Convenient synthesis of Cbz-protected β-amino ketones by a copper-catalysed conjugate addition reaction

Article abstract of DOI:10.1016/S0040-4039(02)00654-8

A convenient synthesis of Cbz-protected β-amino ketones is reported. Benzyl carbamates and α,β-unsaturated ketones furnish the conjugate addition products in the presence of a Cu(II) catalyst under mild conditions. Other weakly basic nitrogen nucleophiles

Full text of DOI:10.1016/S0040-4039(02)00654-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3891–3894
Convenient synthesis of Cbz-protected b-amino ketones by a
copper-catalysed conjugate addition reaction
Tobias C. Wabnitz and Jonathan B. Spencer*
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
Received 29 March 2002; accepted 2 April 2002
Abstract—A convenient synthesis of Cbz-protected b-amino ketones is reported. Benzyl carbamates and a,b-unsaturated ketones
furnish the conjugate addition products in the presence of a Cu(II) catalyst under mild conditions. Other weakly basic nitrogen
nucleophiles can also be used in this reaction. © 2002 Elsevier Science Ltd. All rights reserved.
philes to a,b-unsaturated enones.4 A large number of
nucleophiles have been used in this reaction. Some
reactive alkyl and aryl amines can be added to CꢀC
multiple bonds without further activation, but with
other nitrogen sources it is normally necessary to per-
form the reaction in the presence of acid5 or base6
catalysts. To circumvent disadvantages associated with
the use of such additives, considerable effort has been
spent towards the development of alternative methods.
Apart from the novel sequential substitution/conjugate
addition methodology of Gomtsyan7 and the aziridino
alcohol rearrangement by Tu,8 these efforts have so far
been focussed on Lewis acid mediated conjugate addi-
tion processes. Very recently an efficient catalytic ver-
sion employing CeCl3–NaI has been developed by the
Bartoli group.9 However, most methods for intermolec-
ular conjugate addition to unsaturated ketones reported
to date describe the addition of alkyl or aryl amines,
which may be difficult to transform into other amino
compounds in the course of a multistep synthesis.
The synthesis of b-amino carbonyl compounds contin-
ues to attract attention due to the importance of this
structural motif in organic chemistry. For example,
b-amino acids occur in nature both in their free form
and in peptides. Various synthetic b-amino acids show
interesting pharmacological properties and serve as pre-
cursors in the synthesis of b-lactams, an important class
of antibiotics.1 Similarly, b-amino ketones are impor-
tant intermediates in the synthesis of natural products
and antibiotics. They are also useful precursors for the
generation of b-amino alcohols, which are common
reagents in the preparation of fine chemicals and
pharmaceuticals.2
The classical method for the synthesis of b-amino
ketones is the Mannich reaction of methyl ketones,
amines and paraformaldehyde. Although recent
advances have made this route more attractive, Man-
nich reactions often suffer from the drawbacks of long
reaction times and harsh reaction conditions, which
impair the applicability in the synthesis of complex
molecules.3 Another common route to b-amino ketones
is the amine alkylation of b-haloketones, but owing to
simplicity and atom economy, the more widely used
method is the conjugate addition of nitrogen nucleo-
We recently reported the conjugate addition of benzyl
carbamate to a,b-unsaturated enones catalysed by
cationic palladium complexes,10 leading to b-amino
O
O
R3 R4 O
R4
O
Cu(OTf)2
O
NH2
O
N
H
R1
R3
R1
CH3CN, r. t.
R2
R2
1a
2
3
Scheme 1. Copper-catalysed addition of benzyl carbamate to a,b-unsaturated ketones.
Keywords: benzyl carbamate; conjugate addition; nitrogen nucleophiles; copper; b-amino ketones.
* Corresponding author. Tel.: +44 1223 331696; fax: +44 1223 336362; e-mail: jbs20@cam.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00654-8

3892
T. C. Wabnitz, J. B. Spencer / Tetrahedron Letters 43 (2002) 3891–3894
ketones bearing a benzyloxycarbonyl (Cbz) moiety
which can easily undergo further conversions using
well-established protective group chemistry.11 During
our ongoing investigations of the scope and the mecha-
nism of this process, we discovered that the palladium
catalyst could be substituted by much cheaper copper
compounds. We wish to report our results on a very
mild and highly efficient copper-catalysed conjugate
addition reaction of unactivated benzyl carbamate and
related nucleophiles to a,b-unsaturated ketones
(Scheme 1).
plexes did not catalyse the reaction at all, nor,
surprisingly, did typical Lewis acid catalysts such as
Ni(ClO4)2 or Yb(OTf)3 which have been found to be
effective in related conjugate addition reactions.14 The
best results were obtained when a 0.7 M solution of the
unsaturated ketone, 10% of the copper catalyst and 1.5
equiv. of benzyl carbamate (1a) in acetonitrile was
stirred at room temperature. Conveniently, the reaction
could be performed in commercially available analytical
grade solvents and inert atmosphere conditions were
not necessary.
A variety of copper(II) compounds, such as CuCl2,
A range of simple a,b-unsaturated ketones were
screened and the results are summarised in Table 1. The
efficiency of the transformation was found to be
strongly dependent on the structure of the acceptor
molecule. Terminal enones were highly reactive and
apart from the desired compounds diaddition products
Cu(SbF6)2 or Woodward’s copper carbene complex,13
12
could be used in this transformation. The highest reac-
tion rates were observed with commercially available
Cu(OTf)2, which was superior to the palladium cata-
lysts in terms of turnover frequency. Copper(I) com-
Table 1. Conjugate addition of benzyl carbamate (1a) to a,b-unsaturated ketones
entrya
1
yield[%]b
81
α,β-enone
product
byproductsb
time
4 h
Cbz
N
O
O
Cbz
Cbz
N
H
O
O
O
(18%)
2a
3a
3b
4a
Cbz
O
O
Ph
N
Ph
53
2
12 h
Ph
Ph
N
Ph
H
O
(37%)
4b
2b
O
O
O
-
3
99
81
87
3 h
1 h
Cbz
Cbz
N
H
Ph
2c
2d
3c
3d
O
-
-
4
N
H
H
N
5c
O
O
12 h
Cbz
Cbz
O
2e
2f
3e
H
N
6c
75
47
-
12 h
48 h
12 h
48 h
O
3fd
3g
O
O
O
7
Cbz
Cbz
Cbz
N
H
N
H
N
H
2g
(16%)
4g
O
O
-
8
Cbz
28
-
N
H
2h
2i
3he
O
9
no reaction
-
Ph
aBenzyl carbamate 1a (1.5 mmol) was added to a solution of 2 (1.0 mmol) and Cu(OTf)2 (0.1 mmol) in CH3CN (1.5 ml) and
stirred at room temperature. bIsolated yields after column chromatography. cAt -35 °C to avoid decomposition. dd.r. 6:1. ed.r.
10:1.

T. C. Wabnitz, J. B. Spencer / Tetrahedron Letters 43 (2002) 3891–3894
3893
could be isolated (entries 1, 2). Good to excellent yields
of the b-amino ketones were obtained with disubsti-
tuted internal enones (entries 3–6). In analogy to the
palladium-catalysed process reported earlier, sub-
stituents other than a proton on the a-carbon of the
acceptor molecule led to a dramatic loss of reactivity
(entries 8, 9). Although 3h could only be isolated in
modest yield, a high diastereomeric ratio was observed.
Good diastereocontrol was also observed when the
g-substituted cyclohexenone 2f was used (entry 6). The
reaction was thermodynamically controlled in some
cases with the equilibrium position determining the
maximum yield. Unreacted starting materials could be
reisolated.
amine 6d reacted readily with 2c to give the desired
adduct 7d in moderate yield in addition to the
intramolecular cyclisation product 8d (entry 4). The
oxazolidinone 6b and benzaldehyde oxime (6c) were
also effective nucleophiles and furnished the addition
products in good yields (entries 2, 3), confirming our
initial assumption that weakly basic nitrogen sources
are particularly suited for this reaction, as they do not
bind too strongly to the transition-metal catalyst.
In conclusion, we have demonstrated that Cbz-pro-
tected b-amino ketones can be prepared selectively in a
simple, Cu(OTf)2-catalysed conjugate addition reaction
under very mild conditions. Apart from experimental
simplicity, the advantages of this methodology are the
use of a cheap catalyst and the insensitivity of the
reaction mixture towards air and moisture. We are
currently investigating the development of an enan-
tioselective catalytic process and the use of chiral nitro-
gen nucleophiles as well as acceptor molecules other
than a,b-unsaturated ketones. Our results will be
reported in due course.
To explore the effect of placing additional steric
demands on the nitrogen nucleophile, the alkylated
carbamates 1b–1d were employed in the addition reac-
tion (Table 2). It was found that these reagents still
gave good yields with methylvinylketone (2a) (entries
1–3), but when 2c was used as an acceptor, a pro-
nounced decrease in yield was observed with increasing
steric congestion (entries 4–6). This observation also
explains why the expected cyclisation product was not
detected in earlier experiments with the dienone 2g;
instead, products arising from single and double addi-
tion to the acceptor were isolated (entry 7, Table 1).
Experimental
Representative experimental procedure as used in the
preparation of 3c: Copper(II) triflate (36 mg, 0.1 mmol)
and the ketone 2c (160 mg, 1.0 mmol) were dissolved in
acetonitrile (1.5 ml). Benzyl carbamate (1a) (227 mg,
1.5 mmol) was added. The light blue solution was
stirred at room temperature and conversion was moni-
tored by TLC. After the starting material had been
consumed, the reaction mixture was adsorbed onto
silica gel and the product was isolated by column
chromatography (eluting solvent ether/petrol ether 3:1).
Yield: 307 mg (99%). 1H NMR (400 MHz, CDCl3)
For further exploration of the structural types of nucleo-
philes which can be used in this reaction, we turned
our attention towards the use of other unactivated,
non- or only weakly basic nitrogen sources (Table 3).
We were pleased to find that fluorenylmethyl carbamate
(6a) gave excellent yield in the addition reaction, but
due to the low solubility of 6a in acetonitrile long
reaction times were necessary (entry 1). The hydroxyl-
Table 2. Effect of alkyl substituents at the carbamate nitrogen atom
entrya
1
product
nucleophile
H
time
24 h
yield[%]b
83
α,β-enone
O
Cbz
Cbz
2a
N
N
N
Cbz
1b
5a
5b
O
O
H
2
3
48 h
48 h
74
63
2a
2a
N
Cbz
1c
H
Cbz
N
N
Cbz
1d
1b
5c
O
24 h
4
2c
Cbz
Cbz
71
Ph
Ph
N
5d
5e
O
51
5
6
2c
2c
1c
1d
48 h
48 h
N
-
no reaction
a1 (1.5 mmol) was added to a solution of 2 (1.0 mmol) and Cu(OTf)2 (0.1 mmol) in CH3CN (1.5 ml) and stirred at room
temperature. bIsolated yields after column chromatography.

3894
T. C. Wabnitz, J. B. Spencer / Tetrahedron Letters 43 (2002) 3891–3894
Table 3. Addition of other weakly basic nitrogen nucleophiles to the acceptor 2c
entrya
yield[%]b
92
nucleophile
Fmoc NH2
product
byproductsb
time
48 h
O
Fmoc
-
1
Ph
Ph
N
H
6a
O
7a
O
O
HN
O
-
-
2
24 h
91
N
O
6b
7b
7c
7d
HO
Ph
O
H
N
+
N
Ph
Ph
Ph
H
3
4
24 h
1 h
70
62
O
-
6c
Ph
H
N
O
O
N
Cbz
N
HO
Cbz
OH
Cbz
Cbz
(23%)
N
OH
8dc
6d
a6 (1.5 mmol) was added to a solution of 2c (1.0 mmol) and Cu(OTf)2 (0.1 mmol) in CH3CN (1.5 ml) and stirred at room
temperature. bIsolated yields after column chromatography. cOnly one diastereomer was detected by NMR.
l=7.93 (d, J=7.5 Hz, 2H), 7.56 (t, J=7.4 Hz, 1H),
7.44 (mc, 2H), 7.40–7.20 (m, 5H), 5.45 (br s, 1H), 5.09
(s, 2H), 4.05 (mc, 1H), 3.35 (dd, J=16.7, 4.7 Hz, 1H),
3.06 (dd, J=16.7, 5.9 Hz, 1H), 1.70–1.60 (m, 2H), 0.94
(t, J=7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
l=199.3 (Cquart), 156.5 (Cquart), 137.3 (Cquart), 137.0
(Cquart), 133.7 (aryl-CH), 129.1 (aryl-CH), 128.9 (aryl-
CH), 128.7 (aryl-CH), 128.5 (aryl-CH), 128.4 (aryl-
CH), 66.9 (CH2), 50.4 (CH), 42.7 (CH2), 27.6 (CH2),
11.2 (CH3). IR (film) wmax/cm−1=3321, 2963, 1681,
1534, 1279, 1245, 1217, 1075, 1026, 970. HRMS (ESI+)
m/z calcd for C19H21NO3Na (M++Na) 334.1419, found
334.1432.
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