Stereoselective synthesis of tetrasubstituted 2,3-dihydrofurans by one-step cyclization of β-ketosulfides of benzothiazole and aldehydes in ionic liquids

Article abstract of DOI:10.1021/jo026849a

A stereoselective synthesis of tetrasubstituted 2,3-dihydrofurans was carried out in n-butylpyridinium tetrafluoroborate ([bpy⁺][BF₄^-]) as solvent. The reaction proceeds smoothly in one step starting from simple materials

Full text of DOI:10.1021/jo026849a

Ster eoselective Syn th esis of Tetr a su bstitu ted 2,3-Dih yd r ofu r a n s
by On e-Step Cycliza tion of â-Ketosu lfid es of Ben zoth ia zole a n d
Ald eh yd es in Ion ic Liqu id s
Vincenzo Calo`,† Fernando Scordari,‡ Angelo Nacci,*,† Emanuela Schingaro,‡
Lucia D’Accolti,† and Antonio Monopoli†
Istituto di Chimica dei Composti Organometallici - ICCOM, Department of Chemistry,
University of Bari, Via Amendola 173, 70126 - Bari, Italy, and Department of Geomineralogy,
University of Bari, Via Orabona 4, 70126 - Bari, Italy
nacci@chimica.uniba.it
Received December 13, 2002
A stereoselective synthesis of tetrasubstituted 2,3-dihydrofurans was carried out in n-butylpyri-
dinium tetrafluoroborate ([bpy+][BF4-]) as solvent. The reaction proceeds smoothly in one step
starting from simple materials such as aldehydes and â-ketosulfides of benzothiazole. A comparison
between several ionic liquids (ILs) is presented, and the role of the benzothiazolyl moiety is discussed.
Workup proved to be very easy and recycling of IL possible.
In tr od u ction
alkenes of the carbenoid species generated by rhodium-
11
or copper-12 mediated decomposition of diazocarbonyl
Dihydrofurans and furans are two of the most impor-
tant heterocycles commonly found in a wide variety of
naturally occurring substances and possessing a multi-
plicity of biological activities.1 Among them, 2,3-dihydro-
furans have gained importance as structural features of
natural products such as aflatoxins,2 as well as solvents,
monomers for the synthesis of biodegradable polymers
(e.g., naturally occurring polyethers),3 and other useful
synthetic intermediates.4
Their synthetic significance has prompted a search for
better methods of synthesis by using simple and feasible
approaches. One of the most important methodologies is
based on metal-promoted processes which involve radical
intermediates, generated by Mn(III),5 Ce(IV),6 and Co-
(II)7 salts, or by Pd-,2a,8 Sc-,9 and Mo-10 catalyzed cycliza-
tion. Besides them, also 1,3-dipolar cycloaddition to
compounds has also become an additional important
route in the synthesis of dihydrofurans.
The second attractive approach to dihydrofuran de-
rivatives involves, in a one-pot process, nucleophilic
cascade reactions initiated by an attack of stabilized
carbanions on suitable electrophiles, followed by a cy-
clization step. Nevertheless, these methods require ap-
propriate reagents, such as 2-alkenyl-1,3-dicarbonyl com-
pounds,13 R-halo-enones14 and -enoates,15 phosphonium16
or arsonium ylides,17 and others.18
In this latter context, during our development of clean
(6) (a) Roy, S. C.; Mandal, P. K. Tetrahedron 1996, 52, 2193-2198.
(b) Nair, V.; Mathew, J .; Radhakrishnan, K. V. J . Chem. Soc., Perkin
Trans. 1 1996, 12, 1487-1492. (c) Nair, V.; Mathew, J . J . Chem. Soc.,
Perkin Trans. 1 1995, 3, 187-188. (d) Lee, Y. R.; Kim, B. S.; Kim, D.
H. Tetrahedron 2000, 56, 8845-8853.
(7) Iqbal, J .; Bhatia, B.; Nayyar, N. K. Tetrahedron 1991, 47, 6457-
6468.
* Corresponding author.
† Department of Chemistry, University of Bari.
(8) (a) Alonso, I.; Carretero, J . C.; Garrido, J . L.; Magro, V.; Pedregal,
C. J . Org. Chem. 1997, 62, 5682-5683. (b) Garrido, J . L.; Alonso, I.;
Carretero, J . C. J . Org. Chem. 1998, 63, 9406-9413.
(9) Evans, D. A.; Sweeney, Z. K.; Rovis., T.; Tedrow, J . S. J . Am.
Chem. Soc. 2001, 123, 12095-12096.
(10) McDonald, F. E.; Connolly, C. B.; Gleason, M. M.; Towne, T.
B.; Treiber, K. D. J . Org. Chem. 1993, 58, 6952-6953.
(11) (a) Davies, H. M.; Ahmed, G.; Calvo, R. L.; Churchill, M. R.;
Churchill, D. G. J . Org. Chem. 1998, 63, 2641-2645. (b) Hamaguchi,
M.; Matsubara, H.; Nagai, T. Tetrahedron Lett. 2000, 41, 1457-1460.
(c) Wang, Y.; Zhu, S. Tetrahedron 2001, 57, 3383-3387. (d) Lee, Y. R.;
Suk, J . Y. Tetrahedron 2002, 58, 2359-2367.
‡ Department of Geomineralogy, University of Bari.
(1) (a) Dean, F. M. Advances in Heterocyclic Chemistry; Katritzky,
A. R., Ed.; Academic: New York, 1982; Vol. 30, pp 167-238. (b) Dean,
F. M.; Sargent, M. V. Comprehensive Heterocyclic Chemistry; Bird, C.
W., Cheeseman, G. W. H., Eds.; Pergamon: New York, 1984; Vol. 4,
Part 3, pp 531-598. (c) Nakanishi, K. Natural Products Chemistry;
Kodansha Ltd.; Academic: New York, 1974. (d) Fraga, B. M. Nat. Prod.
Rep. 1992, 9, 217. (e) Merrit, A. T.; Ley, S. V. Nat. Prod. Rep. 1992, 9,
243. (f) Vernin, G. The Chemistry of Heterocyclic Flavoring and Aroma
Compounds; Ellis Horwood: Chichester, 1982.
(2) (a) Schabbert, S.; Schaumann, E. Eur. J . Org. Chem. 1998, 1873-
1878. (b) Schuda, P. F. Top. Curr. Chem. 1980, 91, 75-111.
(3) (a) Boeckman, R. K., J r.; Charette, A. B.; Asberom, T.; J ohnston,
B. H. J . Am. Chem. Soc. 1991, 113, 5337. (b) Nicolaou, K. C.; Reddy,
K. R.; Skokotas, G.; Sato, F.; Xiao, X.-Y.; Hwang, C.-K. J . Am. Chem.
Soc. 1993, 115, 3558-3575. (c) Ireland, R. E.; Meissner, R. S.;
Rizzacasa, M. A.; J . Am. Chem. Soc. 1993, 115, 7166-7172.
(4) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795-819. (b) For a more
detailed description about synthetic transformations of 2,3-dihydro-
furans, see http://www.hwsands.com/snapshotpgs/chem23dh.htm.
(5) (a) Nishino, H. Bull. Chem. Soc. J pn. 1985, 58, 1922-1927. (b)
Nguyen, V.-H.; Nishino, H.; Kurosawa, K. Synthesis 1997, (8), 899-
908. (c) Garzino, F.; Me´ou, A.; Brun, P. Tetrahedron Lett. 2000, 41,
9803-9807.
(12) (a) Alonso, M. E.; Morales, A.; Chitty, W. J . Org. Chem. 1982,
47, 3747-3754. (b) Alonso, M. E.; J ano, P.; Hernandez, M. I.; Green-
berg, R. S.; Wenkert, E. J . Org. Chem. 1983, 48, 3047-3050.
(13) (a) Antonioletti, R.; Bovicelli, P.; Malancona, S. Tetrahedron
2002, 58, 589-596. (b) Antonioletti, R.; Righi, G.; Olivieri, L.; Bovicelli,
P. Tetrahedron Lett. 2000, 41, 10127-10130 and references therein.
(14) Arai, S.; Nakayama, K.; Suzuki, Y.; Hatano, K.; Shioiri, T.
Tetrahedron Lett. 1998, 39, 9739-9742.
(15) Hagiwara, H.; Sato, K.; Suzuki, T.; Ando, M. Tetrahedron Lett.
1997, 38, 2103-2106.
(16) Dauben, W. G.; Hart, D. J . Tetrahedron Lett. 1975, 49, 4353-
4356.
(17) Moorhoff, C. M. Tetrahedron Lett. 1996, 37, 9349-9352.
10.1021/jo026849a CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/01/2003
4406
J . Org. Chem. 2003, 68, 4406-4409

Synthesis of Tetrasubstituted 2,3-Dihydrofurans
SCHEME 1
SCHEME 2
SCHEME 3
organic syntheses by using environmentally friendly
reaction media such as ionic liquids, we were attracted
by the enhanced reactivity exhibited by charged nucleo-
philes in these alternative solvents, certainly due to the
low solvation toward the anions. Concerning this argu-
ment, we recently reported the stereoselective synthesis
of trans-disubstituted cyclopropanes by reaction of ben-
zothiazolic â-ketosulfides 1 as pronucleophiles with acryl-
ates as Michael acceptor, in the presence of sodium
hydrogencarbonate as base. In this process, the tetrabu-
tylammonium bromide (TBAB), used as solvent, was
essential to efficiently promote the reaction, preventing
some drawbacks such as the use of strong bases, lack of
stereoselectivity, and ring cleavage (Scheme 1).19
As an extension of this study, we now describe herein
further synthetic utility of this method as a novel simple
stereoselective synthesis of substituted dihydrofurans by
using aldehydes as electrophiles.
Resu lts
Initial investigations aimed at the synthesis of oxiranes
were performed by using the synthetic procedure depicted
in Scheme 1, choosing the model reaction between
â-ketosulfide 1a and benzaldehyde. However, instead of
the expected oxirane 2a , trans-2,3-dihydrofuran 3a (yield
45%), 2-(butylsulfanyl)benzothiazole 4, and 0.5 equiv of
starting aldehyde were isolated after extraction from the
ionic liquid (Scheme 2).
The choice of the 2-thiobenzothiazolyl moiety was
reasonable considering its double nature of electron-
withdrawing group, which increased the acidity of R-me-
thylene protons, and its good leaving group properties.
Reaction monitoring did not exhibit any intermediate,
but when the reaction temperature was decreased to 50
°C, a GC-MS analysis revealed the formation of an
intermediate species with m/z ) 311, subsequently
isolated and identified as 3-(benzothiazol-2-ylsulfanyl)-
4-phenylbut-3-en-2-one 6a . On the basis of these findings,
a plausible reaction mechanism (Scheme 3) envisages the
initial nucleophilic attack by the stabilized carbanion 1a -
on aldehyde followed by neutralization and dehydration
steps. Once formed, the vinyl sulfide 6a undergoes a
Michael addition by the anion 1a -, affording the enolate
(18) For further synthetic methods of dihydrofuran see also: (a)
Dyker, G.; Tho¨ne, A. Tetrahedron 2000, 56, 8669-8672. (b) Mukherjee,
A. K.; Agosta, W. C. J . Chem. Soc., Chem. Commun. 1994, 1821-1822.
(c) Me´lot, J . M.; Texier-Boullet, F.; Foucaud, A. Tetrahedron 1988, 44,
2215-2224. (d) Boberg, F.; Garburg, K.-H., Go¨rlich, K.-J .; Pipereit, E.;
Redelfs, E.; Ruhr, M. J . Heterocycl. Chem. 1986, 23, 1853-1859. (e)
Gianturco, M. A.; Friedel, P.; Flanagan, V. Tetrahedron Lett. 1965,
(23), 1847-1852.
(19) Calo`, V.; Nacci, A.; Lopez, L.; Lerario, V. Tetrahedron Lett. 2000,
41, 8977-8980.
J . Org. Chem, Vol. 68, No. 11, 2003 4407

Calo` et al.
TABLE 1. Op tim iza tion of Rea ction Con d ition s in th e
Syn th esis of Dih yd r ofu r a n 3a a
TABLE 2. Syn th esis of 2,3-Dih yd r ofu r a n s in Ion ic
Liqu id sa
ketosulfide
aldehyde
R1
2,3-dihydrofuran
run
(1) R
T/°C
yields%b [t/h] E:Zc
1
2
3
4
5
6
7
8
9
(1a ) CH3
(1a ) CH3
(1a ) CH3
(1a ) CH3
(1a ) CH3
(1a ) CH3
(1b) Ph
Ph
r.t. 3a
r.t. 3b
50 3c
r.t. 3d
r.t. 3e
93 [1.5]
85 [4]
72 [29]
84 [3.3]
80 [4]
80 [5.5]
85 [9]
82 [12]
82 [38]
97:3
95:5
98:2
>99:1
92:8
CH3(CH2)6
CH3(CH2)12
4-NO2C6H4
4-ClC6H4
3-CH3OC6H4 r.t. 3f
Ph
run
solvent
TBAB
base (equiv) T [°C] time (h) yields (%)b
1
2
3
4
5
6
7
8
9
NaHCO3 (2.5) 110
NaHCO3 (2.5) 110
NaHCO3 (2.5) r.t.
1.5
4
24
91c
85
<5
87
28
85
87
93
85
80
95:5
DMA
DMA
DMA
50 3g
50 3h
50 3i
98:2d
>99:1d
>99:1d
(1b) Ph
(1b) Ph
CH3(CH2)6
CH3(CH2)12
K2CO3 (2.5)
r.t.
22
24
16
24
1.5
36
44
[bmim+]Br- NaHCO3 (2.5) r.t.
a
b
[bmim+]Br- K2CO3 (2.5)
r.t.
r.t.
r.t.
r.t.
r.t.
Same procedure as reported in Table 1. Isolated products.
[bmim+]I-
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (1)
c Evaluated by GLC. Evaluated by 1H NMR.
d
-
[bpy+][BF4-
]
]
]
[bpy+][BF4-
SCHEME 4
10 [bpy+][BF4
K2CO3 (0.1)
a
Typical procedure: to the solvent (3 g of IL or 5 mL of DMA),
stirred and heated at the reaction temperature, were added
b
ketosulfide 1a (4,5 mmol), aldehyde (2,2 mmol), and base. Iso-
lated products. c In this case a further purification step by column
chromatography was necessary to eliminate the byproduct 4.
anion 7a , which gives rise to the cyclization product
trans-2,3-dihydrofuran 3a . When tetrabutylammonium
bromide (TBAB) was used as reaction medium, the
leaving group Btz-S- led to a side-reaction with the
solvent consisting of a nucleophilic displacement on the
ammonium cation, which affords the byproduct 4 and
tributylamine (Table 1, run 1).
The reaction did not occur on replacing ketosulfides 1
by R-halogenated ketones,20 thus showing the importance
of benzothiazole as activating group for this process. In
addition, the reaction carried out on simple ketones as
electrophiles afforded very low conversions. On the basis
of these results, by choosing [bpy+][BF4-] as solvent and
K2CO3 (2.5 equiv) as base, we applied this method to
other substrates as listed in Table 2.
Thus, to obtain complete conversion of aldehyde, 2
equiv of ketosulfides 1a and sodium hydrogencarbonate
were necessary. A similar reaction pathway has been
recently reported in the synthesis of dihydrofurans by
using R-haloenones as substrates under PTC conditions.14
To obtain milder reaction conditions, we tested the use
of a stronger base such as K2CO3 and a number of low-
melting ionic liquids. Optimization experiments were
performed on the model reaction affording dihydrofuran
3a , and results are summarized in Table 1.
The method proved to be of general applicability on
aldehydes, although a slightly higher reaction tempera-
ture (50 °C) was required for aliphatic ones (runs 3, 8,
9). In addition, a great benefit of this protocol arises from
the simplicity of the separation procedure, which can be
performed by diethyl ether extraction of the reaction
products, thus leaving the ionic liquid which can be
recycled. This latter operation can be smoothly ac-
complished since the reaction byproduct Btz-SH (or its
potassium salt), being insoluble in Et2O, remains dis-
solved into the ionic liquid.
It is noteworthy that 2,3-dihydrofurans 3a -i can be
further converted into other synthetic intermediates. A
first example is the oxidation to the corresponding furans
by treatment with chemical manganese dioxide (CMD).21
For this purpose, a benzene solution of dihydrofuran 3g
was refluxed for 36 h in the presence of an excess (12
equiv) of activated MnO2, affording the tetrasubstituted
furan 8g (Scheme 4).
When the reaction temperatures were decreased, low
yields were obtained both in DMA and in 1-butyl-3-
methylimidazolium bromide ([bmim+]Br-) as solvents
(runs 3, 5). However, replacement of NaHCO3 with K2-
CO3 as base led to a great increase of yields, while among
the various low-melting ionic liquids investigated, 1-bu-
tylpyridinium tetrafluoroborate ([bpy+][BF4-]) furnished
highest reaction rates (runs 6-8). Reaction at room
temperature occurred also in DMA although with de-
creased reaction rate (run 4). It is noteworthy that the
base may be used even in catalytic amounts (runs 9-10).
These latter findings are not surprising since some
reaction intermediates, such as anion 5a or the leaving
group Btz-S-, can behave as a base to deprotonate the
ketosulfide 1a (see Scheme 3).
Alternatively, an interesting transformation is the
removal of benzothiazolic group, leaving a thiolic func-
tionality on dihydrofuran ring. This can be done by
(20) Either R-chloroacetophenone or R-chloroacetone treated with
benzaldehyde in the same reaction conditions did not afford any
products.
(21) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K., Anzai,
M.; Ando, A.; Shioiri, T. Synlett 1998, 35-36.
4408 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of Tetrasubstituted 2,3-Dihydrofurans
(3 g) and heated at the reaction temperature. To the stirred
molten salt were added ketosulfide 1 (4.48 mmol), aldehyde
(2.24 mmol), and potassium carbonate (5.60 mmol). The
reaction was monitored by GLC until consumption of the
reagents. After completion of the reaction, the mixture was
extracted four times with 20 mL of ethyl ether. The collected
organic fractions were concentrated under vacuum and filtered
to separate the insoluble residual 2-mercaptobenzothiazole.
Then, after drying on Na2SO4 and complete solvent evapora-
tion, dihydrofurans products were obtain as oils or yellow
solids in almost 95% purity.
SCHEME 5
When tetrabutylammonium bromide (TBAB) was used as
solvent, the reaction mixture was extracted with 80 mL of
hexane for 1 h in a Soxhlet apparatus. After solvent evapora-
tion, the oily residue was chromatographed on silica gel (eluent
petroleum ether/ethyl acetate) to separate the byproducts 4
and tributylamine. Instead, when the reaction was carried out
in dimethylacetamide (DMA), the reaction mixture was treated
with aqueous HCl (30 mL) and extracted with 3 × 30 mL
portions of diethyl ether. The organic layers were dried on Na2-
SO4, and the solvent evaporated under vacuum. The oily
residue was chromatographed on silica gel (eluent petroleum
ether/ethyl acetate) to give purified dihydrofurans 3a -i.
Typ ica l P r oced u r e for Oxid a tion to Tetr a su bstitu ted
F u r a n s. To a 20 mL benzene solution of dihydrofuran 3g (1.0
g, 2.0 mmol) was added 2.09 g (24 mmol) of activated
manganese dioxide, and the suspension was refluxed for 36
h. After the completion of reaction, the solvent was removed
in vacuo and the mixture chromatographed on silica gel (eluent
hexane/ethyl acetate 5/1) to give 0.92 (92%) of tetrasubstituted
furan 8g.
Typ ica l P r oced u r e for Deb lock in g Ben zot h ia zolic
Gr ou p . A 20 mL benzene solution containing 2.0 g (5.4 mmol)
of dihydrofuran 3a , 0.51 g (8.2 mmol) of ethylene glycol, and
90 mg (0.54 mmol) of p-toluensulfonic acid was refluxed
overnight in a round-bottomed flask equipped with a Dean-
Stark apparatus. Then, the mixture was washed with 20 mL
of aqueous NaHCO3. After drying and solvent removal, trans-
(()-4-(benzothiazol-2-yl)sulfanyl-2(2-methyl-[1,3]dioxolan-2-
yl)-5-methyl-3-phenyl-2,3-dihydrofuran (9a ) was isolated as
pale yellow solid (yield 95%).
treating dihydrofuran 9a , bearing the protected carbonyl
moiety, with an excess of ethylmagnesium bromide,
providing trans-2-methyl-5-(2-methyl-[1,3]dioxolan-2-yl)-
4-phenyl-4,5-dihydrofuran-3-thiol (10a ) and 2-ethylben-
zothiazole (11). These compounds derived from a nucleo-
philic displacement carried out by the Grignard reagent
onto the C-2 position of benzothiazolic ring (Scheme 5).
Further attempts are in progress to find reaction condi-
tions for deblocking the entire S-Btz group.
A further question concerns the stereoselectivity of the
cyclizations. These occurred in most cases with a high
degree of trans stereoselectivity (trans/cis ratio > 98:2)
probably due to the major thermodynamic stability of
trans isomer. The trans configurational assignment of the
predominant isomer of compounds 3a -i has been un-
equivocally established by NMR, mainly by analysis of
chemical shifts, coupling constants, and NOESY experi-
ments, subsequently confirmed by X-ray diffraction (see
Supporting Information).
In conclusion, a convergent stereoselective synthesis
of highly substituted dihydrofurans has been described.
By using a ionic liquid as solvent, the following advan-
tages have been achieved: (i) very mild reaction condi-
tions, such as room temperature and catalytic amounts
of base, (ii) enhanced yields and shorter reaction times
compared with analogous processes in molecular solvents,
(iii) easy workup and recycling of reaction medium
possible. In addition, most of the starting reagents, such
as aldehydes and ketosulfides 1, are commercially avail-
able compounds or can be easily prepared via costless
synthesis. For these reasons, we believe that this method
could provide a new viable access to dihydrofurans.
In a three-necked round-bottomed flask, equipped with a
condenser, 1.0 g (2.4 mmol) of protected dihydrofuran 9a was
dissolved, under nitrogen atmosphere, in 20 mL of dry THF.
Then, 3.5 mmol of ethylmagnesium bromide was added by
syringe, and the mixture was refluxed monitoring by GLC until
the disappearance of starting material (48 h ca.). Silica gel
chromatography of the reaction mixture (eluent petroleum
ether/ethyl acetate 6/1) gave 0.53 g (78%) of trans-(()-2-
methyl-5-(2-methyl-[1,3]dioxolan-2-yl)-4-phenyl-4,5-dihydro-fu-
ran-3-thiol (10a ) together with 0.31 g of 2-ethylbenzothiazole24
(11).
Exp er im en ta l Section
Ack n ow led gm en t. This work was in part finan-
cially supported by Ministero dell’Universita` e della
Ricerca Scientifica e Tecnologica, Rome, and the Uni-
versity of Bari (National Project: “Stereoselezione in
Sintesi Organica: Metodologie ed Applicazioni”).
Butylmethylimidazolium iodide and butylpyridinium tet-
rafluoroborate were prepared according to the literature.22
Ketosulfides 1a ,b were prepared according to our procedure.23
The stereochemistry of dihydrofurans was secured by NMR
signals and by NOESY experiment, subsequently confirmed
by X-ray diffraction (see Supporting Information).
Su p p or tin g In for m a tion Ava ila ble: Physical and spec-
tral data of compounds 3a -i, 6a , 8g, 9a , 10a , phase-sensitive
NOESY 1H NMR experiment of dihydrofuran 3b, and crystal-
lographic data for compound 3a . This material is available free
of charge via the Internet at http://pubs.acs.org.
Gen er a l P r oced u r es for th e Syn th esis of 2,3-Dih yd r o-
fu r a n s. A Pyrex reaction flask was charged with ionic liquid
(22) (a) Huddleston, J . G.; Visser, A. E.; Reichert, W. M.; Willauer,
H. D.; Broker, G. A.; Rogers R. D. Green Chem. 2001, 3, 156-164. (b)
Behar, D.; Neta, P.; Schultheisz, C. J . Phys. Chem. A 2002, 106, 3139-
3147.
J O026849A
(23) Calo`, V.; Fiandanese, V.; Nacci, A.; Volpe, A. Tetrahedron 1996,
52, 2155-2166.
(24) Katritzky, A. R.; Kuzmierkiewicz, W.; Aurrecoechea, J . M. J .
Org. Chem. 1987, 52, 844-849.
J . Org. Chem, Vol. 68, No. 11, 2003 4409