Mn-mediated oxidative radical cyclization of 2-(azidomethyl)phenyl isocyanides with carbazate: access to quinazoline-2-carboxylates

Article abstract of DOI:10.1039/d0nj00479k

Mn-TBHP mediated oxidative radical cyclization of 2-(azidomethyl)phenyl isocyanides using methyl carbazate has been described. This procedure is realized through a cascade radical addition and aromatization process with high atom economy to furnish various heterocyclic C2 diversified quinazoline-2-carboxylate derivatives.

Full text of DOI:10.1039/d0nj00479k

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Mn-mediated oxidative radical cyclization of
2-(azidomethyl)phenyl isocyanides with carbazate:
Cite this:DOI: 10.1039/d0nj00479k
access to quinazoline-2-carboxylates†
Gujjenahalli Ramalingaiah Yogesh Kumar, Noor Shahina Begum * and
Khan Mohammed Imran
Received 28th January 2020,
Accepted 29th March 2020
Mn-TBHP mediated oxidative radical cyclization of 2-(azidomethyl)phenyl isocyanides using methyl
carbazate has been described. This procedure is realized through a cascade radical addition and aromatization
process with high atom economy to furnish various heterocyclic C2 diversified quinazoline-2-carboxylate
derivatives.
DOI: 10.1039/d0nj00479k
rsc.li/njc
the previous studies, the work was mainly focused on the functional
group, such as an aldehyde, a ketone or an amine, that reacts with
Introduction
Quinazoline derivatives belong to nitrogen-containing hetero- an oxalate or oxoacetate, involving two steps. Despite the advances
cycles present in a wide variety of bioactive natural products.1 in developing different synthetic strategies, many methods still have
Specifically quinazoline and its derivatives represent a medicinally drawbacks such as harsh conditions, and use of noble metal alloy
and pharmaceutically important class that is found as the core catalysts and pre-functional groups. These limitations impede the
structural skeleton in a variety of drug molecules such as prazosin2 application of quinazoline derivatives in pharmaceutical synthesis.
and lapatinib.3 They exhibit a wide range of biological and To overcome this drawback and establish more efficient methods
pharmaceutical activities that include anti-cancer,4 anti-viral5 and in continuation of our effort towards the construction of
and anti-tuberculosis properties.6 Quinazolines have also been C2 diversified carboxylate quinazoline derivatives for new drug
employed as ligands for benzodiazepine and GABA receptors in the discovery, we hypothesized isocyanides as versatile building
CNS7 and also as DNA binders.8 This large interest in medicinal blocks as they have been widely applied in the synthesis of
chemistry stimulated the development of new variants of quinazo- numerous nitrogen containing compounds.11 Recently, Ezaki
line derivatives by exploring novel synthetic methods. The reported the preparation of quinazoline derivatives by using
construction of C2-diversified carboxylate quinazoline derivatives 1-(1-azidomethyl)-2-isocyanoarenes with NaH.12 Li also showed
has gained considerable attention in recent years. In this that isocyanides serve not only as nucleophiles but also as
direction, work is underway in our laboratory. There are reports efficient radical acceptors to produce imidoyl radical intermediates
of the classical synthetic approach to construct 2-carboxylate for subsequent reactions.13 In the past few years, elegant
quinazolines. Ferrini developed 2,4-disubstituted quinazolines advances have been made in the development of use of carba-
from 2-aminoacetophenone and ethyl 2-chloro-2-oxoacetate.9a zates as the precursors of alkoxycarbonyl radicals since carbazates
Yuan synthesized 2-carboxylate quinazoline by platinum/iridium (ROCONHNH2) are usually stable solids and are readily available.
alloy-mediated cyclocondensation of 2-(aminomethyl)aniline In 2016, Gao et al.14a developed an iron-catalyzed oxidative addition
with ethyl 2-oxoacetates.9b Wenlong reported the condensation of alkoxycarbonyl radicals to heterocyclic rings by using carbazates
of 2-aminobenzamide with diethyl oxalate leading to the synthesis as the source of ester groups. In 2014, Pan et al.14b reported radical
of 2-carboxylate quinazolines.9c Apart from these methods, there are arylalkoxycarbonylation of 2-isocyanobiphenyl with carbazates to
other methods too for 2-carboxylate quinazoline synthesis.10 How- give phenanthridine-6-carboxylates. Encouraged by these results,
ever, there are several limiting factors hindering the preparation of herein, we report a novel and practical method for the synthesis
2-carboxylate quinazolines with large molecular diversity. In most of of the second position functionalized quinazoline derivatives by
using 1-(1-azidomethyl)-2-isocyanoarenes.
Free radical reactions are a powerful tool in organic synthesis.
With their significant potential, this strategy has captured the
attention of synthetic chemists. These reactions are applied to a
range of organic transformations because of their unique advan-
tages such as excellent reactivity, mild conditions, functional group
Department of Studies in Chemistry, Bangalore University, Jnana Bharathi Campus,
Bangalore 560056, Karnataka, India. E-mail: noorsb@bub.ernet.in
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra of the
products and crystallographic information for 3g. CCDC 1911289. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/d0nj00479k
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Table 1 Optimization studies for manganese-mediated radical cyclization
of 2-(azidomethyl)phenyl isocyanides (1a) with methyl carbazate (2a)
Entry
Promoter
Additive
Solvent
Yield (%)
1
2
3
4
5
6
7
8
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3Á2H2O
Mn(OAc)3
TBHP
TBPB
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
PhF
CH3CN
EtOAc
Dioxane
EtOAc
EtOAc
45
20
ND
35
ND
ND
35
ND
15
25
55
65
20
48
35
25
Trace
Trace
ND
ND
K2S2O8
TBHP (70 %wt)
Ag2CO3
AgOAc
(NH4)2S2O8
CH3COOH
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
9
10
11
12
13
14
15
16
17
18
19
20
Mn(acac)3
Fe(acac)2
FeCl3
EtOAc
EtOAc
EtOAc
EtOAc
FeCl2Á4H2O
Cu(OAc)2
Oxone
EtOAc
Reaction conditions: 1a (0.63 mmol), 2a (1.26 mmol), promoter (0.63 mmol),
radical initiator (1.89 mmol, 5 M in decane), and solvent (8 mL) under a
N2 atmosphere for 12 h at 80 1C. TBHP (tert-butyl hydroperoxide) (5 M in
decane), TBHP (entry 4) (70% solution in water). TBPB (tert-butyl peroxy
benzoate).
Scheme 1 Comparison with previous work.
tolerance, and atom economy. In this paper we report a convenient
and an efficient method for the tandem synthesis of 2-quinazoline
carboxylates using 2-(azidomethyl)phenyl isocyanides along with
carbazates, in the presence of Mn(OAc)3Á2H2O as a promoter and
TBHP as a co-oxidant. This procedure is realized through a cascade
radical addition and aromatization process with high atom
economy and represents the first example of the use of a
carbazate as an alkoxycarbonyl radical precursor in isocyanide
insertion for direct conversion of 2-(azidomethyl)phenyl isocyanides
to quinazoline-2-carboxylate derivatives (Scheme 1).
that EtOAc was the best solvent as it gave the product in 65%
yield (Table 1, entry 12). Further optimization was carried out by
testing the efficiencies of various promoters, but the results
showed that the reaction yield decreased with Mn(OAc)3, Mn(acac)3,
Fe(acac)2, FeCl3, FeCl2Á4H2O, Cu(OAc)2, and oxone (Table 1, entries
14–20). The conditions given in entry 12 of Table 1 are found to be
the most suitable as they gave a high yield.
With the optimal reaction conditions in hand, we turned our
attention to the scope for the substrates 1-(1-azidomethyl)-
2-isocyanoarene compounds for the tandem cyclization and
C2-diversified carboxylation (Table 2). Various functional groups
Results & discussion
We started our studies on the feasibility of the oxidative radical such as methoxy, methyl, fluoro, chloro, and bromo were
reaction by using 2-(azidomethyl)phenyl isocyanides (1a) (0.63 mmol) tolerated well under the present oxidative conditions, affording
with methyl carbazate (2a) (1.26 mmol) in the presence of the products in moderate yields. We studied the effects of the
manganese(III) acetate dihydrate salts (Mn(OAc)3Á2H2O) (0.63 mmol) substituents at different positions on the aromatic ring with the
as a radical-mediated catalyst and TBHP (1.89 mmol) used as a isocyanide group. As expected, aromatic rings possessing electron-
co-oxidant. The reaction proceeded at 80 1C in toluene for 12 h. donating groups (3b–3f; Table 2) gave better yields than those
The desired C2 diversified carboxylation product of methyl possessing electron-withdrawing groups (3h–3m; Table 2). 2-(Azi-
quinazoline-2-carboxylate (3a) was obtained in 45% isolated domethyl)phenyl isocyanides bearing electron-donating groups
yield (Table 1, entry 1). To improve the yield, the reaction was at the para and meta positions gave better yields (3b, 3c, and 3d;
carried out by using various oxidants such as TBPB, K2S2O8, Table 2) than those bearing ortho substituents (3e, 3g, and 3k;
TBHP (70% wt) (Table 1, entry 4), Ag2CO3, AgOAc, (NH4)2S2O8, Table 2), which is attributed to the steric effect. Notably, the
and CH3COOH (Table 1, entries 2–8). Comparable results were halides were intact and the corresponding products were obtained
observed for reactions in TBHP (70% wt) (Table 1, entry 4). in moderate yields (3g–3m; Table 2), enabling further derivatizations
However, the product yield did not increase with the other through metal-catalyzed cross-coupling reactions. We also tested the
oxidants. In order to further improve the reaction yield, we azidomethane carbon substituent (1-(1-azidoethyl)-2-isocyano-
examined the effect of various solvents such as DMF, PhF, benzene) and noticed that the corresponding product was obtained
CH3CN, EtOAc and dioxane (Table 1, entries 9–13). We observed in 58% yield (3f). Further, when the isocyanide ring bore both
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Table 2 Substrate scope for methyl carbazate
Scheme 3 Proposed radical pathway for methyl quinazoline-2-
carboxylate product formation.
radicals may be accelerated by single-electron transfer along with
the formation of Mn(IV) species.15 The C–N bond cleavage of the
methyl carbazate forms an alkoxycarbonyl radical (I) with the
release of molecular N2 through stepwise hydrogen abstraction;
this radical (I) attacks the R–NC bond of 2-(azidomethyl)phenyl
isocyanide (1a) to form an imidoyl radical intermediate (II); this
intermediate undergoes intermolecular cyclization with the azido
group to give a cyclized aminyl radical (III) by nitrogen loss. Finally,
hydrogen abstraction of the radical intermediate (III) by the tert-
butoxy or tert-butyl peroxy radicals leads to the desired product (3a).
In conclusion, we have developed a novel and practical method for
the synthesis of C2 diversified methyl quinazoline-2-carboxylate
derivatives from 2-(azidomethyl)phenyl isocyanides (1a).
Reaction conditions: 1a (0.63 mmol), 2a (1.26 mmol), Mn(OAc)3Á2H2O
(0.63 mmol), TBHP (1.89 mmol, 5 M in decane), and EtOAc (8 mL) for
12 h at 80 1C.
electron donating and electron withdrawing substituents at
different positions, the yield of the corresponding product was
55% (3g; Table 2).
To have a better understanding of the functionalization of
2-(azidomethyl)phenyl isocyanides, some mechanistic experiments
were carried out. The radical inhibitor 2,2,6,6-tetramethylpiperidine-
1-oxyl (TEMPO) (2.0 equiv.) was added to the reaction mixture; the
desired product was not observed and the TEMPO-COOMe (3aa)
adduct was detected by LCMS (Scheme 2). The radical inhibitor
(TEMPO) had a large negative impact on the reaction efficiency with
methyl carbazate (2a), which provided evidence favoring the free
radical mechanism.
Based on the above experimental results, a mechanism is
proposed (Scheme 3). Initially, Mn(OAc)3Á2H2O-assisted homolysis
of TBHP generates tert-butoxy and tert-butyl peroxy radicals.14c–g
With the aid of Mn(III), the homolysis of TBHP into tert-butoxy
Conclusions
In summary, a cascade synthesis of methyl quinazoline-2-carb-
oxylates using 2-(azidomethyl)phenyl isocyanides with methyl
carbazate has been reported. This protocol provides a novel,
general, reliable, straightforward, atom efficient approach to
methyl quinazoline-2-carboxylate (3a). Furthermore, the utility of
this approach can be applied to late-stage functionalization and
modification of pharmaceutically and biologically active molecules.
Experimental
General
NMR spectra were recorded on 400 MHz and 500 MHz spectro-
Scheme 2 Control experiments for mechanistic studies.
meters in CDCl3 or DMSO-d6. Tetramethylsilane (TMS; d = 0.00 ppm)
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served as an internal standard for 1H NMR. The corresponding
Methyl 5-methoxyquinazoline-2-carboxylate (3c). Prepared
residual nondeuterated solvent signal (DMSO-d6, d = 2.4 ppm; as per the general experimental procedure. Brown solid (62%,
CDCl3, d = 7.25 ppm) served as an internal standard. All the 62 mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point
13C NMR experiments were run in CDCl3 and DMSO-d6 on (1C): 131–133. IR (KBr, cmÀ1): 2948, 2359, 2103, 1726, 1607,
100 MHz and 125 MHz spectrometers. The solvent signal 1559, 1479, 1381, 1329, 1139, 771, 730. 1H NMR (CDCl3,
(CDCl3, d = 77.01 ppm; DMSO-d6, d = 39.55 ppm) was used as 400 MHz): d 9.53 (s, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.58 (d,
an internal standard for 13C NMR. Data are reported as follows: J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.10 (s, 6H). 13C{1H}
chemical shifts in ppm (d), multiplicity (s = singlet, t = triplet, NMR (CDCl3, 100 MHz): d 164.25, 160.93, 155.37, 151.67,
q = quartet, m = multiplet), and coupling constants (Hz). 141.96, 130.61, 126.04, 118.27, 112.59, 56.27, 53.54. HRMS
IR spectra were measured using an FT-IR spectrometer. (ESI-TOF) (m/z): [M + H]+ calcd for C11H10N2O3H 219.077; found
Mass spectra were obtained for the final compound with an 219.0772.
ESI-Q-TOF Mass Spectrometer (HRMS). For all intermediates
Methyl 5-methylquinazoline-2-carboxylate (3d). Prepared as
mass spectra were obtained by LCMS (ESI) m/z. Flash column per the general experimental procedure. Yellow solid (60%, 61
chromatography was carried out by packing glass columns with mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point (1C):
commercial silica gel 230–400 mesh (commercial suppliers) and 141–143. IR (KBr, cmÀ1): 3016, 2095, 1734, 1609, 1565, 1328,
1
thin-layer chromatography was carried out using silica gel GF-254. 1199, 1148, 799. H NMR (DMSO-d6, 400 MHz): d 9.83 (s, 1H),
All catalysts, reagents, starting materials and coupling partners 7.99–7.97 (m, 2H), 7.68 (d, J = 5.2 Hz, 1H), 3.94 (s, 3H), 2.79
were procured from commercial suppliers. Solvents were used for (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz): d 167.25, 156.37,
the reaction, workup and purification.
140.33, 136.80, 134.29, 129.50, 128.23, 127.81, 118.23, 53.04,
19.59. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C11H10N2O2H
203.0821; found 203.0819.
Methyl 8-methylquinazoline-2-carboxylate (3e). Prepared as
per the general experimental procedure. Pale-yellow solid (55%,
General experimental procedure for synthesizing methyl
quinazoline-2-carboxylate derivatives
In a 20 mL screw-cap reaction vial 2-(azidomethyl)phenyl isocyanides 58 mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point
(1a) (1.0 equiv., 0.63 mmol, 0.1 mg), Mn(OAc)3Á2H2O (1.0 equiv., (1C): 120–122. IR (KBr, cmÀ1): 2916, 2100, 1734, 1612, 1566,
1
0.63 mmol, 0.16 g), NH2NHCOOMe (2.0 equiv., 1.26 mmol, 0.11 g), 1477, 1303, 1140, 804, 771. H NMR (CDCl3, 400 MHz): d 9.49
and TBHP (5 M in decane) (3 equiv., 1.89 mmol, 0.38 mL) were (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.67 (t, J = 8.0 Hz, 1H), 4.11
added followed by the addition of ethyl acetate (8 mL). The vial was (s, 3H), 2.87 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz): d 164.61,
capped and placed in a pre-heated (80 1C) metal block for 12 h. After 161.07, 151.88, 149.21, 138.36, 134.81, 129.55, 125.17, 124.81,
the completion of the reaction (monitored by TLC), the reaction 53.38, 16.94. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
mixture was cooled to room temperature, and diluted with ethyl
C
11H10N2O2H 203.0821; found 203.0819.
acetate, which was washed with brine (3 Â 20 mL) and water (3 Â
Methyl 4-methylquinazoline-2-carboxylate (3f). Prepared as
20 mL); the combined organic layers were dried over anhydrous per the general experimental procedure. Brown solid (58%, 57
Na2SO4 and evaporated under reduced pressure. The crude products mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point (1C):
were purified by flash column chromatography using ethyl acetate 98–100. (KBr, cmÀ1): 2956, 2359, 1730, 1613, 1570, 1254, 1204,
and n-hexane to afford the desired products.
770. 1H NMR (CDCl3, 400 MHz): d 8.25 (d, J = 8.0 Hz, 1H), 8.18
Methyl quinazoline-2-carboxylate (3a). Prepared as per the (d, J = 8.4 Hz, 1H), 7.98 (t, J = 6.8 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H),
general experimental procedure. White solid (65%, 68 mg). 4.11 (s, 3H), 3.07 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz):
Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point (1C): d 169.89, 164.67, 151.84, 149.41, 134.47, 130.11, 129.59, 125.06,
121–123. IR (KBr, cmÀ1): 3060, 2955, 2100, 1731, 1615, 1557, 124.59, 53.63, 21.98. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
1
1491, 1319, 1153, 977, 803, 781, 746, 647. H NMR (DMSO-d6,
C
11H10N2O2H 203.0821; found 203.0821.
400 MHz): d 9.75 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.15–8.11
Methyl 6-fluoro-8-methoxyquinazoline-2-carboxylate (3g). Pre-
(m, 2H), 7.90–7.89 (m, 1H), 3.95 (s, 3H). 13C{1H} NMR (CDCl3, pared as per the general experimental procedure. Brown solid
100 MHz): d 164.31, 161.21, 152.52, 150.03, 135.13, 130.02, (55%, 56 mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point
129.58, 127.19, 125.14, 53.70. HRMS (ESI-TOF) (m/z): [M + H]+ (1C): 158–160. IR (KBr, cmÀ1): 3261, 2958, 2106, 1724, 1615, 1561,
1
calcd for C10H8N2O2H 189.0664; found 189.0664.
1323, 1243, 1192, 1143, 966, 840. H NMR (DMSO-d6, 400 MHz):
Methyl 6-methoxyquinazoline-2-carboxylate (3b). Prepared d 9.65 (s, 1H), 7.57–7.52 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H). 13C{1H}
as per the general experimental procedure. Brown solid (62%, NMR (CDCl3, 125 MHz): d 164.13, 161.89, 160.38, 157.74, 151.23,
62 mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point 139.76, 126.53, 104.28, 101.65, 56.86, 53.71. 19F NMR (376 MHz,
(1C): 158–160. IR (KBr, cmÀ1): 2954, 2359, 2102, 1727, 1617, CDCl3): À110.38 to À110.39 (d, 1F). HRMS (ESI-TOF) (m/z):
1560, 1490, 1302, 1229, 834, 659. 1H NMR (DMSO-d6, 400 MHz): [M + H]+ calcd for C11H9FN2O3H 237.0675; found 237.0674.
d 9.59 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H),
Methyl 6-fluoroquinazoline-2-carboxylate (3h). Prepared as
7.64 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H). 13C{1H} NMR (CDCl3, per the general experimental procedure. Yellow solid (55%,
100 MHz): d 164.40, 160.29, 159.13, 150.68, 146.23, 131.05, 56 mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point
128.36, 126.57, 103.75, 55.29, 53.52. HRMS (ESI-TOF) (m/z): (1C): 160–162. IR (KBr, cmÀ1): 2954, 2105, 1732, 1622, 1560,
[M + H]+ calcd for C11H10N2O3H 219.0770; found 219.0773.
1493, 1445, 1296, 1155, 997, 835. H NMR (CDCl3, 400 MHz):
1
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d 9.54 (s, 1H), 8.34–8.31 (q, 1H), 7.82–7.78 (m, 1H), 7.65 (d, J = Conflicts of interest
7.6 Hz, 1H), 4.13 (s, 3H). 13C{1H} NMR (CDCl3, 125 MHz):
There are no conflicts to declare.
d 164.19, 163.11, 161.07, 160.68, 152.22, 147.30, 132.70,
126.02, 110.61, 53.88. 19F NMR (376 MHz, CDCl3): À121.98 to
À122.02 (m, 1F). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
Acknowledgements
C
10H7FN2O2H 207.057; found 207.0565.
We thank M. Srinivas (SFSL Bangalore) for technical assistance
in recording the spectra of the compounds.
Methyl 5-fluoroquinazoline-2-carboxylate (3i). Prepared as
per the general experimental procedure. Pale-yellow solid (55%,
56 mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point
(1C): 177–179. IR (KBr, cmÀ1): 3279, 2959, 2359, 2103, 1728,
Notes and references
1
1622, 1568, 1316, 1143, 766, 726. H NMR (CDCl3, 500 MHz):
d 9.59 (s, 1H), 7.85–7.68 (m, 3H), 4.09 (s, 3H). 13C{1H} NMR
(CDCl3, 125 MHz): d 164.03, 161.22, 158.57, 156.47, 152.75,
130.35, 126.25, 123.05, 119.45, 53.86. 19F NMR (376 MHz,
DMSO-d6): À121.10 to À121.12 (d, 1F). HRMS (ESI-TOF) (m/z):
[M + H]+ calcd for C10H7FN2O2H 207.057; found 207.0569.
Methyl 5-bromoquinazoline-2-carboxylate (3j). Prepared as
per the general experimental procedure. Pale-yellow gummy
solid (52%, 53 mg). Rf (40% ethyl acetate/n-hexane) = 0.2.
Melting point (1C): 126–130. IR (cmÀ1): 2954, 2359, 2096, 1728,
1624, 1550, 1438, 1293, 950, 645. 1H NMR (CDCl3, 500 MHz):
d 9.86 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.88
(d, J = 7.6 Hz, 1H), 4.14 (s, 3H). 13C {1H} NMR (CDCl3, 125 MHz):
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d
163.94, 161.26, 153.52, 151.51, 135.47, 133.73, 129.43,
124.46, 121.79, 53.96. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C10H7BrN2O2H 266.9769; found 268.9821.
3 (a) T. H. O. Munnink, E. G. E. de Vries, S. R. Vedelaar,
¨
H. T. Bosscha, C. P. Schroder, A. H. Brouwers and M. N. Lub-
Methyl 8-bromoquinazoline-2-carboxylate (3k). Prepared as
per the general experimental procedure. Pale-yellow solid (50%,
52 mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point
(1C): 114–116. IR (KBr, cmÀ1): 3278, 2957, 2359, 1705, 1604,
1537, 1241, 1066, 764. 1H NMR (DMSO-d6, 400 MHz): d 9.78
(s, 1H), 8.21 (t, J = 7.2 Hz, 2H), 8.04 (t, J = 8.0 Hz, 1H), 3.96
(s, 3H). 13C{1H} NMR (CDCl3, 100 MHz): d 163.99, 161.74,
153.41, 147.82, 138.49, 130.38, 126.78, 126.36, 125.08, 53.70.
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C10H7BrN2O2H
266.9769; found 268.9753.
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Methyl 7-chloroquinazoline-2-carboxylate (3l). Prepared as
per the general experimental procedure. Pale-yellow solid (52%,
53 mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point
(1C): 137–139. IR (KBr, cmÀ1): 3043, 2946, 2359, 1732, 1610,
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1
1554, 1440, 1298, 1208, 1139, 1068, 651, 619. H NMR (CDCl3,
400 MHz): d 9.54 (s, 1H), 8.28 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H),
7.75 (d, J = 8.8 Hz, 1H), 4.13 (s, 3H). 13C{1H} NMR (CDCl3,
100 MHz): d 163.98, 160.91, 153.44, 150.58, 141.64, 131.23,
128.59, 128.37, 123.46, 53.71. HRMS (ESI-TOF) (m/z): [M + H]+
calcd for C10H7ClN2O2H 223.0274; found 223.0271.
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Methyl 5-chloroquinazoline-2-carboxylate (3m). Prepared as
per the general experimental procedure. Yellow solid (51%,
50 mg). Rf (40% ethyl acetate/n-hexane) = 0.2. Melting point 10 (a) K. Yoshikawa, S. Kobayashi, Y. Nakamoto, N. Haginoya,
(1C): 143–145. IR (KBr, cmÀ1): 3281, 3051, 2359, 1736, 1605,
1541, 1215, 1141, 720, 685. 1H NMR (DMSO-d6, 400 MHz):
d 9.83 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H),
7.87 (t, J = 8.0 Hz, 1H), 3.96 (s, 3H). 13C{1H} NMR (CDCl3,
125 MHz): d 164.12, 161.76, 153.19, 146.90, 135.03, 134.27,
130.10, 126.45, 126.17, 53.86. HRMS (ESI-TOF) (m/z): [M + H]+
calcd for C10H7ClN2O2H 223.0274; found 223.0271, 225.0374.
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