as catalysts for the R-amido alkylation reactions of weak
trialkylsilyl nucleophiles by cyclic N-acyliminium ions.
Despite the high potential synthetic importance of this
process,9 it is remarkable that the catalytic variant has
received so little attention.8a,10,11 Thus, the development of
highly efficient, general, and practical catalytic systems for
the R-amido alkylation of silicon-based nucleophiles is
greatly desirable, notably for industrial applications. We
report herein that R3SiNTf2 reagents outperform the catalytic
activity of the scarce known catalysts.8a,10,11 The applicability
of this protocol has been demonstrated through the realization
of a broad range of reactions, using chiral cyclic N-acyl-
iminium ion precursors derived from L-malic acid or suc-
cinimide and conventional trialkylsilyl nucleophiles (Figure
1).12
Table 1. R-Amidoalkylations with 4,5-Diacetoxy Lactams
1a-c Derived from L-Malic Acid
run
R
NuSiR3 solvent
time
trans/cis
yield, %a
1
2
3
Bn
1a 2a CH2Cl2 15 min 3at/c >95/5
1a 2a CH3CN 30 min 3at/c >95/5
1a 2b CH2Cl2 15 min 3bt/c 90/10
90
80
81
90
84
55
87
e
86g
82i
78
85
50
Bn
Bn
4b Bn
1a 2c CH2Cl2 1 h
3ct/c >99/1c
5
6
Bn
Bn
1a 2d CH2Cl2 15 min 3dt/c 60/40
1a 2d CH3CN 15 min 3dt/c 60/40
1a 2e CH2Cl2 15 min 3et/c 34/66
1a 2e CH3CN 15 min
7d Bn
8
Bn
9f Bn
1a 2f CH2Cl2 15 min 3ft/c >99/1
10h allyl 1b 2g CH3CN 15 min 3gt/c 85/15
11j allyl 1b 2g CH3CN 1 h 30 3gt/c 85/15
12 PMB 1c 2a CH2Cl2 15 min 3ht/c >95/5
13 PMB 1c 2a CH3CN 15 min 3ht/c >95/5
a Yield of isolated 3, after chromatography, from reactions carried out
on a 0.4 mmol scale, except for the result in run 11. b 1.8 equiv of 2c was
used to guarantee complete conversion. c A 3:1 ratio of stereoisomers was
formed at the branched enolizable carbon of the cyclic ketone. d 2 equiv of
2e and 9 mol % of HNTf2 were used to guarantee a clean reaction. e The
hydroxy lactam 4 (not shown) was obtained quantitatively. f 9 mol % of
catalyst was used to guarantee complete conversion. g No reaction in
CH3CN. h 2 equiv of 2g were used to suppress the formation of hydroxy
lactam. i No reaction in CH2Cl2. j The reaction was carried out on a 2 g
scale.
Figure 1. Silicon-based nucleophiles examined throughout this
work.
12
The capacity of Me3SiNTf2 to efficiently catalyze the
nucleophilic substitution reactions of N-acyliminium ion
precursors was initially investigated through a model reaction
between the known diacetoxy lactam 1a8b,13 and the trimeth-
ylsilyl enol ether derived from pivalone 2a (Table 1, runs
1-2). Adding 5 mol % of a dichloromethane solution of
HNTf2 to a mixture of 1a and 2a at 0 °C led to a rapid
process to give within 15 min the desired products 3at and
3ac in good yield and high dr. This reaction could be carried
out in either dichloromethane or acetonitrile with equal
success (runs 1-2). By direct comparison, the reaction was
completed with turnover frequency more than 8 orders of
magnitude higher than the TIPSOTf-catalyzed reactions,8a
confirming that the Lewis acidity of TMSNTf2 outperforms
that of the trialkylsilyl triflates.1a,2a,b,12 Using the optimal
conditions (5 mol % HNTf2, c ) 0.25 M, 0 °C), the reactivity
of various trialkylsilyl nucleophiles 2b-g toward 4,5-diacet-
oxy lactams 1a-c bearing different protecting groups on
nitrogen was systematically examined in CH3CN and CH2Cl2
(runs 3-13). Me3SiNTf2 showed high applicability and in
all circumstances quite better catalytic activity than TIPSOTf.8a
In general, reactions carried out in CH2Cl2 gave higher yields,
and equal stereoselectivities, than those performed in CH3CN
(see runs 1 versus 2, 5 versus 6, 7 versus 8, 9 and 12 versus
13) although this trend could be occasionally reversed (runs
10 and 11). For this reason, it is recommended to test both
solvents whenever investigating a new reaction with this
catalytic system.
(9) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(10) For recent examples of truly catalytic (catalyst loading <10 mol
%) nucleophilic substitution reactions of N-acyliminium ion precursors using
TMSOTf see: (a) Barrett, A. G. M.; Quayle, P. J. Chem. Soc., Chem.
Commun. 1981, 1076. (b) Bernardi, A.; Micheli, F.; Potenza, D.; Scolastico,
C.; Villa, R. Tetrahedron Lett. 1990, 31, 4949. (c) Pilli, R. A.; Dias, L. C.
Synth. Commun. 1991, 21, 2213. (d) Ahman, J.; Somfai, P. Tetrahedron
1992, 48, 9537. (e) Arndt, H. D.; Polborn, K.; Koert, U. Tetrahedron Lett.
1997, 38, 3879. (f) D’ Oca, M. G. H.; Pilli, R. A.; Vencato, I. Tetrahedron
Lett. 2000, 41, 9709. (g) Sugiura, M.; Kobayashi, S. Org. Lett. 2001, 3,
477.
(11) Recently, Kobayashi and co-workers reported efficient nucleophilic
substitution reactions of methoxy and acetoxy N-carbonyl piperidine
derivatives by trialkylsilyl nucleophiles catalyzed by 10 mol % of various
metal triflates: (a) Okitsu, O.; Suzuki, R.; Kobayashi, S. Synlett 2000, 989.
(b) Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809.
(12) The stepwise formation of Me3SiNTf2 by protodesilylation between
HNTf2 and either 2b or 2d and its subsequent use (5 mol %) to catalyze
R-amido alkylations has been realized. The rate and the profile of the
reactions compare well with those of the HNTf2 variant (more details are
given in the Supporting Information). These results support the occurrence
of R3SiNTf2 as an active catalyst in the present work, but the possibility
that HNTf2 itself also contributes in the mechanism, notably in the first
turnover, cannot be ruled out. For similar examples where R3SiNTf2 have
been claimed to be formed in situ, see refs 1a, 2a, 4, 5, and 6.
(13) Louwrier, S.; Ostendorf, M.; Boom, A.; Hiemstra, H.; Speckamp,
W. N. Tetrahedron 1996, 52, 2603.
The fast transformation achieved even in the reaction of
the presumably moderate nucleophile 2g (runs 10-11) may
be the reflection of the higher Lewis acidity of TIPSNTf2
over Me3SiNTf2, as previously demonstrated by the Ghosez
group.2b This R3SiNTf212 class of catalysts also showed clear
advantages in terms of selectivity as no Friedel-Crafts
(F-C) adducts were generated in this particular case.8a
Importantly, the process was compatible with a semiprepara-
tive scale, thus opening opportunities for industrial applica-
tions. For example, reaction between 1b and 2g was
successfully achieved on a 2 g scale at 0 °C to provide the
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Org. Lett., Vol. 7, No. 23, 2005