Synthesis of 2-aminobenzoxazoles and 3-aminobenzoxazines via palladium-catalyzed aerobic oxidation of o -aminophenols with isocyanides

Article abstract of DOI:10.1021/jo400002f

A Pd-catalyzed aerobic oxidation of o-aminophenols and isocyanides for the synthesis of 2-aminobenzoxazoles and 3-aminobenzoxazines has been achieved in an air atmosphere. The procedure constructs 2-aminobenzoxazoles and 3-aminobenzoxazines with moderate to excellent yields and a broad substrate scope. Apart from experimental simplicity, this methodology has the advantages of mild reaction conditions and easily accessible starting materials. Furthermore, the utility of this method has also been successfully applied to the synthesis of other types of useful nitrogen heterocycles.

Full text of DOI:10.1021/jo400002f

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Article
Synthesis of 2-Aminobenzoxazoles and 3-Aminobenzoxazines via
Palladium-Catalyzed Aerobic Oxidation of o-Aminophenols with Isocyanides
Bifu Liu, Meizhou Yin, Hanling Gao, Wanqing Wu, and Huanfeng Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400002f • Publication Date (Web): 11 Mar 2013
Downloaded from http://pubs.acs.org on March 12, 2013
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Synthesis of 2-Aminobenzoxazoles and 3-Aminobenzoxazines via
Palladium-Catalyzed Aerobic Oxidation of o-Aminophenols with
Isocyanides
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Bifu Liu, Meizhou Yin, Hanling Gao, Wanqing Wu, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
jianghf@scut.edu.cn
Abstract: A Pd-catalyzed aerobic oxidation of o-aminophenols and isocyanides to the
synthesis of 2-aminobenzoxazoles and 3-aminobenzoxazines has been achieved under
air atmosphere.
The procedure constructs 2-aminobenzoxazoles and
3-aminobenzoxazines with moderate to excellent yields and a broad substrate scope.
Apart from experimental simplicity, this methodology has advantages of mild reaction
conditions and easily accessible starting materials. Furthermore, the utility of this
method is also successfully applied to the synthesis of other types of useful nitrogen
heterocycles.
INTRODUCTION
Benzoxazoles and benzoxazines are ubiquitous heterocyclic scaffolds found in many
bioactive natural products, pharmaceuticals, and agrochemicals.1 Among them,
2-aminobenzoxazoles and 3-aminobenzoxazines have been extensively studied for
their biological and therapeutic activities (Figure 1). They have been used as tyrosine
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kinase inhibitors for the treatment of cancers (VEGFR-2),2 5-HT receptors antagonists
for the treatment of Alzheimer’s disease and schizophrenia,3 dual orexin receptor
antagonist for the treatment of insomnia (MK-4305),4 and GABA receptor inhibitor
for anxiolytic and anticonvulsant (etifoxine).5
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Figure 1. Aminobenzoxazole and aminobenzoxazine moieties in drugs.
Consequently, considerable efforts have been made to develop efficient methods for
their synthesis (Scheme 1). The classical approach is the nucleophilic substitution of
appropriately 2-substituted benzoxazoles with amines. However, this method always
needs inconvenient multistep, harsh reagents and conditions, or produces undesirable
byproducts during the preparation of the 2-substituted benzoxazoles.6 A more general
method is the cyclodesulfurization of an intermediary thiourea, which usually
involves toxic heavy-metal oxide or potentially explosive oxidant for this
transformation.7 Over the past decade, directly oxidative C-H amination of
benzoxazoles to construct 2-aminobenzoxazoles has been extensively investigated.8
However, such transformations typically require initial chlorination of the amine or
harsh conditions, and the use of expensive 2-unsubstituted benzoxazoles.9 Previously
reported synthetic approaches to generate 2-amino-benzoxazoles directly from
2-aminophenols may need multistep for the preparation of proper amine surrogates
prior to cyclization.10 Therefore, exploring atom and/or step efficiency and
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environmentally friendly processes are highly desirable.
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Scheme 1. Typical methods for synthesis of 2-aminobenzoxazoles.
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Isocyanides, a kind of unsaturated molecule similar to carbon monoxide, are the best
known amphoteric reagents. Although the extremely unpleasant odor and toxicity of
isocyanides (especially for cyclohexyl isocyanide), isocyanides have played an
irreplaceable important role in modern organic chemistry. Since the pioneering work
of Ugi and Passerini11, isocyanides have been widely applied to construct various
nitrogen-containing heterocycles for their superior capability to rapidly create
molecular diversity.12 However, palladium-catalyzed processes that involve
isocyanide insertion to assemble N-containing heterocycles were relatively
undervalued and have drawn great attention only in very recent years.13 Recently, we
reported a palladium-catalyzed tandem reaction of o-aminophenols, bromoalkynes
and isocyanides to give 4-amino-benzo[b][1,4]oxazepines.14 During the course of the
study, we occasionally observed a small amount of 2-(tert-butylamino)-benzoxazole
along with the major product. This intriguing result suggested that o-aminophenols
and isocyanides might have a distinct reactivity difference from the three-component
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tandem reaction, which prompted us to investigate this unique transformation in detail.
As part of our ongoing programs on palladium-catalyzed cascade reactions involving
isocyanide insertion15, herein, we report a convenient and convergent method for the
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synthesis
of
2-aminobenzoxazoles
and
3-aminobenzooxazines
via
palladium-catalyzed aerobic oxidation of o-aminophenols and isocyanides.
RESULTS AND DISCUSSION
To explore this approach, we selected o-aminophenol (1a) and tert-butylisocyanide
(2a) as the model substrates for reaction development and screened several
transition-metal catalysts in common solvents for their catalytic activities (Table 1).
Initially, we preformed this palladium-catalyzed aerobic oxidation of 1a with 2a under
the optimized conditions of our previous work.14 To our delight, the reaction gave the
expected 2-(tert-butylamino)-benzoxazole (4aa) in 56% yield and unexpected
unsubstituted benzoxazole 3aa in 15% yield in the presence of Pd(PPh3)2Cl2 (5 mol %)
and PPh3 (10 mol %) in dioxane at 80 oC for 2 h (entry 1). However, the yield of 4aa
slightly decreased to 43% in the absence of PPh3 (entry 2) and further optimization
revealed that base was unnecessary for this reaction (entry 3). To our surprise, when
the reaction was catalyzed by Pd(PPh3)2Cl2 with no any bases and phosphines, no 4aa
but
40%
yield
of
N-(tert-butyl)-2-(tert-butylimino)-2H-benzo[b][1,4]oxazin-3-amine
(5aa)
was
detected (entry 4). Among the Pd (0) catalysts tested, Pd(PPh3)4 was the best choice
for the formation of 4aa (entries 5, 6). Further screening of the catalytic reaction
conditions indicated that the cyclization product 4aa could not be formed without a
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palladium catalyst (entries 7-9). The yield of 4aa was increased, and the side product
3aa was reduced by decreasing the reaction temperature to room temperature (entries
10, 11). The screening of solvents showed that dioxane was the optimal solvent
(entries 12-15). The reaction proceeded well in air, but only 9% of 4aa was obtained
under argon atmosphere (entry 16). As expected, a higher yield (compared with entry
4) of 5aa was formed when the substrates were combined in a 1:2.4 ratio under the
treatment of Pd(PPh3)2Cl2 (entry 17). Further investigation revealed that 50 oC was the
most suitable reaction temperature for the formation of 5aa (entries 18, 19). On the
basis of screening of various palladium(II) salts, the highest yield for the formation of
5aa was achieved when PdCl2 was used (entries 20-23). Surprisingly, 4aa was
obtained in 87% yield while no 5aa was detected with Pd(OAc)2 in test (entry 23).
Notably, the reaction didn’t perform well for the formation of 5aa under argon
atmosphere (entry 24).
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Table 1. Optimization of Reaction Conditions a
entry
catalyst/ligand
base
solvent
temperature yield (3a)
yield
yield
(o C)
80
80
80
80
80
80
80
80
80
50
(%)
15
12
5
(4a) (%)b
(5a) (%)
Pd(PPh3)2Cl2/PPh
1
2
Cs2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
56
43
60
-
-
-
3
3
Pd(PPh3)2Cl2
Cs2CO3
Pd(PPh3)2Cl2/PPh
3
-
-
-
-
-
-
-
-
-
4
Pd(PPh3)2Cl2
Pd2(dba)3
Pd(PPh3)4
-
7
40
-
5
10
-
78
87
-
6
9
-
7
-
8
CuI
-
-
-
9
Cu(OAc)2
Pd(PPh3)4
-
-
-
10
-
92
5
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16c
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24c
Pd(PPh3)4
Pd(PPh )
-
-
-
-
-
-
-
-
-
-
-
-
-
-
dioxane
toulene
DMSO
DMF
rt
rt
-
-
99 (95)
-
15
78
91
83
9
-
7
3
4
4
4
4
4
Pd(PPh )
rt
-
3
Pd(PPh )
rt
-
6
3
CH CN
Pd(PPh )
rt
-
11
-
3
3
Pd(PPh )
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
rt
-
3
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Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
PdCl2
80
50
rt
9
4
-
-
79
90
85
98 (92)
79
61
-
-
-
50
50
50
50
50
2
4
8
3
12
-
PdBr2
-
PdI2
-
Pd(OAc)2
PdCl2
87
4
38
a
Reaction conditions: All reactions were performed with 1a (0.5 mmol), 2a (0.6 mmol, entries 1-16) or 2a (1.2 mmol, entries
17-24), catalyst (5 mol %), ligand (10 mol %), base (1.0 mmol), and 2.0 mL solvent under air atmosphere for 2 h unless
otherwise noted. b Yields and conversions analyzed by GC/MS are based on 1a. Number in parentheses is isolated yield.
c
Reaction performed under N2 atmosphere.
Substrate Scope for the Synthesis of 2-Aminobenzoxazoles. With the optimum
reaction conditions in hand (Table 1, entry 11), we turned our attention to the scope of
the palladium-catalyzed aerobic oxidative synthesis of 2-aminobenzoxazoles by using
various o-aminophenols as the substrates (Table 2). Generally, o-aminophenols with
electron-donating groups (Me, OMe, t-Bu) and weakly or moderately
electron-withdrawing groups (F, Cl, Br) afforded the corresponding
2-aminobenzoxazoles 4ba-4ha in excellent yields within 2 hours (entries 2-8).
Importantly, the successful preparation of 4ga and 4ha with intact chlorine or bromine
provided good opportunities for further formation of C-C or C-heteroatom bonds by
transition-metal-catalyzed coupling reactions. The treatment of acetyl, ester and
4,6-dichloro-substituted o-aminophenols could also generate the corresponding
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products 4ia-4ka in good yields but requiring higher temperatures and longer reaction
time (entries 9 and 11). However, the reaction activity of the o-aminophenols with
strong electron-withdrawing groups (NO2 and CN) was much lower than those with
electron-donating groups (Me, OMe, t-Bu) and moderately electron-withdrawing
groups (F, Cl, Br). Importantly, the methylsulfonyl and sulfonamide groups on
o-aminophenols were also tolerated in this transformation and gave the desired
products 4pa-4qa in good yields (entries 16 and 17). Importantly, we were pleased to
find that 3-amino-2-naphthol (1r) and 3, 3'-dihydroxybenzidine (1s) were also
compatible with this reaction system, generating the corresponding products in 96%
and 83% yields, respectively (entries 18 and 19). The reaction with heterocyclic
substrates such as 3-aminopyridin-2-ol (1t) was slower than o-aminophenols and gave
the corresponding product 4ta in moderate yield (entry 20). However, under the
present reaction conditions, only a trace amount of 4ua was detected when
2-amino-3-pyridinol (1u) was employed as the coupling partner (entry 21). The
observed lower reactivity for this type of substrate might stem from the low
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nucleophilicity of the aminopyridinols.
Table 2. Scope of o-Aminophenols for the Synthesis of 2-Aminobenzoxazoles a
entry
o-aminophenols (R1)
1a (R1 = H)
tert-butyl isocyanide (2a)
products
4aa
yield (%) b
1
2
3
4
5
6
95
93
91
96
93
92
2a
2a
2a
2a
2a
2a
1b (R1 = 4-Me)
1c (R1 = 5-Me)
1d (R1 = 4-OMe)
1e (R1 =4-t-Bu)
1f (R1 = 5-F)
4ba
4ca
4da
4ea
4fa
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1g (R1 = 4-Cl)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
4ga
4ha
4ia
7
94
93
87
84
85
84
75
88
78
88
85
96
4
5
6
7
8
9
1h (R1 = 4-Br)
1i (R1 = 4-COOMe)
1j (R1 = 3-COMe)
1k (R1 = 4,6-dichloro)
1l (R1 = 3-NO2)
8
9 c
10 c
11 c
12 d
13 d
14 d
15 d
16 c
17 c
18
4ja
4ka
4la
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13
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1m (R1 = 4-NO2)
4ma
4na
4oa
4pa
4qa
4ra
1n (R1 = 5-NO2)
1o (R1 = 4-CN)
1p (R1 = 4-methylsulfonyl)
1q (R1 = 4-sulfonamide)
19 e
83
2a
4sa
20 d, ,f
67
2a
2a
4ta
21 d, f, g
trace
4ua
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), dioxane (2.0 mL), at room temperature, under air atmosphere for 2 h unless
otherwise noted. b Isolated yield. 50 C for 8h. d 80 C for 12h. e 1.2 mmol of 1a was added. f 2.0 mL of DMSO was added
c
o
o
instead of dioxane. g 1u was recovered.
Moreover, various isocyanides were also applied to probe the scope of the reaction
substrates (Table 3). Fortunately, almost all the isocyanides were found suitable for
this transformation, affording the corresponding 2-aminobenzoxazoles in good to
excellent yields. Even if sterically bulky isocyanides such as 1,1,3,3-tetramethylbutyl
isocyanide (2b) and 2,6-dimethylphenyl isocyanide (2h) were used, the corresponding
4ab and 4ah were obtained in 89% and 85% yields, respectively (entries 1 and 7).
However, 4ag was obtained in 75% yield when 1-isocyano-4-methoxybenzene (2g)
was used (entry 6). In addition to the secondary (2d and 2f), tertiary (2a and 2b), and
aromatic isocyanides (2g and 2h), primary isocyanides (2c and 2e) were also effective
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in affording the corresponding 2-aminobenzoxazoles in good yields (entries 2 and 4).
Nevertheless, ethyl isocyanoacetate wasn’t effective under this set of conditions (entry
7
8
9
8).
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Table 3. Scope of Isocyanides for the Synthesis of 2-Aminobenzoxazoles a
entry
1
o-aminophenol (1a)
isocyanides (R2)
2b (R2 = 1,1,3,3-
tetramethylbutyl)
2c (R2 =
products yield (%) b
89
1a
4ab
2
81
1a
4ac
2-Morpholinoethyl)
2d (R2 = c-Hex)
2e (R2 = n-Bu)
2f (R2 = Bn)
3c
4
93
96
95
75
85
1a
1a
1a
1a
1a
4ad
4ae
4af
5
2g (R2 = 4-OMe-Ph )
2h (R2 =
4ag
4ah
6
7
2,6-dimethylbenzyl)
2i (R2 =
8
trace
1a
4ai
CH2COOC2H5)
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), dioxane (2.0 mL), at room temperature, under air atmosphere for 2 h unless
otherwise noted. b Isolated yield. c 1a was recovered.
Substrate Scope for the Synthesis of 3-Amino-2H-benzoxazines. The efficiency of
the expeditious palladium-catalyzed aerobic oxidative cyclization process for
2-aminobenzoxazoles
prompted
us
to
examine
the
synthesis
of
3-amino-2H-benzoxazines from o-aminophenols and two molecular isocyanides. As
shown in Table 4, the scope of o-aminophenols 1 for the aerobic oxidative cyclization
reaction was explored under the standard reaction conditions (Table 1, entry 20). The
method tolerated a wide range of substituents on o-aminophenols, including halogen,
acetyl, cyano, ester, nitro, and sulfonyl groups (Table 4). The results demonstrated
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that the electronic effect on o-aminophenols had only a little influence on the
formation of the desired 3-amino-2H-benzoxazines. In general, aryl rings substituted
with electron-rich functional groups (entries 2-5) and weakly or moderately
electron-withdrawing groups (entries 6-8) fared better than those with
electron-withdrawing groups (entries 9-15). Reactions of substrates bearing sulfonyl
groups led to excellent yields (entries 16-17), and most impressively even the
aminopyridinols with low nucleophilicity could also undergo the oxidative cyclization
efficiently and gave the corresponding products in good yields (entries 20-21).
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12
13
14
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17
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Table 4. Scope of o-Aminophenols for the Synthesis of 3-Amino-2H-benzoxazines a
t-Bu
NH2
OH
N
NH
N
PdCl2, 5 mol %
R1
R1
+
t-Bu
N
dioxane, 50 oC, air
t-Bu
O
1
2a
5
entry
1
o-aminophenols (R1)
1a (R1 = H)
tert-butyl isocyanide (2a) products yield (%) b
92
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
5aa
5ba
5ca
5da
5ea
5fa
1b (R1 = 4-Me)
1c (R1 = 5-Me)
1d (R1 = 4-OMe)
1e (R1 =4-t-Bu)
1f (R1 = 5-F)
2
96
90
97
95
93
89
87
78
77
82
86
83
85
87
89
86
97
3
4
5
6
1g (R1 = 4-Cl)
5ga
5ha
5ia
7
1h (R1 = 4-Br)
8
9 c
10 c
11 c
12d
13d
14d
15d
16 d
17 d
18
1i (R1 = 4-COOMe)
1j (R1 = 3-COMe)
1k (R1 = 4,6-dichloro)
1l (R1 = 3-NO2)
1m (R1 = 4-NO2)
1n (R1 = 5-NO2)
1o (R1 = 4-CN)
5ja
5ka
5la
5ma
5na
5oa
5pa
5qa
5ra
1p (R1 = 4-methylsulfonyl)
1q (R1 = 4-sulfonamide)
19 e
2a
5sa
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20 d,,f
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76
2a
2a
5ta
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21 d,,f
5ua
7
8
9
a
o
Reaction conditions: 1a (0.5 mmol), 2a (1.2 mmol), dioxane (2.0 mL), 50 C, under air atmosphere for 2 h unless otherwise
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noted. b Isolated yield. c 4 h. d 8 h. e 2.4 mmol of 1a was added. f 2.0 mL of DMSO was added instead of dioxane.
Moreover, we were pleased to find that various isocyanides could be successfully
extended to the corresponding 3-amino-2H-benzoxazines in good to excellent yields
(Table 5, entries 1-7). Unfortunately, when ethyl isocyanoacetate was applied to this
process under the optimized reaction conditions, the desired product was detected by
GC-MS, the reaction system was very complicated and failed to obtain the pure
product
(entry
8).
Furthermore,
we
were
able
to
access
3-amino-2H-benzo[b][1,4]oxazin-2-ones by a one-pot simple acid hydrolysis
sequence. Addition of HOAc to the reaction mixture (after the formation of 5aa was
completed) and subsequent heated at 80 oC for 12
h
generated
3-(tert-butylamino)-2H-benzo[b][1,4]oxazin-2-one (6aa) in an excellent 88 % yield
(Table 5, entry 9). This process, providing one of the simplest methods for the
synthesis of this class of valuable 3-aminobenzoxazin-2-ones, involved two steps
including cyclization reaction and simple acid hydrolysis.
Table 5. Scope of Isocyanides for the Synthesis of 3-Amino-2H-benzoxazines a
R2
NH2
OH
N
NH
PdCl2, 5 mol %
R2
N
+
R2
dioxane, 50 oC, air
O
N
1a
2
5
entry
1
o-aminophenol (1a)
isocyanides (R2)
2b (R2 = 1,1,3,3-
tetramethylbutyl)
2c (R2 =
products
yield (%) b
94
1a
5ab
2
82
1a
5ac
2-Morpholinoethyl)
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7
1a
1a
1a
1a
2d (R2 = c-Hex)
2e (R2 = n-Bu)
2f (R2 = Bn)
2g (R2 =
5ad
5ae
5af
5ag
3
4
5
6
95
89
94
87
8
9
4-OMe-Ph )
2h (R2 =
7
8
92
complicated
88
1a
1a
1a
5ah
5ai
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2,6-dimethylbenzyl)
2i (R2 =
CH2COOC2H5)
2a (R2 = t-Bu)
9 c
a
o
Reaction conditions: 1a (0.5 mmol), 2a (1.2 mmol), dioxane (2.0 mL), 50 C, under air atmosphere for 2 h unless otherwise
noted. b Isolated yield. c HOAc (5.0 equiv.) was added after 2 h, then12 h under 80 oC.
Application to the Synthesis of Various Other Important N-Heterocycles. With
the above results in hand, we envisioned that other bisnucleophiles could be also
extended to the synthesis of other types of useful nitrogen heterocycles (Table 6). Not
surprisingly, corresponding 6-amino-dibenzo[d,f][1,3]oxazepines (8aa-8ca) were
obtained in good yields when 2'-amino-[1,1'-biphenyl]-2-ols were applied to the
reaction system (entries 1-3). Importantly, the oxidative cyclization could proceed
smoothly by the use of aliphatic alcohols (7d) or aliphatic amines (7e), giving the
desired
2-amino-4H-benzo[d][1,3]oxazines
(8da-8db)
and
2-amino-4H-benzo[e][1,3]oxazines (8ea-8eb), respectively. Unfortunately, when
salicylamide and 2-hydroxybenzothioamide (7f) were employed in this process, only
trace amount of the desired products (8fa) were detected even at raised reaction
temperature.
Fortunately,
2-amino-thiophenol
(7g)
transferred
to
2-(tert-butylamino)benzothiazole (8ga) in 91 % yield. Interestingly, 8ha was obtained
in 88% yield when 2-amino-4-(trifluoromethyl)thiophenol hydrochloride (7h) was
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used, which was caused by the cleavage of the tert-butylamino group. As expected,
when 2-(methylamino)phenol (7i) was examined in the Pd(PPh3)4 catalyst system,
90% yield of the desired product 8ia was obtained. However, no desired product 9
was detected when 7i was conducted in the PdCl2 catalyst system. These results
suggested that the primary amino group was essential for the double insertions of
isocyanides.
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Table 6. Substrate Scope of the Aerobic Oxidative Coupling of Various
Bisnucleophiles and Isocyanides.a
R2
O
n
n
OH
Pd(PPh3)4, 5 mol %
dioxane, RT, air
R1
(n=0,1)
NH
2
+
R
N
R1
NH2
n
N
n
7
2
8
entry
bisnucleophiles (7)
isocyanides (2)
products (8)
yield (%) b
(8aa) 94
(8ba) 85
(8ca) 89
H2N
1
2
3
R1
7a: R1= H;
7b: R1= F;
7c: R1= Cl;
2a
OH
2a
2b
(8da) 95
(8db) 91
OH
4
5
NH2
7d
2a
2b
(8ea) 93
(8eb) 95
OH
NH2
7e
X
X
N
6 c
(8fa) n.r
2a
2a
2a
NH2
t-Bu
O
N
H
X = O,S
OH
7f
7
8
(8ga: R2 = t-BuNH)
91
(8ha: R2 = H) 88
(8ia) 90
H
N
9
N
O
N
OH
7i
t-Bu
N
O
N
10 d
(9) n.d
7i
2a
t-Bu
N
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a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), dioxane (2.0 mL), at room temperature, under air atmosphere for 2 h unless
otherwise noted; n.r = no reaction; n.d = not detected. b Isolated yield. c 80 oC for 12h. d 1.2 mmol of 2a was added, Pd(PPh3)4 was
replaced by PdCl2 (5 mol %), 50 oC for 10h.
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Mechanistic Studies of the Synthesis of 2-Aminobenzoxazoles and
3-Aminobenzoxazines. On the basis of some related work13e,16 and the control
experiments (see the Supporting Information) we proposed the mechanism shown in
Scheme 2. For the formation of 2-aminobenzoxazoles (4), two alternative paths (a and
b) were presented. Initial oxidation of [Pd(PPh3)4] by molecular oxygen affords the
[(η-O2)Pd(PPh3)2] complex.17 In path a, nucleophilic addition of o-aminophenols (2)
to isocyanide (3) gave the carbene intermediate A, which underwent coordination
with Pd(II) species to generate a palladium complex B. Subsequent ligand
dissociation would result in the formation of intermediate C and regenerate the Pd(II)
species. Finally, aerobic oxidation of C provided the final product 4.18 Besides, the
deamination of the intermediate C led to the formation of the side product 3. In path b,
[(η-O2)Pd(PPh3)2] complex reacted with 1 to form intermediate D and H2O2.
Subsequent migratory insertion of 2 would led to the formation of intermediate E,
subsequently reductive elimination to afford 4. At last, the palladium(0) species was
reoxidized to palladium(II) by air in the system to complete the cycle. On the other
hand, compound 3 could not be generated from 4 under the standard conditions (see
the Supporting Information). Thus, the formation of 2-aminobenzoxazoles through
path b was predicted. For the formation of 3-aminobenzoxazines (path c), PdCl2
reacted with 1 to provide intermediate G. The subsequent double insertion reaction
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with 2 led to the formation of the seven-membered azapalladacyclic intermediate H,
which underwent reductive elimination to generate the intermediate I. Immediately,
isomerization of unstable intermediate I gave the final product 3-aminobenzoxazines
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(5).
Scheme 2. Proposed Mechanism
CONCLUSION
In conclusion, a practical and general protocol for the Pd-catalyzed aerobic oxidation
of o-aminophenols with isocyanides to the synthesis of 2-aminobenzoxazoles and
3-aminobenzoxazines has been exploited under aerobic conditions. This method was
applicable to large synthetic scope with wide functional group compatibility for
o-aminophenols and isocyanides, and gave the corresponding products in good to
excellent yields. Further, this transformation was successfully applied to the synthesis
of other types of important N-heterocyclic systems. The readily available starting
reagents and mild conditions were some of the additional features of this protocol.
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EXPERIMENTAL SECTION
5
6
7
8
General Procedures. All reactions were carried out in 10 mL tubes under air atmosphere. TLC
was performed by using commercially prepared 100–400 mesh silica gel plates (GF254) and
visualization was effected at 254 nm. All reagents were purchased as reagent grade and used
without further purification. Melting points were measured with a micro melting point apparatus.
1H NMR spectra were recorded at 400 MHz using TMS as an internal standard and 13C NMR
spectra at 100, using CDCl3. The chemical shifts are referenced to signals at 7.24 and 77.0 ppm,
respectively. IR spectra were obtained either as potassium bromide pellets or as liquid films
between two potassium bromide pellets with an infrared Fourier spectrometer. High-resolution
mass spectra (ESI) were obtained with a LCMS-IT-TOF mass spectrometer.
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General Procedure for the Synthesis of 2-Aminobenzoxazoles. o-Aminophenols 1a-u (0.5
mmol), isocyanides 2a-i (0.6 mmol), Pd(PPh3)4 (5 mol %, 29.0 mg) were stirred at room
temperature in dioxane (2 mL) under air. After stirring for the appropriate time, the reaction
mixture was cooled to room temperature and passed through a short pad of silica gel using a
mixture of ethyl acetate/petroleum ether (5:1) as eluent to accomplish the target
2-aminobenzoxazoles 4 in analytically pure form.
General Procedure for the Synthesis of 3-Aminobenzoxazines. o-Aminophenols 1a-u (0.5
mmol), isocyanides 2a-i (1.2 mmol), PdCl2 (5 mol %, 4.4 mg) were stirred at 50 oC in dioxane (2
mL) under air. After stirring for the appropriate time, the reaction mixture was cooled to room
temperature and passed through a short pad of silica gel using a mixture of ethyl acetate/petroleum
ether (10:1) as eluent to accomplish the target 3-aminobenzoxazines 5 in analytically pure form.
N-(tert-butyl)benzo[d]oxazol-2-amine (4aa) (known compound) 8e,10b: Light yellow solid (90
mg, 95%), mp 100-102 °C. 1H NMR (400 MHz, CDCl3) δ ppm 7.35 (d, J = 8.0 Hz, 1H), 7.23 (d, J
= 7.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 5.77 (br. s, 1H), 1.48 (s, 9H). 13
C
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NMR (100 MHz, CDCl3) δ ppm 161.1, 148.1, 143.0, 123.6, 120.4, 116.1, 108.5, 52.0, 29.2.
N-(tert-butyl)-5-methylbenzo[d]oxazol-2-amine (4ba): Light yellow solid (95mg, 93%), mp
93-95 oC. IR (KBr): 2975, 1765, 1647, 1588, 1243 cm−1. 1H NMR (400 MHz, CDCl3) δ ppm 7.16
(s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.60 (br. s, 1H), 2.37 (s, 3H), 1.47 (s,
9H). 13C NMR (100 MHz, CDCl3) δ ppm 161.3, 146.3, 143.1, 133.2, 121.1, 116.6, 107.8, 51.9,
29.2, 21.4. HRMS (ESI) m/z: calcd for C12H17N2O+ 205.1335; found, 205.1339.
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N-(tert-butyl)-6-methylbenzo[d]oxazol-2-amine (4ca): Yellow solid (93mg, 91%), mp 104-106
oC. IR (KBr): 2972, 1764, 1642, 1579, 1244 cm−1. 1H NMR (400 MHz, CDCl3) δ ppm 7.23 (d, J =
8.0 Hz, 1H), 7.05 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.29 (br. s, 1H), 2.38 (s, 3H), 1.47 (s, 9H). 13
C
NMR (100 MHz, CDCl3) δ ppm 160.6, 148.3, 140.7, 130.5, 124.3, 115.7, 109.1, 51.9, 29.2, 21.4.
HRMS (ESI) m/z: calcd for C12H17N2O+ 205.1335; found, 205.1340.
N-(tert-butyl)-5-methoxybenzo[d]oxazol-2-amine (4da): Brown solid (106mg, 96%), mp
o
1
111-113 C. IR (KBr): 3346, 2966, 1639, 1584, 1154 cm−1. H NMR (400 MHz, CDCl3) δ ppm
7.07 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 2.8 Hz, 1H), 6.53 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 5.91 (br.
s, 1H), 3.75 (s, 3H), 1.44 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 161.9, 156.7, 143.8, 142.6,
+
108.2, 106.7, 101.3, 55.7, 51.8, 29.1. HRMS (ESI) m/z: calcd for C12H17N2O2 , 221.1285; found,
221.1274.
N,5-di-tert-butylbenzo[d]oxazol-2-amine (4ea): Brown solid (121mg, 93%), mp 113-115 oC. IR
1
(KBr): 2963, 1647, 1585, 1429, 1220 cm−1. H NMR (400 MHz, CDCl3) δ ppm 7.44 (d, J = 1.6
Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.05 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 5.20 (br. s, 1H), 1.48 (s,
9H), 1.33 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 161.0, 147.1, 146.0, 142.9, 117.7, 113.4,
107.5, 51.9, 34.8, 31.8, 29.1. HRMS (ESI) m/z: calcd for C15H23N2O+, 247.1805; found, 247.1807.
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o
N-(tert-butyl)-6-fluorobenzo[d]oxazol-2-amine (4fa): Yellow solid (96mg, 92%), mp 85-87 C.
5
6
7
IR (KBr): 2973, 1651, 1593, 1480, 1124 cm−1. 1H NMR (400 MHz, CDCl3) δ ppm 7.26-7.23 (m,
8
9
1H), 6.99 (dd, J1 = 2.4 Hz, J2 = 8.0 Hz, 1H), 6.90-6.85 (m, 1H), 5.29 (br. s, 1H), 1.48 (s, 9H). 13
C
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NMR (100 MHz, CDCl3) δ ppm 161.1, 157.9 (J = 236.8 Hz), 147.7 (J = 14.4 Hz), 139.2, 115.8 (J
= 9.5 Hz), 110.4 (J = 23.5 Hz), 97.3 (J = 28.5 Hz), 52.1, 29.1. HRMS (ESI) m/z: calcd for
C11H14FN2O+, 209.1085; found, 209.1088.
N-(tert-butyl)-5-chlorobenzo[d]oxazol-2-amine (4ga): Yellow solid (105mg, 94%), mp 84-96 oC.
IR (KBr): 2961, 1654, 1573, 1453, 1213 cm−1. 1H NMR (400 MHz, CDCl3) δ ppm 7.29 (d, J = 1.6
Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.94 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 5.68 (br. s, 1H), 1.47 (s,
9H). 13C NMR (100 MHz, CDCl3) δ ppm 161.9, 146.8, 144.4, 129.0, 120.3, 116.2, 109.0, 52.2,
29.1. HRMS (ESI) m/z: calcd for C11H14ClN2O+, 225.0789; found, 225.0786 (100.0%), 227.0776
(32.0%).
5-bromo-N-(tert-butyl)benzo[d]oxazol-2-amine (4ha): Brown solid (125mg, 93%), mp 102-104
oC. IR (KBr): 3148, 2962, 1659, 1570, 1453, 1218 cm−1. 1H NMR (400 MHz, CDCl3) δ ppm 7.42
(s, 1H), 7.09-7.04 (m, 2H), 6.02 (br. s, 1H), 1.46 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm
161.8, 147.1, 144.7, 123.0, 119.0, 116.3, 109.5, 52.2, 29.1. HRMS (ESI) m/z: calcd for
C11H14BrN2O+, 269.0284; found, 269.0287 (100.0%), 271.0267 (98.2%).
methyl-2-(tert-butylamino)benzo[d]oxazole-5-carboxylate (4ia): Yellow solid (108mg, 87%),
mp 184-186 oC. IR (KBr): 3347, 1705, 1642, 1580, 1442, 1289 cm−1. 1H NMR (400 MHz, CDCl3)
δ ppm 8.00 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5.71 (br. s, 1H), 3.87 (s, 3H),
1.47 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 167.2, 161.6, 151.3, 143.3, 126.0, 123.0, 117.6,
+
108.1, 52.2, 52.0, 29.0. HRMS (ESI) m/z: calcd for C13H17N2O3 , 249.1234; found, 249.1230.
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1-(2-(tert-butylamino)benzo[d]oxazol-7-yl)ethanone (4ja): Brown solid (97mg, 84%), mp
5
6
7
o
116-118 C. IR (KBr): 3320, 2973, 1639, 1569, 1430, 1212 cm−1. 1H NMR (400 MHz, CDCl3) δ
8
9
ppm 7.74 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 5.42 (br. s, 1H),
2.88 (s, 3H), 1.48 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 198.1, 160.8, 149.0, 144.3, 125.4,
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+
123.4, 119.5, 112.2, 52.2, 30.9, 28.7. HRMS (ESI) m/z: calcd for C13H17N2O2 , 233.1285; found,
233.1289.
N-(tert-butyl)-5,7-dichlorobenzo[d]oxazol-2-amine (4ka): Brown solid (110mg, 85%), mp
o
143-145 C. IR (KBr): 3153, 2969, 1765, 1662, 1571, 1240 cm−1. 1H NMR (400 MHz, CDCl3) δ
ppm 7.18 (s, 1H), 6.97 (s, 1H), 5.59 (br. s, 1H), 1.47 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm
161.4, 145.2, 143.3, 129.3, 120.7, 115.0, 114.0, 52.5, 29.0. HRMS (ESI) m/z: calcd for
C11H13Cl2N2O+, 259.0399; found, 259.0399 (100.0%), 261.0371(63.9%), 263.0345(10.2%).
N-(tert-butyl)-4-nitrobenzo[d]oxazol-2-amine (4la): Brown solid (99mg, 84%), mp 131-133 oC.
IR (KBr): 2975, 1764, 1645, 1576, 1207 cm−1. 1H NMR (400 MHz, CDCl3) δ ppm 7.94 (d, J = 8.8
Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 8.2 Hz, 1H), 6.21 (br. s, 1H), 1.46 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ ppm 164.1, 150.6, 139.4, 135.7, 119.9, 118.9, 113.6, 53.0, 29.2. HRMS (ESI)
+
m/z: calcd for C11H14N3O3 , 236.1030; found, 236.1031.
N-(tert-butyl)-5-nitrobenzo[d]oxazol-2-amine (4ma): Brown solid (88mg, 75%), mp 168-170 oC.
1
IR (KBr): 3349, 3205, 2968, 1665, 1218 cm−1. H NMR (400 MHz, CDCl3) δ ppm 8.19 (s, 1H),
7.99 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 5.84 (br. s, 1H), 1.53 (s, 9H). 13C NMR (100
MHz, CDCl3) δ ppm 162.4, 152.1, 144.9, 144.1, 117.1, 111.6, 108.0, 52.5, 28.9. HRMS (ESI) m/z:
+
calcd for C11H14N3O3 , 236.1030; found, 236.1033.
N-(tert-butyl)-6-nitrobenzo[d]oxazol-2-amine (4na): Brown solid (103mg, 88%), mp 139-141
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oC. IR (KBr): 3350, 2965, 1667, 1588, 1322, 1281, 1210 cm−1. H NMR (400 MHz, CDCl3) δ
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ppm 8.12 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 8.08 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 5.92 (br. s, 1H),
1.50 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 163.7, 157.1, 147.2, 141.4, 121.1, 114.9, 104.8,
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52.8, 29.0. HRMS (ESI) m/z: calcd for C11H14N3O3 , 236.1030; found, 236.1032.
2-(tert-butylamino)benzo[d]oxazole-5-carbonitrile (4oa): Yellow solid (84mg, 78%), mp 91-93
oC. IR (KBr): 3366, 2970, 2226, 1651, 1584, 1169 cm−1. 1H NMR (400 MHz, CDCl3) δ ppm 8.27
(s, 1H), 7.71-7.67 (m, 2H), 5.89 (br. s, 1H), 1.50 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm
161.7, 154.3, 129.5, 125.2, 125.1, 119.4, 112.3, 109.1, 52.3, 28.7. HRMS (ESI) m/z: calcd for
C12H12N3O-, 214.0986; found, 214.0989.
N-(tert-butyl)-5-(methylsulfonyl)benzo[d]oxazol-2-amine (4pa): Brown solid (118mg, 88%),
mp 134-136 oC. IR (KBr): 3340, 2926, 1646, 1576, 1254, 1140 cm−1. 1H NMR (400 MHz, CDCl3)
δ ppm 7.87 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.48 (br. s, 1H), 3.02 (s, 3H),
1.48 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 161.9, 151.3, 144.3, 136.1, 120.5, 115.4, 108.8,
52.5, 44.9, 28.9. HRMS (ESI) m/z: calcd for C12H17N2O3S+, 269.0954; found, 269.0966.
2-(tert-butylamino)benzo[d]oxazole-5-sulfonamide (4qa): Brown solid (114mg, 85%), mp
139-141 oC. IR (KBr): 3342, 2976, 1725, 1646, 1577, 1154 cm−1. 1H NMR (400 MHz, d-acetone)
δ ppm 7.81 (d, J = 1.2 Hz, 1H), 7.61 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H),
7.01 (br. s, 1H), 6.56 (br. s, 2H), 1.51 (s, 9H). 13C NMR (100 MHz, d-acetone) δ ppm 163.1, 150.9,
145.1, 140.7, 119.9, 114.6, 109.1, 52.7, 29.0. HRMS (ESI) m/z: calcd for C11H16N3O3S+, 270.0907;
found, 270.0899.
N-(tert-butyl)naphtho[2,3-d]oxazol-2-amine (4ra): Brown solid (115mg, 96%), mp 112-114 oC.
1
IR (KBr): 3399, 2970, 1642, 1585, 1444, 1220 cm−1. H NMR (400 MHz, CDCl3) δ ppm
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7.85-7.81 (m, 2H), 7.70 (s, 1H), 7.58 (s, 1H), 7.40-7.34 (m, 2H), 5.66 (br. s, 1H), 1.54 (s, 9H). 13
C
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NMR (100 MHz, CDCl3) δ ppm 162.0, 148.2, 143.5, 131.7, 129.4, 127.5, 127.5, 124.2, 123.7,
111.9, 104.2, 52.3, 29.2. HRMS (ESI) m/z: calcd for C15H17N2O+, 241.1335; found, 241.1332.
N2,N2'-di-tert-butyl-[6,6'-bibenzo[d]oxazole]-2,2'-diamine (4sa): Brown solid (157mg, 83%),
mp 125-127 oC. IR (KBr): 3188, 2964, 1766, 1649, 1463, 1235 cm−1. 1H NMR (400 MHz, CDCl3)
δ ppm 7.44 (s, 2H), 7.42-7.34 (m, 4H), 5.11 (br. s, 2H), 1.50 (s, 18H). 13C NMR (100 MHz, CDCl3)
δ ppm 161.0, 148.8, 142.3, 134.8, 123.0, 116.2, 107.3, 52.1, 29.2. HRMS (ESI) m/z: calcd for
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C22H27N4O2 , 379.2129; found, 379.2128.
o
N-(tert-butyl)oxazolo[4,5-b]pyridin-2-amine (4ta): Brown solid (64mg, 67%), mp 117-119 C.
1
IR (KBr): 3239, 2971, 1765, 1646, 1579, 1402, 1203 cm−1. H NMR (400 MHz, CDCl3) δ ppm
7.88 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.07 (dd, J1 = 4.8 Hz, J2 = 7.6 Hz, 1H), 5.77 (br.
s, 1H), 1.48 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 160.2, 157.7, 138.8, 135.5, 122.9, 120.2,
52.4, 29.1. HRMS (ESI) m/z: calcd for C10H14N3O+, 192.1131; found, 192.1128.
N-(2,4,4-trimethylpentan-2-yl)benzo[d]oxazol-2-amine (4ab): Brown solid (109mg, 89%), mp
o
1
95-97 C. IR (KBr): 2954, 1766, 1651, 1581, 1461, 1244 cm−1. H NMR (400 MHz, CDCl3) δ
ppm 7.35 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.15-7.11 (m, 1H), 7.01-6.97 (m, 1H), 5.70
(br. s, 1H), 1.84 (s, 2H), 1.53 (s, 6H), 1.00 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 160.8,
148.1, 143.1, 123.6, 120.3, 116.1, 108.4, 55.7, 51.8, 31.4, 29.7. HRMS (ESI) m/z: calcd for
C15H23N2O+, 247.1805; found, 247.1807.
N-(2-morpholinoethyl)benzo[d]oxazol-2-amine (4ac): Yellow oil (100mg, 81%). IR (KBr):
3856, 3745, 2926, 1765, 1649, 1398, 1243, 1115 cm−1. 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (d,
J = 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 5.73
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(br. s, 1H), 3.69 (t, J = 4.2 Hz, 4H), 3.54 (t, J = 5.6 Hz, 2H), 2.62 (t, J = 5.8 Hz, 2H), 2.48 (s, 4H).
13C NMR (100 MHz, CDCl3) δ ppm 162.0, 148.5, 142.9, 123.8, 120.8, 116.3, 108.6, 66.8, 56.8,
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+
53.2, 39.0. HRMS (ESI) m/z: calcd for C13H18N3O2 , 248.1394; found, 248.1396.
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N-cyclohexylbenzo[d]oxazol-2-amine (4ad) (known compound)8e,10b: Yellow solid (100mg,
93%), mp 109-111 oC. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz,
1H), 7.13 (t, J = 7.8 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 5.41 (br. s, 1H), 3.80–3.67 (m, 1H),
2.12–2.05 (m, 2H), 1.77–1.74 (m, 2H), 1.65–1.61 (m, 1H), 1.46–1.37 (m, 2H), 1.33–1.19 (m, 3H).
13C NMR (100 MHz, CDCl3) δ ppm 161.5, 148.3, 143.0, 123.8, 120.5, 116.0, 108.6, 52.0, 33.4,
25.4, 24.7.
N-butylbenzo[d]oxazol-2-amine (4ae) (known compound)8d,8e: White solid (91mg, 96%), mp
o
1
90-92 C. H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H),
7.15–7.11 (m, 1H), 7.00–6.96 (m, 1H), 6.15 (br. s, 1H), 3.45 (t, J = 7.2 Hz, 2H), 1.68–1.60 (m,
2H), 1.45–1.38 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ ppm 162.4,
148.3, 142.9, 123.7, 120.4, 115.8, 108.6, 42.7, 31.7, 19.8, 13.6.
N-benzylbenzo[d]oxazol-2-amine (4af) (known compound)8e,10b: White solid ( 106mg, 95%),
mp 110-112 oC. 1H NMR (400 MHz, CDCl3) δ 7.36–7.25 (m, 5H), 7.21–7.19 (m, 2H), 7.13–7.09
(m, 1H), 7.00–6.97 (m, 1H), 6.41 (br. s, 1H), 4.63 (s, 2H). 13C NMR (100 MHz, CDCl3) δ ppm
162.1, 148.4, 142.7, 137.7, 128.7, 127.7, 127.5, 123.9, 120.8, 116.2, 108.7, 46.9.
N-(4-methoxyphenyl)benzo[d]oxazol-2-amine (4ag) (known compound)19: Brown solid (90mg,
75%), mp 137-139 oC. 1H NMR (400 MHz, CDCl3) δ 7.50–7.45 (m, 2H), 7.40 (d, J = 7.6 Hz, 1H),
7.30 (d, J = 8.0 Hz, 1H), 7.21–7.18 (m, 1H), 7.10–7.06 (m, 1H), 6.94–6.91 (m, 2H), 3.80 (s, 3H).
13C NMR (100 MHz, CDCl3) δ ppm 159.4, 156.1, 147.9, 142.1, 131.0, 124.2, 121.4, 121.0, 116.5,
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N-(2,6-dimethylphenyl)benzo[d]oxazol-2-amine (4ah): Yellow solid (101mg, 85%), mp
195-197 oC. IR (KBr): 2920, 1662, 1581, 1461, 1214, 746 cm−1. 1H NMR (400 MHz, d-DMSO) δ
9.53 (br. s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.15–7.11 (m, 4H), 7.02 (t, J =
7.6 Hz, 1H), 2.22 (s, 6H). 13C NMR (100 MHz, d-DMSO) δ ppm 160.3, 148.1, 143.1, 135.6,
135.0, 128.1, 126.8, 123.7, 120.5, 115.8, 108.7, 17.9. HRMS (ESI) m/z: calcd for C15H15N2O+,
239.1179; found, 239.1182.
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N-(tert-butyl)-2-(tert-butylimino)-2H-benzo[b][1,4]oxazin-3-amine (5aa): White solid (126mg,
1
92%), mp 128-130 oC. IR (KBr): 3748, 3375, 2960, 1659, 1613, 1514, 1222, 739 cm−1. H NMR
(400 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 1H), 7.12–6.99 (m, 3H), 6.55 (br. s, 1H), 1.55 (s, 9H),
1.43 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 146.8, 143.5, 138.3, 132.7, 125.4, 123.8, 122.8,
114.6, 53.7, 51.4, 29.6, 28.5. HRMS (ESI) m/z: calcd for C16H24N3O+, 274.1914; found, 274.1916.
N-(tert-butyl)-2-(tert-butylimino)-6-methyl-2H-benzo[b][1,4]oxazin-3-amine (5ba): Light
yellow solid (138mg, 96%), mp 100-102 oC. IR (KBr): 3368, 2966, 1669, 1620, 1579, 1524, 1223,
801 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.79–6.77 (m, 1H),
6.50 (br. s, 1H), 2.32 (s, 3H), 1.50 (s, 9H), 1.38 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm
147.0, 141.4, 138.6, 133.3, 132.3, 125.7, 123.4, 114.2, 53.7, 51.4, 29.6, 28.5, 20.8. HRMS (ESI)
m/z: calcd for C17H26N3O+, 288.2070; found, 288.2073.
N-(tert-butyl)-2-(tert-butylimino)-7-methyl-2H-benzo[b][1,4]oxazin-3-amine (5ca): Light
yellow solid (129mg, 90%), mp 110-112 oC. IR (KBr): 3371, 2967, 1670, 1620, 1588, 1516, 1232,
1164 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.84
(s, 1H), 6.42 (br. s, 1H), 2.33 (s, 3H), 1.50 (s, 9H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
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ppm 146.4, 143.2, 138.5, 132.9, 130.2, 125.1, 124.5, 115.0, 53.7, 51.3, 29.6, 28.6, 20.9. HRMS
(ESI) m/z: calcd for C17H26N3O+, 288.2070; found, 288.2075.
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N-(tert-butyl)-2-(tert-butylimino)-6-methoxy-2H-benzo[b][1,4]oxazin-3-amine (5da): Brown
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solid (147mg, 97%), mp 105-107 C. IR (KBr): 3365, 2968, 1764, 1669, 1580, 1242, 1143, 1045
cm−1. 1H NMR (400 MHz, CDCl3) δ 6.92 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 3.2 Hz, 1H), 6.57–6.55
(m, 2H), 3.81 (s, 3H), 1.51 (s, 9H), 1.38 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 156.2,
147.2, 138.6, 137.9, 133.3, 114.9, 109.5, 109.2, 55.7, 53.7, 51.5, 29.7, 28.6. HRMS (ESI) m/z:
+
calcd for C17H26N3O2 , 304.2020; found, 304.2021.
N,6-di-tert-butyl-2-(tert-butylimino)-2H-benzo[b][1,4]oxazin-3-amine (5ea): White solid
o
1
(156mg, 95%), mp 135-137 C. IR (KBr): 3369, 2965, 2361, 1765, 1579, 1240, 1056 cm−1. H
NMR (400 MHz, CDCl3) δ 7.33 (d, J = 2.0 Hz, 1H), 7.06–7.03 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H),
6.53 (br. s, 1H), 1.54 (s, 9H), 1.41 (s, 9H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm
147.0, 147.0, 141.3, 138.6, 132.0, 122.3, 120.0, 114.0, 53.7, 51.4, 34.3, 31.6, 29.6, 28.6. HRMS
(ESI) m/z: calcd for C20H32N3O+, 330.2540; found, 330.2551.
N-(tert-butyl)-2-(tert-butylimino)-7-fluoro-2H-benzo[b][1,4]oxazin-3-amine (5fa): Brown solid
o
1
(135mg, 93%), mp 102-104 C. IR (KBr): 3374, 2964, 2361, 1764, 1616, 1240 cm−1. H NMR
(400 MHz, CDCl3) δ 7.21–7.18 (m, 1H), 6.80–6.72 (m, 2H), 6.40 (br. s, 1H), 1.48 (s, 9H), 1.36 (s,
9H). 13C NMR (100 MHz, CDCl3) δ ppm 158.5 (J = 240.7 Hz), 146.1, 143.5 (J = 12.3 Hz),
137.4, 129.1, 125.8 (J = 9.2 Hz), 110.6 (J = 22.1 Hz), 102.3 (J = 26.4 Hz), 53.9, 51.4, 29.6, 28.5.
HRMS (ESI) m/z: calcd for C16H23FN3O+, 292.1820; found, 292.1818 .
N-(tert-butyl)-2-(tert-butylimino)-6-chloro-2H-benzo[b][1,4]oxazin-3-amine (5ga):
Light
yellow solid (137mg, 89%), mp 162-164 oC. IR (KBr): 3373, 2963, 2362, 1667, 1611, 1573, 1240
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cm−1. 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 6.92–6.88 (m, 2H), 6.57 (br. s, 1H), 1.48 (s, 9H),
1.36 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 147.2, 142.1, 137.6, 133.8, 128.6, 124.9, 122.4,
115.4, 53.9, 51.7, 29.6, 28.5. HRMS (ESI) m/z: calcd for C16H23ClN3O+, 308.1524; found,
308.1522 (100.0%), 310.1518 (32.0%).
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6-bromo-N-(tert-butyl)-2-(tert-butylimino)-2H-benzo[b][1,4]oxazin-3-amine (5ha): Yellow
o
solid (153mg, 87%), mp 180-182 C. IR (KBr): 3369, 2961, 2361, 1764, 1569, 1242, 1056 cm−1.
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 2.0 Hz, 1H), 7.04 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H),
6.85 (d, J = 8.8 Hz, 1H), 6.57 (br. s, 1H), 1.48 (s, 9H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ ppm 147.2, 142.5, 137.6, 134.2, 127.9, 125.2, 116.0, 115.8, 54.0, 51.7, 29.6, 28.4. HRMS (ESI)
m/z: calcd for C16H23BrN3O+, 352.1019; found, 352.1025 (100.0%), 354.1012 (98.2%).
methyl-3-(tert-butylamino)-2-(tert-butylimino)-2H-benzo[b][1,4]oxazine-6-carboxylate (5ia):
Light yellow solid (129mg, 78%), mp 128-130 oC. IR (KBr): 3367, 2967, 2360, 1724, 1617, 1578,
1237 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.0 Hz, 1H), 7.65 (dd, J1 = 2.0 Hz, J2 = 8.4
Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.49 (br. s, 1H), 3.88 (s, 3H), 1.48 (s, 9H), 1.36 (s, 9H). 13C
NMR (100 MHz, CDCl3) δ ppm 166.7, 146.9, 146.8, 137.2, 132.5, 127.0, 125.9, 124.4, 114.5,
+
54.0, 51.9, 51.6, 29.6, 28.4. HRMS (ESI) m/z: calcd for C18H26N3O3 , 332.1969; found, 332.1977.
1-(3-(tert-butylamino)-2-(tert-butylimino)-2H-benzo[b][1,4]oxazin-5-yl)ethanone
(5ja):
Brown solid (121mg, 77%), mp 125-127 oC. IR (KBr): 3353, 2969, 1765, 1678, 1602, 1240 cm−1.
1H NMR (400 MHz, CDCl3) δ 7.31–7.29 (m, 1H), 7.08 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H), 6.96 (t,
J = 7.8 Hz, 1H), 6.75 (br. s, 1H), 2.77 (s, 3H), 1.47 (s, 9H), 1.36 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ ppm 202.8, 146.3, 143.5, 137.4, 135.6, 131.5, 123.7, 122.2, 117.6, 53.9, 51.4, 32.4, 29.6,
+
28.4. HRMS (ESI) m/z: calcd for C18H26N3O2 , 316.2020; found, 316.2024.
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N-(tert-butyl)-2-(tert-butylimino)-6,8-dichloro-2H-benzo[b][1,4]oxazin-3-amine (5ka): White
solid (140m, 82%), mp 183-185 oC. IR (KBr): 3369, 2991, 1764, 1608, 1564, 1241 1056 cm−1. 1H
NMR (400 MHz, CDCl3) δ 7.15 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.60 (br. s, 1H),
1.47 (s, 9H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 147.3, 138.6, 136.5, 134.6, 128.3,
123.5, 122.7, 119.9, 54.3, 51.9, 29.3, 28.4. HRMS (ESI) m/z: calcd for C16H22Cl2N3O+, 342.1134;
found, 342.1132 (100.0%), 344.1114 (63.9%), 346.1080 (10.2%).
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N-(tert-butyl)-2-(tert-butylimino)-5-nitro-2H-benzo[b][1,4]oxazin-3-amine (5la): Yellow solid
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(137mg, 86%), mp 169-171 C. IR (KBr): 3380, 2989, 1765, 1577, 1242, 1056 cm−1. H NMR
(400 MHz, CDCl3) δ 7.42 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 7.15–7.12 (m, 1H), 6.96 (t, J = 8.0
Hz, 1H), 6.74 (br. s, 1H), 1.47 (s, 9H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 147.6,
144.6, 144.1, 136.3, 127.5, 121.2, 118.7, 117.8, 54.3, 52.3, 29.6, 28.3. HRMS (ESI) m/z: calcd for
+
C16H23N4O3 , 319.1765; found, 319.1770.
N-(tert-butyl)-2-(tert-butylimino)-6-nitro-2H-benzo[b][1,4]oxazin-3-amine (5ma): Yellow
o
1
solid (132mg, 83%), mp 171-173 C. IR (KBr): 3368, 2991, 1765, 1242, 1056 cm−1. H NMR
(400 MHz, CDCl3) δ 8.11 (d, J = 2.8 Hz, 1H), 7.84 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 7.04 (d, J =
8.8 Hz, 1H), 6.61 (br. s, 1H), 1.49 (s, 9H), 1.38 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm
147.8, 147.4, 144.2, 136.2, 133.2, 120.8, 118.2, 114.9, 54.4, 52.0, 29.6, 28.4. HRMS (ESI) m/z:
+
calcd for C16H23N4O3 , 319.1765; found, 319.1767.
N-(tert-butyl)-2-(tert-butylimino)-7-nitro-2H-benzo[b][1,4]oxazin-3-amine (5na): Yellow solid
o
1
(135mg, 85%), mp 171-173 C. IR (KBr): 3359, 2970, 1617, 1555, 1333, 1224 cm−1. H NMR
(400 MHz, CDCl3) δ 7.96–7.93 (m, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.85
(br. s, 1H), 1.50 (s, 9H), 1.38 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 148.3, 142.5, 142.2,
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+
139.3, 136.4, 124.9, 119.9, 110.7, 54.4, 52.3, 29.6, 28.4. HRMS (ESI) m/z: calcd for C16H23N4O3 ,
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319.1765; found, 319.1755.
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3-(tert-butylamino)-2-(tert-butylimino)-2H-benzo[b][1,4]oxazine-6-carbonitrile (5oa): White
solid (130mg, 87%), mp 153-155 oC. IR (KBr): 3362, 2967, 2221, 1765, 1678, 1611, 1568, 1228,
807 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 1.6 Hz, 1H), 7.22 (dd, J1 = 2.0 Hz, J2 = 8.4
Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.59 (br. s, 1H), 1.47 (s, 9H), 1.36 (s, 9H). 13C NMR (100
MHz, CDCl3) δ ppm 147.3, 146.5, 136.4, 133.5, 129.1, 126.4, 118.8, 115.6, 107.4, 54.2, 51.9, 29.6,
28.4. HRMS (ESI) m/z: calcd for C17H23N4O+, 299.1866; found, 299.1877.
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N-(tert-butyl)-2-(tert-butylimino)-6-(methylsulfonyl)-2H-benzo[b][1,4]oxazin-3-amine (5pa):
White solid (156mg, 89%), mp 154-156 oC. IR (KBr): 3363, 2969, 1760, 1679, 1614, 1573, 1311,
1228, 1150 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 2.0 Hz, 1H), 7.52–7.50 (m, 1H), 7.10
(d, J = 8.4 Hz, 1H), 6.59 (br. s, 1H), 3.03 (s, 3H), 1.47 (s, 9H), 1.36 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ ppm 147.4, 147.0, 136.5, 135.8, 133.5, 124.6, 121.6, 115.4, 54.3, 51.9, 44.7, 29.6, 28.4.
HRMS (ESI) m/z: calcd for C17H26N3O3S+, 352.1689; found, 352.1676.
3-(tert-butylamino)-2-(tert-butylimino)-2H-benzo[b][1,4]oxazine-6-sulfonamide (5qa): White
o
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solid (151mg, 86%), mp 200-202 C. IR (KBr): 3365, 2969, 1678, 1615, 1226, 1160 cm−1. H
NMR (400 MHz, d-acetone) δ 7.75 (d, J = 1.6 Hz, 1H), 7.55 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H),
7.26 (d, J = 8.4 Hz, 1H), 6.75 (br. s, 1H), 6.54 (br. s, 2H), 1.51 (s, 9H), 1.40 (s, 9H). 13C NMR
(100 MHz, d-acetone) δ ppm 148.3, 146.5, 140.9, 137.9, 133.6, 124.0, 121.8, 116.0, 54.8, 52.4,
30.5. HRMS (ESI) m/z: calcd for C16H23N4O3S-, 351.1496; found, 351.1488.
N-(tert-butyl)-2-(tert-butylimino)-2H-naphtho[2,3-b][1,4]oxazin-3-amine (5ra): Light yellow
o
1
solid (157mg, 97%), mp 158-160 C. IR (KBr): 3374, 2967, 1764, 1592, 1237 cm−1. H NMR
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(400 MHz, CDCl3) δ ppm 7.62-7.54 (m, 3H), 7.21-7.16 (m, 2H), 6.43 (br. s, 1H), 1.40 (s, 9H),
1.29 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 146.9, 143.3, 138.0, 132.6, 131.3, 130.2, 127.1,
126.7, 124.7, 124.6, 121.9, 110.3, 54.0, 51.6, 29.7, 29.6, 28.6. HRMS (ESI) m/z: calcd for
C20H26N3O+, 324.2070; found, 324.2068.
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N3,N3'-di-tert-butyl-2,2'-bis(tert-butylimino)-2H,2'H-[7,7'-bibenzo[b][1,4]oxazine]-3,3'-dia
mine (5sa): Yellow solid (242mg, 89%), mp 211-213 oC. IR (KBr): 3368, 2966, 1764, 1672, 1617,
1581, 1237 cm−1. 1H NMR (400 MHz, CDCl3) δ ppm 7.26-7.22 (m, 4H), 7.16 (s, 2H), 6.45 (br. s,
2H), 1.43 (s, 18H), 1.34 (s, 18H). 13C NMR (100 MHz, CDCl3) δ ppm 146.8, 143.7, 138.2, 135.2,
+
131.9, 125.6, 122.2, 112.5, 53.9, 51.5, 29.7, 28.6. HRMS (ESI) m/z: calcd for C32H45N6O2 ,
545.3599; found, 545.3597.
N-(tert-butyl)-3-(tert-butylimino)-3H-pyrido[2,3-b][1,4]oxazin-2-amine (5ta): Light yellow
o
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solid (114mg, 83%), mp 115-117 C. IR (KBr): 3364, 2922, 1764, 1662, 1603, 1239 cm−1. H
NMR (400 MHz, CDCl3) δ ppm 7.89 (d, J = 3.6 Hz, 1H), 7.55 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H),
7.05-7.02 (m, 1H), 6.58 (br. s, 1H), 1.48 (s, 9H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm
150.0, 147.0, 140.6, 138.4, 132.9, 128.3, 120.9, 54.3, 51.7, 29.6, 28.5. HRMS (ESI) m/z: calcd for
C15H23N4O+, 275.1866; found, 275.1869.
N-(tert-butyl)-2-(tert-butylimino)-2H-pyrido[3,2-b][1,4]oxazin-3-amine (5ua): Light yellow
o
solid (104mg, 76%), mp 167-169 C. IR (KBr): 3750, 3368, 2963, 1765, 1662, 1609, 1240 cm−1.
1H NMR (400 MHz, CDCl3) δ ppm 8.18 (d, J = 4.4 Hz, 1H), 7.22 (s, 1H), 6.89-6.86 (m, 1H), 6.76
(br. s, 1H), 1.50 (s, 9H), 1.33 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 149.3, 145.9, 144.3,
139.1, 136.9, 121.9, 118.1, 54.1, 52.1, 29.6, 28.4. HRMS (ESI) m/z: calcd for C15H23N4O+,
275.1866; found, 275.1867.
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N-(2,4,4-trimethylpentan-2-yl)-2-((2,4,4-trimethylpentan-2-yl)imino)-2H-benzo[b][1,4]oxazin
-3-amine (5ab): Yellow oil (181mg, 94%). IR (KBr): 3371, 2955, 1673, 1616, 1523, 1224, 748
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9
1
cm−1. H NMR (400 MHz, CDCl3) δ ppm 7.29 (dd, J1 = 1.2 Hz, J2 = 7.6 Hz, 1H), 7.09-7.04 (m,
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1H), 7.02-6.95 (m, 2H), 6.68 (br. s, 1H), 1.91 (s, 2H), 1.73 (s, 2H), 1.55 (s, 6H), 1.44 (s, 6H), 1.03
(s, 9H), 1.02 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm 146.9, 143.5, 137.4, 132.9, 125.4, 123.8,
122.6, 114.6, 57.4, 55.5, 55.2, 51.4, 32.0, 31.9, 31.7, 31.5, 29.7, 29.0. HRMS (ESI) m/z: calcd for
C24H40N3O+, 386.3166; found, 386.3171.
N-(2-morpholinoethyl)-2-((2-morpholinoethyl)imino)-2H-benzo[b][1,4]oxazin-3-amine (5ac):
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Reddish brown oil (159mg, 82%). IR (KBr): 2955, 2856, 1670, 1614, 1116, 752 cm−1. H NMR
(400 MHz, CDCl3) δ ppm 7.26 (d, J = 7.6 Hz, 1H), 7.07-7.03 (m, 1H), 7.00-6.96 (m, 2H), 6.84 (br.
s, 1H), 3.71-3.63 (m, 10H), 3.57-3.53 (m, 2H), 2.65 (t, J = 7.0 Hz, 2H), 2.60 (t, J = 6.2 Hz, 2H),
2.55-2.43 (m, 8H). 13C NMR (100 MHz, CDCl3) δ ppm 147.4, 143.6, 141.3, 132.6, 125.1, 124.2,
123.4, 114.6, 66.9, 66.8, 59.0, 56.6, 53.9, 53.3, 43.4, 37.1. HRMS (ESI) m/z: calcd for
+
C20H30N5O3 , 388.2343; found, 388.2348.
N-cyclohexyl-2-(cyclohexylimino)-2H-benzo[b][1,4]oxazin-3-amine (5ad): Light yellow oil
1
(154mg, 95%). IR (KBr): 3386, 2929, 2854, 1759, 1668, 1613, 1520, 1215 cm−1. H NMR (400
MHz, CDCl3) δ 7.28 (d, J = 7.6 Hz, 1H), 7.07–6.95 (m, 3H), 6.39 (br. s, 1H), 4.01–3.79 (m, 2H),
2.08–2.05 (m, 2H), 1.79–1.73 (m, 6H), 1.66–1.63 (m, 2H), 1.49–1.36 (m, 6H), 1.33–1.18 (m, 4H).
13C NMR (100 MHz, CDCl3) δ ppm 146.9, 143.6, 139.3, 132.9, 124.9, 123.8, 122.9, 114.5, 53.9,
48.9, 33.3, 32.8, 25.8, 25.7, 24.8, 24.7. HRMS (ESI) m/z: calcd for C20H28N3O+, 326.2227; found,
326.2225.
N-butyl-2-(butylimino)-2H-benzo[b][1,4]oxazin-3-amine (5ae): Brown oil (121mg, 89%). IR
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