Copper(II) triflate catalyzed amination and aziridination of 2-Alkyl substituted 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/ja301415k

A method to prepare α-acyl-β-amino acid and 2,2-diacyl aziridine derivatives efficiently from Cu(OTf)₂ + 1,10-phenanthroline (1,10-phen)-catalyzed amination and aziridination of 2-alkyl substituted 1,3-dicarbonyl compounds with PhI=NTs is described. By taking advantage of the orthogonal modes of reactivity of the substrate through slight modification of the reaction conditions, a divergence in product selectivity was observed. In the presence of 1.2 equiv of the iminoiodane, amination of the allylic C-H bond of the enolic form of the substrate, formed in situ through coordination to the Lewis acidic metal catalyst, was found to selectively occur and give the β-aminated adduct. On the other hand, increasing the amount of the nitrogen source from 1.2 to 2-3 equiv was discovered to result in preferential formal aziridination of the C-C bond of the 2-alkyl substituent of the starting material and formation of the aziridine product.

Full text of DOI:10.1021/ja301415k

Article
pubs.acs.org/JACS
Copper(II) Triflate Catalyzed Amination and Aziridination of 2-Alkyl
Substituted 1,3-Dicarbonyl Compounds
Thi My Uyen Ton, Ciputra Tejo, Diane Ling Ying Tiong, and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: A method to prepare α-acyl-β-amino acid and
2,2-diacyl aziridine derivatives efficiently from Cu(OTf)2 +
1,10-phenanthroline (1,10-phen)-catalyzed amination and
aziridination of 2-alkyl substituted 1,3-dicarbonyl compounds
with PhINTs is described. By taking advantage of the
orthogonal modes of reactivity of the substrate through slight
modification of the reaction conditions, a divergence in product selectivity was observed. In the presence of 1.2 equiv of the
iminoiodane, amination of the allylic CH bond of the enolic form of the substrate, formed in situ through coordination to the
Lewis acidic metal catalyst, was found to selectively occur and give the β-aminated adduct. On the other hand, increasing the
amount of the nitrogen source from 1.2 to 2−3 equiv was discovered to result in preferential formal aziridination of the CC
bond of the 2-alkyl substituent of the starting material and formation of the aziridine product.
Within the field of transition-metal-mediated aminations and
aziridinations of activated CH and CC bonds of alkanes
and alkenes with iminoiodanes,3−12 copper catalysis has come
under renewed scrutiny due to its low cost and better
biocompatibility when compared to other metal complexes.4−6
For example, we recently reported one method for amide bond
synthesis that relied on nitrene/imido insertion at the formyl
CH bond of aldehydes with PhINTs or TsNClNa·3H2O
(chloramine-T trihydrate) mediated by an in situ formed CuI +
pyridine catalytic system or CuCl.4b As part of our efforts to
further develop this type of synthetic approach for CN bond
formation,7 we became interested in the potential chemical
reactivity of readily available 2-alkyl substituted 1,3-dicarbonyl
compounds. We reasoned that functionalization of the allylic
CH bonds of the pendant alkyl group of the enolic form of
the substrate could be envisaged on in situ formation of a
putative copper-enolate species.8
INTRODUCTION
■
β-Amino acids and aziridines are immensely important targets
in organic synthesis because of their ability to serve as building
blocks in a wide variety of reactions.1,2 They are also found as a
substructure in numerous bioactive natural products and
pharmaceutically interesting compounds. For this reason,
establishing methods that can construct these two classes of
nitrogen-containing compounds in an efficient manner and
with control of substitution patterns from readily accessible
substrates continues to be actively pursued. Herein, we report
the synthesis of α-acyl-β-amino acid and 2,2-diacyl aziridine
derivatives by copper(II)-catalyzed amination and azidirination
of a common and readily available 2-alkyl substituted 1,3-
dicarbonyl compound with PhINTs (Scheme 1). This
divergence in product selectivity was found to be possible
through slight modification of the reaction conditions.
RESULTS AND DISCUSSION
Scheme 1. Synthesis of α-Acyl-β-amino Acid and 2,2-Diacyl
Aziridine Derivatives from 2-Alkyl Substituted 1,3-
Dicarbonyl Compounds
■
Our studies began with the copper-catalyzed reactions of ethyl
2-methyl-3-oxo-3-phenylpropanoate 1a and PhINTs (Table
1). While initial experiments with either CuI or CuCl gave <1
and 24% yield, respectively, when 1a was treated with 10 mol %
of Cu(OTf)2, PhINTs (2 equiv), and 4 Å molecular sieves
(MS) in CH2Cl2 at room temperature for 18 h, ethyl 2-benzoyl-
1-tosylaziridine-2-carboxylate 2a was obtained in 80% yield
(entry 1). The structure of the nitrogen ring product was
1
determined by H NMR spectroscopy and X-ray crystallog-
raphy of two closely related adducts (vide infra). Although
geminal diacyl aziridines have been reported to exhibit a potent
Received: October 10, 2011
Published: April 1, 2012
© 2012 American Chemical Society
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(entry 15).4d Likewise, a low product yield of 50% or no
reaction was observed on switching the nitrogen source from
PhINTs to PhI(OAc)2 + NH2Ts or TsNNaCl·3H2O (entries
16−17). On the basis of the above results, reaction of 1a in the
presence of 10 mol % of Cu(OTf)2, 1,10-phen (10 mol %),
PhINTs (2 equiv), and 4 Å MS in CH2Cl2 at room
temperature for 18 h provided the optimal conditions.
a
Table 1. Optimization of the Reaction Conditions
b
entry
additive
solvent
yield (%)
1
2
3
4
5
6
7
−
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
80
90
83
12
70
45
70
74
98
60
To define the generality of the present procedure, we next
turned our attentions to the reactions of a series of 2-alkyl
substituted β-ketoesters, and the results are summarized in
Table 2. Using the Cu(OTf)2 + 1,10-phen system, these
1,10-phen
TMP
c
pyridine
bipyridine
terpyridine
picolinic acid
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
Table 2. Copper(II)-Catalyzed Aziridination of 2-Alkyl
a
Substituted β-Ketoesters
d
8
e
9
f
10
g
h
11
43
12
13
14
15
10
27
MeCN
DMSO
THF
i
−
−
j
k
16
CH2Cl2
CH2Cl2
50
l
i
17
−
a
All reactions were carried out at room temperature and 4 Å MS (400
mg) in 2 mL of solvent for 18 h with catalyst/additive/1a/PhINTs
b
c
molar ratio = 1:1:10:20. Isolated yield. Reaction conducted with 20
d
mol % of pyridine. Reaction conducted with 5 mol % of Cu(OTf)2
and 5 mol % of 1,10-phen. Reaction conducted with 20 mol % of
Cu(OTf)2 and 20 mol % of 1,10-phen. Reaction conducted with 1.5
e
f
g
equiv of PhINTs. Reaction conducted in the absence of 4 Å MS.
h
i
Recovery of 1a in 56% yield. Trace amount of product detected on
j
1
the basis of H NMR analysis of the crude mixture. Compound 4
obtained in 47% yield. Reaction conducted with PhI(OAc)2 (2 equiv)
k
a
All reactions were carried out at room temperature and 4 Å MS (400
l
and TsNH2 (2 equiv) in place of PhINTs. Reaction conducted with
mg) in 2 mL of CH2Cl2 for 18 h with Cu(OTf)2/1,10-phen/1/PhI
TsNNaCl·3H2O (2 equiv) in place of PhINTs.
NTs molar ratio = 1:1:10:20. Values in parentheses denote isolated
b
product yields. Reaction conducted with 3 equiv of PhINTs.
c
d
range of bioactivities of current interest, synthetic methods to
prepare this N-heterocycle have remained sparse.13 In this
regard, the unprecedented formation of 2a via a mechanistically
intriguing formal aziridination of a CC bond prompted us to
examine this transformation more closely to establish the
reaction conditions (entries 2−17). This initially revealed that
the addition of 10 mol % of a pyridyl-based additive, which
could act as a ligand for the Cu(II) salt, to have a marked effect
on the aziridination process (entries 2−7). An increase of 3 and
10% in product yield, respectively, was obtained when either
3,4,7,8-tetramethyl-1,10-phenanthroline (TMP) or 1,10-phen
were employed (entries 2−3). On the other hand, lower
product yields were furnished on repeating the reaction with
pyridine, bipyridine, terpyridine, or picolinic acid (entries 4−7).
Lower product yields were also afforded on lowering either the
catalyst loading from 10 to 5 mol % or amount of PhINTs
from 2 to 1.5 equiv (entries 8 and 10). By removing 4 Å MS
from the reaction conditions, a similar outcome along with
recovery of the 2-alkyl substituted β-ketoester substrate in 56%
yield was found (entry 11). In contrast, a further slight increase
in product yield to 98% was obtained when both the catalyst
and 1,10-phen loading was increased from 10 to 20 mol %
(entry 9). Changing the solvent from CH2Cl2 to MeCN,
DMSO, or toluene was found to give either no reaction or 2a in
10−27% yield (entries 12−14). The reaction with THF in place
of CH2Cl2 as the solvent was the only exception, giving
tetrahydro-N-tosylfuran-2-amine 4 as a byproduct in 47% yield
Product obtained as a 1.8:1 mixture of diastereomers. Product
e
obtained as a 1:1 mixture of diastereomers. Product obtained as a
f
3.8:1 mixture of diastereomers. Product obtained as a 1.7:1 mixture of
g
diastereomers. Product obtained as a 1.3:1 mixture of diastereomers.
experiments showed the conditions to be broad, and a variety
of 2-acyl-1-tosylaziridine-2-carboxylates 2b−m could be
obtained in 61−99% yield. This hitherto included 2-alkyl
substituted β-ketoesters containing benzoyl groups bearing
either an electron-donating (1b, Me) or electron-withdrawing
(1c−f, F, Cl, Br, I) group, showing that such moieties were well
tolerated under the reaction conditions. A similar outcome was
found when we examined the reactivity of 2-alkyl substituted β-
ketoesters with a pendant acyl and alkyl group (1g−j),
including ones containing a carboxylic ester (1h−i) or
cyclopropane (1m) moiety. These reactions were found to
proceed well and give the corresponding aziridine adducts 2g−
m in good to excellent yields. With the exception of 2i, the
trisubstituted products were also obtained as a mixture of
diastereomers in cis/trans or trans/cis ratios of up to 3.8:1 in
reactions where R3 ≠ H.
We next sought to evaluate the scope of this new
methodology with respect to other types of 2-alkyl substituted
1,3-dicarbonyl compounds (Table 3). With this in mind, the
reaction behavior of dimethyl 2-methylmalonate 1n was first
tested in the presence of 10 mol % of Cu(OTf)2 and 10 mol %
of 1,10-phen under the standard conditions and found that
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determined on the basis of X-ray crystallographic analysis of
Table 3. Copper(II)-Catalyzed Aziridination of 2-Alkyl
Substituted Malonates and 1,3-Diones
2o and 2s (Figure 1).14 Additionally, no other side products
a
1
were detected by TLC and H NMR analysis of the crude
mixtures.
Further exploration of the reaction conditions found that the
α-acyl-β-amino acid derivative 3 could be selectively formed in
preference to the 2,2-diacyl aziridine 2 by simply reducing the
amount of PhINTs from 2 to 1.2 equiv (Table 4). Under
Table 4. Copper(II)-Catalyzed Amination of 2-Alkyl
Substituted β-Ketoesters 1g, 1l, and 1m, and Malonates 1q−
a
t
a
All reactions were carried out at room temperature and 4 Å MS (400
mg) in 2 mL of CH2Cl2 for 18 h with Cu(OTf)2/1,10-phen/1/PhI
NTs molar ratio = 1:1:10:20. Values in parentheses denote isolated
b
product yields. Reaction conducted with 3 equiv of PhINTs.
a
All reactions were carried out at room temperature and 4 Å MS (400
mg) in 2 mL of CH2Cl2 with Cu(OTf)2/1,10-phen/1/PhINTs
molar ratio = 1:1:10:12 for 0.5−7 h; refer to Supporting Information
for individual reaction times. Values in parentheses denote isolated
b
product yields. Product obtained as a 1:1 mixture of diastereomers.
c
d
Product obtained as a 4.4:1 mixture of regioisomers. Product
obtained as a 1.6:1 mixture of regioisomers and yield estimated on the
basis of 1H NMR analysis with CH2Br2 as the internal reference
standard.
these slightly modified conditions, reactions of 2-alkyl
substituted β-ketoesters 1g, 1l, and 1m as representative
examples with Cu(OTf)2 (10 mol %) and 1,10-phen (10 mol
%) gave the corresponding aminated products 3g, 3l, and 3m in
40−70% yield and as a 1:1 mixture of diastereomers. A similar
outcome was observed with 3q−t obtained in excellent yields of
82−95% from the corresponding selected 2-alkyl substituted
malonates 1q−t under these latter conditions. In the case of
reactions with 1l, 1m, 1r, and 1t, the corresponding alkene
byproducts 5l, 5m, 5r, and 5t were also obtained in 2−45%
yield.
In light of these latter results, we next performed a series of
control experiments to gain a better understanding of the
reaction mechanism (Schemes 2−6). In a first set of
experiments, treating 5r to the conditions depicted in Scheme
2 gave 2r in 40% yield after 3 h. Repeating this transformation
again for a longer reaction time of 4 h, on the other hand, gave
the aziridine product along with compound 3r in 40 and 30%
yield, respectively. Conversion of the β-aminated adduct to 2r
in 99% yield was then accomplished by exposing 3r once more
to the same conditions for 18 h. This indicates that the
aziridination process could proceed via a pathway involving
Figure 1. ORTEP drawings of (a) 2o and (b) 2s with thermal
ellipsoids at 50% probability levels.14
dimethyl 1-tosylaziridine-2,2-dicarboxylate 2n could be afforded
in 92% yield. Under similar conditions, repetition of the
reaction with other 2-alkyl substituted malonates 1o−t gave the
corresponding dialkyl and dibenzyl 1-tosylaziridine-2,2-dicar-
boxylates 2o−t in 60−90% yield. This included one example
where the C−Cl bond remained intact when a chlorine
substituent (2t) was introduced. Likewise, treating the 2-alkyl
substituted 1,3-diones 1u and 1v with the Cu(OTf)2 + 1,10-
phen catalyst system under the standard conditions afforded
the corresponding 1,1′-(1-tosylaziridine-2,2-diyl)-1,3-diones 2u
and 2v in 65 and 99% yield, respectively. In these latter
reactions, the structure of the aziridine products was
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our hands, subjecting 5r to these conditions was found to give
3r in 24% yield. In contrast, the analogous reactions with 5l and
5t led to recovery of only the starting alkene in both instances.
Added to this are our findings that showed 5m to rapidly
decompose in CH2Cl2 over a 30 min period to give a variety of
side products that could not be identified by NMR analysis.
These marked differences in reactivity to those observed for 1r,
1l, 1m, and 1t with PhINTs shown in Table 4 suggest a
pathway involving 1,4-conjugate addition of the aryl sulfona-
mide to an in situ formed alkene to be unlikely. While this
amination path cannot be completely ruled out, if operative, we
posit that it is most probably limited to sterically unhindered 2-
alkyl substituted malonates and, even then, at most provides a
minor contribution to the overall yield.
On the other hand, the premise that the present CN bond
forming processes occur via Cu(II)-mediated transfer of the
nitrene/imido group from PhINTs to the substrate is evident
in two experiments examined in this work. First is the
preferential amination of the α-CH bond of THF to give
compound 4 as a byproduct in the reaction of 1a with PhI
NTs and the oxygen heterocycle as the solvent under the
conditions described in Table 1, entry 15.4d Second is the
markedly lower yield of 2a and substantial recovery of the
substrate observed when the analogous reaction was examined
with CH2Cl2 as the solvent and in the absence of 4 Å MS
(Table 1, entry 11). This would be consistent with competitive
hydrolysis of the nitrene/imido donor due to residual amounts
of H2O present in the reaction mixture.12
Scheme 2. Cu(OTf)2-Catalyzed Reactions of 3r and 5r with
PhINTs
either or both 3 and 5 as intermediates. It additionally suggests
that the origin of the alkene could be due to the direct reaction
of the enolate of 1 with PhINTs presumably via an
addition−elimination process rather than from deamination
of 3.13b Formation of 5 in this manner would be consistent with
our observations showing a marked increase in the amount of
alkene obtained as the acidity of the substrate increased on
going from 2-alkyl substituted malonates to β-ketoesters in
Table 4. It would also explain the NH2Ts and PhI detected by
1H NMR analysis in the crude mixtures of these reactions.
The possibility that in situ formed NH2Ts could then act as
an inhibitor was also ruled out when we examined the reactions
of 1g with 1.2 or 3 equiv of PhINTs and 1.5 equiv of the aryl
sulfonamide under the standard conditions (Scheme 3). In
In a final set of control experiments, we turned our attentions
to the nature of the nitrene/imido transfer in the present
Cu(II)-catalyzed reactions. In an earlier work, the use of the
radical inhibitor butylhydroxytoluene (BHT) was demonstrated
to implicate the possible involvement of radical species in
Ag(I)-catalyzed amination of the CH bond of alkanes with
PhINTs.9 With this in mind, the reactivities of compounds
1r, 3r, and 5r in the presence of 1.5−3 equiv of BHT or 2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO) and 2 equiv of PhI
NTs were first compared (Scheme 5). This revealed a change in
Scheme 3. Cu(OTf)2-Catalyzed Reactions of 1g with PhI
NTs in the Presence NH2Ts
Scheme 5. Cu(OTf)2-Catalyzed Reactions of 1r, 3r, and 5r in
the Presence of a Radical Scavenger
both instances, this revealed the production of the correspond-
ing aziridine and β-aminated adducts 2g and 3g in 99 and 67%
yield and a diastereomeric ratio (d.r.) of 1.9:1 and 1:1,
respectively, comparable to those furnished in the analogous
reactions described in Tables 2 and 4.
In another set of experiments, the interactions of compounds
5l, 5r, and 5t with 1.2 equiv of NH2Ts and 10 mol % of the
Cu(II) + 1,10-phen catalyst system in CH2Cl2 at room
temperature for 4−7 h was next investigated (Scheme 4). In
Scheme 4. Cu(OTf)2-Catalyzed Reactions of 5l, 5r, and 5t
with NH2Ts as the Nitrogen Source
product selectivity in reactions with either 1r or 5r as the
substrate, affording 3r and not 2r in 95 and 32% yield,
respectively (Scheme 5, eq 1). In the latter case, this could be
presumably due to decomposition of PhINTs to NH2Ts by
the metal catalyst,3,12 followed by Cu(II)-mediated 1,4-
conjugate addition of the aryl sulfonamide to the alkene,
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reflecting our earlier findings depicted in Scheme 4. In contrast,
reactions with 3r showed the yield of aziridine 2r to decrease as
the ratio of [BHT]/[PhINTs] increased while replacing the
phenol additive with TEMPO led to only recovery of the β-
aminated substrate in near-quantitative yield (Scheme 5, eq 2).
This trend would account for 3r obtained from 1r shown in
Scheme 5, eq 1 not proceeding on to the aziridine product as
the amount of PhINTs decreases due to the gradual
formation of the β-aminated adduct. It would also be in good
agreement with that reported in works describing Ag(I)-
catalyzed CH bond aminations.9 Overall, these observations
suggest that CH bond amination of 1 to give 3 occurs via a
concerted asynchronous pathway whereas formal aziridination
of 3 or 5 to afford 2 proceeds through a radical-based
mechanism. This latter argument in which the aziridine
formation process occurs via radical species is additionally
corroborated by the lack of stereoselectivity found in a number
of reactions of substrates examined in Table 2.
Scheme 7. Proposed Reaction Pathway for the Formation of
α-Acyl-β-amino Acid and 2,2-Diacyl Aziridine Derivatives
To provide further support for our hypothesis, we next
turned to measuring the deuterium kinetic isotope effect (KIE)
for the present Cu(II)-catalyzed reactions with 1g and d5-1g as
the test substrates under the conditions described in Scheme 6.
Scheme 6. Measurement of the Deuterium Kinetic Isotope
Effect for the Cu(OTf)2-Catalyzed Reactions of 1g and d5-1g
amount of PhINTs, further transfer of the imido/nitrene
group to the CC bond of the copper-enolate of 3 via the
carboradical D would give the aziridine E.11 Presumably, the
acid labile nature of the aziridin-2-ol intermediate results in ring
opening to afford the diamine H that can undergo deaminative
cyclization to provide 2.20 Alternatively, the copper-enolate
species A could directly react with PhINTs to give the
hypervalent iodine(III) adduct F (route b in Scheme 7).13b
Deiodination of this newly formed intermediate would furnish
5. Radical imido/nitrene transfer of the [Cu]NTs species to
the alkene intermediate via the carboradical G would then
complete the aziridination process to deliver 2.
Analysis by GC-MS gave a KIE value of 1.9 that suggested
carbon−hydrogen bond cleavage might be the rate determining
step. This value is in the same range as those previously
reported for metal- and base-mediated concerted nitrene and
carbene reactions, with KIE values of 1.2 to 2.1 depending on
the catalyst and substrate employed.15−17 By contrast, Fe(II)-
and Ru(II)-based intermolecular CH bond aminations,
which are thought to occur by way of a H-atom abstraction/
radical rebound pathway, afford KIE values of greater than
4.4.7a,10
Although highly speculative, the above results led us to put
forward the mechanism outlined in Scheme 7 for the present
Cu(II)-catalyzed amination and aziridination of 2-alkyl
substituted 1,3-dicarbonyl compounds with PhINTs. This
could involve the initial formation of a Cu-1,10-phen species, in
either the monomeric or polymeric form, from reaction of
Cu(OTf)2 and 1,10-phen additive.18 Further reaction of this
Cu-1,10-phen complex with PhINTs generates the putative
highly reactive [Cu]NTs species.19 At the same time,
coordination of the Cu-1,10-phen complex to 1 could occur
and give the copper-enolate species A. Subsequent rate-limiting
transfer of the imido/nitrene group in [Cu]NTs into the
allylic CH bond of this newly formed enolic form of the
substrate via a direct insertion pathway is then thought to
deliver 3 (route a in Scheme 7).8 Under conditions where the
[Cu]NTs species can be rapidly reformed due to an excess
CONCLUSIONS
■
In summary, we have exploited the intriguing reactivities of a
diverse set of 2-alkyl substituted 1,3-dicarbonyl compounds in
the presence of a Cu(II) salt as a catalyst and PhINTs to
prepare α-acyl-β-amino acid and 2,2-diacyl aziridine derivatives.
Complete control of product selectivity in the reaction was
shown to be possible through slight modification of the
reaction conditions. Further investigations are underway to
examine the applications of this reaction to natural products
synthesis and medicinal chemistry and will be reported in due
course.
EXPERIMENTAL SECTION
General Considerations. All reactions were performed in oven-
dried glassware under a nitrogen atmosphere at ambient temperature
■
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unless otherwise stated. PhINTs was prepared following literature
procedures.21 Unless otherwise specified, all reagents and starting
materials were purchased from commercial sources and used as
received. Solvents were purified prior to use following literature
procedures; CH2Cl2 and MeCN were purified prior to use by distilling
over CaH2, and pyridine was distilled over KOH. Analytical thin layer
chromatography (TLC) was performed using a precoated silica gel
plate. Visualization was achieved by UV−vis light (254 nm) followed
by treatment with ninhydrin stain and heating. Flash chromatography
was performed using silica gel using a gradient solvent system
(EtOAc/n-hexane as eluent). Unless otherwise stated, 1H and 13C
NMR spectra were measured on a 300 MHz spectrometer. Unless
otherwise stated, chemical shifts (ppm) were recorded in CDCl3
solution with tetramethylsilane (TMS) as the internal reference
ACKNOWLEDGMENTS
■
This work is supported by a University Research Committee
Grant (RG55/06) from Nanyang Technological University
(NTU). A Nanyang President’s Graduate Scholarship (to
T.M.U.T.) from NTU is also gratefully acknowledged, and we
thank Dr. Yongxin Li of this Division for providing the X-ray
crystallographic data reported in this work.
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■
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1
standard. H NMR product yields were estimated with CH2Br2 as the
internal reference standard. Multiplicities are given as s (singlet), d
(doublet), t (triplet), q (quartet), dd (doublet of doublets), quin
(apparent quintet), or m (multiplet). The number of protons (n) for a
given resonance is indicated by nH, and coupling constants are
reported as a J value in Hz. Low resolution mass spectra were
determined on a mass spectrometer and reported as a ratio of mass to
charge (m/z). High resolution mass spectra (HRMS) were obtained
using an LC-HRMS mass spectrometer. Kinetic isotope measurements
were conducted on a GC-MS mass spectrometer.
General Procedure for the Synthesis of 2-Alkyl 1,3-
Dicarbonyl Compounds 1.22 To a mixture of the 1,3-dicarbonyl
compound (2.0 mmol) and iodoalkane (2.2 mmol) in N,N-
dimethylformamide (5.0 mL) was added K2CO3 (1.5 mmol, 415
mg) at room temperature. The resulting reaction mixture was stirred at
room temperature for 18 h or at 60 °C for 5 h. The reaction was then
quenched with H2O (50 mL) and extracted with EtOAc (3 × 50 mL).
The combined organic layers were dried over Na2SO4, filtered, and
evaporated to dryness. The residue was purified by flash column
chromatography (32:1 → 19:1 n-hexanes/EtOAc as eluent) to give the
title compound.
General Procedure for Cu(II)-Catalyzed Aziridination of 2-
Alkyl 1,3-Dicarbonyl Compounds 1 to 2,2-Diacyl Aziridine
Derivatives 2. To a mixture of Cu(OTf)2 (0.05 mmol, 18.1 mg),
1,10-phen (0.05 mmol, 9.9 mg), and powdered 4 Å MS (400 mg) were
added 2 mL of CH2Cl2. After the mixture was stirred for 1 h, PhI
NTs (1.0 mmol, 373 mg or 1.5 mmol, 560 mg) and 1 (0.5 mmol)
were added. The reaction mixture was stirred for a further 18 h at
room temperature, after which the mixture was filtered through Celite,
washed with EtOAc (50 mL), evaporated to dryness, and purified by
flash column chromatography (4:1 n-hexanes/EtOAc as eluent) to
give the title compound.
General Procedure for Cu(II)-Catalyzed Amination of 2-Alkyl
1,3-Dicarbonyl Compounds 1 to α-Acyl-β-amino Acid Deriva-
tives 3. To a mixture of Cu(OTf)2 (0.05 mmol, 18.1 mg), 1,10-phen
(0.05 mmol, 9.9 mg), and powdered 4 Å MS (400 mg) were added 2
mL of CH2Cl2. After the mixture stirred for 1 h, PhINTs (0.6 mmol,
224 mg) and 1 (0.5 mmol) were added. The reaction mixture was
stirred at room temperature and monitored by TLC analysis. Upon
completion, the mixture was filtered through Celite, washed with
EtOAc (50 mL), evaporated to dryness, and purified by flash column
chromatography (4:1 n-hexanes/EtOAc as eluent) to give the title
compound.
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ASSOCIATED CONTENT
* Supporting Information
́
■
S
̈
Experimental procedures for control reactions, characterization
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
Storcheva, O.; Cokoja, M.; Kuhn, F. E. Dalton Trans. 2011, 40, 5746.
̈
(b) Robert-Peillard, F.; Di Chenna, P. H.; Liang, C.; Lescot, C.; Collet,
F.; Dodd, R. H.; Dauban, P. Tetrahedron Asymmetry 2010, 21, 1447.
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Tetrahedron Lett. 2009, 50, 161. (d) Comba, P.; Haaf, C.; Lienke, A.;
Muruganantham, A.; Wadepohl, H. Chem.Eur. J. 2009, 15, 10880.
(e) Comba, P.; Lang, C.; de Laorden, C. L.; Muruganantham, A.;
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AUTHOR INFORMATION
Corresponding Author
waihong@ntu.edu.sg
■
Notes
The authors declare no competing financial interest.
7349
dx.doi.org/10.1021/ja301415k | J. Am. Chem. Soc. 2012, 134, 7344−7350

Journal of the American Chemical Society
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NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published ASAP on April 18, 2012, with
incorrect graphics for Tables 1 and 4. The corrected version
was reposted on April 19, 2012.
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