Iodocarbocyclization reaction of β-ketoesters and alkynes

Article abstract of DOI:10.1021/ol0710459

Iodocyclopentenes are formed at room temperature upon straight reaction of δ-alkynyl-β-ketoesters with I₂ for several hours. Cyclizations involving terminal and substituted (alkyl, aryl, Br, I) alkynes were accessed. Twelve examples with yields ranging from 20% up to 80% are reported (out of them eight cases are above 60%). These results present the first examples of the iodonium-promoted 5-endo-dig carbocyclization of active methyne substrates onto alkynes.

Full text of DOI:10.1021/ol0710459

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2823-2826
Iodocarbocyclization Reaction of
-Ketoesters and Alkynes
â
Jose´ Barluenga,* David Palomas, Eduardo Rubio, and Jose´ M. Gonza´lez
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”-Unidad Asociada
al CSIC, UniVersidad de OViedo, OViedo 33071, Spain
barluenga@unioVi.es
Received May 4, 2007
ABSTRACT
Iodocyclopentenes are formed at room temperature upon straight reaction of
δ-alkynyl-â-ketoesters with I2 for several hours. Cyclizations
involving terminal and substituted (alkyl, aryl, Br, I) alkynes were accessed. Twelve examples with yields ranging from 20% up to 80% are
reported (out of them eight cases are above 60%). These results present the first examples of the iodonium-promoted 5-endo-dig carbocyclization
of active methyne substrates onto alkynes.
The metal-catalyzed addition reaction of R-to-carbonyl C-H
The Conia-ene reaction is an intramolecular version of this
process that was originally accomplished at rather high
temperature (Figure 1b).4 The cyclization takes place fol-
lowing an exo-dig mode and partial isomerization of the
alkene is observed in the final product. Metal-catalyzed
reactions have been developed to approach this cycloisomer-
ization under milder conditions. Selective exo-dig ring-
closure from ꢀ-alkynyl-â-ketoesters and related malonate
derivatives have often been observed.5 However, the 5-endo-
cyclization of δ-alkynyl-substituted â-ketoesters6 or from the
related 6-sililoxy-5-en-1-ynes7 furnishing cyclopentene de-
rivatives has been less frequently reported. Moreover,
cyclizations leading to substituted indenes were accomplished
via palladium-catalyzed 5-endo carbocyclization reactions of
malonates and related anions onto aryl tethered internal
alkynes.8 A related approach from 2-(o-iodophenyl)malonates
and alkynes was developed.8b,9
bonds toward unactivated alkynes (Figure 1a)1 and related
Figure 1. Inter- and intramolecular addition of an activated C-H
bond to an unactivated alkyne.
(2) (a) Nakamura, M.; Fujimoto, T.; Endo, K.; Nakamura, E. Org. Lett.
2004, 6, 4837-4840. (b) Nakamura, M.; Liang, C.; Nakamura, E. Org.
Lett. 2004, 6, 2015-2017. (c) Ameniya, R.; Fujii, A.; Arisawa, M.;
Yamaguchi, M. J. Organomet. Chem. 2003, 686, 94-100. (d) Arisawa,
M.; Ameniya, R.; Yamaguchi, M. Org. Lett. 2002, 4, 2209-2211. (e) Miura,
K.; Saito, H.; Fujisawa, N.; Wang, D.; Nishikori, H.; Hosomi, A. Org. Lett.
2001, 3, 4055-4057. (f) Yamaguchi, M.; Hayashi, A.; Hirama, M. J. Am.
Chem. Soc. 1993, 115, 3362-3363.
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Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2006, 128, 11368-
11369. (c) Ochiai, M.; Ito, T.; Takaoka, Y.; Masaki, Y.; Kunishima, M.;
Tani, S.; Nagao, Y. J. Chem. Soc., Chem. Commun. 1990, 118-119. (d)
Ochia, M.; Kunishima, M.; Nagao, Y.; Fuji, K.; Shiro, M.; Fujita, E. J.
Am. Chem. Soc. 1986, 108, 8281-8283.
reactions of preformed enolates or active systems2 furnish
valuable synthetic intermediates and are part of more
complex preparative sequences.3
(1) (a) Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am.
Chem. Soc. 2007, 129, 5264-5271. (b) Kuninobu, Y.; Kawata, A.; Takai,
K. Org. Lett. 2005, 7, 4823-4825. (c) Nakamura, M.; Endo, K.; Nakamura,
E. Org. Lett. 2005, 7, 3279-3281. (d) Nakamura, M.; Endo, K.; Nakamura
J. Am. Chem. Soc. 2003, 125, 13002-13003. For a related transformation,
see also: (e) Nishimura, Y.; Ameniya, R.; Yamaguchi, M. Tetrahedron
Lett. 2006, 47, 1839-1843.
10.1021/ol0710459 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/22/2007

Interestingly, Taguchi and Kitagawa established early that
iodonium-triggered reactions are of practical interest to
assemble the related (E)-2-iodomethylenecyclopentane scaf-
fold by promoting the carbocyclization of a titanium enolate
onto the alkyne (Figure 2a).10,11 They expand the scope of
Recently, Liang used an iodination reaction in the presence
of t-BuOK to accomplish the cyclization of 2-(2-ethynyl)-
benzylmalonate derivatives and related methyne active
compounds (Figure 2c).13 The observed 5-exo- and 6-endo-
dig selectivities were shown to be dependent on the starting
material. On this basis, our interest14 in iodination reactions
with concomitant ring-elaboration15 prompted us to inves-
tigate the challenging iodocarbocyclization reaction of an
alkyne and an active methyne compound according to the
more elusive 5-endo-dig mode,16,17 as depicted in Figure 2
(entry d). The feasibility of this entry to cyclopentene
derivatives is established herein.
Initially, different conditions were screened to attempt the
target iodocarbocyclization of 2-acetylhept-5-ynoic acid ethyl
ester 1a to 1-acetyl-3-iodo-2-methylcyclopent-2-enecarboxy-
lic acid ethyl ester 2a (see Table 1). Reactions were
conducted at room temperature, and I2 and IPy2BF4 were
assayed as potential iodinating trigger reagents (1:1 with
respect to 1a). The former gave simpler reaction crudes and
offered better performance for the cyclization. Toluene,
MeCN, and CH2Cl2 were tested as solvents, the latter
allowing the cyclization to occur adequately. The major
competing reaction pathway was the 1,2-addition of I2 across
the alkyne.18 Its impact was minimized by increasing the
dilution from initial 0.3 up to 0.05 M. With use of these
simple experimental conditions, pure 2a was isolated in 70%
yield after reaction for 5 h and chromatographic purification
(Table 1, entry 1).19
Figure 2. Products (E: CO2R) arising from iodocarbocyclization
reactions of ꢀ-alkynylmalonate enolates (entries a,c) and from an
alternative carbotitanation-iodolysis sequence (entry b). Target
transformation (entry d).
The effect of different additives over the outcome of the
reaction in CH2Cl2 was investigated. Addition of NaHCO3
increases the ratio in favor of the iodine 1,2-addition product,
the cyclization showing that an alternative carbotitanation
of the alkyne followed by iodolysis of the resulting C-Ti
bond renders the (Z)-isomers (Figure 2b).12
(12) (a) Kitagawa, O.; Suzuki, T.; Inoue, T.; Taguchi, T. Tetrahedron
Lett. 1998, 39, 7357-730. (b) Kitagawa, O.; Suzuki, T.; Inoue, T.;
Watanabe, Y.; Taguchi, T. J. Org. Chem. 1998, 63, 9470-9475. For an
account on their work on iodocarbocyclization and iodoaminocyclization
reactions see: (c) Kitagawa, O.; Taguchi, T. Synlett 1999, 1191-1199.
(13) Bi, H.-P.; Guo, L.-N.; Duan, X.-H.; Gou, F.-R.; Huang, S.-H.; Liu,
X.-Y.; Liang, Y.-M. Org. Lett. 2007, 9, 397-400.
(14) Recent work: (a) Barluenga, J.; Va´zquez-Villa, H.; Merino, I.;
Ballesteros, A.; Gonza´lez, J. M. Chem. Eur. J. 2006, 12, 5790-5805. (b)
Barluenga, J.; Trincado, M.; Rubio, E.; Gonza´lez, J. M. Angew. Chem.,
Int. Ed. 2006, 45, 3140-3143.
(15) Representative recent work: Worlikar, S. A.; Kesharwani, T.; Yao,
T.; Larock, R. C. J. Org. Chem. 2007, 72, 1347-1350. (b) Amjad, M.;
Knight, D. W. Tetrahedron Lett. 2006, 47, 2825-2828. (c) Zhou, C.;
Dubrovsky, A. V.; Larock, R. C. J. Org. Chem. 2006, 71, 1626-1632. (d)
Hessian, K. O.; Flynn, B. L. Org. Lett. 2006, 8, 243-246.
(16) Recent iodination reactions with ring elaboration: (a) Foot, O. F.;
Knight, D. W.; Low, A. C. L.; Li, Y. F. Tetrahedron Lett. 2007, 48, 647-
650. (b) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292-
10296. Early work: (c) Bew, S. P.; Knight, D. W. Chem. Commun. 1996,
1007-1008.
(17) Related metal-catalyzed 5-endo-dig alkyne carbocyclization by
reaction with the CH bond: (a) Ajamian, A.; Gleason, J. L. Org. Lett. 2003,
5, 2409-2411. (b) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
11492-11493. Ketones: (c) Kel’in, A. V.; Gevorgyan, V. J. Org. Chem.
2002, 67, 95-98. With imines: (d) Kel’in, A. V.; Sromek, A. W.;
Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074-2075. See also: (e)
Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R- Org. Lett. 2007,
9, 1169-1171.
(4) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1-19.
(5) (a) Pe´rez-Herna´ndez, N.; Febles, M.; Pe´rez, C.; Pe´rez, R.; Rodr´ıguez,
M. L.; Foces-Foces, C.; Mart´ın, J. D. J. Org. Chem. 2006, 71, 1139-1151.
(b) Ochida, A.; Ito, H.; Sawamura, M. J. Am. Chem. Soc. 2006, 128, 16486-
16487. (c) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168-
17169. (d) Gao, Q.; Zheng. B.-F.; Li, J.-H.; Yang, D. Org. Lett. 2005, 7,
2185-2187. (e) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am.
Chem. Soc. 2004, 126, 4526-4527. (f) Kitagawa, O.; Fujiwara, H.; Suzuki,
T.; Taguchi, T.; Shiro, M. J. Org. Chem. 2000, 65, 6819-6825. (g) Renaud,
J.-L.; Aubert, C.; Malacria, M. Tetrahedron 1999, 55, 5113-5128. (h)
Bouyssi, D.; Monteiro, N.; Balme, G. Tetrahedron Lett. 1999, 40, 1297-
1300. (i) Cruciani, P.; Stammler, R.; Aubert, C.; Malacria, M. J. Org. Chem.
1996, 61, 2699-2708. (j) Boaventura, M. A.; Drouin, J.; Conia, J. M.
Synthesis 1983, 801-804.
(6) (a) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem.,
Int. Ed. 2004, 43, 5350-5352. (b) McDonald, F. E.; Olson, T. C.
Tetrahedron Lett. 1997, 38, 7691-7692.
(7) Iwasaba, N.; Miura, T.; Kiyota, K.; Kusama, H.; Lee, K.; Lee, P. H.
Org. Lett. 2002, 4, 4463-4466.
(8) (a) Li, Y.; Yu, Z.; Alper, H. Org. Lett. 2007, 9, 1647-1649. (b)
Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem.
2007, 72, 1538-1540. (c) Zhang, D.; Liu, Z.; Yum, E.; Larock, R. C. J.
Org. Chem. 2007, 72, 251-262. (d) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.;
Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2006, 8, 3053-3056. (e) Guo, L.-N.;
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3325-3327.
(9) Zhang, D.; Yum, E. K.; Liu, Z.; Larock, R. C. Org. Lett. 2005, 7,
4963-4966.
(10) Kitagawa, O.; Inoue, T.; Hirano, K.; Taguchi, T. J. Org. Chem.
1993, 58, 3106-3112.
(11) Related cyclizations were described for N-alkyl-N-propargyl-â-
ketoamides using alternative conditions: (a) Cossy, J.; Thellend, A.
Tetrahedron Lett. 1990, 31, 1427-1428. Some examples of related 5-exo-
dig radical cyclizations by atom-transfer reactions of 2-iodo-6-alkynyl esters
have been reported: (c) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989,
54, 3140-3157.
(18) Addition of I2 to alkynes: (a) Larson, S.; Luidhardt, T.; Kabalka,
G. W.; Pagni, R. M. Tetrahedron Lett. 1988, 29, 35-36. (b) Hollins, R.
A.; Campos, M. P. A. J. Org. Chem. 1979, 44, 3931-3934. See also: (c)
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4526.
(19) All new compounds gave NMR spectroscopic and analytical or MS
data in agreement with their proposed structures. For further details see the
Supporting Information.
2824
Org. Lett., Vol. 9, No. 15, 2007

further synthetic elaboration at both sp2 carbon atoms. This
class of compounds was not previously reported in alternative
5-endo-dig approaches.
Table 1. Iodonium-Promoted 5-endo-dig Mode
Carbocyclization of Alkynes and Active Methyne Compoundsa
A tentative mechanistic interpretation to justify the forma-
tion of products 2 might reasonably assume an attack of the
enol tautomer from 1 to the intermediate ion20 resulting in
electrophilic activation of the alkyne21 (Scheme 1).
Scheme 1. Proposed Mechanistic Pathway To Account for the
Formation of Carbocycles 2 from δ-Alkynyl-â-ketoesters 1
The process reported herein allows the synthesis of
tetrasubstituted alkenes by exploiting the reactivity of the
C-I bond to introduce molecular diversity using subsequent
metal-catalyzed cross-coupling reaction steps.22 Several
representative examples show the synthetic utility of the
iodocarbocyclization/cross-coupling tandem sequence for the
conversion of 1a into different types of C-substituted
derivatives, and are summarized in Scheme 2. Also of
a I2 was added to a solution of the corresponding δ-alkynyl-â-ketoester
in CH2Cl2 and then stirring was prolonged for the given time, until TLC
showed the consumption of 1. b Using 0.025 M solution.
Scheme 2. Tetrasubstituted Alkenes upon Novel Tandem
Sequence: Iodocarbocyclization/Cross-Coupling from
δ-Alkynyl-â-ketoesters
whereas i-Pr2NEt or DBU inhibit the reactions. So, addition
of bases was found to be detrimental for the desired
transformation. Conversely, when the cyclization was con-
ducted under the influence of added sulfuric acid (up to 0.5
equiv) the reaction outcome was quite similar to that without
added acid. Furthermore, different metal salts were tested
without showing major impact over the cyclization. Thus,
we further investigated the scope of this novel cyclization
using the above-described conditions for obtaining 2a as the
standard protocol (see Table 1). Both â-ketoester and 1,3-
diketone derivatives (entry 8) enter as substrates in this
process. Internal alkynes wih alkyl and aryl substituents
(entries 5 and 11) were cyclized with this protocol. The
formation of bicyclic skeletons is also possible (entry 9).
Though in modest yield, a terminal alkyne also gave some
alkyaltion product (1j, entry 10), in this case addition of I2
across the alkyne represents the main reaction path. The
process works nicely when haloalkynes (entries 6, 7, and
12) were exposed to the action of iodine, resulting in the
formation of doubly halogenated alkenes with potential for
interest, as expected, the Sonogashira cross-coupling reaction
of 2f with phenylacetylene takes place smoothly at the C-I
bond with total chemoselectivity to furnish a bromine-
containing carbocycle23 that then can be further elaborated
by using the remaining C-Br bond.
(20) Recent theoretical work on halovinyl and bridged halonium ions:
Okazi, T.; Laali, K. K. J. Org. Chem. 2006, 71, 9643-9650.
Org. Lett., Vol. 9, No. 15, 2007
2825

Overall a straightforward access to accomplish the 5-endo-
dig mode carbocyclization of active methyne compounds
onto alkynes (internal and terminal) has been executed. This
process nicely complements the 5-exo-dig regioselectivity
noticed early in related iodonium-promoted carbocycliza-
tion reactions for preformed titanium enolates and paral-
lels the regiocontrol outcome recently reported in several
metal-catalyzed cyclization reactions for the same starting
materials.
Acknowledgment. This research was partially supported
by the Spanish DGI (CTQ2004-08077-C02-01) and the
Consejer´ıa de Cultura del Principado de Asturias (IB05-136)
D.P. wants to thank the Spanish MEC for a fellowship.
(21) A radical pathway may also be considered. We conducted the room
temperature cyclization of 1a, reaction with I2 in CH2Cl2, in the presence
of the radical inhibitor BHT. The reaction time for the consumption of 1a
was the same and 2a was formed in comparable yield. On this basis, we
invoke an ionic reaction path.
(22) Metal Catalyzed Cross-Coupling Reactions; de Meijere, A., Dieder-
ich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(23) 1-Acetyl-2-bromo-3-phenylethynylcyclopent-2-ene carboxylic acid
ethyl ester 6 was isolated in 89% yield after reaction of 2f with
phenylacetylene (1.1 equiv) and (PPh3)2PdCl2-CuI (5 mol %) in Et3N at rt,
for 1 h.
Supporting Information Available: Experimental pro-
cedures, characterization data, 1H and 13C spectra for
compounds 1-5. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0710459
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