Pt-catalyzed cyclization/migration of propargylic alcohols for the synthesis of 3(2H)-furanones, pyrrolones, indolizines, and indolizinones

Article abstract of DOI:10.1016/j.tet.2008.02.103

Several heterocycles such as furanones, pyrrolones, and indolizines, which are of pharmacological importance, are easily accessed via the Pt(II)-catalyzed heterocyclization/1,2-migration of propargylic ketols or hydroxy imine derivatives. This method sidesteps the challenges of traditional heteroaromatic oxygenation strategies such as regioselectivity and functional group tolerance in the syntheses of these heterocycles.

Full text of DOI:10.1016/j.tet.2008.02.103

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 7008e7014
www.elsevier.com/locate/tet
Pt-catalyzed cyclization/migration of propargylic alcohols for the
synthesis of 3(2H)-furanones, pyrrolones, indolizines, and indolizinones
Eric M. Bunnelle, Cameron R. Smith, Sharon K. Lee, Surendra W. Singaram,
*
Allison J. Rhodes, Richmond Sarpong
Department of Chemistry, University of California, Berkeley, CA 94720, USA
Received 9 January 2008; received in revised form 25 February 2008; accepted 28 February 2008
Available online 5 March 2008
Abstract
Several heterocycles such as furanones, pyrrolones, and indolizines, which are of pharmacological importance, are easily accessed via the
Pt(II)-catalyzed heterocyclization/1,2-migration of propargylic ketols or hydroxy imine derivatives. This method sidesteps the challenges of
traditional heteroaromatic oxygenation strategies such as regioselectivity and functional group tolerance in the syntheses of these heterocycles.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
oxygenation (epoxidation) conditions, and (C) the regioselec-
tivity of the initial epoxidation.
The development of efficient and versatile strategies for the
synthesis of heterocycles continues to be of significance in
synthetic organic chemistry. The 3(2H)-furanones are a class
of important heterocycles that are found in a variety of biolog-
ically active natural products such as the eremantholides1 and
jatrophone2 as well as several medicinally active agents.3 Var-
ious methods have been developed for the synthesis of these
heterocycles, including the conversion of 3-alkoxy-furans to
2-alkoxy furanones4 and the reaction of 3-silyloxyfurans
with electrophiles5 such as aldehydes. Most of the current ap-
proaches to furanones remain rather specialized or demand
considerable investment in the preparation of the requisite pre-
cursor substrates.
R2
R2
R2
M
[O]
O
OH
R3
R1
R1
R3
R1
R3
O
1
O
O
2
3
O
R2
R3
R1
O
4
Scheme 1. Proposed access to 3(2H)-furanones.
For example, we have considered a route to 3(2H)-fura-
nones via the oxygenation/rearrangement of furans (e.g., 1,
Scheme 1), which may proceed via the intermediacy of
epoxide 2. However, this approach possesses several distinct
challenges such as (A) the difficulty of synthesis of the requi-
site furan (i.e., 1), (B) the inherent instability of the furan and
other functional groups (e.g., sulfides, aldehydes, etc.) to the
As a result of these challenges, we were encouraged to pur-
sue alternate strategies that would provide ready access to 2
(or an equivalent) in one or two steps en route to an expedient
synthesis of 3(2H)-furanones (i.e., 4). In this article, we
present our efforts that have led to the realization of 3(2H)-fur-
anone compounds in short order.6 An extension of this trans-
formation to the expedient synthesis of other heterocycles
such as pyrrolones, indolizines, and indolizidinones using ni-
trogen nucleophiles was subsequently developed and commu-
nicated by us.7 A comprehensive account of these studies is
presented herein.
* Corresponding author. Tel.:þ1 510 643 6312; fax: þ1 510 642 9675.
E-mail address: rsarpong@berkeley.edu (R. Sarpong).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.103

E.M. Bunnelle et al. / Tetrahedron 64 (2008) 7008e7014
7009
Table 1
PtCl2-catalyzed formation of furanone productsa
2. Results and discussion
Entry
1
Substrate
Product
Yield (%)
As illustrated in Scheme 1, it was envisaged that intermedi-
ates such as 2 could be readily accessed from propargylic
alcohols (e.g., 3) via a carbophilic Lewis acid-mediated
cyclization followed by proton transfer. The viability of this
transformation is supported by several related literature reports
using Ag(I) by Marshall,8 and Au(III) by Liu,9 Larock,10 and
Hashmi11 among others. In turn, rearrangement of 2 could
yield 3(2H)-furanone 4. Investigations of this transformation
began with alkynyl ketone 5 (Scheme 2), which was available
in one-step from 3,4-hexanedione using the method of Chis-
holm.12 Our past success using PtCl2 as a carbophilic Lewis
acid to mediate transformations involving alkynes13 made it
a starting point of our investigations.
O
HO
R
O
O
R
3a (R¼n-Bu)
3b (R¼i-Pr)
3c (R¼2-furyl)
3d (R¼Ph)
4a (R¼n-Bu)
4b (R¼i-Pr)
65
48
38
56
65
48
4c (R¼2-furyl)
4d (R¼Ph)
3e (R¼p-MeOPh)
3f (R¼p-NO2Ph)
4e (R¼p-MeOPh)
4f (R¼p-NO2Ph)
O
O
2
OH
O
R
R
OH
3g (R¼n-Bu)
4g (R¼n-Bu)
4h (R¼Ph)
76
66
89
76
OH
[M]
Bu
Et
Et
Et
Et
[M]
3h (R¼Ph)
Bu
3i
4i
R =
R =
O
O
3j (R¼p-MeSPh)
4j (R¼p-MeSPh)
5
6
O
Ph
HO
Ph
Ph
3
77
O
O
Et
H
Ph
O
4k
Et
Et
Bu
O
O
Bu
Et
Et
3k
Bu
Bu
Et
O
Bu
O
O
O
R1
O
7
8
9
HO
R2
4b
60
Scheme 2. A proposed mechanism for the synthesis of 3(2H)-furanones.
Ph
Bu
O
Bu
4l
Although various Lewis acids (e.g., InCl3, BF3$OEt2) and
Brønsted acids such as HCl were also investigated for the con-
version of 5 to 3(2H)-furanone 9, in the end, PtCl2 proved to
be the ideal catalyst. This was due in part to the operational
simplicity of using the air- and moisture-tolerant Pt(II) salts,
as well as the consistency in yield and amenability to scale
up when this catalyst was used. The reaction can be run at
low catalyst loadings (2 mol % PtCl2), although a longer pe-
riod of time is required for the reaction to reach completion.
However, the use of a 2 mol % PtCl2 loading under an atmo-
3l (R1, R2¼Et, Ph)
3m (R1, R2¼Ph, Et)
Reaction conditions: substrate (0.1 M of substrate), 5 mol % PtCl2 in PhMe
a
at 100 ꢀC for 8 h.
b
An inseparable 1:2 mixture (as determined by 1H NMR) of propargylic
alcohols 3l and 3m was used for the formation of 4l.
In a subset of the transformations of propargylic alcohols
(see 10a and 10b, Scheme 3) studied to date, significant
amounts of enedione products (12a and 12b) were obtained
in addition to the desired 3(2H)-furanone products.15 This ap-
pears to correlate with an increase in the rate of other compet-
ing fragmentation processes relative to the migratory aptitude
of the alkyl substituent alpha to the tertiary alcohol (e.g., the
ethyl group, see 10).
sphere of CO, following the precedent of Furstner,14 leads to
¨
comparable reaction rates as to when a 10 mol % loading is
used. Furthermore, the reaction gave comparable yields in
the presence of 1 equiv of H2O.
As illustrated in Table 1, the reaction is general for a range
of substrates. Significant variability can be achieved at the
alkyne terminus as alkyl (3a and 3b) and aryl substituents (3cef)
are well tolerated (entry 1). In addition, the formation of
spiro-furanone products appears to be general if cyclic sub-
strates are employed (3gej, entry 2). The migrating group is
not restricted to alkyl fragments as phenyl groups migrate
just as readily (entry 3). Furthermore, a high level of versatility
may be achieved in the furanone product by beginning with an
appropriately functionalized propargylic alcohol (3l and 3m,
entry 4). Importantly, sensitive functional groups such as sul-
fides, which will not survive the oxidative transformation of
furans to 3(2H)-furanones (i.e., 1/3, Scheme 1), remain
intact under the PtCl2-catalyzed conditions (see 3j, entry 2).
Insight into the mechanism for the formation of the ene-
dione products was gained upon reaction of 13 (Scheme 4).
O
HO
O
PtCl2 (10 mol %)
PhMe, 100 °C, 3 h
R
+
O
R
O
R
O
10
R =
11
12
a)
b)
31%
31%
39%
36%
R =
Ph
Scheme 3. Divergent reactivity in the PtCl2-catalyzed transformation.

7010
E.M. Bunnelle et al. / Tetrahedron 64 (2008) 7008e7014
O
O
H
PtCl2
Me
OH
Me
Ph
migrates
(10 mol %)
Me
Ph
Me
Ph
(Path A)
PhMe, 100 °C
3 h
O
O
O
14
13
15 (14% yield)
O
H
Me
O
Me
Ph
(Path B)
Isomerization
Ph
Ph
O
O
O
18 (58% yield)
Me
O
17
16
Scheme 4. A possible rationale for the formation of enediones.
Consistent with our initial proposal, whereas 3(2H)-furanone
products such as 15 (14% yield) may arise via a concerted mi-
gration16 involving the Me substituent (see 14, Path A), com-
peting epoxidation by collapse of the zwitterionic intermediate
14 may lead to epoxydihydrofuran 16. In turn, 16 may be con-
verted to the observed enedione products via epoxide opening
and ring fragmentation (path B).17,18 The major E-alkene dia-
stereomer observed for the enedione product (18, 58% yield)19
presumably arises via Pt(II)-catalyzed or thermal isomeriza-
tion of 17 following ring opening under the reaction
conditions.20
Subsequent to the studies on the formation of 3(2H)-fura-
nones, we have discovered that these novel transformations
of tertiary propargylic alcohols are not restricted to cyclizations
involving oxygen nucleophiles (i.e., carbonyl groups), as nitro-
gen nucleophiles readily participate to provide important aza-
heterocycles. For example, indolizines (e.g., 21, Scheme 5)
and related derivatives, which have significant pharmacological
potential,21 may be realized if one begins with the pyridinyl
propargylic alcohol 19. Because of the importance of indoli-
zines from a pharmacological standpoint, a variety of methods
for their syntheses have emerged.22 On the basis of our prece-
dent for the formation of furanones, which was achieved prior
to the initiation of our work with nitrogen nucleophiles, we rea-
soned that substrates such as 19 (Scheme 5), which possess
a pyridine fragment, could participate in metal-catalyzed cyclo-
isomerizations to access a range of nitrogen-containing hetero-
cycles (e.g., indolizines related to 21).
Table 2
Cycloisomerization of terminal alkyne propargylic ester substrates
OPiv
OPiv
Catalyst (5 mol %)
Additive (10 mol %)
N
PhH (0.2 M)
N
R
R
22a (R = H)
22b (R = Bu)
23a (R = H)
23b (R = Bu)
Entry Substrate Catalyst Additive
Temp Time Yield of
(ꢀC) (h)
23 (%)
1
2
22a
22a
PtCl4
PtCl2
d
d
70
70
18
20
34
31
3
22a
PtCl2
70
20
43
R= t-Bu (24)
R= Cy (25)
PR2
4
22a
PtCl2
70
8
79
5
6
7
8
22b
22b
22b
22b
PtCl2
PtCl2
PtCl2
PtCl2
d
24
25
d
70
70
70
40
10
3
81
95
9
36
95
No
reaction
95
9
22b
22b
22b
PtCl2
PtCl2
InCl3
24
25
d
40
40
40
12
36
4
10
11
33
85
under similar conditions.24 Because PtCl2 is less sensitive to
moisture as compared to PtCl4, we continued our studies
with this salt, which greatly simplified the experimental setup.
Further optimization revealed that the introduction of
bulky, electron-rich phosphine ligands such as 2-(di-tert-butyl-
phosphino)biphenyl25 (24, entry 3) or 2-(di-cyclohexylphos-
phino)biphenyl (25, entry 4) led to a pronounced increase in
the yield of the indolizine product 23a, with 25 proving to
Optimization of the general transformation 19/21 was
conducted with propargylic ester 22a (Table 2) prepared
from pyridine-2-carboxaldehyde by the addition of ethynyl
Grignard reagent and subsequent acylation.23 Initially, we
found that both PtCl4 (entry 1) and PtCl2 (entry 2) at
5 mol % loading effected the transformation of 22a (0.20 M
in PhH, 70 ꢀC) to the desired C-1 substituted indolizine 23a
:B
OP
R
H
H
OP
Proton
OP
[Pt]
PtCl2
6-endo-dig
Transfer
N
N
N
R
R
19
20
21
Scheme 5. Proposed hetero-cycloisomerization.

E.M. Bunnelle et al. / Tetrahedron 64 (2008) 7008e7014
7011
be the best additive of those surveyed (79% yield). Phosphine
ligands have been shown to facilitate Pt(II)-catalyzed reactions
involving nitrogen nucleophiles in studies by Widenhoefer on
the hydroamination of olefins.26 In these studies, Widenhoefer
reported that a 1:1 ratio of Pt(II) salt to exogenous phosphine
(Pt/PR3) was critical to success.27 We reasoned that the use of
bulky phosphines would favor the formation of a 1:1 Pt/PR3
complex. It should be noted that in our studies, these ligands
were consistently superior to PPh3 for the formation of indoli-
zines from the corresponding propargylic alcohols.
By direct analogy to our observations involving the fura-
none-forming reactions, we hypothesized that tertiary propar-
gylic alcohol substrates such as 31 (Scheme 6) could provide
a platform for heterocyclizations that involve a 1,2-shift.30
Et
Et
N
OH
OH
[Pt]
Et
PtCl2 (10 mol %)
Et
PhMe, 100 °C, 3 h
N
Bu
TsN
H
TsN
H
Bu
32
The reaction efficiency was substantially different when in-
ternal alkyne substrates (e.g., 22b) were used (entries 5e11).
Similarly in these cases, bulky phosphine additives led to
higher yields of the indolizine products (i.e., 23b, entries 6
and 7) as compared to the cases when phosphines were not
added (entry 5) or when triphenylphosphine was used as the
additive (not shown). For example at 40 ꢀC, there was no re-
action with PtCl2 alone as catalyst (entry 8) whereas with 24
and 25 as additives (entries 9 and 10, respectively), product
formation was observed, with 24 proving to be superior. In-
dium trichloride also catalyzes the indolizine-forming reaction
(entry 11) but the scope was limited to internal alkyne sub-
strates. We believe that the lack of success of InCl3 in catalyz-
ing the cycloisomerization of terminal alkyne substrates may
be the result of the competing formation of indium acetylides
under the reaction conditions, consistent with the observations
of Shibasaki.28
As shown in Figure 1, a range of indolizines are obtained
utilizing either Pt(II) (5 mol % of PtCl2, 10 mol % of 2-(di-
tert-butylphosphino)biphenyl (24), 0.2 M in PhH, 70 ꢀC) or
In(III) (5 mol % of InCl3, 0.2 M in PhH, 70 ꢀC). The pivalate
protective group was found to give the highest yields (see 26e
29) compared to other acyl protecting groups (e.g., acetate and
benzoate) for a range of alkyl-, cycloalkyl-, aryl-, and alkenyl-
substituted indolizines. Silyl protective groups (e.g, TBS) may
also be employed, but the products are generally isolated in
lower yield (57% yield of 30).29 This is likely due to the rel-
ative instability of the corresponding silylated indolizines to-
ward purification.
31
O
Et
Et
Et
O
[Pt]
Et
H
N
N
TsN
H
TsN
H
Bu
Bu
34
33
(71% yield)
Scheme 6. Tandem cyclization/1,2-migration of 31.
In a preliminary study, upon treatment of hydrazone 31
with PtCl2 (10 mol %) for 3 h at 100 ꢀC, pyrrolone 34 was
formed in 71% yield. This transformation likely proceeds
via zwitterion 32 and platina-alkoxide 33, in an analogous
fashion to the furanones.31
Despite our initial success in transforming 31 to pyrrolone
34, the reaction conditions were ineffective at low catalyst
loadings especially for substrates containing a pyridine frag-
ment. Following a comprehensive study of various additives,
solvents, and temperatures, optimized conditions (5 mol %
PtCl2, 10 mol % 2-(di-tert-butylphosphino)biphenyl, 0.1 equiv
Cs2CO3, 100 ꢀC), which were readily applicable to several ter-
tiary propargylic alcohol substrates (35aee, Table 3) were
identified. This provided the corresponding indolizinones
(36aee) in modest to good yields. The addition of substoichio-
metric quantities of a base (Cs2CO3), which may facilitate pro-
ton transfer events prior to the 1,2-migration event, was found
to be critical.32 To probe the nature of the 1,2-migrations, enan-
tioenriched 35a (99.9% ee, Eq. 1) was subjected to the opti-
mized reaction conditions and provided 36a in 97% ee,
which corroborated a highly stereoselective 1,2-migration.33e35
OPiv
OPiv
OPiv
PtCl2(5mol%)
2-(di-tert-butylphosphino)
N
O
OH
N
N
biphenyl, 24 (10 mol %)
Cs2CO3 (0.1 equiv)
Bu
Ph
ð1Þ
N
PhH, 70 °C, 24 h
(40% yield)
N
Bu
23b, 95% (85%)
26, 80% (83%)
27, 99% (92%)
OTBS
Bu
36a (97% ee)
OPiv
OPiv
35a (99.9% ee)
N
N
3. Conclusion
N
Bu
In conclusion, we report an expedient synthesis of 3(2H)-
furanones from propargylic alcohols that may be accessed in
one step from 1,2-diketones using an efficient Rh(I)-catalyzed
alkyne addition developed in the laboratories of Chisholm.
The reaction tolerates sensitive functional groups such as nitro
groups and sulfides, which may be unstable or easily oxidized
28, 79% (81%)
29, 88% (83%)
30, 57%
Figure 1. Pt(II)- and In(III)-catalyzed cycloisomerizations. Yields are indicated
for reactions using PtCl2 and InCl3 (in parentheses). For a full description of
reaction details, including the identity of propargylic ester substrates, see Sup-
plementary data.

7012
E.M. Bunnelle et al. / Tetrahedron 64 (2008) 7008e7014
Table 3
Pt-catalyzed formation of indolizinones
dry, deoxygenated solvents. Toluene and benzene were dis-
tilled over calcium hydride. Platinum catalysts and phosphine
ligands were purchased from Strem or Johnson Matthey. All
other reagents were purchased from Aldrich, Acros, or Lan-
caster and used without further purification. Reaction temper-
atures were controlled by an IKAmagÒ or OptiChemÒ
temperature modulator. Thin layer chromatography (TLC)
was performed using E. Merck silica gel 60 F254 precoated
plates (0.25 mm) and visualized by UVand anisaldehyde stain.
Fisher silica gel 240e400 mesh (particle size 0.032e0.063)
was used for flash chromatography. Pt-catalyzed reactions
PtCl2(5mol%)
2-(di-tert-butylphosphino)
biphenyl, 24 (10 mol %)
Cs2CO3 (0.1 equiv)
O
R
N
OH
R
PhH, 100 °C, time
N
Bu
Bu
Entry
1
Substrate
OH
Time (h)
Product
Yield (%)
O
R
R
1
N
were performed in Schlenk flasks unless otherwise noted. H
N
Bu
and 13C NMR spectra were recorded on a Bruker AV-500 (at
500 MHz and 125 MHz, respectively), Bruker DRX-500 (at
500 MHz and 125 MHz, respectively) or on a Bruker AVB-
400 (at 400 MHz and 100 MHz, respectively) in chloroform-
d or benzene-d6 at 23 ꢀC, unless otherwise stated. Chemical
shifts were referenced to the residual solvent peak, which
35
Bu
36
(a) R¼Et
48
168
120
48
66
40
66
70a
44
(b) R¼Me
(c) R¼3,5-bis(MeO)Ph
(d) R¼Ph
(e) R¼c-C3H5
144
1
was set at d¼7.26 for H NMR and d¼77.0 for 13C NMR,
O
Et
N
Et
N
OH
1
for CDCl3; and d¼7.15 for H NMR and d¼128.6 for 13C
1
NMR, for C6D6. Data for H NMR are reported as follows:
2
48
36
Bu
chemical shifts (d ppm); multiplicity, (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, dd¼doublet of doublet, dt¼doublet of
triplet, dq¼doublet of quartet, qd¼quartet of doublet,
m¼multiplet, br¼broad resonance), coupling constants (Hz),
and integration in parentheses. Data for 13C NMR are reported
in terms of chemical shift. IR spectra were recorded on a Nico-
let MAGNA-IR 850 spectrometer and are reported in fre-
quency of absorption (cmꢁ1). Low and high resolution mass
spectral data were obtained from the University of California,
Berkeley Mass Spectral Facility, on a VG 70-Se Micromass
spectrometer for FAB, and a VG Prospec Micromass spec-
trometer for EI. Enantiomeric excess was determined by
HPLC using a Shimatzu 10A VP series chiral HPLC. Optical
rotation data was obtained using a PerkineElmer 241 Polari-
meter with a 589 nm sodium lamp.
Bu
37
Cs2CO3 was not used as an additive.
38
a
(sulfides) under traditional protocols for the formation of these
heterocycles from the oxygenation of furans or other related
heteroaromatic compounds. The overall transformation is not
restricted to the synthesis of 3(2H)-furanones as indolizines
and indolizinones may also be formed using substrates bearing
a nitrogen nucleophile. While PtCl2 alone, as well as in the
presence of phosphine additives, has been found to be gener-
ally effective, InCl3 has also proven to be a highly competent
catalyst for a subset of these transformations involving internal
alkyne substrates. The work reported herein presents an ob-
served significant effect of bulky electron-rich phosphines on
the hetero-cycloisomerization transformations involving
Pt(II) catalysis, which we anticipate will find wide applicabil-
ity in other cycloisomerization reactions. This work has also
described the competing formation of enedione byproducts
in the Pt-catalyzed cycloisomerization of keto propargyl alco-
hols, and a tentative mechanism for the formation of these
compounds is proposed. Further studies to probe the mecha-
nisms of these transformations, broaden the scope to include
other examples of chirality transfer, and identify conditions
to shorten the reaction times are underway. Additionally, ap-
plications of these heterocycles in natural product synthesis
are currently under investigation and will be reported in due
course.
4.2. Representative procedure for the formation of furanones
4.2.1. 5-Butyl-2,2-diethylfuran-3(2H)-one (4a)
A 20 mL Schlenk tube equipped with a stir bar was charged
with platinum(II) chloride (5 mg, 0.02 mmol, 0.1 equiv). To
the tube was added a solution of 3a (39 mg, 0.2 mmol) in tol-
uene (2.0 mL). The Schlenk tube was sealed, and the reaction
mixture was heated to 100 ꢀC for 3 h, then cooled to 23 ꢀC.
Silica gel (250 mg) was added to the reaction mixture and
the solvent was removed by rotary evaporation. The adsorbed
product was purified by flash chromatography (20 mL silica
gel, 8:1 hexanes/ethyl acetate), to yield 25 mg (65%) of a light
yellow oil. 1H NMR (CDCl3, 500 MHz) d 5.40 (s, 1H), 2.50 (t,
J¼7.0 Hz, 2H), 1.75 (qd, J¼7.3, 1.2 Hz, 4H), 1.65 (dt, J¼15.3,
7.6 Hz, 2H), 1.41 (sext., J¼7.4 Hz, 2H), 0.94 (t, J¼7.4 Hz,
3H), 0.78 (t, J¼7.4 Hz, 6H); 13C NMR (CDCl3, 125 MHz)
d 207.1, 193.5, 104.1, 94.4, 30.5, 28.8, 28.4, 22.3, 13.7, 7.2;
4. Experimental section
4.1. Materials and methods
IR (film) nmax 2970, 2937, 1702, 1596, 1460 cmꢁ1
;
All air or moisture sensitive reactions were conducted in
flame-dried glassware under an atmosphere of nitrogen using
HRMS (EIþ) calcd for [C12H20O2]þ: m/z 196.1463, found
196.1469.

E.M. Bunnelle et al. / Tetrahedron 64 (2008) 7008e7014
7013
4.3. Representative procedure for the formation of indolizines
References and notes
1. Le Quesne, P. W.; Levery, S. B.; Menachery, M. D.; Brennan, T. F.;
Raffauf, R. F. J. Chem. Soc., Perkin Trans. 1 1978, 1572e1580.
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J. Am. Chem. Soc. 1976, 98, 2295e2300; (b) Smith, A. B., III; Guaciaro,
M. A.; Schow, S. R.; Wovkulich, P. M.; Toder, B. H.; Hall, T. W. J. Am.
Chem. Soc. 1981, 103, 219e222.
4.3.1. 3-Butylindolizin-1-yl pivalate (23b)
Platinum(II) chloride (5 mg, 18 mmol) and 2-(di-tert-butyl-
phosphino)biphenyl (11 mg, 36 mmol) were added to a solution
of pivalate 22b (100 mg, 0.36 mmol) in benzene (2 mL) in a 1-
dram vial. The vial was sealed and heated at 70 ꢀC for 3 h. The
mixture was then filtered, concentrated by rotary evaporation,
and purified by flash chromatography (4:1 hexanes/EtOAc) to
yield 95 mg (95%) of 23b as a yellow oil. 1H NMR (500 MHz,
C6D6) d 7.30 (d, J¼9.01 Hz, 1H), 7.04 (d, J¼7.10 Hz, 1H),
6.76 (s, 1H), 6.32 (dd, J¼8.99, 6.42 Hz, 1H), 6.06 (t,
J¼6.76 Hz, 1H), 2.26 (t, J¼7.65 Hz, 2H), 1.40e1.32 (m,
2H), 1.27 (s, 9H), 1.18e1.10 (m, 2H), 0.74 (t, J¼7.34 Hz,
3H); 13C NMR (125 MHz, C6D6) d 175.7, 127.1, 121.3,
120.9, 120.7, 116.1, 114.0, 109.6, 105.0, 38.9, 29.0, 27.0,
25.2, 22.4, 13.6; IR (film) nmax 2958, 2931, 2871, 1749,
1278, 1120, 728 cmꢁ1; HRMS (EI) calcd for [C17H23NO2]þ:
m/z 273.1729, found 273.1732.
3. Shin, S. S.; Byun, Y.; Lim, K. M.; Choi, J. K.; Lee, K.-W.; Moh, J. H.;
Kim, J. K.; Jeong, Y. S.; Kim, J. Y.; Choi, Y. H.; Koh, H.-J.; Park,
Y.-H.; Oh, Y. I.; Noh, M.-S.; Chung, S. J. Med. Chem. 2004, 47, 792e804.
4. Sayama, S. Heterocycles 2005, 65, 1347e1358.
5. Winkler, J. D.; Oh, K.; Asselin, S. M. Org. Lett. 2005, 7, 387e389.
6. A synthesis of 3(2H)-furanones closely related to our work appeared while
´
this work was in progress, see: Kirsch, S. F.; Binder, J. T.; Liebert, C.;
Menz, H. Angew. Chem., Int. Ed. 2006, 45, 5878e5880.
7. For our initial report on these transformations, see: Smith, C. R.; Bunnelle,
E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169e1171.
8. Precedent for a closely related strategy in the synthesis of furans and
butenolides can be found in the work of Marshall, see: Marshall, J. A.;
Wang, X.-J. J. Org. Chem. 1991, 56, 960e969.
9. Liu, Y.; Liu, M.; Guo, S.; Tu, H.; Zhou, Y.; Gao, H. Org. Lett. 2006, 8,
3445e3448.
10. Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164e
11165.
4.4. Representative procedure for the formation of
indolizinones
11. Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem.,
Int. Ed. 2000, 39, 2285e2288.
12. Dhondi, P. K.; Chisholm, J. D. Org. Lett. 2006, 8, 67e69. For more
details, see Supplementary data.
4.4.1. (ꢂ)-3-Butyl-8a-ethylindolizin-1(8aH)-one (36a)
Platinum(II) chloride (3 mg, 12 mmol), 2-(di-tert-butyl-
phosphino)biphenyl (7 mg, 23 mmol), and cesium carbonate
(7 mg, 23 mmol) were added to a solution of (ꢂ)-35a
(50 mg, 0.23 mmol) in benzene (1 mL) and the solution was
heated at 100 ꢀC in a sealed vial with stirring. Once the reac-
tion was judged complete by TLC (48 h) the mixture was con-
centrated by rotary evaporation and the residue purified by
flash chromatography (4:1 hexanes/EtOAc) to yield 33 mg
(0.15 mmol, 66%) of 36a as a yellow oil. 1H NMR
(500 MHz, C6D6) d 5.95 (d, J¼9.28 Hz, 1H), 5.84 (d,
J¼7.07 Hz, 1H), 5.61 (dd, J¼9.26, 5.37 Hz, 1H), 4.99 (t,
J¼6.21 Hz, 1H), 4.82 (s, 1H), 1.92e1.82 (m, 1H), 1.80e
1.64 (m, 3H), 1.16e1.04 (m, 2H), 1.03e0.93 (m, 2H), 0.80
(t, J¼7.41 Hz, 3H), 0.65 (t, J¼7.29 Hz, 2H); 13C NMR
(125 MHz, C6D6) d 201.0, 175.0, 123.7, 122.2, 121.8, 108.1,
98.3, 70.3, 31.4, 28.4, 26.2, 22.1, 13.3, 6.5; IR (film) nmax
2960, 2932, 2873, 1675, 1534, 1433, 725, 689 cmꢁ1; HRMS
(EI) calcd for [C14H19NO]þ: m/z 217.1467, found 217.1467.
13. (a) Bhanu Prasad, B. A.; Yoshimoto, F. K.; Sarpong, R. J. Am. Chem. Soc.
2005, 127, 12468e12469; (b) Pujanauski, B. G.; Bhanu Prasad, B. A.;
Sarpong, R. J. Am. Chem. Soc. 2006, 128, 6786e6787.
14. Furstner, A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005, 127, 8244e8245.
¨
15. Minor amounts of enedione products were observed during the reactions
of substrates 3aef.
16. The a-ketol migration has been shown to be stereospecific. See Ref. 6.
17. This may occur in a stepwise as opposed to a concerted manner. The role
of the cyclopropyl group at the terminus of the alkyne in promoting the
formation of significant amounts of enedione products is under active
investigation.
18. A MeyereSchuster mechanism for the formation of 18 from 13 cannot be
ruled out at this time.
19. The E-diastereomer is supported by NOE analysis of the product 18. For
more information, see Supplementary data.
20. For a recent report of protic acid-catalyzed isomerization of Z-enediones,
see: Crone, B.; Kirsch, S. F. Chem. Commun. 2006, 764e766.
21. Michael, J. P. Nat. Prod. Rep. 1999, 16, 675e696.
22. For recent examples, see: (a) Kaloko, J., Jr.; Hayford, A. Org. Lett. 2005,
7, 4305e4308; (b) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 2074e2075; (c) Seregin, I. V.; Gevorgyan, V.
J. Am. Chem. Soc. 2006, 128, 12050e12051; (d) Marchalin, S.;
´
€
Baumlova, B.; Baran, P.; Oulyadi, H.; Daıch, A. J. Org. Chem. 2006,
71, 9114e9127; (e) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323e4326.
23. For details, see Supplementary data.
Acknowledgements
24. Heating 22a without added catalyst at 120 ꢀC over 48 h yielded minor
amounts of 23a (ca. 15% yield) along with significant byproducts. This
points to a slow and inefficient background reaction.
The authors are grateful to UC Berkeley, Abbott Laborato-
ries, and GlaxoSmithKline for generous financial support,
Johnson Matthey for a gift of PtCl2, Dr. Herman van Halbeek
for help with NOE studies, and to Dr. John Greaves (Mass
Spectral Facility, University of California, Irvine) for HRMS
data for compounds 3b, 10a, and 11.
25. (a) Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org. Chem. 2000, 65,
5334e5341; (b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L.
J. Am. Chem. Soc. 2000, 122, 1360e1370.
26. (a) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070e
1071; (b) Qian, H.; Widenhoefer, R. A. Org. Lett. 2005, 7, 2635e2638.
27. Wang, X.; Widenhoefer, R. A. Organometallics 2004, 23, 1649e1651.
28. Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 13760e13761.
Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.02.103.
29. Previously, PtCl2 was reported to be an ineffective catalyst for the cyclo-
isomerization that results in 30. See Ref. 22c.

7014
E.M. Bunnelle et al. / Tetrahedron 64 (2008) 7008e7014
30. For an example of a-hydroxyiminium 1,2-migration, see: Fenster,
M. D. B.; Patrick, B. O.; Dake, G. R. Org. Lett. 2001, 3, 2109e2112.
31. More recently, following our initial report (Ref. 7), Kirsch and co-workers
have reported that imines may participate in similar transformations, see:
33. Enantioenriched 35a was obtained via preparative chiral column chroma-
tography of the racemate.23
34. Efforts to delineate whether this transformation is stereospecific and the
loss of ee in forming enantioenriched 36a occurs via a competing process
are currently ongoing.
´
Binder, J. T.; Crone, B.; Kirsch, S. F.; Liebert, C.; Menz, H. Eur. J. Org.
Chem. 2007, 1636e1647 and Table 4 therein.
32. The formation of a cesium alkoxide prior to 1,2-migration may also be
important.
35. Liu has recently reported that these reactions may be effected with Cu(I)
salts, see: Yan, B.; Zhou, Y.; Chen, J.; Liu, Y. J. Org. Chem. 2007, 72,
7783e7786.