review molecules, 2005, 10(3) adel mohamed awadallah (a. r. s. ferwanah)
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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 - PowerPoint PPT PresentationTRANSCRIPT
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: [email protected]
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•