An organocatalyzed highly regioselective one-pot approach to the synthesis of tetrahydrobenzofuranones

Article abstract of DOI:10.1016/j.tetlet.2012.04.101

An organocatalyzed highly regioselective synthesis of substituted tetrahydrobenzofuran-4-ones based on the ring opening followed by cyclization of epoxides with enamines of 1,3-cyclohexanediones in a domino fashion is described. It is a high yielding (74-93%) synthetic protocol tolerant to a wide range of substrates. Ambient temperature, organocatalytic approach, atom-economy, and formation of water as the only by-product are some of the attractive features of the present methodology.

Full text of DOI:10.1016/j.tetlet.2012.04.101

Tetrahedron Letters 53 (2012) 3382–3384
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An organocatalyzed highly regioselective one-pot approach to the synthesis
of tetrahydrobenzofuranones
⇑
Ruchi Chawla, Atul K. Singh, Lal Dhar S. Yadav
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An organocatalyzed highly regioselective synthesis of substituted tetrahydrobenzofuran-4-ones based on
the ring opening followed by cyclization of epoxides with enamines of 1,3-cyclohexanediones in a dom-
ino fashion is described. It is a high yielding (74–93%) synthetic protocol tolerant to a wide range of sub-
strates. Ambient temperature, organocatalytic approach, atom-economy, and formation of water as the
only by-product are some of the attractive features of the present methodology.
Received 2 March 2012
Revised 19 April 2012
Accepted 21 April 2012
Available online 27 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Epoxides
1,3-Cyclohexanediones
Tetrahydrobenzofuranones
Regioselective synthesis
The rapid adoption of the field of organocatalysis by synthetic
chemists is, beyond doubt, deeply rooted in its potential for saving
in cost, time and energy, easier experimental procedures, and
reduction in chemical wastes. Among the several generic modes
of activation commonly used in organocatalysis, the renaissance
of enamine chemistry1 in the last decade was embraced by the
chemical community with such great fervor that it almost resulted
in an explosion of research articles and reviews on enamine catal-
ysis2 (secondary amine-catalyzed direct reactions of carbonyl com-
pounds with electrophiles). Secondary amines are very powerful
organocatalysts which can give rise to highly stereoselective trans-
formations of carbonyl compounds into a flourishing pool of indus-
trially and pharmaceutically important structures.3
to activated olefins via ionic8 or radical9 pathways has also been
found to be a reliable method for their synthesis. Furthermore, there
have been reports on the chemo-,10 stereo-,8b,10,11 and regioselec-
tive8a,d,12 one-pot approaches for the synthesis of tetrahydrobenzof-
uranones. A few greener methods have also been developed for the
synthesis of this class of compounds.9b,13 Alternatively, Maiti et al.
reported a CAN-promoted synthesis of trans-2-arylcarbonyl-3-ary-
l(or styryl)-2,3,6,7-tetrahydrobenzofuran-4(5H)-ones by the reac-
tion between 1,3-cyclohexanediones and chalcones.11 Lee et al.
initially utilized Rh(II) complex for the synthesis of 2,3-dihydroben-
zofurans from cyclic diazodicarbonyl compounds14a–f and have
recently reported the same synthesis utilizing AgBF4/[Bmim]BF4-
catalyzed [3+2] cycloaddition.14g
Substituted tetrahydrobenzofuran-4-one (TBF) structure and its
derivatives are an essential part of a variety of natural products and
are widely used in the pharmaceuticals, for example, phyllaemblic
acid methyl ester exhibits significant anti-CVB3 activity4 and
maoecrystal V displays potent and selective inhibitory activity
against HeLa cells5 (Fig. 1). TBFs are also used as valuable synthetic
intermediates and as an annulated structure of 2,3-dihydrofuran,
they also find important applications in the flavor, insecticidal
and fish antifeedant industries.6
Presently, the synthesis of the TBF core is an active area of re-
search and most of the recent reports employ the 1,2- and 1,4-addi-
tion of 1,3-cyclohexanediones to electrophiles for their
construction.7 The oxidative addition of 1,3-dicarbonyl compounds
The recurring use of transition metal catalysis, limited availabil-
ity of general routes for the preparation of various types of 2,3-
dihydrobenzofurans15 as compared to fully aromatic benzo[b]furan
derivatives16 and our ongoing research activities in the field of
organocatalysis for designing heterocycles in a one-pot proce-
dure17 prompted us to devise a new enamine catalyzed synthetic
O
OH
O
OBz
Me
O
OH
O
O
O
MeO2C
O
O
H
H
phyllaemblic acid methyl ester
maoecrystal V
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
Figure 1. Selected examples of natural products containing tetrahydrobenzofura
n-4-one motif.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.101

R. Chawla et al. / Tetrahedron Letters 53 (2012) 3382–3384
3383
O
O
with catalyst 4d may be due to the formation of zwitterionic spe-
cies in THF (Table 1, entry 4). Acyclic amines such as diisopropyl-
amine 4e and dibenzylamine 4f showed poor catalytic activity as
compared to the cyclic secondary amines 4a–c (Table 1, entries
1–3 and 5–6). No product could be isolated in the presence of a ter-
tiary amine like N-methylmorpholine 4g (Table 1, entry 7) which
supports the involvement of an enamine intermediate. With the
appropriate catalyst for the reaction decided, we screened different
solvents and temperatures. Choosing EtOH at ambient temperature
as the solvent decreased the yield of 3a to 56% (Table 1, entry 8).
Less satisfactory results were obtained in CH2Cl2 and toluene com-
pared with Et2O (Table 1, entries 9–11). No significant increase in
the yield was observed when the reaction was performed at
80 °C in THF using 4b as the catalyst (Table 1, entry 12). The opti-
mum catalyst loading for 4b was found to be 20 mol % (Table 1, en-
tries 2, 13 and 14).
O
R
O
R
OH
R
O
O
O
1
3
2
Scheme 1. Retrosynthetic analysis of TBF scaffold.
route to the TBF scaffold from readily available cyclic 1,3-diketones
and epoxides. We envisioned that it might be possible to develop
an organocatalytic reaction for the formation of substituted TBF
skeleton 3 as outlined in Scheme 1. This protocol is based on the
initial regioselective ring opening of epoxides 2 via enamines of
1,3-cyclohexanediones 1 followed by cyclization and dehydration
reactions in a one-pot procedure. We herein report our results
for the first organocatalytic route to TBF structures.
With the optimal conditions in hand, we extended our synthetic
protocol to examine its substrate scope. In Table 2, we have pre-
sented the results of our investigation when a range of epoxides
2 were reacted with two 1,3-cyclohexanediones 1 (R1 = H, CH3)
to afford substituted 2,3,6,7-tetrahydrobenzofuran-4(5H)-ones 3.
A broad range of epoxides were tolerated under the reaction con-
ditions used. In all cases, the enamines of 1 preferably attacked
at the less hindered position of the epoxide ring to afford the cor-
responding 2-substituted products 3 exclusively (Table 2, entries
1–15). This may be attributed to the large size of the nucleophile,
that is, steric factor dominated over the electronic factor in the
epoxide ring opening step, which is in conformity with several ear-
lier observations.18 However, in the case of 2,3-disubstituted epox-
ides the reaction did take place, but relatively lower yields were
obtained (Table 2, entries 16 and 17).
Initial experiments established that the reaction of 1,3-cycloh-
exanediones with epoxides proceeds smoothly in THF at room
temperature in the presence of a secondary amine as the catalyst
to afford substituted 2,3,6,7-tetrahydrobenzofuran-4(5H)-ones.
Such promising findings led us to perform a screening of various
secondary amines, solvents, and reaction temperatures in order
to optimize the conditions for a model reaction between 1,3-cyclo-
hexanedione 1a and styrene oxide 2a. The results of the screening
are summarized in Table 1.
The screening of different secondary amines as catalysts in THF
revealed that 4b was the most effective catalyst at rt in terms of
yield and time (Table 1, entries 1–7). The remarkably lower yield
Table 1
A plausible mechanism for the formation of 2-substituted tetra-
hydrobenzofuran-4-ones 3 is depicted in Scheme 2. The secondary
amine 4b activates 1,3-cyclohexanedione 1 by enamine formation,
which then regioselectively adds to epoxide 2 to give the zwitter-
ion 5. The intramolecular cyclization of 5 to 6 followed by in situ
Screening of reaction conditions for the synthesis of substituted 2,3,6,7-
tetrahydrobenzofuran-4(5H)-ones 3a
O
O
catalyst 4
O
Ph
solvent, rt, time
Ph
O
Table 2
O
Scope and yield of the organocatalytic synthesis of tetrahydrobenzofuran-4(5H)-ones
2a
1a
3a
3a
O
R3
O
O
COOH
N
N
catalyst 4b (20 mol %)
N
H
4c
N
H
O
H
R2
H
R1
R1
R1
R3
O
R2
4b
rt, THF
4a
4d
O
R1
3
1
2
H
O
N
N
H
N
Entry
R1
R2
Ph
R3
Product
Time (h)
Yieldb,c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
42
44
68
37
65
65
36
38
48
45
36
56
70
68
65
58
62
8714g
85
4g
4f
4e
p-ClC6H4
o-ClC6H4
p-MeOC6H4
p-O2NC6H4
p-MeC6H4
Ph
p-ClC6H4
o-ClC6H4
p-MeOC6H4
p-O2NC6H4
p-MeC6H4
Me
Yieldb (%)
84
93
86
89
Entry
Solvent
Catalyst (mol %)
Time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
THF
THF
THF
THF
THF
THF
THF
EtOH
CH2Cl2
Toluene
Et2O
THF
4a (20)
4b (20)
4c (20)
4d (20)
4e (20)
4f (20)
4g (20)
4b (20)
4b (20)
4b (20)
4b (20)
4b (20)
4b (15)
4b (25)
48
42
48
60
52
50
60
45
50
60
53
42
48
42
65
87
77
41
60
58
—
56
76
72
79
88c
65
87
CH3
CH3
CH3
CH3
CH3
CH3
H
9014g
88
86
91
85
88
86
84
85
76
CH3
H
Me
PhOCH2
–(CH2)4–
CH3
H
H
THF
THF
CH3
74
a
b
c
For experimental procedure, see Ref. 19.
Isolated yield of purified product 3.
a
b
c
For experimental procedure, see Ref. 19.
Isolated yield of purified product 3a.
The reaction was performed at 80 °C.
All compounds gave C, H, and N analyses within 0.37% and satisfactory spec-
tral (IR, 1H NMR, 13C NMR, and EIMS) data.

3384
R. Chawla et al. / Tetrahedron Letters 53 (2012) 3382–3384
Ellis Horwood: Chichester, 1982; (c) Kubo, I.; Lee, Y. W.; Balogh-Nair, V.;
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O
Nakanishi, K.; Chapya, A. J. Chem. Soc., Chem. Commun. 1976, 949; (d) Schulte,
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Potrekar, R. A.; Karade, H. N. Tetrahedron Lett. 2003, 44, 6729; (d) Aso, M.; Ojida,
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10. Devi, R. B.; Henrot, M.; Paolis, M. D.; Maddaluno, J. Org. Biomol. Chem. 2011, 9,
6509.
R
N
H
O
4b
O
-H2O
O
1
OH
7
O
H2O
R
O
O
R
O
N
N
3
6
O
O
11. Maiti, S.; Paramasivan, T. P.; Menendez, J. C. Tetrahedron 2010, 66, 9512.
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R
R
2
O
N
14. (a) Lee, Y. R.; Hwang, J. C. Eur. J. Org. Chem. 2005, 1568; (b) Lee, Y. R.; Suk, J. Y.
Tetrahedron 2002, 58, 2359; (c) Lee, Y. R.; Suk, J. Y. Tetrahedron Lett. 2000, 41,
4795; (d) Lee, Y. R. Synth. Commun. 1998, 28, 865; (e) Lee, Y. R.; Suk, J. Y.
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51, 4909; (g) Xia, L.; Lee, Y. R.; Kim, S. H.; Lyoo, W. S. Bull. Korean Chem. Soc.
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5
Scheme 2. Plausible mechanism for the formation of substituted tetra-
hydrobenzofuran-4-ones.
15. (a) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519; (b) Snider, B.
Chem. Rev. 1996, 96, 339.
hydrolysis forms 7 with liberation of the catalyst 4b to complete
the catalytic cycle. The spontaneous dehydration of b-hydroxyke-
tone 7 affords the final product 3.
16. For selected reviews on benzofuran synthesis, see: (a) Cagniant, P.; Cagniant, D.
Adv. Heterocycl. Chem. 1975, 18, 337; (b) Donnelly, D. M. X.; Meegan, M. J. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, 1984; vol. 4, p 657; (c) Kadieva, M. G.; Oganesyan, E. T.
Chem. Heterocycl. Comp. 1997, 33, 1245; (d) Gilchrist, T. L. J. Chem. Soc. Perkin
Trans. 1 2001, 2491; (e) Hou, X.-L.; Yang, Z.; Wong, H. N. C. Prog. Heterocycl.
Chem. 2002, 14, 139; (f) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893; (g) Graening, T.; Thrun, F. In Comprehensive Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K.,
In conclusion, we have developed a facile organocatalytic route
to substituted tetrahydrobenzofuran-4-ones involving the second-
ary amine catalyzed reaction of cyclic 1,3-diones with epoxides in
a one-pot procedure to furnish the desired products in excellent
yields. The straightforward approach, atom-economy, high regi-
oselectivity along with the myriad advantages inherently associ-
ated with organocatalysis establish the present synthetic
protocol as an important entry into tetrahydrobenzofuranone
chemistry.
Eds.; Elsevier: Oxford, 2008; Vol. 3,
p 497; (h) De Luca, L.; Nieddu, G.;
Porcheddu, A.; Giacomelli, G. Curr. Med. Chem. 2009, 16, 1.
17. (a) Singh, A. K.; Chawla, R.; Rai, A.; Yadav, L. D. S. Chem. Commun. 2012, 48,
3766; (b) Rai, A.; Singh, A. K.; Singh, P.; Yadav, L. D. S. Tetrahedron Lett. 2011, 52,
1354; (c) Rai, A.; Singh, A. K.; Singh, S.; Yadav, L. D. S. Synlett 2011, 335.
18. (a) Murthy, S. N.; Madhav, B.; Reddy, V. P.; Rao, K. R.; Nageswar, Y. V. D.
Tetrahedron Lett. 2009, 50, 5009; (b) Suryakiran, N.; Reddy, T. S.;
Venkateswarlu, Y. J. Sulfur Chem. 2007, 28, 513.
Acknowledgments
19. General procedure for the synthesis of compounds 3:
A mixture of 1,3-
cyclohexanedione (1 mmol), epoxide (1 mmol), and pyrrolidine 4b
1
2
(0.2 mmol) in THF was stirred at room temperature for the required time
(Table 2). After completion of the reaction (monitored by TLC), water (5 mL)
was added, and the reaction mixture was extracted with EtOAc (3 Â 5 mL). The
combined organic phases were dried over anhyd Na2SO4, filtered, and
evaporated under reduced pressure. The resulting crude product was purified
by silica gel column chromatography using a mixture of EtOAc–n-hexane as
eluent to afford an analytically pure sample of 3. Physical data of
representative compounds. Compound 3b: Yellow oil, yield 85%. IR (neat)
mmax 834, 908, 995, 1024, 1060, 1184, 1228, 1290, 1402, 1450, 1496, 1632,
We sincerely thank the DST, Govt. of India, for financial support
(DST File No. SR/S1/OC-22/2010) and SAIF, Punjab University,
Chandigarh, for providing microanalyses and spectra.
References and notes
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Stork, G. Med. Res. Rev. 1999, 19, 370; (c) Seebach, D.; Beck, A. K.; Badine, D. M.;
Limbach, M.; Eschenmoser, A.; Treasurywala, A. M.; Hobi, R.; Prikoszovich, W.;
Linder, B. Helv. Chim. Acta 2007, 90, 425.
2. For very recent, representative reviews, see: (a) Jensen, K. L.; Dickmeiss, G.;
Jiang, H.; Albrecht, L.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248; (b) Nielsen,
M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Chem.
Commun. 2011, 47, 632; (c) Stork, G. Tetrahedron 2011, 67, 9754; (d) Trost, B.
M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600; (e) Roca-Lopez, D.; Sadaba, D.;
Delso, I.; Herrera, R. P.; Tejero, T.; Merino, P. Tetrahedron: Asymmetry 2010, 21,
2561; (f) Xu, L.-W.; Li, L.; Shi, X.-H. Adv. Synth. Catal. 2010, 352, 243; Also see:
(g) Wiesner, M.; Upert, G.; Angelici, G.; Wennemers, H. J. Am. Chem. Soc. 2010,
132, 6. and Refs. 2,3 therein.
3. (a) Franke, P. T.; Richter, B.; Jørgensen, K. A. Chem. Eur. J. 2008, 14, 6317; (b) Liu,
G.-S.; Dong, Q.-L.; Yao, Y.-S.; Yao, Z.-J. Org. Lett. 2008, 10, 5393; (c) Itoh, T.;
Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1533; (d) Liu,
K.; Chougnet, A.; Woggon, W.-D. Angew. Chem. Int. Ed. 2008, 47, 5827; (e) Volz,
N.; Bröhmer, M. C.; Nieger, M.; Bräse, S. Synlett 2009, 550.
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2000, 41, 1781; (b) Casey, T. C.; Carlisle, J.; Tisseli, P.; Male, L.; Spencer, N.;
Grainger, R. S. J. Org. Chem. 2010, 75, 7461; (c) Liu, Q.; Wang, Y.-F.; Chen, R.-J.;
Zhang, M.-Y.; Wang, Y.-F.; Yang, C.-R.; Zhang, Y.-J. J. Nat. Prod. 2009, 72, 969.
5. (a) Li, S. H.; Wang, J.; Niu, X. M.; Shen, Y. H.; Zhang, H. J.; Sun, H.-D.; Li, M. L.;
Tian, Q. E.; Lu, Y.; Cao, P.; Zheng, Q. T. Org. Lett. 2004, 6, 4327; (b) Sun, H.-D.;
Huang, S.-X.; Han, Q.-B. Nat. Prod. Rep. 2006, 23, 673; (c) Gong, J.; Lin, G.; Sun,
W.; Li, C.-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 16745.
2951, 3030 cmÀ1 1H NMR (400 MHz; CDCl3) d: 1.95–2.02 (m, 2H), 2.27–2.31
.
(m, 2H), 2.39–2.45 (m, 2H), 3.28 (d, J = 8.5 Hz, 2H), 4.24 (t, J = 8.5 Hz, 1H), 7.15–
7.20 (m, 2H), 7.24–7.30 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 21.5, 23.6, 33.6,
36.2, 86.0, 112.7, 128.5, 129.4, 134.1, 138.5, 177.6, 195.5 ppm. EIMS (m/z) 248,
250 (M+, M++2). Anal. Calcd for C14H13ClO2: C, 67.61; H, 5.27%. Found: C, 67.83;
H, 5.14%. Compound 3i: Yellow oil, yield 86%. IR (neat)
mmax 630, 705, 792, 959,
1048, 1164, 1220, 1401, 1642, 2958, 3062 cmÀ1 1H NMR (400 MHz; CDCl3) d:
.
1.07 (s, 6H), 2.06 (s, 2H), 2.30 (s, 2H), 3.26 (d, J = 8.4 Hz, 2H), 4.22 (t, J = 8.4 Hz,
1H), 7.09–7.15 (m, 1H), 7.19–7.27 (m, 2H), 7.28–7.36 (m, 1H). 13C NMR
(100 MHz, CDCl3) d: 28.4, 29.2, 33.8, 34.7, 37.8, 50.6, 76.7, 111.5, 127.2, 128.5,
129.9, 133.6, 138.1, 176.0, 194.8 ppm. EIMS (m/z) 276, 278 (M+, M++2). Anal.
Calcd for C16H17ClO2: C, 69.44; H, 6.19%. Found: C, 69.81; H, 6.29%. Compound
3l: Yellow oil, yield 88%. IR (neat) mmax 628, 827, 965, 1044, 1162, 1222, 1402,
1640, 2961, 3063 cmÀ1 1H NMR (400 MHz; CDCl3) d: 1.08 (s, 6H), 2.06 (s, 2H),
.
2.31 (s, 2H), 2.37 (s, 3H), 3.25 (d, J = 8.4 Hz, 2H), 4.18 (t, J = 8.4 Hz, 1H), 6.89–
6.95 (m, 2H), 7.04–7.09 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 28.3, 29.1, 33.8,
34.6, 37.9, 50.8, 86.6, 111.4, 128.0, 129.9, 137.1, 138.4, 176.0, 194.6 ppm. EIMS
(m/z) 256 (M+). Anal. Calcd for C17H20O2: C, 79.65; H, 7.86%. Found: C, 79.52; H,
7.54%. Compound 3o: Yellow oil, yield 85%. IR (neat) mmax 702, 757, 910, 997,
1022, 1045, 1054, 1189, 1243, 1227, 1285, 1400, 1452, 1498, 1668, 2942,
3028 cmÀ1 1H NMR (400 MHz; CDCl3) d: 1.93–2.01 (m, 2H), 2.26- 2.31 (m, 2H),
.
2.37–2.44 (m, 2H), 2.51–2.59 (m, 1H), 2.78–2.85 (m, 1H), 3.57 (dd, J = 11.8,
7.5 Hz, 1 H), 3.85 (dd, J = 11.8, 7.2 Hz, 1 H), 3.93–4.09, m, 1H), 6.74–7.18 (m,
5H). 13C NMR (100 MHz, CDCl3) d: 21.3, 23.5, 33.6, 36.2, 87.0, 88.3, 113.6, 114.5,
121.0, 128.9, 155.2, 177.3, 195.9 ppm. EIMS (m/z) 244 (M+). Anal. Calcd for
6. (a)Natural Products Chemistry; Nakanishi, K., Ed.; Kodansha: Tokyo, 1974;
(b)The Chemistry of Heterocyclic Flavoring and Aroma Compounds; Vernin, G., Ed.;
C
15H16O3: C, 73.75; H, 6.60%. Found: C, 73.49; H, 6.72%.