Indium-copper and indium-silver mediated Barbier-Grignard-type alkylation reaction of aldehydes using unactivated alkyl halides in water

Article abstract of DOI:10.1021/jo8000589

(Chemical Equation Presented) An efficient method has been developed for the Barbier-Grignard-type alkylation reaction of aldehydes (including aliphatic version) using unactivated alkyl halides in water in the presence of an In/CuI/I₂ or In/AgI/I₂ system. The reactions proceeded more efficiently in water than in organic solvent. In, CuI or AgI, and I ₂ were all essential for the efficient progress of the reactions. A radical-type reaction mechanism was studied and proposed by using 4-pentenal as substrate.

Full text of DOI:10.1021/jo8000589

out in water3 with the suppression of such side reactions, it will
greatly aid organic chemists.
Indium-Copper and Indium-Silver Mediated
Barbier–Grignard-Type Alkylation Reaction of
Aldehydes Using Unactivated Alkyl Halides in
Water
Until recent decades, the Barbier–Grignard-type allylation,4
benzylation,5 arylation,6 propargylation,7 and alkynylation8
reactions have been successfully developed in aqueous media
using different metals. However, the most difficult challenge is
to develop the Barbier–Grignard-type alkylation reaction of
carbonyl compounds in water using unactivated alkyl halides.
In 2003, Li and co-workers disclosed their pioneering work to
achieve the Barbier–Grignard-type alkylation reaction of alde-
hydes using alkyl iodides, employing a Zn/CuI/InCl system in
aqueous Na2C2O4.9 The method using expensive reagent InCl
was mainly applicable to aromatic aldehydes with an electron-
withdrawing group, and the reaction was not applicable to
aliphatic aldehydes. In addition, the reaction needed to be
performed in Na2C2O4 solution, and byproduct generated from
pinacol coupling of aldehyde was detected. Therefore, it is still
desirable to develop a more efficient and practical method for
the Barbier–Grignard-type alkylation reaction of aldehydes using
unactivated alkyl halides in water.
Zhi-Liang Shen, Yan-Lin Yeo, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of
Physical and Mathematical Sciences, Nanyang Technological
UniVersity, Singapore 637371
teckpeng@ntu.edu.sg
ReceiVed January 10, 2008
Recently, indium has been demonstrated to be an efficient
and promising metal to mediate organic reactions in aqueous
media.10 The utilization of indium species as radical initiator
via SET (single electron transfer) process in several organic
transformations has been reported by Naito et al.11,12 We
envisioned that the generation of water-tolerant neutral free
radical would be the key factor for the success of the reaction.
Herein, we report an efficient method for the Barbier–Grignard-
An efficient method has been developed for the Barbier–
Grignard-type alkylation reaction of aldehydes (including
aliphatic version) using unactivated alkyl halides in water
in the presence of an In/CuI/I2 or In/AgI/I2 system. The
reactions proceeded more efficiently in water than in organic
solvent. In, CuI or AgI, and I2 were all essential for the
efficient progress of the reactions. A radical-type reaction
mechanism was studied and proposed by using 4-pentenal
as substrate.
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of moisture-sensitive organometallic reagents such as Grignard
reagents (RMgX). However, due to the highly reactive nature
of Grignard reagents, several undesired byproducts (arose from
the hydrolysis, Wurtz coupling, and ꢀ-elimination of Grignard
reagent, and the reduction of carbonyl compounds) might be
generated. Therefore, if the reaction can be developed to carry
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3922 J. Org. Chem. 2008, 73, 3922–3924
10.1021/jo8000589 CCC: $40.75 2008 American Chemical Society
Published on Web 04/09/2008

TABLE 1. Optimization of Reaction Conditionsa
TABLE 2. Barbier-Grignard-Type Alkylation Reaction of
Different Aldehydes and Alkyl Halides in Watera
entry
conditions
yield (%)b
1
2
3
4
5
6
7
8
Mg/CuI/InCl2
Sn/CuI/InCl2
Cr/CuI/InCl2
Ge/CuI/InCl2
Mn/CuI/InCl2
Fe/CuI/InCl2
Al/CuI/InCl2
In/CuI/InCl2
InCl2
0
0
0
0
0
trace
48
69
0
9
10
11
12
13
14
15
16
17
18
In/CuI/InCl
In/CuI/InBr
In/CuI/I2
CuI/I2
In/I2
In/CuI
In/CuBr/I2
In/CuCl/I2
In/AgI/I2
65
41
86
0
21
31
63
58
73
a The reactions were carried out at rt for 2 days using benzaldehyde
(0.5 mmol), cyclohexyl iodide (2.5 mmol), metal (3 mmol), copper
iodide (1.5 mmol) or silver iodide (2.5 mmol), additive (0.1 mmol), and
water (10 mL). b Isolated yield based on aldehyde.
type alkylation reaction of aldehydes by using an In/CuI/I2 or
In/AgI/I2 system in water.
Initial studies were focused on the Barbier–Grignard-type
alkylation reaction of benzaldehyde and cyclohexyl iodide in
water employing different metals. The results are summarized
in Table 1.
As shown in Table 1, among the several metals screened,
indium in conjunction with CuI and InCl2 afforded 69% yield
of the corresponding alkylated product (Table 1, entries 1–8).
In addition, it was found that the solo utilization of InCl2
(without In/CuI) afforded no desired product (Table 1, entry
9). Following an attempt to change the use of InCl2 to other
additives (such as InCl, InBr, and I2) showed that the reaction
with the use of a combinatorial system of In/CuI/I2 furnished
the corresponding product in the best yield (86%, Table 1,
entries 10–12). Since I2 is the cheapest and easily available
reagent compared to other additives, it was chosen as the
reaction additive for subsequent reactions.
It is important to note that In, CuI, and I2 are all essential for
the efficient progress of the reaction (Table 1, entries 12–15):
(i) without the use of indium, no desired product was obtained;
(ii) without employing CuI, the product was obtained in lower
yield (21%); (iii) without the addition of I2, the corresponding
product was generated in relatively poor yield of 31%.
Other copper salts such as CuBr and CuCl were also
investigated, but both gave the desired product in lower yields
compared to CuI (Table 1, entries 16 and 17). Interestingly, it
was found that the same reaction could also proceed efficiently
in the presence of the In/AgI/I2 system to give the desired
product in 73% yield (Table 1, entry 18). Therefore, subsequent
works involving various aldehydes and alkyl halides were
carried out using the optimized reaction conditions of In/CuI/I2
and In/AgI/I2 in water.
a The reactions were carried out at rt for 2 days using aldehyde (0.5
mmol), alkyl iodide (2.5 mmol), indium (3 mmol), copper iodide (1.5
mmol) or silver iodide (2.5 mmol), iodine (0.1 mmol), and water (10
mL). b Isolated yield based on aldehyde. c Diastereoselectivity ratio:
49:51. d Diastereoselectivity ratio: 48:52. e Not carried out.
products in poor yields. It seemed that the use of organic
solvents inhibited the occurrence of the Barbier–Grignard-type
alkylation reaction. In addition, it was found that the combina-
tion of organic solvent and water as reaction cosolvent also led
to decreased yield. The results revealed that water was important
for the activation of indium and for scavenging the resulting
alkoxide anion.
It was worthwhile to note that the same reaction performed
in organic solvents, such as CH2Cl2, hexane, THF, MeOH,
CH3CN, and DMSO, proceeded sluggishly to give the desired
Encouraged by the above results, we carried out a wide
variety of aldehydes and alkyl halides under optimized reaction
J. Org. Chem. Vol. 73, No. 10, 2008 3923

SCHEME 1. Mechanism Study Using 4-Pentenal as
Substrate
of the generated alkoxide anion d in the presence of water
afforded the desired product e.
In summary, we have developed an efficient method for the
Barbier–Grignard-type alkylation reaction of different aldehydes
using unactivated alkyl halides in water. This method is
practical, and it works with a wide variety of aldehydes including
aliphatic aldehydes. The mild reaction conditions, moderate to
good yields, and the simplicity of the reaction procedure make
this method attractive for scale-up purposes. Further investiga-
tions regarding the development of an asymmetric version of
Barbier–Grignard-type alkylation reaction of aldehydes in water
are currently in progress.
SCHEME 2. Proposed Reaction Mechanism
Experimental Section
General Procedure for the Barbier–Grignard-Type Alkyla-
tion Reaction of Benzaldehyde in Water. Water (10 mL),
benzaldehyde (0.053 g, 0.5 mmol), and I2 (0.0253 g, 0.1 mmol)
were added to a 10 mL round-bottomed flask. After stirring for
several minutes, then indium (0.344 g, 3 mmol) and copper iodide
(0.286 g, 1.5 mmol) or silver iodide (0.587 g, 2.5 mmol) were added
sequentially to the flask. After stirring for 10 min, cyclohexyl iodide
(0.53 g, 2.5 mmol) was introduced into the reaction system, and it
was stirred vigorously at room temperature for 2 days. After
reaction, 2 mL of aqueous HCl (1 M) was added to the flask, then
it was extracted with diethyl ether (20 mL × 3), washed with brine,
dried over sodium sulfate, filtered, and evaporated to give the oil
residue. It was subjected to silica gel column chromatography using
ethyl acetate and hexane as eluent to afford the desired product as
colorless oil: Rf ) 0.28 (ethyl acetate/hexane, 1:8); FTIR (NaCl,
conditions using In/CuI/I2 and In/AgI/I2 systems in water. The
results are summarized in Table 2.
As shown in Table 2, the Barbier–Grignard-type alkylation
reaction of different aldehydes and alkyl halides proceeded
smoothly in water to generate the corresponding products in
moderate to good yields. In contrast to the reported system,9 it
was noteworthy that even aliphatic aldehydes (hydrocinnama-
ldehyde and nonyl aldehyde) could also react efficiently with
alkyl iodides to furnish the alkylated products in moderate to
good yields (Table 2, entries 11–14). However, with regard to
alkyl bromide, the reaction involving 4-bromobenzaldehyde and
cyclohexyl bromide proceeded sluggishly to give the desired
product in poor yield (<11%).
In order to investigate the reaction mechanism, we continued
to apply the reaction system to 4-pentenal. As shown in Scheme
1, aside from the generation of expected alkylation product 1,
the formation of a furan-type product 2 has also been observed
in the reaction of 4-pentenal with cyclohexyl iodide. It provided
powerful evidence for a radical-type reaction mechanism.
According to this observation, a plausible reaction mechanism
has been proposed as shown in Scheme 2.
1
neat) ν 3440 cm-1; H NMR (300 MHz, CDCl3) δ 0.84–1.29 (m,
5H), 1.34–1.38 (m, 1H), 1.53–1.77 (m, 4H), 1.95–2.00 (m, 2H),
4.33 (d, J ) 7.14 Hz, 1H), 7.22–7.34 (m, 5H) ppm; 13C NMR (75.4
MHz, CDCl3) δ 143.6 (C), 128.1 (CH × 2), 127.3 (CH), 126.6
(CH × 2), 79.3 (CH), 44.9 (CH), 29.3 (CH2), 28.8 (CH2), 26.4
(CH2), 26.1 (CH2), 26.0 (CH2) ppm; HRMS (EI, m/z) [M]+, calcd
for C13H18O 190.1358, found 190.1346.
Acknowledgment. We gratefully acknowledge the Nan-
yang Technological University, Ministry of Education (No.
M45110000) and A*STAR (No. M47110000) for the funding
of this research.
Supporting Information Available: Compound character-
ization data (1H NMR, 13C NMR, IR, and HRMS) and copies
of 1H NMR and 13C NMR spectra of all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
As illustrated in Scheme 2, the reaction was initiated by a
single-electron transfer from indium-copper (or indium-silver)
to alkyl iodide a to generate an alkyl radical b, then it attacked
the aldehyde to furnish a radical intermediate c. Subsequent
indium-promoted reduction of intermediate c and the quenching
JO8000589
3924 J. Org. Chem. Vol. 73, No. 10, 2008