An efficient synthesis of N-substituted 3-nitrothiophen-2-amines

Summary A novel protocol for the synthesis of 3-nitro-N-aryl/alkylthiophen-2-amines in good yields from the reaction of α-nitroketene N,S-aryl/alkylaminoacetals and 1,4-dithiane-2,5-diol in the presence of K2CO3 in refluxing ethanol is described. This transformation generates two C–C bonds in a single operation and presumably proceeds through a reaction sequence comprising 2-mercaptoacetaldehyde generation, nucleophilic carbonyl addition, annelation and elimination steps.


Introduction
Thiophenes constitute an important class of heterocyclic compounds, and are embedded in natural [1] and unnatural [2] organic molecules with diverse biological activities. Among them, many 2-aminothiophenes have reached the market or have undergone extensive pharmacological studies. Representative examples are the neuroleptic olanzapine [3], the 2A3BT family of allosteric modulators of the A1 adenosine receptor, derived from 2-amino-3-benzoylthiophene and compounds such as PD-81,723 and T-62 [4], the non-steroidal anti-inflammatory tinoridine [5] and ranelic acid, whose strontium salt is used as a medication for osteoporosis [6] (Figure 1). Other interesting properties identified in 2-aminothiophene derivatives include GluR6 antagonism [7], antiviral and antitumor activities [8][9][10], inhibition of p53-MDM2 interactions [11] and protein-tyrosine phosphatase 1B inhibition [12]. Furthermore, 2-aminothiophenes have potential applications in the field of functional materials such as liquid crystals [13], nonlinear optical materials (NLOs) [14], organic solar cells [15], photonic polymers [16] and electroluminescent materials [17]. Nitrothiophenes are also important as chemotherapeutic agents and in a few cases both functional groups are combined in the same molecule. For instance, compound I ( Figure 1) is an antitubercular agent that acts by releasing nitric oxide following activation by F420dependent nitroreductase DDN [18]. However, the pharmacological study of this class of compounds is hampered by limitations in existing synthetic methodologies, particularly in the direct preparation of N-substituted amino derivatives. 2-Aminothiophenes have traditionally been synthesized from mercapto-or halogen-substituted thiophenes through nucleophilic displacements [19]. More recently, these derivatives have been assembled from acyclic starting materials by methods such as i) reaction of lithiated 1-alkynes or allenes with substituted phenyl isothiocyanates [20], ii) treatment of N-allylbenzotriazole with substituted phenylisothiocyanates [21] and iii) reaction between phenyl isothiocyanate and electron-deficient allenes catalyzed by PPh 3 [22] (Scheme 1a-c). On the other hand, studies on the synthesis of 3-nitrothiophenes are scarce. One of the traditional methods involves electrophilic aromatic substitution reactions of thiophenes, which introduces substituents at the 2-and 5-positions, but with some drawbacks associated with the lack of regioselectivity and difficult isomer separation [23]. Other methods for the synthesis of 2,3-disubsituted thiophenes include the reactions of (i) 1,4-dithiane-2,5diol with nitroalkenes [24], activated nitriles [25] and cyano-acetamide [26]; (ii) 3-nitrothiophene with Grignard reagents [27] and (iii) 3-bromo-2-silylthiophene with aldehydes [28]. The major drawback of these methods is that none of them allow the simultaneous introduction of 2-amino and 3-nitro substituents (see Scheme 1d for a representative example). Scheme 1: Some strategies for the synthesis of 2-aryl/alkylaminothiophenes and 3-nitrothiophenes.
Multiple bond-forming transformations [29][30][31] are very attractive because of the high synthetic efficiency associated to the formation of several bonds in a single operation. The corresponding reduction in the number of isolation and purification steps and hence in the use of organic solvents and chromatographic stationary phases helps to achieve one of the main goals of green chemistry [32]. In this context, we wish to report herein a new and efficient synthesis of 3-nitro-N-aryl/alkylthiophen-2-amines based on domino reactions between α-nitroketene N,S-aryl/alkylaminoacetals and 1,4-dithiane-2,5diol, the dimer of 2-mercaptoacetaldehyde (Scheme 2). This work emerges as a continuation of our recent efforts directed towards the construction of biologically relevant heterocycles employing multiple bond-forming transformations [33][34][35][36][37][38][39][40].

Results and Discussion
In a preparatory study, the optimization of the reaction between (E)-4-methyl-N-(1-(methylthio)-2-nitrovinyl)aniline (1e, 1 mmol) and 1,4-dithiane-2,5-diol (2, 0.5 mmol, 1 equiv) was performed. Initially, this model reaction was attempted in ethanol and in the absence of base, with negative results ( Table 1, entry 1). In the presence of TEA (1 equiv), it gave 62% yield (Table 1, entry 2), which was increased to 88% when the reaction was performed in refluxing ethanol for 25 min (Table 1, entry 3). In both cases, work-up had the advantage of being very simple. After completion of the reaction, the mixture was poured into water and the precipitated solid was filtered and washed with ethanol to give the pure 3-nitro-N-(p-tolyl)thiophen-2-amine (3e) without the need for chromatography.  [19][20][21], leading to the conclusion that 0.25 equivalents of potassium carbonate were sufficient to promote the desired transformation, but lower amounts led to longer reaction times and diminished yields (Table 1, Table 1 were performed under heating at reflux temperature of the respective solvents used, except reactions corresponding to entries 1 and 2, which were performed at room temperature.

entry 22). All reactions included in
The scope and generality of this transformation was investigated by examining the reaction between a variety of α-nitroketene N,S-anilinoacetals 1 with 1,4-dithiane-2,5-diol (2,  Table 2). The starting materials 1 were readily available by refluxing in ethanol the suitable primary amine and 1,1-bis(methylthio)-2-nitroethylene. Regarding aryl substituents, the thiophene synthesis was compatible with the presence of unsubstituted phenyl rings (compound 3e) and phenyl substituents bearing moderately electron-withdrawing groups such as mand p-halogens and m-trifluoroalkyl substituents (compounds 3a-d and 3l-n), although substrates 1 with aryl rings bearing strongly electron-withdrawing groups such as p-nitro, p-cyano and p-trifluoromethyl failed to afford the final products. Furthermore, it was gratifying to observe that our method was compatible with the presence of electronreleasing substituents at the aromatic ring, including alkyl (compounds 3f-h, 3j, 3o and 3q) and alkoxy (compounds 3i, 3k and 3p) substituents, even at the more hindered ortho-positions (3j, 3k, 3q). The preparation of a compound bearing a 1-naphthylamino substituent (compound 3r) also proceeded unevent-fully. We also investigated the reactions of α-nitroketene N,Salkylaminoacetals and 1,4-dithiane-2,5-diol (2). These reactions provided the desired 2-(alkylamino)-3-nitrothiophenes in excellent yields, albeit with the need for longer reaction times. The method allowed the preparation of compounds bearing linear (compounds 3s-u) and α-branched alkyl substituents (compounds 3v, 3x). Benzyl substituents could also be accommodated, as shown by the efficient preparation of 3y and 3z.

Scheme 3 and
Scheme 3: Synthesis of N-substituted 3-nitrothiophen-2-amines. The structure of the 3-nitro-N-arylthiophen-2-amines 3 was deduced from one-and two-dimensional NMR spectroscopic, microanalytical and mass spectral data, as detailed for 3c as a representative example (see Supporting Information File 1) and confirmed unambiguously by a single-crystal X-ray crystallographic study [41] of 3p ( Figure 2). The transformation leading to compounds 3 presumably proceeds through the initial formation of 2-mercaptoacetaldehyde (4) from the base-promoted decomposition of 1,4dithiane-2,5-diol (2). This would be followed by a formal [3 + 2] annexation via nucleophilic addition of compounds 1 to the carbonyl of intermediate 4 followed by addition of the thiolate anion onto the iminium functionality thus generated to give 5. Subsequent elimination of methylmercaptan and water furnishes the product 3 (Scheme 4).

Scheme 4:
Proposed reaction sequence leading to the formation of 3.

Conclusion
In conclusion, we have developed a very efficient synthesis of a synthetically and biologically relevant class of push-pull heterocyclic compounds under mild conditions and starting from simple acyclic substrates and catalysts. Previously, these compounds were available only through multistep sequences, most notably one involving as the final step an S N Ar reaction with the amine and having the serious limitation of requiring the presence of an additional strong electron-withdrawing group at C-5 [42][43][44]. Our protocol requires only two steps (including the preparation of starting materials 1) and generates two C-C bonds through a sequence of reactions that comprise up to five individual steps and proceeds in excellent yields (93% in average for 26 examples) and atom economies.

Supporting Information
Supporting Information File 1 Experimental procedures, characterization data, details of the NMR structural determination of 3c and copies of 1 H NMR, 13 C NMR and ESI mass spectra of all new compounds 1 and 3.