Suzuki-Miyaura cross-coupling reaction of aryl and heteroaryl pinacol boronates for the synthesis of 2-substituted pyrimidines

Article abstract of DOI:10.1016/j.tet.2011.10.057

Suzuki-Miyaura cross-coupling reaction with 2-heteroarylboronic acids is generally challenging due to these acids easy decomposition. To overcome this problem, we developed a coupling method that uses 2-heteroaryl pinacol boronates in the presence of 1.0

Full text of DOI:10.1016/j.tet.2011.10.057

Tetrahedron 68 (2012) 272e279
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
SuzukieMiyaura cross-coupling reaction of aryl and heteroaryl pinacol boronates
for the synthesis of 2-substituted pyrimidines
*
Shigehiro Asano , Seiji Kamioka, Yoshiaki Isobe
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 August 2011
Received in revised form 12 October 2011
Accepted 14 October 2011
Available online 21 October 2011
SuzukieMiyaura cross-coupling reaction with 2-heteroarylboronic acids is generally challenging due to
these acids easy decomposition. To overcome this problem, we developed a coupling method that uses 2-
heteroaryl pinacol boronates in the presence of 1.0 mol % Pd(OAc)2 and 2.0 mol % S-Phos with 4 equiv
amount of LiOH in dioxane and H2O at 80 ꢀC for 30 min. This developed method allowed for the synthesis
of a wide variety of 2-heteroaryl pyrimidines from 2-chloropyrimidyl derivatives in high yields, and is
also useful in the preparation of various biaryl derivatives from heteroaryl chlorides.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
SuzukieMiyaura cross-coupling reaction
2-Heteroaryl pinacol boronates
2-Chloropyrimidyl derivatives
2-Heteroaryl pyrimidines
Pd(OAc)2/S-Phos
Lithium hydroxide
1. Introduction
2-Aryl or 2-heteroaryl pyrimidines and their derivatives have
recently been reported as inhibitors of tubulin polymerization,1
class 1 phosphatidylinositide 3-kinases (PI3K),2 checkpoint kinase
2 (CHK2),3 and activin like kinase 5 (ALK5),4 and as activators of cell
type-specific NF-kB (Fig. 1).5 The synthesis of these compounds via
transition metal-catalyzed cross-coupling reaction provides an in-
teresting challenge in medicinal chemistry, as it allows a single
common intermediate to be diversified into a large number of re-
lated products. However, cross-coupling reaction of heteroaryl
chlorides, including 2-chloropyrimidyl derivatives, is generally
considered to be difficult,6 because these substrates cannot only
bind to the catalyst metal center and deactivate the catalytic ac-
tivity,7 but also react with the solvent by SNAr-mechanism instead
of the slower cross-coupling reaction.8 Hence, practical methods
that allow efficient cross-coupling reaction of heteroaryl chlorides
are needed.
SuzukieMiyaura cross-coupling reaction is arguably the most
important and widely used method for construction of sp2esp2 car-
bonecarbon bonds.9 Recent pioneering advances in the development
of efficient catalysts have significantly extended the scope of this
reaction with various functionalized boronic acids.10,11 Especially,
problematic cross-couplingreactionswith 2-heteroarylboronic acids,
Fig. 1. Representative drug candidates of 2-aryl or 2-heteroaryl pyrimidines.
which are easily decomposed via protodeboronation, oxidation,
and/or polymerization,12 have been improved by two new methods:
one is the use of palladium precatalyst,13 and the other is masking of
boronic acids to stabilize them as MIDA boronates,14 trifluoroborate
salts,15 or cyclic triboronates.16
* Corresponding author. Tel.: þ81 6 6466 5220; fax: þ81 6 6466 5287; e-mail
address: shigehiro-asano@ds-pharma.co.jp (S. Asano).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.057

S. Asano et al. / Tetrahedron 68 (2012) 272e279
273
Table 1
Several approaches to the construction of various 2-aryl or 2-
heteroaryl pyrimidines using SuzukieMiyaura cross-coupling re-
action with boronic acids or trifluoroborate salts have been repor-
ted.7a,8,10c,12b,d,f,g,14 Some of these approaches focused on the use of
a combination of tert-amyl alcohol and molecular sieves or an
aqueous two-phase system in the presence of a weak base to
suppress both side reactions, i.e., (1) SNAr-reaction at the second
position of the pyrimidine ring and (2) homocoupling reaction of
the boronic acids.17 However, the versatile coupling reactions with
2-chloropyrimidyl derivatives have not sufficiently been explored,
even though a methodology for pharmaco-modulation of 2-
functionalized pyrimidines is required. Therefore, to establish
a more effective method for the synthesis of 2-aryl or 2-heteroaryl
pyrimidines, we focused on stable boronates, such as MIDA boro-
nates and trifluoroborate salts, because stable boronates would
undergo minimal decomposition derived from homocoupling re-
action and protodeboronation, leading to reaction completion. In
the case of MIDA boronates, the challenging cross-coupling re-
action with 2-heteroaryl, vinyl, and cyclopropyl MIDA boronates
was considered feasible. As for the trifluoroboronate salts, they
were seen as able to install heterocyclic building blocks, including
the five-membered 2-heteroaryl ones, onto the aryl or heteroaryl
chlorides. However, MIDA boronates and trifluoroborate salts have
to be prepared from free boronic acids or boronic esters,18,19 re-
quiring long reaction time and/or high palladium loading for effi-
cient coupling reaction.
Considering these drawbacks, we turned our attention to the
stable pinacol boronates as attractive building blocks. Pinacol bor-
onates are not only commercially available, but can also be readily
prepared by several established methods, such as alkylation of
B(OR)3 with aromatic lithium or magnesium reagents.20 In partic-
ular, preparation of pinacol boronates using palladium catalyzed
cross-coupling reaction21 or transition metal-catalyzed direct CeH
borylation22 has great advantage over the use of other stable bor-
onates. Therefore, we undertook a detailed examination of Suzu-
kieMiyaura cross-coupling using the convenient pinacol boronates.
Actually, we examined various bases in aqueous condition to obtain
reaction conditions that would suppress the undesired SNAr-re-
action. After selection of appropriate bases and optimization of the
reaction conditions, we could drive the reaction to completion with
high yield. This new method could be applied to the synthesis of
various biaryl derivatives, including five-membered 2-heteroaryl
and other heteroaryl structures. Moreover, the use of this new
method allows us to overcome the problem of high palladium
loading and long reaction time. Herein, we describe Suzu-
kieMiyaura cross-coupling reaction of heteroaryl chlorides with
aryl or heteroaryl pinacol boronates, including the challenging five-
membered 2-heteroaryl ones, for pharmaco-modulation of 2-aryl
or 2-heteroaryl pyrimidines and their derivatives.
Effects of various bases and solvents on Pd(OAc)2/S-Phos-catalyzed cross-coupling
reactiona
Entry
Base
Solvent (v/v)
Yield (%)
1
2
3
4
5
6
7
8
K3PO4
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
TolueneeH2O (4:1)
n-ButanoleH2O (4:1)
DMFeH2O (4:1)
34
5
22
41
46
9
Trace
Trace
99
97
76
54
78
26
39
87
0
Li2CO3
Na2CO3
K2CO3
Cs2CO3
CsF
KOAc
Et3N
LiOH
NaOH
9
10
11
12
13
14
15
16
17
18
19
20
KOH
Ca(OH)2
Ba(OH)2
LiOH
LiOH
LiOH
LiOH
Dioxane
LiOH (1 equiv)
LiOH (2 equiv)
LiOH (3 equiv)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
DioxaneeH2O (4:1)
61
84
93
a
4-Morpholino-2-chloropyrimidine 1a (1.0 equiv), pinacol boronate
3
(1.2 equiv), Pd(OAc)2 (1 mol %), S-Phos (2 mol %), base (4 equiv), solvent (0.1 mM),
80 ꢀC, 30 min; isolated yields, n¼1.
were similar to that obtained with K3PO4, i.e., poor to moderate
isolated yields (tracee46%, entries 2e8). Among the investigated
bases (entries 1e8), Cs2CO3, which is considered to be the strongest
base, was somehow better than the other bases. This finding in-
dicated that the strength of the base might be important for this
cross-coupling reaction. Based on this speculation, various metal
hydroxides were examined.
As expected, LiOH23 (99%, entry 9) and NaOH (97%, entry 10) ef-
fectively led to the desired coupling product 2a, which was quanti-
tatively produced within 30 min in excellent yield without SNAr-
reaction of the 2-chloropyrimidine 1a7,8 (see Supplementary data,
Fig. S1). In the case of KOH (76%, entry 11), the yield was slightly
less than that obtained with LiOH or NaOH, with occurrence of SNAr-
reaction of 1a, probably due to KOH strong nucleophilicity. On the
other hand, the reaction with Ca(OH)2 (54%, entry 12) or Ba(OH)2
(78%, entry 13), both of which are much milder bases than the alkali
metal hydroxides, did not proceed to completion within 30 min
despite suppression of the side reaction. Although the reaction was
left toproceed for 2 h, the 2-chloropyrimidine 1awas not completely
consumed, giving the desire coupling product 2a in almost the same
yield [Ca(OH)2: 71%, Ba(OH)2: 73%]. These results indicate that the
basicity and nucleophilicity of LiOH and NaOH not only promote the
cross-coupling reaction, but also induce no side reactions, such as
SNAr-reaction of 1a and homocoupling reaction of 3.
As for the reaction solvent, it was investigated in the presence of
LiOH, because LiOH is a much milder base than NaOH, and hence
has advantages regarding suppression of SNAr-reaction. The re-
action using 1.0 mol % Pd(OAc)2 and 2.0 mol % S-Phos with 4 equiv
amount of LiOH in toluene and H2O at 80 ꢀC for 30 min did not
proceed to completion, and the isolated yield was insufficient (26%,
entry 14). Similarly, the use of n-butanoleH2O led to the desired
coupling product 2a in low yield (39%, entry 15) due to SNAr-
2. Results/discussion
Based on the reported aqueous reaction conditions,14 we ex-
amined various bases in the presence of 1.0 mol % Pd(OAc)2 and
2.0 mol % S-Phos in dioxane and H2O at 80 ꢀC for 30 min under N2
(Table 1). As for the substrates for this coupling reaction, 4-
morpholino-2-chloropyrimidine 1a and 4-benzyloxyphenyl pina-
col boronate 3 were used, because they are fundamental structures
of the representative drug candidates CYT9971 and CCT2415533
illustrated in Fig. 1.
7a,13,14
First, we used K3PO4
as a base, since it is often used for
SuzukieMiyaura cross-coupling reaction. The reaction did not
proceed to completion, and the isolated yield was insufficient (34%,
entry 1) due to slow reaction rate. To find an appropriate base, we
examined various weak bases, such as Li2CO3, Na2CO3,12d,15c
K2CO3,8,15a,b Cs2CO3, CsF, KOAc, and Et3N (Table 1). The results

274
S. Asano et al. / Tetrahedron 68 (2012) 272e279
Table 2
reaction of 1a with n-butanol. In the case of DMFeH2O, the yield
was slightly less than that obtained with dioxaneeH2O, again due
to occurrence of SNAr-reaction of 1a (87%, entry 16). Based on these
findings, we concluded that dioxaneeH2O is the best solvent for
this cross-coupling reaction. Next, to confirm the importance of
H2O24 as a co-solvent, we conducted the reaction under anhydrous
conditions25 using 1 mol % Pd(OAc)2 and 2 mol % S-Phos as a cata-
lyst with 4 equiv amount of LiOH as a base in dioxane for 30 min.
Surprisingly, the reaction in absence of H2O did not produce to the
desired product (0%, entry 17). From this result, we concluded that
H2O as a co-solvent is required for smooth progression of this
coupling reaction.
Coupling of the 4-benzyloxyphenylboronic acid pinacol ester
3 to various
2-chloropyrimidines or fused 2-chloropyrimidines 1a
Regarding the reaction temperature, we understood that 80 ꢀC
is necessary for smooth coupling reaction because the reaction did
not proceed to completion at room temperature (7%) and even at
50 ꢀC (29%).
Finally, we tried to optimize the reaction equivalent of LiOH. In
the presence of 1 equiv amount of LiOH, the coupling product was
obtained in moderate yield (61%, entry 18). When 2 or 3 equiv
amount of LiOH was used, the 2-chloropyrimidine 1a was not
completely consumed, although the desired product was obtained
in good to excellent yield (entry 19: 84%, entry 20: 93%). Taken
together, these findings indicate that 1.0 mol % Pd(OAc)2 and
2.0 mol % S-Phos with 4 equiv amount of LiOH in dioxane and H2O
at 80 ꢀC for 30 min represent the ideal conditions for synthesis of 2-
aryl pyrimidine derivatives by SuzukieMiyaura cross-coupling re-
action in a short time under low palladium loading.
To examine the limitations of the selected conditions for Suzu-
kieMiyaura cross-coupling reaction, we used C4-substituted 2-
chloropyrimidines or fused 2-chloropyrimidines, such as quinazo-
line, thieno[3,2-d]pyrimidine, and pyrido[2,3-d]pyrimidine as
building blocks (Table 2). All reactions progressed smoothly with
excellent yields (2aeh, 89e99%) in pyrimidines, whichdlike
1adhave an electron-donating group at the C4-position. In-
terestingly, the desired coupling products were obtained in good to
excellent yields (2i; 91%, 2j; 87%) with compounds having an
electron-withdrawing substituent, such as CF3 or COOH. In the case
of fused pyrimidine chlorides, the coupling reaction led to accept-
able yields (2kem, 72e87%), even though trace amounts of the
corresponding SNAr products were observed. As the 2-
chloropyrimidines and fused 2-chloropyrimidines could be con-
verted to the desired coupling products within 30 min, we believe
that our reaction conditions would be useful for drug discovery,
since 2-aryl-4-substituted pyrimidines are important motifs for
medicinal chemistry research.
Next, we carried out the cross-coupling reaction of C4-substituted
2-chloropyrimidines having an electron-withdrawing substituent or
fused 2-chloropyrimidines in the presence of NaOH as a base. Sur-
prisingly, NaOH, which is stronger base than LiOH, was somehow
worse than LiOH due to occurrence of SNAr-reaction of 1a (2i; 61%, 2j;
79%, 2k; 52%, 2l; 79%, 2m; 64%). The use of C4-substituted 2-
chloropyrimidine having an electron-donating substituent gave al-
most the same reaction yield (2a; 97%). From these findings, we
concludedthatLiOHisidealnotonlyforthedevelopedcross-coupling
reaction, but also for the synthesis of various 2-pyrimidyl derivatives.
As SuzukieMiyaura cross-coupling reaction with heteroaryl
boronates generally gives poor yield, we considered using our op-
timized conditions for coupling reaction with heteroaryl pinacol
boronates 5, such as indolyl, pyrrolyl, pyrazolyl, furanyl, and thio-
phenyl pinacol boronate. As shown in Table 3, SuzukieMiyaura
cross-coupling reaction with 4-morpholino-2-chloropyrimidine 1a
and heteroaryl boronates, such as indolyl boronate or 3-heteroaryl
boronate, gave the corresponding desired products (4aee) in good
yields within 30 min, although about 70% of the Boc group in 4b
was deprotected. Encouraged by these results, we extended our
work to the synthesis of the 2-heteroaryl pyrimidines 4 from the 4-
a
2-Chloropyrimidines 1 (1.0 equiv), pinacol boronate 3 (1.2 equiv), Pd(OAc)2
(1 mol %), S-Phos (2 mol %), LiOH (4 equiv), dioxaneeH2O¼4:1 (0.1 mM), 80 ꢀC,
30 min; isolated yields, n¼1.
bNaOH (4 equiv).
morpholino-2-chloropyrimidine 1a and the five-membered 2-
heteroaryl pinacol boronates, which are more challenging than
other pinacol boronates because of easy decomposition via proto-
deboration in polar-protic reaction media. Fortunately, the selected
boronates produced the desired coupling products in excellent
yields (4fel, 91e99%) with no side reactions.
Next, we conducted the reaction with 2-furylboronic acid in-
stead of the pinacol boronate 5 under the same reaction conditions.

S. Asano et al. / Tetrahedron 68 (2012) 272e279
275
Table 3
Heteroaryl chlorides 1, such as 2-pyridine, 2-quinazoline, 2-
thieno[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, 2-quinoline, 2-
quinoxaline, 2-furo[3,2-c]pyridine, and 2-thieno[3,2-c]pyridine
chlorides, are attractive motifs in medicinal chemistry. Thus, we
turned our attention to the scope and limitations of use of various
heteroaryl chlorides. SuzukieMiyaura cross-coupling reaction with
the labile 2-furyl pinacol boronate 7 and a variety of heteroaryl
chlorides was then investigated under our optimized conditions. As
shown in Table 4, optimal reaction conditions were not limited to 2-
heteroaryl chlorides and gave the corresponding coupling products
in good to excellent yields within 30 min (6aei, 74e99%).26,27
Surprisingly, the challenging 2-furyl pinacol boronate 7 due to its
instability could produce the corresponding coupling product
(6cee, 89e96%) more efficiently than the 4-benzyloxyphenyl
pinacol boronate 3 (2kem, 72e87%). Although a trace amount of
the corresponding hydrolyzed product was observed in the 2-
chloroquinoxaline 6g, the developed method seems to have sig-
nificant advantages in the production of biaryl compounds.
Coupling of aryl or heteroaryl pinacol boronates
5 to the 4-morpholino-2-
chloropyrimidine 1aa
Table 4
Coupling of various heteroaryl chlorides 1 to the 2-furyl pinacol boronate 7a
a
4-Morpholino-2-chloropyrimidine 1a (1.0 equiv), pinacol boronate
5
(1.2 equiv), Pd(OAc)2 (1 mol %), S-Phos (2 mol %), LiOH (4 equiv), dioxaneeH2O¼4:1
(0.1 mM), 80 ꢀC, 30 min; isolated yields, n¼1.
bdeBoc derivative was also isolated (yield¼68%).
c2 h.
a
Compound 1 (1.0 equiv), pinacol boronate 7 (1.2 equiv), Pd(OAc)2 (1 mol %), S-
Phos (2 mol %), LiOH (4 equiv), dioxaneeH2O¼4:1 (0.1 mM), 80 ꢀC, 30 min; isolated
yields, n¼1.
However, the target product 4g was obtained in low yield (28%),
indicating importance of the pinacol boronates. To understand
these differences (pinacol boronate 91% vs boronic acid 28%), we
evaluated the stability of the 2-furyl pinacol boronate and that of
the 2-furylboronic acid under 4 equiv amount of LiOH in dioxane
and H2O at 80 ꢀC. Interestingly, the 2-furyl pinacol boronate was
gradually consumed over 30 min, whereas the 2-furylboronic acid
was perfectly decomposed within 5 min (see Supplementary data,
Fig. S2). These findings indicated the heteroaryl pinacol boronates
were stable enough to provide the desired coupling products.
3. Conclusion
In summary, we succeeded in developing optimum conditions
for SuzukieMiyaura cross-coupling reaction of aryl or heteroaryl
pinacol boronates, including the challenging five-membered 2-
heteroaryl pinacol boronates, to construct 2-aryl or 2-heteroaryl
pyrimidines from 2-chloropyrimidyl derivatives in high yields.
These conditions, which are also useful in the preparation of

276
S. Asano et al. / Tetrahedron 68 (2012) 272e279
various biaryl derivatives from heteroaryl chlorides, allow for use of
low palladium loading and short time coupling reaction. Other than
providing efficient SuzukieMiyaura cross-coupling reaction, the
developed reaction protocol is very convenient in two aspects: (1)
no anhydrous conditions are required; (2) a cheap base (LiOH) is
used. Furthermore, the developed reaction protocol can easily be
used at large scale. Further studies will focus on pharmaco-
modulation of the 2-functionalized pyrimidines using the de-
veloped methodology.
5.10 (s, 2H), 6.34 (d, J¼6.2 Hz, 1H), 7.01 (d, J¼9.0 Hz, 2H), 7.30e7.44
(m, 5H), 8.26 (d, J¼6.2 Hz, 1H), 8.32 (d, J¼9.0 Hz, 2H); 13C NMR
(75 MHz, CDCl3):
d (ppm) 43.6, 46.2, 54.6, 69.9, 100.3, 114.4, 127.5,
128.0, 128.6, 129.5, 131.3, 136.7, 156.1, 160.6, 161.6, 163.4; IR (ATR):
n
(cmꢂ1) 1587, 1566, 1541; HRMS (ESI) m/z calcd for C22H25N4O
(MþH)þ 361.2023, found (MþH)þ 361.2022 (Δ¼ꢂ0.22 ppm); HPLC
purity¼99.3% (tR¼2.05 min, method A).
4.2.3. 2-(4-(Benzyloxy)phenyl)-N-butylpyrimidin-4-amine
(2c). Yield¼89% (colorless oil); 1H NMR (300 MHz, CDCl3):
d (ppm)
4. Experimental section
4.1. General
0.86 (t, J¼7.3 Hz, 3H), 1.33 (m, 2H), 1.48 (m, 2H), 3.24 (m, 2H), 5.02
(s, 2H), 6.06 (d, J¼5.9 Hz, 1H), 6.94 (d, J¼8.8 Hz, 2H), 7.23e7.37 (m,
5H), 8.15 (d, J¼5.9 Hz,1H), 8.24 (d, J¼8.8 Hz, 2H); 13C NMR (75 MHz,
CDCl3):
d (ppm) 13.8, 20.0, 31.3, 41.0, 69.9, 114.4, 114.5, 127.5, 127.9,
Melting points were determined on a Stanford Research Systems
Opti Meit. IR spectra were recorded on a JEOL JIR-SPX60 spectrometer
as ATR. NMR spectra were recorded on a JEOL JNM-LA300 spec-
trometer. Chemical shifts are given in parts per million with tetra-
methylsilane used as internal standard for spectra obtained in
DMSO-d6, CDCl3, and CD3CN. All J values are given in hertz. High-
resolution mass spectra (HRMS) were recorded on a Thermo Fisher
Scientific LTQ orbitrap Discovery MS equipment. Reagents and sol-
vents were used as obtained from commercial suppliers without
further purification. Column chromatography was carried out using
a Yamazen W-prep system, and performed using pre-packed silica-
gel or amino silica-gel columns. Reaction progress was determined
by TLC analysis on a silica-gel or amino silica-gel coated glass plate.
Visualization was done with UV light (254 nm) or iodine. All re-
actions were carried out under a nitrogen atmosphere unless oth-
erwise mentioned. UPLC was performed using a Waters AcquityÔ
system. The sample was dissolved in methanol solution, applied on
128.5,129.5,131.1,136.7,155.6,160.5,162.3,163.6; IR (ATR): n )
(cmꢂ1
1589, 1570; HRMS (ESI) m/z calcd for C21H24N3O (MþH)þ 334.1914,
found (MþH)þ 334.1912 (Δ¼ꢂ0.50 ppm); HPLC purity¼99.9%
(tR¼3.34 min, method A).
4. 2. 4. 2-(4-(Benzyloxy)phenyl)-4-methoxypyrimidine
(2d). Yield¼90% (white solid), mp 95e96 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
(ppm) 4.05 (s, 3H), 5.12 (s, 2H), 6.55 (d, J¼5.9 Hz, 1H), 7.05
(d, J¼9.0 Hz, 2H), 7.32e7.46 (m, 5H), 8.39 (d, J¼9.0 Hz, 2H), 8.44 (d,
J¼5.9 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d (ppm) 53.4, 70.0, 105.4,
114.6, 127.5, 128.0, 128.6, 129.8, 130.4, 136.6, 157.3, 161.0, 164.0,
169.3; IR (ATR):
n
(cmꢂ1) 1583, 1572, 1558; HRMS (ESI) m/z calcd
for C18H17N2O2 (MþH)þ 293.1285, found (MþH)þ 293.1281
(Δ¼ꢂ1.27 ppm); HPLC purity¼99.2% (tR¼3.56 min, method A).
4 . 2 . 5 . 2 - ( 4 - ( B e n z yl o x y ) p h e n yl ) - 4 - b u t o x y p y r i m i d i n e
(2e). Yield¼98% (white solid), mp 49e50 ꢀC; 1H NMR (300 MHz,
a ACQUITY UPLCÒ BEH C18 column (2.1 mmꢁ50 mm, 1.7
m
m), and
CDCl3):
d
(ppm) 0.92 (t, J¼7.3 Hz, 3H), 1.44 (m, 2H), 1.73 (m, 2H),
eluted at 1 mL/min with a 4 min gradient (from 10% B to 90% B:
method A; from 50% B to 90% B: method B), where solvent A is water
(0.1% TFA solution) and solvent B is methanol. The purity of all new
compounds was determined by UPLC and was >95%.
4.40 (t, J¼6.7 Hz, 2H), 5.06 (s, 2H), 6.46 (d, J¼5.9 Hz, 1H), 6.98 (d,
J¼9.0 Hz, 2H), 7.25e7.39 (m, 5H), 8.30 (d, J¼9.0 Hz, 2H), 8.36 (d,
J¼5.9 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d (ppm) 13.9, 19.2, 30.8,
66.0, 70.0, 105.5, 114.6, 127.5, 128.0, 128.6, 129.8, 130.5, 136.7, 157.2,
160.9, 164.0, 169.2; IR (ATR):
n
(cmꢂ1) 1589, 1562; HRMS (ESI) m/z
4.2. General procedure for the synthesis of biaryl compounds
calcd for C21H23N2O2 (MþH)þ 335.1754, found (MþH)þ 335.1752
(Δ¼ꢂ0.51 ppm); HPLC purity¼96.9% (tR¼3.52 min, method B).
To a solution of 2-chloroheteroaryl compound 1 (0.50 mmol) in
1,4-dioxane (4.0 mL) were added pinacol boronate 3, 5, or 7
4.2.6. 2-(4-(Benzyloxy)phenyl)-4-methylpyrimidine (2f). Yield¼99%
(0.60 mmol), Pd(OAc)2 (1.1 mg, 5.0
mmol), S-Phos (4.1 mg,
(white solid), mp 113e114 ꢀC; 1H NMR (300 MHz, CDCl3):
d (ppm)
10.0 mol), and 2 M LiOH solution (1.0 mL, 2.0 mmol) at room
m
2.54 (s, 3H), 5.12 (s, 2H), 6.96 (d, J¼5.1 Hz, 1H), 7.06 (d, J¼9.0 Hz,
temperature, and the mixture was stirred for 30 min at 80 ꢀC under
N2 atmosphere. The reaction was quenched by adding water, and
then the mixture was extracted with ethyl acetate. The organic
layer was washed with brine and dried over anhydrous magnesium
sulfate. After filtration, the solvent was removed in vacuo, and the
residue was purified by silica-gel column chromatography. The
solvent was removed in vacuo, and the residue was triturated with
Et2O to give biaryl compounds.
2H), 7.32e7.46 (m, 5H), 8.39 (d, J¼9.0 Hz, 2H), 8.57 (d, J¼5.1 Hz,1H);
13C NMR (75 MHz, CDCl3):
d (ppm) 24.4, 69.9, 114.7, 117.9, 127.5,
128.0, 128.6, 129.7, 130.7, 136.7, 156.7, 160.8, 164.0, 167.0; IR (ATR):
n
(cmꢂ1
) 1589, 1560; HRMS (ESI) m/z calcd for C18H17N2O
(MþH)þ 277.1335, found (MþH)þ 277.1334 (Δ¼ꢂ0.42 ppm); HPLC
purity¼99.9% (tR¼3.45 min, method B).
4.2.7. 2-(4-(Benzyloxy)phenyl)pyrimidine (2g). Yield¼90% (white
solid), mp 92e93 ꢀC; 1H NMR (300 MHz, CDCl3):
d (ppm) 5.12 (s,
4.2.1. 4-(2-(4-(Benzyloxy)phenyl)pyrimidin-4-yl)morpholine
2H), 7.07 (d, J¼9.0 Hz, 2H), 7.11 (dd, J¼5.0, 5.0 Hz,1H), 7.32e7.46 (m,
(2a). Yield¼99% (white solid), mp 128e130 ꢀC; 1H NMR (300 MHz,
5H), 8.38 (d, J¼9.0 Hz, 2H), 8.74 (d, J¼5.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3):
d
(ppm) 3.64 (m, 4H), 3.74 (m, 4H), 5.05 (s, 2H), 6.28 (d,
CDCl3): d (ppm) 70.0, 114.8, 118.4, 127.5, 128.0, 128.6, 129.8, 130.4,
J¼6.2 Hz, 1H), 6.96 (d, J¼8.8 Hz, 2H), 7.25e7.39 (m, 5H), 8.24 (d,
136.6, 157.1, 161.0, 164.4; IR (ATR): n
(cmꢂ1) 1589, 1562; HRMS (ESI)
J¼6.2 Hz, 1H), 8.26 (d, J¼8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3):
m/z calcd for C17H15N2O (MþH)þ 263.1179, found (MþH)þ 263.1176
(Δ¼ꢂ0.93 ppm); HPLC purity¼99.4% (tR¼3.48 min, method A).
d
(ppm) 44.0, 69.9, 100.2, 114.5, 127.5, 128.0, 128.6, 129.6, 131.1,
136.7, 156.1, 160.1, 161.9, 163.3; IR (ATR): n
(cmꢂ1) 1589, 1566, 1544;
HRMS (ESI) m/z calcd for C21H22N3O2 (MþH)þ 348.1707,
found (MþH)þ 348.1702 (Δ¼ꢂ1.22 ppm); HPLC purity¼99.4%
(tR¼2.77 min, method A).
4 . 2 . 8 . 2 - ( 4 - ( B e n z yl o x y ) p h e n yl ) - 4 - p h e n yl p y r i m i d i n e
(2h). Yield¼89% (white solid), mp 110e111 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
(ppm) 5.14 (s, 2H), 7.10 (d, J¼9.0 Hz, 2H), 7.33e7.52 (m,
9H), 8.20 (m, 2H), 8.54 (d, J¼9.0 Hz, 2H), 8.77 (d, J¼5.1 Hz, 1H); 13C
4.2.2. 2-(4-(Benzyloxy)phenyl)-4-(4-methylpiperazin-1-yl)pyrimi-
NMR (75 MHz, CDCl3): d (ppm) 70.0, 113.8, 114.7, 127.1, 127.5, 128.0,
dine (2b). Yield¼94% (white solid), mp 94e96 ꢀC; 1H NMR
128.6, 128.9, 129.9, 130.8(2), 136.7, 137.0, 157.7, 161.0, 163.7, 164.3; IR
(300 MHz, CDCl3):
d
(ppm) 2.33 (s, 3H), 2.48 (m, 4H), 3.73 (m, 4H),
(ATR):
n
(cmꢂ1) 1589, 1560; HRMS (ESI) m/z calcd for C23H19N2O

S. Asano et al. / Tetrahedron 68 (2012) 272e279
277
(MþH)þ 339.1492, found (MþH)þ 339.1488 (Δ¼ꢂ1.23 ppm); HPLC
purity¼98.6% (tR¼3.71 min, method B).
(MþH)þ 295.1553, found (MþH)þ 295.1552 (Δ¼ꢂ0.63 ppm); HPLC
purity¼99.4% (tR¼2.10 min, method A).
4.2.9. 2-(4-(Benzyloxy)phenyl)-4-(trifluoromethyl)pyrimidine
(2i). Yield¼91% (white solid), mp 127e128 ꢀC; 1H NMR (300 MHz,
4.2.15. tert-Butyl 3-(4-morpholinopyrimidin-2-yl)-1H-pyrrole-1-
carboxylate (4b). Yield¼23% (brown solid), mp 130e131 ꢀC; 1H
CDCl3):
d
(ppm) 5.14 (s, 2H), 7.07 (d, J¼9.0 Hz, 2H), 7.33e7.46 (m,
NMR (300 MHz, DMSO-d6): d (ppm) 1.57 (s, 9H), 3.63 (m, 4H), 3.66
6H), 8.46 (d, J¼9.0 Hz, 2H), 8.95 (d, J¼5.0 Hz,1H); 13C NMR (75 MHz,
(m, 4H), 6.64 (d, J¼6.2 Hz, 1H), 6.80 (m, 1H), 7.27 (m, 1H), 7.80 (s,
CDCl3):
d
(ppm) 70.0, 113.5(2), 114.9, 127.5, 128.1, 128.6, 129.0, 130.4,
1H), 8.20 (d, J¼6.2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6):
d (ppm)
136.5, 155.6, 159.4, 161.7, 165.2; IR (ATR):
n
(cmꢂ1) 1589, 1560;
27.5, 43.6, 65.9, 84.4, 100.9, 111.7, 120.4, 120.6, 128.2, 148.1, 156.0,
HRMS (ESI) m/z calcd for C18H14N2OF3 (MþH)þ 331.1053,
found (MþH)þ 331.1050 (Δ¼ꢂ0.70 ppm); HPLC purity¼99.3%
(tR¼3.61 min, method A).
160.0, 161.5; IR (ATR): n
(cmꢂ1) 1732, 1578, 1549; HRMS (ESI) m/z
calcd for C17H23O3N4 (MþH)þ 331.1765, found (MþH)þ 331.1763
(Δ¼ꢂ0.60 ppm); HPLC purity >99.9% (tR¼2.59 min, method A).
4.2.10. 2-(4-(Benzyloxy)phenyl)pyrimidine-4-carboxylic
acid
4 . 2 .16 . 4 - ( 2 - ( F u ra n - 3 - yl ) p y r i m i d i n - 4 - yl ) m o r p h o l i n e
(2j). Yield¼87% (white solid), mp 160e161 ꢀC; 1H NMR (300 MHz,
(4c). Yield¼95% (pale yellow solid), mp 85e86 ꢀC; 1H NMR
DMSO-d6):
d
(ppm) 5.14 (s, 2H), 7.14 (d, J¼7.5 Hz, 2H), 7.30e7.46 (m,
(300 MHz, DMSO-d6): d (ppm) 3.64 (m, 4H), 3.67 (m, 4H), 6.67 (d,
5H), 7.62 (m, 1H), 8.44 (d, J¼7.5 Hz, 2H), 8.86 (d, J¼4.6 Hz, 1H); 13C
J¼6.2 Hz,1H), 6.95 (dd, J¼1.8, 0.9 Hz,1H), 7.73 (dd, J¼1.8,1.8 Hz,1H),
NMR (75 MHz, DMSO-d6):
d (ppm) 69.8, 115.0, 117.5, 128.1, 128.3,
8.21 (d, J¼6.2 Hz,1H), 8.29 (dd, J¼1.8, 0.9 Hz,1H); 13C NMR (75 MHz,
128.8, 130.1, 130.8, 137.3, 158.5(2), 161.0, 163.6; IR (ATR):
n
(cmꢂ1
)
DMSO-d6):
159.3, 161.5; IR (ATR):
d (ppm) 43.6, 65.8, 101.2, 109.6, 127.4, 144.1, 144.3, 156.0,
1589, 1560; HRMS (ESI) m/z calcd for C18H15N2O3 (MþH)þ 307.1077,
found (MþH)þ 307.1080 (Δ¼0.92 ppm); HPLC purity¼98.2%
(tR¼3.44 min, method A).
n
(cmꢂ1) 1569, 1544; HRMS (ESI) m/z calcd
for C12H14N3O2 (MþH)þ 232.1081, found (MþH)þ 232.1078
(Δ¼ꢂ0.96 ppm); HPLC purity¼99.2% (tR¼1.30 min, method A).
4.2.11. 4-(2-(4-(Benzyloxy)phenyl)-6,7-dimethoxyquinazolin-4-yl)
4.2.17. 4-(2-(Thiophen-3-yl)pyrimidin-4-yl)morpholine
morpholine (2k). Yield¼72% (white solid), mp 98e100 ꢀC; 1H
(4d). Yield¼94% (pale yellow solid), mp 109e110 ꢀC; 1H NMR
NMR (300 MHz, CDCl3):
d
(ppm) 3.65 (m, 4H), 3.88 (m, 4H), 3.92
(300 MHz, DMSO-d6):
d
(ppm) 3.67 (m, 8H), 6.69 (d, J¼6.2 Hz, 1H),
(s, 3H), 3.97 (s, 3H), 5.07 (s, 2H), 7.00 (d, J¼9.2 Hz, 2H), 7.02 (s, 1H),
7.57 (dd, J¼5.0, 3.0 Hz, 1H), 7.74 (dd, J¼5.0, 1.2 Hz, 1H), 8.25 (d,
7.24 (s, 1H), 7.25e7.41 (m, 5H), 8.40 (d, J¼9.2 Hz, 2H); 13C NMR
J¼6.2 Hz,1H), 8.26 (dd, J¼3.0,1.2 Hz,1H); 13C NMR (75 MHz, DMSO-
(75 MHz, CDCl3):
d
(ppm) 50.3, 56.0, 56.2, 66.7, 69.9, 102.3, 107.8,
d6):
d (ppm) 43.6, 65.9, 101.3, 126.5, 127.3, 127.4, 142.2, 156.2, 160.0,
109.7, 114.5, 127.5, 127.9, 128.5, 129.5, 131.5, 136.8, 148.0, 150.1,
161.6; IR (ATR):
n
(cmꢂ1) 1576, 1539; HRMS (ESI) m/z calcd for
154.4, 158.4, 160.4, 164.0; IR (ATR):
n
(cmꢂ1) 1589, 1560; HRMS
C12H14N3OS (MþH)þ 248.0852, found (MþH)þ 248.0849
(Δ¼ꢂ1.06 ppm); HPLC purity¼99.7% (tR¼1.53 min, method A).
(ESI) m/z calcd for C27H28N3O4 (MþH)þ 458.2074, found (MþH)þ
458.2072 (Δ¼ꢂ0.41 ppm); HPLC purity¼97.0% (tR¼3.10 min,
method A).
4.2.18. 4-(2-(1-Methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)morpholine
(4e). Yield¼80% (white solid), mp 125e127 ꢀC; 1H NMR (300 MHz,
4.2.12. 4-(2-(4-(Benzyloxy)phenyl)thieno[3,2-d]pyrimidin-4-yl)mor-
DMSO-d6): d (ppm) 3.63 (m, 4H), 3.66 (m, 4H), 3.86 (s, 3H), 6.59 (d,
pholine (2l). Yield¼87% (white solid), mp 129e130 ꢀC; 1H NMR
J¼6.2 Hz, 1H), 7.92 (s, 1H), 8.17 (d, J¼6.2 Hz, 1H), 8.24 (s, 1H); 13C
(300 MHz, CDCl3):
d
(ppm) 3.87 (m, 4H), 4.04 (m, 4H), 5.12 (s, 2H),
NMR (75 MHz, DMSO-d6): d (ppm) 43.5, 65.8, 100.3, 122.9, 131.5,
7.04 (d, J¼9.0 Hz, 2H), 7.38e7.46 (m, 6H), 7.70 (d, J¼5.5 Hz, 1H),
138.5, 156.0, 159.6, 161.4; IR (ATR): n
(cmꢂ1) 1579, 1560, 1541; HRMS
8.40 (d, J¼9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d
(ppm) 46.3,
(ESI) m/z calcd for C12H16N5O (MþH)þ 246.1349, found (MþH)þ
246.1346 (Δ¼ꢂ1.38 ppm); HPLC purity¼99.3% (tR¼1.11 min,
method A).
66.8, 69.9, 112.2, 114.5, 125.4, 127.5, 128.0, 128.6, 129.6, 131.3, 131.4,
136.8, 158.2, 160.2, 160.4, 162.9; IR (ATR):
n
(cmꢂ1) 1527; HRMS
(ESI) m/z calcd for C23H22N3O2S (MþH)þ 404.1427, found (MþH)þ
404.1418 (Δ¼ꢂ2.40 ppm); HPLC purity >99.9% (tR¼3.04 min,
method A).
4.2.19. 4-(2-(1-Tosyl-1H-pyrrol-2-yl)pyrimidin-4-yl)morpholine
(4f). Yield¼99% (white solid), mp 132e134 ꢀC; 1H NMR (300 MHz,
CDCl3):
d (ppm) 2.36 (s, 3H), 3.49 (m, 4H), 3.69 (m, 4H), 6.27 (d,
4.2.13. 4-(2-(4-(Benzyloxy)phenyl)pyrido[2,3-d]pyrimidin-4-yl)mor-
J¼6.2 Hz, 1H), 6.30 (dd, J¼3.4, 3.4 Hz, 1H), 6.83 (m, 1H), 7.23 (d,
pholine (2m). Yield¼81% (white solid), mp 157e158 ꢀC; 1H NMR
J¼8.3 Hz, 2H), 7.47 (m, 1H), 7.69 (d, J¼8.3 Hz, 2H), 8.08 (d, J¼6.2 Hz,
(300 MHz, CDCl3):
d
(ppm) 3.87 (m, 4H), 3.89 (m, 4H), 5.12
1H); 13C NMR (75 MHz, CDCl3):
d (ppm) 21.6, 43.9, 66.5, 100.5, 111.2,
(s, 2H), 7.05 (d, J¼9.0 Hz, 2H), 7.24e7.45 (m, 6H), 8.15 (dd, J¼8.3,
118.4, 126.4, 127.2, 129.2, 134.9, 137.5, 144.1, 155.1, 158.2, 161.4; IR
1.8 Hz, 1H), 8.59 (d, J¼9.0 Hz, 2H), 8.99 (dd, J¼4.4, 1.8 Hz, 1H); 13C
(ATR):
n
(cmꢂ1) 1587, 1568; HRMS (ESI) m/z calcd for C19H21N4O3S
NMR (75 MHz, CDCl3):
d
(ppm) 50.2, 66.6, 70.0, 109.2, 114.4,
(MþH)þ 385.1329, found (MþH)þ 385.1326 (Δ¼ꢂ0.75 ppm); HPLC
purity¼99.9% (tR¼2.26 min, method A).
119.5, 127.5, 128.0, 128.6, 130.5, 130.7, 133.4, 136.6, 155.9,
161.3(2), 162.2, 165.1; IR (ATR):
n
(cmꢂ1) 1591, 1564, 1533; HRMS
(ESI) m/z calcd for C24H23N4O2 (MþH)þ 399.1816, found (MþH)þ
399.1814 (Δ¼ꢂ0.31 ppm); HPLC purity¼97.7% (tR¼2.85 min,
method A).
4 . 2 . 2 0 . 4 - ( 2 - ( F u ra n - 2 - yl ) p y r i m i di n - 4 - yl ) m o r p h o l i n e
(4g). Yield¼91% (pale yellow solid), mp 131e132 ꢀC; 1H NMR
(300 MHz, DMSO-d6):
d
(ppm) 3.66 (m, 8H), 6.62 (dd, J¼3.5, 1.8 Hz,
1H), 6.69 (d, J¼6.2 Hz, 1H), 7.16 (m, 1H), 7.82 (m, 1H), 8.23 (d,
4.2.14. 4-(2-(1-Methyl-1H-indol-5-yl)pyrimidin-4-yl)morpholine
J¼6.2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6):
d
(ppm) 43.6, 65.8,
(cmꢂ1
)
(4a). Yield¼86% (white solid), mp 126e128 ꢀC; 1H NMR (300 MHz,
101.3,112.0,112.4,144.9,152.4,156.0,156.2,161.4; IR (ATR):
n
DMSO-d6):
d
(ppm) 3.70 (m, 8H), 3.80 (s, 3H), 6.53 (d, J¼3.1 Hz, 1H),
1573, 1543; HRMS (ESI) m/z calcd for C12H14N3O2 (MþH)þ 232.1081,
found (MþH)þ 232.1079 (Δ¼ꢂ0.55 ppm); HPLC purity¼99.2%
(tR¼1.26 min, method A).
6.67 (d, J¼6.2 Hz, 1H), 7.35 (d, J¼3.1 Hz, 1H), 7.46 (d, J¼8.6 Hz, 1H),
8.21 (d, J¼8.6 Hz, 1H), 8.30 (d, J¼6.2 Hz, 1H), 8.60 (s, 1H); 13C NMR
(75 MHz, DMSO-d6)
d (ppm) 32.6, 43.7, 65.9, 100.7, 101.6, 109.3,
120.6, 121.2, 127.9, 129.2, 130.5, 137.8, 156.1, 161.7, 163.6; IR (ATR):
n
4.2.21. 4-(2-(5-Methylfuran-2-yl)pyrimidin-4-yl)morpholine
(cmꢂ1) 1577, 1566, 1543; HRMS (ESI) m/z calcd for C17H19N4O
(4h). Yield¼99% (pale yellow solid), mp 75e78 ꢀC; 1H NMR

278
S. Asano et al. / Tetrahedron 68 (2012) 272e279
(300 MHz, DMSO-d6):
d
(ppm) 2.34 (s, 3H), 3.62 (m, 4H), 3.66 (m,
176.0706, found (MþH)þ 176.0704 (Δ¼ꢂ1.23 ppm); HPLC
purity¼99.7% (tR¼1.00 min, method A).
4H), 6.24 (d, J¼3.3 Hz, 1H), 6.64 (d, J¼6.2 Hz, 1H), 7.06 (d, J¼3.3 Hz
1H), 8.19 (d, J¼6.2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6):
d (ppm)
13.7, 43.6, 65.8, 100.9, 108.5, 113.7, 150.9, 154.1, 156.0, 156.2, 161.4; IR
4.2.28. 4-(2-(Furan-2-yl)-6,7-dimethoxyquinazolin-4-yl)morpholine
(ATR):
n
(cmꢂ1) 1573, 1533; HRMS (ESI) m/z calcd for C13H16N3O2
(6c). Yield¼89% (white solid), mp 165e167 ꢀC; 1H NMR (300 MHz,
(MþH)þ 246.1237, found (MþH)þ 246.1235 (Δ¼ꢂ0.99 ppm); HPLC
purity¼98.3% (tR¼1.61 min, method A).
CDCl3): d (ppm) 3.68 (m, 4H), 3.91 (m, 4H), 3.96 (s, 3H), 3.99 (s, 3H),
6.52 (m, 1H), 7.05 (s, 1H), 7.24 (m, 1H), 7.37 (s, 1H), 7.59 (m, 1H); 13C
NMR (75 MHz, CDCl3): (ppm) 50.2, 56.0, 56.2, 66.6, 102.9, 108.0,
109.9, 111.7, 112.2, 144.4, 148.3, 149.5, 152.0, 153.0, 154.6, 164.0; IR
d
4.2.22. 4-(2-(Benzofuran-2-yl)pyrimidin-4-yl)morpholine
(4i). Yield¼91% (white solid), mp 177e178 ꢀC; 1H NMR
(ATR): n
(cmꢂ1) 1620, 1570, 1544; HRMS (ESI) m/z calcd for
(300 MHz, CDCl3):
d
(ppm) 3.71 (m, 4H), 3.80 (m, 4H), 6.39 (d,
C18H20N3O4 (MþH)þ 342.1448, found (MþH)þ 342.1446
(Δ¼ꢂ0.79 ppm); HPLC purity¼99.7% (tR¼2.07 min, method A).
J¼6.2 Hz, 1H), 7.24 (m, 1H), 7.34 (m, 1H), 7.57 (s, 1H), 7.62 (m,
2H), 8.34 (d, J¼6.2 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d (ppm)
43.9, 66.5, 101.4, 108.5, 112.0, 121.8, 123.1, 125.7, 128.3, 154.0,
4.2.29. 4-(2-(Furan-2-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine
155.6, 156.2, 157.2, 161.6; IR (ATR):
n
(cmꢂ1) 1568, 1547; HRMS
(6d). Yield¼96% (white solid), mp 143e145 ꢀC; 1H NMR (300 MHz,
(ESI) m/z calcd for C16H16O2N3 (MþH)þ 282.1237, found (MþH)þ
282.1235 (Δ¼ꢂ0.81 ppm). HPLC purity¼99.6% (tR¼2.14 min,
method A).
DMSO-d6):
d
(ppm) 3.77 (m, 4H), 3.95 (m, 4H), 6.64 (dd, J¼3.4,
1.7 Hz, 1H), 7.22 (dd, J¼3.4, 0.8 Hz, 1H), 7.47 (d, J¼5.7 Hz, 1H), 7.84
(dd, J¼1.7, 0.8 Hz, 1H), 8.23 (d, J¼5.7 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6):
d (ppm) 45.8, 66.0, 111.7, 112.1(2), 124.6, 134.0, 144.7,
4.2.23. 4-(2-(Thiophen-2-yl)pyrimidin-4-yl)morpholine
152.4, 152.9, 157.6, 162.0; IR (ATR): n
(cmꢂ1) 1541, 1520; HRMS (ESI)
(4j). Yield¼96% (white solid), mp 107e108 ꢀC; 1H NMR
m/z calcd for C14H14N3O2S (MþH)þ 288.0801, found (MþH)þ
288.0800 (Δ¼ꢂ0.37 ppm); HPLC purity¼98.8% (tR¼1.81 min,
method A).
(300 MHz, DMSO-d6):
d (ppm) 3.65 (m, 4H), 3.67 (m, 4H), 6.69 (d,
J¼6.2 Hz, 1H), 7.14 (dd, J¼5.0, 3.7 Hz, 1H), 7.65 (dd, J¼5.0, 1.1 Hz,
1H), 7.83 (dd, J¼3.7, 1.1 Hz, 1H), 8.21 (d, J¼6.2 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6):
d
(ppm) 43.6, 65.8, 101.3, 128.0, 128.1, 129.8,
4.2.30. 4-(2-(Furan-2-yl)pyrido[2,3-d]pyrimidin-4-yl)morpholine
144.0, 156.1, 159.4, 161.3; IR (ATR):
n
(cmꢂ1) 1578, 1533; HRMS
(6e). Yield¼92% (white solid), mp 178e180 ꢀC; 1H NMR (300 MHz,
(ESI) m/z calcd for C12H14ON3S (MþH)þ 248.0852, found (MþH)þ
248.0850 (Δ¼ꢂ1.00 ppm); HPLC purity¼99.1% (tR¼1.61 min,
method A).
CDCl3):
d
(ppm) 3.86 (m, 8H), 6.53 (dd, J¼3.5, 1.7 Hz, 1H), 7.25 (dd,
J¼8.3, 4.4 Hz, 1H), 7.41 (d, J¼3.5 Hz, 1H), 7.60 (d, J¼1.7 Hz, 1H), 8.12
(dd, J¼8.3, 1.8 Hz, 1H), 8.96 (dd, J¼4.4, 1.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3):
d (ppm) 50.0, 66.6, 109.3, 112.1, 114.6, 119.7, 133.8,
4.2.24. 4-(2-(2,20-Bithiophen-5-yl)pyrimidin-4-yl)morpholine
145.2, 152.4, 155.6, 156.0, 161.0, 165.1; IR (ATR): n
(cmꢂ1) 1583, 1562,
(4k). Yield¼99% (yellow solid), mp 162e164 ꢀC; 1H NMR (300 MHz,
1533; HRMS (ESI) m/z calcd for C15H15N4O2 (MþH)þ 283.1190,
found (MþH)þ 283.1187 (Δ¼ꢂ0.95 ppm); HPLC purity¼99.5%
(tR¼1.36 min, method A).
CDCl3):
d
(ppm) 3.67 (m, 4H), 3.78 (m, 4H), 6.28 (d, J¼6.2 Hz, 1H),
7.02 (m, 1H), 7.15 (d, J¼3.9 Hz, 1H), 7.23 (m, 2H), 7.77 (d, J¼3.9 Hz,
1H), 8.20 (d, J¼6.2 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d (ppm) 43.9,
66.5, 100.3, 124.1, 124.3, 124.9, 127.9, 128.7, 137.4, 140.6, 142.5, 156.1,
4.2.31. 2-(Furan-2-yl)quinoline (6f). Yield¼95% (white solid), mp
160.1, 161.5; IR (ATR):
n
(cmꢂ1) 1570, 1535; HRMS (ESI) m/z calcd for
90e91 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
(ppm) 6.72 (dd, J¼3.5,
C16H16N3OS2 (MþH)þ 330.0729, found (MþH)þ 330.0728
(Δ¼ꢂ0.53 ppm); HPLC purity¼99.8% (tR¼2.69 min, method A).
1.8 Hz, 1H), 7.35 (m, 1H), 7.56 (m, 1H), 7.77 (m, 1H), 7.93 (m, 3H),
7.99 (d, J¼8.4 Hz, 1H), 8.40 (d, J¼8.6 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6):
d (ppm) 110.7, 112.6, 117.4, 126.4, 126.9, 128.0, 128.6,
4.2.25. 4-(2-(Benzo[b]thiophen-2-yl)pyrimidin-4yl)-morpholine
130.2, 137.1, 145.0, 147.5, 148.4, 153.1; IR (ATR): n
(cmꢂ1) 1598,
(4l). Yield¼93% (white solid), mp 163e164 ꢀC; 1H NMR (300 MHz,
1556, 1500; HRMS (ESI) m/z calcd for C13H10NO (MþH)þ 196.0757,
found (MþH)þ 196.0754 (Δ¼ꢂ1.28 ppm); HPLC purity¼99.0%
(tR¼1.65 min, method A).
CDCl3):
d
(ppm) 3.67 (m, 4H), 3.79 (m, 4H), 6.32 (d, J¼6.2 Hz, 1H),
7.33 (m, 2H), 7.81 (m, 2H), 8.15 (s, 1H), 8.26 (d, J¼6.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3): d (ppm) 43.9, 66.5, 100.8, 122.5, 124.4, 124.6,
124.8, 125.3, 140.1, 141.4, 144.1, 156.1, 160.5, 161.5; IR (ATR):
n
(cmꢂ1
)
4.2.32. 2-(Furan-2-yl)quinoxaline (6g). Yield¼74% (orange solid),
1570, 1537; HRMS (ESI) m/z calcd for C16H16N3OS (MþH)þ
298.1009, found (MþH)þ 298.1008 (Δ¼ꢂ0.10 ppm); HPLC
purity¼99.3% (tR¼2.54 min, method A).
mp 102e103 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d (ppm) 6.79 (dd,
J¼3.6, 1.7 Hz, 1H), 7.58 (dd, J¼3.6, 0.6 Hz, 1H), 7.81 (m, 2H), 8.05 (m,
3H), 9.38 (m, 1H); 13C NMR (75 MHz, DMSO-d6):
(ppm) 112.9,
113.0, 128.8, 129.0, 129.7, 130.9, 140.6, 141.3, 142.6, 143.5, 146.3,
d
4.2.26. 2-(Furan-2-yl)isonicotinic acid (6a). Yield¼99% (white
150.9; IR (ATR): n
(cmꢂ1) 1612, 1558, 1552; HRMS (ESI) m/z calcd
solid), mp 226e227 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
(ppm) 6.67
for C12H9N2O (MþH)þ 197.0709, found (MþH)þ 197.0709
(Δ¼ꢂ0.01 ppm); HPLC purity¼99.4% (tR¼2.86 min, method A).
(m, 1H), 7.20 (d, J¼3.3 Hz, 1H), 7.69 (d, J¼5.1 Hz, 1H), 7.89 (m, 1H),
8.08 (s, 1H), 8.74 (d, J¼5.1 Hz, 1H), 13.8 (br s, 1H); 13C NMR (75 MHz,
DMSO-d6):
d
(ppm) 109.8, 112.6, 116.9, 121.1, 139.3, 144.8, 149.5,
4.2.33. 4-(Furan-2-yl)furo[3,2-c]pyridine (6h). Yield¼96% (yellow
150.8, 152.4, 166.0; IR (ATR):
n
(cmꢂ1) 1728, 1616, 1562; HRMS (ESI)
oil); 1H NMR (300 MHz, DMSO-d6):
d (ppm) 6.72 (m, 1H), 7.26 (d,
m/z calcd for C10H8NO3 (MþH)þ 190.0499, found (MþH)þ 190.0497
(Δ¼ꢂ0.74 ppm); HPLC purity¼99.3% (tR¼1.52 min, method A).
J¼3.5 Hz, 1H), 7.42 (m, 1H), 7.59 (d, J¼5.7 Hz, 1H), 7.94 (m, 1H), 8.19
(d, J¼2.0 Hz, 1H), 8.45 (d, J¼5.7 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6):
d (ppm) 105.8, 106.0, 110.3, 112.4, 119.2, 142.8, 144.4, 144.8,
4.2.27. 2-(Furan-2-yl)-4-methoxypyridine (6b). Yield¼86% (white
147.3, 153.2, 159.8; IR (ATR): n
(cmꢂ1) 1593, 1560, 1531; HRMS (ESI)
solid), mp 34e36 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d
(ppm) 3.87
m/z calcd for C11H8NO2 (MþH)þ 186.0550, found (MþH)þ 186.0546
(Δ¼ꢂ1.77 ppm); HPLC purity¼98.0% (tR¼1.08 min, method A).
(s, 3H), 6.64 (dd, J¼3.4, 1.7 Hz, 1H), 6.87 (dd, J¼5.7, 2.6 Hz, 1H), 7.09
(d, J¼3.4 Hz, 1H), 7.23 (d, J¼2.6 Hz, 1H), 7.82 (d, J¼1.7 Hz, 1H), 8.37
(d, J¼5.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6):
d
(ppm) 55.4, 103.9,
(cmꢂ1
4.2.34. 4-(Furan-2-yl)thieno[3,2-c]pyridine (6i). Yield¼96% (yellow
108.8, 109.1, 112.3, 144.1, 150.1, 151.0, 153.0, 165.9; IR (ATR):
n
)
oil); 1H NMR (300 MHz, DMSO-d6):
d (ppm) 6.73 (m, 1H), 7.29 (d,
1605, 1577, 1558; HRMS (ESI) m/z calcd for C10H10NO2 (MþH)þ
J¼3.5 Hz, 1H), 7.99 (m, 3H), 8.13 (m, 1H), 8.42 (m, 1H); 13C NMR

S. Asano et al. / Tetrahedron 68 (2012) 272e279
279
124, 13662e13663; (b) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S.
L. Angew. Chem., Int. Ed. 2004, 43, 1871e1876; (c) Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685e4696;
(d) Khanapure, S. P.; Garvey, D. S. Tetrahedron Lett. 2004, 45, 5283e5286;
(e) Guram, A. G.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan, J.;
Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.; Reider, P. J. Org. Lett.
2006, 8, 1787e1789.
(75 MHz, DMSO-d6):
d (ppm) 111.0, 112.3, 116.6, 122.8, 129.4, 130.1,
142.1, 143.6, 144.8, 148.4, 153.8; IR (ATR):
n
(cmꢂ1) 1587, 1533;
HRMS (ESI) m/z calcd for C11H8NOS (MþH)þ 202.0321, found
(MþH)þ
202.0320
(tR¼1.30 min, method A).
(Δ¼ꢂ0.41 ppm);
HPLC
purity¼99.7%
11. For some representative example of the coupling utilizing the combination of
€
carbenes with different palladium sources, see: (a) Gstottmayr, C. W. K.; Bohm,
Acknowledgements
V. P. W.; Herdtweck, E.; Grosche, M.; Herrmann, W. A. Angew. Chem., Int. Ed.
2002, 41, 1363e1365; (b) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F.
J. Am. Chem. Soc. 2004, 126, 15195e15201; (c) Hadei, N.; Kantchev, E. A. B.;
O’Brien, C. J.; Organ, M. G. Org. Lett. 2005, 7, 1991e1994; (d) Marion, N.; Navarro,
O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128,
4101e4111.
We are grateful to Ms. M. Homma for recording HRMS spectra of
all new compounds.
Supplementary data
12. For some example of the coupling of 2-heterocyclic boronic acids, see: (a)
Burns, M. J.; Fairlamb, I. J. S.; Kapdi, A. R.; Sehnal, P.; Taylor, R. J. Org. Lett. 2007,
9, 5397e5400; (b) Pagano, N.; Maksimoska, J.; Bregman, H.; Williams, D. S.;
Webster, R. D.; Xue, F.; Meggers, E. Org. Biomol. Chem. 2007, 5, 1218e1227; (c)
Guram, A. S.; Wang, X.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J. J.
Org. Chem. 2007, 72, 5104e5112; (d) Gill, G. S.; Grobelny, D. W.; Chaplin, J. H.;
Flynn, B. L. J. Org. Chem. 2008, 73, 1131e1134; (e) Li, J. H.; Zhu, Q. M.; Xie, Y. X.
Tetrahedron 2006, 62, 10888e10895; (f) Yaziji, V.; Coelho, A.; Maatougui, A. E.;
Brea, J.; Loza, M. I.; Garcia-Mera, X.; Sotelo, E. J. Comb. Chem. 2009, 11, 519e522;
(g) Yaziji, V.; Rodrigues, D.; Gutierrez-de-Teran, H.; Coelho, A.; Caamano, O.;
Garcia-Mera, X.; Brea, J.; Loza, M. I.; Cadavid, M. I.; Sotelo, E. J. Med. Chem. 2011,
54, 457e471.
13. Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073e14075.
14. Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961e6963.
15. (a) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302e4314; (b) Barder, T.
E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649e2652; (c) Molander, G. A.; Canturk,
B.; Kennedy, L. E. J. Org. Chem. 2009, 74, 973e980.
Kinetic studies of 1a, 2-furyl pinacol boronate, and
2-furylboronic acid, and 1H and 13C NMR spectra for all new com-
pounds. Supplementary data associated with this article can be
found in online version, at doi:10.1016/j.tet.2011.10.057.
References and notes
1. Burns, C. J.; Harte, M. F.; Bu, X.; Fantino, E.; Joffe, M.; Sikanyika, H.; Su, S.;
Tranberg, C. E.; Wilson, N.; Charman, S. A.; Shackleford, D. M.; Wilks, A. Bioorg.
Med. Chem. Lett. 2009, 19, 4639e4642.
2. Raynaud, F. I.; Eccles, S. A.; Patel, S.; Alix, S.; Box, G.; Chuckowree, A.; Folkes, A.;
Gowan, S.; Brandon, A. D. H.; Stefano, F. D.; Hayes, A.; Henley, A. T.; Lensun, L.;
Pergl-Wilson, G.; Robson, A.; Saghir, N.; Zhyvoloup, A.; McDonald, E.; Shel-
drake, P.; Shuttleworth, S.; Valenti, M.; Wan, N. C.; Clarke, P. A.; Workman, P.
Mol. Cancer Ther. 2009, 8, 1725e1738.
16. Yamamoto, Y.; Takizawa, M.; Yu, X. Q.; Miyaura, N. Angew. Chem., Int. Ed. 2008,
47, 928e931.
17. Anderson, S. C.; Handy, S. T. Synthesis 2010, 16, 2721e2724.
18. (a) Gills, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716e6717; (b) Dick, G.
R.; Knapp, D. M.; Gills, E. P.; Burke, M. D. Org. Lett. 2010, 12, 2314e2317.
19. Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275e286.
20. A review, see: Nesmeyanov, A. N.; Sokolik, R. A. Methods of Elemento-Organic
Chemistry; North-Holland: Amsterdam, 1967; Vol. 1.
21. A review, see: (a) Ishiyama, T.; Miyaura, N. J. Synth. Org. Chem. Jpn. 1999, 57,
503e511; (b) Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2000, 611, 392e402;
(c) Miyaura, N. In Catalytic Heterofunctionalization; Togni, A., Grutzmacher, H. E.,
Eds.; Wiley-VCH: Chichester, UK, 2001, Chapter 1.
3. Caldwell, J. J.; Welsh, E. J.; Matijssen, C.; Anderson, V. E.; Antoni, L.; Boxall, K.;
Urban, F.; Hayes, A.; Raynaud, F. I.; Rigoreau, L. J.; Raynham, T.; Aherne, G. W.;
Pearl, L. H.; Oliver, A. W.; Garrett, M. D.; Collins, I. J. Med. Chem. 2011, 54,
580e590.
4. Gellibert, F.; Fouchet, M. H.; Nguyen, V. L.; Wang, R.; Krysa, G.; de Gouville, A.
C.; Huet, S.; Dodic, N. Bioorg. Med. Chem. Lett. 2009, 19, 2277e2281.
5. Gong, G.; Xie, Y.; Liu, Y.; Rinderspacher, A.; Deng, S. X.; Feng, Y.; Zhu, Z.; Tang, Y.;
Wyler, M.; Aulner, N.; Toebben, U.; Smith, D. H.; Branden, L.; Chung, C.; Schurer,
S.; Vidovic, D.; Landy, D. W. Bioorg. Med. Chem. Lett. 2009, 19, 1191e1194.
6. (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176e4211; (b) Slagt, V.
F.; de Vries, A. H. M.; de Vries, G.; Kellogg, R. M. Org. Process Res. Dev. 2010, 14,
30e47.
7. (a) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358e3366; (b)
Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45,
3484e3488.
8. Fleckenstein, C. A.; Plenio, H. J. Org. Chem. 2008, 73, 3236e3244.
9. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437e3440;
(b) Miyaura, N. J. Organomet. Chem. 2002, 653, 54e57; (c) Miyaura, N. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., de Maijere, A., Eds.; Wiley-
VCH: New York, NY, 2004.
22. (a) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62, 6458e6459; (b)
Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem. 2000, 65,
164e168.
23. Ishikawa, S.; Manabe, K. Chem. Commun. 2006, 2589e2591.
24. (a) Fleckenstein, C. A.; Plenio, H. Chem.dEur. J. 2007, 13, 2701e2716; (b)
Fleckenstein, C. A.; Plenio, H. Chem.dEur. J. 2008, 14, 4267e4279.
25. (a) Chaumeil, H.; Signorella, S.; Drian, C. L. Tetrahedron 2000, 56, 9655e9662;
(b) Chaumeil, H.; Drian, C. L.; Defoin, A. Synthesis 2002, 6, 757e760.
26. Bayliss, T.; Chuchowree, I.; Folkes, A.; Oxenford, S.; Wan, N. C.; Castanedo, G.;
Goldsmith, R.; Gunzner, J.; Heffron, T.; Mathieu, S.; Olivero, A.; Staben, S.; Su-
therlin, D. P.; Zhu, B. Y. US 2008/0242,665 A1, 2008.
10. For some representative example of the coupling utilizing the combination of
the bulky and electron-rich phosphines with different palladium sources, see:
(a) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002,
27. Cho, C. S.; Kim, B. T.; Choi, H. J.; Kim, T. J.; Shim, S. C. Tetrahedron 2003, 59,
7997e8002.