Halonium-initiated electrophilic cascades of 1-alkenoylcyclopropane carboxamides: Efficient access to dihydrofuropyridinones and 3(2H)-furanones

Article abstract of DOI:10.1039/c1cc15319f

Halonium-initiated cascade reaction of 1-alkenoylcyclopropane carboxamides was developed, which leads to the production of dihydrofuropyridinones and 3(2H)-furanones, respectively, depending on the property of substituents on the enone moiety.

Full text of DOI:10.1039/c1cc15319f

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COMMUNICATION
Halonium-initiated electrophilic cascades of 1-alkenoylcyclopropane
carboxamides: efficient access to dihydrofuropyridinones and
3(2H)-furanonesw
Ying Wei, Shaoxia Lin, Juan Zhang, Zaihai Niu, Qiang Fu and Fushun Liang*
Received 26th August 2011, Accepted 11th October 2011
DOI: 10.1039/c1cc15319f
Halonium-initiated cascade reaction of 1-alkenoylcyclopropane
carboxamides was developed, which leads to the production
of dihydrofuropyridinones and 3(2H)-furanones, respectively,
depending on the property of substituents on the enone moiety.
unexpected 1,2-aryl migration, cyclopropane ring-opening and
oxa-cyclization process. While with electron-withdrawing R1
groups, such as 4-nitrophenyl, O-heterocycles 3 were obtained
as the sole product by sequential halo-oxa-cyclization, cyclopropane
ring-opening, alkyl bromide hydrolysis and retro-aldol cascade.
Both 2,3-dihydrofuro[3,2-c]pyridinones and 3(2H)-furanones
constitute the core structures of many naturally occurring
compounds and display important antitumor, antifungal and
antibacterial activities.5
Cascade reactions have attracted considerable attention in
organic synthesis due to the atom-efficient creation of molecular
complexity in a single-step.1 During the course of our study on
the synthetic potential of double EWGs activated cyclopropanes2
toward various carbo- and heterocycles,3 we have developed
an intramolecular Michael addition-initiated cascade cyclization
of readily available 1-alkenoylcyclopropane carboxamides 1
via aza-oxy-carbanion relay under basic conditions.3c In connection
with this work and our recent interest in cationic cascades, we start
to exploit the feasibility of electrophilic cyclization relying upon
utilization of 1 in the presence of a halonium-producing reagent
under acidic conditions (Scheme 1).4 Consequently, we discovered
a strategically novel access to structurally interesting and
biologically important dihydrofuro[3,2-c]pyridinones 2 and/
or 3(2H)-furanones 3, respectively. It was found that the
formation of products 2 and/or 3 depended on the nature of
the b-substituent on the enone moiety. With electron-donating
aromatic R1 substituents like 4-methylphenyl, N/O heterocycles
2 were achieved exclusively via tandem halo-aza-cyclization,
Initially, the model reaction of 1-alkenoyl-N-benzylcyclo-
propane carboxamide (1a) with NBS was examined under
acidic conditions (Table 1). No reaction occurred in the
absence of an acid catalyst (entry 1). The reaction with Lewis
acid catalysts like Cu(OAc)2, CuBr2 and CuBr (10% loading
amount) at 80 1C gave unsatisfactory results (entries 2–4).
Then the reaction was performed in the presence of Brønsted
acid (entries 5–12). To our delight, when formic acid was used both
as the catalyst and solvent at 80 1C, 2,3-dihydrofuro[3,2-c]-
pyridinone 2a (via 1,2-aryl migration) was formed in 81%
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
E
Solvent
T/1C
2a Yield (%)b
1
2
3
4
5
6
7
8
—
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NIS
DCE
DCE
DCE
DCE
HCO2H
DCE
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
80
80
80
80
80
80
80
reflux
reflux
reflux
reflux
reflux
reflux
reflux
n.r.
0
0
Cu(OAc)2
CuBr2
CuBr
HCO2H
HCO2H
HCO2H
HCO2H
MeCO2H
PhCO2H
TsOH
0
81
80
56
81
79
79
80
78
78
0
Scheme 1 Halonium initiated electrophilic cascades of 1-alkenoyl-
cyclopropane carboxamides 1.
9
10
11
12
13
14
Department of Chemistry, Northeast Normal University,
Changchun 130024, China. E-mail: liangfs112@nenu.edu.cn;
Fax: +86 431-85099759
TFA
HCO2H
HCO2H
NCS
w Electronic supplementary information (ESI) available: Experimental
details and characterization of all new compounds and crystal struc-
ture data. CCDC 826841 (2a), 829460 (2i) and 839385 (3b). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc15319f
a
Reactions were carried out with 1a (1.0 mmol), E (1.2 equiv.) and
catalyst (10% loading amount for Lewis acid; 1.2 equiv. for Brønsted
b
acid) in solvent (2.0 mL). Isolated yield. E = electrophile.
c
12394 Chem. Commun., 2011, 47, 12394–12396
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yield, whereas the expected halo-aza-cyclization/oxa-cyclization
product 4 was not observed (entry 5). The structure of 2a was
confirmed unambiguously by X-ray single crystal diffraction.6
The amount of formic acid could be reduced to 1.2 equiv. in
DCE (entry 6). Among the solvents tested, MeCN was more
efficient and was selected for the following investigation
(entries 7 and 8). Besides HCO2H, both aliphatic acids like
MeCO2H and aromatic acids like PhCO2H proved to be
suitable, giving 2a in high yields (entries 9 and 10). Strong acids
such as TsOH and TFA also work well (entries 11 and 12).
NIS showed comparable reactivity to NBS, but NCS was
inefficient (entries 13 and 14).
Then, the scope of the substituents on the a,b-unsaturated
enone moieties of substrates 1 was investigated. In particular,
substrates 1g–v bearing various R1 groups (aryl, heteroaryl
and alkyl) at the b-position of the enone moiety were subjected
to the reaction sequences. It was found that the substrates
containing an electron-rich R1 group (i.e., 4-methoxyphenyl,
2-methoxyphenyl, 3,4-methylenedioxyphenyl, 4-dimethylamino-
phenyl, 2-methylphenyl) and a heteroaryl group (i.e., 2-thienyl)
gave 2g–l in high yields (79–87%, entries 7–12). The reaction
of substrate 1m with a 2-furyl group gave a complex mixture
(entry 13). While the substrates containing phenyl (1n) and
an electron-deficient group like 4-chlorophenyl (1o) gave 2n
and 2o, respectively, in moderate yields (entries 14 and 15). In
the reaction mixture, halo-oxa-cyclization product 3a was
separated, in respective 41% yield for 1n and 47% yield for
1o. When strong electron-withdrawing aromatic groups
(i.e. 4-nitrophenyl) and heteroaromatic groups (i.e. 4-pyridyl)
were introduced, 3(2H)-furanones 3a–f could be obtained as the
sole product in 81–89% yields (entries 16–22).7 For substrate
1v with an alkyl substituent (R1 = t-C4H9), the corresponding
3(2H)-furanone 3a was obtained in 89% yield (entry 23).8 The
structures of 2i and 3b were further confirmed by X-ray single
crystal diffraction (Fig. S1 in the ESIw).6 All the above results
indicated the efficiency and scope of the cascade reaction
reported here.
With the optimal conditions established above (Table 1,
entry 8), the scope and generality of the cascade reaction
were investigated. Thus, a range of reactions was carried out
with various substrates 1 in the presence of NBS and HCO2H
(Table 2). The amide scope was examined first. All of the
reactions based on N-alkylamide substrates 1a–d proceeded
efficiently to afford dihydrofuro[3,2-c]pyridinones 2a–d in high
yields (entries 1–4). For 1-alkenoylcyclopropaneamide 1e bearing
a methyl group on the cyclopropane ring, the reaction furnished
the corresponding 2,3-dihydrofuro[3,2-c]pyridinone 2e as a single
regioisomer (entry 5). However, the reaction with an N-aryl
counterpart, i.e., 1f, as the substrate, did not occur (entry 6).
On the basis of all the results described above, a possible
mechanism for the cascade transformation of highly functionalized
substrates 1 (R1 = EDG) into 2 is depicted in Scheme 2. Initially,
bromonium ion intermediate I is formed via electrophilic
activation of the alkene. Then, intramolecular aza-cyclization
(in a 6-endo-tet fashion)9 takes place, giving the b-amino-a-
brominated intermediate II. Upon subsequent deprotonation
of the ammonium ion with the release of succinimide, spiro-
cyclic intermediate III is generated. Promoted by the neigh-
bouring group participation,10 a bromide is removed, giving
the aziridinium ion IV.11 1,2-Aryl migration on IV furnishes
iminium ion V,12 followed by b-H elimination13 with the
formation of VI. Finally, bromide triggered ring-opening of
activated cyclopropane14 and recyclization (intramolecular oxa-
cyclization) furnish the N,O-bicyclic product 2 (VI - VII - 2).
It should be noted that the dual role of NBS is critical in the
Table
2 Bromonium-initiated cascade reactions leading to
dihydrofuro[3,2-c]pyridinones 2 and 3(2H)-furanones 3a
Entry
1
R1
R2
R3 2/3 Yield (%)b
1
2
3
4
5
6
7
8
1a 4-MeC6H4
1b 4-MeC6H4
1c 4-MeC6H4
1d 4-MeC6H4
1e 4-MeC6H4
1f 4-MeC6H4
1g 4-MeOC6H4
1h 2-MeOC6H4
Bn
2-Cl-C6H4CH2
4-MeC6H4CH2
BnCH2
Bn
Ph
H
H
H
H
2a 81
2b 80
2c 85
2d 83
Me 2e 81
H
H
H
H
H
H
H
H
H
2f
0
Bn
Bn
2g 84
2h 83
2i 87
2j 86
2k 79
2l 80
cascade transformation: (i) as
a bromonium-producing
9
1i 3,4-OCH2OC6H3 Bn
10
11
12
13
14
1j 4-Me2NC6H4
1k 2-MeC6H4
1l 2-thienyl
1m 2-furyl
Bn
Bn
Bn
Bn
Bn
c
2m
—
1n C6H5
2n 50
3a 41
2o 44
3a 47
3a 87
3a 89
3b 86
3c 89
3d 88
15
1o 4-ClC6H4
Bn
H
16
17
18
19
20
21
22d
23
1p 4-NO2C6H4
1q 4-pyridyl
Bn
Bn
H
H
H
H
H
1r 4-NO2C6H4
1s 4-NO2C6H4
1t 4-NO2C6H4
1u 4-NO2C6H4
1p 4-NO2C6H4
1v t-C4H9
2-Cl-C6H4CH2
4-MeC6H4CH2
BnCH2
Bn
Bn
Me 3e 85
H
H
3f 81
3a 89
Bn
a
Reactions were carried out with 1 (1.0 mmol), NBS (1.2 equiv.) and
b
HCO2H (1.2 equiv.) in MeCN (2.0 mL). Isolated yield. Complex
d
mixture was obtained. With HOAc as the catalyst instead of
c
Scheme 2 Possible mechanism for the formation 2,3-dihydro-
furo[3,2-c]pyridinones 2.
HCO2H. The pendant ester group is –O2CMe in 3f.
c
This journal is The Royal Society of Chemistry 2011
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107, 3117; (f) C. A. Carson and M. A. Kerr, Chem. Soc. Rev., 2009,
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4 For representative cascades initiated by halonium ion activation,
see: (a) M. Sasaki and A. K. Yudin, J. Am. Chem. Soc., 2003,
125, 14242; (b) Y.-Y. Yeung, X. Gao and E. J. Corey, J. Am.
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Acad. Sci. U. S. A., 2010, 107, 20655; (j) L. Zhou, J. Chen,
C. K. Tan and Y.-Y. Yeung, J. Am. Chem. Soc., 2011, 133, 9164.
5 For dihydrofuropyridinones, see: (a) G. H. Syoboda, G. H. Poore,
P. J. Simpson and G. B. Boder, J. Pharm. Sci., 1966, 55, 758;
(b) B. Wolters and U. Eilert, Planta Med., 1981, 43, 166; (c) L. K.
Basco, S. Mitaku, A. L. Skaltsounis, N. Ravelomanantsoa,
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2005, 58, 315; (e) T. Fukuda, Y. Yamaguchi, R. Masuma,
H. Tomoda and S. Omura, J. Antibiot., 2005, 58, 309; (f) Y. Sugie,
S. J. Truesdell, J. W. Wong, N. Yoshikawa, A. Sugiura, EP 999212
A1. For 3(2H)-furanones, see: (g) A. B. Smith III, M. A. Guaciaro,
S. R. Schow, P. M. Wovku-lich, B. H. Toder and T. W. Hall, J. Am.
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Scheme 3 Possible mechanism for the formation of 3(2H)-furanones 3.
reagent to initiate the aza-cyclization, followed by the 1,2-aryl
migration; and (ii) as a potential BrÀ nucleophile to open the
cyclopropane ring for further oxa-cyclization. Moreover, the
duty of carboxylic acid is supposed to activate the carbonyl
groups in both substrates 1 and NBS.4c,4g The 1,2-aryl migration
involved in the reaction, to the best of our knowledge, represents
the first example in the a,b-unsaturated enone system via halogen
activation.
The possible mechanism for the formation of 3(2H)-furanones
3 from substrates 1 (R1 = EWG) is shown in Scheme 3.
Halo-oxa-cyclization takes place first (in a 5-exo-tet fashion),9
giving oxonium intermediate VIII and its resonance structure,
iminium IX. Secondly, carboxylic acid-mediated cyclopropane
ring-opening affords 3(2H)-furanone X.14 Thirdly, due to
the neighbouring group participation by oxygen (X - XI),10
the alkyl bromide X is readily hydrolyzed to the alcohol XII.
The final 3(2H)-furanone 3 is produced via a retro-aldol with
the release of the corresponding aldehydes.15
6 See ESIw for details.
7 It was noteworthy that, in the separate reactions of 1n–p (entries
14–22), arylaldehyde side products R1CHO could be observed on
TLC plates.
8 Electronic property of aromatic groups on the enones plays a key
role in the selective halo-aza/oxa-cyclization, see: D. F. Shellhamer,
K. J. Davenport, H. K. Forberg, M. P. Herrick, R. N. Jones,
S. J. Rodriguez, S. Sanabria, N. N. Trager, R. J. Weiss,
V. L. Heasley and J. A. Boatz, J. Org. Chem., 2008, 73, 4532. While
the steric effect from the t-butyl group may be responsible for the
observed halo-oxa-cyclization.
9 J. E. Baldwin, Chem. Commun., 1976, 734.
10 B. Capon and S. P. McManus, Neighboring Group Participation,
Plenum, New York, 1976, vol. 1.
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Chem. Soc., 2008, 130, 14984; (d) S. B. D. Jarvis and
A. B. Charette, Org. Lett., 2011, 13, 3830.
In summary, we have developed a novel strategy for the
synthesis of biologically important dihydrofuro[3,2-c]pyridinones
and 3(2H)-furanones via a carboxylic acid-catalyzed halonium-
initiated cascade process. The one-pot reaction features readily
available starting materials, mild conditions, high efficiency,
and high chemo- and regioselectivity.
Financial support from the NSFC (No. 20972027 and
21172034) and Training Fund of NENU’s Scientific Innovation
Project (NENU-STC08013) is gratefully acknowledged.
Notes and references
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c
12396 Chem. Commun., 2011, 47, 12394–12396
This journal is The Royal Society of Chemistry 2011