5654 J . Org. Chem., Vol. 65, No. 18, 2000
Cui and Brown
HRMS calcd for C12H17N 175.1361, found 175.1341. The major
isolated byproduct was 2,2′-dimethyl bipyridine (yield 20%).
2-Meth yl-6-cyclop en tylp yr id in e: yield 46%, from 2-meth-
yl-6-bromopyridine and cyclopentylmagnesium bromide; oil;
HRMS calcd for C11H15N 161.1204, found 161.1192. The major
isolated byproduct was 2,2′-dimethylbipyridine (yield 30%).
2-Cycloh exylp yr id in e: yield 72%, from 2-bromopyridine
products. One of the simplest approaches involves cy-
clization reactions initiated by bromonium or iodonium
complexes of pyridines having chiral groups at the 2 and/
or 6 position. Herein we describe the syntheses of some
simple 2-substituted and 2,6-disubstituted pyridine de-
rivatives (6-10) and the kinetics of the reaction of their
bromonium ions with 4-penten-1-ol. In particular, we are
interested in the effects of the substituents on the kinetics
of the reaction and whether there is a deuterium kinetic
isotope effect (dkie) on the cyclization reaction with
4-penten-1-ol-OD. In the case of the bromonium ion of
2-(-)-menthylpyridine, we describe the preliminary re-
sults of its effectiveness in promoting asymmetric cy-
clizations of 4-penten-1-ol and 4-pentenoic acid.
and cyclohexylmagnesium bromide; oil; HRMS calcd for C11H15
161.1204, found 161.1185.
N
2-Cyclop en tylp yr id in e: yield 80% from 2-bromopyridine
and cyclopentylmagnesium bromide; oil; HRMS calcd for
C
10H13N 147.1048, found 147.1037.
(-)-2-Men th ylp yr id in e.7 Magnesium turnings (0.5 g, 20
mmol) in dry THF (15 mL) were activated by stirring with a
few drops of 1,2-dibromoethane under nitrogen. After 5 min,
a few drops of a solution of 1.87 mL of (-)-menthyl chloride
(10 mmol) in THF (10 mL) was added, and warming to about
60 °C started the reaction. The remaining (-)-menthyl chloride
solution was added dropwise and the mixture heated at 60 °C
with stirring for another 6 h. After cooling, unreacted mag-
nesium was filtered under nitrogen, rinsed with THF, and
dried. From the weight of the residual magnesium, the
theoretical amount of (-)-menthylmagnesium chloride Grig-
nard reagent was estimated to be 9 mmol (90%). It was then
added over 30 min to a stirred solution of 2-bromopyridine (0.7
g, 5 mmol) and 20 mg of Ni(dppp)Cl2 in THF (35 mL) at 0 °C
under nitrogen. The mixture was then stirred at room tem-
perature for 40 h. The reaction was quenched with saturated
aqueous NH4Cl and diluted with enough water to dissolve
precipitated magnesium salts. The aqueous layer was ex-
tracted with CH2Cl2 and the combined organic layers were
washed with brine, dried over Na2CO3 and the solvent
evaporated. The remaining brown oil was purified by column
chromatography (hexane/EtOAc: 5/1, Rf ) 0.45): yield 25%;
HRMS calcd for C15H23N 217.1830, found 217.1832.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Dichloromethane and hexane
were purified as described.5 1,2-Dichloroethane (Aldrich, HPLC
grade) was used as supplied. Chemicals, including pyridine
halides, (-)-menthol, Ni(dppp)Cl2 [1,3-bis(diphenylphosphino)-
propane]dichloronickel (II), and all the unsaturated alcohols
and acids used in this study, were purchased from Aldrich and
used without further purification. 4-Penten-1-ol-OD was pre-
pared as previously described;1c 1H NMR analyses indicated
less than 2% residual H in the hydroxyl group.
Spectrophotometric kinetic measurements were obtained
using an OLIS modified Cary 17 UV-vis spectrophotometer
or an Applied Photophysics SX-17MV stopped-flow reaction
analyzer. GC analyses were carried on a Helwett-Packed 6890
gas chromatograph with a 30-m Supelco â-Dex 390 column or
a Chiraldex γ-Dex BP column.
Syn th esis. Grignard reagents were prepared in a standard
manner by adding a solution of an organic halide to magne-
sium ribbons which had been dried under nitrogen by flaming.
Magnesium was usually used in 20% excess over the halide
to exhaust the latter. After completion of the addition, the
mixture was refluxed for another 1 h to ensure the reaction.
A general procedure for the cross-coupling reaction of alkyl
Grignard reagents with pyridine halides was used.6 In a 100
mL two-necked flask, equipped with a pressure-equalizing
dropping funnel, a reflux condenser attached to a nitrogen line
and a stirring bar, were placed 30 mg (0.055 mmol) of
Ni(dppp)Cl2, 5 mmol of pyridine halide, and 50 mL of dried
THF; the nickel complex was insoluble in the mixture. The
freshly prepared Grignard reagent (5.5 mmol in THF, prepared
as above) was added to the mixture with stirring under
nitrogen at room temperature over 30 min. The mixture
changed from brown-red to dark black. After refluxing for a
given period of time (based on the TLC), the mixture was
hydrolyzed with dilute hydrochloric acid under ice bath cooling.
The organic layer and ether extracts of the aqueous layer were
combined, washed with water, NaHCO3 solution, and water,
and then dried over anhydrous Na2CO3. After evaporation of
solvent the crude product was purified further by silica gel
column chromatography using ethyl acetate and hexane.
Physical data for the following compounds are given in the
Supporting Information.
The (-)-menthyl chloride used above was prepared in 93%
yield from (-)-menthol as described:8 oil; bp 56.0-56.5 °C/2.0
mmHg.
2,6-Di(-)-m en th ylp yr id in e: oil; yield 7%, from 2,6-dichlo-
ropyridine and (-)-menthylmagnesium chloride; Rf ) 0.72
(silica gel TLC hexane/EtOAc: 5/1); HRMS calcd for C25H41
N
355.3239, found 355.3212. The major isolated byproducts are
2-menthylpyridine (10%) and 2-chloro-6-menthylpyridine
(5%): HRMS calcd for C15H22NCl 251.1441, found 251.1429.
The bis(2-substitutedpyridine)bromonium triflates (P2-
BrOTf) were prepared according to our previous method.2
Unfortunately, the dicyclohexyl and dicyclopentyl pyridines
gave the corresponding protonated pyridinium triflate salts
instead of the desired bromonium triflate complexes through
this process.
Gen er a l P r oced u r e for th e Rea ction of Bis((-)-2-
m en th ylp yr id in e)br om on iu m Tr ifla te w ith Un sa tu r a ted
Alcoh ols a n d Acid s. To a flame-dried 50 mL flask, was added
bis(2(-)-menthylpyridine)bromonium triflate (0.2 mmol) and
20 mL of freshly distilled CH2Cl2 under nitrogen. The flask
was then cooled to -78 °C, and a solution of unsaturated
alcohol or acid (0.18 mmol) in dry CH2Cl2 (5 mL) was added
via a Sage-pump over 1 h. The solution was stirred for another
3 h at -78 °C and then quenched by addition of saturated NH4-
Cl aqueous solution. The organic layer was washed with H2-
SO4 (10%, 3 × 30 mL), saturated NaHCO3 solution (3 × 30
mL), brine (3 × 30 mL) and then dried over anhydrous Na2-
CO3. After filtration, the solvent was evaporated carefully to
afford the product.
2,6-Dicycloh exylp yr id in e: yield 85%, from 2,6-dichloro-
pyridine and cyclohexylmagnesium bromide; pale yellow oil;
HRMS calcd for C17H25N 243.1987, found 243.1981.
The corresponding racemic compounds were prepared with
bis(collidine)bromonium triflate through a similar procedure
at room temperature.
2,6-Dicyclop en tylp yr id in e: yield 78%, from 2,6-dichloro-
pyridine and cyclopentylmagnesium bromide; pale brown oil;
HRMS calcd for C15H21N 215.1674; found 215.1678.
The aqueous acidic washes were made basic with NaOH (3
M) and extracted with CH2Cl2. The combined organic layer
was dried over NaCO3 and evaporated to recover (-)-2-
menthylpyridine (about 95% recovery) as a pale yellow oil.
2-Meth yl-6-cycloh exylp yr id in e: yield 54%, from 2-meth-
yl-6-bromopyridine and cyclohexylmagnesium bromide; oil;
(5) Perrin, D. D.; Armagero, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals, 2nd ed.; Pergamon Press: Oxford 1980; p 204.
(6) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.;
Kodama, S.-i.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc.
J pn. 1976, 49, 1958.
(7) Brunner, H.; Storiko, R.; Nuber, B. Tetrahedron: Asymmetry
1998, 9, 407.
(8) Smith, J . G.; Wright, G. F. J . Org. Chem. 1952, 17, 1116.