Preparation, properties, and reductive alkylation of arylhydrazides

Article abstract of DOI:10.1139/v98-125

1 [-Acy]-2-arylhydrazines (1), readily obtained in high yield from the condensation of arylhydrazines and the appropriate liquid carboxylic acid (2), underwent reductive alkylation with the same or different liquid carboxylic acids (2) and NaBH₄ to give 1-acyl-2-alkyl-2-arylhydrazines (3) in good to moderate yields. The carboxylic acid has both the role of supplying the entering alkyl group and of acting as solvent. Most likely, it also modifies the BH₄^- anion to an active reducing agent under those conditions. The ¹H NMR criteria for identifying the location of acylation of hydrazines and E and Z isomers are given. The MS spectra of the prepared hydrazides were analyzed in order to identify relevant structural features leading to specific fragmentations.

Full text of DOI:10.1139/v98-125

1180
Preparation, properties, and reductive alkylation
of arylhydrazides
Giancarlo Verardo, Nicoletta Toniutti, and Angelo G. Giumanini
Abstract: 1-Acyl-2-arylhydrazines (1), readily obtained in high yield from the condensation of arylhydrazines and the
appropriate liquid carboxylic acid (2), underwent reductive alkylation with the same or different liquid carboxylic acids
(2) and NaBH4 to give 1-acyl-2-alkyl-2-arylhydrazines (3) in good to moderate yields. The carboxylic acid has both
–
the role of supplying the entering alkyl group and of acting as solvent. Most likely, it also modifies the BH4 anion to
1
an active reducing agent under those conditions. The H NMR criteria for identifying the location of acylation of
hydrazines and E and Z isomers are given. The MS spectra of the prepared hydrazides were analyzed in order to
identify relevant structural features leading to specific fragmentations.
Key words: 1-acyl-2-arylhydrazine, 1-acyl-2-alkyl-2-arylhydrazine, reductive alkylation, sodium tetrahydroborate,
carboxylic acid.
Résumé : La condensation d’arylhydrazines et d’acides carboxyliques liquides appropriés (2) conduit facilement aux 1-
acyl-2-arylhydrazines (1) avec d’excellents rendements; celles-ci, par alkylation réductrice avec les mêmes (ou d’autres)
acides carboxyliques (2) liquides et du NaBH4, conduisent aux 1-acyl-2-alkyl-2-arylhydrazines (3) avec des rendements
qui vont de bons à moyens. L’acide carboxylique joue à la fois le rôle de source du groupe méthyle qui entre et de
–
solvant. Il est probable qu’il modifie aussi l’anion BH4 afin qu’il devienne un agent réducteur actif dans ces
1
conditions. On présente les critères de RMN du H permettant d’identifier la position de l’acylation des hydrazines et
les isomères E et Z. On a analysé les SM des hydrazides préparés dans le but d’identifier les caractéristiques
structurales pertinentes aux fragmentations spécifiques.
Mots clés : 1-acyl-2-arylhydrazine, 1-acyl-2-alkyl-2-arylhydrazine, alkylation réductrice, tétrahydroborate de sodium,
acide carboxylique.
[Traduit par la Rédaction] Verardo et al. 1187
focused our attention on arylhydrazides as better substrates
for selective alkylation.
The use of carboxylic acids in combination with NaBH4
was found to effect N-alkylation of aliphatic as well as aro-
matic amines (1), nevertheless, the synthetic utility of this
method was never developed to date on hydrazines and de-
rivatives. The direct reductive alkylation of phenylhydrazine
with carboxylic acid and NaBH4 gave a mixture of products
resulting from different multiple alkylations as well as
acylation of the hydrazine.2 In fact, it is well established that
alkylation of alkyl- or arylhydrazines occurs preferentially
on the substituted nitrogen atom (2), however, this reaction
usually requires the use of protecting groups to limit or
avoid multiple alkylations. For this reason, it has been per-
formed on hydrazones or acylhydrazines. The resulting alkyl
derivatives could be either hydrolyzed to remove the pro-
tecting group and give 1,1-disubstituted hydrazines or re-
duced to yield trisubstituted hydrazines (3). Herein, we
Hydrazides are an important class of compounds not only
in organic synthesis, but also for industrial applications.
Arylhydrazides (1) and 1-acyl-2-alkyl-2-arylhydrazines
(3) were used in the preparation of herbicides (4),
antiinflammatory indoles (5), derivatives with antimicrobial
(6) or antimycotic activity (7, 8).
We now report the preparation and full characterization of
some arylhydrazides (1) and their reductive alkylation with
carboxylic acids and NaBH4 combination as the method of
choice for preparation of 1-acyl-2-alkyl-2-arylhydrazines
(3). This simple, inexpensive, high-yielding method is also
proposed as a one-pot procedure in which the carboxylic
acid acts as acylating as well as alkylating agent. The MS
and NMR spectra of these hydrazides were carefully dis-
cussed because literature data were sparse and scattered.
Received January 2, 1998.
G. Verardo, N. Toniutti, and A.G. Giumanini.1 Department
of Chemical Sciences and Technologies, University of Udine,
I-33100 Udine, Italy.
1-Acyl-2-arylhydrazines (1a–f) were readily obtained by
heating
the
corresponding
carboxylic
acid
and
arylhydrazines without any condensing agent (9). This direct
approach seems scarcely known and even less attended (10,
11). In producing 1-acyl-2-arylhydrazine instead of its iso-
mer 1-acyl-1-arylhydrazine, the carboxylic acid here be-
haves in the same way as other acylating agents, frequently
1
Author to whom correspondence may be addressed.
Telephone: +39-432-558 870. Fax: +39-432-558 803. E-mail:
gverardo@tin.dstc.uniud.it
G. Verardo et al. Unpublished results.
2
Can. J. Chem. 76: 1180–1187 (1998)
© 1998 NRC Canada

Verardo et al.
Table 1. Physical data of 1-acyl-2-aryl-hydrazines
1181
Fig 1.
(1).
R1
O
H
R1
H
O
Compounda
R
R1
Yieldb
mp (°C)c
1a
1b
1c
1d
1e
1f
H
H
H
H
NO2
Me
H
Me
Et
Pr
Me
Me
50%
85%
80%
75%
81%
75%
144d
129e
157f
110g
213
H
N1
N1
H
N
N
Ar
Ar
E
Z
132
the different environment by showing two peaks at ca.
6.0 ppm in CDCl3 and ca. 8.0 in DMSO-d6 (13). After com-
paring these data with the spectra of our 1-acyl-2-
arylhydrazines (1) (see Table 2), we confirmed their identifi-
cation.
Of all the hydrazides 1a–f, only 1-acetyl-2-(4-
nitrophenyl)hydrazine (1e) did not show the E/Z isomerism
in the NMR. The H-decoupled 13C-NMR spectra of 1a–f
showed extensive doubling of the several peaks, but again
1e did not exhibit this feature, a good indication that it was
present in a single conformation.
aAll solid compounds were analyzed for C, H, and N,
and results agreed to ±0.5% of theoretical values.
bYield of isolated product.
cMidpoint of narrow range.
dLiterature (4) 145°C.
eLiterature (5) 129°C.
fLiterature (5) 157°C.
gLiterature (5) 96°C.
used for hydrazines, such as esters, anhydrides, and acyl
chlorides (12).
The mass spectra of 1a–f and of their 1,1-isomers 1a′–f′
differed in a number of features (Table 2 and experimental
part). The latter showed weaker parent ions, which under-
went extensive fragmentations to the RCO+ acyl ions and
the R+ ions (likely in a rearranged form, whenever possible).
Intense peaks at m/z 77 and 78 (corresponding to peaks at
m/z 122, 123 for 1e′ and 91, 92 for 1f′ deriving from the sub-
stituted phenyl group) were detected. But their most impres-
sive feature was the production of an outstanding peak at
All the starting hydrazides 1a–f were characterized and
their properties compared with literature data (Tables 1 and
2). The correct structural identification of the arylhydrazides
1
1a–f was essentially based on their H NMR features. Upon
accurate examination of the available literature data, we made
the following observation. Although 1-acyl-1-substituted-
hydrazines usually exhibit the E/Z amide isomerism (Fig. 1),
which doubles all the hydrogen resonances, their primary
amino group hydrogens appear as singlets at ca.
3.8–4.8 ppm in CDCl3 and 4.2–5.3 ppm in DMSO-d6 (13).
Completely different NMR features are recognized when
the acyl and the aryl (or alkyl) groups are located on differ-
ent nitrogens (that is, for 1-acyl-2-substituted derivatives).
The hydrogen belonging to the amide function shows up as
two unequal resonances with a separation of ca. 0.3–0.7 ppm
both in CDCl3 (at ca. 7.4 ppm) and in DMSO-d6 (at ca.
9.0 ppm) (13). Interestingly, the amino proton also reflects
+
m/z 105 for PhN2 (or the corresponding charged fragment
from 1e′ and 1f′), always accompanied by a weak peak at m/z
108 for the formula of phenylhydrazine (or the correspond-
ing substituted phenylhydrazine from the parent ions 1e′ and
+
1f′). A possible mechanism for the formation of ArN2 in-
volves a few rearrangements before cleavage of the parent
ion of 1a′–f′, eq. [1].
Ar
Ar
H
.
.
N
N
N
NH2
[1]
O
HO
R1
R1
Ar
Ar
H
.
H
R
1
N
NH
N
N
.
Ar
N
N
+
.
R1
H
HO
OH
O
R1
1b'-f'
The 1,2-isomers 1b–f also yielded all these ions, with the
relevant difference that the ion at m/z 105 (or the correspond-
ing charged fragment from 1e and 1f) was hardly discernible
and that the ion at m/z 108 (or the corresponding peak for the
formula of substituted phenylhydrazine from the parent ions 1e
and 1f), due to the loss of ketene from the parent ion, was the
base peak. The mass spectrum of 1a is quite different from
1b–f as the first most intense peak was the molecular ion (m/z
136), and the second one was the peak at m/z 107 (PhN2H2 ).
On the contrary, the ion at m/z 108 was scarcely present.
+
© 1998 NRC Canada

1182
Can. J. Chem. Vol. 76, 1998
Table 2. Spectroscopic and MS data of 1-acyl-2-arylhydrazines (1).
Product IR (KBr) ν (cm–1)
1H NMR δ, J (Hz)
13C NMR δ
MS (70 eV) m/z (%)
1a
1b
1c
3310 s, 3204 s, 3072 s,
3026 s, 2907 m, 1690
vs, 1663 vs, 1604 s,
1505 s, 1394 vs, 1200
m, 874 s, 755 vs, 702
vs
3270 s, 3072 m, 1670
vs, 1617 vs, 1500 s,
1485 vs, 1437 vs,
1372 s, 1300 s, 1250
s, 1010 s, 766 vs, 700
vs
3310 vs, 3270 vs, 3039
s, 2980 s, 2940 s,
1650 vs, 1609 vs,
1557 vs, 1497 vs,
1464 vs, 1227 s, 1150
s, 1043 s, 944 s, 760
vs, 694 vs
3296 vs, 3236 vs, 3085
s, 3045 s, 2966 s,
2940 s, 2880 m, 1681
vs, 1642 vs, 1622 vs,
1576 vs, 1510 vs,
1445 s, 1120 s, 957 s,
760 vs, 694 vs, 502
vs
6.65–6.85 (m, 3H, Harom), 7.10–7.25 (m, 2H,
Harom), 8.11 (d, 1H, HCϭO, J = 10.5, rotamer
A), 8.13 (s, 1H, HCϭO, rotamer B), 7.80 (app d,
1H, N-H, J = 2.7, rotamer A), 8.01 (s, 1H, N-H,
rotamer B), 9.45 (d, 1H, N-H, J = 10.8, rotamer
A), 9.72 (app d, 1H, N-H, J = 2.2, rotamer B)b
2.03 (s, 3H, CH3, rotamer A), 2.09 (s, 3H, CH3,
rotamer B), 5.84 (br s, 1H, N-H, rotamer A),
6.18 (app d, 1H, N-H, J = 3.9, rotamer B),
6.72–6.96 (m, 3H, Harom), 7.15 (br s, 1H, N-H,
rotamer A), 7.19–7.33 (m, 2H, Harom), 7.63 (s,
1H, N-H, rotamer B)a
149.3, 149.4,
136 (M+, 100), 108
155.8, 156.6,
165.8, 166.1,
185.8, 186.5,
197.7, 204.8b
(12), 107 (73), 92
(12), 91 (16), 78
(10), 77 (50), 65
(19), 64 (10), 51
(20), 39 (10)
19.1, 20.9,
150 (M+, 62), 108
(100), 107 (37), 93
(27), 92 (28), 91
(12), 78 (13), 77
(43), 65 (12), 51
(14), 43 (19), 39 (10)
164 (M+, 68), 108
(100), 107 (31), 93
(50), 92 (18), 78
(19), 77 (37), 66
(17), 65 (15), 57
(16), 54 (19), 51
(14), 39 (11)
112.4, 113.48,
121.2, 121.2,
129.1, 129.5,
147.0, 147.8,
170.2, 176.9a
1.05–1.25 (m, 3H, CH3), 2.27 (q, 2H, CH2, J = 7.5, 8.0, 8.9, 23.9,
rotamer A), 2.45 (q, 2H, CH2, J = 7.5, rotamer
B), 5.80 (br s, 1H, N-H, rotamer A), 6.15 (br s,
1H, N-H, rotamer B), 6.70–6.95 (m, 3H, Harom),
7.03 (br s, 1H, N-H, rotamer A), 7.15–7.30 (m,
2H, Harom), 7.50 (br s, 1H, N-H, rotamer B)a
26.9, 111.7,
112.9, 120.6,
128.5, 128.8,
146.5, 147.4,
173.2a
1d
0.89 (t, 3H, CH3, J = 7.3), 1.50–1.85 (m, 2H,
CH2), 2.10 (t, 2H, CH2, J = 7.5, rotamer A),
2.33 (t, 2H, CH2, J = 7.5, rotamer B), 5.85 (br s,
1H, N-H, rotamer A), 6.30 (br s, 1H, N-H,
rotamer B) 6.60–6.90 (m, 3H, Harom), 7.10–7.30
(m, 2H, Harom), 7.38 (br s, 1H, N-H, rotamer A),
8.15 (br s, 1H, N-H, rotamer B)a
14.9, 19.3, 20.2, 178 (M+, 27), 108
34.3, 37.3,
113.6, 114.6,
122.1, 130.3,
130.5, 148.6,
149.3, 174.7,
180.8a
(100), 107 (18), 93
(78), 92 (20), 78
(13), 77 (30), 71
(16), 66 (28), 65
(20), 51 (12), 43
(35), 41 (66), 39 (25)
1e
1f
3315 vs, 3290 vs, 3091
m, 3006 m, 2933 m,
1655 vs, 1592 vs,
1504 vs, 1320 vs,
1257 vs, 1115 vs,
1008 s, 837 vs, 749 s
3289 vs, 3252 vs, 3026
s, 1666 vs, 1600 vs,
1547 vs, 1520 vs,
1381 vs, 1241s, 1150
m, 1000 s, 824 vs,
751 vs
1.98 (s, 3H, CH3), 6.79 (app d, 2H, Harom, J = 8.7), 20.5, 110.5,
195 (M+, 26), 154 (8),
153 (100), 123 (9),
108 (10), 107 (10),
106 (12), 43 (32)
8.08 (app d, 2H, Harom, J = 8.7), 9.01 (s, 1H, N-
125.8, 138.0,
H), 9.97 (s, 1H, N-H)b
154.9, 169.2b
1.90 (s, 3H, CH3, rotamer A), 2.02 (s, 3H, CH3,
rotamer B), 2.23 (s, 3H, CH3, rotamer A), 2.24
(s, 3H, CH3, rotamer B), 5.85 (br s, 1H, N-H,
rotamer A), 6.19 (br s, 1H, N-H, rotamer B),
6.50–6.70 (m, 2H, Harom), 6.85–7.00 (m, 2H,
Harom), 7.46 (br s, 1H, N-H, rotamer A), 8.26 (br
s, 1H, N-H, rotamer B)a
19.7, 21.1, 21.3, 164 (M+, 90), 121 (64),
113.1, 114.2,
130.2, 130.4,
130.9, 145.5,
146.2, 171.2,
177.9a
122 (100), 121 (91),
107 (27), 106 (62),
91 (30), 77 (32), 65
(13), 43 (18)
aSolvent:CDCl3.
bSolvent: DMSO-d6.
The GC–MS analysis of the intact reaction mixtures, after
removal of excess acid, showed that the 1,1-isomer was usu-
ally present in small concentrations (<5%). In the course of
the GC analyses we observed that 1-acyl-2-arylhydrazines
(1) isomerized extensively to the 1,1-isomer when they were
injected using CH2Cl2 as solvent. We assumed that this was
the result of the formation of HCl in the injector, kept at
250°C, which catalyzed the 1,2-migration of the acyl group.
We submitted the 1-acyl-2-arylhydrazines 1b–f to
reductive alkylation using an excess of either the same (R1 =
R2, eq. [2]), or different (R1 ≠ R2, eq. [2]) carboxylic acids
and NaBH4.
CH2R2
N
O
O
NaBH4
NH
[2]
+
R2COOH
NH
R1
NH
R1
R
2
3
1
R
© 1998 NRC Canada

Verardo et al.
1183
Table 3. Physical data of 1-acyl-2-alkyl-2-aryl-hydrazines (3).
observation made by Gribble et al. (1). The proposed mecha-
nism turned out to be correct when we tested the reaction
between 1-acyl-2-phenylhydrazine (1b) and butanal in the
presence of NaBH4 (21) (see experimental part). The reac-
tion afforded 1-acyl-2-butyl-2-phenylhydrazine (3d) in 50%
yield together with some unreacted 1-acyl-2-phenyl-
hydrazine.
The reductive alkylation of 1-aryl-2-acylhydrazines with
carboxylic acids and NaBH4 is a valid alternative method to
the usual reductive alkylation with carbonyl compounds due
to the high yields and easy procedure. The reaction implied
the use of few and readily available reagents. The carboxylic
acid plays the role of solvent, acylating agent, source of en-
tering alkyl group, modifier of NaBH4 reactivity, and acid
catalyst.
When we applied our procedure of reductive alkylation
with carboxylic acids and NaBH4 to phenylhydrazine hydro-
chloride, after neutralization with the minimum amount of
10% aqueous NaOH, we observed the formation of the cor-
responding 1-acyl-2-phenylhydrazine only, but no formation
of the alkylated product. This result was consistent with de-
composition of acyloxyborohydride species in the presence
of water as reported in literature (22).
Moreover, NaBH4 is a mild and selective reagent. The
GC–MS analysis revealed that neither any amide was re-
duced nor N—N bond was cleaved by NaBH4. Even in 6 M
H2SO4 at 80°C, sodium borohydride left 1-acetyl-2-butyl-2-
phenylhydrazine (3d) unchanged; only some 2-butyl-2-
phenylhydrazine was detected as the usual hydrolysis prod-
uct obtainable under acidic conditions.
Compounda
R
H
H
H
H
H
H
H
R1
R2
H
Me
Et
Pr
H
Et
Pr
Me
Me
Yieldb
15%
76%
77%
80%
20%
76%
70%
67%
71%
mp (°C)c
94d
87
93
94
80
72
90e
144f
100
3a
3b
3c
3d
3e
3f
3g
3h
3i
Me
Me
Me
Me
Et
Et
Pr
Me
Me
NO2
Me
aAll solid compounds were analyzed for C, H, and N, and results
agreed to ±0.5% of theoretical values.
bYield of isolated product.
cMidpoint of narrow range.
dLiterature (8) 94°C.
eRecrystallized at –20°C.
fLiterature (11) 144°C.
In the former case the reaction can be easily carried out in
a stepwise, one-pot procedure. The synthetic route reported
herein promised to be an easy way to obtain monoalkylated
arylhydrazides compared to previously described methods,
mostly affording fair yields of impure products (14–18).
Most of the alkylated products (3), prepared and character-
ized herein, were never synthesized before. The results are
summarized in Table 3, and the spectroscopic and MS prop-
erties are collected in Table 4.
The structural identification of products 3a–i were based
both on chemical degradation and spectroscopic investiga-
tions. It was reported that treatment of azo compounds with
Zn in aqueous HCl effected the reductive cleavage of the
NN double bond (19). It is reasonable to conclude that the
conversion went through the intermediacy of hydrazines. We
applied this treatment to 3b and 3d and obtained N-ethyl and
N-butylaniline, respectively, as the only aromatic amines, as
While the reductive alkylation of N-acyl-N′-arylhydrazines
was applicable to 1b–f, the only exception was 1a, which re-
sisted N′-ethylation by acetic acid – NaBH4 under the stan-
dard condition.
1
determined by GC–MS analysis. The H NMR spectra of 3b
Phenylhydrazine hydrochloride, (4-methylphenyl)hydrazine
hydrochloride, phenylhydrazine, (4-nitrophenyl)hydrazine,
and NaBH4 pellets were purchased from Aldrich, Italy, Mi-
lan. Solvents were used as received. The GC–MS analyses
were performed with a Fisons Trio 2000 mass spectrometer,
working in the positive ion 70 eV electron impact mode.
Spectra were recorded in the range 35–500 u. Injector tem-
perature was kept at 250°C, and the column (Supelco
SPBTM-5, 30 m long, 0.32 mm i.d.) temperature was pro-
grammed from 60 to 300°C with a gradient of 10°C/min.
The GC analyses performed, keeping the injector at 250°C
on pure 1-acyl-2-arylhydrazines (1), showed, at times, the
formation of isomeric 1-acyl-1-arylhydrazines; the reaction
was relevant when very dilute CH2Cl2 solutions were used,
but did not occur with other solvents. The IR spectra were
and 3d showed two relatively sharp singlets each at 7.66,
8.32 ppm and 7.50, 8.10 ppm, respectively, in CDCl3 for the
E and Z amide hydrogens. This assignment turned out to be
correct upon comparison with the range for this proton in
the spectra of 1a–f (7.03–7.46 ppm and 7.50–8.26 ppm in
CDCl3). The 13C NMR spectra were consistent with the data
obtained from the proton spectra. As expected, the IR spec-
tra for 3b and 3d showed single NH bands. The common
features in the mass spectra of 3b and 3d are illustrated in
Scheme 1. The outlined patterns of fragmentations were
found in all other N-alkyl arylhydrazides 3a, c, e–i. Analo-
1
gously, the H and 13C NMR spectra of these compounds re-
peated quite consistently the features outlined above for 3b
and 3d.
A likely mechanism of the reductive alkylation of 1-acyl-
2-arylhydrazines 1 with the carboxylic acids 2 implies the
reduction of 2 to aldehydes 4 by the action of some
borohydride species formed in solution (20) and subsequent
condensation of aldehydes with 1 to an easily reducible
iminium ion 5 (Scheme 2). This rationale is consistent with
the formation of traces of ethanal-phenylhydrazone from the
reaction of phenylhydrazine with acetic acid and NaBH4
(see footnote 2) as detected by GC–MS and confirmed the
obtained
with
a
Nicolet
FT-IR
Magna
550
spectrophotometer using KBr technique for solids in the
range 4000–400 cm–1. The H and 13C NMR spectra were
1
recorded in CDCl3 or DMSO-d6 at room temperature on a
Bruker AC-F 200 spectrometer at 200 and 50 MHz, respec-
tively. The NMR peak locations are reported as δ-values
from TMS (1H NMR) and the central peak of CDCl3 or
DMSO-d6 (13C NMR). Some H multiplets are characterized
1
by the term app (apparent): this refers only to their
© 1998 NRC Canada

1184
Can. J. Chem. Vol. 76, 1998
Table 4. Spectroscopic and MS data of 1-acyl-2-alkyl-2-arylhydrazines (3).
Product IR (KBr) ν (cm–1)
1H NMR δ, J (Hz)
13C NMR δ
MS (70 eV) m/z (%)
3a
3256 vs, 3019 s, 2880 1.93 (s, 3H, CH3, rotamer A), 2.01 (s, 3H,
18.9, 20.8, 40.5,
41.9, 112.9, 113.2,
119.5, 120.5,
164 (M+, 42), 122 (45),
121 (100), 107 (33),
106 (19), 105 (60), 104
(12), 93 (8), 92 (33),
78 (9), 77 (60), 65 (8),
51 (16), 43 (16)
m, 2808 m, 1675
vs, 1605 vs, 1530
vs, 1504 vs, 1377 s,
1281 vs, 1220 s,
1120 s, 1038 s, 756
vs, 694 vs
CH3, rotamer B), 3.03 (s, 3H, N-CH3,
rotamer A), 3.08 (s, 3H, N-CH3, rotamer B),
6.65–6.95 (m, 3H, Harom), 7.13–7.31 (m, 3H,
2Harom + N-H, rotamer A), 8.05 (br s, 1H,
N-H, rotamer B)a
128.9, 129.2,
149.1, 149.2,
169.2, 176.9a
3b
3263 vs, 3032 m, 2986 1.05–1.22 (m, 3H, CH3), 1.94 (s, 3H, CH3,
11.8, 12.4, 20.3,
21.8, 47.3, 49.8,
114.3, 115.2,
120.4, 121.7,
130.1, 130.5,
149.6, 149.9,
170.9, 177.9a
178 (M+, 44), 136 (21),
135 (85), 121 (51), 120
(15), 119 (100), 107
(91), 105 (10), 104
(24), 79 (11), 78 (12),
77 (96), 51 (24), 43
(22)
m, 2940 m, 2861 m,
1683 vs, 1598 vs,
1551 s, 1499 vs,
1387 vs, 1295 s,
1269 s, 1144 m,
1045 m, 755 vs, 702
vs
rotamer A), 1.98 (s, 3H, CH3, rotamer B),
3.33–3.55 (m, 2H, N-CH2), 6.70–6.95 (m,
3H, Harom), 7.10–7.35 (m, 2H, Harom), 7.66
(br s, 1H, N-H, rotamer A), 8.32 (br s, 1H,
N-H, rotamer B)a
3c
3270 vs, 3030 m, 2964 0.95 (t, 3H, CH3, J = 7.4, rotamer A), 0.97 (t,
11.3, 19.0, 19.1,
19.7, 20.9, 54.0,
56.6, 112.9, 113.7,
119.4, 120.5,
192 (M+, 43), 163 (13),
150 (8), 149 (33), 134
(12), 133 (75), 132
(30), 122 (11), 121
(100), 108 (7), 107
(54), 106 (25), 105
(14), 104 (36), 91 (10),
79 (9), 78 (10), 77
(68), 51 (14), 43 (30),
41 (11)
s, 2935 s, 2880 m,
1665 vs, 1600
3H, CH3, J = 7.4, rotamer B), 1.55–1.70 (m,
2H, CH2), 2.01 (s, 3H, CH3, rotamer A),
2.03 (s, 3H, CH3, rotamer B), 3.32–3.47 (m,
2H, N-CH2), 6.75–6.92 (m, 3H, Harom),
7.21–7.35 (m, 3H, 2Harom + N-H)a
vs,1532 vs, 1500 vs,
1370 vs, 1288 vs,
1236 m, 1194 m,
1140 m, 1045 m,
756 vs, 670 vs
129.1, 129.3,
148.5, 148.9,
169.2, 176.4a
3d
3235 s, 3035 m, 2964
m, 2923 m, 1654
vs, 1602 s, 1542 vs,
1496 vs, 1458 s,
1374 s, 1291 s,
1219 m, 994 m, 746
s
0.91–1.00 (m, 3H, CH3), 1.25–1.45 (m, 2H,
CH2, rotamer A), 1.47–1.63 (m, 2H, CH2,
rotamer B), 1.97 (s, 3H, CH3, rotamer A),
2.00 (s, 3H, CH3, rotamer B), 3.35–3.45 (m,
2H, N-CH2), 6.72–6.95 (m, 3H, Harom),
7.15–7.45 (m, 2H, Harom), 7.50 (br s, 1H, N-
H, rotamer A), 8.10 (br s, 1H, N-H, rotamer
B)a
13.8, 13.8, 19.1,
20.1, 20.6, 20.7,
27.7, 28.4, 51.9,
54.6, 112.8, 113.7,
119.1, 120.4,
206 (M+, 19), 163 (17),
132 (15), 122 (10), 121
(100), 120 (15), 119
(55), 118 (10), 107
(24), 106 (33), 105
(12), 104 (27), 91 (10),
78 (10), 77 (65), 51
(14), 43 (20), 41 (18)
178 (M+, 38), 122 (70),
121 (100), 107 (43),
106 (32), 105 (63), 104
(23), 93 (9), 92 (26),
79 (10), 78 (14), 77
(71), 65 (8), 52 (8), 51
(22), 39 (8)
206 (M+, 24), 150 (12),
149 (30), 133 (68), 122
(10), 121 (100), 120
(16), 107 (40), 106
(43), 105 (12), 104
(32), 91 (11), 78 (12),
77 (74), 57 (9), 51
(15), 43 (15), 41 (12)
234 (M+, 16), 191 (10),
164 (19), 147 (10), 132
(13), 122 (9), 121
129.0, 129.2,
148.5, 148.9,
169.4, 176.4a
3e
3f
3256 s, 3052 m, 2992
m, 1675 vs, 1616
vs, 1543 s, 1510 vs,
1346 s, 1273 s,
1194 m, 1128 m,
766 s, 707 s
1.05–1.25 (m, 3H, CH3), 2.30 (q, 2H, CH2, J = 8.5, 9., 24.4, 27.4,
7.5, rotamer A), 2.41 (q, 2H, CH2, J = 7.5,
rotamer B), 3.10 (s, 3H, N-CH3, rotamer A),
3.11 (s, 3H, N-CH3, rotamer B), 6.70–6.95
(m, 3H, Harom), 7.05 (br s, 1H, N-H, rotamer
A), 7.15–7.40 (m, 2H, Harom), 7.95 (br s,
1H, N-H, rotamer B)a
0.93 (t, 3H, CH3, J = 7.4, rotamer A), 0.94 (t,
3H, CH3, J = 7.4, rotamer B), 1.06 (t, 3H,
CH3, J = 7.4, rotamer A), 1.18 (t, 3H, CH3,
J = 7.4, rotamer B), 1.52–1.70 (m, 2H,
CH2), 2.13–2.43 (m, 2H, CH2), 3.20–3.45
(m, 2H, N-CH2), 6.73–6.95 (m, 3H, Harom),
7.10–7.30 (m, 3H, 2Harom + N-H, rotamer
A), 7.70 (br s, 1H, N-H, rotamer B)a
40.6, 42.2, 112.8,
113.2, 119.5,
120.5, 129.0,
129.3, 149.3,
149.5, 172.9,
179.0a
3210 s, 3040 s, 2980
s, 2887 m, 1675 vs,
1602 vs, 1504 vs,
1471 vs, 1379 s,
1240 s, 1194 s,
8.4, 9.7, 11.3, 11.4,
18.9, 19.8, 24.3,
27.4, 54.0, 56.7,
112.8, 113.7,
119.1, 120.4,
129.0, 129.3,
1148 m, 930 m, 753
vs, 687 s
148.7, 150.0,
172.9, 179.3a
13.8, 17.7, 19.0,
20.1, 27.5, 28.5,
32.8, 36.0, 51.9,
54.7, 112.8, 113.8,
119.0, 120.4,
3g
3243 s, 3045 m, 2973
s, 2947 s, 2887 s,
1675 vs, 1609 vs,
1550 s, 1510 vs,
1458 s, 1379 s,
1300 m, 1227 m,
1150 m, 1100 m,
977 m, 750 vs
0.80–1.00 (m, 6H, CH3), 1.20–1.80 (m, 6H,
CH3), 2.05–2.35 (m, 2H, CH2), 3.25–3.45
(m, 2H, N-CH2), 6.65–6–95 (m, 3H, Harom),
7.05–7.30 (m, 3H, Harom + N-H, rotamer A),
8.00 (br s, 1H, N-H, rotamer B)a
(100), 120 (10), 119
(47), 107 (12), 106
(27), 104 (11), 77 (32),
43 (10), 41 (12)
128.9, 129.3,
148.7, 149.0,
172.3, 178.6a
© 1998 NRC Canada

Verardo et al.
1185
Table 4 (concluded).
Product IR (KBr) ν (cm–1)
1H NMR δ, J (Hz)
13C NMR δ
MS (70 eV) m/z (%)
3h
3270 s, 3091 m, 2990
m, 2947 m, 1682
vs, 1590 vs, 1504
vs, 1326 vs, 1280
vs, 1201 s, 1128 vs,
825 s, 746 s, 687 s
1.16 (app t, 3H, CH3, J = 7.0), 1.96 (s, 3H,
CH3, rotamer A), 1.99 (s, 3H, CH3, rotamer
B), 3.50–3.78 (m, 2H, N-CH2), 6.76 (app d,
2H, Harom, J = 9.3, rotamer A), 6.84 (app d,
2H, Harom, J = 9.5), 10.4 (br s, 1H,N-H)b
11.4, 20.3, 45.9,
110.4, 110.6,
125.6, 137.3,
137.8, 153.4,
154.8, 168.4,
169.0b
11.2, 11.7, 19.8,
20.8, 21.3, 47.0,
49.5, 114.2, 114.9,
129.4, 130.1,
130.4, 130.7,
146.9, 147.1,
170.2, 177.2a
223 (M+, 15), 181 (35),
180 (30), 166 (62), 164
(100), 152 (46), 149
(11), 134 (22), 122
(11), 121 (11), 106
(13), 77 (11), 43 (20)
192 (62), 150 (20), 149
(100), 135 (40), 134
(17), 133 (98), 121
(92), 120 (20), 118
(28), 91 (81), 77 (41),
65 (20), 43 (18)
3i
3197 m, 3086 m, 2987 1.05 (t, 3H, CH3, J = 7.1, rotamer A), 1.06 (t,
s, 2931 s, 1695 vs,
1616 vs, 1520 vs,
1403 vs, 1340 vs,
1256 vs, 1194 s,
1137 m, 1083 s,
1026 m, 822 vs, 762
s
3H, CH3, J = 7.1, rotamer B), 1.89 (s, 3H,
CH3, rotamer A), 1.91 (s, 3H, CH3, rotamer
B), 2.10 (s, 3H, CH3, rotamer A), 2.15 (s,
3H, CH3, rotamer B), 3.25–3.40 (m, 2H, N-
CH2), 6.55–6.75 (m, 2H, Harom), 6.85–7.00
(m, 2H, Harom), 7.45 (br s, 1H, N-H, rotamer
A), 8.05 (br s, 1H, N-H, rotamer B)a
aSolvent: CDCl3.
bSolvent: DMSO-d6.
Scheme 1.
appearance and may be an oversimplification. Elemental
analysis were performed with a Carlo Erba Mod. 1106 ele-
mental analyzer.
Preparation of 1-formyl-2-phenylhydrazine (1a)
1-Formyl-2-phenylhydrazine (1a) was prepared as de-
scribed procedure (9) by heating
a
mixture of
© 1998 NRC Canada

1186
Can. J. Chem. Vol. 76, 1998
Scheme 2.
phenylhydrazine (5 mL, 46 mmol) and 50% HCOOH
(18 mL, 240 mmol) at 120°C for 15 min. After the mixture
was allowed to stand at rt, crystals of product precipitated;
the resulting solid was recrystallized from EtOH and hexane.
phenylhydrazine (3), 400 mmol of HCOOH, and 70 mmol of
NaBH4 (pellets). In the case of 3a, twice crystallization from
hot Et2O was necessary to purify the desired product impure
of 1-acetyl-2-formyl-2-phenylhydrazine.
In the case of 3e, the reaction mixture containing 30% of
unreacted reagent, was isolated in neutral form as explained
in Procedure A and treated again with HCOOH and NaBH4.
At the end of reaction GC–MS analysis revealed the pres-
ence of product 3e and a trace of unreacted 1c. The reaction
mixture was treated as in Procedure A. The physical and
spectroscopic data of 3a and 3e are reported in Tables 3 and
4.
Preparation of 1-acyl-2-arylhydrazines (1b–e)
The arylhydrazine (30 mmol) was added at rt to the ap-
propriate carboxylic acid (2, 750 mmol), and the resulting
mixture was stirred at 80°C for 1.5 h. Most of the acid was
distilled off; the warm residue was treated with Et2O or hex-
ane and the crystals of the desired products 1b–e precipi-
tated. The products were further purified by recrystallization
from hexane and the minimum amount of EtOH. Their phys-
ical and spectroscopic data are collected in Tables 1 and 2.
Procedure B
One-pot preparation of 1-acetyl-2-ethyl-2-(4-methyl-
phenyl)hydrazine (3i). Preparation of 1-acetyl-2-(4-
methylphenyl)hydrazine (1f)
(4-Methylphenyl)hydrazine hydrochloride (2.1 g, 13 mmol)
was heated at 80°C for 15 h in acetic acid (20 mL,
320 mmol) with sodium acetate (1.1 g, 14 mmol) to allow
the formation of 1-acetyl-2-(4-methylphenyl)hydrazine (1f),
as revealed by GC–MS. The temperature was allowed to de-
crease to 60°C when NaBH4 pellets (2.2 g, 58 mmol) were
added portionwise. After all pellets were dissolved, GC–MS
Procedure A
Preparation of 1-acyl-2-alkyl-2-arylhydrazines (3b–d, 3f–i)
Sodium borohydride (pellets, 1.5 g, 40 mmol) was added
portionwise to a mixture of 1-acyl-2-phenylhydrazine (1,
13 mmol) in carboxylic acid (2, 200 mmol) at ca. 60°C un-
der vigorous stirring. The reaction usually required about 1 h
for completion and could be considered completed soon af-
ter the sodium borohydride pellets were completely dis-
solved. The solvent was then partly distilled off under
reduced pressure and, after neutralization of the residue with
NaOH–Na2CO3 solution at ca. 0°C, the product was ex-
tracted with CH2Cl2 (20 mL × 5). Whenever after addition
of NaBH4 a too dense mixture resulted, distillation of the
analysis
revealed
1-acetyl-2-ethyl-2-(4-methylphenyl)-
hydrazine (3i) as the sole volatile product. The reaction mix-
ture was treated as described in Procedure A. Procedure B
was repeated, obviously without the addition of NaBH4, in
order to obtain 1-acetyl-2-(4-methylphenyl)hydrazine (1f); it
was recrystallized from EtOH and hexane. The physical and
spectroscopic data of 1f are reported in Tables 1 and 2 and
3i in Tables 3 and 4.
solvent was avoided and only
a
treatment with
NaOH–Na2CO3 solution followed by CH2Cl2 extraction was
performed. After the combined organic extracts were dried
(Na2SO4) and the solvent was removed under reduced pres-
sure, the product was crystallized from hexane by the addi-
tion of the minimum amount of EtOH. The physical and
spectroscopic data of 3 are shown in Tables 3 and 4.
Reductive alkylation of 1-acyl-2-phenylhydrazine (1b) with
butanal and NaBH4
A solution of aqueous 3 M H2SO4 (1.4 mL, 0.46 mmol)
and butanal (0.18 mL, 2 mmol) in THF (3 mL) was slowly
added to an open vessel containing a solution of 1-acetyl-2-
phenylhydrazine (1b, 0.2 g, 1.33 mmol) in THF (10 mL) and
MeOH (1.3 mL), while NaBH4 pellets (0.17 g, 4.5 mmol)
were added portionwise at 0°C (±5°C) under magnetic
Preparation of 1-acyl-2-methyl-2-phenylhydrazine (3a, 3e)
Procedure A was followed except that warming was pre-
vented, keeping the temperature at 0–5°C, and that the
amounts of reagents used were 13 mmol of 1-acyl-2-
© 1998 NRC Canada

Verardo et al.
1187
2. A.F. Hegarty. In The chemistry of the hydrazo, azo and azoxy
groups. Edited by S. Patai. John Wiley & Sons, London, New
York, Sydney, and Toronto. 1975. pp. 647–651.
3. J.W. Timberlake and J.C. Stowell. In The chemistry of the
hydrazo, azo and azoxy groups. Edited by S. Patai. John Wiley
& Sons, London, New York, Sydney, and Toronto. 1975.
pp. 69–79.
stirring. The mixture was stirred for an additional hour at rt,
diluted with H2O, made strongly alkaline with NaOH (cool-
ing), and extracted with CH2Cl2. After solvents were dis-
tilled off, 1-acetyl-2-butyl-2-phenylhydrazine (3d, 40%
yield) and 1-acetyl-2-phenylhydrazine (1b, 43% yield) were
separated by crystallization from Et2O.
4. A. Go, M. Ito, K. Endo, and H. Mukoda. Japanese patent JP
04005282 A2 920109 (C.A. 116, 168361, 1992).
5. G. Winters and N. Di Mola. German patent DE
2442667 750313 (C.A. 83, 28096, 1975).
6. Zh.V. Molodykh, B.I. Buzykin, M.A. Kudrina, L.P. Sysoeva,
N.G. Gazetdinova, I.D. Neklesova, and Yu.P. Kitaev. Khim.-
Farm. Zh. 14, 33 (1980) (C.A. 93, 94943, 1980).
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Hyg. Abt. 1: Orig. Reihe A, 232, 119 (1975) (C.A. 83, 72591,
1975).
Reductive cleavage of 1-acetyl-2-ethyl-2-phenylhydrazine
(3b) and of 1-acetyl-2-butyl-2-phenylhydrazine (3d)
Treatment of 0.22 mmol of either 1-acetyl-2-ethyl-2-
phenylhydrazine
(3b)
or
of
1-acetyl-2-butyl-2-
phenylhydrazine (3d) in 37% HCl (3 mL) with Zn dust
(0.6 g, 9.2 mmol) at 70°C for ca. 16 h gave N-ethylaniline
and N-butylaniline, respectively, as the sole GC–MS prod-
ucts. The original products were completely transformed.
Mass spectra of 1-acyl-1-arylhydrazines
8. Y. Usui and C. Matsumura. Yakugaku Zasshi, 87, 43 (1967)
(C.A. 67, 32382, 1967).
9. E. Müller. In Methoden der organischen chemie. Vol. 10/2.
Edited by Houben-Weyl. George Verlag, Stuttgart. 1967.
pp. 355–357.
10. M.J. Hearn and J.E. Grimwade. Org. Prep. Proced. Int. 12, 249
(1980).
11. M.J. Kornet, T.T. Tita, and A.P. Thio. Synth. Commun. 16,
1261 (1986).
12. B.C. Challis and J.A. Challis. In Comprehensive organic
chemistry. Vol. 2. Edited by I.O. Sutherland. Pergamon Press,
Oxford, New York, Toronto, Sydney, Paris, and Frankfurt.
1979. p. 1047.
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(1952).
15. D.H.R. Barton and E. Doris. Tetrahedron Lett. 37, 3295
(1996).
1-Formyl-1-phenylhydrazine (1a′), MS, m/z: 136 (M+, 16),
107 (11), 106 (13), 105 (80), 93 (26), 92 (8), 91 (8), 78 (20),
77 (100), 66 (7), 51 (19), 39 (7); 1-acetyl-1-phenylhydrazine
(1b′), MS, m/z: 150 (M+, 10), 108 (18), 107 (7), 105 (49), 93
(18), 92 (6), 78 (13), 77 (64), 51 (23), 43 (100); 1-propionyl-
1-phenylhydrazine (1c′), MS, m/z: 164 (M+, 4), 119 (5), 108
(10), 105 (53), 93 (25), 78 (41), 77 (100), 66 (10), 57 (93),
52 (14), 51 (39), 50 (16), 39 (11); 1-butyril-1-
phenylhydrazine (1d′), MS, m/z: 178 (M+, 7), 108 (21), 105
(26), 93 (27), 78 (18), 77 (68), 71 (89), 66 (9), 51 (25), 43
(100), 41 (77), 39 (21); 1-acetyl-1-(4-nitrophenyl)hydrazine
(1e′), MS, m/z: 195 (M+, 6), 153 (20), 123 (4), 122 (6), 76
(13), 74 (6), 50 (14), 43 (100), 41 (12); 1-acetyl-1-(4-
methylphenyl)hydrazine (1f′), MS, m/z: 164 (M+, 10), 122
(13), 119 (96), 107 (9), 106 (15), 92 (13), 91 (100), 77 (8),
65 (25), 43 (99).
16. V.N. Barinova, V.G. Voronin, V.P. Zhestkov, and Yu.N.
Portnov. Zh. Org. Khim. 20, 1765 (1984).
17. G. Barattini. Gazz. Chim. Ital. 58, 821 (1926).
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chemistry. Vol. 2. Edited by I.O. Sutherland. Pergamon Press,
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1979. pp. 1051–1052.
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New York, Chichester, Brisbane, Toronto, and Singapore.
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Financial support was obtained from the Italian National
Research Council (95.01044.CT03, 96.027420.CT03 to
AGG) and Italian Ministry of University, Sciences and Tech-
nology (MURST 40% and 60% 1993–95 to AGG, MURST
60% 1994–96, and MURST 40% 1995 to GV). The authors
1
are grateful to Dr. P. Martinuzzi for recording H and 13C
NMR spectra and Mr. P. Padovani for expert instrumental
maintenance.
20. P. Marchini, G. Liso, A. Reho, F. Liberatore, and F.M.
Moracci. J. Org. Chem. 40, 3453 (1975).
21. G. Verardo, A.G. Giumanini, P. Strazzolini, and M. Poiana.
Synthesis, 121 (1993).
22. G.W. Gribble and C.F. Nutaitis. Org. Prep. Proced. Int. 17, 317
(1985).
1. G.W. Gribble, P.D. Lord, J. Skotnicki, S.E. Dietz, J.T.J. Eaton,
and J.L. Johnson. J. Am. Chem. Soc. 96, 7812 (1974).
© 1998 NRC Canada