Rhodium-catalyzed carbonylation of 3-acyloxy-1,4-enynes for the synthesis of cyclopentenones

Article abstract of DOI:10.1021/ol300330t

Functionalized cyclopentenones were synthesized by a Rh-catalyzed carbonylation of 3-acyloxy-1,4-enynes, derived from alkynes and α,β-unsaturated aldehydes. The reaction involved a Saucy-Marbet 1,3-acyloxy migration of propargyl esters and a [4 + 1] cycloaddition of the resulting acyloxy substituted vinylallene with CO.

Full text of DOI:10.1021/ol300330t

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1584–1587
Rhodium-Catalyzed Carbonylation of
3-Acyloxy-1,4-enynes for the Synthesis of
Cyclopentenones
Xiaoxun Li,† Suyu Huang,† Casi M. Schienebeck,† Dongxu Shu,‡ and Weiping Tang*,†
School of Pharmacy and Department of Chemistry, University of Wisconsin, Madison,
Wisconsin 53705, United States
wtang@pharmacy.wisc.edu
Received February 9, 2012
ABSTRACT
Functionalized cyclopentenones were synthesized by a Rh-catalyzed carbonylation of 3-acyloxy-1,4-enynes, derived from alkynes and R,β-
unsaturated aldehydes. The reaction involved a SaucyꢀMarbet 1,3-acyloxy migration of propargyl esters and a [4 þ 1] cycloaddition of the
resulting acyloxy substituted vinylallene with CO.
The transition-metal-catalyzed cycloaddition reaction is
one of the most efficient ways to access ring systems.1
Formation of cyclopentenones via PausonꢀKhand cy-
cloaddition has proven to be extremely valuable for the
synthesis of natural products and pharmaceutical agents.2
However, transition-metal-catalyzed intermolecular Pausonꢀ
Khand reactions are still challenging for the synthesis of
various monocyclic cyclopentenones. Even in the case of
intramolecular reactions, the scope of alkenes is often
limited. Efficient synthesis of cyclopentenones with diverse
substitutions and functionalities are still highly desirable and
continue to stimulate the development of novel cycloaddition
reactions.2f
We herein report an efficient synthesis of highly function-
alized cyclopentenones 4 and 5 from 3-acyloxy-1,4-enyne 3
via a Rh(I)-catalyzed carbonylation reaction (Scheme 1).
Since substrate 3 could be conveniently prepared from the
addition of terminal alkyne 1 to R,β-unsaturated aldehyde 2
followed by esterification, this carbonylation reaction offered
an efficient protocol to access functionalized cyclopente-
nones, which are present in many bioactive natural products
and pharmaceuticals. For examples, 5-alkylidene-cyclopent-
2-enones such as clavulones2g and punaglandins2h display
anti-inflammatory and antitumor activities respectively.
We and others have demonstrated that 3-acyloxy-1,
4-enynes with a terminal alkyne (3, R1 = H) can serve as
† School of Pharmacy.
‡ Department of Chemistry.
(1) For selected reviews on transition metal catalyzed cycloadditions,
see: (a) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49. (b)
Fruhauf, H. W. Chem. Rev. 1997, 97, 523. (c) Aubert, C.; Buisine, O.;
Malacria, M. Chem. Rev. 2002, 102, 813. (d) Evans, P. A. Modern
Rhodium-Catalyzed Organic Reactions: Wiley-VCH: Weinheim, 2005. (e)
Michelet, V.; Toullec, P. Y.; Genet, J. P. Angew. Chem., Int. Ed. 2008, 47,
4268. (f) Yu, Z.; Wang, Y.; Wang, Y. Chem.;Asian J. 2010, 5, 1072. (g)
Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791. (h) Aubert,
C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Chem.
Rev. 2011, 111, 1954.
(2) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.;
Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977. For selected
reviews on PausonꢀKhand reactions, see: (b) Gibson, S. E.; Mainolfi,
N. Angew. Chem., Int. Ed. 2005, 44, 3022. (c) Park, J. H.; Chang, K. M.;
Chung, Y. K. Coord. Chem. Rev. 2009, 253, 2461. (d) Habermann, J.
Curr. Org. Chem. 2010, 14, 1139. (e) Lee, H. W.; Kwong, F. Y. Eur. J.
Org. Chem. 2010, 789. For a recent review on synthesis of cyclopente-
nones, see: (f) Gibson, S. E.; Lewis, S. E.; Mainolfi, N. J. Organomet.
Chem. 2004, 689, 3873. For selected bioactive cyclopentenones, see: (g)
Kikuchi, H.; Tsukitani, Y.; Iguchi, K.; Yamada, Y. Tetrahedron Lett.
1982, 23, 5171. (h) Baker, B. J.; Okuda, R. K.; Yu, P. T. K.; Scheuer, P. J.
J. Am. Chem. Soc. 1985, 107, 2976.
r
10.1021/ol300330t
Published on Web 03/02/2012
2012 American Chemical Society

We were pleased to find that [Rh(CO)2Cl]2 was indeed
able to facilitate both the 1,3-acyloxy migration of pro-
pargyl ester 3a and [4 þ 1] cycloaddition of the resulting
vinylallene with CO (entry 1, Table 1). A mixture of
isomeric alkylidene cyclopentenones 4a and 5a was ob-
served. We then examined various other Rh(I) catalysts
(entries 2ꢀ5). A slightly better yield was obtained using the
[Rh(COD)Cl]2 catalyst(entry 2). Wealsotried substrate3b
bearing a pivalate group (entry 6). The combined yield and
the ratio of 4b and 5b were similar to results from acetate
shown in entry 2. Since acetate is generally easier to be
removed, we decided to focus on acetate 3a for further
optimization of the conditions. Dichloroethane (DCE)
provided the best results among solvents we screened
(entries 2 and 7ꢀ9). We then examined the effect of
temperature (entries 10ꢀ12). The best result was obtained
at 40 °C (entry 11). Product 5a could be separated from
minor isomer 4a and isolated in 70% yield.
For all entries in Table 1, the ratios of 4a/5a did not
change significantly. They ranged from 1:3 to 1:3.5. We
observed no obvious change to the ratio of 4a/5a when
the mixture of two products was treated with bases
(e.g., DBU, DBN, DMAP, DABCO, DIPEA, or Et3N).
When dppf was employed as the ligand, the ratio of
4a/5a became 1:1 after the carbonylation. Most other
ligands (e.g., dppe, dppp, and dppb) had no effect on the
ratio.
Scheme 1. Carbonylation of 3-Acyloxy-1,4-enyne for the
Synthesis of Cyclopentenones
a five-carbon building block for [5 þ 1]3 and [5 þ 2]4
cycloadditions with CO and alkynes respectively. Both
cycloadditions involved a Rh-catalyzed 1,2-acyloxy migra-
tion of propargyl esters, a process first described by
Rautenstrauch in 1984 using a Pd(II) catalyst.5
We found that propargyl esters with an internal alkyne
underwent 1,3-acyloxy migration to form an acyloxy sub-
stituted allene intermediate in several Rh-catalyzed cas-
cade reactions.6 The 1,3-acyloxy migration of propargyl
esters was first discovered by Saucy and Marbet using a
Ag(I) catalyst.7 Trapping the resulting allene intermediate
has been realized in tandem reactions catalyzed by Ag(I),
Cu(I), Pt(II), and Au(I) complexes.8 We envisioned that a
new carbonylation method could be realized for the synthe-
sis of cyclopentenones if a Rh(I) complex was able to
catalyze the SaucyꢀMarbet rearrangement of 3-acyloxy-1,-
4-enynes with an internal alkyne (3, R1 ¼ H) and a [4 þ 1]
cycloaddition of the resulting vinylallene with CO.9
Table 1. Screening of Catalysts and Conditions for Carbonyla-
tion of 3-Acyloxy-1,4-enynesa
(3) Brancour, C.; Fukuyama, T.; Ohta, Y.; Ryu, I.; Dhimane, A. L.;
Fensterbank, L.; Malacria, M. Chem. Commun. 2010, 46, 5470.
(4) Shu, X.-Z.; Huang, S.; Shu, D.; Guzei, I. A.; Tang, W. Angew.
Chem., Int. Ed. 2011, 50, 8153.
(5) (a) Rautenstrauch, V. J. Org. Chem. 1984, 49, 950. (b) Rautenstrauch,
V. Tetrahedron Lett. 1984, 25, 3845.
(6) (a) Shu, D.; Li, X.; Zhang, M.; Robichaux, P. J.; Tang, W. Angew.
Chem., Int. Ed. 2011, 50, 1346. (b) Li, X.; Zhang, M.; Shu, D.;
Robichaux, P. J.; Huang, S.; Tang, W. Angew. Chem., Int. Ed. 2011,
50, 10421. (c) Huang, S.; Li, X.; Lin, C. L.; Guzei, I. A.; Tang, W. Chem.
Commun. 2012, 48, 2204.
(7) Saucy, G.; Marbet, R.; Lindlar, H.; Isler, O. Helv. Chim. Acta
1959, 42, 1945.
(8) For a leading review on π-acidic metal catalyzed 1,3-acyloxy
migration of propargyl esters, see: (a) Wang, S.; Zhang, G.; Zhang, L.
Synlett 2010, 692. For selected related reviews on π-acidic metal
catalyzed reactions, see: (b) Marion, N.; Nolan, S. P. Angew. Chem.,
entry
conditions
yield (4 þ 5)
53%
1
[Rh(CO)2Cl]2 (5 mol %), DCE, 60 °C
[Rh(COD)Cl]2 (5 mol %), DCE, 60 °C
[Rh(CO)2(acac)] (5 mol %), DCE, 60 °C 10%
[Rh(PPh3)3Cl] (5 mol %), DCE, 60 °C
[Rh(COD)2]BF4 (5 mol %), DCE, 60 °C
[Rh(COD)Cl]2 (5 mol %), DCE, 60 °C
[Rh(COD)Cl]2 (5 mol %), toluene, 60 °C 43%
[Rh(COD)Cl]2 (5 mol %), dioxane, 60 °C 46%
[Rh(COD)Cl]2 (5 mol %), CH3CN, 60 °C 33%
2
55%
3
4
30%
trace
56%
5
6b
7
€
Int. Ed. 2007, 46, 2750. (c) Furstner, A.; Davies, P. W. Angew. Chem., Int.
Ed. 2007, 46, 3410. (d) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (e)
Hashmi, A. S. K. Angew. Chem., Int. Ed. 2008, 47, 6754. (f) Jimenez-
Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (g) Gorin,
D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351.
(9) For rhodium-catalyzed [4 þ 1] cycloaddition of vinylallene with
CO, see: (a) Murakami, M.; Itami, K.; Ito, Y. Angew. Chem., Int. Ed.
1995, 34, 2691. (b) Murakami, M.; Itami, K.; Ito, Y. J. Am. Chem. Soc.
1997, 119, 2950. (c) Murakami, M.; Itami, K.; Ito, Y. J. Am. Chem. Soc.
1999, 121, 4130. (d) Murakami, M.; Itami, K.; Ito, Y. Organometallics
1999, 18, 1326. For iron-mediated [4 þ 1] cycloadditions, see: (e)
Sigman, M. S.; Kerr, C. E.; Eaton, B. E. J. Am. Chem. Soc. 1993, 115,
7545. (f) Sigman, M. S.; Eaton, B. E. J. Org. Chem. 1994, 59, 7488. (g)
Sigman, M. S.; (h) Eaton, B. E.; Heise, J. D.; Kubiak, C. P. Organome-
tallics 1996, 15, 2829. (i) Sigman, M. S.; Eaton, B. E. J. Am. Chem. Soc.
1996, 118, 11783.
8
9
10
11
[Rh(COD)Cl]2 (5 mol %), DCE, 80 °C
[Rh(COD)Cl]2 (5 mol %), DCE, 40 °C
38%
81%
(70%, Z/E = 7:1)c
12
[Rh(COD)Cl]2 (5 mol %), DCE, rt
40%
a Unless noted otherwise, substrate 3a was employed. The combined
yield and the ratio of 4a and 5a were determined by 1H NMR. The ratio
of 4a/5a ranged from 1:3 to 1:3.5. All reactions were carried out under a
CO balloon for 8 h. b Substrate 3b was employed. The ratio of 4b/5b was
1:3.5. c Isolated yield of 5a. The Z/E ratio was determined by 1H NMR.
Org. Lett., Vol. 14, No. 6, 2012
1585

Similar results (yield of 5c and ratios of 4c/5c) were
observed for substrate 3c (Scheme 2). The conversion was
low for substrate 3d with a phenyl substituted alkene. After
40 h, product 5d was isolated in 20% yield and 60%
starting material was recovered. The yield of product 5d
could not be improved by varying the temperature or CO
pressure.
Table 2. Carbonylation of 3-Acyloxy-1,4-enynesa
For substrate 3e with a trisubstituted olefin, isomer 4e
became the major product (condition a, Scheme 2). The
ratio of isomers 4e/5e was about 7:1 based on the 1H NMR
of the crude product. After purification by silica gel
column chromatography, however, we found that the ratio
of 4e/5e varied each time. We suspected that isomer 5e with
a tetrasubstituted olefin might become more stable and the
isomerization from 4e to 5e occurred during purification.
Indeed, when the crude product from the Rh-catalyzed
carbonylation was treated with 2.0 equiv of triethylamine,
isomer 4e was not detected and product 5e was isolated in
86% yield. This greatly simplified the purification and
characterization of the cyclopentenone product.
Scheme 2. Carbonylation of 3-Acyloxy-1,4-enyne with Di- and
Trisubstituted Alkenes
The scope of the carbonylation was examined more
extensively for substrates with a trisubstituted olefin
(Table 2). Substrates 3eꢀ3k could be easily prepared from
the addition of various terminal alkynes to commercially
available tiglic aldehyde followed by acetylation. For
substrate 3f with a phenyl substituted alkyne, a complex
mixture was observed. Enynes 3gꢀ3k with various alkyl
groups on the alkyne termini all participated in the tandem
reaction. The yield became lower for substrate 3k with a
siloxy group on the propargylic position.
a Conditions: [Rh(COD)Cl]2 (5 mol %), CO (1 atm), 40 °C, DCE,
8ꢀ20 h, then Et3N (2.0 equiv). The ratios of Z/E isomer were determined
by 1H NMR of the crude product. b Isolated yield of the Z-isomer unless
noted otherwise. c Isolated yield of the mixture of Z- and E-isomers.
d Isolated yield of E-isomer. e The reaction was run at 5 atm of CO.
Substrate 3l with an n-Bu group on the alkene could also
be tolerated. Based on results for substrate 3d in Scheme 2,
it appeared that the introduction of a phenyl substituent to
the terminal position of the alkene decreased the reactivity
of the substrate significantly. We were pleased to find that
product 5m could be prepared in 51% yield under similar
conditions. The yield of this product could be further
improved to 65% with higher CO pressure. The carbony-
lation worked smoothly for substrates 3n and 3o, where
the internal position of the alkene had an ethyl or aryl
substituent.
Bicyclic products 5p, 5q, and 5r were also prepared in
good yields from the corresponding 3-acyloxy-1,4-enynes.
This provided an easy access to 5ꢀ5, 5ꢀ6, and 5ꢀ7 fused
compounds with a highly functionalized cyclopentenone.
No desired cyclopentenone product was observed for
substrates 3s and 3t. When we tried to prepare tertiary
propargyl esters with a trisubstituted alkene, they under-
went isomerization to form a mixture of conjugated enynes
during the preparation.
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Org. Lett., Vol. 14, No. 6, 2012

(Scheme 3). Product 1,3-diketone 6q could be isolated in
68% yield after two steps. The NMR spectra of dike-
tone 6q, however, was complex due to the presence of
different enols. The 1,3-diketone was then further
alkylated with methyl acrylate.10 Bicyclic compound 7
could be isolated in high yield and clearly character-
ized. Monocyclic cyclopentenone 8 was obtained in
50% overall yield from substrate 3e.
Scheme 3. Functionalization of Cyclpentenones Derived Car-
bonylation of 3-Acyloxy-1,4-enynes
The mechanism for the carbonylation of 3-acyloxy-1,-
4-enynes was proposed in Scheme 4. The alkenyl substituted
propargyl ester 3 could undergo a Rh-catalyzed 1,3-acy-
loxy migration to form allene intermediate 10.6 The co-
ordination of the acyloxy group to Rh may favor the
formation of metallocyclopentene intermediate 11, which
will produce the Z-isomer of cyclopentenones 4 or 5 after
CO insertion and reductive elimination.
In summary, we have developed an efficient method for
the synthesis of various highly functionalized monocyclic
and bicyclic cyclopentenones from readily available 3-acy-
loxy-1,4-enynes. The combination of the novelreactivityof
a Rh(I) catalyst for promoting 1,3-acyloxy migration of
propargyl esters and its ability to facilitate a carbonylation
reaction made this tandem transformation possible. The
acyloxy group in the propargyl ester starting material not
only eliminates the need for the preformation of allenes but
also provides a useful handle for further selective function-
alizations of the cyclopentenone products.
Scheme 4. Proposed Mechamism for the Carbonylation of
3-Acyloxy-1,4-enynes
Acknowledgment. We thank the NIH (R01 GM088285),
the Chinese Scholarship Council (to S.H.), and the Univer-
sity of Wisconsin for financial support and a Young In-
vestigator Award (to W.T.) from Amgen.
For many cyclopentenone products in Table 2, the
major Z-isomer was separated and isolated for clear
characterization. The combined yield of both isomers
would be slightly higher. The Z/E ratio of product 5 is
actually inconsequential after hydrolysis of the enol ester.
The mixture of carbonylation products derived from sub-
strate 3q was then directly treated with K2CO3 in methanol
1
Supporting Information Available. HNMR, 13CNMR,
IR, and HRMS for starting materials and products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(10) Ye, W.; Xu, J.; Tan, C. T.; Tan, C. H. Tetrahedron Lett. 2005, 46,
6875.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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