Chemoselective Synthesis of Structurally Diverse 3,4

Jan 24, 2018 - Department of Chemistry and Life Science, Zhejiang Normal University, Jinhua 321004, P. R. China. J. Org. Chem. , 2018, 83 (4), pp 2219...
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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* Department of Chemistry and Life Science, Zhejiang Normal University, Jinhua 321004, P. R. China S Supporting Information *

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-(4Hbenzo[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.

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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 catalysts because the strategy of using controls such as substrate, temperature, and solvent for chemodiversity has been a longstanding challenge.1−3 Among the many heteroaromatic compounds, benzothiazine 4−10 and 3,4-dihydroquinazoline11−15 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 2aminophenyl acrylates with isothiocyanates to construct both benzothiazine and 3,4-dihydroquinazoline skeletons catalyzed by different lanthanide complexes;16 Kobayashi et al. reported © 2018 American Chemical Society

that both benzothiazine and 3,4-dihydroquinazoline skeletons were synthesized by substrate-controlled chemoselective reaction (Scheme 1a).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 1b).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 oisothiocyanato-(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.

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RESULTS AND DISCUSSION As part of our heterocyclic chemistry and medicinal chemistry research program, many efforts have been made on the development of new domino 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 reaction of o-isothiocyanato-(E)-cinnamaldehydes with α-halocarbonyl compounds (Scheme 2).19 We envisioned that the domino reaction between o-isothiocyanato(E)-cinnamaldehydes and amines would occur to afford one or Received: December 11, 2017 Published: January 24, 2018 2219

DOI: 10.1021/acs.joc.7b03120 J. Org. Chem. 2018, 83, 2219−2226

Article

The Journal of Organic Chemistry Scheme 1

Scheme 2. Potential Strategies for the Domino Reaction

electron-deficient double bond to undergo an intramolecular Michael addition (path a) to give the desired product 4H-3,1benzothiazine 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 s) 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, the use of methanol gave the best results, affording the desired product 4H-3,1-benzothiazine 3aa in 95% yield. 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 s, giving the 4H-3,1-benzothiazines 3aa− ga in excellent yields. For example, the 4H-3,1-benzothiazines were obtained in the domino reaction of an electronwithdrawing 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)-cinnamaldehydes with an electron-donating substituent on the 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. Another cyclic secondary amine 2b, as well as acyclic secondary amines 2c−h, could be efficiently

two different products. In this domino reaction, only the 4H3,1-benzothiazine derivatives A would be obtained when the amines are secondary amines (SA); replace the secondary amines with primary amines (PA), and 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 oisothiocyanato-(E)-cinnamaldehyde 1a and pyrrolidine 2a as the model substrates under different conditions at room temperature (Table 1). Surprisingly, the domino reaction was completed in 30 s 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 Table 1. Reaction of o-Isothiocyanato-(E)-cinnamaldehyde 1a and Pyrrolidine 2a under Different Conditionsa

entry

solvent

yield (%)b

1 2 3 4 5 6

THF methanol DCM acetone toluene H2O

92 95 93 94 94 −

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. 2220

DOI: 10.1021/acs.joc.7b03120 J. Org. Chem. 2018, 83, 2219−2226

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The Journal of Organic Chemistry Table 2. Reaction Scopes in the Domino Reaction of oIsothiocyanato-(E)-cinnamaldehydes 1 with Secondary Amines 2a

entry

R1

1

R2 R3 (2)

3/yield (%)b

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

H 3-Br 4-Br 4-CH3 5-CH3 4-OCH3 3-NO2 4-Cl H H H H H H H

1a 1b 1c 1d 1e 1f 1g 1g 1a 1a 1a 1a 1a 1a 1a

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)

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

a

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). Scheme 3

The reaction was also proven effective and convenient 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). 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 similar reaction conditions. Interestingly, a product 5ai which contains thiourea and an acetal group was isolated in high yield by a similar treatment of oisothiocyanato-(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 γposition of β,γ-unsaturated dimethyl acetal (Michael-type reaction, not the aldol-type reaction),20 followed by elimination of a methoxyl group to afford the cyclized product 4H-3,1benzothiazine 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 acetals. From a synthetic point of view, a onepot 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 one-pot and 4H-3,1-benzothiazine derivative 6ai was 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 benzylamine (entries 2−4), arylamines (entries 5−9), alkylamine (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 substituents on on the aryl ring of arylamines 2 (entries 7−9), while an electron-

See Experimental Section. bIsolated yields.

applied in the reaction to provide the desired 4H-3,1benzothiazines 3ab−ah. Again, short reaction times were observed, and the products were also obtained in excellent 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 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 electrondonating group (Table 3, entry 3), and the products were isolated in high yields, respectively. Furthermore, other alkyl Table 3. Reaction Scopes in the Domino Reaction of oIsothiocyanato-(E)-cinnamaldehydes 1 with Primary Amines 2a

a

entry

R1

1

R2

4/yield (%)b

1 2 3 4 5 6 7

H H H H H 4-Br 5-CH3

1a 1a 1a 1a 1a 1c 1e

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

4ai/93 4aj/80 4ak/88 4al/91 4am/86 4cl/90 4el/85

See Experimental Section. bIsolated yields. 2221

DOI: 10.1021/acs.joc.7b03120 J. Org. Chem. 2018, 83, 2219−2226

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The Journal of Organic Chemistry Scheme 4

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

a

entry

R1

1

R2

6/yield (%)b

E/Zc

1 2 3 4 5 6 7 8 9 10 11

H 5-CH3 4-OCH3 4-Cl H H H H H H H

1a 1e 1f 1g 1a 1a 1a 1a 1a 1a 1a

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)

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

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

See Experimental Section. bIsolated yields. cDetermined by 1H NMR.

withdrawing substituent on aryl ring of arylamines 2 tended to decrease the reactivity and yield (entries 5 and 6). Arylamines with electron-donating substituents on the ortho, meta, or para positions (entries 7−9), as well as o-isothiocyanato-(E)cinnamaldehydes 1 with substituents on the aromatic ring (entries 2−4), afford 4H-3,1-benzothiazine derivatives 6 with slightly inferior yields (entries 7−9). The reaction with alkylamine 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 was used as a nucleophile. Subsequently, secondary amines also proved to 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 6

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CONCLUSION In summary, with o-isothiocyanato-(E)-cinnamaldehydes 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 3,4dihydroquinazolines by switching substrates or catalysts. The 4H-3,1-benzothiazines (C−N formation) were obtained in excellent yield within 30 s when the o-isothiocyanato-(E)cinnamaldehydes reacted with secondary amines while replacing the secondary amines with primary amines afforded the 3,4-dihydroquinazolines (C−S formation) in high yields within a very short time (in 5 min). Interestingly, not the aldoltype product but the Michael-type product 4H-3,1-benzothiazine derivatives which contained a methoxyvinyl group were isolated with high selectivity when the reaction of oisothiocyanato-(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

Scheme 5

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DOI: 10.1021/acs.joc.7b03120 J. Org. Chem. 2018, 83, 2219−2226

Article

The Journal of Organic Chemistry

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 (ESITOF) 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). 13C 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. 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). 13C 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). 13C 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

catalyst-free conditions at low cost, making it an ideal alternative to existing methods.

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EXPERIMENTAL SECTION

General Methods. NMR spectra were recorded with tetramethylsilane as the internal standard. TLC was performed on glassbacked 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 a 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 hertz (Hz). ESI-HRMS spectra were 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, and 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. 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. 2223

DOI: 10.1021/acs.joc.7b03120 J. Org. Chem. 2018, 83, 2219−2226

Article

The Journal of Organic Chemistry 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 (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 °C. 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 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-4yl)acetaldehyde (4aj). Pale yellow solid (25 mg, 80% yield), decomposition temperature 181 °C. 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). 13C 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-tetrahydroquinazolin4-yl)acetaldehyde (4ak). Yellow solid (28 mg, 88% yield), mp 92−95 °C. 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 (27 mg, 91% yield), mp 66−69 °C. 1 H 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. 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). 13C 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-4yl)acetaldehyde (4cl). White solid (34 mg, 90% yield), mp 77−80 °C. 1 H 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). 13 C 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-4yl)acetaldehyde (4el). White solid (26 mg, 85% yield), mp 68−71 °C. 1 H 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 (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 4H3,1-Benzothiazines 3. A mixture of o-isothiocyanato-(E)-cinnamaldehyde 1a (3.78 g, 20 mmol) and pyrrolidine 2a (1.7 g, 24 mmol) was stirred in methanol (200 mL) at room temperature for 5 min, and 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 3,4Dihydroquinazolines 4. A mixture of o-isothiocyanato-(E)-cinnamaldehyde 1a (3.78 g, 20 mmol) and aniline 2i (2.2 g, 24 mmol) was stirred in methanol (200 mL) at room temperature for 20 min, and 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), and then 12 M of hydrochloric acid (0.1 mol %) was added and stirred for 10 min. After that, aniline 2i (22 mg, 0.24 mmol) was added and stirred for another 40 min. Then the methanol was removed, and toluene (1 mL) was added. The mixture was refluxed for 2 h, and 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-2amine (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, 2224

DOI: 10.1021/acs.joc.7b03120 J. Org. Chem. 2018, 83, 2219−2226

Article

The Journal of Organic Chemistry

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, 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). 13C 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), 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), and then phenylacetyl chloride (92 mg, 0.6 mmol) was added and stirred for 2 h. 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-

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. (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). 13C 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. (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 (ESITOF) 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 = 2225

DOI: 10.1021/acs.joc.7b03120 J. Org. Chem. 2018, 83, 2219−2226

Article

The Journal of Organic Chemistry TOF) m/z: [M + H]+ Calcd for C26H24ClN2O2S 463.1242; found 463.1237.

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

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03120. 1 H NMR and 13C NMR spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jian-Wu Xie: 0000-0002-4982-4671 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support from the National Natural Science Foundation of P. R. of China (no. 21272214).

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REFERENCES

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DOI: 10.1021/acs.joc.7b03120 J. Org. Chem. 2018, 83, 2219−2226