Highly regioselective synthesis of 2,3,5-trisubstituted furans via phosphine-catalyzed ring-opening cycloisomerization reactions of cyclopropenyl dicarboxylates

Article abstract of DOI:10.1055/s-0030-1259904

Different 2,3,5-trisubstituted furans have been regioselectively synthesized through a ring-opening cycloisomerization of functionalized cyclopropenyl carboxylates with moderate to excellent yields by using tri(2-furanyl)phosphine as the catalyst. Georg T

Full text of DOI:10.1055/s-0030-1259904

LETTER
931
Highly Regioselective Synthesis of 2,3,5-Trisubstituted Furans via
Phosphine-Catalyzed Ring-Opening Cycloisomerization Reactions of
Cyclopropenyl Dicarboxylates
S
ynthesis
iof 2,3,5
e
-Trisubstituted F
C
urans hen,a Shengjun Ni,a Shengming Ma*a,b
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. of China
Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, P. R. of China
b
Fax +86(21)62609305; E-mail: masm@sioc.ac.cn
Received 3 December 2010
Dedicated to Professors Xiyan Lu and Lixin Dai
EWG EWG
R1
R2
EWG
EWG
Abstract: Different 2,3,5-trisubstituted furans have been regiose-
lectively synthesized through a ring-opening cycloisomerization of
functionalized cyclopropenyl carboxylates with moderate to excel-
lent yields by using tri(2-furanyl)phosphine as the catalyst.
1. I–
R33P
?
2. R2X
R1
previous work
I
this work
Key words: furans, regioselectivity, ring-opening cycloisomeriza-
tion, cyclopropenes, tri(2-furanyl)phosphine
Scheme 1
Initial attempt to promote ring-opening cycloisomeriza-
tion of readily available cyclopropene 1a led to disap-
pointing results using triphenylphosphine as the catalyst
in toluene at 100 °C; no reaction occurred and 1a was re-
covered in 84% yield as determined by 1H NMR spectro-
scopic analysis (Table 1, entry 1). Trialkylphosphine
derivatives, such as trimethylphosphine and tricyclohexyl-
phosphine, are ineffective in this reaction at 100 °C
(Table 1, entries 3 and 4). Under the similar conditions,
when tris(o-tolyl)phosphine, tris(4-methoxyphenyl)phos-
phine, 3-(diphenylphosphino)cyclohexanone 3, or diphe-
nylphosphine was employed as catalyst, the
corresponding furan 2a could not be obtained either
(Table 1, entries 5–8). To our delight, trace of product 2a
was observed with tri(1-naphthyl)phosphine as the cata-
lyst (Table 1, entry 9). When tri(2,4,6-trimethoxyphe-
nyl)phosphine was used, the yield was slightly higher
(Table 1, entry 10). Gratifyingly, the use of tri(2-fura-
nyl)phosphine led to formation of 2a in 78% yield with 1a
being recovered in 10% yield (Table 1, entry 11). By con-
ducting the reaction at 150 °C, complete conversion of 1a
was reached, and the corresponding product 2a was ob-
tained in 90% isolated yield (Table 1, entry 12). Forma-
tion of product 2a was not observed when nitrogen-
containing nucleophilic catalysts, such as DMAP, DBU,
and DABCO, were employed (Table 1, entries 13–15).
The reaction could not occur without any catalyst
(Table 1, entry 2).
Organophousphorus compounds have been widely used
in synthetic organic chemistry.1 For example, phosphines
have been extensively used as ligands in the transition-
metal-catalyzed reactions.2 They are also used as reagents
in the Wittig reaction,3 Staudinger reaction,4 and Mitsuno-
bu reaction,5 etc. Furthermore, phosphines can be used as
a class of nucleophilic organocatalysts, which was first re-
ported in late 1960s.6 Recently, since two types of phos-
phine-catalyzed reactions, that is, the isomerization of
a,b-ynones and the [3+2] cycloaddition of 2,3-butadi-
enoates or 2-butynoates with electron-deficient olefins,
were independently developed by Lu’s group and Trost’s
group, reports of phosphines as nucleophilic catalysts
have grown significantly.7 Cyclopropenes, highly strained
but readily accessible carbocyclic molecules, have been
shown to possess interesting reactivities in organic syn-
thesis.8 There are many reports on the ring-opening reac-
tions of cyclopropenes in the literature. Transition metals,
such as Rh, Ru, Pd, Cu, Au, Fe, Ag, etc. have been found
to be good catalysts in these reaction.9 In 2003, we report-
ed an X– (X = I, Br) triggered ring-openging coupling
reaction of functionalized cyclopropenes with organic
halides, imines, or 1,1-bis(phenylsulfonyl)ethylene
(Scheme 1).10 However, to the best of our knowledge, the
ring-opening reaction of cyclopropenes catalyzed by or-
ganocatalyst has not been reported so far.11 Herein, we
wish to report the first phosphine-catalyzed ring-opening
cycloisomerization reaction of cyclopropenyl dicarboxy-
lates for the highly regioselective synthesis of 2,3,5-
trisubstituted furans.
Then the solvent effect was examined, and different sol-
vents provided different outcomes for this reaction
(Table 2). No reaction occurred in MeNO2, MeCN, Et2O,
CH2Cl2, or THF (Table 2, entries 2–6). Low conversion
was observed in NMP, DCE, or dioxane (Table 2, entries
SYNLETT 2011, No. 7, pp 0931–0934
x
x.
x
x.
2
0
1
1
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1259904; Art ID: W32910ST
© Georg Thieme Verlag Stuttgart · New York

932
J. Chen et al.
LETTER
Table 1 Cycloisomerization of 1a under Different Reaction Condi-
Table 2 Cycloisomerization of 1a in Different Solventa
tions with Organocatalystsa
O
MeO2C CO2Me
CO2Me
OMe
MeO2C CO2Me
catalyst (10 mol%)
toluene, temp, time
CO2Me
OMe
(2-furanyl)3P (10 mol%)
n-Bu
n-Bu
n-Bu
solvent, temp, time
n-Bu
O
O
PPh2
1a
1a
2a
2a
3
Entry Solvent
Temp
(°C)
Time
(h)
Yield
Recoveryof
1a (%)
Entry Catalyst
Temp Time Yield
Recovery
of 1a (%)
(%)
89 (90b)
n.r.
n.r.
n.r.
n.r.
n.r.
2
(°C)
100
100
100
100
100
100
100
100
100
(h)
60
48
48
48
48
48
48
25
48
48
96
31
48
48
48
(%)
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
8
1
2
toluene
MeNO2
MeCN
Et2O
150
100
100
70
31
72
72
96
72
96
72
72
96
72
–
1
2
Ph3P
84
84
80
66
88
87
81
83
53
52
10
–
82
–
3
82
3
Me3P
4
80
4
Cy3P
5
CH2Cl2
THF
70
85
5
(2-MeC6H4)3P
(4-MeOC6H4)3P
Ph2PH
6
100
100
100
100
100
68
6
7
NMP
84
7
8
DCE
4
79
8
3
9
dioxane
DMF
22
53
9
(1-naphthyl)3P
10
complicated 12
10
11
12
13
14
15
[2,4,6-(MeO)3C6H2]3P 100
17
a The reaction was conducted in a Schlenk tube with a screw cap, and
the yield was determined by 1H NMR spectroscopic analysis with
MeNO2 as the internal standard.
(2-furanyl)3P
(2-furanyl)3P
DMAP
100
150
100
100
100
78
89 (90b)
n.r.
n.r.
n.r.
b The numbers in the parenthesis are the isolated yield of 2a.
71
71
53
product was obtained in 39% yield (Table 3, entry 13);
with R being 4-MeC6H4, the product was obtained in 62%
yield (Table 3, entry 14); with R being 4-MeO2CC6H4 or
4-O2NC6H4, the reaction was complicated and no except-
ed product was obtained (Scheme 2). In addition, to test
the practicability of the catalytic system, the reaction was
carried out in gram scale (5.0 mmol) of 1a in the presence
of 10 mol% of tri(2-furanyl)phosphine. The desired prod-
uct was obtained in 95% yield (Table 3, entry 2).
DBU
DABCO
a The reaction was conducted in a Schlenk tube with a screw cap and
the yield was determined by 1H NMR spectroscopic analysis with
MeNO2 as the internal standard.
b The numbers in the parenthesis are the isolated yields of 2a.
7–9). Using DMF as the solvent the reaction was compli-
cated and 12% yield of 1a was recovered (Table 2, entry
10). In conclusion, toluene is the optimal solvent for this
transformation (Table 2, entry 1).
MeO2C CO2Me
P(2-furanyl)3 (10 mol%)
complicated
toluene, 150 °C
With the optimized conditions in hand (Table 2, entry 1),
the scope of the reaction was explored (Table 3). With R
being alkyl (Table 3, entries 1–3), cyclohexyl (Table 3,
entry 4), Bn (Table 3, entry 5), PhCH2CH2 (Table 3, entry
6), protected alcohol, such as TBSOCH2CH2 (Table 3,
entry 7), TBSOCH2CH2CH2 (Table 3, entry 8), and
THPOCH2CH2 (Table 3, entry 9), the reaction proceeded
smoothly to afford the corresponding 2,3,5-trisubstituted
furans in excellent yields. However, with R bearing the
unprotected hydroxyl group, the reaction could not occur
and cyclopropene 1i was recovered in 66% yield as deter-
mined by 1H NMR spectroscopic analysis (Table 3, entry
10). Interestingly, for substrates with R being relatively
bulky t-Bu, the reaction could also occur in 86% yield
(Table 3, entry 12). For cyclopropenyl dicarboxylates,
differently substituted aryl group R has an important in-
fluence on the reaction. For example, with R being Ph, the
EWG
EWG = CO2Me or NO2
Scheme 2
A plausible mechanism for this ring-opening cycloi-
somerization reaction is depicted in Scheme 3. Initial at-
tack of the tri(2-furanyl)phosphine at the 2-position of
cyclopropene 1a results in the formation of zwitterionic
phosphonium adduct I. Isomerization from I gives inter-
mediate II, which allows the cyclization to generate the
cyclic zwitterion III.12 Finally, elimination of the phos-
phine catalyst furnishes the furan product 2a.13 The prod-
uct is the same as the one which was obtained in
Synlett 2011, No. 7, 931–934 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,3,5-Trisubstituted Furans
933
MeO2C CO2Me
Table 3 The Scope of Phosphine-Catalyzed Cycloisomerization
Reactions of Cyclopropenyl Dicarboxylatesa
CO2Me
MeO2C CO2Me
CO2Me
OMe
n-Bu
PR3
1a
(2-furanyl)3P (10 mol%)
toluene, 150 °C
n-Bu
OMe
O
R
R
O
2a
1
2
Entry
R
Time
Isolated yield
(h)
31
18
24
24
19.5
24
24
24
25
24
24
19
34
24
of 2 (%)
OMe
MeO2C
O
1
2
1a n-Bu
2a 90
2a 95b
2b 81
2c 94
2d 90
2e 94
2f 92
2g 90
2h 86
–
n-Bu
CO2Me
CO2Me
n-Bu
–
+
1a n-Bu
+PR3
I
R3P
III
3
1b n-C8H17
1c cyclohexyl
1d Bn
4
OMe
CO2Me
5
–O
n-Bu
6
1e PhCH2CH2
1f TBSOCH2CH2
1g TBSOCH2CH2CH2
1h THPOCH2CH2
1i HOCH2CH2
1j n-Bud
R3+P
7
II
R = 2-furanyl
8
Scheme 3 Plausible mechanism of phosphine-catalyzed ring-
opening cycloisomerization
9
c
10
11
12
13
14
–
References and Notes
2j 85
2k 86
2l 39
(1) Quin, L. D. A Guide to Organophosphorus Chemistry;
Wiley: New York, 2000.
(2) (a) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
(b) Börner, A. Phosphorus Ligands in Asymmetric
Catalysis: Synthesis and Applications; Wiley-VCH:
Weinheim, 2008.
(3) Wittig, G.; Geissler, G. Justus Liebigs Ann. Chem. 1953,
580, 44.
(4) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
(5) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380.
(6) (a) Rauhut, M.; Currier, H. US 3074999, 1963. (b) Rauhut,
M.; Currier, H. Chem. Abstr. 1963, 58, 11224a. (c) Morita,
K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41,
2815.
(7) (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
(b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346,
1035. (c) Lu, X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 12,
1985. (d) Ye, L.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008,
37, 1140. (e) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev.
2009, 38, 3102.
(8) (a) Binger, P.; Büch, H. M. Top. Curr. Chem. 1987, 135, 77.
(b) Nakamura, M.; Isobe, H.; Nakamura, E. Chem. Rev.
2003, 103, 1295. (c) Fox, J. M.; Yan, N. Curr. Org. Chem.
2005, 9, 719. (d) Rubin, M.; Rubina, M.; Gevorgyan, V.
Synthesis 2006, 1221. (e) Rubin, M.; Rubina, M.;
Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (f) Marek, I.;
Simaan, S.; Masarwa, A. Angew. Chem. Int. Ed. 2007, 46,
7364. (g) Magnus, P.; Littich, R. Org. Lett. 2009, 11, 3938.
(h) Patel, P. R.; Boger, D. L. J. Am. Chem. Soc. 2010, 132,
8527.
1k t-Bu
1l Ph
1m 4-MeC6H4
2m 62
a The reaction was conducted by using 1 (0.20 mmol) and tri(2-fura-
nyl)phosphine (0.02 mmol) in toluene (0.1 M) at 150 °C in a Schlenk
tube with a screw cap.
b Conditions: 5.0 mmol of 1a were used in this reaction.
c No expected product was obtained and cyclopropene 1i was recov-
ered in 66% yield as determined by 1H NMR spectroscopic analysis.
d Diethyl 2-butylcycloprop-2-ene-1,1-dicarboxylate (1j) was used.
RuCl2(PPh3)3-catalyzed cycloisomerization reaction of
cyclopropene 1a.9o
In conclusion, we have developed a highly regioselective
synthesis 2,3,5-trisubstituted furans14 via phosphine-cata-
lyzed ring-opening cycloisomerization reactions of cyclo-
propenyl dicarboxylates.15 Further studies in this area by
using the intermediates formed in Scheme 3 are currently
under way in our laboratory.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(9) (a) Weiss, R.; Schlierf, C. Angew. Chem. Int. Ed. Engl. 1971,
10, 811. (b) Komendatov, M. I.; Dommin, I. N.; Bulucheva,
E. V. Tetrahedron 1975, 31, 2495. (c) Cho, S. K.;
Liebeskind, L. S. J. Org. Chem. 1987, 52, 2631. (d) Padwa,
A.; Kassir, J. M.; Xu, S. L. J. Org. Chem. 1991, 56, 6971.
(e) Semmelhack, M. F.; Ho, S.; Cohen, D.; Steigerwald, M.;
Lee, M. C.; Lee, G.; Gilbert, A. M.; Wulff, W. D.; Ball, R.
Financial support from the Major State Basic Research and De-
velopment Program (2009CB825300) and National Natural Science
Foundation of China (20732005) is greatly appreciated. We thank
Mr. Xiaobing Zhang in this group for reproducing the results in ent-
ries 4, 7, and 14 in Table 3.
Synlett 2011, No. 7, 931–934 © Thieme Stuttgart · New York

934
J. Chen et al.
LETTER
G. J. Am. Chem. Soc. 1994, 116, 7108. (f) Müller, P.;
Granicher, C. Helv. Chim. Acta 1995, 78, 129. (g) Padwa,
A.; Kassir, J. M.; Xu, S. L. J. Org. Chem. 1997, 62, 1642.
(h) Ma, S.; Zhang, J. J. Am. Chem. Soc. 2003, 125, 12386.
(i) Chuprakov, S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463.
(j) Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem. Int.
Ed. 2007, 46, 7364. (k) Wang, Y.; Fordyce, E. A. F.; Chen,
F. Y.; Lam, H. W. Angew. Chem. Int. Ed. 2008, 47, 7350.
(l) Hoveyda, A. H.; Lombardi, P. J.; O’Brien, R. V.;
Zhugralin, A. R. J. Am. Chem. Soc. 2009, 131, 8378.
(m) Li, C.; Zeng, Y.; Zhang, H.; Feng, J.; Zhang, Y.; Wang,
J. Angew. Chem. Int. Ed. 2010, 49, 6413. (n) Miege, F.;
Meyer, C.; Cossy, J. Org. Lett. 2010, 12, 4144. (o) Chen, J.;
Ma, S. Chem. Asian J. 2010, 5, 2415.
(13) (a) Trost, B. M.; Li, C. J. Am. Chem. Soc. 1994, 116, 3167.
(b) Zhang, C.; Lu, X. Synlett 1995, 645. (c) Du, Y.; Lu, X.;
Zhang, C. Angew. Chem. Int. Ed. 2003, 42, 1035.
(14) Davies, H. M. L.; Romines, K. R. Tetrahedron 1988, 44,
3343.
(15) Representative Procedure for the Synthesis of 2-
Methoxy-3-methoxycarbonyl-5-butylfuran (2a) in a 5.0
mmol Scale
To a Schlenk reaction tube with a screw cap, evacuated and
backfilled with argon, were added sequentially (2-furanyl)3P
(116 mg, 0.50 mmol), cyclopropenyl dicarboxylate 1a
(1.058 g, 4.99 mmol), and toluene (50 mL). The resulting
mixture was refluxed at 150 °C. After 18 h the reaction was
over (monitored by TLC). Evaporation and column
chromatography on silica gel (eluent: PE–EtOAc = 20:1)
afforded the desired product 2a9o (1.005 g, 95% yield); oil.
1H NMR (400 MHz, CDCl3): d = 6.15 (t, J = 1.0 Hz, 1 H,
CH=), 4.05 (s, 3 H, CO2CH3), 3.76 (s, 3 H, OCH3), 2.47 (td,
J = 7.4, 0.8 Hz, 2 H, =CCH2), 1.60–1.50 (m, 2 H, CH2),
1.40–1.29 (m, 2 H, CH2), 0.90 (t, J = 7.4 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 163.6, 161.0, 146.0, 105.8,
91.2, 57.9, 51.0, 29.5, 27.1, 22.0, 13.7. MS (EI): m/z = 212
(19.03) [M+], 169 (100) [M+ – C3H7]. IR (neat): 2955, 2873,
1720, 1607, 1470, 1407, 1278, 1212, 1191, 1138, 1088 cm–1.
(10) (a) Ma, S.; Zhang, J.; Cai, Y.; Lu, L. J. Am. Chem. Soc. 2003,
125, 13954. (b) Ma, S.; Zhang, J.; Lu, L.; Jin, X.; Cai, Y.;
Hou, H. Chem. Commun. 2005, 909. (c) Chen, J.; Ma, S.
J. Org. Chem. 2009, 74, 5595. (d) Chen, J.; Xin, N.; Ma, S.
Tetrahedron Lett. 2009, 50, 3175.
(11) In 2007, Gevorgyan and coworkers reported a phosphine-
catalyzed sila-Morita–Baylis–Hillman reaction of
cyclopropenes, but no ring-opening reaction occurred in this
reaction. See: Chuprakov, S.; Malyshev, D. A.; Trofimov,
A.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 14868.
(12) (a) Ohe, K.; Fujita, M.; Matsumoto, H.; Tai, Y.; Miki, K.
J. Am. Chem. Soc. 2006, 128, 9270. (b) Peng, L.; Zhang, X.;
Ma, M.; Wang, J. Angew. Chem. Int. Ed. 2007, 46, 1905.
Synlett 2011, No. 7, 931–934 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.