A new approach to nicotine: Symmetry consideration for synthesis design

Article abstract of DOI:10.1002/hlca.200490241

A synthesis of nicotyrine (9), and hence formally racemic nicotine, was carried out by elaboration of the 1:1 adduct 2 of cycloocta-1,5-diene and chlorosulfonyl isocyanate (CISO₂-NCO). Transformation of adduct 2 into carbamate 4 was followed by ozonolysis, tosylation, and NaH treatment, which led to pyrrolidinylpiperidinone 6. LiAIH₄ Reduction, debenzylation, and aromatization yielded 2.

Full text of DOI:10.1002/hlca.200490241

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Helvetica Chimica Acta Vol. 87 (2004)
A New Approach to Nicotine: Symmetry Consideration for Synthesis Design
by Tse-Lok Ho* and Eugene V. Kuzakov
Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan, Republic of China
(e-mail: tlho@cc.nctu.edu.tw)
A synthesis of nicotyrine (9), and hence formally racemic nicotine, was carried out by elaboration of the
1:1 adduct 2 of cycloocta-1,5-diene and chlorosulfonyl isocyanate (ClSO2ÀNCO). Transformation of adduct 2
into carbamate 4 was followed by ozonolysis, tosylation, and NaH treatment, which led to pyrrolidinylpiper-
idinone 6. LiAlH4 Reduction, debenzylation, and aromatization yielded 2.
Nicotine (1) is widely occurring in the plant kingdom and a most well-known
member of alkaloids [1]. It is the addictive constituent of tobacco and, therefore, its
effects are directly related to the socioeconomic issue of tobacco smoking, although
scientific evidence has exonerated the carcinogenic role for nicotine1). Historically
significant is the fact that Pictet and Rotschy at the University of Geneva described the
first synthesis of (Æ)-nicotine in 1904 via nornicotyrine, which arose from pyrolysis of 1-
(pyridin-3-yl)-1H-pyrrole [2]. This key step is now regarded as involving a [1,5]-
sigmatropic rearrangement that achieved the bonding reorganization (N-to-C shift of
the pyridin-3-yl group followed by C-to-N move of an H-atom) [3]. Practically all the
later syntheses started from pyridine derivatives in which a C-substituent is located at
C(3) [4] (an exception is a biomimetic route [5]; for a preparation of nicotyrine from 3-
iodopyridine, see [5b]).
Our interest in a synthesis of nicotine stemmed from an analysis of bond
connectivity in relation to hidden symmetry elements [6]. It was noted that an
intermediate containing a 1,8-diaminooct-4-ene unit or some modifications thereof (see
Fig. 1) would be viable because simultaneous addition of a single C-chain and one of
the N-atoms to the CˆC bond would provide all the skeletal atoms of nicotine.
Regioselectivity in the addition is not an issue because of the inherent molecular
symmetry that is exhibited by the oct-4-ene derivative (see Fig. 2).
Fig. 1. Assembly mode of Nicotiana alkaloids
1
)
Nornicotine is a probable carcinogen due to its transformation into an N-nitrosamine derivative.
Interestingly, it shows promise in alleviating Alzheimer×s disease.
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

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Fig. 2. Assembly mode evolved from Fig. 1
Further consideration of the scheme led to a refinement. As a result, we decided to
develop a route starting with cycloocta-1,5-diene. Not only the starting material fulfills
our symmetry consideration, but the 1:1-adduct 2 (RˆSO2Cl) of cycloocta-1,5-diene
and chlorosulfonyl isocyanate (ClSO2ÀNCO) that we require is a known compound
[7]. Accordingly, our work began by aminolysis of 2 (RˆH) with benzylamine. The
ring opening with benzylamine afforded b-aminoamide 3 that was subsequently
protected by reaction with methyl carbonochloridate. Ozonolysis of carbamate 4
followed by a reductive workup with NaBH4 yielded diol 5. One of the CH2OH centers
is separated from the N-atoms by four and six bonds, while the other CH2OH center is
related to both N-atoms by five bonds. Activation of both OH groups of 5 to induce
twofold intramolecular N-alkylations may lead to a fused diazabicyclo[5.4.0]undecane
or hexahydronicotine derivative 6. We were quite confident that the second cyclization
would proceed rapidly to give a pyrrolidine product hence that our expectation of a

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nicotine synthesis would be achievable. Therefore, tosylation of diol 5 was carried out.
As partial cyclization of the ditosylate already occurred, we treated the crude product
mixture with NaH to complete the formation of 6. While lactam 6 was obtained as a
diastereoisomer mixture due to epimerization of the ditosylate prior to or during
cyclization, it should be emphasized that the alternative mode of cyclization was not
observed.
At this stage, we attempted to transform the piperidinone moiety of 6 into a
pyridin-2(1H)-one. Due to unsatisfactory direct dehydrogenation or transformations
involving a-halogenation and dehydrohalogenation, we next reduced 6 with LiAlH4 to
N-benzylhexahydronicotine (7) [8]. Hydrogenolysis of 7 furnished hexahydronicotine
(8) [7] but its partial aromatization was technically tricky. Total dehydrogenation to
afford nicotyrine (9) was accomplished by heating with Se powder. This represents a
formal synthesis of nicotine as the selective reduction of the pyrrole ring is known
[1][9].
In summary, we report a new route to the nicotine alkaloids based on symmetry
consideration, proceeding via the same intermediate as described in the pioneering
work of Pictet and Rotschy [2] on its centenary.
We thank the National Science Council of ROC for financial support.
Experimental Part
General. Column chromatography (CC): Merck silica-gel (63 200 mesh). TLC: Merck silica-gel 60 F 254
.
plates. M.p.: uncorrected; Laboratory Devices. IR Spectra: Bio-Rad FTS 165; nÄ in cmÀ1 1H-and 13C-NMR
Spectra: Varian Unity-300; CDCl3 as solvent unless otherwise indicated; d in ppm, J in Hz. EI-MS: Trio-2000
and Jeol SX-102A; ionization potential 70 eV.
8-Amino-N-benzylcyclooct-4-ene-1-carboxamide (3). Benzylamine (9.0 g, 84 mmol) was mixed with a soln.
of lactam 2 (10.6 g, 70 mmol) in dry toluene (60 ml), and the mixture was refluxed under N2 for 36 h. The cooled
mixture was evaporated, and the residue was subjected to distillation at <1408/1 Torr to remove excess
benzylamine. The remaining viscous oil (15.5 g) was directly used for derivatizing into the carbamate. For
characterization, a portion of this oil was shaken with a sufficient amount of 6n HCl, and the aq. phase was
washed twice with CH2Cl2, basified with 10% NaOH soln. to pH 10 and extracted with CH2Cl2. The combined
org. extract was dried (Na2SO4) and evaporated: 3. Yellow oil. IR: 3416 (NÀH), 2932 (CÀH), 1644 (CˆO).
1H-NMR: 1.65 2.27 (m, 8 H); 2.49 (m, 1 H); 3.29 (m, 1 H); 4.33 (d, J ˆ 5.4, 2 H); 5.53 (dm, J ˆ 10.5, 1 H); 5.66
(dm, J ˆ 10.5, 1 H); 7.17 7.27 (m, 5 H); 8.01 (br., NH). 13C-NMR: 23.27 (t); 24.65 (t); 28.14 (t); 36.14 (t); 42.68
(t); 47.23 (d); 51.57 (d); 126.88 (d); 127.23 (2C, d); 128.30 (2C, d); 128.86 (d); 130.98 (d); 138.74 (s); 176.47 (s).
.
‡
EI-MS: 258 (12, M ), 162 (13), 162 (17), 124 (19), 123 (25), 107 (12), 106 (38), 97 (18), 96 (18), 91 (100). HR-
.
‡
MS: 258.1727 (C16H22N2O ; calc. 258.1733).
{8-[(Benzylamino)carbonyl]cyclooct-4-en-1-yl}carbamic Acid Methyl Ester (4). A stirred soln. of crude 3
(15.0 g), pyridine (5.1 g), and N,N-dimethylpyridin-4-amine (DMAP; 0.05 g) in dry CH2Cl2 (50 ml) was cooled
to 08 and treated with a soln. of methyl carbonochloridate (6.04 g in 15 ml of dry CH2Cl2) via dropwise addition
during 20 min. Stirring was continued for 2 h at 08 and 3 h at r. t. Then the mixture was poured into cold H2O
(100 ml). The aq. phase was washed with CH2Cl2 (20 ml), the combined org. soln. washed twice with cold H2O,
dried (Na2SO4), and evaporated, and the crude product chromatographed (SiO2, AcOEt/hexane 4 :6): 4 (10.6 g,
48% over 2 steps). IR: 3315 (NÀH), 2945 (CÀH), 1698, 1657 (CˆO). 1H-NMR: 1.66 2.34 (m, 8 H); 2.68 (m,
1 H); 3.52 (s, 3 H); 4.16 (m, 1 H); 4.31 (d, J ˆ 5.4, 2 H); 5.45 (d, J ˆ 8.1); 5.58 (m, 2 H); 5.65 (m, 2 H); 7.15 7.25
(m, 5 H). 13C-NMR: 22.69 (t); 25.59 (t); 27.83 (t); 33.15 (t); 43.01 (t); 48.50 (d); 50.57 (d); 51.88 (q); 126.90 (d);
.
‡
127.21 (2C, d); 128.24 (2C, d); 129.83 (d); 130.06 (d); 138.33 (s); 156.54 (s); 174.45 (s). EI-MS: 316 (16, M ), 288
(11), 162 (46), 149 (14), 128 (16), 108 (15), 107 (18), 106 (100), 91 (90), 79 (17). HR-MS: 316.1791
.
‡
(C18H24N2O3 ; calc. 316.1787).
{2-[(Benzylamino)carbonyl]-5-hydroxy-1-(3-hydroxypropyl)pentyl}carbamic Acid Methyl Ester (5). A
stream of O3/O2 was bubbled through a soln. of 3 (7.5 g, 24 mmol) in MeOH/CH2Cl2 1:1 (40 ml) at À 808 until a

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blue color appeared and a crystalline precipitate formed (after ca. 1.25 h). The soln. was purged with N2 while
maintaining the low temp. until the blue color disappeared. Dimethyl sulfide (11 ml) and then NaBH4 (4.5 g,
0.12 mol) were added in portions under N2. After the addition, the cooling bath was removed, and the mixture
was stirred for 1 h. Solvents were evaporated, and the residue was washed with H2O and CH2Cl2, collected, and
dried to constant weight. Recrystallization of the solid gave 5 (6.82 g, 82%). M.p. 158 1618. (MeOH/AcOEt
1:2). IR: 3305, 3280 (NÀH, OÀH), 2951 (CÀH), 1695, 1630 (CˆO). 1H-NMR ((D5)pyridine): 1.87 2.40 (m,
8 H); 3.02 (m, 1 H); 3.67 (s, 3 H); 3.88 (m, 4 H); 4.59 (m, 1 H); 4.71 (d, J ˆ 5.4, 2 H); 5.21 (s, OH); 7.18 7.33 (m,
3 H); 7.52 (d, J ˆ 7.5, 2 H); 8.22 (d, J ˆ 9.0, 1 H); 9.53 (t, J ˆ 6.0, 1 H). 13C-NMR: 27.02 (t); 30.06 (t); 30.26 (t);
31.62 (t); 43.12 (t); 51.43 (q); 52.66 (d); 54.00 (d); 61.73 (t); 61.80 (t); 126.94 (d); 127.89 (2C, d); 128.50 (2C, d);
.
‡
140.05 (s); 157.83 (s); 174.25 (s). EI-MS: 352 (3, M ), 207 (44), 162 (112), 132 (110), 106 (82), 105 (88), 91
.
‡
(99), 90 (77), 76 (54). HR-MS: 352.1995 (C18 H28N2O5 ; calc. 352.1997).
2-(1-Benzyl-2-oxopiperidin-3-yl)pyrrolidine-1-carboxylic Acid Methyl Ester (6). To a soln. of 5 (3.05 g,
8.7 mmol) and Et3N (1.93 g, 19 mmol) in anh. THF (80 ml), a soln. of TsCl (4.12 g, 22 mmol) in THF (20 ml) was
added dropwise within 15 min at 08. The mixture was warmed to r. t. while stirring for 3 h, and then brought to
reflux for 6 h. After cooling, the solvent was evaporated, and the residue was dissolved in CH2Cl2 (70 ml). The
soln. was washed twice with sat. NaHCO3 soln. and brine, dried (Na2SO4) and evaporated: mixture of ditosylate
and partially cyclized product (3.82 g) (by NMR). This residue was dissolved in anh. THF (70 ml), the soln.
cooled to 08, and NaH (1.73 g, 60% dispersion in mineral oil, 43.5 mmol) added under N2. After 20 min, the
cooling bath was removed and the mixture refluxed for 7 h. After cooling, the mixture was partitioned between
CH2Cl2 (70 ml) and H2O (100 ml), the aq. phase extracted with more CH2Cl2 (2 Â 30 ml), the combined org.
phase washed with brine, dried (Na2SO4) and evaporated, and the the residue subjected to CC (silica gel, 30%
AcOEt/hexane): 6 (1.46 g, 53% over 2 steps), 1 :1 mixture of the erythro-and threo-isomers. IR: 2948, 2871
(CÀH), 1694, 1627 (CˆO). 1H-NMR: 1.50 1.78 (m, 8 H); 2.06 (m, 1 H); 3.09 (m, 2 H); 3.20 (m, 1 H); 3.31 (m,
1 H); 3.59 (s, 3 H); 4.49 (br., 2 H); 4.57 (m, 1 H); 7.13 7.24 (m, 5 H). 13C-NMR: 21.76 (t); 21.88 (t); 23.55, 23.97
(2t, 2 isomers); 27.41, 28.07 (2t, 2 isomers); 42.98, 44.36 (2d, 2 isomers); 46.97 (t); 49.75 (t); 51.80, 52.07 (2q, 2
isomers); 57.46, 58.06 (2d, 2 isomers); 126.94 (d); 127.68 (2C, d); 128.24 (2C, d); 137.17 (s); 155.50 (s); 170.36,
.
‡
170.65 (2s, 2 isomers). EI-MS: 316 (47, M ), 257 (68), 189 (100), 160 (13), 159 (16), 128 (76), 128 (75), 91 (90),
.
‡
82 (15). HR-MS: 316.1787 (C18H24N2O3 ; calc. 316.1787).
N-Benzylhexahydronicotine ( ˆ 1-Benzyl-3-(1-methylpyrrolidin-2-yl)piperidine; 7). A soln. of 6 (0.3 g,
0.95 mmol) in anh. THF (3 ml) was added dropwise to a stirred suspension of LiAlH4 (0.18 g, 4.72 mmol) in
THF (7 ml) under N2. The mixture was refluxed for 12 h, cooled, and quenched with wet THF, then with H2O.
Addition of 1n NaOH (5 ml) led to a precipitate that was filtered. The filter cake was washed with THF and
MeOH (10 ml each), and the org. solns were combined and evaporated. The residue was partitioned between
H2O (15 ml) and CH2Cl2 (3 Â 10 ml), and usual workup led to 7 (0.24 g).
Hexahydronicotine ( ˆ 3-(1-Methylpyrrolidin-2-yl)piperidine; 8). Compound 7 (0.24 g) was debenzylated
under hydrogenolysis conditions. The crude product was percolated through a SiO2 column with 40% AcOEt/
hexane: 8 (0.14 g).
Nicotyrine ( ˆ 3-(1-Methyl-1H-pyrrol-2-yl)pyridine; 9). A soln. of 7 (0.11 g, 0.33 mmol) in CH2Cl2 (2 ml)
was added dropwise to Se powder (0.47 g, 5.9 mmol). The solvent was carefully evaporated and the mixture was
heated at 250 2608 for 30 h under N2. The mixture was cooled and the residue scratched off from the flask,
smashed to a fine powder in a mortar, and extracted with boiling CH2Cl2 (20 ml). Filtration and evaporation left
a black mass which was chromatographed (SiO2, 15 30% AcOEt/hexane: 9 (0.02 g , 18%). 1H-NMR: 3.65 (s,
3 H); 6.21, 6.27, 6.75 (br., 1 H each); 7.30 (dm, J ˆ 7.8, 1 H); 7.68 (dm, J ˆ 7.8, 1 H); 8.50 (d, J ˆ 3.9, 1 H); 8.66
(br., 1 H). 13C-NMR: 35.02 (q); 108.16 (d); 109.72 (d); 123.18 (d); 124.68 (d); 129.21 (s); 130.72 (s); 135.44 (d);
.
‡
147.58 (d); 149.12 (d). EI-MS: 158 (100, M ), 157 (39), 130 (11).
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Received June 7, 2004