210

CHAPTER 5

Study on Lewis acid catalyzed tetrazole synthesis:

Zirconium(IV) chloride catalyzed tetrazole synthesis

Part-1

Tetrazoles in organic synthesis

211

5.1.1. Introduction

Tetrazoles are a class of heterocycles with a wide range of applications

which are currently receiving considerable attention and the literature on tetrazole is

expanding rapidly.1

This functional group has a role in coordination chemistry as a

ligand,2,3,4

as well as in various materials sciences applications including

photography and specialty explosives.5

Extensive work has also been carried out in

the field of medicinal chemistry, where tetrazoles are frequently used as

metabolically stable surrogates for carboxylic acids.6,7

Less appreciated, but of

enormous potential, are the many useful transformations that make tetrazoles

versatile intermediates en route to substituted tetrazoles and especially to other

5-membered ring heterocycles via Huisgen rearrangement.8,9

The prime reason for

the scarcity of practical applications for these sophisticated tetrazole-based reactions

is the lack of appealing synthetic routes to the key intermediates 5-substituted

tetrazoles. Tetrazoles readily tolerate a wide range of chemical environments and

new uses for this unique family of heterocycles continue to emerge in both materials

science, and pharmaceutical applications.

5-Substituted tetrazoles that contain a free N-H bond are frequently referred

as tetrazolic acids, and exist as a nearly equal ratio of 1H- and 2H–tautomeric forms

(Fig 5.1, 1 and 2, respectively)10

although it is sometimes also convenient to

describe them as imidoyl azides 3. It should be stated that tetrazolic acid structures

that appear throughout this chapter are assumed to be mixtures of both 1H- and 2H-

tautomers. Previous studies have shown that the two positional isomers 1 and 2 may

be differentiated on the NMR time scale.11

Recently, Sadlej-Sosnowska has applied

calculated natural bond orbital analysis to a series of 5-substituted tetrazoles and

212

N

determined that 2H –tautomers (2) are the more stable isomers, although they were

found to have a larger degree of electron delocalization than 1H tautomers (1).12

This consideration, in combination with steric factors, may support the observation

that N-alkylation of tetrazolic acids often places the substituent on the N2 position.13

4

3 4

3

O 5

N N 5

N N

NH R R

OH 1 N H

1

R R N NH

2 1 2 N3

2 3

(1H) (2H)

Figure 5.1: Tetrazolic acids are bioisosteres of carboxylic acids

The free N-H bond of tetrazoles makes them acidic molecules, and not

surprisingly it has been shown that both the aliphatic and aromatic hetero cycles

have pKa values that are similar to corresponding carboxylic acids (4.5-4.9 vs 4.2-

4.4, respectively) due to the ability of the moiety to stabilize a negative charge by

electron delocalization.13-16

Tetrazole nitrogens have a considerable amount of local electron density,

which consequently leads to a wide range of stable metallic and molecular

complexes.17

Furthermore, the tetrazole ring possesses a strong electron-

withdrawing inductive effect (-I) which surpasses the weak mesomeric effect (+ M),

therefore, the ring is a deactivating group.1

5.1.1.1. Aromaticity

The tetrazole ring is a 6π-azapyrrole-type system.1, 14

Reactivity of 5-

substituted tetrazoles permits them to be classified as aromatic compounds.1, 18

In

tetrazoles, two of the six π-electrons required by the Huckel rule are provided by the

lone pair of one nitrogen while the remaining four π-electrons are provided by the

other four atoms of the ring.

213

5.1.1.2. Tetrazolate anions: acidity

5-Substituted tetrazoles display an acidity comparable with the corresponding

carboxylic acids.1, 14

One difference between the tetrazole ring and the carboxylic

acid group is the annular tautomerism of the tetrazoles. Substituents at C-5 have

effects similar to those for carboxylic acids, while in general, 5-aryltetrazoles are

stronger acids. The increased acidity is ascribed to the enhanced resonance

stabilization in the 5-phenyltetrazole anion relative to benzoate.1b

The tetrazolate

anions are easily generated with metal hydroxides and are stable in hot alcoholic and

aqueous solutions. 1, 19

N NH Cl

CsOH.H2O Cl

N N Cs

N N

MeOH, r.t N N

Scheme 5.1: Example of a metal tetrazolate salt

5.1.1.3. Solubility

5-Substituted tetrazoles are generally soluble in polar organic solvents such as

ethyl acetate and DMSO, but under basic conditions they can be easily soluble in

water. Very polar tetrazole derivatives such as pyridine tetrazoles and pyrrolidine

tetrazoles are soluble in water therefore the extraction from water can be

problematic.

5.1.2. Literature reports for tetrazole Synthesis

Tetrazoles are generally prepared by the reaction of a hydrazoic acid source

with a nitrile, in an inert solvent at high temperatures. Mostly, these transformations

were carried out in acidic media20

using tin or silicon azides in the presence of

Lewis acids as catalyst.21,22

214

N

N

The earliest published methods for the preparation of 5-substituted tetrazoles

were reactions of nitriles with azides.7,23

In fact, the first method to appear in the

literature was the reaction of hydrazoic acid (HN3) with organic cyanides in 1932.24

This process is generally thought to occur by a concerted 1,3-dipolar cycloaddition

mechanism, in which the nitrile acts as the dipolarophile towards the azide, which

serves as the 1,3-dipolar species in the cycloaddition. Protonation of the tetrazolium

anion upon workup provides the tetrazolic acid. In literature a two-step mechanism

has also been reported.25

A great disadvantage to this procedure is that

hydrazoic acid in organic solution is toxic and extremely explosive, and has a low

boiling point (37 °C).

R CN HN3, hea t, H2O R N

N (CH3)2NH HN N

Scheme 5.2: Reaction of hydrazoic acid with organic cyanide

5.1.2.1. Tetrazole synthesis using sodium azide

Katam et al. reported an alternative method to prepare tetrazole rings using

Zn/Al hydrotalcite as heterogeneous catalyst.26

The anionic [Zn-Al-Cl], with

[Zn]/[Al] ratio of 3 to 1, is synthesized by co-precipitation at pH 9. This

methodology requires relative high temperature and long reaction times in DMF,

with the use of Zn which requires additional treatment of the waste water.

NaN3 N

CN Zn/Al hydrotalcite N

H

R DMF

120-130 oC, 12h

R 69-91%

Scheme 5.3: Zn/Al hydrotalcite catalyzed synthesis of 5-substituted-tetrazoles

215

N

5.1.2.2. Using ammonium and trialkyl ammonium azides

The reaction of nitriles with the ammonium and trialkyl ammonium azides in

organic solvents such as dimethylformamide has been found fifteen years ago by

Lofquist and Finnegan27

to be a general method to give good yields of 5-substituted

tetrazoles. The reactive azide species is prepared in situ by reaction of sodium azide

and the appropriate ammonium or trialkyl ammonium chloride. In addition, this

protocol for the synthesis of tetrazole rings is accompanied by the sublimation of

explosive NH4N3.28,29

The sublimation of explosive NH4N3 also occurs when other

aprotic solvents instead of the DMF are used for the reaction.

CN

NH4N3

DMF

120-125 oC, 7h

N NH

N

N

75%

Scheme 5.4: Synthesis of 5-phenyltetrazole with ammonium azide

Koguro et al. reported a variant by using triethyl amine hydrochloride in

toluene.30

In this procedure, the authors proposed that the intermediate complex

[Et3N.HN3] is first ionized as Et3NH+

and N3-, then, each of these react with the

triple bond of the nitrile group to produce the tetrazole. When an aromatic solvent

such as toluene is used, both the cation and the anion are not solvated, and the

reaction thus proceeds smoothly.

R C N +

Et3NH N3

Tolue ne

8 0-115 oC

N3

R C NH.NEt3

N N HCl N N

N

R N R N

1-30h H.NEt3 H

Scheme 5.5: Synthesis of tetrazoles with triethylammonium azide

216

5.2.2.3. Trialkyltin azides

Methods for the tetrazole formation from organic-soluble reagents

trimethylstannyl31

or tri-n-butylstannyl azides32,33

are more commonly utilized in

larger scale than the sodium azide/ ammonium salt protocols.

Duncia and Carini,34

looking for a good alternative method to synthesize

sartans and using the biphenylnitrile I as a model system, discovered that both

trimethyl- and n-butyltin azides react forming the trialkyltin-tetrazole adducts.

However, removal and disposal of stoichiometric (highly toxic) residual organotin at

the end of the reaction is a major drawback of this methodology.32

The treatment of

the starting nitrile II with trimethyl- or tri-n-butyltin azide32

in toluene or xylene at

refluxing gives the corresponding tetrazole. The insoluble tin-tetrazole adducts III

precipitate and when the reaction is finished, the product is simply filtered and dried.

Subsequent acid hydrolysis yields the desired tetrazole.

SnMe3

N N N

N NH

Me Me

Me3SnN3, Tol, 24h, heat

85%

N N Me N N

H

89%

I

II III

Scheme 5.6: Synthesis of sartans precursor using trimethyltin azide

5.2.2.4. Trimethylsilyl azide

Trimethylsilyl azide has been reported to react with nitriles to give

5-substituted tetrazoles.35

It is an attractive azide source due to its stability

and relatively high boiling point (105 °C). However, benzonitrile reacts

with only very low conversion and orthosubstituted benzonitriles fail to undergo the

reaction.

217

TMSN3 under solvent free conditions

Pizzo et al. recently reported the use of TMSN3 in solvent free conditions.36

Catalytic amount of tetrabutylammonium fluoride (TBAF) is used for the anionic

activation of the silicon-nitrogen bond.37

The use of TBAF has the advantage to

activate the azide nucleophile and deprotects the N-silylated products. This catalytic

system is relatively efficient and a wide range of tetrazoles are obtained in 1 to 48

hours at 120 °C.

1.5 eq TMSN3

CN 0.5 eq TBAF .3H2O N NH

120oC 24h N N

Scheme 5.7: Synthesis of tetrazoles with TMSN3 in the presence of TBAF

TMSN3 in the presence of trimethyl aluminium

A method using trimethylsilyl azide was recently described by Lilly chemists Huff

and Staszak,38

who showed that an equimolar mixture of trimethylaluminium and

trimethylsilyl azide in hot toluene is an efficient combination to prepare 5-

substituted tetrazoles. However, highly hindered nitriles resulted in poor conversion

and the results are similar to those obtained using nBu3SnN3. Therefore, it is likely

that trimethylaluminium simply acts as a Lewis acid under these reaction conditions

and does not form (Me2AlN3)2.

H

CN N N

N T MSN3 (CH3)3Al N

N N

T oluene, 80 oC, 87%

Scheme 5.8: Synthesis of tetrazoles with TMSN3 in the presence of Me3Al

218

TMSN3 in the presence of dibutyltin oxide as catalyst

The use of trimethylsilyl azide in the presence of a catalytic amount of

dibutyltin oxide to convert nitriles into tetrazoles has been developed.39-41

CN

Br TMSN3, (CH3)2SnO

PhCH3, 93 oC, 80%

N N

N NH

Br

Scheme 5.9: Synthesis of tetrazoles with TMSN3 in the presence of dibutyltin oxide as catalyst

In the general procedure the nitrile is treated in toluene at high temperature

for 24 to 72 hours, with 2 equiv. of trimethylsilyl azide and 0.1 equiv. of dibutyltin

oxide to provide the desired tetrazole. However in some cases, full conversion is

obtained using 1 equiv. of tin reagent and 5 equiv. of TMSN3 at 100 °C.

5.2.2.5. Aluminum azide

Aluminum azides have already been reported by Wiberg and Michaud in a

1957 German patent.42

The Al(N3)3 can be prepared by treatment of AlCl3 with 3

equiv. of NaN3 in THF at reflux.43

However, using aluminum azide for the

preparation of tetrazoles, two moles of HN3 is formed for every mole of product

during the acidic quench of the reaction. The mechanism proposed proceeds through

intramolecular delivery of N3- from Al(N3)3 complexed with the nitrile.

R CN

H

Al(N3)3 N N

R

R N Al(N3)2

N

THF, 80oC

N

R

N N

Al(N3)2

(N3)2Al

N N

R N

N N N

N N N

Scheme 5.10: Proposed mechanism for the tetrazole formation with Al(N3)3

219

5.1.3. General mechanism of tetrazole synthesis

The common direct method to from tetrazoles is via the formal [2+3]

cycloaddition of azides and nitriles. However, evidence in the literature indicates

that the mechanism of the reaction is different for different azide species.

When an organic azide is used as the dipole, only certain highly activated

nitriles can be competent dipolarophiles. In these cases the reaction is regioselective,

and only the 1-alkylated product is observed.44

It is commonly accepted that in these

cases the reaction occurs via a traditional [2+3] mechanism.

N N N N

+ N EWG N N

[2+3]

N N

EWG N N

EWG N

X H H

Scheme 5.11: [2+3] cycloaddition

The great interest to us here is the mechanism behind the formally

similar addition of azide salts and nitriles to give 1H- tetrazoles. It has been

known that simple heating of certain azide salts with a nitrile in solution (typically

100-150 oC) produces the corresponding tetrazole in high yield (Scheme 5.12). This

variant is much more synthetically useful, as the scope of nitriles that are competent

reactants in this reaction is very broad, in contrast with the case of organic azide. In

addition, a wide variety of metal-azide complexes are competent azide donars.39,45

N N 1) Heat

+ N 2) H2O

R N X

N N

R N

N

H

N N

R N

N H

R= C, N, S; X= H, NHR3, M

Scheme 5.12

Several possible reaction pathways have been investigated.28,46

220

A. Neutral cycloaddition.

When the azide is bound to an organic substrate, it seems clear that the

reaction proceeds by a traditional concerted [2+3] mechanism. It is possible that

azide salt species simply play the role of a covalently bound azide, a situation very

similar electronically to that of organic azides. The ∆G≠

calculations shows47

that the

intermediates such as those shown in Fig 5.2, are not stable and a concerted [2+3]

cycloaddition is the most likely pathway for the bimolecular addition of nonionic

azides to nitriles.

R1

N N N

R N

Figure 5.2

N

N N

R R1

In the context of the concerted cycloaddition, two different isomers of

tetrazole, 1,5- and 2,5-disubstituted, can be formed.

N N

N N

N N

N N

R R R1

R1

N N

+ N

T S1

R1

1,5-tetrazole

R1

R N N N N

R1 N N

N N R R

T S2 2,5-tetrazole

Scheme 5.13: Neutral Cycloaddition

Experimentally, the 1-substituted tetrazole is exclusively formed, and this is

consistent with the ∆G≠

calculations which show that TS1, for all substituents, is

considerably lower than TS2.

221

B. Anionic cycloaddition

In reactions where NaN3 is added to nitrile in nonprotic organic solvents,

such as dimethylformamide (DMF) or glyme, it has been found that the yields are

generally lower, and higher temperatures are required. Here also, there are two

possible mechanisms, assuming the cation does not play a role, either a direct [2+3]

cycloaddition or a two-step sequence wherein the azide first nucleophilically attacks

the nitrile, followed by ring closer. In this section the barriers for the cycloaddition

of the azide anion to nitriles have been calculated.

As in the case of the neutral [2+3] cycloaddition, the barrier for anionic [2+3]

cycloaddition decreases with increasing electron-withdrawing potential of the

substituent on the nitrile. The geometry of the transition state of anionic reactions is

more asymmetric than for neutral reactions. The Cnitrile-Nazide distance is significantly

shorter than the Nnitrile-Nazide distance. The difference grows with the electron-

withdrawing potential of the substituent and for very strong electron-withdrawing

groups like RSO2, an intermediate such as that shown in Figure 5.3 could be found.

Despite the existence of this intermediate for the strongly activated nitriles, the ∆G≠

of

the transition state for the ring closing turns out to be identical to the ∆G≠

for concerted

[2+3] transition state. The two pathways have therefore essentially the same rate.47

N N

N R N

C. Proton Involvement

Figure 5.3

Koldobskii et al.48

showed the main result of the calculations (energy of

intermediate formation) is that when a proton is available, the reaction proceeds via

222

the protonated intermediate P, as shown in scheme 5.15. The transition state leading

to the formation of intermediate P involves the activation of the nitrile by a proton,

facilitating the attack of the azide on carbon of the nitrile. From intermediate P,

simple 1, 5-cyclization occurs to give the 1H –tetrazole. This mechanism is

consistent with the available experimental results and with similar known

mechanisms for related reactions involving nucleophilic attack on nitriles.

R'

N N R'

N H R2'NH H N

+ N

H

H N N

N N

N N

H

N N

N N R N

R N N N

R1

R

R N R N

TS1 Intermediate P TS2

Scheme 5.14

223

CHAPTER 5

Study on Lewis acid catalyzed tetrazole synthesis

Part-2

Zirconium(IV) chloride catalyzed synthesis of 5-

substituted 1H –tetrazoles

224

5.2.1. Introduction:

Tetrazoles have applications in both materials science and pharmaceuticals.

Tetrazoles can tolerate a wide range of chemical environments, from strongly acidic

to basic as well as oxidizing and reducing conditions. Tetrazole play important roles

in coordination chemistry, as useful ligands, and in medicinal chemistry, as stable

bioisosteres of carboxylic acids. Since the acidity of tetrazole group corresponds

closely with that of carboxylic acid, replacement of C-terminal amino acid residue

with a tetrazole analogue often improves the biological activity of parent peptides.

They are used in the construction of potential anti-inflammatory,49

central nervous

stimulants,50

hypertensives,51

glycosidase inhibitors,52

antibiotic, and antiviral

agents53

in addition to their use in the treatment of cancer,54

and heart diseases.55

They found applications in the automobile inflator industry, and also as catalyst in

asymmetric synthesis. Tetrazoles are widely used in various material sciences,

including photography, information recording systems, and also found as a precursor

of carbenes in flash vacuum pyrolysis.56

N N

O N N O

N N N

N S N N O

N N Cl HN N N

N H N S

Antihypertensive drug Cl HN

(Avapro) Antibacterial activity Antifungal activity

225

N

N

CF3

N N N

F3C N N N H

F3C N

N

O O

Heart dise ase

N Cl N

N

N O N

Anticancer activity

N O

O

Anti-inflamatry (Cilostazol)

Figure 5.4: Example of bio-active tetrazole derivatives

5.2.2. Review of literature

Consequently, a large number of methods have been developed for

the syntheses of tetrazoles through the [2+3] cycloaddition of nitriles with

azide in the presence of several Lewis acid catalysts. A recent publication described

the use of Lewis acid catalyst for the generation of tetrazoles from a series of

nitriles.57,58

Amantini et al (2004)36

: Tetrabutylammonium fluoride (TBAF) is an efficient

catalyst in the [3 + 2] cycloaddition reaction of organic nitriles with trimethylsilyl

azide (TMSN3) in solventless conditions. The corresponding 5-substituted 1H-

tetrazoles were obtained under mild conditions and in 80−97% yields.

1.5 equiv. TMSN3 H

0.5, equiv. TBAF. 3H2O N N R N R

50-120° C N N

Scheme 5.16

Hanessian et al (2010)57

: Aliphatic azidonitriles separated by three or four carbon

atoms undergo facile cyclo additions in the presence of BF3.OEt2 at room

temperature or lower, to give bicyclic tetrazoles. 1-Azido-[2-aryl-1,3-dioxolanyl]-

glycerols afford oxabicyclic tetrazoles with trimethylsilyl cyanide (TMSCN).

226

N

N

Aspects of these facile proximity-induced 1,3-dipolar cyclo additions are discussed

with mechanistic interpretations.

R

HO R O

O N3 TMSCN, BF 3.OEt2

R

R O MeNO2, 0°C to rt N

N

Scheme 5.17

Habibi et al (2011)58

: An efficient method for the preparation of arylaminotetrazole

derivatives is reported using aluminium chloride as an effective Lewis acid.

Generally, 5-arylamino-1H-tetrazole isomer can be obtained from arylcyanamides

carrying electron-withdrawing substituents on the aryl ring. As the electropositivity

of the substituent is increased, the product is shifted toward the formation of 1-aryl-

5-amino-1H-tetrazole isomer.

HN C

N + NaN3

AlCl3

N NH

R N

R N

or N

NH2

N

R DMF, 120°C N N N H

Scheme 5.18

Lakshmi Kantam et al. (2005)59

: Nanocrystalline ZnO is an effective

heterogeneous catalyst for the [2+3]-cycloaddition of sodium azide with nitriles to

afford 5-substituted 1H-tetrazoles in good yields.

CN + NaN3

H

Nano ZnO N N

DMF, 120-130 oC N N

R R

Scheme 5.19

Yield 69-82%

Demko et al. (2001)60

: The addition of sodium azide to nitriles to give 1H-tetrazoles

is shown to proceed readily in water with zinc salts as catalysts. The scope of the

227

reaction is quite broad; a variety of aromatic nitriles, activated and unactivated alkyl

nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown

to be viable substrates for this reaction.

R C N

1.1 eq. NaN3

1.0 eq. Z nBr2 N N R

Water ref lux N NH

R= Aryl, Alkyl, Vinyl, SR, NR2 52-96%

Scheme 5.20

Su et al. (2006)61

: A series of 1-substituted 1H-1,2,3,4-tetrazole compounds

have been synthesized in good yields from amines, triethyl orthoformate,

and sodium azide through the catalyzed reaction with Yb(OTf)3. In that, some of the

1-substituted 1H-1,2,3,4-tetrazole compounds showed strong phytocial activity.

R NH2 + HC(OC2H5)3 + NaN3

Yb(OTf)3 (20 mol %) N N R N

CH3OC2H4O H, 100 oC N

Scheme 5.21

Kundu et al. (2009)62

: A simple, efficient, and general method has been developed

for the synthesis of 1-substituted-1H-1,2,3,4- tetrazoles via a three-component

condensation of amine, trimethylorthoformate, and sodium azide in presence of a

catalytic amount of indium triflate under solvent-free conditions. The reaction

proceeds smoothly to generate the corresponding 1-substituted tetrazoles in

moderate to excellent yields under heating.

In(OTf)3 (5 mol%) N N R NH2 + CH(OMe)3 + NaN3 N N

100 oC R

Scheme 5.22

228

Eshghi et al. (2011)63

: Ferric hydrogensulfate catalyzed the synthesis of

5-substituted 1H-tetrazoles via [2 + 3] cycloaddition of nitriles and sodium

azide.This method has the advantages of high yields, simple methodology, and easy

workup. The catalyst can be recovered by simple filtration and reused delivering

good yields.

RCN Fe(HSO4)3 (10 mol%) N N

R N NaN3, DMF, 120

oC N

Scheme 5.23

Venkateshwarlu, et al. (2009)64

: Cadmium chloride (CdCl2) has been found to be

an efficient for a neat [2+3]-cycloaddition of NaN3with nitriles to afford 5-

substituted 1H-tetrazoles in good yields.

CN

R + NaN3

H

CdCl2 N

N

DMF, 80 oC R N N

Scheme 5.24

Habibi, et al. (2010)65

: An efficient method for preparation of 5-arylamino-1H-

tetrazole and 1-aryl-5-amino-1H-tetrazole derivatives is reported using FeCl3-SiO2

as an effective heterogeneous catalyst. Generally, when the substituent in

arylcyanamide is a strongly electron-withdrawing group, the position of the

equilibrium would shift toward 5-arylamino-1H-tetrazole, whereas with an electron-

releasing substituent, the position of the equilibrium would shift toward 1-aryl-5-

amino-1H-tetrazole.

H F eCl3-SiO2

N C N + NaN3

H R NH2

N N N

N R + N N

R DMF, 110 oC N N N

H

Scheme 5.25

229

Venkateshwarlu, et al. (2009)66

: Sb2O3 was found to be effective as a catalyst for a

smooth [2+3] cycloaddition of sodium azide with nitriles to afford 5-1H-tetrazoles

in good yields.

CN

R + NaN3

H Sb2O3 N N

DMF, 120-130 oC R N N

Scheme 5.26

Habibi, et al. (2012)67

: ZnO is an effective heterogeneous catalyst for the

reaction between arylcyanamides with sodium azide to synthesize the

arylaminotetrazoles in good yields. This method has advantages of good yields,

simple methodology, short reaction times, and easy workup. Furthermore, the

catalyst can subsequently be reused for several times without any significant loss of

activity.

H Z nO (cat)

R N C N + NaN3

H R NH2

N N N N

R + N N DMF, 120

oC N N N H

Scheme 5.27

Das et al. (2009)68

: An advantageous synthesis of 5-substituted 1H-tetrazoles has

been developed by treatment of organic nitriles with NaN3 in the presence of iodine

or the heterogeneous catalyst, silica supported sodium hydrogen sulfate

(NaHSO4.SiO2).

R CN + NaN3

NaHSO4.SiO 2 or I2

DMF or 2-butanone

120 oC or 75 oC

2-18 h

HN N

N

R N

79-92%

Scheme 5.28

Hajra et al. (2006)69

: A versatile and highly efficient protocol for the synthesis of

1,5-disubstituted tetrazoles has been developed by metal triflate catalyzed one-pot

230

2

1

reaction of alkenes, NBS, nitriles, and TMSN3. Among the metal triflates, Zn(OTf)2

was found to be the best catalyst. Use of different combinations of alkenes and

nitriles generate a variety of 1,5-disubstituted tetrazoles containing an additional α-

bromo functionality of the N1-alkyl substituent.

R1 R

M(OTf)n (5 mo l%), NBS (1.2 equiv)

TMSN3 (1.5 equiv)

R

3CN, 25

oC

N N N

R3 N R2

R1,R2 =alkyl, aryl, H

R3= alkyl, aryl

5.2.3. Objective

Scheme 5.29

R Br

A large number of methods have been reported in the literature for

the syntheses of tetrazoles through the [2+3] cycloaddition of nitriles with azide

in the presence of several catalysts. However, in spite of their potential utility, many

of these reported methods suffer from drawbacks like the use of toxic, corrosive

metals and harsh reaction conditions, unsatisfactory yields, and expensive,

limited availability of reagent, longer reaction time, etc. So we wanted to develop a

simple and efficient method for the synthesis of tetrazoles using a common Lewis acid

as catalyst.

5.2.4. Present work

In recent years zirconium(IV) chloride has been used as an ideal Lewis acid

in many important organic transformations, since it is an efficient, stable,

inexpensive, environmentally friendly and convenient catalyst for the preparation of

useful synthetic intermediates, carbon-carbon bond formation,70

protection71

and

deprotection,72

reduction reactions,73

and miscellaneous applications.74,75

Zirconium

belongs to the group IV transition metals and it is abundant in earth, which makes it

231

less costly and readily available and also zirconium(IV) chloride have low toxicity

[LD (ZrCl4, oral rate) = 1688 mg/kg] and is not considered particularly poisonous,76,77

thus, the zirconium(IV) compounds can be considered as safe potential catalysts in

organic synthesis.

H

R NaN3, ZrCl4 (2 0 mol%) N

N CN

DMF, 120 oC R N N

(1-20) (1a -20 a)

Scheme 5.30: Zirconium(IV) chloride catalyzed tetrazole synthesis

To our knowledge there is no method reported in the literature for the

synthesis of 5-substituted 1H-tetrazoles from nitriles using zirconium(IV)

chloride as a catalyst. Therefore, in this chapter we wish to report a comprehensive

study of the reactions between various nitriles and sodium azide in the

presence of catalytic amount of zirconium(IV) chloride to provide tetrazole

(Scheme 5.30).

5.2.5. Results and discussion

In the beginning, the reaction between benzonitrile (1) and sodium azide

was carried out using zirconium(IV) chloride (20 mol%) in DMF (10 vol) that led

to the formation of 5-substituted 1H-tetrazole (1a) in (92%) yield. With this

encouraging result, next to evaluate the solvent effect, we investigated the reaction

under similar conditions using various solvents and the results are summarized in

Table 5.1.

232

1 1a

Entrya

Solvent Time (h)b

Yield (%)c

1 Water 6.0 10-15

2 DMSO 6.0 60

3 Toluene 6.0 -

4 DMF 6.0 92

Table 5.1: Synthesis of tetrazoles in different solvents

CN + NaN3

H

ZrCl4 (20 m ol%) N N

N N

a Nitriles (1 eq.), azide (1.3 eq.), ZrCl4 (20 mol%), Solvents (10 vol), at 120

oC

b Reactions were monitored by LC-MS

c Isolated yield

In toluene as solvent, the reaction did not proceed and in DMSO only 60 % of

the product was formed along with several unwanted side products. After substantial

experimentation with different solvents, DMF was found to be superior to the other

solvents.

We next, investigated the amount of zirconium(IV) chloride required to

catalyze the transformation. As less as 10 mol% of ZrCl4 afforded the products in

50% yield, after 12 h. By using 15 mol% of ZrCl4, though product yields were

improved to 70%, the reaction time almost remained same as that of 10 mol %. On

the other hand, using 20 mol% of zirconium(IV) chloride as a catalyst the reaction

afforded 92% yield in 6 h.

233

F

Table 5.2. Synthesis of 5-substituted 1H-tetrazoles in presence of ZrCl4 from nitriles

H

NaN3, ZrCl4 N N

CN

R DMF, 120 oC N N

R

Entrya

Substrate Product Time (h)b

Yield (%)c

H

1 CN

N N

4.0 92

Cl

2 CN

N N

1a Cl

H N

N 6.0 65

N N

2a

H N

3 N 4.0 56 CN

N N 3a

4 Br

H

Br N N

5.0 72

CN 4a N N

H N

5 N 5.0 59†

CN 5a N N

F

C N

H

Cl N 6 N

4.0 91

C l Cl 6a N N

C l

CN H

N N †

7 NO2

N N

O2N 7a

5.0 87

CN

8 Cl

F Cl H N

N †

N N F 8a

5.0 42

234

H

N

CN MeO

N N

9 F

4.5 75

Me O N N

F 9a

CN

M e H N

N 10 O2N

4.0 68†

Me

NO2

N N

10a

CN

11 F3C

CF3 H N

N

6.0 65

N N

11a

CN

12

MeO

OH

MeO

HO

H N

N

N N

12a

6.0 56

†

C N

13 F3C

CF3 H N

N F

6.0 52†

N N

13a F

CN F H

14 F N N

†

OMe

MeO

N N

14a

5.0 60

CN

15 F

F H

N 6.0 51

†

CF3

CN

16

N N

F3C 15a

H N

N O 2N

5.0 70

NO 2

N N

16a

235

N

H

19

CN H

17 N N EtO †

O Et

N N

17a

4.0 90

CN

F F N

N

18 Me

6.0 41†

N N

Me 18a

F H

CN N N

F CF3

N

CF 3 19a

6.0 44†

CN H

N N

20 N N

20a

5.0 78†

a Nitriles (1 eq.), azide (1.3 eq.), ZrCl4 (20 mol%), DMF (10 vol), at 120

oC

b Reactions were monitored by LC-MS

c Isolated yield

† Novel compounds

To check the versatility of zirconium(IV) chloride catalyzed [2+3]

cycloaddition reaction, various substituted nitriles (1-20) have been made to react

with sodium azide using ZrCl4 (20 mol%) in DMF (10 vol) solution and the results

were summarized (Table 5.2).

In general, high yields of tetrazoles were obtained with 20 mol% of ZrCl4 at

120oC in DMF. Aromatic substrates bearing functional groups such as –CH3, -OMe,

-Cl, -Br, - NO2, and –CH(CH3)2 all reacted successfully to give the corresponding

tetrazoles (Table 5.2) in good to excellent yields irrespective of the substituent

position on the aromatic ring. This reaction works with disubstituted electron

withdrawing groups to the phenyl ring such as –F, -CF3, but the yield was relatively

lower (Table 5.2 Entry 18, 19). The protonation of tetrazole in presence of acid was

236

N

previously observed.26

Similarly, during the course of the reaction in presence of

ZrCl4 and while work up using HCl, protonation of some tetrazoles (13a, 15a, 19a)

were observed. According to literature the proton may adds to the nitrogen atom in

the fourth position.

5.2.6. Plausible mechanism

In reactions where NaN3 is added to nitriles in aprotic organic solvents, such

as dimethylformamide (DMF), there are two possible mechanisms shown here.

(i) Direct [2+3] cycloaddition:

LA N

N

N N H

HN N

R C N + N N N

Na R N R N

Na

Scheme 5.31: Step-1

(ii) Two step-mechanism sequence wherein the azide first nucleophilically attacks

the nitrile, followed by ring closure.

LA Na

R C N + N

N

N

N N

H HN N

R N N

R N

Scheme 5.32: Step-2

5.2.7. Conclusion

In summary, we have developed simple and highly efficient protocol for the

synthesis of 5-substituted 1H-tetrazole from nitriles by treating with sodium azide in

the presence of zirconium(IV) chloride as a catalyst. The merits of this method

includes (a) very simple and mild reaction conditions, easy work up, and highly

yielding process (b) readily available, low toxic and easy - handling catalyst (c) low

237

amount of catalyst used. This method has wide scope for further applications, as the

catalyst is cheap and easily available commercially.

5.2.8. Experimental Section

General experimental procedure for the synthesis of 5-substituted 1H–

tetrazoles

To a stirred solution of nitrile (1 mmol), and sodium azide (1.3 mmol) in dry

DMF was added zirconium(IV) chloride (20 mol%) and the mixture was heated to

120 ˚C for the appropriate time as mentioned in Table 5.2. After completion of the

reaction (reaction monitored by TLC), the catalyst was removed by filtration and

filtrate was treated with ethyl acetate and 4 N HCl and stirred vigorously. The

resultant organic layer was separated and the aqueous layer was extracted with ethyl

acetate. The combined organic layer was washed with water, brine and dried over

sodium sulfate, concentrated to furnish the desired tetrazoles. When ever necessary,

the obtained products were purified by crystallization using petroleum ether/ethyl

acetate (1:1).

5.2.9. Characterization of the products

The IR, LC-MS and 1H-,

13C-, NMR data of some unknown compounds are

given below.

5-(3-Fluorobenzyl)-1H-tetrazole (5a): White solid; mp132–133 ˚C.IR (neat): 2989,

1614 cm-1

.1H NMR (DMSO-d6, 400MHz): δ = 7.37–7.42 (m, 1H), 7.09–7.17 (m,

3H), 4.34 (s, 2H).13

C NMR (DMSO-d6, 100MHz): δ = 163.86, 161.43, 138.99,

131.13, 125.32, 116.21, 114.44, 29.01. MS: m/z Calcd for C8H7FN4: 178.17;

Found: 179.2 (M+). Anal. Calcd for C8H7FN4: C, 53.93; H, 3.96; F, 10.66; N, 31.45.

Found: C, 54.80; H, 3.99, N, 32.22

238

4.2.2. 5-(3,4-Dichlorobenzyl)-1H-tetrazole (6a): White solid; mp 153–154 ˚C. IR

(neat): 3395, 1560 cm-1

.1H NMR (DMSO-d6, 400MHz): δ = 7.60–7.62 (m, 2H),

7.26–7.29 (m, 1H), 4.33 (s, 2H).13

C NMR (DMSO-d6, 100MHz): δ = 155.33, 137.37,

131.51 131.44, 131.25, 130.28, 129.77, 28.40. MS: m/z Calcd for C8H6Cl2N4:

229.07; Found: 230.0 (M+). Anal. Calcd for C8H6Cl2N4: C, 41.95; H, 2.64; Cl,

30.95; N, 24.46; Found: C, 42.80; H, 3.06, N, 25.61.

4.2.3. 5-(2-Methyl-5-nitrophenyl)-1H-tetrazole (7a): Pale yellow solid; mp

202203 ˚C. IR (neat): 2486, 1519 cm-1

.1H NMR (DMSO-d6, 400MHz): δ = 8.64 (s,

1H), 8.31–8.34 (m, 1H), 7.6 (d, J= 8.4 Hz, 1H), 2.67 (s, 3H).13

C NMR (DMSO-d6,

100MHz): δ = 155.86, 146.36, 145.86, 133.45, 126.03, 125.40, 124.54, 21.56. MS:

m/z Calcd for C8H7N5O2: 205.17; Found: 206.2 (M+). Anal. Calcd for C8H7N5O2: C,

46.83; H, 3.44; N, 34.13; O, 15.60. Found: C, 47.20; H, 3.91, N, 35.20.

4.2.4. 5-(2-Chloro-3-fluorophenyl)-1H-tetrazole (8a): Off-white solid; mp 183–

184 ˚C. IR (neat): 2738, 1572 cm-1

.1H NMR (DMSO-d6, 400MHz): δ = 7.66–7.71

(m, 2H), 7.59–7.64 (m, 1H). 13

C NMR (DMSO-d6, 100MHz): δ = 159.61, 157.62,

153.90, 129.68, 127.72, 126.91, 119.65. MS: m/z Calcd for C7H4ClFN4: 198.58;

Found: 199.2 (M+). Anal. Calcd for C7H4ClFN4: C, 42.34; H, 2.03; Cl, 17.83; F,

9.57; N, 28.21. Found: C, 43.50; H, 3.01, N, 29.60.

4.2.5. 5-(3-Methyl-4-nitrophenyl)-1H-tetrazole (10a): Pale yellow solid; mp 229–

230 ˚C. IR (neat): 2744, 1610,1505 cm-1

.1H NMR (DMSO-d6, 400MHz): δ = 8.08–

8.11 (m, 1H), 8.18–8.22 (m, 1H), 2.62 (s, 1H). 13

C NMR (DMSO-d6, 100MHz): δ =

155.67, 150.29, 134.41, 131.34, 129.37, 125.99, 19.99. MS: m/z Calcd for

C8H7N5O2: 205.17; Found: 204.0 (M-). Anal. Calcd for C8H7N5O2: C, 46.83; H,

3.44; N, 34.13; O, 15.60. Found: C, 47.50; H, 3.81, N, 35.73.

239

4.2.6. 2-Methoxy-4-(1H-tetrazol-5-yl)phenol (12a): Off-white solid; mp 211–212

˚C. IR (neat): 3206, 1606,1508 cm-1

.1H NMR (DMSO-d6, 400MHz): δ = 7.58 (d, J =

4.0, 1H), 7.50 (d, J = 8, 1H), 6.97 (d, J = 8.0, 1H), 3.86 (s, 3H). 13

C NMR (DMSO-d6,

100MHz): δ = 155.66, 149.93, 148.56, 120.85, 116.53, 115.32, 111.21, 56.22. MS: m/z

Calcd for C8H8N4O2: 192.17; Found: 193.2 (M+). Anal. Calcd for C8H8N4O2: C, 50.00;

H, 4.20; N, 29.15; O, 16.65. Found: C, 51.12; H, 4.99, N, 30.93.

4.2.7. 5-(4-Fluoro-2-(trifluoromethyl)phenyl)-1H-tetrazole (13a): Light brown

color solid; mp 147–149 ˚C. IR (neat): 3357, 2215,1611 cm-1

.1H NMR (DMSO-d6,

400MHz): δ = 7.65 (d, J = 8.0, 1H), 7.01 (d, J = 2, 1H), 6.83 (d, J = 8.0, 1H), 6.69

(s, 2H). 13

C NMR (DMSO-d6, 100MHz): δ = 153.58, 136.76, 132.2–133.22,

1244.65, 121.94, 117.76, 116.04, 111.29, 92.11. MS: m/z Calcd for C8H4F4N4:

232.14; Found: 231.0 (M-). Anal.Calcd for C8H4F4N4: C, 41.39; H, 1.74; F, 32.74;

N, 24.14. Found: C, 42.11; H, 1.97, N, 25.11.

4.2.8. 5-(2-Fluoro-5-methoxyphenyl)-1H-tetrazole (14a): Off-white solid; mp

141–142 ˚C.IR (neat): 2839, 1500 cm-1

.1H NMR (DMSO-d6, 400MHz): δ = 7.53 (m,

1H), 7.45 (t, 1H), 7.22 (m, 1H), 3.83 (s, 3H). 13

C NMR (DMSO-d6, 100MHz): δ =

156.17, 154.99, 152.56, 119.30, 118.11, 114.05, 113.32, 56.31. MS: m/z Calcd for

C8H7FN4O: 194.17; Found: 195.2 (M+). Anal.Calcd for C8H7FN4O: C, 49.49; H,

3.63; F, 9.78; N, 28.86; O, 8.24. Found: C, 50.33; H, 4.65, N, 29.92.

240

5.2.9.1. Spectras

H N

N

F N N

1H NMR (400 MHz, DMSO-d6) of compound 5a

H N

N

F N N

13

C NMR (100 MHz, DMSO-d6) of compound 5a

241

H

Cl N N

Cl N N

1H NMR (400 MHz, DMSO-d6) of compound 6a

H Cl N

N

Cl N N

13C NMR (100 MHz, DMSO-d6) of compound 6a

242

H N N

N N

O2N

1H NMR (400 MHz, DMSO-d6) of compound 7a

H N N

N N

O2N

13C NMR (100 MHz, DMSO-d6) of compound 7a

243

F Cl H N

N

N N

1H NMR (400 MHz, DMSO-d6) of compound 8a

F Cl H

N N

N N

13C NMR (100 MHz, DMSO-d6) of compound 8a

244

Me H N

N O2N

N N

1H NMR (400 MHz, DMSO-d6) of compound 10a

Me H N

N O2N

N N

1H NMR (100 MHz, DMSO-d6) of compound 10a

245

MeO H N N

HO N N

1H NMR (400 MHz, DMSO-d6) of compound 12a

MeO H N N

HO N N

13C NMR (100 MHz, DMSO-d6) of compound 12a

246

CF3 H

N N F

N N

1H NMR (400 MHz, DMSO-d6) of compound 13a

CF3 H N N

F

N N

13

C NMR (100 MHz, DMSO-d6) of compound 13a

247

F H N N

N N

MeO

1H NMR (400 MHz, DMSO-d6) of compound 14a

F H N N

N N

MeO

13C NMR (100 MHz, DMSO-d6) of compound 14a

248

F H

N N

N N

MeO

249

H N N

N N

O2N

250

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LIST OF PUBLICATION

1. Iodine-catalyzed one-pot synthesis of amides from nitriles via Ritter reaction.

Theerthagiri, P.; Lalitha, A.; Arunachalam, P.N. Tetrahedron Lett. 2010, 51,

2813-2819.

2. Benzylation of β-dicarbonyl compounds and 4-hydroxycoumarin using

TMSOTf catalyst: A simple, mild, and efficient method. Theerthagiri, P.;

Lalitha, A. Tetrahedron Lett. 2010, 51, 5454-5458.

3. Zn(OTf)2-catalyzed direct cyanation of benzylic alcohols-a novel synthesis of

α-aryl nitriles. Theerthagiri, P.; Lalitha, A. Tetrahedron Lett. 2012, 53, 5535-

5538.

4. Iodine-catalyzed N-alkylation of tosylhydrazones with benzylic alcohols.

Theerthagiri, P.; Lalitha, A. J. Iran. Chem. Soc. 2013, 10, 717-724.

5. Zirconium (IV) chloride catalyzed - Novel synthesis of 5-Substituted-1H-

tetrazole from nitriles and sodium azide. Theerthagiri, P.; Lalitha, A.

(Communicated)