Organocatalytic asymmetric allylic carbon–carbon bond formation

Abstract

Organocatalytic allylic C–C bond-forming addition of activated alkylidenes to alkyl and aryl nitroalkenes has been achieved with high diastereo- and enantioselectivity. Chiral tertiary amine catalysts are used to give allyl intermediates which exhibit γ-selectivity in the C–C bond forming step. The reactions proceed with up to >99 : 1 syn : anti ratio for both the alkyl- and aryl nitroalkenes with up 96% and 98% ee, respectively. The products of this conjugate addition are transformed into a range of intermediates, such as optically active conjugated dienes and 1-substituted tetralones, which are difficult to access via alternative methods.

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Introduction

One of the fundamental reactions in organic chemistry is that between active methylene compounds and carbonyl compounds to give unsaturated (Knoevenagel) condensation products.¹ Since the first reports by Knoevenagel² and the classic papers on the efficient synthesis and reactivity of such systems³ (e.g. alkylidene malonates, cyanoacetates, and malononitriles), attention from the synthetic community has been continuous.⁴ Activated alkylidene structures are common intermediates in complex molecule synthesis, where their electrophilic character has been especially exploited.⁵

As part of our recent research on organocatalyzed asymmetric reactions,⁶ we have introduced a new concept exploiting the latent nucleophilic reactivity of activated alkylidenes for performing allylic aminations with excellent regio- and stereocontrol.⁷ This concept relies on the deprotonation of an allylic hydrogen by a chiral base.

Scheme 1 shows the activated alkylidene systems (1), which undergo a stereoselective electrophilic addition leading to a substitution of the allylic C–H bond with the electrophile (E) via a chiral ion-pair intermediate.

Scheme 1 Organocatalytic asymmetric electrophilic addition to allylic C–H bonds.

Asymmetric functionalization of the allylic position plays an important role in organic chemistry due to the great utility of the optically active allylic compounds formed e.g. as intermediates in total synthesis.⁸ Catalysis using chiral metal complexes, to give π-allyl-metal intermediates, which undergo nucleophilic addition, is a well developed method for asymmetric allylic functionalization.⁹

The organocatalyzed asymmetric C–C bond formation by addition of carbon-electrophiles to the allylic position of activated alkylidenes has not yet been investigated in great detail. A recent letter¹⁰ presenting the asymmetric direct vinylogues Michael reaction of activated alkenes with aromatic nitroalkenes prompted us to present a full account of our contribution towards organocatalyzed asymmetric C–C bond formation by addition of carbon-electrophiles to the allylic position of activated alkylidenes.

Results and discussion

Our studies commenced by examining the feasibility of the reaction between the alkylidene malononitrile 3a derived from 1-tetralone and Michael-acceptor trans-β-nitrostyrene 4a in the presence of different cinchona alkaloid derivatives under various reaction conditions [eqn (1), Table 1].¹¹ The reaction was found to take place smoothly, with near quantitative conversion to the γ−substituted product as well as traces of side products. To our surprise, the ¹H NMR spectrum of the reaction mixture showed only one diastereoisomer. This turned out to be the case for all screening experiments.

Table 1 Initial Screening^a

Entry	Cat./mol%	Temp./°C	Solvent (0.25 M)	Time/h	Conv. (%)^b	dr (syn/anti)^b	ee (%)^c
a Reaction performed at a 0.15 mmol scale (3a) with 1.5 eq. of 4a. b Determined by ^1H NMR analysis of the crude mixture. c Of the syn-isomer, determined by CSP-HPLC analysis (see Experimental section for details). d Reaction mixture is heterogenous. TBME = tert-butyl methyl ether. 1,2-DCE = 1,2-dichloroethane.
1	(DHQ)2AQN (10)	−15	CH2Cl2	16	>95	>99:1	+50
2	(DHQ)2PHAL (10)	−15	CH2Cl2	24	95	>99:1	+61
3	(DHQ)2PYR (10)	−15	CH2Cl2	16	>95	>99:1	+76
4	(DHQD)2PYR (10)	−15	CH2Cl2	14	>95	>99:1	−86
5	(DHQD)2PYR (10)	−15	Toluene	14	95	>99:1	−88
6	(DHQD)2PYR (10)	−15	1,2-DCE	20	>95	>99:1	−88
7	(DHQD)2PYR (10)	−40	CH2Cl2	40	>95	>99:1	−92
8	(DHQD)2PYR (10)	−40	THF	20	95	>99:1	−86
9	(DHQD)2PYR (10)	−40	THF/Tol 1:4	20	68	>99:1	−90
10	(DHQD)2PYR (10)	−40	TBME	20	11^d	>99:1	−90
11	(DHQD)2PYR (10)	−40	EtOAc	20	70	>99:1	−95
12	(DHQD)2PYR (10)	−40	acetone	25	>95	>99:1	−95

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A screening of reaction conditions in CH₂Cl₂ showed that (DHQD)₂PYR was the most effective catalyst at −15 °C giving 95% conversion with 86% ee (entry 4). The quasienantiomer (DHQ)₂PYR gave the opposite configuration as expected with 76% ee (compare entries 3 and 4). Lower temperatures slightly improved the enantiocontrol (86% ee at −15 °C and 92% ee at −40 °C, entries 4 and 7). Poor conversion in the case of TBME as the solvent is attributed to low solubility of the starting materials. Surprisingly, acetone was identified as the best solvent for this reaction (95% conversion, >99:1 dr and 95% ee, entry 12), which is unusual for chiral ion-pair based reactions, and improves the enantioselectivity of the reaction compared to CH₂Cl₂. It should be noted that the reaction also proceeds in EtOAc with excellent enantioselectivity (entry 11). The use of 1.5 equiv. of the nitroalkene was found to be beneficial to the reaction rate.

The scope of the asymmetric allylic C–C bond-forming reaction was probed using a range of nitroalkenes 4 reacting with alkylidene malononitriles 3a [eqn (2), Table 2].

Table 2 Reaction scope with respect to the electrophile (4)^a

Entry	R^3	Yield^b(%)	dr^c (syn/anti)	ee^d(%)
a Reaction carried out with 0.25 mmol of 3a and 1.5 eq. of 4, values in parenthesis obtained with the quasienantiomer (DHQ)2PYR in acetone/THF (3:1). b Isolated yield. c Determined by ^1H NMR. d Of the syn-isomer determined by CSP-HPLC (see Experimental section). e Reaction carried out in acetone/EtOAc (1:1, 0.25 M).
1	C6H5	5a-98(95)	>99:1( >99:1)	95(89)
2^e	2-naphthyl	5b-98	>99:1	92
3	2-thienyl	5c-93	>99:1	97
4	2-furyl	5d-99	13:1	94
5	4-MeO–C6H4	5e-97	>99:1	98
6	4-NO2–C6H4	5f-99(92)	>99:1( >99:1)	95(90)
7	4-Br–C6H4	5g-96	>99:1	96
8	2-Cl–C6H4	5h-97	>99:1	53
9	3-NO2–C6H4	5i-92	>99:1	91
10	c-hexyl	5j-82	>99:1	96
11	n-pentyl	5k-99	19:1	94

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Aryl and heteroaryl nitroalkenes reacted cleanly to give the desired products in 92–99% yield with 92–98% ee (Table 2, entries 1–7, 9) with the exception of 2-Cl-trans-β-nitrostyrene (97% yield and 53% ee, entry 8). This lower selectivity is possibly due to the closeness of the ortho-substituent to the new C–C bond. Aromatic substrates with a para- or meta-substituent reacted in a comparable way to the benchmark reaction regardless of the electron density of the aryl ring. The alkyl substituted nitroalkenes also reacted smoothly to give high yields and enantioselectivities (82 and 99% yield, 96 and 94% ee, entries 10 and 11). Only in two cases did we observe the formation of the anti-diastereomer, although in very small amounts (entry 4, 13:1 and entry 11, 19:1). Our experiments so far indicate, that the excellent diastereomeric ratios observed are due to kinetic control and, therefore, not due to base-mediated equilibration of the γ-stereocenter.

The generality of the allylic functionalization as demonstrated in Table 2 prompted us to investigate the reaction for a series of alkylidene malononitriles 3b–i with trans-β-nitrostyrene 4a. The results are presented in Table 3.

Table 3 Reaction scope with different activated alkylidenes 3b–i^a

Entry	Substrate		Product	Yield (%)^b	dr (syn/anti)^c	ee (%)^d
a Reaction carried out with 0.25 mmol of 3 and 1.5 eq. of 4a at −40 °C in acetone (0.25 M) in the presence of 10 mol% (DHQD)2PYR, value in parenthesis obtained with the quasienantiomer (DHQ)2PYR in acetone/THF (3:1). b Isolated yield. c Determined by ^1H NMR. d Of the syn-isomer determined by CSP-HPLC (see Experimental section). e Reaction carried out in EtOAc (0.25 M). f No conversion observed, even at higher temperatures.
1^e		3b		5l-96	15:1	92
2		7-MeO-3c		5m-96(94)	>99:1( >99:1)	96(86)
3		6-MeO-3d		5n-99	>99:1	94
4		5-MeO-3e		5o-90	>99:1	93
5		6,7-MeO-3f		5p-99	>99:1	80
6		5,7-Me-3g		5q-95	>99:1	91
7		7-NO2-3h		—^f	—	—
8		3i		5r-95	>99:1	74

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Increasing the ring-size to seven carbon atoms (3b) afforded similar results to the six-membered system with the enantioselectivity remaining high at 92% ee and a small decrease in diastereoselectivity (15:1, Table 3, entry 1). Many important bioactive compounds contain a methoxy-substituted aromatic ring fused with a cyclohexane ring. We were therefore pleased that placing a methoxy group in the 5, 6, or 7 position gave high enantioselectivity (93, 96 and 94% ee), yield (90, 96 and 99%) and diastereocontrol (>99:1 in all cases) (Table 3, entries 2–4). An alkylidene possessing the ubiquitous 6,7-dimethoxy motif (3f) reacted cleanly to give good, if slightly lower enantiocontrol (99% yield and 80% ee, entry 5). The 5,7-dimethyl substituted compound (3g) reacted with high yield and stereocontrol (95%, 91% ee, entry 6). Surprisingly the introduction of a nitro-group in the 7-position of the alkylidene (3h) completely retarded the reaction even at higher temperatures. Finally the 4-chromanone derived alkylidene (3i) gave 95% yield and 75% ee (entry 8).

The absolute configuration of the products was established to be (2S,3R) by examination of an X-ray crystal structure obtained from the 4-Br substituted nitrostyrene (5g) (Table 4, Fig. 1).^12,13

Table 4 Crystallographic data for 5g and 6

	5g	6
Formula, weight	C21H16BrN3O2	C21H17N3O2
Crystal system	orthorhombic	monoclinic
a, Å	6.7062 (5)	8.990 (1)
b, Å	12.4969 (10)	23.048 (2)
c, Å	22.780 (2)	15.980 (1)
α, deg	90	90
β, deg	90	96.130 (3)
γ, deg	90	90
Volume, Å^3	1909.1 (3)	3292.1 (4)
Temperature	150 (1)	100 (1)
Space group	P2(1)2(1)2(1)	P2(1)/c
Z, Z′	4, 4	8, 2
µ	2.174	0.091
N meas	38312	65363
N unique	5814	4696
R int	0.043	0.081
R(F), all	0.061	0.107
R w(F2), all	0.064	0.148
Flack	−0.01 (1)	N/A

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Fig. 1 X-ray crystal structure of (2S,3R)-5g (most hydrogen atoms have been omitted for clarity).

To show the ease with which the present reaction allows access to larger quantities of enantiopure material, we subjected 10 mmol of alkylidene 3a and 1.1 eq. nitroalkene 4a to the standard reaction conditions in the presence of 3 mol% of (DHQD)₂PYR [eqn (3)]. After the nucleophile had been consumed as judged by TLC-analysis the product was filtered through a short pad of silica to remove the catalyst. Recrystalization from EtOH afforded the Michael adduct as a single stereoisomer in 84% yield.

During the course of our initial studies we sometimes noted the formation of intensely coloured orange/red reaction mixtures, especially when the catalytic reactions were carried out at higher temperatures. The origin of this phenomenon was identified to be the formation of an interesting, highly conjugated three ring system. Optically active diene 6 (structure confirmed by X-ray analysis,¹²Scheme 2) arises from an intramolecular cyclisation between the nitroalkane and one of the cyano groups followed by tautomerization. Previous reports on similar ring-closures performed under harsher conditions¹⁴ yielded the fully aromatized compounds. Different bases were evaluated for this transformation (Scheme 2) and quinidine was found to give the highest isolated yield.¹⁵ A chiral base is obviously not necessary to effect this transformation, however, the efficiency of quinidine compared to achiral bases tested combined with its low cost renders this the best alternative. In fact, the high loadings necessary of e.g. Et₃N to afford even low isolated yields of diene 6 leads to an erosion of the optical purity (>99.9% ee to 93% ee). This observation might be ascribed to racemization through a retro-Michael mechanism, being increasingly favored under high base concentrations.

Scheme 2 Ring-closing reaction of 5a to afford optically active diene 6 under different conditions. To the right, X-ray crystal structure of 6 (most hydrogen atoms have been omitted for clarity).

As mentioned in the introduction, activated alkylidene systems are related to their parent carbonyl compounds through Knoevenagel condensation with malononitrile. Obviously, the reverse transformation—i.e. the formation of the carbonyl compound from the Knoevenagel condensation product—does not have much synthetic relevance, unless the formation of the activated alkylidene system allows for chemical transformations not possible with the parent carbonyl compound. The similarity between the CO and the C=C(CN)₂ functionality has been noted by several groups.¹⁶ The similarity, however, is of course only qualitative, and in fact very fundamental differences in reactivity do exist. As we have demonstrated here and previously,⁷ the formation of an activated alkylidene system permits deprotonation in the α-position of the group (the γ-position of the alkylidene system), thereby enabling chiral base-catalyzed asymmetric reactions to be performed. To the best of our knowledge, similar transformations cannot be carried out on the parent carbonyl compound. Thus, the C(CN)₂ group can be regarded as a transient activating group in a synthetic sequence towards the catalytic asymmetric functionalization of the carbonyl compound. In fact, the justification of this indirect α-functionalization of carbonyl compounds is increased, when efficient direct approaches to the same transformation are not available—as is indeed currently the case for substituted 1-tetralones (Scheme 3).¹⁷

Scheme 3 Indirect catalytic asymmetric functionalization of 1-tetralone, via carbonyl activation, chiral base chemistry, and oxidative cleavage.

The desired oxidative cleavage could be carried out using potassium permanganate in a mixture of acetone and water at ambient temperature [eqn (4)]. After column chromatography, optically active substituted 1-tetralone 7 was obtained as a single stereoisomer in 77% yield.

Conclusions

In conclusion, we have presented a direct organocatalytic enantioselective C–C bond forming reaction in the allylic position of activated alkylidene systems. The reaction is broad in scope and takes place with excellent regio- and diastereoselectivity, and with good to excellent enantioselectivity for both aryl and alkyl nitroalkenes. Furthermore, we have demonstrated the synthetic utility of the optically active products by performing reactions exploiting the electron-deficient alkylidene double bond. Thus, oxidative cleavage of the alkylidene moiety allows for the preparation of optically active substituted 1-tetralones.

Experimental

General Methods

NMR spectra were acquired on a Varian AS 400 spectrometer, running at 400 and 100 MHz for ¹H and ¹³C, respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent signals. ¹³C NMR spectra were acquired on a broad band decoupled mode. Mass spectra were recorded on a micromass LCT spectrometer using electrospray (ES⁺) ionization techniques. Flash column chromatography (FC) was carried out using the FlashMaster II from Jones Chromatography with columns containing silica gel. Analytical thin layer chromatography (TLC) was performed using pre-coated aluminium-backed plates (Merck Kieselgel 60 F254) and visualized by ultraviolet irradiation or KMnO₄ dip. Optical rotations were measured on a Perkin-Elmer 241 polarimeter. The enantiomeric excess (ee) of the products was determined by chiral stationary phase HPLC (Daicel Chiralpak AS/AD or Daicel Chiralcel OD columns).

Materials

Analytical grade solvents were used as received. For flash chromatography (FC) silica gel was purchased from Iatron Laboratories Inc. (Iatrobeads 6RS-8060) or from Fluka (Silica gel 60, 230–400 mesh). All catalysts are commercially available and were used as received. Alkylidene malononitriles 3a and 3c-j were prepared from the corresponding commercially available ketone and malononitrile by Al₂O₃-mediated Knoevenagel condensation.¹⁸3b was prepared by condensing commercially available 1-benzosuberone with malononitrile in the presence of catalytic amounts of triethylamine.¹⁹ Nitroalkenes 4a,c-i were obtained from commercial suppliers and used as received. Naphthyl-substituted nitroalkene 4b was prepared by Henry-reaction,²⁰ followed by elimination.²¹ Alkyl-substituted nitroalkenes 4j-k were prepared according to a literature procedure.²¹

Representive procedure for the enantioselective addition of alkylidene malononitriles to conjugated nitroalkenes. Alkylidene malononitrile 3a (0.25 mmol, 48.5 mg) and trans-β-nitrostyrene (0.375 mmol, 56.1 mg) were mixed in a glass flask equipped with a magnetic stirring bar. Solvent (1.0 mL) was added, and the mixture was cooled to −78 °C. At this temperature (DHQD)₂PYR (10 mol%, 0.025 mmol, 22 mg) was added, and the resulting mixture was placed at −40 °C for the time specified below. The mixture was then cooled to −78 °C and passed quickly through a short pad of iatrobeads (elute Et₂O) to remove the catalyst. The pure product was obtained by FC on iatrobeads eluting with CH₂Cl₂/n-hexane (50 : 50 to 100 : 0).

(S,R)-2-[2-(2-Nitro-1-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5a). The title compound was obtained according to the general procedure (reaction time 29 h, reaction with (DHQ)₂PYR 80 h) as a white crystalline solid (mp = 157–160 °C), yield 98%. ¹H NMR (CDCl₃) δ 8.08 (d, J 7.9 Hz, 1H), 7.60 (dt, J 7.6, 1.1 Hz, 1H), 7.26–7.44 (m, 7H), 4.70 (dd, J 12.6, 10.2 Hz, 1H), 4.42 (dd, J 12.6, 5.1 Hz, 1H), 3.64 (dt, J 11.4, 3.4 Hz, 1H), 3.46 (td, J 11.0, 4.9 Hz, 1H), 3.02 (ddd, J 18.5, 11.9, 6.3 Hz, 1H), 2.88 (dd, J 18.6, 7.3 Hz, 1H), 1.94–2.03 (m, 1H), 1.77–1.85 (m, 1H). ¹³C NMR (CDCl₃) δ 174.5, 139.5, 136.0, 134.5, 130.0, 129.4 (2C), 128.7, 128.6, 127.8, 127.7 (2C), 127.3, 113.1 (2C), 81.0, 78.6, 44.7, 44.5, 25.4, 24.0. HRMS calc.: C₂₁H₁₇N₃NaO₂ 366.1218; found: 366.1224. [α]_D²⁰ − 214 (c = 1.0, CH₂Cl₂, 91% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (90:10)]; flow rate 1.0 mL min⁻¹; τ_major = 13.5 min, τ_minor = 11.8 min (95% ee).

(S,R)-2-[2-(1-Naphthalen-2-yl-2-nitro-ethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5b). The title compound was obtained according to the general procedure (reaction time 29 h) as a pale yellow crystalline solid (mp = 184–186 °C), yield 98%. ¹H NMR (CDCl₃) δ 8.11 (d, J 8.0 Hz, 1H), 7.91 (d, J 8.4 Hz, 1H), 7.84 (m, 2H), 7.70 (s, 1H), 7.62 (t, J 7.6 Hz, 1H), 7.53 (m, 2H), 7.36–7.46 (m, 3H), 4.81 (dd, J 12.5, 10.0 Hz, 1H), 4.50 (dd, J 12.5, 5.0 Hz, 1H), 3.76 (dt, J 11.8, 3.5 Hz, 1H), 3.64 (td, J 11.7, 4.9 Hz, 1H), 3.08 (ddd, J 18.0, 11.8, 6.0 Hz, 1H), 2.88 (dd, J 18.8, 7.7 Hz, 1H), 1.95–2.05 (m, 1H), 1.77–1.86 (m, 1H). ¹³C NMR (CDCl₃) δ 174.5, 139.4, 134.4, 133.2 (2C), 133.0, 130.0, 129.5, 128.6, 127.7 (4C), 127.2, 126.7, 126.6, 124.0, 113.1 (2C), 80.9, 78.5, 44.6, 44.5, 25.5, 23.9. [α]_D²⁰ − 190 (c = 0.5, CH₂Cl₂, 92% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (80 : 20)]; flow rate 1.0 mL min⁻¹; τ_major = 11.2 min, τ_minor = 12.4 min (92% ee).

(S,R)-2-[2-(2-Nitro-1-thiophen-2-yl-ethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5c). The title compound was obtained according to the general procedure (reaction time 30 h) as a pale yellow crystalline solid (mp = 150–152 °C), yield 93%. ¹H NMR (CDCl₃) δ 8.01 (d, J 8.0 Hz, 1H), 7.58 (t, J 7.5 Hz, 1H), 7.39 (t, J 7.7 Hz, 1H), 7.33 (d, J 7.7 Hz, 1H), 7.29–7.30 (m, 1H), 6.98–6.99 (m, 2H), 4.66 (d, J 12.7, 9.9 Hz, 1H), 4.45 (dd, J 12.6, 5.2 Hz, 1H), 3.85 (dt, J 10.4, 5.2 Hz, 1H), 3.58 (td, J 11.0, 3.7 Hz, 1H), 3.04–3.07 (m, 1H), 2.91–2.94 (m, 1H), 1.99–2.08 (m, 2H). ¹³C NMR (CDCl₃) δ 174.0, 139.4, 138.1, 134.5, 129.9, 128.6, 127.8, 127.3, 127.0, 125.8, 113.0, 112.9, 81.3, 79.0, 45.8, 40.0, 25.5, 24.2. HRMS calc.: C₁₉H₁₅N₃NaO₂S 372.0783; found: 372.0791. [α]_D²⁰ − 260 (c = 1.0, CH₂Cl₂, 93% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min⁻¹; τ_major = 15.4 min, τ_minor = 13.9 min (97% ee).

(S,R)-2-[2-(1-Furan-2-yl-2-nitro-ethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5d). The title compound was obtained according to the general procedure (reaction time 30 h) as a pale yellow crystalline solid (mp = 165–167 °C), yield 93%. ¹H NMR (CDCl₃) δ 7.99 (d, J 8.0 Hz, 1H), 7.56 (t, J 7.6 Hz, 1H), 7.36–7.40 (m, 2H), 7.31 (d, J 7.7 Hz, 1H), 6.32 (m, 1H), 6.26 (d, J 3.3 Hz, 1H), 4.73–4.78 (m, 1H), 4.39 (dd, J 12.7, 4.1 Hz, 1H), 3.68–3.70 (m, 2H), 3.00–3.04 (m, 1H), 2.90–2.92 (m, 2H), 2.06–2.08 (m, 1H), 1.80–1.85 (m, 1H). ¹³C NMR (CDCl₃) δ 174.1, 148.9, 143.5, 139.8, 134.6, 130.1, 128.8, 128.2, 127.5, 113.3, 113.1, 110.8, 110.0, 81.8, 76.5, 43.5, 39.0, 25.8, 24.7. HRMS calc.: C₁₉H₁₅N₃NaO₃ 365.1011; found: 365.1006. [α]_D²⁰ − 321 (c = 1.0, CH₂Cl₂, 99% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min⁻¹; τ_major = 15.2 min, τ_minor = 13.7 min (95% ee).

(S,R)-2-{2-[1-(4-Methoxy-phenyl)-2-nitro-ethyl]-3,4-dihydro-2H-naphthalen-1-ylidene}-malononitrile (5e). The title compound was obtained according to the general procedure (reaction time 30 h) as a pale yellow crystalline solid (mp = 163–166 °C), yield 97%. ¹H NMR (CDCl₃) δ 8.07 (d, J 8.0 Hz, 1H), 7.59 (t, J 7.6 Hz, 1H), 7.40 (t, J 7.7 Hz, 2H), 7.33 (d, J 7.7 Hz, 1H), 7.18 (d, J 8.5 Hz, 1H), 6.90 (d, J 8.5 Hz, 1H) 4.65 (dd, J 12.4, 10.6 Hz, 1H), 4.39 (dd, J 12.5, 5.1 Hz, 1H), 3.79 (s, 3H), 3.58 (td, J 11.3, 3.4 Hz, 1H), 3.41 (dt, J 10.9, 5.0 Hz, 1H), 3.01 (m, 1H), 2.87 (dd, J 18.5, 6.4 Hz, 1H), 1.95–1.99 (m, 1H) 1.80–1.85 (m, 1H). ¹³C NMR (CDCl₃) δ 174.8, 159.6, 139.5, 134.5, 130.0, 128.8 (2C), 128.6, 127.8, 127.6, 127.3, 114.7, 113.1 (2C), 78.8, 78.7, 55.2, 44.9, 43.8, 25.5, 24.0. HRMS calc.: C₂₂H₁₉N₃NaO₃ 396.1324; found: 396.1315 [α]_D²⁰ − 204 (c = 1.0, CH₂Cl₂, 81% ee). The ee was determined by HPLC using a Chiralcel OD column [hexane/i-PrOH (80 : 20)]; flow rate 1.0 mL min⁻¹; τ_major = 28.2 min, τ_minor = 23.4 min (98% ee).

(S,R)-2-{2-[2-Nitro-1-(4-nitro-phenyl)-ethyl]-3,4-dihydro-2H-naphthalen-1-ylidene}-malononitrile (5f). The title compound was obtained according to the general procedure (reaction time 30 h, reaction with (DHQ)₂PYR 80 h) as a pale yellow crystalline solid (mp = 196–199 °C), yield 99%. ¹H NMR (CDCl₃) δ 8.27 (d, J 8.6 Hz, 2H), 8.10 (d, J 8.0 Hz, 1H), 7.63 (t, J 7.6 Hz, 1H), 7.49 (d, J 8.6 Hz, 2H), 7.44 (t, J 7.7 Hz, 1H), 7.37 (d, J 7.8 Hz, 1H) 4.73 (dd, J 12.8, 10.1 Hz, 1H), 4.46 (dd, J 13.0, 4.5 Hz, 1H), 3.59–3.67 (m, 2H), 2.95–2.99 (m, 2H), 2.07–2.03 (m, 1H) 1.70–1.75 (m, 1H). ¹³C NMR (CDCl₃) δ 173.1, 148.1, 143.4, 139.0, 134.8, 130.2, 128.9, 128.7 (2C), 127.6, 127.5, 124.6 (2C), 113.0, 112.8, 81.5, 77.9, 44.2, 44.1, 25.3, 24.0. [α]_D²⁰ − 223 (c = 1.0, CH₂Cl₂, 85% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min⁻¹; τ_major = 40.2 min, τ_minor = 35.1 min (95% ee).

(S,R)-2-{2-[1-(4-Bromo-phenyl)-2-nitro-ethyl]-3,4-dihydro-2H-naphthalen-1-ylidene}-malononitrile (5g). The title compound was obtained according to the general procedure (reaction time 30 h) as a pale yellow crystalline solid (mp = 195–197 °C), yield 96%. ¹H NMR (CDCl₃) δ 8.07 (d, J 8.0 Hz, 1H), 7.60 (t, J 7.0 Hz, 1H), 7.53 (d, J 8.5 Hz, 1H), 7.42 (t, J 7.4 Hz, 1H), 7.34 (d, J 7.6 Hz, 1H), 7.15 (d, J 8.4 Hz, 2H) 4.66 (dd, J 12.8, 10.5 Hz, 1H), 4.40 (dd, J 12.8, 5.0 Hz, 1H), 3.58 (td, J 11.5, 3.5 Hz, 1H), 3.40–3.46 (m, 1H), 2.91–2.98 (m, 2H), 1.97–2.02 (m, 1H) 1.76–1.81 (m, 1H). ¹³C NMR (CDCl₃) δ 174.3, 139.6, 135.3, 134.9 (2C), 130.4, 129.7 (2C), 128.9, 127.9, 127.7, 123.1, 113.3, 113.2, 81.4, 78.6, 44.7, 44.3, 25.7, 24.2. [α]_D²⁰ − 185 (c = 1.0, CH₂Cl₂, 91% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min⁻¹; τ_major = 10.1 min, τ_minor = 9.4 min (96% ee).

(S,R)-2-{2-[1-(2-Chloro-phenyl)-2-nitro-ethyl]-3,4-dihydro-2H-naphthalen-1-ylidene}-malononitrile (5h). The title compound was obtained according to the general procedure (reaction time 29 h) as a pale yellow crystalline solid (mp = 164–166 °C), Yield 97%. The compound was found to exist as a 1 : 4 mixture of rotameric isomers at room temperature (at 60 °C in CDCl₃ the signals in the ¹H NMR spectrum merge into one set of broadened signals). ¹H NMR (CD₂Cl₂, 0 °C) δ 8.04 (d, J 7.8 Hz, 1H), 7.61 (t, J 7.6 Hz, 1H), 7.14–7.46 (m, 6H), 4.65 (dd, J 12.7, 10.1 Hz, 0.8H), 4.44 (dd, J 12.7, 5.1 Hz, 1.2 H), 4.16 (td, J 10.9, 5.1 Hz, 1.0H), 3.66 (dt, J 11.2, 3.5 Hz, 0.8H), 3.52 (td, J 11.5, 5.3 Hz, 0.2H), 3.21 (ddd, J 18.4, 11.3, 6.2 Hz, 0.8H), 2.91 (dd, J 18.8, 7.0 Hz, 1.2 H), 1.94–2.11 (m, 1.0H), 1.70–1.82 (m, 1.0H). ¹³C NMR (CD₂Cl₂, 0 °C)* δ 174.5, 140.3, 135.2, 134.7, 134.8, 134.3, 134.2, 131.8, 130.6, 130.5, 130.3, 129.9, 129.0, 128.7, 128.4, 128.0, 127.8, 127.7, 127.2, 113.5, 113.4, 81.5, 78.4, 76.0, 46.8, 45.2, 40.8, 39.7, 26.0, 25.5, 24.6, 24.0. HRMS calc.: C₂₁H₁₆ClN₃NaO₂ 400.0829; found: 400.0764. [α]_D²⁰ − 108 (c = 0.5, CH₂Cl₂, 53% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (80 : 20)]; flow rate 1.0 mL min⁻¹; τ_major = 9.0 min, τ_minor = 8.1 min (53% ee). *The ¹³C NMR spectrum contains extra signals due to the presence of distinct rotameric isomers.

(S,R)-2-{2-[2-Nitro-1-(3-nitro-phenyl)-ethyl]-3,4-dihydro-2H-naphthalen-1-ylidene}-malononitrile (5i). The title compound was obtained according to the general procedure (reaction time 29 h) as a pale yellow crystalline solid (mp = 214–216 °C²²), yield 92%. ¹H NMR (CDCl₃) δ 8.25 (dt, J 7.3, 2.1 Hz, 1H), 8.14 (t, J 2.0 Hz, 1H), 8.10 (d, J 7.7 Hz, 1H), 7.62–7.70 (m, 3H), 7.45 (t, J 7.9 Hz, 1H), 7.39 (d, J 8.0 Hz, 1H), 4.75 (dd, J 13.3, 10.4 Hz, 1H), 4.46 (dd, J 13.0, 4.5 Hz, 1H), 3.58–3.76 (m, 2H), 2.96–3.08 (m, 2H), 2.07 (m, 1H), 1.75 (m, 1H). ¹³C NMR (CD₂Cl₂) δ 173.7, 148.9, 139.9, 138.7, 134.9, 134.1, 130.9, 130.6, 128.9, 128.0, 127.5, 124.0, 123.5, 113.4 (2C), 82.0, 78.3, 44.5, 44.4, 25.5, 24.3. HRMS calc.: C₂₁H₁₆N₄NaO₄ 411.1069; found: 411.1015 [α]_D²⁰ − 209 (c = 0.5, CH₂Cl₂, 91% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (75 : 25)]; flow rate 1.0 mL min⁻¹; τ_major = 11.8 min, τ_minor = 9.6 min (91% ee).

(S,R)-2-[2-(1-Cyclohexyl-2-nitro-ethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5j). The title compound was obtained according to the general procedure (reaction time 30 h) as a yellow oil, yield 82%. ¹H NMR (CDCl₃) δ7.91 (d, J 8.0 Hz, 1H), 7.50 (t, J 7.5 Hz, 1H), 7.32 (t, J 7.7 Hz, 1H), 7.26 (d, J 7.7 Hz, 1H), 4.40 (dd, J 13.6, 4.4 Hz, 1H), 4.18 (dd, J 13.6, 7.0 Hz, 1H), 3.43 (dt, J 11.0, 3.6 Hz, 1H), 2.96–3.00 (m, 2H), 2.31–2.36 (m, 2H), 2.06–2.14 (m, 1H) 1.70–1.84 (m, 5H) 1.54 (d, J 12.3 Hz, 1H) 1.10–1.31 (m, 5H), 0.92(dd, J 12.5, 3.3 Hz, 1H). ¹³C NMR (CDCl₃) δ 175.0, 138.6, 133.5, 129.0, 128.3, 128.1, 126.6, 112.7 (2C), 80.7, 77.1, 43.2, 38.0, 32.1, 28.6, 25.3, 24.9, 22.6, 14.2. HRMS calc.: C₂₁H₂₃N₃NaO₂ 372.1688; found: 372.1695. [α]_D²⁰ − 353 (c = 1.0, CHCl₃, 96% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min⁻¹; τ_major = 12.2 min, τ_minor = 9.2 min (96% ee).

(S,R)-2-[2-(1-Nitromethyl-hexyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5k). The title compound was obtained according to the general procedure (reaction time 30 h) as a yellow oil, yield 99%. ¹H NMR (CDCl₃) δ 7.93 (d, J 8.0 Hz, 1H), 7.53 (t, J 7.6 Hz, 1H), 7.36 (t, J 7.7 Hz, 1H), 7.29 (d, J 7.7 Hz, 1H), 4.38 (dd, J 12.6, 7.3 Hz, 1H), 4.20 (dd, J 12.7, 6.1 Hz, 1H), 3.34 (dt, J 8.6, 4.3 Hz, 1H), 2.43–2.48 (m, 1H), 2.15–2.18 (m, 2H), 1.44–1.46 (m, 2H) 1.25–1.32 (m, 6H) 0.86–0.89 (m, 3H). ¹³C NMR (CDCl₃) δ 175.6, 139.9, 134.2, 129.7, 129.2, 128.5, 127.5, 113.4, 113.1, 81.8, 77.1, 43.2, 38.0, 32.1, 28.6, 25.3, 24.9, 22.6, 14.2. HRMS calc.: C₂₀H₂₃N₃NaO₂ 360.1688; found: 360.1700. [α]_D²⁰ − 391 (c = 1.0, CHCl₃, 94% ee). The ee was determined by HPLC using a Chiralcel OD column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min⁻¹; τ_major = 22.2 min, τ_minor = 13.8 min (94% ee).

(S,R)-2-[6-(2-Nitro-1-phenyl-ethyl)-6,7,8,9-tetrahydro-benzocyclohepten-5-ylidene]-malononitrile (5l). The title compound was obtained according to the general procedure (reaction time 24 h) as a white solid. The compound was obtained as a 1 : 15 mixture of diastereomers (anti : syn), yield 96% (of both diastereomers).
syn-diastereomer. ¹H NMR (CDCl₃) δ 7.49 (t, J 6.5 Hz, 1H), 7.40 (t, J 7.6 Hz, 1H), 7.23–7.36 (m, 5H), 7.14 (d, J 6.3 Hz, 2H), 4.56 (dd, J 12.4, 10.8 Hz, 1H), 4.39 (dd, J 12.4, 8.6 Hz, 1H), 3.60 (dt, J 11.6, 4.1 Hz, 1H), 3.30 (td, J 10.8, 3.7 Hz, 1H), 2.71–2.87 (m, 2H), 1.61–1.83 (m, 4H). ¹³C NMR (CDCl₃) δ 183.6, 138.8, 135.5, 133.2, 132.0, 130.8, 129.4 (2C), 128.6, 128.4, 128.0 (2C), 127.4, 111.5 (2C), 88.2, 78.7, 46.5, 44.8, 35.8, 33.2, 21,7. HRMS calc.: C₂₂H₁₉N₃NaO₂ 380.1375; found: 380.1376. [α]_D²⁰ − 202 (c = 0.25, CH₂Cl₂, 92% ee). After separation of the diastereomers by FC (Et₂O/hexane 0 : 100 to 50 : 50), the ee of the syn-diastereomer was determined by HPLC using a Chiralpak AS column [hexane/i-PrOH (85 : 15)]; flow rate 1.0 mL min⁻¹; τ_major = 14.9 min, τ_minor = 13.8 min (92% ee).

(S,R)-2-[7-Methoxy-2-(2-nitro-1-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5m). The title compound was obtained according to the general procedure (reaction time 27 h, reaction with (DHQ)₂PYR 80 h) as a a pale yellow crystalline solid (mp = 163–166 °C), yield 96%. ¹H NMR (CDCl₃) δ 7.54 (d, J 2.5 Hz, 1H), 7.34–7.40 (m, 3H), 7.27 (m, 3H), 7.23 (d, J 8.5 Hz, 1H), 4.71 (dd, J 12.7, 10.3 Hz, 1H), 4.44 (dd, J 12.7, 4.9 Hz, 1H), 3.87 (s, 3H), 3.60 (td, J 11.4, 3.3 Hz, 1H), 3.49 (td, J 10.8, 5.0 Hz, 1H), 2.95 (m, 1H), 2.79 (dd, J 18.0, 6.2 Hz, 1H), 1.96 (m, 1H) 1.78 (m, 1H). ¹³C NMR (CDCl₃) δ 174.6, 158.1, 136.0, 131.6, 131.0 (2C), 129.3 (2C), 128.6, 128.2, 127.6, 122.6, 113.2, 113.1, 111.4, 80.8, 78.6, 55.6, 44.6, 44.5, 25.8, 23.2. HRMS calc.: C₂₂H₁₉N₃O₃Na 396.1324; found: 396.1324. [α]_D²⁰ − 165 (c = 1.0, CH₂Cl₂, 86% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min⁻¹; τ_major = 11.7 min, τ_minor = 8.7 min (96% ee).

(S,R)-2-[6-Methoxy-2-(2-nitro-1-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5n). The title compound was obtained according to the general procedure (reaction time 27 h) as a a pale yellow crystalline solid (mp = 157–159 °C), yield 99%. ¹H NMR (CDCl₃) δ 8.13 (d, J 8.9 Hz, 1H), 7.34–7.40 (m, 3H), 7.27 (d, J 7.7 Hz, 2H), 6.80 (d, J 2.0 Hz, 1H), 4.72 (dd, J 12.6, 10.5 Hz, 1H), 4.42 (dd, J 12.7, 4.9 Hz, 1H), 3.91 (s, 3H), 3.58 (td, J 11.5, 3.3 Hz, 1H), 3.46 (dt, J 10.9, 4.8 Hz, 1H), 3.02 (ddd, J 18.3, 12.0, 6.1 Hz, 1H), 2.83 (dd, J 18.5, 6.5 Hz, 1H), 1.95 (m, 1H) 1.74 (m, 1H). ¹³C NMR (CDCl₃) δ 173.4, 164.5, 142.2, 136.2, 130.9, 129.4 (2C), 128.7, 127.7 (2C), 120.6, 114.8, 113.8, 113.7, 113.5, 78.6, 77.8, 55.7, 44.6, 44.5, 25.2, 24.3. HRMS calc.: C₂₂H₁₉N₃NaO₃ 396.1324; found: 396.1302. [α]_D²⁰ − 430 (c = 1.0, CH₂Cl₂, 89% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min⁻¹; τ_major = 15.3 min, τ_minor = 13.1 min (94% ee).

(S,R)-2-[5-Methoxy-2-(2-nitro-1-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5o). The title compound was obtained according to the general procedure (reaction time 30 h) as a yellow crystalline solid (mp = 189–192 °C), yield 90%. ¹H NMR (CDCl₃) δ 7.67 (d, J 8.0 Hz, 1H), 7.34–7.42 (m, 4H), 7.27 (d, J 6.9 Hz, 2H), 7.14 (d, J 8.3 Hz, 1H), 4.70 (dd, J 12.6, 10.5 Hz, 1H), 4.38 (dd, J 12.6, 4.9 Hz, 1H), 3.92 (s, 3H), 3.58 (td, J 11.5, 3.2 Hz, 1H), 3.44 (td J 10.9, 4.9 Hz, 1H), 2.74–2.81 (m, 2H), 1.83–1.90 (m, 2H). ¹³C NMR (CDCl₃) δ 175.2, 157.6, 136.4, 129.6 (2C), 129.0, 128.7 (2C), 128.5, 128.3, 128.0, 120.5, 115.5, 113.4, 81.3, 78.7, 55.9, 44.9, 44.5, 25.2, 19.2. [α]_D²⁰ − 201 (c = 1, CH₂Cl₂, 93% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (95 : 5)]; flow rate 1.0 mL min⁻¹; τ_major = 15.3 min, τ_minor = 13.7 min (93% ee).

(S,R)-2-[6,7-Dimethoxy-2-(2-nitro-1-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5p). The title compound was obtained according to the general procedure (but at a temperature of −25 °C, reaction time 29 h) as a yellow crystalline solid (mp = 191–193 °C), yield 99%. ¹H NMR (CDCl₃) δ 7.62 (s, 1H), 7.26–7.41 (m, 5H), 6.73 (s, 1H), 4.74 (dd, J 12.8, 10.2 Hz, 1H), 4.45 (dd, J 12.7, 4.6 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.45–3.60 (m, 2H), 3.02 (m, 1H), 2.79 (dd, J 17.6, 7.2 Hz, 1H), 1.92–2.01 (m, 1H), 1.73–1.79 (m, 1H). ¹³C NMR (CDCl₃) δ 173.2, 154.5, 147.7, 136.3, 134.7, 129.3 (2C), 128.6, 127.6 (2C), 120.0, 114.0, 113.8, 111.5, 110.1, 78.7, 77.6, 56.1 (2C), 44.7, 44.3, 25.5, 24.0. HRMS calc.: C₂₃H₂₁N₃NaO₄ 426.1430; found: 426.1440 [α]_D²⁰ − 381 (c = 0.5, CH₂Cl₂, 80% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (75 : 25)]; flow rate 1.0 mL min⁻¹; τ_major = 9.8 min, τ_minor = 7.8 min (80% ee).

(S,R)-2-[5,7-Dimethyl-2-(2-nitro-1-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-ylidene]-malononitrile (5q). The title compound was obtained according to the general procedure (reaction time 30 h) as a yellow crystalline solid (mp = 150–152 °C), yield 95%. ¹H NMR (CDCl₃) δ 7.72 (s, 1H), 7.34–7.41 (m, 3H), 7.31 (s, 1H), 7.26 (d, J 6.3 Hz, 1H), 4.71 (dd, J 12.6, 10.8 Hz, 1H), 4.38 (dd, J 12.6, 4.8 Hz, 1H), 3.58 (td, J 11.5, 3.3 Hz, 1H), 3.41 (td J 1.1, 4.8 Hz, 1H), 2.70 (dd, J 8.8, 3.9 Hz, 2H), 2.39 (s, 3H), 2.27 (s 3H), 1.83–1.97 (m, 2H). ¹³C NMR (CDCl₃) δ 176.0, 138.0, 137.6, 137.0, 136.3, 134.9, 129.6 (2C), 129.0 (2C), 128.0, 127.9, 127.0, 113.6 (2C), 80.4, 78.8, 44.8, 44.6, 25.8, 22.2, 21.1, 19.8. [α]_D²⁰ − 191 (c = 1, CH₂Cl₂, 91% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (98 : 2)]; flow rate 1.0 mL min⁻¹; τ_major = 21.6 min, τ_minor = 14.0 min (91% ee).

(S,R)-2-[3-(2-Nitro-1-phenyl-ethyl)-chroman-4-ylidene]-malononitrile (5r). The title compound was obtained according to the general procedure (reaction time 29 h) as a yellow crystalline solid (mp = 150–152 °C), yield 95%. ¹H NMR (CDCl₃) δ 8.25 (d, J 8.2 Hz, 1H), 7.61 (t, J 7.2 Hz, 1H), 7.29–7.45 (m, 5H), 7.15 (t, J 7.3 Hz, 1H), 7.06 (d, J 8.4 Hz, 1H), 4.85 (dd, J 12.9, 10.6 Hz, 1H), 4.50 (dd, J 12.9, 5.3 Hz, 1H), 4.04–4.15 (m, 2H), 3.73 (td, J 10.9, 5.4 Hz, 1H), 3.31 (d, J 11.4 Hz, 1H). ¹³C NMR (CDCl₃) δ 165.2, 156.0, 137.7, 135.3, 129.6 (2C), 129.0, 128.0 (2C), 127.8, 122.3, 118.5, 114.8, 113.0, 112.8, 78.9, 77.4, 66.5, 43.4, 42.8. [α]_D²⁰ − 289 (c = 0.5, CH₂Cl₂, 74% ee). The ee was determined by HPLC using a Chiralpak AD column [hexane/i-PrOH (75 : 25)]; flow rate 1.0 mL min⁻¹; _major = 7.2 min, τ_minor = 6.6 min (75% ee).

Procedure for large scale preparation of 5a. Alkylidene malononitrile 3a (10.0 mmol, 1.94 g) and trans-β-nitrostyrene 4a (11.0 mmol, 1.64 g) were mixed in a glass flask equipped with a magnetic stirring bar. Acetone (40.0 mL) was added, and the mixture was cooled to −78 °C. At this temperature (DHQD)₂PYR (3 mol%, 0.3 mmol, 260 mg) was added, and the resulting mixture was placed at −40 °C for 37 h (until 3a had be consumed, as observed on TLC). The mixture was then cooled to −78 °C and passed quickly through a short pad of silica (elute Et₂O) to remove the catalyst. The solvent was then removed in vacuo. The pure product was obtained in 84% yield and >99% ee after recrystalization in EtOH (725 mL).

Procedure for cyclization of 5a to 6. 5a (103.2 mg, 0.30 mmol, >99.9% ee) was added to a screw capped plastic vial equipped with a magnetic stirring bar. Then quinidine (10 mol%, 9.8 mg, 0.03 mmol) was added, followed by addition of CH₂Cl₂ (1.5 mL). The mixture was stirred at ambient temperature for 15 h, at which time the colour of the mixture is intensely red. The solution was then quickly passed through a short pad of SiO₂ to remove the catalyst. The pure compound 6 was obtained by FC on SiO₂ eluting with CH₂Cl₂/Et₂O (100:0 to 95:5) in 81% yield.

3-Amino-2-nitro-1-phenyl-1,9,10,10a-tetrahydro-phenanthrene-4-carbonitrile (6). The title compound was obtained according to the procedure above as a brightly yellow crystalline solid (mp = 116–118 °C). ¹H NMR (CDCl₃) δ 9.41–10.38 (br s, 1H), 7.9 (d, J 7.9 Hz, 1H), 7.46 (t, J 7.5 Hz, 1H), 7.22–7.37 (m, 7H), 6.00–6.79 (br s, 1H), 4.44 (d, J 2.2 Hz, 1H), 3.03–3.21 (m, 3H), 2.30–2.38 (m, 1H), 2.11–2.22 (m, 1H). ¹³C NMR (CDCl₃) δ 167.5, 144.7, 143.4, 139.3, 133.2, 132.2, 129.4, 128.9 (2C), 127.3, 126.5, 126.3 (2C), 126.2, 117.1, 115.0, 99.8, 47.6, 43.9, 32.7, 29.1. HRMS calc.: C₂₁H₁₇N₃NaO₂ 366.1218; found: 366.1224. [α]_D²⁰ − 347 (c = 0.5, CH₂Cl₂, 98% ee). The ee was determined by HPLC using a Chiralcel OD column [hexane/i-PrOH (80 : 20)]; flow rate 1.0 mL min⁻¹; τ_major = 19.1 min, τ_minor = 29.0 min (98% ee).

Procedure for the oxidative cleavage of 5a to 7. A flask equipped with a magnetic stirring bar was charged with 5a (113.3 mg, 0.33 mmol, >99.9% ee), KMnO₄ (130.4 mg, 0.83 mmol), and anh. MgSO₄ (44.0 mg). Then acetone (2 mL) and water (3 mL) was added, and the mixture was stirred at ambient temperature for 1 h. At this time the mixture was passed through a short pad of SiO₂ with EtOAc/CH₂Cl₂ (1 : 1) to remove residual KMnO₄ and MnO₂. More water was added and the organic phase separated, and the aqueous phase was extracted twice with CH₂Cl₂. The combined organic phases were concentrated under reduced pressure to afford the crude product (by ¹H found to be consisting of the ketone along with traces of starting material and unidentified by-products). The pure product was obtained after FC on SiO₂ eluting with Et₂O/pentane (1 : 1) in 77% yield.

2-(2-Nitro-1-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-one (7). The title compound was obtained according to the procedure above as a white crystalline solid (mp = 112–114 °C). ¹H NMR δ 8.03 (d, J 7.8 Hz, 1H), 7.49 (t, J 7.5 Hz, 1H), 7.21–7.37 (m, 7H), 5.11 (dd, J 12.9, 5.5 Hz, 1H), 4.77 (dd, J 12.9, 9.8 Hz, 1H), 4.06 (td, J 9.5, 5.6 Hz, 1H), 2.79–3.02 (m, 3H), 1.97–2.04 (m, 1H), 1.66–1.75 (m, 1H). ¹³C NMR δ 198.3, 143.4, 137.4, 133.8, 132.0, 128.9 (2C), 128.7, 128.2 (2C), 127.8, 127.6, 126.8, 79.0, 49.3, 43.0, 27.6, 26.3. HRMS calc.: C₁₈H₁₇NNaO₃ 318.1106; found: 318.1008. [α]_D²⁰ − 15 (c = 0.5, CH₂Cl₂, >99.9% ee). The ee was determined by HPLC using a Chiralcel OD column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min⁻¹; τ_major = 18.2 min, τ_minor = 25.3 min (>99.9% ee).

Acknowledgements

This work was made possible by a grant from The Danish National Research Foundation and EU-HMPT-CT-2001-00317. We are grateful to Dr. Jacob Overgaard for X-ray crystallographic analysis and to Karen Skov for performing HRMS-analysis.

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Footnote

† CCDC reference numbers [285436 and 285437]. For crystallographic data in CIF or other electronic format see DOI: 10.1039/b514564c

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