Synthesis of tetrasubstituted 2-aryl-3-arylsulfonyl pyrroles: Unexpected regioselectivity in directed ortho-metallation reactions

Article abstract of DOI:10.1055/s-2007-1000880

3-Arylsulfonyl pyrroles can be readily obtained from 3-Br-TIPS pyrrole via halogen-metal exchange and subsequent sulfonylation. The regioselectivity of the subsequent directed ortho-metallation (DOM) reaction in order to functionalise the C-2 position dep

Full text of DOI:10.1055/s-2007-1000880

LETTER
185
Synthesis of Tetrasubstituted 2-Aryl-3-arylsulfonyl Pyrroles: Unexpected
Regioselectivity in Directed ortho-Metallation Reactions
S
ynthesis of Tetras
i
ubstitu
c
ted 2-Aryl-
k
3-arylsulfonyl Pyrr
B
oles ailey, Emmanuel Demont,* Neil Garton, Hui-Xian Seow
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park,
Third Avenue, Harlow, Essex, CM19 5AW, UK
Fax +44(127)9627685; E-mail: emmanuel.h.demont@gsk.com
Received 10 September 2007
Indeed, N-sulfonylation of pyrrole is straightforward but
these derivatives can have stability issues, as the N–S
bond can be cleaved under acidic or basic conditions. This
is not the case when the sulfonyl group is carbon-linked to
Abstract: 3-Arylsulfonyl pyrroles can be readily obtained from 3-
Br-TIPS pyrrole via halogen–metal exchange and subsequent sulfo-
nylation. The regioselectivity of the subsequent directed ortho-met-
allation (DOM) reaction in order to functionalise the C-2 position
depends on the nature of the base (LTMP, n- or s-BuLi) and the N- the pyrrole ring.
substituent (SEM or Boc) used. The bulk of the N-substituent also
strongly influences the yield of the subsequent Suzuki coupling
with 2-iodo-3-arylsulfonyl pyrrole derivatives.
For this reason, during the course of our work, 2-aryl-3-
arylsulfonyl pyrroles (Figure 2) became key intermedi-
ates capable of further functionalisation at the N-1 and C-
5 positions using well-precedented reactions (alkylation,
acylation, halogenation).
Key words: phenylsulfonyl fluoride, 3-sulfonyl pyrrole, directed
ortho-metallation, palladium, Suzuki coupling
R3
O
H
The pyrrole core has attracted considerable synthetic in-
terest for many years since it occurs in many alkaloids1
and therapeutic agents,2 including the world’s best-selling
drug Lipitor (1; Figure 1).
N
N
R4
R1
R1
SO2
SO2
R2
R2
O
OH OH
O
Figure 2 Disubstituted pyrroles as useful templates for further
functionalisation.
N
O-
1/2 Ca2+
H
N
The retrosynthesis envisioned for the model compound 2-
phenyl-3-phenylsulfonyl pyrrole (2) is depicted in
Scheme 1 and involves regioselective halogenation via di-
rected ortho-metallation (DOM) of the appropriately pro-
tected 3-phenylsulfonyl pyrrole 3, followed by Suzuki
coupling and deprotection. DOM has already been suc-
cessfully described in the case of 3-sulfonyl furans.3
1
F
Figure 1 Example of therapeutic agent containing a pyrrole
nucleus.
Due to its electron-rich nature, the pyrrole nucleus can be
easily oxidised in vitro and in vivo. One of the options to
overcome this issue is to introduce electron-withdrawing
substituents such as sulfonyl, carbonyl or amide moieties.
The synthesis of 3-sulfonyl pyrroles has been described
previously and can be mainly obtained via: a) rearrange-
ment of 2-sulfinyl or 2-sulfonyl pyrroles;4 b) [4+1]-5or
DG
DG
H
N
N
N
X
SO2
SO2
SO2
deprotection
Suzuki
directed ortho-
metallation
2
3
Scheme 1 Retrosynthesis of 2-phenyl-3-phenylsulfonyl pyrrole. X = halogen, DG = directing group.
SYNLETT 2008, No. 2, pp 0185–0188
x
x.
x
x.
2
0
0
7
Advanced online publication: 21.12.2007
DOI: 10.1055/s-2007-1000880; Art ID: D28307ST
© Georg Thieme Verlag Stuttgart · New York

186
N. Bailey et al.
LETTER
[3+2]-annulation6 followed by oxidation of the intermedi-
ate 3-pyrroline; c) cycloaddition involving sydnone or N-
acyl pyrroles and alkynyl sulfones.7,8 In our case, because
of the wide range of arylsulfonyl chlorides commercially
available, we chose to synthesise this derivative via func-
tionalisation of the 3-lithio-TIPS pyrrole derivative, easily
obtained from commercially available 3-bromo-TIPS pyr-
role 4 (Scheme 2).9
DG
N
DG
N
H
N
N
a
b
+
D
D
SO2
SO2
SO2
SO2
5b
6a–c
7a–c
8
Scheme 3 Reagents and conditions: (a) Boc2O, DMAP, MeCN,
25 °C, 6a (98%) or NaH, DMF, 0 °C then SEMCl, 6b (81%), or NaH,
DMF, 0 °C then PhSO2Cl, 6c (84%); (b) base, THF, –78 °C then
CD3OD; 6a,7a: DG = Boc; 6b,7b: DG = SEM; 6c,7c: DG = PhSO2.
R
N
Si
N
Si
N
a
SO2
To our surprise, incorporation of deuterium occurred at
both C-2 and C-5 positions (Table 1, entry 1).13 One ex-
planation for this lack of selectivity is the combined bulk
of the Boc and sulfonyl groups, which prevents access to
the C-2 proton for the large LTMP. This ratio was unaf-
fected by increasing the temperature before adding the
trapping reagent, but this rise in temperature was limited
to –45 °C due to the instability of the lithiated intermedi-
ate. A complete selectivity in favour of the C-2 position
could be obtained when n-BuLi or s-BuLi were used (en-
tries 2 and 3), but significant amounts of partially deuter-
ated pyrrole 8 were obtained in each case. Moreover, we
were more interested in using non-nucleophilic bases as
we wanted to transfer this methodology to functionalised
arylsulfonyl derivatives.
Br
Li
4
5a R = TIPS
5b R = H
b
Scheme 2 Reagents and conditions: (a) n-BuLi, THF, –78 °C,
10 min then PhSO2F, –78 °C; (b) TBAF, THF, 0 °C, 63% (2 steps).
Following halogen–metal exchange the intermediate
could be quenched with phenylsulfonyl fluoride, easily
available from the corresponding sulfonyl chloride,10 in
order to avoid formation of the 3-chloro derivative.11
As F– is a byproduct of the reaction, 5a was often accom-
panied by small amounts (ca. 15%) of the deprotected pyr-
role 5b. As the pyrrole nitrogen needed to be
appropriately substituted for the following DOM step, it
proved easier to operate the functionalisation at C-3 and
deprotection in one pot and 5b was obtained from 3-bro-
mo-TIPS pyrrole 4 in 63% overall yield.
Hence, we decided to use SEM as a less hindered N-sub-
stituent as it has been shown to be as efficient as the Boc
group in DOM reactions albeit at higher temperatures.14 In
this case, pyrrole 6b was ortho-metallated with complete
regioselectivity at C-2 using LTMP as a base (entry 4). It
is interesting to note that using phenyl sulfone as a direct-
ing group led again to poor selectivity, confirming the ma-
jor role of steric hindrance in this reaction (entry 6). DOM
reactions using SEM as the directing group could be per-
formed at low temperature and the proton-exchange was
rapid (<10 min, see entry 5).
The first attempt of regioselective DOM was performed
following the procedure described by Fowler and Levy,12
using the Boc-protected pyrrole 6a (DG = Boc, Scheme 3)
and LTMP as a base. Deuterated methanol was used as
trapping agent.
Table 1 Regioselectivity of Deuteration of 3-Phenylsulfonyl pyrrole 6a–c following Directed ortho-Metallation
Entry DG
Basea
7/8b
%D incorporated in 7b
%D incorporated in 8b
C-2
23
82
50
90
90
45
C-4
5
C-5
60
0
Total
88
C-2
C-4
C-5
Total
1
2
3
4
5
6
Boc
LTMP
n-BuLi
s-BuLi
LTMP
LTMP
LTMP
>95:5
67:33
67:25
>95:5
>95:5
>95:5
Boc
0
82
59
38
0
0
0
2
59
40
Boc
0
0
50
SEM
SEM
SO2Ph
0
0
90c
90d
95
0
0
0
50
a Reaction conditions: base, THF, –78 °C, 50 min then CD3OD, –78 °C, 5 min.
b Determined using 1H NMR of the crude reaction. No evidence of any deuteration of the phenyl ring attached to SO2 was observed in all cases.
c Isolated yield: 89%.
d Reaction time of 10 min prior to addition of CD3OD.
Synlett 2008, No. 2, 185–188 © Thieme Stuttgart · New York

LETTER
Synthesis of Tetrasubstituted 2-Aryl-3-arylsulfonyl Pyrroles
187
Using iodine as a trapping agent under the same condi-
tions gave pyrrole 9 (Scheme 4), which could now be re-
acted in Suzuki couplings. However, the conditions of the
Suzuki reaction had to be optimised, again probably due
to the steric hindrance around the iodine.15 Standard con-
ditions [PhB(OH)2, Pd(PPh3)4, K2CO3, toluene–EtOH
(1:1), reflux] gave a complex mixture in which both 10
and the reduced adduct 6b were present in small quantities
(<20%). Synthetically useful yields were obtained only
when conditions reported by Buchwald16 were used
[Pd(OAc)2, K3PO4, PhB(OH)2, 14, toluene]. However, the
temperature needed to be lowered from 100 °C to 50 °C in
order to avoid reduction of the intermediate and formation
of 6b.17 Overall, the C-2 phenyl adduct could be obtained
in 85% yield.
References and Notes
(1) (a) Pinder, A. R. In The Alkaloids, Vol. 12; Grundon, M. F.,
Ed.; Chemical Society: London, 1982. (b) Massiot, G.;
Delaude, C. In The Alkaloids, Vol. 27; Manske, R. H. F., Ed.;
Academic Press: New York, 1986, Chap. 3.
(2) A search for the pyrrole core in WDI database retrieved
more than 160 hits.
(3) Hartman, D. G.; Halczenko, W. Tetrahedron Lett. 1987, 28,
3241.
(4) (a) DeSales, J.; Greenhouse, R.; Muchowski, J. M. J. Org.
Chem. 1982, 47, 3668. (b) Ortiz, C.; Greenhouse, R.
Tetrahedron Lett. 1985, 26, 2831.
(5) (a) Padwa, A.; Norman, B. H. Tetrahedron Lett. 1988, 29,
3041. (b) Padwa, A.; Norman, B. H. J. Org. Chem. 1990, 55,
4801.
(6) (a) Burley, I.; Hewson, A. T. Synthesis 1995, 1151. (b) For
a related approach using 2-substituted vinamidinium salts,
see: Gupton, J. T.; Krolikowski, D. A.; Yu, R. H.; Riesinger,
S. W.; Sikorski, J. A. J. Org. Chem. 1990, 55, 4735.
(7) (a) Dalla Croce, P.; Gariboldi, P.; La Rosa, C. J. Heterocycl.
Chem. 1987, 24, 1793. (b) Castro, J.; Coteron, J. M.; Fraile,
M. T.; Garcia-Ochoa, S.; Gomez de las Heras, F.; Martin-
Cuesta, A. Tetrahedron Lett. 2002, 43, 1851. (c) Chen, Z.;
Trudell, M. L. Tetrahedron Lett. 1994, 35, 9649.
(8) This list is not exhaustive. See for examples: (a) Moranta,
C.; Molins-Pujol, A. M.; Pujol, M. D.; Bonal, J. J. Chem.
Soc., Perkin Trans. 1 1998, 3285. (b) Barnes, K. D.; Ward,
R. J. Heterocycl. Chem. 1995, 32, 871.
SEM
R
N
SEM
N
N
a
b
I
SO2
SO2
SO2
10 R = SEM
11 R = CH2OH
12 R = H
9
6b
c
d
(9) For the synthesis from TIPS pyrrole, see: Kozikowski, A. P.;
O
Cheng, X.-M. J. Org. Chem. 1984, 49, 3239.
(10) Ichihara, J.; Matsuo, T.; Hanafusa, T.; Ando, T. J. Chem.
Soc., Chem. Commun. 1986, 793.
N
e, f
P(Cy)2
H
(11) For difference of reactivity of sulfonyl chloride and fluoride
on a-functionalisation of enolate, see: (a) Hirsch, E.; Hünig,
S.; Reißig, H.-U. Chem. Ber. 1982, 115, 399. (b) Kende, A.
S.; Mendoza, J. S. J. Org. Chem. 1990, 55, 1125.
(c) Sandanayaka, V. P.; Zask, A.; Venkatesan, A. M.; Baker,
J. Tetrahedron Lett. 2001, 42, 4605. (d) For application to
sulfonylation of aryl metal, see: Frye, L. L.; Sullivan, E. L.;
Cusack, K. P.; Funaro, J. M. J. Org. Chem. 1992, 57, 697.
(e) In our case, use of phenylsulfonyl chloride gave almost
quantitatively the corresponding 3-Cl pyrrole.
SO2
Me2N
14
13
Scheme 4 Reagents and conditions: (a) LTMP, THF, –78 °C then
I2, 96%; (b) PhB(OH)2, Pd(OAc)2, K3PO4, 14, toluene, 50 °C, 85%;
(c) BF3·Et2O, CH2Cl2, 0 °C; (d) Triton B, MeCN, reflux, 73% (2
steps); (e) NaH, DMF, 0 °C then MeI, 86%; (f) MeOCHCl2, AlCl3,
(CH2Cl)2, –30 °C to 0 °C, 77%.
(12) Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.;
Levy, A. B. J. Org. Chem. 1981, 46, 157.
(13) The cooperative effects of meta-related directed metallation
groups usually give excellent selectivity. See Table 3, p. 885
in: Snieckus, V. Chem. Rev. 1990, 90, 879.
(14) (a) Edwards, M. P.; Ley, S. V.; Lister, S. G.; Palmer, B. D.
J. Chem. Soc., Chem. Commun. 1983, 630. (b) Muchowski,
J. M.; Solas, D. R. J. Org. Chem. 1984, 49, 203.
Deprotection of the pyrrole 10 was performed using the
method described by Muchowski et al.14b,18 to afford the
pyrrole 12 in good yields via the formation of 11. Further
reactions of pyrrole 12 proceeded as expected in good
yields and with complete regioselectivity towards formy-
lation or alkylation to give compounds such as 13.19,20
(c) Edwards, M. P.; Ley, S. V.; Lister, S. G.; Palmer, B. D.;
Williams, D. J. J. Org. Chem. 1984, 49, 3503. (d) Edwards,
M. P.; Doherty, A. M.; Ley, S. V.; Organ, H. M. Tetrahedron
1986, 42, 3723.
Overall, we have described an efficient synthesis of 2-
phenyl-3-phenylsulfonyl pyrrole thanks to a precise
choice of directing group during the DOM step and con-
ditions of reaction for the Suzuki coupling. This deriva-
(15) In a previous attempt using 2-Br-3-PhSO2 pyrrole, no Suzuki
coupling was effective, possibly due to the acidity of the N-
1 hydrogen; results to be published.
tive is
a
useful building block for further
(16) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L.
functionalisation, allowing the regioselective synthesis of
tetrasubstituted pyrroles. The full scope of this methodol-
ogy will be reported in due course.
J. Am. Chem. Soc. 1999, 121, 9550.
(17) At 100 °C, the ratio of 10 and 6b was 1.85:1 according to the
1H NMR of the crude reaction. This ratio was at least 95:5 at
50 °C. Lower temperatures were not considered.
(18) For deprotection under acidic conditions, see:
(a) Matthews, D. P.; Whitten, J. P.; McCarthy, J. R.
J. Heterocycl. Chem. 1987, 24, 689. (b) See also ref. 14d.
(19) Regioselectivity of every reaction leading to 13 was
confirmed unambiguously by NOE experiments. Compound
Acknowledgment
We thank Mr. Christopher Seaman for NMR support.
Synlett 2008, No. 2, 185–188 © Thieme Stuttgart · New York

188
N. Bailey et al.
LETTER
13 (pale yellow solid) has the following characteristics: mp
152–153 °C. 1H NMR (400 MHz, CDCl3): d = 3.67 (s, 3 H),
7.14 (d, J = 6.8 Hz, 2 H), 7.28 (d, J = 7.2 Hz, 2 H), 7.42–7.48
this temperature for 50 min. Iodine (1.22 g, 4.82 mmol, 1.25
equiv) in THF (7 mL) was slowly added via syringe over 1
min. After 2 min, the mixture was partitioned between
EtOAc (100 mL) and a 10% aq Na2S2O3 solution (100 mL).
The two layers were vigorously stirred for 5 min. Brine (10
mL) was added and the two layers were separated. The
aqueous layer was extracted with EtOAc (20 mL) and the
combined organic layers were washed with brine (50 mL),
dried over MgSO4 and concentrated in vacuo. Purification of
the residue by flash chromatography on silica gel
(isohexane–EtOAc, 95:5 → 4:1) gave 2-iodo-3-(phenyl-
sulfonyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-
pyrrole (9; 1.71 g, 96%) as a white solid; mp 75–76 °C. 1H
NMR (400 MHz, CDCl3): d = 0.02 (s, 9 H), 0.94 (t, J = 8.8
Hz, 2 H), 3.54 (t, J = 8.8 Hz, 2 H), 5.29 (s, 2 H), 6.94 (d, J =
3.2 Hz, 1 H), 7.13 (d, J = 3.2 Hz, 1 H), 7.52–7.63 (m, 3 H),
8.06 (d, J = 6.4 Hz, 2 H).13C NMR (100.6 MHz, CDCl3): d =
0.0, 19.1, 68.0, 76.9, 81.1, 114.4, 127.5, 128.8, 130.3, 131.1,
134.2, 143.8. MS (ESI): m/z = no molecular ion.
(m, 5 H), 7.51–7.55 (m, 1 H), 7.55 (s, 1 H), 9.65 (s, 1 H). 13
C
NMR (100.6 MHz, CDCl3): d = 34.4, 124.1, 125.1, 127.2,
127.3, 128.4, 128.6, 130.1, 130.6, 130.8, 132.7, 142.0,
143.1, 180.0. MS (ESI): m/z = 326.0 [M + H]+.
(20) Typical Procedures:
Compound 5b: To a solution of 3-bromo-1-[tris(1-methyl-
ethyl)silyl]-1H-pyrrole (12.8 g, 42.4 mmol, 1 equiv) in THF
(200 mL) at –78 °C under nitrogen was slowly added n-BuLi
(2.5 M in hexanes, 17.8 mL, 44.5 mmol, 1.05 equiv) over 3
min and the resulting mixture was stirred for 15 min at this
temperature. Phenylsulfonyl fluoride (7.5 g, 46.6 mmol, 1.1
equiv) in THF (20 mL) was added via syringe over 5 min and
the resulting mixture was stirred for 45 min at this
temperature, then partitioned between EtOAc (200 mL) and
brine (100 mL). The two layers were separated and the
aqueous phase was extracted with EtOAc (20 mL). The
combined organic phases were washed with brine (2 × 50
mL), dried over MgSO4 and concentrated in vacuo. The
residue was dissolved in THF (200 mL) and TBAF (1 M in
THF, 42 mL, 1 equiv) was added and the resulting mixture
was stirred for 30 min and then dissolved with EtOAc (200
mL). The organic phase was washed with a sat. aq NaHCO3
solution (3 × 30 mL), dried over MgSO4 and concentrated in
vacuo. Purification of the residue by flash chromatography
on silica gel (isohexane–EtOAc, 3:1 → 1:1) gave 3-(phen-
ylsulfonyl)-1H-pyrrole (5b; 5.53 g, 63%) as a white solid;
mp 145–145 °C. 1H NMR (400 MHz, CDCl3): d = 6.48 (m,
1 H), 6.78 (m, 1 H), 7.38 (m, 1 H), 7.45–7.55 (m, 3 H), 7.92
(m, 2 H).13C NMR (100.6 MHz, CDCl3): d = 108.4, 120.4,
122.4, 124.6, 127.2, 129.0, 132.6, 143.3. MS (ESI): m/z =
208.1 [M + H]+.
Compound 10: A flask was charged under nitrogen with 2-
iodo-3-(phenylsulfonyl)-1-({[2-(trimethylsilyl)eth-
yl]oxy}methyl)-1H-pyrrole (9; 1.04 g, 2.25 mmol, 1 equiv),
Pd(OAc)2 (50 mg, 0.22 mmol, 0.1 equiv), K3PO4 (952 mg,
4.49 mmol, 2 equiv), 2¢-(dicyclohexylphosphanyl)-N,N-
dimethyl-2-biphenylamine (176 mg, 0.45 mmol, 0.2 equiv)
and PhB(OH)2 (411 mg, 3.37 mmol, 1.5 equiv), then toluene
(20 mL) was added and the resulting mixture was stirred at
50 °C for 4 h and then cooled to r.t. The mixture was
dissolved with EtOAc (50 mL) and the organic phase was
washed with a sat. NaHCO3 solution, then with brine, dried
over MgSO4 and concentrated in vacuo. Purification of the
residue by flash chromatography on silica gel (isohexane–
EtOAc: 9:1 → 3:1) gave 10 (790 mg, 85%) as pale yellow
oil. 1H NMR (400 MHz, CDCl3): d = 0.0 (s, 9 H), 0.83 (t,
J = 8.4 Hz, 2 H), 3.36 (t, J = 8.4 Hz, 2 H), 5.01 (s, 2 H), 6.87
(d, J = 2.8 Hz, 1 H), 6.92 (d, J = 2.8 Hz, 1 H). 7.26–7.56 (m,
10 H).13C NMR (100.6 MHz, CDCl3): d = 0.0, 67.7, 77.4,
111.6, 124.8, 128.4, 129.4, 129.9, 130.1, 130.7, 132.9,
133.6, 137.7, 144.7. MS (ES): m/z = 413.9 [M + H]+.
Compound 9: To a solution 3-(phenylsulfonyl)-1-({[2-
(trimethylsilyl)ethyl]oxy}methyl)-1H-pyrrole (1.3 g, 3.86
mmol, 1 equiv) in THF (30 mL) at –78 °C under nitrogen
was added LTMP (0.5 N in THF, 8.9 mL, 4.45 mmol, 1.15
equiv) over 1 min and the resulting mixture was stirred at
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