Pd(0)-Catalyzed Direct Inter- And Intramolecular C-H Functionalization of 4-Carboxyimidazoles

Article abstract of DOI:10.1055/s-0040-1708003

The palladium-catalyzed arylation and alkenylation of N -substituted methyl imidazole-4-carboxylates are described through inter- and intramolecular pathways. Both direct C2-H and C5-H arylation and alkenylation proceed under Pd(0)/Cu(I) cooperative catal

Full text of DOI:10.1055/s-0040-1708003

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–G
letter
A
en
S. Frippiat et al.
Letter
Synlett
Pd(0)-Catalyzed Direct Inter- and Intramolecular C–H Functional-
ization of 4-Carboxyimidazoles
Steven Frippiata
Antoine Peressona
Thibaut Perseb
C5-arylated
compounds
C2-arylated or
vinylated compounds
MeO2C
MeO2C
Pd0
K2CO3
N
N
N
Pd0 / CuI
DBU
(Het)
Ar
Yvan Ramondenca
Cédric Schneidera
Olivier Querolleb
Patrick Angibaudb
Virginie Ponceletb
Lieven Meerpoelc
Vincent Levachera
Laurent Bischoffa
Christine Baudequin*a
Christophe Hoarau*a
H
MeO2C
N
N
N
1,4-dioxane
1,4-dioxane
H
Bn
n
Y = CH2 or O
(Het)Ar–X
or vinyl–Br
Y
MeO2C
N
N
n = 0–2
H or Br
Y
R or R'
R
Bn
5 examples
15 examples
a Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France
christine.baudequin@univ-rouen.fr
christophe.hoarau@insa-rouen.fr
b Janssen Research & Development, Division of Janssen-Cilag S.A. Campus de Maigremont, BP615, 27106 Val de Reuil Cedex, France
c Janssen Research & Development, Division of Janssen-Cilag a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium
Received: 05.02.2020
Accepted after revision: 29.02.2020
Published online: 17.03.2020
One modern synthetic alternative is focused on the late-
stage palladium-catalyzed C–H functionalization reactions
from C2, C4, and C5 unsubstituted imidazoles.8–12 In partic-
ular, Pd(0)-catalyzed C–H (hetero)arylation of N-substitut-
ed imidazoles with aryl halides at C2 and/or C5 positions
has been widely studied by Bellina and Rossi group.12 As
some remarkable progresses, the orthogonal C2–H versus
C5–H arylation of N-substituted imidazoles have been de-
veloped, respectively, under base-assisted Pd(0)/Cu(I) coop-
erative catalysis and Pd(0)-catalyzed concerted metalation–
deprotonation (CMD), taking advantage of the acidic and
the nucleophilic specific characters of the C2 and C5 sites,
respectively.12b,i Although less reactive, the C4 position of
the imidazole ring can also be functionalized through spe-
cific C–H activation methodology.13 Inspired by the pio-
neering work of Suzuki on intramolecular C–H arylation of
N-bromophenyl imidazole-4-carboxamide,14 and in line
with our ongoing interest into the regioselective Pd(0)-cat-
alyzed C–H arylation and alkenylation with halides of
(oxa)thiazole-4-carboxylates,15 as well as imidazole-5-car-
boxylates,16 we turned our attention to the 4-carboxyimid-
azole series. Unlike the parent imidazole, the presence of an
ester function at C-4 offers several new synthetic and meth-
odological opportunities. Indeed, the carboxylate group
may be easily removed by catalytic extrusion of volatile CO2
or converted into a wealth of other moieties and can be
used as leaving group in various decarboxylative couplings
with formation of C–C or C–heteroatom bonds.17
DOI: 10.1055/s-0040-1708003; Art ID: st-2020-d0075-l
Abstract The palladium-catalyzed arylation and alkenylation of N-sub-
stituted methyl imidazole-4-carboxylates are described through inter-
and intramolecular pathways. Both direct C2–H and C5–H arylation and
alkenylation proceed under Pd(0)/Cu(I) cooperative catalysis and Pd(0)
catalysis, respectively, in low-polarity 1,4-dioxane solvent. The method-
ology gives access to C2 (hetero)aryl or alkenyl imidazoles as well as in-
novative C2- and C5-arylated fused imidazoles tricycles with a five- to
seven-membered middle ring.
Key words C–H functionalization, palladium catalysis, imidazole,
arylation, alkenylation
Imidazoles are abundantly present in various naturally
occurring and biologically active compounds,1 pharmaceu-
ticals,2 and materials.3 This class of azaheterocycle is em-
ployed to produce N-heterocyclic carbenes (NHC) used as li-
gands in various transition-metal complexes in homoge-
neous catalysis4 and organocatalysis.5 Imidazolium-based
ionic liquids are also often considered as green reaction
media due to their unique chemical and physical properties.6
In this context, a concise synthetic access towards imid-
azole cores is of high importance. Since the last decades, the
synthesis of imidazoles over numerous standard condensa-
tion reactions has been intensively reported.7 The main
drawback arises from the introduction at an early stage of
the adequate functional group that compromises the subse-
quent cyclization sequence.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Frippiat et al.
Letter
Synlett
Herein, we have turned our attention to an exhaustive
study of selective C2–H and C5–H arylations of methyl N-
substituted imidazole-4-carboxylates with aryl halides un-
der Pd(0) catalysis through both inter- and intramolecular
pathways. The latter approach provides access to innovative
nonaromatic imidazoles based tricycles offering potential
for applications in the pharmaceutical area.
We started our investigations by selecting methyl N-
benzylimidazole-4-carboxylate (1a) as substrate, which
was readily prepared by N-benzylation of commercially
available methyl imidazole-4-carboxylate under SN2-type
nucleophilic substitution using NaH as base and benzyl bro-
mide as electrophile.18,19 The first study of Pd(0)-catalyzed
C–H arylation of 1a with of 4-bromotoluene (1.2 equiv) was
carried out using Pd(OAc)2 as catalyst, PPh3 as ligand (Table
1), and Cu(I) to functionalize selectively the C-2 site in ac-
cordance with the work reported by Bellina and Rossi.12i In
our hands, the reaction was found to be inefficient in the
standard highly polar DMF solvent with both potassium
and cesium carbonates leading mainly to degradation of
starting material 1a (Table 1, entry 1). However, in the less
polar solvent 1,4-dioxane, the Pd(0)-catalyzed and CuI-as-
sisted C–H arylation of 1a with bromotoluene provided se-
lectively the C2–H arylated imidazole-4-carboxylate 3a in
34% yield (Table 1, entry 2).
Three additional bases, Cs2CO3, CsF, and DBU, were then
evaluated. Cs2CO3 proved to be deleterious to the C–H aryla-
tion process leading mainly to degradation of the starting
material 1a (Table 1, entry 3). On the other hand, CsF and
DBU were found more efficient than K2CO3, since the C2-
arylated imidazole-4-carboxylate 3a was produced in 51%
and 76% yields, respectively (Table 1, entries 4 and 5).
Changing the electrophile to p-iodotoluene, keeping DBU as
base, led to the production of 3a in an excellent 95% isolated
yield (Table 1, entry 6). Then, the C–H arylation of the
methyl imidazole-4-carboxylate 1a with p-iodotoluene was
carried out under microwave irradiation, using the opti-
mized conditions. However, in this case, the use of PPh3 as
ligand, which is prone to C–P cleavage reactions,20,21 led to
the introduction of a phenyl group into C-2 of the imidazole
1a as a side product. A replacement PCy3·HBF4 ligand was
then employed and in this case, the C-2-arylated imidazole-
4-carboxylate 3a was obtained as a single product in 66%
yield after 20 min irradiation (Table 1, entry 7). Lower
amounts of CuI reduced the efficiency of the C–H arylation
process with p-bromotoluene (Table 1, entry 8). More im-
portantly, without the copper additive, very poor reactivity
was observed (Table 1, entries 9–11) using DBU, Cs2CO3, and
K2CO3 as bases, suggesting that the standard carbonate-as-
sisted palladium-catalyzed C–H arylation process is not op-
erative.
With these optimal catalytic conditions, the scope of
the intermolecular arylation of the imidazole 1a with dif-
ferent bromo- and iodoarene electrophiles was investigat-
ed.22,23 Interestingly, the methodology was found to be ef-
fective over a wide range of aryl bromides incorporating
electron-withdrawing and electron-donating groups. Nota-
bly, a broad series of C2-arylated imidazoles flanked with
methyl (3a), methoxy (3b), cyano (3c–e), fluoro (3f), trifluo-
romethyl (3g), nitro (3h), methyl ketone (3i), and methyl
ester (3j) groups was successfully isolated in moderate to
good yields (Scheme 1). The yields could be significantly
improved by using aryl iodides as electrophiles, as exempli-
fied by methyl C2-arylated imidazole-4-carboxylates 3b,
3d, 3g, and 3f. Importantly, the protocol was also efficient
with bromoheterocycles as electrophiles. Indeed, several
methyl C2-heteroarylated-imidazole-4-carboxylates were
synthetized in the presence of representative heterocycles
such as pyridine (3k), pyrimidine (3l), furan (3m), and 5-
methylthiophene (3n). In additional studies, reactions were
performed under microwave irradiation using iodoarenes.
Although the time of the reaction was reduced to 20 min
compared to conventional heating, in most of cases, lower
yields were observed, with methyl imidazole-4-carboxyl-
ates 3b,c,f,h–n being obtained in a range of poor to moder-
ate yields (10–56%).
Table 1 Optimization of the Palladium-Catalyzed Intermolecular Di-
rect C–H Arylation of 1a
Pd(OAc)2 (5 mol%)
PPh3 (10 mol%)
CuI (X equiv)
base (2 equiv)
solvent, 140 °C, 18 h
MeO2C
H
MeO2C
H
N
N
N
N
H
Me
Br
Bn
Bn
Me
1a
3a
2a (1.2 equiv)
Entry
Base
Solvent
CuI (n equiv)
Yield (%)b
1
K2CO3
K2CO3
Cs2CO3
CsF
DMF
2
2
2
2
2
2
2
1
–
–
–
< 5
34
4
2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
3
4
51
76
95a
66c
65
<5
< 5
< 5
5
DBU
6
DBU
7
DBU
8
DBU
9
DBU
10
11
Cs2CO3
K2CO3
a Using 4-iodotoluene (1.2 equiv) as electrophile instead of 4-bromotolu-
ene.
b Yield of isolated compound.
c Reaction conditions: 1a (1 equiv), 4-iodotoluene (1 equiv), Pd(OAc)2 (5
mol%), PCy3·HBF4 (10 mol%), DBU (2 equiv), CuI (2 equiv), in 1,4-dioxane
([1a] = 0.16 M), 210 °C, 20 min under microwave irradiation.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

C
S. Frippiat et al.
Letter
Synlett
in 2014 to afford the corresponding C2-alkenylated imidaz-
oles.26 In this context, C–H alkenylation of 1a with alkenyl
halides was then examined. However, applying the above-
optimized protocol, the direct alkenylation of 1a with the
2-bromostyrene failed. Meanwhile, in accordance with our
previous observations in C–H alkenylation of 4,4′-dial-
kylimidazolone series,27 the direct C–H alkenylation reac-
tion of 1a with the 2-bromostyrene was found to be effec-
tive when simply replacing PPh3 by P(o-tolyl)3 as ligand. In
this case, the expected alkenylated imidazoles 3o–p were
produced in 67% and 81% yields, respectively, from the cor-
responding bromoalkene coupling partners (Scheme 1).
In continuation of this selective intermolecular C2–H
(hetero)arylation of compound 1a, we then turned our at-
tention to the development of an intramolecular C–H aryla-
tion protocol starting from methyl 1-(2-bromobenzyl)-1H-
imidazole-4-carboxylate (4a). Surprisingly, the optimized
protocol used for intermolecular C2–H arylation of 1a was
ineffective. Furthermore, using the same biscatalytic mode,
but using carbonate bases was also found to be ineffective.21
However, on the basis of our previous investigations into re-
gioselective copper-free Pd(0)-catalyzed and carbonate-as-
sisted arylation of oxa(thia)zole-4-carboxylates,15f,g intra-
molecular C–H arylation of 4a was achieved under standard
catalysis, using Pd(OAc)2, carbonate bases, and various
phosphines in 1,4-dioxane. The results are summarized in
Table 2 and show clearly that under these conditions a mix-
ture of 4-carboxyimidazole-based tricyclic heterocycles
possessing both imidazol-2-yl-aryl (5A–C2) and imidazole-
5-yl-aryl (5A–C5) systems could be identified, with isomer
5A–C5 being the major product. Good performance in the
direct C5–H arylation was observed using K2CO3 as base and
PPh3 as well as electron-rich PCy3·HBF4 and electron-poor
P(4-FC6H4)3 as ligand, providing the 4-carboxyimidazole-
based tricyclic heterocycle 5A–C5 in a range of 70–81% iso-
lated yields (Table 2, entries 1–3). Only the bidendate ligand
dppb proved to be less effective (Table 2, entry 4). The ob-
served C5–H selectivity using K2CO3 and electron-rich or
electron-poor phosphines as optimal reagents indicate a
carbonate-assisted CMD-based process which, probably
due to steric hindrance, was not appropriate for the intra-
molecular arylation of imidazole 1a reported above. In ac-
cordance with our observations in the (oxa)thiazole-4-car-
boxylate series, the acetate-assisted metalation–deprotona-
tion process was also found to be ineffective with
compound 4a (Table 2, entry 5). In addition, with stronger
bases such as Cs2CO3, the intramolecular C–H arylation
of 4a proceeded less efficiently, as the 4-carboxyimidazole-
based tricyclic heterocycle 5A–C5 was still isolated, as the
main product, although in a poor 35% yield (Table 2,
entry 6).
Pd(OAc)2 (5 mol%)
PPh3 (10 mol%)
DBU (2 equiv), CuI (2 equiv)
1,4-dioxane, 140 °C, 18 h
MeO2C
MeO2C
N
N
N
N
(Het)Ar
or vinyl
(Het)Ar–X or vinyl–Br
(1.2 equiv)
Bn
Bn
3b–p
1a
MeO2C
MeO2C
N
N
N
OMe
CN
N
3b
Bn
3c
Bn
[Br] = 37%, [I] = 57% (47%)a
[Br] = 86% ([I] = 56%)a
NC
CN
MeO2C
MeO2C
N
N
N
N
3d
Bn
3e
Bn
[Br] = 30%, [I] = 69%
[Br] = 86%
MeO2C
MeO2C
N
N
N
N
F
CF3
3f
Bn
3g
Bn
[Br] = 49%, [I] = 86% (28%)a
[Br] = 56%, [I] = 88%
MeO2C
MeO2C
N
N
N
N
NO2
O
3h
Bn
3i
Bn
[Br] = 77% ([I] = 56%)a
[Br] = 46%, [I] = 46% (49%)a
MeO2C
MeO2C
N
N
N
N
CO2Me
N
3j
Bn
3k
Bn
[Br] = 80% ([I] = 37%)a
[Br] = 90% ([I] = 26%)a
MeO2C
MeO2C
R
N
N
N
N
N
N
Y
3l
Bn
Bn
3m, Y = O, R = H 3n, Y = S, R = Me
[Br] = 72% (11%)a [Br] = 47% (10%)a
[Br] = 86% (20%)a
MeO2C
MeO2C
N
N
N
N
Ph
3o
Bn
3p
Bn
[Br] = 67%b
[Br] = 81%b
Scheme 1 Scope of (hetero)aryl and alkenyl halide substrates. a Yields
obtained under microwave irradiation conditions (Table 1, entry 7) are
given in brackets. b P(o-tolyl)3 phosphine ligand was used instead of PPh3.
As previously mentioned, regioselective direct arylation
to afford the C-2- or C-5-arylated imidazole compounds has
attracted a lot of attention during the past decades. Howev-
er, the C2–H alkenylation of unsubstituted imidazoles has
been less successful in contrast to benzofused azole deriva-
tives such as benzimidazole under Pd (with or without cop-
per co-catalysis) from the corresponding alkenyl bro-
mides.24,25 Nevertheless, a Pd-catalyzed cross-dehydrogena-
tive coupling reaction was successfully developed by Ong
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

D
S. Frippiat et al.
Letter
Synlett
Table 2 Optimization of the Reaction Conditions of Palladium-Cata-
lyzed Intramolecular C–H Arylation of 4a
ready been reported via a radical cyclization, although with
lower yield and selectivity.18a With these promising results
in hand, the preparations of imidazole-based seven-mem-
bered tricyclic heterocycles 7 and 8 were next investigated.
However, in this case, we found that the ring-closing reac-
tion occurred mainly at the C5 site of the imidazole ring
leading to the 7–C5 and 8–C5 isomers in moderate 61% and
62% yields, a significant reduction of selectivity in favor of
the less steric hindered C2–H site were observed and the 7–
C2 and 8-C2 isomers were isolated in more significant
yields (39% and 37%, respectively). Unfortunately, this
methodology failed to prepare the imidazole-based eight-
membered tricyclic heterocycles.
MeO2C
N
Pd(OAc)2 (5 mol%)
ligand (10 mol%)
N
base (2 equiv)
1,4-dioxane, 140 °C, 18 h
5A–C5
MeO2C
H
N
N
H
MeO2C
N
N
4a
Br
5A–C2
Entry
Ligand
PPh3
Base
Yield (%)a,b
5A–C5
Yield (%)a,b 5A–C2
MeO2C
N
1
2
3
4
5
6
7
8
K2CO3
70
81
81
42
nd
3
N
PCy3·HBF4
K2CO3
K2CO3
K2CO3
KOAc
9
Pd(OAc)2 (5 mol%)
PCy3⋅HBF4 (10 mol%)
K2CO3 (2 equiv)
1,4-dioxane, 140 °C, 18 h
n
Y
P(4-FC6H4)3
dppb
17
nd
nd
3
R
5–8–C5
MeO2C
N
N
H
PCy3·HBF4
PCy3·HBF4
Pt-Bu2Me·HBF4
Pt-Bu3·HBF4
R = H or F
Y = CH2 or O
n = 0–2
H
MeO2C
N
N
Cs2CO3 35
n
4b–e
Y
Br
R
K2CO3
K2CO3
79
23
7
Y
27
n
a Reaction conditions: 4a (1 equiv), Pd(OAc)2 (5 mol%), ligand (10 mol%),
base (2 equiv), 1,4-dioxane (0.16 M), 140 °C, 18 h.
b Yield of isolated product.
5–8–C2
R
MeO2C
N
N
MeO2C
N
F
Having previously highlighted the shift of selectivity
from the more sterically hindered C-5 site to the less steri-
cally hindered C-2 site through K2CO3-assisted CMD in ox-
azole and thiazole-4-carboxylate series by using bulky li-
gands,15f,g the behavior of the intramolecular C–H arylation
of 4a regarding the regioselectivity was examined with in-
creasing phosphine bulk. Firstly, Pt-Bu2Me gave predomi-
nantly the same 5A–C5 isomer ratio in a good 79% yield (Ta-
ble 2, entry 7). However, on further increasing the bulk of
the phosphine, and using the most sterically hindered Pt-
Bu3·HBF4, the imidazole-based tricyclic heterocycle 5A–C2
was formed in a slight excess compared to its regioisomer
5A–C5 (Table 2, entry 8). Overall, full inversion of the regio-
selectivity was not observed as anticipated.
The production of 4-carboxyimidazole-based tricyclic
heterocycles 5–8 embedding with five- to seven-membered
central rings was finally investigated starting from various
methyl N-alkylated imidazole-4-carboxylates 4b–g using
the optimized PCy3·HBF4 ligand. Results are depicted in
Scheme 2. The para-fluorinated imidazole-based tricyclic
heterocycle 5B–C5 was produced in an excellent 90% yield,
the 5B–C2 isomer being isolated in a very small amount
(8%). Similarly, for the preparation of five-membered medi-
um-ring models, the imidazole-based six-membered tricy-
clic heterocyclic 6–C5 was also successfully obtained as the
major product in an excellent 81% yield. Again, the alterna-
tive isomer 6–C2 was produced as the only side product in
9% yield. Formation of compounds 6–C5 and 6–C2 has al-
N
F
5B–C5, 90%
5B–C2, 8%
MeO2C
N
N
MeO2C
N
N
6–C5, 81%
6–C2, 9%
MeO2C
N
N
MeO2C
N
N
7–C5, 61%
8–C5, 62%
7–C2, 39%
MeO2C
N
N
MeO2C
N
N
O
O
8–C2, 37%
Scheme 2 Synthesis of 4-carboxyimidazole-based tricyclic heterocycles
Finally, regarding the reactivity and the regioselectivity
observed within this direct intramolecular and intermolec-
ular C–H arylation in the imidazole-4-carboxylate series,
using both Pd(0)- or Pd(0)/CuI-cooperative catalysis, some
observations about the modes of carbonate-assisted meta-
lation–deprotonation can be proposed (Figure 1). First, we
assumed that the standard K2CO3-assisted CMD-based reac-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

E
S. Frippiat et al.
Letter
Synlett
tivity could not proceed at both the highly sterically hin-
dered C2–H and C5–H sites of 1a (model A and B) whilst, for
the intramolecular pathway from compound 4a, the reac-
tivity could be recovered due to a decrease of steric con-
straints. In that case, the C5–H vs C2–H competition was
observed, showing that the energetic barriers might be very
close (mode C and D). Naturally, the intramolecular direct
C2–H arylation pathway under Pd(0)/CuI-cooperative catal-
ysis is disfavored by the difficulty of achieving consecutive
generation of imidazole-2-yl copper as well as the oxidative
addition of Pd(0) to the aryl halide moiety within the same
molecule, prior to the key intramolecular transmetalation.
On the other hand, the CuI co-catalyst, only being efficient
for intermolecular C2–H arylation of 1a, the CMD mode
from the N-(CuI)-chelated imidazole-4-carboxylate com-
plex reported by the Gorelsky group (model E and G),28
might be discarded here in favor of the generation of a im-
idazole-2-yl copper intermediate (model F), in accordance
to the suggestion by Bellina and Rossi.12f
selective direct C2–H (het)arylation and alkenylation of N-
benzyl imidazole-4-carboxylates with bromo- and io-
do(het)arenes and bromoalkenes under Pd(0)/Cu(I)-cooper-
ative catalysis has been described giving an efficient access
to a broad library of C-2-functionalized methyl imidazole-
4-carboxylate compounds. In contrast to previous observa-
tions in N-substituted 4-nitroimidazole-4-carboxylates,29 in
our case the intermolecular CMD-based reactivity does not
operate at C5 when both C4 and the imidazole nitrogen are
substituted. Conversely, using N-(o-halogenobenzyl) imid-
azole-4-carboxylates as starting materials, arylation oc-
curred under K2CO3-assisted CMD-based conditions to pro-
duce novel C-5-arylated fused imidazoles with five- to sev-
en-membered central rings as major products. The
standard cooperative Pd(0)/Cu(I) catalysis proved inopera-
tive in the intramolecular pathway, possibly due to the dif-
ficulty of forming the imidazole-2-yl copper intermediate
followed by the oxidative addition of Pd(0) to the aryl ha-
lide moiety. Moreover, a loss of C-5–H vs C2–H selectivity
was clearly observed during the preparation of seven-mem-
bered tricyclic imidazole-based heterocycles, probably due
to the increased size of the linker. Additional studies are
currently ongoing further functionalize these tricyclic scaf-
folds further in order to generate chemical diversity.
In summary, this work reports the first full investigation
of palladium-catalyzed direct C–H functionalization of N-
substituted imidazole-4-carboxylates. In particular, the first
(i) Palladium-catalyzed CMD-type process:
O
OMe
Ar
Pd O
N
N
N
N
MeO
O
Ar Pd
O
Funding Information
O
H
O
H
O
This work has been partially supported by the Institut National des
Sciences Appliquées Rouen (INSA), the Rouen University, the Centre
National de la Recherche Scientifique (CNRS), the EFRD, the European
Interreg IV A France (Channel), and Labex SynOrg (ANR-11-LABX-
Ph
Ph
Mode A: Inactive
O
Mode B: Inactive
O
0029).
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nstitut
N
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ldes
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es
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Acknowledgment
Pd
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Pd
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We thank the CRIHAN for software optimization and technical support.
Mode C: Active
Mode D: Active
Supporting Information
Supporting information for this article is available online at
(ii) CuI-assisted Pd(0)-catalyzed and Pd(0)/Cu(I) cooperative process:
https://doi.org/10.1055/s-0040-1708003.
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MeO
References and Notes
O
O
Pd
Pd
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Figure 1 Plausible intermediates in the catalytic C–H arylation
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

G
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Letter
Synlett
(21) See the Supporting Information for more details.
3 H, CH3). 13C NMR (75 MHz, CDCl3):  = 163.5 (C=O), 149.5 (C2,
Cqim), 139.7 (C4′, Cqarom), 135.9 (C1′, Cqbenzyl), 132.9 (C4im, Cq),
129.3 (2 × CH), 129.2 (2 × CH), 129.1 (2 × CH), 128.4 (CHbenzyl),
127.1 (C5, CHim), 126.9 (2 × CHbenzyl), 126.5 (Cq), 51.8 (OCH3),
51.0 (NCH2), 21.4 (CH3). IR (ATR): 3125, 3079, 2920, 2850, 1689,
1549, 1330, 1227, 1004, 725 cm–1. HRMS: Anal. Calcd for
(22) General Procedure for Pd-Catalyzed Intermolecular Direct
C2–H Arylation of Methyl N-Benzyl-1H-imidazole 4-carbox-
ylate under Thermic Conditions
Methyl 1-benzyl-1H-imidazole-4-carboxylate (1a, 80 mg, 0.37
mmol, 1 equiv), the requisite halide 2 (1.2 equiv), Pd(OAc)2 (18
mol, 5 mol%), PPh3 (37 mol, 10 mol%), CuI (0.74 mmol, 2
equiv), and anhydrous DBU (0.74 mmol, 2 equiv) were placed in
a dry sealed tube containing a magnetic stir bar. The tube was
evacuated and back-filled with nitrogen three times before
adding anhydrous 1,4-dioxane (2.5 mL). The tube was sealed
and heated to 140 °C for 18 h. The reaction was filtered through
a Celite® pad (washing with DCM and EtOAc). The solvents were
removed under reduced pressure, and the crude product was
then purified by column chromatography (DCM to DCM/EtOAc,
9:1).
C
19H19N2O2 [M + H]+: 307.1447; found: 307.1455.
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2015, 80, 2103.
(23) Compound 3a was prepared according to the general procedure.
The crude product was purified by flash chromatography to
afford 3a in 76% yield using the aryl bromide and 95% yield
using the aryl iodide as a pale yellow solid; mp 89–90 °C. 1H
NMR (300 MHz, CDCl3):  = 7.64 (s, 1 Him, H5), 7.46 (d, J = 8.0 Hz,
2 Harom), 7.35–7.33 (m, 3 Hbenzyl), 7.22 (d, J = 8.0 Hz, 2 Harom),
7.09–7.07 (m, 2 Hbenzyl), 5.19 (s, 2 H), 3.89 (s, 3 H, OMe), 2.38 (s,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G