Chemoselective oxidative debenzylation of tertiary N-benzyl amines

Article abstract of DOI:10.1039/b000071j

Treatment of tertiary amines containing one or more N-benzyl protecting groups with aqueous ceric ammonium nitrate results in clean N-debenzylation to afford the corresponding secondary amine.

Full text of DOI:10.1039/b000071j

Chemoselective oxidative debenzylation of tertiary N-benzyl amines
a
a
b
a
a
Steven D. Bull, Stephen G. Davies,* Garry Fenton, Andrew W. Mulvaney, R. Shyam Prasad and
a
Andrew D. Smith
a
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, UK OX1 3QY.
E-mail: steve.davies@chem.ox.ac.uk
Rh oˆ ne-Poulenc Rorer, Rainham Road South, Dagenham, Essex, UK RM10 7XS
b
Received (in Liverpool, UK) 4th January 2000, Accepted 25th January 2000
Treatment of tertiary amines containing one or more N-
benzyl protecting groups with aqueous ceric ammonium
nitrate results in clean N-debenzylation to afford the
corresponding secondary amine.
Differentially protected homochiral lithium amide additions to
a,b-unsaturated esters have proved to be an extremely versatile
route for the asymmetric synthesis of homochiral b-amino acids
1
23
and b-lactams.
In the course of studies directed towards
extending the versatility of this lithium amide methodology, the
synthetic applications of a novel debenzylation reaction ob-
served when tert-butyl 3-[benzyl(4-methoxybenzyl)amino]-
3
-phenylpropionate 1 was treated with aqueous ceric ammo-
nium nitrate (CAN) are reported herein. Thus, while treatment
of 1 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
resulted as expected in smooth cleavage of the 4-methoxy-
benzyl protecting group to afford tert-butyl 3-benzylamino-
3
-phenylpropionate 2, treatment of 1 with 2.1 equiv. of CAN in
CH CN–H O afforded a 50+50 mixture of the monodeprotected
3
2
products 2 and tert-butyl 3-(4-methoxybenzylamino)-3-phenyl-
propionate 3 (Scheme 1). It is noteworthy that in both cases the
isolated products were those resulting from cleavage of the
primary benzylic amine; the secondary benzylic centre (b-
centre) remained unaffected under these conditions. This lack of
selectivity for deprotection of tertiary amine 1 is in direct
contrast to the well-established use of CAN for the orthogonal
deprotection of 4-methoxybenzyl ethers in the presence of O-
benzyl ethers.4
This unexpected reaction implies oxidation at the tertiary
nitrogen atom rather than at the arene ring since the outcome of
the reaction is unaffected by arene substitution and therefore
should be equally applicable to debenzylation of simple tertiary
benzylamines. Thus, treatment of tribenzylamine 4 with CAN
gave dibenzylamine 5 in 90% yield after chromatographic
5
purification to remove benzaldehyde. The chemoselectivity of
Scheme 2 Reagents and conditions: i, CAN (2.1 equiv.), CH
3 2
CN–H O
this oxidative debenzylation protocol for tertiary amines was
confirmed by treating dibenzylamine 5 with excess CAN (10
equiv.), which resulted in essentially quantitative recovery of
starting material. Treatment of tertiary amine 6, which contains
two N-benzylic and one a-substituted N-benzylic groups,
resulted in chemoselective monodebenzylation to afford ex-
(5+1); ii, CAN (10.0 equiv.), CH CN–H O (5+1).
3
2
clusively secondary amine 7 in 79% isolated yield. Similarly, N-
debenzylation of homochiral tertiary amine 8, which contains
one N-benzylic and two a-substituted N-benzylic protecting
groups, occurred without epimerisation, to afford homochiral
2
secondary amine 9 {[a]
.5, CHCl
D
215.8 (c 1.0, CHCl
3
); lit. 216.3 (c
1
3
)} in 86% isolated yield. Extension of this method-
ology to the deprotection of tertiary amines containing either
two or one benzylic groups was also demonstrated via treatment
of tertiary amines 10 and 12 to afford secondary amines 11
{
[a]
D
3
246.4 (c 1.0, CHCl )} and 13 in 85 and 64% isolated
yield respectively (Scheme 2). The lower isolated yield for
amine 13 was a result of its inherent volatility, however, no
1
other product was detected in the H NMR spectrum obtained
from the crude reaction mixture.
Since benzyl groups are commonly employed as protecting
groups for other heteroatom functionality the chemoselectivity
of this transformation was examined by carrying out the CAN-
mediated tertiary amine debenzylation protocol on a range of
perbenzylated N,N-dibenzylamines which also contained ben-
Scheme 1 Reagents and conditions: i, DDQ, CH
2 2 2
Cl –H O (5+1); ii, CAN
(
2.1 equiv.), CH CN–H O (5+1).
3
2
DOI: 10.1039/b000071j
Chem. Commun., 2000, 337–338
This journal is © The Royal Society of Chemistry 2000
337

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ation protection–deprotection methodology and to regeneration
of polymer supports in combinatorial chemistry. Investigations
are currently underway to determine the reaction mechanism of
this transformation.
The authors wish to acknowledge Rhône-Poulenc Rorer Ltd.
A. D. S) and Oxford Asymmetry International plc (R. S. P.)
(
together with the EPSRC for CASE awards.
Notes and references
1
S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 2, 183;
S. G. Davies, O. Ichihara and I. A. S. Walters, Synlett, 1993, 461; S. G.
Davies, N. M. Garrido, O. Ichihara and I. A. S. Walters, J. Chem. Soc.,
Chem. Commun., 1993, 1153; S. G. Davies, M. E. Bunnage and C. J.
Goodwin, J. Chem. Soc., Perkin Trans. 1, 1993, 1375; S. G. Davies,
M. E. Bunnage and C. J. Goodwin, Synlett, 1993, 731; S. G. Davies, O.
Ichihara and I. A. S. Walters, Synlett, 1994, 117; S. G. Davies, M. E.
Bunnage, A. J. Burke and C. J. Goodwin, Tetrahedron: Asymmetry,
1
994, 5, 203; S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin
Trans. 1, 1994, 1129; S. G. Davies, O. Ichihara and I. A. S. Walters,
J. Chem. Soc., Perkin Trans. 1, 1994, 1141; S. G. Davies, M. E.
Bunnage, C. J. Goodwin and O. Ichihara, Tetrahedron, 1994, 50, 3975;
S. G. Davies, O. Ichihara, I. Lenoir and I. A. S. Walters, J. Chem. Soc.,
Perkin Trans. 1, 1994, 1411; S. G. Davies, M. E. Bunnage, A. N.
Chernega and C. J. Goodwin, J. Chem. Soc., Perkin Trans. 1, 1994,
2
373; S. G. Davies, M. E. Bunnage and C. J. Goodwin, J. Chem. Soc.,
Perkin Trans. 1, 1994, 2385; S. G. Davies, J. F. Costello and O. Ichihara,
Tetrahedron: Asymmetry, 1994, 5, 1999; S. G. Davies, M. E. Bunnage,
A. J. Burke and C. J. Goodwin, Tetrahedron: Asymmetry, 1995, 6, 165;
S. G. Davies, A. J. Edwards and I. A. S. Walters, Recl. Trav. Chim.
Pays-Bas, 1995, 114, 175; S. G. Davies and G. D. Smyth, Tetrahedron:
Asymmetry, 1996, 7, 1001; S. G. Davies and G. D. Smyth, Tetrahedron:
Asymmetry, 1996, 7, 1005; S. G. Davies and G. D. Smyth, Tetrahedron:
Asymmetry, 1996, 7, 1273; S. G. Davies and O. Ichihara, Tetrahedron:
Asymmetry, 1996, 7, 1919; S. G. Davies and D. J. Dixon, Chem.
Commun., 1996, 1797; S. G. Davies, A. J. Burke and C. J. R.
Hedgecock, Synlett., 1996, 621; S. G. Davies and G. D. Smyth, J. Chem.
Soc., Perkin Trans. 1, 1996, 2467; S. G. Davies and O. Ichihara,
J. Synth. Org. Chem. Jpn., 1997, 55, 26; S. G. Davies J. G. Urones,
N. M. Garrido, D. Diez and S. H. Dominguez, Tetrahedron: Asymmetry,
Scheme 3 Reagents and conditions: i, CAN (2.1 equiv.), CH
3 2
CN–H O
(5+1).
zyl ethers, benzyl esters, benzyl phenolates and benzyl thiolates.
Thus, treatment of 14–17 resulted in clean N-deprotection to
afford the mono-N-debenzylated secondary amines 18, 19
6
{
2
[a]
D
238.6 (c 1.0); lit. [a]
D
for ent-19 40.4 (c 1.0)}, 20 {[a]
D
8.3 (c 1.2} and 21 {[a]
isolated yields (Scheme 3).
D
221.9 (c 1.1)} in good to excellent
With this chemoselective debenzylation of tertiary amines in
hand, the application of this novel cleavage protocol for solid
phase synthesis was apparent. Thus, consecutive reductive
1
997, 8, 2683; S. G. Davies, D. R. Fenwick and O. Ichihara,
7
alkylation of aminomethyl polystyrene resin 22 with hexanal
Tetrahedron: Asymmetry, 1997, 8, 3387; S. G. Davies and D. J. Dixon,
J. Chem. Soc., Perkin Trans. 1, 1998, 2629; S. G. Davies and D. J.
Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 2635;
S. G. Davies, I. Brackenridge, D. R. Fenwick, O. Ichihara and M. E. C.
Polywka, Tetrahedron, 1999, 55, 533; S. G. Davies, J. G. Urones, N. M.
Garrido, D. Diez and S. H. Dominguez, Tetrahedron: Asymmetry, 1999,
afforded polymer supported tertiary amine 23, which was
treated with CAN to afford dihexylamine 24 in 72% overall
yield over the five steps (Scheme 4). This cleavage protocol
constitutes a novel oxidative traceless linker synthesis of
8
secondary amines on a solid support and is of potential further
1
0, 1637; S. G. Davies, G. D. Smyth and A. M. Chippindale, J. Chem.
utility in that cleavage of the secondary amine liberates formyl
Soc., Perkin Trans. 1, 1999, 3089; S. G. Davies, N. M. Garrido, P. A.
McGee and J. P. Shilvock, J. Chem. Soc., Perkin Trans. 1, 1999, 3105;
S. G. Davies and O. Ichihara, Tetrahedron Lett., 1999, 40, 9313.
S. G. Davies and D. R. Fenwick, J. Chem. Soc., Chem. Commun., 1995,
2
1
9
21
polystyrene resin 25 (nmax 1700 cm ; lit. 1700 cm ), thus
affording the possibility of resin recycling.
2
1
109; S. G. Davies and D. R. Fenwick, Chem. Commun., 1997, 565;
D. R. Fenwick, D. Phil. Thesis, University of Oxford, 1996.
S. G. Davies and O. Ichihara, Tetrahedron Lett., 1998, 39, 6045.
C. Murakata and T. Ogawa, Carbohydr. Res., 1992, 234, 75.
Representative protocol: To a solution of N-benzylated tertiary amine (1
3
4
5
mmol) in CH
2.1 equiv.) and the reaction mixture stirred for 2 h. The reaction mixture
was neutralised with NaHCO (aq), extracted with Et O, dried
MgSO ), and the solvent and benzaldehyde removed in vacuo to afford
3 2
CN–H O (5+1), at room temperature, was added CAN
(
3
2
(
4
a crude oil which was purified by chromatography to afford the desired
secondary amine.
6
H. Kubota, A. Kubo, M. Takahashi, R. Shimizu, T. Da-te, K. Okamura
and K. Nunami, J. Org. Chem., 1995, 60, 6776.
Scheme 4 Reagents and conditions: i, CH
trimethyl orthoformate; ii, NaBH (10.0 equiv.), DMF–EtOH (3+1); iii,
CAN (5.0 equiv.), CH CN–H O (5+1), room temp.
3 2 4
(CH ) CHO (5.0 equiv.),
7 S. Kobayashi and Y. Aoki, J. Comb. Chem., 1999, 1, 371.
8 For examples of traceless synthesis of amines on solid supports, see: S.
Brandtner, S. Bräse, D. Enders, J. Köbberling, R. Lazny and M. Wang,
Tetrahedron. Lett., 1999, 11, 2105; A. R. Brown, J. R. Morphy, Z.
Rankovic and D. C. Rees, J. Am. Chem. Soc., 1997, 119, 3288; J. R.
Morphy, Z. Rankovic and D. C. Rees, Tetrahedron. Lett., 1996, 37,
4
3
2
In conclusion, treatment of N-benzyl tertiary amines with
CAN results in smooth N-debenzylation to afford the corre-
sponding secondary amines with complete chemoselectivity.
While some N-debenzylations may be achieved under hydro-
genolytic conditions in acid,10 this novel debenzylation under
oxidative conditions adds considerable versatility to N-benzyl-
3
209.
Y. Bing and L. Wenbao, J. Org. Chem., 1997, 62, 9347.
0 For example, see: J. P. Li, J. Org. Chem., 1975, 40, 3414.
9
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Communication b000071j
338
Chem. Commun., 2000, 337–338