Evidence for a boroxinate based Bronsted acid derivative of VAPOL as the active catalyst in the catalytic asymmetric aziridination reaction

Article abstract of DOI:10.1021/ja904589k

(Figure Presented) Studies are described that were designed to determine the structure of the active catalyst in the asymmetric catalytic aziridination of imines with ethyl diazoacetate (AZ reaction). Evidence suggests that the active catalyst contains a

Full text of DOI:10.1021/ja904589k

Published on Web 10/08/2009
Evidence for a Boroxinate Based Brønsted Acid Derivative of VAPOL as the
Active Catalyst in the Catalytic Asymmetric Aziridination Reaction
Gang Hu, Li Huang, Rui H. Huang, and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received June 5, 2009; E-mail: wulff@chemistry.msu.edu
Scheme 2
Investigations over the past decade have inveterated the privi-
leged nature of VAPOL (and VANOL) as a ligand in the catalytic
asymmetric aziridination reaction (AZ reaction) of imines with diazo
compounds.1,2 With ethyl diazoacetate (EDA, 2), ethyl aziridine-
2-carboxylates are obtained with high cis-selectivity and enanti-
oselectivity from benzhydryl imines derived from a range of
aldehydes including 1°, 2°, and 3° aliphatic aldehydes and from a
range of electron-rich and -poor aryl aldehydes (Scheme 1).1g More
recently, we reported that even higher asymmetric inductions could
be obtained with certain substituted benzhydryl imine derivatives.1h
Our studies have revealed that the procedure for catalyst formation
generates a mixture of two species which we tentatively identified
as mesoborate 5 and pyroborate 6 (Scheme 1).1g The present work
suggests that the active catalyst is not a Lewis acid of the type 5 or
6 but in fact a Brønsted acid of singular structure.
Scheme 1
which one of the three borons forms a spiroborate anion (boroxinate)
with a molecule of VAPOL.
The crystal structure of 7 reveals that three of the methyl groups
in the tetramethylammonium ion have close contacts with the
aromatic rings of the boroxinate anion (Figure 1). These contacts
are less than the sum of the van der Waals radii of an sp3 carbon
(2.0 Å) and an sp2 carbon (1.7 Å) and are reminiscent of the
cation-π interactions described by Dougherty and Stauffer.4,5 These
interactions occur with one of the phenanthrene rings of the VAPOL
ligand and also with one of the phenyloxy rings of the boroxinate
core which folds up to meet the tetramethylammonium cation. The
twist angle about the biaryl axis is 55° in boroxinate 7 which is to
be compared with 79° in the free VAPOL ligand.6
1
The structural assignment of pyroborate 6 was based on its H
and 11B NMR spectra and on its high resolution mass spectrum.1g
Efforts to obtain solid state structural support for the assignment
of pyroborate 6 were thwarted by the fact that 6 is not crystalline.
In this regard, we were drawn to a report by Aldridge and co-
workers who were able to structurally characterize a bis-Lewis base
adduct of a simple pyroborate and acetate ion.3 In the procedure
for the generation of 6 shown in Scheme 1, the excess B(OPh)3 is
not removed under high vacuum. In an effort to generate a cleaner
sample of pyroborate 6, the procedure outlined in Scheme 2 was
developed with the more volatile BH3 ·Me2S which resulted in a
11:88 mixture of mesoborate 5 to pyroborate 6 with e10% of
unreacted VAPOL remaining. Subsequent treatment of this mixture
with 1 equiv of tetramethylammonium acetate followed by crystal-
lization from CH2Cl2 and pentane gave diffraction quality crystals.
X-ray diffraction analysis of these crystals revealed that the
compound produced from this reaction was not the bis-Lewis base
adduct of pyroborate 6 and an acetate ion. Quite remarkably, these
crystals proved to be the ion pair 7 consisting of the tetramethy-
lammonium cation and an anion formed from a boroxine ring in
Figure 1. Crystal structure of the boroxinate ammonium salt 7 visualized
by the Mercury Program.
The redistribution of the pyroborate 6 into the boroxinate 7
mediated by an acetate ion was quite unexpected. In an effort to
determine if this was a function of the bidentate nature of the acetate
ion, an attempt was made to trap the pyroborate 6 with a
monodentate Lewis base, 4-dimethylamino pyridine (DMAP), that
we hoped would mimic the imine substrates in the AZ reaction.
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J. AM. CHEM. SOC. 2009, 131, 15615–15617 15615

C O M M U N I C A T I O N S
Treatment of the 11:88 mixture of 5 and 6 generated as shown in
Scheme 2 with 1 equiv of DMAP gave the DMAP complex 8 which
crystallized from solution in 23% yield. As indicated in Figure 2,
this compound also has a boroxinate core that is complexed with
a protonated DMAP. The key interaction in this complex is the
hydrogen bond between the protonated nitrogen and one of the
oxygens of the boroxine ring that is attached to the four-coordinate
boron in which the N-O distance is 2.850 Å. The hydrogen was
initially located closer to the nitrogen than to the oxygen, and further
refinement was consistent with proton transfer to the nitrogen with
an N-H bond of 1.006 Å. The hydrogen bond also appears to be
bifurcated7,8 with an additional interaction with one of the oxygens
on the VAPOL ligand. The H-Oboroxine distance is 1.844 Å, and
the H-OVAPOL distance is 2.458 Å.9 There also appears to be a
π-π stacking interaction10 (3.489 Å) between a phenanthrene ring
of the VAPOL ligand and the pyridinium ion of the protonated
DMAP. The two ring systems are 6.5° from parallel. Finally, there
appears to be a CH-π interaction5 (3.244 Å) between an ortho-
hydrogen on the DMAP ring and one of the phenoxy rings of the
boroxine system. It is interesting to note that this phenoxy ring
seems to have folded to meet the DMAP unit, whereas the other
phenoxy ring is projected out away from the boroxinate complex
(Figure 2).
mesoborate 5 at 9.51 ppm, and that for the pyroborate 6 at 9.22
ppm (Figure 3, spectrum d).
1
Figure 3. (a and d) 11B and H NMR spectra of a mixture of 4, 5, and 6.
(b and e) 11B and 1H NMR spectra of DMAP complex 8. (c and f): 11B and
1H NMR spectra of 5, 6, and imine complex 10.
We have recently shown that tetrabutyldianisylmethyl (BUDAM)
imines of the type 9 (Scheme 3) will react with ethyl diazoacetate
in the presence of the VAPOL-B(OPh)3 catalyst to gives aziridines
with exceptionally high asymmetric inductions.1h Treatment of the
mixture of 5 and 6 prepared as indicated in Scheme 2 with 1 equiv
of the imine 9 leads to the formation of a complex that did not
form single crystals. This complex has been tentatively assigned
as the ion pair 10 consisting of the VAPOL boroxinate anion and
the protonated form of imine 9. This assignment is made on the
Figure 2. Crystal structure of boroxinate-pyridinium complex 8 visualized
by the Mercury Program.
The11B and 1H NMR spectra of the DMAP-boroxinate complex
8 are quite distinctive (Figure 3, spectra b and e). Three-coordinate
borate esters typically have broad absorptions for the boron between
16-20 ppm in CDCl3. The 11B NMR spectrum of B(OPh)3 reveals
an absorption at 16.5 ppm. The unsymmetrical pyroborate 6 has
two broad absorptions at 18.3 and 16.2 ppm in CDCl3, and for
comparison this spectrum is shown in Figure 3 (spectrum a).1g Since
11B is a quadrapole, the sharpness of the absorption is related to
the spherical symmetry around the boron, and this is reflected in
the appearance of the 11B NMR spectrum of the DMAP complex
8 (Figure 3, spectrum b). The two three-coordinate borons in 8
appear as a very broad absorption at 19.31 ppm, and the four-
coordinate boron as a very sharp peak at 5.54 ppm with an
integration of 2:1, respectively (not shown). An upfield shift for
the four coordinate boron is expected as a result of the increased
electron density around the boron in the borate anion. For example,
the 11B NMR absorption for LiB(OPh)4 is at 3.0 ppm.11 We are
not aware of any boroxinate structures with which to compare the
11B shifts in the DMAP complex 8, but an adduct of piperidine
and trimethylboroxine has been reported to have two signals in
CD2Cl2 at 32.4 and 6.0 ppm.12
1
basis of its 11B and H NMR spectra, part of which are shown in
Figure 3 (spectra c and f). The 11B NMR spectrum reveals a sharp
peak for 10 at 5.7 ppm similar to that observed for the DMAP
complex 8 (5.5 ppm). In addition, a bay region doublet for 10 is
observed at 10.35 ppm which is also similar to that observed for
the DMAP complex 8 (10.38 ppm). The proton of the protonated
DAMP in 8 is found at 12.32 ppm, and that for the protonated
imine 9 in 10 is found at 13.65 ppm (see Supporting Information).
The initial preparation of the mixture of 5 and 6 from VAPOL
and 2 equiv of BH3 · Me2S (Scheme 2) was developed with the
intention of optimizing the formation of the pyroborate 6. This
stoichiometry does not provide enough boron for the formation of
1
the boroxinate 10, and this is presumably the reason that the H
NMR spectrum of 10 reveals the substantial presence of the
mesoborate 5 (9.51 ppm) and the pyroborate 6 (9.22 ppm) (Figure
3, spectrum f). However, if 10 is prepared from VAPOL, 4 equiv
of B(OPh)3, 1 equiv of H2O, and then 3 equiv of imine 9, a clean
solution of 10 is generated containing 1% VAPOL, <1% of 5, and
5% of 6 (see Supporting Information). The viability of the species
10 to function as a catalyst for the AZ reaction was then examined.
Treatment of 9 and EDA with 5 mol % of 10 gave the aziridine 12
The most distinctive absorption for the DMAP complex 8 in the
1H NMR spectrum is the bay-region doublet at 10.38 ppm (Figure
3, spectrum e). The bay proton of VAPOL (Hb in 4 in Scheme 1)
is a very useful spectroscopic handle since it is shifted downfield
by ∼2 ppm from all other protons in the VAPOL ligand. The bay
proton for free VAPOL is found at 9.77 ppm, that for the VAPOL
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C O M M U N I C A T I O N S
Scheme 3
Brønsted acid, but given the structure of the DMAP boroxinate
1
complex 8 and the similarities of the H and 11B NMR spectra of
8 and 10, it is considered likely that the imine 9 is bound in 10 in
a protonated form and that the AZ reaction involves a chiral
Brønsted acid and not a chiral Lewis acid as had been assumed.15
The implications of the discovery of this new class of chiral
Brønsted acids will be reported in due course.
Acknowledgment. This work was supported by NIH Grant GM
63019. We thank Daniel Holmes for assistance with NMR
experiments.
Supporting Information Available: Synthetic procedures and
spectral data for all new compounds and X-ray diffraction data and cif
files for 7 and 8. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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in 99% yield and 98% ee which compares with the reported data
for this reaction in the AZ reaction (98% yield and 99% ee).1h,13
The ion pair 10 generated from the imine 9 will also catalyze the
reaction of an imine with a different N-substituent. The aziridine
14 was produced in 84% yield and 89% ee, and we have previously
observed that this aziridine can be obtained from imine 13 in 78%
yield and 90% ee with catalysts generated from B(OPh)3.1g,13
The original optimized procedure1g for the preparation of the
aziridination catalyst involved reacting VAPOL with 3 equiv of
B(OPh)3, and this is consistent with a boroxinate as the active
catalyst. The same 1:3 stoichiometry was also optimal in a catalyst
for an asymmetric heteroatom Diels-Alder reaction.14 Neither
procedure however involved the addition of any H2O. The formation
of a boroxine requires 3 equiv of H2O. The success and reproduc-
ibility of the AZ reaction apparently have depended on the fact
that commercial B(OPh)3 is never pure and contains partially
hydrolyzed boron-containing compounds.
Thus if the boroxinate is the active catalyst in the AZ reaction,
then after the aziridine is liberated, the resulting species would be
the protonated boroxinate 11 although we have not been able to
detect this species. Treatment of 10 with 1.2 equiv of EDA results
in the quantitative formation of 12 and to the loss of all absorptions
below 10 ppm in the 11B NMR (see Supporting Information).
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