One-pot synthesis of E-alkylidene derivatives of 3H-furan-2-ones from 4-pentynoic acid and aldehyde

Article abstract of DOI:10.1055/s-2005-865203

4-Pentynoic acid reacts with aldehyde under the co-catalyst system of Wilkinson's complex and 2-aminopyridine to give E-alkylidene derivatives of 3H-furan-2-one through the transition metal-catalyzed cyclization of 4-pentynoic acid followed by condensatio

Full text of DOI:10.1055/s-2005-865203

LETTER
1113
One-Pot Synthesis of E-Alkylidene Derivatives of 3H-Furan-2-ones from
4-Pentynoic Acid and Aldehyde
O
ne-PotSynth
u
esisof
E
-A
l
n
kylidene
D
er
g
ivatives -Gon Lim, Bong-Il Kwon, Moon-Gun Choi, Chul-Ho Jun*
Center for Bioactive Molecular Hybrid (CBMH) and Department of Chemistry, Yonsei University, Seoul 120-749, Korea
Fax +82(2)31472644; E-mail: junch@yonsei.ac.kr
Received 7 February 2005
acid and aldehyde using a co-catalyst system of Wilkin-
son’s complex and 2-aminopyridine.
Abstract: 4-Pentynoic acid reacts with aldehyde under the co-cata-
lyst system of Wilkinson’s complex and 2-aminopyridine to give E-
alkylidene derivatives of 3H-furan-2-one through the transition
metal-catalyzed cyclization of 4-pentynoic acid followed by con-
densation of the resulting lactone with aldehyde.
The reaction of benzaldehyde (1a) and 4-pentynoic acid
(2) in the presence of (PPh3)3RhCl (3, 5 mol%) and 2-ami-
no-3-picoline (4a, 40 mol%) was performed at 100 °C in
toluene for 3 hours to afford (E)-3-benzylidene-3H-furan-
2-one (5a)7 in a 74% isolated yield (82% yield by GC) af-
ter chromatographic isolation (Table 1, entry 1). When the
reaction was carried out without 4a under identical reac-
tion conditions, only 5-methylenedihydrofuran-2-one (6)8
was obtained.
Key words: lactone, lactam, Wilkinson’s complex, aldehyde, 4-
pentynoic acid
Interest in the chemistry of 5-substituted E-alkylidene de-
rivatives of 3H-furan-2-one has recently emerged because
of its potential antifungal uses such as preserving agricul-
tural crops and wooden products.1 However, only a few
synthetic methods for these compounds have been report-
ed,2–4 and many individual reaction steps2 or high pressure
reaction conditions3 are required to obtain these com-
pounds.
From these results, the reaction mechanism can be in-
ferred as described in Scheme 1. Initially 4-pentynoic acid
(2) undergoes cyclization under catalyst 3 to furnish 6.
The rhodium-catalyzed cyclization of alkynoic acid 2 to
alkylidene lactone 6 was previously reported.9 Lactone 6
might be further isomerized to the more stable lactone 7.10
Subsequent condensation of 7 with benzaldehyde (1a) in
the presence of base 4a leads to loss of water and 5a. Since
condensation of 7 with aldehydes was known to proceed
via the basic metal salt, sodium acetate,11 various bases
including sodium acetate were applied to the one-pot
transformation of 1a and 2 to 5a (Table 1). All bases ex-
cept 2-aminopyridine derivatives were ineffective.
Among various 2-aminopyridine derivatives (Table 1,
entries 1–3), 2-aminopyridine showed the best reactivity.
Interestingly, 4-aminopyridine (Table 1, entry 4) or sodi-
um acetate (entry 8) did not show any reactivity.
Recently, we developed an efficient co-catalytic system of
Wilkinson’s complex and 2-amino-3-picoline for the in-
termolecular hydroacylation of alkenes or alkynes with al-
dehydes giving ketones or a,b-enones.5,6 During the
course of our studies on this intermolecular hydroacyla-
tion of various functionalized alkynes, we found that the
reaction of benzaldehyde (1a) with 4-pentynoic acid (2) in
the presence of Wilkinson’s complex (3) and 2-amino-3-
picoline (4a) resulted in (E)-3-benzylidene-3H-furan-2-
one (5a) exclusively instead of the expected hydroacyla-
tion product, a,b-enone6 (Equation 1). Herein, we report
an unprecedented one-pot synthesis of E-alkylidene de-
rivatives of 3H-furan-2-one derived from 4-pentynoic
Table 1 Reaction of Benzaldehyde (1a) and 4-Pentynoic Acid (2)
with Various Bases 4a
Entry
Base 4
5a (%)b
H
O
O
1
2
3
4
5
6
7
8
2-Amino-3-picoline (4a)
2-Amino-6-picoline (4b)
2-Aminopyridine (4c)
4-Aminopyridine (4d)
Pyridine (4e)
74
45
75
0
Ph
O
Ph
H
(PPh3)3RhCl (3)
2-amino-3-picoline (4a)
H
1a
CH3
5a
O
+
toluene, 100 °C, 3 h
O
OH
CO2H
2
Ph
0
hydroacylation product
Aniline (4f)
0
Equation 1
Cyclohexylamine (4g)
Sodium acetate (4h)
0
0
SYNLETT 2005, No. 7, pp 1113–1116
Advanced online publication: 14.04.2005
DOI: 10.1055/s-2005-865203; Art ID: U04105ST
© Georg Thieme Verlag Stuttgart · New York
0
2.
0
5.
2
0
0
5
a Reagents: 1a (0.216 mmol), 2 (0.432 mmol), 3 (0.011 mmol), 4
(0.086 mmol) in toluene at 100 °C for 3 h.
b Isolated yields.

1114
S.-G. Lim et al.
LETTER
Ph
Ph
O
O
O
NH
olefin
isomerization
O
O
3
8
3
O
O
O
2
OH
O
4c
3
2
6
7
10
7
OH
O
O
Ph NH2
–Ph NH2
-H2O
O
Ph
1a
4a
9
5a
O
5a
Scheme 1 Proposed mechanism for the reaction of 1a and 2 under
the co-catalyst systems of 3 and 4a.
Scheme 2 Proposed reaction mechanism of aldimine 8 and 2.
was confirmed when compound 5a was allowed to react
with aniline at 100 °C for 12 hours to give 9 in 76% iso-
lated yield (Equation 2).
When the reaction was carried out with various aldehydes
1 (Table 2, entries 1–6), corresponding (E)-3-arylidene-5-
methyl-3H-furan-2-one 5 was isolated in fairly good
yields.
In conclusion, we have demonstrated a highly efficient
one-pot synthesis of E-alkylidene derivatives of 3H-fu-
ran-2-one from 4-pentynoic acid and aldehyde under a
Rh(I) catalyst and 2-aminopyridine. In addition, a novel
direct one-pot synthesis of lactam was achieved by use
of aldimine instead of aldehyde. Detailed mechanistic
studies on the role of 2-aminopyridine, and further appli-
cations of this one-pot reaction with various alkynoic
acids and aldehydes are underway.
It is interesting to note that even with ferrocenecarboxal-
dehyde (1g), a good yield of the corresponding compound
5g was obtained (Table 2, entry 7). However, with an ali-
phatic aldehyde such as cyclohexanecarboxaldehyde
(1h), only a trace amount (4%) of 5h was produced
(Table 2, entry 8). The reason must be that the reaction of
aromatic aldehyde with 2 leads to an extended conjuga-
tion of lactone 7 with the aromatic group of the aldehyde
through condensation while that of aliphatic aldehyde
with 2 does not. This hypothesis can be proven by the re-
action of 2 with 1-cyclohexenecarboxaldehyde (1i),
which gives an 81% isolated yield of the extended conju-
gation compound 5i (Table 2, entry 9).
Acknowledgment
This work was supported by the Center for Bioactive Molecular
Hybrid (CBMH).
Another interesting thing to note was that the use of
aldimine instead of aldehyde led to the formation of
lactam: aldimine 8 reacted with 2 at 100 °C for 24 hours
to give lactam 9 in 82% isolated yield (Equation 2).
References
(1) (a) Rossi, R.; Bellina, F.; Mannina, L. Tetrahedron 1997, 53,
1025. (b) Bellina, F.; Carpita, A.; De Santis, M.; Rossi, R.
Tetrahedron 1994, 50, 12029.
(2) Rossi, R.; Bellina, F.; Bechini, C.; Mannina, L.; Vergamini,
P. Tetrahedron 1998, 54, 135.
(3) Huang, Y.; Alper, H. J. Org. Chem. 1991, 56, 4534.
(4) (a) Rao, Y. S. Chem. Rev. 1976, 76, 625. (b) Rao, Y. S.
Chem. Rev. 1964, 64, 353.
(5) For intermolecular hydroacylation using various aldehydes
or aldimines with alkenes see: (a) Jun, C.-H.; Lee, D.-Y.;
Lee, H.; Hong, J.-B. Angew. Chem. Int. Ed. 2000, 39, 3070.
(b) Jun, C.-H.; Hong, J.-B. Org. Lett. 1999, 1, 887. (c) Jun,
C.-H.; Lee, D.-Y.; Hong, J.-B. Tetrahedron Lett. 1997, 38,
6673. (d) Jun, C.-H.; Huh, C.-W.; Na, S.-J. Angew. Chem.
Int. Ed. 1998, 37, 145. (e) Jun, C.-H.; Lee, H.; Hong, J.-B. J.
Org. Chem. 1997, 62, 1200.
H
O
N
3 (5 mol%)
N
H
4c (40 mol%)
(1)
H
8
+
2
toluene, 100 °C, 24 h
CH3
9
81% isolated yield
(100% GC yield)
(1.2 equiv)
9
(2)
5a
+
Ph NH2
(1 equiv)
76% isolated yield
(100% GC yield)
toluene, 100 °C, 12 h
(6) For intermolecular hydroacylation using various aldehydes
with alkynes see: Jun, C.-H.; Lee, H.; Hong, J.-B.; Kwon,
B.-I. Angew. Chem. Int. Ed. 2002, 41, 2146.
Equation 2
(7) The E-stereochemistry of compounds 5a, 5c, and 5d was
determined by NOESY spectroscopic analysis.
The reaction mechanism of this transformation is shown
in Scheme 2. After the initial formation of 7 from 2, it re-
acts with 8 under base 4c to generate 10. The intermediate
10 undergoes b-elimination to afford aniline and lactone
5a, which reacts further with aniline to produce lactam
9.12 The transformation mechanism of 5a with aniline to 9
(8) The reaction of 4-pentynoic acid (2) and (PPh3)3RhCl (3, 5
mol%) was performed in benzene-d6 at 100 °C for 3 h to
afford a 100% yield of 5-methylenedihydrofuran-2-one (6);
the structure was confirmed by 1H NMR spectroscopy. 1H
NMR (benzene-d6): d = 4.60–4.58 (m, 1 H), 4.03–4.01 (m, 1
H), 2.29–2.20 (m, 2 H), 2.12–2.03 (m, 2 H).
Synlett 2005, No. 7, 1113–1116 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of E-Alkylidene Derivatives of 3H-Furan-2-ones
1115
Table 2 Reaction of Aldehydes 1 with 2a
Entry
1
Aldehyde 1
Product 513
Isolated yield (%)b
83 (100)
CHO
H
O
O
H
1a
H
H
CH3
O
5a
2
3
4
5
6
7c
91 (100)
88 (95)
72 (81)
82 (95)
75 (82)
78 (93)
CHO
H
O
MeO
1b
MeO
H
CH3
5b
CHO
H
O
O
F
1c
F
H
CH3
5c6
H
CHO
O
O
F3C
F3C
1d
H
CH3
5d6
CHO
H
O
O
S
S
H
1e
CH3
5e
5f
CHO
H
O
O
1f
H
CH3
H
CHO
O
Fe
O
Fe
H
CH3
O
1g
5g
8c
4 (7)
CHO
H
O
H
CH3
1h
5h
5i
9c
81 (94)
H
O
O
CHO
H
CH3
1i
a Reagents: 1 (0.216 mmol), 2 (0.432 mmol), 3 (0.011 mmol), 4c (0.086 mmol) in toluene at 100 °C for 12 h.
b GC yields are given in parentheses.
c The reaction was carried out at 100 °C for 24 h.
Synlett 2005, No. 7, 1113–1116 © Thieme Stuttgart · New York

1116
S.-G. Lim et al.
LETTER
Anal. Calcd for C13H9F3O2: C, 61.42; H, 3.57. Found: C,
(9) (a) Marder, T. B.; Chan, D. M.-T.; Fultz, W. C.; Calabrese,
J. C.; Milstein, D. J. Chem. Soc., Chem. Commun. 1987,
1885. (b) Chan, D. M.-T.; Marder, T. B.; Milstein, D.;
Taylor, N. J. J. Am. Chem. Soc. 1987, 109, 6385.
(10) (a) Jun, C.-H.; Hwang, D.-C.; Na, S.-J. Chem. Commun.
1998, 1405. (b) Reger, D. L.; Garza, D. G.; Baxter, J. C.
Organometallics 1990, 9, 873.
(11) Egorova, A. Y.; Reshetov, P. V.; Morozova, N. A.;
Sedavkina, V. A. In Chemistry of Heterocyclic Compounds;
Plenum Pub. Co.: New York, 1997, 910.
(12) Moneer, A. I.; Salem, A.; Mohamed el-kasaby, A. J. Chem.
Soc. Pak. 1987, 9, 245.
61.34; H, 3.47.
Compound 5e: IR (KBr): 3058, 2987, 1765, 1638, 1424,
1266, 894, 746 cm–1. 1H NMR (250 MHz, CDCl3): d = 2.19
(s, 3 H), 6.19 (s, 1 H), 7.27 (s, 1 H), 7.41–7.31 (m, 2 H), 7.59
(d, J = 1.6 Hz, 1 H). 13C NMR (62.9 MHz, CDCl3): d = 14.9,
102.2, 124.1, 127.2, 127.4, 127.4, 129.7, 137.3, 157.5,
170.3. MS (EI, 70 eV): m/z (%) = 18 (8), 43 (41), 77 (8), 96
(4), 121 (78), 164 (21), 192 (100) [M + H+]. HRMS: m/z
calcd for C10H8O2S [M + H]+: 192.0245, found: 192.0249.
Anal. Calcd for C10H8O2S: C, 62.48; H, 4.19. Found: C,
62.51; H, 4.28.
(13) General Procedure for One-Pot Synthesis of (E)-Alkylidene
Derivatives of 3H-Furan-2-ones from 4-Pentynoic Acid and
Aldehyde
Compound 5f: IR (KBr): 3053, 2992, 1770, 1632, 1424,
1266, 1169, 930, 741 cm–1. 1H NMR (250 MHz, CDCl3):
d = 2.23 (s, 3 H), 6.40 (s, 1 H), 7.44 (s, 1 H), 7.57–7.49 (m,
2 H), 7.65 (dd, J = 1.6, 7.0 Hz, 1 H), 7.89–7.82 (m, 3 H), 7.99
(s, 1 H). 13C NMR (62.9 MHz, CDCl3): d = 15.1, 102.4,
125.6, 126.1, 127.1, 127.8, 128.0, 128.9, 129.0, 131.2,
132.9, 133.5, 134.0, 134.2, 158.5, 170.2. MS (EI, 70 eV):
m/z (%) = 43 (29), 115 (7.7), 139 (5.2), 165 (100), 208
(23.6), 236 (58.2) [M + H+]. HRMS: m/z calcd for C16H12O2
[M + H]+: 236.0837; found: 236.0817. Anal. Calcd for
C16H12O2: C, 81.34; H, 5.12. Found: C, 81.36; H, 5.13.
Compound 5g: IR (KBr): 3053, 2987, 1755, 1638, 1617,
1424, 1271, 889, 741 cm–1. 1H NMR (250 MHz, CDCl3):
d = 2.12 (s, 3 H), 4.18 (s, 5 H), 4.57–4.52 (m, 4 H), 6.02 (s,
1 H), 7.16 (s, 1 H). 13C NMR (62.9 MHz, CDCl3): d = 15.0,
70.1, 70.5, 72.0, 100.2, 102.5, 121.8, 136.3, 155.0, 170.0.
MS (EI, 70 eV): m/z (%) = 43 (7), 56 (14), 121 (42), 223
(55), 229 (22), 266 (52), 294 (100) [M + H+]. HRMS: m/z
calcd for C16H14O2 Fe [M + H]+: 294.0343; found: 294.0311.
Anal. Calcd for C16H14 FeO2: C, 65.33; H, 4.80. Found: C,
63.63; H, 5.00.
A screw-capped pressure vial (1 mL) was charged with
benzaldehyde (1a, 22.9 mg, 0.216 mmol), 4-pentynoic acid
(2, 42.3 mg, 0.432 mmol), (PPh3)3RhCl (3, 10 mg, 0.011
mmol), 2-aminopyridine (4c, 8.1 mg, 0.086 mmol), and
toluene (0.2 mL). The reaction mixture was stirred at 100 °C
for 12 h. After the reaction reached completion, the mixture
was purified by column chromatography (n-hexane–ethyl
acetate, 5:1) to give 5a (33.3 mg, 83%).
Compound 5a: IR (KBr): 3058, 2982, 2931, 1770, 1734,
1668, 1602, 1424, 1266, 899, 746 cm–1. 1H NMR (250 MHz,
CDCl3): d = 2.19 (s, 3 H), 6.29 (s, 1 H), 7.28 (s, 1 H), 7.46–
7.34 (m, 3 H), 7.56–7.53 (m, 2 H). 13C NMR (62.9 MHz,
CDCl3): d = 15.0, 102.1, 125.5, 128.5, 129.1, 130.1, 134.0,
135.2, 158.4, 170.0. MS (EI, 70 eV): m/z (%) = 43 (100), 63
(9), 89 (9), 115 (54), 158 (21), 186 (84) [M + H+]. HRMS:
m/z calcd for C12H10O2 [M + H]+: 186.0681; found:
186.0683.
Compound 5b: IR (KBr): 3058, 2987, 2839, 1770, 1638,
1601, 1510, 1428, 1266, 899, 746 cm–1. 1H NMR (250 MHz,
CDCl3): d = 2.18 (s, 3 H), 3.85 (s, 3 H), 6.26 (s, 1 H), 6.94
(d, J = 8.4 Hz, 2 H), 7.23 (s, 1 H), 7.51 (d, J = 8.4 Hz, 2 H).
13C NMR (62.9 MHz, CDCl3): d = 14.9, 55.6, 102.0, 114.7,
123.1, 128.0, 131.9, 134.0, 157.3, 161.2, 170.0. MS (EI, 70
eV): m/z (%) = 43 (11), 102 (11), 115 (3.6), 145 (100), 173
(4.3), 188 (17.3), 216 (62.6) [M + H+]. HRMS: m/z calcd for
C13H12O3 [M + H]+: 216.0786, found: 216.0782. Anal. Calcd
for C13H12O3: C, 72.21; H, 5.59. Found: C, 72.36; H, 5.48.
Compound 5c: IR (KBr): 3053, 2986, 1770, 1632, 1509,
1418, 1263, 895, 737 cm–1. 1H NMR (250 MHz, CDCl3):
d = 2.20 (s, 3 H), 6.24 (s, 1 H), 7.16–7.04 (m, 2 H), 7.23 (s,
1 H), 7.56–7.51 (m, 2 H). 13C NMR (62.9 MHz, CDCl3):
d = 15.0, 101.8, 116.3, 116.6, 125.3, 131.6, 131.9, 132.1,
132.7, 161.6, 165.6, 170.0. MS (EI, 70 eV): m/z (%) = 43
(60), 83 (5), 107 (6), 133 (48), 176 (21), 204 (100) [M + H+].
Anal. Calcd for C12H9FO2: C, 70.58; H, 4.44; found: C,
70.44; H, 4.51.
Compound 5d: IR (KBr): 3053, 2990, 1778, 1638, 1601,
1510, 1426, 1327, 899, 746 cm–1. 1H NMR (250 MHz,
CDCl3): d = 2.23 (s, 3 H), 6.27 (m, 1 H), 7.28 (s, 1 H), 7.70–
7.58 (m, 4 H). 13C NMR (62.9 MHz, CDCl3): d = 15.2,
102.0, 126.0, 126.1, 126.2, 127.8, 130.0, 131.7, 138.7,
160.2, 169.4. MS (EI, 70 eV): m/z (%) = 43 (85), 133 (8),
164 (7), 183 (10), 235 (6), 254 (100) [M + H+]. HRMS: m/z
calcd for C13H9O2F3 [M + H]+: 254.0555; found: 254.0557.
Compound 5h: IR (KBr): 3052, 2984, 2933, 2853, 1776,
1648, 1421, 1267, 913, 704 cm–1. 1H NMR (250 MHz,
CDCl3): d = 1.71–0.89 (m, 10 H), 2.11 (s, 3 H), 2.36–2.32
(m, 1 H), 5.83 (s, 1 H), 6.44 (d, J = 9.84 Hz, 1 H). 13C NMR
(62.9 MHz, CDCl3): d = 14.8, 25.6, 25.8, 32.2, 39.8, 101.1,
126.4, 144.8, 155.7. MS (EI, 70 eV): m/z (%) = 43 (42), 67
(10), 82 (38), 110 (100), 124 (7), 149 (5), 192 (29) [M + H+].
Compound 5i: IR (KBr): 2941, 2859, 1779, 1632, 1602,
1439, 1296, 909, 741 cm–1. 1H NMR (250 MHz, CDCl3):
d = 1.77–1.60 (m, 4 H), 2.13 (s, 3 H), 2.36–2.26 (m, 4 H),
6.06 (s, 1 H), 6.33 (t, J = 3.98 Hz, 1 H), 6.87 (s, 1 H). 13
C
NMR (62.9 MHz, CDCl3): d = 14.8, 21.6, 22.4, 26.9, 27.1,
99.8, 102.8, 122.0, 136.5, 138.4, 142.4, 155.3. MS (EI, 70
eV): m/z (%) = 43 (79), 80 (100), 91 (53), 111 (24), 119 (31),
147 (61), 190 (79) [M + H+]. HRMS: m/z calcd for C12H14O2
[M + H]+: 190.0994; found: 190.0993.
Compound 9: IR (KBr): 3062, 1772, 1701, 1622, 1498,
1367, 1161, 910, 733 cm–1. 1H NMR (250 MHz, CDCl3):
d = 2.09 (s, 3 H), 6.19 (s, 1 H), 7.35–7.32 (m, 2 H), 7.58–
7.37 (m, 7 H), 7.72–7.69 (m, 2 H). 13C NMR (62.9 MHz,
CDCl3): d = 15.0, 99.6, 128.0, 128.1, 129.0, 129.3, 129.4,
130.0, 130.2, 131.1, 135.1, 136.1, 146.3, 169.5. MS (EI, 70
eV): m/z (%) = 51 (6), 77 (43), 118 (67), 218 (17), 232 (34),
261 (100) [M + H+]. HRMS: m/z calcd for C18H15NO [M +
H]+: 261.1154; found: 291.1154. Registry Number: 165263-
88-7.
Synlett 2005, No. 7, 1113–1116 © Thieme Stuttgart · New York