Indium/copper-mediated conjugate addition of unactivated alkyl iodides to α,β-unsaturated carbonyl compounds in water

Article abstract of DOI:10.1016/j.tetlet.2008.12.079

An efficient method for the conjugate addition of unactivated alkyl iodides to α,β-unsaturated carbonyl compounds using indium/copper in water is described. The reactions proceed more efficiently in water than in organic solvents. In, CuI, and InCl_3<

Full text of DOI:10.1016/j.tetlet.2008.12.079

Tetrahedron Letters 50 (2009) 1051–1054
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium/copper-mediated conjugate addition of unactivated alkyl iodides
to
a,b-unsaturated carbonyl compounds in water
*
Zhi-Liang Shen, Hao-Lun Cheong, Teck-Peng Loh
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the conjugate addition of unactivated alkyl iodides to a,b-unsaturated carbonyl
Received 13 November 2008
Revised 9 December 2008
Accepted 16 December 2008
Available online 24 December 2008
compounds using indium/copper in water is described. The reactions proceed more efficiently in water
than in organic solvents. In, CuI, and InCl3 are all essential for efficient reaction. Formation of a symmet-
rical vic-diarylalkane is observed when an aryl-substituted alkene is used as substrate.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indium
Copper
Conjugate addition
a,b-Unsaturated carbonyl compounds
Alkyl iodide
Water
Conjugate addition of alkyl groups to
a,b-unsaturated carbonyl
the conjugate addition of unactivated alkyl iodides to a,b-unsatu-
compounds is a versatile synthetic method for the construction of
C–C bonds.1 Among the various methods available, the most com-
monly employed strategies involve the use of organometallic spe-
cies such as Grignard reagents (RMgX) or organolithium (RLi)
reagents.2 However, the use of these highly reactive organometal-
lic reagents can lead to undesired side reactions such as hydrolysis,
Wurtz coupling, b-elimination of the organometallic reagent, and
the reduction of carbonyl compounds. Also, 1,2-addition of the al-
kyl group to the carbonyl group can compete with the 1,4-conju-
gate addition reaction. If this reaction could be developed to take
place in water3 without the above-mentioned side reactions, it
would greatly aid organic chemists.
The pioneering works by Luche, Li, Naito, and others have
shown that it is possible to carry out alkyl additions to conjugated
systems in water.4–6 Unfortunately, in most cases, the use of harsh
reaction conditions such as ultrasonication, inert atmospheres,
cosolvent systems, and the narrow substrate scope limit their
applicability to complex molecule synthesis. Therefore, the devel-
opment of more general and practical methods for alkyl addition
rated carbonyl compounds (including a chiral version) using
indium/copper in water.8–10 In addition, the formation of symmet-
rical vic-diarylalkanes was observed when aryl-substituted alkenes
were used as the substrate.
Initial studies focused on the reaction of a,b-unsaturated ester 1
and cyclohexyl iodide under different reaction conditions.
As shown in Table 1, it was found that the combination of In/
CuI/InCl3 (6:3:0.1) was an efficient system for activation of the con-
jugate addition reaction in water. The reaction proceeded smoothly
at room temperature to generate the corresponding adduct 2 in
80% yield (entry 1). It is important to note that, without the use
of CuI, the reaction proceeded sluggishly to give the desired prod-
uct in poor yield (entry 2). Without the addition of InCl3, the yield
of the product decreased to 54% (entry 3). In addition, it was found
that the use of the metal (i.e., indium) was also indispensable (en-
try 4). Among the several metals screened, indium proved to be the
best for this reaction. The following order was apparent for activa-
tion of the conjugate alkylation: In > Zn > Al > Sn. Other copper and
silver compounds such as CuBr, CuCl, and AgI were also investi-
gated, but all gave the products in lower yields in comparison to
CuI (entries 5–7). It was worthwhile to note that the reactions pro-
ceeded more efficiently in water than in organic solvents such as
MeOH, THF, CH2Cl2, DMF, DMSO, and hexane. Furthermore, the
reactions were carried out without an inert atmosphere and ultra-
sonication was unnecessary.
to
a,b-unsaturated carbonyl compounds under mild conditions is
highly desirable. In previous reports, our group has described in-
dium/copper- and indium/silver-mediated Barbier–Grignard-type
alkylation reactions of imines and aldehydes using unactivated al-
kyl iodides in water.7 In continuation of our work to develop alkyl-
ation reactions in water, herein, we report an efficient method for
With optimized reaction conditions in hand, we next applied
the reaction system to various
pounds and alkyl iodides. As illustrated in Table 2, the reactions
a,b-unsaturated carbonyl com-
* Corresponding author. Tel.: +65 65138203; fax: +65 67911961.
E-mail address: teckpeng@ntu.edu.sg (T.-P. Loh).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.079

1052
Z.-L. Shen et al. / Tetrahedron Letters 50 (2009) 1051–1054
Table 1
proceeded sluggishly to give the desired product in poor yield
Optimization of the reaction conditionsa
(<20%). The desired product was not obtained when the reaction
was carried out using substrate 1 and tert-butyl iodide.
It was gratifying to find that even cyclic enones such as cyclo-
hexenone and cyclopentenone also reacted efficiently with differ-
ent alkyl iodides to furnish the desired 1,4-addition products in
moderate to good yields (Table 3). The formation of 1,2-addition
products was not detected.
O
conditions
H2O
+
I
O
Ph
OEt
Ph
OEt
1
2
With the success of the reactions above, we further applied this
Entry
Conditions
Yieldb (%)
reaction system to a,b-unsaturated carbonyl compounds with chi-
ral auxiliary groups in the hope of providing an efficient method
for the synthesis of chiral carbonyl compounds.
1
2
3
4
5
6
7
In/CuI/InCl3
In/InCl3
In/CuI
80
<20
54
0
68
<50
48
CuI/InCl3
Three typical chiral auxiliaries, (ꢀ)-8-phenylmenthol, (S)-4-
benzyl-2-oxazolidinone, and (1S)-(ꢀ)-2, 10-camphorsultam were
In/CuBr/InCl3
In/CuCl/InCl3
In/AgI/InCl3
incorporated into a,b-unsaturated carbonyl compounds for asym-
metric induction in the conjugate addition reactions. As outlined
a
The reactions were carried out at rt for one day using In (3 mmol), CuX (X = Cl,
,b-unsaturated ester 1 (0.5 mmol),
in Table 4, the conjugate addition of alkyl iodides to ,b-unsatu-
a
Br, I) or AgI (1.5 mmol), InCl3 (0.05 mmol),
cyclohexyl iodide (2.5 mmol), and water (10 mL).
a
rated carbonyl compounds with chiral auxiliary groups proceeded
efficiently in water to afford the desired products in moderate to
b
Isolated yield.
Table 2
Conjugate addition of alkyl iodides to various
a
,b-unsaturated estersa,11
Table 3
Conjugate addition of alkyl iodides to various cyclic enonesa,11
O
In/CuI/InCl3
H2O
R''
O
+
R'
' I
O
In/CuI/InCl3
H2O
R''
O
R
R'
R
R'
+
R'
' I
R
R'
R
R'
Yieldb (%)
Entry
1
a
,b-Unsaturated ester
Alkyl iodide
Yieldb (%)
80
Entry
1
Enone
Alkyl iodide
O
I
O
O
O
O
Ph
Ph
OEt
OEt
85
I
O
O
O
2
3
4
5
6
7
8
9
84
I
2
3
4
5
6
7
8
78
I
70
I
Ph
Ph
OEt
OEt
73 (dr 52:48)c
73
I
I
O
O
70
I
I
I
I
I
I
45
Ph
Ph
OtBu
OMe
I
75 (dr 31:69)c
O
O
O
53
I
I
I
I
O
61
84
76
48
OMe
O
81 (dr 63:37)c
83 (dr 53:47)c
74
n
Pentyl
OMe
O
OEt
O
O
10
Ph
O
OMe
a
The reactions were carried out at rt for one day using In (3 mmol), CuI
(1.5 mmol), InCl3 (0.05 mmol),
(2.5 mmol), and water (10 mL).
a,b-unsaturated ester (0.5 mmol), alkyl iodide
O
9
65
I
b
Isolated yield.
c
Diastereoselectivity was determined by 1H NMR and 13C NMR analyses.
a
The reactions were carried out at rt for one day using In (3 mmol), CuI
(1.5 mmol), InCl3 (0.05 mmol),
(2.5 mmol), and water (10 mL).
a,b-unsaturated ketone (0.5 mmol), alkyl iodide
proceeded efficiently in water at ambient temperature. The desired
products were obtained in moderate to good yields. In contrast, the
reaction between a,b-unsaturated ester 1 and cyclohexyl bromide
b
Isolated yield.
c
Diastereoselectivity was determined by 1H NMR and 13C NMR analyses.

Z.-L. Shen et al. / Tetrahedron Letters 50 (2009) 1051–1054
1053
Table 4
O
Conjugate addition of alkyl iodides to chiral
a
,b-unsaturated esters and amidesa,11
In(Cu) InI
H2O
R
O
R'
R''
.
R-I
R
R'
R''
.
In/CuI/InCl3
H2O
O
R''
O
+
R'' I
R
R'
R
R'
a
b
c
Entry
1
a
,b-Unsaturated compound
Alkyl iodide
Yieldb (%)
50
drc
In+
In
R
O
R
O
H2O
30:70
I
R'
R''
R'
R''
O
d
e
2
3
4
5
6
52
51
86
86
92
34:66
34:66
44:56
41:59
46:54
I
O
Ph
Scheme 2. Proposed reaction mechanism.
I
I
I
A plausible reaction mechanism is proposed (Scheme 2). The
reaction is possibly initiated by a single-electron transfer from in-
dium/copper to alkyl iodide a to generate an alkyl radical b. This
I
O
O
O
N
I
radical can attack the
a,b-unsaturated carbonyl compound via
Ph
1,4-conjugate addition to furnish a radical intermediate c. Subse-
quent indium-promoted reduction of intermediate c and quench-
ing of the generated anion d in the presence of water affords the
expected product e.
H
7
8
60
40:60
I
H
O
In summary, we have developed an efficient method for the
84
80
48:52
38:62
I
N
conjugate addition of alkyl iodides to
compounds using indium/copper in water at room temperature.
This method works with a wide variety of ,b-unsaturated car-
bonyl compounds. The mild reaction conditions, moderate to good
yields, and the simplicity of the reaction procedure make this
method an attractive alternative to conventional methods using
highly reactive organometallic reagents in anhydrous conditions.
a,b-unsaturated carbonyl
S
9
O
O
a
a
The reactions were carried out at rt for one day using In (3 mmol), CuI
,b-unsaturated compound (0.5 mmol), alkyl iodide
(1.5 mmol), InCl3 (0.05 mmol),
(2.5 mmol), and water (10 mL).
a
b
Isolated yield.
Diastereoselectivity was determined by 1H NMR and 13C NMR analyses.
c
Acknowledgments
good yields. However, only poor to moderate diastereoselectivities
were achieved.
We gratefully acknowledge the Nanyang Technological
Of mechanistic interest is the formation of a symmetrical vic-
diarylalkane when an aryl-substituted alkene was used as the
substrate. As shown in Scheme 1, when 4-acetoxystyrene 3 was re-
acted with 2-iodopropane, alkylative dimerization of 3 exclusively
gave symmetrical vic-diarylalkane 4 in 53% yield and 1:1 dr. The
structure was confirmed by X-ray crystallographic analysis. The
reaction most likely proceeds via the addition of an alkyl radical
to arylalkene 3 to form a benzyl radical. Dimerization of the thus
formed benzyl radical then affords symmetrical vic-diarylalkane
4. This result provides strong support for a radical-type reaction
mechanism in this type of addition reaction, including the above-
mentioned conjugate addition reactions.
University, Ministry of Education (No. M45110000), and A STAR
S.E.R.C. (No. 0721010024) for the funding of this research.
*
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.079.
References and notes
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I
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Chem., Int. Ed. 2005, 44, 5560.
53% yield
1:1 dr
AcO
3
4
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P.; Li, C. J. Chem. Rev. 2007, 107, 2546; (b) Chauhan, K. K.; Frost, C. G. J. Chem.
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L.; Allavena, C. Tetrahedron Lett. 1988, 29, 5369; (c) Dupuy, C.; Petrier, C.;
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Springer, R.; Zeitz, H. G.; Giese, B. Helv. Chim. Acta 1992, 75, 638; (f) Luche, J. L.;
Allavena, C.; Petrier, C.; Dupuy, C. Tetrahedron Lett. 1988, 29, 5373;
Scheme 1. Formation of symmetrical vic-diarylalkane 4 and the X-ray crystallo-
graphic structure of 4 (CCDC 694091).

1054
Z.-L. Shen et al. / Tetrahedron Letters 50 (2009) 1051–1054
(g) Pietrusiewicz, K. M.; Zablocka, M. Tetrahedron Lett. 1988, 29, 937; (h) Roth,
M.; Damm, W.; Giese, B. Tetrahedron Lett. 1996, 37, 351; (i) Suarez, R. M.;
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sulfone, see: (a) Huang, T.; Keh, C. C. K.; Li, C. J. Chem. Commun. 2002, 2440; (b)
Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Org. Lett. 2002, 4, 131.
6. Recently, Jang and co-workers demonstrated that alkyl addition to
a
,b-
11. General procedure for the conjugate addition of cyclohexyl iodide to
unsaturated carbonyl compound 1: To a 10 mL round-bottomed flask were
added water (10 mL), ,b-unsaturated carbonyl compound (0.1021 g,
a,b-
unsaturated carbonyl compounds could be achieved using In, EPHP (1-
ethylpiperidinium hypophosphite), CTAB (cetyltrimethylammonium bromide)
and ABCVA (4,40-azobis(4-cyanovaleric acid)) at 80 °C in aqueous media under
an argon atmosphere. See: Jang, D. O.; Cho, D. H. Synlett 2002, 631.
7. (a) Shen, Z. L.; Cheong, H. L.; Loh, T. P. Chem.-Eur. J. 2008, 14, 1875; (b) Shen, Z.
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Chem. 2008, 73, 3922.
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a
1
0.5 mmol), and InCl3 (0.011 g, 0.05 mmol). After stirring for several minutes,
indium (0.344 g, 3 mmol), copper iodide (0.286 g, 1.5 mmol), and cyclohexyl
iodide (0.525 g, 2.5 mmol) were added sequentially. The reaction mixture was
stirred vigorously at room temperature for one day. After completion, the
reaction mixture was extracted using diethyl ether (20 mL ꢁ 3), and the
combined organics were washed with brine, dried over anhydrous sodium
sulfate, filtered, and evaporated in vacuo to give the crude product. Silica gel
column chromatography using ethyl acetate and hexane as eluent afforded the
desired product 2, 0.115 g (80% yield) as a colorless oil. Rf = 0.57 (ethyl acetate/
hexane = 1/8); FTIR (NaCl, neat)
m ;
1732 cmꢀ1 1H NMR (300 MHz, CDCl3) d
0.96–1.44 (m, 6H), 1.24 (t, J = 7.15 Hz, 3H), 1.47–1.90 (m, 8H), 2.22 (dd,
J = 15.04, 7.48 Hz, 1H), 2.37 (dd, J = 15.09, 6.16 Hz, 1H), 2.56–2.62 (m, 2H), 4.12
(q, J = 7.17 Hz, 2H), 7.16–7.29 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3) d 173.9
(C), 142.6 (C), 128.3 (CH ꢁ 4), 125.7 (CH), 60.2 (CH2), 40.6 (CH), 40.3 (CH), 36.5
(CH2), 33.8 (CH2), 33.4 (CH2), 29.9 (CH2), 29.2 (CH2), 26.8 (CH2), 26.7 (CH2), 26.7
(CH2), 14.3 (CH3) ppm; HRMS (EI, m/z) [M]+, calcd for C19H28O2 288.2089,
found 288.2051.