Solvent free oxidative radical substitution process. Synthesis of pyrrole fused systems

Article abstract of DOI:10.1016/j.tetlet.2010.09.025

A xanthate-based, solvent free, homolytic substitution on selected substituted pyrrole systems is described. Additionally, a practical entry for the rapid construction of pyrrole fused systems using this solventless radical addition followed by a double nucleophilic alkylation sequence, is also reported.

Full text of DOI:10.1016/j.tetlet.2010.09.025

Tetrahedron Letters 51 (2010) 6000–6002
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent free oxidative radical substitution process. Synthesis of pyrrole
fused systems
⇑
Edwin Flórez-López, Liliana B. Gomez-Pérez, Luis D. Miranda
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacan, México D.F. 04510, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A xanthate-based, solvent free, homolytic substitution on selected substituted pyrrole systems is
described. Additionally, a practical entry for the rapid construction of pyrrole fused systems using this
solventless radical addition followed by a double nucleophilic alkylation sequence, is also reported.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 13 August 2010
Revised 7 September 2010
Accepted 8 September 2010
Available online 21 September 2010
Pyrrole fused cyclic systems are broadly distributed in nature.1
These motifs are part of the framework of a number of natural and
synthetic molecules, some of which display antitumor and
anti-HIV activity, as well as antibacterial, analgesic, and antiin-
flammatory properties.2 Ketorolac, 1 a five-membered pyrrole
fused system for example, is a prescription synthetic medicine
approved for the short-term treatment of moderate to severe pain
(Fig. 1).3 Poligotin B (2) and pilogotin A (3) are examples of a six-
membered pyrrole fused systems which were isolated from the
extracts of Poliganotum sibircum.4 A seven-membered pyrrole fused
systems is found in the natural product dehydrotuberoestemonine
4 that was isolated from Esteromona tuberose.5 Thus, the develop-
ment of practical protocols that provide rapid access to pyrrole
fused systems is of great synthetic significance.
organic synthesis is less known.10 Indeed, the concept of solvent
free radical reactions3 might appear to be counterintuitive since
a high radical concentration could well favor undesired fast radical
dimerization and/or combination reactions. Nevertheless, given
the mechanism of xanthate-based radical reactions, (Scheme 1),
O
Me
OR
H
O
O
Me
O
CO2H
H
N
H
H
N
N
O
Et
O
H
2
3
, R = Et, Poligotin B
1
4
, R = H, Poligotin A
Intermolecular oxidative homolytic substitution of aromatic
heterocyclic systems is a synthetically important C–C bond forma-
tion process, which often gives access to molecular scaffolds which
can be difficult to construct by other methods.6
Figure 1.
EWG-H2C
S
We have previously shown that certain substituted pyrrole
derivatives could be alkylated in synthetically useful yields via a
xanthate-based homolytic oxidative substitution process.7 Condi-
tions typical of this process involve the slow addition of dilauroyl
peroxide (used as both the initiator and oxidant) to a boiling,
1,2-dichloroethane solution of the xanthate and the substituted
pyrrole derivatives.6a We wondered if the product yields in these
oxidative radical substitution processes could be improved by con-
ducting the reactions under solvent free conditions. In the mecha-
nism of xanthate-based radical chemistry depicted in Scheme 1,
the radical 6 derived from the thermal fragmentation of a suitable
initiator reacts with the thiocarbonyl group to afford the key inter-
mediate radical 7a that evolves to the desired radical 8 by a revers-
ible b-fragmentation.8 Solvent free radical polymerization
reactions are now well documented,9 but except for some scat-
tered examples, the use of such methodology in free radical based
Initiator
S
R1
EWG-H2C
S
O
6
S
Et
7b
EWG-H2C
Et
S
O
5
R1
Et
5
5
S
O
5'
R1
S
S
EWG-CH2
EWG-H2C
8
O
7a
Et
R
N
H
O
10a-c
DLP
R
EWG
R
O
EWG
N
H
N
H
O
9
15a-c
EWG = Electronwithdrawing group
⇑
Corresponding author. Tel.: +52 55 56 22 44 40; fax: +52 55 56 16 22 17.
E-mail address: lmiranda@unam.mx (L.D. Miranda).
Scheme 1. Mechanism for the xanthate-based radical chemistry.8
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.025

E. Flórez-López et al. / Tetrahedron Letters 51 (2010) 6000–6002
6001
Table 1
an excess of the xanthate radical precursor 5 should favor the
Annulation process of adducts 15a–c
reversible degenerate formation of the stabilized radical species
7b.8 This addition/elimination process between the species 8 and
7a could well serve as a relatively long lived reservoir of the radical
8, until the latter has encountered a suitable radical trap, for exam-
ple, a substituted pyrrole such as 10a–c (Scheme 1).8 Indeed, Zard
and co-workers have reported that high substrate concentrations
(ca. 0.25 mol) are associated with improved product yields in xan-
thate-based radical reactions.8 Building up on this effect we
hypothesized that the xanthate-based technology might be used
in oxidative homolytic substitutions under solvent free conditions
for selected substrates, specifically if an excess of a liquid starting
xanthate is used (Scheme 1).
Entry
1
Reagent
Product
Yield (%)
COOEt
COOEt
16a R = p-tol (85)
16b R = H (78)
16c R = Ph (77)
Br
Br
R
O
N
N
19a
2
COOEt
COOEt
17a R = p-tol (81)
17b R = H (78)
17c R = Ph (85)
R
O
Br
Br
2
3
19b
19c
3
COOEt
COOEt
18a R = p-tol (75)
18b R = H (77)
18c R = Ph (70)
R
O
Br
Br
N
To test our hypothesis we chose the reaction between the 2-p-
toluoylpyrrole derivative 10 and the liquid xanthate 11 to afford
the ethyl ester of the non-steroidal antiinflammatory agent tol-
metin (12, Scheme 2). After considerable experimentation, it was
found that the optimal conditions involved the use of 2.0 equiv
of the xanthate and 2.0 equiv of DLP. Interestingly the excess of
the liquid xanthate served as the solvent for the solid pyrrole sub-
strate resulting in the formation of a homogeneous medium. Thus,
the solid DLP (mp 55 °C) was added portionwise at the end of each
minute, during a 10-min period, to the reaction mixture that was
maintained at 100 °C (CAUTION if the DLP is added in one portion
a violent reaction is observed). After each addition of DLP, gas evo-
lution (CO2), accompanied by a slight rise in the temperature, was
observed. Indeed, in some cases, if the size and timing of the DLP
additions were carefully adjusted, the reaction temperature
(100 °C) could be maintained without external heating. Under
the optimized conditions the expected product 12 was obtained
in a yield similar to that observed under typical solution conditions
(65% in refluxing dichloroethane, addition of DLP for 8 h). Hydroly-
sis of 12 under standard conditions afforded the non-steroidal anti-
inflammatory agent tolmetin11 13 in quantitative yield (65%
overall yield from 10).
1. 20%NaOH(aq),
ether, reflux.
COOH
16c
N
2. HCl, AcOEt,
reflux.
O
1
Scheme 4. Synthesis of ketorolac (1).
16–18 were then efficiently constructed when adducts of the free
radical process 15a–c simply were submitted to a double alkyl-
ation process with a suitable
a,x-dibromoalkyl compound 19a–c
under basic phase-transfer conditions (Table 1).12 It is noteworthy
that all of these strategically substituted pyrrole fused systems
represent valuable synthetic intermediates in the construction of
pharmacologically important natural or synthetic targets. Along
this line, the potent analgesic ketorolac 1 was obtained by the
hydrolysis/decarboxylation process of 16c in good yields as de-
scribed previously (Scheme 4).12a Thus the synthesis of this latter
product was accomplished in three steps from readily available
2-benzoylpyrrole in 44% overall yield.
We then turned our attention to the use of this process to con-
struct pyrrole fused systems using the disubstituted pyrrole deriv-
atives obtained from the solvent free direct alkylation of selected
substituted pyrroles with malonyl xanthate derivative 14. Thus
the solvent free radical alkylation reactions proceeded in generally
good yields when 2-p-toluoyl, 2-formyl, and 2-benzoyl pyrroles
were used as the radical acceptor (15a–c Scheme 3). Then, the cor-
responding five-, six-, and seven-membered pyrrole fused systems
The unprecedented xanthate-based homolytic solvent free sub-
stitution of selected pyrrole derivatives described in the present
Letter, demonstrates that the high selectivity of a free radical pro-
cess even under putatively high radical concentration conditions.
Additionally, the radical addition/double alkylation sequence fea-
tured in this Letter represents a practical entry for the rapid con-
struction of pyrrole fused systems.
Acknowledgments
O
Financial support from the DGAPA, UNAM (project PAPIIT-
IN213407) is gratefully acknowledged. We also thank R. Patiño,
A. Peña, E. Huerta and E. García-Rios, L. Velasco, and J. Pérez for
technical support. EFL is a CONACyT graduate scholarship holder.
Solvent-free
O
DLP, 10 min
EtO
+
OR
N
N
EtO
S
65%
O
CH3
O
CH3
S
10
11
12
R = OEt
NaOH,
MeOH, 24h.
100%
Supplementary data
13 R = H, Tolmetin
Supplementary data (experimental procedures and 1H and 13C
NMR spectra for all new compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2010.09.025.
Scheme 2. Synthesis of tolmetin (13).
COOEt
COOEt
Xth
COOEt
COOEt
R
COOEt
COOEt
References and notes
14
R
N
H
+
N
i
O
ii
O
1. (a)For reviews on pyrrole, see: Comprehensive Heterocyclic Chemistry; Sundberg,
R. J., Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996;
Vol. 2, pp 119–206; (b) Sobenina, L. N.; Demenev, A. P.; Mikhaleva, A. L. Chem.
Rev. 2004, 104, 2481.
2. d’Ischia, M.; Napolitano, A.; Pezzella, A.. In Comprehensive Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J.,
Eds.; Elsevier, 2008; Vol. 3, pp 353–588.
R
n
N
H
15a R=p-Tol (66%)
15b R = H (65%)
15c R = Ph (72%)
16a-c n = 1
17a-c
O
n = 2
18a-c n = 3
10a R=p-Tol
10b R = H
1oc R = Ph
Scheme 3. Reagents and conditions: (i) DLP, solvent free conditions, 10 min; (ii)
K2CO3, NBu4Br, 2 h, 19a–c, see Table 1.
3. Muchowski, J. M.. In Advances in Medicinal Chemistry; Jai Press Inc., 1992; Vol. 1.
p 109.

6002
E. Flórez-López et al. / Tetrahedron Letters 51 (2010) 6000–6002
4. (a) Sun, L.-R.; Wang, S.-X.; Li, X. J. Asian Nat. Prod. Res. 2005, 7, 127; (b)
Dinsmore, A.; Mandy, K.; Michael, J. P. Org. Biomol. Chem. 2006, 4, 1032.
5. (a) Tanis, S. P.; Raggonlb, J. W. J. Org. Chem. 1987, 52, 819; (b) Jiang, R. W.; Hon,
P. M.; Zhou, Y.; Chan, Y. M.; Xu, Y. T.; Xu, H. X.; Greger, H.; Shaw, P. C.; But, P. H.
J. Nat. Prod. 2006, 69, 749; (c) Frankowski, K. J.; Golden, J. E.; Zeng, Y.; Lei, Y.;
Aubé, J. J. Am. Chem. Soc. 2008, 130, 6018; (d) Zhou, X.; Leung, P. H. H.; Li, N.; Ye,
Y.; Zhang, L.; Zuo, Z.; Lin, G. Planta Med. 2009, 75, 575; (e) Lin, W.-H.; Ye, Y.; Xu,
R.-S. J. Nat. Prod. 1992, 55, 571.
6. For a review see: (a) Bowman, W. R.; Storey, J. M. D. Chem. Soc. Rev. 2007, 1803;
(b) Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S. J. Chem. Soc., Perkin Trans. 1
2002, 2747. and references therein.
7. (a) Osornio, Y. M.; Cruz-Almanza, R.; Jiménez-Montaño, V.; Miranda, L. D. Chem.
Commun. 2003, 2316; (b) Guerrero, M. A.; Miranda, L. D. Tetrahedron Lett. 2006,
47, 2517; (c) Guadarrama-Morales, O.; Méndez, F.; Miranda, L. D. Tetrahedron
Lett. 2007, 48, 4515; (d) Reyes-Gutiérrez, P. E.; Torres-Ochoa, R. O.; Martínez,
R.; Miranda, L. D. Org. Biomol. Chem. 2009, 7, 1388; See also: (e) Furst, L.;
Matsuura, B. S.; Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. Org. Lett.
2010, 12, 3104.
8. (a) Quiclet-Sire, B.; Zard, S. Z. Chem. Eur. J. 2006, 12, 6002; (b) Quiclet-Sire, B.;
Zard, S. Z. Top. Curr. Chem. 2006, 264, 201; (c) Zard, S. Z. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M., Eds.; Wiley VCH: Weinhem, 2001; p 90; (d) Zard,
S. Z. Angew. Chem., Int. Ed. 1997, 36, 672; (e) Quiclet-Sire, B.; Zard, S. Z. Pure
Appl. Chem. 1997, 69, 645; (f) Zard, S. Z. Actual. Chim. 1993, 10.
9. Odell, P. G.; Listigovers, N. A.; Quinlan, M. H.; Georges, M. K. ACS Symp. Ser.
1998, 713, 80.
10. (a) Jereb, M.; Zupan, M.; Stavber, S. Helv. Chim. Acta 2009, 92, 555; (b) Metzger,
J. O.; Mahler, R.; Francke, G. Liebigs Ann. Recl. 1997, 11, 2303; (c) Metzger, J. O.;
Mahler, R. Angew. Chem., Int. Ed. Engl. 1995, 34, 902–904.
11. Carson, J. R.; McKinstry, D. N.; Wong, S. J. Med. Chem. 1971, 14, 646.
12. (a) Artis, D. R.; Cho, I.-S.; Muchowski, J. M. Can. J. Chem. 1992, 70, 1838;
(b) Schloemer, G. C.; Greenhouse, R.; Muchowski, J. M. J. Org. Chem. 1994, 59,
5230.