2934
J . Org. Chem. 1996, 61, 2934-2935
Sch em e 1
1,1,1-Tr im eth ylh yd r a zin iu m Iod id e: A
Novel, High ly Rea ctive Rea gen t for
Ar om a tic Am in a tion via Vica r iou s
Nu cleop h ilic Su bstitu tion of Hyd r ogen
Philip F. Pagoria,* Alexander R. Mitchell, and
Robert D. Schmidt
Lawrence Livermore National Laboratory, Mail Stop L-282,
P.O. Box 808, Livermore, California 94551
Received December 22, 1995
Vicarious nucleophilic substitution (VNS) of hydrogen
is a well-established procedure for the introduction of
carbon nucleophiles into electrophilic aromatic rings.1,2
The reaction involves the addition of a carbanion bearing
a leaving group (X) to an electrophilic aromatic ring and
subsequent rearomatization by loss of the leaving group
through elimination as HX (Scheme 1, Z ) CH2). This
reaction has been applied to a wide variety of nitroarenes
and nitro-substituted heterocycles.2
Sch em e 2
Ta ble 1. Am in a tion of 3-Su bstitu ted Nitr oben zen es w ith
TMHI
By analogy, VNS reactions can also take place with
amine nucleophiles. Such reagents are of the common
form XNH2, where X is an auxiliary group capable of
stabilizing a negative charge and of being eliminated as
HX, thus driving rearomatization of the σ-intermediate
adduct (Scheme 1, Z ) NH). Meisenheimer and Patzig3
reported in 1906 that 1,3-dinitrobenzene reacts with
hydroxylamine in the presence of strong base to yield 2,4-
dinitrophenylene-1,3-diamine, one of the first examples
of amination by VNS of hydrogen. In more recent years,
a number of reagents (including 4-amino-1,2,4-triazole4
and substituted sulfenamides5 ) have been developed
which facilitate the amination of nitroaromatic com-
pounds by VNS of hydrogen under mild conditions.
These reagents have proven to give regioselective ami-
nation under mild conditions in fair to high yields.
These results prompted us to investigate the use of
1,1,1-trimethylhydrazinium iodide (TMHI)6 (1) as a VNS
reagent for the introduction of amino groups into ni-
troaromatic substrates. We reasoned that TMHI (or its
corresponding ylide, which may be produced upon reac-
tion with strong base) should be sufficiently nucleophilic
to attack nitro-substituted aromatic rings, with the
neutral trimethylamine serving as an efficient leaving
group. We have found that when TMHI reacts with
various nitroarenes, the amino functionality is introduced
in good to excellent yields.
isomer ratios
compd
R
% yield
a
b
c
2
3
4
5
6
7
8
9
H
85
84
82
95
66
84
76
41
61
38
32
0
90
45
45
20
39
35
49
71
10
47
38
44
na
27
19
29
0
8
17
36
CH3
Cl
COOH
OCH3
F
I
CN
Methyl iodide reacts with 1,1-dimethylhydrazine in THF
at room temperature to give the desired 1,1,1-trimeth-
ylhydrazinium iodide (1) as white plates, mp 233-235
°C, in 81% yield after recrystallization from 95% EtOH
(Scheme 2). The solid is stable at room temperature for
at least several months in the absence of moisture.
The efficacy of TMHI as a VNS aminating agent was
tested by reaction with a variety of nitroarenes, including
the 3-substituted nitroarenes used by Katritzky and
Laurenzo in their study of 4-amino-1,2,4-triazole.4a In
general, the reaction was conducted as follows: TMHI
was dissolved in a solution of the nitroaromatic substrate
in dry DMSO. Solid alkoxide base (potassium tert-
butoxide or sodium methoxide) was then added in one
portion with stirring, after which the solution turned
deep red and the odor of trimethylamine was noted.
After 4-17 h of stirring at room temperature, the
reaction was quenched with 10% HCl. Precipitated solids
were collected by suction filtration. The remaining
solution was extracted with ethyl acetate, and the
products were isolated by silica gel chromatography (9:1
petroleum ether/acetone). As all the products in this
study are known compounds, their identity was con-
The preparation of quaternized hydrazine halides,
including TMHI, has been previously reported.6-9 These
compounds can be prepared by reaction of 1,1-disubsti-
tuted hydrazine with an alkyl halide, the alkylation
generally occurring at the more substituted nitrogen.7
(1) Makosza, M.; Winiarski, J . Acc. Chem. Res. 1987, 20, 282.
(2) Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C.
Nucleophilic Aromatic Substitution of Hydrogen; Academic: San Diego,
1994; pp 59-66.
(3) Meisenheimer, J .; Patzig, E. Ber. Dtsch. Chem. Ges. 1906, 39,
2533-42.
(4) (a) Katritzky, A. R.; Laurenzo, K. S. J . Org. Chem. 1986, 51,
5039. (b) Katritzky, A. R.; Laurenzo, K. S. J . Org. Chem. 1988, 53,
3978.
(5) Makosza, M.; Bialecki, M. J . Org. Chem. 1992, 57, 4784.
(6) Omietanski, G. M.; Sisler, H. H. J . Am. Chem. Soc. 1956, 78,
1211.
(7) Sisler, H. H.; Omietanski, G. M.; Rudner, B. Chem. Rev. 1957,
57, 1021.
(8) (a) Westphal, O. Ber. Dtsch. Chem. Ges. B 1941, 74, 759. (b)
Westphal, O. Ber. Dtsch. Chem. Ges. B 1941, 74, 1365.
(9) Harries, C.; Haga, T. Ber. Dtsch. Chem. Ges. 1898, 31, 56.
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