Synthesis of Alkylated Pyrimidines via Photoinduced Coupling Using Benzophenone as a Mediator

Article abstract of DOI:10.1021/acs.joc.6b03058

The synthesis of alkylated pyrimidines was achieved via benzophenone-mediated photoinduced coupling between saturated heterocycles and sulfonylpyrimidines. The pyrimidine ring was selectively introduced at the nonacidic C(sp³)-H bond proximal to heteroatoms including oxygen, nitrogen, and sulfur. This is a coupling reaction mediated solely by photoexcited benzophenone, an organic molecule, without the aid of any metallic catalysts or reagents.

Full text of DOI:10.1021/acs.joc.6b03058

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Article
Synthesis of Alkylated Pyrimidines via Photoinduced
Coupling Using Benzophenone as a Mediator
Shin Kamijo, Kaori Kamijo, and Toshihiro Murafuji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b03058 • Publication Date (Web): 14 Feb 2017
Downloaded from http://pubs.acs.org on February 14, 2017
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Synthesis of Alkylated Pyrimidines via Photoinduced Coupling Using
Benzophenone as a Mediator
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Shin Kamijo,* Kaori Kamijo, and Toshihiro Murafuji
Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Yamaguchi
7
53ꢀ8512, Japan
TOC
ABSTRACT: The synthesis of alkylated pyrimidines was achieved via benzophenoneꢀmediated
photoinduced coupling between saturated heterocycles and sulfonylpyrimidines.
The
3
pyrimidine ring was selectively introduced at the nonacidic C(sp )–H bond proximal to
heteroatoms including oxygen, nitrogen, and sulfur. This is a coupling reaction mediated
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solely by photoexcited benzophenone, an organic molecule, without the aid of any metallic
catalysts or reagents.
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INTRODUCTION
Molecules containing a pyrimidine ring are critically important for life since their derivatives,
including cytosine, thymine, uracil, guanine, and adenine, are fundamental building blocks of
1
DNA and RNA. The pyrimidine core can also be found in a variety of biologically active
compounds, so the pyrimidine ring is considered to be one of the most privileged scaffolds in
2
the field of pharmaceutical sciences (Figure 1). For example, Gleevec is a commercialized
3
tyrosine kinase inhibitor for leukemia treatment, which works only for targeting cancer.
4
MKꢀ0457 is another drug candidate for cancer that acts as an aurora kinase inhibitor. Crestor
is a wellꢀknown drug for dyslipidemia treatment, which inhibits the enzyme HMGꢀCoA
5
reductase.
The recent advancements of medicinal chemistry have brought attention to
pyrimidine derivatives attached with an alkyl side chain, such as Raltegravir and XL413.
Raltegravir, containing the pyrimidineꢀbased core, is an antiretroviral drug for treatment of HIV
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infection. XL413 inhibits cell division and is thus considered as a potent anticancer agent.
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Most of these molecules contain a pyrimidine ring as the core structure, so contributions to the
development of new synthetic methods for pyrimidine derivatives are of great importance.
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Figure 1. Representative Drugs and Drug Candidates Containing a Pyrimidine Core
Direct introduction of alkyl chains to nitrogenꢀcontaining sixꢀmembered heteroaromatics
often poses a challenge. The Friedel–Crafts reaction, for instance, is a standard method for
alkylation of benzene rings; however, this strategy is not suited for pyrimidines due to the lack
of nucleophilicity caused by the high electronegativity of the nitrogen atoms. Additionally, the
coordinating ability of the nitrogen atom generally deactivates Lewis acids. Nucleophilic
aromatic substitution is a promising option for direct alkylation of such electronꢀdeficient
pyrimidines, although loss of regioselectivity can be a problem depending on substitution
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patterns of the starting pyrimidines (Figure 2). To circumvent the regioselectivity issue,
alkylated pyrimidines are often prepared by assembly of several fragments through the
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formation of the pyrimidine ring itself, such as dehydrative condensation of 1,3ꢀdicarbonyl
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derivatives and amidines.
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Figure 2. The General Reactivity Order of the Halogenated Pyrimidines for Nucleophilic
Aromatic Substitution
Advancement of coupling strategies now allows the direct introduction of alkyl chains onto
pyrimidine rings. The Negishi coupling is reported to be effective for synthesis of alkylated
8b,10
pyrimidines from alkylzinc species and halogenated pyrimidines (a, Scheme 1).
Recently,
the MacMillan group applied the photoredox Ir catalysis to introduce cyclic amine and ether
1
1
moieties to pyrimidines (b, Scheme 1).
Despite that these reactions are efficiently promoted
by a catalytic amount of an Ir complex (<2 mol %), there are several limitations. For instance,
only electronꢀrich amines, such as Nꢀphenyl pyrrolidine and Nꢀphenyl morpholine, are suitable
since the single electron transfer (SET) process plays an important role for introducing an amine
moiety, and only two pyrimidine derivatives bearing tetrahydropyran moiety are prepared.
Our coupling strategy is based on a radical reaction, in which a carbon radical is generated
3
via homolytic cleavage of a nonacidic C(sp )–H bond by making use of a highly reactive oxyl
1
2,13,14,15
radical species derived from a photoexcited aryl ketone (c, Scheme 1).
Detailed
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reaction pathway for the preparation of alkylated pyrimidines 3 was planned as illustrated in
Scheme 2. The carbon radical A, generated via hydrogen abstraction from the starting
substance 1 by the oxyl radical species of the photoexcited aryl ketone along with formation of
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1
3a
the ketyl radical B, adds to sulfonylated pyrimidine 2 furnishing the radical C.
Liberation of
the sulfonyl radical from C completes rearomatization and provides the desired product 3.
The aryl ketone is regenerated when the hydrogen atom is transferred from B to the liberated
1
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sulfonyl radical.
In this communication, we report a novel method for direct alkylation of
pyrimidines starting from saturated heterocycles, such as ethers, carbamates, amide, and sulfide,
and sulfonylpyrimidines via photoinduced coupling using benzophenone (Ph CO), an organic
2
molecule, as a mediator. The present transformation accomplishes direct substitutive
3
introduction of a pyrimidine ring at the nonacidic C(sp )–H bonds proximal to heteroatoms,
including oxygen, nitrogen and sulfur, under neutral conditions at ambient temperature without
the aid of any metallic catalysts or reagents utilizing a unified protocol.
Scheme 1. Preparation of Alkylated Pyrimidines by Coupling Strategies
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Scheme 2. A Proposed Reaction Pathway for Aryl Ketone-Mediated Photoinduced
Preparation of Alkylated Pyrimidines
RESULTS AND DISCUSSION
Prior to optimizing the reaction conditions, we designed 2ꢀmethanesulfonylpyrimidine 2a as a
coupling partner due to the excellent leaving ability of the sulfonyl unit in our series of related
3
13,17
substitutive functionalizations of nonacidic C(sp )–H bonds (Table 1).
Among the aryl
1
3,14
ketones examined, benzophenone (Ph
2
CO)
exhibited a higher catalytic activity compared to
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3a, 18
13b
4
ꢀbenzoylpyridine (4ꢀBzPy)
and 2ꢀchloroanthraquinone (2ꢀClAQ)
for the coupling
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between tetrahydrofuran (THF, 1a) and 2a (entries 1–3).
The pyrimidine ring was
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chemoselectively introduced at the C–H bond adjacent to the oxygen atom of the starting ether
1a, and the 2ꢀarylated adduct 3a was formed. It is important to note that the coupling took
place regioselectively at the sulfonylated carbon center to provide the 2ꢀalkylated pyrimidine 3a
and no adduct derived via the substitution at the chlorinated carbon center was observed. It
should be also emphasized that the coupling between THF 1a, an inherently reactive substance,
and highly electronꢀdeficient 4,6ꢀdichloroꢀ2ꢀmethanesulfonylpyrimidine 2a was smoothly
promoted by a catalytic amount of Ph CO (0.1 equiv). The coupling took place in a range of
2
14a,h
solvents, including CH Cl , benzene, CH CN, and CH CN/H O (2:1),
and the adduct 3a was
2
2
3
3
2
furnished in essentially the same yields (69–74%, entries 1 and 4–6). The solvent screening
revealed that the present transformation proceeds even in the presence of water. When THF
was employed as a solvent (123 equiv to 2a), the reaction completed in a shorter reaction time
and gave a higher yield of 3a (entry 7).
a
Table 1. Optimization of Reaction Conditions
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entry aryl ketone
solvent
CH Cl
CH Cl2
time, h yield, %
c
d
e
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Ph
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CO
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4ꢀBzPy
2ꢀClAQ
2
CH
benzene
CH CN
CN/H
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Cl
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Ph CO
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69
86
2
Ph
Ph
Ph
2
2
2
CO
3
5
CO CH
CO
3
2
O (2:1) 10
f
THF
3.5
a
Conditions: THF 1a (10 equiv), sulfonylpyrimidine 2a (1 equiv), Ph
2 2 2
CO (0.1 equiv), CH Cl (0.1 M),
photoꢀirradiation under an Ar atmosphere using a mediumꢀpressure Hg lamp at rt unless otherwise noted.
b
c
d
Yield determined by NMR analysis. Isolated yield. The sulfonylpyrimidine 2a was recovered in
e
f
76% yield. The sulfonylpyrimidine 2a was recovered in 16% yield. THF 1a was employed as a
solvent (123 equiv to 2a).
With the standard reaction conditions in hand, we investigated the generality of the
2
Ph COꢀcatalyzed photoinduced coupling by utilizing a variety of saturated heterocycles 1b–i
and 4,6ꢀdichloroꢀ2ꢀmethanesulfonylpyrimidine 2a (Scheme 3). The reactions employing
tetrahydropyran 1b, oxepane 1c, and oxetane 1d as starting substances gave rise to the
corresponding adducts 3b–d in 29% to 68% yields. Accordingly, the ethereal C–H bonds of 4ꢀ
2
0
to 7ꢀmembered cyclic ethers were successfully arylated irrespective of the ring size.
The
couplings of 5ꢀ to 7ꢀmembered azacycles 1e–g took place selectively at the C–H bond adjacent
2
1,22
to the nitrogen atom and the 2ꢀarylated adducts 3e–g were produced in good yields.
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reaction employing pyrrolidone 1h produced the adduct 3h (71%) with the C–C bond formation
at the carbon center next to the nitrogen atom as well. To highlight the synthetic versatility of
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4
,6ꢀdichloroꢀ2ꢀmethanesulfonylpyrimidine 2a as a scaffold, we subjected pyrrolidone 1h under
anionic conditions (eq 1). The nucleophilic aromatic substitution took place regioselectively at
the sulfonylated carbon center and the C–N bond was formed in 44% yield (3h’). This result
clearly shows that pyrimidine isomers can be selectively prepared starting from the same
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3
combination of the substances merely by choosing the appropriate reaction conditions.
The
coupling using tetrahydrothiophene 1i under the catalytic conditions proceeded with similar
2
4
selectivity but with a lower yield of the expected adduct 3i (31%).
In this case, the
25,26,27
employment of a stoichiometric amount of Ph CO improved the product yield up to 72%.
2
Scheme
3.
Coupling
between
Saturated
Heterocycles
and
a,b
4
,6-Dichloro-2-methanesulfonylpyrimidine
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Conditions as described in entry 1 of Table 1, unless otherwise noted. Isolated yield. The starting
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carbamates 1e–g (5 equiv) was employed. Isolated yield of 3f’ in twoꢀstep after Boc deprotection of
e
f
the coupling adduct 3f. Irradiated with an LED lamp (365 nm). The sulfonylpyrimidine 2a was
g
recovered in 65% yield. Ph
2
CO (1 equiv) was employed.
We next explored the applicability and reactivity of sulfonylpyrimidines 2b–f to the present
photoinduced coupling in combination with THF 1a (Table 2).
Electronꢀdonating
methoxyꢀsubstituted sulfonylpyrimidine 2b and nonꢀsubstituted sulfonylpyrimidine 2c showed
lower reactivity and the respective adducts 3j and 3k were formed in 48% and 42% yields when
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the reaction was conducted with a stoichiometric amount of Ph CO in THF (entries 1 and 2).
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These results clearly indicated the superior reactivity of the electronꢀdeficient chlorinated
pyrimidine 2a to the electronꢀrich methoxy and nonꢀsubstituted pyrimidines 2b and 2c. Such
reactivity difference was probably caused by the electronꢀrich nature of the carbon radical A
generated from THF 1a (vide supra, Scheme 2). Nevertheless, the low reactivity of
pyrimidines 2b and 2c could be successfully made up by conducting the reaction with a
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stoichiometric amount of Ph CO in THF solvent to some extent, giving the corresponding
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adducts 3j and 3k in moderate yields (48% and 42%, respectively). On the other hand, the
reaction of 2,6ꢀdichloroꢀ4ꢀmethanesulfonylpyrimidine 2d was smoothly catalyzed by Ph CO
2
(
0.1 equiv) to provide the adduct 3l in 75% yield (entry 3). It is important to note that the
coupling took place regioselectively at the sulfonylated carbon center to give 4ꢀsubstituted
pyrimidine 3l in this case. The monoꢀchlorinated sulfonylpyrimidines 2e and 2f again showed
lower reactivities, and the expected adducts 3m (72%) and 3n (31%) were obtained after
subjecting them to a stoichiometric amount of Ph CO in THF (entries 4 and 5).
2
a,b
Table 2. Coupling between THF and Sulfonylated Pyrimidines
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entry pyrimidine 2 time, h product 3 yield, %
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24
48
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75
c
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3
72
31
a
Conditions: THF 1a (0.1 M, 123 equiv), sulfonylpyrimidines 2 (1 equiv), Ph
2
CO (1 equiv),
photoꢀirradiation under an Ar atmosphere using a mediumꢀpressure Hg lamp at rt unless otherwise noted.
b
c
Isolated yield. The reaction was conducted using THF 1a (10 equiv), sulfonylated pyrimidine 2d (1
equiv), and Ph CO (0.1 equiv) in CH Cl (0.1 M) with photoꢀirradiation under an Ar atmosphere using a
mediumꢀpressure Hg lamp at rt.
2
2
2
To demonstrate the utility of the newly developed coupling reaction and to show the synthetic
applicability of the derived coupling products, we prepared an analogue of the aurora kinase
4
inhibitor, MKꢀ0457 (Figure 1), using the dichloropyrimidine substituted with the azacycle 3e
(
Scheme 4). The Ph
2
COꢀcatalyzed photoinduced coupling between the pyrrolidine derivative
28
1
e and sulfonylpyrimidine 2a furnished the corresponding adduct 3e in ca. 67% yield even
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when the amount of the starting substance 1e was reduced to 2 equiv, although a longer reaction
time was required (cf. 80% in 6 h, Scheme 3). The derived 3e was then subjected to the
reaction with methylpiperazine to furnish the adduct 4 in 91% yield. Subsequent coupling
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2
9
with the Bocꢀprotected aminopyrazole under a palladium catalyst and basic treatment for
deprotection of the Boc group on the pyrazole ring gave rise to the target molecule 5 in 81%
30
yield.
Alternatively, the coupling of 3e with the Bocꢀprotected aminopyrazole, then
introduction of the methylpiperazine unit furnished the same product 5 as well. We thus
achieved the synthesis of the MKꢀ0457 analogue 5 in three steps starting from
4,6ꢀdichloroꢀ2ꢀmethanesulfonylpyrimidine 2a, which clearly indicated its advantage as a
scaffold leading to pyrimidine derivatives with a wide array of substituents.
Scheme 4. Preparation of an Analogue of the Aurora Kinase Inhibitor, MK-0457
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CONCLUSION
In conclusion, we have developed a preparation method for alkylated pyrimidines via
2
Ph COꢀmediated photoinduced coupling starting from saturated heterocycles and
sulfonylpyrimidines.
This is a coupling reaction mediated solely by photoexcited
benzophenone, an organic molecule, without the aid of any metallic catalysts or reagents. The
present transformation allows direct substitutive introduction of pyrimidine rings at nonacidic
3
C(sp )–H bonds proximal to heteroatoms, including oxygen, nitrogen and sulfur, under neutral
reaction conditions at ambient temperature. Moreover, we disclosed that the catalytic coupling
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is operative for highly electronꢀdeficient dichlorinated sulfonylpyrimidines, which highlights
their utility as a scaffold for the construction of molecules having a pyrimidine core.
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EXPERIMENTAL SECTION
General Information. All reactions sensitive to air or moisture were carried out under an
argon atmosphere with anhydrous conditions unless otherwise noted. Analytical TLC was
performed on E. Merck silica gel 60 F254 preꢀcoated plates. Column chromatography was
performed using silica gel (Fuji Silysia and KANTO), NH silica gel (Fuji Silysia), or a
1
13
prepacked column using with a Biotage Isolera. The H and C NMR spectra were recorded
on a Bruker AVANCE IIIꢀ400 or Bruker DRX500 spectrometer. Chemical shifts are reported
1
in δ (ppm) relative to residual solvent signals [ H NMR: CHCl
3
(7.26), DMSOꢀd
6
(TMS, 0.00);
13
3 6
C NMR: CDCl (77.0), DMSOꢀd (39.52)]. Signal patterns are indicated as s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. IR spectra were recorded on
a JASCO FT/IRꢀ4100 spectrometer. HRMS were recorded on a Bruker Daltonics micrOTOF
II. Melting points were measured on a Cornes MPA100 micro melting point apparatus. UV
irradiation was carried out by using a Riko 100 W mediumꢀpressure mercury lamp, an LED
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lamp
of
KEYENCE
UVꢀ400
with
UVꢀ50A
or
UVꢀ50H
(365
nm).
4
4
,6ꢀDichloroꢀ2ꢀmethanesulfonylpyrimidine 2a (Tokyo Chemical Industry Co., LTD.) and
,6ꢀdimethoxyꢀ2ꢀmethanesulfonylpyrimidine 2b (Wako Pure Chemical Industries, Ltd.) were
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0
commercially available.
Preparation of the starting sulfonylpyrimidines.
2
-(Methylsulfonyl)pyrimidine (2c). To a CH Cl solution (32 mL) of 2ꢀmethylthiopyrimidine
2 2
(
323 mg, 2.56 mmol) was added m-CPBA (~77 wt%, 1.26 g, 5.63 mmol) at 0 ºC. The solution
was stirred at room temperature for 16 h and treated with sat. aq Na S O . The mixture was
2
2
3
extracted with CH Cl , washed with sat. aq NaHCO , water, and brine, dried over Na SO , and
2
2
3
2
4
concentrated. The residue was purified by flash column chromatography (silica gel, 10%
AcOEt in hexane to AcOEt) to provide the sulfonylpyrimidine 2c in 70% yield (281 mg) as a
3
1
colorless solid.
[CAS: 14161ꢀ09ꢀ2]: colorless solid; mp 67.7ꢀ69.5 ºC; IR (ATR) 3081, 3074, 3026, 3004, 2925,
–
1 1
1
564, 1549, 1387, 1306, 1214, 1126, 959, 824, 780, 730, 625 cm ; H NMR (400 MHz, CDCl )
3
31 13
3
δ 3.37 (3H, s), 7.59 (1H, t, J = 4.8 Hz), 8.95 (2H, d, J = 4.8 Hz) ; C NMR (100 MHz, CDCl )
+
δ 39.2, 123.9, 158.6, 166.2; HRMS (APCI) calcd for C H N O S [M+H] 159.0223, found
5
7
2
2
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59.0221.
,4-Dichloro-6-(methylsulfonyl)pyrimidine (2d). To
a
THF solution (15 mL) of
10
11
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13
14
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19
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60
,4,6ꢀtrichloropyrimidine (1.08 g, 5.88 mmol) was added NaSMe (15% in water, 2.68 mL, 6.18
mmol) at 3 ºC (cooled with an ice bath). The solution was gradually warmed to room
temperature for 4 h. The reaction was quenched with water and the mixture was extracted with
32
ether, washed with brine, dried over Na SO , and concentrated.
The residue was directly
2
4
used for the next step without further purification (white solid, 1.13 g; The purity of
2
,6ꢀdichloroꢀ4ꢀmethylthiopyrimidine
was
ca.
77%
and
contaminated
with
dichloro(methylthio)pyrimidine regioisomer, two chloro(dimethylthio)pyrimidines, and starting
2
,4,6ꢀtrichloropyrimidine.). The m-CPBA oxidation and the purification furnished the desired
33
sulfonylpyrimidine 2d as a pure form in 69% yield in two steps (915 mg) as a colorless solid.
[
CAS: 1048389ꢀ45ꢀ2]: colorless solid; mp 101.5ꢀ102.3 ºC; IR (ATR) 3111, 3032, 3002, 2923,
–
1
1
1542, 1524, 1311, 1279, 1223, 1182, 1141, 961, 838, 747, 617 cm ; H NMR (400 MHz,
1
3
CDCl ) δ 3.30 (3H, s), 7.96 (1H, s); C NMR (100 MHz, CDCl ) δ 39.3, 116.3, 161.4, 165.7,
3
3
+
1
68.5; HRMS (APCI) calcd for C H Cl N O S [M+H] 226.9443, found 226.9430.
5 5 2 2 2
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2
-Chloro-4-(methylsulfonyl)pyrimidine (2e). The compound 2e was obtained in 84% yield in
two steps (1.09 g) as a pure form from 2,4ꢀdichloropyrimidine (1.00 g, 6.75 mmol) through
0
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0
2
ꢀchloroꢀ4ꢀmethylthiopyrimidine (ca. 91% purity with contamination of its regioisomer)
3
4,35
followed by the procedures for preparation of the compounds 2c and 2d.
35
36
[
CAS: 1233026ꢀ31ꢀ7] ; colorless solid; mp 91.3ꢀ92.1 ºC ; IR (ATR) 3116, 3019, 3003, 2921,
–1
1
1
552, 1540, 1412, 1347, 1315, 1188, 1160, 1129, 960, 818, 753, 683, 618 cm ; H NMR (400
13
MHz, CDCl ) δ 3.30 (3H, s), 7.95 (1H, d, J = 4.8 Hz), 9.00 (1H, d, J = 4.8 Hz); C NMR (100
3
MHz, CDCl ) δ 39.1, 114.9, 161.9, 162.8, 168.0; HRMS (APCI) calcd for C H ClN O S
3
5
6
2
2
+
[M+H] 192.9833, found 192.9835.
4
-Chloro-6-(methylsulfonyl)pyrimidine (2f). The compound 2f was obtained in 82% yield in
two steps (1.59 g) as a pure form from 4,6ꢀdichloropyrimidine (1.50 g, 10.0 mmol) through
4
ꢀchloroꢀ6ꢀmethylthiopyrimidine
(ca.
93%
purity
with
contamination
of
(dimethylthio)pyrimidine and starting 4,6ꢀtrichloropyrimidine) followed by the procedures for
35,37
preparation of the compounds 2c and 2d.
35
[
CAS: 89283ꢀ46ꢀ5] : colorless solid; mp 127.4ꢀ128.1 ºC; IR (ATR) 3103, 3081, 3018, 2932,
–
1 1
1
547, 1534, 1442, 1308, 1284, 1135, 973, 903, 765, 746, 722, 610 cm ; H NMR (400 MHz,
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9
13
CDCl ) δ 3.28 (3H, s), 8.05 (1H, s), 9.15 (1H, s); C NMR (100 MHz, CDCl ) δ 39.4, 118.1,
3
3
+
1
59.2, 164.4, 166.6; HRMS (APCI) calcd for C H ClN O S [M+H] 192.9833, found 192.9829.
5 6 2 2
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General Procedure for Benzophenone-catalyzed photoinduced coupling: (entry 1 in Table
). A CH Cl solution (2 mL, 0.1 M) of 4,6ꢀdichloroꢀ2ꢀmethanesulfonylpyrimidine 2a (45.4 mg,
1
0
2
2
.2 mmol, 1 equiv), THF 1a (162 ꢀL, 2.0 mmol, 10 equiv), and benzophenone (3.64 mg, 0.02
®
mmol, 0.1 equiv) was prepared in a Pyrex test tube under an argon atmosphere. The test tube
was placed at ca. 5 cm distance from a mediumꢀpressure Hg lamp and was irradiated at room
temperature for 5 h. The mixture was concentrated and the residue was purified by flash
column chromatography (YMC DispoꢀpackAT SILꢀ25, hexane to 5% AcOEt in hexane) to
provide the coupling adduct 3a in 74% yield (32.2 mg) as a colorless oil.
4
,6-Dichloro-2-(tetrahydrofuran-2-yl)pyrimidine (3a). [CAS: 1483355ꢀ82ꢀ3]: IR (ATR) 3094,
–
1
1
3042, 2978, 2951, 2875, 1523, 1376, 1308, 1227, 1114, 1064, 846, 808 cm ; H NMR (400
MHz, CDCl ) δ 1.93ꢀ2.13 (3H, m), 2.34ꢀ2.48 (1H, m), 3.96ꢀ4.03 (1H, m), 4.14ꢀ4.21 (1H, m),
3
13
5
8
.03 (1H, dd, J = 7.6, 5.6 Hz), 7.28 (1H, s); C NMR (100 MHz, CDCl
3
) δ 25.7, 32.3, 69.7,
+
0.6, 119.6, 162.1, 172.9; HRMS (APCI) calcd for C H Cl N O [M+H] 219.0086, found
8
9
2
2
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2
2
2
2
2
2
3
3
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3
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3
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5
5
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6
2
19.0101.
4
,6-Dichloro-2-(tetrahydro-2H-pyran-2-yl)pyrimidine (3b). 29% yield (13.7 mg); colorless oil;
0
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2
3
4
5
6
7
8
9
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2
3
4
5
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7
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IR (ATR) 3080, 3035, 2937, 2862, 2847, 1525, 1373, 1320, 1264, 1226, 1082, 1047, 807, 784,
–
1 1
711 cm ; H NMR (400 MHz, CDCl ) δ 1.54ꢀ1.64 (1H, m), 1.64ꢀ1.84 (3H, m), 1.92ꢀ2.10 (2H,
3
m), 3.62 (1H, ddd, J = 11.6, 11.6, 2.0 Hz), 4.20ꢀ4.26 (1H, m), 4.50ꢀ4.58 (1H, m), 7.30 (1H, s);
13
C NMR (100 MHz, CDCl
3
) δ 23.3, 25.2, 31.3, 69.0, 80.0, 119.8, 162.2, 171.2; HRMS (APCI)
+
calcd for C H Cl N O [M+H] 233.0243, found 233.0245.
9
11
2
2
4
,6-Dichloro-2-(oxepan-2-yl)pyrimidine (3c). 68% yield (33.6 mg); colorless oil; IR (ATR)
–
1
1
3092, 3040, 2926, 2856, 1541, 1524, 1375, 1226, 1130, 1106, 846, 809, 698 cm ; H NMR
(
400 MHz, CDCl ) δ 1.55ꢀ1.81 (4H, m), 1.83ꢀ1.99 (3H, m), 2.08ꢀ2.17 (1H, m), 3.76 (1H, ddd, J
3
=
12.0, 6.4, 4.4 Hz), 4.09 (1H, ddd, J = 12.0, 7.6, 4.4 Hz), 4.71 (1H, dd, J = 10.4, 4.0 Hz), 7.27
13
(
1H, s); C NMR (100 MHz, CDCl
3
) δ 26.2, 26.6, 31.0, 35.1, 69.2, 81.5, 119.5, 162.0, 172.7;
+
HRMS (APCI) calcd for C H Cl N O [M+H] 247.0399, found 247.0387.
1
0
13
2
2
4
,6-Dichloro-2-(3,3-dimethyloxetan-2-yl)pyrimidine (3d). 45% yield (20.8 mg); colorless oil;
IR (ATR) 3092, 3038, 2960, 2932, 2873, 1524, 1464, 1388, 1374, 1228, 1104, 993, 846, 811,
–
1 1
7
13 cm ; H NMR (400 MHz, CDCl ) δ 0.91 (3H, s), 1.52 (3H, s), 4.48 (1H, d, J = 5.6 Hz),
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13
4
.52 (1H, d, J = 5.6 Hz), 5.48 (1H, s), 7.30 (1H, s); C NMR (100 MHz, CDCl ) δ 22.0, 27.0,
3
+
4
1.4, 82.1, 90.2, 119.6, 162.1, 170.4; HRMS (APCI) calcd for C H Cl N O [M+H] 233.0243,
9
11
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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34
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40
41
42
43
44
45
46
47
48
49
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59
60
found 233.0251.
tert-Butyl 2-(4,6-dichloropyrimidin-2-yl)pyrrolidine-1-carboxylate (3e). 80% yield (51.0 mg),
rotamer ratio = 62:38; colorless oil; IR (ATR) 3091, 2976, 2930, 2879, 1693, 1528, 1390, 1365,
–1
1
3
1159, 1117, 844, 812, 771 cm ; H NMR (400 MHz, CDCl ) δ 1.18 (5.58H, s), 1.41 (3.42H, s),
1
.79ꢀ2.07 (3H, m), 2.29ꢀ2.46 (1H, m), 3.44ꢀ3.53 (0.38H, m), 3.54ꢀ3.62 (0.62H, m), 3.62ꢀ3.71
(
1H, m), 4.81 (0.62H, dd, J = 8.0, 4.8 Hz), 4.92 (0.38H, dd, J = 8.4, 3.6 Hz), 7.20 (0.38H, s),
1
3
7.25 (0.62H, s); C NMR (100 MHz, CDCl ) δ 23.5, 23.9, 28.1, 28.4, 32.6, 33.5, 46.9, 47.1,
3
6
2.5, 62.7, 79.4, 79.6, 118.8, 119.1, 153.7, 154.5, 161.8, 161.9, 173.5, 174.1; HRMS (APCI)
+
calcd for C H Cl N O [M+H] 318.0771, found 318.0755 (minor signal), calcd for
13
18
2
3
2
+
C H Cl N [M–Boc+2H] 218.0246, found 218.0242 (major signal).
8
10
2
3
4,6-Dichloro-2-(piperidin-2-yl)pyrimidine hydrochloride (3f’). The benzophenoneꢀcatalyzed
photoinduced
coupling
between
NꢀBoc
piperidine
1f
and
4
,6ꢀdichloroꢀ2ꢀmethanesulfonylpyrimidine 2a was carried out followed by the general
procedure for preparation of the compound 3a, and the yield of the expected adduct 3f was
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5
5
6
determined to be 72% based on the NMR analysis of the mixture after brief separated on silica
gel column chromatography. The mixture was treated with HCl/dioxane (4 N, 3 mL) in
dioxane (3 mL) at room temperature for 2 h. After volatiles were removed with evaporation,
0
1
2
3
4
5
6
7
8
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2
3
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the residue was diluted with ether (~30 mL) and water then sat. aq NaHCO was added. Then,
3
the mixture was extracted with ether (~30 mL ×1, ~15 mL ×2) washed with water and brine,
dried over K CO , and filtered. The filtrate was added HCl/dioxane (4 N, 6 mL) and
2
3
evaporated; CAUTION: Concentration of the derived amine without salt formation causes
undesired reactions. The obtained white solid was washed with ether and was dried under
vacuum to provide the salt 3f’ in 58% yield (31.3 mg) in two steps as an offꢀwhite solid.
2
1
08.9 ºC (decomp.); IR (ATR) 3085, 3044, 2872 (br), 2706 (br), 2534 (br), 1537, 1423, 1389,
–1
1
312, 1234, 1121, 819 cm ; H NMR (400 MHz, DMSOꢀd ) δ 1.59ꢀ1.88 (5H, m), 2.17ꢀ2.28
6
(
1H, m), 2.94ꢀ3.10 (1H, m), 3.29ꢀ3.38 (1H, m), 4.44ꢀ4.55 (1H, m), 8.15 (1H, s), 9.30 (1H, brs),
13
9.98 (1H, brs); C NMR (100 MHz, DMSOꢀd ) δ 21.2, 21.5, 28.4, 43.9, 58.5, 121.2, 161.6,
6
+
1
66.7; HRMS (APCI) calcd for C H Cl N [M–Cl] 232.0403, found 232.0400.
9
12
2
3
tert-Butyl 2-(4,6-dichloropyrimidin-2-yl)azepane-1-carboxylate (3g). 85% yield (58.6 mg),
rotamer ratio = 53:47; colorless oil; IR (ATR) 3090, 2973, 2927, 2854, 1688, 1526, 1392, 1364,
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7
8
9
–1
1
1
156, 1099, 986, 811, 703 cm ; H NMR (400 MHz, CDCl ) δ 1.18ꢀ1.88 (15H, m), 1.88ꢀ2.01
3
(
1H, m), 2.31 (0.53H, ddd, J = 14.4, 8.8, 5.2 Hz), 2.41ꢀ2.52 (0.47H, m), 3.15 (0.47H, dd, J =
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5.2, 11.6 Hz), 3.23 (0.53H, dd, J = 14.8, 11.6 Hz), 3.92ꢀ4.02 (0.47H, m), 4.08ꢀ4.17 (0.53H, m),
4.93 (0.53H, dd, J = 12.0, 5.2 Hz), 5.14 (0.47H, dd, J = 12.4, 6.0 Hz), 7.19 (0.47H, s), 7.23
1
3
(
0.53H, s); detectable signals of C NMR (100 MHz, CDCl ) δ 25.9, 26.6, 28.3, 28.4, 29.37,
3
2
9.44, 30.0, 30.2, 33.6, 33.7, 43.5, 44.1, 61.4, 62.9, 79.68, 79.71, 118.8, 119.1, 155.5, 156.2,
+
1
61.8, 161.9, 173.8, 174.4; HRMS (APCI) calcd for C H Cl N [M–Boc+2H] 246.0559,
1
0
14
2
3
found 246.0559.
5-(4,6-Dichloropyrimidin-2-yl)pyrrolidin-2-one (3h). 71% yield (32.8 mg); offꢀwhite solid; mp
1
1
2
47.7ꢀ149.0 ºC; IR (ATR) 3208, 3080, 3045, 3033, 2961, 2924, 1683, 1530, 1404, 1374, 1304,
–1
1
285, 1229, 1128, 814, 768, 679 cm ; H NMR (400 MHz, CDCl ) δ 2.25ꢀ2.53 (3H, m),
3
1
3
.60ꢀ2.71 (1H, m), 4.86 (1H, dd, J = 8.4, 4.8 Hz), 6.83 (1H, brs), 7.31 (1H, s); C NMR (100
MHz, CDCl ) δ 26.9, 29.5, 58.5, 120.0, 162.4, 171.4, 178.2; HRMS (APCI) calcd for
3
+
C H Cl N O [M+H] 232.0039, found 232.0031.
8
8
2
3
4
,6-Dichloro-2-(tetrahydrothiophen-2-yl)pyrimidine (3i). [CAS: 1542343ꢀ51ꢀ0]: 31% yield
(
14.4 mg); colorless oil; IR (ATR) 3098, 3034, 2933, 2860, 1540, 1522, 1440, 1372, 1226, 1092,
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5
5
5
5
5
6
–1
1
8
6
6
42, 812 cm ; H NMR (400 MHz, CDCl ) δ 2.07ꢀ2.20 (1H, m), 2.28 (1H, ddddd, J = 6.0, 6.0,
3
.0, 6.0, 6.0 Hz), 2.37ꢀ2.55 (2H, m), 2.93ꢀ3.02 (1H, m), 3.05ꢀ3.16 (1H, m), 4.64 (1H, dd, J = 6.4,
0
1
2
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5
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8
9
0
1
2
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9
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
.4 Hz), 7.22 (1H, s); C NMR (100 MHz, CDCl ) δ 31.5, 34.0, 35.3, 52.7, 119.0, 161.9, 173.9;
3
+
HRMS (APCI) calcd for C H Cl N S [M+H] 234.9858, found 234.9862.
8
9
2
2
4
,6-Dimethoxy-2-(tetrahydrofuran-2-yl)pyrimidine (3j). 48% yield (50.5 mg) [0.5 mmol scale
reaction]; colorless oil; IR (ATR) 3090, 2977, 2953, 2872, 1584, 1561, 1462, 1398, 1375, 1255,
–
1 1
1
187, 1160, 1050, 986, 830 cm ; H NMR (500 MHz, CDCl ) δ 1.93ꢀ2.03 (1H, m), 2.07ꢀ2.20
3
(
2H, m), 2.25ꢀ2.34 (1H, m), 3.94 (6H, s), 3.96ꢀ4.03 (1H, m), 4.18 (1H, dd, J = 14.5, 7.0 Hz),
13
4.93 (1H, dd, J = 7.5, 5.0 Hz), 5.90 (1H, s); C NMR (126 MHz, CDCl
3
) δ 25.8, 31.5, 53.9,
+
6
2
2
9.4, 81.2, 87.8, 170.4, 171.6; HRMS (APCI) calcd for C H N O [M+H] 211.1077, found
10
15
2
3
11.1074.
-(Tetrahydrofuran-2-yl)pyrimidine (3k). 42% yield (12.7 mg); colorless oil; IR (ATR) 3039,
–1 1
2975, 2950, 2871, 1561, 1426, 1362, 1061, 923, 804, 631 cm ; H NMR (400 MHz, CDCl ) δ
3
1
7
6
.95ꢀ2.14 (3H, m), 2.36ꢀ2.49 (1H, m), 3.95ꢀ4.05 (1H, m), 4.14ꢀ4.23 (1H, m), 5.06ꢀ5.12 (1H, m),
13
.18 (1H, t, J = 5.2 Hz), 8.72 (2H, d, J = 5.2 Hz); C NMR (100 MHz, CDCl
3
) δ 25.8, 32.4,
+
9.4, 81.4, 119.5, 157.2, 171.0; HRMS (APCI) calcd for C H N O [M+H] 151.0866, found
8
11
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51.0862.
2
,4-dichloro-6-(tetrahydrofuran-2-yl)pyrimidine (3l). [CAS: 1878833ꢀ95ꢀ4]: 75% yield (33.0
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13
14
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16
17
18
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42
43
44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
mg); colorless oil; IR (ATR) 3126, 3087, 2981, 2952, 2875, 1556, 1523, 1299, 1237, 1073, 874,
–
1 1
823 cm ; H NMR (400 MHz, CDCl ) δ 1.84ꢀ2.07 (3H, m), 2.42ꢀ2.55 (1H, m), 3.95ꢀ4.02 (1H,
3
1
3
m), 4.02ꢀ4.10 (1H, m), 4.93 (1H, dd, J = 7.6, 5.6 Hz), 7.48 (1H, s); C NMR (100 MHz,
CDCl
3
) δ 25.5, 32.8, 69.6, 79.6, 115.9, 160.2, 163.1, 177.2; HRMS (APCI) calcd for
+
C H Cl N O [M+H] 219.0086, found 219.0101.
8
9
2
2
2
-Chloro-4-(tetrahydrofuran-2-yl)pyrimidine (3m). [CAS: 1850883ꢀ75ꢀ8]: 72% yield (26.5
mg); colorless oil; IR (ATR) 3145, 3115, 3078, 3039, 2979, 2952, 2874, 1570, 1541, 1430, 1341,
–1
1
1
193, 1179, 1071, 925, 851, 830, 739, 658 cm ; H NMR (400 MHz, CDCl ) δ 1.83ꢀ2.06 (3H,
3
m), 2.40ꢀ2.53 (1H, m), 3.94ꢀ4.00 (1H, m), 4.02ꢀ4.08 (1H, m), 4.93 (1H, dd, J = 8.0, 5.6 Hz),
1
3
7
.43 (1H, dd, J = 4.8, 0.8 Hz), 8.56 (1H, d, J = 4.8 Hz); C NMR (100 MHz, CDCl
3
) δ 25.5,
+
32.8, 69.4, 79.8, 115.4, 159.8, 160.9, 175.9; HRMS (APCI) calcd for C H ClN O [M+H]
8
10
2
1
85.0476, found 185.0484.
4
-Chloro-6-(tetrahydrofuran-2-yl)pyrimidine (3n). [CAS: 1823913ꢀ80ꢀ9]: 31% yield (11.4
mg); colorless oil; IR (ATR) 3052, 2979, 2952, 2873, 1565, 1530, 1453, 1315, 1097, 1069, 927,
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5
5
5
5
5
5
6
–1
1
8
75, 741 cm ; H NMR (400 MHz, CDCl ) δ 1.85ꢀ2.07 (3H, m), 2.41ꢀ2.54 (1H, m), 3.95ꢀ4.03
3
13
(
(
1H, m), 4.05ꢀ4.11 (1H, m), 4.96 (1H, dd, J = 8.0, 5.6 Hz), 7.54 (1H, s), 8.89 (1H, s); C NMR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
100 MHz, CDCl
3
) δ 25.5, 32.7, 69.4, 79.8, 117.6, 158.3, 162.0, 174.0; HRMS (APCI) calcd for
+
C H ClN O [M+H] 185.0476, found 185.0490.
8
10
2
Preparation of 1-(4,6-dichloropyrimidin-2-yl)pyrrolidin-2-one (3h’, equation 1): To a
THF solution (2 mL) of pyrrolidinone 1h (34.1 mg, 0.40 mmol, 1 equiv) was added NaH (60%
in mineral oil, 16.0 mg, 0.40 mmol, 1 equiv) at 0 ºC under an argon atmosphere. After stirring
ca. 40 min at 0 ºC, a THF solution (1 mL) of 4,6ꢀdichloroꢀ2ꢀmethanesulfonylpyrimidine 2a
(
91.0 mg, 0.40 mmol, 1 equiv) was added. The solution was gradually warmed to room
temperature and stirred for 3 h. The reaction was quenched with water at 0 ºC, and the mixture
was extracted with AcOEt, washed with water and brine, dried over Na SO , and concentrated.
2
4
The residue was purified by flash column chromatography (YMC DispoꢀpackAT SILꢀ25, 10%
AcOEt in hexane to AcOEt) to provide the adduct 3h’ in 44% yield (40.5 mg) as a white solid.
[
CAS: 1289134ꢀ74ꢀ2]: mp 140.2ꢀ142.1 ºC; IR (ATR) 3126, 3117, 2993, 2923, 2902, 1746, 1557,
–
1 1
1
515, 1440, 1420, 1265, 1183, 1146, 1092, 821, 809, 771 cm ; H NMR (400 MHz, CDCl ) δ
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.13 (2H, quintet, J = 7.6 Hz), 2.67 (2H, t, J = 7.6 Hz), 4.04 (2H, t, J = 7.6 Hz), 7.09 (1H, s);
13
C NMR (100 MHz, CDCl ) δ 17.5, 33.4, 48.0, 115.8, 156.8, 162.1, 173.5; HRMS (APCI)
3
10
11
12
13
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+
calcd for C H Cl N O [M+H] 232.0039, found 232.0037.
8
8
2
3
A Route for Preparation of the aurora kinase inhibitor analogue (5, Scheme 4):
A
CH Cl solution (5 mL, 0.1 M) of 4,6ꢀdichloroꢀ2ꢀmethanesulfonylpyrimidine 2a (113.5 mg, 0.5
2
2
mmol, 1 equiv), NꢀBoc pyrrolidine 1e (171.2 mg, 1.0 mmol, 2 equiv), and benzophenone (9.11
®
mg, 0.05 mmol, 0.1 equiv) was prepared in a Pyrex test tube under an argon atmosphere. The
test tube was placed at ca. 5 cm distance from a mediumꢀpressure Hg lamp and was irradiated at
room temperature for 24 h. The mixture was concentrated and the residue was purified by
flash column chromatography (silica gel, 5% AcOEt in hexane to AcOEt) to provide the
coupling adduct 3e in ca. 67% yield (105.9 mg, contaminated with a small amount of
inseparable impurities) as a colorless oil.
To a THF solution (5 mL) of the dichloropyrimidine substituted with the azacycle 3e (58.5
i
mg, ca. 0.183 mmol) and Pr
2
NEt (38.0 ꢀL, 0.221 mmol) was added methylpiperazine (21.5 ꢀL,
0
.193 mmol) at 0 ºC under an argon atmosphere. The solution was warmed to room
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temperature and stirred until the starting material 3e was consumed. The mixture was
extracted with AcOEt, washed with water and brine, dried over Na SO , and concentrated.
2
4
0
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0
The residue was purified by flash column chromatography (YMC DispoꢀpackAT NH2ꢀ25, 25%
AcOEt in hexane to AcOEt) to provide the product 4 in 91% yield (64.3 mg, contaminated with
5
% CH Cl ) as a colorless syrup.
2 2
Compound 4. rotamer ratio = 71:29; IR (ATR) 3096, 2972, 2938, 2875, 2794, 1692, 1570, 1532,
–
1 1
1449, 1391, 1155, 998, 973, 917, 807, 771 cm ; H NMR (400 MHz, CDCl ) δ 1.18 (6.39H, s),
3
1
3
.40 (2.61H, s), 1.74ꢀ1.99 (3H, m), 2.18ꢀ2.35 (1H, m), 2.28 (3H, s), 2.39 (4H, t, J = 5.2 Hz),
.36ꢀ3.71 (6H, m), 4.65 (0.71H, dd, J = 8.4, 4.0 Hz), 4.77 (0.29H, dd, J = 8.4, 3.2 Hz), 6.27
1
3
(
0.29H, s), 6.31 (0.71H, s); detectable signals of C NMR (100 MHz, CDCl ) δ 23.2, 23.6, 28.2,
3
2
8.5, 32.2, 33.0, 43.7, 43.8, 46.0, 46.7, 46.9, 54.38, 54.42, 62.2, 62.7, 78.8, 78.9, 98.6, 99.0,
+
154,3, 154.4, 160.0, 160.3, 162.6, 170.9, 171.9; HRMS (APCI) calcd for C H ClN O [M+H]
18
29
5
2
+
3
2
82.2004, found 382.2002 (minor signal), calcd for C H ClN [M–Boc+2H] 282.1480, found
13 21 5
82.1465 (major signal).
The starting substance 4 (63.0 mg, contaminated with 8% CH Cl , 0.162 mmol, 1 equiv),
2
2
t
5ꢀaminoꢀ1ꢀ butoxycarbonylꢀ3ꢀmethylpyrazole (35.2 mg, 0.178 mmol, 1.1 equiv), Pd(OAc)
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(
(
3.64 mg, 0.0162 mmol, 0.1 equiv), Xantphos (18.8 mg, 0.0324 mmol, 0.2 equiv), and Cs CO3
2
68.7 mg, 0.211 mmol, 1.3 equiv) were dissolved in dioxane (2 mL, 0.08 M) under an argon
10
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atmosphere, and the solution was stirred at 80 ºC for 14.5 h. After cooling at 0 ºC, MeOH (2
mL) and 1 N NaOH aq (1 mL) were added and the solution was stirred at room temperature for
5
0 min. The mixture was extracted with CH Cl and AcOEt, washed with water and brine,
2 2
dried over Na SO , and concentrated. The residue was purified by PTLC (NH silica gel
2
4
[
WAKO], CH Cl /MeOH = 40:1) to provide the product 5 in 81% yield (61.3 mg, contaminated
2 2
with 32% CH Cl ) as a pale brown syrup.
2
2
Analogue of the Aurora Kinase Inhibitor, MK-0457 (5). rotamer ratio = 75:25 in CDCl and
3
rotamer ratio = 64:36 in DMSOꢀd ; IR (ATR) 3253 (br), 2973, 2934, 2873, 2845, 2793, 1674,
6
–1
1
1
585, 1553, 1481, 1445, 1400, 1287, 1161, 1121, 1000, 769, 699 cm ; H NMR (400 MHz,
CDCl ) δ 1.22 (6.75H, s), 1.42 (2.25H, s), 1.68ꢀ2.07 (3H, m), 2.15ꢀ2.34 (1H, m), 2.28 (3H, s),
3
2.29 (3H, s), 2.34ꢀ2.48 (4H, m), 3.39ꢀ3.78 (6H, m), 4.61 (0.75H, dd, J = 8.8, 3.6 Hz), 4.75
(
0.25H, brd, J = 8.0 Hz), 5.81 (1H, brs), 6.34 (1H, brs), 7.81 (0.25H, brs), 8.22 (0.75H, brs),
1
1
1.2 (1H, brs); H NMR (400 MHz, DMSOꢀd
6
) δ 1.13 (5.76H, s), 1.37 (3.24H, s), 1.71ꢀ1.98 (3H,
m), 2.12ꢀ2.29 (1H, m), 2.17 (3H, s), 2.19 (3H, s), 2.29ꢀ2.39 (4H, m), 3.29ꢀ3.59 (6H, m), 4.45
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