DABCO-catalyzed reaction of α-halo carbonyl compounds with dimethyl acetylenedicarboxylate: A novel method for the preparation of polysubstituted furans and highly functionalized 2H-pyrans

Full text of DOI:10.1021/jo050903g

SCHEME 1
DABCO-Catalyzed Reaction of r-Halo
Carbonyl Compounds with Dimethyl
Acetylenedicarboxylate: A Novel Method
for the Preparation of Polysubstituted
Furans and Highly Functionalized
2H-Pyrans
Mingjin Fan,† Zeyi Yan,† Weimin Liu,‡ and
Yongmin Liang*,†,‡
SCHEME 2
State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, P. R. China, and
Lanzhou Institute of Chemical Physics, Chinese Academy of
Science, Lanzhou 730000, P. R. China
liangym@lzu.edu.cn
Received May 6, 2005
polysubstituted furans and highly functionalized pyr-
ans.5,6 We work in this field and have recently reported
a novel method for the synthesis of polysubstituted
furans via an ammonium ylide route.7 Based on our
research, the various polysubstituted furans were ob-
tained by the reaction of dimethyl acetylenedicarboxylate
(DMAD) with ammonium ylides in the presence of
anhydrous K2CO3 at room temperature (Scheme 1). This
procedure was then extended to a “one-pot” and catalytic
process (Scheme 2). For better understanding of the
mechanism and the scope of application of this type of
reaction, R-chloro-2-acetylthiophene 2a was chosen as
reactant for the model reaction to optimize reaction
conditions. DMAD was treated with 2.0 equiv of 2a in
the presence of 20 mol % of DABCO and 2.0 equiv of
anhydrous K2CO3 in various solvents at room tempera-
ture. We surprisingly found that a new ring adduct 4a
was formed as a major product along with the formation
of a small amount of the polysubstituted furan 3a in
Polysubstituted furans and highly functionalized 2H-pyrans
were prepared in good yields by DABCO-catalyzed reactions
of R-halo carbonyl compounds with dimethyl acetylenedi-
carboxylate (DMAD) at room temperature.
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Furan and pyran are important building blocks in
many natural compounds having important biological
activities1,2and are also widely used as intermediates in
organic and pharmaceutical synthesis.3,4 These facts have
led to the exploring of new methods for the synthesis of
† Lanzhou University.
‡ Chinese Academy of Science.
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Rodriguez, A. D. Tetrahedron 1995, 51, 4571. (d) Zinsmeister, H. D.;
Becker, H.; Eicher, T. Angew. Chem., Int. Ed. Engl. 1991, 30, 130 (e)
Wurzel, G.; Becker, H. Phytochemistry 1990, 29, 2565. (f) Zinsmeister,
H. D.; Becker, H.; Eicher, T. Angew. Chem., Int. Ed. Engl. 1991, 30,
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10.1021/jo050903g CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/02/2005
8204
J. Org. Chem. 2005, 70, 8204-8207

TABLE 1. Reactions of r-Chloroketone 2a with DMAD
TABLE 2. Reactions of DMAD with Various
Catalyzed by DABCO in Various Solvents
r-Chloroketones
entry
R
time, h
product (yield, %)a
2a
2b
2c
2d
2e
2f
thiophen-2-yl
5-bromothiophen-2-yl
Ph
p-Br-Ph
p-CH3-Ph
4
6
2
3
2
2
6
5
3a (19)
3b (19)
3c (24)
3d (19)
3e (28)
3f (48)
3g (18)
3h (28)
4a (62)
4b (39)
4c (57)
4d (56)
4e (60)
4f (41)
4g (23)
4h (39)
product (yield, %)c
entry
solvent
CH2Cl2
MeCN
Et2O
DMSO
THF
MeCN/Et2O (1:1)
MeCN/THF (1:1)
time, h
3a
4a
1
2
3
4
5
6
7
6a
2
10
19
7
22
6
19
22
37
36
12
14
14
62
48
p-CH3O-Ph
24a
2
2g
2h
2,4-dimethylbenzenyl
1,2,3,4-terthydro-
naphthalen-5-yl
6b
4
a Isolated yields.
3
a Heat to reflux. b Heat to 50 °C. c Isolated yields.
To test this strategy for the synthesis of polysubsti-
tuted furans exclusively, we used R-bromoketones instead
of R-chloroketones in this process and got excellent
results using CH2Cl2 as a solvent. In the reaction of
DMAD with R-bromoketones (2.0 equiv) in the presence
of 20 mol % of DABCO and 2.0 equiv of anhydrous K2-
CO3 in CH2Cl2 at room temperature, trace or no 2H-pyran
was produced. We got polysubstituted furans in good to
excellent yields exclusively (Table 3). Comparing the
results obtained from R-bromoketones and R-chloroke-
tones, we can choose different R-halo carbonyl com-
pounds, R-bromo or R-chloro, to get different products,
pyrans or furans, according to our requests.
We also used this method in the synthesis of tetrasub-
stituted furans and got good results as well. For example,
R-bromoketone 2q reacted with DMAD in the presence
of 20 mol % of DABCO and 2.0 equiv of anhydrous K2-
CO3 in toluene under reflux, giving a moderate yield of
the tetrasubstituted furan 3i, which can be efficiently
transformed to a tetrahydrofuran lignan10 (Scheme 3).
When the procedures described above were conducted
using R-halo ester, acid, or acetylamine to obtain furans
various solvents (Table 1), which is obviously different
from the results we obtained previously via the reaction
between the quaternary ammonium salt of R-chloro-2-
acetylthiophene and DMAD.7 From the results we can
see that the reactions proceeded very slowly in CH2Cl2,
Et2O, and THF at room temperature and the reaction
mixture needed to be heated to get moderate yields
(entries 1, 3, and 5). In MeCN and DMSO, although the
reactions completed within 2 h, low yields were observed
because of the formation of many byproducts (entries 2
and 4). The reaction in mixed solvents, such as MeCN/
Et2O (1:1), MeCN/THF (1:1), and especially MeCN/ Et2O
(1:1) (entry 6), was better than the other ones and needed
no heating or long reaction time to give good yields. So
MeCN/Et2O (1:1) was chosen as the most effective solvent
for the reactions of R-chloroketones with DMAD at room
temperature.
Then we examined the reaction of various R-chloroke-
tones with DMAD under the chosen reaction conditions.
To enhance the selectivity, we used an excess of R-chlo-
roketones (3.0 equiv) and anhydrous K2CO3 (3.0 equiv)
with the intention to get 2H-pyran derivatives exclu-
sively. All results are summarized in Table 2. In the
presence of a catalytic amount of DABCO (20 mol %) and
K2CO3 (3.0 equiv) in MeCN/Et2O (1:1) at room temper-
ature, 2H-pyran derivatives 4 rather than expected
furans 3 were formed as major products (entries 2a-e,
2g, 2h). Only for 2f, furan derivatives 3f and 2H-pyran
derivatives 4f were produced almost equally. In most
cases, the generation of furan 3 and 2H-pyran 4 was not
greatly effected by changes in the R group except that
when R was changed to a large group, a lower yield was
obtained because of the steric hindrance (entries 2g and
2h). The structures of furan 3 and 2H-pyran 4 were
determined by NMR spectra, MS, HRMS data of all
compounds, and X-ray diffraction for 3c8 and 4e.9
(8) Crystal data for 3c: C14H12O5, mp 68-70 °C; chemical formula
weight 260.24; monoclinic space group P2(1)/c, a ) 14.698(2), b )
11.720(1), c ) 7.3105(7) Å; R ) 90.00°, â ) 97.916(9)°, γ ) 90.00°, V )
1247.3(2) Å3. T ) 290(2) K, Z ) 4, Dc ) 1.386 Mg/m3, µ ) 0.106 mm-1
,
λ ) 0.71073 Å, F (000) 544, crystal size 0.52 × 0.48 × 0.48 mm3, 2255
independent reflections [R(int) ) 0.0122]; reflections collected 2690;
refinement method, full-matrix least-squares on F2; goodness-of-fit on
F2 1.073; final R indices [I > 2δ(I)] R1 ) 0.0383, wR2 ) 0.1038, R indices
(all data) R1 ) 0.0524, wR2 ) 0.0138. Extinction coefficient 0.126(7).
Largest diff. peak and hole 0.173 and -0.163 e Å-3
.
(9) Crystal data for 4e: C24H22O6, mp 148-150 °C; chemical
formula weigh 406.42; monoclinic space group P2(1)/c, a ) 7.468(2), b
) 19.811(5), c ) 14.249(4) Å; R ) 90.00°, â ) 96.801(4)°, γ ) 90.00°, V
) 2093.2(10) Å3. T ) 291(2) K, Z ) 4, Dc ) 1.290 Mg/m3, µ ) 0.093
mm-1, λ ) 0.71073 Å, F (000) 856, crystal size 0.56 × 0.45 × 0.34 mm3,
3872 independent reflections [R(int) ) 0.0168]; reflections collected
10796; refinement method, full-matrix least-squares on F2; goodness-
of-fit on F2 1.102; final R indices [I > 2δ(I)] R1 ) 0.0370, wR2 ) 0.1028,
R indices (all data) R1 ) 0.0448, wR2 ) 0.1064. Extinction coefficient
0.0088(13). Largest diff. peak and hole 0.171 and -0.146 e Å-3
.
(10) Pei, W.-W.; Pei, J.; Li, S.-H.; Ye, X. -L Synthesis 2000, 14, 2069.
J. Org. Chem, Vol. 70, No. 20, 2005 8205

tigations,11,12 a plausible mechanism for the reaction of
R-halo carbonyl compounds with DMAD is outlined in
Scheme 5. In this process, a R-halo carbonyl compound
2 undergoes SN2 displacement with tertiary amine
DABCO to give a quaternary ammonium salt a. Depro-
tonation of a with mild base (anhydrous K2CO3) forms
the ylide b, which undergoes Michael addition to DMAD
to give intermediate c. On the one hand, intermediate c
undergoes a [1,3] acyl migration to form an ylide inter-
mediate d. Then the facile enolation takes place to give
furan 3 by a cyclization reaction and regenerates the
catalyst DABCO. On the other hand, intermediate c
undergoes a [1,-3] proton migration to form another ylide
intermediate f, which undergoes SN2 displacement with
a second molecule of the R-halo carbonyl compound to
give a quaternary ammonium salt g. Deprotonation and
then enolization of g in the presence of anhydrous K2-
CO3 form intermediate h. The enolate oxygen of h attacks
nucleophilically the other DMAD carbon to generate the
2H-pyran 4 with recycling of DABCO. In the reaction of
R-bromoketone with DMAD, the low yield of 2H-pyran 4
may be ascribed to the steric hindrance of the bromide
atom. It is difficult for the sterically more hindered
R-bromoketone to undergo SN2 displacement in the
transformation of f to g, formation of furan 3 then
proceeding faster than the formation of 2H-pyran 4. The
sterically less hindered R-chloroketones showed opposite
reactivities. So 2H-pyran derivatives 4 and furan deriva-
tives 3 were formed as major products in the reactions
of R-chloroketones and R-bromoketone with DMAD,
respectively.
TABLE 3. Reactions of DMAD with Various
r-Bromoketones
entry
R
time, h
product (yield, %)a
2i
thiophen-2-yl
5-bromothiophen-2-yl
Ph
p-Br-Ph
p-CH3-Ph
4
6
3
3
3
4
4
5
3a (78)
3b (33)
3c (83)
3d (89)
3e (92)
3f (57)
3g (64)
3h (67)
2j
2k
2l
2m
2n
2o
2p
p-CH3O-Ph
2,4-dimethylbenzenyl
1,2,3,4-terthydro-
naphthalen-5-yl
a Isolated yields.
SCHEME 3
In conclusion, we have developed a convenient method
for the synthesis of polysubstituted furans and highly
functionalized 2H-pyrans. In view of the mild reaction
conditions and the availability of the starting materials,
this procedure should be suited for the preparation of
sensitive furans and highly functionalized 2H-pyrans on
a large scale. Further studies are under way in our
laboratory to extend this mild annulation strategy to
synthesis of other classes of heteroromatic compounds.
SCHEME 4
Experimental Section
Using 2a as Example. DABCO (0.1 mmol) was added to a
stirred solution of 2a (1.5 mmol) in 6 mL of MeCN/Et2O (1:1),
and the mixture was stirred at room temperature (25-30 °C)
for 30 min. Anhydrous K2CO3 (1.5 mmol) was added, followed
by dimethyl acetylenedicarboxylate (0.5 mmol). The reaction was
stirred at room temperature until thin layer chromatographic
analysis showed complete consumption of the dimethyl acety-
lenedicarboxylate. H2O (10 mL) was added to the mixture and
extracted thrice with 15 mL of CH2Cl2. The combined extracts
were washed with H2O and brine and then dried (MgSO4). The
solvent was evaporated under reduced pressure, and the residue
was purified by flash chromatography on silica column to give
the 2H-pyran 4a.13
(11) Hori, M.; Kataoka, T.; Shimizu, H.; Tsutsumi, K.; Hu, Y.-Z.;
Nishigiri, M. J. Chem. Soc., Perkin Trans. 1 1990, 1, 39.
(12) Higo, M.; Mukaiyama, T. Tetrahedron Lett. 1970, 29, 2565.
(13) Spectral data for 4a: 1H NMR (300 MHz, CDCl3) δ 3.59(s,
3H), 3.78(s, 3H), 5.94(s, 1H), 6.01(s, 1H), 7.07-7.13(m, 2H), 7.47(d, J
) 4.8 Hz, 1H), 7.53(d, J ) 2.7 Hz, 1H), 7.61(d, J ) 3.9 Hz, 1H), 7.72(d,
J ) 4.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 52.3, 53.2, 72.5, 97.6,
110.8, 128.5, 128.7, 128.8, 130.2, 134.6, 135.3, 136.0, 142.8, 144.6, 154.6,
164.0, 169.8, 187.0. IR (KBr) v 2953, 1741, 1710, 1658, 1412, 1254,
1086, 756 cm-1. MS m/z (%) 390(M+, 2.92), 359(0.79), 331(52.84), 111-
or 2H-pyrans, the method becomes invalid. Only addition
products were observed in some cases (Scheme 4).
It is worthy to note that these reactions do not take
place in the absence of DABCO, which suggests that the
tertiary amine is required as a catalyst in this procedure.
On the basis of above observations and previous inves-
(100). HRMS calcd for C18H14O6S2 (M
408.0567.
+ NH4) 408.0570, found
8206 J. Org. Chem., Vol. 70, No. 20, 2005

SCHEME 5
Other detailed experimental procedures are presented in
Supporting Information.
Supporting Information Available: Experimental pro-
cedures and spectral data of all compounds and single-crystal
X-ray crystallographic data for compounds 3c and 4e in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank the NSF-20021001,
NSF-20172024 and the “Hundred Scientist Program”
from the Chinese Academy of Sciences for the financial
support of this work.
JO050903G
J. Org. Chem, Vol. 70, No. 20, 2005 8207