Diisopropylethylamine Research Articles

Triphosgene as highly efficient reagent for the solid-phase coupling of N-alkylated amino acids—total synthesis of cyclosporin O

A novel, highly efficient and racemization free coupling procedure for sterically hindered N-alkyl amino acids has been developed using triphosgene and a combination of diisopropylethyl amine (DIEA) and collidine at room temperature. Its efficiency was demonstrated by comparison with other coupling methods for N-alkylated amino acids and by solid-phase synthesis of the immunosuppressant Cyclosporin O which was obtained in excellent purity and yield.

The fluorous Swern and Corey–Kim reactions: scope and mechanism

Protocols for the efficient preparation of 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-8-methanesulfenyloctane and 1,1,1,2,2,3,3,4,4-nonafluoro-6-methanesulfenylhexane (fluorous dimethyl sulfide) and for their oxidation to the corresponding sulfoxides (fluorous dimethyl sulfoxide) are reported. The lower molecular weight sulfoxide, in conjunction with oxalyl chloride and Hunig's base, brings about the oxidation of diversely functionalized primary and secondary alcohols to aldehydes and ketones in excellent yield. The fluorous sulfoxide is efficiently recovered for reuse by a simple continuous fluorous extraction and hydrogen peroxide oxidation protocol. The whole process is odor-free. A deuterium-labeling experiment is used to demonstrate that the oxidations take place via the classical Swern mechanism, i.e. by intramolecular hydride abstraction from a sulfur ylid. Corey–Kim oxidations may be performed with the higher molecular weight fluorous sulfide, although recycling is not as efficient.

Ring fused 1,2,5-thiadiazoles from oximes and trithiazyl trichloride

Trithiazyl chloride 1 converts the oximes of simple cyclic ketones into fused 1,2,5-thiadiazoles and bis-1,2,5-thiadiazoles in mild one-pot reactions. Cyclopentanone oxime gives the bisthiadiazole 3 (20%) in which all four methylene groups have been functionalised. Indan-1-one oxime 4 gives the thiadiazole 5 (63%), and tetralone oximes 6 and 8 give the bisthiadiazole 7 in low yields (20%) in complex reactions. Benzosuberone oxime 11 however gives only the monothiadiazole 12 (30%) which is not converted further with more trimer 1. These reactions probably occur by mechanisms analogous to those proposed earlier for the conversion of alkenes, alkynes, active methylene compounds and enamines into 1,2,5-thiadiazoles. Bisthiadiazole 3, a reactive analogue of fluorene, condenses with p-anisaldehyde to give 13 and is oxidised by PCC to the fluorenone analogue 15 in low yield; 15 is formed directly from cyclopentane-1,3-dione with trimer 1. Ketone 15 condenses with malononitrile and Hunig's base to give the dicyanomethylene derivative 17 (94%) which forms a black metallic 1 ∶ 1 complex with TTF at room temperature.

A convenient biphasic process for the monosilylation of symmetrical 1, n-primary diols

A simple and mild biphasic process was developed for the selective protection of one of two chemically equivalent primary hydroxyl groups in 1, n-diols using t-butyldiphenyl silyl chloride in diisopropyl ethyl amine and dimethyl formamide.

Trialkylsilane Monolayers Covalently Attached to Silicon Surfaces: Wettability Studies Indicating that Molecular Topography Contributes to Contact Angle Hysteresis

Chemically grafted monolayers of trialkylsilanes were prepared by reaction of (primarily) alkyldimethylchlorosilanes with silicon wafers under three conditions: in the vapor phase at elevated temperature (60−70 °C), in toluene in the presence of ethyldiisopropylamine (EDIPA) at room temperature, in toluene/EDIPA at 60−70 °C. It was determined that reactions at the solution−solid interface are very slow in the later stages of the reaction and that long reaction times are necessary to achieve maximum bonding density. The bonding density is determined and can be controlled by the reaction conditions. The highest carbon content on the surface (assessed by X-ray photoelectron spectroscopy) as well as the highest contact angles were obtained using vapor phase reactions. A series of nine H(CH2)nMe2Si− surfaces was prepared with n = 1, 2, 3, 4, 8, 10, 12, 18, and 22. Water contact angles (θA/θR = ∼105°/∼94°) are independent of chain length, indicating that these surfaces project disordered methyl groups toward the probe fluid and that water does not penetrate the monolayers. Hydrophobization is achieved topologically: the monolayers prevent water from penetrating and interacting with residual silanols. n-Hexadecane and methylene iodide contact angles decrease with increasing chain length for this series, indicating that these probe fluids penetrate the monolayers and interact with methylene groups. These chemically grafted monolayers differ in structure from those prepared by self-assembly in that the distance between molecules is significantly greater and that all molecules are covalently attached to the substrate. The contact angle hysteresis for these surfaces is a function of alkyl group structure and bonding density: mobile surfaces with flexible chains or rotational mobility and rigid surfaces that pack well exhibit low hysteresis, whereas rigid surfaces that cannot pack well exhibit high hysteresis. We argue that molecular level topography (roughness and rigidity) is responsible for the observed hysteresis.

Synthesis of 9-fluorenylmethyl esters using 9-fluorenylmethylchloroformate

9-Fluorenylmethyl esters of amino acids were synthesized by reacting 9-fluorenylmethylchloroformate with N-protected amino acids in the presence of diisopropylethylamine (DIPEA) as base and 4-dimethylaminopyridine (DMAP) as catalyst.

A new method for deprotection of benzothiazolesulfonamides using a thiol and base

Benzothiazolesulfonamides of primary and secondary amines are efficiently cleaved by a nucleophilic aromatic substitution with a thiol and a base such as potassium t-butoxide or diisopropylethyl amine in DMF.

Selective Syntheses of Bis[1,2]dithiolo[1,4]thiazines and Bis[1,2]dithiolopyrroles from Hünig's Base

The reaction of N,N-diisopropylethylamine (Hunig's base) and disulfur dichloride in 1,2-dichloroethane, in the presence of DABCO, gives 4-ethylbis[1,2]dithiolo[5,4-b][4‘,5‘-e][1,4]thiazine-3,5-dithione (1), or, by addition of oxygen donors, the 3-oxo-5-thione 2 or 3,5-dione 3 derivatives are selectively obtained. When the first reaction is performed in boiling chlorobenzene, 4-ethylbis[1,2]dithiolo[4,5-b][5‘,4‘-d]pyrrole-3,5-dithione (4) is obtained by sulfur extrusion from 1, and in the presence of oxygen donors, the 3-oxo-5-thione 5 or 3,5-dione 6 derivatives are selectively obtained. Some interconversions of compounds 1−6 are described, and a coherent set of reaction pathways for the formation of all six products is proposed. X-ray diffraction shows that the new bis-dithiolothiazine ring system of 1−3 is folded out of planarity about the thiazine N−S vector, with the N-ethyl group folded back over the thiazine ring in a scorpion-like conformation. The new bis-dithiolopyrrole ring system of 4−6 is plana...

Phosphapalladacycle-Catalyzed Heck Reactions for Efficient Synthesis of Trisubstituted Olefins: Evidence for Palladium(0) Intermediates

The coupling reaction of 1,1-disubstituted olefins (α-methylstyrene, n-butyl methacrylate) with various aryl bromides (Heck reaction) has been studied as a new concept to synthesize trisubstituted olefins. Surprisingly, the nature of the base dramatically influences the product distribution. Thus, a systematic investigation on the role of base in Heck reactions of 1,1-disubstituted olefins was performed. Less coordinating bases like NaOAc, NaOBz or Na2CO3 yield a statistical distribution of regioisomers with the terminal olefin 10 as the major product. However, by using amines like Bu3N or diisopropylethylamine (DIPEA) as base internal olefins can be synthesized with high selectivities. With phosphapalladacycle 3 as catalyst precursor, we were able to obtain catalyst turnover numbers up to 1000, while Pd(OAc)2/2PPh3 was one order of magnitude less active. Analysis of the reaction profile by kinetic investigations led to the postulation of a reduction and subsequent oxidative addition of the catalyst precursor 3 to form 12 as catalytically active intermediate.

Facile preparation of chloromethylaryl solid supports using methanesulfonyl chloride and Hunig's base

Several commercially available hydroxymethylaryl resins were converted to their corresponding chloromethyl analogs by simple treatment with methanesulfonyl chloride and Hunig's base in DMF at 25 °C over 3 days. This mild method gave quantitative conversions as determined by elemental analysis and 13C NMR.

Applications of Sugar Nitrones in Synthesis: The Total Synthesis of (+)-Polyoxin J1

A convergent synthesis of the peptidyl nucleoside antibiotic (inhibitor of chitin biosynthesis) polyoxin J (2) by coupling of 5-O-carbamoyl polyoxamic acid (3) and thymine polyoxin C (4) is described. These compounds were prepared by chain elongation and amination of sugar-derived aldehydes employing their nitrones as iminium derivatives and the furan ring as a masked carboxyl. Thus, the stereoselective addition of 2-lithiofuran to the l-threose derived N-benzyl nitrone 5 followed by reduction of the resulting hydroxylamine to amine, carbamoylation of the free hydroxy group, and oxidative cleavage of the furan ring to the carboxylate group gave a protected derivative of 3 (30%). The same method was followed for the synthesis of the ribofuranosyl α-amino acid nucleoside 4 (12.6%) starting from the d-ribose derived nitrone 6. The final coupling was performed by the N-hydroxysuccinimide active ester method in DMSO with the Hunig base (i-Pr2EtNH) using a derivative of 3 and unprotected 4.

Cycloadditions of Cephalosporins. A Comprehensive Study of the Reaction of Cephalosporin Triflates with Olefins, Acetylenes, and Dienes To Form [2 + 2] and [4 + 2] Adducts

Novel polycyclic cephalosporins are formed by the reaction of cephalosporin triflates with various unsaturated compounds in the presence of Hunigs base. 2,3-Fused cyclobutane and cyclobutene cephems are obtained with olefins and acetylenes, respectively, whereas [4 + 2] cycloadducts are obtained with furan. The reaction has been rationalized by invoking the intermediacy of a strained 6-membered cyclic allene. The allene undergoes an orbital symmetry allowed concerted π2s + π2a cycloaddition with olefins and acetylenes and a π4s + π2s cycloaddition with furan. The regiochemistry of the [2 + 2] cycloadducts is independent of the substitution of the unsaturated component and of the oxidation state of the cephalosporin sulfur atom. However in the case of the [4 + 2] adducts, the sulfur oxidation state determines the regiochemistry of the addition. Carbacephalosporins also participate in this reaction with olefins but require a stronger base such as DBU. Thus the reaction described provides a facile, one-step ...

Synthesis and activities of cyclic thrombin-receptor-derived peptide analogues of the Ser42-Phe-Leu-Leu-Arg46 motif sequence containing d-Phe and/or d-Arg

Cyclic analogues of the active thrombin receptor peptide SFLLR (TRP42–46) containingd-Phe and/ord-Arg have been prepared by the solid-phase method, purified by reversed-phase HPLC and bioassayed in a rat smooth muscle contractile assay. Cyclization was achieved by forming an amide linkage between the-NH2 and-COOH groups of the two leucine residues located at the N- and C-terminal positions of the linear protected precursor H2N-Leu-Arg(Pmc)-Y-Phe-Leu-OH (Y=Gly,Acp) using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoroborate borate (HBTU) or 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as coupling reagents andN,N′-diisopropylethylamine (DIPEA) in high dilution. Their structure was confirmed by fast by fast atom bombardment mass spectrometry and NMR methods. The cyclic peptides c-fLLrG, c-fLLRG, c-FLLrG and c-fLLrAcp, c-FLLrAcp so synthesized were assessed for their contractile activity in a rat gastric longitudinal muscle bioassay system which has been used previously to evaluate the biological activities of linear thrombin-receptor-derived polypeptides such as SFLLR (P5) and SFLLR-NH2 (P5-NH2).

Racemization studies of Fmoc-Cys(Trt)-OH during stepwise Fmoc-Solid phase peptide synthesis

In conventional stepwise Fmoc solid phase peptide synthesis, diisopropylethylamine (DIEA) base-catalyzed acylation methods lead to considerable amounts of racemization of Fmoc-Cys(Trt) residues during the activation/coupling process. The epimerization can be reduced to a negligible degree, via a base-free activation step.

Synthesis and reactions of chloroazodienes. A new and general synthesis of pyridazines

Abstract The reaction of dichlorohydrazones with Hunig's base gives 4-chloroazodienes, which were found to combine with a variety of electron rich olefins to yield chloro-substituted tetrahydropyridazines. These chloroazodiene cyclizations are best characterized as inverse electron demand, 4+2 hetero Diels-Alder reactions that maintain a high degree of regio- and stereochemical control. The chloro-substituted tetrahydropyridazines that are formed give high yields of substituted pyridazines upon treatment with base. The sequence of a chloroazodiene cyclization to a tetrahydropyridazine followed by an aromatization constitutes a new and general synthesis of substituted pyridazines.

Application of 2-Chlorotrityl Chloride in Convergent Peptide Synthesis

Fmoc/tBu-protected peptides, synthesized on 2-chlorotrityl resin (CLTR), have been quantitatively esterified by treatment with 2-chlorotrityl chloride (Clt-chloride) and diisopropylethylamine (DIPEA). The obtained peptide Clt-esters have been deprotected at the Nα-function and subsequently condensed in solution to larger peptides. The Clt-function of the obtained products could be selectively removed by treatment with acetic acid.

1,8-diazabicyclo [5.4.0] undec-7-ene: A remarkable base in the epoxidation of α, β-unsaturated-δ-lactones and other enones with anhydrous t-BuOOH

1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) has been studied for the epoxidation of electron deficient alkenes with anhydrous t-BuOOH (TBHP) in dichloroethane. Steric demands are higher than that for alkaline H 2O 2- DBU is recognised as a remarkable base in these oxidations as other bases such as triethyl amine, diisopropylethyl amine, and 1,4-diazabicyclo[2.2.2]octane (DABCO) are absolutely inefficient. DBU is effective in promoting the oxidation of α, β-unsaturated δ-lactones where most of conventional methods either fail or perform poor.

Application of 2-chlorotrityl chloride in convergent peptide synthesis

Abstract Fmoc/tBu-protected peptides, synthesized on 2-chlorotrityl resin (CLTR), have been quantitatively esterified by treatment with 2-chlorotrityl chloride (Clt-chloride) and diisopropylethylamine (DIPEA). The obtained peptide Clt-esters have been deprotected at the Nα-function and subsequently condensed in solution to larger peptides. The Clt-function of the obtained products could be selectively removed by treatment with acetic acid.

Styrylpyridine—amine exciplexes: sunstituent effects

Fluorescent exciplexes were observed between excited para-substituted trans-styrylpyridines (n-StP, n=2,3,4 and XCN, Cl, H, (CH3)2CH, CH3, CH3O) and three tertiary amines, i.e. diisopropyl ethylamine, tributylamine and triethylamine) in n-hexane at room temperature. The exciplex emission for the 2-StP—amine system was extremely weak. The maximum fluorescence energies were correlated with the values of Rehm and Weller, except for those for the StP with cyano groups. There was better correlation when a stronger electron-donating amine was used. The quenching rate constansts increase as ΔGO for electron transfer becomes more exergonic, except for the case of cyano derivatives. The exciplex fluorescent energies also showed a linear correlation with the Hammett σp constants, again except for the cyano derivatives. The calculated dipole moments for the styrylpyridine—amine exciplexes are larger than those for stilbene—amine exciplex systems.

Free radical copolymerization of electron‐rich vinyl monomers with acrylonitrile complexed to zinc chloride

AbstractThe spontaneous free radical copolymerizations of a series of electron‐rich olefins with acrylonitrile (AN) complexed to zinc chloride (ZnCl2) have been investigated in solution. With styrene (St) and 2‐vinylnaphthalene, an alternating copolymerization occurred without added initiator at 40°C. Using p‐methylstyrene as the electron‐rich olefin, no‐initiator spontaneous alternating copolymerization was observed at 30°C. Copolymer formed in an amount equal to that of the ZnCl2 used. With p‐methoxystyrene (pMeOSt) and with isobutyl vinyl ether (IBVE), the copolymerizations were conducted in the presence of ethyldiisopropylamine (EDIA) to inhibit cationic homopolymerization of these monomers. The copolymerization with pMeOSt proceeded to high yield, but the copolymers were rich in pMeOSt and the rates were slow presumably due to competitive complexation of ZnCl2 with the methoxy‐substituent. Using IBVE only low yields of a random copolymer were obtained, and again competitive coordination with ZnCl2 appears responsible. The small molecules accompanying these spontaneous copolymerizations were shown by GC/MS to possess cyclobutane and Mayo adduct structures. The mechanism of these spontaneous copolymerizations cannot be decided on the basis of the small molecules formed, but the increases of copolymer molecular weight with time at constant yield speaks for a diradical mechanism.