Angewandte
Chemie
CÀH Activation
À
Palladium-Catalyzed Enantioselective C H Arylation for the Synthesis
of P-Stereogenic Compounds**
Zi-Qi Lin, Wei-Zhen Wang, Shao-Bai Yan, and Wei-Liang Duan*
Abstract: A palladium-catalyzed enantioselective CÀH aryla-
tion of N-(o-bromoaryl)-diarylphosphinic amides is described
for the synthesis of phosphorus compounds bearing a P-
stereogenic center. The method provides good enantioselectiv-
ities and high yields. The products were readily transformed
into P-chiral biphenyl monophosphine ligands.
lecular arylation or cyclization reactions using either chiral
[9d,j,m,p]
[9i,l,u]
phosphines
or N-heterocyclic carbenes
as ligands,
thus resulting in the construction of complex molecules with
[9]
good to excellent enantioselectivities. However, enantiose-
lective CÀH activation has been rarely involved in reactions
[
12,13]
for P-chiral phosphine synthesis.
Biphenyl-based monophosphine ligands developed by
Buchwald et al. have attracted extensive attention because
of their wide application in an array of reactions, including CÀ
C and CÀX bond formation and gold-catalyzed cyclization
P
-stereogenic phosphorus compounds are of great interest
in the fields of agrochemicals, insecticides, and materials, and
[
1,2]
they are especially important ligands for catalysis.
conventional methods of constructing P-chiral compounds
are mostly based on optical resolution methods with stoi-
chiometric amounts of chiral reagents. Recently, a few
examples of the construction of P-chiral compounds through
asymmetric catalysis have been reported. Typical examples
include either palladium/platinum- or ruthenium-catalyzed
The
[14]
processes.
However, chiral biphenyl monophosphorus
ligands have received less attention with respect to their
[3]
[15]
investigation and synthesis.
Inspired by elegant works
[
9]
involving enantioselective CÀH activation reactions, and
[
4]
as a continuation of our interest in the synthesis of chiral
[
16]
phosphines, we herein report a palladium-catalyzed CÀH
arylation reaction for the synthesis of enantioenriched P-
chiral compounds. These compounds can be useful precursors
for chiral biphenyl monophosphine ligands.
[
5]
arylation/alkylation of secondary phosphines and palla-
dium/platinum-catalyzed asymmetric addition of phosphorus
[
6]
nucleophiles to electrophiles, thus affording P-stereogenic
compounds with good to excellent enantioselectivities.
Despite such impressive progress, the development of new
pathways to construct P-chiral phosphines remains a challeng-
ing problem and is highly desired.
We began by examining the intramolecular cyclization
reaction of N-(o-bromophenyl)-N-methyl-diphenylphos-
phinic amide (1a) with a palladium catalyst in the presence
of various phosphorus ligands. The use of (R)-binap and
Pd(OAc) as the catalyst in the presence of K CO in toluene
Transition-metal-catalyzed CÀH bond activation has
2
2
3
received extensive attention over the past few decades, and
great advances in this area have recently been made.
at 1208C successfully generated the desired product in 90%
yield, but with only 3% enantiomeric excess (ee; Table 1,
entry 1). Further screening of an array of bidentate phosphine
ligands, including DIPAMP, TangPhos, Me-DuPhos, and
Chiraphos, was slightly successful, and up to 7% ee of the
product was obtained (entries 2–5). Next, the monophospho-
rus ligand (S)-methoxy-MOP (L6) and phosphoramidite L7
were examined, and the ee values of the products were
increased slightly to 12 and 19% (entries 6 and 7), respec-
tively. The use of the readily available TADDOL-based N-Et
phosphoramidite ligand L8a improved the ee value to 78%.
The examination of other bases revealed that K PO provided
[7]
A
tremendous number of compounds have been constructed
from simple, unfunctionalized molecules with high efficacy.
However, enantioselective CÀH activation reactions are still
in their infancy, likely because of the lack of efficient
[8]
protocols to control stereoselectivity during the reaction.
Recently, a few successful examples of asymmetric CÀH
[9]
activation based on the use of transition metals (e.g., Pd,
[
10]
[11]
Rh, and Ir ) in combination with suitable chiral ligands
have been reported. In the case of a palladium catalyst, Yu
et al. described an elegant and highly successful strategy using
a monoprotected amino acid as the ligand in enantioselective
3
4
comparable results to K CO and that others afforded inferior
2
3
[8c,9b]
CÀH activation reactions.
Other efficient pathways have
ee values and yields (entries 9–14). Changing the solvent to
1,2-dichloroethane (DCE), 1,4-dioxane, t-AmOH, and DMF
did not enhance the stereoselectivity (entries 15–18). How-
ever, changing the substituent groups on the nitrogen atom of
the TADDOL ligands revealed that the N-methyl-substituted
ligand L8b generated 82% ee of the product in 95% yield
been focused primarily on palladium(0)-catalyzed intramo-
[
*] Z.-Q. Lin, W.-Z. Wang, S.-B. Yan, Prof. Dr. W.-L. Duan
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
(entries 20–23). Furthermore, when the reaction temperature
345 Lingling Road, Shanghai 200032 (China)
was reduced to 808C, the ee value of the product was
improved to 90% (entry 26). In contrast, at 608C, almost
similar stereoselectivity was observed (entry 28). Lastly, when
[Pd (dba) ] was used as the palladium precursor or an N-(o-
E-mail: wlduan@mail.sioc.ac.cn
[
**] This work was financially supported by the National Basic Research
Program of China (973 Program 2010CB833300) and NSFC
(
20902099, 21172238, and 21472218).
2
3
iodophenyl)-substituted amide was used as the starting
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!
Lin, Zi-Qi
