Synthesis of interesting β-nitrohydrazides through a thiourea organocatalysed aza-Michael addition

Abstract

The synthesis of antimicrobial β-nitrohydrazides, as the target product of our reaction, is reached for the first time under organocatalytic enantioselective conditions. We accomplish this goal by using a thiourea organocatalysed aza-Michael addition reaction of hydrazide to nitroalkenes, furnishing final products with good yields and good enantiomeric ratios. The developed methodology is one of the rare examples of catalytic reactivity using hydrazide where the reaction proceeds through its N² atom. Our developed strategy extends the generality of this area of research due to the difficulties of designing new nitrogen nucleophiles with high activity, and in addition, this is one of the scarce examples where nitroalkenes and chiral thioureas have been used in asymmetric organocatalytic aza-Michael addition reactions.

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Introduction

β-Nitrohydrazides have been found to exhibit interesting biological properties and some patents have focused on their synthesis.¹ However, the only asymmetric synthesis of these compounds was reached by starting from the corresponding hydrazones and nitromethane and using a stoichiometric amount of a silicon Lewis acid promoter (Scheme 1, route a).^1b In order to avoid the synthesis of the corresponding hydrazones and the use of a stoichiometric charge of the chiral promoter, we envisaged that a more straightforward organocatalytic aza-Michael addition reaction^2,3 of hydrazide to nitroalkenes should be an interesting and rapid approach for achieving the same final goal (Scheme 1, route b).

Scheme 1 Synthetic approaches to chiral β-nitrohydrazides.

As β-nitrohydrazides, many other important biomolecules also bear stereogenic centers containing C–N bonds.⁴ For this purpose, the aza-Michael addition reaction is one of the most important protocols for C–N bond formation and this field has undergone an impressive growth in the last decade, and special improvements have been achieved concerning the area of asymmetric organocatalysis.^2,5 Valuable Michael acceptor substrates as well as attractive nitrogen-containing nucleophiles have been successfully explored affording biologically and synthetically important building blocks such as α-⁶ or β-amino acids⁷ or 1,2-diamines,⁸ depending on the starting materials.

Moreover, hydrazide is a privileged structural motif present in many bioactive compounds with biological properties.⁹ Its use as starting material is however highly challenging, due to the necessary regiochemistry control on its ambident reactivity between the two competitive amine groups present in the structure. Its reactivity through the N¹ has been explored in cross-coupling reactions or in Michael addition reactions (Scheme 2, routes a and b, respectively),¹⁰ whereas its reactivity through the N² has been almost limited to the synthesis of hydrazones (Scheme 2, route c).¹¹ Consequently, the successful development of new methodologies of N² Michael addition reactions still represents an active synthetic challenge, and only Feng and co-workers have recently reported a pioneering example using a chiral metal Lewis acid (Scheme 2, route d).¹²

Scheme 2 Mode of reactivity exhibited by N-acylhydrazides.

In connection with this, we disclose here our results concerning a pioneering strategy for the synthesis of chiral β-nitrohydrazides via thiourea-catalysed aza-Michael addition reaction of hydrazides to nitroalkenes (Scheme 3). To the best of our knowledge this is the first enantioselective organocatalysed example using hydrazide as suitable nucleophile in an aza-Michael addition reaction through its N² group. Based on our own experience activating the versatile nitro group¹³ in different organocatalytic reactions,¹⁴ we envisioned that catalysts acting through hydrogen bond interactions might be a useful tool to explore this ambiphilic reactivity. One of the main organocatalytic structures covering this large group is the thiourea–urea derivatives.^14–16 In this context, a suitable activation of the nitro group through hydrogen bonds of a thiourea moiety with a reasonable concomitant coordination of the hydrazide group by an amine group present in the same catalyst, could drive the attack over the nitroalkene promoting this aza-Michael addition reaction in a bifunctional fashion (Fig. 1).^17,18

Scheme 3 Test reaction to explore the thiourea catalysed aza-Michael addition.

Fig. 1 Mechanistic hypothesis for a bifunctional mode of action.

Results and discussion

In order to check the viability of the aforementioned hypothesis, we firstly evaluated the efficiency of catalyst 3a¹⁹ in the addition of hydrazides 1a–c to nitrostyrene 2a as model reaction (Scheme 3).

To our delight, we obtained preliminary promising results in terms of reactivity and enantioselectivity using hydrazide 1b (75 : 25 e.r. and >95% yield), even if the reaction has a considerable background at room temperature (see ESI† for values). In this context, it is noteworthy that we perform the reaction without excess of reactants in order to decrease the background reaction and additionally as an attractive feature from an atom economy point of view.²⁰ Poorer results were reached with organocatalysts 3b,²¹ 3c,²² 3d,²³ and 3e²⁴ tested under similar reaction conditions using hydrazide 1b (Scheme 3). Moreover, the final products were interestingly the result of the N² attack by the hydrazide to the nitroalkene, complementing in this sense the reactivity observed so far in the literature with this kind of substrates for Michael addition reactions.

Encouraged by these results, and having identified Takemoto's catalyst 3a as the best one, we continued the screening varying different parameters in the reaction model in order to reach the optimal reaction conditions (Table 1) (see ESI† for a more complete screening).

Table 1 Screening of the reaction conditions^a

Entry	Solvent (mL)	3a (mol %)	T (°C)	Time (h)	Yield^b (%)	e.r.^c
a Experimental conditions: to a solution of thiourea 3a and nitrostyrene 2a (0.1 mmol) in the corresponding solvent, hydrazide 1b (0.1 mmol) was added at the indicated temperature. After a reasonable reaction time, product 4ba was isolated by flash chromatography (Hex–EtOAc, 7 : 3).b After isolation by column chromatography.c Determined by chiral HPLC analysis (Chiralpak IC, 80 : 20 Hex–EtOAc, 1 mL min^−1).
1	Toluene (0.5)	20	r.t.	72	12	56 : 44
2	Xylene (0.5)	20	r.t.	48	24	55 : 45
3	CH3CN (0.5)	20	r.t.	48	>95	75 : 25
4	CHCl3 (0.5)	20	r.t.	72	33	52 : 48
5	CH2Cl2 (0.5)	20	r.t.	48	70	55 : 45
6	THF (0.5)	20	r.t.	78	91	55 : 45
7	EtOAc (0.5)	20	r.t.	20	79	65 : 35
8	CH3CN (0.5)	20	5	84	87	77 : 23
9	CH3CN (0.5)	10	5	40	>95	67 : 33
10	CH3CN (0.25)	10	5	42	>95	80 : 20
11	CH3CN (0.5)	20	−27	93	91	82 : 18
12	CH3CN (0.5)	10	−27	72	88	82 : 18
13	CH3CN (0.25)	10	−27	84	>95	88 : 12
14	CH3CN (0.25)	5	−27	72	79	86 : 14
15	CH3CN (0.25)	20	−35	48	12	70 : 30
16	CH3CN (0.5)	10	−35	120	27	75 : 25

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In an initial screening of solvents at room temperature (entries 1–7), CH₃CN (entry 3) and EtOAc (entry 7) were identified as the solvents of choice for further variations, since they led to the highest values of enantiomeric ratio. Although we also continued with EtOAc in the ensuing screenings (see ESI†), we finally decided to proceed with CH₃CN because slightly better results were rendered for similar conditions. It was found that lowering the temperature to 5 or −27 °C improved enantiomeric ratios were achieved, although longer reaction times were required (entries 8 and 11). Decreasing the catalyst loading until 10 or 5 mol%, and increasing the concentration of the reaction mixture had a positive effect on the enantioselectivity without altering the final yield (entries 13 and 14). Unfortunately, experiments made lowering further the temperature to −35 °C afforded poorer enantioselectivities and yields (entries 15 and 16). Finally, the combination of 10 mol% of catalyst 3a cooling down the reaction mixture to −27 °C in 0.25 mL of CH₃CN, led to a slight increase in the asymmetric induction as well as in the yield, providing the best reaction conditions (entry 13).

Subsequently, and with the best reaction conditions in hand, we proceeded to evaluate the scope and limitations of this aza-Michael reaction testing different nitroalkenes bearing electron-withdrawing and electron-donating groups, as well as aliphatic nitroolefins (Table 2).

Table 2 Scope of the thiourea catalysed aza-Michael reaction^a

Entry	R′	3a (mol%)	CH3CN (mL)	Time (h)	Product	Yield^b (%)	e.r.^c
a Experimental conditions: To a solution of thiourea 3a and nitroalkenes 2a–l (0.1 mmol) in CH3CN, hydrazide 1b (0.1 mmol) was added at −27 °C. After the corresponding reaction time, products 4ba–bl were isolated by flash chromatography (Hex–EtOAc, 7 : 3).b After isolation by column chromatography.c Determined by chiral HPLC analysis (Chiralpak IC, 80 : 20 Hex–EtOAc, 1 mL min^−1).d Reaction performed with 0.5 mmol of nitroalkene 2a.e Value obtained after recrystallization.f Reaction performed at −35 °C.
1^d	Ph, 2a	10	0.25	72	4ba	82	86 : 14
2	4-F-C6H4, 2b	10	0.25	72	4bb	53	88 : 12
3	4-Cl-C6H4, 2c	20	1	72	4bc	82	85 : 15
4	4-Br-C6H4, 2d	20	0.5	96	4bd	86	82 : 18
5	4-Br-C6H4, 2d	20	1	96	4bd	39	86 : 14
6	3,4-Cl2-C6H3, 2e	20	1	72	4be	88	86 : 14
7	4-MeO-C6H4, 2f	10	0.25	120	4bf	83	78 : 22
8	4-MeO-C6H4, 2f	20	1	120	4bf	22	84 : 16
9	2-MeO-C6H4, 2g	20	0.5	120	4bg	72	83 : 17
10	2-MeO-C6H4, 2g	20	1	120	4bg	40	84 : 16 (>99 : 1)^e
11	4-Me-C6H4, 2h	20	1	96	4bh	62	84 : 16
12	4-BnO-C6H4, 2i	20	0.5	120	4bi	42	85 : 15
13	2-furyl, 2j	10	0.25	120	4bj	55	92 : 8
14^f	Cy, 2k	20	0.5	72	4bk	40	64 : 36
15^f	PhCH2CH2, 2l	20	0.5	120	4bl	47	63 : 37

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As shown in Table 2, hydrazide 1b was successfully added to different electron-rich and electron-poor nitroalkenes rendering final adducts 4 with moderate to high yields and good enantiomeric ratios. In some cases, slightly modified reaction conditions were required to improve the results. For example, we observed higher enantioselectivities in some cases under more diluted conditions although with poorer yields (compare entries 4 and 5, 7 and 8, 9 and 10). The data do not suggest a clear correlation between the electronic properties of nitroalkenes and the enantioselectivity, although longer reaction times were required with electron-donor groups in the aromatic ring of the nitroolefins. Notably, using a heteroaromatic nitroalkene afforded the highest value of enantiomeric ratio (entry 13). In contrast, poorer results were furnished with aliphatic nitroolefins even to lower temperature and prolonged reaction times (entries 14 and 15). As a consequence, we cannot rule out a possible π-stacking interaction between the hydrazide and the aromatic ring of nitroalkenes,²⁵ which might play an important role determining the preferred orientation in the attack. The lack of such interaction could justify the poor enantioselectivities observed using aliphatic substituents. We also scaled up the reaction to 0.5 mmol (entry 1) and it is worthwhile to note that similar results were provided to those previously furnished with 0.1 mmol (Table 1, entry 13).

The straightforward procedure for obtaining the final goal described here is simpler and “greener” than the pioneering protocol reported by Leighton and co-workers,^1b because it is not necessary the use of stoichiometric amounts of the silicon Lewis acid promoter (1.3 equiv.). Additionally, a diastereomeric mixture (1 : 2) of the promoter is used in the patent and the absolute configuration for final products is not provided. Moreover, tedious conditions, anhydrous solvents or reagents and inert atmosphere are not required, as they are in the organometallic version. Furthermore, our most accessible catalyst 3a compared with that used in the reported patent makes our procedure a more attractive alternative for this chiral version.

In order to determine the absolute configuration of our products, single crystal was grown from adduct 4bg, and the stereochemical outcome was determined to be S for final product (Fig. 2).²⁶

Fig. 2 X-ray crystal structure of (S)-4bg.

We propose the following transition state to explain the role of the catalyst 3a based in previous mode of activation by this structure (Fig. 3). The generally accepted mechanism in Michael addition reactions involves a suitable bidentate activation between the thiourea moiety and the nitro group, since the activation of nitroolefins by thiourea 3a has been earlier invoked in other processes.²⁷ However, we cannot discard a reasonable simultaneous coordination of the hydrazide group by the amine group in a bifunctional fashion (Fig. 3).¹⁸ The most acidic proton in N¹ (TS) could be involved in the assistance of the aza-Michael addition through a transient N–H bond coordination, since the deprotonation of the hydrazide is unlikely due to the pK_a values of both species.²⁸ According to this stereochemical model, the amine would drive the approach of the nucleophile to the Si face of the nitroalkene affording the S absolute configuration in all final adducts, which is consistent with the observed results in our products.

Fig. 3 Bifunctional mode of action.

In order to support our proposed mechanism (Fig. 1 and 3), we performed different ¹H-NMR experiments (Fig. 4–6). First, catalyst 3a (0.01 mmol), and hydrazide 1b (0.01 mmol) in CD₃CN (0.5 mL) were analysed separately in two NMR tubes at room temperature (Fig. 4, spectra 1 and 2). Subsequently, a mixture of both, catalyst 3a and hydrazide 1b in the same concentration in CD₃CN, was analysed by ¹H-NMR (Fig. 4, spectrum 3). Interestingly, the signals belonging to the N¹H and N²H of the hydrazide disappeared in the latter spectrum, supporting a possible interaction between the NH's of the hydrazide and the catalyst.

Fig. 4 ¹H-NMR experiments performed in CD₃CN with thiourea 3a and hydrazide 1b (400 MHz).

Additionally, in order to discard the attribution of this interaction to the thiourea group, we repeated the same experiments with thiourea 3f²⁹ without the basic moiety (Fig. 5). In this case, in the experiment using a mixture of thiourea 3f and hydrazide 1b (Fig. 5, spectrum 3), the signals belonging to the NH groups of the hydrazide remained unaltered.

Fig. 5 ¹H-NMR experiments performed in CD₃CN with thiourea 3f and hydrazide 1b (400 MHz).

We have also performed the same experiments in the presence of an external base (Fig. 6). By similitude with the basic moiety in the thiourea 3a we chose Et₃N for such a purpose. After to repeat the same NMR experiment for each species, we observed that the signals belonging to the NH groups of the hydrazide disappeared as a consequence of their interaction with the Et₃N, as hypothesised. We envision that the same interaction should occur in our catalyst 3a.

Fig. 6 ¹H-NMR experiments performed in CD₃CN with Et₃N and hydrazide 1b (400 MHz).

All these facts could be also in agreement with our initial proposed hypothesis and the aforementioned TS concerning a plausible interaction between the basic moiety in the catalyst and the hydrazide, which would help to drive the enantioselective attack over the nitroalkene favouring a more rigid transition state. According to this theory, chiral thioureas in absence of a basic scaffold in their structures afforded poorer results in terms of both, reactivity and enantioselectivity (see ESI† for more experiments) (Fig. 7).

Fig. 7 Thioureas 3g,³⁰ 3h,³¹ 3i^14b explored in absence of the basic moiety in their structures. (Reaction conditions: to a solution of thiourea 3g–i (20 mol%) and nitrostyrene 2a (0.1 mmol) in CH₃CN (0.5 mL), hydrazide 1b (0.1 mmol) was added at room temperature).

Conclusions

In summary, we have reported an unprecedented approach of thiourea-catalysed aza-Michael addition reaction of hydrazides to nitroalkenes providing easy access to inspiring building blocks with biological activity.¹ This work could be a pivotal precedent in this area of research due to the difficulties to design new nitrogen nucleophiles with high activity, and in addition, this is one of the scarce examples where nitroalkenes³² and chiral thiourea catalysts^{18b,32d,e,g,33} have been used in asymmetric organocatalytic aza-Michael addition reactions. Further studies are being carried out in order to understand the role of the catalyst in this reaction and to clarify the function of the basic moiety of the catalyst and its possible coordination with the hydrazide.^34,35 Moreover, studies applying these hydrazides in different Michael addition reactions are actively on-going in our laboratory.

Experimental section

Representative procedure for thiourea organocatalysed aza-Michael reaction of hydrazides to nitroalkenes

To a solution of thiourea 3a (0.01 or 0.02 mmol) and nitroalkenes 2a–l (0.1 mmol) in CH₃CN (0.25, 0.5 or 1 mL), hydrazide 1b (0.1 mmol) was added in a test tube at −27 °C (or −35 °C). After the corresponding reaction time (see Table 2), the residue was purified by flash chromatography (SiO₂, n-hexane–EtOAc 7 : 3) to afford final adducts 4. Yields and enantiomeric ratios are reported in Table 2.

(S)-4-Nitro-N′-(2-nitro-1-phenylethyl)benzohydrazide (4ba)

Compound 4ba was obtained as a white solid after 84 h of reaction at −27 °C in >95% yield (32 mg). M.p. 134–136 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 258.8 nm): t_major = 13.8 min; t_minor = 16.8 min. [α]²⁴_D = +19.3 (c = 0.20, acetone, 88 : 12 e.r.). ¹H NMR (400 MHz, CD₂Cl₂) δ 8.24–8.27 (m, 2H), 7.78–7.81 (m, 2H), 7.60–7.61 (m, 1H, NH), 7.40–7.46 (m, 5H), 5.41 (dd, J = 2.8, 5.7 Hz, 1H, NH), 4.95 (ddd, J = 2.8, 4.3, 8.6 Hz, 1H), 4.84 (dd, J = 8.6, 12.7 Hz, 1H), 4.66 (dd, J = 4.3, 12.7 Hz, 1H). ¹³C NMR (100 MHz, CD₂Cl₂) δ 166.4 (1C), 150.3 (1C), 138.3 (1C), 136.4 (1C), 129.6 (1C), 129.5 (2C), 128.6 (2C), 128.0 (2C), 124.3 (2C), 79.6 (1C), 62.5 (1C). IR (KBr film) (cm⁻¹) ν 3277, 2924, 2854, 1621, 1593, 1561, 1537, 1524, 1456, 1426, 1376, 1345, 1313, 1299, 719, 701, 690. HRMS (ESI+) calcd C₁₅H₁₄N₄NaO₅ 353.0856; found 353.0865 [M⁺ + Na].

(S)-N′-(1-(4-Fluorophenyl)-2-nitroethyl)-4-nitrobenzohydrazide (4bb)

Compound 4bb was obtained as an orange solid after 72 h of reaction at −27 °C in 53% yield (18.4 mg). M.p. 165–167 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 260.0 nm): t_major = 13.1 min; t_minor = 15.9 min. [α]²⁵_D = +18.0 (c = 0.94, acetone, 88 : 12 e.r.). ¹H NMR (400 MHz, CD₃COCD₃) δ 9.68 (br s, 1H, NH), 8.28–8.32 (m, 2H), 8.01–8.04 (m, 2H), 7.57–7.60 (m, 2H), 7.12–7.18 (m, 2H), 5.70 (br s, 1H, NH), 5.11 (dd, J = 7.4, 12.8 Hz, 1H), 4.97–5.00 (m, 1H), 4.86 (dd, J = 6.0, 12.8 Hz, 1H). ¹³C NMR (100 MHz, CD₃COCD₃) δ 167.1 (1C), 164.7 (d, J = 245.0 Hz, 1C), 151.6 (1C), 140.5 (1C), 135.2 (m, 1C), 132.0 (d, J = 8.4 Hz, 2C), 130.5 (2C), 125.4 (2C), 117.2 (d, J = 21.6 Hz, 2C), 80.3 (1C), 63.1 (1C). IR (KBr film) (cm⁻¹) ν 3261, 2924, 2854, 1631, 1597, 1554, 1510, 1462, 1427, 1378, 1344, 1317, 1224, 1192, 1124, 1105, 963, 887, 864, 849, 831, 818, 690. HRMS (ESI+) calcd C₁₅H₁₃FN₄NaO₅ 371.0762; found 371.0742 [M⁺ + Na].

(S)-N′-(1-(4-Chlorophenyl)-2-nitroethyl)-4-nitrobenzohydrazide (4bc)

Compound 4bc was obtained as an orange solid after 72 h of reaction at −27 °C in 82% yield (29,9 mg). M.p. 146–148 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 258.8 nm): t_major = 13.5 min; t_minor = 16.4 min. [α]²⁵_D = +20.3 (c = 0.24, acetone, 80 : 20 e.r.). ¹H NMR (400 MHz, CD₂Cl₂) δ 8.25–8.28 (m, 2H), 7.79–7.82 (m, 2H), 7.58–7.59 (m, 1H, NH), 7.41 (s, 4H), 5.38 (dd, J = 2.9, 5.7 Hz, 1H, NH), 4.93–4.97 (m, 1H), 4.81 (dd, J = 8.4, 12.8 Hz, 1H), 4.63 (dd, J = 4.5, 12.8 Hz, 1H). ¹³C NMR (100 MHz, CD₂Cl₂) δ 166.5 (1C), 150.4 (1C), 138.1 (1C), 135.4 (1C), 135.0 (1C), 129.7 (2C), 129.5 (2C), 128.6 (2C), 124.3 (2C), 79.3 (1C), 61.8 (1C). IR (KBr film) (cm⁻¹) ν 3274, 2924, 2854, 1733, 1674, 1653, 1603, 1558, 1520, 1491, 1378, 1342, 1259, 1175, 1138, 1090, 1068, 1015, 868, 850. HRMS (ESI+) calcd C₁₅H₁₃ClN₄NaO₅ 387.0467; found 387.0488 [M⁺ + Na].

(S)-N′-(1-(4-Bromophenyl)-2-nitroethyl)-4-nitrobenzohydrazide (4bd)

Compound 4bd was obtained as a yellow solid after 96 h of reaction at −27 °C in 86% yield (35.2 mg). M.p. 152–154 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 258.8 nm): t_major = 13.3 min; t_minor = 16.1 min. [α]²⁵_D = +22.9 (c = 0.69, acetone, 82 : 18 e.r.). ¹H NMR (400 MHz, CD₃COCD₃) δ 9.56 (br s, 1H, NH), 8.15–8.17 (m, 2H), 7.88–7.90 (m, 2H), 7.42–7.45 (m, 2H), 7.36–7.38 (m, 2H), 5.62 (br s, 1H, NH), 4.97 (dd, J = 7.3, 12.9 Hz, 1H), 4.83–4.87 (br m, 1H, NH), 4.74 (dd, J = 5.9, 12.9 Hz, 1H). ¹³C NMR (100 MHz, CD₃COCD₃) δ 167.0 (1C), 151.6 (1C), 140.5 (1C), 138.5 (1C), 133.5 (2C), 132.1 (2C), 130.5 (2C), 125.4 (2C), 123.9 (1C), 80.0 (1C), 63.2 (1C). IR (KBr film) (cm⁻¹) ν 3314, 2924, 2854, 1646, 1597, 1543, 1522, 1460, 1376, 1350, 1306, 1073, 1011, 876, 849, 828, 772, 724. HRMS (ESI+) calcd C₁₅H₁₃BrN₄NaO₅ 430.9962; found 430.9947 [M⁺ + Na].

(S)-N′-(1-(3,4-Dichlorophenyl)-2-nitroethyl)-4-nitrobenzohydrazide (4be)

Compound 4be was obtained as an orange solid after 72 h of reaction at −27 °C in 88% yield (35.1 mg). M.p. 70–75 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 258.8 nm): t_major = 11.9 min; t_minor = 14.2 min. [α]²⁵_D = +35.8 (c = 0.35, CHCl₃, 83 : 17 e.r.). ¹H NMR (400 MHz, THF-d₈) δ 9.57 (d, J = 5.5 Hz, 1H, NH), 8.25–8.28 (m, 2H), 7.90–7.93 (m, 2H), 7.74 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.43 (dd, J = 2.0, 8.3 Hz, 1H), 5.84 (dd, J = 3.7, 5.5 Hz, 1H, NH), 4.91 (m, 2H), 4.74–4.80 (m, 1H). ¹³C NMR (100 MHz, THF-d₈) δ 166.4 (1C), 150.8 (1C), 139.6 (1C), 139.5 (1C), 133.2 (1C), 133.0 (1C), 131.4 (1C), 131.1 (1C), 129.3 (2C), 129.0 (1C), 124.2 (2C), 78.8 (1C), 61.9 (1C). IR (KBr film) (cm⁻¹) ν 3286, 3108, 2959, 2927, 2857, 1659, 1601, 1554, 1526, 1469, 1377, 1346, 1299, 1198, 1134, 1111, 1076, 1032, 1014, 952, 868, 850, 826, 718, 683. HRMS (ESI+) calcd C₁₅H₁₃Cl₂N₄O₅ 399.0258; found 399.0234 [M⁺ + H].

(S)-N′-(1-(4-Methoxyphenyl)-2-nitroethyl)-4-nitrobenzohydrazide (4bf)

Compound 4bf was obtained as a yellow solid after 120 h of reaction at −27 °C in 83% yield (29.9 mg). M.p. 109–111 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 260.0 nm): t_major = 21.4 min; t_minor = 27.7 min. [α]²⁵_D = +21.8 (c = 0.63, acetone, 78 : 22 e.r.). ¹H NMR (400 MHz, CDCl₃) δ 8.24–8.27 (m, 2H), 7.78–7.81 (m, 2H), 7.73–7.74 (m, 1H, NH), 7.31–7.34 (m, 2H), 6.90–6.93 (m, 2H), 5.31–5.33 (m, 1H, NH), 4.89–4.93 (m, 1H), 4.79 (dd, J = 8.9, 12.4 Hz, 1H), 4.58 (dd, J = 4.0, 12.4 Hz, 1H), 3.81 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 166.1 (1C), 160.2 (1C), 149.9 (1C), 137.7 (1C), 128.8 (2C), 128.2 (2C), 127.5 (1C), 124.0 (2C), 114.6 (2C), 79.7 (1C), 61.7 (1C), 55.3 (1C). IR (KBr film) (cm⁻¹) ν 3287, 3110, 2924, 2854, 1663, 1603, 1547, 1515, 1463, 1377, 1348, 1306, 1279, 1253, 1178, 1134, 1112, 1027, 868, 851, 834, 719, 683. HRMS (ESI+) calcd C₁₆H₁₆N₄NaO₆ 383.0962; found 383.0942 [M⁺ + Na].

(S)-N′-(1-(2-Methoxyphenyl)-2-nitroethyl)-4-nitrobenzohydrazide (4bg)

Compound 4bg was obtained as a yellow solid after 120 h of reaction at −27 °C in 72% yield (25.9 mg). M.p. 134–137 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 262.4 nm): t_major = 17.2 min; t_minor = 24.2 min. [α]²⁵_D = +15.2 (c = 0.63, acetone, 83 : 17 e.r.). ¹H NMR (400 MHz, CDCl₃) δ 8.25–8.28 (m, 2H), 7.80–7.83 (m, 2H), 7.64 (br d, J = 4.7 Hz, 1H, NH), 7.33–7.37 (m, 2H), 6.94–7.00 (m, 2H), 5.77 (br s, 1H, NH), 5.09–5.13 (m, 1H), 4.88 (dd, J = 8.7, 12.6 Hz, 1H), 4.68 (dd, J = 4.0, 12.6 Hz, 1H), 3.91 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 165.6 (1C), 157.1 (1C), 149.7 (1C), 137.8 (1C), 130.2 (1C), 128.5 (1C), 128.2 (2C), 123.8 (2C), 123.6 (1C), 120.9 (1C), 111.0 (1C), 77.8 (1C), 59.1 (1C), 55.5 (1C). IR (KBr film) (cm⁻¹) ν 3289, 3266, 2925, 2866, 1648, 1598, 1537, 1523, 1489, 1464, 1374, 1342, 1324, 1241, 1110, 869, 848, 764. HRMS (ESI+) calcd C₁₆H₁₆N₄NaO₆ 383.0962; found 383.0941 [M⁺ + Na].

(S)-4-Nitro-N′-(2-nitro-1-(p-tolyl)ethyl)benzohydrazide (4bh)

Compound 4bh was obtained as a yellow solid after 96 h of reaction at −27 °C in 62% yield (21.3 mg). M.p. 100–102 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 260.0 nm): t_major = 15.9 min; t_minor = 19.4 min. [α]²⁴_D = +24.5 (c = 0.81, acetone, 78 : 22 e.r.). ¹H NMR (400 MHz, THF-d₈) δ 9.53 (br d, J = 5.7 Hz, 1H, NH), 8.26 (d, J = 8.9 Hz, 2H), 7.92 (d, J = 8.9 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 5.63 (dd, J = 3.6, 5.7 Hz, 1H, NH), 4.86–4.94 (m, 2H), 4.66–4.75 (m, 1H), 2.31 (s, 3H). ¹³C NMR (100 MHz, THF-d₈) δ 166.2 (1C), 150.7 (1C), 139.9 (1C), 139.0 (1C), 135.5 (1C), 130.0 (2C), 129.3 (2C), 128.7 (2C), 124.2 (2C), 79.7 (1C), 62.8 (1C), 21.2 (1C). IR (KBr film) (cm⁻¹) ν 3263, 2924, 2855, 1651, 1600, 1548, 1526, 1459, 1422, 1378, 1346, 1307, 1224, 896, 873, 850, 822, 791, 778, 722, 695. HRMS (ESI+) calcd C₁₆H₁₆N₄NaO₅ 367.1013; found 367.1003 [M⁺ + Na].

(S)-N′-(1-(4-(Benzyloxy)phenyl)-2-nitroethyl)-4-nitrobenzohydrazide (4bi)

Compound 4bi was obtained as a yellow solid after 120 h of reaction at −27 °C in 42% yield (18.3 mg). M.p. 149–151 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 260.0 nm): t_major = 19.9 min; t_minor = 26.1 min. [α]²⁵_D = +27.1 (c = 0.36, acetone, 85 : 15 e.r.). ¹H NMR (400 MHz, CDCl₃) δ 8.27–8.30 (m, 2H), 7.78–7.81 (m, 2H), 7.47 (br s, 1H, NH), 7.33–7.47 (m, 7H), 7.00–7.02 (m, 2H), 5.31 (br s, 1H, NH), 5.08 (s, 2H), 4.92 (dd, J = 3.8, 8.9 Hz, 1H), 4.80 (dd, J = 9.0, 12.3 Hz, 1H), 4.59 (dd, J = 3.9, 12.3 Hz, 1H). ¹³C NMR (100 MHz, CD₃COCD₃) δ 167.0 (1C), 161.0 (1C), 151.6 (1C), 140.7 (1C), 140.6 (1C), 139.2 (1C), 131.1 (2C), 130.5 (2C), 130.3 (2C), 129.7 (1C), 129.5 (2C), 125.4 (2C), 116.7 (2C), 80.5 (1C), 71.4 (1C), 63.4 (1C). IR (KBr film) (cm⁻¹) ν 3386, 2924, 2854, 1650, 1603, 1553, 1538, 1513, 1465, 1377, 1344, 1327, 1231, 1178, 1002, 870, 852, 840, 747, 719, 696. HRMS (ESI+) calcd C₂₂H₂₀N₄NaO₆ 459.1275; found 459.1254 [M⁺ + Na].

(S)-N′-(1-(Furan-2-yl)-2-nitroethyl)-4-nitrobenzohydrazide (4bj)

Compound 4bj was obtained as an orange solid after 120 h of reaction at −27 °C in 55% yield (17.6 mg). M.p. 145–147 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 258.8 nm): t_major = 17.7 min; t_minor = 19.7 min. [α]²⁴_D = +28.8 (c = 0.34, acetone, 92 : 8 e.r.). ¹H NMR (400 MHz, CD₂Cl₂) δ 8.26–8.30 (m, 2H), 7.83–7.86 (m, 2H), 7.64 (br d, J = 5.9 Hz, 1H, NH), 7.47 (dd, J = 0.8, 1.8 Hz, 1H), 6.40–6.43 (m, 2H), 5.44–5.46 (m, 1H, NH), 5.00–5.05 (m, 1H), 4.89 (dd, J = 8.4, 13.3 Hz, 1H), 4.77 (dd, J = 4.9, 13.3 Hz, 1H). ¹³C NMR (75 MHz, THF-d₈) δ 166.0 (1C), 151.4 (1C), 150.7 (1C), 143.8 (1C), 139.7 (1C), 129.3 (2C), 124.2 (2C), 111.1 (1C), 109.4 (1C), 76.7 (1C), 57.0 (1C). IR (KBr film) (cm⁻¹) ν 3276, 2922, 2852, 1737, 1699, 1651, 1598, 1558, 1521, 1460, 1377, 1345, 1013. HRMS (ESI+) calcd C₁₃H₁₂N₄NaO₆ 343.0649; found 343.0649 [M⁺ + Na].

(S)-N′-(1-Cyclohexyl-2-nitroethyl)-4-nitrobenzohydrazide (4bk)

Compound 4bk was obtained as an orange solid after 72 h of reaction at −27 °C in 40% yield (13.4 mg). M.p. 91–93 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ= 258.8 nm): t_major = 12.1 min; t_minor = 16.8 min. [α]²⁵_D = −11.1 (c = 0.12, acetone, 64 : 36 e.r.). ¹H NMR (400 MHz, CD₃COCD₃) δ 9.63 (br s, 1H, NH), 8.31–8.35 (m, 2H), 8.07–8.10 (m, 2H), 5.35–5.38 (m, 1H, NH), 4.72 (dd, J = 4.2, 13.4 Hz, 1H), 4.63 (dd, J = 7.7, 13.4 Hz, 1H), 3.58–3.64 (m, 1H), 1.89–1.93 (m, 2H), 1.65–1.80 (m, 3H), 1.15–1.34 (m, 6H). ¹³C NMR (100 MHz, CD₃COCD₃) δ 167.0 (1C), 151.6 (1C), 140.6 (1C), 130.5 (2C), 125.4 (2C), 78.3 (1C), 65.1 (1C), 40.8 (1C), 30.8 (2C), 30.2 (2C), 28.0 (1C). IR (KBr film) (cm⁻¹) ν 3295, 2927, 2854, 1658, 1601, 1552, 1526, 1451, 1347, 1300, 1109, 1014, 868, 849, 718. HRMS (ESI+) calcd C₁₅H₂₀N₄NaO₅ 359.1326; found 359.1313 [M⁺ + Na].

(S)-4-Nitro-N′-(1-nitro-4-phenylbutan-2-yl)benzohydrazide (4bl)

Compound 4bl was obtained as an orange solid after 120 h of reaction at −35 °C in 47% yield (16.8 mg). M.p. 115–117 °C. The e.r. of the product was determined by HPLC using a Daicel Chiralpak IC column (n-hexane–EtOAc = 80 : 20, flow rate 1 mL min⁻¹, λ = 258.8 nm): t_major = 12.7 min; t_minor = 14.4 min. [α]²⁵_D = −10.5 (c = 0.31, acetone, 63 : 37 e.r.). ¹H NMR (400 MHz, CD₃COCD₃) δ 9.65 (br s, 1H, NH), 8.32–8.35 (m, 2H), 8.11–8.14 (m, 2H), 7.27 (br d, J = 4.4 Hz, 4H), 7.16–7.21 (m, 1H), 5.50–5.53 (br m, 1H, NH), 4.74 (dd, J = 7.2, 13.4 Hz, 1H), 4.68 (dd, J = 5.0, 13.4 Hz, 1H), 3.74–3.81 (m, 1H), 2.85–2.96 (m, 2H), 1.96–2.09 (m, 1H), 1.83–1.92 (m, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 166.3 (1C), 150.0 (1C), 140.4 (1C), 137.5 (1C), 128.7 (2C), 128.3 (2C), 128.2 (2C), 126.5 (1C), 124.0 (2C), 78.2 (1C), 58.5 (1C), 32.2 (1C), 31.9 (1C). IR (KBr film) (cm⁻¹) ν 3362, 3292, 3103, 3025, 3002, 2926, 2853, 1659, 1597, 1548, 1519, 1495, 1470, 1454, 1414, 1383, 1352, 1316, 1297, 1112, 1083, 1011, 910, 867, 847, 792, 754, 713, 696. HRMS (ESI+) calcd C₁₇H₁₈N₄NaO₅ 381.1169; found 381.1163 [M⁺ + Na].

Acknowledgements

We thank the Spanish Ministry of Economía y Competitividad (MICINN. Madrid. Spain. Project CTQ2010-19606) and the Government of Aragón (Zaragoza. Spain. Research Group E-10) for financial support of our research. We thank Dr Pablo J. Sanz Miguel (ISQCH) and Prof. M. Concepción Gimeno (ISQCH) for X-ray structure analysis. We are also grateful to Prof. Luca Bernardi for his useful comments.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 959956. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra47925k

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