The Barbier - Grignard-type carbonyl alkylation using unactivated alkyl halides in water

Article abstract of DOI:10.1021/ja029649p

The aqueous Barbier-Grignard-type alkylation of aldehydes with unactivated alkyl iodides and bromides was developed. By using a combination of zinc and cuprous iodide, catalyzed by indium(I) chloride, we successfully added tertiary, secondary, and primary alkyl halides to various aromatic aldehydes in 0.07 M aqueous Na₂C₂O₄. A mechanistic rationale for the success of the reaction has been proposed. Copyright

Full text of DOI:10.1021/ja029649p

Published on Web 03/14/2003
The Barbier-Grignard-Type Carbonyl Alkylation Using Unactivated Alkyl
Halides in Water
Charlene C. K. Keh, Chunmei Wei, and Chao-Jun Li*
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118
Received December 9, 2002; E-mail: cjli@tulane.edu
Scheme 1
There has been considerable recent attention toward the develop-
ment of Barbier-Grignard-type reactions in water.1 This interest
is evident in the number of topical and excellent reviews that have
illuminated the advantages of using aqueous organometallic reac-
tions over those occurring in organic solvent2 in synthesis.3 For
instance, the protection-deprotection processes for certain acidic-
hydrogen-containing functional groups can be avoided, which
contributes to the overall synthetic efficiency.4 Additionally, water-
soluble compounds, such as carbohydrates, can be directly reacted
without the need for derivatization, and water-soluble catalysts can
be reused for an extended period of time, which reduces operational
cost.5 However, while the allylation,6 propargylation,7 benzylation,8
arylation/vinylation,9 and alkynylation10 of carbonyl compounds,
along with the aldol-type reaction,11 have been successful with
various metals in water, a high yield Barbier-Grignard-type
carbonyl alkylation with nonactivated halides in water has yet to
be developed.12
This is largely due to the fact that a highly reactive metal is
required to break the nonactivated carbon-halogen bond (as well
as to react with the carbonyl once the organometallic intermediate
is formed). However, even if the desired intermediate is successfully
generated, various competing side reactions may occur when
utilizing a highly reactive metal, for example, the reduction of
water, the reduction of starting materials, the hydrolysis of the
organometallic intermediate, and pinacol-coupling. Essentially,
these difficulties have prevented the further development of
aqueous organometallic reactions onto simple alkyl halides. Further-
more, on the basis of our unsuccessful attempts in the past, it
was ascertained that to overcome this seemingly insurmountable
dilemma, a particular balance between metal reactivity and side
product conversion must be achieved without severely compromis-
ing the yield of the desired alkylated product. Herein, we are
gratified to report an efficient Barbier-Grignard-type alkylation
of aldehydes in water. In the presence of CuI, Zn, and catalytic
InCl, in dilute aqueous sodium oxalate, simple alkyl halides reacted
with aldehydes at room temperature, under an atmosphere of air,13
to yield the desired nucleophilic addition products in moderate to
high yields.
Table 1. Optimization Conditions
entry
conditionsa
solvent
yield (%)b
1
2
3
InCl/Zn
H2O
H2O
H2O
H2O
H2O
H2O
0
InCl/TBDMSCl/Zn/CuBr
InCl/Zn/CuI
Zn/CuI
30c
13:33:54
0:38:62
no reaction
no reaction
0:12:88d
no reaction
0:25:75
0:36:64
6:12:82
no reaction
trace
13:17:71
4
5
6
InCl/CuBr
InCl/CuI
7
8
9
10
11
12
13
14
InCl/Zn/CuI
InCl/CuBr
InCl/Zn/CuI
InCl/Zn/CuI
InCl/Zn/CuI
InCl/CuI
0.07 M Na2C2O4
0.07 M Na2C2O4
0.07 M K2C2O4
0.07 M KOAc
0.05 M Na2C2O4
0.05 M Na2C2O4
0.05 M Na2C2O4
0.05 M Na2C2O4
InCl/Zn
Zn/CuI
a 18 h reaction at room temperature, based upon 20 mg (0.153 mmol) of
p-cyanobenzaldehyde. b Yield from crude 1H NMR, ratio of unreacted
aldehyde:pinacol:desired product. c Isolated yield. d 0.10 equiv of InCl, 3
equiv of CuI, 5 equiv of isopropyl iodide, 6 equiv of Zn.
Further experiments showed that the optimized conditions only
utilize Zn, CuI, and a catalytic amount of InCl in 0.07 M aqueous
Na2C2O4 (entry 7). The use of aqueous Na2C2O4 was intended to
activate zinc (by dissolving zinc oxide) under neutral conditions.
1
A 12:88% ratio was obtained, as seen from the H NMR of the
reaction mixture, of pinacol product to desired alkylated product,
respectively, based upon the aldehyde. As seen in Table 1, other
aqueous media with KOAc, NaOAc, K2C2O4 were also investigated
but provided poorer results relative to sodium oxalate. Without zinc,
there was no reaction (entry 12); without CuI (entry 13), there was
only a trace amount of the alkylated product; without InCl (entry
14), there was an incomplete conversion of the aldehyde. Similar
conditions but in water (entries 3-6) showed there was either an
incomplete conversion of the aldehyde along with a higher amount
of pinacol-coupling product or no reaction. Additionally, when the
reaction was carried out in organic solvents such as THF, methanol,
and methylene chloride, no desired reaction product was observed.
Also, with an even lower concentration of sodium oxalate (entry
11), there was an incomplete conversion of the aldehyde. Therefore,
on the basis of these results, we concluded that the best conditions
are shown in entry 7.
The investigation started with the reaction of isopropyl iodide
and p-cyanobenzaldehyde (Scheme 1), in the presence of InCl and
Zn, in water with no desired product (Table 1, entry 1), but we
found that with the addition of TBDMSCl and CuBr, there was a
30% isolated yield of the alkylated product (entry 2). Motivated
by this initial result, we looked at the usage of other additives such
as Bu3SnH, (Me3Sn)2, (Me3Ge)2, and (Me3Si)2 in water.14 Even
though these reactions, based upon NMR conversions, did give the
desired product in varying yields, the reaction conditions were still
undesirable because the conversion of aldehyde was not complete
and/or there were large amounts of undesired pinacol-coupled
product. The addition of organic cosolvents and sodium dodecyl
sulfate seemed to hinder the reaction.
Subsequently, a variety of aldehydes and alkyl halides were
examined to generate the Barbier-Grignard alkylation products by
the standard conditions (Scheme 2). Table 2 provides details of
the conditions and results of a series of aldehydes15 and alkyl halides
utilized in the methodology. Several conclusions may be drawn
from the results obtained.
9
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J. AM. CHEM. SOC. 2003, 125, 4062-4063
10.1021/ja029649p CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
Acknowledgment. We are grateful to NSF (CAREER) and the
NSF-EPA joint program for a sustainable environment for partial
support of our research. C.C.K.K. thanks the Louisiana Board of
Regents for a Graduate Fellowship.
Supporting Information Available: Representative experimental
procedure and the full characterization of all new compounds (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
Table 2. Alkylation of Various Aldehydes
2
entry
RCHO
R X
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-CNC6H4CHO
4-CNC6H4CHO
4-CNC6H4CHO
4-CNC6H4CHO
4-CNC6H4CHO
4-CNC6H4CHO
4-CNC6H4CHO
4-BrC6H4CHO
4-ClC6H4CHO
PhCHO
3-MeC6H4CHO
4-CH3C6H4CHO
4-CF3C6H4CHO
4-MeOC6H4CHO
3-HOC6H4CHO
3-ClC6H4CHO
cyclohexyl iodide
cyclohexyl bromide
cyclopentyl iodide
isopropyl iodide
tert-butyl iodide
1-iodo-2-methylpropane
1-iodohexane
cyclohexyl iodide
cyclohexyl iodide
cyclohexyl iodide
cyclohexyl iodide
isopropyl iodide
isopropyl iodide
cyclohexyl iodide
isopropyl iodide
cyclohexyl iodide
71
41
67
85
30
32
14
58
53
46
47
30
83
56
47
66
References
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(3) For representative general reviews regarding organic reactions in water,
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Aldrichimica Acta 1991, 24, 59. Li, C. J.; Chan, T. H. Organic Reactions
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a Isolated yields were reported.
(5) For a recent asymmetric example, see: Uozumi, Y.; Shibatomi, K. J. Am.
Chem. Soc. 2001, 123, 2919.
(6) Nokami, J.; Otera, J.; Sudo, T.; Okawara, R. Organometallics 1983, 2,
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asymmetric example, see: Loh, T. P.; Hu, Q. Y.; Chok, Y. K.; Tan, K.
T. Tetrahedron Lett. 2001, 42, 9277.
Scheme 3. Proposed Mechanism for the Metal-Mediated Addition
of Alkyl Halides to Aldehydes in Water
(7) Issac, M. B.; Chan, T. H. J. Chem. Soc., Chem. Commun. 1995, 1003.
Yi, X. H.; Meng, Y.; Li, C. J. Chem. Commun. 1998, 449. Mitzel, T. M.;
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M.; Miyaura, N. J. Org. Chem. 2000, 65, 4450. Hayashi, T.; Ishigedani,
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Soc. 2000, 122, 9538.
(10) Wei, C. M.; Li, C. J. Green Chem. 2002, 4, 39. For a leading reference
on alkyne-carbonyl addition in organic solvent, see: Carreira, E. M. Acc.
Chem. Res. 2000, 33, 373 and references cited therein.
First, having an electron-withdrawing group (CN, entries 1-7,
Br and Cl, entries 8 and 9, respectively) in the 4-position activates
the aldehyde toward alkylation,16 relative to benzaldehyde. Second,
secondary alkyl iodides provide higher yields of the desired products
(entries 1, 3, 4) than both primary alkyl iodides (entries 6 and 7)
and tertiary alkyl iodide (entry 5). Third, the presence of an electron-
withdrawing group appears to increase the yield of the reaction
(compare entries 12 and 13).17 Fourth, an aldehyde bearing a
hydroxyl group does not prevent it from reacting under the current
reaction conditions.
(11) Chan, T. H.; Li, C. J.; Wei, Z. Y. J. Chem. Soc., Chem. Commun. 1990,
505.
(12) Conjugated addition and imine additions have been reported before;
however, unlike the aldehyde addition, the intermediates in these reactions
are stabilized by the carbonyl or the aryl groups, respectively; for examples,
see: Huang, T. S.; Keh, C. C. K.; Li, C. J. Chem. Commun. 2002, 2440.
Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Org. Lett. 2002, 4, 131.
(13) Li, C. J. Acc. Chem. Res. 2002, 35, 533.
In summary, we have developed the Barbier-Grignard-type
alkylation of aldehydes in water. A tentative mechanism for the
reaction is proposed (Scheme 3) in which the alkyl iodide is reacted
with zinc (activated by copper as in the case of the zinc-copper
couple) to form a radical anion, which then reacts with the aldehyde.
A possible electron transfer from the indium(I) to the carbonyl
oxygen could generate an indium(II) alkoxylate that hydrolyzes to
give the alkylated product, which potentially benefits the alkylation
slightly. The scope, mechanism, and applications of this reaction
are under further investigation.
(14) Further details are provided in the Supporting Information.
(15) No reaction was observed with aliphatic aldehydes such as undecanal,
2,2-dimethylpropionaldehyde, cyclohexancarboxaldehyde. Ketones such
as benzophenone, acetophenone, 2-hexanone, cyclohexanone, and cyclo-
pentanone also did not result in the desired product along with unsaturated
carbonyls such as 4-hexen-3-one and 2,2-dimethyl-4-pentenal.
(16) When 4-nitrobenzaldehyde was used, the reaction mixture 1H NMR
showed an inseparable mix of reduced products. This was attributed to
some reduction of the nitro group under the reaction conditions.
(17) 2,4-Dimethylbenzaldehyde and 2,4-bis(trifluoromethyl)benzaldehyde were
compared in an analogous manner but had poor isolated yields of 17 and
8%, respectively, possibly due to steric effects.
JA029649P
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J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003 4063