Preparation of 2,5-disubstituted furans from terminal ynones and aldehydes with CrCl2, Me3SiCl, and H2O

Article abstract of DOI:10.1055/s-2001-17478

Treatment of α,β-acetylenic ketones with chromium(II) in the presence of aldehydes, Me₃SiCl and water in THF gives 2,5-disubstituted furans in good to excellent yields.

Full text of DOI:10.1055/s-2001-17478

1614
LETTER
Preparation of 2,5-Disubstituted Furans from Terminal Ynones and
Aldehydes with CrCl2, Me3SiCl, and H2O
P
reparation of 2,5-
a
D
isubstitut
z
ed
F
urans uhiko Takai,* Ryotaro Morita, Shuji Sakamoto
Department of Applied Chemistry Faculty of Engineering, Okayama University, Tsushima, Okayama 700-8530, Japan
Fax +81(86)2518094; E-mail: ktakai@cc.okayama-u.ac.jp
Received 15 July 2001
a major product, and 2a was not observed (Equation 2). In
addition, the 2,5-disubstituted furan 4a was obtained un-
expectedly in 5% yield. Because such a one-pot formation
of a furan via cross-coupling of an ynone and an aldehyde
is useful,3 we explored the optimum reaction conditions
for the synthesis.
Abstract: Treatment of , -acetylenic ketones with chromium(II)
in the presence of aldehydes, Me3SiCl and water in THF gives 2,5-
disubstituted furans in good to excellent yields.
Keywords: ynone, furan, chromium(II)
One-electron transfer to , -unsaturated ketones produces
radical enolate species which can undergo further reac-
tions. Among the possible reductants, chromium(II) has a
mild reducing ability, and so the one-electron reduction of
enones proceeds without affecting the coexisting alde-
hydes. This enables chromium(II) to be used in cross-cou-
pling reactions of enones and aldehydes.1a,b,2 In this
communication, we report on reactions between ynones
and aldehydes initiated with chromium(II). When the re-
actions are conducted in the presence of Me3SiCl and wa-
ter, 2,5-disubstituted furans are produced via cross-
coupling of the two carbonyl compounds.3
O
Bu4NF
CrCl2, Me3SiCl
DMF, 0 °C, 4 h
R1CHO +
R2
THF
1a
1 = n-C8H17
R2 = Ph(CH2)2
25 °C, 10 min
R
OH
R2
R1
O
R1
R2
+
(2)
OH
3a 32%
4a 5%
Equation 2
The yield of the furan 4a increased to 51% by changing
the solvent from DMF to THF and stirring the mixture for
24 h.5 Moreover, addition of 1.0 equiv of water to the mix-
ture increased the yield to 80% (Equation 3). Further ad-
dition of water (5.0 equiv), however, resulted in a
decrease in the yield (31%). When D2O was used in the re-
action, deuterium was incorporated at the 3 position of 4a
in 70% content.
A mixture of ynone 1a and nonanal was treated with CrCl2
in DMF at 25 °C. The aldehyde was consumed in 30 min,
and the Baylis-Hillman-type adduct 2a was obtained as a
major product (37% yield) after hydrolysis (Equation 1).
In the case of the internal ynone 1b, the coupling product
2b, having a Z-configuration, was obtained in 44% yield.4
The reaction was accelerated and the yield increased to
66% by addition of Et2AlCl.
O
R2
R1
O
CrCl2, Me3SiCl
OH
O
CrCl2
(8.0 equiv.)
R1CHO
O
+
R2
(3)
THF, 25 °C, 24 h
n-C8H17
R' (1)
R'
1a
1 = n-C8H17
R2 = Ph(CH2)2
+
n-C8H17CHO
(D)
4a
DMF, 25 °C
R
2
R
R
(2.0 equiv.)
1
additive
none
D2O
51%
80% (D: 70%)
a: R = H
additive none
none
0.5 h 37%
3 h 44%
R' = Ph(CH2)2
b: R = Bu
Equation 3
Et2AlCl (2.0 equiv.) 2 h 66%
Equation 1
The results of the synthesis of 2,5-disubstituted furans
from ynones and aldehydes are shown in the Table. Be-
cause organochromium reagents add selectively to alde-
hydes, the furan formation can be accomplished without
affecting the coexisting ketone group (Table, entry 5).6
Because reduction of the substituted ynone 1b with CrCl2
did not proceed in THF at 25 °C (95% recovery after stir-
ring for 24 h), a 2,3,5-trisubstituted furan could not be ob-
tained. In order to reduce the amount of the chromium
salt, a catalytic cycle with manganese as a reductant of
chromium(III) was examined.7 However, the yield of 4a
The reaction course changed markedly when Me3SiCl
was present in the reaction mixture.2b For example, treat-
ment of a mixture of 1a (2.0 equiv) and nonanal with
CrCl2 (8.0 equiv) in the presence of Me3SiCl (6.0 equiv)
in DMF at 0 °C for 4 h, followed by desilylation with
Bu4NF (4.0 equiv), gave the cross Pinacol-type diol 3a as
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1614,1616,ftx,en;Y14001st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Preparation of 2,5-Disubstituted Furans
1615
Table Synthesis of 2,5-Disubstituted Furansa
CrIIIO
R1
O
HO
O
O
O
R1
R1
R2
O
R2
R2
R2
R1
CrCl2, Me3SiCl, H2O
5
R1CHO
R2
+
9
R1CHO
1. R1CHO
2. H2O
THF, 25 °C, 24 h
CrII
CrII
OH
Entry
R1
R2
Yield /%b
OCrIII
CrIIIO
O
HO
O
1
2
3
4
5
6
7
8
n-C8H17
Ph(CH2)2
(4a)
80
31c
65
73
79
72
57
70
R2
R1
R2
R1
R2
6
H2O
CrIII
7
8
H3O+
(D3O+)
c-C6H11
Ph
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
c-C6H11
c-C6H11
c-C6H11
O
O
CrIIIO
O
(D)
R2
(D)
R1
R2
R2
MeCO(CH2)8
Ph(CH2)2
c-C6H11
Ph
R1
H2O
(D)
11
CrII
R1CHO
12
OH
O
R1
OCrIII
R2
R1
R2
O
O
(D)
CrIII
R2
10
H
a Reactions were conducted on a 1.0 mmol scale. Ynone (2.0 mmol),
CrCl2 (8.0 mmol), Me3SiCl (6.0 mmol), and water (1.0 mmol) were
used per mmole of an aldehyde.
(D)
(D)
13
b Isolated yields.
Scheme 1
c CrCl2 (0.8 mmol), Mn (8.0 mmol), Me3SiCl (6.0 mmol), and water
(1.0 mmol) were used per mmole of nonanal.
pentyn-3-one (0.32 g, 2.0 mmol) in THF (10 mL) was added at
25 °C. After stirring for 24 h at 25 °C, the reaction mixture was
poured into water (10 mL). The mixture was extracted with ether
(3 20 mL) and the organic extracts were dried over anhydrous
magnesium sulfate and concentrated. Purification by column chro-
matography on silica gel (hexane) gave 2-octyl-5-(2-phenyleth-
yl)furan 4a in 80% yield (0.23 g, 0.80 mmol). 4a: bp 130 °C (bath
temp, 0.2 Torr); IR (neat): 3028, 2953, 2926, 2855, 1567, 1497,
1455, 1015, 780, 749, 698, 666 cm–1; 1H NMR (CDCl3): 0.89 (t,
J = 6.8 Hz, 3 H), 1.28–1.32 (m, 10 H), 1.58–1.65 (m, 2 H), 2.57 (t,
J = 7.7 Hz, 2 H), 2.86–2.96 (m, 4 H), 5.84 (s, 2 H), 7.17–7.30 (m, 5
H); 13C NMR (CDCl3): 14.1, 22.7, 28.1, 28.2, 29.2, 29.2, 29.3,
30.0, 31.9, 34.5, 104.9, 105.5, 125.9, 128.3, 128.4, 141.5, 153.4,
154.9.
became 31% yield, probably due to the slow reaction (Ta-
ble, entry 2).
A plausible mechanism for the formation of the Baylis–
Hillman-type adduct and furan, promoted by chromi-
um(II), is shown in Scheme 1. One-electron reduction of
the acetylenic ketone 5 with Cr(II) gives the allenyl eno-
late radical 6. Under anhydrous conditions, an aldol reac-
tion of 6 with an aldehyde proceeds and a second one-
electron reduction gives 7. In contrast to the case of enone,
cyclopropanol formation from 7 does not occur,2a and the
Baylis–Hillman type adduct 8 is produced as a major
product after hydrolysis. When Me3SiCl and water are
added to the reaction mixture, hydrochloric acid is gener-
ated in situ.8 Protonation of the enolate 6 followed by a
Acknowledgement
Financial support by a Grant-in-Aid for Scientific Research on Prio-
rity Area No. 412 from the Ministry of Education, Science, Sports
and Culture of Japan is gratefully acknowledged.
second one-electron reduction proceeds to give the
-
chromioenone 10. When the amount of protons is insuffi-
cient, 8 and 9 are obtained as byproducts.5 Addition of 10
to an aldehyde9 followed by ring closure and elimination
produces the 2,5-disubstituted furan 13.10 This mecha-
nism explains the incorporation of deuterium at the 3-po-
sition of 13 when D2O was used.11,12
References and Notes
(1) (a) For intramolecular carbon-carbon bond formation
between , -acetylenic ketones and carbonyl groups with
chromium(II), see: Smith, A. B. III Strategies and Tactics in
Organic Synthesis; Lindberg, T., Ed.; Academic Press:
Orlando, 1984, 252. (b) See also: Smith, A. B. III;
Levenberg, P. A.; Suits, J. Z. Synthesis 1986, 184.
(2) (a) Toratsu, C.; Fujii, T.; Suzuki, T.; Takai, K. Angew.
Chem. Int. Ed. 2000, 39, 2725. (b) Takai, K.; Morita, R.;
Toratsu, C. Angew. Chem. Int. Ed. 2001, 40, 1116.
(3) (a) Holand, S.; Mercier, F.; Le Goff, N.; Epsztein, R. Bull.
Soc. Chim. Fr. 1972, 4357. (b) Nishio, T.; Omote, Y. J.
Chem. Soc., Perkin Trans. 1 1979, 1703. (c) Sato, F.;
Katsuno, H. Tetrahedron Lett. 1983, 24, 1809.
In conclusion, , -acetylenic ketones are reduced with
chromium(II) in DMF to give allenyl enolate radicals,
which add to aldehydes to give Baylis-Hillman-type prod-
ucts. When the reductions are conducted in the presence
of Me3SiCl and water in THF, 2,5-disubstituted furans are
produced in good to excellent yields.
Typical Procedure
(Table 1, entry 1) To a mixture of CrCl2 (0.98 g, 8.0 mmol) in THF
(14 mL) was added Me3SiCl (0.76 mL, 6.0 mmol) and a THF solu-
tion of water (1.0 mmol), and the mixture was stirred at 25 °C for
20 min. A solution of nonanal (0.14 g, 1.0 mmol) and 5-phenyl-1-
(4) The stereochemistry was assigned by an NOE experiment.
Synlett 2001, No. 10, 1614–1616 ISSN 0936-5214 © Thieme Stuttgart · New York

1616
K. Takai et al.
LETTER
(5) The compounds 2a, 14 (a mixture of stereoisomers), and 15
were also obtained in addition to the furan 4a (Figure).
(11) The pathway for the formation of a furan can be written as in
Scheme 2. However, the allenylic chromium species 17,
which is similar to 16, usually adds to an aldehyde at the -
position via a six-membered transition state to give a
propargylic product selectively (Equation 5). For reactions
of allenylic chromium reagents with carbonyl compounds,
see: (a) Delbecq, F.; Baudouy, R.; Goré, J. Nouv. J. Chim.
1979, 3, 321. (b) Place, P.; Venière, C.; Goré, J.
OH
O
O
OH
O
R1
R1
R2
R2
R1
R2
R1
14
15
3%
2a 13%
21%
OH
OH
Tetrahedron Lett. 1981, 37, 1359.
R1 = n-C8H17 R2 = Ph(CH2)2
OCrIII
OSiMe3
R2
OSiMe3
CrII
Figure
Me3SiCl
R2
R2
CrIII
6
16
(6) The following functional substrates were recovered under
the standard reaction conditions (Table, entry 1)due to the
mild nucleophilicity of the organochromium reagent: 1-
dodecene (94%); 1-dodecyne (95%); 1-chlorododecane
(99%); ethyl octanoate (92%); nonanenitrile (97%); 3-
phenylpropyl acrylate (89%); nonanal ethylene acetal
(92%); 4-phenyl-2-butanone (98%).
R1CHO
H2O
(D2O)
CrIIIO
OSiMe3
R2
O
R1
O
OCrIII
R1
R2
R2
R1
(D)
13
(D)
(7) Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349.
(8) When the reaction of 1a and nonanal was conducted with 1.0
equiv of hydrochloric acid in ether instead of Me3SiCl and
water, only the furan 4a was obtained in 19% yield along
with 14 and 15 both in 15% yield, and 59% of 1a was
recovered. The result suggests that Me3SiCl accelerates the
reduction of 1a with chromium(II), and also suppresses the
formation of 14. The latter effect of Me3SiCl is still obscure.
(9) Knochel, P.; Rao, J. Tetrahedron 1993, 49, 29.
(10) When the E-isomer of -hydroxy , -enone 15 was left to
stand for several hours in CDCl3 (an NMR tube), it
spontaneously isomerized and cyclized to furan 4a
(Equation 4).
Scheme 2
CrCl2
(5)
81%
PhCHO +
OP(OPh)2
O
THF
25 °C, 24 h
HO
Ph
OH
CrIII
Ph
not detected
17
Equation 5
O
R1
R2
- H2O
O
R1
(4)
R2
(12) In the case of SmI2, one-electron transfer to a ketone
proceeds smoothly. Thus, carbon-carbon bond formation at
the -position of an , -unsaturated ester occurred via
radical addition with a proton source. See: (a) Otsubo, K.;
Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986, 27,
5763. (b) Fukuzawa, S.-I.; Seki, K.; Tatsuzaka, M.; Mutoh,
K. J. Am. Chem. Soc. 1997, 119, 1482.
CDCl3
15
OH
4a
R
1 = n-C8H17, R2 = Ph(CH2)2
Equation 4
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