Rearrangement of alkynyl sulfoxides catalyzed by gold(I) complexes

Article abstract of DOI:10.1021/ja070789e

A series of gold(I)-catalyzed rearrangement reactions of alkynyl sulfoxides are reported. Homopropargylsulfoxides are rearranged to benzothiepinones or benzothiopines, while α-thioenones are formed in the reaction of propargylsulfoxides. The proposed mech

Full text of DOI:10.1021/ja070789e

Published on Web 03/20/2007
Rearrangement of Alkynyl Sulfoxides Catalyzed by Gold(I) Complexes
Nathan D. Shapiro and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received February 3, 2007; E-mail: fdtoste@berkeley.edu
Table 1. Au(I)-Catalyzed Rearrangement of Homopropargyl
Recently, gold-carbenoid species have been proposed as inter-
Sulfoxides
mediates in gold-catalyzed enyne rearrangements.1 Additionally,
the reaction of gold complexes with propargyl esters has been
developed as an alternative approach to metal carbenoids capable
of effecting olefin cyclopropanation;2,3 however, to date, the reaction
of electrophilic metals with alkynes has not been amenable to the
generation of R-carbonyl carbenoids analogous to those traditionally
formed in situ from transition-metal-catalyzed decomposition of
R-diazocarbonyl compounds.4,5 We recently described a rearrange-
ment of homopropargyl azides to pyrroles in which gold(I) promotes
addition of a leaving-group-bearing nucleophile (Nu ) N) to an
acetylene and subsequent loss of the leaving group (LG ) N2) (eq
1).6 On the basis of this reactivity principle, we envisioned that
R-carbonyl metal carbenoids could be generated from alkynes via
a gold(I)-catalyzed rearrangement in which sulfoxides serve the
role of nucleophile (Nu ) O) and latent leaving group (LG ) R2S).
a Conditions: (A) sulfoxide (0.2 M in CH2Cl2), 5% IMesAuCl, 5%
AgSbF6, rt; (B) sulfoxide (0.2 M in CH2Cl2), 5% Ph3PAuCl, 5% AgSbF6,
rt. b At 60 °C in dichloroethane with 5 Å sieves. c With 5 Å sieves.
In order to explore this hypothesis, homopropargyl sulfoxide 1
subsequent cycloisomerization of propargyl ketone 21 (eq 3).10
was treated with 5 mol % of Ph3PAuCl/AgSbF6 in dichloromethane.
Gratifyingly, this reaction produced 1-benzothiepin-4-one 3, pre-
sumably via the desired R-carbonyl carbenoid intermediate 2, albeit
in only 34% yield (eq 2). While switching to an electron-deficient
phosphine ligand resulted in a decreased yield, the use of an
N-heterocyclic carbene (IMes) ligated gold(I) complex as catalyst
dramatically improved the yield of ketone 3 to 94%. Under these
conditions, a wide range of homopropargyl arylsulfoxides under-
went the gold-catalyzed rearrangement to benzothiepinones (Table
1). The reaction proceeded smoothly when the aryl group of the
sulfoxide was substituted with electron-withdrawing (entry 1) or
electron-donating groups (entry 2), although the latter underwent
the gold-catalyzed rearrangement with increased yield. Substitution
at the homopropargyl (entry 3) and propargyl (entry 4) position of
the sulfoxide is tolerated; however, the latter required slightly
elevated temperatures to afford 11 in 76% yield. Notably, one
diastereomer (illustrated) of phenyl-substituted propargyl sulfoxide
(()-12 was significantly more reactive than the other in the gold-
(I)-catalyzed rearrangement, affording 13 in 94% yield (entry 5).7
The triphenylphosphinegold(I)-catalyzed reaction of a sulfoxide
(14) containing an alkyne substituted with an electron-deficient aryl
group8 (entry 6) or an ester (entry 7) produced the anticipated
benzothiepinones 15 and 17 in 63 and 91% yield, respectively. In
sharp contrast, the gold(I)-catalyzed reaction of alkyl-substituted
alkyne 18 afforded benzothiopine 19 in 64% yield (entry 8).9 On
the basis of this reaction, 1,4-diyne 20 was converted to furan 22
in 56% yield by a gold(I)-catalyzed sulfoxide rearrangement and
A proposed mechanism for the gold-catalyzed rearrangement of
homopropargyl sulfoxides is detailed in Scheme 1. Coordination
of cationic gold(I) to the alkyne induces nucleophilic addition of
the sulfoxide oxygen. When the alkyne is terminal or substituted
with an electron-withdrawing group, 5-exo-dig cyclization of the
nucleophile onto the internal carbon of the alkyne is favored,
yielding intermediate 23. On the other hand, when the alkyne is
substituted with an alkyl group, 25 is generated by a 6-endo-dig
cyclization. After cyclization, gold(I)-assisted sulfide release pro-
Scheme 1. Proposed Mechanism of Au-Catalyzed
Rearrangement
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10.1021/ja070789e CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654. (c) Luzung, M. R.;
Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858. (d)
Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442. (e) Lo´pez, S.;
Herrero-Go´mez, E.; Pe´rez-Gala´n, P.; Nieto-Oberhuber, C.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2006, 45, 6029. (f) Horino, Y.; Luzung,
M. R.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 11364. (g) Lee, J. H.;
Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 912. For a review, see: (h)
Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.
duces gold-carbenoid intermediate 24 or 26. The observation that
gold(I)-catalyzed rearrangement of sulfimine 27 proceeded in 88%
yield to furnish N-tosyl enamine 28 (eq 4) is consistent with the
proposal that the carbonyl oxygen in the product is transferred from
the sulfoxide. Finally, carbenoids 24 and 26 undergo intramolecular
Friedel-Crafts alkylation to produce the observed products and
liberate the cationic gold(I) catalyst.11-13
(2) For the reactions of Au-carbenoid intermediates generated from propargyl
esters, see: (a) Miki, K.; Ohe, K.; Uemura, S. J. Org. Chem. 2003, 68,
8505. (b) Fu¨rstner, A.; Hannen, P. Chem. Commun. 2004, 2546. (c)
Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
Soc. 2005, 127, 18002. (d) Ohe, K.; Fujita, M.; Matsumoto, H.; Tai, Y.;
Miki, K. J. Am. Chem. Soc. 2006, 128, 9270. (e) Gorin, D. J.; Dube, P.;
Toste, F. D. J. Am. Chem. Soc. 2006, 128, 14480.
(3) For generation and reactions of furylcarbenoid intermediates, see: (a) Miki,
K.; Nishino, F.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 5260.
(b) Miki, K.; Yokoi, T.; Nishino, F.; Kato, Y.; Washitake, Y.; Ohe, K.;
Uemura, S. J. Org. Chem. 2004, 69, 1557. For an excellent review, see:
(c) Miki, K.; Uemura, S.; Ohe, K. Chem. Lett. 2005, 34, 1068.
(4) For reviews, see: (a) Wee, A. G. H. Curr. Org. Synth. 2006, 3, 499. (b)
Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861. (c)
Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1. (d) Ye,
T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091. (e) Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Doyle M. P.,
McKervey, M. A., Ye, T., Eds.; Wiley: New York, 1998. (f) Metal-
Carbenes in Organic Synthesis; Zaragoza-Dorwald, F., Ed.; Wiley-
VCH: Weinheim, Germany, 1998.
(5) For gold-catalyzed reaction of R-diazoesters, see: (a) Fructos, M. R.;
Belderrain, T. R.; de Fre´mont, P.; Scott, N. M.; Nolan, S. P.; D´ıaz-Requejo,
M. M.; Pe´rez, P. J. Angew. Chem., Int. Ed. 2005, 44, 5284. (b) Fructos,
M. R.; de Fre´mont, P.; Nolan, S. P.; D´ıaz-Requejo, M. M.; Pe´rez, P. J.
Organometallics 2006, 25, 2237.
(6) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
11260.
Gold(I) complexes also catalyze the conversion of propargyl
sulfoxides to R-thioenones in high yields (eqs 5 and 6).14 In this
case, (dimethylsulfide)gold(I) chloride proved to be the optimal cata-
lyst,15 affording enones 31 from propargyl sulfoxides 29 with excel-
lent tolerance for substitution on the alkyne and the sulfoxide.
Additionally, secondary and tertiary propargyl sulfoxides react under
these conditions to provide trisubstituted (eq 6) and tetrasubstituted
alkenes.16 For example, sulfoxide 32 underwent gold(I)-catalyzed
rearrangement to enone 33 in preference to cycloisomerization of
the 1,5-enyne.1d In analogy to the mechanism described in Scheme
1, this rearrangement is postulated to proceed through gold(I)-
promoted sequential 5-endo-dig cyclization/cleavage of the S-O
bond leading to gold(I)-carbenoid intermediate 30 which undergoes
a 1,2-sulfide shift.17,18
(7) The less reactive diastereomer of (()-12 (characterized by X-ray crystal-
lography; see Supporting Information) proceeded to only 15% conversion
after reaction at 35 °C for 24 h.
(8) Under all conditions examined, the unsubstituted aryl derivative produced
only a trace of the desired benzothiepinones.
(9) The sulfone derivative of 19 was characterized by X-ray crystallography
(see Supporting Information).
(10) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem.,
Int. Ed. 2000, 39, 2285.
(11) (a) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993,
115, 8669. (b) Etkin, N.; Babu, S. D.; Fooks, C. J.; Durst, T. J. Org.
Chem. 1990, 55, 1093.
(12) An inverse secondary kinetic isotope effect of 0.96 was observed for
deuterated 34-d1. This is consistent with previously measured kinetic
isotope effects for Friedel-Crafts alkylations; for example, see: Nakane,
R.; Kurihara, O.; Takematsu, A. J. Org. Chem. 1971, 36, 2753. Similarly,
a KIE of 1.0 was found in the cyclization of 1-d1.
In conclusion, we have developed a series of gold(I)-catalyzed
rearrangements of alkynyl sulfoxides to benzothiepinones, benzo-
thiopines, or R-thioenones. The reactions are postulated to proceed
via an R-carbonyl gold-carbenoid intermediate formed through
oxygen atom transfer from the sulfoxide. Importantly, these inter-
mediates show reactivity (electrophilic aromatic substitution, 1,2-
thio migration) analogous to those generated from metal-promoted
decomposition of R-diazocarbonyl compounds. In a broader sense,
the reactions reported herein provide an entry into metal carbenoids
and support the importance of these intermediates in metal-promoted
rearrangement of alkynes. Further investigation into the mechanism
of these transformations and the nature of the intermediates is
ongoing.
(13) Homopropargyl sulfoxide 36, in which the ortho-positions of the aromatic
ring are substituted, rearranged to enone 37 via a proposed mechanism
involving a 1,2-H shift of the intermediate carbene.
(14) For the rearrangements of aryl propargylsulfoxides, see: (a) Majumdar,
K. C.; Thyagarajan, B. S. J. Chem. Soc., Chem. Commun. 1972, 83. (b)
Baudin, J.-B.; Julia, S. A.; Lorne, R. Synlett 1991, 509. (c) Majumdar, K.
C.; Ghosh, S. K. Tetrahedron Lett. 2002, 43, 2123.
(15) The use of cationic phosphinegold(I) complexes as catalysts led to
drastically reduced yields. The use of AuCl as a catalyst for reaction
conducted at high concentrations led to formation of dimer 38 along with
disulfide 39.
Acknowledgment. We gratefully acknowledge NIHGMS (R01
GM073932-01), Merck Research Laboratories, Bristol-Myers Squibb,
Amgen Inc., GlaxoSmithKline, Eli Lilly & Co., Pfizer, AstraZeneca,
Novartis, and Boehringer Ingelheim for funding.
(16) See Supporting Information for additional examples.
(17) For 1,2-thio migration of Rh(II) carbenes, see: Xu, F.; Shi, W.; Wang, J.
J. Org. Chem. 2005, 70, 4191.
(18) The lack of sulfide cross-over in the gold-catalyzed rearrangement of 27b
and 27c is consistent with an intramolecular sulfide shift.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) For recent examples involving Au-carbenoid intermediates in the
cycloisomerization of enynes, see: (a) Nieto-Oberhuber, C.; Mun˜oz, M.
P.; Bun˜uel, E.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2004, 43, 2402. (b) Mamane, V.; Gress, T.; Krause, H.;
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