Metal free C-H functionalization of diazines and related heteroarenes with organoboron species and its application in the synthesis of a CDK inhibitor, meriolin 1

Article abstract of DOI:10.1039/c6ob00526h

Here, we report a metal-free cross-coupling reaction of diazines and related heteroarenes with organoboron species via C-H functionalization. The optimized conditions represent a metal-free method for the activation of aryl/heteroarylboronic acids, which undergo coupling with diazines and related heteroarenes. Optimized conditions also find application in the synthesis of a pyrimidine-based potent CDK inhibitor, meriolin1.

Full text of DOI:10.1039/c6ob00526h

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Metal free C–H functionalization of diazines and
related heteroarenes with organoboron species
and its application in the synthesis of a CDK
inhibitor, meriolin 1†
Cite this: DOI: 10.1039/c6ob00526h
Thanusha Thatikonda, Umed Singh, Srinivas Ambala, Ram A. Vishwakarma and
Parvinder Pal Singh*
Here, we report a metal-free cross-coupling reaction of diazines and related heteroarenes with organo-
boron species via C–H functionalization. The optimized conditions represent a metal-free method for the
activation of aryl/heteroarylboronic acids, which undergo coupling with diazines and related hetero-
arenes. Optimized conditions also find application in the synthesis of a pyrimidine-based potent CDK
inhibitor, meriolin 1.
Received 9th March 2016,
Accepted 5th April 2016
DOI: 10.1039/c6ob00526h
www.rsc.org/obc
Diazines, particularly pyrimidine and its benzofused deriva- eroarenes but again specific to quinoline only and with a pre-
tives have occupied an important and significant position in functionalized one at that, i.e., quinoline N-oxide. In continu-
the chemical space because of their ubiquitous occurrence in ation of our work concerning functionalization of electron-
natural,1 pharmaceutical,2 agro,3 electronic and photonic pro- deficient heteroarenes,10 here we report a general method for
ducts.4 A few examples of pyrimidine containing pharma- the C–H functionalization of pyrimidine and its derivatives.
ceutical and photonic products are shown in Fig. 1.4,5
The optimized method involves metal-free conditions for the
Considering the importance and applications of aryl substi- activation of aryl boronic acids. Moreover, the optimized con-
tuted pyrimidines and their derivatives, the development of ditions work very well with other heteroarenes such as
new synthetic methods for the preparation of functionalized pyrazine, quinoxalines, quinoline, pyridine and quinazolines.
pyrimidine is highly required. Historically, this was achieved In addition, we have also demonstrated its application in the
via cross-coupling reactions by using pre-functionalized pyri- synthesis of a marine-derived pyrimidine-based potent CDK
midine.6 Recently, Verbitskiy et al.7 developed the SNH method inhibitor, meriolin 1.
for the functionalization of pyrimidines, which were found
To start, 5-bromo-2-chloropyrimidine 1 and phenylboronic
suitable with electron-rich heteroarenes. In the present acid 2 were selected as coupling partners. The initial reaction
decade, the direct C–H functionalization of electron-deficient was performed under previously developed redox-based condi-
heteroarenes8 has received considerable attention, which is tions10a involving iron(II) acetylacetonate [Fe(acac)2] and
mainly exploited for azines (pyridine and its derivatives). Pyri- K2S2O8, but no coupling was observed (Table 1, entry 1). Next,
midine also represents an electron-deficient system and in the reaction was tried under Baran’s conditions,8a and a cross-
comparison to pyridine, the presence of the second N-atom coupled product was observed in a yield of 15% (Table 1, entry
further significantly decreases the electron density, but this 2). Next, when the reaction was tried with iron(II) acetyl-
has been less explored under C–H functionalization methods. acetonate [Fe(acac)2] and K2S2O8 at 110 °C, the formation of
In the literature, three metal-catalyzed reports are available, coupled product 3a was observed in a yield of 15% (Table 1,
where pyrimidine was used as a substrate (Fig. 2)8a–c but all entry 3). Surprisingly, by changing the solvents to acetone :
these reported methods are highly specific to one example water, 3a was observed in a yield of 53% (Table 1, entry 4).
only. Very recently, Antonchick and co-workers9 reported a Further rise in the temperature increased the yield of 3a to
metal-free method for the arylation of electron-deficient het- 61% (Table 1, entry 5). The coupling was observed at high
temperatures, which in turn suggested that the metal salts
might not be required for the activation of arylboronic acid. In
this direction, series of reactions were performed under metal-
free conditions (Table 1, entries 6–8) and to our delight, the
acetone : water system at 160 °C also gave the coupled product
Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine and
Academy of Scientific and Innovative Research, Canal Road, Jammu 180001, India.
E-mail: ppsingh@iiim.ac.in; Fax: +91-191-2586333; Tel: +91-191-2585006-13
†Electronic supplementary information (ESI) available: Copies of NMR and
3a in a yield of 63% (Table 1, entry 8).
mass spectra of synthesized compounds. See DOI: 10.1039/c6ob00526h
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Fig. 1 Examples of pyrimidine containing products.
heteroarylboronic acids such as 2-aminopyrimidinyl-5-boronic
acid and (6-methoxypyridin-3-yl)boronic acid, and gave the
corresponding coupled products 3e and 3f. Other substituted
pyrimidine derivatives such as 2-amino-5-bromopyrimidine
when tried with phenylboronic acid, gave 67% of the corres-
ponding coupled product 4a. 2-Amino-5-bromopyrimidine
upon reaction with para- and meta-substituted electron-rich
arylboronic acids gave the corresponding coupled products
(4b–4e) in moderate to good yields. On the other hand, ortho-
substituted arylboronic acids and electron-withdrawing group
containing arylboronic acids also underwent coupling but gave
comparatively lower yields of the corresponding coupled pro-
ducts (4f–4k). When 5-bromopyrimidine and 2-aminopyr-
imidine were tried with phenylboronic acid, corresponding
coupled products 5a and 6a were obtained in moderate yields.
When un-substituted pyrimidine was tried with phenylboronic
acid, 4th-substitued regio-isomer 7a was observed in a yield of
37% along with a trace amount of the 2-substituted regio-
isomer. Under optimized conditions, quinazoline also under-
went coupling and provided the 4th-substituted regio-isomeric
product 8a in a yield of 38%. With pyrazine and 2,3-dimethyl-
pyrazine, corresponding coupled products 9a and 10a were
obtained in yields of 55 and 59%, respectively. Further, benzo-
fused diazine such as 2-methylquinoxaline also underwent
coupling with unsubstituted and substituted (3-methyl,
4-methyl and 4-bromo) phenylboronic acids, and gave the
corresponding coupled products 11a–11d in moderate to good
yield.
Fig. 2 C–H functionalization of electron-deficient heteroarenes.
When the reaction was conducted in water alone, 51% of
coupled product 3a was observed (Table 1, entry 9), however, at
room temperature, no coupling was observed (Table 1, entry
10). Other solvent systems were also tried (Table 1, entries
11–17), but none gave any advantage. Among various reaction
conditions, metal-free peroxysulfate (K2S2O8) at 160 °C in
acetone : water was found to be the best (Table 1, entry 8).
With the optimized reaction conditions in hand, investi-
gation towards substrate scope was tried (Scheme 1). As shown
in Scheme 1, both the substrates with varying substituents
afforded the corresponding coupled products 3–11 in a moder-
ate to good yields. In a few cases, trace amounts of biphenyl
and bis-addition products were also detected as by-products
(<10%). Under optimized conditions, 5-bromo-2-chloropyr-
imidine 1 reacted smoothly with various substituted aryl
boronic acid and gave coupled products 3b–3d in moderate to
good yields. 5-Bromo-2-chloropyrimidine also reacted well with
Next, the optimized metal-free peroxysulfate-mediated con-
ditions were further extended to azines also. Substituted pyri-
dine and its benzofused derivatives 12 were explored, which
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Table 1 Optimization studiesa
Yieldd (%)
Entry
Catalyst (mol%)
Solvent (v/v = 2 : 1)
PTCb
Acid
Tc (°C)
T (h or min)
3a
3a′
1e
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Fe(acac)2 (20)
Ag(NO3)2 (20)
Fe(acac)2 (50)
Fe(acac)2 (50)
Fe(acac)2 (50)
DCM : H2O
DCM : H2O
DCM : H2O
Acetone : H2O
Acetone : H2O
DCM : H2O
Acetone : H2O
Acetone : H2O
H2O
Acetone : H2O
DCE : H2Ob
ACN : H2O
EtOH : H2O
DMSO : H2Ob
DMF : H2Ob
EAA : H2Ob
TBAB
—
TFA
TFA
rt
rt
110
110
160
90
110
160
160
rt
160
160
160
160
160
160
160
24 h
24 h
8 h
8 h
1 h
18 h
3 h
45 min
3 h
24 h
3 h
3 h
—
15
15
53
61
30
21
63
51
—
13
15
11
—
—
—
—
—
—
—
5
7
TBAB
TFA
—
—
8
10
—
—
—
—
—
—
—
—
3 h
3 h
3 h
3 h
Acetylacetone : H2O
3 h
Reaction conditions: a 5-Bromo-2-chloropyrimidine 1 (0.25 mmol), 2 (0.375 mmol), K2S2O8 (0.75 mmol) and solvents (3 mL). b Phase-transfer cata-
lyst, DCE = 1,2-dichloroethane, DMSO = dimethylsulfoxide, DMF = dimethylformamide, EAA = ethylacetoacetate. c Represent bath temperature
(reactions were performed in a sealed tube, details are provided in Experimental section). d Isolated yields. e 2 (0.275 mmol) was used.
gave the single regio-isomeric products in good to moderate sulfate radical II or peroxy disulfate I to afford the protonated
yields (Scheme 2). Both pyridines and quinolines reacted with required product 3 along with either the sulfate ion (IV) or
phenylboronic acid under optimized conditions and furnished sulfate ion/sulfate radical pairs (IV or II). The generated sulfate
moderate to good yield of the corresponding coupled products radical (II) might further be involved in the propagation of
(13a–13d).
Further, the reactivity of other organoboron species such as heteroarenes, which in turn avoid the use of an external acid.
potassium organo trifluoroborate salts and arylboronic acid As pyrimidine is present in a large number of natural and
chains, while hydrogen sulfate (IV) in the protonation of
pinacol ester were also tested (Table 2). Phenylboronic acid other products,1–4 the optimized method finds application in
pinacol ester underwent cross-coupling smoothly with the synthesis of such molecules. In the present case, the
2-amino-5-bromopyrimidine and gave 2-amino-5-bromo-4- concept has been successfully demonstrated by synthesizing
phenylpyrimidine in 55% yield (Table 2, entry 2). Similarly, meriolin 1.5d
phenyltrifluoroborate and 4-methylphenyltrifluoroborate also
Meriolins represent a derivative of the 7-azaindole moiety,
underwent coupling with 2-amino-5-bromopyrimidine and which was designed by Meijer and co-workers and given the
gave desired coupled products in good yield (Table 2, entries 3 name meriolin, as the structure represents two marine natural
and 4).
products variolin and meridianin.12 The meriolins are known
The control experiments in the presence of a free-radical as highly potent CDK-based anti-cancer agents. Regarding the
scavenger such as (2,2,6,6-tetramethylpiperidin-1-yl)oxyl synthesis, four methods were reported in the literature5d,13–15
(TEMPO) drastically suppressed the formation of coupled (Fig. 4), wherein three involved palladium-based catalyses for
product 3a (Scheme 3), suggesting the radical mechanism. the construction of final molecules. Here, we have developed a
Based on the present results and literature precedents,8a,b the metal-free method for the construction of meriolin 1 under
following plausible mechanistic cascade is proposed for the optimized conditions. By using optimized conditions, when
present coupling reaction (Fig. 3). The peroxydisulfate upon 2-aminopyrimidine 1 was treated with N-Boc protected 7-aza-
heating generates the sulfate anion radical (II) which activates indole boronate ester 21a, coupling and Boc-deprotection
arylboronic acid 2 and generates aryl radical III. The aryl occurred in a single step and meriolin 1 was obtained in an
radical III then reacts further with in situ generated heteroar- overall yield of 35% (Fig. 4). Other protected groups such as
ene salt 1′ 10b,11,12 and produces cationic radical intermediate methyl (21b), tosyl (21c) and dimethyl carbamoyl (21d) were
V, which undergoes single electron transfer (SET) with either also tried but none gave any improvement. However, with tosyl
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Scheme 1 Coupling of diverse diazines with un/substituted (hetero)arylboronic acids. a Reaction conditions: heteroarene 1 (0.25 mmol), 2
(0.375 mmol), K2S2O8 (0.75 mmol), acetone/water (v/v = 2 : 1) at 160 °C (reactions were performed in a sealed tube), 45 min.
Table 2 Coupling with different organoboron speciesa
Entry
(Z =)
(R1 =)
4 (isolated yield %)
Scheme 2 Coupling of diverse azines with un/substituted phenylboro-
nic acids. a Reaction conditions: azine 4 (0.25 mmol), 2 (0.375 mmol), 1b
–B(OH)2
H
H
67
55
K2S2O8 (0.75 mmol), acetone/water (v/v = 2 : 1) at 160 °C (reactions were
performed in a sealed tube), 45 min; b isolated yield.
2
3
4
–BF3K
–BF3K
H
CH3
51
54
and dimethyl carbamoyl, the starting materials viz. 21c and
21d were observed as such in the reaction mixture, which in
turn suggested that the presence of these groups stabilizes the
C–B bond and makes the substrates inactive for reaction.
Reaction conditions: a heteroarene 1 (0.25 mmol), 2 (0.375 mmol),
acetone/water, K2S2O8 (0.75 mmol), 160 °C (reactions were performed
in a sealed tube), 1 h. b 45 min.
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1
Merck flash silica gel of 230–400 mesh size. H NMR spectra
were recorded with Bruker 400 and 500 MHz NMR instru-
ments. Chemical data for protons are reported in parts per
million (ppm, scale) downfield from tetramethylsilane and are
referenced to the residual proton in the NMR solvent (CDCl3:
δ 7.26, or other solvents as mentioned). All the NMR spectra
were processed in either MestReNova or Bruker software. Mass
spectra were recorded with a HRMS instrument.
Scheme 3 Coupling in the presence of a radical scavenger.
General procedure
Cross-coupling of electron deficient heteroarenes (diazines
and azines) with organo boron species. To a 100 mL sealed
tube were added heteroarenes 1 (0.25 mmol), aryl/heteroaryl
boronic acid or aryl/heteroaryl boronic acid pinacol ester 2
(0.375 mmol), K2S2O8 (0.75 mmol), and 3 mL of acetone/water
(2 : 1). The tube was sealed with a back seal stopper, heated at
160 °C for 45 min–1 h. After completion of the reaction as
monitored by TLC, the heating was stopped and the reaction
mixture was allowed to cool down to room temperature. Then
the reaction mixture was diluted with ethyl acetate and washed
with saturated sodium bicarbonate solution. The layers were
separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic layer was dried over Na2SO4
and concentrated under reduced pressure. The crude products
were purified on a silica gel column using hexane/EtOAc.
Synthesis of bioactive synthetic hybrid meriolin 1. To a
Fig. 3 Plausible mechanism.
100 mL sealed tube were added 2-aminopyrimidine
1
(0.25 mmol), 7-azaindole boronate ester 6 (0.375 mmol), and
K2S2O8 (0.75 mmol) in 6 ml of acetone/water (2 : 1). The tube
was sealed with a back seal stopper, and heated at 160 °C for
2 h. After completion of the reaction as monitored by TLC, the
heating was stopped and the reaction mixture was allowed to
cool down to room temperature. Then the reaction mixture
was diluted with dichloromethane and washed with saturated
sodium bicarbonate solution. The layers were separated, and
the aqueous layer was extracted with dichloromethane. The
combined organic layer was dried over Na2SO4 and concen-
trated under reduced pressure. The crude products were puri-
fied on a silica gel column using DCM/MeOH.
Conclusions
In conclusion, we have developed a general, transition metal-
free method for the generation of aryl/heteroaryl radicals,
which undergo smooth coupling with less-explored electron-
deficient heteroarenes such as a pyrimidine and its derivatives.
In addition, optimized conditions also work with other sub-
strates such as pyrazine, quinoxalines, pyridine, quinoline,
and quinazolines. The optimized conditions avoid the need
for an external strong acid. The present methodology was also
successfully utilized for the synthesis of meriolin 1.
Spectral data of compounds
5-Bromo-2-chloro-4-phenylpyrimidine (3a). White solid
(43 mg, 63%); mp 105 °C; TLC Rf = 0.6 (10% EtOAc/hexane);
1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.84 (dd, J = 13.4, 7.3
Hz, 2H), 7.52 (q, J = 5.6 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
Experimental section
General information
All reactions were performed in an ace pressure tube bushing 166.93, 162.2, 159.78, 135.59, 130.96, 129.41, 128.39, 117.20;
type, back seal, volume 100 mL, L × O.D. 17.8 cm × 38.1 mm HRMS (ESI+) (m/z) calcd for C10H779BrClN2 [M + H] 268.9481
(sealed tube). Analytical thin layer chromatography was per- found 268.9467, calcd for C10H781BrClN2 [M + H] 270.9461
formed using TLC pre-coated silica gel 60 F254 Merck (20 × found 270.9445.
20 cm). TLC plates were visualized by exposing to UV light or
5-Bromo-2-chloro-4-(m-tolyl)pyrimidine (3b). Yellow solid
1
by iodine vapors or immersion in an acidic staining solution (38 mg, 55%); mp 97 °C; TLC Rf = 0.7 (10% EtOAc/hexane); H
of p-anisaldehyde followed by heating on a hot plate. The NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H),
organic solvent was concentrated by rotary evaporation on a 7.42–7.33 (m, 2H), 2.44 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
BUCHI-Switzerland R-120 rotary evaporator and a vacuum 167.20, 162.18, 159.72, 138.36, 135.53, 131.73, 129.89, 128.20,
pump V-710. Flash column chromatography was performed on 126.49, 117.26, 21.45; HRMS (ESI+) (m/z) calcd for
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Fig. 4 Synthesis of meriolin 1. a Reaction conditions: 2-amino pyrimidine 1 (0.25 mmol), 21 (0.375 mmol), acetone/water, K2S2O8 (0.75 mmol),
160 °C (reactions were performed in a sealed tube), 2 h.
C11H979BrClN2 [M + H] 282.9638 found 282.9629, calcd for 137.66, 134.11, 132.30, 130.45, 129.04 (q, J = 3.60 Hz), 127.79
C11H981BrClN2 [M + H] 284.9617 found 284.9603.
5-Bromo-2-chloro-4-(4-iso-propylphenyl)pyrimidine
(q, J = 3.83 Hz), 125.09 (q, J = 272.34 Hz), 118.59; GC-MS (EI)
(3c). m/z (relative intensity): 337.8 (M+, 24.6), 257.1 (99.99), 230.0
Colorless oil (51 mg, 56%); TLC Rf = 0.7 (10% EtOAc/hexane); (8.73), 194.0 (3.82), 176.0 (12.01), 145.1 (8.80), 100.1 (3.77),
1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.80 (d, J = 8.3 Hz, 69.1 (7.34).
2H), 7.36 (d, J = 8.3 Hz, 2H), 3.00 (dd, J = 13.8, 6.9 Hz, 1H),
5-Bromo-2-chloro-[4,5′-bipyrimidin]-2′-amine (3e). White
1.29 (d, J = 6.9 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 166.79, solid (31 mg, 43%); mp 123 °C; H NMR (400 MHz, CDCl3) δ
162.21, 159.68, 133.07, 129.54, 126.53, 125.45, 116.96, 34.16, 8.98 (s, 2H), 8.74 (s, 1H), 5.51 (s, 2H); 13C NMR (101 MHz,
30.93, 23.75; HRMS (ESI+) (m/z) calcd for C13H1379BrClN2 [M + mixture of CDCl3 and CD3OD) δ 159.10, 158.42, 157.96, 155.88,
H] 310.9951 found 310.9927, calcd for C13H1381BrClN2 [M + H] 155.56, 115.63, 111.92; HRMS (ESI+) (m/z) calcd for
1
312.9930 found 312.9912.
5-Bromo-2-chloro-4-(3-(trifluoromethyl)phenyl)pyrimidine C8H681BrClN5 [M + H] 287.9475 found 287.9460.
C8H679BrClN5 [M + H] 285.9495 found 285.9481, calcd for
(3d). Colorless oil (31 mg, 41%); TLC Rf = 0.5 (10% EtOAc/
5-Bromo-2-chloro-4-(6-methoxypyridin-3-yl)pyrimidine (3f).
hexane); 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.11 (s, 1H), White solid (16 mg, 21%); mp 117 °C; 1H NMR (400 MHz,
8.04 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.68 (t, J = 7.8 CDCl3) δ 8.82 (d, J = 2.2 Hz, 1H), 8.76 (s, 1H), 8.13 (dd, J = 8.7,
Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 166.74, 164.04, 161.44, 2.4 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 4.02 (s, 3H); 13C NMR
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(126 MHz, CDCl3) δ 165.56, 164.14, 162.39, 159.83, 148.84, 135.34, 131.93, 130.23, 129.97, 128.17, 108.13, 20.92, 18.83;
139.62, 124.86, 116.67, 110.80, 54.03; HRMS (ESI+) (m/z) calcd HRMS (ESI+) (m/z) calcd for C12H13BrN3 [M + H] 278.0293
for C10H879BrClN3O [M + H] 299.9539 found 299.9541, calcd found 278.0284.
for C10H881BrClN3O [M + H] 301.9519 found 301.9519.
5-Bromo-4-(4-chlorophenyl)pyrimidin-2-amine (4h). White
5-Bromo-4-phenylpyrimidin-2-amine (4a). White solid solid (37 mg, 52%); mp 163 °C; TLC Rf = 0.7 (30% EtOAc/
1
(42 mg, 67%); mp 153 °C; TLC Rf = 0.6 (30% EtOAc/hexane); hexane); H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.69 (d, J =
1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.72–7.66 (m, 2H), 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 5.23 (s, 2H); 13C NMR
7.49–7.45 (m, 3H), 5.25 (s, 2H); 13C NMR (126 MHz, CDCl3) δ (126 MHz, CDCl3) δ 163.93, 161.66, 161.10, 136.14, 135.73,
165.24, 161.67, 160.88, 137.40, 129.90, 128.91, 128.16, 106.42; 130.46, 128.43, 106.17; HRMS (ESI+) (m/z) calcd for
HRMS (ESI+) (m/z) calcd for C10H979BrN3 [M + H] 249.9980 C10H8BrClN3 [M + H] 283.9590 found 283.9601.
found 249.9965, calcd for C10H981BrN3 [M + H] 251.9959 found
251.9945.
5-Bromo-4-(3-chlorophenyl)pyrimidin-2-amine (4i). Yellow
solid (30 mg, 42%); mp 121 °C; TLC Rf = 0.7 (30% EtOAc/
1
5-Bromo-4-(p-tolyl)pyrimidin-2-amine (4b). White solid hexane); H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.70 (t, J =
(35 mg, 53%); mp 149 °C; TLC Rf = 0.7 (30% EtOAc/hexane); 1.7 Hz, 1H), 7.61 (dt, J = 7.4, 1.5 Hz, 1H), 7.46–7.38 (m, 2H),
1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.62 (d, J = 8.1 Hz, 5.25 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 163.74, 161.60,
2H), 7.27 (d, J = 7.8 Hz, 2H), 5.34 (s, 2H), 2.41 (s, 3H); 13C NMR 161.13, 138.97, 134.23, 129.99, 129.45, 129.10, 127.18, 106.18;
(126 MHz, CDCl3) δ 165.16, 161.69, 160.79, 158.56, 134.54, HRMS (ESI+) (m/z) calcd for C10H8BrClN3 [M + H] 283.9590
128.91, 128.84, 106.34, 21.47; HRMS (ESI+) (m/z) calcd for found 283.9581.
C11H11BrN3 [M + H] 264.0136 found 264.0130.
5-Bromo-4-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (4j).
5-Bromo-4-(m-tolyl)pyrimidin-2-amine (4c). Yellow solid White solid (34 mg, 42%); mp 129 °C; TLC Rf = 0.5 (30%
1
(40 mg, 60%); mp 139 °C; TLC Rf = 0.7 (30% EtOAc/hexane); EtOAc/hexane); H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.83
1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.51–7.43 (m, 2H), (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 5.27 (s, 2H); 13C
7.35 (t, J = 7.6 Hz, 1H), 7.28 (s, 1H), 5.24 (s, 2H), 2.42 (s, 3H); NMR (126 MHz, CDCl3) δ 162.80, 160.59, 160.13, 139.69,
13C NMR (126 MHz, CDCl3) δ 165.49, 161.68, 160.78, 158.55, 130.65 (q, J = 32.63 Hz), 128.39, 124.14 (q, J = 3.7 Hz), 122.81
137.36, 130.62, 129.36, 127.99, 126.01, 106.44, 21.46; HRMS (q, J = 272.46 Hz), 105.13; HRMS (ESI+) (m/z) calcd for
(ESI+) (m/z) calcd for C11H11BrN3 [M + H] 264.0136 found C11H8BrF3N3 [M + H] 317.9854 found 317.9841.
264.0122.
5-Bromo-4-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine (4k).
5-Bromo-4-(4-(tert-butyl)phenyl)pyrimidin-2-amine
(4d). Colorless oil (28 mg, 31%); TLC Rf = 0.5 (30% EtOAc/hexane);
White solid (44 mg, 57%); mp 145 °C; TLC Rf = 0.7 (30% 1H NMR δ (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.93 (s, 1H), 7.87
1
EtOAc/hexane); H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.9 Hz,
(d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 5.21 (s, 2H), 1.35 (s, 1H), 5.18 (s, 2H); 13C NMR δ 163.53, 161.70, 161.25, 158.54,
9H); 13C NMR (126 MHz, CDCl3) δ 164.03, 160.64, 159.80, 138.05, 132.32, 128.61, 126.53 (q, J = 3.79 Hz), 126.16 (q, J =
152.17, 133.44, 127.65, 124.11, 105.31, 33.82, 30.19; HRMS 3.84 Hz), 123.86 (q, J = 272.35 Hz), 106.15; HRMS (ESI+) (m/z)
(ESI+) (m/z) calcd for C14H17BrN3 [M + H] 306.0606 found calcd for C11H8BrF3N3 [M + H] 317.9854 found 317.9833.
306.0594.
5-Bromo-4-phenylpyrimidine (5a). Yellow solid (30 mg,
(4e). 51%); mp 113 °C; TLC Rf = 0.5 (20% EtOAc/hexane); H NMR
1
5-Bromo-4-(2,4,5-trimethylphenyl)pyrimidin-2-amine
Red oil (48 mg, 65%); TLC Rf = 0.7 (30% EtOAc/hexane); 1H (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.92 (s, 1H), 7.82 (dd, J = 6.7,
NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.03 (s, 1H), 6.95 (s, 2.9 Hz, 2H), 7.51 (dd, J = 4.9, 1.6 Hz, 3H); 13C NMR (101 MHz,
1H), 5.32 (s, 2H), 2.26 (s, 6H), 2.21–2.08 (s, 3H); 13C NMR CDCl3) δ 164.34, 160.15, 156.91, 136.77, 130.35, 129.28, 128.31,
(126 MHz, CDCl3) δ 167.81, 161.60, 159.82, 137.69, 135.09, 119.19; HRMS (ESI+) (m/z) calcd for C10H8BrN2 [M + H]
133.93, 132.24, 131.61, 128.78, 108.16, 19.60, 19.25, 18.78; 234.9871 found 234.9857.
HRMS (ESI+) (m/z) calcd for C13H15BrN3 [M + H] 292.0449
found 292.0428.
4-Phenylpyrimidin-2-amine (6a). White solid (18 mg, 43%);
mp 135 °C; TLC Rf = 0.4 (30% EtOAc/hexane); 1H NMR
5-Bromo-4-(o-tolyl)pyrimidin-2-amine (4f). Colorless oil (400 MHz, CDCl3) δ 8.37 (d, J = 5.4 Hz, 1H), 8.01–7.96 (m, 2H),
(21 mg, 32%); TLC Rf = 0.7 (30% EtOAc/hexane); 1H NMR 7.47 (dd, J = 5.0, 1.8 Hz, 3H), 7.05 (d, J = 5.4 Hz, 1H), 5.52 (s,
(400 MHz, CDCl3) δ 8.43 (s, 1H), 7.36–7.32 (m, 1H), 7.31–7.26 2H); 13C NMR (101 MHz, CDCl3) δ 165.56, 163.28, 158.67,
(m, 2H), 7.21–7.16 (m, 1H), 5.20 (s, 2H), 2.21 (s, 3H); 13C NMR 137.23, 130.61, 128.77, 127.06, 107.78; HRMS (ESI+) (m/z)
(126 MHz, CDCl3) δ 167.58, 161.50, 160.08, 137.61, 135.11, calcd for C10H10N3 [M + H] 172.0875 found 172.0857.
130.36, 129.23, 127.78, 125.80, 108.18, 19.36; HRMS (ESI+) (m/z)
4-Phenylpyrimidine (7a).8a Yellow oil (15 mg, 37%); TLC Rf =
1
calcd for C11H1179BrN3 [M + H] 264.0131 found 264.0128, calcd 0.6 (30% EtOAc/hexane); H NMR (400 MHz, CDCl3) δ 9.28 (s,
for C11H1181BrN3 [M + H] 266.0116 found 266.0108.
1H), 8.77 (d, J = 5.3 Hz, 1H), 8.10 (dd, J = 6.5, 3.0 Hz, 2H), 7.73
5-Bromo-4-(2,5-dimethylphenyl)pyrimidin-2-amine
(4g). (dd, J = 5.3, 1.1 Hz, 1H), 7.57–7.43 (m, 3H); HRMS (ESI+) (m/z)
Yellow solid (24 mg, 34%); mp 168 °C; TLC Rf = 0.7 (30% calcd for C10H9N2 [M + H] 157.0766 found 157.0761.
1
EtOAc/hexane); H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.15
4-Phenylquinazoline (8a). Red oil (20 mg, 38%); TLC Rf = 0.6
(s, 2H), 6.99 (s, 1H), 5.30 (s, 2H), 2.34 (s, 3H), 2.16 (s, 3H); 13C (10% EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H),
NMR (126 MHz, CDCl3) δ 167.79, 161.56, 159.95, 137.48, 8.06 (m, 2H), 7.85 (m, 1H), 7.71 (m, 2H), 7.57–7.48 (m, 4H);
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13C NMR (126 MHz, CDCl3) δ 167.41, 153.61, 150.03, 136.02,
4-Bromo-2-phenylpyridine (13b).8e Colorless oil (20 mg,
132.72, 129.05, 128.91, 127.84, 127.62, 126.73, 126.09, 122.13; 34%); TLC Rf = 0.8 (10% EtOAc/hexane); 1H NMR (400 MHz,
HRMS (ESI+) (m/z) calcd for C14H11N2 [M + H] 207.0922 found CDCl3) δ 8.51 (d, J = 5.3 Hz, 1H), 8.00–7.93 (m, 2H), 7.90 (d, J =
207.0905.
1.4 Hz, 1H), 7.48 (dd, J = 12.5, 5.1 Hz, 3H), 7.41 (dd, J = 5.2,
2-Phenylpyrazine (9a).10a Light yellow solid (22 mg, 55%); 1.6 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 158.93, 150.38,
mp 119 °C; TLC Rf = 0.5 (10% EtOAc/hexane); 1H NMR 138.07, 133.51, 129.64, 128.90, 127.03, 125.29, 123.97; HRMS
(400 MHz, CDCl3) δ 9.02 (d, J = 1.5 Hz, 1H), 8.61 (dd, J = 2.4, (ESI+) (m/z) calcd for C11H9BrN [M + H] 233.9918 found
1.6 Hz, 1H), 8.49 (d, J = 2.5 Hz, 1H), 8.03–7.99 (m, 2H), 233.9906.
7.50–7.45 (m, 3H); HRMS (ESI+) (m/z) calcd for C10H9N2
[M + H] 157.0766 found 157.0764.
4-Methyl-2-phenylquinoline (13c).8f Colorless oil (20 mg,
36%); TLC Rf = 0.8 (10% EtOAc/hexane); 1H NMR (400 MHz,
2,3-Dimethyl-5-phenylpyrazine (10a). Light yellow oil (27 mg, CDCl3) δ 8.13–8.05 (m, 3H), 7.92 (dd, J = 8.4, 0.9 Hz, 1H),
59%); 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.98 (d, J = 7.3 7.67–7.61 (m, 2H), 7.46 (m, 3H), 7.38 (m, 1H), 2.69 (s, 3H);
Hz, 2H), 7.51–7.41 (m, 3H), 2.61 (s, 3H), 2.58 (s, 3H); 13C NMR 13C NMR (126 MHz, CDCl3) δ 156.08, 147.13, 143.77, 138.83,
(126 MHz, CDCl3) δ 153.25, 151.95, 150.88, 139.70, 138.26, 129.28, 128.30, 128.16, 127.75, 126.52, 126.25, 125.00, 122.58,
130.65, 130.50, 128.12, 23.72, 23.21; HRMS (ESI+) (m/z) calcd 118.76, 17.98; HRMS (ESI+) (m/z) calcd for C16H14N [M + H]
for C12H13N2 [M + H] 185.1079 found 185.1071.
220.1126 found 220.1122.
2-Methyl-3-phenylquinoxaline (11a). Red oil (34 mg, 62%);
6-Bromo-4-chloro-2-phenylquinoline (13d). White solid
TLC Rf = 0.6 (10% EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ (41 mg, 52%); mp 110 °C; TLC Rf = 0.7 (10% EtOAc/hexane);
8.06–7.95 (m, 2H), 7.68–7.62 (m, 2H), 7.60–7.55 (m, 2H), 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 2.1 Hz, 1H), 8.12 (dd,
7.47–7.40 (m, 3H), 2.70 (s, 3H); 13C NMR (126 MHz, CDCl3) δ J = 8.1, 1.5 Hz, 2H), 8.02 (d, J = 9.0 Hz, 1H), 7.97 (s, 1H), 7.82
154.93, 152.56, 141.24, 141.00, 139.02, 129.78, 129.27, 129.24, (dd, J = 9.0, 2.2 Hz, 1H), 7.54–7.49 (m, 3H); 13C NMR
129.03, 1128.95, 128.60, 128.32, 24.42; HRMS (ESI+) (m/z) (126 MHz, CDCl3) δ 156.54, 146.59, 140.93, 137.11, 133.07,
calcd for C15H13N2 [M + H] 221.1079 found 221.1082.
130.68, 129.04, 127.98, 126.42, 125.25, 120.37, 118.73, 117.83;
2-Methyl-3-(m-tolyl)quinoxaline (11b). Red oil (34 mg, 58%); HRMS (ESI+) (m/z) calcd for C15H1079BrClN [M + H] 317.9685
TLC Rf = 0.7 (10% EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ found 317.9672, calcd for C15H1079BrClN [M + H] 319.9665
8.14–8.03 (m, 2H), 7.76–7.68 (m, 2H), 7.48–7.45 (m, 1H), found 319.9650.
7.43–7.38 (m, 2H), 7.30 (dd, J = 4.5, 2.5 Hz, 1H), 2.77 (s, 3H),
tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
2.45 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 155.18, 152.66, pyrrolo[2,3-b]pyridine-1-carboxylate (21).13 1H NMR
δ
141.19, 140.97, 138.95, 138.42, 129.78, 129.71, 129.58, 129.23, (400 MHz, CDCl3) δ 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 8.18 (dd, J =
129.22, 128.40, 128.29, 125.94, 24.39, 21.53; HRMS (ESI+) (m/z) 7.8, 1.7 Hz, 1H), 7.98 (s, 1H), 7.14 (dd, J = 7.8, 4.8 Hz, 1H), 1.59
calcd for C16H15N2 [M + H] 235.1235 found 235.1227.
(s, 9H), 1.30 (s, 12H).
4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (meriolin
2-Methyl-3-(p-tolyl)quinoxaline (11c).10a Red oil (32 mg,
54%); TLC Rf = 0.7 (10% EtOAc/hexane); 1H NMR (400 MHz, 1). Yellow solid (28 mg, 35%); mp 222 °C; TLC Rf = 0.5 (10%
CDCl3) δ 8.06–7.93 (m, 2H), 7.69–7.60 (m, 2H), 7.51–7.45 (m, MeOH/DCM); 1H NMR δ (500 MHz, DMSO) δ 12.20 (s, 1H),
2H), 7.26 (d, J = 7.8 Hz, 2H), 2.71 (s, 3H), 2.38 (s, 3H); 13C NMR 8.93 (dd, J = 7.9, 1.5 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.29 (dd,
(101 MHz, CDCl3) δ 154.99, 152.61, 141.08, 139.02, 136.16, J = 4.6, 1.6 Hz, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.19 (dd, J = 7.9,
129.58, 129.23, 129.21, 129.15, 128.91, 128.24, 24.41, 21.35; 4.7 Hz, 1H), 7.07 (d, J = 5.3 Hz, 1H), 6.52 (s, 2H); 13C NMR δ
HRMS (ESI+) (m/z) calcd for C16H15N2 [M + H] 235.1235 found (126 MHz, DMSO) δ 163.40, 162.04, 157.09, 149.19, 143.42,
235.1227.
130.72, 128.44, 117.78, 116.70, 112.42, 104.97; HRMS (ESI+)
2-(4-Bromophenyl)-3-methylquinoxaline (11d). Yellow solid (m/z) calcd for C11H10N5 [M + H] 212.0936 found 212.0918.
1
(38 mg, 51%); TLC Rf = 0.8 (10% EtOAc/hexane); mp 89 °C; H
NMR (400 MHz, CDCl3) δ 8.13–8.04 (m, 2H), 7.78–7.71 (m, 2H),
7.70–7.63 (m, 2H), 7.58–7.51 (m, 2H), 2.78 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 153.73, 152.17, 141.24, 140.95, 137.81,
Acknowledgements
130.67, 129.53, 129.17, 128.29, 123.62, 117.31, 24.27; HRMS This work was supported by Council of Scientific and Indus-
(ESI+) (m/z) calcd for C15H1179BrN2 [M + H] 299.0184 found trial Research (CSIR)-New Delhi with research grant #BSC0108
299.0168, calcd for C15H1181BrN2 [M + H] 301.0163 found and #BSC0205. TT, US and SA thank CSIR and UGC for their
301.0149.
Fellowship. IIIM communication no. IIIM/1855/2015.
4-Methyl-2-phenylpyridine (13a).8d Colorless oil (19 mg,
44%); TLC Rf = 0.7 (10% EtOAc/hexane); 1H NMR (400 MHz,
CDCl3) δ 8.48 (d, J = 5.0 Hz, 1H), 7.90 (dd, J = 8.3, 1.3 Hz, 2H),
7.48 (s, 1H), 7.42–7.33 (m, 3H), 6.99 (dd, J = 5.0, 0.7 Hz, 1H),
2.35 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 157.35, 149.31,
148.01, 139.39, 128.91, 128.74, 127.01, 123.23, 121.74, 21.29;
HRMS (ESI+) (m/z) calcd for C12H12N [M + H] 170.0970 found
170.0965.
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