Metal-Free Three-Component Domino Approach to Phosphonylated

Letter pubs.acs.org/OrgLett

Metal-Free Three-Component Domino Approach to Phosphonylated Triazolines and Triazoles Shakir Ahamad,†,‡ Ruchir Kant,§ and Kishor Mohanan*,†,‡ †

Medicinal & Process Chemistry Division and §Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, P.O. Box 173, Lucknow 226031, India ‡ Academy of Scientific and Innovative Research, New Delhi 110001, India S Supporting Information *

ABSTRACT: An efficient, three-component domino reaction between aldehydes, amines, and the Bestmann−Ohira reagent is reported that enables a general, mild, and straightforward access to 1,4,5-trisubstituted 1,2,3-triazolines and triazoles. The reaction proceeds through a domino-condensation/1,3-dipolar cycloaddition sequence to afford the triazoline derivatives with excellent diastereoselectivity. Moreover, when both amine and aldehyde employed for this reaction are aromatic, a spontaneous oxidation afforded 1,4,5-trisubstituted triazoles in moderate yields.

1,4,5-Trisubstituted triazolines are an important class of heterocycle which in addition to their exceptional biological profiles1 serve as versatile precursors to important compounds such as aziridines,2 triazoles,3 and β-amino alcohols (Figure 1).4

However, this approach is effective only for the activated olefins, limiting the applications of this method to a few useful examples. An alternative process that relies on the cycloaddition reactions of various diazo compounds with preformed Schiff bases is also in use to achieve the synthesis of triazolines.6 Despite the fact that these reactions are well-established, most such reactions exhibit a narrow substrate scope and require elevated temperature or catalysts, preventing the use of these methods in chemical biology. In this respect, novel protocols for the mild, efficient, cost-effective, and stereoselective synthesis of triazolines are highly desirable. The ready availability, mild reaction conditions, and high functional group tolerance make dimethyl α-diazo-β-oxopropylphosphonate (Bestmann−Ohira reagent, BOR) a frequently used reagent for the synthesis of homologated alkynes from aldehydes bearing fragile functional groups.7 Later, notable reports by Namboothiri and Smietana, as well as recent advances, have shown that the dimethyl (diazomethyl)phosphonate anion (DAMP) generated in situ from BOR could be employed as a versatile 1,3-dipole for the synthesis of phosphonylpyrazoles.8−10 However, to the best of our knowledge, the application of BOR in the synthesis of heterocyclic compounds remains limited to the synthesis of phosphonylpyrazoles. The relevance of triazolines and triazoles as key structural constituents of numerous biologically active compounds inspired us to investigate further the utility of BOR in devising novel protocols for accessing this particular class of compound (Figure 1). We speculated that if an in situ generated Schiff base was treated with BOR, it would undergo a dipolar cycloaddition reaction to generate the triazoline molecule. For this strategy to be successful, Schiff base formation and the subsequent cyclization would have to be

Figure 1. Selected examples for bioactive triazoline and triazole derivatives.

The most direct and common method for the synthesis of substituted triazolines is through the 1,3-dipolar cycloaddition reaction of azides with activated olefins (Figure 2, eq 1).5

Received: December 3, 2015

Figure 2. Synthesis of 1,4,5-trisubstituted triazolines. © XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.5b03437 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters faster than the undesired aldehyde homologation by in situ generated DAMP anion from BOR. Our hypothesis was successfully realized herein, demonstrating for the first time that BOR can be employed in a domino multicomponent reaction involving aldehydes and amines for the diastereoselective synthesis of 1,4,5-trisubstituted 1,2,3-triazolines (Figure 2, eq 2). Of note, this reaction proceeds through trans-selective cyclization with respect to 5-aryl/alkyl substitution and phosphonate. Notably, the phosphonyltriazolines are stable and the conversion to aziridines through denitrogenation has not been observed under the present reaction conditions. Furthermore, an attempt to expand the scope of the reaction revealed that phosphonyltriazoles could be synthesized if arylamines are employed in the reaction instead of aliphatic ones. Our hypothesis was initially tested by performing a reaction between benzaldehyde 1a, n-propylamine 3a, and BOR 2 in the presence of potassium carbonate in methanol, and pleasingly, the reaction afforded 4-phosphonyltriazoline 4a in 80% yield with excellent diastereoselectivity. Upon further optimization of the reaction conditions, the diastereoselective formation of 1,2,3triazolines was achieved without the aid of a base and desiccant with the same yield, and these optimized conditions were selected for further studies (Scheme 1).

Scheme 2. Substrate Scope for the Multicomponent Reaction: Variation of Aldehydesa

Scheme 1. Synthesis of 1,2,3-Triazolines

Having identified the conditions for the synthesis of triazolines, we next examined the scope of this facile threecomponent reaction. n-Propylamine 3a was selected as the amine participant to validate the scope of the aldehyde moiety (Scheme 2). Interestingly, electron-neutral and electron-releasing substituents at the 4-position of the aromatic aldehyde were found to be equally efficient and did not influence the efficiency of the present domino reaction (4b−d), while electron-withdrawing substituents such as nitro- and trifluoromethyl groups failed to deliver the product. Importantly, a boronic acid moiety was demonstrated to be compatible with the reaction, and triazoline 4d was obtained in 77% yield. Subsequently, various aldehydes having electronically different substituents at different positions were reacted with propylamine in the presence of BOR and proven to be effective (4e−g). A variety of hydroxyaryl aldehydes were tolerated and provided the triazolines in good yields (4h− j). The reaction attempted with ferrocenecarboxaldehyde also worked well (4k). When aryl aldehydes were replaced by heteroaryl and aliphatic aldehydes, the reaction proceeded smoothly leading to the formation of the corresponding triazolines, albeit in moderate yields (4l−q). For instance, cinnamaldehyde underwent facile reaction with tert-butylamine to afford the product 4q in 67% yield, and the structure of 4q was confirmed by X-ray diffraction analysis.11 Notably, the reaction carried out using terephthalaldehyde afforded the anticipated bistriazoline 4s in 78% yield. Scheme 3 illustrates the scope of the amine component in the reaction. The reaction was found to be high yielding in most cases where linear aliphatic amines were used (4t−w). Besides linear amines, tert-butyl- and allylamines afforded the triazoline derivatives in good yields (4x,y). The reaction proceeded well

a

Yields given are isolated after SiO2 column chromatographic purification. b2.5 equiv of 3a was used. cWith 4.0 equiv of each 2 and 3a.

with isopropyl and benzylamine yielding the triazoline derivatives in moderate yields (4z,aa). Phenethyl-, cyclohexyl-, and adamantylamines were also suitable partners for the reaction, affording the products in good yields (4ab−ad). Interestingly, the reaction was feasible with amines bearing additional functional groups, and the reaction was tolerant of functional groups such as hydroxyl and disubstituted amines. The reaction was also explored using various substituted aliphatic amines such as diethylaminoethylamine and morpholinopropylamine (4af,ag). The broad substrate scope exhibited by the reaction prompted us to explore the possibility of using aromatic amines, and surprisingly, the reaction involving aniline, benzaldehyde, and BOR led to the formation of phosphonyltriazole (Figure 2, eq 2). Presumably, the initially formed triazoline derivative undergoes a spontaneous air oxidation to afford triazoles, constituting an efficient, single-step protocol for synthesizing densely functionalized triazoles from readily available starting materials. This multicomponent strategy provides an efficient alternative to the metal- and organocatalyzed cycloaddition reactions for the synthesis of substituted triazoles.12,13 In view of the extensive applications of 1,4,5-trisubstituted 1,2,3-triazoles in the pharmaceutical industry as HIV protease inhibitors, anticancer drugs, antituberculosis drugs, antifungal agents, anticancer drugs, and antibacterial drugs, this metal-free synthesis of triazole was further investigated for better reaction conditions.14 Further B

DOI: 10.1021/acs.orglett.5b03437 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Substrate Scope for the Multicomponent Reaction: Variation of Aminesa

Scheme 4. Substrate Scope for the Multicomponent Reaction: Synthesis of Triazolesa

a Yields given are of isolated products after SiO2 column chromatographic purification.

Scheme 5. Proposed Mechanistic Pathway a

Yields given are of isolated products after SiO2 column chromatographic purification. b2.0 equiv of K2CO3 was used.

development of the reaction revealed the need for a mild organic/inorganic base in a stoichiometric amount to deliver the triazole derivative in a reasonable yield. This observation may be attributed to the lower basicity of aromatic amines in comparison to aliphatic amines, and a brief screening of various bases showed that K2CO3 provided the product 6a in 45% yield. Subsequent to the optimization of the reaction conditions, we next explored the generality of this unique strategy for triazole synthesis (Scheme 4). The reaction proceeded well with a series of anilines bearing diverse substitutions at the 4-position of the arene ring, and the corresponding triazole derivatives were isolated in modest yields (6a−e). Notably, the reaction worked well with 3- and 3,4-disubstituted anilines to generate the corresponding triazoles in good yields (6f−h). Next, aldehyde scope was examined for the reaction using 4-iodoaniline as the amine substrate, and electronically different substituents have barely shown any influence on the outcome of the reaction. For instance, substrates with electron-rich and electron-withdrawing substitutions at the 4-position of the aryl ring furnished the synthetically useful iodoaryltriazoles in reasonable yield (6i−l). Remarkably, the reaction attempted with furfural was effective, and the product was obtained in 43% yield (6m). The reactions attempted with aliphatic aldehydes were unsuccessful. In accordance with the previous reports on the synthesis of phosphonylpyrazoles, a mechanistic rationale for this dominomulticomponent synthesis of triazolines and triazoles is proposed as shown in Scheme 5. The reaction is likely to be initiated by in situ generation of Schiff base I. Next, dimethyl diazomethylphosphonate (DAMP) anion generated in situ from BOR undergoes nucleophilic addition to the intermediate I. The resulting intermediate II would subsequently undergo a 5-endodig cyclization to afford the product 4. When amine and aldehyde

moieties are aromatic, product 4 further undergoes a spontaneous air-assisted oxidative aromatization to provide triazole derivatives 6. In summary, a metal-free, efficient, facile, and simple threecomponent synthesis of 1,4,5-trisubstituted triazolines and triazoles has been developed. The reaction proceeds under mild conditions (room temperature and no catalyst/base) and employs inexpensive and readily available aldehydes, amines, and BOR, making this strategy a versatile and unique method for accessing a novel class of phosphonylated triazolines and triazoles with consistently high efficiency in the former case. Given the relevance of these heterocyclic scaffolds in the agrochemical and pharmaceutical industries, we anticipate that this new method for the synthesis of phosphonyltriazoles will find potential applicability. C

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Organic Letters

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b03437. X-ray data for 4q (CIF) Detailed experimental procedures, complete characterization data, and copies of NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from CSIR-CDRI and UGC-New Delhi (Junior Research Fellowship to S.A.) is gratefully acknowledged. We thank Dr. Tejender S. Thakur, MSB division, CSIR-CDRI, for supervising the X-ray data collection and structure determination. We thank the SAIF division for analytical support. CDRI Communication No. 9157.

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DEDICATION Dedicated with best regards to Dr. Vijay Nair on the occasion of his 75th birthday. REFERENCES

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DOI: 10.1021/acs.orglett.5b03437 Org. Lett. XXXX, XXX, XXX−XXX