Ene reaction using the iminium salt generated by the oxidation of aminoketene silyl aetal

Article abstract of DOI:10.1246/cl.2009.732

Ene reaction of various olefins proceeded with the iminium salt generated by the oxidation of aminoketene silyl acetal to give addition products in good yields. Copyright

Full text of DOI:10.1246/cl.2009.732

732
Chemistry Letters Vol.38, No.7 (2009)
Ene Reaction Using the Iminium Salt Generated by the Oxidation
of Aminoketene Silyl Aetal
Makoto Shimizu,ꢀ Hiroyuki Itou, Takuya Iwao, and Yuki Umeda
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu 514-8507
(Received May 15, 2009; CL-090484; E-mail: mshimizu@chem.mie-u.ac.jp)
Ene reaction of various olefins proceeded with the iminium
salt generated by the oxidation of aminoketene silyl acetal to
give addition products in good yields.
Table 1. Imino ene reaction of 2-phenylpropene with an imini-
um salt under various conditionsa
DDQ (1.0 equiv)
OEt
OTMS
NBn2
CO2Et
NEt3 (4.0 equiv)
5-20 min
LA (2.0 equiv)
Bn2N
+
Ph
Ph
Solvent, Temp.
3a (x equiv)
1
4a
18-20 h
Whereas carbonyl ene reactions offer useful methodologies
for C–C bond forming reactions in a stereocontrolled manner,
their imino versions have not been widely exploited.1 This is
in part due to the lack of powerful activation methods for the
imino moieties in ene reactions, since the imino ene reaction in-
volves larger energies for activation than their carbonyl counter-
parts.1a,2 We have been interested in activation methods for
imino moieties by transforming into iminium species. Intriguing
reactivity of the iminium salts generated by the oxidation of alu-
minum enolate derivatives has enabled the use of ꢀ-imino esters
as acceptors of two nucleophiles (eq 1).3 Generation of iminium
species by the oxidation of the intermediary enolates was ex-
tended to the use of aminoketene silyl acetal, readily isolable
enolate derivatives as starting materials, and this methodology
offers a simple approach to a variety of ꢀ-amino esters in a short
sequence (eq 2).4 When these iminium salts are used as eno-
philes, this methodology offers a rapid preparation of homoallyl-
ic amines. This paper describes a facile imino ene reaction using
the iminium salt 2 generated by the oxidation of aminoketene
silyl acetal 1 (eq 3).
Entry Olefin/equiv Solvent Lewis acid Temp/ꢁC 4a/%b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
2.0
1.5
1.2
1.0
4.0
4.0
4.0
4.0
MeCN
DMF
EtCN
MeCN BF3 Et2O
THF
CH2Cl2 BF3 Et2O
PhMe BF3 Et2O
EtCN BF3 Et2O
EtCN BF3 Et2O
EtCN BF3 Et2O
EtCN BF3 Et2O
EtCN BF3 Et2O
EtCN BF3 Et2O
EtCN BF3 Et2O
EtCN BF3 Et2O
EtCN BF3 Et2O
none
none
TiCl4
ꢂ45–rt
ꢂ60–rt
ꢂ78–rt
ꢂ45–rt
ꢂ78–rt
ꢂ78–rt
ꢂ78–rt
ꢂ78–rt
ꢂ78–rt
ꢂ78–rt
ꢂ78–rt
ꢂ78–rt
ꢂ78–rt
ꢂ78–rt
ꢂ78–rt
ꢂ78–rt
10
45
8
.
26
50
60
17
63
70
67
70
65
36
62
36
27
.
BF3 Et2O
.
.
.
.
.
.
.
c
.
d
.
e
f
.
.
aCarried out according to the typical procedure (Ref. 5).
bIsolated yield. Without NEt3 treatment. di-Pr2NEt was used
c
in place of NEt3. ei-Pr2NH was used in place of NEt3. fPyridine
was used in place of NEt3.
Et2AlCl , EtAlCl2
(PhCOO)2
+
Et
R
PMP
PMP
Et
R
PMP
N
N
N
Nu-
ð1Þ
ð2Þ
ð3Þ
CO2Et
-
R
CO2Et EtCN, -20 oC to rt
CO2Et
of the olefin (Entries 9 and 11). When the reaction was carried
out without NEt3 treatment, a much decreased amount of the ad-
duct was obtained (Entry 13). Diisopropylethylamine could be
used with almost equal efficiency as base, whereas diisopropyl-
amine and pyridine were not effective (Entries 14–16). Under
the optimum conditions a variety of olefins were subjected to
the imino ene reaction, and Table 2 summarizes the results.
As shown in Table 2, methylidenecyclopentane and its
cyclohexane and cyclooctane analogues gave the adduct in good
yields, in which methylidenecyclohexane needed 4 equivalents
of the olefin for completion of the addition (Entries 1–3).
Cyclopropyl derivatives also served as good enes to give the
adducts in moderate to good yields (Entries 4–6). We also at-
tempted to use tri- and tetra-substituted olefins such as 2-meth-
yl-2-butene and 2,3-dimethyl-2-butene as enes. However, no ad-
duct arising from the ene reaction was observed.
Nu
PhCO2
+
NBn2
NBn2
CO2Et
OEt
OTMS
DDQ
RMgX
Bn2N
ArO-
R
CO2Et
R2
+
NBn2
R2
R1
NBn2
CO2Et
OEt
OTMS
R1
DDQ
3
Bn2N
ArO-
CO2Et
4
1
2
The initial examination was carried out to find optimum imi-
no ene reaction conditions using 2-phenylpropene (3a) as nucle-
ophile, and Table 1 summarizes the results.
In the absence of an added Lewis acid the reaction gave the
adduct in low to moderate yields, whereas TiCl4 was not an ef-
fective promoter (Entries 1–3). When the reaction was carried
A possible reaction mechanism is depicted in Scheme 1.
First, oxidation of the amino ketene silyl acetal 1 with DDQ
gives the iminium salt 2, which in turn is attacked by olefin to
give the initial adduct 5. This adduct is further deprotonated
by the dibenzylamino moiety to give the second iminium salt
6. This species is finally neutralized with the added base to give
.
out in the presence of BF3 Et2O in THF, CH2Cl2, or EtCN, mod-
erate to good yields of the adducts were obtained (Entries 5, 6,
and 8). The best result was realized using 1.2 or 2.0 equivalents
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.7 (2009)
733
Table 2. Imino ene reaction of the iminium salt with various
olefinsa
This work was supported by Grants-in-Aid for Scientific Re-
search (B) and Priority Areas from MEXT and JSPS.
DDQ (1 equiv), Olefin (x equiv),
OEt
OTMS
.
NEt3 (4 equiv)
BF3 OEt2 (2 equiv)
References and Notes
1
Product
Bn2N
EtCN, -78 oC ~ rt, 18-19 h
a) For a review, see: R. M. Borzilleri, S. M. Weinreb, Synthe-
sis 1995, 347. b) M. Yamanaka, A. Nishida, M. Nakagawa,
Org. Lett. 2000, 2, 159. c) K. Mikami, T. Yajima, M.
Kaneko, Amino Acids 1998, 14, 311. d) A. R. Ofial, H. Mayr,
Angew. Chem., Int. Ed. Engl. 1997, 36, 143. e) A. R. Ofial, H.
Mayr, J. Org. Chem. 1996, 61, 5823. f) K. Sato, T. Koga, K.
Masuya, K. Tanino, I. Kuwajima, Synlett 1996, 751. g) T.
Cohen, A. Onopchenko, J. Org. Chem. 1983, 48, 4531.
B. E. Thomas, IV, K. N. Houk, J. Am. Chem. Soc. 1993, 115,
790.
a) For reviews, see: M. Shimizu, I. Hachiya, I. Mizota,
Chem. Commun. 2009, 874; M. Shimizu, Pure Appl. Chem.
2006, 78, 1867. b) M. Shimizu, Y. Niwa, T. Nagai, I.
Hachiya, Heterocycles 2007, 72, 127; Y. Niwa, M. Shimizu,
J. Am. Chem. Soc. 2003, 125, 3720; M. Shimizu, Y. Niwa,
Tetrahedron Lett. 2001, 42, 2829; Y. Niwa, K. Takayama,
M. Shimizu, Bull. Chem. Soc. Jpn. 2002, 75, 1819; Y. Niwa,
K. Takayama, M. Shimizu, Tetrahedron Lett. 2001, 42,
5473.
5-20 min
4
1
Entry
1
x/equiv
Product 4
Yield/%b
55
Olefin
NBn2
1.2
CO2Et
NBn2
CO2Et
2
3
4.0
1.2
62
82
2
3
NBn2
CO2Et
Bn
Bn
NBn2
CO2Et
4
3.0
94c
nC7H15
nC7H15
NBn2
CO2Et
5
6
3.0
3.0
43c
49
4
5
T. Iwao, M. Shimizu, Heterocycles 2009, 77, 767; M.
Shimizu, H. Itou, M. Miura, J. Am. Chem. Soc. 2005, 127,
3296.
A typical procedure for the preparation of ethyl 2-dibenzyl-
amino-4-phenylpent-4-enoate (4a) is as follows: Under an
argon atmosphere, A solution of 2-phenylpropene (3a)
NBn2
CO2Et
aCarried out according to the typical procedure (Ref. 5).
.
(21.2 mg, 0.18 mmol) in EtCN (2.0 mL) and of BF3 Et2O
bIsolated yield. Z:E = >99:1.
c
(34.3 mg, 0.300 mmol) in EtCN (1.0 mL) were added suc-
cessively to a mixture of dibenzylaminoketene ethyl tri-
methylsilyl acetal (1) (0.30 mL, 0.150 mmol, 0.5 M in
CH2Cl2) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) (35.1 mg, 0.15 mmol) in EtCN (0.5 ml) at ꢂ78 ꢁC.
The reaction mixture was allowed to warm to ambient tem-
perature with stirring for 19 h. Et3N (0.08 mL, 0.600 mmol)
was added to the mixture, and the whole was stirred for an
additional 20 min. The reaction was quenched with sat aq
NaHCO3, and the whole mixture was extracted with ethyl
acetate (10 mL ꢃ 3). The combined extracts were washed
with brine, dried over anhydrous Na2SO4, and concentrated
in vacuo. The crude product was purified by preparative TLC
on silica gel (eluent: EtOAc/toluene = 1/50, and then
CH2Cl2) to give ethyl 2-dibenzylamino-4-phenylpent-4-
enoate (4a) (70%, 41.9 mg) as a colorless oil. 1H NMR
(500 MHz, CDCl3): ꢁ 1.31 (t, J ¼ 7:0 Hz, 3H), 2.89 (dd,
J ¼ 7:2, 14.6 Hz, 1H), 3.09 (dd, J ¼ 7:8, 14.6 Hz, 1H),
3.50 (d, J ¼ 13:7 Hz, 2H), 3.53 (dd, J ¼ 7:2, 7.8 Hz, 1H),
3.94 (d, J ¼ 13:7 Hz, 2H), 4.16 (dq, J ¼ 7:0, 10.6 Hz, 1H),
4.26 (dq, J ¼ 7:0, 10.6 Hz, 1H), 5.05 (d, J ¼ 1:0 Hz, 1H),
5.32 (d, J ¼ 1:0 Hz, 1H), 7.12–7.29 (m, 15H); 13C NMR
(67.8 MHz, CDCl3): ꢁ 14.6, 35.9, 54.5, 59.5, 60.1, 115.2,
125.9, 126.8, 127.3, 128.1, 128.2, 128.7, 139.4, 140.0,
144.3, 172.3. IR (neat): 3852, 3125, 2359, 2341, 1727,
OEt
Bn2N
CO2Et
Cl
Bn2N
Cl
O
DDQ
O
OEt
OTMS
MXn
BF3.Et2O
Cl
Bn2N
Cl
O
O
NC
O
MXn
1
NC
CN
CN
ArO-
+
+
NBn2
NBn2
ArO-
CO2Et
CO2Et
R
2
3
Base
NBn2
CO2Et
H
NBn2
CO2Et
H
+
NBn2
CO2Et
+
R
R
ArO-
R
ArO-
4
5
6
Scheme 1.
the ene adduct 4. Since the added base promoted the reaction and
that the high stereoselectivity was observed presumably by an
intramolecular deprotonation, an involvement of a stepwise
mechanism was proposed.
In conclusion, we have found that a facile imino ene reaction
proceeds with the iminium salt generated by the oxidation of
amino ketene silyl acetal. Since a variety of ꢀ-amino esters were
produced in good yields, the present methodology offers a useful
addition to the existing imino ene reactions.
1557, 1494, 1454, 1172, 1027, 777, 744, 697, 668 cmꢂ1
;
HRMS (EI) m=z: Mþ calcd for C27H29NO2, 399.2198; found
399.2200.
Published on the web (Advance View) June 20, 2009; doi:10.1246/cl.2009.732