An allenic Pauson-Khand-type reaction: a reversal in pi-bond selectivity and the formation of seven-membered rings.

Article abstract of DOI:10.1021/ol025955w

[reaction: see text] Treatment of alkynyl allenes with [Rh(CO)(2)Cl](2) results in a formal [2 + 2 + 1] cycloaddition reaction. This reaction occurs with complete regioselectivity for a variety of substrates affording only 4-alkylidene cyclopentenones in

Full text of DOI:10.1021/ol025955w

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1931-1934
An Allenic Pauson−Khand-Type
Reaction: A Reversal in π-Bond
Selectivity and the Formation of
Seven-Membered Rings
Kay M. Brummond,* Hongfeng Chen, Kimberly D. Fisher, Angela D. Kerekes,
Brenden Rickards, Peter C. Sill, and Steven J. Geib†
Department of Chemistry, UniVersity of Pittsburgh,
Pittsburgh, PennsylVania 15260, and Department of Chemistry,
West Virginia UniVersity, Morgantown, West Virginia 26506
kbrummon@pitt.edu
Received April 1, 2002
ABSTRACT
Treatment of alkynyl allenes with [Rh(CO)2Cl]2 results in a formal [2 + 2 + 1] cycloaddition reaction. This reaction occurs with complete
regioselectivity for a variety of substrates affording only 4-alkylidene cyclopentenones in good yields. Moreover, seven-membered rings have
been prepared in high yields.
The formal [2 + 2 + 1] cycloaddition reaction involving
alkenes, alkynes, and a CO source is a powerful strategy for
effecting formation of cyclopentenones.1 Research in our
laboratory provided the first examples of an intramolecular,
metal-mediated allenic [2 + 2 + 1] cycloaddition reaction
for the synthesis of R-alkylidene cyclopentenones2 and
4-alkylidene cyclopentenones.3 This strategy has subse-
quently been developed as a generally useful synthetic
method.4 It was demonstrated that the substitution profile
of the allene had an influence on the regiochemical course
of this reaction. While this regiochemical control element
proved to be exceedingly useful in the synthesis of
hydroxymethylacylfulvene4a,b and our approach to 15-deoxy-
∆
12,14-PGJ2, the allenic Pauson-Khand reaction would be
more versatile and amenable to target-oriented synthesis if
the regioselectivity could be controlled by simply altering
the reaction conditions.
To amplify the overall utility of this method, we sought
control elements that might induce preferential cyclization
with the terminal π-bond of the allene, affording 4-alkylidene
† Corresponding author for information regarding X-ray crystallographic
data.
(1) For reviews, see: (a) Brummond, K. M.; Kent, J. L. Tetrahedron
2000, 56, 3263. (b) Chung, Y. K. Coord. Chem. ReV. 1999, 188, 297. (c)
Jeong, N. In Transition Metals in Organic Synthesis; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, Germany, 1998; Vol. 1, p 560. (d) Ingate,
S. T.; Marco-Contellas, J. Org. Prep. Proced. Int. 1998, 30, 123. (e) Geis,
O.; Schmalz, H. G. Angew. Chem. 1998, 110, 955. (f) Schore, N. E. In
ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F. A.,
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N. E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 5, p 1037. (h) Schore, N. E. Chem. ReV.
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(b) Brummond, K. M.; Lu, J.; Petersen, J. L. J. Am. Chem. Soc. 2000, 122,
4915. (c) Xiong, H.; Hsung, R. P.; Wei, L. L.; Berry, C. R.; Mulder, J. A.;
Stockwell, B. Org. Lett. 2000, 2869. (d) Ahmar, M.; Locatelli, C.;
Colombier, D.; Cazes, B. Tetrahedron Lett. 1997, 38, 5281. (e) Perez-
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Chem. 2001, 624, 73. (g) Pagenkopf, B. L.; Belanger, D. B.; O’Mahony,
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2407.
10.1021/ol025955w CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/09/2002

cyclopentenones. While exploring the silicon-tethered allenic
Pauson-Khand reaction, we screened numerous metals other
than Mo(CO)6 in an effort to find reaction conditions that
would be compatible with the silicon tether. During the
course of these investigations, we found that upon treatment
of the silicon-tethered alkynyl allene 1 with [Rh(CO)2Cl]2,
conditions reported independently by Narasaka5 and Jeong6
the reaction occurred exclusively with the external π-bond
of the allene to give only the 4-alkylidene cyclopentenone 2
in 76% yield with no formation of the R-alkylidene cyclo-
pentenone (eq 1).7 In contrast, Mo(CO)6 gives only R-alkyl-
idene cyclopentenone 3 in 48% yield. Observations have
been made that are consistent with this reactivity pattern;
for instance, rhodium-Vinylallene complexes have been
investigated and a crystal structure was obtained indicating
an η2 coordination of the rhodium at the terminal allenic
π-bond.8 However, reactivities inconsistent with our observa-
tions have also been reported.9
Table 1. Rhodium-Catalyzed Silicon-Tethered Allenic
Pauson-Khand Reaction
cross-conjugated triene (eq 2). This triene also results from
a selective reaction with the distal double bond of the allene
and will be reported on shortly.11 Allene 14 gave only the
R-alkylidene cyclopentenone 16 in 95% yield when 125 mol
% Mo(CO)6 (DMSO, toluene, 100 °C) was used for the
cyclization reaction (eq 2).3 Similarly, allene 17 was
subjected to [Rh(CO)2Cl]2 and afforded only 18 in 45% yield
(eq 3). This somewhat low yield was attributed to the
volatility of compound 18. We have reported previously that
treatment of alkynyl allene 17 with Mo(CO)6 gives a 68%
yield of 19.3
Similarly, in a more functionalized example, alkynyl allene
4 gave only 4-alkylidene cyclopentenone 5 in 64% yield
(entry 1, Table 1). A variety of functional groups on the
terminus of the alkyne were tolerant of the reaction condi-
tions. For example, replacement of the hydrogen with a
trimethylsilyl (6), n-butyl (8), or phenyl (10) group gave good
yields of the corresponding cycloadducts 7, 9, and 11 (entries
2-4, Table 1). Subjection of alkynyl allenes 6, 8, and 10 to
Mo(CO)6 afforded only recovered starting material.10 Sub-
stituting the terminus of the allene with a longer alkyl chain
gave 12 that cyclized to afford the cycloadduct 13 in 55%
yield (entry 5, Table 1).
To determine if this reversal in the regioselectivity was a
consequence of the silicon tether, cyclization substrates
containing all-carbon tethers were examined. Treatment of
alkynyl allene 14 with 5 mol % [Rh(CO)2Cl]2 (toluene, CO
(1 atm), 90 °C) produced compound 15 in 62% yield along
with a 30% yield of a byproduct that was characterized as a
(5) Koga, Y.; Kobayashi, T.; Narasaka, K. Chem. Lett. 1998, 249.
(6) Jeong, N.; Lee, S.; Sung, B. K. Organometallics 1998, 17, 3642.
(7) During these investigations in our laboratory, Narasaka published a
similar result as a single example while exploring the scope of these novel
reaction conditions. Kobayahi, T.; Koga, Y.; Narasaka, K. J. Organome-
tallics 2001, 624, 73.
(8) Murakami, M.; Itami, K.; Ito, Y. Angew. Chem., Int. Ed. Engl. 1995,
34, 2691.
(9) Oh, C. H.; Jung, S. H.; Rhim, C. Y. Tetrahedron Lett. 2001, 42,
8669. Wender, P. A.; Glorious, F.; Husfield, C. O.; Langkopf, E.; Love, J.
A. J. Am. Chem. Soc. 1999, 121, 5348. Wender, P. A.; Jenkins, T. E.; Suzuki,
S. J. Am. Chem. Soc. 1995, 117, 1843.
(10) Brummond, K. M.; Sill, P.; Rickards, B.; Geib, S. Tetrahedron Lett.
2002, 43, 3735.
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Org. Lett., Vol. 4, No. 11, 2002

yield of cycloadduct 29 using [Rh(CO)2Cl]2 (entry 5, Table
2) and a 50% yield of a cross-conjugated triene.11 Conditions
to control the formation of this byproduct were found.
Treament of 28 with 10 mol % [Ir(COD)Cl]2 in toluene and
1 atm of CO afforded an 88% yield of a 4:1 ratio of 29 (R
) TMS) to desilylated enone (R ) H).13 Alkynyl allene 30
possessing a methyl group on the terminus of the alkyne
cyclized to give 31 in 47% yield using [Ir(COD)Cl]2 (entry
6, Table 2). Similarly, 32 possessing a phenyl group on the
alkyne afforded 33 in 60% yield (entry 7, Table 2).
Moreover, [Rh(CO)2Cl]2 shows good functional group
compatibility. For example, alkynyl allene 34 possessing a
carboxylic acid side chain cyclized to give only compound
35 in 67% yield (entry 8, Table 2). Treatment of 34 with
Mo(CO)6 resulted in decomposition of the starting material.
Alkynyl allene 36 cyclized to afford only 4-alkylidene
cyclopentenone 37 in 75% yield (entry 9, Table 2).
Table 2. Allenic Pauson-Khand Reaction
The formation of seven-membered carbocycles has been
somewhat elusive compared to that of six-membered car-
bocycles. However, recent discoveries are beginning to
change this reality. There are now a variety of methods,
including [4 + 3]14 and [5 + 2]15 cycloaddition protocols,
for the preparation of seven-membered carbocycles. Seven-
membered rings have only recently been obtained using the
Pauson-Khand reaction. Cazes was the first to demonstrate
this using an alkynyl allene; however, the reactions lacked
regioselectivity and as a result afforded mixtures of [5-7]
and [5-6] ring systems in moderate yields.16 Perez-Castells
has also shown that seven-membered rings can be formed
with tethers possessing indoles and pyroles.17 Nevertheless,
medium-sized rings remain decidedly difficult to obtain using
the Pauson-Khand reaction.18 Since the rhodium(I)-catalyzed
allenic Pauson-Khand reaction appears to be very selective
toward the distal double bond of the allene in all cases, it
was reasoned that this might be the case for alkynyl allenes
possessing longer tethers. To test this generalization, alkynyl
allene 38 was subjected to [Rh(CO)2Cl]2 and gave only the
[5-7] ring system 39 in 60% yield. This remarkable reversal
(11) Brummond, K. M.; Chen, H.; Sill, P.; You, L., manuscript in
preparation.
(12) Kerekes, A. D. Ph.D. Thesis, West Virginia University, Morgantown,
West Virginia, 2001.
(13) Shibata, T.; Takagi, K. J. Am. Chem. Soc. 2000, 122, 9852
(14) Noyori, R.; Hayakawa, Y. Org. React. 1983, 29, 163. Hoffmann,
H. M. R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1. Mann, J. Tetrahedron
1986, 42, 4611. Hosimi, A.; Tominaga, Y. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
5, Chapter 5.1, pp 593-615. Rigby, J. Org. React. 1997, 51, 351. Harmata,
M. 1997, 53, 6235. Harmata, M.; Sharma, U. Org. Lett. 2000, 2, 2703.
Aungst, R. A.; Funk, R. L. Org. Lett. 2001, 3, 3553.
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117, 4720. Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc. 1998,
120, 10976. Wender, P. A.; Husfield, C. O.; Langkopf, E.; Love, J. A. J.
Am. Chem. Soc. 1998, 120, 1940. Wender, P. A.; Husfield, C. O.; Langkopf,
E.; Love, J. A.; Pleuss, N. Tetrahedron 1998, 54, 7203. Trost, B. M.; Toste,
F. D.; Shen, H. J. Am. Chem. Soc. 2000, 122, 2379. Trost, B. M.; Shen, H.
C. Org. Lett. 2000, 2, 2523. Wender, P. A.; Gamber, G. G.; Scanio, M. J.
C. Angew. Chem., Int. Ed. 2001, 40, 3895.
(16) Ahmar, M.; Locatelli, C.; Colombier, D.; Cazes, B. Tetrahedron
Lett. 1997, 38, 5281.
(17) Perez-Serrano, L.; Casarruubios, L.; Dominguez, G.; Perez-Castells,
J. Chem. Comm. 2001, 2602
(18) Krafft, M. E.; Fu, Z.; Bonaga, L. V. R. Tetrahedron Lett. 2001, 42,
1427. Lovely, C. J.; Seshadri, H.; Wayland, B. R.; Cordes, A. W. Org.
Lett. 2001, 3, 2607. Mukai, C.; Sonobe, H.; Kim, J. S.; Hanaoka, M. J.
Org. Chem. 2000, 65, 6654.
On the basis of the examples in eqs 1-3, we continued to
examine the regioselectivity issue using other alkynyl allenes,
and these are depicted in Table 2. Allene 20 cyclized to give
only 21 in 64% yield, for which an X-ray crystal structure
was obtained (entry 1, Table 2). Allenyne 22, possessing a
tert-butyl group on the terminus of the allene, cyclized to
give only a 22% yield of the [6-5] ring system 23 (entry 2,
Table 2). This same allene cyclized to give only the
corresponding R-alkylidene cyclopentenone in 56% yield
using Mo(CO)6.12 1,1,3-Trisubstituted allene 24 cyclized
using [Rh(CO)2Cl]2 in 56% yield affording spirocycle 25
(entry 3, Table 2). 3,3-Disubstituted allene 26 cyclized to
give 27 in 32% yield (entry 4, Table 2). An allene possessing
an heptyl group at the terminus, 28, cyclized to give a 30%
Org. Lett., Vol. 4, No. 11, 2002
1933

Table 3. [5-7] Ring System
Figure 1. X-ray structure of 41.
in regioselectivity has now resulted in a synthetic alternative
for the preparation of seven-membered rings using an allenic
Pauson-Khand-type reaction. Next, alkynyl allene possess-
ing an isopropyl group on the terminus of the alkyne and
only hydrogen on the distal position of the allene 40 was
subjected to the same conditions to afford a 76% yield of
the [5-7] ring system 41 as a crystalline compound from
which an X-ray crystal structure was obtained (Figure 1).
Similarly, 42 possessing a phenyl group on the terminus of
the alkyne cyclized to afford only 43 in 77% yield.
In conclusion, we are examining the scope and limitations
of the [Rh(CO)2Cl]2-catalyzed allenic Pauson-Khand reac-
tion. The results delineated above extend the scope and
overall utility of the allenic Pauson-Khand reaction for the
assembly of substructures not readily obtained using alterna-
tive protocols. The ring systems prepared provide convincing
evidence for the remarkable regiochemical preference for the
reaction to occur with the distal double bond of the allene.
Efforts to further delineate the scope of the allenic Pauson-
Khand reaction and validate its usefulness in natural product
synthesis are underway in our laboratories.
(19) Sample experimental procedure for rhodium-catalyzed allenic Pau-
son-Khand reaction: 3-isopropyl-2-oxo-2,4,5,7-tetrahydro-1H-azulene-6,6-
dicarboxylic acid diethyl ester (41). To a flame-dried test tube equipped
with a magnetic stir bar were added 2-(2,3-butadienyl)-2-(5-methyl-3-
hexynyl)malonic acid diethyl ester (40, 0.048 g, 0.16 mmol) and toluene
(0.5 mL). The test tube was evacuated and charged with CO three times,
and then [Rh(CO)2Cl]2 (3.2 mg, 0.008 mmol) was added. The mixture was
stirred and heated at 90 °C overnight under CO (1 atm). The solvent was
removed in vacuo, and the residue was purified by preparative TLC (SiO2,
75:25 hexanes/ether, Rf ) 0.4) to afford title compound 41 as a pale yellow
oil that solidified in the freezer to afford a colorless solid (0.0400 g, 76%):
1H NMR (300 MHz, CDCl3) δ 5.70 (t, J ) 6.5 Hz, 1 H), 4.14 (q, J ) 7.2
Hz, 4 H), 2.86-2.75 (m, 6 H), 2.30-2.26 (m, 2 H), 1.20 (t, J ) 7.2 Hz, 6
H), 1.16 (d, J ) 7.1 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 204.6, 171.5,
165.7, 147.8, 138.9, 125.5, 120.9, 61.5, 58.2, 40.8, 31.0, 30.3, 24.8, 24.7,
20.3, 14.0; IR (neat) 1732, 1695, 1227, 1201, 1183, 1271, 2963, 2934, 2874
cm-1; EI-HRMS calcd for C19H26O5 [M+] m/z 334.1780, found 334.1787.
Acknowledgment. We thank the National Institutes of
Health (GM54161) for financial support of this work.
Supporting Information Available: Characterization
data and full experimental procedures are provided for
compounds 14-18 and 20-45.19 This material is available
free of charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 4, No. 11, 2002