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Development of Divergent Synthetic Methods of Pyrimidobenzothiazine and Related Tricyclic Heterocycles

  • Tsukasa Mizuhara
Chapter
Part of the Springer Theses book series (Springer Theses)

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 SNAr 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.

Keywords

General Procedure Flash Chromatography Sodium Hydride Single Electron Transfer Directing Group 
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, 15, 16], imines [17, 18, 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 Open image in new window

Entry

Cu salt (equiv)

Solvent

Time (min)

Yield (%) b

1

CuO (1.0)

DMF

20

No reaction

2

Cu(OH)2 (1.0)

DMF

20

No reaction

3

Cu(OTf)2 (1.0)

DMF

20

No reaction

4

Cu(tfa)2 (1.0)

DMF

20

No reaction

5

Cu(OAc)2 (1.0)

DMF

20

61

6

Cu(OAc)2 (1.0)

MeCN

60

11

7

Cu(OAc)2 (1.0)

Dioxane

60

11

8

Cu(OAc)2 (1.0)

DMF

60

30

9

Cu(OAc)2 (2.0)

DMF

15

27

10 c

Cu(OAc)2 (1.0)

DMF

20

70

11 c,d

Cu(OAc)2 (1.0)

DMF

20

56

a After completion of C–H hydroxylation (monitored by TLC), the reaction mixture was evaporated and treated with triphosgene (1.05 equiv) and Et3N (4.0 equiv) in CH2Cl2 at 0 °C to rt for 1 h (Condition A)

b Isolated yields

c After completion of C–H hydroxylation (monitored by TLC), the reaction mixture was treated with TMEDA (4.0 equiv) at 130 °C for 1 min. In this case, TMEDA (additional 4.0 equiv) was used for the next step instead of Et3N (Condition B)

d Reaction was carried out under air

TMEDA = N,N,N′,N′-tetramethylethylenediamine

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 Open image in new window

Entry

Substrate (R)

Product

Yield (%) b

1

18b (OMe)

20b

64 (53)

2

18c (Me)

20c

61 (54)

3

18d (Br)

20d

45 (37)

4

18e (CO2Me)

20e

46 (43)

5

18f (CF3)

20f

43 (38)

6

18 g (NO2)

20g

19 (16)

a These reactions were carried out using the optimized procedure (Condition B, Table 2.1, entry 10)

b Isolated yields. Yields in parentheses indicate those of the reactions at condition A (Table 2.1, entry 5)

To confirm the actual source of ortho-hydroxyl group, the author carried out the C–H hydroxylation reaction using H 2 18 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 2 18 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 CHCl3n-hexane to give the title compound 18a as colorless crystals (6.62 g, 82 %): mp 88–89 °C (from CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 SNAr-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, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 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 (SNAr) reaction. This report encouraged the author to examine the coupling of haloarenes 6aa and heterocumulenes by SNAr reaction for the synthesis of PD 404182 derivatives [54, 55, 56, 57, 58, 59, 60, 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 Open image in new window

Entry

X

Base (equiv)

Solvent

Time (h)

Yield (%) b

1

Br

NaH (5)

DMF

6

75

2

Br

NaH (5)

MeCN

4

Trace

3

Br

NaH (5)

THF

4

Trace

4

Br

NaH (2)

DMF

12

88

5

Br

None

DMF

12

12

6

Br

Et3N (2)

DMF

12

Trace

7

Br

KH (2)

DMF

6

Trace

8

Br

NaOt-Bu (2)

DMF

6

27

9

F

NaH (2)

DMF

12

86

a All reactions were carried out at 80 °C with 2 or 5 equiv of CS2 (corresponding to the base loading)

b Isolated yields

With knowledge of the optimized conditions, the author examined the reaction of several substituted substrates (Table 2.4). Substrates 6bd having a methoxy, methyl, or fluoro group at the 4-position provided the corresponding cyclized products 7bd 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

Entry

Substrate

Product

Yield (%) b

 

Open image in new window

Open image in new window

 

1

6b (R = OMe, X = F)

7b (R = OMe)

95

2

6c (R = Me, X = Br)

7c (R = Me)

88

3

6d (R = F, X = Br)

7d (R = F)

76

4

6e (R = NO2, X = F)

7e (R = NO2)

(73) c

 

Open image in new window

Open image in new window

 

5

6

6f (R = OMe)

6 g (R = NO2)

7f (R = OMe)

7 g (R = NO2)

17

(57) c

7

Open image in new window

12

Open image in new window

13

18

8

Open image in new window

14

Open image in new window

15

71

9

Open image in new window

16

Open image in new window

17

>99

a Unless otherwise stated, reactions were carried out with CS2 (2.0 equiv) and NaH (2.0 equiv) in DMF at 80 °C for 12 h

b Isolated yields

c Yields in parentheses indicate those of the reactions at rt

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

Entry

Substrate

R-NCX

Product

Yield (%) b

 

Open image in new window

 

Open image in new window

 

1

2

6aa (X = Br)

6ab (X = F)

BnNCS

18

82

97

3 c

6ab

t-BuNCS

Open image in new window

19

62 d,e

4

6ab

BnNCO

Open image in new window

20

>99

5 c

6ab

t-BuNCO

Open image in new window

 
   

21 (Y = Nt-Bu, Z = O)

22 (Y = O, Z = Nt-Bu)

54

18 e

6

6ab

PhNCO

Open image in new window

23

>99

7

Open image in new window

24

t-BuNCS

Open image in new window

25

49 e

a Unless otherwise stated, reactions were carried out with R-NCX (2.0 equiv) and NaH (2.0 equiv) in DMF at rt for 2–3 h

b Isolated yields

c These reactions were carried out at 80 °C

d A trace amount of regioisomeric N-arylation product was also formed

e Isolated as a single isomer

This reaction would proceed via a nucleophilic addition of the amidine moiety to heterocumulene followed by an intramolecular SNAr 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 SNAr-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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 CHCl3n-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.

Footnotes

  1. 1.

    In the previous reports, compound 1 was obtained via benzo-1,2-dithiole-3-thiones and 2-(1,4,5,6-tetrahydro-2-pyrimidinyl)benzenethiol in 3 % yield from 2-chlorobenzyl chloride, see [1, 2, 3] Open image in new window

  2. 2.

    See [4, 5].

  3. 3.

    For reviews on transition-metal-catalyzed directed C–H activations, See [7, 8, 9].

  4. 4.

    See [10, 11, 12, 13].

  5. 5.

    For a review on Cu-mediated C–H functionalization, see [23].

  6. 6.

    For a review on high-valent Cu(III) species in catalysis, see [31].

  7. 7.

    See [32, 33, 34, 35, 36].

  8. 8.

    Because the separation of 23b and the by-product 20a was difficult, separation by alumina column chromatography was necessary before carbonylation.

  9. 9.

    Examples for the reaction mechanism including the ligand exchange are shown above (Scheme 2.8).

  10. 10.

    Different reaction pathways are not excluded at present. Some examples are shown above (Scheme 2.9).

  11. 11.

    For reviews on transition-metal-catalyzed carbon–heteroatom bond formation, see [38, 39, 40, 41].

  12. 12.

    For recent examples of the transition-metal-catalyzed coupling reaction of haloarene and hetelocumulenes, see [41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53].

  13. 13.

    For examples of the transition-metal-free coupling reaction of haloarene and hetelocumulenes, see [58, 59, 60, 61].

  14. 14.

    A reason for the significant countercation effect (NaH vs. KH) on the reactivity is unclear.

  15. 15.

    For related reactions of electron-deficient (haloaryl)isothiocyanates, see [62, 63, 64].

  16. 16.

    For reviews on nucleophilic aromatic substitution reaction, see [65, 66].

  17. 17.

    For examples on nucleophilic aromatic substitution reaction, see [67, 68, 69, 70, 71, 72, 73].

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Copyright information

© Springer Japan 2013

Authors and Affiliations

  1. 1. University of MassachusettsAmherstUSA

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