Reductive coupling of aromatic oxims and azines to 1,2-diamines using Zn-MsOH or Zn-TiCl4

Article abstract of DOI:10.1016/S0040-4039(01)00178-2

The reduction of aromatic aldoxims and azines with Zn in the presence of MsOH or TiCl₄ afforded N,N′-unsubstituted 1,2-diamines in one-step. The reductive coupling with Zn-MsOH gave meso 1,2-diamines selectively, whereas dl 1,2-diamines were fo

Full text of DOI:10.1016/S0040-4039(01)00178-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2365–2368
Reductive coupling of aromatic oxims and azines to 1,2-diamines
using Zn-MsOH or Zn-TiCl4
Naoki Kise* and Nasuo Ueda
Department of Biotechnology, Faculty of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
Received 4 January 2001; accepted 26 January 2001
Abstract—The reduction of aromatic aldoxims and azines with Zn in the presence of MsOH or TiCl4 afforded N,N%-unsubstituted
1,2-diamines in one-step. The reductive coupling with Zn-MsOH gave meso 1,2-diamines selectively, whereas dl 1,2-diamines were
formed selectively by the reduction with Zn-TiCl4. © 2001 Elsevier Science Ltd. All rights reserved.
Since reductive coupling of imines (imino-pinacol cou-
pling) is a useful method for the synthesis of 1,2-
diamines, numerous methods have been reported using
Zn,1 low-valent titanium,2 SmI2,3 other metal reducing
agents,4 and electroreduction.5 These methods, how-
ever, afforded N,N%-disubstituted 1,2-diamines from
imines. In order to obtain N,N%-unsubstituted 1,2-
diamines, it was necessary to remove the substituents
on the nitrogen atoms. The reductive coupling of
of an acid (5 equiv.) in acetonitrile (runs 2–4). As an
acid, MsOH afforded the best yield (65%, dl:meso=
25:75) of 1,2-diphenyl-1,2-diaminoethane (2a) (run 2).
When the reduction with Zn-MsOH in acetonitrile was
carried out at −20°C, a similar result was obtained (2a:
60%, dl:meso=27:73). Other acids, TfOH and H2SO4,
also gave 2a in moderate yields (runs 3 and 4), whereas
TFA and AcOH brought about poor results (2a:<5 and
0%, respectively). The reduction of 1a with Zn-MsOH
in THF increased meso selectivity in 2a (dl:meso=
15:85), although the yield of 2a was decreased to some
extent (run 5). The reduction of 1a did not occur using
Pb, Sn, or Mg in place of Zn under the same conditions
as in run 2. Next, the reactions were carried out in the
presence of a metal chloride in THF (runs 6–10). The
reduction with Zn-TiCl4 afforded 2a in 81% yield (run
6). Other metals, such as Mg and Li, also gave 2a in
moderate yields (runs 7 and 8). On the other hand, the
use of ZrCl4 or CeCl3 as an additive yielded benzyl-
amine (3a) as a main product (runs 9 and 10). The
reaction with Zn-Me3SiCl1d,8,9 was not effective for the
reduction of 1a (2a:<5%) and most of 1a was recovered.
silylimines with NbCl4(THF)2 or low-valent titanium7
6
and that of dibenzylidine sulfamides with Zn-TMSCl8
have been reported as alternative methods for easy
access to N,N%-unsubstituted 1,2-diamines. Herein we
report that the reductive coupling of aromatic aldoxims
and azines was achieved using Zn-MsOH and Zn-TiCl4
(Eq. (1)). These reactions provide a useful method for
the one-pot synthesis of N,N%-unsubstituted 1,2-
diamines from readily available aromatic oxims and
azines. We also found that the reductions with Zn-
MsOH and those with Zn-TiCl4 showed different
diastereoselectivities in the resulting 1,2-diamines.
Ar
Ar
Ar
Zn-additive
N
Ar
or
Ar
N
N
H2N
NH2
Table 2 shows the results of the reactions of several
aromatic aldoxims with Zn-MsOH and with Zn-TiCl4
at ambient temperature. In the reductions with Zn-
MsOH, aromatic aldoxims para-substituted by an
electron-donating group (1b–d) afforded 1,2-diaryl-1,2-
diamines 2b–d in good yields, whereas those para-sub-
stituted by an electron-withdrawing group (1e,f)
brought about amines 3e,f as major products. The
reactions of o-bromobenzaldoxim (1h) and 1-naphthyl-
aldoxim (1i) resulted in exclusive formation of amines
3h,i, and only small amounts of 1,2-diamines 2h,j were
obtained, probably due to the steric hindrance.
On the contrary, the reductions with Zn-TiCl4
OH
(1)
The results of the reduction of benzaldoxim (1a) with a
metal (5 equiv.) at room temperature are summarized in
Table 1. In the absence of an additive, 1a was recovered
completely (run 1). Therefore, the presence of an addi-
tive was crucial for the reductive coupling of 1a. First,
the reactions were carried out with Zn in the presence
Keywords: reductive coupling; oxim; azine; 1,2-diamine.
* Corresponding
author.
Fax:
+81-857-31-5636;
e-mail:
kise@bio.tottori-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00178-2

2366
N. Kise, N. Ueda / Tetrahedron Letters 42 (2001) 2365–2368
Table 1. Reductive coupling of benzaldoxim
metal (5 equiv.)-
additive (2.5-5 equiv.)
Ph
Ph
Ph
Ph
H
+
NH2
3a
N
25°C
solvent
H2N
NH2
OH
2a
1a
Run
Metal-additive (equiv.)
Solvent
Yielda (%)
2a (dl/meso)b
3a
1
2
3
4
5
6
7
8
9
Zn-none
CH3CN
CH3CN
CH3CN
CH3CN
THF
THF
THF
THF
THF
0
0
18
21
45
16
3
9
8
51
66
Zn-MsOH (5)
Zn-TfOH (5)
Zn-H2SO4 (5)
Zn-MsOH (5)
Zn-TiCl4 (2.5)
Mg-TiCl4 (2.5)
Li-TiCl4 (2.5)
Zn-ZrCl4 (2.5)
Zn-CeCl3 (2.5)
65 (25/75)
53 (25/75)
42 (35/65)
56 (15/85)
81 (55/45)
52 (70/30)
47 (53/47)
11 (35/65)
0
10
THF
a Isolated yields.
b Determined by 1H NMR.
Table 2. Reductive coupling of aromatic aldoxims
Ar
H2N
Ar
NH2
Ar
+
Ar
H
Zn-additive
NH2
N
25°C
OH
3
2
1
c
1
Ar
Yielda (%) with Zn-MsOHb
Yielda (%) with Zn-TiCl4
2 (dl/meso)d
3
2 (dl/meso)d
3
1b
1c
1d
1e
1f
1g
1h
1i
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-NCC6H4
p-Me2NC6H4
1-Furyl
m-BrC6H4
o-BrC6H4
1-Naphthyl
2-Naphthyl
67 (23/77)
70 (20/80)
56 (30/70)
11 (36/64)
9 (33/67)
19 (35/65)
46 (31/69)
17 (25/75)
19 (20/80)
50 (37/63)
14
17
32
78
86
50
41
42
44
19
88 (58/42)
90 (63/37)
79 (55/45)
68 (62/38)
78 (67/33)
79 (57/43)
71 (49/51)
67 (27/73)
63 (40/60)
60 (45/55)
B2
B2
3
3
22
3
4
7
5
B2
1j
1k
a Isolated yields.
b With Zn (5 equiv.) and MsOH (5 equiv.) in acetonitrile.
c With Zn (5 equiv.) and TiCl4 (2.5 equiv.) in THF.
d Determined by 1H NMR spectra. Ref. 11.
gave 1,2-diamines in moderate to high yields irrespec-
tive of the aryl group in 1. In addition, the reactions of
1 with Zn-TiCl4 generally afforded dl-2 selectively,
while those with Zn-MsOH produced meso-2
preferentially.
diamines 2. Similarly to the results obtained from
aromatic aldoxims (Table 2), the reductions with Zn-
MsOH gave meso-2 selectively. The reductions with
Zn-TiCl4 brought about better yields and dl selectivity
in 2. Since it is generally accepted that a low-valent
titanium2,10 is generated from metal–TiCl4, the sub-
strate is reduced by a low-valent titanium in the reduc-
tion with Zn-TiCl4. On the other hand, the reduction
with Zn-MsOH proceeds through electron transfer
As exemplified in Table 3, aromatic aldehyde azines 4
could be employed as effective substrates for the reduc-
tive coupling to prepare N,N%-unsubstituted 1,2-

N. Kise, N. Ueda / Tetrahedron Letters 42 (2001) 2365–2368
Table 3. Reductive coupling of aromatic azines
Ar
2367
Ar
Ar
Ar
Zn-additive
N
+
Ar
N
NH2
25°C
H2N
NH2
4
3
2
c
4
Ar
Ph
Yielda (%) with Zn-MsOHb
Yielda (%) with Zn-TiCl4
2 (dl/meso)d
3
2 (dl/meso)d
3
4a
4b
4c
4d
4e
4f
62 (20/80)
41 (30/70)
57 (30/70)
26 (36/64)
18 (44/56)
B2
19
13
13
35
65
95
37
33
73 (72/28)
68 (77/23)
58 (78/22)
59 (63/37)
55 (50/50)
58 (82/18)
61 (74/26)
46 (70/30)
10
6
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-NCC6H4
p-Me2NC6H4
1-Furyl
26
13
23
32
11
5
4g
4h
22 (44/56)
17 (37/63)
m-BrC6H4
a Isolated yields.
b With Zn (10 equiv.) and MsOH (10 equiv.) in THF.
c With Zn (10 equiv.) and TiCl4 (5 equiv.) in THF.
d Determined by 1H NMR spectra. Ref. 11.
Table 4. Reductive coupling of O-methyloxim and hydrazones
Ph
Ph
NH2
Ph
Ph
H
X
Zn-additive
+
NH2
3a
N
25°C
H2N
2a
5-8
Yielda (%) with Zn-MsOHb
Yielda (%) with Zn-TiCl4
c
X
2a (dl/meso)d
3a
2a (dl/meso)d
3a
5
6
7
8
OMe
NHPh
NHTs
NHCO2Me
65 (23/77)
50 (25/75)
47 (28/72)
49 (28/72)
28
33
31
33
76 (60/40)
0
57 (44/56)
22 (36/64)
B2
46
18
54
a Isolated yields.
b With Zn (5 equiv.) and MsOH (5 equiv.) in acetonitrile.
c With Zn (5 equiv.) and TiCl4 (2.5 equiv.) in THF.
d Determined by 1H NMR spectra.
from Zn to the substrate activated by MsOH. There-
fore, it seems that these methods show different
diastereoselectivities.
A typical procedure is as follows (Table 1, run 2): zinc
powder (Wako Pure Chemical Industries Ltd) was
washed successively with 1 M HCl, water, and ether
and dried in vacuo. To a solution of benzaldoxim (0.24
g, 2 mmol) in dry acetonitrile (10 mL) was added
freshly distilled MsOH (0.65 mL, 10 mmol) and zinc
powder (0.65 g, 10 mmol) at 0°C under an atmosphere
of nitrogen, and the mixture was stirred for 8 h at room
temperature. The mixture was diluted with 1 M HCl
(20 mL), filtered to remove unreacted zinc, and then
extracted with dichloromethane twice. The water layer
was basified (pH 10) with 3 M NaOH and filtered. The
filtrate was extracted with dichloromethane three times
and the organic layer was washed with water, dried
over magnesium sulfate, and concentrated. After
removal of the solvent, 1,2-diphenyl-1,2-diaminoethane
(2a) was isolated as a diastereomeric mixture (65%
yield, dl:meso=25:7510) by column chromatography on
The reactions of O-methylbenzaldoxim 5 and benzalde-
hyde hydrazones 6–8 were attempted using Zn-MsOH
or Zn-TiCl4 as shown in Table 4. The results obtained
from 5 were similar to those from benzaldoxim (Table
1, runs 2,6). Hydrazones 6–8 also gave 2a in moderate
yields, although considerable amounts of 3a were
formed.
In conclusion, aromatic aldoxims and azines readily
available from aromatic aldehydes were effectively
transformed to the corresponding N,N%-unsubstituted
1,2-diaryl-1,2-diamines by reductive coupling with Zn
in the presence of MsOH or TiCl4. As an additive, the
use of MsOH selectively led to meso 1,2-diamines,
while that of TiCl4 to dl 1,2-diamines.

2368
N. Kise, N. Ueda / Tetrahedron Letters 42 (2001) 2365–2368
basic alumina (hexane/ethyl acetate). Recrystallization
of the mixture from hexane/ethyl acetate (10/1) gave
pure meso-2a in 35% yield.
J. Org. Chem. 1999, 64, 7665.
5. Shono, T.; Kise, N.; Shirakawa, E.; Matsumoto, H.;
Okazaki, E. J. Org. Chem. 1991, 56, 3063.
6. Roscamp, E. J.; Pedersen, S. F. J. Am. Chem. Soc. 1987,
109, 3152.
7. Betschart, C. A.; Schmidt, B.; Seebach, D. Helv. Chim.
Acta 1988, 71, 1999.
References
1. (a) Kise, N.; Oike, H.; Okazaki, E.; Yoshimoto, M.;
Shono, T. J. Org. Chem. 1995, 60, 3980; (b) Shimizu, M.;
Iida, T.; Fujisawa, T. Chem. Lett. 1995, 609; (c) Dutta,
M. P.; Baruah, B.; Boruah, A.; Prajapati, D.; Sandhu, J.
S. Synlett 1998, 857; (d) Alexakis, A.; Aujard, I.; Man-
geney, P. Synlett 1998, 873.
2. (a) Periasamy, M.; Reddy, M. R.; Kanth, J. V. B. Tetra-
hedron Lett. 1996, 37, 4767; (b) Liao, P.; Huang, Y.;
Zhang, Y. Synth. Commun. 1997, 27, 1483; (c) Taluldar,
S.; Banerji, A. J. Org. Chem. 1998, 63, 3468; (d) Li, J.;
Wang, S.; Hu, J.; Chen, W. Tetrahedron Lett. 1999, 40,
1961; (e) Periasamy, M.; Srinivas, G.; Karunakar, G. V.;
Bharathi, P. Tetrahedron Lett. 1999, 40, 7577 and refer-
ences cited therein.
8. Pansare, S.; Malusare, M. G. Tetrahedron Lett. 1996, 37,
2859.
9. Shono, T.; Kise, N.; Nomura, R.; Yamanami, A. Tetra-
hedron Lett. 1993, 34, 3577.
10. For recent reports of pinacol coupling with a low valent
titanium, see: (a) Clerici, A.; Clerici, L.; Porta, O. Tetra-
hedron Lett. 1996, 37, 3035; (b) Balu, N.; Nayak, S. K.;
Banerji, A. J. Am. Chem. Soc. 1996, 118, 5932; (c)
Gansa¨uer, A. Synlett 1997, 363. (d) Barden, M. C.;
Schwartz, J. J. Org. Chem. 1997, 62, 7520; (e) Matsubara,
S.; Hashimoto, Y.; Okano, T.; Utimoto, K. Synlett 1999,
1411; (f) Tsuritani, T.; Ito, S.; Shinokubo, H.; Oshima,
K. J. Org. Chem. 2000, 65, 5066.
11. The diastereomeric ratios of 2 were determined by their
1H NMR spectra. The chemical shifts (l) of methyn
protons adjacent to the nitrogen atom in 2 were as
follows: dl-2a 4.09; meso-2a 4.01; dl-2b 4.07; meso-2b
3.95; dl-2c 4.01; meso-2c 3.93; dl-2d 3.99; meso-2d 3.97;
dl-2e 4.14; meso-2e 4.09; dl-2f 4.01; meso-2f 3.86; dl-2g
4.28; meso-2g 4.22; dl-2h 4.03; meso-2h 3.96; dl-2i 4.67;
meso-2i 4.71; dl-2j 5.11; meso-2j 5.23; dl-2k 4.42; meso-2k
4.29.
3. (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi,
F.; Raimondi, L. Tetrahedron Lett. 1998, 39, 3333; (b)
Machrouhi, F.; Namy, J.-L. Tetrahedron Lett. 1999, 40,
1315 and references cited therein.
4. For recent reports, see: (a) Baruah, B.; Prajapati, D.;
Sandhu, J. S. Tetrahedron Lett. 1995, 36, 6747; (b) Rieke,
R. D.; Kim, S.-H. J. Org. Chem. 1998, 63, 5235; (c)
Hatano, B.; Ogawa, A.; Hirao, T. J. Org. Chem. 1998, 63,
9421; (d) Hirao, T.; Hatano, B.; Imamoto, Y.; Ogawa, A.
.
.