Synthesis of alkyl alkynyl ketones by Pd/light-induced three-component coupling reactions of iodoalkanes, CO, and 1-alkynes

Article abstract of DOI:10.1021/ol1007668

Under photoirradiation conditions using xenon light, in the presence of a catalytic amount of PdCl₂(PPh₃)₂ with triethylamine as a base, a three-component coupling reaction of iodoalkanes, carbon monoxide, and terminal alkynes proceeded to give alkyl alkynyl ketones in good yields.

Full text of DOI:10.1021/ol1007668

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2410-2413
Synthesis of Alkyl Alkynyl Ketones by
Pd/Light-Induced Three-Component
Coupling Reactions of Iodoalkanes, CO,
and 1-Alkynes
Akira Fusano, Takahide Fukuyama, Satoshi Nishitani, Takaya Inouye, and
Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture UniVersity,
Sakai, Osaka 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
Received April 1, 2010
ABSTRACT
Under photoirradiation conditions using xenon light, in the presence of a catalytic amount of PdCl2(PPh3)2 with triethylamine as a base, a
three-component coupling reaction of iodoalkanes, carbon monoxide, and terminal alkynes proceeded to give alkyl alkynyl ketones in good
yields.
Alkynyl ketones are contained in several biologically active
molecules1 and play a crucial role as key intermediates in
the synthesis of natural compounds2 and in heterocyclic
systems.3 Although the most common route for the synthesis
of alkynyl ketones is the acylation reaction of alkynyl
organometallic reagents with acid chlorides,4 a three-
component approach comprising organo halides, carbon
monoxide, and terminal alkynes based on transition-metal-
catalyzed carbonylation represents a more straightforward
approach in terms of simplicity, which makes it possible to
avoid the preparation of somewhat unstable acid chlorides.5,6
For the past decade, significant efforts have been made to
improve carbonylative approaches, and several mild reaction
conditions have been found thus far. However, the system
remains largely restricted to the use of aryl or vinyl halides;
aliphatic halides are not necessarily applicable due to the
(1) (a) Faweett, C. H.; Firu, R. D.; Spencer, D. M. Physiol. Plant Pathol.
1971, 1, 163. (b) Imai, K. J. Pharm. Soc. Jpn. 1956, 76, 405. (c) Chowdhury,
C.; Kundu, N. G. Tetrahedron 1999, 55, 7011. (d) Quesnelle, C. A.; Gill,
P.; Dodier, M.; St. Laurent, D.; Serrano-Wu, M.; Marinier, A.; Martel, A.;
Mazzucco, C. E.; Stickle, T. M.; Barrett, J. F.; Vyas, D. M.; Balasubra-
manian, B. N. Bioorg. Med. Chem. Lett. 2003, 13, 519.
(2) (a) Kalinin, V. N.; Shostakovsky, M. V.; Ponamaryov, A. B.
Tetrahedron Lett. 1990, 31, 4073. (b) Ciattini, P. G.; Morera, E.; Ortar, G.;
Rossi, S. S. Tetrahedron 1991, 47, 6449. (c) Torri, S; Okumoto, H.; Xu,
L.-H.; Sadakane, M.; Shostakovsky, M. V.; Ponomaryov, A. B.; Kalinin,
V. N Tetrahedron 1993, 49, 6773. (d) Bernard, D.; Daniel, C.; Robert, L.
Tetrahedron Lett. 1996, 37, 1019. (e) Marco-Contelles, J.; de Opazo, E. J.
Org. Chem. 2002, 67, 3705. (f) Forsyth, C. J.; Xu, J.; Nguyen, S. T.; Samdai,
I. A.; Briggs, L. R.; Rundberget, T.; Sandvik, M.; Miles, C. O. J. Am. Chem.
Soc. 2006, 128, 15114. (g) Tietze, L. F.; Singidi, R. R.; Gericke, K. M.;
Bockemeier, H.; Laatsch, H. Eur. J. Org. Chem. 2007, 5875.
(4) (a) Davis, R. B.; Scheiber, D. H. J. Am. Chem. Soc. 1956, 78, 1675.
(b) Normant, J. F. Synthesis 1972, 63. (c) Logue, M. W.; Moore, G. L. J.
Org. Chem. 1975, 40, 131. (d) Schmidt, U.; Schwochau, M. Chem. Ber.
1964, 97, 1649. (e) Birkofer, L.; Ritter, A.; Uhlenbrauck, H. Chem. Ber.
1963, 96, 3280. (f) Walton, D. R. M.; Waugh, F. J. Organomet. Chem.
1972, 37, 45. (g) Logue, M. W.; Teng, K. J. Org. Chem. 1982, 47, 2549.
(5) (a) Kobayashi, T.; Tanaka, M. J. Chem. Soc., Chem. Commun. 1981,
333. (b) Delaude, L.; Masdeu, A. M.; Alper, H. Synthesis 1994, 1149. (c)
Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1991, 32, 6449. (d)
Mohamed Ahmed, M. S.; Mori, A. Org. Lett. 2003, 5, 3057. (e) Liang, B.;
Huang, M.; You, Z.; Xiong, Z.; Lu, K.; Fathi, R.; Chen, J.; Yang, Z. J.
Org. Chem. 2005, 70, 6097. (f) Iizuka, M.; Kondo, Y. Eur. J. Chem. 2007,
(3) (a) Sheng, H.; Lin, S.; Huang, Y. Tetrahedron Lett. 1986, 27, 4893.
(b) Torii, S.; Okumoto, H.; Xu, L. H.; Sadakane, M.; Shostakovsky, M. V.;
Ponomaryov, A. B.; Kalinin, V. N. Tetrahedron 1993, 49, 6773. (c)
Mohamed, S.; Mohamed, A.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7,
4487. (d) Aradi, A.; Aschi, M.; Marinelli, F.; Verdecchia, M. Tetrahedron
2008, 64, 5354. (e) Bannwarth, P.; Valleix, A.; Gree, D.; Gree, R. J. Org.
Chem. 2009, 74, 4646.
5180. (g) Liu, J.; Chen, J.; Xia, C. J. Catal. 2008, 253, 50
.
(6) For recyclable reaction media and catalyst, see: (a) Fukuyama, T.;
Yamaura, R.; Ryu, I. Can. J. Chem. 2005, 83, 711. (b) Rahman, M. T.;
Fukuyama, T.; Kamata, N.; Sato, M.; Ryu, I. Chem. Commun. 2006, 2236
.
10.1021/ol1007668  2010 American Chemical Society
Published on Web 04/21/2010

low reactivity of sp3-carbon-halogen bonds toward oxidative
addition with palladium.7
were indispensable for this reaction system. When a quartz
linear or a weaker xenon lamp (300 W) was used, the yield
of 3a considerably decreased, suggesting that the conversion
of 1a to 3a was extremely sensitive to the power of the light
source as well as to the wavelength.
We recently reported that radical/metal hybrid reactions
under photoirradiation conditions8 accelerated the atom-
transfer carbonylation of alkyl halides leading to carboxylic
acid esters, amides, and related heterocycles.9,10 In these
reactions, it is assumed that the intervention of a free-radical
mechanism will generate acylpalladium intermediates, thus
representing a radical/metal collaboration system. Herein, we
report that such a strategy was applied successfully to a
carbonylative Sonogashira reaction using alkyl iodides, CO,
and terminal alkynes, which gave good yields of alkyl
alkynyl ketones (Scheme 1).
Table 1. Pd/Light-Induced, Three-Component Coupling
Reaction of 1-Iodooctane (1a) with Phenylacetylene (2a) and
1-Octyne (2b)
Scheme 1
.
Carbonylative Sonogashira Coupling Reaction
Leading to Alkynyl Ketones
iodoalkane,
alkyne
yielda
product (%)
entry
catalyst
solvent
1
2
3
1a, 2a
1a, 2a
1a, 2a
1a, 2a
1a, 2b
1a, 2a
C6H6/H2O(10/1)
C6H6
PdCl2(PPh3)2 C6H6
PdCl2(PPh3)2 C6H6/H2O(10/1)
PdCl2(PPh3)2 C6H6/H2O(10/1)
PdCl2(PPh3)2 C6H6/H2O(10/1)
3a
3a
3a
3a
3b
3b
<1
16
Pd(PPh3)4
19
4
71b
40b
88b
5c
6d
a Yields were determined from 1H NMR using tetrachloroethane as an
internal standard. b Isolated yield by silica gel chromatogryaphy. c Nonanoic
acid anhydride was formed as byproduct (22%). d Reaction was carried out
using 5.2 equiv of 2b.
When 1-iodooctane (1a) and phenylacetylene (2a) were
exposed to photocarbonylation conditions (irradiation with
a 500 W xenon lamp through Pyrex under 45 atm of CO
pressure) in the presence of a catalytic amount of
PdCl2(PPh3)2, the desired alkynyl ketone 3a was obtained
in 19% yield (Table 1, entry 3). The use of Pd(PPh3)4 as a
catalyst led to a slight decline in the yield of 3a (entry 2),
but the addition of water to the reaction system of
PdCl2(PPh3)2 improved the yield of 3a to as high as 71%
(entry 4).11 Both the catalyst and photoirradiation conditions
In contrast with the above case of phenylacetylene (2a),
under similar conditions, treatment of 1-octyne (2b) with
1-iodooctane (1a) resulted in the corresponding alkynyl
ketone 3b in 40% yield (entry 5). In this reaction, nonanoic
acid anhydride (4) was also formed as a byproduct. However,
the use of a large excess of 1-octyne (5.2 equiv relative to
1a) resulted in a notable yield enhancement in which the
corresponding alkynyl ketone 3b was obtained in 88% yield
(entry 6).
Primary alkyl iodides with various substituents or struc-
tures were applied to the present alkyl alkynyl ketone
synthesis (Table 2). A variety of functional groups were
tolerated in these reactions. Thus, when 1-chloro-8-iodooc-
tane (1b) was used, the corresponding alkynyl ketone 3c was
obtained in good yield (entry 3). Similarly, alkyl iodides,
which had methyl ester or TBS ether, also gave the desired
coupling compounds (entries 4 and 5). Secondary and tertiary
alkyl iodides reacted with phenylacetylene (2a) to give the
corresponding alkynyl ketones in good yields (entries 6-10).
The coupling reaction of aliphatic acetylene, such as 1-octyne
(2b), with secondary and tertiary substrates also proceeded
in good yields (entries 11 and 12), whereas trimethylsily-
lacetylene (2c) gave moderate yields of the desired products
(entries 13-15).
(7) Eckhardt, M; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642. Also
see the following reviews: (a) Frisch, A. C.; Beller, M. Angew. Chem., Int.
Ed. 2005, 44, 674. (b) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004,
346, 1525. (c) Rudolph, A.; Lautens, L. Angew. Chem., Int. Ed. 2009, 48,
2656.
(8) For previous efforts on metal-catalyzed carbonylation under pho-
toirradiation conditions, see: (a) Kondo, T.; Sone, Y.; Tsuji, Y.; Watanabe,
Y. J. Organomet. Chem. 1994, 473, 163. (b) Ishiyama, T.; Murata, M;
Suzuki, A.; Miyaura, N. J. Chem. Soc., Chem. Commun. 1995, 295.
(9) For atom transfer carbonylation reactions, see: (a) Ryu, I.; Nagahara,
K.; Kambe, N.; Sonoda, N.; Kreimerman, S.; Komatsu, M. Chem. Commun.
1998, 1953. (b) Nagahara, K.; Ryu, I.; Komatsu, M.; Sonoda, N. J. Am.
Chem. Soc. 1997, 119, 5465. (c) Kreimerman, S.; Ryu, I.; Minakata, S.;
Komatsu, M. Org. Lett. 2000, 2, 389. Also see a review: (d) Ryu, I. Chem.
Soc. ReV. 2001, 30, 16
.
(10) For radical/metal hybrid reactions, see: (a) Ryu, I.; Kreimerman,
S.; Araki, F.; Nishitani, S.; Oderaotoshi, S.; Minakata, S.; Komatsu, M.
J. Am. Chem. Soc. 2002, 124, 3812. (b) Fukuyama, T.; Nishitani, S.; Inouye,
T.; Morimoto, K.; Ryu, I. Org. Lett. 2006, 8, 1383. (c) Fukuyama, T.;
Inouye, T.; Ryu, I. J. Organomet. Chem. 2007, 692, 685. Also see a review:
We also examined radical cascade sequences accompany-
ing ring-opening or ring-closing processes (Scheme 2). The
reaction of cyclopropylmethyl iodide (1j) and 2a afforded
the alkynyl ketone 3p, which possessed an olefin structure
generated from the ring-opening of a cyclopropylcarbinyl
(d) Ryu, I. Chem. Rec. 2002, 2, 249
.
(11) Acceleration by water may be concerned with the fact that in the
absence of water the reaction mixture became a suspension due to the
gradually formed amine-HI salt, which is supposed to prevent effective
photoirradiation. In the presence of water, we observed that a clear solution
was maintained during the photoirradiation reaction.
Org. Lett., Vol. 12, No. 10, 2010
2411

Table 2. Synthesis of Acetylenic Ketones by a
Scheme 2. Cascade Radical Carbonylation Reactions
Three-Component Coupling Reactiona
radical.12 When the reaction of 5-iodo-1-pentene (1k) and
2a was carried out, alkynyl ketone 3q bearing a cyclopen-
tanone scaffold was formed through a carbonylation-
cyclization-carbonylation-alkynylation sequence. These
results show that Pd/light-assisted carbonylation reactions
can combine well with radical cascade pathways.
Scheme 3. Possible Reaction Mechanism
The proposed mechanism for Pd/light-assisted carbony-
lation is shown in Scheme 3, using 1k to 3q as an example.
In the first step, alkyl iodide reacts with Pd(0) under
irradiation to afford alkyl radical A and Pd(I)I via a one-
electron transfer.13 The resulting alkyl radical A traps CO
to form acyl radical B and then affords alkyl radical C
through 5-exo cyclization of acyl radical B. The acyl radical
(12) (a) Bowry, V. W.; Ingold, K. U. J. Am. Chem. Soc. 1991, 113,
5699. (b) Newcomb, M. Tetrahedron 1993, 49, 1151.
(13) For precedents of electron transfer from low-valent palladium and
platinum complexes, see: (a) Kramer, A. V.; Osborn, J. A. J. Am. Chem.
Soc. 1974, 96, 7832. (b) Kramer, A. V.; Labinger, J. A.; Bradley, J. S.;
Osborn, J. A. J. Am. Chem. Soc. 1974, 96, 7145. Miyaura and co-workers
also proposed an electron transfer from Pd(0) to alkyl iodides to afford a
radical pair (Pd(I)I + alkylradical); see ref 8b.
a Conditions: 1 (0.5 mmol); 2 (1.2-1.3 equiv); catalyst, PdCl2(PPh3)2
(5 mol %); base, NEt3 (1.2-1.4 equiv); benzene (5 mL); H2O (0.5 mL);
CO (45 atm); light (500 W xenon lamp, Pyrex). b Isolated yield by silica
gel chromatography. c Acetylene (5 equiv) was used.
2412
Org. Lett., Vol. 12, No. 10, 2010

species D generated from CO and alkyl radical C couples
with Pd(I)I to lead to acylpalladium intermediate E and gives
the alkynyl ketone through an intermediate F. In this reaction
mechanism, a rather unfamiliar Pd(I)I-type species is pos-
tulated. This may exist in an equilibrium with PdI dimer14
under photoirradiation conditions.15
to alkynyl ketones that was affected by a Pd/light combined
system. This protocol employs readily available alkyl iodides
and terminal alkynes and could become a standard method
for alkynyl ketone synthesis.
Acknowledgment. T.F. and I.R. thank JSPS and MEXT
Japan for funding. We thank Prof. Armido Studer for
stimulating discussions on the mechanism involving persis-
tent radicals.
In summary, we have demonstrated a three-component
coupling reaction of alkyl iodides, CO, and alkynes leading
(14) For photogeneration of Pd radical from Pd dimer complex, see:
Lemke, F. R.; Kubiak, C. P. J. Organomet. Chem. 1989, 373, 391.
•
(15) It would be also possible to assume that C(O)Pd(II)I might exist
Supporting Information Available: Experimental pro-
cedure and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
as a persistent radical. For the persistent radical effect, see the following
reviews: (a) Fischer, H. Chem. ReV. 2001, 101, 3581. (b) Studer, A.
Chem.sEur. J. 2001, 7, 1159. (c) Studer, A. Chem. Soc. ReV. 2004, 33,
267. (d) Studer, A.; Schulte, T. Chem. Rec 2005, 5, 27. Also see: (e)
Focsaneanu, K. S.; Aliaga, C.; Scaiano, J. C. Org. Lett. 2005, 7, 4979.
OL1007668
Org. Lett., Vol. 12, No. 10, 2010
2413