Metal-and Oxidant-Free Synthesis of Quinazolinones from β‑Ketoesters with o‑Aminobenzamides via Phosphorous Acid- Catalyzed Cyclocondensation and Selective C −C Bond Cleavage
Metal-and Oxidant-Free Synthesis of Quinazolinones from β‑Ketoesters with o‑Aminobenzamides via Phosphorous Acid- Catalyzed Cyclocondensation and Selective C −C Bond Cleavage
Metal-and Oxidant-Free Synthesis of Quinazolinones from β‑Ketoesters with o‑Aminobenzamides via Phosphorous Acid- Catalyzed Cyclocondensation and Selective C −C Bond Cleavage
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INTRODUCTION
N-Heterocyclic compounds are the most abundant and integral
of 2-amino-thiophenols/anilines with -diketones for the
synthesis of benzothiazoles and benzimidazoles has been
scaolds that occur ubiquitously in a large number of bioactive explored. However, the protocol is not well suited for 2-aryl-
natural products, synthetic drugs, pharmaceuticals, and agro- substituted N-heterocycles. Therefore, highly general and
chemicals.1 Among the various N-heterocycles, quinazolinones metal- and oxidant-free syntheses of quinazolinones or other
are a privileged class of compounds with a diverse spectrum of N-heterocycles, especially with broad substrate scope, still
biological activities and therapeutic potential.2,3 Quinazolinones remain highly desirable.
are commonly prepared by the condensation of o-amino- The CC bond is the most fundamental bond and is
benzamides with aldehydes4 using oxidants or carboxylic acid widespread in organic compounds. CC bond cleavage is a
derivatives5 under harsh conditions. Recently, oxidative topic of signicant importance in organic synthesis, which
condensations of the alcohol,6 methylarene,7 or amines8 with allows the construction of a new CC bond directly from inert
o-aminobenzamides have also been developed. However, starting materials. Hence, many strategies, such as strained
despite these notable advances,9 they generally suer from molecules (three- or four-membered ring compounds) and
one or more drawbacks, such as requirement of stoichiometric chelation assistance, have been employed for this purpose.13
or excess amounts of strong oxidants, high temperatures, and Although signicant advances have been made in the past
transition metal catalysts. Thus, undesired side reactions decades, the development of selective CC bond cleavage by a
inevitably take place, which decrease the selectivity to catalytic reaction is a challenging problem in organic chemistry,
quinazolinones. For example, most of the procedures are not especially for the cleavage of unstrained CC bonds. To meet
well suited for 2-alkyl-substituted quinazolinones,48 because this challenge, transition metals are frequently employed.14
aliphatic aldehydes or the in situ-generated aliphatic aldehydes However, it is particularly of interest to achieve CC bond
are chemically unstable under harsh conditions. In addition, cleavage by metal-free strategies, which are still scarce.12a,15
transition metal catalyzed syntheses of quinazolinones starting Herein, in continuation of our ongoing research on the
from other substrates have also been extensively studied.9,10 synthesis of N-heterocycles,7b,16 we report a general and
Transition metals are toxic and must be carefully removed from ecient method for the preparation of quinazolinones from the
the products, especially for the drug and pharmaceutical readily available -ketoesters via phosphorous acid-catalyzed
industry. In this respect, a metal- and oxidant-free strategy cyclocondensation and selective CC bond cleavage eq 1. This
would be a promising choice, but it has not been frequently reaction takes place under mild conditions to produce both 2-
used for the synthesis of quinazolinones.11 Although oxidants alkyl-substituted and 2-aryl-substituted quinazolinones in
and/or metals are also generally required for the synthesis of excellent yields with a high tolerance to a variety of functional
other N-heterocycles, metal- and oxidant-free methods have groups.
been developed, especially for benzothiazoles and benzimida-
zoles.12 A notable case is reported by Yu, Bao, and co- Received: April 26, 2015
workers,12a in which a convenient TsOH-catalyzed cyclization
a
Reaction conditions: 2-aminobenzamide 1 (0.2 mmol), -ketoester 2 (0.26 mmol), 50% H3PO3 (10 mol %, 0.02 mmol), EtOH (0.5 mL) in 5 mL
Schlenk tube, 50 C, 15 h. bIsolated yield. c80 C, 24 h. d100 C, 24 h.
(130 C; Table 3, entry 14). The above results showed that CC bond cleavage to produce both 2-alkyl- and 2-aryl-
reactions using -diketones as the substrates were sensitive to substituted benzothiazoles 7 and benzothiazoles 8 in excellent
the steric hindrance of the substrates and the aryl-substituted - yields, respectively. As described above, Bao has reported a
diketones were inactive in this cyclocondensation reaction (vide similar method for the synthesis of benzothiazoles and
infra). benzimidazoles using -diketones as the substrates.12a Although
In addition to quinazolinones, this strategy was also the strong Brnsted acid was used, low eciency was observed
applicable to the formation of other N-heterocycles such as for the substrates with bulky substituents. Release of half of the
benzimidazoles 7 and benzothiazoles 8. As shown in Table 4, o- substituents, especially for bulky substituents, was another
phenylenediamine 5 and o-aminothiophenol 6 readily reacted drawback of the protocol. In contrast to the reported method,
with various -ketoesters via cyclocondensation and selective this phosphorous acid-catalyzed reaction system employs -
C DOI: 10.1021/acs.joc.5b00937
J. Org. Chem. XXXX, XXX, XXXXXX
The Journal of Organic Chemistry Article
a
Reaction conditions: 2-aminobenzamide 1 (0.2 mmol), -diketone 4 a
Reaction conditions: o-substituted aniline 5 or 6 (0.2 mmol), -
(0.26 mmol), 50% H3PO3 (10 mol %, 0.02 mmol), EtOH (0.5 mL) in ketoester 2 (0.26 mmol), 50% H3PO3 (10 mol %, 0.02 mmol), EtOH
5 mL Schlenk tube, 50 C, 15 h. bIsolated yield. c80 C, 24 h. d100 C, (0.5 mL) in 5 mL Schlenk tube, 50 C, 15 h. bIsolated yield. c80 C,
24 h. e130 C, 24 h. 24 h.
ketoesters as the substrates, and the CC cleavage is selectively intermediate I, followed by protonation to give ketiminium II.
occurred to incorporate the bulky substituents into N- The intramolecular nucleophilic addition of II produces the
heterocycles highly eciently, with only the small groups adduct III. Finally, the desired product 3 was obtained by the
released. Furthermore, this protocol is not sensitive to the steric CC bond cleavage under acidic conditions. At this stage, the
hindrance of the substituents, and is applicable to 2-aryl- reason for the highest performance of phosphorous acid
substituted N-heterocycles. Therefore, the present nding remains unclear, which is an ongoing research in our laboratory.
shows many advantages over the previously reported method, In conclusion, by the use of easily available phosphorous acid
especially in terms of green reagent, high compatibility with and ketoesters, we have developed a general and ecient
aryl-substitutes, and high atom-economy. method for the preparation of quinazolinones under metal- and
In order to clarify the reaction pathway, the reaction of 2- oxidant-free conditions, which features a broad range of
aminobenzamide 1a (0.2 mmol) with ethyl acetoacetate 2a substrate scope. The available substrates, ease of operation,
(0.26 mmol) was traced by GC and GC-Mass under the excellent yield, and selectivity make it very practical for the
synthesis of N-heterocycles.
optimum conditions (Scheme 1). After 6 h, quinazolinone 3a
and imine Ia were observed in 36% and 57% yields,
respectively. By prolonging the reaction time to 15 h, the EXPERIMENTAL SECTION
imine Ia was completely converted to 3a. Therefore, imine Ia General Information. Except where otherwise noted, all
probably served as the reaction intermediate. reactions were carried out in Schlenk tubes under N 2
As shown in Scheme 2, this reaction probably proceeds via a atmosphere. Reagents were used as received unless otherwise
typical Brnsted acid-catalyzed mechanism,18 which is similar noted. 1H and 13C NMR spectra were recorded on a 400 MHz
to that of Baos work.12a Initially, in the presence of H3PO3, the spectrometer (400 MHz for 1H and 100 MHz for 13C NMR
condensation reaction of 1 with 2 takes place to generate imine spectroscopy). CDCl3 or DMSO-d6 was used as the solvent.
D DOI: 10.1021/acs.joc.5b00937
J. Org. Chem. XXXX, XXX, XXXXXX
The Journal of Organic Chemistry Article
Scheme 2. Proposed Mechanism (s, br, 1H), 8.29 (d, J = 7.3 Hz, 1H), 7.77 (t, J = 7.6 Hz 1H),
7.71 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 2.85 (q, J =
7.6 Hz, 2H), 1.46 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) 164.4, 157.6, 149.5, 134.8, 127.2, 126.3, 126.2, 120.5,
29.1, 11.5.
2-Propylquinazolin-4(3H)-one (3c).10i Following the gen-
eral procedure, the crude product was puried by column
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2H), 3.56 (s, 3H); 13C NMR (100 MHz, CHCl3) 161.8, 21.2, 14,6, 9.5. HRMS (EI) m/z: [M]+ calcd. for C12H12N2O
152.7, 148.6, 134.7, 127.0, 126.8, 126.5, 121.5, 71.1, 59.3. 200.0950; found 200.0936.
2-Phenylquinazolin-4(3H)-one (3h).6b Following the gen- 2-(4-Fluorophenyl)-6-methylquinazolin-4(3H)-one (3n).
eral procedure, the crude product was puried by column Following the general procedure, the crude product was
chromatography on silica gel and eluted with ethyl acetate/ puried by column chromatography on silica gel and eluted
petroleum ether (1/4) to aord a white solid. Yield: 40.4 mg, with ethyl acetate/petroleum ether (1/4) to aord a white
91%; mp: 235236 C. 1H NMR (400 MHz, CDCl3) 12.09 solid. Yield: 46.2 mg, 91%; mp: 280283 C. 1H NMR (400
(s, br, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.30 (dd, J = 6.5, 3.0 Hz, MHz, DMSO-d6) 12.51 (s, br, 1H), 8.288.21 (m, 2H), 7.96
2H), 7.85 (d, J = 7.9 Hz, 1H), 7.837.77 (m, 1H), 7.627.55 (s, 1H), 7.707.62 (m, 2H), 7.447.35 (m, 2H), 2.47 (s, 3H);
(m, 3H), 7.51 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz,
13
C NMR (100 MHz, DMSO-d6) 164.5 (d, JCF = 247.8 Hz),
CDCl3) 164.0, 151.8, 149.5, 134.9, 132.8, 131.6, 129.0, 128.0, 162.7, 151.2, 147.2, 136.9, 136.5, 130.7 (d, JCF = 8.8 Hz),
127.5, 126.7, 126.3, 120.8. 129.8 (d, JCF = 2.8 Hz), 127.9, 125.8, 121.1, 116.2 (d, JCF =
2-(4-Fluorophenyl)quinazolin-4(3H)-one (3i).6b Following 21.9 Hz), 21.4. HRMS (EI) m/z: [M]+ calcd. for C15H11FN2O
the general procedure, the crude product was puried by 254.0847; found 254.0854.
column chromatography on silica gel and eluted with ethyl 2-Cyclopropyl-6-chloroquinazolin-4(3H)-one (3o).10a Fol-
acetate/petroleum ether (1/3) to aord a white solid. Yield: lowing the general procedure, the crude product was puried
42.7 mg, 89%; mp: 291294 C. 1H NMR (400 MHz, DMSO- by column chromatography on silica gel and eluted with ethyl
d6) 8.288.23 (m, 2H), 8.16 (d, J = 7.9 Hz, 1H), 7.84 (t, J = acetate/petroleum ether (1/4) to aord a white solid. Yield:
40.9 mg, 93%; mp: 292295 C. 1H NMR (400 MHz, DMSO-
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7.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H),
7.40 (t, J = 8.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) d6) 12.49 (s, br, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.71 (d, J = 8.7
Publication Date (Web): September 11, 2015 | doi: 10.1021/acs.joc.5b00937
164.5 (d, JCF = 247.7 Hz), 162.7, 151.9, 149.1, 135.1, 130.9 (d, Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 2.001.94 (m, 1H), 1.10
JCF = 8.9 Hz), 129.7, 127.9, 127.1, 126.3, 121.4, 116.1 (d, JCF 1.06 (m, 2H), 1.041.01 (m, 2H); 13C NMR (100 MHz,
= 21.7 Hz). DMSO-d6) 161.8, 160.9, 149.4, 134.6, 129.6, 129.0, 125.2,
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (3j).6b Follow- 122.3, 14.2, 10.1.
ing the general procedure, the crude product was puried by 6-Chloro-2-(4-methoxyphenyl)quinazolin-4(3H)-one
column chromatography on silica gel and eluted with ethyl (3p).10c Following the general procedure, the crude product
acetate/petroleum ether (1/4) to aord a white solid. Yield: was puried by column chromatography on silica gel and eluted
46.9 mg, 93%; mp: 276280 C. 1H NMR (400 MHz, DMSO- with ethyl acetate/petroleum ether (1/3) to aord a white
d6) 12.41 (s, br, 1H), 8.19 (d, J = 8.9 Hz, 2H), 8.13 (dd, J = solid. Yield: 50.9 mg, 89%; mp: 290292 C. 1H NMR (400
7.9, 1.0 Hz, 1H), 7.847.77 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), MHz, DMSO-d6) 12.56 (s, br, 1H), 8.18 (d, J = 8.7 Hz, 2H),
7.48 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H); 8.05 (d, J = 2.1 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.71 (d, J =
13
C NMR (100 MHz, DMSO-d6) 162.8, 162.3, 152.3, 149.4, 8.7 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) 162.5, 161.9, 152.8, 148.2, 135.1,
135.0, 129.9, 127.8, 126.6, 126.3, 125.3, 121.2, 114.5, 55.9.
130.7, 130.1, 125.3, 125.0, 122.4, 114.5, 56.0.
2-(4-Nitrophenyl)quinazolin-4(3H)-one (3k).6b Following
5-Fluoro-2-propylquinazolin-4(3H)-one (3q). Following the
the general procedure, the crude product was puried by general procedure, the crude product was puried by column
column chromatography on silica gel and eluted with ethyl chromatography on silica gel and eluted with ethyl acetate/
acetate/petroleum ether (1/1) to aord a yellow solid. Yield: petroleum ether (1/5) to aord a white solid. Yield: 37.9 mg,
47.0 mg, 88%; mp: >300 C. 1H NMR (400 MHz, DMSO-d6) 92%; mp: 216220 C. 1H NMR (400 MHz, CDCl3) 11.81
12.79 (s, br, 1H), 8.438.37 (m, 4H), 8.19 (d, J = 7.7 Hz, (s, 1H), 7.68 (dd, J = 13.6, 8.0 Hz, 1H), 7.49 (d, J = 8.2 Hz,
1H), 7.89 (t, J = 7.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.59 (t, J 1H), 7.157.05 (m, 1H), 2.75 (t, J = 7.6 Hz, 2H), 1.961.86
= 7.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) 162.5, (m, 2H), 1.07 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
151.2, 149.5, 148.8, 139.0, 135.3, 129.8, 128.2, 127.8, 126.4, CDCl3) 161.8, 161.3 (d, JCF = 263.8 Hz), 158.0, 151.5, 135.1
124.1, 121.7. (d, JCF = 10.4 Hz), 123.1, 112.8 (d, JCF= 20.3 Hz),110.4, 37.5,
2-(4-Pyridinyl)quinazolin-4(3H)-one (3l).1c Following the 20.8, 13.6. HRMS (EI) m/z: [M]+ calcd. for C11H11FN2O:
general procedure, the crude product was puried by column 206.0856, found 206.0849.
chromatography on silica gel and eluted with ethyl acetate/ 5-Fluoro-2-(4-methoxyphenyl)quinazolin-4(3H)-one
petroleum ether (1/2) to aord a pale yellow solid. Yield: 38.4 (3r).5e Following the general procedure, the crude product was
mg, 86%; mp: 281284 C. 1H NMR (400 MHz, DMSO-d6) puried by column chromatography on silica gel and eluted
12.65 (s, br, 1H), 8.79 (d, J = 5.5 Hz, 2H), 8.19 (d, J = 7.5 Hz, with ethyl acetate/petroleum ether (1/2) to aord a white
1H), 8.12 (d, J = 5.9 Hz, 2H), 7.88 (t, J = 7.1 Hz, 1H), 7.79 (d, solid. Yield: 46.4 mg, 86%; mp: 289292 C. 1H NMR (400
J = 8.0 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz, MHz, DMSO-d6) 12.42 (s, br, 1H), 8.19 (d, J = 8.8 Hz, 2H),
DMSO-d6) 162.5, 151.0, 150.7, 148.7, 140.3, 135.2, 128.2, 7.78 (dd, J = 13.9, 8.2 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.22
127.8, 126.4, 122.0, 121.9. (dd, J = 10.7, 8.4 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 3.85 (s,
2-Cyclopropyl-6-methylquinazolin-4(3H)-one (3m). Fol- 3H); 13C NMR (100 MHz, DMSO-d6) 162.6, 161.0 (d, JCF
lowing the general procedure, the crude product was puried = 261.1 Hz), 160.1, 153.3, 151.6, 135.5 (d, JCF = 10.6 Hz),
by column chromatography on silica gel and eluted with ethyl 130.1, 124.7, 123.8 (d, JCF = 4.0 Hz), 114.5, 112.9 (d, JCF =
acetate/petroleum ether (1/4) to aord a white solid. Yield: 20.4 Hz), 110.6, 56.0.
38.0 mg, 95%; mp: 252256 C. 1H NMR (400 MHz, CDCl3) 2-(Methoxymethyl)-3-methyl-quinazolin-4(3H)-one (3s).
11.81 (s, br, 1H),8.04 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.50 Following the general procedure, the crude product was
(d, J = 8.3 Hz, 1H), 2.47 (s, 3H), 2.021.95 (m, 1H), 1.32 puried by column chromatography on silica gel and eluted
1.28 (m, 2H), 1.151.09 (m, 2H); 13C NMR (100 MHz, with ethyl acetate/petroleum ether (1/4) to aord a pale yellow
CDCl3) 164.1, 157.1, 147.8, 136.2, 135.7, 126.8, 125.6, 120.1, liquid. Yield: 38.8 mg, 95%. 1H NMR (400 MHz, CDCl3)
F DOI: 10.1021/acs.joc.5b00937
J. Org. Chem. XXXX, XXX, XXXXXX
The Journal of Organic Chemistry Article
8.288.23 (m, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.67 (d, J = 7.3 33.1 mg, 93%; mp: 243245 C. 1H NMR (400 MHz, DMSO-
Hz, 1H), 7.46 (t, J = 6.8 Hz, 1H), 4.55 (s, 2H), 3.67 (s, 3H), d6) 12.22 (s, br, 1H), 7.73 (dd, J = 13.9, 7.8 Hz, 1H), 7.38 (d,
3.45 (s, 3H); 13C NMR (100 MHz, CDCl3) 162.3, 152.5, J = 8.2 Hz, 1H), 7.247.13 (m, 1H), 2.33 (s, 3H); 13C NMR
146.7, 134.1, 127.3, 127.2, 126.7, 120.8, 73.8, 58.5, 30.3. HRMS (100 MHz, DMSO-d6) 161.0 (d, JCF = 260.8 Hz), 159.5,
(EI) m/z: [M]+ calcd. for C11H12N2O2 204.0886; found 155.9, 151.7, 135.3 (d, JCF = 10.5 Hz), 123.1, 112.6 (d, JCF=
204.0876. 20.3 Hz), 110.6, 21.7.
3-Methyl-2-phenylquinazolin-4(3H)-one (3t).16a Following 5-Fluoro-2-(1-methylethyl)quinazolin-4(3H)-one (3z1).
the general procedure, the crude product was puried by Following the general procedure, the crude product was
column chromatography on silica gel and eluted with ethyl puried by column chromatography on silica gel and eluted
acetate/petroleum ether (1/4) to aord a white solid. Yield: with ethyl acetate/petroleum ether (1/5) to aord a white
44.4 mg, 94%; mp: 134138 C. 1H NMR (400 MHz, CDCl3) solid. Yield: 37.1 mg, 90%; mp: 212214 C; 1H NMR (400
8.33 (d, J = 7.8 Hz, 1H), 7.787.73 (m, 2H), 7.577.52 (m, MHz, CDCl3) 11.16 (s, br, 1H), 7.707.64 (m, 1H), 7.50 (d,
2H), 7.517.48 (m, 4H), 3.50 (s, 3H); 13C NMR (100 MHz, J = 8.2 Hz, 1H), 7.117.05 (m, 1H), 3.052.94 (m, 1H), 1.42
CDCl3) 162.7, 156.1, 147.3, 135.3, 134.3, 130.1, 128.9, 127.9, (d, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) 161.8,
127.5, 127.0, 126.7, 120.5, 34.2. 161.4 (d, JCF = 263.7 Hz), 161.4 (d, JCF = 3.0 Hz), 151.5,
2-(1-Methylethyl)quinazolin-4(3H)-one (3u).10i Following 134.9 (d, JCF = 10.3 Hz), 123.3 (d, JCF = 4.2 Hz), 112.8 (d,
the general procedure, the crude product was puried by JCF= 20.4 Hz), 110.5, 34.8, 20.3. HRMS (EI) m/z: [M]+ calcd.
column chromatography on silica gel and eluted with ethyl for C11H11FN2O 206.0848; found 206.0851.
acetate/petroleum ether (1/4) to aord a white solid. Yield: 2,3-Dimethylquinazolin-4(3H)-one (3z2).16a Following the
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34.2 mg, 91%; mp: 224226 C. 1H NMR (400 MHz, CDCl3) general procedure, the crude product was puried by column
Publication Date (Web): September 11, 2015 | doi: 10.1021/acs.joc.5b00937
11.57 (s, br, 1H), 8.30 (d, J = 7.1 Hz, 1H), 7.77 (t, J = 7.5 Hz, chromatography on silica gel and eluted with ethyl acetate/
1H), 7.72 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 3.05 (m, petroleum ether (1/4) to aord a white solid. Yield: 33.4 mg,
1H), 1.45 (d, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) 96%; mp: 112114 C. 1H NMR (400 MHz, CDCl3) 8.23
164.1, 160.8, 149.5, 134.7, 127.4, 126.3, 126.2, 120.7, 34.9, 20.4. (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.59 (d, J = 8.1 Hz,
2,6-Dimethylquinazolin-4(3H)-one (3v).1c Following the 1H), 7.42 (t, J = 7.5 Hz, 1H), 3.60 (s, 3H), 2.60 (s, 3H); 13C
general procedure, the crude product was puried by column NMR (100 MHz, CDCl3) 162.2, 154.4, 147.2, 134.1, 126.7,
chromatography on silica gel and eluted with ethyl acetate/ 126.5, 126.3, 120.2, 31.0, 23.6.
petroleum ether (1/4) to aord a white solid. Yield: 33.1 mg, 3-Methyl-2-(1-methylethyl)quinazolin-4(3H)-one (3z3).
95%; mp: 248250 C. 1H NMR (400 MHz, CDCl3) 12.16 Following the general procedure, the crude product was
(s, br, 1H), 8.06 (s, 1H), 7.57 (s, br, 2H), 2.58 (s, 3H), 2.48 (s, puried by column chromatography on silica gel and eluted
3H); 13C NMR (100 MHz, CDCl3) 164.4, 152.5, 147.4, with ethyl acetate/petroleum ether (1/4) to aord a white
136.5, 136.3, 126.8, 125.5, 120.0, 21.9, 21.2. solid. Yield: 37.6 mg, 93%; mp: 7982 C. 1H NMR (400
2-Ethyl-6-methylquinazolin-4(3H)-one (3w).16a Following MHz, CDCl3) 8.24 (d, J = 8.8 Hz, 1H), 7.69 (t, J = 7.6 Hz,
the general procedure, the crude product was puried by 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 3.66 (s,
column chromatography on silica gel and eluted with ethyl 3H), 3.243.14 (m, 1H), 1.37 (d, J = 6.7 Hz, 6H); 13C NMR
acetate/petroleum ether (1/4) to aord a white solid. Yield: (100 MHz, CDCl3) 162.8, 161.1, 147.3, 133.9, 127.1, 126.6,
35.3 mg, 94%; mp: 224226 C. 1H NMR (400 MHz, CDCl3) 126.1, 120.2, 32.1, 30.0, 20.8. HRMS (EI) m/z: [M]+ calcd. for
11.86 (s, br, 1H), 8.07 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.59 C12H14N2O 202.1148; found 202.1156.
(d, J = 1.8 Hz, 1H), 2.82 (q, J = 7.6 Hz, 2H), 2.49 (s, 3H), 1.45 2-Methyl-1H-benzo[d]imidazole (7a).12a Following the
(t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) 164.3, general procedure, the crude product was puried by column
156.7, 147.5, 136.5, 136.2, 127.0, 125.6, 120.2, 29.0, 21.2, 11.6. chromatography on silica gel and eluted with ethyl acetate/
6-Chloro-2-ethylquinazolin-4(3H)-one (3x).16a Following petroleum ether (1/50) to aord a white solid. Yield: 25.1 mg,
the general procedure, the crude product was puried by 95%; mp: 179181 C. 1H NMR (400 MHz, CDCl3) 9.69 (s,
column chromatography on silica gel and eluted with ethyl br, 1H), 7.56 (dd, J = 6.0, 3.2 Hz, 2H), 7.22 (dd, J = 6.0, 3.2 Hz,
acetate/petroleum ether (1/3) to aord a white solid. Yield: 2H), 2.66 (s, 3H); 13C NMR (100 MHz, CDCl3) 151.4,
38.9 mg, 94%; mp: 253256 C. 1H NMR (400 MHz, DMSO- 138.7, 122.1, 114.4, 14.9.
d6) 12.12 (s, br, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.62 (s, 1H), 2-Propyl-1H-benzo[d]imidazole (7b).16a Following the
2.63 (s, 2H), 1.25 (s, 2H), 13C NMR (100 MHz, DMSO-d6) general procedure, the crude product was puried by column
161.7, 159.9, 148.2, 134.7, 130.4, 129.4, 125.1, 122.5, 11.7. chromatography on silica gel and eluted with ethyl acetate/
2-(tert-Butyl)-6-chloroquinazolin-4(3H)-one (3y). Follow- petroleum ether (1/50) to aord a white solid. Yield: 29.8 mg,
ing the general procedure, the crude product was puried by 93%; mp: 158160 C. 1H NMR (400 MHz, CDCl3) 11.05
column chromatography on silica gel and eluted with ethyl (s, 1H), 7.56 (dd, J = 5.8, 3.1 Hz, 2H), 7.21 (dd, J = 5.9, 3.1 Hz,
acetate/petroleum ether (1/3) to aord a white solid. Yield: 2H), 2.96 (t, J = 7.5 Hz, 2H), 1.961.84 (m, 2H), 0.98 (t, J =
42.9 mg, 91%; mp: 228232 C. 1H NMR (400 MHz, CDCl3) 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) 155.6, 138.5,
10.84 (s, br, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.69 (dd, J = 8.9, 122.1, 114.5, 31.1, 21.7, 13.8.
2.3 Hz, 1H), 7.67 (d, J = 4.9 Hz, 1H), 1.48 (s, 9H); 13C NMR 2-(Methoxymethyl)-1H-benzo[d]imidazole (7c).10b Follow-
(100 MHz, CDCl3) 162.6, 162.3, 147.7, 134.9, 132.1, 129.4, ing the general procedure, the crude product was puried by
125.5, 121.6, 37.5, 28.2. HRMS (EI) m/z: [M]+ calcd. for column chromatography on silica gel and eluted with ethyl
C12H13ClN2O 236.0711; found 236.0704. acetate/petroleum ether (1/50) to aord a white solid. Yield:
5-Fluoro-2-methylquinazolin-4(3H)-one (3z).1c Following 29.5 mg, 91%; mp: 142144 C. 1H NMR (400 MHz, CDCl3)
the general procedure, the crude product was puried by 7.60 (dd, J = 5.8, 3.1 Hz, 2H), 7.25 (dd, J = 6.0, 3.1 Hz, 2H),
column chromatography on silica gel and eluted with ethyl 4.78 (s, 2H), 3.47 (s, 3H); 13C NMR (100 MHz, CDCl3)
acetate/petroleum ether (1/5) to aord a white solid. Yield: 151.5, 122.5, 115.1, 68.3, 59.0.
G DOI: 10.1021/acs.joc.5b00937
J. Org. Chem. XXXX, XXX, XXXXXX
The Journal of Organic Chemistry Article
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petroleum ether (1/50) to aord a yellow liquid. Yield: 33.3 (3) (a) Malecki, N.; Carato, P.; Rigo, B.; Goossens, J. F.; Houssin, R.;
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I DOI: 10.1021/acs.joc.5b00937
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