Regioselective 5-, 4-, and 2-substitution of (S)-6-chloronicotine and 4-substitution of (S)-5-chloronicotine

Article abstract of DOI:10.1002/ejoc.200600415

A variety of novel 2-, 4-, and 5-substituted 6-chloronicotine and 4-substituted 5-chloronicotine derivatives have been synthesized in a regioselective manner in moderate to high yield from (S)-6-chloronicotine and (S)-5-chloronicotine, respectively. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600415

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600415
Regioselective 5-, 4-, and 2-Substitution of (S)-6-Chloronicotine and
4-Substitution of (S)-5-Chloronicotine
Florence F. Wagner[a] and Daniel L. Comins*[a]
Keywords: Nicotine / Lithiation / Iodine dance / Regioselectivity
A variety of novel 2-, 4-, and 5-substituted 6-chloronicotine
and 4-substituted 5-chloronicotine derivatives have been
synthesized in a regioselective manner in moderate to high
yield from (S)-6-chloronicotine and (S)-5-chloronicotine,
respectively.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
(S)-Nicotine (1), the classical agonist of the nicotinic ace-
tylcholine receptors (nAChR), 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) and Alzheimer’s disease (AD).[1] Both neuro-
degenerative disorders have emerged as a major public health
concern as a consequence of the post World War II baby
boom and the changes in the global population age profile.
Nicotine is not suitable for therapeutical use due to its un-
desirable side effects.[2] As a consequence, there is a con-
siderable interest in synthesizing selective nAChR ligands
for the development of neurodegenerative disorder drugs
which possess the positive effect of nicotine without harm-
ful 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. Our group has been developing syn-
theses of nicotine derivatives using natural (S)-nicotine
itself as an inexpensive starting material. Previous work in-
cludes the synthesis of 4-substituted derivatives via an N-
acylpyridinium salt of nicotine,[3] 5-alkylation by the re-
ductive disilylation of nicotine,[4] and 2- and 6-substitution
of the pyridine ring of nicotine using regioselective depro-
tonations.[5] Following in this vein, we report herein the re-
gioselective substitution of (S)-6-chloronicotine (2) by di-
rected lithiation of the pyridine ring (Figure 1).
Figure 1. (S)-Nicotine (1) and (S)-6-chloronicotine (2).
Results and Discussion
The deprotonation at the 5-position of 2, using the well-
described ortho-directing effect of the chlorine atom,[6] was
attempted first. Surprisingly, the lithiation of 6-chloronico-
tine (2) could not be effected by using up to 3 equiv. of
LDA. Treatment of 2 with 1.1 equiv. of the stronger base
LiTMP in THF at –78 °C, followed by addition of the ap-
propriate electrophile, afforded the 5-substituted derivatives
3a–h (Table 1). This facile reaction allows the regioselective
introduction of various functional groups at the 5-position
of 2. The addition of iodomethane was problematic afford-
ing a complex mixture of 6-chloro-5-methyl-, and 6-chloro-
5-ethylnicotine that could not be separated by chromatog-
raphy (Entry 8).
Initially, we thought 6-chloro-4-iodonicotine (4a) would
be easily accessible through an iodine dance reaction[7] on
6-chloro-5-iodonicotine (3a). However, multiple attempts
using LDA or LiTMP in various amounts led to its forma-
tion in only very low yield, whereas diiodinated 6 and 2-
iodinated 5a were observed (Table 2). More interestingly,
treatment of 6-chloronicotine (2) with 3.0 equiv. of LiTMP
followed by the addition of only 1.0 equiv. of iodine re-
sulted in the near quantitative formation of 5a (Table 3). A
related attempt using another electrophile, C2Br2Cl4, under
the same conditions failed and afforded (S)-5-bromo-6-
chloronicotine (3c) and (S)-2,5-dibromo-6-chloronicotine.
[a] Department of Chemistry, North Carolina State University,
Raleigh, NC 27695-8204, USA
Fax: +1-919-515-9371
E-mail: daniel_comins@ncsu.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Substitution of (S)-6-Chloronicotine and (S)-5-Chloronicotine
SHORT COMMUNICATION
Table 1. Substitution at the 5-position of the pyridine ring of (S)- the diiodide 6 and the 5-lithiated 6-chloronicotine interme-
6-chloronicotine (2) using LiTMP.
diate I. Intermediate I then attacks 6 and affords 5-lithiated
6-chloro-2-iodonicotine intermediate III and 3a which reen-
ters the reaction cycle. Quenching with a saturated aqueous
solution of sodium hydrogencarbonate provides compound
5a in very good yield. To provide evidence for this mecha-
nism, 6-chloro-5-iodonicotine (3a) was added to a mixture
of 1.0 equiv. of 2,2,6,6-tetramethylpiperidine with 2.0 equiv.
of LiTMP at –78 °C for 1 h. After workup, 6-chloro-2-
iodonicotine (5a) was the major product observed by crude
1H NMR spectroscopy (purity Ͼ95%).
Entry[a]
Electrophile E+
Product, E
Yield[b] [%]
1
2
3
4
5
6
7
8
I2
C2Cl6
3a, I
3b, Cl
3c, Br
74
87[c]
37
45
63
C2Br2Cl4
ClSiPhMe2
MeSSMe
ClSnBu3
ethyl formate
MeI
3d, SiPhMe2
3e, SMe
3f, SnBu3
3g, CHO
3h, Me
Although other 2-substituted 6-chloronicotines can likely
be prepared from 5a using lithium/halogen exchange or
cross-coupling reactions, a direct route from 2 was devel-
oped. Treatment of 6-chloronicotine (2) with nBuLi/LiD-
MAE[8] in toluene at –78 °C, followed by addition of the
electrophile, afforded the desired products 5b–f in moderate
to good yields (Table 4). It is noteworthy that the same reac-
tion in hexanes, a common solvent for this base complex,[8]
did not lead to product formation, and starting material
was recovered. The use of the more polar solvent toluene
is believed to break up aggregates and improve solubility
allowing the deprotonation at the 2-position to occur.
Remarkably, regioselective formation of 4-substituted 6-
66
58
[d]
–
[a] Reactions were run on a 0.25–3.0 mmol scale. [b] Isolated yield
after radial PLC. [c] 3b was dehalogenated to afford nicotine using
10% Pd/C, H2 in MeOH in Ͼ99% ee. [d] Reaction resulted in an
inseparable mixture of 3h and (S)-6-chloro-5-ethylnicotine.
The proposed halogen dance mechanism for the forma-
tion of 5a is depicted in Scheme 1. The first lithiation oc-
curs at the 5-position as discussed previously (Table 1) to
give pyridyllithium compound I which on addition of iod-
ine affords 3a. A second equivalent of LiTMP deprotonates chloronicotines 4a–i was achieved by simple treatment of 6-
the 2-position of 3a. This intermediate II might be stabi- chloronicotine (2) with 1.1 equiv. of nBuLi in THF at
lized by complexation to the pyrrolidine nitrogen atom. The –78 °C (Table 5). In particular, 6-chloro-4-iodonicotine (4a)
2-lithiated intermediate II reacts with another equivalent of was prepared in 80% yield. This directed ortho-metalation
3a by abstracting the iodine atom at the 5-position to form (DoM)[6,9] is obviously effected by intramolecular coordina-
Table 2. Attempts at forming (S)-6-chloro-4-iodonicotine (4a) by an iodine dance reaction on (S)-6-chloro-5-iodonicotine (3a).
Entry[a]
Conditions
Product
Ratio[b]
[c,d]
1
2
3
4
1.0 equiv. LDA, THF, –78 °C, 2 h
1.0 equiv. LDA, THF, –78 °C, 30 min
2.0 equiv. LDA, THF, –78 °C, 2 h
1.2 equiv. LiTMP, THF, –78 °C, 1 h
6
–
3a, 4a
2:1
2:1:1
1:2:2
3a, 4a, 6
3a, 5a, 6
1
[a] Reactions were run on a 0.1–0.5 mmol scale. [b] Ratio determined by H NMR spectroscopy. [c] 52% isolated yield after radial PLC.
[d] Traces of 4a.
Table 3. Iodine dance reactions starting from (S)-6-chloronicotine (2).
Entry[a]
1
Conditions
Product
Ratio[b]
1:2
2.0 equiv. LiTMP, THF, –78 °C, 1 h
1.0 equiv. of I2, –78 °C, 1 h
3.0 equiv. LiTMP, THF, –78 °C, 1 h
1.0 equiv. of I2, –78 °C, 1 h
6,5a
2
5a,4a, 6
Ͼ95:5[c,d]
1
[a] Reactions were run on a 0.1–0.5 mmol scale. [b] Ratio determined by H NMR spectroscopy. [c] 95% isolated yield of 5a after radial
PLC. [d] Crude product contained traces of 4a and 6.
Eur. J. Org. Chem. 2006, 3562–3565
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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F. F. Wagner, D. L. Comins
SHORT COMMUNICATION
Scheme 1. Proposed mechanism for the formation of 5a by an iodine dance reaction.
Table 4. Substitution at the 2-position of the pyridine ring of (S)-
6-chloronicotine (2) using nBuLi/LiDMAE.
Table 5. Regioselective substitution at the 4-position of the pyridine
ring of (S)-6-chloronicotine (2).
Entry[a]
Electrophile E+
Product, E
Yield[b] [%]
Entry[a] Electrophile E+
Product, E
4a, I
Yield[b] [%]
1
2
3
4
C2Cl6
MeSSMe
ClSnBu3
5b, Cl
5c, SMe
5d, SnBu3
5e, CHO
72[c]
53
42
1
2
3
4
5
6
7
8
I2
D2O
C2Cl6
80
79
4b, D
4c, Cl
4d, Br
4e, CHO
4f, SnBu3
4g, SMe
63[c]
27
ethyl formate
57
C2Br2Cl4
ethyl formate
ClSnBu3
MeSSMe
PhCHO
[a] Reactions were run on a 1.0 mmol scale. [b] Isolated yield after
radial PLC. [c] 5b was dehalogenated to afford nicotine using 10%
Pd/C, H2 in MeOH in Ͼ99% ee.
62
51
34
4h–i, CH(OH)Ph
65[d]
[a] Reactions were run on a 0.5–3.0 mmol scale. [b] Isolated yield
after radial PLC. [c] 4c was dehalogenated to afford nicotine using
10% Pd/C, H2 in MeOH in Ͼ99% ee. [d] 1:1 ratio of diastereomers.
tion of nBuLi to the pyrrolidine nitrogen atom during the
deprotonation step. Finally, we developed a methodology
for the synthesis of 4,5-disubstituted nicotines (Scheme 2).
(S)-5,6-Dichloronicotine was treated with zinc powder in a
1.0  solution of HCl in acetic acid at 60 °C for 2 h to af-
ford (S)-5-chloronicotine (7) in 65% yield with only 12% of
the over-reduced product, nicotine (1).
(S)-5-Chloronicotine (7) was treated with 1.1 equiv. of
nBuLi in THF at –78 °C to effect a DoM reaction at the 4-
position. Upon addition of electrophiles, 4-substituted 5-
chloronicotine derivatives 8a–g were obtained in moderate
to good yield (Table 6).
Scheme 2. Regioselective dehalogenation.
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Eur. J. Org. Chem. 2006, 3562–3565

Substitution of (S)-6-Chloronicotine and (S)-5-Chloronicotine
SHORT COMMUNICATION
Fellowship for a second-year graduate student, and Eli Lilly for the
Eli Lilly Research Fellowship for a third-year graduate student.
Table 6. Regioselective substitution at the 4-position of the pyridine
ring of (S)-5-chloronicotine (6a).
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Entry[a]
Electrophile E+
Product, E
Yield[b] [%]
1
2
3
4
5
6
7
D2O
I2
MeSSMe
ethyl formate
ClSnBu3
ClSiMe2Ph
TMSCl
8a, D
8b, I
8c, SMe
8d, CHO
8e, SnBu3
8f, SiMe2Ph
8g, TMS
80
65
68
55
58
39
56
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Conclusions
In summary, a variety of novel 2-, 4-, and 5-substituted
6-chloronicotines have been synthesized in a regioselective
manner from (S)-6-chloronicotine in moderate to high
yield. Our previous studies[3–5] and the new methodologies
described herein provide new routes to a plethora of inter-
esting and potentially useful compounds based on nicotine.
All positions on the pyridine ring of (S)-nicotine can now
be regioselectively substituted. In particular, an iodine atom
can be introduced at the 2-, 4-, or 5-positions of 6-chloroni-
cotine and at the 4-position of 5-chloronicotine providing
intermediates for sequential cross-coupling reactions.[10] Ef-
forts are underway to expand the scope of these methods
and to apply them to the preparation of potential pharma-
ceuticals, insecticides, synthetic intermediates, and novel li-
gands for catalytic asymmetric synthesis. Our goal is to
transform commercially available (S)-nicotine from an un-
derutilized natural product to a useful member of the chiral
pool.[11]
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization, and NMR spectro-
scopic data for 3a–g, 4a–i, 5a, 5b–f, 6, 7, and 8b–g.
Acknowledgments
NMR and mass spectra were obainted at the NCSU instrumen-
tation laboratories, which were established by grants from the
North Carolina Biotechnology Center and the National Science
Foundation (Grants CHE-9121380 and CHE-9509532). F. F. W.
thanks GlaxoSmithKline for the Burroughs-Wellcome Research
[11] H.-U. Blaser, Chem. Rev. 1992, 92, 935–952.
Received: May 12, 2006
Published Online: July 3, 2006
Eur. J. Org. Chem. 2006, 3562–3565
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3565