Organocatalyzed anion relay leading to functionalized 2,3-dihydrofurans

Article abstract of DOI:10.1021/ol401881n

A DABCO-mediated organocatalyzed anion relay cascade based on 1-cinnamoylcyclopropanecarboxamides has been developed and applied in the construction of 2,3-dihydrofurans with the original alkene and amide functionalities intact. In the aza-oxy-carbanion relay process, DABCO provides both the electron source and sink. The enolate anion-triggered ring opening of the cyclopropane is ascribed to the key step in the anion relay cascade.

Full text of DOI:10.1021/ol401881n

ORGANIC
LETTERS
2013
Vol. 15, No. 15
3978–3981
Organocatalyzed Anion Relay Leading
to Functionalized 2,3-Dihydrofurans
Mengru Li,† Shaoxia Lin,† Zhiyong Dong,† Xintong Zhang,‡ Fushun Liang,*,†,‡ and
Jingping Zhang*,†
Department of Chemistry, and Key Laboratory for UV-Emitting Materials and
Technology of Ministry of Education, Northeast Normal University,
Changchun 130024, China
liangfs112@nenu.edu.cn
Received June 21, 2013
ABSTRACT
A DABCO-mediated organocatalyzed anion relay cascade based on 1-cinnamoylcyclopropanecarboxamides has been developed and applied in
the construction of 2,3-dihydrofurans with the original alkene and amide functionalities intact. In the aza-oxy-carbanion relay process, DABCO
provides both the electron source and sink. The enolate anion-triggered ring opening of the cyclopropane is ascribed to the key step in the anion
relay cascade.
The dihydrofuran ring system is widely found in the
molecular skeleton of naturally occurring and biologically
active substances (e.g., clerodin, azadirachtin, and austo-
cystin A).1,2 2,3-Dihydrofurans are also versatile building
blocks in organic transformation, e.g. in the synthesis
of highly functionalized tetrahydrofurans with high
stereoselectivity.3 To date, a few synthetic methods have
been documented toward 2,3-dihydrofurans, such as
[3 þ 2] annulations of 1,3-dicarbonyl compounds with
appropriate olefins,4,5 cyclization of R-ketosulfides of
benzothiazole or R-ketopolyfluoroalkanesulfones with
(4) (a) Aso, M.; Ojida, A.; Yang, G.; Cha, O. J.; Osawa, E.;
Kamematsu, K. J. Org. Chem. 1993, 58, 3960. (b) Heiba, E. I.; Dessau,
R. M. J. Org. Chem. 1974, 39, 3456. (c) C-alis-kan, R.; Pekel, T.; Watson,
W. H.; Balci, M. Tetrahedron Lett. 2005, 46, 6227. (d) Zhang, Y.; Raines,
A. J.; Flowers, R. A., II. Org. Lett. 2003, 5, 2363. (e) Antonioletti, R.;
Righi, G.; Oliveri, L.; Bovicelli, P. Tetrahedron Lett. 2000, 41, 10127.
(f) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Tetrahedron. 1991, 47, 6457.
(g) Yoshida, J.; Yano, S.; Ozawa, T.; Kawabata, N. J. Org. Chem. 1985,
50, 3467.
† Department of Chemistry.
‡ Key Laboratory for UV-Emitting Materials and Technology of Ministry
of Education.
(1) (a) Nakanishi, K. Natural Products Chemistry; Kodansha Ltd.,
Academic: New York, 1974. (b) Meyers, A. I. Heterocycles in Organic
Synthesis; John Wiley & Sons: New York, 1974. (c) Dean, F. M. In Advances
in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic: New York,
1982; Vol. 30, p 167. (d) Dean, F. M.; Sargent, M. V. In Comprehensive
Heterocyclic Chemistry; Bird, C. W., Cheeseman, G. W. H., Eds.;
Pergamon: New York, 1984; Vol. 4, Part 3, p 531. (e) Vernin, G. The
Chemistry of Heterocyclic Flavoring and Aroma Compounds; Ellis
Horwood: Chichester, U.K., 1982. (f) Danheiser, R. L.; Stoner, E. J.;
Kojama, H.; Yamashita, D. S.; Klade, C. A. J. Am. Chem. Soc. 1989,
111, 4407. (g) Fraga, B. M. Nat. Prod. Rep. 1992, 9, 217. (h) Merrit,
A. T.; Ley, S. V. Nat. Prod. Rep. 1992, 9, 243.
(5) (a) Roy, S. C.; Mandal, P. K Tetrahedron 1996, 52, 2193.
ꢀ
(b) Garzino, F.; Meou, A.; Brun, P. Tetrahedron Lett. 2000, 41, 9803.
(c) McDonald, F. E.; Connolly, C. B.; Gleason, M. M.; Towne, T. B.;
Treiber, K. D. J. Org. Chem. 1993, 58, 6952. (d) Lee, Y. R.; Kim, B. S.;
Kim, D. H. Tetrahedron 2000, 56, 8845. (e) Bar, G.; Parson, A. F.;
Thomas, C. B. Tetrahedron Lett. 2000, 41, 7751.
(6) (a) Calo, V.; Scordari, F.; Nacci, A.; Schingaro, E.; D’Accolti, L.;
Monopoli, A. J. Org. Chem. 2003, 68, 4406. (b) Xing, C.; Zhu, S. J. Org.
Chem. 2004, 69, 6486.
(2) Kilroy, T. G.; O’Sullivan, T. P.; Guiry, P. J. Eur. J. Org. Chem.
2005, 23, 4929.
(3) (a) Hou, X.-L.; Yang, Z.; Yeung, K.-S.; Wong, H. N. C. Prog.
Heterocycl. Chem. 2005, 17, 142. (b) Elliott, M. C. J. Chem. Soc., Perkin
Trans. 1 2002, 2301. (c) Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100,
2407. (d) Mueller, P.; Bernardinelli, G.; Allenbach, Y. F.; Ferri, M.;
Grass, S. Synlett 2005, 1397. (e) Ishitani, H.; Achiwa, K. Heterocycles
1997, 46, 153.
(7) (a) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 1046.
(b) Davies, H. M.; Ahmed, G.; Calvo, R. L.; Churchill, M. R.; Churchill,
D. G. J. Org. Chem. 1998, 63, 2641. (c) Hamaguchi, M.; Matsubara, H.;
Nagai, T. Tetrahedron Lett. 2000, 41, 1457. (d) Alonso, M. E.; Jano, P.;
Hernandez, M. I.; Green-berg, R. S.; Wenkert, E. J. Org. Chem. 1983,
48, 3047. (e) Wang, Y.; Zhu, S. Tetrahedron 2001, 57, 3383.
€
r
10.1021/ol401881n
Published on Web 07/19/2013
2013 American Chemical Society

aldehydes,6 and the transition-metal-catalyzed reactions of
R,β-unsaturated enones, vinyl ethers, or aldehydes with
varied diazo compounds.7 Dihydrofurans can also be
obtained by the ring enlargement of suitably substituted
cyclopropanes, catalyzed by Lewis acids, metals, or strong
oxidizing agents,8 which has become a complementary but
powerful approach.
Anion relay chemistry (ARC) has been demonstrated as
an effective protocol for diversity-oriented construction of
natural and unnatural molecules of higher complexity, and
tremendous progress has been made.9 The group of Smith
III has presented a variety of elegant Brook-rearrangement-
based anion relay reactions over the past decade. Recently,
we reported a Michael addition-initiated aza-oxy-carbanion
relay by the reaction of 1-cinnamoylcyclopropanecarbox-
amides with selected electrophiles (Scheme 1, left pathway).10
In continuation of this work, we wish to explore the
possibility of an organocatalyzed anion relay cascade
(Scheme 1, right pathway).11 As a result, a new concept
of an organocatalyzed anion relay cascade is established
and has been applied in the construction of functionalized
2,3-dihydrofurans.
Initially, the model reaction of 1-cinnamoyl-N-benzyl-
cyclopropanecarboxamide 1a was examined under basic
conditions (Table 1).12 No reaction occurred by the utiliza-
tion of Et3N as the base in DMSO at 110 °C, and the
substrate may be retractable quantitatively (entry 1).
In the reaction with DBU (1.2 equiv) as the base, substrate
1a decomposed completely within 0.5 h (entry 2). To our
delight, DABCO (1.0 equiv) gave the expected (E)-N-
benzyl-2-(4-methylstyryl)-4,5-dihydrofuran-3-carboxamide
2a in 90% yield under otherwise identical conditions
(entry 3).13 The amount of DABCO could be reduced to
be 0.2 equiv without significantly sacrificing the yield
(entry 4). A further decrease of the amount of DABCO
to 0.1 equiv or lowering the temperature to 90 °C may lead
to dramatically decreased yields (entries 5 and 6). Other
solvents, such as DMF, toluene, DCE, MeCN, and THF
proved to be inferior to DMSO (entries 7ꢀ11).
Table 1. Optimization of the Reaction Conditionsa
Scheme 1
base
t
time
(h)
2a yield
(%)b
entry
(equiv)
solvent
(°C)
1
2
3
Et3N (1.0)
DBU (1.2)
DABCO
(1.0)
DMSO
DMSO
DMSO
110
12
0.5
3
n.r.
0
110
110
90
4
DABCO
(0.2)
DMSO
DMSO
DMSO
DMF
110
3
89
67
45
76
5
5
DABCO
(0.1)
110
4
(8) (a) Alonso, M. E.; Morales, A. J. Org. Chem. 1980, 45, 4530.
(b) Yadav, V. K.; Balamurugan, R. Org. Lett. 2001, 3, 2717.
(c) Bowman, R. K.; Johnson, J. S. Org. Lett. 2006, 8, 573. (d) Bernard,
A. M.; Frongia, A.; Piras, P. P.; Secci, F.; Spiga, M. Org. Lett. 2005, 7,
4565. (e) Lee, P. H.; Kim, J. S.; Kim, S. Tetrahedron Lett. 1993, 34, 7583.
(f) Nakajima, T.; Segi, M.; Mituoka, T.; Fukute, Y.; Honda, M.; Naitou,
K. Tetrahedron Lett. 1995, 36, 1667. (g) Zhang, R.; Liang, Y.; Zhou, G.;
Wang, K.; Dong, D. J. Org. Chem. 2008, 73, 8089.
6
DABCO
(0.2)
90
3.5
1
7
DABCO
(0.2)
110
8
DABCO
(0.2)
toluene
DCE
110
12
12
12
12
(9) For reviews on ARC: (a) Smith, A. B., III; Wuest, W. M. Chem.
Commun. 2008, 5883. (b) Smith, A. B., III; Adams, C. M. Acc. Chem.
Res. 2004, 37, 365. (c) Moser, W. H. Tetrahedron 2001, 57, 2065. For
elegant work by Smith: (d) Smith, A. B., III; Kim, W. S.; Tong, R. B.
Org. Lett. 2010, 12, 588. (e) Smith, A. B., III; Tong, R. B. Org. Lett. 2010,
12, 1260. (f) Smith, A. B., III; Kim, W. S. Proc. Natl. Acad. Sci. U.S.A.
2011, 108, 6787. (g) Smith, A. B., III; Tong, R. B.; Kim, W. S.; Maio,
W. A. Angew. Chem., Int. Ed. 2011, 50, 8904. (h) Smith, A. B., III; Han,
H.; Kim, W. S. Org. Lett. 2011, 13, 3328. (i) Smith, A. B., III; Hoye,
A. T.; Martinez-Solorio, D.; Kim, W.-S.; Tong, R. B. J. Am. Chem. Soc.
2012, 134, 4533. (j) Sokolsky, A.; Smith, A. B., III. Org. Lett. 2012, 14,
4470. (k) Sanchez, L.; Smith, A. B., III. Org. Lett. 2012, 14, 6314. For
multicomponent ARC, see: (l) Bevarie-Baez, N. O.; Kim, W.-S.; Smith,
A. B.; Xian, M., III. Org. Lett. 2009, 11, 1861. For carbon-to-carbon
ARC: (m) Zheng, P. G.; Cai, Z. X.; Garimallaprabhakaran, A.;
Rooshenas, P.; Schreiner, P. R.; Harmata, M. Eur. J. Org. Chem.
2011, 27, 5255. For dianion relay: (n) Li, H.; Liu, L.; Wang, Z.; Zhao,
F.; Zhang, S.; Zhang, W.-X.; Xi, Z. Chem.;Eur. J. 2011, 17, 7399.
Other examples: (o) Gao, L.; Lin, X.; Lei, J.; Song, Z.; Lin, Z. Org. Lett.
2012, 14, 158. (p) Yan, L.; Sun, X.; Li, H.; Song, Z.; Liu, Z. Org. Lett.
2013, 15, 1104.
9
DABCO
(0.2)
reflux
reflux
reflux
0
10
11
DABCO
(0.2)
MeCN
THF
0
DABCO
(0.2)
0
a Reactions were carried out with 1a (1.0 mmol) and the base in
solvent (4.0 mL). b Isolated yield.
Under the optimized conditions (Table 1, entry 4), a
range of reactions were carried out with various substrates
1 (Table 2). The substituents R1 on substrates 1 may be
(12) In the cases of tertiary amine as the base, the intramolecular aza-
Michael addition is inhibited. See: (a) Reference 10. (b) Li, Y.; Xu, X.;
Tan, J.; Liao, P.; Zhang, J.; Liu, Q. Org. Lett. 2010, 12, 244. (c) Liu, J.;
Lin, S.; Ding, H.; Wei, Y.; Liang, F. Tetrahedron Lett. 2010, 51, 6349.
(13) The CdC double bond in all the products is in (E)-conformation,
which were assigned based on the 1H NMR spectra and single-crystal
data. Also refer to: Sonye, J. P.; Koide, K. Org. Lett. 2006, 8, 199.
(10) Our work on ARC: (a) Liang, F.; Lin, S.; Wei, Y. J. Am. Chem.
Soc. 2011, 133, 1781. (b) Lin, S.; Wei, Y.; Liang, F.; Zhao, B.; Liu, Y.;
Liu, P. Org. Biomol. Chem. 2012, 10, 4571.
(11) For selected papers on organocascade catalysis, see: (a)Grondal,
C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167. (b) Jones, S.; Simmons,
B.; Mastracchio, A.; MacMillan, D. Nature 2011, 475, 183.
Org. Lett., Vol. 15, No. 15, 2013
3979

Table 2. DABCO-Catalyzed Anion Relay Leading to
Functionalized 2,3-Dihydrofuransa
yield
(%)b
entry
1
R1
R2
R3
2
1
2
1b
1c
4-MeOC6H4
3,4-
Bn
Bn
H
H
2b
2c
76
86
Figure 1. ORTEP drawing of 2n.
OCH2OC6H3
C6H5
3
1d
1e
1f
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
4-
H
H
H
H
H
H
H
H
H
2d
2e
2f
94
90
91
92
43
86
84
0
amide group to other types of functionalities (Scheme 2).
The reaction of pent-4-ene-1,3-dione 3 in the presence of
0.2 equiv of DABCO proceeded smoothly, affording the de-
sired product, (E)-(2-(4-methylstyryl)-4,5-dihydrofuran-
3-yl)(phenyl)methanone (4), in 81% yield (eq 1). However,
the reaction of 1-cyclopropyl-3-(p-tolyl)prop-2-en-1-one 5
did not occur, with the substrate intact (eq 2).
4
2-ClC6H4
4-ClC6H4
3-NO2C6H4
4-pyridyl
2-thienyl
2-furyl
5
6
1g
1h
1i
2g
2h
2i
7
8
9
1j
2j
10
11
1k
1l
t-Bu
2k
2l
4-MeC6H4
89
MeC6H4CH2
2-
12
1m
4-MeC6H4
H
2m
92
ClC6H4CH2
Ph
Scheme 2. Further Scope Extension
13c
14c
15c
16
1n
1o
1p
1q
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
H
2n
2o
2p
2q
83
82
86
84
4-MeOC6H4
4-ClC6H4
Bn
H
H
Me
a Reactions were carried out on a 1.0 mmol scale in DMSO (4.0 mL)
for 1ꢀ5 h with DABCO (0.2 equiv) as the catalyst unless otherwise
noted. b Yield of isolated product. c 1.2 equiv of DABCO was used.
either electron-rich or -deficient aryl groups (entries 1ꢀ6),
and heteroaryls such as the 4-pyridyl, 2-thienyl, and 2-furyl
group (entries 7ꢀ9). However, when R1 equals an alkyl
group such as tert-butyl, the reaction was inert, presum-
ably due to the steric effect (entry 10).14 The scope ofthe R2
group on the N-atom of the amide group was also inves-
tigated. Substituent R2 may be either alkyls (entries 1ꢀ12)
or aryls (entries 13ꢀ15). It should be noted that 1.2 equiv
of DABCO was used in the reactions with N-aryl sub-
stituents.15 Substrate 1q containing a methyl group on the
cyclopropyl ring afforded the trisubstituted 2,3-dihydro-
furan 2q in 84% yield (entry 16). The structure of 2n was
confirmed by X-ray single crystal diffraction (Figure 1).16
All the above results indicated the efficiency of the orga-
nocatalyzed anion relay cascade.
Scheme 3. Proposed Organocatalyzed Anion Relay Mechanism
In the following work, we further extended the scope of
the organocatalyzed anion relay reaction by varying the
On the basis of all the results describedabove, along with
our previous work,10 an organocatalyzed anion relay
mechanism for the formation of functionalized 2,3-
dihydrofuran was proposed, as depicted in Scheme 3.
(14) Substrates 1 with other types of alkyl substituents such as
methyl, n-butyl, etc. on the β-position of the unsaturated enone moiety
were not easy to prepare.
(15) The N-aryl amides display relatively stronger acidity than the
corresponding N-alkyl counterparts, and the N-aryl amide functionality
might consume a certain amount of DABCO.
(16) CCDC 946390 (2n) contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. See the Supporting Information.
(17) For a minireview on conjugate additions-triggered tandem
transformation, see: (a) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed.
2006, 45, 354. For a recent review on organocatalytic asymmetric aza-
Michael addition, see: (b) Enders, D.; Wang, C.; Liebich, J. X. Chem.;
Eur. J. 2009, 15, 11058.
3980
Org. Lett., Vol. 15, No. 15, 2013

Initially, intermolecular Michael addition by DABCO
generates the enolate anion I.17 Then, an oxyanion-
triggered 1,3-sigmatropic carbon rearrangement takes
place, giving the tertiary carbanion II, which is stabilized
by the adjacent CdC double bond and the electron-with-
drawing amide group. Exocyclic double-bond migration
gives rise to the secondary carbanionIII. A rapid elimination
of DABCO (to complete the catalytic cycle) delivers the
final product 2. In the reaction, DABCO tunes the reac-
tivity as a chemical switch and causes the ring opening of
cyclopropane to occur. From the electron point of view,
DABCO provides both an electron source and sink.
In summary, an organocatalyzed anion relay chemistry
has been developed based on doubly electron-withdrawing
group activated cyclopropanes. The tertiary amine-
mediated anion relay cascade not only provides a novel
method for the ring opening of the cyclopropanes8,18 but
also an efficient strategy toward highly functionalized
2,3-dihydrofurans. Further work on anion relay cascades
and the application in the construction of various fused
heterocycles is in progress.
Acknowledgment. Financial support from NSFC
21172034, NCET-11-0611, the Department of Science
and Technology of Jilin Province (201215002), and the
Fundamental Research Funds for the Central Universities
(11SSXT129 and 12SSXT132) is gratefully acknowledged.
Supporting Information Available. Experimental de-
tails and characterization for all new compounds and
crystal structure data (CIF file). This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) (a) Yang, W.; Xu, L.; Chen, Z.; Zhang, L.; Miao, M.; Ren, H.
Org. Lett. 2013, 15, 1282. (b) Zhang, Z.; Zhang, Q.; Sun, S.; Xiong, T.;
Liu, Q. Angew. Chem., Int. Ed. 2007, 46, 1726. (c) Baldwin, J. E.;
Villarica, K. A.; Freedberg, D. I.; Anet, F. A. L. J. Am. Chem. Soc.
1994, 116, 10845. (d) Baldwin, J. E.; Burrell, R. C. J. Org. Chem. 1999,
64, 3567.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 15, 2013
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