Communication
ChemComm
and Related Methodology, ed. H. G. Brittain, Academic Press, San
Diego, 2013, vol. 38, pp. 367–406.
steps (previously 13 steps). It is worth noting that the bromide
serves both as a directing group for the innate selectivity of the
dearomatization and as a handle for C–H annulation. The
selectivity of the hydride reduction step is also remarkable,
giving dihydropyridine 42, in that very little ester reduction is
observed and the reduction regiochemistry is absolute.
15 For reviews on pyridinium dearomatization, see: (a) J. A. Bull,
J. J. Mousseau, G. Pelletier and A. B. Charette, Chem. Rev., 2012,
112, 2642; (b) G. Bertuzzi, L. Bernardi and M. Fochi, Catalysts, 2018,
8, 632; (c) S. Sowmiah, J. M. S. S. Esperança, L. P. N. Rebelo and
C. A. M. Afonso, Org. Chem. Front., 2018, 5, 453.
16 R. A. Shenvi, D. P. O’Malley and P. S. Baran, Acc. Chem. Res., 2009,
42, 530.
17 M. M. Nebe and T. Opatz, Adv. Heterocycl. Chem., 2017, 122, 191.
18 A. Bari, A. Iqbal, Z. A. Khan, S. A. Shahzad and M. Yar, Synth.
Commun., 2020, 2572.
In conclusion, this study has shown the innate reactivity
trends associated with N-alkyl pyridinium electrophiles.
The effects of substitution patterns have revealed outcomes
in organometallic additions that are systematic and easily
employed in first-pass retrosynthetic analyses. These data serve
to delineate reactivity that, prior to this study, were limited and
not conclusively understood. In some instances of the current
work, the selectivity proved quite high, and could be easily
utilized in multistep synthesis, as shown by the concise
construction of 3. It is hoped that the lessons learned will
be broadly helpful to practitioners ambitious to utilize the
inherent advantages of dearomative synthetic approaches.
The expansion upon these findings and their application to
future synthetic targets is anticipated to be reported by our
group in due course.
19 T. E. Mu¨ller, K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada,
Chem. Rev., 2008, 108, 3795.
20 T. Gaich and P. S. Baran, J. Org. Chem., 2010, 75, 4657.
21 S. W. M. Crossley and R. A. Shenvi, Chem. Rev., 2015, 115, 9465.
22 For a review on dearomative total synthesis, see: S. P. Roche and
J. A. Porco Jr., Angew. Chem., Int. Ed., 2011, 50, 4068.
23 For a review on heterocyclic dearomatization, see: (a) Q. Ding,
X. Zhou and R. Fan, Org. Biomol. Chem., 2014, 12, 4807;
(b) R. Lavilla, J. Chem. Soc., Perkin Trans. 1, 2002, 1141;
(c) D. L. Comins, K. Higuchi and D. W. Young, Adv. Heterocycl.
Chem., 2013, 110, 175.
24 D. Wong, Z. Wang, Z. Liu, M. Huang, J. Hu and P. Yu, Org. Lett.,
2019, 21, 4459.
25 D. J. Robinson, S. P. Spurlin, J. D. Gorden and R. R. Karimov,
ACS Catal., 2020, 10, 51.
26 To our knowledge, only a terse singular study investigated the
regioselectivity of Grignard additions into 3,5-disubstituted alkyl-
pyridiniums, see: R. E. Lyle and E. White, J. Org. Chem., 1971,
36, 772.
27 D. L. Comins and J. D. Brown, Tetrahedron Lett., 1986, 27, 2219.
28 D. L. Comins and J. D. Brown, Tetrahedron Lett., 1986, 27, 4549.
29 D. L. Comins and Y. C. Myoung, J. Org. Chem., 1990, 55, 292.
30 R. Yamaguchi, Y. Nakazono and M. Kawanisi, Tetrahedron Lett.,
1983, 24, 1801.
31 R. Yamaguchi, E. Hata, T. Matsuki and M. Kawanisi, J. Org. Chem.,
1987, 52, 2094.
32 T. J. Donohoe, M. J. Connolly and L. Walton, Org. Lett., 2009,
11, 5562.
33 A. B. Charette, M. Grenon, A. Lemire, M. Pourashraf and J. Martel,
J. Am. Chem. Soc., 2001, 123, 11829.
34 A. Lemire, D. Beaudoin, M. Grenon and A. B. Charette, J. Org. Chem.,
2005, 70, 2368.
35 A. B. Charette, S. Mathieu and J. Martel, Org. Lett., 2005, 7, 540.
36 D. L. Comins, R. R. Goering, S. P. Joseph and S. O’Connor, J. Org.
Chem., 1990, 55, 2574.
37 D. L. Comins, S. P. Joseph and R. R. Goehring, J. Am. Chem. Soc.,
1994, 116, 4719.
38 J. Streith, A. Boiron, T. Sifferlen, C. Strehler and T. Tschamber,
Tetrahedron Lett., 1994, 35, 3927.
39 Cu and Zn organometallic species were briefly investigated. See ESI†
for details.
40 Dihydropyridine 31 was isolated as a 9 : 1 mixture of the propargyl
and allenyl addition products, respectively.
41 T. Holm, Acta Chem. Scand., 1991, 45, 276.
Financial support provided by Florida State University. We
thank Xinsong Lin for assistance with X-ray data collection and
structure determination. We thank Prof. James Frederich and
Prof. Igor Alabugin for vibrant and helpful discussions.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 E. J. Corey, Molecules and Medicine, John Wiley & Sons, Hoboken,
2007.
2 K. C. Nicolaou and T. Montagnon, Molecules that Changed the World,
Wiley-VCH, Weinheim, 2008.
3 Heterocycles in Natural Product Synthesis, ed. K. C. Majumdar and
S. K. Chattopadhyay, Wiley-VCH, Weinheim, 2011.
4 Modern Heterocyclic Chemistry, ed. J. Alvarez-Builla, J. J. Vaquero and
J. Barluenga, Wiley-VCH, Weinheim, 2011.
5 J. A. Joule and K. Mills, Heterocyclic Chemistry at a Glance, John Wiley
& Sons, West Sussex, 2013, vol. 4.
6 E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem., 2014,
57, 10257.
7 B. J. Huffman and R. A. Shenvi, J. Am. Chem. Soc., 2019, 141, 3332.
8 M. Baumann and I. R. Baxendale, Beilstein J. Org. Chem., 2013,
9, 2265.
9 R. Vardanyan, Piperidine-Based Drug Discovery, Elsevier, Amsterdam, 2017.
10 G.-Q. Liu and T. Opatz, Recent Advances in the Synthesis of
42 M.-L. Bennasar, T. Roca, M. Monerris, C. Juan and J. Bosch,
Tetrahedron, 2002, 58, 8099.
43 A. G. Schultz, L. Flood and J. P. Springer, J. Org. Chem., 1986, 51,
838.
44 A. Lemire, M. Grenon, M. Pourashraf and A. B. Charette, Org. Lett.,
2004, 6, 3517.
45 T. Kiguchi, C. Hashimoto, T. Naito and I. Ninomiya, Heterocycles,
1982, 19, 1873.
46 I. Ninomiya, C. Hashimoto, T. Kiguchi and T. Naito, J. Chem. Soc.,
Perkin Trans. 1, 1984, 2911.
47 I. Ninomiya, C. Hashimoto, T. Kiguchi and T. Naito, J. Chem. Soc.,
Perkin Trans. 1, 1985, 941.
¨
Piperidines: Functionalization of Preexisting Ring Systems, in Advances
in Heterocyclic Chemistry, ed. E. F. V. Scriven, C. A. Ramsden, Academic
Press, San Diego, 2018, vol. 125, pp. 107–234.
11 P. Ashok, H. Lathiya and S. Murugesan, Eur. J. Med. Chem., 2014,
97, 928.
12 A. L. Devereaux, S. L. Mercer and C. W. Cunningham, ACS Chem.
Neurosci., 2018, 9, 2395.
13 E. G. Rowley, S. Sehgel and S. D. Crawford, Insecticidal Despyrrole
Analogs of Lisuride and Lysergamides, US Pat., WO2007/128409 A1,
2007.
48 I. Ninomiya, C. Hashimoto, T. Kiguchi and T. Naito, Chem. Pharm.
Bull., 1986, 34, 2799.
14 D. Germann, G. Ma, F. Han and A. Tikhomirova, Chapter Eight –
Paroxetine Hydrochloride, in Profiles of Drug Substances, Excipients,
2696 | Chem. Commun., 2021, 57, 2693À2696
This journal is The Royal Society of Chemistry 2021