Platinum(II)-catalyzed cyclizations forming quaternary carbon centers, using enesulfonamides, enecarbamates, or enamides as nucleophiles

Article abstract of DOI:10.1021/ol062939g

(Chemical Equation Presented) Cyclic enesulfonamides, enecarbamates, or enamides tethered to an alkyne cyclize readily with use of platinum(II) chloride. This reaction generates quaternary-substituted carbon centers within simple spiro-fused or more compl

Full text of DOI:10.1021/ol062939g

ORGANIC
LETTERS
2007
Vol. 9, No. 2
367-370
Platinum(II)-Catalyzed Cyclizations
Forming Quaternary Carbon Centers,
Using Enesulfonamides, Enecarbamates,
or Enamides as Nucleophiles
Tyler J. Harrison, Brian O. Patrick,† and Gregory R. Dake*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia,
VancouVer, British Columbia, Canada, V6T 1Z1
gdake@chem.ubc.ca
Received December 4, 2006
ABSTRACT
Cyclic enesulfonamides, enecarbamates, or enamides tethered to an alkyne cyclize readily with use of platinum(II) chloride. This reaction
generates quaternary-substituted carbon centers within simple spiro-fused or more complex tri- and tetracyclic heterocyclic ring systems. The
yields for this process range from 50% to 83%.
Additions of carbon-based nucleophiles to activated C-C
π systems are of fundamental importance in synthetic organic
chemistry. Classically, this process is facilitated by the use
of electron-deficient acceptors (enones, ynones, enoates, etc.).
Recent intense study has examined the activation of C-C
π-systems toward nucleophilic attack with use of catalytic
amounts of metal salts.1 Important examples of this reac-
tivity paradigm forming C-C bonds include the addition
of â-dicarbonyl compounds (Conia-ene),2 enol silyl ethers,3
allylsilanes or allylstannanes,4 and functionalized indoles5
to alkynes or alkenes activated by electrophilic metal salts.
In each of these cases, quite reactive π-nucleophiles are
used.
In the context of developing reactions suitable for the
synthesis of ring skeletons related to structurally complex
alkaloids, our group has been studying the use of enecar-
bamate and enesulfonamide (N-carbamoyl or N-sulfonyl
enamines) functional groups as pronucleophiles in metal-
catalyzed reactions.6 The use of these enamine deriVatiVes
as π-nucleophiles in the metal-catalyzed formation of
(4) (a) See ref 1b. (b) Ferna´ndez-Rivas, C.; Me´ndez, M.; Nieto-
Oberhuber, C.; Echavarren, A. M. J. Org. Chem. 2002, 67, 5197-5201.
(c) Mart´ın-Matute, B.; Bun˜uel, E.; Mendez, M.; Nieto-Oberhuber, C.;
Ca´rdenas, D. J.; Echavarren, A. M. J. Organomet. Chem. 2003, 687, 410-
419. (d) Asao, N.; Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 1999,
121, 3797-3798. (e) Yoshikawa, E.; Gevorgyan, V.; Asao, N.; Yamamoto,
Y. J. Am. Chem. Soc. 1997, 119, 6781-6786. (f) Asao, N.; Yoshikawa, E.;
Yamamoto, Y. J. Org. Chem. 1996, 61, 4874-4875. (g) Asao, N.;
Matsukawa, Y.; Yamamoto, Y. Chem. Commun. 1996, 1513-1514. (h)
Matsukawa, Y.; Asao, N.; Kitahara, H.; Yamamoto, Y. Tetrahedron 1999,
55, 3779-3790.
(5) (a) Liu, C.; Widenhoefer, R. A. Chem. Eur. J. 2006, 12, 2371-2382.
(b) Han, X.; Widenhoefer, R. A. Org. Lett. 2006, 8, 3801-3804. (c) Liu,
C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126,
3700-3701. (d) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126,
10250-10251.
† Professional Officer: UBC X-ray Structural Laboratory.
(1) (a) Me´ndez, M.; Mamane, V.; Furstner, A. Chemtracts 2003, 16,
397-425. (b) Me´ndez, M.; Echavarren, A. M. Eur. J. Org. Chem. 2002,
15-28. (c) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215-236. (d)
Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382.
(2) (a) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem.,
Int. Ed. 2004, 43, 5350-5352. (b) Kennedy-Smith, J. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526-4527. (c) Kuninobu, Y.;
Kawata, A.; Takai, K. Org. Lett. 2005, 7, 4823-4825. (d) Corkey, B. K.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168-17169. (e) Gao, Q.;
Zheng, B.-F.; Li, J.-H.; Yang, D. Org. Lett. 2005, 7, 2185-2188.
(3) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.;
Lalonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991-5994.
(6) (a) Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023-5026. For
an example of a cyclization of an ene-yne sulfonamide: (b) Marion, F.;
Coulomb, J.; Courillon, C.; Fensterbank, L.; Malacria, M. Org. Lett. 2004,
6, 1509-1511. For a recent rhodium(I)-catalyzed process: (c) Kim, H.;
Lee, C. J. Am. Chem. Soc. 2006, 128, 6336-6337.
10.1021/ol062939g CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/16/2006

quaternary-substituted carbon atoms represents an impor-
tant, yet unexplored, challenge. In considering a 3-substituted
piperidene derivative of general structure a (Scheme 1), it
Scheme 2. Evaluation of Metal Salts for Cyclization
Scheme 1
was envisioned that addition of an electrophilic metal species
would activate the alkyne toward nucleophilic attack to give
intermediate b. In this instance, an additive would be
necessary to (a) intercept the putative intermediary azacar-
benium ion and (b) provide a means by which to protonate
the organometallic intermediate and “turn over” the catalytic
metal species.7 It was reasoned that an alcohol could serve
both roles. The products thus formed would be hemiaminals
of general structure c. Presumably, compounds such as c
could be further processed synthetically as required. This
speculative reaction, as written, would form a heteroatom-
containing spirocyclic ring system through the construction
of a quaternary substituted carbon atom.8 A singular example
recently published by the Toste group using a silyl enol ether-
based substrate prompts us to disclose our results.3 This
report describes our successful investigations using ene-
sulfonamides and structurally related compounds in metal-
catalyzed reactions forming quaternary carbon centers.
Our investigation began by subjecting enesulfonamide 1
to a set of electrophilic metal salts (Scheme 2). In initial
experiments the desired cyclization took place, but we found
the characterization of diastereomeric hemiacetal products
(cf. c, Scheme 1) awkward. A one-pot cyclization-reduction
sequence was developed to resolve that problem. In these
experiments, 1 was treated with a metal salt (5 mol %) and
2 equiv of methanol in toluene (0.1 M). With the starting
material consumed, the reaction mixture was cooled to room
temperature and 1.2 equiv of triethylsilane followed by 1.0
equiv of BF3‚OEt2 was added.9 This second step removed
the hemiaminal functionality, making characterization of the
reaction products simpler. Of the metal salts surveyed, the
use of platinum chloride as a catalyst resulted in the
formation of 2 as a single isomer in 80% yield.10 Interest-
ingly, a 1:1 mixture of platinum chloride and silver triflate
enabled the complete formation of (or complete isomerization
to) compound 3 in 80% yield.11 Other silver salts were less
effective.12 The selective migration process proved advanta-
geous as compound 3 could be converted in a few steps to
a mixture of nitramine and isonitramine (Scheme 3).13
A
Scheme 3. Conversion of 3 to Isonitramine and Nitramine
concerted effort to optimize reaction yields or diastereose-
lectivities in this synthesis was not undertaken. Finally, the
use of a cationic gold catalyst in the cyclization of 1 was
briefly examined. This catalyst is very active, allowing the
reaction typically run at 50-80 °C to be performed at room
temperature in high yield (92%). Unfortunately, both isomers
2 and 3 were obtained. Consequently, the conditions with
platinum chloride became our standard.
(10) No reaction was observed when compound 1 was treated with either
hydrochloric acid or trifluoroacetic acid.
(7) (a) Charruault, L.; Michelet, V.; Taras, R.; Gladiali, S.; Geneˆt, J.-P.
Chem. Commun. 2004, 850-851. (b) Nevado, C.; Charruault, L.; Michelet,
V.; Nieto-Oberhuber, C.; Mun˜oz, M. P.; Me´ndez, M.; Rager, M.-N.; Geneˆt,
J.-P.; Echavarren, A. M. Eur. J. Org. Chem. 2003, 706-713. (c) Me´ndez,
M.; Mun˜oz, M. P.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am.
Chem. Soc. 2001, 123, 10511-10520. (d) Me´ndez, M.; Mun˜oz, M. P.;
Echavarren, A. M. J. Am. Chem. Soc. 2000, 122, 11549-11550.
(8) For reviews, see: (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369-
396. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5363-5367. (c) Denissova, I.; Barriault, L. Tetrahedron 2003, 59,
10105-10146. (d) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001,
40, 4591-4597.
(11) For previous use of mixtures of platinum salts with silver trifluo-
rosulfonate, see: (a) Ghosh, A. K.; Matsuda, H. Org. Lett. 1999, 1, 2157-
2159. (b) Pignat, K.; Vallotto, J.; Pinna, F.; Strukul, G. Organometallics
2000, 19, 5160-5167. (c) Jia, B.; Lu, W.; Oyamada, J.; Kitamura, T.;
Matsuda, K.; Irie, M.; Fujiwara, Y. J. Am. Chem. Soc. 2000, 122, 7252-
7263. (d) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara,
Y. Science 2000, 287, 1992-1995. (e) Fu¨rstner, A.; Voigtla¨nder, D.;
Schrader, W.; Giebel, D.; Reetz, M. T. Org. Lett. 2001, 3, 417-420. (f)
Oyamada, J.; Kitamura, T. Tetrahedron 2006, 62, 6918-6925.
(12) Either AgPF6 or AgSbF6 with platinum salts resulted in mixtures.
(13) (a) Alonso, E. R.; Tehrani, K. A.; Boelens, M.; De Kimpe, N. Synlett
2005, 1726-1730. (b) Deyine, A.; Poirier, J.-M.; Duhamel, L.; Duhamel,
P. Tetrahedron Lett. 2005, 46, 2491-2493.
(9) Yamazaki, H.; Horikawa, H.; Nishitani, T.; Iwasaki, T. Chem. Pharm.
Bull. 1990, 38, 2024-2026.
368
Org. Lett., Vol. 9, No. 2, 2007

With the standard conditions established, a survey of
reaction scope was undertaken (Scheme 4). Both five- and
Scheme 5. Arylalkynes Generate Tetracycles
Scheme 4. Evaluation of Heterocycle Scope
Cyclization of compound 16c having an electron-donating
methoxy function on the arene ring gave a 65% yield of 17c
and 18c in 19:1 ratio. Replacing this donating group with
an electron-withdrawing function as with CF3 (in 16d) did
shift the reaction toward a “5-exo” mode of initial cyclization,
although not to a great extent (67%, 1:1 mixture of 17d:
18d).
Pleased by the efficient formation of quaternary carbon
atoms using this method, we recognized that this methodol-
ogy could provide an effective entry to alkaloid ring systems
structurally related to fawcettidine.15 Enamides 19a-d were
synthesized by condensing an appropriate amine with a
δ-ketoester precursor. The enamides were typically formed
as ∼3:1 mixtures of alkene isomers favoring the tetrasub-
stituted enamide. The ratio of inseparable alkene isomers
could not be manipulated further. In the event, subjecting
19a to 5 mol % of platinum chloride provided the desired
tricyclic ring system embedded within fawcettidine in 83%
yield (Scheme 6). In this case methanol is not required as
seven-membered heterocyclic substrates 4 and 5 participate
in the reaction, although the yield for the conversion of 5 is
moderate (entries a and b). As the p-toluenesulfonyl protect-
ing group can be difficult to remove, alternative functional
groups such as carbamates and amides were examined. tert-
Butyl and methyl carbamoyl enamines 6 and 7 cyclize
effectively in 69% and 73% yields, respectively (entries c
and d). Interestingly, the cyclization of 7 provided a 12.5:1
mixture of exocyclic alkene 12 and its structural isomer
(similar to 3). The reaction also proceeded smoothly with
use of alkynyl iodide 8, providing the synthetically useful
vinyl iodide 13 in 74% yield. The alkene stereochemistry of
13 was established by using X-ray crystallography. Enamide
14 also can be used in the platinum-catalyzed cyclization
reaction to give aminals 15 in 81% yield. Compounds 15
decomposed upon treatment with triethylsilane and BF3‚OEt2.
Interestingly, in examining substituent effects on the
alkyne, we found that capture of the intermediary azacar-
benium ion could be achieved using an internal nucleophile
in a Friedel-Crafts/Pictet-Spengler-type process (Scheme 5).14
Treatment of 16a, a compound having a 1-phenyl substituent
on the alkyne, with 10 mol % of PtCl2 gave a 4:1 mixture
of tetracycles 17a and 18a in 78% yield. These structures
were determined with X-ray crystallography. As the p-
toluenesulfonyl protecting group was expected to have steric
properties that should influence the regioselectivity of this
cyclization reaction, the cyclization of 16b was attempted.
Somewhat surprisingly, 16b gave a negligibly different
product distribution. Modification of the electronic properties
of the arene substituent proved to be more significant.
Scheme 6. Fawcettidine Model Studies
the azacarbenium ion generated from 19a can undergo proton
loss. Other substrates structurally related to 19a cyclized
efficiently with these conditions. Common protecting groups
such as benzyl and tert-butyldiphenylsilyloxy are compatible
with these reaction conditions. A noteworthy point is the
requirement for the addition of 10-20 mol % of 2,6-lutidine
and 2 equiv of methanol to the reaction of 19c (R )
CH2CH2CHdCH2). In the absence of these additional
reagents, significant amounts of byproducts that we suspect
(15) (a) Ishii, H.; Yasui, B.; Harayama, T.; Inubushi, Y. Tetrahedron
Lett. 1966, 7, 6215-6219. (b) Inubushi, Y.; Ishii, H.; Harayama, T.; Burnell,
R. H.; Ayer, W. A.; Altenkirk, B. Tetrahedron Lett. 1967, 8, 1069-1072.
(c) Burnell, R. H. J. Chem. Soc. 1959, 3091-3093.
(14) Another example of Friedel-Crafts trapping of an intermediate in
metal catalysis: Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am.
Chem Soc. 2005, 127, 6178-6179.
Org. Lett., Vol. 9, No. 2, 2007
369

arise from aza-Cope-aza-Prins sequences16 of the intermedi-
ary azacarbenium ion were observed. With the addition of
these reagents to the reaction of 19c, a 68% yield of 20c
was obtained.
In summary, platinum chloride is a useful catalyst for the
formation of quaternary carbon centers embedded within
simple spiro-fused and more complex tri- and tetracyclic
heterocyclic systems.17 In each of these examples, enamines
derivatized with an electron-withdrawing group serve as the
π nucleophile. The products obtained from these processes
should serve as useful intermediates in either the construction
of alkaloid natural products or, potentially, compounds
having “natural product-like structure” of interest to the
pharmaceutical industry. Further applications and explora-
tions of this methodology are underway in our laboratory.
Acknowledgment. The authors thank the University of
British Columbia, the Natural Science and Engineering
Research Council (NSERC) of Canada, the Canada Founda-
tion for Innovation (CFI), and Merck-Frosst and Glaxo
SmithKline for the financial support of our programs. T.J.H.
thanks NSERC for PGS A and PGS B graduate fellowships.
(16) (a) Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T.; McClure, M. S.;
Wang, Q. J. Org. Chem. 2002, 67, 5928-5937. (b) Overman, L. E. Acc.
Chem. Res. 1992, 25, 352-359.
(17) Representative procedure for cyclization reaction: To a flask
charged with 61 mg of 1 (0.20 mmol) and 2.7 mg of PtCl2 (0.01 mmol)
was added 2 mL of toluene followed by 17 µL of methanol (0.42 mmol)
and the reaction was stirred for 3 h at 80 °C before being cooled to rt. To
the resulting brown reaction mixture was added 49 µL of triethylsilane (0.31
mmol) followed by 26 µL of boron trifluoride diethyletherate (0.21 mmol)
and stirring was continued at rt for 30 min. The resulting black reaction
mixture was diluted with 5 mL of diethyl ether, filtered through a pipet of
silica gel, and concentrated by rotary evaporation in vacuo to afford a crude
brown oil. Purification of the crude material by column chromatography
on silica gel (8:1 hexanes:ethyl acetate) afforded 49 mg (80 %) of 2 as a
colorless film.
Supporting Information Available: Experimental pro-
cedures and characterization data for previously unreported
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL062939G
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Org. Lett., Vol. 9, No. 2, 2007