Indium - Copper-mediated barbier - Grignard-type alkylation reaction of imines in aqueous media

Article abstract of DOI:10.1021/ol702263b

An efficient system of In/Cul/InCl₃ was developed for Barbier-Grignard-type alkylation reactions of simple imines, using a one-pot condensation of various aldehydes, amines (including aliphatic and chiral version), and alkyl iodides in water or

Full text of DOI:10.1021/ol702263b

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5413-5416
Indium
Barbier
−
−
Copper-Mediated
Grignard-Type Alkylation
Reaction of Imines in Aqueous Media
Zhi-Liang Shen and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371, Singapore
teckpeng@ntu.edu.sg
Received September 20, 2007
ABSTRACT
An efficient system of In/CuI/InCl3 was developed for Barbier−Grignard-type alkylation reactions of simple imines, using a one-pot condensation
of various aldehydes, amines (including aliphatic and chiral version), and alkyl iodides in water or aqueous media. The reactions proceeded
efficiently at room temperature to give the desired products in moderate to good yields. Good diastereoselectivities were obtained when using
L
-valine methyl ester as substrate.
Amines are important compounds which are featured in a
wide variety of drugs and natural products. Among the many
synthetic methods available for the synthesis of amines, the
addition of organometallics to imines provides one of the
most straightforward methods to amines.1,2 Unfortunately,
due to the labile nature of imines and moisture-sensitive
organometallics, most of these reactions have to be carried
out under strictly anhydrous conditions. In recent years, there
have been some successes in carrying out metal-mediated
allylation reactions with zinc and indium in aqueous media.3,4
However, the corresponding alkylation of imines is more
difficult to achieve and has been the target of research by
numerous groups.5-9 Unfortunately, these methods are mainly
applicable to more reactive imines such as oxime ethers,
hydrazones, and glyoxylate imines.6,7 The limited scope in
these reported systems encourages us to search for new
metal-mediated alkylation reactions of simple imines in
aqueous media. Therefore, the development of new metal-
mediated alkylation reactions of simple imines in aqueous
media remains a challenge for organic chemists. If successful,
this method can also be used to replace or substitute Grignard
reagents and will greatly aid organic chemists. In this Letter,
(3) Allylation of imines in aqueous media is mostly limited to activated
imines, such as sulfonimines, tosyl and aryl hydrazones, glyoxylic oxime
ethers, etc. For examples, see: (a) Piao, X.; Jung, J. K.; Knag, H. Y. Bull.
Korean Chem. Soc. 2007, 28, 139 and references cited therein. (b) Chan,
T. H.; Lu, W. Tetrahedron Lett. 1998, 39, 8605. (c) Lu, W.; Chan, T. H.
J. Org. Chem. 2000, 65, 8589. (d) Lu, W.; Chan, T. H. J. Org. Chem.
2001, 66, 3437. (e) Kumur, H. M. S.; Anjaneyulu, S.; Reddy, E. J.; Yadav,
J. S. Tetrahedron Lett. 2000, 41, 9311. (f) Ritson, D. J.; Cox, R. J.; Berge,
J. Org. Biomol. Chem. 2004, 2, 1921. (g) Bernardi, L.; Cere, V.; Fermoni,
C.; Pollicino, S.; Ricci, A. J. Org. Chem. 2003, 68, 3348. (h) Miyabe, H.;
Yamaoka, Y.; Naito, T.; Takemoto, Y. J. Org. Chem. 2003, 68, 6745. (i)
Miyabe, H.; Yamaoka, Y.; Naito, T.; Takemoto, Y. J. Org. Chem. 2004,
69, 1415.
(4) Organic reactions in water; for reviews, see: (a) Herrer´ıas, C. I.;
Yao, X. Q.; Li, Z. P.; Li, C. J. Chem. ReV. 2007, 107, 2546. (b) Chauhan,
K. K.; Frost, C. G. J. Chem. Soc., Perkin Trans. 1 2000, 3015. (c) Ranu,
B. C. Eur. J. Org. Chem. 2000, 2347. (d) Babu, G.; Perumal, P. T. Aldrichim.
Acta 2000, 33, 16. (e) Loh, T. P. In Science of Synthesis; Yamamoto, H.,
Ed.; Georg Thieme Verlag: New York, 2004; p 413. (f) Li, C. J.; Chan, T.
H. Tetrahedron 1999, 55, 11149. (g) Li, C. J. Chem. ReV. 2005, 105, 3095.
(h) Li, C. J. Chem. ReV. 1993, 93, 2023.
(1) For reviews, see: (a) Bloch, R. Chem. ReV. 1998, 98, 1407. (b)
Volkmann, R. A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 1, Chapter
1.12, pp 355, and references cited therein. (c) Friestad, G. K. Tetrahedron
2001, 57, 5461. (d) Denmark, S. E.; Nicaise, O. J.-C. Chem. Commun. 1996,
999.
(2) For examples, see: (a) Miyoshi, N.; Ikehara, D.; Kohno, T.; Matsui,
A.; Wada, M. Chem. Lett. 2005, 34, 760. (b) Hatano, M.; Suzuki, S.;
Ishihara, K. J. Am. Chem. Soc. 2006, 128, 9998. (c) Saito, S.; Hatanaka,
K.; Yamamoto, H. Synlett 2001, 1859 and references cited therein.
(5) Huang, T.; Keh, C. C. K.; Li, C. J. Chem. Commun. 2002,
2440.
(6) Liu, X. Y.; Zhu, S. Z.; Wang, S. W. Synthesis 2004, 683.
10.1021/ol702263b CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/01/2007

we report an efficient method for the alkylation of a wide
variety of imines via a one-pot condensation of aldehyde,
amine (including aliphatic and chiral version), and alkyl
iodide using indium-copper in aqueous media.
Initial studies were focused on the one-pot reaction of
benzaldehyde, aniline, and cyclohexyl iodide under different
conditions.
DMSO, and hexane afforded the desired product in much
lower yields. With the optimized reaction conditions in hand,
we applied this reaction system to various aldehydes, amines,
and alkyl iodides.
As shown in Table 2, the one-pot reaction involving
various aldehydes, amines, and secondary alkyl iodides11
As shown in Table 1, it was found that the combination
of In/CuI/InCl3 was an efficient system for the activation of
Table 2. One-Pot Alkylation Reaction of Imines in Watera
Table 1. Optimization of Reaction Conditionsa
entry
conditions
yield (%)b
1
2
3
4
5
6
In/CuI/InCl3
In/InCl3
In/CuI
CuI/InCl3
In/CuBr/InCl3
In/CuCl/InCl3
97
17
53
0
63
36
a The reaction was carried out at rt for 1 day, using In(6 equiv), CuI (4
equiv), InCl3 (0.1 equiv), aldehyde (1 equiv), amine (1.2 equiv), alkyl iodide
(5 equiv), and water (10 mL). b Isolated yield.
imine alkylation in water, to generate the corresponding
product in 97% yield (entry 1). It is important to note that
the reaction without the use of CuI gives the desired product
only in 17% yield (entry 2, mainly giving imine self-coupling
product).10 In addition, it was observed that the reaction
proceeded sluggishly to produce the desired product only in
53% yield without the addition of InCl3 (entry 3). Moreover,
it was found that the use of metal (here indium) is also
indispensable for the occurrence of this alkylation reaction.
Without it, no desired product was formed (entry 4). Among
the several metals screened, indium proved to be the best
for this reaction, and the metals exhibited the following order
for the activation of the imine alkylation reaction: In > Zn
> Al > Sn. Other copper compounds such as CuBr and CuCl
were also investigated, but all gave the products in lower
yields in comparison with CuI (entries 5-6).
a Unless otherwise noted, the reaction was carried out at rt for 1 day,
using In(6 equiv), CuI (4 equiv), InCl3 (0.1 equiv), aldehyde (1 equiv),
amine (1.2 equiv), alkyl iodide (5 equiv), and water (10 mL). b Isolated
yield. c Using MeOH:H2O ) 1:1. d Using 2 equiv of amine. e Diastereo-
selectivity ratio: 50:50. f Diastereoselectivity ratio: 60:40.
It was worthwhile to note that the same reactions carried
out in organic solvents such as MeOH, THF, CH2Cl2, DMF,
(7) For reviews, see: (a) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004,
1140 and references cited therein. (b) Miyabe, H.; Naito, T. Org. Biomol.
Chem. 2004, 2, 1267. For examples, see: (c) Miyabe, H.; Ueda, M.; Naito,
T. J. Org. Chem. 2000, 65, 5043. (d) Miyabe, H.; Ueda, M.; Nishimura,
A.; Naito, T. Tetrahedron 2004, 60, 4227. (e) Miyabe, H.; Ueda, M.;
Nishimura, A.; Naito, T. Org. Lett. 2002, 4, 131. (f) Miyabe, H.; Ueda,
M.; Naito, T. Chem. Commun. 2000, 2059. (g) Ueda, M.; Miyabe, H.;
Nishimura, A.; Sugino, H.; Naito, T. Tetrahedron: Asymmetry 2003, 14,
2857. (h) Miyabe, H.; Nishimura, A.; Ueda, M.; Naito, T. Chem. Commun.
2002, 1454. (i) Ueda, M.; Miyabe, H.; Sugino, H.; Naito, T. Org. Biomol.
Chem. 2005, 3, 1124.
proceeded efficiently in water at ambient temperature to
generate the corresponding alkylation products in moderate
to excellent yields. It was gratifying to find that even aliphatic
amines such as benzylamine could also react efficiently with
different aldehydes and secondary alkyl iodides to furnish
the desired products in moderate to good yields (entries 7-9,
11, 12, and 14).
(8) Cannella, R.; Clerici, A.; Pastori, N.; Regolini, E.; Porta, O. Org.
Lett. 2005, 7, 645.
(9) For the alkylation of aldehydes in aqueous media, see: Keh, C. C.
K.; Wei, C. M.; Li, C. J. J. Am. Chem. Soc. 2003, 125, 4062.
(10) Kalyanam, N.; Rao, G. V. Tetrahedron Lett. 1993, 34, 1647.
(11) For primary iodide and tertiary iodide, the one-pot reactions of
benzaldehyde, aniline, and n-hexyl iodide or tert-butyl iodide proceeded
sluggishly under optimized conditions to give the desired products in very
low yields.
5414
Org. Lett., Vol. 9, No. 26, 2007

Table 3. One-Pot Alkylation Reaction of Imines with Various
Chiral Aminesa
Table 4. One-Pot Alkylation Reaction of Imines with L-Valine
Methyl Estera
a Unless otherwise noted, the reaction was carried out at rt for 1 day,
using In(6 equiv), CuI (4 equiv), InCl3 (1 equiv), aldehyde (1 equiv), amine
(2 equiv), alkyl iodide (5 equiv), MeOH (5 mL), and H2O (5 mL). b Isolated
yield. c Using InCl3 (0.1 equiv). d Not determined.
With the possibility of using aliphatic amines such as
benzylamine for this one-pot reaction in water, we continued
to apply this reaction system to chiral amines in the hope of
providing a new method for the synthesis of enantiomerically
enriched amino compounds.
As indicated in Table 3, using L-valine methyl ester as
substrate, it was found that the one-pot reaction proceeded
more efficiently in a mixture of MeOH and H2O (1:1) than
in water or MeOH, to give the desired product in good yields
and diastereoselectivities (77% yield, 92:8 dr, entries 2-4).
In addition, it was observed that the utilization of 1 equiv of
InCl3 helped to increase the reaction yield from 65% to 77%
(entries 1 and 2). When the optimized reaction conditions
were extended to other chiral amines, in all cases the
reactions proceeded efficiently to furnish the desired products
in moderate to good yields and lower diastereoselectivities
(entries 5-8). Therefore, L-valine methyl ester was used as
a chiral amine in subsequent reactions with various aldehydes
and secondary alkyl iodides.
As shown in Table 4, the one-pot reaction employing
various aldehydes and alkyl iodides condensed efficiently
with L-valine methyl ester to generate the desired products
in moderate to good yields and good diastereoselectivities.
It is worthy to note that even aliphatic aldehydes (hydro-
cinnamaldehyde and nonyl aldehyde, entries 5, 6, 10, 11,
15, and 16) are also good substrates for this reaction. In all
cases, the reactions proceeded efficiently in aqueous media
to give the desired products in good yields and enantio-
selectivities.
a The reaction was carried out at rt for 1 day, using In(6 equiv), CuI (4
equiv), InCl3 (1 equiv), aldehyde (1 equiv), amine (2 equiv), alkyl iodide
(5 equiv), MeOH (5 mL), and H2O (5 mL). b Isolated yield.
The chiral auxiliary can be easily removed by reported
procedures (DIBAL-H reduction followed by Pb(OAc)4- or
H5IO6-mediated oxidative cleavage of the corresponding
amino alcohol) to afford the optically active amines.12 With
use of this method, the absolute configuration of the product
was determined as shown in Scheme 1.
A plausible reaction mechanism is proposed (Scheme 2).
The reaction was initiated by a single-electron transfer from
(12) (a) Loh, T. P.; Chen, S. L. Org. Lett. 2002, 4, 3647. (b) Lee, C. L.
K.; Loh, T. P. Org. Lett. 2005, 7, 2965.
(13) Yang, T. K.; Chen, R. Y.; Lee, D. S.; Peng, W. S.; Jiang, Y. Z.;
Mi, A. Q.; Jong, T. T. J. Org. Chem. 1994, 59, 914.
Org. Lett., Vol. 9, No. 26, 2007
5415

Scheme 1. Determination of Absolute Configuration
Scheme 2. Proposed Reaction Mechanism
indium-copper to alkyl iodide a to generate an alkyl radical
reaction procedure make this method attractive for scale-up
purposes.
b. This radical attacked the imine to furnish a radical inter-
mediate c. Subsequent indium-promoted reduction of inter-
mediate c and the quenching of the generated amino anion
d in the presence of water afforded the desired product e.
Acknowledgment. We gratefully acknowledge Nanyang
Technological University, Ministry of Education (No.
M45110000) and A* STAR (No. M47110000) for the
funding of this research.
In summary, we have developed an efficient method for
the Barbier-Grignard-type alkylation reaction of imines
using a one-pot condensation of various aldehydes, amines,
and secondary alkyl iodides in water or aqueous media. This
method is practical and it works with a wide variety of
aldehydes, amines, and secondary alkyl iodides. The mild
reaction conditions, moderate to good yields, good to
excellent diastereoselectivities, and the simplicity of the
Supporting Information Available: Additional experi-
mental procedures and spectral data for reaction products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL702263B
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Org. Lett., Vol. 9, No. 26, 2007