Microwave-assisted intramolecular [2 + 2] allenic cycloaddition reaction for the rapid assembly of bicyclo[4.2.0]octa-1,6-dienes and bicyclo[5.2.0]nona- 1,7-dienes

Article abstract of DOI:10.1021/ol051115g

(Chemical Equation Presented) Microwave irradiation of alkynyl allenes affords an intramolecular [2 + 2] cycloaddition reaction. This cycloaddition provides an efficient route to bicyclomethylenecyclobutenes. The reaction occurs with complete regioselecti

Full text of DOI:10.1021/ol051115g

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3473-3475
Microwave-Assisted Intramolecular
[2 2] Allenic Cycloaddition Reaction
for the Rapid Assembly of
+
Bicyclo[4.2.0]octa-1,6-dienes and
Bicyclo[5.2.0]nona-1,7-dienes
Kay M. Brummond* and Daitao Chen
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
kbrummon@pitt.edu
Received May 12, 2005
ABSTRACT
Microwave irradiation of alkynyl allenes affords an intramolecular [2
+ 2] cycloaddition reaction. This cycloaddition provides an efficient route
to bicyclomethylenecyclobutenes. The reaction occurs with complete regioselectivity for the distal double bond of the allene for the selective
formation of a variety of hetero- and carbocyclic substrates. Bicyclo[4.2.0]octadienes and bicyclo[5.2.0]nonadienes have been prepared in
high yield.
Since the pioneering work of Gedye1 and Giguere/Majetich2
in 1986, microwave irradiation (MWI) has frequently been
employed as a thermal source for many organic reactions.
Advantages to MWI include minimization of thermal de-
composition of reagents and products by eliminating potential
temperature gradients and localized overheating, which are
common to conventional heating methods. In addition, MWI
also greatly accelerates reaction rates and typically provides
better yields with fewer byproducts.3 During our studies on
the scope and limitations of the formal Rh(I)-catalyzed allenic
Alder-ene reaction, we turned to thermal conditions to test
whether the Rh(I) catalyst is indeed necessary for the
cycloisomerization process. Interestingly, exposure of alkynyl
allene 1 to MWI did produce a 10% yield of the formal
Alder-ene product, triene 2. More surprisingly though was
the formation of the [2 + 2] cycloadduct 3 as the major
product in 66% yield (eq 1).
[2 + 2] Cycloaddition reactions between an allene and an
alkene are well documented and constitute a powerful method
for the synthesis of methylenecyclobutane derivatives via
photochemical initiation and Lewis acid and transition metal
promotion.4 On the other hand, only scattered reports have
appeared on [2 + 2] cycloaddition reactions between an
alkyne and an allene. Cook observed a [2 + 2] cycloadduct
as a byproduct during a molybdenum-mediated intramolecu-
lar allenic Pauson-Khand reaction.5 Similarly, Hammond
(1) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge,
L Rousell, J. Tetrahedron Lett. 1986, 27, 279.
(2) Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron
Lett. 1986, 27, 4945.
(3) For reviews, see: Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43,
6250. Varma, R. S. Pure Appl. Chem. 2001, 73, 193. Nuchter, M.;
Ondruschka, B.; Bonrath, W.; Gum, A. Green Chem. 2004, 6, 128.
has reported
a molybdenum-catalyzed intramolecular
[2 + 2] cycloaddition for the preparation of bicyclo- and
heterobicyclo-gem-difluorocyclobutenes.6 Finally, Tamura
10.1021/ol051115g CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/13/2005

has demonstrated an intermolecular [2 + 2] cycloaddition
reaction between an alkyne and an allene. The scope of the
latter reaction appears somewhat limited since only two
examples were reported.7
Table 1. Formation of Bicycloalkadienesa
This novel microwave-assisted reaction and the potential
synthetic utility of the structurally distinct products inspired
us to investigate the scope and limitations of this rare
[2 + 2] cycloaddition reaction. The results obtained to date
are reported herein. We began our investigations by screening
a variety of conditions to find the optimal procedure for the
[2 + 2] cycloaddition. For these studies, it seemed most
advantageous to perform the reaction on substrates that are
not capable of undergoing an allenic Alder-ene reaction.
Initially, allenyne 4 (entry 1) was heated to 110 °C in toluene
for 15 min. These conditions afforded only starting materials
1
on the basis of the H NMR spectrum of the concentrated
reaction. Therefore, it was decided that higher temperatures
were needed to effect this cycloaddition reaction. Higher
temperatures (>200 °C) were obtained by doping the toluene
with an ionic liquid, 1-ethyl-3-methylimidazolium hexafluo-
rophosphate.8 Heating compound 4 to 220 °C for 15 min
showed mostly the [2 + 2] cycloadduct 23 with only a small
amount of starting material. This reaction was repeated at
250 °C for 15 min, at which time only cycloadduct 23 was
obtained in 74% yield after purification via column chro-
matography. This same reaction was repeated at 280 °C for
15 min, but the higher temperature gave a dark brown
solution and a black gel at the bottom of the reaction vial.
1
The H NMR spectrum of the crude material showed that
the starting material had decomposed. On the basis of these
experiments, the ideal conditions for performing these allenic
[2 + 2] cycloaddition reactions are a 3 M solution of 1-ethyl-
3-methylimidazolium hexafluorophosphate in toluene at 250
°C (MWI) for 15 min. Next, the scope of this reaction was
investigated by subjecting alkynyl allenes possessing a wide
range of substituents and functionality to the optimized
formal cycloaddition reaction conditions. Allenyne 5, also
possessing a phenyl group on the terminus of the alkyne but
an additional methyl group on the allene, gave cyclobutene
(4) Padwa, A.; Meske, M.; Murphree, S.; Watterson, S. H.; Ni, Z. J.
Am. Chem. Soc. 1995, 117, 7071. Padwa, A.; Lipka, H.; Watterson, S. H.;
Murphree, S. S. J. Org. Chem. 2003, 68, 6238. Snider, B. B.; Ron, E. J.
Org. Chem. 1986, 51, 3643. Aben, R. W. M.; Braverman, S.; Scheeren, H.
W. Eur. J. Org. Chem. 2003, 894. Skattebol, L.; Stenstrom, Y. Tetrahedron
Lett. 1983, 24, 3021. Hansen, T. V.; Skattebol., L.; Stenstrom, Y.
Tetrahedron 2003, 59, 3461. Dauben, W. G.; Rocco, V. P.; Shapiro, G. J.
Org. Chem. 1985, 50, 3155. Narasaka, K.; Hayashi, Y.; Shimadzu, H.;
Niihata, S. J. Am. Chem. Soc. 1992, 114, 8869. Hayakawa, K.; Aso, K.;
Shiro, M.; Kanematsu, K. J. Am. Chem. Soc. 1989, 111, 5312. Yoshida,
M.; Hidaka, Y.; Nawata, Y.; Rudzinski, J. M.; Osawa, E.; Kanematsu, K.
J. Am. Chem. Soc. 1988, 110, 1232, 1238.
(5) Cao, H.; Flippen-Anderson, J.; Cook, J. M. J. Am. Chem. Soc. 2003,
125, 3230.
(6) Shen, Q.; Hammond, G. B. J. Am. Chem. Soc. 2002, 124, 6534.
(7) For an intermolecular [2 + 2] cycloaddition reaction, see: Kimura,
M.; Horino, Y.; Wakamiya, Y.; Okajima, T.; Tamaru, Y. J. Am. Chem.
Soc. 1997, 119, 10869. Horino, Y.; Kimura, M.; Tanaka, S.; Okajima, T.;
Tamaru, Y. Chem. Eur. J. 2003, 9, 2419.
(8) This is an alternative to using rather expensive ionic liquids as the
solvent. This technique of using an ionic liquid as a “doping agent” to
increase the ability of the solution to absorb microwave energy was first
introduced by Ley. See: Ley, S. V.; Leach, A. G.; Storer, R. I. J. Chem.
Soc. 2001, 358. Also, the solvent selection proved to be crucial to the success
of these reactions. A variety of solvents commonly used for MWI were
examined, and it was found that DMSO or DMF led to decomposition.
a Conditions: toluene, ionic liquid (1-ethyl-3-methylimidazolium hexaflu-
orophosphate), microwave irradiation at 250 °C for 15 min. b Isolated a
7% yield of the triene. c Isolated a 30% yield of the triene. d Isolated a 10%
yield of the triene. e Recovered an equal amount of starting material.
f Microwave irradiation at 280 °C for 15 min. g Isolated a 28% yield of the
triene.
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Org. Lett., Vol. 7, No. 16, 2005

24 in a 63% yield (entry 2). Addition of a methyl group on
the terminus of the allene did not appear to significantly
affect the efficiency of this [2 + 2] cycloaddition process;
however, a 7% yield of the triene was also observed.
Substitution of the terminus of the alkyne with either a TMS
(entry 3) or an alkyl group (C4H9, entry 4) gave only
unreacted starting material under the standard reaction
conditions. Attempts have not been made to optimize the
reaction conditions for these substrates.
Next, in connection with the expansion of our diverging
strategy for accessing libraries of small molecules possessing
structurally unique scaffolds from a pivotal substrate, the
[2 + 2] cycloaddition of amino acid containing allenynes
was investigated.9 Placement of a phenyl group on the
terminus of the alkyne (R1 ) Ph, entry 5) gave a 60% yield
of the [2 + 2] cycloadduct 27 (entry 5). For this series of
substrates, an alkyl group on the terminus of the alkyne was
tolerated as evidenced by enyne 9 (R1 ) Me) affording an
81% yield of compound 28. Reaction of an allenyne 10
possessing terminal alkyne gave only decomposition (entry
7). Alternatively, addition of methyl group to the terminus
of the allene and alkyne gave only the triene in 54% yield
and none of the [2 + 2] cycloadduct 30 (entry 8).
The phenyl propiolamide containing allene 12 afforded
60% yield of the cycloadduct 31 (entry 9). However, an alkyl
propiolamide 13 gave a 21% yield of cycloadduct 32
combined with a 30% yield of the triene (entry 10). Next,
cycloaddition of alkynone-containing allenes were attempted.
Again the substituent on the terminus of alkynes appeared
to be a controlling factor in the efficiency of these reactions,
with the phenyl group giving the highest conversions
(compare entries 11, 12, 14, and 15 to 16 and 17). An olefin
on the terminus of the alkyne was also tolerated and afforded
good yields of cycloadduct 35 (entry 13). Interestingly,
increasing the tether length by one methylene unit afforded
the bicyclo[5.2.0]nona-1,7-diene 40 in 83% yield (entry 18).
This is a rare example of forming a medium-sized ring using
a [2 + 2] cycloaddition reaction. Finally, the allenic ester
22 gave a 47% yield of the bicyclic lactone 41 and a 28%
yield of the triene.
In summary, we have discovered a microwave-assisted
[2 + 2] cycloaddition reaction of an alkynyl allene that
provides bicyclomethylenecyclobutenes in good to excellent
yield. Details concerning the mechanism of the thermal
[2 + 2] cycloaddition reaction of allenes remain unclear even
though it has been extensively studied.10 Convincing argu-
ments for both a stepwise biradical mechanism and a
concerted mechanism based upon frontier molecular orbital
theory have been made. The substrates described within this
manuscript are different from those previously reported and
may assist in shedding light on this much-debated topic. We
are continuing our studies into the scope and limitations of
this new method and also investigating the synthetic utility
of the cycloadducts. These results will be reported in due
course.
Acknowledgment. We gratefully acknowledge the fi-
nancial support provided by the National Institutes of Health
(P50 GM067982).
Supporting Information Available: Data and experi-
mental procedures for all unknown compounds in Table 1.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL051115G
(10) Pasto, D. J. J. Am. Chem. Soc. 1979, 101, 37. Dolbier, W. R.;
Weaver, S. L. J. Org. Chem. 1990, 55, 711. Pasto, D. J.; Kong, W. J. Org.
Chem. 1988, 53, 4807. Pasto, D. J.; Sugi, K. D.; Alonso, D. E. J. Org.
Chem. 1992, 57, 1146.
(9) Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245.
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