A silver-catalyzed spirocyclization of alkynyl silyl enol ethers

Article abstract of DOI:10.1002/chem.201200116

A silver(I)-catalyzed intramolecular addition reaction of silyl enol ethers to alkynes was developed. Alkynyl silyl enol ethers were treated in a one-pot reaction with AgNTf₂, directly followed by addition of N-iodosuccinimide (NIS) in ClCH₂CH₂Cl, which provided exclusively the E-alkenyl iodide derivatives in good yields. Although the silver-catalyzed cycloisomerization of bicycloalkanone proved to be difficult, iodo-demetalation makes it possible to obtain alkenyl iodide derivative. The X-ray crystal structure of tricyclic alkenyl iodide showed an E-configured exo double bond, thus, providing evidence for the iodo-demetalation of intermediate C with the NIS reagent. In light of this result, we considered the possibility that a similar silver-catalyzed pathway could account for activated alkynes. The reaction allows the diastereoselective synthesis of a variety of spiro compounds.

Full text of DOI:10.1002/chem.201200116

DOI: 10.1002/chem.201200116
A Silver-Catalyzed Spirocyclization of Alkynyl Silyl Enol Ethers
Christian Schꢀfer, Michel Miesch, and Laurence Miesch*[a]
Spiro compounds are of great interest because of their
We began our investigation by examining the cyclization
using various silver catalysts with different solvents for the
reaction of compound 1 (Table 1). Interestingly, the use of
AgNTf2 alone led to spiro compounds 2a and 2b with the
special conformational features and their structural implica-
tions on biological systems.[1] The presence of the sterically
constrained spiro structure in various natural products sub-
stantially promotes interest in the investigation of spiro
compounds.[2] The Conia-ene cyclization is one of the pro-
cesses during which a quaternary center is formed by the
pericyclic reaction of an enolizable carbonyl group with an
alkyne. However, the need for high temperatures limits the
synthetic utility of this reaction.[3] On the other hand, transi-
tion-metal-catalyzed versions[4] proceed under mild condi-
tions at lower temperatures. Toste and co-workers have re-
ported a phosphine–gold(I)-catalyzed version for the intra-
molecular addition of a b-ketoester to an unactivated
alkyne.[5] In a similar reaction, Davies and Detty-Mambo
demonstrated the cycloisomerization of unactivated ketones
with alkynes under gold catalysis.[6] In recent years, silver
salts have gained increasing interest in homogeneous cataly-
sis owing to their mildness and efficiency.[7] More recent re-
views discuss the current revolution in silver chemistry. Cat-
alysis with silver salts has become widespread due to the
s and p Lewis acidic properties of silver(I) complexes,[8]
which lead to a variety of chemical transformations.[9] There-
fore, exploring new catalytic reactions with silver complexes
is of great interest. For this reason, we focused on silver-cat-
alyzed cycloisomerization to study the behavior of alkynyl
silyl enol ethers.
Table 1. Screening of solvents and catalysts (IPr=1,3-bis(2,6-diisopropyl-
phenyl)imidazol-2-ylidene).
Entry Catalyst
Solvent
T
Yield
2a/2b
[8C] [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
IPrAuCl/AgOTf ClCH2CH2Cl
IPrAuCl/AgNTf2 ClCH2CH2Cl
84
84
20
20
20
20
20
82
12 (63) 100:0
66
67
78
2.5:1
17:1
16:1
20:1
–
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
Ag2CO3
–
ClCH2CH2Cl
CH2Cl2
THF
acetone
toluene
CH3CN
41 (40)
[c]
–
76
7 (65)
–
9:1
1:5
–
[c]
ClCH2CH2Cl/MeOH 20
toluene[a]
20
20
20
20
56 (12)
1:38
[c]
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
–
–
–
–
–
[c]
[d]
–
[a] Toluene was not distilled before use. [b] Yields in parentheses corre-
spond to the deprotected starting material. [c] Only deprotection of the
starting material occurred. [d] The starting material was recovered.
Mainly used as cocatalysts in gold catalysis, silver salts,
such as AgBF4, AgSbF6, and AgPF6, are very hygroscopic,
causing difficulties in properly weighing the reagent and
keeping the reaction medium nonacidic. In contrast, AgNTf2
(Tf=triflyl)[10] is known to be more stable and easier to
handle than its congeners. Thus, this reagent proved to be
an efficient catalyst for nucleophilic additions to alkynes.[11]
For this purpose, we envisaged the use of AgNTf2 as a poten-
tially valuable candidate for the cycloisomerization of silyl
alkynyl enol ethers.
same yield as that observed under gold catalysis (Table 1,
entry 3). Furthermore, the yield could be improved by using
CH2Cl2 or toluene as the solvent (Table 1, entries 4 and 7).
Control experiments revealed that silver carbonate or the
corresponding free amine, that is, triflimide, could not cata-
lyze the reaction of silyl alkynyl enol ethers to form spiro
compounds, and no reaction occurred under metal-free con-
ditions. Likewise, the unsilylated ketones could not be trans-
formed into the spiro compounds.
Having found that AgI-catalyzed cycloisomerization
favors the 5-exo-dig cyclization process, we evaluated the
scope of the reaction by using various alkynyl cycloalka-
nones. The reaction proved to be quite general, although the
yield is dependent upon both the substrate and the solvent
(Table 2, entries 1, 2, 13–16, and 19). Interestingly, in most
cases that use CH2Cl2 as the solvent, the exo regioisomer is
favored, except for entries 6, 18, and 22 in Table 2, whereas
the endo compound is obtained in toluene except for cyclo-
[a] Dipl.-Ing. C. Schꢀfer, Dr. M. Miesch, Dr. L. Miesch
Laboratoire de Chimie Organique Synthꢁtique, Institut de Chimie
UMR 7177, Universitꢁ de Strasbourg, 1 rue Blaise Pascal
BP 296/R8, 67008 Strasbourg-Cedex (France)
Fax : (+)33368851754
E-mail: l.miesch@unistra.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200116.
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Chem. Eur. J. 2012, 18, 8028 – 8031

COMMUNICATION
Table 2. AgI-catalyzed spirocyclization.
Entry[a]
Substrate
Solvent
Product
Yield
[%][a]
a/b
1
2
toluene
CH2Cl2
47
35
100:0
5:1
4
Scheme 1. The formal total synthesis of (Æ)-erythrodiene (TBS=tert-
butyldimethylsilyl).
3
4
toluene
CH2Cl2
76
78
9:1
16:1
2
6
In this way, by starting from compound 23, a mixture of
spiroketones 24 and 25 was obtained (Scheme 1), the first of
which was elaborated into spirobicyclic sesquiterpene (Æ)-
erythrodiene by Huang and Forsyth.[12]
5
6
toluene
CH2Cl2
74
62
1:9[b]
0:100
A tentative mechanism for this Ag-catalyzed cycloisom-
erization reaction is outlined in Scheme 2. Based on the fact
that alkynyl silyl enol ethers 1a and 1b are present as a 2:1
mixture, it seems that under silver catalysis isomerization
from 1a to 1b takes place.[13] Complexation of the silver salt
to the alkynyl moiety would initiate this process. After the
complexation step, intermediate A could undergo an ene–
yne cycloisomerization assisted by the alkyne activation[14]
and the presence of the oxygen atom to yield the intermedi-
ate silver complex B. Then, proton migration would give
product C. Subsequent protonolysis of the alkenyl–silver
species and hydrolysis of the silyl enol ether would afford
either the 5-exo-dig isomer 2a[15] or further isomerization of
exo-silyl enol ether D in the presence of HNTf2 would lead
(via E) to the endo product 2b. The isomerization step has
been proven by the treatment of 20a with HNTf2, which
gave compound 20b in 97% yield (Scheme 3).[16]
To further highlight the potential of this new silver-cata-
lyzed spirocyclization, we attempted to trap the newly
formed alkenyl–silver intermediate prior to protonation
with a source of electrophilic iodine.[17] This type of transfor-
mation would be of high synthetic interest because it would
lead to alkenyl iodides.[18]
Thus, alkynyl silyl enol ethers were treated in a one-pot
reaction with AgNTf2 (5 mol%), directly followed by addi-
tion of N-iodosuccinimide (NIS) in ClCH2CH2Cl, which pro-
vided exclusively the E-alkenyl iodide derivatives in good
yields (Table 3).[19] It should be noted that in this case no
6-endo compounds were isolated and the reaction of 1 with
NIS alone led exclusively to the a-halogenated derivative of
the desilylated starting material.[16]
7
8
toluene
CH2Cl2
48 (4)
58 (9)
1:2[b]
2:1[b]
8
9
10
toluene
CH2Cl2
64 (12)
71 (15)
0:100
100:0
10
11
12
toluene
CH2Cl2
72
83
1:25[c]
28[c]:1
12
14
16
13
14
toluene
CH2Cl2
trace
trace
1:2
100:0
15
16
toluene
CH2Cl2
0 (31)
13 (59)
–
100:0
17
18
toluene
CH2Cl2
74
75
0:100
1:7
18
20
22
19
20
toluene
CH2Cl2
25 (25)
59 (23)
1:3
100:0
21
22
toluene
CH2Cl2
74 (10)
49 (35)
0:100
0:100
Although the silver-catalyzed cycloisomerization of
bicycloACHTNUTRGNE[UNG 3.2.0]alkanone 13 proved to be difficult, iodo-de-
[a] Yields in parentheses correspond to the deprotected starting material.
[b] The product of a 6-endo cyclization reaction is obtained instead of the
5-exo product. [c] Obtained as a mixture of diastereoisomers.
metalation makes it possible to obtain alkenyl iodide deriva-
tive 31. The X-ray crystal structure of tricyclic alkenyl
iodide 31 (Figure 1) showed an E-configured exo double
bond, thus, providing evidence for the iodo-demetalation of
intermediate C with the NIS reagent.[17]
In light of this result, we considered the possibility that
a similar silver-catalyzed pathway could account for activat-
ed alkynes. To our delight, subjecting alkynoate 35 to the
pentanone and cyclohexanone derivatives (Table 2, entries 1
and 3) for which the exo regioisomer is always the major
product. Silyl alkynyl enol ethers derived from larger rings
furnished 6-endo-dig cyclization products (Table 2, entries 5,
7, 8).
Chem. Eur. J. 2012, 18, 8028 – 8031
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8029

L. Miesch et al.
ety of spiro compounds. Taken
together, the silver catalysis and
iodo trapping provides alkenyl
iodides that are valuable syn-
thons in organic synthesis and
allows further functionalization
by using Pd-catalyzed cross-
coupling chemistry. Reactions
with more complex substrates,
as well as asymmetric versions
of this reaction, are currently
under investigation in our labo-
ratory.
Scheme 2. Mechanistic proposal for the AgNTf2-mediated cyclization reac-
tions.
Table 3. Ag-catalyzed formation of alkenyl iodides.
silver-catalyzed cycloisomerization conditions afforded spi-
roester 36 in 81% yield (Scheme 4).
In summary, a silver(I)-catalyzed intramolecular addition
reaction of silyl enol ethers to alkynes has been developed.
The reaction allows the diastereoselective synthesis of a vari-
Entry
1
Substrate
Product
Yield
[%]
13
68
67
2
3
Scheme 3. Isomerization of compound 20a into 20b (DCE=dichloro-
ethene).
4
5
6
7
81
79
54
80
Scheme 4. Spirocyclization of silyl enol ether 35.
8
9
78
73
Figure 1. ORTEP diagram of tricyclic alkenyl iodide 31 with thermal
ellipsoids at the 50% probability level.[20]
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Spirocyclization of Alkynyl Silyl Enol Ethers
COMMUNICATION
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Acknowledgements
Support for this work was provided by CNRS and the Universitꢁ de
Strasbourg. The authors are grateful to Dr. Fabien Gagosz (Ecole Poly-
technique, Palaiseau, France) for helpful discussions. C.S. thanks MRT
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Keywords: homogeneous catalysis
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·
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Received: January 11, 2012
Published online: June 1, 2012
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