Mechanistically diverse copper-, silver-, and gold-catalyzed acyloxy and phosphatyloxy migrations: Efficient synthesis of heterocycles via cascade migration/cycloisomerization approach

Article abstract of DOI:10.1021/ja072446m

A set of cycloisomerization methodologies of alkynyl ketones and imines with concurrent acyloxy, phosphatyloxy, or sulfonyloxy group migration, which allow for the efficient synthesis of multisubstituted furans and N-fused heterocycles, has been developed

Full text of DOI:10.1021/ja072446m

Published on Web 07/21/2007
Mechanistically Diverse Copper-, Silver-, and Gold-Catalyzed
Acyloxy and Phosphatyloxy Migrations: Efficient Synthesis of
Heterocycles via Cascade Migration/Cycloisomerization
Approach
Todd Schwier, Anna W. Sromek, Dahrika M. L. Yap, Dmitri Chernyak, and
Vladimir Gevorgyan*
Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
Received April 7, 2007; E-mail: vlad@uic.edu
Abstract: A set of cycloisomerization methodologies of alkynyl ketones and imines with concurrent acyloxy,
phosphatyloxy, or sulfonyloxy group migration, which allow for the efficient synthesis of multisubstituted
furans and N-fused heterocycles, has been developed. Investigation of the reaction course by way of
employing 17O-labeled substrates allowed for elucidation of the mechanisms behind these diverse
transformations. It was found that, while the phosphatyloxy migration in conjugated alkynyl imines in their
cycloisomerization to N-fused pyrroles proceeded via a [3,3]-sigmatropic rearrangement, the analogous
cycloisomerization of skipped alkynyl ketones proceeds through two consecutive 1,2-migrations, resulting
in an apparent 1,3-shift, followed by a subsequent 1,2-migration through competitive oxirenium and
dioxolenylium pathways. Investigations of the 1,2-acyloxy migration of conjugated alkynyl ketones en route
to furans demonstrated the involvement of a dioxolenylium intermediate. The mechanism of cycloisomer-
ization of skipped alkynyl ketones containing an acyloxy group was found to be catalyst dependent; Lewis
and Brønsted acid catalysts caused an ionization/SN1′ isomerization to the allene, followed by cycloisomer-
ization to the furan, whereas transition metal catalysts evoked a Rautenstrauch-type mechanistic pathway.
Furthermore, control experiments in the cycloisomerization of skipped alkynyl ketones under transition metal
catalysis revealed that, indeed, these reactions were catalyzed by transition metal complexes as opposed
to Brønsted acids resulting from hydrolysis of these catalysts with eventual water. Further synthetic utility
of the obtained phosphatyloxy-substituted heterocycles was demonstrated through their efficient employment
in the Kumada cross-coupling reaction with various Grignard reagents.
Introduction
ingly, numerous methods have been developed for the assembly
of the furan and pyrrole ring,4,5 among which transition metal-
Furans and pyrroles are frequently occurring heterocyclic units
found in numerous naturally occurring and biologically active
molecules,1 and they find broad application as synthetic
intermediates2 and in the material sciences.3 Thus, not surpris-
catalyzed cycloisomerizations,6 perhaps, are the most general
and powerful approaches toward these heterocycles.
Recently, we reported the Cu-catalyzed cycloisomerization
of alkynyl imines and ketones to afford monocyclic and fused
pyrroles and furans.6n,p It was proposed that the alkynyl imine
or ketone 1 undergoes a base-assisted prototropic 1,3-H shift,
leading to allene 2 which, upon a copper-catalyzed cycloisomer-
ization, transforms into pyrrole or furan 3 (eq 1). This
(1) (a) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213. (b) Hou, X. L.; Yang,
Z.; Wong, H. N. C. In Progress in Heterocyclic Chemistry; Gribble, G.
W., Gilcrist, T. L., Eds.; Pergamon: Oxford, 2003; Vol. 15, p 167. (c)
Keay, B. A.; Dibble, P. W. In ComprehensiVe Heterocyclic Chemistry II;
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methodology, however, is limited to the synthesis of hetero-
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J. AM. CHEM. SOC. 2007, 129, 9868-9878
10.1021/ja072446m CCC: $37.00 © 2007 American Chemical Society

Cascade Migration/Cycloisomerization Mechanism
A R T I C L E S
cycles lacking substituents at the C-3 and C-4 positions, as the
hydrogen substituent at C-4 of heterocycle 3 arises from the
prototropic 1,3-H migration and H at C-3 comes from the
cycloisomerization of 2 to 3.
As a partial solution to this problem, we have recently
developed a set of methods for the synthesis of pyrroles and
furans 6 possessing a thio-6m or halogen6f substituent at C-3
of heterocycle. These novel transition metal-catalyzed cascade
transformations involve isomerization of 4 into allene 5,
followed by cycloisomerization of the latter into 6, during which,
a 1,2-shift of the thio- or halogen group occurs (eq 2). Aiming
allene 8, followed by its cycloisomerization to 9. In the latter
case, a prototropic rearrangement of 7 gives rise to allene 10,
which cycloisomerizes with concomitant 1,2-migration into
furan 11.
Herein, we describe a more detailed study of the scope and
mechanisms of different modes of cycloisomerization8 of
alkynyl ketones and cyclic imines proceeding with concurrent
migration of acyloxy and phosphatyloxy groups to produce
multisubstituted furans and fused pyrroles, together with the
synthetic application of the obtained heterocyclic phosphates
in Kumada cross-coupling reactions.
at expanding the scope of the migrating group (MG), we
explored the possibility of engaging a 1,3-migration of different
oxygen-based migrating groups, known to occur in propargyl/
allenyl systems via a [3,3]-sigmatropic shift.7 It was found,
however, that depending on the substitution pattern in 7 and/or
reaction conditions, different regioisomeric products 9 or 11
were formed (eq 3).6a It was reasoned that, in the former case,
the expected [3,3]-shift of the migrating group occurs to produce
Results and Discussion
Synthesis of Trisubstituted Heterocycles via [3,3]-Phos-
phatyloxy Migration in Conjugated Alkynyl Ketones and
Imines. Our initial attempts explored the possibility of engaging
a [3,3]-phosphatyloxy migration in alkynyl ketones 12 into 13
as an approach toward furans 14 (Scheme 1). To this end,
cycloisomerization of several phosphatyloxy alkynyl ketones9
was examined in the presence of CuCl (5 mol %) in DMA.
Since this transformation no longer involves a base-assisted
prototropic H shift, we tested this reaction in the absence of
amine. We were pleased to find that under these conditions the
cycloisomerization proceeded smoothly, furnishing the corre-
sponding furans 14a and 14b in good yield. Although CuCl
appeared to be a poor catalyst for the cycloisomerization of
phenyl-substituted 12c, we found that the employment of AgBF4
in dichloroethane at 80 °C gave the desired furan 14c in good
yield (Scheme 1).
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Scheme 1. Cascade [3,3]-Migration/Cycloisomerization of
Phosphatyloxy Alkynyl Ketones into Furans
a Run with 5 mol % AgBF4 in dichloroethane at 80 °C.
Next, we investigated the applicability of this approach for
the synthesis of phosphatyloxy-substituted indolizines 17 (Scheme
2). It was found that the cycloisomerization of alkynyl pyridines
15 under the same conditions proceeded uneventfully to furnish
the desired indolizines 17a-e in good to excellent yields. Of
(7) (a) Zhao, J.; Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
7436. (b) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442. (c)
Wang, S.; Zhang, L. Org. Lett. 2006, 8, 4585. (d) Wang, S.; Zhang, L. J.
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Soc. 2006, 128, 12614. (f) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804.
(g) Schlossarczyk, H.; Sieber, W.; Hesse, M.; Hansen, H.-J.; Schmid, H.
HelV. Chim. Acta 1973, 56, 875.
(8) Preliminary results of this work (Schemes 4, 8, and 9, Table 1, and portions
of Table 3) have been previously communicated (see ref 6h). All other
results described herein (Schemes 5-7, 10-16, Tables 2, 4, 5, and part of
Table 3) are new.
(9) See the Supporting Information for synthesis of starting materials.
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A R T I C L E S
Schwier et al.
Scheme 2. Cascade [3,3]-Migration/Cycloisomerization of
Scheme 4
Phosphatyloxy Alkynyl Pyridines into Indolizines
(Scheme 4). The same reaction in the presence of Et3N additive,
however, produced the other regioisomer, 23b, as a major
product. Intrigued by this finding, we decided to investigate
the latter transformation further, as it may provide access to
heterocycles of a different substitution pattern. Switching to
phenyl and tert-butyl alkynyl ketones resulted in increases in
both the yields and the regioselectivity of the products (Table
1). Thus, a series of alkynyl ketones 22 with different acyloxy
groups, under these reaction conditions, underwent smooth
cycloisomerization to produce acyloxy furans 23 in good to
excellent yields.
We propose the following plausible mechanisms to account
for the observed unusual regiochemistry of the cycloisomer-
ization products obtained (Scheme 5). The upper path A depicts
the formation of allene 25 from 24 via a base-assisted prototropic
shift which, upon metal activation of the carbonyl, forms
dioxolenylium species 26. Subsequent transformation of the
latter to furan 27 occurs by an intramolecular AdN-E process.12
Alternatively (path B), 24 could undergo a Rautenstrauch-type13
metal-assisted 1,2-acyloxy14 migration15 via dioxolenylium
species16 28 to give metal carbenoid 29. Intramolecular attack
of the ketone to give 30, followed by tautomerization, gives
furan 27. While, on the basis of our current studies, we cannot
rule out either mechanistic pathway, the prerequisite of base
for the selective formation of the observed regioisomer of furan
23b over 23a (Scheme 4) supports possible involvement of
allene intermediate 25.17
We hypothesized that the acyloxy group migration may also
proceed via a three-membered oxirenium species (Scheme 6),
analogously to sulfur and halogen group migrations reported
earlier.6f,m The involvement of either dioxolenylium (Scheme
5) or oxirenium (Scheme 6) motifs could be established through
reaction of a labeled substrate 24. While dioxolenylium-
involving pathways A and B both lead to the same isotopomer
27 (Scheme 5), a migration occurring via oxirenium intermedi-
ates (paths A′ and B′) would lead to a different isotopomer 29
(Scheme 6).
To test the above hypothesis, we synthesized 17O-enriched
339 and subjected it to the cycloisomerization conditions
(Scheme 7). The reaction was stopped at about 60% conversion.
NMR analysis indicated that the reaction resulted in the
formation of a 7:1 mixture of isotopomeric furans 34 and 35.
note, while the standard cycloisomerization of alkynyl imines
to give monosubstituted indolizines required 50 mol % Cu
salts,6p this novel cascade [3,3]-migration/cycloisomerization
protocol proceeded efficiently in the presence of 5 mol % of
CuCl only (Scheme 2).
It deserves mentioning that in both cases (Schemes 2 and 3)
we did not observe the intermediate allenes (13 and 16), which
supports their formation at the rate-limiting event. In an effort
to obtain a better understanding of the mechanism behind the
propargyl-allenyl isomerization and their subsequent transfor-
mation into heterocycles, we investigated the cycloisomerization
of phosphoryl oxygen [17O]-enriched alkynyl pyridine 18, the
labeled analogue of 15c (Scheme 3), by means of 17O NMR
spectroscopy.10 It was reasoned that if the isomerization indeed
proceeds via a [3,3]-sigmatropic shift, the oxygen label should
be located at the phosphate ester position in the intermediate
allene 19 and, thus, in the indolizine, as shown in 20.
Unsurprisingly, the NMR spectrum of the isolated indolizine
product displayed a broad signal at 71 ppm corresponding to
the bridging phosphate oxygen.11 Only traces of the phosphoryl
oxygen signal, resulting from formation of 21, were detected.
Thus, the selective formation of 20 strongly supports the
mechanistic rationale involving a propargyl-allenyl isomeriza-
tion proceeding via a sigmatropic [3,3]-phosphatyloxy shift
(Schemes 1-3).
Synthesis of Trisubstituted Furans via 1,2-Migration of
Acyloxy Group in Conjugated Alkynyl Ketones. Encouraged
by the successful development of conditions for the efficient
[3,3]-migration/cycloisomerization of phosphatyloxy-containing
propargyl ketones, we next turned our attention to the elabora-
tion of analogous transformations involving acyloxy systems.
Our initial attempts at migration/cycloisomerization were disap-
pointing. In the presence of catalytic CuCl, acetate 22a gave a
low yield of the expected cycloisomerization product 23a7 and
trace amounts of an unexpected regioisomeric product 23b
Scheme 3. Cycloisomerization of Labeled Phosphatyloxy Alkynyl Pyridine 18
9
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Cascade Migration/Cycloisomerization Mechanism
A R T I C L E S
Table 1. Cascade 1,2-Migration/Cycloisomerization of Acyloxy
Alkynyl Ketones 22 into Furans 23
successful cycloisomerization of various alkynyl ketones to
furans (vide supra), we proposed that a propargyl-allenyl
isomerization of isomeric propargyl ketone 36 via a [3,3]-
migration might provide access to allene 37, the fully substituted
analogue of 10 (eq 3), which, upon cycloisomerization with
subsequent 1,2-migration, would lead to fully substituted furan
38 (eq 4). Additionally, if successful, formation of allenyl
intermediate 37 would provide additional support for our
mechanistic proposal above (Scheme 5, path A).
First, we examined the potential migration of acyloxy group
in 39 (Y ) CR4) en route to tetrasubstituted furan 40. Our
optimization studies indicated that several metal salts are able
to efficiently catalyze this transformation (Table 2). While the
silver salts AgBF4 and AgOTf proved efficient for the cycloi-
somerization of tert-butyl-substituted 39b (entries 5 and 7), they
were less desirable for n-butyl-substituted 39a (entries 4 and
6). However, it was found that Cu(OTf)2 was effective for the
formation of n-butyl-substituted furan 40a (entry 1). AuCl3
t
n
worked reasonably well with both Bu- and Bu-substituted
substrates (entries 10 and 11). Interestingly, Lewis acids18 also
were effective in promoting this transformation (entries 13-
16). Remarkably, even Brønsted acid (HOTf) efficiently cata-
lyzed this transformation (entry 17).
Next, cycloisomerization of several differently substituted
propargyl acetates and pivaloates 39 under the optimized
a Run on 1.0 mmol scale.
(13) For Rautenstrauch-type 1, 2-acyloxy migrations, see: (a) Marion, N.; Nolan,
S. P. Angew. Chem., Int. Ed. 2007, 46, 2750. (b) Marion, N.; D´ıez-
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Int. Ed. 2006, 45, 3647. (c) Fehr, C.; Galindo, J. Angew. Chem., Int. Ed.
2006, 45, 2901. (d) Pujanauski, B. G.; Prasad, B. A. B.; Sarpong, R. J.
Am. Chem. Soc. 2006, 128, 6786. (e) Marco-Contelles, J.; Arroyo, N.;
Anjum, S.; Mainetti, E.; Marion, N.; Cariou, K.; Lemie´re, G.; Mourie´s,
V.; Festerbank, L.; Malacria, M. Eur. J. Org. Chem. 2006, 4618. (f) Faza,
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Additionally, it was found that the recovered starting material
showed no additional signals in the 17O spectrum, thus indicating
no scrambling during the reaction. Furthermore, resubmission
of the isolated furans to the reaction conditions did not result
in a discernible change in the ratio of 34:35, thus ruling out
possible scrambling of the product. These observations confirm
that the major product, furan 34, arises through either of the
mechanistic pathways outlined in Scheme 5, with migration
occurring via a dioxolenylium species. Formation of minor
product 35, however, is consistent with either of the two
mechanisms depicted in Scheme 6 or an irreversible ionization/
recombination to form the allene (see below, Scheme 11).
Synthesis of Tetrasubstituted Furans via a Cascade
Migration in Skipped Alkynyl Ketones. Encouraged by
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(11) For discussions on 17O NMR of phosphates in cyclic and biological systems,
see: (a) Tsai, M.-D.; Bruzik, K. In Biological Magnetic Resonance, Vol.
5; Berliner, L. J., Reuben, J., Eds.; Plenum Press: New York, 1983; Chapter
4, p 129. (b) Gordillo, B.; Eliel, E. L. J. Am. Chem. Soc. 1991, 113, 2172.
(c) Sopchik, A. E.; Cairns, S. M.; Bentrude, W. G. Tetrahedron Lett. 1989,
30, 1221. (d) Eliel, E. L.; Chandrasekaran, S.; Carpenter, L. E., II; Verkade,
J. G. J. Am. Chem. Soc. 1986, 108, 6651. (e) Sammons, R. D.; Frey, P. A.;
Bruzik, K.; Tsai, M.-D. J. Am. Chem. Soc. 1983, 105, 5455.
(16) (a) Allen, A. D.; Kitamura, T.; McClelland, R. A.; Stang, P. J.; Tidwell, T.
T. J. Am. Chem. Soc. 1990, 112, 8873. (b) Lorenz, W.; Maas, G. J. Org.
Chem. 1987, 52, 375.
(17) For base-assisted propargyl-allenyl isomerization, see refs 6h, 6n, 6p, and
(a) Sonye, J. P.; Koide, K. J. Org. Chem. 2006, 71, 6254. (b) Huang, J.;
Xiong, H.; Hsung, R. P.; Rameshkumar, G.; Mulder, J. A.; Grebe, T. P.
Org. Lett. 2002, 4, 2417.
(18) For Lewis acid-catalyzed substitution of acyloxy groups in propargyl
systems, see: (a) Netz, A.; Polborn, K.; No¨th, H.; Mu¨ller, T. J. J. Eur. J.
Org. Chem. 2005, 1823. (b) Schwier, T.; Rubin, M.; Gevorgyan, V. Org.
Lett. 2004, 6, 1999. (c) Mu¨ller, T. J. J. Eur. J. Org. Chem. 2001, 2021.
(12) See ref 6m for details.
9
J. AM. CHEM. SOC. VOL. 129, NO. 32, 2007 9871

A R T I C L E S
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Scheme 5. Proposed Mechanisms for Cycloisomerization of Acyloxy Alkynyl Ketones into Furans via Dioxolenylium Intermediates
Scheme 6. Alternative Mechanisms for Cycloisomerization of Acyloxy Alkynyl Ketones into Furans via Oxirenium Intermediates
Scheme 7. Cycloisomerization of 17O-Labeled Acyloxy Alkynyl
Ketone 33
Table 2. Optimization of Acyloxy Migration/Cycloisomerization
entry
R1
[M] (mol %)
solvent
yield 40, %a
1
2
3
4
5
6
7
8
9
nBu (a)
tBu (b)
nBu (a)
“
Cu(OTf)2 (5)
“
PdCl2(MeCN)2 (5)
AgBF4 (5)
“
AgOTf (5)
“
AgSb6 (5)
PtCl2 (5)
AuCl3 (5)
AuCl3 (5)
AuCl(PEt3) (5) +
AgPF6 (5)
TMSOTf (10)
Sn(OTf)2 (10)
Sc(OTf)3 (10)
Zn(OTf)2 (10)
HOTf (10)
PhMe
“
“
DCM
“
PhMe
“
“
“
“
“
“
78
66
72
50b
99
60
88
50
43
72
62
tBu (b)
nBu (a)
tBu (b)
nBu (a)
“
conditions was examined. It was found that the cascade
cycloisomerization of 39 proceeded smoothly to produce fully
substituted furan 40 in good to excellent yields (Table 3).
Noteworthy, lengthened reaction times were required for the
reaction of pivaloates as compared to the corresponding acetate
(entries 2 and 9 vs 1 and 8, respectively). As the TMS-
substituted alkyne function in 39i is incompatible with silver
salts,19 employment of AuCl3 gave the desired furan 40i in good
yield (entry 10). Remarkably, this cascade method allowed for
efficient synthesis of fused furan 40g (entry 7), bicyclic scaffold
inaccessible by our previous cycloisomerization techniques.6n
Next, we examined possible cascade involving migration of
phosphatyloxy group cycloisomerization (Scheme 8). It was
found that 41, in the presence of AgBF4 in dichloromethane at
room temperature, smoothly converted to allene 42, thus
providing evidence for the formation of allenyl intermediates
in the reaction.20 Subsequent treatment of the allene 42 with
10
11
12
tBu (b)
nBu (a)
“
complex mixture
13
14
15
16
17
tBu (b)
DCM
63
72
65
56
80
“
“
“
“
“
“
“
“
a NMR yield. b Run at 0 °C.
AgBF4 in dichloroethane at 60 °C afforded furan 43 in 77%
yield. Additionally, the latter conditions were effective for the
formation of furan 43 directly from the propargyl phosphate
41 (Scheme 8).
Aiming at expanding the scope of this transformation, we
examined the analogous transformation of propargyl tosylates
under similar reaction conditions. Unexpectedly, our attempts
to synthesize 44 led to the direct formation of tosyl allene 45
(19) Orsini, A.; Viterisi, A.; Bodlenner, A.; Weibel, J.-M.; Pale, P. Tetrahedron
Lett. 2005, 46, 2259.
(20) This is in contrast to the analogous acyloxy system where attempts at
isolation or independent preparation of the allenes failed.
9
9872 J. AM. CHEM. SOC. VOL. 129, NO. 32, 2007

Cascade Migration/Cycloisomerization Mechanism
A R T I C L E S
Thus, labeled acetate 529 was tested under several reaction
conditions proved efficient in catalyzing this transformation
(Table 4). When subjected to the CuCl/Et3N conditions, carbonyl
oxygen-labeled 53 was formed as a minor product, with the
major product being the ester oxygen-labeled 54 (entry 1). More
remarkably, reactions using AgBF4, AuCl3, or Cu(OTf)2 (entries
2, 3, and 4) gave 54 exclusively. Furthermore, the Lewis acids
Sn(OTf)2 and TMSOTf (entries 5 and 6) gave mixtures of nearly
equal amounts of isotopomers 53 and 54. Employment of the
Brønsted acid (TfOH, entry 7) also resulted in the formation of
a mixture of isotopomers (Table 4).21
Table 3. Sequential [3,3]/1,2-Acyloxy Migration/Cycloisomerization
In light of the recent observations that eventual Brønsted acids
are the true catalysts in some transition metal-catalyzed trans-
formations,22 we investigated what role, if any, Brønsted acids
may play in the herein described cycloisomerization reaction.23
To this end, in the test experiment, we examined the cycloi-
somerization of 39b in the presence of Brønsted base additive,
which is expected to quench eventual Brønsted acids which may
be present in the reaction media. It was found that hindered
base, 2,4,6-tri-tert-butylpyrimidine (TTBP),24 serves the pur-
pose: addition of 15 mol % of TTBP to a reaction mixture
containing 10 mol % TfOH completely shuts down the reaction,
which is otherwise complete in 6 h (Table 5, entry 1). With
this tool in hand, we then examined cycloisomerization of 39b
catalyzed by several transition metal catalysts in the presence
and absence of TTBP (entries 2-6). It was found that in all
cases, the reaction course was unaffected by the presence of
the base: the reactions with TTBP additive proceeded with rates
comparable to those lacking the base, thus ruling out possible
involvement of Brønsted acids in these transition metal-catalyzed
transformations. Moreover, it was found that the cycloisomer-
ization of 52 in the presence of Au catalyst and TTBP (Table
4, entry 8) did not change the isotopomeric distribution over
the base-free experiment (entry 3).
Based on the results of the labeling studies, we believe that
the cycloisomerization of acetates follows one of two mecha-
nistic pathways, depending on the catalyst. Transition metal
catalysts such as Ag(I), Au(III), and Cu(II) likely cause an initial
1,2-migration to form a metal carbenoid (Scheme 10, lower
path). Subsequent cycloisomerization of this intermediate then
provides the corresponding furan (Scheme 16). Alternatively,
with Lewis/Brønsted acid catalysts, such as TMSOTf, Sn(OTf)2,
and HOTf, or under high-temperature conditions, a partial
ionization of the propargyl acetate 36 to a propargylium/
allenylium cation25 occurs during which the 17O label is
scrambled, consistent with the observed mixture of isotopomers
53 and 54 (Schemes 10 and 11). To obtain additional support
for the ionization mechanism, we tested cycloisomerization of
a Run on 1.0 mmol scale. b Run on 0.5 mmol scale. c Run in toluene.
(Scheme 9). When subjected to AgBF4 in dichloroethane at
60 °C, allene 45 was smoothly converted to the tosyl-substituted
furan 46 in 82% yield.
Understandably, we were interested in establishing the
mechanism behind the cascade cycloisomerization in skipped
systems. From the outset, we postulated two general mechanisms
to explain the formation of furans from propargyl-substituted
ketones. The first operates via an allenyl intermediate 48 (or
37, as depicted in eq 4), whereas the second goes through
carbenoid species 50 (Scheme 10). If one of the oxygens in the
migrating group is selectively labeled, as in 47, it would be
possible to distinguish between the two mechanistic paths. Thus,
as depicted in the upper pathway, 47 first undergoes a [3,3]-
shift, with “inversion” of the labeled oxygen to form allene 48.
A subsequent 1,2-shift via a dioxolenylium species would result
in a second “inversion” to produce the YdO oxygen-labeled
furan 49. Alternatively, if 47 undergoes a 1,2-shift to form metal
carbenoid 50, the label would be located at the bridged oxygen
atom. The intramolecular nucleophilic attack and subsequent
cycloisomerization proceeds with no migration, so the label
would remain at the bridged oxygen position in the furan
product 51.
(21) Triflic acid was tested as a potential catalyst in the base-free reactions
depicted in Schemes 1 and 2 but failed to result in product formation.
(22) There has been a recent discussion on the role of Brønsted acids in
homogenous transition metal-catalyzed reactions. For the most relevant
references, see: (a) Hashmi, A. S. K. Catal. Today 2007, 122, 211. (b) Li,
Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett.
2006, 8, 4175. (c) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya,
M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179. (d) Rhee, J. U.; Krische, M. J.
Org. Lett. 2005, 7, 2493.
(23) The authors wish to acknowledge one of the referees, who brought our
attention to this possibility.
(24) For use of TTBP as a TfOH scavenger, see for example: Crich, D.;
Vinogradova, O. J. Org. Chem. 2006, 71, 8473.
(25) For discussions on propargyl/allenyl cations, see: (a) Olah, G. A.;
Krishnamurti, R.; Prakash, G. K. S. J. Org. Chem. 1990, 55, 6061. (b)
Olah, G. A.; Spear, R. J.; Westerman, P. W.; Denis, J.-M. J. Am. Chem.
Soc. 1974, 96, 5855.
9
J. AM. CHEM. SOC. VOL. 129, NO. 32, 2007 9873

A R T I C L E S
Schwier et al.
Scheme 8. Sequential Phosphatyloxy Migration/Cycloisomerization
Scheme 9. Sequential Tosyloxy Migration/Cycloisomerization
Table 5. Effect of Brønsted Base on Cycloisomerization with
Different Catalysts
% conversion of 39b
% conversion of 39b
(with TTBP)a,b
Scheme 10. Proposed Mechanisms for Sequential Migration/
Cycloisomerization of Labeled 47
entry
cat. (mol %)
(no base)a
1
2
3
4
5
6
TfOH (10)
100c
100e
100e
100e
100f
100e
<1d
100e
100e
100e
100f
100e
Cu(OTf)2 (5)
PdCl2(MeCN)2 (5)
AgOTf (5)
PtCl2 (5)
AuCl3 (5)
a Based on GC analysis. Yields comparable to those reported in Table
2. b 1.5 equiv (vs catalyst) of 2,4,6-tri-tert-butylpyrimidine (TTBP) added.
c Reaction complete after 6 h. d Reaction checked after 24 h. e Reaction
complete within 30 min. f Reaction complete within 3.5 h.
Scheme 11. Proposed Mechanisms for Formation of Allene 37
from 36
Table 4. Cycloisomerization of Carbonyl-Labeled 52
phosphates and acetates were following distinct mechanistic
pathways. Thus, we decided to further investigate the mechanism
of this intriguing transformation using labeled phosphates.
Initially, we subjected phosphoryl oxygen-labeled 599 to the
conditions under which the allene could be obtained (Scheme
13). Surprisingly, the obtained allene 60 maintained the phos-
phoryl oxygen-labeling pattern, with no traces of the other
isotopomer, thus completely ruling out possible inVolVement of
[3,3]-sigmatropic shift in this transformation! Moreover, con-
version of the allene 60 to furan resulted in the formation of
phosphoryl oxygen-labeled 61 as a major component over the
bridged oxygen-labeled 62. Similar results were obtained when
alkyne 59 was converted directly to the furan under elevated
temperatures. In a control experiment, 59 rapidly (ca. in 10 min)
isomerized to the allene with 10 mol % triflic acid. Consistent
with an ionization pathway, as experienced with acetates, allene
60 was formed accompanied with comparable amounts of its
isotopomer.28 When left for over 15 h, the cycloisomerization
of isotopomeric allenes proceeded to give furans 61 and 62 in
83% combined yield.
entry
cat. (mol %)
solvent
ratio (53:54)
yield, %
1
2
3
4
5
6
7
8
CuCl (5) + Et3N (20)
AgBF4 (5)
AuCl3 (10)
Cu(OTf)2 (10)
Sn(OTf)2 (10)
TMSOTf (10)
HOTf (10)
DMA
DCM
PhMe
PhMe
DCM
“
38:62
0:100
0:100
0:100
38:62
42:58
26:74
0:100
89a,b
69
64
84
42
51a
80
“
“
AuCl3 (5) + TTBP (10)
84
a NMR of recovered starting material showed no formation of another
isotopomer. See Supporting Information for details. b Run at 130 °C.
acetate 39b in the presence of an external nucleophile, methallyl
TMS (Scheme 12).26 Unsurprisingly, the 1,5-enyne 57 was
obtained in high yield, along with small amounts of the allene
58.27 Further studies indicated that enyne 57 does not convert
to allene 58 under the reaction conditions. As the allylation of
propargylic acetates is known to follow an SN1 mechanism,18
these results support the proposed ionization pathway (Scheme
11).
Since allenes were cleanly obtained in the cycloisomerization
of propargyl phosphates and tosylates, it occurred to us that
Apparently, the mechanism of migration of the phosphatyloxy
group presented an interesting challenge. Involvement of the
allene was demonstrated, as it was isolated and shown to con-
vert to the furan. Furthermore, the position of the oxygen
(26) For Lewis acid-catalyzed allylation of propargyl acetates with allylsilanes,
see refs 18b and 18c.
(27) For mechanistic discussions on regioselectivity of nucleophilic attacks on
proparyl cations, see ref 18c.
(28) Due to severe signal overlap, quantification of isotopomers was not possible.
9
9874 J. AM. CHEM. SOC. VOL. 129, NO. 32, 2007

Cascade Migration/Cycloisomerization Mechanism
A R T I C L E S
Scheme 12. Allylation of Acetate 39b
Scheme 13. Sequential Migration/Cycloisomerization of Phosphoryl Oxygen-Labeled 59
Scheme 14. Mechanisms for Formation of Phosphatyloxy-Substituted Allene 67
Scheme 15. Proposed Mechanisms for Conversion of Allene 67
to Furans 72 and 74
label ruled out a [3,3]-sigmatropic shift (Scheme 10, upper path)
as the product allene 60 from alkyne 59 possessed the oxygen
label solely at the phosphoryl oxygen (Scheme 13). Such a
migration would have resulted in the other isotopomer, and
ionization would result in the formation of both. It was clear
that both of these proposed mechanisms were in disagreement
with the obtained experimental results. To rationalize the
selective formation of the observed isotopomer of allene, we
propose the following potential mechanisms (Scheme 14). The
first path (path A) presumes two consecutive 1,2-migrations
via dioxolenylium species (64 and 66) and carbenoid intermed-
iate 65. Net retention of the YdO label is the result of two
“inversions.” Alternative path B occurs via two retentive 1,2-
shifts proceeding through oxirenium entities 68 and 70 and
carbenoid 69, which is isotopomeric to carbenoid 65 (Scheme
14). While path A is more consistent with previous mechanistic
studies, based on our current results, we cannot rule out
path B.
The formation of two furan isotopomers in the cycloisomer-
ization of isotopomerically pure allene 60 (Scheme 13) can be
explained via two competing mechanisms for the 1,2-phos-
phatyloxy migration (Scheme 15). Apparently, “retentive” 1,2-
migration via oxirenium species 71 would provide the major
isotopomer, phosphoryl oxygen-labeled furan 72, whereas 1,2-
migration via dioxolenylium species 73 produces furan 74, with
the bridged oxygen labeled.
substituted ketones depends on both the nature of the migrating
group and catalyst employed. A generalized mechanism for these
transformations is depicted in Scheme 16. Our initial postulate
that allene 37 could be accessed via a [3,3]-sigmatropic
migration is in conflict with our current experimental data
(Scheme 16). In the case of acyloxy migration in the presence
of transition metal catalysts, the metal carbenoid 75, formed
via a 1,2-migration, could be trapped by the carbonyl oxygen
of the ketone to give furan 38 directly (Rautenstrauch-type).
Alternatively, metal carbenoid 75 could be trapped by the
carbonyl of the ester moiety to give the allene 37. A 1,2-
migration via a dioxolenylium would result in the formation of
furan 38 with inversion of the 17O label. As the isotopomeric
outcome is the same in either of these two mechanisms, neither
Our mechanistic studies discussed above suggest that the
mechanism for the migration/cycloisomerization of propargyl-
9
J. AM. CHEM. SOC. VOL. 129, NO. 32, 2007 9875

A R T I C L E S
Schwier et al.
Scheme 16. Generalized Mechanism for Migration/
Cycloisomerization of 36 to 38
Table 6. Cross-Coupling of Phosphatyloxy-Substituted
Heteroaromatics
mechanistic possibility can be ruled out. Analogous transforma-
tion in the presence of Lewis acids proceeds with substantial
17O scrambling in the product, which implies formation
of scrambled allene 37 via an SN1′ mechanism. In the cycloi-
somerization of phosphates, the first step is likely also a
1,2-migration via a dioxolenylium species to metal carbenoid
75. However, since the allene 37 was isolated without formation
of furan 38, a second 1,2-migration, also through a dioxoleny-
lium intermediate via attack of the phosphoryl oxygen at
the carbenoid center, produces the observed allene with
exclusive retention of the 17O label. The 1,2-migration required
to go from allene 37 to furan 38 likely follows two competing
mechanistic pathways, among which a retentive 1,2-migration
via oxirenium species predominates, producing furan 38 with
the 17O label at the YdO position as a major isotopomer
(Scheme 16).
Kumada Cross-Coupling of Hetaryl Phosphates. To dem-
onstrate the synthetic utility of the obtained phosphatyloxy-
substituted heteroaromatics, we examined their reactions with
Grignard reagents under Kumada cross-coupling conditions. It
deserves mentioning that, while successful examples of Kumada
cross-coupling of Grignard reagents with enol phosphates29 and
aryl phosphates30 are well precedented, to the best of our
knowledge, no examples of the analogous reaction involving
heteroaromatic phosphates have ever been reported. We have
found that Kumada cross-coupling of furyl- and indolizinyl
phosphates is possible. Substantial optimization indicated that
this transformation proceeded most efficiently in the presence
of Pd2dba3/CyPF-tBu31 combination. The scope of cross-
coupling was examined employing these optimized conditions
(Table 6). Kumada cross-coupling of phosphatyloxy-containing
furans 14c and indolizines 17b proceeded smoothly with various
Grignard reagents to give C-3-substituted furans 76a-d and
C-1-substituted indolizines 77a-d in good to excellent yields
(Table 6).
a NMR yield.
Conclusion
In summary, we have developed different modes of cascade
cycloisomerizations of alkynyl ketones and imines proceeding
via various types of migration of acyloxy, phosphatyloxy, and
tosyloxy groups to give multisubstituted furans and indolizines
in good to high yields. This set of methodologies allows for
the efficient synthesis of tri- and tetrasubstituted furans and
N-fused heterocycles. Mechanistic studies employing 17O-
labeled starting materials indicated that the reaction mechanism
depends on the cyclization mode and nature of the migrating
group. It was shown that 1,3-phosphatyloxy migration in the
cycloisomerization of conjugated alkynyl imines proceeds via
a [3,3]-shift. The 1,2-migration of the acyloxy group in
conjugated alkynyl ketones was found to proceed via a
dioxolenylium intermediate. In contrast to acyloxy migration
in conjugated alkynyl ketones, the mechanism of acyloxy
migration in skipped systems depends on the reaction conditions.
While Lewis and Brønsted acids and transition metal complexes
catalyze the cycloisomerization of skipped alkynyl ketones, they
follow different mechanistic pathways! When an acid (either
Lewis or Brønsted) catalyst is used, formation of the post-
ulated allenyl intermediate occurs through an SN1′ pathway.
However, when transition metal catalysts are used, the cyclo-
(29) For Kumada cross-coupling of enol phosphates, see: (a) Kobayashi, Y.;
Takeuchi, A.; Wang, Y.-G. Org. Lett. 2006, 8, 2699. (b) Larsen, U. S.;
Mariny, L.; Begtrup, M. Tetrahedron Lett. 2005, 46, 4261. (c) Verboom,
R. C.; Persson, B. A.; Baeckvall, J.-E. J. Org. Chem. 2004, 69, 3102. (d)
Hayashi, T.; Konishi, M.; Okamoto, Y.; Kabeta, K.; Kumada, M. J. Org.
Chem. 1986, 51, 3772. (e) Sahlberg, C.; Quader, A.; Claesson, A.
Tetrahedron Lett. 1983, 24, 5137. (f) Hayashi, T.; Fujiwa, T.; Okamoto,
Y.; Katsuro, Y.; Kumada, M. Synthesis 1981, 1001.
(30) For Kumada cross-coupling of aryl phosphates, see: (a) Huang, W. G.;
Jiang, Y. Y.; Li, Q.; Li, J.; Li, J. Y.; Lu, W.; Cai, J. C. Tetrahedron 2005,
61, 1863. (b) Hayashi, T.; Katsuro, Y.; Okamoto, Y.; Kumada, M.
Tetrahedron Lett. 1981, 22, 4449.
(31) (R)-(-)-Di-tert-butyl-{1-[(S)-2-(dicyclohexylphosphanyl)ferrocenyl]ethyl}-
phosphine [158923-11-6], Strem catalog no. 26-0975. For examples on use,
see: (a) Ferna´ndez-Rodr´ıguez, M. A.; Shen, Q.; Hartwig, J. F. Chem. Eur.
J. 2006, 30, 7782. (b) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2005, 44, 1371.
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9876 J. AM. CHEM. SOC. VOL. 129, NO. 32, 2007

Cascade Migration/Cycloisomerization Mechanism
A R T I C L E S
63.2 (d, J ) 5.5 Hz), 63.1 (d, J ) 5.5 Hz), 37.7 (d, J ) 5.5 Hz), 17.4,
15.3 (d, J ) 5.5 Hz), 12.8.
39. To a round-bottomed two-necked flask were successively
isomerization follows either a Rautenstrauch-type 1,2-migration
of the acyloxy group followed by the cycloisomerization to the
furan directly or, alternatively, two 1,2-migrations of the acyloxy
group to form the postulated allenyl intermediate, which
cycloisomerizes into the furan via another 1,2-acyloxy shift.
Furthermore, control experiments and 17O-labeling studies
demonstrated that the transition metal-catalyzed reactions were
actually catalyzed by the metal and not by eVentual protons.
The analogous cycloisomerization of skipped phosphatyloxy
alkynyl ketones was also shown to be induced by both Brønsted
acid and transition metal catalysts. As in acetates, acids in-
duce an ionization to form the allene via an SN1′ mechanistic
pathway, whereas under transition metal catalysis, the allene
forms via two 1,2-phosphatyloxy migrations. Furthermore, as
an extension, we demonstrated the synthetic utility of phos-
phatyloxy furans and indolizines in the efficient Kumada cross-
coupling reaction.
added anhydrous THF (10 mL) and 3,3-dimethyl-1-butyne (0.62 mL,
n
5.0 mmol). The solution was cooled to -78 °C, and BuLi (2.5 M,
2.1 mL, 5.2 mmol) in hexanes was added dropwise. The resulting
solution was allowed to warm to room temperature. To an additional
50 mL round-bottomed two-necked flask the appropriate dione (4.8
mmol) was dissolved in anhydrous THF (10 mL). The dione solution
was cooled to -78 °C, and the acetylide solution from the first flask
was added slowly via cannula to the dione solution at -78 °C. The
resulting solution was allowed to warm to room temperature, then
cooled down again to -78 °C, and acetic anhydride (0.76 mL, 8.0
mmol) was added. The reaction mixture was brought to room
temperature, and the solution was then poured into a separatory funnel
containing saturated NH4Cl(aq) (200 mL) and diethyl ether (50 mL).
After extraction, the organic layer was separated, dried (MgSO4),
concentrated, and purified (silica gel) to afford pure acetoxy propargyl
ketone 39.
41. To a round-bottomed, two-necked flask were successively added
anhydrous THF (10 mL) and 3,3-dimethyl-1-butyne (0.62 mL, 5.0
mmol). The solution was cooled to -78 °C while stirring, and BuLi
Experimental Section
n
(2.5 M, 2.2 mL, 5.5 mmol) was added dropwise. The flask was removed
from the cooling bath and allowed to warm to room temperature. Benzil
(1.05 g, 5.0 mmol) was dissolved in anhydrous THF (10 mL) in a 50
mL round-bottomed, two-necked flask. The solution was cooled to -78
°C, and the acetylide solution from the first flask was transferred
dropwise via cannula. The resulting purple-black solution was allowed
to warm to room temperature while stirring and then cooled to -78
°C again. Diethylchlorophosphate (0.8 mL, 5.5 mmol) and anhydrous
triethylamine32 (0.8 mL, 5.5 mmol) were successively added. The
solution was allowed to return to room temperature. The resulting amber
solution was then poured into a separatory funnel containing 300 mL
of saturated NH4Cl solution and 50 mL of diethyl ether. After thorough
extraction, the organic layer was separated, dried (MgSO4), and
concentrated. The resulting residue was purified by column chroma-
tography (silica gel, 1:3 ethyl acetate/hexanes) to afford pure 41 (653
mg, 30%) and a second fraction of slightly contaminated 41 (878 mg,
Concise representative procedures for the preparation of starting
materials are provided here. Detailed procedures for the preparation of
all starting materials, as well as for the cycloisomerization reactions,
can be found in the Supporting Information.
12a. The preparation of 12a is representative. To a microreactor
were sequentially added DMAP (11 mg, 0.09 mmol), anhydrous
dichloromethane (1 mL), triethylamine (91 µL, 0.65 mmol), 5-hydroxy-
3-decyne-2-one (93 µL, 0.50 mmol), and diethylchlorophosphate (94
µL, 0.65 mmol). The reaction mixture was stirred at room temperature
for 2.5 h until judged complete by TLC and GC analysis. The reaction
mixture was washed with saturated sodium chloride solution (10 mL),
the aqueous layer was extracted twice with dichloromethane (3 mL),
and the organic extracts were dried over sodium sulfate and then
concentrated. The residue was purified by column chromatography
(silica gel, 1:2 ethyl acetate/hexanes) to afford 12a (111 mg, 73%). 1H
NMR (500.13 MHz, CDCl3) δ 5.09 (q, J ) 6.85 Hz, 1H), 4.18-4.10
(m, 4H), 2.35 (s, 3H), 1.87 (dt, J ) 15.04 Hz, J ) 7.52 Hz, 2H), 1.51-
1.43 (m, 2H), 1.37-1.29 (m, 10H), 0.93-0.85 (m, 3H). 13C NMR
(125.77 MHz, CDCl3) δ 184.1, 88.4, 85.5, 67.6, 64.6, 36.2, 36.1, 33.0,
31.5, 24.7, 22.8, 16.6, 16.5, 14.4. LRMS m/z (M+ + H, 275), 155 (100),
99 (100).
1
41%). H NMR (500.13 MHz, CDCl3) δ 7.89 (d, J ) 8.4 Hz, 2H),
7.70 (dd, J ) 7.8 Hz, J ) 0.9 Hz, 2H), 7.43-7.34 (m, 4H), 7.26 (t, J
) 7.7 Hz, 2H), 4.24-4.10 (m, 2H), 4.07-3.97 (m, 2H), 1.31 (t, J )
7.1 Hz, 3H), 1.24 (t, J ) 8.1 Hz, 3H), 1.23 (s, 9H). 13C NMR (125.76
MHz, CDCl3) δ 191.6, 137.8, 134.1, 133.0, 131.0, 129.7, 129.1, 128.0,
127.8, 103.8, 82.6, 75.3, 64.1 (d, J ) 38.9 Hz), 64.1 (d, J ) 39.0 Hz),
30.6, 28.3, 16.5 (d, J ) 12.7 Hz), 16.4 (d, J ) 12.8 Hz). 31P NMR
(202.46 MHz) δ -7.30. LRMS m/z 428 (M+, 15), 155 (66), 105 (PhCO,
100).
15a. The preparation of 15a is representative. To a solution of
2-ethynyl pyridine (300 µL, 3 mmol) in THF (10 mL) at -78 °C was
added, dropwise, nBuLi (2.67 M, 1.2 mL, 3.3 mmol). The reaction
mixture was stirred for a further 5 min before being brought to 0 °C
and stirred for 20 min. The reaction mixture was returned to -78 °C,
and butyraldehyde (280 µL, 3.3 mmol) was added slowly. The reaction
mixture was brought to and stirred at 0 °C for 30 min and treated with
chlorodiethylphosphate (564 µL, 3.9 mmol). The reaction mixture was
brought to room temperature and stirred for an hour, until TLC analysis
indicated the reaction was complete. The reaction mixture was diluted
with ether (90 mL) and poured into saturated NH4Cl(aq) (75 mL). The
organic phase was washed (saturated NH4Cl(aq), 75 mL), dried
(MgSO4), filtered, and concentrated. The residue was purified by
column chromatography (silica gel, EtOAc) to afford 15a as a viscous
oil (880 mg, 2.8 mmol, 94%). 1H NMR (500.13 MHz, CDCl3) δ 8.24
(d, J ) 4.0 Hz, 1H), 7.36 (tt, J ) 7.8 Hz, J ) 1.9 Hz, 1H), 7.11 (d, J
) 7.9 Hz, 1H), 6.92-6.97 (m, 1H), 4.87-4.93 (m, 1H), 3.78-3.90
(m, 4H), 1.52-1.67 (m, 2H), 1.21-1.30 (sext, J ) 7.3 Hz, 2H), 0.98-
1.04 (m, 6H), 0.65 (t, J ) 7.4 Hz, 3H). 13C NMR (125.76 MHz, CDCl3)
δ 149.3, 141.6, 135.5, 126.5, 122.6, 85.4, 84.9, 67.2 (d, J ) 5.5 Hz),
45. To a 25 mL round-bottomed, two-necked flask were successively
added anhydrous THF (10 mL) and 3,3-dimethyl-1-butyne (5.0 mmol,
0.62 mL). The solution was allowed to cool to -78 °C while stirring,
and nBuLi (2.5 M, 2.2 mL, 5.5 mmol) in hexanes was added dropwise.
The reaction mixture was allowed to warm to room temperature.
Separately, a round-bottomed, two-necked 50 mL flask was successively
loaded with benzil (5.0 mmol, 1.05 g) and anhydrous THF (10 mL).
The solution was stirred and cooled to -78 °C, and the acetylide
solution was then transferred dropwise to the benzil solution via cannula.
The resulting solution was allowed to reach room temperature before
being returned to -78 °C and treated sequentially with p-toluenesulfonyl
chloride (1.05 g, 5.5 mmol) in anhydrous THF (1 mL) and anhydrous
triethylamine (0.77 mL, 5.5 mmol), successively added. The flask was
then removed from the cooling bath and allowed to warm to room
temperature. The solution was then poured into a separatory funnel
containing saturated NH4Cl(aq) (300 mL) and diethyl ether (50 mL).
(32) Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889.
9
J. AM. CHEM. SOC. VOL. 129, NO. 32, 2007 9877

A R T I C L E S
Schwier et al.
After thorough extraction, the organic layer was separated, dried-
(MgSO4), and concentrated. The residue was purified by column
chromatography(silica gel, 1:10 ethyl acetate/hexanes) to afford pure
45 (1.32 g, 60%) as a yellow oil which solidifies upon refrigeration.
1H NMR (500.13 MHz, CDCl3) δ 7.81 (dd, J ) 8.3 Hz, J ) 1.2 Hz,
2H), 7.63 (d, J ) 8.4 Hz, 2H), 7.56 (t, J ) 7.4 Hz, 1H), 7.41 (t, J )
7.8 Hz, 2H), 7.32-7.38 (m, 5H), 7.10 (d, J ) 7.9 Hz, 2H), 2.35 (s,
3H), 1.01 (s, 9H). 13C NMR (125.76 MHz, CDCl3) δ 196.6, 192.2,
145.1, 137.0, 136.2, 133.3, 132.8, 132.7, 129.6, 129.5, 128.8, 128.6,
128.3, 128.1, 120.5, 36.0, 27.4, 21.6.
Acknowledgment. The support of the National Institutes of
Health (GM-64444) and National Science Foundation (CHE-
0710749) is gratefully acknowledged.
Supporting Information Available: General methods, ex-
perimental procedures for the preparation of starting materials,
and analytical and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA072446M
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9878 J. AM. CHEM. SOC. VOL. 129, NO. 32, 2007