Thermal and palladium-catalyzed [3 + 2] synthesis of cyclopentadienone acetals from cyclopropenone acetals and acetylenes

Article abstract of DOI:10.1021/ol0483450

(Chemical Equation Presented) Substituted cyclopentadienone acetals (CPDAs) were synthesized by a thermal or palladium-catalyzed [3 + 2] cycloaddition reaction of a substituted cyclopropenone acetal to an electron-deficient acetylene. The synthesis afford

Full text of DOI:10.1021/ol0483450

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3569-3571
Thermal and Palladium-Catalyzed
[3 2] Synthesis of Cyclopentadienone
Acetals from Cyclopropenone Acetals
and Acetylenes
+
Hiroyuki Isobe,† Sota Sato, Takatsugu Tanaka, Hidetoshi Tokuyama, and
Eiichi Nakamura*
Department of Chemistry, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
nakamura@chem.s.u-tokyo.ac.jp
Received August 20, 2004
ABSTRACT
Substituted cyclopentadienone acetals (CPDAs) were synthesized by a thermal or palladium-catalyzed [3
+
2] cycloaddition reaction of a
substituted cyclopropenone acetal to an electron-deficient acetylene. The synthesis afforded di-, tri-, and tetrasubstituted CPDAs of considerable
structural varieties that undergo Diels Alder reaction to produce bicyclo[2.2.1]heptenes.
−
The chemistry of cyclopentadienone and its acetal (CPDA)
has seen its revival in recent years through development of
useful applications in the synthesis of functional polycyclic
compounds.1,2 The range of these applications, however,
remains rather limited due to the small variety of available
derivatives.3,4 We report here the synthesis of substituted
CPDAs (E in Scheme 1) by thermal or palladium-catalyzed
[3 + 2] cycloaddition of a substituted cyclopropenone acetal
(CPA, A)5-7 to an electron-deficient acetylene (D). The
synthesis afforded di-, tri-, and tetrasubstituted CPDAs of
considerable structural variety previously not available. The
utilities of the new CPDAs are illustrated with their Diels-
Alder reaction and a formal [2 + 2 + 2] construction of a
substituted benzene.
Thermolysis of the CPA (A) results in reversible cleavage
of the C-C σ-bonds5 to generate an equilibrating mixture
of dipoles B and C (Scheme 1, route a)8 that might undergo
[3 + 2] cycloaddition to an acetylene to give a CPDA, but
the reaction of an unsubstituted CPA 1 with a disubstituted
acetylene does not give the desired cycloadduct.5 To the
contrary, we found that thermal or Pd-catalyzed [3 + 2]
cycloaddition of substituted derivatives (2-9) gives a variety
of the cycloadducts (E; Figure 1, yields of thermal reaction
in italic and Pd-catalyzed reaction in bold).9
† PRESTO, Japan Science and Technology Agency.
(1) Hill, J. P.; Jin, W.; Kosaka, A.; Fukushima, T.; Ichihara, H.;
Shimomura, T.; Ito, K.; Hashizume, T.; Ishii, N.; Aida, T. Science 2004,
304, 1481-1483. Watson, M. D.; Fechtenko¨tter, A.; Mu¨llen, K. Chem. ReV.
2001, 101, 1267-1300. Jux, N.; Holczer, K.; Rubin, Y. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1986-1990. Tobe, Y.; Kubota, K.; Naemura, K. J.
Org. Chem. 1997, 62, 3430-3431.
(2) Khan, F. A.; Prabhudas, B.; Dash, J. J. Prakt. Chem. 2000, 342, 512-
517.
(3) Ogliaruso, M. A.; Romanelli, M. G.; Becker, E. I. Chem. ReV. 1965,
65, 261-367.
The thermal reaction is described first. It is moderate-
yielding but quite general, taking place with excellent
(5) Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1986, 108, 6695-
6713. Boger, D. L.; Brotherton-Pleiss, C. E. In AdVances in Cycloaddition;
Padwa, A., Ed.; JAI Press: London, 1990; pp 147-219, Boger, D. L.
Chemtracts: Org. Chem. 1996, 9, 149-189.
(6) Nakamura, M.; Isobe, H.; Nakamura, E. Chem. ReV. 2003, 103,
1295-1326.
(7) Yamago, S.; Nakamura, E. Org. React. 2002, 61, 1-215.
(8) Tokuyama, H.; Isaka, M.; Nakamura, E. J. Am. Chem. Soc. 1992,
114, 5523-5530.
(4) Newcomer, J. S.; McBee, E. T. J. Am. Chem. Soc. 1949, 71, 946-
956. Vogel, E.; Wyes, E.-G. Angew. Chem. 1962, 74, 489. DePuy, C. H.;
Ponder, B. W.; Fritzpatrick, J. D. Angew. Chem. 1962, 74, 489. Eaton, P.
E.; Hudson, R. A. J. Am. Chem. Soc. 1965, 87, 2769-2771.
10.1021/ol0483450 CCC: $27.50
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Published on Web 09/08/2004

group,8 and regioselectively gives the tetrasubstituted CPDA
14d in 40% yield. The observed regioselectivity conforms
to our previous mechanistic proposal that there is a mobile
equilibrium between B and C via CPA.8 The yields of the
thermal reactions are generally moderate. Nonetheless, the
results indicated that the substituted CPDAs are easy to
handle and therefore synthetically useful.
Scheme 1. [3 + 2] Synthesis of Cyclopentadienone Acetala
Encouraged by this finding, we investigated transition
metal catalysis seeking milder reaction conditions (Scheme
1, route b). We examined a number of transition metal
complexes for the reaction of 11 with 1 equiv of 3 in toluene.
We found that Pd(OAc)2 (generally 1 mol %) is the best
catalyst, allowing the reaction to proceed at room temper-
ature. For instance, the reaction gave 14b in 44, 29, and 4%
in the presence of Pd(OAc)2, Pd2(dba)3, and Pd(PPh3)4,
respectively (all with 5 mol % catalyst loading).10,11
We obtained here some interesting pieces of information
relevant to the reaction mechanism: Freshly recrystallized
Pd(OAc)2 is the reagent of choice, and its activity diminishes
in the presence of a phosphine, suggesting that the phosphine
ligand and a reactant competitively bind to the Pd vacant
site. The use of THF instead of a nonpolar solvent such as
toluene improves the product yield from 36 to 62%.12 The
material balance of the acetylene 11 was generally over 90%,
and dimerization of CPA into (E,E)-diene H was the major
side reaction (several % to ca. 20% based on CPA). The
use of 2 equiv of CPA therefore gives a much improved
product yield (e.g., from 62 to 87%).
a A: R1 ) R2 ) H (1); R1 ) Et, R2 ) H (2); R1 ) Ph, R2 ) H
(3); R1 ) 1-naphthyl, R2 ) H (4); R1 ) Ph, R2 ) CO2i-Pr (5); R1
) 4-MeOC6H4, R2 ) H (6); R1 ) 4-ClC6H4, R2 ) H (7); R1 )
1-hydroxycyclohexyl, R2 ) H (8); R1 ) SiMe3, R2 ) H (9). D:
R3 ) SO2CF3, R4 ) Ph (10); R3 ) R4 ) CO2Me (11); R3 ) CO2Me,
R4 )H(12);R3 )Ph,R4 )CO2Me(13).X,X)-CH2C(CH3)2CH2-,
Y ) CH2C(CH3)2CH2OH.
regioselectivity. For instance, ethyl-CPA 2 reacts with
ethynyl sulfone 10 via B to afford the [3 + 2] cycloadduct
14a in 67% yield, and Ph-CPA 3 reacts with dimethyl
acetylenedicarboxylate (11) also via B in 40% yield. Interest-
ingly, the product selectivity entirely reverses in the reaction
of 1-naphthyl-CPA 4, where the reaction took place via the
regioisomer C. The disubstituted CPA 5 preferentially
generates B, wherein the vinyl anion is stabilized by the ester
The formation of the dimer exclusively in the (E,E)-
geometry (e.g., 15; H: R1 ) Ph, R2 ) H) provides a
mechanistic hint. Transition metal-mediated ring opening of
a cyclopropene generates a metal complex of a vinyl
carbene,5,11,13,14 but, in the case of the electron-rich CPA,
the ring opening generates a vinylmetal (F and G in Scheme
1) that is, in fact, a resonance isomer of the corresponding
carbene complex.15 As previously shown for Ag(I)- or Cu(I)-
mediated ring opening of substituted CPAs,15 the vinylmetal
may be produced first in the form of F but then slowly
isomerize to G (likely in slow equilibrium with each other
depending on the substituent). We therefore suggest (Scheme
1) that the (Z)-vinylpalladium(II) F undergoes irreversible
[3 + 2] cycloaddition to the acetylene to give the CPDA E,
while the (E)-vinylpalladium G competitively dimerizes by
(9) Being similar to the thermal reaction of an unsubstituted CPA (ref
5), the thermal equimolar reaction of a substituted CPA 9 with methyl
propionate afforded the product of C-H carbene insertion to the acetylenic
C-H bond (30%) in addition to a small amount of the [3 + 2] cycloadduct
(6%). The Pd-catalyzed reaction, on the other hand, afforded exclusively
the [3 + 2] cycloadduct (vide infra).
(10) Reaction in the presence of metal complexes such as Mn(CO)6,
Fe3(CO)12, Co2(CO)8, Ni(cod)2, ZrCp2Cl2, Mo(CO)6, Ru3(CO)12, W(CO)6,
and IrCl(CO)(PPh3)2 gave none or very little of the desired product.
(11) Binger, P.; Biedenbach, B. Chem. Ber. 1991, 124, 2165-2170.
(12) Note that the yield of the Pd-catalyzed reaction is better than that
of the thermal reaction (62 vs 40%; comparison made by using equimolar
amounts of 3 and 11).
Figure 1. CPDAs obtained by thermal and Pd-catalyzed [3 + 2]
cycloaddition. Yields of the thermal reaction are shown in italic
and those of the Pd(OAc)2-catalyzed reaction (catalyst load: 1 mol
%) in bold. See Supporting Information for details. Stoichiometry
of the reactants: a1.2 equiv of CPA; b2.0 equiv of CPA; c1.0 equiv
(13) Baird, M. S. Chem. ReV. 2003, 103, 1271-1294.
(14) Binger, P.; Bu¨ch, H. M. Top. Curr. Chem. 1987, 135, 77-151.
Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115,
8130-8145.
d
e
of CPA; 2.0 equiv of 12. Compound 15 (H: R1 ) Ph, R2 ) H)
was isolated as a side product in 22% yield.
(15) Yu, Y.; Yamanaka, M.; Nakamura, E. Org. Lett. 1999, 1, 407-
409.
3570
Org. Lett., Vol. 6, No. 20, 2004

reacting with another molecule of CPA to give the (E,E)-
An interesting application of the [3 + 2] cycloadduct is
its conversion to a substituted benzene through thermolytic
removal of a dialkoxycarbene moiety from the bicyclo[2.2.1]
skeleton (the carbene moiety was identified as tetraalkoxy-
ethylene 23) (Scheme 2). Thermolysis of the norbornadiene
dimer.16
The Pd-catalyzed [3 + 2] cycloaddition afforded a variety
of CPDAs as shown in Figure 1 (yields in bold).17 The
catalyzed reaction is generally higher-yielding than the
thermal reaction, while they are sometimes complementary;
for instance, the sulfone product 14a and the tetrasubstituted
CPDA 14d can be synthesized only by or in much better
yield by the thermal route. In contrast to the thermal reaction,
the 1-naphthyl-CPA reacted with the same regioselectivity
as that of other compounds (14e vs others such as 14a,b,f).
The reaction conditions are mild enough to tolerate the
presence of free hydroxy, halogen, and silyl groups and likely
a variety of other functional groups. Electron-deficient
acetylenes of reasonably wide structural varieties serve as
acceptors of the cycloaddition. The reaction of methyl
propiolate gave a 1,4-disubstituted CPDA (14k) as a
thermally stable compound.9 Interestingly, the regioselectivity
of the reaction of methyl phenylpropiolate reversed to give
CPDA 14l in 96%.18
Scheme 2. Conversion of Diels-Alder Adduct 19 to a
Substituted Benzene 22
adduct 19 in refluxing tetralin gave the substituted biphenyl
22 in 78% yield. As shown by color coding, this benzene
synthesis formally comprises a [2 + 2 + 2] assembly of the
aromatic ring from three components.
In summary, we found that substituted CPAs undergo [3
+ 2] cycloaddition to electron-deficient acetylenes to give a
variety of new substituted CPDAs. As viewed from the
perspective of the metal-catalyzed ring-cleavage/cyclo-
addition reactions of cyclopropenes, the present reaction
provides a unique example of a [3 + 2] reaction rather than
a [1 + 2] cycloaddition reaction leading to three-membered
rings that has been the only reaction type thus far ob-
served.6,13,14
Among various possible applications of the densely
functionalized cyclopentadienes thus synthesized, one is a
Diels-Alder reaction with an olefin. The new CPDA
derivatives are thermally stable enough not to undergo
Diels-Alder dimerization,2,4 but they undergo clean Diels-
Alder reaction with activated and unactivated olefins to give
bicylo[2.2.1]heptenes (Figure 2). Thus, the CPDA 14b reacts
Acknowledgment. We thank H. Inoue for his earlier
contribution. We are grateful to Prof. M. Murata and
Dr. N. Matsumori for their valuable suggestions in NMR
measurement. This study was financially supported by
Monbukagakusho, Japan (Grant-in-Aid for Scientific Re-
search, Specially Promoted Research, and the 21st Century
COE Program for Frontiers in Fundamental Chemistry to
E.N.) and SUNBOR (to H.I.).
Supporting Information Available: Details of the ex-
perimental procedure, characterization of products (PDF),
and X-ray crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Figure 2. Bicylo[2.2.1]heptenes obtained by Diels-Alder reaction
of CPDA 14b with olefins. Origins of the moieties are shown in
colors: CPA in blue, acetylene in red, and dienophile in green. 16
resulted from maleic anhydride, 17 from acrylonitrile, 18 from
ethylene, 19 from norbornadiene, 20 from ethyl vinyl ether, and
21 from furan.
OL0483450
(16) Dimerization reaction of CPA needs an oxidant, which remains
unidentified. Given the facts that the dimer forms much in excess of the
amount of the Pd(II) catalyst and that CPDA 14j was obtained, under a
nitrogen atmosphere, in 100% yield based on the acetylene, it is likely that
the excess CPA acted as the oxidant.
(17) Under Pd(OAc)2-catalyzed conditions, unsubstituted CPA 1 did not
give the corresponding CPDA and instead underwent [2 + 2] dimerization
[ref 5].
(18) This regioselectivity is inconsistent with the simple mechanism that
F initially undergoes conjugate addition to the electron-deficient acetylene.
(19) Chen, C.-H.; Rao, P. D.; Liao, C.-C. J. Am. Chem. Soc. 1998, 120,
13254-13255.
with maleic anhydride and acrylonitrile to give the hindered
cycloadducts 16 and 17 in quantitative yield. It also reacts
with atmospheric pressure ethylene, norbornadiene, and ethyl
vinyl ether to give 18-20, respectively, in excellent yield.
Notably, furan also takes part in the Diels-Alder reaction
as a dienophile.19
Org. Lett., Vol. 6, No. 20, 2004
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