One-pot reductive amination of aldehydes and ketones with α-picoline-borane in methanol, in water, and in neat conditions

Article abstract of DOI:10.1016/j.tet.2004.06.045

A one-pot reductive amination of aldehydes and ketones with amines using α-picoline-borane as a reducing agent is described. The reaction has been carried out in MeOH, in H₂O, and in neat conditions in the presence of small amounts of AcOH. This is a highly efficient and mild procedure that is applicable for a wide variety of substrates. In particular, this is the first successful demonstration that this type of reaction can be carried out in water and in neat conditions.

Full text of DOI:10.1016/j.tet.2004.06.045

Tetrahedron 60 (2004) 7899–7906
One-pot reductive amination of aldehydes and ketones with
a-picoline-borane in methanol, in water, and in neat conditionsq
*
Shinya Sato, Takeshi Sakamoto, Etsuko Miyazawa and Yasuo Kikugawa
Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan
Received 23 April 2004; revised 8 June 2004; accepted 9 June 2004
Available online 7 July 2004
Abstract—A one-pot reductive amination of aldehydes and ketones with amines using a-picoline-borane as a reducing agent is described.
The reaction has been carried out in MeOH, in H2O, and in neat conditions in the presence of small amounts of AcOH. This is a highly
efficient and mild procedure that is applicable for a wide variety of substrates. In particular, this is the first successful demonstration that this
type of reaction can be carried out in water and in neat conditions.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In a search for alternatives to the cyanohydroborates as
reductants for reductive amination, the use of NaBH(OAc)3
has been reported.3e Although this reagent reduces imines
selectively over carbonyl compounds in 1,2-dichloroethane,
solvents such as methanol or water are not suitable because
of rapid reduction of the carbonyl compound or because of
decomposition of the reducing agent in water. In addition,
this reagent has only one available hydrogen in a molecule
and 1.3–1.6 mol equiv of the reagent are necessary for the
In biological and chemical systems, one-pot reductive
amination of aldehydes and ketones is an important
transformation, which allows the direct conversion of
carbonyl compounds into amines using simple operations.1
A variety of reducing agents, such as sodium cyanoborohy-
dride (NaBH3CN),1a,2 sodium triacetoxyborohydride
[NaBH(OAc)3],3 pyridine-borane (pyr-BH3),4 Ti(Oi-Pr)4/
NaBH4,5 borohydride exchange resin,6 Zn(BH4)2/SiO2,7
4a
reaction. Reductive aminations with pyr-BH3 and metha-
4b
9
Bu3SnH/SiO2,8 and PhSiH4/Bu2SnCl2 have been devel-
˚
nolic pyr-BH3 in the presence of 4 A molecular sieves were
oped for this conversion.
also reported. Very recently, it has been reported that amine-
boranes possess interesting properties that could overcome the
disadvantages of using NaBH4 and NaBH3CN.10 It was
previously reported that pyr-BH3 was found to be superior to
NaBH3CN for the reductive amination of aldehydes with
piperidines.4c Usually pyr-BH3 from commercial sources
was utilized without further purification,11 because this
reagent is quite unstable to heat and attempted distillation of
the liquid residue at reduced pressures sometimes resulted in
violent decompositions.12 Thus, extreme care must be used
if this reagent is handled in large quantities. Industrial
applications seem problematic, despite the availability of a
patented method for purification, because of this instability
that also leads to difficulty of storage for extended periods.13
Therefore, introduction of new reagents that alleviate or
eliminate the above-mentioned problems would be a useful
contribution to synthetic organic chemistry. We have
approached this challenge to discover a new reagent and
methodology from the view point of both process chemistry
and green chemistry.
The choice of the reducing agent is very critical to the
success of the reaction, since the reducing agent must reduce
imines selectively over aldehydes or ketones. The reductive
aminations with NaBH3CN are successfully carried out
using a five-fold excess of amine at pH 6–8.2b However, the
use of expensive and highly toxic NaBH3CN that carries the
risk of having residual cyanide in the product as well as in
the work-up stream, makes this procedure less attractive.
Clearly the use of NaBH3CN is not acceptable in the context
of green synthesis, especially in industry.
q Supplementary data associated with this article can be found in the online
version, at doi: 10.1016/j.tet.2004.06.045
Keywords: Reductive amination; Picoline-borane; Water solvent; Neat
condition.
*
Corresponding author. Tel.: þ81-49-271-7680; fax: þ81-49-271-7984;
e-mail address: kikugawa@josai.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.045

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S. Sato et al. / Tetrahedron 60 (2004) 7899–7906
Table 1. Reductive amination of carbonyl compounds with pic-BH3 in MeOH–AcOH (10:1)a
Entry
1
Carbonyl compound
Amine
Time (h)
Product
Yield (%)
2
95
1
1
2
4
6
3
5
7
2
3
2
1
76
72
1
1
4
18
60
8
9
5
6
7
1
1
73
82c
62d
10
2
11
13
15
1b
12
12
1
14
10
8
1
1
80e
77
16
18
17
19
9
4
2
10
24
73
20
20
21
11
4
72
72
22
22
12
13
20
20
4
6
24
30
52
45
23
25
14
15
2
4
6
6
89
79
24
24
26

S. Sato et al. / Tetrahedron 60 (2004) 7899–7906
7901
Yield (%)
95
Table 1 (continued)
Entry
Carbonyl compound
Amine
Time (h)
17
Product
16
2
27
27
28
17
4
2
6
80
29
31
33
18
19
1
3
95
73
30
30
32
4
20
21
30
30
1
1
73
98
9
34
37
35
22
40
76
36
38
a
Equimolar equiv of carbonyl compounds, amines, and pic-BH3 was used.
Minute.
Without addition of AcOH.
Two equiv of 2-phenethylamine were used.
Three equiv of acetaldehyde were used.
b
c
d
e
2. Results and discussion
and gave the desired products in good to excellent yields as
shown in Table 1.
2.1. Reductive amination in MeOH with
a-picoline-borane
Equimolar amounts of amine, carbonyl compounds, and
pic-BH3 were generally used for the reaction. For most
ketones, reactions were improved by the addition of AcOH.
However, for hexanal (12), a better result was obtained
without addition of AcOH (Table 1, entry 6). Recently 2-
ethylaminopyridine (17) was synthesized from 2-amino-
pyridine (10) in three steps.15 According to the present
method 17 was obtained from 10 and acetaldehyde in a one-
pot operation in 80% yield (Table 1, entry 8). More recently,
the direct reductive amination of mucochloric acid has been
reported and compound 38 was obtained in 65% yield using
3 equiv of NaBH(OAc)3 in CH2Cl2–AcOH for 24 h at
room temperature.16 According to the present method 38
was obtained from the same starting compounds in 76%
yield for 40 h (Table 1, entry 22).
In the course of our investigations of the chemistry of
amine-boranes, we have found that a-picoline-borane (pic-
BH3) is a cheap and commercially available alternative to
NaBH3CN or pyr-BH3 for the purpose of reductive
amination reaction. Pic-BH3 is superior to pyr-BH3 in the
following respects. (1) Pic-BH3 is a commercially available
crystalline solid (mp 44–45 8C) that is more stable to heat
than pyr-BH3 (melting point of pic-BH3 was not changed
after it was heated to above 150 8C). (2) Pic-BH3 can be
purified by recrystallization from hexane and be stored for
long periods without noticeable decomposition. It was
reported in the recently published Callery bulletin14 that
above a temperature 54 8C, pyr-BH3 undergo a self-
sustaining exothermic decomposition that may cause fire
or explosions. The shelf-life of pyr-BH3 is 6 months.
2.2. Reductive amination in water
The direct reductive amination reactions were carried out in
MeOH–AcOH (10:1) using pic-BH3 as a reducing agent.
The reductive amination of a wide variety of aldehydes and
ketones with primary and secondary amines was successful
It is generally accepted that strict anhydrous conditions
are favorable to generate imines or imminium ions, which
are subsequently reduced by the reducing agents. Therefore,
combinations of a reducing agent and dry molecular

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S. Sato et al. / Tetrahedron 60 (2004) 7899–7906
Table 2. Reductive amination of carbonyl compounds with pic-BH3 in H2O–AcOH (10:1)
Entry
1
Carbonyl compound
Amine
Time (h)
2
Product
Yield (%)
91
1
1
2
6
3
7
2
3
1
3
71
59
1
1
10
11
42
13
4
5
1
88
34
2
5a
73b
12
18
6
7
1
91c
4
2
43
28
17
90
27
27
8
9
4
2
6
1
51
94
29
30
30
31
45
33
46
10
11
12
1
4.5
9
97
74
91
44
32
30
30
37
34
13
14
30
1
90
35
48
50
1
1
3
3
3d
47
49
15
30
a
Minute.
Without addition of AcOH.
Four equiv of cyclohexanecarboxaldehyde were used.
Plus benzyl alcohol (77%).
b
c
d

S. Sato et al. / Tetrahedron 60 (2004) 7899–7906
Table 3. Solvent-free reductive amination of carbonyl compounds with pic-BH3
7903
Entry
Carbonyl compound
Amine
Time (h)
Product
Yield (%)
48a
1
24
1
1
47
49
51
48
50
52
2
3
10
72
76a
66a
1
1
4
5
6
7
8
2
1
99
77b
91
2
2
3
12
13
2
4
63.5
72
20
20
21
22
87
20
120
27
8
4
53
29
9
3.5
3.5
15.5
48
63
94
27
10
11
12
2
4
30
30
31
78
9
65c
65c
1
1
54
56
55
13
24
57
a
Three equiv of amine were used.
Without addition of AcOH.
Minimum amounts of MeOH were added to dissolve the solid 56.
b
c
sieves2,3a,d,4b,17,18 or anhydrous MgSO4 or Na2SO4 or
titanium(IV) isopropoxide21 were employed for imine or
imminium ion formation and subsequent reduction. How-
ever, it is operationally troublesome to keep anhydrous
conditions during a reaction and we, therefore, have tried a
solvent system containing a small amount of water
(MeOH–AcOH–H2O (10:1:1)). We have tried several
examples of reductive amination reactions using the above
19
20

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S. Sato et al. / Tetrahedron 60 (2004) 7899–7906
solvent system and found that yields of products are slightly
lowered, but practically the same, compared with those in
the methanol solvent system.
and the product (5.05 g, 94%) was obtained in high yield.
Several carbonyl compounds and amines reacted in this way
and the results are presented in Table 3.
Encouraged by the above results, we have conducted the
same reductive amination reaction in water. Water is a
cheap, nontoxic, nonflammable, and environmentally
benign solvent. As a consequence of serious pollution
problems, the use of organic transformations in water is
presently undergoing a very rapid growth.22 On the other
hand, it is generally accepted that dehydration is one of the
reactions that is difficult to carry out in water.23 Reductive
amination in solvents containing water has not been
reported except for some aldehydes which are only available
commercially as aqueous solution.24 This is because the
equilibrium formation of imines or imminium ions from
carbonyl compounds and amines by elimination of water
molecules is favored in anhydrous conditions and would be
expected to be highly disfavored in water.
The reaction proceeded smoothly even in the case of water
soluble amines to afford the corresponding products in good
yields (Table 3, entries 2 and 3).
Generally, aromatic ketones are poor substrates for
reductive amination protocols. In the reductive amination
of acetophenone with benzylamine, the desired product was
obtained with NaBH(OAc)3 in 10 days in 55% yield3e and
with a combination of pyr-BH3 and dry molecular sieves in
10% yield.4b Furthermore, 1-phenylethanol, the reduction
product of acetophenone, is the only isolable product from
the reactions of aliphatic amines with acetophenone using
pyr-BH3 and acetic acid.4a On the other hand, in this neat
condition using pic-BH3 as a reducing agent, reductive
amination of acetophenone proceeded smoothly to afford
the corresponding amines in good yields for 72 h (Table 3,
entries 6 and 7).
First, we carried out the reductive amination of cyclohex-
anone (30) (200 mg, 2.04 mmol) with aniline (2) (190 mg,
2.04 mmol) using pic-BH3 (218 mg, 2.04 mmol) in H2O
(5 mL) and AcOH (0.5 mL) at room temperature for 2 h.
Although the reaction should occur in the heterogeneous
phase, the reaction mixture seemed to be homogeneous and
after usual work up cyclohexylphenylamine (31) (334 mg,
94%) was obtained in high yield (Table 2, entry 9). The
same reaction was conducted in larger scale (30, 3.0 g; 2,
2.85 g; pic-BH3, 3.27 g; H2O, 50 mL; AcOH, 5 mL; room
temperature; 3.5 h) and 31 (5.09 g, 95%) was obtained in a
similar yield. This reaction is successful in water although it
involves the elimination of a molecule of water. Several
carbonyl compounds and amines reacted in this way and the
results are presented in Table 2.
Solvent-free reductive amination seems to hold promise to
be a highly useful technique, especially for industry.
Nevertheless, workup processes, except for a few examples,
invariably involve the use of solvent. Therefore, since the
use of solvent should be minimized as far as possible, or
even avoided altogether, devising workup conditions on a
case by case basis would be necessary. However, this
solvent-free process using pic-BH3 throws a challenge to the
existing reductive amination procedures, which use ecolo-
gically harmful solvents and toxic reagents.
3. Conclusion
Reductive amination reactions with highly water soluble
amines do not proceed satisfactorily (Table 2, entries 14 and
15). On the other hand, reactions with poorly water-soluble
carbonyl compounds and amines proceed smoothly to give
high yields of the products. Although, the exact role of water
in these reactions is still not well understood, this might be
ascribed to promotion of hydrophobic association of
carbonyl compounds, amines, and pic-BH3 in water, when
respective substrates are poorly soluble in water. This could
facilitate smooth formation of imines or imminium ions and
subsequent reduction by pic-BH3. In addition, a good
selectivity of pic-BH3 for reduction of imines over
carbonyls is assumed.
Pic-BH3 is a thermally stable transparent solid and can be
stored on a shelf for months without appreciable loss of
reducing ability. The use of pic-BH3 eliminates the
problems encountered with the use of other reducing agents
such as NaBH3CN, NaBH(OAc)3 and pyr-BH3. Especially,
the use of water as solvent and/or solvent-free conditions
can offer a great opportunity for green chemistry. In
summary, we have developed an expeditious, easy-to-
handle and environmentally friendly approach to the
synthesis of a variety of amines through a three-component
one-pot reaction of carbonyl compounds, amines, and pic-
BH3.
2.3. Solvent-free reductive amination
4. Experimental
4.1. General
Finally, we have undertaken the reductive amination in neat
conditions. Many organic solvents are ecologically harmful,
and the best solvent formulation from an ecological point of
view is no solvent.25
All melting points were determined with a Yanagimoto hot-
stage melting point apparatus and are uncorrected. 1H NMR
spectra were measured at 270 MHz on a JEOL JNM-EX270
spectrometer with tetramethylsilane (Me4Si) as an internal
reference and CDCl3 as the solvent, unless otherwise noted.
1H NMR spectral data are reported in parts per million (d)
relative to Me4Si. IR spectra were recorded on a JASCO IR
810 spectrophotometer. Mass spectra were obtained with a
JEOL JMS-700 spectrometer with a direct inlet system at
Initially, we carried out the solvent-free reductive amination
of cyclohexanone (3.00 g, 30.57 mmol) with aniline (2.85 g,
30.57 mmol) using pic-BH3 (3.27 g, 30.57 mmol) at room
temperature for 6 h. After the usual workup cyclohexyl-
phenylamine (4.36 g, 81%) was obtained. The same
reaction was conducted by the addition of AcOH (0.5 mL)

S. Sato et al. / Tetrahedron 60 (2004) 7899–7906
7905
70 eV. Elemental analyses were performed in the Micro-
analytical Laboratory of this University.
was washed with brine (15 mL), dried over Na2SO4, and
concentrated. The crude product was chromatographed on a
column of silica gel with AcOEt–n-hexane (1:3) to afford
cyclohexylphenylamine (31) (334 mg, 94%).
All starting carbonyl compounds and amines were pur-
chased from Tokyo Kasei Kogyo Co., Ltd and a-picoline-
borane was obtained from Shiroi Yakuhin Co., Ltd and used
without further purification.
4.3.1. N-Benzylindoline (42). Oil. IR (neat): 3030, 2920,
1
2830, 1610, 1490 cm21; H NMR (270 MHz) d 2.96 (t,
J¼8.3 Hz, 2H), 3.30 (t, J¼8.3 Hz, 2H), 4.24 (s, 2H), 6.50 (d,
J¼7.8 Hz, 1H), 6.66 (t, J¼7.2 Hz, 1H), 7.00–7.12 (m, 2H),
7.20–7.40 (m, 5H); 13C NMR (68 MHz) d 28.6, 53.6, 53.7,
106.9, 117.6, 124.4, 127.0, 127.2, 127.8, 128.3, 129.9,
138.3, 152.4; EI-MS m/z 209 (Mþ, 100), 132 (35.54), 118
(29.45), 91 (96.68); HR-MS (EI) m/z for C15H15N Calcd
209.1204, found 209.1214.
4.2. Typical procedure for the preparation of 3 in
MeOH–AcOH
To benzaldehyde (1) (200 mg, 1.88 mmol) and aniline (2)
(176 mg, 1.88 mmol) in MeOH–AcOH (10:1, 5.5 mL) was
added pic-BH3 (201 mg, 1.88 mmol) and the reaction
mixture was stirred for 2 h at room temperature. After the
reaction, MeOH was evaporated in vacuo and 10% HCl
(10 mL) was added to the residue. The aqueous solution was
stirred for 0.5 h at room temperature, and Na2CO3 (ca.
2.5 g) and H2O (10 mL) were added under cooling to make
the solution alkaline. The aqueous layer was extracted with
AcOEt (30 mL£2), and the combined organic layer was
washed with brine (15 mL), dried over Na2SO4, and
concentrated. The crude product was chromatographed on
a column of silica gel with AcOEt–n-hexane (1:6) to afford
benzylphenylamine (4) (329 mg, 95%).
4.3.2. Benzyl-bis-cyclohexylmethylamine (43). Oil. IR
(neat): 3030, 2930, 2850, 2800, 1610, 1500, 740, 700 cm21
;
1H NMR (270 MHz, DMSO-d6) d 0.62–0.82 (m, 4H),
0.98–1.86 (m, 18H), 2.08 (d, J¼7.1 Hz, 4H), 3.42 (s, 2H),
7.16–7.36 (m, 5H); 13C NMR (68 MHz) d 26.3, 27.0, 31.9,
36.1, 59.9, 62.0, 126.3, 127.8, 128.7, 140.6; EI-MS m/z 299
(Mþ, 1.89), 216 (100), 91 (39.61); HR-MS (EI) for C21H33N
Calcd 299.2613, found 299.2610.
4.3.3. N-Cyclohexyl-p-anisidine (45). Oil. IR (neat): 3380,
2930, 2850, 1620, 1510 cm21; 1H NMR (270 MHz, DMSO-
d6) d 1.00–1.39 (m, 5H), 1.52–1.76 (m, 3H), 1.83–1.96 (m,
2H), 2.99–3.15 (m, 1H), 3.62 (s, 3H), 4.85 (d, J¼7.9 Hz,
1H), 6.50 (d, J¼8.7 Hz, 2H), 6.68 (d, J¼8.9 Hz, 2H); 13C
NMR (68 MHz) d 25.1, 26.0, 33.6, 52.8, 55.8, 114.7, 114.8,
141.4, 151.6; EI-MS m/z 205 (Mþ, 68.28), 162 (100); HR-
MS (EI) for C13H19NO Calcd 205.1467, found 205.1464.
4.2.1. Hexylphenethylamine (15). Oil. IR (neat): 3300,
1
3030, 2930, 2860, 2820, 1610, 1500, 700 cm21; H NMR
(270 MHz) d 0.87 (t, J¼6.6 Hz, 3H), 1.15–1.60 (m, 9H),
2.60 (t, J¼7.3 Hz, 2H), 2.76–2.92 (m, 4H), 7.15–7.35 (m,
5H); 13C NMR (68 MHz) d 14.1, 22.7, 27.1, 30.1, 31.8,
36.5, 49.9, 51.3, 125.9, 128.3, 128.5, 140.0; FAB-MS
(3-nitrobenzyl alcohol) m/z 206 (MþþH); HR-MS (FAB)
for C14H23N Calcd 206.1909 (MþþH), found 206.1912.
4.3.4. (4-Chlorophenyl)cyclohexylamine (46). Oil. IR
(neat): 3420, 2930, 2860, 1600, 1500 cm21 1H NMR
;
4.2.2. 4-Cyclohexylaminobenzonitril (33). White crystals.
Mp 114–116 8C (AcOEt–n-hexane); IR (KBr): 3330, 2940,
2850, 2210, 1610, 1530 cm21; 1H NMR (270 MHz) d 1.10–
1.48 (m, 5H), 1.60–1.84 (m, 3H), 1.96–2.10 (m, 2H), 3.20–
3.38 (m, 1H), 4.11 (br s, 1H), 6.52 (dt, J¼8.7, 2.1 Hz, 2H),
7.39 (dt, J¼8.4, 2.0 Hz, 2H); 13C NMR (68 MHz) d 24.8,
25.7, 33.0, 51.2, 97.7, 112.2, 120.5, 133.5, 150.3; EI-MS m/z
200 (Mþ, 32.83), 157 (100). Anal. Calcd for C13H16N2: C,
77.96; H, 8.05; N, 13.99, found: C, 77.71; H, 8.20; N, 13.82.
(270 MHz) d 1.05–1.46 (m, 5H), 1.50–1.83 (m, 3H), 1.95–
2.10 (m, 2H), 3.14–3.26 (m, 1H), 3.52 (br s, 1H), 6.49 (dt,
J¼8.7, 2.7 Hz, 2H), 7.08 (dt, J¼8.7, 2.6 Hz, 2H); 13C NMR
(68 MHz) d 25.0, 25.9, 33.3, 51.8, 114.0, 121.1, 128.9,
145.8; EI-MS m/z 211 (Mþþ2, 16.84), 209 (Mþ, 51.68),
166 (100); HR-MS (EI) for C12H16ClN Calcd 209.0971,
found 209.0990.
4.3.5. N,N-Dipropylbenzylamine (48). Oil. IR (neat):
1
2960, 2880, 2800, 1610, 1500, 740, 700 cm21; H NMR
4.2.3. N-Cyclohexylindoline (35). Oil. IR (neat): 2930,
1
(270 MHz) d 0.86 (t, J¼7.4 Hz, 6H), 1.40–1.55 (m, 4H),
2.37 (t, J¼7.3 Hz, 4H), 3.55 (s, 2H), 7.18–7.36 (m, 5H); 13C
NMR (68 MHz) d 12.0, 20.3, 55.9, 58.7, 126.4, 127.9, 128.6,
140.3; EI-MS m/z 191 (Mþ, 2.33), 162 (38.96), 91 (100); HR-
MS (EI) for C13H21N Calcd 191.1674, found 191.1672.
2850, 1610, 1490 cm21; H NMR (270 MHz) d 1.02–1.95
(m, 10H), 2.93 (t, J¼8.4 Hz, 2H), 3.28–3.42 (m, 3H), 6.40
(d, J¼8.1 Hz, 1H), 6.57 (td, J¼7.3, 0.9 Hz, 1H), 6.98–7.09
(m, 2H); 13C NMR (68 MHz) d 26.1, 26.2, 28.4, 28.8, 46.7,
54.6, 106.7, 116.4, 124.2, 127.0, 129.9, 151.0; EI-MS m/z
201 (Mþ, 46.36), 158 (100); HR-MS (EI) for C14H19N
Calcd 201.1517, found 201.1525.
4.3.6. N-Benzylpyrrolidine (50). Oil. IR (neat): 3040,
;
2970, 2800, 1610, 1500 740, 700 cm21 1H NMR
(270 MHz) d 1.70–1.87 (m, 4H), 2.43–2.58 (m, 4H), 3.61
(s, 2H), 7.19–7.36 (m, 5H); 13C NMR (68 MHz) d 23.4,
54.1, 60.7, 126.8, 128.1, 128.9, 139.3; EI-MS m/z 161 (Mþ,
34.21), 91 (100), 84 (49.07), 70 (32.29); HR-MS (EI) for
C11H15N Calcd 161.1204, found 161.1205.
4.3. Typical procedure for the preparation of 31 in
H2O–AcOH
A mixture of cyclohexanone (30) (200 mg, 2.04 mmol),
aniline (2) (190 mg, 2.04 mmol), and pic-BH3 (218 mg,
2.04 mmol) was stirred for 1 h at room temperature in H2O–
AcOH (10:1, 5.5 mL). After the reaction, 10% Na2CO3
(20 mL) was added and the aqueous solution was extracted
with AcOEt (30 mL£2), and the combined organic layer
4.4. Typical procedure for the preparation of 22 in neat
condition
To acetophenone (20) (1.00 g, 8.32 mmol), benzylamine (4)

7906
S. Sato et al. / Tetrahedron 60 (2004) 7899–7906
B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
3849. (f) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G.
Tetrahedron Lett. 1990, 31, 5595.
(0.89 g, 8.32 mmol), and AcOH (0.3 mL) was added pic-
BH3 (0.89 g, 8.32 mmol) over 5 min and the reaction
mixture was stirred for 72 h. After the reaction, 10% HCl
(10 mL) was added and the aqueous solution was stirred for
0.5 h at room temperature. Na2CO3 (ca. 2.5 g) and H2O
(10 mL) were added to the solution under cooling to make
the solution alkaline. The aqueous layer was extracted with
AcOEt (30 mL£2), and the combined organic layer was
washed with brine (15 mL), dried over Na2SO4, and
concentrated. The crude product was chromatographed on
a column of silica gel with AcOEt–n-hexane (1:3) to afford
N-benzyl-1-phenylethylamine (22) (1.53 g, 87%).
4. (a) Pelter, A.; Rosser, R. M. J. Chem. Soc., Perkin Trans. 1
1984, 717. (b) Bomann, M. D.; Guch, I. C.; DiMare, M. J. Org.
Chem. 1995, 60, 5995. (c) Moormann, A. E. Synth. Commun.
1993, 23, 789.
5. (a) Miriyala, B.; Bhattacharyya, S.; Williamson, J. S. Tetra-
hedron 2004, 60, 1463. (b) Kumpaty, H. J.; Williamson, J. S.;
Bhattacharyya, S. Synth. Commun. 2003, 33, 1411. (c) Neidigh,
K. A.; Avery, M. A.; Williamson, J. S.; Bhattacharyya, S.
J. Chem. Soc., Perkin Trans. 1 1998, 2527. (d) Bhattacharyya, S.
J. Org. Chem. 1995, 60, 4928. (e) Bhattacharyya, S.;
Chatterjee, A.; Williamson, J. S. Synlett 1995, 1079.
6. Yoon, N. M.; Kim, E. G.; Son, H. S.; Choi, J. Synth. Commun.
1993, 23, 1595.
4.4.1. Benzylpropylamine (52). Oil. IR (neat): 3320, 3070,
3030, 2960, 2930, 2880, 2820, 1610, 1500, 740, 700 cm21
;
1H NMR (270 MHz) d 0.92 (t, J¼7.4 Hz, 3H), 1.45–1.61
(m, 3H), 2.60 (t, J¼7.3 Hz, 2H), 3.79 (s, 2H), 7.19–7.36 (m,
5H); 13C NMR (68 MHz) d 11.8, 23.2, 51.3, 53.9, 126.6,
127.9, 128.1, 140.3; EI-MS m/z 149 (Mþ, 3.56), 120
(28.15), 91 (100); HR-MS (EI) for C10H15N Calcd
149.1204, found 149.1226.
7. Ranu, B. C.; Majee, A.; Sarkar, A. J. Org. Chem. 1998, 63, 370.
8. Hiroi, R.; Miyoshi, N.; Wada, M. Chem. Lett. 2002, 274.
9. Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1745.
10. Alexandre, F.-R.;Pantaleone, D. P.;Taylor, P. P.;Fotheringham,
I. G.; Ager, D. J.; Turner, N. J. Tetrahedron Lett. 2002, 43, 707.
11. (a) Miller, V. R.; Ryschkewitsch, G. E.; Chandra, S. Inorg.
Chem. 1970, 9, 1427. (b) Brown, H. C.; Murray, K. J.; Murray,
L. J.; Snover, J. A.; Zweifel, G. J. Am. Chem. Soc. 1960, 82,
4233. (c) Ashby, E. C. J. Am. Chem. Soc. 1959, 81, 4791.
12. (a) Ryschkewitsch, G. E.; Birnbaum, E. R. Inorg. Chem. 1965,
4, 575. (b) Baldwin, R. A.; Washburn, R. M. J. Org. Chem.
1961, 26, 3549. (c) Brown, H. C.; Domash, L. J. Am. Chem.
Soc. 1956, 78, 5384.
4.4.2. Allylbenzylamine (55). Oil. IR (neat): 3300, 3060,
1
3020, 2910, 2800, 1640, 1600, 1495, 695 cm21; H NMR
(270 MHz) d 1.44 (s, 1H), 3.28 (dt, J¼5.9, 1.2 Hz, 2H), 3.79
(s, 2H), 5.11 (dd, J¼10.2, 1.3 Hz, 1H), 5.20 (dq, J¼17.1,
1.5 Hz, 1H), 5.85–6.04 (m, 1H), 7.20–7.38 (m, 5H); 13C
NMR (68 MHz) d 51.8, 53.3, 115.9, 126.8, 128.0, 128.3,
136.6, 140.1; EI-MS m/z 147 (Mþ, 22.95), 120 (7.78), 91
(100); HR-MS (EI) for C10H13N Calcd 147.1048, found
147.1049.
13. JP Patent 112,988, 1995..
14. Amine Borane; Callery Chemical Technical Bulletin, 2002, p 9.
15. Krein, D. M.; Lowary, T. L. J. Org. Chem. 2002, 67, 4965.
16. Zhang, J.; Blazecka, P. G.; Davidson, J. G. Org. Lett. 2003, 5,
553.
4.4.3. N-Benzyl-2,4,5-trichloroaniline (57). White crys-
tals. Mp 46–49 8C (n-hexane); IR (KBr): 3420, 1600, 1500,
1
700 cm21; H NMR (270 MHz) d 4.36 (d, J¼5.4 Hz, 2H),
17. Dinsmore, C. J.; Zartman, C. B. Tetrahedron Lett. 2000, 41,
6309.
4.73 (bs, 1H), 6.68 (s, 1H), 7.23–7.43 (m, 6H); 13C NMR
(68 MHz) d 47.9, 112.1, 117.6, 119.3, 127.2, 127.6, 128.8,
129.7, 131.5, 137.4, 143.1; EI-MS m/z 291 (Mþþ6, 0.76),
289 (Mþþ4, 6.57), 287 (Mþþ2, 20.37), 285 (Mþ, 21.49),
208 (3.48), 91 (100). Anal. Calcd for C13H10Cl3N: C, 54.48;
H, 3.52; N, 4.89, found: C, 54.49; H, 3.31; N, 4.77.
18. Beshore, D. C.; Dinsmore, C. J. Org. Lett. 2002, 4, 1201.
19. (a) Rompaey, K. V.; Van den Eynde, I.; Kimpe, N. D.;
´
Tourwe, D. Tetrahedron 2003, 59, 4421. (b) Kobayashi, S.;
Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407.
20. Coe, J. W.; Vetelino, M. G.; Bradlee, M. J. Tetrahedron Lett.
1996, 37, 6045.
21. Bhattacharyya, S. Tetrahedron Lett. 1994, 35, 2401. Later it
was reported that titanium(IV) isopropoxide acts as a Lewis
acid to produce an aminocarbinolatotitanium(IV) complex
intermediate which is reduced either directly or via transient
imminium species. See Bhattacharyya, S.; Neidigh, K. A.;
Avery, M. A.; Williamson, J. S. Synlett 1999, 1781. Ref. 5c,d.
Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A. J. Org.
Chem. 1990, 55, 2552.
5. Supplementary material
1H NMR spectra of all products reported in Table 1–3.
References and notes
22. (a) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751.
´
(b) Lubineau, A.; Auge, J.; Queneau, Y. Synthesis 1994, 741.
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24. Reductive amination of aqueous formaldehyde (10 equiv, 37%
in H2O) with amines using NaBH3CN (3 equiv.) in CH3CN is
reported (Ref. 2a). Recently, the reductive amination of aqueous
formaldehyde (30% in H2O) and glutaraldehyde (25% in H2O)
with 1-phenylpiperazine in 1,2-dichloroethane using
NaBH(OAc)3 (4 equiv.) is reported (Ref. 3c).
3. (a) Zhang, J.; Blazecka, P. G.; Davidson, J. G. Org. Lett. 2003,
´
¨
5, 553. (b) Hammarstrom, L. G. J.; Smith, D. B.; Talamas,
F. X.; Labadie, S. S.; Krauss, N. E. Tetrahedron Lett. 2002, 43,
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1201. (d) Dinsmore, C. J.; Zartman, C. B. Tetrahedron Lett.
2000, 41, 6309. (e) Abdel-Magid, A. F.; Carson, K. G.; Harris,
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