Spirocyclic dihydropyridines by electrophile-induced dearomatizing cyclization of N-alkenyl pyridinecarboxamides

Article abstract of DOI:10.1021/ol400571j

On treatment with acylating or sulfonylating agents, N-alkenyl pyridine carboxamides (N-pyridinecarbonyl enamines) undergo a dearomatizing cyclization initiated by pyridine acylation and followed by intramolecular trapping of the resulting pyridinium cation. The products are spirocyclic dihydropyridines which may be further elaborated to spirocyclic heterocycles with drug-like features.

Full text of DOI:10.1021/ol400571j

ORGANIC
LETTERS
2013
Vol. 15, No. 8
1922–1925
Spirocyclic Dihydropyridines by
Electrophile-Induced Dearomatizing
Cyclization of N‑Alkenyl
Pyridinecarboxamides
Jemma Senczyszyn, Heloise Brice, and Jonathan Clayden*
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
clayden@man.ac.uk
Received March 1, 2013
ABSTRACT
On treatment with acylating or sulfonylating agents, N-alkenyl pyridine carboxamides (N-pyridinecarbonyl enamines) undergo a dearomatizing
cyclization initiated by pyridine acylation and followed by intramolecular trapping of the resulting pyridinium cation. The products are spirocyclic
dihydropyridines which may be further elaborated to spirocyclic heterocycles with drug-like features.
Spiropiperidine compounds display a wide range of
biological activities, and the spiropiperidine motif is con-
sidered a privileged scaffold in drug discovery.1 The bio-
logical activity of 2,8-diazaspiro[4.5]decanes alone spans a
range of therapeutic areas and has so far been associated with
NOP receptor ligands,2 NPY Y5 receptor antagonists,3 GlyT1
receptor antagonists4 and tryptase inhibitors (Figure 1).5
The synthesis of functionalized piperidines directly from
corresponding pyridines by nucleophilic dearomatization
is an attractive strategy.6 While the dearomatization
of neutral pyridines requires powerful, organometallic
nucleophiles, more activated pyridinium cations are readily
attacked by weaker, neutral nucleophiles such as silyl enol
ethers.7 N-Triflation with triflic anhydride promotes the
attack of electron-rich arenes on the resulting pyridinium
cation.8 By tethering the nucleophile to the pyridine ring,
(1) Mullen, P.; Miel, H.; McKervey, M. A. Tetrahedron Lett. 2010,
51, 3216. Krafft, A. A.; Kurt, A.; Maier, A.; Thomas, A. W.; Zimmerli,
D. Synthesis 2005, 3245. DeSimone, R. W.; Currie, K. S.; Mitchell, S. A;
Darrow, J. W.; Pippin, D. A. Comb. Chem. High Throughput Screening
2004, 7, 473. Bignan, G. C.; Battista, K.; Connolly, P. J.; Orsini, P. J.;
Liu, J.; Middleton, S. A.; Reitz, A. B. Bioorg. Med. Chem. Lett. 2005, 15,
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Zhang, H.; Fawzi, A.; Tulshian, D. B. Bioorg. Med. Chem. Lett. 2009,
19, 1164.
(3) Takahashi, T.; Haga, Y.; Sakamoto, T.; Moriya, M.; Okamoto,
O.; Nonoshita, K.; Shibata, T.; Suga, T.; Takahashi, H.; Hirohashi, T.;
Sakuraba, A.; Gomori, A.; Iwaasa, H.; Ohe, T.; Ishihara, A.; Ishii, Y.;
Kanatani, A.; Fukami, T. Bioorg. Med. Chem. Lett. 2009, 19, 3511.
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Thomas, A.; Zimmerli, D. Bioorg. Med. Chem. Lett. 2006, 16, 4321.
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De Garavilla, L.; Wang, Y.; Minor, L. K.; Tongue, B. A.; Barnakov,
A. N.; Lewandowski, F.; Milligan, C.; Spurlino, J. C.; Abraham, W. M.;
Boswell-Smith, V.; Page, C. P.; Maryanoff, B. E. Bioorg. Med. Chem.
Lett. 2008, 18, 2114.
(6) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem.
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D. L.; Abdullah, A. H. J. Org. Chem. 1982, 47, 4315. Sperger, C. A.;
Wanner, K. T. Tetrahedron. 2009, 65, 5824. Charette, A. B.; Grenon, M.;
Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123,
11829. Clayden, J.; Hamilton, S. D.; Mohammed, R. T. Org. Lett. 2005,
7, 3673. Arnott, G.; Clayden, J.; Hamilton, S. D. Org. Lett. 2006, 8, 5325.
Akiba, K.; Nishihara, Y.; Wada, M. Tetrahedron Lett. 1983, 24, 5269.
Bennasar, M.-L.; Juan, C.; Bosch, J. Tetrahedron Lett. 2001, 42, 585.
Bosch, J.; Bennasar, M.-L. Synlett 1995, 587. Katritzky, A. R.; Zhang,
S.; Kurz, T.; Wang, M. Org. Lett. 2001, 3, 2807. Brice, H.; Clayden, J.;
Hamilton, S. Beilstein J. Org. Chem 2010, 6, 22.
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Charette, A. B. Org. Lett. 2006, 8, 2985. Lemire, A.; Beaudoin, D.;
Grenon, M.; Charette, A. B. J. Org. Chem. 2005, 70, 2368. Comins,
D. L.; Sahn, J. J. Org. Lett. 2005, 7, 5227. Charette, A. B.; Grenon, M.;
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r
10.1021/ol400571j
Published on Web 04/03/2013
2013 American Chemical Society

fused or spirocyclic dihydropiperidines may be generated.
We have shown that when N-aryl or N-heteroaryl pyridi-
necarboxamides are treated with triflic anhydride, dearo-
matizing cyclization reactions9 ensue, giving spirocyclic
dihydropyridines in which the second spirocyclic ring is
fused with an aromatic ring.10
Scheme 1. Spirocycles from N-Alkenyl Isonicotinamidesa
a With 2,6-lutidine (1 equiv) as base. b With 2,6-di-tert-butyl-4-methyl-
pyridine (3 equiv) as base. Tf = SO2CF3.
rearrangement of lutidine.12 Switching the base to 2,6-di-
tert-butyl-4-methylpyridine avoided this side reaction. Using
just 1 equiv of this base still however led to low conversion;
with 3 equiv the yield of the reaction increased to 59%.
The same conditions converted a series of N-alkenyliso-
nicotinamides 1bꢀ1i incorporating variously substituted
alkenes to a range of spirocyclic dihydropyridines 2(Table 1).
Enamides 1aꢀb derived from aldehydes gave dihydro-
pyridines 2aꢀb spiro-linked with pyrrolinones (entries 1
and 2), and Figure 2a shows the X-ray crystal structure of
2b.13 Enamides 1dꢀ1i from ketones also cyclized in generally
good yields, with the alkene generated by the cyclization
preferring to lie exocyclic to the new pyrrolidinone ring
(entries 4ꢀ10). Enamides derived from cyclic ketones gave
tricyclic products 2eꢀi. In some cases, for example with the
unsubstituted enamine 1c, a hydrated product 6c was isolated.
While1e cyclized to 2e under the standard reaction conditions,
the aminal 6e was formed when 1e was cyclized under less
basic conditions, possibly because the intermediate acyl imi-
nium corresponding to 4 persists until aqueous workup. 6h
and 6i were likewise formed after acid workup. Figure 2b
shows the X-ray crystal structure of 6e.13
Cyclization of unsymmetrically substituted isonicotin-
amides creates a new stereogenic center but without diastereo-
selectivity (entries 9ꢀ13): the chloropyridines 1h and 1i
gave diastereoisomeric mixtures of the ring-fused spiro-
cycles 6h and 6i. Cyclization onto quinolines was also
successful, with 1jꢀl yielding spirocyclic dihydroquino-
lines 2jꢀl in moderate to good yield. 1l behaved like 1e,
giving a hydrated product 6l under less basic conditions.
Formation of hydrated adducts of 6 is discussed further
below (Scheme 4)
Figure 1. A selection of bioactive spirocyclic piperidines.
We now report that simple N-alkenyl pyridinecarbox-
amides also undergo dearomatizing spirocyclization and
generate a versatile range of unsaturated 2,8-diazaspiro-
[4.5]decanes, which are readily convertible into drug-like
scaffolds.11
N-Alkenyl pyridinecarboxamides 1 were made by one of
two methods. In method A, N-acylation of the imine
formed from benzylamine and an aldehyde or ketone gave
the N-acylenamine. Thus 1a was formed in 72% yield
by acylation with isonicotinoyl chloride condensation of
N-benzylpropionaldimine in the presence of molecular
sieves (Scheme 1). In method B, an N-allyl amide was
isomerized to an N-acyl enamine by a Ru catalyst. Thus 1a
was alternatively formed in 66% yield from N-allyl-N-
benzylnicotinamide.
In a preliminary experiment to establish the feasibility of
cyclizing N-vinyl isonicotinamides, 1a was treated with triflic
anhydride in the presence of 2,6-lutidine in dichloromethane.
A dearomatizing cyclization gave the spiropiperidine 2a in
44% yield, presumably by N-triflation to yield 3, followed
by cyclization to 4 and loss of a proton to reform the
enamine. The only observable side product of the reaction
was the sulfinate 5, suggesting competitive triflation and
ꢀ
ꢀ
(9) Ortız, F. L.; Iglesias, M. J.; Fernandez, M. J.; Sanchez, C. M. A.;
ꢀ
Gomez, G. R. Chem. Rev. 2007, 107, 1580. Clayden, J.; Knowles, F. E.;
Baldwin, I. R. J. Am. Chem. Soc. 2005, 127, 2412. Ahmed, A.; Bragg,
R. A.; Clayden, J.; Tchabanenko, K. Tetrahedron Lett. 2001, 42, 3407.
Bragg, R. A.; Clayden, J.; Bladon, M.; Ichihara, O. Tetrahedron Lett.
2001, 42, 3411. Clayden, J.; Menet, C. J.; Mansfield, D. J. Chem.
Commun. 2002, 38. Ahmed, A.; Clayden, J.; Rowley, M. Synlett. 1999,
1954. Clayden, J.; Turnbull, R.; Pinto, I. Org. Lett. 2004, 6, 609.
Clayden, J.; Turnbull, R.; Helliwell, M.; Pinto, I. Chem. Commun.
2004, 2430.
Yields from reactions promoted by triflic anhydride
were moderate to excellent but were reducedwith extended
reaction times, presumably as a result of decomposition in
the presence of the triflic acid generated in the reaction.
Despite the longer reaction times required, generally higher
yields of cyclized products 7, 8, and 9 were obtained when
alternative electrophiles to triflic anhydride such as methyl
chloroformate, 2,2,2-trichloroethoxycarbonyl chloride (TrocCl),
(10) Arnott, G.; Brice, H.; Clayden, J.; Blaney, E. Org. Lett. 2008, 10,
3089. Brice, H.; Clayden, J. Chem. Commun. 2009, 1964.
(11) For related examples, see: Sainsbury, M.; Uttley, N. I. J. Chem.
Soc., Perkin Trans. 1 1977, 2109. Naito, T.; Miyata, O.; Ninomiya, I.
J. Chem. Soc., Chem. Commun. 1979, 517. Parameswarappa, S. G.;
Pigge, F. C. J. Org. Chem. 2012, 77, 8038. Parameswarappa, S. G.; Pigge,
F. C. Tetrahedron Lett. 2011, 52, 4357. Parameswarappa, S. G.; Pigge,
F. C. Org. Lett. 2010, 12, 3434. For a review of the chemistry of
enamides, see: Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455.
(12) Binkley, R. W.; Ambrose, M. G. J. Org. Chem. 1983, 48, 1776.
(13) X-ray data for 2b and 6e have been deposited with the Cam-
bridge Crystallographic Database, deposition numbers 926563 (2b) and
926562 (6e).
Org. Lett., Vol. 15, No. 8, 2013
1923

However, no diastereoselectivity resulted from the use
of (ꢀ)-menthyl chloroformate,14 and in some cases (7e, 7f)
∼20% of a double bond regioisomer (7e0, 7f0) was also
isolated. A moderate yield of 10e was obtained by treating
1e with trifluoroacetic anhydride, and no cyclization
resulted when the pyridine ring was alkylated, rather than
acylated: isonicotinamide 1a with methyl triflate returned
the N-methyl pyridinium salt in 97% yield. As with triflic
anhydride, cyclization of 1i with chloroformates gave
hydrated structures 11i, 12i.
Table 1. Dihydropyridines by Spirocyclization with Triflic
Anhydride
Figure 2. X-ray crystal structures of (a) 2b and (b) 6e.
Compounds with a spirocyclic piperidine structure iso-
meric with that of 2 or 7ꢀ9 exhibit properties that make
them suitable as potential smoking cessation remedies,15
and with these targets in mind we synthesized the N-alkenyl
picolinamide 13 and the N-alkenyl pyrimidinecarboxamide
15 shown in Scheme 2. Treatment of each with activating
electrophiles led to dearomatizing cyclization and the for-
mation of spirocyclic products 14 and 16 as principally one
of the two possible diastereoisomers, but these products
were extremely unstable.16
The products of the dearomatizing spirocyclizations;2,
7ꢀ9, 14, and 16;contain up to three acylenamine-
like double bonds suitable for further elaboration, and in
some cases this functionality made the products somewhat
unstable on standing. In some instances, but especially
for 16, it was impossible to fully purify the dearomatized
a Conditions Tf2O, base, CH2Cl2, 0 °C, 2 h. b With 2,6-lutidine
(1 equiv) as base. c With 2,6-di-tert-butyl-4-methylpyridine (3 equiv) as
base. d Based on 29% recovered starting material. e Structures of 6 below.
f With 2,6-di-tert-butyl-4-methylpyridine (1 equiv) as base. g After standing
in CDCl3.
or (ꢀ)-menthyl chloroformate were used to activate the
pyridinecarboxamide, with 2,6-lutidine as base (Table 2).
Spirocyclic dihydropyridines were obtained most success-
fully using menthylchloroformate asanactivatingreagent,
owing to the increased stability of N-menthyldihydropyr-
idine products toward rearomatization and decomposi-
tion than comparable N-methyl and N-Troc compounds.
(14) Comins, D. L.; Hong, H.; Salvador, J. M. J. Org. Chem. 1991, 56,
7197.
(15) Bhatti, B. S.; Miller, C. H.; Schmitt, J. D. 2006 WO2006023630;
Bhatti, B. S.; Miller, C. H.; Schmitt, J. D. 2004 WO2004005293.
(16) Attempted cyclization of nicotinamides (3-pyridinecarboxamides)
gave complex inseparable mixtures of products arising from cyclization into
both the 2- and 4-positions of the pyridine.
ꢀ
(17) H-Cube system purchased from Thales-Nano, Zahony u. 7,
H-1031 Budapest, Hungary.
1924
Org. Lett., Vol. 15, No. 8, 2013

Table 2. Dihydropyridines by Spirocyclization with
Chloroformates
Scheme 2. Dearomatizing Cyclization of Pyrimidinecarboxa-
mides and Picolinamidesa
a 5ꢀ9:1 mixture of diastereoisomers.
Scheme 3. Reduction and Deprotection; Men = (ꢀ)-Menthyl
(all as 1:1 mixtures of diastereoisomers)a
a H2, p bar, Pd/C, EtOH, EtOAc, H-cube. b (1) KOH, MeOH, 120 °C,
16 h; (2) HCl, MeOH.
a With trichloroethyl, methyl, or (ꢀ)-menthyl chloroformate as
electrophile: conditions ROCOCl, 2,6-lutidine, CH2Cl2, 0 °Cꢀrt, 2 h.
b 1:1 dr. c Yield of regioisomer 7e0 or 7f0 (structure below). d Carried out
on a 2 g scale. k With trifluoroacetic anhydride as electrophile.
Scheme 4. Nucleophilic Trapping of the Intermediate
spirocycles from their decomposition products. However,
hydrogenation of selected dihydropyridines 2, 7, and 9 using
a flow hydrogenation apparatus (H-Cube)17 gave stable
spirocyclic piperidines 20, 24, and 25 (at higher pressures) or
dihydropiperidines 19, 22, and 23 (at lower pressures, where
only the double bond in the five-membered ring was
hydrogenated) as shown in Scheme 3. 20 and 25 were readily
deprotected by methanolysis of the carbamate. The alkenes
in 2a could also be functionalized by bromoetherification to
give first 17 and then, with greater quantities of NBS, 18.
As an alternative strategy for stabilizing the unsaturated
products, inclusion of an alcohol in the reaction mixture
during the dearomatizing cyclization allowed the spiro-
cycles to be trapped as aminals 27, as shown in Scheme 4.
In conclusion, we report that N-alkenyl isonicotinamides
and their congeners undergo spirocyclizing dearomatization
to yield partially saturated heterocyclic products on treat-
ment with sulfonating or acylating agents.
Acknowledgment. We are grateful to the EPSRC for
studentships (to J.S. and H.B.) and to GlaxoSmithKline
for support (CASE award to H.B.).
Supporting Information Available. Experimental de-
tails and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
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