Cyclopentadienone synthesis by rhodium(I)-catalyzed [3 + 2] cycloaddition reactions of cyclopropenones and alkynes

Article abstract of DOI:10.1021/ja065868p

The Rh(I)-catalyzed [3 + 2] cycloaddition of cyclopropenones and alkynes is found to provide a highly efficient and regiocontrolled route to cyclopentadienones (CPDs), building blocks of widespread use in the synthesis of natural and non-natural products, therapeutic leads, polymers, dendrimers, devices, and antigen presenting scaffolds. The versatility of the method is explored with 23 examples representing a wide range of alkyne variations (arylalkyl-, dialkyl-, heteroarylalkyl-) and diaryl- as well as arylalkylcyclopropenones. The reactions often proceed in high yield using minimal catalyst loadings and in all cases examined proceed with high or complete regioselectivity. The reaction is readily scalable to produce gram quantities of cycloadduct and provides a unique and versatile route to CPDs that would be otherwise difficult to obtain. Copyright

Full text of DOI:10.1021/ja065868p

Published on Web 10/27/2006
Cyclopentadienone Synthesis by Rhodium(I)-Catalyzed [3 + 2] Cycloaddition
Reactions of Cyclopropenones and Alkynes
Paul A. Wender,* Thomas J. Paxton, and Travis J. Williams
Departments of Chemistry and of Molecular Pharmacology, Stanford UniVersity, Stanford, California 94305-5080
Received August 12, 2006; E-mail: email: wenderp@stanford.edu
Cyclopentadienones1 (CPDs) are members of a diverse class of
fascinating molecules with demonstrated value and even broader
potential in synthesis, biology, materials science, and nanotech-
nology. They have been used as 2π or 4π components in
cycloaddition approaches to highly substituted arenes,2 as ligands
in a range of coordination complexes,3a including ruthenium
catalysts for reversible reductions of π systems,3b,c and as polymer
cross-linking agents.4 CPDs have been proposed as biosynthetic
intermediates5 and have been used as building blocks in the
synthesis of natural products (e.g., hirsutic acid),6a molecules of
theoretical interest (e.g., cubane and tetrahedrane),6b,c therapeutic
leads,7 and a remarkable variety of novel polymers, dendrimers,
and devices.8
Scheme 1. The [3 + 2] and [2 + 2 + 1] Cycloadditions to Form
CPDs
a Reaction run using 1 mol % [RhCl(CO)2]2, toluene (0.3 M), 80 °C, 2
h. bReaction run using 5 mol % [RhCl(CO)2]2, toluene (0.3 M), 110 °C, 24
h.
Table 1. [3 + 2] Reactions of 1 with Substituted Phenylacetylenes
The synthesis of CPDs has been achieved in various ways:
elimination reactions of substituted cyclopentenones,9 condensations
of propanones with R-diketones10 and carbonylations of metalla-
cyclopentadienes.11 An approach of historical and contemporary
significance involves the metal mediated or catalyzed formal [2 +
2 + 1] cycloaddition of 2 equiv of one alkyne and carbon monoxide
(CO).12 The use of two different alkynes in the catalyzed three-
component process is not known and is complicated by the potential
formation of up to 10 hetero- and homocoupled products. Many
creative strategies have been developed to address these inherent
chemo- and regioselectivity problems. Tethering two different
alkynes has proven effective, and the use of temporary silicon
tethers by Pearson simplifies the problem of post cycloaddition
tether removal.13 Boger and Nakamura have reported that cyclo-
propenone ketals, either thermally (via dipolar cycloaddition)14a or
with a Pd(OAc)2 catalyst,14b undergo cycloaddition with various π
systems to provide CPDs after ketal hydrolysis. As part of our
studies on metal-catalyzed cycloadditions, we have found that
cyclopropenones serve as excellent 3-carbon components in Rh(I)-
catalyzed [3 + 2] cycloadditions with a wide range of alkynes,
providing CPDs selectively and in high yield.
The essence of this new approach to CPDs is shown in Scheme
1. When commercially available diphenylcyclopropenone (1, 1.5
equiv) and alkyne 2 (1 equiv) are heated in toluene for 2 h at 80
°C with 1 mole percent [RhCl(CO)2]2, the [3 + 2] cycloadduct 3
is obtained in 94% yield. Significantly, only one regioisomer is
produced, and its structure was established by X-ray crystallography.
Moreover, the reaction is scalable by 2 orders of magnitude: 3
can be prepared in 85% yield on a multigram scale. In contrast,
attempts to produce 3 through a [2 + 2 + 1] cycloaddition by
heating alkyne 2, diphenylacetylene, and [RhCl(CO)2]2 (5 mole
percent) in toluene under an atmosphere of CO for a prolonged
period at higher temperature (24 h, 110 °C) produced only trace
amounts of 3 (<1% by GC/MS) along with traces of tetracyclone
(12) and various quinones. Lower catalyst loading (0.1 mole
percent) in the reaction of 1 and 2 is possible, but the yield is lower
and the reaction time longer (69%, 9 h at 80 °C). In the absence of
catalyst, the reaction of 1 and 2 does not occur. Other transition
entry
R
conditions
product
yieldb
1
2
3
4
CH3
2 h, 80 °C
3
4
5
6
7
8
9
10
11
12
94%
97%
91%
71%
99%
64%
37%
42%
35%
17%
CH2OCH3
C(O)CH3
Cl
C(O)NH2
CH(OH)CH3
CN
4 h, 110 °C
18 h, 110 °C
6 h, 110 °C
12 h, 80 °C
23 h, 110 °C
11 h, 110 °C
3 h, 110 °C
21 h, 60 °C
65 h, 80 °C
5
6c
7d
8
CHO
9e
10f
CtC-Ph
Ph
a Reaction run using 1.5 equiv 1, 1 mol % [RhCl(CO)2]2, toluene (0.3
M). b Isolated yields. c [RhCl(CO)2]2, 2 mol %. d [RhCl(CO)2]2, 5 mol %.
e [RhCl(CO)2]2, 10 mol %. f Compound 1, 1 equiv.
metal catalysts [Pd(OAc)2, trans-IrCl(CO)(PPh3)2], Lewis acids
[Ti(OiPr)4, MgBr2‚Et2O], or Brønsted acids (TsOH) afford at most
trace quantities of 3.
This Rh(I)-catalyzed [3 + 2] cycloaddition tolerates a broad range
of aryl alkyne substituents (Table 1): methyl-, methoxymethyl-,
methyl ketone-, chloride-, and amide-functionalized phenylacet-
ylenes all react efficiently and regioselectively (entries 1-5). Free
alcohol, nitrile, aldehyde, and even 1,3-diyne moieties also react
to provide CPDs with high regioselectivity (entries 6-9). In the
case of diphenyl-1,3-butadiyne, formation of 11 is accompanied
by formation of its decarbonylative [4 + 2] dimer (11a, not shown)
and higher oligomers (Supporting Information). In each case, the
observed regiochemistry is consistent with observations of Pauson-
Khand reactions of analogous aryl alkynes.15 Diphenylacetylene
reacts slowly with 1 (entry 10). Terminal alkynes (phenylacetylene,
1-octyne, and acetylene) and dimethyl acetylene dicarboxylate do
not afford CPDs under these conditions. In these cases, only
decarbonylation of 1 and trimerization of the alkyne are observed.
Functionalized aryl alkynes also react efficiently (Table 2). The
electron-rich alkyne 13 selectively provides 14 in 94% yield (entry
1). Similarly, electron-deficient alkynes 15, 17, and 19 afford
cycloadducts 16, 18, and 20, respectively, in high yields (entries
9
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J. AM. CHEM. SOC. 2006, 128, 14814-14815
10.1021/ja065868p CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 4. [3 + 2] Reactions of 33 with Alkynes
Table 2. [3 + 2] Reactions of 1 with Substituted Arylacetylenes
entry
R, R
′
conditions
product
yieldb
entry
R
conditions
product
yieldb
1
2
3
4
5
p-OCH3, CH3 (13)
p-C(O)CH3, CH2OCH3 (15)
p-CF3, CH3(17)
o-F, CH3(19)
o-CH3, CH3(21)
2.5 h, 80 °C
5 h, 110 °C
6.5 h, 110 °C
20 h, 80 °C
5 h, 110 °C
14
16
18
20
22
94%
78%
91%
77%
98%
1c
2c
3d
Ph
CH3 (2)
C(O)CH3 (35)
17.5 h, 110 °C
7.5 h, 110 °C
5 h, 110 °C
3
34
36
57%
44%
61%
a Toluene (0.3 M). b Isolated yields. c 1.1 equiv 33; 1 mol % [RhCl(CO)2]2.
d 1.1 equiv 33; 5 mol % [RhCl(CO)2]2.
a Reaction run using 1.5 equiv 1, 1 mol % [RhCl(CO)2]2, toluene (0.3
M). b Isolated yields.
The functional group tolerance observed among alkynes and the
broad range of alkynes highlight important distinctions between
reactions of cyclopropenones and cyclopropenone ketals. This [3
+ 2] cycloaddition offers a unique and versatile route to a range
of CPDs and novel CPD-derived scaffolds, polycycles, and materi-
als. Further studies will be reported in due course.
Table 3. [3 + 2] Reactions of 1 with Other Alkynes
Acknowledgment. This work was funded by National Science
Foundation grant CHE-0450638.
Supporting Information Available: Experimental details and
characterization data for all cycloadducts, including X-ray information
for 3, 11a, and 16. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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in situ from 1,2-diiodobenzene and zinc in ethanol (1.7 M).
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21, entries 4-5) are well tolerated.
Importantly, the reaction is not limited to aryl alkynes. Enynes,
heteroaryl alkynes, benzyne, and even 4-octyne all undergo selective
[3 + 2] cycloadditions (Table 3). For example, enyne 23 can be
converted to 24 in 88% yield (entry 1). Furan 25 and pyridine 27
both react to give CPDs 26 and 28, respectively (entries 2-3).
4-Octyne gives 30 in 65% yield, and benzyne (prepared from the
in situ reduction of 1,2-diiodobenzene, see Supporting Information)
reacts to provide indenone 32 in a 69% yield (entries 4-5).
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give the corresponding CPDs (Table 4). 33 reacts with diphenyl-
acetylene to give 3 in 57% yield (entry 1) and alkynes 2 and 35
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In summary, the Rh(I)-catalyzed [3 + 2] cycloaddition of
cyclopropenones and alkynes is shown to provide an efficient and
regioselective route to CPDs. Diaryl- and arylalkylcyclopropenones
can be used as the 3C component in combination with aryl-,
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