Applied Catalysis A: General 203 (2000) 307–310

The unexpected formation ofN-benzylated tertiary amines fromtheir corresponding CBZ-protected precursors

Mark Camerona,∗, Robert D. Wilsonb,1

a Department of Process Research, Merck Research Laboratories, Merck& Co. Inc., P.O. Box 2000, Rahway, NJ 07065, USAb Department of Process Research, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU,

UK

Received 29 September 1999; received in revised form 15 February 2000; accepted 16 February 2000

Abstract

The unexpected formation ofN-benzyl tertiary amines was observed during the hydrogenolysis of their correspondingCBZ-protected secondary amines, indicating a potential problem for the industrial application of a process otherwise thoughtto be robust. The reaction is favoured by low hydrogen availability, and under such conditions competitive formation ofN-benzyl analogues occurs rather than affording exclusively the expected free amine. © 2000 Elsevier Science B.V. All rightsreserved.

Keywords:Benzylation; Hydrogenolysis; Palladium catalysts; Phosphines

1. Introduction

An important advantage for the protection of aminesby a benzyloxycarbonyl (CBZ) group is the cleandeprotection back to the parent amine by catalytic hy-drogenolysis over heterogeneous palladium catalysts[1]. Convention describes that cleavage of the carba-mate occurs with the formation of toluene and the car-bamic acid; the latter spontaneously decarboxylatesto release carbon dioxide and the free amine [2,3].We were therefore surprised to find that in severalautoclave reactions at 40 psig hydrogen pressure, thehydrogenolysis of the N-CBZ-spiroindoline methane-

∗ Corresponding author.E-mail addresses:mark cameron@merck.com (M. Cameron),robertwilson@merck.com (R.D. Wilson).

1 Co-corresponding author.

sulphonamide (1), a key intermediate in the synthesisof an orally active growth hormone secretagogue [4]did not cleanly afford the amine2, but also generatedthe N-benzylated analogue3 in 6–10% yield. Fur-thermore, we observed that this phenomena was notlimited to our substrate but was also seen for severalother CBZ-protected secondary amines, indicating apotential problem for the industrial application of aprocess otherwise thought to be robust. The resultsof our investigations indicate thatN-benzyl forma-tion predominates under conditions of poor hydrogenavailability whereas under conditions of high hy-drogen availabilityN-benzyl formation is negligible.Additional experiments led us to postulate the in-volvement of a palladiump-benzyl complex [5,6],resulting from the insertion of a Pd(0) hydride into theCBZ group, in the formation ofN-benzyl compoundsfrom their CBZ protected analogues.

0926-860X/00/$ – see front matter © 2000 Elsevier Science B.V. All rights reserved.PII: S0926-860X(00)00491-9

308 M. Cameron, R.D. Wilson / Applied Catalysis A: General 203 (2000) 307–310

Table 1The effect of stirring rate, hydrogen addition temperature, and pressure upon the hydrogenolysis of1a

H2 addition temperature (◦C) H2 pressure (psig) Stirring rate (rpm) Assay (LC area %)

1 2 3

65 14 700 44.0 52.6 3.4100 18.0 54.3 27.7

20 14 700 0.1 99.6 0.3100 20.8 75.6 3.6

a Reaction conditions: CBZ-spiroindoline1 (25 mmol), 10% by weight Pd/C (10%) in ethanol 65◦C, reaction time=2 h.

2. Experimental

2.1. Typical procedure for palladiumacetate/phosphine reactions

To a solution of CBZ-spiroindoline (1; 2.00 g,5.00 mmol) and hydrazine hydrate (0.125 g, 2.50mmol) in degassed anhydrous THF (30 ml) at 65◦Cunder an atmosphere of nitrogen was added TFP(0.116 g, 0.50 mmol) followed by palladium acetate(0.56 g, 2.5 mmol). Upon addition of the palladiumacetate, the mixture turned black in colour and aslurry was formed. The reaction mixture was stirredat 65◦C for 72 h after which time HPLC analysisshowed the reaction to be complete (<0.02 area%CBZ-spiroindoline remaining). The mixture was fil-tered hot through Solka-Floc (8 g). The filtrate wasevaporated to residue and eluted through silica gel.Fractions containing the desired compound were col-lected and volatiles evaporated in vacuo to afford3 in 58% yield. Compound3 gave a satisfactorymicro-analysis and showed appropriate spectroscopicdata (1H NMR, 13C NMR, IR and LCMS).

3. Results and discussion

Upon examination of our autoclave reaction condi-tions it was noted that3 was formed when poor stir-ring and hydrogen addition at 65◦C were employed.A series of experiments was therefore performed inorder to determine the effect each had on the forma-tion of 3 (Table 1). At a relatively high stirring rate(700 rpm) at 40 psig hydrogen pressure and hydrogenadded at 65◦C the clean formation of2 was observed,with only trace levels of3 present. Maintaining thesame conditions but reducing the hydrogen pressure

to 14 psig led to low levels of theN-benzyl compoundnow being formed. However, a combination of low-ering the hydrogen pressure to 14 psig and reducingthe stirring rate from 700 to 100 rpm resulted in a dra-matic increase in the amount ofN-benzyl compoundformed from 3 to 28%.

Hydrogen pressure and stirring rate are known [1]to have an effect on the availability of hydrogen onthe catalyst’s surface, therefore, the results indicatethat poor hydrogen availability was a major factor inthe formation of3. The importance of hydrogen avail-ability in the formation of3 was further highlightedby the result obtained when the addition of hydrogen(14 psig) was made at 20◦C with a poor stirring rateof 100 rpm. The addition of hydrogen at room tem-perature allows for the efficient pre-reduction of thecatalyst before hydrogenolysis of the spiroindoline.Indeed, under these conditions3 was obtained in only3% yield. However, when the addition of hydrogen(14 psig) was made at 65◦C with a poor stirring rateof 100 rpm, a mixture of1, 2 and3 was obtained in18, 54 and 28% yields, respectively.

Further evidence (Table 3) to support the hypothe-sis thatN-benzyl formation was linked to low hydro-gen availability, was obtained in experiments wherethe surface hydrogen availability was reduced by in-creasing the amount of catalyst added to a solutionof 1 in an alcohol, followed by the rapid addition ofa chemical hydrogen transfer reagent (1 mol equiva-lence), such as ammonium formate. Entry 4 (Table 2)

M. Cameron, R.D. Wilson / Applied Catalysis A: General 203 (2000) 307–310 309

Table 2The influence of hydrogen availability on the formation of3a

Entry Catalystloading(% w/w Pd/C)

Mol eq ofHCO2NH4 withrespect to1

Ratio 3:2by HPLCassay

1 2.5 1 0.252 7.5 1 0.613 22.5 1 0.824 50.0 1 2.03

a Reaction conditions: CBZ-spiroindoline1 (25 mmol) inethanol 20◦C, reaction time=2 h.

shows quite clearly that reducing hydrogen availabil-ity at the catalyst’s surface, by increasing the catalystloading for a given amount of ammonium formate, re-sults in predominant formation of3.

Further studies into the nature of the reaction re-vealed that the formation of3 was not simply due tooxidative addition of the CBZ group to Pd(0), fol-lowed by reductive elimination of theN-benzyl com-pound, since no reaction was observed when1 wastreated with various sources of Pd(0), e.g., Pd(PPh3)4,Pd2dba3, Pd(OAc)2/Et3N, Pd[PPh2CH2CH2PPh2] orPd/C. This suggested a palladium hydride specieswas required for the formation of3. Attempts toprepare such a species led us to discover that theformation of3 was not limited to hydrogenolysis re-actions over Pd/C, but was also generated in 6% yieldwhen Pd(OAc)2/hydrazine was employed for the re-duction. Furthermore, the yield could be increasedby the addition of phosphine (Table 3). In the caseof tris (2-furyl)phosphine (TFP), the reaction nowafforded3 not as a minor process impurity but as the

Table 3Influence of phosphines on the % yield for the conversion of1 to3a

Phosphine 1 2 3

TFP 27.0 58.0(C6F5)3P 43.3 51.4(o-MeOC6H4)3P 60.6 42.9Ph3P 10.8 49.0 40.0Et3P 8.5 52.0 39.0Ph2P(CH2)2PPh2 24.5 46.0 33.0(r-MeOC6H4)3P 5.7 16.0 31.0(o-CH3C6H4)3P 34.0 16.0 11.0

a Reaction conditions: CBZ-spiroindoline1 (5 mmol), phos-phine (0.5 mmol) Pd(OAc)2 (2.5 mmol) hydrazine (2.5 mmol) inTHF 65◦C, reaction time=72 h.

major product in 58% yield (Table 3). The heteroge-neous nature of the reaction precluded investigationby solution NMR to ascertain the nature of the palla-dium species generated. However, examination of thesolid, isolated and examined under inert conditions,by X-ray photon spectroscopy (XPS) showed thatthe palladium species from Pd(OAc)2/N2H4, whichafforded 3 in only 6% yield, was an approximate1:1 mix of Pd(II) and Pd(0), while in contrast, thepalladium species from Pd(OAc)2/TFP/N2H4 was inthe zero valent state. The necessity for the presenceof a hydride source in order to generate3 coupledwith XPS result suggests that a hydride of Pd(0)may be involved in the formation of3. XPS couldnot distinguish whether the data obtained for thesolid prepared from Pd(OAc)2/TFP/N2H4 was dueto a discrete palladium hydride complex or a pal-ladium metal hydride. Although no direct evidencewas obtained for the mechanism one possibility mayinvolve insertion of a palladium hydride into theCBZ group resulting in the formation of ap-benzylcomplex,p-benzyl complexes of the platinum groupare involved in a number of reactions either by im-plication or direct observation, [5,6], this complexmay either be trapped by the parent amine to givethe N-benzylated product or hydride to give toluene.The reaction was not limited to our substrate butwas observed for other CBZ-protected secondaryamines as well. For example,N-CBZ-piperidine, andN-CBZ-4-benzylpiperidine afforded theirN-benzylanalogues in 20 and 41% yield, respectively. Sub-stituted benzyloxycarbonyls analogues of1, such as4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxy-carbonyl, also gave their correspondingN-benzylderivatives in 58 and 5% yields, respectively. How-ever, the reaction appeared to be specific for sec-ondary amines becauseN-CBZ protected derivativesof primary amines such as aniline and phenylalaninemethyl ester, under the same conditions, only gavetheir corresponding free amines.

4. Conclusion

In summary, our results indicate an alternativepathway for the cleavage of CBZ-protected secondaryamines, which has no literature precedent, and resultsin the formation ofN-benzyl amines. The reaction

310 M. Cameron, R.D. Wilson / Applied Catalysis A: General 203 (2000) 307–310

is heterogeneous, appears to require a palladium hy-dride species and is favoured by low hydrogen avail-ability. Under such conditions competitive formationof N-benzyl analogues occurs rather than affordingexclusively the expected free amine.N-Benzyl forma-tion is negligible under conditions of high hydrogenavailability, which can be achieved by pre-saturationof the catalyst with hydrogen, 40 psig hydrogen pres-sure and efficient stirring throughout the reaction.

Acknowledgements

We thank Dr. D.J. Kennedy for NMR interpreta-tion, P.V. Byway for mass spectral measurements, andDr. A. Crossley (Materials Characterisation Services,

Atomic Energy Association, Harwell, Didecot, UK)for X-Ray Photon Spectroscopy analysis.

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