Efficient synthetic protocol for substituted guanidines via copper(I)-mediated intermolecular amination of isothiourea derivatives

Amination of S-methyl-N,N′-bis-Boc-isothiourea with either primary or sterically hindered secondary amines promoted by copper(I) chloride and K₂CO₃ gave N,N′-bis-Boc protected guanidines in good to excellent yields under mild reaction conditions.     

Catalytic guanylation of aliphatic,aromatic, heterocyclic primary and secondary amines using nanocrystalline zinc(II) oxide

Nanocrystalline ZnO was found to be a highly efficient heterogeneous catalyst for the guanylation of amines with various carbodiimides to afford N,N′,N″-trisubstituted guanidines in excellent yields. Structurally divergent aliphatic, aromatic, heterocyclic primary and secondary amines were converted to the corresponding N,N′,N″-trisubstituted guanidines using optimal conditions. The catalyst was easy to handle even under atmospheric conditions and can be easily recovered by centrifugation and reused for five cycles with consistent activity.     

Convenient access to sterically hindered C2 chiral 2,2,5,5-tetraphenyltetrahydrofuran-3,4-diols: intramolecular selective 1,4-cyclocondensation of (2R,3R)- and (2S,3S)-1,1,4,4-tetraphenylbutanetetraols

Sterically hindered C₂ chiral (3R,4R)- and (3S,4S)-2,2,5,5-tetraphenyltetrahydrofuran-3,4-diols have been conveniently prepared in a very high yield via heterogeneous intramolecular selective 1,4-cyclocondensation of (2R,3R)- and (2S,3S)-1,1,4,4-tetraphenylbutanetetraol in concentrated hydrohalic acids, respectively. Preliminary examination of additives for the Barbas–List reaction showed that in certain cases, the hindered C₂ chiral tetrahydrofuran-3,4-diols were better chiral auxiliaries than enantiopure (R)- and (S)-1,1′-bi-2-naphthols.     

Enantioselective addition of dialkylzinc to aldehydes catalyzed by (S)-2-(N,N-disubstituted aminomethyl)indoline

Chiral di- or triamines, (S)-2-(N,N-disubstituted aminomethyl)indoline 1a–d, derived from (S)-indoline-2-carboxylic acid were efficient chiral catalysts for the enantioselective addition of dialkylzincs to aldehydes. The best results were obtained by employing 15 mol% of (S)-2-(4-methylpiperazin-1-ylmethyl)indoline 1c, and chiral secondary alcohols were obtained in up to 97% ee.     

Efficient preparation of Ellman’s imines from trifluoromethyl ketones promoted by zirconium(IV) tert-butoxide

An efficient synthesis of chiral N-tert-butanesulfinyl trifluoromethyl ketimines by using zirconium(IV) tert-butoxide is described. Compared to conventional titanium(IV) ethoxide, this protocol gave better result especially for sterically hindered ketones. In addition to the high reactivity, a high degree of enantiopurity of the N-tert-butanesulfinyl group is retained.     

Preparation of N-alkyl-N′-carboalkoxy guanidines: unexpected effective trans-alkoxylation transforming the 2,2,2-trichloroethoxycarbonyl into various carbamates

A range of N-alkyl-N′-Boc guanidines was simply synthezized from monoprotected Boc-1H-pyrazole-1-carboxamidine by reaction with primary amines. Synthesis of the hindered (R)-N-methylbenzyl-N′-Troc guanidine was achieved from the corresponding thiourea by the action of ammonia. Transformation of the Troc group into others carbamate groups, including Boc, was simply obtained by refluxing in the appropriate alcohol.     

N,N′,N″-Tri-Boc-guanidine (TBG): a common starting material for both N-alkyl guanidines and amidinoureas

In this Letter, we describe the unexpected reaction pattern of N,N′N″-tri-Boc-guanidine (TBG) with amines at room temperature and under reflux conditions affording N-substituted guanidines and amidinoureas, potentially important compounds with extensive applications in medicinal chemistry. This investigation shows that TBG is an excellent, readily available common starting material for the synthesis of various N-alkyl guanidines as well as N-alkyl-N′-substituted amidinoureas by simply manipulating the reaction conditions.     

Synthesis and Characterization of Novel Methyl (3)5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates

Series of methyl 3- and 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates were developed and regioselectively synthesized as novel heterocyclic amino acids in their N-Boc protected ester form for achiral and chiral building blocks. In the first stage of the synthesis, piperidine-4-carboxylic and (R)- and (S)-piperidine-3-carboxylic acids were converted to the corresponding β-keto esters, which were then treated with N,N-dimethylformamide dimethyl acetal. The subsequent reaction of β-enamine diketones with various N-mono-substituted hydrazines afforded the target 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates as major products, and tautomeric NH-pyrazoles prepared from hydrazine hydrate were further N-alkylated with alkyl halides to give 3-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates. The structures of the novel heterocyclic compounds were confirmed by ¹H-, ¹³C-, and ¹⁵N-NMR spectroscopy and HRMS investigation.     

Base controlled (1,1)- and (1,2)-hydrophosphination of functionalized alkynes

The (1,1)- and (1,2)-addition of diphenylphosphine to 3-butyn-2-one and ethyl propiolate can be controlled chemoselectively by regulating the amount of triethylamine as the external base and in the presence of the chiral organopalladium(II) template derived from (R)-N,N-dimethyl-1-(1-naphthyl)ethylamine.     

Synthesis of chiral 2-(anilinophenylmethyl)pyrrolidines and 2-(anilinodiphenylmethyl)pyrrolidine and their application to enantioselective borane reduction of prochiral ketones as chiral catalysts

Chiral diamines, 2-(anilinophenylmethyl)pyrrolidines and 2-(anilinodiphenylmethyl)pyrrolidine, were prepared from N-(tert-butoxycarbonyl)pyrrolidine or (S)-proline as a starting material, respectively. These chiral diamines were efficient for the catalytic enantioselective borane reduction of acetophenone. Using (S)-2-(anilinodiphenylmethyl)pyrrolidine, chiral secondary alcohols were obtained from prochiral ketones with good to excellent enantiomeric excesses (up to 98% ee).     

Convergent procedure for the synthesis of trifluoromethyl-containing N-(pyridinyl-triazolyl)pyrimidin-2-amines

This study describes a simple and efficient procedure to synthesize a novel series of fourteen 4-substituted N-(5-pyridinyl-1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyrimidin-2-amines, where the 4-substituents are H, CH₃, C₆H₅, 4-FC₆H₄, 4-CH₃C₆H₄, 4-CH₃OC₆H₄ and 2-Furyl; from the cyclocondensation reaction of N-[5-(pyridinyl)-1H-1,2,4-triazol-3-yl]guanidines with 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones. The reactions were carried out in ethanol under reflux for 18 h and led to 40-68% yields. N-(Pyridyl-triazolyl)guanidine precursors were further obtained from reactions of cyanoguanidine with nicotinic or isonicotinic acid hydrazides and the halogenated enones from trifluoroacetylation of enolethers or acetals.     

Enantioselective synthesis of (−)-(1R,2R)-1,2-dihydrochrysene-1,2-diol

A general chiral building block containing the 1R,2R-trans-diol moiety was constructed utilizing the stereoselective Shi-epoxidation reaction on a tetralone scaffold assembled by a Negishi cross-coupling on N,N-diethylbenzamide. Further elaboration of this chiral building block into polycyclic aromatic compounds was demonstrated with the total synthesis of the precursor for the most carcinogenic metabolite of chrysene, (−)-(1R,2R)-1,2-dihydrochrysene-1,2-diol in 87% ee.     

Intramolecular asymmetric C–H insertion of N-arylalkyl,N-bis(trimethylsilyl)methyldiazoamides mediated by chiral rhodium(II) catalysts. Synthesis of (R)-β-benzyl-γ-aminobutyric acid

The enantio- and site-selectivity of the intramolecular C–H insertion reactions of acyclic N-arylalkyl, N-bis(trimethylsilyl)methyl α-diazoacetamides, and α-carboalkoxy-α-diazoacetamides 1a–g, catalyzed by chiral Rh(II) carboxamidates and Rh(II) carboxylates were studied. In general, the reaction showed good to excellent chemoselectivity. Regioselectivity for most of the reactions was high, but was also found to be influenced by the structure of the diazo substrate and the chiral Rh(II) catalyst employed. The highest enantioselectivity for the reactions catalyzed by chiral Rh(II) carboxamidates was 69% and Rh₂(4R-MEOX)₄ was found to be the most effective. For the chiral Rh(II) carboxylate catalyzed reactions, the highest ee obtained was 75% and Rh₂(S-PTTL)₄ is the optimal catalyst. The method was applied toward the synthesis of a GABA analogue, (R)-β-benzyl-γ-aminobutyric acid.     

Reversal of enantioselectivity using tethered bisguanidine catalysts in the aza-Henry reaction

A series of chiral guanidines were synthesized and shown to efficiently catalyze the aza-Henry reaction. Modifications of the catalyst structure revealed important selectivity trends as well as an intriguing reversal in stereoselectivity with bisguanidine variants. These compounds were applied to the aza-Henry reaction between N-Boc imines and nitroalkanes generating the β-nitroamines in up to 77% ee and up to 20:1 diastereoselectivity.     

Synthesis of novel chiral NiII complexes of dehydroalanine Schiff bases and their reactivity in asymmetric nucleophilic addition reactions. Novel synthesis of (S)-2-carboxypiperazine

New chiral Ni^II complexes of Schiff bases of dehydroalanine with modified chiral auxiliaries (S)-2-N-[N′-(3,4-dichlorobenzyl)prolyl]aminobenzophenone (3,4-DCBPB), (S)-2-N-[N′-(3,4-dimethylbenzyl)prolyl]aminobenzophenone (3,4-DMBPB), (S)-2-N-[N′-(2-chlorobenzyl)prolyl]aminobenzophenone (2-CBPB), and (S)-2-N-[N′-(2-fluorobenzyl)prolyl]-aminobenzophenone (2-FBPB) have been synthesized. Asymmetric Michael addition reactions of primary and secondary amines and thiols to the dehydroalanine moieties of the complexes were studied. (S)-2-FBPB was found to be the best chiral auxiliary in terms of both selectivity of the reactions (de ～92–96%) and reactivity of the complexes. A novel synthetic route toward (S)-2-carboxypiperazine was developed based on the auxiliary.     

The first bismuth(III)-catalyzed guanylation of thioureas

This work describes the first catalytic bismuth-promoted synthesis of polysubstituted guanidines in good yields through the guanylation reaction of N-benzoyl or N-phenylthioureas with primary and secondary amines, but now employing equimolar amounts of each organic reagent. Both bismuth iodine and bismuth nitrate were efficient as inorganic thiophiles at only 5 mol % in relation to substrates, being the first example of inorganic thiophiles acting in guanylation at catalytic levels.     

A new entry for the synthesis of N-acyl-N′-substituted guanidines

An efficient synthesis of N-acyl-N′-substituted guanidines by condensation reaction of thiourea and (Me₃Si)₂NH in the presence of EDCI is described. Various guanidines were synthesized in a simple manner.     

Two chiral mononuclear and one-dimensional cadmium(II) complexes constructed by (1R,2R)-N1,N2-bis(pyridinylmethyl)cyclohexane-1,2-diamine derivatives: Effect of positional isomerism

Reactions of (1R,2R)-N¹,N²-bis(pyridinylmethyl)cyclohexane-1,2-diamine derivatives, (1R,2R)-2-bpcd and (1R,2R)-3-bpcd [(1R,2R)-2-bpcd = (1R,2R)-N¹,N²-bis(pyridin-2-ylmethyl)cyclohexane-1,2-diamine, (1R,2R)-3-bpcd = (1R,2R)-N¹,N²-bis(pyridin-3-ylmethyl)cyclohexane-1,2-diamine], with CdI₂ in an analogous way led to the formation of a chiral discrete mononuclear complex and a chiral one-dimensional polymeric chain, respectively, which may be attributed to the positional isomerism of the ligands. The chiral organic ligands and complexes display luminescent properties indicating that they may have a potential application as optical materials. Powder second-harmonic generation (SHG) efficiency measurement shows that the SHG efficiency of the complexes is approximately 0.3 and 0.45 times that of KDP, respectively.     

Enantioselective synthesis of (S)-N,N-diethyl-2-formyl-2-(methoxymethoxy)butyramide,a key intermediate for 20(S)-camptothecin analogues,via asymmetric bromolactonization

A new enantioselective synthetic method for enantiomerically pure (S)-N,N-diethyl-2-formyl-2-(methoxymethoxy)butyramide 5, a versatile key intermediate has been developed employing asymmetric bromolactonization using (S)-proline as the chiral auxiliary.     

Application of new chiral auxiliaries,trans-2-(N-arylsulfonyl-N-benzyl)cyclohexanols,in an asymmetric radical cyclization

New chiral auxiliaries, trans-2-(N-arylsulfonyl-N-benzyl)cyclohexanols, were prepared and applied to an asymmetric radical cyclization.