Base-mediated tandem reaction consisting of an acyl shift strategy leading to 4,5-disubstiuted furan-2(5H)-ones

Article abstract of DOI:10.1002/adsc.201000762

The first example of the synthesis of 4,5-disubstiuted furan-2(5H)-ones by base-mediated tandem acyl shift/cyclization/decarbonylation reactions of aroylmethyl 2-alkynoates has been developed. This new and inexpensive tandem route allows both a C-O bond a

Full text of DOI:10.1002/adsc.201000762

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DOI: 10.1002/adsc.201000762
Base-Mediated Tandem Reaction Consisting of an Acyl Shift
Strategy Leading to 4,5-Disubstiuted Furan-2(5H)-ones
Yong Lei,a Zhi-Qiang Wang,a Ye-Xiang Xie,a Shang-Ci Yu,a Bo-Xiao Tang,a
and Jin-Heng Lia,b,*
a
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal
University, Changsha 410081, Peopleꢀs Republic of China
Fax : (+86)-731-8887-2101; phone: (+86)-731-8887-2101; e-mail: jhli@hunnu.edu.cn
College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, Peopleꢀs Republic of China
b
Received: October 11, 2010; Revised: November 23, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000762.
Abstract: The first example of the synthesis of 4,5-
disubstiuted furan-2(5H)-ones by base-mediated
tandem acyl shift/cyclization/decarbonylation reac-
tions of aroylmethyl 2-alkynoates has been devel-
oped. This new and inexpensive tandem route
allows both a C O bond and a Csp Csp bond
forming in one step involving an unprecedented
acyl rearrangement process.
The acyl shift is an important method in organic
chemistry,[7,8] particularly in peptide chemistry[7] and
carbohydrate chemistry.[8] Despite these achieve-
ments, the acyl shift among enol esters remains less
explored.[7,8] Here, we report a novel tandem route,
involving an acyl shift/cyclization/decarbonylation
process, to furan-2(5H)-ones (Scheme 1).
During our ongoing studies on the reaction be-
tween a-sp3-carbons of ketones with alkynes,[9] we
found an interesting transformation: 2-oxo-2-phenyl-
ethyl 3-phenylpropiolate (1a) underwent an unprece-
dented decarbonylation process with 2 equivalents of
KOAc to afford 4,5-diphenylfuran-2(5H)-one (2a) in
a 10% yield (entry 1, Table 1). We were pleased to
3
2
À
À
À
Keywords: acyl shift; base; C C bond formation;
cyclization; decarbonylation; furan-2(5H)-ones
Tandem reactions have become a powerful tool for ef- find that the yield was enhanced to 46% using
ficient construction of important molecules from 4 equivalents of KOAc (entry 2), and 5 equivalents of
readily accessible intermediates in organic synthesis.[1] KOAc gave the identical results (entry 3). It is note-
Utilization of substrates with several common func- worthy that the reaction cannot take place without
tional groups, such as a C C bond and diverse car- bases (entry 4).[10] The results demonstrated that the
ꢀ
bonyls (ester, ketone and/or aldehyde), should make reaction temperature affected the reaction (entries 2,
the tandem reaction much more attractive both fun- 5 and 6). Substrate 1a could be consumed completely
À
damentally and synthetically because a C O bond at 1208C in 5 h, affording the identical yield to that at
and a remote carbon nucleophile bond can be 1008C (entry 5). However, the activity of substrate 1a
À
formed simultaneously. Based on these substrates, the was lowered sharply at 808C (entry 6). To our delight,
tandem synthesis of furan-2(5H)-ones,[2–5] important the yield was increased to 66% in anhydrous MeCN
units in various natural products and biologically medium, and to 70% in anhydrous MeCN combined
active compounds,[6] through a transition metal-cata- with 4ꢁ molecular sieve (entries 7 and 8).
lyzed[3,4] or an acid-mediated process[2c,5] has been re-
ported. However, furan-2(5H)-one backbones are
often restricted to those methods that utilize an acid
(or its derivatives) for the intramolecular oxygen-nu-
cleophile addition with an alkyne. Therefore, the de-
velopment of new valuable tandem strategies, involv-
ing a carbon-nucleophile addition process with al-
kynes, for preparing this class of compounds with a
new structural feature ready for further elaboration is
still interesting.
Scheme 1. Base-mediated tandem reaction consisting of an
acyl shift strategy.
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Yong Lei et al.
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Table 1. Screening for reaction conditions.[a]
With the optimal reaction conditions in hand, we
examined the substrate scope (Table 2). It was pleas-
ing to find that several functional groups, such as
methyl, chloro, fluoro, bromo, methoxy, and nitro, on
the aryl ring of the 2-oxo-2-arylethyl moiety were tol-
erated, but the properties of these groups affected the
yields: the weakly electron-withdrawing groups (Br or
Cl) afforded good yields, whereas both electron-do-
nating and strongly electron-withdrawing groups low-
ered the yield (entries 1–8). While treatment of
methyl-substituted substrate 1b, for instance, with
KOAc gave the target product 2b in 56% yield
(entry 1), substrate 1e bearing a bromo group afford-
ed 88% yield (entry 4). Although propiolate 1h with a
nitro group was consumed completely in 2 h, the yield
was reduced to 48% (entry 7). Gratifyingly, substrates
1j–1m, bearing methyl, methoxy or chloro groups on
the aryl ring of the 3-arylpropiolate moiety, were also
suitable for the reaction under the optimal conditions
(entries 9–12). For example, substrates 1j and 1m,
Entry KOAc (equiv.) T [oC] Time [h] Isolated yield [%]
1
2
3
4
5
6
2
4
5
0
4
4
4
4
100
100
100
100
120
80
24
24
24
24
5
24
24
24
10
46
47
0
48
trace
66
70
7[b]
8[b,c]
100
100
[a]
Reaction conditions: 1a (0.3 mmol), base and MeCN
(2 mL).
In anhydrous MeCN (2 mL).
4ꢁ molecular sieve (200 mg).
[b]
[c]
Table 2. KOAc-mediated synthesis of furan-2(5H)-ones.[a]
Entry
Substrate 1
Product 2
t [h]
Yield [%][b]
1
2
3
R=Me
R=Cl
R=F
1b
1c
1d
R=Me
R=Cl
R=F
2b
2c
2d
42
10
10
56
82
63
4
5
6
7
8
1e
1f
1g
1h
1i
2e
2f
2g
2h
2i
10
70
10
2
88
48
81
48
67
14
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Base-Mediated Tandem Reaction Consisting of an Acyl Shift Strategy
Table 2. (Continued)
Entry
Substrate 1
Product 2
t [h]
Yield [%][b]
9
10
11
R=Me
R=MeO
R=Cl
1j
1k
1l
R=Me
R=MeO
R=Cl
2j
2k
2l
8
8
5
83
80
74
12
13
1m
1n
2m
2n
8
8
66
57
14
15
1o
1p
2o
2p
10
18
59
55
16
17
1q
1r
2q
2r
7
8
38
47
18
1s
1t
2s
2t
5
50
19
20
trace
[a]
Reaction conditions: 1a (0.3 mmol), anhydrous KOAc (4 equiv.), 4ꢁ molecular sieve (200 mg) and anhydrous MeCN
(2 mL) at 1008C.
Average isolated yield of two runs.
[b]
bearing a para- or an ortho-methyl group, underwent
Notably, substrate 1u, having a methyl group on the
the reaction with KOAc smoothly in 83% and 66% a-position of the carbonyl moiety, afforded two prod-
yields, respectively (entries 9 and 12). It was noted ucts: a cyclization/decarbonylation product 2a and a
that the reaction of thiophen-2-yl substrate 1n was cyclization product 3u [Eq (1), Scheme 2]. Interest-
successfully run under the same conditions (entry 13). ingly, product 3u could be transferred to product 2a
For the reactions of aliphatic alkynes 1o or 1p, moder- under fresh basic conditions. No cross-reacted prod-
ate yields were still achieved (entries 14 and 15). In- ucts were observed by GC-MS analysis when sub-
terestingly, vinyl ketones 1q–1s were also suitable for strates 1a and 1n were simultaneously reacted with
the reaction resulting the corresponding (Z)-5-ethyli- KOAc in one-pot.[11] The above results suggest that
denefuran-2
ACHTUNGTRENNUNG(5H)-ones 2q–2s in moderate yields (en- the reaction proceeds via an intramolecular process,
tries 16–18). However, 2-oxopropyl 3-phenylpropio- and the decarbonylation step took place after the cy-
late (2t) has no activity under the standard conditions
ACHTUNGTRENNUNG
(entry 19).
Adv. Synth. Catal. 2011, 353, 31 – 35
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Yong Lei et al.
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Scheme 2. Control experiments.
Scheme 3. Possible mechanism.
(2) and (4)]. Moreover, no deuterated product 5 was the mechanism, we deduce that aryl groups on the a-
observed using CD3CO2K and CD3CN, suggesting the position of the ketone can stabilize the anionic inter-
transfer of the proton is not from the base and solvent mediate D by an electron effect; however, alkyl
[Eq. (3)]. Based on these results, we deduce that the groups without this effect result in no reaction.
transfer of the proton is from both substrate and
water [Eqs. (2) and (3)].
The present results show that molecular sieve could
improve the reaction in terms of yields. The reason
Consequently, a possible mechanism was proposed may be that molecular sieve can absorb water from
as outlined in Scheme 3. Reaction of substrate 1 with the reaction system and restrain hydrolysis of the
KOAc affords intermediate A. Intermediate A under- alkyne.
goes acyl shift to yield intermediate B,[8] followed by
In summary, we have described a novel method for
cyclization to give intermediate 3. Intermediate 3 is the synthesis of furan-2(5H)-ones by base-mediated
not stable, and undergoes the decarbonylation/proto- tandem acyl shift/cyclization/decarbonylation reac-
nation reaction to afford the target products 2. We do tions of aroylmethyl 2-alkynoates. This novel and in-
not rule out another mechanism including the retro- expensive tandem route allows the construction of
3
Claisen-type rearrangement,[11] followed by deproto- some new bonds, including a C O bond and a Csp
nation with base to afford intermediate D. Based on
À
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Adv. Synth. Catal. 2011, 353, 31 – 35

Base-Mediated Tandem Reaction Consisting of an Acyl Shift Strategy
Csp2 bond, in one step. Work to extend this transfor-
mation in organic synthesis is currently underway.
2002, 2324; f) M. V. N. De Souza, Mini-Rev. Org. Chem.
2005, 2, 139.
[3] Pd: a) A. Arcadi, A. Burini, S. Cacchi, M. Delmastro,
F. Marinelli, B. R. Pietroni, J. Org. Chem. 1992, 57, 976;
b) X. Lu, X. Huang, S. Ma, Tetrahedron Lett. 1993, 34,
5963; c) A. Arcadi, S. Cacchi, G. Fabrizi, F. Marinelli,
Synlett 1993, 65; d) R. Rossi, F. Bellina, M. Biagetti, L.
Mannina, Tetrahedron Lett. 1998, 39, 7599; e) S. Rous-
set, M. Abarbri, J. Thibonnet, A. DuchÞne, J.-L. Par-
rain, Org. Lett. 1999, 1, 701; f) E. Negishi, A. Alimarda-
nov, C. Xu, Org. Lett. 2000, 2, 65; g) S. Ma, Z. Gu, J.
Am. Chem. Soc. 2005, 127, 6182; h) Z. Gu, K. Wang,
W. Shu, S. Ma, J. Am. Chem. Soc. 2007, 129, 10948;
Ag: i) J. Castafier, J. Pascual, J. Chem. Soc. 1958, 3962;
j) F. Serratosa, Tetrahedron 1961, 185; Hg: k) H. Saimo-
to, M. Shinoda, S. Matsubara, K. Oshima, T. Hiyama,
H. Nozaki, Bull. Chem. Soc. Jpn. 1983, 56, 3088; Au:
l) Y. Liu, F. Song, S. Guo, J. Am. Chem. Soc. 2006, 128,
11332; Rh: m) M. Alfonsi, A. Arcadi, M. Chiarini, F.
Marinelli, J. Org. Chem. 2007, 72, 9510; Cu: n) S.
Inack-Ngi, R. Rahmani, L. Commeiras, G. Chouraqui,
J. Thibonnet, A. Duchene, M. Abarbri, J.-L. Parrain,
Adv. Synth. Catal. 2009, 351, 779.
Experimental Section
Typical Experimental Procedure for Base-Mediated
Tandem Reaction Consisting of an Acyl Shift
Strategy
A mixture of substrate 1 (0.3 mmol), anhydrous KOAc
(4 equiv.), 4ꢁ molecular sieve (100 mg) and anhydrous
MeCN (2 mL) was stirred in a Schlenk tube at 1008C (oil
bath temperature) under an argon atmosphere until com-
plete consumption of starting material as monitored by TLC
and GC-MS analysis. Then the mixture was filtered through
a column, washed with diethyl ether, and evaporated under
vacuum. The residue was purified by flash column chroma-
tography (hexane/ethyl acetate) to afford the pure product
2.
4,5-Diphenylfuran-2(5H)-one (2a):[12] Yellow solid, mp
1
149–1518C (uncorrected); H NMR (500 MHz, CDCl3): d=
7.38–7.42 (m, 2H), 7.31–7.36 (m, 8H), 6.55 (d, J=1.5 Hz,
1H), 6.33 (d, J=1.5 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d=172.6, 165.8, 134.9, 131.3, 129.7 (2C), 129.2, 129.0, 127.9,
127.6, 114.7, 84.4; IR (KBr): n=1748 cmÀ1; LR-MS (EI,
70 eV): m/z (%)=236 (M+, 44), 207 (15), 131 (34), 102
(100), 77 (19).
[4] B. G. Van den Hoven, B. ElAli, H. Alper, J. Org.
Chem. 2000, 65, 4131.
[5] Y. S. Rao, R. Filler, Tetrahedron Lett. 1975, 16, 1457.
[6] For selected papers, see: a) S. P. Brown, N. C. Goodwin,
D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125,
1192; b) E. Lattmann, D. C. Billington, C. A. Langley,
Drug Des. Discovery 1999, 16, 243; c) M. Pour, M.
ˇ
ˇ
ˇ
Spulꢃk, V. Balsꢃnek, J. Kunes, V. Buchta, K. Waisser,
Bioorg. Med. Chem. Lett. 2000, 10, 1893; d) S. Manfre-
dini, S. Vertuani, B. Manfredi, G. Rossoni, G. Calviello,
P. Palozza, Bioorg. Med. Chem. Lett. 2000, 8, 2791;
Acknowledgements
We thank the Scientific Research Fund of Hunan Provincial
Education Department (Nos. 08C582 and 08A037), and Na-
tional Natural Science Foundation of China (No. 20872112)
for financial support.
ˇ
e) M. Pour, M. Spulꢃk, V. Buchta, P. Kubanovꢃ, M.
ˇ
Voprsꢃlovꢃ, V. Wsꢄl, H. Fꢃkovꢃ, P. Koudelka, H.
Pourovꢃ, R. Schiller, J. Med. Chem. 2001, 44, 2701; f) P.
Vasanthanathan, M. Lakshmi, B. Arockia, A. K. Gupta,
S. G. Kaskhedikar, Chem. Pharm. Bull. 2006, 54, 583;
g) T. Hosoe, T. Iizuka, S. Komai, D. Wakana, T. Itaba-
shi, K. Nozawa, K. Fukushima, K. Kawai, Phytochemis-
try 2005, 66, 2776.
References
[1] For selected reviews, see: a) P. J. Parsons, C. S. Penkett,
A. J. Shell, Chem. Rev. 1996, 96, 195; b) L. F. Tietze,
Chem. Rev. 1996, 96, 115; c) K. C. Nicolaou, T. Montag-
non, S. A. Snyder, Chem. Commun. 2003, 551; d) A.
Ajamian, J. L. Gleason, Angew. Chem. 2004, 116, 3842;
Angew. Chem. Int. Ed. 2004, 43, 3754; e) J.-C. Wasilke,
S. J. Obrey, R. T. Baker, G. C. Bazan, Chem. Rev. 2005,
105, 1001; f) D. Enders, C. Grondal, M. R. Huttl,
Angew. Chem. 2007, 119, 1590; Angew. Chem. Int. Ed.
2007, 46, 1570; g) K. C. Nicolaou, D. J. Edmonds, P. G.
Bulger, Angew. Chem. 2006, 118, 7292; Angew. Chem.
Int. Ed. 2006, 45, 7134; h) N. T. Patil, Y. Yamamoto,
Chem. Rev. 2008, 108, 3395.
[2] For reviews on the synthesis of furan-2(5H)-ones, see:
a) Y. S. Rao, Chem. Rev. 1976, 76, 625; b) D. W. Knight,
Contemp. Org. Synth. 1994, 1, 287; c) E. Negishi, M.
Kotora, Tetrahedron 1997, 53, 6707; d) R. Bruckner,
Curr. Org. Chem. 2001, 5, 679; e) N. B. Carter, A. E.
Nadany, J. B. Sweeney, J. Chem. Soc. Perkin Trans. 1
[7] H. Paulus, Chem. Soc. Rev. 1998, 27, 375.
[8] a) W. A. Bonner, J. Org. Chem. 1959, 24, 1388; b) R. W.
Binkley, Modern carbohydrate chemistry, Marcel
Dekker, Inc., New York, 1988, p 143; Et3N: c) H. G.
Liu, C. S. Wu, J. F. Wang, D. Y. Yang, Tetrahedron Lett.
2003, 44, 3137; Pt: d) B. G. Pujanauski, B. A. B. Prasad,
R. Sarpong, J. Am. Chem. Soc. 2006, 128, 6786.
[9] Z.-Q. Wang, Y. Liang, Y. Lei, M.-B. Zhou, J.-H. Li,
Chem. Commun. 2009, 5242.
[10] See the Supporting Information for the detailed data
[Table S1 and Eq. (S1)].
[11] a) L. Claisen, Ber. Dtsch. Chem. Ges. 1912, 45, 3157;
b) M. Hiersemann, U. Nubbemeyer, The Claisen Rear-
rangement, Wiley-VCH, Weinheim, 2007; c) S. J.
Rhoads, N. R. Raulins, Org. React. 1975, 22, 1; d) F. E.
Ziegler, Chem. Rev. 1988, 88, 1423.
[12] I. Sapountzis, W. Dohle, P. Knochel, Chem. Commun.
2001, 2068.
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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