism for the ruthenium photocatalysis of pyrazoles [4].*

**11** (or **13**) to give **VII•+**. The radical cation **VIII•+** is formed when **VII•+** undergoes a fast ring-opening and trapping with the arenediazonium salt **10** (or **12**). The newly formed **VIII•+** can either (i) quench the excited catalyst thereby closing the photocatalytic cycle or (ii) become involved in a radical chain process by oxidizing another molecule of **11** (or **13**). As a result of the dominance of the radical chain process, the

arenediazonium **10** (or **12**) is used in slight excess to activate the catalyst and produce the oxidant [Ru(bpy)33+] salt. The intermediate **IX** then undergoes cyclization followed by loss of water to produce the pyrazole.

## *2.4.3 Copper-catalyzed reaction of α, β-Cyanoesters and Hydrazines*

In another recent report, Cu(I) catalyst, Cu(PPh3)2NO3 was used to synthesize 1,5-disubstituted pyrazoles from hydrazines **22** and α,β-unsaturated cyanoester **23** under ultrasound irradiation (**Figure 8**) [5]. This efficient route uses short reaction times, moderate temperatures, facile work-ups, high regioselectivity and yields [5].

From a mechanistic perspective, the authors proposed that copper coordinates easily to π-bonds and heteroatoms. This would lead to the formation of the C-N bond via an oxidative addition followed by reductive elimination, similar to that observed in Pd(0) cross coupling reactions [5].
