Wittig rearrangement of 3-furylmethyl ethers: Facile synthesis of 3-metyl-2-furylmethanols and 3-furylethanols

Article abstract of DOI:10.3987/COM-08-S(F)40

Wittig rearrangement of 3-furylmethyl ethers 1a-i was investigated. Deprotonation of 3-furylmethyl ethers 1a-i with bases, such as BuLi and LDA, occurred preferentially at the allylic, propargylic, benzylic positions and α-position adjacent to carbonyl gr

Full text of DOI:10.3987/COM-08-S(F)40

HETEROCYCLES, Vol. 77, No. 1, 2009
433
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 433 – 444. © The Japan Institute of Heterocyclic Chemistry.
Received, 5th July, 2008, Accepted, 30th July, 2008, Published online, 31st July, 2008.
DOI: 10.3987/COM-08-S(F)40
WITTIG REARRANGEMENT OF 3-FURYLMETHYL ETHERS:
FACILE SYNTHESIS OF 3-METYL-2-FURYLMETHANOLS AND
3-FURYLETHANOLS
Masayoshi Tsubuki,* Hiroyuki Okita, Kazunori Kaneko, Atsushi Shigihara,
and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa,
Tokyo 142-8501, Japan
e-mail:tsubuki@hoshi.ac.jp
Abstract – Wittig rearrangement of 3-furylmethyl ethers 1a-i was investigated.
Deprotonation of 3-furylmethyl ethers 1a-i with bases, such as BuLi and LDA,
occurred preferentially at the allylic, propargylic, benzylic positions and
α-position adjacent to carbonyl group giving the corresponding anions, which
underwent 2,3- and 1,2-rearrangements to afford 3-methyl-2-furylmethanols 2a-i
and 3-furylethanols 3a-f,h,i. Synthesis of naginata ketone and dendrolasin was
achieved employing the Wittig rearrangement as a key step.
INTRODUCTION
The synthesis of furan derivatives has attracted great interest because of the importance of natural and
1
2
synthetic furans and the synthetic versatility of furans. Numerous efforts have been devoted to the
3
preparation of furans and functionalization of the furan ring. As a part of our continuing work on the
synthesis of biologically active natural compounds using furylmethanols, we were interested in
developing a new method for the synthesis of furylmethanols. Previously, we have reported that the
Wittig rearrangement of 2- and 3-furylmethyl ethers provides an efficient method for the preparation of
4
2
-furylmethanol derivatives. Recently, we have successfully applied this rearrangement to the
5
a
5b
5c
stereoselective synthesis of furanocyclic diterpene skeleton, steroidal side chain, and OSW-1 and its
5
d
thiazole analogue. In the present study we further investigate the Wittig rearrangement of 3-furylmethyl
ethers and apply the rearrangement to the synthesis of naturally occurring terpenoids, naginata ketone and
dendrolasin.
-
-----------------------------------------------------------------------------------------------------------------------------
Dedicated to Dr. Keiichiro Fukumoto, Professor Emeritus of Tohoku University, on the occasion of his
th
7
5 birthday.

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HETEROCYCLES, Vol. 77, No. 1, 2009
RESULTS AND DISCUSSION
The Wittig rearrangement of allyl 3-furylmethyl ether 1 could theoretically afford both 2,3-rearranged
6
products 2 and 4 and 1,2-rearranged products 3 and 5 depending on the position, either α- or α’-position,
of deprotonation (Scheme 1). We first evaluated the relative thermodynamic stabilities of anions 1α and
1
α’ using ab initio calculations involving full optimizations with the GAUSSIAN 92 quantum
7
mechanical package. The calculations show that the energy minimums of the 1a-d α anions were favored
by 7.9-17.9 kJ/mol over the energy minimums of the 1a-d α’ anions at the RHF/6-31+G* level. This
result suggests that the Wittig rearrangement of allyl 3-furylmethyl ethers 1a-d would proceed through
deprotonation mainly at the α position, yielding 2a-d and 3a-d.
OH R3
R3
R1
O
R2 R1
OH R2
[
2,3]
1,2]
[2,3]
[1,2]
O
α'
4
2
R2
R2
O
R2
O
O
base
base
R1
R1
O
R1
O
O
α
OH R3
R3
R3
R3
R3
R2
R1
1α'
1
1α
[
1
2
3
1
2
3
1
1
a (R =R =R =H); 1b (R =R =H, R =Me);
R1
OH R2
1
2
3
1
2
3
c (R =Me, R =R =H); 1d (R =R =Me, R =H)
O
O
5
3
Scheme 1. Wittig rearrangement of allyl 3-furylmethyl ethers 1
With this result in mind, the Wittig rearrangement of allyl 3-furylmethyl ether 1a was initially studied
8
under standard conditions. Allyl 3-furylmethyl ethers 1a was prepared in 80% yield from by reaction of
3
-furanmethanol with allyl bromide in DMF using 1.8 equiv. of NaH. The results of the rearrangement
are shown in Table 1. Reaction of 1a with base brought about selective deprotonation at the expected α
1
2
3
position to give 1α anion (R =R =R =H), which went through sigmatropic rearrangement to afford
α-ethenyl-3-methyl-2-furanmethanol 2a as a major product, together with α-ethenyl-3-furanethanol 3a.
Treatment of 1a with 2 equiv. of n-BuLi in THF gave 2,3- and 1,2-rearranged products 2a and 3a in a
ratio of ca. 2:1, and there remained 50% of starting material 1a (entry 1). In contrast, the reaction
completed with 5 equiv. of n-BuLi (entry 2). The rearrangement proceeded at -30 to -20 °C when n-BuLi
was employed as a base in THF. A large excess (10 equiv.) of LDA in THF gave a slightly higher ratio
(
ca. 2.6:1) than the ratio obtained by using n-BuLi (entry 4), whereas use of TMEDA (12 equiv.) as an
additive in pentane-THF (v/v=9:1) resulted in the recovery of starting material again (entry 3). Treatment
of 1a with s-BuLi (5 equiv.) in THF at -78 °C produced 2a and 3a in a ratio of ca. 2.3:1, which is similar
to that obtained with LDA (entry 5). Fortunately, reaction of 1a with t-BuLi (4 equiv.) in THF at -78 °C
furnished preferentially 2a (entry 6).

HETEROCYCLES, Vol. 77, No. 1, 2009
435
Table 1. Wittig rearrangement of allyl 3-furylmethyl ether 1a
O
+
OH
O
O
O
OH
2a
1
a
3a
Product distribution (%) a
Conditions
Solvent
1a b others
Entry Base (equiv.)
Additive
Temp.
2a
3a
-78→0°C
3
4
16
33
18
50
1
n-BuLi (2 eq)
n-BuLi (5 eq)
THF
THF
-78→0°C
67
2
3
35
29
18 c
n-BuLi (5 eq) pentane-THF TMEDA -78→0°C
v/v=9:1) (12 equiv.)
(
4
5
6
LDA (10 eq)
s-BuLi (5 eq)
t-BuLi (4 eq)
THF
THF
THF
-78→0°C
-78°C
72
70
28
30
<5
-78°C
>95
a
b
Determined by 270 MHz NMR analysis of the crude products.
Recovered starting material. Undentified products were formed.
c
We next examined the Wittig rearrangement of 3-furylmethyl ethers 1b-i as shown in Table 2.
Compounds 1b-i were prepared by the same method as above 1a. Reactions of 1b-f,h were conducted
using n-BuLi (5 equiv.), s-BuLi (5 equiv.), and t-BuLi (4 equiv.) as a base in THF. LDA was employed
for substrates 1g,i, and products were isolated as the corresponding methyl esters. Methallyl ether 1b gave
preferentially 2,3-rearranged product 2b, together with 1,2-rearranged product 3b (entries 1-3), while
crotyl ether 1c and prenyl ether 1d produced mainly 1,2-rearranged products 3c,d, respectively (entries
4-8). The effect of methyl group at the terminal alkene was apparent from the decreased reactivity toward
BuLis; starting material 1c,d were recovered (entries 6 and 7) and reaction of 1d with t-BuLi was
sluggish (entry 9). Rising temperature from -78 to 0 °C in the case of entry 9 brought about the formation
of complex mixtures. Propargyl ether 1e gave predominantly 2e using s- and t-BuLi (entries 11 and 12),
although treatment with n-BuLi gave almost equal amounts of 2e and 3e (entry 10). Reaction of benzyl
ether 1f with n- and s-BuLi gave mostly 3f (entries 13 and 14), whereas reaction with t-BuLi afforded 2f
as a major product (entry 15). 3-Furylmethyloxyacetic acid 1g gave cleanly 2,3-rearranged methyl ester
3
g as a sole product (entry 16), whereas the corresponding propionic acid 1i gave equal amounts of 2i and
i (entry 20). Compound 1h gave predominantly 1,2-rearranged product 3h (entries 17-19), in contrast
3
allyl ether 1a gave mainly 2,3-rearranged product 2a (Table 1). The threo/erythro stereochemistries were
9
1
tentatively assigned based on Nakai’s observation, in which the H NMR signal ascribed to CHOH in
threo isomer is observed further upfield than that of erythro isomer. The threo isomer, the major product
3
h, shows a triplet due to CHOH at δ 4.04 (J= 7.1 Hz), while erythro isomer presents a distorted triplet
due to CHOH at δ 4.17 (J= 5.9 Hz).

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HETEROCYCLES, Vol. 77, No. 1, 2009
Table 2. Wittig rearrangement of 3-furylmethyl ethers 1b-i a
R1
R1
R2 OH
R1
G
O
G
+
O R2
O
G
R2 OH
O
1b-i
2b-i
3b-i
Substrate
R1 R2
Product distribution (%) b
Entry
G
Base
Yield (%) [2,3] product 2
[1,2] product 3
1
2
3
4
5
6
7
8
9
1
b CH =C(Me)-
H
H
H
H
H
n-BuLi
s-BuLi
t-BuLi
n-BuLi
s-BuLi
t-BuLi
n-BuLi
s-BuLi
t-BuLi
n-BuLi
s-BuLi
t-BuLi
n-BuLi
s-BuLi
t-BuLi
75
63
68
60
64
78
<5
21
40
46
22
>95
79
76
>95
79
-
52
8
11
82
93
36
H
2
1c MeCH=CH-
H
H
H
H
70
66
34
(E/Z=82/18)
c
c
2
4
1d Me C=CH-
48
53
<5
21
-
48
92
89
18
7
2
d
-
10
11
12
13
1e HC≡CH-
67
69
46
72
44
64
60
48
56
c
c
1f
Ph
c
1
1
4
5
64
100 e
16
1g
CO H
H
H
H
LDA
n-BuLi
0
2
1h CH =CH-
Me
89 (80/20) f
86 (70/30) f
84 (78/22)
51
11
14
16
17
18
19
2
s-BuLi
t-BuLi
LDA g
f
6
0
e
e
20
1i
CO H
H
Me
52
49
2
a
Reactions were carried out with base in THF at -78°C. n-BuLi (5 equiv.) was employed and the reaction
was allowed to warm to 0°C. s-BuLi (5 equiv.) was employed. t-BuLi (4 equiv.) was employed. LDA (4
b
equiv.) was employed and the reaction was allowed to warm to 0°C. Determined by 270 MHz NMR
c
d
e
analysis of the crude products. Starting material was recovered. Reaction was sluggish. Isolated as
f
the corresponding methyl ester. The ratio of the threo to the erythro product is given in the parentheses.
LDA (10 equiv.) was employed.
g
1
0
We further applied this rearrangement to the synthesis of naturally occurring terpenoids dendrolasin and
1
1
naginata ketone. The synthesis of dendrolasin was achieved as follows (Scheme 2). Etherification of
-furanmethanol 6 with geranyl bromide in the presence of NaH gave geranyl ether 7 in 70% yield.
3
OH
O
i
ii
R
O
6
O
O
7
8 R=OH
iii
iv
9
R=OAc
0 R=H
1
Scheme 2. Reagents and conditions: i, geranyl bromide, NaH, DMF, 70%; ii, s-BuLi, THF, -78°C, 82%;
iii, Ac O, pyridine, 91%; iv, Li, EtNH , 39%
2
2

HETEROCYCLES, Vol. 77, No. 1, 2009
437
Treatment of 7 with n-BuLi (5 equiv.) gave almost starting material together with trace amount of
,2-rearranged product 8, indicating lower reactivity of 7 toward BuLis. Next, excess n-BuLi (20 equiv.)
1
was used to produce the desired product 8 in 27% yield together with starting material. Treatment of 7
with t-BuLi (5 equiv.) in THF at -78 to -25 °C afforded 8 in 51% yield and starting material. Pleasingly,
reaction of 7 with s-BuLi (5 equiv.) at -78 °C in THF afforded 8 in 82% yield, although the reasons for
the improvement of the yield are unclear. Attempts to convert 8 into dendrolasin by deoxygenation under
1
2
Barton’s method were unsuccessful. Thus, alcohol 8 was acetylated to 9 in 91% yield, which was
1
3
treated with lithium in EtNH
2
to give dendrolasin 10 in 39% yield. The spectroscopic data obtained
1
0c
were identical with those reported.
Nginata ketone 11 was also prepared by MnO oxidation of 2d in poor yield, 11%, due to its high
2
volatility (eq. 1).
MnO2
CH Cl
eq. 1
O
O
2
2
OH
O
1
1
2
d
Thus, we have disclosed the Wittig rearrangement of 3-furylmethyl ethers leading to
-methyl-2-furylmethanols and 3-furylethanols. Regarding the formation of [1,2] rearranged product, the
3
use of n-BuLi is superior to the use of s- and t-BuLi, whereas the use of t-BuLi is suitable for the
formation of [2,3] rearranged product rather than the use of n- and s-BuLi. Synthesis of dendrolasin and
naginata ketone has been succeeded in employing the Wittig rearrangement of 3-furylmethyl ethers as a
key step.
EXPERIMENTAL
1
13
IR spectra were obtained using a JASCO FT/IR-200 spectrophotometer. H- and C-NMR spectra were
1
13
obtained on a JEOL JNM-LA270 ( H-NMR: 270 MHz, C-NMR: 67.8 MHz) instrument for solutions in
1
CDCl , and chemical shifts are reported on the δ scale using TMS as an internal standard of δ 0.00 for H
3
1
3
NMR spectra and CDCl as an internal standard of δ 77.00 for C NMR spectra, respectively. MS spectra
3
were measured with a JEOL JMS-600 spectrometer. Elemental analyses were performed on a
Yanaco-MT5.
General procedure for etherification of 3-furanmethanol
To a solution of allylic halide (36.7 mmol) and 3-furanmethanol (2.00 g, 20.4 mmol) in DMF (50 mL)
was added NaH (ca. 60 % purity, 1.47 g, ca. 36.7 mmol) at 0 °C and stirring was continued for 8 h at rt.

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HETEROCYCLES, Vol. 77, No. 1, 2009
The reaction was carefully quenched with sat. aq. NH
extracted with Et O and CH Cl (v/v, 2:1), and the combined organic layers were washed with brine. The
organic layer was dried over Na SO and evaporated to give a residue, which was chromatographed on
silica gel (80 g, n-hexane/Et O=95:5) to afford 3-furylnmethyl ether as a colorless oil.
Allyl 3-furylmethyl ether (1a)
0% yield; bp 70 °C (18 mmHg). IR 2860, 1500 cm ; H-NMR δ 4.00 (2H, dt, J= 1.5 and 5.6 Hz), 4.39
2H, d, J= 0.3 Hz), 5.20 (1H, dd, J= 1.5 and 10.4 Hz), 5.28 (1H, dd, J= 1.5 and 17.3 Hz), 5.93 (1H, ddt,
4
Cl solution in ice bath. The reaction mixture was
2
2
2
2
4
2
-1 1
8
(
1
3
J= 1.5, 10.4, and 17.3 Hz), 6.42 (1H, brs), 7.39-7.41 (2H, m); C-NMR δ 63.7, 71.3, 110.8, 117.6, 122.7,
+
1
35.1, 141.1, 143.7; MS (EI): 138 (M ); HRMS (EI) calcd for C
8
H
10
O
2
: 138.0681. Found: 138.0682.
8 10 2
Anal. Calcd for C H O : C, 69.54; H, 7.30. Found: C, 69.29; H, 7.39.
Methallyl 3-furylmethyl ether (1b)
-
1 1
8
4
1
8% yield; bp 75 °C (18 mmHg). IR 2850, 1500 cm ; H-NMR δ 1.75 (3H, s), 3.90 (2H, s), 4.36 (2H, s),
1
3
.91 and 4.98 (each 1H, each brs), 6.42 (1H, brs), 7.40 (2H, brd, J= 1.8 Hz); C-NMR δ 19.4, 63.0, 73.7,
+
10.2, 112.3, 122.3, 140.5, 142.0, 143.2; MS (EI): 152 (M ); HRMS (EI) calcd for C
9
H
12
O
2
: 152.0837.
Found: 152.0854. Anal. Calcd for C
Crotyl 3-furylmethyl ether (E/Z=82:18) (1c)
2% yield; bp 50 °C (16 mmHg). IR 2850, 1500 cm ; H-NMR (E isomer) δ 1.72 (3H, dd, J= 1.2 and 6.1
Hz), 3.92 (2H, dd, J= 1.2 and 6.1 Hz), 4.36 (2H, brs), 5.54-5.79 (2H, m), 6.42 (1H, brs), 7.39-7.40 (2H,
9 12 2
H O : C, 71.02; H, 7.95. Found: C, 71.32; H, 7.95.
-1 1
5
1
3
+
m); C-NMR (E isomer) δ 17.6, 62.9, 70.5, 110.3, 123.3, 127.4, 129.5, 140.5, 143.1; MS (EI): 152 (M );
HRMS (EI) calcd for C : 152.0837. Found: 152.0842. Anal. Calcd for C : C, 71.02; H, 7.95.
Found: C, 71.35; H, 7.98.
Prenyl 3-furylmethyl ether (1d)
7% yield; bp 90 °C (15 mmHg). IR 2850, 1500 cm ; H-NMR δ 1.66 and 1.75 (each 3H, each brs), 3.97
H
9 12
O
2
9 12 2
H O
-1 1
8
1
3
(
2H, d, J= 6.7 Hz), 4.37 (2H, s), 5.34-5.40 (1H, m), 6.43 (1H, brs), 7.38-7.41 (2H, m); C-NMR δ 18.0,
+
2
5.7, 63.1, 66.3, 110.4, 120.9, 122.5, 137.2, 140.6, 143.2; MS (EI): 166 (M ); HRMS (EI) calcd for
10 14 2 14 2
C H O : 166.0993. Found: 166.0988. Anal. Calcd for C10H O : C, 72.26; H, 8.49. Found: C, 72.36; H,
8
.56.
Propargyl 3-furylmethyl ether (1e)
6% yield.
Benzyl 3-furylmethyl ether (1f)
14
7
15
9
3
8
7% yield.
-Furylmethoxyacetic acid (1g)
5% yield; bp 190 °C (9 mmHg). IR 3450, 3150, 1735 cm ; H-NMR δ 4.13 (2H, s), 4.54 (2H, s), 6.45
-
1 1
1
3
(
1H, d, J= 1.2 Hz), 7.42 (1H, d, J= 1.2 Hz), 7.45 (1H, brs); C-NMR δ 64.3, 65.9, 110.3, 120.7, 141.2,

HETEROCYCLES, Vol. 77, No. 1, 2009
439
+
1
43.6, 175.4; MS (EI): 152 (M ); HRMS (EI) calcd for C
for C ·0.2H O: C, 52.73; H, 5.31. Found: C, 52.69; H, 5.27.
Allyl 1-(3-furyl)ethyl ether (1h)
8% yield; bp 98 °C (8 mmHg). IR 2860, 1500 cm ; H-NMR δ 1.44 (3H, d, J= 6.1 Hz), 3.85 and 3.95
each 1H, each ddt, J=1.2, 5.5, and 12.8 Hz), 4.47 (1H, q, J= 6.1 Hz), 5.15 (1H, dq, J= 1.2 and 10.4 Hz),
.25 (1H, dq, J= 1.2 and 17.1 Hz), 5.90 (1H, ddt, J= 5.5, 10.4, and 17.1 Hz), 6.40 (1H, d, J= 1.8 Hz), 7.36
7 8 4
H O : 152.0837. Found: 152.0854. Anal. Calcd
7
H
8
O
4
2
-1 1
6
(
5
13
(
1H, brs), 7.39 (1H, t, J= 1.8 Hz); C-NMR δ 22.2, 68.8, 68.9, 108.5, 116.6, 127.5, 135.0,139.4, 143.2;
+
MS (EI): 152 (M ); HRMS (EI) calcd for C
9
H
12
O
2
: 152.0837. Found: 152.0839. Anal. Calcd for
C H O : C, 71.02; H, 7.95. Found: C, 70.23; H, 7.83.
9
12
2
2
-(3-Furylmethoxy)propionic acid (1i)
6% yield; bp 180 °C (5 mmHg). IR 3460, 3150, 1730 cm ; H-NMR δ 1.49 (3H, d, J= 7.5 Hz), 4.10 (1H,
-1 1
7
q, J= 7.5 Hz), 4.42 and 4.58 (each 1H, each d, J= 12.5 Hz), 6.45 (1H, brs), 7.40 (1H, brs), 7.45 (1H, brs),
1
3
+
9
.58 (1H, brs); C-NMR δ 18.3, 63.2, 72.9, 110.3, 121.2, 141.0, 143.5, 178.5; MS (EI): 170 (M ); HRMS
EI) calcd for C : 170.0579. Found: 170.0585. Anal. Calcd for C : C, 56.46; H, 5.92. Found:
C, 56.24; H, 5.96.
Geranyl 3-furylmethyl ether (7)
0% yield; bp 182 °C (6 mmHg). IR 2820, 1060 cm ; H-NMR δ 1.60 and 1.65 (each 3H, each brs), 1.68
3H, d, J= 1.2 Hz), 1.95-2.15 (4H, m), 4.00 (2H, d, J= 6.7 Hz), 4.37 (2H, s), 5.09 (1H, tt, J= 1.2 and 6.7
(
8
H
10
O
4
8 10 4
H O
-1 1
7
(
13
Hz), 5.37 (1H, dt, J= 1.2 and 6.7 Hz), 6.42 (1H, d, J= 1.8 Hz), 7.39 (2H, brd, J= 1.8 Hz); C-NMR δ 16.3,
17.5, 25.6, 26.2, 39.5, 62.9, 66.2, 110.3, 120.6, 122.4, 123.9, 131.5, 140.3, 140.5, 143.1; MS (EI): 234
+
(
M ); HRMS (EI) calcd for C15
H
22
O
2
: 234.1619. Found: 234.1619. Anal. Calcd for C15
H
22
O
2
: C, 76.88; H,
9
.46. Found: C, 76.63; H, 9.53.
General procedure for Wittig rearrangement of 3-furylmethyl ether
To a solution of 3-furylmethyl ether (1a-i, 7) (1.0 mmol) in THF (10 mL) was added dropwise a base
n-BuLi 1.6 M in hexane, 3.12 mL, 5.0 mmol; s-BuLi 1 M in cyclohexane, 5.0 mL, 5.0 mmol; t-BuLi 1.6
(
M in pentane, 2.5 mL, 4.0 mmol; LDA 4.0 mmol) at -78 °C under Ar. After stirring for 1 h (the reaction
mixture was allowed to warm to 0 °C in the cases of n-BuLi), the reaction mixture was quenched with sat.
4
aq. NH Cl solution, and the solvent was removed under vacuum. The residue was extracted with
pentane-Et O (1:1, v/v). The extract was washed with brine and dried over Na SO . Evaporation of the
2
2
4
solvent gave a residue, which was chromatographed on silica gel (50 g, n-hexane/AcOEt=95:5) to afford
rearrangement products, respectively. Yields and the ratio of product distribution are shown in Tables 1
and 2. All the rearranged products were isolated by either careful column chromatography or
derivatization.

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HETEROCYCLES, Vol. 77, No. 1, 2009
α-Ethenyl-3-methyl-2-furanmethanol (2a)
-1 1
Colorless oil; IR 3400, 2940, 990 cm ; H-NMR δ 2.06 (3H, s), 5.20-5.23 (1H, m), 5.27 (1H, d, J= 12.2
Hz), 5.35 (1H, d, J= 17.1 Hz), 6.06-6.18 (1H, m), 6.20 (1H, d, J= 1.8 Hz), 7.28 (1H, d, J= 1.8 Hz);
1
3
+
C-NMR δ 9.6, 67.1, 113.2, 115.6, 116.7, 137.1, 141.2, 149.1; MS (EI): 138 (M ); HRMS (EI) calcd for
C H O : 138.0681. Found; 138.0671.
8
10
2
α-Ethenyl-3-furanethanol (3a)
Colorless oil; IR 3380, 2930, 1020 cm ; H-NMR δ 2.63 and 2.71 (each 1H, each dd, J= 7.3 and 14.6 Hz),
.28 (1H, brd, J= 5.5 Hz), 5.15 (1H, dt, J= 10.4 Hz), 5.28 (2H, d, J= 17.1 Hz), 5.93 (1H, ddd, J=6.7, 10.4,
-1 1
4
1
3
and 17.1 Hz), 7.31 (1H, brs), 7.38 (1H, d, J=1.8 Hz); C-NMR δ 32.8, 72.4, 111.5, 115.2, 120.4, 140.1,
+
1
40.3, 143.0; MS (EI): 138 (M ); HRMS (EI) calcd for C
8
H
10
O
2
: 138.0681. Found; 138.0683.
3
-Methyl-α-(1-methylethenyl)-2-furanmethanol (2b)
-1 1
Colorless oil; IR 3410, 2950, 1010 cm ; H-NMR δ 1.69 (3H, s), 2.06 (3H, s), 4.99 (1H, q, J=1.2 Hz),
1
3
5
.14 and 5.18 (each 1H, each s), 6.20 (1H, d, J=1.8 Hz), 7.28 (1H, d, J= 1.8 Hz); C-NMR δ 9.6, 18.9,
+
6
9.4, 110.7, 113.1, 117.0, 141.1, 144.6, 148.7; MS (EI): 152 (M ); HRMS (EI) calcd for C
9 12 2
H O :
1
52.0837. Found: 152.0844.
1
6
α-(1-Methylethenyl)-3-furanethanol (3b)
-1 1
Colorless oil; IR 3450, 2940, 1020 cm ; H-NMR δ 1.79 (3H, s), 2.64 (1H, dd, J= 7.9 and 14.6 Hz), 2.73
(1H, dd, J= 4.9 and 14.6 Hz), 4.21 (1H, dd, J= 4.9 and 7.9 Hz), 4.88 (1H, brs), 4.98 (1H, d, J= 1.8 Hz),
1
3
6
1
3
.33 (1H, brs), 7.32 (1H, brs), 7.38 (1H, d, J=1.8 Hz); C-NMR δ 18.2, 31.3, 75.3, 111.4, 111.5, 121.0,
+
40.3, 143.1, 146.7; MS (EI): 152 (M ); HRMS (EI) calcd for C
9
H
12
O
2
: 152.0837. Found: 152.0831.
-Methyl-α-1-propenyl-2-furanmethanol (E/Z=82:18) (2c)
-1 1
Colorless oil; IR 3380, 2920, 1020 cm ; H-NMR (E isomer) δ 1.73 (3H, d, J= 6.2 Hz), 2.05 (3H, s), 5.17
1H, d, J=6.5 Hz,), 5.74 (1H, dq, J=6.2 and 15.3 Hz), 5.83 (1H, dd, J= 6.5 and 15.3 Hz), 6.19 (1H, d,
(
1
3
J=1.8 Hz), 7.27 (1H, d, J= 1.8 Hz); C-NMR (E isomer) δ 9.6, 17.8, 67.0, 113.1, 116.1, 127.8, 130.3,
+
+
1
1
41.0, 149.8; MS (EI): 152 (M ); MS (EI): 152 (M ); HRMS (EI) calcd for C
9 12 2
H O : 152.0837. Found:
52.0837.
α-1-Propenyl-3-furanethanol (E/Z=82:18) (3c)
-1 1
Colorless oil; IR 3430, 2860, 960 cm ; H-NMR (E isomer) δ 1.70 (3H, d, J= 6.1 Hz), 2.60 (1H, dd, J=
.7 and 14.6 Hz), 2.66 (1H, dd, J= 6.1 and 14.6 Hz), 4.21 (1H, q, J= 6.7 Hz), 5.53 (1H, ddd, J= 1.2, 6.7,
and 15.3 Hz), 5.70 (1H, dq, J= 6.1 and 15.3 Hz), 6.31 (1H, brs), 7.30 (1H, brs), 7.37 (1H, d, J=1.8 Hz);
6
1
3
+
C-NMR (E isomer) δ 17.7, 33.1, 72.4, 111.5, 120.7, 127.3, 133.1, 140.2, 142.9; MS (EI): 152 (M );
HRMS (EI) calcd for C H O : 152.0837. Found: 152.0842.
9
12
2
3
-Methyl-α-(2-methyl-1-propenyl)-2-furanmethanol (2d)

HETEROCYCLES, Vol. 77, No. 1, 2009
441
-1 1
Colorless oil; IR 3360, 2920, 1020 cm ; H-NMR δ 1.73 and 1.75 (each 3H, each brs), 2.05 (3H, s), 5.43
1
3
(
1H, d, J=8.7 Hz,), 5.64 (1H, d, J=8.7 Hz), 6.16 (1H, d, J=1.6 Hz), 7.27 (1H, d, J= 1.6 Hz); C-NMR δ
+
9
.6, 18.6, 25.8, 62.8, 113.0, 115.6, 124.1, 135.7, 140.9, 150.4; MS (EI): 166 (M ); HRMS (EI) calcd for
C
10
H
14
O
2
: 166.0993. Found: 166.0991.
α-(2-Methyl-1-propenyl)-3-furanethanol (3d)
-1 1
Colorless oil; IR 3430, 2860, 1020 cm ; H-NMR δ 1.66 and 1.73 (each 3H, each d, J= 1.2 Hz), 2.59 (1H,
dd, J= 5.5 and 14.0 Hz), 2.65 (1H, dd, J= 6.7 and 14.0 Hz), 4.50 (1H, dd, J= 6.1 and 6.7 Hz), 5.22 (1H,
1
3
dm, J= 8.6 Hz), 6.32 (1H, brs), 7.29 (1H, brs), 7.37 (1H, d, J=1.8 Hz); C-NMR δ 18.2, 25.7, 33.2, 68.4,
+
1
11.5, 120.8, 127.1, 135.8, 140.2, 142.8; MS (EI): 166 (M ); HRMS (EI) calcd for C H O : 166.0993.
1
0
14
2
Found: 166.0991.
α-Ethynyl-3-methyl-2-furanmethanol (2e)
-1 1
Colorless oil; IR 3290, 2920, 990 cm ; H-NMR δ 2.10 (3H, s), 2.62 (1H, s), 5.47 (1H, brs), 6.21 (1H, d,
1
3
J= 1.6 Hz), 7.31 (1H, d, J= 1.8 Hz); C-NMR δ 9.7, 56.2, 74.0, 81.1, 113.5, 117.7, 141.7, 146.6; MS
+
(
EI): 136 (M ); HRMS (EI) calcd for C
8
H
8
2
O : 136.0524. Found; 136.0515.
α-Ethynyl-3-furanethanol (3e)
-1
1
Colorless oil; IR 3290, 2950, 2120 cm ; H-NMR δ 2.48 (1H, d, J= 2.2 Hz), 2.82 and 2.88 (each 1H,
1
3
each dd, J= 4.2 and 14.6 Hz), 4.51 (1H, t, J= 4.2 Hz), 6.40 (1H, brs), 7.38 (2H, brs); C-NMR δ 33.2,
+
6
1.9, 73.4, 84.2, 111.6, 119.2, 140.7, 142.9; MS (EI): 136 (M ); HRMS (EI) calcd for C
8
H
8
O
2
: 136.0524.
Found; 136.0502.
-Methyl-α-phenyl-2-furanmethanol (2f)
Colorless oil; IR 3400, 2920, 1450, 1020 cm ; H-NMR δ 2.00 (3H, s), 5.84 (1H, brs), 6.18 (1H, d, J=
3
-1 1
1
3
1
.8 Hz), 7.24-7.42 (6H, m); C-NMR δ 9.7, 68.1, 113.2, 116.9, 126.2, 127.6, 128.3, 14.3, 141.4, 149.7;
+
MS (EI): 188 (M ); HRMS (EI) calcd for C12
H
12
2
O : 188.0837. Found; 188.0828.
α-Phenyl-3-furanethanol (3f)
-1
1
Colorless oil; IR 3400, 2920, 1450, 1020 cm ; H-NMR δ 2.83 (2H, d, J= 6.6 Hz), 4.79 (1H, t, J= 6.6 Hz),
1
3
6
1
1
.20 (1H, brs), 7.23 (1H, brs), 7.23-7.40 (6H, m); C-NMR δ 34.9, 74.0, 111.3, 120.7, 125.8, 127.6,
+
28.3, 140.3, 142.9, 143.7; MS (EI): 188 (M ); HRMS (EI) calcd for C12
88.0818.
12 2
H O : 188.0837. Found;
Methyl 2-hydroxy-2-(3-methyl-2-furyl)acetate (2g)
-1 1
Colorless oil; IR 3520, 2940, 1740, 1060 cm ; H-NMR δ 2.08 (3H, s), 3.80 (3H, s), 5.21 (1H, d, J= 4.9
13
Hz), 6.22 (1H, d, J= 1.8 Hz), 7.28 (1H, d, J= 1.8 Hz); C-NMR δ 9.5, 53.1, 64.9, 113.2, 118.9, 141.9,
+
1
45.7, 172.3; MS (EI): 170 (M ); HRMS (EI) calcd for C
8
H
10
O
4
: 170.0579. Found; 170.0590.
α-Ethenyl-3-ethyl-2-furanmethanol (2h)

442
HETEROCYCLES, Vol. 77, No. 1, 2009
-1 1
Colorless oil; IR 3430, 2930, 1030 cm ; H-NMR δ 1.16 (3H, t, J= 7.2 Hz), 2.47 (2H, q, J= 7.2 Hz),
.20-5.23 (1H, m), 5.25-5.40 (2H, m), 6.05-6.20 (1H, m), 6.26 (1H, d, J= 1.8 Hz), 7.28 (1H, d, J= 1.8
5
1
3
+
Hz); C-NMR δ 14.1, 17.8, 77.4, 111.9, 115.6, 116.7, 140.9, 141.3, 149.7; MS (EI): 152 (M ); HRMS
EI) calcd for C : 152.0837. Found: 152.0810.
α-Ethenyl-2-methyl-3-furanethanol (3h)
(
9 12 2
H O
-1 1
Colorless oil; IR 3410, 2930, 1030 cm ; H-NMR (threo) δ 1.21 (3H, d, J= 7.1 Hz), 2.78 (1H, quint, J=
.1), 4.04 (1H, t, J= 7.1 Hz), 5.10-5.30 (2H, m), 5.75-5.92 (1H, m), 6.34 (1H, brs), 7.31 (1H, brs), 7.39
7
13
+
(
1H, brs); C-NMR δ 16.9, 36.6, 76.9, 109.9, 116.5, 126.1, 138.8, 139.6, 143.0; MS (EI): 152 (M );
HRMS (EI) calcd for C H O : 152.0837. Found: 152.0823.
9
12
2
Methyl 2-hydroxy-2-(3-methyl-2-furyl)propionate (2i)
-1 1
Colorless oil; IR 3520, 2940, 1740, 1060 cm ; H-NMR δ 1.81 (3H, s), 2.05 (3H, s), 3.79 (3H, s), 6.18
1
3
(
1H, d, J= 1.8 Hz), 7.24 (1H, d, J= 1.8 Hz); C-NMR δ 10.2, 24.1, 53.2, 72.6, 114.4, 116.7, 140.4, 147.9,
+
1
74.9; MS (EI): 184 (M ); HRMS (EI) calcd for C
9
H
12
O
4
: 184.0735. Found; 184.0755.
Methyl 3-(3-furyl)-2-hydroxy-2-methylpropionate (3i)
-1 1
Colorless oil; IR 3410, 2920, 1740, 1020 cm ; H-NMR δ 1.47 (3H, s), 2.74 and 2.92 (each 1H, each d,
1
3
J= 14.3 Hz), 3.75 (3H, s), 6.26 (1H, brs), 7.33 (2H, brs); C-NMR δ 25.7, 35.8, 52.7, 74.8, 111.8, 118.9,
+
1
40.7, 142.7, 176.7; MS (EI): 184 (M ); HRMS (EI) calcd for C
9
H
12
O
4
: 184.0735. Found; 184.0755.
(
E)-α-(2.6-Dimethyl-1,5-heptadienyl)-3-furanethanol (8)
Treatment of 7 with sec-BuLi afforded the corresponding geraniol 8 in 82% yield. Colorless oil; IR 3450,
-1 1
2
900, 1010 cm ; H-NMR δ 1.60 and 1.68 (each 3H, each brs), 1.64 (3H, d, J= 1.2 Hz), 1.95-2.15 (4H,
m), 2.59 (1H, dd, J= 5.5 and 14.7 Hz), 2.66 (1H, dd, J= 6.7 and 14.7 Hz), 4.51 (1H, dq, J= 1.8 and 6.7
Hz), 5.00-5.15 (1H, m), 5.22 (1H, dq, J= 1.2 and 8.5 Hz), 6.32 (1H, brs), 7.28 (1H, brs), 7.36 (1H, t,
13
J=1.8 Hz); C-NMR δ 16.6, 17.6, 25.6, 26.3, 33.1, 39.5, 68.4, 111.5, 120.8, 123.8, 126.8, 131.7, 139.0,
+
1
40.2, 142.8; MS (EI): 234 (M ); HRMS (EI) calcd for C15
H
22
O
2
: 234.1618. Found: 234.1603.
(
E)-α-(2.6-Dimethyl-1,5-heptadienyl)-3-furanethanol acetate (9)
A solution of alcohol 8 (27 mg, 0.115 mmol), Ac O (150 mg, 1.47 mmol), and pyridine (200 mg, 2.53
mmol) in CH Cl was stirred for 3 h at 0 °C. The reaction mixture was poured into water and the product
was extracted with Et O-hexane (v/v=1:1). The organic layer was washed successively with saturated
2
2
2
2
aqueous KHSO
4
, brine, sat. aq. NaHCO
3
, and brine, and dried over Na
2
SO
4
. Evaporation of the solvent
O-hexane (v/v=1:49) to
gave a residue, which was purified by silica gel column chromatography using Et
2
-1 1
give acetate 9 (29 mg) in 91% yield. Colorless oil; IR 2880, 1710, 1020 cm ; H-NMR δ 1.59 and 1.68
each 3H, each brs), 1.64 (3H, d, J= 1.2 Hz), 2.02 (3H, s), 1.95-2.15 (4H, m), 2.62 and 2.76 (each 1H,
(

HETEROCYCLES, Vol. 77, No. 1, 2009
443
each dd, J= 6.7 and 14.7 Hz), 5.04 (1H, brt, J= 6.7 Hz), 5.13 (1H, dd, J= 1.2 and 9.1 Hz), 5.62 (1H, dt, J=
+
6
.7 and 9.1 z), 6.28 (1H, d, J= 1.2 Hz), 7.23 (1H, brs), 7.33 (1H, t, J=1.8 Hz); MS (EI): 216 (M -AcOH);
24 3
HRMS (EI) calcd for C17H O - AcOH: 216.1514. Found: 216.1514.
Dendrolasin (10)
To a stirred solution of acetate 9 (18 mg, 0.065 mmol) in EtNH (3 mL) was added portionwisely Li
2
metal (9 mg, 1.3 mmol) at 2 °C and the reaction mixture was stirred for 4 h at the same temperature. After
filtration of excess Li metal, filtrate was condensed to give a residue, which was purified by silica gel
column chromatography using hexane to give dendrolasin 10 (5 mg) in 39% yield. The spectroscopic data
1
0c
obtained were identical with those reported.
Naginata ketone (11)
A mixture of alcohols 2d and 3d (231 mg, 2d/3d=21:79, 1.39 mmol), obtained by treatment of 1d with
s-BuLi, and MnO (4.8 g, 55.2 mmol) in CH Cl (50 mL) was stirred for 8 h at rt. After filtration of
inorganic material, filtrate was condensed to give a residue, which was purified by silica gel column
chromatography using Et O-pentane (v/v=1:49) to give naginata ketone 11 (5.4 mg) in 11% yield based
2
2
2
2
11b
on 2d. The spectroscopic data obtained were identical with those reported.
ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology of Japan, and by the Open Research Center Project.
REFERENCES AND NOTES
1
.
(a) C. Djerassi, in ‘Dictionary of Natural Porducts,’ Chapman & Hall, London, 1994. (b) M. Regitz,
in ‘Science of Synthesis’,Vol. 9, ed. by G. Maas, Thieme, Stuttgart, 2001.
2
.
(a) B. H. Lipshutz, Chem. Rev., 1986, 86, 795. (b) T. Hurst, in ‘Rodd’s Chemistry of Carbon
nd
nd
Compounds, 2 Ed.’, 2 suppl., Vol. IVA, chap. 2, ed. by M. Sainsbury, Elsevier, Amsterdam,
977.
1
3
.
(a) C. B. Bird and G. W. H. Cheesman, in ‘Comprehensive Heterocyclic Chemistry’, Vol. 4, p. 89,
ed. by A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984., 1977, 3, 215. (b) R. Vieser
and W. Eberbach, Tetrahedron., 1995, 36, 4405 and references cited therein.
4
5
.
.
(a) M. Tsubuki, H. Okita, and T. Honda, J. Chem. Soc., Chem. Commun., 1995, 2135. (b) M.
Tsubuki, T. Katama, H. Okita, M. Arai, A. Shigihara, and T. Honda, Chem. Commun, 1999, 2263.
(a) M. Tsubuki, K. Takahashi, and T. Honda, J. Org. Chem., 2003, 68, 10183. (b) M. Tsubuki, A.

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HETEROCYCLES, Vol. 77, No. 1, 2009
Ohinata, T. Tanaka, K. Takahashi, and T. Honda, Tetrahedron, 2005, 61, 1095. (c) M. Tsubuki, S.
Matsuo, and T. Honda, Tetrahedron Lett., 2008, 49, 229. (d) M. Tsubuki, S. Matsuo, and T. Honda,
Heterocycles, in press. (COM-07-S(N)3)
6
7
.
.
B. Cazes and S. Julia, Synth. Commun., 1977, 113.
MO calculations were performed using the IBM RS/6000 version of the GAUSSIAN 92 suite of
programs.
8
.
For recent reviews, see (a) J. A. Marshall, ‘Comprehensive Organic Synthesis;’ Vol. 3, ed. by B. M.
Trost and I. Fleming, Pergamon Press: New York, 1991, pp. 975-1014. (b) T. Nakai and K. Mikami,
Org. React. 1994, 46, 105. (c) K. Tomooka, ‘The Chemistry of Organolithium Compounds;’ ed. by Z.
Rappoport and I. Marek, Wiley, New York, 2004, pp. 749-828.
9
1
.
K. Mikami, Y. Kimura, N. Kishi, and T. Nakai, J. Org. Chem., 1983, 48, 279.
0. For the isolation of dendrolasin, see (a) A. Quilico, F. Piozzi, and M. Pavan, Tetrahedron, 1957, 1,
77. (b) T. Sakai, K. Nishimura, and Y. Hirose, Bull. Chem. Soc. Jpn., 1965, 38, 381. For the
synthesis of dendrolasin, see (c) A. Chakraborty, G. K. Kar, and J. K. Ray, Tetrahedron, 1997, 53,
513 and references cited therein.
1
8
1
1. For the isolation of naginata ketone, see (a) Y. Fujita and T. Ueda, Chem. & Ind., 1960, 236. For the
synthesis of naginata ketone, see (b) G. Büchi, E. Kovats, P. Enggist, and G. Uhde, J. Org. Chem.,
1
968, 33, 1227. (c) G. Cahiez, P. Y. Chavant, and E. Metais, Tetrahedron Lett., 1992, 33, 5245 and
references cited therein.
1
1
1
2. D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans. 1, 1975, 157.
3. W. G. Dauben and D. J. Hart, J. Am. Chem. Soc., 1977, 99, 7307.
4. R. Boese, D. F. Harvey, M. J. Malaska, and K. P. C. Vollhardt, J. Am. Chem. Soc., 1994, 116,
1
1153.
1
1
5. R. Noyori, T. Sato, and H. Kobayashi, Bull. Chem. Soc. Jpn., 1983, 56, 2661.
6. S. P. Tanis and P. M. Herrinton, J. Org. Chem., 1983, 48, 4572.