Amino acids as the nitrogen-containing motifs in copper-catalyzed domino synthesis of N -heterocycles

Article abstract of DOI:10.1021/jo2002227

A copper-catalyzed domino method for synthesis of quinazolinones has been developed using readily available α-amino acids as the nitrogen-containing motifs. The domino process underwent Ullmann-type N-arylation, decarboxylation, aerobic oxidation, and intramolecular addition. This method should provide a new and useful strategy for construction of N-heterocycles.

Full text of DOI:10.1021/jo2002227

ARTICLE
pubs.acs.org/joc
Amino Acids as the Nitrogen-Containing Motifs in Copper-Catalyzed
Domino Synthesis of N-Heterocycles
Wei Xu and Hua Fu*
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. China
S Supporting Information
b
ABSTRACT: A copper-catalyzed domino method for synthesis
of quinazolinones has been developed using readily available R-
amino acids as the nitrogen-containing motifs. The domino
process underwent Ullmann-type N-arylation, decarboxylation,
aerobic oxidation, and intramolecular addition. This method
should provide a new and useful strategy for construction of
N-heterocycles.
’ INTRODUCTION
Recently, copper-catalyzed Ullmann-type couplings have
made great achievement,10 and some N-heterocycles were
synthesized through the couplings by other groups11 and us12
(including synthesis of quinazolinones by using 2-halobenzoic
acid derivatives and amidines as the substrates12a). However, the
reactions above were performed under conditions of air extru-
sion, and the precursors required possession of the correspond-
ing functional groups before domino synthesis of N-heterocycles,
so the scopes of the substrates are limited. To the best of our
knowledge, there is no previous report of preparation of N-
heterocycles through copper-catalyzed Ullmann-type coupling
under air together with aerobic oxidative CꢀH activation. R-
Amino acids are more readily available than other compounds in
nature and are among the most attractive nitrogen-containing
motifs.13 Herein, a copper-catalyzed domino protocol is de-
signed for synthesis of quinazolinones as shown in Figure 1.
We hope that the domino reactions work in the following
pathways under air: N-arylation, decarboxylation, aerobic oxida-
tion, and intramolecular addition in reactions of substituted
2-halobenzamides and R-amino acids.
Nitrogen-containing heterocycles are ubiquitous subunits of a
variety of biologically active substances,1 and they have been
assigned as privileged structures in drug development because
N-heterocyclic moieties often exhibit improved solubilities and
can facilitate salt formation properties, both of which are
important for oral absorption and bioavailability.2 For example,
quinazolinone derivatives that widely occur in natural products
show various biological and pharmacological activities.3 They
exhibit many central nervous system effects, cardiovascular and
antiinflammatory activity, and act as psychotropic, hypnotic,
cardiotonic, and antihistamine agents.3 They are potent anti-
bacterial, antifungal, antiviral, antimycobacterial, and antimalarial
substances.4 Quinazolinone derivatives are also used as inhibitors
of various enzymes including monoamine oxidase, aldose re-
ductase, tumor necrosis factor R, and thymidylate synthase.4,5
Although some methods for syntheses of quinazolinone deriva-
tives have been developed,3,6 the common starting materials, o-
amino or o-nitro benzoic acid derivatives, often are not readily
available or are difficult to prepare. In addition, the traditional
single-step procedure affording only one new chemical bond
needs time-consuming and costly syntheses, tedious workup, and
purification of precursors as well as protection/deprotection of
functional groups. Efficient assembly of complex molecules from
readily available building blocks is an important task for organic
chemists.7 The domino reaction has thus emerged as a powerful
tool for this purpose in which a series of chemical processes can
be controlled in a one-pot operation, which potentially mini-
mizes requisite reagents, separation processes, waste, energy,
time, and cost.8 However, the domino process terminates when
some unactivated CꢀH bond appears on the road of cascade
reactions. Recently, the direct functionalization of CꢀH bonds
has made great progress,9 but the domino synthesis of complex
molecules combined with CꢀH activation still is very limited.
Herein, we report an efficient domino strategy for synthesis of
quinazolinone derivatives through CꢀH amidation.
’ RESULTS AND DISCUSSION
At first, 2-bromobenzamide (1a) and L-valine (2d) were used
as the model substrates to optimize reaction conditions including
catalysts, bases, solvents, and reaction temperatures under air
(1 atm). As shown in Table 1, four solvents were tested in the
presence of 0.1 equiv of CuI and 3 equiv of K2CO3 (relative to
amount of 2-bromobenzamide) at 120 °C under air (entries
1ꢀ4), and DMSO provided the highest yield (entry 2). We
screened various copper catalysts (entries 5ꢀ10), and CuBr
showed the best activity (entry 5). Effect of bases were also
investigated (compare entries 5, 11ꢀ14), and K2CO3 provided
the best result (entry 5). Interestingly, addition of small amount
Received: February 3, 2011
Published: April 06, 2011
r
2011 American Chemical Society
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Table 1. Copper-Catalyzed Domino Reaction of 2-Bromo-
benzamide (1a) with L-Valine (2d) Leading to 2-Isopropyl-
quinazolin-4(3H)-one under Air: Optimization of Conditionsa
entry
cat.
CuI
base
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
K2CO3 DMF
40
CuI
K2CO3 DMSO
44
CuI
K2CO3 ethylene glycol
K2CO3 DMA
trace
0
Figure 1. Our copper-catalyzed domino strategy for synthesis of
quinazolinones using amino acids as nitrogen-containing motifs.
CuI
CuBr
CuCl2
Cu2O
CuO
K2CO3 DMSO
K2CO3 DMSO
K2CO3 DMSO
K2CO3 DMSO
60
48
of ethylene glycol improved the reactivity of the substrates
(compare entries 5, 15, and 16), and one possible reason is that
ethylene glycol could promote the dissolving power of R-amino
acids and act as the ligand in the Ullman-type N-arylation.
We investigated the scope of copper-catalyzed domino reac-
tions of substituted 2-halobenzamides with R-amino acids under the
optimized conditions (using 10 mol % of CuBr as the catalyst, 3
equiv of K2CO3 as the base (relative to amount of 2-halobenza-
mides), and DMSO/ethylene glycol as the solvent). As shown in
Table 2, the corresponding quinazolinones were obtained in mod-
erate to good yields for various examined substrates at 110ꢀ120 °C.
For substituted 2-halobenzamides, the aryl iodides and bromides
almost exhibited similar yields (compare entries 6 and 20), but aryl
chloride did not work. The 2-halobenzamides containing electron-
withdrawing groups provided lower yields than ones containing
electron-donating groups. For R-amino acids, their differences of
reactivity depended on the chains of R-amino acids, and the R-amino
acids containing the bulky chains afforded higher yields. One possible
reason is that the imine intermediates (see II and IV in Scheme 2)
containing the bulky chains (stronger electron-donating power) are
of higher stability during domino reactions. Unexpectedly, the
domino reaction for glycine needed using ethylene glycol as the
solvent (entry 1). The copper-catalyzed domino reactions of sub-
stituted 2-halobenzamides with R-amino acids showed the good
tolerance of the functional groups in the substrates including the
amide, nitro, CꢀCl, and ether bond.
38
45
Cu(OAc)2 K2CO3 DMSO
37
10 CuCl
11 CuBr
K2CO3 DMSO
Cs2CO3 DMSO
K3PO4 DMSO
51
42
12 CuBr
13 CuBr
14 CuBr
15 CuBr
16 CuBr
trace
10
KOH
DMSO
Na2CO3 DMSO
trace
64
K2CO3 DMSO/ethylene glycol (20:1)
K2CO3 DMSO/ethylene glycol (75:1)
72
a Reaction conditions: 2-bromobenzamide (1a) (0.3 mmol), L-valine
(2d) (0.9 mmol), catalyst (0.03 mmol), base (0.9 mmol), solvent
(3 mL) under air. b Isolated yield.
Scheme 1. (A) Copper-Catalyzed Ullmann-Type Coupling
of 2-Bromobenzamide (1a) with R-Aminobutanoic Acid (2b)
To Form N-Arylation Product (4) under Nitrogen Atmo-
sphere. (B) Aerobic Oxidation and Addition of 4 To Yield
2-Ethylquinazolin-4(3H)-one (3b) under Our Standard
Conditions
We explored the copper-catalyzed domino reaction mechan-
ism by performing the following control experiments as shown in
Scheme 1. Copper-catalyzed Ullmann-type coupling of 2-bro-
mobenzamide with R-aminobutanoic acid (2b) provided N-
arylation product (4) in 79% yield under nitrogen atmosphere
(extrusion of air) (Scheme 1A), and only a small amount of
quinazoline was observed (6% yield). Compound 4 transformed
into 2-ethylquinazolin-4(3H)-one (3b) in 52% yield under our
standard conditions (Scheme 1B).
’ CONCLUSION
We have developed a simple and efficient copper-catalyzed
domino method for construction of quinazolinones. The protocol
uses cheap and readily available CuBr as the catalyst, substituted
2-halobenzamides and R-amino acids as the starting materials, and
economical and environmentally friendly air as the oxidant, and the
corresponding quinazolinones were obtained in moderate to good
yields. The domino reactions underwent copper-catalyzed Ull-
mann-type coupling, aerobic oxidation, CꢀH amidation, and
decarboxylation process. To the best of our knowledge, this is the
first example of constructing N-heterocycles via Ullmann-type
A possible mechanism for domino reactions of substituted
2-halobenzamides with R-amino acids is suggested in Scheme 2.
The Ullmann-type coupling of 2-halobenzamide (1) with R-
amino acid (2) first provides I. Then, intermediate I can undergo
two pathways (pathways A and B). For pathway A, aerobic
oxidation of I gives II, intramolecular cycloaddition of II provides
III,14 and decarboxylation of III affords the target product (3).
For pathway B, decarboxylation of I first occurs to lead to IV, and
intramolecular cycloaddition of IV yields V.14 Finally, aerobic
oxidation of V provides 3.
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Table 2. Copper-Catalyzed Domino Synthesis of Quinazolinonesa
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Table 2. Continued
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Table 2. Continued
a Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), CuBr (0.03 mmol), K2CO3 (0.9 mmol), DMSO (2.96 mL), ethylene glycol (0.04 mL) under air.
b Isolated yield (reaction temperature and time in parentheses). c Using ethylene glycol as the solvent.
(see Table 2 for details). After completion of the reaction, the resulting
solution was cooled to room temperature and filtered, and the solvent of
filtrate was removed with the aid of a rotary evaporator. The residue was
purified by column chromatography on silica gel using petroleum
ether/ethyl acetate (3:1 to 1:1) as eluent to provide the desired
product (3).
Scheme 2. Possible Mechanism for Synthesis of Quinazoli-
none Derivatives
Quinazolinone-4(3H)-one (3a)15. Eluent: petroleum ether/ethyl
1
acetate (1:2). Yield: 21 mg (49%). White solid. H NMR (DMSO-d6,
600 Mz): δ 12.23 (s, br, 1H), 8.13 (d, 1H, J = 8.3 Hz), 8.1 (s, 1H), 7.82
(t, 1H, J = 7.6 Hz), 7.67 (d, 1H, J = 8.3 Hz), 7.53 (t, 1H, J = 7.6 Hz). 13C
NMR (DMSO-d6, 150 MHz): δ 161.2, 149.3, 145.9, 134.8, 127.8, 127.3,
126.3, 123.2. ESIMS: [M ꢀ H]ꢀ m/z 145.3.
2-Ethylquinazolinone-4(3H)-one (3b)16. Eluent: petroleum ether/
ethyl acetate (1:2). Yield: 21 mg (40%). White solid. Mp: 229ꢀ231 °C
(lit.16 mp 231ꢀ233 °C). 1H NMR (CDCl3, 300 MHz): δ 11.96 (s, br,
1H), 8.29 (d, 1H, J = 7.4 Hz), 7.80ꢀ7.70 (m, 2H), 7.46 (t, 1H, J = 8.3
Hz), 2.85 (q, 2H, J = 5.7 Hz), 1.46 (t, 3H, J = 7.6 Hz). 13C NMR (CDCl3,
75 MHz): δ 164.7, 158.0, 149.9, 135.1, 127.6, 126.7, 126.6, 120.9, 29.5,
11.9. ESIMS: [M þ H]þ m/z 175.1, [M þ Na]þ m/z 197.1.
2-Propylquinazolinone-4(3H)-one (3c)12a. Eluent: petroleum ether/
ethyl acetate (1:1). Yield: 28 mg (50%). White solid. Mp: 200ꢀ202 °C
(lit.12a mp 198ꢀ200 °C). 1H NMR (DMSO-d6, 600 Mz): δ 12.18 (s, br,
1H), 8.11 (d, 1H, J = 7.9 Hz), 7.78 (t, 1H, J = 7.2 Hz), 7.62 (d, 1H, J = 7.9
Hz), 7.47 (d, 1H, J = 7.2 Hz), 2.60 (t, 2H, J = 7.9 Hz), 1.83ꢀ1.74 (m,
2H), 0.96 (t, 3H, J = 7.2 Hz). 13C NMR (DMSO-d6, 75 MHz): δ 161.8,
157.3, 148.9, 134.2, 126.8, 125.8, 125.6, 120.8, 36.3, 20.2, 13.5. ESIMS:
[M þ H]þ m/z 189.0, [M þ Na]þ m/z 211.0.
coupling under air and aerobic oxidative CꢀH functionalization.
This method should provide a new and useful strategy for
construct of N-heterocycles.
2-(1-Methylethyl)quinazolinone-4(3H)-one (3d)17. Eluent: petro-
leum ether/ethyl acetate (1:1). Yield: 41 mg (72%). White solid. Mp:
225ꢀ228 °C (lit.17 mp 212ꢀ214 °C). 1H NMR (CDCl3, 300 MHz): δ
11.85 (s, br, 1H), 8.30 (d, 1H, J = 7.6 Hz), 7.79ꢀ7.70 (m, 2H), 7.46 (t,
1H, J = 6.9 Hz), 3.11ꢀ3.02 (m, 1H), 1.46 (d, 6H, J = 6.9 Hz). 13C NMR
(CDCl3, 75 MHz): δ 164.7, 161.3, 149.9, 135.0, 127.7, 126.6, 121.1,
35.3, 20.7. ESIMS: [M þ H]þ m/z 189.1
’ EXPERIMENTAL SECTION
General Procedure for Domino Reactions of Substituted
2-Halobenzamides with r-Amino Acids Leading to Quina-
zolinones. A 25 mL flask equipped with a magnetic stirring bar was
charged with substituted 2-halobenzamide (1) (0.3 mmol), R-amino
acid (2) (0.6 mmol), K2CO3 (0.9 mmol, 124 mg), and CuBr (0.03
mmol, 4.3 mg) in DMSO (2.96 mL) and ethylene glycol (0.04 mL). The
mixture was allowed to stir under air (1 atm) at 110ꢀ120 °C for 6ꢀ15 h
2-(2-Methylpropyl)quinazolinone-4(3H)-one (3e)18. Eluent: petro-
leum ether/ethyl acetate (1:1). Yield: 42 mg (70%). White solid. Mp:
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194ꢀ196 °C. 1H NMR (CDCl3, 300 MHz): δ 12.24 (s, br, 1H), 8.29 (d,
1H, J = 7.9 Hz), 7.79ꢀ7.70 (m, 2H), 7.46 (t, 1H, J = 7.9 Hz), 2.68 (d, 2H,
J = 7.6 Hz), 2.42ꢀ2.28 (m, 1H), 1.07 (d, 6H, J = 6.5 Hz). 13C NMR
(CDCl3, 75 MHz): δ 164.8 156.7, 149.8, 135.1, 127.6, 126.6, 126.5,
120.8, 45.1, 28.3, 22.7. ESIMS: [M þ H]þ m/z203.1, [M þ Na]þ m/z225.0.
2-(1-Methylpropyl)quinazolinone-4(3H)-one (3f)19. Eluent: petro-
leum ether/ethyl acetate (1:1). Yield: 40 mg (66%) using 2-bromoben-
zamide as the substrate; 41 mg (67%) using 2-iodobenzamide as the
J = 8.9 Hz), 2.74ꢀ2.63 (m, 1H), 1.87ꢀ1.73 (m, 1H), 1.64ꢀ1.50
(m, 1H), 1.25 (d, 3H, J = 6.9 Hz), 0.85 (t, 3H, J = 7.6 Hz). 13C NMR
(DMSO-d6, 75 MHz): δ 161.6, 161.0, 147.6, 134.4, 130.2, 129.2, 40.4,
27.5, 18.1, 11.6. HR-MS: [M þ H]þ m/z calcd for C12H14ClN2O
237.0795, found 237.0796.
2-sec-Butyl-7-nitroquinazolin-4(3H)-one (3n). Eluent: petroleum
ether/ethyl acetate (1:1). Yield: 38 mg (52%). Light yellow solid. Mp:
1
208ꢀ210 °C. H NMR (DMSO-d6, 600 Mz): δ 12.60 (s, br, 1H), 8.35
1
(d, 2H, J = 8.6 Hz), 8.22 (dd, 1H, J = 2.1, 2.1 Hz), 2.82ꢀ2.70 (m, 1H),
1.93ꢀ1.80 (m, 1H), 1.70ꢀ1.56 (m, 1H), 1.31 (d, 3H, J= 6.5 Hz), 0.91 (t, 3H,
J = 6.9 Hz). 13C NMR (DMSO-d6, 75 MHz): δ 163.6, 161.0, 151.2, 149.3,
128.1, 125.3, 121.9, 119.6, 40.4, 27.5, 18.1, 11.6. ESIMS: [M þ H]þ m/z248.0.
6-Methyl-2-propylquinazolinone-4(3H)-one (3o)22. Eluent: petro-
leum ether/ethyl acetate (1:1). Yield: 24 mg (40%). White solid. Mp:
225ꢀ227 °C (lit.22 mp 244.3ꢀ244.8 °C). 1H NMR (CDCl3, 300 MHz):
δ 11.90 (s, br, 1H), 8.07 (d, 1H, J = 1.7 Hz), 7.60 (dd, 2H, J = 0.7,
1.7 Hz), 2.77 (t, 2H, J = 7.9 Hz), 2.50 (s, 3H), 1.98ꢀ1.86 (m, 2H), 1.08
(t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 164.6, 156.2, 147.8,
136.8, 136.6, 127.3, 125.9, 120.5, 38.0, 21.6, 21.3, 14.1. ESIMS: [M þ
H]þ m/z 203.2.
substrate. White solid. Mp: 171ꢀ173 °C. H NMR (DMSO-d6, 300
MHz): δ 12.15 (s, br, 1H), 8.11 (d, 1H, J = 7.9 Hz), 7.78 (t, 1H, J = 6.9
Hz), 7.63 (d, 1H, J = 8.3 Hz), 7.47 (t, 1H, J = 8.3 Hz), 2.75ꢀ2.63 (m,
1H), 1.89ꢀ1.75 (m, 1H), 1.65ꢀ1.51 (m, 1H), 1.26 (d, 3H, J = 6.9 Hz),
0.86 (t, 3H, J = 7.6 Hz). 13C NMR (DMSO-d6, 75 MHz): δ 162.0, 161.0,
148.9, 134.2, 127.0, 126.0, 125.7, 121.0, 40.4, 27.5, 18.2, 11.7. ESIMS:
[M þ H]þ m/z 203.1.
2-Phenylquinazolin-4(3H)-one (3g)12a. Eluent: petroleum ether/
ethyl acetate (3:1). Yield: 48 mg (72%). White solid. Mp: 235ꢀ237 °C
(lit.12a mp 236ꢀ237 °C). 1H NMR (DMSO-d6, 300 MHz): δ 12.54 (s, br,
1H), 8.21ꢀ8.16 (m, 3H), 7.85 (t, 1H, J = 7.6 Hz), 7.75(d, 1H, J = 8.3 Hz),
7.63ꢀ7.50 (m, 4H). 13C NMR (DMSO-d6, 75 MHz): δ 162.2, 152.3,
148.7, 134.6, 132.7, 131.3, 128.6, 127.7, 127.5, 126.5, 125.8, 121.0. ESIMS:
[M þ H]þ m/z 223.2.
6-Methyl-2-(1-methylethyl)quinazolinone-4(3H)-one (3p)22. Elu-
ent: petroleum ether/ethyl acetate (1:1). Yield: 31 mg (51%). White solid.
Mp: 237ꢀ239 °C (lit.22 mp 244.3ꢀ244.8 °C). 1H NMR (DMSO-d6, 300
MHz): δ 12.05 (s, br, 1H), 7.88 (s, 1H), 7.59 (dd, 1H, J = 1.7, 2.1 Hz), 7.51
(d, 1H, J = 8.3 Hz), 2.94ꢀ2.80 (m, 1H), 2.43 (s, 3H), 1.25 (d, 6H, J = 6.9
Hz). 13C NMR (DMSO-d6, 75 MHz): δ 161.9, 160.6, 146.9, 135.5, 126.8,
125.0, 120.7, 33.2, 20.8, 20.4. ESIMS: [M þ H]þ m/z 203.2.
2-p-Tolylquinazolin-4(3H)-one (3h)20. Eluent: petroleum ether/ethyl
acetate (3:1). Yield: 50 mg (70%). White solid. Mp: 261ꢀ263 °C (lit.20 mp
1
261ꢀ263 °C). H NMR (DMSO-d6, 300 MHz): δ 12.48 (s, br, 1H),
8.18ꢀ8.10 (m, 3H), 7.83 (t, 1H, J = 7.9 Hz),.7.74 (d, 1H, J = 7.2 Hz), 7.51
(t, 1H, J = 6.5 Hz), 7.35 (d, 2H, J = 6.5 Hz), 2.40 (s, 3H). 13C NMR
(DMSO-d6, 75 MHz): δ 162.3, 152.2, 148.8, 141.4, 134.5, 129.9, 129.2,
127.7, 127.3, 126.4, 125.9, 120.1, 21.0. ESIMS: [M ꢀ H]ꢀ m/z 237.6.
2-(2-Thienyl)quinazolinone-4(3H)-one (3i)21. Eluent: petroleum
ether/ethyl acetate (3:1). Yield: 48 mg (70%). White solid. Mp:
275ꢀ276 °C (lit.21 mp 275ꢀ276 °C). 1H NMR (DMSO-d6, 300
Mz): δ 12.70 (s, br, 1H), 8.28 (d, 1H, J = 3.4 Hz), 8.17 (d, 1H, J =
7.9 Hz), 7.92 (d, 1H, J = 4.8 Hz), 7.85 (t, 1H, 7.2 Hz), 7.70 (d, 1H, J = 8.3
Hz), 7.53 (t, 1H, 7.2 Hz), 7.29 (t, 1H, J = 3.8 Hz), 13C NMR (DMSO-d6,
75 MHz): δ 161.8, 148.6, 147.8, 137.4, 134.7, 132.2, 129.4, 128.5, 126.9,
126.3, 126.3, 12.9. ESIMS: [M þ H]þ m/z 229.2.
6-Methyl-2-(2-methylpropyl)quinazolinone-4(3H)-one (3q). Elu-
ent: petroleum ether/ethyl acetate (1:1). Yield: 45 mg (70%). White
solid. Mp: 225ꢀ227 °C. 1H NMR (DMSO-d6, 300 MHz): δ 12.07 (s, br,
1H), 7.87 (s, 1H), 7.60 (dd, 1H, J = 2.1, 2.1 Hz), 7.50 (d, 1H, J = 8.3 Hz),
2.46 (d, 2H, J = 7.2 Hz), 2.42 (s, 3H), 2.24ꢀ2.11 (m, 1H), 0.93 (d, 6H, J
= 6.5 Hz). 13C (DMSO-d6, 75 MHz): δ 161.8, 155.8, 146.9, 135.5, 135.4,
126.7, 125.0, 120.5, 43.3, 27.0, 22.1, 20.8. HR-MS [M þ H]þ m/z calcd
for C13H17N2O 217.1341, found 217.1343.
6-Methyl-2-(1-methylpropyl)quinazolinone-4(3H)-one (3r). Eluent:
petroleum ether/ethyl acetate (1:1). Yield: 45 mg (70%). White solid.
Mp: 209ꢀ211 °C. 1H NMR (DMSO-d6, 300 MHz): δ 12.04 (s, br, 1H),
7.90 (s, 1H), 7.60 (d, 1H, J = 8.3 Hz), 7.51 (d, 1H, J = 8.3 Hz), 2.71ꢀ2.60
(m, 1H), 2.43 (s, 3H), 1.86ꢀ1.72 (m, 1H), 1.63ꢀ1.49 (m, 1H), 1.24 (d,
3H, J = 6.9 Hz), 0.84 (t, 3H, J = 7.2 Hz). 13C NMR (DMSO-d6, 75
MHz): δ 161.9, 161.0, 146.9, 135.5, 135.4, 126.8, 125.0, 126.0, 40.3,
27.5, 20.7, 18.2, 11.7. HR-MS: [M þ H]þ m/z calcd for C13H17N2O
217.1341, found 217.1341.
2-sec-Butyl-6-methoxyquinazolin-4(3H)-one (3s). Eluent: petro-
leum ether/ethyl acetate (1:1). Yield: 36 mg (52%). White solid. Mp:
197ꢀ199 °C. 1H NMR (DMSO-d6, 300 MHz): δ 12.09 (s, br, 1H), 7.57
(d, 1H, J = 8.9 Hz), 7.48 (d, 1H, J = 2.4 Hz), 7.37 (dd, 1H, J = 2.1, 2.1
Hz), 3.86 (s, 3H), 2.71ꢀ2.59 (m, 1H), 1.86ꢀ1.71 (m, 1H), 1.63ꢀ1.49
(m, 1H), 1.23 (d, 3H, J = 6.6 Hz), 0.84 (t, 3H, J = 7.2 Hz). 13C NMR
(DMSO-d6, 75 MHz): δ 161.8, 158.5, 157.2, 143.4, 128.6, 123.7, 121.6,
105.6, 55.5, 40.2, 27.5, 18.2, 11.7. ESIMS: [M þ H]þ m/z 233.1.
6-Chloro-2-(2-methylpropyl)quinazolinone-4(3H)-one (3j)12a. Elu-
ent: petroleum ether/ethyl acetate (1:1). Yield: 35 mg (52%). White
solid. Mp: 248ꢀ250 °C (lit.12a mp 248ꢀ250 °C). 1H NMR (DMSO-d6,
300 MHz): δ 12.34 (s, br, 1H), 8.01 (d, 1H, J = 2.4 Hz), 7.79 (dd, 1H, J =
2.8, 2.4 Hz), 7.62 (d, 1H, J = 8.6 Hz), 2.61ꢀ2.50 (m, 2H), 1.81ꢀ1.68 (m,
2H), 0.94 (t, 3H, J = 7.8 Hz). 13C NMR (DMSO-d6, 75 MHz): δ 160.8
158.0, 147.5, 134.3, 130.1, 129.0, 124.6, 122.0, 36.3, 20.1, 13.4. ESIMS:
[M þ H]þ m/z 223.1.
6-Chloro-2-(1-methylethyl)quinazolinone-4(3H)-one (3k). Eluent:
petroleumether/ethyl acetate (1:1). Yield: 41 mg(61%). White solid. Mp:
245ꢀ247 °C. 1H NMR (DMSO-d6, 300 MHz): δ 12.33 (s, br, 1H), 8.02
(d, 1H, J = 2.4 Hz), 7.80 (dd, 1H, J = 2.4, 2.8 Hz), 7.64 (d, 1H, J = 8.6 Hz),
2.89 (m, 1H), 1.26 (d, 6H, J = 6.9 Hz). 13C NMR (DMSO-d6, 75 MHz): δ
162.2, 161.0, 147.6, 134.4, 130.2, 129.3, 124.7, 122.2, 33.3, 20.3. HR-MS:
[M þ H]þ m/z calcd for C11H12ClN2O 223.0638, found 223.0639.
6-Chloro-2-(2-methylpropyl)quinazolinone-4(3H)-one (3l). Eluent:
petroleum ether/ethyl acetate (1:2). Yield: 40 mg (56%). Yellow solid.
Mp: 228ꢀ230 °C. 1H NMR (DMSO-d6, 300 MHz): δ 12.36 (s, br, 1H),
8.02 (d, 1H, J = 2.4 Hz), 7.80 (dd, 1H, J = 2.4, 2.4 Hz), 7.63 (d, 1H, J =
8.6 Hz), 2.48 (d, 2H, J = 7.2 Hz), 2.25ꢀ2.11 (m, 1H), 0.93 (d, 6H, J = 6.5
Hz). 13C (DMSO-d6, 75 MHz): δ 160.9, 157.4, 147.6, 134.4, 130.1,
129.1, 124.7, 122.0, 43.3, 27.0, 22.1. HR-MS: [M þ H]þ m/z calcd for
C12H14ClN2O 237.0795, found 237.0800.
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proce-
b
dures, characterization data, and H and 13C NMR spectra of
1
these synthesized compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
6-Chloro-2-(1-methylpropyl)quinazolinone-4(3H)-one (3m). Elu-
ent: petroleum ether/ethyl acetate (1:1). Yield: 43 mg (60%). Yellow
solid. Mp: 201ꢀ203 °C. 1H NMR (DMSO-d6, 300 MHz): δ 12.33 (s, br,
1H), 8.02 (d, 1H, J = 2.4 Hz), 7.80 (dd, 1H, J = 2.8, 2.4 Hz), 7.64 (d, 1H,
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: fuhua@mail.tsinghua.edu.cn.
3851
dx.doi.org/10.1021/jo2002227 |J. Org. Chem. 2011, 76, 3846–3852

The Journal of Organic Chemistry
ARTICLE
’ ACKNOWLEDGMENT
Adv. Synth. Catal. 2010, 352, 1033. (i) Gong, X.; Yang, H.; Liu, H.; Jiang,
Y.; Zhao, Y.; Fu, H. Org. Lett. 2010, 12, 3128.
(13) (a) Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2010, 132, 1798. (b)
Bi, H.-P.; Zhao, L.; Liang, Y.-M.; Li, C.-J. Angew. Chem., Int. Ed. 2009,
48, 792.
We thank the National Natural Science Foundation of China
(Grant No. 20972083) and the Ministry of Science and Tech-
nology of China (2009ZX09501-004) for financial support.
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(15) Shemchuk, L. A.; Chernykh, V. P.; Arzumanov, P. S.; Krys’kiv,
O. S. Russ. J. Org. Chem. 2007, 43, 719.
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