Ortho-Directed Palladium-Catalyzed Direct C-H Functionalization of 3-Picolinyl- A nd 3-(2-Cyanoethyl)pyrimidin-4(3 H)-ones with Aryl Halides

Article abstract of DOI:10.1055/s-0040-1707523

The ortho-directed palladium-catalyzed direct C-H arylation of 3-picolinylpyrimidin-4-one was achieved by using various aryl halides. The method was extended to C-H arylation of pyrimidin-4-ones containing a methoxy group and an aryl group at the C5 site. The 2-cyanoethyl substituent was also evaluated as an ortho-directing group. The method gives access to novel N-substituted 2-aryl or 2,5-diaryl pyrimidin-4-ones. A standard three-step deprotection sequence for the picolinyl group was also studied.

Full text of DOI:10.1055/s-0040-1707523

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©
Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
letter
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Synlett
S. C. Ruiz et al.
Letter
Ortho-Directed Palladium-Catalyzed Direct C–H Functionalization
of 3-Picolinyl- and 3-(2-Cyanoethyl)pyrimidin-4(3H)-ones with
Aryl Halides
Sandra Collado Ruiz
Mickaël Muselli
O
O
R1
R2
R1
R2
Ar-X, Pd(OAc)2, CuI
CsF
N
N
Steven Frippiat
N
H
N
Ar
Thierno Mamoudou Diallo
Anissa Mohamed-Cherif
Vincent Levacher
2
0 examples, R1 = H, OMe or Ar group, R2 = -(CH2)-2-pyridyl or (CH2)2CN, (X = I, Br)
up to 75% yield; possible removal of 2-picolyl group
Christine Baudequin*
Laurent Bischoff*
Christophe Hoarau*
Normandie University, COBRA, UMR 6014 et FR 3038, University of Rouen;
INSA Rouen; CNRS, IRCOF, 1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex,
France
christine.baudequin@univ-rouen.fr
laurent.bischoff@univ-rouen.fr
christophe.hoarau@insa-rouen.fr
Received: 09.03.2020
Accepted after revision: 27.03.2020
Published online: 05.05.2020
O
HN
N
N
O
N
N
DOI: 10.1055/s-0040-1707523; Art ID: st-2020-d0141-l
N
N
N
N
Abstract The ortho-directed palladium-catalyzed direct C–H arylation
of 3-picolinylpyrimidin-4-one was achieved by using various aryl ha-
lides. The method was extended to C–H arylation of pyrimidin-4-ones
containing a methoxy group and an aryl group at the C5 site. The 2-
cyanoethyl substituent was also evaluated as an ortho-directing group.
The method gives access to novel N-substituted 2-aryl or 2,5-diaryl py-
rimidin-4-ones. A standard three-step deprotection sequence for the
picolinyl group was also studied.
Bu
Irbesartan
Antihypertensive
Luotonin A
Human DNA topoisomerase I inhibitor
O
HO
H
N
N
N
O
O
N
COCF3
H
H
N
N
N
O
2
H N
N
O
O
N
Key words palladium catalysis, arylation, C–H functionalization, Su-
zuki coupling, pyrimidinones
Isentress
HIV integrase inhibitor
Elastase inhibitor
Phase I
F
F
Figure 1 Pharmaceutical molecules and biomolecules incorporating a
,3-diazol-4-one core
The transition-metal-catalyzed direct C–H functional-
ization of heterocycles has emerged as a powerful atom-
and step-economical synthetic alternative to conventional
cross-coupling reactions. The method is particularly useful
when halogenated or metalated heterocycles are unavail-
able or to extend the chemical space of functionalization
1
1
ular direct C2–H heteroarylation of 3-[(2-bromoquinolin-3-
yl)methyl]quinazolin-4(3H)-one in a total synthesis of lu-
otonin quinoline alkaloids.6
(
4
site diversity). Previously, important families of 1,3-diazol-
-one nonaromatic heterocycles, such as quinazolinones,
pyrimidinones, imidazolones, and imidazolopyrimidinones
We recently investigated a palladium(0)-catalyzed, cop-
per-assisted, direct C(2)–H arylation of 4,4′-dialkyl- and 4-
arylidene imidazolones, applied to the design of novel
green fluorescent protein (GFP)-like and Kaede protein flu-
(hypoxanthines), which are widely used in pharmaceutical
2
7,8
science as biomolecules (Figure 1), have been mainly pre-
pared by means of various condensation reactions.
orophores for bioimaging. The method was subsequently
3
shown to be effective in direct C(2)–H heteroarylation of
9
In the field of palladium-catalyzed C–C bond formation,
only the Liebeskind–Srogl cross-coupling of C-2-halogenat-
ed diazol-4-ones with boronic acids has been reported.4
Moreover the direct C–H functionalization of 1,3-diazolone
nonaromatic heterocycles remains sparsely investigated.
Harayama first reported a palladium-catalyzed intramolec-
quinazolinones (Figure 2). In our ongoing investigations on
challenging 1,3-diazol-4-one nonaromatic heterocycles, we
turned our attention to an important class of N-substituted
pyrimidin-4-ones present in many biologically active com-
,5
2
pounds, such as inhibitors of HIV integrase and elastase.
Here, an ortho-directed direct C(2)–H arylation of various
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
S. C. Ruiz et al.
Letter
pyrimidin-4-ones with aryl halides is reported under coop-
erative Pd(0)/Cu(I) catalysis. Two ortho-directing groups,
known as directed metalation groups (DMGs), flanking the
nitrogen atom were screened, including pyridine and nitrile
substituents that are highly amenable toward N-substitu-
tion. Subsequent removal of the DMG was also explored to
produce N(3)–H free pyrimidinones. The sequential Suzu-
ki–Miyaura cross-coupling of N-substituted 5-bromopy-
rimidin-4-one, followed by direct C(2)–H functionalization
with aryl halides to produce disubstituted 2,5-pyrimidin-4-
ones was also examined.
fold excess of the electrophile, CuI (2 equiv) and CsF (1.2
equiv) in DMF at 150 °C for 18 hours (entry 11). Under
these conditions, the 2-arylated N-picolinylpyrimidin-4-
one 1bA was obtained in 74% isolated yield.
Table 1 Direct C–H Arylation of N-Benzyl and N-Picolinyl Pyrimidi-
nones by Using Various Catalysts: Optimization of the Experimental
Conditionsa
NC
I
A
Y
(1–2 equiv)
Y
O
N
O
N
Pd(OAc)2 (10 mol%)
[Cu] (1–2 equiv), PPh3 (20 mol%)
Quinazolin-4-ones
Imidazolin-4-ones
N
N
Harayama (2003, 2004)
Hoarau/Bischoff (2015, 2016)
base (2 equiv)
DMF, 150 °C, 18 h
(
intramolecular)
R
O
O
Besson/Fruit (2016)
R
Ar
1
a (Y = CH)
CN
(
intermolecular)
O
N
N
N
N
1b (Y = N)
1aA (Y = CH)
bA (Y = N)
R
Py
1
H
H
R
N
N
b
Entry
Y
[Cu] (Cu/ArX)
Base
Temp (°C) Yield (%)
O
H
R
1c
NRd
CH
CH
CH
N
–
KOAc
CO
130
130
130
130
130
130
130
130
150
150
150
N
DMG
2c
3
4
5
6
7
8
9
–
K
NRd
14
54
52
29
63
54
48
56
74
2
3
N
H
This work: Pyrimidin-4-ones
CuBr·SMe
2
(1:1)
DBU
DBU
CsF
Figure 2 Direct C(2)-H functionalization of 1,3-diazol-4-ones hetero-
cycles: previous studies on the synthesis of quinazolin-4-ones and imid-
azole-4-ones, and our new synthesis of pyrimidin-4-ones
2
CuBr·SMe (1:1)
N
CuBr·SMe
CuBr·SMe
CuBr·SMe
CuBr·SMe
CuI (2:2)
CuBr·SMe
CuI (2:2)
2
2
2
2
(1:1)
(1:1)
(1:2)
(2:2)
N
3 4
K PO
N
DBU
CsF
Our initial exploration of the palladium-catalyzed direct
C–H arylation of 3-benzylpyrimidin-4(3H)-one (1a) with 4-
iodobenzonitrile (A) was performed under standard condi-
tions with Pd(OAc) and PPh as catalyst and ligand, respec-
tively. In a broad screening of bases, acetate and carbonate,
which the Harayama group previously found to be active in
intramolecular C(2)–H arylation of quinazolines, did not
give the expected C(2)-arylated pyrimidin-4-one 1aA (Table
, entries 1 and 2). To overcome this difficulty and, on the
N
N
DBU
DBU
CsF
2
3
10
N
2
(2:2)
1
1e
N
6
a
Reaction conditions: [Pd] (10 mol%), ligand (20 mol%), 1a or 1b (0.5
mmol), base (2 equiv), 130 or 150 °C, 18 h.
Yield of isolated product after flash chromatography.
b
c
PCy
3
ligand and Ar-X = A (1 equiv).
NR = no reaction.
b (1.0 mmol) .
1
d
e
7,8
basis of our experience in the imidazole-4-one series, we
turned immediately to the use of copper(I) salts as additives
in combination with DBU as a base. In this case, when
1
We then examined the scope of aryl iodides and bro-
CuBr·SMe was used as a copper source, the C(2)-arylated
mides as electrophiles under the optimized reaction condi-
tions (Scheme 1). Aryl bromide or iodide electrophiles sub-
stituted with electron-withdrawing groups, including sev-
eral chemically sensitive groups (–CN, –CHO, –NO , –CF , or
2
pyrimidin-4-one 1aA was isolated, albeit in a poor 14%
yield (entry 3). We next focused our attention on the use of
a picolinyl group (in compound 1b), a known ortho-direct-
ing group in direct C–H arylations of the azole series,10 in-
cluding the 4,4′-arylidene imidazolones investigated in our
2
3
–CO Me) at the para- or meta-positions, performed well in
2
the C(2)–H arylation of 1b, leading to an initial set of C(2)-
arylated N-picolinylpyrimidin-4-ones 1bB–bF in yields of
40 to 75%. In contrast, although the reaction proceeded
smoothly with electron-rich aryl halides over 18 hours, the
phenylated product 1bG and the 4-methoxyphenylated
product 1bH were obtained in only modest yields of 59 and
47%, respectively, over a longer 42 hour reaction time. Like-
wise, the para-tolyl product 1bI was obtained in only 34%
yield. Contrary to our observations in the 4-arylidene se-
8
laboratory. In this case, the yield of the C(2)–H arylation
product 1bA increased markedly to 54% under the same
catalytic conditions (entry 4). Interestingly, we observed
that the soft base CsF was equally effective (entry 5),
whereas the reaction was less effective in the presence of
potassium phosphate (entry 6). A further examination into
the influence of copper stoichiometry using two different
bases (DBU and CsF) and two sources of copper (CuBr·SMe2
and CuI) at 130 or 150 °C (entries 7–11) led to the following
combination of optimal catalyst/reaction conditions: a two-
8
ries, 2-bromofuran was identified as one of the few effec-
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
Synlett
S. C. Ruiz et al.
Letter
tive coupling partners among a range of halogenated het-
erocycles (thiophene, pyridine, quinoline), giving the 2-fu-
ranyl derivative 1bJ in moderate yield (50%).
at N(3)–H through the Michael addition reaction of pyrimi-
din-4(1H)-one with acrylonitrile.12 It was observed that
C(2)–H arylation of N-(2-cyanoethyl)pyrimidin-4(3H)-one
with para-cyano- and para-nitrophenyl iodide gave the
corresponding products 2A and 2B, albeit in lower yields
(52 and 49%, respectively) than those of the corresponding
picolinyl analogues.
N
(Het)Ar-X
N
O
N
O
N
Pd(OAc)2 (10 mol%)
CuI (2 equiv), PPh3 (20 mol%)
N
N
O
Ar-I (2 equiv)
Pd(OAc)2 (10 mol%)
CuI (2 equiv), PPh3 (20 mol%)
O
H
CsF (1.2 equiv)
DMF, 150 °C, 18 h
(Het)Ar
R1
R2
R1
R2
1b
1bA–J
N
N
CsF (1.2 equiv)
DMF, 150 °C, 18 h
N
H
N
Ar
N
N
N
O
O
O
1
2
2A–B
3A–G
4A
2
3
4
(R = H, R = (CH2)2CN)
1
3
2
(R = 4-R C6H4, R = (CH2)-2-pyridyl)
(R = OMe, R2 = (CH2)-2-pyridyl)
N
N
N
1
CN
N
N
N
O
O
H
1
bA
1bB
1bC
CN
CN
N
CN
N
O
[
X = Br] : yield = 71%
[X = I] : yield = 40% [X = Br] : yield = 75%
N
N
2A
2B
CN
NO2
N
N
N
X = [I] : yield = 51% or 52%a
X = [I] : yield = 49%a
O
O
O
N
N
N
N
N
N
O
O
N
N
N
N
1bD
1bE
1bF
CO2Me
NO2
CF3
N
N
[X = I] : yield = 74%
[X = I] : yield = 63%
[X = Br] : yield = 62%
3A
3B
CN
N
CO2Me
X = [I] : yield = 79%
X = [I] : yield = 59%
N
N
N
O
O
N
O
O2N
O2N
N
N
N
N
N
O
N
N
O
N
N
1bG
1bH
OMe
1bI
Me
N
3
C
3D
NO2
CN
CN
CN
[X = I] : yield = 26%
[X = I] : yield = 26%
[X = Br] : yield = 34%
or 59%a
or 47%a
X = [I] : yield = 26%
X = [I] : yield = 45%
N
NC
N
NC
N
O
O
O
N
N
N
O
N
N
N
3E
3F
1bJ
2
CO Me
X = [I] : yield = 27%
X = [I] : yield = 34%
[X = Br] : yield = 50%
Scheme 1 Pd-catalyzed direct C–H arylation of N-picolinylpyrimidin-
4
(1H)-one with aryl halides. a Reaction time 42 h.
MeO
N
N
O
O
MeO
N
N
N
At this stage, the C(2)–H arylation process was evaluated
N
on pyrimidin-4-ones with various substituents at the N(3)
and C(5) positions (Scheme 2). On the assumption that a cy-
ano group is highly amenable toward a range of functional-
izations and might act as a coordinating group through the
formation of dimers, the 2-cyanoethyl group was selected
as a potential directing group. This was readily introduced
3
G
4A
CN
X = [I] : yield = 51%
X = [I] : yield = 67%
Scheme 2 Pd-catalyzed direct C–H arylation of C5-substituted pyrim-
11
idinones. a Pd(dppf)Cl (10 mol%) was used instead of a mixture of
2
Pd(OAc) (10 mol%) and PPh (20 mol%).
2
3
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
Synlett
S. C. Ruiz et al.
Letter
Next we examined the C(2)-H arylation reaction of C(5)-
arylated 3-picolinylpyrimidin-4(3H)-ones to give products
O
O
N
N
N
O
mCPBA
O
O
O
O
3A–G. To this end, we took advantage of the high electron
(1 equiv)
O
density at C(5)–H to prepare 5-iodopyrimidin-4(3H)-one by
treatment of commercially available pyrimidin-4(3H)-one
N
N
N
O
CH2Cl2
0 °C, 24 h
95%
140 °C, 18 h
80%
N
N
N
13
with iodine. A set of 5-arylated N-picolinylpyrimidin-4-
ones 3A–G were then prepared in good yields through in-
troduction of a picolinyl group at N(3)–H, followed by palla-
dium-catalyzed Suzuki-coupling reactions with various
1
bA
5
6
CN
CN
CN
LiOH
THF/H O (4:1)
5 °C, 10 min
2
3
then 110 ºC, 45 min
88%
9
aryl halides, including electron-deficient 4-iodobenzoni-
trile, 1,4-iodonitrobenzene, and methyl 4-iodobenzoate. By
applying the previously optimized protocol for C(2)–H ary-
lation of nonsubstituted N(3)-picolinylpyrimidin-4(3H)-
one with haloarenes, the 2,5-diarylated pyrimidin-4-ones
O
NH
N
7
3A–G were obtained in isolated yields of 26 to 79% (Scheme
CN
2). Note that these 2,5-diaryl-3-picolinylpyrimidin-4(3H)-
Scheme 3 Picolinyl cleavage through a Boekelheide rearrangement
ones containing an embedded push–pull electronic system
represent innovative structural analogues of 4-arylidene
8
imidazolone-based GFP protein fluorophores.
ole, and pyridoimidazole series, respectively, an external
base-assisted concerted metalation–deprotonation might
occur through coordination to the picolinyl group of the
aryl halopalladium active complex generated by oxidative
addition of Pd(0) to the C–X bond [Figure 3; (A)]. In con-
trast, on the basis of reports on the C(2)–H arylation in the
imidazole series by the group of Bellina and Rossi and by
other groups,23 it is possible that an Ar–Cu complex might
be generated to act as a transmetalating agent in a standard
Pd(0)-catalyzed cross-coupling cycle, namely Pd(0)/Cu(I)
cooperative catalysis. In this case, two external base-assist-
ed C(2)–H activation processes can be suggested: a concert-
ed cupration–deprotonation involving CuI coordinated to
the DMG instead of the N(1)-site [Figure 3 (B)], or a carban-
ionic-type cupration involving CuI bound to the N(1) site
while the DMG is locked in through double CuI coordina-
tion, additionally involving the carbonyl function [Figure 3 (C)].
As a final demonstration of the robustness of the proto-
14
col in this series, 5-methoxypyrimidin-4(3H)-one, which
is used as a pharmaceutical scaffold in drug design, was
evaluated as a substrate. Pleasingly, and despite the higher
electron density of the pyrimidin-4-one ring, C(2)–H aryla-
tion of 1b with 4-iodobenzonitrile proceeded successfully
under the optimized reaction conditions to give the C(2)-
arylated 5-methoxypyrimidin-4-one 4A in 67% yield
22
(Scheme 2).
Our final investigations were directed toward the evalu-
ation of the three-step removal of the picolinyl protecting
group from 3-picolinyl C(2)-arylated pyrimidin-4-one 1bA
as a selected substrate by using a Boekelheide rearrange-
15,16
ment (Scheme 3).
In the first step, the pyridine moiety
was oxidized by treatment with mCPBA to give the pyrimid-
inone N-oxide 5 in 95% yield. A subsequent Boekelheide re-
arrangement by treatment with acetic anhydride following
the reported procedure led to the -acetoxy pyrimidinone 6
in 80% isolated yield. Finally, treatment with LiOH afforded
the N(3)–H free C(2)-arylated pyrimidinone 7 in 67% yield
over the three-step sequence. Removal of the 2-cyanoeth-
yl group from the nitrogen atom through a base-promoted
retro-Michael reaction was also envisaged. However,
deprotection of the 2-cyanoethylpyrimidinone 2A by using
such nucleophilic bases as diethylamine or DBU in acetoni-
trile proceeded in only 20% yield.
This palladium-catalyzed C(2)–H arylation of pyrimi-
din-4-ones promoted by an N(3)-protecting group with CuI
as additive and a carbonate base might involve various
C(2)–H metalation–deprotonation pathways. Notably, as-
suming that CuI can bind to the N(1) site, thereby reinforc-
ing the acidity of C(2)–H, several base-assisted metalation–
deprotonation models might be postulated involving vari-
ous key roles of the N(3)-protecting group (Figure 3). First-
X
O
O
Cu N
O
N
N
N
N
17
X
Pd
Cu
N
N
N
X
Ar
H
H
Cu
Cu
N
H
Base
18
X
X
Base
Base
Cu
A
B
X
C
Figure 3 Three possible models of C(2)–H activation in base-assisted
Pd(II)-catalyzed C(2)–H arylation of 3-picolinylpyrimidin-4-one in the
presence of a Cu(I) additive
In summary, we have reported the first examples of
C(2)–H arylation of pyrimidin-4-ones by aryl halides by us-
ing picolinyl or 2-cyanoethyl directing groups that can pro-
mote the catalytic metalation key step and which are re-
movable and/or chemically scalable.24 The synthetic pro-
cess tolerates a broad variety of aryl halides, as well as the
presence of functionalities sensitive to nucleophilic attack.
19
20
ly, as supported by the work of the Huang, Gorelsky, and
Blagg groups in the (benzo)oxa(thia)zole, (benzo)imidaz-
21
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
Synlett
S. C. Ruiz et al.
Letter
The 5-arylated pyrimidin-4-ones were found to be useful
substrates for producing 2,5-diarylated N-picolinylpyrimi-
din-4-ones that are structurally related to imidazolone-
based GFP protein fluorophores. Additionally, 5-methoxy-
pyrimidin-4-one, actively used in drug design, also reacted
successfully, providing access to C(2)-arylated 5-methoxy-
pyrimidin-4-ones. Finally, the removal of the picolinyl pro-
tecting group through a three-step oxidation/Boekelheide
rearrangement/hydrolysis sequence was demonstrated.
(3) For selected reviews on quinazolinone syntheses, see:
(
(
a) Rohokale, R. S.; Kshirsagar, U. A. Synthesis 2016, 48, 1253.
b) Maiden, T. M. M.; Harrity, J. P. A. Org. Biomol. Chem. 2016, 14,
8014. (c) Kshirsagar, U. A. Org. Biomol. Chem. 2015, 13, 9336.
(
(
d) He, L.; Li, H.; Chen, J.; Wu, X.-F. RSC Adv. 2014, 4, 12065.
e) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetra-
hedron 2005, 61, 10153. For selected articles on pyrimidinone
syntheses, see: (f) Ramanjulu, J. M.; DeMartino, M. P.; Lan, Y.;
Marquis, R. Org. Lett. 2010, 12, 2270. (g) Jeong, J. U.; Chen, X.;
Rahman, A.; Yamashita, D.; Luengo, J. I. Org. Lett. 2004, 6, 1013.
(h) Jezewski, A.; Jurczak, J.; Lidert, Z.; Tice, C. M. J. Heterocycl.
Chem. 2001, 38, 645. (i) Takahashi, T.; Hirokami, S.; Nagata, M.
J. Chem. Soc., Perkin Trans. 1 1998, 2653. (j) Salimbeni, A.;
Canevotti, R.; Paleari, F.; Poma, D.; Caliari, S.; Fici, F.; Cirillo, R.;
Renzetti, A.; Subissi, A.; Belvisi, L.; Bravi, G.; Scolastico, C.;
Giachetti, A. J. Med. Chem. 1995, 38, 4806. (k) Pinner, A. Chem.
Ber. 1889, 22, 1612. For selected articles on imidazolone synthe-
ses, see: (l) Wu, L.; Burgess, K. J. Am. Chem. Soc. 2008, 130, 4089.
Funding Information
This work was partially supported by INSA Rouen, Rouen University,
CNRS, EFRD, European INTERREG IV A France (Channel) and Labex
SynOrg (ANR-11-LABX-0029). S.C.-R., M.M., and S.F. are grateful to the
Region Normandie for grants.()
(m) Baranov, M. S.; Solntsev, K. M.; Lukyanov, K. A.; Yampolsky,
I. V. Chem. Commun. 2013, 49, 5778. (n) Baldridge, A.; Samanta,
S. R.; Jayaraj, N.; Ramamurthy, V.; Tolbert, L. M. J. Am. Chem. Soc.
Supporting Information
2011, 133, 712.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707523.
(
4) For reviews on the Liebeskind–Srogl cross-coupling reaction,
see: (a) Cheng, H.-G.; Chen, H.; Liu, Y.; Zhou, Q. Asian J. Org.
Chem. 2018, 7, 490. (b) Prokopcová, H.; Kappe, C. O. Angew.
Chem. Int. Ed. 2009, 48, 2276.
5) For the Liebeskind–Srogl cross-coupling reaction at a carbon
atom of the quinazolinone, pyrimidinone or imidazolone
nucleus, see: (a) Kriščiūnienė, V.; Matulevičiūtė, G.; Paliulis, O.;
Rollin, P.; Šačkus, A. Heterocycles 2016, 93, 150. (b) Gosling, S.;
Rollin, P.; Tatibouët, A. Synthesis 2011, 3649. (c) Sun, Q.;
Suzenet, F.; Guillaumet, G. J. Org. Chem. 2010, 75, 3473.
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References and Notes
(
2
(1) For reviews on Pd-catalyzed direct C(sp )–H arylation of hetero-
cycles (C–H/C–X couplings), see: (a) Verbitskiy, E. V.; Rusinov,
G. L.; Chupakhin, O. N.; Charushin, V. N. Synthesis 2018, 50, 193.
(b) Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K. Chem. Rev.
2017, 117, 9302. (c) Abdoli, M.; Mirjafary, Z.; Saeidian, H.;
(d) Prokopcová, H.; Pisani, L.; Kappe, C. O. Synlett 2007, 43.
Kakanejadifard, A. RSC Adv. 2015, 5, 44371. (d) Liang, Y.; Wnuk,
S. F. Molecules 2015, 20, 4874. (e) Rossi, R.; Bellina, F.; Lessi, M.;
Manzini, C. Adv. Synth. Catal. 2014, 356, 17. (f) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed. 2012, 51, 8960.
(e) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.;
Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349.
f) Oumouch, S.; Bourotte, M.; Schmitt, M.; Bourguignon, J.-J.
(
Synthesis 2005, 25.
(
(
g) Zhao, D.; You, J.; Hu, C. Chem. Eur. J. 2011, 17, 5466.
h) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem. Int. Ed.
(
6) (a) Harayama, T.; Morikami, Y.; Shigeta, Y.; Abe, H.; Takeuchi, Y.
Synlett 2003, 847. (b) Harayama, T.; Hori, A.; Serban, G.;
Morikami, Y.; Matsumoto, T.; Abe, H.; Takeuchi, Y. Tetrahedron
2009, 48, 9792. (i) Bellina, F.; Rossi, R. Tetrahedron 2009, 65,
10269. (j) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174. (k) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
2004, 60, 10645.
(
(
(
7) Muselli, M.; Baudequin, C.; Hoarau, C.; Bischoff, L. Chem.
(
(
l) Campeau, L.-C.; Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058.
m) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
Commun. 2015, 51, 745.
8) Muselli, M.; Baudequin, C.; Perrio, C.; Hoarau, C.; Bischoff, L.
Chem. Eur. J. 2016, 22, 5520.
9) Laclef, S.; Harari, M.; Godeau, J.; Schmitz-Afonso, I.; Bischoff, L.;
Hoarau, C.; Levacher, V.; Fruit, C.; Besson, T. Org. Lett. 2015, 17,
(2) For selected reviews on quinazolinone activities, see: (a) Gatadi,
S.; Lakshmi, T. V.; Nanduri, S. Eur. J. Med. Chem. 2019, 170, 157.
(b) Khan, I.; Zaib, S.; Batool, S.; Abbas, N.; Ashraf, Z.; Iqbal, J.;
Saeed, A. Bioorg. Med. Chem. 2016, 24, 2361. (c) Michael, J. P.
Nat. Prod. Rep. 2004, 21, 650. For selected articles on pyrimidi-
none activities, see: (d) Sharma, R.; Gawande, D. Y.; Mohan, C.;
Goel, R. K. Med. Chem. Res. 2016, 25, 1420. (e) Sagong, H. Y.;
Bauman, J. D.; Patel, D.; Das, K.; Arnold, E.; LaVoie, E. J. J. Med.
Chem. 2014, 57, 8086. (f) Bellomo, A.; Celebi-Olcum, N.; Bu, X.;
Rivera, N.; Ruck, R. T.; Welch, C. J.; Houk, K. N.; Dreher, S. D.
Angew. Chem. Int. Ed. 2012, 51, 6912. (g) Summa, V.; Petrocchi,
A.; Matassa, V. G.; Taliani, M.; Laufer, R.; De Francesco, R.;
Altamura, S.; Pace, P. J. Med. Chem. 2004, 47, 5336. For selected
patents on imidazolone activities, see: (h) Chen, Y.; O’Connor, S.
J.; Guan, D.; Newcom, J.; Chen, J.; Yi, L.; Zhang, H.; Hunyadi, L.
M.; Natero, R. WO 2004058727, 2004. (i) Murugesan, N.; Tellew,
J. E.; Macor, J. E.; Gu, Z. WO 200001389, 2000. (j) Murugesan, N.;
Tellew, J. E.; Macor, J. E.; Gu, Z. US 20020143024, 2002.
1
700.
(
10) For a selected article on the use of picolinyl group and picolin-
amide derivatives as ortho-directing groups, see: Pradhan, S.;
De, P. B.; Punniyamurthy, T. J. Org. Chem. 2017, 82, 4883.
11) For a recent review, see: Ping, Y.; Wang, L.; Ding, Q.; Peng, Y.
Adv. Synth. Catal. 2017, 359, 3274.
12) Arumugam, J.; Brown, H. A.; Jacobs, H. K.; Gopalan, A. S. Synthe-
sis 2011, 57.
13) Sakamoto, T.; Kondo, Y.; Watanabe, R.; Yamanaka, H. Chem.
Pharm. Bull. 1986, 34, 2719.
14) 5-Methoxypyrimidin-3(4H)-one was synthesized according to
the reported procedure, see: Myllymäki, M. J.; Käsnänen, H.;
Kataja, A. O.; Lahtela-Kakkonen, M.; Saario, S. M.; Poso, A.;
Koskinen, A. M. P. Eur. J. Med. Chem. 2009, 44, 4179.
15) Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286.
(
(
(
(
(
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
Synlett
S. C. Ruiz et al.
Letter
(
16) For the deprotection of the pyridinyl group by Boekelheide rear-
(24) 4-[6-Oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-2-
yl]benzonitrile (1bA); Typical Procedure
rangement, see: (a) Mizuno, Y.; Endo, T.; Miyaoka, T.; Ikeda, K.
J. Org. Chem. 1974, 39, 1250. (b) Endo, T.; Ikeda, K.; Kawamura,
Y.; Mizuno, Y. J. Chem. Soc., Chem. Commun. 1973, 673.
An oven-dried screw-cap tube (10 mL) containing a magnetic
stirrer bar was charged with N-picolinylpyrimidin-4(3H)-one
(0.5 mmol), Pd(OAc) (10 mol%), PPh (20 mol%), CuI (2 equiv),
(
17) Andreotti, D.; Miserazzi, E.; Nalin, A.; Pozzan, A.; Profeta, R.;
Spada, S. Tetrahedron Lett. 2010, 51, 6526.
2
3
and CsF (1.2 equiv). A solution of 4-iodobenzonitrile (2 equiv) in
(18) For selected articles on N-ethylcyano deprotection, see:
DMF (1.5 mL) was added and tube was purged with N and the
2
(
(
a) Tolstyakov, V. V. Chem. Heterocycl. Compd. 2017, 53, 719.
b) Tanino, T.; Yamaguchi, M.; Matsuda, A.; Ichikawa, S. Eur. J.
tube was sealed. The mixture was stirred at 150 °C for 18 h then
diluted with CH Cl and filtered through a pad of cotton wool.
2
2
Org. Chem. 2014, 1836. (c) Touti, F.; Avenier, F.; Lefebvre, Q.;
Maurin, P.; Hasserodt, J. Eur. J. Org. Chem. 2010, 1928. (d) Liao,
Y.; Robinson, B. H. Tetrahedron Lett. 2004, 45, 1473. (e) Duncia, J.
V.; Pierce, M. E.; Santella, J. B. III. J. Org. Chem. 1991, 56, 2395.
19) Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.; Larsen,
R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 3674.
The solution was then washed with 5% aq ammonia (2 × 25 mL)
and brine (2 × 25 mL), dried (Na SO ), filtered, and concentrated
2
4
in vacuo. The crude product was purified by flash column chro-
matography (silica gel, PE–EtOAc) to give a brown solid; yield:
144 mg (74%); mp 98–100 °C (CH Cl –pentane).
(
2
2
IR (ATR): 3070, 2922, 2852, 2236, 1674, 1497, 1179, 838, 757,
–1 1
(20) Gorelsky, S. I. Organometallics 2012, 31, 794.
555 cm . H NMR (300 MHz, CDCl ):  = 8.50 (ddd, J = 4.8, 1.6,
3
(
21) Macdonald, J.; Oldfield, V.; Bavetsias, V.; Blagg, J. Org. Biomol.
Chem. 2013, 11, 2335.
0.9 Hz, 1 H, Hpyr), 8.01 (d, J = 6.6 Hz, 1 H, C6–H), 7.72–7.62 (m, 5
H, Harom, Hpyr), 7.22–7.19 (m, 2 H, Hpyr), 6.53 (d, J = 6.6 Hz, 1 H,
13
(22) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. Eur. J.
Org. Chem. 2006, 693.
C5-H), 5.16 (s, 2 H, N–CH2). C NMR (75 MHz, CDCl ):  = 161.2
3
(C ), 159.8 (C ), 154.2 (C ), 152.1 (CH), 149.2 (CH), 138.6 (C ),
q
q
q
q
(
23) (a) Lesieur, M.; Lazreg, F.; Cazin, C. S. J. Chem. Commun. 2014,
136.5 (CH), 132.0 (2 × CHarom), 128.8 (2 × CHD), 122.4 (CH),
121.8 (CH), 117.7 (Cq), 114.5 (CH), 113.7 (C ), 50.3 (N–CH ).
5
0, 8927. (b) Storr, T. E.; Baumann, C. G.; Thatcher, R. J.; De
Ornellas, S.; Whitwood, A. C.; Fairlamb, I. J. S. J. Org. Chem. 2009,
4, 5810. (c) Storr, T. E.; Firth, A. G.; Wilson, K.; Darley, K.;
Baumann, C. G.; Fairlamb, I. J. S. Tetrahedron 2008, 64, 6125.
q
2
+
HRMS (ESI-TOF): m/z [M + H] calcd for C17H13N O: 289.1089;
4
7
found: 289.1093.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F