Palladium-catalyzed N-arylation of 3-functionalized 2-amino-4,5- dimethylpyrroles

Article abstract of DOI:10.1080/00397911.2010.492073

A versatile class of 2-aminopyrroles containing various electron-withdrawing substituents at the 3-position have been N-arylated on the amine using a palladiumcatalyzed cross-coupling reaction. Using this methodology, a pyrimidone-based tricyclic system has been prepared in just one step from a starting 2-aminopyrrole.

Full text of DOI:10.1080/00397911.2010.492073

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Palladium-Catalyzed N-Arylation
of 3-Functionalized 2-Amino-4,5-
dimethylpyrroles
Carlos P. Griswold a , Nisaraporn Suthiwangcharoen a , Steven M.
Pochini a & Chad E. Stephens a
a Department of Chemistry and Physics , Augusta State University ,
Augusta , Georgia , USA
Published online: 20 Apr 2011.
To cite this article: Carlos P. Griswold , Nisaraporn Suthiwangcharoen , Steven M. Pochini & Chad E.
Stephens (2011) Palladium-Catalyzed N-Arylation of 3-Functionalized 2-Amino-4,5-dimethylpyrroles,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:11, 1672-1681, DOI: 10.1080/00397911.2010.492073
To link to this article: http://dx.doi.org/10.1080/00397911.2010.492073
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Synthetic Communications1, 41: 1672–1681, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.492073
PALLADIUM-CATALYZED N-ARYLATION OF
3-FUNCTIONALIZED 2-AMINO-4,5-
DIMETHYLPYRROLES
Carlos P. Griswold, Nisaraporn Suthiwangcharoen,
Steven M. Pochini, and Chad E. Stephens
Department of Chemistry and Physics, Augusta State University,
Augusta, Georgia, USA
GRAPHICAL ABSTRACT
Abstract A versatile class of 2-aminopyrroles containing various electron-withdrawing
substituents at the 3-position have been N-arylated on the amine using a palladium-
catalyzed cross-coupling reaction. Using this methodology, a pyrimidone-based tricyclic
system has been prepared in just one step from a starting 2-aminopyrrole.
Keywords 2-Aminopyrrole; DPEphos; N-arylation; palladium-catalyzed; pyrrolo[2,3-d]
pyrido[1,2-a]pyrimidine; xantphos
INTRODUCTION
2-Amino-4,5-dimethylpyrroles (1) containing various functional groups at the
3-position are readily prepared by a one-pot reaction that involves condensation of
acetoin with a primary amine, followed by reaction of the intermediate a-aminoke-
tone with a functionalized acetonitrile.[1–3] Possible substituents at the 3-position of
these pyrroles include CN, CO2R, SO2R, and others. Because a substituted amine
must be used in the synthesis or else a pyrazine is obtained, the 1-position of the
pyrrole is typically substituted with either an alkyl or aryl group (Fig. 1).
These 2-aminopyrroles have served as building blocks to various bicyclic ring
systems. Examples include pyrrolo[1,2-a]pyrimidines,[4] pyrrolo[2,3-d]pyrimidines,[5]
pyrrolo[2,3-b]pyridines,[6] pyrrolo[2,3-d][1,3]oxazines,[7] pyrrolo[3,2-b][1,4]thia-
zines,[8] pyrrolo[2,3-e][1,3,4]thiadiazines,[9] and others.[10] These pyrroles have also
served as precursors to 5-hydroxy-2-aminoindoles.[11] Some of these fused-ring
derivatives possess interesting biological activity.[5,11]
Received December 8, 2009.
Address correspondence to Chad E. Stephens, Department of Chemistry and Physics, Augusta
State University, Augusta, GA 30904, USA. E-mail: cstephe7@aug.edu
1672

PALLADIUM-CATALYZED N-ARYLATION
1673
Figure 1. Structure of 2-amino-4,5-dimethypyrroles 1.
The transition metal–catalyzed N-arylation of amines has been a highly active
area of research in the past decade, with palladium-catalyzed reactions receiving a
large focus.[12,13] To date, however, there has been no report of N-arylation chemis-
try with the title 2-aminopyrroles. The development of a transition metal–catalyzed
N-arylation method would thus expand the scope of chemistry that is possible with
these compounds and would also allow for construction of novel types of fused-ring
systems. Herein, we present the first N-arylations of pyrroles 1. We also illustrate the
use of this N-arylation chemistry for the construction of a pyrimidine-based tricyclic
system in just one step from a starting 2-aminopyrrole.
RESULTS AND DISCUSSION
As a model reaction, we first explored the N-arylation of 3-(phenylsulfonyl)-
pyrrole 1a with 4-bromobenzaldehyde to give product 6a (Table 1). We initially
chose to use Pd2dba3 as a palladium(0) catalyst and xantphos as a bidentate ligand.
This catalyst–ligand system has been used previously for the N-arylation of
amines,[14,15] as well as for other nitrogen-containing functional groups.[16–18] As
Table 1. Yield data for model N-arylation reaction
Entry
Ligand
Base
Solvent
Yielda (%)
1
2
3
4
5
6
7
Xantphos
DPEphos
X-phos
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
DME
37
37
33
Xantphos
Xantphos
Xantphos
Xantphos
11
CsOAc
Cs2CO3
Cs2CO3
Traceb
Traceb
Traceb
Toluene
aIsolated yield of pure product after column chromatography.
bBased on TLC comparison to an authentic sample.

1674
C. P. GRISWOLD ET AL.
shown in Table 1, use of this catalyst system (1.5 mol% Pd2dba3, 3 mol% xantphos),
along with Cs2CO3 (1.4 eq.) as base and 1,4-dioxane as solvent (entry 1), gave
N-arylated product 6a in 37% purified yield after heating at 100 ꢀC overnight
(18 h). The use of DPEphos, another bidentate ligand,[19] or X-phos, a sterically
hindered monodentate ligand,[20] afforded no improvement in yield compared to
xantphos (entries 2 and 3). The use of K3PO4 as base (entry 4) gave a much lesser
yield compared to Cs2CO3, whereas the use of the weaker base CsOAc (entry 5) gave
only a trace of product. Similarly, only a trace of product was formed when either
DME (dimethoxyethane) or toluene were used as solvent in place of 1,4-dioxane
(entries 6 and 7). Ultimately, our best yield of 37% (entry 1) was considered reason-
able given that the starting pyrrole was consumed in the reaction and that a signifi-
cant amount of darkening typically occurred in all reactions (an indication of
decomposition). The yield is also reasonable considering that these amines are
known to have much reduced nucleophilicity, likely due to their substantial enamine
character[3] and the steric hindrance of the two substituents at the 1- and 3-positions
of the pyrrole.
With a working procedure in hand [Pd2dba3 (2 mol%), xantphos (4.5 mol%),
Cs2CO3, 1,4-dioxane: conditions A], we further explored the scope of this chemistry
by reacting a variety of 2-aminopyrroles with different aryl bromides (Table 2). The
starting pyrroles were substituted at the 3-position with either a sulfone (phenyl or
methyl), ethyl ester, or a cyano group. In each case, the alkyl group on the nitrogen
of the pyrrole was benzyl. The benzyl group can be subsequently removed from the
pyrrole in some cases (see Ref. 5). Substituents on the aryl bromides employed were
electron withdrawing, electron donating, or simply hydrogen.
As shown in Table 2, we were able to readily N-arylate the various 2-aminopyr-
roles with aryl bromides containing different electron-withdrawing groups. Yields
when using such activated aryl bromides ranged from 37 to 86% yield (entries
1–11), with the yield for our model reaction (entry 1) ultimately being the lowest.
In contrast to-these good results, when using bromobenzene or aryl bromides con-
taining electron-donating groups such as 4-bromotoluene or 4-bromoanisole, the
coupling reaction was more sluggish and generally gave only trace amounts of pro-
duct when using conditions A. A single exception was the coupling of the 3-cyano
pyrrole with bromobenzene, which gave a reasonable yield of 37% when using our
original conditions (entry 12). This favorable result may be due to the low steric
demand of the cyano group at the 3-position compared to the other functional
groups, such as the ester or sulfonyl.
Ultimately, we were able to obtain reasonable yields for couplings with bromo-
benzene simply by doubling the amount of palladium catalyst and ligand (conditions
B, entries 13–16). The use of additional catalyst led to an increase in yield for the
coupling of the 3-cyano pyrrole with bromobenzene from 37% to 60% (compare
entries 12 and 13). It also allowed for coupling of the 3-methylsulfonyl pyrrole with
4-bromotoluene in reasonable yield (22%, entry 17). However, other attempted
couplings with substrates containing electron-donating groups, such as with
4-bromoanisole (entry 18), were still generally unsuccessful.
Next, in an effort to construct a tricyclic system using this chemistry, we
performed the coupling reaction between ester-substituted pyrrole 1b and
2-bromopyridine. In this case, annulation can occur via intramolecular addition of

PALLADIUM-CATALYZED N-ARYLATION
1675
Table 2. Yield data for various N-arylations of pyrroles 1
Entry
W
R
Conditions
Product
Yielda
%
1
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Me
SO2Me
SO2Me
CO2Et
CN
CHO
COMe
CN
NO2
CHO
NO2
Cl
A
A
A
A
A
A
A
A
A
A
A
A
B
6a
6b
6c
6d
6e
6f
37
55
59
76
68
86
60
86
72
43
72
37
60
15
71
55
22
2
3
4
5
6
7
6g
6h
6i
8
CN
COMe
CO2Me
Cl
9
10
11
12
13
14
15
16
17
18
CN
CN
6j
6k
6l
CN
CN
H
H
6l
SO2Ph
SO2Me
CO2Et
SO2Me
CN
H
B
6m
6n
6o
6p
6q
H
B
H
Me
B
B
OMe
B
Traceb
aIsolated yield of pure product after column chromatography.
bBased on 1H NMR of the partially purified product.
the pyridine nitrogen to the ester group after the N-arylation.[21] As shown in
Scheme 1, this reaction gave pyrimidone-based tricyclic 7a in modest yield (20%)
when using conditions A. However, this was improved to 65% when using conditions
B. An analogous coupling with 5-cyano-2-bromopyridine proceeding readily using
conditions A, giving 7b in 82% yield. In this latter case, no reaction took place when
Scheme 1. Synthesis of pyrimidone-based tricyclics 7a and 7b.

1676
C. P. GRISWOLD ET AL.
the catalyst and ligand were omitted, indicating that the reaction is indeed catalytic.
It is noteworthy that this tricyclic ring system has been studied as a potential scaffold
for antibacterial agents[22] and has recently been prepared by others using an alter-
native approach that involves formation of the pyrrole ring as the last step.[23]
CONCLUSION
In conclusion, we have described the first N-arylations of a versatile class of
3-functionalized 2-aminopyrroles. This palladium-catalyzed coupling proceeds most
readily when using aryl bromides that are activated by an electron-withdrawing sub-
stituent, although good yields have also been obtained when using bromobenzene
through use of additional catalyst and ligand. Consistent with other N-arylations
with the palladium=xantphos system, the reaction does not proceed well when using
deactivated aryl bromides, although one coupling with 4-bromotoluene has been
achieved. Finally, using this N-arylation chemistry, a pyrimidone-based tricyclic sys-
tem has been prepared in just one step from an ester-substituted 2-aminopyrrole.
EXPERIMENTAL
NMR spectra were recorded on a Bruker 300 Avance spectrometer. The
residual solvent peak (dimethyl sulfoxide, DMSO) was used as internal standard
(2.49 ppm for proton, and 39.5 ppm for carbon). Infrared (IR) spectra were recorded
on a Perkin-Elmer Spectrum 100 Fourier transform (FT)–IR spectrometer using
attenuated total reflectance (ATR). Melting points were recorded in open capillaries
using a Mel-Temp 1201D apparatus and are uncorrected. Elemental analyses were
performed by Atlantic Microlab, Inc. Starting 2-aminopyrroles were prepared
according to the literature.[1–3] All other reagents were commercial and used as
received.
Conditions A: Representative Procedures for 4-(1-Benzyl-4,5-
dimethyl-3-phenylsulfonylpyrrol-2-ylamino)benzaldehyde (6a)
A mixture of 2-amino-1-benzyl-4,5-dimethyl-3-phenylsulfonylpyrrole (1a)
(0.204 g, 0.6 mmol), 4-bromobenzaldehyde (0.122 g, 0.66 mmol), Pd2(dba)3 (11 mg,
0.012 mmol, 2 mol%), xantphos (15.6 mg, 0.027 mmol, 4.5 mol%), cesium carbonate
(0.274 g, 0.84 mmol), and anhydrous 1,4-dioxane (1–2 mL) was heated at 100–
105 ꢀC (oil bath) under nitrogen atmosphere for 18 h. The resulting dark suspension
was then diluted with water and extracted with EtOAc. Purification of the extract by
column chromatography (silica gel) using a gradient of hexanes–ethyl acetate (5:1 to
2:1) as eluent gave, following concentration of pure fractions, a yellow powdery solid
(0.088 g, 37%). Recrystallization from EtOH, followed by drying in vacuo, gave fine
yellow=orange crystals, mp 177–179 ꢀC. IR (cmꢁ1): 3310, 3058, 3033, 2929, 2805,
2731, 1682, 1599, 1583, 1297, 1159, 828, 744, 689, 586, 553, 507. 1H NMR
(DMSO-d6): 1.96 (s, 3H), 2.07 (s, 3H), 4.89 (s, 2H), 6.50 (br d, J ¼ 7.5 Hz, 2H),
6.97 (d, J ¼ 7.5 Hz, 2H), 7.22–7.29 (m, 3H), 7.38 (m, 2H), 7.51 (m, 1H), 7.57 (d,
J ¼ 8.8 Hz, 2H), 7.63 (d, J ¼ 7.9 Hz, 2H), 8.73 (s, NH), 9.68 (s, CHO). 13C NMR
(DMSO-d6): 9.6, 9.8, 45.8, 112.9, 113.0, 114.3, 124.7, 126.2, 126.4, 127.3, 127.4, 128.6,

PALLADIUM-CATALYZED N-ARYLATION
1677
128.9, 129.8, 131.5, 132.5, 136.8, 143.3, 152.8, 190.4. Analysis for C26H24N2O3S
(444.55): calcd. C, 70.25; H, 5.45; N, 6.31; found C, 70.41; H, 5.35; N, 6.37.
Analytical Data for Other Compounds Prepared Using Conditions A
1-[(1-Benzyl-4,5-dimethyl-3-phenylsulfonylpyrrol-2-ylamino)phenyl]-
ethanone (6b). Tan=orange crystals (toluene=hexanes), mp 152–154 ꢀC. IR (cmꢁ1):
3354, 3060, 2952, 2936, 1668, 1600, 1585, 1357, 1284, 1260, 1132, 833, 737, 722, 695.
1HNMR (DMSO-d6): 1.95 (s, 3H), 2.06 (s, 3H), 2.43 (s, 3H), 4.88 (s, 2H), 6.44
(broad d, J ¼ 7.8 Hz, 2H), 6.97 (d, J ¼ 7.2 Hz, 2H), 7.20–7.31 (m, 3H), 7.38 (t,
2H), 7.52 (t, 1H), 7.62–7.68 (m, 4H), 8.53 (s, NH). 13C NMR (DMSO-d6): 9.6, 9.8,
26.1, 45.7, 112.6, 112.8, 114.1, 124.5, 126.2, 126.4, 127.3, 127.5, 128.6, 128.9,
130.1, 130.3, 132.4, 136.9, 143.4, 151.5, 195.6.
4-(1-Benzyl-4,5-dimethyl-3-phenylsulfonylpyrrol-2-ylamino)benzonitrile
(6c). Tan crystals (MeOH), mp 149–150 ꢀC. IR (cmꢁ1): 3321, 3053, 3033, 2927,
1
2220, 1607, 1511, 1404, 1310, 1301, 1164, 1134, 1083, 831, 745, 719, 689. H NMR
(DMSO-d6): 1.96 (s, 3H), 2.07 (s, 3H), 4.87 (s, 2H), 6.44 (broad d, J ¼ 7.0 Hz,
2H), 6.96 (d, J ¼ 7.2 Hz, 2H), 7.22–7.31 (m, 3H), 7.40–7.43 (m, 4H), 7.50–7.54 (m,
1H), 7.63 (d, J ¼ 8.2 Hz, 2H), 8.66 (s, NH). 13C NMR (DMSO-d6): 9.5, 9.8, 45.7,
99.1, 112.9, 113.5, 114.9, 119.9, 124.7, 126.2, 126.3, 127.3, 128.6, 128.9, 129.6,
132.5, 133.3, 136.8, 143.3, 151.2.
1-Benzyl-4,5-dimethyl-2-(4-nitrophenyl)amino-3-phenylsulfonylpyrrole
(6d). Amber crystals (EtOH), mp 206–208 ꢀC. IR (cmꢁ1): 3306, 3065, 3032, 2926,
1
1594, 1497, 1321, 1298, 1272, 1164, 1134, 1109, 1082, 842, 743, 721, 688. H NMR
(DMSO-d6): 1.98 (s, 3H), 2.08 (s, 3H), 4.89 (s, 2H), 6.45 (broad s, 2H), 6.95 (d,
J ¼ 7.2 Hz, 2H), 7.20–7.30 (m, 3H), 7.38–7.43 (m, 2H), 7.52 (t, 1H), 7.65 (d,
J ¼ 7.2 Hz, 2H), 7.91 (d, J ¼ 9.0 Hz, 2H), 9.04 (s, NH). 13C NMR (DMSO-d6): 9.6,
9.8, 45.8, 112.7, 113.1, 114.7, 125.0, 125.7, 126.2, 126.4, 127.3, 128.7, 129.0, 129.0,
132.6, 136.7, 138.3, 143.2, 153.5.
4-(1-Benzyl-4,5-dimethyl-3-methylsulfonylpyrrol-2-ylamino)benzalde-
hyde (6e). Yellow amorphous solid. IR (cmꢁ1): 3309, 3023, 2925, 2816, 2740, 1680,
1
1600, 1582, 1525, 1403, 1292, 1221, 1159, 1113, 950, 827, 762, 733, 697. H NMR
(DMSO-d6): 1.98 (s, 3H), 2.14 (s, 3H), 2.93 (s, 3H), 4.93 (s, 2H), 6.59 (d, J ¼ 8.1 Hz,
2H), 7.00 (d, J ¼ 7.0 Hz, 2H), 7.20–7.32 (m, 3H), 7.64 (d, J ¼ 8.5 Hz, 2H), 8.62 (s,
NH), 9.68 (s, CHO). 13C NMR (DMSO-d6): 9.6, 9.7, 44.9, 45.6, 112.9, 113.0,
114.6, 124.2, 126.4, 127.3, 127.3, 128.6, 129.1, 131.7, 137.0, 153.3, 190.4.
1-Benzyl-4,5-dimethyl-3-methylsulfonyl-2-(4-nitrophenyl)aminopyrrole
(6f). Light orange needles (Et2O=hexanes), mp 125–127 ꢀC. IR (cmꢁ1): 3290, 3003,
2926, 1599, 1509, 1498, 1324, 1302, 1289, 1270, 1109, 951, 838, 771, 736, 690.
1H NMR (DMSO-d6): 2.03 (s, 3H), 2.14 (s, 3H), 2.95 (s, 3H), 4.94 (s, 2H), 6.57
(broad d, J ¼ 7.4 Hz, 2H), 6.99 (d, J ¼ 7.2 Hz, 2H), 7.20–7.31 (m, 3H), 7.99 (d,
J ¼ 8.8 Hz, 2H), 8.92 (s, NH). 13C NMR (DMSO-d6): 9.6, 9.6, 44.8, 45.7, 112.7,
113.1, 114.9, 124.6, 125.9, 126.4, 127.3, 128.4, 128.6, 136.9, 138.3, 153.9.

1678
C. P. GRISWOLD ET AL.
1-Benzyl-2-(4-chlorophenyl)amino-4,5-dimethyl-3-methylsulfonylpyr-
role (6g). Tan solid, mp 109–111 ꢀC. IR (cmꢁ1): 3347, 3030, 2925, 1591, 1534, 1491,
1287, 1114, 950, 822, 761, 731, 696. 1H NMR (DMSO-d6): 1.98 (s, 3H), 2.11 (s, 3H),
2.89 (s, 3H), 4.91 (s, 2H), 6.48 (d, J ¼ 8.3 Hz, 2H), 6.99 (d, J ¼ 7.3 Hz, 2H), 7.11 (d,
J ¼ 8.5 Hz, 2H), 7.16–7.32 (m, 3H), 7.85 (s, NH). 13C NMR (DMSO-d6): 9.5, 9.7,
44.9, 45.5, 112.7, 113.9, 114.8, 121.6, 123.6, 126.4, 127.2, 128.6, 128.7, 130.8,
137.2, 146.4.
Ethyl 1-Benzyl-2-(4-cyanophenyl)amino-4,5-dimethylpyrrole-3-carbox-
ylate (6h). Amber oil. IR (cmꢁ1): 3313, 2926, 2869, 2217, 1678, 1606, 1590, 1510,
1
1440, 1407, 1113, 829, 729, 696. H NMR (DMSO-d6): 0.91 (t, 3H), 1.98 (s, 3H),
2.14 (s, 3H), 3.92 (q, 2H), 4.97 (s, 2H), 6.55 (d, J ¼ 8.5 Hz, 2H), 6.95 (d, J ¼ 7.2 Hz,
2H), 7.20–7.29 (m, 3H), 7.46 (d, J ¼ 8.4 Hz, 2H), 8.46 (s, NH). 13C NMR (DMSO-
d6): 9.5, 10.8, 13.9, 45.4, 58.4, 98.4, 106.5, 113.5, 114.9, 120.1, 123.4, 126.2, 127.1,
128.6, 131.5, 133.3, 137.6, 152.1, 163.8.
2-(4-Acetylphenyl)amino-1-benzyl-4,5-dimethylpyrrole-3-carbonitrile
(6i). Pale yellow=colorless crystals (MeOH), mp 150–151 ꢀC. IR (cmꢁ1): 3239, 3071,
2942, 2922, 2212, 1660, 1589, 1580, 1269, 1171, 745, 698. 1H NMR (DMSO-d6): 1.98
(s, 3H), 2.04 (s, 3H), 2.43 (s, 3H), 4.99 (s, 2H), 6.65 (d, J ¼ 8.6 Hz, 2H), 6.95 (d,
J ¼ 7.1 Hz, 2H), 7.18–7.30 (m, 3H), 7.77 (d, J ¼ 8.6 Hz, 2H), 8.71 (s, NH). 13C NMR
(DMSO-d6): 9.74, 9.74, 26.1, 45.9, 87.7, 112.6, 115.2, 115.8, 123.8, 126.2, 127.3,
127.9, 128.6, 130.4, 134.2, 137.0, 150.4, 195.6.
Methyl 4-(1-Benzyl-3-cyano-4,5-dimethylpyrrol-2ylamino)benzoate (6j).
Coarse yellow crystals (MeOH), mp 156–157 ꢀC. IR (cmꢁ1): 3266, 3171, 3068, 3035,
1
2956, 2211, 1692, 1606, 1539, 1435, 1282, 1271, 1170, 1116, 769, 746, 696. H NMR
(DMSO-d6): 1.98 (s, 3H), 2.04 (s, 3H), 3.75 (s, 3H), 4.98 (s, 2H), 6.65 (d, J ¼ 6.9 Hz,
2H), 6.95 (d, J ¼ 7.5 Hz, 2H), 7.20–7.30 (m, 3H), 7.74 (d, J ¼ 8.8 Hz, 2H), 8.46 (s,
NH). 13C NMR (DMSO-d6): 9.8, 9.8, 45.9, 51.5, 87.8, 112.8, 115.2, 115.9, 119.4,
123.8, 126.2, 127.3, 128.6, 131.1, 134.3, 137.0, 150.4, 166.0.
1-Benzyl-2-(4-chlorophenyl)amino-4,5-dimethylpyrrole-3-carbonitrile
(6k). Amber oil. IR (cmꢁ1): 3303, 3067, 3032, 2922, 2864, 2214, 1594, 1543, 1490,
1
1421, 1241, 1089, 819, 731, 697, 670. H NMR (DMSO-d6): 1.96 (s, 3H), 2.00 (s,
3H), 4.97 (s, 2H), 6.60 (d, J ¼ 8.6 Hz, 2H), 6.93–6.96 (m, 2H), 7.15 (d, J ¼ 8.6 Hz,
2H), 7.20–7.28 (m, 3H), 8.21 (s, NH). 13C NMR (DMSO-d6): 9.8, 9.8, 45.8, 87.0,
115.0, 115.0, 116.1, 122.0, 123.3, 126.2, 127.3, 128.7, 129.0, 135.6, 137.2, 145.0.
Conditions B
The procedure was similar to the representative procedure described pre-
viously, except that 4 mol% of Pd2(dba)3 and 9 mol% of xantphos were used.
Data for Compounds Prepared Using Conditions B
1-Benzyl-4,5-dimethyl-2-phenylaminopyrrole-3-carbonitrile (6l). Amber
crystals (cyclohexane), mp 133–135 ꢀC. IR (cmꢁ1): 3308, 3105, 3060, 3026, 2917,
2861, 2203, 1603, 1593, 1546, 1495, 1442, 1406, 1304, 749, 739, 689. 1H NMR

PALLADIUM-CATALYZED N-ARYLATION
1679
(DMSO-d6): 1.95 (s, 3H), 2.02 (s, 3H), 4.97 (s, 2H), 6.59 (d, J ¼ 8.6 Hz, 2H), 6.70 (t,
1H), 6.96 (d, J ¼ 8.2 Hz, 2H), 7.12 (t, 2H), 7.16–7.28 (m, 3H), 8.04 (s, NH). 13C NMR
(DMSO-d6): 9.7, 9.7, 45.7, 86.9, 113.4, 114.8, 116.2, 118.6, 123.0, 126.2, 127.2, 128.6,
129.1, 136.1, 137.2, 146.0.
1-Benzyl-4,5-dimethyl-2-phenylamino-3-phenylsulfonylpyrrole
(6m).
Colorless crystals (EtOAc), mp 184–186 ꢀC. IR (cmꢁ1): 3366, 3061, 2947, 2923,
1601, 1530, 1394, 1286, 1160, 1133, 1080, 826, 750, 720, 702, 690. 1H NMR
(DMSO-d6): 1.92 (s, 3H), 2.03 (s, 3H), 4.89 (s, 2H), 6.44 (d, J ¼ 7.7 Hz, 2H), 6.70
(t, 1H), 6.98 (d, J ¼ 7.0 Hz, 2H), 7.04 (t, 2H), 7.26–7.38 (m, 5H), 7.50 (t, 1H), 7.58
(d, J ¼ 7.4 Hz, 2H), 7.76 (s, NH). 13C NMR (DMSO-d6): 9.5, 9.8, 45.7, 112.4,
112.8, 113.6, 118.4, 123.8, 126.2, 126.4, 127.2, 128.6, 128.8, 128.9, 132.3, 132.5,
137.2, 143.6, 146.8.
1-Benzyl-4,5-dimethyl-3-methylsulfonyl-2-phenylaminopyrrole
(6n).
Light tan=colorless crystals (EtOAc=hexanes), mp 162–163 ꢀC. IR (cmꢁ1): 3347,
3015, 2924, 1602, 1534, 1497, 1401, 1356, 1285, 1116, 961, 762, 749, 742, 728, 699.
1H NMR (DMSO-d6): 1.98 (s, 3H), 2.12 (s, 3H), 2.88 (s, 3H), 4.91 (s, 2H), 6.50 (d,
J ¼ 7.6 Hz, 2H), 6.68 (m, 1H), 7.00 (d, J ¼ 7.5 Hz, 2H), 7.10 (t, 2H), 7.22–7.30 (m,
3H), 7.65 (s, NH). 13C NMR (DMSO-d6): 9.5, 9.7, 44.9, 45.5, 112.5, 113.4, 113.6,
118.3, 123.3, 126.4, 127.2, 128.6, 129.0, 131.5, 137.3, 147.2.
Ethyl 1-Benzyl-4,5-dimethyl-2-phenylaminopyrrole-3-carboxylate (6o).
Amber oil. IR (cmꢁ1): 3348, 3031, 2925, 2863, 1689, 1602, 1551, 1495, 1409, 1225,
1
1113, 1066, 748, 725, 693. H NMR (DMSO-d6): 0.98 (t, 3H), 1.95 (s, 3H), 2.12 (s,
3H), 3.95 (q, 2H), 4.95 (s, 2H), 6.52 (d, J ¼ 7.7 Hz, 2H), 6.65 (t, 1H), 6.97 (d,
J ¼ 7.5 Hz, 2H), 7.07 (t, 2H), 7.20–7.30 (m, 3H), 7.54 (s, NH). 13C NMR (DMSO-
d6): 9.5, 10.9, 14.0, 45.4, 58.3, 105.2, 113.5, 114.4, 118.0, 122.4, 126.2, 127.0, 128.5,
128.8, 134.7, 137.9, 147.7, 164.3.
1-Benzyl-4,5-dimethyl-2-(4-methylphenyl)amino-3-methylsulfonylpyr-
role (6p). Light tan=colorless crystals (EtOAc=hexanes), mp 148–150 ꢀC. IR
(cmꢁ1): 3376, 3017, 2938, 1529, 1510, 1286, 1108, 957, 944, 814, 769, 740, 700.
1H NMR (DMSO-d6): 1.96 (s, 3H), 2.11 (s, 3H), 2.15 (s, 3H), 2.87 (s, 3H), 4.89 (s,
2H), 6.42 (d, J ¼ 8.3 Hz, 2H), 6.91 (d, J ¼ 8.5 Hz, 2H), 6.99 (d, J ¼ 7.3 Hz),
7.22–7.32 (m, 3H), 7.47 (s, NH). 13C NMR (DMSO-d6): 9.5, 9.7, 20.1, 45.0, 45.5,
112.4, 113.2, 113.5, 123.2, 126.4, 126.9, 127.2, 128.6, 129.5, 132.0, 137.4, 144.7.
Synthesis of Tricyclic Compounds 7a and 7b
These compounds were prepared according to the previous representative pro-
cedure using a 2-bromopyridine and either conditions A or B as noted in the text.
1-Benzyl-2,3-dimethylpyrido[1,2-a]pyrrolo[2,3-d]pyrimidine-4-one (7a).
Yellow crystals, mp 185–185.5 ꢀC (MeOH). IR (cmꢁ1): 3099, 3036, 2917, 2851,
1
1683, 1637, 1485, 1430, 1129, 771, 730, 690. H NMR (DMSO-d6): 2.15 (s, 3H),
2.48 (s, 3H), 5.43 (s, 2H), 7.05–7.08 (m, 3H), 7.22–7.29 (m, 3H), 7.49 (d, J ¼ 9.0 Hz,
1H), 7.62 (m, 1H), 8.90 (d, J ¼ 7.3, 1H). 13C NMR (DMSO-d6): 9.6, 9.9, 44.4, 100.6,
108.9, 112.5, 125.0, 126.4, 126.4, 127.2, 128.7, 129.3, 133.4, 137.9, 146.3, 147.0, 153.9.

1680
C. P. GRISWOLD ET AL.
Analysis for C19H17N3O (303.36): calcd. C, 75.23; H, 5.65; N, 13.85; found C, 74.99;
H, 5.67; N, 13.81.
1-Benzyl-7-cyano-2,3-dimethylpyrido[1,2-a]pyrrolo[2,3-d]pyrimidine-4-
one (7b). Fibrous yellow needles, mp 223–224 ꢀC (MeOH). IR (cmꢁ1): 3065, 3020,
2920, 2850, 2230, 1705, 1635, 1525, 1446, 1350, 1287, 827, 727, 688. 1H NMR
(DMSO-d6): 2.17 (s, 3H), 2.36 (s, 3H), 5.45 (s, 2H), 7.06 (d, J ¼ 7.5 Hz, 2H),
7.23–7.30 (m, 3H), 7.54 (d, J ¼ 9.4 Hz, 1H), 7.74 (d, J ¼ 2.0 and 9.4 Hz, 1H), 9.37
(d, J ¼ 2.0 Hz, 1H). 13C NMR (DMSO-d6): 9.6, 9.8, 44.6, 97.3, 101.0, 110.0, 116.7,
126.1, 126.5, 127.3, 128.7, 130.3, 131.2, 135.0, 137.5, 145.1, 146.3, 153.0. Analysis
for C20H16N4O (328.37): calcd. C, 73.15; H, 4.91; N, 17.06; found C, 73.06; H,
4.93; N, 17.03.
ACKNOWLEDGMENTS
We thank our department and the Pamplin College of Arts and Sciences for
funding of this research.
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