Directed lithiation of N -benzenesulfonyl-3-bromopyrrole. Electrophile-controlled regioselective functionalization via dynamic equilibrium between C-2 and C-5 lithio species

Article abstract of DOI:10.1021/ol100810c

(Figure presented) Directed lithiation of N-benzenesulfonyl-3-bromopyrrole (1) with LDA in THF at -78 °C generated C-2 lithio species 3 selectively. Reactions of 3 with reactive electrophiles produced the corresponding 2-functionalized pyrroles 4. On the

Full text of DOI:10.1021/ol100810c

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2734-2737
Directed Lithiation of
N-Benzenesulfonyl-3-bromopyrrole.
Electrophile-Controlled Regioselective
Functionalization via Dynamic
Equilibrium between C-2 and C-5 Lithio
Species
Tsutomu Fukuda,† Takeshi Ohta,† Ei-ichi Sudo,† and Masatomo Iwao*,‡
Graduate School of Science and Technology, and Department of Applied
Chemistry, Faculty of Engineering, Nagasaki UniVersity, 1-14 Bunkyo-machi,
Nagasaki 852-8521, Japan
iwao@nagasaki-u.ac.jp
Received April 13, 2010
ABSTRACT
Directed lithiation of N-benzenesulfonyl-3-bromopyrrole (1) with LDA in THF at -78 °C generated C-2 lithio species 3 selectively. Reactions
of 3 with reactive electrophiles produced the corresponding 2-functionalized pyrroles 4. On the other hand, quenching with less reactive
electrophiles generated the corresponding 5-substituted pyrroles 5. The latter unusual functionalization at C-5 could be rationalized by dynamic
equilibrium between C-2 and C-5 lithio species.
Directed lithiation1 of N-protected pyrroles followed by
reaction with electrophiles has been employed as a reliable
way to produce 2-substituted pyrroles. Although a number
of N-protecting groups have been developed as the directing
groups to facilitate R-lithiation of the pyrrole ring,2 C-2
versus C-5 regioselectivity in the lithiation of 3-substituted
pyrroles has been modestly investigated. In 1985, Iwao and
Kuraishi reported for the first time that N,N-diethyl-1-
† Graduate School of Science and Technology.
(2) (a) Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.; Levy,
A. B. J. Org. Chem. 1981, 46, 157–164 (DG ) Boc and SO2Ph). (b)
Martinez, G. R.; Grieco, P. A.; Srinivasan, C. V. J. Org. Chem. 1981, 46,
3760–3761 (DG ) NMe2). (c) Edwards, M. P.; Ley, S. V.; Lister, S. G.;
Palmer, B. D. J. Chem. Soc., Chem. Commun. 1983, 630–633 (DG ) SEM).
(d) Muchowski, J. M.; Solas, D. R. J. Org. Chem. 1984, 49, 203–205 (DG
) SEM). (e) Katritzky, A. R.; Akutagawa, K. Org. Prep. Proc. Int. 1988,
20, 585–590 (DG ) CO2Li). (f) Gharpure, M.; Stoller, A.; Bellamy, F.;
Firnau, G.; Snieckus, V. Synthesis 1991, 1079–1082 (DG ) CONLit-Bu).
(g) Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem.
2000, 65, 3587–3595 (DG ) SO2NMe2).
‡ Department of Applied Chemistry, Faculty of Engineering.
(1) For reviews, see: (a) Snieckus, V. Chem. ReV. 1990, 90, 879–933.
(b) Rewcastle, G. W.; Katritzky, A. R. AdV. Heterocycl. Chem. 1993, 56,
155–302. (c) Gray, M.; Tinkl, M.; Snieckus, V. ComprehensiVe Organo-
metallic Chemistry II; McKillop, A., Ed.; Pergamon: Oxford, 1995; Vol.
11, Chapter 1. (d) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552–560. (e) Clayden, J.
Organolithiums: SelectiVity for Synthesis; Pergamon: Oxford, 2002. (f)
Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int.
Ed. 2004, 43, 2206–2225.
10.1021/ol100810c  2010 American Chemical Society
Published on Web 05/20/2010

methylpyrrole-3-carboxamide could be lithiated at C-2 with
sec-BuLi-TMEDA.3 On the other hand, Meijer and co-
workers demonstrated that the lithiation of N-Boc-3-hexyl-
pyrrole proceeded at C-5 selectively on treatment with
lithium 2,2,6,6-tetramethylpiperidide (LTMP).4 Demont and
co-workers indicated that the regioselectivity of the lithiation
of 3-benzenesulfonylpyrroles depended on the nature of the
base (LTMP, n- or sec-BuLi) and the N-protecting group
(Boc, SO2Ph, SEM).5 Robertson et al. showed that 3-chloro-
N-(p-toluenesulfonyl)pyrrole was lithiated at C-2 with n-
BuLi.6 Recently, we have reported that N-benzenesulfonyl-
3-bromopyrrole (1) could also be lithiated at C-2 with lithium
diisopropylamide (LDA), and this key reaction has been
employed in the synthesis of rationally designed analogues
of the antitumor marine alkaloid lamellarin D.7 In this letter,
we describe detailed investigations on the directed lithiation
of 1.
preferential deuteration at C-5 rather than C-2 (entry 3). More
bulky LTMP might deprotonate at the less congested C-5
preferentially. Lithium isopropylcyclohexylamide (LICA)
displayed a selectivity similar to that of LDA (entry 4).
Lithium hexamethyldisilazide (LHMDS) was totally inef-
fective for the lithiation of 1 apparently due to its lower
basicity9 (entry 5). Utilization of diethyl ether or toluene
instead of THF increased C-5 selectivity (entries 6-9). These
results might be accounted for by higher aggregation of the
amide bases in the less polar solvents.10 The bulky aggregates
might deprotonate at the less congested C-5 preferentially.
Although deuterium incorporation was quite modest,11 selec-
tive C-5 lithiation was achieved using LTMP as a base in
toluene (entry 9). Unfortunately, however, use of more base
(2.4 equiv) or a longer reaction time (12 h) resulted in the
loss of high C-5 selectivity (entries 10 and 11). Further
attempts to effect selective C-5 lithiation were not performed
because we discovered a practical Br-Li exchange route to
generate the C-5 lithio species (vide infra).
First, we investigated regioselectivity via deuteration
experiments (Table 1). Treatment of 1 with 1.2 equiv of LDA
Having established the conditions for efficient and selective
C-2 lithiation, we next examined the functionalization of the
lithiated 1. Thus, 1 was treated with 1.2 equiv of LDA in
THF at -78 °C for 1 h, and the resulting C-2 lithio species
3 was reacted with 1.8 equiv of an appropriate electrophile
under the conditions A (-78 °C, 1 h) or B (-78 °C, 1 h
f 0 °C, 3 h). After the usual workup, products were
isolated by column chromatography. As shown in Table
2, in the reactions with methyl chloroformate, chlorotri-
methylsilane, diphenyl disulfide, 1,2-dibromo-1,1,2,2-
tetrafluoroethane, iodine, p-methoxybenzaldehyde, and
tert-butyl isocyanate, the corresponding 2-functionalized
pyrroles 4a-g were obtained exclusively in excellent
yields (entries 1-8). In the reactions with p-methoxy-
benzoyl chloride, however, the unexpected 5-acylated
Table 1. Survey of Reaction Conditions for Regioselective
Lithiation of 1
deuterium incorporationc
2 yield C-2 C-5 total
ratio
(C-2:C-5)
entry
base
LDA
LDA
LTMP
LICA
solvent
(%)b
(%) (%)
(%)
1
THF
THF
THF
THF
91
92
95
95
94
97
99
96
98
98
94
70
70
27
65
0
17
32
15
∼0
3
2
3
58
4
72
73
85
69
0
48
57
54
11
21
51
97:3
96:4
32:68
94:6
2d
3
4
1
pyrrole 5h was detected as a minor product by H NMR
5
6
7
8
LHMDS THF
0
-
LDA
LDA
LTMP
LTMP
LTMP
LTMP
Et2O
toluene
Et2O
31
25
39
11
18
36
35:65
56:44
28:72
1:>99
14:86
29:71
analysis (entries 9 and 10). More surprisingly, when dim-
ethylcarbamoyl chloride was used as an electrophile, 5-func-
tionalized pyrrole 5i was generated as the major product
(entry 11). Similar C-5-preferred formylation was also
observed in the reaction with N,N-dimethylformamide (entry
12). Especially when N,N-diethylformamide was reacted
under the conditions B, 5j was isolated as the sole product
(entry 14). In contrast, the reaction with ethyl formate, a more
reactive formylating agent for organolithiums, gave the
normal 2-formylated isomer 4j exclusively (entry 15). This
striking change of regioselectivity dependent on the reactivity
of electrophiles was also observed in the silylation reactions
with sterically demanding triisopropylsilyl chloride and
triisopropylsilyl triflate (entries 16-19). The less reactive
9
toluene
toluene
toluene
10e
11f
15
a MeOD (3.0 equiv) was added as a THF solution. b Isolated yield.
c
Determined by H NMR analysis (400 MHz). d Lithiation for 3 h. e 2.4
1
equiv of LTMP. f Lithiation for 12 h.
in THF at -78 °C for 1 h followed by quenching with MeOD
gave the deuterated pyrrole 2 in 91% yield after chromato-
graphic purification. The 400 MHz 1H NMR analysis of the
product indicated 72% total deuterium incorporation and
excellent C-2 regioselectivity8 (entry 1). A longer lithiation
time (3 h) did not improve the total deuterium incorporation
(entry 2). Utilization of LTMP instead of LDA resulted in
(8) Ortho-directing effect of bromine has been reported, see: (a) Arroyo,
Y.; Rodr´ıguez, J. F.; Sanz-Tejedor, M. A.; Santos, M. Tetrahedron Lett.
2002, 43, 9129–9132. (b) Mongin, F.; Marzi, E.; Schlosser, M. Eur. J. Org.
Chem. 2001, 2771–2777. (c) Lulin´ski, S.; Serwatowski, J. J. Org. Chem.
2003, 68, 5384–5387.
(3) Iwao, M.; Kuraishi, T. Tetrahedron Lett. 1985, 26, 6213–6216.
(4) Groenendaal, L.; Van Loo, M. E.; Vekemans, J. A. J. M.; Meijer,
E. W. Synth. Commun. 1995, 25, 1589–1600.
(5) Bailey, N.; Demont, E.; Garton, N.; Seow, H.-X. Synlett 2008, 185–
188.
(9) The pKa values of LTMP, LDA, and LHMDS are 37.3, 35.7, and
29.5, respectively. See: ref 1c.
(6) Robertson, J.; Kuhnert, N.; Zhao, Y. Heterocycles 2000, 53, 2415–
2420.
(10) Rutherford, J. L.; Collum, D. B. J. Am. Chem. Soc. 2001, 123,
199–202, and references cited therein.
(7) Ohta, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. J. Org. Chem. 2009,
74, 8143–8153.
(11) LTMP was precipitated as white crystalline solid at -78 °C. This
might be the reason for inefficient lithiation of 1 with LTMP in toluene.
Org. Lett., Vol. 12, No. 12, 2010
2735

Table 2. Selective C-2 Lithiation of 1 Followed by Reactions with Electrophiles
entry
electrophilea
conditionsb
products
E
yield (%)c
ratio (4:5)d
1
2
3
4
5
6
7
8
ClCO2Me
TMSCl
PhSSPh
BrCF2CF2Br
I2
p-MeOC6H4CHO
t-BuNCO
t-BuNCO
p-MeOC6H4COCl
p-MeOC6H4COCl
ClCONMe2
HCONMe2
HCONEt2
HCONEt2
HCO2Et
A
A
A
A
A
A
A
B
A
B
B
A
A
B
A
A
B
A
B
4a,5a
4b,5b
4c,5c
4d,5d
4e,5e
4f, 5f
4g,5g
4g,5g
4h,5h
4h,5h
4i, 5i
4j, 5j
4j, 5j
4j, 5j
4j, 5j
4k,5k
4k,5k
4k,5k
4k,5k
CO2Me
TMS
SPh
Br
86
84
99
90
99
86
24
95
15
70
22
76
4
24
71
1
45
59
82
d
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
86:14
97:3
16:84
35:65
28:72
1:>99
>99:1
1:>99
1:>99
86:14
95:5
I
CH(OH)(C6H4OMe-p)
CONHt-Bu
CONHt-Bu
COC6H4OMe-p
COC6H4OMe-p
CONMe2
CHO
CHO
CHO
CHO
TIPS
9
10
11
12
13
14
15
16
17
18
19
TIPSCl
TIPSCl
TIPSOTf
TIPSOTf
TIPS
TIPS
TIPS
a Electrophile (1.8 equiv) was added as a THF solution. b A: -78 °C, 1 h. B: -78 °C, 1 h f 0 °C, 3 h. c Isolated yield. Determined by H NMR
analysis (400 MHz).
1
chloride was reacted at C-5 exclusively, whereas the more
reactive triflate was combined at C-2 selectively.
To explain these unusual electrophile-controlled regiose-
lective functionalizations12 of 3, the following experiments
were carried out (Scheme 1). Treatment of N-benzenesulfo-
hand, quenching the lithio species after reaction with 1.0
equiv of diisopropylamine at -78 °C for 1 h produced a
mixture of 5a and 4a (80:20) in 95% yield. Moreover, 4a
was obtained in excellent yield and in high purity by warming
the mixture of 7 and diisopropylamine in THF to 0 °C and
quenching with methyl chloroformate.
The results shown above suggest that the lithio species 3
and 7 are in dynamic equilibrium14 via 1 in the presence of
diisopropylamine (Scheme 2). The C-2 lithio species 3 is
apparently more stable than the C-5 lithio species 7.
However, 3 may be less reactive to electrophiles than 7
owing to the steric and electron-withdrawing effects of the
adjacent 3-bromo group. In the reaction with reactive
electrophiles such as methyl chloroformate and methyl
formate, the reaction rate between 3 and electrophiles may
be much faster than the equilibration rate from 3 to 7. This
difference allows the selective functionalization at C-2 to
yield 4. On the other hand, in the reactions with less reactive
electrophiles such as N,N-diethylformamide and triisopro-
Scheme 1
. Reactivity of 5-Lithiopyrrole 7 Generated by
Regioselective Br-Li Exchange of 6
(12) Similar electrophile-controlled regioselective functionaliza-
tion has been reported in the directed lithiation of the 1,3-
dimethoxybenzene-Cr(CO)3 complex and related compounds. See: (a)
Schmalz, H.-G.; Volk, T.; Bernicke, D.; Huneck, S. Tetrahedron 1997, 53,
9219–9232. (b) Michon, C.; Murai, M.; Nakatsu, M.; Uenishi, J.; Uemura,
M. Tetrahedron 2009, 65, 752–756.
nyl-2,4-dibromopyrrole (6)13 with 1.1 equiv of n-BuLi in
THF at -78 °C for 0.5 h followed by a reaction with methyl
chloroformate gave 5-methoxycarbonylated pyrrole 5a in
excellent yield. This result clearly indicated that the C-5 lithio
species 7 was generated via regioselective Br-Li exchange,
and this species did not isomerize to the corresponding C-2
lithio species 3 under the reaction conditions. On the other
(13) Compound 6 was readily prepared in two steps from N-benzene-
sulfonylpyrrole. See Supporting Information. We thank Mariko Okamoto
for the synthesis of 6.
(14) Dynamic equilibrium of organolithiums has been observed in
sparteine-mediated enantioselective functionalization of benzylic anions. See
ref 1d.
2736
Org. Lett., Vol. 12, No. 12, 2010

give 5-functionalized pyrrole 5. The unusual electrophile-
controlled regioselective functionalization of 3 was rational-
ized by assuming dynamic equilibrium between C-2 and C-5
lithio species. The reactions described herein may be useful
for the regioselective synthesis of a variety of 2,3- and 2,4-
disubstituted pyrroles15 in view of the further possibility to
functionalize the pyrrole ring using specific reactivity bro-
mine.
Scheme 2
.
Rationale for Electrophile-Controlled Regioselective
Functionalization of 1
Acknowledgment. We thank the Japan Society for the
Promotion of Science (JSPS) for financial support (No.
20310135).
Supporting Information Available: Experimental details
including analytical and spectroscopic data and 1H NMR and
13C NMR spectra of all compounds synthesized in this work.
This material is available free of charge via the Internet at
http://pubs.acs.org.
pylsilyl chloride, the equilibration rate may be faster than
the reaction rate with the electrophiles. As a result, such
electrophiles react with more reactive 7 rather than 3 to give
the unusual 5-functionalized pyrrole 5 preferentially.
In conclusion, we have discovered that N-benzenesulfonyl-
3-bromopyrrole (1) can be lithiated at C-2 selectively with
LDA in THF at -78 °C. The C-2 lithio species 3 thus
generated was trapped with a number of reactive electrophiles
to give 2-functionalized pyrrole 4 in good yields. On the
other hand, 3 was reacted with less reactive electrophiles to
OL100810C
(15) For regioselective syntheses of 2,3- and 2,4-disubstituted pyrroles,
see: (a) Franc, C.; Denonne, F.; Cuisinier, C.; Ghosez, L. Tetrahedron Lett.
1999, 40, 4555–4558. (b) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc.
1998, 120, 2817–2825. (c) Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am.
Chem. Soc. 2005, 127, 5970–5978. (d) Beck, E. M.; Hatley, R.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2008, 47, 3004–3007.
Org. Lett., Vol. 12, No. 12, 2010
2737