Efficient, intermolecular, oxidative radical alkylation of heteroaromatic systems under "tin-free" conditions

Article abstract of DOI:10.1039/b306966d

Novel and efficient radical alkylation of several heterocyclic systems including pyrroles, indoles, furan and thiophenes is described using xanthate based radical chemistry. The present methodology could be used to provide rapid access to various nonstero

Full text of DOI:10.1039/b306966d

Efficient, intermolecular, oxidative radical alkylation of heteroaromatic
systems under “tin-free” conditions
Yazmin M. Osornio, Raymundo Cruz-Almanza, Vicente Jiménez-Montaño and Luis D. Miranda*
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior S. N., Ciudad
Universitaria, Coyoacán, México, D. F. 04510, México. E-mail: mirandald@correo.unam.mx; Fax: (+52)
55 56 16 22 17; Tel: (+52) 55 56 22 44 40
Received (in Cambridge, UK) 18th June 2003, Accepted 21st July 2003
First published as an Advance Article on the web 1st August 2003
Novel and efficient radical alkylation of several heterocyclic
systems including pyrroles, indoles, furan and thiophenes is
Table 1 Radical alkylation of different heteroaromatic systemsa
described using xanthate based radical chemistry. The
present methodology could be used to provide rapid access
to various nonsteroidal antiinflammatory drugs.
Entry
Substrate
Xanthate
Product
The alkylation of aromatic systems is an important carbon–
carbon bond formation process that is used to provide access to
diverse synthetically and pharmacologically important mole-
cules. Electrophilic alkylation, which can be used for such
purposes, is often associated with the generation of undesired
rearranged products. This is generally not the case with
oxidative radical alkylation.1–4 Whereas the intramolecular
oxidative radical alkylation of homocyclic and heterocyclic
aromatic systems has been quite intensively studied, and is
frequently of preparative value,1,2 much less information exists
regarding the intermolecular process.3–4 In part, this is because
product yields are often low, unless a large excess (15–20
equiv.) of the aromatic substrate is used.3a Recently Zard and
coworkers2 have annelated five, six, and seven-membered rings
to an aromatic nucleus, exploiting the xanthate based radical
chemistry. These reactions not only can be conducted in the
absence of heavy metals, and under tin-free conditions, but also
the premature reduction of the intermediate radicals is easily
avoided.5 Indeed, free radicals generated from xanthates have a
comparatively long lifetime and can add to unactivated olefins,
reactions which are inefficient otherwise.5 In this report we
demonstrate that under xanthate-mediated radical conditions
the intermolecular oxidative radical alkylation of various
heteroaromatic systems can be effected in preparatively useful
yields even when the aromatic substrate is not used in excess.
The proposed mechanism to the reaction is depicted in
Scheme 1. a-Acetyl or a-acetonyl radical 2 generated by the
action of dilauroyl peroxide (DLP) on xanthate 1, adds to the
heteroaromatic system 3 producing the conjugated radical 4.
Aromatized derivative 5 could then be produced either by a
DLP-mediated oxidative pathway in a chain reaction (Scheme
1, path i)2 or by a direct abstraction of the hydrogen by the alkyl
radical derived from fragmentation of the peroxide in a non-
chain process (path ii). According to both mechanisms a
stoichiometric amount of the peroxide would be required to
1
69%
2
74% (81%)
65% (79%)
3
4
5
86%
46%
18%
65%
6
7
60%
8
44% (71%)
a Yields in parentheses are based on recovered starting material.
Scheme 1 Proposed mechanism for homolytic alkylation.
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CHEM. COMMUN., 2003, 2316–2317
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complete the reaction. At the present time we do not have
evidence to strongly support or eliminate either mechanism.
The initial experiments were carried out on 2-acylpyrroles.
Thus, portionwise addition of a stoichiometric amount of
lauroyl peroxide (over 12 h) to a boiling solution of pyrrole 6 (1
equiv.) and xanthate 7 (1.2 equiv.) in dichloroethane (2 mL
mmol21) led to alkylation at C-5 and furnished 8 in good yield.†
Under identical reaction conditions, acetonyl radical derived
from xanthate 9 efficiently added to pyrroles 6 and 11 to furnish
10 and 12 respectively (Table 1, entries 2 and 3). The
regiochemistry of these reactions is in accordance with SOMO–
HOMO predictions.3d Similarly the 5-benzoylpyrrol-2-yl ace-
tate derivative 14 could be prepared in very high yield (Table 1,
entry 4). This molecule contains the basic structural features of
the important non-steroidal antiinflammatory agents tolmetin
and amtolmetin guacil,6 both of which should be accessible
using the methodology described herein. Thiophene and furan
systems can also be alkylated. This is illustrated by the synthesis
of 16 and 19, which were obtained by radical addition of the
appropriate xanthate to 15 and 18, respectively (Table 1, entries
5 and 6). In the case of the thiophene system, a significant
quantity of the 2,3-disubstituted derivative 17 was also
generated. The reaction of indole 20 and xanthate 9 gave the
2-substituted compound 21 with high regioselectivity, a pre-
viously observed phenomenon,3a fully consistent with the
significant HOMO coefficient at C-2 of indole3e (Table 1, entry
7). It is worth noting that electrophilic substitution reactions of
indole, including alkylations, occur at C-3.
2-Arylpropionic acids constitute a large class of nonsteroidal
antiinflammatory drugs, which are used worldwide. A concise
approach to 2-heteroarylpropionic acids consists in simply
using the secondary xanthate 25 (Table 2). The tiaprofenic acid
ester 26 was thus prepared in good yield from commercially
available 2-benzoylthiophene 24. Likewise the reaction of the
xanthate 25 and pyrrole 13 afforded 2-(5-benzoylpyrrol-
2-yl)propionic acid ethyl ester 27 in high yield along with small
quantities of recovered starting material.
Even though the process has not yet been fully optimised it is
clear that the xanthate-mediated intermolecular oxidative
radical alkylation of various heteroaromatic systems can be
effected in preparatively useful yields. The present radical
based, tin-free approach could be used, in principle, to provide
rapid access to various medicinally important compounds, such
as nonsteroidal antiinflammatory drugs.
Notes and references
† Typical experimental procedure: A solution of the xanthate (1.2 mmol)
and the heteroaromatic compound (1 mmol) in degassed 1,2-dichloroethane
(2 mL mmol21) was heated at reflux, and a solution of dilauroyl peroxide
(1–1.2 mmol) in 1,2-dichloroethane (0.5 mL mmol21) was added dropwise
over a 12 h period. The reaction was monitored by TLC. The solvent was
removed under reduced pressure and the crude residue was purified by
chromatography on a silica gel column (ethyl acetate/hexane) to furnish the
desired product. Selected spectroscopic data: 8 as a white solid m.p. 57–59
°C; IR (KBr cm21): 2929, 1727, 1659; 1H NMR (300 MHz, CDCl3) d/ppm:
9.48 (s, 1H), 6.86 (d, J = 3.9 Hz, 1H), 6.17 (d, J = 3.9 Hz, 1H), 4.18 (q,
J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.67 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) d/ppm: 179.3, 168.9, 135.9, 132.4, 124.1, 110.7,
61.4, 32.5, 32.4, 14.1. HRMS FAB (M + 1, m/z) calcd for C10H14O3N1:
196.0974, found: 196.097. 14 m.p. 156–158 °C (Lit.7 158–159 °C); HRMS
FAB (M + 1, m/z) calcd for C15H16O3N1: 258.1130, found: 258.1139. 21 as
a white solid m.p. 25–26 °C. (Lit.8 24.5–25 °C), HRMS FAB (M + 1, m/z)
calcd for C12H14O2N1: 204.1025, found: 204.1017.
1 (a) A. Studer, in Radicals in Organic Synthesis, ed. P. Renaud and M.
Sibi, Wiley VCH, Weinheim, 2001, vol. 2, pp. 62–76; (b) J. A. Murphy
and M. S. Sherburn, Tetrahedron, 1991, 47, 4077; (c) F. Suzuki and K.
Kuroda, J. Heterocycl. Chem., 1993, 30, 811; (d) Y. Antonio, E. de la
Cruz, E. Galeazzi, A. Guzman, B. L. Bray, R. Greenhouse, L. J. Kurz, D.
A. Lustig, M. L. Maddox and J. M. Muchowski, Can. J. Chem., 1994, 72,
15; (e) C. T. Tim, K. Jones and J. Wilkinson, Tetrahedron Lett., 1995, 36,
6743; (f) S. Osaki, H. Mitoh and H. Ohmori, Chem. Pharm. Bull., 1996,
44, 2020; (g) P. A. Dobbs, K. Jones and K. T. Veal, Tetrahedron, 1997,
53, 8287; (h) F. Aldabbagh, W. R. Bowman and E. Mann, Tetrahedron
Lett., 1997, 38, 7937; (i) F. E. Ziegler and M. Belema, J. Org. Chem.,
1997, 62, 1083; (j) C. J. Moody and C. L. Norton, J. Chem. Soc., Perkin
Trans. 1, 1997, 2639; (k) D. Harrowen and M. I. T. Nunn, Tetrahedron
Lett., 1998, 39, 5875; (l) F. Aldabbagh, W. R. Bowman, E. Mann and A.
M. Z. Slawin, Tetrahedron, 1999, 55, 8111; (m) J. Marco-Contelles and
M. Rodríquez-Fernández, Tetrahedron Lett., 2000, 41, 381; (n) W. R.
Bowman and E. Mann, J. Chem. Soc., Perkin Trans. 1, 2000, 2991.
2 (a) F. Gagosz and S. Z. Zard, Org. Lett., 2002, 4, 4345; (b) T. Kaoudi, B.
Quiclet-Sire, S. Seguin and S. Z. Zard, Angew. Chem., Int. Ed., 2000, 39,
732; (c) J. Axon, L. Boiteau, J. Boivin, J. E. Forbes and S. Z. Zard,
Tetrahedron Lett., 1994, 35, 1719; (d) A. Liard, B. Quiclet-Sire, R. N.
Saicic and S. Z. Zard, Tetrahedron Lett., 1997, 38, 1759; (e) N. Cholleton
and S. Z. Zard, Tetrahedron Lett., 1998, 39, 7295; (f) T.-M. Ly, B.
Quiclet-Sire, B. Sortais and S. Z. Zard, Tetrahedron Lett., 1999, 40,
2533.
3 (a) E. Baciocchi, E. Muraglia and G. Sleiter, J. Org. Chem., 1992, 57,
6817; (b) E. Baciocchi and E. Muraglia, Tetrahedron Lett., 1993, 34,
3799; (c) I.-S. Cho and J. M. Muchowski, Synthesis, 1991, 567; (d) D. R.
Artis, I.-S. Cho and J. M. Muchowski, Can. J. Chem., 1992, 70, 1838; (e)
D. R. Artis, I.-S. Cho, S. Jaime-Figueroa and J. M. Muchowski, J. Org.
Chem., 1994, 59, 2456.
4 Radical alkylation of heteroaromatic compounds with organic peroxides:
(a) M. Yoshida, T. Yoshida, M. Kobayashi and N. Kamigata, J. Chem.
Soc., Perkin Trans. 1, 1989, 909; (b) M. Aiura and Y. Kanaska, Chem.
Pharm. Bull., 1975, 23, 2835; (c) R. Bonnet, P. Cornell and A. F.
McDonagh, J. Chem. Soc., Perkin Trans. 1, 1976, 794.
We thank DGAPA (205901) for generous financial support
and Dr. Joseph M. Muchowski for many friendly discussions.
Also we thank R. Patiño, J. Pérez, L. Velasco, H. Rios, N.
Zavala, E. Huerta and A. Peña for technical support.
Table 2 Synthesis of 2-heteroarylpropionic acid derivativesa
Entry
Substrate
Xanthate
Product
5 S. Z. Zard, in Radicals in Organic Synthesis, ed. P. Renaud and M. Sibi,
Wiley VCH, Weinhem, 2001, pp. 90–108; S. Z. Zard, Angew. Chem., Int.
Ed. Engl., 1997, 36, 672.
6 (a) T. Y. Shen, Angew. Chem., Int. Ed. Engl., 1972, 6, 460; (b) D.
Lednicer and L. A. Metscher, The Organic Chemistry of Drug Synthesis,
Wiley, New York, 1977, vol. 1, pp. 85–92, 267–277; D. Lednicer and L.
A. Metscher, The Organic Chemistry of Drug Synthesis, Wiley, New
York, 1980, vol. 2, pp. 63–83; (c) K. Hino, H. Nakamura, Y. Nagai, H.
Uno and H. Nishimura, J. Med. Chem., 1983, 26, 222; (d) C. Giordano,
G. Castaldi and F. Uggeri, Angew. Chem., Int. Ed. Engl., 1984, 23, 413;
(e) J. P. Rieu, A. Boucherle, H. Course and G. Mounzin, Tetrahedron,
1986, 42, 4095; (f) The Merck Index, 11th edn., Merck, Rahway, NJ,
1989.
1
75%
2
81% (90%)
7 J. F. P. Andrews, M. P. Jackson and C. J. Moody, Tetrahedron., 1993, 49,
7353.
8 J. Gudjons, R. Oehl and P. Rosenmund, Chem. Ber., 1976, 109, 3282.
a Yields in parentheses are based on recovered starting material.
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