Vicinal C-functionalization of alkenes. Pd/light-induced multicomponent coupling reactions leading to functionalized esters and lactones

Article abstract of DOI:10.1021/ol200536h

Under photoirradiation conditions using a xenon light, and in the presence of PdCl₂(PPh₃)₂ as a catalyst, four-component coupling reactions comprising of R-substituted iodoalkanes, alkenes, carbon monoxide, and alcohols pr

Full text of DOI:10.1021/ol200536h

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2114–2117
Vicinal C-Functionalization of Alkenes.
Pd/Light-Induced Multicomponent
Coupling Reactions Leading to
Functionalized Esters and Lactones
Akira Fusano, Shuhei Sumino, Takahide Fukuyama, 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 February 28, 2011
ABSTRACT
Under photoirradiation conditions using a xenon light, and in the presence of PdCl2(PPh3)2 as a catalyst, four-component coupling reactions
comprising of R-substituted iodoalkanes, alkenes, carbon monoxide, and alcohols proceeded smoothly to give functionalized esters in good
yields. When alkenyl alcohols were used as acceptor alkenes, three-component coupling reactions accompanied by intramolecular esterification
proceeded to give lactones in good yields. The present reaction system represents the vicinal C-functionalization of alkenes.
In terms of the high throughput and efficiency required
to construct organic compounds with structural diversity
in one pot, multicomponent reactions (MCRs) have at-
tracted more and more interest in recent years.1,2 MCRs
involving CO as one of the components allow for direct
incorporation of CO as a carbonyl function into carbonyl-
containing products, and we are particularly interested in
strategies involving radical reactions.3,4 We previously
found that metal/hν-induced systems5 caused acceleration
(5) For previous efforts on metal-catalyzed carbonylation under
photoirradiation 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.
(6) (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. (d) Fusano, A.; Fukuyama, T.; Nishitani, T.;
Inouye, T.; Ryu, I. Org. Lett. 2010, 12, 2410. (e) Ryu, I. Chem. Rec. 2002,
2, 249.
(7) (a) Liang, Bo.; Liu, J.; Gao, Y. X.; Wongkhan, K.; Shu, D. X.;
Lan, Y.; Li, A.; Batsanov, A. S.; Howard, J. A. H.; Marder, T. B.;
Chen, J. H.; Yang, Z. Organometallics 2007, 26, 4756. (b) Dai, M.;
Wang, C.; Dong, G.; Xiang, J.; Luo, T.; Liang, B.; Chen, J.; Yang, Z.
Eur. J. Org. Chem. 2003, 4346. (c) Yamamoto, Y.; Maekawa, H.;
Goda, S.; Nishiguchi, I. Org. Lett. 2003, 5, 2755. (d) Yokota, T.;
Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2002, 67, 5005. (e) Brechot, P.;
Chauvin, Y.; Commereuc, D.; Saussine, L. Organometallics 1990, 9,
26. (f) Tamaru, Y.; Hojo, M.; Higashimura, H.; Yoshida, Z. J. Am.
Chem. Soc. 1988, 110, 3994.
(1) (a) Bienayme, H.; Hulme, C.; Oddon, G; Schmitt, P. Chem.;Eur.
J. 2000, 6, 3321. (b) Multicomponent Reactions; Zhu, J., Bienayme, H.,
Eds.; Wiley-VCH: Weinheim, 2005.
(2) For radical multicomponent reactions, see: (a) Multicomponent
Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005; pp
169À198. Also see reviews: (b) Malacria, M. Chem. Rev. 1996, 96, 289.
(c) Godineau, E.; Landais, Y. Chem.;Eur. J. 2009, 15, 3044.
(3) For reviews on radical carbonylation reactions using carbon
monoxide, see: (a) Ryu, I.; Sonoda, N. Angew. Chem., Int. Ed. 1996,
35, 1050. (b) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96,
177. For a review on acyl radial chemistry, see: Chatgilialoglu, C.; Crich,
D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991.
(4) For atom-transfer carbonylations, see: (a) Nagahara, K.; Ryu,
I.; Komatsu, M.; Sonoda, N. J. Am. Chem. Soc. 1997, 119, 5465. (b)
Ryu, I.; Nagahara, K.; Kambe, N.; Sonoda, N.; Kreimerman, S.;
Komatsu, M. Chem. Commun 1998, 1953. (c) Kreimerman, S.; Ryu, I.;
Minakata, S.; Komatsu, M. Org. Lett. 2000, 2, 389. (d) Ryu, I.;
Niguma, T.; Minakata, S.; Komatsu, M. Tetrahedron Lett. 1997, 38,
7883. (e) Kobayashi, S.; Kawamoto, T.; Uehara, S.; Fukuyama, T.;
Ryu, I. Org. Lett. 2010, 12, 1548. Also see a review: Ryu, I. Chem. Soc.
Rev. 2001, 30, 16.
r
10.1021/ol200536h
Published on Web 03/25/2011
2011 American Chemical Society

of the atom-transfer carbonylation of alkyl iodides leading
to carboxylic acid esters, amides, and alkynyl ketones.6
Vicinal carbon functionalization of alkenes is an impor-
tant challenge in multicomponent reactions. Whereas typi-
cal processes with incorporation of CO involve double
alkoxycarbonylation of alkenes,7 reactions attaining the
introduction of an alkyl unit and CO into vicinal carbons
of alkenes are scarce.8 In a related study, we previously
reported on the photoinduced addition of R-phenylseleno-
substituted esters to alkenes and CO to give 4-keto acyl
selenides as products.9 However, a simple ester synthesis has
yet to be attained. In this paper, we report that Pd/light-
induced radical carbonylation of various R-substituted
iodoalkanes allows for vicinal carbon-functionalization of
alkenes leading to esters (Scheme 1).
Table 1. Pd/Light Induced, Four-Component Coupling Reac-
tion of Ethyl Iodoaceate (1a) with 1-Octene (2a), Ethanol (3a),
and Carbon Monoxidea
entry
base
solvent
time (h)
yieldb (%)
1
Et3N
C6H6
8
14
16
8
72
25
21
77
82
57
2c
3d
4
Et3N
C6H6
Et3N
C6H6
K2CO3
K2CO3
K2CO3
C6H6
5
6e
toluene
toluene
14
14
a Conditions: 1a (0.5 mmol), 2a (10 equiv), 3a (40 equiv), CO (45
atm), PdCl2(PPh3)2 (5 mol %), base (1.1 equiv), DMAP (10 mol %),
solvent (5 mL), H2O (10 μL). b Isolated yield of 4a after silica gel
chromatography. c The reaction was carried out without PdCl2(PPh3)2.
d The reaction was performed under 80 °C without photoirradiation
conditions. e Dichloro[1,3-bis(diisopropylphenyl)imidazolylidene](3-chloro-
pyridyl)palladium(II) was used as a Pd catalyst. Iodoalkane 5 was formed
as byproduct (16%).
Scheme 1. Strategies for Four-Component Coupling Reactions
of R-Iodoalkanes, Alkenes, CO, and Alcohols Leading to Esters
reactions (Table 2). In contrast to 1a, the reaction of ethyl
bromoacetate (1b) was sluggish, giving a 26% yield of 4a
(entry 2). Benzyl alcohol (3b) gave the anticipated diester 4b in
a 67% yield (entry 3). In the reaction with methanol, dimethyl
ester 4c, arising from the further transesterification of an ethyl
ester, was formed in 70% yield (entry 4). Terminal olefins
having a chlorine atom or a phenyl group also worked well to
give the corresponding diesters 4d and 4e in good yields
(entries 5 and 6). Cycloheptene (2d) also gave the correspond-
ing diester 4f in a 51% yield as a single trans diastereomer
(entry 7). The reaction of perfluorohexyl iodide (1c) with 2a
or 2c afforded the corresponding esters 4g or 4h in 84 and
76% yields, respectively (entries 8 and 9). Iodoacetonitrile
(1d) and iodomethyl phenyl sulfone (1e) gave the anticipated
cyano ester 4i and sulfone ester 4j in 64 and 56% yields,
respectively (entries 10 and 11). In a radical cascade sequence
involving the incorporation of two molecules of CO, the
reaction of 1a with 1,5-hexadiene (2e) was carried out,
which gave the desired diester (4k) bearing a cyclopenta-
none scaffold via a five-component coupling reaction
(entry 12). The relatively low yield of 4k was the result of
the competitive formation of singly carbonylated product
4l (24% yield).
When a benzene solution of ethyl iodoacetate (1a),
1-octene (2a), and ethanol (3a) was exposed to photoirra-
diation conditions (irradiation with a 500 W xenon lamp
through Pyrex) under 45 atm of CO pressure in the presence
of PdCl2(PPh3)2 (5 mol %), a base (1.1 equiv of NEt3 and 10
mol % of DMAP), and a small amount of water (ca. 1
equiv), the desired diester 4a was obtained in 72% yield after
chromatographic purification (Table 1, entry 1). In the
absence of Pd catalyst, the reaction was sluggish (entry 2).
The combination of photoirradiation conditions and Pd
catalyst was essential to obtain 4a in a good yield (entry 3).
The reaction using K2CO3 as a base was also effective,
which gave 77% of 4a (entry 4).10 The use of toluene as a
solvent also gave a good yield of 4a (entry 5). NHC Pd
complex also worked to give diester4a, but was less effective
(entry 6).
A variety of R-substituted iodoalkanes, alkenes, and alco-
hols participate in the present four-component coupling
We next examined cyclizative three-component coupling
reactions, using alkenyl alcohols 6, which also worked well to
give the desired ester-functionalized lactones (Table 3). Thus,
when ethyl iodoacetate (1a) was treated with 4-penten-1-ol
(6a) and carbon monoxide in the presence of PdCl2(PPh3)2
and triethylamine under standard conditions, the reaction
proceeded smoothly to give δ-lactone 7a in a 77% yield
(entry 1). The reaction of 4-buten-1-ol (6b) also worked to
give γ-lactone 7b in a good yield (entry 2). Perfluorohexyl
iodide (1c) also worked well to give the corresponding
lactones 7c and 7d in good yields (entries 3 and 4). We also
examined the synthesis of seven-membered ring lactone 7e
(8) (a) Urata, H.; Kinoshita, Y.; Asanuma, T.; Kosukegawa, O.;
Fuchikami, T. J. Org. Chem. 1991, 56, 4996. (b) Tsuji, J.; Sato, K.;
Nagashima, H. Tetrahedron Lett. 1982, 23, 893. (c) Tsuji, J.; Sato, K.;
Nagashima, H. Tetrahedron 1985, 41, 5003.
(9) Ryu, I.; Muraoka, H.; Kambe, N.; Komatsu, M.; Sonoda, N. J.
Org. Chem. 1996, 61, 6396.
(10) When the reaction was performed without DMAP, the yield of
diester 4a dropped to 53%. In this case, the iodoalkane 5 arising from the
addition of 1a to 2a was also obtained in 24% yield.
Org. Lett., Vol. 13, No. 8, 2011
2115

Table 2. Four-Component Coupling Reactions Leading to Estersa
a Conditions: 1 (0.5 mmol), 2 (10 equiv), 3 (40 equiv), CO (45 atm), PdCl2(PPh3)2 (5 mol %), K2CO3 (1.1À1.4 equiv), DMAP (10 mol %), toluene (5
mL), H2O (10 μL). b Isolated yield after silica gel chromatography. c C6H6 and Et3N were used. d BnOH (5.0 equiv) was used. e CO (65 atm) and
PdCl2(PPh3)2 (20 mol %) were used.
using 6c. In this case, due to the competition of ionic
cyclization giving a tetrahydropyran ring, the yield of ε-
lactone 7e was moderate (entry 5).
A possible reaction mechanism for the present multicom-
ponent coupling reaction is shown in Scheme 2. Alkyl
radicals are formed via cleavage of the IÀC bond of 1a,
which may be triggered by single electron transfer from the
photoirradiated Pd(0) complex.11,12Addition of the radicals
to alkene then takes place to give alkyl radicals. The sub-
sequent iodine atom transfer form 1a affords iodoalkane 5.
The reaction between alkyl radical and Pd(I) to give alkyl
palladium might take place but scarcely contributes in this
reaction mechanism, judging from the fact that β-hydrogen
elimination product was not observed. Probably pressurized
CO drives these equilibriums to afford the acylradical inter-
mediate, which would be trapped by Pd(I)I to form acylpal-
ladium species, precursors for the diester 4a. Persistent
radical character of Pd(I) species may be supported by the
dimerization behavior.13,14
(11) For examples of an electron transfer from low-valent palladium
or platinum complexes to iodoalkanes, 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. (c)
Knochel, P.; Manolikakes, G. Angew. Chem., Int. Ed. 2009, 48, 205.
Also see ref 6b.
(12) For SET-induced radical reactions of perfluoroalkyl iodides,
see: (a) Chen, Q. Y.; Yang, Z. Y.; Zhao, C. X.; Qiu, Z. M. J. Chem. Soc.,
Perkin Trans. 1 1988, 563. (b) Qiu, Z. M.; Burton, D. J. J. Org. Chem.
1995, 60, 5570. (c) Yoshida, M.; Iizuka, M. J. Fluorine Chem. 2009, 130,
926.
(13) For reviews on persistent radical effect, see: (a) Fischer, H.
Chem. Rev. 2001, 101, 3581. (b) Studer, A. Chem.;Eur. 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.
(14) For photogeneration of Pd radical from Pd dimer complex, see:
Lemke, F. R.; Kubiak, C. P. J. Organomet. Chem. 1989, 373, 391.
2116
Org. Lett., Vol. 13, No. 8, 2011

Table 3. Three-Component Coupling Reactions Leading to
Lactonesa
Scheme 2. Possible Reaction Mechanism
and CO also worked well to give the corresponding
functionalized lactones. These reactions represent the vic-
inal carbon-functionalization of alkenes.
a Conditions: 1 (0.25 mmol), 6 (5 equiv), CO (45 atm), PdCl2(PPh3)2
(5 mol %), Et3N (1.1À1.4 equiv), DMAP (10 mol %), toluene (5 mL),
H2O (50 μL). b Isolated yield after silica gel chromatography. c DMAP
(20 mol %) and CO (80 atm) were used.
Acknowledgment. We thank JSPS, MEXT Japan, and
Scientific Research on Innovative Areas (No. 2105) for
generous funding of this work.
In summary, we have demonstrated novel four-compo-
nent coupling reactions leading to functionalized esters,
which use R-substituted iodoalkanes, alkenes, CO, and
alcohols under Pd/light combined conditions. A three-
component reaction using iodoalkanes, alkenyl alcohols,
Supporting Information Available. Experimental proce-
dure and compound characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org
Org. Lett., Vol. 13, No. 8, 2011
2117