N-trialkylsilyl Bistrifluoromethanesulfonimides (R3SiNTf 2) are powerful catalysts for the highly efficient α-amido alkylation reactions of silicon-based nucleophiles

Article abstract of DOI:10.1021/ol052357j

(Chemical Equation Presented) In situ formed N-trialkylsilyl bistrifluoromethanesulfonimides (R₃SiNTf₂) species have been shown to efficiently catalyze the nucleophilic substitution reactions of chiral 5-oxypyrrolidin-2-ones by silic

Full text of DOI:10.1021/ol052357j

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5335-5337
N-Trialkylsilyl
Bistrifluoromethanesulfonimides
(R3SiNTf2) Are Powerful Catalysts for the
Highly Efficient
Reactions of Silicon-Based Nucleophiles
r-Amido Alkylation
Raja Ben Othman, Till Bousquet, Mohamed Othman, and Vincent Dalla*
Unite´ de Recherche en Chimie Organique et Macromole´culaire, Faculte´ des Sciences
et Techniques de l’UniVersite´ du HaVre, 25 rue Philippe Lebon, BP 540,
76058 Le HaVre Cedex, France
Vincent.dalla@uniV-lehaVre.fr
Received September 29, 2005
ABSTRACT
In situ formed N-trialkylsilyl bistrifluoromethanesulfonimides (R3SiNTf2) species have been shown to efficiently catalyze the nucleophilic
substitution reactions of chiral 5-oxypyrrolidin-2-ones by silicon-based nucleophiles. The reaction rates were significantly accelerated in
comparison to the cases where the usual triflate catalysts are used. Adducts were obtained in high yields and usual stereoselectivities within
short reaction times, and the process was compatible with a semipreparative scale.
Recently, the Ghosez and Mikami groups have independently
documented the effectiveness of trimethylsilyl bistrifluo-
romethanesulfonimide (Me3SiNTf2) and their trialkylsilyl
analogues R3SiNTf2 as strong oxophilic Lewis acid cata-
lysts.1,2 Such reagents, which either can be synthesized before
use or prepared in situ by protodesilylation of the precatalyst
HNTf2 with a silicon-based olefin, have been recognized to
possess substantial better Lewis acidity than their triflate
analogues. Subsequently, these reagents appeared to be
practical and highly efficient catalysts for various C-C bond
forming reactions including 4 + 2 cycloadditions,1a,2a,b
Mukaiyama aldol1b,2c,3 and Mukaiyama Michael reactions,4
1,2-additions of allylsilanes and alcynylsilanes to aldehydes
and acetals,4 1,4 additions of allylsilanes to enones,4,5 C-gly-
cosidation,4 as well as aromatic electrophilic substitutions1b
and 2 + 2 cycloadditions between TBS silyl enol ethers and
methyl acrylate.6
During our continuous research effort in the chemistry of
triflates7 and N-acyliminium ions,8 we have been interested
in exploring the competence of the HNTf2/R3SiNTf2 systems
(3) Ishihara, K.; Hiraiwa, Y.; Yamamoto, H. Synlett 2001, 1851.
(4) Cossy, J.; Lutz, F.; Alauze, V.; Meyer, C. Synlett 2002, 45.
(5) Kuhnert, N.; Peverley, J.; Robertson, J. Tetrahedron Lett. 1998, 39,
3215.
(6) Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2005, 127,
3668.
(1) (a) Mathieu, B.; Ghosez, L. Tetrahedron Lett. 1997, 38, 5497. (b)
Ishii, A.; Kotera, O.; Saeki, T.; Mikami, K. Synlett 1997, 1145.
(2) (a) Matthieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219. (b) Mathieu,
B.; de Fays, L.; Ghosez, L. Tetrahedron Lett. 2000, 41, 9561. (c) Kotera,
O.; Motoyama, Y.; Tanaka, Y.; Mikami, K. Inorg. Chem. Commun. 1998,
1, 10.
(7) (a) Gasparik, V.; Dalla, V.; Decroix, B. Synlett 2002, 528. (b) Dalla,
V.; Decroix, B. Tetrahedron Lett. 2002, 43, 1657. (c) Tranchant, M.-J.;
Dalla, V.; Jabin, I.; Decroix, B. Tetrahedron 2002, 58, 8425.
(8) (a) Ben Othman, R.; Fousse, A.; Bousquet, T.; Othman, M.; Dalla,
V. Org. Lett. 2005, 7, 2825. (b) Szemes, F.; Fousse, A.; Ben Othman, R.;
Bousquet, T.; Othman, M.; Dalla, V. Synthesis. In press.
10.1021/ol052357j CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/20/2005

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
5336
Org. Lett., Vol. 7, No. 23, 2005

inseparable diastereoadducts 3gt and 3gc in 78% yield (dr
) 6:1, run 11). This new R-amido alkylation of a conjugated
enolate such as 2g with chiral N-allyl azacycles under
catalytic conditions is interesting in its own right and further
raises the prospect that combining this process with a ring-
closing metathesis could provide a new entry into azabicyclo-
[5.3.0]decane scaffolds by entailing two important catalytic
reactions as key steps.14 Finally, this example also demon-
strates that the useful allyl protecting group is well tolerated,
as also is the PMB group (runs 12-13).15
reactive pyrrolidinones 7 and 9 bearing chiral auxiliaries at
nitrogen8a and the trimethylsilyl enol ether derived from
acetophenone (Scheme 1). While the reaction of 7 with 2b
Scheme 1
To extend the scope of our process, we next shifted toward
examining various 4-tert-butyldimethylsilyloxy-5-acetoxy
N-acyliminium cation precursors 5a,b (Table 2). This more
Table 2. R-Amidoalkylations with 4-tert-Butyldimethyl-
silyloxy-5-diacetoxy Lactams 5a,b Derived from L-Malic Acid
catalyzed by 5 mol % of TIPSOTf8a needed 15 h to reach
completion, the Me3SiNTf2-catalyzed variant12 was acceler-
ated by a 3-fold factor to give the expected adduct 8 (two
diastereoisomers, 1.5:1 ratio) within 5 h. Also, the bicyclic
lactam 9 gave approximately 40% conversion to 10 (two
diastereoisomers, 1:1 ratio) after 3 h under guidance of Sc-
(OTf)3,11 whereas the amido alkylation catalyzed by Me3-
time, yield,
a
substrate
R
NuSiR3 min
%
adduct trans/cis
5ab,c
5ab
5a
5af
5a
5bb
Bn
Bn
Bn
Bn
Bn
PMB
2a
2c
2d
2e
2f
10
30
15
15
15
15
84
90
82
91
55g
95
6at (70), 6ac (14)
6bt (76),d 6bc (14)e
6ct/c 40/60
6dt (33), 6dc (48)
6et/c >99/1
12
SiNTf2 went almost to completion under the same period
of time (see the Supporting Information for more details).
To summarize, we have demonstrated that the HNTf2-
R3SiNTf2 systems efficiently catalyze the R-amido alkylation
of conventional silicon-based nucleophiles by chiral cyclic
N-acyliminium ion precursors derived from L-malic acid and
succinimide. The method also encompasses the presumably
weak nucleophilic TIPS enol ether derived from butynone.
In terms of catalytic activity, this simple approach outper-
forms the systems previously known, and harnesses the
distinct advantage of trialkylsilyltriflimides to provide a truly
practical and environmentally benign class of catalyst for
the synthesis of optically enriched azacycles. The high
reaction rate displayed by this new amido alkylation proce-
dure is likely to be the result of the outstanding Lewis acidity
of R3SiNTf2 (and/or Brønsted acidity of HNTf2),1a,2a,b,12 which
contributes to accelerate the N-acyliminium ion formation,
i.e., the expected rate-limiting step in such reactions.
2a
6ft (75), 6fc (20)
a Yield of isolated 6, after chromatography, from reactions carried out
on a 0.4 mmol scale. b 10 mol % of catalyst was used and the reaction was
carried out in CH2Cl2. c A complex mixture was obtained in CH3CN. d A
2:1 ratio of stereoisomers was formed at the branched enolizable carbon of
the cyclic ketone. e A ratio of stereoisomers >95:5 was formed at the
branched enolizable carbon of the cyclic ketone. f 9 mol % of catalyst and
2.5 equiv of the nucleophile were required to guarantee high yield. g This
moderate yield was reproducibly obtained although the reaction proceeded
cleanly.
hindered class of substrates also displayed high latitude and
excellent reactivity toward nucleophiles, as demonstrated by
the good yields and short reaction times observed in almost
all of the reactions investigated. In contrast to the case of
the diacetoxy lactams 1a-c, CH3CN and CH2Cl2 proved
complementary solvents with the silyl ethers 5a,b. As
previously observed independently by Kobayashi11b and us,8a
no evidence supporting a general substrate enforced stereo-
control was found, and the stereochemical preference of the
reaction seems to be mainly governed by the steric demand
of the incoming nucleophile.
Acknowledgment. The “Region Haute-Normandie” and
“the Reseau PUNCH Orga” are gratefully acknowledged for
a doctoral grant (T.B.) and financial support. Mathilde Pierre
is acknowledged for practical participation to this work
Finally, the net advantage of the HNTf2/Me3SiNTf2 system
was clearly demonstrated in the reactions between the weakly
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Such applications have been fully realized in our lab and will be
published soon.
(15) The alkylations examined herein afforded comparable stereoselec-
tivities as those catalyzed by TIPSOTf or promoted by conventional Lewis
acids; see ref 8a.
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