Novel synthesis of thiazolo/thienoazepine-5,8-diones from dihalo cyclic 1,3-diketones and mercaptonitrile salts

Abstract

An efficient approach to thiazolo[4,5-b]azepine-5,8-diones and thieno[3,2-b]azepine-5,8-diones has been developed via a domino synthesis of multifunctionalized thiazoles/thiophenes and further intramolecular cyclization. This transformation proceeded rapidly under mild conditions without use of metal catalyst.

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Fused azepinediones, such as DGAT1 inhibitor 1 (ref. 1) and antitumor agents 2 (ref. 2) have drawn much attention due to their various biological activities (Fig. 1). Moreover, they are important synthetic intermediates of numerous biologically active fused heterocycles in drug discoveries,^3–7 such as αVβ3 antagonists 3 (ref. 3) CDK and GSK-3 inhibitors 4 (Paullones).⁴ Thus, tremendous efforts have been devoted to the development of versatile methods for constructing these fused cyclic cores.^8–12 However, very few research focused on the construction of heterocyclic fused azepinediones due to difficulty of synthesis, though they may possess potential biological activities. To the best of our knowledge, there was no report on the preparation of thiazolo[4,5-b]azepine-5,8-diones, while the synthesis of thieno-[3,2-b]azepine-5,8-diones were only limited to Kunick's¹³ and Kirsch's¹⁴ reports via 3-aminothiophene-2-carboxylic acid alkyl esters through many steps. Meanwhile, high reaction temperature, prolonged reaction time and tedious procedures were also required.^13,14 Thus, it is necessary to develop a mild and straightforward approach to construct novel thiazolo/thieno-azepine-5,8-diones.

Fig. 1 Representative active fused azepinediones and their derivatives.

Recently, we developed a sequential one-pot synthesis of multifunctionalized thiazoles/thiophenes 7 from mercaptonitrile salts 5 and in situ generated monohalo acyclic 1,3-dicarbonyl compounds 6. This transformation involved a regio-selective elimination of a –COR₄ group (Scheme 1a).¹⁵ Inspired by this work, we envisaged that keto esters 10 would be obtained if replacing 6 with monohalo cyclic 1,3-diketones 8 (Scheme 1b). In this case, the reaction of salts 5 and cyclic 1,3-diketones 8 would provide valuable intermediates 10, which could undergo the intramolecular cyclization to form the novel thiazolo/thieno-fused heterocycles 11 (Scheme 1c). However, preliminary experiments disclosed that the reaction of 5 with 8 did not afford the expected thiazoles/thiophenes 10.¹⁶ Fortunately, when dihalo cyclic 1,3-diketones 9 were used, key intermediates 10 were smoothly isolated (Scheme 1d).

Scheme 1 Synthesis of thiazoles/thiophenes and thiazolo/thieno-fused heterocycles.

Encouraged by above results, we selected the reaction of potassium methyl N-cyanodithioimidocarbonate 5a with 2,2-dibromoindane-1,3-dione 9a as model to optimize the reaction conditions. An equimolar mixture of 5a and 9a was stirred for 2 hours at room temperature in the presence of Et₃N in ethanol, affording 10a in 35% yield (entry 1, Table 1). Increasing the amount of 5a from 1.0 equiv. to 2.0 equiv., the yield was significantly increased up to 75% (entry 2 vs. entry 3, Table 1). However, more than 2.0 equiv. of 5a did not improve the yield further (entry 3 vs. entry 4, Table 1). Among the screened bases, including no base, inorganic and organic bases (entries 3 and 5–10, Table 1), Et₃N was the best one (entry 3, Table 1). Increasing or decreasing the amount of Et₃N slightly influenced the yield (entries 11 and 12, Table 1). When the reaction was conducted at 0 °C or 50 °C, the yield was not improved either (entries 13 and 14, Table 1). Finally, 2,2-dichloroindane-1,3-dione 9a′ was used instead of 9a, leading to a slightly lower yield (entry 3 vs. entry 15, Table 1).

Table 1 Optimization of reaction conditions^a

Entry	5a (equiv.)	Base	10a yield^b (%)
a Reaction conditions: 9a (0.5 mmol, 1.0 equiv.), 5a, base (0.5 mmol, 1.0 equiv.) in EtOH (2 mL) at rt for 2 h.b Isolated yields.c 0.5 equiv. of Et3N was used.d 2.0 equiv. of Et3N was used.e Reaction occurred at 0 °C.f Reaction occurred at 50 °C.g 2,2-Dichloroindane-1,3-dione 9a′ was used instead of 9a.
1	1	Et3N	35
2	1.5	Et3N	52
3	2	Et3N	75
4	2.5	Et3N	74
5	2	—	39
6	2	K2CO3	52
7	2	NaHCO3	55
8	2	NaOAc	65
9	2	NaOEt	67
10	2	DBU	71
11	2	Et3N	68^c
12	2	Et3N	58^d
13	2	Et3N	54^e
14	2	Et3N	69^f
15	2	Et3N	71^g

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Subsequently, the reaction scope was explored under the optimized reaction conditions (entry 3, Table 1). Various dihalo cyclic 1,3-diketones, including five-membered rings 9a–c and six-membered rings 9d–f, were reacted with 5a affording the corresponding thiazole derivatives 10a–f in moderate to good yields (entries 1–6, Table 2). Dihalo cyclic 1,3-diketones fused aromatic ring 9a and 9b led to superior yields compared to 9c–f. As expected, asymmetric substrate 9b formed two isomers (10b and 10b′) without significant selectivity (entry 2, Table 2). Considering the significance of 2-aminothiazoles in drug design, 10g containing a phenylamino group was also prepared from 5b and 9a in 43% yield (entry 7, Table 2). Furthermore, the reaction was expanded to the synthesis of poly-substituted thiophenes. Reactions of potassium (2,2-dicyano-1-methylthioethen-1-yl)-thiolate 5c with 9a and 9c–f provided the corresponding thiophene derivatives 10h–l in 55–82% yields, respectively.

Table 2 Domino synthesis of multifunctionalized thiazoles and thiophenes 10 from 9 and 5^a

Entry	5	9	Product 10	Yield^b (%)
a Reaction conditions: 5 (1 mmol, 2.0 equiv.), 9 (0.5 mmol, 1.0 equiv.), Et3N (0.5 mmol, 1.0 equiv.) in EtOH (2 mL) at rt for 2 h.b Isolated yields.
1	5a	9a	10a	75
2	5a			70 (10b/10b′ = 1 : 1)
3	5a			65
4	5a			68
5	5a			59
6	5a			52
7		9a		43
8		9a		82
9	5c	9c		64
10	5c	9d		71
11	5c	9e		55
12	5c	9f		57

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With a series of functionalized thiazoles and thiophenes 10 in hand, we turned our attention to their intramolecular cyclizations. Optimization studies¹⁷ revealed that the cyclization of 10c could proceed efficiently in the presence of NaOEt in ethanol for 0.5 h at room temperature. Under above conditions, a series of thiazolo[4,5-b]azepine-5,8-diones (11a–d) and thieno[3,2-b]azepine-5,8-diones (11e and f) were prepared from precursors 10 in excellent yields (Table 3). And the structure of compound 11c was unambiguously confirmed by X-ray diffraction study (Fig. 2). However, the cyclization of 10d–f and 10j–l failed to afford fused eight-membered lactam rings, which could be attributed to the instability of the products in the presence of nucleophiles.¹⁸

Table 3 Synthesis of thiazolo/thienoazepine-5,8-diones 11^a,b

a Reaction conditions: 10 (0.2 mmol, 1.0 equiv.), NaOEt (0.4 mmol, 2.0 equiv.) in EtOH (2 mL) at rt for 0.5 h.b Isolated yields.

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Fig. 2 X-ray of compound 11c.

In order to demonstrate the synthetic utility of this novel synthetic method, 11c was treated with phenylhydrazine hydrochloride under Fischer indole synthetic conditions,¹² affording thiazoloazepino-indol-5-one 13 in 53% yield (Scheme 2). Compound 13 is under research for potential biological activities due to its structural similarity to Paullones 4, which are potent CDK and GSK-3 inhibitors as shown in Fig. 1.

Scheme 2 Synthesis of thiazole analogue of Paullone 13.

A possible domino reaction pathway for the construction of thiazoles/thiophenes was proposed and illustrated in Scheme 3. Dihalo cyclic 1,3-diketone 9 was first attacked by 5 affording intermediate 14, which was converted to 15 via retro Claisen condensation¹⁹ in the presence of base. Then anion 15 underwent Thorpe–Ziegler cyclization to furnish intermediate 16. Subsequently, the halogen of 16 was attacked by thiolate anion 5 via halophilic reaction,²⁰ followed by proton transfer from the alcohol, affording the desired product 10. This accounted for the fact that the reaction required two equivalents of 5 (entries 1–4, Table 1).

Scheme 3 Possible domino reaction pathway.

Conclusions

In summary, we have developed a mild and efficient strategy for the synthesis of thiazolo[4,5-b]azepine-5,8-diones and thieno[3,2-b]azepine-5,8-diones from dihalo cyclic 1,3-diketones and mercaptonitrile salts via domino S_N2 substitution/retro Claisen condensation/Thorpe–Ziegler cyclization/halophilic reaction and further cyclization. This method has been successfully applied in the rapid synthesis of a thiazole analogue of Paullone and the further extension will be disclosed in due course.

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (no. 21272009).

Notes and references

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Footnote

† CCDC 969335. For crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra46606j

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