Conjugate addition of allyl stannanes with concomitant triflation

Article abstract of DOI:10.1021/ol702996t

A new method for the conjugate addition of allyltributylstannane with concomitant triflation is described. This reaction works with functionalized enones, enals, enoates, and vinylogous esters. The resulting vinyl triflates can be used for intramolecular Heck reactions to afford the products of 5-exo-trig cyclization.

Full text of DOI:10.1021/ol702996t

ORGANIC
LETTERS
2008
Vol. 10, No. 5
869-872
Conjugate Addition of Allyl Stannanes
with Concomitant Triflation
Ellen D. Beaulieu, Leah Voss, and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley,
Berkeley, California 94720-1460
trauner@berkeley.edu
Received December 12, 2007
ABSTRACT
A new method for the conjugate addition of allyltributylstannane with concomitant triflation is described. This reaction works with functionalized
enones, enals, enoates, and vinylogous esters. The resulting vinyl triflates can be used for intramolecular Heck reactions to afford the products
of 5-exo-trig cyclization.
Multicomponent C-C bond-forming reactions are becoming
more common in synthetic chemistry as the desire for step
Scheme 1. Reactions Involving Allyl Trifloxy Cations
economy increases.1 The design of these reactions requires
a careful balance between reactivity and compatibility of the
components while aiming to generate complexity without
prefunctionalization. In our continuing interest in the reactiv-
ity of the allylic trifloxy cation, we have developed a new
multicomponent reaction that yields allylated vinyl triflates
from enones under mild conditions.
Triflic anhydride is a valuable reagent for the electrophilic
activation of simple carbonyl compounds.2 Recently, we
demonstrated that the activation of enones with triflic an-
hydride can produce an allylic trifloxy cation, which can
subsequently undergo several new transformations (Scheme
1).3 If this reactive intermediate is generated in the absence
of a suitable nucleophile, deprotonation will afford a mixture
of dienes.3b If instead it is generated in the presence of an
electron-rich arene, nucleophilic attack of the arene is
competitive with deprotonation, and Friedel-Crafts triflation
adducts can be isolated in good yield.3a,b The treatment of
aryl vinyl ketones with triflic anhydride can afford a trifloxy
pentadienyl cation capable of undergoing a Nazarov triflation.3c
To expand the scope of C-C bond-forming triflations, we
(1) Multicomponent Reactions; Zhu, J., Bienyame´, H., Eds.; Wiley
VCH: Weinheim, 2005.
(2) Barazenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron
investigated alternative nucleophiles. Suitable candidates
would exhibit comparable nucleophilicity to electron-rich
arenes, which are viable nucleophiles for intermolecular
Friedel-Crafts triflations.3b Furthermore, the nucleophile
should exhibit low basicity such that the nucleophilic addition
is competitive with deprotonation. It also must selectively
2000, 56, 3077-3119.
(3) (a) Grundl, M. A.; Trauner, D. Org. Lett. 2006, 8, 23-25. (b) Grundl,
M. A.; Kaster, A.; Beaulieu, E. D.; Trauner, D. Org. Lett. 2006, 8, 5429-
5432. (c) Liang, G.; Xu, Y.; Seiple, I. B.; Trauner, D. J. Am. Chem. Soc.
2006, 128, 11022-11023.
10.1021/ol702996t CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/31/2008

Table 1. R,â-Unsaturated Ketones Employeda
a Reagents and reaction conditions: enone (1 equiv), DTBP (1.5 equiv), stannane (1.2 equiv), 4 Å molecular sieves (100 mg/mmol enone), and triflic
anhydride (1.2 equiv) in a 2:1 acetonitrile/methylene chloride mixture at 0 °C. b Yields are given for isolated products.
react with the allylic trifloxy cation in the presence of other
electrophiles such as triflic anhydride. With these consider-
ations in mind, we selected allyltributylstannane. The Mayr
scales for nucleophilicity indicated that this reagent exhibits
comparable nucleophilicity to electron-rich arenes.4 Also,
previous studies illustrated that this nucleophile was compat-
ible with silyl triflate activation of enones,5 making allyl-
tributylstannane an attractive candidate for use with triflic
anhydride activation.
One problematic aspect of this reaction concerned the
sequestration of tin residues upon workup. Among a host of
papers concerning the removal of tin residues,7 we found
that alkaline workups prior to column chromatography were
critical to the facile separation of tin byproducts.8 Treatment
of the reaction mixture with aqueous sodium hydroxide
hydrolyzed residual triflic anhydride, neutralized triflic acid,
sequestered tin residues, and was crucial to the isolation of
triflation adducts in high yield.
To develop our new method, we selected enone 1a as the
model substrate. Enone 1a possess a phenyl group in the
â-position capable of resonance stabilization of the carboca-
tion, an advantageous characteristic in triflic anhydride
activation. After screening a number of solvents, additives,
and workup procedures, standard conditions were deter-
mined.6 All reactions were run in a 2:1 mixture of acetoni-
trile/methylene chloride in the presence of 2,6-di-tert-
butylpyridine (DTBP) and 4 Å molecular sieves at 0 °C.
Table 1 shows the results from reactions with a number
of substituted enones. Substrates 1a,b were prepared from
(4) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-
77.
(5) (a) Kim, S.; Lee, J. M. Synth. Commun. 1991, 21, 25-29. (b)
Kamenecka, T. M.; Overman, L. E. Tetrahedron Lett. 1994, 35, 4279-
4282. (c) Paterson, I.; Steven, A.; Luckhurst, C. A. Org. Biomol. Chem.
2004, 2, 3026-3038. (d) Gotchev, D. B.; Comins, D. L. J. Org. Chem.
2006, 71, 9393-9402. (e) Miller, K. A.; Martin, S. F. Org. Lett. 2007, 9,
1113-1116.
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Org. Lett., Vol. 10, No. 5, 2008

Scheme 2. Intramolecular Heck Cyclizations of Allylated
Table 2. Employing Alternative R,â-Unsaturated Carbonyl
Compoundsa
Vinyl Triflates
the absence of resonance stabilization. When pulegone (1l)
was subjected to the reaction, vinyl triflate 2l possessing an
all carbon quaternary center was isolated in good yield.
Next, we attempted to expand the scope of the reaction
by varying the type of carbonyl compound employed. To
this end, we treated enals, enoates, enamides, and vinylogous
esters to the optimized reaction conditions with varying
degrees of success (Table 2). Enal 1m11 underwent allylative
triflation in high yield. Vinyl triflate 2m was isolated as a
single olefin isomer, as assessed by NOESY correlation data
(see Supporting Information). Commercially available cou-
marins 3a,b also performed well in the reaction.12
While linear enoates such as methyl R-methylcinnamate
yielded a complex mixture of products, the conformationally
restricted enoate 3c13 proved a viable substrate for our
method. By contrast, no products from enamides such as 5
were isolable. Perhaps the most unusual result in this series
was the successful allylation of vinylogous ester 6 to generate
the â-alkoxy vinyl triflate 7. Such allylation with concomitant
regioselective installation of the vinyl triflate would be
challenging via conventional cuprate chemsitry due to facile
â-elimination of the alkoxy substituent. The use of triflic
anhydride circumvents the formation of the problematic
metallo enolate intermediate.
a Reagents and reaction conditions: enone (1 equiv), DTBP (1.5 equiv),
stannane (1.2 equiv), 4 Å molecular sieves (100 mg/mmol enone), and triflic
anhydride (1.2 equiv) in a 2:1 acetonitrile/methylene chloride mixture at 0
°C. b Yields are given for isolated products.
the corresponding vinylogous ester.9 Substrates 1c-k were
prepared according to a procedure developed by Strauss and
co-workers for ionic liquid-mediated aldol condensation.10
From Table 1, it is apparent that â-aryl-substituted enones
undergo the reaction in good to excellent yields. These are
robust substrates presumably due to their ability to stabilize
the developing positive charge in the allylic tifloxy cation.
This stabilization can be enhanced by the introduction of
electron-donating substituents on the aromatic ring (substrates
1b, 1d,e) which lend modest increases in yield. Ortho
substitution is tolerated (substrates 1f,g). Other electron-rich
arenes such as the substituted furan in enone 1h also are
suited for charge stabilization and perform well in the
reaction. Gratifyingly, electron-deficient arenes also exhibit
adequate stabilization without a severe decrease in yield.
Electron-withdrawing substituents in the para position (sub-
strates 1i-k) are compatible. The reaction also proceeds in
Vinyl triflates can be used in a host of transition metal-
mediated reactions.14 Indeed, vinyl triflates 2c-l and 4c
represent viable substrates for an intramolecular Heck
reaction. Treatment of 2e with Pd(OAc)2 in the presence of
(11) Desmond, R.; Mills, S. G.; Volante, R. P.; Shinkai, I. Tetrahedron
Lett. 1988, 29, 3895-3898.
(12) These compounds were isolated using a fluoride workup as described
in the Supporting Information.
(13) (a) Jackson, J. A.; Hammond, G. B.; Wiemer, D. F. J. Org. Chem.
1989, 54, 4750-5754. (b) Hutton, T. K.; Muir, K. W.; Procter, D. J. Org.
Lett. 2003, 5, 4811-4814.
(14) Ritter, K. Synthesis 1993, 735-762.
(6) Full details of reaction optimization can be found in the Supporting
Information.
(7) Davies, A. G. Organic Synthesis: Tin/Lithium Transmetallation, the
Stille Reaction, and the Removal of Tin Residues. In Organotin Chemistry,
2nd ed.; Wiley-VCH: Weinheim, 2004; pp 373-382 and the references
therein.
(15) For recent examples of ketene acetal triflates in cross-coupling
reactions, see: Stille: (a) Nicolaou, K. C.; Pihko, P. M.; Bernal, F.;
Frederick, M. O.; Qian, W.; Uesaka, N.; Diedrichs, N.; Hinrichs, J.; Koftis,
T. V.; Loizidou, E.; Petrovic, G.; Rodriquez, M.; Sarlah, D.; Zou, N. J.
Am. Chem. Soc. 2006, 128, 2244-2257. Suzuki: (b) Sasaki, M.; Fuwa,
H.; Inoue, M.; Tachibana, K. Tetrahedron Lett. 1998, 39, 9027-9030. (c)
Bartali, L.; Larini, P.; Guarna, A.; Occhiato, E. G. Synthesis 2007, 1733-
1737. Negishi: (d) Kadota, I.; Takamura, H.; Sato, K.; Yamamoto, Y.
Tetrahedron Lett. 2001, 42, 4729-4731. (e) Kadota, I.; Kadowaki, C.;
Takamura, H.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 6199-6202. (f)
Kadota, I.; Takamura, H.; Sato, K.; Yamamoto, Y. J. Org. Chem. 2002,
67, 3494-3498.
(8) Renaud, P.; Lacoˆte, E.; Quaranta, L. Tetrahedron Lett. 1998, 39,
2123-2126.
(9) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 6797-6798.
(10) Kreher, U. P.; Rosamilia, A. E.; Raston, C. L.; Scott, J. L.; Strauss,
C. R. Org. Lett. 2003, 5, 3107-3110.
Org. Lett., Vol. 10, No. 5, 2008
871

K2CO3 and 1,2-bis(diphenylphosphino)ethane (dppe) af-
forded the product of 5-exo-trig cyclization, 8, in good yield
(Scheme 2). While triflates formed from ester carbonyl
compounds have been utilized in a variety of transition metal-
mediated cross-coupling reactions,15 they have been un-
derutilized in Heck-type reactions. Treatment of 4c under
the same reaction conditions afforded the product of 5-exo-
trig cyclization, 9, in good yield.
chemistry to alternative classes of nucleophiles and a more
detailed study of the operative mechanisms in triflic anhy-
dride activation are areas of ongoing investigation.
Acknowledgment. Financial support by Novartis and the
Alfred P. Sloan Foundation is gratefully acknowledged.
E.D.B. thanks the National Science Foundation for a Gradu-
ate Research Fellowship.
Supporting Information Available: Spectroscopic and
analytical data for compounds 1f-h, k, 2a-m, 3c, 4a-c,
5, 7-9. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have presented an operationally simple
conjugate allyl addition with concomitant triflation. The
reaction proceeds under essentialy neutral conditions and
works well with certain substrates that would perform poorly
with conventional cuprate chemistry. Extension of this
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