Development of Divergent Synthetic Methods of Pyrimidobenzothiazine and Related Tricyclic Heterocycles

Abstract

Cu(II)-mediated novel oxidative intermolecular ortho C–H functionalization using tetrahydropyrimidine as the directing group has been investigated. Reaction of 2-phenyl-1,4,5,6- tetrahydropyrimidine with Cu(OAc)₂ in the presence of H₂O in DMF followed by triphosgene treatment affords pyrimido[1,2-c][1,3]benzoxazine derivatives in good yields. This reaction is applicable to the formations of C–N and C–S bonds using various nucleophiles. In addition, a simple and practical synthetic method of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic heterocycles by S_NAr reaction has also been developed. Treatment of 2-(2-haloaryl)tetrahydropyrimidines with NaH and heterocumulene such as CS₂, isothiocyanates, and isocyanates in DMF provides the desired cyclization products regioselectively. These methods provide direct access to PD 404182 and related compounds.

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

2.1 Cu(II)-Mediated Ortho-Selective Intermolecular C–H Functionalization

3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182, 1, Fig. 2.1) is a promising anti-HIV agent lead discovered by a random screening project. To develop the highly potent derivatives, it is valuable to establish practical and short-step synthetic approaches for the preparation of several derivatives¹,² .The author planned to develop a diversity-oriented approach to synthesize tricyclic heterocycles related to PD 404182 based on the sp ²-carbon–heteroatom (O, N, and S) bond formations (Scheme 2.1). It was expected that the ortho-selective introduction of a heteroatom on 2-phenyl-1,4,5,6-tetrahydropyrimidine derivatives 3 [6], which is easily obtained from the corresponding benzaldehydes 2, followed by functional group transformations leads to various types of heterocycles 5 including PD 404182.

Fig. 2.1

Structure of PD 404182

Scheme 2.1

Synthetic scheme for PD 404182 derivatives via carbon–heteroatom bond formation

Directing group-assisted intermolecular C–H functionalization is considered to be one of the most promising approaches for constructions of various heterocycles, providing several biologically active compounds since a new or carbon–heteroatom bond is selectively formed at a non-functionalized position proximal to the directing group. (Scheme 2.2)³, ⁴. In general, C–H functionalization proceeds via metallacycle formation by oxidative addition of transition-metal and subsequent coordination of nucleophile and reductive elimination. Recent research has revealed that nitrogen-containing functional groups such as pyridines [14–16], imines [17–19], oxazolines [20, 21], and amidines [22] effectively act as directing groups for regioselective C–H functionalization.

Scheme 2.2

Carbon–heteroatom bond formation by C–H functionalization

Cu-mediated reactions⁵ have facilitated the synthesis of biologically active compounds because of its cost, earth abundance, and lower toxicity. Reinaud and co-workers have reported a Cu-mediated ortho-hydroxylation reaction of benzamide 6 using a carboxyl group as a directing group (Scheme 2.3, eq 1) [24]. Yu et al. (eq 2) [25] and Chatani et al. (eq 3) [26] have independently reported Cu-mediated oxidative intermolecular C–H functionalization using a pyridine moiety as a directing group. The author designed an experiment for the oxidative introduction of heteroatoms by aromatic C–H functionalization with the assistance of an ortho-tetrahydropyrimidinyl group (eq 4).

Scheme 2.3

Cu-mediated intermolecular C–H functionalization

A few recent reports have revealed that amidine moieties effectively act as directing groups for the ortho-selective C–H functionalization (Scheme 2.4). Inoue and co-workers have reported ortho-selective arylation of 2-arylimidazolines with aryl halides in the presence of a Ru(II)–phosphine complex [22]. The reaction of 2-phenylimidazoline 13 with 1.2 equiv of bromobenzene using [RuCl₂(η ⁶-C₆H₆)]₂ yielded the mono- and diarylated products (14 and 15) in a 64 % yield and in 31:69 ratio (eq 1). Buchwald and co-workers have reported the formation of aryl-benzimidazole 17 by Cu(OAc)₂-catalyzed oxidative cyclization of amidine 16 [27]. The best result was obtained by using 15 mol % of Cu(OAc)₂ and 2–5 equiv of HOAc under an O₂ atmosphere. In this reaction, an amidine moiety acts as a directing group as well as a nucleophile. These contributions prompted the author to investigate a tetrahydropyrimidine group-assisted regioselective C–H functionalization.

Scheme 2.4

Amidine directed regioselective C–H functionalization

The author initially investigated the reaction conditions for C–H hydroxylation (Table 2.1). In the presence of H₂O (1.0 equiv), treatment of 2-phenyl-1,4,5,6-tetrahydropyrimidine (18a) with CuO, Cu(OH)₂, Cu(OTf)₂ or Cu(tfa)₂ (1.0 equiv) in DMF at 130 °C under an O₂ atmosphere led to the recovery of unchanged starting material and the desired C–H oxidation did not occur (entries 1–4). Using Cu(OAc)₂, [25, 26] however, led to the formation of the desired ortho-hydroxylated compound 19a (ca. 69 % yield) although the product yield of compound 19a was poorly reproducible because of its high basicity. The author then attempted to isolate 20a as the tricyclic PD 404182 derivative: after the disappearance of 18a (monitored by TLC), the solvent was evaporated in vacuo and the treatment with triphosgene (1.05 equiv) and triethylamine (4.0 equiv) in CH₂Cl₂ afforded pure 20a in a yield of 61 % (entry 5, Condition A). When acetonitrile or dioxane was used as the solvent instead of DMF, yields of 20a decreased considerably (11 %, entries 6 and 7). Lowering the loading of Cu(OAc)₂ to 0.2 equiv also resulted in a decreased yield for 20a (30 %, entry 8), which indicates low catalyst efficiency. When using 2.0 equiv of Cu(OAc)₂, the yield also decreased contrary to the author’s expectation (27 %, entry 9).

Table 2.1 Optimization of reaction conditions for C–H hydroxylation^a

Considering that the ortho-hydroxylated product 19a may form a complex with the Cu salt, the author further optimized the reaction conditions including the carbonylation procedure. Initially, N,N,N′,N′-tetramethylethylenediamine (TMEDA) was added as a bidentate ligand to the oxidative C–H functionalization reaction mixture and this resulted in the complete inhibition of the desired transformation. Similarly, use of TMEDA instead of triethylamine as a base for the carbonylation did not improve the yield of 20a. On the other hand, treatment with TMEDA (4.0 equiv) at 130 °C for 1 min after the C–H hydroxylation followed by the carbonylation using additional TMEDA (4.0 equiv) increased the yield to 70 % (entry 10, Condition B). The reaction under air resulted in a decreased yield (56 %, entry 11).

Using the condition B, the author examined the reaction of several substituted substrates (Table 2.2). Substitution with electron-donating groups such as methoxy (18b, entry 1) or methyl groups (18c, entry 2) was tolerated to afford the desired products 20b and 20c in 64 % and 61 % yields, respectively. The chemoselectivity of this reaction was evaluated by a reaction where aryl bromide 18d was used and the desired product 20d was obtained in a 45 % yield (entry 3). Methoxycarbonyl (entry 4) and trifluoromethyl groups (entry 5) had relatively small effects on the reactivity of these substrates and the use of the highly electron-deficient arene 18 g bearing a nitro group decreased the yield considerably (19 %, entry 6). These results indicate that this reaction is sensitive to the presence of electron-withdrawing groups on the aromatic ring. In all cases, reactions under condition A gave less favorable results.

Table 2.2 Cu-mediated C–H hydroxylation of Para-substituted-2-phenyl-1,4,5,6-tetrahydro- pyrimidines ^a

To confirm the actual source of ortho-hydroxyl group, the author carried out the C–H hydroxylation reaction using H ¹⁸₂ O under an Ar atmosphere (Scheme 2.5). This reaction provided compound 20a with ¹⁶O, suggesting that ortho-hydroxyl group was derived from Cu(OAc)₂ [25] Notably, the reaction under an Ar atmosphere gave the product in low yield, suggesting that molecular O₂ participates in the reoxidation of the Cu catalyst.

Scheme 2.5

C–H hydroxylation reaction with H ¹⁸₂ O

Next, the author investigated the ability of other amidine analogues to function as directing groups (Fig. 2.2). The reaction of the N-methylated analog 21 and 2-phenylimidazole 22 did not produce the desired ortho-hydroxylated products under the standard reaction conditions and the starting materials were recovered. Unexpectedly, the five-membered ring amidine in 13 was not effective as a directing group either. These results suggest that subtle differences in the intermediate formed by a Cu salt and a directing group strongly affect the reactivity of the substrates.

Fig. 2.2

Various amidine analogs used for the ortho-hydroxylation experiments

Although the exact mechanism of the ortho C–H oxidation is unclear, on the basis of these observations and the seminal work of others, the author proposes the two possible reaction mechanisms (Scheme 2.6): a single electron transfer (SET) pathway (A) [25, 28] and electrophilic substitution pathway (B) [27]. In pathway A, Cu–N adduct II is initially formed by the reaction of compound I with Cu(OAc)₂ [29, 30]. A SET from an aryl ring to the coordinated Cu(II) led to radical cation intermediate III. Intramolecular acetate transfer followed by another SET step and transfer of a proton yielded the acetoxylated compound V. Subsequent hydrolysis gave an ortho-hydroxylated product VI. The observed ortho-selectivity could be attributed to an intramolecular transfer of the coordinating group on the Cu atom. Alternatively, in pathway B, addition of a π-system to the Cu center yielded metallacycle VII. Compound V was formed through rearomatization and subsequent reductive elimination. These mechanisms are supported by the findings that the presence of an electron-withdrawing group on the benzene ring considerably decreased the product yields. Recently, involvement of Cu(III) species in the C–H oxidation reaction has been demonstrated.⁶, ⁷ Therefore, it is possible that this reaction proceeded via the formation of Cu(III)–substrate I complex.

Scheme 2.6

Proposed reaction mechanisms

Finally, the author investigated C–N and C–S bond formations (Scheme 2.7). The author found that the reaction of amidine 18a with Cu(OAc)₂ (1.0 equiv) and tert-butyl carbamate (3.0 equiv) in DMF at 100 °C for 40 min directly afforded the tricyclic aniline derivative (23a) in 53 % yield. This reaction occurred by cyclization involving the elimination of tert-butoxide. p-Toluenesulfonamide [37] also reacted with 18a under identical condition to afford 23b in 47 % yield after alumina column chromatography⁸ followed by treatment with triphosgene–Et₃N. In addition, the reaction with CS₂ in 1,4-dioxane at 130 °C directly gave pyrimido[1,2-c][1,3]benzothiazine derivative 24. The C–N and C–S bond forming reactions can be explained by a similar mechanism as depicted in Scheme 2.7 including ligand exchange step.⁹, ¹⁰

Scheme 2.7

C–N and C–S bond formations with various nucleophiles. Reagents and conditions: (a) Cu(OAc)₂, BocNH₂, O₂, DMF, 100 °C, 53 %; (b) (i) Cu(OAc)₂, TsNH₂, O₂, DMF, 130 °C; (ii) triphosgene, Et₃N, CH₂Cl₂, 0 °C to rt, 47 % (2 steps); (c) Cu(OAc)₂, CS₂, O₂, 1,4-dioxane, 130 °C, 11 %

Scheme 2.8

Proposed reaction mechanisms of C–N and C–S bond formations

Scheme 2.9

Alternative proposed reaction mechanisms with BocNH₂ and CS₂

In conclusion, the author has developed a Cu-mediated oxidative ortho C–H functionalization using tetrahydropyrimidine as a directing group. This reaction was applied to 2-phenyl-1,4,5,6-tetrahydropyrimidines having an electron-donating or a weak electron-withdrawing group to afford the corresponding pyrimido[1,2-c][1,3]benzoxazine derivatives. Use of tert-butyl carbamate, p-toluenesulfonamide, or CS₂ instead of H₂O promotes the introduction of a nitrogen or sulfur functionality to give pyrimido[1,2-c]quinazoline or pyrimido[1,2-c][1,3]benzothiazine derivative, respectively.

2.1.1 Experimental Section

2.1.1.1 General Methods

All moisture-sensitive reactions were performed using syringe-septum cap techniques under an Ar atmosphere and all glasswares were dried in an oven at 80 °C for 2 h prior to use. Melting points were measured by a hot stage melting point apparatus (uncorrected). For flash chromatography, Wakogel C-300E (Wako) or aluminum oxide 90 standardized (Merck) was employed. ¹H-NMR spectra were recorded using a JEOL AL-400 or a JEOL ECA-500 spectrometer, and chemical shifts are reported in δ (ppm) relative to Me₄Si (CDCl₃) as internal standards. ¹³C-NMR spectra were recorded using a JEOL AL-400 or JEOL ECA-500 spectrometer and referenced to the residual CHCl₃ signal. ¹⁹F-NMR spectra were recorded using a JEOL ECA-500 and referenced to the internal CFCl₃ (δ _F 0.00 ppm). ¹H-NMR spectra are tabulated as follows: chemical shift, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant(s), and number of protons. Exact mass (HRMS) spectra were recorded on a JMS-HX/HX 110A mass spectrometer. Infrared (IR) spectra were obtained on a JASCO FT/IR-4100 FT-IR spectrometer with JASCO ATR PRO410-S.

2.1.1.2 General Procedure for Preparation of the Substrates. Synthesis of 2-Phenyl-1,4,5,6-tetrahydropyrimidine (18a)

To a solution of benzaldehyde (5.00 g, 47.1 mmol) in t-BuOH (470 mL) was added propylenediamine (3.84 g, 51.8 mmol). After being stirred at 70 °C for 30 min, K₂CO₃ (19.53 g, 141.3 mmol) and I₂ (14.95 g, 58.8 mmol) were added. After being stirred at same temperature for 3 h, the reaction mixture was quenched with sat. Na₂SO₃ until the iodine color disappeared. The organic layer was separated and concentrated in vacuo. The resulting solid was dissolved with H₂O, and then pH was adjusted to 12–14 with 2 N NaOH. The whole was extracted with CHCl₃ and dried over MgSO₄. After concentration, the resulting solid was recrystallized from CHCl₃–n-hexane to give the title compound 18a as colorless crystals (6.62 g, 82 %): mp 88–89 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1618 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.83–1.85 (m, 2H, CH₂), 3.49 (t, J = 5.9 Hz, 4H, 2 × CH₂), 5.02 (br s, 1H, NH), 7.34–7.38 (m, 3H, Ar), 7.63–7.66 (m, 2H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.7, 42.3 (2C), 126.0 (2C), 128.2 (2C), 129.6, 137.3, 154.5; Anal. calcd for C₁₀H₁₂N₂: C, 74.97; H, 7.55; N, 17.48. Found; C, 74.79; H, 7.53; N, 17.43.

2.1.1.3 2-(4-Methoxyphenyl)-1,4,5,6-tetrahydropyrimidine (18b)

p-Methoxybenzaldehyde (1.36 g, 10 mmol) was subjected to the general procedure. Colorless crystals (1.40 g, 74 %): mp 132–134 °C (from CHCl₃–n-hexane); IR (neat) cm^-1: 1611 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.81–1.87 (m, 2H, CH₂), 3.49 (t, J = 5.7 Hz, 4H, 2 × CH₂), 3.81 (s, 3H, OCH₃), 4.87 (br s, 1H, NH), 6.86 (d, J = 9.4 Hz, 2H, Ar), 7.60 (d, J = 9.4 Hz, 2H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.9, 42.4 (2C), 55.2, 113.5 (2C), 127.2 (2C), 130.0, 153.9, 160.6; Anal. calcd for C₁₁H₁₄N₂O: C, 69.45; H, 7.42; N, 14.73. Found: C, 69.18; H, 7.46; N, 14.58.

2.1.1.4 2-(4-Tolyl)-1,4,5,6-tetrahydropyrimidine (18c)

p-Tolualdehyde (1.20 g, 10 mmol) was subjected to the general procedure. Colorless crystals (1.03 g, 59 %): mp 120–121 °C (from CHCl₃–n-hexane); IR (neat) cm^-1: 1615 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.82–1.85 (m, 2H, CH₂), 2.35 (s, 3H, CH₃), 3.49 (t, J = 5.7 Hz, 4H, 2 × CH₂), 4.90 (br s, 1H, NH), 7.15 (d, J = 8.3 Hz, 2H, Ar), 7.54 (d, J = 8.3 Hz, 2H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.8, 21.2, 42.3 (2C), 125.8 (2C), 128.9 (2C), 134.5, 139.5, 154.3; Anal. calcd for C₁₁H₁₄N₂: C, 75.82; H, 8.10; N, 16.08. Found: C, 75.76; H, 8.01; N, 15.91.

2.1.1.5 2-(4-Bromophenyl)-1,4,5,6-tetrahydropyrimidine (18d)

p-Bromobenzaldehyde (1.85 g, 10 mmol) was subjected to the general procedure. Colorless crystals (1.82 g, 76 %): mp 174–175 °C (from CHCl₃–n-hexane); IR (neat) cm^-1: 1619 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.81–1.88 (m, 2H, CH₂), 3.49 (t, J = 5.7 Hz, 4H, 2 × CH₂), 4.81 (br s, 1H, NH), 7.48 (d, J = 8.8 Hz, 2H, Ar), 7.53 (d, J = 8.8 Hz, 2H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.7, 42.4 (2C), 123.8, 127.6 (2C), 131.4 (2C), 136.3, 153.5; Anal. calcd for C₁₀H₁₁BrN₂: C, 50.23; H, 4.64; N, 11.72. Found: C, 50.20; H, 4.51; N, 11.66.

2.1.1.6 Methyl 4-(1,4,5,6-tetrahydropyrimidin-2-yl)benzoate (18e)

Methyl 4-formylbenzoate (1.00 g, 6.09 mmol) was subjected to the general procedure. Colorless crystals (1.63 g, 80 %): mp 152–153 °C (from CHCl₃–n-hexane); IR (neat) cm^-1: 1721 (C=O), 1620 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.83–1.89 (m, 2H, CH₂), 3.52 (t, J = 5.7 Hz, 4H, 2 × CH₂), 3.92 (s, 3H, OCH₃), 5.04 (br s, 1H, NH), 7.72 (d, J = 8.5 Hz, 2H, Ar), 8.02 (d, J = 8.5 Hz, 2H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.5, 42.3 (2C), 52.1, 126.0 (2C), 129.5 (2C), 130.8, 141.5, 153.6, 166.6; Anal. calcd for C₁₂H₁₄N₂O₂: C, 66.04; H, 6.47; N, 12.84. Found: C, 65.76; H, 6.28; N, 12.69.

2.1.1.7 2-[4-(Trifluoromethyl)phenyl]-1,4,5,6-tetrahydropyrimidine (18f)

p-(Trifluoromethyl)benzaldehyde (1.74 g, 10 mmol) was subjected to the general procedure. Colorless crystals (1.71 g, 75 %): mp 176–177 °C (from CHCl₃–n-hexane); IR (neat) cm^-1: 1620 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.83–1.89 (m, 2H, CH₂), 3.51 (t, J = 5.7 Hz, 4H, 2 × CH₂), 4.92 (br s, 1H, NH), 7.61 (d, J = 8.3 Hz, 2H, Ar), 7.76 (d, J = 8.3 Hz, 2H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.6, 42.4 (2C), 122.6, 125.2 (q, J = 3.7 Hz, 2C), 126.4 (2C), 131.4 (d, J = 32.3 Hz), 140.7, 153.3; ¹⁹F-NMR (500 MHz, CDCl₃) δ: −62.6; Anal. calcd for C₁₁H₁₁F₃N₂: C, 57.89; H, 4.86; N, 12.28. Found: C, 57.89; H, 4.82; N, 12.29.

2.1.1.8 2-(4-Nitrophenyl)-1,4,5,6-tetrahydropyrimidine (18g)

p-Nitrobenzaldehyde (1.51 g, 10 mmol) was subjected to the general procedure. Yellow crystals (1.63 g, 80 %): mp 169–171 °C (from CHCl₃–n-hexane); IR (neat) cm^-1: 1623 (C=N), 1519 (NO₂), 1339 (NO₂); ¹H-NMR (400 MHz, CDCl₃) δ: 1.85-1.90 (m, 2H, CH₂), 3.54 (t, J = 5.6 Hz, 4H, 2 × CH₂), 5.08 (br s, 1H, NH), 7.83 (d, J = 9.1 Hz, 2H, Ar), 8.20 (d, J = 9.1 Hz, 2H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.4, 42.3 (2C), 123.4 (2C), 127.0 (2C), 143.2, 148.3, 152.7; Anal. calcd for C₁₀H₁₁N₃O₂: C, 58.53; H, 5.40; N, 20.48. Found: C, 58.61; H, 5.45; N, 20.48.

2.1.1.9 1-Methyl-2-phenyl-1,4,5,6-tetrahydropyrimidine (21)

Benzaldehyde (1.06 g, 10 mmol) and N-methyl- propandiamine (0.97 g, 11 mmol) was subjected to the general procedure. Product was used to next step without further purification. Yellow oil (1.49 g, 85 %); IR (neat) cm^-1: 1600 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.92–1.98 (m, 2H, CH₂), 2.74 (s, 3H, NCH₃), 3.27 (t, J = 5.6 Hz, 2H, CH₂), 3.51 (t, J = 5.2 Hz, 2H, CH₂), 7.32–7.40 (m, 5H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 22.0, 40.3, 45.0, 49.0, 127.9 (2C), 128.0 (2C), 128.4, 138.1, 159.1; HRMS (EI): m/z calcd for C₁₁H₁₃N₂ [M–H]⁻ 173.1084; found: 173.1082.

2.1.1.10 General Procedure for the C–O Bond Formation (Condition B). Synthesis of 3,4-dihydro-2H-pyrimido- [1,2-c][1,3]benzoxazin-6-one (20a)

DMF (0.83 mL) and water (4.5 μL, 0.25 mmol) were added to a flask containing 18a (40.1 mg, 0.25 mmol) and Cu(OAc)₂ (45.4 mg, 0.25 mmol) under an O₂ atmosphere. After being stirred at 130 °C for 20 min, N,N,N′,N′-tetramethylethylenediamine (TMEDA, 150 μL, 1 mmol) was added. After being stirred at same temperature for 1 min, the reaction mixture was concentrated in vacuo. To a solution of residue and TMEDA (150 μL, 1 mmol) in CH₂Cl₂ (16.6 mL) was added dropwise a solution of triphosgene (77.9 mg, 0.26 mmol) in CH₂Cl₂ (1.7 mL) at 0 °C. After being stirred at rt for 1 h under an Ar atmosphere, the mixture was quenched with sat. NH₄Cl, and CH₂Cl₂ was removed in vacuo. The resulting mixture was made basic with 28 % NH₄OH. The whole was extracted with EtOAc and washed with sat. NH₄Cl–28 % NH₄OH, brine, and dried over MgSO₄. After concentration, the residue was purified by flash chromatography over silica gel with n-hexane–EtOAc (1:1) to give the title compound 20a as colorless solid (35.2 mg, 70 %): mp 146–147 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1730 (C=O), 1647 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.98-2.04 (m, 2H, CH₂), 3.68 (t, J = 5.6 Hz, 2H, CH₂), 3.95 (t, J = 6.0 Hz, 2H, CH₂), 7.14 (d, J = 8.3 Hz, 1H, Ar), 7.23–7.30 (m, 1H, Ar), 7.48–7.51 (m, 1H, Ar), 8.02 (d, J = 7.8 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.3, 42.5, 44.1, 116.2, 125.0, 125.5, 127.8, 129.0, 132.9, 147.5, 150.4; HRMS (FAB): m/z calcd for C₁₁H₁₁N₂O₂ [M + H]⁺ 203.0821; found: 203.0813.

2.1.1.11 3,4-Dihydro-2H-9-methoxypyrimido[1,2-c][1,3]benzoxazin-6-one (20b)

2-(4-Methoxyphenyl)-1,4,5,6-tetrahydropyrimidine 18b (47.6 mg, 0.25 mmol) was subjected to the general procedure. Pale yellow solid (37.3 mg, 64 %): mp 160–161 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1731 (C=O), 1650 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 1.97–2.02 (m, 2H, CH₂), 3.64 (t, J = 5.7 Hz, 2H, CH₂), 3.85 (s, 3H, OCH₃), 3.92 (t, J = 6.0 Hz, 2H, CH₂), 6.59 (d, J = 2.3 Hz, 1H, Ar), 6.79 (dd, J = 8.6, 2.3 Hz, 1H, Ar), 7.90 (d, J = 8.6 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 20.5, 42.5, 44.0, 55.7, 100.0, 108.8, 112.6, 126.6, 142.7, 147.8, 151.7, 163.3; HRMS (FAB): m/z calcd for C₁₂H₁₃N₂O₃ [M + H]⁺ 233.0926; found: 233.0921.

2.1.1.12 3,4-Dihydro-2H-9-methylpyrimido[1,2-c][1,3]benzoxazin-6-one (20c)

2-(4-Tolyl)-1,4,5,6-tetrahydropyrimidine 18c (43.6 mg, 0.25 mmol) was subjected to the general procedure. Yellow solid (32.8 mg, 61 %): mp 153–154 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1736 (C=O), 1650 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 1.98-2.02 (m, 2H, CH₂), 2.40 (s, 3H, CH₃), 3.66 (t, J = 5.4 Hz, 2H, CH₂), 3.93 (t, J = 6.0 Hz, 2H), 6.93 (s, 1H, Ar), 7.05 (d, J = 8.0 Hz, 1H, Ar), 7.88 (d, J = 8.0 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 20.4, 21.5, 42.5, 44.1, 113.4, 116.2, 125.2, 126.2, 143.0, 144.0, 148.0, 150.4; HRMS (FAB): m/z calcd for C₁₂H₁₃N₂O₂ [M + H]⁺ 217.0977; found: 217.0979.

2.1.1.13 9-Bromo-3,4-dihydro-2H-pyrimido[1,2-c][1,3]benzoxazin-6-one (20d)

2-(4-Bromophenyl)-1,4,5,6-tetrahydropyrimidine 18d (59.8 mg, 0.25 mmol) was subjected to the general procedure. Pale yellow solid (31.3 mg, 45 %): mp 206–207 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1729 (C=O), 1651 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 1.98–2.03 (m, 2H, CH₂), 3.65 (t, J = 5.7 Hz, 2H, CH₂), 3.93 (t, J = 6.0 Hz, 2H, CH₂), 7.31 (d, J = 1.7 Hz, 1H, Ar), 7.37 (dd, J = 8.6, 1.7 Hz, 1H, Ar), 7.87 (d, J = 8.6 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 20.3, 42.6, 44.2, 115.2, 119.4, 126.4, 126.8, 128.4, 142.1, 147.0, 150.7; HRMS (FAB): m/z calcd for C₁₁H₁₀BrN₂O₂ [M + H]⁺ 280.9926; found: 280.9922.

2.1.1.14 3,4-Dihydro-2H-9-(methoxycarbonyl)pyrimido[1,2-c][1,3]benzoxazin-6-one (20e)

2-[(4-Methoxycarbonyl) phenyl]1,4,5,6-tetrahydropyrimidine 18e (54.6 mg, 0.25 mmol) was subjected to the general procedure. Pale yellow solid (30.2 mg, 46 %): mp 136–137 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1741 (C=O), 1718 (C=O), 1644 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 2.00–2.05 (m, 2H, CH₂), 3.70 (t, J = 5.4 Hz, 2H, CH₂), 3.94–3.96 (m, 5H, CH₂, OMe), 7.78 (d, J = 1.4 Hz, 1H, Ar), 7.88 (dd, J = 8.6, 1.4 Hz, 1H, Ar), 8.09 (d, J = 8.6 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 20.2, 42.5, 44.4, 52.6, 117.6, 119.7, 125.6, 125.8, 134.3, 142.2, 147.1, 150.2, 165.4; HRMS (FAB): m/z calcd for C₁₃H₁₃N₂O₄ [M + H]⁺ 261.0875; found: 261.0874.

2.1.1.15 3,4-Dihydro-2H-9-(trifluoromethyl)pyrimido[1,2-c][1,3]benzoxazin-6-one (20f)

2-[4-(Trifluoromethyl)phenyl]-1,4,5,6-tetrahydropyrimidine 18f (57.1 mg, 0.25 mmol) was subjected to the general procedure. Yellow solid (28.8 mg, 43 %): mp 141–142 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1739 (C=O), 1650 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 2.00–2.05 (m, 2H, CH₃), 3.70 (t, J = 5.7 Hz, 2H, CH₂), 3.95 (t, J = 6.0 Hz, 2H, CH₂), 7.40 (d, J = 1.1 Hz, 1H, Ar), 7.49 (dd, J = 8.0, 1.1 Hz, 1H, Ar), 8.15 (d, J = 8.0 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.3, 42.7, 44.5, 113.9 (q, J = 4.1 Hz), 119.3, 121.6 (q, J = 3.6 Hz), 124.5, 126.7, 134.7 (q, J = 33.7 Hz), 141.8, 146.9, 150.4; ¹⁹F-NMR (500 MHz, CDCl₃) δ: –63.0; HRMS (FAB): m/z calcd for C₁₂H₁₀F₃N₂O₂ [M + H]⁺ 271.0694; found: 271.0692.

2.1.1.16 3,4-Dihydro-2H-9-nitropyrimido[1,2-c][1,3]benzoxazin-6-one (20g)

2-(4-Nitrophenyl)-1,4,5,6-tetrahydropyrimidine 18 g (51.3 mg, 0.25 mmol) was subjected to the general procedure. Yellow solid (11.9 mg, 19 %): mp 235–236 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1732 (C=O), 1641 (C=N), 1531 (NO₂), 1349 (NO₂). ¹H-NMR (400 MHz, CDCl₃) δ: 2.01–2.07 (m, 2H, CH₂), 3.72 (t, J = 5.6 Hz, 2H, CH₂), 3.96 (t, J = 6.0 Hz, 2H, CH₂), 8.00 (d, J = 2.2 Hz, 2H, Ar), 8.08 (dd, J = 8.8, 2.2 Hz, 1H, Ar), 8.22 (d, J = 8.8 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.1, 42.6, 44.5, 112.2, 119.4, 121.4, 127.1, 141.3, 146.4, 150.3, 150.5; HRMS (FAB): m/z calcd for C₁₁H₁₀N₃O₄ [M + H]⁺ 248.0671; found: 248.0670.

2.1.1.17 C–N Bond Formation with BocNH₂. Synthesis of 3,4-Dihydro-2H,6H-pyrimido[1,2-c]quinazolin-6(7H)-one (23a)

DMF (0.83 mL) was added to a flask containing 18a (40.1 mg, 0.25 mmol), Cu(OAc)₂ (45.4 mg, 0.25 mmol) and tert-butyl carbamate (87.9 mg, 0.75 mmol) under an O₂ atmosphere. After being stirred at 100 °C for 40 min, the mixture was concentrated in vacuo. The residue was purified by flash chromatography over aluminum oxide with CHCl₃–MeOH (1:0 to 99:1) to give 23a as colorless solid (26.5 mg, 53 %): mp 250–251 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1682 (C=O), 1616 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.95–2.00 (m, 2H, CH₂), 3.67 (t, J = 5.6 Hz, 2H, CH₂), 3.94 (t, J = 6.0 Hz, 2H, CH₂), 6.86 (d, J = 8.0 Hz, 1H, Ar), 7.09–7.13 (m, 1H, Ar), 7.38–7.42 (m, 1H, Ar), 8.07 (d, J = 8.0 Hz, 1H, Ar), 8.30 (br s, 1H, NH); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.3, 40.8, 44.5, 114.6, 116.5, 123.0, 125.8, 132.0, 136.5, 145.7, 151.2; HRMS (FAB): m/z calcd for C₁₁H₁₂N₃O [M + H]⁺ 202.0980; found: 202.0988.

2.1.1.18 C–N Bond Formation with TsNH₂. Synthesis of 7-Tosyl-3,4-dihydro-2H,6H-pyrimido[1,2-c]quinazolin-6(7H)-one (23b)

DMF (0.83 mL) was added to a flask containing 18a (40.1 mg, 0.25 mmol), Cu(OAc)₂ (45.4 mg, 0.25 mmol) and p-toluene sulfonamide (85.6 mg, 0.5 mmol) under an O₂ atmosphere. After being stirred at 130 °C for 20 min, the mixture was concentrated in vacuo. The residue was subjected to flash chromatography over aluminum oxide with CHCl₃–MeOH (95:5) to give crude ortho-amidated compound. To a solution of the ortho-amidated compound and Et₃N (145 μL, 1.0 mmol) in CH₂Cl₂ (16.6 mL) was added dropwise a solution of triphosgene (77.9 mg, 0.26 mmol) in CH₂Cl₂ (1.7 mL) at 0 °C. After being stirred at rt for 1 h under an Ar atmosphere, the mixture was quenched with sat. NaHCO₃, and CH₂Cl₂ was removed in vacuo. The whole was extracted with EtOAc and washed with sat. NaHCO₃, brine, and dried over MgSO₄. After concentration, the residue was purified by flash chromatography over silica gel with n-hexane–EtOAc (1:1) to give 23b as colorless solid (42.2 mg, 47 %): mp 159–161 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1695 (C=O), 1644 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.85–1.91 (m, 2H, CH₂), 2.46 (s, 3H, CH₃), 3.63 (t, J = 5.7 Hz, 2H, CH₂), 3.75 (t, J = 6.2 Hz, 2H, CH₂), 7.27–7.31 (m, 1H, Ar), 7.37 (d, J = 8.3 Hz, 2H, Ar), 7.48–7.53 (m, 1H, Ar), 7.87 (d, J = 8.5 Hz, 1H, Ar), 8.03 (d, J = 8.3 Hz, 2H, Ar), 8.07 (dd, J = 8.0, 1.7 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.5, 21.8, 41.8, 44.6, 120.3, 121.0, 125.7, 126.4, 128.4 (2C), 129.8 (2C), 131.3, 134.6, 136.7, 144.5, 145.4, 148.3; HRMS (FAB): m/z calcd for C₁₈H₁₈N₃O₃S [M + H]⁺ 356.1069; found: 356.1074.

2.1.1.19 C–S Bond Formation with CS₂. Synthesis of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazine-6-thione (24)

To a solution of 18a (40.1 mg, 0.25 mmol), Cu(OAc)₂ (45.4 mg, 0.25 mmol) in 1,4-dioxane (0.83 mL) was added CS₂ (0.045 mL, 0.75 mmol) under an O₂ atmosphere. After being stirred at 130 °C for 15 min, the mixture was concentrated. The residue was purified by flash chromatography over silica gel with n-hexane–EtOAc (9:1) to give the title compound 24 as pale yellow solid (6.6 mg, 11 %): mp 139–141 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1624 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 2.01–2.07 (m, 2H, CH₂), 3.76 (t, J = 5.6 Hz, 2H, CH₂), 4.45 (t, J = 6.2 Hz, 2H, CH₂), 7.03 (dd, J = 7.8, 1.5 Hz, 1H, Ar), 7.28–7.33 (m, 1H, Ar), 7.41 (ddd, J = 8.0, 7.6, 1.5 Hz, 1H, Ar), 8.20 (dd, J = 8.0, 1.2 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 21.6, 45.5, 48.6, 121.6, 126.5, 127.5, 128.9, 131.1, 131.8, 144.2, 189.8; Anal. calcd for C₁₁H₁₀N₂S₂: C, 56.38; H, 4.30; N, 11.95. Found: C, 56.23; H, 4.44; N, 11.85.

2.2 S_NAr-Type C–S, C–N, or C–O Bond Formation with Heterocumulenes

The C–H functionalization methodology described in Chap 2.1 provides a facile access to tricyclic heterocycles related to PD 404182; however, C–S bond formation failed to synthesize several derivatives with the pyrimido[1,2-c][1,3]benzothiazin-6-imine scaffold because of the low yield.

The transition-metal-catalyzed carbon–heteroatom bond formations such as Ullmann–Goldberg reactions and Buchwald–Hartwig cross coupling are becoming a powerful methods for construction of various heterocycles.¹¹, ¹² Orain and co-workers have reported a Pd-catalyzed intramolecular S-arylation of thioureas 2 to yield 3,4-dihydro-2H-benzo[e][1,3]thiazin-2-imine derivatives 3 (Scheme 2.10, eq 1) [43] Thioureas were easily obtained by the reaction of 2-halobenzyl-amine derivatives 1 and isothiocyanates. Bao and co-workers have reported the formation of 2-amino-benzothiazoles 5 by CuI-catalyzed coupling of 2-haloanilines 4 and isothiocyanates (eq 2) [44] Li and co-workers have revealed that thses 2-aminobenzothiazole formation reactions were assisted by an Fe(III) catalyst [45]. These reactions proceed via nucleophilic addition of aniline to isothiocyanate followed by transition-metal-catalyzed intramolecular S-arylation.

With these findings [38–53], the author investigated the transition-metal (Pd, Cu, Fe, etc.) catalyzed coupling of haloarenes 6aa and heterocumulenes. During examination of the coupling reaction of 6aa with CS₂ (Scheme 2.11, eq 1), the author noticed that the desired compound 7a was formed without using a transition-metal catalyst (eq 2).

There are several reports of transition-metal-free C–S bond formation. Kobayashi and co-workers have reported the coupling reaction of 2-chloropyridine derivatives 8 with CS₂ (Scheme 2.12, eq 1) [57]. In this reaction, S-functionality is introduced at electronically activated C-2 position through the aromatic nucleophilic substitution (S_NAr) reaction. This report encouraged the author to examine the coupling of haloarenes 6aa and heterocumulenes by S_NAr reaction for the synthesis of PD 404182 derivatives [54–61].¹³ After the authors’ report, [59] Xi and co-workers reported [59] DBU-promoted tandem reaction of 2-haloanilines 10 and CS₂ (eq 2) [60].

Scheme 2.10

Examples of transition-metal-catalyzed coupling of haloarene and heterocumulene

The author initially examined the reaction of 6aa [6] with 5 equiv of sodium hydride and CS₂ (Table 2.3). The desired reaction efficiently proceeded in DMF to give 7a in 75 % yield (entry 1). In contrast, when acetonitrile or THF was used as the solvent instead of DMF, yields of 7a decreased considerably (entries 2 and 3). A decreasing amount of sodium hydride and CS₂ (2.0 equiv) slightly improved the yield of 7a (88 %) under the reaction for 12 h (entry 4). The reaction in the absence of sodium hydride provided a yield of 7a of only 12 % (entry 5). The author next screened several bases such as triethylamine, potassium hydride¹⁴ and sodium tert-butoxide (entries 6-8): sodium hydride was the most effective (entry 4). The fluoride 6ab gave a comparable result with the bromide 6aa to afford 7a in 86 % yield under optimized conditions (entry 9).

Table 2.3 Optimization of reaction conditions with CS₂ ^a

With knowledge of the optimized conditions, the author examined the reaction of several substituted substrates (Table 2.4). Substrates 6b–d having a methoxy, methyl, or fluoro group at the 4-position provided the corresponding cyclized products 7b–d in good-to-excellent yields (76–95 %, entries 1–3). Whereas the reaction of 6e bearing the 4-nitro group at 80 °C resulted in the formation of a complex mixture, the reaction at room temperature gave the cyclization product 7e in 73 % yield (entry 4). A methoxy group on the 5-position considerably diminished the reactivity, affording 7f in only 17 % yield (entry 5). This was presumably due to increased electron density at the carbon substituted by a bromine atom. In the case of 6 g bearing a 5-nitro group, the corresponding product 7 g was obtained by the reaction at room temperature (entry 6), similarly to 6e (entry 4). Pyridine derivatives 12 and 14 showed different reactivity depending on the position of the nitrogen atom: the 2-bromopyridine derivative 14 gave a better result (71 %, entry 8) than the 3-bromopyridine derivative 12 (18 %, entry 7). The naphthalene derivative 16 afforded the tetracyclic compound 17 in quantitative yield (entry 9).

Table 2.4 Reaction of substituted 2-(2-halophenyl)-1,4,5,6-tetrahydropyrimidines^a

To further expand this methodology for the construction of other heterocyclic frameworks, the author investigated the reaction using isothiocyanates or isocyanates¹⁵ as heterocumulene (Table 2.5). When benzylisothiocyanate was employed, the reaction of 6aa or 6ab efficiently proceeded to give the corresponding N-arylated product 18 in 82 % or 97 % yields, respectively (entries 1 and 2). The reaction with tert-butylisothiocyanate exclusively furnished an S-arylated product 19 as a single isomer (entry 3). These results indicate that the regioselectivity of the reaction can be perfectly switched by changing a substituent on the nitrogen atom. As expected, the reaction of 6ab with benzylisocyanate provided an N-arylated product 20 in quantitative yield (entry 4) as in the case with isothiocyanate (entries 1 and 2). Interestingly, tert-butylisocyanate showed moderate selectivity to mainly afford an N-arylation product 21 (54 %), formed by the arylation at the more bulky position, as well as an O-arylation product 22 (18 %, entry 5). Phenylisocyanate also provided an N-arylated product 23 (entry 6). The 2-phenylimidazoline derivative 24 (a 5-membered-ring amidine congener) also provided the corresponding S-arylated product 25 in a slightly decreased yield (49 %, entry 7).

Table 2.5 Reaction with isothiocyanates or isocyanates^a

This reaction would proceed via a nucleophilic addition of the amidine moiety to heterocumulene followed by an intramolecular S_NAr reaction¹⁶, ¹⁷ of the resulting adducts such as B (Scheme 2.13). Nonactivated aromatic rings efficiently reacted under relatively mild conditions, so two molecules of the heterocumulene may be involved in the reaction to form the intermediate C in which the amidine moiety can be a more powerful electron-withdrawing group suitable for the S_NAr-type reaction. The regioselectivity in the nucleophilic attack on the aromatic ring (Y vs. Z) is controlled by a subtle balance of inherent nucleophilicity and steric hindrance of these functionalities.

Scheme 2.11

Synthesis of PD 404182 Derivatives 7a by the coupling of haloarene and heterocumulene. TMEDA N,N,N′,N′-tetramethylethylenediamine

The author finally focused on the synthesis of PD 404182 (26) (Scheme 2.14). Hydrolysis of the carbamodithioate derivative 7a followed by treatment with cyanogen bromide [3] readily afforded the desired compound 26. The same compound was also obtained in a single step by heating compound 19 in trifluoroacetic acid in the presence of molecular sieves.

Scheme 2.12

Examples of transition-metal-free coupling of haloarene and heterocumulene

Scheme 2.13

Proposed reaction mechanisms

Scheme 2.14

Synthesis of PD 404182. Reagents and conditions: (a) NaOH, MeOH-H₂O (9:1), reflux; (b) BrCN, EtOH, reflux, 61 % (2 steps); (c) TFA, MS4Å, CHCl₃, reflux, 85 %

In conclusion, the author developed a simple and practical synthetic method for tricyclic heteroarenes related to PD 404182. This reaction provides divergent access to several related heterocycles under mild conditions without a powerful activating group.

2.2.1 Experimental Section

2.2.1.1 General Methods

All moisture-sensitive reactions were performed using syringe-septum cap techniques under an Ar atmosphere and all glasswares were dried in an oven at 80 °C for 2 h prior to use. Melting points were measured by a hot stage melting point apparatus (uncorrected). For flash chromatography, Wakogel C-300E (Wako) or aluminum oxide 90 standardized (Merck) was employed. ¹H-NMR spectra were recorded using a JEOL AL-400 or a JEOL ECA-500 spectrometer, and chemical shifts are reported in δ (ppm) relative to Me₄Si (CDCl₃) as internal standards. ¹³C-NMR spectra were recorded using a JEOL AL-400 or JEOL ECA-500 spectrometer and referenced to the residual CHCl₃ signal. ¹⁹F–NMR spectra were recorded using a JEOL ECA-500 and referenced to the internal CFCl₃ (δ _F 0.00 ppm). ¹H-NMR spectra are tabulated as follows: chemical shift, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant(s), and number of protons. Exact mass (HRMS) spectra were recorded on a JMS-HX/HX 110A mass spectrometer. Infrared (IR) spectra were obtained on a JASCO FT/IR-4100 FT-IR spectrometer with JASCO ATR PRO410-S.

2.2.1.2 General Procedure for Preparation of the Substrates. 2-(2-Bromophenyl)-1,4,5,6-tetrahydropyrimidine (6aa)

To a solution of 2-bromobenzaldehyde (5.55 g, 30.0 mmol) in t-BuOH (280 mL) was added propylenediamine (2.45 g, 33.0 mmol). The mixture was stirred at 70 °C for 30 min, and then K₂CO₃ (12.4 g, 90.0 mmol) and I₂ (9.52 g, 37.5 mmol) were added. After being stirred at same temperature for 3 h, the mixture was quenched with sat. Na₂SO₃ until the iodine color disappeared. The organic layer was separated and concentrated in vacuo. The resulting solid was dissolved with H₂O, and then pH was adjusted to 12–14 with 2 N NaOH. The whole was extracted with CHCl₃. The extract was dried over Na₂SO₄. After concentration, the resulting solid was recrystallized from CHCl₃–n-hexane to give the compound 6aa as colorless crystals (6.63 g, 92 %): mp 136–137 °C; IR (neat) cm⁻¹: 1625 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 1.81-1.86 (m, 2H, CH₂), 3.42 (t, J = 5.7 Hz, 4H, 2 × CH₂), 4.83 (br s, 1H, NH), 7.18 (ddd, J = 8.0, 7.7, 1.7 Hz, 1H, Ar), 7.27-7.31 (m, 1H, Ar), 7.41 (dd, J = 7.7, 1.7 Hz, 1H, Ar), 7.53 (d, J = 8.0 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 20.5, 42.2 (2C), 120.7, 127.3, 129.9, 130.2, 132.7, 139.3, 155.3; HRMS (FAB): m/z calcd for C₁₀H₁₂BrN₂ [M + H]⁺ 239.0184; found: 239.0185.

2.2.1.3 2-(2-Fluorophenyl)-1,4,5,6-tetrahydropyrimidine (6ab)

2-Fluorobenzaldehyde (1.24 g, 10.0 mmol) was subjected to the general procedure. Colorless crystals (1.28 g, 71 %): mp 112–113 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1629 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.82–1.88 (m, 2H, CH₂), 3.49 (t, J = 5.7 Hz, 4H, 2 × CH₂), 5.33 (br s, 1H, NH), 7.03 (ddd, J = 11.9, 8.2, 1.1 Hz, 1H, Ar), 7.14 (ddd, J = 7.8, 7.8, 1.1 Hz, 1H, Ar), 7.29–7.34 (m, 1H, Ar), 7.80 (ddd, J = 7.8, 7.8, 2.0 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.6, 42.2 (2C), 115.8 (d, J = 23.2 Hz), 124.2 (d, J = 3.3 Hz), 124.5 (d, J = 11.6 Hz), 130.5 (d, J = 3.3 Hz), 130.7 (d, J = 8.3 Hz), 151.5, 160.1 (d, J = 247.5 Hz); ¹⁹F-NMR (500 MHz, CDCl₃) δ: –116.1; Anal. calcd for C₁₀H₁₁FN₂: C, 67.40; H, 6.22; N, 15.72. Found: C, 67.15; H, 6.32; N, 15.63.

2.2.1.4 2-(2-Fluoro-4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine (6b)

2-Fluoro-4-methoxybenzaldehyde (0.77 g, 5.0 mmol) was subjected to the general procedure. Pale yellow crystals (0.70 g, 67 %): mp 77 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1623 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.82-1.88 (m, 2H, CH₂), 3.48 (t, J = 5.7 Hz, 4H, 2 × CH₂), 3.79 (s, 3H, OCH₃), 5.13 (br s, 1H, NH), 6.56 (dd, J = 13.8, 2.6 Hz, 1H, Ar), 6.69 (dd, J = 8.8, 2.6 Hz, 1H, Ar), 7.77 (dd, J = 8.8, 8.8 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 20.8, 42.2 (2C), 55.5, 101.5 (d, J = 27.6 Hz), 110.2 (d, J = 2.4 Hz), 116.7 (d, J = 10.8 Hz), 131.3 (d, J = 6.0 Hz), 151.4 (d, J = 2.4 Hz), 160.7 (d, J = 205.1 Hz), 161.7 (d, J = 30.0 Hz); ¹⁹F-NMR (500 MHz, CDCl₃) δ: –113.8; Anal. calcd for C₁₁H₁₃FN₂O: C, 63.45; H, 6.29; N, 13.45. Found: C, 63.38; H, 6.29; N, 13.49.

2.2.1.5 2-(2-Bromo-4-methylphenyl)-1,4,5,6-tetrahydropyrimidine (6c)

2-Bromo-4-methylbenzaldehyde (1.00 g, 5.0 mmol) was subjected to the general procedure. Colorless crystals (1.11 g, 88 %): mp 128–129 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1639 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.83-1.89 (m, 2H, CH₂), 2.31 (s, 3H, CH₃), 3.46 (t, J = 5.7 Hz, 4H, 2 × CH₂), 4.65 (br s, 1H, NH), 7.07–7.10 (m, 1H, Ar), 7.27–7.35 (m, 2H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.7, 20.8, 42.3 (2C), 120.4, 128.1, 130.1, 133.2, 136.5, 140.3, 155.3; Anal. calcd for C₁₁H₁₃BrN₂: C, 52.19; H, 5.18; N, 11.07. Found: C, 52.37; H, 5.21; N, 11.12.

2.2.1.6 2-(2-Bromo-4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine (6d)

2-Bromo-4-fluorobenzaldehyde (1.02 g, 5.0 mmol) was subjected to the general procedure. Colorless crystals (1.25 g, 97 %): mp 130 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1623 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 1.83-1.87 (m, 2H, CH₂), 3.44 (t, J = 6.0 Hz, 4H, 2 × CH₂), 4.42 (br s, 1H, NH), 7.01 (ddd, J = 8.6, 8.3, 2.7 Hz, 1H, Ar), 7.27 (dd, J = 8.3, 2.7 Hz, 1H, Ar), 7.40 (dd, J = 8.6, 5.7 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 20.5, 42.3 (2C), 114.6 (d, J = 20.4 Hz), 120.0 (d, J = 24.0 Hz), 121.1 (d, J = 9.6 Hz), 131.4 (d, J = 8.4 Hz), 135.6 (d, J = 3.6 Hz), 154.5, 162.2 (d, J = 251.9 Hz); ¹⁹F-NMR (500 MHz, CDCl₃) δ: –116.1. Anal. calcd for C₁₀H₁₀BrFN₂: C, 46.72; H, 3.92; N, 10.90. Found: C, 46.64; H, 3.87; N, 10.97.

2.2.1.7 2-(2-Fluoro-4-nitrophenyl)-1,4,5,6-tetrahydropyrimidine (6e)

2-Fluoro-4-nitrobenzaldehyde (0.68 g, 4.0 mmol) was subjected to the general procedure. Yellow crystals (0.69 g, 77 %): mp 141–142 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1625 (C=N), 1603 (NO₂), 1519 (NO₂); ¹H-NMR (400 MHz, CDCl₃) δ: 1.84-1.90 (m, 2H, CH₂), 3.50 (t, J = 5.7 Hz, 4H, 2 × CH₂), 5.51 (br s, 1H, NH), 7.90–8.02 (m, 3H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 20.4, 44.8 (2C), 112.0 (d, J = 30.0 Hz), 119.2 (d, J = 3.6 Hz), 130.5 (d, J = 12.0 Hz), 131.9 (d, J = 3.6 Hz), 148.8 (d, J = 9.6 Hz), 149.8, 159.4 (d, J = 251.9 Hz); ¹⁹F-NMR (500 MHz, CDCl₃) δ: –111.8; Anal. calcd for C₁₀H₁₀FN₃O₂: C, 53.81; H, 4.52; N, 18.83. Found: C, 54.05; H, 4.53; N, 19.05.

2.2.1.8 2-(2-Bromo-5-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine (6f)

2-Bromo-5-methoxybenzaldehyde (0.86 g, 4.0 mmol) was subjected to the general procedure. Colorless crystals (0.98 g, 91 %): mp 124 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1626 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 1.84–1.89 (m, 2H, CH₂), 3.46 (t, J = 6.0 Hz, 4H, 2 × CH₂), 3.79 (s, 3H, OCH₃), 4.63 (br s, 1H, NH), 6.76 (dd, J = 9.2, 3.2 Hz, 1H, Ar), 6.98 (d, J = 3.2 Hz, 1H, Ar), 7.39 (d, J = 9.2 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 20.6, 42.3 (2C), 55.5, 110.9, 115.0, 116.9, 133.5, 140.0, 155.3, 158.9; Anal. calcd for C₁₁H₁₃BrN₂O: C, 49.09; H, 4.87; N, 10.41. Found: C, 49.21; H, 4.84; N, 10.44.

2.2.1.9 2-(2-Bromo-5-nitrophenyl)-1,4,5,6-tetrahydropyrimidine (6g)

2-Bromo-5-nitrobenzaldehyde (0.58 g, 2.5 mmol) was subjected to the general procedure. Yellow crystals (0.41 g, 58 %): mp 139–141 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1631 (C=N), 1608 (NO₂), 1524 (NO₂); ¹H-NMR (400 MHz, CDCl₃) δ: 1.87–1.93 (m, 2H, CH₂), 3.50 (t, J = 5.7 Hz, 4H, 2 × CH₂), 4.59 (br s, 1H, NH), 7.72 (d, J = 8.8 Hz, 1H, Ar), 8.03 (dd, J = 8.8, 2.7 Hz, 1H, Ar), 8.27 (d, J = 2.7 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.5, 42.4 (2C), 124.4, 125.3, 128.3, 134.0, 140.5, 147.1, 153.4; Anal. calcd for C₁₀H₁₀BrN₃O₂: C, 42.27; H, 3.55; N, 14.79. Found: C, 42.55; H, 3.80; N, 14.52.

2.2.1.10 2-(3-Bromopyridin-4-yl)-1,4,5,6-tetrahydropyrimidine (12)

3-Bromoisonicotinaldehyde (0.93 g, 5.0 mmol) was subjected to the general procedure. Yellow solid (0.73 g, 61 %): mp 141 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1630 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.84-1.90 (m, 2H, CH₂), 3.46 (t, J = 5.7 Hz, 4H, 2 × CH₂), 4.93 (br s, 1H, NH), 7.35 (d, J = 4.6 Hz, 1H, Ar), 8.50 (d, J = 4.6 Hz, 1H, Ar), 8.70 (s, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.3, 42.3 (2C), 118.8, 124.5, 145.9, 148.5, 152.4, 153.0; Anal. calcd for C₉H₁₀BrN₃: C, 45.02; H, 4.20; N, 17.50. Found: C, 44.74; H, 4.13; N, 17.43.

2.2.1.11 2-(2-Bromopyridin-3-yl)-1,4,5,6-tetrahydropyrimidine (14)

2-Bromonicotinaldehyde (0.93 g, 5.0 mmol) was subjected to the general procedure. Yellow solid (1.14 g, 95 %): mp 106–108 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1626 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.84–1.89 (m, 2H, CH₂), 3.44 (t, J = 5.9 Hz, 4H, 2 × CH₂), 4.89 (br s, 1H, NH), 7.27–7.30 (m, 1H, Ar), 7.72 (dd, J = 7.6, 2.0 Hz, 1H, Ar), 8.35 (d, J = 4.8, 2.0 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.3, 42.3 (2C), 122.7, 136.1, 138.7, 140.1, 150.1, 153.8; HRMS (FAB): m/z calcd for C₉H₁₁BrN₃ [M + H]⁺ 240.0136; found: 240.0139.

2.2.1.12 2-(1-Bromonaphthalen-2-yl)-1,4,5,6-tetrahydropyrimidine (16)

1-Bromo-2-naphthaldehyde (0.94 g, 4.0 mmol) was subjected to the general procedure. Colorless crystals (1.04 g, 90 %): mp 151–153 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1625 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.89–1.95 (m, 2H, CH₂), 3.52 (t, J = 5.7 Hz, 4H, 2 × CH₂), 4.72 (br s, 1H, NH), 7.47-7.62 (m, 3H, Ar), 7.77–7.82 (m, 2H, Ar), 8.33 (d, J = 8.5 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.7, 42.5 (2C), 121.2, 126.8, 126.9, 127.6, 127.6, 127.9, 128.1, 132.1, 134.2, 137.5, 156.1; Anal. calcd for C₁₄H₁₃BrN₂: C, 58.15; H, 4.53; N, 9.69. Found: C, 58.02; H, 4.47; N, 9.71.

2.2.1.13 2-(2-Bromophenyl)-4,5-dihydro-1H-imidazole (24)

2-Bromobenzaldehyde (0.93 g, 5.0 mmol) was subjected to the general procedure using ethylenediamine (0.33 g, 5.5 mmol) instead of propylenediamine. Colorless crystals (0.77 g, 68 %): mp 98–99 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1619 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 3.79 (s, 4H, 2 × CH₂), 4.99 (br s, 1H, NH), 7.25 (ddd, J = 8.0, 7.5, 1.7 Hz, 1H, Ar), 7.33 (ddd, J = 8.0, 7.5, 1.1 Hz, 1H, Ar), 7.58 (dd, J = 8.0, 1.1 Hz, 1H, Ar), 7.64 (d, J = 8.0, 1.7 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 50.6 (2C), 120.8, 127.4, 131.0, 131.2, 133.0, 133.2, 164.4; HRMS (FAB): m/z calcd for C₉H₁₀BrN₂ [M + H]⁺ 225.0027; found: 225.0030.

2.2.1.14 General Procedure for Cyclization Using CS₂. 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzo- thiazine-6-thione (7a)

To a mixture of 6aa (59.8 mg, 0.25 mmol) and NaH (20.0 mg, 0.50 mmol; 60 % oil suspension) in DMF (0.83 mL) was added CS₂ (30.5 μL, 0.50 mmol) under an Ar atmosphere. After being stirred at 80 °C for 12 h, the mixture was concentrated in vacuo. The residue was purified by flash chromatography over silica gel with n-hexane–EtOAc (9:1) to give the compound 7a as a pale-yellow solid (51.4 mg, 88 %). Spectral data were in good agreement with compound 24 in Chap. 2.

2.2.1.15 3,4-Dihydro-9-methoxy-2H,6H-pyrimido[1,2-c][1,3]benzothiazine-6-thione (7b)

The fluoride 6b (52.1 mg, 0.25 mmol) was subjected to the general procedure. Pale yellow solid (62.6 mg, 95 %): mp 120–122 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1624 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 2.00–2.05 (m, 2H, CH₂), 3.71 (t, J = 5.4 Hz, 2H, CH₂), 3.83 (m, 3H, OCH₃), 4.42 (t, J = 6.3 Hz, 2H, CH₂), 6.46 (d, J = 2.3 Hz, 1H, Ar), 6.83 (dd, J = 9.0, 2.3 Hz, 1H, Ar), 8.12 (d, J = 9.0 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 21.6, 45.3, 48.7, 55.6, 104.9, 114.9, 119.2, 130.7, 133.3, 143.9, 161.6, 189.7; Anal. calcd for C₁₂H₁₂N₂OS₂: C, 54.52; H, 4.58; N, 10.60. Found: C, 54.22; H, 4.62; N, 10.47.

2.2.1.16 3,4-Dihydro-9-methyl-2H,6H-pyrimido[1,2-c][1,3]benzothiazine-6-thione (7c)

The bromide 6c (63.3 mg, 0.25 mmol) was subjected to the general procedure. Colorless solid (54.6 mg, 88 %): mp 146–147 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1620 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.99–2.06 (m, 2H, CH₂), 2.35 (m, 3H, CH₃), 3.73 (t, J = 5.6 Hz, 2H, CH₂), 4.43 (t, J = 6.2 Hz, 2H, CH₂), 6.82 (d, J = 1.0 Hz, 1H, Ar), 7.10 (dd, J = 8.3, 1.0 Hz, 1H, Ar), 8.07 (d, J = 8.3 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 21.2, 21.6, 45.4, 48.7, 121.6, 123.8, 128.7, 128.7, 131.6, 141.8, 144.2, 190.0; Anal. calcd for C₁₂H₁₂N₂S₂: C, 58.03; H, 4.87; N, 11.28. Found: C, 57.84; H, 4.85; N, 11.19.

2.2.1.17 9-Fluoro-3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazine-6-thione (7d)

The bromide 6d (64.3 mg, 0.25 mmol) was subjected to the general procedure. Colorless solid (47.9 mg, 76 %): mp 185 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1630 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 2.01–2.06 (m, 2H, CH₂), 3.73 (t, J = 5.7 Hz, 2H, CH₂), 4.42 (t, J = 6.0 Hz, 2H, CH₂), 6.73 (dd, J = 8.0, 2.9 Hz, 1H, Ar), 6.98 (ddd, J = 8.9, 8.9, 2.9 Hz, 1H, Ar), 8.22 (dd, J = 8.9, 5.4 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 21.5, 45.4, 48.7, 108.1 (d, J = 24.0 Hz), 115.1 (d, J = 22.8 Hz), 122.7 (d, J = 3.6 Hz), 131.7 (d, J = 9.6 Hz), 134.0 (d, J = 8.4 Hz), 143.4, 163.9 (d, J = 255.5 Hz), 188.9; ¹⁹F-NMR (500 MHz, CDCl₃) δ: –106.9; Anal. calcd for C₁₁H₉FN₂S₂: C, 52.36; H, 3.60; N, 11.10. Found: C, 52.10; H, 3.48; N, 11.15.

2.2.1.18 3,4-Dihydro-9-nitro-2H,6H-pyrimido[1,2-c][1,3]benzothiazine-6-thione (7e)

Using the general procedure, the fluoride 6e (55.8 mg, 0.25 mmol) was allowed to react with CS₂ at rt for 12 h. Pale yellow solid (50.7 mg, 73 %): mp 192–193 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1620 (C=N), 1598 (NO₂), 1520 (NO₂); ¹H-NMR (500 MHz, CDCl₃) δ: 2.05-2.09 (m, 2H, CH₂), 3.81 (t, J = 5.7 Hz, 2H, CH₂), 4.44 (t, J = 6.0 Hz, 2H, CH₂), 7.90 (d, J = 1.7 Hz, 1H, Ar), 8.06 (dd, J = 9.0, 1.7 Hz, 1H, Ar), 8.40 (d, J = 9.0 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 21.4, 45.8, 48.5, 117.0, 121.4, 130.7, 131.2, 133.8, 142.9, 149.0, 187.9; Anal. calcd for C₁₁H₉N₃O₂S₂: C, 47.30; H, 3.25; N, 15.04. Found: C, 47.07; H, 3.19; N, 14.99.

2.2.1.19 3,4-Dihydro-10-methoxy-2H,6H-pyrimido[1,2-c][1,3]benzothiazine-6-thione (7f)

The bromide 6f (67.3 mg, 0.25 mmol) was subjected to the general procedure. Pale yellow solid (11.3 mg, 17 %): mp 136 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1625 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.99–2.07 (m, 2H, CH₂), 3.76 (t, J = 5.7 Hz, 2H, CH₂), 3.86 (s, 3H, OCH₃), 4.46 (t, J = 6.2 Hz, 2H, CH₂), 6.94 (d, J = 8.8 Hz, 1H, Ar), 7.02 (dd, J = 8.8, 2.7 Hz, 1H, Ar), 7.75 (d, J = 2.7 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 21.6, 45.5, 48.6, 55.6, 111.6, 119.8, 123.0, 123.4, 127.6, 144.2, 159.2, 189.9; HRMS (FAB): m/z calcd for C₁₂H₁₃N₂OS₂ [M + H]⁺ 265.0469; found: 265.0461.

2.2.1.20 3,4-Dihydro-10-nitro-2H,6H-pyrimido[1,2-c][1,3]benzothiazine-6-thione (7g)

Using the general procedure, the bromide 6 g (71.0 mg, 0.25 mmol) was allowed to react with CS₂ at rt for 12 h. Yellow solid (39.6 mg, 57 %): mp 176–177 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1627 (C=N), 1605 (NO₂), 1523 (NO₂); ¹H-NMR (500 MHz, CDCl₃) δ: 2.05-2.10 (m, 2H, CH₂), 3.81 (t, J = 5.4 Hz, 2H, CH₂), 4.44 (t, J = 6.0 Hz, 2H, CH₂), 7.18 (d, J = 8.9 Hz, 1H, Ar), 8.23 (dd, J = 8.9, 2.9 Hz, 1H, Ar), 9.09 (d, J = 2.9 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 21.3, 45.6, 48.6, 122.7, 124.6, 125.4, 127.4, 139.2, 142.4, 146.9, 187.3; HRMS (FAB): m/z calcd for C₁₁H₁₀N₃O₂S₂ [M + H]⁺ 280.0214; found: 280.0211.

2.2.1.21 3,4-Dihydro-2H,6H-pyrimido[1,2-c]pyrido[4,3-e][1,3]thiazine-6-thione (13)

The bromide 12 (60.0 mg, 0.25 mmol) was subjected to the general procedure. Orange solid (10.8 mg, 18 %): mp 205–207 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1619 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 2.03–2.09 (m, 2H, CH₂), 3.79 (t, J = 5.6 Hz, 2H, CH₂), 4.44 (t, J = 6.1 Hz, 2H, CH₂), 8.01 (d, J = 5.4 Hz, 1H, Ar), 8.36 (s, 1H, Ar), 8.51 (d, J = 5.4 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 21.4, 45.7, 48.4, 121.3, 128.2, 132.9, 142.6, 143.2, 148.3, 188.5; HRMS (FAB): m/z calcd for C₁₀H₁₀N₃S₂ [M + H]⁺ 236.0316; found: 236.0311.

2.2.1.22 3,4-Dihydro-2H,6H-pyrimido[1,2-c]pyrido[3,2-e][1,3]thiazine-6-thione (15)

The bromide 14 (60.0 mg, 0.25 mmol) was subjected to the general procedure. Colorless solid (41.9 mg, 71 %): mp 141–142 °C (from CHCl₃–n-hexane); IR (neat) cm-1: 1621 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 2.02–2.08 (m, 2H, CH₂), 3.76 (t, J = 5.6 Hz, 2H, CH₂), 4.45 (t, J = 6.2 Hz, 2H, CH₂), 7.22 (dd, J = 8.0, 4.5 Hz, 1H, Ar), 8.46 (dd, J = 8.0, 1.6 Hz, 1H, Ar), 8.54 (dd, J = 4.5, 1.6 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 21.3, 45.7, 48.6, 122.2, 124.0, 136.5, 143.8, 151.9, 153.3, 190.8; Anal. calcd for C₁₀H₉N₃S₂: C, 51.04; H, 3.85; N, 17.86. Found: C, 50.88; H, 3.95; N, 17.82.

2.2.1.23 2,3-Dihydronaphtho[2,1-e]pyrimido[1,2-c][1,3]thiazine-12(1H)-thione (17)

The bromide 16 (72.3 mg, 0.25 mmol) was subjected to the general procedure. Pale yellow solid (73.4 mg, >99 %): mp 230–231 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1620 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 2.06-2.12 (m, 2H, CH₂), 3.82 (t, J = 5.5 Hz, 2H, CH₂), 4.50 (t, J = 6.2 Hz, 2H, CH₂), 7.58-7.63 (m, 2H, Ar), 7.75 (d, J = 9.0 Hz, 1H, Ar), 7.83-7.86 (m, 1H, Ar), 7.96-8.00 (m, 1H, Ar), 8.26 (d, J = 8.8 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 21.5, 45.7, 48.7, 123.0, 124.0, 124.7, 126.0, 127.1, 127.3, 128.3, 128.4, 129.7, 133.9, 144.8, 188.4; Anal. calcd for C₁₅H₁₂N₂S₂: C, 63.35; H, 4.25; N, 9.85. Found: C, 63.36; H, 4.03; N, 9.70.

2.2.1.24 General Procedure for Cyclization Using Isothiocyanates or Isocyanates. N-Benzyl-3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-6(7H)-thione (18)

To a mixture of the fluoride 6ab (44.6 mg, 0.25 mmol) and NaH (20.0 mg, 0.50 mmol; 60 % oil suspension) in DMF (0.83 mL) was added benzylisothiocyanate (66.0 μL, 0.50 mmol) under an Ar atmosphere. After being stirred at rt for 2 h, EtOAc was added. The resulting solution was washed with sat. NaHCO₃, brine, and dried over Na₂SO₄. After concentration, the residue was purified by flash chromatography over aluminum oxide with n-hexane–EtOAc (29:1) to give the title compound 18 as a colorless solid (74.7 mg, 97 %): mp 137 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1635 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 2.02-2.07 (m, 2H, CH₂), 3.67 (t, J = 5.2 Hz, 2H, CH₂), 4.43 (t, J = 6.0 Hz, 2H, CH₂), 6.01 (br s, 2H, CH₂), 6.99 (d, J = 8.6 Hz, 1H, Ar), 7.15–7.36 (m, 7H, Ar), 8.18 (d, J = 7.4 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 21.7, 44.8, 50.3, 54.5, 115.6, 119.6, 124.4, 126.0, 126.2 (2C), 127.2, 128.8 (2C), 132.2, 135.6, 137.5, 143.2, 177.6; Anal. calcd for C₁₈H₁₇N₃S: C, 70.33; H, 5.57; N, 13.67. Found: C, 70.31; H, 5.66; N, 13.69.

2.2.1.25 N-(tert-Butyl)-3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (19)

Using the general procedure, the fluoride 6ab (44.6 mg, 0.25 mmol) was allowed to react with tert-butylisothiocyanate (63.4 μL, 0.50 mmol) at 80 °C for 2 h and purified by flash chromatography over aluminum oxide with n-hexane–EtOAc (1:0 to 9:1). Pale yellow solid (42.7 mg, 62 %): mp 62 °C (from n-hexane): IR (neat) cm⁻¹: 1622 (C=N), 1598 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.39 (s, 9H, 3 × CH₃), 1.88–1.94 (m, 2H, CH₂), 3.62 (t, J = 5.6 Hz, 2H, CH₂), 3.87 (t, J = 6.2 Hz, 2H, CH₂), 7.11 (dd, J = 8.0, 1.2 Hz, 1H, Ar), 7.20 (ddd, J = 8.0, 7.3, 1.2 Hz, 1H, Ar), 7.31 (ddd, J = 8.0, 7.3, 1.4 Hz, 1H, Ar), 8.18 (dd, J = 8.0, 1.4 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 21.9, 30.0 (3C), 45.1, 45.4, 54.1, 124.5, 126.0, 127.8, 128.4, 129.0, 130.1, 138.3, 148.0; HRMS (FAB): m/z calcd for C₁₅H₂₀N₃S [M + H]⁺ 274.1378; found: 274.1375.

2.2.1.26 N-Benzyl-3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-6-one (20)

Using the general procedure, the fluoride 6ab (44.6 mg, 0.25 mmol) was allowed to react with benzylisocyanate (61.6 μL, 0.50 mmol) at rt for 2 h and purified by flash chromatography over aluminum oxide with n-hexane–EtOAc (1:0 to 9:1). White solid (74.8 mg, >99 %): mp 105–107 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1672 (C=O), 1625 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.97–2.03 (m, 2H, CH₂), 3.67 (t, J = 5.5 Hz, 2H, CH₂), 3.99 (t, J = 6.0 Hz, 2H, CH₂), 5.29 (s, 2H, CH₂), 6.93 (d, J = 8.3 Hz, 1H, Ar), 7.09 (dd, J = 8.0, 7.3 Hz, 1H, Ar), 7.23–7.35 (m, 6H, Ar), 8.18 (d, J = 8.0 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.6, 41.8, 44.5, 47.0, 114.1, 117.8, 122.7, 126.1, 126.4, 127.3, 127.3, 128.6, 128.8, 132.0, 136.4, 138.0, 145.3, 150.8; Anal. calcd for C₁₈H₁₇N₃O: C, 74.20; H, 5.88; N, 14.42. Found: C, 73.90; H, 6.04; N, 14.12.

2.2.1.27 N-(tert-Butyl)-3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-6-one (21) and N-(tert-Butyl)-3,4-dihydro-2H- pyrimido[1,2-c][1,3]benzoxazin-6-imine (22)

Using the general procedure, the fluoride 6ab (44.6 mg, 0.25 mmol) was allowed to react with tert-butylisocyanate (57.1 μL, 0.50 mmol) at 80 °C for 2 h and purified by flash chromatography over aluminum oxide with n-hexane–EtOAc (1:0 to 9:1).

Compound 21: pale yellow oil (34.9 mg, 54 %): IR (neat) cm⁻¹: 1679 (C=O), 1631 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.68 (s, 9H, 3 × CH₃), 1.86–1.92 (m, 2H, CH₂), 3.61 (t, J = 5.5 Hz, 2H, CH₂), 3.77 (t, J = 6.2 Hz, 2H, CH₂), 7.07-7.11 (m, 1H, Ar), 7.25–7.27 (m, 1H, Ar), 7.33-7.37 (m, 1H, Ar), 7.95 (dd, J = 7.8, 1.2 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.9, 30.4 (3C), 41.3, 44.6, 59.6, 119.5, 122.5, 122.6, 125.9, 129.3, 138.8, 147.3, 151.7; HRMS (FAB): m/z calcd for C₁₅H₂₀N₃O [M + H]⁺ 258.1606; found: 258.1604.

Compound 22: colorless crystals (11.4 mg, 18 %): mp 53–55 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1637 (C=N), 1613 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 1.35 (s, 9H, 3 × CH₃), 1.91–1.96 (m, 2H, CH₂), 3.59 (t, J = 5.7 Hz, 2H, CH₂), 3.79 (t, J = 6.0 Hz, 2H, CH₂), 7.01 (d, J = 8.0 Hz, 1H, Ar), 7.12 (dd, J = 7.7, 7.4 Hz, 1H, Ar), 7.40 (ddd, J = 8.0, 7.4, 1.4 Hz, 1H, Ar), 8.00 (dd, J = 7.7, 1.4 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 21.0, 30.8 (3C), 43.4, 44.3, 52.5, 115.1, 116.6, 123.5, 125.5, 132.0, 139.1, 143.8, 150.6; HRMS (FAB): m/z calcd for C₁₅H₂₀N₃O [M + H]⁺ 258.1606; found: 258.1602.

2.2.1.28 N-Phenyl-3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-6-one (23)

Using the general procedure, the fluoride 6ab (44.6 mg, 0.25 mmol) was allowed to react with phenylisocyanate (54.5 μL, 0.50 mmol) at rt for 2 h and purified by flash chromatography over aluminum oxide with n-hexane–EtOAc (1:0 to 9:1). White solid (69.6 mg, >99 %): mp 225–226 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1684 (C=O), 1629 (C=N); ¹H-NMR (400 MHz, CDCl₃) δ: 1.97-2.03 (m, 2H, CH₂), 3.69 (t, J = 5.6 Hz, 2H, CH₂), 3.95 (t, J = 6.0 Hz, 2H, CH₂), 6.37 (d, J = 8.3 Hz, 1H, Ar), 7.08–7.12 (m, 1H, Ar), 7.22–7.34 (m, 3H, Ar), 7.46-7.61 (m, 3H, Ar), 8.19 (dd, J = 7.9, 1.6 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 20.5, 41.5, 44.6, 115.1, 117.2, 122.8, 125.9, 128.8, 129.3 (2C), 130.1 (2C), 131.6, 137.2, 139.6, 145.4, 150.2; Anal. calcd for C₁₇H₁₅N₃O: C, 73.63; H, 5.45; N, 15.15. Found: C, 73.41; H, 5.27; N, 15.11.

2.2.1.29 N-(tert-Butyl)-2,3-dihydroimidazo[1,2-c][1,3]benzothiazin-5-imine (25)

Using the general procedure, the bromide 24 (112.5 mg, 0.50 mmol) was allowed to react with tert-butylisothiocyanate (126.8 μL, 1.00 mmol) at rt for 3 h and purified by flash chromatography over aluminum oxide with n-hexane–EtOAc (1:0 to 9:1). White solid (63.0 mg, 49 %): mp 140–142 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1625 (C=N), 1604 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 1.37 (s, 9H, 3 × CH₃), 3.93–4.03 (m, 4H, 2 × CH₂), 7.17 (d, J = 8.0 Hz, 1H, Ar), 7.22 (dd, J = 8.0, 7.7 Hz, 1H, Ar), 7.37 (dd, J = 7.7, 7.4 Hz, 1H, Ar), 8.19 (d, J = 7.4 Hz, 1H, Ar); ¹³C-NMR (125 MHz, CDCl₃) δ: 30.1 (3C), 49.2, 52.2, 53.9, 121.8, 124.5, 126.0, 128.5, 131.5, 132.9, 134.6, 154.5; HRMS (FAB): m/z calcd for C₁₄H₁₈N₃S [M + H]⁺ 260.1221; found: 260.1219.

2.2.1.30 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (26)

Synthesis from 7a: 0.1 M solution of NaOH in a mixed solvent of MeOH/H₂O (9:1; 5 mL) was added to a flask containing 7a (58.6 mg, 0.25 mmol). After being stirred under reflux for 12 h, the mixture was concentrated in vacuo [azeotroped with MeOH (×2) and CHCl₃ (×2)]. The residue was suspended with anhydrous EtOH (1 mL), and BrCN (53.0 mg, 0.50 mmol) was added under an Ar atmosphere. After being stirred under reflux for 2 h, 2 N NaOH was added to the mixture. The whole was extracted with CHCl₃, and dried over Na₂SO₄. After concentration, the residue was purified by flash chromatography over aluminum oxide with n-hexane–EtOAc (9:1) to give the title compound 26 as white solid (33.2 mg, 61 % in 2 steps).

Synthesis from 19: TFA (2 mL) was added to a mixture of 19 (54.7 mg, 0.20 mmol) in small amount of CHCl₃ (1 or 2 drops) and MS4Å (300 mg, powder, activated by heating with Bunsen burner). After being stirred under reflux for 1 h, the mixture was concentrated in vacuo. To a stirring mixture of this residue in CHCl₃ was added dropwise Et₃N at 0 °C to adjust pH to 8–9. The whole was extracted with EtOAc. The extract was washed with sat. NaHCO₃ (×2), brine, and dried over Na₂SO₄. After concentration, the residue was purified by flash chromatography over aluminum oxide with n-hexane–EtOAc (9:1) to give the title compound 26 as white solid (36.9 mg, 85 %).

Compound 26: mp 105 °C (from CHCl₃–n-hexane); IR (neat) cm⁻¹: 1621 (C=N), 1578 (C=N); ¹H-NMR (500 MHz, CDCl₃) δ: 1.95-2.00 (m, 2H, CH₂), 3.69 (t, J = 5.5 Hz, 2H, CH₂), 4.02 (t, J = 6.1 Hz, 2H, CH₂), 7.04 (dd, J = 7.5, 1.1 Hz, 1H, Ar), 7.17 (br s, 1H, NH), 7.21–7.24 (m, 1H, Ar), 7.34 (ddd, J = 7.5, 7.5, 1.4 Hz, 1H, Ar), 8.22 (dd, J = 7.5, 1.4 Hz, 1H, Ar); ¹³C-NMR (100 MHz, CDCl₃) δ: 21.1, 43.8, 44.9, 123.5, 126.2, 126.8, 128.8, 128.9, 130.5, 146.6, 153.4; Anal. calcd for C₁₁H₁₁N₃S: C, 60.80; H, 5.10; N, 19.34.