Several reactions of tantalum-imine complexes with isocyanates, a hydrazone, and imides

We have revealed that tantalum-imine complexes reacted regioselectively with phenyl or benzyl isocyanate to afford α -amino amides in high yields. The reaction provides a general method of α - amino amides from various imines and isocyanates using a low-valent tantalum prepared from TaCl 5 and Zn in situ . In addition, we have found a novel reaction of a tantalum-imine complex with a hydrazone and imides to afford heterocyclic compounds in good yields.


Introduction
2][3][4] In many cases, they were formed in situ via ligand-metal exchange followed by a loss of β-hydrogen of an amide moiety, 5 migration of an alkyl group to an (iminoacyl)metal, 6 and reduction of a low-valent complex with phosphaazaallene. 7In the last decade, several examples of convenient syntheses of metal-imine complexes, which were formed by direct reactions of imines with metals or metal salts, have been reported. 8As for group 5 metals, many niobium-imine and tantalum-imine complexes have been postulated as intermediates in several organometallic transformations, 3 whereas only a few have been isolated and crystallographically characterized. 9In 1987, Pedersen et al. reported that treatment of aldimines with NbCl 3 (dme) followed by carbonyl compounds gave β-amino alcohols in good yields.3e They discussed in the paper that these reactions cyclohexyl isocyanate.The reaction proceeded to give the desired α-amino amide although the yield was low (Table 1, entry 1).The reaction system was rather messy, and it was found that the use of an excess amount of the isocyanate decreased the yield of the desired product and led to an increase of unknown insoluble by-products (Table 1, entry 2).We then decided to change the work up procedure to more harsh conditions, which meant using aqueous 10% KOH and stirring for 1 h at room temperature, in order to deactivate the unreacted isocyanate.As expected, the yield was improved (Table 1, entry 3) although a by-product, which was thought to be a urea derivative of the product, was still obtained.Further optimization of the reaction conditions revealed that the use of a slight excess of the imine led to an increased yield, up to 90% in 24 h (entry 5).Benzyl isocyanate also gave a promising result (entry 7).In this case, phenyl and benzyl isocyanates seemed more suitable than cyclohexyl isocyanate.

Table 1. Optimization of the reaction conditions
Encouraged by these results, we next investigated the substrate scope of this reaction (Table 2).In the cases of N-(4-substituted-benzylidene)benzylamine derivatives, the desired products were obtained in high yields (entries 1-3, 9-11), although the formation of Ta-imine complexes from benzylamine derivatives with electron-withdrawing substituents proceeded slowly.N-Benzylidenebenzylaniline and aldimines prepared from heteroaromatic aldehydes and benzylamine also required longer reaction time to form the corresponding Ta-imine complexes in good yields.The aliphatic imine derived from cyclohexanecarboxyaldehyde, and the ketimine derived from cyclohexanone also worked well to afford the corresponding products in good or moderate yields, respectively (Table 2, entry 14, Scheme 2).Scheme 2. The reaction of the ketimine with isocyanate.
In addition, it was found that aldimines derived from chiral amines moderately influenced the stereochemical outcome of subsequent additions of Ta-imine complexes to isocyanates (Table 2, entries 6-8, 15-17).

Table 2. Substrate scope
These results suggested that this strategy might provide a general preparation method for natural and unnatural α-amino amides including α,α-disubstituted α-amino amides. 11,12Further investigation into asymmetric version of this reaction is in progress.

Reactions with a hydrazone and imides
Next we turned our attention to reactions of 2 with carbonyl compounds.It was also reported that 2 reacted with carbonyl compounds to afford β-amino alcohols in good yields.On the other hand, it was revealed by Arai et al. that homo-pinacol coupling of an imine proceeded to give diamine derivalites in good yield using a low-valent niobium prepared from NbCl 5 and Zn. 13 Although it was known that 2 did not react with imines, it was thought that it might react with imine equivalents such as hydrazones to give diamine equivalents.Acylhydrazones 14 are known to be useful imine equivalents because they are solids in many cases and very stable even in the cases of acylhydrazones derived from aliphatic imines.Therefore, we decided to conduct a cross coupling reaction of 2 that was prepared in situ with the benzoylhydrazone derived from hydrocinnamaldehyde.It turned out that the reaction proceeded to give a crystalline compound, whose structure was determined by X-ray crystal structural analysis (Scheme 3). 15heme 3. The reaction of Ta-imine complex with benzoylhydrazone.The compound has a highly complicated structure, which is composed of one imine and two benzoylhydrazones (Figure 1).This odd molecule inspired us to try reactions of tantalum-imine complexes with imides to afford interesting heterocyclic compounds.Indeed, the reactions of a tantalum-imine complex with N-methylphthalimide (10a) and N-methylsucciimide (10b) gave highly functionalized heterocyclic compounds in moderate yields with moderate to good diastereoselectivities, although N-benzylmaleimide (10c) resulted in the formation of a complex mixture (Table 3).

Conclusions
In summary, we have demonstrated the synthetic utilities of tantalum-imine complexes for the syntheses of α-amino amides and heterocyclic compounds.It was found that α-amino amides were readily prepared from imines and isocyanates using a low-valent tantalum generated from TaCl 5 and Zn.A wide variety of imines and isocyanates were applicable, and various α-amino amides were synthesized in high yields.In addition, the first example of the reactions of tantalum-imine complexes with imides was reported, which gave heterocyclic derivatives.These results suggested further applicability of tantalum-imine complexes as useful intermediates in organic synthesis.Further investigations along this line are now in progress.

Experimental Section
General Procedures.Melting points were uncorrected.IR spectra were measured with JASCO FT/IR-610 spectrometers. 1 H and 13 C NMR spectra were recorded on a JEOL JNM-LA300, JNM-LA400, ECX-400 or ECX-600 spectrometer in CDCl 3 unless otherwise noted.
Tetramethylsilane (TMS) served as an internal standard (δ = 0 ppm) for 1 H NMR and CDCl 3 as an internal standard (δ = 77.0ppm) for 13 C NMR. FAB-MS and ESI-MS spectra were measured with JEOL JMS-MS700V and Bruker Daltonics BioTOF II, respectively.X-ray crystal structure analysis was performed on a Rigaku R-AXIS RAPID AUTO.Preparative thin-layer chromatography was carried out using Wakogel B-5F.1,2-Dimethoxyethane (DME) was distilled from ketyl and stored with Na under argon.Dehydrated benzene was purchased from Wako Pure Chemical Industries Ltd. Zinc powder was purchased from Nacalai Tesque and used after washing with 1N HCl, water, and ethanol successively and dried at 200 °C for 12 h.
Typical experimental procedure (Table 1, entry 5).Under argon atmosphere, DME (0.25 ml) was added to a suspension of TaCl 5 (144 mg, 0.40 mmol) and Zn (32 mg, 0.49 mmol) in benzene (0.25 ml), and the mixture was stirred at room temperature for 1 h.N-Benzylidenebenzylamine (1a) (93 mg, 0.48 mmol) in benzene (0.50 ml) was added to the resulting green-brown suspension at the same temperature, and the mixture was stirred for 1 h.The color of the suspension changed to dark red.Phenyl isocyanate (48 mg, 0.40 mmol) in benzene (0.50 ml) was then added, and the mixture was stirred at room temperature for 24 h.The reaction was stopped by addition of aqueous 10% KOH (5 ml) and ether (5 ml), and the mixture was stirred vigorously for 30 min until the brown mixture became white suspension.The white solid was filtered off through celite ® and the residue was washed with ether (10 ml, 3 times).The filtrate and the washes were combined and extracted with ether (10 ml, 2 times).The organic layer was combined and washed with brine and dried over Na 2 SO 4 .The crude product was purified by P-TLC (CH 2 Cl 2 -EtOH, 30:1) to afford 2-(benzylamino)-N,2-diphenylacetamide (5a) (115 mg, 90%).