Desulfonylative radical ring closure onto aromatics. A modular route to benzazepin-2-ones and 5-arylpiperidin-2-ones

Article abstract of DOI:10.1021/ol3005276

Adducts from the intermolecular radical addition of N-xanthylacetyl-N- methanesulfanilides to Boc-protected allylamine undergo ring closure with loss of a methanesulfonyl radical to give benzazepin-2-ones. Upon deprotection and exposure to triethylamine,

Full text of DOI:10.1021/ol3005276

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2018–2021
Desulfonylative Radical Ring Closure onto
Aromatics. A Modular Route to
Benzazepin-2-ones and
5-Arylpiperidin-2-ones
Nicolas Charrier, Zhibo Liu, and Samir Z. Zard*
ꢀ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique,
91128 Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received March 1, 2012
ABSTRACT
Adducts from the intermolecular radical addition of N-xanthylacetyl-N-methanesulfanilides to Boc-protected allylamine undergo ring closure with
loss of a methanesulfonyl radical to give benzazepin-2-ones. Upon deprotection and exposure to triethylamine, these compounds rearrange into
5-aryl-2-piperidones. This approach also represents a useful route to benzazepin-2-ones unsubstituted on the nitrogen atom of the azepinone ring.
Ready access to novel, variously substituted heterocyclic
and heteroaromatic compounds is a central concern in
medicinal chemistry.1 In this respect, 3-arylpiperidines,
and related structures, are of particular importance in view
of their interesting opioid2 and dopaminergic activity.3
One example is preclamol (Figure 1), noted to be the
first selective D2-like dopamine autoreceptor agonist. Such
dopaminergic substances have potential for the treat-
Figure 1. Examples of 3-aryl-piperidine drugs.
ment of depression and drug addiction, Parkinson’s and
Alzheimer’s diseases, and schizophrenia.
The identification of 3-arylpiperidines as inhibitors of
the steroid 5R-reductase,4 as ligands of the σ receptor,5 and
(1) (a) Ward, R. A.; Kettle, J. G. J. Med. Chem. 2011, 54, 4670. (b)
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(2) Iorio, M. A. J. Med. Chem. 1978, 21, 812.
as antagonists of the tachykinin system6 increases their
importance as a class with privileged pharmacological
structures. Thus, piperidone UK-224,671 is a potent,
€
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D. S.; Newman, S. D.; Jones, B. C. J. Med. Chem. 2002, 45, 5365.
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Giomini, C.; Lamartina, S.; Monteagudo, E.; Ontoria, J. M.; Orsale,
M. V.; Palumbi, M. C.; Pesci, S.; Roscilli, G.; Scarpelli, R.; Schultz-
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r
10.1021/ol3005276
Published on Web 03/30/2012
2012 American Chemical Society

selective antagonist of the neurokinin 2 receptor,6c while
MK-4827 developed by Merck has entered clinical trials as
an antitumor drug (Figure 1).7
Scheme 2. First Example of an Aryl-piperidone Synthesis
Most routes to 3-arylpiperidines involve organometallic
couplings starting with pyridines.8 Examples include Heck9
or Suzuki10 couplings and nickel catalyzed cross-couplings
between arylmagnesium bromides and 3-bromopyridines,11
followed by complete or partial reduction of the resulting
3-aryl-substituted pyridine nucleus.
Scheme 1. Initial Strategy
reaction and, finally, spontaneous rearrangement of the free
amine 5 into the more stable 5-aryl-piperidin-2-one 6 after
deprotection of the amino group and treatment with base.
This plan was readily reduced to practice on example 6a
depicted in Scheme 2. However, while the first dilauroyl
peroxide (DLP)15 initiated intermolecular radical addition
to give 2a and 2b was efficient, the ring closure step leading
to the tetralone proceeded in variable and also in signifi-
cantly lower yields in comparison to our earlier study.14
One possible explanation was the partial destruction of the
Boc-protecting group by the lauric acid produced in the
medium. Prolonged heating in refluxing chlorobenzene in
the presence of even a weak acid such as lauric acid could
result in slow decomposition of the relatively sensitive Boc-
group. Indeed, in the case of 2b, its cyclization into 3b was
markedly improved (from 26% to 43%) by replacing DLP
with di-tert-butyl peroxide (DTBP), which does not liber-
ate any acidic product upon thermolysis or induced de-
composition (see also below).
We recently reported a radical based approach relying
on a 1,4-aryl group migration from sulfonamides.12 In
continuation of our study of the degenerative radical
exchange of dithiocarbonates (xanthates) and related
derivatives,13 we have conceived of an alternative route
that takes advantage of the possibility of annelation by a
radical cyclization onto aromatic rings.
Our initial plan, portrayed in Scheme 1, involves forma-
tion of an R-tetralone 3 by additionꢀcyclization of a phena-
cyl xanthate 1 and Boc-protected allylamine,14 followed by
ring expansion into lactone 4 through a BaeyerꢀVilliger
Nevertheless, our hopes for expanding the scope of this
approach were ultimately dashed by the unreliability of the
BaeyerꢀVilliger reaction. For reasons still unclear, the
BaeyerꢀVilliger reaction on R-tetralones 3 proved highly
capricious.16 For instance, no lactone 4b was formed upon
treatment of 3b with peracid under otherwise identical
conditions to those used for cyclizing 3a.
(8) For recent syntheses of 3-arylpiperidines, see: (a) Wong, Y.-S.;
ꢁ
Marazano, C.; Gnecco, D.; Genisson, Y.; Chiaroni, A.; Das, B. C. J.
Org. Chem. 1997, 62, 729. (b) Lindermann, U.; Reck, G.; Wulff-Molder,
D.; Wessig, P. Tetrahedron 1998, 54, 2529. (c) Klumpp, D. A.; Garza,
M.; Jones, A.; Mendoza, S. J. Org. Chem. 1999, 64, 6702. (d) Johnson,
T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123, 1004. (e) Liu,
D.-G.; Gao, Y.; Wang, X.; Kelley, J. A.; Burke, T. R., Jr. J. Org. Chem.
Faced with this unexpected setback, we decided to
examine in parallel another potentially efficient strategy
relying this time on the ability to construct benzazepinones
by direct radical ring closure.17 This approach is illustrated
by the transformation pictured in Scheme 3 starting from
xanthate 7. The radical addition to Boc-protected allyla-
mine furnisheda highyield ofthenormaladduct 8. Further
exposure to stoichiometric amounts of DLP in refluxing
chlorobenzene accomplished the cyclization and delivered
benzazepinone 9 in 50% yield. Finally, deprotection of the
amine with TFA and heating with triethylamine induced
an efficient rearrangement into piperidone 10.
ꢁ
ꢁ
2002, 67, 1448. (f) Amat, M.; Canto, M.; Llor, N.; Ponzo, V.; Perez, M.;
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Bosch, J. Angew. Chem., Int. Ed. 2002, 41, 335. (g) Amat, M.; Canto, M.;
Llor, N.; Escolano, C.; Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem.
2002, 67, 5343. (h) Colpaert, F.; Mangelinckx, S.; De Kimpe, N. J. Org.
Chem. 2011, 76, 234.
(9) (a) Nilsson, K.; Hallberg, A. J. Org. Chem. 1992, 57, 4015.
(b) Buchner, I. K.; Metz, P. Tetrahedron Lett. 2001, 42, 5381.
€
(10) (a) Ali, N. M.; McKillop, A.; Mitchnell, M. B.; Rebelo, R. A.;
Wallbank, P. J. Tetrahedron 1992, 48, 8117. (b) Tagata, T.; Nishida, M.
J. Org. Chem. 2003, 68, 9412. (c) Cioffi, C. L.; Spencer, W. T.; Richards,
J. J.; Herr, R. J. J. Org. Chem. 2004, 69, 2210.
(11) (a) Hacksell, U.; Arvidsson, L.-E.; Svensson, U.; Nilsson, L. G.
J. Med. Chem. 1981, 24, 1475. (b) Tagat, J. R.; McCombie, S. W.;
Barton, B. E.; Jackson, J.; Shortall, J. Bioorg. Med. Chem. Lett. 1995, 18,
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(12) (a) Georghe, A.; Quiclet-Sire, B.; Vila, X.; Zard, S. Z. Org. Lett.
2005, 7, 1653. (b) Georghe, A.; Quiclet-Sire, B.; Vila, X.; Zard, S. Z.
Tetrahedron 2007, 63, 7187. For a synthesis of 4-arylpiperidinones, see:
Vila, X.; Zard, S. Z. Heterocycles 2006, 70, 45.
(13) For reviews on the xanthate radical addition-transfer process,
see: (a) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672. (b)
Quiclet-Sire, B.; Zard, S. Z. Chem.;Eur. J. 2006, 12, 6002. (c) Quiclet-
Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264, 201. (d) Zard, S. Z. Aust.
J. Chem. 2006, 59, 663. (e) Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205. (f)
Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem. 2011, 83, 519.
(14) Liard, A.; Quiclet-Sire, B.; Saicic, R.; Zard, S. Z. Tetrahedron
Lett. 1997, 38, 1759.
(15) Dilauroyl peroxide is sometimes sold under lauroyl peroxide.
Placing the peroxide between parentheses in the reaction schemes
indicates that it is used in substoichiometric amounts as an initiator.
Otherwise, it is both the initiator and the stoichiometric oxidant in
mediating ring closure on the aromatic ring and rearomatization.
(16) For a recent review, see: ten Brink, G.-J.; Arends, I. W. C. E.;
Sheldon, R. A. Chem. Rev. 2004, 104, 4105.
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Chem., Int. Ed. 2000, 39, 731.
Org. Lett., Vol. 14, No. 8, 2012
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13a allows the correct alignment of the orbital containing
the free electron with the antibonding orbital of the NꢀS
bond, and the scission can occur. A similar arrangement
in intermediate radical 20, with the smaller indoline ring,
is significantly more strained and therefore energetically
more costly.
Scheme 3. Second Route to Aryl-piperidones
Table 1. Examples of N-Unsubstituted 5-Aryl-2-piperidones
Expanding the range of substrates is crucial if this
approach is to have any utility in medicinal chemistry.
We therefore examined anilines as potential precursors
since numerous substituted anilines are commercially
available. To this end, we prepared a number of xanthates
11aꢀg (Scheme 4 and Table 1) from a range of anilines,
using a methanesulfonamide as the blocking group on
nitrogen. It is necessary to have a substituent on the
nitrogen for the radical cyclization on the aromatic ring
to occur. The choice of the sulfonamide was made initially
because of the simplicity of their synthesis and the desire to
avoid rotamers which complicate spectroscopic descrip-
tion. Furthermore, the presence of the sulfonyl group
should facilitate the transamidation step by improving
the leaving group ability of the aniline nitrogen.
The synthesis of the xanthates and the first intermole-
cular addition to Boc-protected allylamine proceeded un-
eventfully to give adducts 12aꢀg (Scheme 4 and Table 1).
However, when the ring closure was performed by heating
adduct 12a with DLP in refluxing chlorobenzene, we were
surprised to find that the sulfonamide group was absent
in the product 15a, which was obtained in 27% yield
(Scheme 4). Following our observation above concerning
the possible deleterious role of lauric acid, we replaced
DLP with DTBP and were pleased to find that the yield of
benzazepinone 15a jumped to a respectable 73%.
The intermediate radical 13a clearly undergoes a frag-
mentation of the NꢀSO2Me bond with the formation of a
methanesulfonyl radical. This latter can extrude sulfur
dioxide to give a methyl radical, which could in principle
participate in propagating the radical chain since the
thermal decomposition of DTBP also leads to methyl
radicals. The resulting intermediate 14a then tautomerizes
to give the observed benzazepinone 15a.
We had extensively used methanesulfanilides in the
synthesis of indolines without observing such a frag-
mentation.18 For a more direct comparison, we prepared
adduct 19 by addition of cyanomethyl xanthate 18 to N-
allyl-N-methanesulfonyl-4-iodoaniline 17 and subjected it
to the same cyclizing conditions as those used for 12a
(Scheme 4). This furnished N-methanesulfonylindoline 21
in 66% yield and none of the desulfonoylated material 22.
Presumably, the more flexible benzazepinone structure in
The loss of the sulfonamide group eliminated the need
for a subsequent deprotection step and had otherwise no
deleterious effect on the rest of the sequence. The equili-
brium still favored the formation of the desired aryl piper-
idones. Thus, in the case of 15a, removal of the Boc-
protecting group and treatment with triethylamine afforded
the desired arylpiperidone 16a in 55% yield (Scheme 4).
Substitution ofthe aromatic ringallowsthe introduction
of a broad diversity in the structures, as shown by the
examples collected in Table 1. In some cases (160c,f,g), we
found that acetylation of the liberated aniline with acetic
anhydride increased the efficiency of the product isolation.
(18) (a) Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Chem. Commun.
2002, 1692. (b) Ly, T.-M.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z.
Tetrahedron Lett. 1999, 40, 2533.
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Org. Lett., Vol. 14, No. 8, 2012

Scheme 4. Unexpected Loss of a Methanesulfonyl Group
Scheme 5. Examples of Benzazepinones
benzazepinone skeleton. Three examples are depicted in
Scheme 5, as an illustration of the possibilities.20 The
rapid synthesis of the boronate substituted benzazepi-
none 24c is particularly interesting as such derivatives
would be exceedingly tedious to make by traditional
routes.
In summary, we have described a convenient ap-
proach to both benzazepinones and 5-aryl-2-piperidi-
nones, unsusbtituted on the ring nitrogen. It illustrates
the potential of radical chemistry in providing medic-
inal and heterocyclic chemists with a concise access to
novel compounds not readily available by more estab-
lished methods.
The possibility of introducing fluorine groups, as in 16e,
160c, and 160g, is particularly noteworthy, in view of the
importance of organofluorine derivatives for the pharma-
ceutical and agrochemical industries. Finally the tolerance
of the process to the presence of chlorine, bromine, and
especially iodine (16a,b,d) opens up further avenues for
diversification through numerous powerful organometal-
lic couplings (e.g., Suzuki, Sonogashira, Heck, Stille, and
BuchwaldꢀHartwig couplings).
While the purpose of this work was originally to establish an
easy access to arylpiperidones, the importance of the benza-
zepinone intermediates 15 must nevertheless be underscored.
Indeed, benzazepines and benzazepinones belong to one
of the most studied classes of pharmacophores.19 The
present route to N-unsubstituted benzazepinones 15
allies simplicity, cheapness, convergence, and flexibility.
The Boc-protected allylamine used as the olefinic trap in
the above transformations can be replaced with other
alkenes, in line with our earlier work on the degenerative
radical additionꢀtransfer of xanthates and related deri-
vatives. This provides a simple means for introducing
side chains bearing various functional groups into the
Acknowledgment. We dedicate this paper with respect
and admiration to Dr. Stuart W. McCombie, formerly of
Schering-Plough. N.C. and Z.L. thank Ecole Polytechni-
ꢁ
que for a scholarship. We thank Xuan Xiao and Aurelie
Josselin, who participated in this project as undergraduate
interns.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data and copies of 1H and 13
C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(19) See for example: Zhang, A.; Neumeyer, J. L.; Baldessarini, R. J.
Chem. Rev. 2007, 107, 274.
(20) It is interesting to note that benzazepin-2-ones may also be
obtained by a Beckmann rearrangement of the oximes derived from
R-tetralones such as 3. For an example, see: Cordero-Vargas, A.; Quiclet-
Sire, B.; Zard, S. Z. Bioorg. Med. Chem. 2006, 14, 6165.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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