C O M M U N I C A T I O N S
Table 2. Scope of the Carbene-Catalyzed â-Alkylation of Michael
To obtain insight into the origin of the difference in reactivity
between the carbene derived from 1 and a phosphine (see above),
we examined the deuterium-exchange process illustrated in eq 3.
Scrambling occurs to a large extent with 10% 1, whereas little
exchange is observed in the presence of PBu3.13
Acceptorsa
In conclusion, we have demonstrated that, for a range of Michael
acceptors, a nucleophilic catalyst can transiently transform the
normally electrophilic â carbon into a nucleophilic site through an
addition-tautomerization sequence. Specifically, we have estab-
lished that an N-heterocyclic carbene can catalyze â-alkylations of
a variety of R,â-unsaturated esters, amides, and nitriles that bear
pendant leaving groups. We anticipate that it will be possible to
exploit this intriguing umpolung reactivity in a variety of contexts.
Acknowledgment. Support has been provided by the NIH
(NIGMS, R01-GM62871 and R01-GM57034), the German Aca-
demic Exchange Service (postdoctoral fellowship to C.F.), a Robert
T. Haslam graduate fellowship (to S.W.S.), NSERC of Canada
(postdoctoral fellowship to D.A.P.), Merck Research Laboratories,
and Novartis. Funding for the MIT Department of Chemistry
Instrumentation Facility has been furnished in part by the NSF
(CHE-9808061 and DBI-9729592).
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
References
(1) For leading references, see: Powell, D. A.; Maki, T.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 510-511.
(2) For overviews of processes catalyzed by nucleophilic carbenes, see: (a)
Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506-7510. (b) Nair, V.;
Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130-5135.
(3) For a review of processes catalyzed by nucleophilic phosphines, see:
Methot, J. L.; Roush, W. R. AdV. Synth. Catal. 2004, 346, 1035-1050.
(4) For precedent in a more highly activated substrate, see: Enders, D.; Breuer,
K.; Teles, J. H.; Ebel, K. J. Prakt. Chem. 1997, 339, 397-399.
(5) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239-258. (b)
Umpoled Synthons; Hase, T. A., Ed.; Wiley: New York, 1987.
(6) For pioneering studies wherein addition of a catalyst to the carbonyl carbon
of an R,â-unsaturated aldehyde, followed by deprotonation of the aldehyde
proton, leads to nucleophilicity at the â position, see: (a) Burstein, C.;
Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205-6208. (b) Sohn, S.
S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370-
14371. Of course, this approach can be applied to R,â-unsaturated
aldehydes but not to esters, amides, or nitriles.
a Ar ) p-anisyl. b Isolated yield (average of two experiments). c 20% 1
was used, with dioxane as the solvent.
amines (entries 6-8) and phosphines (entries 9-10), including
PBu3, are essentially inactive as catalysts. With respect to the base,
Cs2CO3 affords a somewhat lower yield than anhydrous K3PO4
(entry 11), whereas KOt-Bu is not suitable (entry 12). Regarding
the solvent, 1,4-dioxane and EtOAc may be employed (entries 13
and 14), whereas N,N-dimethylacetamide may not (entry 15). The
reaction is sluggish at room temperature (entry 16), and no
cyclization is observed if the carbene precursor or the base is
omitted (entries 17 and 18).
We were pleased to determine that cyclizations of a range of
substrates proceed smoothly under our standard reaction conditions
(Table 2). With respect to the leaving group, not only bromides
(entry 1), but also tosylates (entry 2) and even chlorides (entry 3;
cf. eq 2), can be employed. Furthermore, R,â-unsaturated allyl esters
(entry 4), Weinreb amides (entry 5), and nitriles (entries 6 and 7)
cyclize with good efficiency. The method may be applied to the
synthesis of an oxygen heterocycle (entry 8), as well as six-
membered rings (entry 9). Interestingly, four-membered rings can
even be generated, albeit in modest yield (entry 10).12
(7) For leading references, see: Basavaiah, D.; Rao, A. J.; Satyanarayana, T.
Chem. ReV. 2003, 103, 811-892.
(8) In a study of the Stetter reaction, an undesired adduct arising from
reactivity at the â position of an R,â-unsaturated amide was produced in
up to 54% yield in the presence of 1.0 equiV of PBu3: Gong, J. H.; Im,
Y. J.; Lee, K. Y.; Kim, J. N. Tetrahedron Lett. 2002, 43, 1247-1251.
(9) (a) Krafft, M. E.; Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127, 10168-
10169. (b) Krafft, M. E.; Seibert, K. A.; Haxell, T. F. N.; Hirosawa, C.
Chem. Commun. 2005, 5772-5774.
(10) For reports of the parent carbene (Ar ) Ph), see: (a) Enders, D.; Breuer,
K.; Raabe, G.; Runsink, J.; Teles, J. H.; Melder, J.-P.; Ebel, K.; Brode, S.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1021-1023. (b) Enders, D.;
Balensiefer, T. Acc. Chem. Res. 2004, 37, 534-541. (c) See also:
Walentowski, R.; Wanzlick, H.-W. Z. Naturforsch., B: Chem. Sci. 1970,
25, 1421-1423.
(11) For an early study of electronic effects on a process catalyzed by
nucleophilic triazole-derived carbenes, see: Teles, J. H.; Melder, J.-P.;
Ebel, K.; Schneider, R.; Gehrer, E.; Harder, W.; Brode, S.; Enders, D.;
Breuer, K.; Raabe, G. HelV. Chim. Acta 1996, 79, 61-83.
(12) Notes: (a) An R,â-unsaturated phenyl ketone can be cyclized, but a
significant amount of the â,γ-unsaturated enone is produced. (b) We have
not yet been able to achieve efficient seven-membered ring formation or
intermolecular â-alkylation. (c) Substrates in which the olefin has a Z,
rather than an E, configuration cyclize less rapidly. (d) Under our standard
conditions, we have not been able to effectively cyclize R-substituted
enoates.
Clearly, tautomerization is a critical step in our proposed catalytic
cycle, leading to nucleophilicity at the â carbon (Figure 1, AfB).
(13) In a competition experiment between the alkyl bromide and the alkyl
chloride illustrated in entries 1 and 3 of Table 2, comparable reaction
rates were observed, consistent with the hypothesis that cyclization may
not be the turnover-limiting step for these substrates. In contrast, for the
homologous substrates (six-membered ring formation), the chloride is
essentially unreactive under the conditions in which the bromide cyclizes.
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