Quinine catalysed asymmetric Michael additions in a sustainable solvent

Abstract

Diethyl carbonate is shown to be a suitable, sustainable solvent in which to carry out quinine catalysed asymmetric Michael additions of malononitriles to enones. Both malonitrile and α-substituted malononitriles can be used as substrate and the results suggest that π–π stacking interactions between the (hetero)aromatic rings of the catalyst and substrates are important in determining the degree of asymmetric induction.

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Introduction

Over the last decade there has been an explosion of interest in asymmetric organocatalysis.¹ Whilst the initial advances in this area were made using unmodified natural products such as proline,² other amino acids³ and cinchona alkaloids⁴ as catalysts, the recent trend has been towards the use of highly modified natural products or totally synthetic catalysts.^1,5 These non-natural catalysts often offer improved solubility and enhanced reactivity compared to the direct use of natural products as catalysts, but sacrifice the green characteristics associated with using unmodified natural products⁶ due to the need to carry out multi-step transformations to prepare the catalyst.

Another aspect of organocatalysis that has been rather neglected is the reaction solvent, even though this usually constitutes the bulk of the reaction mass. Amino acid catalysed reactions are often carried out in solvents such as DMF or DMSO to facilitate the solubility of the zwitterionic catalyst.^1–3,7 Other organocatalysed reactions have been carried out in solvents such toluene, acetonitrile, dichloromethane or chloroform.^1–7 However, these solvents are petrochemically derived and have hazards associated with their toxicity; potential to generate contaminated aqueous waste and potential to generate NO_x/SO_x on incineration.⁸ In some cases, organocatalysed reactions can be carried out under solvent-free conditions,⁹ and water¹⁰ and ionic liquids¹¹ have both been used as alternative solvents for organocatalysed reactions. However, the green credentials of these solvents have been questioned¹² and water is known to inhibit some proline catalysed reactions.¹³

To overcome the solvent limitations associated with the use of unmodified natural products as organocatalysts, we have recently reported the use of ethylene 1 or propylene 2 carbonate as green polar aprotic solvents for amino acid catalysed reactions.¹⁴ Cyclic carbonates 1 and 2 have high dielectric constants (90 and 65 respectively¹⁵). In contrast, acyclic carbonates such as dimethyl 3 and diethyl 4 carbonate have a much lower dielectric constant (3.1 (ref. 16)) and so can be considered as apolar solvents (Fig. 1). Carbonates 1–4 have also been used as solvents for uncatalysed and metal catalysed reactions¹⁷ and are used as electrolytes for lithium ion batteries.¹⁸ The green credentials of carbonates 1–4 are supported by their low toxicities,^16,17 facile hydrolysis to innocuous by-products¹⁹ and green syntheses^16,20 with the potential to utilize waste carbon dioxide in their syntheses.²¹ Compounds 1–3 were included in a recent listing of industrially recommended green solvents.²² In this manuscript we show that acyclic carbonate 4 can be used as a green solvent for quinine catalysed Michael additions.

Results and discussion

In 2009,²³ Lattanzi and coworkers reported that unmodified quinine 5 would catalyse the asymmetric addition of malononitrile 6 to aryl vinyl ketones 7 to give Michael adducts 8 with 74–95% enantiomeric excess under optimized conditions (−18 °C and 10 mol% catalyst) as shown in Scheme 1.²⁴ Whilst this 100% atom economical reaction is synthetically attractive as it produces richly functionalised products, it does have two drawbacks: the reaction times were 60–186 hours and high yields and enantioselectivities were only obtained in petrochemically derived aromatic hydrocarbon solvents (toluene or xylene) which are less than ideal solvents, especially from an environmental impact perspective.²² Therefore, we felt that this reaction would allow us to extend our previous work on carbonate solvents for organocatalysed reactions to a different class of catalysts and reactions. The choice of solvent for asymmetric organocatalysed reactions is a non-trivial undertaking as efficient asymmetric induction often relies on non-covalent interactions and hydrogen bonds.^1–5 These are easily disrupted by polar solvents or even by non-polar solvents which can act as hydrogen bond acceptors. Thus, even though diethyl carbonate has low polarity there was still the possibility that it would act as a Lewis base, disrupting any hydrogen bonds between the quinine and substrates.

Scheme 1 Quinine catalysed asymmetric Michael additions.

Fig. 1 Structures 1–5.

Initial studies were carried out using chalcone 7a as the Michael acceptor with 1.2 equivalents of malonitrile 6 and with 20 mol% of quinine to increase the reaction rate. The results of this study are shown in Table 1. Entries 1 and 2 confirm the results of Lattanzi and coworkers showing that high chemical yields are obtained in both toluene and methanol, but high levels of asymmetric induction are only obtained in the very non-polar solvent. Entries 3–5 then show that the use of polar cyclic carbonates as solvents give product 8a in high yield, but with greatly reduced enantiomeric excess compared to reactions carried out in toluene. The use of enantiomerically pure propylene carbonate was also not advantageous in this case (compare entries 4 and 5). In addition, a minor side product was observed in these reactions. This was isolated and determined to be cyclohexanol derivative 9a (Fig. 2) resulting from a tandem double Michael addition of malonitrile to two molecules of chalcone 7a followed by an intramolecular aldol reaction. The structure and formation of racemic 9a in related racemic Michael additions has been reported before, as has the relative stereochemistry of its four stereocentres.²⁵

Table 1 Michael addition of malononitrile 6 to chalcone 7a

Entry	Solvent	t (h)	T (°C)	7a : 6	Yield^a (%)	8a : 9a	ee^b (%)
a Isolated yield of 8a + 9a after purification by flash chromatography. Compounds 8a and 9a were not readily separable.b Ee of compound 8a determined by chiral HPLC on a Chiralpak AD-H column.
1	Toluene	20	18	1 : 1.2	98	1 : 0	87
2	MeOH	20	18	1 : 1.2	90	1 : 0	0
3	1	20	18	1 : 1.2	82	4.4 : 1	11
4	RS–2	20	18	1 : 1.2	80	11.6 : 1	12
5	R–2	20	18	1 : 1.2	80	13.5 : 1	12
6	3	20	18	1 : 1.2	98	8.8 : 1	48
7	3	72	0	1 : 1.2	98	4.3 : 1	31
8	4	20	18	1 : 1.2	95	21 : 1	56
9	4	72	0	1 : 1.2	98	1 : 1	52
10	4	72	−20	1 : 1.2	98	1 : 1.7	47
11	4	20	30	1 : 5	98	1 : 0	58
12	4	20	18	1 : 5	98	1 : 0	60
13	4	20	0	1 : 5	98	1 : 0	62
14	4	48	−10	1 : 5	96	1 : 0	64
15	4	72	−20	1 : 5	90	1 : 0	64
16	4	72	−40	1 : 5	80	1 : 0	65

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Fig. 2 Structure 9a–c.

The mode of action of quinine in this reaction likely involves it acting as a Brønsted base to remove one of the acidic protons from malonitrile. Thus, to get efficient asymmetric induction during the Michael addition of the resulting malonitrile anion, it is necessary for the chiral cation and achiral anion to form a tight ion pair. It is also likely that π–π interactions between the aromatic rings of quinine and enone 7 are important to organise the reaction components and maximise the asymmetric induction, since only aryl enones form effective substrates for this reaction.²³ A polar solvent (such as cyclic carbonates 1 and 2) would disrupt both the tight ion pair and any π–π interactions, thus resulting in the significantly reduced asymmetric induction. To overcome this problem, the use of much less polar, acyclic carbonate solvents 3 and 4 was therefore investigated. The use of dimethyl carbonate as solvent at either 18 or 0 °C (entries 6 and 7) gave the same chemical yield as a reaction in toluene, but whilst the enantioselectivity increased relative to the use of cyclic carbonates as solvent, it was still only around half that observed in toluene. The use of diethyl carbonate as solvent gave even better results (entry 8), with a high yield and a high ratio of 8a : 9a, though the enantiomeric excess of product 8a was still only moderate. Attempts to increase the enantioselectivity of the reaction by lowering the reaction temperature (entries 9 and 10) were unsuccessful as not only did the enantiomeric excess of compound 8a decrease as the temperature was lowered, but the amount of by-product 9a formed increased significantly and at −20 °C it became the major product (entry 10). The reduction in enantioselectivity at lower temperature was traced to an uncatalysed Michael addition occurring upon addition of water and warming the reaction mixture. This could be avoided by quenching the reactions with dilute hydrochloric acid rather than water.

The use of other cinchona alkaloids as catalysts was briefly investigated under the conditions of Table 1, entry 9. However, under these conditions quinidine, cinchonine and cinchonidine gave compound 9a as the only product in 84, 55 and 59% chemical yield respectively.

To avoid the formation of by-product 9, the ratio of malononitrile 6 to chalcone 7a was increased to 5 : 1. As shown in Table 1, entry 11, this resulted in the exclusive formation of product 8a in excellent chemical yield and with further improved enantiomeric excess even from a reaction carried out at 30 °C. It was then possible to further increase the enantioselectivity to 64% by lowering the reaction temperature to −20 °C (entries 12–16). Reactions carried out with 30 mol% of quinine did not result in higher enantioselectivities.

The quinine catalysed Michael addition of malononitrile to three other α,β-unsaturated ketones 7b–d was also investigated in diethyl carbonate and the results are shown in Table 2. For substrates 7b and 7c the enantioselectivities at −20 °C were essentially identical to those obtained using substrate 7a (compare Table 1, entry 15 with Table 2, entries 4 and 8). The chemical yields obtained using substrates 7a and 7b were also very similar, whilst electron-rich substrate 7c was less reactive.

Table 2 Michael addition of malononitrile 6 to enones 7b–d

Entry	Enone	t (h)	T (°C)	7b–d : 6	Yield^a (%)	8 : 9	ee^b (%)
a Isolated yield of 8b,c + 9b,c after purification by flash chromatography.b Ee of compounds 8b,c determined by chiral HPLC on a Chiralpak AD-H column.
1	7b	24	18	1 : 1.2	72	8.5 : 1	45
2	7b	72	−20	1 : 1.2	81	5.2 : 1	44
3	7b	24	18	1 : 5	73	1 : 0	58
4	7b	72	−20	1 : 5	91	1 : 0	64
5	7c	24	18	1 : 1.2	90	10.8 : 1	54
6	7c	72	−20	1 : 1.2	41	0.2 : 1	54
7	7c	24	18	1 : 5	79	1 : 0	54
8	7c	72	−20	1 : 5	72	1 : 0	65

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Benzylidene acetone 7d was not a substrate for the reaction. These results suggest the importance of π–π interactions involving an aromatic ring at the R² position of substrate 7 in obtaining good levels of asymmetric induction.

If steric factors were responsible for the asymmetric induction, then we reasoned that increasing the size of the malonitrile enolate would increase the facial discrimination between the enantiotopic faces of the enone and result in higher levels of asymmetric induction. Therefore, we investigated the Michael addition of α-monosubstituted malonitrile derivatives 10a–l to chalcone 7a to give ketones 11a–l as shown in Scheme 2. The results of this study are given in Table 3. Initially a series of arylmethyl substituted malonitriles 10a–i were used to see if π–π interactions involving the aryl ring would improve the enantioselectivity. Dinitrile 10a was however not encouraging, giving compound 11a²⁶ with only moderate enantiomeric excess and in very low yield after a reaction carried out for 72 hours at room temperature (entry 1). However, introducing a halogen substituent into the 4-position of dinitrile 10 had a highly beneficial effect on both the yield and enantioselectivity of the reactions, giving compounds 11b,c with 94 and 89% enantiomeric excess respectively (entries 2 and 3). Moving the halogen to the 3-position of the aromatic ring (10d) retained the improved yield, but not the enhanced enantioselectivity (entry 4), whilst moving it to the 2-position of the aromatic ring (10e) lowered both the yield and enantioselectivity to values similar to those seen for unsubstituted substrate 10a.

Scheme 2 Quinine catalysed asymmetric Michael additions of α-monosubstituted malononitriles.

Table 3 Quinine catalysed Michael addition of α-substituted malononitriles 10a–i to enone 7a

Entry	10	Solvent	t (h)	T (°C)	Yield^a (%)	ee^b (%)
a Isolated yield of 11a–i after purification by column chromatography.b Ee determined by chiral HPLC on a Chiralpak AD-H column.c Using 5 equivalents of 10b.
1	a	5	72	18	12	46
2	b	5	72	18	41	94
3	c	5	72	18	39	89
4	d	5	72	18	32	47
5	e	5	72	18	19	50
6	f	5	72	18	47	91
7	g	5	72	18	22	77
8	h	5	72	18	52	80
9	i	5	72	18	65	20
10	a	5	168	18	54	40
11	b	5	168	18	63	50
12	c	5	168	18	56	77
13	d	5	168	18	46	50
14	e	5	168	18	68	33
15	f	5	168	18	72	78
16	h	5	168	−20	33	46
17	i	5	168	−20	63	21
18^c	b	5	72	18	57	50
19	j	5	72	18	44	48
20	j	5	168	18	61	48
21	k	5	72	18	57	46
22	k	5	168	18	73	50
23	l	5	72	18	88	38
24	b	Toluene	72	18	62	76
25	b	Acetone	72	18	24	11
26	b	EtOAc	72	18	31	61
27	b	Cymene	72	18	49	68

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Other substituents at the 4-postion of the aromatic ring of substrates 10 were also beneficial with the most positive effects being seen with strongly electron withdrawing groups such as nitro (10f) and trifluoromethyl (10h) whilst an electron donating methoxy substituent had a beneficial effect on the enantioselectivity, but not on the yield (entries 6–8). Substrate 10i with fluorine substituents at all positions of the aromatic ring gave product 11i in good chemical yield but with very low enantiomeric excess (entry 9).

In an attempt to improve the chemical yields of these reactions, the reaction times were extended to 168 hours with substrates 10a–f. This was successful in raising the chemical yields of products 11a–f (entries 10–15), but also resulted in a decrease in the enantiomeric excess of products 11a–f, except for product 11d. This suggests that compounds 11a–i can undergo slow racemisation under the reaction conditions, presumably by a retro-Michael/Michael addition process. In the case of substrates 10h,i the extended reaction time experiments were carried out at −20 °C in an attempt to improve the enantioselectivity of the reactions since these two substrates had given reasonable chemical yields after 72 hours at room temperature. However, for substrate 10h this had a negative impact on both the yield and enantiomeric excess of product 11h (entry 16), whilst for product 11i, there was no significant difference in the yield or enantiomeric excess (entry 17). An attempt was also made to increase the chemical yield by using five equivalents of malononitrile 10b (entry 18). However, whilst this did result in a modest increase in chemical yield (compare entries 2 and 18), this was at the expense of a major reduction in enantioselectivity. It may be that the large excess of 10b present in this reaction increases the polarity of the reaction solvent and hence destabilises π–π interactions between the catalyst and substrates.

The study was then extended to non-aromatic malononitriles 10j–l to investigate if the aryl group present in substrates 10a–i was important for asymmetric induction. The results (entries 19–23) showed that for these substrates which lack an aromatic ring, the enantiomeric excess of the products was 38–50%, values which are comparable with the worst performing aromatic substrates under the same conditions (entries 1, 4, 5, 9–11, 13, 14, 16 and 17), but much lower than the best of the aryl methyl malonitriles (entries 2, 3, 6–8, 12 and 15).

Finally, we screened a number of other solvents using substrate 10b at 18 °C for 72 hours (entries 24–27). Toluene gave product 11b with inferior enantiopurity compared to a reaction carried out in diethyl carbonate (compare entries 2 and 24). Other green solvents were also tested, but acetone and ethyl acetate both gave product 11b in low yield and in the case of acetone with very low enantiopurity (entries 25 and 26). Cymene (4-isopropyl-toluene) which is available from limonene gave 11 in lower yield and enantiomeric purity than the reaction carried out in toluene (compare entries 24 and 27).

The above results are not consistent with simple steric or electronic effects being responsible for the magnitude of the asymmetric induction, though they do suggest that substituents at the 4-position of substrate 10 will be beneficial whilst those at other positions of the aromatic ring will be detrimental. In particular, both electron donating (10g) and electron withdrawing (10b,c,h) substituents gave products with higher enantiomeric excesses than that of the unsubstituted substrate 10a. It may be that π–π stacking between substrate 10 and quinine 5 and/or enone 7a are important for the asymmetric induction, and substituents at the 2- or 3-positions of the aryl ring of substrates 10 disrupt this π–π stacking. This is consistent with the results obtained with substrates 10j–l which lack an aromatic ring and so cannot benefit from these favourable π–π interactions.

Conclusions

We have shown that diethyl carbonate can replace toluene as a solvent for quinine catalysed Michael additions of malonitrile derivatives to enones. The chemical yields and enantioselectivities were highly variable which may be due to the complex nature of the intermolecular interactions in this system as the degree of asymmetric induction is likely to be influenced by both the tightness of an ion pair and the nature of the π–π interactions between the enone, malononitrile and quinine. Most solvents have the potential to disrupt these interactions, but it appears that diethyl carbonate is better than other green solvents in this respect.

Experimental

Instrumentation

¹H and ¹³C NMR spectra were recorded on a Bruker Avance 300 or Jeol Oxford 400 spectrometer at resonance frequencies of 300/400 and 75/100 MHz respectively. ¹⁹F NMR spectra were recorded on the Oxford 400 spectrometer at a resonance frequency of 367 MHz. Electrospray ionization (ESI) mass spectra were recorded on a Bruker Daltronics microTOF spectrometer. Infrared spectra were recorded on a Bruker Vertex 70 instrument equipped with “Specac” Golden Gate Single Reflection Diamond ATR accessories. Chiral HPLC was performed using an Agilent 1220 Infinity LC series system comprising binary pumping modules, a diode array detector and autosampler. The column, solvent and flow rate are given for each compound. Automated flash chromatography was carried out on a Biotage isolera four system. Melting points were obtained using a Gallenkamp melting point apparatus. Optical rotations were measured at 20 °C on a Jasco DIP-370 polarimeter using a 10 cm curvette. The sample concentration is reported in g per 100 mL of the specified solvent.

General procedure for the preparation of racemic samples of compounds 8a–d and 11a–i

Enone 7a–d (0.2 mmol) and DABCO (5.0 mg, 0.04 mmol) were dissolved in MeOH (2 mL). Malononitrile 6 or 10a–i (0.24 mmol) was added and the reaction mixture was stirred at 20 °C for 20 h. The solvent was then removed in vacuo and the residue recrystallized from Et₂O to give racemic samples of compounds 8a,b,d and 11a–i. Compound 8c is an oil and was used without purification.

General procedure for the Michael addition of malononitrile to enones 7a–c

Enone 7a–c (0.2 mmol) and quinine (12.9 mg, 0.04 mmol) were dissolved in diethyl carbonate (3 mL). Malononitrile 6 (66.7 mg, 1.0 mmol) was added and the reaction mixture was stirred at between 30 and −40 °C for 20–72 h. Then, 2 M HCl was added, the organic layer separated, washed with deionised water, then dried with magnesium sulphate. The solvent was then removed in vacuo and the residue purified by flash chromatography (CH₂Cl₂) to give compound 8a–c. The enantiomeric excess of compounds 8a–c was determined by chiral HPLC using a Chiralpak AD-H column (hexane–ⁱPrOH 80 : 20, 1 mL min⁻¹, detection at 254 nm).

(S)-2-Cyano-3,5-diphenyl-5-oxo-pentanonitrile 8a^23,27,28. Obtained as a white solid (49.3 mg, 90%) with 64% enantiomeric excess (t_R = 5.9 (minor) and 7.9 (major) minutes). Mp 109–113 °C (lit²⁷ 109–111 °C); [α]²⁰_D −7.8 (c = 0.2, CHCl₃) (lit²⁸ [α]²⁵_D −12.5 (c = 0.2, CHCl₃)); ν_max(ATR) 3048, 2984, 2911, 2400 and 1627 cm⁻¹; δ_H 7.99 (2H, d J 8.6 Hz, ArH), 7.64 (1H, t J 7.4 Hz, ArH), 7.6–7.4 (7H, m, ArH), 4.67 (1H, d J 5.0 Hz, CHCN), 3.97 (1H, dt J 8.4, 5.3 Hz, PhCH), 3.74 (1H, dd J 18.4, 8.3 Hz, CH₂); 3.66 (1H, dd J 18.6, 5.6 Hz, CH₂); δ_C 196.8, 136.6, 135.8, 134.3, 129.4, 129.3, 129.0, 128.2, 128.1, 111.9, 111.8, 41.3, 40.2, 28.9; m/z (ESI) found 297.1004, C₁₈H₁₄N₂ONa (M + Na)⁺ requires 297.0998.

(S)-3-(4-Chlorophenyl)-2-cyano-5-phenyl-5-oxo-pentano-nitrile 8b²³. Obtained as a white solid (56.1 mg, 91%) with 64% enantiomeric excess (t_R = 5.6 (minor) and 8.3 (major) minutes). Mp 124–127 °C (lit²³ 132–134 °C); [α]²⁰_D −8.1 (c = 0.2, CHCl₃) (lit²³ [α]²⁵_D −9.0 (c = 0.3, CHCl₃) for sample with 92% ee); ν_max(ATR) 2884, 1681 and 1597 cm⁻¹; δ_H 7.98 (2H, d J 7.2 Hz, ArH), 7.65 (1H, t J 7.4 Hz, ArH), 7.52 (2H, t J 7.8 Hz, ArH), 7.5–7.4 (4H, m, ArH), 4.64 (1H, d J 5.0 Hz, CHCN), 3.96 (1H, dt J 8.2, 5.4 Hz, PhCH), 3.71 (1H, dd J 18.5, 8.3 Hz, CH₂); 3.62 (1H, dd J 18.4, 5.5 Hz, CH₂); δ_C 193.6, 135.6, 135.3, 134.9, 134.3, 129.6, 129.4, 129.0, 128.1, 111.6, 111.4, 40.7, 40.0, 28.7; m/z (ESI) found 331.0605, C₁₈H₁₃N₂O³⁵ClNa (M + Na)⁺ requires 331.0605.

(S)-3-(4-Methoxyphenyl)-2-cyano-5-phenyl-5-oxo-pentano-nitrile 8c^23,28. Obtained as a colourless oil (43.7 mg, 72%) with 65% enantiomeric excess (t_R = 7.9 (minor) and 12.7 (major) minutes). [α]²⁰_D −7.0 (c = 0.2, CHCl₃) (lit²⁸ [α]²⁵_D −11.0 (c = 0.2, CHCl₃)); ν_max(ATR) 3377, 2224, 1731, 1681 and 1581 cm⁻¹; δ_H 7.98 (2H, dd J 8.5, 1.4 Hz, ArH), 7.64 (1H, tt J 7.4, 1.4 Hz, ArH), 7.51 (2H, t J 7.3 Hz, ArH), 7.38 (2H, d J 8.7 Hz, ArH), 6.96 (2H, d J 8.8 Hz, ArH), 4.63 (1H, d J 5.0 Hz, CHCN), 3.93 (1H, dt J 8.3, 5.3 Hz, ArCH), 3.83 (3H, s, OCH₃), 3.72 (1H, dd J 18.4, 8.4 Hz, CH₂); 3.62 (1H, dd J 18.5, 5.5 Hz, CH₂); δ_C 196.9, 160.2, 135.9, 134.3, 129.3, 129.0, 128.5, 128.2, 114.7, 112.1, 111.8, 55.4, 40.7, 40.3, 29.2; m/z (ESI) found 327.1102, C₁₉H₁₆N₂O₂lNa (M + Na)⁺ requires 327.1104.

General procedure for the Michael addition of α-substituted malononitriles 10a–i to enone 7a

Enone 7a (41.6 mg, 0.2 mmol) and quinine (12.9 mg, 0.04 mmol) were dissolved in diethyl carbonate (3 mL). α-Substituted malononitrile²⁹10a–i (0.24 mmol) was added and the reaction mixture was stirred at 18 or −20 °C for 72 or 168 h. Then, the organic layer was washed with 2 M HCl (2 × 4 mL) and deionised water (1 × 4 mL), and dried (MgSO₄). The solvent was removed in vacuo and the residue purified by automated column chromatography (6 : 1 cyclohexane–EtOAc) to give compounds 11a–i as white solids. The enantiomeric excess of compounds 11a–i was determined by chiral HPLC using a chiralpak AD-H column (hexane–ⁱPrOH 80 : 20, 1 mL min⁻¹, detection at 254 nm).

(S)-4,4-Dicyano-1,3,5-triphenylpentan-1-one 11a²⁶. Obtained as a white solid (8.8 mg, 12%) with 46% enantiomeric excess from a reaction at 18 °C for 72 h (t_R = 10.1 (minor) and 19.5 (major) minutes). Mp 119–124 °C; [α]²³_D −10.2 (c = 1, CHCl₃); ν_max(ATR) 3030, 2981, 2390 and 1690 cm⁻¹; δ_H 7.95 (2H, dd J 8.5, 1.4 Hz, ArH), 7.7–7.3 (13H, m, ArH), 4.2–4.0 (2H, m, CH₂CO + CHPh), 3.8–3.6 (1H, m, CH₂CO), 3.06 (1H, d J 13.7, PhCH₂), 2.85 (1H, d J 13.6, PhCH₂); δ_C 195.1, 136.0, 135.7, 133.8, 132.2, 130.1, 129.2, 129.1, 128.94, 128.87, 128.8, 128.7, 128.1, 115.3, 114.4, 47.3, 45.2, 42.4, 41.4; m/z (ESI) found 387.1469, C₂₅H₂₀N₂ONa (M + Na)⁺ requires 387.1468.

(S)-5-(4-Bromophenyl)-4,4-dicyano-1,3-diphenylpentan-1-one 11b. Obtained as a yellow solid (36.3 mg, 41%) with 94% enantiomeric excess from a reaction at 18 °C for 72 h (t_R = 13.9 (minor) and 29.4 (major) minutes). Mp 172–177 °C; [α]²³_D −2.4 (c = 1, CHCl₃); ν_max(ATR) 3030, 2981, 2400 and 1700 cm⁻¹; δ_H 7.95 (2H, d J 8.5 Hz, ArH), 7.6–7.2 (10H, m, ArH), 7.20 (2H, d J 8.4 Hz, ArH), 4.2–4.0 (2H, m, CH₂CO + CHPh), 3.73 (1H, dd J 23.0, 8.9 Hz, CH₂CO), 3.03 (1H, d J 13.7, ArCH₂), 2.80 (1H, d J 13.7, ArCH₂); δ_C 195.0, 136.5, 135.9, 133.7, 132.2, 131.8, 131.4, 129.3, 129.2, 129.1, 128.8, 128.1, 123.3, 115.2, 114.3, 47.7, 45.1, 42.1, 41.7; m/z (ESI) found 467.0599, C₂₅H₁₉N₂O⁸¹BrNa (M + Na)⁺ requires 467.0553.

(S)-5-(4-Chlorophenyl)-4,4-dicyano-1,3-diphenylpentan-1-one 11c. Obtained as a white solid (31.1 mg, 39%) with 89% enantiomeric excess from a reaction at 18 °C for 72 h (t_R = 12.8 (minor) and 27.7 (major) minutes). Mp 129–132 °C; [α]²³_D −8.8 (c = 1, CHCl₃); ν_max(ATR) 3030, 2981, 2390 and 1688 cm⁻¹; δ_H 7.96 (2H, dd J 8.5, 1.5 Hz, ArH), 7.6–7.3 (12H, m, ArH), 4.2–4.0 (2H, m, CH₂CO + CHPh), 3.77 (1H, dd J 15.7, 1.1 Hz, CH₂CO), 3.36 (1H, d J 14.0, ArCH₂), 3.08 (1H, d J 14.0, ArCH₂); δ_C 195.1, 136.6, 136.0, 135.4, 133.6, 131.6, 130.3, 130.1, 129.2, 129.1, 128.8, 128.1, 127.3, 115.2, 114.4, 48.0, 44.1, 41.6, 38.7; m/z (ESI) found 421.1082, C₂₅H₁₉N₂O³⁵ClNa (M + Na)⁺ requires 421.1078.

(S)-5-(3-Chlorophenyl)-4,4-dicyano-1,3-diphenylpentan-1-one 11d. Obtained as a yellow solid (36.6 mg, 46%) with 50% enantiomeric excess from a reaction at 18 °C for 168 h (t_R = 11.1 (minor) and 18.9 (major) minutes). Mp 130–132 °C; [α]²³_D −8.4 (c = 0.5, CHCl₃); ν_max(ATR) 3030, 2981, 2390 and 1690 cm⁻¹; δ_H 7.95 (2H, d J 7.6 Hz, ArH), 7.7–7.2 (12H, m, ArH), 4.2–4.0 (2H, m, CH₂CO + CHPh), 3.8–3.6 (1H, m, CH₂CO), 3.03 (1H, d J 13.7, ArCH₂), 2.81 (1H, d J 13.8, ArCH₂); δ_C 194.9, 136.0, 135.4, 134.7, 134.1, 133.8, 130.2, 130.1, 129.3, 129.2, 129.1, 128.9, 128.8, 128.3, 128.1, 115.1, 114.1, 47.4, 44.9, 41.9, 41.5; m/z (ESI) found 421.1106, C₂₅H₁₉N₂O³⁵ClNa (M + Na)⁺ requires 421.1078.

(S)-5-(2-Chlorophenyl)-4,4-dicyano-1,3-diphenylpentan-1-one 11e. Obtained as a white solid (9.9 mg, 19%) with 50% enantiomeric excess from a reaction at 18 °C for 72 h (t_R = 9.5 (minor) and 17.1 (major) minutes). Mp 161–165 °C; [α]²³_D +1.6 (c = 1, CHCl₃); ν_max(ATR) 3030, 2981, 2390 and 1665 cm⁻¹; δ_H 7.95 (2H, d J 7.3 Hz, ArH), 7.7–7.2 (12H, m, ArH), 4.2–4.0 (2H, m, CH₂CO + CHPh), 3.73 (1H, dd J 22.5, 8.2 Hz, CH₂CO), 3.03 (1H, d J 13.7, ArCH₂), 2.81 (1H, d J 13.8, ArCH₂); δ_C 194.9, 136.0, 135.5, 135.0, 133.8, 131.5, 130.6, 129.3, 129.2, 129.1, 128.9, 128.8, 128.1, 115.1, 114.2, 47.3, 45.1, 41.7, 41.5; m/z (ESI) found 421.1081, C₂₅H₁₉N₂O³⁵ClNa (M + Na)⁺ requires 421.1078.

(S)-4,4-Dicyano-5-(4-nitrophenyl)-1,3-diphenylpentan-1-one 11f. Obtained as an orange solid (38.4 mg, 47%) with 91% enantiomeric excess from a reaction at 18 °C for 72 h (t_R = 27.5 (minor) and 52.8 (major) minutes). Mp 140–146 °C; [α]²³_D −6.0 (c = 1, CHCl₃); ν_max(ATR) 3030, 2981, 2340 and 1687 cm⁻¹; δ_H 8.26 (2H, d J 8.8 Hz, ArH), 7.96 (2H, d J 8.5 Hz, ArH), 7.7–7.3 (10H, m), 4.2–4.0 (2H, m, CH₂CO + CHPh), 3.75 (1H, dd J 16.3, 1.9 Hz, CH₂CO), 3.17 (1H, d J 13.6, ArCH₂), 2.93 (1H, d J 13.6, ArCH₂); δ_C 194.8, 148.2, 139.3, 135.9, 135.2, 133.9, 131.2, 129.4, 129.3, 128.9, 128.8, 128.1, 124.1, 114.8, 113.8, 47.5, 44.7, 41.9, 41.5; m/z (ESI) found 432.1355, C₂₅H₁₉N₃O₃Na (M + Na)⁺ requires 432.1319.

(S)-4,4-Dicyano-5-(4-methoxyphenyl)-1,3-diphenylpentan-1-one 11g. Obtained as a yellow solid (17.3 mg, 22%) with 77% enantiomeric excess from a reaction at 18 °C for 72 h (t_R = 12.5 (minor) and 28.4 (major) minutes). Mp 167–169 °C; [α]²³_D +2.6 (c = 1, CHCl₃); ν_max(ATR) 3030, 2981, 2350 and 1690 cm⁻¹; δ_H 7.96 (2H, d J 8.5 Hz, ArH), 7.7–7.3 (8H, m, ArH), 7.27 (2H, d J 8.6 Hz, ArCH), 6.92 (2H, d J 8.7 Hz, ArH), 4.2–4.0 (2H, m, CH₂CO + CHPh), 3.82 (3H, s, OCH₃), 3.8–3.7 (1H, m, CH₂CO), 3.06 (1H, d J 13.8, ArCH₂), 2.84 (1H, d J 13.8, ArCH₂); δ_C 195.1, 159.9, 136.0, 135.7, 133.7, 131.3, 129.2, 129.0, 128.9, 128.8, 128.1, 124.1, 115.5, 114.5, 114.2, 55.2, 47.1, 45.6, 41.7, 41.4; m/z (ESI) found 418.1598, C₂₆H₂₂N₂O₂Na (M + Na)⁺ requires 417.1573.

(S)-4,4-Dicyano-1,3-diphenyl-5-(4-trifluoromethylphenyl) pentan-1-one 11h. Obtained as a white solid (45.1 mg, 52%) with 2% enantiomeric excess from a reaction at 18 °C for 72 h (t_R = 14.2 (minor) and 28.6 (major) minutes). Mp 146–148 °C; [α]²³_D −5.2 (c = 1, CHCl₃); ν_max(ATR) 3030, 2981, 2390 and 1690 cm⁻¹; δ_H 7.96 (2H, d J 7.3 Hz, ArH), 7.7–7.3 (12H, m, ArH), 4.2–4.0 (2H, m, CH₂CO + CHPh), 3.73 (1H, dd J 25.0, 10.3 Hz, CH₂CO), 3.12 (1H, d J 13.6, ArCH₂), 2.89 (1H, d J 13.6, ArCH₂); δ_C 195.0, 136.5, 136.3, 135.8, 133.7, 131.4 (q J 33.0 Hz), 130.7, 129.4, 129.3, 129.1, 128.9, 128.1, 125.9 (q J 3.5 Hz), 47.8, 45.0, 42.3, 41.7; δ_F −62.7; m/z (ESI) found 455.1371, C₂₆H₁₉N₂OF₃Na (M + Na)⁺ requires 455.1342.

(S)-4,4-Dicyano-5-(pentafluorophenyl)-1,3-diphenyl-pentan-1-one 11i. Obtained as a white solid (57.2 mg, 63%) with 21% enantiomeric excess from a reaction at −20 °C for 168 h (t_R = 6.7 (minor) and 10.3 (major) minutes). Mp 139–143 °C; [α]²³_D −9.2 (c = 1, CHCl₃); ν_max(ATR) 3030, 2981, 2390 and 1690 cm⁻¹; δ_H 7.96 (2H, d J 7.3 Hz, ArH), 7.7–7.3 (8H, m, ArH), 4.3–4.0 (2H, m, CH₂CO + CHPh), 3.75 (1H, dd J 16.8, 2.0 Hz, CH₂CO), 3.28 (1H, d J 14.4, ArCH₂), 3.03 (1H, d J 14.4, ArCH₂); δ_C 194.7, 144.9, 135.8, 135.0, 133.9, 129.5, 129.0, 128.8, 128.6, 128.5, 128.1, 122.1, 114.4, 113.5, 113.0, 47.7, 43.0, 41.5, 30.1; δ_F −159.7 (2F, tt J 17.8, 12.0 Hz), −150.8 (1F, t J 22.0 Hz), −137.9 (2F, dd J 25.5, 11.6 Hz); m/z (ESI) found 477.0988, C₂₅H₁₅N₂OF₅Na (M + Na)⁺ requires 477.0997.

(S)-4,4-Dicyano-1,3-diphenylpentan-1-one 11j. Obtained as a white solid (35 mg, 61%) with 48% enantiomeric excess from a reaction at 18 °C for 168 h (t_R = 7.4 (minor) and 9.7 (major) minutes). Mp 93–95 °C; [α]²⁰_D −3.2 (c = 0.5, CHCl₃); ν_max(ATR) 2970, 2850, 1690 and 1680 cm⁻¹; δ_H 7.92 (2H, d J 8.6 Hz, ArH), 7.6–7.3 (8H, m, ArH), 4.05–3.85 (2H, m, CH₂CO + CHPh), 3.64 (1H, dd J 16.9, 2.7 Hz, CH₂CO), 1.64 (3H, s, CH₃); δ_C 193.0, 136.0, 135.4, 133.8, 129.1, 129.0, 128.8, 128.1, 123.5, 116.3, 115.3, 47.4, 40.9, 36.8, 23.8; m/z (ESI) found 311.1160, C₁₉H₁₆N₂ONa (M + Na)⁺ requires 311.1155.

(S)-4,4-Dicyano-1,3-diphenylhept-6-en-1-one 11k³⁰. Obtained as a white solid (46 mg, 73%) with 50% enantiomeric excess from a reaction at 18 °C for 168 h (t_R = 7.8 (minor) and 12.1 (major) minutes). Mp 90–93 °C; [α]²⁰_D −2.4 (c = 0.5, CHCl₃); ν_max(ATR) 3090, 2980 and 1688 cm⁻¹; δ_H 7.91 (2H, d J 7.0 Hz, ArH), 7.6–7.3 (8H, m, ArH), 5.90 (1H, ddt J 17.0, 10.1, 7.2 Hz, =CH), 5.41 (1H, dd J 10.0, 0.6 Hz, =CH₂), 5.32 (1H, dd J 16.9, 1.3 Hz, =CH₂), 4.1–3.9 (2H, m, CH₂CO + CHPh), 3.7–3.5 (1H, m, CH₂CO), 2.51 (1H, dd J 14.0, 7.5 Hz, CH₂CH=), 2.40 (1H, dd J 14.0, 7.1 Hz, CH₂CH=); δ_C 193.0, 136.0, 135.5, 133.8, 129.1, 129.0, 128.9, 128.8, 128.6, 128.1, 123.4, 115.2, 114.5, 46.1, 43.1, 41.3, 40.4; m/z (ESI) found 337.1301, C₂₁H₁₈N₂ONa (M + Na)⁺ requires 337.1311.

(S)-4,4-Dicyano-1,3-diphenylhept-6-yn-1-one 11l. Obtained as a white solid (55 mg, 88%) with 38% enantiomeric excess from a reaction at 18 °C for 72 h (t_R = 8.9 (minor) and 12.8 (major) minutes). Mp 104–108 °C; [α]²⁰_D −1.8 (c = 0.5, CHCl₃); ν_max(ATR) 3350, 3050, 3040, 2982 and 1710 cm⁻¹; δ_H 7.92 (2H, d J 7.2 Hz, ArH), 7.6–7.3 (8H, m, ArH), 4.20 (1H, dd J 10.6, 3.0 Hz, CHPh), 4.05 (1H, dd J 17.4, 10.6 Hz, CH₂CO), 3.67 (1H, dd J 17.3, 3.1 Hz, CH₂CO), 2.78 (1H, dd J 16.8, 2.7 Hz, CH₂CC), 2.56 (1H, dd J 16.9, 2.7 Hz, CH₂CC), 2.46 (1H, t J 2.6 Hz, CCH); δ_C 194.8, 136.0, 134.5, 133.8, 129.2, 129.1, 128.8, 128.7, 128.1, 114.6, 113.9, 75.9, 74.6, 45.1, 42.0, 40.9, 27.3; m/z (ESI) found 335.1144, C₂₁H₁₆N₂ONa (M + Na)⁺ requires 335.1155.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of the ¹H, ¹³C and ¹⁹F NMR spectra of all new compounds and chiral HPLC traces for compounds 8a–c and 11a–i. See DOI: 10.1039/c4ra12132e

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