Chemo-, regio-, and enantioselective synthesis of allylic nitrones via rhodium-catalyzed addition of oximes to allenes

Article abstract of DOI:10.1039/c9cc03391b

The first chemo-, regio-, and enantioselective rhodium-catalyzed addition of oximes to allenes is reported. Using a Rh(i)/Josiphos catalyst system under mild conditions, the construction of allylic C-N bonds instead of C-O bonds was achieved. This method permits the atom-economic synthesis of branched allylic nitrones in good to quantitative yields with excellent enantioselectivities.

Full text of DOI:10.1039/c9cc03391b

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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DOI: 10.1039/C9CC03391B
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Chemo-, Regio-, and Enantioselective Synthesis of Allylic Nitrones
via Rhodium-Catalyzed Addition of Oximes to Allenes
Received 00th January 20xx,
Accepted 00th January 20xx
Yu-Hsuan Wang and Bernhard Breit*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: The first chemo-, regio-, and enantioselective rhodium-
Herein, we reported the first enantioselective
catalyzed addition of oximes to allenes is reported. Using Rh(I) intermolecular hydroamination of oximes to allenes using a
/Josiphos catalyst system under mild conditions, the construction of rhodium catalyst, producing versatile branched allylic nitrones
allylic C−N bonds instead of C−O bonds were achieved. This method (Scheme 1, lower part).
permits the atom-economic synthesis of branched allylic nitrones in
Previous work by Takemoto et al.:
good to quantitative yields and excellent enantioselectivities.
N
NOH
LG
Pd(PPh3)4
ZnEt2
Pd(COD)Cl2
Ar
O
Ar
N
O
R
+
R
R
Ar
Chiral nitrones are useful building blocks that can undergo
a variety of reactions and play an important role in the history
of cycloaddition reaction.1-3 The most important reaction is the
1,3-dipolar cycloaddition (1,3-DC), which was used for the
preparation of numerous synthetic targets and a diverse array
of heterocyclic compounds.4-8 Oximes are also attractive
synthetic reagents and have been widely used in both metal-
free and metal-involved chemistry since they are both nitrogen
and oxygen nucleophiles.9 Due to their potential applications,
we became interested in the development of a feasible
strategy employing oximes as selective nitrogen nucleophiles
for the addition to allenes to furnish chiral allylic nitrones as
versatile organic building blocks.10
This work:
NOH
Ar
R
[Rh]/Josiphos
acidic co-catalst
O
Highly chemo-, regio-,
and enantioselective
+
R
•
Ar
N
Ar
Ar
Scheme 1. Transition metal catalyzed addition of oximes
The initial reactions were conducted with benzophenone
oxime 1a (1.0 equiv.) and cyclohexylallene 2 (1.5 equiv.) as
model substrates (Table 1). In the presence of [Rh(COD)Cl]2
(2.5 mol%) and racemic ligand DCPB (L1, 10 mol%) in
nitromethane at 80°C, the desired product 3a was obtained in
87% yield by employing benzoic acid (entry 2, 20 mol%) as a
Brønsted acid cocatalyst. The effect of the acid cocatalyst on
reaction efficiency was enormous (compare entries 1 and 2).
Inspired by these results, various chiral bidentate diphosphine
ligands with different backbones were tested in this model
reaction containing Brønsted acid cocatalyst. While many
standard privileged chiral ligands led to poor results, a
promising enantioselectivity was obtained by employing the
chiral ferrocene based ligand L4 (entries 5 and 6). After
screening all the parameters of the reaction conditions, we
were pleased to find out that p-methoxybenzoic acid as
additive gave the desired allylic nitrone 3a in 96% yield with a
remarkable 92% ee (entry 6).
Over the past years, the metal-catalyzed enantioselective
reactions of oximes mostly provided access to oxime ethers
rather than N-functionalized nitrones.11-18 To the best of our
knowledge, rhodium-catalyzed asymmetric hydroamination of
oximes to allenes has not been investigated. In 2005,
Takemoto et al. reported
a palladium-catalyzed allylic
substitution of oximes, which depending on the reaction
medium provided access to either N- or O- allylation products.
(Scheme 1, upper part).19 Based on our previous results on
rhodium-catalyzed addition of pronucleophiles to allenes20 and
alkynes,10 we speculated that the addition of a hydroxylamines
to allenes in the presence of an appropriate rhodium catalyst
and acidic cocatalyst might give access towards synthetically
valuable branched allylic nitrones .
Table 1. Ligand screening and optimization of reaction
conditions
*Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse
21, 79104 Freiburg im Breisgau, Germany, E-mail: bernhard.breit@chemie.uni-
freiburg.de
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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[a] Isolated yield and the ee value was deterDmOinI:e1d0.b10y3Vc9ihe/wCir9aAClrtHiCclP0e3LO3Cn9.li1nBe
[b] 4 mmol scale reaction was carried out.
[Rh(COD)Cl]2 (2.5 mol%)
Ligand (10 mol%)
Additive (20 mol%)
Ph
NOH
O
+
Ph
N
Cy
•
MeCN (0.4 M), 80oC, 18 h

Ph
Ph
Cy
3a
The allenes with a cycloalkyl substituent containing five, six,
and seven membered rings were suitable substrates (3a–c).
Also, protected alcohols were tolerated in the reaction (3d–h).
Allenes bearing various functional groups, such as phenyl (2i),
phthalimide (2j), nitrile (2k), and thioethers (2l), reacted
1
2
, 1.5 equiv.
, 1.0 equiv.
0.2 mmol scale
O
O
O
PPh2
PPh2
t-Bu2P
PR2
2
O
H
Ph
P
R12P
Fe
Fe
Me
L3
SL-J688-2,
Me
PCy2
Cy2P
O
smoothly
with
good
to
excellent
yields
and
SL-J003-1, : R1 = Cy, R2 = Cy
SL-J009-1, : R1 = Cy, R2 = t-Bu
L1
L2
DCPB,
(S)-SegPhos,
L4
enantioselectivities. At this point, the assignment of the
absolute configuration was accomplished by an X-ray
crystallographic analysis of 3l. Furthermore, branched allylic
nitrone 3a was synthesized under scope conditions on gram
scale in 94% yield and 92% ee, which indicated the practicality
of this method.
L5
: R1 = Ph, R2 = Cy
, L6
SL-J001-1
Entry
Ligand
L1
Additive
Yield[a]
9
ee[b]
rac
rac
36
1
2
3
4
5
6
7
8
-
L1
PhCOOH
PhCOOH
PhCOOH
PhCOOH
87
43
8
L2
Next, we moved on to expand the scope with respect to
oxime derivatives, which can be easily obtained by a simple
condensation of ketones with hydroxylamine (Table 3).22 As
the electronegativity of the halogen in para-position
decreases, a significant increase in yield from 75% to 99% was
observed while maintaining high enantioselectivity (3m–o).
Further exploration of electronic effects showed that electron-
withdrawing and electron-donating groups in either meta or
para positions are well compatible with the reaction
conditions (3p–t). Even di-substituted benzophenone oximes
effectively furnished the corresponding products as well (3u
and 3v).
L3
78
L4
96
96
35
8
82
L4
p-OMeC6H4COOH
PhCOOH
92
L5
28
L6
PhCOOH
10
[a] Isolated yield of the branched product 3a. [b] The enantiomeric
excess of 3a was determined by chiral HPLC.
With the optimid conditions in hand, we first explored the
scope of terminal allenes, which were readily prepared in one
or two steps from either commercial or known starting
materials (Table 2).21
Table 3. Scope of the rhodium-catalyzed coupling of
cyclohexylallene with aryl oximes[a]
Table 2. Scope of the rhodium-catalyzed coupling of
[Rh(COD)Cl]2 (2.5 mol%)
benzophenone oxime with allenes[a]
Ar
L4
(10 mol%)
NOH
Ar
p-OMePhCOOH (20 mol%)
O
+
Ar
N
Cy
•
[Rh(COD)Cl]2 (2.5 mol%)
MeCN (0.4 M), 80oC, 18 h
Ar
Ph
L4
(10 mol%)
Cy
3m-v[a]
NOH
Ph
p-OMePhCOOH (20 mol%)
O
+
Ph
N
R
•
1m-v
2
, 1.5 equiv.
, 1.0 equiv.
Hal
0.2 mmol scale
MeCN (0.4 M), 80oC, 18 h
Ph
R
R
1
2a-l
3a-l[a]
, 1.0 equiv.
, 1.5 equiv.
Ph
0.2 mmol scale
R
Ph
Ph
O
Ph
O
O
O
N
Ph
N
Ph
N
Ph
N
R
O
O
N
O
Ph
PhO
N
N
Cy
3a[b]
Cp
3b
86% yield, 92%ee
Chp
3c
84% yield, 82%ee 77% yield, 90%ee
Hal
Cy
3m
Cy
R
Cy
3d
3p
3r
,
Hal = F:
75% yield, 89% ee
3n
,
R = CF3:
,
R = Me:
94% yield, 92%ee
69% yield, 85% ee
3q
77% yield, 90% ee
3s
1.20 gram
Hal = Cl:
84% yield, 84% ee
3o
,
R = NO2:
,
R = OMe:
,
85% yield, 90% ee
70% yield, 92% ee
Ph
Ph
Ph
Hal = Br:
,
O
O
O
99% yield, 89% ee
Ph
N
Ph
N
Ph
Ph
N
RO
RO
OMe
OMe
MeO
2
3
3
3e
3g
3i
R = Ph: , 62% yield, 90% ee R = Ph: , 99% yield, 85% ee
3f 3h
R = Bn: , 87% yield, 87% ee R = Bz: , 93% yield, 84% ee 93% yield, 81%ee
OMe
Bn
O
OMe
O
MeO
MeO
O
Bn
N
N
N
Ph
Ph
Ph
Cy
MeO
Cy
3u
83% yield, 87% ee
Cy
3v
80% yield, 90% ee
O
O
O
Ph
N
Ph
N
Ph
N
3t
75% yield, 91% ee
=
PhthN
NC
PhO2S
3
3
3
3j
3k
3l
X-Ray
91% yield, 85%ee 85% yield, 81% ee 86% yield, 78%ee
[a] Isolated yield and the ee value was determined by chiral HPLC.
2 | J. Name., 2012, 00, 1-3
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To explore the potential utility of this methodology for
synthesis, chiral allylic nitrone 3a was subjected to various
transformations (Scheme 2). Hydrogenation of 3a gave the
nitrone 4a in 4 h, whereas a prolonged reaction time (over-
night) afforded the hydroxylamine 4b by further addition of
hydrogen across the nitrone moiety. Addition of ethyl
magnesium chloride in the presence of 10 mol% ZnCl2 allowed
the 1,2-addition product 5. Nitrone 3a could be
chemoselectively reduced to hydroxylamine 6a with sodium
cyanoborohydride. Alternatively, deoxygenation led to the
imine 7a. Both 6a and 7a could be further reduced
chemoselectively to the corresponding secondary amines 6b
and 7b, respectively. Moreover, imine 7a can be hydrolysed to
the corresponding primary amine and protected as the
corresponding benzoate 7c.
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DOI: 10.1039/C9CC03391B
MeO2C
Ph
CO2Me
MeO2C
Ph
H
H
CO2Me
Ph
O
O
O
+
N
N
N
Ph
Ph
Ph
Cy
Cy
Cy
9a
9b
85% yield, 93%ee,
9b'
= 11:1
9b 9b'
90% yield, 92%ee
/
PhO2S
Ph
H
Ph(O)C
H
MeO2C CF3
Ph
Ph
Ph
Ph
O
O
O
N
N
N
Ph
Cy
Cy
9d
Cy
9e
9c
85% yield, 93%ee
84% yield, 92%ee
80% yield, 96%ee
[a] Scope conditions. [b] The ee values were determined by chiral
HPLC. [c] The regioselectivity was determined by 1H NMR analysis of
the crude reaction mixture.
Ph
Ph
Ph
Ph
(b)
(a)
(d)
(e)
OH
O
OH
H
Ph
N
Ph
N
Ph
Cy
6a
N
Ph
N
On the basis of these experiments and our previous
Cy
4b
Cy
4a
Cy
6b
investigations on allene chemistry,10,
the reaction
23-25
,
75% yield, 92% ee
80% yield, 93% ee
76% yield, 94% ee 70% yield, 94% ee
7b
mechanism can be proposed as depicted in Scheme 3.
Oxidative addition of benzoic acid to Rh(I) and
hydrometalation of allene forms Rh(III) π-allyl complex A (step
I). Then, exchange with benzophenone oxime, which is in
equilibrium with its nitrone tautomer,26-29 leads to an
equilibrium of π- and σ-allyl complexes B and B’ (step II).
Finally, reductive elimination of B and B’, which presumably
undergoes an intramolecular attack of the lone-pair of the
adjacent nitrogen, leads to the branched allylic nitrone
product along with regeneration of the rhodium catalyst (step
,
Ph
90% yield, 93% ee
O
Ph
N
Cy
3a
(d)
Ph
Ph
Ph
NHBz
OH
Ph
N
N
Et
Cy
(c)
(f)
(g)
Cy
7a
Cy
5
7c
60% yield, 92% ee
74% yield, 93% ee
68% yield, 94% ee
Scheme 2. Synthetic transformations of chiral allylic nitrones:
(a) Pd/C (10 mol%), H2 (1 atm), PhMe, r.t., 4 h. (b) Pd/C (10
mol%), H2 (1 atm), PhMe, r.t., overnight. (c) EtMgCl (1.3
equiv.), ZnCl2 (10 mol%), THF, r.t., 2 h. (d) NaBH3CN (1 equiv.),
2N HCl (2 equiv.), MeOH, 0 ℃, 20 min. (e) Zn (5 equiv.), 2N HCl,
reflux, 1 h. (f) TiCl4 (7 equiv.), LiAlH4 (5 equiv.), NEt3 (45 equiv.),
THF, 30 min. (g) 2N HCl, Et2O, r.t., overnight; then NEt3 (4
equiv.), benzoyl chloride (1.5 equiv.), DCM, r.t., overnight.
III).
Ph
O
Ph
N
R
HA +
R
•
[Rh]I
N
III
I
Ph
Ph
Ph
O
A
[Rh]III
O
N
III
III
[Rh]
Ph
R
[Rh]
R
Inspired by these synthetic possibilities, the one-pot
synthesis of rhodium-catalyzed hydroamination of oximes
towards allylic nitrones, followed by 1,3-dipolar cycloaddition
reaction, was conducted (Table 4). The reaction proceeded
smoothly employing alkyne 8 containing electron withdrawing
group to furnish isoxazoline 9 in good yield and excellent
enantiomeric excess (9a-e).
R
B
B'
II
A
HA
OH
Ph
H
O
N
N
Ph
Ph
Ph
Scheme 3. Proposed catalytic cycle for the Rh-catalyzed
addition of benzophenone oxime to allene.
Table 4. Scope of one-pot synthesis via 1,3-dipolar
cycloaddition reaction.[a]
To conclude, we have developed the first chemo-, regio-,
and enantioselective coupling of benzophenone oximes with
allenes via a rhodium/Josiphos catalyst system to afford
branched allylic nitrones in good to excellent yields and
excellent enantioselectivities. The protocol was found to be
applicable to a broad range of substituted benzophenone
oximes and functionalized allenes. A subsequent 1,3-dipolar
cycloaddition could generate N-allylated chiral isoxazoles,
demonstrating the potential for N-allylated chiral heterocycles.
Further mechanistic studies and exploration of the synthetic
R1
R2
R1
R2
[Rh]
NOH
Ph
Ph
Ph
8,
1.2 equiv.
O
+
Cy
•
N
1h, 80 o
C
Ph
Cy
1
2
9
, 1.0 equiv.
, 1.5 equiv.
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potential of N-allylated chiral nitrones are being pursued in our 21. For syntheses of allenes employed in this work see the
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DOI: 10.1039/C9CC03391B
laboratory.
Supporting Information.
22. For syntheses of oxime derivatives employed in this work see
the Supporting Information.
23. C. Li, M. Kähny and B. Breit, Angew. Chem., 2014, 126,
14000-14004.
24. K. Xu, N. Thieme and B. Breit, Angew. Chem., 2014, 126,
7396-7399.
25. U. Gellrich, A. Meißner, A. Steffani, M. Kähny, H.-J. Drexler, D.
Heller, D. A. Plattner and B. Breit, J. Am. Chem. Soc., 2014,
136, 1097-1104.
Acknowledgements
This work was supported by the DFG and the Fonds of the
Chemical Industry. We thank Umicore, BASF and Wacker for
generous gifts of chemicals, Dr. Daniel Kratzert for X-ray crystal
structure analysis, Dr. Manfred Keller for NMR analysis.
26. R. Grigg, H. Q. N. Gunaratne and J. Kemp, J. Chem. Soc.,
Perkin Trans. 1, 1984, 41-46.
Conflicts of interest
There are no conflicts to declare.
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Jones, J. Chem. Soc., Perkin Trans. 1, 1984, 47-57.
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2016, 6, 22161-22173.
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Scheme for Table of Contents
Ar
[Rh]/Josiphos
NOH
Ar
p-OMePhCOOH
PCy2
Me
O
Cy2P
Ar
N
Fe
+
R
•
Ar
MeCN, 80oC, 18 h
R
22 examples
up to 99% yield
up to 92% ee
Josiphos SL-J003-1
5. K. V. Gothelf and K. A. Jørgensen, Chem. Rev., 1998, 98, 863-
910.
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4 | J. Name., 2012, 00, 1-3
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