Indium (Zinc)-copper-mediated barbier-type alkylation reaction of nitrones in water: Synthesis of amines and hydroxylamines

Article abstract of DOI:10.1021/ol8027362

An efficient method for the Barbier-type alkylation reaction of various nitrones (including chiral version) and alkyl halides in water is described. The amines and hydroxylamines can be obtained in good yields, depending on the judicious choice of the metal complexes used.

Full text of DOI:10.1021/ol8027362

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1209-1212
Indium (Zinc)-Copper-Mediated
Barbier-Type Alkylation Reaction of
Nitrones in Water: Synthesis of Amines
and Hydroxylamines
Yong-Sheng Yang, Zhi-Liang Shen, 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 November 26, 2008
ABSTRACT
An efficient method for the Barbier-type alkylation reaction of various nitrones (including chiral version) and alkyl halides in water is described.
The amines and hydroxylamines can be obtained in good yields, depending on the judicious choice of the metal complexes used.
In recent years, there has been great interest in the develop-
ment of organic reactions in aqueous media,1 especially
Barbier-type reactions in aqueous media.2 The use of water
as a solvent in organic synthesis has many advantages from
both economical and environmental aspects.3 In conjunction
with our interest in the development of new organic reactions
in aqueous media for the functionalization of biomolecules,
our group has extensively studied the indium- or zinc-
mediated allylation and alkylation reactions of carbonyl
compounds and imines in aqueous media.2e-g,4 Most of the
previously reported metal-mediated alkylation reactions were
focused on the use of activated imines, such as sulfonimines,
tosyl, aryl hydrazones, and glyoxylic oxime ethers, etc.5
However, due to the unstable nature of most imines, only
limited imines could be employed in aqueous reactions.
Successful cases usually employed methanol and water as
(1) Organic reactions in water, for reviews see: (a) Li, C. J. Acc. Chem.
Res. 2002, 35, 533. (b) Herrerías, C. I.; Yao, X. Q.; Li, Z. P.; Li, C. J.
Chem. ReV. 2007, 107, 2546. (c) Chauhan, K. K.; Frost, C. G. J. Chem.
Soc., Perkin Trans. 1 2000, 3015. (d) Ranu, B. C. Eur. J. Org. Chem. 2000,
2347. (e) Babu, G.; Perumal, P. T. Aldrichimica Acta 2000, 33, 16. (f)
Loh, T. P. In Science of Synthesis; Yamamoto, H., Ed.; Georg Thieme
Verlag: New York, 2004; p 413. (g) Li, C. J.; Chan, T. H. Tetrahedron
1999, 55, 11149. (h) Li, C. J. Chem. ReV. 2005, 105, 3095. (i) Li, C. J.
Chem. ReV. 1993, 93, 2023. (j) Li, C. J.; Chen, L. Chem. Soc. ReV. 2006,
35, 68. (k) Dallinger, D.; Kappe, C. O. Chem. ReV. 2007, 107, 2563. (l)
Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209. (m) Lindstro¨m,
U. M. Chem. ReV. 2002, 102, 2751.
(3) (a) Garner, P. P.; Parker, D. T.; Gajewski, J. J.; Lubineau, A.; Ange,
J.; Queneau, Y.; Beletskaya, I. P.; Cheprakov, A. V.; Fringuelli, F.; Piermatti,
O.; Pizzo, F.; Kobayashi, S. In Organic Synthesis in Water; Grieco, P. A.,
Ed.; Blackie Academic & Professional: London, UK, 1998. (b) Organic
Reactions in Water: Principles, Strategies and Applications; Lindstro¨m,
U. M., Ed.; Blackwell Publishing: Oxford, 2007. (c) Li, C. J.; Chan, T. H.
In ComprehensiVe Organic Reactions in Aqueous Media, 2nd ed; John Wiley
& Sons, Inc.: Hoboken, NJ, 2007.
(4) (a) Wang, R. B.; Lim, C. M.; Tan, C. H.; Lim, B. K.; Sim, K. Y.;
Loh, T. P. Tetrahedron: Asymmetry 1995, 6, 1825. (b) Li, X. R.; Loh, T. P.
Tetrahedron: Asymmetry 1996, 7, 1535. (c) Loh, T. P.; Cao, G. Q.; Pei, J.
Tetrahedron Lett. 1998, 39, 1453. (d) Loh, T. P.; Li, X. R. Eur. J. Org.
Chem. 1999, 1893. (e) Loh, T. P.; Zhou, J. R.; Yin, Z. Org. Lett. 1999, 1,
1855. (f) Loh, T. P.; Zhou, J. R. Tetrahedron Lett. 1999, 40, 9115. (g)
Loh, T. P.; Zhou, J. R. Tetrahedron Lett. 2000, 41, 5261. (h) Loh, T. P.;
Huang, J. M.; Xu, K. C.; Goh, S. H.; Vittal, J. J. Tetrahedron Lett. 2000,
41, 6511. (i) Loh, T. P.; Song, H. Y. Synlett 2002, 2119. (j) Loh, T. P.;
Yin, Z.; Song, H. Y.; Tan, K. L. Tetrahedron Lett. 2003, 44, 911. (k) Huang,
J. M.; Xu, K. C.; Loh, T. P. Synthesis 2003, 755.
(2) (a) Keh, C. C. K.; Wei, C. M.; Li, C. J. J. Am. Chem. Soc. 2003,
125, 4062. (b) Zhang, W. C.; Li, C. J. J. Org. Chem. 1999, 64, 3230. (c)
Li, C. J. Tetrahedron 1996, 52, 5643. (d) Chan, T. H.; Isaac, M. B. Pure
Appl. Chem. 1996, 68, 919. (e) Shen, Z. L.; Loh, T. P. Org. Lett. 2007, 9,
5413. (f) Shen, Z. L.; Cheong, H. L.; Loh, T. P. Chem.-Eur. J. 2008, 14,
1875. (g) Shen, Z. L.; Yeo, Y. L.; Loh, T. P. J. Org. Chem. 2008, 73,
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10.1021/ol8027362 CCC: $40.75
Published on Web 02/12/2009
2009 American Chemical Society

cosolvent. To the best of our knowledge, the analogous
metal-mediated alkylation reactions of more stable nitrones
using alkyl halides in water have not been investigated.
Herein, we report an efficient method for the alkylation of a
wide variety of nitrones promoted by indium (zinc)-copper
in aqueous media. The amines and hydroxylamines can be
obtained depending on the judicious choice of the metal
complexes used.
Table 2. Alkylation Reactions of Nitrones in Water
Initial studies were focused on the alkylation reaction of
nitrone 1a and cyclohexyl iodide 2 under different reaction
conditions. The results are summarized in Table 1.
Table 1. Optimization of Reaction Conditionsa
yield (%)b
entry
conditions
3a
4a
1
2
3
4
Sn/CuI
Mg/CuI
In/CuI
In
0
0
82
6
0
0
0
0
5
CuI
0
0
6
7
8
9
In/CuBr
In/CuCl
In/AgI
In/AgBr
In/AgCl
Fe/CuI
Al/CuI
Zn/CuI
Zn
Zn/CuBr
Zn/CuCl
Zn/AgI
Zn/AgBr
Zn/AgCl
44
34
61
40
29
0
0
0
0
0
0
0
0
0
10
11
12
13
14
15
16
17
18
19
0
11
38
90
42
72
60
79
60
58
0
0
0
0
a Reaction was carried out at rt for 1 day, using In or Zn (2 mmol), CuI
(1 mmol), 1a (0.5 mmol), cyclohexyl iodide (2 mmol), and water (10 mL).
b Isolated yield.
a Isolated yield. b Diastereomeric ratio: 54:46. c Diastereomeric ratio:
98:2.
As shown in Table 1, among the different metals inves-
tigated, indium and zinc (good reducing metals with high
potential to mediate organic transformations via single-
electron transfer process) were observed to be effective
metals for the activation of the alkylation reaction of 1a in
water to obtain the corresponding amine 3a and hydroxy-
lamine 4a in 82 and 90% yields, respectively (Table 1, entries
3 and 13). It was worth noting that without the use of CuI
in In/CuI or Zn/CuI system, the reaction proceeded sluggishly
to give the desired product in lower yield (Table 1, entries
4 and 14). In addition, the utilization of other copper salts
instead of CuI produced the corresponding products in
relatively low yields (Table 1, entries 6 and 7). Moreover,
when silver salts were used, the desired product was obtained
in lower yield as compared to the reactions carried out using
copper iodide (Table 1, entries 8-10). It was also found that
the use of metal such as indium is indispensable for the
occurrence of this alkylation reaction (Table 1, entry 5).
Interestingly, when Zn/CuI was used as reaction promoter,
(5) (a) Piao, X.; Jung, J. K.; Kang, 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, 3467. (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.
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Org. Lett., Vol. 11, No. 6, 2009

we found that the product was hydroxylamine 4a rather than
amine 3a. Furthermore, it was observed that these reactions
proceeded in lower yields in organic solvents than in water.
For example, only 30 and 18% yields of amines were
obtained using CH3CN and MeOH as solvents for the In/
CuI system, and 31 and 21% yields of the hydroxylamines
were obtained using CH3CN and MeOH as solvents for the
Zn/CuI system.
By using the optimized reaction conditions (In/CuI or Zn/
CuI), we further explored this reaction for various nitrones
and alkyl iodides in water. The results are summarized in
Table 2 and Table 3.
when primary iodides such as n-butyl iodide was used in
the reaction.
As shown in Table 3, Zn/CuI also efficiently mediated
the alkylation reactions of various nitrones in aqueous media
at ambient temperature. The corresponding alkylated hy-
droxylamines were obtained in moderate to good yields. The
reaction proceeded more efficiently for the substrate 1a and
cyclohexyl iodide yielding the product in 90% (Table 3, entry
2). Interestingly, this alkylation reaction could proceed
smoothly using butyl iodide to afford the product in moderate
yield (Table 3, entry 1). It was also found that a moderate
yield of the desired product was obtained when 1i and chiral
nitrone 1h were used as substrates (Table 3, entries 11 and
12). The structures of products 4f (see Supporting Informa-
tion for details) and 4i (Figure 1) were further confirmed by
a single crystal X-ray diffraction analysis.6
Table 3. Alkylation Reactions of Nitrones in Water
Figure 1. ORTEP diagram of the single-crystal X-ray structure of
compound 4i.
A plausible reaction mechanism was proposed to account
for the alkylation reaction (Scheme 1). The reaction was
Scheme 1. Proposed Reaction Mechanism
a Isolated yield. b Diastereomeric ratio: 55:45. c Diastereomeric ratio:
88:12.
As shown in Table 2, In/CuI efficiently mediated the
alkylation reactions of various nitrones in water at ambient
temperature to afford the corresponding alkylated amines in
moderate to good yields. It is noted that when alkyl
substituted nitrone 1b was used, the reaction also proceeded
efficiently with isopropyl iodide to furnish the desired product
in good yield (Table 2, entry 5). It was gratifying to find
that the alkylation reaction using In/CuI worked efficiently
for chiral nitrone 1h and afforded the desired product in good
yield and high diastereoselectivity (98:2 dr, Table 2, entry
13). This provides a potentially efficient method for the
synthesis of chiral amines. No desired product was obtained
initiatedbyasingle-electrontransfer(SET)fromindium-copper
to alkyl iodide a to generate an alkyl radical b. This radical
b attacked the nitrone to furnish a radical intermediate c.
Subsequent indium-promoted reduction followed by the
quenching of water afforded hydroxylamine d. Finally, d
was further reduced via indium-mediated SET process to give
the desired amine e.7
(6) Crystallographic data (including structure factors) for compounds
4f and 4i (CCDC 703861 and 703862) reported in this paper have been
deposited with the Cambridge Crystallographic Data Center. See Supporting
Information for details.
Org. Lett., Vol. 11, No. 6, 2009
1211

In summary, we have developed an efficient method for
the Barbier-type alkylation reaction of different nitrones and
alkyl halides in water. This finding sheds light on the fact
that the alkylation reaction in the presence of In/CuI or Zn/
CuI allows easy construction of a large library of amines or
hydroxylamines. The mild reaction conditions, moderate to
good yields, and the simplicity of the reaction procedure
make this method attractive for scale-up purposes. Efforts
to apply this method for the synthesis of complex molecules
as well as expanding it to the intramolecular version are
currently in progress.
Acknowledgment. We thank Dr Yong-Xin Li (Nanyang
Technological University) for X-ray analyses. We gratefully
acknowledge the Nanyang Technological University and
Singapore Ministry of Education Academic Research Fund
Tier 2 (No. T206B1221 and T207B1220RS) for funding of
this research.
Supporting Information Available: Additional experi-
ment procedures, spectra data for all the compounds, and
two CIF files. This material is available free of charge via
the Internet at http://pubs.acs.org.
(7) Cicchi, S.; Bonanni, M.; Cardona, F.; Revuelta, J.; Goti, A. Org.
Lett. 2003, 5, 1773.
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