Electrophile-induced dearomatizing spirocyclization of N- arylisonicotinamides: A route to spirocyclic piperidines

Article abstract of DOI:10.1021/ol801092s

(Chemical Equation Presented) Treatment of N-arylisonicotinamides with trifluoromethanesulfonic anhydride triggers intramolecular nucleophilic attack of the aryl ring on the 4-position of the pyridinium intermediate. The products are spirocyclic dihydropy

Full text of DOI:10.1021/ol801092s

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3089-3092
Electrophile-Induced Dearomatizing
Spirocyclization of
N-Arylisonicotinamides: A Route to
Spirocyclic Piperidines
Gareth Arnott,†,§ Heloise Brice,† Jonathan Clayden,*,† and Emma Blaney‡
School of Chemistry, UniVersity of Manchester, Oxford Road,
Manchester M13 9PL, U.K., and GlaxoSmithKline, New Frontiers Science Park,
Third AVenue, Harlow CM19 5AW, U.K.
clayden@man.ac.uk
Received May 12, 2008
ABSTRACT
Treatment of N-arylisonicotinamides with trifluoromethanesulfonic anhydride triggers intramolecular nucleophilic attack of the aryl ring on the
4-position of the pyridinium intermediate. The products are spirocyclic dihydropyridines which can be converted to valuable spirocyclic piperidines
related to biologically active molecules such as MK-677.
Piperidines spiro-linked with other heterocyclic rings are
widespread as structural elements in numerous classes of
pharmaceutically active molecules1,2 and are considered
“privileged structures” as components of G-protein coupled
receptor (GPCR) ligands.3 Functionalized piperidines may
be made efficiently from pyridines, since electrophilic attack
at nitrogen creates a powerfully electrophilic pyridinium
cation to which nucleophiles may be added.4 Although most
work in this area has employed reactive anionic nucleophiles,
Corey and Tian have shown recently that N-triflylpyridinium
† University of Manchester.
‡ GlaxoSmithKline.
§ Current address: Department of Chemistry and Polymer Science,
University of Stellenbosch, South Africa.
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10.1021/ol801092s CCC: $40.75
Published on Web 06/14/2008
2008 American Chemical Society

cations are sufficiently electrophilic that they may be attacked
by nucleophiles even as weak as simple
In a preliminary experiment (Scheme 1), we treated the
simple anilide 1a, formed in one step from isonicotinoyl
chloride and m-anisidine, with triflic anhydride at -30 °C.
Warming to 0 °C returned 20% of the spirocyclic dihydro-
pyridine 2a.
arenes.5Dearomatizing addition of arenes to the N-triflyl pyri-
dinium salts yields 4-aryl-1,4-dihydropyridines. The fact that
N-sulfonylpyridinium cations may be trapped in situ by nu-
cleophiles which are unreactive toward the sulfonylating agent
raised the possibility that cyclization reactions of pyridines
containing a tethered latent nucleophile may be successful
Scheme 1. Spirocyclization of an N-Anisylisonicotinamide
The favored conformation of secondary anilides such as
1a places the two aryl rings trans to one another, but their
tertiary analogues prefer conformations in which the two
rings lie cis8 and are therefore better orientated for cycliza-
tion. We therefore repeated the cyclization with 1a’s N-
methylated analogue 1b (Table 1, entry 2). The yield of
Figure 1. Dihydropyridines by dearomatizing (a) addition (ref 5)
and (b) spirocyclization (this work).
(Figure 1).6 In this paper, we show that the target spirocycles
are formed when dearomatizing cyclization7 of an N-arylisoni-
cotinamide is triggered by N-sulfonylation in the presence of a
hindered base. The reaction generates valuable benzo-fused
spirocyclic dihydropyridines.
Table 1. Optimizing the Spirocyclization
starting
yield
(%)
entry
material 1
R )
additive
product 2
1
2
3
4
5
6
1a
1b
1b
1b
1b
1c
H
2a
2b
2b
2b
2b
2c
20
47
54
70
99
87
Me
Me
Me
Me
Bn
(4) For leading references, see: Arnott, G.; Clayden, J.; Hamilton, S. D.
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M.-L. Synlett 1995, 587.
Et3N
DMAP
pyridine
2,6-lutidine
spirocyclic product obtained increased to 47%. Extending
the reaction time led to decomposition, and reasoning that
this was caused by the triflic acid generated during the
reaction, we repeated the cyclization in the presence of a
series of bases (Table 1, entries 3-6). Satisfyingly, with
pyridine the yield of the cyclized dihydropyridine 2b
increased to 99% (Table 1, entry 5). Likewise, cyclization
of the N-benzyl anilide 1c in the presence of 2,6-lutidine
gave 2c in 87% yield (Table 1, entry 6).9The X-ray crystal
structure of 2b is illustrated in Figure 2.10
(5) Corey, E. J.; Tian, Y. Org. Lett. 2005, 7, 5535.
(6) For early examples of intramolecular trapping of N-alkyl pyridinium
salts, see: Weller, D. D.; Luellen, G. R. Tetrahedron Lett. 1981, 22, 4381.
Weller, D. D.; Stirchak, E. P.; Weller, D. L. J. Org. Chem. 1983, 48, 4597.
(7) For a general discussion of dearomatizing cyclization reactions, see:
Ort´ız, F. L.; Iglesias, M. J.; Ferna´ndez, M. J.; Sa´nchez, C. M. A.; Go´mez,
G. R. Chem. ReV. 2007, 107, 1580. Clayden, J. In Strategies and Tactics in
Organic Synthesis; Harmata, M., Ed.; Academic Press: New York, 2004;
Vol. 4, pp 72-96. 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. Dearomatizing cyclization onto unactivated het-
eroaromatic rings has been reported: see (for cyclization onto pyridines):
Clayden, J.; Hamilton, S. D.; Mohammed, R. T. Org. Lett. 2005, 7, 3673.
(cyclization onto pyrroles): Clayden, J.; Turnbull, R.; Pinto, I. Org. Lett.
2004, 6, 609. (cyclization onto thiophenes): Clayden, J.; Turnbull, R.;
Helliwell, M.; Pinto, I. Chem. Commun. 2004, 2430.
A range of variously substituted anilide starting materials
3-8 were made and treated with electrophiles under similar
conditions to establish the scope of the cyclization reaction
to 9-14 (Scheme 2 and Table 2). In general, electron-rich
anilides 3-5 performed the most satisfactorily (Table 2,
(8) Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K. J. Am.
Chem. Soc. 1992, 114, 10649. Azumaya, I.; Kagechika, H.; Fujiwara, Y.;
Itoh, M.; Yamaguchi, K.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 2833.
(9) Although pyridine gave an excellent yield of 2b, we found
2,6-lutidine to be generally more applicable to less reactive substrates.
(10) X-ray crystal data for 2b have been deposited with the Cambridge
Crystallographic Data Centre, deposition nno. 676939.
(11) H-cubeTM manufactured by ThalesNano. See: Desai, B.; Kappe,
O. J. Comb. Chem. 2005, 7, 641.
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Org. Lett., Vol. 10, No. 14, 2008

Table 2. Scope of the Spirocyclization
Figure 2.
X-ray crystal structure of 2b.10
entries 1-10). Low yields were obtained from electron-
deficient anilides 7 and 8 (Table 2, entries 12, 13) Some of
a regioisomeric product (10′, 11′, and 14′) was formed when
the substrates were meta-substituted (Table 2, entries 7-10
and 13).
Scheme 2. Scope of the Spirocyclization
The generally high-yielding cyclizations of the electron-
rich substrates prompted us to try cyclizations of similar
compounds to give challenging but also more versatile
products. Some success was obtainedsfor example, while
an electron-withdrawing N-protecting group (Boc or MeSO2)
slowed down the cyclization, 3,5-dimethoxy-substituted 3d
and 3e still gave good yields of cyclized products 9d and 9e
(Table 2, entries 4 and 5). Triflic anhydride activation was
required for all but the most reactive substrates, but the
electron-rich anilide 3b also cyclized to 9f in excellent yield
on treatment with an excess of methyl chloroformate (Table
2, entry 6).
Compounds related to the isonicotinamides were also studied
(Scheme 3). Isonicotinic esters cyclized slowly, but the lower
degree of activation and the less favorable s-cis conformation
of these molecules conspired to make these cyclizations
significantly less efficient. Nonetheless, 16 was obtained in
yields of 30-43% when the cyclization of 15 was performed
in refluxing dichloromethane or dichloroethane.
The isomeric nicotinamide 17 yielded principally the
rearomatized pyridine 18 arising from nucleophilic attack
of the aryl ring on the 4-position of the pyridine and
elimination of trifluoromethylsulfinate, while cyclization of
the picolinamide 19 was followed by ring-opening of the
resulting 1,2-dihydropyridine to form the dienal 20.
All of the valuable spirocyclic targets related to the
products contain a fully saturated piperidine ring. We
a Eith MeOCOCl (5 equiv). 9f carries a NCO2Me substituent. b Isolated
as an inseparable mixture. c Using Et3N as base.
therefore explored the hydrogenation of the dihydropyridines
9 to yield piperidines 21. High pressures of hydrogen were
required for complete reduction of the dihydropyridines,
which was carried out efficiently using a commercial H-cube
hydrogenation flow apparatus.11 After reduction, it proved
feasible to deprotect the N-benzyl-substituted lactam 21b by
oxidation,12 yielding 21c, and the triflyl group by dissolving
metal reduction, yielding 21e.
(12) Gigg, R.; Conant, R. J. Chem. Soc., Chem. Commun. 1983, 465.
Org. Lett., Vol. 10, No. 14, 2008
3091

Scheme 3
.
Related Cyclizations
Scheme 5. Synthesis of a Spirocyclic Piperidine
of the N-sulfonylamide 22 (which was made from 1a) with
triflic anhydride and 2,6-lutidine returned the cyclized
dihydropyridine 23 in 68% yield. Reduction of this product
to the spirocycle 27 was achieved by partial hydrogenation
to 24, demethylation with boron tribromide, and formation
of the triflate ester 25. Further hydrogenation gave the
spiropiperidine-oxindole 26. A final reduction of the lactam
ring with superhydride followed by triethylsilane yielded the
benzo-fused spirocycle 27.
MK-677 is a growth hormone receptor 1a secretagogue
containing the otherwise unfunctionalised benzo-fused spi-
rocyclic piperidine core of 27.2 Although simple phenyl
Scheme 4. Spiropiperidines by Hydrogenation
Acknowledgment. We acknowledge the support of Glaxo-
SmithKline, the EPSRC, and the National Science Founda-
tion of South Africa. We thank Mr. James Clayton for
synthetic assistance and Dr. Madeleine Helliwell for deter-
minining the X-ray crystal structure of 2b.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
substituents had failed to cyclize in good yield (Table 2, entry
11), we succeeded in synthesizing compounds in this class
by a reduction strategy exemplified in Scheme 5. Treatment
OL801092S
3092
Org. Lett., Vol. 10, No. 14, 2008