Palladium-catalyzed carbonylative cyclization of unsaturated aryl iodides and dienyl triflates, iodides, and bromides to indanones and 2-cyclopentenones

Article abstract of DOI:10.1021/ja0212009

Indanones and 2-cyclopentenones have been successfully prepared in good to excellent yields by the palladium-catalyzed carbonylative cyclization of unsaturated aryl iodides and dienyl triflates, iodides, and bromides, respectively. The best results are obtained by employing 10 mol % of Pd(OAc)₂, 2 equiv of pyridine, 1 equiv of n-Bu₄NCl, 1 atm of CO, a reaction temperature of 100 °C, and DMF as the solvent. This carbonylative cyclization is particularly effective on substrates that contain a terminal olefin. The proposed mechanism for this annulation includes (1) Pd(OAc)₂ reduction to the active palladium(0) catalyst, (2) oxidative addition of the organic halide or triflate to Pd(0), (3) coordination and insertion of carbon monoxide to produce an acylpalladium intermediate, (4) acylpalladation of the neighboring carbon-carbon double bond, (5) reversible palladium β-hydride elimination and re-addition to form a palladium enolate, and (6) protonation by H₂O to produce the indanone or 2-cyclopentenone.

Full text of DOI:10.1021/ja0212009

Published on Web 03/29/2003
Palladium-Catalyzed Carbonylative Cyclization of Unsaturated
Aryl Iodides and Dienyl Triflates, Iodides, and Bromides to
Indanones and 2-Cyclopentenones
Steve V. Gagnier and Richard C. Larock*
Contribution from the Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50010
Received September 23, 2002; E-mail: larock@iastate.edu
Abstract: Indanones and 2-cyclopentenones have been successfully prepared in good to excellent yields
by the palladium-catalyzed carbonylative cyclization of unsaturated aryl iodides and dienyl triflates, iodides,
and bromides, respectively. The best results are obtained by employing 10 mol % of Pd(OAc)2, 2 equiv of
pyridine, 1 equiv of n-Bu4NCl, 1 atm of CO, a reaction temperature of 100 °C, and DMF as the solvent.
This carbonylative cyclization is particularly effective on substrates that contain a terminal olefin. The
proposed mechanism for this annulation includes (1) Pd(OAc)2 reduction to the active palladium(0) catalyst,
(2) oxidative addition of the organic halide or triflate to Pd(0), (3) coordination and insertion of carbon
monoxide to produce an acylpalladium intermediate, (4) acylpalladation of the neighboring carbon-carbon
double bond, (5) reversible palladium â-hydride elimination and re-addition to form a palladium enolate,
and (6) protonation by H2O to produce the indanone or 2-cyclopentenone.
Scheme 1
Introduction
2-Cyclopentenones are found in many natural products or
used as building blocks for the development of other biologically
active compounds. For instance, tetrahydrodicranenone B has
shown antimicrobial and antihypertensive properties,1 while
indanocine has been identified as having antiproliferative
activity.2 Because of the importance of 2-cyclopentenones3 and
indanones,4 numerous synthetic methods for their preparation
have been developed.
A number of palladium-catalyzed annulation processes have
been reported for the synthesis of carbo- and heterocycles.5
Yamamoto et al. have synthesized indenols and indanones
through a palladium-catalyzed annulation of internal alkynes
by aromatic aldehydes (Scheme 1).6 A number of substituted
indenol derivatives have been prepared by treating o-bromoben-
zaldehydes with various internal alkynes in the presence of a
palladium catalyst. Upon further heating, these indenol deriva-
tives isomerize to the corresponding indanones. We have also
reported the synthesis of indenones using similar starting
materials and slightly modified palladium conditions.7
Negishi and co-workers have extensively explored palladium-
catalyzed carbonylative cyclization reactions which produce a
variety of cyclic ketones. They were able to produce 2-cyclo-
pentenones and indenones through the palladium-catalyzed
carbonylation of 1-iodo-1,4-alkadienes and o-iodostyrene de-
rivatives.8 When o-iodostyrene (1) was reacted under their
palladium conditions without MeOH present, indenone 2 and
indanone 3 were produced in 50 and 9% yields, respectively
(eq 1). When MeOH was added to the reaction and the amount
of CO was increased to 40 atm, 2 was produced in a 2% yield
along with a 74% yield of indanone 4 and a 2% yield of ester
5 (eq 2).
(1) Trost, B. M.; Pinkerton, A. B. Org. Lett. 2000, 2, 1601.
(2) Leoni, L. M.; Hamel, E.; Genini, D.; Hsiencheng, S.; Carrera, C. J.; Cottam,
H. B.; Carson, D. A. J. Natl. Cancer Inst. 2000, 92, 217.
(3) (a) Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385. (b) Trost, B.
M.; Krische, M. J. Synlett 1998, 1. (c) Kirmse, W. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1164. (d) Geis, O.; Schmalz, H. G. Angew. Chem., Int. Ed.
1998, 37, 911.
(4) (a) Heaney, H. ComprehensiVe Organic Synthesis; Pergamon Press: Oxford,
New York, Seoul, Tokyo, 1991; Vol. 2. (b) Immer, H.; Bagli, J. F. J. Org.
Chem. 1968, 33, 2457. (c) House, H. O.; Hudson, C. B. J. Org. Chem.
1970, 35, 647. (d) House, H. O.; McDaniel, W. C. J. Org. Chem. 1977,
42, 2155. (e) Abraham, E. M.; Prasad, R. S. Tetrahedron Lett. 1974, 971.
(5) (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996,
96, 635. (b) Negishi, E.; Coperet, C.; Ma, S.; Liou, S.; Liu, F. Chem. ReV.
1996, 96, 365. (c) Pfeffer, M. Recl. TraV. Chim. Pays-Bas 1990, 109, 567.
(d) Schore, N. E. Chem. ReV. 1988, 88, 1081. (e) Larock, R. C. J.
Organomet. Chem. 1999, 576, 111. (f) Larock, R. C. PerspectiVes in
Organopalladium Chemistry for the XXI Century; Elsevier Press: Lausanne,
Switzerland, 1999; p 111. (g) Larock, R. C. Pure Appl. Chem. 1999, 71,
1435.
We wish to report at this time a novel palladium-catalyzed
carbonylative cyclization of unsaturated aryl iodides and dienyl
(7) (a) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999, 121,
3238. (b) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58,
4579.
(8) Negishi, E.; Coperet, S. M.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J. M. J.
Am. Chem. Soc. 1996, 118, 5919.
(6) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett. 1999, 40,
4089.
9
4804
J. AM. CHEM. SOC. 2003, 125, 4804-4807
10.1021/ja0212009 CCC: $25.00 © 2003 American Chemical Society

Preparation of Indanones and 2-Cyclopentenones
A R T I C L E S
Table 1. Synthesis of Cyclic Ketonesa
triflates, iodides, and bromides which provides a highly efficient
new route to indanones and 2-cyclopentenones, respectively.
Results and Discussion
Our initial work was aimed at developing a set of palladium
conditions that would work well for a variety of substrates to
produce 2-cyclopentenones and indanones. The original set of
palladium conditions used included 10 mol % Pd(OAc)2, 2 equiv
of pyridine, 1 equiv of n-Bu4NCl, 1 atm of CO, DMF as the
solvent, and a reaction temperature of 100 °C. These carbonyl-
ative palladium conditions were developed within the Larock
group for the synthesis of coumarins.9 Using o-iodostyrene as
the model system, we discovered that indanone (6) was produced
in a quantitative yield after 8 h (eq 3). A few experiments were
performed to examine the effect of each key reagent on the yield,
beginning with the chloride source. When n-Bu4NCl was
removed from the reaction mixture, the reaction time increased
to 18 h, and the yield of indanone decreased to 66%. In a second
experiment, the amount of pyridine was lowered to 1 equiv,
which lowered the yield of 6 to 93%. Also, when the pyridine
base was replaced by NEt3, only a trace of indanone was
observed, with no evidence of any other products. Last, the
palladium catalyst was reduced to 5 mol %, which increased
the reaction time to 18 h and lowered the yield of 6 to 76%.
Therefore, the standard conditions for this palladium transfor-
mation are those employed in eq 3 (henceforth identified as
procedure A).
This palladium-catalyzed carboannulation has been extended
to other aryl systems to explore the generality of this reaction
and produce substituted indanone derivatives (Table 1). Styryl
derivatives that are substituted next to the aromatic ring by either
a Procedure A includes 10 mol % of Pd(OAc)2, 2 equiv of pyridine, 1
equiv of n-Bu4NCl, 1 atm of CO, a reaction temperature of 100 °C, and
DMF as the solvent. In procedure B, the 10 mol % of Pd(OAc)2 in procedure
A is replaced with 10 mol % pf Pd(dba)2. b All reported yields are for
isolated products.
(9) Kadnikov, D. V.; Larock, R. C. Org. Lett. 2000, 2, 3643.
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J. AM. CHEM. SOC. VOL. 125, NO. 16, 2003 4805

A R T I C L E S
Gagnier and Larock
an aryl or an alkyl group work well (entries 2 and 3). Aryl
iodides 7 and 9 both reacted under the standard palladium
conditions to provide the desired indanone products 8 and 10
in 100 and 60% yields, respectively. Unfavorable steric inter-
actions between the phenyl group and the organopalladium
intermediate may occur during the cyclization, accounting for
the lower yield with starting material 9 (see the later mechanistic
discussion). Styryl derivative 11, which contains an internal
carbon-carbon double bond, failed to cyclize to the desired
indanone (entry 4). Presumably, steric interactions between the
aryl- or acylpalladium intermediate and the methyl group do
not allow the palladium to add across the carbon-carbon double
bond. Starting materials, which contain electron-donating meth-
oxy groups on the arene, cyclize to the desired indanones (entries
5 and 6). However, when a methoxy group is placed ortho to
the iodide, the yield drops substantially, presumably due to steric
hindrance to oxidative addition (entry 6).
derivatives. In our system, a proton is incorporated into the
product to form the indanone or 2-cyclopentenone. One possible
source of this proton might be the solvent DMF. Therefore, an
experiment was carried out replacing DMF with DMA under
the standard palladium conditions and employing 1 as the
starting material. It was discovered that indanone (6) was still
produced in a near quantitative yield in the same 8 h reaction
time. A second possible proton source is water. Water could
be introduced into the system by either n-Bu4NCl or DMF,
because both of these materials are hygroscopic. Another
experiment was carried out with 1, in which 4 equiv of D2O
was added (eq 4).
In addition to reactions which form 5,6 ring-fused ketones, a
few examples have been attempted which would lead to a 5,5
ring-fused system. However, both heterocyclic iodide 17 and
vinylic triflate 19 produced simple carboxylic acid derivatives,
rather than the desired cyclic ketones (entries 7 and 8). The
failure of these substrates to cyclize to the ketones can be
attributed to the ring strain introduced in trying to form a 5,5
ring-fused system. The anticipated acylpalladium intermediate
may not be able to properly coordinate to the nearby olefin and
subsequently add across the carbon-carbon double bond.
Instead, the corresponding hydrolysis products 18 and 20 are
produced.
The indanone product recovered in a 95% yield contained
55% deuterium in the 2-position, and no deuterium incorporation
was found in the 3-position. In a separate experiment, it was
found that indanone itself will incorporate 55% deuterium at
the 2-position under the standard palladium conditions when 4
equiv of D2O is added. Therefore, the results from the
experiment in eq 4 only suggest that the palladium intermediate
formed after addition across the carbon-carbon double bond
does not directly incorporate a proton from water. The deuterium
is apparently only introduced later, after the indanone product
has been formed.
Vinylic derivatives, which contain a triflate, bromide, or
iodide, are able to cyclize to 5,6 ring-fused cyclopentenones
efficiently (entries 9-11). Vinylic triflate 21 reacted under the
standard palladium conditions to produce cyclopentenone 22
in a 95% yield after 12 h (entry 9). The corresponding vinylic
bromide 23 and vinylic iodide 24 also gave high 87 and 86%
yields, respectively, of cyclopentenone 22 (entries 10 and 11).
However, the reaction times for both 23 and 24 increased to 72
h. It should also be noted that vinylic bromide 23 required 10
mol % of Pd(dba)2, instead of 10 mol % Pd(OAc)2, as the
palladium catalyst (procedure B). When 23 was allowed to react
using Pd(OAc)2 as the catalyst, palladium black precipitated
out of solution after only 1 h, and only a trace of indanone 22
was detected after 72 h. Precipitated palladium black was only
found when reacting vinylic bromides and no other starting
materials. Vinylic iodides 25 and 27, which were synthesized
from R- and â-tetralone, respectively, also produced high 85
and 98% yields, respectively, of the corresponding cyclopen-
tenones (entries 12 and 13).
A 5,7 ring-fused cyclopentenone has also been prepared from
vinylic bromide 29 in a 98% yield (entry 14). Finally, acyclic
vinylic iodide 31 afforded cyclopentenone 32 in a 70% yield
after 24 h (entry 15).
The mechanism for this process was not clearly understood
initially, because the products differed significantly from those
reported in Negishi’s earlier work.8,10 Negishi’s products (see
eq 2) are presumably derived from the â-hydride elimination
of an organopalladium intermediate to form indenones or
insertion of a second CO under high pressures to form ester
In another mechanistic reaction, styryl derivative 34, which
contains two deuteria at the terminal positions of the olefin,
was allowed to react under the standard palladium conditions
(eq 5). Indanone was obtained in an overall 86% yield. It was
found that 35% deuterium was incorporated into the 3-position
and 12% deuterium was incorporated into the 2-position. The
deuterium incorporation in the 3-position suggests that a
deuterium is migrating from the 2-position. The relatively low
percentage of deuterium at the 2-position can be explained by
deuterium-proton exchange occurring with the H2O present
under the reaction conditions, after the 2,3-dideuterioindanone
is formed. From these mechanistic studies, the following
mechanism for this transformation is proposed (Scheme 2): (1)
Pd(OAc)2 reduction to the active palladium(0) catalyst; (2)
oxidative addition of the aryl iodide to Pd(0); (3) coordination
and insertion of carbon monoxide to produce an acylpalladium
intermediate; (4) acylpalladation of the neighboring carbon-
carbon double bond; (5) reversible palladium â-hydride elimina-
tion and re-addition to form a palladium enolate; and (6)
protonation by H2O to produce the indanone and a Pd(II) salt,
which is once again reduced to Pd(0).
Indenone was also prepared and reacted under the standard
palladium conditions to see if it can be reduced to indanone.
After 12 h, the only material found in the reaction mixture was
indenone itself, which was recovered in an 80% yield. This
(10) Negishi, E.; Coperet, S. M.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J. M. J.
Am. Chem. Soc. 1996, 118, 5904.
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Preparation of Indanones and 2-Cyclopentenones
A R T I C L E S
Scheme 2
visualization was effected with short wavelength UV light (254 nm)
and a basic KMnO4 solution (3 g of KMnO4 + 20 g of K2CO3 + 5 mL
of NaOH (5%) + 300 mL of H2O). All melting points are uncorrected.
Low resolution mass spectra were recorded on a Finnigan TSQ700
triple quadrupole mass spectrometer (Finnigan MAT, San Jose, CA).
High-resolution mass spectra were recorded on a Kratos MS50TC
double focusing magnetic sector mass spectrometer using EI at 70 eV.
Reagents and Starting Materials. All reagents were used directly
as obtained commercially unless otherwise noted. Pyridine, DMF,
DMA, THF, hexanes, ethyl acetate, and ethyl ether were purchased
from Fisher Scientific Co. n-Bu4NCl was purchased from Lancaster
Synthesis, Inc. 1-Indanone, 3,4,5-trimethoxybenzyl alcohol, 3,4-
dimethoxybenzaldehyde, cyclohexanone, R-tetralone, â-tetralone, cy-
cloheptanone, ethyl 2-cyclohexanonecarboxylate, ethyl 2-cyclopen-
tanonecarboxylate, 4-octyne, methyltriphenylphosphonium bromide,
iodomethane-d3, and n-BuLi were purchased from Aldrich Chemical
Co., Inc. 2-Iodobenzaldehyde,11 1-iodo-2-vinylbenzene, 1-iodo-2-iso-
propenylbenzene,10 1-iodo-2-propenylbenzene,10 4,5-dimethoxy-2-iodo-
benzaldehyde,12 2-iodo-3,4,5-trimethoxybenzaldehyde,13 4-iodo-3-n-
propylhepta-1,3-diene,14 indenone,15 and (methyl-d3)triphenylphos-
phonium iodide16 were prepared according to previous literature
procedures.
General Procedure for the Palladium-Catalyzed Carbonylative
Cyclization of Unsaturated Aryl Iodides and Dienyl Triflates,
Iodides, and Bromides. The appropriate aryl iodide, dienyl triflate,
dienyl bromide or dienyl iodide (0.5 mmol), Pd(OAc)2 (0.05 mmol),
pyridine (1.0 mmol), n-Bu4NCl (0.5 mmol), and DMF (5 mL) were
placed in a 4 dram vial. The reaction mixture was placed under a CO
atmosphere provided by a balloon and allowed to stir at 100 °C for the
designated time. The reaction was diluted with saturated aqueous NH4-
Cl (50 mL), extracted with diethyl ether (3 × 25 mL), and dried (Na2-
SO4). The solvent was evaporated under reduced pressure, and the
product was isolated by column chromatography.
reaction supports the idea that after the palladium â-hydride
elimination, the palladium hydride never dissociates completely
from the indenone, but rather adds back to the C-C double
bond, eventually forming a palladium enolate. It has been
suggested that Hofmann elimination of the n-Bu4NCl salt by
pyridine provides the proton which appears in the final product,
but omission of the n-Bu4NCl still affords a 66% yield of
indenone, ruling out this process as the sole source of protons
appearing in the final product. Water present in the reaction
mixture appears to be the most likely source of these protons.
Conclusion
Indanones and 2-cyclopentenones have been successfully
prepared by the palladium-catalyzed carbonylative cyclization
of unsaturated aryl iodides and dienyl triflates, iodides, and
bromides in moderate to excellent yields. A number of ketone
derivatives have been prepared. However, it has been observed
that a terminal olefin is required to obtain high yields;
presumably this is due to steric hindrance to alkene insertion
by the more hindered olefin. Several bicyclic cyclopentenones
containing 5,6 and 5,7 fused-rings have been prepared in
excellent yields. However, 5,5 ring-fused products cannot be
obtained.
Several mechanistic experiments employing D2O have been
performed which help explain the mechanism for this process.
It is likely that this palladium transformation is forming an
indenone intermediate, which is coordinated to a palladium
hydride species. This palladium hydride adds back across the
carbon-carbon double bond to form a palladium enolate, which
is protonated by H2O.
Acknowledgment. We gratefully acknowledge partial finan-
cial support from the Petroleum Research Fund administered
by the American Chemical Society. We also thank Johnson
Matthey, Inc., and Kawaken Fine Chemicals Co., Ltd., for the
palladium acetate.
Supporting Information Available: Characterization, includ-
1
ing H and 13C NMR spectra, for all indanones and 2-cyclo-
pentenones in Table 1 and preparative procedures and charac-
terization for compounds 9, 13, 15, 17, 19, 21, 23, 24, 25, 27,
29, and 34 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
JA0212009
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commercially prepared 60-mesh silica gel plates (Whatman K6F), and
9
J. AM. CHEM. SOC. VOL. 125, NO. 16, 2003 4807