Eco-friendly N-acyliminium ion chemistry: solvent-free HNTf2 and TIPSOTf-catalyzed α-amidoalkylation of silicon-based π-nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2006.04.090

The α-amidoalkylation of silicon-based π-nucleophiles is efficiently catalyzed by HNTf₂ or TIPSOTf at very low levels of loading in neat conditions.

Full text of DOI:10.1016/j.tetlet.2006.04.090

Tetrahedron Letters 47 (2006) 4477–4480
Eco-friendly N-acyliminium ion chemistry: solvent-free
HNTf2 and TIPSOTf-catalyzed a-amidoalkylation
of silicon-based p-nucleophiles
´
Marie-Jose Tranchant, Charlotte Moine, Raja Ben Othman, Till Bousquet,
Mohamed Othman and Vincent Dalla*
URCOM, Faculte´ des Sciences et Techniques de l’Universite´ du Havre, BP 540, 25 rue Philippe Lebon, 76058 Le Havre Cedex, France
Received 13 March 2006; revised 5 April 2006; accepted 7 April 2006
Available online 11 May 2006
Abstract—The a-amidoalkylation of silicon-based p-nucleophiles is efficiently catalyzed by HNTf2 or TIPSOTf at very low levels of
loading in neat conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
C–C bond forming reactions between weak carbon
nucleophiles and N-acyliminium ions generated from
cyclic N,O-acetals represent an important field of
research in organic chemistry to provide useful a-func-
tionalized amino compounds.1 While these a-amido-
alkylation reactions have been routinely promoted by
highly reactive, but also often toxic Lewis acids such
as TiCl4, BF3–OEt2, SnCl4, etc., the development of safe
procedures for their production has recently become a
subject of intensive investigation.2–6
amidoalkylation process highly efficient,5,6 with the
more favorable cases now successful at the remarkable
level of 0.3 mol %.
The two generic N-acyliminium ion precursors 1a (Table
1) and 1b (Table 2) were initially used as representative
N,O-acetals. The feasibility studies were undertaken
using the highly reactive carbamate 1a9 and common sil-
icon-based p-nucleophiles (1.4 equiv). The results are
summarized in Table 1. The initial experiments using
HNTf2 as a catalyst immediately revealed that a sol-
vent-free approach was possible with this reagent.
According to previous literature10 and control experi-
ments,6 HNTf2 is assumed to be the pre-catalyst which
generates Me3SiNTf2 as an active species by
protodesilylation.
Our group has recently contributed to the development
of improved conditions for N-acyliminium ion chemis-
try by documenting the use of TIPSOTf5 and HNTf2
6
as practical and highly efficient substitutes for the con-
ventional, but quite instable, TMSOTf7 to catalyze the
amidoalkylation of silicon-based nucleophiles by five-
membered ring N-acyliminium ion precursors. Typi-
cally, these reactions were achieved in presence of cata-
lyst in the range of 2–10 mol % in dichloromethane or
acetonitrile as a solvent. In an international context
where ‘green chemistry’ is paramount,8 we report in this
note the success of such reactions under solvent-free
conditions as a key improvement. These new conditions
now provide a totally eco-friendly, yet powerful C–C-
bond forming process that work under very mild condi-
tions. Overall, this modification renders the catalytic
HNTf2 gave a prompt allylation reaction at a remark-
able level of 0.3 mol % (run 1, A).11 In terms of catalyst
loading, this example represents by far the most efficient
C–C bond forming process between a N,O-acetal and a
carbon nucleophile. We were surprised to observe that
the amount of catalyst should be slightly increased when
using the much more nucleophilic trimethylsilyl enol
ethers12 (runs 2–4 A). Interestingly, the catalyst loading
varies with the Lewis base properties of the accordant
carbonyl moiety. Indeed, 1 mol % of HNTf2 was neces-
sary to catalyze the amidoalkylation of the silyl enol
ether of acetophenone (run 2, A), while a level of
5 mol % was necessary for the amidoalkylation of the
silyl enol ether of cyclohexanone and that of the silyl
*
Corresponding author. Tel.: +33 02 32 74 44 01; fax: +33 02 32 74 43
91; e-mail: vincent.dalla@univ-lehavre.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.090

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M.-J. Tranchant et al. / Tetrahedron Letters 47 (2006) 4477–4480
Table 1. Reactions of N,O-acetal 1a and generic silicon-based p-nucleophiles catalyzed by HNTf2 and TIPSOTf under solvent-free conditions
1.4 equiv NuSiMe3
OMe
Nu
N
N
or
A
cat. HNTf2
BnO
O
BnO
O
cat. TIPSOTf B
1a
2a-g
Entry
1
NuSiMe3
SiMe3
A, time (yield %)a
Nu adduct
B, time (yield %)a
2a
0.3 mol %, 3 h 30 min (92)
Not attempted
OSiMe3
Ph
O
2
3
1 mol %,b 30 min (97)
5 mol %,d 1 h (100)
0.3 mol %, 4 h 30 minc (98)
1 mol %, 2 h 30 min (100)
2b
Ph
OSiMe3
2c
O
OSiMe3
OMe
O
2d
4
5
5 mol %,d 30 min (90)
1 mol %, 24 he
OMe
O
OSiiPr3
CO2Me
5 mol %, 1 h 30 minc (75)
5 mol %, 1 h 30 minc (47)
O
2e
OMe
5 mol %, 5 min (99)f
2 mol %, 24 h (70% conv)g
Not attempted
O
O
2f
6
OSiMe3
O
a Isolated yields.
b Less than 10% conversion was achieved when 0.3 mol % HNTf2 was used.
c Time not optimized.
d Less than 10% conversion was achieved when 1 mol % HNTf2 was used.
e Less than 10% conversion was achieved.
f Ratio threo/erythro = 8.5/1.
g Determined by 1H NMR spectroscopy.
ketene acetal derived from 2-methyl propionic acid
methyl ester to proceed efficiently (runs 3–4, A). These
results may be explained by assuming a product inhibi-
tion mode upon a ditopic binding of Me3SiNTf2 by the
keto and the urethane groups of the Mannich adducts
2b–c. This phenomenon is likely to partially alter the
catalytic turnover (Fig. 1).13 We anticipated by replacing
Me3SiNTf2 with the more hindered and less oxophilic
TIPSOTf13 the (limited) adverse effect should be over-
ridden and thus restore a fully efficient catalytic amido-
alkylation process. This was confirmed when the
Mannich reactions of the silyl enol ethers of aceto-
phenone and cyclohexanone were efficiently catalyzed
by only 0.3 mol % and 1 mol % of TIPSOTf, respectively
(runs 2–3, B).
oxy-5-acetoxy N-acyliminium cation precursor 1b
(Table 2).
In our precedent study, the reaction of 1b with the tri-
methylsilyl enol ether of acetophenone catalyzed by
HNTf2 either in dichloromethane or acetonitrile as sol-
vents performed poorly.15 Similarly, the amidoalkyl-
ation involving the trimethylsilyl enol ethers of
cyclohexanone and pivalone completed at a relatively
high level of catalyst loading, that is, 10 mol %.6 These
three reactions thus served as an excellent measure for
further confirmation regarding the benefits of this sol-
vent-free approach. The results obtained herein clearly
demonstrate the advantage of the present method (runs
2–4). Remarkably, the amidoalkylation of the trimethyl-
silyl enol ethers of acetophenone and pivalone pro-
ceeded efficiently at a level of 0.5 mol % of catalyst
loading. It should be noticed that the reaction presented
in run 2 (method A) succeeded on a one gram scale.
On the other hand, no improvement was observed for the
formation of the ester 2d, the two oxygen atoms wherein
may themselves coordinate the catalyst (run 4, B). Using
HNTf2 as catalyst, the more challenging TIPS enol ether
derived from methyl pyruvate was amidoalkylated in
good yield within short reaction time. In contrast, a less
selective reaction took place when TIPSOTf was
employed, with several unidentified side-products being
formed (run 5, A vs B). This solvent-free approach
proved to be also successful for the vinylogous N-acyl-
iminium ion trapping by 2-trimethysilyloxyfuran14 with
a catalytic activity very similar to that of the acyclic silyl
ketene acetal analog (run 6 A–B versus run 4 A–B).
However, it is worth mentioning that, in stark contrast
to the results obtained with 1a, the amidoalkylation of
allyltrimethylsilane (run 1) proceeded with moderate
efficiency. Obviously, the procedure carried out in sol-
vent is more adapted for this specific case.5,6 This is
one of the rare cases we have identified to date that
works less favorably than its variant in solution. The
N-acyliminium ions derived from 2-oxy pyrrolidines
N-carbamate are considered to be more reactive than
those originating from hydroxylactam derivatives.9
Hence, the need for less loading of HNTf2 in the amid-
oalkylation of the trimethylsilyl enol ether of aceto-
In order to expand the scope of our process, we then
shifted toward examining the 4-tert-butyldimethylsilyl-

M.-J. Tranchant et al. / Tetrahedron Letters 47 (2006) 4477–4480
4479
Table 2. Reactions of N,O-acetal 1b and generic silicon-based p-nucleophiles catalyzed by HNTf2 and TIPSOTf under solvent-free conditions
OTBDMS
OTBDMS
1.4-2 equiv NuSiMe3
or
O
OAc
N
O
Nu
N
cat. HNTf2
A
Ph
Ph
cat. TIPSOTf B
1b
3a-d
Entry
1
NuSiMe3
SiMe3
A, time (yield %)a
Nu adduct
B, time (yield %)a
3a
2 mol %, 3 h 30 min (48)
2 mol %, 3 h (43)
2 equiv
OSiMe3
O
2b
0.5 mol %, 4 hc (89)d
0.5 mol %, 4 h, quantitativee
3b
Ph
1.4 equiv
Ph
OSiMe3
O
3c
3
2 mol %, 2 hc (86)f
0.5 mol %, 3 h (90)g
Not attempted
2 equiv
OSiMe3
5 mol %, 4 hc (77)h
Not attempted
3d
4
O
2 equiv
a Isolated yields.
b The reaction catalyzed by HNTf2 was performed on a one gram scale.
c Time not optimized.
d Two separable diastereomers obtained (cis adduct, 19%, trans adduct, 70%).
e Estimated by 1H NMR spectroscopy (trans/cis ratio ꢀ 5/1).
f Two separable diastereomers obtained (cis adduct, 24%, trans adduct, 62%).
g Based on conversion, measured by 1H NMR spectroscopy, with a trans/cis ratio ꢀ 5/1.
h Two separable diastereomers obtained (cis adduct, 13%, trans adduct, 64%).
O
OTIPS
OAc
N
2 equiv
N
O
Si
O
0.3 mol% HNTf2
rt, 10 min
O
OBn
N
O
1c
4 82%
OSiMe3
OAc
O
OAc
O
2 equiv
O
N
Figure 1. Product inhibition mode by Me3SiNTf2 (the substituents on
silicon have been omitted for clarity).
O
OAc
Ph
N
1 mol% HNTf2
rt, 30 min
Ph
1d
Scheme 1.
5 90%, trans/cis = 95/5
phenone by 1b (Table 2, run 2) than in that involving 1a
(Table 1, run 2) seems astonishing and is actually in line
with the product inhibition event discussed above
(Fig. 1).
Finally, the challenging (due to the dienic nature of the
related N-acyliminium ion) N-propenyl-5-methoxy lac-
tam 1e was subjected to a set of reactions in the presence
of 5 mol % of HNTf2 or TIPSOTf under neat condi-
tions. Of the nucleophiles tested [H2C@C(Ph)(OSiMe3),
H2C@C(tBu)(OSiMe3), H2C@CH–CH2SiMe3], only the
former gave the expected adduct 6 after a sluggish reac-
tion (Scheme 2), bracketing the weak reactivity expected
for 1e and the threshold nucleophilicity required for an
addition.12 Thus, it seems that silyl enol ethers whose
nucleophilicity is at the same order of magnitude to that
of the trimethylsilyl enol ether of acetophenone have set
The practicality of our solvent-free amidoalkylation is
further exemplified with the Mannich reactions of the
crystalline acetoxy lactams 1c and 1d (Scheme 1). The
two attempted reactions produced the desired adducts
4 and 5 at very low catalyst loadings within short reac-
tion times and good yields. It is worth noting that the
Mannich reaction of 1c with a sterically demanding
TIPS enol ether required only 0.3 mol % of HNTf2.
These results emphasize the synthetic usefulness of this
solvent-free conversion.

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M.-J. Tranchant et al. / Tetrahedron Letters 47 (2006) 4477–4480
5. Ben Othman, R.; Fousse, A.; Bousquet, T.; Othman, M.;
OSiMe3
Ph
2 equiv
Dalla, V. Org. Lett. 2005, 7, 2825.
6. Ben Othman, R.; Bousquet, T.; Othman, M.; Dalla, V.
Org. Lett. 2005, 7, 5335.
O
OMe
N
O
Nu
N
5 mol % catalyst , rt
7. For recent examples of truly catalytic (catalyst loading
<10 mol %) nucleophilic substitution reactions of N-
acyliminium ion precursors using TMSOTf: (a) Barrett,
A. G. M.; Quayle, P. J. Chem. Soc., Chem. Commun. 1981,
1076; (b) Bernardi, A.; Micheli, F.; Potenza, D.; Scolas-
tico, 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. M.; Pilli, R. A.; Vencato,
I. Tetrahedron Lett. 2000, 41, 9709; (g) Sugiura, M.;
Kobayashi, S. Org. Lett. 2001, 3, 477.
8. (a) Anastas, P. T.; Warner, J. C. Green Chemistry, Theory
and Practice; Oxford University Press: Oxford, 1998; (b)
Green Chemistry, Frontiers in Benign Chemical Synthesis
and Processes; Anastas, P. T., Williamson, T. C., Eds.;
Oxford University Press: Oxford, 1998; (c) Clark, J.;
Macquarrie, D. Handbook of Green Chemistry and Tech-
nology; Blackwell Science, 2002; (d) Eissen, M.; Metzger,
J. O.; Schmidt, E.; Schneidewind, U. Angew. Chem. Int.
Ed. 2002, 41, 414.
6
1e
catalyst
time
7 h
yield %
76
HNTf2
TIPSOTf
7 h
76
Scheme 2.
a critical limit for reactivity toward the iminium cation
of 1e.12,16 In our previous work, we observed a signifi-
cant accelerating effect in the amidoalkylation reactions
involving weakly reactive N-acyliminium ion precursors
by changing TIPSOTf with the outstanding oxophilic
R3SiNTf2 species as catalysts.6 Obviously, this clear-
cut effect can be rationalized by assuming that the N-
acyliminium ion formation, which is generally accepted
as the rate-determining step in these reactions, is greatly
accelerated by R3SiNTf2 species. In the transformations
of 1e, we have clearly shown that the reaction rate is
insensitive to the nature of the catalyst, suggesting that
in the present case the rate-limiting step is the trapping
of the accordant stabilized iminium cation.
9. D’Oca, M. G. M.; Moraes, L. A. B.; Pilli, R. A.; Eberlin,
M. N. J. Org. Chem. 2001, 66, 3854, and references cited
therein.
10. See Ref. 6 and Refs. 1–6 cited therein.
11. Typical procedure: To a mixture of carbamate 1a (235 mg,
1 mmol) and allyltrimethylsilane (0.22 mL, 1.4 mmol) was
added under an argon atmosphere 0.3 mol % of HNTf2
(0.5 M solution in dichloromethane, 6 lL). After 3 h
30 min of vigorous stirring, the mixture was purified on
a short column of silica gel, eluting with cyclohexane/
EtOAc 7/3, to give the known allylated adduct 2a in 92%
yield.
12. Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003,
36, 66.
13. For a contribution describing the outstanding oxophilic
properties of R3SiNTf2, see: (a) Mathieu, B.; Ghosez, L.
Tetrahedron Lett. 1997, 38, 5497; (b) Mathieu, B.; Ghosez,
L. Tetrahedron 2002, 58, 8219.
In summary, a key improvement in the a-amidoalkyl-
ation of generic p-nucleophiles by cyclic N,O-acetals cat-
alyzed by HNTf2 and TIPSOTf has been realized upon
achieving these reactions under solvent-free condi-
tions.17 This refinement has led to a simple and totally
eco-friendly procedure, now enabling the use of very
low levels of catalyst loading, in the range of 0.3–
5 mol %. We believe that this method improves consid-
erably the usability of amidoalkylation, and trust it will
find use in the scientific community. We are currently
applying this solvent-free approach to the synthesis of
complex aza-bicyclo compounds and our first results
in this area will be published shortly.
14. For an ealier report describing the vinyloguous amido-
alkylation of TMSF catalyzed by 10 mol % of TMSOTf in
dichloromethane, see Ref. 7f.
References and notes
15. Unpublished results from our group.
16. In the reaction of the trimethylsilyl enol ether of pivalone
H2C@C(tBu)(OSiMe3) using either HNTf2 or TIPSOTf,
a white precipitate rapidly appeared and no reaction
occurred. However, the corresponding Mannich product
1. Reviews: (a) Speckamp, W. N.; Molenaar, M. J. Tetra-
hedron 2000, 56, 3817; (b) Maryanoff, B. E.; Zhang, H.-C.;
Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev.
2004, 104, 1431.
could be obtained in
a correct yield of 64% by
performing the reaction in dichloromethane under forced
conditions, that is, by using 20 mol % of TIPSOTf and
4 equiv of the silyl enol ether within a long reaction
period of 20 h. The nucleophilicity of this enol ether is
not reported in the Mayr’s scale, but can be compared to
that of the trimethylsilyl enol ether of acetone, which is
slightly inferior to that of the trimethylsilyl enol ether of
acetophenone. Allyltrimethylsilane, however, consider-
ably lacks nucleophilicity for addition to the iminium
cation.
2. Recently, Kobayashi and co-workers reported efficient
nucleophilic substitution reactions of 2-methoxy and 2-
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.
3. Recently, Pilli and co-workers reported some Mannich
reactions catalyzed by HCl and carried out in water in the
presence of SDS as a surfactant. Unfortunately, the
reaction was restricted to b-substituted enol ethers: Pilli,
R. A.; Camilo, N. S. Tetrahedron Lett. 2004, 45, 2821.
4. Recently, Pilli and co-workers implemented allylation and
Mannich reactions performed in the organoindate(III)
ionic liquid BMI–InCl4: Pilli, R. A.; Robello, L. G.;
Camilo, N. S.; Dupont, J.; Lapis, A. A. M.; da Silveiro
Neto, B. A. Tetrahedron Lett. 2006, 47, 1669.
17. As this work was in progress, Matsumara and co-workers
reported that the Mannich reaction between N,O-acetals
and methylene actives catalyzed by 10 mol % of various
Brønsted- and Lewis acids under solvent-free conditions
proceeded with more efficiency than those carried out in
dichloromethane Matsumara, Y.; Ikeda, T.; Onomura, O.
Heterocycles 2006, 67, 113.