Synthesis of 3-arylpiperidines by a radical 1,4-aryl migration

Article abstract of DOI:10.1021/ol0503642

(Chemical Equation Presented) A route to 3-arylpiperidines, 3-arylpyridines, and 5-arylpiperidin-2-ones involving a radical 1,4-aryl migration has been explored. The sequence requires a xanthate addition to an N-allylarylsulfonamide, followed by acetylation and treatment with dilauroyl peroxide to give the 1,4-aryl transfer product, which upon acidic hydrolysis affords the desired piperidine derivative.

Full text of DOI:10.1021/ol0503642

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1653-1656
Synthesis of 3-Arylpiperidines by a
Radical 1,4-Aryl Migration
Alexandru Gheorghe, Be´atrice Quiclet-Sire, Xavier Vila, and Samir Z. Zard*
Laboratoire de Synthe`se Organique, De´partement de Chimie, EÄ cole Polytechnique,
Route de Saclay, 91128 Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received February 21, 2005
ABSTRACT
A route to 3-arylpiperidines, 3-arylpyridines, and 5-arylpiperidin-2-ones involving a radical 1,4-aryl migration has been explored. The sequence
requires a xanthate addition to an N-allylarylsulfonamide, followed by acetylation and treatment with dilauroyl peroxide to give the 1,4-aryl
transfer product, which upon acidic hydrolysis affords the desired piperidine derivative.
3-Arylpiperidines have been thoroughly investigated since
the early 1980s in view of their interesting opioid1 and
dopaminergic activity.2 One of the most interesting of these
is preclamol (Figure 1), reported to be the first selective D2-
like dopamine autoreceptor agonist. Potent dopaminergic
substances, such as preclamol and related compounds, have
potential for the treatment of schizophrenia, Parkinson’s
disease, depression, and drug addiction. Moreover, in the
Figure 1. Preclamol, a dopamine autoreceptor agonist.
past few years, the identification of 3-arylpiperidines as
antagonists of the tachykinin system,3 as inhibitors of the
steroid 5R-reductase4 or as ligands to the σ receptor,5 makes
In contrast with their interesting pharmacological profile,
few methods to construct 3-arylpiperidines have been
reported to date.6 The majority are based on a nickel cross-
coupling between an arylmagnesium bromide and a bro-
mopyridine,7 a Heck8 or a Suzuki9 coupling. The resulting
substituted pyridine is then reduced.
We now present a new synthesis of 2-substituted 5-arylpi-
peridines obtained via a key step involving a radical 1,4-
aryl transfer. Our synthetic design, depicted in Scheme 1,
relies on the rich chemistry of xanthates10 and starts from
N-allylsulfonamides 1a-g.
them even more interesting targets.
(1) Iorio, M. A. J. Med. Chem. 1978, 21, 812.
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10.1021/ol0503642 CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/17/2005

Scheme 1. Synthesis of â-Arylacetamides 5
When a solution of olefin 1 and xanthate 2 (1.5 equiv) in
by the additional electron withdrawing effect of the acetyl
group, and a consequent increase in the energy gap with the
SOMO of the radical (note that all radicals derived from
xanthates 2 are electrophilic in chararcter). Thus, the radical
addition was carried out by using nonacetylated olefins, and
protection of the nitrogen atom was performed later in the
synthetic sequence. The addition products 4 were subjected
to the action of the peroxide to trigger the intramolecular
radical 1,4-aryl migration for the formation of the â-arylac-
etamides 5, precursors of the desired 3-arylpiperidines.
1,2-dichloroethane (DCE) was heated to reflux in the
presence of a small amount of lauroyl peroxide (DLP),
adducts 3 were obtained in good yield. Because the subse-
quent radical transposition step proceeded in low yield with
nonprotected sulfonamides 3 (vide infra), these adducts were
protected as the corresponding acetamides with either acetyl
chloride or acetic anhydride. Interestingly, when the acetyl
group was first introduced on the allyl sulfonamides 1, the
radical addition proceeded in significantly lower yield. For
example, addition of xanthate 2h onto olefin 1h afforded
4h in only 42% yield. This was a consistent observation and
appears to be due to the lowering of the HOMO of the olefin
The key aryl migration to give 5 proceeds by the mech-
anism depicted in Scheme 2. There are many examples of
radical aryl migrations in the literature, the most extensively
investigated being 1,2-aryl migrations (neophyl rearrange-
ment),11 but 1,4- and 1,5-aryl migrations12 have also been
the subject of several studies. Aryl migrations are not restrict-
ed to movement from a carbon centered to a carbon centered
radical. The aryl transfer from an aryl sulfonamide to a
carbon centered radical was first described by Speckamp in
1972.13,14 With this process it is possible to transfer electron
rich and poor arenes. Sulfonamides arising from cyclization
(6) For recent syntheses of 3-arylpiperidines, see: (a) Wong, Y.-S.;
Marazano, C.; Gnecco, D.; Ge´nisson, 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. 2002, 67,
1448. (f) Amat, M.; Canto´, M.; Llor, N.; Ponzo, V.; Pe´rez, M.; 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.
(7) (a) Hacksell, U.; Arvidsson, L.-E.; Svensson, U.; Nilsson, L. G. J.
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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.
(10) (a) Quiclet-Sire, B.; Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997,
36, 672. (b) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur Silicon Relat.
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90.
(11) Urry, W. H.; Kharasch, M. S. J. Am. Chem. Soc. 1944, 66, 1438.
(12) For a review on radical aryl migration reactions, see: (a) Studer,
A.; Bossart, M. Tetrahedron 2001, 57, 9649. (b) Studer, A.; Bossart, M. In
Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, Germany, 2001; Vol. 2, p 62.
(13) Loven, R.; Speckamp, W. N. Tetrahedron Lett. 1972, 13, 1567.
(14) For other examples of sulfur to carbon radical aryl migrations, see:
(a) Ko¨hler, J. J.; Speckamp, W. N. Tetrahedron Lett. 1977, 18, 631. (b)
Ko¨hler, J. J.; Speckamp, W. N. Tetrahedron Lett. 1977, 18, 635. (c)
Speckamp W. N.; Ko¨hler, J. J. J. Chem. Soc., Chem. Commun. 1978, 166.
(d) Ko¨hler, H. J.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1980,
142. (e) Clive, D. L. J.; Boivin, T. L. B. J. Org. Chem. 1989, 54, 1997. (f)
Motherwell, W. B.; Pennell, A. M. K. J. Chem. Soc., Chem. Commun. 1991,
1654
Org. Lett., Vol. 7, No. 8, 2005

The aryl transfer products 5 were obtained in moderate to
good yield (Scheme 1). In some examples we also recovered
unreacted or deacetylated starting material, as well as what
appeared to be the product of the reduction of radical I, which
could account for the moderate yield in some runs. Previous
trials showed 2-propanol to be the best hydrogen atom
donating solvent, in comparison with toluene, cyclohexane,
or isopropyl acetate. The use of carbamate instead of acetyl
derivatives resulted in lower yields.
Scheme 2. Mechanism of 1,4-Aryl Transfer
From the data in Scheme 1, it seems that the nature of the
phenyl substituent X does not affect greatly the course of
the reaction, as in both series of electron withdrawing and
electron donating groups examples of good yields are found.
As for the R substituent on the carbonyl group, it can be
concluded that the best yields are found when there is an
aliphatic ester or amide moiety (4a, R ) OMe, 71%; 4d,
R,R′ ) lactone, 70%; 4e, R ) piperidine, 70%). In the case
of precursors 4f and 4h, the yield was lowered because of a
competing cyclization of the intermediate radical (corre-
sponding to I in Scheme 2) onto the thiophenyl and phenyl
rings respectively to give the corresponding tetralone.17 The
best yield was obtained with sulfonamide 4g, in which the
aryl ring bears a cyano group and there is a bulky tert-butyl
substituent on the carbonyl.
With compounds 5 in hand, we examined their conversion
into piperidine derivatives. Acid hydrolysis of the acetamido
group and subsequent cyclization afforded the desired
substituted piperidines (Table 1). If the R substituent of the
to the aromatic ring and products of direct reduction have
also been observed as side-products in these reactions.
Hitherto, nearly all the examples of sulfur to carbon 1,4-
aryl migrations use toxic tin hydrides. The present approach
is not only tin-free, but also avoids high dilution and is
experimentally very easy to perform. Lauroyl peroxide is
simply added portion-wise to a refluxing solution of adduct
4 in a mixture of 2-propanol and 1,2-dichloroethane. 2-Pro-
panol is a key element of the process. As outlined in Scheme
2, radical I must have enough lifetime to be able to undergo
the desired aryl shift. Even though 2-propanol is capable of
hydrogen atom transfer to a secondary radical such as I,15
this process is relatively slow and does not compete
efficiently with the ipso substitution leading to III. Extrusion
of sulfur dioxide would then give a highly reactive electro-
philic amidyl radical IV, which now is rapidly reduced by
the 2-propanol. Hence the need to introduce an acetyl group
in the first place. In its absence, the sequence would have
furnished a much less reactive and more problematic aminyl
radical. As for the ketyl radical derived from 2-propanol, it
is simply oxidized into acetone by the peroxide, which must
therefore be used in stoichiometric amounts. It is also
possible that hydrogen abstraction from 2-propanol takes
place at the level of radical III. Such amidosulfonyl radicals
are electrophilic and loss of sulfur dioxide may be too slow
to compete with the hydrogen abstraction.16 This of course
has no practical consequence on the outcome since ultimately
amide 5 is formed through both pathways.
Table 1. Synthesis of 5-Arylpiperidines,
5-Arylpiperidin-2-ones, and 5-Arylpyridines
acetamide
X
R
heterocycle
5a
5b
5c
5f
5h
5h
4-Me
4-Me
4-tBu
4-CF3
4-Me
4-Me
OMe
Bn
cyclohexyl
2-thiophenyl
Ph
7 (88%)
8a (85%)
8b (65%)
8c (77%)
8d (89%)
9 (83%)
Ph
transfer product 5 is an alkyl or aryl group, the product
obtained is an imine, which can be either reduced to the
desired piperidine or oxidized to the corresponding pyridine.
If the R radical is an alkoxy or an amine, the product is a
piperidin-2-one.
877. (g) da Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F.
Tetrahedron Lett. 1997, 38, 137. (h) da Mata, M. L. E. N.; Motherwell, W.
B.; Ujjainwalla, F. Tetrahedron Lett. 1997, 38, 141. (i) Bonfand, E.;
Forslund, L.; Motherwell, W. B.; Va´zquez, S. Synlett 2000, 475.
(15) (a) Liard, A.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996,
37, 5877. (b) Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1998, 39, 9435.
Org. Lett., Vol. 7, No. 8, 2005
1655

Hydrolysis was performed with concentrated HCl (Table
1), and the desired imines were used without purification as
the hydrochlorides or the free imines. Reduction with sodium
cyanoborohydride provided the desired 5-arylpiperidines in
good yield and diastereoselectivity. In the case of acetamide-
acetal 5i, a cyclization induced by p-toluene sulfonic acid
afforded piperidine 8e in good yield (Scheme 3). This is an
Scheme 4. Synthesis of 2,5-Diarylpiperidines
Scheme 3. Synthesis of Nicotinic Acid Derivative 8e
piperidine 13 was obtained as a single diastereomer in
excellent yield. With ethylenediamine, a second cyclization
occurred and bicyclo derivative 14 was obtained as a mixture
of two separable diastereomers in a 5:1 ratio (72%).
alternative route into nicotinic acid derivatives, and the
unsaturation and iodine present in the molecule offer many
possibilities for further functionalization.
The present approach to aryl substituted piperidines can
be expanded by exploiting another sequence involving a 1,2-
aryl migration we recently described.18 As shown in Scheme
4, addition of xanthate 2j to an olefin such as 10 results in
the formation of derivative 11 in 60% yield through 1,2-
shift of the trifluoromethylphenyl group and â-elimination
of an ethyl sulfonyl radical.
Exposure of compound 11 to ammonia or a primary amine
and sodium cyanoborohydride gave rise to the desired
piperidine derivative. Thus, treatment of ester 11 with an
excess of ammonium acetate and sodium cyanoborohydride
in refluxing ethanol afforded the piperidine 12 in good yield
and as a 5:1 mixture of diastereomers which could be
separated by chromatography. When the reaction was
performed with cyclopropylamine, however, the trisubstituted
In summary, we have described a powerful, flexible, and
convergent general strategy for constructing aryl substituted
piperidines using readily available and cheap starting mate-
rial. This approach, in combination with an earlier one
involving addition of a xanthate to protected allylamine
followed by ring-closure,19 opens up a direct access to a vast
number of more or less complex piperidine structures of
interest to medicinal chemists. The sequence can be modified
to provide the equally important substituted pyridines. It is
also worth stressing the function group tolerance, in particular
for aromatic iodides since these can act as springboards for
numerous further transition metal based transformations.
Supporting Information Available: Detailed experi-
mental procedures and spectra data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Moutrille, C.; Zard, S. Z. Chem. Commun. 2004, 1848. (b)
Montermini, F.; Lacoˆte, E.; Malacria, M. Org. Lett. 2004, 6, 921.
(17) Liard, A.; Quiclet-Sire, B.; Saicic, R. N.; Zard, S. Z. Tetrahedron
Lett. 1997, 38, 1759.
OL0503642
(18) Ouvry, G.; Zard, S. Z. Synlett 2003, 1627.
(19) Boivin, J.; Pothier, J.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 3701.
1656
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