Organocatalytic synthesis of enantioenriched 1,2,4-triazolines containing a chiral quaternary carbon center

Abstract

An efficient asymmetric cyclization reaction of amino-acid-derived isothiocyanates with azodicarboxylates is described. The chiral 1,2,4-triazolines are prepared in good yield (up to 87%) and enantioselectivities (up to 95% ee).

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Triazoles are one of the most important classes of heterocycles because of their broad biological activities such as antiviral, antiepileptic, anticancer, and anti-HIV activities.¹ Many triazoles are used in pharmaceuticals, agrochemicals, corrosion inhibitors, photographic materials, dyes, etc.² Therefore, it is important to develop novel methods for the synthesis of structurally diverse triazoles. 1,2,4-Triazolines, one type of important triazole related compounds bearing a potential chiral carbon center at the C-3 position, exhibit good antiviral, anticancer, anti-inflammatory, and anticonvulsant properties.³ The racemic synthesis of 1,2,4-triazolines has been reported extensively;⁴ however, the asymmetric synthetic methods are very limited.⁵ In 2010, Jørgensen and co-workers reported preliminary results for the asymmetric synthesis of 1,2,4-triazolines by phase transfer catalysis.^5a Then, Feng,^5b Huang,^5c and Shi^5d reported the synthesis of chiral 1,2,4-triazolines independently. In these studies, α-isocyano esters (I) or azlactones (II) reacted with azadicarboxylates to generate the target chiral triazolines (Scheme 1). In 2013, Shi and co-workers reported an efficient [3 + 2] reaction of 3-aminooxindole derived isothiocyanates (III) with azodicarboxylates, producing spirooxindoles in high yields and enantioselectivities.⁶ α-Isothiocyanato esters (IV), which can be readily prepared from commercially available amino acids, are useful reactants in the catalytic asymmetric addition reactions with aldehydes,⁷ ketones,⁸ or imines,⁹ affording chiral cyclic thiocarbamates in good experimental results. Inspired by Shi's work,⁶ we assumed that the amino acid derived α-isothiocyanato esters would be good reactants in the catalytic asymmetric addition to azodicarboxylates. Such a reaction will produce chiral polysubstituted 1,2,4-triazolines bearing a carboxylic functional group at the C-3 position and sulfur substitution at the C-5 carbon (Scheme 1b), and provide an alternative pathway leading to chiral 1,2,4-triazolines. Also, the corresponding products can be converted into structural diversity chiral nitrogen containing heterocycles easily. Herein, we report this chiral tertiary amine catalyzed [3 + 2] reaction of α-isothiocyanato esters with azodicarboxylates, leading to polysubstituted 1,2,4-triazolines in good yields and enantioselectivities.

Scheme 1 Strategy for the synthesis of polysubstituted chiral 1,2,4-triazolines.

In the initial study, the phenyl glycine derived isothiocyanato ester 1a was used as reactant to react with di-tert-butyl azodicarboxylate 2a in the promotion of cinchonine 3a. As expected, the desired product 4a was obtained in a high yield (96%), albeit with a low enantioselectivity (19% ee). We tried to improve the stereocontrol ability of the catalyst by modifying the 9-OH group of cinchonine and cinchonidine. As shown in Table 1, the modified catalysts 3b–d gave 4a in low yields and enantioselectivities (Table 1, entries 2–4). Quinidine 3e and its derivatives 3f–3j were then used as catalysts (Table 1, entries 5–10). Among them, 3f has the best enantioselective control ability (68% ee) (Table 1, entry 6). A comparison of the results gave by catalysts 3d and 3f showed that the methoxy group of 3f benefited the enantioselectivity of 4a significantly; therefore, modified catalysts 3k and 3l were synthesized and used in this reaction. However, no better result was obtained (Table 1, entries 11 and 12). Bifunctional catalysts 3m–3r have been extensively used as chiral organocatalysts, but they were not suitable promoters for this transformation (Table 1, entries 13–18). Therefore, catalyst 3f was selected as the optimal catalyst for further investigating the reaction conditions.

Table 1 Screening catalysts

Entry	3	T (°C)	Time (h)	Yield^a (%)	ee^b (%)
a Isolated yield.b Determined by chiral HPLC.
1	3a	10	16	96	19
2	3b	10	120	10	<5
3	3c	20	96	11	<5
4	3d	10	144	25	−40
5	3e	10	21	64	<5
6	3f	20	92	22	−68
7	3g	20	36	14	−62
8	3h	20	76	9	−58
9	3i	20	53	16	46
10	3j	20	70	29	<−5
11	3k	20	104	19	58
12	3l	20	104	14	69
13	3m	10	66	29	<5
14	3n	10	66	29	<5
15	3o	10	53	29	<5
16	3p	10	120	20	29
17	3q	10	65	10	19
18	3r	20	144	20	<5

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With the optimal catalyst in hand, other reaction conditions were investigated for further improving the yield and enantioselectivity. First, solvents were screened. As shown in Table 2, m-xylene was the best solvent for this transformation. Not only the yield increased to 70%, but the enantioselectivity excess was enhanced to 78% (Table 2, entry 7). Then, this reaction was carried out at a low temperature (−20 °C). The enantioselectivity was further improved to 86% ee (Table 2, entry 8). Additives also affected the reaction outcomes. The yield and enantioselectivity of 4a increased to 77% and 89% ee when Na₂SO₄ was added to the reaction (Table 2, entry 9).

Table 2 Further optimization of reaction conditions

Entry	Solvent	Time (h)	Yield^a (%)	ee^b (%)
a Isolated yield.b Determined by chiral HPLC.c At −20 °C.d 20 mg Na2SO4 was added.
1	Et2O	89	11	71
2	MTBE	89	21	65
3	^nBu2O	71	52	75
4	DCM	73	55	49
5	CHCl3	92	22	68
6	Toluene	73	48	78
7	m-Xylene	64	56	78
8	m-Xylene	70	57	86^c
9	m-Xylene	96	77	89^c^,^d

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The substrate scope of the reaction was investigated under the optimal reaction conditions. First, the substituent effects of isothiocyanato esters 1 were studied. The results are shown in Table 3. Electron-withdrawing group substituted isothiocyanates were good reaction partners in this reaction, leading to the chiral 1,2,4-triazolines 4b–4e in good yields and enantioselectivities (Table 3, entries 2–5). The low yield of product 4f (15%) was partially caused by the steric influence of the o-substituent (Table 3, entry 6). We found the electron-donating groups of compounds 1 could give the products 4h–4j in high enantioselectivities, albeit the yield decreased slightly (Table 3, entries 8–10). The 2,5-dimethyl-phenyl-substituted isothiocyanate did not participate in this reaction (Table 3, entry 11). This was probably caused by the steric effect of the bulky o-methyl group. The alkyl groups of compounds 2 and 1 were then investigated. We found the yields increased greatly when the tert-butyl group of 2 was replaced by iso-propyl and ethyl groups, albeit the enantioselectivities decreased (Table 3, entries 12 and 13). These results indicated this transformation would be speeded if an azodicarboxylate bearing small alkyl group was introduced as acceptor. So, compounds 1 having o-substituted phenyls, which could not react with di-tert-butyl azodicarboxylate efficiently (Table 3, entries 6 and 11), were used as donors to react with di-iso-propyl and ethyl azodicarboxylates, respectively (Table 3, entries 17–20). As expected, these reactions took place smoothly, giving the products in moderate to good yields and high to excellent enantioselectivities. Particularly, the highest enantioselectivity (95% ee) in this work was obtained in the reaction of 2-Cl phenyl substituted isothiocyanate with diisopropyl azodicarboxylate (Table 3, entry 17). The damage of enantioselectivities of products 4l and 4m could be complemented through increasing the bulk of alkyl group of isothiocyanate 1. For example, the enantioselectivities increased greatly when we used ethyl and isopropyl isothiocyanato esters as donors (Table 3, entries 14–16). The absolute configuration (S) of compound 4q was determined by single crystal X-ray analysis (see ESI†).¹⁰ The absolute configuration of compounds 4 and 5 were assigned accordingly.

Table 3 Substrate scope

Entry	4	Ar	R^1	R^2	Time (h)	Yield^a (%)	ee^b (%)
a Isolated yield.b Determined by chiral HPLC.c Not determined.d At 20 °C.e At 50 °C.
1	4a	Ph	Me	^tBu	96	77	89
2	4b	4-ClC6H4	Me	^tBu	91	75	88
3	4c	4-FC6H4	Me	^tBu	120	68	88
4	4d	4-CF3C6H4	Me	^tBu	64	65	82
5	4e	3-CF3C6H4	Me	^tBu	70	70	71
6	4f	2-ClC6H4	Me	^tBu	120	15	Nd^c
7	4g	4-F-3-MeC6H3	Me	^tBu	88	70	85
8	4h	4-MeOC6H4	Me	^tBu	120	54	85^d
9	4i	4-VillylOC6H4	Me	^tBu	120	53	84^d
10	4j	4-BnOC6H4	Me	^tBu	120	56	84^d
11	4k	2,5-2MeC6H3	Me	^tBu	24	Trace	Nd
12	4l	Ph	Me	^iPr	79	72	38
13	4m	Ph	Me	Et	26	76	14
14	4n	Ph	Et	^iPr	24	49	49
15	4o	Ph	^iPr	Et	57	78	62
16	4p	Ph	^iPr	^iPr	108	51	76
17	4q	2-ClC6H4	Me	^iPr	64	58	95
18	4r	2-ClC6H4	Me	Et	94	87	83
19	4s	2,5-2MeC6H3	Me	^iPr	216	41	77^e
20	4t	2,5-2MeC6H3	Me	Et	72	44	72^e

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Enantioenriched compounds 4 can be readily converted into other 1,2,4-triazolines under mild reaction conditions. As described in Scheme 2, the alkylation of compound 4q with benzyl bromide or allylic bromide afforded novel triazolines 5a and 5b in good yields (Scheme 1, eqn (1) and (2)). Furthermore, compound 4q could couple with phenylboronic acid and give product 5c in a high yield (Scheme 1, eqn (3)). Importantly, the enantioselectivity of 4q was transformed into the corresponding products completely.

Scheme 2 Transformation of product 4q.

Conclusion

In conclusion, an efficient organocatalytic method was developed for the synthesis of chiral 1,2,4-triazolines, in which, the amino-acid-derived isothiocyanato esters were used as the donors for the first time. Triazoline products were obtained in good yields and good to excellent enantioselectivities, and could be converted into other compounds without the loss of enantioselectivities.

Acknowledgements

We are grateful for financial support from NSFC (21472150, 21272002), the Fundamental Research Funds for the Central Universities (XDJK2013B028) and the Program for New Century Excellent Talents in Universities (NCET-12-0929).

Notes and references

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10. CCDC 1043418 (4q) contains the supplementary crystallographic data for this paper.†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1043418. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra28800f

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