Copper(II) triflate catalyzed amination of 1,3-dicarbonyl compounds

Article abstract of DOI:10.1002/chem.201201219

A method to prepare α,α-acyl amino acid derivatives efficiently by Cu(OTf)₂+1,10-phenanthroline (1,10-phen)-catalyzed amination of 1,3-dicarbonyl compounds with PhI=NSO₂Ar is described. The mechanism is thought to initially involve aziridination of the enolic form of the substrate, formed in situ through coordination to the Lewis acidic metal catalyst, by the putative copper-nitrene/imido species generated from the reaction of the metal catalyst with the iminoiodane source. Subsequent ring opening of the resultant aziridinol adduct under the Lewis acidic conditions then provided the α-aminated product. The utility of this method was exemplified by the enantioselective synthesis of a precursor of 3-styryl-2-benzoyl-L-alanine. Copyright

Full text of DOI:10.1002/chem.201201219

FULL PAPER
DOI: 10.1002/chem.201201219
Copper(II) Triflate Catalyzed Amination of 1,3-Dicarbonyl Compounds
Thi My Uyen Ton, Fanny Himawan, Joyce Wei Wei Chang, and Philip Wai Hong Chan*[a]
Abstract: A method to prepare a,a-
acyl amino acid derivatives efficiently
the Lewis acidic metal catalyst, by the
putative copper–nitrene/imido species
generated from the reaction of the
metal catalyst with the iminoiodane
source. Subsequent ring opening of the
resultant aziridinol adduct under the
Lewis acidic conditions then provided
the a-aminated product. The utility of
this method was exemplified by the
enantioselective synthesis of a precur-
sor of 3-styryl-2-benzoyl-l-alanine.
by
CuACHTUNGTRENNUNG(OTf)2 +1,10-phenanthroline
(1,10-phen)-catalyzed amination of 1,3-
dicarbonyl compounds with PhI=
NSO2Ar is described. The mechanism
is thought to initially involve aziridina-
tion of the enolic form of the substrate,
formed in situ through coordination to
Keywords: amination · copper · di-
carbonyl compounds · homogenous
catalysis · iminoiodanes
Introduction
An ongoing challenge in medicinal chemistry is the design
of new compounds containing unnatural a-amino acids,
those outside the set of 20 used by nature, which can exhibit
novel modes of therapeutic activity.[1] For this reason, the
development of novel routes to new members of this im-
mensely important class of biomolecules from readily availa-
ble and inexpensive substrates and catalytic systems contin-
ues to be actively pursued in organic synthesis.[2]
Scheme 1. Copper(II)-catalyzed reactivities of b-dicarbonyl compounds
with PhI=NSO2Ar.
Transition-metal-catalyzed nitrogen-atom and -group
transfer reactions have become one of the most powerful
and convenient synthetic routes to amines and amine deriva-
tives over the years.[3–8] Recently, this included renewed in-
terest in the development of this approach by using copper
catalysis, owing to its low cost and better biocompatibility
when compared to other metal complexes.[3–6] For example,
we reported a method for the synthesis of a-acyl b-amino
acid derivatives that relied on nitrene/imido insertion into
of 1,3-dicarbonyl compounds (Scheme 1b). We reasoned
that insertion of a putative metal–nitrene/imido species into
ꢀ
the a-C H bond of the substrate would represent an attrac-
tive synthetic approach to ketone-substituted a-amino acid
derivatives, a new of class of biomolecules that would be of
interest in drug discovery.[1] Herein, we disclose details of
this efficient synthetic method to this novel class of a-amino
acid derivatives that relies on the copper(II)-catalyzed che-
moselective amination of 1,3-dicarbonyl compounds with
ꢀ
the b-methylene C H bond of 2-alkyl-substituted 1,3-dicar-
bonyl compounds with PhI=NTs as the nitrogen source and
a CuACHTUNGTRENNUNG
(OTf)2 +1,10-phen catalyst system (Scheme 1a).[4a] By
ꢀ
increasing the amount of the iminoiodane, preferential
PhI=NSO2Ar. The application of this catalytic C N bond-
ꢀ
formal aziridination of the C C bond of the 2-alkyl substitu-
formation process to the enantioselective synthesis of a pre-
cursor of 3-styryl-2-benzoyl-l-alanine in two steps is also
presented.
ent of the starting material to give 2,2-diacyl aziridines
could be realized. Further exploration of this field led us to
investigate the potential chemical reactivity at the a-position
Results and Discussion
[a] T. M. U. Ton, F. Himawan, Dr. J. W. W. Chang,
Prof. Dr. P. W. H. Chan
Following our success by using CuACTHNUTRGNEUNG(OTf)2 +1,10-phen to
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
Fax : (+65)6791-1961
E-mail: waihong@ntu.edu.sg
effect amination and aziridination of 2-alkyl-substituted 1,3-
dicarbonyl compounds with PhI=NTs, we chose this catalytic
system and ethyl 3-oxo-3-phenylpropanoate (1a) as a model
substrate to test the feasibility of our hypothesis (Table 1).
Subjecting 1a and 2 equivalents of PhI=NTs to 10 mol% of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201219.
CuACTHUNTRGENNG(U OTf)2, 10 mol% of 1,10-phen, and 4 ꢀ molecular sieves
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Additive
Solvent
Yield [%][b]
2a
3a
1
2
3
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
N
1,10-phen
terpy
pyridine
picolinic acid
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
–
–
–
–
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH3CN
PhCH3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
99
58
12
76
47
74
51
42
73[g]
24
37
60
69
3
–
8
42
–
10
–
–
–
–
20
–
16
16
20
10
16
8
23
31
9
4
5[c]
6[d]
7[e]
8[f]
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CuO
CuCl2
CuBr2
CuOTf
Cu2O
CuCN
CuCl
CuBr
CuI
–
68
12
–
–
30
–
76
24
34
68
–
–
–
–
–
–
CuO
CuOTf
G
1,10-phen
1,10-phen
–
–
11
12
–
(oct)4]
10
[a] All reactions were carried out at room temperature in CH2Cl2 for 6 h
in the presence of powdered 4 ꢀ MS (400 mg) with catalyst/ligand/1a/
PhI=NTs at a molar ratio of 1:1:10:20. [b] Isolated yield. [c] Reaction
Figure 1. ORTEP drawings of a) 2a and b) 3a with thermal ellipsoids at
the 50% probability level.[9]
conducted with 5 mol% of Cu
ACHTUNGTRENNUNG
1.5 equivalents of PhI=NTs. [e] PhI=NTs was replaced by PhIAHCTUNGTRENNUNG
TsNH2. [f] PhI=NTs was replaced by PhI=O and TsNH2. [g] Tetrahydro-
N-tosylfuran-2-amine (4) was additionally obtained in 26% yield.
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
(MS) in dichloromethane at room temperature for 6 h gave
the best result (Table 1, entry 1). Under these conditions,
ethyl 3-oxo-3-phenyl-2-(tosylamino)propanoate (2a) was ob-
tained in near quantitative yield. On the other hand, lower
product yields were found when terpyridine (terpy), pyri-
dine, or picolinic acid were used in place of 1,10-phen as
ligand (Table 1, entries 2–4). The reactions with terpy or
pyridine as ligand also afforded ethyl 3-oxo-3-phenyl-2,2-
bis(tosylamino)propanoate (3a) in 8 and 42% yield, respec-
tively (Table 1, entries 2 and 3). The structure of both the
a,a-acyl amino acid derivative and the diaminated by-prod-
N
E
ACHTUNGTRENNUNG
1
uct were determined by H NMR measurements and X-ray
crystallography (Figure 1).[9] A similar outcome was ob-
tained on lowering the catalyst loading from 10 to 5 mol%
or lowering the amount of PhI=NTs from 2 to 1.5 equiva-
lents, changing the nitrogen source from PhI=NTs to TsNH2
and either PhIACHTUNGTRENNUNG(OAc)2 or PhI=O, or changing the solvent
from dichloromethane to THF, CH3CN, or toluene (Table 1,
entries 5–11). The reaction with THF in place of dichloro-
methane as solvent was found to give tetrahydro-N-tosylfur-
an-2-amine (4) as an additional by-product in 26% yield
(Table 1, entry 9).[4e] Likewise, control experiments with Cu-
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Amination of 1,3-Dicarbonyl Compounds
FULL PAPER
Table 2. CuACHTUNGTRENNUNG
(OTf)2-catalyzed amination of b-ketoesters 1a–r.[a]
We next turned our attention to define the scope of this
methodology with respect to other types of 1,3-dicarbonyl
compounds (Table 3). With this in mind, the amination of
dimethyl malonate (1s) with PhI=NTs was first tested in the
Entry
Product
Yield [%][b]
Table 3. CuACHTNUTRGNE(UNG OTf)2-catalyzed amination of malonic esters and 1,3-diones
2b, R1 =H, R2 =Ns
2c, R1 =OMe, R2 =Ts
2d, R1 =Me, R2 =Ts
2e, R1 =F, R2 =Ts
94
97
93
96
94
95
1s–g.[a]
1
2
3
4[c]
5[c]
6[c]
7[c]
2 f, R1 =Cl, R2 =Ts
2g, R1 =Br, R2 =Ts
2h, R1 =NO2, R2 =Ts
[d]
–
Entry
Product
Yield [%][b]
1
2
2s, R=Me
2t, R=Et
87
99
99
98
53
88
70
8[c]
2i
99
3[c]
4
2u, R=iPr
2v, R=tBu
2w, R=Ph
2x, R=allyl
2y, R=Ph
2z, R=tBu
5[c]
6[c]
7
9
2j, R=tBu
2k, R=iPr
81
83
10[c]
[d]
8
–
11[c]
12
2l
93
88
9
10
11
2a, R=Me
2ß, R=tBu
2 ?, R=Ph
98
66
62
2m
[a] All reactions were carried out at room temperature in CH2Cl2 in the
presence of powdered 4 ꢀ MS (400 mg) with Cu(OTf)2/1,10-phen/1/PhI=
NTs at a molar ratio of 1:1:10:20 for 6 h. [b] Isolated yield. [c] Reaction
carried out at 08C. [d] Recovery of the starting material in near quantita-
tive yield.
13
14
15
2n, X=O
2o, X=S
2p, X=NMe
93
95
92
AHCTUNGTRENNUNG
16
17
2q
2r
94
[e]
presence of 10 mol% of Cu
phen under the standard conditions, and dimethyl 2-(tosyl-
amino)malonate (2s) could be afforded in 87% yield
ACHTUNGRTEN(NUNG OTf)2 and 10 mol% of 1,10-
–
AHCTUNGTRENNUNG
[a] All reactions were carried out at room temperature in CH2Cl2 in the
presence of powdered 4 ꢀ MS (400 mg) with Cu(OTf)2/1,10-phen/1/PhI=
G
(Table 3, entry 1). Under similar conditions, repetition of
the reaction with other malonic esters 1t–y gave the corre-
sponding dialkyl and diphenyl 2-(tosylamino)malonates 2t–y
in 53–99% yield (Table 3, entries 2–7). This included one
example that tolerated the introduction of a phenyl substitu-
ent (2y) at the a-position of the substrate (Table 3, entry 7).
However, replacing the phenyl substituent at this position
with a presumably more bulky tert-butyl group (2z) was
found to result in recovery of the substrate in near quantita-
tive yield (Table 3, entry 8). On the other hand, the reaction
could be extended to the 1,3-diones 1a–g to give the corre-
sponding 3-(tosylamino)pentane-2,4-diones 2a–g in 62–98%
yield (Table 3, entries 9–11).
NSO2Ar at a molar ratio of 1:1:10:20 for 2–6 h; refer to the Experimental
Section for individual reaction times. [b] Isolated yield. [c] Reaction car-
ried out at 08C. [d] Trace amount of product detected on the basis of
1H NMR analysis of the crude mixture, along with recovery of the start-
ing material in near quantitative yield. [e] Mixture of unknown side prod-
1
ucts formed, based on H NMR analysis of the crude mixture.
parable outcome was found when the reactivity of b-ketoest-
ers with a pendant alkane or cycloalkane moiety was exam-
ined, as in 1j–m (Table 2, entries 9–12). These reactions
proceeded well and gave the corresponding a-aminated ad-
ducts 2j–m in excellent yields. Substrates containing a furan
(1n and 1q), thiophene (1o), or N-methyl-substituted pyr-
role (1p) moiety were well tolerated under the reaction con-
ditions, providing the corresponding a-aminated products
2n–q in 92–95% yield (Table 2, entries 13–16). Changing
the nitrogen source from PhI=NTs to PhI=NNs was also
found to have no effect, with the analogous reaction of 1a
with the last nitrogen source giving 2b in a comparable
yield of 94% (Table 2, entry 1). In our hands, the reaction
of the cyclic b-ketoester 1r was the only example that gave
a mixture of decomposition products that could not be iden-
To gain an insight into the possible mechanism, we per-
formed competition experiments on the CuII-catalyzed ami-
nation reactions of 1c–h. This gave logACHTUNRTGNEUNG(kX/kH) values of 0.06
(1c), 0.01 (1d), ꢀ0.03 (1e), ꢀ0.11 (1 f), ꢀ0.12 (1g), and
ꢀ0.35 (1h), suggesting that electron-donating substituents
accelerate whereas electron-withdrawing substituents retard
the amination process. Fitting (by least squares method) the
logACHTNURGTNE(UGN kX/kH) data with the sp scale gave rise to good linearity
(R2 =0.975) with a 1 value of ꢀ0.39 (Figure 2).[10] The small
and negative 1 value indicates that only a moderate positive
charge is built up in the transition state.[11] This value was
1
tified by H NMR analysis of the crude mixture (Table 2,
entry 17).
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P. W. H. Chan et al.
Figure 2. Linear free-energy correlation of logACHTUNRGTNEUNG(kX/kH) versus sp for the
copper(II)-catalyzed amination of 1,3-dicarbonyl compounds 1c–h with
PhI=NTs.
Scheme 3. Tentative proposed mechanism for the copper(II)-catalyzed
amination of 1,3-dicarbonyl compounds with PhI=SO2Ar.
found to be similar to that reported for CuII-catalyzed
alkene aziridinations (ꢀ0.6), in which an asynchronous tran-
sition state was proposed.[5g]
A plausible mechanism for the present CuII-catalyzed
amination reaction is outlined in Scheme 3. This involves
the initial formation of a Cu–1,10-phen species from the re-
While isolation of tetrahydro-N-tosylfuran-2-amine (4),
obtained from the reaction of 1a with PhI=NTs in THF cat-
alyzed by CuACHTUNGTRENNUNG(OTf)2 +1,10-phen (Table 1, entry 9), was fortu-
action of CuACTHGUNETRNNU(G OTf)2 and the 1,10-phen additive in either the
monomeric or polymeric form.[12] Further reaction of this
Cu–1,10-phen complex with PhI=NSO2Ar generates the pu-
tative highly reactive [Cu]=NSO2Ar species.[13] At the same
time, coordination of the Cu–1,10-phen complex to 1 would
occur to give the copper-enolate species A. In a manner
similar to the analogous aminations of silyl enol ethers and
b-enamino esters,[8,14] subsequent addition of the nitrene/
imido group in [Cu]=NSO2Ar to the C=C bond of this
newly formed copper-enolate via the carboradical B would
give intermediate C. Presumably, the acid-labile nature of
the aziridin-2-ol intermediate formed results in ring opening
of the cyclic moiety to provide the product 2.
itous, the result argues in favor of a mechanistic pathway in-
volving a CuII-mediated nitrene/imido transfer process.[4e]
The radical nature of this step was implied by our results
showing decomposition of 1a to a variety of unknown side
products when the substrate was treated with PhI=NTs and
the CuII catalyst in the presence of 2,2,6,6-tetramethylpiperi-
din-1-yl)oxyl (TEMPO) or N-tert-butyl-a-phenylnitrone
(PBN) under the conditions described in Scheme 2. These
Having established an efficient route to a,a-acyl amino
acid derivatives, we applied this new methodology to the
synthesis of the chiral N-acyl-protected quaternary a-amino
ethyl ester 6 (Scheme 4). At room temperature, nosyl depro-
tection of 2b in CH3CN/DMSO (49:1 v/v) was achieved
with p-methoxyphenylthiol in the presence of K2CO3 base.
Scheme 2. Control experiments with 1a, 1d and 1e catalyzed by Cu-
ACHTUNGTRENNUNG(OTf)2 +1,10-phen.
latter results are also in good agreement with previous
works using radical inhibitors to implicate the possible in-
volvement of radical species in the respective AgI- and CuII-
ꢀ
catalyzed amination of C H bonds of alkanes and 2-alkyl-
substituted 1,3-dicarbonyl compounds with PhI=NTs.[4a,7]
Additionally, coordination of the metal catalyst to the sub-
strate was shown to be important, based on our observations
for the CuII-mediated control experiments of cyclopentane-
1,3-dione (1d) or cyclohexane-1,3-dione (1e) with PhI=NTs
(Scheme 2). These tests only afforded the recovery of the
substrate in near quantitative yield and led us to surmise
that the present CuII-catalyzed amination process occurs via
a copper-enolate species.
Scheme 4. Synthesis of chiral 3-styryl-2-benzoyl-l-alanine derivative
from 2b.
6
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Amination of 1,3-Dicarbonyl Compounds
FULL PAPER
tion of the starting material 1, the crude mixture was filtered through
Celite, washed with EtOAc (50 mL), evaporated to dryness, and purified
by silica gel flash column chromatography (eluent: n-hexane/EtOAc 4:1)
to give the a-aminated product 2.
This was then followed by protection of the resultant free
amine with acetic anhydride and Et3N in dichloromethane
to give the N-acyl-protected intermediate 5 in 81% yield
over two steps. Subsequent treatment of this newly formed
adduct with a toluene solution containing cinnamyl acetate,
Ethyl 2-(4-methylphenylsulfonamido)-3-oxo-3-phenylpropanoate (2a):
Reaction time=6 h, white solid; mp 109–1108C; 1H NMR (400 MHz):
d=7.98 (d, J=7.3 Hz, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.62 (t, J=7.4 Hz,
1H), 7.47 (t, J=7.7 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 5.97 (d, J=9.2 Hz,
1H), 5.58 (d, J=8.7 Hz, 1H), 3.97 (m, 2H), 2.38 (s, 3H), 1.05 ppm (t, J=
7.1 Hz, 3H); 13C NMR (100 MHz): d=190.3, 167.0, 144.0, 136.5, 134.6,
133.5, 130.2, 129.7, 129.4, 128.8, 128.4, 127.3, 62.6, 60.9, 21.5, 13.7 ppm;
IR (neat): n˜ =3356, 1748, 1692, 1344, 1163, 1020 cmꢀ1; HRMS: m/z calcd
for C18H20NSO5: 362.1062 [M+H]+; found: 362.1057.
[Pd
phosphino)-1,1’-binaphthyl), and tBuOK afforded the al
ACHTUNGTRENNUNG
ated product 6 in 82% yield and 84% ee.[15]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Conclusion
Ethyl 2-(4-nitrophenylsulfonamido)-3-oxo-3-phenylpropanoate (2b): Re-
action time=6 h, white solid; mp 97–1008C; 1H NMR: d=8.29 (d, J=
8.4 Hz, 2H), 8.05 (d, J=8.7 Hz, 2H), 8.02 (d, J=7.8 Hz, 2H), 7.67 (t, J=
7.2 Hz, 1H), 7.52 (t, J=7.5 Hz, 2H), 6.44 (d, J=8.1 Hz, 1H), 5.73 (d, J=
8.7 Hz, 1H), 4.01 (q, J=6.9 Hz, 2H), 1.05 ppm (t, J=7.2 Hz, 3H);
13C NMR: d=189.7, 165.5, 150.3, 145.6, 135.0, 133.3, 129.4, 129.0, 128.6,
124.3, 63.0, 60.8, 13.7 ppm; IR (neat): n˜ =1748, 1682, 1643, 1531, 1350,
1169, 1092 cmꢀ1; HRMS: m/z calcd for C17H17N2SO7: 393.0756 [M+H]+;
found: 393.0771.
In summary, we have developed a mild and highly efficient
copper(II)-catalyzed methodology for the amination of 1,3-
dicarbonyl compounds with PhI=NSO2Ar as nitrogen
source. The catalytic system is inexpensive and extremely
simply formed in situ from CuACHTNUTRGNENG(U OTf)2 and 1,10-phen. The re-
action was shown to tolerate a wide variety of substrates to
give the corresponding a-aminated products for applications
in natural product synthesis and medicinal chemistry, as ex-
emplified by the preparation of a chiral quaternary a-amino
acid derivative. Further exploration of the scope and syn-
thetic utility of the present reaction are currently underway
and will be reported in due course.
Ethyl 3-(4-methoxyphenyl)-2-(4-methylphenylsulfonamido)-3-oxopro
ACHTUNGTRENNUNGoAHCTUNGTRENNNUG
ACHTUNGTRENNUNGpan-
ate (2c): Reaction time=6 h, white solid; mp 135–1388C; 1H NMR
(400 MHz): d=7.99 (d, J=7.6 Hz, 2H), 7.73 (d, J=6.8 Hz, 2H), 7.24 (d,
J=6.8 Hz, 2H), 6.94 (d, J=7.6 Hz, 2H), 6.10 (d, J=8.4 Hz, 1H), 5.55 (d,
J=8.4 Hz, 1H), 3.96 (m, 2H), 3.88 (s, 3H), 2.38 (s, 3H), 1.05 ppm (t, J=
7.1 Hz, 3H); 13C NMR (100 MHz): d=188.3, 166.4, 164.9, 144.0, 136.7,
132.0, 129.8, 127.4, 126.4, 114.2, 62.7, 60.7, 55.8, 21.6, 13.8 ppm; IR (neat):
n˜ =3385, 1748, 1682, 1344, 1163, 1094 cmꢀ1
C19H22NSO6: 392.1168 [M+H]+; found: 392.1173.
Ethyl 3-(4-methylphenyl)-2-(4-methylphenylsulfonamido)-3-oxopropan
ate (2d): Reaction time=6 h, white solid; mp 110–1138C; 1H NMR: d=
7.88 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.28–7.23 (m, 4H), 5.97
(d, J=8.7 Hz, 1H), 5.55 (d, J=8.7 Hz, 1H), 3.96 (m, 2H), 2.42 (s, 3H),
2.38 (s, 3H), 1.05 ppm (t, J=7.2 Hz, 3H); 13C NMR: d=189.7, 166.2,
145.9, 143.9, 136.7, 132.0, 129.6, 129.5, 127.3, 62.6, 60.8, 21.8, 21.4,
; HRMS: m/z calcd for
Experimental Section
ACHTUNGTRENNUNGo-
AHCTUNGTRENNUNG
General remarks: All reactions were performed under a nitrogen atmos-
phere at ambient temperature unless otherwise stated. PhI=NTs,[16] PhI=
ACHTUNGTRENNUNG
O[17] and [Ru(TTP)(CO)][18] were prepared according to known literature
procedures. Unless specified, all reagents and starting materials were pur-
chased from commercial sources and used as received. Solvents were pu-
rified prior to use following literature procedures; CH2Cl2 and CH3CN
were purified prior to use by distilling over CaH2, pyridine was distilled
over KOH, and benzaldehyde was distilled under reduced pressure. Ana-
lytical thin layer chromatography (TLC) was performed by using precoat-
ed silica gel plates. Visualization was achieved by UV/Vis light (254 nm),
followed by treatment with ninhydrin stain and heating. Flash chroma-
tography was performed using silica gel with a gradient solvent system
(eluent: EtOAc/n-hexane). Unless otherwise stated, 1H and 13C NMR
spectra were measured on a Bruker AV 300 MHz spectrometer. Unless
otherwise stated, chemical shifts (ppm) were recorded in CDCl3 solution
with tetramethylsilane (TMS) as the internal reference standard. Multi-
plicities are given as: s (singlet), brs (broad singlet), d (doublet), t (trip-
let), q (quartet), dd (doublet of doublets) or m (multiplet). The number
of protons (n) for a given resonance is indicated by nH and coupling con-
stants are reported as J values in Hz. Low resolution mass spectra were
determined by using a Finnigan LCQ Deca XP Max mass spectrometer
and reported as a ratio of mass to charge (m/z). High resolution mass
spectra (HRMS) were obtained by using a Waters Q-TOF mass spec-
trometer. Enantiomeric excess (ee) values were determined by Shimadzu
high performance liquid chromatography (HPLC) analysis using a CHIR-
ALCEL OJ-H column. Optical rotations were measured in CHCl3 on a
Schmidt–Haensch polarimeter with a sodium vapor lamp at 589 nm and a
1 cm cell (c given in g/100 mL).
13.5 ppm; IR (neat): n˜ =3325, 1751, 1690, 1344, 1163, 1092, 1070 cmꢀ1
HRMS: m/z calcd for C19H22NSO5: 376.1219 [M+H]+; found: 376.1216.
Ethyl 3-(4-fluorophenyl)-2-(4-methylphenylsulfonamido)-3-oxopropano-
ate (2e): Reaction time=6 h, white solid; mp 115–1188C; 1H NMR
;
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(400 MHz): d=8.05 (m, 2H), 7.73 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.2 Hz,
2H), 7.16 (d, J=8.2 Hz, 2H), 6.01 (d, J=8.7 Hz, 1H), 5.55 (d, J=8.7 Hz,
1H), 3.97 (m, 2H), 2.39 (s, 3H), 1.05 ppm (t, J=7.3 Hz, 3H); 13C NMR
(100 MHz): d=188.9, 166.1, 144.2, 136.5, 132.5, 132.4, 129.9, 127.5, 116.4,
116.2, 62.9, 61.0, 21.7, 13.7 ppm; IR (neat): n˜ =3356, 1747, 1681, 1337,
1234, 1161, 1090 cmꢀ1; HRMS: m/z calcd for C18H19NSO5: 380.0968
[M+H]+; found: 380.0972.
Ethyl 3-(4-chlorophenyl)-2-(4-methylphenylsulfonamido)-3-oxopropan
AHCTUNGTRENNUNG
ACHTUNGTRENNUNGo-
ate (2 f): Reaction time=6 h, white solid; mp 118–1208C;1H NMR
(400 MHz): d=7.95 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H), 7.46 (d,
J=8.7 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 5.94 (d, J=8.7, 1H), 5.53 (d, J=
8.5 Hz, 1H), 3.98 (m, 2H), 2.39 (s, 3H), 1.06 ppm (t, J=7.1 Hz, 3H);
13C NMR (100 MHz): d=189.3, 166.4, 144.3, 144.2, 141.4, 136.5, 130.9,
129.8, 129.3, 127.4, 63.0, 61.0, 21.6, 13.8 ppm; IR (neat): n˜ =3300, 1734,
1687, 1342, 1165, 1109, 1088 cmꢀ1; HRMS: m/z calcd for C18H19NSO5Cl:
396.0672 [M+H]+; found: 396.0671.
Ethyl 3-(4-bromophenyl)-2-(4-methylphenylsulfonamido)-3-oxopropan
AHCTUNGTRENNUNG
ACHTUNGTRENNUNGo-
ate (2g): Reaction time=6 h, white solid; mp 130–1338C; 1H NMR
(400 MHz): d=7.88 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.60 (d,
J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 5.91 (d, J=9.2 Hz, 1H), 5.49 (d,
J=8.8 Hz, 1H), 3.94 (m, 2H), 2.37 (s, 3H), 1.04 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz): d=189.5, 165.8, 144.1, 136.4, 132.2, 130.8, 130.1,
129.7, 129.3, 127.3, 62.8, 60.9, 21.5, 13.7 ppm; IR (neat): n˜ =3325, 1751,
1690, 1344, 1163, 1092, 1070 cmꢀ1; HRMS: m/z calcd for C18H19NSO5Br:
440.0167 [M+H]+; found: 440.0146.
General procedure for Cu
dicarbonyl compounds 1 to a,a-acyl amino acid derivatives 2: CH2Cl2
(2 mL) was added to a mixture of Cu(OTf)2 (0.05 mmol), 1,10-phen
(0.05 mmol), and powdered 4 ꢀ MS (400 mg) at 08C or room tempera-
ture. After stirring for 1 h at the same temperature, PhI=NTs or PhI=
NNs (1 mmol) was added, followed by the 1,3-dicarbonyl compound 1
(0.5 mmol). The reaction was monitored by TLC. On complete consump-
ACHTUNGRTENUN(NG OTf)2 +1,10-phen-catalyzed amination of 1,3-
AHCTUNGTRENNUNG
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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P. W. H. Chan et al.
Ethyl 2-(4-methylphenylsulfonamido)-3-oxo-3m-tolylpropanoate (2i):
Reaction time=6 h, white solid; mp 95–988C; 1H NMR (400 MHz): d=
7.80–7.77 (m, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.43–7.41 (m, 1H), 7.35 (dd,
J=7.7 Hz, J=7.5 Hz, 1H), 7.23 (d, J=8.1 Hz, 2H), 6.06 (d, J=9.2 Hz,
1H), 5.58 (d, J=8.8 Hz, 1H), 3.96 (m, 2H), 2.39 (s, 3H), 2.37 (s, 3H),
1.04 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz): d=190.3, 166.1, 143.9,
138.8, 136.6, 135.4, 133.5, 129.8, 129.7, 128.7, 127.3, 126.6, 126.5, 62.6,
60.9, 21.5, 21.3, 13.7 ppm; IR (neat): n˜ =3328, 1755, 1682, 1598, 1454,
1337, 1164 cmꢀ1; HRMS: m/z calcd for C18H19NSO5Cl: 376.1219 [M+H]+
; found: 376.1215.
Ethyl 3-(1-methyl-1H-pyrrol-2-yl)-2-(4-methylphenylsulfonamido)-3-oxo-
propanoate (2p): Reaction time=2 h, white solid; mp 100–1038C;
1H NMR (400 MHz): d=7.70 (d, J=8.0 Hz, 2H), 7.22–7.27 (m, 3H), 6.89
(s, 1H), 6.18 (dd, J=2.4, J=4.0 Hz, 1H), 6.02 (d, J=8.8 Hz, 1H), 5.29 (d,
J=8.8 Hz, 1H), 3.95–4.04 (m, 2H), 3.79 (s, 3H), 2.38 (s, 3H), 1.11 ppm
(t, J=7.2 Hz, 3H); 13C NMR
133.5, 129.7, 127.8, 122.6, 109.4, 62.4, 60.8, 37.6, 21.5, 13.8 ppm; IR (neat):
n˜ =3305, 2981, 1750, 1645, 1337, 1265 cmꢀ1
HRMS: m/z calcd for
C17H21N2SO5: 365.1171 [M+H]+; found: 365.1166.
ACHTUNGTRENN(UNG 100 MHz): d=178.5, 166.7, 143.7, 136.8,
;
Ethyl 3-(furan-3-yl)-3-oxo-2-(tosylamino)propanoate (2q): Reaction
time=2 h, yellow solid; obtained as two ketone/enol tautomers in a ratio
Ethyl 4,4-dimethyl-2-(4-methylphenylsulfonamido)-3-oxopentanoate (2j):
Reaction time=3 h, pale yellow solid; mp 85–878C; 1H NMR: d=7.73
(d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 5.84 (d, J=9.6 Hz, 1H), 5.08
(d, J=9.6 Hz, 1H), 3.98 (dq, J=2.1, J=7.2 Hz, 2H), 2.41 (s, 3H), 1.15 (s,
9H), 1.13 ppm (t, J=7.2 Hz, 3H); 13C NMR: d=205.0, 166.2, 143.9,
136.5, 129.6, 127.3, 62.4, 58.6, 44.9, 26.1, 21.5, 13.7 ppm. IR (neat): n˜ =
3340, 3019, 2960, 1749, 1715, 1599, 1344, 1163 cmꢀ1; HRMS: m/z calcd for
C16H24NSO5: 342.1375 [M+H]+; found: 342.1386.
1
of 2:1; mp 116–1198C; H NMR: d=12.74 (s, 0.5H), 8.33 (s, 1H), 8.29 (s,
0.5H), 7.73 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 1H), 7.44 (s, 1H), 7.40
(s, 0.5H), 7.29–7.25 (m, 3H), 7.02 (d, J=1.3 Hz, 0.5H), 6.77 (d, J=
1.3 Hz, 1H), 6.16 (d, J=9.0 Hz, 1H), 6.06 (s, 0.5H), 5.17 (d, J=9.0 Hz,
1H), 3.90–4.04 (m, 2H), 3.71–3.68 (m, 1H), 2.40 (s, 1.5H), 2.38 (s, 3H),
1.07 (t, J=7.1 Hz, 3H), 0.87 ppm (t, J=7.1 Hz, 1.5H); 13C NMR: d=
184.4, 170.7, 168.2, 166.1, 149.9, 147.5, 144.4, 144.1, 143.6, 142.8, 137.1,
136.3, 129.7, 129.4, 127.5, 127.3, 124.4, 120.0, 110.2, 108.8, 98.4, 62.8, 62.7,
61.2, 21.5, 21.4, 13.7, 13.5 ppm; IR (neat): n˜ =3348, 3021, 1748, 1688,
Ethyl 4-methyl-2-(4-methylphenylsulfonamido)-3-oxopentanoate (2k):
Reaction time=3 h, yellow oil; obtained as two ketone/enol tautomers in
a ratio of 0.9:1; 1H NMR: d=12.62 (s, 1H), 7.73 (d, J=8.2 Hz, 1.8H),
7.68 (d, J=8.2 Hz, 2H), 7.31–7.26 (m, 3.8H), 6.05 (d, J=8.4 Hz, 0.9H),
5.92 (s, 1H), 4.82 (d, J=8.4 Hz, 0.9H), 4.38–4.20 (m, 1.8H), 4.05 (q, J=
7.1 Hz, 2H), 3.48–3.43 (m, 0.9H), 3.04–2.95 (m, 1H), 2.41 (s, 5.7H), 1.20–
0.86 ppm (m, 17.1H); 13C NMR: d=204.3, 186.1, 170.3, 166.1, 144.0,
143.4, 136.8, 136.4, 129.5, 129.4, 129.3, 127.6, 127.2, 97.8, 62.8, 62.6, 60.9,
38.2, 29.5, 21.44, 21.37, 19.2, 18.3, 17.6, 13.8, 13.5 ppm; IR (neat): n˜ =
3280, 3024, 2984, 2940, 1732, 1599, 1339, 1215, 1094 cmꢀ1; HRMS: m/z
calcd for C15H22NSO5: 328.1219 [M+H]+; found: 328.1210.
1647, 1622, 1599, 1287, 1215, 1163 cmꢀ1
; HRMS: m/z calcd for
C16H18NSO6: 352.0855 [M+H]+; found: 352.0850.
Dimethyl 2-(4-methylphenylsulfonamido)malonate (2s):[19] Reaction
time=6 h, pale yellow solid; obtained as a mixture with TsNH2; mp 117–
1188C; 1H NMR (400 MHz, CD3COCD3): d=7.80 (d, J=8.4 Hz, 2H),
7.49 (d, J=9.2 Hz, 2H), 4.79 (d, J=9.2 Hz, 1H), 3.61 (s, 6H), 2.43 ppm
(s, 3H); 13C NMR
ACTHNUTRGNE(NUG 100 MHz): d=166.0, 143.5, 141.5, 129.5, 126.1, 59.0,
52.6, 20.5 ppm; HRMS: m/z calcd for C12H16NSO6: 302.0698 [M+H]+;
found: 302.0706.
Diethyl 2-(4-methylphenylsulfonamido)malonate (2t): Reaction time=
6 h, yellow oil; 1H NMR: d=7.73 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz,
2H), 5.64 (d, J=8.4 Hz, 1H), 4.66 (d, J=8.7 Hz, 1H), 4.12 (q, J=7.2,
4H), 2.41 (s, 3H), 1.19 ppm (t, J=6.9 Hz, 6H) 13C NMR: d=165.6, 144.0,
136.5, 129.7, 127.3, 62.8, 58.8, 21.5, 13.8 ppm; IR (neat): n˜ =3362, 3096,
1746, 1645, 1344, 1302, 1288, 1163, 1094 cmꢀ1; HRMS: m/z calcd for
C14H20NSO6: 330.1011 [M+H]+; found: 330.1024.
Ethyl 3-(cyclopropyl)-2-(4-methylphenylsulfonamido)-3-oxopropanoate
(2l): Reaction time=3 h, colorless oil; obtained as two ketone/enol tau-
1
tomers in a ratio of 2:1; H NMR: d=12.66 (s, 0.5H), 7.73 (d, J=8.2 Hz,
3H), 7.30 (d, J=8.2 Hz, 3H), 5.92 (d, J=7.9 Hz, 1H), 5.75 (s, 0.5H), 4.87
(d, J=7.9 Hz, 1H), 4.33 (q, J=7.1, 1H), 4.09 (q, J=7.1 Hz, 2H), 2.42 (s,
4.5H), 2.27–2.14 (m, 1.5H), 1.39–0.85 ppm (m, 10.5H); 13C NMR: d=
200.1, 166.0, 143.9, 136.5, 129.7, 129.3, 127.7, 127.3, 92.7, 65.3, 63.2, 62.6,
21.5, 18.6, 15.9, 13.9, 13.8, 13.3, 13.0, 12.8, 9.2 ppm; IR (neat): n˜ =3281,
2982, 2938, 1748, 1713, 1078 cmꢀ1; HRMS: m/z calcd for C15H21NSO5:
326.1062 [M+H]+; found: 326.1069.
Diisopropyl 2-(tosylamino)malonate (2u): Reaction time=6 h, pale
1
yellow oil; H NMR: d=7.74 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H),
5.68 (d, J=8.4 Hz, 1H), 4.99–4.90 (m, 2H), 4.57 (d, J=8.4 Hz, 1H), 2.41
(s, 3H), 1.12–1.06 ppm (m, 12H); 13C NMR: d=165.2, 143.9, 136.6, 129.7,
127.3, 70.8, 59.0, 21.5, 21.4, 21.3 ppm; IR (neat): n˜ =3497, 3237, 1742,
1599, 1283, 1156, 1101 cmꢀ1; HRMS: m/z calcd for C16H24NSO6: 358.1324
[M+H]+; found: 357.1323.
Ethyl 3-(1-adamantyl)-3-oxo-2-(tosylamino)propanoate (2m): Reaction
time=4 h, pale yellow solid; mp 110–1138C; 1H NMR: d=7.73 (d, J=
8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 5.85 (d, J=9.6 Hz, 1H), 5.08 (d, J=
9.6 Hz, 1H), 3.98 (m, 2H), 2.41 (s, 3H), 2.02 (m, 3H), 1.77–1.67 (m,
12H), 1.12 ppm (t, J=7.2 Hz, 3H); 13C NMR: d=205.1, 166.3, 143.9,
136.6, 129.6, 127.4, 62.3, 58.0, 47.1, 38.6, 37.6, 36.4, 36.2, 27.8, 27.6, 21.5,
Di-tert-butyl 2-(tosylamino)malonate (2v): Reaction time=6 h, pale
1
yellow solid; mp 113–1158C; H NMR (400 MHz): d=7.71 (d, J=8.4 Hz,
13.8 ppm; IR (neat): n˜ =3317, 3019, 2911, 2853, 1748, 1707, 1599 cmꢀ1
HRMS: m/z calcd for C22H30NSO5: 420.1845 [M+H]+; found: 420.1847.
Ethyl 3-(furan-2-yl)-2-(4-methylphenylsulfonamido)-3-oxopropanoate
;
2H), 7.27 (d, J=8.4 Hz, 2H), 5.72 (d, J=8.8 Hz, 1H), 4.39 (d, J=8.4 Hz,
1H), 2.36 (s, 3H), 1.33 ppm (s, 18H); 13C NMR (100 MHz): d=164.7,
143.8, 136.7, 129.6, 127.3, 83.6, 60.0, 27.6, 21.4 ppm. IR (neat): n˜ =3362,
3020, 2982, 2934, 1738, 1599, 1371, 1348, 1163, 1144 cmꢀ1; HRMS: m/z
calcd for C18H28NSO6: 386.1637 [M+H]+; found: 386.1620.
(2n): Reaction time=2 h, white solid; mp 102–1048C; 1H NMR
(400 MHz): d=7.72 (d, J=8.4 Hz, 2H), 7,66 (s, 1H), 7.41 (d, J=3.6 Hz,
1H), 7.25 (d, J=8.4 Hz, 2H), 6.60 (dd, J=1.6 Hz, J=2.0 Hz, 1H), 5.94
(d, J=8.8 Hz, 1H), 5.35 (d, J=8.8 Hz, 1H), 4.03 (q, J=4.0 Hz, 2H), 2.39
(s, 3H), 1.10 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz): d=178.4,
165.8, 149.8, 148.3, 144.0, 136.5, 129.7, 127.3, 121.1, 113.0, 62.8, 60.7, 21.5,
13.8 ppm; IR (neat): n˜ =3302, 3019, 1751, 1685, 1599, 1463, 1221,
1163 cmꢀ1; HRMS: m/z calcd for C16H18NSO6: 352.0855 [M+H]+; found:
352.0852.
Diphenyl 2-(4-methylphenylsulfonylamido)malonate (2w): Reaction
time=6 h, white solid; mp 166–1698C; 1H NMR: d=7.69 (d, J=8.20 Hz,
2H), 7.43–7.17 (m, 10H), 7.00 (d, J=7.80 Hz, 2H), 6.70 (s, 1H),
2.36 ppm (s, 3H); 13C NMR: d=162.9, 150.2, 144.2, 137.2, 129.8, 129.7,
129.6, 127.4, 126.9, 120.8, 120.5, 90.6, 72.7, 21.6 ppm; IR (neat): n˜ =3404,
3021, 1767, 1090 cmꢀ1; HRMS: m/z calcd for C22H20NSO6: 3426.1062
[M+H]+; found: 426.1069.
Diallyl 2-(4-methylphenylsulfonamido)malonate (2x): Reaction time=
6 h, white solid; mp 84–868C; 1H NMR (400 MHz): d=7.74 (d, J=
8.2 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 5.82–5.73 (m, 2H) 5.67 (d, J=
8.5 Hz, 1H), 5.30–5.22 (m, 4H), 4.73 (d, J=8.60 Hz, 1H), 4.55 (dd, J=
5.70 Hz, J=1.02 Hz, 4H), 2.42 ppm (s, 3H); 13C NMR (100 MHz): d=
165.2, 144.1, 136.4, 130.6, 129.7, 127.3, 119.5, 67.1, 58.7, 21.6 ppm; IR
(neat): n˜ =3019, 1744, 1634, 1163, 1092, 988, 930 cmꢀ1; HRMS: m/z calcd
for C16H20NSO6: 354.1011 [M+H]+; found: 354.1000.
Ethyl 3-(thiophen-2-yl)-2-(4-methylphenylsulfonamido)-3-oxopropanoate
(2o): Reaction time=2 h, pale yellow solid; mp 118–1218C; 1H NMR
(400 MHz): d=7.98 (d, J=4.0 Hz, 1H), 7.76 (d, J=5.2 Hz, 1H), 7.71 (d,
J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.17 (dd, J=5.2 Hz, J=4.0 Hz,
1H), 5.93 (d, J=8.8 Hz, 1H), 5.40 (d, J=8.8 Hz, 1H), 3.97–4.06 (m, 2H),
2.39 (s, 3H), 1.10 ppm (t, J=7.2 Hz, 3H); 13C NMR
ACTHNUTRGNEUNG(100 MHz): d=182.7,
165.9, 144.1, 140.2, 136.5, 136.4, 135.3, 129.7, 128.7, 127.3, 62.8, 61.6, 21.5,
13.7 ppm; IR (neat): n˜ =3424, 3020, 1750, 1675, 1520, 1411, 1357, 1217,
1165 cmꢀ1; HRMS: m/z calcd for C16H18NS2O5: 368.0626 [M+H]+; found:
368.0635.
Diethyl 2-(4-methylphenylsulfonamido)-2-phenylmalonate (2y): Reaction
time=6 h, white solid; mp 110–1158C; 1H NMR (400 MHz): d=7.53 (d,
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www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Amination of 1,3-Dicarbonyl Compounds
FULL PAPER
J=7.4 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.21–7.14 (m, 3H), 7.07 (d, J=
8.1 Hz, 2H), 6.30 (s, 1H), 4.23–4.17 (m, 4H), 2.34 (s, 3H), 1.23 ppm (t,
J=7.2 Hz, 6H); 13C NMR (100 MHz): d=166.9, 142.9, 138.5, 133.6,
129.0, 128.7, 128.6, 128.4, 128.0, 127.8, 126.9, 63.1, 21.4, 13.8 ppm; IR
(neat): n˜ =3435, 2957, 2926, 2853, 1740, 1456, 1094, 1016 cmꢀ1; HRMS:
m/z calcd. for C20H24SNO6: 406.1324 [M+H]+; found: 406.1310.
Presidentꢂs Graduate Scholarship (to TMUT) and an Undergraduate Re-
search Experience on Campus stipend (to FM) from NTU are gratefully
acknowledged, and we thank Dr. Yongxin Li of this division for provid-
ing the X-ray crystallographic data reported in this work.
N-(2,4-dioxopentan-3-yl)-4-methylbenzenesulfonamide (2a): Reaction
time=6 h, white solid; mp 166–1698C; 1H NMR: d=7.71 (d, J=8.2 Hz,
2H), 7.33 (d, J=8.2 Hz, 2H) 6.22 (s, 1H), 2.44 (s, 3H), 1.88 ppm (s, 6H);
13C NMR: d=194.2, 144.4, 136.7, 130.2, 127.5, 110.2, 22.3, 21.8 ppm; IR
(neat): n˜ =3374, 1745, 1599, 1159, 1093 cmꢀ1; HRMS: m/z calcd for
C12H16NO4S: 270.0800 [M+H]+; found: 270.0808.
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Oslund, T. M. Mavromoustakos, G. Kokotos, Bioorg. Med. Chem.
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Jones, S. Hameed, J. Enzyme Inhib. Med. Chem. 2011, 26, 668–680;
c) B. H. Patel, A. M. Mason, H. Patel, R. C. Coombes, S. Ali,
A. G. M. Barrett, J. Org. Chem. 2011, 76, 6209–6217; d) Z. I. Kuvae-
va, D. V. Lopatik, T. A. Nikolaeva, A. N. Knizhnikova, V. E. Naide-
nov, M. M. Markovich, Pharm. Chem. J. 2010, 44, 307–309; e) N.
Franz, H. A. Klok, Macromol. Chem. Phys. 2010, 211, 809–820;
f) M. K. Renner, Y. C. Shen, X.-C. Cheng, P. R. Jensen, W. Frank-
moelle, C. A. Kauffman, W. Fenical, E. Lobkovsky, J. Clardy, J. Am.
Chem. Soc. 1999, 121, 11273–11276.
4-Methyl-N-(2,2,6,6-tetramethyl-3,5-dioxoheptan-4-yl)benzenesulfona-
mide (2b): Reaction time=6 h, white solid; mp 146–1488C; 1H NMR
(400 MHz): d=7.68 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 5.81 (d,
J=10.0 Hz, 1H), 5.36 (d, J=10.0 Hz, 1H), 2.39 (s, 3H), 1.08 ppm (s,
18H); 13C NMR (100 MHz): d=208.0, 144.2, 135.5, 129.7, 127.8, 59.8,
44.3, 27.1, 21.5 ppm; IR (neat): n˜ =1719, 1697, 1643, 1342, 1165,
1092 cmꢀ1; HRMS: m/z calcd for C18H28NSO4: 354.1739 [M+H]+; found:
354.1740.
[2] For selected reviews, see: a) S. M. So, H. Kim, L. Mui, J. Chin, Eur.
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1571–1586.
N-(1,3-dioxo-1,3-diphenylpropan-2-yl)-4-methylbenzenesulfonamide
(2g): Reaction time=6 h, white solid; mp 166–1698C; 1H NMR
(400 MHz): d=7.90 (d, J=8.8 Hz, 4H), 7.65 (d, J=8.4 Hz, 2H), 7.59 (t,
J=7.2 Hz, 2H) 7.42 (t, J=8.0 Hz, 4H), 7.14 (d, J=8.0 Hz, 2H), 6.26 (s,
2H), 2.33 ppm (s, 3H); 13C NMR (100 MHz): d=191.9, 144.0, 136.0,
134.4, 134.0, 129.7, 129.1, 128.9, 63.8, 21.5 ppm; IR (neat): n˜ =1697, 1674,
1639, 1597, 1335, 1161, 1090 cmꢀ1; HRMS: m/z calcd for C22H20NSO4:
394.1113 [M+H]+; found: 394.1132.
Ethyl 3-oxo-3-phenyl-2,2-bis(tosylamino)propanoate (3a): Reaction
time=6 h, white solid; mp 155–1598C; 1H NMR (400 MHz): d=8.07 (d,
J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 4H), 7.53 (t, J=7.6 Hz, 1H), 7.37 (t,
J=7.6 Hz, 2H), 7.23 (d, J=8.0 Hz, 4H), 6.83 (bs, 2H), 3.42 (m, 2H), 2.38
(s, 6H), 0.57 ppm (t, J=7.2 Hz, 3H); 13C (100 MHz) NMR: d=185.7,
164.0, 143.9, 137.2, 134.1, 132.4, 129.7, 129.4, 128.7, 127.6, 74.1, 63.6, 21.6,
12.8 ppm; IR (neat): n˜ =3018, 2954, 2922, 2852, 1751, 1691, 1452, 1377,
1167 cmꢀ1; HRMS: m/z calcd for C25H26S2N2O7Na: 553.1079 [M+Na]+;
found: 553.1077.
Tetrahydro-N-tosylfuran-2-amine (4):[4e] 1H NMR (400 MHz): d=7.80 (d,
J=8.1 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 5.93 (d, J=8.7 Hz, 1H), 5.31–
5.37 (m, 1H), 3.66–3.70 (m, 2H), 2.42 (s, 3H), 2.05–2.16 (m, 1H), 1.78–
1.95 ppm (m, 3H); 13C NMR (100 MHz): d=143.2, 138.6, 129.5, 127.0,
84.9, 67.2, 32.5, 23.9, 21.5 ppm; MS (ESI): m/z: 242 [M+H]+.
Ethyl 2-acetamido-3-oxo-3-phenylpropanoate (5):[20] Yellow solid;
1H NMR (400 MHz): d=8.08 (d, J=8.4 Hz, 2H), 7.58 (t, J=7.4 Hz, 1H),
7.46 (t, J=8.0 Hz, 2H), 7.18 (d, J=7.2 Hz, 1H), 6.22 (d, J=7.6 Hz, 1H),
4.12 (q, J=7.2 Hz, 2H), 2.07 (s, 3H), 1.10 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz): d=191.7, 170.0, 166.6, 134.2, 134.0, 129.4, 128.5,
62.2, 58.0, 22.6, 13.6 ppm; MS (ESI): m/z: 250 [M+H]+.
ꢀ
[4] For selected examples on copper-catalyzed C H bond aminations,
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pionate (6): The enantiomeric excess of 6 was determined to be 84% ee
by HPLC analysis (CHIRALCEL OJ-H, n-hexane/2-propanol 9:1). Pale
yellow solid; mp 124–1278C; ½aꢁ2D1 =+31.8 (c=0.5, CHCl3); 1H NMR
(400 MHz): d=7.88 (d, J=7.2 Hz, 2H), 7.51 (t, J=7.6 Hz, 1H), 7.39 (t,
J=7.6 Hz, 2H), 7.28–7.20 (m, 5H), 7.16 (s, 1H), 6.40 (d, J=16.0 Hz,
1H), 5.99–5.91 (m, 1H), 4.31–4.18 (m, 2H), 3.37 (d, J=7.6 Hz, 2H), 1.89
(s, 3H), 1.18 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz): d=191.4,
169.5, 168.6, 136.9, 135.0, 133.0, 128.5, 128.3, 127.6, 126.2, 122.6, 70.1,
63.2, 37.2, 22.9, 14.0 ppm; IR (neat): n˜ =3435, 1765, 1740, 1327, 1260,
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1157, 1094, 1016 cmꢀ1
[M+H]+; found: 366.1711.
; HRMS: m/z calcd for C22H24NO4: 366.1705
Acknowledgements
This work is supported by a University Research Committee Grant
(RG55/06) from Nanyang Technological University (NTU). A Nanyang
Chem. Eur. J. 2012, 00, 0 – 0
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www.chemeurj.org
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Received: April 10, 2012
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!

Amination of 1,3-Dicarbonyl Compounds
FULL PAPER
Homogeneous Catalysis
T. M. U. Ton, F. Himawan,
J. W. W. Chang,
P. W. H. Chan* ............... &&&& — &&&&
Copper(II) Triflate Catalyzed Amina-
tion of 1,3-Dicarbonyl Compounds
Iminoiodanes aminate: A method to
prepare a,a-acyl amino acid deriva-
tives efficiently by CuACTHNUTRGNENUG(OTf)2 +1,10-
phenanthroline-catalyzed amination of
1,3-dicarbonyl compounds with PhI=
NSO2Ar is described (see scheme).
The utility of the method was exempli-
fied by the enantioselective synthesis
of a precursor of 3-styryl-2-benzoyl-l-
alanine.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!