Cyclization of 1,1-Disubstituted Alkenes to Cyclopentenes

Article abstract of DOI:10.1021/jo991311z

A general method for the cyclization of an unactivated 1,1-disubstituted alkene such as 1 to the corresponding cyclopentene 5 is described. Bromination followed by the addition of strong base in the same pot gave the vinyl bromide 3, which reacted further in situ to give the alkylidene carbene 4. This then inserted 1,5 into a C-H bond to give the cyclopentene 5.

Full text of DOI:10.1021/jo991311z

J . Org. Chem. 1999, 64, 9673-9678
9673
Cycliza tion of 1,1-Disu bstitu ted Alk en es to Cyclop en ten es
Douglass F. Taber,* Thomas E. Christos, Timothy D. Neubert, and Dolly Batra†
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
Received August 17, 1999
A general method for the cyclization of an unactivated 1,1-disubstituted alkene such as 1 to the
corresponding cyclopentene 5 is described. Bromination followed by the addition of strong base in
the same pot gave the vinyl bromide 3, which reacted further in situ to give the alkylidene carbene
4. This then inserted 1,5 into a C-H bond to give the cyclopentene 5.
Sch em e 1
In tr od u ction
Cyclopentene intermediates are important synthons for
a variety of natural products.1 We have been exploring
the preparation of cyclopentenes by the 1,5 C-H inser-
tion of intermediate alkylidene carbenes. The alkylidene
carbenes can be generated from ketones using diazophos-
phonates or trimethyl silyldiazomethane.2,1a They can
also be prepared by converting the ketone to the vinyl
halide, followed by exposure of the vinyl halide to
potassium bis(trimethylsilyl)amide (KHMDS) to effect
3,1k
R-elimination.
We thought that it might be possible
to extend this reaction to a simple alkene such as 1
(Scheme 1). Bromination should give 2, and dehydrobro-
mination would be expected to give 3, setting the stage
for in situ elimination and insertion.4
Resu lts a n d Discu ssion
Sch em e 2
We have prepared 1 (Scheme 2) from (S)-glycidol by
Grignard opening followed by ketalization.4 The acetonide
1 was purified on a multigram scale by distillation. As
we had hypothesized, bromination followed by exposure
to KHMDS nicely cyclized 1 to 5. This procedure required
some optimization. The ketal tended to participate in the
bromination, so it was necessary to effect bromination
in ether at -78 °C and then immediately add the
KHMDS (freshly titrated) before allowing the reaction
to come to room temperature. Under these conditions,
cyclization proceeded in good yield.
* To whom correspondence should be addressed. Tel.: 302-831-2433.
Fax: 302-831-6335. E-mail: taberdf@Udel.edu.
Our next objective was to explore the general utility
of this protocol for the preparation of cyclopentene
derivatives, using substrates with unactivated methylene
C-H bonds.1a,j,5 The one-pot protocol for the cyclization
gave low yields with alkenes 7-9, so we prepared the
long-chain dibromides 10-12 (Scheme 3). We were able
to effect the desired insertion by treatment of 10, 11, and
12 with 2.5 equiv of KHMDS to obtain the cyclopentenes
13, 14, and 15a ,b (Scheme 3).
We then returned to the one-pot bromination/cycliza-
tion protocol. To this end, alkene 16 (Scheme 4) was
prepared by reacting 2-methylallylmagnesium chloride
with 4-phenoxybutyl bromide. Cyclization of 16 by ad-
dition of bromine followed by KHMDS gave a 27% yield
of the desired cyclopentene 17. We prepared and cyclized
the dibromide intermediate 18 (Scheme 4) and the vinyl
bromide intermediate 19 in an attempt to determine the
factor that lowered the yield of the C-H insertion
† Undergraduate research participant.
(1) For leading references to cyclopentene construction by inter-
molecular C-H insertion of an alkylidene carbene, see: (a) Gilbert, J .
C.; Giamualva, D. H.; Weerasooriya, U. J . Org. Chem. 1983, 48, 8,
5251. (b) Dreiding, S.; Huguet, J .; Karpf, M. Tetrahedron Lett. 1983,
24, 4177. (c) Gilbert, J . C.; Giamualva, D. H.; Blaze. M. E. J . Org. Chem.
1985, 50, 0, 2557. (d) Ochiai, M.; Kunishima, M.; Tani, S. J . Am. Chem.
Soc. 1991, 113, 3135. (e) Taber, D. F.; Walter, R.; Meagley, R. P. J .
Org. Chem. 1994, 59, 6014. (f) Tani S.; Kato, A.; Kunishima, M.
Tetrahedron Lett. 1994, 35, 7253. (g) Stang, J .; Williamson, B. L.;
Tywinski, R. R. J . Am. Chem. Soc. 1994, 116, 93. (h) Taber, D. F.;
Walter, R.; Meagley, R. P. Tetrahedron Lett. 1994, 43, 7909. (i) Kim,
S.; Cho, C. M. Tetrahedron Lett. 1995, 27, 4845. (j) Ohira, S.; Sawamoto,
T.; Yamoto, M. Tetrahedron Lett. 1995, 36, 1537. (k) Taber, D. F.;
Meagley, R. P.; Doren, D. J . J . Org. Chem. 1996, 61, 1, 5723. (l) Taber,
D. F.; Christos, T. E. J . Org. Chem. 1996, 61, 2081. (m) Taber, D. F.;
Yu, H. J . Org. Chem. 1997, 62, 2, 1687. For reviews, see: (n) Taber,
D. F. In Methods of Organic Chemistry; Helmchen, G., Ed.; Georg
Thieme Verlag Stuttgurt; New York, 1995; Vol. E21; p 1127. (o) Kirmse,
W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1164.
(2) Ohira, S.; Okai, K.; Moritani, T. J . Chem. Soc., Chem. Commun.
1992, 72, 721.
(3) (a) Taber, D. F.; Sahli, A.; Yu, H.; Meagley, R. P. J . Org. Chem.
1995, 60, 6571.
(4) For a preliminary account of the cyclization of 1 to 5, see: Taber,
D. F.; Christos, T. E. J . Am. Chem. Soc. 1999, 121, 5589.
(5) For a summary of the relative rates of insertion into C-H bonds,
see: Wolinsky, J .; Clark, G. W. J . Org. Chem. 1976, 41, 745.
10.1021/jo991311z CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/04/1999

9674 J . Org. Chem., Vol. 64, No. 26, 1999
Taber et al.
Sch em e 3
Sch em e 5
Ta ble 1. Op tim iza tion of th e Cycliza tion of Alk en yl
Br om id e 21 to Cyclop en ten e 22
entry solvent
T (°C)
base (3 equiv) time (h) yield (%)
1
2
3
4
5
6
7
8
9
DME
DME
DME
DME
Et2O
toluene
benzene
DMF
-78 to +25
KHMDS
KHMDS
LiHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
17
2
24
2
2
2
2
2
24
2
2
70
70
0
69
68
52
51
53
0
25
25
25
25
25
25
25
25
25
25
CCl4
10 THF
11 p-dioxane
67
75
cyclizations was due to the deactivation of the methylene
undergoing C-H insertion. The methylene at the cycliza-
tion center in substrate 16 is deactivated due to its γ
relationship with the phenoxy group.6 To solve this
deactivation problem, we turned to the alkenyl bromide
21 (Scheme 5). Bromide 21 was prepared by coupling
5-phenoxypentyl bromide with 2-methylallylmagnesium
chloride to obtain alkene 20, which was brominated and
then treated with DBU.
We first addressed the cyclization of the alkenyl
bromide 21. We found (Table 1) that the best results were
obtained using p-dioxane/KHMDS (3 equiv)/25 °C. With
these results in hand, we tried the bromination of alkene
20, followed by cyclization of the crude dibromide to 22
using the optimized conditions. This protocol gave a 50%
overall yield of the desired cyclopentene.
Sch em e 4
To address the compatibility of this protocol with other
protecting groups, alcohol 23 was prepared (Scheme 6)
by coupling 1-bromohexanol with 2-methylallylmagne-
sium chloride. Alcohol 23 was then alkylated with benzyl
bromide to give alkene 24 (Scheme 6). Application of the
optimized bromination/cyclization protocol, for the con-
version of 20 to 22, to alkene 24 gave a 50% yield of an
80:20 mixture of 25 and unreacted 24 (Scheme 6). All of
the alkene 24 had been consumed in the bromination
step, so we concluded that a reduction must have
intervened.
The dibromide 26 was prepared from 24 (Scheme 6),
and cyclization conditions were optimized to minimize
the amount of 24 obtained from the reaction (Table 2).
Lower temperature and longer reaction time were found
to be the key factors in optimizing this reaction.
We tried the one-pot bromination/cyclization of 24
using the optimized lower temperature conditions for the
cyclization. This reaction gave a 57% overall yield of the
desired cyclopentene 25. Under these conditions, less
product. However, each of the cyclizations proceeded in
only mediocre yield.
We hypothesized that the moderate yield from these
(6) (a) Taber, D. F.; Song, Y. J . Org. Chem. 1996, 61, 6706. (b)
Hennessy, M. J . Ph.D. Thesis, University of Delaware, 1998. (c) Stork,
G.; Nakatani, K. Tetrahedron Lett. 1995, 36, 1537.

Cyclization of 1,1-Disubstituted Alkenes to Cyclopentenes
J . Org. Chem., Vol. 64, No. 26, 1999 9675
Sch em e 6
resulting dibromides with strong base can proceed ef-
ficiently. The last procedure illustrated (Scheme 7) ap-
pears to be a general one-pot protocol for effecting this
transformation.7
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR (at 300 MHz) and 13C NMR
(at 75 MHz) spectra were obtained as solutions in deuterio-
chloroform (CDCl3). The infrared (IR) spectra were determined
as neat oils on a Perkin-Elmer model 1650 FTIR spectrometer.
Mass spectra (MS) were obtained using FTMS at an ionizing
potential of 70 eV. Substances for which C, H analysis are not
reported were purified as specified and gave spectroscopic data
consistent with being >95% the assigned structure. Rf values
indicated refer to thin-layer chromatography (TLC) on 5.0 ×
10 cm, 250 mm analytical plates coated with silica gel 60, F254
,
developed in the solvent system indicated. Materials were
visualized using 5% phosphomolybdic acid in ethanol as stain.
Elemental analysis was carried out by Quantitative Technolo-
gies Inc., Whitehouse, NJ . Column chromatography was
carried out on an Isco MPLC using silica gel 60 particle size
0.015-0.040 mm. The solvent mixtures reported are volume/
volume mixtures. All glassware was oven dried, and reactions
were carried out under a flow of dry nitrogen. Reactions were
chilled to the desired temperature using a Neslab CC-100II
immersion cooler. Ethylene glycol dimethyl ether (DME), tert-
butyl methyl ether (MTBE), p-dioxane, and 0.5 M potassium
bis(trimethylsilyl)amide (KHMDS) in toluene were from Ald-
rich Sure-Seal bottles kept under dry nitrogen. All reactions
were stirred magnetically, unless otherwise noted.
2,2-Dim eth yl-4-(3-m eth yl-bu t-3-en yl)[1,3]d ioxola n e (1).
To a suspension of magnesium turnings (1.10 g, 45.2 mmol)
and 1,2 dibromoethane (0.11 mL, 1.13 mmol) in Et2O (50 mL)
chilled to 0 °C was added methallyl chloride (4.1 g, 45.2 mmol)
over 20 min. This was allowed to stir for 2 h at 0 °C and then
at room temperature for 1 h. The reaction mixture was then
chilled to -78 °C, and (S)-glycidol 1 (0.84 g, 11.31 mmol) in
10 mL of ether was added over 10 min. The reaction mixture
was allowed to warm to room temperature over 30 min then
stirred for an additional 1 h. The mixture was partitioned
between aqueous NH4Cl and, sequentially, CH2Cl2 and EtOAc.
The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. The crude diol (1.20 g, 9.23 mmol) was
dissolved in 20 mL of 2,2 dimethoxypropane at room temper-
ature, and TsOH (0.18 g, 0.92 mmol) was added. After 30 min
at room temperature, the mixture was partitioned between
saturated aqueous NaHCO3 and EtOAc. The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo. The
residue was distilled bulb to bulb (bp0.5 (pot) ) 50-55 °C) to
give 1.41 g (90% yield) of 1 as a thin clear oil (TLC Rf ) 0.45,
5% EtOAc/hexane): [R]D -7.0° (c 1.00, MeOH); 1H NMR δ 4.72
(d, J ) 10.0 Hz, 2H), 4.10 (m, 2H), 3.55 (m, 1H), 2.21-2.01
(m, 2H), 1.85-1.60 (m, 5H), 1.41 (s, 3H), 1.39 (s, 3H); HRMS
calcd mass 170.253221, measured mass 170.254782; IR cm-1
2986 (s), 1741 (m), 1650 (m), 1455 (m), 1371 (m); 13C NMR δ
C 145.0, CH 75.4, CH2 110.1, 69.4, 33.8, 31.6, CH3 75.7, 26.9,
25.7, 22.5.
Ta ble 2. Op tim iza tion of th e Cycliza tion of Dibr om id e
26 to Cyclop en ten e 25a
T
time
entry
solvent
(°C)
base
(h) % 25 % 24
1
2
3
4
5
6
7
8
9
10
11
12
13
Et2O
Et2O
Et2O
-20 KHMDS
-30 KHMDS
-10 KHMDS
48
48
48
48
48
48
48
48
48
48
48
48
48
90
80
84
93
84
93
93
94
50
0
10
20
16
7
16
7
7
6
50
0
0
DME/dioxane 1/1 -10 KHMDS
Et2O/dioxane 4/1 -10 KHMDS
DME
THF
Et2O/dioxane 4/1 -20 KHMDS
Et2O
diglyme
Et2O/DMPU
DME/dioxane 1/1 -20 KHMDS
DME/dioxane 1/2 -20 KHMDS
-20 KHMDS
-20 KHMDS
-20 NaHMDS
-20 KHMDS
-20 KHMDS
0
96
96
4
4
a
All reactions assessed by 1H NMR to deteremine the % 24
versus 25.
Sch em e 7
2,2,7-Tr im eth yl-1,3-d ioxa sp ir o[4.4]n on -6-en e (5). The
acetonide 1 (1.6 g, 9.4 mmol) in 200 mL of Et2O was chilled to
-78 °C. Br2 (1.50 g, 9.4 mmol, neat) was then added over 2
min, and the reaction was allowed to stir for 20 min. A solution
of KHMDS (0.5 M in toluene, 75.3 mL, 37.65 mmol) was added
over 10 min while the temperature was maintained below -65
°C. After the addition, the reaction was warmed to room
temperature over 2 h and then stirred for 24 h. The mixture
was partitioned between saturated aqueous NaHCO3 and
EtOAc. The combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. The residue was distilled bulb to
bulb (bp0.5 (pot) ) 60 °C - 65 °C) to give 1.13 g (72% yield) of
than 1% of 24 was observed in the product. These
cyclization conditions were also applied to substrates 27
and 20 (Scheme 7) to obtain the desired cyclopentenes
in 59% and 53% yields respectively, with less than 1% of
27 and of 20 observed in the reaction mixtures.
Con clu sion
We have demonstrated that the generation of alkyl-
idene carbenes by the bromination of unactivated 1,1-
disubstituted alkenes followed by the treatment of the
(7) Although all of the work described here is based on bromides,
we have observed that chlorination followed by exposure to KHMDS
works equally well.

9676 J . Org. Chem., Vol. 64, No. 26, 1999
Taber et al.
5 as a thick clear oil (TLC Rf ) 0.50, 10% ethyl acetate/
extract was combined, dried (Na2SO4), and concentrated in
vacuo. The residue was then chromatographed to give the
corresponding dibromide (13, 75% yield; 14, 65% yield; 15, 80%
yield). The dibromide was dried by azeotroping with toluene
under reduced pressure.
Gen er a l P r ep a r a tion of Cyclop en ten es 13, 14, a n d
15a ,b. The dibromide in ether (0.1 M) was cooled to -78 °C
under nitrogen, and KHMDS (2.5 equiv) was added dropwise.
The reaction was allowed to warm to room temperature and
then allowed to stir for 18 h. The reaction mixture was then
partitioned between saturated aqueous NaHCO3 and EtOAc,
and the combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. The residue was chromatographed to
give the cyclopentene products as colorless oils.
1-ter t-Bu tyld im eth ylsilyloxym eth yl-3-d ecylcyclop en -
ten e (13): TLC Rf ) 0.43 (100% petroleum ether); 1H NMR δ
5.49 (bs, 1H), 4.23 (s, 2H), 2.64 (s, 1H), 2.01-2.10 (m, 3H),
1.10-1.54 (m, 19H), 0.89 (s, 9H), 0.83-0.89 (m, 3H), 0.04 (s,
6H); 13C NMR δ 129.2, 62.6, 45.4, 36.1, 31.9, 30.4, 29.9, 29.7,
29.4, 28.0, 22.7, 18.4, 14.1, -5.3; IR cm-1 2924 (s), 2853 (m),
1077 (w). Anal. Calcd for C22H44OSi: C, 74.92; H, 12.58.
Found: C, 74.83; H, 12.45.
1
hexane): [R]D -13.5 (c 1.00, CHCl3); H NMR δ 5.35 (s, 1H),
3.82 (s, 2H), 2.41 (m, 1H), 2.21-2.02 (m, 3H), 1.79 (s, 3H), 1.40
(s, 3H), 1.39 (s, 3H); HRMS calcd mass 169.122855, measured
mass 169.123422; IR cm-1 3048.0 (b), 2934 (s), 1660 (w), 1368
(s); 13C NMR δ C 146.2, 108.7, 93.0, CH 127.0, CH2, 73.2, 37.0,
35.0, CH3 26.8, 16.9.
2-Tr id ecylp r op -2-en -1-ol (6). TMEDA (43.5 mL, 0.288
mol) was added dropwise over 60 min to n-BuLi (125 mL of a
2.30 M solution) at -78 °C. After 30 min, methallyl alcohol
(14.5 mL, 0.173 mol) was added dropwise over 5 min. The
cooling bath was removed, and the reaction was allowed to
stir at room temperature for 18 h. The reaction mixture was
again cooled to -78 °C, and 1-bromododecane (17.5 mL, 0.072
mol) in petroleum ether (100 mL) was added. The mixture was
allowed to stir at room temperature for an additional 18 h and
then was chilled to 0 °C and quenched with 50 mL of 10%
aqueous HCl. The mixture was partitioned between Et2O and
H2O. The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. Bulb-to-bulb distillation of the residue
gave a colorless oil (8.0 g, 46% yield) that became a semisolid
upon standing: TLC (Rf ) 0.5, 20% MTBE/petroleum ether);
1H NMR δ 5.00 (s, 1H), 4.86 (s, 1H), 4.07 (s, 2H), 2.11 (t, J )
1-Tr ityloxym eth yl-3-d ecylcyclop en ten e (14): TLC Rf )
6.7 Hz, 3H), 1.12-1.63 (m, 22H), 0.85 (t, J ) 6.6 Hz, 3H); 13
C
0.38 (100% petroleum ether); H NMR δ 7.41-7.52 (m, 6H),
1
NMR δ C 149.3, CH2 108.9, 65.9, CH3 33.0, 31.9, 29.6, 29.5,
29.4, 29.3, 27.8, 22.7, CH3 14.1. Anal. Calcd for C16H32O: C,
79.93; H, 13.42. Found: C, 79.75; H, 13.60.
7.21-7.34 (m, 9H), 5.73 (bs, 1H), 3.61 (s, 2H), 2.74 (s, 1H),
2.20-2.32 (m, 1H), 2.01-2.20 (m, 1H), 1.34-1.55 (m, 20H),
0.87 (t, J ) 6.8 Hz, 3H); 13C NMR δ 144.3, 141.1, 129.9, 128.6,
127.7, 126.9, 63.5, 45.5, 36.2, 32.6, 31.9, 30.2, 29.9, 29.7, 29.7,
29.4, 28.0, 22.7; IR cm-1 2927 (s), 2855 (m), 1650 (w). Anal.
Calcd for C35H44O: C, 87.45; H, 9.23. Found: C, 87.38; H, 9.15.
3-Decyl-5-ter t-b u t yld im et h ylsilyloxy-1-m et h ylcyclo-
p en ten e (15a ): TLC Rf ) 0.45 (100% petroleum ether); 1H
NMR δ 5.39 (d, J ) 1.4 Hz, 1H), 4.51-4.62 (m, 1H), 2.40-
2.54 (m, 1H), 1.74 (s, 3H), 1.21-1.64 (15H), 0.90-1.01 (m, 6H),
0.93 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 13C NMR δ 141.92,
130.78, 79.30, 42.43, 41.85, 36.69, 31.95, 29.86, 29.69, 29.37,
29.06, 27.86, 25.92, 22.72, 18.23, 14.12, 13.73; IR cm-1 3390
(bw), 2926 (s), 2854 (s), 1712 (bs), 1463 (m). Anal. Calcd for
Gen er a l P r oced u r e for Alk en e Silyl Eth er s. ter t-Bu tyl-
(2-tr id ecyla llyloxy)d im eth ylsila n e (7). To a room-temper-
ature solution of 6 in dry CH2Cl2 (0.1 M) were added imidazole
(3 equiv) and DMAP (0.15 equiv) followed by (tert-butyldi-
methyl)silyl chloride (2 equiv) in CH2Cl2. When the reaction
was complete (followed by TLC), the reaction was partitioned
between saturated aqueous NaHCO3 and CH2Cl2, and the
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo. The residue was then chromatographed to give
7 (87% yield) as colorless oil: TLC Rf ) 0.35 (100% petroleum
ether); 1H NMR δ 5.02 (s, 1H), 4.81 (s, 1 H), 4.07 (s, 2H), 2.01
(t, J ) 6.6 Hz, 2H), 1.27-1.97 (m, 25H), 0.08 (s, 6H), 0.13-
0.94 (s, 9H), 1.27-1.97 (m, 25H); 13C NMR δ C 148.8, CH2
108.2, 65.9, 32.8, 32.0, 29.7, 29.6, 29.6, 29.4, 27.9, 22.7, 18.4,
CH3 25.9, 14.1; IR cm-1 2926 (s), 2854 (s), 1655 (w), 1463 (m).
Anal. Calcd for C22H46OSi: C, 74.50; H, 13.07. Found: C, 74.25;
H, 13.15.
C
22H44OSi: C, 74.92; H, 12.58. Found: C, 74.80; H, 12.65.
3-Decyl-5-ter t-b u t yld im et h ylsilyloxy-1-m et h ylcyclo-
p en ten e (15b): TLC Rf ) 0.30 (100% petroleum ether); 1H
NMR δ 5.41 (d, J ) 0.81 Hz, 1H), 4.62-4.75 (m, 1H), 2.73 (s,
1H), 1.72 (s, 3H), 1.64-1.93 (m, 2H), 1.26-1.37 (m, 18H),
0.83-0.94 (m, 3H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13
C
2-Tr ityloxym eth ylp en ta d ec-1-en e (8). To a solution of
triphenylmethyl chloride (4.17 g, 15.0 mmol) and DBU (2.66,
17.5 mmol) in 25 mL of CH2Cl2 at room temperature was added
alcohol 6 (2.59 g, 10.8 mmol). The mixture was stirred at room
temperature for 18 h. The reaction mixture was partitioned
between CH2Cl2 and H2O. The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo. The residue was
chromatographed to give 8 (5.60 g, 11.6 mmol, 93% yield) as
a thick colorless oil: TLC Rf ) 0.38, 100% petroleum ether;
1H NMR δ 7.40-7.51 (m, 5H), 7.22-7.34 (m, 10H), 5.32 (d, J
) 1.4 Hz, 1H), 5.02 (s, 1H), 3.63 (s, 2H), 2.02 (t, J ) 6.8 Hz,
2H), 1.11-1.34 (m, 20H), 0.89-0.94 (m, 5H); 13C NMR δ C
146.9, 144.3, CH2 128.7, 127.7, 126.9, 109.4, 66.5, 33.6, 31.9,
29.5, 29.4, 27.7, 22.7, CH3 14.1; IR cm-1 3426 (bw), 2925 (s),
1448 (m). Anal. Calcd for C35H46O: C, 87.08; H, 9.60. Found:
C, 87.20; H, 9.75.
3-ter t-Bu tyld im eth ylsiloxy-2-m eth ylp en ta d ecen e (9).
The same procedure was used as for the synthesis of 7 to
obtain 9 as a clear oil (76% yield): TLC Rf ) 0.85 (100%
petroleum ether): 1H NMR δ 4.81 (s, 1H), 4.72 (s, 1H), 4.01
(t, J ) 6.7 Hz, 1H), 1.73 (s, 3H), 1.34-1.62 (m, 8H), 0.86-0.93
(m, 5H), 0.90 (s, 9H), 0.045 (s, 6H); 13C NMR δ C 148.1, CH
76.9, CH2 110.4, 36.4, 32.0, 29.7, 29.6, 29.5, 25.6, 22.7, 18.4,
CH3 25.9, 17.2, 14.1; IR cm-1 2923 (s), 2852 (m), 1713 (w), 1447
(w). Anal. Calcd for C22H46OSi: C, 74.50; H, 13.22; O. Found:
C, 74.32; H, 13.20.
NMR δ 141.16, 132.25, 79.66, 43.04, 41.37, 36.65, 31.91, 29.86,
29.66, 29.33, 28.03, 25.94, 22.68, 18.31, 14.10, 13.92; IR cm-1
3366 (bw), 2925 (s), 2854 (s), 1712 (m), 1376 (m). Anal. Calcd
for C22H44OSi: C, 74.92; H, 12.58. Found: C, 74.72; H, 12.40.
Gen er a l P r oced u r e for Cou p lin g Br om id es w ith 2-Me-
th yla llylm a gn esiu m Ch lor id e. 2-Meth yl-7-p h en oxyh ep t-
1-en e (16). To a flask containing 4-phenoxybutyl bromide (10.4
g, 45.0 mmol), CuI (857 mg, 50.0 mmol), and anhydrous Et2O
(220 mL) at 0 °C was added 2-methylallylmagnesium chloride
(100 mL, 50.0 mmol, 0.5 M in THF) dropwise over 10 min.
The mixture was stirred at ambient temperature for 2 h. The
mixture was poured into saturated aqueous NH4Cl (400 mL)
followed by the addition of Et2O (200 mL). The mixture was
filtered through a bed of Celite using Et2O (100 mL). The
organic layer was separated, dried (MgSO4), and concentrated
under reduced pressure. The residual oil was chromatographed
to obtain 16 (7.2 g, 35.3 mmol, 78% yield) as a clear oil: TLC
1
Rf (5% EtOAc/hexane) ) 0.73; H NMR δ 1.39-1.57 (m, 4H),
1.72 (s, 1H), 1.80 (t, J ) 7.0 Hz, 2H), 2.04 (t, J ) 6.6 Hz, 2H),
3.95 (t, J ) 6.5 Hz, 2H), 4.69 (dd, J ) 7.2 Hz, J ) 0.8 Hz, 2H),
6.83-6.96 (m, 3H), 7.21-7.32 (m, 2H); 13C NMR δ CH3: 20.92
CH2: 24.3, 25.9, 27.8, 36.3, 66.3, 108.5 CH: 113.1, 119.0, 127.9
C: 144.3, 157.7; IR 3072, 2936, 2860, 1649, 1601, 1587 cm-1
;
MS m/z 204 (25), 148 (5), 133 (10), 120 (13), 110 (100); calcd
for C14H20O 204.151 415, found 204.150 699.
2-(2-P h en oxyeth yl)-1-m eth ylcyclop en ten e (17). To 16
(2.29 mmol) and Et2O (50 mL) in a 200 mL flask chilled to
-78 °C was added bromine (780 mg, 4.90 mmol) dropwise over
5 min with stirring. After 30 min at -78 °C, KHMDS (39.2
mL, 19.6 mmol, 0.5 M in toluene) was added dropwise over 5
min, with stirring, at -78 °C. The mixture was stirred for 17
Gen er a l P r ep a r a tion of Dibr om id es 10-12. Bromine
(1.0 equiv) was added to the substrate in dry ether (0.1 M) at
-78 °C under nitrogen. When bromination was complete
(followed by TLC), the reaction mixture was quenched with
10% Na2S2O3 and then extracted with EtOAc. The organic

Cyclization of 1,1-Disubstituted Alkenes to Cyclopentenes
J . Org. Chem., Vol. 64, No. 26, 1999 9677
h at ambient temperature. The reaction mixture was parti-
tioned between Et2O and, sequentially, saturated aqueous
NaHCO3 and H2O. The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. The re-
sidual oil was chromatographed to afford the cyclopentene 17
(0.27 g, 1.32 mmol, 27% yield) as a clear oil: TLC Rf (5%
EtOAc/hexane) ) 0.73; 1H NMR δ 1.42-1.56 (m, 1H), 1.72 (s,
3H), 1.74-1.92 (m, 2H), 2.15-2.19 (m, 1H), 2.19-2.25 (m, 2H),
2.76-2.89 (m, 1H), 3.98 (t, J ) 6.8 Hz, 2H), 5.31 (t, J ) 1.7
Hz, 1H), 6.83-6.96 (m, 3H), 7.21-7.28 (m, 2H); 13C NMR δ
CH3: 15.7 CH2: 29.2, 34.1, 34.3, 65.1 CH: 41.1, 112.9, 118.3,
126.3, 126.9 C: 139.0, 157.6; IR 3039, 2934, 1600, 1497, 1245
cm-1; MS m/z 202 (18), 109 (50), 108 (100), 107 (15); calcd for
(22). To 1,1-disubstituted alkene 20 (2.29 mmol) and 3/1
p-dioxane/DME (50 mL) in a 200 mL flask chilled to -20 °C
was added bromine (366 mg, 2.29 mmol) dropwise over 5 min
with stirring. After 30 min at -20 °C, KHMDS (13.8 mL, 6.90
mmol, 0.5 M in toluene) was added dropwise over 5 min, with
stirring, at -20 °C. The mixture was stirred for 48 h at -20
°C. The reaction mixture was partitioned between Et2O and,
sequentially, saturated aqueous NaHCO3 and H2O. The com-
bined organic extracts were dried (MgSO4) and concentrated
under reduced pressure. The residual oil was chromatographed
to afford the cyclopentene 22 (0.26 g, 1.21 mmol, 53% yield)
1
as a clear oil: TLC Rf (5% EtOAc/hexane) ) 0.75; H NMR δ
1.34-1.57 (m, 3H), 1.72 (s, 3H), 1.75-1.83 (m, 2H), 2.01-2.18
(m, 1H), 2.19-2.25 (m, 2H), 2.66 (bs, 1H), 3.95 (t, J ) 6.6 Hz,
2H), 5.29 (s, 1H), 6.82-2.96 (m, 3H), 7.21-7.31 (m, 2H); 13C
NMR δ CH3 15.2, CH2 26.1, 29.3, 31.2, 34.9, 66.5, CH 44.1,
113.0, 118.9, 127.1, 127.9, C 138.9, 157.6; IR 3037, 2937, 1609,
1586, 1497, 880 cm-1; MS m/z 216 (53), 123 (70), 122 (100),
120 (75), 107 (66); calcd for C15H20O 216.151 415, found
216.149 759.
C
14H18O 202.135 765, found 202.136 123.
Gen er a l P r oced u r e for th e Br om in a tion of Alk en es.
1,2-Dibr om o-2-m eth yl-7-p h en oxyh ep ta n e (18). To a 100
mL flask containing 16 (1.5 g, 7.35 mmol) and Et2O (50 mL)
at -50 °C was added bromine (1.18 g, 7.35 mmol) dropwise
over 5 min. The solution was stirred at -50 °C for 30 min.
The reaction mixture was partitioned between Et2O and,
sequentially, saturated aqueous NaHCO3 and H2O. The com-
bined organic extracts were dried (MgSO4) and concentrated
under reduced pressure. The residual oil was chromatographed
to afford 18 (2.5 g, 6.87 mmol, 93%) as a clear oil: TLC Rf (5%
8-Meth yln on -8-en -1-ol (23). The same procedure was used
as in the synthesis of 16 (5.7 g, 36.5 mmol, 66% yield) to yield
23 as a clear oil: TLC Rf (30% EtOAc/hexane) ) 0.45; 1H NMR
δ 1.21-1.41 (m, 9H), 1.50-1.61 (m, 2H), 1.71 (s, 3H), 2.00 (t,
J ) 7.2 Hz, 2H), 3.64 (t, J ) 6.6 Hz, 2H), 4.67 (d, J ) 7.7 Hz,
2H); 13C NMR δ CH3 20.7, CH2 23.8, 24.1, 25.8, 25.9, 27.7, 31.0,
1
EtOAc/hexane) ) 0.62; H NMR δ 1.42-1.63 (m, 4H), 1.78-
1.97 (m, 7H), 3.83 (q, J ) 10.5, 2H), 3.97 (t, J ) 6.6, 2H), 6.83-
6.97 (m, 3H), 7.22-7.31 (m, 2H); 13C NMR δ CH3: 29.2 CH2:
24.2, 24.4, 27.6, 40.6, 40.9, 66.2 CH: 113.0, 119.1, 127.9 C:
66.4, 157.6; IR 2940, 2864, 1600, 1586, 1497, 1471 cm-1. MS
m/z 366 (4), 364 (8), 362 (4), 135 (4), 133 (5), 119 (9), 117 (10),
109 (100); calcd for C14H20Br2O 361.988 088, found 361.987 000.
(E/Z)-1-Br om o-2-m eth yl-7-p h en oxyh ep t-1-en e (19). A
flask containing a stirring solution of 18 (3.0 g, 8.3 mmol), DBU
(3.1 g, 20.2 mmol), and benzene (30 mL) was heated to reflux
for 7 h. The cooled solution was acidified to pH ) 2 using 1 N
aqueous HCl. The reaction mixture was partitioned between
Et2O and H2O. The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. The re-
sidual oil was chromatographed to afford 21 (2.3 g, 8.1 mmol,
98% yield) as a clear oil: TLC Rf (5% EtOAc/hexane) ) 0.62;
1H NMR δ 1.39-58 (m, 4H), 1.71-1.86 (m, 5H), 2.09-2.29 (m,
2H), 3.91-4.02 (m, 2H), 5.89 (d, J ) 1.2 Hz, 1H), 6.82-7.01
(m, 3H), 7.21-7.34 (m, 2H); 13C NMR δ (major isomer) CH3
17.5, OCH2 66.1, dCHBr 99.7, (minor isomer) CH3 20.6, OCH2
66.2, dCHBr 99.2; IR 2938, 2860, 1600, 1497, 1472 cm-1; MS
m/z 384 (10), 282 (10), 135 (16), 133 (16), 109 (100); calcd for
36.2, 108.1, C 144.3; IR 3334, 3073, 2930, 2856, 1649, 885 cm-1
;
MS m/z 156 (3), 141 (3), 138 (13), 123 (100), 110 (58), 109 (61);
calcd for C10H20O 156.151 415, found 156.150 419.
9-Ben zyloxy-2-m eth yl-1-n on en e (24). To a flask contain-
ing 23 (3.0 g, 19.2 mmol) and DMF (5 mL) was added sodium
hydride (770 mg, 19.2 mmol, 60% in mineral oil) portionwise.
After the white suspension was stirred for 30 min at 25 °C,
benzyl bromide (3.3 g, 19.2 mmol) was added dropwise over
10 min. The mixture was stirred at 25 °C for 17 h. The reaction
mixture was partitioned between Et2O and, sequentially, H2O
and brine. The combined organic extracts were dried (MgSO4)
and concentrated under reduced pressure. The residual oil was
chromatographed to obtain 24 (3.5 g, 14.2 mmol, 74% yield)
1
as a clear oil: TLC Rf (5% EtOAc/hexane) ) 0.73; H NMR δ
1.22-1.48 (m, 8H), 1.54-1.63 (m, 2H), 1.70 (s, 3H), 1.99 (t, J
) 7.1 Hz, 2H), 3.46 (t, J ) 6.6 Hz, 2H), 4.50 (s, 2H), 4.67 (d, J
) 7.5 Hz, 2H), 7.24-7.34 (m, 5H); 13C NMR δ CH3 20.9, CH2
24.7, 26.1, 27.8, 27.9, 28.1, 36.3, 70.1, 71.4, 108.1, CH 125.9,
126.1, 126.8, 127.3, 127.5, C 137.2, 144.6; IR 3068, 3029, 2930,
2855, 1648, 1454 cm-1; MS m/z 246 (2), 137 (49), 131 (20), 108
(22), 107 (100), 106 (24); calcd for C17H26O 246.198 366, found
246.197 659.
C
14H19BrO 282.061 926, found 282.061 290.
2-Meth yl-8-p h en oxy-1-octen e (20). The same procedure
was used as in the synthesis of 16 (3.3 g, 15.1 mmol, 92% yield)
to yield 20 as a clear oil: TLC Rf (5% EtOAc/hexane) ) 0.75;
1H NMR δ 1.29-1.53 (m, 6H), 1.71 (s, 3H), 1.79 (m, 2H), 2.01
(m, 2H), 3.95 (t, J ) 6.6 Hz, 2H), 6.88-6.92 (m, 3H), 7.24-
7.30 (m, 2H); 13C NMR δ CH3 20.9, CH2 24.5, 26.1, 27.6, 27.8,
28.8, 36.3, 108.3, CH 113.0, 119.0, 127.9, C 144.5, 157.7; IR
3071, 2932, 2857, 1648, 1601, 1586 cm-1; MS Rf 218 (10), 162
3-(4-Ben zyloxybu tyl)-1-m eth ylcyclop en ten e (25). The
same procedure was used as in the synthesis of 22 (0.28 g,
1.16 mmol, 57% yield) to yield 25 as a clear oil: TLC Rf (5%
1
EtOAc/hexane) ) 0.73; H NMR δ 1.19-1.29 (m, 1H), 1.30-
1.43 (m, 4H), 1.57-1.63 (m, 2H), 1.70 (s, 3H), 1.99-2.09 (m,
1H), 2.19 (bs, 2H), 2.59 (bs, 1H), 3.46 (t, J ) 6.6 Hz, 2H), 4.49
(s, 2H), 5.26 (s, 1H), 7.21-7.33 (m, 5H); 13C NMR δ CH3 15.2,
CH2 23.1, 28.5, 28.6, 29.3, 34.8, 69.0, 71.4, CH 44.3, 125.9,
126.1, 126.3, 126.6, 126.8, 127.5, C 137.2, 138.4; IR 3031, 2930,
2855, 1453, 820 cm-1; MS m/z 244 (0.1), 161 (0.5), 153 (100),
135 (61), 107 (57); calcd for C17H24O 244.182 716, found
244.182 412.
(2), 124 (22), 109 (13), 95 (28), 91 (100); calcd for C15H22
218.167 066, found 218.166 603.
O
(E/Z)-1-Br om o-2-m et h yl-8-p h en oxy-oct -1-en e (21). A
flask containing a stirring solution of 29 (15.0 g, 39.6 mmol),
DBU (14.7 g, 96.4 mmol), and benzene (150 mL) was heated
to reflux for 7 h. The cooled solution was acidified to pH ) 2
using 1 N aqueous HCl. The reaction mixture was partitioned
between Et2O and H2O. The combined organic extracts were
dried (MgSO4) and concentrated under reduced pressure. The
residual oil was chromatographed to afford 21 (8.5 g, 28.6
mmol, 72% yield) as a clear oil: TLC Rf (5% EtOAc/hexane) )
0.69; 1H NMR δ 1.27-1.52 (m, 6H), 1.71-1.82 (m, 5H), 2.11-
2.28 (m, 2H), 3,82-3.96 (m, 2H), 5.88 (d, J ) 1.1 Hz, 1H),
6.82-6.92 (m, 3H), 7.23-7.29 (m, 2H); 13C NMR δ (major
isomer) CH3 17.5, OCH2 66.3, dCHBr 99.5, (minor isomer) CH3
20.6, OCH2 66.2, dCHBr 99.0; IR 2935, 2857, 1600, 1496, 1470,
753 cm-1; MS m/z 298 (8), 296 (8), 123 (23), 122 (13), 94 (100);
calcd for C15H21BrO 296.077 58, found 296.076 303.
9-Ben zyloxy-1,2-dibr om o-2-m eth yln on an e (26). The same
procedure was used as in the synthesis of 18 (7.1 g, 17.4 mmol,
87% yield) to yield 26 as a clear oil: TLC Rf (5% EtOAc/hexane)
) 0.67; 1H NMR δ 1.28-1.41 (m, 7H), 1.41-1.52 (m, 2H),
1.52-1.65 (m, 2H), 1.84 (s, 3H), 1.85-1.89 (m, 1H), 3.47 (t, J
) 6.5, 2H), 3.84 (q, J ) 10.2 Hz, 2H), 4.50 (s, 2H), 7.25-7.35
(m, 5H); 13C NMR δ CH3 29.2, CH2 23.9, 24.6, 27.8, 28.2, 40.7,
41.0, 69.0, 71.4, CH 125.9, 126.1, 126.8, C 66.7, 137.2; IR 2933,
2855, 1453, 1378, 1101 cm-1; MS m/z 298 (8), 296 (8), 123 (23),
122 (130, 94 (100); calcd for C15H21BrO 296.077 58, found
296.076 303.
1-(8-Meth yln on -8-en -1-oxy)d od eca n e (27). To a flask
containing 23 (3.0 g, 19.2 mmol) and DMF (5 mL) was added
sodium hydride (770 mg, 19.2 mmol, 60% in mineral oil)
portionwise. After the white suspension was stirred for 30 min
Gen er a l P r oced u r e for Cycliza tion of 1,1-Disu bstitu t-
ed Alk en es. 3-(3-P h en oxyp r op yl)-1-m eth ylcyclop en ten e

9678 J . Org. Chem., Vol. 64, No. 26, 1999
Taber et al.
at 25 °C, 1-bromododecane (4.7 g, 19.2 mmol) was added
dropwise over 10 min. The mixture was stirred at 25 °C for
17 h. The reaction mixture was partitioned between Et2O and,
sequentially, H2O and brine. The combined organic extract was
dried (MgSO4) and concentrated under reduced pressure. The
residual oil was chromatographed to obtain 27 (5.2 g, 14.1
mmol, 73% yield) as a clear oil: TLC Rf (5% EtOAc/hexane) )
0.77; 1H NMR δ 0.88 (t, J ) 6.9 Hz, 3H), 1.26-1.44 (m, 26H),
1.52-1.59 (m, 4H), 1.71 (s, 3H), 2.00 (t, J ) 7.1 Hz, 2H), 3.39
(t, J ) 6.7 Hz, 4H), 4.66 (d, J ) 6.7 Hz, 2H); 13C NMR δ CH3
12.54, 20.79, CH2 21.14, 24.63, 24.68, 26.02, 26.65, 27.24,
27.41, 27.68, 27.72, 27.82, 27.84, 27.91, 28.09, 28.11, 28.14,
28.26, 32.26, 69.37, 108.01, C 144.52; IR 3074, 2925, 2854,
1649, 1466 cm-1; MS m/z 324 (10), 169 (39), 166 (11), 139 (27),
138 (100); calcd for C22H44O 324.339 26, found 324.338 875.
3-(4-Dod eca n oxybu tyl)m eth yl-1-cyclop en ten e (28). The
same procedure was used as in the synthesis of 22: (0.29 g,
0.80 mmol, 59% yield), clear oil: TLC Rf (5% EtOAc/hexane)
) 0.77; 1H NMR δ 0.88 (t, J ) 6.3 Hz, 3H), 1.19-1.42 (m, 23H),
1.54-1.62 (m, 4H), 1.71 (s, 3H), 2.01-2.12 (m, 1H), 2.17-2.22
(m, 2H), 2.6 (bs, 1H), 3.39 (t, J ) 6.8 Hz, 2H), 3.40 (t, J ) 6.7
Hz, 2H), 5.26 (t, J ) 1.7 Hz, 1H); 13C NMR δ CH3 12.6, 15.2,
CH2 21.2, 23.0, 24.7, 26.4, 27.8, 28.0, 28.11, 28.12, 28.16, 28.27,
28.5, 29.3, 30.4, 34.8, 34.9, 69.40, 69.44, CH 44.3, 127.5, C
138.4; IR 2925, 2854, 1458, 1376, 1117 cm-1; MS m/z 322 (0.2),
279 (0.2), 153 (1.4), 136 (41), 107 (100); calcd for C22H42
322.323 566, found 322.322 845.
O
1,2-Dibr om o-2-m eth yl-8-p h en oxyocta n e (29). The same
procedure was used as in the synthesis of 20 (28.0 g, 74.0
mmol, 82% yield) to yield 29 as a clear oil: TLC Rf (5% EtOAc/
1
hexane) ) 0.69; H NMR δ 1.37-1.59 (m, 6H), 1.76-1.94 (m,
7H), 3.85 (q, J ) 10.3 Hz, 2H), 3.96 (t, J ) 6.5 Hz, 2H), 6.75-
6.95 (m, 3H), 7.25-7.37 (m, 2H); 13C NMR δ CH3 29.15, CH2
23.9, 24.4, 27.3, 27.7, 40.6, 40.9, 66.1, CH 112.9, 119.0, 127.9,
C 66.5, 157.5; IR 2938, 1600, 1585, 1472, 1247, 813 cm-1. This
material decomposed on attempted mass spectrometric analy-
sis.
Ack n ow led gm en t. The authors thank J ohn Kilama
for helpful discussions and Gina Blankenship and J ohn
Gross for NMR spectroscopy.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for compounds 16-28. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O991311Z