Catalytic asymmetric α-iminol rearrangement: New chiral platforms

Article abstract of DOI:10.1021/ja5065685

A series of 19 different asymmetric catalysts were screened in an effort to identify the first chiral catalyst for the rearrangement of α-hydroxy imines to α-amino ketones involving a 1,2-carbon shift. Although aluminate complexes of VAPOL, VANOL, and 7,7'-^tBu₂VANOL were quite effective catalysts giving up to 88% ee, the ne plus ultra catalyst for this reaction was found to be a zirconium complex of VANOL which gives 97 to >99% ee for the majority of the substrates examined. An X-ray diffraction study of the catalyst reveals that the zirconium exists as a homoleptic complex with three VANOL ligands and two protonated N-methyl imidazoles.

Full text of DOI:10.1021/ja5065685

Communication
pubs.acs.org/JACS
Catalytic Asymmetric α‑Iminol Rearrangement: New Chiral Platforms
Xin Zhang,† Richard J. Staples,† Arnold L Rheingold,‡ and William D. Wulff*,†
†Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
‡Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States
S
* Supporting Information
h at 80 °C gives <5% yield of the product (entry 1). However, the
ABSTRACT: A series of 19 different asymmetric catalysts
were screened in an effort to identify the first chiral catalyst
for the rearrangement of α-hydroxy imines to α-amino
ketones involving a 1,2-carbon shift. Although aluminate
complexes of VAPOL, VANOL, and 7,7′-tBu2VANOL
were quite effective catalysts giving up to 88% ee, the ne
plus ultra catalyst for this reaction was found to be a
zirconium complex of VANOL which gives 97 to >99% ee
for the majority of the substrates examined. An X-ray
diffraction study of the catalyst reveals that the zirconium
exists as a homoleptic complex with three VANOL ligands
and two protonated N-methyl imidazoles.
α-iminol rearrangement of 22a does occur slowly at 150 °C
providing racemic 23a in 28% yield in 2 h with 79% conversion
(entry 2). The induction can be increased to 62% ee if the
VANOL BOROX catalyst is assembled from 2,4,6-tri-t-butyl
phenol rather than phenol, however, the reaction is exceedingly
slow even with 25 mol % catalyst (entry 6). The VANOL and
VAPOL hydrogen phosphate catalysts and their derivatives have
proven to be very effective chiral Brønsted acid catalysts for a
number of reactions.9−19 A number of catalysts in this class were
screened (4−9, Scheme 2), and it was found that they were not
very effective (entries 8−13).
Given the fact that α-iminol rearrangement is known to be
accelerated with either an acid or base,1,2 we decided to examine
Shibasaki’s amphoteric catalyst BINOL Al 10 (ALB) which is
very effective in delivering high asymmetric induction in
asymmetric Michael addition reactions.20 The lithium/alumi-
num catalyst 10 prepared from BINOL only provided a very
sluggish reaction. The corresponding aluminum catalysts
prepared from VANOL and VAPOL have not been previously
reported. These catalysts were generated according to Shibasaki’s
procedure from 2 equiv of the ligand and one of LiAlH4 and were
found to be very effective catalysts. Both the VANOL and
VAPOL catalysts 11 and 13 gave quantitative yields of 23a, and
coincidently, both gave 68% ee which was the highest induction
that had observed up to this point. The induction could be
increased to 88% ee with no loss in reactivity with the aluminate
catalyst 12 derived from 7,7′-di-t-butyl VANOL (entry 17).21
We had previously found that a VAPOL zirconium catalyst was
very effective in promoting the Mannich reaction of imines with
ketene acetals.22 In the present investigation, these were found to
be the optimal catalysts for the α-iminol rearrangement. The (R)-
VANOL Zr catalyst 15 gives (S)-23a in 96% yield and 97% ee
after 1 h at 80 °C (entry 20). The corresponding titanium catalyst
14 gives excellent asymmetric induction as well, but the turnover
is much slower (entry 19). The corresponding VAPOL Zr
catalyst 17 gives very poor asymmetric induction (entry 24).
Unlike their corresponding aluminum catalysts, the VANOL and
tBu2VANOL zirconium catalysts 15 and 16 give the same degree
of asymmetric induction, but the latter is a bit slower (entries 20
and 23 vs 16 and 17). The BINOL zirconium catalyst 19 is highly
effective in the catalytic asymmetric Mannich reaction23 but did
not prove to be an effective catalyst for the α-iminol
rearrangement (entry 26). The catalyst loading for the
VANOL Zr catalyst 15 can be lowered to 0.5 mol % and gives
he first examples of the α-iminol rearrangement involving a
T
1,2-carbon shift were reported by Prins and Shoppee in
1943 (Scheme 1).1 A review of the subsequent history appeared
in 2003,2 and there have been a number of examples since.3 Most
often these reactions have been effected thermally (∼150−200
°C) and several others with Brønsted acids (TsOH, HCO2H,
CH3CO2H, HCl, H2SO4),2,3 and in some cases alkoxide bases
have been used.2 The reaction can also be promoted by
transition-metal Lewis acids including scandium, copper, and
zinc triflates.3f,j,r There has been only one report with a chiral
catalyst. A nickel pybox complex and a number of chiral
lanthanide complexes were found to facilitate the reaction,
however, all gave racemic products.3a There is one example of a
catalytic asymmetric Amadori−Heyns rearrangement which
involves a 1,2-hydrogen shift via an intermediary enol.3t
Our interest in the α-iminol rearrangement arose from our
work with chiral catalysts for reactions of imines including
aziridinations,4 aza-Cope rearrangements,5 heteroatom Diels−
Alder reactions,6 and the Ugi reaction.7 These reactions involve a
BOROX catalyst consisting of an ion-pair containing a
boroxinate chiral anion with the gegen cation derived from a
protonated substrate.8 We were thus disappointed to find that
the VANOL and VAPOL BOROX catalysts 1 and 3 are
essentially ineffectual for the α-iminol rearrangement of 22a with
the latter giving 23a as a racemic product (Table 1, entries 4 and
7). The VANOL BOROX catalyst gives only 17% ee. There is not
a significant background reaction since simply heating 22a for 42
Scheme 1
Received: June 30, 2014
Published: September 23, 2014
© 2014 American Chemical Society
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Table 1. Catalyst Screen fot the α-Lminol Rearrangement of
α-Hydroxy Imine 22a
Scheme 2
a
a
All reactions were carried out under nitrogen except where indicated.
For protocols for the preparation of the various catalysts see the SI.
b
c
Isolated yield. Yields in parentheses are NMR yields with Ph3CH as
d
e
dramatic effect on the rate of the reaction; without imidazole
there is no reaction but with 1 equiv the reaction goes to
completion in 1 h. Increasing the amount of N-methyl imidazole
past 1 equiv slows down the reaction; the yield drops to 70% with
2 equiv and to 8% with 20 equiv.
internal standard. Determined by HPLC. 71% of the starting
f
g
material remains. Performed under air in a screw cap vial. 30% of the
starting material remains and a side-product was formed in 50% yield
that is tentatively identified as the imine resulting from oxidation of
23a. 25 mol % PhCO2H was added after the precatalyst was
prepared. See ref 5. The substrate was added to a solution of 15 in
h
i
A survey of the scope of the α-iminol rearrangement is
presented in Table 2. The imines 22 were prepared from the
aldehydes 21 which in turn were prepared by Grignard or
organolithium addition to the commercially available acetal 20.
Exceptionally high asymmetric inductions were observed over a
broad range of substrates including aryl groups with both
electron-rich and electron-poor substituents (i.e., entries 12 and
16). The only really problematic aryl substituent was the para-
trifluoro-methyl group. This substrate reacted very slowly, and
after 30% conversion the α-amino ketone 23n was not detected.
Instead the imine 24n, resulting from oxidation of α-amino
ketone 23n, was isolated in 18% yield. All of the reactions of all of
the substrates in Table 2 were carried out in the presence of air,
but it was found that that the trifluoromethyl substituent 22n
required an inert atmosphere. When the reaction of 22n was
deoxygenated, the α-amino ketone 23n could be isolated in 74%
yield and 73% ee (70 °C, 10 mol % catalyst, 2.5 h), and the imine
24n could not be detected. 1,2-Migrations of aliphatic groups
were also highly efficient and stereoselective. Benzyl and
cyclohexyl substituents gave >99 and 98% ee, respectively,
while the rearrangement of 22p with R = n-hexyl gave 23p in 89%
ee and 95% yield. The absolute configuration of 23a was
j
mesitylene that had been preheated to 160 °C. 5 mol % of a 1:1
k
mixture of Zr(OiPr) + (HOiPr) and N-methylimidazole. 79% of 22a
was unreacted.
23a in 96% yield with 95% ee in 60 min at 80 °C (entry 21). The
most remarkable aspect of catalyst 15 is that its reactions can be
carried out in the presence of air in a screw-cap vial (Table 1,
entries 19−24). The reaction can even be carried out in the
presence of air at 160 °C to give 23a in 95% yield with 89% ee in
30 s. The catalyst is remarkably stable as a solution of 15 in
toluene can be allowed to stand for more than 5 months in the
presence of air at room temperature and will still give a 98% yield
of 23a in exactly the same asymmetric induction (97% ee) as
freshly prepared catalyst (under the conditions in Table 2, entry
1).
The components of the catalyst are the ligand, Zr-
(OiPr)4(HOiPr), and N-methylimidazole in a 2:1:1 ratio.
Variations in the ratio of ligand to zirconium find that there is
no change in induction when it is raised from 1:1 to 2:1 and to
3:1, but the yield does increase from 67 to 98% (see Supporting
Information). However, the amount of N-methylimidazole has a
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Table 2. Scope of the α-Iminol Rearrangement of α-Hydroxy
Imines 22a−q
Scheme 3
a
% yield
% yield
% yield
b
b
b
c
entry series
R
21
22
23
% ee 23
1
2
a
b
c
d
e
f
C6H5
80
83
56
77
67
78
73
49
69
61
77
63
99
53
53
55
89
88
−
94
88
97
2-MeC6H4
2-iPrC6H4
3-MeC6H4
3-ClC6H4
4-MeC6H4
4-nBuC6H4
4-iPrC6H4
4-CyC6H4
4-tBuC6H4
4-PhC6H4
4-MeOC6H4
4-FC6H4
84
d
3
95
−54
4
84
100
93
93
95
93
98
95
97
95
90
90
88
96
98
e
5
92
−93
6
92
98
7
g
h
i
95
99
8
98
99
9
97
94
10
11
12
13
14
15
16
j
100
100
90
>99
>99
k
l
98
d
m
n
n
o
97
> −99
f
4-CF3C6H4
4-CF3C6H4
≤5
−
73
97
g
,
h
74
i
4-MeC(O)
C6H4
100
17
18
19
p
q
r
n-hexyl
71
46
57
88
100
88
95
98
97
89
>99
98
benzyl
cyclohexyl
a
Unless otherwise specified, all reactions were run with 2.5 mol % (R)-
15 in toluene at 0.3 M in 22 (0.1 mmol) at 60 °C for 1 h under air and
went to 100% completion. The catalyst was prepared by stirring a
toluene solution of Zr(OiPr)4{HOiPr) with 2 equiv of (R)-VANOL
b
and 1 equiv of N-methylimidazole at 25 °C for 30 min. Isolated yield.
c
Determined by HPLC. Negative sign means that (R)-23 is formed.
d
e
(S)-VANOL was used. Reaction at 70 °C for 6 h with 5 mol % of
f
(S)-15 under N2. This reaction gives an 18% yield of imine 24n after
19 h at 60 °C along with a 70% recovery of 22n. Reaction at 70 °C
for 2.5 h with 10 mol % catalyst. The reaction mixture was degassed
g
h
i
by the freeze−thaw method. Reaction at 0.1 M in 22 for 3 h.
determined by chemical correlation with the methyl ester of (R)-
phenyl glycine, and the other products were assumed to be of the
same antipode (see Supporting Information (SI)). It was also
found that it was not necessary to carry out the reaction on the
preformed imine. The reaction of aldehyde 21j with aniline gives
the rearranged product (R)-23j in the same yield and % ee as
when starting with the preformed imine 22j (eq 1).
Figure 1. Structure of Zr((S)-VANOL)3(NMI)2 28 (hydrogens and
bromobenzene not shown).
83% recovery. The reduction of 23s with super hydride could
also be used to deliver the syn-diastereomer 27 with >50:1
stereoselectivity if the amino group was first converted to an
acetamide.26,27 Finally, Grignard addition of a phenyl group to
23s can be used to gain facile access to the triphenyl amino
alcohol 26.
A sample of the catalyst prepared from a ratio of
VANOL:Zr:Im = 2:1:1 was grown from bromobenzene, and
single crystals were obtained and characterized by X-ray
diffraction as the complex 28 in Figure 1. The solid-state
structure revealed that the zirconium exists as a six-coordinate
homoleptic complex with three VANOL ligands and is charge
balanced with two protonated N-methyl imidazoles. The
protonated imidazoles are not H-bonded to the dianionic core
but rather are H-bonded to water molecules which in turn are H-
bonded to the oxy-zirconium core. The imidazolium hydrogen
was located, but the protons on water were not. The N−O
distance for the H-bond of the protonated imidazole in the
foreground is 2.701 Å, and the O−O distance for the H-bond for
A number of imines made from substituted anilines were also
investigated with the conditions in Table 2 (Scheme 3).24 The
scale could be increased 40-fold over that used in Table 2 to give
1.22 g of α-amino ketone 23s in 85% yield and 98% ee with 1.5
mol % catalyst at 80 °C in 2 h. The optical purity of a sample of
23s that was 95% ee could be enhanced to ≥99% ee by
crystallization with 82% recovery. The synthetic utility of α-
amino ketone 23s was demonstrated in the synthesis of the
amino alcohols 25−27 all of which are important as chiral ligands
in asymmetric synthesis and catalysis.25 Reduction of 23s with
super hydride gives the amino alcohol 25 with >50:1 selectivity
for the anti-diastereomer. This compound was obtained in 92%
ee, but this could be enhanced to >99% ee by crystallization with
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Scheme 4
the associated water molecule to the anionic core is 2.689 Å. The
same solid-state structure was observed for crystals grown from a
3:1:2 mixture of VANOL:Zr:Im. Each unit cell contains two
zirconium centers. A number of structures of rare earth
complexes have been reported with three BINOL ligands but
not for zirconium.20,28 This is the first homoleptic complex of
zirconium derived from three bis-phenol ligands.
Crystals of zirconium complex 28 (2.5 mol %) were found to
catalyze the α-iminol rearrangement of 22a to give the amino
ketone 23a in 96% yield and 98% ee under the conditions in
Table 2, entry 1. Whether complex 28 (Scheme 4) is the actual
catalyst in solution remains to be determined as does the
mechanism for this reaction. Possibilities to be considered are (1)
the activation of the imine and the alcohol by hydrogen-bond
interactions after proton exchange between the α-iminol and an
imidazole and (2) the Lewis acid/Brønsted acid activation of the
imine by the zirconium and the alcohol by an alkoxide ligand of
the zirconium.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for all new
compounds and X-ray data and pdb file for 28. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
wulff@chemistry.msu.edu
Notes
(16) Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830−
5831.
■
(17) Zheng, W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem. Soc.
2011, 133, 3339−3341.
(18) Snyder, S. A.; Thomas, S. B.; Mayer, A. C.; Breazzano, S. P. Angew.
Chem., Int. Ed. 2012, 51, 4080−4084.
The authors declare no competing financial interest.
(19) Chen, M.-W.; Chen, Q.-A.; Duan, Y.; Ye, Z.-S.; Zhou, Y.-G. Chem.
Commun. 2012, 48, 1698−1700.
ACKNOWLEDGMENTS
■
(20) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 1236−1256.
This work was supported by the National Institute of General
Medical Sciences (GM 094478). We thank Mathew Vetticatt for
his help with graphic analysis.
(21) Guan, Y.; Ding, Z.; Wulff, W. D. Chem.Eur. J. 2013, 19, 15565−
15571.
(22) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew, Chem. Int. Ed. 2001,
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