Synlett 2022; 33(10): 977-982
DOI: 10.1055/a-1809-6545

Mander’s Reagent for the Deoxycyanation of β-Diketones: A Direct Synthesis of Oxoalkenenitriles

Alicia E. Cruz-Jiménez
Jeferson B. Mateus-Ruiz
Carolina Silva-Cuevas
This work was supported by Fondo SEP-Cinvestav 2018 (069). We also thank Conacyt for a Ciencia de Frontera 2019 grant (51493).

In the memory of Prof. Lewis N. Mander


Ethyl cyanoformate and methyl cyanoformate (Mander’s reagent) are both routinely used to perform C-selective ketone alkoxycarbonylations. Interestingly, both reagents were found to yield oxoalkenenitriles through an unprecedented deoxycyanation of 1,3-dicarbonyl compounds (e.g., 2-methylcyclohexane-1,3-dione). Although this method is not general, this is the first time that both Mander’s reagent and ethyl cyanoformate have been used for the deoxycyanation of 1,3-dicarbonyl compounds for the preparation of synthetically useful oxoalkenenitriles. Limitations on the substrate scope of the present method are discussed.

Supporting Information

Publication History

Received: 24 February 2022

Accepted after revision: 26 March 2022

Accepted Manuscript online:
26 March 2022

Article published online:
29 April 2022

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  • References and Notes

  • 1 Mander LN, Sethi SP. Tetrahedron Lett. 1983; 24: 5425
  • 2 Mander LN, Shing TK. M, Yeung YY, Lujan-Montelongo JA. In Encyclopedia of Reagents for Organic Synthesis . Fuchs PL, Bode JW, Charette AB, Rovis T. Wiley; Chichester: 2018. DOI: 10.1002/047084289X.rm168.pub3
  • 3 House HO. Modern Synthetic Reactions, 2nd ed. W. A. Benjamin; Menlo Park: 1972: 763
    • 4a Crabtree SR, Chu WL. A, Mander LN. Synlett 1990; 169
    • 4b Devaux J.-F, Hanna I, Lallemand J.-Y. J. Org. Chem. 1997; 62: 5062
    • 4c Kögl M, Brecker L, Warrass R, Mulzer J. Eur. J. Org. Chem. 2008; 2714
    • 4d Dorich S, Del Valle JR, Hanessian S. Synlett 2014; 25: 799
  • 5 Leung JC, Bedermann AA, Njardarson JT, Spiegel DA, Murphy GK, Hama N, Twenter BM, Dong P, Shirahata T, McDonald IM, Inoue M, Taniguchi N, McMahon TC, Schneider CM, Tao N, Stoltz BM, Wood JL. Angew. Chem. Int. Ed. 2018; 57: 1991
  • 6 Lujan-Montelongo JA, Fleming FF. Org. Synth. 2013; 90: 229
    • 7a Fleming FF, Wang Q, Steward OW. Org. Lett. 2000; 2: 1477
    • 7b Fleming FF, Zhang Z, Wang Q, Steward OW. Angew. Chem. Int. Ed. 2004; 43: 1126
    • 8a Fleming FF, Wei G, Zhang Z, Steward OW. Org. Lett. 2006; 8: 4903
    • 8b Fleming FF, Wei Y, Liu W, Zhang Z. Org. Lett. 2007; 9: 2733
    • 8c Fleming FF, Wei G, Zhang Z, Steward OW. J. Org. Chem. 2007; 72: 5270
    • 8d Fleming FF, Wei Y, Liu W, Zhang Z. Tetrahedron 2008; 64: 7477
    • 8e Lujan-Montelongo JA, Lu P, Liu W, Fleming FF. Chem. Eur. J. 2013; 19: 8746
    • 9a Liu J, Ma D. Angew. Chem. Int. Ed. 2018; 57: 6676
    • 9b Fleming FF, Wei G, Steward OW. J. Org. Chem. 2008; 73: 3674
  • 10 Tietze LF, Vock CA, Krimmelbein IK, Wiegand JM, Nacke L, Ramachandar T, Islam KM. D, Gatz C. Chem. Eur. J. 2008; 14: 3670
  • 11 Audenaert F, De Keukeleire D, Vandewalle M. Tetrahedron 1987; 43: 5593
  • 12 Compared with the reference compound 3-bromocyclohex-2-en-1-one (2ba) (see ref. 6), 3-bromo-2-methyl cyclohex-2-en-1-one (2aa) was much less reactive towards cyanide. This was also the case for 3-iodo-2-methylcyclohex-2-en-1-one (2bb) compared with 3-iodocyclohex-2-en-1-one (2ab). Besides the steric contribution of the 2-methyl group, in silico calculations revealed that the LUMO energies for both 2-methyl brominated and iodinated derivatives (2aa and 2bb), compared with nonmethylated 2ba and 2bb, are +2.3 kcal/mol higher (wb97xd/def2tzvp).
  • 13 Kowalski CJ, Fields KW. J. Org. Chem. 1981; 46: 197
  • 14 Cyclic oxonitrile syntheses yields are sometimes inconsistent and strongly dependent on the substrate and operational conditions; see: Hadi T, Díaz-Rodríguez A, Khan D, Morrison JP, Kaplan JM, Gallagher KT, Schober M, Webb MR, Brown KK, Fuerst D, Snajdrova R, Roiban G.-D. Org. Process Res. Dev. 2018; 22: 871
  • 15 Alagona G, Ghio C. Int. J. Quantum Chem. 2008; 108: 1840
  • 16 Most β-diketone spectra have been acquired using very polar solvents (such as DMSO-d 6), which are known to favor the enol tautomer; see: Lertpibulpanya D., Marsden S. P.; Org. Biomol. Chem.; 2006, 4: 3498; however, nucleophilic solvents were discarded for their incompatibility, as the approach was conceived to involve electrophilic C–O bond activation
  • 17 Li Z, Gevorgyan V. Angew. Chem. Int. Ed. 2011; 50: 2808
  • 18 Tarrade-Matha A, Pillon F, Doris E. Synth. Commun. 2010; 40: 1646
  • 19 Katritzky AR, Akue-Gedu R, Vakulenko AV. ARKIVOC 2007; (iii): 5
  • 20 Wu Y.-Q. In Science of Synthesis, Vol. 18, Chap. 18.1. Knight JC. Thieme; Stuttgart: 2005: 17
  • 21 A related formal two-step C-acylation of β-diketone 2a involving a cyanoacyl group has been reported before. The sequence involves the exposure of a corresponding enol ester derivative to cyanide. The mechanistic proposal involved enol ester cleavage by cyanide, followed by C-attack from the enolate on the acyl cyanide generated in situ; see: Montes IF, Burger U. Tetrahedron Lett. 1996; 37: 1007

    • The C-carboxymethylation of ketones is the main application of Mander’s reagent; apart from the formation of carbonated cyanohydrins (see ref. 2), there are few methods in which cyanoformates are used as a cyanation reagents, see:
    • 22a Tanner DD, Rahimi PM. J. Org. Chem. 1979; 44: 1674
    • 22b Nishihara Y, Inoue Y, Itazaki M, Takagi K. Org. Lett. 2005; 7: 2639
    • 22c Nishihara Y, Inoue Y, Izawa S, Miyasaka M, Tanemura K, Nakajima K, Takagi K. Tetrahedron 2006; 62: 9872
  • 23 Free cyanide can be released by interaction of cyanoformate with Lewis bases, see: Al Matarneh CM, Apostu MO, Mangalagiu II, Danac R. Tetrahedron 2016; 72: 4230
  • 24 Takeuchi H, Kojima T, Egawa T, Konaka S. J. Phys. Chem. 1992; 96: 4389
  • 25 At the M062X/6–311+G(2d,p) level of theory; see SI.
  • 26 The cis-tautomer is 2.3 kcal/mol more stable than the trans-tautomer [M052X/6-311++G(d,p)], see: Bandyopadhyay B, Pandey P, Banerjee P, Samanta AK, Chakraborty T. J. Phys. Chem. A 2012; 116: 3836
  • 27 Also, 8b1 and 8b2 were revealed to be plausible intermediates: after exposing 8b1 to Mander’s reagent for 2 h, a mixture of 37% of the oxonitrilic product 4b and ~40% of recovered 8b1 was detected.
  • 28 After stirring for 2 h, a ~1:1 mixture of Et3N and ethyl cyanoformate remained virtually unchanged. On the other hand, stirring a 1:3 mixture of Et3N and Mander’s reagent for 1 h gave a 50% yield of acylated Et3N; see ref. 23.
  • 29 Unfortunately, attempts to prepare cyclic oxonitrile 4g by using the carbonate derivative methyl (3-oxocyclopent-1-en-1-yl) carbonate were also unfruitful (see SI).
  • 30 The C-carboxymethyl product would be expected to form under thermodynamic conditions if access to carbonate 8b and oxonitrile 4b is kinetically hampered.
  • 31 2-Methyl-3-oxocyclohex-1-ene-carbonitrile (4a); Typical Procedure In a Schlenk flask, Et3N (1 equiv) was added dropwise to a solution of 2a (1 equiv) in anhyd CH2Cl2 (0.1 M), and the mixture was stirred for 10 min at rt. Ethyl cyanoformate (3 equiv) was added in one portion, and the resulting mixture was stirred for 6 h at rt. The mixture was then diluted with H2O and extracted with CH2Cl2 (3×). The organic layer was washed with distilled water, dried (Na2SO4), and concentrated by vacuum distillation at rt. The resulting oil was distilled in a Kugelrohr apparatus to give a colorless oil; yield: 48%. 1H NMR (500 MHz, CDCl3): δ = 2.05–2.12 (m, 5 H) 2.51–2.59 (m, 4 H). 13C NMR (125 MHz, CDCl3): δ = 15.2, 22.4, 28.3, 37.8, 117.1, 125.5, 146.7, 196.8.