Reagents carbonyldiimidazole

FIGURE 6.10 The side chain of histidine is readily acylated (A) by activated residues. The imidazolide produced is an activated species similar to the intermediate generated by reaction (B) of a carboxylic acid with coupling reagent carbonyldiimidazole. (Staab, 1956). Imida-zolides acylate amino and hydroxyl groups. Isomerization of histidyl during activation results from abstraction (C) of the a-proton by the 7t-nitrogen. 

A novel and efficient coupling reagent, carbonyldiimidazole (CDI) was discovered [45] by H.A. Staab in Heidelberg, in 1957. The reactive intermediates, acylimidazoles were known before as potent acylating agents [5,35]. In spite of... 

Treatment of a chiral amine with phosgene is the cheapest way to prepare symmetrical ureas [29]. Nevertheless, due to the toxicity and reactivity of that reagent, it can advantageously be replaced by triphosgene [30] or l,l -carbonyldiimidazole [31-34] or other derivatives such as l,l -carbonyldi-2(lH)-pyridinone [35]. This procedure can be extended to thiophosgene (Scheme 1) and its thio-analogues, such as l,l -thiocarbonyldi-2(lH)-pyridinone to produce thioureas [36] chiral diamines can thus be transformed into the corresponding monoureas or monothioureas. 

Scheme 2-16. Synthesis of pyrrolidine. Reagents and conditions a TCDI (1,1-thiono-carbonyldiimidazole), THF b P(OEt)3, DEAD c H2, Rh/Al203, EtOH d TsOH, aq. MeOH e Bu2SnO, toluene, reflux BnBr, BmN Br f TsCl, Py, 0°C g BnNH2, A h H2, Pd(OH)2/C, EtOH.

It has been reported that high-molecular-weight poly(carbonate)s can be synthesized using A,A -carbonyldiimidazole as a condensing agent under mild conditions.4-5 However, the reagent is very sensitive to moisture and must be handled with extreme care. 

Carbonyldiimidazole. This reagent reacts with acids in DMF, THF, or CHjCN to form acylimidazoles. 

Carbonyldiimidazole does certainly stand out as one of the most remarkable reagents for peptide coupling. Carboxylic acids react readily with this reagent to yield acyl imidazoles which in turn couple with the amino group of a peptide to produce a new acyl-nitrogen linkage with very little racemization. Reaction of the acylimidazolide with other nucleophiles can lead to a variety of carbonyl derivatives (62AG(E)35l). 

Carbonyldiimidazole can also function as a carbonyl equivalent (79TL4517). Condensation of the dianion derived from an a-hydroxy ketone (545) with this reagent provides a general although modest yield approach to tetronic acids (546 equation 7). 

The elimination of water from (3-hydroxy-a-amino acid derivatives 28 is a particularly valuable method for the synthesis of DHAs 29, when the corresponding hydroxy compounds are readily accessible, such as, those of Ser, Thr and Ser( 3-Ph). 93 Some of the reagents recommended for the elimination of water are disuccinimidyl carbonate, 9495 l,l -carbonyl-diimidazole, 96 or a base and acetic anhydride. 97 Reaction of l,l -carbonyldiimidazole with arylidene Ser esters gives the corresponding DHA derivatives. 98 In the, presence of tri-ethylamine with terminally protected Ser and Thr residues in an inert solvent this reagent affords the AAla and AzAbu acid derivatives in good yields 96 (Scheme 10). This is perhaps one of the simplest and cleanest ways to prepare AAla and AAbu derivatives. 

Methyl acetoacetate, 60 p-(Tolylsulfinyl)methyllithium, 115 Intramolecular acylation 1,1 -Carbonyldiimidazole, 66 of organometallic reagents to form carbonyl compounds... 

Methyl esters may be prepared by reaction of the aromatic carboxylic acid with diazomethane (cf. Section 4.2.25, p. 433) or, more conveniently, by reaction with a boron trifluoride-methanol reagent. The latter procedure is illustrated by the preparation of methyl m-chlorobenzoate and dimethyl terephthalate (Expt 6.164). t-Butyl esters may be prepared by conversion of the acid into an N-acylimidazole by reaction with N,N -carbonyldiimidazole, followed by reaction with t-butyl alcohol in the presence of DBU62 (Expt 6.165). 

Chiral nitriles.2 This reagent is recommended for the dehydration in 60% yield of primary amides with an asymmetric center at the a-position to chiral nitriles with negligible racemization. The most satisfactory reagents for dehydration of optically active oximes to chiral nitriles is l,l -carbonyldiimidazole or N,N -tlicyclohexylcarbodiimide. 

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

In addition to moving the sulfonyl chloride earlier in the synthesis, the commercial route also uses an acyl imidazole to form a key amide bond (13.77 — 13.79) instead of an acid chloride (13.67 — 13.70, Scheme 13.12). Carbonyldiimidazole (13.76) is an expensive reagent, but the use of acyl imidazole 13.77 gives many advantages. The yields of the amide-forming reaction are higher, and solvent requirements are greatly simplified. The overall... 

M -Carbonylbis(3-methyiimidazoliuni) triflate (1, m.p. 78-80°). The reagent is prepared by reaction of l,l -carbonyldiimidazole with methyl triflate in CH3N02 at... 

Dehydrative cyclization of A-(4-methoxyphcnyl) protected 7-aminoalcohols 157 by the Staab reagent (1,1 -carbonyldiimidazole, CDI) led to the formation of iV-(4-methoxyphenyl)azetidines 158 (Equation 37) <2004SL2751>. The reactions were carried out in a Kugelrohr apparatus. The imidazole formed in the reaction was separated by filtration through silica gel. 

The team also used A iV-carbonyldiimidazole (CDI) as the coupling reagent to generate sorafinib (1) directly from amines—namely, 4-chloro-3-trifluoromethylaniline... 

AD-mix-P 9-BBN Bn Boc Bz BOM CDI m-CPBA CSA Cy DBU DDQ DEAD DIAD DIBAL-H DIPT DME DMF DMAP DMSO EDC HMPA HOBT KHMDS LDA MEM MOM MoOPH NaHMDS NBS NMM NMO Piv PMB Reagent for Sharpless asymmetric dihydroxylation 9-Borabicyclo[3.3.1 ]nonyl Benzyl t-Butoxy carbonyl Benzoyl B enzyloxy methyl Carbonyldiimidazole m-Chloroperoxybenzoic acid Camphorsulfonic acid Cyclohexyl 1,8 -Diazabicy clo[5.4.0] undec-7-ene 2,3 -Dichloro-5,6-dicyano-p-benzoquinone Diethyl azodicarboxylate Diisopropyl azodicarboxylate Diisobutylaluminum hydride Diisopropyl tartrate Dimethoxyethane A,N-Dimethylformamide 4-Dimethylaminopyridine Dimethyl sulfoxide N-(3-Dimethylaminopropyl)-A -ethylcarbodiimide Hexamethylphosphoramide 1 -Hydroxybenzotriazole Potassium hexamethyldisilazane Lithium diisopropylamide Methoxyethoxymethyl Methoxymethyl Oxidodiperoxymolybdenum(pyridine)(hexamethylphophoramide) Sodium hexamethyldisilazane N - Bromosuccinimide A-Methylmorpholine A-Methylmorpholine A-oxide Pivaloyl /j-Methoxybenzyl... 

Carbonyldiimidazole 820 can be used to convert alcohols into alkyl halides by a one-step reaction using an excess of such reactive halides as allyl bromide or methyl iodide, and 820 can be made even more reactive by quaternization. The disadvantages of 820 are its cost and the fact that phosgene must be used in its preparation. An alternative is 1,1-oxalyldiimidazole 821 (made from 1-trimethylsilylimidazole and oxalyl chloride). Transacylation reactions occur very readily with this reagent (Scheme 176). 

Af-Benzyl-/V- (/V-o-methoxyphcnylcarbamoyl)mcthyl glycine (29) underwent de-hydrative cyclization to 4-benzyl-6-hydroxy-l-o-methoxyphenyl-3,4-dihydro-2(1 H)- pyrazinone (30) (l,r-carbonyldiimidazole, THF, 30 —> 65°C, 17 h 83% other reagents gave lower yields).487... 

Alkyl halides N,N -Carbonyldiimidazole. Dimethyl formamides. Trimethylsilylsilyl polyphosphate. Tripbenylphosphine dihalides. Triphenylphosphine-Diethylazodiear-boxylate-Zinc halide. Vilsmeier reagent. 

V.A-Carbonyldiimidazole (CDI) 15 is another reagent to activate carboxylic acids for nucleophilic substitution at the carbonyl group. ... 

Among the most useful of these azolides is l,l -carbonyldiimidazole (253). This compound is extremely reactive towards nucleophilic reagents because the carbonyl group is subject to electron withdrawal from both sides. Also, although it is very rapidly hydrolyzed by water at room temperature with vigorous carbon dioxide evolution, tihe compound is crystalline, and much more easily handled than phosgene which has similar reactivity. In the formation of 1-acylimidazoles compound (253) reacts in equimolar proportions with a carboxylic acid in an inert solvent to give practically quantitative yields. This reaction comprises a two-step mechanism (Scheme 145) in which the carboxylic acid reacts initially... 

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