Catalytic asymmetric [3,3]-rearrangements of allylic acetimidates

Article abstract of DOI:10.1039/c4cy01749h

A streamlined synthetic access to enantiomerically pure allylic amines as advanced and valuable synthetic building blocks is important for pharmaceutical sciences. The rearrangement of allylic trihaloacetimidates is known as an attractive method to furnis

Full text of DOI:10.1039/c4cy01749h

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Catalytic asymmetric [3,3]-rearrangements of
allylic acetimidates†
Cite this: Catal. Sci. Technol., 2015,
5, 2340
*
J. Moritz Bauer and René Peters
A streamlined synthetic access to enantiomerically pure allylic amines as advanced and valuable synthetic
building blocks is important for pharmaceutical sciences. The rearrangement of allylic trihaloacetimidates is
known as an attractive method to furnish branched chiral allylic trihaloacetamides with high levels of
enantio- and regioselectivity. In the present article we report our studies on the catalytic asymmetric
rearrangement of the corresponding non-halogenated acetimidates, which might provide economic
advantages by avoiding CX3 groups. The regioselective title reaction proceeds with high levels of enantio-
selectivity, provides high yields and requires only low catalyst loadings. In addition, the generated N-acetyl
and N-phenacetyl functionalities offer the option of a subsequent mild enzymatic amide hydrolysis to get
access to nearly enantiopure allylic amines.
Received 30th December 2014,
Accepted 27th January 2015
DOI: 10.1039/c4cy01749h
www.rsc.org/catalysis
In the last few years our group has developed the most
active catalysts for the asymmetric rearrangement of
Introduction
[3,3]-Rearrangements of allylic imidates provide a synthetic
platform for a regioselective access of chiral branched allylic
amines, which are masked as the corresponding amides.1
The thermal sigmatropic [3,3]-rearrangement of allylic
benzimidates was reported as early as 1937 by Mumm and
Möller.2 Allylic benzamides (4 in Scheme 1, R3 = aryl) are con-
veniently formed by this reaction type,3 but are of restricted
synthetic value, because the amide hydrolysis to release the
corresponding allylic amines 5 has been reported as a diffi-
cult task.3b For that reason the rearrangement of allylic
trichloroacetimidates 2 (Scheme 1, R3 = CCl3) has been devel-
oped as a synthetically more attractive alternative, which is
commonly known as Overman rearrangement. Overman
reported in 1974 that this reaction type is significantly accel-
erated by catalytic amounts of soft Lewis acids.4 Based on
these early studies enantioselective rearrangements of allylic
trichloro-5 and trifluoroacetimidates6 (R3 = CF3) were later
advanced, enabling a 2-step transformation of achiral allylic
alcohols 1 to enantioenriched branched allylic amides 4
catalysed by chiral PdIJII)-complexes (Scheme 1). Due to the
strong inductive effect of the CCl3 or CF3 groups, the release
of the unprotected allylic amines 5 from the rearrangement
products is usually readily accomplished.
trifluoroacetimidates,7–9 allowing to reduce the catalyst load-
ings by 1–2 orders of magnitude. At the same time these cata-
lysts enabled the highest levels of enantioselectivity achieved
so far for a broad range of substrates. It became, e.g., possi-
ble to generate N-substituted quaternary stereocenters with
very high levels of enantioselection7b,d or to create a divergent
access towards secondary chiral allylic amines7c,d by variation
of the N-residue R2 in Scheme 1. On the other hand, the
preparation of the trifluoroacetimidates
2 is relatively
tedious, quite expensive, usually makes use of toxic CCl4 and
generates large amounts of PPh3 based waste.10,11 Moreover,
isolation and storage of trifluoroacetimidates is often trou-
bled by their sensitivity towards hydrolysis.
For these reasons our goal was to develop analogous
methods offering a comparable efficiency, but in which the
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55,
D-70569 Stuttgart, Germany. E-mail: rene.peters@oc.uni-stuttgart.de;
Fax: +49 (0)711 68554330; Tel: +49 (0)711 68564330
† Electronic supplementary information (ESI) available: Experimental procedures,
characterisation of all new compounds, NMR spectra, HPLC data. See DOI:
10.1039/c4cy01749h
Scheme 1 The allylic imidate rearrangement.
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CX3-groups would be avoided.12 A synthetically attractive
alternative might be the rearrangement of simple acetimidates
(R3 = CH3 in Scheme 1), because several efficient methods for
the deprotection of acetamides have been reported – either
chemically13 or by hydrolytically active enzymes.14 Depending
on the enzymes used, the latter deprotection strategy might
also allow for the formation of enantiomerically pure amines
by an additional kinetic resolution. This would be appealing
in those cases, where the achieved enantioselectivity would
not fit to the demands for a certain application, e.g., as an
active pharmaceutical ingredient. Moreover, the application
of acetimidates would offer the advantage of an improved
atom-economy.
protecting group for amines.16 Two alternative ways towards
9a were developed and provided useful yields (Scheme 2).
The first route is an optimisation of a previously reported
method7d and starts from N-acetylated p-anisidine 6a. Gener-
ation of the iminochloride 7 and subsequent treatment with
the lithiated allylic alcohol formed 9a in 65% yield over 2
steps after isolation by column chromatography. The other
route used the imidoylbenzotriazole 8a as coupling partner
for the lithium alkoxide of the allylic alcohol 1a.17 In contrast
to iminochloride 7, 8a is stable and can be purified without
significant decomposition, but the overall yield is lower in
that case (39% over 2 steps starting from 6a) as compared to
the method via the iminochloride 7.
The rearrangement of allylic non-halogenated acetimidates
2 (R3 = alkyl) has only been scarcely reported. In 1992 Metz
et al. reported the synthesis of racemic allylic propion-
ylamides (R3 = Et) which proceeded in useful yields utilising
5 mol% of ijPdCl2IJNCPh)2] as catalyst.15 Our group has
reported a single enantioselective example, in which an allylic
N-phenyl acetamide could be prepared with high enantio-
selectivity (ee = 94%).7d In our subsequent studies (see below)
we found that the used reaction conditions were not gener-
ally applicable for other substrates to provide very high
enantioselectivity. Herein we now report a method which (1)
allows for the catalytic asymmetric synthesis of a broad range
of allylic acetamides, (2) proceeds in general with excellent
enantioselectivity and (3) can be executed with low catalyst
loads.
Catalytic model reaction. At the starting point of this
investigation the conditions of the above mentioned single
example for a catalytic asymmetric rearrangement of a non-
halogenated allylic acetimidate7d were used for the re-
arrangement of 9a. The chloride bridged dimeric penta-
phenylferrocene oxazoline palladacycle [PPFOP-Cl]2 (see
Table 1) was used as precatalyst and activated by treatment with
AgNO3 according to the reported protocol.7d,18 Although a
higher precatalyst loading of 1.0 mol% (rather than 0.2 mol%
for the reported example) was used, the enantiomeric excess
of 83% was not satisfactory for the rearrangement of this
substrate (entry 1). With a reduced catalyst loading of
0.5 mol% the enantiomeric excess was further decreased to
78% ee (entry 2). The change from an N-phenyl to a more
electron-rich N-PMP group thus had a negative impact on the
reaction outcome indicating that the previously reported
conditions7d are not generally useful for non-halogenated
acetimidates. To find a more general solution, some alterna-
tive ferrocene based catalysts, which have recently been devel-
oped in our research group, were then examined under reac-
tion conditions that have originally been optimised for the
rearrangement of allylic N-PMP trifluoroacetimidates.7d,8b,9
The pentaphenylferrocene based imidazoline palladacycle
[PPFIP-Cl]2 (ref. 19 and 20) was thus activated by 4 equiv.
(per precatalyst dimer) of AgO2CCF3.7d Earlier we have shown
that 2 equiv. of a silver salt are responsible for an anion
exchange of the strongly binding chloride bridges by a new
anionic ligand. Another two equivalents oxidise the Pd-
centers of PPFOP or PPFIP from PdII to PdIII, leading to
Results and discussion
Optimisation
Substrate preparation. The N-PMP (PMP = p-methoxyphenyl)
protected acetimidate 9a (Scheme 2) was selected as the
model substrate, because the PMP group is often used as a
unique paramagnetic catalysts offering
a
significantly
increased catalytic activity.7f Nevertheless, in the present case
[PPFIP-Cl]2 activated by AgO2CCF3 resulted in a low catalytic
activity, yet promising enantioselectivity (entry 3).
For the bispalladacycle precatalyst [FBIP-Cl]2 (ref. 8b and 21)
and the mixed pallada-/platinacycle [FBIPP-Cl]2 (ref. 9) an oxi-
dation of the catalyst is usually not required for catalytic
activity and activation by silver salts is just necessary for
the chloride ligand exchange. In the present study the
rearrangements could be done at room temperature provid-
ing high yields after reaction times of 3 days using precatalyst
loadings of 1.0 or 2.0 mol% (entries 4 and 6). A reduced load-
ing of 0.5 mol% also gave a high yield at a reaction tempera-
ture of 55 °C (entry 5). In all cases the enantioselectivity
Scheme 2 Two alternative methods for the preparation of model
substrate 9a.
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Table 1 Investigation of different catalysts in the title reaction
#
Precatalyst
X
AgY
Solvent
T [°C]
t [h]
Yielda [%]
eeb
1
2
3
[PPFOP-Cl]2
[PPFOP-Cl]2
[PPFIP-Cl]2
[FBIP-Cl]2
1.0
0.5
1.0
1.0
0.5
2.0
1.0
1.0
1.0
AgNO3
AgNO3
AgO2CCF3
AgOTs
AgOTs
AgOTs
AgNO3
AgNO3
AgNO3
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CHCl3
CHCl3
CH2Cl2
CH2Cl2
CHCl3
50
50
50
25
55
25
50
50
70
24
24
24
72
72
72
24
72
24
97
79
27
93
93
87
53
94
93
83
78
93
89
85
87
98
98
98
4c
5c
6c
7
[FBIP-Cl]2
[FBIPP-Cl]2
[PPFIP-Cl]2
[PPFIP-Cl]2
[PPFIP-Cl]2
8
9
a
b
c
Yield of isolated product.
Determined by HPLC.
Reaction was performed in the absence of proton sponge (PS, 1,8-
bisIJdimethylamino)naphthalene).
was somewhat lower than for the combination ijPPFIP-
Cl]2/AgO2CCF3.
and p-NO2 as an example for a strong π-acceptor very similar
results in terms of product yields and enantioselectivity were
obtained.
Since [PPFIP-Cl]2 activated by AgO2CCF3 gave the highest
enantioselectivity and the combination of ijPPFOP-Cl]2/AgNO3
provided the highest activity, we studied the activation of
[PPFIP-Cl]2 with AgNO3 as well. Gratifyingly, this combination
provided the product with excellent enantioselectivity and an
improved reactivity (entry 7). Either by a prolonged reaction
time or at a reaction temperature of 70 °C 10a was finally
formed in high yields and almost enantiomerically pure
form (entries 8 and 9).
In addition to the parent acetimidate substrates with R2 = H,
we also examined substrates with R2 = Ph. A phenylacetamide
product might create additional opportunities for enzymatic
deprotection by the penicillin-G-amidase (PGA). It was found
that the imidate substrates 9 with R2 = Ph show a very simi-
lar behaviour (entries 6–12) compared to those with R2 = H.
Like before the electronic effect of the substituents R3 on
the N-aryl residues is of only minor importance and in each
case (R3 = NO2, H, OMe) the products were generated in
high yields and with high enantioselectivities (entries 6–8).
It was also possible to significantly reduce the catalyst
loadings without a negative impact on the reaction outcome
as has been demonstrated for substrate 9h. Various
precatalyst loadings ranging from 1.0 mol% to as little as
0.05 mol% were studied and they all provided almost identi-
cal results (entries 8–10). Low catalyst loadings were also
examined for the phenylacetimidates 9i and 9j carrying dif-
ferent alkyl residue R1E and in both cases high product yields
and enantioselectivities were determined (entries 11 & 12).
Substrate scope
Application of [PPFIP-Cl]2 as precatalyst. Under the
optimised conditions various substrate modifications were
studied (Table 2). Substrates 9a–d in which R1E either equals
phenethyl, ethyl, n-propyl or n-pentyl all furnished the corre-
sponding acetamides 10a–d in high yields and with high
enantioselectivity (entries 1–4).
The electronic effect of substituents R3 on the N-aryl resi-
dues is apparently negligible as a comparison of entries 3
and 5 shows. With both p-OMe as an example for a π-donor
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Table 2 Investigation of different substrates in the PPFIP-catalysed title reaction
#
9/10
R1E
R1Z
R2
R3
X
Yielda [%]
eeb
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
h
h
i
IJCH2)2Ph
Et
nPr
nPent
nPr
nPr
nPr
nPr
nPr
nPr
nPent
Et
iPr
iPr
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
OMe
OMe
OMe
OMe
NO2
NO2
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.25
0.05
0.25
0.1
1.0
1.0
1.0
1.0
1.0
93
92
92
91
94
93
90
91
94
92
92
93
84
96
93
96
98
98
96
96
92
94
95
97
97
97
96
94
96
91
95
95
90
98
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9
10
11
12
13
14c
15d
16d
17c
j
k
k
l
m
n
4-NO2–C6H4
IJCH2)2CHCIJMe)2
a
Yield of isolated product. b Determined by HPLC. c Performed in CH2Cl2 at 50 °C for 48 h. d Performed in CH2Cl2 at 25 °C for 72 h.
Next the rearrangement of particularly challenging sub-
strates was investigated, e.g. that of 9k possessing an iPr-
group as R1E. α-Branched alkyl residues are known to retard
allylic imidate rearrangements.1,7a,d In the present study
application of the standard conditions gave 10k in a yield of
84% and with an ee of 91% (entry 13). The results could be
further improved by decreasing the reaction temperature to
50 °C using a prolonged reaction time of 48 h (96% yield,
95% ee, entry 14).
high enantioselectivities. Allylic imidate rearrangements of
substrates of this type are in general inherently difficult,
since the aryl residues accelerate a thermal background
reaction.1,7a,d Nevertheless, at room temperature the products
10l and 10m were obtained in high yields and with high
enantioselectivity after a reaction time of 3 days.
In addition, it is possible to form N-substituted quaternary
stereocenters in excellent yield and with nearly perfect
enantiocontrol as shown for substrate 9n. Obviously, the
remote olefin functionality did not have a negative impact on
the reaction outcome.
Similarly, the rearrangement of substrates carrying aro-
matic residues R1E required a lower reaction temperature for
Table 3 Investigation of different substrates in the FBIP-catalysed title reaction
#
10
R1E
R1Z
R2
R3
Yielda [%]
eeb
1
2
3
4
5
6
7
8
a
e
IJCH2)2Ph
nPr
H
nPr
H
H
H
H
H
H
H
Ph
Ph
Ph
CH3
CH3
OMe
NO2
NO2
OMe
OMe
NO2
OMe
H
93
90
93
95
97
96
84
85
89
90
92
86
89
95
92
90
(ent)-e
h
(ent)-h
(ent)-f
(ent)-o
(ent)-p
nPr
H
nPr
nPr
nPr
nPr
H
H
a
Yield of isolated product. b Determined by HPLC.
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Application of [FBIP-Cl]2 as precatalyst. In addition, the
FBIP-catalysed reaction was applied to substrates differing in
their electronic properties of the N-aryl group and in the C,C
double bond configuration (Table 3).
Also with this bimetallic catalyst a π-donor (p-OMe) and a
π-acceptor IJp-NO2) on the N-aryl residue were both well toler-
ated and very similar results were obtained for substrates car-
rying these substituents (entries 1 and 2). Also less reactive1,8
(Z)-configured substrates 9 provided the corresponding prod-
ucts in high yields and with high enantioselectivity,
irrespective of the use of an electron rich or deficient N-aryl
residue (entries 3 & 5–8). Using the (Z)-configured substrates
resulted in a switch of the absolute configuration of the gen-
erated stereogenic center (determined by HPLC using a chiral
stationary phase). Like other PdIJII) catalysed allylic imidate
rearrangements the reaction is thus stereospecific.1
Scheme 4 Synthesis of the highly enantioenriched primary amine 13
via enzymatic phenylacetamide hydrolysis using penicillin-G-amidase.
through CaH2/celite (1 : 1) under N2. The solvent was removed
by a stream of N2 and then high vacuum was applied. A stock
solution was prepared by the addition of a defined amount of
the corresponding solvent.
b) Activation of [FBIP-Cl]2. To a solution of AgOTs (4.0
equiv.) in dry MeCN (0.5 mL per 5 mg [FBIP-Cl]2) was added
[FBIP-Cl]2 (1.0 equiv.). The mixture was stirred at room tem-
perature for 14 h and then filtered through CaH2/celite (1 : 1)
under N2. The solvent was removed by a stream of N2 and
then high vacuum was applied. A stock solution was prepared
by the addition of a defined amount of the corresponding
solvent.
Amide cleavage
The release of the free amino functionality by cleavage of the
amide moiety was investigated by chemical and enzymatic
means.
Amide cleavage by chemical means. Treatment of allylic
amide 10a with Li[Et3BH] at 0–25 °C for 2 h proceeded
smoothly and provided the PMP-protected amine 11 in high
yield (Scheme 3).13e Comparison of the obtained product by
HPLC using a chiral stationary phase with an authentic sam-
ple prepared by rearrangement of the corresponding
trifluoroacetimidate followed by cleavage of the generated
trifluoroacetamide confirmed the expected (R)-configuration
of 10a.7d
General procedure for the catalytic asymmetric
rearrangement of allylic imidates 9
A dry screw-cap vial was charged with the corresponding
allylic imidate 9 (1.0 equiv.), then vacuum was applied and
the vial was refilled with N2 (3 times). A stock solution of pro-
ton sponge IJ1,8-bis-IJN,N-dimethylamino)naphthalene, PS,
4× mol% [only used in the case of mono-palladacycles]) in the
indicated solvent and a stock solution of the corresponding
activated catalyst in the indicated solvent were added. The
amount of solvent was reduced by a stream of N2 if necessary
(final concentration: 150 μL per 100 μmol of substrate). The
vial was closed by a screw-cap and the mixture was stirred at
the indicated temperature for the indicated time. Subse-
quently, the solvent was removed under reduced pressure
and mesitylene (10 μL per each 50 μmol of substrate) was
added to the crude product as an internal standard followed
by CDCl3 (1 mL) to determine conversion and yield by 1H-NMR.
The crude product was afterwards directly used for silicagel
chromatography to isolate the corresponding allylic amide
10. The purified samples were used to determine the ee value
by HPLC.
Amide cleavage by enzymatic means. To allow deprotection
under very mild conditions, an enzymatic amide hydrolysis
was studied. For that purpose the phenylacetimidate 9h was
rearranged on a 250 mg scale (Scheme 4). After PMP-
deprotection under standard conditions the phenylacetamide
12 was applied to penicillin-G-amidase for 2 days at 38 °C.
The primary amine 13 was formed in high yield (96%) and
with an ee of 97% ((R)-configuration12).
Experimental
Procedures for the activation of pre-catalysts
a) Activation of mono-palladacycles. The corresponding
palladacycle (1.0 equiv.) and the corresponding silver salt
(4.0 equiv.) were suspended in dry CH2Cl2 (0.5 mL per 5 mg
palladacycle) and ultrasonificated for 10 min. The mixture
was stirred at room temperature for 14 h and then filtered
Enzymatic deprotection: IJR)-hex-1-en-3-amine (13)
IJR)-N-IJHex-1-en-3-yl)-2-phenylacetamide 12 (92.0 μmol, 20.0 mg)
was suspended in sodium phosphate buffer (1.0 mL, pH = 7.5,
1 M) and PGA (penicillin-G-amidase from Escherichia coli,
ammonium sulfate suspension, ≥10 units per mg protein,
Scheme 3 Reductive acetamide cleavage.
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30 μL) and toluene (0.1 mL) were added. The flask was closed
and the mixture was stirred at 38 °C for 48 h. Subsequently,
H2O (5 mL) and CH2Cl2 (5 mL) were added, the phases were
separated and the aqueous phase was extracted with CH2Cl2
(2 × 5 mL). The combined organic phases were dried over
Na2SO4 and the solvent removed under reduced pressure.
Mesitylene (10 μL) was added to the crude product as an inter-
nal standard followed by CDCl3 (1 mL) to determine conversion
and yield by 1H-NMR. The crude product was afterwards
dissolved in CH2Cl2 (10 mL) and extracted with aqueous HCl
(3 × 5 mL, 1 M). The pH value of the combined aqueous
phases was adjusted to pH = 14 by addition of aqueous NaOH
(2 M) and the combined aqueous phases were extracted by
CH2Cl2 (3 × 10 mL). The combined organic phases were dried
over Na2SO4 and the solvent was removed under reduced pres-
sure to yield 13 as a colorless oil (88.7 μmol, 8.8 mg, 96%).
C6H13N, MW: 99.18 g mol−1. 1H-NMR (300 MHz, CDCl3): δ =
5.84–5.70 (m, 1H, CHCH2), 5.13–4.95 (m, 2H, CHCH2),
3.32–3.22 (m, 1H, NH2CH), 1.44–1.30 (m, 4H, CH2CH2CH3),
1.25 (bs, 2H, NH2), 0.91 (t, J = 7.1, 3H, CH2CH2CH3). The analyti-
cal data are in accordance with the literature.22 The enantio-
meric excess was determined by HPLC after tosyl protection of
13 (see the ESI†).
3 For efficient catalytic asymmetric rearrangements of
benzimidates, see e.g.: (a) Y. Donde and L. E. Overman,
J. Am. Chem. Soc., 1999, 121, 2933; (b) C. E. Anderson,
Y. Donde, C. J. Douglas and L. E. Overman, J. Org. Chem.,
2005, 70, 648; (c) J. Kang, T. H. Kim, K. H. Yew and
W. K. Lee, Tetrahedron: Asymmetry, 2003, 14, 415.
4 (a) L. E. Overman, J. Am. Chem. Soc., 1974, 96, 597; (b)
L. E. Overman, J. Am. Chem. Soc., 1976, 98, 290; (c) L. E. Overman,
Angew. Chem., Int. Ed. Engl., 1984, 23, 579.
5 (a) C. E. Anderson and L. E. Overman, J. Am. Chem. Soc.,
2003, 125, 12412; (b) S. F. Kirsch, L. E. Overman and
M. P. Watson, J. Org. Chem., 2004, 69, 8101; (c) H. Nomura
and C. J. Richards, Chem. – Eur. J., 2007, 13, 10216; (d)
M. D. Swift and A. Sutherland, Tetrahedron, 2008, 64, 9521.
6 (a) L. E. Overman, C. E. Owen, M. M. Pavan and
C. J. Richards, Org. Lett., 2003, 5, 1809; (b) R. S. Prasad,
C. E. Anderson, C. J. Richards and L. E. Overman,
Organometallics, 2005, 24, 77; (c) C. E. Anderson, Y. Donde,
C. J. Douglas and L. E. Overman, J. Org. Chem., 2005,
70, 648.
7 Monopalladacycles: (a) M. E. Weiss, D. F. Fischer, Z.-q. Xin,
S. Jautze, W. B. Schweizer and R. Peters, Angew. Chem., Int.
Ed., 2006, 45, 5694; (b) D. F. Fischer, Z.-q. Xin and R. Peters,
Angew. Chem., Int. Ed., 2007, 46, 7704; (c) Z.-q. Xin,
D. F. Fischer and R. Peters, Synlett, 2008, 1495; (d) D. F. Fischer,
A. Barakat, Z.-q. Xin, M. E. Weiss and R. Peters, Chem. – Eur. J.,
2009, 15, 8722; (e) R. Peters, Z.-q. Xin and F. Maier, Chem. –
Asian J., 2010, 5, 1770; ( f ) S. H. Eitel, M. Bauer,
D. Schweinfurth, N. Deibel, B. Sarkar, H. Kelm, H.-J. Krüger,
W. Frey and R. Peters, J. Am. Chem. Soc., 2012, 134, 4683.
8 Bispalladacycles: (a) S. Jautze, P. Seiler and R. Peters, Angew.
Chem., Int. Ed., 2007, 46, 1260; (b) S. Jautze, P. Seiler and
R. Peters, Chem. – Eur. J., 2008, 14, 1430; (c) T. Hellmuth,
S. Rieckhoff, M. Weiss, K. Dorst, W. Frey and R. Peters,
ACS Catal., 2014, 4, 1850.
9 Mixed pallada-/platinacycle: M. Weiss, W. Frey and R. Peters,
Organometallics, 2012, 31, 6365.
10 K. Tamura, H. Mizukami, K. Maeda, H. Watanabe and
K. Uneyama, J. Org. Chem., 1993, 58, 32.
11 The preparation of trichloroacetimidates required the use of
toxic trichloroacetonitrile.
12 We have recently also reported a practical asymmetric allyl
carbamate rearrangement for the enantioselective synthesis
of allylic amines: J. M. Bauer, W. Frey and R. Peters, Angew.
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Conclusions
In conclusion, we have identified two catalytic systems, which
are very efficient for the asymmetric rearrangement of allylic
non-halogenated acetimidates. This rearrangement type can
be conducted with a high level of generality and enantio-
selectivity. At elevated temperatures it is possible to perform
the title reaction using very low catalyst loadings without a
decrease of enantioselectivity or yield. Also difficult sub-
strates were found to be tolerated with a high level of effi-
ciency. This enabled, e.g., the formation of N-substituted qua-
ternary stereocenters making use of a trisubstituted olefin
moiety. Besides cleavage of the formed amide functions by
known chemical methods, the products now also offer the
option of enzymatic hydrolytic protocols for the access of
almost enantiopure allylic amines.
Acknowledgements
This work was financially supported by the Deutsche
Forschungsgemeinschaft (DFG, PE 818/4-1 & PE 818/6-1). The
Fonds der Chemischen Industrie (FCI) and the Carl-Zeiss-
Stiftung are acknowledged for PhD fellowships to J.M.B.
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