Preparation of CF3CHO

Hooper, David G.; Loucks, Leon F.; Liu, Michael T. H.

doi:10.1021/ed052p131

Cited by 6 publications

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“…Moreover they are rather unstable, extremely easily hydrated and readily polymerizable 20,21 compounds. In the case of trifluoroacetaldehyde the simplest and more efficient way to get it is the reaction of the stable ethyl 8a, or methyl hemiacetal with diphosphorus pentaoxide at 150°C, 22 in ~ 50% yield. Therefore the generalization of the described preparation 23 of the N-acetyl and N-benzoyl trifluoroacetaldehyde hemiaminals (1, Y = CH 3 CO, PhCO; R = CF 3 ) directly with the ethyl hemiacetal 8a in refluxing dioxane appeared to be the method of choice for preparing various derivatives 1, in particular those with an N-protecting group (Scheme 2).…”

Section: Methodsmentioning

confidence: 99%

Expedient Synthesis of Perhaloaldehyde N-Acyl Hemiaminals

Ingrassia¹

1999

Synthesis

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Various perhaloaldehyde N-acyl hemiaminals 1 are readily prepared in high yields by condensation of amides 7 with easily available perhaloaldehyde O-ethyl hemiacetals 8 or hydrates 9 in the presence of 5 Å molecular sieves.Since the pioneer work of Weygand's group, 1 trifluoroacetaldehyde N-acyl hemiaminals 1 (R = CF 3 ) have been recognized as valuable starting materials for preparing btrifluoroamino acids 2. [2][3][4] Recently we have found that they are also useful for the synthesis of aminophosphonic 5 and aminosulfonic acids 6 3 and 4, respectively, as well as for the N-protected amino sulfinates 5 7 and sulfonamides 6 7 (Scheme 1). Scheme 1Considering the field of antibiotics, 8 the biological activity of the b-trifluoro amino acids 2 or 3 is well established 9,10 and is expected to be also verified with sulfinates 5 and sulfonamides 6, the latter compounds being able to act either as false substrates (SO 2 NH 2 mimic of COO -11 ) or as transition state analogs. 12 From a chemical point of view, the compounds 1 are very stable compounds, 1 compared to their "methylol" counterparts. 13 The same stabilization effect of halogen, particularly fluorine, substitution is also observed with the sulfinates 5 7,14 and the sulfonamides 6, 7,15 and is also expected 16 for the phosphonamide transition state analog 12 derivatives of 3.The original method of Weygand's group for the preparation of hemiaminals 1 by hydrolysis of N-protected a-amino sulfones, 1 requires five steps starting from perfluoroacyl anhydrides. 17 It was soon after followed by description of the simple condensation of fluoroaldehydes, namely trifluoroacetaldehyde, with carboxamides 7. 18 Unfortunately perhalogenated aldehydes are quite difficult to prepare 19 and to handle (gaseous) for the lower homologs of the series. Moreover they are rather unstable, extremely easily hydrated and readily polymerizable 20,21 compounds. In the case of trifluoroacetaldehyde the simplest and more efficient way to get it is the reaction of the stable ethyl 8a, or methyl hemiacetal with diphosphorus pentaoxide at 150°C, 22 in ~ 50% yield. Therefore the generalization of the described preparation 23 of the N-acetyl and N-benzoyl trifluoroacetaldehyde hemiaminals (1, Y = CH 3 CO, PhCO; R = CF 3 ) directly with the ethyl hemiacetal 8a in refluxing dioxane appeared to be the method of choice for preparing various derivatives 1, in particular those with an N-protecting group (Scheme 2). However, with benzyloxycarbonylamide 7a the yield of the reaction leading to 1a hardly reached 42%. Nevertheless, using a commercial solution of ~ 80% of the hemiacetal 8a and ~20% of the hydrate 9a we observed, in presence of 3 Å or 4 Å molecular sieves, a fast reaction with 9a and a very slow (several weeks) one with 8a. With the 5 Å type, known to adsorb ethanol, 24 the latter reaction with 8a is complete, usually within a few days, provided the molecular sieves are properly activated 24 and that their capacity has been ascertained (General Procedure 1, see experimental).In this, the cho...

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Section: Methodsmentioning

confidence: 99%

Expedient Synthesis of Perhaloaldehyde N-Acyl Hemiaminals

Ingrassia¹

1999

Synthesis

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“…TLC: R¡ = 0.27(2:1 hexane/ ethyl acetate). HPLC: tR = 20.91 (47.2%), 22.8 (44.5%), 50 min; 50-90% aqueous CH3CN gradient, flow rate 1 mL/min; YMC NMR (DMSO-de): 0.95 (m, 6 ), 1.42 (s, 9 ), 0.75-1.85 (m, 16 ), 3.1 (m, 2 H), 4.1-4.5 (m, 2 H), 4.85 (m, 1 ), 7.15-7.37 (m, 5 H), 7.5 and 7.72 (2d, 1 H, J = 7), 7.95 and 8.02 (2d, 1H,«7=7), 8.68 (d, 1H,«7 = 7 41.9, 51.5, 51.8, 52.9, 53.0, 53.6, 57.0, 80.5, 97.1, 94.8 (q, J = 30), 97.3 (q, J = 28), 125.7 (q, J = 297), 127. (.RO-JV-IHCyclohexylmethyB-Z-methoxy-Z-oxoethyl]--(phenylmethoxy)carbonyl]-L-Ieucinamide (15).…”

Section: Methodsmentioning

confidence: 99%

“…Drying and concentration gave an oily residue which after flash chromatographic purification (silica gel, 4:1 Hex/EtOAc) yielded 15 (832 mg, 64%). TLC: Rf NMR (CDClg): 0.7-1.8 (m, 22 H), 3.7 (s, 3 ), 4.1-4.25 (br m, 1 H), 4.6 (m, 1 H), (R*)-N-[ 1 -(Cyclohexy lmethy l)-2-hydroxy-2-oxoethy 1]-AP-[(phenylmethoxy)carbonyl]-L-leucinamide (16). NaOH (1 N, 2 mL, 2 mmol) was added to solution of 15 in methanol (13 mL).…”

Section: Methodsmentioning

confidence: 99%

“…The aqueous layer was reextracted with EtOAc (2X25 mL). The combined organic extracts were dried (NagSO^) and concentrated, and the residue was purified by flash chromatography eluting with 9:1:0.1 CHClg/MeOH/AcOH to give 16 (688 mg, 94.8%). TLC: fy= 0.35 (9:1:0.1 CHClg/MeOH/AcOH).…”

Section: Methodsmentioning

confidence: 99%

“…NMR (CDClg): 0.9 (d, 6H,«7= 6), 1.42 (s, 9 ), 0.8-1.8 (m, 16 ), 2.95-3.15 (m, 2 H), 3.71 (s, 3 H), 4.25-4.65 (m, 3 ), 5.08 (d, 1 H, J = 8), (Jf)-JV-[l-(Cyclohexylmethyl)-2-hydroxy-2-oxoethyl]-JV*-[JV-[ (1,1 -dimethylethoxy)carbonyl]-L-phenylalanyl]-L-leucinamide (19). NaOH (1 N,35 mL, 35 mmol) was added to a solution of methyl ester 18 (15.26 g, 28 mmol) in methanol (100 mL).…”

Section: Methodsmentioning

confidence: 99%

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Activated ketone based inhibitors of human renin

Patel¹,

Rielly-Gauvin²,

Ryono³

et al. 1993

J. Med. Chem.

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Application of the concept of activated ketones to the design of novel and potent transition-state analog inhibitors of the aspartyl protease renin is described. Three different classes of peptidic activated ketones were synthesized: 1,1,1-trifluoromethyl ketones, alpha-keto esters, and alpha-diketones. The corresponding alcohols were also evaluated as renin inhibitors in each series. While the trifluoromethyl alcohol 12 (I50 = 4000 nM) was equipotent to the simple methyl alcohol 7 (I50 = 3200 nM), the structurally similar alpha-hydroxy esters (32 and 30, I50's = 5.3 and 4.7 nM, respectively) and alpha-hydroxy ketones (41 and 42, I50 = 23 and 15 nM, respectively) were 150-300-fold more active. The hydrating capability of the activated ketone functionality was important for intrinsic potency in the case of trifluoromethyl ketones, as illustrated by the significantly better activity of trifluoromethyl ketone 13 (I50 = 250 nM) compared to its alcohol analog 12 (I50 = 4000 nM). It was however unimportant for the alpha-keto ester (20 and 31, I50 = 15 and 4.1 nM, respectively) and alpha-diketone (43 and 44, I50 = 52 and 28 nM, respectively) based inhibitors, since their activity was essentially similar to that of the corresponding alcohols. These results collectively suggest that, whereas the trifluoromethyl ketones derive their renin inhibitory potency primarily from their ability to become hydrated, this is not a critical feature for the activity of alpha-dicarbonyl-based inhibitors. The alpha-keto ester and alpha-diketone based renin inhibitors benefit predominantly from the hydrophobic and/or H-bonding type binding interactions of the neighboring ester or acyl group itself, rather than the ability of this group to deactivate the adjacent ketone group and thereby make it susceptible to hydration.

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Pyrolysis of trifluoroacetaldehyde. The formation of trifluoromethane and hexafluoroethane

Liu

Loucks

Hooper

1977

Int J of Chemical Kinetics

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The thermal decomposition of trifluoroacetaldehyde a t temperatures of 471 to 519°C has been studied by measuring the rates of formation of CFIH and C2Fs. It is concluded that the high-pressure reaction mechanism involves a Rice-Herzfeld reaction scheme with firstorder initiation and second-order termination via CF, combination. However, a falloff in reaction rates is observed at pressures below 100 mmHg. The Arrhenius parameters of the three rate constants corresponding to the overall reaction, the initiation reaction, and an abstraction reaction have been evaluated.

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Preparation of CF3CHO

Cited by 6 publications

References 0 publications

Expedient Synthesis of Perhaloaldehyde N-Acyl Hemiaminals

Expedient Synthesis of Perhaloaldehyde N-Acyl Hemiaminals

Activated ketone based inhibitors of human renin

Pyrolysis of trifluoroacetaldehyde. The formation of trifluoromethane and hexafluoroethane

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