Highly chemoselective crossed imino pinacol coupling reaction using the synergetic effect of boron trifluoride etherate and trichloromethylsilane

Article abstract of DOI:10.1055/s-2003-41419

Use of boron trifluoride etherate and trichloromethylsilane in the presence of zinc-copper couple effects a crossed imino pinacol coupling reaction to give 1,2-diamines in good yields with high diastereoselectivities.

Full text of DOI:10.1055/s-2003-41419

LETTER
1635
Highly Chemoselective Crossed Imino Pinacol Coupling Reaction Using the
Synergetic Effect of Boron Trifluoride Etherate and Trichloromethylsilane
Chemoselective
C
rosse
a
d
I
minoPi
k
nacol Coupli
o
ng Reactionto Shimizu,* Ikuhiro Suzuki, Hiroaki Makino
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Fax +81(59)2319413; E-mail: mshimizu@chem.mie-u.ac.jp
Received 19 June 2003
Zn-Cu (2.0 equiv)
BF3·OEt2 (2.2 equiv)
MeSiCl3 (4.0 equiv)
PMP
PMP
O
N
Abstract: Use of boron trifluoride etherate and trichloromethyl-
silane in the presence of zinc-copper couple effects a crossed imino
pinacol coupling reaction to give 1,2-diamines in good yields with
high diastereoselectivities.
NH
Ph
Ph
H
Ph
H
Ph
(1.2 equiv)
(1.0 equiv)
CH3CN, 0 °C → r.t.
40 min
OH
97%
PMP = 4-methoxyphenyl
syn : anti = 65 : 35
Key words: crossed imino pinacol coupling, boron trifluoride
etherate, trichloromethylsilane, 1,2-diamines, zinc-copper couple
Scheme 1
rophenyl aniline (2) as substrates possessing an electron-
donating and an electron-withdrawing substituents on the
aromaic rings, respectively, and the results are summa-
rized in Table 1.
Widespread use of 1,2-diarylethylenediamines coupled
with some difficulties associated with their preparations
prompted us to investigate highly efficient methods for
their synthesis. 1,2-Diamines are useful units for the syn-
thesis of many biologically important natural products as
well as drugs for therapeutic purpose. They also serve as
chiral auxiliaries or metal ligands in catalytic asymmetric
synthesis.1
As shown in Table 1, the combined use of BF3·OEt2 and
MeSiCl3 promoted the desired crossed coupling reaction.
The use of an increased amount of trichloromethylsilane
gave the unsymmetrical 1,2-diamine 3 in good yield with
high diastereoselectivity (entries 1–4). The reaction car-
ried out for a long reaction time decreased the yield of the
product because 1,2-diamine readily underwent cleavage
reaction (entry 5).8 The reactions carried out at lower re-
action temperatures decreased diastereoselectivities of the
products, although the product yields were increased
(entries 7 and 8).
Several strategies have been employed to construct such
units, e.g., introduction of diamino functionalities into
olefins, diols, or their derivatives2 and creation of di-
amines with simultaneous construction of the intercon-
necting carbon-carbon bonds.3 Among such processes, the
crossed imino pinacol coupling of two different imino
compounds is a direct way to synthesize unsymmetrical
1,2-diamines, and therefore, it is one of the most attractive
and useful methods. However, due to the competing
homo-coupling reactions, control of chemoselectivity is
the most difficult problem. Although there exist only lim-
ited examples on intermolecular crossed pinacol coupling
between carbonyl compounds and imines,4 no example is
available for crossed imino pinacol versions due to diffi-
culty to discriminate the subtle difference of reactivity.
Control experiments were carried out as shown in
Schemes 2– 4. In the absence of BF3·OEt2 and MeSiCl3,
the reaction did not proceed (Scheme 2). While in the
presence of MeSiCl3 the coupling reaction gave the
crossed adduct 3 in only 10% yield in a low stereoselec-
tive manner with a concomitant formation of homo-ad-
ducts 1¢ and 2¢(Scheme 3), the presence of BF3·OEt2
effected the formation of the desired adduct 3 with good
diastereoselectivity but in low yield (Scheme 4). Thus, the
synergetic use of BF3·OEt2 and MeSiCl3was proved to be
necessary for the formation of the crossed coupling prod-
uct 3 in acceptable yields.
Recently, we have found that a simple combination of two
different Lewis acids discriminates the difference of reac-
tivity between aldehydes and imines (Scheme 1).5 We,
therefore, consider that the synergetic use of boron triflu-
oride etherate and trichloromethylsilane also recognizes
the difference of reactivity between two imino species.
This paper describes an easy way to the discrimination of
two different imines in imino pinacol coupling, leading to
the chemoselective synthesis of 1,2-diamines.
We next examined the crossed imino pinacol coupling be-
tween the imines, one possessing an electron-donating
and the other an electron-withdrawing substituent on the
aromatic rings, under the best conditions found as in the
above cases, and the results are summarized in Table 2.
As shown in Table 2, the use of halogen as an electron-
withdrawing substituent on the aromatic ring gave the un-
symmetrical 1,2-diamines 6 in good yield with high dias-
tereoselectivities (entries 1–4). The use of the imine
possessing a 2,4-dichlorophenyl moiety gave the crossed
coupling product in low yield with low diasteroselectivity
(entry 5). In this case the homo-coupling product 4¢ was
We initially investigated the reaction conditions for the
crossed imino pinacol coupling using the reaction of N-
benzylidene-p-anisidine (1) and N-benzylidene-p-chlo-
Synlett 2003, No. 11, Print: 02 09 2003. Web: 25 08 2003.
Art Id.1437-2096,E;2003,0,11,1635,1638,ftx,en;U12103ST.pdf.
DOI: 10.1055/s-2003-41419
© Georg Thieme Verlag Stuttgart · New York

1636
M. Shimizu et al.
LETTER
Table 1 The Reaction of N-Benzylidene-p-anisidine with N-Benzylidene-p-chlorophenyl Anilinea
PMP
N
Ar
NH
PMP
Zn-Cu (2.0 equiv)
BF3·OEt2 (2.2 equiv)
MeSiCl3
Ph
H
NH
Ph
(1.0 equiv)
1
Ph
Ph
Ph
HN
C6H4p-Cl
Ar
1' (Ar = PMP)
CH3CN
Time, Temp.
N
HN
C6H4p-Cl
syn-3
2' (Ar = p-ClC6H4)
Ph
H
2
(1.0 equiv)
Entry
MeSiCl3/equiv Time/h
Temp/°C
0–r.t.
0–r.t.
0–r.t.
0–r.t.
0–r.t.
0–r.t.
–45–0
0
3(%)b
54
syn:antic,d
93:7
1¢(%)b
23
2¢ (%)b
1
2
3
4
5
6
7
8
9e
3.5
4.0
4.5
5.0
5.0
5.0
5.0
5.0
5.0
1.0
1.0
1.0
1.0
24.0
0.5
5.8
1.0
1.0
23
18
17
14
14
11
5
63
90:10
90:10
93:7
15
65
14
71
12
53
93:7
15
63
87:13
81:19
89:11
74:26
13
83
6
75
11
11
16
0–r.t.
62
12
a The reaction was carried out according to the typical experimental procedure.6
b Isolated yield.
c Determined by HPLC.
d Determination of the relative stereochemistry, see ref.7,
e EtCN was used as a solvent.
In general, the reaction usually proceeded to give the
crossed coupling products in good yields. The use of
CH2Cl2 as a co-solvent decreased the diastereoselectivi-
ties (entries 2 and 5). However, use of aliphatic and a,b-
unsaturated aldimines did not give the desired coupling
products.
PMP
H
C6H4p-Cl
N
N
Zn-Cu (2.0 equiv)
No Reaction
CH3CN, 0 °C → r.t.
1 h
Ph
Ph
H
1
2
(1.0 equiv)
(1.0 equiv)
Scheme 2
On the basis of the previously reported results from the
crossed pinacol coupling between imines and aldehydes
as well as the present results, we propose a possible reac-
tion mechanism as shown in Scheme 5.
Ar
PMP
NH
Ph
NH
Zn-Cu (2.0 equiv),
MeSiCl3 (5.0 equiv)
1 (1.0 equiv)
2 (1.0 equiv)
Ph
Ph
Ph
+
CH3CN, 0 °C → r.t.
HN
Ar
HN
3
C6H4p-Cl
1 h
1' (Ar = PMP) 10%
2' (Ar = p-ClC6H4) 10%
10%
syn : anti = 63 : 37
Cl
Me Si
Cl
Cl
Me
Cl
F
F
F
F
Cl
F
Cl
F
Scheme 3
B
Si
N
B
10
MetXn
Zn-Cu (2.0 equiv),
BF3·OEt2 (2.2 equiv)
1 (1.0 equiv)
2 (1.0 equiv)
p-ClC6H4
PMP
p-ClC6H4
PMP
Ph
1' (Ar = PMP) 4%
2' (Ar = p-ClC6H4) 7%
N
N
N
+
3
CH3CN, 0 °C → r.t.
34%
Ph
Zn
Ph
Ph
H
H
1 h
syn : anti = 95 : 5
Zn
p-ClC6H4
11
Scheme 4
NH
H2O
Ph
Ph
HN
syn-12
PMP
obtained in 33% yield, presumably because the 2-chloro
moiety prevented the nitrogen atom from coordinating
with the Lewis acidic species. The reaction of various imi-
nes with N-benzylidene-p-bromophenyl aniline was next
investigated, and the results are summarized in Table 3.
Scheme 5
Synlett 2003, No. 11, 1635–1638 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Chemoselective Crossed Imino Pinacol Coupling Reaction
1637
Table 2 The Crossed Imino Pinacol Couplinga
Ar1
N
Ar
NH
Ar1
Zn-Cu (2.0 equiv)
BF3·OEt2 (2.2 equiv)
MeSiCl3 (5.0 equiv)
NH
Ph
Ph
H
Ph
Ph
(1.0 equiv)
4
Ph
HN
Ar
Ar2
HN
4' (Ar = Ar1)
5' (Ar = Ar2)
Ar2
CH3CN, 0 °C → r.t.
N
syn-6
1 h
Ph
H
5
(1.0 equiv)
Entry
Ar1
Ar2
6 (%)b
69
syn:antic
4¢(%)b
10
5¢ (%)b
15
1
2
3
4
5
6
7
8
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeSC6H4
4-FC6H4
87:13
93: 7
92: 8
86:14
54:46
87:13
94: 6
98: 2
4-ClC6H4
71
12
14
4-BrC6H4
4-IC6H4
74
10
13
64
11
15
2,4-Cl2C6H3
4-CF3C6H4
4-EtO2CC6H4
4-ClC6H4
34
33
23
41
15
27
48
12
22
54
9
7
a The reaction was carried out according to the typical experimental procedure.6
b Isolated yield.
c Determined by HPLC.
Table 3 The Reaction of Various Imines with N-Benzylidene-p-bromophenyl Anilinea
PMP
N
Ar'
Ar
NH
PMP
Ar
Zn-Cu (2.0 equiv)
BF3·OEt2 (2.2 equiv)
MeSiCl3 (5.0 equiv)
Ar
H
NH
Ar
(1.0 equiv)
7
Ph
HN
Ar'
C6H4p-Br
Solvent, 0 °C → r.t.
HN
N
7' (Ar' = PMP)
8' (Ar = Ph
C6H4p-Br
1 h
syn-9
Ph
H
Ar '= C6H4p-Br)
8
(1.0 equiv)
Entry
Ar
Solvent
MeCN
9 (%)b
syn:antic
7¢ (%)b
8¢ (%)b
12
1
2
3
4
5
6
1-Naphthyl
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-MeOC6H4
4-MeC6H4
61
64
59
59
33
68d
83:17
83:17
93: 7
92: 8
78:22
93: 7
9
11
14
12
23
12
MeCN/CH2Cl2(9/1)
MeCN
18
18
MeCN
18
MeCN/CH2Cl2(9/1)
29
MeCN
16
a The reaction was carried out according to the typical experimental procedure.6
b Isolated yield.
c Determined by HPLC.
d The reaction time was 5 h.
Synlett 2003, No. 11, 1635–1638 ISSN 1234-567-89 © Thieme Stuttgart · New York

1638
M. Shimizu et al.
LETTER
Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33, 4469.
(f) Takai, K.; Ishiyama, T.; Yasue, H.; Nobunaka, T.; Itoh,
M.; Oshiki, T.; Mashima, K.; Tani, K. Organometallics
1998, 17, 5128. (g) Machrouchi, F.; Namy, J.-L.
A mixture of boron trifluoride etherate and trichlorometh-
ylsilane would form a bimetallic complex 10. On the basis
of reactivity, the nitrogen atom of more basic imine pos-
sessing an electron-donating substituent is coordinated
with the boron atom of boron trifluoride etherate, whereas
the nitrogen atom of less basic imine possessing an elec-
tron-withdrawing substituent is coordinated with the sili-
con atom of trichloromethylsilane. Therefore, the
bimetallic complex discriminates a subtle difference of re-
activity between imino compounds and coordinates to
them. Imines are reduced with zinc via a SET mechanism,
and the subsequent coupling of the radical species to
avoid the repulsion of aromatic rings gives the syn-12.
Tetrahedron Lett. 1999, 40, 1315. (h) Ma, Y.; Zhang, Y.;
Zhou, L. J. Chem. Res. 2000, 250. (i) Taniguchi, N.;
Uemura, M. J. Am. Chem. Soc. 2000, 122, 8301. (j) Liu, Y.-
K.; Zhang, Y.-M.; Liu, X. Chin. J. Chem. 2001, 19, 500.
(5) Shimizu, M.; Iwata, A.; Makino, H. Synlett 2002, 1538.
(6) A typical experimental procedure is as follows: To a
suspension of Zn-Cu (32.7 mg, 0.50 mmol) in MeCN (0.25
mL) was added a mixture of BF3·OEt2 (78.1 mg, 0.55 mmol)
and MeSiCl3 (0.147 mL, 1.25 mmol) in MeCN (1.0 mL) at 0
°C under an argon atmosphere. To the resulting mixture was
added a solution of N-benzylidene-p-anisidine (52.8 mg,
0.25 mmol) and N-benzylidene-p-chlorophenyl aniline (53.9
mg, 0.25 mmol) in acetonitrile (1.25 mL) at 0 °C. After being
stirred at room temperature for 1 h, the reaction was
quenched with sat. aqueous NaHCO3. Usual work-up
followed by purification on preparative silica gel TLC9
deactivated with phosphate buffer gave 1-(4-chloro-
phenylamino)-2-(4-methoxyphenylamino)-1,2-diphenyl-
ethane (76.2 mg, 71%) as a yellow amorphous.
In conclusion, we have developed a new convenient
crossed imino pinacol coupling reaction of various imines
using inexpensive and readily accessible reagents, where
use of the synergetic effect of plural Lewis acids is crucial
for the crossed coupling. This reaction offers a useful
method for a rapid assembly of unsymmetrical syn-1,2-di-
amines using an operationally simple procedure.
(7) The relative stereochemistry of the product was determined
using 1H NMR (NOE) after transforming into the
corresponding imidazolidinone as in the following examples
(Scheme 6).
References
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Cl3COCOCl
DMAP, NEt3
PMP
Ph
O
NH
HN
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PMP
C6H4p-Cl
Ph
N
N
CH2Cl2, 94%
Ph
Ph
C6H4p-Cl
major : minor = 87 : 13
major : minor = 74 : 26
O
O
CAN
C6H4p-Cl
C6H4p-Cl
PMP
Ph
CH3CN-H2O
HN
N
N
N
–15 °C → –10 °C
Ph
Ph
Ph
H H
NOE
H
H
major
70%
0.2 ~ 2.6%
O
CAN
CH3CN-H2O
O
C6H4p-Cl
HN
Ph
C6H4p-Cl
N
PMP
Ph
N
N
–15 °C → –5 °C
Ph
Ph
H
H
H H
minor
NOE
74%
11.2 ~ 11.4%
Scheme 6
(8) Shimizu, M.; Makino, H. Tetrahedron Lett. 2001, 42, 8865.
(9) The buffered silica gel TLC was used for the purification.
The buffered silica gel was prepared by suspending 93 g of
silica gel (Merck 60F254) in 230 mL of phosphate buffer
solution (pH 7.0) for 2 h and dried.
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Synlett 2003, No. 11, 1635–1638 ISSN 1234-567-89 © Thieme Stuttgart · New York