Silver-Catalyzed 7-exo-dig Cyclization of Silylenolether-ynesulfonamides

Article abstract of DOI:10.1002/anie.201510708

Cyclization of silylenolether-ynesulfonamides proceeds at ambient temperature under mild reaction conditions under silver catalysis. Bridged compounds were obtained exclusively through 7-exo-dig reactions. The protocol is applicable to a wide range of substrates, thus leading to azabicyclic frameworks. Dig this! Cyclization of silylenolether-ynesulfonamides proceeds at ambient temperature under mild reaction conditions under silver catalysis. Bridged compounds were obtained exclusively through 7-exo-dig reactions. The protocol is applicable to a wide range of substrates, thus leading to azabicyclic frameworks.

Full text of DOI:10.1002/anie.201510708

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201510708
German Edition: DOI: 10.1002/ange.201510708
Heterocycle Synthesis
Silver-Catalyzed 7-exo-dig Cyclization of Silylenolether-
ynesulfonamides
ClØment F. Heinrich, Indira Fabre, and Laurence Miesch*
Abstract: Cyclization of silylenolether-ynesulfonamides pro-
ceeds at ambient temperature under mild reaction conditions
under silver catalysis. Bridged compounds were obtained
exclusively through 7-exo-dig reactions. The protocol is
applicable to a wide range of substrates, thus leading to
azabicyclic frameworks.
D
uring the past decades, transition-metal-catalyzed cyclo-
isomerization reactions of ene-ynamides have emerged as
extraordinary tools to create molecular complexity, especially
for the synthesis of nitrogen-containing heterocycles.[1,2]
However, formal Conia-ene reactions of ene-ynamides are
noticeably absent. Moreover, 7-exo-dig cyclizations using this
method are exceptional because of the distal location of the
nucleophilic center and the alkyne moiety.[3–5] In addition,
generating a bridged bicyclic system usually requires a-
disubstituted ketones to avoid concomitant formation of spiro
compounds.
Scheme 1. Synthesis of the silyl enol ether 4a. TBAF=tetra-n-butylam-
monium fluoride, TBS=tert-butyldimethylsilyl, Tf =trifluoromethane-
sulfonyl, THF=tetrahydrofuran, TIPS=triisopropylsilyl, Ts =4-toluene-
sulfonyl.
Table 1: Screening of catalysts.
À
Herein we present a versatile, silver-catalyzed C C bond-
forming cyclization reaction of both mono- and disubstituted
silylenolether-ynesulfonamides, thus leading exclusively to
bridged bicyclic keto-enamides.
Entry
Catalyst
t
Yield [%][a]
To this end, the required the silylenolether-ynesulfon-
amide 4a was readily prepared by alkylation of N,N-dimethyl
hydrazones with tosylaziridine[6] followed by the application
of Hsungꢀs copper-catalyzed N-alkynylation[7] reaction, thus
affording the corresponding ynesulfonamide 3a (Scheme 1).
Subsequent treatment of 3a with TBAF and subsequent
addition of TBSOTf/Et3N exclusively provided the kinetic
silyloxy-ene-ynesulfonamide 4a.[8,9]
Previously, we reported a silver-catalyzed Conia-ene
cyclization of alkynyl silyl enol ethers.[4] Thus, we began our
investigations by examining the cyclization of ene-ynesulfon-
amides using various silver and gold catalysts (Table 1).
Because the kinetic silyl enol ether is formed exclusively,
cyclization afforded only the bridged bicyclic compound 5a in
a short time at room temperature, and no spiro compound was
[b]
1
2
3
4
5
6
7
8
Ag2CO3
AgOTs
AgCO2Ph
AgOAc
HNTf2
AgOTf
AgBF4
AgSbF6
16 h
16 h
16 h
–
–
–
–
[b]
[b]
[b]
16 h
30 min
30 min
30 min
30 min
30 min
30 min
30 min
21
90
92
94
98
92
89
9
10
11
AgNTf2
[Au(PPh3)][NTf2]
[Au(JohnPhos)(MeCN)][SbF6]
[a] Yield is that of the isolated product. [b] Only the starting material was
recovered.
observed.[10] Interestingly, the use of silver salts (entries 6–9)
is as effective as gold catalysts (entry 10–11).[11] AgNTf2
(entry 9) was determined to be the most efficacious catalyst
to perform the 7-exo-dig cyclization of silylenolether-ynesul-
fonamides. No conversion with insoluble silver salts was
observed (entries 1–4). Control experiments revealed that
neither silver carbonate nor the corresponding free amide,
that is, triflimic acid, were beneficial to catalyze the trans-
formation of silyl ynesulfonamides to bridged bicyclic com-
pounds, and a low yield was observed under metal-free
conditions (entry 5). Likewise, ketones could not be trans-
formed directly into spiro compounds. An X-ray structural
[*] Dr. C. F. Heinrich, Dr. L. Miesch
Laboratoire de Chimie Organique SynthØtique, Institut de Chimie
1, rue Blaise Pascal, BP296/R8, 67008 Strasbourg (France)
E-mail: lmiesch@unistra.fr
I. Fabre
DØpartement de Chimie
Ecole Normale SupØrieure—PSL Research University
Sorbonne UniversitØs—UPMC Univ Paris 06, CNRS UMR 8640
PASTEUR
24, rue Lhomond, 75005 Paris (France)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201510708.
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Table 2: Cyclization using various cycloalkanones.
determination of the bridged compound 5a provided evi-
dence for the regioselectivity of the reaction.[12]
We next turned our attention to the effect of the solvent in
this cycloisomerization reaction (Figure 1). Whereas the yield
is nearly quantitative in 1,2-dichloroethane, yields decreased
with the use of toluene, dichloromethane, nitromethane, and
diethyl ether, and there was almost no conversion with either
CHCl3 or THF, and no reaction in MeCN, DMF, and MeOH,
which can be attributed to the metal-coordinating properties
of these solvents. Furthermore, the reaction was compatible
with different electron-withdrawing groups on the nitrogen
atom (Scheme 2).
Entry
1[b]
Compound
Product
Yield [%][a]
63
2
3
90
89
4
87
5
6
99
86
Figure 1. Screenings of solvents.
7
63
49
8[b]
[a] Yield is that of the isolated product. [b] The compounds 4d and 4k
were obtained as a mixture of kinetic/thermodynamic compounds.
Scheme 2. Variation of the electron-withdrawing group.
Mbs=p-methoxybenzenesulfonyl, Ns=2-nitrobenzenesulfonyl.
The scope of the reaction was also investigated with
respect to the spacer length (Scheme 3). Although only
kinetic silyl enol ethers are obtained by shortening the spacer
length, a 6-exo-dig cyclization afforded the adduct 5l in
a rather moderate yield. Regarding the formation of the silyl
enol ether, the selectivity decreases as the ynesulfonamide
function is moved further from the ketone. Although the
bridged compound 5m could still be obtained through an 8-
exo-dig cyclization along with a small amount of the
spirocompound 6m. The homologue 4o could not undergo
9-exo-dig cyclization and led only to the spirocompound 6o.
An enantiomerically enriched, disubstituted compound, bear-
ing a three carbon linker chain (5n) could be obtained with
a good yield.
In our pursuit of ene-ynesulfonamide cyclizations, we
have focused on the influence of the substituents on the
ynesulfonamide function (Table 3). The protocol was found to
be general because a wide range of linear or cyclic alkyls,
halogens, protected alcohols, and aromatic substituents react
successfully. The reaction remained diastereoselective with
With the optimal reaction conditions in hand, we exam-
ined various cyclic silyl enol ether substrates for the con-
struction of azabicyclo[m.4.1] frameworks through the 7-
endo-dig cyclization (Table 2).[13] The reaction allowed con-
struction of a variety of ring sizes. The conformationally
flexible acyclic compound 4k as well as the strained cyclo-
butanone derivative 4d led to a mixture of kinetic and
thermodynamic silyl enol ethers. However cyclization could
be achieved in both cases and led to original scaffolds. The
functionalized ketone such 4g could be utilized as well, thus
leading to the corresponding bridged compounds with good
yields. Even larger cyclic ketones, for example, seven- or
eight-membered silyloxy-ynesulfonamides, were suitable
compounds, thus providing the 7-exo-dig compounds 5h and
5i, respectively, in very good yields. It should be noted that an
ester functional group at the bridged position was tolerated as
well (entry 7).
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Table 3: Functionalization of the ynesulfonamide moiety.
Entry
1
Compound
Product
Yield [%][a]
76
2
76
3
4
5
89
91
85
Scheme 3. Modification of the spacer length.
respect to the stereochemistry of the double bond. X-Ray
crystallographic structure determinations of the bridged
bicyclic compounds 5s[14] and 5y (Figure 2)[15] revealed a Z-
configured exo double bond of the latter, and provided
evidence for in situ elimination of the OBn group, thus
leading to allenamide 5s.
6
7
82
68
Finally, we attempted to trap the
newly formed alkenylsilver inter-
mediate species by a source of elec-
trophilic iodine prior to protodeme-
talation (Scheme 4).[4,16] Thus, 4a was
treated in one pot with 1 mol% of
AgNTf2 and 1 equivalent of NIS in
1,2-dichloroethane, thus exclusively
providing the Z-alkenyl iodide deriv-
8
9
78
66
56
ative 7 as confirmed by X-ray crys-
Figure 2. Crystallographic
determination of 5y.
tallographic structural determina-
tion.[17] It should be noted that in
this case the reaction of 4a with NIS
alone led to 7 in low yield (14%).
10
[a] Yield is that of the isolated product.
Scheme 4. Trapping alkenylsilver intermediates. DCE=1,2-dichloro-
ethane, NIS=N-iodosuccinimide.
minimize steric interactions between the R group and the
ene-silyloxy-ring 8c, thus favoring the six-membered 9c.[20]
The intermediates 9a and 9c are obtained by 7-endo-dig
cyclization of 8a and 8c, respectively.[13]
In conclusion, the first formal conia ene cyclization of ene-
ynesulfonamides has been described. Only kinetic TBS silyl
enol ethers were observed, thus providing rapid access to
formal 7-exo-dig nitrogen-containing products. A wide range
The selectivity of these reactions can be rationalized[18] by
analyzing the conformations of the keteneiminium intermedi-
ates (Scheme 5). When R = H, the Z-configured 8a is
preferred. Thus, the six-membered silver sulfonamide-com-
plexed ring[19] 9a is favored and leads to 5a by protodeme-
talation and to 7 by iodo-demetalation. Alternatively, when
R ¼ H, the Z-configured compounds 5p–y are preferred to
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Acknowledgments
Support for this work was provided by CNRS and UniversitØ
de Strasbourg. C.F.H. thanks M.R.T. for a research fellowship.
We thank Dr. Ilaria Ciofini (ParisTech, Paris) for helpful
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contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
Keywords: cyclizations · heterocycles · silver ·
structure elucidation · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 5170–5174
Angew. Chem. 2016, 128, 5256–5260
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[10] DFT calculations support experimental results observed. Refer
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1
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[13] 7-endo-dig cyclization of keteneiminium cation is proposed
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Received: November 18, 2015
Revised: February 5, 2016
Published online: March 22, 2016
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