Mo(CO)- And [Rh(CO)Cl] catalyzed allenic cyclocarbonylation reactions of alkynones: Efficient access to bicyclic dienediones

Article abstract of DOI:10.1021/ol702654x

Allenyl alkynones are efficiently transformed into fused bicyclic dienediones via cyclocarbonylation reaction conditions. Mo(CO)₆/DMSO reaction conditions result in the formation of a bicyclo[3.3.0]octenone ring system, and the [Rh(CO)₂

Full text of DOI:10.1021/ol702654x

ORGANIC
LETTERS
2008
Vol. 10, No. 5
705-708
Mo(CO)6- and [Rh(CO)2Cl]2-Catalyzed
Allenic Cyclocarbonylation Reactions of
Alkynones: Efficient Access to Bicyclic
Dienediones
Kay M. Brummond* and Daitao Chen
Deparment of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
kbrummon@pitt.edu
Received November 1, 2007
ABSTRACT
Allenyl alkynones are efficiently transformed into fused bicyclic dienediones via cyclocarbonylation reaction conditions. Mo(CO)6/DMSO reaction
conditions result in the formation of a bicyclo[3.3.0]octenone ring system, and the [Rh(CO)2Cl]2-catalyzed reaction affords bicyclo[4.3.0]-
nonenone and bicyclo[5.3.0]decenone scaffolds.
Efficient construction of polycyclic cyclopentane-containing
skeletons is a continual interest to the synthetic community.1
Among numerously important cyclopentane derivatives, a
fused bicyclic enedione represents an essential framework
and versatile intermediate in natural product syntheses.2 One
common strategy for accessing the enedione moiety is by
multistep annulation reactions, as demonstrated by Dan-
ishefsky3 and Hassner.4 Another strategy utilizes dicobal-
toctacarbonyl [Co2(CO)8]5 or tungstenpentacarbonyl‚THF
[W(CO)5‚THF]6 mediated cyclocarbonylation reactions on
electron-deficient alkynones. However, the latter protocol has
been limited to the preparation of bicyclo[3.3.0]oct-1-en-3-
ones.
An important variant of the Pauson-Khand-type reaction
involves substituting the alkene moiety with an allene,7 thus
enabling the formation of larger rings. The utility of this
version of the Pauson-Khand-type reaction has been ex-
panded by our ability to control the reacting double bond of
the allene via the transition metal catalyst.
(1) For review see: (a) Kuck, D. Chem. ReV. 2006, 106, 4885-4925.
(b) Booker-Milburn, K. I.; Sharpe, A. J. Chem. Soc., Perkin. Trans. 1 1998,
983-984. (c) Ho, T. L. Carbocyclic construction in terpene synthesis; VCH
Publishers: New York, 1988. (d) Paquette, L. A.; Doherty A. M.
Polyquinane Chemistry. Synthesis and Reactions; Springer-Verlag: Berlin,
Germany, 1987.
(2) (a) Danishefsky, S.; Zamboni, R.; Kahn, M.; Etheredge, S. J. J. Am.
Chem. Soc. 1981, 103, 3460-3467. (b) Danishefsky, S.; Kahn, M.
Tetrahedron Lett. 1981, 22, 485-488. (c) Danishefsky, S.; Kahn, M.
Tetrahedron Lett. 1981, 22, 489-492.
(3) Danishefsky, S.; Etheredge, S. J. J. Org. Chem. 1982, 47, 4791-
4793.
(4) Yechezkel, T.; Ghera, E.; Ostercamp, D.; Hassner, A. J. Org. Chem.
1995, 60, 5135-5142.
(5) Hoye, T. R.; Suriano, J. A. J. Org. Chem. 1993, 58, 1659-1660.
(6) Hoye, T. R.; Suriano, J. A. J. Am. Chem. Soc. 1993, 115, 1154-
1156.
(7) For reviews see: (a) Brummond, K. M. In AdVances in Cycloaddition;
Harmata, M., Ed.; JAI Press Inc.: Stamford, CT, 1999; Vol. 6, pp 211-
237. (b) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2004, 3377-3383.
10.1021/ol702654x CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/31/2008

For example, the reaction of alleneyne A under molyb-
denum hexacarbonyl conditions affords R-alkylidene cyclo-
pentenone B via a selective reaction of the proximal double
bond of the allene (eq 1).8 Alternatively, reaction of alleneyne
Table 1. Mo(CO)6-Catalyzed Cyclocarbonylation Reactions
entry subst prod R1 R2 R3
R4
time (min) yield (%)
1a
2b
1a
1a
1a
1a
1b
1c
1c
1d
1e
1f
2a nBu Me Me Me
10
20
60
90
82
81
e
58
76
75
71
59
86f
63f
61f
2a nBu Me Me Me
2a nBu Me Me Me
2a nBu Me Me Me
A under rhodium(I) conditions gives 4-alkylidene cyclopen-
tenone C resulting from a selective reaction with the distal
double bond of the allene.9 We have extended the scope of
this regioselective cyclocarbonylation reaction to the prepara-
tion of indene-, pentalene-, and azulenediones. These diones
were achieved by an intramolecular reaction of an allene with
an ynone, a rarely used moiety in Pauson-Khand (P-K)
reactions. The results of this study are reported within.
The P-K reaction is one of the most extensively inves-
tigated methods for the formation of cyclopentenones.10
However, limited attention has focused on electron-deficient
alkynes as a reacting partner11 and very few examples have
been reported on the transition metal-catalyzed P-K reaction
of ynones. Moreover, there have been no reports of a P-K
reaction of alleneynones to form richly functionalized
bicyclic dienediones.
3c
4d
5c
2b
2c
2c
H
Me Me Me
60
5
6a
Me Me (-CH2-)5
Me Me (-CH2-)5
7c
60
40
10
10
10
60
8b
2d Me
H
H
Me BzNH
Me BzNH
9a
2e
2f
H
10a
11a
12c
Me Me Me BzNH
1g
1g
2g
2g
H
H
Me Me BzNH
Me Me BzNH
a 120 mol % of Mo(CO)6, 10 equiv of DMSO, 90 °C. b 40 mol % of
Mo(CO)6, 4 equiv of DMSO, 90 °C. c 20 mol % of Mo(CO)6, 2 equiv of
DMSO, CO (1 atm), 90 °C. d 10 mol % of Mo(CO)6, 1 equiv of DMSO,
CO (1 atm), 90 °C. e Reactions did not go to completion even after 5 h,
see text for details. f Compounds 2f and 2g were obtained as ca. 1:1 mixtures
of diastereomers, see the Supporting Information for details.
loading to 20 mol % produced 2a in 81% yield in 1 h (entry
3, Table 1). Lowering the catalyst loading to 10 mol % gave
varying quantities of product 2a along with recovered starting
material 1a (entry 4, Table 1).
The Mo(CO)6-mediated reaction of alkynone 1 to form
bicyclo[3.3.0]octadienedione 2 was first examined. To our
delight, when 1a was subjected to the standard reaction
conditions (1.2 equiv of Mo(CO)6, 10 equiv of DMSO),
product 2a was isolated in 90% yield in less than 10 min
(entry 1, Table 1).
The efficiency of the transformation of 1a to 2a, coupled
with a report from Oh’s laboratory12 prompted us to
investigate the catalytic version of the molybdenum cyclo-
carbonylation reaction. Lowering the quantity of molybde-
num hexacarbonyl to 40 mol % and performing the reaction
under an atmosphere of nitrogen gave product 2a in 82%
yield in 20 min (entry 2, Table 1). Equipping the reaction
with a balloon of carbon monoxide and lowering the catalyst
Next, the scope and limitation of this method for accessing
other bicyclic dienediones was investigated by systematically
varying the substitution on the allene, alkyne, and tether.
Terminal alkynes are compatible with the Mo(0) reaction
conditions but it was found that the yield decreased by 23%
when compared to that of an internal alkyne (compare entries
3 and 5, and entries 10 and 11, Table 1). Interestingly,
annulation of a cyclohexane ring on the tether produced
spirotricyclic dienedione 2c in comparable yield under both
catalytic and stoichiometric reaction conditions (entries 6 and
7, Table 1). Substrates possessing a benzamide group on the
tether afforded bicyclic dienediones 2d-g (entries 8-12,
Table 1).
Selective reaction of the distal double bond of the allene
of substrates 1a-g to give dienediones 2a-g using the Mo-
(0) conditions is attributed to the developing strain in the
bicyclo[3.2.0]heptenone, a product that would arise from the
reaction with the proximal double bond of the allene.
However, by lengthening the tether by one methylene unit,
substrates 3a-d afforded products resulting from the selec-
tive reaction with the proximal double bond of the allene,
R-alkylidene enediones 4a-d (Table 2). Alkyl-, phenyl-, and
TMS-substituted ynones13 all gave the corresponding CO
insertion products (entries 1-6, Table 2). Substitution at the
allene terminus with a methyl group provided only the
(8) (a) Kent, J. L.; Wan, H.; Brummond, K. M. Tetrahedron Lett. 1995,
36, 2407-2410. (b) Brummond, K. M.; Wan, H. Tetrahedron Lett. 1998,
39, 931-934. (c) Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem.
1998, 63, 6535-6545.
(9) (a) Brummond, K. M.; Gao, D. Org. Lett. 2003, 5, 3491-3494. (b)
Brummond, K. M.; Chen, H;, Fisher, K.; Kerekes, A. D.; Rickards, B.;
Sill, P. C.; Geib, S. J. Org. Lett. 2002, 4, 1931-1934. (c) Mukai, C.;
Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett. 2002, 4, 1755-1758.
(d) Mukai, C.; Hirose, T.; Teramoto, S.; Kitagaki, S., Tetrahedron 2005,
61, 10983-10994. (e) Brummond, K. M.; Sill, P.; Rickards, B.; Geib, S. J.
Tetrahedron Lett. 2002, 43, 3735-3738. (f) Kobayashi, T.; Koga, Y.;
Narasaka, K. J. Organomet. Chem. 2001, 624, 73-87.
(10) For recent reviews: see (a) Laschart, S.; Becheanu, A.; Bell, T.;
Baro, A. Synlett 2005, 17, 2547-2570. (b) Gibson, S. E.; Mainolfi, N.
Angew. Chem., Int. Ed. 2005, 44, 3022-3037. (c) Bonaga, L. V. R.; Krafft,
M. E. Tetrahedron 2004, 60, 9795-9833. (d) Brummond, K. M.; Kent, J.
L. Tetrahedron 2000, 56, 3263-3283.
(11) (a) Krafft, M. E.; Romero, R. H.; Scott, I. L. Synlett 1995, 577-
578. (b) Krafft, M. E.; Romero, R. H.; Scott, I. L J. Org. Chem. 1992, 57,
5277-5278. (c) Tang, Y.; Zhang, Y.; Dai, M.; Luo, T.; Deng, L.; Chen, J.;
Yang, Z. Org. Lett. 2005, 7, 885-888.
(12) Gupta, A. K.; Park, D. I.; Oh, C. H. Tetrahedron Lett. 2005, 46,
4171-4174.
(13) Terminal alkynones were not tested in this case due to the volatility
of both starting material and product.
706
Org. Lett., Vol. 10, No. 5, 2008

afforded the cross-conjugated triene 6 in 62% yield as the
only isolated compound (eq 2). Triene 6 is formed as a result
Table 2. Mo(CO)6-Catalyzed Cyclocarbonylation Reactions
entry
subst
prod
R1
R2
time (min)
yield (%)
of the intermediate rhodum metallocycle undergoing a
â-hydride elimination instead of a CO insertion.
The Rh(I)-catalyzed allenic cyclocarbonylation reaction of
alkynones was further explored by testing the feasibility of
forming the bicyclo[5.3.0]decenone ring system. As shown
in Table 4, the cyclization reactions of 7a-c proceeded
1c
2b
3c
4a
5b
6a
7a
3a
3a
3b
3b
3c
3c
3d
4a
4a
4b
4b
4c
4c
4d
TMS
TMS
nBu
nBu
Ph
H
H
H
H
H
H
Me
60
20
60
10
20
10
10
76
75
70
73
84
79
83d
Ph
Ph
a 120 mol % of Mo(CO)6, 10 equiv of DMSO, 90 °C. b 40 mol % of
Mo(CO)6, 4 equiv of DMSO, 90 °C. c 20 mol % of Mo(CO)6, 2 equiv of
DMSO, CO (1 atm), 90 °C. d Combined yield for a 3:1 (E/Z) mixture of
two diastereromers.
Table 4. [Rh(CO)2Cl]2-Catalyzed Cyclocarbonylation Reaction
cyclocarbonylation product 4d in 83% yield (entry 7, Table
2) and none of the triene resulting from a competing
cycloisomerization reaction.14 Catalytic quanitities of mo-
lybdenum hexacarbonyl provided the products 4a-c in 70-
84% yield (entries 1-3 and 5).
Next, we turned our attention to the formation of bicyclo-
[4.3.0]dienediones using substrates 3a-d. On the basis of
previous studies in our group,9b the [Rh(CO)2Cl]2-catalyzed
conditions should selectively react with the distal double
bond of the allene to afford [4.3.0] bicycles (Table 3). Indeed,
entry
subst
prod
R1
time (h)
yield (%)
1
2
3
7a
7b
7c
8a
8b
8c
nBu
Ph
12
6
8
61
69
68
1-cyclohexene
smoothly to give seven-membered rings 8a, 8b, and 8c in
61%, 69%, and 68% yield, respectively.
To the best of our knowledge, this is the first example of
a cyclocarbonylation reaction to form a seven-membered ring
that does not benefit from the Thorpe-Ingold effect or a
conformational restriction imposed by an additional ring in
the tether.9a,b,15 Furthermore, a methyl group on the allene
does not result in formation of the triene product. One
exception occurs with the phenyl-substituted alleneyne 7b,
in which the unstable cross-conjugated triene was isolated
in less than 5% yield (entry 2, Table 4). The carbonyl-
containing tether appears to play an important role in
facilitating the formation of the seven-membered ring,
evidenced by the cyclocarbonylation of alleneyne 9, which
gives only the dienedione 10 in 42% yield (eq 3).
Table 3. [Rh(CO)2Cl]2-Catalyzed Cyclocarbonylation
Reactions
entry
subst
prod
R1
R2
time (min)
yield (%)
1
2
3
4
3a
3b
3c
3d
5a
5b
5c
6
TMS
nBu
Ph
H
H
H
Me
30
30
30
15
51
61
55
62a
Ph
a Yield of the cycloisomerization product 6.
reaction of 3a-c produced the corresponding bicyclo[4.3.0]-
nonadienediones 5a-c in 51-61% yield and substitution at
the alkyne terminus is generally tolerated (entries 1-3, Table
3). However, the methyl-substituted allene 3d failed to give
the dienedione product 5d (entry 4, Table 3), but instead
Attempts to prepare the bicyclo[6.3.0]undecadienedione
skeleton from the corresponding alleneynone were unsuc-
(15) Ahmar, M.; Locatelli, C.; Colombier, D.; Cazes, B. Tetrahedron
Lett. 1997, 38, 5281-5284. Perez-Serrano, L.; Casarrubios, L.; Dominguez,
G.; Perez-Castells, J. Chem. Commun. 2001, 2602-2603. Mukai, C.;
Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett. 2002, 4, 1755-1758.
(14) Brummond, K. M.; Chen, H.; Sill, P. C.; You, L. J. Am. Chem.
Soc. 2002, 124, 15186-15187.
Org. Lett., Vol. 10, No. 5, 2008
707

cessful. The starting material was partially recovered after
14 h under the standard Rh(I) reaction conditions.
Scheme 1. Allenic Cyclocarbonylation Approach to
Grayanotoxin II
Next, with an eye toward the synthesis of grayanotoxin
II,16 the Rh(I)-catalyzed allenic cyclocarbonylation reac-
tion was tested on the model system 13 (Scheme 1). Allenic
alkynone 13 was rapidly obtained from the known alkyne
11 in 4 steps. Subjecting this alleneynone to the stan-
dard Rh(I)-catalyzed cyclocarbonylation reaction condi-
tions afforded the tricyclic core structure 14 in 76% yield.
This ring-forming strategy provides a unique approach to
functionally dense scaffolds that are otherwise difficult to
access.
In summary, the scope of the allenyl cyclocarbonylation
reaction has been extended to ynones, a functional motif that
has seen limited use in Pauson-Khand reactions. The
selective reaction of proximal and distal double bonds of
the allene was controlled by the substrate and the transition
metal catalyst. Substoichiometric quantities of Mo(CO)6
afforded excellent yields of bicyclo[3.3.0]octadienediones
and alkylidene bicyclo[3.3.0]octenediones. The [Rh(CO)2Cl]2-
catalyzed reactions afforded bicyclo[4.3.0]nonadienediones
and bicyclo[5.3.0]decadienediones. The utility of the resulting
functionally dense scaffolds in natural product synthesis and
library preparation will be reported in due course.
Acknowledgment. The authors gratefully acknowledge
the generous financial support provided by the National
Institutes of Health (GM-67982 and GM-54161).
Supporting Information Available: Characterization
data and full experimental procedures are provided for all
new compounds in Tables 1-4, eq 3, and Scheme 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) For biological activity, see: (a) Terai, T.; Osakabe, K.; Katai, M.;
Sakaguchi, K.; Narama, I.; Matsuura, T.; Katakawa, J.; Tetsumi, T. Chem.
Pharm. Bull. 2003, 51, 351-353 and references cited therein. For a total
synthesis of grayanotoxin III, see: (b) Kan, T.; Hosokawe, S.; Nara, S.;
Oikawa, M.; Ito, S.; Matsuda, F.; Shirahama, H. J. Org. Chem. 1994, 59,
5532-5534.
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Org. Lett., Vol. 10, No. 5, 2008