Microwave-assisted preparations of amidrazones and amidoximes

Article abstract of DOI:10.1021/jo061410u

(Chemical Equation Presented) In an operationally straightforward and efficient method, amidrazones 1a-h and amidoximes 2a-h are prepared in yields of 65-87% from imidoylbenzotriazoles 3a-h by microwave heating for 5-20 min with the appropriate hydrazine

Full text of DOI:10.1021/jo061410u

Microwave-Assisted Preparations of Amidrazones and Amidoximes
Alan R. Katritzky,* Niveen M. Khashab, Nataliya Kirichenko, and Anamika Singh
Center for Heterocyclic Compounds, UniVersity of Florida, Department of Chemistry,
GainesVille, Florida 32611-7200
katritzky@chem.ufl.edu
ReceiVed July 6, 2006
In an operationally straightforward and efficient method, amidrazones 1a-h and amidoximes 2a-h are
prepared in yields of 65-87% from imidoylbenzotriazoles 3a-h by microwave heating for 5-20 min
with the appropriate hydrazine or hydroxylamine.
Introduction to Amidrazones
POCl3,4,10a,b (v) dihydroxathiazoledioxides,11 or (vi) ketenimines
(R, R1 ) Ar).12 Further routes to amidrazones include (vii)
reaction of amines with hydrazonoyl halides (X ) Cl, Br),13a,13b,14
(viii) reduction of nitrazones by ammonium sulfide,15a or (ix)
reduction of formazans (R, R1 ) Ar).5 Two possible tautomers
1A and 1B exist for amidrazones (Scheme 2). If N2 is substituted
then amidrazones 1 are fixed in form 1B; otherwise, spectral
data15c suggest that amidrazones exist exclusively in form 1A
(Scheme 2).
Thus, amidrazones are of two major types: class I, which
do not carry a substituent on N2 and exist predominantly in
structure 1A (Scheme 1), and class II, which are substituted on
N2 and exist necessarily as 1B (Scheme 1). Class I compounds
can in turn be divided into eight subclasses (A-H) as shown
in Table 1 (two mono-, three di-, three tri-, one tetra-substituted).
Almost all of these subclasses could potentially be made by
Amidrazones 1 display fungistatic, bacteriostatic, and anti-
mycotic activity1 and also function as herbicides2 and lipoxy-
genase-1 inhibitors.3 Amidrazones are used to prepare 1,2,4-
triazines.4
Reactions of nitriles with hydrazines [Scheme 1, (i)] is
frequently used for the preparation of amidrazones,2,5-7 but the
outcome depends on the nature of the nitrile,7 and further
reaction can give dihydrotetrazines and subsequently tetrazines.5
Alternative methods (Scheme 1) for the synthesis of amidrazones
avoid the use of nitriles by reaction of hydrazine with (ii)
imidates or their salts (X ) O, S; R2 ) Alk),8a,b (iii) imidoyl
halides,5,9 (iv) amides and thioamides in the presence of
(1) Modzelewska-Banachiewicz, B.; Matysiak, J.; Niewiadomy, A. Eur.
J. Med. Chem. 2001, 36, 75.
(2) Haldeman, R. G.; Morin, L. T.; Matsuda, K. Chem. Abstr. 1963, 58,
11276.
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Biophys. Acta 2001, 1549, 88.
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Hamilton, C. S. J. Am. Chem. Soc. 1946, 68, 588.
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2002, 58, 5317.
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10.1021/jo061410u CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/24/2006
J. Org. Chem. 2006, 71, 9051-9056
9051

Katritzky et al.
SCHEME 1. Preparative Routes to Amidrazonesa
a Reagents: i-vi reactions with hydrazine; vii reaction with amine R, R1, R2 ) alkyl or aryl.
nitriles,23,24a-d (ii) thioamides for the preparation of aromatic
amidoximes,23,25a,b (iii) imidates,26a,b or (iv) amidines and their
salts (49-52% yield).26a,27 Alternative routes include (v) reaction
of amines with hydroximic acid chlorides and oximino-
ethers,23,26b,28a-d (vi) reduction of oxyamidoximes,23 (vii) plati-
num catalyzed reduction of nitrosolic and nitrolic acids,23,29 (viii)
aldol condensations of formamidoxime with aromatic alde-
hydes,23 or (ix) oxadiazole ring cleavage.30a,b A single procedure
for the preparation of class II amidrazones includes the reaction
of imidoyl halides31a with arylnitrenium ion (Scheme 4).31b
Moreover, O-substituted amidoximes are prepared directly by
the reaction of amidoximes with methyl iodide or dimethyl
sulfate to give O-methylamidoxime (22% yield)32a,b or acetylene
to yield O-vinylamidoximes (80% yield).33
SCHEME 2. Tautomeric Forms of Amidrazones
one or more of the existing methods; however, literature
substructural searches showed no known examples of com-
pounds of class G. The present work provides an easy access
to novel class G in addition to classes A, B, D, and E. As to
class II, a single example was reported for the preparation of
such compounds as a hydroiodide salt in 75% yield.15d
Amidoximes 2A can be divided into five subclasses (two
mono, two di, one tri) substituted as shown in Table 2. As to
amidoximes 2B, four subclasses (one mono, two di, one tri)
can also exist as shown in Table 3. The 10 reported methods
Introduction to Amidoximes
Amidoximes 2 are biologically active as antitumor agents,16
antimalerial agents,17 and nitric oxide synthase (NOS) sub-
strates.18,19 Amidoximes are prodrugs for amidines20,21 and
intermediates for the preparation of heterocycles such as
oxadiazoles.22 Tautomerism in simple amidoximes had been the
subject of some debate, although most authors accept the
structure of potentially tautomeric amidoximes to be the “amino
oxime” form (2A) and not the “amino hydroxylamine” structure
(2B) (Scheme 3 ).
Thus, similar to amidrazones, amidoximes 2 can be divided
into two classes: class I, which do not carry a substituent on
N2 exist predominantly as structure 2A (Scheme 3), and class
II, which are substituted on N2 exist necessarily as 2B (Scheme
3). Common methods (Scheme 5) for the preparation of class I
amidoximes include reactions of hydroxylamines with (i)
(23) Eloy, F.; Lenaers, R. Chem. ReV. 1962, 62, 155.
(24) (a) Stephenson, L.; Warburton, W. K.; Wilson, M. J. J. Chem. Soc.
C 1969, 6, 861. (b) Street, L. J.; Sternfeld, F.; Jelley, R. A.; Reeve, A. J.;
Carling, R. W.; Moore, K. W.; McKernan, R. M.; Sohal, B.; Cook, S.;
Pike, A.; Dawson, G. R.; Bromidge, F. A.; Wafford, K. A.; Seabrook, G.
R.; Thompson, S. A.; Marshall, G.; Pillai, G. V.; Castro, J. L.; Atack, J.
R.; MacLeod, A. M. J. Med. Chem. 2004, 47, 3642. (c) Kaboudin, B.;
Navaee, K. Heterocycles 2003, 60, 2287. (d) Briggs, L. H.; Cambie, R. C.;
Dean, I. C.; Rutledge, P. S. Aust. J. Chem. 1976, 29, 357.
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Ber. 1886, 1668.
(26) (a) Pinner, A. Ber. Dtsch. Chem. Ges. 1884, 184. (b) Bushey, D.
F.; Hoover, F. C. J. Org. Chem. 1980, 45, 4198.
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Wagner, P. Pol. J. Chem. 2002, 76, 1137.
(28) (a) Baker, K. W. J.; Horner, K. S.; Moggach, S. A.; Paton, R. M.;
Smellie, I. A. S. Tetrahedron Lett. 2004, 45, 8913. (b) Cragg, R. H.; Miller,
T. J. J. Chem. Soc., Dalton Trans. 1982, 907. (c) Gennet, D.; Zard, S. Z.;
Zhang, H. Chem. Commun. 2003, 1870. (d) Johnson, J. E.; Ghafouripour,
A.; Arfan, M.; Todd, S. L.; Sitz, D. A. J. Org. Chem. 1985, 50, 3348.
(29) Wieland, H.; Bauer, H. Ber. 1906, 1480.
(30) (a) Buscemi, S.; Cicero, M. G.; Vivona, N; Caronna, T. J.
Heterocycl. Chem. 1988, 25, 931. (b) Gandolfi, R.; Gamba, A.; Gru¨nanger,
P. Heterocycles 1995, 40, 619.
(16) Flora, K. P.; Riet, B. V.; Wampler, G. L. Cancer Res. 1978, 38,
1291.
(17) Hynes, J. B.; Hack, L. G. J. Med. Chem. 1972, 15, 1194.
(18) Rehse, K.; Brehme, F. Arch. Pharm. Pharm. Med. Chem. 1998,
331, 375.
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B.; Mansuy, D. Biochemistry 1998, 37, 17179.
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Hadva´ry, P.; Mu¨ller, M. H.; Knopp, D.; Levet-Trafit, B.; Lipari, M. T.;
Modi, N. B.; Mu¨ller, M.; Refino, C. J.; Schmitt, M.; Scho¨nholzer, P.; Weiss,
S.; Steiner, B. J. Med. Chem. 1996, 39, 3139.
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Chem. 1980, 45, 4144.
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J. D. Synthesis 2001, 16, 2427.
9052 J. Org. Chem., Vol. 71, No. 24, 2006

MicrowaVe-Assisted Preparations of Amidrazones and Amidoximes
TABLE 1. Eight Class I Amidrazones Existing as 1Aa
mono-N-substituted
di-N-substituted
tri-N-substituted
tetra-N-substituted
subclass
method
A
B
C
D
E
F
G
H
N1
N3
N1N1
N3N3
N1N3
N1N1N3
N1N3N3
N1N1N3N3
i
ii
iii
iv
v
vi
vii
viii
N
R
R
P
N
R
N
N
N
N
R
R
R
R
R
P
N
N
N
N
N
N
N
N
N
N
N
R
R
P
P
R
P
P
P
P
N
P
N
P
R
R
N
P
R
N
N
R
R
N
N
N
R
N
N
P
N
N
P
N
P
P
P
N
P
N
N
N
R
N
N
P
N
N
N
N
P
R
R
R
P
P
N
N
N
P
ix
x
this work
P
N
a R: reported. P: possible but no example reported. N: not possible by reasons of valency.
TABLE 2. Five Subclasses of Amidoximes 2Aa
SCHEME 3. Tautomeric Forms of Amidoximes
mono
di
tri
SCHEME 4. Preparative Routes to Amidoximes of Type
2Aa
subclass
method
A′
B′
C′
D′
E′
N1
O
N1N1
N1O
N1N1O
i
ii
iii
iv
v
vi
vii
viii
N
R
N
N
R
N
N
N
N
R
P
R
P
N
P
P
P
P
N
P
N
N
N
N
N
N
N
N
N
N
N
P
N
N
N
N
N
N
N
N
N
N
N
R
R
N
N
N
R
R
ix
this work
a R: reported. P: possible but not reported. N: not possible by reasons
of valency.
Results and Discussion
Imidoylbenzotriazoles 3 have become important as stable
alternatives to the corresponding imidoyl chlorides.34a-c Re-
cently, we reported a novel procedure for the preparation of
amidines using imidoylbenzotriazoles.35 We have now expanded
the utility of imidoylbenzotriazoles to include the preparation
of amidrazones 1a-h and amidoximes 2a-h.
Imidoylbenzotriazoles 3a-h (Scheme 6) were prepared in
good yields (50-91%) from the reaction of secondary amide
(1 equiv), oxalyl chloride (1 equiv), and benzotriazole (2 equiv)
in the presence of pyridine.35 The crude products were chro-
matographed, after washing with sodium carbonate, on basic
alumina (EtOAc/Hex) to give pure imidoylbenzotriazoles 3a-h
a Reagents: i-vi reactions with hydroxyamine or RONH2; (v) reaction
with amine R, R1, R2 ) alkyl or aryl; (vi) reduction with SO2; (vii) platinum-
catalyzed reduction; (viii) aldol condensation; (ix) photorearrangement of
oxazole ring.
SCHEME 5. Preparative Routes to Amidoximes of Type 2B
(34) (a) Katritzky, A. R.; Hayden, A. E.; Kirichenko, K.; Pelphrey, P.;
Ji, Y. J. Org. Chem. 2004, 69, 5108. (b) Katritzky, A. R.; Huang, T.;
Voronkov, M. V. J. Org. Chem. 2001, 66, 1043. (c) Katritzky, A. R.;
Stevens, C. V.; Zhang, G. F.; Jiang, J.; De Kimpe, N. Heterocycles 1995,
40, 231.
(35) Katritzky, A. R.; Cai, C.; Singh, S. K. J. Org. Chem. 2006, 71,
3375.
for the preparation of 2A and 2B (Schemes 4 and 5) generally
target specific subclasses of amidoximes (Tables 2 and 3). We
now report routes to many classes including class I′ where no
examples have been reported to date.
J. Org. Chem, Vol. 71, No. 24, 2006 9053

Katritzky et al.
SCHEME 7. Preparative Routes to Aminoamidoximes
SCHEME 6. Reactions of Imidoylbenzotriazoles with
Hydrazines and Hydroxylaminesa
Amidrazones 1a-h exhibit tautomerism; thus, it was hard to
assign the NH protons, especially since they were not always
visible.
Reacting imidoylbenzotriazole 3a,b,d with hydrazides (R3-
CONHNH2) in the presence of catalytic amounts of acetic acid
under microwave conditions afforded cyclic 1,2,4-triazoles 4a-
d37a-d (Scheme 6 and Table 5) via a simple intramolecular
condensation followed by the loss of one molecule of water.
Upon completion of the reaction (5-10 min), the sample was
diluted with dichloromethane and then purified using flash
column chromatography to give 4a-d in 77-100% yields.
Novel 4a-d were isolated as white microcrystals and character-
ized by 1H and 13C NMR spectroscopy and elemental analysis.
Amidoximes 2a-h were prepared in 65-81% yields from
the reaction of imidoylbenzotriazoles 3a-f,h with the corre-
sponding hydroxylamines (Scheme 6 and Table 6). Utilizing
microwave irradiation, reaction of imidoylbenzotriazole 3a-
f,h with hydroxylamines reached completion after 5-15 min.
The reaction mixture was then dissolved in dichloromethane
and washed with 10% aqueous Na2CO3. The combined organic
layers were dried over anhydrous MgSO4 and concentrated
under reduced pressure. The residue obtained was purified by
gradient column chromatography (EtOAc/Hex) to obtain pure
amidoximes 2a-h. Structures of novel 2a-h were supported
a For identity of R, R1, and R2, see Tables 4-6.
TABLE 3. Four Subclasses of Amidoximes 2Ba
mono
F′
di
tri
I′
subclass
method
G′
H′
N2
N2O
N1N2
N1N2O
X
N
P
N
P
R
R
N
P
this work
a R: reported. P: possible but not reported. N: not possible by reasons
of valency.
1
1
by elemental analysis and H and 13C NMR spectra. The H
spectra no longer showed signals in the range of 7.0-8.2 ppm
corresponding to the benzotriazole group. Some NH protons
were not visible due to fast exchange.
(Scheme 6). Known 3a-e,g,h and novel 3f were fully charac-
terized by 1H and 13C NMR spectroscopy and in the case of 3f
by elemental analysis. Most imidoylbenzotriazoles are easy to
handle and keep indefinitely; however, we noted slow decom-
position of 1-[phenyl(2-pyridinylimino)methyl]-1H-benzotria-
zole 3g after 3 days.
Aminoamidoximes and Diamidoximes. Aminoamidoximes
6 are compounds with both hydroxylamine and hydrazine
moieties. Previous preparations of such compounds include
reacting oxime chlorides38a or simple amidoximes38b with
hydrazines to give aminoamidoximes in 21-30% yields (Scheme
7). Diamidoximes 7 are compounds with two hydroxylamine
moieties, and to the best of our knowledge, they are not known
in the literature.
Stirring 1 equiv of imidoylbenzotriazoles 3b-d,f with 1.5
equiv of the corresponding hydrazine in the presence of a 7-fold
excess of sodium sulfate for 5-20 min under microwave
irradiation afforded amidrazones 1a-h in 66-85% yields
(Scheme 6 and Table 4). The progress of the reaction was
monitored by TLC. Upon completion of the reaction, water was
added to remove sodium sulfate. The organic layer was extracted
with dichloromethane and then purified using column chroma-
tography to give novel 1a-h as colorless oils. Compound 1e
could be obtained only as a crude; attempted purification led
to complete decomposition. Structures of novel 1a-h were
supported by NMR spectroscopy, mass spectroscopy, and
elemental analysis. The carbonyl peaks of compounds 1c,f-h
were very broad in 13C NMR probably because of intermolecular
hydrogen bonding and/or tautomeric interconversion. The cyclic
triazole structures were excluded for compounds 1a-h by
elemental analysis and MS. However, compound 1c was
smoothly converted into 4-(2-butyl)-3,5-diphenyl-4H-1,2,4-
triazole36 (4e) upon gentle heating (1c melted at 196-198 °C).
Moreover, the melting point of 4e obtained from heating 1c
was 176 °C, which is identical to that of 4-(2-butyl)-3,5-
diphenyl-4H-1,2,4-triazole (see the Experimental Section).
Aminoamidoxime 6 and diamidoxime 7 were prepared
starting from 1H-1,2,3-benzotriazol-1-ylmethanone oxime 5
(Scheme 8). Reagent 5 was prepared from the appropriate oxime
(1 equiv), 1-chloro-1H-benzotriazole (1 equiv), and potassium
tert-butoxide (1.1 equiv) in diethyl ether at -30 °C. The reaction
was stirred at room temperature for 5 h before it was quenched
with water and extracted with dichloromethane. Evaporating the
organic layer afforded oxime 5 in 90% yield. Using a micro-
wave, reagent 5 was reacted with the appropriate hydrazine or
hydroxylamine under mild conditions (see the Experimental
Section) to give 6 or 7, respectively (Scheme 8). Novel 6 and
7 were isolated as viscous oils and were characterized by
1
elemental analysis and H and 13C NMR spectra.
(37) (a) Wiedermannova´, I.; Otyepka, M.; Styskala, J.; Slouka, J.
ARKIVOC 2003, xV, 65. (b) Riedl, Z.; Hajo´s, G.; Ko¨ver, P.; Kollenz, G.
ARKIVOC 2003, V, 62. (c) Wamhoff, H.; Tzanova, M. ARKIVOC 2003, ii,
98. (d) Natarajan, A.; Guo, Y.; Arthanari, H.; Wagner, G.; Halperin, J. A.;
Chorev, M. J. Org. Chem. 2005, 70, 6362.
(38) (a) Armand, J.; Bassinet, P. J. Chem. Res. Synop. 1980 304. (b)
Armand, J. Compt. Seanc. Acad. Sci., Ser. C: Sci. Chim. 1966, 262, 592.
(36) Gautun, O. R.; Carlsen, P. H. J. Acta Chem. Scand. 1991, 45, 609.
9054 J. Org. Chem., Vol. 71, No. 24, 2006

MicrowaVe-Assisted Preparations of Amidrazones and Amidoximes
TABLE 4. Preparation of Amidrazones 1a-h from 3b-d,f
imidoylbenzotriazole 3
R
R1
R2
conditions (T, °C, power, W, time, min)
product
yield, %
3b
3b
3c
3d
3f
3b
3c
3f
Me
Me
Ph
p-Tol
Me
Me
Ph
p-Tol
p-Tol
i-Bu
4-MeOC6H4
i-Bu
p-Tol
i-Bu
H
Ph
PhCO
Ph
4-NO2OC6H4
PhCO
4-ClC6H4CO
COCH3
95, 105, 10
90, 120, 15
120, 130, 15
80, 80, 10
110, 120, 20
120, 125, 12
160, 160, 12
105, 115, 9
1a
1b
1c
1d
1e
1f
85
70
72
82
68
66
87
80
1g
1h
Me
i-Bu
TABLE 5. Preparation of 1,2,4-Triazoles 4a-d from 3a,b,d
imidoylbenzotriazole 3
R
R1
R3
Me
p-Tol
p-Tol
Ph
conditions (T, °C, power, W, time, min)
product
yield, %
3a
3b
3d
3d
Bn
Me
p-Tol
p-Tol
p-Tol
p-Tol
4-MeOC6H4
4-MeOC6H4
80, 120, 10
80, 120, 5
80, 120, 5
80, 120, 10
4a
4b
4c
4d
77
94
100
88
TABLE 6. Preparation of Amidoximes 2a-h
imidoylbenzotriazole 3
R
R1
R4
R5
conditions (T, °C, power, W, time, min)
product
yield, %
3a
3b
3c
3c
3d
3e
3f
Bn
Me
Ph
Ph
p-Tol
Ph
Me
p-Tol
p-Tol
i-Bu
i-Bu
4-MeOC6H4
Ph
H
H
H
Me
H
H
H
Me
H
100, 120, 5
100, 120, 10
100, 120, 5
60, 120, 5
100, 120, 5
80, 120, 5
2a
2b
2c
2d
2e
2f
65
79
68
81
78
80
68
73
Bn
Me
H
H
Me
Bn
H
i-Bu
p-Tol
80, 120, 15
60, 100, 10
2g
2h
3h
2-Furyl
SCHEME 8. Preparation of Aminoamidoxime 6 and Diamidoxime 7
(50%): mp 63-65 °C; 1H NMR δ 1.08 (d, J ) 6.6 Hz, 6H), 2.03-
2.14 (m, 1H), 2.74 (s, 3H), 3.41 (d, J ) 6.6 Hz, 2H), 7.42 (t, J )
7.6 Hz, 1H), 7.54 (t, J ) 7.6 Hz, 1H), 8.07 (d, J ) 8.2 Hz, 1H),
8.48 (d, J ) 8.4 Hz, 1H); 13C NMR δ 14.4, 20.7, 29.9, 58.0, 115.6,
119.5, 124.8, 128.6, 131.3, 146.5, 153.5. Anal. Calcd for
C12H16N4: C, 66.64; H, 7.46; N, 25.90. Found: C, 66.36; H, 7.70;
N, 25.89.
General Procedure for the Preparation of Amidrazones 1a-
h. An intimate mixture of 3 (0.36 mmol), hydrazine (0.43 mmol),
and sodium sulfate (anhydrous, 0.3 g) was stirred in a sealed tube
(10 mL) under microwave irradiation (conditions vary in each case).
After completion of the reaction as indicated by TLC, the reaction
mixture was washed with 5% solution of Na2CO3 (2 × 15 mL)
then the organic layer was extracted with dichloromethane (3 ×
10 mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated under reduced pressure. The residue
obtained was either recrystallized from EtOAc/hex (unless indicated
otherwise) or purified by column chromatography on silica gel with
EtOAc/Hex to give pure 1a-h.
N- (4-Methylphenyl)ethanehydrazonamide (1a): viscous oil
(85%); 1H NMR δ 6.97 (d, J ) 8.4 Hz, 2H), 6.62 (d, J ) 8.4 Hz,
2H), 4.8 (br s, 1H), 2.42 (s, 3H), 2.23 (s, 3H); 13C NMR δ 143.3,
129.7, 125.5, 124.1, 115.2, 20.4, 10.0. Anal. Calcd for C9H13N3:
C, 66.23; H, 8.03; N, 25.74. Found: C, 66.47; H, 8.21; N, 25.70.
General Procedure for the Preparation of Amidoximes 2a-
h. (In the case of 2b, the compound was directly purified by column
without workup). A mixture of the appropriate 3 (0.35 mmol) (see
Scheme 6 and Table 6), hydroxylamine hydrochloride (0.4 mmol),
Conclusion
A simple, efficient, and broadly applicable synthetic meth-
odology for the preparation of amidrazones and amidoximes
under microwave conditions has been developed via the
nucleophilic attack on imidoylbenzotriazoles by hydrazines or
hydroxylamines. The easy accessibility of imidoylbenzotriazoles
from the corresponding amide and the simple workup gives the
approaches substantial utility.
Experimental Section
General Procedure for the Preparation of Imidoylbenzotria-
zoles 3a-h. To a solution of the corresponding amide (5.0 mmol)
in dichloromethane (20 mL) was added dropwise at 0 °C pyridine
(5.5 mmol) followed by oxalyl chloride (5.5 mmol) in dichlo-
romethane (20 mL). Gas evolution was observed during the process.
After the addition, the reaction was continued for 15 min, and then
benzotriazole (10.5 mmol) was added in one portion to the reaction
flask. The ice bath was removed to allow the reaction to continue
at room temperature, and the reaction was monitored by TLC. The
precipitated white solid was filtered off, and sodium bicarbonate
solution (saturated) was added to dilute the reaction mixture.
Aqueous workup gave a crude product that was purified by column
chromatography on basic alumina, using hexanes/EtOAc (8:1) as
eluent to give pure 3a-h in good yields.
N-[(Benzotriazol-1-yl)ethylidene]-2-methyl-1-propanamine (3f).
Recrystallized from EtOAc/hex to give off-white microcrystals
J. Org. Chem, Vol. 71, No. 24, 2006 9055

Katritzky et al.
and Et3N (0.4 mmol) was stirred in a sealed tube (10 mL) under
microwave irradiation (conditions vary in each case). The mixture
was dissolved in dichloromethane and washed with 10% solution
of Na2CO3 (2 × 15 mL). The combined organic layers were dried
over anhydrous MgSO4 and concentrated under reduced pressure.
The residue obtained was purified by gradient column chromatog-
raphy with EtOAc/Hex or recrystallized from EtOAc/hexanes
(unless specified otherwise) to give pure 2a-h.
TLC showed no evidence of stating material 1c. Melting point,
spectral data, and elemental analysis of the obtained solid agreed
with the values reported for compound 4e.
4-(2-Butyl)-3,5-diphenyl-4H-1,2,4-triazole (4e). Recrystallized
1
from ethanol to give white crystals (88%): mp176-177 °C; H
NMR δ 7.70-7.66 (m, 4H), 7.57-7.50 (m, 6H), 3.97 (d, J ) 4.0
Hz, 2H), 1.61-1.49 (m, 2H), 0.52 (d, J ) 4.0 Hz, 6H); 13C NMR
δ 155.8, 129.8, 128.8, 128.7, 127.7, 53.3, 28.4, 20.0. Anal. Calcd
for C18H19N3: C, 77.95; H, 6.90; N, 15.15. Found: C, 77.67; H,
7.00; N, 15.24.
N′-Hydroxy-N-(4-methylphenyl)-2-phenylethanimidamide (2a).
Recrystallized from EtOAc/hexanes to give off-white microcrystals
1
(65%): mp 140-142 °C; H NMR δ 7.14-7.18 (m, 3H), 7.00-
General Procedure for the Preparation of 6 and 7. An intimate
mixture of oxime 5 (0.42 mmol), the appropriate hydrazine or
hydroxylamine (1.05 mmol), and sodium sulfate (anhydrous, 0.1
g) was stirred in sealed tube (10 mL) under microwave irradiation
(115W) at approximately 110 °C (indications) for 10 min. After
completion of the reaction, as indicated by TLC, the reaction
mixture was dissolved in dichloromethane (10 mL) and then washed
with a 5% solution of Na2CO3 (2 × 15 mL). The combined organic
layers were dried over anhydrous MgSO4 and concentrated under
reduced pressure. The residue obtained was washed with benzene
to give the corresponding products as viscous oils.
7.05 (m, 4H), 6.81 (d, J ) 8.2 Hz, 2H), 3.58 (s, 2H), 2.30 (s, 3H);
13C NMR δ 152.6, 136.1, 135.8, 135.0, 129.4, 128.7, 128.2, 126.4,
125.7, 35.04, 20.84. Anal. Calcd for C15H16N2O: C, 74.97; H, 6.71;
N, 11.66. Found: C, 74.77; H, 6.80; N, 11.95.
General Procedure for the Preparation of 4a-d. A mixture
of the appropriate 3 (0.5 mmol) and the corresponding hydrazine
(0.51 mmol) in the presence of a catalytic amount of CH3COOH
(1-2 drops) was stirred in sealed tube (10 mL) under microwave
irradiation (conditions vary in each case). The mixture was dissolved
in dichloromethane and washed with 10% solution of Na2CO3 (2
× 15 mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated under reduced pressure. The residue
obtained was recrystallized from the appropriate solvent (designated
below) to give pure 4a-d as white microcrystals.
3-Benzyl-5-methyl-4-(4-methylphenyl)-4H-1,2,4-triazole (4a).
Recrystallized from CHCl3/MeOH to give white microcrystals
(77%): mp 60-61 °C; 1H NMR δ 7.21 (d, J ) 8.2 Hz, 2H), 7.14-
7.16 (m, 3H), 6.93-6.97 (m, 2H), 6.81 (d, J ) 8.2 Hz, 2H), 3.97
(s, 2H), 2.42 (s, 3H), 2.21 (s, 3H); 13C NMR δ 153.6, 151.9, 139.8,
135.7, 131.0, 130.2, 128.4, 128.2, 126.7, 126.5, 31.4, 21.1, 10.9.
Anal. Calcd for C17H17N3: C, 77.54; H, 6.51; N, 15.96. Found: C,
77.09; H, 6.56; N, 15.94.
N-Hydroxy-N-(4-nitrophenyl)benzenecarbohydrazonamide (6):
1
oil (71%); H NMR δ 8.2 (d, J ) 9.0 Hz, 1H), 8.07 (d, J ) 9.0
Hz, 1H), 7.71-7.68 (m, 2H), 7.44-7.37 (m, 3H), 7.14 (d, J ) 9.3
Hz, 1H), 6.62 (d, J ) 9.0 Hz, 1H); 13C NMR δ 155.8, 144.7, 133.4,
131.0, 128.7, 127.2, 124.7, 119.9, 111.9. Anal. Calcd for
C13H12N4O3: C, 57.35; H, 4.44; N, 20.58. Found: C, 57.58; H,
4.53; N, 20.18.
N-N′-Bis(benzyloxy)ethanimidamide (7): oil (64%); 1H NMR
δ 7.91 (br s, 1H), 7.30-7.35 (m, 10H), 4.94 (s, 2H), 4.74 (s, 2H),
1.92 (s, 3H); 13C NMR δ 154.6, 137.6, 135.6, 129.0, 128.5, 128.3,
128.1, 127.8, 78.6, 75.7, 14.1. Anal. Calcd for C16H18N2O2: C,
71.09; H, 6.71; N, 10.36. Found: C, 71.08; H, 6.75; N, 10.69.
Conversion of N-Benzoyl-N-isobutylbenzenecarbohydra-
zonamide (1c) into 4-(2-Butyl)-3,5-diphenyl-4H-1,2,4-triazole
(4e). Compound 1c was prepared according to the general procedure
for preparation of compounds 1a-h. Compound 4e was prepared
according to the general procedure for preparation of compounds
4a-d. Compound 1c (0.3 mmol) was heated in a tube on a hot-
stage apparatus until it started melting (mp ) 196 °C). The melted
solid was then cooled and dissolved in dichloromethane (1 mL).
Acknowledgment. We thank Dr. Dennis Hall for his help
and useful suggestions.
Supporting Information Available: Characterization data for
compounds 1b-h, 2b-h, and 4b-d. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO061410U
9056 J. Org. Chem., Vol. 71, No. 24, 2006