Microwave-induced organometallic reactions in aqueous media. Use of Ga and Bi for the allylation of aromatic N-oxides and hydrazones

Article abstract of DOI:10.1039/b108525p

Homoallylic hydroxylamines and homoallylic hydrazides were synthesised in excellent yields by the reaction of allylgallium or allylbismuth reagent, generated in situ in the presence of 0.1 equivalent of NH₄Cl-Bu₄NBr, with aldonitrone

Full text of DOI:10.1039/b108525p

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Microwave-induced organometallic reactions in aqueous media.
Use of Ga and Bi for the allylation of aromatic N-oxides
and hydrazones
Dhrubojyoti D. Laskar, Mukut Gohain, Dipak Prajapati* and Jagir S. Sandhu
Department of Organic Chemistry (Drugs), Regional Research Laboratory, Jorhat-785 006,
Assam, India. E-mail: drugs@csir.res.in, drrljt@csir.res.in; Fax: þ91 3763370011
Received (in Montpellier, France) 19th September 2001, Accepted 31st October 2001
First published as an Advance Article on the web
Homoallylic hydroxylamines and homoallylic hydrazides were
synthesised in excellent yields by the reaction of allylgallium
or allylbismuth reagent, generated in situ in the presence of 0.1
equivalent of NH4Cl–Bu4NBr, with aldonitrones and hydrazones
in aqueous media. The reaction rate can be increased dramati-
cally under microwave activation.
Scheme 1
hydrazones 3 in a NH4Cl (or Bu4NBr)–DMF–water system
There has been growing interest in the use of metallic elements1
in aqueous media, as they offer significant advantages over
conventional reactions using dry organic solvents. The devel-
opment of such reactions is of interest because they also offer
the possibility of obtaining environmentally benign reaction
conditions by reducing the burden of organic solvent disposal.2
The study and application of Barbier–Grignard type reactions3
in water is still in its infancy. Since their history is only a
decade old, the full synthetic potential of such reactions is still
waiting to be explored and they need to be expanded.4 The
application of the Grignard reaction in carbon–carbon bond-
forming reactions for large-scale industrial application is lim-
ited5 by the expense of the metal, the anhydrous ether solvents
required and complications of waste solvent disposal. Also, the
addition of organometallic reagents to the C=N double bonds
of imines or hydrazones has been severely affected both by the
poor electrophilicity of the azomethine carbon and by the
tendency of enolisable imines and imine derivatives to undergo
deprotonation rather than addition.6 Nitrones possess the
most highly polarised C=N double bond, which is responsible
for their good electrophilic reactivity, and a reactive oxygen
atom, making them capable of reacting with organometallic
compounds to generate a host of products bearing the
homoallyl group. In continuation of our studies on metal-
mediated organic reactions,7 we report herein the first example
of gallium and bismuth-mediated allylation of various aldo-
nitrones and hydrazones derived from aromatic aldehydes
under microwave irradiation. We paid particular attention to
gallium, a soft low valent and comparatively less studied ele-
ment of group IIIA; there have been only a few examples of
synthetic reactions in the literature8 using gallium, which
belongs to the same group as the extensively studied boron,
aluminium and indium9 elements.
(Scheme 2) to provide the corresponding homoallyl hydrazides
4 and 5 in 60–65% yields after 6–12h. The reaction proceeds
conveniently and no trace of N-allylated product could be
detected. Furthermore, it is to be noted that in aqueous media
many imines are hydrolysed to the corresponding carbonyl
compounds before allylation occurs, thus giving the homo-
allylic alcohols.2 Also it is remarkable to note that indium10
enhances the homocoupling of imines in aqueous media to give
the corresponding 1,2-diamines. But with gallium or bismuth
in our reaction conditions, we have not observed the formation
of any hydrolysed products or 1,2-diamines. Moreover, the
reaction time is reduced dramatically from 6–12h to 4–5 min
when the same experiment was performed in a domestic
microwave oven,11 operating at 2450 MHz frequency. Excel-
lent yields are obtained (580%, see Table 1).
The use of NH4Cl was found to be important, as the ally-
lation did not proceed at all with gallium or bismuth alone,
without NH4Cl. It is obvious that activation of the metal is
needed for this reaction to proceed. Therefore, we tried a
number of alkaline metal salts like NaBr, KBr, MgBr2 and
KCl in aqueous media as additives in place of NH4Cl and
found these to be ineffective or to give poor yields. However,
Bu4NBr was found to quite effective in activating the gallium
or bismuth to give a good yield of the corresponding homo-
allylic hydroxylamines and hydrazides. Roughly 0.1 equiv. of
NH4Cl was found to be sufficient for these reactions and use
of a large excess did not lead to either higher yields or faster
reaction rates. We thus used NH4Cl or Bu4NBr in the standard
reaction conditions to activate commercial gallium or bismuth
Reaction of aldonitrone 1 with allylic bromide in the pre-
sence of gallium or bismuth and ammonium chloride in DMF–
H2O (3 : 1) as the solvent (Scheme 1) produced the corre-
sponding homoallylic hydroxylamines 2 in 60–75% yields.
Analysis of the crude mixture did not indicate the formation of
any other products. Similarly, allylgallium or allylbismuth
reagent stoichiometric amount, (in situ generated) undergo
addition to the carbon–nitrogen double bond of aryl or tosyl
Scheme 2
DOI: 10.1039/b108525p
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Table 1 Ga or Bi=NH4Cl mediated allylation of N-oxides and hydrazonesa
Room temperature
Microwave activation
Reaction time=h
Yield (%)
Ga
Reaction time=min
Yield (%)
Product
Ar
Ga
Bi
Bi
Ga
Bi
Ga
Bi
95
2a
2b
2c
2d
2e
2f
2g
4a
4b
4c
4d
4e
4f
C6H5
6
7
6
7
7
7
8
6
7
7
7
6
6
6
9
9
10
8
12
10
8
11
1260
1260
11
10
11
1265
65
68
63
62
60
60
60
6265
60
60
6265
60
75
70
70
70
65
75
70
4
5
5
5
5
4
4
4
4
5
4
5
5
5
90
9285
86
80
80
85
83
4-ClC6H4
4-CH3C6H4
2-Furyl
2-Thienyl
4-CH3OC6H4
3-NO2C6H4
C6H5
4-ClC6H4
4-CH3C6H4
4-CH3OC6H4
C6H5
4-ClC6H4
C6H5
90
85
83
80
80
5
5
5
80
80
85
5
5
4
65
65
5
5
8952
93
80
82
83
80
4
4
5
5
85
83
63
562
5
5
84
85
a
All the products were characterised by 1H NMR and mass spectrometry and by comparison with authentic samples.
metal and examined its reaction with a number of substrates. It
is interesting to note that the nature of the solvent controlled
the formation of homoallylated products. The reaction failed
to produce any desired compound when THF–H2O (3 : 1) or
THF alone was used as the solvent. Also, no isolable product
was formed when the reaction was run in water or DMF alone.
An organic solvent is required for the reaction to proceed.
After screening the reaction conditions, the optimum medium
for this allylation reaction seems to be a 3 : 1 mixture of DMF–
H2O.
The results in Table 1 reveal the generality of this metho-
dology in terms of structural variations of the nitrone moiety;
in each case homoallylic hydroxylamines were isolated in
excellent yields. Furthermore, electron-donating or -with-
drawing groups on the aromatic ring do not seem to affect the
reaction significantly, either in the yield of the product or
the rate of the reaction. Moreover, the nitro function was
not reduced under the reaction conditions. Thus, 3-nitro-
benzaldehyde nitrone 2g was successfully allylated. Usually,
the nitro group is sensitive to reduction by metals and cannot
be allylated under Barbier conditions.10 In this sense, the use of
an additive as an activating agent is superior to the use of Al,
Fe or NaBH4 reported previously.12 Although the detailed
mechanism of the reaction is not clear, it is likely that NH4Cl
or Bu4NBr affects the generation of an active organogallium or
organobismuth reagent. All the compounds obtained were
characterised by infrared and 1H NMR spectroscopy and
finally by comparison with authentic samples.
Company and Central Drug House (Pvt.) Ltd. (New Delhi),
and used without further purification. All the carbonyl com-
pounds and phenylhydroxylamines used were freshly distilled
and recrystallised before use and their properties checked by
spectroscopic data.
General procedure for the allylation of aldonitrones 1, aryl and
tosyl hydrazones 3 at room temperature
A suspension of bismuth powder (2.08 g, 10 mmol), allyl
bromide (1.8 g, 15 mmol) and ammonium chloride (55 mg, 1
mmol) was taken up in 20 ml of DMF–H2O (3 : 1) in a 150 ml
round-bottomed flask and was stirred at room temperature
until the metal was completely dissolved. To the allylbismuth
reagent generated, a solution of aldonitrone 1a (2.0 g, 10
mmol) in 5 ml DMF was added. The resulting mixture was
stirred at room temperature for 9 h. The reaction was then
quenched with diluted HCl, followed by extraction with ether
(2 Â 20 ml). The combined ether extract was washed with
brine, dried over anhydrous sodium sulfate and the residue
obtained thereafter on evaporation of the solvent was chro-
matographed using ethyl acetate–hexane (1 : 5) to afford the
pure homoallyl product 2a in 75% yield. Similarly, other
aldonitrones 1b–g and hydrazones 3a–f were reacted in the
presence of gallium or bismuth metal and ammonium chloride
and the reaction characteristics are recorded in Table 1. All
the compounds obtained were characterised by infrared and
1H NMR spectroscopy and finally by comparison with
authentic samples. The reaction was found to be equally
effective when 0.1 equiv. of Bu4NBr was used in place of
NH4Cl and the corresponding homoallyl hydroxylamines were
isolated in 60–70% yields.
In conclusion, this simple and easily reproducible technique
using gallium or bismuth13 in aqueous conditions and under
microwave irradiation affords various homoallyl hydrazides
and hydroxylamines of potentially high synthetic utility in
excellent yields and without the formation of any undesirable
side products.
2a: 1H NMR (CDCl3): d 6.62–7.25 (m, 11H, ArH and OH),
5.72–5.90 (m, 1H), 5.12–5.35 (m, 2H), 4.32 (t, J ¼ 7.2, 1H),
2.62–2.78 (m, 2H). MS: m=z 238.
General procedure for the allylation of aldonitrones, aryl and
tosyl hydrazones under microwave irradiations using Ga or Bi
Experimental
Melting points were determined using a Buchi melting point
apparatus and are uncorrected. IR spectra were recorded for
KBr discs on a Perkin–Elmer 240C analyser. 1H NMR spectra
were recorded on 60 MHz spectrometers and chemical shift
values are recorded in d relative to Me4Si as internal standard.
Solvents used were dried according to literature procedures.
All reagents were of commercial quality from freshly opened
containers and were purchased from Aldrich Chemical
In a typical procedure, a mixture of bismuth powder (2.08 g, 10
mmol), allyl bromide (2.4 g, 20 mmol), ammonium chloride
(55 mg, 1 mmol) and hydrazone 3a (2.0 g, 10 mmol) in 20 ml
DMF–H2O (3 : 1) was placed in an Erlenmeyer flask and
heated in a commercial microwave oven operating at 2450
MHz frequency for 5 min (monitored by TLC). The reaction
was then quenched with diluted HCl, followed by extraction
194
New J. Chem., 2002, 26, 193–195

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Chem. Commun., 1999, 2191.
Y. Yamamoto and N. Asao, Chem. Rev., 1993, 93, 2207.
T. D. Waugh, Kirk–Othmer Encyclopedia of Science and Tech-
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R. Bloch, Chem. Rev., 1998, 98, 1407.
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washed with brine, dried over anhydrous sodium sulfate and
the residue obtained on evaporation of the solvent was chro-
matographed using ethyl acetate–hexane (1 : 5) to afford the
corresponding homoallyl hydrazide product 4a in 85% yield.
Similarly, other aryl and tosyl hydrazones and aldonitrones
were reacted with gallium and bismuth in the presence of
ammonium chloride under microwave irradiation and the
reaction characteristics are recorded in Table 1.
4
5
6
7
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1
4a: H NMR (CDCl3): d 8.72(br, NH), 7.05–7.35 (m, 10H,
8
ArH), 5.70–5.92(m, 1H), 5.05–5.22(m, 2H), 4.17 (t,
1H), 2.45–2.60 (m, 2H). MS: m=z 238.
J ¼ 7.2,
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