Asymmetric Michael addition reactions of pyrrolones with chalcones catalyzed by vicinal primary-diamine salts

Abstract

The efficient asymmetric Michael addition reactions of pyrrolones with chalcones catalyzed by a simple and commercially available chiral 1,2-diaminocyclohexane-2-(N-Boc-amino)benzoic acid have been developed to provide the corresponding Michael adducts in good yields (up to 90%) and high enantioselectivities (up to 95% ee).

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Pyrrolones are privileged heterocyclic scaffolds found in a number of natural and synthetic molecules (Fig. 1),¹ which are reported to possess important pharmacological activities, especially antibacterial and antifungal,² anti-tubercular,³ anticonvulsant activity,⁴ immunosuppressive activity,⁵ anticancer activity,⁶ analgesic and anti-inflammatory activity.⁷ Additionally, optical pyrrolones can act as synthetic precursors of some natural products.⁸ In particular, chiral 5-substituted pyrrolones and their derivatives display marvelous biological properties,⁹ which undoubtably increase their importance both in chemical synthesis and synthetic methodologies. Therefore, the exploration of asymmetric reactions from readily available starting material pyrrolones to their 5-substituted derivatives has recently appeared extremely attractive.

Fig. 1 Representative compounds containing pyrrolone scaffold.

In general, these asymmetric reactions include asymmetric Michael addition reaction, asymmetric Aldol condensation reaction and asymmetric Mannich reaction.¹⁰ Recently, some secondary and tertiary amines, such as proline and its derivatives, thioureas, quinines and cinchona alkaloids were reported to catalyze above asymmetric reactions.¹¹ Great improvement has been made in asymmetric Michael addition reaction (Fig. 2). For example, Chen and co-workers achieved satisfied results in the enantio- and diastereoselective Michael reaction of N-Boc pyrrolone with α,β-unsaturated aldehydes catalyzed by proline,¹² Feng's group developed a novel guanidine combining with secondary amine as bifunctional catalysts for the asymmetric Michael reaction of N-Boc pyrrolone with malonates.¹³ However, to the best of our knowledge, chiral primary amine has rarely been used to the 5-deprotonation of pyrrolone pathway,¹⁴ and the poor reactive chalcones have never been reported to proceed asymmetric Michael reaction with pyrrolones. So it still represents a challenging task regarding the reactivity and stereoselectivity of the two relatively inert reactants.

Fig. 2 Asymmetric Michael addition reactions of pyrrolones reported previously.

In our previous report, we have successfully realized the asymmetric Michael addition reactions of furanones with chalcones using simple chiral primary-diamine salts (Scheme 1).¹⁵ As an extension of our work, herein, we wish to disclose an efficient asymmetric Michael addition reaction of pyrrolones with chalcones catalyzed by chiral primary-diamine salts (Table 1).

Scheme 1 Organocatalyzed direct Michael addition reactions of furanones to chalcones.

Table 1 Optimization of reaction conditions^a

Entry	Cat.	Solvent	Additive	T (°C)	Yield^b (%)	dr^c	ee^d (%)
a All reactions were carried out using 1.0 equiv. of 1a (0.15 mmol), 1.5 equiv. of 2a (0.225 mmol), and 20 mol% of catalyst (0.03 mmol), 40 mol% of additive (0.06 mmol).b Isolated yield.c Determined by NMR.d Determined by chiral HPLC analysis.
1	C1	MeOH	A1	r.t.	25	8 : 1	89
2	C2	MeOH	A1	r.t.	Trace	—	—
3	C3	MeOH	A1	r.t.	0	—	—
4	C4	MeOH	A1	r.t.	Trace	—	—
5	C1	MeOH	A2	r.t.	0	—	—
6	C1	MeOH	A3	r.t.	20	12 : 1	93
7	C1	MeOH	A4	r.t.	25	18 : 1	91
8	C1	MeOH	A5	r.t.	27	10 : 1	94
9	C1	MeOH	A5	40	45	1 : 1	55
11	C1	EtOH	A5	40	30	2 : 1	85
12	C1	PhMe	A5	40	48	1 : 1	90
13	C1	PhMe	A6	40	50	3 : 1	91
14	C1	PhMe	A7	40	80	1 : 1	80
15	C1	PhMe	A8	40	65	3 : 2	95

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Our initial investigation began with the reaction of 4-phenyl N-benzyl pyrrolone (1a) and chalcone (2a) using chiral (1R, 2R)-cyclohexane-1,2-diamine (C1, 20 mol%) as catalyst and acetic acid (A1, 40 mol%) as additive in methanol at room temperature, and the desired product 3a was obtained in 25% yield with 8 : 1 dr and 89% ee (Table 1, entry 1). Encouraged by this result, we began the further optimization as follows. Firstly, different chiral primary amine catalysts were screened (Table 1, entries 1–4) and C1 still was the best one. Then, the effect of the additive on the reaction was tested (Table 1, entries 5–8). It can been seen that all selected additives except A2 worked well and A5 is better by comparison (Table 1, entry 8). By raising the reaction temperature from r.t. to 40 °C, the yield of 3a was improved to 45%, unfortunately, its stereoselectivity was significantly decreased (Table 1, entry 9). Furtherly, solvent screening revealed that compound 3a could be obtained in 48% yield with 90% ee in toluene at 40 °C (Table 1, entry 12). In order to further optimize the yield and stereoselectivity, the derivatives of benzoic acid (A6–A8) were examined (Table 1, entries 13–15). The results revealed that, using C1 as catalyst and A8 as additive, the reaction between substrates 1a and 2a in toluene at 40 °C gave the desired product 3a in 65% yield, 3 : 2 dr and 95% ee (Table 2, entry 15).

Table 2 Substrate scope for the Michael addition reaction of 1 and 2^a

Entry	1	Ar2	Ar3	3/yield^b (%)	dr syn : anti^c	ee (%) (syn)^d
a All reactions were carried out using 1.0 equiv. of 1a (0.15 mmol), 1.5 equiv. of 2a (0.225 mmol), and 20 mol% of catalyst (0.03 mmol), 40 mol% of additive (0.06 mmol).b Isolated yield.c Determined by NMR.d Determined by chiral HPLC analysis.
1	1a	Ph	Ph	3a/65	3 : 2	95
2	1b	Ph	Ph	3b/40	2.5 : 1	90
3	1c	Ph	Ph	3c/60	2 : 1	90
4	1a	Ph	3-MeOC6H4	3d/70	4 : 3	90
5	1a	Ph	4-ClC6H4	3e/62	2 : 1	81
6	1a	Ph	3-NO2C6H4	3f/75	2 : 1	92
7	1c	Ph	3-MeOC6H4	3g/64	3 : 1	93
8	1c	Ph	3-MeC6H4	3h/55	5 : 3	85
9	1c	Ph	4-MeC6H4	3i/60	2.5 : 1	85
10	1c	Ph	3-ClC6H4	3j/82	2 : 1	83
11	1c	Ph	4-ClC6H4	3k/64	2 : 1	87
12	1c	Ph	4-FC6H4	3l/55	2 : 1	85
13	1c	4-MeC6H4	Ph	3m/69	5 : 4	84
14	1c	4-MeC6H4	3-MeC6H4	3n/66	1 : 1	85
15	1c	4-MeC6H4	3-BrC6H4	3o/64	2.5 : 1	86
16	1c	4-MeC6H4	4-FC6H4	3p/90	1 : 1	87

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With the optimized conditions in hand, the application scope of the catalytic system was then explored. As shown in Table 2, different 4-aromatic ring substituted N-benzyl pyrrolones react well with variety of chalcones giving the corresponding products 3 in moderate to good yields and high enantioselectivities. For N-benzyl pyrrolones (Table 2, entries 1–3), the electron nature of the substituents on the aromatic ring at the 4-position of N-benzyl pyrrolones (1) did not have an obvious effect on either diastereoselectivity or enantioselectivity when ignoring the fact that 4-bromo substituent decreased the yield (Table 2, entry 2). As regards chalcones, whatever their aromatic rings Ar₂ or Ar₃ contained electron-rich or electron-deficient substituents, the reaction remained stable yields and high enantioselectivities.

NOESY experiments performed on compound 3p,¹⁶ revealed strong correlations between hydrogen 2 and 5, 6, 7, 8 on 3p₁, and no correlations between the hydrogens on Ar₁ and hydrogen 7. As for 3p₂, on the contrary, there were strong correlations between the hydrogens on Ar_1, hydrogen 7, but no correlations between hydrogen 2 and 7, 8. Thus, the NOESY experiments allowed us to confirm the relative configuration of product 3p (Fig. 3). (see ESI†). Unfortunately, we were unable to grow quality crystals to determine compound 3p's absolute configuration.

Fig. 3 NOESY analysis of product 3p.

Conclusions

In conclusion, we have developed an efficient asymmetric Michael addition reaction of 4-aromatic ring substituted N-benzyl pyrrolones with chalcones utilizing the simple and commercially available chiral 1,2-diaminocyclohexane-2-(N-Boc-amino)benzoic acid as the cooperative catalysts. The corresponding Michael addition products were obtained in moderate to good yields (up to 90%) and excellent enantioselectivity (up to 95% ee). Further studies and applications of vicinal primary diamine as catalyst in asymmetric reactions are currently underway in our laboratory.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (no. 81673287).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7ra03069j

‡ These authors contributed equally to the work.

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