Utilization of Nitrilimines and Nitrile oxides in the synthesis of Triazoles and Oxadiazoles

Review

Molecules, 2005, 10(3)

 Adel Mohamed Awadallah

(A. R. S. Ferwanah)

Chemistry Department, Faculty of Science,

Islamic University of Gaza, P. O. Box-108

Gaza, Palestine

E-mail: awada@mail.iugaza.edu

N

NN

N

ON

Nitrilimines and nitrile oxides

Nitrilimines 2, also called nitrile imides, are transient intermediates in solutions. The most common method for their generation is

dehydrohalogenation of hydrazonoyl halides 1 in presence of triethylamine

Cl

NH

N

Ar

REt3N R- C N - N -Ar

+_

21

Nitrile oxides 4 are generated and usually trapped in situ; The most common method for their generation is also dehydrohalogenation of α-chloro-oximes 3 on reaction with a base (usually triethylamine).

Cl

OHN

ArEt3N Ar- C N - O

+ _

43

* 1,3-Dipolar Cycloaddition, Padwa, A. ed.; Wiley-Interscience, New York, 1984.

* Shawali, A. S.; Heterocycles, 1983, 20, 2239; Shawali, A. S.; Chem Rev.; 1993, 93, 2731.

Reactions of Nitrilimines and Nitrile Oxides

i) Replacement reaction with nucleophiles (Nu) leading to acyclic adducts:

• .

Cl

NH

N

Ar

R

Nu

NH

N

Ar

REt3N+ Nu

2

ii) cycloaddition reaction with multiple bonds leading to five-membered heterocycles. The reaction proceeds with: almost complete stereochemical control and a remarkable regiochemical control in many cases

Cl

NH

N

Ar

RX

Y

XY

NN

R

Ar

Et3N+

1

iii) Cyclocondensation reactions with nucleophiles incorporating suitably located electrophilic centers1-Ethoxycarbonyl-1-methylhydrazine readily reacts with the nitrile oxide yielding the acyclic adducts. The latter cyclizes almost quantitatively to the corresponding novel 4,5-dihydro-,1,2,4,5-oxatriazin-6-one 5 by stirring with excess sodium hydride in dry tetrahydrofuran for 30 min. at room temperature.

• Ferwanah, A. R. S.; Awadallah, A. M.; Asian J. Chem.; 1998, 10, 180.

Cl

OHN

Ph

NH

OHN

Y

NCH3

COOEt

NNH2

CH3

COOEt NH

N

ON

CH3

OPh

Et3N

+

5

NaH

THF

On the other handCompletely different modes of reaction were observed

with nitrilimines by M. El-Haddad and H. Dalloul

Reaction of Nitrilimines and Nitrile Oxides with Hydrazines

 Reaction with simple, phenyl-, acetyl- and benzoyl-hydrazines

Nitrilimines undergo 1,3-electrophilic addition with simple, phenyl-, acetyl- and benzoyl-hydrazines leading to the acyclic adducts 6.

Cl

NH

N

Ar

R

NH

NH

N

Ar

R

NR'

HR'

HNNH2

R' = H, Ph, C(O)CH3, C(O)Ph

Et3N+

6

On the other hand

Reaction with methylhydrazineThe reaction with methylhydrazine occurs at the N-Me group rather than the NH2 group leading to the acyclic adducts 7.

Cl

NH

N

Ar

R

N

NH

N

Ar

R

NH2

CH3

CH3

HNNH2

Et3N

+

17

On the other handReaction of nitrilimines with 1-ethoxycarbonyl-2-phenylhydrazine This reaction gave the acyclic adducts 8.

• El-Haddad, M.; Ferwanah, A. R. S.; Awadallah, A. M.; J. Prakt. Chem. 1998, 340, 623.

Cl

NH

N

Ar

Y

N

NH

N

Ar

Y

NH

COOEt

Ph

NH

NH

Ph COOEt

Et3N+

8

Reaction with ethylhydrazinoacetateReaction of C-methoxycarbonyl nitrilimines with ethylhydrazino acetate under smooth conditions gave 4-amino-1-aryl-3-methoxycarbonyl-6-oxo-1,4,5,6-tetrahydro-1,2,4-triazine 9.

Cl

NH

N

Ar

O

MeONH

NH2

COOEt NN

N

Ar

O

NH2

O

MeO

Et3N+

9

* El-Abadelah, M. M.; Nazer, M.; El-Abadlah, N. S.; Meier, H.; J. Prackt. Chem. 1997, 339, 90.

On the other handThe reaction of nitrile oxides with ethyl hydrazine acetate gave the acyclic adducts 11 which resulted from electrophilic addition at the

terminal NH2 followed by oxidation.

• * Awadallah, A. M.; unpublished data.

Cl

OHN

Ar NH

NH2

COOEt

N

NH

N

Ar

OH

COOEt

ON

N

Ar O

NH2

Et3N

+

11

10

Reaction of nitrile oxides with hydrazonesAryl nitrile oxides undergo 1,3-dipolar cycloaddition with alkanone hydrazones 33 to give the cycloaddition product 4-amino-3-aryl-5,5-dialkyl-4,5-dihydro-1,2,4-oxadiazole 11. The reaction with alkanal

hydrazones gave, however, a complex mixture of intractable products, from which the oxadiazole 12 was the major product

• El-Abadelah, M. M.; Hussein, A. Q.; Awadallah, A. M.; Heterocycles 1989, 29, 1957.

Cl

OHN

Ar

R'

R"NNH2

N

ON

Ar R"

R'

NH2

N

ON

Ar EtEt3N

+R' = Et

R" = H- NH3

11 12

On the other handReaction of hydrazones of aryl aldehydes and ketones with nitrile

oxides gave the corresponding acyclic adducts 13 obtained by way of electrophilic addition. 1,3-Dipolar cycloaddition across azomethine л-

bond of the hydrazones was not observed here.

• El-Abadelah, M. M., Nazer, M. Z.; Hussein, A. Q.; Awadallah, A. M.; Rademacher, P.; Woydt; M.; J. Heterocycl. Chem. 1991, 28, 1229.

Cl

OHN

ArR'

Ar'NNH2

NH

N

OHN

Ar

Ar'

R'Et3N+

13

Ring Transformation of 1,2,4-oxadiazolines into 1,3,4-oxadiazoles 

Acylation of the 4-amino-4,5-oxadiazoles in refluxing toluene or treatment of the acyl derivatives of these compounds 14 with

trifluoroacetic anhydride brings up ring transformation to the aromatic 1,3,4-oxadiazoles 15.

N

ON

Ar R"

R'

NH2

N

ON

Ar R"

R'

NH

X

O

O

NN

Ar XXCOCl (CF3CO)2O

r.t.

1415

X = H, CH3, Ph, CH2Cl,

Similarly, 4-amino-4,5-dihydro-1,2,4-oxadiazole are transformed into the corresponding 2-arylamino-1,3,4-oxadiazoles (16, X = O) or

thiadiazoles (17, X = S) via reaction with phenylisocyanate or phenylisothiocyanate, followed by brief treatment of the resulting adducts 15 with trifluoroacetic anhydride at ambient temperature.

• Hussein, A. Q.; El-Abadelah, M. M.; Nazer, M. Z.; Awadallah, A. M.; Rademacher, P.; Bandman, H.; Heterocycles, 1994, 38, 981.

N

ON

Ar R"

R'

NH2

N

ON

Ar R"

R'

NH

NHPh

X

X

NN

Ar NHPh

(CF3CO)2O

r.t.

PhNCX

X = O, S 15

16,17

Reaction of Nitrile oxides with methyl hydrazonesThe reaction of nitrile oxides with methylhydrazones in chloroform was found to constitute a convenient synthetic route to the novel 4,5-

dihydro-6H-1,2,4,5-oxatriazines 18.

Cl

OHN

R

R"

R'NN

H

CH3 N NH

ON

RR'

R"

CH3

Et3N+

CHCl3

18

On the other handRisitano and coworkers obtained the triazoles 19 directly from the appropriate monomethylhydrazones of aryl aldehydes in refluxing

ether for 2 hours.

Cl

OHN

Ar

H

R'NN

H

CH3

N N

OH

N

ArR'

H

CH3

N N

NAr R'

CH3

+ether

reflux

19

Ring Transformation of Oxatriazines into Triazoles1,2,3,4- tetrahydro-1,2,4,5-oxatrazines 18 derived from methylhydrazones of aryl aldehydes underwent ring contaction, via elimination of H2O, to yield the respective 1H-1,2,4-triazoles 19.

• El-Abadelah, M.M.; Hussein, A. Q.; Nazer, M. Z.; Musa, O. M.; Rademacher, P.; Bandmann, H; Heterocycles, 1993, 36, 455.

N NH

ON

RR'

H

CH3

N N

OH

N

RR'

H

CH3

N N

NR R'

CH3

or ACOH

18 19

The reaction of nitrile oxides with 1,1-dimethylhydrazones yields the cycloaddition N,N-dimethylamino-oxadiazolines 20.

Cl

OHN

ArR'

R"NN

CH3

CH3N

ON

Ar R"

R'

NCH3 CH3

Et3N+

20

Reaction of nitrilimines with hydrazones carrying electron withdrawing groups

H N N

COOR NN

NAc

NH

Ar

N NH

NN

Ac

Ar

COOR

Cl

NH

N

Ar

Ac +Et3NR1

R2

R1

R2

COOR3

Me, Me Et, EtR1, R2

R3 Me Me Et Et Et Et Et Et

X Cl Cl Cl Br Cl Cl Cl Cl

a b c d e f g h

R1

R2

21

22

*El-Sawi, E. A.; Awadallah, A. M.; Ferwanah, A. R. S.; Dalloul, H. M.; Asian J. Chem. 2002, 14, 1225.

* Awad, B. M.; Ferwanah, A. R. S.; Awadallah, A. M.; El-Halabi, N. M.; Asian J. Chem. 2002, 14, 1235

Ferwanah also reported the synthesis of another series of these triazoles 23 from the reaction C-Acetyl-N-arylnitrilimines with acetaldehyde, alkanone and cycloalkanone benzoylhydrazones.

Intersting spiro compounds containing heteroatoms were prepared from this reaction.

• Ferwanah, A. R. S. Synth. Commun. 2003, 33, 243.

H N N

COPh

NN

NAc

NH

Ar

COPh

N Me

N CO2EtO

O

Cl

NH

N

Ar

Ac +Et3N/0 oCR1

R2

R1

R2

23

H Me Me

Me Me Me

R1

R2

• Synthesis of Triazole derivatives

NN

N

NH

Ar

COPh

CH3

NNH2

NN

N

NH

Ar

COPh

CH3

NN

OH

NN

N

NH

Ar

COPh

CH3

O

23

C-methoxycarbonyl Hydrazonoyl halides were also found to react with substituted hydrazones of alkanone, cycloalkanone and heterocyclic ketones to give the cycloaddition products 3-methoxycarbonyl-4,5-dihydro-1,2,4-triazoles 24 [26].

• Adel M. Awadallah, Abdel-Rahman S. Ferwanah, Mehtab R. El-Haddad, W. Schrader, Synthesis of Substituted 1,2,4-Triazoles from Reaction of Nitrilimines with Substituted Hydrazones, Asian J. Chem, 2004, 16, 1691.

H N N

X

NN

N

NH

Ar

O

MeO

O

NH

N

Cl

ArO

MeO

X

N COOEt

O

O

+Et3N/0oCR1

R2

R1

R2

MeMe

R1

R2

a b c d e f g h i

X = COPh, COOEt, COCH324

Reaction with OximesAcetone oxime readily react with nitrilimines yielding the unexpected 3-acetyl-4,5-dihydro-5,5-dimethyl-1H-triazoles 25 in moderate yields. An evidence was obtained from 15N-NMR spectra, which displays a doublet for the NH at 284.26 ppm relative to nitromethane (1JN-H =

85Hz; 3JN-CH3 = 2.5Hz).

OH N

CH3

R

NN

NH

Ac

CH3

Ar

R

NN

N R

CH3

Ar

OH

Ac

Cl

NH

N

Ar

Ac +Et3N/0oC

R = CH3, Ph

25

26

15NMR of the compound

Nitrilimines reacted similarly with acetophenone oxime to afford the corresponding triazaoles 25. Similarly, the reaction with 1-methyl-4-piperidone oxime yields the respective spiro triazoles 27 .

• Ferwanah, A. R. S.; Asian J. Chem. 1999, 11, 480.

• Ferwanah, A. R. S.; Awadallah, A. M.; Khafaja, N. A.; Asian J. Chem. 2001, 13, 1203.

OH N N CH3

Cl

NH

N

Ar

Ac N CH3

NN

NH

Ac

Ar

+Et3N/0oC

27

The reaction with cycloalkanone oximes gave the heterocyclic spiro triazoles 28 in moderate yields.

• Ferwanah, A. R. S.; Kandile, N. G.; Awadallah, A. M.; Miqdad, O. A. Synth. Commun. 2002, 32, 2017.

OH N

R

R

Cl

NH

N

Ar

YR

R

NN

NH

Y

Ar

+Et3N/0oC

Y = Ac, 2-naphthoyl

RR

28

On the other handThe reaction of nitrile oxides with oximes was reported to give the 4-

hydoxy-4,5-dihydro-1,2,4-oxadiazolines 29 [30].

• Morrocchi, S.; Ricca, A.; Chim Ind. (Milan), 1967, 49, 629.

OH N

R

R

ON

NH

Ar

R

R

ON

N R

R

OH

Ar

Cl

OHN

Ar +Et3N/0oC

30

29

Ring Transformation of Triazolines into TriazolesReaction of triazoles with acetyl chloride or acetic anhydride gave

the ring transformation product 1-Aryl-3-acetyl-5-methyl-1H-1,2,4-triazole 32 instead of the expected N-acetyl derivative 31.

NN

NH

Ac R

R

ArNN

NAc R

R

Ar

CH3O

NN

NAc

Ar

OCH3

R

R

NN

NAc

Ar

CH3

NN

NAc

Ar

CH3 R

RO

(CH3CO)2O ..

..

..

....

+

..

+ +

31

32

•A. M. Awadallah, "Ring Transformation of Heterocycles, Transformation of 4,5-Dihydro-5,5-Dimethyl-1H-1,2,4-Triazoles into 5-Methyl-1H-1,2,4-Triazoles" Abhath Al-Yarmouk Journal (Series of naural studies) 2001, 10 (2A), 281-289. (Jordan).* Ferwanah, A. R. S.; Kandile, N. G.; Awadallah, A. M.; Miqdad, O. A. Synth. Commun. 2002, 32, 2017.

•Ring Transformation of 1,2,4-triazoles into 1,2,3,5-oxatriazine

N

NH

N

CH3

Ar

OH

NNN

NH

O

CH3

Ar

NNAr

N

OH

CH3

NH

NO

NNNH2

Ar

CH3

N

NN

NH2

Ar

CH3

O

NH2OH - CH3-CH=CH2

M. Wt = (42)

M.Wt = 266

+-

M.Wt = 224

2a

3

1a7

Ar = 4-ClC6H4

8Scheme 2

•

• Complexes of 1,2,4-Triazole oximes

NN

NH

O

CH3

RR

ArN

NNH

N

CH3

RR

Ar

OHN O

N

N

CH3

NH2

Ar

N

NH

R

R

OCH3

N

NH

Ar

M

N

N N

N

N

RR

OCH3

N

N

RR

OCH3

N

Cl

Cl

NH2OH.HCl

NaOAc

reflux

M(OAc)2

ring transformation

1a-e

2a-e 3

4a-e

5a-e, 6a,e

Ar = 4-ClC6H4

5: M = Ni6: M = Pd

Entry

R R

CH3

CH3

a b c d e

Scheme 1

• Complexes of 1,2,4-triazole hydrazones

NN

NH

O

CH3

RR

ArN

NNH

N

CH3

RR

Ar

X

N

NH

R

R

OCH3

N

NH

Ar

Ni

N

N N

N

N

RR

OCH3

N

N

RR

OCH3

N

Cl

Cl

NH

NH

N

N

NH

Ar

R

R

CH3

Ni

N

N

N

N

NH

N

N

Ar

R

R

CH3

NH

N

N

Ar

R

R

CH3

NN

NH

O

CH3

RR

ArNH2X

Ni(OAc)2.4H2Oring transformation

(1a-d)

(2-4)

(5a)

(6a)

(7b,c)

(8b,c)

(2a) X = OH

X= OH, NH2

(3b,c) X = NH2

Entry

R, R

Ar = 4-ClC6H4

a b c d

(1d)

4d X = NHCH3

Ni(OAc)2 .4H2O

CH3

Current Work

Reaction of Nitrilimines with Cyanomethylbenzimidazoles

Cl

NH

N

Ar

Ac

N

NH

NNH

N

NN

NAc

Ar

Et3N/0oC

+

33

.Reaction of Nitrilimines with Acetone Aryledenehydrazone

Cl

NH

N

Ar

Ac

NH2NH2

Ar O

H

CH3

CH3

O

Ar N

H

NCH3

CH3

Ar

NN

N

Ar

CH3

CH3

N

CH3

O H

Ar

NN

N

Ar

CH3

CH3

N

CH3

N HX

Ar N

H

NH2

Et3N/0oC

++ +

34

X - NH2

35

X = OH, NH2

Cl

NH

N

Ar

Ac

NH2NH2

Ar O

H

CH3

CH3

O

Ar N

H

NCH3

CH3

Ar

NN

N

Ar

CH3

CH3

N

CH3

O H

Ar

NN

N

Ar

CH3

CH3

N

CH3

N HX

Ar N

H

NH2

Et3N/0oC

++ +

34

X - NH2

35

X = OH, NH2

ACKNOWLEDGEMENT Dr. Adel AwadallahDr. A. R. S. Ferwana Thank

• * Prof. Dr. Imtithal Al-Sawi , Prof. Dr. Boshra Awad • Ain Shams University• * Prof. Dr. M. El-Abadelah Dr. Jalal Ahmed

Jordan University for doing the NMr Spectra • * Dr. L. Goossen Dr. W. Schrader • Max-Planck Institut fuer Kohlenforschung, Muelheim, Germany • * Our Students and Colleagues • Mrs. Mehtab El-Haddad• Dr. Hany Dalloul• Dr. Nabil El-Halabi• Mr. Omar Miqdad• Mrs. Niveen Khafaja•