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

Abstract

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 [8–10], 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 F420-dependent 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.

Figure 1.

Selected examples of biologically active 2-aminothiophene 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 PPh₃ [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-2,5-diol with nitroalkenes [24], activated nitriles [25] and cyanoacetamide [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 [29–31] 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-2,5-diol, 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 [33–40].

Scheme 2.

Our plan for the synthesis of N-substituted 3-nitrothiophen-2-amines.

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. Then the model reaction was further investigated by employing alternative bases such as 1,4-diazabicyclo[2.2.2]octane (DABCO, Table 1, entry 4), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, Table 1, entry 5), pyridine (Table 1, entry 6), N,N-dimethylaminopyridine (DMAP, Table 1, entry 7), piperidine (Table 1, entry 8), L-proline (Table 1, entry 9), potassium carbonate (Table 1, entry 10), sodium carbonate (Table 1, entry 11) and caesium carbonate (Table 1, entry 12). After identifying potassium carbonate as the optimal base in refluxing ethanol (93% yield), alternative solvents such as methanol (Table 1, entry 13), N,N-dimethylformamide (Table 1, entry 14), acetonitrile (Table 1, entry 15), tetrahydrofuran (Table 1, entry 16), 1,4-dioxane (Table 1, entry 17) and water (Table 1, entry 18) were examined, without affording additional improvements. Finally, the use of substoichiometric amounts of base was examined (Table 1, entries 19–21), 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, entry 22). All reactions included in 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.

Table 1.

Optimization of the synthesis of compound 3e^a.

Entry	Base (1 equiv)	Solvent	Time, min	Yield, %b
1	–	EtOH	60	0b,c
2	TEA	EtOH	180	62b
3	TEA	EtOH	25	88
4	DABCO	EtOH	25	76
5	DBU	EtOH	25	64
6	pyridine	EtOH	30	0
7	DMAP	EtOH	25	44
8	piperidine	EtOH	30	0
9	L-proline	EtOH	30	0
10	K2CO3	EtOH	25	93
11	Na2CO3	EtOH	25	83
12	Cs2CO3	EtOH	25	90
13	K2CO3	MeOH	25	88
14	K2CO3	DMF	25	86
15	K2CO3	CH3CN	30	53
16	K2CO3	THF	30	trace
17	K2CO3	1,4-dioxane	30	22
18	K2CO3	water	30	48
19	K2CO3d	EtOH	25	94
20	K2CO3e	EtOH	25	93
21	K2CO3f	EtOH	25	94
22	K2CO3g	EtOH	30	88

^aAll reactions were performed with a mixture of 1e (1 mmol) and 2 (0.5 mmol). ^bIsolated yield after washing with cold ethanol. ^cReaction performed at room temperature. ^d75 mol %. ^e50 mol %. ^f25 mol %. ^g20 mol %.

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, Scheme 3 and 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 m- and 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 electron-releasing 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 uneventfully. We also investigated the reactions of α-nitroketene N,S-alkylaminoacetals 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.

Synthesis of N-substituted 3-nitrothiophen-2-amines.

Table 2.

Scope of the 2-amino-3-nitrothiophene synthesis.

Compound	R	Time, min	Yield, %
3a	4-FC6H4	25	90
3b	4-ClC6H4	25	92
3c	4-BrC6H4	25	91
3d	4-IC6H4	25	93
3e	C6H5	24	94
3f	4-MeC6H4	23	94
3g	4-EtC6H4	23	95
3h	4-iPrC6H4	22	93
3i	4-MeOC6H4	20	96
3j	2-MeC6H4	22	93
3k	2-MeOC6H4	25	91
3l	3-FC6H4	24	94
3m	3-BrC6H4	24	90
3n	3-F3CC6H4	25	89
3o	3-MeC6H4	24	94
3p	3-MeOC6H4	22	95
3q	2,4-Me2C6H3	23	82
3r	1-naphthyl	25	91
3s	Me	205	93
3t	n-Pr	190	95
3u	n-Bu	190	98
3v	iPr	205	93
3w	cyclopropyl	190	94
3x	cyclohexyl	190	95
3y	Bn	180	92
3z	(R)-α-MeBn	180	96

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).

Figure 2.

X-ray diffraction study of compound 3p.

The transformation leading to compounds 3 presumably proceeds through the initial formation of 2-mercaptoacetaldehyde (4) from the base-promoted decomposition of 1,4-dithiane-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_NAr reaction with the amine and having the serious limitation of requiring the presence of an additional strong electron-withdrawing group at C-5 [42–44]. 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

File 1

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