Indium-silver- and zinc-silver-mediated barbier-grignard-type alkylation reactions of imines by using unactivated alkyl halides in aqueous media

Article abstract of DOI:10.1002/chem.200701468

In the presence of In or Zn/AgI/InCl₃, an efficient and practical method for the Barbier-Grignard-type alkylation reactions of simple imines by using a one-pot condensation of various aldehydes, amines (including the aliphatic and chiral version), and secondary alkyl iodides has been developed. The reaction proceeded more efficiently in water than in organic solvents. Without the use of CuI, it mainly gave the imine self-reductive coupling product, which was not the alkylated product. Good diastereoselectivities (up to 92:8 dr) were obtained when L-valine methyl ester was used as the substrate.

Full text of DOI:10.1002/chem.200701468

FULL PAPER
DOI: 10.1002/chem.200701468
Indium–Silver- and Zinc–Silver-Mediated Barbier–Grignard-Type Alkylation
Reactions of Imines by Using Unactivated Alkyl Halides in Aqueous Media
Zhi-Liang Shen, Hao-Lun Cheong, and Teck-Peng Loh*[a]
Abstract: In the presence of In or Zn/
AgI/InCl3, an efficient and practical
method for the Barbier–Grignard-type
alkylation reactions of simple imines
by using a one-pot condensation of var-
ious aldehydes, amines (including the
aliphatic and chiral version), and sec-
ondary alkyl iodides has been devel-
oped. The reaction proceeded more ef-
ficiently in water than in organic sol-
vents. Without the use of CuI, it mainly
gave the imine self-reductive coupling
product, which was not the alkylated
product. Good diastereoselectivities
(up to 92:8 dr) were obtained when l-
valine methyl ester was used as the
substrate.
Keywords: alkylation · imines · in-
dium · silver · water chemistry
Introduction
Elegant works by Naito et al. have shown the possibility
of carrying out the metal-mediated alkylation of imines in
aqueous media.[4–7] However, most of the reported methods
are only applicable to activated imines, such as oxime
ethers, hydrazones, and glyoxylate imines.[4,5] The limited
scope in these reported systems encourages us to search for
a new metal-mediated alkylation reaction of simple imines
in water.[8] Herein, we report an efficient method for the al-
kylation of a wide variety of imines by means of a one-pot
condensation of aldehydes, amines (including aliphatic and
chiral version), and alkyl iodides by using indium–silver and
zinc–silver in aqueous media.[9,10]
Organic reactions in aqueous media have attracted tremen-
dous attention because of the many advantages that they
offer.[1] For example, organic reactions in aqueous media
allow multistep synthesis to be carried out more efficiently
without the need for protection–deprotection of the func-
tional groups containing acidic protons. Furthermore, com-
pounds containing water molecules or biomolecules can be
used directly. In conjunction with our interest in the devel-
opment of new organic reactions in aqueous media for the
functionalization of biomolecules, our group has extensively
studied the indium- or zinc-mediated allylation reactions of
carbonyl compounds and imines in aqueous media.[2] How-
ever, the analogous metal-mediated alkylation reactions of
simple imines in aqueous media have been more difficult
and challenging. This is due to the following: 1) Simple
imines have lower electrophilicity and, therefore, are less re-
active; 2) simple imines are easier to hydrolyze in water, es-
pecially aliphatic imines; 3) a simple imine is more prone to
undergo a self-coupling reaction to generate diamine than
an alkylation reaction in the presence of a metal;[3] and
4) alkyl halide is less reactive relative to allylic halide.
Results and Discussion
Initial studies were focused on the one-pot reaction of ben-
zaldehyde, aniline, and cyclohexyl iodide by using different
metals in water. The results are summarized in Table 1.
As shown in Table 1, among the several metals investigat-
ed, both zinc and indium were observed to be effective
metals for the activation of the one-pot reaction of benzal-
dehyde, aniline, and cyclohexyl iodide, to afford the corre-
sponding products in 76 and 88% yields, respectively (en-
tries 6–7). It was important to note that, without the use of
AgI, the reaction proceeded sluggishly to give the desired
product in only 17% yield (the major product was the imine
homocoupling product,[3] entry 8). In addition, the use of
InCl3 was also proved to be indispensable for the efficient
progress of the alkylation reaction. Without the addition of
InCl3, a lower yield of the alkylated product was obtained
(51%, entry 9). The utilization of other silver compounds
[a] Z.-L. Shen, H.-L. Cheong, Prof. Dr. T.-P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371
Fax : (+65)679-11-961
E-mail: teckpeng@ntu.edu.sg
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 1875 –1880
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1875

Table 1. Optimization of reaction conditions for the alkylation of imines.
Table 2. One-pot alkylation reactions of simple imines in water.[a]
Entry RCHO
R’NH2
R’’I
Yield [%][b]
In
Zn
Entry
Conditions
Yield [%][a]
1
2
3
4
5
6
7
8
Al/AgI/InCl3
Mg/AgI/InCl3
Fe/AgI/InCl3
Sn/AgI/InCl3
Mn/AgI/InCl3
Zn/AgI/InCl3
In/AgI/InCl3
In/InCl3
<20
<10
32
1
64
83
0
<10
76
88
2
68
85
17
3
94
82
9
In/AgI
51
10
11
12
13
In/AgCl/InCl3
In/Ag2O/InCl3
In/AgI/ZnCl2
Zn/AgI/ZnCl2
57
21
68
66
4
88
76
[a] Isolated yield.
5
67
43
(AgCl, Ag2O) in the place of AgI produced the correspond-
ing product in relatively low yields as compared to AgI (en-
tries 10–11). When other Lewis acid, such as ZnCl2, were
used in place of InCl3, the alkylated products could also be
obtained albeit in low yields (entries 12–13). Furthermore, it
was observed that these reactions proceeded more efficient-
ly in water than in organic solvents.
By using the optimized reaction conditions (In or Zn/AgI/
InCl3), we continued to carry out the one-pot Barbier–
Grignard-type alkylation reaction of simple imines involving
various aldehydes, amines, and alkyl iodides in water. The
results are outlined in Table 2.
As shown in Table 2, indium–silver and zinc–silver effi-
ciently mediated one-pot reactions of various aldehydes,
amines, and alkyl iodides in water at ambient temperature.
The corresponding alkylated products were furnished in
moderate to good yields.[11] It is worth noting that the
indium–silver system works well even for aliphatic amines,
such as benzylamine, to generate the desired products in
moderate to good yields (entries 9–14).
6
90[c]
73[e]
85[e]
68[e,f]
82[e,f]
76[e,f]
45[d]
65
7
8
76
9
30[e,f]
48[e,f]
53[e,f]
10
11
12
72[e,f,g] 39[e,f,h]
With the success of using aliphatic amines, such as benzyl-
amine, for Barbier–Grignard-type alkylation reactions of
imines in water, we were encouraged to apply this reaction
system to chiral imines in the hope of providing a new
method for the synthesis of enantiomerically enriched
amino compounds.
13
14
58[e,f]
16[e,f]
75[e,f]
37[e,f]
By using l-valine methyl ester as a substrate, it was found
that the one-pot reaction involving benzaldehyde and cyclo-
hexyl iodide worked well in the presence of In/AgI/InCl3 (in
a 1:1 mixture of MeOH and H2O) to afford the desired
product both in good yield and with good diastereoselectiv-
ity (77% yield, 89:11 dr).[12] However, a poor yield (<30%)
of the desired product was obtained when the same reaction
was carried out by using Zn/AgI/InCl3. Therefore, In/AgI/
InCl3 was chosen to apply to one-pot alkylation reactions of
[a] Unless otherwise noted, the reaction was carried out at room temper-
ature for 1 d by using In or Zn (6 equiv), AgI (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] Diastereomeric ratio: 55:45. [d] Diastereo-
meric ratio: 50:50. [e] By using MeOH/H2O 1:1. [f] By using 2 equiv of
amine. [g] Diastereomeric ratio: 67:33. [h] Diastereomeric ratio: 65:35.
1876
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Chem. Eur. J. 2008, 14, 1875 –1880

Alkylation Reactions
FULL PAPER
various aldehydes, alkyl iodides, and l-valine methyl ester in
aqueous media. The results are listed in Table 3.
As shown in Table 3, the one-pot reaction employing vari-
ous aldehydes, alkyl iodides, and l-valine methyl ester con-
good yields and diastereoselectivities of the corresponding
products were obtained. The chiral auxiliary can be easily
removed by reported procedures (diisobutylaluminum hy-
dride (DIBAL-H) reduction followed by H5IO6-mediated
oxidative cleavage of the corresponding amino alcohol) to
afford the optically active amines.[13]
A plausible reaction mechanism has been proposed, as
shown in Scheme 1. The reaction was initiated by a single-
electron transfer from indium–silver (or zinc–silver) to alkyl
iodide a to generate an alkyl radical b, which attacked the
imine (which has been activated by InCl3) to furnish a radi-
cal intermediate c. Subsequent indium (or zinc)-promoted
reduction of intermediate c and the quenching of the gener-
ated amino anion d in the presence of water afforded the
desired product e.
Table 3. One-pot alkylation reactions of simple imines by using l-valine
methyl ester.[a]
Entry
1
RCHO
R’I
Yield [%][b]
72
dr
89:11
2
3
82
65
92:8
Conclusion
We have developed an efficient and practical method for
the Barbier–Grignard-type alkylation reaction of simple
imines in aqueous media. This one-pot three-component
condensation of various aldehydes, amines, and alkyl iodides
in aqueous media, in the presence of In or Zn/AgI/InCl3
allows easy construction of a large library of amines. This
method is practical and it works with a wide variety of alde-
hydes, amines (including aliphatic amines), and secondary
alkyl iodides. The mild reaction conditions, moderate to
good yields, good to excellent diastereoselectivities, and the
simplicity of the reaction procedure make this method at-
tractive 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.
90:10
4
53
88:12
5
6
7
8
86
66
74
80
89:11
89:11
85:15
87:13
Experimental Section
General method: Analytical TLC was performed by using Merck 60 F254
precoated silica-gel plates (0.2 mm thickness). Subsequent to elution,
plates were visualized by using UV radiation (254 nm) on Spectroline
Model ENF-24061/F 254 nm. Further visualization was possible by stain-
ing with an acidic solution of ceric molybdate or an ethanol solution of
ninhydrin. Flash-column chromatography was performed by using Merck
silica gel 60 with freshly distilled solvents. 1H and 13C NMR spectra were
recorded on a Bruker Avance DPX 300 and Bruker AMX 400 spectro-
photometer by using TMS as an internal standard. HRMS spectra were
obtained by using Finnigan MAT95XP GC/HRMS (Thermo Electron
Corporation). IR spectra were recorded on a Bio-Rad FTS 165 FTIR
spectrometer. The proportion of diastereomers was determined from the
9
87
72
89:11
86:14
10
[a] The reaction was carried out at room temperature for 1 d by using In
(6 equiv), AgI (4 equiv), InCl3 (1 equiv), aldehyde (1 equiv), amine
(2 equiv), alkyl iodide (5 equiv), MeOH (5 mL), and water (5 mL).
[b] Isolated yield.
1
integration of H and 13C NMR spectra.
densed efficiently in the presence of In/AgI/InCl3 to gener-
ate the desired products in moderate to good yields and
with good diastereoselectivi-
Materials: Deionised water was used in all reactions. All aldehydes were
purified before use. All commercially available amines (nonchiral amine)
and alkyl iodides were used directly without purification. Commercially
ties. It is worth noting that
even aliphatic aldehydes (hy-
drocinnamaldehyde and nonyl
aldehyde, entries 7–10) were
also demonstrated to be good
substrates for this reaction and
Scheme 1. Proposed reaction mechanism.
Chem. Eur. J. 2008, 14, 1875 –1880
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1877

T.-P. Loh et al.
available chiral amines (hydrochloride form) were washed with saturated
aqueous sodium carbonate solution before use. The following commer-
cial-grade reagents were also used without further purification: indium
(powder, À100 mesh, 99.99%, Aldrich), zinc (powder, 98%, Alfa Aesar),
silver(I) iodide (99.9%, Strem), and indium trichloride (Strem).
26.3 ppm (CH2); IR (NaCl, neat): n˜ =3426 cmÀ1 (NH); HRMS (EI): m/z:
calcd for C19H23N: 265.1830; found: 265.1810 [M]+.
N-Phenyl-(2-methyl-1-phenylpropyl)amine (Table 2, entry 5): Rf =0.63
(EtOAc/hexane 1:8); 1H NMR (400 MHz, CDCl3): d=0.91 (d, J=
6.82 Hz, 3H), 0.97 (d, J=6.78 Hz, 3H), 1.97–2.08 (m, 1H), 4.10 (s, 1H),
4.12 (s, 1H), 6.49 (d, J=7.62 Hz, 2H), 6.60 (t, J=7.30 Hz, 1H), 7.03–7.08
(m, 2H), 7.16–7.29 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=147.7
(C), 142.6 (C), 129.0 (2CH), 128.2 (2CH), 127.2 (2CH), 126.8 (CH),
117.0 (CH), 113.2 (2CH), 63.8 (CH), 34.9 (CH), 19.7 (CH3), 18.6 ppm
(CH3); IR (NaCl, neat): n˜ =3426 cmÀ1 (NH); HRMS (EI): m/z: calcd for
C16H19N: 225.1517; found: 224.1434 [MÀH]+.
General procedure for the alkylation reaction of imines derived from an
aromatic amine and aromatic aldehyde: Water (10 mL), aldehyde
(0.5 mmol), amine (0.6 mmol), and InCl3 (0.05 mmol) were added to a
10 mL round-bottomed flask. After stirring for 10 min at room tempera-
ture, indium or zinc (3 mmol), silver iodide (2 mmol), and alkyl iodide
(2.5 mmol) were added sequentially to the reaction system. The reaction
was stirred vigorously at room temperature for 1 d. After reaction, it was
then extracted by using diethyl ether (20 mL”3), washed with brine,
dried over anhydrous sodium sulfate, filtered, and the solvent was evapo-
rated in vacuo to give the crude product. Silica-gel column chromatogra-
phy by using ethyl acetate and hexane as the eluent afforded the desired
product.
N-Phenyl-(2-methyl-1-phenylbutyl)amine (Table 2, entry 6): Rf =0.63
1
(EtOAc/hexane 1:8); H NMR (300 MHz, CDCl3): two isomers: d=0.85–
0.94 (m, 12H), 1.10–1.32 (m, 2H), 1.42–1.65 (m, 2H), 1.76–1.81 (m, 2H),
4.07 (brs, 2H), 4.20 (d, J=5.82 Hz, 1H), 4.29 (d, J=4.89 Hz, 1H), 6.48
(d, J=8.05 Hz, 4H), 6.57–6.62 (m, 2H), 7.02–7.08 (m, 4H), 7.17–
7.21 ppm (m, 10H); 13C NMR (75.4 MHz, CDCl3): two isomers: d=147.7
(2C), 142.9 (C), 142.3 (C), 129.0 (2CH), 129.0 (2CH), 128.2 (2CH),
128.1 (2CH), 127.3 (2CH), 127.0 (2CH), 126.7 (CH), 126.6 (CH), 116.9
(2CH), 113.1 (2CH), 113.1 (2CH), 62.5 (CH), 61.4 (CH), 41.8 (CH), 41.5
(CH), 26.8 (CH2), 25.3 (CH2), 16.1 (CH3), 14.4 (CH3), 12.0 (CH3),
11.8 ppm (CH3); IR (NaCl, neat): n˜ =3428 cmÀ1 (NH); HRMS (EI): m/z:
calcd for C17H21N: 239.1674; found: 238.1592 [MÀH]+.
General procedure for the alkylation reaction of imines derived from ali-
phatic amine (including benzylamine and l-valine methyl ester): MeOH
(5 mL), H2O (5 mL), aldehyde (0.5 mmol), amine (1.0 mmol), and InCl3
(with 0.05 mmol for benzylamine, 0.5 mmol for l-valine methyl ester)
were added to a 10 mL round-bottomed flask. After stirring for 4 h at
room temperature, indium (3 mmol), silver iodide (2 mmol), and alkyl
iodide (2.5 mmol) were added sequentially to the reaction system. The
reaction mixture was stirred vigorously at room temperature for 1 d.
After reaction, it was extracted by using diethyl ether (20 mL”3),
washed with brine, dried over anhydrous sodium sulfate, filtered, and the
solvent was evaporated in vacuo to give the residue. Silica-gel column
chromatography by using ethyl acetate and hexane (with 1% v/v triethyl
amine) as the eluent afforded the desired product.
N-(p-Chlorophenyl)-(1-phenyl-1-cyclohexylmethyl)amine
(Table 2, entry 7): Rf =0.62 (EtOAc/hexane 1:8); 1H NMR (300 MHz,
CDCl3): d=0.88–1.28 (m, 5H), 1.49–1.53 (m, 1H), 1.57–1.76 (m, 4H),
1.84–1.88 (m, 1H), 4.04 (d, J=6.16 Hz, 1H), 4.14 (brs, 1H), 6.39 (d, J=
8.79 Hz, 2H), 6.97 (d, J=8.79 Hz, 2H), 7.17–7.30 ppm (m, 5H);
13C NMR (75.4 MHz, CDCl3): d=146.3 (C), 142.1 (C), 128.8 (2CH),
128.2 (2CH), 127.1 (2CH), 126.9 (CH), 121.4 (C), 114.2 (2CH), 63.4
(CH), 44.8 (CH), 30.1 (CH2), 29.5 (CH2), 26.4 (CH2), 26.3 (CH2),
26.3 ppm (CH2); IR (NaCl, neat): n˜ =3428 cmÀ1 (NH); HRMS (EI): m/z:
calcd for C19H22ClN: 299.1441; found: 299.1432 [M]+.
N-Phenyl-[1-(p-bromophenyl)-1-cyclohexylmethyl]amine
(Table 2, entry 1): Rf =0.61 (EtOAc/hexane 1:8); 1H NMR (300 MHz,
CDCl3): d=0.83–1.26 (m, 6H), 1.49–1.85 (m, 5H), 4.05 (d, J=6.03 Hz,
1H), 4.09 (brs, 1H), 6.44 (d, J=7.80 Hz, 2H), 6.60 (t, J=7.32 Hz, 1H),
7.02–7.07 (m, 2H), 7.13–7.17 (m, 2H), 7.37–7.40 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=147.4 (C), 141.7 (C), 131.3 (2CH), 129.1 (2CH),
120.4 (C), 128.9 (2CH), 117.2 (CH), 113.1 (2CH), 62.9 (CH), 44.7 (CH),
30.1 (CH2), 29.3 (CH2), 26.3 (CH2), 26.3 (CH2), 26.3 ppm (CH2); IR
(NaCl, neat): n˜ =3422 cmÀ1 (NH); HRMS (EI): m/z: calcd for
C19H22NBr: 343.0936; found: 342.0828 [MÀH]+.
N-(m-Methylphenyl)(1-phenyl-1-cyclohexylmethyl)amine
(Table 2, entry 8): Rf =0.61 (EtOAc/hexane 1:8); 1H NMR (300 MHz,
CDCl3): d=1.01–1.23 (m, 5H), 1.49–1.53 (m, 1H), 1.62–1.71 (m, 4H),
1.84–1.88 (m, 1H), 2.17 (s, 3H), 4.08–4.10 (m, 2H), 6.27 (d, J=7.90 Hz,
1H), 6.34 (s, 1H), 6.41 (d, J=7.30 Hz, 1H), 6.92 (t, J=7.70 Hz, 1H),
7.14–7.27 ppm (m, 5H); 13C NMR (75.4 MHz, CDCl3): d=147.8 (C),
142.8 (C), 138.6 (C), 128.9 (CH), 128.1 (2CH), 127.1 (2CH), 126.6 (CH),
117.9 (CH), 114.0 (CH), 110.1 (CH), 63.3 (CH), 44.9 (CH), 30.2 (CH2),
29.4 (CH2), 26.4 (CH2), 26.3 (CH2), 26.3 (CH2), 21.6 ppm (CH3); IR
(NaCl, neat): n˜ =3381 cmÀ1 (NH); HRMS (EI): m/z: calcd for C20H25N:
279.1987; found: 278.1901 [MÀH]+.
N-Phenyl-[1-(p-chlorophenyl)-1-cyclohexylmethyl]amine
(Table 2, entry 2): Rf =0.59 (EtOAc/hexane 1:8); 1H NMR (300 MHz,
CDCl3): d=0.95–1.29 (m, 5H), 1.42–1.85 (m, 6H), 4.07 (s, 1H), 4.09 (s,
1H), 6.43–6.46 (m, 2H), 6.58–6.63 (m, 1H), 7.02–7.08 (m, 2H), 7.19–
7.26 ppm (m, 4H); 13C NMR (75.4 MHz, CDCl3): d=147.4 (C), 141.2
(C), 132.3 (C), 129.1 (2CH), 128.6 (2CH), 128.4 (2CH), 117.2 (CH),
113.2 (2CH), 62.8 (CH), 44.8 (CH), 30.1 (CH2), 29.4 (CH2), 26.3 (CH2),
26.3 (CH2), 26.3 ppm (CH2); IR (NaCl, neat): n˜ =3426 cmÀ1 (NH);
HRMS: m/z: calcd for C19H22ClN: 299.1441; found: 298.1346 [MÀH]+.
N-Benzyl-(1-phenyl-1-cyclohexylmethyl)amine (Table 2, entry 9): Rf =
0.41 (EtOAc/hexane 1:8); 1H NMR (300 MHz, CDCl3): d=0.80–1.26 (m,
5H), 1.37–1.41 (m, 1H), 1.48–1.73 (m, 5H), 1.94–1.98 (m, 1H), 3.35 (d,
J=7.18 Hz, 1H), 3.43 (d, J=13.24 Hz, 1H), 3.62 (d, J=13.25 Hz, 1H),
7.18–7.34 ppm (m, 10H); 13C NMR (75.4 MHz, CDCl3): d=143.0 (C),
140.9 (C), 128.2 (2CH), 128.1 (4CH), 128.0 (2CH), 126.7 (2CH), 68.0
(CH), 51.6 (CH2), 44.3 (CH), 30.2 (CH2), 29.9 (CH2), 26.5 (CH2), 26.3
(CH2), 26.3 ppm (CH2); IR (NaCl, neat): n˜ =3431 cmÀ1 (NH); HRMS
(EI): m/z: calcd for C20H25N: 279.1987; found: 278.1903 [MÀH]+.
N-Benzyl-(1-phenyl-1-cyclopentylmethyl)amine (Table 2, entry 10): Rf =
0.30 (EtOAc/hexane 1:8); 1H NMR (300 MHz, CDCl3): d=0.98–1.11 (m,
1H), 1.23–1.67 (m, 6H), 1.77 (s, 1H), 1.86–1.96 (m, 1H), 2.00–2.14 (m,
1H), 3.32 (d, J=9.06 Hz, 1H), 3.43 (d, J=13.29 Hz, 1H), 3.61 (d, J=
13.29 Hz, 1H), 7.18–7.31 ppm (m, 10H); 13C NMR (75.4 MHz, CDCl3):
d=144.0 (C), 140.9 (C), 128.3 (2CH), 128.1 (4CH), 127.9 (2CH), 126.8
(CH), 126.7 (CH), 68.1 (CH), 51.5 (CH2), 47.4 (CH), 30.5 (CH2), 30.3
(CH2), 25.3 (CH2), 25.0 ppm (CH2); IR (NaCl, neat): n˜ =3418 cmÀ1
(NH); HRMS (EI): m/z: calcd for C19H23N: 265.1830; found: 264.1760
[MÀH]+.
N-Phenyl-[1-(p-methylphenyl)-1-cyclohexylmethyl]amine
(Table 2, entry 3): Rf =0.63 (EtOAc/hexane 1:8); 1H NMR (400 MHz,
CDCl3): d=0.84–0.90 (m, 1H), 0.95–1.26 (m, 5H), 1.50–1.74 (m, 4H),
1.85–1.88 (m, 1H), 2.27 (s, 3H), 4.06 (d, J=6.20 Hz, 1H), 4.09 (brs, 1H),
6.47 (d, J=7.89 Hz, 2H), 6.57 (t, J=7.20 Hz, 1H), 7.01–7.15 ppm (m,
6H); 13C NMR (100 MHz, CDCl3): d=147.8 (C), 139.5 (C), 136.1 (C),
129.0 (2CH), 128.8 (2CH), 127.1 (2CH), 116.8 (CH), 113.1 (2CH), 63.0
(CH), 44.9 (CH), 30.2 (CH2), 29.5 (CH2), 26.4 (CH2), 26.4 (CH2), 26.3
(CH2), 21.0 ppm (CH3); IR (NaCl, neat): n˜ =3424 cmÀ1 (NH); HRMS
(EI): m/z: calcd for C20H25N: 279.1987; found: 278.1897 [MÀH]+.
N-Phenyl-(1-phenyl-1-cyclohexylmethyl)amine (Table 2, entry 4): Rf =
0.57 (EtOAc/hexane 1:8); 1H NMR (400 MHz, CDCl3): d=1.00–1.26 (m,
5H), 1.47–1.54 (m, 1H), 1.60–1.76 (m, 4H), 1.86–1.89 (m, 1H), 4.10 (d,
J=6.32 Hz, 1H), 4.12 (brs, 1H), 6.48 (d, J=7.72 Hz, 2H), 6.59 (t, J=
7.44 Hz, 1H), 7.02–7.06 (m, 2H), 7.18–7.21 (m, 1H), 7.27–7.28 ppm (m,
4H); 13C NMR (75.4 MHz, CDCl3): d=147.8 (C), 142.7 (C), 129.0
(2CH), 128.2 (2CH), 127.2 (2CH), 126.7 (CH), 116.9 (CH), 113.1 (2CH),
63.4 (CH), 44.9 (CH), 30.2 (CH2), 29.4 (CH2), 26.4 (CH2), 26.4 (CH2),
N-Benzyl-(2-methyl-1-phenylpropyl)amine (Table 2, entry 11): Rf =0.30
(EtOAc/hexane 1:8); 1H NMR (400 MHz, CDCl3): d=0.74 (d, J=
6.80 Hz, 3H), 0.97 (d, J=6.67 Hz, 3H), 1.81 (brs, 1H), 1.84–1.92 (m,
1H), 3.34 (d, J=6.96 Hz, 1H), 3.46 (d, J=13.30 Hz, 1H), 3.65 (d, J=
13.29 Hz, 1H), 7.23–7.35 ppm (m, 10H); 13C NMR (75.4 MHz, CDCl3):
1878
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Chem. Eur. J. 2008, 14, 1875 –1880

Alkylation Reactions
FULL PAPER
d=142.9 (C), 141.0 (C), 128.3 (2CH), 128.1 (4CH), 128.0 (2CH), 126.8
(CH), 126.8 (CH), 68.7 (CH), 51.7 (CH2), 34.5 (CH), 19.7 (CH3),
19.5 ppm (CH3); IR (NaCl, neat): n˜ =3401 cmÀ1 (NH); HRMS (EI): m/z:
calcd for C17H21N: 239.1674; found: 238.1589 [MÀH]+.
(CH3), 19.3 (2CH3), 18.7 ppm (CH3); IR (NaCl, neat): n˜ =3443 (NH),
1732 cmÀ1 (C=O); HRMS (EI): m/z: calcd for C16H25NO2: 263.1885;
found: 262.1805 [MÀH]+.
2-{[1-Cyclohexyl-1-(p-bromophenyl)methyl]amino}-3-methylbutyric acid
methyl ester (Table 3, entry 4): Rf =0.61 (EtOAc/hexane 1:8); 1H NMR
(300 MHz, CDCl3): major isomer: d=0.84 (d, J=6.76 Hz, 3H), 0.90 (d,
J=6.78 Hz, 3H), 0.98–1.92 (m, 12H), 2.69 (d, J=6.28 Hz, 1H), 2.87 (brs,
1H), 3.17 (d, J=6.97 Hz, 1H), 3.70 (s, 3H), 7.13 (d, J=8.22 Hz, 2H),
7.40 ppm (d, J=8.22 Hz, 2H); 13C NMR (75.4 MHz, CDCl3): major
isomer: d=175.7 (CO), 141.0 (C), 131.0 (2CH), 130.3 (2CH), 120.7 (C),
66.9 (CH), 64.6 (CH), 51.4 (CH3), 44.1 (CH), 31.6 (CH), 29.9 (CH2), 29.5
(CH2), 26.4 (CH2), 26.1 (2CH2), 19.4 (CH3), 18.6 ppm (CH3); IR (NaCl,
neat): n˜ =3447 (NH), 1734 cmÀ1 (C=O); HRMS (EI): m/z: calcd for
C19H28BrNO2: 381.1303; found: 380.1224 [MÀH]+.
2-{[1-Cyclohexyl-1-(p-methylphenyl)methyl]amino}-3-methylbutyric acid
methyl ester (Table 3, entry 5): Rf =0.61 (EtOAc/hexane 1:8); 1H NMR
(400 MHz, CDCl3): major isomer: d=0.83 (d, J=6.68 Hz, 3H), 0.90 (d,
J=6.76 Hz, 3H), 0.94–1.93 (m, 13H), 2.32 (s, 3H), 2.72 (d, J=6.40 Hz,
1H), 3.14 (d, J=6.88 Hz, 1H), 3.68 (s, 3H), 7.06–7.14 ppm (m, 4H);
13C NMR (100 MHz, CDCl3): major isomer: d=176.4 (CO), 139.4 (C),
136.2 (C), 128.4 (4CH), 66.9 (CH), 64.5 (CH), 51.1 (CH3), 44.5 (CH),
31.8 (CH), 29.9 (CH2), 29.7 (CH2), 26.5 (CH2), 26.2 (CH2), 26.2 (CH2),
21.1 (CH3), 19.4 (CH3), 18.6 ppm (CH3); IR (NaCl, neat): n˜ =3447 (NH),
1734 cmÀ1 (C=O); HRMS (EI): m/z: calcd for C20H31NO2: 317.2355;
found: 316.2272 [MÀH]+.
2-{[1-Cyclohexyl-1-(p-chlorophenyl)methyl]amino}-3-methylbutyric acid
methyl ester (Table 3, entry 6): Rf =0.63 (EtOAc/hexane 1:8); 1H NMR
(300 MHz, CDCl3): major isomer: d=0.83 (d, J=6.75 Hz, 3H), 0.89 (d,
J=6.81 Hz, 3H), 0.95–1.90 (m, 13H), 2.66 (d, J=6.40 Hz, 1H), 3.16 (d,
J=6.75 Hz, 1H), 3.70 (s, 3H), 7.17–7.26 ppm (m, 4H); 13C NMR
(75.4 MHz, CDCl3): major isomer: d=176.2 (CO), 141.1 (C), 132.4 (C),
129.9 (2CH), 127.9 (2CH), 66.7 (CH), 64.6 (CH), 51.3 (CH3), 44.4 (CH),
31.8 (CH), 29.9 (CH2), 29.5 (CH2), 26.4 (CH2), 26.2 (2CH2), 19.5 (CH3),
18.5 ppm (CH3); IR (NaCl, neat): n˜ =3447 (NH), 1732 cmÀ1 (C=O);
HRMS (EI): m/z: calcd for C19H28ClNO2: 337.1809; found: 336.1722
[MÀH]+.
2-[(1-Cyclohexyl-3-phenylpropyl)amino]-3-methylbutyric acid methyl
ester (Table 3, entry 7): Rf =0.30, 0.39 (EtOAc/hexane 1:8); 1H NMR
(300 MHz, CDCl3): major isomer: d=0.86 (d, J=6.66 Hz, 3H), 0.90 (d,
J=6.79 Hz, 3H), 0.94–1.35 (m, 5H), 1.44–1.87 (m, 10H), 2.13 (q, J=
5.12 Hz, 1H), 2.58 (t, J=8.25 Hz, 2H), 2.92 (d, J=6.54 Hz, 1H), 3.59 (s,
3H), 7.04–7.20 ppm (m, 5H); 13C NMR (75.4 MHz, CDCl3): major
isomer: d=176.4 (CO), 143.1 (C), 128.3 (2CH), 128.2 (2CH), 125.5
(CH), 65.5 (CH), 61.3 (CH), 51.2 (CH3), 40.5 (CH), 32.6 (CH2), 32.2
(CH), 31.7 (CH2), 29.3 (CH2), 28.6 (CH2), 26.6 (CH2), 26.6 (CH2), 26.5
(CH2), 19.4 (CH3), 18.9 ppm (CH3); IR (NaCl, neat): n˜ =3449 (NH),
1736 cmÀ1 (C=O); HRMS (EI): m/z: calcd for C21H33NO2: 331.2511;
found: 330.2411 [MÀH]+.
N-Benzyl-(1-phenyl-2-methylbutyl)amine (Table 2, entry 12): Rf =0.38
1
(EtOAc/hexane 1:8); H NMR (300 MHz, CDCl3): two isomers: d=0.70–
0.93 (m, 6H), 0.95–1.26 (m, 1H), 1.32–1.71 (m, 2H), 1.79 (brs, 1H), 3.43–
3.49 (m, 2H), 3.61–3.68 (m, 1H), 7.19–7.35 ppm (m, 10H); 13C NMR
(75.4 MHz, CDCl3): two isomers: d=143.2 (C), 142.7 (C), 141.0 (C),
140.9 (C), 128.3, 128.2, 128.2, 128.2, 128.0, 128.0, 128.0, 126.7, 126.7 (over-
all 20CH), 67.0 (CH), 66.9 (CH), 51.7 (CH2), 51.7 (CH2), 41.4 (CH), 40.9
(CH), 26.1 (CH2), 26.1 (CH2), 15.6 (CH3), 15.3 (CH3), 11.8 (CH3),
11.4 ppm (CH3); IR (NaCl, neat): n˜ =3345 cmÀ1 (NH); HRMS (EI): m/z:
calcd for C18H23N: 253.1830; found: 252.1740 [MÀH]+.
N-Benzyl-[1-(p-bromophenyl)-1-cyclohexylmethyl]amine
(Table 2, entry 13): Rf =0.47 (EtOAc/hexane 1:8); 1H NMR (300 MHz,
CDCl3): d=0.78–1.20 (m, 5H), 1.37–1.73 (m, 6H), 1.88–1.92 (m, 1H),
3.33 (d, J=6.88 Hz, 1H), 3.41 (d, J=13.27 Hz, 1H), 3.60 (d, J=13.23 Hz,
1H), 7.15 (d, J=8.24 Hz, 2H), 7.22–7.31 (m, 5H), 7.44 ppm (d, J=
8.28 Hz, 2H); 13C NMR (75.4 MHz, CDCl3): d=142.1 (C), 140.7 (C),
131.1 (2CH), 129.9 (2CH), 128.3 (2CH), 128.1 (2CH), 126.8 (CH), 120.4
(C), 67.4 (CH), 51.6 (CH2), 44.3 (CH), 30.1 (CH2), 29.7 (CH2), 26.5
(CH2), 26.3 (CH2), 26.2 ppm (CH2); IR (NaCl, neat): n˜ =3350 cmÀ1
(NH); HRMS (EI): m/z: calcd for C20H24BrN: 357.1092; found: 356.1000
[MÀH]+.
N-Benzyl-[1-(p-methylphenyl)-1-cyclohexylmethyl]amine
(Table 2, entry 14): Rf =0.37 (EtOAc/hexane 1:8); 1H NMR (300 MHz,
CDCl3): d=0.75–1.26 (m, 5H), 1.38–1.72 (m, 6H), 1.94–1.98 (m, 1H),
2.34 (s, 3H), 3.32 (d, J=7.12 Hz, 1H), 3.43 (d, J=13.23 Hz, 1H), 3.62 (d,
J=13.24 Hz, 1H), 7.10–7.31 ppm (m, 9H); 13C NMR (75.4 MHz, CDCl3):
d=141.0 (C), 139.9 (C), 136.1 (C), 128.7 (2CH), 128.2 (2CH), 128.1
(2CH), 128.0 (2CH), 126.7 (CH), 67.7 (CH), 51.6 (CH2), 44.3 (CH), 30.3
(CH2), 29.9 (CH2), 26.6 (CH2), 26.4 (CH2), 26.3 (CH2), 21.1 ppm (CH3);
IR (NaCl, neat): n˜ =3402 cmÀ1 (NH); HRMS (EI): m/z: calcd for
C21H27N: 293.2143; found: 292.2065 [MÀH]+.
2-[(1-Cyclohexyl-1-phenylmethyl)amino]-3-methylbutyric acid methyl
ester (Table 3, entry 1): Rf =0.65 (EtOAc/hexane 1:8); 1H NMR
(400 MHz, CDCl3): major isomer: d=0.83 (d, J=6.73 Hz, 3H), 0.90 (d,
J=6.81 Hz, 3H), 0.83–1.01 (m, 2H), 1.04–1.12 (m, 2H), 1.17–1.29 (m,
1H), 1.36–1.39 (m, 1H), 1.45–1.52 (m, 1H), 1.60–1.61 (m, 2H), 1.72–1.83
(m, 2H), 1.89–1.94 (m, 2H), 2.71 (d, J=6.32 Hz, 1H), 3.17 (d, J=
6.92 Hz, 1H), 3.69 (s, 3H), 7.13–7.29 ppm (m, 5H); 13C NMR (100 MHz,
CDCl3): major isomer: d=176.4 (CO), 142.5 (C), 128.6 (2CH), 127.7
(2CH), 126.8 (CH), 67.3 (CH), 64.5 (CH), 51.2 (CH3), 44.4 (CH), 31.8
(CH), 29.9 (CH2), 29.7 (CH2), 26.5 (CH2), 26.2 (CH2), 26.2 (CH2), 19.5
(CH3), 18.6 ppm (CH3); IR (NaCl, neat): n˜ =3445 (NH), 1732 cmÀ1 (C=
O); HRMS (EI): m/z: calcd for C19H29NO2: 303.2198; found: 304.2245
[M+H]+.
2-[(1-Cyclopentyl-1-phenylmethyl)amino]-3-methylbutyric acid methyl
ester (Table 3, entry 2): Rf =0.61 (EtOAc/hexane 1:8); 1H NMR
(300 MHz, CDCl3): major isomer: d=0.81 (d, J=6.78 Hz, 3H), 0.88 (d,
J=6.82 Hz, 3H), 0.99–1.12 (m, 1H), 1.16–1.26 (m, 1H), 1.32–1.46 (m,
2H), 1.48–1.69 (m, 3H), 1.72–1.85 (m, 1H), 1.88–2.13 (m, 3H), 2.70 (d,
J=6.30 Hz, 1H), 3.14 (d, J=8.77 Hz, 1H), 3.70 (s, 3H), 7.14–7.28 ppm
(m, 5H); 13C NMR (75.4 MHz, CDCl3): major isomer: d=176.3 (CO),
143.6 (C), 128.2 (2CH), 127.9 (2CH), 126.9 (CH), 67.6 (CH), 64.4 (CH),
51.2 (CH3), 47.6 (CH), 31.7 (CH), 30.2 (CH2), 30.0 (CH2), 25.4 (CH2),
25.1 (CH2), 19.4 (CH3), 18.5 ppm (CH3); IR (NaCl, neat): n˜ =3447 (NH),
1734 cmÀ1 (C=O); HRMS (EI): m/z: calcd for C18H27NO2: 289.2042;
found: 288.1964 [MÀH]+.
2-[(2-Methyl-1-phenylpropyl)amino]-3-methylbutyric acid methyl ester
(Table 3, entry 3): Rf =0.61 (EtOAc/hexane 1:8); 1H NMR (300 MHz,
CDCl3): major isomer: d=0.73 (d, J=6.81 Hz, 3H), 0.84 (d, J=6.78 Hz,
3H), 0.91 (d, J=6.81 Hz, 3H), 0.96 (d, J=6.69 Hz, 3H), 1.75–1.87 (m,
2H), 1.90 (brs, 1H), 2.72 (d, J=6.39 Hz, 1H), 3.17 (d, J=6.73 Hz, 1H),
3.69 (s, 3H), 7.13–7.30 ppm (m, 5H); 13C NMR (75.4 MHz, CDCl3):
major isomer: d=175.8 (C), 141.7 (C), 128.6 (2CH), 127.9 (2CH), 127.1
(CH), 68.2 (CH), 64.6 (CH), 51.3 (CH3), 34.5 (CH), 31.6 (CH), 19.4
2-[(1-Cyclopentyl-3-phenylpropyl)amino]-3-methylbutyric acid methyl
ester (Table 3, entry 8): Rf =0.43, 0.55 (EtOAc/hexane 1:8); 1H NMR
(300 MHz, CDCl3): major isomer: d=0.96 (d, J=6.72 Hz, 3H), 1.00 (d,
J=6.75 Hz, 3H), 1.20–1.26 (m, 2H), 1.50–2.00 (m, 11H), 2.24–2.30 (m,
1H), 2.52–2.82 (m, 2H), 3.07 (d, J=6.63 Hz, 1H), 3.68 (s, 3H), 7.15–
7.29 ppm (m, 5H); 13C NMR (75.4 MHz, CDCl3): major isomer: d=176.3
(CO), 143.4 (C), 128.3 (2CH), 128.3 (2CH), 125.5 (CH), 64.9 (CH), 60.7
(CH), 51.2 (CH3), 43.0 (CH), 33.5 (CH2), 32.0 (CH), 30.0 (CH2), 29.7
(CH2), 29.6 (CH2), 25.5 (CH2), 25.4 (CH2), 19.6 (CH3), 19.0 ppm (CH3);
IR (NaCl, neat): n˜ =3449 (NH), 1736 cmÀ1 (C=O); HRMS (EI): m/z:
calcd for C20H31NO2: 317.2355; found: 316.2285 [MÀH]+.
3-Methyl-2-[(2-methyl-1-phenethylpropyl)amino]butyric acid methyl
ester (Table 3, entry 9): Rf =0.43, 0.55 (EtOAc/hexane 1:8); 1H NMR
(300 MHz, CDCl3): major isomer: d=0.88 (d, J=3.78 Hz, 3H), 0.90 (d,
J=3.78 Hz, 3H), 0.94 (d, J=6.78 Hz, 3H), 0.98 (d, J=6.76 Hz, 3H),
1.49–1.96 (m, 5H), 2.21 (q, J=5.25 Hz, 1H), 2.67 (t, J=8.35 Hz, 2H),
3.01 (d, J=6.51 Hz, 1H), 3.67 (s, 3H), 7.13–7.29 ppm (m, 5H); 13C NMR
(75.4 MHz, CDCl3): major isomer: d=176.4 (CO), 143.1 (C), 128.3
(2CH), 128.3 (2CH), 125.6 (CH), 65.5 (CH), 62.0 (CH), 51.2 (CH3), 32.5
(CH2), 32.3 (CH), 31.9 (CH2), 30.1 (CH), 19.4 (CH3), 18.9 (CH3), 18.7
Chem. Eur. J. 2008, 14, 1875 –1880
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1879

T.-P. Loh et al.
(CH3), 18.1 ppm (CH3); IR (NaCl, neat): n˜ =3449 (NH), 1736 cmÀ1 (C=
O); HRMS (EI): m/z: calcd for C18H29NO2: 291.2198; found: 290.2117
[MÀH]+.
1999, 1, 1855; f) T. P. Loh, J. R. Zhou, Tetrahedron Lett. 1999, 40,
9115; g) T. P. Loh, J. R. Zhou, Tetrahedron Lett. 2000, 41, 5261;
h) T. P. Loh, J. M. Huang, K. C. Xu, Tetrahedron Lett. 2000, 41, 6511;
i) T. P. Loh, H. Y. Song, Synlett 2003, 2119; j) T. P. Loh, Z. Yin, H. Y.
Song, K. L. Tan, Tetrahedron Lett. 2003, 44, 911; k) J. M. Huang,
K. C. Xu, T. P. Loh, Synthesis 2003, 755.
2-[(1-Cyclohexylnonyl)amino]-3-methylbutyric
acid
methyl
ester
(Table 3, entry 10): Rf =0.53, 0.62 (EtOAc/hexane 1:8); 1H NMR
(300 MHz, CDCl3): major isomer: d=0.86–0.96 (m, 9H), 1.16–1.29 (m,
21H), 1.58–1.85 (m, 6H), 2.11–2.12 (m, 1H), 2.99 (d, J=6.60 Hz, 1H),
3.69 ppm (s, 3H); 13C NMR (75.4 MHz, CDCl3): major isomer: d=176.5
(CO), 65.6 (CH), 61.6 (CH), 51.2 (CH3), 40.7 (CH), 32.1 (CH), 31.9
(CH2), 30.6 (CH2), 30.1 (CH2), 29.6 (CH2), 29.3 (CH2), 29.0 (CH2), 28.9
(CH2), 26.7 (CH2), 26.7 (CH2), 26.6 (CH2), 25.6 (CH2), 22.7 (CH2), 19.3
(CH3), 18.9 (CH3), 14.1 ppm (CH3); IR (NaCl, neat): n˜ =3455 (NH),
1736 cmÀ1 (C=O); HRMS (EI): m/z: calcd for C21H41NO2: 339.3137;
found: 338.3055 [MÀH]+.
[3] a) N. Kalyanam, G. V. Rao, Tetrahedron Lett. 1993, 34, 1647;
b) M. R. Pitts, J. R. Harrison, C. J. Moody, J. Chem. Soc. Perkin
Trans. 1 2001, 9, 955; c) T. Tsukinoki, S. Nagashima, Y. Mitoma, M.
Tashiro, Green Chem. 2000, 2, 117; d) M. P. Dutta, B. Baruah, A.
Boruah, D. Prajapati, J. S. Sandhu, Synlett 1998, 857; e) B. Baruah,
D. Prajapati, J. S. Sandhu, Tetrahedron Lett. 1995, 36, 6747.
[4] For reviews see: a) H. Miyabe, M. Ueda, T. Naito, Synlett 2004,
1140, and references therein; b) H. Miyabe, T. Naito, Org. Biomol.
Chem. 2004, 2, 1267; for examples, see: c) H. Miyabe, M. Ueda, T.
Naito, J. Org. Chem. 2000, 65, 5043; d) H. Miyabe, M. Ueda, A.
Nishimura, T. Naito, Tetrahedron 2004, 60, 4227; e) H. Miyabe, M.
Ueda, A. Nishimura, T. Naito, Org. Lett. 2002, 4, 131; f) H. Miyabe,
M. Ueda, T. Naito, Chem. Commun. 2000, 2059; g) M. Ueda, H.
Miyabe, A. Nishimura, H. Sugino, T. Naito, Tetrahedron: Asymmetry
2003, 14, 2857; h) H. Miyabe, A. Nishimura, M. Ueda, T. Naito,
Chem. Commun. 2002, 1454; i) M. Ueda, H. Miyabe, H. Sugino, T.
Naito, Org. Biomol. Chem. 2005, 3, 1124.
2-[(1-Cyclohexyl-1-phenylmethyl)amino]-2-phenylacetic acid methyl
1
ester:[12] Rf =0.55, 0.59 (EtOAc/hexane 1:8); H NMR (400 MHz, CDCl3):
isomer 1: d=0.83–0.96 (m, 1H), 1.05–1.27 (m, 5H), 1.40–1.43 (m, 1H),
1.55–1.62 (m, 3H), 1.75–1.78 (m, 1H), 1.97–2.00 (m, 1H), 3.41 (d, J=
7.05 Hz, 1H), 3.71 (s, 3H), 4.13 (s, 1H), 7.25–7.33 ppm (m, 10H); isomer
2: d=0.69–0.79 (m, 1H), 0.84–0.94 (m, 1H), 1.02–1.08 (m, 2H), 1.12–1.26
(m, 2H), 1.50–1.56 (m, 3H), 1.69–1.73 (m, 1H), 2.06–2.09 (m, 1H), 2.55
(brs, 1H), 3.01 (d, J=7.81 Hz, 1H), 3.56 (s, 3H), 4.09 (s, 1H), 7.11–7.13
(m, 2H), 7.22–7.33 ppm (m, 8H); 13C NMR (100 MHz, CDCl3): isomer 1:
d=174.5 (CO), 142.2 (C), 138.8 (C), 128.6 (2CH), 128.4 (2CH), 128.1
(2CH), 127.8 (CH), 127.1 (3CH), 67.4 (CH), 62.8 (CH), 51.9 (CH3), 44.3
(CH), 30.0 (CH2), 29.7 (CH2), 26.5 (CH2), 26.2 ppm (2CH2); isomer 2:
d=173.3 (CO), 142.1 (C), 138.3 (C), 128.5 (2CH), 128.1 (4CH), 128.0
(2CH), 127.9 (CH), 126.9 (CH), 64.7 (CH), 62.4 (CH), 52.2 (CH3), 43.9
(CH), 30.2 (CH2), 30.0 (CH2), 26.5 (CH2), 26.2 ppm (2CH2); IR (NaCl,
neat): n˜ =3447 (NH), 1738 cmÀ1 (C=O); HRMS (EI): m/z: calcd for
C22H27NO2: 337.2042; found: 336.1946 [MÀH]+.
[5] For the alkylation of activated perfluorophenyl aromtic aldimines
see: X. Y. Liu, S. Z. Zhu, S. W. Wang, Synthesis 2004, 683.
[6] For the alkylation of simple imines with limited substrates (only
three pieces of data were reported) see: T. Huang, C. C. K. Keh,
C. J. Li, Chem. Commun. 2002, 2440.
[7] Recently, a radical-type alkylation reaction of imines by using Tiiii
+
and PhN2 in acidic aqueous media has been reported with limited
substrates and moderate selectivities: R. Cannella, A. Clerici, N.
Pastori, E. Regolini, O. Porta, Org. Lett. 2005, 7, 645.
[8] For the alkylation of aldehydes in aqueous media see: C. C. K. Keh,
C. M. Wei, C. J. Li, J. Am. Chem. Soc. 2003, 125, 4062.
[9] In the process of our research, studies on Barbier–Grignard-type al-
kylation reactions of simple imines in aqueous media, a comparable
result has been obtained by using a In/CuI/InCl3 system; see: Z. L.
Shen, T.P. Loh, Org. Lett. 2007, in press.
[10] For reviews on indium-mediated organic reactions see: a) T. P. Loh,
G. L. Chua, Chem. Commun. 2006, 2739; b) K. K. Chauhan, C. G.
Frost, J. Chem. Soc. Perkin Trans. 1 2000, 3015; c) P. Cintas, Synlett
1995, 1087; d) J. Podlech, T. C. Maier, Synthesis 2003, 633; e) V.
Nair, S. Ros, C. N. Jayan, B. S. Pillai, Tetrahedron 2004, 60, 1959; f) J.
Auge, N. Lubin-Germain, J. Uziel, Synthesis 2007, 1739.
[11] For primary iodide and tertiary iodide, the one-pot reaction of ben-
zaldehyde, aniline, and n-hexyl iodide or tert-butyl iodide proceeded
sluggishly under optimized conditions to give the desired products
in very low yields. No desired products were obtained when the re-
action system was applied to alkyl bromide and alkyl chloride.
[12] Application of the optimized reaction conditions to other chiral
amines, such as (S)-(+)-2-phenylglycine methyl ester, gave the cor-
responding product in 62% yield, and with a 50:50 dr (separable iso-
mers).
Acknowledgement
We gratefully acknowledge the Nanyang Technological University, A*
STAR (no. M47110000), and Ministry of Education (no. M45110000) for
funding this research.
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Received: September 16, 2007
Published online: December 4, 2007
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