Pt(IV)-catalyzed cyclization of arene-alkyne substrates via C-H bond functionalization

Article abstract of DOI:10.1016/j.tet.2003.05.003

We herein report that PtCl₄ has proven to be a hydroarylation catalyst with an efficiency and substrate scope superior to previously known methods. This catalyst demonstrated consistent performance with arene-yne substrates of diverse structural features, including propargyl ethers, propargylamines, and alkynoate esters, providing good to excellent yields of the 6-endo products (chromenes, dihydroquinolines, and coumarins). In contrast, Pt(II), Pd(II), and Ga(III) salts were shown to be sensitive to the substitution on the alkyne moiety. PtCl₄ is compatible with both terminal and disubstituted alkynes, as well as with various functionalities on the arene ring, including methyl, methoxyl, hydroxyl, protected amine, and halide.

Full text of DOI:10.1016/j.tet.2003.05.003

Tetrahedron 59 (2003) 8859–8868
Pt(IV)-catalyzed cyclization of arene–alkyne substrates via C–H
bond functionalization
Stefan J. Pastine,† So Won Youn† ‡ and Dalibor Sames
,
*
Department of Chemistry, Columbia University, 3000 Broadway MC 3167, New York, NY 10027, USA
Received 11 April 2003; accepted 9 May 2003
Abstract—We herein report that PtCl4 has proven to be a hydroarylation catalyst with an efficiency and substrate scope superior to
previously known methods. This catalyst demonstrated consistent performance with arene–yne substrates of diverse structural features,
including propargyl ethers, propargylamines, and alkynoate esters, providing good to excellent yields of the 6-endo products (chromenes,
dihydroquinolines, and coumarins). In contrast, Pt(II), Pd(II), and Ga(III) salts were shown to be sensitive to the substitution on the alkyne
moiety. PtCl4 is compatible with both terminal and disubstituted alkynes, as well as with various functionalities on the arene ring, including
methyl, methoxyl, hydroxyl, protected amine, and halide.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
In addition to alkane C–H bonds, we began to investigate
functionalization of a broad range of C–H bonds, including
those of arene substrates. Arenes, in comparison to alkanes,
are generally more reactive due to accessibility of various
reactivity modes and mechanisms, intimately linked with
unsaturated arene rings. For instance, a formal process of
C–H bond functionalization may proceed via an electro-
philic substitution mechanism.5 As part of our initial goals
in this area, we have focused our attention on the direct
arylation of hetero-arenes6 and intramolecular hydroaryl-
ation processes (Fig. 1).7 The latter reaction comprises the
subject of this account.
C–H bond functionalization represents a chemical process of
broad synthetic potential owing to two major factors: first, the
ubiquity of C–H bonds in organic compounds and second, a
direct transformation of C–H bonds reduces the number of
reactive groups required for a coupling processes. These
seemingly simple points lead to consequences of significant
importance to both the strategy and practice of organic
synthesis. On a formal level, constraints imposed by current
methodologies would be loosened and new disconnection
strategies for the assembly of organic compounds may be
considered. Such formal analyses influence our choice of
chemical and synthetic problems to undertake.
1.1. Hydroarylation
From theonset ofour program, natural products haveprovided
a complex structural context for our reaction development
program (Fig. 1). For instance, the key step in the synthesis of
rhazinilam involved activation of a sp3 C–H bond (ethyl
group) in the presence of several reactive groups.1 Similarly,
the core of teleocidin B4 was assembled via two tandem C–H
activation/C–C bond formation reactions, transforming
ortho-t-butylaniline to a complex fragment containing two
quaternary centers.2 These investigations led to the develop-
ment of catalytic C–H activation processes, including
hydroxylation of free amino acids in water (Fig. 1),3 and
directed arylation of alkyl groups (not shown).4
Intramolecular hydroarylation, a formal addition of arene
C–H bonds across multiple bonds in an intramolecular
manner, provides a direct route to valuable organic
compounds such as annulated arene heterocycles and
carbocycles. In contrast to the Heck reaction, a hydroaryl-
ation approach not only eliminates the requirement for a
halogen (or triflate) substituent, but also allows for multiple
mechanistic possibilities, which in turn may lead to different
regio-isomeric products (Fig. 2). These alternative mechan-
istic routes include arene metallation-Heck type addition,8
multiple bond activation-electrophilic substitution,9 and
metal-catalyzed Claisen rearrangement (Fig. 3).10,11
Keywords: C–H fuctionalization; C–H activation; platinum(IV);
hydroarylation; alkynes; chromenes; benzopyrans.
2. Results and discussion
*
Corresponding author. Tel.: þ1-212-854-7108; fax: þ1-212-932-1289;
e-mail: sames@chem.columbia.edu
These authors contributed equally to this work.
2.1. Systematic screening study: lead identification
We focused our initial efforts in this area on the cyclization
†
‡
Present address: Department of Chemistry, Pukyong National University,
Busan, Korea.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.05.003

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S. J. Pastine et al. / Tetrahedron 59 (2003) 8859–8868
Figure 1. C–H bond functionalization in complex organic substrates. Overview of Sames group synthetic program.
alkyne activation, as low or no yields of 2 were observed
(,6%, Table 1) in nearly all experiments. A notable
exception was the method based on the use of Pd(OAc)2,
NaOAc, and formic acid which has previously been
developed for the synthesis of coumarins via coupling of
alkynoate esters and electron rich phenols.11a In our screen,
this protocol showed a promising yield of 18%, however,
upon closer examination it showed limited substrate scope
and low isolated yields.
Figure 2. Hydroarylation vs. the Heck reaction.
A related method for the preparation of coumarins via
intramolecular cyclization of aryl alkynoate esters has
recently been disclosed by Fujiwara, utilizing a catalytic
amount of Pd(OAc)2 in TFA–CH2Cl2.12 Surprisingly,
product 2 was not formed under these conditions. The use
of Pd(CH3CN)2Cl2, recently reported to catalyze the
intramolecular reaction between unactivated alkenes and
1,3-diketones, also failed to promote the cyclization
(Table 1).13
Table 1. Selected data from a systematic screening
Figure 3. Intramolecular hydroarylation of alkynes and alkenes offers
alternative mechanistic possibilities.
Catalyst
Solvent
Yield of 2 (1)
Reference
of alkyne substrates, specifically propargylic aryl ethers.
Propargyl ether 1, the parent member of this class, was
selected as the first substrate for screening of a broad
spectrum of metal salts and complexes. We assured that
reagents and catalysts, reported previously to either promote
reactivity of alkenes and alkynes toward nucleophiles or
facilitate metallation of arenes, were included in the screen.
The experiments were conducted in parallel in a reaction
block and analyzed by automated HPLC. Thirty metal salts
and complexes were evaluated under approximately 80
reaction conditions in total (Table 1). Such a matrix rapidly
unveiled the incompetence of many known methods for
AgBF4
AuCl3
GaCl3
Pd(OAc)2/NaOAc
Pd(OAc)2
Pd(CH3CN)2Cl2
PtCl2
CHCl3
Toluene
Toluene
HCO2H
TFA
CH3CN
Toluene
CH2Cl2
Toluene
THF
0 (96)
6 (82)
3 (103)
18 (25)
0 (0)
0 (56)
3 (74)
32 (7)
19 (30)
18 (36)
10
15
16
11
12
13
9
PtCl4
18
Conditions: 5 mol% catalyst, substrate 1 (0.2 M), rt, 12 h. The yield was
determined by HPLC in the presence of an internal standard. 30 metal salts/
complexes were examined under 80 experimental conditions in total.

S. J. Pastine et al. / Tetrahedron 59 (2003) 8859–8868
8861
Historically, silver and mercuric salts have been known to
mediate the cyclization of propargylic aryl ethers, but only
by employing a stoichiometric quantity of the heavy
metal.14 Under the catalytic conditions of our screening,
AgBF4 gave no yield of chromene 2 (Table 1). In more
recent disclosures, AuCl3, GaCl3 and PtCl2 have been
reported to promote the coupling of alkynes with arenes and
heteroarenes. Specifically, AuCl3 has been shown to
catalyze intramolecular reactions of alkynes and furans to
The phenyl substrate 5 turned out to be particularly
interesting. In this case, PtCl4 and PtCl2 were equally
effective in providing 50% yield of desired compound 6a,
while Pd(OAc)2 in TFA generated saturated benzopyran 6c
as the only isolated product in 67% yield. In the case of ester
7, the greater electrophilicity of Pt(IV) vs. Pt(II) became
apparent as PtCl4 yielded 54% of desired chromene 8a,
while only a trace of this product was detected in the
presence of PtCl2. The highly electrophilic conditions of
Pd(OAc)2 in TFA at 508C proved marginally superior to
PtCl4, furnishing 8a in 59% yield.
provide substituted phenols,15 while GaCl3 and PtCl2
16
17
have hitherto been the most efficient catalysts for intra-
molecular electrophilic hydroarylation of terminal alkynes.
Again, all three salts proved ineffective in the cyclization of
1 as only low yields of 2 were observed (,6%, Table 1).
Intrigued by the fact that the Fujiwara method produced the
saturated benzopyran 6c in 67% yield we discovered that the
chromene 6a was reduced under the reaction conditions.
Furthermore, we found that 6a is reduced by TFA itself. In
addition we found that this reaction occurs with substrate
10a, and occurs in other acids as well (Table 3). The futility
of the Fujiwara method can be realized by the fact that the
desired chromene products are not stable under the strong
acidic conditions, which are necessary for the cyclization to
proceed (Pd(OAc)2 in CH2Cl2 or AcOH results in no
reaction).19
We were delighted to uncover an exciting lead, which
unambiguously stood out in the array of experiments owing
to the highest yield of the product. Remarkably, PtCl4 in
CH2Cl2 furnished chromene 2 in 32% HPLC yield (other
solvents also yielded promising results, Table 1). In
contrast, PtCl2 showed no or very low activity under the
same conditions (,3%). This result prompted us to
investigate both the efficiency and scope of Pt(IV)-catalyzed
hydroarylation reactions, and to compare PtCl4 with
PtCl2.18
Table 3. Acid promoted reduction of chromene substrate
2.2. Second generation screening: alkyne substitution
With the establishment of an exciting lead we were prepared
to determine the efficacy of the cyclization protocol with
regard to alkyne substitution. Thus, terminal alkyne 1,
methyl derivative 3, phenyl derivative 5, and alkynoate ester
7 were prepared and subsequently examined (Table 2).
Consistent with the results described above, PtCl4 was the
only catalyst that afforded acceptable isolated yields of
product 2 from terminal alkyne 1 (55%). In the case of
methyl substrate 3, the desired product 4a was isolated in
66% isolated yield using dichloroethane as solvent, and
interestingly increased to 92% yield in dioxane. In contrast,
PtCl2 produced only 25% yield of 4a, and Pd(OAc)2
according to the Fujiwara12 protocol provided none of the
chromene.
Entry
Acid
TFA
MsOH
TfOH
AcOH
Yield 10c (%)
10a (%)
1
2
3
4
5
80
28
22
Trace
Trace
0
21
17
92
96
HCl/Et2O
Yields determined by the mass recovery of the purified reaction mixture and
the ratio was determined by 1H NMR of the mixtutre.
A striking advantage of this PtCl4 catalyzed cyclization is
that a variety of organic solvents can be used, including
polar coordinating solvents (dioxane, THF, EtOAc). Two
interesting solvent effects arose during the optimization
period: (1) the overall cyclization yield and rate of reaction
was found to be generally higher/faster in dioxane vs.
dichloroethane, and (2) the amount of undesired 4-H
chromene isomer was typically higher in dioxane (Table 4).
Table 2. Catalytic cyclization of propargyl ether substrates
Table 4. Dioxane vs. dichloroethane
b
PtCl2 a/b/c
(SM)
c
Pd(OAc)2 a/b/c
(SM)
Substrate
PtCl4a a/b/c
(SM)
1, R¼H
55:0:0 (0)d
92:0:0 (0)f
57:28:0 (0)
54:0:0 (0)
6:0:0 (23)e
25:0:0 (61)e
51:0:0 (30)
,1:0:0 (85)
9:0:0 (40)
0:0:10 (41)
0:0:67 (0)
59:0:0 (0)g
3, R¼Me
5, R¼Ph
7, R¼CO2Me
Substrate
Solvent
Dioxane
ClCH2CH2Cl
Dioxane
ClCH2CH2Cl
Temperature, time
Yield (%) A/B
a
Conditions: 5 mol% PtCl4, (CH2)2Cl2, 708C, 24 h.
5 mol% PtCl2, toluene, 808C, 24 h.
1 mol% Pd(OAc)2, TFA, rt, 1 h.
3 mol% PtCl4, (CH2)2Cl2, rt, 24 h.
Reaction conducted at rt.
b
c
d
e
f
5, R¼H
5, R¼H
9, R¼Me
9, R¼Me
rt, 5 h
57:28
50:5
66:11
49:3
708C, 24 h
rt, 3 h
708C, 5 h
In dioxane at rt, 2 h. 66% yield was obtained in (CH2)2Cl2.
Reaction conducted at 508C. Isolated yields (%) are given in the table.
g
Isolated yields given in table.

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S. J. Pastine et al. / Tetrahedron 59 (2003) 8859–8868
The cyclization of phenyl alkyne substrates 5 and 9 was
achieved at ambient temperature in dioxane, but elevated
temperatures were required to achieve cyclization in
dichloroethane (Table 4). In addition, the overall cyclization
yield was significantly higher (.25%) in dioxane for both
substrates. Unfortunately, the undesired 4-H isomers 6b,
and 10b were also formed to a greater extent in dioxane. In
order to determine if the products were equilibrating under
the reaction conditions the 2-H chromenes 6a and 10a were
subjected to the cyclization protocol and were not found to
isomerize to their 4-H counterparts.
cyclization. We were delighted to find that chiral propargyl
ether 16 afforded chromene 17 in 82% yield while no
racemization was observed (Scheme 2). This finding
significantly expands the scope of this hydroarylation
methodology.22
Noteworthy is the fact that the catalyst exhibits increased
solubility in dioxane over dichlororethane. This may
suggest that the higher reactivity of PtCl4 (in comparison
to PtCl2 and other metal salts) may be related not only to the
higher oxidation state of the platinum metal, but also to the
solubility of the catalyst.20
Scheme 2.
2.4. Electrophilic hydroarylation vs. arene metallation
Since reactions were compatible with a small amount of
water (0.5%), we were able to address the third mechanistic
possibility, namely arene metallation followed by Heck
reaction (path 1, Fig. 3). The cyclization of the geminal
dimethyl substrate 18 in the presence of 1 equiv. of D2O
(Scheme 3) revealed that the deuterium atoms were
incorporated in product 19 at the 3 and 4 positions as
judged by 1H NMR.23 These results suggest three important
mechanistic points: (1) the intermediacy of a vinyl platinum
species, (2) the proton on the arene is released into the
solvent along the reaction path, and (3) reversible metalla-
tion of the arene ring does not occur.
2.3. Electrophilic hydroarylation vs. Claisen
rearrangement
In the next stage of this project, we posed an important
mechanistic question as to whether the cyclization pro-
ceeded via the electrophilic substitution mechanism or via
the Claisen rearrangement manifold. In order to address this
issue, we constructed a substrate probe 11, which in the
event of Claisen rearrangement ought to lead to two
isomeric products 12 and 13 (Scheme 1). This was
confirmed by submitting phenol 11 to the harsh conditions
of thermal rearrangement (2408C),21 and indeed, two
products 12 and 13 were formed in a 7:3 ratio. In contrast,
substrate 11 in the presence of 2 mol% of PtCl4 in dioxane at
ambient temperature afforded 12 in 59% yield, whereas
isomer 13 was not detected in the crude reaction mixture.
Closely linked to these mechanistic considerations was the
important question of whether a stereogenic center in chiral
propargyl ethers would be compromised during the
Scheme 3.
Our results support a mechanistic picture whereby coordi-
nation of PtCl4 activates the alkyne for interception by the
benzene ring (electrophilic hydroarylation, path 2, Fig. 3)
followed by some type of protonation event. However, we
cannot rule out the possibility that coordination of the
alkyne directs the metal to the arene nucleus (ortho-
metallation), and then proceeds through a Heck-type
addition. The latter seems unlikely as only 6-endo products
were formed for 1,5 arene–eyne substrates24 and the
products would have to result from a trans carbo-platination
event.25
2.5. Substrate scope: arene substitution
The utility of Pt(IV)Cl4 for the cyclization of propargyl-aryl
ethers is demonstrated in Tables 5 and 6. This method
demonstrated good compatibility with various functional
groups, including alkyl groups, free phenols (Scheme 1),
protected amines, halides and carbonyls. It was found that,
electron releasing groups generally increased the reactivity
of these substrates and as such higher yields of the
corresponding products are usually obtained. For example,
substrate 20 bearing two methyl groups on the benzene
Scheme 1. Conditions: (a) 2408C, diethyleneglycol; (b) 2 mol% PtCl4,
dioxane, rt.

S. J. Pastine et al. / Tetrahedron 59 (2003) 8859–8868
Table 5. Catalytic cyclization of arene–eyne substrates
8863
Substrate
Conditions
Product
Yield (%)a
20
1% PtCl4, dioxane, rt, 1 h
21
86 (9)
22
24
2% PtCl4, ClCH2CH2Cl, rt, 6 h
3% PtCl4, dioxane, rt, 1 h
23a/23b
25a/25b
67, p-/o-¼9:1
74, p-/o-¼76:24
26
5% PtCl4, ClCH2CH2Cl, rt, 48 h
27a/27b
34
28
30
32
5% PtCl4, ClCH2CH2Cl, rt, 1.5 h
5% PtCl4, ClCH2CH2Cl, 708C, 5.5 h
5% PtCl4, ClCH2CH2Cl, 708C, 5 h
29a/29b
66, p-/o-¼88:12
31
78
33a/33b
68, p-/o-¼4.5:1
34
36
2% PtCl4, dioxane, rt, 3 h
35
92, p-/o-¼5.5:1
82, p-/o-¼78:22
5% PtCl4, ClCH2CH2Cl, 708C, 2 h
37a/37b
38
5% PtCl4, ClCH2CH2Cl, 708C, 1 h
39a/39b
63, p-/o-¼75:25
a
Yields refer to those of pure isolated products. Yield in parenthesis corresponds to the yield of 4H-chromene isomer.
nucleus was converted to the chromene 21 in 86% isolated
yield in the presence of only 1 mol% of PtCl4 (Table 5).
Both the Boc- and Fmoc-protected anilines 22 and 24 were
converted to the corresponding chromenes 23a/23b and
25a/25b in 67 and 74% yield, respectively. Conversion was
also observed with free aniline 26; however, the yield
dropped to 34% and higher temperature and longer reaction
time was required. Substrates, containing an electron-
withdrawing bromine substituent 28 or ketone functionality
34 were also tolerated. In the case of the ketone substrate,
cyclization was achieved in 88% yield with only 2 mol%
PtCl4 in less than 3 h. Substitution in the 2-position was
tolerated as demonstrated by the conversion of the geminal
dimethyl substrates 48, 50, and the 2-cyclopropyl substrate
46, to their corresponding chromenes (Table 6). In addition
to propargyl ethers, propargyl amines 36, 38 were also good
substrates furnishing the corresponding dihydroquinolines
37 and 39 in good yields. Furthermore, coumarin 41, 43a/
43b and dihydronapthalene 45 products were successfully
produced from their corresponding acyclic precursors under
the action of PtCl4. The pyrrole substrate 52 smoothly
cyclized to dihydro-indolizines 53a/53b via a 6-exo mode,

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S. J. Pastine et al. / Tetrahedron 59 (2003) 8859–8868
Table 6. Catlaytic cyclization of arene–eyne substrates
Substrate
Conditions
Product
Yield (%)a
40
42
44
5% PtCl4, ClCH2CH2Cl, 708C, 24 h
5% PtCl4, ClCH2CH2Cl, 708C, 24 h
5% PtCl4, ClCH2CH2Cl, 708C, 24 h
41
72
43a/43b
50
50
45
46
48
15% PtCl4, dioxane, rt, 12 h
1% PtCl4, dioxane, rt, 1 h
47
49
55
90
50
52
3% PtCl4, dioxane, rt, 3 h
51
85
5% PtCl4, ClCH2CH2Cl, 708C, 10 h
53a/53b
72 exo/endo¼63:37
54
56
5% PtCl4, ClCH2CH2Cl, 708C, 38 h
5% PtCl4, ClCH2CH2Cl, 708C, 36 h
55
24
57a/57b
57 E/Z¼1:1
58
5% PtCl4, ClCH2CH2Cl, 708C, 13 h
59a/59b
14 E/Z¼1:14
a
Yields refer to those of pure isolated products.
in 72% yield, while pyrrole 54 with a shorter carbon tether
cyclizes via the 6-endo mode in 24% yield and required
longer reaction time. The furyl-ether 56 expectedly yielded
the exo-cyclization product in 57% yield. Albeit in low
yield, the formation of the 7-membered oxacyle 59a/59b
from furyl-ether 58 stands out as a particularly interesting
case. We believe this product was formed via several
tandem rearrangements starting with a 7-endo cyclization.26
3. Conclusion
In summary, we have developed a mild and neutral method
for hydroarylation of arene–yne substrates with promising
efficiency and scope. PtCl4 demonstrated consistent per-
formance with arene–yne substrates of diverse structural
features, including propargyl ethers, propargyl amines, and
alkynoate esters, providing good to excellent yields of the
6-endo products. In contrast, Pt(II) and Pd(II) salts were
shown to be sensitive to the substitution on the alkyne
moiety. PtCl4 was compatible with both terminal and
disubstituted alkynes, as well as with various functionalities
on the arene ring, including carbonyl, methyl, methoxyl,
hydroxyl, protected amine, halide, and carbonyl. At least
one electron-donating group on the arene ring was required
for the reaction to proceed.
It appears that the presence of at least one electron donating
substituent on the benzene ring was required for the
cyclization to proceed. For example, 4-phenyl-1-butyne
was resistant to cyclization in the presence of either PtCl2 or
PtCl4, providing only recovered starting material at ambient
temperature, with slight decomposition occurring at
elevated temperatures.

S. J. Pastine et al. / Tetrahedron 59 (2003) 8859–8868
8865
Some trends have emerged from the current study regarding
the comparison of PtCl4 with PtCl2.7 For instance, the
activity of PtCl2 and PtCl4 was comparable toward
substrates containing arene rings with two or more
electron-donating substituents. These findings are consistent
with those shown for the cycloisomerization of enynes.18 In
the case of enynes, PtCl2 was sufficiently electrophilic for
the activation of the alkyne toward an intramolecular attack
by an alkene. Electron-rich arenes compare to alkenes in
terms of nucleophilicity and reactivity,27 and thus PtCl2
should be sufficient for facile hydroarylation reaction of
these substrates. However, in the case of arenes of lower
electron density or electron-poor alkynes, PtCl2 does not
exert sufficient activation of the alkyne group and therefore
the more electrophilic PtCl4 is required. The greater
reactivity and scope of PtCl4 may stem not only from the
higher oxidation state of the platinum metal, but also from
the greater solubility of PtCl4 in organic solvents. Faster
rates of PtCl4-catalyzed cyclization reactions in dioxane in
comparison to dichloromethane may also be ascribed to
better solubility of the catalyst in the former solvent.
3H), 4.25 (t, J¼6.6 Hz, 1H), 4.51 (d, J¼6.6 Hz, 2H), 4.71
(sextet, J¼1.7 Hz, 2H), 5.47 (tq, J¼1.7, 3.5 Hz, 1H), 6.65
(br s, 1H), 6.85 (br s, 1H), 6.91 (d, J¼7.5 Hz, 1H), 7.03 (d,
J¼8.2 Hz, 1H), 7.31 (t, J¼7.5 Hz, 2H), 7.40 (t, J¼7.4 Hz,
2H), 7.59 (d, J¼7.4 Hz, 2H), 7.76 (d, J¼7.5 Hz, 2H); 13C
NMR d 17.8, 47.1, 65.6, 66.8, 106.2, 111.1, 116.9, 120.0,
124.0, 124.9, 127.1, 127.7, 129.8, 138.21, 141.3, 143.7,
153.1, 154.8 (One carbon is missing due to overlapping).
HRFABMS m/z 383.1511 (M)þ, calcd for C25H21NO3
383.1521.
4.2.2. (4-Methyl-2H-chromen-5-yl)-carbamic acid 9H-
fluoren-9-ylmethyl ester (25b). A white solid (mp 188–
1908C) (SiO2, hexane/EtOAc¼5:1). IR 3267, 1697, 1604,
1
1525, 1450, 1220, 738 cm21; H NMR d 2.05 (br s, 3H),
4.22 (br s, 1H), 4.45 (dq, J¼1.4, 4.4 Hz, 2H), 4.52 (d,
J¼5.7 Hz, 2H), 5.67 (tq, J¼1.4, 4.4 Hz, 1H), 6.38 (br s, 1H),
6.76 (d, J¼8.0 Hz, 1H), 7.00 (br s, 1H), 7.11 (t, J¼8.0 Hz,
1H), 7.28 (t, J¼7.0 Hz, 2H), 7.37 (t, J¼7.4 Hz, 2H), 7.56
(m, 2H), 7.74 (d, J¼7.5 Hz, 2H); 13C NMR d 20.0, 47.4,
64.4, 67.0, 112.5, 113.8, 118.5, 119.9, 121.18, 124.8, 126.9,
127.6, 128.6, 130.1, 133.0, 141.2, 143.5, 153.9, 155.8.
HRFABMS m/z 383.1511 (M)þ, calcd for C25H21NO3
383.1521.
From a practical standpoint this PtCl4 cyclization method is
user friendly. Reactions can be carried out in air and
rigorous exclusion of moisture is unnecessary since
reactions are typically compatible with a small amount of
water (0.5%). Electrophilic hydroarylation constitutes an
attractive class of transformations, which in contrast to the
Heck reaction, do not require a halide (or triflate) at the site
of the C–C coupling on the arene ring. Furthermore, 6-endo
products are formed exclusively. It appears that PtCl4
possesses a special blend of reactivity and selectivity, as
demonstrated by the selective activation of a triple bond
toward one class of nucleophiles, namely the arenes.28
4.2.3. 7-Methoxy-2H-chromene-4-carboxylic acid
methyl ester (33a).
A
clear oil (SiO2, hexane/
EtOAC¼7:1). IR 2955, 2840, 1732, 1617, 1506, 1257,
1
1028 cm21; H NMR d 3.78 (s, 3H), 3.84 (s, 3H), 4.80 (d,
J¼4.2 Hz), 6.43 (d, J¼2.6 Hz), 6.52 (dd, J¼2.6, 8.7 Hz),
6.74 (t, J¼4.2 Hz, 1H), 7.84 (d, J¼8.7 Hz); 13C NMR d
51.9, 55.3, 64.8, 101.9, 107.4, 112.7, 127.0, 127.3, 128.7,
155.5, 160.9, 165.4. HRFABMS m/z 219.0659 (M2H)þ,
calcd for C12H11O4 219.0657.
4.2.4. 5-Methoxy-2H-chromene-4-carboxylic acid
methyl ester (33b).
A
clear oil (SiO2, hexane/
4. Experimental
4.1. General
EtOAC¼7:1). IR 2952, 2843, 1738, 1606, 1476, 1271,
1249, 1092 cm21; 1H NMR d 3.80 (s, 3H), 3.81 (s, 3H), 4.63
(d, J¼6.24 Hz, 1H), 6.52–6.59 (m, 2H), 7.16 (t, J¼8.3 Hz,
1H); 13C NMR d 51.7, 56.1, 64.2, 104.9, 109.4, 110.8,
124.7, 128.8, 130.3, 155.5, 155.7, 168.6. HRFABMS m/z
219.0650 (M2H)þ, calcd for C12H11O4 219.0657
Nuclear Magnetic Resonance spectra were recorded on
Bruker 300 or 400 Fourier transform NMR spectrometers.
Spectra were recorded in CDCl3 solutions referenced to
TMS or the solvent residual peak. IR spectra were taken as
neat for liquids on NaCl plates, and as KBR pellet for solids
using a Perkin–Elmer 1600 FTIR spectrometer. High
Resolution Mass Spectra were obtained on a JOEL
JMS_HX110 HF mass spectrometer. Flash chromatography
was performed on SILICYCLE silica gel (230–400 mesh).
4.2.5. 1-(8-Methoxy-4-methyl-2H-chromen-6-yl)-etha-
none (35). A white solid (SiO2, hexane/EtOAC¼4:1). IR
1
1673, 1581, 1288, 1216 cm21; H NMR d 2.04–2.05 (m,
3H), 2.54, (s, 3H), 3.89 (s, 3H), 4.89–4.90 (m, 2H), 5.58–
5.62 (m, 1H), 7.39–7.42 (m, 2H); 13C NMR d 18.4, 26.3,
56.2, 66.3, 111.2, 117.2, 118.4, 123.5, 129.2, 129.7, 147.4,
147.5, 196.2. APCI m/z 219.0817 (MþH)þ, calcd for
C13H15O3 219.1021.
4.2. Procedure for catalytic cyclization of arene alkyne
substrates with PtCl4
4.2.6. 7-Methoxy-4-phenyl-2H-quinoline-1-carboxylic
acid methyl ester and 5-methoxy-4-phenyl-2H-quino-
line-1-carboxylic acid methyl ester (39a, 39b). The
mixture of p- and o-isomers was obtained as a yellow
solid (SiO2, hexane/EtOAC¼1:6). IR 1711, 1611, 1441,
1225, 1050 cm21; p-isomer 1H NMR d 3.81 (s, 3H), 3.82 (s,
3H), 4.44 (d, J¼4.6 Hz, 2H), 5.87 (t, J¼4.6 Hz, 1H), 6.59
(dd, J¼2.6, 8.7 Hz, 1H), 6.96 (d, J¼8.7 Hz, 1H), 7.23–7.36
(m, 6H). o-isomer 1H NMR d 3.39 (s, 3H), 3.77 (s, 3H), 4.29
(d, J¼5.1 Hz, 2H), 6.04 (t, J¼5.1 Hz, 1H), 6.66 (dd, J¼1.0,
A solution of substrate (0.2 M) and PtCl4 (1–5%) were
stirred in air until the substrate was completely consumed.
Reactions were monitored by TLC. After completion, the
solvent was evaporated and the products purified by
filtration through silica gel.
4.2.1. (4-Methyl-2H-chromen-7-yl)-carbamic acid 9H-
fluoren-9-ylmethyl ester (25a). A white solid (mp 119–
1218C (dec.)) (SiO2, hexane/EtOAc¼1:5). IR 3297, 1697,
1590, 1527, 1223, 740 cm21; 1H NMR d 1.97 (q, J¼1.7 Hz,

8866
S. J. Pastine et al. / Tetrahedron 59 (2003) 8859–8868
8.2 Hz, 1H), 7.19–7.36 (m, 7H). 13C NMR mixture of p-
and o-isomers: d 42.7, 43.3, 53.1, 53.1, 55.4, 55.5, 108.3,
109.6, 109.8, 116.6, 120.1, 122.2, 124.2, 126.3, 126.7,
127.3, 127.5, 128.0, 128.1, 128.4, 137.4, 138.1, 138.4,
138.7, 139.3, 141.1, 153.9, 154.2, 155.8, 158.7 (two carbons
are missing due to overlapping). HRFABMS m/z 295.1202
(M)þ, calcd for C18H17NO3 295.1208.
165.1. HRFABMS m/z 177.0779 (M)þ, calcd for
C10H11NO2 177.0790.
4.2.12. (5-Methyl-oxepin-3-ylidene)acetaldehyde (59a/
59b). The title compound was obtained as pale yellow oil
as mixture of E and Z isomers. IR 2920, 1724, 1668, 1628,
1446, 1117, 1033 cm21; E-isomer 1H NMR d 2.02 (d,
J¼0.7 Hz, 3H), 4.58 (s, 2H), 5.10 (dd, J¼1.3, 6.8 Hz, 1H),
5.53 (d, J¼7.6 Hz, 1H), 6.62 (d, J¼6.8 Hz, 1H), 7.06 (s,
1H), 10.17 (d, J¼7.6 Hz, 1H); 13C NMR d 27.1, 75.6, 108.9,
121.6, 125.1, 141.6, 148.3, 152.2, 191.2. Z-isomer 1H NMR
d 1.98 (d, J¼0.8 Hz, 3H), 5.06 (s, 2H), 5.14 (dd, J¼1.3,
6.7 Hz, 1H), 5.90 (d, J¼7.8 Hz, 1H), 6.30 (s, 1H), 6.68 (d,
J¼6.7 Hz, 1H), 10.05 (d, J¼7.8 Hz), 13C NMR d 26.9, 67.0,
110.0, 125.4, 129.4, 142.1, 149.6, 153.0, 190.0. APCI m/z
151.0759 (MþH)þ, calcd for C9H11O2 151.1857.
4.2.7. 6,8-Dimethoxy-3,4-dihydro-naphthalene-1-car-
boxylic acid methyl ester (45). A clear oil (SiO2, hexane/
EtOAC¼3:1). IR 1734, 1604, 1210, 1153 cm21; 1H NMR d
2.22–2.28 (m, 3H), 2.66 (t, 2H; Jav¼7.6 Hz), 3.73 (s, 3H),
3.77 (s, 3H), 3.80 (s, 3H), 6.35 (d, J¼2.3 Hz, 1H), 6.38 (d,
J¼2.0 Hz, 1H), 6.48 (t, J¼5.0 Hz, 1H); 13C NMR d 22.7,
28.9, 51.7, 55.3, 55.9, 97.1, 105.2, 114.3, 130.9, 131.6,
139.7, 156.1, 160.3, 170.4. HRFABMS m/z 248.0852 (M)þ,
calcd for C17H12O2 248.1049.
4.3. Preparation of 24
4.2.8. 2,2,5,7-Tetramethyl-2H-chromene (49). A clear oil
(SiO2, hexane/CH2Cl2¼3:1). IR 1614, 1312 cm21; 1H NMR
d 1.40 (s, 6H), 2.23 (s, 3H), 2.25 (s, 3H), 5.58 (d, J¼10 Hz),
6.46–6.52 (m, 3H); 13C NMR d 18.3, 21.3, 27.8, 75.2,
114.8, 117.1, 119.3, 123.2, 129.4, 133.6, 138.6, 152.9.
HRFABMS m/z 188.1215 (M)þ, calcd for C13H16O
188.1201.
To a solution of 267 (198 mg, 1.23 mmol) in aq. dioxane
(3 mL) were added i-Pr2NEt (258 mL, 1.47 mmol) and
FmocCl (360 mg, 1.35 mmol) at 08C. After being stirred at
rt for 30 min, the reaction mixture was extracted with
CH2Cl2, dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica
gel by eluting EtOAc/hexane (1:4).
4.2.9. tert-Butyldimethyl-[3-(2,2,5,7-tetramethyl-2H-
chromen-4-yl)propoxy]silane (51). A clear oil (SiO2,
4.3.1. O-(2-Butynyl)-N-Fmoc-3-aminophenol (24). Iso-
lated in 88% yield as a white solid, mp 143–1468C. IR
3312, 2230, 1732, 1707, 1610, 1541, 1448, 1222,
hexane/CH2Cl2¼3:1). IR 2857, 1612, 1472, 1103 cm21
;
1H NMR d 0.04 (s, 3H), 0.90 (s, 9H), 1.34 (s, 6H), 1.61 (m,
2H), 2.23 (s, 3H), 2.43 (s, 3H), 2.59 (t, Jav¼7.7 Hz, 2H),
3.61 (t, J¼6.2 Hz, 2H), 5.47 (s, 1H), 6.52 (s, 1H), 6.56 (s,
1H); 13C NMR d 25.1, 18.5, 21.2, 23.1, 26.1, 26.9, 31.5,
32.3, 62.4, 74.3, 115.7, 119.7, 125.5, 128.7, 133.6, 133.8,
137.9, 155.4. APCI m/z 361.1644 (MþH)þ, calcd for
C22H37O2Si 361.2563.
1
1025 cm21. H NMR d 1.84 (t, J¼2.3 Hz, 3H), 4.25 (t,
J¼6.5 Hz, 1H), 4.52 (d, J¼6.6 Hz, 2H), 4.61 (q, J¼2.2 Hz,
2H), 6.67 (dd, J¼2.0, 8.2 Hz, 1H), 6.73 (br s, 1H), 6.93 (d,
J¼7.5 Hz, 1H), 7.08 (br s, 1H), 7.18 (t, J¼8.1 Hz, 1H), 7.31
(t, J¼7.4 Hz, 2H), 7.40 (t, J¼7.4 Hz, 2H), 7.60 (d,
J¼7.3 Hz, 2H), 7.76 (d, J¼7.4 Hz, 2H);13C NMR 3.7,
47.1, 56.4, 66.8, 73.9, 83.8, 105.5, 110.1, 111.6, 120.0,
124.9, 127.1, 127.7, 129.71, 138.9, 141.3, 143.7, 153.2,
158.5. HRFABMS m/z 383.1508 (M)þ, calcd for
C25H21NO3 383.1521.
4.2.10. (5,6-Dihydroindolizin-8-yl)acetic acid methyl
ester and (5,6-dihydroindolizine-8-carboxylic acid
methyl ester (53a, 53b). The mixture of exo- and endo-
isomers was obtained as a yellow oil (SiO2, hexane/
EtOAc¼8:1). IR 3103, 1741, 1700, 1605, 1482, 1340,
4.4. Preparation of 32
1
1157, 1081, 857, 727 cm21; exo-isomer H NMR d 2.01
(quintet, J¼6.1 Hz, 2H), 3.18 (td, J¼1.9, 6.3 Hz, 2H), 3.69
(s, 3H), 3.97 (t, J¼5.9 Hz, 2H), 6.13 (t, J¼1.8 Hz, 1H), 6.17
(dd, J¼2.5, 4.0 Hz, 1H), 6.63 (dd, J¼1.5, 4.0 Hz, 1H), 6.72
(dd, J¼1.6, 2.2 Hz, 1H); 13C NMR d 23.3, 25.3, 45.50, 50.8,
106.3, 107.4, 109.4, 123.5, 129.0, 146.6, 167.59. endo-
To a solution of 1-methoxy-3-prop-2-ynyloxy-benzene
(440 mg, 2.71 mmol) in 5 mL of THF was added n-butyl
lithium at 2788C. After 30 min ClCO2Me (230 mL,
3.00 mmol, 1.1 equiv.) was added. The reaction was
allowed to warm to ambient temperature and stirred
overnight. Volatiles were removed and the residue was
purified by column chromatography by eluting with
hexanes/EtOAc (6:1).
1
isomer: H NMR d 2.50 (td, J¼4.6, 7.2 Hz, 2H), 3.30 (d,
J¼1.0 Hz, 2H), 3.67 (s, 3H), 3.92 (t, J¼7.2 Hz, 2H), 5.58 (t,
J¼4.5 Hz, 1H), 6.09 (m, 2H), 6.57 (t, J¼2.0 Hz, 1H); 13C
NMR d 24.6, 38.4, 43.5, 52.1, 104.5, 107.6, 118.0, 121.2,
125.1, 129.7, 171.5. HRFABMS m/z 193.1098 (M)þ, calcd
for C11H15NO2 193.1103.
4.4.1. 4-(3-Methoxyphenoxy)but-2-ynoic acid methyl
ester (32). Isolated in 93% yield as a pale yellow oil. IR
2240, 1716, 1608, 1255, 1206, 1157, 1065 cm21; 1H NMR d
3.79 (s, 3H), 3.81 (s, 3H), 4.80 (s, 2H), 6.51–6.60 (m, 3H),
7.21 (t, J¼8.1 Hz, 1H); 13C NMR d 52.8, 54.9, 55.3, 82.1,
101.5, 106.7, 107.6, 130.0, 153.3, 158.5, 160.8. HRFABMS
m/z 218.0932 (M)þ, calcd for C13H14O3 218.0943.
4.2.11. 5,6-Dihydro-indolizine-8-carboxylic acid methyl
ester (55). A yellow oil (SiO2, hexane/EtOAC¼10:1).
IR 3101, 1718, 1608, 1436, 1270, 1165, 1060, 800,
717 cm21
;
1H NMR 2.62 (td, J¼5.0, 7.1 Hz, 2H), 3.82
(s, 3H), 3.94 (t, J¼7.1 Hz, 2H), 6.15 (dd, J¼2.8,
3.5 Hz, 1H), 6.61 (dd, J¼1.6, 2.5 Hz, 1H), 6.64 (dd,
J¼1.5, 3.6 Hz, 1H), 6.78 (t, J¼5.0 Hz, 1H); 13C NMR d
24.9, 42.9, 51.8, 108.1, 108.7, 121.5, 125.3, 125.4, 128.9,
4.5. Preparation of 38
To a solution of (3-hydroxy-phenyl)-carbamic acid methyl

S. J. Pastine et al. / Tetrahedron 59 (2003) 8859–8868
8867
ester7 (287.4 mg, 1.59 mmol), in DMF (4 mL) was added
NaH (76.2 mg, 1.91 mmol), and 3-phenyl-2-propynl
methanesulfonate (367.0 mg, 1.75 mmol) in 1 mL of
DMF. After 2 h, water was added and the crude product
was extracted with EtOAc (10 mL£3), washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel by
eluting EtOAc/hexane (1:5).
over MgSO4 and concentrated in vacuo. The residue was
purifed by colum chromatography by eluting with hexanes/
CH2Cl2 (8:2).
4.8.1. tert-Butyl-[6-(3,5-dimethylphenoxy)-6-methyl-
hept-4-ynyloxy]dimethylsilane (50). Isolated in 46%
yield as a colorless oil. IR 2858, 2361, 1610, 1595, 1472,
1103 cm21; 1H NMR 0.05 (s, 3H), 0.90 (s, 9H), 1.60 (s, 6H),
1.70 (quintet, Jav¼6.5 Hz, 2H), 2.27–2.36 (m, 8H), 3.66 (t,
J¼6.1 Hz, 2H), 6.68 (s, 1H), 6.84 (s, 2H); 13C NMR d 25.4,
15.1, 18.3, 21.4, 25.9, 30.0, 31.6, 61.5, 72.5, 82.8, 85.6,
119.1, 124.2, 138.2, 155.7. APCI m/z 361.1588 (MþH)þ,
calcd for C22H37O2Si 361.2563.
4.5.1. N-(3-Phenyl-2-propynyl)-N-(methoxycarbonyl)-3-
amino-1-methoxybenzene (38). Isolated in quantitative
yield as a pale yellow oil. IR 2240, 1712, 1603, 1445, 1244,
1
1034 cm21; H NMR d 3.73 (s, 3H), 3.79 (s, 3H), 4.61 (s,
2H), 6.83 (ddd, J¼0.9, 2.1, 7.8 Hz, 1H), 6.94–6.97 (m, 2H),
7.24–7.39 (m, 6H); 13C NMR d 41.0, 53.3, 55.3, 84.1, 84.9,
112.7, 119.2, 122.7, 128.2, 128.3, 129.6, 131.7, 142.5,
155.6, 159.9. HRFABMS m/z 295.1202 (M)þ, calcd for
C18H17NO3 295.1208.
4.9. Preparation of 52
Compound 52 was prepared in the same manner as
described above for the synthesis of 32. 1-Pent-4-ynyl-1H-
pyrrole31 (291 mg, 2.19 mmol), n-BuLi (1.5 mL, 1.6 M
solution in hexanes, 2.40 mmol), and ClCO2Me (204 mL,
2.61 mmol). Purification by column chromatography by
eluting with hexanes/EtOAc (8:1).
4.6. Preparation of entry 44
Compound 44 was prepared in the same manner as
described above for the synthesis of 32. But-3-ynyl-3,5-
dimethoxy-benzene29 (200 mg, 1.05 mmol), n-BuLi
(600 mL, 1.6 M solution in hexanes, 1.10 mmol), and
ClCO2Me (90 mL, 1.6 mmol). Purification by column
chromatography by eluting with hexanes/EtOAc (6:1).
4.9.1. 6-Pyrrol-1-yl-hex-2-ynoic acid methyl ester (52).
Isolated in 77% yield as a clear oil. IR 3100, 2238, 1716,
;
1434, 1261, 1078, 728 cm21 1H NMR d 2.00 (quintet,
J¼6.8 Hz, 2H), 2.26 (t, J¼6.9 Hz, 2H), 3.77 (s, 3H), 4.00 (t,
J¼6.6 Hz, 2H), 6.14 (t, J¼2.1 Hz, 2H), 6.65 (t, J¼2.1 Hz,
2H); 13C NMR d 15.56, 29.07, 47.50, 52.46, 73.55, 87.65,
108.18, 120.35, 153.79. HRFABMS m/z 192.1022
(MþH)þ, calcd for C11H14NO2 192.1025.
4.6.1. 5-(3,5-Dimethoxyphenyl)pent-2-ynoic acid methyl
ester (44). Isolated in 85% yield as a pale yellow oil. IR
2238, 1717, 1597, 1436, 1257, 1206, 1069; 1H NMR d 2.61
(t, J¼7.5 Hz, 2H), 2.83 (t, Jav¼7.5 Hz, 2H), 3.76 (s, 3H),
3.81 (s, 6H), 6.34–6.39 (m, 3H); 13C NMR d20.7, 34.1,
52.5, 54.9, 55.3, 73.5, 88.7, 98.7, 106.4, 141.9, 160.9.
HRFABMS m/z 248.1049 (M)þ, calcd for C17H12O2
248.1049.
4.10. Preparation of 54
Compound 54 was prepared in a three step sequence from
3-pyrrol-1-yl-propan-1-ol32 using Dess–Martin oxidation33
and the Corey–Fuchs34 procedure.
4.7. Preparation of 46
4.10.1. 5-Pyrrol-1-ylpent-2-ynoic acid methyl ester (54).
Isolated in 11% overal yield as a clear oil. IR 3103, 2237,
Compound 46 was prepared in a two step sequence from
3-hydroxy-4,5-dimethoxy-benzoic acid methyl ester
following the procedure of Wipf.30
1716, 1654, 1560, 1258, 1070, 721 cm21 1H NMR d
;
2.75 (t, J¼5.3 Hz, 2H), 3.75 (s, 3H), 4.09 (t, J¼5.3 Hz,
2H), 6.15 (t, J¼1.6 Hz, 2H), 6.67 (t, J¼1.6 Hz, 2H); 13C
NMR d 22.4, 47.2, 52.7, 74.7, 85.2, 108.7, 120.3, 153.5.
HREIMS m/z 177.0800 (M)þ, calcd for C10H11NO2
177.0790.
4.7.1. 3-(1-Cyclopropylprop-2-ynyloxy)-4,5-dimethoxy-
benzoic acid methyl ester (46). A pale yellow oil.
IR 2836, 2117, 1719, 1588, 1502, 1422, 1344, 1226, 1110,
;
765 cm21 1H NMR d 0.56–0.69 (m, 4H), 1.43–1.50
(m, 1H), 2.45 (d, J¼2.0 Hz, 1H), 3.89 (s, 6H), 3.93 (s,
3H), 4.64 (dd, J¼2.0, 6.7 Hz, 1H), 7.31 (d, J¼1.8 Hz, 1H),
7.44 (d, J¼1.8 Hz, 1H); 13C NMR 2.1, 3.5, 15.0, 52.2, 56.2,
61.0, 73.0, 75.0, 79.7, 107.6, 111.8, 124.8, 150.5, 153.0.
APCI m/z 291.0579 (MþH)þ, calcd for C16H19O5
291.1232.
4.11. Preparation of 58
Compound 58 was prepared in the same manner described
above for 38. 3-Furylmethanol (1.5 mL, 17.2 mmol), NaH
(759 mg, 19.0 mmol), and 1-bromo-2-butyne (1.7 mL,
19.0 mmol). Purification by column chromatography by
eluting with hexanes/EtOAC (8:1).
4.8. Preparation of 50
4.11.1. 3-But-2-ynyloxymethylfuran (58). Isolated in 65%
yield as a colorless oil. IR 3132, 2292, 2226, 1503, 1355,
To a solution 48 (195 mg, 1.04 mmol) in 1 mL of HMPA
was added n-BuLi (680 mL, 1.6 M solution in hexanes,
1.09 mmol, 1.05 equiv.) at 08C. After 30 min (3-bromo-
propoxy)-tert-butyl-dimethyl-silane (262 mg, 1.04 mmol)
was added. The reaction was allowed to warm to ambient
temperature and stirred overnight. The reaction was
quenched with water and extracted with pentane dried
1
1159, 1136, 1082, 1064, 874, 795, 602 cm21; H NMR d
1.85 (t, J¼2.3 Hz, 3H), 4.08 (q, J¼2.3 Hz, 2H), 4.43 (s, 2H),
6.41 (d, J¼1.2 Hz, 1H), 7.37 (t, J¼1.6 Hz, 1H), 7.41 (s, 1H).
13C NMR d 3.6, 57.3, 62.4, 74.9, 82.6, 110.4, 121.5, 141.0,
143.3. HREIMS m/z 151.0761 (MþH)þ, calcd for C9H11O2
151.0759.

8868
S. J. Pastine et al. / Tetrahedron 59 (2003) 8859–8868
16. Inoue, H.; Chatani, N.; Murai, S. J. Org. Chem. 2002, 67,
1414.
Acknowledgements
´
´
17. (a) Ref. 9. (b) Martın-Matute, B.; Cardenas, D. J.; Echavarren,
A. M. Angew. Chem. Int. Ed. 2001, 40, 4754. (c) Fu¨stner, A.;
Mamane, V. J. Org. Chem. 2002, 67, 6264.
Generous support for this work was provided by
GlaxoSmithKline, Merck, and Johnson & Johnson
Pharmaceutical R&D. D. S. is a recipient of the Cottrell
Scholar Award of Research Corporation, Alfred P. Sloan
Fellowship, and the Camille Dreyfus Teacher-Scholar
Award. We thank Dr J. B. Schwarz for editorial assistance.
18. In cycloisomerization of enynes PtCl2 showed similar
reactivity to PtCl4, the former being more efficient in many
cases. (a) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem.
´
Soc. 2001, 123, 11863. (b) Mendez, M.; Paz Mun˜oz, M.;
´
Nevado, C.; Cardenas, D. J.; Echavarren, A. M. J. Am. Chem.
Soc. 2001, 123, 10511. (c) Blum, J.; Beer-Kraft, H.; Badrieh,
Y. J. Org. Chem. 1995, 60, 5567. (d) Kobayashi, S.;
Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319.
19. For complete screening, see supporting information in Ref. 7.
20. Degner, M.; Holle, B.; Kamm, J.; Pilbrow, M. F.; Thiele, G.;
Wagner, D.; Weigel, W.; Woditsch, P. Transition Met. Chem.
1975/76, 1, 41.
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