Notes
J . Org. Chem., Vol. 62, No. 5, 1997 1525
the Grignard reagent followed by 85 mg of NiDPPPCl2 (0.16
mmol). The reaction was then set to reflux and the progress
monitored by TLC. After being refluxed for 3 h, the mixture
was cooled to room temperature and quenched with 10 mL of
saturated NH4Cl. Forty milliliters of ether was added, the layers
were separated, and the organic layer was dried over anhydrous
MgSO4. Following solvent removal in vacuo, the crude mixture
was loaded on top of a prepacked silica gel column and flashed
(solvent: 15% ethyl acetate/hexanes), providing 310 mg of 7a
(69% yield) as a clear oil: 1H NMR δ 4.88 (d, J ) 2.2 Hz, 1H),
4.65 (s, 1H), 3.96 (s, 2H), 1.51 (s, 3H), -0.05 (s, 9H); 13C NMR
Sch em e 4
δ 146.85, 106.57, 66.99, 23.20, -1.35; IR (neat) 3330, 3077 cm-1
;
HRMS calcd for C7H16OSi 144.0971, found 144.0973.
2-[(Dim eth ylp h en ylsilyl)m eth yl]-2-p r op en -1-ol (7a ). The
general coupling procedure was followed with two exceptions.
In this case, 5a was the limiting reagent instead of 6a . Second,
Grignard formation of 5a did not proceed in THF, but it did form
in diethyl ether. Thus, 5a was formed in ether, an equal volume
of THF added, and the ether removed by pushing the vapor out
through the reflux condenser where it was collected into a short
path distillation unit that was affixed to the top of the reflux
condenser. With this change to the general procedure, 400 mg
of 6a (4.32 mmol), 2.8 mL of n-butyllithium (4.32 mmol, 1.52 M
solution in hexanes, Aldrich), 532 mg of (chloromethyl)dimeth-
ylphenylsilane (2.88 mmol), 95 mg of magnesium turnings (3.90
mmol), and 65 mg of NiDPPPCl2 (0.12 mmol) provided 416 mg
of 7b (70% yield) as a clear oil. The product was purified by
flash chromatography using 20% ethyl acetate in hexanes: 1H
NMR δ 7.52-7.49 (m, 2H), 7.39-7.33 (m, 3H), 4.90 (d, J ) 1.5
out as it had been previously in the production of 7b.
When this reaction was judged complete by TLC analysis,
pyridine (2 equiv) and acetyl chloride (5 equiv) were
added and the reaction worked up. This sequence allows
for reaction to take place at both the halide and alcohol
site in one operation in a selective fashion.
It is of interest to note that 15 is a substrate for Ni-
catalyzed allylic ionization of the acetate. Further, excess
Grignard reagent could potentially react at the newly
formed ester site. Despite these potential side reactions,
analysis of the reaction mixture by both TLC and proton
NMR spectroscopy indicates that only coupled alcohol
derived from intermediate 16 and acetate 15 are present
at the end of the first and second step in the sequence,
respectively. In fact, most of the reactions reported in
this study are clean “spot-to-spot” transformations, and
we believe that product volitility is the chief contributor
to yield reduction in most cases.
In summary, we have developed a convenient and
general one-pot strategy for the cross coupling of vinyl
halide compounds containing one or more alcohol moi-
eties with Grignard reagents using Ni catalysis. This
procedure involves in situ deprotonation of the alcohol-
(s) with n-butyllithium followed by cross-coupling with
NiDPPPCl2. This preserves the reactivity of the alkoxide
such that it can then be reacted selectively following
coupling as demonstrated by the production of 15.
Hz, 1H), 4.66 (s, 1H), 3.81 (s, 2H), 1.76 (s, 3H), 0.31 (s, 6H); 13
C
NMR (APT) δ 146.17 (+), 138.54 (+), 133.52 (-), 129.12 (-),
127.80 (-), 107.49 (+), 66.86 (+), 22.44 (+), -3.07 (-); IR (neat)
3335, 3070, 3050, 3022 cm-1; HRMS calcd for C12H18OSi
206.1127, found 206.1126.
2-P h en yl-2-p r op en -1-ol (7c). Following the general cou-
pling procedure, 169 mg of 6a (2.12 mmol), 1.39 mL of n-
butyllithium (2.12 mmol, 1.52 M solution in hexanes, Aldrich),
400 mg of bromobenzene (2.55 mmol), 77 mg of magnesium
turnings (3.18 mmol), and 75 mg of NiDPPPCl2 (0.14 mmol)
provided 245 mg of 7c (86% yield) as a pale yellow oil. The
product was purified by flash chromatography using 20% ethyl
acetate in hexanes: 1H NMR δ 7.47-7.26 (m, 5H), 5.48 (s, 1H),
5.26 (s, 1H), 4.55 (br s, 2H), 1.71 (br s, 1H); 13C NMR (APT) δ
147.05 (+), 138.49 (+), 128.24 (-), 127.62 (-), 125.83 (-), 112.09
(+), 64.29 (+); IR (neat) 3350, 3084, 3057, 3032, cm-1; HRMS
calcd for C9H10O 134.0732, found 134.0732.
2-Eth yl-2-p r op en -1-ol (7d ). Following the general coupling
procedure, 261 mg of 6a (2.82 mmol), 1.86 mL of n-butyllithium
(2.82 mmol, 1.52 M solution in hexanes, Aldrich), 400 mg of
bromoethane (3.67 mmol), 110 mg of magnesium turnings (4.52
mmol), and 92 mg of NiDPPPCl2 (0.17 mmol) provided 203 mg
of 7d (83% yield) as a clear oil: the product was purified by flash
chromatography using 20% ethyl acetate in hexanes: 1H NMR
δ 5.00 (s, 1H), 4.86 (s, 1H), 4.08 (br s, 2H), 2.07 (q, J ) 7.4 Hz,
2H), 1.63 (br s, 1H), 1.08 (t, J ) 7.4 Hz, 3H); 13C NMR δ 150.63,
107.89, 65.86, 25.61, 12.06; IR (neat) 3334, 3086 cm-1; HRMS
calcd for C5H10O 86.0732, found 86.0730.
2-[2-[(Tr im eth ylsilyl)m eth yl]-2-p r op en yl]cycloh exa n ol
(9b). Following the general coupling procedure, 115 mg of 8a
(0.66 mmol, 3:1 mixture of diastereomers), 435 µL of n-butyl-
lithium (0.66 mmol, 1.52 M solution in hexanes, Aldrich), 114
mg of (chloromethyl)trimethylsilane (0.93 mmol), 24 mg of
magnesium turnings (0.99 mmol), and 22 mg of NiDPPPCl2 (0.04
mmol) provided 98 mg of 9b (66% yield, 3:1 mixture of diaster-
eomers) as a clear oil that solidified on sitting in the freezer.
The product was purified by flash chromatography using 25%
ethyl acetate in hexanes. Spectral data for the major isomer
are included here: 1H NMR δ 4.67 (br s, 1H), 4.56 (br s, 1H),
3.27 (m, 1H), 2.40 (dd, J ) 14.4, 7.2 Hz, 1H), 2.05-0.84 (m, 13H),
0.04 (s, 9H); 13C NMR (APT) δ 147.71 (+), 108.83 (+), 75.79 (-),
43.12 (+), 43.04 (-), 35.24 (+), 30.93 (+), 26.36 (+), 25.51 (+),
24.75 (+), -1.31 (-); IR (neat) 3366, 3072 cm-1; HRMS calcd
for C13H26OSi 226.1754, found 226.1744.
Exp er im en ta l Section
All reactions were carried out under a positive atmosphere
of dry argon. Diethyl ether (Et2O) and tetrahydrofuran (THF)
solvents were distilled from sodium benzophenone prior to use.
Melting points are uncorrected. NMR spectra were recorded in
CDCl3 at 300 MHz for proton spectra and at 75 MHz for carbon
spectra. Chemical shifts are listed relative to CHCl3 (δ 7.24)
for 1H NMR and (δ 77.00) for 13C NMR. 13C NMR spectra
obtained using the APT pulse sequence (indicated by APT in
parentheses prior to the δ symbol) display positive signals (i.e.,
(+)) for quaternary carbons and carbons that are attached to
an even number of protons. Signals for carbons that are
attached to an odd number of protons are negative (i.e., (-)).
Gen er a l Cr oss-Cou p lin g P r oced u r e. The following pro-
cedure is general for the cross couplings performed in this study,
and any deviations are noted in the directions for specific
compounds.
2-[(Tr im eth ylsilyl)m eth yl]-2-pr open -1-ol (7b). Into a flame-
dried 25 mL round-bottom flask containing a stir bar was added
122 mg of magnesium turnings (5.02 mmol) followed by 15 mL
of dry THF. The Mg surface was activated with three drops of
dibromoethane followed by the addition of 569 µL of (chloro-
methyl)trimethylsilane (500 mg, 4.08 mmol). This mixture was
refluxed for 1 h and then cooled back to room temperature
following formation of 5b. In a separate dried flask, 291 mg of
6a (3.14 mmol) was dissolved in 20 mL of dry THF and 2.06 mL
of n-butyllithium (3.14 mmol, 1.52 M solution in hexanes,
Aldrich) added at 0 °C. After being stirred for 10 min, this
mixture was transferred by cannula into the flask containing
2-(2-P h en yl-2-p r op en yl)cycloh exa n ol (9c). Following the
general coupling procedure, 110 mg of 8a (0.63 mmol, 3:1
mixture of diastereomers), 416 µL of n-butyllithium (0.63 mmol,
1.52 M solution in hexanes, Aldrich), 139 mg of bromobenzene
(0.89 mmol), 23 mg of magnesium turnings (0.95 mmol), and 21