Reagent-Controlled Divergent Synthesis of 2-Amino-1,3-Benzoxazines and 2-Amino-1,3-Benzothiazines

Article abstract of DOI:10.1021/acs.joc.9b02384

A reagent-controlled chemoselective process has been devised for the synthesis of 4H-1,3-benzoxazines and related biologically important heterocycles in high yields under mild conditions. These scaffolds could be efficiently constructed using two different chemoselective reactions that rely on the choice of reagents and reaction conditions. The treatment of various 2-amino-arylalkyl alcohols with isothiocyanates afforded thiourea intermediates, which were reacted in situ with molecular iodine in the presence of triethylamine to give 2-amino-4H-1,3-benzoxazines, whereas the corresponding 2-amino-4H-1,3-benzothiazines were obtained by the reaction of thiourea intermediates in the presence of T3P (a mild cyclodehydrating agent) and triethylamine as the base. The described protocol represents the first example for the synthesis of 4H-1,3-benzoxazines via the dehydrosulfurization method using molecular iodine as the reagent.

Full text of DOI:10.1021/acs.joc.9b02384

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Article
Reagent-Controlled Divergent Synthesis of 2-Amino-1,3-
Benzoxazines and 2-Amino-1,3-Benzothiazines
Venkata Pattabhi Rama Kishore Putta, Nagaraju Vodnala, Raghuram Gujjarappa,
Ujjawal Tyagi, Aakriti Garg, Sreya Gupta, Prasad P. Pujar, and Chandi Charan Malakar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02384 • Publication Date (Web): 11 Dec 2019
Downloaded from pubs.acs.org on December 11, 2019
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Reagent-Controlled
Divergent
Synthesis
of
2-Amino-1,3-
Benzoxazines and 2-Amino-1,3-Benzothiazines
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V. P. Rama Kishore Putta,a,b Nagaraju Vodnala,c Raghuram Gujjarappa,c Ujjawal
Tyagi,c Aakriti Garg,d Sreya Gupta,d, Prasad P. Pujar,b,* and Chandi C. Malakarc,*
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a Department of Medicinal Chemistry, Jubilant Biosys, Bangalore - 560022, Karnataka, India
b Department of Chemistry, CHRIST (Deemed to be University), Bangalore - 560029, India.
Email: prasad.pujar@christuniversity.in
c Department of Chemistry, National Institute of Technology Manipur, Langol, Imphal - 795004, Manipur,
India
Email: cmalakar@nitmanipur.ac.in, chdeepm@gmail.com
d
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
(NIPER), Kolkata, Chunilal Bhawan, 168, Maniktala Main Road, Kolkata - 700054, India
ABSTRACT: A reagent-controlled chemoselective process has been devised for the synthesis of 4H-1,3-
benzoxazines and related biologically important heterocycles in high yields under mild conditions. These
scaffolds could be efficiently constructed using two different chemoselective reactions rely on the choice
of reagents and reaction conditions. The treatment of various 2-amino-arylalkyl alcohols with
isothiocyanates afforded thiourea intermediates, which were reacted in-situ with molecular iodine in the
presence of triethylamine to give the 2-amino-4H-1,3-benzoxazines, whereas the corresponding 2-amino-
4H-1,3-benzothiazines were obtained by the reaction of thiourea intermediates in the presence of T3P (a
mild cyclodehydrating agent) and triethylamine as base. The described protocol represents as the first
example for the synthesis of 4H-1,3-benzoxazines via dehydrosulfurization method using molecular iodine
as reagent.
INTRODUCTION:
The N,O- and N,S-containing six membered heterocycles constitute a diverse range of drug molecules and
herbicides.1 These scaffolds are extensively engaged as the immense building blocks for bioactive
molecules. Benzoxazine derivatives evident interesting biological and pharmaceutical properties such as
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progesterone receptor (PR) modulation, antianxiety (Etifoxine is an anxiolytic and anticonvulsant drug),
anti-HIV, agonist, and antagonist activities (Figure 1, A, B).1 Whereas, benzothiazine skeletons are
ubiquitous bioactive molecules2 and are well studied and extensively appealed in biochemical fields (Figure
1, C-G).2g,3 Favourably, several related molecules such as 2-amino-4H-1,3-benzothiazine scaffolds also
allure unique biological properties4 and have secured increasing attention in the medicinal chemistry. For
example, it was investigated that 2-(4-piperidinamino)-4H-1,3- benzothiazines (Figure 1, D) displays
appreciable cytoprotective properties towards the heart or neurons.4b Recent findings witnessed that the
guanidine, amidine and thiourea embedded scaffolds of 2-amino-1,3-benzothiazine (Figure 1, E, F, G) were
identified as the suitable medicinal compounds for the purpose of neurodegenerative disorders which are
instigated by Alzheimer’s disease and cranial trauma.4d Hence, there have been a noticeable attention
gratified towards the potential applications of 2-amino-4H-1,3-benzothiazine and 2-amino-4H-1,3-
benzoxazine scaffolds.5
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Figure 1. Potential pharmacological agents containing a 2-amino-1,3-benzoxazine and 2-amino-
1,3-benzothiazine structural units.
Due to their immense importance in medicinal chemistry, consequently a spectrum of methods have been
described for their synthesis. Among these approaches, the traditionally and the most extensively attempted
protocols are (i) metal-catalyzed tandem addition-cyclization reactions and oxidative synthesis,3e,6 (ii) non-
metal catalyzed/dehydrosulfurization methods,7 and (iii) non-catalytic approaches.8 A summary of the
known procedures towards the synthesis of 1,3-benzoxazines and 1,3-benzothiazines are presented in
Scheme 1. Jie and co-workers have achieved an easy synthesis of 2-amino-4H-1,3-benzothiazines via the
reaction between o-aminocinnamate and isothiocyanates using YbCl3 as catalyst (Scheme 1e).3e The similar
transformation has also been achieved by Ding et al under the silver-catalyzed reactions of 2-
alkynylbenzenamines with isothiocyanates (Scheme 1f).6c Saunthwal et al described the synthesis of these
scaffolds by the reaction of 2-aminoaryl acrylates with isothiocyanates via in-situ thioamidation reaction
and concomitant chemoselective intramolecular thia-michael addition (Scheme 1g).6g Han and co-workers
have reported an efficient method towards 1,3-benzoxazines by the reaction between aldehydes and 2-
aminobenzylamines or 2-aminobenzyl alcohols via an aerobic oxidative synthesis in the presence of Cu-
catalyst (Scheme 1h).6e A cyclocarbonylation reaction of o-iodoanilines with acid chlorides was
demonstrated by Larksarp and co-workers to afford the synthesis of 1,3-benzoxazines (Scheme 1i).6a
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Various non-catalytic conditions were also reported for the synthesis of these molecules, those include the
reaction between 2-alkynylbenzeneamines and isothiocyanates promoted by silicagel mediated tandem
addition-cyclization (Scheme 1b).8d The reaction of 2-amino chalcones with isothiocyanates could also
deliver these molecules (Scheme 1c),8g and recently, Jun and co-workers have described a microwave-
assisted solid-phase synthesis of 1,3-benzothiazines using BOMBA Resin as support (Scheme 1a).8h
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Scheme 1. Approaches towards the synthesis of 1,3-benzoxazine and 1,3-benzothiazines
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In addition, the metal-free approaches for the synthesis of 1,3-benzothiazines have been also achieved by
the reaction between o-ethynylphenyl isothiocyanates and primary or secondary amines.8e The reaction was
catalyzed by molecular iodine to accomplish the transformation (Scheme 1d). Moreover, these scaffolds
were constructed by dehydrosulfurization method by the reaction of 2-amino benzylalcohols with
isothiocyanates using PhI(OAc)2 and EDPBT as the reagents (Scheme 1k-l).7b,7a
Recently, the dehydrosulfurization technique towards the preparation of 1,3-benzoxazines gained
noteworthy attention and remained as one of the most attractive routes.7a-b,f Murata and co-workers have
reported the preparation of the same scaffolds using Ph3BiCl2 as dehydrosulfurizing agent (Scheme 1j).7f
Several known desulfurization reagents include transition metal salts such as CuCl2,9 NiO,10 HgO,7b.11
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FeCl3 and bronsted acids such as CF3CO2H13 and TfOH,14 and other reagents like TsCl/NaOH,15
LiOH/H2O2,16 polymer supported carbodiimides,17 hypervalent iodine(III),7a 1,10-(ethane-1,2-
diyl)dipyridinium bistribromide (EDPBT)7b and Ar3BiCl2.7f These reagents were extensively served for the
synthesis of 1,3-benzoxazines and 1,3-benzothiazines.1-7 Moreover, these reported conditions suffer from
the disadvantages such as substrate scope, scalability and the long reaction times. Therefore, the
development of an efficient and easy to access approach towards the preparation of 2-amino-1,3-
benzoxazines and 2-amino-1,3-benzothiazines could be an useful tool in organic synthesis. On the other
hand, T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide solution) has been widely
employed in both academia and industry as a mild coupling reagent for the synthesis wide variety of
biologically important molecules.18 It is well documented in literature that T3P is a choice of reagent in
acid-amine coupling reactions, because of its ease of handing and robustness. In this regards, our attention
was drawn to the concept of molecular iodine assisted dehydrosulfurization for the synthesis of 1,3-
benzoxazines and T3P mediated cyclodehydration for the synthesis of 1,3-1,3-benzothiazines. To the best
of our knowledge, these strategies are not much explored in literature till date. Here, we report two different
reagent specific routes for the convenient preparation of 2-amino-1,3-benzoxazines and 2-amino-1,3-
benzothiazines under mild reaction conditions and short reaction time.
RESULTS AND DISCUSSION
To identify suitable experimental conditions for the dehydrosulfurization of thiourea intermediate (3aa),
several reagents were investigated. The intermediate (3aa) was obtained from the reaction between 2-amino
benzylalcohol (1a) and benzoyl isothiocyanate (2a) at room temperature, which was reacted with molecular
iodine in the presence of mild organic bases like DMAP (4-Dimethylaminopyridine), pyridine, Et3N,
DIPEA (N,N-Diisopropylethylamine), DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) and DABCO (1,8-
Diazabicyclo[5.4.0]undec-7-ene) (Table 1, Entries 1-6). Interestingly, it was observed that the reactions
using a combination of organic base and molecular iodine as oxidant afforded excellent yields of the product
1,3-benzoxazine (4aa) ranging from 81-98% (Entries 1-6). However, the bases such as DMAP, pyridine,
Et3N, DIPEA were more efficient to deliver 1,3-benzoxazine (4aa) in slightly better yields (Entries 1 - 4)
than DBU and DABCO (Entries 5-6). In addition, the efficacies of the inorganic bases were also examined.
A varity of inorganic bases such as KOH, LiOH, NH3 and K2CO3 were employed for this transformation
(Entries 7-10). Among the inorganic bases tested, NH3 as base was found to be effective for this
transformation with the formation of the 1,3-benzoxazine (4aa) in 43% yield (Entry 9). However, when the
reactions were carried out only in the presence of iodine, bromine or triethylamine, the formation of 1,3-
benzoxazine (4aa) was not observed (Entries 11-13). It was also noticed that NBS (N-Bromosuccinimide)
and NIS (N-Iodosuccinimide) as oxidant were inefficient for the transformation to yield 1,3-benzoxazine
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(4aa) (Entries 14-15). However, the attempted activating reagents were found to be inactive for the
formation of 1,3-benzoxazine (4aa). Then, varieties of solvents were employed for the described
transformation (Entries 16-21). Among the tested solvents, acetonitrile, 1,4-dioxane, toluene and
dichloromethane were efficient to accomplish the transformation in good yields ranging from 49-68%
(Entries 16-19) and polar-protic solvents such as iso-propanol and water were found to be ineligible to yield
the product 4aa (Entries 20-21). Additionally, better outcomes have not been observed by varying the
amounts of base and oxidizing agent (Entries 22-23). During the survey of the reaction conditions,
surprisingly it was observed that when the reactions were carried out in presence of T3P (2,4,6-Tripropyl-
1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide) as mild cyclodehydrating agent and Et3N as base, the
corresponding 1,3-benzoxazine (4aa) was not formed, rather it gave the 1,3-benzthiazine (5aa) as the
exclusive product (Entries 24-27). These conditions lead us to develop the reagent specific protocols for
the synthesis of both 1,3-benzoxazine (4aa) and 1,3-benzothiazine (5aa). Next, we introduced various
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activating
agents
like
DCC
(N,N'-Dicyclohexylcarbodiimide),
BOP
((Benzotriazol-1-
(1-Ethyl-3-(3'-
yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate),
EDC‧HCl
dimethylaminopropyl)carbodiimide‧hydrochloride), PyBOP ((Benzotriazole-1-yl-oxy-tris-pyrrolidino-
phosphonium hexafluorophosphate) and HATU ((1-[Bis(dimethylamino)methylene]-1H-1,2,3-
triazolo[4,5-b]pyridinium 3-oxid-hexafluorophosphate) as reagents for accelerating this transformation
(Entries 28-32). Nevertheless, no satisfactory results were obtained towards the betterment of the desired
transformation, rather the intermediate 3aa was recovered in all the cases. A Detailed optimization study
(Table 1) showed that the highest yield of the product 1,3-benzoxazine (4aa) was obtained when the
conversion of the intermediate 3aa was performed in the presence of 1.1 equiv. molecular iodine and 2.0
equiv. of Et3N in THF as solvent at room temparature (25 °C) for 5-20 minutes (Table 1, Entry 3).
Consequently, the corresponding product 1,3-benzothiazine (5aa) was obtained in maximum yield when
the reaction was performed using 1.1 equiv. of T3P as cyclodehydrating agent and 2.2 equiv. of Et3N at
room temperature (25 °C) for 5-20 minutes (Table 1, Entry 24). The developed conditions were considered
as the standard reaction conditions to inspect the further scope of the developed methods towards the
synthesis of 1,3-benzoxazines and 1,3-benzothiazines.
Table 1. Screening of the reaction conditions towards the selective synthesis of 1,3-benzoxazine (4aa) and 1,3-
benzothiazine (5aa).a
4aa, % Yieldb
5aa, % Yieldb
Entry
Reaction Conditions
(% Conversion)c
(% Conversion)c
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2
3
4
I2 (1.1 equiv.), DMAP (2 equiv.)
97 (100)
95 (100)
98 (100)
93 (100)
0
0
0
0
I2 (1.1 equiv.), Pyridine (2 equiv.)
I2 (1.1 equiv.), Et3N (2 equiv.)
I2 (1.1 equiv.), DIPEA (2 equiv.)
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I2 (1.1 equiv.), DBU (2 equiv.)
87 (100)
81 (100)
< 10 (60)
< 10 (50)
43 (100)
21 (100)
0 (100)
0 (100)
0 (100)
32 (50)
18 (70)
57 (100)
55 (100)
49 (60)
68 (100)
0 (0)
0
I2 (1.1 equiv.), DABCO (2 equiv.)
I2 (1.1 equiv.), KOH (2 equiv.)
0
7
0
8
I2 (1.1 equiv.), LiOH (2 equiv.)
0
9
I2 (1.1 equiv.), NH3 (2 equiv.)
0
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24d
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27e
28f
29f
30f
31f
32f
I2 (1.1 equiv.), K2CO3 (2 equiv.)
I2 (1.1 equiv.)
0
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0
Br2 (1.1 equiv.)
0
Et3N (2 equiv.)
0
NIS (1.1 equiv.), Et3N (2 equiv.)
NBS (1.1 equiv.), Et3N (2 equiv.)
I2 (1.1 equiv.), Et3N (2 equiv.), MeCN
I2 (1.1 equiv.), Et3N (2 equiv.), 1,4-dioxane
I2 (1.1 equiv.), Et3N (2 equiv.), PhMe
I2 (1.1 equiv.), Et3N (2 equiv.), DCM
I2 (1.1 equiv.), Et3N (2 equiv.), iPrOH
I2 (1.1 equiv.), Et3N (2 equiv.), H2O
I2 (0.5 equiv.), Et3N (2 equiv.)
0
0
0
0
0
0
0
0 (0)
0
38 (50)
97 (100)
trace
0
I2 (1.5 equiv.), Et3N (2.5 equiv.)
T3P (1.1 equiv.), Et3N (2.2 equiv.), MeCN
T3P (1.1 equiv.), Et3N (2.2 equiv.), THF
T3P (1.1 equiv.), Et3N (2.2 equiv.), DCM
T3P (1.1 equiv.), Et3N (2.2 equiv.)
EDC⸳HCl (1.1 equiv.), Et3N (2.2 equiv.), MeCN
DCC (1.1 equiv.), Et3N (2.2 equiv.), MeCN
BOP (1.1 equiv.), Et3N (2.2 equiv.), MeCN
PyBOP (1.1 equiv.), Et3N (2.2 equiv.), MeCN
HATU (1.1 equiv.), Et3N (2.2 equiv.), MeCN
0
95 (100)
< 5
78 (100)
< 5
81 (100)
< 5
69 (100)
< 5 (< 20)
< 5 (< 20)
< 5 (< 20)
< 5 (< 20)
< 5 (< 20)
0
0
0
0
0
a Reactions were carried out using 1.0 mmol 1a, 1.0 mmol 2a in 2 mL THF (Entries 1-15, 22-23) and in 2 mL of MeCN (Entries
24-32) at 25 °C for 5-20 minutes. b Isolated yields. c Conversion was monitored by LC-MS. d T3P anhydride solution ≥50 wt. % in
ethyl acetate was used. e Reaction was carried out without solvent. f Intermediate 3aa was recovered .
Having these optimal results, initially we explored the scope of the reaction by employing various 2-amino-
arylalkyl alcohols (1a-l) with benzoyl isothiocyanate (2a) to obtain the desired products 2-amino-1,3-
benzoxazines (4aa-la). In general, 2-amino-arylalkyl alcohols with different substitution pattern including
electron-withdrawing as well as electron-donating groups could be successfully reacted in this
transformation. The novel transformations proceeded smoothly, and all the reactions were completed within
20 minutes giving the 2-amino-1,3-benzoxazines (4aa-la) in excellent yields (Scheme 2). To evaluate the
efficiency and generality of the reaction, we drawn our attention in exploring other substituents on the
benzylic position of the 1a. These substituents were also well tolerated and delivered the products (4ja-ka)
with moderate to excellent yields. Further, 2-(2-aminophenyl)ethan-1-ol (1l) could be efficiently employed
in the reaction to provide the desired benzo[1,3]oxazepine (4la) in 95% yield (Scheme 2). The structure of
the compound 4fa was further confirmed by X-ray crystallographic data (Provided in SI).
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Scheme 2. Synthesis of 1,3-benzoxazine derivatives using various 2-amino-aralkyl alcohols and ORTEP diagram of
4fa.
Later, the scope of the reaction was also extended by taking various isothiocyanates (2b-n) with 2-
aminobenzylalcohol (1a) to obtain the desired 1,3-benzoxazine derivatives (4ab-an). The aryl and alkyl
isothiocyanates were effectively surveyed for the transformation to afford the desired 1,3-benzoxazine
derivatives (4ab-an) (Scheme 3). It has been realized that the electron-donating groups such as methyl,
methoxy and the electron-withdrawing substituents such as F, CF3, and NO2 groups were well tolerated on
the aromatic moieties of the isothiocyanates. The substrate scope revealed that the nature of functional
groups have no considerable impact towards the outcome of the reactions. Hence, the yield of the desired
products (4ab-an) found to be general (ranging from 89-96%) apart from the electronic nature of the
substituents. Further, scope of the described approach has been verified with isothiocyanates containing
alkyl (2k, 2m-n) and alkyl moiety embedded with hetero-aromatic group (2l) to afford the corresponding
products 4ak, 4am-an and 4al respectively in good yields (Scheme 3).
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Scheme 3. Substrate scope for the synthesis of 1,3-benzoxazine derivatives using various isothiocyanates.
On the other hand, the T3P mediated reaction conditions were investigated for the synthesis of 1,3-
benzothiazine derivatives. It was observed that the developed method was successfully employed on variety
of 2-aminobenzyl alcohols (1a-i) and benzoyl isothiocyanate (2a) to obtain the desired 1,3-benzothiazine
derivatives (5aa-ia) (Scheme 4). The reactions proceeded smoothly in the presence of both electron-
donating group such as methyl and the electron-withdrawing substituents such as F, Cl, CF3 and NO2 on
the aromatic moieties of the isothiocyanates to furnish the expected product 1,3-benzothiazines (5aa-ia) in
yields ranging from 89-98%. The structure of the compound 5fa was further affirmed by X-ray
crystallographic data (Provided in SI).
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Scheme 4. Substrate scope of 2-N-substituted-1,3-benzothiazine derivatives and ORTEP diagram of 5fa.
Further, the reactivity of a broad range of isothiocyanates (2b-l, o-q) was examined by reacting with 2-
aminobenzyl alcohol (1a). It was evident that the isothiocyanates substrates with varieties of functional
groups were permitted a spectrum of 1,3-benzothiazines (5ab-al, ao-aq) in excellent yields (85-96%) under
optimized reaction conditions. Subsequently, the isothiocyanates with ester group and alkyl moiety
embedded furan, and pyridine were also allowed to afford the corresponding products 5ak, 5al and 5aq in
high yields (Scheme 5) under the developed conditions.
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Scheme 5. Substrate Scope of 2-N substituted-1,3-benzothiazine derivatives using isothiocyanates.
To identify the further scope of the developed transformation, the reactivity of 2-aminobenzylalcohol (1a)
with phenyl isoselenocyanate (6a) was investigated under the optimized conditions (Scheme 6). It was
found that the developed conditions can effectively induce the reaction of 1a with 6a which resulted the
desired 1,3-selenazine derivative (8aa) in 90% yield, along with the formation of 1,3-benzoxazine (4ab) in
5% yield as minor product (Scheme 6, Eq. 1). It was also noteworthy that the formation of corresponding
1,3-selenazine (8aa) was reduced remarkably, in case of one-pot manner (Scheme 6, Eq. 2). However, the
formation of 1,3-benzoxazine (4ab) was increased up to 95%, when the reaction was performed in absence
of T3P as cyclodehydrating agent (Scheme 6, Eq. 3). Next, to know the insight into the reaction mechanism,
we have carried out the reactions of the isolated intermediate 3aa as substrate under the standard reaction
conditions. It was found that under the described conditions both the desired products 1,3-
benzoxazines (4aa) and 1,3-benzothiazines (5aa) were obtained in 91% and 86% isolated yields
respectively (Scheme 6, Eq. 5 and 4). To evaluate the practical and synthetic utility of the present protocol,
gram scale synthesis of 1,3-benzoxazine (4aa) (Scheme 6, Eq. 7) and 1,3-benzothiazine (5aa) (Scheme 6,
Eq. 6) were carried out. To our delight, the reaction conditions were efficient to bring about the conversion
affording 1,3-benzoxazine in 97% and 1,3-benzothiazine in 92% yields. Also, we have performed the
derivatization of the 1,3-benzothiazine (5aa) by the removal of N-benzoyl group via base mediated
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hydrolysis followed by N-methylation of the product 9aa using methyl iodide to afford the N-methylated
product 5ar in 30% yield (Scheme 6, Eq. 8).
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Scheme 6. Synthesis of 1,3-benzoselenazines, mechanistic insights, practical and synthetic utility of the developed
reaction conditions.
Having surveyed the experimental results and literature evidences,7a-b,7f,18-20 the plausible mechanism has
been presented for the synthesis of 1,3-benzoxazines and 1,3-benzothiazines (Scheme 7). The proposed
mechanism for the formation of carbodiimide intermediate E via dehydrosulfurization of intermediate C is
well established in literature.19-20 The mechanism is supported by the isolation of precipitated elemental
sulfur.19c In the described method the role of 2.0 equiv. of triethylamine as base seems to be essential. We
considered that the mechanism would be similar to the synthesis of heterocyclic compounds using
dehydrosulfurization reagents such as triphenylbismuth dichloride and hypervalent iodine compounds.
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Hence, we propose that the initial step of the reaction would follow the generation of intermediate B from
the reaction of 2-aminobenzyl alcohol (1a) with phenyl isothiocyanate (2a) followed by nucleophilic attack
of the sulfur atom of B on to the molecular iodine leading to the formation of intermediate C. The
Intermediate C then delivers the desired products 4ab via two different reaction pathways. In path (a), the
intermediate C undergoes intramolecular cyclization to give 1,3-benzoxazine (4ab). Another potential route
could be the formation of carbodiimide intermediate E, which delivers the corresponding 1,3-benzoxozine
(4ab) (path b). On the other hand, the plausible pathway for the formation of 1,3-benzothiazine can be
suggested (Scheme 7) based on the literature evidences.18 The reaction involves the activation of thiourea
moiety A by T3P, leading to the formation of intermediate G. The next step in the suggested mechanism
involves the intramolecular nucleophilic attack of thiol group on to the T3P bound carbon to furnish the
corresponding 1,3-benzothiazines (5ab). The reason for this controlled selectivity of reagents can be
attributed as follows, it is evident from literature that the tendency of T3P towards the water molecule is
greater than the tendency of T3P towards sulfur atom. It is well known that T3P is an excellent coupling
reagent and water scavenger. Moreover, Iodine is recognized as desulfurizing agent, hence it tends to take
up sulfur rather than an oxygen atom to bring about the required chemical transformations.
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Scheme 7. Plausible reaction pathways towards the synthesis of 1,3-benzoxazine and 1,3-benzothiazine.
CONCLUSIONS
In summary, two different reagent-selective methods for the synthesis of 1,3-benzoxazines and 1,3-
benzothiazines have been described. The 2-N-substituted-1,3-benzoxazines were synthesized in moderate
to excellent yields via a simple one-pot two-step reaction involving the reaction between 2-aminobenzyl
alcohols and isothiocyanates in the presence of molecular iodine and base under mild reaction conditions.
Whereas the 2-N substituted-1,3-benzothiazines were obtained in the presence of T3P reagent and base as
reagents. In case of 1,3-benzoxazines, the molecular iodine promoted the successful dehydrosulfurization
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of thiourea which leading to the formation of elemental sulphur. This protocol represents as the first
example for the synthesis of 2-amino 4H-1,3-Benzoxazines via iodine promoted dehydrosulfurization
method.
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EXPERIMENTAL SECTION
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General Methods
All starting materials were purchased from commercial suppliers (Sigma-Aldrich, Alfa-Aesar, SD fine chemicals,
Merck, HI Media) and were used without further purification unless otherwise indicated. All reactions were performed
in a 10 mL round bottom flask with magnetic stirring. Solvents used in extraction and purification were distilled prior
to use. Thin-layer chromatography (TLC) was performed on TLC plates purchase from Merck. Compounds were
visualized with UV light (λ = 254 nm) and/or by immersion in KMnO4 staining solution followed by heating. Products
were purified by CombiFlash MPLC. H (13C) NMR spectra were recorded at 400 (100) MHz on a Brucker
1
spectrometer using CDCl3 and DMSO-d6 as a solvent. The 1H and 13C{1H} chemical shifts were referenced to residual
solvent signals at H/C 7.26 /77.28 (CDCl3) and H/C 2.51 /39.50 (DMSO-d6) relative to TMS as internal standards.
Coupling constants J [Hz] were directly taken from the spectra and are not averaged. Splitting patterns are designated
as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), overlapped and br (broad).
General experimental procedure for the synthesis of 2-amino-1,3-benzoxazines (4aa-la, 4ab-an)
A 10 mL round bottom flask was charged with 2-amino-aralkyl alcohols 1a-l (1.0 mmol), aryl or alkyl isothiocyanates
2a-n (1.0 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature (25 °C) for 5 mins. The
reaction progress was monitored by TLC (SiO2, Hexane/EtOAc = 8:2) and LC-MS. The TLC and LCMS analysis
showed the absence of both the starting materials and the formation of thiourea intermeiate. The reaction was then
cooled to 0 °C, followed by the simultaneous addition of Et3N (2 mmol), I2 (1.1 mmol) and the reaction mixture was
stirred at room temperature (25 °C) for 5-20 mins. After completion of the reaction (progress was monitored by TLC;
SiO2, Hexane/EtOAc = 8:2 and LC-MS), the recation mixture was extracted with ethyl acetate (3 × 15 mL), water
(20 mL). The combined organic layer was washed with sodium thiosulphate solution (3 × 10 mL) and dried over
anhydrous Na2SO4. Solvent was removed under reduced pressure and the remaining residue was purified over
CombiFlash MPLC using DCM/EtOAc = 92:8 as an eluent to obtain the desired 2-amino-1,3-benzoxazines (4aa-la,
4ab-an) in high yields.
General experimental procedure for the synthesis of 2-amino-1,3-benzothiazines (5aa-ia, 5ab-al, 5ao-aq)
A 10 mL round bottom flask was charged with 2-amino-aralkyl alcohols 1a-i (1.0 mmol), aryl or alkyl isothiocyanates
2a-l, 2o-q (1.0 mmol) in MeCN (2 mL) and the reaction mixture was stirred at room temperature (25 °C) for 5 mins.
The reaction progress was monitored by TLC (SiO2, Hexane/EtOAc = 8:2) and LC-MS. The TLC and LCMS analysis
showed the absence of both the starting materials and the formation of thiourea intermeiate. The reaction was then
cooled to 0 °C, followed by the simultaneous addition of Et3N (2.2 mmol), T3P anhydride solution ≥50 wt. % in ethyl
acetate (1.1 mmol) and the reaction mixture was stirred at room temperature (25 °C) for 5-20 mins. After completion
of the reaction (progress was monitored by TLC; SiO2, Hexane/EtOAc = 8:2 and LC-MS), the recation mixture was
extracted with ethyl acetate (3 × 15 mL), water (20 mL). The combined organic layer was washed with sodium
thiosulphate solution (3 × 10 mL) and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure
and the remaining residue was purified over CombiFlash MPLC using Hexane/EtOAc = 70:30 as an eluent to obtain
the desired 2-amino-1,3-benzothiazines (5aa-ia, 5ab-al, 5ao-aq) in high yields.
Experimental procedures and analytical data of synthesized N-((2-(hydroxymethyl)phenyl)carbamothioyl)
benzamide (3aa) and 2-amino-1,3-benzoxazines (4aa-la, 4ab-an)
Synthesis of N-((2-(hydroxymethyl)phenyl)carbamothioyl)benzamide (3aa)
The reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), benzoyl isothiocyanate (2a) (1.0 mmol, 163
mg) in 2 mL THF or 2 mL of MeCN were performed to obtain the desired N-((2-(hydroxymethyl)phenyl)
carbamothioyl)benzamide (3aa) in 99% (283 mg) yield as off-white solid.
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N-((2-(hydroxymethyl)phenyl)carbamothioyl)benzamide (3aa)21 (Table 1, Scheme 6): Off-white solid; Rf = 0.30
(SiO2, Hexane/EtOAc = 7:3); Purification system: Not required; Yield: 283 mg (99%); 1H NMR (400 MHz, DMSO-
d6) δ = 12.32 (br, 1H), 11.54 (br, 1H), 7.98 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.2 Hz, 2H), 7.54-7.45 (m, 3H), 7.29 (m,
2H), 5.42 (s, 1H), 4.49 (s, 2H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 180.6, 168.5, 137.6, 136.5, 133.55,
132.6, 129.15, 128.9, 128.3, 127.5, 127.33, 127.3, 60.5 ppm; HRMS (ESI-QTOF, [M + H]+): calculated for
C15H15N2O2S: 287.0854; found: 287.0850.
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Synthesis of N-(4H-benzo[d][1,3]oxazin-2-yl)benzamide (4aa)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), benzoyl
isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(4H-benzo[d][1,3]oxazin-2-yl)benzamide (4aa) in 98% (247 mg) yield as white
solid.
N-(4H-benzo[d][1,3]oxazin-2-yl)benzamide (4aa) (Table 1, Scheme 2): White solid; Rf = 0.40 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 97:3); Yield: 247 mg (98%); m.p
= 126 - 127 °C; 1H NMR (400 MHz, CDCl3) δ = 12.78 (br, 1H), 8.26 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H),
7.43 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H), 7.19 - 7.12 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 5.42 (s, 2H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ = 179.8, 161.2, 136.6, 132.3, 129.6, 129.4, 128.1, 125.1, 124.5, 119.0, 115.7,
67.6 ppm; MS (APCI): [M + 1]+ = 253.1 (95.83%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H13N2O2:
253.0977; found: 253.0974.
Synthesis of N-(7-methyl-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ba)
According to the general procedure, reactions between 2-amino-4-methylbenzyl alcohol (1b) (1.0 mmol, 137 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(7-methyl-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ba) in 96% (255 mg) yield
as off-white solid.
N-(7-methyl-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ba) (Scheme 2): Off-white solid; Rf = 0.40 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 255 mg (96%); m.p
= 136 - 137 °C; 1H NMR (400 MHz, CDCl3) δ = 12.78 (br, 1H), 8.25 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 5.6 Hz, 1H),
7.43 (t, J = 7.2 Hz, 2H), 6.99 (q, J = 7.2 Hz, 2H), 6.82 (s, 1H), 5.38 (s, 2H), 2.36 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ = 179.7, 161.0, 139.9, 136.7, 132.2, 129.4, 128.0, 125.7, 124.3, 116.2, 116.0, 67.6, 21.2 ppm; MS
(APCI): [M + 1]+ = 267.1 (100%); HRMS (ESI-QTOF, [M + H]+): calculated for C16H15N2O2: 267.1133; found:
267.1129.
Synthesis of N-(8-methyl-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ca)
According to the general procedure, reactions between 2-amino-3-methylbenzyl alcohol (1c) (1.0 mmol, 137 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(8-methyl-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ca) in 90% (240 mg) yield as
off-white solid.
N-(8-methyl-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ca) (Scheme 2): Off-white solid; Rf = 0.40 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 240 mg (90%); m.p
= 124 - 125 °C; 1H NMR (400 MHz, CDCl3) δ = 13.0 (br, 1H), 8.27 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.43
(t, J = 7.2 Hz, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 5.39 (s, 2H), 2.41 (s,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 180.1, 161.2, 136.7, 132.2, 131.5, 129.6, 129.4, 128.2, 124.6, 123.7,
122.0, 118.6, 67.7, 16.21 ppm; MS (APCI): [M + 1]+ = 267.1 (97.6%); HRMS (ESI-QTOF, [M + H]+): calculated
for C16H15N2O2: 267.1133; found: 267.1130.
Synthesis of N-(6-fluoro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4da)
According to the general procedure, reactions between 2-amino-5-fluorobenzyl alcohol (1d) (1.0 mmol, 141 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
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performed to obtain the desired N-(6-fluoro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4da) in 93% (251 mg) yield as
off-white solid.
N-(6-fluoro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4da) (Scheme 2): Off-white solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 251 mg (93%); m.p
= 108 - 109 °C; 1H NMR (400 MHz, CDCl3) δ = 12.80 (br, 1H), 8.24 (d, J = 6.8 Hz, 2H), 7.54 - 7.50 (m, 1H), 7.45 -
7.41 (m, 2H), 7.05 (dt, J = 7.2, 2.8 Hz, 1H), 6.99 - 6.94 (m, 1H), 6.88 (dd, J = 7.6, 2.8 Hz, 1H), 5.38 (s, 2H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ = 179.9, 161.0, 160.8, 159.7 (d, J = 244.7 Hz), 136.4, 132.4, 131.9, 129.4, 128.5,
128.1, 127.3, 120.7, 120.6, 117.2, 117.1, 116.4, 116.2, 112.0, 111.7, 67.1 ppm; MS (APCI): [M + 1]+ = 271.1 (96.7%);
HRMS (ESI-QTOF, [M + H]+): calculated for C15H12FN2O2: 271.0882; found: 271.0880.
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Synthesis of N-(7-fluoro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ea)
According to the general procedure, reactions between 2-amino-4-fluorobenzyl alcohol (1e) (1.0 mmol, 141 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(7-fluoro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ea) in 90% (243 mg) yield as
off-white solid.
N-(7-fluoro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ea) (Scheme 2): Off-white solid; Rf = 0.40 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 243 mg (90%); m.p
= 132 - 133 °C; 1H NMR (400 MHz, CDCl3) δ = 12.89 (br, 1H), 8.25 (d, J = 8.0 Hz, 2H), 7.55 - 7.51(m, 1H), 7.46 –
7.42 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.89 - 6.85 (m, 1H), 6.74 (d, J = 7.6 Hz, 1H), 5.37 (s, 2H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ = 179.9, 163.1 (d, J = 246.3 Hz), 160.4, 136.3, 134.0, 133.9, 132.5, 131.9, 129.5, 128.5, 128.1,
127.3, 126.1, 126.0, 114.8, 114.7, 111.8, 111.6, 103.7, 103.4, 67.2 ppm; MS (APCI): [M + 1]+ = 271.1 (88.6%);
HRMS (ESI-QTOF, [M + H]+): calculated for C15H12FN2O2: 271.0882; found: 271.0879.
Synthesis of N-(8-fluoro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4fa)
According to the general procedure, reactions between 2-amino-3-fluorobenzyl alcohol (1f) (1.0 mmol, 141 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(8-fluoro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4fa) in 92% (249 mg) yield as
off-white solid.
N-(8-fluoro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4fa) (Scheme 2): Off-white solid; Rf = 0.40 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 249 mg (92%); m.p
= 122 - 124 °C; 1H NMR (400 MHz, CDCl3) δ = 12.95 (br, 1H), 8.26 (d, J = 7.2 Hz, 2H), 7.51 (d, J = 7.2 Hz, 1H),
7.44 (t, J = 7.2 Hz, 2H), 7.13 (d, J = 6.4 Hz, 2H), 6.94 (s, 1H), 5.43 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
= 179.7, 160.0 (d, J = 248.8 Hz), 136.4, 132.4, 129.5, 128.5, 128.3, 128.1, 127.6, 127.3, 125.29, 125.23, 121.0, 119.84,
119.81, 116.0, 115.8, 115.5, 67.2 ppm; MS (APCI): [M + 1]+ = 271.3 (97.84%); HRMS (ESI-QTOF, [M + H]+):
calculated for C15H12FN2O2: 271.0882; found: 271.0881.
Synthesis of N-(6-chloro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ga)
According to the general procedure, reactions between 2-amino-5-chlorobenzyl alcohol (1g) (1.0 mmol, 157.6 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(6-chloro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ga) in 90% (258 mg) yield as
off-white solid.
N-(6-chloro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ga) (Scheme 2): Off-white solid; Rf = 0.30 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 258 mg (90%); m.p
= 166 - 167 °C; 1H NMR (400 MHz, CDCl3) δ = 12.79 (br, 1H), 8.24 (d, J = 6.8 Hz, 2H), 7.54 (d, J = 5.6 Hz, 1H),
7.43 (t, J = 7.6 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 5.37 (s, 2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ = 179.6, 160.3, 136.3, 132.4, 130.2, 129.6, 129.4, 128.5, 124.7, 120.6, 117.0, 115.2, 67.0
ppm; HRMS (ESI-QTOF, [M + H]+): calculated for C15H12ClN2O2: 287.0587; found: 287.0580.
Synthesis of N-(7-chloro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ha)
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According to the general procedure, reactions between 2-amino-4-chlorobenzyl alcohol (1h) (1.0 mmol, 157.6 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(7-chloro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ha) in 92% (264 mg) yield as
off-white solid.
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N-(7-chloro-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ha) (Scheme 2): Off-white solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 264 mg (92%); m.p
= 146 - 147 °C; 1H NMR (400 MHz, CDCl3) δ = 12.79 (br, 1H), 8.24 (d, J = 6.8 Hz, 2H), 7.54 (d, J = 5.6 Hz, 1H),
7.43 (t, J = 7.6 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 5.37 (s, 2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ = 179.8, 160.4, 136.3, 135.3, 131.9, 129.5, 128.5, 128.1, 125.6, 125.4, 117.4, 116.0, 67.2
ppm; MS (APCI): [M + 1]+ = 287.0 (92.72%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H12ClN2O2:
287.0587; found: 287.0584.
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Synthesis of N-(7-(trifluoromethyl)-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ia)
According to the general procedure, reactions between 2-amino-4-(trifluoromethyl)benzyl alcohol (1i) (1.0 mmol, 191
mg), benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF
were performed to obtain the desired N-(7-(trifluoromethyl)-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ia) in 91%
(291 mg) yield as off-white solid.
N-(7-(trifluoromethyl)-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ia) (Scheme 2): Off-white solid; Rf = 0.40
(SiO2, Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 291 mg (91%);
m.p = 107 - 108 °C; 1H NMR (400 MHz, CDCl3) δ = 12.89 (br, 1H), 8.25 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.6 Hz,
1H), 7.44 (t, J = 8.0 Hz, 3H), 7.25 (s, 2H), 5.45 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 180.7, 163.6,
136.2, 132.6 (q, J = 247.6 Hz), 129.5, 128.6, 128.1, 127.3, 125.2, 124.9, 124.6, 122.7, 121.9, 121.6, 121.0, 112.8,
111.0, 67.1 ppm; MS (APCI): [M]+ = 320.0 (89.0%); HRMS (ESI-QTOF, [M + H]+): calculated for C16H12F3N2O2:
321.0850; found: 321.0845.
Synthesis of N-(4-methylene-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ja)
According to the general procedure, reactions between 1-(2-aminophenyl)ethen-1-ol (1j) (1.0 mmol, 135 mg), benzoyl
isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(4-methylene-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ja) in 60% (159 mg) yield
as white solid.
N-(4-methylene-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ja) (Scheme 2): White solid; Rf = 0.60 (SiO2,
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Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 97:3); Yield: 159 mg (60%); H
NMR (400 MHz, CDCl3) δ = 12.91 (br, 1H), 8.26 (d, J = 7.4 Hz, 2H ), 7.55 - 7.49 (m, 3H), 7.44 (t, J = 7.6 Hz, 1H),
7.36 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 5.03 (d, J = 13.6 Hz, 2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ = 179.8, 157.3. 150.0, 136.4, 132.7, 132.4, 132.1, 131.2, 129.4, 128.1, 125.6, 123.8, 116.6,
116.3, 91.2 ppm; MS (APCI): [M]+ = 265.1 (100.0%); HRMS (ESI-QTOF, [M + H]+): calculated for C16H13N2O2:
265.0977; found: 265.0970.
Synthesis of N-(4-phenyl-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ka)
According to the general procedure, reactions between 2-aminobenzhydrol (1k) (1.0 mmol, 199 mg), benzoyl
isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(4-phenyl-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ka) in 96% (315 mg) yield as
white solid.
N-(4-phenyl-4H-benzo[d][1,3]oxazin-2-yl)benzamide (4ka) (Scheme 2): White solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 315 mg (96%); m.p
= 178 - 179 °C; 1H NMR (400 MHz, CDCl3) δ = 12.87 (br, 1H), 8.25 (d, J = 7.6 Hz, 2H ), 7.50 (t, J = 7.6 Hz, 1H),
7.43 - 7.39 (m, 7H), 7.38 (t, J = 8 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H
), 6.45 (s, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 179.9, 160.2, 136.8, 136.7, 137.27, 137.22, 129.7, 129.5,
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128.8, 128.1, 128.0, 126.1, 125.0, 122.3, 115.7, 80.5 ppm; MS (APCI): [M]+ = 329.1 (93.79%); HRMS (ESI-QTOF,
[M + H]+): calculated for C21H17N2O2: 329.1290; found: 329.1286.
Synthesis of N-(4,5-dihydrobenzo[d][1,3]oxazepin-2-yl)benzamide (4la)
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According to the general procedure, reactions between 2-aminophenethyl alcohol (1l) (1.0 mmol, 137 mg), benzoyl
isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(4,5-dihydrobenzo[d][1,3]oxazepin-2-yl)benzamide (4la) in 95% (253 mg) yield as
off-white solid.
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N-(4,5-dihydrobenzo[d][1,3]oxazepin-2-yl)benzamide (4la) (Scheme 2): Off-white solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 96:4); Yield: 253 mg (95%); H
NMR (400 MHz, CDCl3) δ = 13.90 (br, 1H), 8.25 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 6.8 Hz,
2H), 7.30 (s, 1H), 7.17 - 6.99 (m, 3H), 4.67 (s, 2H), 3.29 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 178.8,
162.2, 136.8, 135.4, 132.0, 130.2, 129.3, 129.2,128.2,127.7, 124.7, 121.6, 70.0, 35.0 ppm; HRMS (ESI-QTOF, [M
+ H]+): calculated for C16H15N2O2: 267.1133; found: 267.1130.
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Synthesis of N-phenyl-4H-benzo[d][1,3]oxazin-2-amine (4ab)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), phenyl
isothiocyanate (2b) (1.0 mmol, 135 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-phenyl-4H-benzo[d][1,3]oxazin-2-amine (4ab) in 94% (211 mg) yield as off-white
solid.
N-phenyl-4H-benzo[d][1,3]oxazin-2-amine (4ab)7f (Scheme 3, 6 and 7): Off-white solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 211 mg (94%); m.p
= 143 - 144 °C (Lit7f 144 - 147 °C); 1H NMR (400 MHz, CDCl3) δ = 7.47 (d, J = 7.2 Hz, 2H), 7.31 (t, J = 8 Hz, 3H),
7.05 - 6.99 (m, 4H), 5.24 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 151.9, 141.0, 139.6, 129.0, 128.9, 123.7,
123.0, 122.9, 121.0, 120.8, 120.5, 67.7 ppm; MS (APCI): [M]+ = 225.1 (99.85%); HRMS (ESI-QTOF, [M + H]+):
calculated for C14H13N2O: 225.1027; found: 225.1024.
Synthesis of N-(2,4-dimethylphenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ac)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 2,4-
dimethylphenyl isothiocyanate (2c) (1.0 mmol, 163 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL
THF were performed to obtain the desired N-(2,4-dimethylphenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ac) in 98%
(247 mg) yield as off-white solid.
N-(2,4-dimethylphenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ac)7b (Scheme 3): Off-white solid; Rf = 0.30 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 247 mg (98%); m.p
= 163 - 165 °C (Lit7b 163 - 166 °C); 1H NMR (400 MHz, CDCl3) δ = 7.69 (s, 1H), 7.25 - 7.20 (m, 1H), 7.06 (d, J =
7.6 Hz, 1H), 7.01 - 6.98 (m, 3H), 6.85 (d, J = 7.6 Hz, 1H), 5.20 (s, 2H), 2.34 (s, 3H), 2.33 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ = 147.0, 136.3, 133.0, 131.4, 125.4, 124.2, 121.9, 120.1, 118.96, 118.90, 117.8, 115.8, 115.6,
62.9, 16.39, 12.77 ppm; MS (APCI): [M]+ = 253.1 (99.81%); HRMS (ESI-QTOF, [M + H]+): calculated for
C16H17N2O: 253.1340; found: 253.1337.
Synthesis of N-(p-tolyl)-4H-benzo[d][1,3]oxazin-2-amine (4ad)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), p-tolyl
isothiocyanate (2d) (1.0 mmol, 149 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-(p-tolyl)-4H-benzo[d][1,3]oxazin-2-amine (4ad) in 90% (214 mg) yield as off-
white solid.
N-(p-tolyl)-4H-benzo[d][1,3]oxazin-2-amine (4ad)22 (Scheme 3): Off-white solid; Rf = 0.50 (SiO2, Hexane/EtOAc
= 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 214 mg (90%); m.p = 115 - 117 °C
(Lit22 116 - 118°C); 1H NMR (400 MHz, CDCl3) δ = 7.33 (d, J = 8.0 Hz, 2H), 7.27 - 7.23 (m, 1H), 7.12 (d, J = 8.0
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Hz, 2H), 7.08 - 7.04 (m, 1H), 7.03 - 6.98 (m, 2H), 5.25 (s, 2H), 2.32 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
δ = 151.9, 141.3, 136.5, 132.7, 129.4, 129.0, 123.6, 122.8, 121.3, 120.8, 120.5, 67.7, 20.7 ppm; MS (APCI): [M]+ =
239.1 (100%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H15N2O: 239.1184; found: 239.1180.
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Synthesis of N-(2-methoxyphenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ae)
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According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 2-
methoxyphenyl isothiocyanate (2e) (1.0 mmol, 165 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL
THF were performed to obtain the desired N-(2-methoxyphenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ae) in 94% (239
mg) yield as off-white solid.
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N-(2-methoxyphenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ae)7b (Scheme 3): Off-white solid; Rf = 0.40 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 97:3); Yield: 239 mg (94%); m.p
= 110 - 111 °C; 1H NMR (400 MHz, CDCl3) δ = 8.41 - 8.39 (m, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 8.0 Hz,
1H), 7.03 - 696 (m, 4H), 6.87 - 6.85 (m, 1H), 5.24 (s, 2H), 3.88 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ =
151.3, 147.8, 141.8, 128.9, 128.2, 123.5, 123.2, 122.5, 122.2, 121.2, 121.0, 119.0, 109.9, 67.5, 55.6 ppm; MS (APCI):
[M]+ = 255.1 (100%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H15N2O2: 255.1133; found: 255.1129.
Synthesis of N-(4-methoxyphenyl)-4H-benzo[d][1,3]oxazin-2-amine (4af)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 4-
methoxyphenyl isothiocyanate (2f) (1.0 mmol, 165 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL
THF were performed to obtain the desired N-(4-methoxyphenyl)-4H-benzo[d][1,3]oxazin-2-amine (4af) in 90% (229
mg) yield as off-white solid.
N-(4-methoxyphenyl)-4H-benzo[d][1,3]oxazin-2-amine (4af)22 (Scheme 3): Off-white solid; Rf = 0.30 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 229 mg (90%); m.p
= 132 - 133 °C (Lit22 133 - 135 °C); 1H NMR (400 MHz, CDCl3) δ = 7.35 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.6 Hz,
1H), 7.02 - 6.98 (m, 3H), 6.87 (d, J = 7.2 Hz, 2H), 5.21 (s, 2H), 3.79 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
δ = 155.8, 152.3, 141.3, 132.4, 129.0, 123.6, 122.6, 122.5, 120.9, 120.7, 114.1, 67.7, 55.5 ppm; MS (APCI): [M]+ =
255.1 (98.06%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H15N2O2: 255.1133; found: 255.1131.
Synthesis of N-(3-fluorophenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ag)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 3-
fluorophenyl isothiocyanate (2g) (1.0 mmol, 153 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF
were performed to obtain the desired N-(3-fluorophenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ag) in 89% (216 mg)
yield as off-white solid.
N-(3-fluorophenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ag) (Scheme 3): Off-white solid; Rf = 0.40 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 216 mg (89%); m.p
= 120 - 121 °C; 1H NMR (400 MHz, CDCl3) δ = 7.45 (d, J = 7.2 Hz, 1H), 7.28 - 7.19 (m, 2H), 7.05 - 6.99 (m, 4H),
6.73 (t, J = 7.6 Hz, 1H), 5.25 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 163.1 (d, J = 243.3 Hz), 151.2, 141.6
(d, J = 10.7 Hz), 140.4, 129.8 (d, J = 9.8 Hz), 129.1, 123.7, 123.2, 120.9, 120.6, 115.6, 109.6 (d, J = 21.3 Hz), 107.7
(d, J = 80 Hz), 67.8 ppm; MS (APCI): [M]+ = 243.1 (98.81%); HRMS (ESI-QTOF, [M + H]+): calculated for
C14H12FN2O: 243.0933; found: 243.0930.
Synthesis of N-(3,5-bis(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ah)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 3,5-
bis(trifluoromethyl)phenyl isothiocyanate (2h) (1.0 mmol, 271 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg)
in 2 mL THF were performed to obtain the desired N-(3,5-bis(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-2-
amine (4ah) in 95% (342 mg) yield as off-white solid.
N-(3,5-bis(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ah) (Scheme 3): Off-white solid; Rf = 0.30
(SiO2, Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 342 mg (95%);
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m.p = 150 - 151 °C; 1H NMR (400 MHz, CDCl3) δ = 7.83 (s, 2H), 7.51 (s, 1H), 7.28 - 7.24 (m, 1H), 6.05 (d, J = 8.0
Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 5.26 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 150.7, 143.6, 138.2, 132.5
(q, J = 33.27 Hz), 129.3, 124.0, 123.4, 123.2 (q, J = 270.2 Hz), 121.4, 119.8, 119.2, 118.5, 116.0, 68.1 ppm; MS
(APCI): [M]+ = 361.0 (100%); HRMS (ESI-QTOF, [M + H]+): calculated for C16H11F6N2O: 361.0775; found:
361.0772.
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Synthesis of N-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ai)
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According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 4-
(trifluoromethyl)phenyl isothiocyanate (2i) (1.0 mmol, 203 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in
2 mL THF were performed to obtain the desired N-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ai)
in 93% (272 mg) yield as yellow solid.
N-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-2-amine (4ai) (Scheme 3): Yellow solid; Rf = 0.30 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 272 mg (93%); m.p
= 168 - 169 °C; 1H NMR (400 MHz, DMSO-d6) δ = 9.74 (br, 1H), 7.92 (br, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.22 (t, J
= 7.6 Hz, 1H), 7.08 (d, J = 6.8 Hz, 1H), 7.02 - 6.97 (m, 2H), 5.28 (s, 2H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6)
δ = 151.2, 144.2, 141.2, 129.1, 126.2, 125.5 (q, J = 246.27 Hz ), 124.5, 123.5, 122.7, 122.3 (d, J = 34.0 Hz ), 119.3,
67.2 ppm; MS (APCI): [M]+ = 293.1 (99.78%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H12F3N2O:
293.0901; found: 293.0898
Synthesis of N-(2-methyl-4-nitrophenyl)-4H-benzo[d][1,3]oxazin-2-amine (4aj)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 2-methyl-4-
nitrophenyl isothiocyanate (2j) (1.0 mmol, 194 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF
were performed to obtain the desired N-(2-methyl-4-nitrophenyl)-4H-benzo[d][1,3]oxazin-2-amine (4aj) in 91% (258
mg) yield as yellow solid.
N-(2-methyl-4-nitrophenyl)-4H-benzo[d][1,3]oxazin-2-amine (4aj) (Scheme 3): Yellow solid; Rf = 0.20 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 92:8); Yield: 258 mg (91%); m.p
= 186 - 188 °C; 1H NMR (400 MHz, DMSO-d6) δ = 10.15 (br, 1H), 8.04 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.24 (t, J
= 8.0 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.09 (br, 1H), 6.96 (d, J = 8.0 Hz, 2H), 5.19 (s, 2H), 2.22 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, DMSO-d6) δ = 148.5, 142.0, 137.5, 131.9, 129.3, 125.4, 124.8, 123.4, 122.3, 119.9, 115.2, 67.6,
18.41 ppm; MS (APCI): [M]+ = 284.1 (99.78%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H14N3O3:
284.1035; found: 284.1031.
Synthesis of ethyl (4H-benzo[d][1,3]oxazin-2-yl)carbamate (4ak)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg),
ethoxycarbonyl isothiocyanate (2k) (1.0 mmol, 131 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL
THF were performed to obtain the desired ethyl (4H-benzo[d][1,3]oxazin-2-yl)carbamate (4ak) in 96% (211 mg) yield
as white solid.
ethyl (4H-benzo[d][1,3]oxazin-2-yl)carbamate (4ak) (Scheme 3): White solid; Rf = 0.30 (SiO2, Hexane/EtOAc =
8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 211 mg (96%); m.p = 91 - 92 °C; 1H
NMR (400 MHz, CDCl3) δ = 11.0 (br, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.14 - 7.09 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H),
5.31 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 132.8,
129.5, 124.6, 124.4, 118.8, 115.4, 67.6, 61.7, 14.3 ppm; MS (APCI): [M]+ = 221.1 (99.74%); HRMS (ESI-QTOF,
[M + H]+): calculated for C11H13N2O3: 221.0926; found: 221.0920.
Synthesis of N-(furan-2-ylmethyl)-4H-benzo[d][1,3]oxazin-2-amine (4al)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 2-
(isothiocyanatomethyl)furan (2l) (1.0 mmol, 139 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF
were performed to obtain the desired N-(furan-2-ylmethyl)-4H-benzo[d][1,3]oxazin-2-amine (4al) in 92% (210 mg)
yield as off-white solid.
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N-(furan-2-ylmethyl)-4H-benzo[d][1,3]oxazin-2-amine (4al) (Scheme 3): Off-white solid; Rf = 0.30 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 210 mg (92%); m.p
= 106 - 107 °C; 1H NMR (400 MHz, CDCl3) δ = 7.35 (s, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.97
- 6.89 (m, 2H), 6.29 (d, J = 19.2 Hz, 2H), 5.14 (s, 2H), 4.52 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 154.6,
142.3, 142.1, 128.9, 123.4, 122.4, 121.7, 121.0, 110.3, 107.2, 67.5, 38.7 ppm; HRMS (ESI-QTOF, [M + H]+):
calculated for C13H13N2O2: 229.0977; found: 229.0973.
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Synthesis of N-propyl-4H-benzo[d][1,3]oxazin-2-amine (4am)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), propyl
isothiocyanate (2m) (1.0 mmol, 101 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-propyl-4H-benzo[d][1,3]oxazin-2-amine (4am) in 80% (152 mg) yield as viscous
liquid.
N-propyl-4H-benzo[d][1,3]oxazin-2-amine (4am) (Scheme 3): Viscous liquid; Rf = 0.50 (SiO2, Hexane/EtOAc =
8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 80:20); Yield: 152 mg (80%); 1H NMR (400 MHz,
CDCl3) δ = 7.25 - 7.18 (m, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.92 - 6.88 (m, 2H), 5.12 (s, 2H), 4.44 (bs, 1H), 3.29 (t, J =
6.80 Hz, 2H), 1.62 - 1.56 (m, 2H), 0.96 (t, J = 7.20 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 155.2, 142.7,
128.9, 123.4, 122.1, 121.5, 120.9, 67.4, 43.3, 23.0, 11.2 ppm; MS (APCI): [M + 1]+ = 191.3 (98.53%); HRMS (ESI-
QTOF, [M + H]+): calculated for C11H15N2O: 191.1184; found: 191.1180.
Synthesis of N-isopropyl-4H-benzo[d][1,3]oxazin-2-amine (4an)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), isopropyl
isothiocyanate (2n) (1.0 mmol, 101 mg), Et3N (2.0 mmol, 202 mg), I2 (1.1 mmol, 140 mg) in 2 mL THF were
performed to obtain the desired N-isopropyl-4H-benzo[d][1,3]oxazin-2-amine (4an) in 82% (156 mg) yield as viscous
liquid.
N-isopropyl-4H-benzo[d][1,3]oxazin-2-amine (4an) (Scheme 3): Viscous liquid; Rf = 0.45 (SiO2, Hexane/EtOAc
= 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 80:20); Yield: 152 mg (80%); H NMR (400
MHz, CDCl3) δ = 7.24 - 7.17 (m, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.91 - 6.88 (m, 2H), 5.09 (s, 2H), 4.01 - 3.98 (m, 1H),
1.20 (d, J = 6.80 Hz, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 154.4, 142.7, 128.9, 123.4, 122.0, 121.4, 120.9,
67.3, 43.2, 23.1 ppm; MS (APCI): [M + 1]+ = 191.3 (94.55%); HRMS (ESI-QTOF, [M + H]+): calculated for
C11H15N2O: 191.1184; found: 191.1181.
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Experimental procedures and analytical data of synthesized 2-amino-1,3-benzothiazines (5aa-ia, 5ab-al, 5ao-
ar)
Synthesis of N-(4H-benzo[d][1,3]thiazin-2-yl)benzamide (5aa)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), benzoyl
isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in ethyl acetate)
in 2 mL MeCN were performed to obtain the desired N-(4H-benzo[d][1,3]thiazin-2-yl)benzamide (5aa) in 98% (263
mg) yield as white solid.
N-(4H-benzo[d][1,3]thiazin-2-yl)benzamide (5aa)23 (Table 1, Scheme 4): White solid; Rf = 0.60 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 87:13); Yield: 263 mg (98%);
m.p = 123 - 124 °C; 1H NMR (400 MHz, CDCl3) δ = 12.0 (bs, 1H), 8.17 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H),
7.44 (t, J = 7.6 Hz, 2H), 7.32 - 7.27 (m, 1H), 7.17 (d, J = 4.0 Hz, 2H), 7. 2 (d, J = 8.0 Hz, 1H), 4.02 (s, 2H) ppm;
13C{1H} NMR (100 MHz, DMSO-d6) δ = 172.4, 164.5, 138.4, 135.7, 132.5, 129.3, 128.7, 128.5, 127.3, 125.2, 121.6,
119.6, 28.2 ppm; HRMS (ESI-QTOF, [M + H]+): calculated for C15H13N2OS: 269.0748; found: 269.0751.
Synthesis of N-(7-methyl-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ba)
According to the general procedure, reactions between 2-amino-4-methylbenzyl alcohol (1b) (1.0 mmol, 137 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in
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ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(7-methyl-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (5ba) in 95% (268 mg) yield as off-white solid.
N-(7-methyl-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ba) (Scheme 4): Off-white solid; Rf = 0.60 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 90:10); Yield: 268 mg (95%);
m.p = 145 - 146 °C; 1H NMR (400 MHz, DMSO-d6) δ = 11.61 (br, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.2 Hz,
1H), 7.47 (t, J = 7.6 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.94 (d, J = 7.6 Hz, 1H), 3.90 (s, 2H), 2.27 (s, 3H)
ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 170.2 (less intense), 137.9, 135.8, 132.5, 129.3, 128.7, 127.1, 125.8,
119.8, 118.6, 28.0, 21.2 ppm; MS (APCI): [M + 1]+ = 283.1 (100%); HRMS (ESI-QTOF, [M + H]+): calculated for
C16H15N2OS: 283.0905; found: 283.0900.
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Synthesis of N-(8-methyl-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ca)
According to the general procedure, reactions between 2-amino-3-methylbenzyl alcohol (1c) (1.0 mmol, 137 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in
ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(8-methyl-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (5ca) in 90% (254 mg) yield as off-white solid.
N-(8-methyl-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ca) (Scheme 4): Off-white solid; Rf = 0.60 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 90:10); Yield: 254 mg (90%);
m.p = 127 - 128 °C; 1H NMR (400 MHz, DMSO-d6) δ = 11.54 (br, 1H), 8.04 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.2 Hz,
1H), 7.49 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 4.8 Hz, 1H), 7.06 (d, J = 4.8 Hz, 2H), 3.93 (s, 2H), 2.32 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, DMSO-d6) δ = 170.1 (less intense), 138.7, 134.5, 132.8, 130.0, 129.1, 128.7, 125.7, 125.0, 121.9,
28.8, 17.7 ppm; MS (APCI): [M + 1]+ = 283.1 (100%); HRMS (ESI-QTOF, [M + H]+): calculated for C16H15N2OS:
283.0905; found: 283.0902.
Synthesis of N-(6-fluoro-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5da)
According to the general procedure, reactions between 2-amino-5-fluorobenzyl alcohol (1d) (1.0 mmol, 141 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in
ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(6-fluoro-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (5da) in 98% (280 mg) yield as off-white solid.
N-(6-fluoro-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5da) (Scheme 4): Off-white solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 85:15); Yield: 280 mg (98%);
m.p = 106 - 107 °C; 1H NMR (400 MHz, CDCl3) δ = 11.00 (br, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.57 - 7.53 (m, 1H),
7.46 (t, J = 8.0 Hz, 2H), 7.01 (d, J = 6.8 Hz, 2H), 6.90 (d, J = 7.6 Hz, 1H), 3.97 (s, 2H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ = 172.1 (less intense), 162.5, 160.3 (d, J = 250.50 Hz), 134.9, 132.5, 128.7, 128.4, 122.5, 121.9, 121.8,
115.4 (d, J = 22.8 Hz), 114.1 (d, J = 23.7 Hz), 28.9 ppm; MS (APCI): [M + 1]+ = 287.0 (100%); HRMS (ESI-QTOF,
[M + H]+): calculated for C15H12FN2OS: 287.0654; found: 287.0651.
Synthesis of N-(7-fluoro-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ea)
According to the general procedure, reactions between 2-amino-4-fluorobenzyl alcohol (1e) (1.0 mmol, 141 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in
ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(7-fluoro-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (5ea) in 90% (258 mg) yield as off-white solid.
N-(7-fluoro-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ea) (Scheme 4): Off-white solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 85:15); Yield: 258 mg (90%);
m.p = 108 - 109 °C; 1H NMR (400 MHz, DMSO-d6) δ = 11.65 (br, 1H), 8.07 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.2 Hz,
1H), 7.47 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H) 7.00 - 6.94 (m, 2H), 3.94 (s, 2H) ppm; 13C{1H} NMR (100 MHz,
DMSO-d6) δ = 172.0 (less intense), 162.1 (d, J = 242.2 Hz), 140.6, 135.2, 132.7, 129.3, 128.9, 128.8, 117.6, 111.7 (d,
J = 20.1 Hz), 106.9, 27.6 ppm; HRMS (ESI-QTOF, [M + H]+): calculated for C15H12FN2OS: 287.0654; found:
287.0653.
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Synthesis of N-(8-fluoro-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5fa)
According to the general procedure, reactions between 2-amino-3-fluorobenzyl alcohol (1f) (1.0 mmol, 141 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in
ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(8-fluoro-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (5fa) in 89% (255 mg) yield as off-white solid.
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N-(8-fluoro-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5fa) (Scheme 4): Off-white solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 85:15); Yield: 255 mg (89%);
m.p = 124 - 125 °C; 1H NMR (400 MHz, CDCl3) δ = 11.25 (br, 1H), 8.13 (d, J = 6.8 Hz, 2H), 7.53 (d, J = 6.8 Hz,
1H), 7.46 (t, J = 6.4 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 6.97 (d, J = 6.6 Hz, 1H), 4.02 (s, 2H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ = 172.0 (less intense), 164.0, 153.8 (d, J = 251.75 Hz), 134.7, 132.6, 128.9, 128.4, 125.8 (d, J = 8.40
Hz), 122.45, 122.1, 115.2 (d, J = 19.40 Hz), 28.7 ppm; MS (APCI): [M + 1]+ = 287.0 (100%); HRMS (ESI-QTOF,
[M + H]+): calculated for C15H12FN2OS: 287.0654; found: 287.0650.
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Synthesis of N-(6-chloro-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ga)
According to the general procedure, reactions between 2-amino-5-chlorobenzyl alcohol (1g) (1.0 mmol, 157.6 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in
ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(6-chloro-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (5ga) in 95% (287 mg) yield as white solid.
N-(6-chloro-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ga) (Scheme 4): White solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 85:15); Yield: 287 mg (95%);
m.p = 148 - 149 °C; 1H NMR (400 MHz, CDCl3) δ = 11.02 (br, 1H), 8.04 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 7.6 Hz,
1H), 7.41 (t, J = 7.6 Hz, 2H), 7.21 (dd, J = 2.0, 8.4 Hz, 1H) 7.13 (s, 1H), 6.92 (d, J = 7.6 Hz, 1H ), 3.91 (s, 2H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ = 172.1 (less intense), 162.4 (less intense), 137.3, 134.4, 132.6, 130.8, 128.7,
128.6, 128.4, 127.0, 122.3, 121.6, 28.7 ppm; HRMS (ESI-QTOF, [M + H]+): calculated for C15H12ClN2OS: 303.0358;
found: 303.0350.
Synthesis of N-(7-chloro-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ha)
According to the general procedure, reactions between 2-amino-4-chlorobenzyl alcohol (1h) (1.0 mmol, 157.6 mg),
benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in
ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(7-chloro-4H-benzo[d][1,3]thiazin-2-
yl)benzamide (5ha) in 90% (272 mg) yield as white solid.
-(7-chloro-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ha) (Scheme 4): White solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 85:15); Yield: 272 mg (90%);
m.p = 151 - 152 °C; 1H NMR (400 MHz, DMSO-d6) δ = 11.72 (br, 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.2 Hz,
1H), 7.48 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 7.6 Hz, 1H) 7.19 (d, J = 8.0 Hz, 2H), 3.95 (s, 2H) ppm; 13C{1H} NMR (100
MHz, DMSO-d6) δ = 136.3(less intense), 132.7, 132.6, 129.3, 128.9, 128.8, 124.9, 120.5, 27.7 ppm; MS (APCI): [M
+ 1]+ = 303.0 (100%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H12ClN2OS: 303.0358; found: 303.0354.
Synthesis of N-(7-(trifluoromethyl)-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ia)
According to the general procedure, reactions between 2-amino-4-(trifluoromethyl)benzyl alcohol (1i) (1.0 mmol, 191
mg), benzoyl isothiocyanate (2a) (1.0 mmol, 163 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. %
in ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(7-(trifluoromethyl)-4H-benzo[d][1,3]thiazin-
2-yl)benzamide (5ia) in 90% (303 mg) yield as white solid.
N-(7-(trifluoromethyl)-4H-benzo[d][1,3]thiazin-2-yl)benzamide (5ia) (Scheme 4): White solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 86:14); Yield: 303 mg (90%);
m.p = 116 - 117 °C; 1H NMR (400 MHz, DMSO-d6) δ = 11.82 (br, 1H), 8.05 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.2 Hz,
1H), 7.50 - 7.47 (m, 5H), 4.05 (s, 2H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 134.8, 132.8, 129.3, 129.2 (q,
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J = 31.8 Hz), 128.5, 126.1, 124.7 (q, J = 272.1 Hz),121.7, 116.3, 27.9 ppm; MS (APCI): [M + 1]+ = 337.0 (98.57%);
HRMS (ESI-QTOF, [M + H]+): calculated for C16H12F3N2OS: 337.0622; found: 337.0618.
Synthesis of N-phenyl-4H-benzo[d][1,3]thiazin-2-amine (5ab)
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According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), phenyl
isothiocyanate (2b) (1.0 mmol, 135 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in ethyl
acetate) in 2 mL MeCN were performed to obtain the desired N-phenyl-4H-benzo[d][1,3]thiazin-2-amine (5ab) in
96% (231 mg) yield as white solid.
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N-phenyl-4H-benzo[d][1,3]thiazin-2-amine (5ab)24 (Scheme 5 and 7): White solid; Rf = 0.60 (SiO2, Hexane/EtOAc
= 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 88:12); Yield: 231 mg (96%); m.p = 201 - 202
°C (Lit24 203 °C); 1H NMR (400 MHz, CDCl3) δ = 7.41 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 8.0 Hz, 2H), 7.25 (t, J = 7.2
Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.09 - 7.03 (m, 3H), 3.92 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 152.0,
142.9, 142.5, 128.9, 128.4, 126.6, 123.7, 122.1, 121.1, 120.0, 29.9 ppm; MS (APCI): [M + 1]+ = 241.1 (94.62%);
HRMS (ESI-QTOF, [M + H]+): calculated for C14H13N2S: 241.0799; found: 241.0790.
Synthesis of N-(2,4-dimethylphenyl)-4H-benzo[d][1,3]thiazin-2-amine (5ac)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 2,4-
dimethylphenyl isothiocyanate (2c) (1.0 mmol, 163 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt.
% in ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(2,4-dimethylphenyl)-4H-
benzo[d][1,3]thiazin-2-amine (5ac) in 89% (239 mg) yield as off-white solid.
N-(2,4-dimethylphenyl)-4H-benzo[d][1,3]thiazin-2-amine (5ac) (Scheme 5): Off-white solid; Rf = 0.40 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 85:15); Yield: 239 mg (89%);
m.p = 176 - 177 °C; 1H NMR (400 MHz, CDCl3) δ = 7.22 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.12 - 7.07 (m, 2H), 7.02
(d, J = 7.2 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 3.89 (s, 2H), 2.32 (s, 3H), 2.21 (S, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ = 153.6, 142.6, 142.0, 136.0, 130.2, 128.3, 127.2, 126.6, 125.2, 123.9, 122.8,
120.2, 29.7, 21.0, 17.5 ppm; MS (APCI): [M + 1]+ = 269.1 (98.91%); HRMS (ESI-QTOF, [M + H]+): calculated for
C16H17N2S: 269.1112; found: 269.1108.
Synthesis of N-(p-tolyl)-4H-benzo[d][1,3]thiazin-2-amine (5ad)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), p-tolyl
isothiocyanate (2d) (1.0 mmol, 149 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in ethyl
acetate) in 2 mL MeCN were performed to obtain the desired N-(p-tolyl)-4H-benzo[d][1,3]thiazin-2-amine (5ad) in
91% (231 mg) yield as off-white solid.
N-(p-tolyl)-4H-benzo[d][1,3]thiazin-2-amine (5ad)25 (Scheme 5): Off-white solid; Rf = 0.60 (SiO2, Hexane/EtOAc
= 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 90:10); Yield: 231 mg (91%); m.p = 186 - 188
°C (Lit25 188 - 189 °C); 1H NMR (400 MHz, DMSO-d6) δ = 9.32 (br, 1H), 7.71 (s, 2H), 7.24 - 7.15 (m, 2H), 7.08 (d,
J = 8.0 Hz, 2H) 7.02 (d, J = 7.2 Hz, 2H), 4.00 (s, 2H), 2.24 (s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ =
150.7, 145.0, 139.3, 131.7, 129.4, 128.3, 127.2, 123.5, 120.7, 120.5, 29.1, 20.8 ppm; MS (APCI): [M + 1]+ = 255.1
(99.61%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H15N2S: 255.0955; found: 255.0950.
Synthesis of N-(2-methoxyphenyl)-4H-benzo[d][1,3]thiazin-2-amine (5ae)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 2-
methoxyphenyl isothiocyanate (2e) (1.0 mmol, 165 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt.
% in ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(2-methoxyphenyl)-4H-
benzo[d][1,3]thiazin-2-amine (5ae) in 90% (243 mg) yield as white solid.
N-(2-methoxyphenyl)-4H-benzo[d][1,3]thiazin-2-amine (5ae)25 (Scheme 5): White solid; Rf = 0.60 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 90:10); Yield: 243 mg (90%);
m.p = 116 - 118 °C (Lit25 116 - 117 °C); 1H NMR (400 MHz, DMSO-d6) δ = 10.15 (br, 1H), 8.20 (br, 1H), 7.21 -
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7.15 (m, 2H), 7. 01 - 6.88 (m, 5H), 3.94 (s, 2H), 3.75 (s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 152.1,
151.0, 143.23, 128.3, 127.2, 124.3, 123.2, 122.9, 120.9, 120.7, 111.8, 55.9, 28.9 ppm; MS (APCI): [M + 1]+ = 271.1
(98.42%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H15N2OS: 271.0905; found: 271.0900.
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Synthesis of N-(4-methoxyphenyl)-4H-benzo[d][1,3]thiazin-2-amine (5af)
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According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 4-
methoxyphenyl isothiocyanate (2f) (1.0 mmol, 165 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt.
% in ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(4-methoxyphenyl)-4H-
benzo[d][1,3]thiazin-2-amine (5af) in 94% (254 mg) yield as pink solid.
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N-(4-methoxyphenyl)-4H-benzo[d][1,3]thiazin-2-amine (5af)25 (Scheme 5): Pinkish solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 85:15); Yield: 254 mg (94%);
m.p = 180 - 181 °C (Lit25 179 - 180 °C); 1H NMR (400 MHz, DMSO-d6) δ = 9.27 (br, 1H), 7.74 (s, 2H), 7.24 - 7.14
(m, 2H), 7. 00 (d, J = 7.6 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 3.98 (s, 2H), 3.71 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
DMSO-d6) δ = 155.2, 150.7, 145.0, 135.4, 128.3, 127.2, 123.3, 121.9, 120.8, 114.8, 114.2, 113.5, 55.6, 29.1 ppm; MS
(APCI): [M + 1]+ = 271.1 (99.78%); HRMS (ESI-QTOF, [M + H]+): calculated for C15H15N2OS: 271.0905; found:
271.0903.
Synthesis of N-(3-fluorophenyl)-4H-benzo[d][1,3]thiazin-2-amine (5ag)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 3-
fluorophenyl isothiocyanate (2g) (1.0 mmol, 153 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. %
in ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(3-fluorophenyl)-4H-benzo[d][1,3]thiazin-2-
amine (5ag) in 93% (240 mg) yield as white solid.
N-(3-fluorophenyl)-4H-benzo[d][1,3]thiazin-2-amine (5ag) (Scheme 5): White solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 87:13); Yield: 240 mg (93%);
m.p = 189 - 190 °C; 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (br, 1H), 7.94 (br, 1H), 7.52 (br, 1H), 7.32 - 7.17 (m,
3H), 7.08 - 7.04 (m, 2H), 6.79 (t, J = 7.6 Hz, 1H), 4.03 (s, 2H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 162.6
(d, J = 240.9 Hz), 151.0, 144.4, 130.5 (d, J = 10.1 Hz), 128.45, 127.3, 124.7, 120.7, 116.0, 109.2 (d, J = 20..9 Hz),
106.9, 29.0 ppm; HRMS (ESI-QTOF, [M + H]+): calculated for C14H12FN2S: 259.0705; found: 259.0703.
Synthesis of N-(3,5-bis(trifluoromethyl)phenyl)-4H-benzo[d][1,3]thiazin-2-amine (5ah)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 3,5-
bis(trifluoromethyl)phenyl isothiocyanate (2h) (1.0 mmol, 271 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution
(≥50 wt. % in ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(3,5-bis(trifluoromethyl)phenyl)-
4H-benzo[d][1,3]thiazin-2-amine (5ah) in 91% (342 mg) yield as white solid.
N-(3,5-bis(trifluoromethyl)phenyl)-4H-benzo[d][1,3]thiazin-2-amine (5ah) (Scheme 5): White solid; Rf = 0.50
(SiO2, Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 85:15); Yield: 342 mg
(91%); m.p = 139 - 140 °C; 1H NMR [VT@90deg] (400 MHz, DMSO-d6) δ = 9.90 (br, 1H), 8.59 (br, 2H), 7.58 (s,
1H), 7.27 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 6.8 Hz, 1H), 7.08 - 7.03 (m, 2H), 4.08 (s, 2H) ppm; 13C{1H} NMR (100
MHz, DMSO-d6) δ = 150.9, 144.5, 142.7, 131.0 (q, J = 32.5 Hz), 128.6, 127.4, 125.1, 123.8 (q, J = 232.5 Hz), 120.5,
119.2, 114.9, 29.0 ppm; MS (APCI): [M + 1]+ = 377.0 (99.85%); HRMS (ESI-QTOF, [M + H]+): calculated for
C16H11F6N2S: 377.0547; found: 377.0540.
Synthesis of N-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]thiazin-2-amine (5ai)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 4-
(trifluoromethyl)phenyl isothiocyanate (2i) (1.0 mmol, 203 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution
(≥50 wt. % in ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(4-(trifluoromethyl)phenyl)-4H-
benzo[d][1,3]thiazin-2-amine (5ai) in 90% (277 mg) yield as white solid.
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N-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]thiazin-2-amine (5ai) (Scheme 5): White solid; Rf = 0.50 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 85:15); Yield: 277 mg (90%);
m.p = 228 - 229 °C; 1H NMR [VT@90deg] (400 MHz, DMSO-d6) δ = 9.50 (br, 1H), 8.01 (br, 2H), 7.59 (d, J = 7.6
Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.05 - 7.01 (m, 1H), 4.03 (s, 2H)
ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 150.5, 145.0, 144.5, 129.0, 127.3, 126.3, 126.2, 124.7 (q, J = 242.57
Hz), 122.8 (q, J = 32.3 Hz), 122.4, 120.9, 120.6, 119.6, 29.0 ppm; HRMS (ESI-QTOF, [M + H]+): calculated for
C15H12F3N2S: 309.0673; found: 309.0680.
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Synthesis of N-(2-methyl-4-nitrophenyl)-4H-benzo[d][1,3]thiazin-2-amine (5aj)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 2-methyl-4-
nitrophenyl isothiocyanate (2j) (1.0 mmol, 194 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in
ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(2-methyl-4-nitrophenyl)-4H-
benzo[d][1,3]thiazin-2-amine (5aj) in 88% (263 mg) yield as yellow solid.
N-(2-methyl-4-nitrophenyl)-4H-benzo[d][1,3]thiazin-2-amine (5aj) (Scheme 5): Yellow solid; Rf = 0.35 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 80:20); Yield: 263 mg (88%);
m.p = 243 - 245 °C; 1H NMR (400 MHz, DMSO-d6) δ = 10.65 (br, 1H), 8.09 (s, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.21
(d, J = 7.6 Hz, 2H), 7.08 (d, J = 7.2 Hz, 1H), 6.94 - 6.92 (m, 2H), 4.01 (s, 2H), 2.20 (s, 3H) ppm; 13C{1H} NMR (100
MHz, DMSO-d6) δ = 155.1, 153.3, 142.9, 139.9, 131.5, 128.5, 127.3, 125.6, 123.4, 122.8, 122.5, 122.5, 120.8, 117.6,
28.6, 18.1 ppm; HRMS (ESI-QTOF, [M + H]+): calculated for C15H14N3O2S: 300.0806; found: 300.0800.
Synthesis of ethyl (4H-benzo[d][1,3]thiazin-2-yl)carbamate (5ak)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg),
ethoxycarbonyl Isothiocyanate (2k) (1.0 mmol, 131 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt.
% in ethyl acetate) in 2 mL MeCN were performed to obtain the desired ethyl (4H-benzo[d][1,3]thiazin-2-
yl)carbamate (5ak) in 93% (220 mg) yield as white crystalline solid.
Ethyl (4H-benzo[d][1,3]thiazin-2-yl)carbamate (5ak) (Scheme 5): White crystalline solid; Rf = 0.60 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 90:10); Yield: 220 mg (93%);
m.p = 93 - 94 °C; 1H NMR (400 MHz, DMSO-d6) δ = 7.30 - 7.26 (m, 1H), 7.15 - 7.11 (m, 2H), 6.97 (d, J = 8.0 Hz,
1H), 4.21 (q, J = 7.2 Hz, 2H), 3.97 (s, 2H), 1.32 (t, J = 6.8 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ =
161.3, 157.6, 140.0, 128.5, 127.2, 125.1, 120.9, 61.3, 28.1, 14.8 ppm; HRMS (ESI-QTOF, [M + H]+): calculated for
C11H13N2O2S: 237.0697; found: 237.0695.
Synthesis of N-(furan-2-ylmethyl)-4H-benzo[d][1,3]thiazin-2-amine (5al)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 2-
(isothiocyanatomethyl)furan (2l) (1.0 mmol, 139 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. %
in ethyl acetate) in 2 mL MeCN were performed to obtain the desired N-(furan-2-ylmethyl)-4H-benzo[d][1,3]thiazin-
2-amine (5al) in 85% (208 mg) yield as off-white solid.
N-(furan-2-ylmethyl)-4H-benzo[d][1,3]thiazin-2-amine (5al) (Scheme 5): Off-white solid; Rf = 0.40 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 85:15); Yield: 208 mg (85%);
m.p = 104 - 105 °C; 1H NMR (400 MHz, DMSO-d6) δ = 7.75 (s, 1H), 7.55 (s, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.10 (d,
J = 7.6 Hz, 1H), 6.93 (t, J = 7.6 Hz, 2H), 6.36 (s, 1H), 6.29 (s, 1H), 4.54( s, 2H), 3.89 (s, 2H) ppm; 13C{1H} NMR
(100 MHz, DMSO-d6) δ = 153.3, 152.8, 146.2 142.3, 128.2, 127.1, 124.3, 122.9, 120.6, 110.9, 107.7, 38.5, 29.0 ppm;
MS (APCI): [M + 1]+ = 245.1 (99.73%); HRMS (ESI-QTOF, [M + H]+): calculated for C13H13N2OS: 245.0748;
found: 245.0743.
Synthesis of N-(o-tolyl)-4H-benzo[d][1,3]thiazin-2-amine (5ao)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), o-tolyl
isothiocyanate (2o) (1.0 mmol, 149 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in ethyl acetate)
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in 2 mL MeCN were performed to obtain the desired N-(o-tolyl)-4H-benzo[d][1,3]thiazin-2-amine (5ao) in 95% (241
mg) yield as white solid.
N-(o-tolyl)-4H-benzo[d][1,3]thiazin-2-amine (5ao)25 (Scheme 5): White solid; Rf = 0.60 (SiO2, Hexane/EtOAc =
8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 86:14); Yield: 241 mg (95%); m.p = 168 - 169 °C
(Lit25 169 - 170 °C); 1H NMR (400 MHz, DMSO-d6) δ = 10.15 (br, 1H), 7.19 - 7.15 (m, 3H), 7.09 (t, J = 7.2 Hz, 1H)
7.04 - 6.90 (m, 3H), 3.93 (s, 2H), 2.13 (s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 152.5, 142.2, 130.5,
128.3, 127.1, 126.4, 124.1, 123.5, 122.3, 120.9, 119.3, 28.8, 18.3 ppm; MS (APCI): [M + 1]+ = 254.82 (99.74%);
HRMS (ESI-QTOF, [M + H]+): calculated for C15H15N2S: 255.0955; found: 255.0948.
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Synthesis of ethyl 3-((4H-benzo[d][1,3]thiazin-2-yl)amino)propanoate (5ap)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), ethyl 3-
(furfurylthio)propionate (2p) (1.0 mmol, 214 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in
ethyl acetate) in 2 mL MeCN were performed to obtain the desired ethyl 3-((4H-benzo[d][1,3]thiazin-2-
yl)amino)propanoate (5ap) in 93% (246 mg) yield as white solid.
Ethyl 3-((4H-benzo[d][1,3]thiazin-2-yl)amino)propanoate (5ap) (Scheme 5): White solid; Rf = 0.60 (SiO2,
Hexane/EtOAc = 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 90:10); Yield: 246 mg (93%);
m.p = 59 - 60 °C; 1H NMR (400 MHz, CDCl3) δ = 7.25 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 8.0 Hz, 2H), 7.0 (d, J = 7.6
Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.86 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 3.60 (t, J = 6.6 Hz, 2H), 1.27 (t, J = 6.8 Hz,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 172.5, 153.4, 145.7, 128.2, 126.5, 124.4, 123.3, 119.9, 60.6, 37.8,
34.1, 29.9, 14.1 ppm; MS (APCI): [M + 1]+ = 265.1 (99.36%); HRMS (ESI-QTOF, [M + H]+): calculated for
C13H17N2O2S: 265.1010; found: 265.1009.
Synthesis of N-(pyridin-3-yl)-4H-benzo[d][1,3]thiazin-2-amine (5aq)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), 3-pyridyl
isothiocyanate (2q) (1.0 mmol, 136 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in ethyl
acetate) in 2 mL MeCN were performed to obtain the desired N-(pyridin-3-yl)-4H-benzo[d][1,3]thiazin-2-amine (5aq)
in 90% (217 mg) yield as brown solid.
N-(pyridin-3-yl)-4H-benzo[d][1,3]thiazin-2-amine (5aq) (Scheme 5): Brown solid; Rf = 0.15 (SiO2, Hexane/EtOAc
= 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 70:30); Yield: 217 mg (90%); m.p = 145 - 146
°C; 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (br, 1H), 8.92 (br, 1H), 8.32 (br, 1H), 8.20 (d, J = 4.0 Hz, 1H), 7.32 -
7.30 (m, 1H), 7.30 - 7.17 (m, 2H), 7.08 (d, J = 7.6 Hz, 1H), 7.02 - 6.98 (m, 1H), 4.03 (s, 2H) ppm; 13C{1H} NMR
(100 MHz, DMSO-d6) δ = 150.8 (less intense), 144.8, 143.6, 141.7, 137.9, 128.5, 127.3, 123.9, 120.7, 29.02 ppm;
HRMS (ESI-QTOF, [M + H]+): calculated for C13H12N3S: 242.0751; found: 242.0753.
Synthesis of N-methyl-4H-benzo[d][1,3]thiazin-2-amine (5ar)
The reactions of N-(4H-benzo[d][1,3]thiazin-2-yl)benzamide (5aa) (1.0 mmol, 268 mg) was perfomed using K2CO3
(2.0 mmol, 276 mg) in 2 mL MeOH at 80 °C for 2 h to obtain 4H-benzo[d][1,3]thiazin-2-amine (9aa) in 95% (156
mg) yield as off-white solid.
The reactions of 4H-benzo[d][1,3]thiazin-2-amine (9aa) (0.75 mmol, 123 mg), methyl iodide (0.9 mmol, 128 mg),
K2CO3 (1.5 mmol, 276 mg) in 2 mL MeOH at 80 °C for 12 h to obtain N-methyl-4H-benzo[d][1,3]thiazin-2-amine
(5ar) in 30% (40 mg) yield as off-white solid.
N-methyl-4H-benzo[d][1,3]thiazin-2-amine (5ar)26 (Scheme 6): Off-white solid; Rf = 0.40 (SiO2, Hexane/EtOAc
= 8:2); Purification system: CombiFlash MPLC (DCM/EtOAc = 95:5); Yield: 40 mg (30%); 1H NMR (400 MHz,
CDCl3) δ = 7.24 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 7.01 (t, J = 7.1 Hz, 1H), 3.86
(s, 2H), 3.08 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 154.5, 145.9, 128.35, 126.5, 124.5, 123.3, 120.0,
30.0, 29.4 ppm; MS (APCI): [M + 1]+ = 179.1 (99.36%); HRMS (ESI-QTOF, [M + H]+): calculated for C9H11N2S:
179.0642; found: 179.0640.
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Synthesis of N-phenyl-4H-benzo[d][1,3]selenazin-2-amine (8aa)
According to the general procedure, reactions between 2-aminobenzyl alcohol (1a) (1.0 mmol, 123 mg), phenyl
isoselenocyanate (6a) (1.0 mmol, 182 mg), Et3N (2.2 mmol, 222 mg), T3P anhydride solution (≥50 wt. % in ethyl
acetate) in 2 mL MeCN were performed to obtain the desired N-phenyl-4H-benzo[d][1,3]selenazin-2-amine (8aa) in
90% (259 mg) yield as off-white solid.
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6
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8
9
N-phenyl-4H-benzo[d][1,3]selenazin-2-amine (8aa) (Scheme 6): Off-white solid; Rf = 0.50 (SiO2, Hexane/EtOAc
= 8:2); Purification system: CombiFlash MPLC (Hexane/EtOAc = 90:10); Yield: 259 mg (90%); m.p = 211 - 212
°C; 1H NMR (400 MHz, DMSO-d6) δ = 10.36 (br, 2H), 9.45 (br, 1H), 7.85 (br, 1H), 7.28 (t, J = 8.0 Hz, 2H), 7.21 (t,
J = 7.6 Hz, 2H), 7.06 (d, J = 7.6 Hz, 1H), 7.00 (t, J = 7.2 Hz, 2H), 3.97 (s, 2H) ppm; 13C{1H} NMR (100 MHz, DMSO-
d6) δ = 147.9 (less intense), 146.8 (less intense), 141.3(less intense), 129.0, 128.1, 127.3, 125.1, 123.9, 122.9, 121.0,
120.0, 23.3 ppm; HRMS (ESI-QTOF, [M + H]+): calculated for C14H13N2Se: 289.0243; found: 289.0240.
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ASSOCIATED CONTENT
1
The crystallographic data, copies of H NMR, 13C{H} NMR and LC-MS spectra for all synthesized
compounds are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cmalakar@nitmanipur.ac.in, chdeepm@gmail.com
ORCID ID
Venkata Pattabhi Rama Kishore Putta: 0000-0002-3934-8798
Nagaraju Vodnala: 0000-0001-9549-934X
Raghuram Gujjarappa: 0000-0002-2586-3190
Ujjawal Tyagi: 0000-0002-6554-8443
Chandi C. Malakar: 0000-0002-9478-017X
Notes
The authors declare no competing financial interest
ACKNOWLEDGEMENT
CCM thank Science and Engineering Research Board (SERB), Govt. of India and NIT Manipur for
financial support in the form of research grant (ECR/2016/000337). VPRK grateful to the Department of
Medicinal Chemistry, Jubilant Biosys, Bangalore for their analytical support and NV and RG grateful to
Ministry of Human Resource and Development (MHRD), New Delhi for fellowship support.
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