N-acyliminium ion chemistry: Highly efficient and versatile carbon-carbon bond formation by nucleophilic substitution of hydroxy groups catalyzed by Sn(NTf2)4

Article abstract of DOI:10.1002/anie.200906036

(Chemical Equation Presentation) Atom-economical: Unmodified hemiN,O-acetals are used in a catalytic, highly efficient α- amidoalkylation of a broad range of carbon-centered nucleophiles, including silicon-based components, active methylene derivatives, electron-rich arenes, and even simple ketones (see scheme). The reactions proceed in a highly efficient manner and typically require only 1 mol% of the Lewis super-acidic reagent Sn(NTf₂)₄ as the catalyst.

Full text of DOI:10.1002/anie.200906036

Communications
DOI: 10.1002/anie.200906036
Lewis Superacid Catalysis
N-Acyliminium Ion Chemistry: Highly Efficient and Versatile Carbon–
Carbon Bond Formation by Nucleophilic Substitution of Hydroxy
Groups Catalyzed by Sn(NTf2)4
Raja Ben Othman, Radouane Affani, Marie-Josꢀ Tranchant, Sylvain Antoniotti, Vincent Dalla,*
and Elisabet Duꢁach*
N-acyliminium ions are widely used as electrophiles in a-
amidoalkylation reactions. These stabilized carbenium ion
intermediates are typically generated from cyclic N,O-acetals
in acidic medium and usually lead to useful a-functionalized
amino derivatives after intra- or intermolecular trapping by
nucleophiles.[1] Despite the great synthetic possibilities of
such chemistry, catalytic versions have been developed only
quite recently. Indeed, some examples of amidoalkylation
with silicon-based nucleophiles have been reported,[2–5]
though with generally moderate catalytic activity, while
HNTf2 (Tf = trifluoromethanesulfonyl)[6] has proven to be a
more efficient catalyst allowing a broader combination of
donor–acceptor partners under milder reaction conditions.
Although challenging and of practical significance to the
organic chemist, the catalytic a-amidoalkylation of C–H
nucleophiles has been less explored[7,8] with only a few
examples dealing with intermolecular coupling with b-keto
esters or b-diketones,[7] or intramolecular arylation.[8]
The apparent need for an alkoxy or acetoxy aminal
derivative in all these catalytic reactions requires an addi-
tional step which lengthens the procedures. It would therefore
be desirable to use the parent hydroxy aminals themselves as
amidoalkylating agents for more efficient and atom-econom-
ical processes. Owing to the increasing demand for efficient
and environmentally friendly procedures, the development of
catalytic and direct carbon–carbon bond-forming reactions of
unmodified reaction partners is an exciting challenge. To this
end, considerable achievements towards the direct SN1-type
alkylation between carbon nucleophiles and alcohols have
been recently developed despite the poor leaving-group
ability of the hydroxy group.[9–12] However, while most of
the subclasses of stabilized carbenium ions (e.g. benzyl, allyl,
indenyl) have been alkylated using this strategy, similar
reactions using N-acyliminium ions remain unexplored.[13]
Given their ability to catalyze an amidoalkylation process
starting from common N,O-acetals, silyltriflates[2,3] and metal
triflate salts[4,8a,b] may be valuable candidates for this purpose.
However, as the catalytic performance displayed by Sc(OTf)3
was inferior to that of HNTf2 in some challenging amidoal-
kylations,[6a] and the use an acetoxy lactam was necessary to
reach a good overall performance with Bi(OTf)3,[8b] we were
prompted to use stronger s Lewis acids.
Recognizing the Lewis superacidity generally associated
with the metal triflimidate species[14–16] and encouraged by the
excellent activity and broad applicability displayed by HNTf2
in the catalytic a-amidoalkylation of common N,O-acetals,[6]
we explored the activity of triflimidate-based catalysts for the
nucleophilic substitution reaction of the hydroxy group of
hemi-N,O-acetals. We report herein a highly efficient and
general tin(IV) triflimidate[17] catalyzed a-amidoalkylation
reaction of the simplest N-acyliminium ion precursors, that is,
hydroxy aminals, with various carbon-centered nucleophiles
including silicon-based derivatives, b-dicarbonyl compounds,
and electron-rich arenes. Rewardingly, we also document the
first examples of the use of simple ketones as donor
components as a significant bonus in catalytic N-acyliminium
ion chemistry.
In a first set of reactions, 5-hydroxypyrrolidin-2-one 1 was
used as the electrophilic precursor. Because of the lower
stabilizing effect of the lone pair of electrons on nitrogen,
N,O-acetals such as compound 1 are less prone to provide
iminium ions than their 2-alkoxy carbamate analogues.
Hence, the reaction of 1 with the weakly nucleophilic allyl
trimethylsilane was chosen as an inherently difficult bench-
mark coupling reaction in order to identify the best catalytic
[*] Dr. R. Ben Othman,[+] Dr. R. Affani, M.-J. Tranchant, Prof. V. Dalla
URCOM, EA 3221, FR 3038, Facultꢀ des Sciences et Techniques de
l’Universitꢀ du Havre
25, Rue Philippe Lebon, BP 540, 76058 Le Havre (France)
Fax : (+33)2-3274-4391
E-mail: vincent.dalla@univ-lehavre.fr
systems.[18] Preliminary optimization studies unambiguously
[19]
indicated that Sn(NTf2)4
used at a loading of 1 mol%,
Dr. S. Antoniotti, Dr. E. Duꢁach
(Table 1, entry 1) outperforms other triflimidate salts and
[4]
Sc(OTf)3 as well.[20] With Sn(NTf2)4 as the catalyst and
LCMBA. UMR 6001, Universitꢀ de Nice-Sophia Antipolis
C.N.R.S. Institut de Chimie de Nice
28, avenue de Valrose, 06108 Nice (France)
Fax : (+33)4-9207-6125
CH3CN as solvent, reactions of 1 with the more nucleophilic
silyl enol ethers 2b–d were then undertaken, and excellent
yields of the desired adducts 3b–d were uniformly obtained at
room temperature (Table 1, entries 2–6). The inherent weak
reactivity of the hydroxylactams was reflected by the require-
ment of 2–3 equivalents of the sensitive silyl enol ethers to
provide high yields of adducts 3 (cf. entries 3 and 4,
Table 1).[21] We next extended these studies to the reactions
E-mail: dunach@unice.fr
[+] Present address:
Unitꢀ de recherche en Matꢀriaux, Energie et Environnement (MEE)
Universitꢀ de Gafsa, Sidi Ahmed Zarrouk, Gafsa, 2112 (Tunisie)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906036.
776
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Chemie
Table 1: Sn(NTf2)4-catalyzed amidoalkylation of N,O-acetals 1 and 4 with
various silicon-based nucleophiles 2a–e.
this emphasizes that 4 is more reactive than 1 (Table 1,
entries 6–12). When methyl pyruvate derivative 2e was used,
the desired adduct 5e was isolated in only 67% yield, most
likely because of a retro-Mannich addition triggered by the
extreme strength of the Lewis acidic catalyst.[23] Other metal
triflimidate salts such as Bi(NTf2)3, Cu(NTf2)2, In(NTf2)3, and
Mg(NTf)2 were also tested as catalysts (1 mol%) with the
more reactive electrophilic precursor 4. With the particular
exception of Mg(NTf)2, which remained totally inefficient,
these reagents displayed excellent catalytic activity.[22]
In addition to the enolation of 4 with silicon-based
nucleophiles, Sn(NTf2)4 was also found to efficiently catalyze
the alkylation with active methylene derivatives (Table 2,
entries 1 and 2). In terms of eco-compatibility, these trans-
formations are of great interest, as water is the only by-
product released. Good yields of the Mannich-type adducts
7a,b were obtained. Interestingly, the result presented in
entry 2 points out that the extremely high acidic strength of
the tin salt enabled isolation of the Mannich adducts 7b in
synthetically useful yields at a catalyst loading as low as
0.1 mol%.[23] The synthetic potential of this improved proto-
col is further exemplified by the fact that the reaction was
performed on a 500 mg scale. For comparison purpose, a poor
conversion (ca. 20% conv.) was observed when the same
reaction was carried out in the presence of 0.1 mol% HNTf2.
On the other hand, the less reactive hydroxyphtalimide 8
gave the desired b-dicarbonylated adducts 9a–d in almost
quantitative yields with 1 mol% of Sn(NTf2)4 at 608C
(Table 2, entries 3–6).[24] The excellent reaction profiles
observed with 8 at this elevated temperature, even with the
weakly nucleophilic components 6c and 6d (Table 2, entries 5
and 6), may be attributed to the high stability of the
phtalimidic N-acyliminium ion. The distinct advantage of
Sn(NTf2)4 in catalytic N-acyliminium ion chemistry was
further emphasized by the use of ketones as a challenging
class of nucleophiles. We indeed discovered that when we
used only a slight excess amount (2–3 equiv) of six different
and representative ketones, complete conversions and high
yields of the Mannich adducts 9e–j were systematically
obtained after short reaction times (Table 2, entries 7–12).
These remarkable results are the first examples of this type of
direct catalytic a-amidoalkylations, indicating that also simple
ketones could now be considered as adequate donors in
catalytic intermolecular N-acyliminium ion chemistry.[25]
Overall, our results highlight the distinct advantage of
Sn(NTf2)4 in these transformations as the reaction of aceto-
phenone (see Table 2, entry 8) catalyzed by 5 mol% HNTf2
and 1 mol% Bi(NTf2)3 over 9 h in refluxing acetonitrile gave
only moderate conversions of 60% and 43%, respectively.
To further demonstrate the general applicability of tin
triflimidate in these direct alkylations, we briefly investigated
the intramolecular Friedel–Crafts-type reactions of hydroxy
lactams 10a–c. These reactions were carried out using
1 mol% of Sn(NTf2)4 in acetonitrile at room temperature.
The nucleophilic substitution proceeded rapidly with high
efficiency affording the desired arylated products 11a–c in
90–99% yields under unprecedented extremely mild condi-
tions (Table 3). The high reactivity observed with the SnIV
triflimidate Lewis superacid at room temperature is note-
Entry Substrate NuSiR3
Time Product
3 h
Yield [%]
81
1[a,b]
1
1
2[c]
4 h
88
3[a]
4[d]
5[d]
1
1
1
4 h
68
2c
3.5 h 3c
2.25 h
90
93[e]
6[c]
7[a]
1
4
2d
2a
2.25 h 3d
93
94
1 h
8[f]
4
4
4
2b
2b
2c
6 h
92
95
95
9[a]
6 h
5b
10[a]
3.5 h
11[a]
12[f]
13[a]
4
4
4
2d
2d
2 h
2 h
2 h
95[g]
98[g]
67
5d
[a] Conducted with 2 equiv of the nucleophile. [b] Conducted at 508C.
[c] Conducted with 2.5 equiv of the nucleophile. [d] Conducted with
3 equiv of the silyl enol ether. [e] Mixture of diastereoisomers 3:1.
[f] Conducted with 1.5 equiv of the silyl enol ether. [g] Mixture of
diastereoisomers 2.3:1. Abbreviations: Cbz=carbobenzoxy, PMB=
para-methoxybenzyl, TBS=tert-butyldimethylsilyl, TES=triethylsilyl,
TMS=trimethylsilyl.
of the more reactive 2-hydroxy carbamate 4, and the results of
coupling with several nucleophiles 2a–e using Sn(NTf2)4 as
the catalyst are summarized in Table 1, entries 7–13. In almost
all of the examples high efficiency was observed examined
(92–98% yields) with 1.5–2 equivalents of the nucleophile;
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777

Communications
Table 2: Sn(NTf2)4-catalyzed amidoalkylation of N,O-acetals 4 and 8 by
various enol nucleophiles 6a–j.
Table 3: Sn(NTf2)4-catalyzed Friedel–Crafts-type cyclization of hydroxy
lactams 10a–c.
Entry Aminal NuH
t, T
Product
Yield [%]
75
Entry
X–X
Y
Time
Product
(yield [%])
1
2
4
4
30 min, RT
1
2
30 min
11a (99)
11a (>99)
OMe (10a)
20 min[a]
3
4
H (10b)
1 h
1 h
11b (91)[b]
1 h 40, RT
38
81
40 min,[a] RT
CH2–CH2
OMe (10c)
11c (96)
[a] The reaction was carried out in CDCl3 and was monitored by 1H NMR
spectroscopy; a similar reaction rate was measured in CD3CN. [d] The
regioisomer of 11b was obtained in 4% yield.
3[b]
8
8
6a
6b
4 h, 608C
3 h, 608C
>99
>99
worthy, given the weak reactivity displayed by hydroxy
lactams in catalytic intermolecular alkylations.[24,26]
4[b],
In summary, we have found that the extremely active SnIV
triflimidate was able to efficiently catalyze the nucleophilic
substitution reaction of hydroxy groups of unprotected
hydroxy N,O-acetals. The catalytic system relies on the
Lewis superacid properties of triflimidate-based reagents
and requires low catalyst loadings (0.1–1 mol%) and mild
conditions. The coupling reaction shows unprecedented
applicability in terms of carbon nucleophiles, including
allyltrimethylsilane, silyl enol ethers, active methylene deriv-
atives, arenes and even ketones. The scope of catalytic N-
acyliminium ion chemistry is broaden as well as the field of
application of the promising Lewis superacidic tin(IV)
triflimidate catalyst.[27] We believe that this readily available
reagent should now be considered as a privileged candidate
for developing highly efficient Lewis acid catalyzed trans-
formations.
5[b]
8
3 h, 608C
>99
6[c]
8
8
5 h, 508C
4 h, 608C
93
7[b,d]
>99
8[b,d]
8
3 h, 608C
>99
Received: October 27, 2009
Published online: December 17, 2009
9[b,d]
8
8
8
8
4 h, 608C
4 h, 608C
2 h, 608C
6 h, 608C
95
76
79
93
Keywords: acetals · catalysis · Lewis acids · N-acyliminium ions
.
10[b,d]
11[b,e,f]
12[b,e]
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778
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Chemie
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À
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[18] This allylation reaction progressed very smoothly at room
temperature, but complete conversions of 1 were achieved
within short reaction times when the reaction was performed at
508C. See the Supporting Information for details.
[19] This catalyst was prepared according to the method reported in
Ref. [17b] and used as a solvate Sn(NTf2)4·6DMSO.
[20] Yields of 3a: 53% with Bi(NTf2)3, 27% with In(NTf2)3, 24%
with Cu(NTf2)2, 0% with Mg(NTf2)2, 5% with Sc(OTf)3. See the
Suporting Information for more details.
[21] Yields were also typically above 90% when only 2 equiv of silyl
enol ethers 2b–d was used with the methoxy lactam derived from
1 under similar reaction conditions.
[22] Bi(NTf2)3- and In(NTf2)3-catalyzed allylation of 4: 94% and
93% yield, respectively ; Cu(NTf2)2-catalyzed amidoalkylation
of cyclohexanone trimethylsilyl enol ether 2d: 98% yield.
[23] When 1 mol% of Sn(NTf2)4 was used, several side products
formed and 7b was isolated in only 40% yield. A control
experiment proved that Sn(NTf2)4 (1 mol% in CH3CN) medi-
ates the rapid decomposition of the Mannich adduct 7b, most
likely through retro-Mannich pathway triggered by the Lewis
superacidity of the catalyst.
[24] The reaction between 8 and acetylacetone gave a nearly 70%
conversion after 24 h of reaction at room temperature in
Angew. Chem. Int. Ed. 2010, 49, 776 –780
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
779

Communications
acetonitrile. Under similar conditions, the more reactive acetoxy-
does not exceed 30% conversion over 24 h in the presence of
1 mol% of Sn(NTf2)4 or HNTf2.
lactame gave the Mannich adduct 9a quantitatively.
[25] Our results complement the recent development of a copper-
catalyzed oxidative Mannich reaction between tertiary amines
and methyl ketones: Y. Shen, M. Li, S. Wang, T. Zhan, Z. Tan,
C. C. Guo, Chem. Commun. 2009, 953.
[27] During the preparation of this manuscript, Dixon and co-
workers published a thermal, catalytic enantioselective Frie-
del—Crafts-type intramolecular amidoalkylation of in situ
generated hydroxy lactames: M. C. Muratore, C. A. Holloway,
A. W. Pilling, R. I. Storer, G. Trevitt, D. J. Dixon, J. Am. Chem.
Soc. 2009, 131, 10796.
[26] The a-amidoalkylation of the trimethylsilyl enol ether of
acetophenone (3 equiv) by the phtalimidic hydroxy lactam 8
780
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Angew. Chem. Int. Ed. 2010, 49, 776 –780