A Novel Method for the Racemization of 5-Bromonicotine

Full text of DOI:10.1021/jo990152g

J . Org. Chem. 1999, 64, 5299-5300
5299
A Novel Meth od for th e Ra cem iza tion of
-Br om on icotin e
5
Leo S. Bleicher and Nicholas D. P. Cosford*
Received J anuary 27, 1999
In tr od u ction
While significant progress has been made recently in
the field of asymmetric synthesis, not all compounds are
amenable to these approaches, and in many cases clas-
sical resolution can be more cost-effective on a manu-
facturing scale.1 We recently reported a convenient
synthesis of (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)-
pyridine maleate [SIB-1508Y (1)], a neuronal nicotinic
acetylcholine receptor (nAChR) agonist in clinical trials
-3
4
for the treatment of Parkinson’s disease. The synthetic
route proceeded via classical resolution of racemic 5-bro-
monicotine (2) followed by transformation of (S)-2 to 1.
The need to manufacture kilogram quantities of 1
prompted a reexamination of this preparative sequence
and led to the conclusion that an improved classical
resolution coupled with racemization and recycling of the
excess (R)-2 from the mother liquors might provide a
more efficient and cost-effective process. Herein we
describe an efficient laboratory scale method for the
racemization of (R)-enriched 2 which complements
the earlier disclosure on the synthesis of 1.
F igu r e 1. 1H NMR of 3b at 52 °C (left) and at 22 °C.
Resu lts a n d Discu ssion
The racemization of nicotine employing base-catalyzed
deprotonation/protonation of the tertiary C2′ at elevated
temperature has been reported.5 Unfortunately, at-
tempts to racemize 2 using this approach, i.e., KOtBu
derivatives 3a or 3c (Scheme 1). Thermal or strongly
basic (KOH/EtOH) elimination of HCl followed by car-
bamate deprotection provided trans-meta-nicotine 4c.
Removal of the carbamate moiety from 3a or 3c using
,6
1
0% w/w in DME at reflux for 20 h or KOtBu 10% w/w
2
.5% aqueous NaOH in EtOH gave nicotine with net
and phosphazine base P -t-Bu in hexane (10 mol %) in
4
retention of configuration via a double inversion. Fur-
thermore deprotection of 3c in boiling 10% aqueous
boiling toluene for 14 h, failed to racemize the substrate.
A pyridoxal-catalyzed racemization of nornicotine (des-
2 4
H SO , upon basification, also gave nicotine with reten-
7
methyl nicotine) and derivatives has been reported, but
8
tion of configuration. This implies that neither the ring
opening nor ring closure reactions proceed via a discrete
this procedure was clearly not applicable to the racem-
ization of the tertiary amine 2.
carbocation, but that both occur via S
ment.
N
2-type displace-
Examination of the literature revealed that alkyl
chloroformates have been reported to cleave the nicotine
C2′-N bond.8 In these studies phenyl or ethyl chloro-
formate was reacted with nicotine to yield ring-opened
We hypothesized that it might be possible to racemize
,9
3
b by means of acid-catalyzed chloride exchange. Strongly
acidic conditions should effect carbamate removal and
lead to racemization of 3b via chloride exchange, and
base-induced ring closure of this material would provide
racemic 2. In the event, when (R)-enriched 2 (60% ee)
(
1) Reider, P. J .; Davis, P.; Hughes, D. L.; Grabowski, E. J . J . Org.
Chem. 1987, 52, 955-957.
2) Ebbers, E. J .; Ariaans, G. J . A.; Houbiers, J . P. M.; Bruggink,
A.; Zwanenburg, B. Tetrahedron 1997, 53, 9417-9476.
3) Collet, A.; Brienne, M.-J .; J acques, J . Chem. Rev. 1980, 80, 215-
30.
4) Bleicher, L.; Cosford, N. D. P.; Herbaut, A.; McCallum, J . S.;
McDonald, I. A. J . Org. Chem. 1998, 63, 1109-1118.
5) Tsujino, Y.; Shibata, S.; Katsuyama, A.; Kisaki, T.; Kaneko, H.
Heterocycles 1982, 19, 2151-2154.
6) Bowman, E. R.; McKennis, H.; Martin, B. R. Synth. Commun.
982, 12 (11), 871-879.
7) J acob, P. J . Org. Chem. 1996, 61, 2916-2917.
(
was reacted with 1 equiv of phenyl chloroformate, 3b was
(
18
formed as a nonracemic viscous oil {[R]
D
) -20° (c ) 5,
2
EtOH)}. Some concomitant formation of the phenyl
carbamate protected 5-bromo-trans-meta-nicotine ana-
(
(
(
(8) Acheson, R. M.; Ferris, M. J .; Sinclair, N. M. J . Chem. Soc.,
Perkin Trans. 1 1980, 579-585.
(9) Hootele, C.; Lenders, J . P. Chimia 1974, 28, 665-666.
1
(
1
0.1021/jo990152g CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/24/1999

5
300 J . Org. Chem., Vol. 64, No. 14, 1999
Notes
Sch em e 1
logue (4b) was observed, and the product ratio was found
to be solvent dependent. Interestingly, either methylene
chloride or 1,2-dichloroethane as reaction solvent mini-
mized the formation of the alkene 4b, while performing
the reaction in toluene or acetonitrile produced this
material in up to 50% yield. In contrast to 3a , 3b was
stable to mild acid and base. When nonracemic 3b was
heated in concentrated HCl, the phenyl carbamate was
removed and the pyridyl chloride was racemized giving
intermediate 5. Basic workup of the reaction allowed
racemic 2 to be isolated in 87% yield [based on starting
solvents, and the chemical shifts are reported in ppm downfield
from tetramethylsilane, solvent (CDCl
3
δ
C
) 77.00, δ
H
) 7.25;
) 3.30)
DMSO-d ) 39.43, δ ) 2.5; CD OD δ
6
δ
C
H
3
C
) 49.05, δ
H
or added tetramethylsilane served as internal references. Optical
rotations were obtained at 589 nm (sodium D line) using a 1.9
dm cell at 20 °C. Chiral gas chromatographic separations were
conducted on a 20 m × 0.25 mm capillary column coated with
permethylated hydroxypropyl â-cyclodextrin phase at 130 °C
under isothermal conditions with a flow rate of 3.0 mL/min
(carrier gas He), using flame ionization detection.
P h en yl N-{4-Ch lor o-4-[3-(5-br om op yr id in yl)]bu tyl}-N-
m eth ylca r ba m a te (3b). A solution of 2 (60% ee favoring the
R-isomer) (60.2 g, 0.250 mol) was dissolved in dry CH Cl (200
2
2
(R)-enriched 2] over the three steps, and this was
mL) while stirring at ambient temperature. Phenyl chlorofor-
mate (32.7 mL, 0.26 mol) was added via syringe over 30 min,
and the mixture was stirred at room temperature for 3 h. Water
sufficiently pure to use in an optimized classical resolu-
tion procedure.
(10 mL) was added and the solution concentrated in vacuo to
give 3b as a viscous opaque brown oil (108 g). This material was
carried on to the next step without further purification. A portion
of this material was purified by chromatography on silica eluting
Con clu sion
In summary, a procedure for the racemization of (R)-
enriched 2 was devised. This protocol constitutes a novel
use of chloroformate-induced ring opening and halogen
exchange-mediated racemization of substituted pyrroli-
dine derivatives. The method promises to significantly
increase yields obtainable in the resolution sequence and
highlights key differences in reactivity between pyridine
ring substituted and unsubstituted nicotine derivatives.
In view of the recent surge of interest in nicotine
analogues as potential therapeutic agents, the methodol-
ogy described herein should prove to be of utility in the
2 2
with CH Cl :MeOH 98:2 to give a transparent oil. This com-
pound exists as rotamers; pairs of signals at δ 4.9 and 3.0
coalesce in 1H NMR at 52 °C (Figure 1). 1H NMR at 22 °C
3
(CDCl ) δ 8.62 (m, 1H), 8.52 (m, 1H), 7.90 (m, 1H), 7.36 (m, 2H),
7.20 (m, 1H), 7.08 (m, 2H), 4.98 and 4.89 (app dd, J ) 5,9 Hz,
1
1
1
1
H), 3.51 and 3.38 (m, 2H), 3.08 and 3.00 (s, 3H), 2.11 (m, 2H),
.87 (m, 1H), 1.75 (m, 1H); 13C NMR at 22 °C (CDCl
) δ 155.0,
3
51.2 (app d, J ) 6 Hz), 150.9, 150.7, 146.3 (app d, J ) 4 Hz),
39.0, 138.7, 137.1 (app d, J ) 4 Hz), 129.3 (app d, J ) 4 Hz),
25.3 (app d, J ) 7 Hz), 121.6, 120.8 (app d, J ) 5 Hz), 59.0,
1
1
8
53.4, 48.1, 47.8, 36.7, 34.8, 34.3, 25.3, 24.6; [R]
EtOH). Anal. Calcd for: C, 51.34; H, 4.56; N, 7.04. Found: C,
D
) -20° (c ) 5,
5
1.36; H, 4.59; N, 7.06.
preparation of a variety of novel nicotinic agonists and
antagonists.10
R a cem ic 5-Br om o-3-(1-m et h yl-2-p yr r olid in yl)p yr id in e
(
2). 5-Bromo-3-(1-chloro-4-(methyl(phenoxycarbonyl)amino)bu-
tyl)pyridine (3b) (88 g crude) was taken up in 10 M HCl (600
mL) and heated at reflux (internal temperature 105 °C) for 6 h.
The solution was made basic by the addition of NaOH (500 mL
of a 40% solution) while cooling with a dry ice-acetone bath to
maintain temperature below 50 °C. This mixture was extracted
Exp er im en ta l Section
Gen er a l. All reactions, unless otherwise noted, were con-
ducted under an inert atmosphere. Purchased reagents and
solvents were used as received. Column chromatography was
performed on silica gel (35-70 µm). Melting points were obtained
2 2 2 4
with CH Cl (1.2 L) and then dried over Na SO and concen-
trated in vacuo. This material was purified by filtration through
silica eluting with EtOAc:hexane 50:50 w 100:0 to give 2 as a
transparent golden oil (43.6 g, 87% from starting (R)-2) and was
shown to be racemic and identical to an authentic sample of 2.
1
in unsealed capillaries and are uncorrected. H NMR (300 MHz)
1
3
and C NMR (75 MHz) spectra were recorded in the indicated
(
10) Holladay, M. W.; Dart, M. J .; Lynch, J . K. J . Med. Chem. 1997,
4
0 (26), 4169-4194.
J O990152G