Intramolecular [4 + 2] cycloadditions of benzynes with conjugated enynes, arenynes, and dienes

Article abstract of DOI:10.1021/ol051372l

(Chemical Equation Presented) Benzynes generated by the reaction of o-(trimethylsilyl)aryl triflates with TBAT participate in intramolecular [4 + 2] cycloadditions with conjugated enynes, arenynes, and dienes to furnish highly condensed polycyclic aromatic compounds.

Full text of DOI:10.1021/ol051372l

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3917-3920
Intramolecular [4
Benzynes with Conjugated Enynes,
Arenynes, and Dienes
+ 2] Cycloadditions of
Martin E. Hayes, Hiroshi Shinokubo, and Rick L. Danheiser*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
danheisr@mit.edu
Received June 11, 2005
ABSTRACT
Benzynes generated by the reaction of o-(trimethylsilyl)aryl triflates with TBAT participate in intramolecular [4
enynes, arenynes, and dienes to furnish highly condensed polycyclic aromatic compounds.
+
2] cycloadditions with conjugated
In this Letter we describe a new variant of the intramolecular
[4 + 2] cycloaddition of conjugated enynes that provides
an expeditious route to complex, highly condensed polycyclic
aromatic compounds. In this transformation, conjugated
enynes1-3 (and “arenynes”4) combine at room temperature
with substituted benzynes5 in an unusually facile cycload-
dition to generate isoaromatic cyclic allenes of general type
2 (eq 1).6 These highly strained intermediates then rearrange
via either proton or radical-mediated hydrogen atom transfer
pathways1,7 to afford the desired polycyclic aromatic systems
(3).
(1) For recent examples of thermal and Lewis-acid-promoted enyne and
“heteroenyne” cycloadditions, see: (a) Danheiser, R. L.; Gould, A. E.;
Fernandez de la Pradilla, R.; Helgason, A. L. J. Org. Chem. 1994, 59, 5514.
(b) Wills, M. S. B.; Danheiser, R. L. J. Am. Chem. Soc. 1998, 120, 9378.
(c) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776 and
references therein.
(2) Early examples of enyne and arenyne cycloadditions are reviewed
in: Onishchenko, A. S. Diene Synthesis; Israel Program for Scientific
Translations: Jerusalem, 1964; pp 249-254 and 635-637.
(3) For reviews of transition-metal-catalyzed enyne cycloadditions, see:
(a) Rubin, M.; Sromek, A. W.; Gevorgyan, V. Synlett 2003, 2265. (b) Saito,
S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901.
Arynes are fascinating species that engage in a variety of
interesting transformations, including nucleophilic addition
reactions, [2 + 2] cycloadditions, and Diels-Alder reac-
tions.5 Diels-Alder reactions with cisoid dienes such as furan
are especially well-known, though reactions involving acyclic
(4) For recent examples of cycloadditions of conjugated arenynes (the
“Michael-Bucher reaction”), see: (a) Rodr´ıguez, D.; Mart´ınez-Espero´n,
M. F.; Navarro-Va´zquez, A.; Castedo, L.; Dom´ınguez, D.; Saa´, C. J. Org.
Chem. 2004, 69, 3842. (b) Mart´ınez-Espero´n, M. F.; Rodr´ıguez, D.; Castedo,
L.; Saa´, C. Org. Lett. 2005, 7, 2213 and references therein.
(5) Reviews: (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes;
Academic Press: New York, 1967. (b) Gilchrist, T. L. In The Chemistry of
the Functional Groups; Patai, S., Rappaport, Z., Eds.; Wiley: New York,
1983; Supplement C, Chapter 11, pp 383-419. (c) Hart, H. In The Chemistry
of Functional Groups; Patai, S., Rappaport, Z., Eds.; Wiley: New York,
1994; Supplement C2, Chapter 18, pp 1017-1134. (d) Pellissier, H.; Santelli,
M. Tetrahedron 2003, 59, 701.
(6) Transformation 1f2 may proceed via a concerted cycloaddition or
may involve a stepwise mechanism involving an intermediate biradical.
For a discussion of stepwise mechanisms in benzyne cycloadditions, see
ref 5. For a discussion of biradical intermediates in arenyne cycloadditions,
see: Rodr´ıguez, D.; Navarro, A.; Castedo, L.; Dom´ınguez, D.; Saa´, C. Org.
Lett. 2000, 2, 1497.
(7) For mechanistic and theoretical studies on enyne and arenyne
cycloadditions, see: (a) Burrell, R. C.; Daoust, K. J.; Bradley, A. Z.; DiRico,
K. J.; Johnson, R. P. J. Am. Chem. Soc. 1996, 118, 4218. (b) Ananikov, V.
P. J. Phys. Org. Chem. 2001, 14, 109. (c) Rodr´ıguez, D.; Navarro-Va´zquez,
A.; Castedo, L.; Dom´ınguez, D.; Saa´, C. J. Org. Chem. 2003, 68, 1938.
10.1021/ol051372l CCC: $30.25
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dienes are often complicated by competing [2 + 2] cycload-
dition and ene reaction pathways. Surprisingly, only a single
report has previously appeared on the intramolecular Diels-
Alder reaction of benzynes with acyclic dienes.8 In this 1995
study, Buszek obtained the desired Diels-Alder adduct in
only 20-28% yield, although a related cycloaddition with a
cyclic diene (constrained to an s-cis conformation) was found
to proceed in good yield.9 To our knowledge, the intramo-
lecular cycloaddition of an aryne and conjugated enyne (eq
1) has not been described previously, although several
examples of low-yield intermolecular cycloadditions of
benzyne with aryl acetylenes have been reported.10 We
therefore considered it worthwhile to undertake a systematic
investigation of the feasibility and scope of the intramolecular
[4 + 2] cycloaddition of arynes with conjugated enynes and
related species.
Scheme 1. Synthesis of Typical Cycloaddition Substrate
The first subgoal in this study was to identify the optimal
protocol for the generation of arynes in the context of the
proposed cycloaddition. Among the various methods avail-
able for generating benzynes,5 procedures based on the
desilylation of ortho-substituted arenes appeared to be
particularly well suited for our purposes. We chose to utilize
the protocol introduced by Kobayashi involving the fluoride-
induced 1,2-elimination of o-(trimethylsilyl)aryl triflates,
which proceeds under mild conditions and employs readily
available phenol derivatives as substrates.11 Scheme 1
outlines the assembly of a typical benzyne precursor.
Directed metalation of the MOM ether derivative of phenol
with n-BuLi followed by silylation furnished the expected
arylsilane, which in the same flask was subjected to a second
ortho lithiation followed by reaction with DMF. Careful
hydrolysis12 then afforded the known o-silyl salicylaldehyde
5.13 Reductive amination with propargylamine and Sono-
gashira coupling14 with isopropenyl bromide provided enyne
7, which was converted to the desired cycloaddition substrate
by sulfonylation with excess triflic anhydride. An important
consideration in the design of this strategy was the expected
ability of 6 to serve as a common precursor to a variety of
enynes and arenynes required in our projected systematic
study of the scope of the proposed cycloaddition.
CN (1.5 equiv of BHT, rt, 46 h) for benzyne generation
improved the yield to 43%, and reaction with 4 equiv each
of KF and 18-crown-6 (6 equiv of BHT, THF, rt, 24 h) led
to the isolation of the desired product in 79% yield.15 After
considerable experimentation, the optimized procedure out-
lined in eq 2 was developed. Most important to the success
of the reaction is the use of easily handled TBAT16 (n-Bu4-
NSiPh3F2), a commercially available and nonhygroscopic
fluoride source. Best results are obtained when the reaction
is conducted in a dilute (0.005 M) solution in THF in the
presence of 1.5 equiv of BHT.17,18 At higher concentrations
(e.g., 0.1 M), the yield declines to 41%, most likely due to
competing intermolecular side reactions involving the reac-
tive intermediate benzyne.
Initial attempts to effect the desired aryne cycloaddition
using the Kobayashi protocol were disappointing. Although
the desired reaction was observed to take place at room
temperature with 1.5-2.0 equiv of TBAF in THF (0.005-
0.01 M, 1.5 equiv of BHT), the cycloadduct 9 was obtained
in only 24-32% yield. Employing 2 equiv of CsF in CH3-
(8) Buszek, K. R. Tetrahedron Lett. 1995, 36, 9125.
(9) Buszek, K. R.; Bixby, D. L. Tetrahedron Lett. 1995, 36, 9129.
(10) (a) Stiles, M.; Burckhardt, U.; Haag, A. J. Org. Chem. 1962, 27,
4715. (b) Dyke, S. F.; Marshall, A. R.; Watson, J. P. Tetrahedron 1966,
22, 2515. (c) Cobas, A.; Guitia´n, E.; Castedo, L. J. Org. Chem. 1997, 62,
4896.
(11) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211. (b) For an earlier report on the generation of benzynes by fluoride-
promoted elimination of o-(trimethylsilyl)aryl chlorides, see: Cunico, R.
F.; Dexhemier, E. M. J. Organomet. Chem. 1973, 59, 153.
(12) Williams, D. R.; Barner, B. A.; Nishitani, K.; Phillips, J. G. J. Am.
Chem. Soc. 1982, 104, 4708.
(13) O’Connor, K. J.; Wey, S.-J.; Burrows, C. J. Tetrahedron Lett. 1992,
33, 1001.
(14) For a review of alkyne cross-coupling, see: Negishi, E.; Anastasia,
L. Chem. ReV. 2003, 103, 1979.
Having developed optimal conditions for effecting the
desired cycloaddition in the case of enyne 8, we turned our
(15) Interestingly, Kobayashi reports that none of the expected cycload-
duct with furan was obtained when benzyne generation was attempted using
KF under similar conditions (ref 10a).
(16) Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901.
(17) Cycloadduct 9 was obtained in 54% yield when 1.5 equiv of TBAT
and 0.5 equiv of BHT were employed.
3918
Org. Lett., Vol. 7, No. 18, 2005

Table 1. Cycloaddition of Arynes and Conjugated Enynes
Table 2. Cycloaddition of Arynes with Arenynes and
Hetarenynes
a Tetrabutylammonium triphenyldifluorosilicate (n-Bu4NSiPh3F2). b Iso-
lated yields of products purified by column chromatography. c Reaction in
the absence of BHT.
found to proceed smoothly, although substrates lacking
substituents at the internal position of the enyne double bond
give the desired products in low yield (Table 1, entries 2
and 4).19 Attempts to identify byproducts from these reactions
were unsuccessful, and only uncharacterizable polymers were
1
observed by H NMR analysis of the crude products.
Intramolecular cycloadditions also proceed in good yield
in the case of related substrates in which the enyne double
bond is incorporated in an aromatic or heteroaromatic ring.
Table 2 presents several examples of these [4 + 2] cycload-
ditions of benzynes with “arenyne” and “hetarenyne” 4π
components. Interestingly, attempted cycloaddition with the
3-substituted thiophene 23 under our standard conditions
produced a 2:1 mixture of the expected cycloadduct 27 and
a byproduct identified as 28 (Figure 1) in a 45% combined
yield. In this case, reaction is best performed in the absence
of BHT, and under these conditions the desired cycloadduct
a Tetrabutylammonium triphenyldifluorosilicate (n-Bu4NSiPh3F2). b Iso-
lated yields of products purified by column chromatography.
attention to exploring the scope of the reaction with respect
to substitution on the enyne moiety. Table 1 summarizes our
results. Cycloaddition substrates 10-14 were all easily
prepared via terminal acetylene 6 using Sonogashira coupling
reactions with alkenyl halides and triflates (see Supporting
Information). Most of the cycloadditions examined were
(18) Under the same conditions but in the absence of BHT, the
cycloadduct 9 is obtained in only 27% yield. We believe that BHT serves
as a hydrogen and/or proton donor in facilitating the isomerization of cyclic
allene intermediates of type 2 to the aromatic products.
(19) We speculate that substitution at this position suppresses side
reactions of the intermediate cyclic allene 2, possibly including intermo-
lecular trapping by benzyne intermediates.
Org. Lett., Vol. 7, No. 18, 2005
3919

Scheme 2. Study of Intramolecular Cycloaddition of a
Benzyne and Acyclic Diene
Figure 1. Byproduct obtained in cycloaddition of 23 when the
reaction is carried out in the presence of BHT.
is obtained cleanly in 51% yield after purification by column
chromatography. We believe that the formation of 28 likely
proceeds via combination of a phenoxy radical with a thiyl
radical generated by C-S homolysis of a radical intermediate
formed during the isomerization of the cyclic allene involved
in this reaction.
The efficiency of the cycloadditions of conjugated enynes
and arenynes with benzynes generated under the conditions
described here led us to investigate the intramolecular Diels-
Alder reaction of acyclic dienes with benzynes using a similar
protocol. Scheme 2 outlines the synthesis of a Diels-Alder
cycloaddition precursor via a route analogous to that
employed for the preparation of our enyne substrates. In this
case, reductive amination with allylamine followed by
sulfonylation provided 29, which was subjected to cross-
metathesis20 with methyl vinyl ketone and then Wittig
olefination to afford the desired cycloaddition substrate 30.
In contrast to the intramolecular Diels-Alder reactions of
benzynes with acyclic dienes reported previously,8 cycload-
dition of 30 under our conditions proved to be remarkably
efficient. Thus, treatment of 30 with 2.0 equiv of TBAT at
room temperature in THF provided the desired Diels-Alder
adduct 31 in 86% yield after purification by column
chromatography.
a Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168.
1,2-elimination of o-(trimethylsilyl)aryl triflates. In contrast
to most prior enyne and arenyne cycloadditions that require
elevated temperatures, these benzyne cycloadditions proceed
readily at 25 °C. The first example of an efficient intramo-
lecular Diels-Alder reaction of a benzyne with an acyclic
diene has been achieved by employing similar conditions.
Acknowledgment. We thank the National Institutes of
Health (GM 28273) for generous financial support. M.E.H.
was supported in part by a predoctoral fellowship from the
Ford Foundation. We thank Dr. Kazuya Matsunaga and Dr.
Ralf Demuth for important exploratory experiments.
In summary, a new variant of the intramolecular [4 + 2]
cycloaddition of conjugated enynes and arenynes has been
developed that provides access to highly condensed poly-
cyclic aromatic compounds. Crucial to the success of these
reactions is the method for the generation of the benzyne
cycloaddition partners, which involves the TBAT-promoted
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and H NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(20) (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42,
1900. (b) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
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