Reductive coupling of aromatic N,N-acetals using zinc and chlorotrimethylsilane

Article abstract of DOI:10.1016/j.tetlet.2011.04.104

The reductive coupling of aromatic N,N-acetals and N,O-acetal activated by chlorotrimethylsilane proceeded smoothly in the presence of zinc to give the corresponding diamines in good yields.

Full text of DOI:10.1016/j.tetlet.2011.04.104

Tetrahedron Letters 52 (2011) 3467–3469
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Tetrahedron Letters
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Reductive coupling of aromatic N,N-acetals using zinc and chlorotrimethylsilane
⇑
Bunpei Hatano , Tomoharu Tachikawa, Tetsunori Mori, Keita Nagahashi, Tatsuro Kijima
Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Jonan, Yonezawa 992-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reductive coupling of aromatic N,N-acetals and N,O-acetal activated by chlorotrimethylsilane pro-
ceeded smoothly in the presence of zinc to give the corresponding diamines in good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 3 February 2011
Revised 25 April 2011
Accepted 27 April 2011
Available online 5 May 2011
Vicinal diamine function is often present in natural products
and biologically active molecules. Furthermore, in the field of syn-
thetic chemistry, vicinal diamines are frequently used as synthetic
precursors and chiral ligands.1 A number of synthetic methods
have been developed for vicinal diamines. Among them, the reduc-
tive coupling of imines is a simple method for the synthesis of vic-
inal diamines.2 In our previous report, we described how simple
reduction conditions using zinc and chlorotrimethylsilane were
effective for the reductive coupling of aromatic O,O-acetals.3 Here-
in, we report that reductive coupling of aromatic N,N-acetals (1),
which are analogs of imines, proceeded smoothly in the presence
of zinc and chlorotrimethylsilane to give the corresponding dia-
mines (2) in good yields (Scheme 1).4,5
(1g and 1h), also proceeded without difficulty. In 3-pyridyl and
2-thiophenyl N,N-acetals (1i and 1j), similar treatment led to
R1
R1
R1
R1
N
N
Zn / TMSCl
R1
Ar
Ar
Ar
N
R1
CH2Cl2 / rt /overnight
N
R1
R1
1
2
Scheme 1.
At first, we examined the reductive coupling of 1a with zinc in
the presence or absence of additives (Table 1). Though no reductive
coupling took place with zinc alone (entry 1), the addition of
1 equiv of chlorotrimethylsilane (TMSCl) against 1a led to 2a in
79% yield (entry 2). The use of 2 equiv of TMSCl successfully im-
proved the product yield, giving 2a in 83% yield (entry 3).6,7 These
results suggest that TMSCl was employed as an activator of 1a as
well as zinc.8 In this reductive coupling, the substituent of chloros-
ilane influenced the yield of 2a: chlorosilane bearing a bulky alkyl
group, such as TESCl and TBSCl, and tetrachlorosilane resulted in
low yields of 2a (entries 4–6). The use of some additives, such as
ZnCl2, AlCl3, TiCl4,9 and VOCl3,10 also gave 2a in poor yields (entries
7–10).
This reductive coupling using zinc and chlorotrimethylsilane
was useful for other aromatic N,N-acetals 1 as shown in Table
2. The reductive coupling of p-methoxy, p-methyl, p-chloro, o-
chloro (1b, 1c, 1d, and 1e) derivatives proceeded smoothly to
give the corresponding diamines (2b, 2c, 2d, and 2e) in moder-
ate to good yields. In the case of o-bromo derivative (1f), the
reductive coupling also took place in moderate yield with mod-
erate dl-selectivity. The derivatives bearing an electron-with-
drawing group, such as the cyano and trifluoromethyl groups
Table 1
Influence of additives on the reductive coupling of 1a in the presence of zinca
N
N
Zn / additive
N
CH2Cl2 /rt / overnight
N
1a
2a
Entry
Additive
Yield of 2ab (%)
dl/mesoc
1
2
3
4
5
6
7
8
9
—
0
—
TMSCld
TMSCl
TESCl
TBSCl
SiCl4
ZnCl2
AlCl3
TiCl4
VOCl3
79
83
42
26
18
19
38
18
0
54/46
58/42
54/46
51/49
43/57
53/47
47/53
79/21
—
10
a
Reaction conditions: 1a (2.0 mmol), Zn (2.0 mmol), additive (4.0 mmol), CH2Cl2
(5 mL), rt, overnight, under N2.
b
Isolated yield.
c
Determined by 1H NMR of crude 2a.
⇑
Corresponding author.
E-mail address: hatano@yz.yamagata-u.ac.jp (B. Hatano).
d
TMSCl (2.0 mmol) was used.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.104

3468
B. Hatano et al. / Tetrahedron Letters 52 (2011) 3467–3469
Table 2
Reductive coupling of 1 using zinc and TMSCla
N
Zn / TMSCl
R1
R1
N
R1
R1
Ph
OEt
CH2Cl2 / rt /overnight
N
N
Zn / TMSCl
5
Ar
R1
R1
Ar
Ar
N
R1
CH2Cl2 / rt / overnight
R1
N
OEt
N
1
2
Ph
+
Ph
+
Ph
Ph
Ph
Ph
N
OEt
OEt
Ar
R1
1
Yield of 2b (%)
dl/mesoc
84% yield
0% yield
0% yield
2k
6
7
p-MeOC6H4
p-MeC6H4
p-ClC6H4
o-ClC6H4
o-BrC6H4
p-NCC6H4
p-CF3C6H4
3-Pyridyl
Me
Me
Me
Me
Me
Me
Me
Me
1b
1c
1d
1e
1f
1g
1h
1i
66
75
97
77
60
99
80
53
68
82
79
47/53
53/47
53/47
57/43
68/32
47/53
55/45
53/47
49/51
69/31
53/47
Scheme 4.
by the activation of 1 (Scheme 3). Chlorotrimethylsilane serves as
an activator of 1, generating an iminium salt 3,12,13 which leads
a-aryl-a-amino-radical 4 by one-electron
transfer from zinc. Then, the coupling of 4 leads to the correspond-
2-Thiophenyl
Ph
Ph
Me
–(CH2)4–
–(CH2)5–
1j
1k
1l
to the corresponding
ing diamine 2.
a
Compound 1a (2.0 mmol), Zn (2.0 mmol), TMSCl (4.0 mmol), CH2Cl2 (5 mL), rt,
N2, overnight.
The reductive coupling using zinc and chlorotrimethylsilane
was also useful for N,O-acetal. When N,O-acetal 5 was treated with
zinc and chlorotrimethylsilane, the corresponding 1,2-diamine 2k
was obtained in 84% yield (dl/meso = 56/44) without either 2-ami-
noethanol compound 6 or 1,2-diether 7 (Scheme 4).14
In conclusion, the reductive coupling of aromatic N,N-acetals
and N,O-acetal activated by chlorotrimethylsilane proceeded
smoothly in the presence of zinc to give the corresponding dia-
mines in moderate to good yields. Further detailed applications
are now in progress.
b
Isolated yield.
c
Determined by 1H NMR of crude 2.
the corresponding coupling products in moderate yields (2i and
2j). The stereoselectivity of this reductive coupling was some-
what affected by the bulkiness of the amino substituent: the
derivative from pyrrolidine gave the corresponding coupling
product with moderate dl-selectivity, as compared to that from
piperidine (2k and 2l).
In the case of N,N-acetal bearing methallyl group (1m), the cor-
responding coupling product (2m) was obtained in 74% yield
(dl/meso = 50/50) without any cyclization product (Scheme 2).
It is generally accepted that the reductive coupling of N,N-ace-
tals proceeds via a radical process as in the case of reductive cou-
pling of carbonyl compounds.11 Although the detailed pathway is
not clear, in the present reductive coupling using zinc and chloro-
trimethylsilane, the reductive coupling of 1 seemed to be triggered
Acknowledgments
This work was supported by a Grant-in-Aid for Young Scientists
(B) (No. 21750165) from the Japan Society for the Promotion of Sci-
ence (JSPS).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.104.
N
References and notes
N
O
N
Zn / TMSCl
1. For reviews, see: (a) de Figueiredo, R. M. Angew. Chem., Int. Ed. 2009, 48, 1190–
1193; (b) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67,
101–114; (c) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998,
37, 2580–2627.
O
CH2Cl2 / rt /overnight
N
O
1m
2m
74% yield
dl / meso = 50 / 50
2. For
a recent review on reductive coupling of imine, see: Faugeroux, V.;
Genisson, Y. Curr. Org. Chem. 2008, 12, 751–773.
3. Hatano, B.; Nagahashi, K.; Habaue, S. Chem. Lett. 2007, 36, 1418–1419.
4. The use of chlorotrimethylsilane in the presence of zincs is effective for the
reductive coupling of aromatic aldehydes, see: Park, J.-H. S.; Boudjouk, P. J.
Org. Chem. 1988, 53, 5871–5875.
Scheme 2.
5. Only two references were reported for the reductive coupling of N,N-acetals
using low valent titanium, see: (a) Betschart, C.; Schmidt, B.; Seebach, D. Helv.
Chim. Acta 1988, 71, 1999–2021; (b) Betschart, C.; Seebach, D. Helv. Chim. Acta
1987, 70, 2215–2231.
R1
R1
R1
R1
N
TMSCl
N
R1
6. The general procedure for the reductive coupling of N,N-acetal 1: To
a
Ar
N
R1
suspension of zinc (130.8 mg, 2.0 mmol) in CH2Cl2 (5 mL) was added
1
Ar
(2.0 mmol) at room temperature. After cooling in an ice-water bath,
chlorotrimethylsilane (508 L, 4.0 mmol) was added in one portion. The
1
3
l
R1
R1
reaction mixture was stirred for 10 min in an ice bath, and then allowed to
warm to room temperature. After stirring overnight (ca. 14 h) at room
temperature, aqueous NaOH (1 N, 30 mL) was added. The mixture was
stirred for additional 30 min, during which zinc hydroxide precipitated. The
resulting suspension was filtered in suction, and the filtered solid was washed
with CH2Cl2 (3 Â 10 mL). The organic solution was separated and washed with
aqueous NaOH (1 N, 30 mL) and brine (30 mL). After drying over Na2SO4, and
Zn
N
diamine 2
Ar
4
Scheme 3.

B. Hatano et al. / Tetrahedron Letters 52 (2011) 3467–3469
3469
subsequent evaporation, the residue was purified using column
chromatography on silica gel (30 g; eluent, hexane/Et2O = 100:0, 50:50,
0:100, then, Et2O/Et3N = 99:1, 97:3, 95:5, 100 mL Â each). The results are
presented in Tables 1 and 2, Schemes 2 and 4. The physical data of diamine 2
are available as Supplementary data.
11. For a recent review for the reductive coupling of carbonyl compounds and
references cited therein, see: Chatterjee, A.; Joshi, N. N. Tetrahedron 2006, 62,
12137–12158.
12. The NMR study of iminium salt 3 was reported, see: Mayr, H.; Ofial, A. R.;
Würthwein, E.-U.; Aust, N. C. J. Am. Chem. Soc. 1997, 12727–12733.
7. When N,N-acetal 1 was treated with appropriate alkyl bromide in the presence
of zinc and chlorotrimethylsilane, the corresponding alkylation product was
obtained instead of diamine 2, see: Hatano, B.; Nagahashi, K.; Kijima, T. J. Org.
Chem. 2008, 73, 9188–9191.
13. When 1a (49.9 mg, 28 mmol) was treated with TMSCl (60
CDCl3 (0.7 mL) at 50 °C for 5 h under nitrogen, 1H NMR showed a week and
broad signal at 10.6 ppm, which was assigned to 3a, along with the
lL, 0.46 mmol) in
d
broadening signals of 1a.
8. References for activation of zinc by TMSCl, see: (a) Picotin, G.; Miginiac, P. J.
Org. Chem. 1987, 52, 4796–4798; (b) Gawronsky, J. K. Tetrahedron Lett. 1984, 25,
2605–2608.
14. In reductive coupling of N,O-acetals in the presence of titanium(IV) iodide and
zinc, diamines were obtained, see: Yoshimura, N.; Mukaiyama, T. Chem. Lett.
2001, 1334–1335.
9. (a) Duan, X.-F.; Zeng, J.; Lü, J. W.; Zhang, Z.-B. J. Org. Chem. 2006, 71, 9873–
9876; (b) McMurry, J. E. Chem. Rev. 1989, 89, 1513–1524; (c) Kahn, B. E.; Rieke,
R. D. Chem. Rev. 1988, 88, 733–745.
10. (a) Hirao, T.; Hatano, B.; Imamoto, Y.; Ogawa, A. J. Org. Chem. 1999, 64, 7665–
7667; (b) Hatano, B.; Ogawa, A.; Hirao, T. J. Org. Chem. 1998, 63, 9421–9424.