A New, Simple Procedure for the Synthesis of Formyl Amides

Abstract

A simple and mild method for the N-formylation of amines and α-amino esters is described via reaction with 2-chloro-4,6-dimethoxy[1,3,5]triazine and formic acid. The reaction can be accelerated under microwave irradiation and yields the N-formyl species in high yields and without racemization in the case of optically active α-amino esters.

amines - formyl amides - cyanuric acid - formylamino esters - microwave

References

<A NAME="RG30004ST-1">1</A> Jackson A. Meth-Cohn O. J. Chem. Soc., Chem. Commun.  1995,  1319 

<A NAME="RG30004ST-2">2</A> Chen BC. Bednarz MS. Zhao R. Sundeen JE. Chen P. Shen Z. Skoumbourdis AP. Barrish JC. Tetrahedron Lett.  2000,  41:  5453 

<A NAME="RG30004ST-3">3</A> Kobayashi K. Nagato S. Kawakita M. Morikawa O. Konishi H. Chem. Lett.  1995,  575 

<A NAME="RG30004ST-4">4</A> Kakehi A. Ito S. Hayashi S. Fujii T. Bull. Chem. Soc. Jpn.  1995,  68:  3573 

<A NAME="RG30004ST-5">5</A> Martinez J. Laur J. Synthesis  1982,  979 

<A NAME="RG30004ST-6">6</A> Floersheimer A. Kula MR. Monatsh. Chem.  1988,  119:  1323 

<A NAME="RG30004ST-7">7</A> Ugi I. Arora A. Burghard H. Eberle G. Eckert H. George G. Gokel G. Herlinger H. Hinrichs EV. Hoffman P. Kleinmann H. Klusacek H. Lam HL. Marquanding D. Nah HS. Offermann K. Rehn D. Stüber S. Tamasi M. Urban R. Wackerle L. Zahr S. Zychlinski HV. Peptides 1974   Wolman Y. Israel University Press; Jerusalem: 1975.  p.71-92  

<A NAME="RG30004ST-8">8</A> Sheehan JC. Yang DDH. J. Am. Chem. Soc.  1958,  80:  1154 

<A NAME="RG30004ST-9">9</A> Chen FMR. Benoiton NL. Synthesis  1979,  709 

<A NAME="RG30004ST-10">10</A> Giesemann G. Ugi I. Synthesis  1983,  788 

<A NAME="RG30004ST-11">11</A> Reddy PG. Kumar KGD. Baskaran S. Tetrahedron Lett.  2000,  41:  9149 

<A NAME="RG30004ST-12">12</A> Yale HL. J. Org. Chem.  1971,  36:  3238 

<A NAME="RG30004ST-13">13</A> Chancellor T. Morton C. Synthesis  1994,  1023 

<A NAME="RG30004ST-14">14</A> Giard T. Bénard D. Plaquevent JC. Synthesis  1998,  297 

<A NAME="RG30004ST-15">15</A> Hill DR. Hsiao C. Kurukulasuriya R. Wittemberg SJ. Org. Lett.  2002,  4:  111 

<A NAME="RG30004ST-16">16</A> Schmidhammer H. Brossi A. Can. J. Chem.  1982,  60:  3055 

<A NAME="RG30004ST-17">17</A> Duczek W. Deutsch J. Vieth S. Niclas H.-J. Synthesis  1996,  37 

<A NAME="RG30004ST-18A">18a</A> Falorni M. Porcheddu A. Taddei M. Tetrahedron Lett.  1999,  40:  4395 

<A NAME="RG30004ST-18B">18b</A> Falorni M. Giacomelli G. Porcheddu A. Taddei M. J. Org. Chem.  1999,  64:  8962 

<A NAME="RG30004ST-18C">18c</A> Falchi A. Giacomelli G. Porcheddu A. Taddei M. Synlett  2000,  275 

<A NAME="RG30004ST-18D">18d</A> De Luca L. Giacomelli G. Taddei M. J. Org. Chem.  2001,  66:  2534 

<A NAME="RG30004ST-18E">18e</A> De Luca L. Giacomelli G. Porcheddu A. Org. Lett.  2001,  3:  1519 

<A NAME="RG30004ST-18F">18f</A> De Luca L. Giacomelli G. Porcheddu A. Org. Lett.  2001,  3:  3041 

<A NAME="RG30004ST-18G">18g</A> De Luca L. Giacomelli G. Porcheddu A. Org. Lett.  2002,  4:  553 

<A NAME="RG30004ST-18H">18h</A> De Luca L. Giacomelli G. Porcheddu A. J. Org. Chem.  2002,  67:  5152 

<A NAME="RG30004ST-18I">18i</A> De Luca L. Giacomelli G. Porcheddu A. J. Org. Chem.  2002,  67:  6272 

<A NAME="RG30004ST-18J">18j</A> De Luca L. Giacomelli G. Masala S. Porcheddu A. J. Org. Chem.  2003,  68:  4999 

<A NAME="RG30004ST-18K">18k</A> Giacomelli G. Porcheddu A. Salaris M. Org. Lett.  2003,  5:  2715 

<A NAME="RG30004ST-19">19</A> Kaminski ZJ. Tetrahedron Lett.  1985,  26:  2901 

<A NAME="RG30004ST-20">20</A> Kuhnert N. Angew. Chem. Int. Ed.  2002,  41:  1863 

<A NAME="RG30004ST-21">21</A> Kaminski ZJ. Paneth P. O’Leary MH. J. Org. Chem.  1991,  56:  5716 

<A NAME="RG30004ST-22">22</A>

A. Conventional Procedure: Formic acid (0.35 g, 7.62 mmol), benzylamine (0.71 g, 7.62 mmol), 2-chloro-4,6-dimethoxy[1,3,5] triazine (CDMT, 1.47 g, 8.30 mmol), 4-dimethylaminopyridine (DMAP, 0.03 g, 0.2 mmol) and N-methylmorpholine (NMM, 0.92 mL, 8.30 mmol) were placed in this order in a flask containing CH₂Cl₂ (20 mL) and maintained at r.t. The mixture was stirred at reflux (6 h), monitored by TLC in order to control the end of the conversion, then diluted with CH₂Cl₂, washed twice with aq HCl (15 mL), aq NaHCO₃ (15 mL), and brine (10 mL). The organic layer was dried (Na₂SO₄). Removal of the solvent in vacuo gave 0.98 g of chemically pure N-benzylformamide, (95%), mp 57 °C. [12]
B. Microwave Procedure: TEA (1.2 mL, 8.38 mmol) and l-valine methyl ester hydrochloride (1.27 g, 7.62 mmol) were placed in a flask equipped with a reflux condenser, containing CH₂Cl₂ (20.0 mL). Then formic acid (0.35 g, 7.62 mmol), CDMT (1.47 g, 8.30 mmol), DMAP (0.03 g, 0.20 mmol) and N-methylmorpholine (NMM, 0.92 mL, 8.30 mmol) were added in this order. The open flask was irradiated at 35 °C (by modulation of the power) for 6 min in a self-tuning single mode CEM Discover^TM Focused Synthesizer. The solution was cooled rapidly at r.t. by passing compressed air through the 25 microwave cavity for 1 min, then diluted with CH₂Cl₂ and worked up as above. ¹H NMR (300 MHz, CDCl₃): δ = 8.27 (s, 1 H), 6.23 (br s, 1 H), 4.67 (dd, 1 H, J = 9.0, 4.8 Hz), 3.76 (s, 3 H), 2.24-2.17 (m, 1 H), 0.97 (d, 3 H, J = 6.8 Hz), 0.92 (d, 3 H, J = 6.6 Hz).
(S)-Methyl 2-formamido-3-methylbutanoate from method A had [α]_D ²⁵ -27.2 (c 2.0, EtOH). Similarly, (S)-methyl 2-formamidobutanoate, (S)-methyl 2-formamido-3-phenyl-propanoate, and (S)-methyl 2-formamido-4-methyl-pentanoate were recovered and had [α]_D ²⁵ values of -36.1
(c 3.5, EtOH), [13] +85.3 (c 2.3, EtOH), [14] and -43.2 (c 1.2, EtOH), respectively. [13]