Cooperative Effects between Chiral Cpx–Iridium(III) Catalysts and Chiral Carboxylic Acids in Enantioselective C?H Amidations of Phosphine Oxides

Article abstract of DOI:10.1002/anie.201708440

An enantioselective C?H amidation of phosphine oxides by using an iridium(III) catalyst bearing an atropchiral cyclopentadienyl (Cp^x) ligand is reported. A very strong cooperative effect between the chiral Cp^x ligand and a phthaloyl tert-leucine enabled the transformation. Matched–mismatched cases of the different acid enantiomers are shown. The amidated P-chiral arylphosphine oxides are formed in yields of up to 95 % and with excellent enantioselectivities of up to 99:1 er. Enantiospecific reduction provides access to valuable P-chiral phosphorus(III) compounds.

Full text of DOI:10.1002/anie.201708440

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Accepted Article
Title: Cooperative Effects between Chiral CpxIrIII Catalysts and
Chiral Carboxylic Acids in Enantioselective C-H Amidations of
Phosphine Oxides
Authors: Nicolai Cramer, Yun-Suk Jang, and Michael Dieckmann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708440
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10.1002/anie.201708440
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Cooperative Effects between Chiral CpxIrIII Catalysts and Chiral
Carboxylic Acids in Enantioselective C-H Amidations of
Phosphine Oxides
Yun-Suk Jang,[a] Michael Dieckmann[a] and Nicolai Cramer*[a]
14]
Abstract: An enantioselective C-H amidation of phosphine oxides
by using an iridium(III) catalyst bearing an atropchiral
cyclopentadienyl (Cpx) ligand is reported. A very strong cooperative
effect between the chiral Cpx ligand and a phthaloyl tert-leucine
enabled the transformation. Matched-mismatched cases of the
different acid enantiomers are shown. The amidated P-chiral
arylphosphine oxides are formed in yields of up to 95 % and with
excellent enantioselectivities of up to 99:1 er. Enantiospecific
reduction provides access to valuable P-chiral phosphorus(III)
compounds.
functionalizations.[9f,
For related CpxIrIII complexes only an
enantioselective cycloisomerization was reported,[15] leaving a
large untapped potential. Herein, we report a highly selective C-
H amidation of phosphine oxides 1 with azides 2 to provide
access to P-chiral compounds 3 (Scheme 1).
Organophosphorus compounds are a ubiquitous and critically
important class of molecules with widespread applications in
many fields. For instance, chiral phosphorus(III) compounds are
Scheme 1. Enantioselective C–H amidations enabled by a cooperative effect
2]
cornerstone of asymmetric catalysis[1,
Phosphorus(V)
of a chiral CpxIrIII / chiral carboxylic acid pair.
a
compounds have been used as Lewis bases[3] or Bronsted
acids.[4] P-Stereogenic molecules having
stereogenic
a
phosphorus atom are of great interest.[5] Enantiomerically pure
P-chiral compounds were traditionally obtained through different
auxiliary[6] and resolution based methods.[7] More recently,
catalytic asymmetric methods have been devised.[8] However,
these often suffer from scope limitations, harsh conditions and
other shortcomings. The development of efficient catalytic
enantioselective procedure leading to chiral P-chiral compounds
Chang’s proposed catalytic cycle for the IrIII-catalyzed C-H
amidation allows identification of key controlling parameters for
the design of an enantioselective transformation (Scheme 2).[10j]
Initially, dicationic iridium complex I is obtained by iodide
abstraction from dimeric (IrCpXI2)2 complex with AgNTf2. In the
presence of carboxylic acids, I is in equilibrium with its related
monocationic species II bearing one carboxylate group.
Subsequent coordination to the Lewis-basic carbonyl group of
the phosphine oxide substrate gives species III. A rate-limiting
and enantiodetermining cyclometalation presumably operating
by concerted metalation deprotonation (CMD) mechanism[16, 17]
yields iridacycle IV possessing now a stereogenic center at the
phosphorus atom. Subsequent coordination of azide (V),
followed by migratory insertion proceeding with expulsion of
nitrogen, delivers species VI. Finally protodemetalation releases
amidated product 3 and regenerates catalyst II. Since both the
CpX ligand and the carboxylic acid are coordinated to the iridium
metal at intermediate III, we hypothesized that a synergistic
effect between the two chirality sources could enhance the
transmission of the chiral information onto the substrate.
is
a
highly desirable goal and enantioselective C-H
functionalizations of phosphorous-containing substrates offer
vast opportunities.[9] For example Chang’s achiral Cp*IrIII-
catalyzed C-H amidations[10] result in functionalized molecules
that could be elaborated further into valuable P,N-ligands.
However, catalytic-enantioselective iridium-catalyzed C-H
amidations are an unsolved challenge.[11] Chang et al. reported
an asymmetric amidation with the achiral Cp*IrIII complex in
conjunction with a tartaric acid additive, resulting in low
enantioselectivities with a maximum of 32 % ee on two
substrates.[10j] Recently, atropchiral cyclopentadienyl (CpX)
ligands[12] have proven highly valuable in asymmetric catalysis,
especially for ruthenium[13] and rhodiumIII-catalyzed C-H
[a]
Y.-S. Jang, Dr. M. Dieckmann†, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA, BCH 4305
CH-1015 Lausanne (Switzerland)
E-mail: nicolai.cramer@epfl.ch
Homepage: http://isic.epfl.ch/lcsa
[†]
Current address: Syngenta Crop Protection AG,
Schaffhauserstr., CH-4332 Stein, Switzerland
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201708440
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COMMUNICATION
Entry
1[c]
2[c]
3[c]
4[d]
5
Ir
Solvent
DCE
DCE
dioxane
tAmOH
S1
Additive
PivOH
(S)-A1
(S)-A1
(S)-A1
(S)-A1
rac-A1
(S)-A1
-
T [°C] Yield [%][b]
er
64.5:35.5
83:17
87.5:12.5
95:5
98
40
Ir1
Ir1
Ir1
Ir1
Ir1
Ir1
-
72
23
89
23
36
10
83[e]
96:4
0
53
0
93.5:6.5
n.a.
6
S1
0
0
0
0
0
0
0
0
0
0
0
Scheme 2. Catalytic cycle for the asymmetric IrIII C-H amidation.
7
S1
0
n.a.
8
Ir1
Ir1
Ir1
[Cp*IrI2]2
Ir2
Ir3
Ir4
Ir5
Ir6
S1
The enantioselective C-H amidation was initially investigated
with diphenyl cyclohexyl phosphine oxide (1a) and tosyl azide
(2a) (Table 1). Iridium catalyst Ir1 provided in conjunction with
no
AgNTf2
0
n.a.
9
S1
PivOH
(S)-A1
(S)-A1
(S)-A1
(S)-A1
(S)-A1
(S)-A1
19
3
65:35
52:48
94.5:5.5
92:8
10
11
12
13
14
15
16
S1
pivalic acid product 3aa in 98
% yield and a modest
enantioselectivity of 64.5:35.5 er (entry 1). Switching to chiral
carboxylic acid (S)-A1 (vide infra for a detailed study of the
carboxylic acid effect on this transformation) and lowering the
reaction temperature to 23 °C increased gave 3aa in 83:17 er
(entry 2). The selectivity was further improved in dioxane (entry
3). tert-Amyl alcohol as a solvent afforded product 3aa in 95:5 er,
albeit with sluggish reactivity due to poor solubility of the iridium
catalyst (entry 4). A tert-amyl alcohol dioxane mixture solved this
problem, providing 3aa in 83 % yield and 96:4 er at a reaction
temperature of 0 °C (entry 5). Using rac-A1 gave 93.5:6.5 er
with a reduced conversion and yield (entry 6). Control runs
confirmed that the iridium catalyst, AgNTf2 and the carboxylic
acid are essential for the transformation (entries 7-9).
Rechecking pivalic acid with the otherwise optimized conditions
resulted in a low yield and 65:35 er (entry 10) confirming the
critical importance of chiral acid (S)-A1. Using (S)-A1 with
achiral Cp*IrIII catalyst resulted in very poor yield of 3aa and
marginal enantioselectivity (entry 11), underlining once more the
synergistic effect between the chiral acid and the chiral Cpx
ligand. Several additional Cpx ligands were evaluated.
Increasing the size of the substituents R (OiPr, OiPent, OPh)
S1
37
9
S1
S1
33
10
0
95:5
S1
56:44
n.a.
S1
S1
[a] Conditions: 50.0 μmol 1a, 55.0 μmol 2a, 1.00 μmol Ir, 4.25 μmol AgNTf2,
12.0 μmol R*CO2H, 36 h, 0.1ꢀM; [b] NMR yield with internal standard; [c] 18
h; [d] 24 h. [e] twice the scale and isolated yield. S1 = tAmOH / dioxane 4:1
We undertook
a study to investigate the cooperative
interaction[18] of the chiral Cpx-metal complex and the chiral
carboxylic acid additive[19] in greater detail (Scheme 3). The
chiral acid additive is an additional and simple handle to tweak
yield and selectivity with a small set of chiral Cpx ligands. tert-
Leucine derived acid [(S)-A1] performed better in all parameters
than any other chiral carboxylic acids tested. The opposite
enantiomer (R)-A1 was not only dramatically less reactive (15 %
caused
a decrease in yield, while the enantioselectivity
vs 80
% yield), but resulted in a significantly eroded
remained high (entries 12-14). Benzyl (Ir5) and phenyl
substituted ligand (Ir6) were neither active nor selective (entries
15-16).
enantioselectivity (60:40 er vs 96:4 er). This was evidence for a
strong matched-mismatched effect between the Cpx ligand and
the acid. The S-enantiomers of phthaloyl-protected acids,
derived from phenyl alanine (A2) or valine (A3), were inferior to
A1, but still provided product 3aa in 50 % yield and 92:8 er.
Again, the R-enantiomers were much less reactive and selective.
The phthaloyl protecting group displayed a very pronounced
influence on the reactivity. Any replacement, by closely related
congeners [(S)-A4, (S)-A5, (S)-A6, (S)-A7] dramatically reduced
Table 1. Optimization of the conditions for the asymmetric C-H amidation.[a]
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10.1002/anie.201708440
Angewandte Chemie International Edition
COMMUNICATION
the conversion and yield, while the selectivity remained relatively
stable at high levels. In comparison, a selection of other chiral
carboxylic acids (A8-A10) was not suitable at all. With the
countless number of commercial carboxylic acids in addition to
the ones obtainable in a single step from amino acids, one
should be able to identify even better performing examples in
the future.
para-position (entries 2, 5-8). The enantioselectivities are
independent of R1, with a narrow range from 96:4 to 98.5:1.5 er.
Substrates with electron-rich arenes were more reactive than
electron-poor ones. meta-Substituted arenes reacted selectively
with the sterically less hindered ortho-C-H group (entries 3 and
6). The reaction is sensitive to bulk in the ortho-position and no
reaction occurred with o-methyl bearing 1e (entry 4). This fact
was in agreement with the lack of any double amidation
products. R2 was found to have a significant influence on the
reactivity and the selectivity. Small groups like methyl cause a
sluggish and modestly selective amidation (entry 9). Increased
steric demand R2= iPr, Cy, tBu, Ad (entries 11, 1, 12-13) steeply
improve reaction performance, giving products 3 in good yields
and excellent enantioselectivity of up to 98.5:1.5 er. Notably, the
most valuable substrates for envisioned product applications (P-
chiral phosphine ligands or Lewis bases) have exactly such
sterically demanding groups R2. In addition, phosphine amides
were found to be suitable substrates, delivering enantioenriched
products 3ra and 3qa in good yields albeit with a slightly
reduced enantioselectivity (entries 16-17). Finally, different
sulfonyl azides were shown to be competent (entries 18-26).
Almost no change in reactivity and selectivity was found. The
readily cleavable o-nosyl group can be introduced with ease
(entry 18). With a slightly less reactive substrate like 1i, para-
methoxy sulfonyl azide as most electron-rich congener was the
best performer giving 3ie in 75 % yield and 98:2 er (entry 25). X-
ray crystallographic analysis of 3aa unveiled that the absolute
configuration of the products was (R).[20]
Table 2. Scope for the enantioselective phosphine oxide amidation.[a]
Entry 3xy
R1
R2
R3
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
% Yield[b] er
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Me
Bn
1
3ba
3ca
3da
3ea
3fa
H
95
87
72
0
98.5:1.5
2
p-Me
m-Me
o-Me
p-MeO
m-MeO
p-NMe2
p-Cl
97.5:2.5
96:4
3
4
n.a.
5
76
79
80
75
12
39
43
55
68
27
97.5:2.5
97:3
6
3ga
3ha
3ia
7
98:2
8[c]
9
97:3
3ja
H
70:30
10
3ka
H
88.5:11.5
95.5:4.5
97.5:2.5
93.5:6.5
92:8
11[c] 3la
H
Scheme 3. Matched and mismatched effects of the chiral carboxylic acid
additive on the reactivity and selectivity of the C-H amidation.
iPr
Cy
12
13
14
3ma
p-OMe
p-Me
p-Cl
Cy
3na
3oa
Next, the scope of the transformation was explored (Table 2).
It proceeded well with substrates bearing substituents in the
Cy
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10.1002/anie.201708440
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COMMUNICATION
Acknowledgements
Ad
N(iPr)2
N(CH2)5
tBu
Ts
15
16
17
18
19
3pa
3qa
3ra
H
91
60
74
92
85
85
90
81
42
61
72
43
98:2
84.5:15.5
78.5:21.5
98:2
Ts
Ts
H
This work is supported by the Swiss National Science
Foundation (no 157741). We thank Dr. R. Scopelliti and Dr. F.
Fadaei Tirani for X-ray crystallographic analysis of compound
3aa.
H
o-Ns
3bb
3bc
H
tBu
p-Ns
H
98:2
Keywords: Asymmetric Catalysis • C‒H Activation • Iridium •
Chiral Cp Ligand • P-Chirality
20[c] 3bd
H
99:1
tBu
p-Cl-C6H4SO2
p-MeO-C6H4SO2
Ms
tBu
21
22
3be
3bf
H
98.5:1.5
98:2
[1]
Phosphorus(III) Ligands in Homogeneous Catalysis: Design and
Synthesis, (Eds.: P. C. J. Kamer, P. W. N. M. v. Leeuwen), Wiley,
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tBu
H
23[c] 3ib
24[c] 3id
25[c] 3ie
26[c] 3if
p-Cl
p-Cl
p-Cl
p-Cl
97:3
tBu
o-Ns
[2]
[3]
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98:2
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95:5
[5]
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AgNTf2, 24.0ꢀµmol (S)-A1, 0.1 M in tAmOH/dioxane (4:1), 0 °C for 36 h; [b]
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[7]
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yield with a preservation of the enantiomeric purity (Scheme 4).
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followed by treatment with MeOTf and LiAlH4 gave P-chiral
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Scheme 4. o-Nosyl-deprotection of 3bb and enantiospecific reduction of 3ba.
In summary, we have developed a highly enantioselective C-H
amidation of phosphine oxides showcasing the potential of our
chiral Cpx ligand for iridium(III) catalyzed C-H functionalizations.
A very strong cooperative effect between the chiral Cpx ligand
and the readily available phthaloyl tert-leucine enabled this
transformation. We have shown that matched-mismatched
cases of the different acid enantiomers can dramatically
enhance yield and selectivity. Enantiospecific reduction provides
access to valuable P-chiral phosphines for potential application
as ligands and catalysts.
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10.1002/anie.201708440
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Yun-Suk Jang, Michael Dieckmann and
Nicolai Cramer*
Page No. – Page No.
Cooperative Effects between Chiral
CpxIrIII Catalysts and Chiral Carboxylic
Acids in Enantioselective C-H
A cooperative effect between a chiral CpxIrIII complex and chiral carboxylic acid
enables highly enantioselective C-H amidations of phosphine oxides with up to 99:1
er. Matched-mismatched pairs have a dramatic influence on the reactivity and the
selectivity.
Amidations of Phosphine Oxides
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