Chemoselective debenzylation of N-benzyl tertiary amines with ceric ammonium nitrate

Article abstract of DOI:10.1039/b006852g

Treatment of a range of N-benzyl tertiary amines with aqueous eerie ammonium nitrate results in N-debenzylation to afford the corresponding secondary amine. Chemoselective mono-W-debenzylation of N-benzyl tertiary amines is shown to occur in the presence of N-benzyl amides, O-benzyl ethers, O-benzyl esters, O-benzyl phenolates and 5-benzyl ethers. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b006852g

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Chemoselective debenzylation of N-benzyl tertiary amines with
ceric ammonium nitrate
Steven D. Bull,a Stephen G. Davies,*a Garry Fenton,b Andrew W. Mulvaney,a R. Shyam Prasada
and Andrew D. Smitha
1
a The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY. E-mail: steve.davies@chemistry.ox.ac.uk
b Rhône-Poulenc Rorer, Rainham Road South, Dagenham, Essex, UK RM10 7XS
Received (in Cambridge, UK) 22nd August 2000, Accepted 15th September 2000
First published as an Advance Article on the web 30th October 2000
Treatment of a range of N-benzyl tertiary amines with aqueous ceric ammonium nitrate results in N-debenzylation
to afford the corresponding secondary amine. Chemoselective mono-N-debenzylation of N-benzyl tertiary amines
is shown to occur in the presence of N-benzyl amides, O-benzyl ethers, O-benzyl esters, O-benzyl phenolates and
S-benzyl ethers.
perbenzylated substrate has been employed as a deprotection
Introduction
strategy. Thus, while methodology has been developed for the
selective deprotection of O-benzyl esters in the presence of
N-benzyl amines using Pd-catalysed transfer hydrogenation,8
complementary methodology for the chemoselective removal
of an N-benzyl group remains relatively unexplored. We have
observed that in some cases it is possible to control hydrogeno-
lytic deprotection of tertiary amino β-amino esters so that
selective removal of the N-benzyl group in preference to the
N-(α-methylbenzyl) group can be achieved.9 While Pearlman’s
catalyst10 and transfer hydrogenation11 have also been shown in
selected cases to promote N-debenzylation in the presence of
O-benzyl ethers, an oxidative method of N-debenzylation of
tertiary amines would be useful as an alternative to reductive
hydrogenation. Although CAN and DDQ have been widely
used as oxidative agents for the deprotection of methoxy-
The benzyl moiety is one of the most commonly employed pro-
tecting groups for heteroatom functionality in organic synthesis
due to its ease of introduction and inherent stability. A variety
of methodologies have been investigated for benzylic deprotec-
tion,1 with removal via catalytic hydrogenolysis being the
most widely used pathway, particularly for the deprotection
of N-benzyl amines,2 O-benzyl ethers,3 O-benzyl esters,4 and
O-benzyl phenolates.5 Indeed, the susceptibility of N-benzyl
deprotection upon hydrogenolysis has been extensively used
within our laboratory for the asymmetric synthesis of
homochiral β-amino acid derivatives.6 For example, addition
of (R)-N-benzyl-N-α-methylbenzylamide
1 to (E)-methyl
3-(4-benzyloxyphenyl)prop-2-enoate 2 proceeds to give (3S,
αR)-methyl 3-(N-benzyl-N-α-methylbenzylamino)-3-(4-benzyl-
oxyphenyl)propanoate 3 in >95% de and 78% yield. Hydro-
genolysis of 3 to remove the N-benzyl amine and O-benzyl
ether protecting groups and subsequent ester hydrolysis enables
isolation of the homochiral hydrochloride salt of β-tyrosine 4
in excellent yield (Scheme 1).7
13
substituted benzylic protecting groups of alcohol,12 amine9,
and amide functionalities,14 oxidative methods of benzylic
cleavage which do not contain mesomerically donating sub-
stituents are rare. These include the report by Banerji et al. who
have recently shown that certain N-benzyl heterocycles can be
debenzylated upon treatment with TiCl3–Li–I2 in THF in high
yield (Scheme 2).15 Similarly, related oxidative approaches have
Scheme 2 Reagents and conditions: i. TiCl3, Li, THF then I2, RT.
shown that TPAP,16 CuBr–LiOtBu,17 Co()–tBuOOH18 and
PhIO–RuCl2(PPh3)3 19 all have the capacity to oxidise secondary
benzylic amines to imines in high yields (Fig. 1).
Scheme 1 Reagents and conditions: i. (R)-1, Ϫ78 ЊC, THF then NH4Cl
(aq); ii. Pd(OH)2/C, MeOH, H2; iii. HCl (aq).
Although global heteroatom benzylic deprotection can
be readily achieved via hydrogenolysis, there are only a
Towards this aim, preliminary communications upon the
ability of CAN in aqueous MeCN to facilitate the chemo-
selective N-debenzylation of tertiary N-benzyl amines have
few examples where chemoselective debenzylation of
a
DOI: 10.1039/b006852g
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Scheme 5 Reagents and conditions: i. lithium 4-methoxybenzylamide
(1.6 eq.), Ϫ78 ЊC, THF.
Fig. 1
The complete lack of selectivity for deprotection of
tertiary amine 7 with CAN is in sharp contrast to its well estab-
lished use for the deprotection of the 4-methoxy-substituted
benzylic group of N-4-methoxybenzyl-N-benzyl amides24 and
O-methoxybenzyl ethers in the presence of O-benzyl ethers.25
This lack of selectivity implies oxidation at the tertiary nitrogen
centre, rather than at the arene ring, since the outcome of the
reaction is unaffected by arene substitution. Similar ratios of
products have been noted recently by Metz et al.21 for the DDQ
or CAN promoted debenzylation of N-benzyl-N-(4-methoxy-
benzyl)amine 10, which furnished a 55:45 ratio of N-benzyl
11 to N-(4-methoxybenzyl) 12 upon treatment with CAN
(Scheme 6).
been reported by ourselves20 and others,21 and we now report
herein our results, delineating the scope and limitations of this
versatile transformation.
Results and discussion
N-Debenzylation of tertiary N-benzyl ꢀ-amino esters
As part of our continuing programme towards extending the
versatility of our lithium amide conjugate addition method-
ology, a novel debenzylation reaction of tertiary N-benzyl
amines was observed during oxidative deprotection of
tert-butyl 3-[N-benzyl-N-(4-methoxybenzyl)amino]-3-phenyl-
propanoate 7. Tertiary amine 7 was prepared via deprotonation
with n-BuLi of N-benzyl-N-(4-methoxybenzyl)amine 6 (pre-
pared by reductive amination of 4-methoxybenzylamine 5 with
benzaldehyde) at Ϫ78 ЊC and subsequent addition to tert-butyl
cinnamate to give β-amino ester 7 in excellent yield (Scheme 3).
Scheme 6 Reagents and conditions: i. DDQ (1.5 eq.), DCM–H2O
(10:1), 0 ЊC; ii. CAN (2.1 eq.), MeCN–H2O (4:1), 0 ЊC.
Scheme 3 Reagents and conditions: i. PhCHO, EtOH, ∆ then NaBH4;
ii. n-BuLi then tert-butyl cinnamate, THF, Ϫ78 ЊC.
The susceptibility of the unsubstituted N-benzyl group to
undergo oxidative cleavage by CAN suggested that this benzylic
deprotection would be applicable for the debenzylation of other
tertiary N-benzyl amines. Consequently the generality of this
protocol was fully investigated for a range of β-amino esters.
The N-debenzylation of β-amino esters with three benzylic
N-protecting groups was the initial subject of this investigation.
Thus, tert-butyl 3-(N,N-dibenzylamino)-3-phenylpropanoate
13, which contains two N-benzylic and one α-substituted-
N-benzylic group, was prepared by addition of lithium
dibenzylamide to tert-butyl cinnamate in 96% yield. Treat-
ment of 13 with CAN (2.1 eq.) in aqueous acetonitrile
resulted in mono-debenzylation to afford exclusively, by 1H
NMR spectroscopic analysis of the crude reaction mixture, the
known secondary amine 8. Secondary amine 8 was isolated
in 79% yield after chromatography to remove benzaldehyde
(Scheme 7).
As expected,22 treatment of β-amino ester 7 with DDQ
showed selective cleavage of the 4-methoxy-substituted
N-benzyl group, furnishing the known tert-butyl 3-(N-benzyl-
amino)-3-phenylpropanoate 823 and 4-methoxybenzaldehyde.
However, treatment of β-amino ester 7 with CAN (2.1 eq.)
remarkably gave a 50:50 mixture of the two possible cleavage
products N-benzyl 8 and tert-butyl 3-N-(4-methoxybenzyl-
amino)-3-phenylpropanoate 9 (Scheme 4). The identity of
Similarly, N-debenzylation of homochiral tertiary amine
(3R,αS)-tert-butyl
3-(N-benzyl-N-α-methylbenzylamino)-3-
phenylpropanoate 14, which contains one N-benzylic and two
α-substituted N-benzylic protecting groups, gave exclusively
the known (3R,αS)-tert-butyl 3-(N-α-methylbenzylamino)-3-
phenylpropanoate 15 upon treatment with CAN (2.1 eq.).
Secondary amine 15 was isolated in 86% yield after chrom-
atography. Since 15 was a single diastereoisomer, the specific
rotation of (3R,αS)-15 {[α]D23 Ϫ15.8 (c 1.0, CHCl3); lit.26 [α]D21
Ϫ16.3 (c 1.45, CHCl3)} provides confirmation that the stereo-
chemical integrity of 15 is not compromised by the CAN medi-
ated N-benzylic deprotection (Scheme 8).
Scheme 4 Reagents and conditions: i. DDQ (1.2 eq.), DCM–H2O
(5:1), RT; ii. CAN (2.1 eq.), MeCN–H2O (5:1), RT.
secondary amine 9 was confirmed unambiguously by synthesis
via conjugate addition of lithium 4-methoxybenzylamide to
tert-butyl cinnamate in 81% yield (Scheme 5).
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N-benzyl-N-propylamine 20 to tert-butyl crotonate. Treatment
of 18 with aqueous CAN (2.1 eq.) gave the debenzylated sec-
ondary amine 19 in 64% yield, the slightly lower isolated yield
for this debenzylation reaction being attributed to the volatility
of 19 (Scheme 10).
Scheme 7 Reagents and conditions: i. (Bn)2NLi (1.6 eq.), THF,
Ϫ78 ЊC; ii. CAN (2.1 eq.), MeCN–H2O (5:1), RT.
Scheme 10 Reagents and conditions: i. 20 (1.6 eq.), n-BuLi (1.55 eq.),
THF, Ϫ78 ЊC; ii. CAN (2.1 eq.), MeCN–H2O (5:1), RT.
The selective N-debenzylation of β-amino esters with CAN
has been shown to be a facile process. The transformation
proceeds without racemisation of branched benzylic centres,
indicating its utility in asymmetric synthesis.27
N-Debenzylation of N-benzyl tertiary amines
In order to examine further the scope and limitations of this
methodology, tertiary N-benzyl amine tribenzylamine 21 was
subjected to the CAN deprotection conditions. Clean mono-
debenzylation of 21 occurred to afford dibenzylamine 22 and
benzaldehyde, with dibenzylamine 22 being isolated in 90%
yield after chromatography. The selectivity of this oxidative
deprotection for tertiary N-benzyl amines and not secondary
N-benzyl amines was confirmed via treatment of dibenzylamine
22 with CAN which returned starting material in quantitative
yield (Scheme 11).
Scheme 8 Reagents and conditions: i. (S)-1 (1.6 eq.), THF, Ϫ78 ЊC;
ii. CAN (2.1 eq.), MeCN–H2O (5:1), RT.
Extension of this oxidative N-benzyl cleavage method-
ology to the deprotection of tertiary amines containing two
N-benzylic groups was next demonstrated. Thus, (3S,αS)-
isopropyl 3-(N-benzyl-N-α-methylbenzylamino)butanoate 16
was prepared in 85% yield and >95% de by addition of (S)-1 to
isopropyl crotonate. Treatment of β-amino ester 16 with CAN
(2.1 eq.) proceeded with selective N-benzyl cleavage to furnish
(3R,αS)-isopropyl 3-(N-α-methylbenzylamino)butanoate 17 in
85% yield (Scheme 9).
Scheme 11 Reagents and conditions: i. CAN (2.1 eq.), MeCN–H2O
(5:1), RT.
To probe further the range of functionality which could be
tolerated within the parent N-benzyl tertiary amine substrate, a
series of tertiary N,N-dibenzyl-N-alkylamines 23–2828 (Table 1)
was subjected to treatment with CAN (2.1 eq.) as shown in
Scheme 12. For tertiary N-propyl 23, N-butyl 24 and N-hexyl
25 N,N-dibenzylamines the mono-deprotection reaction was
facile, returning the secondary N-benzyl-N-alkylamines 20,
29 and 30 in 54–72% yield after purification. The sterically
hindered N,N-dibenzyl-N-tert-butylamine 26 also underwent
N-debenzylation with CAN, giving N-benzyl-N-tert-butyl-
amine 31 in 68% yield. Attempted deprotection of the N-Me-
and N-Et-substituted tertiary dibenzylamines 27 and 28 proved
unsuccessful under these reaction conditions, with no evidence
for the formation of secondary amines 32 and 33 even upon
treatment with excess CAN and extended reaction times.29
Similarly the CAN debenzylation protocol did not facilitate
deprotection of cyclic tertiary N-benzyl amines, since treatment
of N-benzylpiperidine 34, N-benzylproline ethyl ester 35 and
N-benzylpiperidin-4-one 36 with aqueous CAN showed no
Scheme 9 Reagents and conditions: i. (S)-1 (1.6 eq.), THF, Ϫ78 ЊC;
ii. CAN (2.1 eq.), MeCN–H2O (5:1), RT.
Finally, tertiary amine tert-butyl 3-(N-propyl-N-benzyl-
amino)butanoate 18 containing only one N-benzyl group was
prepared in 79% yield by addition of the lithium amide of
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selective N-deprotection to afford the mono-N-debenzylated
secondary amine 43, leaving the O-benzyl ether moiety intact
(Scheme 14).
Scheme 12 Reagents and conditions: i. CAN (2.1 eq.), MeCN–H2O
(5:1), RT.
Table 1 N-Debenzylation of N,N-dibenzyl-N-alkylamines
R
Yield (%)
23
24
25
26
27
28
Pr
20
29
30
31
32
33
69
72
54
68
—
—
Bu
Hex
tBu
Me
Et
Scheme 14 Reagents and conditions: i. KOtBu, 18-crown-6, BnBr,
THF; ii. CAN (2.1 eq.), MeCN–H2O (5:1), RT.
This methodology was further extended to the mono-
N-deprotection of perbenzylated amino acid derivatives 44, 46
and 48, in order to ascertain the chemoselectivity of this pro-
cess in the presence of O-benzyl esters, O-benzyl phenolates
and S-benzyl ethers. Thus, -Ala, -Tyr and -Cys were per-
benzylated by treatment with K2CO3 and BnBr to afford 44, 46
and 48 in good yield. Reaction of (2S)-benzyl 2-dibenzylamino-
propanoate 44 gave (2S)-benzyl 2-benzylaminopropanoate
45 {[α]D23 Ϫ38.6, c 1.0, MeOH; lit.30 (ent) [α]D25 ϩ40.4, c 1.0,
MeOH} leaving the benzyl ester intact. Furthermore, oxidative
N-debenzylation of the amino functionality of (2S)-benzyl
3-(4-benzyloxyphenyl)-2-dibenzylaminopropanoate 46 and
(2R)-benzyl 3-benzylsulfanyl-2-dibenzylaminopropanoate 48
gave secondary amines (2S)-benzyl 3-(4-benzyloxyphenyl)-2-
benzylaminopropanoate 47 {[α]D24 Ϫ8.3, c 1.2, CHCl3} and
(2R)-benzyl 3-benzylsulfanyl-2-benzylaminopropanoate 49
{[α]D23 Ϫ21.9, c 1.1, CHCl3} respectively in excellent isolated
yields, leaving both the O-benzyl and S-benzyl protecting
groups intact (Scheme 15).
Fig. 2 Compounds inert to N-debenzylation with CAN.
reaction, only returning starting materials, while N-benzyl-
pyrrole 37 polymerised under the reaction conditions (Fig. 2).
Chemoselective N-debenzylation studies
The susceptibility of N-benzyl tertiary amines to undergo
mono-N-debenzylation with CAN led to an investigation of
the chemoselectivity of this transformation. Initial studies in
this area concentrated upon the debenzylation of N-benzyl
tertiary amines in the presence of an N-benzyl amide. Thus,
N,N-dibenzyl-3-dibenzylamino-3-phenylpropionamide 39 was
prepared by addition of lithium dibenzylamide to N,N-
dibenzylcinnamide 38. Treatment of β-amino amide 39 with
CAN (2.1 eq.) resulted in mono-N-debenzylation of the amine
functionality, furnishing secondary amine N,N-dibenzyl-3-
benzylamino-3-phenylpropionamide 40 in 83% yield (Scheme
13).
While traditional protecting group strategies rely upon the
inherent orthogonal chemical reactivity of protecting groups
to establish selective heteroatom deprotection, it is proposed
that the strategy of global benzylic heteroatom protection and
subsequent chemoselective deprotection reported herein is an
alternative protecting group strategy which will find increased
use in organic synthesis.
Conclusion
In conclusion, we have demonstrated that the CAN mediated
N-debenzylation protocol proceeds in uniformly good yields for
acyclic tri-, di- and mono-N-benzyl tertiary amines that do not
contain N-Me or N-Et substituents, with preferential cleavage
of unbranched N-benzylic substituents over α-branched
N-benzylic substituents. N-Benzyl secondary amines are inert
to further oxidation. The CAN mediated N-deprotection is
chemoselective, enabling N-benzyl deprotection in the presence
of N-benzyl amide, O-benzyl ether, O-benzyl ester, O-benzyl
phenolate and S-benzyl ether functionalities. Competitive
experiments with tertiary N-benzyl-N-4-methoxybenzyl-substi-
tuted amines indicate that the outcome of the reaction is
unaffected by arene substitution, implying initial single electron
oxidation by CAN at the tertiary nitrogen centre of the amino
nitrogen rather than at the arene ring of the N-benzyl substi-
tuent. Further mechanistic studies within this area are currently
ongoing to delineate the reaction mechanism of this remarkable
transformation.
Scheme 13 Reagents and conditions: i. N(Bn)2Li (1.6 eq.), THF,
Ϫ78 ЊC; ii. CAN (2.1 eq.), MeCN–H2O (5:1), RT.
Similarly, debenzylation of a tertiary N,N-dibenzylamine
which contained an O-benzyl ether functionality was studied.
Thus, dibenzyl(2-benzyloxyethyl)amine 42 was prepared via
benzylation of 2-(dibenzylamino)ethanol 41 with BnBr in THF.
Treatment of perbenzylated 42 with CAN resulted in chemo-
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Scheme 15 Reagents and conditions: i. K2CO3, BnBr, DMF; ii. CAN (2.1 eq.), MeCN–H2O (5:1), RT; iii. K2CO3, BnBr, EtOH; iv. K2CO3, BnBr,
DMF–H2O.
and warmed to RT. The resultant solution was partitioned
between brine and 1:1 DCM–Et2O and the combined organic
extracts dried (MgSO4), filtered and concentrated in vacuo
before purification by column chromatography.
Experimental
General
All reactions involving organometallic or other moisture-
sensitive reagents were performed under an atmosphere of
nitrogen using standard vacuum line techniques. All glassware
was flame-dried and allowed to cool under vacuum. Tetra-
hydrofuran was distilled under an atmosphere of dry nitrogen
from sodium benzophenone ketyl. n-Butyllithium was used as a
solution in hexanes at the molarity stated. Ceric ammonium
nitrate (A.C.S. grade) was used as supplied. All other solvents
were used as supplied (Analytical or HPLC grade), without
prior purification. Thin layer chromatography was performed
on aluminium sheets coated with 60 F254 silica. Sheets were
visualised using 7% ammonium molybdate in 10% sulfuric
acid–ethanol, iodine, UV light or 1% aqueous KMnO4 solu-
tion. Flash chromatography was performed on Kieselgel 60
silica. Nuclear magnetic resonance (NMR) spectra were
recorded on a Bruker AC 200 (1H: 200 MHz and 13C: 50.3
MHz) or a Bruker DPX 400 (1H: 400 MHz and 13C: 100.6
MHz) spectrometer in the deuterated solvent stated. All chem-
ical shifts (δ) are quoted in ppm and coupling constants (J ) in
Hz. Residual signals from the solvents were used as an internal
reference. 13C multiplicities were assigned using a DEPT
sequence. In all cases, the reaction diastereoselectivity was
Representative procedure 2: for CAN debenzylation
CAN (2.1 eq.) was added portionwise to a stirred solution of
the substrate (1.0 eq.) in MeCN–H2O (5:1) and stirred at RT.
The reaction was quenched by the addition of saturated aque-
ous sodium bicarbonate solution and stirred vigorously for ten
minutes before extracting with Et2O. The combined organic
extracts were dried (MgSO4), filtered and concentrated in vacuo
before purification by column chromatography.
Preparation of N-benzyl-N-(4-methoxybenzyl)amine31
6
Based upon a literature procedure,32 benzaldehyde (5.57 g, 52.5
mmol, 1.05 eq.) and 4-methoxybenzylamine 5 (6.86 g, 50 mmol,
1.00 eq.) were heated at reflux in EtOH (100 ml) before the
addition of NaBH4 (3.18 g, 84 mmol, 1.60 eq.) at 0 ЊC and
warmed to RT. After work-up, concentration in vacuo gave 6 as
a yellow oil (10.8 g, 95%) which was subsequently used without
further purification. δH (200 MHz, CDCl3) 1.72 (1H, br s, NH),
3.76, 3.81 (2 × 2H, s, NCH2 × 2), 3.82 (3H, s, OMe), 6.87–6.91
(2H, m, Ph), 7.27–7.37 (7H, m, Ph).
1
assessed by peak integration in the H NMR spectrum of the
crude reaction mixture. Infrared spectra were recorded on a
Perkin-Elmer 1750 IR Fourier Transform spectrophotometer
using either thin films on NaCl plates (film) or KBr discs (KBr)
Preparation of tert-butyl 3-[N-benzyl-N-(4-methoxybenzyl)-
amino]-3-phenylpropanoate 7
Following representative procedure 1, n-butyllithium (1.6 M,
4.74 ml, 7.6 mmol), 6 (1.78 g, 7.8 mmol) in THF (15 ml) and
tert-butyl cinnamate (1.0 g, 4.9 mmol) in THF (10 ml) gave,
after purification by column chromatography on silica gel
(hexane–Et2O 12:1) 7 as a colourless oil (2.04 g, 96%). Rf 0.25;
C28H33NO3 requires C 77.9; H 7.7; N 3.25; found C 77.5; H 7.5,
as stated. Only the characteristic peaks are quoted in cmϪ1
.
Specific optical rotations were recorded on a Perkin-Elmer 241
polarimeter with a water-jacketed 10 cm cell and are given in
units of 10Ϫ1 deg cm2 gϪ1. Concentrations are quoted in g per
100 ml. Elemental analyses were performed by the micro-
analysis service of the Inorganic Chemistry Laboratory,
University of Oxford.
N 3.2%; νmax/cmϪ1 (film) 2974, 2828 (C–H), 1738 (C᎐O), 1512,
᎐
1456 (OMe bend), 1255 (Ph–O), 1156 (C–O); δH (400 MHz,
CDCl3) 1.35 (9H, s, CO2C(Me)3), 2.72 (1H, dd, J2A,2B 14.4, J2A,3
8.6, C(2)HA), 2.99 (1H, dd, J2B,2A 14.4, J2B,3 6.9, C(2)HB), 3.26
and 3.68 (2 × 2H, ABq, NCH2 × 2), 3.80 (3H, s, OMe), 4.27
(1H, app t, J 7.8, C(3)H), 6.85 (2H, m, Ph(3)H and Ph(5)H
C6H4OMe), 7.21–7.38 (12H, m, Ph); δC (50 MHz, CDCl3) 30.0,
37.2, 53.2, 53.7, 55.2, 59.0, 80.4, 113.6, 126.9, 127.2, 128.0,
128.2, 128.7, 128.8, 130.0, 131.7, 138.5, 139.9, 158.6, 171.1; m/z
APCIϩ 432.3 (MHϩ, 100%), 376.2 (MHϩ Ϫ C4H8, 20%).
Representative procedure 1: for lithium amide additions
n-Butyllithium (1.55 eq.) was added dropwise to a stirred solu-
tion of secondary amine (1.6 eq.) in anhydrous THF at Ϫ78 ЊC
and stirred for thirty minutes under nitrogen. A solution of
the α,β-unsaturated ester (1.0 eq.) in anhydrous THF was
added dropwise via cannula and stirred at Ϫ78 ЊC for two hours
before the addition of saturated aqueous ammonium chloride
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Deprotection of 7 with DDQ
22.8 mmol), (S)-N-benzyl-N-α-methylbenzylamine (5.0 g, 23.5
mmol) in THF (20 ml) and tert-butyl cinnamate (3.0 g, 14.7
mmol) in THF (10 ml) gave, after purification by column
chromatography on silica gel (hexane–Et2O 20:1) 14 as a
colourless oil (5.45 g, 89%). [α]D23 Ϫ4.0 (c 1.0, CHCl3), lit.35 (ent)
[α]D20 ϩ3.9 (c 0.7, CHCl3); δH (400 MHz, CDCl3) 1.22 (9H, s,
OC(Me)3), 1.27 (3H, d, J 6.8, C(α)Me), 2.45–2.60 (2H, m,
C(2)H2), 3.68 (2H, ABq, NCH2), 4.00 (1H, q, J 6.8, C(α)H),
4.41 (1H, dd, J3,2A 9.5, J3,2B 5.6, C(3)H), 7.20–7.49 (15H, m,
Ph).
DDQ (131 mg, 0.58 mmol, 1.2 eq.) was added to a solution of 7
(200 mg, 0.48 mmol, 1.0 eq.) in DCM–H2O (5:1) (3 ml) and
stirred overnight at RT. The solution was poured onto saturated
aqueous sodium bicarbonate solution (20 ml), extracted with
1
DCM (3 × 60 ml), dried and concentrated in vacuo. H NMR
spectroscopic analysis of the crude reaction mixture and
comparison with authentic 1H NMR spectra of tert-butyl
3-(N-benzylamino)-3-phenylpropanoate
8
and tert-butyl
3-(N-4-methoxybenzylamino)-3-phenylpropanoate 9 indicated
the selective cleavage of the 4-OMe substituted benzyl group to
give 8 and 4-methoxybenzaldehyde.
Preparation of (3R,ꢀS)-tert-butyl 3-(N-ꢁ-methylbenzylamino)-
3-phenylpropanoate26 15
Deprotection of 7 with CAN
Following representative procedure 2, CAN (1.10 g, 2 mmol)
was added to 14 (346 mg, 0.83 mmol) in MeCN–H2O (5:1)
(6 ml). Following work-up, the residue was purified by column
chromatography on silica gel (hexane–Et2O 5:1) to give 15 as a
yellow oil (234 mg, 86%). Rf 0.25; [α]D23 Ϫ15.8 (c 1.0, CHCl3);
lit.26 [α]D23 Ϫ16.3 (c 1.45, CHCl3); δH (400 MHz, CDCl3) 1.39
(3H, d, J 6.5, C(α)Me), 1.42 (9H, s, CO2C(Me)3), 1.91 (1H, br s,
NH), 2.59 (1H, dd, J2A,2B 14.7, J2A,3 6.2, C(2)HA), 2.68 (1H, dd,
J2B,2A 14.7, J2B,3 7.9, C(2)HB), 3.70 (1H, q, J 6.5, C(α)H), 4.21
(1H, dd, J3,2B 7.9, J3,2A 6.2, C(3)H), 7.22–7.36 (10H, m, Ph).
Following representative procedure 2, CAN (536 mg, 0.98
mmol, 2.1 eq.) was added to 7 (200 mg, 0.47 mmol, 1.0 eq.) in
MeCN–H2O (5:1) (6 ml) at RT. Following work-up, H NMR
spectroscopic analysis of the crude reaction mixture and com-
parison with authentic 1H NMR spectra of 8 and 9 indicated a
50:50 mixture of secondary amines 8 and 9.
1
Preparation of tert-butyl 3-(N-4-methoxybenzylamino)-3-phenyl-
propanoate 9
Following representative procedure 1, n-butyllithium (1.6 M,
2.38 ml, 3.8 mmol), 4-methoxybenzylamine 5 (538 mg, 3.92
mmol) in THF (10 ml) and tert-butyl cinnamate (0.5 g, 2.45
mmol) in THF (5 ml) gave, after purification by column
chromatography on silica gel (hexane–Et2O 2:1) 9 as a colour-
less oil (673 mg, 81%). Rf 0.3; C21H27NO3 requires C 73.9; H 8.0;
N 4.1; found C 73.5; H 7.75; N 4.0%; νmax/cmϪ1 (film) 3330
Preparation of (3S,ꢁS)-isopropyl 3-(N-benzyl-N-ꢁ-methyl-
benzylamino)butanoate 16
Following representative procedure 1, n-butyllithium (2.5 M,
1.26 mmol, 0.5 ml), (S)-N-benzyl-N-α-methylbenzylamine (250
mg, 1.30 mmol) in THF (3 ml) and isopropyl crotonate (104
mg, 0.81 mmol) in THF gave, after purification by column
chromatography on silica gel (hexane–Et2O 15:1) 16 as a col-
ourless oil (234 mg, 85%). C22H29NO2 requires C 77.8; H 8.6; N
4.1%; found C 77.6; H 8.5; N 4.1%; [α]D24 ϩ4.4 (c 1.0, CHCl3);
(NH), 2924, 2839 (C–H), 1726 (C᎐O), 1514, 1458 (OMe bend),
᎐
1245 (Ph–O), 1151 (C–O); δH (400 MHz, CDCl3) 1.38 (9H, s,
CO2C(Me)3), 1.91 (1H, br s, NH), 2.53 (1H, dd, J2A,2B 15.2,
J2A,3 5.3, C(2)HA), 2.64 (1H, dd, J2B,2A 15.2, J2B,3 8.7, C(2)HB),
3.56 (2H, ABq, NCH2), 3.80 (3H, s, OMe), 4.06 (1H, dd, J3,2B
8.7, J3,2A 5.3, C(3)H), 6.84 (2H, m, Ph(3)H and Ph(5)H
C6H4OMe), 7.25–7.38 (7H, m, Ph); δC (50 MHz, CDCl3) 28.0,
44.2, 50.7, 55.2, 59.0, 80.6, 113.7, 127.3, 128.5, 129.3, 132.4,
142.7, 158.5, 171.1; m/z APCIϩ 342.2 (MHϩ, 60%), 364.2
(MNaϩ, 10%), 286.2 (MHϩ Ϫ C4H8, 100%).
νmax/cmϪ1 (film) 1727 (C᎐O), 1151 (C–O); δ (300 MHz, CDCl )
᎐
H
3
1.12, 1.16 (2 × 3H, d, J 6.2, OCH(Me)2), 1.34 (3H, d, J 6.9,
C(α)Me), 2.07 (1H, dd, J2A,2B 14.2, J2A,3 8.6, C(2)HA), 2.31 (1H,
dd, J2B,2A 14.2, J2B,3 5.1, C(2)HB), 3.39–3.50 (1H, m, C(3)H),
3.63 (1H, d, J 14.9, NCHA), 3.76 (1H, d, J 14.9, NCHB), 3.89
(1H, q, J 6.9, C(α)H), 4.89 (1H, septet, J 6.2, OCH(Me)2), 7.18–
7.43 (10H, m, Ph); δC (100 MHz, CDCl3) 18.7, 21.8, 39.8, 49.7,
50.3, 53.8, 67.4, 126.6, 126.7, 127.8, 128.1, 128.2, 128.3, 142.0,
144.3, 172.1; m/z APCIϩ 340.2 (MHϩ, 100%), 362.1 (MNaϩ,
10%).
Preparation of tert-butyl 3-(N,N-dibenzylamino)-3-phenyl-
propanoate33 13
Following representative procedure 1, n-butyllithium (2.5 M,
3.0 ml, 7.6 mmol), dibenzylamine (1.54 g, 7.8 mmol) in THF
(10 ml) and tert-butyl cinnamate (1.0 g, 4.9 mmol) in THF
(5 ml) gave, after purification by column chromatography on
silica gel (hexane–Et2O 20:1) 13 as a white solid (1.90 g, 96%).
Rf 0.3; δH (200 MHz, CDCl3) 1.34 (9H, s, CO2C(Me)3), 2.72
(1H, dd, J2A,2B 14.4, J2A,3 8.5, C(2)HA), 3.00 (1H, dd, J2B,2A 14.4,
J2B,3 7.1, C(2)HB), 3.27 and 3.72 (2 × 2H, ABq, NCH2 × 2), 4.28
(1H, dd, J3,2A 8.5, J3,2B 7.1, C(3)H), 7.19–7.41 (15H, m, Ph).
Preparation of (3S,ꢀS)-isopropyl 3-(N-ꢁ-methylbenzylamino)-
butanoate 17
Following representative procedure 2, CAN (1.38 g, 2.1 mmol)
was added to 17 (340 mg, 1.0 mmol) in MeCN–H2O (5:1)
(6 ml). Following work-up, the residue was purified by column
chromatography on silica gel (hexane–Et2O 3:1) to give 17 as a
colourless oil (212 mg, 85%). Rf 0.3; [α]D24 Ϫ46.4 (c 1.0, CHCl3);
νmax/cmϪ1 (film) 3339 (NH), 2978, 2932 (C–H), 1728 (C᎐O),
᎐
1109 (C–O); δH (400 MHz, CDCl3) 1.05, 1.24, 1.33 (4 × 3H, d,
C(α)Me, OCH(Me)2 and C(4)H3), 1.53 (1H, br s, NH), 2.32–
2.42 (2H, C(2)H2), 2.98 (1H, app sextet, J 6.2, C(3)H), 3.89
(1H, q, J 6.5, C(α)H), 5.02 (1H, septet, J 6.4, OCH(Me)2), 7.21–
7.33 (5H, m, Ph); δC (50 MHz, CDCl3) 21.4, 21.8, 24.5, 41.0,
47.9, 55.1, 67.5, 126.5, 126.8, 128.3, 146.0, 171.8; m/z APCIϩ
250.2 (MHϩ, 100%), 272.2 (MNaϩ, 20%), 145.9 (MHϩ Ϫ C4H8,
70%); HRMS (CIϩ) C15H24NO2 requires 250.1807; found
250.1808.
Preparation of tert-butyl 3-(N-benzylamino)-3-phenyl-
propanoate23
8
Following representative procedure 2, CAN (1.15 g, 2.1 mmol)
was added to 13 (400 mg, 1.0 mmol) in MeCN–H2O (5:1)
(6 ml). Following work-up, the residue was purified by column
chromatography on silica gel (hexane–Et2O 2:1) to give 8 as a
colourless oil (246 mg, 79%). δH (400 MHz, CDCl3) 1.42 (9H, s,
CO2C(Me)3), 2.14 (1H, br s, NH), 2.58 (1H, dd, J2A,2B 15.2,
J2A,3 5.3, C(2)HA), 2.69 (1H, dd, J2B,2A 15.2, J2B,3 8.7, C(2)HB),
3.64 (2H, ABq, NCH2), 4.13 (1H, dd, J3,2B 8.7, J3,2A 5.3, C(3)H),
7.24–7.43 (10H, m, Ph).
Preparation of N-benzyl-N-propylamine36 20
Based upon a literature procedure,32 benzaldehyde (11.1 g, 105
mmol) and propylamine (5.91 g, 100 mmol) were heated at
reflux in EtOH (50 ml) before addition of NaBH4 (6.05 g, 160
mmol) at 0 ЊC and allowed to warm to RT. After work-up,
concentration in vacuo gave 20 as a colourless oil (13.7 g,
Preparation of (3R,ꢁS)-tert-butyl 3-(N-benzyl-N-ꢁ-methyl-
benzylamino)-3-phenylpropanoate34 14
Following representative procedure 1, n-butyllithium (1.6 M,
3770
J. Chem. Soc., Perkin Trans. 1, 2000, 3765–3774

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92%) which was subsequently used without further purification.
δH (200 MHz, CDCl3) 0.93 (3H, t, J 7.3, NCH2CH2CH3), 1.49–
1.63 (3H, m, NH and NCH2CH2CH3), 2.61 (2H, t, J 7.0,
NCH2CH2CH3), 3.80 (2H, s, NCH2Ph), 7.05–7.35 (5H, m, Ph).
(18 ml) at RT. Following work-up, the residue was purified by
column chromatography on silica gel (hexane–Et2O 1:1 to neat
Et2O) to give 20 as a colourless oil (257 mg, 69% at 80% conver-
sion) with identical spectroscopic properties to those described
previously.
Preparation of tert-butyl 3-(N-propyl-N-benzylamino)butanoate
18
Preparation of N,N-dibenzyl-N-butylamine40 24
Based upon a literature procedure,39 trimethyl orthoformate
(4.0 g, 37.9 mmol), dibenzylamine (5.0 g, 25.3 mmol) and
butyraldehyde (1.8 g, 25.3 mmol) were stirred at RT in MeOH
(100 ml) at pH 6 prior to the portionwise addition of NaBH4
(0.96 g, 25.3 mmol) at 0 ЊC. After sixteen hours, the reaction
was concentrated in vacuo, washed with 10% aqueous citric
acid, extracted with DCM (3 × 100 ml), dried and concentrated
in vacuo. The residue was purified by column chromatography
on silica gel (hexane–Et2O 70:1) to give 24 (4.85 g, 76%) as
a colourless oil. δH (200 MHz, CDCl3) 0.88 (3H, t, J 7.1,
CH2CH2CH3), 1.24–1.55 (2 × 2H, m, CH2CH2CH3), 2.43 (2H,
t, J 7.0, NCH2CH2), 3.57 (4H, s, 2 × NCH2Ph), 7.20–7.40 (10H,
m, Ph).
Following representative procedure 1, n-butyllithium (1.6 M,
6.8 ml, 10.9 mmol), N-propyl-N-benzylamine 20 (1.68 g, 11.3
mmol, 1.6 eq.) in THF (15 ml) and tert-butyl crotonate (1.0 g,
7.03 mmol, 1.0 eq.) in THF (10 ml) gave, after purification by
column chromatography on silica gel (hexane–Et2O 10:1) 18 as
a colourless oil (1.62 g, 79%). νmax/cmϪ1 (film) 2962, 2934
(C–O), 1726 (C᎐O), 1160 (C–O); δ (400 MHz, CDCl3) 0.80
᎐
H
(3H, t, J 7.3, NCH2CH2CH3), 1.05 (3H, d, J 6.7, C(4)H3),
1.37–1.45 (2H, m, NCH2CH2CH3), 1.46 (9H, s, CO2C(Me)3),
2.15 (1H, dd, J2A,2B 14.0, J2A,3 6.5, C(2)HA), 2.32–2.36 (2H, m,
NCH2CH2CH3), 2.51 (1H, dd, J2AB,2A 14.0, J2B,3 7.0, C(2)HB),
3.32 (1H, app sextet, J 7.0, C(3)H), 3.54 (2H, ABq, NCH2Ph),
7.19–7.36 (5H, m, Ph); δC (50 MHz, CDCl3) 11.8, 14.7, 21.7,
28.1, 40.1, 51.9, 53.9, 52.1, 80.0, 126.5, 127.9, 128.6, 141.0,
172.1; m/z APCIϩ 292.2 (MHϩ, 70%), 314.2 (MNaϩ, 20%),
236.1 (MHϩ Ϫ C4H8, 100%); HRMS (CIϩ) C18H30NO2 requires
292.2277; found 292.2281.
Preparation of N-benzyl-N-butylamine41 29
Following representative procedure 2, CAN (2.71 g, 4.94 mmol)
was added to 24 (600 mg, 2.36 mmol) in MeCN–H2O (5:1)
(18 ml) at RT. Following work-up, the residue was purified by
column chromatography on silica gel (gradient elution hexane–
Et2O 1:1 to neat Et2O) to give 29 as a yellow oil (275 mg, 72% at
85% conversion). δH (200 MHz, CDCl3) 0.91 (3H, t, J 7.1,
CH2CH2CH3), 1.29–1.59 (4H, m, CH2CH2CH3), 2.64 (2H, t,
J 7.2, NCH2CH2), 3.80 (2H, s, NCH2Ph), 7.23–7.35 (5H,
m, Ph).
Preparation of tert-butyl 3-(N-propylamino)butanoate 19
Following representative procedure 2, CAN (1.97 g, 3.7 mmol,
2.1 eq.) was added to 18 (500 mg, 1.72 mmol, 1.0 eq.) in
MeCN–H2O (5:1) (6 ml). Following work-up, the residue was
purified by column chromatography on silica gel (hexane–Et2O
2:1) to give 19 as a volatile colourless oil (221 mg, 64%). Rf
(0.3); νmax/cmϪ1 (film) 3337 (NH), 2967 (C–H), 1726 (C᎐O),
᎐
1153 (C–O); δH (400 MHz, CDCl3) 0.91 (3H, t, J 7.4, NCH2-
CH2CH3), 1.09 (3H, d, J 6.4, C(4)H3), 1.42–1.60 (2H, m,
NCH2CH2CH3), 1.44 (9H, s, CO2C(Me)3), 2.22 (1H, dd, J2A,2B
15.0, J2A,3 6.0, C(2)HA), 2.36 (1H, dd, J2B,2A 14.0, J2B,3 6.5,
C(2)HB), 2.48–2.62 (2H, m, NCH2CH2CH3), 3.03 (1H, m,
C(3)H); δC (50 MHz, CDCl3) 11.8, 20.5, 23.4, 28.1, 42.8,
49.0, 50.3, 80.3, 171.8; m/z APCIϩ 202.2 (MHϩ, 10%), 146.1
(MHϩ Ϫ C4H8, 100%); HRMS (CIϩ) C11H24NO2 requires
202.1807; found 202.1806.
Preparation of N,N-dibenzyl-N-hexylamine42 25
Based upon a literature procedure,39 trimethyl orthoformate
(2.4 g, 22.8 mmol), dibenzylamine (3.0 g, 15.2 mmol) and hex-
anal (1.83 ml, 15.2 mmol) were stirred in MeOH (50 ml) at pH6
prior to the portionwise addition of NaBH4 (0.58 g, 15.2 mmol)
at 0 ЊC. After five hours, the reaction was concentrated in vacuo,
partitioned between Et2O and H2O, dried and concentrated
in vacuo to give 25 (3.30 g, 77%) as a pale yellow oil. δH (200
MHz, CDCl3) 0.95 (3H, t, J 6.7, CH2CH3), 1.24–1.60 (8H, m,
CH2CH2CH2CH2CH3), 2.49 (2H, t, J 7.1, NCH2CH2), 3.65
(4H, s, 2 × NCH2Ph), 7.28–7.49 (10H, m, Ph).
Preparation of dibenzylamine37 22
Following representative procedure 2, CAN (2.30 g, 4.2 mmol)
was added to tribenzylamine 21 (575 mg, 2.0 mmol) in MeCN–
H2O (5:1) (6 ml) at RT. Following work-up, the residue was
purified by column chromatography on silica gel (Et2O) to give
dibenzylamine 22 (354 mg, 90%). δH (200 MHz, CDCl3) 3.88
(4H, s, 2 × NCH2Ph), 7.10–7.35 (10H, m, Ph).
Preparation of N-benzyl-N-hexylamine43 30
Following representative procedure 2, CAN (4.09 g, 7.46 mmol)
was added to a stirred solution of 25 (1.0 g, 3.56 mmol) in
MeCN–H2O–THF (6:1:2) (45 ml) at RT. Following work-up,
the residue was purified by Kugelrohr distillation (bp 200 ЊC, 20
mmHg) to give 30 (0.38 g, 54%) as a colourless oil. δH (200
MHz, CDCl3) 0.92–0.98 (3H, m, CH2CH3), 1.35–1.62 (9H, m,
CH2CH2CH2CH2CH3 and NH), 2.70 (2H, t, J 7.2, NCH2CH2),
3.86 (2H, s, NCH2Ph), 7.28–7.42 (5H, m, Ph).
Preparation of N,N-dibenzyl-N-propylamine38 23
Based upon a literature procedure,39 trimethyl orthoformate
(4.0 g, 37.9 mmol), dibenzylamine (5.0 g, 25.3 mmol) and
propionaldehyde (1.47 g, 25.3 mmol) were stirred at RT in
MeOH (100 ml) at pH 6 prior to the portionwise addition of
NaBH4 (0.96 g, 25.3 mmol) at 0 ЊC. After sixteen hours, the
reaction was concentrated in vacuo, washed with 10% aqueous
citric acid and extracted with DCM (3 × 100 ml), dried and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (petrol 40–60–Et2O 70:1) to give
23 (4.45 g, 74%) as a colourless oil. δH (200 MHz, CDCl3) 0.88
(3H, t, J 7.3, CH2CH2CH3), 1.54 (2H, m, CH2CH2CH3), 2.40
(2H, t, J 7.0, NCH2CH2CH3), 3.57 (4H, s, 2 × NCH2Ph), 7.20–
7.42 (10H, m, Ph).
Preparation of N,N-dibenzyl-N-tert-butylamine 26
Benzyl bromide (3.94 g, 23.0 mmol) was added dropwise to a
stirred solution of K2CO3 (3.18 g, 23.0 mmol) and tert-
butylamine (800 mg, 11.0 mmol) in THF–H2O 1:1 (40 ml) at
0 ЊC and allowed to warm to RT. After sixteen hours the mix-
ture was partitioned between H2O and Et2O (3 × 60 ml), dried
1
and concentrated in vacuo. H NMR spectroscopic analysis of
the crude reaction showed a 2:1 ratio of N-benzyl-N-tert-
butylamine to the required N,N-dibenzyl-N-tert-butylamine 26.
The crude material was triturated with DCM and N-benzyl-N-
tert-butylamine was removed by filtration (555 mg, 30%). The
filtrate was evaporated in vacuo and recrystallised from MeOH
to afford 26 as colourless needles (812 mg, 29%), mp 65–66 ЊC.
CAN mediated preparation of N-benzyl-N-propylamine 20
Following representative procedure 2, CAN (2.88 g, 5.26 mmol)
was added to 23 (600 mg, 2.51 mmol) in MeCN–H2O (5:1)
J. Chem. Soc., Perkin Trans. 1, 2000, 3765–3774
3771

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C18H23N requires C 85.3; H 9.15; N 5.55; found C 85.25; H 9.1;
N 5.5%; δH (200 MHz, CDCl3) 1.15 (9H, s, C(CH3)3), 3.72 (4H,
s, 2 × PhCH2), 7.10–7.40 (10H, m, Ph); δC (50 MHz, CDCl3)
27.5, 54.4, 55.7, 126.3, 128.0, 128.5, 143.1; m/z APCIϩ 254
(MHϩ, 60%), 198 (MHϩ Ϫ C4H8, 60%), 164 (MHϩ Ϫ C7H6,
100%), 108 (MHϩ Ϫ C4H8 Ϫ C7H6, 90%).
Attempted oxidative debenzylation of (S)-N-benzylproline ethyl
ester 35
Following representative procedure 2, CAN (1.15 g, 2.1 mmol)
was added to 35 (233 mg, 1.0 mmol) in 5:1 MeCN–H2O (6 ml).
Following work-up, 1H NMR spectroscopic analysis of the
crude reaction showed only starting material (151 mg, 65%
recovery). Repetition of the reaction with CAN (2.30 g, 4.20
mmol, 4.2 eq.) and stirring for 72 hours also returned only
starting material.
Preparation of N-benzyl-N-tert-butylamine44 31
Following representative procedure 2, CAN (1.15 g, 2.10 mmol)
was added to 27 (253 mg, 1.00 mmol) in MeCN–H2O (5:1)
(14 ml) at RT. Following work-up, the residue was purified by
column chromatography on silica gel (gradient elution hexane–
Et2O 1:1 to neat Et2O) to give 31 as a yellow oil (111 mg, 68%).
δH (200 MHz, CDCl3) 1.23 (9H, s, C(CH3)3), 3.77 (2H, s,
PhCH2), 7.35–7.40 (5H, m, Ph).
Attempted oxidative debenzylation of N-benzylpiperidin-4-one
36
Following representative procedure 2, CAN (1.15 g, 2.10 mmol)
was added to 36 (189 mg, 1.00 mmol) in 5:1 MeCN–H2O
(6 ml). Following work-up, 1H NMR spectroscopic analysis
of the crude reaction showed only starting material (130 mg,
69% recovery).
Preparation of N,N-dibenzyl-N-methylamine45 27
Based upon a literature procedure,46 formaldehyde (2 ml),
dibenzylamine (985 mg, 5.0 mmol) and NaBH3CN (500 mg, 8.0
mmol) in MeCN (10 ml) gave 27 as a colourless oil (806 mg,
76%). δH (200 MHz, CDCl3) 2.23 (3H, s, CH3), 3.57 (4H, s,
2 × PhCH2), 7.28–7.40 (10H, m, Ph).
Attempted oxidative debenzylation of N-benzylpyrrole 37
Following representative procedure 2, CAN (1.90 g, 3.46 mmol)
was added to 37 (259 mg, 1.65 mmol) in 5:1 MeCN–H2O
(6 ml). Following work-up, 1H NMR spectroscopic analysis of
the crude product showed a complex mixture of predominantly
polymeric material.
Attempted CAN debenzylation of N,N-dibenzyl-N-methylamine
27
Following representative procedure 2, CAN (1.93 g, 3.52 mmol,
Preparation of N,N-dibenzylcinnamide50 38
2.1 eq.) was added to 27 (354 mg, 1.68 mmol, 1.0 eq.) in
1
Dibenzylamine (18.1 g, 94.5 mmol, 2.1 eq.) was added dropwise
to cinnamoyl chloride (7.5 g, 45 mmol, 1.0 eq.) in DCM
(200 ml) at 0 ЊC and allowed to warm to RT over three hours.
The resultant solution was partitioned between H2O and DCM
(3 × 100 ml), dried and concentrated in vacuo to give a crude
yellow solid which was recrystallised (EtOH) to give 38 (12.4 g,
84%) as white needles. δH (200 MHz, CDCl3) 4.64, 4.73 (2 × 2H,
s, N(CH2Ph)2), 6.92 (1H, d, J 15.4, C(2)H), 7.22–7.51 (15H, m,
Ph), 7.88 (1H, d, J 15.4, C(3)H).
MeCN–H2O (5:1) (6 ml) at RT. Following work-up, H NMR
spectroscopic analysis of the crude reaction mixture showed
only starting material 27.
Attempted CAN Debenzylation of N,N-dibenzyl-N-ethylamine
28
Following representative procedure 2, CAN (613 mg, 1.12
mmol, 2.1 eq.) was added to 28 (120 mg, 0.53 mmol, 1.0 eq.) in
1
MeCN–H2O (5:1) (6 ml) at RT. Following work-up, H NMR
spectroscopic analysis of the crude reaction mixture showed
only starting material 28.
Preparation of N,N-dibenzyl-3-dibenzylamino-3-phenyl-
propionamide 39
Preparation of N-benzylpiperidine47 34
Following representative procedure 1, n-butyllithium (2.5 M,
4.0 ml, 10.0 mmol), dibenzylamine (2.02 g, 10.2 mmol) in THF
(20 ml) and 38 (2.09 g, 6.38 mmol) in THF (15 ml) gave, after
purification by column chromatography on silica gel (pentane–
Et2O 4:1), 39 as a colourless oil (3.25 g, 97%), νmax/cmϪ1 (film)
Piperidine (537 mg, 6.31 mmol), potassium carbonate (435 mg,
3.15 mmol) and benzyl bromide (1.13 g, 6.63 mmol) were sus-
pended in ethanol (20 ml) and stirred for 5 hours. The reaction
mixture was filtered, concentrated in vacuo, redissolved in Et2O,
washed with water, dried (MgSO4) and concentrated in vacuo
to give 34 as a pale yellow oil (867 mg, 79%). δH (200 MHz,
CDCl3) 1.48 (2H, m, C(4)H2), 1.62 (4H, m, C(3)H2 and
C(5)H2), 2.42 (4H, t, J 4.5, C(2)H2 and C(6)H2), 3.52 (2H, s,
PhCH2N), 7.32–7.35 (5H, br s, Ph).
3028 (C–H), 1645 (C᎐O), 1494, 1452; δ (400 MHz, CDCl3)
᎐
H
3.04 (2H, d, J 7.4, CH2CO), 3.34, 3.75 (2 × 2H, d, J 14.0,
N(CH2Ph)2), 4.28 (2H, ABq, PhCH2NCO), 4.53 (3H, m,
PhCH2NCO and PhCHCH2), 7.03–7.42 (25H, m, Ph); δC (100
MHz, CDCl3) 36.04, 48.17, 49.96, 54.59, 60.76, 126.45, 126.85,
127.26, 127.31, 127.56, 128.11, 128.22, 128.30, 128.46, 128.60,
128.83, 128.88, 129.86, 136.49, 137.25, 138.62, 140.01, 171.28;
m/z (APCIϩ) 525 (MHϩ, 100%); HRMS (CIϩ) MHϩ C37H37N2O
requires 525.2906, found 525.2912.
Preparation of N-benzylpyrrole48 37
Following a literature procedure,49 benzyl bromide (1.97 g, 11.5
mmol) was added to pyrrole (670 mg, 10.0 mmol), potassium
tert-butoxide (1.29 g, 11.5 mmol) and 18-crown-6 (264 mg, 1.0
mmol) in Et2O (25 ml). After work-up, purification by Kugel-
rohr distillation (1 mmHg, 100 ЊC) yielded 37 as an amber oil
(1.11 g, 71%). δH (200 MHz, CDCl3) 5.15 (2H, s, NCH2Ph),
6.28 (2H, t, J 2.0, pyrrole CH), 6.75 (2H, m, pyrrole CH), 7.20
(2H, d, J 8.1, Ph), 7.43 (3H, m, Ph).
Preparation of N,N-dibenzyl-3-benzylamino-3-phenyl-
propionamide 40
Following representative procedure 2, CAN (2.34 g, 4.26 mmol)
was added to 39 (1.06 g, 2.03 mmol) in MeCN–H2O (5:1) (6
ml). Following work-up, the residue was purified by column
chromatography on silica gel (Et2O–pentane 2:3) to give 40 as a
colourless oil (733 mg, 83%). νmax/cmϪ1 (film) 3324 (N–H), 3029
Attempted oxidative debenzylation of N-benzylpiperidine 34
(C–H), 1639 (C᎐O), 1452; δ (400 MHz, CDCl ) 2.55 (1H, br s,
᎐
H
3
Following representative procedure 2, CAN (971 mg, 1.77
mmol) was added to 34 (100 mg, 0.57 mmol) in 5:1 MeCN–
H2O (6 ml). Following work-up, 1H NMR spectroscopic
analysis of the crude reaction showed only starting material
(88 mg, 88% recovery).
NH), 2.86 (2H, m, CH2CO), 3.69 (2H, ABq, NHCH2Ph), 4.39
(3H, m, PhCH2NCO and PhCHCH2), 4.63 (2H, ABq, PhCH2-
NCO), 7.10–7.47 (20H, m, Ph); δC (100 MHz, CDCl3) 41.8,
48.1, 49.8, 51.7, 59.7, 126.4, 126.9, 127.4, 127.5, 127.6, 128.2,
128.3, 128.4, 128.6, 128.7, 129.0, 136.2, 137.1, 140.5, 143.1,
3772
J. Chem. Soc., Perkin Trans. 1, 2000, 3765–3774

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171.8; m/z (APCIϩ) 435 (MHϩ, 100%); HRMS (CIϩ) MHϩ
d, J 14.1, 2 × NCHAHBPh), 5.08 (2H, s, PhCH2OAr), 5.19 (2H,
C30H31N2O requires 435.2436, found 435.2448.
ABq, CO2CH2Ph), 6.89 (4H, m, OAr) 7.11–7.52 (20H, m, Ph).
Preparation of N,N-dibenzyl(2-benzyloxyethyl)amine 42
Preparation of (2S)-benzyl 3-(4-benzyloxyphenyl)-2-benzyl-
aminopropanoate 47
To a stirred solution of 2-(N,N-dibenzylamino)ethanol 41 (289
mg, 1.20 mmol) and 18-crown-6 (50 mg) in THF (6 ml) was
added potassium tert-butoxide (161 mg, 1.44 mmol) at RT.
After 30 minutes, benzyl bromide (308 mg, 1.80 mmol) was
added and stirring was continued for a further 16 hours. The
reaction mixture was then poured into water (20 ml), extracted
with Et2O (3 × 20 ml), the combined organic extracts dried
(MgSO4) and concentrated in vacuo. Purification by column
chromatography on silica gel (pentane–Et2O 9:1) gave 42 as a
colourless oil (200 mg, 50%). δH (400 MHz, CDCl3) 2.78 (2H, t,
J 6.0, NCH2CH2O), 3.64 (2H, t, J 6.0, NCH2CH2O), 3.70 (4H,
s, 2 × NCH2Ph), 4.50 (2H, s, OCH2Ph), 7.24–7.42 (15H, m, Ph);
δC (100 MHz, CDCl3) 52.8, 58.9, 69.0, 73.0, 126.8, 127.5, 127.6,
127.7, 127.8, 128.2, 128.3, 128.4, 128.6, 128.8, 138.4, 139.7;
m/z (APCIϩ) 332 (MHϩ); HRMS (CIϩ) C23H25NO requires
332.2014, found 332.2018.
Following representative procedure 2, CAN (190 mg, 0.35
mmol) was added to 46 (90 mg, 0.17 mmol) in 5:1 MeCN–H2O
(5 ml). Following work-up, the residue was purified by column
chromatography on silica gel (gradient elution, 30–40 petrol–
Et2O 7:3 to 1:1) to give 47 as a gum (68 mg, 91%). [α]D24 Ϫ8.3
(c 1.2, CHCl3); νmax/cmϪ1 (film) 3408 (N–H), 1732 (C᎐O), 1512,
᎐
1454 (C–O), 1242, 1160 (C–O); δH (400 MHz, CDCl3) 1.94
(1H, br s, NH), 2.97 (2H, m, ArCH2CH(CO)N), 3.60 (2H,
t, J 6.9, CH(CO)N), 3.68 (1H, d, J 13.1, NCHAHBPh), 3.84
(1H, d, J 13.1, NCHAHBPh), 5.06 (2H, s, PhCH2OAr), 5.12
(2H, ABq, CO2CH2Ph), 6.89 (2H, d, J 8.5 OAr), 7.07 (2H,
d, J 8.5, OAr), 7.25–7.49 (15H, m, Ph); δC (100 MHz, CDCl3)
38.9, 52.0, 62.2, 66.4, 69.9, 114.7, 127.1, 127.5, 128.0, 128.2,
128.4, 128.4, 128.5, 128.6, 129.3, 130.3, 135.6, 137.1, 139.5,
157.6, 174.5; HRMS (CIϩ) MHϩ C30H30NO3 requires 452.2226,
found 452.2224.
Preparation of N-benzyl(2-benzyloxyethyl)amine51 43
Preparation of (2R)-benzyl 3-benzylsulfanyl-2-dibenzylamino-
propanoate 48
Following representative procedure 2, CAN (397 mg, 0.73
mmol) was added to 42 (60 mg, 0.18 mmol) in 5:1 MeCN–H2O
(4 ml). Following work-up, the residue was purified by column
chromatography on silica gel (gradient elution pentane–Et2O
9:1 to 1:1) to give 43 (32 mg, 74%) as a colourless oil. δH (200
MHz, CDCl3) 2.87 (2H, t, J 5.1, NCH2CH2OBn), 3.62 (2H,
J 5.0, NCH2CH2OBn), 3.82 (2H, s, PhCH2N), 4.53 (2H, s,
OCH2Ph) 7.21–7.43 (10H, m, Ph).
-Cysteine hydrochloride monohydrate (878 mg, 5 mmol),
anhydrous potassium carbonate (3.801 g, 27.5 mmol) and
benzyl bromide (3.591 g, 21 mmol) were suspended in DMF
(20 ml) and water (10 ml) was added. After stirring for 5 days,
the mixture was partitioned between Et2O (100 ml) and water
(100 ml) and the combined organic fractions washed with water
(4 × 50 ml), dried (MgSO4) and concentrated in vacuo. Purifi-
cation by column chromatography on silica gel (30–40 petrol–
Et2O 9:1) gave 48 as a pale yellow oil (1.84 g, 77%). [α]D22 Ϫ41.6
Preparation of (2S)-benzyl 2-dibenzylaminopropanoate52 44
-Alanine (1.78 g, 20 mmol), anhydrous potassium carbonate
(8.29 g, 60.0 mmol) and benzyl bromide (10.3 g, 7.13 ml, 60.0
mmol) were suspended in DMF (10 ml). After stirring for 3
days, the reaction mixture was decanted, the supernatant par-
titioned between Et2O (100 ml) and water (100 ml) and the
aqueous phase extracted with Et2O (50 ml). The combined
organic extracts were dried (MgSO4) and concentrated in vacuo
to yield 44 as an amber oil (6.28 g, 87%) which was utilised for
debenzylation reactions without further purification. δH (200
MHz, CDCl3) 1.34 (3H, d, J 7.0, CH3), 3.55 (1H, m, CH3CHN),
3.62 (2H, d, J 13.9, 2 × NCHAHBPh), 3.84 (2H, d, J 14.0,
2 × NCHAHBPh), 5.20 (2H, ABq, CO2CH2Ph), 7.10–7.51 (15H,
m, Ph).
(c 1.8, CHCl3); νmax/cmϪ1 (film) 3017 (C–H), 1731 (C᎐O), 1490,
᎐
1454 (C–O), 1151 (C–O); δH (400 MHz, CDCl3) 2.70 (1H, dd,
J1A,1B 13.5, J1A,2 7.3, SC(1)HAHBC(2)N), 2.82 (1H, dd,
J1B,1A13.5, J1B,28.1, SC(1)HAHBC(2)N), 3.46 (2H, br s, SCH2-
Ph), 3.49 (2H, d, J 14.0, 2 × NCHAHBPh), 3.61 (1H, app. t,
J 7.7, SCH2CHN), 3.86 (2H, d, J 13.7, 2 × NCHAHBPh), 5.19
(1H, d, J 12.3, OCHAHBPh), 5.30 (1H, d, J 12.3, OCHAHBPh),
7.09–7.45 (20H, m, Ph); δC (100 MHz, CDCl3) 30.7, 36.0, 54.5,
60.4, 66.3, 126.9, 127.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.8,
129.0, 129.7, 135.9, 136.0, 137.9, 139.1, 171.2; HRMS (CIϩ)
MHϩ C31H32NO2S requires 482.2154; found 482.2159.
Preparation of (2R)-benzyl 3-benzylsulfanyl-2-benzylamino-
propanoate 49
Preparation of (2S)-benzyl 2-benzylaminopropanoate30 45
Following representative procedure 2, CAN (238 mg, 0.44
mmol) was added to 48 (100 mg, 0.21 mmol) in 5:1 MeCN–
H2O (3 ml). Following work-up, the residue was purified by
column chromatography on silica gel (hexane–Et2O 3:1) to give
49 (70 mg, 86%) as a colourless oil. [α]D23 Ϫ21.9 (c 1.1, CHCl3);
Following representative procedure 2, CAN (385 mg, 0.70
mmol) was added to 44 (120 mg, 0.34 mmol) in 5:1 MeCN–
H2O (6 ml). Following work-up, the residue was purified by
column chromatography on silica gel (pentane–Et2O 3:2) to
give 45 as a colourless oil (85 mg, 96%). [α]D23 Ϫ38.6 (c 1.0,
MeOH), lit.30 (ent) [α]D25 ϩ40.4 (c 1.0, MeOH); δH (200 MHz,
CHCl3) 1.35 (3H, d, J 7.2, CH3), 3.44 (1H, q, J 7.0, CHCH3),
3.74 (2H, ABq, NCH2Ph), 5.19 (2H, s, CO2CH2Ph), 7.30 (5H,
m, Ph), 7.39 (5H, m, Ph).
νmax/cmϪ1 (film) 3412 (N–H), 3025 (C–H), 1728 (C᎐O), 1489,
᎐
1452 (C–O), 1152 (C–O); δH (400 MHz, CDCl3) 2.39 (1H,
br, s, NH), 2.76 (2H, m, SCH2CH(CO)N), 3.51 (1H, t,
J 6.5, CH(CO)N), 3.67 (2H, s, SCH2Ph), 3.69 (1H, d, J 13.2,
NCHAHBPh), 3.86 (1H, d, J 13.1, NCHAHBPh), 5.19 (2H, ABq,
CO2CH2Ph), 7.21–7.54 (15H, m, Ph); δC (100 MHz, CDCl3)
34.0, 36.5, 51.9, 59.9, 66.8, 127.1, 127.3, 128.3, 128.4, 128.5,
128.6, 128.9, 135.5, 137.8, 139.1, 173.3; HRMS (CIϩ)
C24H26NO2S requires 392.1684; found 392.1689.
Preparation of (2S)-benzyl 3-(4-benzyloxyphenyl)-2-dibenzyl-
aminopropanoate52 46
Following a literature procedure,52 -tyrosine (1.81 g, 10 mmol),
anhydrous potassium carbonate (6.10 g, 44.0 mmol) and benzyl
bromide (7.20 g, 5.00 ml, 42.0 mmol) in EtOH (20 ml) gave,
after purification by column chromatography on silica gel (40–
60 petrol–EtOAc 9:1) 46 as a colourless oil (5.21 g, 97%). [α]D23
Ϫ54.5 (c 0.85, CHCl3), lit.52 [α]D25 Ϫ57.0 (c 1.5, CHCl3); δH (200
MHz, CDCl3) 3.02 (2H, m, ArCH2CHCO2), 3.52 (2H, d, J 14.0,
2 × NCHAHBPh), 3.67 (1H, t, J 7.4, ArCH2CHCO2), 3.93 (2H,
Acknowledgements
The authors wish to acknowledge funding from Rhône-Poulenc
Rorer (A. D. S.) and Oxford Asymmetry International Ltd
(R. S. P.) and the EPSRC for CASE awards (to A. D. S. and
R. S. P.).
J. Chem. Soc., Perkin Trans. 1, 2000, 3765–3774
3773

View Online
22 For the selective removal of the N-(3,4-dimethoxybenzyl) protecting
group in the presence of an N-α-methylbenzyl protecting group with
DDQ see ref.9.
23 H. Matsuyama, N. Ito, M. Yoshida, N. Kamigata, S. Sasaki and
M. Iiyoda, Chem. Lett., 1997, 375; K. Ishihara, N. Hanaki,
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24 T. M. Kamenecka and L. E. Overman, Tetrahedron Lett., 1994, 35,
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25 C. Murakata and T. Ogawa, Carbohydr. Res., 1992, 234, 75.
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27 S. D. Bull, S. Delgado-Ballester, S. G. Davies, G. Fenton, P. M. Kelly
and A. D. Smith, Synlett, 2000, 1257.
28 Synthesised from dibenzylamine except for N,N-dibenzylethylamine
28 which is commercially available from Lancaster.
29 For an unsuccessful case of attempted deprotection of N,N-
dimethyl-N-benzylamine with CAN see I. Badea, P. Cotelle and
J.-P. Catteau, Synth. Commun., 1994, 24, 2011.
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