Synthesis of C-4 substituted nicotine derivatives via an N-acylpyridinium salt of (S)-nicotine

Article abstract of DOI:10.1021/ol0520469

(Chemical Equation Presented) A variety of novel nicotine derivatives were prepared from (S)-nicotine via a two-step sequence. Addition of a cuprate reagent to an N-acylpyridinium salt of nicotine, followed by aromatization with elemental sulfur, afforded

Full text of DOI:10.1021/ol0520469

ORGANIC
LETTERS
2005
Vol. 7, No. 22
5059-5062
Synthesis of C-4 Substituted Nicotine
Derivatives via an N-Acylpyridinium Salt
of (S)-Nicotine
Daniel L. Comins,* Laura S. King, Emilie D. Smith, and Florence C. Fe´vrier
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received August 24, 2005
ABSTRACT
A variety of novel nicotine derivatives were prepared from (S)-nicotine via a two-step sequence. Addition of a cuprate reagent to an
N-acylpyridinium salt of nicotine, followed by aromatization with elemental sulfur, afforded C-4 substituted nicotines in moderate to high yield.
Using this method, 4-(dimethylphenylsilyl)nicotine was prepared and oxidized to afford (S)-4-hydroxynicotine.
(S)-Nicotine (1) is the most abundant alkaloid isolated from
the tobacco plant. Of the minor alkaloids studied only
nornicotine (2), metanicotine (3), and anabasine (4) (Figure
1) have been shown to have significant pharmacological
Recently, nicotine was found to have some beneficial
effects on patients suffering from Parkinson’s disease, an-
xiety, schizophrenia, Alzheimer’s disease, ulcerative colitis,
and other CNS disorders.2 Various nuisances associated with
the use of nicotine, which include cardiovascular and gastro-
intestinal systems disturbance, sleep disorder, and addiction,
limit the use of nicotine as a therapeutic agent. One of the
contemporary challenges is to synthesize nonaddictive nico-
tine derivatives that display the same beneficial effects of
nicotine at lower toxicity.
Numerous nicotine analogues with substituted pyridine and
pyrrolidine rings have been synthesized and subjected to
physiological studies. As a result of the difficulty in
substituting nicotine directly and/or regioselectively, analogue
synthesis is often lengthy and low-yielding because of the
necessity to start with non-nicotine starting materials. We
initiated an investigation into the regioselective synthesis of
nicotine derivatives starting from natural (S)-nicotine. This
approach avoids the use of a resolution to obtain enantiopure
material and reduces both the length and the cost of the
synthesis of certain nicotine analogues.
Figure 1. Structures of (S)-nicotine (1), nornicotine (2), metani-
cotine (3), and anabasine (4).
Nicotine’s two nitrogen atoms are both nucleophilic and
can compete for electrophiles. When treating nicotine with
activity; their actions are similar to those of nicotine but are
less potent.1
(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.
(1) Pailer, M. Tobacco alkaloids and Related Compounds; von Euler,
U. S., Ed.; Pergamon Press: New York, 1965; p 15.
10.1021/ol0520469 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/28/2005

iodomethane, Seeman3 observed a 2.5:1 ratio of monoalkyl-
ated products 6 and 5, indicating that the pyrrolidine nitrogen
is about three times more nucleophilic than the pyridine
nitrogen. In nicotine, the pKa of N-1 is 3.04 and the pKa of
N-1′ is 7.84.1
described by Cosford and Bleicher4 being isolated instead.
The use of a bulky chloroformate, such as trans-2-(cumyl)-
cyclohexyl chloroformate6 (to inhibit acylation at the more
hindered pyrrolidine ring nitrogen) led to no reaction with
phenyl Grignard reagent.
Since the use of chloroformates failed to provide the
desired pyridinium salt intermediate, we turned our attention
to the use of hindered and less reactive acyl chlorides. It
was discovered that pivaloyl chloride reacted selectively at
N-1 to form the desired pyridinium salt of nicotine. We then
investigated the reaction of that salt with cuprate reagents
to give N-pivaloyl-1,4-dihydronicotines 10 (Scheme 3).
Scheme 1. Reactions of Nicotine with Electrophiles
Scheme 3. Addition of Cuprate Reagents to C-4 of
N-Acylpyridinium Salt 9
Cosford and Bleicher demonstrated that the pyrrolidine
ring of nicotine can be opened by phenyl chloroformate with
inversion of configuration at C-2′ and subsequently reclosed
with net retention of configuration.4 This conversion is
unfortunate in the sense that N-acylpyridinium salts are
valuable intermediates for pyridine substitution reactions,5
but in this case the pyrrolidine nitrogen wins the acylation
competition, preventing this pathway to substituted nicotines.
Years ago, we reported the copper-mediated addition of
Grignard reagents to N-acylpyridinium salts to access various
C-4 substituted pyridines.5a Since the corresponding reaction
with nicotine would be valuable for preparing analogues, we
initiated a screening of various chloroformates in an attempt
to form the desired pyridinium salt intermediate 8 (Scheme
2).
Initially, the reactivity of the N-pivaloylpyridinium salt
of nicotine with simple alkyl and aryl cuprates was examined.
The cuprates were easily prepared by the transmetalation of
their corresponding Grignard reagent with CuBr‚SMe2. The
results of the addition reactions are presented in Table 1
Table 1. Addition of Organocopper Reagents to 9
Scheme 2. Acylation at N-1 of Nicotine
entrya
R-Metb
conditions
product
yield,c %
71
79
40
64
77
1
2
3
4
5
MeMgBr, CuBr
PhMgBr, CuBr
-78 °C, 3 h
-78 °C, 3 h
10a
10b
10c
10d
10e
n-BuMgBr, CuBr -78 °C, 3 h
BnMgBr, CuBr
11
-78 °C, 3 h
-78 °C, 3 h
-30 °C, 10 h
-78 °C, 3 h
-78 °C, 3 h
-30 °C 10 h
-78 °C, 3 h
-30 °C 10 h
6
7
12
13
10f
10g
76 (52% dr)d
58
8
14
10h
81 (68% dr)d
We first investigated the reaction of phenyl chloroformate,
nicotine, and a Lewis acid. The addition of a Lewis acid
additive, such as boron trifluoride etherate, was intended to
block acylation at N-1′, but the combination failed to produce
the desired pyridinium salt, the ring-opened product 7
a The reactions were generally performed on a 1-3.0 mmol scale in
THF. b The organometallics were prepared in a separate flask (1-2 equiv)
and added to 9 at -78 °C. c Unless indicated, the products were isolated as
1
one diastereomer. d The ratio of diastereomers (dr) was determined by H
NMR.
(3) Seeman, J. I.; Heterocycles 1984, 22, 165.
(4) Bleicher, L. S.; Cosford, N. D. P. J. Org. Chem. 1999, 64, 5299.
(5) (a) Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1982, 47, 4315.
For reviews, see: (b) Comins, D. L.; O’Connor, S. AdV. Heterocycl. Chem.
1998, 44, 199. (c) Comins, D. L.; Joseph, S. P. In AdVances in Nitrogen
Heterocycles; Moody, C. J., Ed.; JAI Press: Greenwich, CT, 1996; Vol. 2,
pp 251-294. (d) Comins, D. L.; Joseph, S. P. Chemistry of Pyridines at
Ring Positions, in Comprehensive Heterocyclic Chemistry, 2nd ed.;
McKillop, A., Ed.; Pergamon Press: Oxford, England, 1996; Vol. 5.
(entries 1-4). The yields range from 40% to 79%, and all
of the 1,4-dihydronicotine products were isolated as a single
diastereomer. The stereochemistry at C-4 was confirmed by
(6) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719.
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Org. Lett., Vol. 7, No. 22, 2005

X-ray crystallography of product 10b. The diastereofacial
selectivity observed in these transformations must be caused
by the pyrrolidine ring acting as a chiral inductor through
complexation of its nitrogen to the organometallic during
the addition step.7
Encouraged by these results, we decided to expand the
scope of this transformation by using some heterocyclic and
functionalized cuprate reagents (Figure 2).
stoichiometric amount of sulfur in refluxing toluene5a,11 was
successful after 1-3 days of heating and provided good
Scheme 4. Aromatization of Dihydropyridines 10 with Sulfur
yields (59-93%) of 4-substituted nicotines 15 (Scheme 4,
Table 2).
Table 2. Aromatization of Dihydropyridines 10 with Sulfur
entrya
10
conditionsb
15
R
yield,c %
Figure 2. Organocopper nucleophiles used in the preparation of
10e-h.
1
2
3
4
5
6
7
8
10a reflux (32 h)
10b reflux (32 h)
10c reflux (32 h)
10d reflux (32 h)
10e reflux (3 d)
10f
10g act. C, reflux (2 d) 15g t-BuOCH2
10h 90 °C (1 d) 15h PhMe2Si
15a Me
15b Ph
15c n-Bu
15d Bn
15e 2-furanyl
15f
79
59
93
64
74
60
68
80
Synthesis of 4-furanyldihydronicotine 10e was achieved
in 77% yield by addition of cuprate 11 to 9 (entry 5). This
cuprate was prepared from lithiation of furan, followed by
addition of freshly made MgBr2 and transmetalation with
CuBr‚SMe2. A benzyloxymethyl group was introduced in
76% yield using higher order cuprate 12, formed from the
transmetalation of the corresponding stannane8 with n-BuLi
and addition of the Lipshutz reagent. Although the yield was
good, the addition resulted in the formation of a mixture of
diastereomers (10f) with a 52% de (entry 6).
Addition of cuprate 13, formed from deprotonation of tert-
butylmethyl ether with s-butyllithium and potassium tert-
butoxide followed by transmetalation with CuBr‚SMe,9 to 9
yielded 58% of product 10g as a single diastereomer along
with 40% of recovered starting material (entry 7).
reflux (3 d)
BnOCH2
a The reactions were generally performed on a 1-3.0 mmol scale in
toluene. b Sublimed sulfur (1.0 equiv) was used. c Yield of products obtained
from radial preparative-layer chromatography.
Aromatization of 4-n-butyl-1,4-dihydronicotine 10c was
achieved in an excellent yield of 93% (entry 3). A temper-
ature of only 90 °C was needed for 4-(dimethylphenylsilyl)-
dihydronicotine 10h (entry 8) to afford an 80% yield of 15h.
In the case of substrate 10g, addition of activated charcoal
was required to provide a 68% yield of the corresponding
nicotine derivative.
To verify that no racemization occurred during the
oxidation step, a method was developed to separate racemic
nicotine by chiral HPLC. All new 4-substituted nicotines
showed >99% ee using this method.
Finally, addition of (dimethylphenylsilyl)cuprate 14, pre-
pared from (dimethylphenylsilyl)magnesium bromide and
CuBr‚SMe2, gave a surprisingly high yield (81%) of 10h;10
however, the stereoselectivity was moderate, as two diaster-
eomers were isolated with a 68% dr (entry 8).
Once a regioselective method had been developed to
synthesize N-acyl-1,4-dihydronicotines, the next step was to
find a mild oxidation to afford 4-substituted nicotines 15.
Early attempts using p-chloranil, o-chloranil, or palladium
on carbon in toluene at reflux proved to be fruitless, as no
reaction occurred after 6 h in each case. The use of a
The analogue 4-(hydroxymethyl)nicotine (15i, R ) HOCH2)
was previously synthesized by Seeman12 as a byproduct (5%
yield) in the development of a ligand for radioimmunoassay
for tobacco alkaloids. Deprotection of the hydroxymethyl
group in compounds 15f and 15g would afford 4-(hy-
droxymethyl)nicotine. Various hydrogenation conditions
were attempted to cleave the benzyl group of 15f. Hydro-
genation using a catalytic amount of Pd/C in ethanol did
not yield any product, whereas use of Pearlman’s catalyst
as well as phase transfer catalysis13 resulted in opening of
the pyrrolidine ring.
(7) For related reactions using chiral auxiliaries, see: (a) Meyers, A. I.;
Oppenlaender, T. J. Am. Chem. Soc. 1986, 108, 1989. (b) Mangeney, P.;
Gosmini, R.; Raussou, S.; Commercon, M.; Alexakis, A. J. Org. Chem.
1994, 59, 1877. (c) Yamada, S.; Ichikawa, M. Tetrahedron Lett. 1999, 40,
4231. (d) Yamada, S.; Morita, C. J. Am. Chem. Soc. 2002, 124, 8184 and
references therein.
(8) Kaufman, T. S. Synlett 1997, 1378.
(9) Corey, E. J.; Eckrich, T. Tetrahedron Lett. 1983, 24, 3165.
(10) For related reactions, see: (a) Comins, D. L.; Killpack, M. O.;
Despagnet, E.; Zeller, E. Heterocycles 2002, 58, 505. (b) Comins, D. L.;
Killpack, M. O. J. Am. Chem. Soc. 1992, 114, 10, 972. (c) Ho¨sl, C. E.;
Wanner, K. T. Heterocycles 1998, 48, 2653
(11) Comins, D. L.; Stroud, E. D.; Herrick, J. J. Heterocycles 1984, 22,
151.
(12) Seeman, J. I.; Chavdarian, C. G.; Secor, H. V.; Osdene, T. S. J.
Org. Chem. 1986, 51, 1548.
(13) Hanesina, S.; Liak, T. J.; Vanasse, B. Synthesis 1981, 397.
Org. Lett., Vol. 7, No. 22, 2005
5061

Cleavage of the tert-butyl ether of 15g using TFA/CH2-
Cl2 followed by an anhydrous workup afforded 98% of
4-(hydroxymethyl)nicotine (15i). This synthesis of (S)-4-
(hydroxymethyl)nicotine was achieved with an overall yield
of 39%.
The presence of a hydroxyl group on the pyridine ring of
nicotine opens up new pathways to regioselective introduc-
tion of substituents via aromatic electrophilic substitution and
directed lithiation. These potential substitution reactions of
4-hydroxynicotine are currently under investigation. The
novel nicotine derivatives and N-acyldihydronicotines pre-
pared in this study are currently being tested for CNS as
well as insecticidal activities.
We next turned our attention to the oxidation of 4-(di-
methylphenylsilyl)nicotine 15h (Scheme 5). A dimethylphen-
In conclusion, a variety of novel 1,4-dihydronicotines and
C-4 substituted nicotines have been synthesized from (S)-
nicotine in moderate to high yield. To the best of our
knowledge, this is the first synthesis of 4-substituted 1,4-
dihydronicotines. We also report the formation and reactivity
of the first N-acylpyridinium salt of nicotine. The two-step
procedure developed for the preparation of 4-substituted
nicotine derivatives is cost-efficient, regioselective, and
resolution-free. The new methodologies described in this
paper provide rich opportunities for exploring new routes to
interesting and potentially useful compounds based on
nicotine.18
Scheme 5. Conversion 4-(dimethylphenylsilyl)nicotine to
4-hydroxynicotine
ylsilyl group has been widely used as a masked hydroxy
group.14 It can easily be oxidized and converted to an
hydroxy group by using Tamao’s procedure (TFA; KHF2,
H2O2).15 Tamao’s conditions resulted in the conversion of
15h to 16 in 30% yield. In this case, formation of nicotine
N-1′-oxide was of concern so milder conditions were
investigated. In a report by Dunogues,16 an aromatic alkoxy-
silane was converted to the corresponding phenol using
potassium fluoride and hydrogen peroxide in ethanol. Similar
conditions proved to be more suitable for the oxidation of
15h. The use of KHF2 and H2O2 in methanol at 55 °C and
modifying the workup afforded 82% of novel 4-hydroxyni-
cotine (16).17
Acknowledgment. NMR and mass spectra were obtained
at NCSU instrumentation laboratories, which were estab-
lished by grants from the North Carolina Biotechnology
Center and the National Science Foundation (Grants CHE-
9121380 and CHE-9509532).
Supporting Information Available: Experimental pro-
cedures for 10 and 15; characterization data and NMR
spectra for compounds 10a-h, 15a-h, and 16; ORTEP
plot and X-ray crystal data for 10b in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0520469
(14) For a review, see: Fleming, I. Chemtracts Org. Chem. 1996, 9, 1.
(15) Tamao, K.; Ishida, N. J. Organomet. Chem. 1984, 269, C37.
(16) Prouilhac-Cros, S.; Babin, P.; Bennetau, B.; Dunogues, J. Bull. Soc.
Chim. Fr. 1995, 132, 513.
(17) Isolated 16 exists in the 4-hydroxypyridine tautomeric form presum-
ably as a result of hydrogen bonding with the pyrrolidine nitrogen.
(18) King, L. S.; Smith, E.; Comins, D. L. U.S. Patent Application 10/
715, 147, Nov 17, 2003.
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Org. Lett., Vol. 7, No. 22, 2005