I2/TBHP-Mediated Oxidative Coupling of Amino-Based Bisnucleophiles and Isocyanides: Access to 2-Aminobenzoxazinones, 2-Aminobenzoxazines, and 2-Aminoquinazolines under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.joc.8b02395

An I₂/tert-butyl hydroperoxide (TBHP)-mediated oxidative coupling reaction of isocyanides with amino-based bisnucleophiles is described for the synthesis of 2-aminobenzoxazinones, 2-aminobenzoxazines, and 2-aminoquinozolines in moderate to exce

Full text of DOI:10.1021/acs.joc.8b02395

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Article
I2/TBHP-mediated Oxidative Coupling of Amino-Based Bisnucleophiles
and Isocyanides: Access to 2-Aminobenzoxazinones, 2-
Aminobenzoxazines and 2-Aminoquinazolines under Metal-free Conditions
Hong-Xia Wang, Tian-Qi Wei, Pei Xu, Shun-Yi Wang, and Shun-Jun Ji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02395 • Publication Date (Web): 11 Oct 2018
Downloaded from http://pubs.acs.org on October 11, 2018
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The Journal of Organic Chemistry
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I2/TBHP-mediated Oxidative Coupling of Amino-Based Bisnucleophiles and
Isocyanides: Access to 2-Aminobenzoxazinones, 2-Aminobenzoxazines and 2-
Aminoquinazolines under Metal-free Conditions
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Hong-Xia Wang,a Tian-Qi Wei,b Pei Xu,b Shun-Yi Wang,b,* and Shun-Jun Jib,*
aSchool of chemistry, biology and materials engineering, Suzhou Univeristy of science and technology.
bKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and
Technology, Soochow University, Suzhou, 215123, P. R. China; E-mail: shunyi@suda.edu.cn;
shunjun@suda.edu.cn
*CORRESPONDING AUTHOR FAX: 86-512-65880307.
O
O
O
R1
OH
R1
R2
N
N
H
NH2
I2 (10 mol %)
or
or
+
C N R2
TBHP (2 equiv)
50 oC, 12 h
N
NH2
NH2
R1
R1
R2
N
N
H
ABSTRACT. An I2/tert-Butyl hydroperoxide (TBHP)-mediated oxidative coupling reaction of
isocyanides with amino-based bisnucleophiles is described for the synthesis of 2-aminobenzoxazinones,
2-aminobenzoxazines and 2-aminoquinozolines in moderate to excellent yields. Furthermore, this
method provide a simple and practical method to construct potential functionalized biologically active
molecules.
KEYWORDS: I2, TBHP, Oxidative Coupling, Isocyanide, Metal-Free
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INTRODUCTION
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2-aminobenzoxazinones, 2-aminobenzoxazines and 2-aminoquinozolines are privileged heterocyclic
scaffolds in bioactive compounds and natural products.1 For example, compound I acts as an inhibitor
of C1r.2 Compound II shows good antiviral activity against HSV-1 protease.3 Etifoxine III is used for
the treatment of anxiety neurosis.4 Compound IV demonstrates nanomolar activity against protein
kinase (MAPK) p38 (Figure 1).5
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O
O
O
O
Cl
N
N
Cbz-Ala-HN
N
N
H
H
I
I Inhibitor of C1r Serine Protease
II Inhibitor of HSV-1 Protease
H
N
O
Cl
O
N
O
N
N
N
N
N
H
H
III Etifoxine
IV Potent p38 Inhibitors
Figure 1. Biologically active 2-aminobenzoxazinones, 2-aminobenzoxazines and 2-
aminoquinozolines
Consequently, intensive efforts have been made for their preparation.1-6 Especially the synthesis of 2-
aminobenzoxazinones have been developed fast during the past decades. However, the methods for their
synthesis mainly located on the Pd(II)-catalyzed reactions (Scheme 1). Houlden’s group realized a
Pd(II)-catalyzed carbonylative method through C-H activation and CO insertion of N-arylureas (Scheme
1, A).7 Similarly, Wu’s group reported a carbonylative synthesis of 2 –aminobenzoxazoles via in situ
formation of N-arylureas by the reaction of isocyanates and 2-bromoanilines (Scheme 1, B).8 In 2013,
Orru et al reported an oxidative reaction of 2-aminobenzoic acids and isocyanides using Pd(II)-catalyst
to give 2-aminobenzoxazinones. The procedure is easy to handle and toxic CO is not required (Scheme
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1, C).9 Although the reported methods have made a great step forward in the production of these
scaffolds, they suffer from the use of transition metals, which limits their applications in medicinal
chemistry. In order to provide a more environmentally friendly strategy, the development of a metal-free
approach is still highly desirable.
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9
Isocyanides are usually used in the construction of nitrogen-containing compounds as vital and
meritorious C1 building blocks.10 Iodine and compounds of iodine-mediated oxidative coupling
reactions are very important for they are more green and less expensive than those transition-metal-
mediated oxidative coupling reactions.11 An procedure of using isocyanides and amines to developed
carbodiimides through I2/CHP-mediated cross-coupling reaction, has been reported in our previous
work.12 The carbonimidic diiodine intermediate was assumed to be an active species in the formation of
carbodiimides. Inspired by our previous work, we herein describe a metal-free I2/TBHP mediated
oxidative coupling reaction of 2-aminobenzoic acid and isocyanides producing various 2 ‑
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aminobenzoxazinones (Scheme 1, D).
Previous work
O
[(MeCN)2Pd(OTs)2] (5 mol %)
H
benzoquinone (2 equiv)
O
O
Houlden's work
A
B
NHCONR2R3
N
NR2R3
TsOH (1 equiv), CO (1 atm)
CH2Cl2, 3-5 h, 18 oC
Pd(OAc)2 (3 mol %)
BuPAd2 (6 mo l%)
Br
O
R1
R1
R2 NCO
+
Wu's work
[Mo(CO)6] (1.5 equiv)
K3PO4/toluene,120 oC
N
O
NHR2
NH2
O
Pd(OAc)2 (5 mol %)
OH
O
R1
R1
C
Orru's work
+
C N R2
R2
1,4-dioxane,75 oC,4 h
4A MS,O2 (1 atm)
NH2
N
N
H
This work
O
O
I2 (10 mol %)
O
R1
OH
+
C N R2
R1
D
R2
TBHP (2 equiv)
50 oC, 12 h
N
N
NH2
H
Scheme 1. Routes toward 2- Aminobenzoxazinones.
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RESULTS AND DISCUSSION
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We investigated the reaction of 2-aminobenzoic acid 1a and tert-butyl isocyanide 2a, in the presence
of 0.2 equiv. of iodine and 2 equiv. of TBHP, using 1,4-dioxane as solvent at 110 °C for 4 h. To our
delight, the desired product 2-(tert-butylamino)-4H-benzo[d][1,3]oxazin-4-one 3a was obtained in 53%
GC-yield (Table 1, entry 1). In the absence of the catalyst, no expected product was observed (Table 1,
entry 2). The yield of 3a decreased when we used different iodine sources like NIS and Bu4NI (Table 1,
entries 3, 4 and 6). We also evaluated other halide-source catalyst such as Bu4NBr, which could not
promote this reaction (Table 1, Entry 5). Further examinations of other kinds of oxidants, such as CHP,
TBHP, O2, TBPB, and K2S2O8 was operated and TBHP proved to be the most efficient oxidant (Table 1,
entries 1, 7-11).
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Various solvents, including THF, MeCN, MTBE, DCE), DMF, toluene and DME were screened
subsequently, which indicated that MTBE was the best solvent (Table 1, entries 12–18). 3a was
obtained in 72% yield by GC, when the reaction was carried out for 12 h. (Table 1, entry 19). The yield
o
of 3a was increased by decreasing the reaction temperature to 50 C (Table 1, entry 20). Further
examination of the amount of I2, showed that 10 mol % I2 gave 3a in 83% GC yield (Table 1, entry 21).
Therefore, optimum reaction conditions was 10 mol % of I2 and 2 equiv. of oxidant TBHP in MTBE at
50 °C for 12 h.
a
Table 1. Optimization of the reaction conditions
O
O
catalyst
oxidant
solvent, 110 oC
OH
O
+
C N
NH2
1a
N
N
H
2a
3a
entry
catalyst (mol%)
I2 (20)
oxidant (equiv.)
solvent
yieldb (%)
1
2
3
4
5
6
TBHPc (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
53
0
28
32
0
--
Bu4NI (20)
NISd (20)
Bu4NBr (20)
NaI (20)
26
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19l
20l,m
21 l,m
22 l,m
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (10)
I2 (5)
--
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
THFg
0
1
2
3
4
5
6
7
8
CHPe(2)
TBPBf (2)
O2
42
13
0
K2S2O8 (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
0
23
18
56
46
0
27
29
72
75
83
67
MeCN
MTBEh
DCEi
9
10
11
12
13
14
15
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17
18
19
DMFj
Toluene
DMEk
MTBE
MTBE
MTBE
MTBE
aReaction conditions: 1a (0.5 mmol), 2a (1.2 equiv., 0.6 mmol), oxidant and catalyst in solvent (3mL) at
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o
b
110 C for 4 h, under air. Yields were determined by GC analysis using biphenyl as an internal
c
d
e
f
standard. TBHP(70% in H2O). NIS = N-iodosuccinimide. CHP = cumene hydroperoxide. TBPB =
tert-butylperoxybenzoate. THF = tetrahydrofuran. MTBE = methyl tert-butyl ether. DCE = 1, 2-
dichloroethane. DMF = N,N-dimethylformamide. DME = 1,2-dimethoxyethane. Reaction time 12 h.
mThe system was carried out at 50 oC.
g
h
i
j
k
l
With this optimized protocol, we tested various substituted anthranilic acids. Results are shown in
Table 2. o-Aminobenzoic acid 1a reacted with 2a to give the desired product 3a in 70% yield.
Noteworthily, 2-aminobenzoic acids bearing electron-donating groups led to the corresponding products
3b-3g in 27-85% yields. When halogen-substituted 2-aminobenzoic acids 1h-1i were subjected to the
reactions, the desired 2-aminobenzoxazinones 3h–3i were observed in good yields (63–70 %).
Unfortunately, the reaction of 2-amino-3-nitrobenzoic acid 1j with 2a was messy due to the presence of
the NO2 group.
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Table 2 Aerobic oxidative coupling of various 2-aminobenzoic acids with 2aa
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O
O
I2 (10 mol%)
TBHP (2 equiv)
O
R1
OH
NH2
R1
+
C N
MTBE (3 mL)
50 oC, 12h
N
N
H
1
2a
3
O
O
O
O
N
O
O
N
N
N
N
H
N
H
H
3a
3c
, 70%
, 53%
O
3b
, 81%
O
O
O
N
MeO
O
O
N
N
H
N
H
N
, 27%
O
N
H
3e
, 85%
O
3d
3f
, 45%
O
F
Cl
O
O
O
MeO
N
N
H
N
N
H
N
N
H
3g
, 57%
O
3i
, 70%
3h
, 63%
O
N
N
H
NO2
3j
, messy
aReaction conditions: compound 1 (0.5 mmol), 2a (1.2 equiv, 0.6 mmol), I2 (10 mol %), TBHP (70% in
H2O) (2 equiv) in MTBE (3 mL) at 50 oC for 12 h. Isolated yields.
Next, the scope of isocyanides was investigated (Table 3). Tertiary aliphatic isocyanides (2b and 2c)
and secondary aliphatic isocyanides (2d and 2e) gave the desired products 3k-3n in moderate yields
(41-58%). Unfortunately, primary aliphatic isocyanide 2f didn’t give the desired product 3o. It is worth
noting that aromatic isocyanides 3,5–dimethylphenylisocyanide 2g and 2,6–dimethylphenylisocyanide
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2h could afford 3p and 3q in 60% and 45% yields, respectively, while Orru’s method could not reach
1
2
3
the same level for these isocyanides.9
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Table 3 Aerobic oxidative coupling of 2-aminobenzoic acid with diverse isocyanidesa
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O
O
I2 (10 mol%)
O
R1
TBHP (2 equiv)
OH
NH2
C N R2
R1
+
N
NH
R2
MTBE (3 mL)
50 oC,12 h
1
2
3
O
O
O
O
N
O
O
N
N
N
N
H
N
H
H
3k
3l
3m
, 55%
, 41%
, 58%
O
N
O
N
O
O
O
O
N
N
H
N
N
H
H
3n
3o
3p
, 60%
, 48%
, trace
O
O
N
N
H
3q
, 45%
aReaction conditions: compound 1 (0.5 mmol), 2 (1.2 equiv, 0.6 mmol), I2 (10 mol %), TBHP
(70% in H2O) (2 equiv) in MTBE (3mL) at 50 oC for 12 h. Isolated yields.
Illustrating the importance of our procedure, we applied it to the late-stage modification of the
bioactive compound (Table 4). When we performed the reaction of galactose derivative 2h with 1b
under optimzed conditions, the desired product 3r was obtained in 68% isolated yield, providing a novel
synthesis protocol for the construction of potential pharmaceutically and biologically active compounds.
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Table 4 Late-stage functionalization of biologically active molecule.a
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O
O
O
I2 (10 mol%)
TBHP (2 equiv)
CN
O
R
OH
+
O
N
N
MTBE (3 mL)
50 oC,12 h
NH2
H
R
1b
2h
3r
, 68%
O
O
O
O
R =
O
O
D-alpha-Galactose
derivative
aReaction condition: compound 1b (0.21 mmol), 2 (1.2 equiv, 0.25 mmol), I2 (10 mol %), TBHP
(70% in H2O) (2 equiv) in MTBE (3mL) at 50 oC for 12 h. Isolated yields.
Additionally, under the optimal conditions, we investigated other amine-based bisnucleophiles, such
as (2-aminophenyl)methanol 1k and 2-(aminomethyl)aniline 1l. Results are listed in Table 5. Reaction
of (2-aminophenyl)methanol 1k with tert-butyl isocyanide 2a furnished the desired product 4 in 54%
yield. When 2-(aminomethyl)aniline 1l was treated with various isocyanides under analogous reaction
conditions, diverse substituted 2-aminoquinozolines 5a-f were obtained in up to 83% yields (Table 5).
Unfortunately, primary aliphatic isocyanide ethyl 2-isocyanoacetate 2i could not afford the desired
product 5d. It is evident that the products have undergone an additional oxidation to aromatize.
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Table 5 Aerobic oxidative coupling of other bisnucleophiles with isocyanidesa
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60
I2 (10 mol %)
TBHP (2 equiv)
OH
NH2
O
+
C N
(1)
(2)
MTBE (3 mL)
50 oC,12 h
N
N
H
1k
2a
4
, 54%
I2 (10 mol %)
TBHP (2 equiv)
NH2
NH2
N
N
C N R2
R2
+
1,4-dioxane (3 mL)
50 oC, 4 h
N
H
2
1l
5
N
N
N
N
N
N
N
N
N
H
H
H
5a
5b
5c
, 68%
, 83%
, 70%
Cl
N
N
N
O
N
N
H
N
N
N
N
H
H
O
5d
5e
5f
, 40%
, 0%
, 40%
aReaction conditions: (1) compound 1k (0.5 mmol), 2a (1.2 equiv, 0.6 mmol), I2 (10 mol %),
TBHP (70% in H2O) (2 equiv) in MTBE (3mL) at 50 oC for 12 h; (2) compound 1l (0.5 mmol),
2 (1.2 equiv, 0.6 mmol), I2 (10 mol %), TBHP (70% in H2O) (2 equiv) in 1,4-dioxane (3mL) at
50 oC for 4 h. Isolated yields.
Based on the results above, a plausible mechanismfor this reaction is depicted in scheme 2. The 1,1-
addition of iodine to isocyanide 2 gives intermediate I.12,13 Then, Intermediate I reacts with 2-
aminobenzoic acid 1, resulting in intermediate II through dehydrohalogenation. HI is oxidized by TBHP
giving iodine and then complete the cycle. Subsequently, second dehydrohalogenation of II occus,
leading to the formation of carbodiimide III (path a) or IV (path b). And then isomerization of IV or
intramolecular cyclization of III frunishes 3.
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1
2
3
H2O
OH
I2
4
C N R2
5
6
7
2
OH
O
8
9
TBHP
TBHP
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11
12
13
14
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17
18
19
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22
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25
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R2
I
N
HI
I
I
HI
O
O
O
path b
OH
NH2
OH
R1
O
R1
R1
R2
b
NH
N
H
IV
N
R2
a
N
1
I
II
path a
O
O
N
O
R1
R2
OH
R1
N
N
H
3
C
N
R2
III
Scheme 2. Proposed mechanism
CONCLUSION
In conclusion, a new and practical I2-TBHP-catalysed oxidative coupling reaction of isocyanides with
active N-H, O-H bonds has been developed. This protocol provides a novel, general, reliable,
straightforward and atom efficient approach leading to 2-aminobenzoxazinones 3, 2-aminobenzoxazines
4 and 2-aminoquinozolines 5 under metal-free conditions. Furthermore, the utility of this approach can
be applied to late-stage modification of pharmaceutically and biologically active molecules.
EXPERIMENTAL SECTION
General Experimental Information. All the solvents for routine isolation of products and chromatography were reagent grade. Flash
chromatography was performed using silica gel (200-300 mesh) with the indicated solvents. Melting points were recorded on an
electrothermal digital melting point apparatus and were uncorrected. IR spectra were recorded on a spectrophotometer using KBr optics.
1H NMR and 13C NMR spectra were recorded on a 400 MHz (1H NMR) and 100 MHz (13C NMR) spectrometer using CDCl3 or DMSO-d6
as solvent and TMS as internal standard. The 1H NMR data are reported as the chemical shift in parts per million, multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet), coupling constant in hertz, and number of protons. High resolution mass spectra were obtained
using a high resolution ESI-TOF mass spectrometer.
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1
General Procedure for the construction of 3
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To a mixture of 2-aminobenzoic acids, (2-aminophenyl)methanol or 2-(aminomethyl)aniline (0.5 mmol), I2 (0.05 mmol), tert-Butyl
hydroperoxide (TBHP, 70% in H2O) (1 mmol) and isocyanide (0.6 mmol) were added in 3 mL MTBE or 1,4-dioxane to test tube. The test
tube was closed. The reaction mixture was stirred at 50 C. When the reactions were completed(checked by TLC), they were cooled to
room temperature, washed with 10 % Na2S2O3 Solution(3*15 mL) and extracted with Ethyl acetate(3*15 mL). The combined organic
layers were dried over Na2SO4. Removal of solvent followed by flash column chromatographic purification afforded products using
petroleum and Ethyl acetate.
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2-(tert-butylamino)-4H-benzo[d][1,3]oxazin-4-one 3a. Light pink solid, m. p.: 132-133 C. IR (neat, ν cm-1) 3298, 2972, 1739. H NMR
(400 MHz, Chloroform-d) : δ 8.01 (d, J = 7.3 Hz, 1H), 7.67 – 7.52 (m, 1H), 7.26 (d, J = 8.9 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 4.97 (s, 1H),
1.49 (s, 9H) ppm. 13C NMR (100 MHz, Chloroform-d): δ 160.4, 152.2, 150.5, 136.6, 128.6, 124.6, 123.5, 113.4, 52.0, 28.9 ppm. HRMS
(ESI) m/z: calcd for C12H15N2O2+ (M+H+): 219.1134, found: 219.1129.
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2-(tert-butylamino)-8-methyl-4H-benzo[d][1,3]oxazin-4-one 3b. White solid, m. p.: 154-155 oC. IR (neat, ν cm-1): 3278, 2963, 1731. 1H
NMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 4.96 (s, 1H), 2.43 (s, 3H),
1.51 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 160.9, 151.01, 149.0, 136.9, 133.0, 126.1, 122.9, 113.1, 51.9, 28.6, 17.4 ppm. HRMS (ESI)
+
m/z: calcd for C13H17N2O2 : (M+H) +: 233.1290, found: 233.1297.
2-(tert-butylamino)-6-methyl-4H-benzo[d][1,3]oxazin-4-one 3c. Light yellow solid, m.p.:166-166 oC. IR (neat, ν cm-1): 3296, 2978, 1736.
1H NMR (400 MHz, Chloroform-d) δ 7.81 (s, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 4.81 (s, 1H), 2.37 (s, 3H), 1.48 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 160.5, 151.8, 148.3, 138.0, 133.4, 128.1, 124.5, 113.1, 52.0, 29.0, 20.9 ppm. HRMS (ESI) m/z: calcd
+
for C13H17N2O2 : (M+H) +: 233.1290, found: 233.1300.
2-(tert-butylamino)-5-methyl-4H-benzo[d][1,3]oxazin-4-one 3d. Light red solid, m.p.: 132-133 oC. IR (neat, ν cm-1): 3294, 2972,1732. 1H
NMR (400 MHz, Chloroform-d) δ 7.44 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 4.87 (s, 1H), 2.70 (s, 3H),
1.47 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 159.6, 152.2, 152.0, 142.8, 135.6, 126.1, 122.7, 112.2, 51.9, 29.0, 22.8 ppm. HRMS (ESI) m/z:
+
calcd for C13H17N2O2 : (M+H) +: 233.1290, found: 233.1290.
2-(tert-butylamino)-6,8-dimethyl-4H-benzo[d][1,3]oxazin-4-one 3e. Pale yellow solid, m. p.: 168-170 oC. IR (neat, ν cm-1): 3293, 2969,
1730. 1H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 2.1 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 4.80 (s, 1H), 2.39 (s, 3H), 2.32 (s, 3H), 1.49
(s, 9H). 13C NMR (100 MHz, CDCl3) δ 161.0, 150.7, 146.8, 138.5, 132.8, 132.6, 125.5, 112.9, 51.8, 28.6, 20.9, 17.3 ppm. HRMS (ESI) m/z:
+
calcd for C14H19N2O2 : (M+H) +: 247.1447, found: 247.1443.
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2-(tert-butylamino)-6-methoxy-4H-benzo[d][1,3]oxazin-4-one 3f. Light yellow solid, m. p.: 128-130 C. IR (neat, ν cm-1): 3296, 2977,
1736. 1H NMR (400 MHz, Chloroform-d) δ 7.41 (d, J = 2.7 Hz, 1H), 7.26 – 7.19 (m, 2H), 4.77 (s, 1H), 3.84 (s, 3H), 1.47 (s, 9H) ppm. 13
C
NMR (100 MHz, Chloroform-d) δ 160.5, 155.9, 151.2, 144.9, 126.6, 126.1, 113.5, 108.4, 55.9, 51.9, 29.0 ppm. HRMS (ESI) m/z: calcd
+
for C13H17N2O3 (M+H+): 249.1239, found: 249.1238.
2-(tert-butylamino)-7-methoxy-4H-benzo[d][1,3]oxazin-4-one 3g. Pale yellow solid, m. p.: 168-170 oC. IR (neat, ν cm-1): 3287, 2958, 1714.
1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 8.7 Hz, 1H), 6.84 – 6.48 (m, 2H), 4.98 (s, 1H), 3.88 (s, 3H), 1.48 (s, 9H). 13C NMR (100
+
MHz, CDCl3) δ 166.6, 159.9, 153.0, 152.9, 130.3, 113.2, 106.4, 106.0, 55.7, 52.0, 28.9 ppm. HRMS (ESI) m/z: calcd for C13H17N2O3
(M+H+): 249.1239, found: 249.1243.
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2-(tert-butylamino)-6-fluoro-4H-benzo[d][1,3]oxazin-4-one 3h. Light orange solid, m.p.: 124-125 oC. IR (neat, ν cm-1): 3296, 1736. H
NMR (400 MHz, Chloroform-d) δ 7.66 (dd, J = 8.0, 2.9 Hz, 1H), 7.34 (td, J = 8.5, 3.0 Hz, 1H), 7.25 (dd, J = 8.7, 4.4 Hz, 1H), 4.89 (s, 1H),
1.48 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 159.6(JC-F, 3.4 Hz), 158.5(JC-F, 242 Hz) 151.7, 147.1(JC-F, 1.3 Hz), 126.6(JC-F, 7.4 Hz),
124.9(JC-F, 23.6 Hz), 114.0(JC-F, 8.6 Hz), 113.4(JC-F, 23.6 Hz), 52.1, 28.9 ppm. HRMS (ESI): m/z: calcd for C12H14N2O2F+: (M+H)+:
237.1039, found: 237.1042.
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2-(tert-butylamino)-6-chloro-4H-benzo[d][1,3]oxazin-4-one 3i. Light purple solid, m.p.: 154-155 C. IR (neat, ν cm-1): 3290, 1748. H
NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 2.5 Hz, 1H), 7.53 (dt, J = 9.0, 2.4 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 4.99 (s, 1H), 1.48 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 159.3, 149.1, 136.8, 128.6, 127.7, 126.3, 114.4, 52.3, 28.9 ppm. HRMS (ESI) m/z: calcd for
C12H14N2O2Cl+: (M+H)+: 253.0714, found: 253.0744.
1
2-(tert-pentylamino)-4H-benzo[d][1,3]oxazin-4-one 3k. Light orange solid, m. p.: 68-69 oC. IR (neat, ν cm-1): 3305, 1739. H NMR (400
MHz, Chloroform-d) δ 8.01 (dd, J = 7.9, 1.6 Hz, 1H), 7.60 (ddt, J = 8.5, 7.0, 1.4 Hz, 1H), 7.31 – 7.22 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H),
4.85 (s, 1H), 1.85 (q, J = 7.5 Hz, 2H), 1.43 (s, 4H), 0.91 (t, J = 7.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 160.3, 152.2, 150.5, 136.6,
+
128.7, 124.6, 123.5, 113.4, 54.8, 33.0, 26.5, 8.4 ppm. HRMS (ESI) m/z: calcd for C13H17N2O2 (M+H+): 233.1290, found: 233.1293.
2-(((3s,5s,7s)-adamantan-1-yl)amino)-4H-benzo[d][1,3]oxazin-4-one 3l. Light pink solid, m. p.: 242-242oC. IR (neat, ν cm-1): 3275, 1736.
1H NMR (400 MHz, Chloroform-d) δ 8.01 (dd, J = 7.9, 1.5 Hz, 1H), 7.73 – 7.49 (m, 1H), 7.36 – 7.19 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H),
4.74 (s, 1H), 2.34 – 2.04 (m, 9H), 1.72 (d, J = 3.0 Hz, 7H). 13C NMR (100 MHz, CDCl3) δ 160.3, 150.6, 136.6, 128.7, 124.6, 123.5, 113.5,
+
52.6, 41.7, 36.4, 29.61 ppm. HRMS (ESI) m/z: calcd for C18H21N2O2 (M+H+): 297.1603, found: 297.1608.
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2-(isopropylamino)-4H-benzo[d][1,3]oxazin-4-one 3m. Yellow solid, m. p.: 195-196 C. IR (neat, ν cm-1): 3298, 1737. H NMR (400
MHz, Chloroform-d) δ 8.02 (dd, J = 7.9, 1.6 Hz, 1H), 7.67 – 7.35 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 4.95 (s, 1H),
4.14 (q, J = 6.6 Hz, 1H), 1.29 (d, J = 6.5 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 160.2, 153.2, 150.7, 136.8, 128.8, 124.3, 123.6, 113.3,
43.8, 22.8 ppm. HRMS (ESI) m/z: calcd for C11H13N2O2+ (M+H+): 205.0977, found: 205.0974.
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2-(cyclohexylamino)-4H-benzo[d][1,3]oxazin-4-one 3n. Pale yellow solid, m. p.: 186-188 oC. IR (neat, ν cm-1): 3290, 1737. 1H NMR (400
MHz, Chloroform-d) δ 8.02 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.37 – 6.94 (m, 2H), 4.85 (s, 1H), 3.82 (d, J = 10.0 Hz, 1H), 2.07
(dd, J = 12.0, 4.6 Hz, 2H), 1.70 (ddt, J = 43.3, 13.4, 4.4 Hz, 3H), 1.44 (q, J = 12.0 Hz, 2H), 1.34 – 1.14 (m, 3H). 13C NMR (100 MHz,
+
CDCl3) δ 160.2, 153.2, 150.8, 136.8, 128.9, 124.3, 123.6, 113.3, 50.3, 33.1, 25.6, 24.8 ppm. HRMS (ESI) m/z: calcd for C14H17N2O2
(M+H+): 245.1290, found: 245.1291.
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2-((3,5-dimethylphenyl)amino)-4H-benzo[d][1,3]oxazin-4-one 3p. White solid, m. p.: 195-196 oC. IR (neat, ν cm-1): 3289, 1731. 1H NMR
(400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.96 (d, J = 6.9 Hz, 1H), 7.82 – 7.70 (m, 1H), 7.48 – 7.32 (m, 3H), 7.28 (t, J = 7.5 Hz, 1H), 6.72 (s,
1H), 2.28 (s, 6H). 13C NMR (100 MHz, DMSO)δ 159.2, 150.6, 149.5, 137.9, 137.7, 136.8, 128.1, 124.7, 124.6, 124.2, 117.3, 113.8, 21.2
ppm. HRMS (ESI) m/z: calcd for C16H15N2O2+ (M+H+): 267.1134, found: 267.1138.
2-((2,6-dimethylphenyl)amino)-8-methyl-4H-benzo[d][1,3]oxazin-4-one 3q. White solid, m.p.: 153-154 oC. IR (neat, ν cm-1): 3258, 1735.
1H NMR (400 MHz, Chloroform-d) δ 7.90 (dd, J = 8.0, 1.5 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.21 – 7.01 (m, 4H), 6.44 (s, 1H), 2.32 (s,
6H), 2.25 (s, 3H).13C NMR (100 MHz, CDCl3) δ 160.6, 151.2, 148.8, 137.3, 135.9, 133.4, 133.2, 128.4, 127.6, 126.4, 123.6, 113.3, 18.7,
17.1 ppm. HRMS (ESI) m/z: calcd for C17H17N2O2+ (M+H+): 281.1290, found: 281.1298.
((3aR,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methyl
4-((8-methyl-4-oxo-4H-
benzo[d][1,3]oxazin-2-yl)aminobenzoate 3r. White solid, m. p.: 119-121 oC. IR (neat, ν cm-1): 3282, 2987, 1738, 1649. 1H NMR (400 MHz,
DMSO-d6) δ 10.73 (s, 1H), 7.97 (d, J = 1.5 Hz, 4H), 7.84 (dd, J = 7.9, 1.5 Hz, 1H), 7.72 – 7.63 (m, 1H), 7.24 (t, J = 7.6 Hz, 1H), 5.49 (d, J
= 4.9 Hz, 1H), 4.66 (dd, J = 7.9, 2.4 Hz, 1H), 4.49 – 4.31 (m, 3H), 4.27 (dd, J = 11.3, 7.6 Hz, 1H), 4.11 (ddd, J = 7.0, 4.7, 1.8 Hz, 1H),
2.62 – 2.41 (m, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 1.30 (d, J = 11.0 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 166.0, 160.3, 148.4, 147.5, 141.8,
137.6, 133.8, 131.0, 126.3, 124.7, 118.2, 113.9, 109.7, 108.8, 96.4, 71.2, 70.7, 70.5, 66.2, 63.8, 26.1, 26.0, 25.0, 24.5, 17.5. HRMS (ESI)
m/z: calcd for C28H31N2O9+ (M+H+): 539.2030, found: 539.2026.
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N-(tert-butyl)-4H-benzo[d][1,3]oxazin-2-amine 4. Brown solid, m. p.: 71 -73 C. IR (neat, ν cm-1): 3263, 2924. H NMR (400 MHz,
DMSO-d6) δ 7.18 – 7.08 (m, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.90 – 6.76 (m, 2H), 6.57 (s, 1H), 5.03 (s, 2H), 1.35 (s, 9H). 13C NMR (100
MHz, CDCl3) δ 154.8, 143.0, 129.0, 123.6, 122.1, 121.5, 121.2, 67.2, 51.2, 29.6 ppm. HRMS (ESI) m/z: calcd for C12H17N2O+(M+H+):
205.1341, found: 205.1349.
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N-(tert-butyl)quinazolin-2-amine 5a. Yellow solid, m. p.: 82-83 C. IR (neat, ν cm-1):3302, 2961, 1620, 1594, 753. H NMR (400 MHz,
Chloroform-d) δ 8.92 (s, 1H), 7.83 – 7.46 (m, 3H), 7.23 – 7.08 (m, 1H), 5.32 (s, 1H), 1.53 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 161.5,
159.2, 152.1, 133.9, 127.5, 126.0, 122.4, 119.9, 51.2, 29.0 ppm. HRMS (ESI) m/z: calcd for C12H16N3 (M+H+): 202.1344, found:
+
202.1350.
N-((3s,5s,7s)-adamantan-1-yl)quinazolin-2-amine 5b. Pale yellow solid, m. p.: 108-109 oC. IR (neat, ν cm-1): 3291, 2905, 1622, 1593, 755.
1H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1H, -CH=N), 7.67 – 7.57 (m, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.17 (ddd, J = 9.2, 5.5, 2.0 Hz,
1H), 2.21 (d, J = 2.5 Hz, 6H), 2.13 (s, 3H), 1.84 – 1.65 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 161.4, 159.2, 152.1, 133.9, 127.5, 125.9,
122.3, 120.0, 51.7, 41.8, 36.7, 29.8 ppm. HRMS (ESI) m/z: calcd for C18H22N3+ (M+H+): 280.1814, found: 280.1817.
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N-cyclohexylquinazolin-2-amine 5c. White solid, m. p.: 108-109 oC. IR (neat, ν cm-1): 3270, 2926, 1619, 1591, 752. H NMR (400 MHz,
Chloroform-d) δ 8.94 (s, 1H), 8.06 – 7.42 (m, 3H), 7.38 – 6.94 (m, 1H), 5.31 (s, 1H), 4.01 (dtd, J = 10.2, 6.6, 4.1 Hz, 1H), 2.14 – 2.08 (m,
2H), 1.76 (dt, J = 13.2, 4.0 Hz, 2H), 1.66 (dt, J = 13.2, 4.0 Hz, 1H), 1.46 (td, J = 14.5, 13.5, 7.6 Hz, 2H), 1.27 (q, J = 11.9 Hz, 3H). 13
C
NMR (100 MHz, CDCl3) δ 162.1, 159.2, 152.4, 134.2, 127.6, 125.6, 122.4, 120.2, 49.7, 33.4, 25.9, 25.0 ppm. HRMS (ESI) m/z: calcd for
C14H18N3+ (M+H+): 228.1501, found: 228.1510.
N-(4-chlorophenyl)quinazolin-2-amine 5e. Brown solid, m. p.: 152-153 oC. IR (neat, ν cm-1): 3256, 2993, 1620, 1600, 1589, 762. 1H NMR
(400 MHz, Chloroform-d) δ 9.09 (s, 1H), 7.88 – 7.68 (m, 5H), 7.47 (s, 1H), 7.39 – 7.29 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 162.0,
+
156.7, 151.5, 138.4, 134.7, 129.0, 127.6, 127.4, 126.5, 124.2, 121.1, 120.3 ppm. HRMS (ESI) m/z: calcd for C14H11ClN3 (M+H+):
256.0642, found: 256.0642.
1
N-(2,6-dimethylphenyl)quinazolin-2-amine 5f. Brown solid, m. p.: 170-170 oC. IR (neat, ν cm-1): 3234, 1618, 1601, 1589, 762. H NMR
(400 MHz, Chloroform-d) δ 9.03 (s, 1H), 7.77 – 7.63 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.30 – 7.23 (m, 1H), 7.16 (s, 3H), 6.87 (s, 1H),
2.28 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 162.6, 152.3, 136.5, 135.8, 134.4, 128.4, 127.6, 127.0, 125.9, 123.2, 122.3, 120.6, 18.9 ppm.
HRMS (ESI) m/z: calcd for C16H16N3+ (M+H+): 250.1344, found: 250.1351.
ASSOCIATED CONTENT
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Supporting Information Available.
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The copies of 1H and 13C NMR spectra of the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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ACKNOWLEDGMENT
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We gratefully acknowledge the National Natural Science Foundation of China (21772137, 21672157),
the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education
Institutions (No. 16KJA150002), the Ph.D. Programs Foundation of PAPD, the project of scientific and
technologic infrastructure of Suzhou (SZS201708), and Soochow University for financial support.
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M.; Jaen, J. C. Benzenesulfonamide derivatives of 2-substituted 4H-3,1-benzoxazin-4-ones and benzthiazin-4-ones as
inhibitors of complement C1r protease Bioorg. Med. Chem. Lett. 1999, 9, 815; (c) Neumann, U.; Schechter, N. M.;
Gütschow, M. Inhibition of human chymase by 2-amino-3,1-benzoxazin-4-ones. Bioorg. Med. Chem. 2001, 9, 947;
(d) Pietsch, M.; Gütschow, M. Synthesis of Tricyclic 1,3-Oxazin-4-ones and Kinetic Analysis of Cholesterol Esterase
and Acetylcholinesterase Inhibition. J. Med. Chem. 2005, 48, 8270. (e) Gütschow, M.; Schlenk, M.; Gäb, J.;
Paskaleva, M.; Alnouri, M. W.; Scolari, S.; Iqbal, J.; Müller, C. E. Benzothiazinones: A Novel Class of Adenosine
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