Regioselective C-2 and C-6 substitution of (S)-nicotine and nicotine derivatives

Article abstract of DOI:10.1021/ol052196j

(Chemical Equation Presented) Regioselective deprotonations of (S)-nicotine and derivatives at the C-2 and C-6 positions of the pyridine ring were performed in good to excellent yields. These methodologies allow the direct introduction of a plethora of fu

Full text of DOI:10.1021/ol052196j

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5457-5460
Regioselective C-2 and C-6 Substitution
of (S)-Nicotine and Nicotine Derivatives
Florence C. Fe´vrier, Emilie D. Smith, and Daniel L. Comins*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received September 12, 2005
ABSTRACT
Regioselective deprotonations of (S)-nicotine and derivatives at the C-2 and C-6 positions of the pyridine ring were performed in good to
excellent yields. These methodologies allow the direct introduction of a plethora of functional groups onto the pyridine ring of nicotine.
(S)-Nicotine (1), the most abundant alkaloid isolated from
fresh Nicotina tabacum,1 has attracted much attention because
of its important pharmacological effects on central nervous
system (CNS) diseases. In particular, (S)-nicotine may have
beneficial effects in the treatment of Parkinson’s disease
(PD), Alzheimer’s disease (AD), and Tourette’s syndrome.2
The neurotransmitter (NT) most consistently implicated in
AD is acetylcholine (ACh). Many groups of compounds have
been isolated from natural sources or synthesized as ligands
for the nicotinic acetylcholine receptors, of which nicotine
and its analogues represent an important class. However,
nicotine is not suitable for therapeutical use due to its
undesirable side effects including the potential for abuse and
actions on the cardiovascular and gastrointestinal systems.3
As a consequence, pharmaceutical reseachers are racing to
synthesize a selective nAChR ligand for the development
of neurodegenerative disorder drugs which possess the
positive effects of nicotine without the compound’s harmful
side effects. The development of new pharmaceuticals based
on the core nicotine structure has been limited by the lack
of synthetic methods for preparing derivatives directly from
natural nicotine. In most previous studies, reagents other than
nicotine were used as starting material for the synthesis of
(S)-nicotine derivatives.2d Since nonchiral compounds have
been used as starting material, a low-yielding resolution was
often required to provide the desired enantiomer. In an
attempt to avoid one or more resolution steps, our attention
turned toward the synthesis of enantioselective nicotine
derivatives using natural (S)-nicotine itself as an inexpensive
starting material.
Lithiation of aromatic and heteroaromatic compounds has
been widely used to introduce various functional groups.4
This reaction is a very attractive functionalization method
as electrophilic substitutions are often difficult on π-deficient
(1) (a) Leete, E.; Mueller, M. J. Am. Chem. Soc. 1982, 104, 6440. (b)
Gorrod, J. W.; Jacob, P., III. Analytical Determination of Nicotine and
Realted Compounds and their Metabolites; Elsevier: New York, 1999. (c)
Pailer, M. Tabacco Alkaloids and Related Compounds; von Euler, U. S.,
Ed.; Pergamon Press: New York, 1965; p 15.
(2) (a) Levin, E. D. J. Neurobiol. 2002, 53, 633. (b) Newhouse, P. A.;
Kelton, M. Pharm. Acta HelV. 2000, 74, 91. (c) Holladay, M. K.; Dart, M.
J.; Lynch, J. K. J. Med. Chem. 1997, 40, 4169. (d) Breining, S. R. Curr.
Top. Med. Chem. 2004, 4, 609.
(3) (a) McDonald, I. A.; Vernier, J.-M.; Cosford, N.; Corey-Naeve, J.
Curr. Pharm. Des. 1996, 2, 357. (b) Cosford, N. D. P.; Bleiker, L.; Dawson,
H.; Whitten, J. P.; Adams, P.; Chavez-Noriega, L.; Correa, L. D.; Crona, J.
H.; Mahaffy, L. S.; Menzaghi, F. M.; Rao, T. S.; Reid, R.; Sacaan, A. I.;
Santori, E.; Stauderman, K.; Whelan, K.; Lloyd, G. K.; McDonald, I. A. J.
Med. Chem. 1996, 39, 3235.
10.1021/ol052196j CCC: $30.25
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heterocycles. To investigate regioselectivity in the deproto-
native metalation of nicotine, several metalating agents were
screened. The choice of base was found to play a crucial
role to access the desired lithiopyridine intermediates.
Recent efforts toward functionalization of pyridines have
focused on the development of directed ortho-metalation
methods (DoM effect).5 The mechanism of this selective
reaction was generally assumed to proceed via the well-
known complex-induced proximity effect (CIPE) between
the ortho-directing group and the lithiating agent promoting
introduction of lithium at the ortho position. In 2000, Fort
and co-workers reported a new base composed of n-BuLi
and Me2N(CH2)2OLi.6 This unimetal superbase called n-BuLi-
LiDMAE induced a regioselective lithiation of pyridine
derivatives even when an ortho-directing group was present
on the heterocyclic ring (Scheme 1). This selectivity strongly
pyridine ring (Scheme 1). The lack of lithiation at the C-2
position of the pyridine is probably due to steric hindrance
resulting from the pyrrolidine ring at C-3. Initially, (S)-6-
chloronicotine (4) was obtained in only 39% yield (Table
1). It is noteworthy to emphasize that this substitution of
Table 1. Formation of (S)-6-Chloronicotine
entrya
n-BuLi (equiv)
T (°C)
solvent system
4 (%)
1
2
3
4
5
6.0
6.0
6.0
5.4
5.4
0
0
-20
0
hexanes
hexanes/THF
hexanes
hexanes
hexanes/toluene
39-60
36
70
65
87
Scheme 1. Fort’s Unimetal Superbase Complexation by the
Pyridine Nitrogen Atom of 2 and Its Complexation with
(S)-Nicotine (1)
-20
a Reactions were run on a 1.0 mmol scale.
(S)-nicotine happens without racemization.7 The main side
reaction was the substitution by a butyl group onto the
pyridine ring at the C-6 position. Interested by the potential
synthetic utility of compound 4, solvent systems, number of
equivalents of base, and temperature were varied. The
reaction outcome was found to be highly sensitive to
solvents. When THF was used as a cosolvent (needed to
dissolve the electrophile) (entry 2), classical nucleophilic
substitution by n-BuLi was observed due to aggregate
disruption. Toluene (entry 5), a less polar solvent, did not
disrupt the aggregate, thus providing a better cosolvent for
this reaction. A lower temperature during the deprotonation
(entries 3 and 5) limited the addition of the butyl group to
the pyridine ring affording higher yields of 6-chloronicotine
(4). The synthesis of 4 was successfully performed on a large
scale (20 mmol) in excellent yield.
Next, the reaction of various representative electrophiles
was examined (Table 2). The addition of electrophiles to
the lithiated nicotine intermediate is very exothermic, which
facilitates the formation of the undesired regioisomer 9. The
low yields of bromination and iodination (entries 2, 3, and
5, respectively) were due to decomposition of the starting
material or butyl addition. The use of C2Br2Cl4 (entry 4)
afforded (S)-6-bromonicotine (8b) in good yield. Among
other examples, (S)-6-(dimethylphenylsilyl)nicotine (8d) and
(S)-6-(tributylstannyl)nicotine (8f) (entries 6 and 8) were
obtained in high yield since these groups cannot be displaced
by n-BuLi to form byproduct 6. The chlorination of
substituted analogues was performed as well and afforded
the C-6 regioisomer preferably (entries 10-12).
contrasted with results observed with the well-known lithium
diisopropylamine (LDA) and alkyllithium bases, which
abstracted exclusively the hydrogen at C-3 in agreement with
the DoM effect. The complete inhibition of the DoM effect
of the C-2 chlorine of 2 with n-BuLi-LiDMAE was
explained by the formation of aggregates between n-BuLi-
LiDMAE and the substrate via lithium complexation by the
pyridine nitrogen atom. The metalation had to be performed
in apolar, noncoordinating solvents such as hexane. Ag-
gregates were assumed first to deliver n-BuLi near the C-6
proton of 6-chloropyridine and second to ensure stabilization
of the formed C-6 lithiated intermediate.6
The reaction of nicotine with n-BuLi-LiDMAE resulted
in the selective deprotonation at the C-6 position of the
(4) (a) Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem. 2002, 653,
150. (b) Queguiner, G.; Marsais, F. Snieckus, V.; Epsztajn, J. AdV.
Heterocycl. Chem., 1991, 52, 187. (c) Snieckus, V. Chem. ReV. 1990, 90,
879.
(5) (a) Beak, P.; Meyers, A. Acc. Chem. Res. 1986, 19, 356. (b) Snieckus,
V. Chem. ReV. 1990, 90, 879. (c) Marsais, F.; Queguiner, G. Tetrahedron
1983, 39, 2009.
(7) Specific rotation for 4: [R]31D -156 (c 1.30, MeCN) [lit. [R]23D -154
(c 1.0, MeCN)]: Roduit, J.-P.; Wellig, A.; Kiener, A. Heterocycles 1997,
45, 1687.
(6) (a) Gros, P.; Fort, Y.; Caube`re, P. J. Chem. Soc., Perkin Trans. 1
1997, 20, 3071. (b) Gros, P.; Fort, Y.; Caube`re, P. J. Chem. Soc., Perkin
Trans. 1 1997, 24, 3597. (c) Choppin, S.; Gros, P.; Fort, Y. Org. Lett. 2000,
2, 803. (d) Gros, P.; Choppin, S.; Mathieu, J.; Fort, Y. J. Org. Chem. 2002,
67, 234.
(8) (a) Schmidt, B.; Neitemeier, V. Synthesis 1998, 1, 42. (b) Dukat,
M.; Dowd, M.; Damaj, M. I.; Martin, B.; El-Zahabi, M. A.; Glennon, R.
A. Eur. J. Med. Chem. 1999, 34, 31. (c) Dukat, M.; Fiedler, W.; Dumas,
D.; Damaj, I.; Martin, B.R.; Rosecrans, J. A.; James, J. R.; Glennon, R. A.
Eur. J. Med. Chem. 1996, 31, 875.
5458
Org. Lett., Vol. 7, No. 24, 2005

yield, and (S)-4-iodonicotine (10) was formed in 24% yield.
In all attempts, the reaction never went to completion and
starting material was recovered.
Reactivity of LiTMP with nicotine (1) was then investi-
gated (Table 4). When nicotine was added to a solution
Table 2. Versatility of the Lithiation of Nicotine and Nicotine
Derivatives via n-BuLi-LiDMAE
Table 4. Electrophile-Dependent Regioselectivity in the
Reaction of Nicotine with LiTMP
entrya
nicotine, R
1, H
1, H
1, H
1, H
1, H
1, H
1, H
1, H
1, H
7a,d SiMe3
7b,d Si(allyl)Me2
7c,e SiMe2Ph
electrophile
8, %
9, %
1b
2
3
4b
5b
6
7
8
9b
10
11
12
C2Cl6
NBS
Br2
C2Br2Cl4
I2
PhSi(Me)2Cl
MeSSMe
ClSnBu3
ethyl formate
C2Cl6
8a, 87
8b, 27
8b, 6
9a, 4
c
c
8b, 67
8c, 55
8d, 92
8e, 70
8f, 55
8g, 26
8h, 53
8i, 56
8j, 43
9b, 21
9c, 4
entrya
electrophile
TMSCl
Cy3SnCl
N-methyl-N-pyridin-2-yl- decomposition of
benzamide electrophile
8, %
9, %
c
9e, 6
1
2
3
8k, 24
9k, 64
9l, 94
c
c
c
c
c
b
C2Cl6
C2Cl6
a Reactions were run on a 1.0-2.0 mmol scale. b Not observed.
a Reactions were run on a 1.0-2.0 mmol scale. b Spectral data matched
the literature.7,8 c Not observed. d Reference 11. e Reference 12.
containing both the base and chlorotrimethylsilane (TMSCl),
the C-2-substituted nicotine 9k was obtained as the major
product in 64% yield and C-6 substituted 8k in 24% yield.
To rationalize these results, it is proposed that LiTMP can
coordinate at the pyrrolidine nitrogen in the transition state
(Figure 1). The C-2 position of the pyridine ring is selectively
Due to the bulky pyrrolidine ring at the C-3 position,
functionalization of the C-2 position of the pyridine ring of
nicotine appeared as the most challenging via lithiation. The
selectivity of various bases was investigated. In 1999, Kondo
and co-workers reported the chemoselective formation of
arylzincates using lithium di-tert-butyltetramethylpiperi-
dinozincate (TMP-zincate) prepared from the addition of di-
tert-butylzinc to a solution of lithium tetramethylpiperidide
(LiTMP).9 Most interestingly, R-metalation of π-deficient
aza-aromatics proceeds smoothly at room temperature to give
the corresponding heteroarylzincates, which react with elec-
trophiles. The R-metalation of pyridine followed by treatment
with I2 gave 2-iodopyridine in 76% yield. Based on this
precedent, the R-metalation of nicotine (1) using TMP-
zincate was therefore attempted (Table 3). When 1.0 equiv
Figure 1. Possible complexation of LiTMP favoring the depro-
tonation at the C-2 position of the pyridine ring of nicotine.
Table 3. Regioselectivity in the Reaction of Nicotine with
TMP-Zincate
deprotonated versus the C-6 position. Once the TMS group
is attached, the coordination of another LiTMP to the
pyridine nitrogen seems to be unlikely because of a steric
effect. This may explain why a disubstituted nicotine was
not obtained. Variation of the number of equivalents of base
showed that the best yield of 9k was achieved using 3.0
equivalents of LiTMP. Given this interesting regioselectivity,
other electrophiles were tested. N-Methyl-N-pyridin-2-yl-
benzamide, which would have allowed access to a phenyl
ketone,10 was not stable in the presence of LiTMP, and
starting material was recovered. However, the installment
entrya
TMP-zincate (equiv)
9c (%)
10 (%)
1
2
1.0
2.0
19
7
24
20
a Reactions were run on a 1.0-2.0 mmol scale.
(9) (a) Imahori, T.; Uchiyama, M.; Sakamoto, T.; Kondo, Y. Chem.
Commun. 2001, 2450. (b) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto,
T. J. Am. Chem. Soc. 1999, 121, 3539.
of TMP-zincate was used as the base followed by addition
of iodine, (S)-2-iodonicotine (9c) was obtained in only 19%
(10) Comins, D. L. Synlett 1992, 615.
Org. Lett., Vol. 7, No. 24, 2005
5459

of a versatile tin functionality was achieved with the synthesis
of compound 9l in an excellent yield of 94%. Future work
will investigate the synthetic utillity of 9l and related
compounds.
lished by grants from the North Carolina Biotechnology
Center and the National Science Foundation (Grant Nos.
CHE-9121380 and CHE-9509532). F.C.F. thanks Glaxo-
SmithKline for the Burroughs-Wellcome Research Fellow-
ship for a second year graduate student and Eli Lilly for the
Eli Lilly Research Fellowship for a third year graduate
student.
In conclusion, a variety of novel, as well as known, C-2-
and C-6-substituted nicotines have been synthesized directly
from (S)-nicotine in moderate to high yield. To the best of
our knowledge, this is the first regioselective deprotonation
of (S)-nicotine. The new methodologies described herein
provide opportunities for exploring new routes to interesting
and potentially useful compounds based on nicotine. Ongoing
studies in our laboratories are directed toward the regiose-
lective substitution of all positions on the pyridine ring of
nicotine, which would in therory provide an easy access to
a plethora of nicotine derivatives.11-13
Supporting Information Available: Experimental pro-
cedures and characterization and NMR data for 8c-f,h-l,
9c,e,k, and 10. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL052196J
(11) Comins, D. L.; Despagnet, E.; U.S. Patent Application No. 60/497,
826.
(12) King, L. S.; Despagnet, E.; Comins, D. L.; U.S. Patent Application
No. 10/715, 147.
(13) Comins, D. L.; King, L. S.; Smith, E. D.; Fe´vrier, F. C. Org. Lett.
2005, 7, 5059.
Acknowledgment. NMR and mass spectra were obainted
at NCSU instrumentation laboratories, which were estab-
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Org. Lett., Vol. 7, No. 24, 2005