Rapid and one-pot synthesis of tri- to tetradeca-deutero nicotines

Article abstract of DOI:10.1016/j.tetlet.2020.151680

A very rapid one-pot synthesis of (±)-nicotine and tri- to tetradeca-deuterated nicotines is described where the synthetic sequence requires less than 4 h.

Full text of DOI:10.1016/j.tetlet.2020.151680

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Rapid and one-pot synthesis of tri- to tetradeca-deutero nicotines
Pashikanti Gouthami a, Gadela Karteek Goud a,b, Prathama S. Mainkar a,b, Srivari Chandrasekhar a,b,
⇑
a Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500007, India
b Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A very rapid one-pot synthesis of ( )-nicotine and tri- to tetradeca-deuterated nicotines is described
where the synthetic sequence requires less than 4 h.
Received 27 December 2019
Revised 24 January 2020
Accepted 26 January 2020
Available online xxxx
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Deuterium
Tetradeca-deuterated
Metabolism
Tobacco
Synthesis of bioactives engaging stereo-flexible strategies has
been in the forefront, which enables access to analogues with ease
for SAR and drug discovery. Recently, the replacement of hydrogen
‘H’ with deuterium ‘D’ has triggered newer interest in pharmaceu-
tical industry [1]. The deuterated version gives prolonged meta-
bolic stability [2]. Several patents have been filed specially in the
domain of pharmaceuticals which highlight the incorporation of
deuteration at key sites of the chosen molecules [3]. The ‘D’ incor-
poration is expected to provide better stability and pKa. To provide
access to deuterated compounds, researchers have developed sev-
eral methods [4]. Major procedure for deuterium incorporated
molecules can be classified into (i) substrate driven where sub-
strate already possess deuterium incorporation. (ii) The second
procedure is to react substrates with deuterated reagents viz.
LiAlD4, NaBD4 etc. (iii) The third procedure may involve transition
metal catalyzed hydrogenation using D2 gas on olefins or alkynes,
(iv) exchange of H with D with catalysts and (v) other base cataly-
sis in presence of D2O is also used for deuteration [5–15].
Genus Nicotiana is one of the largest members of Solanaceae
family. (S)-Nicotine 1 is the major constituent alkaloid of tobacco
(N. rustica, N. tabacum, A. syriaca) along with anatabine, anabasine,
nornicotine and (R)-nicotine (Fig. 1) [18]. While nicotine is
described in the literature as a health hazard, it is also documented
as as a pharmaceutical product for the treatment of Parkinson’s
(PD) and Alzheimer’s diseases (AD), schizophrenia, attention defi-
ciency/hyperactivity and Tourette’s syndrome [19,20]. in addition
to its insecticidal properties [21]. Nicotine has the ability to cross
‘Blood Brain Barrier’ and is extensively metabolized by the liver
to a number of compounds [22]. There is no epidemiological evi-
dence that nicotine acts as a carcinogen, but several experiments
have proved it to stimulate cancer cells [23].
The observation that nicotine undergoes a rapid metabolism in
liver provided a thought to explore if deuterated analog will have
better stability in living systems. Thus, access to deuterium incor-
poration at various sites of nicotine becomes an essential require-
ment for biological studies. The initial attempts to follow some of
the known synthetic methods for nicotine with a few alterations
to access deuterated analogues were only partially successful due
to multiple steps involved in the synthesis.
These methodologies of deuteration enabled researchers to syn-
thesize deuterated FDA approved drugs and one such example is
deutetrarobenazine useful in Huntigton’s disease [16]. The FDA
approval was given for metabolic stability the deuterated version
offered. Our group has been engaged in total synthesis of alkaloids
of medicinal relevance and also deuterated chemicals as building
blocks in drug discovery [17].
We reasoned, that a short synthesis with flexibility in access to
raw materials is essential towards achieving various deuterated
nicotines. To our satisfaction, we were able to synthesize ( )-nico-
tine in a single pot in 4 h of operation.
We envisioned that the coupling of 3-bromo pyridine with N-
methyl succinimide could give the desired product. The advantage
of this methodology was that all the carbons bearing hydrogen
could be converted selectively or totally into ‘D’ bearing carbons
which include even the N-CH3 group. Thus, the reaction of 3-bromo
⇑
Corresponding author at: Department of Organic Synthesis & Process Chem-
istry, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500007,
India.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
https://doi.org/10.1016/j.tetlet.2020.151680
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Gouthami, G. Karteek Goud, P. S. Mainkar et al., Rapid and one-pot synthesis of tri- to tetradeca-deutero nicotines, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2020.151680

2
P. Gouthami et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Various constituents of Tobacco.
pyridine with N-methyl succinimide mediated by n-BuLi at À78 °C
for 1 h generated the adduct A which is in equilibrium with imine
B [24]. Addition of THF followed by LiAlH4 provided ( )-nicotine in
less than 3 h with 65% yield involving minimal purification steps
(Scheme 1). After optimization of this one-pot process for nicotine
synthesis, we looked at various sources of deuteration to synthe-
size deuterated nicotine with varying degrees of D incorporation.
The deuterated N-methyl succinimide was prepared following
the procedures described in Scheme 2. N-methyl succinimide 8
was N-alkylated with either CH3I or CD3I to get 6 or 6-d3 in 92%
yield by treating with K2CO3, acetone and CH3I or CD3I [12].
Thus obtained 6/6-d3 was convened to 6-d4/d7 in CD3OD in pres-
ence of NaOAc in good yields (Scheme 2). This sequence allowed us
access to N-methyl succinimide (6, 6-d3, 6-d4 and 6-d7) with vari-
ous levels of deuteration. With this in hand, the lithiated pyridine
(generated by adding n-BuLi to 3-bromo pyridine 5) was added to
6-d4 to obtain the pyridine-pyrrolidine adduct (Scheme 3a). To the
same flask was added either LiAlH4 or LiAlD4 to generate ( )-
nicotine (7-d4 or 7-d7) in over 65% yield (Scheme 3a). To synthesize
( )-nicotine (7-d3), the lithiated pyridine reaction of n-Buli and
3-bromo pyridine 5 was added to 6 followed by reduction with
LiAlD4 (Scheme 3b).
Scheme 3. Synthesis of 7-d3/d4/d7.
Similarly, the lithiated deuteropyridine (generated by reaction
between n-BuLi and tetradeutero 3-bromopyridine 5-d4) was
allowed to react with 6-d4 or 6-d7 followed by reduction with
LiAlD4 to synthesize ( )-nicotine 7-d11 or 7-d14 respectively, in over
60% yield (Scheme 4).
In conclusion, the shortest synthesis of nicotine is described
with building blocks amenable to deuteration.
Scheme 4. Synthesis of 7-d11/d14 nicotines.
Justification
1. A very fast one-pot synthesis of (+)-nicotine and tri- to tetra-
deca-deuterated nicotines is described where the synthetic
sequence requires less than 4 h.
2. The scheme has the flexibility to allow insertion of deuterium
on any carbon of choice and total substitution of hydrogen with
deuterium.
3. The work will be of interest to synthetic organic chemists and
medicinal chemists as alkaloid analogues with selective or total
deuteration can be synthesized with ease.
4. The manuscript will also interest biologists and pharmacolo-
gists to understand the mechanism of molecules crossing
blood–brain barrier (BBB) and stability of deuterated molecules
in the living systems.
Scheme 1. One-pot synthesis of ( )-nicotine.
CSIR-IICT manuscript communication number
IICT/Pubs./2019/104.
Acknowledgments
The authors thank the Council of Scientific and Industrial
Research, Department of Science and Technology, Government of
Scheme 2. Synthesis of d4/d7-Succinimides.
Please cite this article as: P. Gouthami, G. Karteek Goud, P. S. Mainkar et al., Rapid and one-pot synthesis of tri- to tetradeca-deutero nicotines, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2020.151680

P. Gouthami et al. / Tetrahedron Letters xxx (xxxx) xxx
M. Stoltz, W.-B. Liu, J. Am. Chem. Soc. 140 (2018) 10970–10974;
3
India for research grants. P.G. and G.K.G. thank the Council of
Scientific and Industrial Research (CSIR), New Delhi for research
fellowship. S.C. thanks DST for the J. C. Bose fellowship (SB/S2/
JCB-002/2015) for financial support.
(c) T.R. Puleo, A.J. Strong, J.S. Bandar, J. Am. Chem. Soc. 141 (2019) 1467–1472.
[12] M. Espinal-Viguri, S.E. Neale, N.T. Coles, S.A. MacGregor, R.L. Webster, J. Am.
Chem. Soc. 141 (2019) 572–582.
[13] (a) R. Corbera´n, M. Sanau, E. Peris, J. Am. Chem. Soc. 128 (2006) 3974–3979;
(b) M.B. Skaddan, C.M. Yung, R.G. Bergman, Org. Lett. 6 (2004) 11–13.
[14] J.L. Koniarczyk, D. Hesk, A. Overgard, I.W. Davies, A. McNally, J. Am. Chem. Soc.
140 (2018) 1990–1993.
[15] T. Yamada, M. Kuwata, R. Takakura, Y. Monguchi, H. Sajiki, Y. Sawarna, Adv.
Synth. Catal. (2018) 631–637.
[16] C. Schmidt, Nat. Biotech. 35 (2017) 493–494.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151680.
[17] (a) T. Venkatesh, P.S. Mainkar, S. Chandrasekhar, Org. Biomol. Chem. 17 (2019)
2192–2198;
(b) N. Goli, S. Kallepu, P.S. Mainkar, J.K. Lakshmi, R. Chegondi, S.
Chandrasekhar, J. Org. Chem. 83 (2018) 2244–2249;
References
(c) P. Gouthami, R. Chegondi, S. Chandrasekhar, Org. Lett. 18 (2016) 2044–
2046;
(d) D.M. Lade, A.B. Pawar, P.S. Mainkar, S. Chandrasekhar, J. Org. Chem. 82
(2018) 4998–5004;
(e) S. Chandrasekhar, M. Pendke, C. Muththe, S.M. Akondi, P.S. Mainkar,
Tetrahedron Lett. 53 (2012) 1292–1295;
(f) S. Chandrasekhar, B.V.D. Vijaykumar, B. Mahesh Chandra, Ch. Reddy, R,
Tetrahedron Lett. 52 (2011) 3865–3867.
[1] (a) J. Atzrodt, V. Derdau, T. Fey, J. Zimmermann, Angew Chem. 119 (2007)
7890–7911, Angew. Chem. Int. Ed. 2007, 46, 7744–7765;
(b) T. Junk, W.J. Catallo, Chem. Soc. Rev. 26 (1997) 401–406;
(c) Y. Sawama, Y. Monguchi, H. Sajiki, Synlett 23 (2012) 959–972.
[2] (a) L. Citrome, Int. J. Clin. Pract. 70 (2016) 298–299;
(b) E.M. Coppen, R.A. Roos, Drugs 77 (2017) 29–46;
(c) J. Jankovic, J. Beach, Neurology 48 (1997) 358–362;
(d) C. Kenney, C. Hunter, J. Jankovic, Mov. Disord. 22 (2007) 193–197;
(e) K.E. Anderson, D. Stamler, Davis, D. Mat, R.S.A. Factor, A. Hauser, J. Isojärvi,
F.L. Jarskog, Jimenez-J. Shahed, R. Kumar, J.P. McEvoy, S. Ochudlo, W.G. Ondo,
H.H. Fernandez, The Lancet 4 (2017) 595–604.
[18] (a) L. Metcalf Robert, Insect Control, Ullmann’s Encyclopedia of Industrial
Chemistry, 2007, 7th ed., 9.;
(b) J.F. Whidby, J.I. Seeman, J. Org. Chem. 41 (1976) 1585–1590;
(c) E. Leete, M.E. Mueller, J. Am. Chem. Soc. 104 (1982) 6440–6444.
[19] (a) I.A. McDonald, N. Cosford, J.-M. Vernier, Ann. Rep. Med. Chem. 30 (1995)
41–50;
[3] For patents, see: (a) Li, J.; Suppiah, S.; Kutchcoskie, K. US2005181938, 2005. (b)
Mao, J.; Liu, Z.; Tang, C.; He, Y.; Zhu, J.; Chen, Y.; Mao, Z.; Chai, S.
WO2005050196, 2005. (c) Seto, H.; Fujioka, S.; Yoshida, S. JP2003128692,
2003. (d) Myasoedov, N. F.; Shevchenko, V. P.; Faradzheva, S. V.; Nagaev, I.
RU2108337, 1998. (e) Heung, L. K.; Wicks, G. G. US967653, 1995. (f) Giribone,
D.; Fontana, E. WO2003080587, 2003. (g) Sakai, M.; Sugimoto, Y.
WO2003081229, 2003. (h) Hirota, K.; Sajiki, H. WO03104166, 2003.
[4] (a) J. Atzrodt, V. Derdau, T. Fey, J. Zimmermann, Angew. Chem. Int. Ed. 46
(2007) 7744–7765;
(b) S.P. Arneric, J.D. Brioni, In Neuronal Nicotinic Receptors: Pharmacology
and Therapeutic Opportunities, Wiley-VCH, Weinheim, 1999, pp. 395–397;
(c) S.R. Breining, Top. Med. Chem. 4 (2004) 609–618;
(d) T.T. Talley, S. Yalda, K.Y. Ho, Y. Tor, F.S. Soti, W.R. Kem, P. Taylor,
Biochemistry 45 (2006) 8894–8902;
(e) M.A. Abreo, N.-H. Lin, D.S. Garvey, D.E. Gunn, A.-M. Hettinger, J.T. Wasicak,
P.A. Pavlik, Y.C. Martin, D.L. Donnelly-Roberts, D.J. Anderson, J.P. Sullivan, M.
Williams, S.P. Arneric, M.W. Holladay, J. Med. Chem. 39 (1996) 817–825;
(f) P.A. Newhouse, A. Potter, R.H. Lenox, Med. Chem. Res. 2 (1993) 628–642;
(g) F.-X. Felpin, S. Girard, G. Vo-Thanh, R.J. Robins, J. Villiéras, J. Lebreton, J.
Org. Chem. 66 (2001) 6305–6312;
(b) F. Alonso, I.P. Beletskaya, M. Yus, Chem. Rev. 102 (2002) 4009–4092;
(c) A. Guaragna, S. Pedatella, V. Pinto, G. Palumbo, Synthesis (2006) 4013–
4016;
(d) M.R. Chapelle, B.B. Kent, J.R. Jones, S.Y. Lu, A.D. Morgan, Tetrahedron Lett.
43 (2002) 5117–5118;
(h) J.T. Ayers, R. Xu, L.P. Dwoskin, P.A. Crooks, AAPS J. 7 (2005) 752–758;
(i) M.B. Brennan, Chem. Eng. News. 78 (2000) 23–26.
(e) V. Derdau, Tetrahedron Lett. 45 (2004) 8889–8893.
[5] Z. Zhang, L. Chen, L. Liu, X. Su, J.D. Rabinowitz, J. Am. Chem. Soc. 139 (2017)
14368–14371.
[6] R.A. Arthurs, C.J. Richards, Org. Lett. 19 (2017) 702–705.
[7] (a) W. Li, M.-M. Wang, Y. Hu, T. Werner, Org. Lett. 19 (2017) 5768–5771;
(b) V. Soulard, G. Villa, D.P. Vollmar, P. Renaud, J. Am. Chem. Soc. 140 (2018)
155–158.
[8] H. Sajiki, F. Aoki, H. Esaki, T. Maegawa, K. Hirota, Org. Lett. 6 (2004) 1485–
1487.
[9] (a) E. Khaskin, D. Milstein, ACS Catal. 3 (2013) 448–452;
(b) B. Chatterjee, C. Gunanathan, Org. Lett. 17 (2015) 4794–4797;
(c) B. Chatterjee, V. Krishnakumar, C. Gunanathan, Org. Lett. 18 (2016) 5892–
5895;
[20] (a) M.W. Holladay, M.J. Dart, J.K. Lynch, J. Med. Chem. 40 (1997) 4169–4172;
(b) B. Latli, K. D’Amour, J.E. Casida, J. Med. Chem. 42 (1999) 2227–2234;
(c) S.F. Nielsen, E.Ø. Nielsen, G.M. Olsen, T. Liljefors, D. Peters, J. Med. Chem. 43
(2000) 2217–2226;
(d) G. Mullen, J. Napier, M. Balestra, T. DeCory, G. Hale, J. Macor, R. Mack, J.
Loch, A. Wu, P. Kover, A. Verhoest, E. Sampognaro, Y. Phillips, R. Zhu, E. Murray,
R. Griffith, J. Blosser, D. Gurley, A. Machulskis, J. Zongrone, A. Rosen, J. Gordon,
J. Med. Chem. 43 (2000) 4045–4050;
(e) G. Chelucci, Tetrahedron Asymmetry 16 (2005) 2353–2383.
[21] D. Yildiz, Toxicon. 43 (2004) 619–632.
[22] (a) H.H. Shepard, The Chemistry and Action of Insecticides, McGraw-Hill, New
York, NY, 1951;
(b) J.W. Gorrod, P. Jacob III, Analytical Determination of Nicotine and Related
Compounds and their Metabolites Chapter 1 (1999) 1.
[23] C. Heeschen, J.J. Jang, M. Weis, A. Pathak, S. Kaji, R.S. Hu, P.S. Tsao, F.L. Johnson,
J.P. Cooke, Nat. Med. 7 (2001) 833–839.
(d) L.V.A. Hole, N.K. Szymczak, J. Am. Chem. Soc. 138 (2016) 13489–13492.
[10] J. Sklyaruk, J.C. Borghs, O. El-Sepelgy, M. Rueping, Angew. Chem. Intl. Ed. 58
(2019) 775–779.
[11] (a) M. Han, Y. Ding, Y. Yan, H. Li, S. Luo, A. Adijiang, Y. Ling, J. An, Org. Lett. 20
(2018) 3010–3013;
[24] A. Khan, C.M. Marson, R.A. Porter, Synth. Commun. 31 (2001) 1753–1764.
(b) X. Wang, M.-H. Zhu, D.P. Schuman, D. Zhong, Y.-W. Wang, L.Y. Wu, W. Liu,
Please cite this article as: P. Gouthami, G. Karteek Goud, P. S. Mainkar et al., Rapid and one-pot synthesis of tri- to tetradeca-deutero nicotines, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2020.151680