Synthesis of 2-alkyl- and aryl-3-ethoxycarbonyl-2,5-dihydrofurans through gold-catalyzed intramolecular hydroalkoxylation

Article abstract of DOI:10.1021/jo101474s

Treatment of a wide range of functionalized hydroxyallenic esters with 5 mol % Ph₃PAuCl and 5 mol % AgOTf in CH₂Cl₂ at 25 °C for 1 h produced selectively 2-alkyl- and aryl-3-ethoxycarbonyl-2,5- dihydrofurans in good to exc

Full text of DOI:10.1021/jo101474s

pubs.acs.org/joc
Hoffmann-Roder developed a novel gold-catalyzed cycliza-
Synthesis of 2-Alkyl- and Aryl-3-ethoxycarbonyl-2,5-
dihydrofurans through Gold-Catalyzed
Intramolecular Hydroalkoxylation
tion reaction of highly functionalized R-hydroxyallenes to
the corrersponding 2,5-dihydrofurans.3 On the basis of these
results, valuable cyclization reactions of a variety of hydro-
xyallenes4 and mercaptoallenes5 were demonstrated. We
described a selective synthesis of 2,5-dihydrofuran having
two substituents at the 2- and 3-positions via 5-endo intra-
molecular hydroalkoxylation of allenyne-1,6-diols catalyzed
by gold.6 Recently, the R-hydroxybenzyl allenic esters pos-
sessing hydroxy and methoxy group as electron-donating
group were cyclized to ethyl 2-naphthoates through gold-
catalyzed 6-endo intramolecular hydroarylation.7 However,
an efficient synthetic method for 2,5-dihydrofurans is needed
to overcome the difficult introduction of specific substituents
or the requirements of multistep synthesis. Furthermore,
many synthetic methods required preorganized hydroxyal-
lenes possessing functional groups on the 2- and 3-positions.
Therefore, an alternate method having various functional
group variations on the 2,5-dihydrofuran nucleus is highly
desirable to study structural and biological activity. Espe-
cially, a direct preparation of 3-ethoxycarbonyl-2,5-dihydro-
furans from hydroxyallenes through intramolecular hydro-
alkoxylation is more challenging because of their reactivity
as a Michael acceptor. In the pursuit of an ongoing medicinal
chemistry program, we have been recently interested in
introducing a wide range of substituents on the 2- and
3-positions, especially an ethoxycarbonyl group on the
3-position, of 2,5-dihydrofuran. In this respect, we envi-
sioned that functionalized R-hydroxy allenic esters might
be cyclized to functionalized 2,5-dihydrofurans through
cyclization. In this paper, we report an efficient synthesis
of 2-alkyl- and aryl-3-ethoxycarbonyl-2,5-dihydrofurans
through gold-catalyzed intramolecular hydroalkoxylation
by the 5-endo mode (Scheme 1).
Dahan Eom, Dongjin Kang, and Phil Ho Lee*
Department of Chemistry, Institute for Molecular Science and
Fusion Technology, Kangwon National University,
Chuncheon 200-701, Republic of Korea
phlee@kangwon.ac.kr
Received July 27, 2010
Treatment of a wide range of functionalized hydroxyal-
lenic esters with 5 mol % Ph3PAuCl and 5 mol % AgOTf
in CH2Cl2 at 25 °C for 1 h produced selectively 2-alkyl-
and aryl-3-ethoxycarbonyl-2,5-dihydrofurans in good to
excellent yield through intramolecular hydroalkoxylation
by a 5-endo mode.
First, the functionalized R-hydroxyaryl allenic esters
were selectively prepared from reaction of aldehydes with
Because functionalized 2,5-dihydrofuran is an important
structural motif frequently found in natural products and
has been used as an essential skeleton in pharmaceutics,
development of efficient and versatile synthetic methods for
these compounds has been continuously required,1 and
many synthetic strategies for functionalized 2,5-dihydrofur-
ans have been reported in the literature.2 First, Krause and
(2) (a) Deng, Y.; Shi, Y.; Ma, S. Org. Lett. 2009, 11, 1205. (b) Brasholz,
M.; Ressig, H.-U. Angew. Chem., Int. Ed. 2007, 46, 1634. (c) Hyland, C. J. T.;
Hegedus, L. S. J. Org. Chem. 2006, 71, 8658. (d) Buzas, A.; Istrate, F.;
Gagosz, F. Org. Lett. 2006, 8, 1957. (e) Buzas, A.; Istrate, F.; Gagosz, F. Org.
Lett. 2006, 8, 1957. (f) Kim, J. M.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron
Lett. 2004, 45, 2805. (g) Yang, C.; Murray, W. V.; Wilson, L. J. Tetrahedron
Lett. 2003, 44, 1783. (h) Chen, J.; Song, Q.; Li, P.; Guan, H.; Jin, X.; Xi, Z.
Org. Lett. 2002, 4, 2269. (i) Xi, C.; Kotora, M.; Takahashi, T. Tetrahedron
Lett. 1999, 40, 2375. (j) Tiecco, M.; Testaferri, L.; Santi, C. Eur. J. Org. Chem.
1999, 797. (k) Kim, S.; Kim, K. H. J. Chem. Soc., Perkin Trans. 1 1997, 1095.
(l) Paolucci, C.; Musiani, L.; Venturelli, F.; Fava, A. Synthesis 1997, 1415.
(m) Shieh, S.-J.; Fan, J.-S.; Chandrasekharam, M.; Liao, F.-L.; Wang, S.-L.;
Liu, R.-S. Organometallics 1997, 16, 3987. (n) Hojo, M.; Ishbashi, N.;
Hosomi, A. Synlett 1996, 234. (o) Shieh, S.-J.; Tang, T.-C.; Lee, J.-S.; Lee,
G.-H.; Peng, S.-M.; Liu, R.-S. J. Org. Chem. 1996, 61, 3245. (p) Yamada, O.;
Ogasawara, K. Synlett 1995, 427. (q) Marshall, J. A.; Yu, B. J. Org. Chem.
1994, 59, 324. (r) Hojo, M.; Ohkuma, M.; Ishibashi, N.; Hosomi, A.
Tetrahedron Lett. 1993, 34, 5943. (s) Marshall, J. A.; Pinney, K. G. J. Org.
Chem. 1993, 58, 7180.
(1) (a) Modern Allene Chemistry; Krause, N.; Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, Germany, 2004; Vols. 1 and 2. (b) Yamamoto, Y.;
Takuma, R.; Hotta, T.; Yamashita, K. J. Org. Chem. 2009, 74, 4324. (c)
Bongers, N.; Krause, N. Angew. Chem., Int. Ed. 2008, 47, 2178. (d) Deng, Y.;
Yu, Y.; Ma, S. J. Org. Chem. 2008, 73, 585. (e) Yeom, H.-S.; Shin, S.
Tetrahedron Lett. 2007, 48, 4817. (f) Hashmi, A. S. K.; Blanco, M. C.;
Fischer, D.; Bats, J. W. Eur. J. Org. Chem. 2006, 1387. (g) Alcaide, B.;
Almendros, P.; Rodrıguez-Acebes, R. Chem.;Eur. J. 2005, 11, 5708. (h) Ma,
S.; Gao, W. J. Org. Chem. 2002, 67, 6104. (i) Ma, S.; Gao, W. Tetrahedron
Lett. 2000, 41, 8933. (j) Carda, M.; Castillo, E.; Rodrıguez, S.; Uriel, S.;
Marco, J. A. Synlett 1999, 1639. (k) Saimoto, H.; Yasui, M.; Ohrai, S.;
Oikawa, H.; Yokoyama, K.; Shigemasa, Y. Bull. Chem. Soc. Jpn. 1999, 72,
279. (l) Darcel, C.; Bruneau, C.; Albert, M.; Dixneuf, P. H. Chem. Commun.
1996, 919. (m) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60, 5966. (n)
Marshall, J. A.; Yu, R. H.; Perkins, J. F. J. Org. Chem. 1995, 60, 5550. (o)
Shigemasa, Y.; Yasui, M.; Ohrai, S.; Sasaki, M.; Sashiwa, H.; Saimoto, H.
J. Org. Chem. 1991, 56, 910. (p) Walkup, R. D.; Park, G. Tetrahedron Lett.
1987, 28, 1023. (q) Nikam, S. S.; Chu, K. H.; Wang, K. K. J. Org. Chem. 1986,
51, 745. (r) Sato, F.; Kanbara, H.; Tanaka, Y. Tetrahedron Lett. 1984, 25,
5063. (s) Olsson, L. I.; Claesson, A. Synthesis 1979, 743.
(3) (a) Hoffmann-Roder, A.; Krause, N. Org. Lett. 2001, 3, 2537.
(b) Krause, N.; Hoffmann-Roder, A.; Cansius, J. Synthesis 2002, 1759.
(c) Aksin, O.; Krause, N. Adv. Synth. Catal. 2008, 350, 1106. (d) Poonoth,
M.; Krause, N. Adv. Synth. Catal. 2009, 351, 117.
(4) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485.
(5) Morita, N.; Krause, N. Angew. Chem., Int. Ed. 2006, 45, 1897.
(6) (a) Kim, S.; Lee, P. H. Adv. Synth. Catal. 2008, 350, 547. (b) Kim, S.;
Kang, D.; Shin, S.; Lee, P. H. Tetrahedron Lett. 2010, 51, 1899.
(7) Park, C.; Lee, P. H. Org. Lett. 2008, 10, 3359.
DOI: 10.1021/jo101474s
r
Published on Web 10/13/2010
J. Org. Chem. 2010, 75, 7447–7450 7447
2010 American Chemical Society

Eom et al.
JOCNote
TABLE 1. Synthesis of 2-Aryl-3-ethoxycarbonyl-2,5-dihydrofuran via Gold-Catalyzed Cyclization
entry
catalyst
5 mol % AuCl3
Ar
time (h)
yield (%)a
1
2
3
4
5
6
7
8
Ph (a)
Ph
Ph
15
10
1
1
1
1
1
1
15
30b
80
5 mol % AuCl3/15 mol %AgOTf
5 mol % Ph3PAuCl/5 mol % AgOTf
5 mol % Ph3PAuCl/5 mol % AgOTf
5 mol % Ph3PAuCl/5 mol % AgBF4
5 mol % Ph3PAuCl/5 mol % AgAsF6
5 mol % Ph3PAuCl/5 mol % AgSbF6
5 mol % Ph3PAuCl/5 mol % AgPF6
3-MeO-C6H4 (b)
3-MeO-C6H4
3-MeO-C6H4
3-MeO-C6H4
3-MeO-C6H4
78 (3)c (9)d
32 (10)c (40)d
50 (5)c (27)d
33 (9)c (35)d
68 (3)c (14)d
aIsolated yield. bEthyl 2-ethynyl-3-phenylpropenoate. cEthyl 5-methoxy-2-naphthoate. dEthyl 7-methoxy-2-naphthoate.
SCHEME 1. Selective Synthesis of 2-Alkyl- and Aryl-3-ethoxy-
carbonyl-2,5-dihydrofurans
hydroxyallenes (Table 2). Reaction of ethyl 2-hydroxy-
methyl-2,3-butadienoate (1c) with 5 mol % Ph3PAuCl and
5 mol % AgOTf provided 3-ethoxycarbonyl-2,5-dihydrofur-
an (2c) in 70% yield by the 5-endo mode (entry 1). Under the
optimum reaction conditions, various hydroxyallenes 1d, 1e,
and 1f obtained from aliphatic aldehydes such as n-butanal,
hydrocinnamaldehyde, and cyclohexancarbaldehyde were
converted to 2-alkyl-3-ethoxycarbonyl-2,5-dihydrofuran
catalyzed by gold in good to excellent yields (entries 2, 3,
and 4). Next, intramolecular hydroalkoxylation of a wide
range of hydroxyallenes obtained from aromatic aldehydes
were examined (entries 5-11). The presence of 4-chloro and
2-iodo groups on the phenyl ring did not affect either the
reaction rate or product yield (entries 5 and 6). Hydroxyallenes
(1i and 1j) having a carbonyl group such as 4-acetyl and
4-ethoxycarbonyl on the aromatic ring were smoothly con-
verted to the corresponding dihydrofurans 2i and 2j in 89%
and 97% yield, respectively (entries 7 and 8). Compound 1k
generated from 4-nitrobenzaldehyde was treated with gold
catalyst to produce 2k in 85% yield (entry 9). In the case of
hydroxyallenes derived from aromatic aldehydes possessing
a methyl group as an electron-donating group, yield of
product was low (2l, 49% and 2m, 28%). Therefore,
10 mol % Ph3PAuCl and 10 mol % AgOTf was required to
complete the intramolecular hydroalkoxylation with the
same efficiency. It was gratifying to selectively obtain 2,5-
dihydrofuran 2l possessing a 4-methyl group in 83% yield
(entry 10). When hydroxyallene 1m bearing three methyl
groups was subjected to gold catalyst, the corresponding
3-ethoxycarbonyl-2,5-dihydrofuran 2m was selectively obtained
in 77% yield (entry 11). However, when 1b was treated with gold
catalyst, ethyl 2-naphthoate was contaminated in 12% yield
through intramolecular hydroarylation by the 6-endo mode,
indicating that the reaction pathway (hydroalkoxylation by the
5-endo mode vs hydroarylation by the 6-endo mode) was divided
between the methyl and methoxy groups.
organoindium reagent generated in situ from indium and
ethyl 4-bromobutynoate.8 Intramolecular hydroalkoxyla-
tion 1a and 1b with gold catalyst was initially examined
(Table 1). Treatment of 1a with 5 mol % AuCl3 afforded 2a
in 15% yield (entry 1). Although treatment of 1a with 5 mol
% AuCl3 and 15 mol % AgOTf gave ethyl 2-ethynyl-3-
phenylpropenoate in 30% yield (entry 2), use of 5 mol %
Ph3PAuCl and 5 mol % AgOTf gave 5-endo intramolecular
hydroalkoxylated product 2a in 80% yield in CH2Cl2 at 25 °C
for 1 h (entry 3). Allenic ester 1b having 3-methoxyphenyl
group was treated with 5 mol % of Ph3PAuCl and 5 mol % of
AgBF4 to give ethyl 5-methoxy- and 7-methoxy-2-naphthoate
in 10% and 40% yields, respectively, through intramolecular
hydroarylation by the 6-endo mode and 2b in 32% yield
through intramolecular hydroalkoxylation by the 5-endo mode
(entry 5). To suppress hydroarylation and increase hydroalk-
oxylation, a variety of silver salts such as AgOTf, AgAsF6,
AgSbF6, and AgPF6 were examined (entries 4, 6, 7, and 8). Of
the reactions screened, the best results were obtained from
treatment of 1b with 5 mol % Ph3PAuCl and 5 mol % AgOTf
in CH2Cl2 at 25 °C for 1 h under nitrogen atmosphere, producing
selectively 2b in 78% yield by the 5-endo mode together with
ethyl 2-naphthoate in 12% yield by the 6-endo mode (entry 4).
To demonstrate the efficiency and scope of the present
method, we applied this catalytic system to a wide range of
Next, 2-fold intramolecular hydroalkoxylations were
briefly examined (Scheme 2). 1,4-Diformylbenzene was trea-
ted with organoindium reagent generated in situ from ethyl
4-bromobutynoate (1.5 equiv) and indium (1 equiv) in the
presence of lithium iodide (3 equiv) to produce selec-
tively hydroxyallene 2n in 77% yield, which was smoothly
converted to 2-(4-formylphenyl)-3-ethoxycarbonyl-2,5-dihy-
drofuran (2o) in 85% yield by the 5-endo mode. Again,
indium-mediated allenyl addition to 2o to afford 2p in 60%
(8) MacInnes, I.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1987, 1077.
7448 J. Org. Chem. Vol. 75, No. 21, 2010

Eom et al.
JOCNote
TABLE 2. Synthesis of 3-Ethoxycarbonyl-2,5-dihydrofurans Having 2-Alkyl and Aryl Group via Gold-Catalyzed Cyclization of Hydroxyallene
a10 mol % Ph3PAuCl and 10 mol % AgOTf was used.
SCHEME 2. Synthesis of 1,4-Bis(3-ethoxycarbonyl-2,5-dihy-
drofuran-2-yl)benzene Catalyzed by Gold
yield (dr = 2:1) and sequential gold-catalyzed intramolecu-
lar hydroalkoxylation by the 5-endo mode produced 1,4-
bis(3-ethoxycarbonyl-2,5-dihydrofuran-2-yl)benzene (2q) in
76% yield (dr = 2:1). When 1,4-diformylbenzene was treated
with In (2 equiv), lithium iodide (6 equiv), and ethyl 4-bro-
mobutynoate (3 equiv) for 2-fold allenylation, the desired
diallenyl compound was produced in 18% yield together
with 2n in 70% yield.
In summary, we developed an efficient synthetic method
of 2-alkyl- and aryl-3-ethoxycarbonyl-2,5-dihydrofurans
through gold-catalyzed intramolecular hydroalkoxylation
of hydroxyallenes by a 5-endo mode. This method would
pave a new way to synthetically valuable processes of a wide
range of functionalized 2,5-dihydrofuran derivatives.
Experimental Section
3-Ethoxycarbonyl-2,5-dihydrofuran (2c). To a solution of
5 mol % triphenylphosphine gold chloride (12.4 mg, 0.025
mmol) and 5 mol % silver trifluoromethanesulfonate (6.4 mg,
0.025 mmol) in dry dichloromethane (2.5 mL) under nitrogen
atmosphere was added ethyl 2-hydroxymethyl-2,3-butadieno-
ate (71.1 mg, 0.5 mmol). The reaction mixture was stirred at
room temperature for 1 h. Then, the reaction mixture was
filtered and concentrated under reduced pressure. The residue
J. Org. Chem. Vol. 75, No. 21, 2010 7449

Eom et al.
JOCNote
was purified by flash column chromatography on silica gel
(ethyl acetate:hexane =1:7) to give 3-ethoxycarbonyl-2,5-dihy-
drofuran (49.8 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 6.83
(s, 1H), 4.81(s, 4H), 4.23(q, J= 7.11 Hz, 2H), 1.31 (t, J=7.11Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 162.5, 137.8, 133.1, 76.2,
74.1, 60.7, 14.2; IR (film) 3432, 2924, 1716, 1644, 1376, 1267,
1111, 1065, 895 cm-1; HRMS (EI): m/z calcd for C7H10O3
142.0630, found 142.0635.
Korea government (MEST) (2009-0087013). This work was
supported by the second phase of the Brain Korea 21
Program in 2009. Following are results of a study on the
“Human Resource Development Center for Economic Re-
gion Leading Industry” Project, supported by MEST and
NRF. Dr. Sung Hong Kim at the KBSI (Daegu) is thanked
for obtaining the MS data. The NMR data were obtained
from the central instrumental facility in Kangwon National
University.
Acknowledgment. Dedicated to Professor Jae Jung Ko on
the occasion of his 60th birthday. This work was supported
by the NRL Program funded by the Ministry of Education,
Science & Technology (MEST) and by the National Re-
search Foundation of Korea (NRF) grant funded by the
Supporting Information Available: Experimental procedure
and spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
7450 J. Org. Chem. Vol. 75, No. 21, 2010