Bronsted acid-promoted cyclizations of 1-siloxy-1,5-diynes

Article abstract of DOI:10.1021/ja055054t

We have developed the first HNTf₂-promoted 5-endo-dig cyclizations of 1-siloxy-1,5-diynes, which proceed with concomitant formation of C-Hal bonds as a result of halide abstraction from a halocarbon by the intermediate alkenyl cation. This process is enabled by a chemoselective activation of the more electron-rich siloxy alkyne moiety of the diyne cyclization precursor and represents an efficient and highly diastereoselective method for assembly of a range of β-halo enones. Copyright

Full text of DOI:10.1021/ja055054t

Published on Web 09/08/2005
Brønsted Acid-Promoted Cyclizations of 1-Siloxy-1,5-diynes
Jianwei Sun and Sergey A. Kozmin*
Department of Chemistry, UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received July 26, 2005; E-mail: skozmin@uchicago.edu
Table 1. HNTf2-Promoted Cyclizations of 1-Siloxy-1,5-diynes
Siloxy alkynes represent a versatile synthetic platform for the
development of new C-C bond forming reactions.1-3 We previ-
ously established that soft and hard electrophiles (AuCl and HNTf2)
were capable of efficient activation of siloxy alkynes toward
subsequent intramolecular additions of arenes and alkenes via the
intermediacy of highly reactive ketenium ions.3d,e In this com-
munication, we further expand this broadly useful reactivity concept
and describe the discovery of the first Brønsted acid-promoted
5-endo-dig cyclizations of 1-siloxy-1,5-diynes, which proceed with
concomitant formation of C-Hal bonds as a result of halide
abstraction from a halocarbon by the intermediate alkenyl cation.
This process is enabled by chemoselective activation of an electron-
rich siloxy alkyne moiety of the diyne cyclization precursor.
Excellent diastereoselectivity of the present method combined with
the ability to access a range of â-halo enones compares this
approach favorably to the known methods for preparation of this
class of compounds.4
In the course of our continuing investigation aimed at the
development of new C-C bond forming reactions involving
electron-rich alkynes, we found that treatment of 1-siloxy-1,5-diyne
1 with HNTf2 resulted in efficient formation of enone 2 containing
the â-chloride that originated from CH2Cl2 (Scheme 1).5 Structural
Scheme 1
assignment of 2 was based on COSY, NOESY, HMBC, MS, and
preparation by an independent method.4
Further studies demonstrated that HNTf2 is a highly effective
Brønsted acid promoter.6 Broad evaluation of other Brønsted acids
revealed that only HBF4 or HOTf was capable of promoting siloxy
diyne cyclizations. However, the reactions proceeded with signifi-
cantly lower efficiency (32 and 22% yield, respectively). These
intriguing results could be explained by the increased Brønsted
acidity of HNTf2 in a polar aprotic solvent combined with a low
nucleophilicity of the trifluoromethane sulfonimide anion.7 Interest-
ingly, the use of either CSA or anhydrous HCl resulted in formation
of alternative reaction products.8
The use of other halogen sources, such as CHCl3, CH2Br2, or
MeI, resulted in efficient incorporation of chloride, bromide, and
iodide into the reaction products 2, 3, and 4, respectively (Table 1,
entries 1, 2, and 3). Subjection of phenyl-substituted enynes 5 and
7 to the general reaction protocol efficiently afforded the expected
enones 6 and 8, respectively (entries 4 and 5). These results indicate
that aryl substitution at the 8- and 9-position of the diyne was well
tolerated despite the possible intra- or intermolecular arylation
of the intermediate alkenyl cation (vide infra). Subjection of
3,3-dimethyl diyne 9 to HNTf2 in either CH2Br2 or MeI afforded
a General reaction protocol for CH2Cl2: Trifluoromethanesulfonimide
(0.28 mmol) was dissolved in CH2Cl2 (10 mL), cooled to -78 °C, and
treated with siloxy diyne (0.25 mmol) dissolved in CH2Cl2 (5 mL). The
resulting solution was stirred at -78 °C for 10 min, allowed to reach room
temperature, diluted with CH2Cl2 (30 mL), and subjected to a standard
aqueous work up. The crude product was purified by flash chromatography
on silica gel. b Refers to isolated yields of spectroscopically pure products
that were fully characterized by NMR, IR, and MS.
the expected enones 10 and 11 (entries 6 and 7), indicating that
increased steric congestion at the siloxy alkyne terminus was well
tolerated. Finally, TIPS-protected primary alcohol 12 was retained
under our standard cyclization protocol (entry 8), illustrating
9
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J. AM. CHEM. SOC. 2005, 127, 13512-13513
10.1021/ja055054t CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
tion of efficient generation of highly reactive ketenium ions that
are poised for interception by the proximate alkyne to provide a
simple concept for generating new C-C and C-Hal bonds.
Acknowledgment. This work was supported by the NSF
CAREER (CHE-0447751). We thank Liming Zhang for the initial
studies on cyclizations of siloxy diynes. S.A.K. thanks the Dreyfus
Foundation for a Teacher-Scholar Award, Amgen for a New
Investigator’s Award, and GlaxoSmithKline for a Chemistry
Scholars Award. S.A.K. is a fellow of the Alfred P. Sloan
Foundation.
Supporting Information Available: Full characterization of new
compounds and selected experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) For a review, see: Shindo, M. Synthesis 2003, 2275.
(2) For a review of alkoxy alkynes, see: Arens, J. F. AdVances in Organic
Chemistry Methods and Results; Raphael, R. A., Taylor, E. C., Eds.;
Interscience Publishers: New York, 1960; Vol. 2, pp 117-212.
(3) (a) Schramm, M. P.; Reddy, D. S.; Kozmin, S. A. Angew. Chem., Int.
Ed. 2001, 40, 4274. (b) Sweis, R. F.; Schramm, M. P.; Kozmin, S. A. J.
Am. Chem. Soc. 2004, 126, 7442. (c) Reddy, D. S.; Kozmin, S. A. J.
Org. Chem. 2004, 69, 4860. (d) Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2004, 126, 10204. (e) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc.
2004, 126, 11806.
(4) Popov, S. A.; Tkachev, A. V. Synth. Commun. 2001, 31, 233.
(5) To our knowledge, there are two examples of halide abstraction from
halocarbons by alkenyl cations: (a) Johnson, W. S.; Ward, C. E.; Boots,
S. G.; Gravestock, M. B.; Markezich, R. L.; McCarry, B. E.; Okorie, D.
A.; Parry, R. J. J. Am. Chem. Soc. 1981, 103, 88. (b) Balog, A.; Geib, S.
J.; Curran, D. P. J. Org. Chem. 1995, 60, 345. For other examples of
halide abstraction from hydrocarbons by carbocations, see: (c) White, E.
H.; Tiwari, H. P.; Todd, M. J. J. Am. Chem. Soc. 1968, 90, 4734.
(6) The acidity of HNTf2 was found to be higher than that of HOTf in gas
phase (ref 6a), while the trend in H2O or AcOH is reversed (ref 6b). The
acidity of the two acids in ionic liquid is comparable (ref 6c). (a) Koppel,
I. A.; Taft, R. W.; Anvia, F.; Zhu S.; Hu, L.; Sung, K.; DesMarteau, D.
D.; Yagupolskii, L. M.; Yagupolskii, Y. L.; Ignat’ev, N. V.; Kondratenko,
N. V.; Volkonskii, A. Y.; Vlasov, V. M.; Notario, R.; Maria, P. J. Am.
Chem. Soc. 1994, 116, 3047. (b) Foropoulus, J.; DesMarteau, D. D. Inorg.
Chem. 1984, 23, 3720. (c) Thomazeau, C.; Olivier-Bourbigou, H.; Magna,
L.; Luts, S.; Gilbert, B. J. Am. Chem. Soc. 2003, 125, 5264.
functional group compatibility of the present method to the use of
silyl protecting groups. While a range of 1,5-diynes efficiently
participated in the cyclization process, subjection of the corre-
sponding 1-siloxy-1,6-diynes to HNTf2 afforded a complex product
mixture under the current conditions.
Our mechanistic analysis is presented in Scheme 2. The reaction
begins by protonation of the more electron-rich siloxy alkyne
terminus of diyne A. Attack of the other alkyne moiety onto the
resulting ketenium ion B leads to the 5-endo-dig cyclization,
furnishing alkenyl cation C.9 Subsequent reaction of alkenyl cation
with the halocarbon results in the cleavage of the R-X bond,10
presumably via the intermediacy of halonium ion D.5c We believe
-
that low nucleophilicity of NTf2 is uniquely responsible for
efficient generation and interception of highly reactive cationic
intermediates B and C. Subsequent protodesilylation of silyl dienol
ether E affords the observed halo enone F. While protodesilylation
of E proceeds competitively with the initial protonation of siloxy
alkyne A, silyl dienol ether E can be detected or isolated as an
exclusive reaction product by conducting the reaction with 20-
30 mol % of HNTf2, or by subjecting a diyne to 110 mol % of
HNTf2, followed by treatment with Et3N.11
Interestingly, subjection of diyne 1 to HNTf2 in benzene afforded
tetrasubstituted enone 14 (eq 1) as a single alkene isomer
(dr > 97:3). The outcome of this experiment can be rationalized
by the interception of alkenyl cation C by benzene, demonstrating
that this newly developed concept can be applied to a range of
nucleophiles.
(7) For HNTf2-promoted reactions, see: (a) ref 6b. (b) Kuhnert, N.; Peverley,
J.; Roberston, J. Tetrahedron Lett. 1998, 39, 3215. (c) Ishihara, K.;
Hiraiwa, Y.; Yamamoto, H. Synlett 2001, 1851. (d) Cossy, J.; Lutz, F.;
Alauze, V.; Meyer, C. Synlett 2002, 45. (e) Inanaga, K.; Takasu, K.; Ihara,
M. J. Am. Chem. Soc. 2005, 127, 3668. (f) Zhang, Y.; Hsung, R. P.; Zhang,
X.; Huang, J.; Slafer, B. W.; Davis, A. Org. Lett. 2005, 7, 1047.
(8) Reactions of diyne 1 with CSA and HCl afforded siloxy ester and acid
chloride respectively as shown below.
(9) For comprehensive monographs on the reactivity of alkenyl cations, see:
(a) Stang, P. J.; Rappoport, Z. Dicoordinated Carbocations; Academic
Press: New York, 1997. (b) Stang, P. J.; Rappoport, Z.; Hanack, M.;
Subramanian, L. B. Vinyl Cations; Academic Press: New York, 1979.
(10) We were able to observe BrCH2OMe by GC/MS by conducting the
reaction in the presence of MeOH, which is evident of the generation of
CH2X cations in the reaction mixture.
(11) The second proton required for complete protodesilylation of E may
originate from traces of water that are present in the reaction mixture.
Indeed, the use of 2 equiv of HNTf2 does not alter the efficiency of the
reaction.
In closing, we have developed the first HNTf2-promoted 5-endo-
dig cyclizations of 1-siloxy-1,5-diynes featuring chemoselective
activation of the electron-rich siloxy alkyne moiety and an unusual
halide abstraction by the intermediate alkenyl cation. In addition
to enabling rapid and diastereoselective assembly of a range of
substituted â-halo enones, this process provides another demonstra-
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