diastereoselective construction of a new class of nicotine...

Indian Journal of Chemistry

Vol. 52A, Aug-Sept 2013, pp. 1113-1127

Diastereoselective construction of a new class of nicotine analogues having

contiguous stereocenters via 1,3- dipolar cycloaddition of azomethine ylides

Vadla Rajkumar & Srinivasarao Arulananda Babu*

Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City,

Sector 81, SAS Nagar, Mohali, Manauli PO, Punjab, 140306, India

Email: [email protected]

Received 5 April 2013; revised and accepted 4 June 2013

Diastereoselective synthesis of several nicotine analogues via the intermolecular cycloaddition of azomethine ylides

derived from the condensation reaction of nicotinaldehyde/ picolinaldehyde/ isonicotinaldehyde and

N-methyl glycine/N-benzyl glycine hydrochloride with several readily available electron-deficient 2π components,

(maleimides, dialkyl fumarates, dialkyl maleates and fumaronitrile) is reported. The assembling of a new class of nicotine

analogues/ functionalized 2-pyridylpyrrolidine derivatives having contiguous stereocenters has been accomplished.

The stereochemistry of the representative products is unequivocally established from the single crystal X-ray structure analyses.

Keywords: Pyridine alkaloids, Azomethine ylide, 1,3-Dipolar cycloaddition, Stereoselective synthesis, Nicotine

(S)-Nicotine is one of the numerous chemicals present

in the smoke from tobacco products such as cigarettes,

cigars, and pipes and is the principal alkaloid in

Nicotiana tabaccum. Dried leaves of the tobacco

plants Nicotiana rustica and N. tabacum comprise as

much as 2–8% of (S)-nicotine.1-4

Notably, a large scale

application of nicotine is its use as an insecticide;

approximately 2800 tons of (S)-nicotine is being used

as a crop protectant per year and aqueous solution of

nicotine sulphate are still used throughout the world as

an insecticide.5

Neuronal nicotinic acetylcholine receptors

(nAChRs) exert an important modulatory influence in

the CNS and represent an attractive therapeutic

opportunity for CNS disorders. (S)-Nicotine and

nornicotine (pyridine alkaloids) are known to

modulate neuronal nicotinic acetylcholine receptors

(nAChRs), which affect the central nervous system

(CNS).6-8

In particular, (S)-nicotine has drawn

considerable interest in the last few decades due to its

potential role in the treatment of Parkinson’s disease,

Alzheimer’s disease, anxiety, schizophrenia, uterative

colitis, attention-deficit hyperactivity disorder

(ADHD), smoking cessation, epilepsy, depression and

other central nervous system disorders.9-14

Unfortunately (S)-nicotine, the prototypical agonist of

nAChRs, activates all the subtypes of nAChRs. On the

other hand, there are several detrimental effects

associated with the use of (S)-nicotine, which include

cardiovascular and gastrointestinal systems

disturbance, sleep disturbance and addiction.

Significantly, these unfavourable effects limit the use

of (S)-nicotine as a therapeutic molecule.15,16

Therefore, one of the important goals of the medicinal

chemists is to synthesize nonaddictive analogues of

nicotine that display the same beneficial effects of

(S)-nicotine at lower toxicity with improved safety

profiles.13,14

Considerable effort has been focused on the

development of new synthetic protocols for the

production of nicotine derivatives that would show the

beneficial biological properties at lower toxicity.17,18

Currently, there are some nicotine analogues under

clinical trials. Noticeably, most of the reported

methods have been directed toward the synthesis of

nicotine9-14

and nicotine analogues14,19,20

via

modification on the pyridine ring using nicotine or

other starting materials.

The 1,3-dipolar cycloaddition reaction of

azomethine ylides with electron-deficient olefins is an

excellent protocol for the stereoselective construction

of a variety of natural products possessing pyrrolidine

skeleton and highly functionalized pyrrolidines with

up to four new stereocenters.21-35

Though the

azomethine ylide cycloaddition is a well-known

protocol, however, to the best of our knowledge, only

a few reports are available for the construction of

nicotine derivatives via the intermolecular

INDIAN J CHEM, SEC A, AUG-SEPT 2013

1114

cycloaddition of azomethine ylides with electron-

deficient olefins36,37

(e.g., chalcones, phenylvinyl

sulfone and Knöevenagel adducts prepared from

aromatic aldehydes and malononitrile). Interestingly,

Zhai et al.38

and Bashiardes et al.39

have reported the

synthesis of the conformationally restricted and

annulated nicotine analogues using the intramolecular

azomethine ylide [3+2] cycloaddition strategy.

Considering the important role of nicotine

analogues as nAchR modulators,15-20

herein we report

the diastereoselective synthesis of nicotine derivatives

having contiguous stereocenters via the intermolecular

cycloaddition of azomethine ylide (derived from the

condensation of nicotinaldehyde and N-methyl

glycine/N-benzyl glycine hydrochloride) with

electron-deficient 2π components, like maleimides,

dialkyl fumarates, dialkyl maleates and fumaronitrile

(Scheme 1). Our procedure has led to the synthesis of

a small collection of new nicotine analogues having

contiguous stereocenters, in other words,

functionalized 2-pyridylpyrrolidine derivatives.

Materials and Methods Melting points are uncorrected. IR spectra were

recorded as thin films or KBr pellets. 1H and

13C NMR

spectra were recorded on 400 MHz and 100 MHz

NMR spectrometers, respectively using TMS

as an internal standard. Column chromatography

was carried out on neutral alumina or silica gel

(100-200 mesh). Reactions were performed under an

inert atmosphere. Solutions were dried with anhydrous

MgSO4, and the reagents were added to the reaction

flask through a syringe. Analytical thin layer

chromatography (TLC) was performed on silica plates

or neutral Al2O3 and the components were visualized

by observation under iodine chamber. Isolated yields

of all products are reported (yields were not

optimized). Ratios of diastereomers were

determined from the 1H NMR or

13C NMR of

crude reaction mixture or after isolation.

Synthesis of nicotine analogues (4a-i) and (5a-5i)

A dry flask containing nicotinaldehyde (1a),

sarcosine (2) and malemide derivatives (3a-i) in

1,4-dioxane or toluene or MeCN or EtOH or MeOH

(5 mL) was heated to the appropriate temperature and

time (Tables 1 and 2). Then the reaction mixture was

cooled to rt and subjected to rotary evaporation, which

afforded a crude mixture. Purification of the curde

reaction mixture through neutral alumina column

choromatography (EtOAc/Hexane = 75:25) afforded

the nicotine derivatives (4a-i) and (5a-5i). Reaction

conditions are given in Tables 1 and 2.

(3aR*,4R*,6aS*)-5-Methyl-2-phenyl-4-(pyridin-3-yl)tetrahydro-pyrrolo-[3,4-c]pyrrole-1,3(2H,3aH)-dione (4a)

Colourless solid; M. pt.: 124-126 oC; IR: (KBr, cm

-1):

νmax 1167, 1494, 1702, 2777, 2974; 1H NMR

(400 MHz , CDCl3): δ 2.18 (s, 3H), 2.74 (dd, 1H,

J = 9.5, 6.3 Hz), 3.41 (dd, 1H, J = 8.8, 6.3 Hz), 3.66

(t, 2H, J = 6.4 Hz), 3.60 (t, 1H, J = 6.4 Hz), 7.30-7.50

(m, 6H), 7.71 (d, 1H, J = 7.8 Hz), 8.59 (dd, 1H,

J = 4.7, 1.5 Hz), 8.65 (d, 1H, J = 1.5 Hz); 13

C NMR

(100 MHz, CDCl3): δ 38.8, 44.1, 53.5, 57.5, 70.5,

RAJKUMAR & BABU.: DIASTEREOSELECTIVE SYNTHESIS OF NICOTINE ANALOGUES

1115

123.8, 126.4, 128.8, 129.2, 131.6, 134.5, 135.6, 149.4,

149.6, 176.0, 176.6; HRMS (ESI): Calcd for

C18H18N3O2 [M + H]+ 308.1399, found 308.1393.

(3aR*,4S*,6aS*)-5-Methyl-2-phenyl-4-(pyridin-3-yl)tetrahydro-pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (5a)


-1):

νmax 1197, 1387, 1707, 2848, 2923; 1H NMR

(400 MHz, CDCl3): δ 2.19 (s, 3H); 2.67 (dd, 1H,

J = 9.7, 7.1 Hz), 3.40 (t, 1H, J = 7.1 Hz), 3.54 (t, 1H,

J = 8.5 Hz), 3.63 (d, 1H, J = 8.5 Hz), 3.72 (d, 1H,

J = 9.7 Hz), 7.18-7.43 (m, 6H), 7.59 (d, 1H, J = 7.8

Hz), 8.53 (d, 1H, J = 3.6 Hz), 8.57 (s, 1H); 13

C NMR

(100 MHz, CDCl3): δ 39.7, 44.4, 50.5, 58.5, 71.0,

123.5, 126.2, 128.6, 129.2, 131.8, 132.4, 135.7, 149.6,

174.6, 178.0; HRMS (ESI): Calcd for C18H18N3O2

[M + H]+ 308.1399, found 308.1403.

(3aR*,4R*,6aS*)-5-Methyl-4-(pyridin-3-yl)-2-(p-tolyl)tetrahydro-pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (4b)


-1):

νmax 1169, 1512, 1708, 2835, 2923; 1H NMR

(400 MHz, CDCl3): δ 2.19 (s, 3H),2.39 (s, 3H), 2.74

(dd, 1H, J = 9.4, 6.3 Hz), 3.40 (dd, 1H, J = 8.8, 6.3

Hz), 3.66 (t, 2H, J = 6.1 Hz), 3.60 (t, 1H, J = 8.8 Hz),

7.18-7.35 (m, 5H), 7.70-7.73 (m, 1H), 8.60 (dd, 1H,

J = 4.8, 1.3 Hz), 8.66 (d, 1H, J = 1.7 Hz); 13

C NMR

(100 MHz, CDCl3): δ 21.3, 38.8, 44.1, 53.5, 57.5,

70.5, 123.7, 126.2, 128.9, 129.9, 134.6, 135.5, 138.9,

149.4, 149.6, 176.1,176.8; HRMS (ESI) Calcd for

C19H20N3O2 [M + H]+ 322.1551, found 322.1550.

The corresponding isomer (5b) could not be separated

in pure form as both isomers have similar Rf values. (3aR*,4R*,6aS*)-2-(4-Methoxyphenyl)-5-methyl-4-(pyridin-3-yl)tetrahydro-pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (4c)


-1):

νmax 1187, 1515, 1708, 2786, 2941; 1H NMR

(400 MHz, CDCl3): δ 2.19 (s, 3H), 2.73 (dd, 1H,

J = 9.4, 6.6 Hz), 3.39 (dd, 1H, J = 8.7, 6.5 Hz), 3.64 (t,

2H, J = 6.5 Hz), 3.59 (t, 1H, J = 8.7 Hz), 3.83 (s, 3H),

6.99 (d, 2H, J = 8.9 Hz), 7.23 (d, 2H, J = 8.9 Hz), 7.34

(dd, 1H, J = 7.8, 4.9 Hz), 7.72 (d, 1H, J = 7.8 Hz),

8.59-8.65 (m, 2H); 13

C NMR (100 MHz, CDCl3):

δ 38.8, 44.0, 53.5, 55.5, 57.5, 70.4, 114.5, 123.7,

124.2, 127.7, 134.6, 135.5, 149.4, 149.6, 159.6, 176.3,

176.9; HRMS (ESI): Calcd for C19H20N3O3 [M + H]+

338.1504, found 338.1510. The corresponding isomer

(5c) could not be separated in pure form as both

isomers have similar Rf values.

(3aR*,4S*,6aS*)-2-(4-Chlorophenyl)-5-methyl-4-(pyridin-3-yl)tetra-hydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (5d)


-1):

νmax 1196, 1492, 1706, 2821, 2949; 1H NMR

(400 MHz, CDCl3,): δ 2.19 (s, 3H), 2.68 (dd, 1H,

J = 9.8, 7.2 Hz), 3.40 (t, 1H, J = 7.2 Hz), 3.54 (t, 1H,

J = 8.7 Hz), 3.63 (d, 1H, J = 8.7 Hz), 3.72 (d, 1H,

J = 9.8 Hz), 7.16-7.40 (m, 5H), 7.55-7.58 (m, 1H),

8.53-8.56 (m, 2H); 13


Table 1 – Optimization of the reaction conditions for the synthesis of nicotine analoguesa

Entry Solvent T (oC) t (h) Yieldb (%) dr = 4a:5a

a 1,4-Dioxane (5 mL) 100 3 57 65:35

b 1,4-Dioxane (5 mL) 100 6 86 65:35

c 1,4-Dioxane (5 mL) 100 12 86 65:35

d 1,4-Dioxane (5 mL) 80 6 30 65:35

e 1,4-Dioxane (5 mL) 60 6 <10 N.D.c

f Acetonitrile (5 mL) 82 6 75 65:35

g Toluene (5 mL) 100 6 35 66:34

h EtOH (5 mL) 78 6 55 60:40

i MeOH (5 mL) 64 6 20 60:40 aAll the reactions were carried out using (1a) (0.5 mmol), (2) (0.6 mmol) and (3) (0.5 mmol). bIsolated yields. cN.D. = Not Determined.


1116

Table 2 – Synthesis of nicotine analoguesa

Entry Dipolarophile (3a-h) 4/5 Yield (%) dr = 4:5

1

4a/5a = 93 65:35

2

4b/5b = 78 60:40

3

4c/5c = 85b 56:44

4

4d/5d = 85b 55:45

5

4e/5e = 86b 60:40

6

4f/5f = 87b 56:44

7

4g/5g = 89 57:43

8

4h/5h = 83 52:48

9c

4i/5i = 87 54:46

aAll the reactions were carried out using (1a) (0.75 mmol), (2) (1 mmol) and (3) (0.5 mmol). Isolated yields are given. bThe reactions were carried out for 12 h. cThe reaction was carried out using (1a) (0.5 mmol), (2) (0.6 mmol) and (3) (0.5 mmol).


1117

δ 39.7, 44.3, 50.5, 58.4, 71.0, 123.5, 127.4, 129.4,

130.2, 132.3, 134.3, 135.7, 149.6, 149.7, 174.3, 177.6;

HRMS (ESI): Calcd for C18H17N3O2Cl [M + H]+

342.1009, found 342.1024. The corresponding isomer

(4d) could not be separated in pure form as both


(3aR*,4S*,6aS*)-2-(3,4-Dichlorophenyl)-5-methyl-4-(pyridin-3-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (5e)


-1):

νmax 1192, 1474, 1711, 2824, 2920; 1H NMR

(400 MHz, CDCl3): δ 2.20 (s, 3H), 2.69 (dd, 1H,

J = 9.8, 7.3 Hz), 3.40 (t, 1H, J = 7.3 Hz), 3.55 (t, 1H,

J = 8.6 Hz); 3.64 (d, 1H, J = 8.6 Hz), 3.72 (d, 1H,

J = 9.8 Hz), 7.12 (dd, 1H, J= 8.6, 2.3 Hz), 7.29 (dd,

1H, J = 7.8, 7.0 Hz), 7.38 (d, 1H, J = 2.3 Hz), 7.49 (d,

1H, J = 8.6 Hz), 7.56 (d, 1H, J = 7.8 Hz), 8.55 (s,

2H); 13

C NMR (100 MHz, CDCl3): δ 39.6, 44.3, 50.5,

58.5, 70.9, 123.5, 125.4, 128.0, 130.8, 130.9, 132.2,

132.7, 133.0, 135.6, 149.5, 149.7, 174.0, 177; HRMS

(ESI): Calcd for C18H16N3O2Cl2 [M + H]+ 376.0619,

found 376.0634. The corresponding isomer (4e) could

not be separated in pure form as both isomers have

similar Rf values.

(3aR*,4S*,6aS*)-2-(4-Bromophenyl)-5-methyl-4-(pyridin-3-yl)tetra-

hydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (5f) Colourless solid; M. pt.: 184-186

oC; IR: (KBr, cm

-1):

νmax 1192, 1489, 1705, 2821, 2927; 1H NMR

(400 MHz, CDCl3): 2.21 (s, 3H), 2.69 (dd, 1H, J = 9.7,

7.2 Hz), 3.40 (t, 1H, J = 7.2 Hz), 3.54 (t, 1H, J = 8.2

Hz), 3.64 (d, 1H, J = 8.2 Hz), 3.72 (d, 1H, J = 9.7 Hz),

7.11-7.59 (m, 6H), 8.55-8.57 (m, 2H); 13

C NMR (100

MHz, CDCl3): δ 39.7, 44.3, 50.5, 58.4, 71.0, 122.4,

123.5, 127.7, 130.7, 132.2, 132.3, 135.6, 149.6, 149.7,

174.3, 177.6; HRMS (ESI): Calcd for C18H17N3O2Br

[M + H]+ 386.0504, found 386.0489. The

corresponding isomer (4f) could not be separated in

pure form as both isomers have similar Rf values.

(3aR*,4R*,6aS*)-2-(3,4-Dimethylphenyl)-5-methyl-4-(pyridin-3-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (4g)

Colourless viscous liquid; IR: (CH2Cl2, cm-1

): νmax

1184, 1504, 1712, 2791, 2924; 1H NMR (400 MHz,

CDCl3): δ 2.18 (s, 3H), 2.27 (s, 3H), 2.28 (s, 3H), 2.73

(dd, 1H, J= 9.3, 6.4 Hz), 3.38 (dd, 1H, J = 8.9, 6.4 Hz),

3.59 (t, 1H, J = 8.9 Hz), 3.62-3.66 (m, 2H), 7.01 (dd,

1H, J = 7.9, 2.0 Hz), 7.04 (d, 1H, J = 2.0 Hz), 7.23

(d, 1H, J = 7.9 Hz), 7.32 (dd, 1H, J = 7.8, 4.7 Hz),

7.71 (d, 1H, J = 7.8 Hz), 8.59 (d, 1H, J = 3.7 Hz), 8.64

(s, 1H); 13

C NMR (100 MHz, CDCl3): δ 19.6, 19.9,

38.8, 44.1, 53.6, 57.6, 70.5, 123.7, 123.9, 127.4,

129.1, 130.4, 134.6, 135.6, 137.7, 137.9, 149.4, 149.6,

176.2, 176.8; HRMS (ESI): Calcd for C20H22N3O2

[M+H]+ 336.1712, found 336.1727. The corresponding

isomer (5g) could not be separated in pure form as

both isomers have similar Rf values.

2-(2-Hydroxyethyl)-5-methyl-4-(pyridin-3-yl)tetrahydropyrrolo-

[3,4-c]pyrrole-1,3(2H,3aH)-dione (4h/5h)

Isolated as a mixture of isomers. Yellow viscous

liquid; IR: (CH2Cl2, cm-1

): νmax 1181, 1401, 1698,

2953, 3405; 1H NMR (400 MHz, CDCl3): δ 2.10 (s,

3H), 2.57-2.61 (m, 1H), 3.22-3.25 (m, 1H), 3.37-3.79

(m, 8H), 7.24-7.33 (m, 1H), 7.55-7.69 (m, 1H), 8.57-

8.64 (m, 2H); 13

C NMR (100 MHz, CDCl3): δ 38.7,

39.6, 41.6, 41.7, 44.0, 44.1, 50.4, 53.4, 57.1, 58.1,

59.4, 70.0, 70.6, 123.5, 123.8, 132.7, 134.7, 135.8,

136.1, 149.1, 149.2, 149.3, 149.5, 176.2, 177.6, 178.2,

179.3 (The 13

C NMR given here for mixture of

isomers); HRMS (ESI): Calcd for C14H18N3O3 [M+H]+

276.1348, found 276.1467. The compounds (4h) and

(5h) could not be separated in pure form as both


(3aR*,4R*,6aS*)-5-Methyl-2-propyl-4-(pyridin-3-yl)tetrahydro-pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (4i)


): νmax

1139, 1401, 1712, 2965; 1H NMR (400 MHz, CDCl3):

δ 0.83 (t, 3H, J = 7.4 Hz); 1.54 (dd, 2H, J = 14.9, 7.4

Hz), 2.05 (s, 3H), 2.48 (dd, 1H, J = 8.7, 5.6 Hz), 3.15

(dd, 1H, J = 8.7, 6.3 Hz), 3.37-3.44 (m, 5H), 7.22-7.26

(m, 1H), 7.59-7.62 (m, 1H), 8.50 (dd, 1H, J = 4.8, 1.9 Hz),

8.64 (d, 1H, J = 1.9 Hz); 13

C NMR (100 MHz,

CDCl3): δ 11.2, 21.0, 38.8, 40.4, 44.0, 53.5, 57.4, 70.3,

123.7, 134.7, 135.6, 149.3, 149.4, 177.0, 177.6;

HRMS (ESI): Calcd for C15H20N3O2 [M+H]+

274.1556, found 274.1592.

(3aR*,4S*,6aS*)-5-Methyl-2-propyl-4-(pyridin-3-yl)tetrahydro-pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (5i)


):

νmax 1124, 1403, 1699, 2965; 1H NMR (400 MHz,

CDCl3): δ 0.81 (t, 3H, J = 7.4 Hz), 1.45 (dd, 1H, J = 7.4,

2.0 Hz), 1.48 (dd, 1H, J = 7.4, 1.8 Hz), 2.07 (s, 3H),

2.51 (dd, 1H, J = 9.6, 7.4 Hz), 3.14 (t, 1H, J = 7.4 Hz),

3.29-3.32 (m, 2H), 3.28 (d, 1H, J = 1.3 Hz), 3.45 (d,

1H, J = 8.5 Hz), 3.55 (d, 1H, J = 9.6 Hz), 7.17-7.21 (m,

1H), 7.41-7.44 (m, 1H), 8.41 (d, 1H, J = 1.9 Hz), 8.48

(dd, 1H, J = 4.8, 1.9 Hz); 13

C NMR (100 MHz,

CDCl3): δ 11.3, 21.1, 39.7, 40.6, 44.0, 50.4, 58.3,

70.7, 123.3, 132.4, 135.7, 149.5, 149.6, 175.6, 178.9;


1118


274.1556, found 274.1550. Synthesis of nicotine analogues (6-9)

A dry flask containing picolinaldehyde or

isonicotinaldehyde (1b/1c, 0.75 mmol), sarcosine

(2, 1 mmol) and N-phenyl malemide (3a, 0.5 mmol) in

1,4-dioxane (5 mL) was heated to the appropriate

temperature and time (Scheme 2) and processed as

above to obtain the nicotine derivatives (6-9).

Reaction conditions are given in Scheme 2.

(3aR*,4R*,6aS*)-5-Methyl-2-phenyl-4-(pyridin-2-yl)tetrahydro-pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (6)


-1):

νmax 1198, 1381, 1702, 2793, 2918; 1H NMR

(400 MHz, CDCl3): δ 2.17 (s, 3H), 3.01 (dd, 1H,

J = 9.6, 4.2 Hz), 3.45-3.50 (m, 1H), 3.74-3.79 (m,

1H), 3.84 (dd, 1H, J = 8.7, 3.6 Hz), 4.13 (d, 1H,

J = 3.6 Hz), 7.23-7.51 (m, 7H), 7.68-7.72 (m, 1H),

8.66 (dd, 1H, J = 4.8, 0.8 Hz ); 13

C NMR (100 MHz,

CDCl3): δ 37.9, 45.1, 51.5, 56.7, 72.1, 122.9, 123.9,

126.5, 128.6, 129.1, 132.0, 136.3, 149.9, 157.2, 177.6,

178.2; HRMS (ESI): Calcd for C18H18N3O2 [M + H]+

308.1399, found 308.1407.

(3aR*,4S*,6aS*)-5-Methyl-2-phenyl-4-(pyridin-2-yl)tetrahydro-pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (7)


-1):

νmax 1192, 1384, 1709, 2852, 2925; 1H NMR

(400 MHz, CDCl3): δ 2.25 (s, 3H), 2.72 (dd, 1H, J = 9.6,

7.2 Hz), 3.42 (t, 1H, J = 7.2 Hz), 3.68-3.74 (m, 2H),

3.82 (d, 1H, J = 8.8 Hz), 7.19-7.41 (m, 7H), 7.65-7.69

(m, 1H), 8.60-8.62 (m, 1H); 13

C NMR (100 MHz,

CDCl3): δ 39.9, 44.5, 50.1, 58.5, 74.6, 122.1, 123.1,

126.3, 128.5, 129.1, 131.9, 136.7, 149.4, 157.1, 174.9,

178.1; HRMS (ESI): Calcd for C18H18N3O2 [M+H]+

308.1399, found 308.1393.

5-Methyl-2-phenyl-4-(pyridin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (8/9)

Isolated as a mixture of isomers. Colourless solid;

decomposes after 170oC; IR: (KBr, cm

-1): νmax 1185,

1496, 1703, 2779, 2945; 1H NMR (400 MHz, CDCl3):

δ 2.22 (s, 3H), 2.68-2.75 (m, 1H), 3.34-3.41 (m, 1H),

3.56-3.75 (m, 3H), 7.19-7.52 (m, 7H), 8.59-8.64 (m,

2H); 13

C NMR (100 MHz, CDCl3): δ 39.0, 39.7, 44.1,

44.5, 50.4, 53.4, 57.6, 58.4, 71.4, 72.1, 122.7, 123.1,

126.1, 126.4, 128.6, 128.8, 129.1, 129.2, 131.6, 131.8,

146.2, 148.3, 150.0, 150.3, 174.2, 175.9, 176.4, 177.7

(The 13

C NMR given here for mixture of isomers);


308.1399, found 308.1413. The compounds (8/9)

could not be separated in pure form as the isomers

have similar Rf values.

Synthesis of nicotine derivatives (11/12) and (30/31)

Nicotinaldehyde (1a, 1 mmol), sarcosine (2, 1.2 mmol)

and diethyl fumarate (10a) or dimethyl fumarate (10b)

or fumaronitrile (10e) or diethyl maleate (10c) or

dimethyl maleate (10d) (1 mmol) in 1,4-dioxane


1119

(10 mL) was heated in a dry flask as above to obtain

the crude mixture (Schemes 3 and 4). Purification of

the crude reaction mixture through silica column

choromatography (EtOAc) afforded nicotine

derivatives (11/12) and (30/31). Reaction conditions

are given in Schemes 3 and 4.

(2S*,3R*,4R*)-Diethyl-1-methyl-2-(pyridin-3-yl)pyrrolidine-3,4-

dicarboxylate (11a)

Yellow viscous liquid; IR: (CH2Cl2, cm-1

):

νmax 1187, 1320, 1731, 2936, 2981; 1H NMR

(400 MHz,CDCl3): 0.76 (t, 3H, J = 7.1 Hz), 1.28 (t, 3H,

J = 7.1 Hz), 2.19 (s, 3H), 2.54 (t, 1H, J = 9.8 Hz), 3.48

(dd, 1H, J = 10.8, 7.1 Hz), 3.56-3.77 (m, 5H), 4.19

(q, 2H, J = 7.1 Hz), 7.24-7.28 (m, 1H), 7.67 (d, 1H,

J = 7.9 Hz), 8.51-8.54 (m, 2H); 13

C NMR (100 MHz,

CDCl3): δ 13.5, 14.2, 39.9, 44.6, 52.4, 58.5, 60.8, 61.1,

70.2, 123.3, 134.3, 135.8, 149.1, 150.2, 171.5, 172.7;

CIMS: m/z (%) 308 (20) [M+2]+, 307 (100) [M+1]

+,

293 (10) and 261 (10).

(2R*,3R*,4R*)-Diethyl-1-methyl-2-(pyridin-3-yl)pyrrolidine-3,4-dicarboxylate (12a)

Yellow viscous liquid; IR: (CH2Cl2, cm-1): νmax 1183,

1458, 1734, 2931, 2984; 1H NMR (400 MHz, CDCl3):

δ 1.15 (t, 3H, J = 7.1 Hz), 1.28 (t, 3H, J = 7.1 Hz),


1120

2.09 (s, 3H), 2.69 (dd, 1H, J = 9.7, 8.6 Hz), 3.29

(d, 1H, J = 8.6 Hz), 3.36-3.39 (m, 1H), 3.43 (dd, 1H,

J = 8.6, 5.2 Hz), 3.52 (dd, 1H, J = 9.7, 1.6 Hz), 4.04-

4.24 (m, 4H), 7.29 (dd, 1H, J = 7.8, 4.8 Hz), 7.77-7.80

(m, 1H), 8.53 (d, 2H, J = 2.6 Hz); 13

C NMR

(100 MHz, CDCl3): δ 14.1, 14.2, 39.6, 44.9, 54.8,

58.9, 61.2, 61.4, 72.0, 123.8, 135.5, 136.2, 149.4,

150.0, 172.6, 173.4; CIMS: m/z (%) 307 (100) [M+1]+,

304 (10) and 259 (5).

(2S*,3R*,4R*)-Dimethyl-1-methyl-2-(pyridin-3-yl)pyrrolidine-

3,4-dicarboxylate (11b) Yellow viscous liquid; IR: (CH2Cl2, cm

-1): νmax

1173, 1435, 1736, 2789, 2981; 1H NMR (400 MHz,

CDCl3): δ 2.07 (s, 3H), 2.44 (t, 1H, J = 9.2 Hz), 3.00

(s, 3H), 3.46 (t, 1H, J = 8.8 Hz) 3.49-3.57 (m, 2H),

3.60 (s, 3H); 3.64-3.67 (m, 1H), 7.15 (dd, 1H,

J = 7.9, 4.8 Hz), 7.54 (dd, 1H, J = 7.9, 1.4 Hz), 8.40

(d, 2H, J = 0.8 Hz); 13

C NMR (100 MHz, CDCl3): δ

39.9, 44.3, 51.6, 52.2, 52.5, 58.5, 70.2, 123.2, 134.1,

135.7, 149.1, 150.0, 171.8, 173.1; CIMS: m/z (%)

280 (20) [M+2]+, 279 (100) [M+1]

+, 247 (12)

and 217 (8).

(2R*,3R*,4R*)-Dimethyl 1-methyl-2-(pyridin-3-yl)pyrrolidine-

3,4-dicarboxylate (12b) Yellow viscous liquid; IR: (CH2Cl2, cm

-1): νmax 1180,

1456, 1734, 2800, 2923; 1H NMR (400 MHz, CDCl3):

δ 2.09 (s, 3H), 2.69 (t, 1H, J = 8.6 Hz), 3.31 (d, 1H,

J = 8.6 Hz), 3.36-3.40 (m, 1H), 3.48 (dd, 1H, J = 5.1,

8.6 Hz), 3.52 (dd, 1H, J = 1.2, 9.7 Hz), 3.64 (s, 3H),

3.76 (s, 3H), 7.30 (dd, 1H, J = 7.9, 4.8 Hz), 7.78 (dd,

1H, J = 7.9, 1.7 Hz), 8.53 (d, 2H, J = 1.7 Hz); 13

C NMR (100 MHz, CDCl3): δ 39.5, 44.9, 52.3, 52.6,

54.6, 58.9, 71.8, 123.9, 135.5, 136.1, 149.4, 149.8,

173.1, 173.9; CIMS: m/z (%) 279 (15) [M+1]+, 277

(50), 267 (14) and 262 (50).

(2S*,3R*,4R*)-1-Methyl-2-(pyridin-3-yl)pyrrolidine-3,4-dicarbo-

nitrile (30) Colourless solid; M. pt.: 122-124

oC; IR: (KBr,

cm-1

): νmax 1182, 1443, 2245, 2364, 2853, 2925; 1H NMR (400 MHz, CDCl3): δ 2.22 (s, 3H), 2.66

(t, 1H, J = 9.3 Hz), 3.45-3.50 (m, 1H), 3.62 (dd, 1H,

J = 7.6, 5.4 Hz), 3.67-3.71 (m, 2H), 7.38 (dd, 1H,

J = 7.8, 4.8 Hz), 7.78-7.81 (m, 1H), 8.59 (d, 1H,

J = 2.0 Hz), 8.64 (dd, 1H, J = 4.8, 2.0 Hz); 13

C NMR

(100 MHz, CDCl3): δ 31.1, 39.1, 40.7, 58.2, 68.5,

117.1, 118.1, 123.9, 131.0, 136.0, 149.9, 150.8;

HRMS (ESI): Calcd for C12H13N4 [M+H]+ 213.1140,

found 213.1134.

(2R*,3R*,4R*)-1-Methyl-2-(pyridin-3-yl)pyrrolidine-3,4-dicarbo-


oC; IR: (KBr, cm

-1):

νmax 1159, 1432, 2247, 2850, 2954; 1H NMR (400 MHz,

CDCl3): δ 2.14 (s, 3H), 2.78 (dd, 1H, J = 10.0, 8.7 Hz),

3.06 (dd, 1H, J = 8.7, 5.4 Hz), 3.31-3.36 (m, 2H), 3.50

(dd, 1H, J = 10.0, 1.7 Hz), 7.30 (dd, 1H, J = 7.8, 4.8

Hz) 7.68-7.71 (m, 1H), 8.56-8.57 (m, 2H); 13

C NMR:

(100 MHz, CDCl3): δ 31.0, 38.8, 42.2, 58.4, 71.9,

117.3, 119.4, 124.3, 132.2, 135.0, 149.3, 150.9;

HRMS (ESI): Calcd for C12H13N4 [M + H]+ 213.1140,

found 213.1133.

Synthesis of nicotine analogues (13-18)

Nicotine analogues (13-18) were obtained from

picolinaldehyde (1b) or isonicotinaldehyde (1c) (1 mmol),

sarcosine (2, 1.2 mmol) ) and diethyl fumarate (10a)

or dimethyl fumarate (10b) (1 mmol) in 1,4-dioxane

(10 mL) as above (Scheme 5). Purification of the

curde reaction mixture through silica column


nicotine derivatives (13-18). Reaction conditions are

given in Scheme 5.

(2S*,3R*,4R*)-Diethyl 1-methyl-2-(pyridin-2-yl)pyrrolidine-3,4-

dicarboxylate (13) Yellow viscous liquid; IR: (CH2Cl2, cm

-1): νmax 1178,

1589, 1733, 2778, 2980; 1H NMR (400 MHz, CDCl3):

δ 0.73 (t, 3H, J = 7.2 Hz), 1.23 (t, 3H, J = 7.2 Hz),

2.18 (s, 3H), 2.58 (t, 1H, J = 9.6 Hz), 3.46 (dd, 1H,

J = 10.8, 7.2 Hz), 3.53 (dd, 1H, J = 8.9, 7.9 Hz), 3.66-

3.79 (m, 3H), 3.88 (d, 1H, J = 9.6 Hz), 4.12 (dd, 1H,

J = 7.1, 0.9 Hz), 4.15 (dd, 1H, J = 7.1, 0.9 Hz), 7.13-

7.17 (m, 1H), 7.35 (d, 1H, J = 7.9 Hz), 7.60-7.65

(m, 1H), 8.51-8.53 (m, 1H); 13

C NMR (100 MHz,

CDCl3): δ 13.6, 14.2, 40.0, 44.7, 51.7, 58.3, 60.6, 61.0,

73.7, 122.5, 122.6, 136.5, 148.9, 158.8, 171.7, 172.9;


307.1658, found 307.1699.

(2R*,3R*,4R*)-Diethyl 1-methyl-2-(pyridin-2-yl)pyrrolidine-3,4-


-1): νmax 1182,

1585, 1734, 2782, 2975; 1H NMR (400 MHz, CDCl3):

1.08 (t, 3H, J = 7.1 Hz), 1.24 (t, 3H, J = 7.1 Hz), 2.13

(s, 3H), 2.74 (t, 1H, J = 9.4 Hz), 3.37-3.42 (m, 1H),

3.47 (d, 1H, J = 8.9 Hz), 3.54 (dd, 1H, J = 9.4, 2.3 Hz),

3.64 (dd, 1H, J = 8.9, 5.9 Hz), 3.99-4.10 (m, 2H),

4.16 (dd, 1H, J = 7.2, 1.9 Hz), 4.19 (dd, 1H, J = 7.2, 1.9

Hz), 7.15-7.19 (m, 1H), 7.41 (d, 1H, J = 7.8 Hz), 7.63-

7.67 (m, 1H), 8.54-8.56 (m, 1H); 13

C NMR (100 MHz,


1121

CDCl3): δ 14.0, 14.2, 39.8, 44.9, 53.7, 58.6, 61.0, 61.3,

75.7, 122.5, 122.8, 136.7, 149.3, 159.7, 172.8, 173.4;


307.1658, found 307.1652.

(2S*,3R*,4R*)-Diethyl 1-methyl-2-(pyridin-4-yl)pyrrolidine-3,4-


-1): νmax 1192,

1603, 1733, 2927, 2980; 1H NMR (400 MHz, CDCl3):

δ 0.74 (t, 3H, J = 7.1 Hz), 1.24 (t, 3H, J = 7.1 Hz), 2.16

(s, 3H), 2.50 (dd, 1H, J = 10.2, 9.1 Hz), 3.41-3.47 (m,

1H), 3.53-3.61 (m, 3H), 3.63-3.75 (m, 2H), 4.15 (q, 2H,

J = 7.2 Hz), 7.25 (dd, 2H, J = 4.6, 1.4 Hz), 8.52 (dd,

2H, J = 4.6, 1.4 Hz); 13


δ 13.5, 14.2, 40.0, 44.6, 52.3, 58.5, 60.8, 61.1, 71.7,

123.6, 148.0, 149.5, 171.3, 172.7; HRMS (ESI): Calcd

for C16H23N2O4 [M+H]+ 307.1658, found 307.1670.

Dimethyl 1-methyl-2-(pyridin-4-yl)pyrrolidine-3,4-dicarboxylate

(17/18) Isolated as a mixture of isomers. Yellow viscous


): νmax 1204, 1600, 1736, 2792,

2952; 1H NMR (400 MHz, CDCl3): δ 2.10 (s, 2H); 2.17

(s, 4H), 2.53 (dd, 1H, J = 10.4, 9.1 Hz), 2.69 (dd, 1H,

J = 9.1, 8.5 Hz), 3.10 (s, 4H), 3.32 (s, 1H), 3.44 (dd, 1H,

J = 8.5, 5.1 Hz), 3.49-3.55 (m, 2H), 3.62-3.64 (m, 5H),

3.70 (s, 4H), 3.75 (s, 3H), 7.21-7.32 (m, 4H), 8.51-8.56

(m, 4H); 13

C NMR (100 MHz, CDCl3): δ 39.6, 39.9,

44.4, 45.1, 51.5, 52.2, 52.5, 54.5, 58.5, 58.8, 71.6, 73.0,

123.0, 123.3, 147.8, 149.6, 149.9, 150.0, 171.5, 172.9,

173.0, 173.6 (The 1H NMR and

13C NMR is given here

for mixture of isomers); HRMS (ESI): Calcd for

C14H19N2O4 [M+H]+ 279.1345, found 279.1377.

Synthesis of nicotine derivatives (22-29)

A dry flask containing N-benzyl glycine (21),

triethyl amine and Na2SO4 in toluene (7-10 mL) was

stirred for 1 h and then to the falsk was added

nicotinaldehyde (1a) and N-phenyl malemide (3a) or

diethyl fumarate (10a) or dimethyl fumarate (10b).

The reaction mixture was processed as above to obtain

the crude products (Schemes 4 and 6). Purification of

the curde reaction mixture through silica column


nicotine derivatives (22-29). Reaction conditions are

given in Schemes 4 and 6.


1122

(3aR*,4R*,6aS*)-5-Benzyl-2-phenyl-4-(pyridin-3-yl)tetrahydro-pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (22)

Colourless solid; M. pt.: 70-72 oC; IR: (CH2Cl2, cm

-1):

νmax 1183, 1496, 1713, 2811, 2981; 1H NMR (400

MHz, CDCl3): δ 2.74 (dd, 1H, J = 10.0, 6.2 Hz), 3.22

(d, 1H, J = 13.3 Hz), 3.39-3.45 (m, 2H), 3.55-3.61

(m, 1H), 3.66 (d, 1H, J = 13.3 Hz), 3.98 (d, 1H,

J = 5.5 Hz), 7.19-7.48 (m, 11H), 7.70-7.73 (m, 1H),

8.59 (dd, 1H, J = 4.8, 1.5 Hz),8.69 (d, 1H, J = 1.9 Hz); 13

C NMR (100 MHz, CDCl3): δ 43.8, 53.0, 54.4, 55.9,

68.2, 123.8, 126.4, 127.6, 128.4, 128.6, 128.8, 129.3,

131.6, 134.5, 135.7, 137.2, 149.5, 149.7, 176.2, 176.7;

HRMS (ESI): Calcd for C24H22O2N3 [M+H]+

384.1706, found 384. 1698.

(2S*,3R*,4R*)-Dimethyl 1-benzyl-2-(pyridin-3-yl)pyrrolidine-

3,4-dicarboxylate (24) Colourless solid; M. pt.: 67-69

oC; IR: (KBr, cm

-1):

νmax 1168, 1435, 1735, 2924; 1H NMR (400 MHz,

CDCl3): δ 2.45 (dd, 1H, J = 10.0, 9.0 Hz), 3.12 (s, 3H),

3.16 (d, 1H, J = 13.2 Hz), 3.43 (dd, 1H, J = 9.0, 7.3 Hz);

3.66 (s, 3H), 3.77 (d, 1H, J = 13.2 Hz), 3.73 (d, 1H,

J = 2.5, 7.7 Hz), 3.68 (d, 1H, J = 6.2 Hz), 4.00 (d, 1H,

J = 10.0 Hz), 7.22-7.29 (m, 6H), 7.77-7.80 (m, 1H), 8.52

(dd, 1H, J = 4.8, 1.8 Hz),8.59 (d, 1H, J = 1.8 Hz); 13

C NMR (100 MHz, CDCl3): δ 44.2, 51.6, 51.9,

52.2, 55.0, 57.3, 67.8, 123.3, 127.3, 128.4,

128.6, 134.5, 135.8, 137.6, 149.4, 150.4, 171.7,

173.0; HRMS (ESI): Calcd for C20H23O4N2

[M+H]+ 355.1658, found 355.1646.

(2R*,3R*,4R*)-Dimethyl 1-benzyl-2-(pyridin-3-yl)pyrrolidine-

3,4-dicarboxylate (25) Colourless viscous liquid; IR: (KBr, cm

-1): νmax 1173,

1435, 1735, 2953; 1H NMR (400 MHz, CDCl3): δ 2.63

(dd, 1H, J = 9.9, 9.4 Hz), 3.10 (d, 1H, J = 13.4 Hz),

3.39 (t, 1H, J = 2.1 Hz), 3.37 (1H, brs), 3.48 (dd, 1H,

J = 8.5, 5.4 Hz), 3.64-3.72 (m, 2H), 3.71 (s, 3H), 3.65

(s, 3H), 7.19-7.33 (m, 6H), 7.89-7.92 (m, 1H), 8.55

(dd, 1H, J = 4.7, 1.4 Hz), 8.64 (d, 1H, J = 1.6 Hz); 13

C NMR (100 MHz, CDCl3): δ 44.7; 52.3, 52.5, 54.5,

55.3, 56.7, 69.6, 123.9, 127.2, 128.3, 135.5, 136.4,


1123

137.9, 149.5, 150.0, 173.0, 173.7; HRMS (ESI): Calcd

for C20H23N2O4 [M + H]+ 355.1658, found 355.1652.

Diethyl 1-benzyl-2-(pyridin-3-yl)pyrrolidine-3,4-dicarboxylate

(26/27) Isolated as a mixture of isomers. Colourless viscous


): νmax 1028, 1372, 1731,

2981; 1H NMR (400 MHz, CDCl3): δ 0.79 (t, 3H,

J = 7.1 Hz), 1.18-1.27 (m, 4H), 2.46 (dd, 1H, J = 10.1,

9.2 Hz), 3.18 (d, 1H, J = 13.4 Hz), 3.36-3.52 (m, 2H),

3.64-3.84 (m, 3H), 4.02-4.26 (m, 3H), 7.24-7.39 (m,

6H), 7.81-7.95 (m, 1H), 8.53 (dd, 1H, J = 4.8, 1.6 Hz),

8.64 (d, 1H, J = 1.8 Hz) (The 1H NMR is given here

for major isomer); 13


δ 13.6. 14.1, 14.2, 44.4, 44.8, 51.8, 54.6, 55.1, 55.3,

56.6, 57.3, 60.8, 61.0, 61.1, 61.2, 67.8, 69.8, 123.3

123.8, 127.1, 127.3, 128.2, 128.3, 128.4, 128.6, 134.8,

135.5, 136.0, 136.5, 137.8, 138.1, 149.3, 149.4, 150.1,

150.5, 171.3, 172.5, 172.6, 173.3 (The 13

C NMR is

given here for mixture of isomers). HRMS (ESI):

Calcd for C22H27N2O4 [M + H]+ 383.1965, found

383.1969. (2R*,3R*,4R*)-1-Benzyl-2-(pyridin-3-yl)pyrrolidine-3,4-dicarbo-


oC; IR: (CH2Cl2,

cm-1

): νmax 1027, 1430, 2247, 2364, 2820, 2929; 1H NMR (400 MHz, CDCl3): δ 2.82 (dd, 1H, J = 10.2,

7.9 Hz), 3.22 (dd, 1H, J = 8.6, 5.6 Hz), 3.25 (d, 1H,

J = 13.6 Hz), 3.38-3.42 (m, 1H), 3.46 (dd, 1H, J = 10.2,

2.0 Hz), 3.74 (d, 1H, J = 8.6 Hz), 3.85 (d, 1H, J = 13.6

Hz), 7.22-7.24 (m, 2H), 7.22-7.37 (m, 3H), 7.45 (dd,

1H, J = 7.8, 4.8 Hz), 7.92-7.95 (m, 1H), 8.69-8.70 (m,

1H), 8.79 (d, 1H, J = 1.5 Hz); 13

C NMR (100 MHz,

CDCl3): δ 30.9, 42.0, 55.1, 55.8, 69.8, 117.2, 119.2,

124.5, 127.9, 128.4, 128.8, 132.4, 135.1, 135.8, 149.4,

151.0; HRMS (ESI): Calcd for C18H17N4 [M + H]+

289.1447, found 289.1445.

Results and Discussion Initially, we carried out the trapping of azomethine

ylide generated from nicotinaldehyde (1a) and

sarcosine (2) with N-phenylmaleimide (3a) under

various reaction conditions to get the products (4a)

and (5a) in good yields (Table 1). The reaction of

nicotinaldehyde (1a) and sarcosine (2) with

N-phenylmaleimide (3a) in 1,4-dioxane at 100 °C for

3 h gave the nicotine analogues (4a) and (5a), having

three stereocenters (57% yield, dr = 65:35, Table 1,

entry a). The compounds (4a) and (5a) were isolated

in pure form and characterized by 1H and

13C NMR

spectroscopy. The reaction in 1,4-dioxane at 100 °C

for 6 h or 12 h afforded the nicotine analogues (4a)

and (5a) in very good yields (86%, dr = 65:35, Table 1,

entries b and c). Further, the reaction was performed

in 1,4-dioxane at 80 °C or 60 °C for 6 h, which

afforded the nicotine analogues (4a) and (5a) in 30%

(dr = 65:35) and <10% yields, respectively (Table 1,

entries d and e). These results indicate that lowering

the reaction temperatures gave relatively low yields of

the nicotine analogues but the diastereoselectivity was

unaffected (Table 1, entry d).

The reaction in acetonitrile gave the diastereomers

(4a) and (5a) in good yields (75% yield, dr = 65:35,

Table 1, entry f). The cycloaddition reaction of

azomethine ylide generated from nicotinaldehyde (1a)

and sarcosine (2) with N-phenylmaleimide (3a) in a

less polar solvent, e.g. toluene, gave the diastereomers

(4a) and (5a) in only 35% yields (dr = 66:34, Table 1,

entry g). The low yields in this reaction are perhaps

due to the low solubility of the starting materials in

toluene. Further, we also performed the reaction in

EtOH at 78 °C and MeOH at 64 °C, which gave the

diastereomers (4a) and (5a) in 55% (dr = 60:40) and

20% (dr = 60:40) yields, respectively (Table 1, entries

h and i). The low yields in this case may be due to the

effect of the temperature as the reactions were carried

out at the refluxing temperatures of the corresponding

solvents (EtOH and MeOH). These results are

comparable with the results obtained when the

reactions were performed in 1,4-dioxane at 80 °C or

60 °C for 6 h instead of 100 °C (Table 1, entries d and

e). Hence, we found that the reaction in 1,4-dioxane at

100 °C for 6 h as the best reaction condition, which

gave the nicotine analogues (4a) and (5a) in good

yields (Table 1, entry b).

The generality of this approach was then

established for the diastereoselective synthesis of a

new class of nicotine derivatives having contiguous

stereocenters (Table 2). The intermolecular

cycloaddition of azomethine ylide derived from the

condensation reaction of nicotinaldehyde (1a) and

N-methyl glycine (2) with several symmetrical

dipolarophiles (3b-i) was carried out in 1,4-dioxane

at 100 °C for 6 h or 12 h (Table 2). In all the

reactions, several new nicotine derivatives (4/5) were

obtained in very good yields. Representatively, the

stereochemistry of the nicotine analogue (4b) was

unequivocally established from the X-ray structure

analysis (Fig. 1). In the major compound (4b), it has

been noticed that the stereochemistry is trans with


1124

respect to the aryl and amide moieties (1,2-positions).

Based on the X-ray structure analyses of the molecule

(4b) and the similarity in the 1H /

13C NMR spectral

patterns of the compounds (4a-i), the stereochemistry

of the other products (4a/4c-i) was assigned.

The stereochemistry of the products (5a-i) was

assigned after assigning the stereochemistry of the

compounds (4a-i).

Subsequently, we also carried out the

intermolecular cycloadditions of azomethine ylide

derived from the condensation of picolinaldehyde (1b)

or isonicotinaldehyde (1c) and N-methyl glycine (2)

with N-phenylmaleimide (3a) to get the pyrrolidine

derivatives similar to the nicotine derivatives (4/5)

(Scheme 2). The reaction of picolinaldehyde (1b) or

isonicotinaldehyde (1c) and N-methyl glycine with

N-phenylmaleimide in 1,4-dioxane at 100 °C gave the

corresponding functionalized pyrrolidine derivatives

(6/7) and (8/9) analogous to the compounds (4/5). The

compound (6) was characterized by 1H and

13C NMR

spectroscopy/HRMS and the stereochemistry of the

pyrrolidine derivative (6) was unambiguously

established from the X-ray structure analysis (Fig. 2).

Notably, like in the major compound (4b), the

stereochemistry is trans with respect to the aryl and

amide moieties (1,2-positions) in the major compound

(6). The stereochemistry of the isomer (7) was

assigned after establishing the stereochemistry of the

compound (6). Since compounds (8/9) had the same

Rf value, they could not be separated by the column

chromatographic purification and were isolated as a

mixture of isomers.

Next, we carried out the cycloadditions of

azomethine ylide with diethyl fumarate (10a) or

dimethyl fumarate (10b) in 1,4-dioxane at 100 °C to

get the functionalized pyrrolidine (nicotine)

derivatives having three contiguous stereocenters. The

intermolecular cycloaddition reaction of the


with diethyl fumarate (10a) or dimethyl fumarate

(10b) furnished the corresponding nicotine derivatives

(11a, b) and (12a, b) in good yields (Scheme 3). The

nicotine derivatives (11a, b) and (12a, b) were

characterized by 1H /

13C NMR spectroscopy/mass

analysis.40,41

Successively, we carried out the reactions of

picolinaldehyde (1b) or isonicotinaldehyde (1c) and

N-methyl glycine with diethyl fumarate (10a) or

dimethyl fumarate (10b) in 1,4-dioxane at 100 °C,

which gave the corresponding functionalized

2-pyridylpyrrolidine derivatives (13-18), analogous to

the compounds (11/12) (Scheme 5). The compounds

(13-15) were isolated in pure form. However, since

the compounds (17/18) had the same Rf value, they

could not be separated by column chromatographic

purification and were isolated as a mixture of isomers.

The stereochemistry of the products (13/14) was

assigned on the basis of the similarity in the 1H /

13C

NMR spectral patterns of the compounds (13/14) with

the respective compounds (11a, b) and (12a, b).

Intermolecular cycloaddition reaction of the


and sarcosine (2) with diethyl maleate (10c), furnished

the nicotine derivatives (11a) (37%) and (12a) (46%)

instead of the expected nicotine analogues (19a) and

(20a) (Scheme 7). The 1H /

13C NMR spectra of the

products (11a) and (12a) obtained in this reaction

were same as the products obtained in the reaction of

nicotinaldehyde (1a) and sarcosine (2) with diethyl

fumarate (10a) (Scheme 3). We also observed the

same reactivity pattern in the reaction of

nicotinaldehyde (1a) and sarcosine (2) with dimethyl

maleate (10d), which gave the corresponding products

(11b) and (12b) instead of (19b/20b) (Scheme 7). This

is because at higher temperatures the dipolarophiles

(10c, d) (cis geometry) undergo isomerization

(from cis to trans), generating the corresponding

dipolarophiles (10a, b) (trans geometry), which further

Fig. 1 – X-ray structure (ORTEP) of the nicotine analogue 4b.

Fig. 2 – X-ray structure (ORTEP) of the pyrrolidine derivative (6).


1125

react with the azomethine ylide to give the respective

products (11a, b) and (12a, b).41

The intermolecular cycloaddition of azomethine

ylide derived from condensation of nicotinaldehyde

(1a) and N-benzyl glycine hydrochloride (21) with

N-phenylmaleimide (3a) and dialkyl fumarates (10a, b)

was investigated (Scheme 6). The cycloaddition

reaction with the dipolarophile N-phenylmaleimide (3a)

proceeded in toluene at 100 °C to give the new nicotine

analogues (22/23) (83%, dr = 70:30) Under similar

conditions, the cycloaddition of azomethine ylide

generated from (1a) and N-benzyl glycine

hydrochloride with the dipolarophiles such as dialkyl

fumarates (10a, b) furnished the corresponding nicotine

analogues (24-27) in very good yields (Scheme 6). The

compounds (24) and (25)41

were isolated in pure form,

however, the compounds (23), (26) and (27) could not

be separated from their corresponding isomers by

column chromatographic purification and isolated as a

mixture of isomers (Scheme 6). The nicotine derivative

(24) was characterized by 1H /

13C NMR

spectroscopy/mass analysis and the stereochemistry of

the nicotine analogue (24) was assigned from the X-ray

structure analysis (Fig. 3). The stereochemistry is

cis with respect to the aryl and methyl ester moiety

(1,2-positions) in the major compound (24). After

assigning the stereochemistry of the compound (24),

the stereochemistry of its corresponding isomer (25)

was assigned.

Finally, we carried out the cycloaddition reaction of


and N-benzyl glycine hydrochloride (21) with the

fumaronitrile (10e), in toluene at 100 °C to obtain the

new nicotine analogues (28/29) (90%, dr = 40:60)

(Scheme 4). Likewise, the products (30) (31%) and

(31) (59%) were obtained from the cycloaddition

reaction of azomethine ylide generated from

nicotinaldehyde (1a) and sarcosine (2) with the

fumaronitrile (10e).

The nicotine derivatives (28), (30) and (31) were

characterized by 1H/

13C NMR spectroscopy/mass data.

Stereochemistry of the nicotine analogues (29) and (31)

assigned from the X-ray structure analysis (Fig. 4) was

found to be trans with respect to the aryl and cyano

Fig. 3 – X-ray structure (ORTEP) of the nicotine analogue (24).


1126

moiety (1,2-positions) in the major compounds (29/31).

After assigning the stereochemistry of the products

(29/31), the stereochemistry of the compound (30) was

assigned.

Conclusions The diastereoselective synthesis of various nicotine

derivatives having contiguous stereocenters via the

intermolecular cycloaddition of azomethine ylide

derived from the condensation of nicotinaldehyde and

N-methyl glycine/N-benzyl glycine hydrochloride has

been carried out with several symmetrical

dipolarophiles (maleimides, dialkyl fumarates, dialkyl

maleates and fumaronitrile). The present procedure has

led to the synthesis of a small collection of new nicotine

analogues and functionalized 2-pyridylpyrrolidine

derivatives. Further investigations on biological

activities and application of the compounds obtained in

this work are in progress.

Supplementary Data

Crystallographic data of the X-ray structures

of (4b) = CCDC 931881; (6) = CCDC 931882;

(24) = CCDC 931884; (29) = CCDC 932693; (31) =

CCDC 931883 has been deposited at the Cambridge

Crystallographic Data Centre. These may be obtained

free of charge from the Cambridge Crystallographic

Data Centre, 12, Union Road, Cambridge CB2 1EZ,

UK. Other supplementary data associated with this

article, i e., copy of 1H,

13C NMR data of all the

compounds, are available in the electronic form

at http://www.niscair.res.in/jinfo/ijca/IJCA_52A(8-

9)1113-1127_SupplData.pdf.

Acknowledgement This research was funded by IISER-Mohali and the

Fast Track Young Scientist Scheme (No. SR/FT/CS-

085/2009 dated 18th June 2010), DST, New Delhi. VR

is thankful to IISER-Mohali for a Junior Research

Fellowship. We thank National Institute of

Pharmaceutical Education and Research, Mohali,

India, CSIR-Central Drug Research Institute,

Lucknow, India, and CSIR-Indian Institute of

Chemical Technology, Hyderabad, India, for

providing the mass spectral data.

References 1 Leete E, in Alkaloids, Chemical and Biological Perspectives

Vol. 1, edited by S W Pelletier, (John Wiley & Sons, New

York) 1983, p. 85.

2 Strunz G M & Findlay J A, in The Alkaloids, Chemistry and

Pharmacology, edited by A Brossi, (Academic Press,

Orlando) 1985, Vol. 26, p. 89.

3 Pailer M, in Tobacco Alkaloids and Related Compounds,

edited by U S von Euler, (Pergamon, New York) 1965 p. 15.

4 Gorrod J W & Jacob P, in Analytical Determination of

Nicotine and Related Compounds and Their Metabolites,

(Elsevier, New York) 1999, p. 1.

5 Shepard H H, in The Chemistry and Action of Insecticides,

(McGraw-Hill, New York) 1951.

6 Webster R A, Neurotransmitters, Drugs and Brain Function,

(John Wiley & Sons, Chichester) 2001, p. 1.

7 Lloyd G K & Williams M J, Pharmacol Exp Ther, 292

(2000), 461.

8 Romanelli M N & Gualtieri F, Med Res Rev, 23 (2003) 393.

9 Levin E D, J Neurobiol, 53 (2002) 633.

10 Newhouse P A & Kelton M, Pharm Acta Helv, 74 (2000) 91.

11 Breining S R, Curr Top Med Chem, 4 (2004) 609.

12 Jensen A A, Frølund B, Liljefors T & Krosgsgaard-Larsen P,

J Med Chem, 48 (2005) 4705.

13 Holladay M W, Dart M J & Lynch J K, J Med Chem, 40

(1997) 4169.

14 Wagner, F F & Comins D L, Tetrahedron, 63 (2007) 8065.

15 McDonald I A, Vernier J.-M, Cosford N & Corey-Naeve J,

Curr Pharm Des, 2 (1996), 357.

16 Cosford N D P, Bleiker L, Dawson H, Whitten J P, Adams P,

Chavez-Noriega L, Correa L D, Crona J H, Mahaffy L S,

Menzaghi F M, Rao T S, Reid R, Sacaan A I, Santori E,

Stauderman K, Whelan K, Lloyd G K & McDonald I A, J

Med Chem, 39 (1996) 3235.

17 Smith E D, Février F C & Comins, D L, Org Lett, 8 (2006) 179.

18 Apsunde T D & Trudell M L, Synthesis, 45 (2013) 2120 and

references therein.

19 Gurpinder S, Ishar M P S, Girdhar N K & Singh L, J

Heterocycl Chem, 42 (2005) 1047.

20 Gurpinder S, Munusamy E, Venkatesan S & Ishar M P S,

Heterocycles, 68 (2006) 1409.

21 Harwood L M & Vickers R J, in Synthetic Applications of

1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles

and Natural Products, edited by A Padwa & W H Pearson,

(Wiley, New York) 2003, p. 169.

22 Padwa A, in 1,3-Dipolar Cycloaddition Chemistry, (Wiley,

New York) 1984.

23 Coldham I & Hufton R, Chem Rev, 105 (2005) 2765.

24 Pandey G, Banerjee P & Gadre S R, Chem Rev, 106 (2006) 4484.

25 Nájera C & Sansano J, Org Biomol Chem, 7 (2009) 4567.

26 Huisgen R, Niklas K, Heterocycles, 22 (1984) 21.

27 Rajkumar V, Aslam N A, Reddy C & Babu S A, Synlett,

(2012) 549.

28 Ramesh E, Kathiresan M & Raghunathan R, Tetrahedron

Lett, 48 (2007) 1835.

Fig. 3 – X-ray structures (ORTEP) of (29) and (31).

http://www.niscair.res.in/jinfo/ijca/IJCA_52A(8-9)1113-1127_SupplData.pdf


1127

29 Karthikeyan K, Saranya N, Kalaivani A & Perumal P T,

Synlett, (2010) 2751.

30 Shanmugam P, Viswambharan B, Selvakumar K & Madhavan S,

Tetrahedron Lett, 49 (2008) 2611.

31 Hemamalini A, Nagarajan S, Ravinder P, Subramanian V &

Das T M, Synthesis, (2011) 2495.

32 Purushothaman S, Prasanna R, Niranjana P, Raghunathan R,

Nagaraj S & Rengusamy R, Bioorg Med Chem Lett, 20

(2010) 7291.

33 Kumar R R, Perumal S, Senthilkumar P, Yogeeswari P &

Sriram D, J Med Chem, 51 (2008) 5731.

34 Girgis A S, Eur J Med Chem, 44 (2009) 1257.

35 Nair V, Mathai S, Augustine A, Viji S & Radhakrishnan K V,

Synthesis, (2004) 2617.

36 Pearson W H, in Synthetic Applications of 1,3-Dipolar

Cycloaddition Chemistry Toward Heterocycles and Natural

Products, edited by A Padwa, (Wiley, New York) 2002, p. 170.

37 Ghandi M, Taheri A & Abbasi A, J Heterocycl Chem, 47

(2010) 611.

38 Cheng B & Zhai H, Synlett, (2009) 1955.

39 Bashiardes G, Picard S & Pornet J, Synlett, (2009) 2497.

40 The 1H /13C NMR spectral patterns of the compounds (11a)

and (11b) were similar. Likewise, the 1H /13C NMR spectral

patterns of the compounds (12a) and (12b) were similar. On

the basis of the X-ray structure of the nicotine analogue (24)

(see Fig. 3) and the similarity in the 1H /13C NMR spectral

patterns of the respective compounds (11a, b), with the

compounds (24) and (26), the stereochemistry of the products

(11a, b) and (12a, b) was assigned.

41 Generally, in the major compounds (12a), (14) and (16), it

has been noticed that the stereochemistry is trans with respect

to the aryl and ethyl ester moieties (1,2-positions) which may

be due to steric interactions. Contrary to this observation, we

obtained the compounds (12b) and (25) as the minor isomers

having trans stereochemistry with respect to the aryl and

methyl ester moieties (while using dimethyl fumarate). The

reason is not clear at this stage and further detailed studies are

being carried out to investigate this aspect.

diastereoselective construction of a new class of nicotine...

Documents