KOtBu-Promoted Transition-Metal-Free Transamidation of Primary and

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KOtBu-Promoted Transition-Metal-Free Transamidation of Primary and Tertiary Amides with Amines Tridev Ghosh, Snehasish Jana, and Jyotirmayee Dash* School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A and 2B Raja S. C. Mullick Road, Jadavpur, Kolkata-700032, India

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S Supporting Information *

ABSTRACT: This work discloses transamidation of primary and tertiary amides with a range of aryl, heteroaryl, and aliphatic amines using potassium tert-butoxide. The reaction proceeds at room temperature under transition-metal-free conditions providing secondary amides in high yields. Moreover, reaction of cyclopropyl amine with tertiary amides proceeds with ringopening to provide a rapid access to enamides.

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catalysts work mostly in organic solvents and only limited examples of transamidation are reported under solvent-free conditions. Therefore, development of an operationally simple, straightforward, and high-yielding transition-metal-free green and sustainable synthetic method for transamidation has remained a challenging task over the past two decades. In view of the above perceptions, organocatalyzed transamidations have been described as alternative green methodologies (Scheme 1). In this context, L-proline14 was envisioned as a useful alternative. Subsequently, various groups reported

mide groups are ubiquitously found in many drugs (Figure 1), fine chemicals, and synthetic and biological

Scheme 1. Synthetic Approaches for Transamidation Figure 1. Amide frameworks in bioactive substances.

polymers.1 Amides also serve as potential synthetic precursors for the preparation of natural products,2 pharmaceuticals,3 pesticides,4 and polymers.5 Amides are conventionally prepared by cross-coupling of aromatic or aliphatic amines with activated carboxylic acids.6 Subsequently, nontraditional methods to synthesize amide bonds have been developed. Most of these processes require a stoichiometric amount of the reagents, high temperature to avoid unreactive carboxylateammonium salts formation, and, moreover, substrate engineering of C(acyl)−O or C(acyl)−N bonds. In the past few years, the transamidation has emerged as a convenient, economical, and straightforward alternative for the amide bond formation.7 Transamidation has been reported using metal catalysts8 such as AlCl3, Sc(OTf)3, Ti(NMe2)4,9 polymer-bound HfCl4,10 etc. Lanthanide catalysts (Ce,11 Zr,12 Nb13) have also been reported to promote transamidation. Metal-catalyzed reactions are cost-ineffective, and they produce toxic metal wastes that should be avoided for pharmaceutical processes as well as for environmental safety. In addition, these © XXXX American Chemical Society

Received: July 4, 2019

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DOI: 10.1021/acs.orglett.9b02306 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters the use of ammonium salts,15 N,N-dialkyl formamide dimethyl acetals,16 boric acid derivatives,17 chitosan,18 an imidazole derivatives,19 hypervalent iodine,20 and NEt321 as well as microwave irradiation processes22 for transamidation. Recently, the Szostak group reported LiHMDS23 promoted chemoselective transamidation of amides by N−C(acyl) cleavage at room temperature. In most reactions, DMF and DMAC have been used as amide electrophiles.24 Although these metal-free protocols offer several advantages, these protocols use a stoichiometric or substoichiometric amount catalysts. Furthermore, the metal-free methods are restricted to the reaction of active primary amides with aliphatic amines. Therefore, it is a worthy goal to develop a facile approach for the transamidation of amides with weakly nucleophilic aromatic amines under catalyst-free as well as solvent-free conditions. With these key points in mind, herein we demonstrate the remarkable efficiency of potassium tertbutoxide in promoting transamidation of amides with different amines to provide a diverse range of carboxamides in the absence of solvent. We initially studied the formylation of p-anisidine 1a with dimethyl formamide (DMF) 2a as the formyl source. In order to optimize the reaction conditions, a series of experiments were performed by varying reaction time, temperature, and base. In the absence of any base, a very high temperature and prolonged reaction time were required for the formylation of 1a, providing a poor yield of the transamidation product 3a.25 Subsequently, various commercially available bases such as KOH, K2CO3, Cs2CO3, KOtBu, DBU, and NaOH (Table 1,

15). In the next set of experiments, we optimized the amount of base required for the transformation (Table 1, entries 12− 15). It was observed that the yield of 3a was decreased by decreasing the amount of KOtBu from 200 mol % to 100 mol % (Table 1, entry 12). However, when the amount of base was increased from 200 mol % to 300 mol %, no significant impact on the yield was observed (Table 1, entry 13). Gratifyingly, when the reaction was conducted with 150% KOtBu at room temperature, the product 3a was obtained in 97% yield within 2 h (Table 1, entry 15). Further, when the transamidation was carried out with 1−4 equiv of DMF as the formylating reagent using toluene and THF as the solvents, the amide 3a was obtained in good yield (Table S1, Supporting Information). We then explored the generality of the transamidation using the optimal reaction conditions (Table 1, entry 15). As listed in Scheme 2, the KOtBu mediated transamidation of DMF with a variety of amines produced the expected products in moderate to excellent yields. Anilines containing electrondonating groups (Me, Et, OMe) in the aryl ring reacted to provide the corresponding transamidation products 3a−d in excellent yields (Scheme 2). Aryl amines with electronScheme 2. Scope of the Transamidation of Dimethyl formamide with Amines

Table 1. Optimization of Reaction Conditionsa

entry

base (%mol)

solvent

temp

time (h)

yield (%)

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

KOH (100) K2CO3 (100) Cs2CO3(100) KOtBu (100) NaOH (100) DBU (100) KOtBu (100) KOtBu (100) KOtBu (100) KOtBu (100) KOtBu (100) KOtBu (100) KOtBu (300) KOtBu (200) KOtBu (150)

DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF

rt rt rt rt rt rt rt 80 rt rt rt rt rt rt rt

12 12 12 12 12 12 12 12 8 4 2 2 2 2 2

NR NR NR 85 NR NR 85 85 85 80 75 75 95 95 97

a

Conditions: aniline 2 (0.5 mmol), DMF (10 mmol), KOtBu (0.75 mmol) rt, 2 h. Isolated yields were reported.

entries 1−6) were tested. Among the bases, KOtBu was found to be efficient in promoting the formylation of 1a to afford the product 3a in 85% yield at room temperature for 12 h (Table 1, entry 4). By increasing the reaction temperature (80 °C), no appreciable improvement in the yield of 3a was achieved (Table 1, entry 8). We were delighted to find that the desired product was obtained in 97% yield at room temperature by decreasing the reaction time from 12 to 2 h (Table 1, entry B

DOI: 10.1021/acs.orglett.9b02306 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters withdrawing substituents (Br, F, CN, CF3 etc.) required a relatively longer reaction time (4−6 h) to provide the corresponding transamidation products in high yields (Scheme 2). These results suggest that no significant electronic effect of substituents on reactivity was observed. However, no reaction took place with 2,6-dimethyl aniline, which may be attributed to the steric hindrance at the ortho-positions. The p-nitro aniline was also less reactive under the optimized conditions, providing the product 3t in moderate yield (>50%). Transamidation with 1,2-diammino benzenes provided bis-formylated products (3u and 3v) in good yields. The reaction with oamino phenols afforded the corresponding products in good yields (3f−g). Heteroaromatic amines were efficiently transformed to the corresponding amides (3w−x) in high yields. The reaction was successful with primary amines, providing the corresponding products (3y−z) in good yields. To further ascertain the scope, we examined the reactivity of acetamide 2b with a diverse range of amines (Scheme 3). The

Scheme 4. Transamidation with Cyclopropyl Amine

Scheme 5. Transamidation of Amides with Amines

Scheme 3. Scope of the Transamidation of Acetamide with Amines as the carbonyl source, no product formation was observed (7c, 85%). However, by using benzamide

by using galvainoxyl (2 equiv) as a radical scavenger. These experiments reveal the formation of radical intermediates in the transamidation process.27 Electron paramagnetic resonance (EPR) studies of the reaction mixture containing p-anisidine (1 mmol) and KOtBu (1.5 mmol) in DMF (0.8 mL) after stirring for 1 h showed the formation of strong hyperfine EPR signals for the amine radical (Figure S1, Supporting Information (SI)). This indicates that the reaction proceeds via electron-transfer processes. These observations suggest that a radical pathway is involved for the transamidation (Scheme 7). A Lewis basic amine can coordinate with the potassium cation to form complex A, which instantaneously forms anion B by proton abstraction. Subsequently, a single electron transfer (SET) from B provides the amine radical C,28 which undergoes another SET with the C

DOI: 10.1021/acs.orglett.9b02306 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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Scheme 7. Proposed Mechanism for the N-Formylation of Amines

corresponding amide D to form the radical anion 29 intermediate E. ESI-MS studies of the KOtBu mediated transamidation of DMF with p-anisidine in the presence of TEMPO and galvinoxyl further indicated the formation of the corresponding radical intermediate C (Figure S2, SI). The amine radical C then couples with the intermediate E to generate F, which provides the corresponding N-formylated products. In summary, we have developed an experimentally simple and novel KOtBu mediated transamidation of amides with different amine partners to obtain diverse carboxamides in good to excellent yields. The method is compatible with a range of amines containing various functional groups. The utility of the protocol is further demonstrated by the synthesis of enamides via ring opening of cycloproylamine. Thus, this catalyst-free, metal-free, inexpensive, and easily scalable protocol for amide synthesis would be useful for the synthesis of pharmaceuticals and bioactive molecules.

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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.9b02306. Experimental procedures, 1H NMR and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jyotirmayee Dash: 0000-0003-4130-2841 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Professor Hiriyakkanavar Ila on the occasion of her 75th birthday. J.D. thanks DST-India for a SwarnaJayanti fellowship (DST/SJF/CSA-01/2015-16). This work was supported by DST and CSIR-India for funding. T.G. and S.J. thank CSIR, India for a research fellowship.

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REFERENCES

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DOI: 10.1021/acs.orglett.9b02306 Org. Lett. XXXX, XXX, XXX−XXX