Imino-ene reaction of N-tosyl arylaldimines with α-methylstyrene: Application in the synthesis of important amines

Article abstract of DOI:10.1016/j.tetlet.2005.05.073

Copper(II) or tin(II) trifluoromethanesulfonate in combination with TMSCl effectively activates a C-H bond for the imino-ene reaction of N-tosylarylaldimines with α-methylstyrene. A wide variety of N-tosylarylaldimines were used to give homoallylamines in

Full text of DOI:10.1016/j.tetlet.2005.05.073

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5039–5041
Imino-ene reaction of N-tosyl arylaldimines with
a-methylstyrene: application in the synthesis of important amines
Manoj K. Pandey, Alakesh Bisai, Ankur Pandey and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016, India
Received 14 March 2005; revised 11 May 2005; accepted 18 May 2005
Available online 9 June 2005
Abstract—Copper(II) or tin(II) trifluoromethanesulfonate in combination with TMSCl effectively activates a C–H bond for the
imino-ene reaction of N-tosylarylaldimines with a-methylstyrene. A wide variety of N-tosylarylaldimines were used to give homo-
allylamines in good to excellent yields under mild conditions. The imino-ene adduct was converted into a b-amino ketone. The syn-
thesis of a 2,4-substituted pyrrolidine and a piperidine was also achieved from the imino-ene product via a Mitsunobu reaction and a
Grubbs cyclization, respectively.
Ó 2005 Elsevier Ltd. All rights reserved.
The development of new methods for the preparation of
homoallylamines is important for the synthesis of nitro-
gen-containing compounds. Moreover, these are also
useful building blocks for the synthesis of many natural
products. The obvious procedure for the synthesis of
homoallylic amines is via nucleophilic addition of allyl
metal reagents to imines.1 Alternatively, they can be ob-
tained from imino-ene reactions, which involve addition
of an olefin bearing an allylic hydrogen (ene) to an imine
(enophile).2 The reaction is easy only when the imines
are activated (a-imino esters)3 or the reaction is intramo-
lecular.2,4 Even for these cases, the presence of Lewis
Table 1. Imino-ene reaction of N-tosylbenzaldimine and a-methylstyrene at rta
Ts
NH Ph
M(OTf)2, TMSCl, solvent, rt
Ts
+
Ph
N
1a
Ph
Ph
2a
Entry
M(OTf)2
Solvent
Time
Isolated yield (%)
85
80
63
1
Cu(OTf)2 (10mol%)
Cu(OTf)2 (5 mol %)
Cu(OTf)2 (5 mol %)
Cu(OTf)2 (5 mol %)
Cu(OTf)2 (5 mol %)
Cu(OTf)2 (5 mol %)
Cu(OTf)2 (5 mol %)
Cu(OTf)2 (5 mol %)
Sn(OTf)2 (5 mol %)
THF
THF
CHCl3
10h
10h
2
3
15 h
12 h
2 h
4
CH2Cl2
MeNO2
Benzene
Toluene
THF/CH2Cl2
Toluene
THF/CH2Cl2
Toluene
Toluene
73
80
83
5
6
2.5 h
30min
1.5 h
7
89
b
b
8
91
85
75
9
10Sn(OTf)
45 min
4 h
10h
(5 mol %)
Zn(OTf)2 (5 mol %)
Zn(OTf)2 (10mol%)
2
11
12
44
62
10h
a The amount of TMSCl used was the same as the amount of the Lewis acid.
b The ratio was 1:4.
Keywords: Imino-ene reaction; Lewis acids; Homoallylic amines.
*
Corresponding author. Tel.: +91 512 2597291; fax: +91 512 2597436; e-mail: vinodks@iitk.ac.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.073

5040
M. K. Pandey et al. / Tetrahedron Letters 46 (2005) 5039–5041
Table 2. Imino-ene reaction of a variety of N-tosylarylaldimines and a-methylstyrene at rta
Ts
NH Ph
Ts
N
M(OTf)2, TMSCl, toluene, rt
+
Ph
2b - 2j
X
1b - 1j
X
Entry
Arylaldimine
Homoallylic amine
% Isolated yield (time)
Sn(OTf)2
Cu(OTf)2
1
2
3
4
5
6
7
8
9
1b (X = p-F)
1c (X = p-Cl)
2b
2c
2d
2e
2f
80(20min)
70(35 min)
57 (30min)
91 (15 min)
58 (30min)
73 (15 min)
78 (30min)
68 (35 min)
60(60min)
62 (30min)
65 (75 min)
76 (90min)
88 (90min)
56 (40min)
60(45 min)
57 (90min)
63 (60min)
65 (90min)
1d (X = p-iPr)
1e (X = m-Cl, p-F)
1f (X = m-Br)
1g (X = m-Cl)
1h (X = m-OMe)
1i (X = o,p-di-F)
1j (X = o-Cl)
2g
2h
2i
2j
a 5 mol % of TMSCl was used in combination with 5 mol % of the Lewis acid.
acids such as BF3ÆOEt2, SnCl4, AlCl3 and TiCl4 are re-
quired. Whereas these traditional Lewis acids failed to
activate other imines for intermolecular imino-ene reac-
tions, lanthanoid metals have proved to be very effec-
tive.5 In this letter, we report that the imino-ene
reaction of N-tosylarylaldimines and a-methylstyrene
can be catalyzed using Cu(OTf)2 or Sn(OTf)2 in combi-
nation with TMSCl in an efficient way. We have further
shown the importance of the reaction by the synthesis of
several important amines.
homoallylic amine 2a was isolated in high yield. This
was not surprising as the TMSCl might be preventing
coordination of the amine formed to the Lewis acid, thus
providing high yields of products. The reaction is hardly
affected when the amount of Cu(OTf)2 was reduced to
5 mol % (Table 1; entry 2). Based on a solvent study, tol-
uene was selected for further study (Table 1). In order to
see whether TMSCl is essential with Sn(OTf)2, the imino-
ene reaction was carried out in its absence and the adduct
2a was isolated in 55% yield (reaction time 15 h). This
indicated a different behaviour for these two Lewis acids.
The addition of TMSCl to the Sn(OTf)2-catalyzed reac-
tion improved the yield and reduced the reaction time
(Table 1, entry 9). Zn(OTf)2 was also assessed, but it
proved to be inferior (Table 1, entries 11 and 12). Under
the optimized conditions (Table 1, entry 7), other silyl
A systematic study was carried out for the reaction of N-
tosylbenzaldimine 1a and a-methylstyrene under various
conditions. It was observed that there was no reaction in
the presence of 10mol % of Cu(OTf) 2 (reaction time
15 h). However, on addition of TMSCl, the expected
Ph
1. Mg, MeOH, reflux, 8 h
Ph
Ph3P, DIAD,
Ts
OH
Ph
2. CbzCl, NaHCO3, toluene
NH
THF, 0 °C-rt
Ph
N
Ph
N
Ts
91%
Ph
30%
Cbz
4
6
5
1. BH3.DMS, THF, rt, 12 h
2. 30% H2O2, aq NaOH, 0 °C, 2 h
94%
1. OsO4 (2 mol%), NMO,
n-BuOH-acetone-water , rt, 2 h
Ts
Ts
NH Ph
2. NaIO4, THF-water, rt, 30 min
NH
O
Ph
Ph
Ph
2a
86%
3
Br
,
75%
Ph
NaH, THF, 60 °C, 12 h
Ph
Ph
1. Mg, MeOH, reflux, 4 h
2. CbzCl, NaHCO3, toluene
Grubbs' (1st gen.), CH2Cl2,
reflux, 12 h
NTs Ph
90%
Ph
84%
N
Cbz
Ph
7
N
Ts
9
8
Scheme 1. Conversion of an imino-ene adduct into various synthetic intermediates.

M. K. Pandey et al. / Tetrahedron Letters 46 (2005) 5039–5041
5041
reagents such as TIPSOTf (2 h, 60% yield), TBDMSCl
Acknowledgements
(12 h, 10% yield), TBDPSCl (12 h, 28% yield) and 1,2-
bis (chlorodimethylsilyl)ethane (10h, 71%) were tested,
so, it was concluded that TMSCl is optimal.
V.K.S. thanks the Department of Science and Technol-
ogy, India, for a research grant. A.B. thanks CSIR, New
Delhi, for a senior research fellowship.
In order to explore the generality of the reaction, it was
extended to a variety of aldimines 1 using a general
procedure: a solution of a N-tosylimine 1 (0.5 mmol)
and metal triflate (5 mol %) in toluene (2 mL) was
treated with 1.5 equiv of a-methylstyrene solution in
toluene (1 mL) followed by TMSCl (5 mol % from a
stock solution) at rt. The reaction mixture was stirred
for an appropriate period of time. It was worked up
by partitioning the reaction mixture between EtOAc
and water. The organic layer was washed with brine
and dried. Solvent removal and purification over silica
gel (10% EtOAc in hexane) provided homoallylic amines
2 (Table 2). As shown in Table 2, copper and tin triflate
were both used but consistently, the latter required a lit-
tle longer time for completion of the reaction.
References and notes
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