Chemoselective Synthesis of Structurally Diverse 3,4

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Chemoselective Synthesis of Structurally Diverse 3,4dihydroquinazoline-2(1H)-thiones and 4H-benzo[d][1,3]thiazines Jian-Lian Dong, Pei-Shun Wei, Li-Si-Han Yu, and Jian-Wu Xie J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03120 • Publication Date (Web): 24 Jan 2018 Downloaded from http://pubs.acs.org on January 25, 2018

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The Journal of Organic Chemistry

Chemoselective Synthesis of Structurally Diverse 3,4-dihydroquinazoline-2(1H)-thiones and 4H-benzo[d][1,3]thiazines Jian-Lian Dong, Pei-Shun Wei, Li-Si-Han Yu, Jian-Wu Xie* Department of Chemistry and Life Science, Zhejiang Normal University, Jinhua 321004, P. R. China

ABSTRACT:

An

efficient,

mild

and

substrate/catalyst-controlled

chemoselective

reaction

of

o-isothiocyanato-(E)-cinnamaldehyde with amines has been established, producing three types of six membered heterocycles: 2-(4H-benzo[d][1,3]thiazin-4-yl)acetaldehydes, 2-(2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetaldehydes and (E)-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazines. The reaction scopes were quite broad and excellent yield was achieved. This method is extremely efficient and practical and can be conducted on a gram-scale with slightly inferior reactivity under catalyst-free conditions at low cost making it an ideal alternative to existing methods. INTRODUCTION Developing more effective strategies for the synthesis of structurally diverse compound collections is important in synthetic organic and medicinal chemistry, because the chemical and biological properties are usually intrinsically correlated to molecular structure. As such, the development of synthetic processes to construct structurally diverse compound collections from identical substrates represents a formidable challenge and has gained a great deal of attention. The selective transformations are an enduring topic because the efficient and selective transformations open new possibilities for the construction of complex molecules in synthetic organic and medicinal chemistry. However, the most practical solutions of selective transformations from the same starting materials into two or more different products often rely on the ACS Paragon Plus Environment

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catalysts because the strategy of using controls such as substrate, temperature, solvent to chemodiversity has been a longstanding challenge.1-3 Among the many heteroaromatic compounds, benzothiazine4-10 and 3,4-dihydroquinazoline

11-15

have recently attracted much attention because they are valuable heterocyclic

moieties with broad biological and pharmaceutical activities. Therefore, a few excellent protocols have been devoted to obtain these valuable heterocycles. The most frequently used methods are the domino Michael addition/cyclization procedures. For example, Shen et al. developed a catalyst-controlled chemoselective reaction of 2-aminophenyl acrylates with isothiocyanates to construct both benzothiazine and 3,4-dihydroquinazoline skeletons catalyzed by different lanthanide complexes;16 Kobayashi et al. reported that both benzothiazine and 3,4-dihydroquinazoline skeletons were synthesized by substrate-controlled chemoselective reaction (Scheme 1: a).17 Very recently, Xu's group developed a solvent-controlled catalyst-free chemoselective reaction for the construction of both benzothiazine and 3,4-dihydroquinazoline skeletons (Scheme 1: b).3b However, it remains highly desirable to develop chemoselective reactions using controls to construct these valuable heterocyclic moieties under mild conditions as well as avoiding the need for

toxic

metal

catalysts.

Herein,

we

present

an

efficient

chemoselective

reaction

of

o-isothiocyanato-(E)-cinnamaldehyde with amines under mild conditions, which efficiently afforded both benzothiazine derivatives and 3,4-dihydroquinazoline derivatives in moderate to high yields and with a broad substrate scope.

Scheme 1 ACS Paragon Plus Environment

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The Journal of Organic Chemistry RESULTS AND DISCUSSION

As part of our heterocyclic chemistry and medicinal chemistry research program, many efforts have been made on the development of domino new reactions for the construction of a collection of drug-like small molecules with diverse heterocyclic moieties over the past several years.18 Recently, we have successfully

developed

an

unexpected

domino

AMBH/alkylation/aldol

o-isothiocyanato-(E)-cinnamaldehydes with α-halocarbonyl compounds (Scheme 2).

19

reaction

of

We envisioned that

the domino reaction between o-isothiocyanato-(E)-cinnamaldehydes and amines would be happened to afford one or two different products. In this domino reaction, only the 4H-3,1-benzothiazine derivatives A would be obtained when the amines are secondary amines (SA); replace the secondary amines with primary amines

(PA),

two

possible

structural

isomers

(4H-3,1-benzothiazine

derivatives

A

and

3,4-dihydroquinazolines B) would be obtained (Scheme 2). In preliminary experiments, we investigated the reaction by selecting o-isothiocyanato-(E)-cinnamaldehyde 1a and pyrrolidine 2a as the model substrates under different conditions at room temperature (Table 1). Surprisingly, the domino reaction completed in 30 seconds in THF in the absence of any catalysts to afford the desired product 4H-3,1-benzothiazine 3aa in high yields. Obviously, the secondary amines first attacked the isothiocyanate group to yield the corresponding thiourea intermediate; then the S-terminus of thiourea attacked the electron deficient double bond to undergo an intramolecular Michael addition (path a) to give the desired product 4H-3,1-benzothiazine 3aa. Subsequently, the effects of solvent on the reactivity were investigated. We were pleased to find that the domino reaction proceeded smoothly in all organic solvents and the reaction was completed in a short time (within 30 seconds) to provide the desired product 4H-3,1-benzothiazine 3aa in excellent yields. No product was detected when water was used as solvent due to the low solubility of 1a in water. Among the solvents examined, use of methanol gave the best results, affording the desired product 4H-3,1-benzothiazine 3aa in 95% yield.

ACS Paragon Plus Environment


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Scheme 2 Potential Strategies for the Domino Reaction Table 1 Reaction of o-Isothiocyanato-(E)-cinnamaldehyde 1a and Pyrrolidine 2a under Different Conditionsa

entry

yield (%)b

1

Sol. THF

2

Methanol

92 95

3

DCM

93

4

Acetone

94

5

Toluene

94

6

H2O

-

a

Unless otherwise noted, reactions were performed with 0.10 mmol of 1a, 0.12 mmol of 2a, in 1.0 mL of solvent at

room temperature for 30 s; bIsolated yields.

With the optimal results in hand, we explored the scope of the reaction by employing various o-isothiocyanato-(E)-cinnamaldehydes 1a-g and secondary amines 2a-h. The results are shown in Table 2. The

scope

of

the

domino

reaction

was

shown

to

be

quite

broad

with

respect

to

o-isothiocyanato-(E)-cinnamaldehydes 1. In general, o-isothiocyanato-(E)-cinnamaldehydes with different substitution patterns including electron-withdrawing as well as electron-donating groups could be successfully applied in this reaction. The novel transformations proceeded smoothly and all the reactions were completed within 30 seconds, giving the 4H-3,1-benzothiazines 3aa-3ga in excellent yields. For ACS Paragon Plus Environment

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example, pure the 4H-3,1-benzothiazines were obtained in the domino reaction of an electron-withdrawing substituent on the aryl ring of o-isothiocyanato-(E)-cinnamaldehyde 1b in excellent yields (96-98% yield, entries 2, 3, 7 and 8); o-isothiocyanato-(E)-cinnamaldehyde with electron-donating substituent on aromatic ring were also well tolerated in the reactions and provided high yields (93-96% yield, entries 4-6). To evaluate the generality and efficiency of the reaction, we became interested in exploring other secondary amines. Other cyclic secondary amine 2b, as well as acyclic secondary amines 2c-h, could be efficiently applied in the reaction to provide the desired 4H-3,1-benzothiazines 3ab-3ah. Again short reaction times were observed, and the products were also obtained in excellent yields. Table 2 Reaction Scopes in the Domino Reaction of o-Isothiocyanato-(E)-cinnamaldehydes 1 with Secondary Amines 2a

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 a

R1 (1) H (1a) 3-Br (1b) 4-Br (1c) 4-CH3 (1d) 5-CH3 (1e) 4-OCH3 (1f) 3-NO2 (1g) 4-Cl (1g) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a)

R2

R3 (2)

C4H8(2a) C4H8(2a) C4H8(2a) C4H8(2a) C4H8(2a) C4H8(2a) C4H8(2a) C4H8(2a) C5H10(2b) Isopropyl Isopropyl (2c) Benzyl Benzyl (2d) Benzyl Methyl (2e) Cyclohexyl Cyclohexyl (2f) Allyl Allyl (2g) Ethyl Ethyl (2h)

3/Yields (%)b) 3aa/95 3ba/98 3ca/98 3da/95 3ea/96 3fa/93 3ga/96 3ha/98 3ab/97 3ac/95 3ad/96 3ae/98 3af/97 3ag/96 3ah/94

See the experiment section; b Isolated yields.

As described in Scheme 2, two possible structural isomers would be obtained by a similar treatment of o-isothiocyanato-(E)-cinnamaldehydes with primary amines in place of secondary amines. To evaluate the generality and efficiency of this reaction, primary amines 2i-l were utilized in the reaction with ACS Paragon Plus Environment


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o-isothiocyanato-(E)-cinnamaldehydes under catalyst-free conditions (Table 3). Interestingly, only one of the two

possible

structural

isomers,

3,4-dihydroquinazolines

4

was

exclusively

obtained.

o-Isothiocyanato-(E)-cinnamaldehyde 1a also reacted with aromatic primary amines bearing both an electron-withdrawing (Table 3, entry 2) and an electron-donating group (Table 3, entry 3), and the products were isolated in high yields, respectively. Furthermore, other alkyl primary amines 2l and 2m (Table 3, entries 4 and 5), as well as o-isothiocyanato-(E)-cinnamaldehydes 1c and 1e (Table 3, entries 6 and 7), could be efficiently applied in the reaction to provide the desired products. Again short reaction times were observed and the products were obtained in high yields. In addition, 3,4-dihydroquinazoline-2(1H)-thione 4aA was obtained in moderate yield under the same reaction conditions when the primary amines were replaced with ammonia (Scheme 3, Eq.1). The reaction was also proven effectively and conveniently to prepare the six membered heterocycles (4H-3,1-benzothiazine derivatives and 3,4-dihydroquinazolines) on a gram-scale with slightly inferior reactivity (Scheme 3, Eq.2). Table 3 Reaction Scopes in the Domino Reaction of o-Isothiocyanato-(E)-cinnamaldehydes 1 with Primary Amines 2a

Entry 1 2 3 4 5 6 7 a

R1 H H H H H 4-Br 5-CH3

R2 C6H5(2i) p-ClC6H4 (2j) p-MeOC6H4 (2k) PhCH2 (2l) n-Butyl (2m) PhCH2 (2l) PhCH2 (2l)

(1) (1a) (1a) (1a) (1a) (1a) (1c) (1e)

See the experiment section; b Isolated yields.


4/Yields (%)b 4ai/93% 4aj/80% 4ak/88% 4al/91% 4am/86% 4cl/90% 4el/85%

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Scheme 3

Scheme 4 Having succeeded in synthesizing both benzothiazines 3 and 3,4-dihydroquinazolines 4 from o-Isothiocyanato-(E)-cinnamaldehyde 1, we turned our attention to the possible construction of more structurally diverse compound collections from identical substrates under the similar reaction conditions. Interestingly, a product 5ai which contains thiourea and an acetal group was isolated in high yield by a similar treatment of o-isothiocyanato-(E)-cinnamaldehyde 1a with primary amine 2i catalyzed by trace hydrochloric acid (Scheme 4). To our surprise, the S-terminus of thiourea, not the N-terminus of thiourea, served as a nucleophile site to react with the γ-position of β,γ-unsaturated dimethyl acetal (Michael-type reaction, not the Aldol-type reaction)20, following elimination a methoxyl group to afford the cyclizing product 4H-3,1-benzothiazine derivative 6ai with excellent selectivity (E/Z ratio = 98:2). Toxic metal catalysts are avoided in this transformation and this method constitutes a new more efficient approach for the addition of nucleophiles at the γ-position of β,γ-unsaturated acetal. From a synthetic point of view, a one-pot synthesis is a strategy to improve the efficiency of a chemical reaction because it would avoid a lengthy separation process and purification of the intermediate chemical compounds that would save time and resources while increasing chemical yield. To our delight, the reaction of 1a with 2i proceed smoothly in ACS Paragon Plus Environment


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Table 4 Synthesis of Different Substituted 4H-3,1-Benzothiazine Derivativesa

Entry 1 2 3 4 5 6 7 8 9 10 11 a

R1 (1) H (1a) 5-CH3 (1e) 4-OCH3 (1f) 4-Cl (1g) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a)

R2 C6H5(2i) PhCH2 (2l) PhCH2 (2l) PhCH2 (2l) p-ClC6H4 (2j) m-ClC6H4 (2n) p-MeOC6H4 (2k) m-MeOC6H4 (2o) o-MeOC6H4 (2p) (R)-α-phenylethanamine (2q) n-Butyl (2m)

6/Yields (%)b 6ai/81 6el/75 6fl/72 6gl/83 6aj/65 6an/63 6ak/82 6ao/78 6ap/75 6aq/66 6am/65

E/Zc 94:6 98:2 99:1 99:1 92:8 90:10 98:2 97:3 97:3 98:2 94:6

See the experiment section; b Isolated yields; c Determined by 1H NMR.

one-pot and 4H-3,1-benzothiazine derivative 6ai were obtained in high yield without isolation of intermediate

5ai.

Then

the

scope

of

this

transformation

was

extended

to

various

o-isothiocyanato-(E)-cinnamaldehydes 1 and amines 2. As shown in Table 4, the reaction scopes proved to be broad and the novel transformations were highly selective. For example, the reaction shows wide applicability to various primary amines including benzyl amine (entries 2-4), aryl amines (entries 5-9), alkyl amine (entry 11), and chiral amine (entry 10). Good yields and excellent selectivities were obtained in the domino reaction of o-isothiocyanato-(E)-cinnamaldehydes 1 with electron-donating substituenton on aryl ring of aryl amines 2 (entries 7-9), while an electron-withdrawing substituent on aryl ring of aryl amines 2 tended to decrease the reactivity and yield (entries 5-6). Aryl amines with electron-donating substituents on the ortho, meta or para positions (entries 7-9), as well as o-isothiocyanato-(E)-cinnamaldehydes 1 with substituent on the aromatic ring (entries 2-4), afford 4H-3,1-benzothiazine derivatives 6 with slightly inferior yields (entries 7-9). The reaction with alkyl amine 2m gave desired products 6am in moderate yields and high selectivity (entry 11). Especially, moderate yields and excellent selectivity were observed when (R)-α-phenylethanamine 2q used as a nucleophile. Subsequently, the secondary amines were also proved to ACS Paragon Plus Environment

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be effective in the reaction under the same reaction conditions. For example, the domino reaction of o-isothiocyanato-(E)-cinnamaldehydes (1a and 1d) with secondary amine pyrrolidine 2a proceeded smoothly to afford desired products 6aa and 6da, respectively, in good yields (Scheme 5). In addition, 4H-3,1-benzothiazine derivative 6gl was readily converted to multifunctionalized 4H-3,1-benzothiazine derivative 7gl in excellent yield when it was treated with phenylacetyl chloride and triethylamine in dichloromethane (Scheme 6).

Scheme 5

Scheme 6 CONCLUSION In summary, with o-isothiocyanato-(E)-cinnamaldehyde as powerful and versatile precursors and because of the high reaction efficiency, excellent selectivity and yields, and good functional-group compatibility (38 examples), we have developed a facile chemoselective reaction to provide a valuable access to a wide range of 4H-3,1-benzothiazines and 3,4-dihydroquinazolines switched by substrates or catalysts. The 4H-3,1-benzothiazines (C-N formation) were obtained in excellent yield within 30 seconds when the o-isothiocyanato-(E)-cinnamaldehydes react with secondary amines; while when replace the second amines with primary amines, the 3,4-dihydroquinazolines (C-S formation) were afforded in high yields within a very short time (in 5 minutes). Interestingly, not the Aldol-type products but the Michael-type products 4H-3,1-benzothiazine derivatives which contained a methoxyvinyl group were isolated with high ACS Paragon Plus Environment


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selectivity when the reaction o-isothiocyanato-(E)-cinnamaldehydes with amines was catalyzed by trace hydrochloric acid and then refluxed in toluene in one-pot. This method is extremely efficient and practical and can be conducted on a gram-scale with slightly inferior reactivity under catalyst-free conditions at low cost making it an ideal alternative to existing methods. EXPERIMENTAL SECTION General Methods NMR spectra were recorded with tetramethylsilane as the internal standard. TLC was performed on glass-backed silica plates. Column chromatography was performed using silica gel (150-200 mesh) eluting with ethyl acetate and petroleum ether. All NMR spectra were recorded on 600 or 400 MHz MHz instrument. Chemical shifts (δ) are reported in ppm downfield from CDCl3 (δ = 7.26 ppm) or DMSO (δ = 2.50 ppm) for 1H NMR and relative to the central CDCl3 resonance (δ = 77.0 ppm) or DMSO resonance (δ = 39.5 ppm) for 13C NMR spectroscopy. Coupling constants (J) are given in Hz. ESI-HRMS spectrometer was measured with an ion trap mass spectrometer. o-Isothiocyanato-(E)-cinnamaldehydes 1 were prepared according to literature procedures.19, 21 1. General Procedure for the Preparation of 4H-3,1-Benzothiazines 3. A mixture of o-isothiocyanato-(E)-cinnamaldehyde 1a (18.9 mg, 0.1 mmol) and pyrrolidine 2a (8.5 mg, 0.12 mmol) were stirred in methanol (1.0 mL) at room temperature for 30 s, then flash chromatography on silica gel (25% ethyl acetate/petroleum ether) gave 3aa as a white solid (25 mg, 95% yield). 2-(2-(pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3aa)19. Colorless oily liquid (25 mg, 95% yield). 1H NMR (600 MHz, CDCl3) δ 9.69 (s, 1H), 7.23 (td, J = 7.7, 1.4 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 7.07 (dd, J = 7.5, 1.2 Hz, 1H), 6.97 (td, J = 7.4, 1.0 Hz, 1H), 4.50 (dd, J = 8.4, 5.9 Hz, 1H), 3.69 (s, 2H), 3.55 (s, 2H), 3.01 (ddd, J = 17.7, 8.4, 1.6 Hz, 1H), 2.84 (dd, J = 17.7, 5.8 Hz, 1H), 1.95 (dd, J = 11.8, 5.8 Hz, 4H). 13C NMR (151 MHz, CDCl3) δ 199.5, 151.4, 145.4, 128.6, 126.0, 124.9, 122.8, 121.1, 50.2, 47.9, 47.9, 37.4, 25.0, 25.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H16N2OS+H, 261.1056; found 261.1052.


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2-(5-bromo-2-(pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ba). Colorless oily liquid (33 mg, 98% yield). 1H NMR (600 MHz, CDCl3) δ 9.73 (d, J = 1.5 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.11 – 7.01 (m, 2H), 5.02 (dd, J = 10.4, 3.6 Hz, 1H), 3.61 (d, J = 91.2 Hz, 4H), 2.95 (ddd, J = 17.4, 10.4, 2.2 Hz, 1H), 2.68 (dd, J = 17.4, 3.6 Hz, 1H), 1.96 (d, J = 5.7 Hz, 4H). 13C NMR (151 MHz, CDCl3) δ 199.3, 151.7, 147.4, 129.4, 126.5, 124.4, 121.5, 120.5, 48.1, 47.9, 47.9, 36.8, 25.0, 25.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H16BrN2OS, 339.0161; found 339.0149. 2-(6-bromo-2-(pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ca). Colorless oily liquid (33 mg, 98% yield). 1H NMR (600 MHz, CDCl3) δ 9.66 (s, 1H), 7.31 (dd, J = 8.5, 2.3 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 4.45 (dd, J = 8.3, 5.8 Hz, 1H), 3.66 (s, 2H), 3.53 (s, 2H), 2.99 (ddd, J = 17.9, 8.4, 1.5 Hz, 1H), 2.82 (dd, J = 17.8, 5.8 Hz, 1H), 1.97 – 1.91 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 197.8, 150.6, 143.6, 130.4, 127.6, 125.5, 122.0, 113.5, 49.0, 47.0, 47.0, 35.8, 23.9, 23.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H16BrN2OS, 339.0161; found 339.0134. 2-(6-methyl-2-(pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3da). Colorless oily liquid (26 mg, 95% yield). 1H NMR (600 MHz, CDCl3) δ 9.68 (s, 1H), 7.06 – 7.00 (m, 2H), 6.87 (s, 1H), 4.44 (dd, J = 8.4, 5.8 Hz, 1H), 3.71 – 3.64 (m, 2H), 3.54 (s, 2H), 3.00 (ddd, J = 17.6, 8.5, 1.7 Hz, 1H), 2.82 (ddd, J = 17.7, 5.8, 0.8 Hz, 1H), 2.29 (s, 3H), 1.94 (dd, J = 11.9, 5.8 Hz, 4H). 13C NMR (151 MHz, CDCl3) δ 199.6, 150.9, 142.9, 132.3, 129.3, 126.4, 124.7, 120.9, 50.3, 47.9, 47.9, 37.5, 25.0, 25.0, 20.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H19N2OS, 275.1213; found 275.1210. 2-(7-methyl-2-(pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ea). Colorless oily liquid (26 mg, 96% yield). 1H NMR (600 MHz, CDCl3) δ 9.67 (s, 1H), 6.95 (d, J = 7.2 Hz, 2H), 6.79 (d, J = 7.6 Hz, 1H), 4.47 (dd, J = 8.3, 5.9 Hz, 1H), 3.68 (d, J = 16.5 Hz, 2H), 3.54 (s, 2H), 2.99 (ddd, J = 17.6, 8.4, 1.7 Hz, 1H), 2.82 (dd, J = 17.3, 5.6 Hz, 1H), 2.30 (s, 3H), 1.97 – 1.90 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 199.7, 151.4, 145.2, 138.4, 125.7, 125.4, 123.6, 118.2, 50.4, 47.9, 47.9, 37.3, 25.0, 25.0, 21.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H19N2OS, 275.1213; found 275.1195. ACS Paragon Plus Environment


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2-(6-methoxy-2-(pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3fa). Colorless oily liquid (27 mg, 93% yield). 1H NMR (600 MHz, CDCl3) δ 9.69 (s, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.81 (dd, J = 8.7, 2.8 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 4.45 (dd, J = 8.2, 5.9 Hz, 1H), 3.78 (s, 3H), 3.66 (s, 2H), 3.53 (s, 2H), 3.06 – 2.95 (m, 1H), 2.84 (dd, J = 17.8, 5.8 Hz, 1H), 1.98 – 1.91 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 199.5, 155.3, 150.1, 139.0, 125.8, 122.0, 114.1, 111.2, 55.5, 50.1, 47.8, 47.8, 37.6, 25.0, 25.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H19N2O2S, 291.1162; found 291.1153. 2-(5-nitro-2-(pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ga). Colorless oily liquid (29 mg, 96% yield). 1H NMR (600 MHz, CDCl3) δ 9.73 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 7.8, 1.3 Hz, 1H), 7.38 – 7.30 (m, 2H), 5.14 (dd, J = 9.7, 4.1 Hz, 1H), 3.55 (d, J = 163.2 Hz, 4H), 3.08 – 2.94 (m, 2H), 1.98 (d, J = 5.1 Hz, 4H).

13

C NMR (151 MHz, CDCl3) δ 198.7, 152.6, 148.1, 146.7, 130.3, 128.1, 118.7, 116.2, 48.1,

47.7, 47.7, 33.0, 24.9, 24.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H15N3O3S+H, 306.0907; found 306.0903. 2-(6-chloro-2-(pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ha). Colorless oily liquid (29 mg, 98% yield). 1H NMR (600 MHz, CDCl3) δ 9.67 (s, 1H), 7.17 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 4.46 (dd, J = 8.3, 5.9 Hz, 1H), 3.67 (s, 2H), 3.53 (s, 2H), 3.00 (ddd, J = 17.9, 8.3, 1.3 Hz, 1H), 2.83 (dd, J = 17.9, 5.8 Hz, 1H), 1.98 – 1.91 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 198.9, 151.6, 144.1, 128.5, 127.0, 126.1, 125.8, 122.5, 50.0, 48.0, 48.0, 36.9, 25.0, 25.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H16ClN2OS, 295.0666; found 295.0694. 2-(2-(piperidin-1-yl)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ab). Colorless oily liquid (27 mg, 97% yield). 1H NMR (600 MHz, CDCl3) δ 9.70 – 9.64 (m, 1H), 7.23 (td, J = 7.8, 1.5 Hz, 1H), 7.13 – 7.07 (m, 2H), 7.00 (td, J = 7.4, 1.2 Hz, 1H), 4.54 (dd, J = 8.2, 6.1 Hz, 1H), 3.79 – 3.68 (m, 4H), 2.94 (ddd, J = 17.6, 8.2, 1.8 Hz, 1H), 2.82 (ddd, J = 17.6, 6.1, 1.0 Hz, 1H), 1.68 (dd, J = 11.2, 5.6 Hz, 2H), 1.62 – 1.57 (m, 4H). 13

C NMR (151 MHz, CDCl3) δ 199.5, 153.3, 145.2, 128.5, 125.8, 125.0, 123.2, 121.5, 49.9, 47.8, 47.8, 37.5,

26.0, 26.0, 25.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H19N2OS, 275.1213; found 275.1197. ACS Paragon Plus Environment

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2-(2-(diisopropylamino)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ac). Colorless oily liquid (27 mg, 95% yield). 1H NMR (600 MHz, CDCl3) δ 9.76 – 9.59 (m, 1H), 7.22 (td, J = 7.8, 1.5 Hz, 1H), 7.08 (ddd, J = 17.9, 7.7, 1.2 Hz, 2H), 6.97 (td, J = 7.4, 1.3 Hz, 1H), 4.48 (dd, J = 8.0, 6.2 Hz, 1H), 4.16 (s, 2H), 2.97 – 2.77 (m, 2H), 1.38 (dd, J = 19.0, 6.7 Hz, 12H). 13C NMR (151 MHz, CDCl3) δ 199.6, 150.7, 145.3, 128.3, 125.6, 124.8, 122.7, 121.6, 49.5, 49.0, 49.0, 37.9, 22.1, 22.1, 20.9, 20.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H23N2OS, 291.1526; found 291.1531. 2-(2-(dibenzylamino)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ad). Colorless oily liquid (37 mg, 96% yield). 1H NMR (600 MHz, CDCl3) δ 9.56 (s, 1H), 7.33 (t, J = 7.3 Hz, 4H), 7.28 – 7.23 (m, 7H), 7.13 (ddd, J = 22.5, 7.7, 1.1 Hz, 2H), 7.02 (td, J = 7.4, 1.2 Hz, 1H), 4.88 (d, J = 15.4 Hz, 2H), 4.75 (d, J = 15.8 Hz, 2H), 4.55 (dd, J = 7.9, 6.3 Hz, 1H), 2.96 – 2.77 (m, 2H).

13

C NMR (151 MHz, CDCl3) δ 199.1, 154.0, 145.2,

137.7, 128.7, 128.7, 128.7, 128.7, 128.7, 128.6, 127.6, 127.6, 127.6, 127.4, 127.4, 127.4, 125.9, 125.2, 123.5, 121.6, 51.2, 49.9, 49.9, 37.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H23N2OS, 387.1526; found 387.1537. 2-(2-(benzyl(methyl)amino)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ae). Colorless oily liquid (30 mg, 98% yield). 1H NMR (600 MHz, CDCl3) δ 9.61 (s, 1H), 7.33 (t, J = 7.4 Hz, 2H), 7.29 – 7.22 (m, 4H), 7.1 – 7.13 (m, 1H), 7.10 (dd, J = 7.5, 1.4 Hz, 1H), 7.01 (td, J = 7.4, 1.2 Hz, 1H), 4.87 – 4.76 (m, 2H), 4.55 (dd, J = 8.1, 6.1 Hz, 1H), 3.16 (s, 3H), 2.94 (ddd, J = 17.7, 8.2, 1.6 Hz, 1H), 2.82 (ddd, J = 17.7, 6.1, 0.8 Hz, 1H). 13

C NMR (151 MHz, CDCl3) δ 199.3, 153.9, 145.2, 137.6, 128.7, 128.7, 128.6, 127.4, 127.3, 125.9, 125.2,

125.1, 123.3, 121.4, 54.4, 49.9, 37.6, 36.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2OS, 311.1213; found 311.1203. 2-(2-(dicyclohexylamino)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3af). Colorless oily liquid (25 mg, 96% yield). 1H NMR (600 MHz, CDCl3) δ 9.65 (s, 1H), 7.22 (td, J = 7.8, 1.4 Hz, 1H), 7.12 – 7.04 (m, 2H), 6.96 (td, J = 7.4, 1.1 Hz, 1H), 4.50 – 4.42 (m, 1H), 3.67 (s, 2H), 2.97 – 2.72 (m, 2H), 2.14 (s, 4H), 1.82 (d, J = 13.3 Hz, 4H), 1.73 (d, J = 12.1 Hz, 2H), 1.63 (dd, J = 35.1, 12.5 Hz, 4H), 1.37 – 1.27 (m, 4H), 1.21 – 1.11 ACS Paragon Plus Environment


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(m, 2H). 13C NMR (151 MHz, CDCl3) δ 199.7, 151.3, 145.2, 128.3, 125.6, 124.7, 122.7, 121.8, 58.9, 58.9, 49.5, 38.0, 32.3, 30.9, 26.5, 26.5, 26.4, 26.4, 25.6, 25.6, 25.6, 25.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H31N2OS, 371.2152; found 371.2145. 2-(2-(divinylamino)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ag). Colorless oily liquid (27 mg, 96% yield). 1H NMR (600 MHz, CDCl3) δ 9.64 (s, 1H), 7.25 – 7.21 (m, 1H), 7.13 – 7.07 (m, 2H), 7.00 (t, J = 7.4 Hz, 1H), 5.83 (ddd, J = 22.1, 10.6, 5.5 Hz, 2H), 5.20 – 5.14 (m, 4H), 4.51 (dd, J = 8.1, 6.2 Hz, 1H), 4.31 (d, J = 14.4 Hz, 2H), 4.09 (dd, J = 16.2, 5.5 Hz, 2H), 2.90 (ddd, J = 17.6, 8.2, 1.6 Hz, 1H), 2.79 (dd, J = 17.6, 6.1 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 199.3, 153.1, 145.1, 133.6, 133.6, 128.5, 125.8, 125.1, 123.3, 121.5, 117.0, 117.0, 50.6, 49.7, 49.7, 37.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H19N2OS, 287.1213; found 287.1225. 2-(2-(diethylamino)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde (3ah) 19. Colorless oily liquid (24 mg, 94% yield). 1H NMR (600 MHz, CDCl3) δ 9.65 (s, 1H), 7.26 – 7.19 (m, 1H), 7.12 – 7.05 (m, 2H), 6.97 (td, J = 7.4, 1.1 Hz, 1H), 4.50 (dd, J = 8.1, 6.1 Hz, 1H), 3.65 (dq, J = 14.0, 7.0 Hz, 2H), 3.55 (dq, J = 14.1, 7.0 Hz, 2H), 2.91 (ddd, J = 17.6, 8.2, 1.8 Hz, 1H), 2.79 (ddd, J = 17.6, 6.0, 0.8 Hz, 1H), 1.20 (t, J = 7.1 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 199.5, 152.1, 145.5, 128.5, 125.8, 124.9, 122.8, 121.4, 49.7, 43.5, 43.5, 37.5, 14.1, 14.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H19N2OS, 263.1213; found 263.1212. 2. General Procedure for the Preparation of 3,4-Dihydroquinazolines 4. A mixture of o-isothiocyanato-(E)-cinnamaldehyde 1a (18.9 mg, 0.1 mmol) and aniline 2i (11 mg, 0.12 mmol) were stirred in methanol (1.0 mL) at room temperature for 5 min., then flash chromatography on silica gel (25% ethyl acetate/petroleum ether) gave 4ai as a white solid (26 mg, 93% yield). 2-(3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetaldehyde (4ai). Pale yellow solid (26 mg, 93% yield), decomposition temperature 181℃. 1H NMR (600 MHz, DMSO) δ 11.04 (s, 1H), 9.48 (t, J = 2.0 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.36 (m, 3H), 7.29 – 7.26 (m, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 7.04 (t, J = 7.5, 1.0 Hz, 1H), 5.41 (dd, J = 7.4, 4.2 Hz, 1H), 3.01 (m, 1H), 2.86 (m, 1H). 13C NMR (151 ACS Paragon Plus Environment

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MHz, DMSO) δ 200.7, 176.8, 144.4, 135.2, 135.2, 129.5, 129.5, 129.2, 128.0, 126.2, 126.2, 123.6, 121.8, 114.5, 58.7, 49.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H15N2OS 283.0900; found 283.0897. 2-(3-(4-chlorophenyl)-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetaldehyde (4aj). Pale yellow solid (25 mg, 80% yield), decomposition temperature 181℃. 1H NMR (600 MHz, CDCl3) δ 9.61 (s, 1H), 9.52 (s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.26 (dd, J = 15.4, 1.1 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 5.33 (dd, J = 8.3, 3.7 Hz, 1H), 3.12 (m, 1H), 3.01 (dd, J = 17.1, 3.5 Hz, 1H).

13

C NMR (151 MHz, CDCl3) δ 198.2, 177.2, 142.1, 134.3, 130.0, 130.0, 129.9, 129.9,

129.4, 126.0, 126.0, 124.3, 120.9, 114.2, 58.9, 48.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H14ClN2OS 317.0510; found 317.0509. 2-(3-(4-methoxyphenyl)-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetaldehyde (4ak). Yellow solid (28 mg, 88% yield), mp 92 - 95℃. 1H NMR (600 MHz, CDCl3) δ 9.61 (s, 1H), 9.39 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.24 (dd, J = 7.7, 1.1 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H), 7.06 (t, J = 7.5, 0.9 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 7.8 Hz, 1H), 5.33 (dd, J = 8.3, 3.8 Hz, 1H), 3.84 (s, 3H), 3.11 (m, 1H), 3.03 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 198.5, 177.5, 159.2, 136.4, 134.4, 129.6, 129.3, 126.0, 124.0, 121.6, 121.0, 114.8, 114.3, 114.1, 59.2, 55.5, 48.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16N2O2S 313.1005; found 313.1006. 2-(3-benzyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetaldehyde (4al). White solid (27mg, 91% yield), mp 66 - 69℃. 1H NMR (600 MHz, CDCl3) δ 9.59 (s, 1H), 9.31 (s, 1H), 7.36 (d, J = 7.0 Hz, 2H), 7.30 (t, J = 6.9, 4.8 Hz, 3H), 7.24 – 7.19 (m, 1H), 7.01 (dd, J = 9.2, 7.4 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 5.92 (d, J = 15.2 Hz, 1H), 5.08 (dd, J = 8.2, 4.0 Hz, 1H), 4.70 (d, J = 15.2 Hz, 1H), 2.93 (dd, J = 17.8, 8.2 Hz, 1H), 2.78 (dd, J = 17.8, 3.9 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 198.5, 177.8, 135.8, 134.2, 129.1, 129.1, 128.9, 128.9, 128.1, 127.9, 125.7, 124.1, 121.3, 113.8, 55.2, 53.2, 48.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H17N2OS 297.1058; found 297.1054.



Page 16 of 24

2-(3-butyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetaldehyde (4am). Pale yellow oily liquid (23 mg, 86% yield). 1H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 8.90 (s, 1H), 7.25 (dd, J = 13.8, 6.4 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 8.3, 4.1 Hz, 1H), 4.71 – 4.59 (m, 1H), 3.33 – 3.22 (m, 1H), 2.94 (m, 2H), 1.71 (dd, J = 15.5, 7.8 Hz, 2H), 1.35 (dd, J = 15.1, 7.5 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H).

13

C NMR (100 MHz, CDCl3) δ 198.8, 176.8, 134.3, 129.1, 125.8, 123.9, 121.2,

113.7, 54.3, 52.3, 48.4, 29.8, 19.9, 13.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H19N2OS 263.1213; found 263.1206. 2-(3-benzyl-6-bromo-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetaldehyde (4cl). White solid (34mg, 90% yield), mp 77 - 80℃. 1H NMR (600 MHz, CDCl3) δ 9.61 (s, 1H), 9.27 (s, 1H), 7.37 – 7.29 (m, 6H), 7.18 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 5.88 (d, J = 15.1 Hz, 1H), 5.05 (dd, J = 8.1, 4.0 Hz, 1H), 4.67 (d, J = 15.1 Hz, 1H), 2.93 (dd, J = 18.2, 8.2 Hz, 1H), 2.80 (dd, J = 18.2, 4.0 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 198.0, 177.7, 135.6, 133.3, 132.1, 129.0, 129.0, 128.6, 128.3, 128.0, 123.2, 116.2, 115.4, 55.2, 52.5, 48.2, 29.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16BrN2OS 375.0161; found 375.0155. 2-(3-benzyl-7-methyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetaldehyde (4el). White solid (26 mg, 85% yield), mp 68 - 71℃. 1H NMR (600 MHz, CDCl3) δ 9.60 (s, 1H), 8.89 (s, 1H), 7.38 – 7.27 (m, 6H), 6.89 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.70 (s, 1H), 5.94 (d, J = 15.2 Hz, 1H), 5.03 (dd, J = 8.2, 4.0 Hz, 1H), 4.66 (d, J = 15.2 Hz, 1H), 2.91 (m, 1H), 2.76 (dd, J = 17.6, 3.8 Hz, 1H), 2.29 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 198.6, 177.8, 139.4, 135.9, 134.1, 128.9, 128.0, 128.0, 127.9, 125.5, 124.9, 118.5, 114.2, 55.2, 53.1, 48.4, 29.7, 21.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2OS 311.1213; found 311.1205. 2-(2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetaldehyde (4aA). White oily liquid (26 mg, 65% yield). 1H NMR (600 MHz, DMSO) δ 10.61 (s, 1H), 9.64 (t, J = 2.0 Hz, 1H), 8.75 (s, 1H), 7.21 – 7.17 (m, 1H), 7.16 (d, J = 7.3 Hz, 1H), 6.99 (dd, J = 7.5, 1.0 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 5.00 (td, J = 5.8, 2.9 Hz, 1H), 2.81 ACS Paragon Plus Environment

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(dd, J = 5.9, 2.0 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 201.7, 175.5, 135.2, 128.9, 126.3, 123.6, 120.7, 114.6, 51.6, 49.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C10H11N2OS+H 207.0587; found 207.0581.

3. General Procedure for the Scalability of the Synthesis of 4H-3,1-Benzothiazines 3.

A mixture of o-isothiocyanato-(E)-cinnamaldehyde 1a (3.78 g, 20 mmol) and pyrrolidine 2a (1.7 g, 24 mmol) were stirred in methanol (200 mL) at room temperature for 5 min., then flash chromatography on silica gel (25% ethyl acetate/petroleum ether) gave 3aa as a white solid (4.73 g, 91% yield).

4. General Procedure for the Scalability of the Synthesis of 3,4-Dihydroquinazolines 4

A mixture of o-isothiocyanato-(E)-cinnamaldehyde 1a (3.78 g, 20 mmol) and aniline 2i (2.2 g, 24 mmol) were stirred in methanol (200 mL) at room temperature for 20 min., then flash chromatography on silica gel (25% ethyl acetate/petroleum ether) gave 4ai as a white solid (5.07 g, 90% yield).

5. General Procedure for the Preparation of 4H-3,1-Benzothiazines 6. The o-isothiocyanato-(E)-cinnamaldehyde 1a (38 mg, 0.2 mmol) was dissolved in methanol (2.0 mL), then 12 M of hydrochloric acid (0.1 mol%) was added and stirred for 10 minutes. After that, aniline 2i (22 mg, 0.24 mmol) was added and stirred for another 40 minutes. Then the methanol was removed and toluene (1 mL) was added. The mixture was refluxed for 2 h, then flash chromatography on silica gel (25% ethyl acetate/petroleum ether) gave 6ai as a white solid (48 mg, 81% yield). (E)-4-(2-methoxyvinyl)-N-phenyl-4H-benzo[d][1,3]thiazin-2-amine (6ai). Yellow oily liquid (48 mg, 81% yield); E:Z=94:6; 1H NMR (600 MHz, CDCl3) δ 7.43 (d, J = 7.7 Hz, 2H), 7.31 (dd, J = 11.2, 4.6 Hz, 2H), 7.25 – 7.20 (m, 1H), 7.15 (d, J = 7.3 Hz, 1H), 7.11 – 7.04 (m, 3H), 6.41 (d, J = 12.6 Hz, 1H), 4.94 (dd, J = 12.6, 9.0 Hz, 1H), 4.67 (d, J = 9.0 Hz, 1H), 3.51 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 150.6, 129.0, 129.0, 128.4, 128.4, 125.9, 125.9, 123.9, 123.9, 123.8, 123.6, 123.6, 121.1, 121.1, 101.1, 56.4, 43.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H17N2OS 297.1056; found 297.1055. ACS Paragon Plus Environment


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(E)-1-(2-(3,3-dimethoxyprop-1-en-1-yl)phenyl)-3-phenylthiourea (5ai). Yellow oily liquid (29 mg, 93% yield). 1H NMR (600 MHz, CDCl3) δ 7.93 (s, 1H), 7.61 – 7.57 (m, 1H), 7.43 – 7.40 (m, 1H), 7.40 – 7.37 (m, 4H), 7.35 (dd, J = 7.4, 1.8 Hz, 1H), 7.33 (dd, J = 6.8, 1.3 Hz, 1H), 7.26 (dd, J = 6.5, 2.0 Hz, 1H), 6.89 (d, J = 16.1 Hz, 1H), 6.16 (dd, J = 16.1, 4.9 Hz, 1H), 4.93 (dd, J = 5.0, 1.1 Hz, 1H), 3.35 (s, 6H). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H21N2O2S 329.1318; found 329.1313. (E)-N-benzyl-4-(2-methoxyvinyl)-7-methyl-4H-benzo[d][1,3]thiazin-2-amine (6el). Yellow oily liquid (49 mg, 75%yield); E:Z=98:2; 1H NMR (600 MHz, CDCl3) δ 7.37 – 7.28 (m, 4H), 7.25 (dd, J = 9.7, 4.1 Hz, 1H), 7.03 – 6.96 (m, 2H), 6.85 (d, J = 7.7 Hz, 1H), 6.34 (d, J = 12.6 Hz, 1H), 4.91 (dd, J = 12.6, 8.7 Hz, 1H), 4.70 (s, 2H), 4.58 (d, J = 8.7 Hz, 1H), 3.49 (s, 3H), 2.31 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 150.0, 138.7, 138.2, 128.7, 128.7, 128.0, 128.0, 127.5, 127.5, 125.6, 125.6, 124.4, 124.4, 120.8, 102.1, 56.3, 46.5, 43.0, 21.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H21N2OS 325.1369; found 325.1366. (E)-N-benzyl-6-methoxy-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazin-2-amine (6fl). Yellow oily liquid (49 mg, 72% yield); E:Z=99:1; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.27 (m, 5H), 7.12 (d, J = 8.6 Hz, 1H), 6.82 (dd, J = 8.6, 2.9 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 6.39 (d, J = 12.6 Hz, 1H), 4.92 (dd, J = 12.5, 8.7 Hz, 1H), 4.71 (s, 2H), 4.59 (d, J = 8.7 Hz, 1H), 3.79 (s, 3H), 3.53 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.2, 150.3, 138.2, 128.7, 128.7, 127.9, 127.9, 127.5, 127.5, 124.6, 113.4, 113.4, 111.5, 111.5, 101.5, 56.4, 55.6, 46.5, 43.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H21N2O2S 341.1318; found 341.1307. (E)-N-benzyl-6-chloro-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazin-2-amine (6gl). Yellow oily liquid (55 mg, 83% yield); E:Z=99:1; 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.24 (m, 5H), 7.20 (dd, J = 8.4, 2.4 Hz, 1H), 7.10 (dd, J = 10.4, 5.4 Hz, 2H), 6.40 (d, J = 12.5 Hz, 1H), 4.88 (dd, J = 12.5, 8.9 Hz, 1H), 4.71 (s, 2H), 4.58 (d, J = 8.8 Hz, 1H), 3.54 (s, 3H).

13

C NMR (101 MHz, CDCl3) δ 150.7, 138.3, 128.7, 128.7, 128.3,

128.3, 127.9, 127.9, 127.6, 127.6, 126.0, 125.6, 125.6, 125.2, 100.8, 56.5, 46.5, 42.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H18ClN2OS 345.0823; found 345.0821.


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(E)-N-(4-chlorophenyl)-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazin-2-amine (6aj). Yellow oily liquid (43 mg, 65% yield); E:Z=92:8; 1H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 7.30 – 7.25 (m, 3H), 7.17 (d, J = 7.1 Hz, 1H), 7.09 (dd, J = 11.2, 4.1 Hz, 2H), 6.43 (d, J = 12.6 Hz, 1H), 4.93 (dd, J = 12.5, 9.0 Hz, 1H), 4.71 (d, J = 8.9 Hz, 1H), 3.54 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 150.78, 129.0, 129.0, 129.0, 128.7, 128.7, 128.5, 128.5, 125.9, 125.9, 124.2, 124.2, 122.3, 122.3, 100.7, 56.4, 43.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16ClN2OS 331.0666; found 331.0669. (E)-N-(3-chlorophenyl)-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazin-2-amine (6an). Yellow oily liquid (42 mg, 63% yield); E:Z=90:10; 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.25 – 7.14 (m, 4H), 7.10 – 7.01 (m, 3H), 6.42 (d, J = 12.5 Hz, 1H), 4.93 (dd, J = 12.5, 9.0 Hz, 1H), 4.69 (d, J = 8.9 Hz, 1H), 3.53 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.8, 134.5, 130.0, 129.9, 129.9, 128.5, 128.5, 125.9, 125.9, 124.1, 124.1, 123.5, 121.3, 119.2, 100.7, 56.4, 43.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16ClN2OS 331.0666; found 331.0669. (E)-N-(4-methoxyphenyl)-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazin-2-amine (6ak). Yellow oily liquid (54 mg, 82% yield); E:Z=98:2; 1H NMR (600 MHz, CDCl3) δ 7.25 (d, J = 8.5 Hz, 2H), 7.20 – 7.12 (m, 2H), 7.02 (dd, J = 12.5, 5.0 Hz, 2H), 6.88 – 6.82 (m, 2H), 6.40 (d, J = 12.6 Hz, 1H), 4.93 (dd, J = 12.5, 9.1 Hz, 1H), 4.65 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H), 3.51 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 156.3, 150.6, 128.3, 128.3, 125.8, 125.8, 123.9, 123.4, 123.4, 116.5, 116.5, 114.9, 114.1, 114.1, 101.0, 56.4, 55.5, 43.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2O2S 327.1162; found 327.1159. (E)-N-(3-methoxyphenyl)-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazin-2-amine (6ao). Yellow oily liquid (51 mg, 78% yield); E:Z=97:3; 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.18 (m, 3H), 7.15 (d, J = 7.1 Hz, 1H), 7.07 (dd, J = 15.0, 7.6 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 8.2, 2.2 Hz, 1H), 6.41 (d, J = 12.5 Hz, 1H), 4.94 (dd, J = 12.5, 9.0 Hz, 1H), 4.67 (d, J = 9.0 Hz, 1H), 3.79 (s, 3H), 3.51 (s, 3H).

13

C NMR (101

MHz, CDCl3) δ 160.2, 150.6, 129.6, 129.6, 128.4, 128.4, 125.8, 125.8, 123.9, 123.9, 113.4, 109.5, 109.5,



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106.9, 101.0, 56.4, 55.3, 43.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2O2S 327.1162; found 327.1159. (E)-N-(2-methoxyphenyl)-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazin-2-amine (6ap). Yellow oily liquid (49 mg, 75% yield); E:Z=97:3; 1H NMR (400 MHz, CDCl3) δ 8.79 – 8.59 (m, 1H), 7.28 (dd, J = 4.4, 2.2 Hz, 2H), 7.17 – 7.05 (m, 2H), 7.03 – 6.95 (m, 2H), 6.86 (dd, J = 5.9, 3.5 Hz, 1H), 6.40 (d, J = 12.5 Hz, 1H), 4.96 (dd, J = 12.5, 8.8 Hz, 1H), 4.66 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H), 3.49 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.1, 147.9, 144.5, 129.9, 128.3, 125.9, 125.9, 125.3, 124.4, 123.4, 122.6, 122.6, 121.0, 120.0, 109.9, 56.3, 55.7, 43.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2O2S 327.1162; found 327.1159. 4-((E)-2-methoxyvinyl)-N-((R)-1-phenylethyl)-4H-benzo[d][1,3]thiazin-2-amine (6aq). Yellow oily liquid (43 mg, 66%yield); E:Z=98:2; 1H NMR (600 MHz, CDCl3) δ 7.38 (d, J = 8.0 Hz, 2H), 7.35 – 7.30 (m, 2H), 7.27 – 7.20 (m, 2H), 7.12 – 7.07 (m, 2H), 7.02 (t, J = 7.4, 1.1 Hz, 1H), 6.37 (t, J = 13.1 Hz, 1H), 5.37 (s, 1H), 4.94 – 4.83 (m, 1H), 4.59 (dd, J = 8.8, 3.7 Hz, 1H), 3.49 (d, J = 10.0 Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 150.0, 143.9, 128.6, 128.6, 128.6, 128.3, 128.3, 128.3, 127.2, 127.2, 126.3, 126.3, 125.7, 125.7, 123.7, 123.7, 101.8, 56.3, 43.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H21N2OS 325.1369; found 325.1367. (E)-N-butyl-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazin-2-amine (6am). Yellow oily liquid (36 mg, 65% yield); E:Z=94:6; 1H NMR (600 MHz, CDCl3) δ 7.27 – 7.22 (m, 1H), 7.15 (dd, J = 7.9, 1.1 Hz, 1H), 7.13 – 7.10 (m, 1H), 7.03 (t, J = 7.4, 1.3 Hz, 1H), 6.39 (d, J = 12.6 Hz, 1H), 4.93 (dd, J = 12.6, 8.8 Hz, 1H), 4.61 (d, J = 8.8 Hz, 1H), 3.52 (s, 5H), 1.63 – 1.55 (m, 2H), 1.45 – 1.37 (m, 2H), 1.25 (s, 1H), 0.95 (t, J = 7.4 Hz, 3H). 13

C NMR (151 MHz, CDCl3) δ 150.0, 128.3, 128.3, 125.7, 125.7, 125.7, 123.5, 123.5, 101.8, 56.3, 43.1,

42.9, 31.8, 20.1, 13.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H21N2OS 277.1369; found 277.1367. (E)-4-(2-methoxyvinyl)-2-(pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazine (6aa). White oily liquid (44 mg, 80% yield). 1H NMR (600 MHz, CDCl3) δ 7.21 (td, J = 7.8, 1.4 Hz, 1H), 7.13 – 7.07 (m, 2H), 6.96 (td, J = 7.4, 1.2 Hz, 1H), 6.41 (d, J = 12.6 Hz, 1H), 4.96 (dd, J = 12.5, 9.0 Hz, 1H), 4.62 (d, J = 9.0 Hz, 1H), 3.63 (s, 4H), ACS Paragon Plus Environment

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3.52 (s, 3H), 1.95 – 1.90 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 152.9, 150.0, 146.2, 128.2, 128.2, 125.5, 125.5, 124.7, 124.7, 122.6 (J = 11.5 Hz), 102.0, 56.4, 47.8, 42.8, 25.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H19N2OS 275.1213; found 275.1209. (E)-4-(2-methoxyvinyl)-6-methyl-2-(pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazine (6da). White oily liquid (44 mg, 75% yield). 1H NMR (600 MHz, CDCl3) δ 7.02 (s, 2H), 6.90 (d, J = 0.5 Hz, 1H), 6.42 (d, J = 12.5 Hz, 1H), 4.96 (dd, J = 12.5, 9.0 Hz, 1H), 4.58 (d, J = 9.0 Hz, 1H), 3.68 – 3.57 (m, 4H), 3.54 (s, 3H), 2.30 (s, 3H), 1.97 – 1.91 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 152.3, 149.8, 143.7, 132.0, 128.9, 128.9, 126.0, 126.0, 124.5, 122.4, 102.2, 56.4, 47.8, 42.8, 25.1, 21.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H21N2OS 289.1369; found 289.1367. 6. Synthesis of 4H-3,1-Benzothiazine 7gl. The 4H-3,1-benzothiazine derivative 6gl (103 mg, 0.3 mmol) and triethylamine (121 mg, 1.2 mmol) were dissolved in DCM (6.0 mL), then phenylacetyl chloride (92 mg, 0.6 mmol) was added and stirred for 2 hours. After that, the DCM was removed, and flash chromatography on silica gel (4% ethyl acetate/petroleum ether) gave 7gl as a white solid (126 mg, 91% yield). (E)-N-benzyl-N-(6-chloro-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazin-2-yl)-2-phenylacetamide

(7gl).

White solid (126 mg, 91% yield). 1H NMR (600 MHz, CDCl3) δ 7.30 (t, J = 7.0 Hz, 4H), 7.28 – 7.24 (m, 3H), 7.22 (dt, J = 9.0, 2.8 Hz, 2H), 7.16 (dd, J = 13.4, 7.8 Hz, 3H), 7.12 (d, J = 2.2 Hz, 1H), 6.24 (d, J = 12.6 Hz, 1H), 5.28 (d, J = 15.9 Hz, 1H), 5.06 (d, J = 15.9 Hz, 1H), 4.67 (dd, J = 12.6, 8.7 Hz, 1H), 4.45 (d, J = 8.7 Hz, 1H), 3.94 (s, 2H), 3.39 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 172.2, 154.3, 151.0, 141.3, 137.2, 134.5, 132.8, 129.6, 129.4, 129.6, 129.4, 128.8, 128.7, 128.7, 128.4, 128.4, 127.6, 127.3, 127.1, 126.0, 125.5, 100.3, 56.4, 50.7, 42.8, 42.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H24ClN2O2S 463.1242; found 463.1237. ASSOCIATED CONTENT Supporting Information ACS Paragon Plus Environment


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The Supporting Information is available free of charge on the ACS Publications website at DOI: xxx. 1

H NMR and 13C NMR spectra for all new compounds (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We are grateful for the financial support from the National Natural Science Foundation of P. R. of China (No. 21272214). REFERENCES 1. Review: (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Shenvi, R. A.; O’Malley, D. P.; Baran, P. S. Acc. Chem. Res. 2009, 42, 530. (c) Mahatthananchai, J.; Dumas, A. M.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 10954. 2. (a) J. Mahatthananchai, A. M. Dumas, and J. W. Bode, Angew. Chem., Int. Ed. 2012, 51, 10954 and references cited therein. (b) Yang, W.; Wang, J. Y.; Wei, Z. L.; Zhang, Q.; Xu, X. X. J. Org. Chem. 2016, 81, 1675 and references cited therein. (c) Zhu, B.; Lee, R.; Li, J. T.; Ye, X. Y.; Hong, S. N.; Qiu, S.; Coote, M. L.; Jiang, Z. Y. Angew. Chem., Int. Ed. 2016, 55, 1299. 3. Temperature-Controlled see: (a) Hu, J. L.; Zhang, Q.; Yuan, H. J.; Liu, Q. J. Org. Chem. 2008, 73, 2442. Solvent-Controlled see: (b) Xie, T.; Xiao, Y.; Zhao, S.; Hu, X. Q.; Xu, P. F. J. Org. Chem. 2016, 81, 10499. (c) Ramachandran P. V. and Chanda P. B. Org. Lett. 2012, 14, 4346. Substrate-Controlled see: (d) He, Y. Y.; Sun, X. X.; Li, G. H.; Mei, G. J.; Shi, F. J. Org. Chem., 2017, 82, 2462. 4. Nishio T. J Org Chem, 1997, 62, 1106. 5. Bricher, S. F. PCT WO 1993/04047, 1993. ACS Paragon Plus Environment

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6. Dukat, M.; Alix, K.; Worsham, J.; Khatri, S.; Schulte, M. K. Bioorg. Med. Chem. Lett. 2013, 23, 5945. 7. Alanie, A.; Gobbi, L. C.; Kolczewski, S.; Luebbers, T.; Peters, J.; Steward, L. US 2006/252779, 2006. 8. Saunthwal, R. K.; Patel, M.; Kumar, S.; Verma, A. K. Tetrahedron Lett. 2015, 56, 677. 9. Su, Y.; Guo, Q.; Wang, G.; Guo, S. PCT CN 1683349, 2005. 10. Patil, V. S.; Padalkar, V. S.; Sekar, N. J. Fluoresc. 2014, 24, 1077. 11. Barazarte, A.; Camacho, J.; Dominguez, J.; Lobo, G.; Gamboa, N.; Rodrigues, J.; Capparelli, M. V.; Alvarez-Larena, A.; Andujar, S.; Enriz, D.; Charris, J. Bioorg. Med. Chem. 2008, 16, 3661. 12. Dixit, Y.; Dixit, R.; Gautam, N.; Gautam, D. C. Nucleos. Nucleot. Nucl. 2009, 28, 998. 13. Gautam, N.; Garg, A.; Gautam, D. C. Nucleos. Nucleot. Nucl. 2015, 34, 40. 14. Goyal, K.; Gautam, N.; Khandelwal, N.; Gautam, D. C. Nucleos. Nucleot. Nucl. 2013, 32, 81. 15. Matysiak, J. Bioorg. Med. Chem. 2006, 14, 2613. 16. (a) Hua, L.; Yao, Z. G.; Xu, F.; Shen, Q. RSC Adv. 2014, 4, 3113. (b) Huang, J.; Yu, Y.; Hua, L.; Yao, Z. G.; Xu, F.; Shen, Q. Chin Sci Bull, 58, 717. 17. Fukamachi, S.; Konishi, H.; Kobayashi, K. Synthesis 2010, 10, 1593. 18. (a) Ping, X. N.; Wei, P. S.; Zhu, X. Q.; Xie, J. W. J. Org. Chem. 2017, 82, 2205. (b) Zeng, X. M.; Xie, J. W. J. Org. Chem. 2016, 81, 3553. (c) Zeng, X. M.; Meng, C. Y.; Bao, J. X.; Xu, D. C.; Xie, J. W.; Zhu, W. D. J. Org. Chem. 2015, 80, 11521. 19. Wei, P. S.; Wang, M. X.; Xu, D. C.; Xie, J. W. J. Org. Chem. 2016, 81, 1216. 20. Usually, only Aldol-type reaction was observed when a nucleophile reacted with an acetal, for example: (a) Umebayashi, N.; Hamashima, Y.; Hashizume, D.; Sodeoka, M. Angew. Chem. Int. Ed. 2008, 47, 4196. (b) Kobayashi, S.; Arai, K.; Yamakawa, T.; Chen, Y.; Salter, M. M.; Yamashitaa, Y. Adv. Synth. Catal. 2011, 353, 1927. (c) Schneider, U.; Dao, H. T.; Kobayashi, S. Org. Lett. 2010, 12, 2488. (d) Zerth, H. M.; Leonard, N. M.; Mohan, R. S. Org. Lett. 2003, 5, 55. (e) Downey, C. W.; Johnson, M. W.; Trac, K. J. J. Org. Chem. 2008, 73, 3299. (f) Qin, B.; Schneider, U. J. Am. Chem. Soc. 2016, 138, 13119. (g) Suzuki, I.; Yasuda, M.; Baba, A. ACS Paragon Plus Environment


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Chem. Commun. 2013, 49, 11620. 21 (a) Hull, R.; Swain, M. L. J. Chem. Soc., Perkin Trans. 1: Org. Biomol. Chem. 1976, 653. (b) Farrand, R.; Hull, R. Organic Syntheses 1983, 61, 71.


Chemoselective Synthesis of Structurally Diverse 3,4

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