Chiral calcium-binol phosphate catalyzed diastereo- And enantioselective synthesis of syn-1,2-disubstituted 1,2-diamines: Scope and mechanistic studies

Article abstract of DOI:10.1002/chem.201405286

A highly enantioselective, chiral, Lewis acid calcium-bis(phosphate) complex, Ca[3a] which catalyzes the electrophilic amination of enamides with azodicarboxylate derivatives 2 to provide versatile chiral 1,2-hydrazinoimines 4 is disclosed. The reaction g

Full text of DOI:10.1002/chem.201405286

DOI: 10.1002/chem.201405286
Full Paper
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Enamide Amination
Chiral Calcium–BINOL Phosphate Catalyzed Diastereo- and
Enantioselective Synthesis of syn-1,2-Disubstituted 1,2-Diamines:
Scope and Mechanistic Studies**
Claudia Lalli,[a] Audrey Dumoulin,[a] Clꢀment Lebꢀe,[a] Fleur Drouet,[a] Vincent Guꢀrineau,[a]
David Touboul,[a] Vincent Gandon,[a, b] Jieping Zhu,[c] and Gꢀraldine Masson*[a]
Abstract: A highly enantioselective, chiral, Lewis acid calci-
um–bis(phosphate) complex, Ca[3a]n, which catalyzes the
electrophilic amination of enamides with azodicarboxylate
derivatives 2 to provide versatile chiral 1,2-hydrazinoimines
4 is disclosed. The reaction gives an easy entry to optically
active syn-1,2-disubstituted 1,2-diamines 6 in high yields
with excellent enantioselectivities, after a one-pot reduction
of the intermediate 1,2-hydrazinoimines 4. The geometry
and nature of the N-substituent of the enamide affect dra-
matically both the reactivity and the enantioselectivity. Al-
though the calcium–bis(phosphate) complex was a uniquely
effective catalyst, the exact nature of the active catalytic spe-
cies remains unclear. NMR spectroscopy and MS analysis of
the various calcium complexes Ca[3]n reveals that the cata-
lysts exist in various oligomer forms. The present mechanis-
tic study, which includes nonlinear effects and kinetic meas-
urements, constitutes a first step in understanding these cal-
cium–bis(phosphate) complex catalysts. DFT calculations
were carried out to explore the mechanism and the origin of
the enantioselectivity with the Ca[3]n catalysts.
Introduction
chiral diamine–Cu(OTf)2 (OTf: trifluoromethanesulfonate) com-
plexes as catalysts.[6] In 2010, Feng and co-workers developed
a chiral N,N-dioxide–Cu(OTf)2 complex that catalyzed asymmet-
ric a-amination of (Z)-enamides.[7] Surprisingly, although chiral
Brønsted acids catalyze many nucleophilic additions of enecar-
bamates with several electrophiles,[8] there is no example of
enantioselective a-aminations of enamides (enecarbamates)
mediated by Brønsted acids.[9]
Chiral vicinal diamines[1] are versatile motifs frequently encoun-
tered in natural products and pharmaceuticals,[1,2a] and they
have been employed as chiral auxiliaries and ligands in asym-
metric catalysis.[1,2b] Many efforts have been made in the devel-
opment of asymmetric catalytic methods for the preparation
of these compounds.[1,3] Among various synthetic approaches,
the nucleophilic addition of enamide derivatives to an electro-
philic nitrogen atom, “N+”, is an efficient approach for obtain-
ing diverse diamines.[4] The first enantioselective amination of
(E)-enecarbamates, derived from acetophenones with azodicar-
boxylates,[5] was described by Matsubara and Kobayashi with
In continuation with our efforts directed towards the devel-
opment of chiral phosphoric acid catalyzed enantioselective
transformations,[8g–k,u,v,10] we initiated studies aimed at develop-
ing a chiral phosphoric acid catalyzed amination of enamides
with azodicarboxylates (Scheme 1). We recently achieved
[a] Dr. C. Lalli, A. Dumoulin, C. Lebꢀe, Dr. F. Drouet, V. Guꢀrineau,
Dr. D. Touboul, Prof. Dr. V. Gandon, Dr. G. Masson
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles CNRS
LabEx CHARM3AT
Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex (France)
Fax: (+33)1-6907-7247
E-mail: geraldine.masson@cnrs.fr
[b] Prof. Dr. V. Gandon
Universitꢀ Paris Sud, ICMMO (UMR CNRS 8182)
LabEx CHARM3AT, 91405 Orsay (France)
[c] Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
EPFL-SB-ISIC-LSPN, 1015 Lausanne (Switzerland)
[**] BINOL=1,1’-binaphthalene-2,2’-diol
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405286.
Scheme 1. Catalytic enantioselective a-amination of enamides.
Chem. Eur. J. 2014, 20, 1 – 10
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a highly enantioselective amination of (E)-enamides, to yield
optically active 1,2-hydrazinoimines 4, in which the chiral calci-
um–organophosphate proved to be a more effective catalyst
for this transformation than the corresponding chiral phospho-
ric acid.[11] The resulting chiral imines 4 were hydrolyzed or re-
duced in situ to produce chiral 2-hydrazinoketones 5 or syn-
1,2-disubstituted 1,2-diamines 6, respectively, in good yields
with excellent enantioselectivity. This article describes the full
details of the catalytic asymmetric amination with investiga-
tions of phosphoric acids coordinated with alkaline-earth-metal
ions as the catalytic system. The scope and limitations of this
amination of enamides have also been further examined. De-
tailed mechanistic studies, combining mass spectrometry, NMR
spectroscopic analysis, nonlinear effects, and DFT calculations,
are also described to identify the active catalyst species.
Table 1. Catalyst screening for the synthesis of 1,2-hydrazinoketones.[a]
Entry
1
R3 (3 or M[3]n)
5
Yield
[%][b]
ee
[%][c]
Results and Discussion
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(E)-1a
(Z)-1a
(E)-1b
(Z)-1b
(E)-1a
(E)-1a
C6H5 (3ar)[d,e]
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
29
99
56
62
66
74
82
75
57
44
59
92
94
85
82
65
79
57
23
56
18
79
76
80
89
71
80
18
77
47
35
28
88
78
85
91
83
95
91
85
83
0
C6H5 (3ar)[d]
Initial studies were conducted by examining the addition of
(E)-N-(1-phenylpropenyl)acetamide (1a) to diisopropylazodicar-
boxylate (2) as the aminating agent in the presence of a chiral
phosphoric acid, 3, derived from (R)-1,1’-binaphthalene-2,2’-
diol ((R)-BINOL) or octahydro-(R)-BINOL (purified by silica gel
column chromatography, Table 1). When 3a was used as cata-
lyst, a mixture of the desired 1,2-hydrazinoimine 4a and the
corresponding 2-aminoketone 5a was observed. Although the
addition of molecular sieves in the reaction prevented the hy-
drolysis of the unstable N-acylimine 4a, the enantioselectivities
and yields were always determined for compound 5a, ob-
tained after in situ hydrolysis of 4a under acidic conditions
(33% HBr in AcOH). Phosphoric acid screening in CH2Cl2 at
À358C revealed that the less hindered acid 3a was the most
effective catalyst for the amination of enamide 1a in terms of
enantioselectivity and yield. Surprisingly, we noticed that the
enantioselectivities (78–89%) and yields (from 45% to quanti-
tative) under the optimal conditions varied considerably de-
pending on the batch of 3a that was used. Ding and co-work-
ers observed previously that the treatment of chiral phosphoric
acid with an acid improved the catalytic activity in the enantio-
selective transformation.[12a] Shortly afterwards, Ishihara and co-
workers and also List and co-workers demonstrated the forma-
tion of a variable amount of alkali– or alkaline-earth-metal–
phosphoric acid complexes during the purification procedure
of 3, which could explain the improvement of the catalytic ac-
tivity after acid washing of the catalyst.[12] Based on these im-
portant works, we hypothesized that the formation of these
phosphate salts might explain the nonreproducible results.[12a]
However, when acid-washed catalyst was used, although the
results was reproducible, the enantiomeric excess was signifi-
cantly lower than with nonacidified phosphoric acid 3a. To re-
cover the initial enantiomeric values, we reasoned that phos-
phate salt impurities originating from the silica gel might
4-MeOC6H4 (3br)[d]
4-ClC6H4 (3cr)[d]
CH(C6H5)2 (3dr)[d]
4-tBuC6H4 (3er)[d]
4-NO2C6H4 (3 fr)[d]
2-naphthyl (3gr)[d]
2,4,6-(iPr)3C6H5 (3hr)[d]
C6H5[H8] (3ir)[d,f]
4-ClC6H4 [H8] (3jr)[d,f]
[g]
3ar
Li[3ar]
Na[3ar]
Ca[3ar]n
Ba[3ar]2
Mg[3ar]2
Ag[3ar]2
Ca[3ar]n
Ca[3ar]n
Ca[3ar]n
4
À67
91
À96
[h]
Ca[3ar]n
Ca[3as]n
[i]
[a] General conditions: 1/2/cat.=1.0:5.0:0.1 in CH2Cl2 (c=0.1) at À358C,
followed by acid hydrolysis with 33% HBr in AcOH. [b] Yields refer to
chromatographically pure products. [c] Enantiomeric excesses were deter-
mined by chiral HPLC analysis. [d] Purified on silica gel. [e] Without molec-
ular sieves. [f] Derived from octahydro-(R)-BINOL. [g] Washed with HCl
after purification on silica gel. [h] Toluene was used as the solvent. [i] Cal-
cium–phosphate catalyst prepared from (S)-BINOL.
phosphoric acid 3a. The lithium and barium phosphates cata-
lyzed the reaction with increased enantioselectivity (Table 1,
entries 13 and 16). To our delight, the chiral calcium–phos-
phate catalyst Ca[3aR]n provided the adduct with higher enan-
tioselectivities (Table 1, entry 15).[18] The absolute configuration
of 5a was determined to be S by comparison of the sign of its
optical rotation with that in the literature data.[6,7] Importantly,
the calcium–(S)-BINOL phosphate catalyst, Ca[3aS]n, afforded
the same enantioselectivity with an opposite sense of asym-
metric induction (Table 1, entry 23). The effects of the alkene
geometry and the N-protecting group of the enamides were
then addressed. It was observed that changing the double-
bond geometry from E to Z resulted in a dramatic loss in reac-
define
a
better chiral environment.[8u,11,13–17] We initiated
screening of the catalyst system by using various alkali- or al-
kaline-earth-metal-linked (R)-BINOL phosphoric acids, M[3a]n.
Sodium- and magnesium-derived phosphates afforded the
product 5a with similar ee values to those with acid-washed
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tivity. For instance, the reaction of the Z isomer 1a occurred
only at room temperature to afford the racemic product 5a in
low yield (Table 1, entry 19). Similarly, (Z)-enecarbamate 1b
was a poor substrate that gave the corresponding ketone in
low yield but with reversed enantioselectivity to that obtained
with (E)-1a (Table 1, entry 21). On the other hand, (E)-enecarba-
mate 1b reacted smoothly to afford the product with almost
no enantioselectivity (Table 1, entry 20).
Table 3. Scope of the enantioselective one-step synthesis of 1,2-hydrazi-
noamines catalyzed by a calcium–phosphate.[a]
Entry
1
Product
6
Yield [%][b]
84
ee [%][c]
After obtaining these preliminary results, we started to opti-
mize a catalytic asymmetric synthesis of enantioenriched 1,2-
diamines through reduction of 1,2-hydrazinoimines 4 (Table 2).
To avoid problems with hydrolysis of the unstable compounds
6a
92[d]
2
3
6d
6e
88
84
88[d]
Table 2. Survey of reaction conditions for the synthesis of 1,2-hydrazinoa-
mines.[a]
93[d]
4
5
6
6 f
88
91
93
88[d]
85[d]
83[d]
6g
6h
Entry
Ca[3]n
Hydride
2
6
Yield
[%][b]
ee
[%][c,d]
1
2
3
4
5
6
7
Ca[3aR]n
Ca[3aR]n
Ca[3aR]n
Ca[3gR]n
Ca[3hR]n
Ca[3aR]n
Ca[3aR]n
BH3·THF
NaBH3CN
NaBH4
NaBH4
NaBH4
2a
2a
2a
2a
2a
2b
2c
6a
6a
6a
6a
6a
6b
6c
52
56
84
35
30
68
65
77
79
92
92
89
71
75
NaBH4
NaBH4
7
6i
87 (78)
57[d] (57[d,e]
)
[a] General conditions: 1/2/Ca[3]n =1.0:5.0:0.1 in CH2Cl2 (c=0.1) at
À358C, followed by addition of NaBH4 at À78 to À458C in MeOH. MS:
molecular sieves. [b] Yields refer to chromatographically pure products.
[c] Enantiomeric excesses were determined by chiral HPLC analysis.
[d] d.r.>95:5.
8
9
6j
67 (81)[d] 22 (37[e]
)
6k
<10%
n.d.[f]
4, we decided to concentrate our efforts on the development
of a one-pot a-amination/reduction process. Amination of en-
amide (E)-1a followed by in situ reduction with BH3·THF or
NaBH3CN gave syn-6a with moderate yield and ee value,
whereas NaBH4 afforded the syn-1,2-diamine 6a in high dia-
stereo- and enantioselectivity.[19,20] Unfortunately, attempts to
improve the reaction yield or enantioselectivity by varying the
phosphate ligands of the calcium-complex catalyst were un-
successful. As Table 2 shows, in contrast to the results with the
phosphoric acid catalysts (Table 1), the size of the R3 group
only has very little influence on the asymmetric induction.
However, better yields were still observed with 10 mol% of
Ca[3aR]n. Upon further optimization of the reaction conditions,
it was found that this one-pot process was rather sensitive to
the alkyl group of 2. Ethyl- and benzylazodicarboxylates 2b
and 2c gave slightly lower enantioselectivities (Table 2, en-
tries 6 and 7) than isopropylazodicarboxylate 2a.
10
11
6l
87
99
94[d]
6m
95[d]
[a] General conditions: 1/2/Ca[3]n =1.0:5.0:0.1 in CH2Cl2 (c=0.1) at
À358C, followed by addition of NaBH4 in MeOH. [b] Yields refer to chro-
matographically pure products. [c] Enantiomeric excesses were deter-
mined by chiral HPLC analysis. [d] d.r.>95:5. [e] Result with chiral phos-
phoric acid 3a. [f] d.r.=1:1. n.d. not determined.
Table 3. A wide range of (E)-enamides 1, derived from aromatic
ketones bearing substituents with various electronic and steric
properties, provided the desired syn-1,2-diamines 6 with excel-
lent enantioselectivities. For example, the enamide bearing
a p-trifluoromethylphenyl group provided the corresponding
The substrate scope of the one-pot sequential catalytic
asymmetric amination–diastereoselective imine reduction pro-
cess under the optimized reaction conditions is summarized in
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diamine 6e in 84% yield with 93% ee (Table 3, entry 3). In
a similar manner, the electron-rich p-methoxyphenyl-substitut-
ed enamide 1g led to product 6g in 91% yield with 85% ee
(Table 3, entry 5). In addition, the (E)-N-(1-(naphthalen-2-yl)pro-
penyl)acetamide (1h) was a suitable substrate and provided
the diamine product 6h with a high yield and good enantiose-
lectivity (Table 3, entry 6). Surprisingly, heteroatom substitution
in the aryl moiety seems to seriously impact the enantioselec-
tivity. Indeed, we obtained a nearly racemic product 6j with
thiophenyl-substituted enamide 1j, whereas up to 37% ee was
observed when chiral phosphoric acid 3a was used instead.
The appropriate cyclic enamide also afforded the desired prod-
uct 6i, but low enantioselectivity was observed with both cal-
cium–phosphate and phosphoric acid catalysts (Table 3,
entry 7). Notably, contrary to previous reports, high yields and
high enantioselectivities can be obtained even with a longer
alkyl chain in linear enamides (Table 3, entries 10 and 11).[7]
Although the precise nature of the active catalyst remains
unknown, oligomeric forms of the chiral calcium–phosphate
catalyst have been proposed in the literature.[12b–e,21,22] To gain
information on the structure of the catalyst and mechanism for
the electrophilic amination of enamides, a series of experi-
ments have been performed. Firstly, the 31P NMR spectrum of
Ca[3aR]n shows the emergence of a broad signal of an oligo-
meric form. We then analyzed a series of asymmetric calcium
complexes by MALDI-TOF mass spectrometry, which allows
facile and precise characterization of labile organic species co-
ordinated to Ca2+ ions. The MS spectrum of Ca[3aR]n showed
a strong peak at m/z 1577.24 and weak peaks at m/z 1039.15,
2076.29, and 2615.24 (Figure 1). This indicates that Ca[3aR]n is
an oligomeric species with the formation of monometallic
Ca[3aR]2, dimetallic Ca2[3aR]3 and (Ca[3aR]2)2, and trimetallic
Ca3[3aR]5 species (Figure 2). Although the same pattern of oli-
gomeric species was found for Ca[3gR]n, many more oligomeric
species were observed with the calcium complex derived from
unsubstituted BINOL phosphate, Ca[3kR]n (R3: H). On the other
hand, fewer oligomer structures existed with calcium complex
Ca[3hR]n, and diphosphate calcium salt Ca[3hR]2 was assigned
as the major peak in the mass spectrum (Figure 1). This study
indicates that the hindrance of the substituents at the 3,3’-po-
sitions has an effect on the structural complexity of the oligo-
meric species of Ca[3]n. Evaluation by DFT computations of the
dimerization energy between calcium complexes of type
Ca[3R]2 and (Ca[3R]2)2 exhibiting phenyl, 2,4,6-trimethylphenyl,
and 2,4,6-triisopropylphenyl at the 3,3’-positions clearly sup-
ported this hypothesis (see the Supporting Information). In ad-
dition, no free phosphate peaks were detected in any of the
spectra, which strongly indicates that free phosphoric acid is
not the active catalyst.
A negative correlation ((+)-nonlinear effect, NLE) was ob-
served between the ee value of chiral Ca[3aR]n and the ee
value of the 2-hydrazinoketone 5a (Figure 3).[23] Notably, the
enantiomeric excess was dramatically reduced. For instance,
the use of 10 mol% of a calcium–BINOL phosphate catalyst
that contained 95% of Ca[3aR]n and 5% of Ca[3aS]n gave 2-hy-
drazinoketone 5 with only 24% ee. Moreover, the evolution of
the enantioselectivity in relation to the reaction time was
Figure 1. Mass spectra of Ca[3aR]n, Ca[3gR]n, Ca[3hR]n, and Ca[3kR]n.
checked by using Ca[3aR]n with an optical purity of 80%: three
reactions were run simultaneously under the same conditions
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Scheme 2. Possible equilibrium between Ca[3aR]n and Ca[3aS]n.
Figure 2. Possible intermediates in the asymmetric electrophilic a-amination
of enamides 1.
Figure 4. Comparison of the formation rates of 5a with Ca[3aR]n and
Ca[3aRS]n as catalysts.
enamides is outlined in Scheme 3. NMR spectroscopic analyses,
ESI MS analyses, nonlinear effects, and kinetic studies suggest-
ed that the catalyst components, Ca[3a]n, are in equilibrium
between various forms.[21,22] As a result, the active catalyst is
still ambiguous. However, based on density functional theory
(DFT) calculations (see below), we propose that the chiral,
Figure 3. Correlation between the enantiomeric excess of Ca[3a]n and the
enantiomeric excess of 5a.
but quenched at different times (1–24 h). The ee values were
constant with the progress of reaction (values of 15, 14, 14,
and 16%, respectively, were obtained). This nonlinear effect
confirms that the oligomeric species Ca[3aR]n are the active
catalysts, rather than the CaII-free phosphoric acid or
mono(phosphate) salt.[19,20] This remarkably strong negative
linear effect may be explained with the MLn model of Kagan
and co-workers,[23d,24,25] in which there is an equilibrium with
homochiral and heterochiral adducts exhibiting different cata-
lytic activity. Therefore, according to this model, the nonlinear
effects resulted from the formation of the heterochiral dimer
complexes Ca[3aRS]n over the homochiral adducts (Ca[3aR]n
and Ca[3aS]n); the heterochiral complexes are much more reac-
tive than the homochiral complexes in forming the racemic 5a
(Scheme 2).[26] To support this, we performed kinetic experi-
ments by measuring the rate of conversion of 5a with
10 mol% of Ca[3aR]n and 10 mol% of Ca[3aRS]n, respectively
(Figure 4). As expected, the reaction rate increased significantly
when the heterochiral dimer complexes Ca[3aRS]n were used as
the catalyst.
On the basis of the experimental results obtained above,
a plausible catalytic cycle for the electrophilic amination of the
Scheme 3. Assumed reaction pathway for the enantioselective a-amination
of enamides 1.
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Lewis acid calcium–bis(phosphate) complex Ca[3a]2 could be
an active species and act as a bifunctional catalyst. The coordi-
nation of calcium to the azodicarboxylate oxygen atom would
afford the activated form 7 and would, at the same time, dis-
criminate the two prochiral faces. Meanwhile, the secondary
enamide would form a hydrogen bond with the phosphoryl
oxygen atom and be positioned close to the azodicarboxylate
in 8. A pseudo-intramolecular si-face attack of enamide 1 onto
azodicarboxylate 2 would then occur to form S-chiral 1,2-hy-
drazinoimines 4. The zwitterionic species 9 would then under-
go a proton transfer to generate monocoordinate complex 10,
which would dissociate to form the stable dicoordinate com-
plex 7. The presence of a free HN group in 1 is a requirement
for efficiency, because no reaction occurred with a tertiary en-
amide (Table 3, entry 9).[27]
continuum model (PCM). We found that amination of an acet-
amide can be catalyzed by a calcium–phosphate complex.
Figure 5 shows the transition states corresponding to the
(Re,Si)- and (Si,Re)-face attacks of the acetamide. Such CÀN
bond formation leads to the S and R enantiomers, respectively,
((S)-TS1 and (R)-TS2)). In both optimized structures, calcium is
bonded to one of the azadicarboxylate carbonyl groups. On
the other hand, the acetamide NH functionality establishes
a hydrogen bond with one of the phosphate oxygen atoms
bonded to calcium. The lowest lying transition state is (S)-TS1
(DDG° =1.1 kcalmolÀ1), which is consistent with the experi-
mentally obtained products when an (R)-phosphate catalyst is
used. Other details regarding the energy data of this transfor-
mation can be found in the Supporting Information.
This mechanism is supported by density functional theory
(DFT) computations. The structures were optimized by using
Gaussian 09 software at the B3LYP level of DFT.[28] All atoms
were described by the 6-31G(d) basis set. Calculations were
performed by using a simplified calcium–bis(phosphate) cata-
lyst of R,R configuration, dimethylazodicarboxylate, and (E)-N-
(prop-1-enyl)acetamide. Single-point energy calculations were
carried out at the MP2(full) level with the 6-311G(d,p) basis set
on every element (Figure 5). This level was also chosen to
obtain the solvation energy in CH2Cl2 by using the polarizable
Conclusion
In summary, the chiral, Lewis acid calcium–bis(phosphate)
complex Ca[3a]2 was revealed to be an efficient enantioselec-
tive catalyst for the amination of enamides with diisopropyl-
azodicarboxylate to provide versatile chiral 1,2-hydrazinoi-
mines. A sequence of asymmetric a-amination and imine re-
duction leads to 1,2-diamines in excellent yields and enantiose-
lectivities. A combination of 31P NMR spectroscopy, MS analysis,
and nonlinear effects demonstrate that Ca[3a]n exists in oligo-
meric form. In addition, the strong negative NLE and kinetic
studies indicate that heterocatalysts exhibited a higher activity
than chiral ones. The elucidation of the mechanism of this
enantioselective amination by calcium–bis(phosphate) complex
catalysts has been unusually challenging owing to difficulty in
establishing the exact nature of the active species in these het-
erogeneous systems. However, DFT studies provided evidence
that a chiral, Lewis acid calcium–bis(phosphate) complex of
type Ca[3a]2 could be an active species. In addition, this com-
putational study has resulted in a refined transition-state
model that explains the origins of enantioselectivity. The key
stabilizing forces favoring the transition state of the fast-react-
ing enantiomer are hydrogen bonding and coordination inter-
actions between the enamide and the azodicarboxylate.
Experimental Section
General
All reactions were carried out under an argon atmosphere in dried
glassware with magnetic stirring. Solvents were distilled by stan-
dard methods. Reagents were purchased from commercial suppli-
ers and used without further purification unless otherwise noted.
Flash column chromatography was carried out by using 40–63 mm
particle sized silica gel. Analytical thin layer chromatography plates
(silica gel 60 F254) were analyzed by irradiation with a 254 nm UV
light and by submersion in an ethanolic phosphomolybdic acid so-
lution. Melting points were recorded by using a melting point ap-
paratus and are uncorrected. Infrared spectra were recorded on
neat samples on a 100 FTIR spectrometer, and the characteristic IR
absorption frequencies are reported in cmÀ1. Optical rotations
were performed on a polarimeter (589 nm) by using a 700 mL cell
with a pathlength of 1 dm. Proton (1H) NMR spectra were recorded
Figure 5. B3LYP/6-31G(d)-optimized transition states for the electrophilic
amination of enamides (distances in ꢂ).
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at 500 MHz or at 300 MHz, carbon (13C) NMR spectra were recorded
at 75 MHz, and phosphorus (31P) NMR spectra were recorded at
202 MHz. NMR experiments were carried out in CDCl3 or in
[D6]DMSO. Chemical shifts (d) are reported in parts per million
(ppm) relative to the residual solvent as an internal reference (1H:
7.26 ppm, 13C: 77 ppm for CHCl3; 1H: 2.50, 13C: 39 ppm for
[D6]DMSO). Data are reported as follows: chemical shift, multiplicity
(s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet), coupling
constants (J, in Hz) and integration. Mass spectra were obtained
from an AEI MS-9 instrument by using electron spray ionization.
The HRMS data were measured on a MALDI-TOF type of instru-
ment for the high-resolution mass spectra. Calcium–phosphate
salts were analyzed by MALDI-TOF matrices by using the aprotic
matrix trans-2-[3-(4-tert-butylphenyl)-2-methylpropenylidene] malo-
nonitrile (DCTB). Enantiomeric excesses were determined by HPLC
or supercritical fluid chromatography (SFC) with diode-array UV de-
tectors by using Chiralpak AD-H, IA, and IB columns.
[M+Na]+: 402.2005; found: 402.2010; chiral SFC (Chiralpak IA, CO2/
MeOH (96/4), flow rate=4.0 mLminÀ1, 205 nm): major isomer (S,S):
tR =2.1 min; minor isomer (R,R): tR =2.9 min.
Acknowledgements
Financial support from CNRS is gratefully acknowledged. C.L,
A.D., C.L., and F.D thank ICSN for postdoctoral and doctoral fel-
lowships. V.G. thanks UPS, IUF, CRIHAN (project 2006–013), and
B. Iorga for his kind help on the use of the ICSN computational
cluster.
Keywords: amination · calcium · diamines · enamides ·
nonlinear effects
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Preparation and NMR data for the catalyst Ca[3aR]n
Ca(OiPr)2 (0.05 mmol) was added to a solution of (R)-3,3’-bis(4-
phenyl)-1,1’-binaphthylphosphate (0.10 mmol; washed with 1m
HCl) in CH2Cl2/MeOH (1/1; 2 mL), and the solution was stirred at
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in vacuo; CH2Cl2 was then added and removed in vacuo again.
This solvent addition–removal sequence was repeated twice, and
the desired Ca[3aR]n was obtained as a white solid in quantitative
1
yield. H NMR (300 MHz, [D6]DMSO): d=8.19–7.92 (m, 16H), 7.56–
7.33 (m, 16H), 7.32–7.19 (m, 4H), 7.14–6.94 ppm (m, 4H); 31P NMR
(202 MHz, [D6]DMSO): d=2.77 ppm; 31P NMR (202 MHz, CD2Cl2):
d=1.20 ppm;
MS
(MALDI):
m/z
1039
[M(n=2)+H+],
2077 [2M(n=2)+H+].
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General procedure for the amination reaction of enamides
and subsequent reduction to provide syn-1,2-diamines 6
The reaction was carried out under an argon atmosphere in dried
glassware, with a magnetic stirring bar. The (E)-enamide (0.1 mmol)
was dissolved in CH2Cl2 (0.7 mL) in a flask containing activated
powdered 4 ꢂ molecular sieves. The solution was stirred at room
temperature for 10 min, before being cooled to À358C and stirred
for an additional 10 min. Diisopropylazodicarboxylate (0.5 mmol)
was added, and the reaction mixture was stirred for 10 min. The
calcium–phosphate complex (0.01 mmol) in CH2Cl2 (0.3 mL) was
then added, and the reaction mixture was stirred for 44 h at
À358C. The mixture was cooled to À788C, and then MeOH (1 mL)
and NaBH4 (1 mmol) were added. The reaction mixture was al-
lowed to warm to À458C and stirred for 3 h. The mixture was fil-
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rated NH4Cl aqueous solution, and the organic phase was washed
with brine, dried over Na2SO4, and concentrated under vacuum.
Purification of the crude product by flash column chromatography
over silica gel (50% EtOAc in heptane as the eluent) afforded the
desired product 6a as a colorless oil in 84% yield. [a]2D3 =93.3 (92%
ee, c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): mixture of rotamers
(rot.): d=7.44–7.35 (m, 2H), 7.35–7.26 (m, NH and 3HAr), 5.93–5.82
(NH, 0.7H, rot. 1), 5.81–5.73 (NH, 0.3H, rot. 2), 5.10–4.82 (m, 2H),
4.82–4.74 (m, 1H), 4.68–4.54 (m, 1H), 1.92/1.90 (s and s, 3H, rot. 1
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129.3 (2C), 128.4, 127.4 (2C), 70.1, 69.1, 57.2, 56.1, 23.3, 22.2/22.1
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2937, 1749, 1701, 1661, 1535, 1384, 1374, 1307, 1225, 1108, 764,
701 cmÀ1; ESI-HRMS (positive ion): m/z calcd for C19H29N3O5Na
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Received: September 15, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPER
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Enamide Amination
C. Lalli, A. Dumoulin, C. Lebꢀe, F. Drouet,
V. Guꢀrineau, D. Touboul, V. Gandon,
J. Zhu, G. Masson*
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Carbon–nitrogen bond formation: A
highly efficient electrophilic amination
of enamides catalyzed by a chiral calci-
um–phosphate complex has been de-
veloped. In general, syn-1,2-diamines
were obtained in high yields with excel-
lent diastereo- and enantioselectivities
(see scheme; MS=molecular sieves). A
combined approach of NMR spectrosco-
py, MS analysis, and DFT calculations
was utilized to obtain better insight into
the mechanistic features of the calcium-
catalyzed amination reaction.
Chiral Calcium–BINOL Phosphate
Catalyzed Diastereo- and
Enantioselective Synthesis of syn-1,2-
Disubstituted 1,2-Diamines: Scope
and Mechanistic Studies
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Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
10
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!