Efficient oxidative radical spirolactamization

Article abstract of DOI:10.1039/b705397e

An efficient xanthate-based method for the preparation of azaspirocyclic cyclohexadienones via an ipso oxidative radical cyclization of p-oxygenated N-benzylacetamides and N-phenetylacetamide is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b705397e

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Efficient oxidative radical spirolactamization{
Tannya R. Ibarra-Rivera,a Rocio Ga´mez-Montan˜o*a and Luis D. Miranda*b
Received (in Cambridge, UK) 11th April 2007, Accepted 22nd May 2007
First published as an Advance Article on the web 14th June 2007
DOI: 10.1039/b705397e
method for the preparation of highly substituted azaspirocyclic
An efficient xanthate-based method for the preparation
of azaspirocyclic cyclohexadienones via an ipso oxidative
radical cyclization of p-oxygenated N-benzylacetamides and
N-phenetylacetamide is described.
cyclohexadienones via an ipso oxidative radical cyclization of
p-oxygenated N-benzylacetamides and homologs thereof (e.g.,
Scheme 1).12 Our studies commenced with the readily available
xanthate 5a,13 which upon reaction with a slight excess (1.2 equiv.)
of dilauroyl peroxide in 1,2-dichloroethane at reflux temperature,
was converted exclusively into the spirocyclic derivative 6.14 Under
the same conditions, the p-hydroxylated compound 5b also gave 6
in nearly quantitative yield.
Azaspirocyclic cyclohexadienones are pivotal synthetic intermedi-
ates in the preparation of an extensive range of biologically active
molecules.1 Recently the azaspirocyclic core was shown to be
present in annosqualine 1, a natural product isolated from the
stems of Annona Squamosa (Fig. 1).2 Furthermore, the reduced
congeners 2-azaspiro[4.5]decane and 2-azaspiro[5.5]undecane have
a variety of biological activities.3 For instance, the azaspirane 2 has
inhibitory action in KB cells and cells of human mammary cancer
grown in tissue culture.4 The spiropiperidine BL17435 is an
antiviral and L6873846 is a potent and selective s-receptor ligand
(Fig. 1).
To investigate the scope of the spirolactamization process, a
series of p-alkoxylated N-benzyl and N-phenethylacetamido
derivatives (Table 1) was prepared and subjected to the above
reaction conditions. The expected spirolactams were obtained as
the exclusive, or major products in all cases. It is noteworthy that
the presence of one or more substituents (MeO, Me, Br) ortho or
meta to the p-alkoxyl moiety does not derail the spirocyclization
process (entries 1–5) and a p-isopropoxy group also leads to the
expected product (entry 7). Furthermore, 3-azaspiro[5.5]undecane
systems (e.g., compounds 20a and 20b; entry 7) are readily
generated starting from N-p-alkoxylphenethylacetamides.
Secondary xanthates can also be used, in which case azaspiro-
cyclohexadienones containing a methyl substituent a to the lactam
carbonyl group are produced (entry 6). The remaining
N-substituent in the starting materials does not have to be a
tert-butyl group, since the N-isopropyl (entry 7) and the
N-dimethoxylphenethyl (entry 11) compounds also gave rise to
spiro products. The xanthate 21 is a particularly interesting
substrate since the formation of both 2-azaspiro[4.5]decane and
3-azaspiro[5.5]undecane systems is possible (entry 8). Nevertheless,
the only spiro product isolated (65% yield), containing the
[4.5]decane system, was compound 22. Finally, the formation of
the spiro compound 24, derived from the naphthalene precursor 23
indicates that this process does indeed have considerable scope
(entry 9).
Several strategies have been reported for the construction of
azaspirocyclic cyclohexadienone systems. The formation of
azaspirocycles from p-MeO-benzene derivatives was observed in
the acid-catalyzed cyclization of aromatic diazoacetamides7 and
also in the intramolecular addition of stabilized enolates to
(g6-arene)ruthenium complexes.8 Radical spirocyclization onto a
p-MeO-aryl ring was first observed by Hey and Todd9 in 1967, but
the process was of limited synthetic value. Zard and co-workers
have observed the formation of one azaspirocyclic cyclohexadie-
none in moderate yield, by a nickel/acetic acid induced oxidative
ipso-type radical cyclization onto p-MeO-benzenoid systems.10
Very recently, Gonzalez-Lopez de Turiso and Curran11 reported a
similar (TMS)3SiH-mediated cyclization, but only low yields of the
spirocyclic systems were obtained. Herein, we describe an efficient
A possible mechanistic rationalization for the formation of the
spiro compounds is depicted in Scheme 2. The cyclohexadienyl
radical 26 produced from the ipso-cyclization, is then oxidized to
the oxonium ion 27, or the corresponding protonated species, by
lauroyl peroxide. The oxonium ion would then be transformed
into the observed product in the reaction medium or upon workup
of the reaction mixture. The success of the reaction is dependent on
Fig. 1 Azaspirocycles.
aFacultad de Qu´ımica, Universidad de Guanajuato, Noria Alta S/N,
Guanajuato, Me´xico C.P. 36050
bInstituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico,
Circuito Exterior S. N., Ciudad Universitaria, Coyoaca´n, Me´xico
D. F. 04510, Me´xico. E-mail: lmiranda@sevidor.unam.mx;
Fax: (+52) 55 56 16 22 17; Tel: (+52) 55 56 22 44 40
{ Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data for all new compounds. See DOI: 10.1039/
b705397e
Scheme 1
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Table 1
Entry Xanthate
Azaspirocycle
1
2
3
Scheme 2
the use of slightly more than one equivalent of the peroxide, and
this stoichiometry is consistent with the proposed oxidation
mechanism.
The efficacy of the ipso cyclization may be a consequence of
both a polarity match between the attacking electrophilic radical
and the nucleophilic ipso benzenoid carbon (para to the methoxyl
group) as well as to the formation of the highly resonance
stabilized radical 26.
In short, we have developed a novel, simple, and efficient
procedure for the synthesis of highly functionalized 2-azaspiro-
[4.5]decan-3-ones and 3-azaspiro[5.5]undecan-4-ones. We are
currently studying the synthetic consequences of, and the
mechanistic questions which, have been raised by the results
described herein.
4
5
We thank CONACYT (J42673Q) for financial support and Dr
Joseph M. Muchowski for many helpful discussions. Also we
thank R. Patin˜o, J. Pe´rez, L. Velasco, H. Rios, N. Zavala, E.
Huerta and A. Pen˜a, for technical support.
Notes and references
1 (a) D. J. Wardrop, M. S. Burge, W. Zhang and J. A. Ortiz, Tetrahedron
Lett., 2003, 44, 2587; (b) G. M. Rishton and M. A. Schwartz,
Tetrahedron Lett., 1988, 29, 2643.
6
2 Y. L. Yang, F.-R. Chang and Y.-C. Wu, Helv. Chim. Acta, 2004, 87,
1392.
3 (a) W. M. Kazmierski, E. Furfine, A. Spaltenstein and L. L. Wright,
Bioorg. Med. Chem. Lett., 2002, 12, 3431; (b) C. R. Albrightson,
P. J. Bugelski, T. A. Berkhout, B. Jackson, W. D. Kerns, A. J. Organ
and A. M. Badger, J. Pharmacol. Exp. Ther., 1995, 272, 689.
4 (a) L. M. Rice, B. S. Sheth and J. W. Wheeler, J. Heterocycl. Chem.,
1973, 10, 731; (b) A. M. Badger, T. M. Newman-Tarr and J. L.
Satterfield, Inmunopharmacology, 1997, 37, 53.
7
5 G. S. Gandhi, K. Shuck, J. D. Lear, G. R. Diekmann, W. F. DeGrado,
R. A. Lamb and L. H. Pinto, J. Biol. Chem., 1999, 274, 5474.
6 C. A. Maier and B. Wu¨nsch, J. Med. Chem., 2002, 45, 438.
7 G. M. Rishton and M. A. Schwartz, Tetrahedron Lett., 1988, 29, 2643.
8 (a) F. C. Pigge, S. Fang and N. Rath, J. Am. Chem. Soc., 2006, 128,
3498, and references therein.
9 D. H. Hey and A. R. Todd, J. Chem. Soc. C, 1967, 1518.
10 J. Boivin, M. Yousfi and S. Z. Zard, Tetrahedron Lett., 1997, 38, 5985.
11 F. Gonzalez-Lopez de Turiso and D. P. Curran, Org. Lett., 2005, 7, 151,
and references cited therein.
12 For references on ipso-type radical cyclization onto other substituted
aromatic systems, see: furans: (a) S. Guindeuil and S. Z. Zard, Chem.
Commun., 2006, 665; (b) A. Demircan and P. Parsons, Eur. J. Org. Chem.,
2003, 1729; pyrroles: (c) K. Jones, T. C. T. Ho and J. Wilkinson,
Tetrahedron Lett., 1995, 36, 6743; (d) C. Escolano and K. Jones,
Tetrahedron Lett., 2000, 41, 8951; (e) C. Escolano and K. Jones,
Tetrahedron, 2002, 58, 1453; benzofurans: (f) A. S. Kyei, K. Tchabanenko,
J. E. Baldwin and R. M. Adlington, Tetrahedron Lett., 2004, 45, 8931;
indoles: T. Hilton, T. C. T. Ho, G. Pljevaljcic and K. Jones, Org. Lett.,
2000, 2, 2639; benzene: H. Ohno, S.-I. Maeda, M. Okumura,
R. Wakayama and T. Tanaka, Chem. Commun., 2002, 316.
8
9
a
Xtht = SC(S)OEt.
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13 B. Quiclet-Sire and S. Z. Zard, Chem. Eur. J., 2006, 12, 6002.
14 Typical procedure for radical spirocyclization. A deaerated solution of the
corresponding xanthate (1.0 mmol) in 1,2-dichloroethane (5 mL) was
heated at reflux and 10% mol lauryl peroxide (1.2–1.5 mmol) was then
added every 1 h until complete consumption of the xanthate was
observed by TLC. The solvent was removed under reduced pressure
and the residue purified by chromatography on a silica gel column
(hexane–EtOAc) to furnish the desired product. Selected spectral data
for 6. IR (neat, cm21): 1676, 1628; 1H NMR (300 MHz, CDCl3) d 6.96
(d, 2H, J = 10.2 Hz), 6.34 (d, 2H, J = 10.2 Hz), 4.49 (s, 2H), 2.54 (s, 2H),
1.43 (s, 9H); 13C NMR (300 MHz, CDCl3) d 185.0, 171.6, 150.1,
129.3, 54.6, 53.0, 42.6, 40.8, 27.6; EI-MS m/z (%) 219 (M+, 65);
HRMS (FAB+) m/z calc. for C13H18NO2 (M + H+) 220.1338, found
220.1337.
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