Indium-mediated propargylation of imines and imine oxides in aqueous media: Propargylation of >C=N- centres

Article abstract of DOI:10.1016/S0040-4039(03)01640-X

The indium-catalysed coupling of propargyl bromide with a variety of imines and imine oxides afforded the corresponding propargylated products in high yields under mild conditions.

Full text of DOI:10.1016/S0040-4039(03)01640-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6755–6757
Indium-mediated propargylation of imines and imine oxides in
aqueous media: propargylation of ꢀCꢁN- centres
Dipak Prajapati,* Dhrubojyoti D. Laskar, Baikuntha J. Gogoi and Gitali Devi
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785 006 Assam, India
Received 6 March 2003; revised 17 June 2003; accepted 27 June 2003
Abstract—The indium-catalysed coupling of propargyl bromide with a variety of imines and imine oxides afforded the
corresponding propargylated products in high yields under mild conditions.
© 2003 Elsevier Ltd. All rights reserved.
There has been growing interest in the use of reactions
of metallic elements1 in aqueous media, as they offer
significant advantages over conventional reactions in
dry organic solvents. The development of such reac-
tions also offers the possibility of obtaining environ-
mentally benign reaction conditions.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.4 The application of the
Grignard reaction in carbonꢂcarbon bond-forming
reactions for large-scale industrial application is
limited5 by the expense of the metal, the anhydrous
ether solvents required and complications of waste sol-
vent disposal. The use of water as solvent could reduce
or eliminate environmental damage by organic wastes.6
Barbier-type reactions have been used to allylate car-
bonyl compounds promoted by various metals.3 Also,
propargyl halides add to aldehydes in the presence of
tin,7 indium,8 zinc,9 and lead.10 Even unconventional
them capable of reacting with organometallic com-
pounds to generate a host of products. In continuation
of our studies on metal mediated Barbier-type allyla-
tions,14 we report herein an efficient indium mediated
propargylation of various imines 1 and imine oxides 4
derived from aromatic aldehydes in aqueous media.
The reactions proceed in high yields at room tempera-
ture without the formation of any side products. In
contrast to a very recent report,15 the indium mediated
alkynylation of aldehydes under thermal conditions
gave a benzylic alcohol as a by-product along with the
homoalkynyl alcohols (Scheme 1).
substrates
such
as
nitrobenzene11
and
diphenyldiselenide12 undergo Barbier-type alkylations
in aqueous media. However, the addition of
organometallic reagents to the CꢁN double bonds of
imines or imine oxides has been severely restricted both
by the poor electrophilicity of the azomethine carbon
and by the tendency of enolisable imines and imine
derivatives to undergo deprotonation rather than addi-
tion.13 Nitrones possess both a highly polarised CꢁN
double bond, which is responsible for their good elec-
trophilic reactivity, and a reactive oxygen atom, making
Scheme 1.
In a typical procedure, indium metal powder (1.14 g, 10
mmol) was added at 0°C to a solution of propargyl
bromide (1.18 g, 10 mmol) in 10 ml of THF–H2O (2:1)
in a 100 ml flask and the mixture stirred. To this
mixture was added Bu4NBr (0.33 g, 1 mmol) and then
the mixture was stirred for 20 min to give a clear
solution. Imine 1a (2.25 g, 10 mmol) was added in
portions and the resulting mixture was stirred at room
temperature for 7 h. After completion (as monitored by
Keywords: indium; imines; nitrones; propargyl bromide.
* Corresponding author. E-mail: dr dprajapati@yahoo.co.uk; drugs
–
@csir.res.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01640-X

6756
D. Prajapati et al. / Tetrahedron Letters 44 (2003) 6755–6757
TLC), the reaction mixture was quenched by the addi-
tion of dilute HCl (2 ml) and the resulting mixture was
poured into ice water, extracted with CH2Cl2 (3×20 ml),
the extract washed with bicarbonate solution, brine and
the combined organic layers dried over anhydrous
Na2SO4. Evaporation of the solvent gave a crude
product which was subjected to column chromatogra-
phy using petroleum ether/CHCl3 (2:3) as eluent to
afford 3a (80%). When propargyl bromide was replaced
by propargyl chloride in the above reaction, the cou-
pling proceeded efficiently and the corresponding
alkynylated product 3a was obtained in 75% yield after
9 h. Similarly, the alkynylindium reagent added to the
carbonꢂnitrogen double bond of aldonitrone 4a and
hydrazone 1g in a Bu4NBr–THF–H2O system. The
reaction proceeded conveniently and no trace of N-
alkynylated product could be detected. However, a
ketimine (derived from acetophenone and aniline) did
not undergo alkynylation with propargyl bromide even
after 16 h of stirring at room temperature. Increasing
the reaction time further gave no significant improve-
ment and resulted in decomposition of the starting
Table 1. Indium-mediated alkynlation of imines 1 and imine oxides 4

D. Prajapati et al. / Tetrahedron Letters 44 (2003) 6755–6757
6757
of us (D.D.L.) thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi for the award
of a senior research fellowship.
materials. It is relevant to note that during allylations
in aqueous media many imines are hydrolysed to the
corresponding carbonyl compounds before allylation
occurs, thus giving the homoallylic alcohols.2 Also, it is
notable that indium promotes15 the homocoupling of
imines in aqueous media to give the corresponding
1,2-diamines. However, with indium activated by
Bu4NBr10 under our reaction conditions, we observed
neither the formation of hydrolysed products nor 1,2-
diamines.
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The use of Bu4NBr was found to be important, as the
alkynylation did not proceed at all with indium alone.
It is obvious that activation of the metal is needed for
this reaction to proceed. Approximately 0.1 equiv. of
Bu4NBr was found to be sufficient for these reactions
and the use of a large excess did not lead either to
higher yields or faster reaction rates. It is also interest-
ing to note that the nature of the solvent controlled the
formation of homoalkynylated products. The reaction
failed to produce any desired compound when THF
alone was used as the solvent. Also, no isolable product
was formed when the reaction was run in water or
DMF alone. After screening the reaction conditions,
the optimum solvent for this propargylation reaction
was seen to be a 2:1 mixture of THF–H2O.
The results in Table 1 reveal the generality of this
methodology in terms of structural variations of the
imine, nitrone or hydrazone moiety; in each case
homoalkynylic products were isolated in good yields.
Furthermore, electron-donating or withdrawing groups
on the aromatic ring did not seem to affect the reaction
significantly, either in the yield of the product or the
rate of the reaction. Moreover, a nitro function was not
reduced under the reaction conditions. Thus, 4-
nitrobenzaldehyde imine 1d was successfully propargy-
lated. Usually, a nitro group is sensitive to reduction by
metals and is not tolerated under Barbier conditions.16
In this context, the use of an additive as an activating
agent is superior to the use of Al, Fe or NaBH4
reported previously.17 Although the detailed mechanism
of the reaction is not clear, it is likely that Bu4NBr
effects the generation of an active organoindium
reagent.10 All the compounds obtained were character-
1
ised by IR and H NMR spectroscopy, and finally, by
comparison with authentic samples.
In conclusion, this simple and easily reproducible tech-
nique using indium under aqueous conditions affords
various homoalkynyl amines and homoalkynyl hydroxyl-
amines of potentially high synthetic utility in high yields
and without the formation of any undesirable side
products.
Acknowledgements
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1647–1648.
17. Valkmann, R. A. In Comprehensive Organic Synthesis,
Addition to CꢂX y Bonds, Part I; Schreiber, S. L., Ed.;
Pergamon: Oxford, 1991; Vol. 1, pp. 355–396.
The authors thank the Department of Science and
Technology, New Delhi for financial assistance and one