Racemic synthesis of 2′-substituted nicotine analogs

Article abstract of DOI:10.1002/jhet.841

The chemical and pharmacological properties of 2′-substituted nicotines are poorly understood relative to other substituted nicotines. We developed a practical synthesis of the key intermediate (6)-2′- cyanonicotine using the Polonovski reaction. Alkylation of (6)-2′- cyanonicotine with Grignard reagents led to several 2′-alkylnicotines; (6)-2′-aminomethylnicotine, (6)-2′-hydroxymethylnicotine, and (6)-2′- carbamoylnicotine were also synthesized..

Full text of DOI:10.1002/jhet.841

January 2012
Racemic Synthesis of 20-Substituted Nicotine Analogs
161
Anne Rouchaud and William R. Kem*
Department of Pharmacology and Therapeutics, University of Florida, College of Medicine,
Gainesville, Florida 32610-0267
*E-mail: wrkem@ufl.edu
Received August 29, 2010
DOI 10.1002/jhet.841
Published online 18 October 2011 in Wiley Online Library (wileyonlinelibrary.com).
The chemical and pharmacological properties of 20-substituted nicotines are poorly understood rela-
tive to other substituted nicotines. We developed a practical synthesis of the key intermediate (6)-20-
cyanonicotine using the Polonovski reaction. Alkylation of (6)-20-cyanonicotine with Grignard reagents
led to several 20-alkylnicotines; (6)-20-aminomethylnicotine, (6)-20-hydroxymethylnicotine, and (6)-20-
carbamoylnicotine were also synthesized.
J. Heterocyclic Chem., 49, 161 (2012).
INTRODUCTION
In this work, we report new synthetic methods for
obtaining the following 20-nicotine derivatives: (6)-20-
cyanonicotine 3, (6)-20-methylnicotine 5, (6)-20-ethyl-
nicotine 6, (6)-20-n-propylnicotine 7, (6)-20-aminome-
thylnicotine 8, (6)-20-hydroxymethylnicotine 9, and
(6)-20-carbamoylnicotine 10. The pharmacological prop-
erties of these racemic nicotines and their enantiomers,
separated by chiral HPLC, will be reported elsewhere.
Deficits in brain nicotinic acetylcholine receptor
(nAChR) expression have been reported in neurodege-
nerative and mental diseases [1,2]. Therefore, nicotinic
acetylcholine agonists are being developed to alleviate
these deficits [3,4]. Nicotine addiction is also being
treated with nAChR agonists, including nicotine [5,6]. A
variety of nicotine analogs have been synthesized and
tested pharmacologically, largely by equilibrium radioli-
gand binding assays. Synthetic methods for preparing ra-
cemic 10, 30-, 40-, and 50- substituted nicotine analogs
have been reported. Also, 20-methyl- and 20-ethyl-nico-
tine were reported to displace the binding of radiola-
beled methylcarbamylcholine to rat brain nAChRs that
bind nicotine with high affinity [7]. However, their
method of synthesis was not reported.
Methods for the synthesis of the 30-, 40-, and 50-substi-
tuted nicotine derivatives are listed in Scheme 1. 40-Meth-
ylnicotine and 50-methylnicotine, 40-cyanonicotine and 50-
cyanonicotine, 40-carbamoylnicotine and 50-carbamoylni-
cotine, and 40-hydroxymethylnicotine were obtained by
multistep transformations of (S)-cotinine; 50-cyanonicotine
was also prepared from (S)-nicotine [8–10]. N-3-Pyridyli-
denemethylamine with succinic anhydride gave 30-methyl-
nicotine and 30-carboxynicotine [11]. The 30-, 40-, and 50-
carboxynicotines were transformed into the corresponding
amides, aminomethylnicotines, and hydroxymethylnico-
tines [12–15]. Most of the reactions were nonstereospe-
cific and generated mixture of diastereoisomers; however,
some procedures were stereospecific and gave specific
enantiomers.
RESULTS AND DISCUSSION
Initially, we examined the preparation of (6)-20-meth-
ylnicotine by reacting 2-methyl-1-pyrroline with 3-pyri-
dylmagnesium bromide (Scheme 2).
Reaction of an organometallic reagent with a cyclic
imine group has been described in the literature. Meth-
yllithium has been added to a 1-alkyl-3,4-dihydroisoqui-
noline to generate 1-alkyl-1-methyl-1,2,3,4-tetrahydroi-
soquinoline [16]. Allylmagnesium bromide has been
reacted with 2-methyl-1-pyrroline, giving a 2-allyl-2-
methyl-pyrrolidine [17].
In this work, 3-pyridylmagnesium bromide [18], 3-
pyridylmagnesium chloride [19], and 3-pyridyllithium
[18] were prepared from 3-bromopyridine. The addition
of each of these organometallics to 2-methyl-1-pyrroline
was attempted at ꢀ50ꢁC or ꢀ78ꢁC. In the case of the
addition of pyridylmagnesium bromide or chloride, bo-
ron trifluoride-diethyl etherate was added before the
addition of the Grignard reagent. However, 20-methyl-20-
(pyridyl-3)-pyrrolidine was not obtained.
The imine bond can be activated by quaternization to
allow the nucleophilic addition of a Grignard reagent.
C
V
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162
A. Rouchaud and W. R. Kem
Vol 49
Scheme 1
For instance, methyl iodide was added to 1-methyl-3,4-
dihydroisoquinoline, generating the iminium salt 1,2-di-
methyl-3,4-dihydroisoquinolinium iodide [20]. This imi-
nium salt is more reactive than the imine. Methylmagne-
sium chloride reacted with the iminium, generating
1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinoline. Another
example is the reaction of methylmagnesium chloride
with the iminium salt N-isopropylidene-4-chloropiperidi-
nium chloride giving 1-tert-butyl-4-chloropiperidine
[21].
Expecting a higher reactivity for the iminium salt
than for the imine, in this research 2-methyl-1-pyrroline
was transformed with methyl iodide into the iminium
1,2-dimethyl-1-pyrrolinium iodide (Scheme 2). The con-
densation of this iminium with 2 or 5 equiv of 3-pyri-
dylmagnesium bromide or chloride was attempted in
THF or in the mixture of THF with diethyl ether, first at
0ꢁC, then at room temperature and in some cases ending
with heating to reflux. However, 20-methylnicotine was
never obtained.
Scheme 2
In another approach, the iminium 1,2-dimethyl-1-pyr-
rolinium iodide in dichloromethane was reacted with an
aqueous solution of potassium cyanide at rt (Scheme 2).
The 1,2-dimethyl-2-cyanopyrrolidine was obtained in
95% yield. Its condensation with 5 equiv of 3-pyridyl-
magnesium bromide was attempted in THF at 0ꢁC,
followed by rt and in some cases by heating to reflux.
However, the Bruylants reaction did not take place and
20-methylnicotine was never obtained [22–24]. It only
resulted in recovered starting material.
Journal of Heterocyclic Chemistry
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Racemic Synthesis of 20-Substituted Nicotine Analogs
163
Scheme 3
Scheme 5
The probable reason that the condensations of 3-pyri-
dylmagnesium chloride or bromide with 2-methyl-1-pyr-
roline, 1,2-dimethyl-1-pyrrolinium iodide or 1,2-di-
methyl-2-cyano-pyrrolidine did not succeed is steric
hindrance due both to the reagents and to the desired
product, 20-methylnicotine. Also, deprotonation of the
methyl group of the 2-methyl-1-pyrroline and the imi-
nium salt was probably competing with the desired addi-
tion, which would explain the recovery of the starting
imine or iminium.
normal phase (silica gel) HPLC into the trans and cis
isomers.
The cyano group in amino nitrile 3 is in an a-position
relative to the tertiary amine. Replacement of this cyano
group with an alkyl substituent was accomplished by a
Bruylants reaction with an organomagnesium compound
[22–24]. Displacement of the cyano group leads to an
intermediate, stabilized iminium carbocation, which
reacts further with the nucleophile alkyl organomagne-
sium (Scheme 4). The reaction of 5 equivalents of
methyl-, ethyl-magnesium bromide, or n-propylmagne-
sium chloride with amino nitrile 3 in THF at ꢀ10ꢁC
generated (6)-20-methyl- (5), (6)-20-ethyl- (6), and (6)-
20-n-propylnicotine (7) with yields of 95%, 92%, and
94%, respectively.
To circumvent these problems, we developed a practi-
cal synthesis of the key intermediate (6)-20-cyanonico-
tine 3 using the Polonovski reaction [25,26]. The N-
oxides 2 of nicotine were reacted with trifluoroacetic
anhydride; the iminium intermediate then reacted with
the cyano ion (Scheme 3). In practice, (S)-nicotine 1
was transformed by m-CPBA into the diastereomeric
mixture of N-oxides 2 with a yield of 97%. Trifluoro-
acetic anhydride transformed in dichloromethane at 0ꢁC
Transformations of the cyano group of the amino
nitrile 3 gave several (6)-20-derivatives of nicotine
(Scheme 5). DIBALH in toluene at ꢀ78ꢁC reduced the
amino nitrile 3, providing (6)-20-aminomethylnicotine 8
in 59% yield.
To obtain (6)-20-hydroxymethylnicotine 9, (6)-20-
aminomethylnicotine 8 was first treated with sodium ni-
trite in aqueous acetic acid; then, the reaction mixture
was made alkaline and extracted with dichloromethane.
After rotary evaporation, the resulting organic extract
was treated with potassium hydroxide in methanol, giv-
ing 9 in 35% yield.
0
0
the N-oxides 2 to D1 ,2 iminium trifluoroacetate. There-
after, addition of solid potassium cyanide to the reaction
mixture yielded (6)-20-cyanonicotine 3 (58% from 2).
Small amounts of the 50-cyanonicotine diastereomers 4
(12%) were also formed; these were separated by
Scheme 4
Hydrolysis of (6)-20-cyanonicotine 3 in a mixture of
trifluoroacetic acid and sulfuric acid (4:1) gave (6)-20-
carbamoylnicotine 10 in 51% yield.
EXPERIMENTAL
General. ESI-HRMS were performed on a Agilent 6210
TOF mass spectrometer. GC/CI analyses were performed on a
Thermo Trace GC DSQ—Single Quadrupole. The 1H-NMR
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A. Rouchaud and W. R. Kem
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1
cis-50-Cyanonicotine (4b). H-NMR (300 MHz, CDCl3): d
8.55 (dd, 1 H, J ¼ 1.8, 4.8 Hz, ArH), 8.53 (d, 1 H, J ¼ 2.1
Hz, ArH), 7.74 (dt, 1 H, J ¼ 7.8, 2.1 Hz, ArH), 7.30 (ddd, 1
H, J ¼ 8.1, 5.1, 0.9 Hz, ArH), 3.39 (t, 2 H, J ¼ 7.1 Hz), 2.33
(s, 3 H, NCH3), 2.29 (m, 3 H), 1.88 (m, 1 H). 13C-NMR (75.3
MHz, CDCl3): d 149.6 (CH), 149.5 (CH), 138.5 (C), 134.9
(CH), 124.1 (CH), 117.0 (CN), 68.1 (CH), 55.9 (CH), 39.0
(CH3), 34.2 (CH2), 28.7 (CH2). ESI-HRMS: m/z ¼ 188.1176
(calculated for [M þ H]þ: 188.1182).
spectra were recorded in CDCl3 at 300 MHz with a Varian
Mercury 300 and are reported in ppm from internal TMS on
the d scale. The 13C-NMR spectra were recorded in CDCl3 at
75.4 MHz with a Varian Mercury 300 instrument. Flash chro-
matographies were performed on silica gel (Fisher, Silica Gel
Sorbent, 230–400 Mesh) or on alumina (Aluminoxid 90, Ac-
tivity II-III, EMD) columns.
Nicotine-N-oxides (2). To a solution of (S)-nicotine (4 mL,
25.04 mmol) in CH2Cl2 (120 mL) at 0ꢁC was added a 70%
aqueous m-CPBA (6.172 g, 25.04 mmol). After stirring 1 h 30
at 0ꢁC under argon, the reaction mixture was concentrated
in vacuo to a volume of 10 mL and then poured over alumina
and chromatographed using CH2Cl2/CH3OH (98:2 to 95:5) as
eluent to afford a diasteromeric mixture of trans- and cis-nico-
tine-N-oxide 2 (4.354 g, 24.4 mmol, 97%).
(6)-20-Cyanonicotine (3). Trifluoroacetic anhydride (3.42
mL, 24.4 mmol) was slowly added under argon atmosphere to
a solution of N-oxides 2 (2.177 g, 12.2 mmol) in dry methyl-
ene chloride (30 mL) cooled to 0ꢁC. The resulting mixture
was stirred at 0ꢁC for 1 h and at room temperature for 15 min.
Following this period, excess solid potassium cyanide (1.586
g, 24.4 mmol) was added to the reaction mixture and vigorous
stirring was continued for 3 h. The reaction mixture was then
basified with saturated aqueous sodium carbonate and
extracted with methylene chloride (3ꢂ 40 mL). The combined
organic layers were dried over anhydrous magnesium sulfate
and concentrated. After column chromatography of the crude
product on silica gel (CH2Cl2/CH3OH/NH4OH concentrated
95:5:0.1), pure (6)-20-cyanonicotine 3 was obtained as a color-
less oil (1.325 g, 7.08 mmol, 58%) as well as cis- and trans-
50-cyanonicotine 4 (0.274 g, 1.46 mmol, 12%) as a colorless
oil.
1H-NMR (300 MHz, CDCl3) 3: d 8.86 (d, 1 H, J ¼ 2.4 Hz,
ArH), 8.61 (dd, 1 H, J ¼ 1.8, 4.8 Hz, ArH), 7.90 (dt, 1 H, J ¼
8.1, 2.4 Hz, ArH), 7.34 (ddd, 1 H, J ¼ 8.1, 5.1, 0.9 Hz, ArH),
3.37 (m, 1 H), 2.71 (m, 1 H), 2.57 (m, 1 H), 2.25 (s, 3 H,
NCH3), 2.16–2.02 (m, 3 H). 13C-NMR (75.3 MHz, CDCl3): d
150.0 (CH), 148.0 (CH), 134.1 (CH), 133.9 (C), 123.5 (CH),
116.8 (CN), 69.7 (C), 53.8 (CH2), 43.1 (CH2), 36.2 (CH3),
21.1 (CH2). ESI-HRMS: m/z ¼ 188.1175 (calculated for [M þ
H]þ: 188.1182).
(6)-20-Methylnicotine (5). A solution of methylmagnesium
bromide (3M solution in ether, 445 lL, 1.335 mmol) was
added dropwise to a solution of 20-cyanonicotine 3 (50 mg,
0.27 mmol) in THF (2 mL) cooled to ꢀ10ꢁC. The mixture
was stirred at ꢀ10ꢁC for 1 h followed by 1 h at room tempera-
ture and then hydrolyzed by a saturated aqueous solution of
NH4Cl (5 mL). The mixture was extracted with methylene
chloride. The organic extracts were dried and evaporated to
give an oil, which was purified by flash chromatography on
silica gel (CH2Cl2/CH3OH/NH4OH concentrated 95:5:0.1) to
give (6)-20-methylnicotine 5 as a clear oil (45.2 mg, 0.26
mmol, 95%). 1H-NMR (300 MHz, CDCl3): d 8.71 (d, 1 H, J
¼ 1.5 Hz, ArH), 8.45 (dd, 1 H, J ¼ 1.8, 4.8 Hz, ArH), 7.81
(dt, 1 H, J ¼ 8.1, 1.8 Hz, ArH), 7.23 (ddd, 1 H, J ¼ 8.1, 5.1,
0.6 Hz, ArH), 3.11 (m, 1 H), 2.70 (m, 1 H), 2.12 (s, 3H,
NCH3), 1.90 (m, 4H) 1.34 (s, 3H, CH3). 13C-NMR (75.3 MHz,
CDCl3): d 148.6 (CH), 147.7 (CH), 143.0 (C), 134.2 (CH),
123.1 (CH), 64.1 (C), 53.4 (CH2), 43.3 (CH2), 34.9 (CH3),
22.0 (CH2), 16.9 (CH3). ESI-HRMS: m/z ¼ 177.1381 (calcu-
lated for [M þ H]þ: 177.1386); 353.2686 (calculated for [2M
þ H]þ: 353.2700).
(6)-20-Ethylnicotine (6). A solution of ethylmagnesium
bromide (1M solution in THF, 1.23 mL, 1.23 mmol) was
added dropwise to a solution of 20-cyanonicotine 3 (46 mg,
0.25 mmol) in THF (1 mL) cooled to ꢀ10ꢁC. The mixture
was stirred at ꢀ10ꢁC for 1 h then at room temperature for 16
h. After addition of a saturated aqueous solution of NH4Cl (3
mL), the mixture was extracted with methylene chloride. The
organic extracts were dried and evaporated to give an oil,
which was purified by flash chromatography on silica gel
(CH2Cl2/CH3OH/NH4OH concentrated 95:5:0.1) to give (6)-
1
20-ethylnicotine 6 as a clear oil (44 mg, 0.23 mmol, 92%). H-
Subsequently, the mixture of cis- and trans-50-cyanonicotine
4 was separated by HPLC with a Beckman Coulter Ultrasphere
silica column (10ꢂ 250 mm), using a 2% B to 20% B 25 min
gradient (solvent A: Hexane-DEA [99.5, 0.5 v/v]; solvent B:
EtOH-DEA [99.5, 0.5]), preceded by 10 min elution at 2% B.
The flow rate was 2.7 mL/min and column temperature was
24ꢁC. The eluate was monitored at 260 nm. In this way, trans-
50-cyanonicotine (4a, 182 mg, 8%) eluting at 17.8 min and
cis-50-cyanonicotine (4b, 91 mg, 4%) eluting at 25.7 min were
isolated.
NMR (300 MHz, CDCl3): d 8.55 (d, 1 H, J ¼ 2.7 Hz, ArH),
8.47 (dd, 1 H, J ¼ 1.8, 4.8 Hz, ArH), 7.59 (dt, 1 H, J ¼ 8.1,
2.1 Hz, ArH), 7.27 (ddd, 1 H, J ¼ 7.8, 5.1, 0.6 Hz, ArH), 2.92
(m, 1 H), 2.48 (m, 1 H), 2.27 (m, 2 H), 2.10 (s, 3 H, NCH3),
1.93 (m, 4 H), 1.60 (m, 1 H), 0.83 (t, 3 H, J ¼ 7.2 Hz). 13C-
NMR (75.3 MHz, CDCl3): d 149.3 (CH), 147.8 (CH), 136.6
(C), 135.3 (CH), 122.9 (CH), 67.6 (C), 53.9 (CH2), 36.7
(CH2), 35.1 (CH3), 29.1 (CH2), 22.0 (CH2), 10.0 (CH3). ESI-
HRMS: m/z ¼ 191.1548 (calculated for [M þ H]þ: 191.1543);
381.3008 (calculated for [2M þ H]þ: 381.3013).
1
trans-50-Cyanonicotine (4a). H-NMR (300 MHz, CDCl3):
(6)-20-n-Propylnicotine (7). A solution of n-propylmagne-
sium chloride (2M solution in ether, 334 lL, 0.67 mmol) was
added dropwise to a solution of 20-cyanonicotine 3 (25 mg,
0.13 mmol) in THF (1 mL) cooled to ꢀ10ꢁC. The mixture
was stirred at ꢀ10ꢁC for 1 h then at room temperature for 16
h. After addition of a saturated aqueous solution of NH4Cl (3
mL), the mixture was extracted with methylene chloride. The
organic extracts were dried and evaporated to give an oil,
which was purified by flash chromatography on silica gel
(CH2Cl2/CH3OH/NH4OH concentrated 95:5:0.1) to give (6)-
d 8.57 (d, 1 H, J ¼ 2.1 Hz, ArH), 8.54 (dd, 1 H, J ¼ 1.8, 4.8
Hz, ArH), 7.65 (dt, 1 H, J ¼ 8.1, 1.8 Hz, ArH), 7.29 (ddd, 1
H, J ¼ 8.1, 5.1, 0.9 Hz, ArH), 4.16 (d, 1 H, J ¼ 8.1 Hz), 3.59
(t, 1 H, J ¼ 7.2 Hz), 2.45 (m, 2 H), 2.30 (s, 3 H, NCH3), 2.19
(m, 1 H), 1.80 (m, 1 H). 13C-NMR (75.3 MHz, CDCl3): d
149.6 (CH), 149.5 (CH), 135.0 (CH), 134.1 (C), 123.9 (CH),
117.5 (CN), 65.4 (CH), 56.9 (CH), 36.8 (CH3), 33.4 (CH2),
28.7 (CH2). ESI-HRMS: m/z ¼ 188.1176 (calculated for [M þ
H]þ: 188.1182).
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Racemic Synthesis of 20-Substituted Nicotine Analogs
165
20-n-propylnicotine 7 as a clear oil (25 mg, 0.12 mmol, 94%).
1H-NMR (300 MHz, CDCl3): d 8.54 (d, 1 H, J ¼ 2.1 Hz,
ArH), 8.46 (dd, 1 H, J ¼ 1.5, 4.8 Hz, ArH), 7.57 (dt, 1 H, J ¼
8.1, 1.8 Hz, ArH), 7.26 (ddd, 1 H, J ¼ 8.1, 4.8, 0.6 Hz, ArH),
2.89 (m, 1 H), 2.47 (m, 1 H), 2.21 (m, 2 H), 2.10 (s, 3 H,
NCH3), 1.99 (m, 3 H), 1.52 (td, 1 H, J ¼ 5.1, 12.0 Hz), 1.20
(m, 2 H), 0.93 (t, 3 H, J ¼ 7.2 Hz). 13C-NMR (75.3 MHz,
CDCl3): d 149.3 (CH), 147.8 (CH), 137.0 (C), 135.2 (CH),
122.9 (CH), 67.1 (C), 53.7 (CH2), 39.1 (CH2), 37.3 (CH2),
35.2 (CH3), 22.2 (CH2), 19.0 (CH2), 15.1 (CH3). ESI-HRMS:
m/z ¼ 205.1695 (calculated for [M þ H]þ: 205.1699).
bined organic extracts were dried over MgSO4 and concen-
trated in vacuo. The crude mixture was purified by flash
chromatography on silica gel (CH2Cl2/CH3OH/NH4OH con-
centrated 95:5:0.1) to give (6)-20-carbamoylnicotine 10 as a
yellow solid (50 mg, 0.24 mmol, 51%). 1H-NMR (300
MHz, CDCl3): d 8.54 (d, 1 H, J ¼ 2.1 Hz, ArH), 8.51
(dd, 1 H, J ¼ 1.2, 4.8 Hz, ArH), 7.59 (dt, 1 H, J ¼ 7.8,
2.1 Hz, ArH), 7.48 (bs, 1H), 7.29 (ddd, 1 H, J ¼ 8.1, 4.8,
0.9 Hz, ArH), 6.58 (bs, 1H), 3.11 (m, 1 H), 2.56 (m, 3
H), 2.03 (m, 2 H), 1.99 (s, 3 H, NCH3). 13C-NMR (75.3
MHz, CDCl3): d 177.8 (C), 149.8 (CH), 148.6 (CH), 136.4
(CH), 133.7 (C), 122.8 (CH), 73.7 (C), 54.9 (CH2), 38.7
(6)-20-Aminomethylnicotine (8). A solution of 20-cyanoni-
cotine 3 (324 mg, 1.73 mmol) in toluene (12.4 mL) was
treated at ꢀ78ꢁC with DIBALH (8.65 mL of a 1.0M solution
in hexane, 8.65 mmol). After the reaction mixture had been
stirred for an additional 3 h at ꢀ78ꢁC, it was quenched by
slow addition of a saturated aqueous solution of NH4Cl. The
resulting mixture was allowed to warm to room temperature.
The organic layer was separated, and the aqueous layer was
extracted with methylene chloride. The combined organic
extracts were dried over MgSO4 and concentrated in vacuo.
The crude mixture was purified by flash chromatography on
silica gel (CH2Cl2/CH3OH/NH4OH concentrated 95:5:0.1) to
give (6)-20-aminomethylnicotine 8 as a clear oil (195.1 mg,
1.02 mmol, 59%) as well as nicotine (11 mg, 0.07 mmol, 4%).
1H-NMR (300 MHz, CDCl3): d 8.60 (d, 1 H, J ¼ 2.7 Hz,
ArH), 8.48 (dd, 1 H, J ¼ 1.8, 4.8 Hz, ArH), 7.64 (dt, 1 H, J ¼
8.1, 1.8 Hz, ArH), 7.28 (ddd, 1 H, J ¼ 8.1, 4.8, 0.9 Hz, ArH),
3.21 (d, 1 H, J ¼ 12.9 Hz), 3.03 (d, 1 H, J ¼ 12.9 Hz), 3.00
(m, 1 H), 2.74 (m, 1 H), 2.18 (m, 2 H), 2.17 (s, 3 H, NCH3),
1.93 (m, 2 H), 1.32 (bs, 2 H, NH2). 13C-NMR (75.3 MHz,
CDCl3): d 149.1 (CH), 148.0 (CH), 138.3 (C), 135.0 (CH),
123.2 (CH), 68.0 (C), 54.8 (CH2), 46.5 (CH2), 36.5 (CH2),
35.5 (CH3), 22.5 (CH2). ESI-HRMS: m/z ¼ 192.1490 (calcu-
lated for [M þ H]þ: 192.1495).
(CH2), 37.4 (CH3), 23.0 (CH2). ESI-HRMS: m/z
¼
206.1283 (calculated for [M þ H]þ: 206.1288); 411.2495
(calculated for [2M þ H]þ: 411.2503).
Acknowledgments. Support of this research by the Florida Bio-
medical Program (BM013) and the National Institutes of Health
(5RO1MH61412) is gratefully acknowledged. We thank the
Mass Spectrometry Laboratory at the University of Florida for
recording the mass spectra and Dr. Ferenc Soti for his comments
on the manuscript.
REFERENCES AND NOTES
[1] Newhouse, P. A.; Sunderland, Y.; Tariot, P. N.; Blumhardt,
C. L.; Weingartner, H.; Mellow, A. Psychopharmacology 1988, 95,
171.
[2] Freedman, R.; Hall, M.; Adler, L. E.; Leonard, S. Biol Psy-
chiatry 1995, 38, 22.
[3] Freedman, R.; Olincy, A.; Buchanan, R. W.; Harris, J. G.;
Gold, J. M.; Johnson, L.; Allensworth, D.; Guzman-Bonilla, A. G.;
Bettye, B. A.; Clement, M. S. W.; Ball, M. P.; Kutnick, C. J.; Pender,
V.; Laura F.; Martin, L. F.; Stevens, K. M.; Wagner, B. D.; Zerbe, G.
O.; Soti, F.; Kem, W. R. Am J Psychiat 2008, 165, 1040.
[4] Taly, A.; Corringer, P.-J.; Guedin, D.; Lestage, P.;
Changeux, J.-P. Nat Rev Drug Discov 2009, 8, 733.
[5] Benowitz, N. L. N Engl J Med 2010, 362, 2295.
[6] Rollema, H.; Coe, J. W.; Chambers, L. K.; Hurst, R. S.;
Stahl, S. M.; Williams, K. E. Trends Pharmacol Sci 2007, 28, 316.
[7] Wang, D. X.; Booth, H.; Lerner-Marmarosh, N.; Osdene, T.
S.; Abood, L. G. Drug Development Res 1998, 45, 10.
[8] Peterson, L. A.; Trevor, A.; Castagnoli, N., Jr. J Med Chem
1987, 30, 249.
(6)-20-Hydroxymethylnicotine (9). A solution of 8 (51 mg,
0.27 mmol) in 50% aqueous acetic acid (2 mL) was treated
with NaNO2 (37 mg, 0.54 mmol), and the resulting mixture
was stirred at room temperature for 24 h. The reaction mixture
was then basified with 40% aqueous NaOH and extracted with
methylene chloride. The organic extract was treated with a so-
lution of 5% KOH/MeOH (5 mL) for 4 h. The reaction mix-
ture was washed with water, and the organic layer was concen-
trated in vacuo. Chromatographic purification (SiO2, elution
with CH2Cl2/CH3OH/NH4OH concentrated 95:5:0.1) of the
[9] Hubert-Brierre, Y.; Herlem, D.; Khuong-Huu, F. Tetrahe-
dron 1975, 31, 3049.
residue afforded (6)-20-hydroxymethylnicotine
9 (18 mg,
[10] Lin, N. H.; Carrera, G. M., Jr.; Anderson, D. J. J Med
Chem 1994, 37, 3542.
0.095 mmol, 35%) as a colorless oil. 1H-NMR (300 MHz,
CDCl3): d 8.55 (d, 1 H, J ¼ 2.4 Hz, ArH), 8.49 (dd, 1 H, J ¼
1.5, 4.5 Hz, ArH), 7.59 (dt, 1 H, J ¼ 8.4, 1.8 Hz, ArH), 7.28
(ddd, 1 H, J ¼ 8.1, 4.8, 0.9 Hz, ArH), 3.97 (d, 1 H, J ¼ 10.5
Hz), 3.79 (d, 1 H, J ¼ 10.5 Hz), 3.16 (m, 1 H), 2.88 (m, 1 H),
2.39 (m, 1 H), 2.14 (s, 3 H, NCH3), 1.95 (m, 3 H). 13C-NMR
(75.3 MHz, CDCl3): d 148.7 (CH), 148.3 (CH), 138.4 (C),
134.7 (CH), 123.3 (CH), 67.6 (C), 63.0 (CH2), 55.3 (CH2),
36.7 (CH2), 35.2 (CH3), 22.7 (CH2). ESI-HRMS: m/z ¼
193.1330 (calculated for [M þ H]þ: 193.1335); 385.2585 (cal-
culated for [2M þ H]þ: 385.2598).
[11] Cushman, M.; Castagnoli, N., Jr. J Org Chem 1972, 37,
1268.
[12] Ennifar, S. PCT Int Appl WO 064,478 A2 0607 (2007).
[13] Pozdnev, V. F. Tetrahedron Lett 1995, 36, 7115.
[14] Bachmann, M. F.; Maurer, P. PCT Int Appl WO 009,116
A2 0129 (2004).
[15] Pierce, J. H.; Richards, H. C.; Shoppee, C. W.; Stephenson,
R. J.; Summers, G. H. R. J Chem Soc 1955, 694.
[16] Czarnocki, Z.; Suh, D.; MacLean, D. B.; Hultin, P. G.;
Szarek, W. A. Can J Chem 1992, 70, 1555.
(6)-20-Carbamoylnicotine (10). A solution of 20-cyanoni-
cotine 3 (89 mg, 0.48 mmol) in 4 mL of a solution TFA/con-
centrated H2SO4 (4:1) was stirred at 50ꢁC for 20 h. After
cooled at 0ꢁC, the mixture was basified by addition of NH4OH
concentrated and extracted with methylene chloride. The com-
[17] Arai, T.; Abe, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron
Lett 2004, 45, 5921.
[18] Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods,
M. F.; Salzmann, T. N.; Christensen, B. G. J Med Chem 1987,
30, 871.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A. Rouchaud and W. R. Kem
Vol 49
[19] Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais,
[23] Frances, B.; Gouarderes, C.; Moisand, C.; Cros, J.; Jimonet,
P.; Moy, L.; Chiaroni, A.; Riche, C.; Grierson, D. S.; Husson, H. P.
Eur J Med Chem 1992, 27, 369.
F.; Queguiner, G. Tetrahedron Lett 1999, 40, 4339.
[20] Heer, J. P.; Harling, J. D.; Thompson, M. Synth Commun
2002, 32, 2555.
[24] Rouchaud, A.; Braekman, J.-C. Eur J Org Chem 2009,
2666.
[21] Amato, J. S.; Chung, J. Y. L.; Cvetovich, R. J.; Gong, X.;
McLaughlin, M.; Reamer, R. A. J Org Chem 2005, 70, 1930.
[22] Rouchaud, A.; Kem, W. R. J Heterocycl Chem 2010, 47,
569.
[25] Grierson, D. S.; Harris, M.; Husson, H. P. J Am Chem Soc
1980, 102, 1064.
[26] Grierson, D. S. Org React 1990, 39, 85.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet