Chemoselective, Regioselective, and E/Z-Diastereoselective Synthesis of 2-Alkylidenetetrahydrofurans by Sequential Reactions of Ambident Dianions and Monoanions

Article abstract of DOI:10.1021/jo034966f

A number of novel β-ketoesters were prepared by regioselective alkylation reactions of simple β-ketoester dianions. The cyclization of the dianions of these 1,3-dicarbonyl derivatives with 1-bromo-2-chloroethane afforded a variety of 2-alkylidenetetrahydr

Full text of DOI:10.1021/jo034966f

Ch em oselective, Regioselective, a n d E/Z-Dia ster eoselective
Syn th esis of 2-Alk ylid en etetr a h yd r ofu r a n s by Sequ en tia l
Rea ction s of Am bid en t Dia n ion s a n d Mon oa n ion s
Peter Langer* and Esen Bellur
Institut fu¨r Chemie und Biochemie der Ernst-Moritz-Arndt-Universita¨t Greifswald, Soldmannstrasse 16,
17487 Greifswald, Germany
peter.langer@uni-greifswald.de
Received J uly 4, 2003
A number of novel â-ketoesters were prepared by regioselective alkylation reactions of simple
â-ketoester dianions. The cyclization of the dianions of these 1,3-dicarbonyl derivatives with 1-bromo-
2-chloroethane afforded a variety of 2-alkylidenetetrahydrofurans with very good regioselectivity
and E/Z-diastereoselectivity. These products were deprotonated to give novel ambident carbanions.
The alkylation of these carbanions with alkyl halides proceeded with very good regioselectivity
and E/Z-diastereoselectivity and allowed a convenient synthesis of a great variety of new
2-alkylidenetetrahydrofurans.
In tr od u ction
terrestric acid which are metabolites of Penicillium
charlesii and Penicillium terrestre, respectively.9 Bicyclic
2-alkylidenetetrahydrofurans have been used as direct
precursors for the synthesis of the natural spiroketal
chalcogran.10
We have recently reported the synthesis of function-
alized 2-alkylidenetetrahydrofurans by cyclization of free
and masked 1,3-dicarbonyl dianions11 with a variety of
dielectrophilic reagents.12 In this context, we have re-
cently shown that simple derivatives are available by
domino SN/SN reactions of 1,3-dicarbonyl dianions with
1-bromo-2-chloroethane.13a The use of the mixed dihalide
was mandatory, because cyclization reactions of dianions
with 1,2-difunctional alkylhalides can suffer from many
side reactions (e.g., polymerization, elimination, monoalky-
lation, or SET processes).14-17 For example, the reaction
2-Alkylidenetetrahydrofurans represent versatile syn-
thetic building blocks. For example, they can be used as
direct precursors for the preparation of functionalized
tetrahydrofurans and furans which occur in a variety of
natural products such as nactin derivatives, tetronasin,
or tetronomycin.1-5 In addition, they have been used for
the synthesis of terpenes6a,b and medium-sized lactones.7
2-Alkylidenetetrahydrofurans are interesting also in their
own right; they are of considerable pharmacological
relevance8 and occur in a number of natural products.
This includes for example charlic and charolic acids and
* Author to whom correspondence should be addressed. Fax: +3834
864373.
(1) (a) For review, see: Boivin, T. L. B. Tetrahedron 1987, 43, 3309
and references therein. (b) Barrett, A. G. M.; Sheth, H. G. J . Org. Chem.
1983, 48, 5017. (c) Rao, Y. S. Chem. Rev. 1976, 76, 625. (d) Pattenden,
G. Prog. Chem. Nat. Prod. 1978, 35, 133. (e) Knight, D. W. Contemp.
Org. Synth. 1994, 1, 287. (f) Gerlach, H.; Wetter, H. Helv. Chim. Acta
1974, 57, 2306. (g) Schmidt, U.; Gombos, J .; Haslinger, E.; Zak, H.
Chem. Ber. 1976, 109, 2628. (h) Bartlett, P. A.; Meadows, J . D.; Ottow,
E. J . Am. Chem. Soc. 1984, 106, 5304. (i) Bryson, T. A. J . Org. Chem.
1973, 38, 3428. (j) Yamaguchi, M.; Hirao, I. Chem. Lett. 1985, 337.
(2) For the synthesis of nonactates from 2-alkylidenetetrahydro-
furans, see: Lygo, B.; O’Connor, N.; Wilson, P. R. Tetrahedron 1988,
22, 6881.
(9) Arai, H.; Miyajima, H.; Mushiroda, T.; Yamamoto, Y. Chem.
Pharm. Bull. 1989, 12, 3229.
(10) Mori, K.; Sasaki, M.; Tamada, S.; Suguro, T.; Masuda, S.
Tetrahedron 1979, 35, 1601.
(11) For reviews of cyclization reactions of free and masked 1,3-
dicarbonyl dianions, see: (a) Langer, P. Chem.sEur. J . 2001, 7, 3858.
(b) Langer, P. Synthesis 2002, 441.
(12) (a) Weiler, L. J . Am. Chem. Soc. 1970, 92, 6702. (b) Seebach,
D.; Ehrig, V. Angew. Chem. 1974, 86, 446; Angew. Chem., Int. Ed. Engl.
1974, 13, 401.
(3) For information about tetronasin, see: Boons, G.-J .; Clase, J .
A.; Lennon, I. C.; Ley, S. V.; Staunton, J . Tetrahedron 1995, 51, 5417
and references therein.
(4) For information about tetronomycin, see: Iqbal, J .; Pandey, A.;
Chauhan, B. P. S. Tetrahedron 1991, 47, 4143.
(5) Booth, P. M.; Fox, C. M. J .; Ley, S. V. J . Chem. Soc., Perkin
Trans. 1 1987, 121.
(6) (a) Marvell, E. N.; Titterington, D. Tetrahedron Lett. 1980, 2123.
(b) Tsuji, J .; Kobayashi, Y.; Kataoka, H.; Takahashi, T. Tetrahedron
Lett. 1980, 1475.
(7) Wang, T.; Chen, J .; Landrey, D. W.; Zhao, K. Synlett 1995, 543.
(8) For carbohydrate derived bicyclic 2-alkylidenetetrahydrofurans,
see: (a) Al-Tel, T. H.; Voelter, W. J . Chem. Soc., Chem. Commun. 1995,
239. (b) Al-Tel, T. H.; Meisenbach, M.; Voelter, W. Liebigs Ann. 1995,
689.
(13) (a) Langer, P.; Holtz, E.; Karime´, I.; Saleh, N. N. R. J . Org.
Chem. 2001, 66, 6057. (b) See also: Lambert, P. H.; Vaultier, M.;
Carrie´, R. J . Org. Chem. 1985, 50, 5352.
(14) For cyclization reactions of dianions with difunctional alkyl
halides, see: (a) Bahl, J . J .; Bates, R. B.; Beavers, W. A.; Mills, N. S.
J . Org. Chem. 1976, 41, 1620. (b) Hirai, K.; Iwano, Y. Tetrahedron
Lett. 1979, 2031. (c) Bilyard, K. G.; Garratt, P. J .; Hunter, R.; Lete, E.
J . Org. Chem. 1982, 47, 4731.
(15) Recently, the two-step synthesis of annelated imidazoles by
cyclization of dilithiated 2-methylbenzimidazole with 1-bromo-2-chlo-
roethane has been reported. McClure, J . R.; Custer, J . H.; Schwarz,
H. D.; Lill, D. A. Synlett 2000, 710.
(16) The cyclization of 1-bromo-2-chloroethane with the dianion of
2-methylindole, generated by the use of Lochmann-Schlosser base:
Katritzky, A. R.; Fali, C. N.; Li, J . J . Org. Chem. 1997, 62, 4148.
10.1021/jo034966f CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/15/2003
9742
J . Org. Chem. 2003, 68, 9742-9746

Synthesis of 2-Alkylidenetetrahydrofurans
TABLE 1. P r od u cts a n d Yield s
SCHEME 1. Syn th esis of
2-Alk ylid en etetr a h yd r ofu r a n s 3
ratio of
E to Z
(3)
2
3
δ
δ
2,3
R1
R2
[%]a [%]a [ppm]b [ppm]c
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
propyl
hexyl
heptyl
octyl
decyl
i-Bu
isopentyl Ot-Bu
benzyl Ot-Bu
(CH2)3Cl OMe
(CH2)6Cl Ot-Bu
OMe
H
H
H
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
90
71
77
87
60
44
98
57
77
80
49
66
53
43
41
45
48
40
44
91
49
82
4.78
4.78
4.78
4.78
4.79
4.78
4.79
4.90
5.20
4.79
5.43
6.55
5.30
5.25
5.32
5.23
5.20
165.89 <2:98
165.89 <2:98
165.93 <2:98
165.92 <2:98
165.95 <2:98
165.94 <2:98
165.89 <2:98
167.38 <2:98
168.18 >98:2
165.82 <2:98
167.81 >98:2
189.96 >98:2
168.10 >98:2
167.20 >98:2
168.70 >98:2
168.40 >98:2
168.00 >98:2
OMe
Ph
OEt
Ot-Bu
OMe
OMe
OEt
75d
74d
65d
68d
80d
H
Me
Et
of 1,3-dicarbonyl dianions with 1,2-dibromo- or 1,2-
diiodoethane resulted in the oxidation of the dianion
rather than cyclization.18,19 Open-chained products were
obtained, however, in only low yield in the presence of
catalytic amounts of CuCl.20 The use of 1,2-dichloroeth-
ane resulted in elimination of hydrogen chloride.20 The
reaction of 1,3-dicarbonyl dianions with higher 1,n-
dibromoalkanes (n ) 3 or higher) gave mixtures of open-
chained 1:1 and 2:1 condensation products.21
Herein, we report a significant extension of our original
methodology for the synthesis of 2-alkylidenetetrahydro-
furans. The preparative scope of the cyclization was
successfully extended to the use of ketone-derived 1,3-
dicarbonyl compounds and to derivatives containing a
bulky or functionalized side chain. In this context, we
report the generation of dianions of halo-substituted 1,3-
dicarbonyl compounds and their application in synthesis.
In addition, we report the generation of carbanions of
2-alkylidenetetrahydrofurans and their synthetic ap-
plication. The alkylation of the ambident carbanions
proceeded with very good regioselectivity and E/Z-dia-
stereoselectivity and allowed an efficient and indepen-
dent preparation of a variety of new 2-alkylidenetetrahy-
drofurans. Most products are not directly available by
cyclization of the corresponding dianions with 1-bromo-
2-chloroethane or by other methods.
a
b
Yields of isolated products. Chemical shift (1H NMR, CDCl3)
of the hydrogen atom of the exocyclic double bond of 3. c Chemical
shift (13C NMR, CDCl3) of the carbonyl group of 3. See ref 13a.
d
and 2j. An excellent yield (91%) was obtained for chloro-
substituted tetrahydrofuran 3j. By use of the dianion of
methyl 4-methoxyacetoacetate as a starting material, the
methoxy-substituted tetrahydrofuran 3k was prepared
for the first time. In addition, the novel tetrahydrofuran
3l was prepared from benzoylacetone. 1,3-Diketone-
derived 2-alkylidenetetrahydrofurans have not been pre-
pared so far by our methodology. The synthesis of
2-alkylidenetetrahydrofurans 3m -q has been previously
reported by us.13a
All 2-alkylidenetetrahydrofurans were formed with
excellent C,O regioselectivity.22 The products containing
a substituent at the tetrahydrofuran moiety were isolated
as the Z-configured isomers (except for 3i, 3k , 3p , and
3q), as a result of the steric interaction of the substituent
with the bulky ester group. In the case of 3l-o the
E-configured isomers were obtained; these isomers are
thermodynamically more stable, because of the electro-
static repulsion of the oxygen atoms and the absence of
a stereodirecting substituent.23 Products 3i, 3k , 3p , and
3q were isolated as the E-configured isomers, despite the
presence of a substituent at the tetrahydrofuran moiety.
This can be explained (except for 3i) by the small size
and thus low stereodirecting effect of these substituents.
The ester moiety also seems to have some influence: the
Z-configured isomers are obtained for the tert-butyl esters
3a -h and 3j. The E-configured isomer is obtained for the
methyl ester 3i, presumably because of the less severe
steric interaction between the ester and the alkyl group.
A slow E/Z-isomerization upon standing at room tem-
perature was observed for several products.
Resu lts a n d Discu ssion
A number of novel â-ketoesters 2 were prepared by
reaction of 1,3-dicarbonyl dianions with alkyl iodides.
This includes both branched and unbranched derivatives
and the chloro-substituted â-ketoesters 2i and 2j which
were prepared from 1-chloro-3-iodopropane and 1-chloro-
6-iodohexane, respectively. The cyclization of the dianions
of these â-ketoesters (generated by means of 2 equiv of
LDA) with 1-bromo-2-chloroethane afforded the novel
2-alkylidenetetrahydrofurans 3a -j (Scheme 1, Table 1).
To our surprise, the chloro group proved to be compatible
with the LDA-mediated generation of the dianions of 2i
(22) For stereoelectronic considerations related to the regioselectivity
of cyclizations, see: Baldwin, J . E.; Kruse, L. I. J . Chem. Soc., Chem.
Commun. 1977, 233.
(17) Branda¨nge, S.; Lindqvist, B. Acta Chem. Scand. 1989, 43, 807.
(18) Hampton, K. G.; Light, R. J .; Hauser, C. R. J . Org. Chem. 1965,
30, 1413.
(19) Barry, C. E., III; Bates, R. B.; Beavers, W. A.; Camou, F. A.;
Gordon, B., III; Hsu, H. F.-J .; Mills, N. S.; Ogle, C. A.; Siahaan, T. J .;
Suvannachut, K.; Taylor, S. R.; White, J . J .; Yager, K. M. Synlett 1991,
207.
(23) For the configuration of 1,3-dicarbonyl enolates, see: (a)
Rhoads, S. J .; Holder, R. W. Tetrahedron 1969, 25, 5443. (b) Miller,
B.; Margulies, H.; Drabb, T., J r.; Wayne, R. Tetrahedron Lett. 1970,
3801. (c) Miller, B.; Margulies, H.; Drabb, T., J r.; Wayne, R. Tetrahe-
dron Lett. 1970, 3805. (d) Entenmann, G. Tetrahedron Lett. 1975, 4241.
(e) Cambillau, C.; Sarthou, P.; Bram, G. Tetrahedron Lett. 1976, 281.
For a review of the structure of lithium enolates, see: (f) Seebach, D.
Angew. Chem. 1988, 100, 1685; Angew. Chem., Int. Ed. Engl. 1988,
27, 1624.
(20) Hampton, K. G.; Christie, J . J . J . Org. Chem. 1976, 41, 2772.
(21) Sum, P.-E.; Weiler, L. Can. J . Chem. 1977, 55, 996.
J . Org. Chem, Vol. 68, No. 25, 2003 9743

Langer and Bellur
ratio of
TABLE 2. P r od u cts a n d Yield s
SCHEME 2. Lith ia tion a n d Alk yla tion of
2-Alk ylid en etetr a h yd r ofu r a n s 3
4
δ
E to Z
(4)
entry
R1
R2
R3
hexyl
heptyl
octyl
[%]a [ppm]b
57
49c 169.23 >98:2
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
H
H
H
H
H
OEt
OEt
OEt
OEt
Ot-Bu ethyl
Ot-Bu propyl
Ot-Bu heptyl
Ot-Bu i-Bu
169.22 >98:2
51
48
51
45
91
40
42
45
40
169.27 >98:2
169.25 >98:2
168.52 >98:2
168.62 >98:2
168.66 >98:2
168.85 >98:2
168.10 >98:2
168.18 >98:2
168.54 >98:2
167.42 >98:2
166.87 >98:2
169.73 >98:2
169.27 >98:2
168.45 >98:2
169.28 >98:2
169.61 >98:2
169.20 2:1
decyl
Ot-Bu allyl
Ot-Bu benzyl
Ot-Bu (CH2)6Cl
j
k
l
Ot-Bu CH2CO2Me 25
m
n
o
p
q
r
s
t
u
v
w
CH2CO2Me Ot-Bu
H
32
79
38
43
41
45
42
38
92
74
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OEt
Ot-Bu decyl
OMe hexyl
Ot-Bu hexyl
isopentyl
benzyl
benzyl
(CH2)3Cl
(CH2)5Cl
hexyl
The configuration of 2-alkylidenetetrahydrofurans 3
was proven by NOESY experiments and by comparison
of the chemical shifts of the hydrogen atoms of the
exocyclic double bond with those of related compounds
(Table 1).8,24 As expected, characteristic chemical shifts
in the range of δ ) 5.15-5.31 and δ ) 4.70-4.90 were
observed for all E- and Z-configured ester-substituted
2-alkylidenetetrahydrofurans, respectively. Likewise, a
characteristic chemical shift (δ ) 6.55) was observed for
the E-configured phenyl-substituted 2-alkylidenetetrahy-
drofuran 3l. The E-configured ester-substituted 2-alkyli-
denetetrahydrofurans generally showed a characteristic
carbonyl 13C NMR resonance in the range of δ ) 168.0-
170.0 ppm. In contrast, resonances in the range of δ )
165.0-166.0 ppm were observed for the Z-configured
isomers. An independent proof of the configuration was
established by crystal structure analysis of related
compounds.25
benzyl
H
H
Me
Et
propyl
168.79 2:1
168.14 >98:2
167.29 >98:2
hexyl
OMe
isopentyl
74d 168.10 >98:2
a
b
Isolated yields. Chemical shift (13C NMR, CDCl3) of the
carbonyl group of 4. c An unknown impurity could not be sepa-
rated. Starting material could not be separated.
d
To study the preparative scope of our methodology, the
substituents of the starting materials were systematically
varied (Table 2). The reaction of lithiated 3m with hexyl,
heptyl, octyl, and decyl iodide afforded the 2-alkylidene-
tetrahydrofurans 4a -d in good yields. The use of the
corresponding bromides was again unsatisfactory. The
direct synthesis of 2-alkylidenetetrahydrofurans contain-
ing a substituent at the exocyclic double bond is disad-
vantageous for two reasons: (a) We have found that the
cyclization of the corresponding sterically encumbered
dianions with 1-bromo-2-chloroethane often proceeds only
in low yields.13a (b) In addition, the starting materials
are often not commercially available, and double alky-
lation may occur during their synthesis. The deprotona-
tion and subsequent alkylation of tert-butyl ester 3n with
ethyl, propyl, and heptyl iodide afforded the E-configured
tetrahydrofurans 4e-g. The use of isobutyl iodide, a
branched electrophile, resulted in the formation of 4h in
acceptable yield. The allyl- and benzyl-substituted de-
rivatives 4i and 4j were prepared by reaction of 3n with
allylbromide and benzylbromide, respectively. Treatment
of lithiated 3n with 1-chloro-6-iodohexane afforded the
chloro-substituted 2-alkylidenetetrahydrofuran 4k with
very good chemoselectivity. The reaction of 3n with
methyl bromoacetate afforded a separable mixture of the
regioisomeric products 4l and 4m . The reaction of lithi-
ated 2-alkylidenetetrahydrofuran 3o with isopentyl io-
dide afforded the E-configured tetrahydrofuran 4n with
very good regioselectivity. The reaction of 3o with ben-
zylbromide gave a separable mixture of the monoben-
zylated and double-benzylated products 4o and 4p .
Treatment of lithiated 3o with 1-chloro-3-iodopropane
and 1-chloro-5-iodopentane afforded the chloro-substi-
tuted 2-alkylidenetetrahydrofurans 4q and 4r with very
good chemoselectivity. The 2-alkylidenetetrahydrofurans
Our initial attempts to realize a deprotonation of the
simple 2-alkylidenetetrahydrofuran 3m failed. Only start-
ing material was recovered by treatment of 3m with LDA
and subsequent addition of methyl or hexyl iodide. The
use of n-BuLi resulted in decomposition. After many trial
experimentations we have found that optimal conditions
for the alkylation of 3m require the presence of HMPA
(1.6 equiv) and the use of an excess (1.8 equiv) of LDA.
Treatment of the carbanion of 3m with hexyl iodide
afforded 2-alkylidenetetrahydrofuran 4a in good yield
(Scheme 2, Table 2). No product could be isolated by the
use of hexyl bromide. The formation of 4a can be
explained by the generation of the novel ambident
carbanion A which can be regarded as a lithiated R,â-
unsaturated ester. The alkylation of A proceeded with
high regioselectivity at the R-carbon atom to give inter-
mediate B. A rearrangement of the double bond afforded
4a which is thermodynamically more stable than B,
because of the conjugation of the double bond and the
carbonyl group. 2-Alkylidenetetrahydrofuran 4a was
isolated exclusively as the E-configured isomer, despite
the presence of an additional substituent at the exocyclic
double bond. This can again be explained by thermody-
namic reasons.
(24) (a) Langer, P.; Freifeld, I. Chem.sEur. J . 2001, 7, 565. (b)
Langer, P.; Armbrust, H.; Eckardt, T. Chem.sEur. J . 2002, 8, 1443.
(c) Langer, P.; Holtz, E.; Saleh, N. N. R. Chem.sEur. J . 2002, 8, 917.
(25) These crystal structure analyses include compound 5h in ref
13a and recently prepared 4-methoxy-2-alkylidenetetrahydrofurans.
9744 J . Org. Chem., Vol. 68, No. 25, 2003

Synthesis of 2-Alkylidenetetrahydrofurans
1-iodo-3-methylbutane (4.492 g, 22.00 mmol) at -78 °C. The
temperature was allowed to rise to ambient during 14 h, and
the solution was stirred at room temperature for 2 h. To the
solution was added hydrochloric acid (200 mL, 10%), and the
mixture was extracted with diethyl ether (4 × 250 mL). The
organic layers were dried over Na2SO4 and filtered, and the
solvent of the filtrate was removed in vacuo. The residue was
purified by chromatography (silica gel, n-hexane f n-hexane/
EtOAc ) 50:1) to give 2g (4.495 g, 98%) as a yellow oil. 1H
NMR (CDCl3, 300 MHz): δ ) 0.86-0.89 (d, J ) 9.0 Hz, 6 H),
1.13-1.19 (m, 2 H), 1.48 (s, 9 H), 1.56-1.63 (m, 3 H), 2.50 (t,
J ) 7.4 Hz, 2 H), 3.34 (s, 2 H). 13C NMR (CDCl3, 50 MHz): δ
) 21.3, 22.4, 27.8, 27.9, 38.2, 43.1, 50.6, 81.8, 166.5, 203.5. IR
(neat, cm-1): ν˜ ) 3005 (w), 2957 (s), 2935 (s), 2905 (m), 2872
(m), 1739 (s), 1715 (s), 1643 (m), 1469 (m), 1459 (m), 1411 (m),
1394 (m), 1386 (w), 1369 (s), 1319 (s), 1252 (s), 1149 (s), 1111
(w), 1074 (w), 950 (w), 843 (w). MS (EI, 70 eV): m/z (%) ) 228
(M+, 5), 183 (15), 171 (15), 155 (100). Anal. Calcd for C13H24O3
(228.331): C, 68.38; H, 10.59. Found: C, 68.19; H 10.91.
SCHEME 3. Syn th esis of Bicyclic
Tetr a h yd r ofu r a n 4x
4a -r were formed with very good E-diastereoselectivity,
due to thermodynamic reasons (vide supra).
Rep r esen ta tive Exp er im en ta l P r oced u r e of th e Cy-
cliza tion of 1,3-Dica r bon yl Dia n ion s w ith 1-Br om o-2-
ch lor oeth a n e. LDA was prepared by addition of n-BuLi
(13.75 mL, 21.90 mmol, 15% in n-hexane) to a solution of
diisopropylamine (3.08 mL, 21.90 mmol) in THF (100 mL). To
this solution was added 2g (2.000 g, 8.76 mmol) at 0 °C. The
solution was stirred at 0 °C for 1 h. To this solution was added
1-bromo-2-chloroethane (0.80 mL, 9.64 mmol) at -78 °C. The
temperature was allowed to rise to ambient during 14 h, and
the solution was refluxed for 2 h. To the solution was added
hydrochloric acid (150 mL, 10%), and the mixture was ex-
tracted with diethyl ether (4 × 250 mL). The organic layers
were dried over Na2SO4 and filtered, and the solvent of the
filtrate was removed in vacuo. The residue was purified by
chromatography (silica gel, n-hexane/EtOAc ) 100:1 f 1:1)
The alkylation of 2-alkylidenetetrahydrofurans 3p and
3q, containing a methyl and ethyl substituent at the
tetrahydrofuran moiety, was next studied. The reaction
of 3p and 3q with hexyl iodide and propyl iodide afforded
the alkylated 2-alkylidenetetrahydrofurans 4s and 4t ,
respectively. However, the E/Z-diasterestereoselectivity
was low (2:1). The reaction of 3b with 1-iododecane
afforded 4u . Tetrahydrofuran 4v was prepared by alky-
lation of the methoxy-substituted derivative 3k with
1-iodohexane. The reaction of tetrahydrofuran 3f with
1-iodohexane gave 4w . The products 4u -w were formed
with very good E-diastereoselectivity. The diastereose-
lectivity of the synthesis of 4s-w was dependent on the
starting materials. An isomerization upon standing at
room temperature was observed for several products.
This might explain the formation of isomeric mixtures
in the case of 4s,t. The configuration of 2-alkylidenetetra-
hydrofurans 4, containing a tetrasubstituted exocyclic
double bond, was established by analysis of the carbonyl
13C NMR resonances (Table 2) and by comparison with
related compounds (e.g., Table 1).8,24
1
to give 3g (1.068 g, 48%) as a yellow oil. H NMR (CDCl3, 300
MHz): δ ) 0.88-0.92 (2 × d, J ) 6.0 Hz, 6 H), 1.19-1.29 (m,
2 H), 1.48 (s, 9 H), 1.64-1.74 (m, 2 H), 2.12-2.23 (m, 1 H),
2.70-2.74 (m, 1 H), 3.48-4.11 (dq, J ) 7.2 Hz, 1 H), 4.23-
4.32 (dq, 1 H), 4.44-4.51 (m, 1 H), 4.79 (s, 1 H). 13C NMR
(CDCl3, 50 MHz ): δ ) 22.2, 22.6, 27.9, 28.3, 29.4, 30.2, 36.6,
44.0, 72.2, 78.9, 89.1, 165.9, 175.0. IR (neat, cm-1): ν˜ ) 2958
(s), 2932 (s), 2905 (m), 2871 (m), 1710 (s), 1687 (m), 1647 (s),
1469 (w), 1455 (w), 1390 (m), 1366 (m), 1328 (w), 1303 (w),
1282 (w), 1247 (w), 1214 (s), 1168 (s), 1143 (s), 1030 (s), 966
(w), 805 (w). MS (EI, 70 eV): m/z (%) ) 254 (M+, 14), 197 (52),
181 (100). Anal. Calcd for C15H26O3 (254.369): C, 70.82; H,
10.30. Found: C, 70.41; H, 9.93. The synthesis of 3m -r has
been previously reported.13a
The synthesis of the bicyclic tetrahydrofuran 3r was
recently reported by us.13a The reaction of lithiated 3r
with benzylbromide afforded the benzylated 2-alkyli-
denetetrahydrofuran 4x (Scheme 3). This experiment
showed that the regioselectivity was changed from R- to
γ-attack by the presence of a substituent at the R-posi-
tion, which is due to steric reasons. The exocyclic double
bond was formed with low E/Z-diasterestereoselectivity
(2:1).
Rep r esen ta tive Exp er im en ta l P r oced u r e for th e Alk y-
la tion of 2-Alk ylid en etetr a h yd r ofu r a n s. LDA was pre-
pared by addition of n-BuLi (1.36 mL, 2.17 mmol, 15% in
n-hexane) to a solution of diisopropylamine (0.31 mL, 2.17
mmol) in THF (17 mL) at 0 °C. To this solution was added
HMPA (0.34 mL, 1.92 mmol) at 0 °C, and the mixture was
stirred for 20 min at this temperature. To the solution was
added 3m (0.200 g, 1.28 mmol) at -78 °C, and the solution
was stirred for 1 h. To the solution was added 1-iodohexane
(0.21 mL, 1.41 mmol) at -78 °C, and the temperature was
allowed to rise to ambient during 14 h. The solution was stirred
at room temperature for 5 h. To the solution was added
hydrochloric acid (20 mL, 1 M), and the mixture was extracted
with diethyl ether (4 × 50 mL). The organic layers were dried
over Na2SO4 and filtered, and the solvent of the filtrate was
removed in vacuo. The residue was purified by chromatogra-
phy (silica gel, n-hexane f n-hexane/EtOAc ) 50:1) to give
4a (0.175 g, 57%) as a colorless oil. 1H NMR (CDCl3, 300
MHz): δ ) 0.88 (t, J ) 6.6 Hz, 3 H), 1.28 (t, J ) 4.1 Hz, 3 H),
1.30-1.40 (m, 8 H), 2.06 (quint, J ) 7.5 Hz, 2 H), 2.26 (t, J )
7.8 Hz, 2 H), 3.06 (t, J ) 7.8 Hz, 2 H), 4.14 (t, J ) 7.2 Hz, 2
H), 4.19 (q, J ) 4.2 Hz, 2 H). 13C NMR (CDCl3, 75 MHz ): δ )
14.0, 14.4, 22.6, 24.4, 26.0, 28.4, 29.2, 30.9, 31.7, 59.2, 71.1,
In conclusion, we have reported an efficient method
for the chemoselective, regioselective, and E/Z-diastereo-
selective synthesis of a variety of 2-alkylidenetetrahy-
drofurans which are of pharmacological relevance and
represent useful synthetic building blocks.
Exp er im en ta l Section
Rep r esen ta tive Exp er im en ta l P r oced u r e for th e Alk y-
la tion of 1,3-Dica r bon yl Dia n ion s. LDA was prepared by
addition of n-BuLi (25.10 mL, 40.00 mmol, 15% in n-hexane)
to a solution of diisopropylamine (5.60 mL, 40.00 mmol) in
THF (100 mL). To this solution was added tert-butylacetoac-
etate (3.30 mL, 20.00 mmol) at 0 °C. The deep-yellow clear
solution was stirred at 0 °C for 1 h. To this solution was added
J . Org. Chem, Vol. 68, No. 25, 2003 9745

Langer and Bellur
103.0, 169.2, 170.3. IR (neat, cm-1): ν˜ ) 2957 (s), 2928 (s),
2858 (m), 1697 (s), 1635 (s), 1459 (w), 1372 (w), 1315 (w), 1294
(m), 1252 (w), 1175 (m), 1109 (s), 1055 (m). MS (EI, 70 eV):
m/z (%) ) 240 (M+, 96), 211 (36), 195 (100), 156 (40). The exact
molecular mass m/z ) 240.1725 ( 2 mDa [M+] for C14H24O3
was confirmed by HRMS (EI, 70 eV). Anal. Calcd for C14H24O3
(240.34): C, 69.97; H, 10.07. Found: C, 69.56; H, 9.95.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods, experimental procedures, analytical data, and
spectroscopic data of all new compounds; copies of 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O034966F
9746 J . Org. Chem., Vol. 68, No. 25, 2003