Efficient syntheses of heterocycles and carbocycles by electrophilic cyclization of acetylenic aldehydes and ketones

Article abstract of DOI:10.1021/ol049690s

Highly substituted oxygen heterocycles can be prepared in good yields at room temperature by reacting o-(1-alkynyl)-substituted arene carbonyl compounds with NBS, I₂, ICI, p-O₂NC₆H₄SCl, or PhSeBr and various alc

Full text of DOI:10.1021/ol049690s

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1581-1584
Efficient Syntheses of Heterocycles and
Carbocycles by Electrophilic Cyclization
of Acetylenic Aldehydes and Ketones
Dawei Yue, Nicola Della Ca`, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received February 21, 2004
ABSTRACT
Highly substituted oxygen heterocycles can be prepared in good yields at room temperature by reacting o-(1-alkynyl)-substituted arene carbonyl
compounds with NBS, I2, ICl, p-O NC H SCl, or PhSeBr and various alcohols or carbon-based nucleophiles. Naphthyl ketones and iodides are
2
6 4
readily prepared by the reaction of 2-(1-alkynyl)arene-carboxaldehydes with I2 and simple olefins or alkynes.
The electrophilic cyclization of functionally substituted
alkenes has provided an extremely useful route for the
synthesis of a wide variety of heterocyclic and carbocyclic
compounds, which have often proven to be useful as
intermediates in the synthesis of natural products and
pharmaceuticals.1 The analogous chemistry of alkynes has
been far less studied, although it would appear to be a very
promising route to an extraordinary range of useful, func-
tionally substituted heterocycles and carbocycles.2 Our recent
work has indicated that benzothiophenes,3 isoquinolines,4 and
isocoumarins5 can be easily synthesized by the electrophilic
cyclization of appropriate functionally substituted alkynes
using iodine-, sulfur-, and selenium-containing electrophiles
under exceptionally mild reaction conditions. Others have
recently reported a number of very useful analogous iodine-
promoted cyclizations of functionally substituted alkynes.6
Recently, Yamamoto reported an interesting cyclization
of acetylenic aldehydes to 1-alkoxy-1H-isochromenes cata-
lyzed by palladium.7 The Pd(II) salt employed was claimed
to exhibit a dual role as both a Lewis acid and a transition-
metal catalyst. In a more recent study, the analogous
preparation of 1H-isochromenes has been achieved upon
reaction of bis(pyridine) iodonium tetrafluoroborate (IPy2-
BF4) and HBF4 with the same acetylenic carbonyl precursors
in the presence of various nucleophiles.8 The use of expensive
(6) (a) Barluenga, J.; Trincado, M.; Rubio, E.; Gonza’lez, J. M. Angew.
Chem., Int. Ed. 2003, 42, 2406. (b) Knight, D. W.; Redfern, A. L.; Gilmore,
J. J. Chem. Soc., Perkin Trans. 1 2002, 622. (c) Arcadi, A.; Cacchi, S.;
Giuseppe, S. D.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409. (d)
Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron Lett. 2001, 42,
2859. (e) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron 2001,
57, 2857. (f) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001,
5, 651. (g) Djuardi, E.; McNelis, E. Tetrahedron Lett. 1999, 40, 7193. (h)
Marshall, J. A.; Yanik, M. M. J. Org. Chem. 1999, 64, 3798. (i) Arcadi,
A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett 1999, 1432. (j)
Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Chem. Commun.
1998, 2207. (k) Redfern, A. L.; Gilmore, J. Synlett 1998, 731. (l) Ren, X.-
F.; Konaklieva, M. I.; Shi, H.; Dicy, H.; Lim, D. V.; Gonzales, J.; Turos,
E. J. Org. Chem. 1998, 63, 8898. (m) Bew, S. P.; Knight, D. W. J. Chem.
Soc., Chem. Commun. 1996, 1007. (n) El-Taeb, G. M. M.; Evans, A. B.;
Jones, S.; Knight, D. W. Tetrahedron Lett. 2001, 42, 5945.
(1) (a) Lotagawa, O.; Inoue, T.; Taguchi, T. ReV. Heteroatom Chem.
1996, 15, 243. (b) Frederickson, M.; Grigg, R. Org. Prep. Proc. Int. 1997,
29, 33. (c) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321.
(2) (a) Drenth, W. In Chemistry of Triple-Bonded Functional Groups;
Patai, S., Ed.; J. Wiley: Chichester, UK, 1994; Vol. 2, pp 873-915. (b)
Schmid, G. H. In The Chemistry of the Carbon-Carbon Triple Bond; Patai,
S., Ed.; J. Wiley: Chichester, UK, 1978; Vol. 1, pp 275-341.
(3) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905.
(4) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67,
3437.
(7) (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem.
Soc. 2002, 124, 764. (b) Nakamura, H.; Ohtaka, M.; Yamamoto, Y.
Tetrahedron Lett. 2002, 43, 7631.
(8) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. J.
Am. Chem. Soc. 2003, 125, 9028.
(5) Yao, T.; Larock, R. C. Tetrahedron Lett. 2002, 43, 7401.
10.1021/ol049690s CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/13/2004

Based on the above optimization efforts, the combination
of 1.2 equiv of nucleophile, 1 equiv of K2CO3, 1.2 equiv of
I2, and the use of CH2Cl2 as the solvent at room temperature
gave the best results. This procedure has been used as our
standard reaction conditions for subsequent electrophilic
cyclizations. To test the generality of this chemistry, acety-
lenic aldehydes bearing different substituents on the carbon-
carbon triple bond were synthesized in high yields by the
palladium/copper-catalyzed coupling of o-bromobenzalde-
hyde and the corresponding terminal alkynes.11 The resulting
acetylenic aldehydes were then allowed to react under our
standard electrophilic cyclization conditions to afford the
corresponding 1H-isochromene products in good to excellent
yields. The results are summarized in Table 1.
Scheme 1
Alkynes bearing an aromatic ring, as well as alkyl and
vinylic substituents, all react well with methanol, n-butanol,
and 2-iodobenzyl alcohol to provide the desired iodocycliza-
tion products in very good yields (entries 1-3, 8, and 11).
Interestingly, not only alcohols but also an electron-rich
aromatic compound like N,N-dimethylaniline can be used
as a nucleophile, affording iodocyclization products in
generally good to excellent yields (entries 4, 9, and 12).
Pyridine derivative 16 readily reacted under our standard
conditions using I2 or ICl and provided the desired iodo-
cyclization product in a 64% yield (entries 13 and 14). In
all cases, reactions with readily available, inexpensive iodine
gave higher yields of isochromene product than the Barlu-
enga process, which used the expensive iodonium salt and
HBF4 (compare Barluenga’s results in parentheses with ours).
IPy2BF4, together with B(OMe)3 or HBF4, and the relatively
complicated stepwise procedure employed make this ap-
proach a bit unwieldy synthetically. Furthermore, the scope
of this cyclization has yet to be reported.
We simultaneously found that this three-component reac-
tion9 proceeds smoothly by using various electrophiles such
as I2, ICl, NBS, p-O2NC6H4SCl, and PhSeBr to generate the
corresponding iodine-, bromine-, sulfur-, and selenium-
substituted heterocycles in high yields under very mild
reaction conditions. Herein, we wish to report a more
convenient and efficient approach to these types of hetero-
cycles involving electrophilic cyclization using a range of
electrophiles and nucleophiles.
Our initial studies were aimed at finding optimal reaction
conditions for the electrophilic cyclization of the o-(1-
alkynyl)benzaldehydes. Our investigation began with the
reaction of o-(phenylethynyl)benzaldehyde (1), methanol, and
I2 (Scheme 1). The reaction was first attempted using 0.25
mmol of o-(phenylethynyl)-benzaldehyde (1), 1.2 equiv of
methanol, 1 equiv of K2CO3, and 1.2 equiv of I2 in CH2Cl2
at room temperature.
Iodocyclization proceeded smoothly and provided an 88%
yield of the desired isochromene product 2. Other solvents
such as CH3CN and DMF were also investigated and proved
to be far less effective. KHCO3 and NEt3 were also
investigated as bases. While KHCO3 provided a slightly
lower yield of the desired product than K2CO3, NEt3 proved
to be ineffective and none of the desired product was
detected. Although CH2Cl2 is not a good solvent for K2CO3,
the presence of K2CO3 was crucial for a clean, high-yielding
reaction. K2CO3 is presumed to neutralize the byproduct HI
of the electrophilic cyclization, which can also react with
the acetylenic aldehyde and generate the corresponding
pyrilium salt.10 The use of methanol as the reaction solvent
resulted in a lower yield. Use of 1.2 equiv of I2 has proven
to be sufficient to achieve a high yield. Further increasing
the amount of I2 did not give better yields.
To further explore the scope of this cyclization, NBS was
also used and provided a decent yield of the desired
cyclization product (entry 5). Commercially available sulfur
and selenium electrophiles have also been employed in this
process and have been found to provide very good yields of
the desired cyclization products using methanol as the
nucleophile (entries 6, 7, and 10). The reactions with p-O2-
NC6H4SCl were complete in a shorter period of time and
gave higher yields of products than those with PhSeBr.
R-Acetylenic aryl ketones are also viable substrates for
cyclization (see entry 15). It should be noted, however, that
ketone 18 reacted smoothly with I2 to provide a 90% yield
of the 5-exo-dig cyclization product 19, rather than the six-
membered ring ether formed by the electrophilic cyclization
of benzaldehyde derivatives. The use of K2CO3 again
provides very mild basic conditions and avoids the acid-
initiated, partial decomposition of this cyclization product
described in Barluenga’s publication.8
Interestingly, when we followed the stepwise procedure
described in Barluenga’s paper, we were unable to get high
yields of the desired iodocyclization products. Instead, an
unreactive solid, presumed to be the pyrilium salt, was
generated. On the basis of this observation, a possible
mechanism is proposed in Scheme 2. We believe that these
cyclizations proceed by anti attack of the electrophile and
(11) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter
5, pp 203-229. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467.
(9) For a recent review on multicomponent reactions, see, for instance:
Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(10) Tovar, J. D.; Swager, T. M. J. Org. Chem. 1999, 64, 6499.
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Org. Lett., Vol. 6, No. 10, 2004

Table 1. Electrophilic Cyclization of Acetylenic Aldehydes, Imines, and Ketonesa
a All reactions were run under the following conditions, unless otherwise specified. To a solution of 2.5 mL of CH2Cl2 containing 0.25 mmol of the
alkyne, 0.30 mmol of the nucleophile, and 0.25 mmol of K2CO3 was added 0.30 mmol of electrophile under stirring, and the resulting mixture was further
stirred at room temperature for the desired time. b Barluenga’s yields are reported in parentheses. c Reaction was run on a 1.0 mmol scale; the 0.25 mmol
scale reaction provides an 88% yield of compound 2.
Org. Lett., Vol. 6, No. 10, 2004
1583

again, the use of readily available, easily handled I2 greatly
simplifies the procedure developed by Barluenga.
Scheme 2
We believe that this approach to carbo- and heterocycles
should prove to be quite useful in synthesis, particularly when
one considers that there are many ways to transform the
resulting halogen, sulfur, and selenium functional groups into
other substituents. For instance, the resulting heterocyclic
iodides should be particularly useful intermediates in many
palladium-catalyzed processes such as Sonogashira,11 Su-
zuki,13 and Stille14 cross-couplings and Heck reactions.15
Acknowledgment. We gratefully acknowledge the Na-
tional Science Foundation and the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, for partial support of this research.
the carbonyl to produce a pyrilium intermediate. Before it
forms an insoluble precipitate,10 the pyrilium intermediate
is immediately trapped by the nucleophile present in the
reaction mixture.
Our study has also shown that substituted naphthalenes
can be synthesized in high yields by using alkenes or alkynes
as the trapping reagent12 (Scheme 3) and that the use of the
Supporting Information Available: Experimental pro-
cedures and characterization data for all starting materials
and products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL049690S
(12) (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y.
J. Am. Chem. Soc. 2002, 124, 12650. (b) Asao, N.; Nogami, T.; Lee, S.;
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T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2003, 42, 3504. (d) Barluenga,
J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. Org. Lett. 2003, 5,
4121.
Scheme 3
(13) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Lloyd-
Williams, P.; Giralt, E. Chem. Soc. ReV. 2001, 30, 145. (c) Suzuki, A. In
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Chemistry for Organic Synthesis; 2002; Vol. 1, p 767. (b) Kosugi, M.;
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Reagents in Organic Synthesis; Heck, R. F., Ed.; Academic Press: San
Diego, 1985; pp 276-287.
more sophisticated iodonium reagent IPy2BF4 employed by
Barluenga12b for this same process is not necessary. Once
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Org. Lett., Vol. 6, No. 10, 2004