Aminoborohydrides. 13. facile reduction of N -alkyl lactams with 9-borabicyclo[3.3.1]nonane (9-BBN) and lithium aminoborohydrides (LAB) reagents

Two methods to reduce N -alkyl lactams to the corresponding cyclic amines using 9-borabicyclo[3.3.1]nonane (9-BBN) and lithium aminoborohydride (LAB) reagents are reported. The lactam reductions required 2.2 molar equivalents of 9-BBN or 1.5 molar equivalents of LAB reagent and were complete within two hours in refluxing THF (65 °C). Reductions with these reagents are chemoselective and complementary in nature. A lactam can be reduced in the presence of an ester with 9BBN. At lowered temperature, an ester can be reduced in the presence of lactam with LAB reagents. At elevated temperature, LAB reagents act as powerful reducing agents, and reduce both lactam and ester functional groups in a difunctional molecule. The reaction products were easily isolated in good to excellent yields after simple work-ups.


Introduction
The reduction of lactams to the corresponding cyclic amines is an important transformation in the synthesis of biologically active plant alkaloids and pharmaceutical compounds. 1Many reagents are available for the reduction of lactams to amines including diisobutylaluminum hydride, 2 alane, 3 sodium bis(2-methoxyethoxy)aluminum hydride, 4 rhodium-catalyzed hydrosilylation, 5 and sodium borohydride, 6 lithium aluminum hydride (LiAlH 4 ) 7 and boranetetrahydrofuran (BH 3 -THF). 8Of these reagents, LiAlH 4 and BH 3 -THF have been two of the most commonly used reagents for the reduction of lactams in the literature.However, both of these reagents have some serious drawbacks.Both LiAlH 4 and BH 3 -THF are highly pyrophoric reagents. 9In addition, LiAlH 4 tends to form strong emulsions during the aqueous work-up due to the formation of aluminum oxides.An excess of the expensive borane reagent is required for complete substrate reduction due to the strong complexation of BH 3 to the amine products.We were interested in developing new methods for lactam reduction using easy to handle reagents such as 9-borabicyclo[3.3.1]nonane(9-BBN) and lithium aminoborohydride (LAB) reagents.Lithium aminoborohydrides are a new, powerful, selective and non-pyrophoric class of reducing agents.Lithium aminoborohydrides are able to reproduce in air virtually all of the transformations now carried out with LiAlH 4 including the reduction of amides and lactams. 109-Borabicyclo [3.3.1]nonane is a regioselective hydroboration agent and chemoselective reducing agent for the reduction of aldehydes, ketones, acid chlorides, amides and lactams. 11Herein we report the results of our comparative study on the reduction of lactams with these reagents.

Reduction of lactams with 9-borabicyclo[3.3.1]nonane
In our study, we investigated the reduction of 5-and 6-membered N-alkyl lactams using 9-BBN as the reducing agent.Half molar (0.5 M) solutions of 9-BBN in tetrahydrofuran (THF) were prepared by quickly weighing out a calculated amount of commercial 9-BBN crystals in air and dissolving the reagent in anhydrous THF.Initially, when only a theoretical amount of 9-BBN (2.0 molar equivalents) was used and/or the reductions were attempted at room temperature (25 °C), a mixture of amine product and unreduced substrate was isolated.We then employed a slight excess of 9-BBN (2.2 molar equivalents) reagent and carried out the reductions in refluxing THF (65 °C) to insure complete and rapid reduction of the lactam substrates.1-Benzylpyrrolidin-2-one was refluxed in THF with 2.2 molar equivalents of 9-BBN and the reaction was monitored by 11 B-NMR and FTIR spectroscopy.At 1 h, the characteristic 9-BBN singlet at δ = +27 ppm was absent from the 11 B-NMR spectra and the lactam carbonyl peak (ν = 1659 cm -1 ) had disappeared from the FTIR spectra.After a simple non-oxidative work-up with ethanolamine in pentane to separate the amine product from the 9-BBN by-product, 1-benzyl-pyrrolidine (1) was isolated in very high yield as the sole reduction product as determined by 1 H-NMR, 13 C-NMR and HRMS analysis (eq 1).

Reduction of lactams with lithium aminoborohydrides
Initially, we postulated that LAB reagents would be able to perform a selective reduction of Nalkyl lactams to give either a cyclic amine or an amino alcohol, which would be similar to the selective reduction of tertiary amides using the LAB reagents.10a,b However, reduction of N-alkyl lactams with LAB reagents gave only the corresponding cyclic amine products, regardless of the steric requirements of the amino group contained in the LAB reagent.The reduction of 1-benzylpyrrolidin-2-one using 1.5 molar equivalents of LiH 3 BNMe 2 gave 1 in 86 % isolated yield.In a similar manner, the reduction of 1-benzylpyrrolidin-2-one with the sterically more demanding LiH 3 BN(i-Pr) 2 also gave 1 in 86 % isolated yield (eq 2).

Equation 2
The reduction of 1-benzylpyrrolidin-2-one was carried out by adding the neat lactam substrate to a 1 M solution of LAB reagent in THF and heating the reaction to reflux (65 °C).The reduction of 1-benzyl-pyrrolidin-2-one in refluxing THF using only one molar equivalent of LiH 3 BNMe 2 gave 1 and some unreacted starting material.Therefore, 1.5 molar equivalents of LAB reagent were subsequently used per mole of substrate to insure rapid and complete reduction of the lactam functional group.The lactam reduction was easily monitored by FTIR spectroscopy for the disappearance of the characteristic lactam carbonyl peak of 1-benzylpyrrolidin-2-one at ν = 1659 cm -1 .Upon completion of the reduction, the amine product 1 was easily isolated after a simple aqueous work-up.
The reduction of a lactam containing a moderately sterically bulky N-alkyl group with LiH 3 BNMe 2 gave a good yield of the amine product.The reduction of 1-cyclohexyl-pyrrolidin- Reduction of high molecular weight lactams with LiH 3 BNMe 2 gave high yields of the amine products indicating that LiH 3 BNMe 2 completely reduced the lactam substrates.When 1-octylpyrrolidin-2-one was refluxed in THF for 2 h with LiH 3 BNMe 2 , compound 4 was isolated from the reaction mixture in 89 % isolated yield (Table 2, Example 3).The reduction of 1-dodecylpyrrolidin-2-one with LiH 3 BNMe 2 gave 5 in 96 % yield (Table 2, Entry 4).The progress of the lactam reductions with LAB reagents was easily monitored by FTIR spectroscopy for the disappearance of the lactam carbonyl peaks for the 5-and 6-membered N-alkyl lactams at ν = 1705 -1660 cm -1 .Most of the reductions with LAB reagents were essentially complete after refluxing in THF for 2 h and the amine products were easily isolated after a simple aqueous work-up.
Lithium dimethylaminoborohydride was not able to reduce the secondary lactam, oxindole.When oxindole was added to a 1 M THF solution of LiH 3 BNMe 2 , an exothermic reaction ensued and a white solid precipitated out of solution.The lactam carbonyl peak at ν = 1732 cm -1 decreased over a 2 h reaction period.After 2 h, the reaction was quenched with deuterium oxide (D 2 O), and then 3 M HCl was added.After extracting the reaction mixture with ether, the starting material was recovered in 85 % yield (Table 2, Example 5).In this example, LiH 3 BNMe 2 may have acted as a lithium amide base.The acidic nitrogen proton (pKa ~ 15) of the lactam was possibly deprotonated by LiH 3 BNMe 2 resulting in a THF-insoluble lithium salt of oxindole, that was not reduced by the remaining LAB reagent.However, this hypothesis was not confirmed by deuterium incorporation into the recovered starting material.

Table 2. Reduction of lactams with lithium dimethylaminoborohydride
a All reactions carried out on a 10 mmol scale unless otherwise noted.b Isolated yields.c All compounds were characterized by 1 H-NMR, 13 C-NMR and HRMS.d 5 mmol scale reaction.e Recovered yield of starting material.
Most N-alkyl lactams were effectively and exclusively reduced to the corresponding cyclic amine products by LAB reagents.However, there are caveats for these reductions.One N-alkyl lactam substrate underwent ring-opening with the LAB reagents to give some of an amino alcohol product.Reduction of 1-phenyl-pyrrolidin-2-one at 25 °C with LiH 3 BNMe 2 gave a mixture of 1-phenyl-pyrrolidine (2) (68 % by GC) and 4-phenylamino-butan-1-ol (10) (32 % by GC) in 85 % yield (Table 3, Example 1).Subsequent reduction of this substrate at 25 °C with a LAB reagent that contained a sterically hindered amino group did not seem to significantly change the product ratio.The reduction of 1-phenyl-pyrrolidin-2-one with LiH 3 BN(i-Pr)

Complementary reductions with 9-BBN and LAB reagents
The complementary nature of 9-BBN and LAB reagents was demonstrated in the reduction of a difunctional molecule that contains both an ester group and a lactam group, 1-benzyl-5-oxopyrrolidine-3-carboxylic acid methyl ester.The lactam group in this molecule was chemoselectively reduced using 2.5 molar equivalents of 9-BBN.FTIR analysis of the reaction product revealed that the ester group was left intact after the reduction.The amino ester product, 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (11), was isolated from the reaction mixture in 86 % isolated yield (Scheme 1, top right).Since 9-BBN is a mild Lewis acid that does not coordinate to the amine product, only a 2.5 equivalents of 9-BBN was required for complete reduction of the lactam functional group.A similar reduction can be carried out using BH 3 -THF as the reducing agent, but only a moderate yield of the amine product was obtained when a stoichiometric amount of BH 3 -THF was utilized for reduction.8b,c The reduction of 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with LiH 3 BNMe 2 was dependent upon both the reagent stoichiometry and the reaction temperature.The reduction of esters with LAB reagents is quite facile even at room temperature or at reduced temperatures.10b In contrast, the reduction of lactams with LAB reagents required elevated temperature (65 °C) or extended periods (8 h) at room temperature.Due to the difference in reactivity of these functional groups, we were able to selectively reduce an ester group with LiH 3 BNMe 2 in the presence of a lactam group.At -10 °C, the ester in this substrate was chemoselectively reduced by stirring with 1.1 molar equivalents of LiH 3 BNMe 2 .The alcohol product, 1-benzyl-4-hydroxymethyl-pyrrolidin-2-one (12), was obtained in 96 % isolated yield.FTIR analysis of the reaction product indicated that the lactam group remained intact after reduction (Scheme 1, bottom center).A similar reaction can be carried out with LAH-SiO 2 , which selectively reduces an ester in the presence of a lactam. 12t elevated temperature (65 °C) and using excess of reagent, LAB reagents act as powerful reagents and are able to reduce both lactam and ester groups.When 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester was refluxed in THF (65 °C) with 2.5 equivalents of LiH 3 BNMe 2 , both the ester and the lactam groups were completely reduced within 2 h as determined by FTIR analysis of a reaction aliquot.The amino alcohol product, (1-benzyl-pyrrolidin-3-yl)-methanol (13), was obtained in 88 % isolated yield (Scheme 1, top left).

Scheme 1. Complementary reductions with 9-BBN and LAB reagents.
A similar transformation can be carried out with the powerful LiAlH 4 , which reduces both lactam and ester groups.7b However, reductions using the non-pyrophoric LAB reagents holds a significant advantage over reductions using the pyrophoric LiAlH 4 .

Conclusions
Two new methods for the reduction of N-alkyl lactams to the corresponding cyclic amine products using 9-BBN and LAB reagents have been developed.Reductions with these reagents are complementary in nature.Since 9-BBN is a chemoselective reducing agent, the reduction of a lactam in the presence of an ester is possible.At lowered temperature (10 °C), LAB reagents can selectively reduce an ester in the presence of lactam.At elevated temperature (65 °C), LAB reagents act as powerful reducing agents, and reduce both lactam and ester functional groups.
In addition to being selective reducing agents, 9-BBN and LAB have many attractive qualities that make these reagents useful for the reduction of lactams.A large excess of either 9-BBN or LAB reagents is not necessary for complete substrate reduction.Both reagents are easy to handle in the laboratory.9-Borabicyclo[3.3.1]nonane is a nonvolatile solid that can be quickly weighed out in air.Lithium aminoborohydrides are non-pyrophoric reagents that can be easily handled in air.In contrast to LiAlH 4 , LAB reagents do not form strong emulsions during the aqueous work-up.Finally, reduction of lactams with 9-BBN and LAB reagents employ simple work-ups and give the cyclic amine products in good to excellent isolated yields.

Experimental Section
General Procedures.All substrates were obtained from commercial sources.All operations were carried out under a nitrogen atmosphere.All glassware, syringes and needles were oven dried and cooled to room temperature before use.Tetrahydrofuran was freshly distilled from sodium and benzophenone.Anhydrous diethyl ether was purchased and used directly. 11B-NMR spectra were obtained on a Bruker ACF Multiprobe 250 MHz NMR.Chemical shifts are reported relative to BF3-Et2O in δ ppm with upfield peaks assigned as negative. 1H-NMR and 13 C-NMR spectra were obtained on a Varian Unity Plus Multiprobe 500 MHz.Chemical shifts are reported relative to TMS in δ ppm.Mass spectra were obtained on an Applied BioSystems Mariner Mass Spectrometer.Atomic mass units are reported as a mass to charge ratio (m/z).IR spectra were obtained on a Perkin-Elmer 1600 Series FTIR spectrometer.Units are reported as wavenumbers (ν) in cm -1 .Reaction products were analyzed on a HP 5890 Series II gas chromatograph attached to a HP 3392A integrator.Products were separated using a 50 m methylsiloxane capillary column with helium as a carrier gas.

Representative procedure for synthesis of lithium dimethylaminoborohydride (1 M solution in THF)
A dry 125-mL serum vial fitted with a rubber septum and equipped with a magnetic stir bar was charged with dimethylamine-borane (5.89 g, 100 mmol) and anhydrous THF (60 mL).At 0 °C, n-butyllithium in hexanes (40 mL, 2.5 M, 100 mmol) was added dropwise via syringe.After stirring at 0 °C for 1 h, an aliquot was taken and analyzed by 11 B-NMR spectroscopy. 11B-NMR analysis (80.25 MHz, THF) showed the solution to be lithium dimethylaminoborohydride δ= -15.5 ppm (q, J = 85 Hz).

Table 3 .
Reduction of 1-Phenyl-pyrrolidin-2-one with LAB Reagents THF a Product ratios determined by capillary GC. b Isolated yields.