A Convenient and Concise Metal-Free Approach to Functionalized Bicyclic Pyrimidinones from Oxazine-2,6-diones

Article abstract of DOI:10.1055/s-0037-1609364

The synthesis of previously unreported pyrazolo-pyrimidinones and isoxazolo-pyrimidinones are achieved via metal-free coupling of oxazine-2,6-diones with pyrazolidinone and isoxazolidinone, respectively. The synthesis provides easy access to a variety of novel 2-dimensional building blocks that can be derivatized to generate a range of drug- and agro-like molecules.

Full text of DOI:10.1055/s-0037-1609364

SYNTHESIS
0
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1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, 2087–2093
paper
2087
en
A. Shirsale et al.
Paper
Synthesis
A Convenient and Concise Metal-Free Approach to Functionalized
Bicyclic Pyrimidinones from Oxazine-2,6-diones
Ashwini Shirsalea
Yogesh Patila
R2
H
N
R1
O
R1
N
O
R2
R3
Hünig's base
+
R3
Girish K. Rawala
Jagadish Pabbaa
Guillaume Berthonb
Ravindra P. Sonawanea
Vikas Sikervar*a
N
N
O
H
toluene, 50–110 °C
X
X
O
O
X = O, N(Boc)
R1 = H, NH(Boc)
6 examples
up to 65% yield
a Syngenta Biosciences Pvt Ltd, Goa 403110, India
vikas.sikervar@syngenta.com
b Syngenta Crop Protection AG, 4332 Stein AG,
Switzerland
Received: 31.01.2018
Accepted after revision: 22.02.2018
Published online: 20.03.2018
Combination of novel heterocycles with divergent func-
tional groups represents a powerful technique in finding
novel active ingredients (AIs) for drug and agrochemical
use. One such example is the discovery of indazolo-
quinazolinone 4, which is a combination of indazole with
quinazolininone and is a potent inhibitor of phosphodi-
esterase.2
Furthermore, such heterocycles with additional handle
for derivatization unfold opportunities to expedite the pro-
cess of finding new leads for drug discovery and agrochem-
ical development. Pyrazolone, pyrimidinone, and isoxazole
have been long proven privileged heterocycles, which have
shown relevant biological activities for agrochemical tar-
gets (Figure 2).3 As part of our ongoing hit discovery pro-
gram for the agrochemical development we were interested
in the synthesis of fused pyrazolo-pyrimidinone and isox-
azolo-pyrimidinone heterocycles, which could be easily
DOI: 10.1055/s-0037-1609364; Art ID: ss-2018-t0063-op
Abstract The synthesis of previously unreported pyrazolo-pyrimidi-
nones and isoxazolo-pyrimidinones are achieved via metal-free cou-
pling of oxazine-2,6-diones with pyrazolidinone and isoxazolidinone, re-
spectively. The synthesis provides easy access to a variety of novel 2-
dimensional building blocks that can be derivatized to generate a range
of drug- and agro-like molecules.
Key words isoxazolidinone, pyrazolidinone, oxazine-2,6-dione, metal-
free coupling
Quinazolinones are privileged heterocycles found in
several natural products and biologically active compounds
in both fused and stand-alone heterocyclic structures (Fig-
ure 1).1 Luotonin A represents one such example from
quinazolinone family of natural product, which is isolated
from Chinese herbal medicinal plant Peganum nigellastrum.1
SO2Me
O
F
O
O
N
O
O
O
F
N
I
N
N
H
CF3
N
N
N
O
N
N
N
N
N
N
O
2, Luotonin A
3, Mackinazolinone
1, Quinazolininone
5, Sedaxane
6, Proquinazid
7, Balance Flexx
Fungicide
Fungicide
Herbicide
O
N
O
F
N
N
O
Cl
N
4, Phosphodiesterase inhibitor
8, Clomazone
Figure 1 Biologically relevant heterocycles with fused pyrimidinone
Herbicide
Figure 2 Commercially available agrochemicals with isoxazole, pyrim-
idinone, and pyrazole motives
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 2087–2093

2088
A. Shirsale et al.
Paper
Synthesis
derivatized to generate a library of agrolike targets. Howev-
er, to the best of our knowledge bicyclic pyrimidinones 9
and 10 where R2 and R3 are not fused with additional
phenyl ring or have handles for derivatization such as 11
have never been reported in literature (Figure 3).
2-phenylquinazolin-4-one (15) (Scheme 1). The current
work utilizes the dual reactivity of oxazine-2,6-dione and
base-catalyzed coupling of Boc-protected pyrazolidinone in
the absence of any metal. It gives access to non-flat and
non-aromatic substitutions/fusions on R2, R3 and opportu-
nity to vary functional group diversification on nitrogen
atom after Boc deprotection, which was not possible with
earlier methods. It is noteworthy that previous methods
suffer from the drawback that they cannot be used for the
synthesis of such stand-alone bicyclic pyrimidinone struc-
tures like 11.
R4
R4
O
H2N
R1
R2
N
R1
R2
N
O
N
O
OEt
R5
R5
N
N
N
O
N
O
R3
O
9
10
11
Preliminary investigation started with the exploration
of model coupling reaction of oxazine-2,6-dione 20 and the
in situ generated sodium salt of isoxazolidin-3-one 19 in
the presence of water.5 But the reaction led only to decom-
position and no isolable product was obtained. We were de-
lighted to learn that the reaction proceeded smoothly in the
presence of Hünig’s base (diisopropylethylamine, DIPEA)
and toluene at 50 °C to furnish 2,3-dihydroisoxazolo[2,3-
a]pyrimidin-7-one 21 in 33% yield (Scheme 2).
Figure 3 Fused hybrid bicyclic pyrimidinones
Only few approaches are reported in literature for the
construction of central core of fused bicyclic pyrimidinone
9. Pal, Wang, and Wu have independently reported the syn-
thesis of indazoloquinazolinone derivatives from isatoic an-
hydride.2,4 Pal’s and Wang’s method rely on the metal-cata-
lyzed (Pd or Cu) coupling of o-halobenzaldehyde with ben-
zohydrazide while Wu has reported two approaches, first
involving dual-metal-catalyzed intramolecular oxidative C–
H amination and second featuring Cu-catalyzed C–OMe
bond cleavage and intramolecular amination of 3-anilino-
H
O
N
O
O
N
NaOH, H2O
+
N
N
O
H
O
O
r.t. to 50 °C
0%
O
19
20
21
H
O
Previous Works
N
O
O
N
DIPEA (1.5 equiv)
+
Wang, X. et al. and
Pal, M. et al.
N
N
O
H
O
O
toluene, 50 °C
33%
O
H
N
O
19
20
21
O
Ph
Pd(PPh3)4
BINAP
OHC
X
N
N
H
Ph
Scheme 2 Model coupling reaction
N
+
NH2
or
N
The coupling reaction proceeds smoothly using amino-
substituted isoxazolidin-3-one 22 as well to form bicyclic
heterocycle 23 in 39% yield (Scheme 3). X-ray crystallo-
graphic data of compound 23 confirmed the regioselective
addition and the formation of bicyclic structure. The reac-
tion was found to be general for both isoxazolidin-3-one as
well as different oxazine-2,6-diones. For instance, the cou-
pling reaction of isoxazole 22 and aryl-substituted oxazine-
2,6-dione 25 proceeds under similar conditions to form
amino-substituted heterocycle 26 in 40% yield.
CuBr, Cs2CO3
12
13
X = Br or I
14
Wu, H. et al
O
Ph
NH
O
Ph
N
X
Pd(OAc)2, AgOAc
N
N
N
or
N
Cu(OAc)2, t-BuOK
15
14
X = H or OMe
Coupling of isoxazolidinone 22 and ester-substituted di-
hydroisoxazole 27 also proceeded efficiently to form 2-D
amino ester bicyclic building block 28 in 56% yield (Scheme
3). The starting material anhydride 27 can be prepared fol-
lowing the literature procedure by Beccalli et al.6,7 (Scheme 4).
We next turned our attention towards the coupling re-
action of pyrazolidinone 328 and oxazine-2,6-dione 33. To
our delight, the reaction proceeded smoothly to furnish
pyrazolo[1,5-a]pyrimidin-7-one 34 in 40% yield. N-Boc
deprotection of 34 using 2,2,2-trifluoroacetic acid (TFA)
leads to the formation of pyrazolo[1,5-a]pyrimidin-7-one
This work
H
N
R2
R3
R1
O
R1
R2
R3
N
O
Hünig's base
+
N
O
N
toluene, 100 °C
H
X
X
O
O
X = O, N(Boc)
R1 = H, NH(Boc)
16
17
18
Scheme 1 Strategies for the synthesis of central core of 2,3-dihydropy-
razolo[1,5-a]pyrimidin-7-one
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 2087–2093

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Synthesis
H
N
H
N
BocHN
O
BocHN
H
O
O
N
DIPEA
(2.2 equiv)
DIPEA (1.5 equiv)
toluene, 110 °C
TFA
(10 equiv)
O
N
N
+
O
H
N
H
N
+
N
Boc
O
O
toluene, 100 °C
12 h
O
CH2Cl2
54%
N
O
O
39%
N
22
20
23
32
O
33
40%
O
34
Boc
H
H
N+
N
TFA (10 equiv)
97%
F3C
O–
N
N
O
O
O
24
N
N
H
X-ray of 23
O
X-ray of 35
35
O
O
H
O
DIPEA
(1.5 equiv)
H
O
TFA
(8 equiv)
Cl
OEt
N
O
N
N
OEt
Cl
+
N
toluene,100 °C
12 h
Boc
O
CH2Cl2
54%
N
N
Cl
H
BocHN
DIPEA
(1.7 equiv)
N
BocHN
BocHN
O
65%
32
27
O
36
O
N
Boc
Cl
+
N
N
O
toluene, 110 °C
40%
H
O
O
CO2Et
O
26
N
O
22
25
O
N
H
O
N
H
O
DIPEA
(1.5 equiv)
OEt
O
O
N
BocHN
N
OEt
37
+
O
N
H
toluene, 100 °C
12 h
N
O
Scheme 5 Synthesis of pyrazolo[1,5-a]pyrimidin-7-ones 35 and 37
O
27
O
O
22
28
56%
Scheme 3 1-D and 2-D building blocks of dihydroisoxazolopyrimidi-
carboxylic acid building blocks, which could potentially be
further derivatized to generate library of agro- and drug-
like targets (Scheme 6).
none
H
O
O
DMF (2.4 equiv)
NH2OH·HCl (1.8 equiv)
N
O
EtO
Cl
OEt
NaH (4 equiv)
O
EtO2C
O
EtOH, reflux
quant
CO2Et
THF/DMF
N
POCl3 (1.6 equiv)
CCl4, reflux, 3 h
O
0 °C to r.t.
N
N
29
30
N
O
62%
N
H
H
N
Cl
O
TFA
O
Br
38
O
N
37
O
(1.2 equiv)
73%
F
H2SO4 (4.5%)
1,4-dioxane
F
O
O
F
N
CO2Et
NaH (4 equiv)
THF/DMF
0 °C to r.t.
O
N
H
CO2Et
44%
N
31
27
O
Cl
N
Scheme 4 Synthesis of ester-substituted oxazine-2,6-dione 27
N
N
F
F
O
Cl
F
H
N
39
O
35, which could be derivatized for SNAr, alkylation, or acyla-
tion reactions for expedited library synthesis.
Cl
(1.2 equiv)
81%
The structure of pyrazolopyrimidinone 35 was further
confirmed using X-ray crystallography. Ester-substituted
oxazine-2,6-dione 27 also underwent reaction with pyrazo-
lidinone 32 under similar condition to form pyrazolo-
pyrimidinone 36 in 65% yield (Scheme 5).
To showcase the utility of the two-dimensional pyrazo-
lo-pyrimidinone building block, the free ‘N’ was derivatized
via alkylation and SNAr substitution reactions to generate
Scheme 6 Synthesis of pyrazolo[1,5-a]pyrimidin-7-one carboxylic ac-
ids 38 and 39
In conclusion, we have developed a one-step synthesis
to construct bicyclic pyrazolo-pyrimidinones and isoxazo-
lo-pyrimidinones via coupling of oxazine-2,6-diones with
pyrazolidione and isoxazolidinone, respectively. The se-
quence provides easy access to unknown drug- and agro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 2087–2093

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Synthesis
like heterocyclic building blocks, which can be derivatized
to generate library of compounds that will expedite the lead
generation process in agrochemical- and drug discovery.
tert-Butyl N-(6-Methyl-7-oxo-2,3-dihydroisoxazolo[2,3-a]pyrimi-
din-3-yl)carbamate (23)
To a solution of tert-butyl N-(3-oxoisoxazolidin-4-yl)carbamate (22;
3.88 g, 19.2 mmol) in toluene (50 mL) was added DIPEA (3.7 g, 28.8
mmol, 1.5 equiv). The reaction mass was stirred for 10 min and to it
was added 5-methyl-3H-1,3-oxazine-2,6-dione (20; 2.44 g, 19.2
mmol, 1 equiv). The reaction mass was then heated at 100 °C over-
night. The TLC indicated consumption of starting material. The reac-
tion mass was diluted with H2O and extracted with EtOAc (3 × 25 mL),
the combined organic layers were dried (Na2SO4), and concentrated to
obtain the crude product, which was purified by column chromatog-
raphy to obtain the desired product 23 as a white solid; yield: 2.0 g
(39%); mp 188–190 °C.
All reactions were performed under N2 atmosphere. Analytical grade
solvents were used without any further purification. 1H and 13C NMR
spectra were recorded on a Bruker Avance II-400 spectrometer using
CHCl3 as internal standard. LCMS was recorded in Spectra were re-
corded on a Mass Spectrometer from Agilent Technologies (6410 Tri-
ple Quadruple Mass Spectrometer) equipped with an electrospray
source [Polarity: Positive and Negative Polarity Switch, Capillary: 4.00
kV, Fragmentor: 100.00 V, Gas Temperature: 350 °C, Gas Flow: 11
L/min, Nebulizer Gas: 45 psi, Mass range: 110–1000 Da, DAD Wave-
length range: 210–400 nm. Column: KINETEX EVO C18, length 50
mm, diameter 4.6 mm, particle size 2.6 μm. Column oven tempera-
ture 40 °C. Solvent gradient: A: H2O with 0.1% formic acid/MeCN
(95:5 v/v). B: MeCN with 0.1% formic acid. Gradient: 0 min 90% A, 10%
B; 0.9–1.8 min 0% A, 100% B, 2.2–2.5 min 90% A, 10% B. Flow rate 1.8
mL/min]. Chemical shift values are given in ppm (δ) relative to CHCl3
(7.27 ppm), DMSO (2.54 ppm) and coupling constants J are given in
hertz (Hz). IR spectra were recorded on Shimadzu DRS Prestige 21
spectrophotometer. Column chromatographic purifications were per-
formed on a CombiflashRf (Teledyne Isco) with silica gel using the
mobile phase indicated.
IR (KBr): 3358, 1687, 1670, 1531, 1170, 964 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.71 (s, 1 H), 5.64 (br d, J = 5.87 Hz, 1
H), 5.45 (br d, J = 6.72 Hz, 1 H), 4.96 (br t, J = 8.31 Hz, 1 H), 4.44 (t, J =
8.68 Hz, 1 H), 2.09 (s, 3 H), 1.44 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 153.8, 150.0, 147.9, 124.6, 80.2, 76.2,
74.4, 52.9, 27.2, 12.1.
HRMS-ESI: m/z calcd for C12H17N3O4 (M + H): 268.1297; found:
268.1290.
For details of X-ray crystal data of 23, see ref. 10.
(6-Methyl-7-oxo-2,3-dihydroisoxazolo[2,3-a]pyrimidin-3-yl)am-
monium 2,2,2-Trifluoroacetate (24)
5-Methyl-3H-1,3-oxazine-2,6-dione (20)
Compound 20 was prepared according to the literature report.9
To a solution of 23 (0.410 g, 1.53 mmol) in CH2Cl2 (7 mL) was added
TFA (1.74 g, 15.3 mmol, 10 equiv) and the reaction mixture was
stirred at r.t. overnight. TLC of the reaction mass indicated consump-
tion of the starting material. The reaction mixture was then concen-
trated and the desired product 24 was isolated as its TFA salt off-
white solid; yield: 0.420 g (97%); mp 110–112 °C.
To a mixture of NaOCl solution (4.99%, 10 mL) and NaOH (1.6 g, 40
mmol) cooled at 0 °C was added dropwise a precooled (0 °C) solution
of 3-methylpyrrole-2,5-dione (3.55 g, 32 mmol) in H2O (14 mL). The
reaction mixture was then stirred at the same temperature for 4 h to
obtain a clear solution. After completion of reaction (monitored by
TLC), dilute H2SO4 was added until pH 3 to form a white precipitate,
which was filtered and dried to obtain the desired product as a white
solid; yield: 1.8 g (44%); mp 115–117 °C.
IR (KBr): 2985, 2675, 1662, 1535, 1207, 1174, 1132, 840 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 1.95–2.06 (m, 3 H), 4.64 (dd, J =
9.72, 5.44 Hz, 1 H), 4.93 (t, J = 8.93 Hz, 1 H), 5.27 (dd, J = 7.64, 5.69 Hz,
1 H), 7.94 (s, 1 H), 8.61–9.10 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 153.8, 149.6, 148.7, 125.1, 72.1,
52.1, 12.7.
IR (KBr): 2970, 2910, 2162, 1753, 1172, 813, 549 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 1.67–1.87 (m, 3 H), 7.38–7.55 (m, 1
.
19F NMR (377 MHz, DMSO-d6): δ = –73.62.
H), 11.16–11.47 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 161.2, 148.9, 141.6, 103.1, 11.9.
HRMS-ESI: m/z calcd for C7H10N3O2 (M + H): 168.0768; found:
168.0764.
MS (ESI): m/z = 125.8 (M – H).
tert-Butyl N-[5-(3,5-Dichlorophenyl)-7-oxo-2,3-dihydroisoxazo-
lo[2,3-a]pyrimidin-3-yl]carbamate (26)
6-Methyl-2,3-dihydroisoxazolo[2,3-a]pyrimidin-7-one (21)
To a solution of isoxazolidin-3-one (19; 0.070 g, 0.80 mmol) in tolu-
ene (3 mL) was added DIPEA (0.155 g, 1.2 mmol, 1.5 equiv) at r.t. The
reaction mixture was stirred for 5 min and to it was added 5-methyl-
3H-1,3-oxazine-2,6-dione (20; 0.152 g, 1.2 mmol, 1.5 equiv) at once
and the mixture was stirred at 50 °C for 2 h. After completion of the
reaction (TLC monitoring), the reaction mass was concentrated on a
rotavap and the crude product thus obtained was purified by column
chromatography to obtain the desired product 21 as a yellow solid;
yield: 0.040 g (33%); mp 122–124 °C.
To a solution of tert-butyl N-(3-oxoisoxazolidin-4-yl)carbamate (22;
2.21 g, 10.9 mmol) in toluene (30 mL) was added DIPEA (2.4 g, 18.6
mmol, 1.7 equiv). After stirring for 10 min, 4-(3,5-dichlorophenyl)-
3H-1,3-oxazine-2,6-dione (25; 1.7 g, 10.9 mmol, 1 equiv) was added
and the reaction mixture was heated at 100 °C for 14 h. After comple-
tion of the reaction (TLC monitoring), the reaction mass was concen-
trated under reduced pressure and purified by column chromatogra-
phy to obtain the desired product 26 as a off-white solid; yield: 1.72 g
(40%); mp 198–201 °C.
1H NMR (400 MHz, CDCl3): δ = 2.05–2.17 (m, 3 H), 3.46–3.59 (m, 2 H),
4.64–4.81 (m, 2 H), 7.61–7.75 (m, 1 H).
IR (KBr): 3345, 1682, 1599, 1520, 1443, 1371 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.10 (s, 2 H), 7.80–7.90 (m, 1 H),
7.76 (t, J = 1.65 Hz, 1 H), 7.23 (s, 1 H), 5.58 (br d, J = 8.44 Hz, 1 H), 4.95
(t, J = 8.74 Hz, 1 H), 4.40 (br t, J = 8.07 Hz, 1 H), 3.38–3.44 (m, 1 H),
3.12–3.32 (m, 1 H), 1.44 (s, 8 H), 1.38 (br s, 1 H), 1.29 (br s, 2 H), 1.10
(s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 151.1, 147.8, 123.4, 68.4, 31.8, 12.0.
HRMS-ESI: m/z calcd for C7H8N2O2 (M + H): 153.0664; found:
153.0653.
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Synthesis
13C NMR (100 MHz, DMSO-d6): δ = 156.5, 155.5, 155.1, 154.0, 139.4,
1H NMR (400 MHz, CDCl3): δ = 1.34–1.53 (m, 3 H), 2.21–2.38 (m, 3 H),
135.2, 130.2, 125.9, 110.2, 79.8, 73.6, 54.5, 28.5.
4.39–4.55 (m, 2 H), 8.56–8.77 (m, 1 H).
HRMS-ESI: m/z calcd for C7H10N3O2 (M + H): 398.0674; found:
13C NMR (100 MHz, CDCl3): δ = 160.6, 159.9, 146.6, 136.2, 111.3, 63.7,
398.0667.
13.5, 11.3.
MS (ESI): m/z = 199.8 (M + H).
Ethyl 4-Methyl-5-oxo-2H-isoxazole-3-carboxylate (30)
Prepared as reported in the literature.7
Ethyl 3-(tert-Butoxycarbonylamino)-6-methyl-7-oxo-2,3-dihy-
droisoxazolo[2,3-a]pyrimidine-5-carboxylate (28)
To a solution of diethyl 2-methyl-3-oxobutanedioate (29; 3 g, 0.014
mol) in EtOH (30 mL) was added NH2OH·HCl (1.74 g, 0.025 mol). The
reaction mass was heated at 78 °C for 14 h. After completion of the
reaction (TLC monitoring), the mixture was directly concentrated un-
der reduced pressure. The residue was triturated 3 times with petro-
leum ether to obtain the desired product 30 as a white solid; yield:
2.5 g (quant); mp 68–70 °C.
IR (KBr): 3610, 3116, 1728, 1398, 1238 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 1.30 (t, J = 7.09 Hz, 3 H), 1.91 (s, 3
H), 4.32 (q, J = 7.09 Hz, 2 H).
To a solution of tert-butyl N-(3-oxoisoxazolidin-4-yl)carbamate (22;
2.44 g, 12.1 mmol) in toluene (40 mL) was added DIPEA (2.34 g, 18.1
mmol, 1.5 equiv). After stirring for 10 min, ethyl 5-methyl-2,6-dioxo-
3H-1,3-oxazine-4-carboxylate (27; 2.4 g, 12.1 mmol, 1 equiv) was
added and the reaction mixture was heated at 100 °C for 14 h. After
completion of the reaction (TLC monitoring), the reaction mass was
concentrated under reduced pressure and purified by column chro-
matography to obtain the desired product 28 as a off-white solid;
yield: 2.29 g (56%); mp 140–142 °C.
.
IR (KBr): 3352, 3315, 2978, 1712, 1514, 1236, 1166 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 172.2, 159.9, 153.5, 153.2, 62.0, 14.3,
7.0.
1H NMR (400 MHz, CDCl3): δ = 1.38–1.43 (m, 3 H), 1.43–1.48 (m, 9 H),
2.24–2.33 (m, 3 H), 4.39–4.46 (m, 2 H), 4.46–4.51 (m, 1 H), 4.93–5.15
(m, 1 H), 5.31–5.60 (m, 2 H).
MS (ESI): m/z = 169.8 (M – H).
13C NMR (100 MHz, CDCl3): δ = 164.5, 154.7, 154.4, 149.9, 147.8,
126.5, 80.8, 75.4, 61.9, 53.8, 27.8, 13.7, 11.7.
Ethyl 2-(Dimethylamino)-5-methyl-6-oxo-1,3-oxazine-4-carbox-
ylate (31)
Prepared as reported in the literature.7
HRMS-ESI: m/z calcd for C15H21N3O6 (M + H): 340.1508; found:
340.1493.
To a mixture of DMF (2.08 mL, 0.026 mol) and CCl4(38 mL) was added
POCl3(1.73 mL, 0.018 mol) dropwise at 0 °C. The reaction mass was
stirred for 30 min at 0 °C and then at r.t. for 15 min. The reaction mass
was again cooled to 0 °C and solid ethyl 4-methyl-5-oxo-2H-isoxaz-
ole-3-carboxylate (30; 2 g, 0.011 mol) was added. The reaction mix-
ture was stirred for 1 h at 0 °C, for 1 h at r.t., and finally heated for 4 h
at 80 °C. After completion of the reaction (TLC monitoring) the mix-
ture was cooled using ice-water bath and quenched with sat. aq NaH-
CO3(30 mL) under cooling condition. The mixture was then extracted
with CH2Cl2 (3 × 70 mL) and the combined organic layers were
washed with brine, dried (Na2SO4), and concentrated under vacuum.
The crude mixture thus obtained was purified by column chromatog-
raphy to obtain the desired product 31 as a white solid; yield: 1.65 g
(62%); mp 56–58 °C.
4-Phenyl-3H-1,3-oxazine-2,6-dione (33)
Prepared as per the literature protocol.7
To a mixture of ethyl 3-oxo-3-phenylpropanoate (10 g, 52.026 mmol)
and methyl carbamate (3.9 g, 52.026 mmol, 1 equiv) was added POCl3
(30 mL, 318.6 mmol). The reaction mixture was heated at 90 °C for 3
h. After completion of the reaction (monitored by TLC and LCMS), the
excess of POCl3 was evaporated on a rotavap under reduced pressure.
The solid was then washed with toluene (3 × 25 mL), then Et2O (3 × 25
mL), and finally with EtOH (3 × 25 mL) to obtain the desired product
33 a off-white solid, which was used as such in the next step; yield:
5.8 g (59%); mp 209–211 °C.
IR (KBr): 3143, 3111, 1768, 1755, 1693, 1485, 1371, 993, 763, 565 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.77–7.80 (m, 2 H), 7.48–7.63 (m, 4
.
IR (KBr): 2981, 2945, 1730, 1020, 866, 756, 729 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.33–1.45 (m, 3 H), 1.92–2.07 (m, 3 H),
H), 6.01 (s, 1 H).
2.96–3.26 (m, 6 H), 4.26–4.48 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 164.9, 160.8, 157.3, 153.9, 103.3, 61.4,
13C NMR (100 MHz, DMSO-d6): δ = 160.1, 156.8, 149.5, 132.2, 129.1,
127.4, 92.0.
36.9, 35.7, 13.6, 10.6.
HRMS-ESI: m/z calcd for C10H7NO3 (M + H): 190.0504; found:
MS (ESI): m/z = 226.8 (M + H).
190.0514.
Ethyl 5-Methyl-2,6-dioxo-3H-1,3-oxazine-4-carboxylate (27)
tert-Butyl 7-Oxo-5-phenyl-2,3-dihydropyrazolo[1,5-a]pyrimidine-
1-carboxylate (34)
To a solution of ethyl 2-(dimethylamino)-5-methyl-6-oxo-1,3-ox-
azine-4-carboxylate (31; 1 g, 0.004 mol) in 1,4-dioxane (46 mL) was
added 4.5% H2SO4(prepared by diluting 1 mL of concd H2SO4to 22 mL
with H2O) and the reaction mixture was heated at 100 °C for 1 h. After
completion of the reaction (TLC monitoring), the mixture was cooled
to r.t. The reaction mass was extracted with EtOAc (3 × 30 mL) and the
combined organic layers were washed with H2O and aq NaHCO3, and
dried (Na2SO4). Evaporation of the solvent afforded a crude mixture,
which was purified by column chromatography to obtain the desired
product 27 as a white solid; yield: 0.39 g (44%); mp 90–92 °C.
To a solution of tert-butyl 3-oxopyrazolidine-1-carboxylate (32; 0.2 g,
1 mmol) in toluene (5 mL) was added DIPEA (0.258 g, 2 mmol, 2.2
equiv) at r.t. under stirring followed by the addition of 4-phenyl-3H-
1,3-oxazine-2,6-dione (33; 0.189 g, 1 mmol, 1 equiv). The reaction
mixture was stirred overnight at 100 °C. After completion of the reac-
tion (TLC monitoring), the mixture was concentrated under reduced
pressure and was directly loaded on a silica gel column for purifica-
tion to obtain the desired product 34 as an off-white solid; yield: 0.14
g (40%); mp 147–149 °C.
IR (KBr): 3109, 2985, 1726, 1396 cm–1
.
IR (KBr): 2978, 2353, 1734, 1687, 1670, 1606, 1292, 1157, 1080 cm–1
.
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1H NMR (400 MHz, CDCl3): δ = 1.47–1.58 (m, 9 H), 3.16–3.33 (m, 2 H),
4.11–4.25 (m, 2 H), 6.73–6.81 (m, 1 H), 7.37–7.51 (m, 3 H), 7.83–7.96
(m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 160.0, 158.3, 156.7, 154.5, 135.6,
130.1, 128.4, 126.6, 108.2, 84.2, 48.4, 31.7, 27.5.
um and isolated as the TFA salt 37; yellow solid; yield: 0.84 g (54%);
mp 80–82 °C.
IR (KBr): 3163, 2983, 1726, 1712, 1649, 1230 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 1.21–1.34 (m, 3 H), 1.93–2.14 (m, 3
H), 3.16–3.30 (m, 2 H), 3.40–3.50 (m, 2 H), 4.22–4.36 (m, 2 H), 6.96–
7.29 (m, 1 H).
HRMS-ESI: m/z calcd for C17H19N3O3 (M + H): 314.1504; found:
314.1489.
13C NMR (100 MHz, DMSO-d6): δ = 165.4, 158.8, 155.5, 147.9, 120.3,
61.3, 43.1, 31.9, 14.0, 11.3.
19F NMR (377 MHz, DMSO-d6): δ = –74.11.
5-Phenyl-2,3-dihydro-1H-pyrazolo[1,5-a]pyrimidin-1-ium-7-one
2,2,2-Trifluoroacetate (35)
HRMS-ESI: m/z calcd for C10H14N3O3 (M + H): 224.1030; found:
224.1036.
To a solution of tert-butyl 7-oxo-5-phenyl-2,3-dihydropyrazolo[1,5-
a]pyrimidine-1-carboxylate (34; 2.03 g, 6.48 mmol) in CH2Cl2 (40 mL)
was added TFA (7.4 g, 64.8 mmol, 10 equiv) slowly at 10 °C and the
reaction mass was stirred at r.t. overnight. After completion of the re-
action (TLC and LCMS), CH2Cl2 was evaporated on a rotavap under re-
duced pressure. The solid gummy mass was then triturated 3–4 times
with Et2O to afford 35 as a off-white solid; yield: 1.16 g (54%); mp
189–191 °C.
1-[(4-Chlorophenyl)methyl]-6-methyl-7-oxo-2,3-dihydropyrazo-
lo[1,5-a]pyrimidine-5-carboxylic Acid (38)
To a suspension of NaH (0.043 g, 1.8 mmol, 4 equiv) in anhyd THF (2
mL) was added dropwise at 0 °C, a solution of ethyl 6-methyl-7-oxo-
2,3-dihydro-1H-pyrazolo[1,5-a]pyrimidin-1-ium-5-carboxylate
2,2,2-trifluoroacetate (37; 0.15 g, 0.44 mmol) in DMF (0.5 mL). After
stirring the reaction mass for 10 min, a solution of 1-(bromomethyl)-
4-chlorobenzene (0.109 g, 0.53 mmol, 1.2 equiv) in THF (0.5 mL) was
added dropwise, which led to precipitation of the reaction mass. To
the same reaction mass was added THF (6 mL) and DMF (1.5 mL) and
stirring was continued for 1 h at r.t. The reaction mixture was then
acidified with aq 2 N HCl and extracted with EtOAc (3 × 50 mL). The
combined organic layers were washed with brine, dried (Na2SO4), and
concentrated under reduced pressure to obtain the crude product,
which was triturated with Et2O to isolate the desired product 38 as a
yellow solid; yield: 0.104 g (73%); mp 164–166 °C.
IR (KBr): 3215, 1643, 1492, 1386, 945, 779, 694 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 3.25–3.38 (m, 2 H), 3.41–3.55 (m, 2
H), 6.72–6.87 (m, 1 H), 7.13–7.29 (m, 1 H), 7.38–7.52 (m, 3 H), 7.95–
8.09 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 158.8, 158.0, 156.6, 136.1, 130.1,
128.6, 126.6, 105.8, 42.8, 32.5.
19F NMR (377 MHz, DMSO-d6): δ = –73.43.
HRMS-ESI: m/z calcd for C12H12N3O (M + H): 214.0975; found:
214.0981.
For details of X-ray crystal data of 35, see ref. 10.
IR (KBr): 2353, 1712, 1680, 1664, 1554, 1384, 1217, 1168 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 2.10 (s, 3 H), 3.09 (br t, J = 7.52 Hz,
2 H), 3.40 (br t, J = 7.70 Hz, 2 H), 4.22 (s, 2 H), 7.37–7.47 (m, 4 H),
13.21–14.01 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 166.5, 157.6, 156.9, 149.0, 134.4,
132.2, 130.7, 128.1, 120.5, 56.0, 47.2, 29.4, 11.1.
O1-tert-Butyl O5-Ethyl 6-Methyl-7-oxo-2,3-dihydropyrazolo[1,5-
a]pyrimidine-1,5-dicarboxylate (36)
To a solution of tert-butyl 3-oxopyrazolidine-1-carboxylate (32; 1.5 g,
8.1 mmol) in toluene (25 mL) was added DIPEA (1.55 g, 12 mmol, 1.5
equiv). The reaction mixture was stirred for 10 min followed by the
addition of ethyl 5-methyl-2,6-dioxo-3H-1,3-oxazine-4-carboxylate
(27; 1.6 g, 8.1 mmol, 1 equiv) and stirred overnight at 100 °C. After
completion of the reaction (TLC monitoring), the reaction mass was
concentrated under reduced pressure, and the crude mass thus ob-
tained was purified by column chromatography to obtain the desired
product 36 as a yellow solid; yield: 1.7 g (65%); mp 124–126 °C.
HRMS-ESI: m/z calcd for C15H14ClN3O3 (M + H): 320.0802; found:
320.0792.
1-[3-Chloro-5-(trifluoromethyl)-2-pyridyl]-6-methyl-7-oxo-2,3-
dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic Acid (39)
To a suspension of NaH (0.043 g, 1.8 mmol, 4 equiv) in anhyd THF (2
mL) at 0 °C was added dropwise a solution of ethyl 6-methyl-7-oxo-
2,3-dihydro-1H-pyrazolo[1,5-a]pyrimidin-1-ium-5-carboxylate
2,2,2-trifluoroacetate (38; 0.15 g, 0.44 mmol) in DMF (0.5 mL). After
stirring the reaction mixture for 10 min, 2,3-dichloro-5-(trifluoro-
methyl)pyridine (0.115 g, 0.53 mmol, 1.2 equiv) was added dropwise,
followed by the addition of THF (6 mL) and DMF (1.5 mL). The reac-
tion mass was stirred for 1 h at r.t., then acidified with aq 2 N HCl, and
extracted with EtOAc (3 × 50 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated under reduced
pressure to obtain a crude mass. Trituration with Et2O and cooling to
0 °C afforded the desired product 39 as an off-white solid; yield: 0.135
g (81%); mp 185–187 °C.
IR (KBr): 2985, 1739, 1718, 1676, 1373, 1301, 1236, 1161, 846 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.37–1.45 (m, 3 H), 1.45–1.55 (m, 9 H),
2.26–2.37 (m, 3 H), 3.18–3.29 (m, 2 H), 4.07–4.22 (m, 2 H), 4.36–4.48
(m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 164.8, 157.0, 155.8, 154.0, 147.0,
125.3, 84.4, 61.8, 48.5, 31.4, 27.4, 13.7, 11.7.
HRMS-ESI: m/z calcd for C15H21N3O5 (M + H): 324.1559; found:
324.1558.
Ethyl 6-Methyl-7-oxo-2,3-dihydro-1H-pyrazolo[1,5-a]pyrimidin-
1-ium-5-carboxylate 2,2,2-Trifluoroacetate (37)
To the solution of O1-tert-butyl O5-ethyl 6-methyl-7-oxo-2,3-dihydro-
pyrazolo[1,5-a]pyrimidine-1,5-dicarboxylate (36; 1.5 g, 4.6 mmol) in
CH2Cl2 (20 mL) at 10 °C was added dropwise TFA (4.2 g, 37 mmol, 8
equiv) at r.t. and the reaction mixture was stirred at r.t. for 12 h. After
completion of the reaction, the reaction mass was concentrated under
reduced pressure. The gummy residue obtained was triturated with
Et2O to obtain a yellow solid, which was then dried under high vacu-
IR (KBr): 2922, 1734, 1672, 1554, 1323, 1136, 1051 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 2.04 (s, 3 H), 3.20–3.44 (m, 8 H),
4.16 (br t, J = 7.40 Hz, 2 H), 8.58–8.61 (m, 1 H), 8.65 (s, 1 H), 13.39–
13.88 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 166.5, 157.7, 156.9, 156.2, 149.7,
142.5, 136.5, 123.8, 123.0, 122.7, 121.4, 121.1, 119.9, 51.3, 30.3, 11.1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 2087–2093

2093
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Synthesis
HRMS-ESI: m/z calcd for C14H10ClF3N4O3 (M + H): 375.0472; found:
375.0465.
(2) Kumar, K. S.; Kumar, P. M.; Rao, V. S.; Jafar, A. A.; Meda, C. L. T.;
Kapavarapu, R.; Parsac, K. V. L.; Pal, M. Org. Biomol. Chem. 2012,
10, 3098.
(3) Giornal, F.; Pazenok, S.; Rodefeld, L.; Lui, N.; Vors, J.; Leroux, F. R.
J. Fluorine Chem. 2013, 152, 2.
Funding Information
(4) (a) Qiao, R.; Ye, L.; Hu, K.; Yu, S.; Yang, W.; Liu, M.; Chen, J.; Ding,
J.; Wu, H. Org. Biomol. Chem. 2017, 15, 2168. (b) Chen, D.; Dou,
G.; Li, Y.; Liu, Y.; Wang, X. J. Org. Chem. 2013, 78, 5700. (c) Yang,
W.; Ye, L.; Huang, D.; Liu, M.; Ding, J.; Chen, J.; Wu, H. Tetrahe-
dron 2013, 69, 9852. (d) Yang, W.; Chen, J.; Huang, X.; Ding, J.;
Liu, M.; Wu, H. Org. Lett. 2014, 16, 5418. (e) Yang, W.; Qiao, R.;
Chen, J.; Huang, X.; Liu, M.; Gao, W.; Ding, J.; Wu, H. J.
Org. Chem. 2015, 80, 482.
We thank Syngenta Research & Technology Centre, Goa for providing
the research facility and thank the management for supporting this
work.
)(
Acknowledgment
We thank Mark Montgomery for providing the X-ray data.
(5) Dunn, A. D.; Kinnear, K. I.; Norrie, R.; Ringan, N.; Martin, D. J.
Heterocycl. Chem. 1987, 24, 175.
(6) Beccalli, E. M.; Marchesini, A.; Molinari, H. Tetrahedron Lett.
1986, 27, 627.
Supporting Information
(7) Beccalli, E. M.; Marchesini, A. J. Org. Chem. 1987, 52, 3426.
(8) Gould, E.; Lebl, T.; Slawin, A. M. Z.; Reid, M.; Smith, A. D. Tetra-
hedron 2010, 66, 8992.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609364.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(9) Bobek, M.; Kuhar, S.; Bloch, A. J. Med. Chem. 1979, 22, 592.
(10) CCDC 1818542 (23) and 1818638 (35) contain the supplemen-
tary crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 2087–2093