Synthesis of nicotine and diverse analogues using intramolecular [3+2] cycloaddition

Article abstract of DOI:10.1055/s-0029-1217746

A new methodology is described for the novel and rapid synthesis of nicotine and its analogues from nicotinaldehyde. The major feature of the methodology is the highly effective intramolecular [3+2] cycloaddition of azomethine ylides. The reaction was stu

Full text of DOI:10.1055/s-0029-1217746

LETTER
2497
Synthesis of Nicotine and Diverse Analogues Using Intramolecular
[3+2] Cycloaddition
Synthesis of
Nicot
e
ine and Div
o
erse Analogu
r
es ge Bashiardes,* Sébastien Picard, Jacques Pornet
Département de Chimie, Synthèse et Réactivité des Substances Naturelles, SFA-CNRS UMR 6514, Université de Poitiers,
40 Avenue du Recteur Pineau, 86022 Poitiers, France
E-mail: george.bashiardes@univ-poitiers.fr
Received 24 June 2009
R2
R2
n
n
Abstract: A new methodology is described for the novel and rapid
synthesis of nicotine and its analogues from nicotinaldehyde. The
major feature of the methodology is the highly effective intramolec-
ular [3+2] cycloaddition of azomethine ylides. The reaction was
studied using conventional thermal and microwave irradiation con-
ditions.
Si
N
H
N
N
N
desilylation
R1
R1
6
7
n
Si
Key words: intramolecular dipolar cycloaddition, nicotinoid het-
erocycles, microwaves
intramolecular
CHO
CHO
[3+2] cycloaddition
5
4
N
N
Scheme 1 Retrosynthetic strategy for the synthesis of a series of
novel nicotinoid compounds
(–)-Nicotine 1 is an alkaloid present in tobacco and a wide
variety of other plants. It targets and activates nicotinic
acetylcholine receptors (nAChRs). Nicotine and its ana-
logues appeared to be attractive candidates for the therapy
of central nervous system disorders such as Alzheimer’s,
Parkinson’s, and Tourette’s diseases.1 Since the first syn-
thesis by Pictet in 1904, numerous syntheses of nicotine
and its analogues have been reported.2 Zhai and co-work-
ers reported the synthesis of the annulated analogue 2 us-
ing an intramolecular azomethine ylide–alkene [3+2]
cycloaddition from 4-allyl-3-pyridinecarboxaldehyde (3;
Figure 1).3 Starting from nicotinaldehyde 4, we describe
herein the divergent synthesis of heterocyclic nicotine an-
alogues 6 using an intramolecular [3+2] cycloaddition,
which can lead to further nicotine analogues 7 by a desi-
lylation reaction (Scheme 1).
temperature, protected the aldehyde function. A further
addition of n-BuLi afforded the required organolithium
intermediate lithiated at the C4 position specifically. This
intermediate then reacted with either dimethylvinyl-
chorosilane (8a) or allyldimethylchlorosilane (8b), to af-
ford, after hydrolysis, compounds 5a and 5b in 63% and
45% yields, respectively.
n
Si
1. Me2N(CH2)2N(Li)Me
CHO
CHO
–78 °C
2. n-BuLi –40 °C
4
3. 8a or 8b
N
N
5a n = 0, 63%
5b n = 1, 45%
Si
Cl
Si
Cl
H
8a
8b
Scheme 2 Synthesis of key intermediate 5 for the synthesis of sila-
nicotinoids
N
CHO
N
H
3
1
2
N
N
N
H
H
N
H
N
N
CO2Me
CO2Et
CO2H
CO2Et
Figure 1 Nicotine (1), a nicotine analogue (2) and a 4-allylnicotin-
aldehyde precursor to nicotine analogues
Bn
9a
9d
9b
9c
H
N
CO2Me
CO2H
As outlined in Scheme 2, the synthesis of 5 was per-
formed in one step from 3-pyridinecarboxaldehyde (4).
Firstly, an ortho-lithiation method, developed by Comins
and co-workers,4,5 proved to be a convenient technique
with which to protect the aromatic aldehyde, followed, in
situ, by the formation of the aryllithium species using ex-
cess n-BuLi. Thus, mixing N,N,N¢-trimethylethylene-
diamine and n-BuLi in the presence of 4, at low
N
H
N
H
9e
9f
Figure 2 a-Amino acids and a-amino esters used in cycloadditions
with 5
n
n
Si
9a–f
with or without
solvent
Si
R2
CHO
N
(Δ) reflux or MW
SYNLETT 2009, No. 15, pp 2497–2499
Advanced online publication: 27.08.2009
x
x
.x
x
.2
0
0
9
R1
N
6
N
5
DOI: 10.1055/s-0029-1217746; Art ID: D16809ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 3 [3+2] Cycloaddition between compounds 5 and 9

2498
G. Bashiardes et al.
LETTER
The next step involved the cycloaddition of compounds On performing the cycloaddition using allylic aldehyde
5a and 5b by condensation with an a-amino acid or a-ami- 5b under thermal conditions with any a-amino ester, the
no ester 9a–f (Figure 2), which led directly to the expect- reaction afforded a number of products, including a non-
ed nicotinic analogues 6. The cycloadditions were condensed secondary product derived from a Si-induced
performed successfully by condensation of 5 and 9 in tol- intramolecular rearrangement of the starting allylic alde-
uene (for a-amino ester) or xylene (for a-amino acid) un- hyde (Scheme 4). Indeed, aldehyde 5b, in the presence of
der conventional thermal conditions or under microwave a-amino ester 9d, led to a 1:1:1 mixture of 5b/6f/10 under
irradiation (Scheme 3). Tricyclic and tetracyclic nicotinic conventional thermal conditions, but gave exclusively 10
analogues 6 were isolated (Figure 3) in excellent yields under microwave irradiation (Table 1, Entry 6). Even
under both conditions (Table 1). Under conventional ther- when attempting to perform the cycloaddition with other
mal conditions, the reaction was complete after several a-amino esters 9b and 9c, under mild microwave condi-
hours at reflux. Under microwave conditions, the reaction tions (temperature set to 80 °C), the exclusive formation
was performed without solvent or, in two cases, with a of 10 was still observed. We had previously reported this
few drops of xylene (entries 1 and 4). Microwave irradia- type of rearrangement in a similar series of compounds.6
tion reduced the time of the reaction and significantly in- Unexpectedly, however, the cycloaddition between alde-
creased the yield (particularly for entries 3 and 4). hyde 5b and a-amino ester 9f, afforded the required nico-
Moreover, an added advantage of microwave irradiation tinic tetracyclic compound 6g quantitatively. This
conditions resided in the observation that the crude reac- reaction was also achieved under microwave irradiation
tion mixture was practically devoid of side products, al- without solvent. Looking into the same rearrangement re-
lowing a very simple purification by filtration on a short action that provided oxasilole 10, under toluene reflux in
column of silica gel without prior work-up.
the absence of any reagent, 5b led solely to 10 in 20 hours
in 90% yield, while under microwave irradiation, in ab-
sence of solvent, the reaction was essentially quantitative
and was complete within one hour (Scheme 4).
Table 1 Comparative Yield of Cycloaddition Reactions
Entry Reagents Product
Thermal
Microwave
Temp Time Yield TempTime Yield
(°C)
reflux 24 91
reflux 95
(h) (%)
(°C) (min) (%)
130 60 94a
O
Si
N
Si
CHO
1
2
3
4
5
6
7
5a + 9a
5a + 9b
5a + 9c
5a + 9e
5a + 9f
5b + 9d
5b + 9f
6a
6b
6c
6d
6e
6f
10
5b
6
130
5
99
N
90% (Δ, reflux, 20 h)
99% (MW, 130 °C, 1 h)
reflux 16 69
reflux 16 70
reflux 16 84
130 15 91
130 45 95a
130 10 99
Scheme 4 Oxasilole rearrangement
Finally, silyl-substituted compounds 6 were further trans-
formed into a new series of nicotinic analogues by a desi-
lylation reaction using fluoride reagents such as TBAF or
CsF (Scheme 5). The resulting analogues 7 (Figure 4)
were obtained in satisfactory yields of 54% to 60%
(Table 2). Thus, for entries 1 to 3, the reaction was com-
plete after several hours at THF reflux using four equiva-
lents of TBAF. However, these conditions were not
suitable for analogue 6e (entry 4), which required CsF in
HMPA under microwave irradiation in order to afford the
desired product 6e in 57% yield.
80
24 37
20 99
80 30
0
6g
110
110 15 99
a A few drops of xylene were added.
CO2Me
CO2Et
Si
Si
Si
N
N
N
Bn
6a
6b
6c
N
N
N
CO2Me
R2
R2
Si
Si
Si
N
N
N
N
fluoride agent
R1
6d
6e
R1
N
N
6
N
7
N
CO2Me
Si
N
Si
CO2Et
Scheme 5 Desilylation of compounds 6
N
N
In conclusion, by our methodology,7 a large number of di-
versified nicotine analogues were successfully synthe-
sized in good to excellent overall yields. The preparation
of aldehyde 5 is rather straightforward, while almost all
the other reagents are inexpensive and easily accessible.
6g
6f
N
Figure 3 Structures of compounds 6a–g obtained by [3+2] cycload-
dition
Synlett 2009, No. 15, 2497–2499 © Thieme Stuttgart · New York

LETTER
Synthesis of Nicotine and Diverse Analogues
2499
–78 °C. After 30 min, 3-pyridinecarboxaldehyde (10 mmol)
was slowly added and the resulting mixture was stirred for
30 min at –78 °C. A further solution of n-BuLi (1.6 M in
hexanes, 20 mmol) was added slowly and the reaction was
stirred continuously at –48 °C for 3 h. The reaction was
cooled to –78 °C, and a solution of dimethylvinylchloro-
silane (30 mmol) was slowly added. The mixture was stirred
at –78 °C for 30 min then allowed to warm to room temper-
ature. The reaction was quenched with brine and then
extracted with diethyl ether. The organic layer was washed
with brine, dried (MgSO4) and evaporated. The crude
mixture was purified on silica gel (pentane–EtOAc, 1:1) to
provide the product in 63% yield as a viscous yellow oil. 1H
NMR (CDCl3, 300 MHz): d = 10.19 (s, 1 H, CH=O), 9.03 (s,
1 H, H2), 8.75 (d, J = 4.8 Hz, 1 H, H6), 7.63 (d, J = 4.8 Hz,
1 H, H5), 6.40 (dd, J = 20.3, 14.6 Hz, 1 H, Hc), 6.10 (dd, J =
14.6, 3.4 Hz, 1 H, Hb), 5.80 (dd, J = 20.3, 3.4 Hz, 1 H, Ha),
0.45 (s, 6H, SiMe2); 13C NMR (CDCl3, 300 MHz): d = 192.2
(CH=O), 153.5 (C6), 152.9 (C2), 150.2 (C4), 136.8 (CH=),
135.5 (C3), 133.5 (CH2=), 130.3 (C5), –2.9 (SiMe2).
3,8,8-Trimethyl-1,2,3,3a,8,8a-hexahydro-3,5-diaza-8-
silacyclopenta[a]indene-2-carboxylic acid methyl ester
(6b): Thermal conditions: A solution of 5a (1 mmol) and
sarcosine methyl ester 9b (2 mmol) in toluene (10 mL), was
stirred and heated at reflux for 6 h. After evaporation of the
solvent under reduced pressure, the crude product was
purified by short column chromatography on silica gel
(CH2Cl2–MeOH, 95:5) to provide the product in 95% yield
as viscous yellow oil. Microwave conditions: In a pyrex tube
(2 × 15 mm), 5a (1 mmol) and sarcosine methyl ester 9b
(2 mmol) were submitted to microwave irradiation (CEM
Discover apparatus; 50 W, 130 °C) for 5 min. After cooling,
the crude mixture was purified by short column chromato-
graphy on silica gel (CH2Cl2–MeOH, 95:5) to provide the
product in 99% yield. 1H NMR (CDCl3, 300 MHz): d = 8.65
(s, 1 H, H4), 8.50 (d, J = 4.6 Hz, 1 H, H6), 7.42 (d, J = 4.6
Hz, 1 H, H7), 4.57 (dd, J = 7.4, 4.5 Hz, 1 H, H3a), 3.88–3.90
(m, 1 H, H2), 3.74 (s, 3 H, OMe), 2.55 (s, 3 H, NMe), 2.12–
2.14 (m, 3 H, H1 and H8a), 0.37 (s, 3 H, SiMe), 0.27 (s, 3 H,
SiMe); 13C NMR (CDCl3, 300 MHz): d = 173.7 (C=O),
149.7 (C7a), 147.4 (C4), 147.3 (C6), 146.1 (C3b), 126.9 (C7),
70.9 (C3a), 68.32 (C2), 50.9 (OMe), 35.7 (NMe), 28.7 (C1),
27.3 (C8a), –2.0 (SiMe), –3.7 (SiMe).
1-Methyl-5-pyridin-3-yl-pyrrolidine-2-carboxylic acid
methyl ester (7b): A solution of 6b (1 mmol) and TBAF (1
M in THF, 4 mL, 4 mmol) was stirred and heated at reflux
for 5 h. After cooling to room temperature, the reaction was
quenched with water and then extracted with EtOAc. The
organic layer was washed with brine, dried (MgSO4) and
evaporated under reduced pressure. The crude mixture was
purified on silica gel (CH2Cl2–MeOH) to provide the
product in 55% yield as a viscous yellow oil. 1H NMR
(CDCl3, 300 MHz): d = 8.6 (s, 1 H, Hb), 8.50 (d, J = 4.2 Hz,
1 H, Hf), 7.67 (d, J = 7.8 Hz, 1 H, Hd), 7.26 (dd, J = 7.8, 4.2
Hz, 1 H, He), 4.06 (dd, J = 8.5, 6.7 Hz, 1 H, H5), 3.95 (dd,
J = 8.1 Hz, 1 H, H2), 3.74 (s, 3 H, OMe), 2.40–2.60 (m, 1 H,
H4), 2.26–2.36 (m, 1 H, H3), 2.24 (s, 3 H, NMe), 1.86–2.04
(m, 1H, H3), 1.76–1.80 (m, 1H, H4); 13C NMR (CDCl3, 300
MHz): d = 174.3 (C=O), 149.2 (Cb), 148.4 (Cf), 139.3 (Cc),
134.7 (Cd), 123.5 (Ce), 65.9 (C2), 64.5 (C5), 51.1 (OMe),
35.0 (NMe), 34.0 (C4); 27.7 (C3).
Table 2 Desilylation Reaction of Compounds 6
Entry
Reagent Fluoride agent Products
Yield (%)
1
2
3
4
5
6a
6b
6c
6e
6e
TBAF
TBAF
TABF
TBAF
CsF
nicotine (7a)
60
55
54
0
7b
7c
no reaction
7d
57
CO2Me
N
N
7a
N
7b
N
CO2Me
N
CO2Et
N
Bn
7d
7c
N
N
Figure 4 A new series of nicotine analogues
The cycloaddition reaction, performed under thermal or
microwave conditions, provides a primary set of nicotine
analogues containing an extra fused heterocyclic ring. The
last step is a desilylation reaction which provides a sec-
ondary set of compounds. Our methodology is amenable
to combinatorial or parallel synthetic techniques, allowing
the construction of chemical libraries.
References and Notes
(1) (a) McDonald, I. A.; Cosford, N.; Vernier, J.-M. Ann. Rep.
Med. Chem. 1995, 30, 41. (b) Decker, M. W.; Arneric, S. P.
In Neuronal Nicotinic Receptors: Pharmacology and
Therapeutic Opportunities; Arneric, S. P.; Brioni, J. D.,
Eds.; Wiley-VCH: Weinheim, 1999, 395.
(2) For a review, see: Wagner, F. F.; Comins, D. L. Tetrahedron
2007, 63, 8065; and references therein.
(3) (a) Zhai, H.; Liu, P.; Luo, S.; Fang, F.; Zhao, M. Org. Lett.
2002, 4, 4385. (b) Luo, S.; Fang, F.; Zhao, M.; Zhai, H.
Tetrahedron 2004, 60, 5353. (c) Yang, X.; Luo, S.; Fang, F.;
Liu, P.; Lu, Y.; He, M.; Zhai, H. Tetrahedron 2006, 62,
2240.
(4) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078.
(5) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1990, 55, 69.
(6) Bashiardes, G.; Chaussebourg, V.; Laverdan, G.; Pornet, J.
Chem. Commun. 2004, 122.
(7) Synthesis of 4-(dimethylvinylsilanyl)pyridine-3-
carboxaldehyde (5a); Typical Procedure: A solution of
n-BuLi (1.6 M in hexanes, 11.2 mmol) was slowly added to
a solution of N,N,N¢-trimethylethylenediamine (12 mmol) in
anhydrous THF (40 mL), which was stirred and cooled at
Synlett 2009, No. 15, 2497–2499 © Thieme Stuttgart · New York

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