Regio- and stereoselective synthesis of ensulfonamides/enamides via catalyst-free intermolecular addition of indoles/pyrroles/imidazole to allenamides

Abstract

A catalyst-free intermolecular addition of indoles, pyrroles, and imidazole to allenamides is reported. The reaction proceeds smoothly at 80 °C and provides a series of (E)-ensulfonamide derivatives in high yields with excellent regioselectivity. Two enamides 3k and 3l can also obtained when using acyl in place of tosyl as an amino-protecting group of allenamides.

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Sulfonamide functional groups have long been acclaimed as important structural motifs in drug discovery since the identification of a series of sulfonamide-containing drugs, such as sulfamethoxazole as an antibacterial agent, azosemide as a diuretic agent, sumatriptan as an antimigraine agent, and celecoxib as a COX-2 specific anti-inflammatory agent.¹ The introduction of a sulfonamide group is often a useful practice in medicinal chemistry for improving pharmacological potency and/or the absorption, distribution, metabolism, and excretion (ADME) properties of the lead compound. Moreover, they are also important protected intermediates of primary and secondary amines with interesting biological activities.² On the other hand, as the derivatives of sulfonamides, ensulfonamides are versatile building blocks that can be utilized in the heterocycle construction, asymmetric hydrogenation, and synthesis of bioactive molecules.³ Consequently, the interest in ensulfonamides has been long standing and the effective synthesis of these motifs, especially the stereocontrolled version, is still in urgent need. So far, ensulfonamides can be assembled by palladium(II)-catalyzed vinyl transfer from vinyl ethers to sulfonamides,⁴ Pd-catalyzed “Wacker-type” oxidative amidation of alkene,⁵ the functionalization of ynamides⁶ and rhodium(II)-mediated transformations of N-sulfonyl-1,2,3-triazoles.⁷ The functionalization of allenamides,⁸ which contain the desired sp² carbon attached directly to the amide, stands out as an attractive alternative protocol for accessing ensulfonamides. Usually, the “electron-rich” π systems of allenamides are susceptible to electrophilic activation by transition metal⁹ or Brønsted acid¹⁰ providing zwitterionic intermediate, which can smoothly undergo condensation with a variety of nucleophilic agents. In contrast, they are robust to nucleophilic attack at the allene terminal carbons without catalyst. Yoshinao Tamaru and coworkers reported the first example that indole and methylindole served as a C-nucleophile proceeds nucleophilic addition at the allene terminal carbons of N-tosyl-4-vinylidene-2-oxazolidinone I at 80 °C under neutral conditions, but they provided a mixture of (E)-II and (E)-III in comparable amounts because of an intramolecular migration of the sulfonyl group from N to C2′ (Fig. 1).¹¹

Fig. 1 Intermolecular addition of indoles to N-tosyl-4-vinylidene-2-oxazolidinone.

Our group have recently reported the gold catalyzed intermolecular [2 + 2] and [3 + 2] cycloaddition reaction of allenamides with olefins, azomethine imines and nitrones to provide multifunctional cyclobutanes, bipyrazolidin-1-one adducts and 4-methyleneisoxazolidine derivatives.¹² In continuation of our program geared towards the functionalization of allenamides,¹³ we describe here a catalyst-free intermolecular addition of indoles, pyrroles, and imidazole to allenamides, providing (E)-ensulfonamides/enamides in high yields with excellent regioselectivity.

Our initial studies focused on the reaction of tosyl N-allenamide (1a) with N-methylindole (2a) for the optimization of reaction conditions (Table 1). Gratifyingly, the reaction outcome generally shows a regiochemical preference for the nucleophilic C3 attack by indole on the C3′ position of the allenamide providing (E)-ensulfonamide 3a as the only isomer in 54% yield together with minor amounts of C2-addition products of indole (>20 : 1 ratio) at 120 °C in toluene after 25 h. Encouraged by these results, three other solvents, CHCl₃, CH₃CN, DCE were subsequently examined, and DCE showed the best reaction medium in terms of the yield (Table 1, entries 2–4). Variation of the number of equivalents of 2a from 3.0 to 2.0 lowed the conversion of 3a to 76% (Table 1, entry 5). The dramatically regio- and stereoselectivity was due to several reasons: firstly, the thermodynamic stability of the product. Secondly, C3 position of indole shows stronger nucleophilicity. Lastly, C2′ of the allenamide was to be nucleophilic centre because the electronic bias can be exerted through delocalization of the nitrogen lone pair of allenamide toward the allenic moiety. The structure and stereochemical identity of this adduct could be determined by the spectral analysis (J_HC=CH > 12 Hz). Moreover, the structure of 3a can be corroborated through 3k (Table 2), which is consistent with literature.¹⁴

Table 1 Screening of the optimal conditions^a,b

Entry	Solvent	Temp (°C)	Time (h)	Isolated yield (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol) and solvent (anhydrous; 3 mL).b Only one isomer was observed by NMR (see S3–S5).c 1a (0.1 mmol), 2a (0.2 mmol).
1	Toluene	120	25	54
2	CHCl3	80	17	89
3	CH3CN	80	24	69
4	DCE	80	5	92
5^c	DCE	80	9	76

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Table 2 Variation of the allenamides 1^a,b

Entry	Allenamide, 1	Product, 3	Yield^c (%)
a Reagents and conditions: 1 (0.1 mmol), 2a (0.3 mmol) and DCE (anhydrous; 3 mL) at 80 °C.b In all cases, only one isomer was observed by NMR (see S5–S11).c Isolated yield.
1
2	1a, R = H	3a	92
3	1b, R = F	3b	95
4	1c, R = MeO	3c	72
5
6	1d, R = H	3d	77
7	1e, R = Me	3e	82
8	1f, R = F	3f	92
9	1g, R = Br	3g	90
10			62
11			96
12			93
13			80
14			50

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With the optimized reaction conditions in hand, we turned our attention to the scope of the intermolecular addition with respect to allenamides 1 and indoles 2 (Tables 2 and 3). As shown in Table 2, we were pleased to find that a series of allenamides with different substitution patterns worked very well in this reaction. 4-F- or 4-MeO-substituted benzyl allenamides were suitable for accessing ensulfonamides 3b and 3c in 95% and 72% yield in the presence of N-methylindole 2a. Phenyl allenamide 1d provided the desired ensulfonamide 3d in 77% yield. Subsequently, the substitution effect on the aryl ring of aryl allenamide was examined. While allenamides 1e, 1f and 1g bearing a 4-Me, 4-F or 4-Br group delivered 3e, 3f and 3g in high yields, 3,5-dimethoxy substituted aryl allenamide 1h gave the corresponding product 3h in moderate yield. When n-butyl allenamide 1i and phenylethyl allenamide 1j was utilized as the reactant, the addition products 3i and 3j were obtained in 96% and 93% yield, respectively. The reaction is also efficient with allenamides using acyl in place of tosyl as an amino-protecting group. Thus, 2-oxazolidinone allenamide 1k and 1l with an acyl substituent provided the corresponding adducts 3k and 3l in 80% yield and 50% yield respectively.

Table 3 Variation of the indoles 2^a,b

Entry	Indole, 2	Product, 4	Yield^c (%)
a Reagents and conditions: 1a (0.1 mmol), 2 (0.3 mmol) and DCE (anhydrous; 3 mL) at 80 °C.b The ratio was determined by NMR (see S11–S13).c Isolated yield of the major product.d 1a (0.3 mmol)/2 (0.1 mmol).
1
2	2b, R^2 = H	4b (C3/C2 = 20/1)	97
3	2c, R^2 = 5-OMe	4c (C3/C2 = 17/1)	90
4	2d, R^2 = 5-F	4d (C3/C2 = 16/1)	95
5^d	2e, R^2 = 5-Br	4e (C3/C2 = 19/1)	61
6	2f, R^2 = 4-Me	4f (C3/C2 = 5/1)	75
7	2g, R^2 = 7-Me	4g (C3/C2 = 7/1)	70
8			75
9			70
10			71
11			82
12			80
13			81

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We next set out to explore the scope of indoles 2 in the presence of allenamide 1a (Table 3). The optimal conditions were found to be applicable to a wide range of indole derivants 2b–m and several substituents, such as Me, MeO, F, Br and benzyl on the indole ring were tolerated well. Indole 2b, 5-MeO or 5-F-substituted indole derivatives 2c–d were successfully converted into 4b–c in high yield which suggests that the electronic effect of substituents on the aromatic ring of indole does not affect the intermolecular addition of allenamides. But 5-bromoindole 2e gave the corresponding products 4e in moderate yield only when increasing the amount of 1a to 3 equivalent. 4-Methylindole and 7-methylindole provided the C3-addition products in good yield together with minor amounts of C2-adducts which were unseparated.¹⁵ Indoles bearing a 2-Me or N-benzyl were also viable to furnish 4h and 4j in 75% yield and 71% yield. Notably, 3-methylindole 2i could also provide the adduct 4i at the C2-position of indole in 70% yield due to the migration of the allyl group from C3 to C2 of indole. Interestingly, the catalyst-free intermolecular addition protocol was extended to pyrrole leading to C2-addition product 4k as the major isomer in 82% yield,¹⁵ while N-methylpyrrole provided C2-addition product 4l in 80% yield together with isolated C3-adduct in 15% yield.¹⁶ The regiochemical preference for the C2-position due to the more resonant type of the intermediate. Remarkably, imidazole is also an efficient nucleophile, which provided the C4-adduct 4m as the only isomer. As expected, the use of indole, pyrroles, and imidazole as nucleophile provided the desired (E)-ensulfonamides in good yield and high regioselectivity.

According to the report of Yoshinao Tamaru,¹¹ we gave a plausible mechanism for this transformation in Scheme 1. The π*(C2′=C3′)–δ*(N–SO₂) interaction makes the LUMO (C2′=C3′) low in energy and the double bond an excellent electron acceptor. Thus the nucleophilic addition of indoles providing (E)-3, in a sense, might be regarded as electrophilic aromatic substitution of 1; that is, despite the fact that 1 is a neutral species, it is even capable of undergoing the Friedel–Crafts type electrophilic aromatic substitution in the absence of any Lewis acid catalysts. Electrophilic addition of 1 to indoles and aromatization by deprotonation would provide (E)-3.

Scheme 1 Plausible mechanism.

Conclusions

In conclusion, we have developed a catalyst-free intermolecular addition of indole, pyrroles, and imidazole toward the distal double bond of allenamides. The reaction proceeds smoothly at 80 °C and provides a series of (E)-ensulfonamide/enamide derivatives in high yields with excellent regioselectivity. Further study of allenamides is currently ongoing in our laboratory.

Acknowledgements

Financial support by the Fundamental Research Funds of Central Universities, Southwest University for Nationalities (2015NZYQN19) are gratefully acknowledged.

Notes and references

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15. The ratio of C3/C2 was determined by NMR, see the ESI†.
16. The NMR spectra of C3-addition product of N-methylpyrrole, see the ESI†.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra10569b

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