A convenient synthesis of 2-alkyl-2-methyltetrahydrofurans from 4- methylalk-4-en-1-ols catalyzed by iodine

Article abstract of DOI:10.1055/s-1998-2080

Cyclization of 4-methylalk-4-en-1-ols in the presence of a catalytic amount of iodine in dichloromethane gave exclusively 2-alkyl-2- methyltetrahydrofurans under mild conditions in high yields.

Full text of DOI:10.1055/s-1998-2080

June 1998
SYNTHESIS
835
A Convenient Synthesis of 2-Alkyl-2-methyltetrahydrofurans from 4-Methylalk-4-en
1-ols Catalyzed by Iodine
Kyoung Mahn Kim, Dong Ju Jeon, Eung K. Ryu*
Korea Research Institute of Chemical Technology, P. O. Box 107, Yusong, Taejon 305-600, Korea
Fax +82(42)8610307; E-mail: ekryu @pado.krict.re.kr
Received 5 August 1997; revised 15 October 1997
Abstract: Cyclization of 4-methylalk-4-en-1-ols in the presence
of a catalytic amount of iodine in dichloromethane gave exclu-
sively 2-alkyl-2-methyltetrahydrofurans under mild conditions in
high yields.
Key words: iodine catalyst, non-iodine containing cyclic etherifi-
cation, 4-methylalk-4-en-1-ols, 2-alkyl-2-methyltetrafurans
The iodine mediated electrophilic cyclization of unsatur-
ated alcohols to substituted tetrahydrofurans is a useful
procedure for the stereocontrolled synthesis of these com-
pounds and polyether antibiotics.1 Furthermore, the stereo-
controlled haloetherifications of 4-methylalk-4-en-1-ols 1
in aqueous sodium hydrogen carbonate/acetonitrile/io-
dine or the protected 4-methylpent-4-en-1-ols in iodine/
acetonitrile/0°C resulted in formation of the 2-iodometh-
yl-2-methyltetrahydrofurans were well documented.1,2
However, we recently reported unanticipated results from
the reaction of 2-(b-methylallyl)phenols and 2-isobute-
Scheme 1
nylphenols with iodine in nonpolar aprotic solvents af-
fording the corresponding 2,2-dimethyl-2,3-dihydro-
benzofurans without iodine containing products.3a Simi-
ble bond generating tertiary carbocation. The steric hin-
drance of 4-methyl group may be effective to prohibit
addition of iodine to the double bond.
larly, the iodine-catalyzed g-lactonization of g-methyl-g,d-
pentenoic acids resulted in the corresponding g,g-dimeth-
yl-g-butyrolactones with trace amounts of iodolactoniza-
tion products.3b In continuing our study, we wish to report
Various 4-hydroxymethyl-2,2-dimethyltetrahydrofurans
2a–e were obtained in good yields through the iodine-cat-
alyzed reaction of the corresponding 4-methylpent-4-en-
1-ols 1a–e. Similarly, 4-methyl-2,2-diphenylhex-4-en-1-
ol (1g) and 4-methyl-2,2-diphenylhept-4-en-1-ol (1h)
gave almost quantitatively the corresponding 2-ethyl-2-
methyl-4,4-diphenyltetrahydrofuran (2g) and 2-methyl-
4,4-diphenyl-2-propyltetrahydrofuran (2h), respectively
(Scheme 1). The reaction of 2,2-bis(2-methallyl)propane-
1,3-diol (3) with iodine under the same conditions gave 3,
3,8,8-tetramethyl-2,7-dioxaspiro[4,4]nonane (4) in 84 %
yield (Scheme 2).
that extention of our systems to 4-methyl-4-alken-1-ols 1
offered very effective synthetic method of 2-alkyl-2-me-
thyltetrahydrofurans 2 under mild reaction conditions and
easy workups.
In order to optimize the conditions for iodine-catalyzed
cyclization, we examined solvent effect on 4-methyl-2,2-
diphenyl-pent-4-enol (1f) as a model substrate with iodine
(0.2 equiv.) in various solvents at room temperature for 30
minutes. 4-Methyl-2,2-diphenylpent-4-enol (1f) with io-
dine (0.2 equiv.) was completely cyclized to 2,2-dimethyl-
4,4-diphenyltetrahydrofuran (2f) without any formation of
iodinatedproductsinnonpolaraproticsolventssuchashex-
ane, benzene, diethyl ether, and dichloromethane. But the
reaction in polar aprotic or protic solvents such as tetrahy-
drofuran, N,N-dimethylformamide, or methanol gave a
mixture of 2f and the iodinated products.
Although the reaction was conducted in an anhydrous
nonpolar aprotic solvent to avoid the external proton
source which may generate hydrogen iodide from io-
dine,3–4 it was assumed that the reaction of 4-methylalk-4-
en-1-ol 1 with iodine should generate hydrogen iodide.
The key feature of the mechanism may involve the addi-
tion of hydrogen iodide, which is initially formed by the
1–2 R1
R2
R3 1–2 R1
R2
R3
a
b
c
H
CH3
CH2OH
CH2OH
H
H
H
H
e
f
g
h
Benzyl CH2OH
H
H
Ph
Ph
Ph
Ph
Ph
Ph
CH2OH3 CH2OH
n-Butyl CH2OH
CH3
CH2CH3
d
interaction of iodine with free hydroxy group, to the dou- Scheme 2

836
Short Papers
SYNTHESIS
Table. Synthesis of 2-Alkyl-2-methyltetrahydrofurans from 4-Methylalk-4-en-1-ols Catalyzed by Iodinea
Product
Yieldb
(%)
bp (°C/Torr)
or mp (°C)
Molecular
formulac
IRd (neat)
n
1H NMRe (CDCl3/TMS)
C–O (cm–1) d, J (Hz)
2a
67
71
72
95
97
72/0.01
72/0.03
80/0.01
94~95/0.01
135/0.01
51
C7H14O2
C8H16O2
C9H18O2
C11H22O2
C14H20O2
C18H20O
1049
1.22 (s, 3H), 1.30 (s, 3H), 1.46 (dd, 1H, J = 12.4), 1.90 (dd, 1H, J =
12.4), 2.62 (m, 1H, J = 7.2), 2.77 (br, OH), 3.58 (dd, 2H, J = 7.2), 3.66
(dd, 1H, J = 9.0), 3.97 (dd, 1H, J = 9.0)
2b
2c
2d
2e
1041
1047
1054
1045
1.12 (s, 3H), 1.28 (s, 6H), 1.50 (d, 1H), J = 12.8), 1.71 (d, 1H, J =
12.8), 2.90 (br, OH), 3.46 (q, 2H, J = 9.0), 3.49 (d, 1H, J = 9.0), 3.78
(d, 1H, J = 9.0)
0.88 (t, 3H), 1.24 (s, 3H), 1.28 (s, 3H), 1.36–1.58 (m, 2H), 1.57 (s,
2H), 2.31 (br, OH), 3.51 (d, 2H), 3.53 (d, 1H, J = 9.2), 3.77 (d, 1H, J
= 9.2)
0.91 (t, 3H), 1.25 (s, 3H), 1.28 (s, 3H), 1.36–1.63 (m, 6H), 1.58 (d,
2H), 2.57 (br, OH), 3.48 (s, 2H), 3.50 (d, 1H, J = 9.2), 3.75 (d, 1H, J
= 9.2)
1.23 (s, 3H), 1.26 (s, 3H), 1.51 (d, 1H, J= 13), 1.74 (d, 1H, J = 13),
2.29 (br, OH), 2.80 (q, 2H, J = 13.4), 3.43 (q, 2H, J = 11), 3.72 (q, 2H,
J = 9.2), 7.17–7.33 (m, 5H)
2f
83
98
1050
1061
1.24 (s, 6H), 2.66 (s, 2H), 4.49 (s, 2H), 7.17–7.36 (m, 10H)
2g
125~126/0.001 C19H22O
0.89 (t, 3H, J = 7.4), 1.09 (s, 3H), 1.52 (m, 2H), 2.59 (q, 2H, J = 12.8),
4.32 (d, 1H, J = 9.4), 4.56 (d, 1H, J = 9.4), 7.14–7.37 (m, 10H)
2h
4
98
84
152/0.001
C20H24O
C11H20O2
1060
1040
0.85 (t, 3H, J = 7.0), 1.06 (s, 3H), 1.28–1.47 (m, 2H), 2.57 (q, 2H, J =
12.4), 4.29 (d, 1H, J = 9.4), 4.55 (d, 1H, J = 9.4), 4.55 (d, 1H, J = 9.4),
7.12–7.34 (m, 10H)
35–36/0.001
1.23 (s, 6H), 1.15 (s, 6H), 1.73 (s, 4H), 3.54 (d, 2H, J = 8.4), 3.73 (d,
2H, J = 8.4)
a Substrate and iodine (0.2 eq.) in CH2Cl2 were allowed to react for 30 min.
b Isolated yield after column chromatography using Merck silica gel (70–230 mesh).
c Satisfactory microanalyses obtained: C ± 0.32, H ± 0.29.
d Obtained by Shimadzu IR-435 spectrometer.
e Recorded on a Bruker AM-300 spectrometer with TMS as internal standard.
(1) Harding, K. E.; Tiner, T. H. In Comprehensive Organic Synthe-
The attempted reaction of pent-4-en-1-ol, 5-methylhex-4-
en-1-ol, and hex-4-en-1-ol (a mixture of E and Z isomers)
gave a mixture of iodinated and noniodinated cyclized
products, respectively.
sis; Vol. 4; Trost, B. M., Ed.; Pergamon: New York, 1991; p 363.
Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321.
Harmanage, J. C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4,
1711.
(2) Rychnasky, S. D.; Bartlett, D. A. J. Am. Chem. Soc. 1981, 103,
3963.
2-Methyl-2-(b-methalyl)propane-1,3-diol (1b); Typical Proce-
dure:
Williams, D. R.; White, F. H. J. Org. Chem. 1987, 52, 5067.
Tamaru, Y.; Kawamura, S.; Yoshida, Z. Tetrahedron Lett. 1985,
26, 2885.
Williams, D. R.; White, H. F. Tetrahedron Lett. 1986, 27, 2195.
Tamaru, Y.; Hojo, M.; Kawamura, S.; Sawada, S.; Yoshida, Z.
J. Org. Chem. 1987, 52, 4062.
Compound 1b5 was obtained by reduction of diethyl methyl (b-meth-
allyl)malonate4a with LiAlH4 in Et2O.
4-Methyl-2,2-diphenylpent-4-en-1-o1 (1f); Typica1 Procedure:
Compound 1f7 was obtained by reduction of 4-methyl-2,2-diphenyl-
pent-4-enoic acid6 with LiAlH4 in Et2O.
Labelle, M.; Guindon, Y. J. Am. Chem. Soc. 1989, 111, 2204.
(3) a) Kim, K. M.; Ryu, E. K. Heterocycles 1995, 41, 219.
b) Kim, K. M.; Ryu, E. K. Tetrahedron Lett. 1996, 37, 1441.
(4) a) Arnold, R. T.; De Moura Campos, M.; Lindsay, K. L. J. Am.
Chem. Soc. 1953, 75, 1044.
4-Butyl-4-hydroxymethyl-2,2-dimethyltetrahydrofuran (2d);
Typical Procedure:
b) De Moura Campos, M. J. Am. Chem. Soc. 1954, 76, 4480.
(5) Wasson, B. K.; Gleason, C. H.; Levi, I.; Parker, J. M.; Thompson,
L. M.; Yates, C. H. Can. J. Chem. 1961, 39, 923.
(6) Arnold, R. T.; Searles, S. Jr. J. Am. Chem. Soc. 1949, 71, 1150.
Craig, P. N.; Witt, I. H. J. Am. Chem. Soc. 1950, 72, 4925.
Arnold, R. T.; Lindsay, K. L. J. Am. Chem. Soc. 1953, 75, 1048.
Slutsky, J; Kwart, H. J. Am. Chem. Soc. 1973, 95, 8678.
(7) Shishido, K.; Umimoto, K.; Shibuya, M. Heterocycles, 1994, 38,
641.
Iodine (0.05 g, 0.2 mmol) was added to a stirred solution of 1d (0.20 g,
5 mmol) in anhyd CH2Cl2. After stirring for 30 min, the organic layer
was quenched with a 5 % aq Na2S2O3 to remove iodine. After usual
extractive workup, the crude product was purified on silica gel column
chromatography using EtOAc/ hexane (1:10) as an eluent to give 2d
(0.19 g, 95 %).
The other tetrahydrofurans 2a–2h and 4 were obtained in the same
manner.