1,2-addition of phenylacetylene to aldimines catalyzed by InCl 3/CuCl in water under Barbier conditions

Article abstract of DOI:10.1055/s-0030-1259679

A new and efficient method for the preparation of various propargylamines has been achieved by the simple Barbier-Grignard-type reaction of phenylacetylene with a variety of ald-imines under aqueous conditions, catalyzed by a bimetallic In-Cu system. Geor

Full text of DOI:10.1055/s-0030-1259679

LETTER
627
1,2-Addition of Phenylacetylene to Aldimines Catalyzed by InCl3/CuCl in
Water under Barbier Conditions
1
,2-Addition of Ph
i
enylace
p
tylene to
A
l
a
dimines k Prajapati,*a Rupam Sarma,a Debajyoti Bhuyan,a Wenhao Hub
a
Medicinal Chemistry Division, CSIR-North East Institute of Science & Technology, Jorhat-7850 06, Assam, India
Fax +91(376)2370011; E-mail: dr_dprajapati2003@yahoo.co.uk
b
Department of Chemistry, East China Normal University, Shanghai-200062, P. R. of China
Received 21 October 2010
of enolizable imines to undergo deprotonation rather than
addition.12 To circumvent these problems, several meth-
ods have been explored, for example, activation of the
C=N bond either by N-substitution with electron-with-
drawing group or by N-coordination to a Lewis acid.13
Hoveyda and co-workers14 used a Zr(IV) complex, Li de-
veloped a Cu(I) complex of pyridyl-bisoxazoline15 that
was able to promote the direct alkyne-imine addition in
toluene and in water. Knochel and co-workers16 described
the addition of functionalized alkynes to enamines cata-
lyzed by Cu(I)–Quinap. Finally, Jiang and Si17 reported
the zinc acetylide addition to reactive ketoimines in the
presence of a chiral amino alcohol under mild reaction
conditions.18
Following our interest in organometallic reactions,19 we
have focused on developing metal-catalyzed practical C–
C bond-formation reactions. As such, we report herein an
indium-copper bimetallic catalytic system for effective
1,2-addition of phenylacetylene to a variety of aldimines
in aquous medium. Initially, we examined the addition
reaction of phenylacetylene with 4-methoxybenzylidene-
4-methylaniline derived from 4-methoxy benzaldehyde
and p-toluidine. However, when we reacted 1 equivalent
each of phenylacetylene and imine with 0.5 equivalent of
indium(III) chloride and copper(I) chloride in water at
room temperature, we did not observe the desired addition
reaction due to the poor electrophilicity of the azomethine
carbon.
Abstract: A new and efficient method for the preparation of vari-
ous propargylamines has been achieved by the simple Barbier–
Grignard-type reaction of phenylacetylene with a variety of ald-
imines under aqueous conditions, catalyzed by a bimetallic In–Cu
system.
Key words: aldimines, water, indium chloride, copper chloride,
propargylamines
There has been growing interest in the use of reactions of
metallic elements in aqueous media,1 as they offer signif-
icant advantages over conventional reactions in dry or-
ganic solvents. The development of such reactions also
offer the possibility of obtaining environmentally benign
reaction conditions.2 The study and application of
Barbier–Grignard type reactions3 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 use of water as solvent could reduce or eliminate en-
vironmental damage by organic wastes.5
Furthermore, the addition of terminal alkynes to imines or
carbonyl compounds, is of great interest because of the
versatility of the corresponding propargylic amines or al-
cohols.6 While several catalytic methods are known to
promote the addition of acetylenes to aldehydes in very
high yields,7 only very recently a limited number of orga-
nometallic systems has been reported to afford propargyl-
amines.8 Stoichiometric amounts of strong bases such as
organolithium, organomagnesium, or dialkylzinc9 re-
agents are widely used for this type of reaction. Intrinsic
drawbacks, however, such as the use of stoichiometric
amounts of metal reagents and a separate step for metal
acetylide preparation make it difficult to achieve an atom-
economical process with high total efficiency. The in situ
catalytic generation of metal nucleophiles and their use in
carbon–carbon bond-forming reactons10,11 is currently a
major interest in organic synthesis. Thus, the development
of an alkynylation of various imines using a catalytic
amount of metal is in high demand. However, the addition
of organometallic reagents to the C=N double bond of
imines has been severely restricted both by the poor elec-
trophilicity of the azomethine carbon and by the tendency
R2
R2
NH
In–Cu
N
+
Ph
H2O, 40 °C
R1
R1
Ph
1
2
3
Scheme 1
It was found that after addition of 1.2 mol% of InCl3 and
12 mol% of CuCl, the reaction improved dramatically. So,
the addition of a terminal alkyne to an imine could pro-
ceed smoothly to give the desired propargylamine in ex-
cellent yields when 1.2 mol% of InCl3 and 12 mol% of
CuCl were used in the reaction mixture (Scheme 1). The
reactions proceeded in high yields at room temperature
without formation of any side products. However, when
the reaction was carried out at an elevated temperature
SYNLETT 2011, No. 5, pp 0627–0630
x
x.
x
x.
2
0
1
1
Advanced online publication: 23.02.2011
DOI: 10.1055/s-0030-1259679; Art ID: D28110ST
© Georg Thieme Verlag Stuttgart · New York

628
D. Prajapati et al.
LETTER
Table 1 In–Cu-Catalyzed Addition of Phenylacetylene to Aldi-
mines in Water
ring at room temperature. Elevating the temperature to
60 °C and increasing the reaction time further gave no sig-
nificant improvement and resulted in decomposition of
the starting materials. It is relevant to note that, during al-
lylations in aqueous media, many imines are hydrolyzed
to the corresponding carbonyl compounds before allyla-
tion occurs, thus giving the homoallylic alcohols.2 Also, it
is notable that indium promotes21 the homocoupling of
imines in aqueous media to give the corresponding 1,2-di-
amines. However, with the In–Cu bimetallic combination,
we observed neither the formation of hydrolyzed products
nor 1,2-diamines. The results in Table 1 reveal the gener-
ality of this methodology in terms of structural variations
of the aldimine. In each case, homoalkynylic products
were isolated in high yields. Furthermore, electron-donat-
ing 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, p-nitrobenzaldehyde imine 1i was successfully pro-
pargylated. Usually, a nitro group is sensitive to reduction
by metals and is not tolerated under Barbier conditions.22
Remarkably, the reaction with imines bearing an electron-
withdrawing group on the nitrogen atom such as N-
tosylimines is not so effective, and the corresponding N-
sulfonyl propargylic amines were obtained in 60–65%
yields, but superior to the 43% yield reported by Carreira
et al.23 These experiments demonstrate that the combina-
tion of a catalytic amount of indium chloride and a cata-
lytic amount of copper chloride showed catalytic activity,
and the best yield of the desired product was obtained
without the use of any base.
Entry Imine 1
Propargy- Time
Yield
(%)b
lamines 3 (h)a
1
2
1a
1b
1c
1d
1e
1f
R1 = 4-MeOC6H4
R2 = 4-MeC6H4
3a
3b
3c
3d
3e
3f
4
8525a
8225a
8025b
7825a
8125c
8025a
8325b
8025a,b
7525b
65
R1 = 4-MeC6H4
R2 = Ph
3.5
4
3
R1 = 4-MeC6H4
R2 = 4-MeC6H4
4
R1 = 4-ClC6H4
R2 = 4-MeC6H4
4
5
R1 = 4-ClC6H4
3.5
4.5
4
R2 = 4-MeOC6H4
6
R1 = Ph
R2 = Ph
7
1g
1h
1i
R1 = Ph
3g
3h
3i
R2 = 4-MeOC6H5
8
R1 = 4-ClC6H4
R2 = Ph
4
9
R1 = 4-O2NC6H4
R2 = Ph
3.5
5
10
11
1j
R1 = 4-MeC6H4
3j
R2 = 4-MeC6H4SO2
1k
R1 = Ph
3k
5
60
R2 = 4-MeC6H4SO2
a When carried out at r.t., reactions took 9–12 h to reach completion.
b Yield refers to pure isolated products, fully characterized by 1H
NMR and IR spectroscopy and by comparison with authentic sam-
ples.
Although the route for addition of alkynes to imines has
not been established experimentally, it is believed that
both the metal salts play a crucial role in the transforma-
tion. A probable pathway is shown in Scheme 2. It is pro-
posed that an indium alkynylide is formed from
phenylacetylene and indium chloride,24 and this then at-
(40 °C), the reaction time reduced to a great extent with-
out affecting the yield.20
This is in contrast to an earlier report,21 where the indium-
mediated alkynylation of aldehydes under thermal condi-
tions gave benzylic alcohols as byproducts along with the
homoalkynyl alcohols. During our investigation, it was
found that CuCl alone also provided the desired product,
albeit in low conversions, whilst addition of 1.2 mol%
InCl3 promotes this reaction. The use of 1.2 mol% InCl3
as co-catalyst was necessary for the reaction to go to com-
pletion. The conversion was decreased when a smaller
amount of CuCl was used. When PdCl2 or AlCl3 was used
in place of InCl3 for activation, the reaction did not pro-
ceed effectively. Among various bicatalytic systems, it
was found that the desired addition product was formed
by using InCl3–CuCl in water and without the addition of
any base. The reaction was generalized by employing var-
ious aldimines, and the results obtained are summarized in
Table 1.
R2
NH
H
R1
Ph
+
InCl3
CuCl
Ph
H
CuCl
In(III)
R2
H
N
Ph
H
R1
In(III)
Ph
R2
H
CuCl
Ph
In(I)
N
When a ketimine derived from acetophenone and aniline
was used in the reaction, alkynylation of the aldimine with
phenyl acetylene did not occur even after 16 hours of stir-
R1
Scheme 2
Synlett 2011, No. 5, 627–630 © Thieme Stuttgart · New York

LETTER
1,2-Addition of Phenylacetylene to Aldimines
629
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tacks the CuCl-activated electrophilic carbon atom of the
aldimine. The proposed mechanism is also in agreement
with the fact that the reaction is sluggish in the absence of
the indium catalyst and also when the amount of CuCl is
decreased.
In conclusion, the In–Cu-catalyzed Barbier–Grignard-
type reaction of phenylacetylene with aldimines with C–
H activation has been developed under aqueous condi-
tions and in excellent yields. This bimetallic catalyzed
one-pot synthesis of various propargylamines is simple,
high yielding, and environment friendly and will consti-
tute a useful alternative to the commonly accepted proce-
dures. The scope, mechanism, and synthetic application of
this reaction is under investigation.
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Acknowledgment
The research was supported by CSIR, New Delhi and NSFC, China
under joint collaborative programme. We thank B. J. Gogoi for his
help in carrying out some experiments. R.S. thanks CSIR, New
Delhi for the award of a Research Fellowship.
References and Notes
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(20) General Experimental Procedure for the Addition of
Alkynes 1 to Aldimines 2
Aldimine 1a (0.225 g, 1 mmol) in a round-bottomed flask
was treated with InCl3 (0.0026 g, 1.2 mol%), CuCl (0.120 g,
12 mol%), phenyl acetylene (0.12 g, 1.2 mmol), and H2O (2
mL). The mixture was then stirred at r.t. for 20 min and then
at 40 °C for 4 h. Stirring was continued until no further
increase of the reaction product as monitored by 1H NMR.
After completion, the product was extracted with Et2O or
EtOAc (3 × 30 mL). The combined organic layers were
washed with H2O and dried over anhyd Na2SO4.
Evaporation of the solvent gave a crude product which was
subjected to column chromatography on silica gel with
EtOAc–hexane (1:6) as eluent to afford exclusively the
corresponding propargylamine 3a in 85% yield.
Conpound 3b: IR (liquid film): nmax = 3410, 2230, 1615,
1510, 1325, 1185 cm–1. 1H NMR (300 MHz, CDCl3): d =
2.20 (s, 3 H), 4.12 (br, 1 H), 5.21 (s, 1 H), 6.84–7.01 (m, 3
H), 7.18–7.36 (m, 7 H), 7.40–7.48 (m, 2 H), 7.62 (d, J = 8.5
Hz, 2 H). 13C NMR (75 MHz, CDCl3): d = 21.3, 50.6, 85.2,
89.0, 115.1, 119.2, 123.1, 127.5, 128.3, 128.5, 129.3, 129.6,
132.1, 137.2, 138.2, 146.8. MS: m/z = 297 [M+].
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630
D. Prajapati et al.
LETTER
121.2, 127.0, 127.8, 128.4, 128.6, 129.1, 129.2, 129.8,
Compound 3h: mp 185–86 °C. 1H NMR (300 MHz, CDCl3):
d = 2.24 (s, 3 H), 4.83 (br, 1 H), 5.48 (d, 1 H), 7.18–7.24
(m, 2 H), 7.32–7.48 (m, 8 H), 7.59–7.65 (m, 2 H), 7.76 (d,
J = 8.5 Hz, 2 H). 13C NMR (75 MHz, CDCl3): d = 21.4, 50.1,
85.6, 87.2, 120.0, 127.2, 127.6, 128.2, 128.6, 128.8, 129.0,
129.6, 131.5, 137.4, 137.8, 144.5. MS: m/z = 361 [M+].
Compound 3j: mp 192–193 °C, 1H NMR (300 MHz,
CDCl3): d = 2.28 (s, 3 H), 2.34 (s, 3 H), 4.82 (br, 1 H), 5.42
(d, 1 H), 7.10–7.31 (m, 9 H), 7.38 (d, J = 8.5 Hz, 2 H), 7.68
(d, J = 8.5 Hz, 2 H). 13C NMR (75 MHz, CDCl3): d = 21.3,
21.7, 50.2, 85.6, 87.0, 121.3, 127.1, 127.8, 128.4, 129.0,
129.2, 129.8, 130.2, 132.0, 136.2, 137.4, 138.6, 145.8. MS:
m/z = 375 [M+].
130.2, 132.1, 136.2, 137.3, 138.6, 145.8. MS: m/z = 361
[M+].
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Compound 3k: mp 197–199 °C. 1H NMR (300 MHz,
CDCl3): d = 2.33 (s, 3 H), 4.80 (br, 1 H), 5.50 (d, 1 H), 7.19–
7.42 (m, 10 H), 7.55 (d, J = 8.5 Hz, 2 H), 7.70 (d, J = 8.5 Hz,
2 H). 13C NMR (75 MHz, CDCl3): d = 21.8, 49.8, 85.6, 87.0,
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