Regioselective couplings of dibromopyrrole esters

Article abstract of DOI:10.1055/s-2006-950305

The regioselectivity of the Suzuki couplings of several 4,5- and 3,4-dibromopyrrole-2-carboxylate esters has been studied. In general, regioselectivity can be achieved for initial coupling at the more electron-deficient site (C5 and C3, respectively). At

Full text of DOI:10.1055/s-2006-950305

PAPER
3883
Regioselective Couplings of Dibromopyrrole Esters
R
egioselective
c
Couplings
o
of Dibromop
t
yrrole
t
Esters T. Handy,*1 Yanan Zhang
Department of Chemistry, Binghamton University, Binghamton, NY 13902, USA
Fax +1(615)8985182; E-mail: shandy@mtsu.edu
Received 25 May 2006; revised 7 July 2006
H
H
N
Abstract: The regioselectivity of the Suzuki couplings of several
Ar"
Ar
CO2Et
halogenation
coupling
N
CO2Et
4,5- and 3,4-dibromopyrrole-2-carboxylate esters has been studied.
In general, regioselectivity can be achieved for initial coupling at
the more electron-deficient site (C5 and C3, respectively). At the
same time, conversions are often modest (40–60%) and attempts to
force the reactions to higher conversions often lead to competitive
dicoupling.
Ar'
x3
triple
halogenation
triple
coupling
H
H
N
N
Ar"
Ar
CO2Et
Ar'
CO2Et
Key words: Suzuki cross-coupling, regioselectivity, electronic ef-
fects, pyrroles, palladium
Scheme 1
To study this polycoupling option for shortening the syn-
thesis of polysubstituted pyrroles and, in particular, the
lamellarins, the first stage was the preparation of the re-
quired dibromopyrrole esters. Two compound types were
explored: 4,5-dibromopyrrole-2-carboxylates and 3,4-di-
bromopyrrole-2-carboxylates.7 For the 4,5-dibromopyr-
role-2-carboxylate ester 1 (Scheme 2), direct bromination
of ethyl pyrrole-2-carboxylate is known to afford this
product in good yield.4 On the basis of previous work in
the Suzuki coupling of 4-bromopyrrole esters, it was ex-
pected that the pyrrole nitrogen would need to be protect-
ed to avoid extensive dehalogenation at C4.8 As a result,
two dibromopyrrole esters were prepared: ethyl-protected
compound 2 and methoxycarbonyl-protected compound 3
(Scheme 2). These two protecting groups were selected to
study the effect of the protecting group (in particular its
influence on the electronics of the pyrrole ring) on the re-
gioselectivity of the Suzuki coupling.
As part of our ongoing interest in the synthesis of the
lamellarin family of natural products (which have at their
core a 3,4,5-triarylpyrrole-2-carboxylate),2 we have been
interested in methods to improve upon our first generation
approach.3 In particular, it was noted that much of the syn-
thesis (six of eleven steps) is devoted to the three haloge-
nation–coupling sequences required for the installation of
each of the three aryl rings attached to the pyrrole core.
Since these sequences are the key to the goal of function-
alizing an intact pyrrole core, they cannot be avoided, and
yet they contribute greatly to the length and linearity of
the synthesis. Indeed, this is a common problem found in
the utilization of cross-coupling methods for the installa-
tion of multiple subunits on an intact aryl or hetaryl core.
As a result, any effort to significantly shorten the existing
synthetic approach must address those halogenation–cou-
pling sequences.
One interesting option would be to employ one-pot regio-
selective polycouplings of polyhalopyrrole precursors.
Di- or even tribromopyrrole esters can be readily prepared
in one step by direct bromination of the starting nonhalo-
genated pyrrole ester.4 Then, if each of the brominated
sites could be sequentially coupled with a high degree of
regioselectivity in a second step, the six steps required in
the first generation approach would be reduced to two
steps – a dramatic improvement (Scheme 1). However, al-
though regioselective couplings of a number of polyhalo-
hetarenes are known,5 pyrroles had not been studied
previously.6 As a result, the first stage in realizing this
goal was to study the regioselectivity of the Suzuki cou-
pling of a number of dibromopyrrole esters to determine
conditions that would be appropriate for achieving regio-
selectivity in these couplings.
Et
N
Br
CO2Et
EtI, NaH
DMF
78%
Br
H
N
2
Br
Br
CO2Et
CO2Me
N
MeOCOCl
Bu4NI, K2CO3
DMF, 91%
1
Br
Br
CO2Et
3
Scheme 2
For the 3,4-dibromopyrrole esters, known pyrrole 4 was
the starting point (Scheme 3).9 Monolithiation in tetrahy-
drofuran with n-butyllithium occurred exclusively at the
a-bromide. Subsequent quenching with methyl chlorofor-
mate afforded methyl ester 5. Since it was expected that
the triisopropylsilyl group would not survive the Suzuki
coupling reaction conditions,8 it was removed and the pyr-
role nitrogen was protected with a methoxycarbonyl
SYNTHESIS 2006, No. 22, pp 3883–3887
x
x
.x
x
.
2
0
0
6
Advanced online publication: 12.10.2006
DOI: 10.1055/s-2006-950305; Art ID: M03706SS
© Georg Thieme Verlag Stuttgart · New York

3884
S.T. Handy, Y. Zhang
PAPER
Et
TIPS
TIPS
N
Ar
Br
CO2Et
CO2Et
N
ArB(OH)2
Pd(PPh3)4
aq Na2CO3
N
n-BuLi
Br
CO2Me
Et
N
then
MeOCOCl
66%
Br
Br
CO2Et
11
+
Br
Br
Br
Br
toluene–EtOH (3:1)
95 °C, 44%
4
5
Et
N
2
CO2Me
N
Ar
Ar
1. TBAF, THF
61%
Ar = p-MeOC6H4
CO2Me
12
2. MeOCOCl
K2CO3, Bu4NI
DMF, 86%
Br
Br
Scheme 5
6
Scheme 3
equivalents of boronic acid were not successful, with the
addition of more boronic acid simply leading to the com-
petitive formation of dicoupled product 12.
group under conditions developed in our laboratory for
poorly nucleophilic pyrroles (Scheme 3).10
Although regioselectivity could be achieved, the modest
conversion was disappointing. It was felt that the methoxy-
carbonyl-protected compound 3 (Scheme 6) might afford
better results, since the electron-withdrawing nature of the
methoxycarbonyl group should facilitate the Suzuki cou-
pling reaction.13 In the event, application of the optimal
conditions identified for 2 did lead to C5-arylated product
13 forming along with significant amounts of diarylated
product 14. Because of the presumed higher reactivity of
this substrate, it was felt that lower temperatures should
still afford coupling, but with greater selectivity. Indeed,
the same conditions were employed at a lower tempera-
ture to afford only 13, which was isolated in 56% yield
(Scheme 6).
A second variation in the 3,4-dibromopyrrole ester series
was also explored (Scheme 4). Since application to the
lamellarins would require the presence of a 5-aryl group,
it was decided to examine the effect of the presence of
such a group on the regioselectivity of the couplings.
These compounds were prepared from 5-bromopyrrole
ester 7, obtained by the method of Cava.11 Suzuki cou-
pling of the C5 bromide with p-methoxyphenylboronic
acid afforded 5-arylpyrrole 8 in 83% yield (Scheme 4).
Dibromination with N-bromosuccinimide then afforded
compound 9, which was protected as a methoxycarbonyl
derivative 10 under our standard conditions.
BOC
N
p-MeOC6H4B(OH)2
H
N
Pd(PPh3)4
NBS
Ar
CO2Me
N
CO2Me
Br
CO2Me
Ar
Br
CO2Et
aq Na2CO3, DMF
110 °C, 83%
DMF, 90%
ArB(OH)2
Pd(PPh3)4
aq Na2CO3
8
7
CO2Me
N
Ar = p-MeOC6H4
13
Br
Br
CO2Et
+
CO2Me
N
MeOCOCl
Bu4NI, K2CO3
H
N
toluene–EtOH (3:1)
65 °C, 56%
CO2Me
N
Ar
Br
Ar
Br
3
CO2Me
CO2Me
Ar
Ar
CO2Et
DMF, 91%
Ar = p-MeOC6H4
Br
Br
9
10
14
Scheme 4
Scheme 6
With all the desired coupling precursors in hand, efforts
were directed at studying the regioselectivity of these cou-
plings. For ethyl-protected pyrrole ester 2, the first at-
tempt was made using the palladium acetate conditions
which had proven successful for regioselective couplings
of N-ethyl-4,5-dibromopyrrole-2-carboxaldehyde.6a
Much to our surprise, no coupling occurred at all. A brief
survey of other reaction conditions showed that palladium
acetate was ineffective in combination with several differ-
ent bases and solvents.12 Fortunately, with tetrakis(triphe-
nylphosphine)palladium(0), coupling did occur. In
particular, the combination of this catalyst with aqueous
sodium carbonate in a mixture of toluene and ethanol pro-
vided the best results (Scheme 5). The only coupling
product that could be detected was that of coupling at C5,
isolated in 44% yield. The remainder of the material was
recovered 2. Attempts to push this reaction further to com-
pletion by increasing the reaction time, temperature, or
Armed with this interesting result, we applied the same
conditions to 3,4-dibromopyrrole ester 6 (Scheme 7). In
particular, it was felt that even better regioselectivity
might be achieved, since the closer proximity of the elec-
tron-withdrawing ester to the 3-position should lead to
greater electronic differentiation between C3 and C4 than
was present in the 4,5-dibromo compounds.
Rather surprisingly, application of our previously de-
scribed 1H NMR method for predicting the site and order
of coupling in polyhalohetarenes did not support this as-
sumption.14 Indeed, the data obtained for isopropyl pyr-
role-2-carboxylate shows essentially no difference
between the chemical shifts (and thus the electronics) of
C5 and C3, with both appearing at 6.8 ppm.15 Interesting-
ly, the presence of an N-alkoxycarbonyl group does make
these two positions different, with the data reported for
BOC-protected isopropyl pyrrole-2-carboxylate showing
Synthesis 2006, No. 22, 3883–3887 © Thieme Stuttgart · New York

PAPER
Regioselective Couplings of Dibromopyrrole Esters
3885
that the C5 position is more electron-deficient than C3 ther the major product or at least as a significant fraction
(7.25 and 6.85 ppm, respectively).16
of the coupling products (entries 4 and 5).
In the event, coupling of 6 afforded nearly equal amounts One last substrate was also explored: pyrrole ester 9
of C3-monocoupled product 15 and C3,4-dicoupled prod- (Scheme 9). It was expected that these couplings might be
uct 16 (Scheme 7). Thus, it does not appear that proximity a little more challenging, since the pyrrole core is less
aids in improving the selectivity for monocoupling. An- electron-deficient and thus less reactive. Further, the pos-
other issue that may be operational in this particular cou- sibility of competitive dehalogenation at C4 was another
pling is steric hindrance resulting from the presence of the issue.8 As it turned out, dehalogenation was not observed
carboxylate at C2 – a feature not present in the previous in these Suzuki couplings. Indeed, they were highly regio-
substrates.
selective for coupling at C3. Unfortunately, they also
failed to proceed to completion. Even the use of three
equivalents of the boronic acid afforded only 40% of the
coupling product 19 and 58% recovered 9 (Scheme 9). No
traces of double coupling were ever observed, even after
prolonged reaction times.
CO2Me
N
CO2Me
ArB(OH)2
Pd(PPh3)4
aq Na2CO3
CO2Me
N
Br
Ar
Ar
CO2Me
15
+
toluene–EtOH (3:1)
65 °C, 42%
ArB(OH)2
Pd(PPh3)4
aq Na2CO3
Br
Br
CO2Me
N
H
N
H
6
(32% of 16)
N
CO2Me
Ar
Br
Ar
Br
CO2Me
CO2Me
Ar = p-MeOC6H4
benzene–MeOH (3:1)
Ar
Ar
Br
16
19
9
Ar = p-MeOC6H4
Scheme 7
Entry Equiv of
Temp
(°C)
Yield
(9/19)
ArB(OH)2
If one assumes that there is a steric effect at work, then the
C5-arylated substrates should result in a coupling precur-
sor that is more controlled by just electronic effects and
therefore more selective. To that end, compound 10 was
studied (Scheme 8). Under the lower-temperature cou-
pling conditions, the reaction still proceeded well to af-
ford 58% of the monocoupled product 17 as well as 22%
of recovered 10 (Table in Scheme 8, entry 3). Only 12%
of the dicoupled product 18 was observed – much less
than was observed in the coupling of 6. As a result, it does
appear as if steric effects may be responsible for the poor-
er selectivity in the Suzuki coupling of 6. Decreasing the
reaction temperature further did largely eliminate the di-
coupled product, but also lowered the conversion (entries
1 and 2). Curiously, changing the solvent to N,N-dimeth-
ylformamide led to a dramatic increase in the amount of
dicoupling, with the dicoupled product 18 forming as ei-
1
2
3
1.1
1.3
1.3
75
60
65
53:37
73:18
58:40
Scheme 9
In conclusion, regioselectivity is clearly achievable in Su-
zuki couplings of dihalopyrrole-2-carboxylate esters. The
selectivity is always in favor of the more electron-defi-
cient site, as is expected. There is some influence of steric
effects on the selectivity of the reaction as well, as shown
by a comparison of the results for compounds 6 and 10.
Unfortunately, while high regioselectivity can be
achieved, conversions tend to be low. Forcing the reac-
tions to higher conversions generally results in the forma-
tion of more dicoupled product. Efforts are ongoing to
further optimize these reactions and to develop more gen-
eral coupling conditions that will enable clean and high-
yielding monocouplings for all of these systems and better
application to one-pot double couplings and, ultimately,
the lamellarins.
CO2Me
N
Ar
Br
CO2Me
ArB(OH)2
Pd(PPh3)4
aq Na2CO3
CO2Me
N
Ar
Ar
Br
CO2Me
Proton (1H) and carbon (13C) NMR spectra were recorded on Bruker
AM-360 MHz or AM-300 MHz spectrometers as solutions in
CDCl3. Chemical shifts are reported in parts per million. Infrared
(IR) spectra were taken on a Perkin-Elmer Spectrum Bx spectro-
photometer. Reactions were monitored by thin-layer chromatogra-
phy (TLC) with precoated silica gel plates from Sorbent
Technologies. Silica gel (100–200 mesh) was used for all flash col-
umn chromatography. All solvents were reagent grade and used as
received unless stated otherwise. All non-aqueous reactions were
performed under an atmosphere of argon or nitrogen.
17
+
benzene–MeOH (3:1)
Br
CO2Me
N
10
Ar = p-MeOC6H4
Ar
Ar
CO2Me
Entry
Temp
(°C)
Yield
(10/17/18)
Ar
1
2
50
60
65
50
60
44:35:9
38:49:6
22:58:12
62:19:4
27:28:41
18
3
4a
5a
a DMF as the solvent.
2-Ethyl 1-Methyl 4,5-Dibromo-1H-pyrrole-1,2-dicarboxylate
(3)
Scheme 8
To a soln of ester 110 (84.5 mg, 0.285 mmol) in DMF (2.0 mL) was
added sequentially methyl chloroformate (0.11 mL, 1.42 mmol),
Synthesis 2006, No. 22, 3883–3887 © Thieme Stuttgart · New York

3886
S.T. Handy, Y. Zhang
PAPER
K2CO3 (196.6 mg, 1.42 mmol), and Bu4NI (105.1 mg, 0.285 mmol).
The resulting mixture was stirred at r.t. for 10 h. The reaction was
then quenched with H2O (10 mL) and the mixture was extracted
with Et2O (3 × 10 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo.
IR (neat): 2950, 2915, 2847, 1697, 1608, 1574, 1539, 1452, 1439,
1386, 1249, 1208, 1178, 1102, 1054, 1022, 840, 763 cm–1.
1H NMR (360 MHz, CDCl3): d = 7.27 (d, J = 7.2 Hz, 2 H, ArH),
6.99 (d, J = 7.2 Hz, 2 H, ArH), 3.89 (s, 3 H, OMe), 3.85 (s, 3 H,
OMe), 3.73 (s, 3 H, OMe).
Yield: 92.2 mg (91%); white solid; mp 61–63 °C.
1H NMR (360 MHz, CDCl3): d = 6.98 (s, 1 H, ArH), 4.24 (q, J = 7.2
Hz, 2 H, CH2), 3.93 (s, 3 H, OMe), 1.30 (t, J = 5.4 Hz, 3 H, CH3).
13C NMR (90 MHz, CDCl3): d = 160.6, 160.2, 138.4, 131.9, 121.6,
120.9, 114.0, 107.4, 101.6, 55.3, 51.4, 36.3.
HRMS (EI): m/z calcd for C15H13Br2NO5: 444.9273; found:
444.9275.
Dimethyl 3,4-Dibromo-1H-pyrrole-1,2-dicarboxylate (6)
The procedure reported for preparing 3 from 1 was used to prepare
compound 6 from methyl 3,4-dibromopyrrole-2-carboxylate (30
mg, 0.106 mmol).9
Ethyl 4-Bromo-1-ethyl-5-(4-methoxyphenyl)-1H-pyrrole-2-car-
boxylate (11)
To a soln of 2 (50 mg, 0.154 mmol), PMPB(OH)2 (25.7 mg, 0.169
mmol), and Pd(PPh3)4 (3.6 mg, 0.003 mmol) in toluene–EtOH (3:1,
1.3 mL) was added 2 M aq Na2CO3 (0.17 mL). The mixture was
stirred at 95 °C for 20 h. The reaction was then quenched with H2O
(25 mL) and the mixture was extracted with EtOAc (2 × 15 mL).
The combined organic layers were washed with H2O and brine, and
then dried (MgSO4). The solvent was removed in vacuo. The result-
ing residue was chromatographed (silica gel, EtOAc–hexanes, 1:3).
Yield: 31 mg (86%); white solid; mp 58–59 °C.
IR (neat): 3117, 2951, 1704, 1516, 1488, 1431, 1373, 1343, 1244,
1194, 1113, 1068, 956, 820, 759 cm–1.
1H NMR (360 MHz, CDCl3): d = 6.82 (s, 1 H, ArH), 3.88 (s, 3 H,
OMe), 3.87 (s, 3 H, OMe).
13C NMR (90 MHz, CDCl3): d = 160.2 (2 C), 128.0, 127.4, 107.0,
100.1, 51.4, 38.8.
Yield: 23.0 mg (44%); white solid; mp 107–109 °C.
HRMS (EI): m/z calcd for C8H7Br2NO4: 338.8802; found:
338.8800.
IR (neat): 3250, 2990, 2917, 1680, 1610, 1556, 1508, 1470, 1433,
1409, 1311, 1264, 1177, 1136, 1025, 841 cm–1.
1H NMR (360 MHz, CDCl3): d = 7.26 (d, J = 7.2 Hz, 2 H, ArH),
7.05 (s, 1 H, ArH), 7.00 (d, J = 7.2 Hz, 2 H, ArH), 4.22 (m, 4 H,
CH2), 3.86 (s, 3 H, OMe), 1.35 (t, J = 7.2 Hz, 3 H, CH3), 1.18 (t,
J = 5.4 Hz, 3 H, CH3).
13C NMR (90 MHz, CDCl3): d = 160.1, 136.4, 129.1, 127.4, 121.3,
120.8, 114.0, 55.3, 47.2, 37.4, 16.7.
Methyl 3,4-Dibromo-5-(4-methoxyphenyl)-1H-pyrrole-2-car-
boxylate (9)
To a soln of ester 711 (300 mg, 0.99 mmol), PMPB(OH)2 (300 mg,
1.97 mmol), and Pd(PPh3)4 (57.0 mg, 0.049 mmol) in DMF (15 mL)
was added 2 M aq Na2CO3 (1.5 mL). The mixture was stirred at
110 °C for 12 h. The reaction was then quenched with H2O (25 mL)
and the mixture was extracted with EtOAc (3 × 20 mL). The com-
bined organic layers were washed with H2O (20 mL) and brine (20
mL), and then dried (MgSO4). The solvent was removed in vacuo.
The resulting residue was chromatographed (silica gel, EtOAc–hex-
anes, 1:4). This gave arylated ester 8.
HRMS (EI): m/z calcd for C15H16BrNO3: 337.0453; found:
337.0455.
2-Ethyl 1-Methyl 4-Bromo-5-(4-methoxyphenyl)-1H-pyrrole-
1,2-dicarboxylate (13)
Yield: 252 mg (83%).
To a soln of 3 (20 mg, 0.059 mmol), PMPB(OH)2 (9.8 mg, 0.065
mmol), and Pd(PPh3)4 (3.6 mg, 0.003 mmol) in toluene–EtOH (3:1,
0.25 mL) was added 2 M aq Na2CO3 (0.05 mL). The mixture was
stirred at 65 °C for 30 h. The reaction was then quenched with H2O
(25 mL) and the mixture was extracted with EtOAc (2 × 15 mL).
The combined organic layers were washed with H2O (10 mL) and
brine (10 mL), and then dried (MgSO4). The solvent was removed
in vacuo. The resulting residue was chromatographed (silica gel,
EtOAc–hexanes, 1:4); this gave 13 (56%) along with recovered 3
(22%).
1H NMR (360 MHz, CDCl3): d = 9.54 (br s, 1 H, NH), 7.52 (d,
J = 7.2 Hz, 2 H, ArH), 6.93 (m, 3 H, ArH), 6.43 (d, J = 3.6 Hz, 1 H,
ArH), 3.86 (s, 3 H, OMe), 3.82 (s, 3 H, OMe).
To a soln of ester 8 (59.6 mg, 0.258 mmol) in DMF (5 mL) was add-
ed, at 0 °C, NBS (96.4 mg, 0.542 mmol) in portions. The mixture
was allowed to warm to r.t. over 4 h. The reaction was then
quenched with H2O (10 mL) and the mixture was extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed
with H2O (10 mL) and brine (10 mL) and then dried (MgSO4). The
solvent was removed in vacuo; this afforded 9 as a solid.
Yield: 12.1 mg (56%); white solid; mp 111–112 °C.
IR (neat): 2950, 2920, 2845, 1698, 1608, 1575, 1540, 1450, 1439,
1382, 1247, 1201, 1178, 1106, 1053, 841 cm–1.
1H NMR (360 MHz, CDCl3): d = 7.28 (d, J = 7.2 Hz, 2 H, ArH),
7.05 (s, 1 H, ArH), 6.99 (d, J = 7.2 Hz, 2 H, ArH), 4.28 (q, J = 7.2
Hz, 2 H, CH2), 3.85 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 1.35 (t,
J = 7.2 Hz, 3 H, CH3).
Yield: 90.5 mg (90%); mp 92–94 °C.
IR (neat): 3278, 2994, 2919, 1681, 1610, 1555, 1506, 1470, 1432,
1407, 1300, 1267, 1177, 1139, 1026, 837 cm–1.
1H NMR (360 MHz, CDCl3): d = 9.48 (br s, 1 H, NH), 7.59 (d,
J = 7.2 Hz, 2 H, ArH), 6.98 (d, J = 7.2 Hz, 2 H, ArH), 3.89 (s, 3 H,
OMe), 3.85 (s, 3 H, OMe).
13C NMR (90 MHz, CDCl3): d = 160.4, 134.1, 129.2, 129.0, 126.3,
122.6, 119.9, 114.5, 108.1, 100.9, 55.4, 52.1.
13C NMR (90 MHz, CDCl3): d = 160.4, 160.2, 138.4, 130.1, 127.1,
121.6, 120.9, 114.0, 57.6, 55.3, 37.4, 17.2.
HRMS (EI): m/z calcd for C16H16BrNO5: 381.0351; found:
381.0354.
HRMS (EI): m/z calcd for C13H11Br2NO3: 386.9201; found:
386.9200.
Dimethyl 4-Bromo-3-(4-methoxyphenyl)-1H-pyrrole-1,2-dicar-
boxylate (15)
To a soln of 6 (25 mg, 0.106 mmol), PMPB(OH)2 (9.8 mg, 0.065
mmol), and Pd(PPh3)4 (3.6 mg, 0.003 mmol) in toluene–EtOH (3:1,
0.25 mL) was added 2 M aq Na2CO3 (0.05 mL). The mixture was
stirred at 65 °C for 30 h. The reaction was then quenched with H2O
Dimethyl 3,4-Dibromo-5-(4-methoxyphenyl)-1H-pyrrole-1,2-
dicarboxylate (10)
The procedure reported for preparing 3 from 1 was used to prepare
compound 10 from ester 9 (50.0 mg, 0.130 mmol).
Yield: 52.0 mg (91%); white solid; mp 89–91 °C.
Synthesis 2006, No. 22, 3883–3887 © Thieme Stuttgart · New York

PAPER
Regioselective Couplings of Dibromopyrrole Esters
Yield: 8.5 mg (40%); solid; mp 135–136 °C.
3887
(25 mL) and the mixture was extracted with EtOAc (2 × 15 mL).
The combined organic layers were washed with H2O (10 mL) and
brine (10 mL), and then dried (MgSO4). The solvent was removed
in vacuo. The resulting residue was chromatographed (silica gel,
EtOAc–hexanes, 1:3).
IR (neat): 3218, 2917, 2849, 1681 1612, 1468, 1437, 1407, 1249
1179, 1031, 833, 747 cm–1.
1H NMR (360 MHz, CDCl3): d = 9.18 (br s, 1 H, NH), 7.65 (d,
J = 7.2 Hz, 2 H, ArH), 7.36 (d, J = 7.2 Hz, 2 H, ArH), 6.98 (m, 4 H,
ArH), 3.85 (s, 3 H, OMe), 3.84 (s, 3 H, OMe), 3.70 (s, 3 H, OMe).
Yield: 11.3 mg (42%); white solid; mp 97–99 °C.
IR (neat): 2950, 2922, 1694, 1613, 1547, 1509, 1456, 1377, 1290,
1245, 1174, 1106, 1037, 840 cm–1.
1H NMR (360 MHz, CDCl3): d = 7.21 (d, J = 7.2 Hz, 2 H, ArH),
6.91 (d, J = 7.2 Hz, 2 H, ArH), 6.84 (s, 1 H, ArH), 3.87 (s, 3 H,
OMe), 3.83 (s, 3 H, OMe), 3.58 (s, 3 H, OMe).
13C NMR (90 MHz, CDCl3): d = 161.2, 159.3, 133.4, 131.9, 129.2,
125.6, 123.3, 118.4, 114.5, 113.7, 113.3, 113.0, 55.6, 55.3, 51.7.
HRMS (EI): m/z calcd for C20H18BrNO4: 415.0566; found:
415.0566.
13C NMR (90 MHz, CDCl3): d = 161.8, 160.1, 137.3, 131.5, 130.4,
128.0, 127.4, 122.4, 108.1, 99.8, 55.1, 51.4, 38.8.
Acknowledgement
HRMS (EI): m/z calcd for C15H14BrNO5: 367.0177; found:
367.0176.
The author thanks the Research Foundation, the Leukemia Research
Foundation, and Middle Tennessee State University for financial
support of this research.
Dimethyl 4-Bromo-3,5-bis(4-methoxyphenyl)-1H-pyrrole-1,2-
dicarboxylate (17)
References
To a soln of 10 (20 mg, 0.045 mmol), PMPB(OH)2 (8.2 mg, 0.054
mmol), and Pd(PPh3)4 (2.6 mg, 0.002 mmol) in benzene–MeOH
(3:1, 0.20 mL) was added 2 M aq Na2CO3 (0.10 mL). The mixture
was stirred at 65 °C for 30 h. The reaction was then quenched with
H2O (25 mL) and the mixture was extracted with EtOAc (2 × 15
mL). The combined organic layers were washed with H2O (10 mL)
and brine (10 mL), and then dried (MgSO4). The solvent was re-
moved in vacuo. The resulting residue was chromatographed (silica
gel, EtOAc–hexanes, 1:3).
(1) Current address: Department of Chemistry, Middle
Tennessee State University, Murfreesboro, TN 37132, USA.
(2) Handy, S. T.; Zhang, Y. Org. Prep. Proced. Int. 2005, 37,
411.
(3) Handy, S. T.; Zhang, Y.; Bregman, H. J. Org. Chem. 2004,
69, 2362.
(4) Hodge, P.; Richard, R. J. Chem. Soc. 1965, 459.
(5) For a review, see: Schröter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245.
Yield: 12.2 mg (58%); white solid; mp 120–122 °C.
(6) Recently, two reports of regioselective couplings of pyrroles
have appeared: (a) Handy, S. T.; Sabatini, J. J. Org. Lett.
2006, 8, 1537. (b) Schröter, S.; Bach, T. Synlett 2005, 1957.
(7) The one remaining isomeric dibromopyrrole ester (3,5-
dibromo) has also been prepared. The regioselectivity of the
Suzuki couplings of this substrate exhibit an unusual solvent
dependency that remains under investigation.
(8) Handy, S. T.; Bregman, H.; Lewis, J.; Zhang, Y.
Tetrahedron Lett. 2003, 44, 427.
(9) Bray, B.; Mathies, P.; Naef, R.; Solas, D.; Tidwell, T.; Artis,
D.; Muchowski, J. J. Org. Chem. 1990, 55, 6317.
(10) Handy, S. T.; Sabatini, J. J.; Zhang, Y.; Vulfova, I.
Tetrahedron Lett. 2004, 45, 5057.
IR (neat): 2952, 1699, 1611, 1547, 1507, 1453, 1375, 1290, 1247,
1176, 1106, 1031, 839 cm–1.
1H NMR (360 MHz, CDCl3): d = 7.36 (d, J = 7.2 Hz, 2 H, ArH),
7.28 (d, J = 7.2 Hz, 2 H, ArH), 7.01 (d, J = 7.2 Hz, 2 H, ArH), 6.93
(d, J = 7.2 Hz, 2 H, ArH), 6.84 (s, 1 H, ArH), 3.86 (s, 3 H, OMe),
3.85 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 3.59 (s, 3 H, OMe).
13C NMR (90 MHz, CDCl3): d = 161.812, 158.6, 137.7, 132.0,
131.7, 130.6, 130.3, 129.9, 127.9, 126.9, 122.3, 114.0, 113.0, 99.4,
55.2, 55.0, 50.9, 38.6.
HRMS (EI): m/z calcd for C22H20BrNO5: 433.0699; found:
433.0701.
(11) Rawal, V. H.; Jones, R. J.; Cava, M. P. J. Org. Chem. 1987,
51, 19.
(12) Bases tried include the following: Na2CO3, K2CO3, Cs2CO3,
K3PO4, and Ba(OH)2. Solvents tried include the following:
DMF, EtOH–toluene, acetone, and H2O.
(13) Fauvarque, J.-F.; Pfleuger, F.; Troupel, M. J. Organomet.
Chem. 1981, 208, 419.
(14) Handy, S. T.; Zhang, Y. Chem. Commun. 2006, 299.
(15) Harbuck, J. W.; Rapoport, H. J. Org. Chem. 1972, 37, 3618.
(16) Donohoe, T. J.; Guyo, P. M.; Beddoes, R. L.; Helliwell, M.
J. Chem. Soc., Perkin Trans. 1 1998, 667.
Methyl 4-Bromo-3,5-bis(4-methoxyphenyl)-1H-pyrrole-2-car-
boxylate (19)
To a soln of 9 (20 mg, 0.051 mmol), PMPB(OH)2 (10.2 mg, 0.067
mmol), and Pd(PPh3)4 (3.0 mg, 0.0026 mmol) in benzene–MeOH
(0.20 mL, 3:1) was added 2 M aq Na2CO3 (0.10 mL). The mixture
was stirred at 65 °C for 12 h. The reaction was then quenched with
H2O (5 mL) and the mixture was extracted with EtOAc (3 × 5 mL).
The combined organic layers were washed with H2O (5 mL) and
brine (5 mL), and then dried (MgSO4). The solvent was removed in
vacuo. The resulting residue was chromatographed (silica gel,
EtOAc–hexanes, 1:4).
Synthesis 2006, No. 22, 3883–3887 © Thieme Stuttgart · New York