BOROX catalysis: Self-assembled AMINO-BOROX and IMINO-BOROX chiral Bronsted acids in a five component catalyst assembly/ catalytic asymmetric aziridination

Article abstract of DOI:10.1021/jo301064u

A five-component catalyst assembly/aziridination reaction is described starting from an aldehyde, an amine, ethyl diazoacetate, B(OPh)₃, and a molecule of a vaulted biaryl ligand (VAPOL or VANOL). A remarkable level of chemoselectivity was observed since, while 10 different products could have resulted from various reactions between the five components, an aziridine was formed in 85% yield and 98% ee and only two other products could be detected in 3% yield. Studies reveal that the first in a sequence of three reactions is an exceedingly rapid amine-induced assembly of an AMINOBOROX chiral Bronsted acid species from VAPOL and B(OPh)₃, which is followed by imine formation from the amine and aldehyde and the concomitant formation of an IMINO-BOROX chiral Bronsted acid and finally the reaction of the imine with ethyl diazoacetate mediated by the IMINO-BOROX catalyst to give aziridine-2-carboxylic esters with very high diastereo- and enantioselectivity.

Full text of DOI:10.1021/jo301064u

Article
pubs.acs.org/joc
BOROX Catalysis: Self-assembled AMINO-BOROX and IMINO-BOROX
Chiral Brønsted Acids in a Five Component Catalyst Assembly/
Catalytic Asymmetric Aziridination
Anil K. Gupta, Munmun Mukherjee, Gang Hu, and William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
S
* Supporting Information
ABSTRACT: A five-component catalyst assembly/aziridina-
tion reaction is described starting from an aldehyde, an amine,
ethyl diazoacetate, B(OPh)3, and a molecule of a vaulted biaryl
ligand (VAPOL or VANOL). A remarkable level of chemo-
selectivity was observed since, while 10 different products
could have resulted from various reactions between the five
components, an aziridine was formed in 85% yield and 98% ee
and only two other products could be detected in 3% yield.
Studies reveal that the first in a sequence of three reactions is
an exceedingly rapid amine-induced assembly of an AMINO-
BOROX chiral Brønsted acid species from VAPOL and
B(OPh)3, which is followed by imine formation from the
amine and aldehyde and the concomitant formation of an
IMINO-BOROX chiral Brønsted acid and finally the reaction of the imine with ethyl diazoacetate mediated by the IMINO-BOROX
catalyst to give aziridine-2-carboxylic esters with very high diastereo- and enantioselectivity.
enantioselectivities. The purpose of the present work is to
provide an insight to and support for the operation of this five-
component catalyst assembly/catalytic asymmetric aziridina-
tion.
1. INTRODUCTION
Over the past decade we have developed a catalytic asymmetric
aziridination of imines with diazo compounds (AZ reaction)
with a chiral Brønsted acid prepared from either of the vaulted
biaryl ligands VAPOL 3 or VANOL 4, B(OPh)3, and an imine
(Figure 1A).1−4 This AZ reaction is highly enantioselective and
diastereoselective giving either cis-1,2 or trans-aziridines2,3 with a
variety of imines and diazo compounds. Shortcomings of the
optimized protocol include the need to generate a precatalyst
from the VAPOL or VANOL ligand and B(OPh)3 and the need
to prepare an imine from an aldehyde and an amine. The need
to prepare the imine has limited the scope of the AZ reaction
since many types of aliphatic aldehydes do not form stable
imines. We recently reported a solution to these limitations
with the development of a three-component catalytic
asymmetric aziridination that starts from an amine, an aldehyde
and a diazo compound (Figure 1B).5 In the course of studying
factors that affect catalyst formation and in investigating the
processes involved in the three-component catalytic asymmetric
aziridination, and in examining the relationship between these
two processes, we have discovered that this reaction is actually a
five-component process in which the catalyst is assembled by
the amine from the ligand and B(OPh)3 and then the catalyst
causes imine formation and then finally, aziridine formation
(Figure 1C).6 The possible combinations of all of the outcomes
of all the different known reactions between the five species
shown in Figure 1C would lead to a mixture of 10 different
products (Figure 8) and yet a solution of these five-species
leads to the formation of the aziridine in very high yields and
2. RESULTS AND DISCUSSION
Base-Induced Formation of BOROX Catalysts from
VAPOL and B(OPh)3. The VAPOL ligand and commercial
B(OPh)3 will react when heated to give a precatalyst, which is a
mixture of the mesoborate 10 (B1) and the pyroborate 11 (B2)
with the latter typically predominating in ratios ranging from
4:1 to 20:1 depending on the exact protocol for catalyst
formation (Scheme 1).1a Treatment of the mixture of 10 and
11 with imine 1 at room temperature leads to the formation of
the chiral boroxinate 9 (B3).3b,7 Since this species has a
boroxine ring as its core, we have decided to classify this family
of catalysts as BOROX catalysts. The BOROX species 9 is an
ion pair consisting of a protonated base (imine) as the cation
and a chiral polyborate as the anion in the form of a boroxinate:
a boroxine in which one of the borons is four-coordinate. It has
been shown that the active catalyst in the catalytic aziridination
reaction3b,7 is an IMINO-BOROX catalyst of the type 9. This
BOROX species is presumed to be the active catalyst in an aza-
Diels−Alder reaction as well.8 We have recently reported that
the chiral boroxinate 9a (B3) can also be generated upon
Received: June 13, 2012
Published: September 4, 2012
© 2012 American Chemical Society
7932
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
makes them difficult to discern. At a greater expansion, the
absorptions at δ = 16−19 ppm for the first five entries in Figure
3 are clearly visible (see Supporting Information). Weaker
bases such as aniline are also strong enough to induce
boroxinate formation but the cut off in basicity seems to be
near that of dimethyl acetamide (pKb = −0.5) which generates
the boroxinate 9g in only 18% yield. Aldehydes are not strong
enough bases to induce the formation of a boroxinate. Ethyl
diazoacetate (EDA) does not induce the formation of a
boroxinate, but nonetheless there is a very rapid reaction (≤10
min) leading to the alkylation of one of the phenol functions of
VAPOL via a formal insertion of a carbene into the O−H bond
which results in the formation of the ester 12 in 80% yield
(Table 1, entry 6 and Scheme 2).11
Predicted Structures of IMINO-BOROX Species 9a and
AMINO-BOROX Species 9d by DFT Calculations. We have
previously reported the solid-state structure of the imino-
BOROX catalyst-substrate complex 9a.7a The X-ray analysis
revealed the presence of a number of noncovalent interactions
between the protonated substrate as it is bound to the anionic
boroxinate catalyst. The protonated amine 6 should have a very
different binding mode in the boroxinate species 9d due to the
absence of the benzylidene group on the nitrogen atom and the
presence of an ammonium ion with three hydrogens capable of
H-bonding to the anionic boroxinate platform. Unfortunately,
the boroxinate complex 9d could not be induced to form single
crystals suitable for X-ray analysis.
Therefore, computational methods were undertaken to
explore the possible structures of the AMINO-BOROX 9d.
Calculations were preformed using Gaussian 03 at B3LYP/6-
31g* level of theory.12 As a prelude, computations were first
performed on the IMINO-BOROX 9a since the results could be
compared with the solid state structure determined by X-ray
analysis.7a The results of DFT calculations on 9a are shown in
Figure 4 and are very similar to the structure determined by X-
ray. There are some differences as one might expect for a
substrate-catalyst complex in the gas phase versus solid state.
The strongest noncovalent interaction would be expected to be
the H-bond between the protonated iminium and the
boroxinate core. As in the solid state this was found to be
with oxygen-2 of the boroxinate core with a calculated distance
of 1.73 vs 2.02 Å in the solid state (d1 in Figure 4). Common to
both structures is the edge-face interaction (CH−π) between of
one of the aryl rings of the MEDAM group (see Table 2) with
one of the phenyl rings of the VAPOL ligand (d2 in Figure 4).13
This distance in the calculated structure is 3.92 Å and it is 4.42
Å in the solid state. It should be noted that the CH−π
interaction distances are by convention indicted as the distance
between the carbon bearing the hydrogen and the centroid of
the benzene ring participating in the interaction.14 There are
also differences in the orientation of the phenyl group of the
benzaldehyde imine relative to one of the phenanthrene walls
of the VAPOL ligands (d3 in Figure 4). The contact distance is
about the same (3.56 vs 3.44 Å) but the angle between the
planes containing these two rings increases from 4 to 39° in the
calculated structure. This twisting of the phenyl ring in the
calculated structure allows for a closer edge-face interaction
between one of the phenoxy groups of the boroxinate core and
the phenyl group of the benzaldehyde imine (d4, Figure 4).
This distance is 4.66 Å in the calculated structure and 5.52 Å in
the solid state. This phenoxy group of the boroxinate core in
the calculated structure also moves about a half an angstrom
closer for a better CH−π interaction with one of the methyl
Figure 1. (A) Catalytic asymmetric aziridination of imines. (B) Three-
component catalytic asymmetric aziridination. (C) Five-component
catalyst assembly/catalytic asymmetric aziridination.
treatment of a mixture of the VAPOL ligand 3 and 3 equiv of
commercial B(OPh)3 with the imine 1a at room temperature in
a few minutes, conditions under which VAPOL and B(OPh)3
do not react.7a The question then naturally arises: what other
species can induce the formation of the chiral boroxinate
complex 9?9
A series of NMR experiments were carried out to probe the
effectiveness of various bases to induce the formation of the
boroxinate catalyst 9 (B3) and the data are presented in Table
1 and in Figures 2 and 3. In the absence of a base, mixing (S)-
VAPOL and B(OPh)3 does not result in any detectable amount
of a boroxinate (B3) species (entry 10, Table 1 and Figures 2
and 3). The 1H NMR spectrum of the bay region indicates the
presence of unreacted VAPOL (δ 9.77 ppm), a very small
amount (5%) of the mesoborate 10 (B1) (δ 9.55 ppm) and a
slightly larger amount (18%) of the pyroborate 11 (B2) (δ 9.22
ppm).10 Primary, secondary and tertiary amines all induce the
formation of an AMINO-BOROX catalyst 9 (B3), which displays
a characteristic bay proton doublet at δ ∼10.3 ppm and a sharp
resonance in the 11B NMR spectrum at δ ∼5−6 ppm. While the
four-coordinate boron in boroxinate 9 is a relatively sharp
absorption (δ ∼5−6), the two three coordinate borons in 9
have broad resonances at δ = 16−19 ppm which is the region
expected for all three coordinate borate esters. The broadness
of the absorption at δ = 16−19 ppm makes accurate integration
difficult, and in addition, the expansion level shown in Figure 3
7933
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
Scheme 1
a
Table 1. Base-Induced Boroxinate Formation from (S)-VAPOL and B(OPh)3
b
c
d
e
entry
base
(S)-VAPOL 3 (% unreacted)
% yield 10 (B1)
% yield 11 (B2)
% yield 9 (B3)
9
9(B3) δ (ppm) (1H; 11B)
1
2
Et3N
8
<1
3
<1
<1
<1
<1
<1
<1
<1
<1
<1
5
<1
<1
<1
<1
<1
<1
24
33
27
18
63
74
50
76
61
<1
18
<1
<1
<1
9b
9c
9d
9a
9e
9f
10.25, 5.37
10.31, 5.18
10.37, 5.48
10.31,5.51
10.29, 5.56
i-Pr2NH
f
3
Ar2CHNH2
fg
4
Ar2CHNCHPh ,
11
24
15
32
37
52
57
5
C6H5NH2
h
6
N2CHCO2Et
7
MeCONMe2
t-BuCHO
C6H5CHO
no base
9g
9h
9i
10.15,5.78
8
9
10
9j
a
Base (0.20 mmol) was added to a solution of 0.10 mmol of (S)-VAPOL and 0.30 mmol of commercial B(OPh)3 in 1.0 mL of CDCl3 at 25 °C and
b
1
allowed to stir 10 min before spectra were taken. All yields are H NMR yields with Ph3CH as internal standard. Bay region doublet at δ = 9.77
c
d
e
1
ppm. Bay region doublet at δ = 9.55 ppm. Bay region doublet at δ = 9.22 ppm. Chemical shifts for bay region doublet in H NMR and four-
f
g
h
coordinate boron in 11B NMR. Ar = 3,5-Me2-4-OMeC6H2(imine 1a, Scheme 1); Ar2CH = MEDAM, see Table 2. Reference 6. This reaction
produces an 80% yield of the monoalkylation product 12 (Scheme 2).
7934
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
1
Figure 2. H NMR spectra of the bay region of VAPOL boroxinate 9 with the bases in Table 1.
Figure 3. 11B NMR spectra of the VAPOL boroxinate catalyst 9 with the bases in Table 1.
groups on the back-end aryl substituent of the MEDAM group
(d5 in Figure 4).
The iminium ion in 9a and the ammonium ion in 9d both have
the protonated nitrogen H-bonded to O-2 of the boroxinate
core, but the head groups of the nitrogen substituent (MEDAM
group) are on opposite sides of the boroxinate platform. In 9a
the MEDAM group has an edge-face interaction with the
phenyl substitutent of VAPOL and in 9d, the MEDAM group
has an edge-face interaction with the C-ring of VAPOL (d4′ in
Figure 5). Both complexes were also examined with
BHandHLYP/6-31g* level of theory and the results were not
significantly different from that with B3LYP/6-31g*.15
Possible Complications for the Five-Component
Catalyst Assembly/Aziridination. As discussed above, the
monoalkylated VAPOL derivative 12 is formed upon treatment
of VAPOL with EDA in the presence of B(OPh)3 (Table 1,
entry 6). However, there is no reaction between VAPOL and
EDA in the absence of B(OPh)3. Nonetheless, this presents at
The calculated structure for the BOROX species 9d is
presented in Figure 5. The key interactions between the
cationic protonated amine and the anionic boroxinate core are
the two hydrogen bonds from the ammonium ion to O-1 and
O-2 of the boroxinated anion (see Scheme 1 for boroxinate
numbering). The hydrogen bond to O-2 (d1′ = 1.75 Å) is
slightly shorter than that to O-1 (d2′ = 1.96 Å) consistent with
the computational finding that the electron density of the
boroxinate core is highest at O-2 (see Supporting Information).
A similar computational finding has been previously reported
for the VANOL boroxinate core.3b There is also a short
distance between the ammonium nitrogen and the centroid of
the A-ring of one of the phenanthrene units in the VAPOL
ligand (d3′ = 3.21 Å) which is indicative of a NH-π interaction.
7935
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
in the presence of VAPOL. Nor is there any reaction between
benzaldehyde and EDA in either the presence or absence of 4 Å
molecular sieves at 25 °C after 24 h. Thus, the possible
competing reaction between the aldehyde and EDA mediated
by B(OPh)3 is a real concern for the success of the
multicomponent catalyst assembly/aziridination outlined in
Figure 1C.
Scheme 2
Different Protocols for the Multicomponent Aziridi-
nation. With the demonstration that an amine can induce
catalyst assembly, a study of the effects of variation in the
conditions for catalyst assembly on the multicomponent
aziridination (MCAZ) was then explored (Table 2). In the
first experiment, the VAPOL ligand A (3) was mixed with 3
equiv of B(OPh)3 B (8) and 20 equiv of amine C (6) and
stirred in toluene at 80 °C for 0.5 h to ensure formation of the
boroxinate catalyst and thus avoid any possibility of alkylation
of VAPOL by the EDA. This was followed by the addition of
the benzaldehyde D (7a) and 4 Å MS which was stirred for 2 h
to ensure imine formation. Upon addition of EDA E (2) the
mixture was stirred at 25 °C for 24 h to give the aziridine 5a in
92% yield and 95% ee (procedure I).
A true multicomponent reaction involves the reaction of
three or more reagents added simultaneously.17 Multicompo-
nent reactions that involve reaction between two reagents and
then interception of the resulting intermediate by the addition
of a third reagent are sequential component reactions.17−20
Hence, procedure I in Table 2 can be viewed as an example of a
sequential component aziridination reaction as the addition of
EDA was delayed for 2 h to ensure formation of the imine.19
However, when EDA was added immediately after the
aldehyde, essentially the same results were obtained (proce-
dures I vs IIA). This suggests that the present work is an
example of a true MCAZ and this will be further verified by the
data associated with Table 3. The data in Table 2 reveals that
essentially the same results are obtained whether the precatalyst
is first generated and employed in the multicomponent
least one potential problem in a five-component catalyst
assembly/aziridination of the type shown in Figure 1C. The
VAPOL ligand could be disenabled by a B(OPh)3 induced
reaction with EDA before amine can assemble the catalyst from
the ligand and B(OPh)3. A second possible complication is an
unwanted reaction between the aldehyde and EDA. In fact,
several different products are known from the reaction of
benzaldehyde and EDA mediated by Lewis or Brønsted acids.16
Indeed, in a control experiment, the reaction of benzaldehyde
and 1.14 equiv of ethyl diazoacetate mediated by 14 mol %
B(OPh)3 gave the five products shown in Scheme 2 with the
major component as the β-keto ester 17a and its tautomer 16a
in a total of 55% yield. In a separate control experiment, it was
found that there is no reaction between benzaldehyde and EDA
Figure 4. Calculated structure of IMINO-BOROX 9a. (A) Calculated B3LYP/6-31g* structure visualized by the Mercury Program (C, gray; O, red; N,
blue; B, pink). Hydrogen atoms omitted for clarity (except N−H). Some secondary interactions are highlighted: d1 = 1.73 Å (H-bonding), d2 = 3.92
Å (CH−π), d3 = 3.56 Å (CH−π or π−π stack), d4 = 4.66 Å (CH−π), d5 = 4.02 Å (CH−π). (B) Space-filling rendition of 9a with the same
orientation and showing hydrogens. The boroxinate anion is given in green and the iminium cation is in traditional colors.
7936
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
Figure 5. Calculated structure of AMINO-BOROX 9d. (A) Calculated B3LYP/6-31g* structure visualized by the Mercury Program (C, gray; O, red;
N, blue; B, pink). Hydrogen atoms omitted for clarity (except N−H). Some secondary interactions are highlighted: d1′ = 1.75 Å (H-bonding), d2′ =
1.96 Å (H-bonding), d3′ = 3.21 Å (CH−π or cation−π), d4′ = 4.18 Å (CH−π). (B) Space-filling rendition of 9d with the same orientation and
showing hydrogens. The boroxinate anion is given in green and the ammonium cation is in traditional colors.
aziridination or whether the boroxinate catalyst is directly
generated by treating a mixture of VAPOL and B(OPh)3 with
the amine C (procedures IIA vs IIB). It was also revealed that
no advantage is to be gained by generating the AMINO-BOROX
catalyst by heating to 80 °C rather than simply stirring at room
temperature (procedures IIA vs IIIA and IIB vs IIIB). The use
of the aldehyde D as the limiting reagent (0.6 equiv) leads to
the complete shutdown of the reaction (procedure IIIC). This
suggests that the amine C is a competitive inhibitor of the
imine in binding to the boroxinate catalyst and this issue will be
taken up in greater detail below (Tables 5 and 6). Water is
needed for catalyst formation and its addition in procedures IIB
and IIIB was done to compensate for any lack of water present
in commercial B(OPh)3.7a
Effect of the Order of Addition on the Multi-
component Aziridination. That the aziridination reaction
of focus here is in fact a true multicomponent reaction and in
fact is a five-component catalyst assembly/catalytic asymmetric
aziridination as indicated in Figure 1C is supported by the
results of procedures IV and V in Table 3. The successful
aziridination from the reaction where the EDA (E) is added
before the aldehyde (D) reveals that imine formation can occur
in the presence of EDA (procedure IV). The VAPOL ligand is
not alkylated by the EDA under these conditions (Table 3,
procedure IV) as might have been expected from the results in
entry 6 of Table 1. This reveals that once the VAPOL
boroxinate B3 catalyst 9a is generated, the VAPOL ligand is
protected from alkylation.
the amine, which is added last, can quickly assemble the catalyst
such that the ligand is protected from alkylation by the EDA.
The speed at which catalyst assembly occurs is indicated by
procedure VI in Table 3. When the first four components
including EDA are dissolved in toluene and then 2 min later the
amine is added, no aziridine formation is observed. A very
complex reaction mixture is observed and the products are
indicated in Figure 6 and include products from the reaction of
EDA with both the aldehyde and the imine, however, no
detectable amount of the aziridine 5a could be observed. The
major product is the imine 1a (34%) and there is also a
considerable amount of the unreacted amine 6 (40%). Since the
aldehyde is partially consumed in the formation of the β-keto
ester 17a (23%) and its tautomer 16a (5%), the presence of the
unreacted amine 6 may lead to its selective binding to the
catalyst thus preventing aziridination of the imine if indeed any
boroxinate catalyst was formed at all in this reaction. As a
control, the same reaction in which the amine is not added at all
was also carried out (Table 2, procedure VII) and this gave a
product mixture that was shown to have a very similar profile to
the reaction of benzaldehyde 7a and ethyl diazoacetate 2
promoted by B(OPh)3 (Scheme 2). The combined results from
procedures V and VI in Table 3 make it clear that the assembly
of the catalyst by the amine is exceedingly fast. The events that
occur in the two minutes prior to amine addition in procedure
VI are sufficient to completely thwart catalyst assembly and
aziridination.
Catalyst Loading, N-Substituent and Ligand Screen-
ing. The catalytic asymmetric synthesis of aziridines from
imines and diazo compounds has been honed with both
benzhydryl and bis-(3,5-dimethylanisyl)methyl (MEDAM)
substituents on the imine nitrogen.1−4 Thus, the multi-
component aziridination was examined with both benzhydryl
amine 6′ and the MEDAM amine 6 and the results with
benzaldehyde are shown in Table 4. In addition, the reaction of
both amines were screened with both VANOL and VAPOL
catalysts and the catalyst loading profile was explored as well.
These reactions were screened with catalyst generated by
The results from procedure V in Table 3 where the amine C
is added last reveals that this is a five-component reaction
where both the catalyst assembly and the aziridination reaction
can be carried out simultaneously. Since the amine is added last,
considerable concern arose from the results in Table 1 (entry
6) that suggest that the VAPOL ligand may be alkylated before
the catalyst is generated. That is why in procedure V all five of
the components were added in the order shown without
solvent, and at the end, solvent was added to effect dissolution.
That this provides for a successful aziridination indicates that
7937
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
a
Table 2. Protocol Dependence of the Multicomponent Aziridination
a
All reactions were performed with 0.025 mmol (S)-VAPOL A (5 mol%), 0.075 mmol B(OPh)3 B (15 mol%), 0.50 mmol amine C (1.0 equiv),
0.525 mmol benzaldehyde D (1.05 equiv) and 0.60 mmol of EDA E (1.2 equiv) in 1.0 mL of toluene at 25 °C for 24 h. In each case, 150 mg
b
powdered 4 Å MS was added immediately preceding benzaldehyde. Isolated yield after chromatography on silica gel. Analysis of the crude reaction
c
mixture indicates ≥50:1 cis/trans selectivity for 5a. In each case <1% 18a and 19a are formed. Determined on purified cis-5a by HPLC.
procedure IIIA since this is experimentally the simplest to
perform and it gives the same outcome as the other procedures
(Tables 2 and 3). This is not always true for catalysts generated
from some imines. As was found for the reactions of the
corresponding imines,1b the multicomponent aziridination of
benzaldehyde with MEDAM amine 6 gives higher yields and
asymmetric inductions than the benzhydryl amine 6′. None-
theless, the aziridines from benzhydryl amines can in most cases
7938
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
a
Table 3. Effects of Order of Addition on the Multicomponent Aziridination
a
b
All reactions were performed as described in Table 2. Isolated yield after chromatography on silica gel. Analysis of the crude reaction mixture
c
d
indicates ≥50:1 cis:trans selectivity for 5a. Determined on purified cis-5a by HPLC. The diazo compound E is added to a mixture of A, B and C
and then toluene is added and the mixture stirred at 25 °C for 1 h after which 4 Å powdered molecular sieves and D are added and the mixture
stirred for 24 h at 25 °C. A mixture of A, B, 4 Å MS, D, E and C, added in that order, was dissolved in toluene and the resulting solution allowed to
stir for 24 h at 25 °C. A 3% yield of enamines 18a and 19a was observed. A mixture of A, B, 4 Å MS, D and E, added in that order, was dissolved in
toluene and the resulting solution allowed to stir for 2 min at 25 °C before C was added and the resulting solution stirred for 24 h at 25 °C. The
e
f
g
h
products of this reaction are shown in Figure 6. Same as procedure VI except that C was not added. The products from this reaction are 13a (5%),
14a (<1%), 15a (5%), 16a (11%), 17a (38%) and 12 (37%).
observation that added water can greatly slow down the
aziridination of imines7a Finally, in the optimization studies it
was noted that 4 Å molecular sieves was superior to 5 Å
molecular sieves which gives more unknown side-products and
a lower yield of the aziridine (entries 7 vs 9).
Sequence of the Final Steps in the Five-Component
Catalyst Assembly/Aziridination. The data in Table 3
indicates that instead there is a very rapid assembly of a
boroxinate species from the VAPOL ligand and B(OPh)3
mediated by the amine 6 which gives rise to the AMINO-
BOROX species 9d. At this point the question arises as to the
subsequent order of events. In one extreme, a small amount of
imine 1 could be formed and then immediately converted to
aziridine 5 before the rest of the imine is formed (B to D in
Figure 7). In the other extreme, the process could first proceed
to give complete conversion of the amine and aldehyde to the
imine 1 and only then does the imine 1 react with EDA 2 under
the ageis of the IMINO-BOROX catalyst 9a to give the aziridine 5
(C to D in Figure 7). The last entry in Table 2 suggests that it
is the latter since the presence of excess amine over aldehyde
(0.6 equiv) results in the complete suppression of aziridine
formation. This issue was further probed with additional
experiments and the results are presented in Tables 5 and 6.
The multicomponent aziridination of benzaldehyde 7a with
benzhydryl amine 6′ was examined with different amounts of
benzaldehyde ranging from 0.6 to 1.0 equiv and the results are
presented in Table 5. Just as with the reaction of the MEDAM
amine 6 with 0.6 equiv of benzaldehyde (Table 2, entry 6), the
reaction of benzhydryl amine 6′ with 0.6 equiv of benzaldehyde
results in essentially no formation of aziridine 5a′ (1%) even
though benzaldehyde is essentially completely transformed into
the imine 1a′ and 98% of this imine remains unreacted after 24
h (Table 5, entry 5). The amount of aziridine 5a′ formed with
Figure 6. Products from the reaction with procedure VI in Table 3.
be crystallized to ≥99% ee which is important to note upon
considering that benzhydryl amine 6′ is commercially available
while the MEDAM amine 6 is not.1a Also as was observed with
the corresponding imines, the multicomponent aziridinations
with VAPOL and VANOL catalysts are very similar with a
slight edge in asymmetric induction to the VAPOL catalyst.1a,b
The optimal catalyst loading for the reaction with the MEDAM
amine is 3−5 mol %. This reaction does not go to completion
in 24 h with 1 mol % of either the VANOL or VAPOL catalyst
but both go to completion with a 3 mol % catalyst loading. The
reaction is severly impeded by the absence of molecular sieves
and gives only a 35% yield of the aziridine 5a along with a 52%
yield of the unreacted imine 1a generated from amine 6 and
benzaldehyde (entry 8) and this is consistent with the previous
7939
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
a
Table 4. Catalyst Loading, N-Substituent and Ligand Screening
b
c
d
d
entry
ligand
PG
catalyst x mol %
% yield 5a/5a′
% ee 5a/5a′
cis/trans
% yield enamine
1
(S)-VAPOL
(R)-VANOL
(S)-VAPOL
(S)-VANOL
(S)-VAPOL
(R)-VANOL
(S)-VAPOL
(S)-VAPOL
(S)-VAPOL
(S)-VANOL
(S)-VAPOL
(S)-VANOL
(S)-VAPOL
(S)-VANOL
CHPh2
10
10
5
85
77
77
72
90
93
98
91
−88
92
25:1
50:1
9
15
6
2
CHPh2
3
CHPh2
50:1
4
CHPh2
5
91
50:1
7
e
5
MEDAM
MEDAM
MEDAM
MEDAM
MEDAM
MEDAM
MEDAM
MEDAM
MEDAM
MEDAM
10
98
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
<1
<1
<1
<1
2
e
6
10
−96
98
7
5
5
5
5
3
3
1
1
fg
8
(35) ,
h
9
70
98
95
98
97
10
11
12
13
14
95
92
<1
5
94
6
(20)
(31)
<1
<1
a
Unless otherwise specified, all reactions were performed with procedure IIIA in Table 2 with 0.5 mmol of amine 6/6′ (0.5 M) with 1.05 equiv of
b
benzaldehyde 7a and 1.2 equiv of EDA 2 and went to 100% completion. Isolated yield after chromatography on silica gel. Yield in parentheses
c
determined from the 1H NMR spectrum of the crude reaction mixture with Ph3CH as internal standard. Determined on purified cis-5a or cis-5a′ by
d
e
f
1
HPLC. Determined from the H NMR spectra of the crude reaction mixture. Reaction performed with procedure IIA in Table 2. Reaction
g
1
performed without 4 Å molecular sieves. The H NMR spectra of the crude reaction mixture indicates the presence of 52% unreacted imine 1a.
h
Reaction performed with 5 Å molecular sieves.
0.9 equiv of benzaldehyde (entry 2) is nearly the same as with
1.0 equiv (entry 1). However, it should be noted that with 0.9
equiv, 8% of the imine 1a′ remains unreacted, whereas with 1.0
equiv of benzaldehyde, the imine 1a′ is nearly completely
consumed (1% unreacted). This suggests there is an
equilibrium between the boroxinate 9d containing a protonated
amine and the boroxinate 9a containing a protonated imine
(Scheme 3). Given the fact that imines are ∼103 times less basic
than amines,21 even when the amount of excess amine is equal
to the amount of catalyst (0.9 equiv 7a added, entry 2), there
appears to be enough of the IMINO-BOROX catalytst 9a present
in solution containing the activated imine to allow the reaction
to proceed in 24 h. It should be pointed out that factors other
than basicity may affect the equilibrium of AMINO-BOROX and
IMINO-BOROX species (see below, Table 6). Even if the
equilibrium between 9d′ and 9a′ is facile (Figure 7), the
reaction greatly slows when equal amounts of amine 6′ and
imine 1a′ are present since the amount of unreacted imine 1a′
is 8% when the reaction with 10% excess amine 6′ is stopped
after 24 h (entry 2). This suggests that the greater base strength
of the amine 6′ greatly favors the AMINO-BOROX species 9d′
over that of the IMINO-BOROX 9a′ when the concentrations of
the amine and imine are similar. In the normal protocol for the
multicomponent catalytic asymmetric aziridination (Table 4), a
slight excess of aldehyde (1.05 equiv) is typically used which
assures complete consumption of the amine and avoidance of a
slow down during the end of the reaction.
amounts of four different nitrogen bases and the results are
presented in Table 6. In the absence of any added base, the
reaction gives aziridine 5a′ in 85% isolated yield and 90% ee
which is nearly the same as has been previously reported for
this reaction in chloroform.1a In these reactions, a boroxinate
species is assembled by treating VAPOL and 3 equiv of
B(OPh)3 with the base at room temperature for 1 h and then
adding the imine 1a′ and the EDA to consummate the reaction.
These conditions directly generate the situation indicated in
Figure 5C where only the imine and EDA substrates are
present. The difference is that the reaction begins with an
AMINO-BOROX catalyst rather than an IMINO-BOROX catalyst.
The reaction in the presence of 10 mol % of benzhydryl amine
6′ (Table 6, entry 5) gives nearly the same yield as the reaction
without base, and this mirrors the result in entry 2 of Table 5.
The only difference is that none of the imine 1a′ remains at the
end of the reaction with the preformed imine. However, the
reaction with 20 mol % of benzhydryl amine 6′ slows the
reaction dramatically and 86% of the imine 1a′ remains after 24
h. Similar results are seen with 10 mol % Et3N and 10 mol %
benzhydryl amine 6′ (entries 2 vs 5), however, with 20 mol %
Et3N the reaction is completely stopped and no detectable
amount of the aziridine is observed (entries 2 and 3).
Aniline is a weaker base than aliphatic amines and this can be
correlated with its decreased ability to slow the reaction since
even with 20 mol % aniline there is 32% conversion of the
imine giving a 20% isolated yield of aziridine 5a′ (entry 10).
These results further suggest that an equilibrium is present
between an AMINO-BOROX and an IMINO-BOROX species
(Scheme 3). The fact that there is nearly complete reaction
To further examine the effect of the base strength of other
species present in the reaction mixture, the aziridination of the
preformed imine 1a′ was carried out in the presence of varying
7940
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
Figure 7. Time course of events in the five-component catalyst assembly/AZ reaction. (A) Time zero. (B) Assembly of AMINO-BOROX 9d. (C)
Formation of Imine 1 and IMINO-BOROX catalyst 9a. (D) Catalytic asymmetric aziridination.
a
Table 5. Multicomponent Aziridination with a Deficiency of Benzaldehyde
bc
,
d
b
b
b
entry
7a x equiv
% yield cis-5a′
% ee cis-5a′
cis/trans
% yield 18a′ + 19a′
unreacted 1a′ (%)
1
2
3
4
5
1.0
0.9
0.8
0.7
0.6
77(78)
90
89
25:1
25:1
9
8
1
8
75(73)
6
4
1
50:1
<1
<1
<1
94
96
98
>50:1
50:1
a
The catalyst 9a′ was prepared by reaction of 0.5 mmol (1 equiv) of amine 6′ with 10 mol %(S)-VAPOL and 30 mol % commercial B(OPh)3 in
CHCl3 for 1 h at 25 °C. After 1 h at 25 °C, 150 mg of powdered 4 Å molecular sieves and x equiv of benzaldehyde were added to the catalyst to give
b
a solution 0.5 M in amine. EDA (1.2 equiv) was added and the reaction mixture stirred for 24 h at 25 °C. Determined from the 1H NMR spectrum
c
d
of the crude reaction mixture with Ph3CH as internal standard. Yields in parentheses are after isolation by silica gel chromatography. Determined
on purified 5a′ by HPLC.
when 10 mol % Et3N or 10 mol % Ph2CHNH2 are added
suggests that even when there is a 1:1 mixture of the AMINO-
BOROX and the IMINO- BOROX species there is still enough of
the IMINO-BOROX species present such that the reaction can
still go forward. To this point, the reader’s attention should be
brought to the fact that although these reactions were
performed with 10 mol % catalyst, the aziridination reaction
with benzhydryl imines can be effected under these conditions
with as little as 0.25 mol % catalyst.1a
The ability of the amine to inhibit the reaction does correlate
to some degree with the basicity of the amine, but there are
obviously other factors that must contribute to the magnitude
of the equilibrium constant indicated in Scheme 3. This is most
clear in the reaction with added DMAP. Although less basic
7941
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
Scheme 3
a
Table 6. AZ Reaction of Preformed Imine 1a′ with Added Bases
b
c
,d
e
c
c
c
entry
pKa
base
none
Et3N
base x mol %
% yield 5a′
% ee 5a′
cis/trans
% yield 18a′ + 19a′
unreacted 1a′(%)
1
2
3
4
5
6
7
8
9
10
0
10
20
40
10
20
10
20
10
20
83(85)
71(77)
<1
90
86
100:1
25:1
10
9
<1
6
10.75
89
92
<1
86
96
80
5
<1
10.60
9.20
4.60
Ph2CHNH2
DMAP
77(80)
10
89
27:1
12:1
10
2
<1
<1
C6H5NH2
73(78)
17(20)
88
86
33:1
23:1
8
6
68
a
Unless otherwise specified, the boroxinate catalyst 9 was prepared in CHCl3 from 10 mol % (S)-VAPOL, 30 mol % commercial B(OPh)3 and x mol
% of a base to induce boroxinate formation. After 1 h at 25 °C, 100 mol % of imine 1a′ and 120 mol % EDA 2 were added to the catalyst and the
b
aziridination reaction carried out with 1.0 mmol of imine (0.5 M) for 24 h at 25 °C. All bases were purified by either distillation or sublimation.
c
d
Determined from the 1H NMR spectrum of the crude reaction mixture with Ph3CH as internal standard. Yields in parentheses are after isolation
e
by silica gel chromatography. Determined on purified 5a′ by HPLC.
than aliphatic amines, DMAP completely stops the reaction
upon addition of just 10 mol % (Table 6, entry 7). In this case,
any equilibrium between the AMINO-BOROX and IMINO-
BOROX species may be determined by more than just the
relative basicity of the amine and the imine. This equilibrium
may be shifted to the AMINO-BOROX further than might be
predicted from the basicity alone. The crystal structure of the
AMINO-BOROX species containing DMAP reveals the presence
of noncovalent interactions in addition to the H-bond between
the protonated base and the boroxinate anion.7b Specifically,
there is a π−π stacking interaction between the pyridinium
cation and one of the phenanthrene rings of the VAPOL ligand
and there is a CH−π interaction between one of the ortho-
hydrogen of the pyridinium cation and one of the phenoxy
groups of the boroxinate core.7b These results are consistent
with the view that the catalytic cycle for the multicomponent
catalyst assembly/aziridination involves the complete (or nearly
complete) formation of the imine before the aziridination
reaction can commence (Figure 5B to C).
Brønsted acid which has a boroxinate core comprised of a chiral
polyborate that is assembled in situ from a vaulted biaryl ligand
(VANOL or VAPOL) and 3 equiv of B(OPh)3 by the amine
substrate. The present work shows that this is actually a five-
component process involving both catalyst assembly and a
catalytic asymmetric aziridination reaction where the catalyst is
assembled by one of the substrates before it is consumed. A
solution of these five components has the potential to create a
chaotic array of products (Figure 8) and yet there is order
which leads to the formation of aziridines in very high yields,
diastereoselectivities and enantioselectivities. This order is
imposed by the amine in causing an exceedingly fast assembly
of the boroxinate catalyst from the ligand and B(OPh)3. Once
the catalyst is assembled, it is protected from alkylation by the
diazo compound, and since the B(OPh)3 is consumed, the
epoxidation reaction of the diazo compound and the aldehyde
is thwarted. This then permits the formation of an imine from
the aldehyde and amine and the resulting imine binds in its
protonated form to the boroxinate catalyst, thereby generating
a chiral Brønsted acid derived from the imine. This is followed
by binding of the diazo compound to the chiral boroxinate
catalyst in such proximity to the bound iminium that an
aziridine is formed with high diastereo- and enantioselection.3b
CONCLUSIONS
■
The practicing chemist now has at one’s avail a multi-
component asymmetric catalytic method for the preparation
of aziridines directly from aldehydes, an amine and a diazo
compound.5 The chiral catalyst for this reaction is a chiral
7942
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
Figure 8. Chemoselectivity in the 5-component catalyst assembly/catalytic asymmetric aziridination.
mm × 300 mm column, 9:1 hexanes/EtOAc as eluent, gravity column)
afforded pure cis-aziridine 5a as a white solid (mp 107−108 °C on
99.8% ee material) in 98% isolated yield (230 mg, 0.490 mmol); cis/
trans > 50:1. Enamine side products: <1% yield of 18a and <1% yield
of 19a. The optical purity of 5a was determined to be 98% ee by
HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-
propanol at 226 nm, flow-rate 0.7 mL/min): retention times; Rt =
9.26 min (major enantiomer, 5a) and Rt = 12.52 min (minor
enantiomer, ent-5a). Spectral data for 5a: Rf = 0.42 (1:9 EtOAc/
hexane); 1H NMR (CDCl3, 500 MHz) δ 0.98 (t, 3H, J = 7.1 Hz), 2.18
(s, 6H), 2.24 (s, 6H), 2.55 (d, 1H, J = 6.8 Hz), 3.10 (d, 1H, J = 6.6
Hz), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H) 3.87−3.97 (m, 2H), 7.09
(s, 2H), 7.18 (s, 2H), 7.21−7.24 (m, 3H), 7.36 (d, 2H, J = 7.3 Hz);
13C (CDCl3, 125 MHz) δ 14.0, 16.16, 16.22, 46.3, 48.2, 59.5, 59.6,
60.5, 77.0, 127.2, 127.4, 127.7, 127.8, 127.9, 130.59, 130.60, 135.3,
137.8, 138.0, 156.0, 156.1, 168.0; IR (thin film) 2961 vs, 1750 vs, 1414
vs, 1202 vs cm−1; Mass spectrum: m/z (% rel intensity) 473 M+
(0.27), 284(78), 283 (100), 268 (34), 253 (20), 237 (11), 210(10),
117 (18), 89 (11); Anal. calcd for C30H35NO4: C, 76.08; H, 7.45; N,
3. EXPERIMENTAL SECTION
General Procedure for Multicomponent Aziridination with
Benzaldehyde. (2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-
dimethylphenyl)methyl)-3-phenylaziridine-2-carboxylate 5a (Table
4, entry 7). To a 10 mL flame-dried single-necked round-bottom flask
equipped with a stir bar and filled with argon was added (S)-VAPOL
(14 mg, 0.025 mmol), B(OPh)3 (22 mg, 0.075 mmol) and amine 6
(149.7 mg, 0.5000 mmol). Dry toluene (1 mL) was added under an
argon atmosphere to dissolve the reagents. The flask was fitted with a
rubber septum and a nitrogen balloon. The reaction mixture was
stirred at room temperature for 1 h. Thereafter, 4 Å Molecular Sieves
(150 mg, freshly flame-dried) was added followed by the addition of
the aldehyde 7a (52.0 μL, 0.525 mmoL, 1.05 equiv). To this solution
was rapidly added ethyl diazoacetate (EDA) 2 (62 μL, 0.60 mmoL, 1.2
equiv). The resulting mixture was stirred for 24 h at room
temperature. The reaction was diluted by addition of hexane (6
mL). The reaction mixture was then filtered through a Celite pad to a
100 mL round-bottom flask. The reaction flask was rinsed with EtOAc
(3 mL × 3) and the rinse was filtered through the same Celite pad.
The resulting solution was then concentrated in vacuo followed by
exposure to high vacuum (0.05 mmHg) for 1 h to afford the crude
aziridine as an off-white solid.
2.96. Found: C, 76.31; H, 7.28; N, 2.82; [α]23 +41.3 (c 1.0, EtOAc)
D
on 99% ee material (HPLC). These spectral data match those
previously reported for this compound.1b
The cis/trans ratio was determined by comparing the 1H NMR
integration of the ring methine protons for each aziridine in the crude
reaction mixture. The cis (J = 7−8 Hz) and the trans (J = 2−3 Hz)
coupling constants were used to differentiate the two isomers. The
yields of the acyclic enamine side products 18a and 19a were
(2R,3R)-Ethyl 1-Benzhydryl-3-phenylaziridine-2-carboxylate 5a′
(Table 4, entry 3). Aldehyde 7a (52.0 μL, 0.525 mmol, 1.05 equiv) was
reacted according to the general Procedure described above with (S)-
VAPOL as ligand. Purification of the crude aziridine by silica gel
chromatography (30 mm × 300 mm column, 19:1 hexanes/EtOAc as
eluent, gravity column) afforded pure cis-aziridine 5a′ as a white solid
(mp. 127.5−128.5 °C) in 77% isolated yield (138 mg, 0.390 mmol);
cis/trans 50:1. Enamine side products: 6% yield of enamines. The
optical purity of 5a′ was determined to be 92% ee by HPLC analysis
1
determined by H NMR analysis of the crude reaction mixture by
integration of the N-H proton relative to the that of the cis-aziridine
methine protons with the aid of the isolated yield of the cis-aziridine.
Purification of the crude aziridine by silica gel chromatography (30
7943
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944

The Journal of Organic Chemistry
Article
(CHIRALCEL OD-H column, 90:10 hexane/2-propanol at 226 nm,
flow-rate 0.7 mL/min): retention times; Rt = 9.01 min (major
enantiomer, 5a′) and Rt = 4.67 min (minor enantiomer, ent-5a′).
Spectral data for 5a′: Rf = 0.3 (1:9 EtOAc/hexanes); 1H NMR
(CDCl3, 500 MHz) δ 0.95 (t, 3H, J = 7.3 Hz), 2.64 (d, 1H, J = 6.8
Hz), 3.19 (d, 1H, J = 6.8 Hz), 3.91 (q, 2H, J = 7.1 Hz), 3.93 (s, 1H),
7.16−7.38 (m, 11H), 7.47 (d, 2H, J = 7.1 Hz), 7.58 (d, 2H, J = 7.6
Hz); 13C NMR (CDCl3, 125 MHz) δ 13.9, 46.4, 48.0, 60.6, 77.7,
127.2, 127.3, 127.4, 127.5, 127.8, 127.8, 128.5, 135.0, 142.4, 142.5,
167.8 (one sp2 carbon not located); [α]20D = +33.4 (c 1.0, CH2Cl2) on
91% ee material (HPLC). These spectral data match those previously
reported for this compound.1a
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Cliford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision
D.01; Gaussian, Inc.: Wallingford, CT, 2004.
(13) For reviews, see: (a) Nishio, M. Tetrahedron 2005, 61, 6923−
6950. (b) Nishio, M. H., M.; Umezawa, Y. The CH/π Interaction:
Evidence, Nature, and Consequences; Wiley-VCH: Weinheim, 1998.
(14) Plevin, M. J.; Bryce, D. L.; Boisbourier, J. J. Nat. Chem. 2010, 2,
466.
ASSOCIATED CONTENT
* Supporting Information
■
S
(15) BHandHLYP is considered to be a better method for the case of
hydrogen bonding interactions, see: (a) Zhao, Y.; Truhlar, D. G. J.
Chem. Theory Comput. 2005, 1, 415. (b) Yu, W.; Liang, L.; Lin, Z.;
Ling, S.; Haranczyk, M.; Gutowski, M. J. Comput. Chem. 2009, 30, 589.
(16) (a) Li, W.; Wang, J.; Hu, X.; Shen, K.; Wang, W.; Chu, Y.; Lin,
L.; Liu, X.; Feng, X. J. Am. Chem. Soc. 2010, 132, 8532−8533.
(b) Hashimoto, T.; Miyamoto, H.; Naganawa, Y.; Maruoka, K. J. Am.
Chem. Soc. 2009, 131, 11280−11281. (c) Liu, W.-J.; Lv, B.-D.; Gong,
L.-Z. Angew. Chem., Int. Ed. 2009, 48, 6503−6506. (d) Trost, B. M.;
Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131, 1674−1675.
(e) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2008,
130, 2434−2435. (f) Hasegawa, K.; Arai, S.; Nishida, A. Tetrahedron
2006, 62, 1390−1401. (g) Dudley, M. E.; Morshed, M. M.; Brennan,
C. L.; Islam, M. S.; Ahmad, M. S.; Atuu, M.-R.; Branstetter, B.;
Hossain, M. M. J. Org. Chem. 2004, 69, 7599−7608. (h) Yao, W.;
Wang, J. Org. Lett. 2003, 5, 1527−1530. (i) Jiang, N.; Wang, J.
Tetrahedron Lett. 2002, 43, 1285−1287. (j) Mahmood, S. J.; Hossain,
M. M. J. Org. Chem. 1998, 63, 3333−3336. (k) Holmquist, C. R.;
Roskamp, E. J. J. Org. Chem. 1989, 54, 3258−3260.
NMR analysis of boroxinate catalyst formation and of reactions
of 7a with 2, order of addition and stoichiometry studies and
DFT calculations and pdf files for 9a and 9b. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*wulff@chemistry.msu.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Institute of General
Medical Sciences (GM 094478).
■
REFERENCES
■
(1) (a) Zhang, Y.; Desai, A.; Lu, Z.; Hu, G.; Ding, Z.; Wulff, W. D.
Chem.−Eur. J. 2008, 14, 3785−3803. (b) Mukherjee, M.; Gupta, A. K.;
Lu, Z.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010, 75, 5643−5660.
(2) Huang, L.; Zhang, Y.; Staples, R. J.; Huang, R. H.; Wulff, W. D.
Chem.−Eur. J. 2012, 18, 5302−5313.
(17) (a) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44,
1602−1634. (b) Multicomponent Reactions; Zhu, J.; Bienayme, H.,
Eds.; Wiley-VCH: Weinheim, 2005. (c) de Graaff, C.; Ruijter, E.;
Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969−4009. (d) Domling, A.;
̈
Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
(3) (a) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132,
13100−13103. (b) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am.
Chem. Soc. 2010, 132, 13104−13107.
(18) For multicomponent aziridinations with nonchiral catalysts, see:
(a) Nagayama, S.; Kobayashi, S. Chem. Lett. 1998, 685−686. (b) Kubo,
T.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 2000, 625−626. (c) Yadav,
J. S.; Reddy, B. V. S.; Rao, M. S.; Reddy, P. N. Tetrahedron Lett. 2003,
44, 5275−5278. (d) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. N.; Rao, M.
S. Synthesis 2003, 1387−1390. (e) Ishii, Y.; Sakaguchi, S. Bull. Chem.
Soc. Jpn. 2004, 77, 909−920.
(4) For a review, see: Zhang, Y.; Lu, Z.; Wulff, W. D. SynLett 2009,
2715−2739.
(5) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011, 13,
5866−5869.
(6) This is a five-component process involving five different
components, but a seven-component process in terms of the total
number of components (3 molecules of B(OPh)3).
(19) For a sequential component aziridination with a chiral catalyst,
see: Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445−2447.
(20) For a stoichiometric asymmetric multicomponent aziridination,
see: (a) Minakata, S.; Ando, T.; Nishimura, M.; Ryu, I.; Komatsu, M.
Angew. Chem., Int. Ed. 1998, 37, 3392−3394. (b) Nishimura, M.;
Minakata, S.; Takahashi, T.; Oderaotoshi, Y.; Komatsu, M. J. Org.
Chem. 2002, 67, 2101−2110.
(7) (a) Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff, W.
D. J. Am. Chem. Soc. 2010, 132, 14669−14675. (b) Hu, G.; Huang, L.;
Huang, R. H.; Wulff, W. J. Am. Chem. Soc. 2009, 131, 15615−15617.
(8) Newman, C. A.; Antilla, J. C.; Chen, P.; Wulff, W. D. J. Am. Chem.
Soc. 2007, 129, 7216−7217.
(9) We have observed before that DMAP can cause the formation of
a boroxinate species from VAPOL and B(OPh)3 (ref 7b).
(10) The amount of B1 and B2 varies with the purity of commercial
B(OPh)3 which is partially hydrolyzed. Purified B(OPh)3 does not
react with VAPOL to give any detectable amounts of B1 or B2.7a
Commercial B(OPh)3 was used in Table 1.
(21) Favrot, J.; Vocelle, D.; Sandorfy, C. Photochem. Photobiol. 1979,
30, 417−421.
(11) This product is sometimes observed at the end of an
aziridination reaction (ref 1a).
(12) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J.
B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
7944
dx.doi.org/10.1021/jo301064u | J. Org. Chem. 2012, 77, 7932−7944