*2.1. Synthesis of Tetrasubstituted Nitroalkenes*

We started the investigations by exploring a two-step synthetic strategy for the synthesis of tetrasubstituted nitroalkenes (Scheme 1). The first reaction involves the formation of acrylates **2a**–**f**, by reaction of different commercially available ketones **1a**–**f**, using Horner–Wadstworth–Emmons reaction conditions [9]. The results are summarized in Table 1.

**Scheme 1.** Synthesis of acrylates intermediates (**2**).

**Table 1.** Synthesis of acrylate intermediates **2a**–**f**.


<sup>a</sup> Determined by 1H-NMR. <sup>b</sup> Yield was determined after purification using column chromatography.

Compounds **2a**–**f** were obtained after reaction of the corresponding commercially available ketones with trimethylphosphonoacetate and sodium hydride in THF for 24 h with good to moderate yields and excellent diastereoselectivities after purification with

column chromatography. The reactions were performed at room temperature, but with compounds **2c**, **2d** and **2f** (Table 1, entries 3,4,6) it was necessary to heat the reaction to 66 ◦C. Their E/Z ratio was checked by 1H-NMR of reaction crude. The low yield observed for the isolation of pure product **2c** (Table 1, entry 3) can be explained by its high volatility, and optimization of the product isolation is underway.

Then, our efforts were concentrated on the nitration reaction of these acrylate intermediates using common nitration reagents such as HNO3 [10,11]. However, the use of nitric acid mainly led to the formation of products with the nitro group on the aromatic ring, and the yields after purification were very low (<10%). Furthermore, several problems were also detected during the isolation process. Selective nitration conditions for double bonds were also considered, but no formation of the desired nitroalkane was observed. Thus, alternative strategies involving the condensation between acetophenone and ethyl nitroacetate or the reaction between phenylacetylene with ethyl nitroacetate catalyzed by indium salts were also explored, [12–15] but without any satisfactory results (see Supplementary Materials).

Finally, Buevich and co-workers reported the first example of a α-nitro addition to a cinammic ester for the synthesis of dehydrophenylalanine derivatives, which are precursors of α-amino acids, by utilizing a CAN-NaNO2 system [16]. Therefore, we decided to investigate the methodology for the synthesis of target tetrasubstituted nitroalkenes **3a**–**f** starting from acrylates **2a**–**f** (Scheme 2).

**Scheme 2.** Synthesis of tetrasubstituted nitroalkenes **3a**–**f**.

The results are summarized in Table 2.

**Table 2.** Synthesis of tetrasubstituted nitroalkenes **3a**–**f**.


<sup>a</sup> Isolated yield after purification with column chromatography. <sup>b</sup> Side-product (Z)-methyl 4,4,4-trifluoro-3- (4-nitrophenyl)but-2-enoate was obtained in 76% yield. <sup>c</sup> Reaction did not occur, unreacted starting material was recovered.

The nitration reaction of acrylates led to the formation of the corresponding tetrasubstituted nitroacrylates **3a**–**f** in low to moderate yields after chromatographic purification, and typically in a 6/4 diasteoisomeric ratio, except in the case of **3d,** when a single isomer was isolated. In case of nitroacrylates **3a**,**e** (Table 2, entries 1 and 5), two different fractions corresponding to the two separated diastereoisomers were obtained after purification., while for product **3f** (Table 2, entry 6) a single fraction containing both, non-separable, isomers, was obtained after chromatography.

The nitration of acrylate **2b** (Table 2, entry 2), did not lead to the formation of the corresponding nitroacrylate **3b**, but (Z)-methyl 4,4,4-trifluoro-3-(4-nitrophenyl)but-2-enoate was obtained as major compound in this reaction in 76% yield. The nitration of acrylate **2c** (Table 2, entry 3) did not afford any product.

As previously mentioned, in the nitration of acrylates **2a**,**e** (Table 2, entries 1 and 5), it was possible to separate the two diastereoisomers. In order to clarify the configuration of the two products, additional NMR experiments were conducted on the isomers of compound **3a** (Figure 2).

**F**

**Figure 2.** Further NMR experiments performed for tetrasubstituted nitroacrylate **3a.** (**a**): NMR spectra of a mixture fraction of compound **3a**. (**b**): NOE contact observed between OMe and Ph groups in the more abundant form of the tetrasubstituted nitroacrylate **3a**. (**c**): structures of nitroacrylates **3a–***Z* and **3a–***E*.

A chemical shift study on the methoxy group signal of both Z/E forms of the tetrasubstituted nitroalkene **3a** has been performed, using a NOESY experiment. As illustrated in Figure 2a, the OMe group of the molecule is more shielded (3.55 ppm) in the more abundant form, suggesting that it can be near to the shielding cone of the aromatic ring (corresponding to the (*E*) isomer), while it resonates at 3.8 ppm in the less abundant isomer of Figure 2a.

NOESY experimental results, showing through-space correlation within the molecule, were also acquired to predict if the more abundant isomer of the synthetized tetrasubstituted nitroalkene corresponds to (*E*) or (*Z*), considering that the NOE contact between the methoxy group and the phenyl ring can only be observed in the (*E*) isomer. The analysis of NOE contacts suggested that the significant cross peak between the OMe group and phenyl ring (Figure 2b) is present only in the major isomer that can be determined to have the (*E*) configuration (product **3a**–*E*).
