Addition of silylated carbon nucleophiles to iminium and cyclic N-acyliminium ions promoted by InCl3

Article abstract of DOI:10.1016/S0040-4039(00)01828-1

InCl₃ was used as Lewis acid in the addition of silyl enolates and allyltrimethylsilane to aromatic aldimines and cyclic N-acyliminium ions derived from 5-acetoxylactams affording β-aminocarbonyl systems and allyl adducts, respectively, in reas

Full text of DOI:10.1016/S0040-4039(00)01828-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9939–9942
Addition of silylated carbon nucleophiles to iminium and
cyclic N-acyliminium ions promoted by InCl3
a,
a
a
Dennis Russowsky, * Rog e´ rio Zen Petersen, Marla Narciso Godoi and
b
Ronaldo Aloise Pilli
a
Instituto de Qu ´ı mica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 91501-970, Brazil
b
Instituto de Qu ´ı mica, Universidade Estadual de Campinas, Campinas, SP 13083-970, Brazil
Received 29 September 2000; revised 16 October 2000; accepted 19 October 2000
Abstract
InCl was used as Lewis acid in the addition of silyl enolates and allyltrimethylsilane to aromatic
3
aldimines and cyclic N-acyliminium ions derived from 5-acetoxylactams affording b-aminocarbonyl
systems and allyl adducts, respectively, in reasonable to good yields. The diastereofacial selectivity of
cyclic N-acyliminium ions was investigated. © 2000 Elsevier Science Ltd. All rights reserved.
1
–4
The Mannich reaction is a powerful tool in the construction of b-aminocarbonyl systems.
1
In the bimolecular version of the classical Mannich reaction, the use of preformed or in situ
5
6,7
generated iminium or N-acyliminium ions and carbon nucleophiles has greatly expanded the
versatility of this methodology allowing the use of milder reaction conditions and the introduc-
tion of elements of regio- and stereoselective control.
The intensive research on new types of Lewis acids as activating agents, e.g. zirconium and
palladium complexes and rare earth triflates, in aldol-type Mannich reaction has enlarged the
field of its applications.
8
9
10
Recently, the use of InCl as a Lewis acid in a multicomponent aldol-type Mannich reaction
3
1
1,12
in aqueous media
was reported. However, the aqueous media protocol lacks generality due
to the lower solubility and/or stability of the reactants and products.
Despite the use of InCl in a three-component Mannich reaction, to the best of our knowledge
3
there has been no report on the employment of InCl to promote the generation of iminium ions
3
from aldimines and/or cyclic N-acyliminium ions to carry out the bimolecular aldol-type
Mannich reaction.
This prompted us to disclose our preliminary results using InCl as an activating agent of
3
aromatic aldimines as well as to promote the generation of cyclic N-acyliminium ions and their
reactions with silylated carbon nucleophiles in organic media.
*
Corresponding author. E-mail: dennis@iq.ufrgs.br
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01828-1

9940
Firstly, we investigated the use of catalytic amounts (10 mol%) of InCl in the addition
3
reaction of silyl enolates 1a,b to aromatic aldimines 2a–e in dichloromethane (Scheme 1) at 0°C
for 1.5 h which afforded the corresponding secondary b-aminocarbonyl compounds 3a–h in
good yields (Table 1).
Scheme 1.
Table 1
Preparation of secondary b-aminocarbonyls 3a–h
a
Entry
Silyl enolates 1a,b
Aldimines 2a–e
Product (%)
1
2
1
3
R
R
Ar
R
1
2
3
4
5
6
7
8
Ph
Ph
Ph
MeO
MeO
MeO
MeO
MeO
H
H
H
Me
Me
Me
Me
Me
Ph
Ph
Ph
3a (70)
3b (82)
3c (75)
3d (85)
3e (85)
3f (80)
3g (70)
p-BrꢀC H4
Ph
Ph
p-BrꢀC H4
Ph
6
p-BrꢀC H4
Ph
Ph
p-BrꢀC H4
Ph
Ph
6
6
6
CH Ph
*CH(CH )Ph
2
b
3h (75)
3
a
The spectroscopic data of all compounds are in agreement with the proposed structures.
The diastereoisomeric ratio was determined by GC of the crude mixture.
b
The reaction of chiral aldimine 2e derived from (S)-phenylethylamine with 1b (entry 8)
produced b-aminoester 3h in good yield as a 3:1 diastereoisomeric mixture and the relative
stereochemistry of the major product was not determined.
Next, we observed that InCl is able to promote the reaction of cyclic N-acyliminium ions
3
precursors 4a–d with nucleophiles 1a,b and allyltrimethylsilane (6) (Scheme 2) under the same
reaction conditions leading to 5-substituted lactams 7a–i in reasonable to good yields (Table 2).
In these cases, the best results were obtained using 60 mol% of InCl3.
It should be noted that the formation of adducts 7 was not observed in the absence of InCl
3
11
and the utilization of the aqueous media protocol described by Loh afforded the correspond-
ing 5-hydroxylactam derivatives due to the preferential attack of water to the highly reactive
N-acyliminium ion species 5 (Scheme 2).
The diastereoisomeric ratio was determined by GC analysis of the crude mixtures and the
trans relative stereochemistry of the major product 7b (entry 2) was established after analysis of
7
the multiplicity and coupling constants of the H and H protons and this was extended to the
4
5
3
other related compounds: H (Fig. 1, A) displays a doublet ( J 6.9 Hz at l 5.12) due to the
4
unique coupling with the cis H b proton.
3

9941
Scheme 2.
Table 2
Preparation of 5-substituted lactams 7a–i
a
b
Entry
Nucleophile
5-Acetoxylactams 4a–d
Cis/trans (%)
Products
3
4
5
2
R
R
R
R
X
(%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
6
6
6
6
H
H
OAc
H
OAc
H
H
H
OAc
H
Et
–
9:91
25:75
4:94
2:98
–
25:75
66:34
50:50
H
H
H
Me
Me
H
H
H
COPh
COPh
COPh
7a (15)
7b (65)
7c (50)
7d (80)
7e (85)
7f (50)
7g (70)
7h (65)
7i (50)
OAc
OAc
OAc
OAc
H
OAc
OTBS
OAc
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
CO Me
2
CO Me
2
CHꢁCH2
CHꢁCH2
CHꢁCH2
CHꢁCH2
H
a
The diastereoisomeric ratio was determined by GC of the crude mixture.
The spectroscopic data of all compounds are in agreement with the proposed structures.
b
Figure 1.
3
On the other hand, the observation of the H proton as a triplet ( J 6.3 Hz at l 4.00) is due
5
to the vicinal coupling with the two exocyclic a-carbonyl protons.
13
The preference for trans addition is in accordance with previous results and is rationalized
by the intervention of transition states A and B where the preferential approach of the
nucleophile occurs at the opposite face of the acetoxy group in the cyclic N-acyliminium ion
(
Fig. 1, B and C).

9942
Accordingly, an increase in the steric bulkiness of the nucleophilic carbon significantly
improves the diastereoselection and preparatively useful results were observed for the reaction of
the N-acyliminium ion derived from tartaric acid with silylketene acetal 1b (entries 4 and 5) and
from that derived from malic acid with silylenol ether 1a (entry 2).
A representative procedure for the preparation of 7b follows: 60 mol% of previously dried
InCl was suspended in 1 mL of dried CH Cl in a flask adapted with an argon atmosphere and
3
2
2
a magnetic stirrer at 0°C. A solution of 4b (0.5 mmol) in CH Cl (0.5 mL) was added in one
2
2
portion. After 10 min, 1a (0.75 mmol) was added dropwise over a 3 min period, and the reaction
mixture was maintained at 0°C for 3 h. The reaction was terminated by the addition of a
saturated solution of NaHCO (1 mL). The mixture was diluted with CH Cl (5 mL), the
3
2
2
organic phase was separated, dried over MgSO and the solvent was removed under vacuum.
4
The crude mixture was purified by column chromatography on silica gel using hexane/ethyl
acetate (75:25 v/v) to afford 7b in 65% yield.
In conclusion, the use of InCl as a catalyst in the bimolecular Mannich reaction is a viable
3
methodology for synthesizing b-aminocarbonyl targets in moderate to good yields. The good
diastereofacial selectivity observed with derivatives of malic and tartaric acid (entries 2, 4 and 5,
Table 2) is promising and further studies are needed to disclose the structural features
controlling the stereochemical outcome of the intermolecular addition of carbon nucleophiles to
iminium and cyclic N-acyliminium ions. Studies on the simple diastereoselection using InCl as
3
an activator are currently under investigation.
Acknowledgements
This work was supported by grants from Conselho Nacional de Desenvolvimento Cient ´ı fico
e Tecnol o´ gico (CNPq-grant 523069/95-2) and Funda c¸ a˜ o de Amparo a` Pesquisa do Estado do
Rio Grande do Sul (FAPERGS-grant 96/50208-3). Professor Beatriz Tenius is acknowledged for
her generous support. The authors acknowledge CAPES (R.Z.P), FAPERGS (M.N.G.) and
CNPq (R.A.P.) for the fellowships.
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