Reductive alkylation of nitrobenzene promoted by zinc and tin in protic solvents

Article abstract of DOI:10.1016/S0040-4039(00)00529-3

Barbier-type organometallic reactions of nitrobenzene with organic halides in protic solvents produce directly N,N-dialkylanilines. With allyl bromide, best yields are obtained using zinc in an aqueous monobasic sodium phosphate solution in the presence of cuprous iodide or tin in methanol. The latter procedure is also successful in the case of benzyl bromide and primary alkyl iodides. Control experiments exclude a mechanism of reduction followed by nucleophilic alkylation and show that the reaction is initiated by a nucleophilic attack of the organometallic species on the nitro group. Similar reactions with Grignard reagents under anhydrous conditions are reported to have a completely different outcome. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00529-3

Tetrahedron Letters 41 (2000) 4827±4830
Reductive alkylation of nitrobenzene promoted by zinc
and tin in protic solvents
Lothar W. Bieber,* Rosenildo C. da Costa and Margarete F. da Silva
Departamento de QuõÂmica Fundamental, Universidade Federal de Pernambuco, Cidade UniversitaÂria,
5
0670-901 Recife-PE, Brazil
Received 4 January 2000; revised 29 March 2000; accepted 30 March 2000
Abstract
Barbier-type organometallic reactions of nitrobenzene with organic halides in protic solvents produce
directly N,N-dialkylanilines. With allyl bromide, best yields are obtained using zinc in an aqueous mono-
basic sodium phosphate solution in the presence of cuprous iodide or tin in methanol. The latter procedure
is also successful in the case of benzyl bromide and primary alkyl iodides. Control experiments exclude a
mechanism of reduction followed by nucleophilic alkylation and show that the reaction is initiated by a
nucleophilic attack of the organometallic species on the nitro group. Similar reactions with Grignard
reagents under anhydrous conditions are reported to have a completely di€erent outcome. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: Barbier reactions; alkyl halides; nitro compounds; solvent and solvent e€ects.
In recent years, the in situ addition of organic halides to carbonyl compounds promoted by
various metals in aqueous medium has found increasing applications even for the synthesis of
1
complex molecules. Initially restricted to allylic halides, the methodology has now been extended
2
3
4
5
6
to a-bromo ketones and esters, to propargylic, benzylic, and even saturated halides. In sharp
contrast to this great variability of the organometallic component of the reaction, the electro-
philes used in most cases have been aldehydes and ketones; a few reports deal with carboxylic
7,8
9
derivatives and with electron de®cient alkenes. Some nitrogen containing substrates can also
react in special cases, for example, sulfonimines,10 immonium ions and oximes. In order to
evaluate the synthetic potential of such simple and environmentally clean reactions, we directed
our interest to unconventional, non-carbon electrophiles. Organic nitro compounds possess a
formal positive charge on the nitrogen and therefore should be highly reactive towards nucleo-
philes. However, with few exceptions, their synthetic use remains restricted to reductions leading
to hydroxylamines, amines or several other dimeric intermediates.13
11
12
*
Corresponding author. Tel: (55)81-2718441; fax: (55)81-2718442; e-mail: lothar@dqfex.ufpe.br
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00529-3

4
828
ꢀ1†
In our ®rst attempts, we reacted nitrobenzene (1) with allyl bromide (2a) and zinc dust at room
temperature in a concentrated aqueous solution of monobasic sodium phosphate producing diallyl
aniline (3a) as the main product together with considerable amounts of monoallyl aniline (4a) and
N,O-diallyl-N-phenylhydroxylamine (5a) (Eq. (1), Table 1, entry 1); a trace of aniline was also
detected. Investigating the in¯uence of di€erent metal salts on the reaction, we found that the
addition of cuprous iodide improved the yield of 3a and reduced the relative amounts of 4a and 5a
signi®cantly (entry 2). Still better yields of 3a were produced with tin powder in water:methanol,
3
:1 (entry 3); this reaction was much slower, but no 5a at all was formed. Finally, the best results
were obtained with tin in pure, undried methanol: 3a was produced in 90% yield with 6% of the
monoalkylated 4a as the only side product (entry 4). More importantly, the same procedure was
also successful with benzyl bromide and, in moderate yields, even with methyl and ethyl iodide
(entries 5 to 7). The possibility of reduction of 1 prior to alkylation could be excluded on the basis
of the following control experiments:
(
(
(
i) Nitrobenzene alone was readily reduced to aniline by zinc in monobasic phosphate
solution, but was nearly unreactive in the presence of tin in methanol; only traces of
aniline were detected after 20 h.
ii) The possible reduced intermediates nitrosobenzene, phenylhydroxylamine, azoxy-
benzene and aniline produced only a few percent of both 3 and 4 with zinc and only
traces with tin under standard conditions.
iii) Similar trace amounts of allylated anilines were observed, when allyl bromide was
reacted ®rst with tin in water (20 h) and then nitrobenzene or aniline was added; a
second amount of halide 2a, added at this stage, which would enable S -type alkylations,
N
had no e€ect.
Table 1
Reductive alkylation of nitrobenzenea

4
829
Based on these results, we conclude that the reduction/alkylation process can account only for a
small part of 3 and 4 and the main reaction seems to proceed via nucleophilic additions of organo-
metallic intermediates to the highly electron de®cient nitrogen. A possible mechanism is proposed
in Scheme 1.
Scheme 1. Proposed mechanism for reductive alkylation of nitrobenzene
In the ®rst step, an organometallic species formed in situ attacks the nitro group and produces
the intermediate 6 already postulated by Bartoli for the analogous reaction under anhydrous
conditions.1
4,15
In protic solvent, 6 can eliminate water to the oxoammonium ion 7. Oxoammonium
salts are highly electrophilic and some stable representatives have been used as oxidizing
reagents.16 In protic medium, they are expected to exist in equilibrium with the corresponding
17
nitrones 8. In fact, compounds of type 8 have been isolated in good yield after aqueous work-up,
15
when nitroarenes were reacted with crotyl magnesium chloride in THF. Under our conditions, a
second attack of organometallic reagent on 7 leads to the N-oxide 9 which is readily reduced to
the ®nal product 3.18 The formation of the intermediates 7 and 9 must be very fast to explain the
high yield of 3. A concurrent reduction, however, may lead to some hydroxylamine 10 and then
to the monoalkyl aniline 4; the latter two products have been isolated on reductive work-up of the
14
anhydrous reaction. Alternatively, 10 can be alkylated on the oxygen atom by excess of halide 2
to produce 5. Indeed, when we reacted phenylhydroxylamine with allyl bromide in the presence of
2
+
Zn ions, but in the absence of metallic zinc, we isolated high yields of 5 even in monobasic
phosphate solution (pH ꢁ4). Furthermore, an analoguous reaction has been observed on electrolysis
of 1 in the presence of n-butyl iodide in DMF.19
We obtained further support for the intermediates 7 and 8 by the reaction of the easily accessible
nitrone 8b (R=Ph)17 with benzyl bromide and tin under the conditions of entry 5 (Table 1) 25%
yield of 3 was produced as the main product. As the heterogeneous reaction of the halide 2b with
tin is rather slow, several side products due to solvolysis or reduction were also observed (benz-
aldehyde, its dimethyl acetal, azobenzene, benzyl and benzylidene aniline).
In conclusion, the mechanism presented here corresponds in the ®rst steps to that proposed by
On the other hand, the same
Bartoli for the reaction of allylic Grignard reagents in THF.1
4,15
author observed a completely di€erent behaviour with benzylic and primary alkylic Grignard

4
830
reagents; in these cases, the main reaction was a conjugate addition to the ring in ortho- or para-
position leading to ring-substituted nitrosobenzenes after work-up.20 Similarly, organometallic
additions to nitrones in aprotic solvents are known to occur on the carbon atom under aprotic
conditions.1
5,17
On the basis of our observations, we can conclude that the protic medium not
only changes the relative electrophilicity of di€erent positions in the substrate 1 towards the ®rst
attack of certain organometallic reagents, but also enables the following reaction sequence:
transformation to the even more reactive oxoammonium ion 7, second addition of the nucleo-
phile and ®nal reduction to 3. In contrast to the allylation of benzaldehyde, where allyltin(II)
bromide or diallyltin dibromide react under aqueous conditions,21 these preformed reagents
produced only trace amounts of allylated products in the case of 1 and can be excluded as the
reactive intermediates. For this reason, radicals or radical anions have to be considered.
The described transformations represent the ®rst example of Barbier-type reactions with non-
carbon electrophiles in protic media. They provide direct access to N,N-dialkyl anilines starting
from nitrobenzene. Although monoalkylation or introduction of two di€erent substituents is not
yet possible, this procedure may be useful for the preparation of benzyl- or allyl-protected anilines.
More detailed studies on mechanism and scope of this reaction are in progress.
Acknowledgements
Â
This work was supported by CNPq (Brasilia). We thank Ms. Erida M. A. Pequeno for GC/MS
analyses.
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