PtIV-catalyzed cyclization of arene-alkyne substrates via intramolecular electrophilic hydroarylation

Article abstract of DOI:10.1021/ol034177k

(Figure presented) 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.

Full text of DOI:10.1021/ol034177k

ORGANIC
LETTERS
PtIV-Catalyzed Cyclization of
Arene−Alkyne Substrates via
Intramolecular Electrophilic
Hydroarylation
2003
Vol. 5, No. 7
1055-1058
Stefan J. Pastine, So Won Youn, and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
sames@chem.columbia.edu
Received January 31, 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.
Intramolecular hydroarylation, a formal addition of arene
C-H bonds across multiple bonds in an intramolecular
manner, provides a direct route to valuable organic com-
pounds such as annulated arene heterocycles and carbocycles.
In contrast to the Heck reaction, a hydroarylation approach
not only eliminates the requirement for a halogen (or triflate)
substituent but also allows for multiple mechanistic pos-
sibilities, which in turn may lead to different regioisomeric
products (Figure 1). These alternative mechanistic routes
We focused our initial efforts in this area on the cyclization
of alkyne substrates, specifically propargylic aryl ethers.
Figure 1. Hydroarylation vs Heck reaction.
Figure 2. Intramolecular hydroarylation of alkynes and alkenes.
Alternative mechanistic possibilities: (1) metalation-alkene/alkyne
insertion, (2) alkene/alkyne activation-electrophilic substitution,
(3) metal-mediated Claisen rearrangement. X ) O, S, NR.
include arene metalation-Heck-type addition,1 multiple bond
activation-electrophilic substitution,2 and metal-catalyzed
Claisen rearrangement (Figure 2).3,4
10.1021/ol034177k CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/11/2003

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 metalation 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, for complete data, see
the Supporting Information).
intramolecular cyclization of aryl alkynoate esters had
previously been disclosed, utilizing a catalytic amount of Pd-
(OAc)2 in TFA-CH2Cl2.5
Surprisingly, no desired product 2 was 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 cy-
clization (Table 1).6
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.7
Under the catalytic conditions of our screening, AgBF4 gave
poor yields of chromene 2 (<5%, 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
provide substituted phenols,8 while GaCl39 and PtCl210 have
hitherto been the most efficient catalysts for intramolecular
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).
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 PtCl2.11
First, we proceeded to examine the scope of PtCl4 in terms
of the alkyne substituent. 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 increased to 92% yield
in dioxane. In contrast, PtCl2 produced only 25% yield of
4a, and Pd(OAc)2 according to the Fujiwara5 protocol
Table 1. Selected Data from a Systematic Screening
catalyst
AgBF4
AuCl3
GaCl3
Pd(OAc)2/NaOAc
Pd(OAc)2
Pd(CH3CN)2Cl2
PtCl2
solvent
yield of 2 (1)a
ref
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)
3
8
9
4
5
6
2
11
P tCl4
a 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. Thirty
metal salts/complexes were examined under 80 experimental conditions in
total. For complete data see the Supporting Information.
Such a matrix rapidly unveiled the incompetence of many
known methods for 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.4 In our screen,
this protocol showed a promising yield of 18%; however,
upon closer examination, it showed limited substrate scope
and low isolated yields (<23%, see the Supporting Informa-
tion). A related method for the preparation of coumarins via
(5) Jia, C.; Piao, D.; Kitamura, T.; Fujiwara, Y. J. Org. Chem. 2000,
65, 7516-7522 and references therein.
(6) Pei, T.; Wiedenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290-
11291.
(1) (a) Kakiuchi, F.; Yamauchi, M.; Chatani, N.; Murai, S. Chem. Lett.
1996, 111-112. (b) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2001, 123, 9692-9693. (c) Boele, M. D. K.; van
Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.;
Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586-1587. (d) Baran,
P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 7904-7905.
(2) Chatani, N.; Inoue, H.; Ikeda, T.; Murai, S. J. Org. Chem. 2000, 65,
4913-4918.
(7) (a) Reference 3. (b) Larock, R. C.; Harrison, L. W. J. Am. Chem.
Soc. 1984, 106, 4218-4227.
(8) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000,
122, 11553-11554.
(9) Inoue, H.; Chatani, N,; Murai, S. J. Org. Chem. 2002, 67, 1414-
1417.
(10) (a) Reference 2. (b) Mart´ın-Matute, B.; Ca´rdenas, D. J.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2001, 40, 4754-4757. (c) Fu¨stner, A.;
Mamane, V. J. Org. Chem. 2002, 67, 6264-6267.
(11) In cycloisomerization of enynes, PtCl2 showed reactivity similar to
that of PtCl4, the former being more efficient in many cases. (a) Fu¨rstner,
A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001, 123, 11863-11869. (b)
Me´ndez, M.; Paz Mun˜oz, M.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A.
M. J. Am. Chem. Soc. 2001, 123, 10511-10520. (c) Blum, J.; Beer-Kraft,
H.; Badrieh, Y. J. Org. Chem. 1995, 60, 5567-5569. (d) PtCl4-catalyzed
addition of carbamates to enones. Kobayashi, S.; Kakumoto, K., Sugiura,
M. Org. Lett. 2002, 4, 1319-1322.
(3) Koch-Pomeranz, U.; Hansen, H.-J.; Schmid, H. HelV. Chim. Acta
1973, 56, 2981-3004.
(4) (a) There is yet another mechanistic possibility involving hydro-
metalation of triple carbon-carbon bond, generating an alkenylmetal species,
followed by intramolecular substitution of the arene ring. Hydropalladation
has been proposed to be the first step in the intermolecular cyclization of
alkynoate esters and phenols. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc.
1996, 118, 6305-6306. (b) See also: Larock, R. C.; Dotty, M. J.; Tian,
Q.; Zenner, J. M. J. Org. Chem. 1997, 62, 7536-7537.
1056
Org. Lett., Vol. 5, No. 7, 2003

Scheme 1
Table 2. Catalytic Cyclization of Propargyl Ether Substrates
a
b
c
PtCl4
PtCl2
Pd(OAc)2
substrate
1, R ) H
3, R ) Me
5, R ) Rh
a:b:c (SM)
a:b:c (SM)
a:b:c (SM)
We continued to elucidate the scope of the new methodol-
ogy, this time in terms of the benzene ring substitution. This
method demonstrated good compatibility with various func-
tional groups, including alkyl groups, protected amines, and
halides (Table 3). It was found that electron-releasing groups
55:0:0 (0)d
92:0:0 (0)f
50:5:0 (0)
54:0:0 (0)d
6:0:0 (23)e
25:0:0 (23)e
51:5:0 (30)
<1:0:0 (85)
9:0:0 (40)
0:0:10 (41)
0:0:67 (0)
59:0:0 (0)g
7, R ) CO2Me
a Conditions: 5 mol % PtCl4, (CH2)2Cl2, 70 °C, 24 h. b Conditions: 5
mol % PtCl2, toluene, 80 °C, 24 h. c Conditions: 1 mol % Pd(OAc)2,
CH2Cl2/TFA, 3:1, rt, 1 h. d Conditions: 3 mol % PtCl4, (CH2)2Cl2, rt, 24
h. e Reaction conducted at room temperature. f In dioxane, rt, 2 h. 66% yield
was obtained in (CH2)2Cl2. g Reaction conducted at 50 °C. Isolated yields
are given in the table.
Table 3. Catalytic Cyclization of Selected Substrates
provided none of the chromene. 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. Subsequently, we found that this compound was
formed by the reduction of chromene product 6a under the
reaction conditions. Furthermore, TFA itself was able to
reduce 6a to 6c in 80% isolated yield as demonstrated by a
control experiment.12 In the case of ester 7, the greater
electrophilicity of Pt(IV) vs Pt(II) became apparent as PtCl4
yielded 54% of desired chromeme 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 proved margin-
ally superior to PtCl4, furnishing 8a in 59% yield. Thus, in
the case of alkynoate esters, PtCl4 provides a mild and neutral
alternative to the Fujiwara method.
Noteworthy is the fact that PtCl4 is more soluble in organic
solvents than PtCl2. Also, PtCl4-catalyzed cyclization of
alkyne substrates occurs at faster rates in solvents that
solubilize the catalyst to a greater extent as demonstrated in
the case of substrate 3 (dioxane vs dichloromethane, see
above and also the Supporting Information). 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.13
The next issue was whether a stereogenic center in chiral
propargyl ethers would be compromised during the cycliza-
tion. We were delighted to find that chiral propargyl ether 9
afforded chromene 10 in 82% yield while no racemization
was observed (Scheme 1). This finding significantly expands
the scope of this hydroarylation methodology.14
a Conditions: 1 mol % PtCl4, dioxane, rt. 10% of 4H-chromene was
also formed. b Conditions: 5 mol % PtCl4, (CH2)2Cl2, rt. c Conditions: 5
mol % PtCl4, (CH2)2Cl2, 70 °C. d Conditions: 5 mol % PtCl2, toluene, 80
°C. Reaction times differ for each substrate; see the Supporting Information.
(12) Apparently, TFA functions at the reductant in this case. It appears
that formation of a stabilized cation via protonation of the chromene product
is the prerequisite for the subsequent reduction (ester 8a is stable in TFA).
We have not been able to find precedent for this transformation.
(13) Degner, M.; Holle, B.; Kamm, J.; Pilbrow, M. F.; Thiele, G.;
Wagner, D.; Weigel, W.; Woditsch, P. Transition Met. Chem. 1975/76, 1,
41-47.
generally increased the reactivity of these substrates and as
such higher yields of the corresponding products were
obtained. For example, substrate 11 bearing two methyl
groups on the benzene nucleus was converted to chromene
Org. Lett., Vol. 5, No. 7, 2003
1057

12 in 86% isolated yield in the presence of only 1 mol % of
PtCl4 (Table 3). Boc-protected aniline 13 was converted to
the chromenes 14a and 14b in 69% yield as a 9:1 mixture.
Conversion was also observed with free aniline 15; however,
the yield dropped to 34%. Note that in the case of electron-
rich arenes the less electrophilic PtCl2 gave results compa-
rable to PtCl4 (substrates 11, 13, and 15). Substrate 17,
containing an electron-withdrawing bromine substituent,
afforded a 68% yield of desired products 18a/18b (96:4)
under the action of PtCl4. In addition to propargyl ethers,
propargyl aniline 19 was also a good substrate as it furnished
an 82% yield of dihydroquinoline 20a/20b (78:22). For both
of theses substrates (18 and 19), PtCl4 afforded higher yields
in comparison to PtCl2. The higher electrophilicity of PtCl4
became particularly advantageous in the case of electron-
poor alkynes. Alkynoate esters 21, 23, and 25 were converted
to the corresponding chromene 22, coumarin 24, and fused
furo-dihydropyran 26, respectively, in good yields in the
presence of PtCl4. PtCl2 was ineffective with these substrates,
producing low yields (13-29%) of the corresponding
products. 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, the simple arylbu-
tyne 27 was unreactive in the presence of either PtCl2 or
PtCl4, providing only recovered starting material.
features, including propargyl ethers, propargylamines, 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.
The greater reactivity and scope of PtCl4 (vs PtCl2) 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 dioxane. These
reactions were also compatible with a small amount of water
(0.5%); however, the rates were reduced (see the Supporting
Information).
It appears that PtCl4 possesses a special blend of reactivity
and selectivity, as it selectively activated the triple bond
toward one class of nucleophiles, namely the arenes.15 Thus,
the competing processes, including the interception of
activated alkynes (and alkenes) by other nucleophiles (alkene,
alkyne, H2O, functional groups), must be considerably
slower. It is precisely the rate differences of these competing
processes that ultimately determine the distribution of
products that are obtained.
Acknowledgment. Generous support for this work was
provided by GlaxoSmithKline 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.
In summary, we have developed a mild and neutral method
for hydroarylation of arene-yne substrates with promising
efficiency and scope. PtCl4 demonstrated consistent perfor-
mance with arene-yne substrates of diverse structural
(14) Direct cycloaddition of propargyl alcohols with phenols have been
reported. However, these methods do not provide access to chiral chromenes
with asymmetric control: (a) Bigi, F.; Carloni, S.; Maggi, R.; Muchetti,
C.; Sartori, G. J. Org. Chem. 1997, 62, 7024-7027. (b) Nishibayashi, Y.;
Inada, Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 77900-
7901. For other synthetic approaches to chromenes, see: (c) Portscheller,
J. L.; Malinakova, H. C. Org. Lett. 2002, 4, 3679-3681 and references
therein. For syntheses of fused polycyclic arenes via cyclization of
2-alkynylbiaryls, see: (d) Goldfinger, M. B.; Crawford, K. B.; Swager, T.
M. J. Am. Chem. Soc. 1997, 119, 4578-4593 and references therein. (e)
Reference 11c.
Supporting Information Available: The entire Experi-
mental Section, complete data for systematic screening,
experimental details, and compound spectral characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL034177K
(15) Chisholm, M. H.; Clark, H. C. Acc. Chem. Res. 1973, 6, 202-209.
1058
Org. Lett., Vol. 5, No. 7, 2003