Unexpected formation of tetrasubstituted 2,3-dihydrofurans from the reactions of β-keto polyfluoroalkanesulfones with aldehydes

Article abstract of DOI:10.1021/jo049317y

Catalyzed by piperidine, the reactions of β-keto polyfluoroalkanesulfones with aromatic aldehydes afforded the unexpected tetrasubstituted 2,3-dihydrofurans in good yields, probably proceeding through the normal Knoevenagel condensation products. This rea

Full text of DOI:10.1021/jo049317y

SCHEME 1
SCHEME 2
Un exp ected F or m a tion of Tetr a su bstitu ted
2,3-Dih yd r ofu r a n s fr om th e Rea ction s of
â-Keto P olyflu or oa lk a n esu lfon es w ith
Ald eh yd es
Chunhui Xing and Shizheng Zhu*
Key Laboratory of Organofluorine Chemistry, Shanghai
Institution of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin lu, Shanghai 200032, P. R. China
kanesulfonyl)methanes with aromatic aldehydes provided
Knoevenagel condensation products (Scheme 2).5d
zhusz@mail.sioc.ac.cn
Received April 23, 2004
In this paper, we report the unexpected formation of
tetrasubstituted trans-2,3-dihydrofurans under Biginelli7
or Knoevenagel condensation reaction conditions when
â-keto polyfluoroalkanesulfones such as RfSO2CH2COR
(Rf ) ClC4F8, R ) Ph (1a ) or CH3 (1b)) are reacted with
aromatic aldehydes. Our results are somewhat related
to those of Calo et al.,6 who reported that reactions of
â-keto sulfides with aldehydes in ionic liquids also
directly afford tetrasubstituted 2,3-dihydrofurans. The
importance of dihydrofuran derivatives is apparent as
they are present in a large variety of naturally occurring
substances and are precursors of furans by oxidation.8
In addition, the introduction of fluoroalkanesufonyl group
on dihydrofuran may confer improved biological or physi-
cal activities.
Initially, we tried to synthesize polyfluoroalkanesulfo-
nyl-substituted dihydropyrimidinones by the Biginelli
reaction.7 When a mixture of 1a , benzaldehyde (2a ), and
urea was refluxed for 24 h in ethanol, one solid product
was isolated by chromatography column in low yield. To
our surprise, the 1H NMR showed it had 17 protons,
which is more than we expected. Moreover, D2O-
exchanging experiments did not show activated protons
in this compound. It was clear that the product is not
the expected dihydropyrimidinone derivative, which has
only 13 protons, two of which could be exchanged by D2O.
On the basis of the NMR spectral data and elemental
analysis, the product was identified as the dihydrofuran
derivative 2-benzoyl-4-(4-chloro-1,1,2,2,3,3,4,4-octafluo-
robutane-1-sulfonyl)-3,5-diphenyl-2,3-dihydrofuran 3a a .
Encouraged by the unexpected formation of a dihydro-
furan derivative, we tried to optimize this reaction.
Abstr a ct: Catalyzed by piperidine, the reactions of â-keto
polyfluoroalkanesulfones with aromatic aldehydes afforded
the unexpected tetrasubstituted 2,3-dihydrofurans in good
yields, probably proceeding through the normal Knoevenagel
condensation products. This reaction provided an efficient
and novel method for the stereoselective synthesis of fluorine-
containing tetrasubstituted trans-2,3-dihydrofurans.
Per(poly)fluoroalkanesulfonyl groups, RfSO2, are one
of the strongest electron-withdrawing groups which can
activate R-C-H bonds and adjacent olefins or function
as nucleofugic leaving groups having an electron pair to
form sulfinate anions.1 Due to their manifold reactivities,
per(poly)fluoroalkanesulfonyl groups are of special inter-
est in organic chemistry, especially in organofluorine
chemistry. R-Perfluoroalkanesulfonyl acetate esters are
moderately active methylene compounds that are widely
used in the synthesis of heterocycles and unsaturated
sulfonyl esters.2 The Knoevenagel condensation reaction
between R-perfluoroalkanesulfonyl acetate esters or â-ke-
to aryl sulfones and aldehydes is well-known. Recently,
Hanack2 and others3 reported that perfluoroalkanesulfo-
nyl acetonitriles and esters can easily undergo Knoev-
enagel condensation with aromatic aldehydes to give
2-aryl-1-perfluoroalkanesulfonyl acrylonitriles and 3-aryl-
2-perfluoroalkanesulfonyl-2-propenoates (Scheme 1).
In 1973, Koshar et al. reported improved and conve-
nient methods for preparing bis(perfluoroalkylsulfonyl)-
methanes from perfluoroalkylsulfonyl fluorides and pre-
paring a variety of substituted â-disulfones by organo-
metallic reactions, alkylations, and halogenations of the
methylene disulfones or derivatives.4 Our laboratory has
also studied chemical transformations of these com-
pounds.5 We found that the reactions of bis(perfluoroal-
(5) (a) Zhu, S. Z.; Xu, G. L.; Qin, C. Y.; Xu, Y.; Chu, Q. L.;
DesMarteau, D. D. Heteroatom Chem. 1999, 10, 147. (b) Zhu, S. Z.;
Pennington, W. T.; DesMarteau, D. D. Inorg. Chem. 1995, 34, 792. (c)
Zhu, S. Z. Heteroatom Chemistry 1994, 5, 9. (d) Zhu, S. Z. Synthesis
1994, 261. (e) Zhu, S. Z. J . Fluorine Chem. 1993, 64, 47. (f) Zhu, S. Z.;
Li, A. W. J . Fluorine Chem. 1993, 60, 175.
(6) Calo, V.; Scordari, F.; Nacci, A.; Schingaro, E.; D’Accolti, L.;
Monopoli, A. J . Org. Chem. 2003, 68, 4406.
(7) (a) Bose, D. S.; Fatima, L.; Mereyala, H. B. J . Org. Chem. 2003,
68, 587. (b) Saloutin, V. I.; Burgart, Y. V.; Kuzueva, O. G.; Kappe, C.
O.; Chupakhin, O. N. J . Fluorine Chem. 2000, 103, 17.
(8) For synthetic methods of substituted dihydrofuran derivatives,
see: (a) Antonioletti, R.; Malancona, S.; Bovicelli, P. Tetrahedron 2002,
58, 8825. (b) J iang, Y.; Ma, D. Tetrahedron: Asymmetry 2002, 13, 1033.
(c) Carrido, J . L.; Alonso, I.; Carretero, J . C. J . Org. Chem. 1998, 63,
9406. (d) Hagiwara, H.; Sato, K.; Nishino, D.; Hoshi, T.; Suzuki, T.;
Ando, M. J . Chem. Soc., Perkin Trans. 1 2001, 2946. (e) Wang, Y. L.;
Zhu, S. Z. Tetrahedron 2001, 57, 3383. (f) Melikyan, G. G.; Vostrowsky,
O.; Bauer, W.; Bestmann, H. J .; Khan, M.; Nicholas, K. M. J . Org.
Chem. 1994, 59, 222.
(1) (a) Hendrickson, J . B.; Bergeron, R.; Giga, A.; Sternbach, D. J .
Am. Chem. Soc. 1973, 95, 3412. (b) Hendrickson, J . B.; Giga, A.;
Wareing, J . J . Am. Chem. Soc. 1974, 96, 2275. (c) Bordwell, F. G.;
Vanier, N. R.; Matthews, W. S.; Hendrickson, J . B.; Skipper, P. L. J .
Am. Chem. Soc. 1975, 97, 7160. (d) Hendrickson, J . B.; Boudreaux, G.
J .; Palumbo, P. S. J . Am. Chem. Soc. 1986, 108, 2358. (e) Hendrickson,
J . B.; Sternbarch, D. D.; Bair, K. W. Acc. Chem. Res. 1977, 10, 306.
(2) (a) Hanack, M.; Bailer, G.; Hackenberg, J .; Subramanian, L. R.
Synthesis 1991, 1205. (b) Menke, O.; Steinhuber, E.; Martinez, A. G.;
Subramanian, L. R.; Hanack, M. Synthesis 1994, 1291.
(3) Goumont, R.; Magder, K.; Tordeux, M.; Marrot, J .; Terrier, F.;
Wakselman, C. Eur. J . Org. Chem. 1999, 2969.
(4) Koshar, R. J .; Mitsch, R. A. J . Org. Chem. 1973, 38, 3358.
10.1021/jo049317y CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/19/2004
6486
J . Org. Chem. 2004, 69, 6486-6488

TABLE 1. Rea ction of 1a w ith Ar om a tic Ald eh yd es
u n d er Kn oeven a gel Con d en sa tion Con d ition s
SCHEME 3
entry
Ar in 2
C6H5 (2a )
productc
3a a
ratiod
yielda (%)
1
92
94
95
2
p-BrC6H4 (2b)
p-NO2C6H4 (2c)
p-CH3C6H4 (2d )
3a b
3b
4
3a c
3a d + 4a d 11
3:2
4:5
5
p-CH3OC6H4 (2e) 3a e + 4a e11
a
Isolated yield based on 1a . b 1a /2c 1:0.6 (equiv). c 3a d and 4a d ,
3a e and 4a e could not be separated by column chromatography.
d
Determined by 1H NMR.
We found that 3a a could also be isolated as the sole
product in 92% yield when 1a was reacted with 2a
under Knoevenagel condensation conditions, but the
expected Knoevenagel condensation product, 2-(4-chloro-
1,1,2,2,3,3,4,4-octafluorobutane-1-sulfonyl)-1,3-diphenyl-
propenone 4a a , was not detected (Scheme 3). It was
obvious that this reaction is different from the reaction
of â-keto aryl sulfones or R-perfluoroalkanesulfonyl ac-
etate esters (Scheme 1).
SCHEME 4
TABLE 2. Ca ta lytic Activity of Differ en t Am in es in th e
Mod el Rea ction
The five-membered heterocyclic structure of 3a a
was further established by single-crystal X-ray diffraction
analysis,9,10 which indicated a trans conformation be-
tween the aryl (Ph, C-25) and the benzoyl (PhCO, C-26)
groups. Moreover, the coupling constant between the
C-25 proton and the C-26 proton was 3.0 Hz in the
1H NMR of 3aa, which also confirmed the trans conforma-
tion.8c,d
To explore the scope of this reaction, we investigated
a variety of substituted aromatic aldehydes under Kno-
evenagel condensation conditions. As shown in Table 1,
benzaldehyde (2a ), 4-bromobenzaldehyde (2b), and 4-ni-
trobenzaldehyde (2c) reacted with 1a and produced
tetrasubstituted 2,3-dihydrofuran as the sole product in
high yield (Table 1, entries 1-3). With an aldehyde
bearing an electron-donating group, such as 2d , two
products, 3a d and 4a d (the Knoevenagel product), were
obtained in a ratio of 3:2. These could not be fully
separated due to their similar polarity (Table 1, entry
4). Another electron-rich aldehyde, 2e, gave a similar
result (Table 1, entry 5).
entry
base (equiv)
time (h)
yielda (%)
1
2
3
4
5
piperidine(0.2)
piperidine(1)
Et3N(1)
PhCH2NH2(1)
PhNH2(1)
5
1
2
1
1
86
84
84
traceb
a
b
Isolated yield based on 2a . Not isolated.
product which reacts further with an additional 1 equiv
of 1a to yield the final product 3. If piperidine was
replaced by inorganic alkalis, such as K2CO3, NaOH,
NaH, etc., no reaction occurred. It could be explained by
their poor solubility in toluene.
The catalytic activity of different amines was investi-
gated (Table 2). We found that increasing piperidine to
1 equiv (based on 1a ) accelerated the reaction (Table 2,
entry 2). Triethylamine can also catalyze this reaction
well except for appreciably longer reaction times (Table
2, entry 3). However, aniline and benzylamine, the
weaker bases, have little catalytic activity (Table 2,
entries 4 and 5). Under the optimized reaction conditions
(1 equiv of piperidine), we synthesized a series of tetra-
substituted 2,3-dihydrofuran derivatives. All of these
results are listed in Table 3.
In further studies, it was found that piperidine
is crucial in this reaction process, and acetic acid is
unnecessary. When the product mixture of 3 and 4
was treated with 1a and piperidine in toluene, the
Knoevenagel product, 4, was transformed completely to
a dihydrofuran derivative 3 (Scheme 4). On the basis of
these facts, it is concluded that 4 is the intermediate
(9) Crystal data for compound 3a a : C27H17ClF8O4S, MW ) 624.92,
monoclinic, P2[1]/C, Mo KR, final R indices [I > 2σ(I)], R1 ) 0.1086,
wR2 ) 0.2887, a ) 12.689(3) Å, b ) 11.775(2) Å, c ) 19.050(4) Å, R )
90°, â ) 104.04°, γ ) 90°, V ) 2761.3(10) Å3, T ) 293(2) K, Z ) 4,
reflections collected/unique: 7878/6341 (Rint ) 0.0357), no observation
[I > 2σ(I)] 4004, parameters 372.
(11) We synthesized 4a d and 4a e by another method. 1H NMR data
(300 MHz, CDCl3): 4a d δ 8.08 (1H, s), 7.95 (2H, d, J ) 7.5 Hz), 7.27-
7.62 (5H, m), 7.11 (2H, d, J ) 8.1 Hz), 2.32 (3H, s); 4a e δ 8.04 (1H, s),
7.96 (2H, d, J ) 7.2 Hz), 7.36-7.59 (5H, m), 6.79 (2H, d, J ) 8.7 Hz),
3.77 (3H, s). Other spectral data will be reported in detail. Manuscript
in preparation.
(10) The bond length of C23-C24 is 1.363 Å, which shows the
double-bonded character; the bond length of C25-C26 is 1.556 Å.
J . Org. Chem, Vol. 69, No. 19, 2004 6487

TABLE 3. Syn th esis of Tetr a su bstitu ted
SCHEME 5
tr a n s-2,3-Dih yd r ofu r a n sa
entry
1
Ar in 2
time (h) product yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a C6H5 (2a )
1
1
1
1.5
1.5
1
1
1.5
1
3a a
3a b
3a c
3a d
3a e
3a f
3a g
3a h
3a j
3ba
3bc
3bd
3bi
84
87
90
78
80
85
88
82
85
70
92
72
54
1a p-BrC6H4 (2b)
1a p-NO2C6H4 (2c)
1a p- CH3C6H4 (2d )
1a p-CH3OC6H4 (2e)
1a p-ClC6H4 (2f)
1a m-ClC6H4 (2g)
1a o-ClC6H4 (2h )
1a 4-pyridyl (2j)
1b C6H5 (2a )
3
0.5
3
1b p-NO2C6H4 (2c)
1b p-CH3C6H4 (2d )
1b 2-furyl (2i)
trans-2,3-dihydrofurans. A rational reaction mechanism
is presented. Further studies for application of this
methodology are ongoing in our laboratory.
10
a
b
1:2 1.05:0.5 (equiv). Isolated yield based on aldehydes.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Syn th esis of Tetr a su bsti-
tu ted tr a n s-2,3-Dih yd r ofu r a n s. A mixture of ClC4F8SO2CH2-
COPh 1a (356 mg, 0.84 mmol), benzaldehyde 2a (43 mg, 0.4
mmol), and piperidine (0.078 mL, 0.8 mmol) in toluene (16 mL)
was heated at reflux for 1 h with azeotropic removal of water
using a Dean-Stark trap. TLC analysis indicated the reaction
was completed. The mixture was cooled to room temperature,
the solvent was removed under reduced pressure, and chroma-
tography (SiO2, hexane/ethyl ether, 10:1) afforded 3a a (213 mg,
84%).
A possible mechanism similar to that reported by Calo
et al.6 is shown in Scheme 5. First, the reaction of 1 with
2 gives the Knoevenagel condensation product R-poly-
fluoroalkanesulfonyl-R,â-unsaturated ketone 4 as the
intermediate. Compound 4 could be a better electrophilic
Michael acceptor than R-polyfluoroalkanesulfonyl-R,â-
unsaturated esters. The newly formed carbon-carbon
double bond is readily attacked by the anion of 1. Then,
a Michael addition affords the enolate anion 5. Finally,
the subsequent intramolecular nucleophilic displacement
of 5 gave the cycloadduct 3. During ring closure, the two
large neighboring groups (Ar and ArCO) preferably
formed trans conformation for the sake of stereohin-
drance.
Ack n ow led gm en t. This work is dedicated to Pro-
fessor Li-Xin Dai on the occasion of his 80th birthday.
Financial support of this work by the National Science
Foundation of China is gratefully acknowledged (Nos.
20032010, 20372077).
In summary, we have found that the reaction of â-keto
polyfluoroalkanesulfones with aldehydes is different from
the traditional Knoevenagel condensation reaction. This
reaction proceeds past the initial condensation product
to provide an efficient and novel method for the stereo-
selective synthesis of fluorine-containing tetrasubstituted
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal method, spectral data of compounds 3a a -3bi, a n d X-ray
crystallographic files for 3a a . This material is available free
of charge via the Internet at http://pubs.acs.org.
J O049317Y
6488 J . Org. Chem., Vol. 69, No. 19, 2004