Facile synthesis of N-aryl pyrroles via Cu(II)-mediated cross coupling of electron deficient pyrroles and arylboronic acids

Article abstract of DOI:10.1021/jo016131f

N-arylation of electron-deficient pyrroles has been achieved by cross-coupling with arylboronic acids at room temperature in the presence of stoichiometric amounts of copper(II) acetate. The generality of this reaction has been established with variously substituted pyrroles as well as boronic acids. A key intermediate in the synthesis of a matrix metalloprotease inhibitor has been acheived using this methodology.

Full text of DOI:10.1021/jo016131f

J . Org. Chem. 2002, 67, 1699-1702
1699
as well as their benzofused counterparts) and function-
alized arenes that included the Cu(II)-mediated coupling
of azoles and arylboronic acids,4a,4b arylsiloxanes,5 and
arylstannanes6 developed by Lam et al., arylbismuths,7
and aryllead,8 there were only limited reports on the
coupling of pyrroles and aryl halides, all at elevated
temperature.2e,3c,d Buchwald described in a recent account
the coupling of 3,5-dimethylphenyl iodide and pyrrole by
heating a mixture of the two in dioxane at 110 °C in the
presence of CuI.2e Hartwig also observed the palladium-
mediated coupling of unsubstituted pyrrole and aryl
halide, under the optimal conditions that normally
worked well on amines.3c,3d Lam et al.4a reported that the
coupling of pyrroles and indoles with arylboronic acids
gave very little (<3%) desired product. As such, we
postulated that since the azoles employed in the coupling
reactions are more electron deficient than pyrrole, elec-
tron deficient pyrroles, a priori, ought to exhibit reac-
tivities in the coupling reactions similar to azoles. To test
this idea, the protocol employed by Lam et al. to couple
azoles and arylboronic acids (vide infra) was chosen based
on its mild conditions and ready availability of starting
materials as well as its minimal cost.4a
To our delight, when a mixture of ethyl 5-formylpyr-
role-3-glyoxalate 39 (1.0 equiv), 4-bromophenylboronic
acid (2.0 equiv), Cu(OAc)2 (1.5 equiv), and pyridine (2.0
equiv) in methylene chloride (5 mL) was stirred at room-
temperature open to air for 2 days, all the pyrrole was
consumed and the desired coupling product was isolated
in almost quantitative yield. Encouraged by this facile
union, a systematic study was conducted to investigate
the generality of this coupling reaction, as well as the
scope and limitations.
F a cile Syn th esis of N-Ar yl P yr r oles via
Cu (II)-Med ia ted Cr oss Cou p lin g of Electr on
Deficien t P yr r oles a n d Ar ylbor on ic Acid s
Shu Yu, J ames Saenz, and J ayaram K. Srirangam*
Chemical Research and Development,
Pfizer Global Research & Development-La J olla,
3565 General Atomics Court, San Diego, California 92121
jay.srirangam@pfizer.com
Received September 20, 2001
Abstr a ct: N-Arylation of electron-deficient pyrroles has
been achieved by cross-coupling with arylboronic acids at
room temperature in the presence of stoichiometric amounts
of copper(II) acetate. The generality of this reaction has been
established with variously substituted pyrroles as well as
boronic acids. A key intermediate in the synthesis of a matrix
metalloprotease inhibitor has been acheived using this
methodology.
AG3433 (1) is a potent inhibitor of matrix metallopro-
teases (MMPs) currently undergoing preclinical evalua-
tion.1 During the course of the chemical development of
this antiangiogenic drug, an easy entry into an N-
arylpyrrole (2), a key intermediate in the synthesis of
AG3433 was required. Of the several routes, the discon-
nection of the C-N bond between the pyrrole nitrogen
atom and the biphenyl moiety, was among the most
convergent and very appealing. In the synthetic direction,
it required the formation of the C-N bond between the
nitrogen atom on an electron deficient pyrrole and a
properly functionalized arene.
Since electronic effects are expected to play a major
role in such coupling reactions, a study of the reaction
with variously substituted pyrroles as well as boronic
acids was undertaken. As indicated in Tables 1 and 2,
for the boronic acid part, electron-releasing groups
facilitated the coupling reaction when holding the pyrrole
(3) (a) Hartwig, J . F. Angew. Chem., Int. Ed. 1998, 37, 2047-2067.
(b) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1998, 120, 7369-
7370. (c) Mann, G.; Hartwig, J . F.; Driver, M. S.; Fernandez-Rivas, C.
J . Am. Chem. Soc. 1998, 120, 827-828. (d) Hartwig, J . F.; Kawatsura,
M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J . Org.
Chem. 1999, 64, 5575-5580. (e) Alcazar-Roman, L. M.; Hartwig, J .
F.; Rheingold, A. L.; Liable-Sands, L. M.; Guzei, I. A. J . Am. Chem.
Soc. 2000, 122, 4618-4630. (f) Lee, S.; J ørgensen, M.; Hartwig, J . F.
Org. Lett. 2001, 3, 2729-2732.
(4) (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J .; Winters,
M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-
2944. (b) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933-2936. (c) Collman, J . P.; Zhong, M.
Org. Lett. 2000, 2, 1233-1236. (d) Collman, J . P.; Zhong, M.; Zeng, L.;
Costanzo, S. J . Org. Chem. 2001, 66, 1528-1531. (e) Lam, P. Y. S.;
Vincent, G.; Clark, C. G.; Deudon, S.; J adhav, P. K. Tetrahedron Lett.
2001, 42, 3415-3418.
(5) (a) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.;
DeShong, P.; Clark, C. G. J . Am. Chem. Soc. 2000, 122, 7600-7601.
(b) Lam, P. Y. S.; Deuton, S.; Hauptman, E.; Clark, C. G. Tetrahedron
Lett. 2001, 42, 2427-2429.
(6) (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J .; Averill,
K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674-676.
(7) (a) Arnauld, T.; Barton, D. H. R.; Doris, E. Tetrahedron 1997,
53, 4137-4144. (b) Cundy, D. J .; Forsyth, S. A. Tetrahedron Lett. 1998,
39, 7979-7982.
C-N cross-coupling of aryl halides with amines has
been the subject of studies in recent years.2,3,4b,6 Although
there existed ample precedence of the transition metal
promoted cross-coupling of azoles (imidazoles, pyrazoles
(1) Deal, J . G.; Bender, S. L.; Chong, W. K. M.; Duvadie, R. K.;
Caldwell, A. M.; Li, L.; McTigue, M. A.; Wickersham, J . A.; Appelt, K.;
Almassy, R. J .; Shalinsky, D. R.; Daniels, R. G.; McDermott, C. R.;
Brekken, J .; Margosiak, S. A.; Kumpf, R. A.; Abreo, M. A.; Burke, B.
J .; Register, J . A.; Dagostino, E. F.; Vanderpool, D. L.; Santos, O.
Presented at the 217th National Meeting of the American Chemical
Society, Anaheim, CA, March 21-25, 1999, MEDI-197.
(2) (a) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 2000, 65, 1144-
1157. (b) Wolfe, J . P.; Tomori, H.; Sadighi, J . P.; Yin, J .; Buchwald, S.
L. J . Org. Chem. 2000, 65, 1158-1174. (c) Harris, M. C.; Buchwald,
S. L. J . Org. Chem. 2000, 65, 5327-5333. (d) Old, D. W.; Harris, M.
C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403-1406. (e) Klapars, A.;
Antilla, J . C.; Huang, X.; Buchwald, S. L. J . Am. Chem. Soc. 2001,
123, 7727-7729. (f) Antilla, J . C.; Buchwald, S. L. Org. Lett. 2001, 3,
2077-2079.
(8) (a) Elliott, G. I.; Konopelski, J . P. Org. Lett. 2000, 2 (20), 3055-
3057. (b) Lopez-Alvarado, P.; Avendano, C.; Menendez, J . C. J . Org.
Chem. 1995, 60, 5678-5682.
(9) Demopoulos, B. J .; Anderson, H. J .; Loader, C. E.; Faber, K. Can.
J . Chem. 1983, 61, 2415-2422.
10.1021/jo016131f CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/02/2002

1700 J . Org. Chem., Vol. 67, No. 5, 2002
Notes
Ta ble 2. Cu (OAc)2-Med ia ted Cr oss-Cou p lin g of
Ta ble 1. Cu (OAc)2-Med ia ted Cr oss-Cou p lin g of
Ar ylbor on ic Acid a n d Eth yl 5-F or m ylp yr r ole-3-
glyoxa la te 3
Ar ylbor on ic Acid s a n d 2-Acetylp yr r ole
releasing groups (4-methoxy, 4-benzyloxy, and 4-dim-
ethylamino) and weak electron-withdrawing substituents
(4-iodo and 4-bromo) reacted smoothly with excellent
yields (entries 1-5). In contrast, the boronic acids with
strong electron-withdrawing substituents such as 4-acetyl
or 4-cyano group, reacted very sluggishly. The coupling
between 2-acetylpyrrole and 4-acetylbenzene boronic acid
took 7 days, while the coupling of 4-cyanophenylboronic
acid was even slower. For reasons not clear, heterocyclic
boronic acids did not couple with electron-deficient pyr-
roles very well. Among 3-pyridylboronic acid, 3-thienyl-
boronic acid, and 2-furanylboronic acid, only 3-thienyl-
boronic acid coupled with 5-formylpyrrole-3-glyoxalate (3)
in moderate yield (4 days, 44%), the other two did not
yield any coupled product even after prolonged reaction
time (14 days).
When holding the arylboronic acid part constant, as
4-methoxy or 4-bromo, and varying the pyrrole portion,
it could be concluded that the 2-substitution had a much
more profound effect on the reactivity of pyrroles than
the 3-substitution, as indicated in Tables 2 and 3. While
the reactions of 4-methoxy- and 4-bromophenylboronic
acids with 2-acetylpyrrole was complete in a couple of
days (entries 1 and 5 in Table 2), their reactions with
ethyl pyrrole-3-glyoxalate were incomplete even after
prolonged reaction time (entries 1 and 2 in Table 3).
Considering that the difference in electron-withdrawing
abilities between the acetyl group and ethoxyglyoxalyl
group is minimal, the aforementioned stronger 2-substi-
tution effect might in part be attributed to the chelation
of carbonyl oxygen to the pyrrole nitrogen-Cu complex.
When the 2- and 3- positions were both occupied by
electron-withdrawing groups, the reaction occurred with
the most ease (Table 1). Here even the 4-acetyl- and
4-(trifluoromethyl)phenylboronic acids reacted smoothly.
No coupling was observed with pyrrole itself, even with
4-methoxyphenylboronic acid.
a
This was an estimate yield based on proton NMR and HPLC.
After chromatography, 125 mg (64%) of the starting material (3)
was isolated; the desired product 5b was isolated with an
inseparable impurity. Together they constituted 68 mg (22%) of
the mass. b Balanced with 43% recovered pyrrole starting material
(3). c Balanced with 54% recovered pyrrole starting material (3).
moiety constant. While 4-methoxy-, 4-methyl-, 4-iodo-,
and 4-bromophenylboronic acids (entries 1, 4, 6, and 7
in Table 1) were completely consumed within 2 days, it
took 4-acetyl boronic acid 8 days to complete (see entry
9 in Table 1). A similar trend was observed with
2-acetylpyrrole (Table 2). Boronic acids with electron

Notes
J . Org. Chem., Vol. 67, No. 5, 2002 1701
Ta ble 3. Cu (OAc)2-Med ia ted Cr oss-Cou p lin g of Ar ylbor on ic Acid a n d Eth yl P yr r ole-3-glyoxa la te
Sch em e 1. Syn th esis of In ter m ed ia te 2
A large variety of functional groups survived in these
Extending the reaction time did not seem to help (entry
5 in Table 1).
coupling processes, including nitro, ether, ester, ketone,
aldehyde, amide, bromo, and iodo groups. The results
demonstrate this coupling process as a highly specific
transformation with no significant complications caused
by other reaction pathways, such as, Ullmann coupling
reactions. Survival of the aryliodide functionality, con-
sidering that copper at all oxidation states was available
in the reaction vessel, is remarkable. In addition, since
many of the functional groups in Tables 1 and 2, such as
iodo, bromo, benzyloxy, amide, aldehyde, ketone, etc., are
eligible for further elaboration, this coupling reaction
should be of general use in N-arylpyrrole synthesis.
A detailed mechanistic study is beyond the scope of this
investigation. A plausible mechanism can be that the
deprotonated pyrrole coordinates with Cu(II) first, fol-
lowed by transmetalation. In the presence of air, this
species could be oxidized to Cu(III) which readily go
through reductive elimination to afford the N-arylpyrrole.
It appears that the proposed mechanism agreed with the
structure reactivity studies.
Returning to where this study began, this technology
was successfully applied to the synthesis of compound
2, which is a pivotal intermediate in the synthesis of the
MMP inhibitor AG3433 (vide supra). As indicated in
Scheme 1, boronic acid 11 was prepared in excellent yield
from the corresponding bromide 10, which is com-
mercially available. The coupling of this boronic acid and
pyrrole 3 was uneventful. The electron-deficient pyrrole
3 was completely consumed in 3 days and afforded
compound 2 in 93% yield.
It appeared that the coupling reactions were also
sensitive to steric hindrance. The phenyl boronic acids
with ortho substitutions reacted sluggishly, in sharp
contrast to the corresponding boronic acids with para
substitutions. For example, the coupling of ethyl 5-formyl-
pyrrole-3-glyoxalate and p-methoxyphenylboronic acid
took 2 days and afforded the corresponding N-(p-meth-
oxyphenyl)pyrrole in 95% yield (entry 1 in Table 1).
Under identical reaction conditions, o-methoxyphenyl-
boronic acid gave only a meager 14% yield (entry 2 in
Table 1). A similar trend was observed with p-tolylboronic
acid and o-tolylboronic acid (entries 4 and 5 in Table 1).
In summary, N-arylpyrroles can be prepared from
arylboronic acids and electron-deficient pyrroles via a
Cu(OAc)2-mediated coupling reaction at room tempera-
ture in air. These reaction conditions are compatible with
a variety of functional groups. This coupling reaction

1702 J . Org. Chem., Vol. 67, No. 5, 2002
Notes
The mixture was thoroughly degassed by alternately connecting
the flask to vacuum and nitrogen. This red solution was then
heated at 80 °C for 18 h at which time it was observed that all
the bromide was consumed (HPLC). The solvent was removed
by Kugelrohr distillation. The residue was preadsorbed onto
silica gel and was subjected to flash chromatography using
hexanes/EtOAc (6:1 f 2:1) to afford 2.78 g (91%) of the desired
works the best on electron-rich boronic acids and is
sensitive to steric hindrance. Although intrinsically
cheap, this methodology does require stoichiometric
amounts of Cu(OAc)2 to mediate the coupling reaction.
Exp er im en ta l Section
1
product as a white solid: mp 190.5-191.5 °C; H NMR δ 1.41
1
All melting points are uncorrected. H and 13C NMR spectra
(s, 12H), 7.63 (d, J ) 8.1 Hz, 2H), 7.65-7.80 (m, 4H), 7.96 (d, J
) 8.1 Hz, 2H); 13C NMR δ 25.3, 83.9, 111.1, 118.8, 126.4, 127.7,
132.5, 135.4, 141.6, 145.4; FTIR (NaCl) 1331, 1366, 1462, 1605,
were recorded on Bruker 300 and 75.5 MHz instruments,
respectively, using CDCl3 as the solvent. Electron spray low-
resolution spectra were determined at an ionizing voltage of 70
eV. Methylene chloride was used as received. Column chroma-
tography was carried out on Universal silica gel (32-63 µm)
using the indicated solvents as eluents. HRMS data were
determined on Micromass Q-Tof-2 mass spectrometer. Ethyl
pyrrole-3-glyoxalate and ethyl 5-formylpyrrole-3-glyoxalate were
prepared according to literature procedure.9
2226 cm-1; MS (ES) m/z 306.1 (M + 1). Anal. Calcd for C19H20
-
NO2B: C, 74.78; H, 6.61; N, 4.59. Found: C, 74.72; H, 6.64; N,
4.59.
To a solution of 2.38 g (7.80 mmol) of the above boronate in
80 mL of acetone were added at room temperature 5.06 g (23.6
mmol) of NaIO4, 1.34 g (17.4 mmol) of NH4OAc, and 80 mL of
water. The thick suspension was allowed to stir at room
temperature for 18 h at which time all the boronate was
consumed (TLC). Acetone was removed in vacuo, and the
aqueous solution was basified with 80 mL of 2 M NaOH. The
aqueous solution was washed once with CH2Cl2 (discarded). This
aqueous solution was acidified with concentrated HCl to pH )
3 and chilled in ice bath for 2 h. The precipitate was filtered,
washed with water, and air-dried. The off white solid was
purified by flash chromatography using hexanes/THF (1:1) to
give 1.58 g (91%) of the desired boronic acid as a white solid:
mp 230-233 °C; 1H NMR (300 MHz, THF-d8) δ 7.65 (d, J ) 8.4
Hz, 2H), 7.65-7.80 (dd, J ) 8.4 and 8.4 Hz, 4H), 7.90 (d, J )
8.4 Hz, 2H); 13C NMR (75.5 MHz, THF-d8) δ 107.6, 114.5, 121.3,
122.2, 123.8, 128.7, 131.0, 136.7, 141.6; FTIR (NaCl) 1333, 1377,
1462, 1603, 2224 cm-1. Anal. Calcd for C13H10NO2B: C, 70.01;
H, 4.52; N, 6.28. Found: C, 70.08; H, 4.76; N, 6.06.
Eth yl N-(4′-Cya n obip h en yl-4-yl)-5-for m ylp yr r ole-3-gly-
oxa la te (2). This compound was prepared according to the
general procedure. The pyrrole starting material was completely
consumed after 3 days. After workup and purification a total of
347 mg (93%) of the arylpyrrole was isolated as a yellowish
solid: mp 159-161 °C; 1H NMR δ 1.47 (t, J ) 7.2 Hz, 3H), 4.47
(q, J ) 7.2 Hz, 2H), 7.53 (d, J ) 8.7 Hz, 2H), 7.70-7.85 (m, 7H),
8.13 (dd, J ) 1.5 and 0.9 Hz, 1H), 9.73 (d, J ) 0.6 Hz, 1H); 13C
NMR δ 14.0, 62.6, 111.7, 116.0, 118.6, 122.4, 124.6, 126.4, 127.8,
132.7, 133.2, 136.9, 138.1, 140.1, 144.0, 161.7, 177.6, 179.2; FTIR
(NaCl) 1377, 1462, 1537, 1682, 1721, 2228 cm-1; MS (ES) m/z
373.1 (M + 1), 299.0; Anal. Calcd for C22H16N2O4: C, 70.96; H,
4.33; N, 7.52. Found: C, 71.26; H, 4.37; N, 7.33.
Gen er a l P r oced u r e for th e Cu (OAc)2-Med ia ted Cou -
p lin g of P yr r oles a n d Ar ylbor on ic Acid s. To a 25 mL one-
neck round-bottom flask fitted with a magnetic stirring bar was
added 1.00 mmol of the pyrrole, 1.50 mmol of Cu(OAc)2, 2.00
mmol of the boronic acid, and 2.00 mmol of pyridine in that
order, followed by 5.0 mL of methylene chloride. The flask was
fitted with a male gas inlet (CHEMGLASS CG-1014-14;10 used
to reduce the evaporation of the solvent), and the dark blue
mixture was allow to stir at room-temperature open to air.
Note: the reactions will not proceed to completion in the absence
of air. The reaction was followed with TLC until all the pyrrole
was consumed. The mixture was then poured into 25 mL of
water and extracted with ethyl acetate (25 mL × 3). The
combined organic layer was washed with water, brine, and dried
over MgSO4, and the solvent was removed in vacuo. The residue
was preadsorbed onto silica gel and subjected to gradient flash
chromatography using hexanes and ethyl acetate (6:1 to 1:1) to
afford the desired N-arylpyrroles. Thus, the reaction of ethyl
5-formylpyrrole-3-glyoxalate (3, 195 mg, 1 mM) and p-methox-
yphenylboronic acid (304 mg, 2mM) in methylene chloride
afforded, after purification, eth yl N-(p-m eth oxyp h en yl)-5-
for m ylp yr r ole-3-glyoxa la te (5a , 285 mg, 95%); mp 96-97 °C;
1H NMR δ 1.42 (t, J ) 7.2 Hz, 3H), 3.87 (s, 3H), 4.40 (q, J ) 7.2
Hz, 2H), 6.99 (dd, J ) 6.6 and 2.1 Hz, 2H), 7.30 (dd, J ) 6.9 and
2.4 Hz, 2H), 7.70 (d, J ) 1.5 Hz, 1H), 7.99 (d, J ) 1.2 Hz, 1H),
9.62 (s, 1H); 13C NMR δ 13.9, 55.4, 62.4, 114.3, 121.8, 122.7,
126.9, 130.4, 133.4, 136.7, 159.9, 161.8, 177.7, 179.3; FTIR (NaCl)
1256, 1375, 1464, 1514, 1676, 1719 cm-1; MS (ES) m/z 302.1 (M
+ 1), 228.0. Anal. Calcd for C16H15NO5: C, 63.78; H, 5.02; N,
4.65. Found: C, 63.95; H, 5.07; N, 4.62.
Ack n ow led gm en t. The authors wish to thank Drs.
Kim Albizati, Victor Snieckus, and Mike Deason for
their valuable suggestions and help with the manuscript
and Dr. Matt Renner for the HRMS data.
4′-Cya n o-4-bip h en ylbor on ic Acid (17). 4′-(4,4,5,5-Tetr a -
m eth yl-1,3,2-dioxabor olan -2-yl)-biph en yl-4-car bon itr ile. To
a 250 mL round-bottom flask charged with 2.79 g (11.0 mmol)
of bis(pinacolato)diboron, 2.94 g (30.0 mmol) of KOAc, and 245
mg (0.30 mmol) of Pd(dppf)Cl2 was added a solution of 2.58 g
(10.0 mmol) of 4-bromo-4′-cyanobiphenyl in 60 mL of DMSO.
Su p p or tin g In for m a tion Ava ila ble: Preparation and full
characterization of compounds in Tables 1-3. This material
is available free of charge via the Internet at http://pubs.acs.org.
(10) CHEMGLASS Catalog 2000, p 5.
J O016131F