Rhodium-catalyzed approach to Mannich-type products using aldimine, α,β-unsaturated ester, and hydrosilane

Article abstract of DOI:10.1039/b202773a

A rhodium-catalyzed method for the synthesis of β-amino esters was accomplished in a one-pot procedure from aldimine, α,β-unsaturated ester and hydrosilane.

Full text of DOI:10.1039/b202773a

Rhodium-catalyzed approach to Mannich-type products using aldimine,
a,b-unsaturated ester, and hydrosilane†
Takako Muraoka, Shin-ichi Kamiya, Isamu Matsuda* and Kenji Itoh
Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University,
Chikusa, Nagoya 464-8603, Japan. E-mail: matsudai@apchem.nagoya-u.ac.jp; Fax: 81-52-789-3205;
Tel: 81-52-789-5113
Received (in Cambridge, UK) 20th March 2002, Accepted 1st May 2002
First published as an Advance Article on the web 16th May 2002
A rhodium-catalyzed method for the synthesis of b-amino
esters was accomplished in a one-pot procedure from
aldimine, a,b-unsaturated ester and hydrosilane.
even in the presence of 1 mol% of 4a when the reaction was
conducted for 24 h at 25 °C (entry 2 in Table 1). In addition to
6a (31%), TsNH2 was obtained in 40% yield after chromato-
graphic purification of the crude mixture. Since an aldimine 1a
is immediately hydrolyzed in aqueous EtOH to afford TsNH2
and benzaldehyde, the concomitant formation of TsNH2 reflects
the relative quantity of aldimine 1a remaining intact under the
given reaction conditions. A neutral and zero-valent rhodium
complex, Rh4(CO)12 (4b), also showed a similar catalytic
efficiency for this Mannich-type reaction, though more vigor-
ous conditions were required for the complete conversion of 1a
(entry 3 in Table 1). The yield of 6a increased dramatically in
the reaction catalyzed by [Rh(cod){P(OPh)3}2]OTf (4c) under
conditions similar to the reaction using 4a (entry 5 in Table 1).
The solvent used for this reaction significantly affected both the
rate and the product yield (entries 5, 7, and 8 in Table 1). These
results suggest that CH2Cl2 is the solvent of choice in the
reactions using 4c as the catalyst precursor. In contrast, this
coupling reaction gave a sluggish result when a mixture of
[Rh(dppe)Cl]2 and AgOTf (4d, dppe = 1,2-bis(diphenylphos-
phino)ethane) was used as a catalyst precursor instead of 4c
(entry 9 in Table 1). Thus, it is deduced that the best result for
this Mannich-type transformation is obtained by the combina-
tion of 4c as the catalyst precursor and CH2Cl2 as the solvent.
On the basis of the preliminary information, several types of
aldimines (1) were subjected to the present three-component
Mannich-type reactions of an aldimine with an enolate
component are some of the most important and versatile tools to
construct b-amino carbonyl compounds. These reactions pro-
vide useful routes for the synthesis of b-amino esters which are
useful as the immediate precursors of b-lactams and b-amino
acids.1 Recent patterns of these reactions are categorized as the
combination of aldimines and enoxysilanes with the assistance
of some types of Lewis acid,2,3 though some exceptions have
been reported.4 The advantages for the use of enoxysilanes as a
nucleophile are widely accepted, however, some troublesome
procedures are required for their isolation in sufficient pu-
rity.5
On the other hand, the transition-metal-catalyzed carbon–
carbon bond forming reaction is regarded as one of the most
convenient and facile tools for constructing a designed molecule
in the past decades.6 In particular, it is fascinating that several
bonds are formed in an orderly manner in a one-pot reaction of
more than three starting substrates under almost neutral
conditions.7 We have found that some types of rhodium
complex enable multi-component couplings including a hydro-
silane as a starting component.8 In these reactions, some have
indicated that rhodium enolate plays an important role as a key
intermediate in these multi-component couplings. The forma-
tion of a rhodium enolate is elucidated by the insertion of an
a,b-unsaturated carbonyl compound into the Rh–H bond
generated by the oxidative addition of a hydrosilane to a low
valent rhodium metal. The resultant enolate possesses sufficient
nucleophilicity to attack an appropriate electrophile.8a,b,o Along
this line, we attempted to design a facile route to b-amino esters
(Scheme 1). We report herein a rhodium-catalyzed method to
give a Mannich-type product from the reaction of an aldimine
with an a,b-unsaturated ester and a hydrosilane.
coupling in the presence of 1 mol% of the rhodium( ) catalyst.
I
Selected results are summarized in Table 2. The reactivity of 1
for this reaction was significantly affected by the structure and
electronic properties of both R1 and R2. The 4-methylbenzene-
sulfonyl group on the imino-nitrogen showed a remarkable
influence on increasing the yield of 6 in comparison with the
Table 1 Rhodium-catalyzed Mannich-type reaction of aldimine 1a with 2
and 3a
First of all, a CH2Cl2 solution containing aldimine 1a, methyl
acrylate (2), diethylmethylsilane (3), and
1 mol% of
[Rh(cod)(PPh3)2]OTf (4a, cod = cycloocta-1,5-diene) was
heated for 5 h at 45 °C to afford the N-diethylmethylsilyl-b-
amino ester, 5a, corresponding to 6a. Protodesilylation of 5a in
acidic aqueous EtOH afforded the b-amino ester 6a in 81%
yield as a mixture of two diastereomers (syn+anti = 46+54,
entry 1 in Table 1). The structure of 6a was assigned on the basis
of its 1H and 13C NMR, IR, and combustion analysis. This three-
component coupling of 1a, 2, and 3 proceeded incompletely
Catalyst
Conditions
°C/h
Yield of 6acd TsNH2
(syn+anti)
Entry
precursorb Solvent
(%)e
1
2
3
4
5
6
7
8
9
4a
4a
4b
4b
4c
4c
4c
4c
4d
CH2Cl2
CH2Cl2
C6H6
45/5
81 (46+54)
31 (48+52)
82 (65+35)
40 (53+47)
96 (32+68)
69 (44+56)
78 (39+61)
92 (47+53)
28 (60+40)
—
40
—
49
—
—
—
—
27
25/24
85/88
25/24
45/6
25/21
70/28
85/69
25/24
C6H6
CH2Cl2
CH2Cl2
THF
C6H6
CH2Cl2
a A mixture of 1a (1 mmol), 2a (2 mmol) and 3 (2 mmol) in 2 ml of solvent
was added to a solution (4 ml) of 4 (1 mol% for 1a) and the resulting mixture
was then stirred under the conditions shown above. b 4a: Rh(cod)(P-
Ph3)2]OTf, 4b: Rh4(CO)12
,
4c: [Rh(cod){P(OPh)3}2]OTf, 4d:
Scheme 1
[Rh(dppe)Cl]2 + 2 AgOTf. c The ratio of the two diastereoisomers was
determined by 1H NMR analysis. d Isolated yield. e The yield of recovered
TsNH2 after chromatographic purification.
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b2/b202773a/
1284
CHEM. COMMUN., 2002, 1284–1285
This journal is © The Royal Society of Chemistry 2002

other aldimines derived from benzaldehyde (Table 1 and entries
1–5 in Table 2). b-Amino esters (6b–e) were obtained in modest
yields from the corresponding aldimine (entries 2–5 in Table 2).
N-Benzyl-N-2-methoxyphenylamine (7e, 15% based on the
starting 1e) was isolated in addition to the expected product 6e
(60%) when 1e was reacted with 2 and 3 even in the presence of
the less active catalyst, 4a (entry 5 in Table 2). The formation of
7e suggests that there is another path catalyzed by 4, i.e.,
hydrosilylation, to consume 1e in a one-pot reaction of 1e, 2 and
3. Furthermore, a similar three-component coupling was tested
using several aldimines derived from the condensation between
TsNH2 and other aldehydes (entries 6–10 in Table 2). The
presence of a methoxy group at the ortho-position on the phenyl
ring of R1 affects the reaction rate to form 6. The reaction of N-
new route to design certain types of b-amino carbonyl
compounds under almost neutral conditions.
In summary, a useful method for the synthesis of b-amino
esters has been developed. This methodology provides a
convenient route for Mannich-type transformation of the
aldimines with an a,b-unsaturated ester and a hydrosilane in the
catalysis of a cationic rhodium( ) complex. In this reaction, the
I
rhodium enolate plays an important role in the nucleophilic
attack on the sp2 carbon of the aldimine. Since only a few
examples have been reported for Mannich-type transformation
catalyzed by a transition metal complex,9 this article describes
good examples for the application of transition metals as
catalysts of Mannich-type reactions.
(2-methoxybenzylidene)-4-methylbenzenesulfonamide
(1h)
Notes and references
completed within 4 h afforded the corresponding b-amino ester
(6h) in 93% yield (entry 8 in Table 2). A similar effect was
expected when an aldimine possessing an ortho-hydroxy group
on the phenyl ring of R1 is employed in place of 1h, though a
longer reaction time was required for the complete consumption
of 1i (entry 9 in Table 2). It is noteworthy that nucleophilic
attack on 1j selectively proceeds in a 1,2-fashion to give 6j in
56% yield (entry 10 in Table 2). In contrast to these
observations, the corresponding 6 was not obtained at all in the
reaction of an aldimine bearing an aliphatic substituent on the
imino-nitrogen. For example, N-cyclohexyl aldimine 1k could
not be converted into the b-amino esters under similar reaction
conditions, but 1k remained intact (entry 11 in Table 2).
In all the examples presented here, the reaction path was
generally controlled to afford a b-amino ester, whereas the
diastereoselectivity of the products is moderate and both
diastereomers are inseparable through column chromatography
at this stage (Table 1 and 2). Although numerous examples of
the Mannich-type reaction for aldimines with enoxysilanes are
reported, the general procedure for controlling the diaster-
eochemistry has not been established.3 Therefore, the present
three-component coupling retains a sufficient usefulness in
synthetic organic chemistry despite this defect. It discloses a
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Table 2 Rhodium-catalyzed Mannich-type reaction of aldimine 1 with 2
and 3a
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1
Product
Entry
R1
R2
Time/h (%)b
syn+antic
32+68
1
2
3
4
5
6
7
8
9
1a Ph
1b Ph
1c Ph
1d Ph
p-Ts
p-ClC6H4
Ph
p-MeOC6H4 15
o-MeOC6H4
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
6
20
27
6a (96)
6b (87) 51+49
6c (82) 54+46
6d (71) 51+49
1e Ph
4
5
30
4
8
48
6e (60)de 42+58
1f p-ClC6H4
1g p-MeOC6H4
1h o-MeOC6H4
1i o-HOC6H4
1j (E)-PhCHNCH
1k Ph
6f (76)
29+71
6g (95)e 41+59
6h (93) 50+50
6i (75)
6j (56)f 37+63
6k (0)
38+62
10
11
Cyclohexyl 24
—
a A mixture of 1 (1 mmol), 2 (2 mmol) and 3 (2 mmol) in 2 ml of solvent
was added to a 4 ml solution of 4c (1 mol% for 1) and the resulting mixture
was then refluxed for the period shown above. b Isolated yield. c The ratio
of the two diastereoisomers was determined by 1H NMR analysis. d Another
product, N-benzyl-N-2-methoxyphenylamine (7e), was concomitantly ob-
tained in 15% yield with 6e. e 4a was used for catalyst precursor instead of
4c. f TsNH2 was recovered in 32% yield.
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120, 2474; T. Soga, H. Takenoshita, M. Yamada and T. Mukaiyama,
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