Rhodium(III)-Catalyzed Enantiotopic C?H Activation Enables Access to P-Chiral Cyclic Phosphinamides

Article abstract of DOI:10.1002/anie.201606637

Compounds with stereogenic phosphorus atoms are frequently used as ligands for transition-metal as well as organocatalysts. A direct catalytic enantioselective method for the synthesis of P-chiral compounds from easily accessible diaryl phosphinamides is presented. The use of rhodium(III) complexes equipped with a suitable atropochiral cyclopentadienyl ligand is shown to enable an enantiodetermining C?H activation step. Upon trapping with alkynes, a broad variety of cyclic phosphinamides with a stereogenic phosphorus(V) atom are formed in high yields and enantioselectivities. Moreover, these can be reduced enantiospecifically to P-chiral phosphorus(III) compounds.

Full text of DOI:10.1002/anie.201606637

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Communications
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International Edition: DOI: 10.1002/anie.201606637
German Edition: DOI: 10.1002/ange.201606637
Chiral Cp Ligands
À
Rhodium(III)-Catalyzed Enantiotopic C H Activation Enables Access
to P-Chiral Cyclic Phosphinamides
Yang Sun and Nicolai Cramer*
Abstract: Compounds with stereogenic phosphorus atoms are
frequently used as ligands for transition-metal as well as
organocatalysts. A direct catalytic enantioselective method for
the synthesis of P-chiral compounds from easily accessible
diaryl phosphinamides is presented. The use of rhodium(III)
complexes equipped with a suitable atropochiral cyclopenta-
À
dienyl ligand is shown to enable an enantiodetermining C H
activation step. Upon trapping with alkynes, a broad variety of
cyclic phosphinamides with a stereogenic phosphorus(V) atom
are formed in high yields and enantioselectivities. Moreover,
these can be reduced enantiospecifically to P-chiral
phosphorus(III) compounds.
C
hiral phosphorus compounds are tightly linked to many
major developments in homogeneous enantioselective catal-
ysis. PIII compounds are used as ligands in transition-metal
catalysis and as organocatalysts,[1] and PV compounds as Lewis
bases[2] and Brønsted acid catalysts.[3] Largely, the chirality is
located in their respective backbones (chiral axis, stereogenic
carbon center) instead of being caused by a stereogenic
phosphorus atom. One might expect a better transfer of
chirality during the transformation by a stereogenic phos-
phorus atom because of its closer proximity to the catalytic
center. Although P-stereogenic ligands were proven very
efficient[4] and stereochemically stable,[5] their relatively low
number reflects difficulties in their synthesis.[6] Methods for
their preparation comprise the formation and separation of
diastereomeric mixtures, as well as other resolution tech-
niques.[7] More-recent approaches involve desymmetrization
reactions and catalytic asymmetric methods.[8] However,
these are often limited in their scope, and additional methods
enabling access to different substitution patterns would be of
high synthetic value.
À
Scheme 1. Enantioselective C H activation of diaryl phosphinamides
enables access to P-chiral heterocycles 4.
p-unsaturation,[12c–f,i–q] insertions of diazo esters,[12g] or the
generation of axial chirality by locking the conformation[12h,r]
(Scheme 1). To the best of our knowledge, in contrast to
II [8h,13]
À
asymmetric C H functionalizations catalyzed by Pd ,
Pd0,[8e–g,14] or IrI,[15] no example in which the C H activation
À
step is enantiodetermining has been reported for RhIII
catalysis. If the two difficulties of this step—enantioselection
and reversibility—could be addressed, such sequence would
offer great advantages. The intermediate would allow product
diversification using different downstream trapping agents.
Ideally, the selectivity would be independent of the used
trapping agent, enabling access to a broad variety of attractive
products.
À
The creation of P-stereogenic centers by C H function-
alization remains underdeveloped. So far, Pd0-catalyzed
processes comprising intramolecular cyclizations with
À
Catalytic C H functionalization has become a powerful
strategy to access building blocks from simple starting
materials.[9,10] In particular, Cp*RhIII complexes were found
to enable a myriad of directed arene functionalizations.[11]
Recently, chiral cyclopentadienyl ligands allowed the devel-
opment of several asymmetric variants.[12] However, in any
reported case, the enantiodetermining step proceeds after the
appended aryl halides were reported.[8e–g] Chang et al. dis-
III
À
closed a moderately enantioselective Ir -catalyzed C H
amidation,[8i] and Han et al. showed a highly selective PdII-
À
catalyzed C H arylation of phosphinamides with aryl boronic
acids.[8h] Because of their ability to act as directing groups for
À
À
Csp2 H activation step, consisting of selective additions across
C H functionalizations[16] as well as because of their synthetic
utility, phosphinamides 1 represent a valuable substrate class
for our envisioned enantioselective RhIII process. Herein, we
report a highly enantioselective access to cyclic phosphin-
amides 4 possessing a chiral phosphorus(V) atom.
[*] Y. Sun, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA, BCH 4305
We initially explored this transformation using diphenyl-
phosphinamide 1a and diphenylacetylene (5a; Table 1).
Several members of our atropochiral Cpx ligands were
tested and afforded the desired cyclic phosphinamide 4aa
(entries 1–6). The best enantioselectivities were obtained with
1015 Lausanne (Switzerland)
E-mail: nicolai.cramer@epfl.ch
Homepage: http://isic.epfl.ch/lcsa
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201606637.
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[a]
Table 2: Evaluation of the nitrogen substituent.[a]
À
Table 1: Optimization of the enantiotopic C H activation.
Entry 4xa
Ar
% Conversion[b] % Yield[b] e.r.[c]
1
2
3
4
5
6
7
8
4ba Ph
63
59
50
75
30
26
55
34
72
17
53
52
85
93:7
93:7
4ca
4-CF3-C6H4
4da 4-CN-C6H4
92.5:7.5
91:9
90:10
88:12
94:6
4ea
4 fa
4-NO2-C6H4
2,6-F-C6H3
Entry Changes from optimal
conditions
% Conversion[b] % Yield[b] e.r.[c]
4ga C6F5
4ha 3,5-F-C6H3
4aa 3,5-CF3-C6H3 100
100
87
1
2
3
4
5
none
100
85
56
75
54
72
34
85
70
44
65
44
72
26
40
78
50
15
30
74
29
10
47
95:5
95:5
91:9
84:16
93.5:6.5
93:7
76:24
89:11
95:5
95:5
Rh2 instead of Rh1
Rh3 instead of Rh1
Rh4 instead of Rh1
Rh5 instead of Rh1
Rh6 instead of Rh1
without K2CO3
[a] Conditions: 0.05 mmol 4x, 0.075 mmol 5a, 1.00 mmol Rh1, 1.00 mmol
(PhCO2)2, 0.1 mmol Ag2CO3, 0.05 mmol K2CO3, 0.25m in tBuOH, 908C
for 16 h. [b] Yields determined through NMR spectroscopy with internal
standard. [c] Determined by chiral HPLC.
6
7
8
KH2PO4 instead of K2CO3 61
and a clean reaction, while giving as well the best enantio-
selectivity (entry 8).
Next, the scope of the cyclization was investigated
(Scheme 2). Irrespective of the substituent of the aryl group
of the phosphinamide substrate 1x, constantly high levels of
9
K3PO4 instead of K2CO3
94
70
10
11
12
13
14
15
16
KOtBu instead of K2CO3
CuCO3 instead of Ag2CO3 40
AgOAc instead of Ag2CO3 48
92.5:7.5
83:17
89:11
93:7
92:8
90:10
92.5:7.5
in DCE
94
39
30
63
in toluene
in MeCN
in dioxane
[a] Conditions: 0.05 mmol 1a, 0.075 mmol of 5a, 1.00 mmol Rh1,
1.00 mmol (PhCO2)2, 0.1 mmol Ag2CO3, 0.05 mmol K2CO3, 0.25m in
tBuOH, 908C for 16 h. [b] Yields determined through NMR spectroscopy
with internal standard. [c] Determined by chiral HPLC.
the parent ligand Rh1 (R = OMe) and its slightly bulkier
congener Rh2 (R = OiPr). Other Cp substituents provided
reduced selectivities. In addition, larger ligands displayed
reduced reactivity. Being more easily accessible, Rh1 was
chosen for all further studies. Next, the relevance of the
inorganic base was evaluated. Its omission caused a very large
drop in reactivity (34% conversion) and a poor enantiose-
lectivity of 76:24 (entry 7). Other bases like KH2PO4, K3PO4
and tBuOK were inferior to K2CO3 (entries 8–10). Solely
potassium phosphate gave a similar enantioselectivity, but
a
slightly reduced reactivity. Among several oxidants
screened, silver carbonate proved to be the reagent of
choice (entries 11 and 12). The transformation can be
conducted in dichloroethane (DCE) as alternative solvent
with a minor reduction in yield and selectivity (entry 13).
Other solvents such as toluene, acetonitrile, or dioxane
caused a strong reduction in conversion, yield, and selectivity
(entries 14–16).
With the optimized conditions, the steric and electronic
influence of the aryl substituent on the nitrogen atom of the
phosphinamide substrate was investigated (Table 2). A sub-
strate with a simple phenyl group largely reduced the
conversion and the yield of product 4 (entry 1). Strongly
electron-withdrawing groups in the para-position provided
enhanced reactivity (entries 2–4), whereas steric hindrance in
the ortho-positions (entry 5) is detrimental. Overall, the 3,5-
bis(trifluoromethyl)phenyl group provided a high reactivity
Scheme 2. Scope for the enantioselective phosphinamide cyclization:
0.1 mmol 1x, 0.15 mmol 5y, 5.00 mmol Rh1, 5.00 mmol (PhCO2)2,
0.2 mmol Ag2CO3, 0.1 mmol K2CO3, 0.25 m in tBuOH, 908C for 16 h;
yields of isolated products; e.r. determined by chiral HPLC; PMP: p-
methoxyphenyl; Ar=3,5-bis(trifluoromethyl)phenyl. [a]>20:1 regiose-
lectivity. [b] with 10.0 mmol Rh1 and (PhCO2)2. [c] 18:1 regioselectivity.
2
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enantioselectivity were obtained. Few substrates have sol-
As PIII-chiral compounds play an important role as ligands
ubility issues (e.g. 1l), causing a reduction in yield (4la).
Concerning the alkyne acceptors, diaryl alkynes with elec-
tron-rich aryl substituents displayed higher reactivity than the
ones with more electron-poor aryl groups. As an example for
a dialkyl alkyne, 3-octyne provided the corresponding prod-
uct 4ad in 96:4 e.r. An electronically differentially substituted
diaryl alkyne (5e) resulted in the formation of 4ae and 4ae’
(with the same enantioselectivity) in a 1.8:1 ratio, which
indicates favoring a placement of the electron-poor portion
adjacent to the nitrogen atom. Notably, unsymmetrical
alkynes reacted with outstanding regioselectivities > 20:1.
We found a large difference in the regioselectivities achiev-
able with Rh1 compared to the standard Cp*RhIII catalyst
that is used to prepare the racemic samples. Most often only
one single regioisomer (having the aryl group adjacent to the
nitrogen atom) could be detected for Rh1. In contrast, the
selectivity for transformations with the Cp* ligand was poor
to modest, ranging from 1.2:1 to 5:1 (mostly around 2:1). This
showcases the great importance of tailored ligands not only
for enantioselectivity challenges but also for regioisomeric
issues.[17] The absolute configuration of the products 4 was
unambiguously established by X-ray crystallographic analysis
of 4ka to be (R) (see the Supporting Information).[18]
for enantioselective transition-metal catalysis, a stereospecific
reduction of 4aa was performed (Scheme 4).[19] This substrate
class proved to be prone towards racemization during the
reaction. However, under carefully chosen conditions high
levels of enantiospecificity (es) were obtained. A combination
of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and HSiCl3
gave diaryl aminophosphane 6 in good yields in 97% es
with retention of the configuration.
Scheme 4. Enantiospecific reduction of 4aa with retention of configu-
ration; Ar=3,5-bis(trifluoromethyl)phenyl.
In conclusion, we have reported a chiral enantioselective
synthesis of cyclic phosphinamides with
a stereogenic
phosphorus(V) atom catalyzed by a CpxRhIII complex. The
transformation relies on an enantiodetermining cyclometala-
tion. The added base minimizes the reversibility of the
cyclometalation step ensuring high enantiomeric ratios of the
cyclic phosphinamides. The products can be reduced enantio-
specifically to PIII-chiral compounds, making this method
attractive to access P-chiral phosphine ligands.
For some insights into the mechanism, in particular of the
enantiodetermining steps, deuteration experiments were
performed (Scheme 3). First, 1a was exposed to the reaction
conditions in tBuOD without the alkyne. A higher deutera-
tion degree of 1a was observed without K2CO3 (53% vs.
12%). This suggests that K2CO3 reduces the reversibility of
À
the C H activation. Conducting similar experiments in the
presence of diphenylacetylene (5a) confirmed the signifi-
cantly lower deuterations of 1a in the presence of K2CO3. In
agreement with the optimization studies, the mitigated
reversibility of the enantiodetermining steps is essential for
high enantioselectivity. Moreover, no deuterated product 4aa
was found, indicating that the free NH group of 1a is required
Acknowledgements
This work was supported by the European Research Council
(ERC Grant 257891) and the Swiss National Science Foun-
dation (Consolidator Grant 157741). We thank Dr. R.
Scopelliti for X-ray crystallographic analysis of compound
4ka.
À
as directing group for the C H activation with this catalyst
system.
À
Keywords: asymmetric catalysis · C H activation ·
chiral Cp ligands · P-chirality · rhodium
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Received: July 11, 2016
Revised: August 5, 2016
Published online: && &&, &&&&
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Chiral Cp Ligands
Y. Sun, N. Cramer*
&&&& — &&&&
Rhodium(III)-Catalyzed Enantiotopic
À
C H Activation Enables Access to P-
Chiral Cyclic Phosphinamides
A broad variety of cyclic phosphinamides
with a stereogenic phosphorus(V) atom
could be obtained in high enantioselec-
tivities from easily accessible diaryl
phosphinamides using rhodium(III)
complexes equipped with an atropochiral
cyclopentadienyl ligand. The transforma-
tion builds upon an enantiodetermining
À
C H activation step.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!