An improved synthesis of β-Nicotyrine from the dehydrogenation of nicotine: Comparison of conventional and microwave-assisted reactions

Article abstract of DOI:10.1081/SCC-120023988

β-Nicotyrine, a minor tobacco alkaloid, can be rapidly prepared in good yield from the dehydrogenation of S-(-)-nicotine over MnO₂ with microwave irradiation. This method is superior to dehydrogenation reactions that utilize S-(-)-nicotine and MnO₂ in a variety of solvents under reflux.

Full text of DOI:10.1081/SCC-120023988

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An Improved Synthesis of β-Nicotyrine from the
Dehydrogenation of Nicotine: Comparison of
Conventional and Microwave-Assisted Reactions
a
a
Xiaochen Wei & Peter A. Crooks
a
Department of Pharmaceutical Sciences , College of Pharmacy , University of Kentucky ,
Lexington, Kentucky, USA
Published online: 15 Aug 2006.
To cite this article: Xiaochen Wei & Peter A. Crooks (2003) An Improved Synthesis of β-Nicotyrine from the Dehydrogenation
of Nicotine: Comparison of Conventional and Microwave-Assisted Reactions, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 33:19, 3305-3315
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 19, pp. 3305–3315, 2003
An Improved Synthesis of b-Nicotyrine
from the Dehydrogenation of Nicotine:
Comparison of Conventional and
Microwave-Assisted Reactions
Xiaochen Wei and Peter A. Crooks*
Department of Pharmaceutical Sciences,
College of Pharmacy, University of Kentucky,
Lexington, Kentucky, USA
ABSTRACT
b-Nicotyrine, a minor tobacco alkaloid, can be rapidly prepared in
good yield fromthe dehydrogenation of S-(-)-nicotine over MnO
with microwave irradiation. This method is superior to dehydrogena-
2
2
tion reactions that utilize S-(-)-nicotine and MnO in a variety of
solvents under reflux.
Key Words: b-Nicotyrine; Nicotine; Dehydrogenation; Microwave
irradiation.
*
Correspondence: Peter A. Crooks, Department of Pharmaceutical Sciences,
College of Pharmacy, University of Kentucky, 800 Rose Street, Lexington,
Kentucky 40536-0082, USA; Fax: 859-257-7585; E-mail: pcrooks@uky.edu.
3
305
DOI: 10.1081/SCC-120023988
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3
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Wei and Crooks
INTRODUCTION
b-Nicotyrine was first isolated as a minor alkaloid from the leaves of
Nicotiana tabacum plants and from cigarette smoke condensate almost a
[1]
hundred years ago. The biosynthetic pathway for the formation of this
alkaloid in the plant is still not fully understood, and it is likely that
b-nicotyrine is formed from the exposure of S-(-)-nicotine to sunlight,
[
2]
during the curing of tobacco leaves. b-Nicotyrine may also be formed
during the combustion of cigarettes, as a pyrrolytic product in cigarette
[3]
smoke. The presence of b-nicotyrine in environmental tobacco smoke
[
4,5]
and waste water has also been reported.
One report has proposed that
[
6]
b-nicotyrine is a metabolite of nicotine. The metabolism of b-nicotyrine
has been thoroughly investigated, not only because of its toxicity, but
also because of the toxic properties of some of its metabolic intermedi-
[7,8,9]
ates.
Many different synthetic approaches to the preparation of
b-nicotyrine have been reported. They can be classified into three different
strategies: (a) linking of the pyridine and pyrrole rings, e.g., by the
reaction of 1-methyl-2-pyrrolyl-zinc chloride with 3-bromopyridine in
[
10]
the presence of PdCl (dppd) as a catalyst; (b) pyrrole ring formation on
2
[
11–14]
a pyridino precursor molecule,
isoxazole-pyrrole rearrangement reaction,
dioxo-1-(pyridin-3-yl)butane with methylamine in aqueous methanol,
e.g., utilization of the 2,3-dihydro-
[
11,13]
or by the treatment of 1,4-
[
12]
[
14]
or under the catalysis of acidic Amberlyst resin; and (c), by the
0
dehydrogenation of S-(-)-nicotine or 3 ,4 -dehydronicotine over a variety
0
of catalysts (Fig. 1). This latter approach was the initial method utilized by
[
15]
Pictet for the preparation of b-nicotyrine using AgO as catalyst.
Because of the low cost and availability of S-(-)-nicotine, a number of
different catalysts have been utilized for the preparation of b-nicotyrine
fromthe dehydrogenation of S-(-)-nicotine. For example, in addition to
[
16]
AgO, other dehydrogenation reagents, such as platinum-on-asbestos,
N
N
dehydrogenation
CH3
CH3
N
N
S-(-)-Nicotine
β−Nicotyrine
Figure 1. Dehydrogenation of nicotine.

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b-Nicotyrine
3307
Leiten ueber quartz at 570 C, hydrous zirconium
[17]
ꢀ
[18]
palladiumblack,
ꢀ
[19]
oxide at 500 C, palladium-asbestos at 230–280 C,
ꢀ
[20,21]
[22]
V O , have
2 5
been used, many of these dehydration reactions require very high
temperatures. Also, photo-oxidation of nicotine to b-nicotyrine in the
[
23]
presence of 9,10-dicyanoanthracene or TiO2
nicotyrine fromthe reaction of a dilute solution of S-(-)-nicotine in
or the preparation of b-
[
24]
benzene with benzophenone has been reported.
Although these
dehydrogenation methods are the most direct methods of synthesis of
b-nicotyrine, the reaction conditions usually are very harsh, and often
require high temperatures, gas phase reactions, and expensive catalysts.
In addition, generally, only low to moderate yields at best are obtained.
In the search for a more facile and practical method for the efficient
dehydrogenation of S-(-)-nicotine to b-nicotyrine, we considered MnO2
as a potential candidate. Manganese dioxide is a very versatile oxidant,
and is often utilized in the oxidation of alcohols to carbonyl compounds
under relatively mild conditions. More importantly, Bonnaud and
[
25]
Bigg
over MnO in refluxing THF in yields ranging from0–72%. In addition,
have reported the dehydrogenation of pyrrolidine derivatives
2
microwave irradiation has been used in such organic reactions to increase
[
26,27]
yields and shorten reaction times. Application of this technique to
the preparation of pyrroles fromthe corresponding pyrrolidine precursor
[
28]
has also been reported.
In this communication, we report on the
MnO -catalyzed dehydrogenation of S-(-)-nicotine to b-nicotyrine both
2
in refluxing solvents and under microwave irradiation.
EXPERIMENTAL
1
H NMR spectra were recorded on a Varian 300 MHz NMR spectro-
meter. All spectra were referenced and chemical shifts determined using
tetramethylsilane (TMS) as the internal standard. Mass spectra were
obtained on an Agilent 6890 GC incorporating an Agilent 7683 auto-
sampler and an Agilent 5973 MSD (Agilent Technologies, Willmington,
DE) interfaced to a Hewlett-Packard KAYAK XM600 computer
(Hewlett-Packard Co., Palo Alto, CA) with MSD Productivity Chem-
Station Software (Rev. C.00.01) (Agilent Technologies, Palo Alto, CA)
for analysis and data processing. An HP-5MS GC column (30 m Â
0
.25 mm I.D. Â 0.25 mmfilmthickness) (Agilent Co., Willmington, DE)
was utilized for analyses, with ultra pure heliumas carrier gas at a flow
rate of 1.0 mL/min and an average velocity of 38 cm/s in constant flow
mode. The temperature at the injection port, MS interface, electron
impact source, and mass filter was set constant at 280, 280, 230,

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308
Wei and Crooks
ꢀ
ꢀ
and 150 C, respectively. The oven temperature was initially set at 120 C
ꢀ
ꢀ
ꢀ
and increased to 160 C at the rate of 10 C/min; after holding at 160 C for
ꢀ
one minute, the oven temperature was increased to 275 C at the rate of
ꢀ
6
0 C/min and held at this temperature for 10 min, to elute possible high
boiling point interfering impurities. The MS analyzer was set in the scan
mode. A domestic microwave oven (Samsung, 1200 W) was used for all
microwave irradiation reactions, and a Branson sonicator (Shelton, CT)
operating at 50–60 Hz and 1 amp was used in sonications.
S-(-)-Nicotine and all organic solvents were purchased fromAldrich
Milwaukee, WI). Silica gel (for general column chromatography use,
0–200 mesh) and active MnO were obtained fromFisher Scientific
(
6
2
(
Pittsburgh, PA) and Fluka (Milwaukee, WI), respectively.
Oxidation of Nicotine over MnO in Refluxing Xylene
2
S-(-)-Nicotine (1.62 g, 10 mmol) was refluxed in xylene (50 mL) with
active MnO (8 g, 92 mmol) for 5 h. The reaction mixture was filtered
2
through Celite, and the filtrate was washed with 0.1 N HCl (2 Â 10 mL).
After the evaporation of the xylene under vacuum, the brownish oily
residue was purified by silica gel column chromatography using
CH Cl -CH OH (99:1) as eluent to afford b-nicotyrine (0.60 g, yield
2
2
1
3
3
8%). H-NMR (CDCl ): ꢀ 3.65 (3H, s), 6.23–6.25 (1H, m), 6.29–6.31
3
(
8
(
1H, m), 6.77–6.78 (1H, t), 7.30–7.35 (1H, m), 7.69–7.73 (1H, m),
þ
.52–8.54 (1H, m), and 8.69–8.70 (1H, m). MS: m/z 158 (M , 100), 159
þ
MH , 11), 157 (53), 143 (4.5), 130 (20), 116 (9.3), 89 (8.3), 78 (5.4).
Oxidation of Nicotine over MnO /Silica Gel in
2
Xylene in the Presence of Air
A xylene solution (50 mL) of S-(-)-nicotine (1.62 g, 10 mmol) con-
taining MnO (7 g, 80 mmol) ground to a fine powder with silica gel in
2
a mortar (13 g) was refluxed for 1.5 h while bubbling a stream of air
through the reaction mixture. The mixture was cooled, filtered, and the
filtrate was recovered. The dark-colored precipitate was sonicated
(
The xylene and CHCl filtrates were combined and evaporated to dryness
3 Â 10 min) in CHCl (3 Â 50 mL), and the resulting mixture filtered.
3
3
under reduced pressure. The brownish oily residue was purified by silica
gel column chromatography using CH Cl -CH OH (99:1) as eluent to
2
2
3
afford b-nicotyrine (0.71 g, yield 45%). The NMR and MS spectra were
identical to authentic b-nicotyrine.

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b-Nicotyrine
3309
Microwave-Assisted Dehydrogenation of
Nicotine over MnO /Silica Gel
2
A dry mixture of S-(-)-nicotine (1.62 g, 10 mmol) and MnO (7 g,
2
80 mmol) was ground to a fine powder with silica gel (13 g) with a
mortar and a pestle, and the mixture was irradiated in a microwave
oven for 3 min. After cooling, the irradiated mixture was then repeatedly
sonicated in CHCl (3 Â 50 mL). The combined CHCl solutions were
3
3
evaporated to dryness under vacuum. The resulting brownish oily residue
was purified by silica gel column chromatography using CH Cl –CH OH
2
2
3
(
99:1) as eluent to afford b-nicotyrine (1.19 g, yield 75%). The NMR and
MS spectra were identical to those of an authentic sample of b-nicotyrine.
RESULTS AND DISCUSSION
[
29,30]
After its introduction in 1946,
MnO (manganese dioxide) was utilized extensively in the oxidation of
active or freshly precipitated
2
a variety of organic compounds. Due to its high selectivity and mild
reaction conditions, MnO is often the first choice for the oxidation of
2
primary or allylic alcohols to the corresponding carbonyl compounds. A
variety of solvents have been utilized in such oxidation reactions, i.e.,
saturated hydrocarbons, benzene, toluene, chloroform, methylene chlo-
ride, diethyl ether, THF, acetone, ethyl acetate, DMSO, DMF, glacial
acetic acid, pyridine, and acetonitrile. According to Bonnaud and
[25]
Bigg,
THF is a suitable solvent for the dehydrogenation of pyrroli-
dines to pyrroles, affording yields around 70%. However, when THF was
used as solvent in the oxidation of nicotine to b-nicotyrine in our hands,
the yield was consistantly below 30%. Chloroform, benzene, water,
toluene, pyridine, methylene chloride, diethyl ether, acetonitrile, acetone,
and xylene, were also utilized as solvents in this reaction, with the best
yield obtained being only 38%, when refluxing in xylene for 5 h.
Longer reaction times (e.g., 60 h) did not lead to an increase in yield.
On monitoring the reaction by GC/MS, b-nicotyrine was observed to be
the only reaction product together with unreacted nicotine. After 5 h
reflux, the peak area ratio of nicotine to b-nicotyrine reached 1 to 1,
and did not change after longer refluxing times.
Silica gel utilized in column chromatography usually has a very large
surface area, for example, 60–200 mesh silica gel has a surface area
2
around 800 m /g.
[31]
This matrix can be effectively utilized to embed
reactant(s) on the surface of the silica gel, leading to an increase in surface
area and a considerable increase in reaction rate. The most convenient

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Wei and Crooks
procedure for embedding MnO onto the surface of silica gel is to grind a
2
mixture of these two solids in a mortar to a very fine powder. This
32]
[
procedure is known as ‘‘doping’’.
There is evidence to suggest that molecular oxygen may be involved
[
33]
in dehydrogenations catalyzed by MnO2.
the ‘‘doping’’ process with an aeration methodology and modified the
Accordingly, we combined
procedure as follows. MnO was doped onto silica gel by grinding the
2
two solids to a very fine powder in a mortar. Nicotine free base was then
added to the solid mixture. The resulting mixture was ground for a few
more minutes, and transferred to a round-bottomed flask containing
xylene. The mixture was heated under reflux for 5 h. After work-up,
the yield of b-nicotyrine was increased from38% to over 40%.
Monitoring the reaction by GC/MS showed most of nicotine disappeared
after 5 h and only one product, b-nicotyrine, was observed on the total
ion chromatogram. Because of the high adsorption activity of the large
surface of silica gel, both the reactant and product(s) could be adsorbed
very tightly on the surface. This could be one of the reasons for the low
yield in spite of the fact that most of the nicotine has disappeared.
Sonication has been used for desorption of organic compounds from
[34,35]
silica gel.
Thus, the dark-colored solids resulting fromfiltration of
the xylene mixture were sonicated in chloroform, and the chloroform
solution was analyzed by the GC/MS. b-Nicotyrine accounted for 54%
of the total peak area (Fig. 2); however, several other components were
0
also present, and were identified as: N -formylnornicotine (26%); cotinine
(
9%); 3-(pyrrol-2-yl)pyridine or b-nornicotyrine (8%); N-methylnicotina-
mide (2.8%) and a trace amount of unreacted nicotine. The isolated
yield for b-nicotyrine was 45% after combining xylene filtrate and the
chloroformextracts and fractionating the imx ture by silica gel
chromatography. Since only trace amounts of nicotine are left, the low
yield apparently is due to the oxidation of nicotine to the other four
by-products.
Application of microwave irradiation in organic synthesis was first
26]
[
reported in the mid-1980s (
then, this technique has become very popular in preparative organic
and the references cited therein). Since
[27]
synthesis (
and the references cited therein). In 1999 alone, approxi-
mately 700 publications on the application of microwave irradiation in
organic synthesis were cited. This increase in popularity stems mainly
from the demand for shorter reaction times. In addition, the development
of solvent-free techniques, which also shortens purification times,
has contributed significantly to the increased use of microwave-assisted
or ‘‘accelerated’’ organic reactions. Microwave-assisted dehydrogenation
[
28]
of pyrrolidine derivatives over MnO2 has been reported,
but no

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b-Nicotyrine
3311

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b-Nicotyrine
3313
comparisons have been made between standard dehydrogenation
reactions in solution and microwave-assisted solvent-free methodologies.
In this study, we obtained b-nicotyrine in 75% yield after a 3-min
microwave irradiation of nicotine ‘‘doped’’ on a mixture of MnO and
2
silica gel, prepared as described above with sonication-assisted work-up
and separation. The chloroformextracts obtained after sonication were
analyzed by GC/MS (Fig. 3). A small amount (6.5%) of nicotine
remained in the reaction mixture; however, only trace amounts of
0
b-nornicotyrine, cotinine, and N -formylnornicotine were detected (less
than 5% total). Longer microwave irradiation times did not improve the
yield of b-nicotyrine, and no dehydrogenation product could be detected
when the reaction was carried out in the absence of MnO2.
SUMMARY
b-Nicotyrine has been prepared fromthe dehydrogenation of
nicotine over MnO in refluxing xylene and also by a microwave-assisted
2
technique. Superior yields (ꢁ75%) were obtained by the microwave-
assisted technique in much shorter reaction times when compared to
the yields obtained in refluxing xylene in the presence of MnO2.
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Received in the USA April 3, 2003

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