Phosphine-catalyzed [3 + 2] annulations of γ-functionalized butynoates and 1 C,3 O-bisnucleophiles: Highly selective reagent-controlled pathways to polysubstituted furans

Article abstract of DOI:10.1021/ol200940a

In this paper, a reagent-controlled [3 + 2] annulation of γ-functionalized butynoates 1 and 1C,3O-bisnucleophiles 2 is reported, which leads to three distinct furan skeletons 3-5. A PPh₃ catalyst preferentially attached the β-position of 1a, fa

Full text of DOI:10.1021/ol200940a

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3068–3071
Phosphine-Catalyzed [3 þ 2] Annulations
of γ-Functionalized Butynoates and
1C,3O-Bisnucleophiles: Highly Selective
Reagent-Controlled Pathways to
Polysubstituted Furans
Jian Hu, Yabing Wei, and Xiaofeng Tong*
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China
University of Science and Technology, Meilong Road No. 130, Shanghai, 200237, China
tongxf@ecust.edu.cn
Received April 12, 2011
ABSTRACT
In this paper, a reagent-controlled [3 þ 2] annulation of γ-functionalized butynoates 1 and 1C,3O-bisnucleophiles 2 is reported, which leads to
three distinct furan skeletons 3ꢀ5. A PPh3 catalyst preferentially attached the β-position of 1a, facilitating R-addition to furnish Type I annulations.
With the assistance of Ag2O, Type II annulations were achieved via selective γ-substitution. In the absence of the PPh3 catalyst, the reagent
Cs2CO3 promoted β-addition to realize Type III annulations.
Polysubstituted furans represent an important class of
five-membered heterocycles that appear widely in
the structure of natural products,1 therapeutic agents,2
and fine chemicals.3 Therefore, numerous protocols
have been developed for the synthesis of polysubsti-
tuted furans.4 Herein, we report a novel diversity-
oriented strategy for furan synthesis based on the
reactions of γ-functionalized butynoate 1 and 2 in a
(1) For representative furan-contained nature products, see:
(a) Rodriguez, A. D. Tetrahedron 1995, 51, 4571. (b) Cimino, G.; Stefano,
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S. R.; Claudia, M.; Youngd, M.; Bolzani, V. D. S.; Silva, D. H. S Nat.
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J. Am. Chem. Soc. 1982, 104, 6463. (b) Flynn, B. L.; Hamel, E.; Jung,
M. K. J. Med. Chem. 2002, 45, 2670. (c) Kerr, D. J.; Hamel, E.; Jung,
M. K.; Flynn, B. L. Bioorg. Med. Chem. 2007, 15, 3290. (d) Khan, M. W.;
Alam, M. J.; Rashid, M. A.; Chowdhury, R. Bioorg. Med. Chem. 2005,
13, 4796. (e) Hofnung, M.; Quillardet, V. M.; Touati, E. Res. Microbiol.
2002, 153, 427.
(3) (a) Wong, H. N. C.; Yang, Y. Tetrahedron. 1994, 50, 9583.
(b) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64, 7687.
(4) For recent reviews, see: (a) Brown, R. C. D. Angew. Chem., Int. Ed.
2005, 44, 850. (b) Cacchi, S. J. Organomet. Chem. 1999, 576, 42. (c) Keay,
B. A. Chem. Soc. Rev. 1999, 28, 209. (d) Hou, X. L.; Cheung, H. Y.; Hon,
T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron
1998, 54, 1955. (e) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076.
(5) For reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res.
2001, 34, 535. (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004,
346, 1035. (c) Lu, X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 77, 1985.
(d) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T.
Acc. Chem. Res. 2006, 39, 520. (e) Ye, L. W.; Zhou, J.; Tang, Y. Chem.
Soc. Rev. 2008, 37, 1140. (f) Kwong, C. K.-W.; Fu, M. Y.; Lam, C. S.-L.;
Toy, P. H. Synthesis 2008, 2307.
r
10.1021/ol200940a
Published on Web 05/16/2011
2011 American Chemical Society

reagent-controlled manner, leading to three distinct
molecular skeletons 3ꢀ5 (Scheme 1).
In 2003, Krische and co-workers originally employed 1a
(LG = OAc) as starting material for convergent furan
derivative synthesis with the use of an excessive PPh3
reagent, in which the involved zwitterionic intermediate
A is proposed to exhibit nucleophilicity to undergo intra-
molecular acyl-substitution (Scheme 2).9 Encouraged by
these results, we envisioned that the carbanion of A would
also be capable of serving as a base to deprotonate
pronucleophile, generating intermediate B with three
contiguous electrophilic centers (R-, β-, and γ-position).
Logically, every two of these three centers could attach
with a 1,n-bisnucleophile to furnish a annulation process
(Scheme 2). Moreover, butynoate 1 itself also bears two
electrophilic centers available for nucleophilic attack, 1,
4 -addtion at the β-position, and SN2-subtitution at the
γ-position.10 Therefore, one can imagine that the reaction
between butynoate 1 and bisnucleophile would suffer from
serious selectivity issues in the presence of a phosphine
catalyst.
Because the aforementioned selectivity is likely to be a
difficult challenge, we decided to pursue a more viable
objective where compound 2a was selected as 1C,3O-
bisnucleophile to avoid the regioselectivity problem arising
from a bisnucleophile partner. With these considerations
in mind, we initiated our study by evaluating the reaction
of 1a and 2a in DMSO at 80 °C with 20 mol % PPh3 as a
catalyst (Table 1, entry 1). To our delight, compound 3aa
was exclusively isolated in 91% yield. Thus, the PPh3-
catalyzed formal [3 þ 2] annulation (Type I) of 1a and 2a
was realized, in which both RC and βC of 1a are incorpo-
rated into a furan product. Surprisingly, additional base
was found to be nonessential for the reaction although
byproduct HOAc was generated. Several bases, such as
K2CO3, Na2CO3, Cs2CO3, and Ag2O, have been tested
and found not to impose any positive influence on the
reaction, in terms of reaction rate and yield.
Scheme 1. Reagent-Controlled Synthesis of Furan Derivatives
The phosphines (PR3) have been remarkably effective
catalysts for cycloadditions of electron-deficient CꢀC
multibond systems.5 Their basic success is derived from
their strong nucleophilicity as a Lewis base for the forma-
tion of phosphinium-containing zwitterions via 1,4-addi-
tion of PR3 to electron-deficient systems. While various
electron-deficient systems, such as allenoates,6 alkenes,7
and alkynes,8 have been well studied, relatively little
attention has been focused on γ-functionalized butynoate
1, and to date there has been only one report concerning
this substrate (Scheme 2).
Scheme 2. Reactivity Profile of γ-Functionalized Butynoate 1
Table 1. Scope of Type I Annulationsa
(6) For recent examples, see: (a) Sun, J.; Fu, G. C. J. Am. Chem. Soc.
2010, 132, 4568. (b) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc.
2010, 132, 2550. (c) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2009, 131,
14231. (d) Xiao, H.; Chai, Z.; Zheng, C.-W.; Yang, Y.-Q.; Liu, W.;
Zhang, J.-K.; Zhao, G. Angew. Chem., Int. Ed. 2010, 49, 4467. (e) Wang,
T.; Ye, S. Org. Lett. 2010, 12, 4168. (f) Xu, S.; Zhou, L.; Ma, R.; Song,
H.; He, Z. Org. Lett. 2010, 12, 544. (g) Wang, Z.; Castellano, S.;
Kinderman, S. S.; Argueta, C. E.; Beshir, A. B.; Fenteany, G.; Kwon,
O. Chem.;Eur. J. 2010, 17, 649. (h) Zhang, X.-C.; Cao, S.-H.; Wei, Y.;
Shi, M. Org. Lett. 2011, 13, 1142. (i) Han, X.; Wang, Y.; Zhong, F.; Lu,
Y. J. Am. Chem. Soc. 2011, 133, 1726.
(7) For recent examples, see: (a) Cai, L.; Zhang, B.; Wu, G.; Song, H.;
He, Z. Chem. Commun. 2011, 47, 1045. (b) Wang, D.-W.; Syu, S.; Hung,
Y.-T.; Chen, P.; Lee, C.-J.; Chen, K.-W.; Chen, Y.-J.; Lin, W. Org.
Biomol. Chem. 2011, 9, 363. (c) Zhong, F.; Wang, Y.; Han, X.; Huang,
K.-W.; Lu, Y. Org. Lett. 2011, 13, 1310. (d) Jiang, Y.-Q.; Shi, Y.-L.; Shi,
M. J. Am. Chem. Soc. 2008, 130, 7202. (e) Zhou, R.; Wang, J.; Song, H.;
He, Z. Org. Lett. 2011, 13, 580. (f) Zheng, S.; Lu, X. Org. Lett. 2009, 11,
3978.
Entry
1 (R1)
2 (R2, E)
2a (Ph, CN)
3 (yield %)b
1
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1b (Ph)
1b (Ph)
1c (Bu)
3aa (91)
3ab (62)
3ac (92)
3ad (94)
3ae (71)
3af (82)
3ag (63)
3ah (56)
3ba (56)
3bf (65)
3ca (32)
2
2b (4-MeO-C6H4, CN)
2c (4-Br-C6H4, CN)
2d (4-Cl-C6H4, CN)
2e (2-furan, CN)
2f (2-thiophene, CN)
2g (Me, acetyl)
3
4
5
6
7
8
2h (Ph, CO2allylic)
2a (Ph, CN)
9
10
11
2f (2-thiophene, CN)
2a (Ph, CN)
a For reaction conditions, see Supporting Information. b Isolated
yield.
(8) For recent examples, see: (a) Wilson, J. E.; Sun, J.; Fu, G. C.
Angew. Chem., Int. Ed. 2010, 49, 161. (b) Chung, Y. K.; Fu, G. C. Angew.
Chem., Int. Ed. 2009, 48, 2225. (c) Meng, L.-G.; Hu, B.; Wu, Q.-P.;
Org. Lett., Vol. 13, No. 12, 2011
3069

After establishing the optimized conditions (Tables
S1ꢀS2 in Supporting Information), we set out to investi-
gate the scope of Type I annulations and the results are
summarized in Table 1. In general, the reactions produce
fully substituted furans 3 in medium to excellent yields
from a wide arrange of substrates 2 with substituted phenyl
groups, heteroaromatic rings, and alkyl groups. The elec-
tron-withdrawing group of substrates 2 imposes some
effect on the results; the cyano affords the best results
while the acyl and ester give lower yields probably due to
their weaker electron-withdrawing effect. One limitation in
the case of 1a, however, is the unavoidable result of the C2
methyl in products 3, which can be complemented by the
use of γ-substituted substrate 1, such as 1b and 1c,
although the corresponding yields are somewhat lower
(entries 9ꢀ11, Table 1).
intramolecular and intermolecular pathways.12 Finally,
the additionꢀelimination process takes place to regenerate
the catalyst and give product 3aa.
Scheme 3. Proposed Mechanism for Type I Annulations
To better understand the mechanism of the Type I
annulations, deuterium-labeled 2a-D (50% D) was sub-
jected to the same conditions. Compound 3aa was ob-
tained in a yield less than that of 2a but with 51% D at
its methyl group (eq 1). Interestingly, when the reaction of
1a and 2a-D was conducted in the presence of D2O
(1.0 equiv) under otherwise identical conditions, the deu-
terium rate was increased to 99% at the same carbon
(eq 1). These results strongly indicated the formation
of intermediate(s) featuring a carbanion located at the
γ-carbon of butynoate 1a.
Onthebasisoftheseobservations, areactionmechanism
is proposed (Scheme 3). Addition of catalyst to 1a gen-
erates zwitterionic intermediate A-1. In the presence of
2a, A-1 works as a base to initiate H-transfer, leading to
the formation of intermediate B-1 and a nucleophile.11
Then, R-addition and elimination of acetate produce
intermediate C, which is converted to intermediate F via
double continuous steps of H-transfer and isomerization.
The results of deuterium-labeling experiments strongly
implied that the involved H-transfer occurs through both
While R-addition is an overwhelming reactivity for
intermediate B-1, we believe that the unique function of
allylic acetate at its γ-carbon might also be available for
SN2-substitution. To access the feasibility of this postu-
lation, substrates 1 with various leaving groups were
explored, as well as several additives. To our delight, it
was eventually identified that the reaction of 1d with
bromine as a leaving group and 2a in the presence of
20 mol % PPh3 with the assistance of Ag2O exclusively
afforded furan 4da in 85% yield (entry 1, Table 2). Thus,
Type II annulation was realized, which incorporated βC
and γC of butynoate 1d into a furan cycle. It was worth
noting that, with the use of Cs2CO3 instead of Ag2O, the
reaction of 1d and 2a just gave compound 3aa in 37% yield
(entry 2, Table 2), demonstrating the crucial role of Ag2O
on regioselectivity. However, without PPh3, only Ag2O
reagent could not promote any reactions between 1d and
2a, and both substrates were recovered, suggesting that
Ag2O did not work as a base in this transformation. The
generality of Type II annulations was also investigated,
and the results are shown in Table 2.
Lianga, M.; Xue, S. Chem. Commun. 2009, 6089. (d) Sampath, M.; Loh,
T.-P. Chem. Sci. 2010, 1, 739. (e) Liu, B.; Davis, R.; Joshi, B.; Reynolds,
D. W. J. Org. Chem. 2002, 67, 4595. (f) Sriramurthy, V.; Barcan, G. A.;
Kwon, O. J. Am. Chem. Soc. 2007, 129, 12928. (g) Sriramurthy, V.;
The proposed mechanism of Type II annulations is
presented in Scheme 4. Apparently, the combination of a
bromine leaving group and Ag2O additive facilitates SN2
substitution at the γ-carbon of intermediate B-2, switching
the reaction pathway to yield intermediate H, which
ultimately accomplished Type II annulations.
ꢀ
Kwon, O. Org. Lett. 2010, 12, 1084. (h) Tejedor, D.; Santos-Exposito,
ꢀ
ꢀ
A.; Mendez-Abt, G.; Ruiz-Perez, C.; Garcıa-Tellado, F. Synlett 2009,
1223. (i) Yavari, I.; Souri, S.; Sirouspour, M.; Djahaniani, H. Synthesis
2006, 3243.
(9) Jung, C.-K.; Wang, J.-C.; Krische, M. J. J. Am. Chem. Soc. 2004,
126, 4118.
(10) (a) Tejedor, D.; Lpez-Tosco, S.; Gonzlez-Platas, J.; Garca-
Tellado, F. Chem.;Eur. J. 2009, 15, 838. (b) Maezaki, N.; Yagi, S.;
Ohsawa, S.; Ohishib, H.; Tanaka, T. Tetrahedron 2003, 59, 9895.
(11) (a) Trost, B. M.; Li, C. J. J. Am. Chem. Soc. 1994, 116, 3167.
(b) Trost, B. M.; C. Li, J. J. Am. Chem. Soc. 1994, 116, 10819. (c) Trost,
B. M.; Dake, G. R. J. Org. Chem. 1997, 62, 5670. (d) Dake, G. R.; Trost,
B. M. J. Am. Chem. Soc. 1997, 119, 7595. (e) Zhang, C.; Lu, X. Synlett
1995, 645. (f) Alvarez-Ibarra, C.; Csaky, A. G.; delaOliva, C. G. Tetra-
hedron Lett. 1999, 40, 8465. (g) Liu, B.; Davis, R.; Joshi, B.; Reynolds,
D. W. J. Org. Chem. 2002, 67, 4595. (h) Lu, C.; Lu, X. Org. Lett. 2002, 4,
4677.
(12) (a) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.;
Liu, S.; Li, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470. (b) Mercier,
E.; Fonovic, B.; Henry, C.; Kwon, O.; Dudding, T. Tetrahedron Lett.
2007, 48, 3617. (c) Liang, Y.; Liu, S.; Xia, Y.; Li, Y.; Yu, Z.-X. Chem.;
Eur. J. 2008, 14, 4361.
(13) The compounds 4 and 5 were distinguished by comparison of
authentic samples according to the following literatures: (a) Suhre,
M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925. (b) Kadota, J.;
Komori, S.; Fukumoto, Y.; Murai, S. J. Org. Chem. 1999, 64, 7523.
3070
Org. Lett., Vol. 13, No. 12, 2011

results indicated that the PPh3 catalyst played a crucial role
in regioselectivity possibly due to its stronger nucleophili-
city than that of 2, which would enable the β-position of 1
being preferentially occupied by PPh3 over 2.
Table 2. Scope of Type II Annulationsa
Table 3. Scope of Type III Annulationsa
Entry
2 (R, E)
4 (yield %)b
1
2a (Ph, CN)
2a (Ph, CN)
4da (85)
3aa (37)c
4db (66)
4dc (92)
4dd (96)
4di (81)
4de (87)
4df (90)
4dg (63)
4dj (44)
4dk (75)
4dl (45)
2
3
2b (4-MeO-C6H4, CN)
2c (4-Br-C6H4, CN)
2d (4-Cl-C6H4, CN)
2i (4-NO2-C6H4, CN)
2e (2-furan, CN)
4
Entry
1 (LG)
2 (R2, E)
5 (yield %)b
5
6
1
2
3
4
1a (OAc)
1d (Br)
2a (Ph, CN)
5aa (23)
5aa (18)
5ag (59)
5am (73)
7
2a (Ph, CN)
8
2f (2-thiophene, CN)
2g (Me, acetyl)
1a (OAc)
1a (OAc)
2g (Me, acetyl)
2m (Me, CO2Et)
9
10
11
12
2j (cyclohexane-1,3-dione)
2k (C5H11, CN)
a For reaction conditions, see Supporting Information. b Isolated
yield.
2l (diethyl 3-oxopentanedioate)
a For reaction conditions, see Supporting Information. b Isolated
yield. c Cs2CO3 was used instead of Ag2O.
In summary, we have developed [3 þ 2] annulations
between γ-functionalized butynoates 1 and 1C,3O-bisnu-
cleophiles 2 in a reagent-controlled manner, leading to
three distinct furan skeletons with high selectivity. The
PPh3 catalyst enables R-addition of 2 to 1 to be favorable,
and fully substituted furans 3 are obtained in good to
excellent yields. In the absence of the PPh3 catalyst, a
normal β-addition takes up the reactivity of 1a, affording
furan derivatives 5. For butynoate 1d, γ-substitution ex-
clusively generates a third furan skeleton 4 with the
combination of the PPh3 catalyst and the reagent Ag2O.
The following facts may contribute to the high selectivity:
(1) PPh3 catalyst exhibits stronger affinity toward the
β-position of butynoate 1 than that of 1C,3O-bisnucleo-
philes 2, diminishing the competition from the addition of
2 to the β-position of 1; (2) to form AgBr, precipitation
might provide a powerful driving force to facilitate γ-
substitution.
Scheme 4. Proposed Mechanism for Type II Annulations
As expected, the reagent Cs2CO3 could promote
β-addition of 2a to 1a in the absence of the PPh3 catalyst,
which was followed by γ-substitution and isomerization
to furnish Type III annulation although the resulting
new isomer13 5aa was isolated only in 23% yield (entry 1,
Table 3). Interestingly, substrate 1d gave the same product
but with a lower yield (entry 2, Table 3). When substrates
2g and 2m were used, the corresponding yields were
increased to 59% and 73%, respectively, implying that
β-addition strongly relied on the pKa value of 2. These
Acknowledgment. Support of this work by NSFC (No.
21002025) and Shanghai Municipal Committee of Science
and Technology (No. 09ZR1408500) is greatly appre-
ciated. This work is also supported by the Fundamental
Research Funds for the Central Universities.
Supporting Information Available. Experimental pro-
cedures and copies of NMR spectra for all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 12, 2011
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