A highly expedient protocol for a catalytic Appel-type dehydration of amides to nitriles has been developed that employs oxalyl chloride and triethylamine along with triphenylphosphine oxide as a catalyst. The reactions are usually complete in less than 10 min with only a 1 mol % catalyst loading. The reaction scope includes aromatic, heteroaromatic, and aliphatic amides, including derivatives of α-hydroxy and α-amino acids

Aleksandr E. Rubtsov (3600614)

Andrei Malkov (1248999)

Elena I. Denisova (4753035)

Sergei A. Shipilovskikh (4623688)

Vladimir Yu Vaganov (7163633)

English

Loughborough University Institutional Repository

Dehydration of Amides to Nitriles under Conditions of a Catalytic Appel Reaction Sergei A. Shipilovskikh,† Vladimir Yu. Vaganov,† Elena I. Denisova,† Aleksandr E. Rubtsov,*† Andrei V. Malkov*‡§ † Department of Chemistry Perm State University, Bukireva 15, Perm 614990, Russia  ‡ Department of Chemistry, Loughborough University, Loughborough, Leics LE11 3TU, UK § Department of Organic Chemistry, RUDN University, 6 Miklukho-Maklaya Street, Moscow 117198, Russia Supporting Information Placeholder    ABSTRACT: A highly expedient protocol for a catalytic Appel-type dehydration of amides to nitriles has been developed, which employs oxalyl chloride, triethylamine and triphenylphosphine oxide as a catalyst. The reactions are usually complete in less than 10 min with only 1 mol % of catalysts loading. The reaction scope includes aromatic, heteroaromatic and aliphatic amides, includ-ing derivatives of α-hydroxy and α-amino acids. Chemical compounds with the nitrile functional group serve as useful precursors in the manufacture of a large variety of con-sumer products, such as polyamides, pigments and dyes, phar-maceuticals, agrochemicals and many other substances.1 The nitrile group has a rich chemistry, since it can be conveniently converted to other functional groups.2 Also, the nitrile pharma-cophore plays a significant role in modulating the biological ac-tivity of synthetic medicinal drugs3 and natural products.4     The synthesis of nitriles by the dehydration of primary am-ides is a well-known process; numerous methods have been de-veloped and used by practicing chemists for over a century.5  In the last few years, a number of new methods have emerged for carrying out an efficient dehydration of amides to nitriles. Among the new reagents, [Et2NSF2]BF4 (XtalFluor-E)6 and sil-icotungstate [n-Bu4N]4[α-H4SiW11O39]7 were introduced. Also, metal catalyzed dehydration has been carried out in the presence of silanes,8 N-methyl-N-(trimethylsilyl)trifluoroacetamide9 and acetonitrile.10  However, in many instances the practicality of the methods is offset by the toxicity of the reagents, slow reaction times, nar-row scope and the laborious workup needed to remove the side products. Therefore, the development of convenient, practical methods for converting amides to nitriles still holds its rele-vance.  The Appel11 reaction, which employs a combination of Ph3P, CCl4 and Et3N, belongs to a group of highly versatile tools that, among other useful transformation,12 can be used for the syn-thesis of nitriles from amides (Scheme 1, A).   Scheme 1. Dehydration of amides to nitriles by Appel reac-tion.  However, the original Appel protocol has a number of weak-nesses. First of all, exposure to CCl4 can lead to kidney damage, it is also a suspected carcinogen. Furthermore, it contributes to depletion of the ozone layer and can no longer be used.13 Sec-ondly, stoichiometric use of Ph3P results in the formation of large quantities of Ph3PO, which complicates the isolation and purification of the target products. Therefore, the development of a catalytic version of the Appel dehydration of amides, where CCl4 as a source of chloride is replaced by a safer alternative, and the phosphorus reagent is used as an organic catalyst, while keeping the universal application scope of the original method, would make it significantly more attractive from the practical  standpoint. Our work was inspired by the recent reports of Den-ton14 and others,15 who have demonstrated that running some reactions under the Appel conditions can be efficient using cat-alytic Ph3PO in the presence of oxalyl chloride.  In this work, we present an adaptation of this protocol to a mild and facile conversion of amides to nitriles using as low as 1 mol % loading of Ph3PO (Scheme 1, B).  Table 1. Optimization of reaction conditions.a  entry (COCl)2 (equiv) Ph3PO (mol %) Et3N (equiv) solvent conv  (%)b 1 1 - - MeCN 0c 2 1 - 1 MeCN 0d 3 1 100 - MeCN 25 4 1 10 1 MeCN 14 5 1 10 2 MeCN 29 6 1 10 3 MeCN 45 7 2 10 3 MeCN 100 8 2 10 2 MeCN 75 9 2 5 3 MeCN 100 10 2 2 3 MeCN 100 11 2 1 3 MeCN 100 12 2 1 3 Et2O 87 13 2 1 3 CH2Cl2 85 14 2 1 3 toluene 77 15 2 1 3 dioxane 31 aGeneral conditions: benzamide 1a (0.25 mmol), Ph3PO, Et3N, dry MeCN (1ml), dropwise addition of neat (COCl)2. The reactions were carried out for 10 min at rt before an aliquot (50 µL) was taken, quenched with aqueous MeCN (1 mL) and analyzed by GC. bConversion to nitrile 2a was calculated from GC. cAfter 10 min, according to GC, the reaction mixture contained 1a (70%) and ben-zoyl isocyanate 3a (ca. 25%). dAfter 10 min, according to GC, the reaction mixture contained 1a (60%), benzoyl isocyanate 3a (ca. 21%) and some unidentified by-products. The investigation commenced with establishing the best con-ditions for the dehydration of amides which employ benzamide 1a as a model substrate (Table 1). First, the role of each reagent was evaluated. Thus, oxalyl chloride on its own did not produce benzonitrile 2a (entry 1). Instead, a slow formation of benzoyl isocyanate 3a was observed, mirroring published data.16 This reaction is likely to proceed through the initial O-acylation of 1a to give oxalyl imidate 4 followed by cyclization into unstable 2-phenyloxazolin-4,5-dione 5, which then forms benzoyl isocy-anate 3a (Scheme 2). Addition of triethylamine to the reaction mixture did not alter the reaction outcome (entry 2), which con-trasts with the previously reported formation of benzonitrile 2a when benzamide 1a was treated with oxalyl chloride in the pres-ence of 2.6-lutidine.16a  Scheme 2. Formation of benzoyl isocyanate 3a.  The use of stoichiometric quantities of Ph3PO and (COCl)2 without triethylamine resulted in a low conversion of 1a into 2a (entry 3). With 10 mol % of Ph3PO and 1 equiv each of oxalyl chloride and trimethylamine, benzonitrile 2a was formed in a 14% conversion (entry 4), which increased to 29% and 45% when triethylamine was used in two- and threefold excess, re-spectively (entries 5 and 6). Full conversion was achieved when the amount of (COCl)2 was doubled to 2 equiv (entry 7). Note that the reaction was complete in less than 10 min. A threefold excess of triethylamine appears to be crucial, as reducing it to 2 equiv slowed the reaction down (entry 8).  Next, the effect of the catalyst loading was investigated (en-tries 9-11). Pleasingly, Ph3PO performed efficiently even when the loading was as low as 1 mol % (entry 11). With benzamide 1a, the catalyst content could be further reduced, but for inves-tigating the reaction scope, 1 mol % proved to be most suitable. The influence of the solvent was briefly assessed (entries 12-15). Despite some good conversions achieved in Et2O and CH2Cl2 (entries 12, 13), MeCN remained the best choice. Other solvents, such as toluene and dioxane, proved inferior (entries 14, 15). Thus, the conditions in entry 11 were taken as optimal.  To investigate the reaction scope, the substrates were selected to represent diverse compound classes. The results are collected in Figure 1. On a standard 2 mmol scale, benzonitrile 2a was isolated in a 98% yield. The reaction worked equally well on a 1 g (8.3 mmol) scale giving 2a in a 92% yield. Aromatic amides 1b-1f mirrored the reactivity of the model benzamide 1a furnish-ing the respective nitriles 2b-2f in high yields. A set of hetero-cyclic amides 1g-1j were next assessed. 2-Cyanothiophene 2g, 3-cyanopyridine 2h and 2-cyanoquinoline 2i were accessed in high yields. In this series, it is worth highlighting the efficient synthesis of the 3-cyanotetrahydroisoquinoline derivative 2j from the corresponding amide 1j. This compound serves as a precursor to the respective axially chiral tetrahydroisoquinoline-N,N’-dioxide, which belongs to a group of highly competent Lewis base catalysts for asymmetric crotylation of carbonyl compounds that are currently under investigation in our labora-tories.17 Unsaturated cinnamamide 1k, aliphatic linear (1l, 1m) and branched (1n, 1o) amides were converted into the respective nitriles in good yields, though their reactivity was somewhat lower compared to the aromatic analogues. The same applied to the functionalized derivatives 1p-r, which included phenoxya-cetamide 1p and phthalimide protected amino acid amides 1q and 1r. It has to be noted that the corresponding t-Boc-protected amino acids did not give the desired nitrile. Instead, numerous side-products were formed, which most likely resulted from the reaction of the N-Boc group with oxalyl chloride, similar to the reaction shown in Scheme 2.    Figure 1. Catalytic dehydration scope. General conditions: am-ide 1 (2.0 mmol), Ph3PO (1 mol %), Et3N (3 equiv), dry MeCN (8 mL), dropwise addition of (COCl)2 (2 equiv). The reactions were carried out for 10 min at rt. Yields of the isolated com-pounds are given.  Based on the experimental observations and the published data on the catalytic Appel reaction,14-15 we suggest two possible mechanistic pathways for this dehydration reaction (Scheme 2). Both cycles start with a quick formation of the intermediate chlorophosphomium chloride B upon treatment of tri-phenylphosphine oxide A with (COCl)2, as demonstrated by Denton with the aid of 31P NMR spectroscopy.14d Next, in the catalytic cycle 1, intermediate B, in the presence of Et3N, reacts with amide 1 via oxygen to form first species D followed by species E, which then undergoes elimination to furnish nitrile 2 and to regenerate triphenylphosphine A; such a sequence was proposed by Appel.11 The pathway outlined in the catalytic cycle 2 that proceeds via formation of N-acyltriphenylphosphine im-ide F was originally rejected by Appel11 because F was deemed too stable. Nonetheless, we decided to revisit this mechanistic option (see Supporting Information for details). N-Benzoyltri-phenylphosphine imide synthesized by a literature method18 was first treated with 3 equiv of Et3N in MeCN. After 10 min at rt, conversion to nitrile 2a reached 30%. However, when Et3N was used in a combination with 1 equiv of (COCl)2, a complete con-version to 2a was achieved almost instantaneously, thus making this route highly probable. Currently, by monitoring the reaction by NMR, we were unable to distinguish whether it proceeds through the intermediacy of D or F (or both) due to fast reaction times. Therefore, both catalytic cycles could be considered via-ble options.19  Scheme 3. Possible catalytic cycles for dehydration of amides to nitriles mediated by phosphine oxide.   In conclusion, we have developed a highly expedient protocol for a catalytic Appel-type dehydration of amides to nitriles cat-alyzed by triphenylphosphine oxide The salient features of the method are (i) operationally simplicity, (ii) low catalyst loading (1 mol %), (iii) fast reaction times, (iv) mild conditions and (v) wide reaction scope that includes aromatic, heteroaromatic and aliphatic amides, including functionalized derivatives.  ASSOCIATED CONTENT  Supporting Information Experimental procedures; 1H and 13C NMR spectra for new com-pounds.  The Supporting Information is available free of charge on the ACS Publications website.  AUTHOR INFORMATION Corresponding Author *E-mail: A.Malkov@lboro.ac.uk *E-mail: Rubtsov@psu.ru Author Contributions The manuscript was written through contributions of all authors. ACKNOWLEDGMENT  The authors thank Russian Science Foundation for grant 15-13-00092. We also acknowledge RUDN University and the Ministry of Education and Science of the Russian Federation (the Agreement 02.A03.21.0008) for access to the analytical facilities (HRMS). REFERENCES (1) (a) Fatiadi, A. J., Preparation and synthetic applications of cyano compounds. In Triple-Bonded Functional Groups, Patai, S.; Rappoport, Z., Eds. John Wiley & Sons, Ltd.: Chichester, UK., 1983; Vol. 2. (b) Miller, J. S.; Manson, J. L. Acc. Chem. Res. 2001, 34, 563-570. (2) (a) Gaspar, B.; Carreira, E. M., Angew. Chem. 2007, 119, 4603-4606. (b) Kukushkin, V. Y.; Pombeiro, A. J. L. Chem. Rev. 2002, 102, 1771-1802.  (3) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53, 7902-7917. (4) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597-606. (5) (a) Smith, M. B.; March, J., Eliminations. In March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Sixth ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2006; pp 1549-1550. (b) Bhattacharyya, N. K.; Sangeeta, J. S. J.; Bhutia, T. Y.; Adhikary, G. Int. J. Chem. App. 2012, 4, 295-304. (6) Paquin, J.-F.; Keita, M.; Vandamme, M. Synthesis 2015, 47, 3758-3766. (7) Itagaki, S.; Kamata, K.; Yamaguchi, K.; Mizuno, N. ChemCatChem 2013, 5, 1725-1728. (8) (a) Elangovan, S.; Quintero-Duque, S.; Dorcet, V.; Roisnel, T.; Norel, L.; Darcel, C.; Sortais, J.-B. Organometallics 2015, 34, 45214528. (b) Zhou, S.; Addis, D.; Das, S.; Junge, K.; Beller, M. Chem. Commun. 2009, 45, 4883-4885. (c) Xue, B.; Sun, H.; Wang, Y.; Zheng, T.; Li, X.; Fuhr, O.; Fenske, D. Chem. Commun. 2016, 86, 148-150. (9) (a) Enthaler, S.; Inoue, S.. Chem.-Asian J. 2012, 7, 169-175. (b) Enthaler, S.. Chem.—Eur. J. 2011, 17, 9316-9319. (10) Zhang, W.; Haskins, C. W.; Yang, Y.; Dai, M. Org. Biomol. Chem. 2014, 12, 9109-9112. (11) Appel, R.; Kleinstück, R.; Ziehn, K. D. Chem. Ber. 1971, 104, 1030-1034. (12) (a) Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801-811. (b) Lee, R. J.; Lindley, M. R.; Pritchard, G. J.; Kimber, M. C. Chem. Commun. 2017, 53, 6327-6330. (13) Dow, K.; Downing, T. E., An Atmospheric Life Time of 85 Years has been Ascribed to CCl4. In The Atlas of Climate Change, University of California Press: Berkeley, 2006. (14) (a) Denton, R. M.; An, J.; Adeniran, B. Chem. Commun. 2010, 46, 3025-3027. (b) Denton, R. M.; Tang, X.; Przeslak, A. Org. Lett. 2010, 12, 4678-4681. (c) An, J.; Denton, R. M.; Lambert, T. H.; Nacsa, E. D. Org. Biomol. Chem. 2014, 12, 2993-3003. (d) Denton, R. M.; An, J.; Adeniran, B.; Blake, A. J.; Lewis, W.; Poulton, A. M. J. Org. Chem. 2011, 76, 6749-6767. (15) (a) Rajendran, K. V.; Gilheany, D. G. Chem. Commun. 2012, 48, 817-819. (b) Nikitin, K.; Müller-Bunz, H.; Gilheany, D. Chem. Commun. 2013, 49, 1434-1436. (c) Yu, T. Y.; Wang, Y.; Xu, P. F. Chem.—Eur. J. 2014, 20, 98-101. (d) Kenny, N. P.; Rajendran, K. V.; Gilheany, D. G. Chem. Commun. 2015, 51, 16561-16564. (16) (a) Couturier, M.; Caron, L.; Tumidajski, S.; Jones, K.; White, T. D. Org. Lett. 2006, 8, 1929-1932. (b) Speziale, A. J.; Smith, L. R. J. Org. Chem. 1963, 28, 1805-1811. (17) (a) Incerti-Pradillos, C. A.; Kabeshov, M. A.; O'Hora, P. S.; Shipilovskikh, S. A.; Rubtsov, A. E.; Drobkova, V. A.; Balandina, S. Y.; Malkov, A. V. Chem.—Eur. J. 2016, 22, 14390-14396. (b) O'Hora, P. S.; Incerti-Pradillos, C. A.; Kabeshov, M. A.; Shipilovskikh, S. A.; Rubtsov, A. E.; Elsegood, M. R.; Malkov, A. V. Chem.—Eur. J. 2015, 21, 4551-4555. (18) Froyen, P. Phosphorus, Sulfur Silicon Relat. Elem. 1993, 78, 161-171. 19. One of the reviewers suggested another possible mechanistic scenario for the dehydration of amides using the same set of reagents: imidate 4 formed by O-acylation of 1 (Scheme 2) reacts with tri-phenylphosphine oxide to give the active intermediate D which is then deprotonated by triethylamine to yield 2 (Scheme 3). While we cannot rule out such a possibility, our optimization experiments (Table 1, en-tries 1 and 2) suggest that if the imidate 4 was formed in appreciable quantities, we should have observed formation of the respective acyl isocyanates, which were not detected under the optimized reaction con-ditions. Therefore, this route appears to be less likely than the two shown in Scheme 3.     

Dehydration of amides to nitriles under conditions of a catalytic appel reaction

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Dehydration of amides to nitriles under conditions of a catalytic appel reaction

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