Magnesiation Employing Grignard Reagents and Catalytic Amine. Application to the Functionalization of N-Phenylsulfonylpyrrole

Article abstract of DOI:10.1021/ol036288p

(Matrix presented) N-Phenylsulfonylpyrrole 1 is magnesiated by treatment with isopropylmagnesium chloride and catalytic diisopropylamine. Reaction with various electrophiles, including palladium-catalyzed aryl- and heteroaryl cross-coupling, provides 2-su

Full text of DOI:10.1021/ol036288p

ORGANIC
LETTERS
2004
Vol. 6, No. 2
293-296
Magnesiation Employing Grignard
Reagents and Catalytic Amine.
Application to the Functionalization of
N-Phenylsulfonylpyrrole
Andrew Dinsmore,* David G. Billing, Karen Mandy, Joseph P. Michael,
Daniel Mogano, and Shivaputra Patil
Molecular Sciences Institute, School of Chemistry, UniVersity of the Witwatersrand,
PO Wits, 2050, South Africa
andy@aurum.wits.ac.za
Received November 24, 2003
ABSTRACT
N-Phenylsulfonylpyrrole 1 is magnesiated by treatment with isopropylmagnesium chloride and catalytic diisopropylamine. Reaction with various
electrophiles, including palladium-catalyzed aryl- and heteroaryl cross-coupling, provides 2-substituted phenylsulfonylpyrroles in moderate to
good yields.
N-Sulfonylpyrroles are more crystalline, less electron-rich,
and hence easier to handle than the parent unprotected
pyrroles. During an investigation of their application in
natural product synthesis, we became interested in extending
the magnesiation protocol of Kondo et al.1 to N-phenylsul-
fonylpyrrole 1. The original ortho magnesiation methodology
had made use of Hauser or magnesium bis-amide bases and
had been applied to N-phenylsulfonylindoles and thiophenes.
Here we report the results of this study and show that the
original methodology can be made catalytic with respect to
the amine employed.
Lithiation of pyrrole 1 followed by reaction with various
electrophiles has been reported to give 2-functionalized
pyrroles in variable yields.4,5 Efficient lithiations of N-
vinylpyrrole6 and N-BOC pyrrole7 have also been reported.
The magnesium amide bases (Hauser bases and bis-diamide-
Mg species) offer a practical and economically attractive
alternative to lithium bases, and various applications have
been recently reviewed.8
We began our investigation by trying to extend the work
of Kondo to N-phenylsulfonylpyrrole 1, which was readily
made by reacting pyrrole and phenylsulfonyl chloride in
dichloromethane employing sodium hydroxide as a base, as
described by Shastri.9 A number of attempts to repeat the
method of Ottoni10 yielded no detectable sulfonylpyrrole 1.
Previous studies have demonstrated that the reaction of
N-phenylsulfonylpyrrole 1 with electrophiles requires Lewis
acid activation. Under these conditions and in contrast to
more bulky N-protecting groups, the sulfonyl-protected
pyrroles generally give mixtures of 2- and 3-substituted
products,2 though selectivity for the 2- or 3-position can be
achieved by careful selection of electrophile and Lewis acid.3
(3) Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J. J. Org. Chem.
1983, 48, 3214-3219.
(4) Grieb, J. G.; Ketcha, D. M. Synth. Commun. 1995, 25, 2145-2154.
(5) Shiao, M.-J.; Shih, L.-H.; Chia, W.-L.; Chau, T.-Y. Heterocycles
1991, 32, 2111-2118.
(6) Malkina, A. G.; Tarasova, O. A.; Verkruijsse, H. D.; van der Kerk,
A. C. H. T. M.; Brandsma, L.; Trofimov, B. A. Recl. TraV. Chim. Pays-
Bas 1995, 114, 18-21.
(1) Kondo, Y.; Yoshida A.; Sakamoto T. J. Chem. Soc., Perkin Trans.
1 1996, 2331-2332.
(2) Cadamuro, S.; Degani, I.; Dughera, S.; Fochi, R.; Gatti, A.; Piscopo,
L. J. Chem. Soc., Perkin Trans. 1 1993, 273-284.
(7) Hasan, I.; Marinelli, E. R.; Li-Chang Chang Lin, Fowler, F. W.; Levy,
A. B. J. Org. Chem. 1981, 46, 157-164.
(8) Henderson, K. W.; Kerr W. J. Chem. Eur. J. 2001, 7, 3430-3437.
10.1021/ol036288p CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/30/2003

Our initial investigations employed an approximately 1 M
solution of PrMgBr, prepared in THF and subsequently
stirred with (iPr)2NH. Following exposure of pyrrole 1 to a
2-fold excess of this reagent and subsequent quenching with
iodine, we isolated the desired 2-iodinated pyrrole 2 in 54%
yield (Scheme 1).11
represented in Scheme 2.13 The approach described here
represents a new and atom-economical methodology.
We found that the PrMgBr, when prepared as a 1 M
i
i
solution in THF, was only partially soluble at room tem-
perature. The magnesiations described above had to be
conducted at a minimum temperature of 45 °C to allow all
the reactants to remain in solution, without which a good
conversion does not occur. An improvement came with
i
Scheme 1. Iodination of N-Phenylsulfonylpyrrolea
application of PrMgCl. This Grignard reagent, when pre-
pared as a 1 M solution in THF, is completely soluble at
room temperature, allowing the subsequent metalation to be
conducted at room temperature and giving an increase in
the isolated yield of iodopyrrole 2 to 75%. Wondering if a
potentially non-redox-active Grignard reagent would further
improve the yields, we repeated the magnesiation employing
an approximately 1 M solution of PhMgCl, but yields were
reduced.
a Conditions are described in the text.
Though this represented a promising result, we found that
stock solutions of the putative (iPr)2NMgBr were significantly
unstable at room temperature, turning dark brown and
depositing a solid over the course of a few days. Given that
during the magnesiation the amine is presumably regenerated,
we wondered if the reaction could be made catalytic with
respect to the amine. This proved to be the case; a 2.5-fold
excess of iPrMgBr stirred with pyrrole 1 and to which 5 mol
% (with respect to the pyrrole) of (iPr)2NH was added yielded
the iodosulfonylpyrrole 2 in a 65% isolated yield following
an iodine quench. The 2-iodopyrrole 2 could be conveniently
isolated and purified by recrystallization. Without any added
(iPr)2NH, no iodopyrrole was detected (although it has been
We examined the reaction of the magnesiopyrrole with a
number of different electrophiles as shown in Table 1. With
Table 1. Results of Addition of Magnesio-pyrrole to Different
Electrophiles
electrophile
TMS-OTfc
R
product
yieldb(%)
-TMS
3
4
5
6
7
8
9
10
11
12
57
γ-butyrolactoned
allyl bromidee
DMFf
-CO(CH2)3OH
-CH2CHdCH2
-CHO
-C(CH3)2OH
-CHOHPh
52 (78)
52 (78)
48 (73)
45 (97)
57 (75)
5
73
24 (53)
32 (44)
i
previously been shown that PrMgCl can deprotonate sub-
stituted pyridines at reflux in THF12). That the Mg-amide is
the catalytically active species was supported by the replace-
ment of (iPr)2NH with triethylamine in the above procedure.
No iodopyrrole was detected following workup, suggesting
that the amine does not simply exert a deaggregation effect.
Significantly, we found that catalytic diethylamine was also
ineffective but can offer no explanation.
acetoneg
benzaldehydeh
trimethyl boratei
iodobenzenek
2-chloropyridinel
2-chloroquinoline
j
-B(OH)2
-C6H5
-pyrid-2-yl
-quinolin-2-ylm
a Magnesiation protocol: either A (2.5 equiv of iPrMgBr (1 M in THF)/5
This approach would appear to be an obvious solution to
the problem of equilibration of metal amide-carbon acid
and metal carbanion-amine combinations, represented in
Scheme 2, though we can find no description of such a
i
i
mol % Pr2NH/16 h/50 °C) or B (2.5 equiv of PrMgCl (1 M in THF)/5
i
mol % Pr2NH/16 h/rt). b Isolated yield. Yield based on recovered starting
material shown in brackets. c A, then 1.2 equiv of TMSOTf, 0 °C, 20 min.
d A, then 1.5 equiv of γ-butyrolactone/1 h/50 °C. e A, then allyl bromide/1
h/50 °C. f A, then DMF/1 h/50 °C. g A, then acetone/0.5 h/50 °C. h A, then
PhCHO/0.5 h/50 °C. i A, then B(OMe)3/1 h/50 °C. j N-Desulfonylated
boronic acid isolated. k B, then 2 equiv of iodobenzene/5 mol % Pd(Ph3P)4/
45 h/rt. l B, then 0.5 equiv of ZnCl2/2 equiv of 2-chloropyridine/2 mol %
PdCl2dppf/48 h/rt. m B, as in footnote l, but employing 2-chloroquinoline.
Scheme 2. Equilibration of Metal Amides/Carbon Acids
TMS-Cl, no reaction was detected, but with the more
reactive TMS-OTf, a 57% isolated yield of the TMS
substituted pyrrole 3 was obtained. Allylation, ring opening
of γ-butyrolactone, formylation,14 and addition to carbonyl
groups all proceeded to give the expected products 4-8 in
moderate isolated yields. Addition of trimethyl or triisopropyl
borate to the magnesiopyrrole gave an immediate exothermic
previous approach. The closest is perhaps the recent results
from the group of Eaton, wherein an effective excess of
“butyl-magnesium” is employed to force the equilibrium
(9) Zelekin, A.; Shastri, V. R.; Langer, R. J. Org. Chem. 1999, 64, 3379-
3380.
(10) Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915-13928.
(11) This compound is described in the literature, though no characteriza-
tion is given. See: Sakamoto, T.; Ohsawa, K. J. Chem. Soc., Perkin Trans.
1 1999, 2323-2326.
(12) Bonet, V.; Mongin, F.; Tre´court, F.; Que´guiner, G. J. Chem. Soc.,
Perkin Trans. 1 2000, 4245-4249.
(13) Zhang, M.-X.; Eaton P. E. Angew. Chem., Int. Ed. 2002, 41, 2169-
2171.
(14) Characterization data for product 6 were identical to those published;
see: Muratake, H., Natsume, M. Heterocycles 1990, 31, 683-690.
294
Org. Lett., Vol. 6, No. 2, 2004

reaction. Following hydrolysis and workup, however, we
isolated principally the parent unsubstituted pyrrole 1. Small
amounts of what appeared to be the desulfonylated pyrrole-
2-boronic acid 9 were isolated, but we have not been able
to improve the yield of this product above ca. 5%.
We investigated extension of the methodology to provide
aryl- and heteroaryl-substituted pyrroles. The magnesio-
i
pyrrole prepared from pyrrole 1 and either PrMgCl or
iPrMgBr was found to undergo a Kumada-type coupling with
iodobenzene in the presence of catalytic Pd(Ph3P)4 to give
the 2-phenylsulfonylpyrrole 10.15
Heteroaryl-substituted pyrroles offer attractive targets, as
they can provide novel physical properties, particularly when
they have the potential for metal complexation.16 Attempts
to cross-couple 2-chloropyridine with the magnesiopyrrole,
prepared as described above, failed using either Pd(Ph3P)4
or NiCl2dppe catalysis. 2-Bromopyridine and even 2-iodo-
pyridine17 failed to give any detectable cross-coupling
product with the magnesiopyrrole employing palladium
catalysis.
Figure 1. PLUTO diagram for 12. For clarity, the perchlorate anion
and H-bonded EtOH have been omitted.
workup, only trace quantities of the desired pyrid-3-yl
coupled product as judged by GCMS analysis.
A solution to this impasse was found by employing a
variation on conditions recently described18 to allow the
heteroaryl-coupling of furyllithium species. Thus, pretreat-
ment of the magnesiopyrrole with a submolar equivalent of
zinc chloride followed by 2-chloropyridine and finally
catalytic PdCl2dppf gave an immediate exothermic reaction.
Following workup, the desired 2-(pyrid-2-yl)pyrrole 11 was
isolated in 24% yield (54% on the basis of recovered starting
material) and proved to have identical properties to those
described in the literature.19
This methodology was extended to provide the novel
2-quinolyl-substituted phenylsulfonylpyrrole 12, the structure
of which was confirmed by single-crystal X-ray analysis
carried out on the perchlorate salt (Figure 1). The structure
shows a pyramidal arrangement of substituents around the
nitrogen, consistent with previous crystal structures describ-
ing compounds containing the N-phenylsulfonyl substruc-
ture.20
Since we were able to readily prepare gram quantities of
2-iodopyrrole 2 without any chromatography using our
methodology, we investigated application of this compound
in coupling reactions. Attempted Stille-type coupling with
tributylstannylbenzene gave no detectable product. Applica-
tion of stoichiometric copper(I) thiophenecarboxylate21 (CuTC)
(which we have previously found useful for accomplishing
otherwise refractory heteroaryl Stille-type couplings22) to a
mixture of iodopyrrole 2 and tributylstannylbenzene in
N-methylpyrrolidine gave no detectable reaction. In addition,
attempts to achieve the low-temperature homocoupling of
the 2-iodopyrrole 2 using the general method of Liebeskind23
also failed, the only isolated product being the deiodinated
pyrrole 1. Suzuki-type coupling of the iodopyrrole with
phenylboronic acid was found to be successful, yielding the
2-phenylpyrrole 10, identical to that prepared from the
Kumada reaction described above, in a yield of 33% (Scheme
3).
Attempts to undertake a palladium-catalyzed Kumada-type
coupling between the magnesiopyrrole and 3-bromopyridine
failed to give any detectable cross coupling. Even addition
of a submolar equivalent of zinc chloride prior to addition
of the 3-bromopyridine and PdCl2dppf gave, following
Scheme 3. Suzuki Coupling of 2-Iodopyrrole
(15) This compound is described in ref 4, though the spectroscopic details
differ from those of the compound we have isolated.
(16) See for example: Wu, F.; Chamchoumis, C. M.; Thummel, R. P.
Inorg. Chem. 2000, 39, 584-590.
(17) We found that this was best prepared from 2-bromopyridine by the
exchange method of Que´guiner (Tre´court, F.; Breton, G.; Bonnet, V.;
Mongin, F.; Marsais, F.; Que´guiner, G. Tetrahedron 2000, 56, 1349-1360)
In conclusion, a novel and highly atom-efficient protocol
for the functionalization of N-sulfonylpyrrole has been
developed by utilizing a Grignard reagent as a thermody-
namic base and catalytic amine to function as the kinetically
i
using PrMgCl and subsequent quenching with iodine. Intriguingly, the
i
apparently equivalent PrMgBr gave no insertion of magnesium and only
bromopyridine was isolated.
(18) Gauthier, D. R., Jr.; Szumigala, R. H., Jr.; Dormer, P. G.; Armstrong,
J. D., III; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 3, 375-378.
(19) This compound was previously made by a copper-mediated addition
of the lithio-pyrrole derived from 1 to an acyl-pyridinium species followed
by oxidation, as described in ref 5.
(21) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-
2749.
(20) The geometry of a number of structures containing N-phenylsulfonyl-
pyrrole and -indole components has been reviewed (Beddoes, R. L.; Dalton,
L.; Joule, J. A.; Mills, S. O.; Street, J. D.; Watt, C. I. F. J. Chem. Soc.,
Perkin Trans. 2 1986, 787-797).
(22) Dinsmore, A.; Garner, C. D.; Joule, J. A. Tetrahedron 1998, 54,
3291-3302.
(23) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62,
2312-2313.
Org. Lett., Vol. 6, No. 2, 2004
295

competent mediator. This combination has been applied to
provide various 2-substituted phenylsulfonylpyrroles. Aryl
and heteroaryl couplings of the putative intermediate mag-
nesiopyrrole are possible, though conditions to achieve this
need to be carefully selected to have any success.
2053652. Financial support from the University of the
Witwatersrand is also gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, product characterization, and a CIF file containing
details of the XRD characterization of compound 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This material is based on work
supported by the National Research Foundation under Grant
OL036288P
296
Org. Lett., Vol. 6, No. 2, 2004