Tin-free radical sequences under acidic conditions. Convergent access to azole-containing structures

Article abstract of DOI:10.1021/ol0270024

(equation presented) Various xanthates add efficiently to olefins bearing [1,2,4]triazole, imidazole, or benzimidazole moieties in the presence of camphorsulfonic acid via a radical chain reaction initiated by a small amount of lauroyl peroxide. The adducts may be transformed to more complex molecules by implementing a further radical cyclization.

Full text of DOI:10.1021/ol0270024

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4345-4348
Tin-Free Radical Sequences under
Acidic Conditions. Convergent Access
to Azole-Containing Structures
Fabien Gagosz and Samir Z. Zard*
Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique,
91128 Palaiseau, France
zard@poly.polytechnique.fr
Received October 1, 2002
ABSTRACT
Various xanthates add efficiently to olefins bearing [1,2,4]triazole, imidazole, or benzimidazole moieties in the presence of camphorsulfonic
acid via a radical chain reaction initiated by a small amount of lauroyl peroxide. The adducts may be transformed to more complex molecules
by implementing a further radical cyclization.
Azole subunits are frequently present in biologically active
compounds. This is the case for the marketed drugs riza-
triptan1 used in the treatment of migraine and the antifungal
sertaconazole2 or the promising PBI antitumor agent.3 As a
consequence, much ongoing effort has been devoted to the
development of practical synthetic routes to the various
classes of such heteroarenes. In this context, new free radical
methods for the synthesis of heterocyclic compounds are
gaining increasing importance.4 However, with the exception
of the cyclization protocols extensively developed by Bow-
man and co-workers,5 general approaches for the introduction
of azole and related heteroaromatic structures have not been
widely studied.
(1) Street, L. J.; Baker, R.; Davey, W. B.; Guiblin, A. R.; Jelley, R. A.;
Reeve, A. J.; Routledge, H.; Sternfeld, F.; Watt, A. P.; Beer, M. S.;
Middlemiss, D. N.; Noble, A. J.; Stanton, J. A.; Scholey, K.; Hargreaves,
R. J.; Sohal, B.; Graham, M. I.; Matassa, V. G. J. Med. Chem. 1995, 38,
1799.
(2) Raga, M. M.; Moreno-Manas, M.; Cuberes, M. R.; Palacin, C.;
Castello, J. M.; Ortiz, J. A. Arzneim. Forsch. 1992, 42, 691.
(3) Sternfeld, F.; Baker, R.; Broughton, H. B.; Guiblin, A. R.; Jelley, R.
A. Bioorg. Med. Chem. Lett. 1996, 6, 1825.
(4) For reviews, see: (a) Bowman, W. R.; Cloonan, M. O.; Krintel, S.
L. J. Chem. Soc., Perkin Trans. 1 2001, 2885. (b) Bowman, W. R.; Bridge,
C. F.; Brookes, P. J. Chem. Soc., Perkin Trans. 1 2000, 1. (c) Aldabbagh,
F.; Bowman, W. R. Contemp. Org. Synth. 1997, 4, 261.
Furthermore, most of the reported procedures concern
cyclization with triazoles,6 pyrazoles,5a indoles,7 pyrroles,5b,c,e,8
imidazoles,5c-e and benzimidazoles5d,f and are based on the
use of tin reagents leading to the well-known difficulties with
purification and toxicity.
10.1021/ol0270024 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/02/2002

As part of our continuing work in radical chemistry, we
have devised a flexible and efficient approach to the synthesis
of [1,2,4]triazole, imidazole, and benzimidazole derivatives.
Our synthetic design, depicted in Scheme 1, relies on the
case of xanthate 1d and olefin 2d, the presence of the acid
proved to be more crucial since the 79% yield of adduct 3f
dramatically falls to 0% yield when addition of CSA was
omitted.10 This modified protocol turned out to be quite
efficient, as demonstrated by the examples shown in Table
1. Many functional groups may be tolerated in the xanthate
Scheme 1. Synthetic Route to Functionalized Nitrogen
Heterocycles
Table 1. Radical Additions of Xanthates to Olefins 2a-d in
the Presence of Camphorsulfonic Acid
rich chemistry of xanthates.9 Thus, radical addition of
xanthate 1 to olefin 2 would lead directly to a variety of
functionalized nitrogen heterocycles 3. However, since the
xanthate functionality is sensitive to nucleophilic attack, this
radical addition fails with substrates containing basic nitrogen
functionality. We therefore modified our normal experimental
procedure by adding 1 equiv of camphorsulfonic acid (CSA)
for each basic site on the olefin. Under these conditions, the
reaction proceeded more cleanly in the case of olefins 2a,b
and the presence of acid was indispensable to obtaining
xanthate adducts with olefins 2c-e.
Indeed, when a solution of xanthate 1a, olefin 2a (2 equiv),
and CSA (2 equiv) in 1,2-dichloroethane (1 M) was heated
to reflux in the presence of a catalytic amount of lauroyl
peroxide (DLP), the 60% yield of adduct 3a obtained without
the presence of the acid was improved to 75% yield. In the
(5) (a) Allin, S. A.; Barton, W. R. S.; Bowman, W. R.; McInally, T.
Tetrahedron Lett. 2002, in press. (b) Allin, S. A.; Barton, W. R. S.; Bowman,
W. R.; McInally, T. Tetrahedron Lett. 2001, 42, 7887. (c) Aldabbagh, F.;
Bowman, W. R.; Mann, E.; Slawin, A. M. Z. Tetrahedron 1999, 55, 8111.
(d) Aldabbagh, F.; Bowman, W. R. Tetrahedron 1999, 55, 4109. (e)
Aldabbagh, F.; Bowman, W. R.; Mann, E. Tetrahedron Lett. 1997, 38, 7937.
(f) Aldabbagh, F.; Bowman, W. R. Tetrahedron Lett. 1997, 38, 3793.
(6) Marco-Contelles, J.; Rodr´ıguez-Ferna´ndez, M. J. Org. Chem. 2001,
66, 3717.
(7) (a) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. J. Org. Chem.
2001, 66, 7547. (b) Byers, J. H.; Kosterlitz, J. A.; Steinberg, P. L. C. R.
Acad. Sci. Paris, Chem. 2001, 4, 471. (c) Ziegler, F. E.; Belema, M. J.
Org. Chem. 1997, 62, 1083. (d) Moody, C. J.; Norton, C. L. J. Chem. Soc.,
Perkin Trans. 1 1997, 2639. (e) Moody, C. J.; Norton, C. L. Tetrahedron
Lett. 1995, 36, 9051.
a The adduct was obtained in 60% yield without addition of CSA.
b Tetralone 4 was also isolated in 10% yield. c Rapid degradation was
observed and no adduct was obtained when CSA was not added.
(8) Antonio, Y.; De La Cruz, E.; Galeazzi; E.; Guzman, A.; Bray, B. L.;
Greenhouse, R.; Kurtz, L. J.; Lustig, D. A.; Maddox, M. L.; Muchowski,
J. M. Can. J. Chem. 1994, 72, 15.
(9) (a) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur Silicon 1999,
137. (b) Quiclet-Sire, B.; Zard S. Z. Angew. Chem., Int. Ed. Engl. 1997,
36, 672.
(10) Rapid degradation of the starting material was observed.
(11) For the synthesis of tetralones by radical cyclisation, see: Liard,
A.; Quiclet-Sire, B.; Saicic, R. N.; Zard, S. Z. Tetrahedron Lett. 1997, 38,
1759.
(12) For the synthesis of benzazepinones by radical cyclization, see:
Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard S. Z. Angew. Chem., Int. Ed.
2000, 39, 731.
as well as in the olefinic partner, allowing the synthesis of
a variety of functionalized nitrogen heterocycles.
More complex molecules may be constructed by further
transformation of the xanthate adduct. In the case of adducts
3b and 3c, refluxing in 1,2-dichloroethane with 1 equiv of
CSA and the gradual addition of a stoichiometric amount of
peroxide induced ring closure onto the aromatic ring to give
the corresponding tetralone 4 in 75% yield and benz-
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Org. Lett., Vol. 4, No. 24, 2002

such as a phenyl or an aldehyde on the imidazole ring was
necessary to perform the oxidative radical cyclization with
Bu3SnH.5c,e In the present case, CSA plays a double role by
externally activating and directing the cyclization to give
pyrrolo[1,2-a]imidazole 6 as the sole product in 56% yield.13
The same transformation was attempted with xanthate
adduct 3d, but in this case, no cyclized product was formed.
This might be explained by a negligible activating effect of
CSA on the much less basic [1,2,4]triazole.
Scheme 2. Radical Transformation of Adducts 3b and 3c
Benzimidazole derivatives in contrast proved to be as good
substrates as imidazoles for the radical cyclization. The
combined activating effect of the acid and the fused phenyl
group resulted in significant ring closure from the outset.
Thus, when a solution of xanthate 1a, olefin 2e (2 equiv),
and CSA (2 equiv) in 1,2-dichloroethane (1 M) was refluxed
in the presence of lauroyl peroxide (DLP), an inseparable
mixture of xanthate adduct 7a (51%) and pyrrolo[1,2a]-
benzimidazole 8a (27%) was produced. This mixture was
submitted again to radical cyclization conditions to finally
give tricycle 8a in 57% over the two steps (Scheme 4). The
azepinone 5 in 36% yield, respectively (Scheme 2).11,12
Interestingly, the yield of tetralone 4 is higher than the
average yield (30-70%) observed earlier11 and may be
attributed to an activation of the carbonyl function by CSA,
making the aromatic more reactive toward the attack of an
alkyl radical with nucleophilic character. Indeed, in an
ancillary study, we found that adding CSA increased
significantly the yield of tetralone.
Scheme 4. Radical Cascades with Olefin 2e
Alternatively, the xanthate group in adduct 3f may be used
to implement a radical cyclization on the imidazole ring.
Under the same conditions of radical cyclization, regio-
selective ring closure occurred at the C-2 position of
imidazole as shown in Scheme 3. This selectivity must be
contrasted with observations made by Bowman and co-
workers, who found that the presence of activating groups
Scheme 3. Radical Cyclization of Xanthate Adduct 3f
same sequence of addition/cyclization was applied to xan-
thates 1c and 1d to respectively give pyrrolo[1,2a]benz-
imidazole 8b and 8c in 37 and 57% yields.
It is worth pointing out that this simple protocol gives a
rapid access to polyfunctionalized compounds possessing the
(13) For radical additions to positively charged heteroaromatics, see: (a)
Minisci, F.; Citterio, A.; Vismara, E.; Giordano, C. Tetrahedron 1985, 41,
4157 and references cited therein. (b) Minisci, F.; Vismara, E.; Romano,
V. Tetrahedron Lett. 1985, 26, 4803. (c) Barton, D. H. R.; Garcia, B.; Togo,
H.; Zard, S. Z. Tetrahedron Lett. 1986, 27, 1327.
Org. Lett., Vol. 4, No. 24, 2002
4347

ideally suited for further transformations. In the presence of
nucleophiles such as amines or alcohols, the oxazolidine
moiety is easily displaced. Amides 9a,b and ester 9c were
thus readily prepared in excellent yield (Scheme 5).
In summary, these preliminary results demonstrate the
compatibility of the xanthate methodology with an anhydrous
acidic medium and its potential for the convergent construc-
tion of nitrogen-containing heteroaromatics. This tin-free
protocol is quite general, proceeds under mild conditions,
and tolerates many functional groups.
Scheme 5. Transformation of Pyrrolo[1,2a]benzimidazole 8c
Acknowledgment. We wish to thank Rhodia Chimie Fine
for generous financial support to F.G. and Drs. Jean-Marc
Paris and Franc¸ois Metz of Rhodia for friendly discussions.
Supporting Information Available: Detailed experi-
mental procedures and spectral data for olefins 2a-e, radical
adducts 3a-f, and cyclized compounds 4-6, 8a-c, and 9a-
c. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL0270024
tricyclic core of the potent PBI antitumor agents.3,14 Pyrrolo-
[1,2a]benzimidazole 8c is especially interesting since it
possesses an activated carboxylic acid functionality that is
(14) For a review of the synthesis of the pyrrolo[1,2-a]benzimidazole
antitumor agents, see: Skibo, E. B.; Islam, I.; Schultz, W. G.; Zhou, R.;
Bess, L.; Boruah, R. Synlett 1996, 297.
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