Enantioselective Michael addition of malonates to α,β-unsaturated ketones catalyzed by 1,2-diphenylethanediamine

Abstract

A general and highly enantioselective Michael addition of malonates to cinnamones and chalcones has been developed. The commercially available 1,2-diphenylethanediamine could be directly utilized as the organocatalyst to furnish the desired adducts in satisfactory yield (61–99%) and moderate to excellent enantiopurity (65 to >99% ee). β-Ketoester was also a competent donor and was employed to construct densely functionalized cyclohexenones via a tandem Michael-aldol condensation process.

1,2-Diphenylethanediamine could be directly utilized to promote the Michael addition of malonates and β-ketoesters to various α,β-unsaturated ketones.

Introduction

The direct Michael addition of stabilized carbon-centered nucleophiles to electron-poor olefins is widely recognized as a highly atom-economic carbon–carbon bond-forming reaction in organic synthesis. Therefore, the development of an enantioselective catalytic protocol for this conversion has constituted an actively pursued field in the past decades.¹ Although significant progress has been achieved with metal complexes,^1a–c recently the well-designed organocatalyst has played an impressive role in this field as well.^1d,1e Particularly, the organocatalytic Michael addition of malonates to α,β-unsaturated ketones will produce versatile adducts, which can be readily converted to the corresponding δ-ketoesters as useful synthetic building blocks after decarboxylation.² Pioneering work, the first highly enantioselective truly organocatalytic reaction of this type was developed by Jørgensen using an imidazoline catalyst in 2003.^2a Subsequently, other organocatalysts such as proline-derived tetrazole,^2b,3 metal salts of carboxylic acids,⁴ phase-transfer catalysts,⁵ various chiral thioureas,⁶ proline-derived guanidines,⁷ primary amines⁸ and their derivates⁹ have been introduced to catalyze this reaction. Despite excellent enantiopurities having been achieved in a few cases, nevertheless some of the established approaches suffer from several drawbacks to a certain extent, such as narrow substrate scope and restriction to a special combination of nucleophile and electrophile type. Moreover, among all these well-demonstrated organocatalytic Michael reactions, those untransformed and simple molecules are always not the preferred catalysts as a consequence of inferior enantioselectivity and poorer reactivity, high degrees of optical purity and reactivity need to be achieved in the presence of modified organocatalysts in most cases. As we all know, these employed optimal organocatalysts should usually been prepared from commercially available precursors or naturally occurring compounds after several-step, even multi-step transformation.^{2,3,5a,5b,6–9} The costly preparative procedure hence impairs the synthetic efficiency and practicality to a certain extent. Therefore, the development of highly general asymmetric Michael addition promoted by simple and commercially available molecules is clearly in high demand.¹⁰

In this context, chiral vicinal 1,2-diamines, mainly cyclohexane-1,2-diamines (CHDA)¹¹ and 1,2-diphenylethanediamine (DPEN)¹² emerged as a class of efficient and commercially available primary amine catalysts.¹³ These diamines enabled the stereoselective functionalization of a variety of steric-constraint carbonyl compounds, including aliphatic and aromatic ketones,^{11a–c,12h,12i} α-branched substituted aldehydes,^11d,11e and α,β-unsaturated carbonyl compounds.^11f,12a–g A range of versatile building blocks were smoothly constructed in a highly enantioenriched fashion via enamine,^{11a,11b,11d,12h} iminium,^11f,12a–f enamine–iminium^11c,11e,12g and dienamine¹²ⁱ activation modes. As part of our continuous efforts in developing asymmetric Michael addition of unactivated α,β-unsaturated ketones,¹⁴ we disclosed herein a highly enantioselective Michael addition of malonates to cinnamones^{2–4,6a–c,8–9} and chalcones^{5,6d–f,8b,15} catalyzed by a structurally simple DPEN.

Results and discussion

Instead of the often-used CHDA, the moisture- and air-stable, commercially inexpensive DPEN was initially utilized to screen the optimal conditions due to its operational simplicity. Gratifyingly, the Michael reaction between β-naphthyl-substituted cinnamone 1a and diethyl malonate 2a proceeded smoothly to afford the desired adduct 3aa with promising enantiopurity (92% ee) in the presence of acetic acid (Table 1, entry 1). In order to further improve the reactivity, we then turned our attention to examine the effect of other acidic additive. It was revealed that a significant decrease of catalytic capability was observed in the case of stronger acid (entries 2 and 3). Subsequently the model reaction was performed with a range of aromatic carboxylic acids. Although most of aromatic acid furnished 3aa with diminished yield and optical purity (entries 4–7 vs. entry 1), the enhancement of reactivity was fortunately observed with o-phthalic acid and salicylic acid (SA) (entries 8 and 9). In particular, the dicarboxylic acid, o-phthalic acid, gave rise to complete conversion after 144 hours, together with 95% ee.^11e,16 The effect of different solvents was successively investigated with SA (entries 10–13). The protic solvent, EtOH, gave the best enantioselectivity and ether led to a considerable improvement of reaction rate. Meanwhile, the model reaction went to completion after 96 hours with maintained enantiomeric excess when exposed to o-phthalic acid in EtOH (entry 14), however, sluggish transformation was detected in ether because of poor solubility of this catalyst system. Moreover, reducing the amount of malonate resulted in substantial decrease of reactivity (entry 15). The model reaction didn't occur in the absence of acidic additive (entry 16). Meanwhile, higher reactivity was observed under neat condition (entry 17).

Optimization of reaction conditions^a.

Entry	Additive	Solvent	Time (h)	Yieldb (%)	eec (%)
1	HOAc	Toluene	168	86	92
2	TFA	Toluene	168	79	96
3	TsOH	Toluene	168	30	97
4	BA	Toluene	168	82	81
5	PNBA	Toluene	168	65	71
6	ONBA	Toluene	168	64	72
7	OFBA	Toluene	168	77	61
8	o-Phthalic acid	Toluene	144	95	95
9	SA	Toluene	168	91	88
10	SA	CHCl3	168	91	90
11	SA	Et2O	72	97	90
12	SA	THF	168	91	88
13	SA	EtOH	168	75	96
14	o-Phthalic acid	EtOH	96	95	94
15d	o-Phthalic acid	EtOH	168	99	94
16e		EtOH	168	NR
17f	o-Phthalic acid		30	99	90

^aUnless otherwise noted, the reaction was performed with 0.2 mmol of 1a, 4 mmol of malonate 2a, 20 mol% (R,R)-DPEN and 40 mol% acid in 1 mL of solvent at rt. TFA = trifluoroacetic acid, TsOH = p-toluenesulfonic acid, BA = benzoic acid, PNBA = p-nitrobenzoic acid, ONBA = o-nitrobenzoic acid, OFBA = o-fluorobenzoic acid, SA = salicylic acid. NR = no reaction.

^bIsolated yield.

^cDetermined by chiral HPLC.

^dConducted with 2 mmol of malonate 2a.

^ePerformed in the absence of acid.

^f0.6 mL (4 mmol) malonate 2a was used as the solvent.

Once the optimal reaction conditions have been established, the substrate scope of this Michael addition was extended to a variety of cinnamones and malonates. As summarized in Table 2, this catalytic approach was not sensitive to the electronic property of cinnamones. The electron-neutral benzylideneacetone 1b reacted properly with diethyl malonate 2a to generate 3ab in synthetically useful yield and good enantioselectivity (Table 2, entry 1). The electron-deficient α,β-unsaturated ketones 1c–1g were well tolerated by this catalytic system and enabled access to the expected adducts 3ac–3ag in a highly enantioselective manner (entries 2–6). Meanwhile, the electron-rich cinnamones 1h and 1i are also suitable acceptors for this conversion (entries 7 and 8). On the other hand, the position of substituent on the phenyl ring exerted negligible affect on this titled Michael reaction. Almost identical isolated yields were obtained in the case of the sterically congested ortho-substituted enone 1d in comparison with the meta-substituted 1e and para-substituted 1f (entry 3 vs. entries 4 and 5). In contrast with bulky α-naphthyl-containing 1j, better catalytic performance in terms of reactivity and enantiocontrol was achieved when β-naphthyl-embedded acceptor 1a was utilized (entry 9 vs. entry 10). The heteroaromatic substrates 1k and 1l served as appropriate acceptors as well, however, a modified condition was required for 1k to achieve synthetically useful conversion (entries 11 and 12). In addition to aromatic substrates, the aliphatic enones 1m and 1n were also compatible with this catalytic strategy, but with slightly poorer reactivity (entries 13 and 14). Notably, variation of R₂ ketone substituent indicated that enone 1o possessing a sterically more demanding ethyl group also participated in this conjugate addition (entry 15). Cyclic enones^{2b,3,4b,6a,6g,7,17} were suitable acceptors as well, generating the corresponding adducts 3ap and 3aq with good enantioselectivities (entries 16 and 17).

Substrate scope of Michael addition of malonates to cinnamones and its analogues^a.

Entry	R 1	R 2	2	3	Time (h)	Yieldb (%)	eec (%)
1	Ph	Me (1b)	2a	3ab	168	75	91
2	p-FC6H4	Me (1c)	2a	3ac	168	99	95
3	o-ClC6H4	Me (1d)	2a	3ad	168	99	96
4	m-ClC6H4	Me (1e)	2a	3ae	168	99	94
5	p-ClC6H4	Me (1f)	2a	3af	168	99	95
6	p-BrC6H4	Me (1g)	2a	3ag	168	70	93
7	p-MeC6H4	Me (1h)	2a	3ah	168	85	94
8	p-MeOC6H4	Me (1i)	2a	3ai	168	92	96
9	1-Naphthyl	Me (1j)	2a	3aj	168	97	96
10	2-Naphthyl	Me (1a)	2a	3aa	96	95	94
11d	2-Furanyl	Me (1k)	2a	3ak	168	84	86
12	2-Thiophenyl	Me (1l)	2a	3al	168	97	92
13	Me	Me (1m)	2a	3am	168	70	86
14d	n-Bu	Me (1n)	2a	3an	168	65	95
15	Ph	Et (1o)	2a	3ao	168	61	91
16e	–(CH2)3– (1p)		2a	3ap	168	71	82
17	–(CH2)4– (1q)		2a	3aq	96	97	87

^aUnless otherwise noted, the reaction was performed with 0.2 mmol of 1, 4 mmol of malonate 2a, 20 mol% (R,R)-DPEN and 40 mol% o-phthalic acid in 1 mL of EtOH at rt.

^bIsolated yield.

^cDetermined by chiral HPLC.

^dPerformed with 40 mol% SA in ether.

^e2 mmol of malonate 2a was used.

With respect to the donor, good enantiomeric excess was obtained for dimethyl ester 2b, and lower reactivity was detected for diisopropyl ester 2c but without compromising the optical purity (Table 3, entries 1 and 2). In contrast, dibenzyl malonate 2d afforded desired adduct 3da with relatively poorer optical purity (entry 3). Meanwhile, the reaction was totally inert in the case of di-tert-butyl malonate. Moreover, methyl-substituted malonate 2e was also compatible with this catalytic protocol, but relatively lower reactivity was observed (entry 4).

Substrate scope of malonates^a.

Entry	2	3	Yieldb (%)	eec (%)
1	2b	3ba	81	90
2	2c	3ca	65	93
3	2d	3da	92	74
4	2e	3ea	72	95

^aUnless otherwise noted, the reaction was performed with 0.2 mmol of 1a, 4 mmol of malonate 2, 20 mol% (R,R)-DPEN and 40 mol% o-phthalic acid in 1 mL of EtOH at rt for 168 h.

^bIsolated yield.

^cDetermined by chiral HPLC.

With the exception of cinnamones, our catalytic protocol was also applicable to chalcones, a class of challenging substrates for iminium ion activation.¹⁸ Only moderate isolated yield was obtained when performed with o-phthalic acid in EtOH, whereas the reactivity could be effectively improved when conducted with salicylic acid in ether (Table 4, entry 1). Again, this Michael reaction was independent of the electronic nature of substituents on each aromatic ring of chalcones. Both the electron-rich chalcones 4b and 4f, and the electron-poor chalcones 4c, 4g and 4i worked smoothly with diethyl malonate 2a, forming the expected adducts with complete conversion in highly enantioenriched fashion (entries 2, 3, 6, 7 and 9). Only slightly reduced yield was detected for enone 4d bearing a bulky naphthyl group at the β-site, along with 94% ee (entry 4). The heteroaromatic chalcones 4e and 4h underwent clean reactions and gave rise to the desired adducts 5e and 5h in acceptable yields and moderate to excellent enantioselectivities (entries 5 and 8). The absolute configuration of 3 and 5 was confirmed to be S via comparison of HPLC traces and optical rotation value with that of literatures reported.^2b,6e

Substrate scope of the Michael addition of malonate to chalcones^a.

Entry	Ar1	Ar2	5	Yieldb (%)	eec (%)
1	Ph	Ph (4a)	5a	75 (55)d	92 (98)d
2	p-MeC6H4	Ph (4b)	5b	98	98
3	p-ClC6H4	Ph (4c)	5c	99	94
4	2-Naphthyl	Ph (4d)	5d	88	94
5	2-Thiophenyl	Ph (4e)	5e	83	65
6	Ph	p-MeC6H4 (4f)	5f	99	99
7	Ph	p-ClC6H4 (4g)	5g	99	>99
8	Ph	2-Thiophenyl (4h)	5h	65	96
9	p-ClC6H4	p-ClC6H4 (4i)	5i	99	93

^aUnless otherwise noted, the reaction was performed with 0.2 mmol of 4, 4 mmol of malonate 2a, 20 mol% (R,R)-DPEN, 40 mol% salicylic acid in 1 mL of ether at rt for 168 h.

^bIsolated yield.

^cDetermined by chiral HPLC.

^dCarried out with o-phthalic acid in 1 mL of EtOH.

In addition to malonates, we were pleased to find that β-ketoester was also competent donor for this catalytic protocol.¹⁹ After further optimization of reaction conditions, we found that the cascade Michael-aldol condensation process between cinnamones 1 and ethyl benzoylacetate 2f readily occurred with 30 mol% of TFA in chloroform, delivering highly functionalized cyclohexenones 6 as an inseparable mixture of diastereomers. (See Table S1 in the ESI†). Both the electron-deficient cinnamones and the electron-rich cinnamones were well tolerated (Table 5, entries 2–4). The bulky naphthyl group-containing enone 1a and the heteroaromatic substrate 1l were compatible with this catalytic protocol as well, leading to the formation of annulated product 6e and 6f with high levels of enantiopurities (entries 5 and 6). The absolute stereochemistry of cyclohexenone 6 was determined to be S via conversion of 6a to known compound after a simple decarboxylation (see eqn S(1) in the ESI†).^19b Notably, cyclohexenones and their derivates constituted crucial skeletal components common in enormous natural products and pharmaceutical molecules.²⁰

Domino reaction for the synthesis of cyclohexenone^a.

Entry	Ar	6	Yieldb (%)	drc	eed (%)
1	Ph (1b)	6a	97	77 : 23	96/97
2	p-ClC6H4 (1f)	6b	97	79 : 21	87/87
3	p-BrC6H4 (1g)	6c	92	80 : 20	95/97
4	p-MeOC6H4 (1i)	6d	99	66 : 34	92/90
5	2-Naphthyl (1a)	6e	99	53 : 47	89/87
6	2-Thiophenyl (1l)	6f	94	60 : 40	92/90

^aUnless otherwise noted, the reaction was performed with 0.2 mmol of 1, 0.4 mmol of 2f, 20 mol% (R,R)-DPEN and 30 mol% TFA in 1 mL of CHCl₃ at rt for 120 h.

^bIsolated yield of the diastereomeric mixture.

^cDiastereomeric ratio (dr) was determined by ¹H NMR analysis of the crude mixture; major isomer: trans.

^dDetermined by chiral stationary-phase HPLC.

To demonstrate the synthetic potential of this organocatalytic asymmetric process, base-controlled chemoselective conversion of Michael adduct 5a were conducted in the presence of iodine.²¹ α-Hydroxylation of malonate moiety occurred smoothly to provide α-hydroxyl malonate 7 almost without compromise of enantiopurity, when treated with a catalytic amount of NaOAc (Scheme 1). Moreover, the adduct 5a could be converted to phenyl ester 8 by brief exposure to meta-chloroperoxybenzoic acid (m-CPBA) without deterioration of optical purity. This Baeyer–Villiger oxidation proceeded with exclusive regioselectivity. Lastly, transesterification of crude 8 worked properly with NaBH₄ in MeOH to afford methyl ester in 86% yield, albeit a slight deterioration of optical purity was detected.

Scheme 1. Synthetic transformation of adduct 5a.

To account for the observed stereochemical outcome of this Michael addition, a bifunctional catalytic model was proposed in Scheme 2.^12g Initially, benzylideneacetone 1b was activated via formation of iminium ion with one amino group of vicinal diamine catalyst. Another amino group of DPEN could be engaged in hydrogen-bonding interaction with the carbonyl moiety of ethyl malonate. As a result, the donor was restricted to attack Re face of enone, thereby leading to the generation of S-configured adduct 3ab. In the case of ethyl benzoylacetate, the formation of enamine intermediate allowed the following intramolecular aldol reaction to construct cyclohexanone.^19b After final dehydration, the cyclohexenone 6a was therefore obtained.

Scheme 2. Proposed reaction pathway.

Conclusions

In conclusion, we have developed a general and enantioselective Michael addition of malonate to cinnamones and chalcones. The commercially available DPEN could be utilized as the organocatalyst to furnish the desired adducts in satisfactory yield (61–99%) and moderate to excellent enantiopurity (65 to >99% ee). This catalytic protocol was also applicable to β-ketoester and constructed a densely functionalized cyclohexenone via a tandem Michael-aldol condensation process. Furthermore, profound synthetic manipulation could be performed on the resulting adduct to construct various optically active building blocks.

Conflicts of interest

There are no conflicts to declare.