Rhodium-catalyzed addition of alkynes to activated ketones and aldehydes

Article abstract of DOI:10.1021/ol0525260

(Chemical Equation Presented) The rhodium-catalyzed addition of alkynes to 1,2-diketones, 1,2-ketoesters, and aldehydes provides a method for the synthesis of tertiary alkynyl alcohols under mild conditions. The reaction tolerates many functional groups (

Full text of DOI:10.1021/ol0525260

ORGANIC
LETTERS
2006
Vol. 8, No. 1
67-69
Rhodium-Catalyzed Addition of Alkynes
to Activated Ketones and Aldehydes
Pawan K. Dhondi and John D. Chisholm*
Department of Chemistry, 1-014 Center for Science and Technology,
Syracuse UniVersity, Syracuse, New York 13244
jdchisho@syr.edu
Received October 18, 2005
ABSTRACT
The rhodium-catalyzed addition of alkynes to 1,2-diketones, 1,2-ketoesters, and aldehydes provides a method for the synthesis of tertiary
alkynyl alcohols under mild conditions. The reaction tolerates many functional groups (such as carboxylic acids) that are incompatible with
other methods. The alkyne addition reaction proceeds best using bulky phosphine ligands such as 2-(di-tert-butylphosphino)biphenyl. This
method fills a void in the more common zinc-catalyzed processes, which give poor yields with enolizable 1,2-dicarbonyl substrates.
Great strides have been made in the development of catalytic
methods for the addition of alkynes to aldehydes, ketones,
and imines.1,2 Such transformations have attracted consider-
able interest due to the versatility of the alkyne addition
products which are useful intermediates in the synthesis of
complex molecules.3 Although the development of catalytic
methods for the addition of alkynes to aldehydes and ketones
has received significant attention, the catalytic addition of
alkynes to 1,2-dicarbonyl compounds has been explored in
only a cursory fashion. Although catalytic zinc conditions
are compatible with 1,2-dicarbonyls, they are limited to non-
enolizable systems, with enolizable 1,2-dicarbonyls providing
only low yields.4
Rhodium acetylides provide a useful solution to this limita-
tion of catalytic zinc chemistry. Use of catalytic amounts of
Rh(acac)(CO)2 in the presence of phosphine ligands has been
shown to form acetylides with nucleophilic properties.5 These
rhodium acetylides act as selective nucleophiles under mild
conditions. Indeed, alkyne addition reactions catalyzed by
rhodium complexes tolerate functional groups (such as
unprotected alcohols and carboxylic acids) that are not
tolerated by many other metal-catalyzed alkyne addition
reactions.
(1) For recent reviews, see: (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann,
N. Eur. J. Org. Chem. 2004, 4095. (b) Wei, C.; Li, Z.; Li, C.-J. Synlett
2004, 1472. (c) Pu, L. Tetrahedron 2003, 59, 9873. (d) Frantz, D. E.; Fa¨ssler,
R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000, 33, 373.
(2) For some selected examples, see: (a) Frantz, D. E.; Fa¨ssler, R.;
Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806. (b) Anand, N. K.;
Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687. (c) Fa¨ssler, R.;
Tomooka, C. S.; Frantz, D. E.; Carreira, E. M. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5843. (d) Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett.
2002, 4, 4143. (e) Gao, G.; Xie, R.-G.; Pu, L. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5417. (f) Liu, L.; Wang, R.; Kang, Y.-F.; Chen, C.; Xu, Z.-Q.;
Zhou, Y.-F.; Ni, M.; Cai, H.-Q.; Gong, M.-Z. J. Org. Chem. 2005, 70,
1084. (g) Lu, G.; Li, X.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew. Chem.,
Int. Ed. 2003, 42, 5057. (h) Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun.
2002, 1524. (i) Tzalis, D.; Knochel, P. Angew. Chem. Int. Ed. 1999, 38,
1463. (j) Cozzi, P. G.; Alesi, S. Chem. Commun. 2004, 2448. (k) Wei, C.;
Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584. (l) Koradin, C.; Gommermann,
N.; Polborn, K.; Knochel, P. Chem.-Eur. J. 2003, 9, 2797. (m) Takita, R.;
Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. Org. Lett. 2005, 7, 1363
and references therein.
(3) (a) Fettes, A.; Carreira, E. M. J. Org. Chem. 2003, 68, 9274. (b)
Reber, S.; Kno¨pfel, T. F.; Carreira, E. M. Tetrahedron 2003, 59, 6813. (c)
Maezaki, N.; Tominaga, H.; Kojima, N.; Yanai, M.; Urabe, D.; Tanaka, T.
Chem. Commun. 2004, 406. (d) Crimmins, M. T.; She, J. J. Am. Chem.
Soc. 2004, 126, 12790.
(4) Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451.
(5) Lerum, R. V.; Chisholm, J. D. Tetrahedron Lett. 2004, 45, 6591.
10.1021/ol0525260 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/08/2005

Initial attempts focused on the addition of 1-octyne to ethyl
pyruvate (Table 1). Only when the phosphine was changed
provided a 50% yield of product, whereas one equivalent
gave a modest 26% yield. Increasing the amount of octyne
(2) in relation to ethyl pyruvate (1) to more than one
equivalent did not produce any increase in yield due to alkyne
dimerization.8
Table 1. Phosphine Ligand Screen
Once reaction conditions were optimized, a survey of
electrophiles was performed (Table 2).
Table 2. Variation of the Electrophile
entry
ligand
yield (%)
1
2
3
4
5
6
7
triphenylphosphine (6)
13
9
tris(o-methoxyphenyl)phosphine (7)
tri-o-tolylphosphine (8)
dppfa (9)
2-(dicyclohexylphosphino)biphenyl (4)
2-(di-tert-butylphosphino)biphenyl (5)
tri-tert-butylphosphine (10)
24
26
71
83
95
a Only 5 mol % of dppf was used.
to the bulky, electron-rich 2-(di-tert-butylphosphino)bi-
phenyl6 (5) and tri-tert-butylphosphine (10) did the yields
become excellent (Table 1, entries 6 and 7). Triaryl phos-
phines were much less effective ligands for this transforma-
tion (Table 1, entries 1-4). Control experiments showed that
both the rhodium complex and the phosphine ligand were
required for activity, precluding a phosphine-catalyzed
process and implicating a rhodium-phosphine complex as
the active catalyst. In support of this hypothesis, numerous
literature reports describe activation of the C-H bond of
monosubstituted alkynes using rhodium-phosphine com-
plexes.7
With the realization that the reaction required a bulky,
electron-rich phosphine, 2-(di-tert-butylphosphino)biphenyl
5 was chosen as the ligand of choice. This decision was based
on the ease of handling of this stable, white solid in contrast
to tri-tert-butylphosphine (10), which oxidizes quickly when
exposed to air.
Other parameters were then modified to determine the
optimal reaction conditions. Temperatures as low as 40 °C
were found to give excellent yields of the alkyne addition
product. Further optimization showed that use of 3 mol %
of Rh(acac)(CO)2 and 9 mol % of phosphine 5 gave an
optimal yield with a minimum of catalyst. Use of THF
instead of 1,4-dioxane provided a small increase in yield.
The ratio of alkyne to dicarbonyl was also assessed.
Lowering the amount of ethyl pyruvate to two equivalents
Reaction of 2,3-butanedione (12), 3,4-hexanedione (14),
and ethyl pyruvate (1) gave excellent yields of alkyne
addition products with 4-pentyn-1-ol (11). Alkyl aldehydes
also gave good yields of addition product, whereas aromatic
aldehydes gave lower yields unless they were highly
activated, as in the case of 4-nitrobenzaldehyde 23.
Different alkynes were also evaluated as coupling partners
(Table 3). As in the case of 4-pentyn-1-ol (11), unprotected
alcohols are well tolerated in the rhodium-catalyzed alkyne
addition reaction. Aromatic alkynes such as phenylacetylene
(26) also provide excellent yields of product. To further
demonstrate the functional-group tolerance of the reaction,
an alkyne containing a carboxylic acid was also used as a
nucleophile providing an excellent yield of addition product
(Table 3, entry 8).
(6) (a) Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org. Chem. 2000, 65,
5334. (b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360.
(7) (a) Esteruelas, M. A.; Lahoz, F. J.; Onate, E.; Oro, L. A.; Rodriguez,
L.; Steinert, P.; Werner, H. Organometallics 1996, 15, 3436. (b) Zargfarian,
D.; Chow, P.; Taylor, N. J.; Marder, T. B. J. Chem. Soc., Chem. Commun.
1989, 9, 540. (c) Garcia Alonso, F. J.; Ho¨hn, A.; Wolf, J.; Otto, H.; Werner,
H. Angew. Chem., Int. Ed. Engl. 1985, 24, 406.
(8) (a) Singer, H.; Wilkinson, G. J. Chem. Soc. A 1968, 4, 849. (b)
Yoshikawa, S.; Kiji, J.; Furukawa, J. Makromol. Chem. 1977, 178, 1077.
(c) Lee, C.-C.; Lin, Y.-C.; Liu, Y.-H.; Wang, Y. Organometallics 2005,
24, 136.
68
Org. Lett., Vol. 8, No. 1, 2006

Scheme 1. Proposed mechanism for the Rh-catalyzed alkyne
Table 3. Variation of the Alkyne Nucleophile
addition
Reductive elimination then provides the propargylic alcohol
product, regenerating the active catalyst.
In summary, a rhodium-catalyzed method for the addition
of alkynes to aldehydes, 1,2-diketones, and 1,2-ketoesters
under mild conditions has been described. The reaction
tolerates the presence of a variety of functional groups
including unprotected alcohols and carboxylic acids. Studies
to elucidate the reaction mechanism, the development of an
enantioselective variant, and the application of this reaction
to the synthesis of bioactive substances are currently
underway.
a 3,4-Hexanedione (14) was used instead of 2,3-butanedione (12). b One
equivalent of triethylamine was added.
Acknowledgment. Acknowledgment is made to the
Donors of the American Chemical Society Petroleum
Research Fund, for support of this research.
A proposed reaction mechanism is shown in Scheme 1.
Displacement of one carbon monoxide ligand by a phosphine
is well precedented9 for Rh(acac)(CO)2, and this is assumed
to be the first step. Coordination of the alkyne to the newly
formed Rh complex followed by insertion of the metal into
the alkyne C-H bond provides rhodium acetylide 42.
Rhodium complexes similar to intermediate 42 have been
isolated by Esteruelas and Werner.7a Coordination of the
carbonyl to the alkynylrhodium 42 is followed by carbon-
carbon bond formation, leading to rhodium alkoxide 44.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0525260
(9) (a) Serron, S.; Huang, J.; Nolan, S. P. Organometallics 1998, 17,
534. (b) Pruchnik, F. P.; Smolenski, P.; Wajda-Hermanowicz, K. J.
Organomet. Chem. 1998, 570, 63.
Org. Lett., Vol. 8, No. 1, 2006
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