Sequential rhodium-catalyzed stereo- and regioselective addition of organoboron derivatives to the alkyl 4-hydroxy-2-alkynoates/lactonizaction reaction

Article abstract of DOI:10.1021/jo701629t

(Chemical Equation Presented) The sequential rhodium-catalyzed addition/lactonization reaction of organoboron derivatives to alkyl 4-hydroxy-2-alkynoates would constitute a novel methodology for the synthesis of 4-aryl/heteroaryl/vinyl-2(5H)-furanones wit

Full text of DOI:10.1021/jo701629t

Sequential Rhodium-Catalyzed Stereo- and Regioselective Addition
of Organoboron Derivatives to the Alkyl 4-Hydroxy-2-Alkynoates/
Lactonizaction Reaction
Maria Alfonsi,† Antonio Arcadi,*,† Marco Chiarini,‡ and Fabio Marinelli†
Department of Chemistry, Chemical Engineering and Materials, UniVersity of L’Aquila, Via Vetoio-67010
Coppito (AQ), Italy, and Department of Food Science, UniVersity of Teramo, Via Carlo R. Lerici,
1-64023 Mosciano Sant’Angelo (TE), Italy
arcadi@uniVaq.it
ReceiVed July 25, 2007
The sequential rhodium-catalyzed addition/lactonization reaction of organoboron derivatives to alkyl
4-hydroxy-2-alkynoates would constitute a novel methodology for the synthesis of 4-aryl/heteroaryl/
vinyl-2(5H)-furanones with an excellent control of the regio- and chemoselectivity. The role played by
rhodium precatalyst, ligands, reaction medium, and the feature of organoboron derivatives has been
explored.
Introduction
fermentation of the basidiomycete Incrustoporia carneola, are
especially valuable as wide-spectrum antifungal agents.3 4-Sub-
stituted 2(5H)-furanone is a subunit in Rubrolides B, a family
of biologically active marine ascidian (tunicate) metabolites that
have been isolated from Ritterella Rubra, and Synoicum
bolchmanni, which are potent antibiotics and show selective
inhibition of protein phosphatases 1 and 2A, significant cyto-
toxicity against P-388 suspension cultures of mouse lymphoid
neoplasm and monolayer cultures of human lung carcinoma (A-
549), human colon carcinoma (HT-29), and human melanoma
(Mel-28).4 Compounds containing the 2(5H)-furanone scaffold
have also been evaluated as insecticides, herbicides, seed plant
regulators, allergy inhibitors, cyclooxygenase inhibitors, and
phospholipase A2 inhibitors.5 4-(1-Alkynyl)-2(5H)-furanones
were found to exhibit potent cytotoxicity.6 As valuable synthetic
intermediates, 2(5H)-furanones are frequently utilized as key
intermediates to construct complex molecules7 and also appear
as a substructure in peptide analogues and HIV-1 protease
Compounds containing the 2(5H)-furanone moiety are im-
portant synthetic targets1 due to their presence as a subunit in
many natural products2 and, more precisely, they may play a
significant role in the discovery of new therapeutic agents. A
series of 3-aryl-5-substituted-2(5H)-furanones related to incrus-
toporine, a natural compound isolated from the extract of
† University of L’Aquila.
‡ University of Teramo.
(1) (a) Xu, H.-W.; Wang, J.-F.; Liu, G.-Z.; Hong, G.-F.; Liu, H. M. Org.
Biomol. Chem. 2007, 5, 1247-1250. (b) Raju, R.; Allen, L. J.; Le, T.;
Taylor, C. D.; Howell, A. R. Org. Lett. 2007, 9, 1699-1701. (c) Patil, S.
N.; Liu, F. Org. Lett. 2007, 9, 195-198. (d) Vaz, B.; Dom´ınguez, M.;
Alvarez, R.; de lera, A. R. Chem. Eur. J. 2007, 13, 1273-1290. (e) Adrio,
J.; Carretero, J. C. J. Am. Chem.2007, 129, 778-779. (f) Krishna, P. R.;
Narsingam, M. J. Comb. Chem. 2007, 9, 62-69. (g) Brasholz, M.; Reissig,
H.-U. Synlett 2007, 1294-1298. (h) Ducheˆne, A.; Thibonnet, J.; Parrain,
J.-Luc; Anselmi, E.; Abarbri, M. Synthesis 2007, 597-607. (i) Li, Y.; Zhang,
T.; Li, Y.-L. Tetrahedron Lett. 2007, 48, 1503-1505. (j) Bassora, B. K.;
Da Costa, C. E.; Gariani, R. A.; Comasseto, J. V.; Dos, Santos, A. A.
Tetrahedron Lett. 2007, 48, 1485-1487. (k) Chavan, S. P.; Thakkar, M.;
Kalkote, U. R. Tetrahedron Lett. 2007, 48, 643-6477. (l) Albrecht, U.;
Langer, P. Tetrahedron 2007, 63, 4648-4654. (m) Aquino, M.; Bruno, I.;
Riccio, R.; Gomez-Paloma, L. Org. Lett. 2006, 8, 4831-4834. (n) Maulide,
N.; Marko´, I. E. Org. Lett. 2006, 8, 3705-3707. (o) Ma, J.; Wang, S. H.;
Tian, G. R. Synth. Commun. 2006, 36, 1229-1233. (p) Chen, G.; Fu, C.;
Ma, S. Tetrahedron 2006, 62, 4444-4452. (q) Cho, C. S.; Shim, S. H.
Tetrahedron Lett. 2006, 47, 3835-3837. (r) Langer, P. Synlett 2006, 3369-
3381. (s) Bouillon, J. P.; Kikelj, V.; Tinant, B.; Harakat, D.; Portella, C.
Synthesis 2006, 1050-1056.
(3) Vale-Silva, L. A.; Buchta, V.; Vokurkova`, D.; Pour, M. Bioorg. Med.
Chem. Lett. 2006, 16, 2492-2495 and references cited therein.
(4) Ortega, M. J.; Zubia, E.; Ocanˇa, G. M.; Naranjo, S.; Salva`, J.
Tetrahedron 2000, 56, 3963-3967.
(5) (a) Brima, T. S. U.S. Patent Appl. 635,338, 1984; Chem. Abstr. 1991,
114, 185246. (b) Tanabe, A. JP 63,211,176 [88,211,276], 1988; Chem. Abstr.
1996, 110, 94978. (c) Ducharme, Y.; Gauthier, J. Y.; Prasit, P.; Leblanc,
Y.; Wang, Z.; Leger, S.; Therien, M. PCT Int. Appl. WO 9500, 501, 1995;
Chem. Abstr. 1996, 124, 55954. (d) Lee, G. C. M.; Garst, M. E. PCT Int.
Appl. WO 9116,055; Chem. Abstr. 1992, 116, 59197m.
(2) Iimura, S.; Overman, L. E.; Paulini, R.; Zakarian, A. J. Am. Chem.
Soc. 2006, 128, 13095-13101.
(6) Bellina, F.; Falchi, E.; Rossi, R. Tetrahedron 2003, 59, 9091-9100.
10.1021/jo701629t CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/06/2007
9510
J. Org. Chem. 2007, 72, 9510-9517

Sequential Rh-Catalyzed Addition/Lactonization
inhibitors.8 Because of their importance in both chemical and
pharmaceutical research, a number of syntheses of 2(5H)-
furanones have been reported9 and many of them rely upon
transition metal-catalyzed methodologies. Among them, ruthe-
nium-catalyzed carbonylative cyclization of allenols10 and enyne
methatesis11 resulted as valuable synthetic procedures. Cross-
coupling reaction such as Sonogashira,12 Stille,6,13 and Suzuki-
Miyaura14 reactions have been studied. Cyclization of allenic
acid derivatives and (Z)-enynols provides the title compounds
by means of the catalysis of Ag(I),15 Au (III),16 and Pd(II).17
Access to the 2(5H)-furanone skeleton can be accomplished
through palladium-mediated cyclization-carbonylation18 or
coupling-cyclization19 reactions of propargylic esters. Pal-
ladium-catalyzed reaction of unsaturated triflates and halides
with methyl-4-hydroxy-2-butenoate and its tetrahydropyranyl
derivative afforded 4-aryl- and 4-vinyl-2(5H)-furanones through
an in situ vinylic substitution/annulation sequence.20 As part of
an ongoing program, devoted to the use of transition metal
SCHEME 1
SCHEME 2
catalyzed reactions of alkynes bearing proximate suitable
functionalities to obtain cyclic derivatives,21 some of us have
been involved in the development of a regioselective synthesis
of 3-aryl- and 3-vinylfuran-2(5H)-ones 3 through sequential
palladium-catalyzed hydroarylation and hydrovinylation/lacton-
ization reactions of alkyl 4-hydoxy-2-alkynoates 1 with aryl/
vinyl halides/triflates.22 Subsequently, this methodology has been
extended by Oh and co-workers23 for the use of organoboronic
acids for palladium-catalyzed arylative lactonizations of 1.
Organoboron reagents offer significant advantages. They are
easily accessed by a variety of routes and the inorganic
byproducts of the reaction with boron derivatives are nontoxic
and can be removed by simple workup procedures. However,
the regioselectivity control of the reaction resulted in a dramatic
influence by the reaction conditions, features of the substrates
and the catalytic system. Moreover, conversely to the easy
accomplishment of the synthesis of 3-substituted-2(5H)-fura-
nones 3, the regioselective control required to generate 4-sub-
stituted-2(5H)-furanones 4 as an exclusive regioisomer through
the sequential palladium-catalyzed addition of organoboron
derivatives 2 to alkyl 4-hydroxy-2-alkynoates 1/lactonization
reactions has not been accomplished (Scheme 1).
Regioselective hydroarylation/hydrovinylation of â-(2-ami-
nophenyl)-R,â-ynones with arylboronic acids or potassium aryl
and vinyl trifluoroborates in the presence of Rh(acac)(C2H2)/
dppf as catalyst, followed by heterocyclization accomplished
the synthesis of functionalized 4-aryl and 4-vinylquinolines.24
Consequently, it was thought that Rh(I)-catalyzed addition of
organoboron derivatives 2 to alkyl 4-hydoxy-2-alkynoates 1
(Scheme 2) would allow the regioselective formation of
4-substituted-2(5H)-furanones 4.
(7) (a) Brimble, M. A.; Robinson, J. E.; Merten, J.; Beuzenberg, V.;
Dragunow, M.; Holland, P.; Mountfort, D. Synlett 2006, 1610-1613. (b)
Mahajan, V. A.; Borate, H. B.; Wakarkar, R. D. Tetrahedron 2006, 62,
1258-1272. (c) Stecko, S.; Pasniczek, K.; Jurczak, M.; Urbanczyk-
Lipkowska, Z.; Chmielewski, M. Tetrahedron: Asymmetry 2006, 17, 68-
78. (d) Roush, W. R.; Limberakis, C.; Kunz, R. K.; Barda, D. A. Org. Lett.
2002, 4, 1543- 1546. (e) Concello´n, J. M.; Riego, F.; Bernard, P. L. Org.
Lett. 2002, 4, 1303-130. (f) Makabe, H.; Hattori, Y.; Tanaka, A.; Oritani,
T. Org. Lett. 2002, 4, 1083-1085. (g) Renard, M.; Ghosez, L. A.
Tetrahedron 2001, 57, 2597-2608.
(8) Chio, Y.; Choo, H.; Chong, Y.; Lee, S.; Olgen, S.; Schinazi, R. F.;
Chu, C. K. Org. Lett. 2002, 4, 305-307.
(9) (a) Maulide, N.; Marko´, I. E. Org. Lett. 2006, 8, 3705-3707. (b)
Tejedor, D.; Santos-Expo´sito, A.; Garc´ıa-Tellado, F. Synlett 2006, 1607-
1610. (c) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2003, 125, 1192-1194. (d) Holton, R. A.; Kim, H. B. Tetrahedron
Lett. 1986, 27, 2191-2194. (e) Guntrum, E.; Kuhn, W.; Spo¨nlein, W.; Ja¨ger,
V. Synthesis 1986, 921-925. (f) Rao, Y. S. Chem. ReV. 1976, 76, 625-
693.
(10) Yoneda, E.; Kaneko, T.; Zhang, S.-W.; Onitsuka, K.; Tkahashi, S.
Org. Lett. 2000, 2, 441-443.
(11) Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1, 277-
279.
(12) (a) Boukouvalas, J.; Coˆte´, S.; Ndzi, B. Tetrahedron Lett. 2007, 48,
105-107. (b) Ma, S.; Shi, Z.; Yu, Z. Tetrahedron Lett. 1999, 40, 2393-
2396.
(13) Carter, N. B.; Mabon, R.; Walmsley, R.; Richecouer, A. M. E.;
Sweeney, J. B. Synlett 2006, 1747-1749.
(14) (a) Wu, J.; Zhang, L.; Gao, K. Eur. J. Org. Chem. 2006, 5260-
5263. (b) Wu, J.; Zhang, L.; Luo, Y. Tetrahedron Lett. 2006, 47, 6747-
6750. (c) Aquino, M.; Bruno, R.; Riccio, L.; Gomez-Paloma, L. Org. Lett.
2006, 8, 4831-4834. (d) Song, Y. S.; Lee, Y-J.; Kim, B. T.; Heo, J.-N.
Tetrahedron Lett. 2006, 47, 7427-7430. (e) El Murr, M. D.; Nowaczyk,
S.; Le Gall, T.; Mioskowski, C. Eur. J. Org. Chem. 2006, 1489-1498. (f)
Ahmed, Z.; Langer, P. Eur. J. Org. Chem. 2006, 1057-1060. (g) Mathews,
C. J.; Taylor, J.; Tyte, M. J.; Worthington, P.A. Synlett 2005, 538-540.
(h) Kalbalka, G. W.; Dong, G.; Venkataiah, B. Tetrahedron Lett. 2004, 45,
5139-5141. (i) Wu, J.; Zhu, Q.; Wang, L.; Fathi, R.; Yang, Z. J. Org.
Chem. 2003, 68, 670-673. (j) Yao, M.-L.; Deng, M.-Z. J. Org. Chem.
2000, 65, 5034-5036.
(15) Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997,
62, 367-371.
(16) (a) Liu, Y.; Song, F.; Guo, G. J. Am. Chem. Soc. 2006, 128, 11332-
11333. (b) Kang, J.-E.; Lee, E.-S.; Park, S.-I.; Shin, S. Tetrahedron Lett.
2005, 46, 7431-7433.
(17) (a) Gu, Z.; Ma, S. Angew. Chem., Int. Ed. 2006, 45, 6002-6005.
(b) Ma, S. M. Pure Appl. Chem. 2006, 78, 197-208. (c) Ma, S. M.; Gu, Z.
H.; Deng, Y. Q. Chem. Commun. 2006, 94-96. (d) Ma, S.; Yu, Z. Chem.
Eur. J. 2004, 10, 2078-2087.
The Rh(I)-catalyzed reaction of alkyl 4-hydoxy-2-alkynoates
1 with organoboron derivatives 2 was then investigated. The
detailed report of the results obtained follows.
Results and Discussion
Since Miyaura et al.25 demonstrated in 1997 that arylboronic
acid may be add efficiently to Michael acceptors in the presence
(21) (a) Abbiati, G.; Arcadi, A.; Beccalli, E.; Bianchi, G.; Marinelli, F.;
Rossi, E. Tetrahedron 2006, 62, 3033-3039.
(22) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P. Eur.
J. Org. Chem. 1999, 3305-3313. (b) Arcadi, A.; Bernocchi, E.; Burini,
A.; Cacchi, S.; Marinelli, F.; Pietroni, B. Tetraherdon Lett. 1989, 30, 3465-
3468. (c) Arcadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.; Marinelli, F.;
Pietroni, B. Tetraherdon 1988, 44, 481-490.
(18) Kato, K.; Nouchi, H.; Ishikura, K.; Takaishi, S.; Motodate, S.;
Tanaka, H.; Okudaira, K.; Mochida, T.; Nishigaki, R.; Shigenobu, K.; Akita,
H. Tetrahedron 2006, 62, 2545-2554.
(19) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 1993, 65-
68.
(20) (a) Cacchi, S.; Ciattini, P. G.; Morera, E.; Pace, P. Synlett 1996,
545-546. (b) Ciattini, P. G.; Ortar, G. Synthesis 1986, 70-71. (d) Harnisch,
W.; Morera, E.; Ortar, G. J. Org. Chem. 1985, 50, 1990-1992.
(23) Oh, C. H.; Park, S. J.; Ryu, J. H.; Gupta, A. K. Tetraherdon Lett.
2004, 45, 7039-7042.
(24) Abbiati, G.; Arcadi, A.; Marinelli, F.; Rossi, E.; Verdecchia, M.
Synlett 2006, 3218-3224.
(25) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229-4231.
J. Org. Chem, Vol. 72, No. 25, 2007 9511

Alfonsi et al.
TABLE 1. Optimization Studies
entry
solventa
T (°C)/t (h)
catalyst
ligand
3a (% yield)b
4a (% yield)b
5a (% yield)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
dioxane/H2O 10/1
dioxane/H2O 10/1
dioxane/H2O 10/1
dioxane/H2O 10/1
dioxane/H2O 10/1
dioxane/H2Oc 10/1
dioxane/H2O 10/1
dioxane/H2O 10/1
dioxane/H2O 10/1
dioxane/H2O 10/1
dioxane/H2O 10/1
dioxane/H2Od 10/1
dioxane/H2Oe 10/1
dioxane/H2Od,f 10/1
EtOH
100/3
100/6
100/3
100/1
100/0.5
100/0.5
100/23
100/0.5
100/1
100/0.5
100/0.5
100/1.0
40/24
40/24
100
100
100/6.5
40/1.5
rt/3.5
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)Cl]2 (3 mol %)
Rh(acac)(C2H4)2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
Rh(acac)(C2H4)2 (3 mol %)
[Rh(cod)OH]2 (1.5 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (3 mol %)
[Rh(cod)OH]2 (1.5 mol %)
dppf (6 mol %)
dppf (6 mol %)
dppf (6.6 mol %)
10
4
69
42
44
50
26
11
55
20
28
7
18
27
52
35
34
PPh3 (6 mol %)
PPh3 (6 mol %)
6 (6 mol %)
5
7 (6 mol %)
dppe (6 mol %)
dppp (6 mol %)
dppb (6 mol %)
dppb (6 mol %)
dppb (6 mol %)
dppb (6 mol %)
dppb (6 mol %)
dppf (6.6 mol %)
8 (6 mol %)
5
7
31
41
88
90
63
53
40
9
9
9
40
42
23
16
22
18
30
15
EtOH
H2O
H2Og
9 (6 mol %)
10 (6 mol %)
10 (6 mol %)
H2Oh
toluene/H2O 1/1
100/1.0
10
a All reactions were carried out with 5 equiv of 2a/1 equiv of 1a, unless otherwise indicated. b Yields are based on products isolated by column
chromatography. c 2a/1a ) 2.5. d 2a/1a ) 2.0. e 2a was recovered in a 15% yield. f 1a and 2a were recovered in a 82% and 61% yield, respectively. g 2a
was recovered in a 71% yield. h 2a was recovered in a 50% yield.
CHART 1
The reaction of 4-hydroxy-4-methyl-pent-2-ynoic acid ethyl ester
1a and PhB(OH)2 2a has been chosen as a model system with
the aim of optimizing conditions for the rhodium-catalyzed
synthesis of 4-substituted-2(5H)-furanones 4 (Table 1). The 5,5-
dimethyl-4-phenyl-5H-furan-2-one 4a was isolated in a 69%
yield together with the regioisomer 3a (10% yield) by reacting,
in dioxane/water 10/1 (v/v), 1 equiv of 1a with 5 equiv of 2a,
using [Rh(cod)(OH)]2/1,1′-bis(diphenylphosphino)ferrocene (dppf)
as catalyst; the formation of 5a (20% yield) as byproduct was
also observed (Table 1, entry 1).24,27d The use of [Rh(cod)OH]2/
dppf resulted in a more active catalytic system with respect to
[Rh(cod)Cl]2/dppf and Rh(acac)(C2H4)2/dppf (Table 1, entries
1-3), even if the latter combination was highly selective.29
(26) (a) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem.
Soc. 2007, 129, 5356-5357. (b) Miyamura, S.; Satoh, T.; Miura, M. J.
Org. Chem. 2007, 72, 2255-2257. (c) Yoshida, S.; Yorimitsu, H.; Oshima,
K. Synlett 2007, 1622-1624. (d) Bai, T.; Ma, S.; Jia, G. Tetrahedron 2007,
63, 6210-6215. (e) Frost, C. G.; Penrose, S. D.; Lambshead, K.; Raithby,
P. R.; Warren, J. E.; Gleave, R. Org. Lett. 2007, 9, 2119-2112. (f) Kurihara,
K.; Sugishita, N.; Ospita, K.; Piao, D.; Yamamoto, Y.; Miyaura, N. J.
Organomet. Chem. 2007, 692, 428-435. (g) Martina, S. L. X.; Jagt, R. B.
C.; de Vries J. G.; Feringa, B. L.; Minnaard, S. Chem. Commun. 2006,
4093-4095. (h) Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem.
Soc. 2006, 128, 6304-6305. (i) Nishimura, T.; Hirabayashi, S.; Yasuhara,
Y.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 2556-2557. (j) Toullec, P.
Y.; Jagt, R. B. C.; de Vries, J. C.; Feringa, B. L.; Minnaard, A. J. Org.
Lett. 2006, 8, 2715-2718. (k) Duan, H.-F.; Jia, Y.-X.; Zhou, Q.-L. Org.
Lett. 2006, 8, 2567-2569. (l) Vandyck, K.; Matthys, B.; Willen, M.;
Robeyns, K.; Meervelt, L. V.; Van der Eychen, J. Org. Lett. 2006, 8, 363-
366. (m) Chen, F. X.; Kina, A.; Hayashi, T. Org. Lett. 2006, 8, 341-344.
(n) Navarre, L.; Darses, S.; Geneˆt, J.-P. AdV. Synth. Catal. 2006, 348, 317-
322. (o) Suzuki, K.; Kondo, K.; Aoyama, T. Synthesis 2006, 1360-1364.
(p) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829-2844. (q)
Fagnou, K.; Lautens. M. Chem. ReV. 2003, 103, 169-196.
SCHEME 3
of rhodium(I) catalysts, growing attention has been devoted to
the development of new reactions by using a combination of
rhodium catalyst and organoboron reagents. The rhodium
catalysis allowed the addition of arylboronic acids and their
analogues to the carbon-carbon and carbon-heteroatom mul-
tiple bonds.26 The rhodium-catalyzed addition of organoboron
derivatives to alkynes27 has definite advantages over other
methods due to high regioselectivity and high stereoselectivity,
which may obtain feasible sequential addition-cyclization
reactions of alkynes bearing proximate suitable functionalities.28
(27) (a) Genin, E.; Michelet, V.; Geneˆt, J.-P. J. Organomet. Chem. 2004,
689, 3820-3830. (b) Genin, E.; Michelet, V.; Geneˆt, J.-P. Tetrahedron Lett.
2004, 45, 4157-4161. (c) Lautens, M.; Yoshida, M. J. Org. Chem. 2003,
68, 762-769. (d) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J.
Am. Chem. Soc. 2001, 123, 9918-9919.
9512 J. Org. Chem., Vol. 72, No. 25, 2007

Sequential Rh-Catalyzed Addition/Lactonization
TABLE 2.
entry
catalytic system
time (h)/T (°C)
4a (% yield)
5a (% yield)
6a (% yield)a,b
1
2
3
4
5
[Rh(cod)OH]2/dppb (3 mol %)/(6 mol %)
[Rh(cod)OH]2/dppb (3 mol %)/(6 mol %)
[Rh(cod)OH]2/dppe (3 mol %)/(6 mol %)
[Rh(cod)OH]2/dpped (3 mol %)/(6 mol %)
[Rh(cod)OH]2/dppef (3 mol %)/(6 mol %)
28/40c
10
42
31
14
25
2/100c
45
64
31
11
1/100d
1.5/100e
1.0/100d
27
40
a Yields are based on products isolated by column chromatography. b Reactions carried out in dioxane/water (10/1). c 1a:2b ) 1:1. d 1a:2b ) 2:1. e 1a:2b
) 3:1. f The reaction was carried out in dry 1,4-dioxane.
Further study was undertaken to improve the reaction by varying
a series of parameters (ligand, Rh/ligand ratio, solvent, tem-
perature, 1a/2a ratio) with [Rh(cod)OH]2 as a precatalyst. The
use of [Rh(cod)OH]2 without the addition of phosphine ligands
also resulted in efficiently promoting the reaction, however, with
no improvements in terms of selectivity (Table 1, entry 4). The
combination of [Rh(cod)OH]2 with PPh3 has proven to be
unsuitable and generally resulted in low selectivity (Table 1,
entries 5 and 6). The choice of the bulky, electron-rich 2-(di-
tert-butylphosphino)biphenyl 6 as ligand (Chart 1), which was
reported to have beneficial effects on the rhodium-catalyzed
addition of alkynes to 1,2-diketones, 1,2-ketoesters, and alde-
hydes,30 failed in reaching high selectivity (Table 1, entry 7).
Chelating bisphosphine ligands gave discrepant results. The
features of the bisphosphine ligands played a pivotal role in
determining the outcome of the reaction. Even if it has been
postulated that excellent catalytic activities could arise from
diphosphine ligands based on the xantene backbone,31 our
experiments obtained a complex reaction mixture (Table 1, entry
8) from the catalytic system [Rh(cod)OH]2/9,9-dimethyl-4,5-
bis(diphenylphosphino)xantene (Chart 1, xantphos 7) under
normal reaction conditions. Whereas 5a (53% yield) formation
prevailed with 1,2-bis(diphenylphosphino)ethane (dppe) (Table
1, entry 9), improvement of the target 4a yield was observed
by increasing the distance between the two phosphorus atoms
in the series dppe, 1,3-bis(diphenylphosphino)propane (dppp),
and 1,4-bis(diphenylphosphino)butane (dppb) (Table 1, entries
10 and 11). Among the examined bisphosphine ligands, dppb
was significantly effective (Table 1, entry 10). Other improve-
ments were attempted in order to completely reverse the
selectivity toward 5a. Surprisingly, the use of a smaller amount
of boronic acid (2 equiv) essentially provided a similar high
chemical yield as 5 equiv of 2a (Table 1, entry 12). At a
temperature as low as 40 °C, it was found to exclusively obtain
4a in a 63% yield (Table 1, entry 13); however, at said
temperature, the ratio 2a/1a resulted in a determining factor for
the resulting arylative lactonization process (Table 1, entry 14).
After screening the solvent, it was found that the use of
ethanol instead of 1,4-dioxane was detrimental to the selectivity
of the reaction (Table 1, entries 15 and 16). The reaction was
also carried out in neat water32 and in a biphasic water/toluene
system27a,b by associating the [Rh(cod)OH]2 with water-soluble
ligands 8-9 (Chart 1). Surprisingly enough, even if disappoint-
ing results were observed from a synthetic point of view (Table
1, entries 17-19), the reaction in water led to the formation of
4a as a single regioisomer. Conversely, in the biphasic water/
toluene system, we observed a lack of regioselectivity (Table
1, entry 20). One common feature may be extrapolated from
these examples. It seems that the reaction selectivity may be
strongly influenced by the reaction medium, temperature, and
precatalyst feature. It is worth noting that the formation of 5a
has been observed by using [Rh(cod)OH]2 as a precatalyst even
under reaction conditions where an excess of arylboronic acid
is used in the presence of a large excess of water. It may be
ruled out that the formation of 5a is caused by the entropy-
driven association because its formation has not been observed
in water.27a,b On the basis of previous results reported by Hayashi
and co-workers,27d the role played by the phenylboroxine 2b in
the reaction outcome was explored (Scheme 3; Table 2).
It is presumed that phenylboronic acid 2a is in equilibrium
with arylboroxine 2b and water under reaction conditions. This
equilibrium should influence the reaction stoichiometry with
no bearing on the coupling process. By contrast, results clearly
point out the drastic effect of the triphenylboroxine 2b besides
the 1a/2b ratio, ligand, and temperature of the resulting
reaction.33 Indeed the reaction of an equimolecular amount of
1a with phenylboroxine 2b, in the presence of a rhodium-dppe
catalytic system in 1,4-dioxane/H2O at 100 °C for 2 h, gave a
45% yield of the dibutenolide derivative 5a together with the
derivative 4a (Table 2, entry 2). The formation of 5a in a better
yield was observed by reacting the boroxine 2b with excess
alkyne 1a (Table 2, entry 3). A different reactivity of boroxines33
compared to the corresponding boronic acid derivatives can be
suggested. Similarly, a drastic effect of the boron reagent has
also been reported in the nickel-catalyzed 1,2-addition of
arylboroxines to aromatic aldehydes.34 The formation of the
tributenolide derivative 6a was observed when the 1a excess
was increased (Table 2, entry 4) or in dry solvent, using 1,4-
dioxane (dried with molecular sieves). The results of Table 2
highlight the importance of the temperature, the boroxine/alkyne
ratio, and the amount of water in determining the rhodium
coming back to the catalytic cycle after it effects the dimerization
and trimerization of alkyne 1a resulting in 5a and 6a.
(28) (a) Miura, T.; Murakami, M. Chem. Commun. 2007, 217-224. (b)
Harada, Y.; Nakanishi, J.; Fujihara, H.; Tobisu, M.; Fukumoto, Y.; Chatani,
N. J. Am. Chem. Soc. 2007, 129, 5766-5761. (c) Miura, T.; Shimada, M.;
Murakami, M. Tetrahedron 2007, 63, 6131-6140. (d) Chen, Y.; Lee, C. J.
Am. Chem. Soc. 2006, 128, 15598-15599. (e) Shintani, R.; Yamagami,
T.; Hayashi, T. Org. Lett. 2006, 8, 4799-4801. (f) Kinder, R. E.;
Windenhoefer, R. A. Org. Lett. 2006, 8, 1967-1969. (g) Miura, T.;
Shimada, M.; Murakami, M. Synlett 2005, 667-669. (h) Miura, T.;
Murakami, M. Org. Lett. 2005, 7, 3339-3341. (i) Shitani, R.; Okamoto,
K.; Hayashi, T. Chem. Lett. 2005, 34, 1294-1295. (j) Matsuda, T.; Makino,
M.; Murakami, M. Chem. Lett. 2005, 34, 1416-1417. (k) Miura, T.; Sasaki,
T.; Nakazawa, H.; Murakami, M. J. Am. Chem. Soc. 2005, 127, 1390-
1391. (l) Miura, T.; Shimada, M.; Murakami, M. J. Am. Chem. Soc. 2005,
127, 1094-1095. (m) Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama,
K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54-55.
(29) NMR and GC-MS analysis showed that its regioisomeric purity is
higher than 96%.
(30) Dhondi, P. K.; Chisholm, J. D. Org. Lett. 2006, 8, 67-69.
(31) (a) Bruss, A. J.; Gelesky, M. A.; Machado, G.; Dupont, J. J. Mol.
Catal. A: Chem. 2006, 252, 212-218. (b) Bronger, R. P. J.; Bermon, J. P.;
Herwig, J.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. AdV. Synth. Catal.
2004, 346, 789-799.
(32) Wu, W.; Li, C.-J. Chem. Commun. 2003, 1668-1669.
(33) Miura, T.; Takahashi, Y.; Muratami, M. Chem. Commun. 2007,
595-597.
(34) Arao, T.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2007, 48, 4115-
4117.
J. Org. Chem, Vol. 72, No. 25, 2007 9513

Alfonsi et al.
TABLE 3.
9514 J. Org. Chem., Vol. 72, No. 25, 2007

Sequential Rh-Catalyzed Addition/Lactonization
Table 3 (Continued)
a Yields are based on products isolated by column chromatography. b Procedure A: The reaction was carried out at 100 °C in dioxane/water (10/1), using
the following molar ratios: 1:2:[Rh(cod)OH]2:dppb) 1:2:0.03:0.06. c 5a was isolated in a 9% yield. d Procedure B: The reaction was carried at 100 °C in
dioxane/water (10/1), using the following molar ratios: 1:2:Rh(acac)(C2H4)2:dppf) 1:5:0.03:0.066. e 5g was isolated in a 19% yield. f Procedure C: The
reaction was carried out at 100 °C in dioxane/water (10/1), using the following molar ratios: 1:2:[Rh(cod)OH]2:dppb) 1:5:0.03:0.06. g 5g was isolated in
a 9% yield. h 5h was isolated in a 16% yield.
J. Org. Chem, Vol. 72, No. 25, 2007 9515

Alfonsi et al.
SCHEME 4
SCHEME 5
SCHEME 6
A subsequent investigation was carried out to study the scope
of the rhodium-catalyzed alkylative lactonization; results are
summarized in Table 3.
The reactivity of various alkyl 4-hydroxy-2-alkynoates 1
bearing dialkyl, arylalkyl, diaryl- and aryl groups at the
propargyl position was studied. Interestingly, the rhodium-
catalyzed reaction of the tertiary propargylic alcohol derivatives
resulted in reversal of the regioselectivities compared to those
observed in their palladium-catalyzed process.23 Moreover, by
contrast with the results obtained in the palladium-catalyzed
alkylative lactonization of 1 with organoboronic acids, the
bulkiness of groups near the triple bond did not affect the
regioselectivity of the rhodium-catalyzed reaction, which was
directed by the ester group. Further studies35 have been described
since Pellicciari’s36 first report regarding the rhodium-catalyzed
isomerization of propargyl alcohols directly attached to an ester.
Under the reaction conditions used, the γ-hydroxy-R,â-alkynoate
1f selectively underwent the sequential rhodium-catalyzed
alkylative lactonization rather than the isomerization to the
corresponding γ-oxo-R,â-alkenoate/coupling reaction. To shed
light on this point, isomerization of 1f was attempted under basic
conditions (Scheme 4).
The base-promoted isomerization of electron-deficient pro-
pargylic alcohols to the corresponding enones and its mechanism
has been previously explored.37 The prevailing E-selectivity in
the isomerization reaction of 1f is presumably due to the
equilibration of (Z)-8 to (E)-7 in dioxane at 100 °C in the
presence of triethylamine (Et3N) as suggested in the literature.38
Subsequently, 1f afforded the formation in a 82% yield of the
two regioisomer derivatives 9-10 (9:10 ) 1:1) through a one-
flask two-step process involving Et3N-promoted isomerization
of 1f to the corresponding enone derivatives 7 and 8, followed
by rhodium-catalyzed conjugate addition of the aryl boronic acid
2a (Scheme 5). Most likely the reaction temperature is
responsible for the lack of regioselectivity control of the
rhodium-catalyzed conjugate addition step. It was previously
reported that the treatment of ethyl 4-aryl/heteroaryl-4-hydroxy-
2-butynoate with (S)-alanine and other (S)-amino acid benzyl
esters at rt in ethanol in the presence of Et3N may provide a
general, regioselective entry into N-(3-aryl/heteroaryl-1-ethoxy-
carbonyl-3-oxopropyl) (S)-amino acid esters through sequential
base-catalyzed isomerization/conjugate addition.39
Interestingly enough, the rhodium-catalyzed reaction of 1f
with 2a in the presence of Et3N in domino conditions allowed
the isolation of the 4-oxo-4-tolylbutyric acid ethyl ester 11 (15%
yield) together with the furanone 4l (27% yield) and 9-10 (7%
yield) derivatives (Scheme 6).
The one-pot isomerization/hydrogenation reaction of 4-aryl-
4-hydroxy-2-alkynoates, under basic conditions, has been previ-
ously reported to occur by means of the in situ generated
palladium hydride.37d â-Aryl40/alkyl elimination reactions on an
alkoxorhodium41 intermediate derived from tertiary propargyl
alcohol have not been observed. The formation of allenic and
propargylic arenes previously reported to occur in the palladium-
catalyzed reaction of propargylic alcohol derivatives with
arylboronic acids may also be ruled out in all examined cases.42
Finally, it is worth noting that the addition of organorhodium
intermediates onto the ester moiety of 1 was never observed
under the present reaction conditions. Both rhodium-catalyzed
intramolecular28k and intermolecular26b arylation on the carbonyl
carbon of esters have been reported. As far as organoboron
derivatives are concerned, the process tolerates aryl-/heteroaryl
boronic acids, their corresponding pinacol esters, and aryl-/
vinyltrifluoroborate salts. The latter derivatives have emerged
as promising new compounds that can overcome certain
limitations of other organoboron derivatives.43 According to the
literature,44 the yield of 4-aryl/heteroaryl/2(5H)-furanones start-
ing from pinacol ester derivatives 2f,g was lower than that
observed starting from boronic acids. According to the results
observed with the model system, the use of [RhOH(cod)]2/dppb
as the catalytic system (procedure A) accomplished the forma-
tion of the target 4-substituted-2(5H)-furanones 4 still in good
yield with excellent regioselectivity by reducing the quantity
of orgaboron reagent from 5 to 2 equiv. Multiple addition
derivatives were detected as byproducts. The best selectivity
was observed by using Rh(acac)(C2H4)2/dppf (procedure B).
Nonetheless, to achieve satisfactory results from a synthetic
(35) (a) Yamabe, H.; Mizuno, A.; Kusama, H.; Iwasawa, N. J. Am. Chem.
Soc. 2005, 127, 3248-3249. (b) Shitani, R.; Okamoto, K.; Hayashi, T. J.
Am. Chem. Soc. 2005, 127, 2872-2873.
(36) Saah, M. K. D.; Pellicciari, R. Tetrahedron Lett. 1995, 36, 4497-
(40) Nishimura, T.; Katoh, T.; Hayashi, T. Angew. Chem., Int. Ed. 2007,
46, 4937-4939.
4500.
(37) (a) Sonye, J. P.; Koide, K. J. Org. Chem. 2007, 72, 1846-1848.
(b) Sonye, J. P.; Koide, K. J. Org. Chem. 2006, 71, 6254-6257. (c) Sonye,
J. P.; Koide, K. Org. Lett. 2006, 8, 199-202. (d) Arcadi, A.; Cacchi, S.;
Marinelli, F.; Misiti, D. Tetrahedron Lett. 1988, 29, 1457-1460.
(38) Bernotas, R. C. Synlett 2004, 2165-2167.
(39) Arcadi, A.; Bernocchi, E.; Cacchi, S.; Marinelli, F.; Scarinci, A.
Synlett 1991, 177-178.
(41) Fujiwara, H.; Ogasawara, Y.; Yamaguchi, K.; Mizuno, N. Angew.
Chem., Int. Ed. 2007, 46, 5202-5204.
(42) Yoshida, M.; Gotou, T.; Ihara, M. Tetrahedron Lett. 2004, 45, 5573-
5575.
(43) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275-286.
(44) Nambo, M.; Noyori, R.; Itami, K. J. Am. Chem. Soc. 2007, 129,
8080-8081.
9516 J. Org. Chem., Vol. 72, No. 25, 2007

Sequential Rh-Catalyzed Addition/Lactonization
µmol), and phenylboronic acid (133 mg, 1.1 mmol; 2a) was added
ethyl 4-hydroxy-4-methyl-2-pentynoate (85 mg, 0.55 mmol; 1a),
1,4-dioxane (2.0 mL), and water (0.2 mL). The mixture was stirred
at 100 °C for 1 h. Subsequently, the solvent was removed by
evaporation. The residue was purified by chromatography on silica
gel (230-400 mesh), eluting with n-hexane/ethyl acetate 80:20
mixture to afford 5,5-dimethyl-4-phenyl-5H-furan-2-one 4a (92 mg,
90% yield).
General Procedure B. Typical procedure B is given for the
reaction of 4-hydroxy-4-p-tolylbute-2-ynoic acid ethyl ester 1f with
3-metoxybenzeneboronic acid 2i giving 4-(3-methoxyphenyl)-5-p-
tolyl-5H-furan-2-one 4m (entry 15, Table 3). To a mixture of Rh-
(acac)(C2H4)2 (5 mg, 19.0 µmol), 1,1′-bis(diphenylphosphino)-
ferrocene (dppf) (23 mg, 41.0 µmol), and 3-metoxybenzeneboronic
acid (478 mg, 3.15 mmol; 2i) was added 4-hydroxy-4-p-tolylbute-
2-ynoic acid ethyl ester (137 mg, 0.63 mmol; 1f), 1,4-dioxane (3.0
mL), and water (0.3 mL), and the mixture was stirred at 100 °C
for 1.5 h. Subsequently, the solvent was removed by evaporation.
The residue was purified by chromatography on silica gel (230-
400 mesh), eluting with n-hexane/ethyl acetate 90:10 mixture, to
afford 4-(3-methoxyphenyl)-5-p-tolyl-5H-furan-2-one 4m (113 mg,
80% yield).
point of view the quantity of organoboron derivative must be
increased to 5 equiv.
Conclusion
In conclusion, a new approach to the synthesis of 4-aryl/
heteroaryl/vinyl-2(5H)-furanones through a sequential regiose-
lective rhodium-catalyzed addition/lactonization reaction of alkyl
4-hydroxy-2-alkynoates with organoboron derivatives was
developed. The rhodium-catalyzed reaction of alkyl 4-hydroxy-
2-alkynoates bearing a tertiary propargylic alcohol group
resulted in reversal of the regioselectivity compared to that
observed in the palladium-catalyzed process. In addition, the
regioselective outcome of the rhodium-catalyzed reaction of
alkyl 4-hydroxy-2-alkynoates bearing a secondary propargylic
alcohol is not affected by the bulkiness of groups close to the
C-C triple bond. Moreover, the reaction is carried out under
neutral conditions. [RhOH(cod)]2/dppb was the more effective
catalytic system, but multiple addition derivatives may be
observed as side products. The organoboron derivative feature
also plays a pivotal role in determining the formation of the
multiple addition byproducts. When Rh(acac)(C2H4)2/dppf was
used as a catalytic system an excellent selectivity was achieved.
Acknowledgment. This work was financed by the Ministero
dell’Universita` e della Ricerca, Rome, and by the University
of L’Aquila.
Experimental Section
Supporting Information Available: Experimental information
including characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
General Procedure A. Typical procedure A is given for the
reaction of ethyl 4-hydroxy-4-methyl-2-pentynoate 1a with phe-
nylboronic acid 2a giving 5,5-dimethyl-4-phenyl-5H-furan-2-one
4a (entry 1, Table 3). To a mixture of [Rh(cod)OH]2 (7.4 mg, 16.0
µmol), 1,4-bis(diphenylphosphino)butane (dppb) (14 mg, 33.0
JO701629T
J. Org. Chem, Vol. 72, No. 25, 2007 9517