C O M M U N I C A T I O N S
confirmed to be (S)-configuration by comparing with authentic
sample prepared through a chiral pool route starting from (S)-lactic
acid (see Supporting Information). The stereochemistries of other
anilidess2b, 2e-2g, which have positive [R]D values like 2a, 2c,
2dswere also tentatively predicted to be (S)-configuration.
We next attempted the synthesis of optically active atropisomeric
lactams by applying the present catalytic asymmetric N-arylation
to an intramolecular version. The reaction with anilide 3a (X ) Y
) CH2, R ) H) prepared from 3-(2-iodophenyl)propanoate was
conducted under various conditions. After an extensive survey of
chiral phosphine ligands (SEGPHOS and ligands shown in ref 7),
we found that, in the presence of Cs2CO3 in toluene, the reaction
using (S)-BINAP-Pd(OAc)2 catalyst gives the lactam product 4a
in 70% ee and 95% yield (eq 3). Although several bases and
solvents were further employed for improvement of the enantio-
selectivity, better results could not be obtained. On the other hand,
the reaction with 2,5-bis-tert-butylanilide 3b (X ) Y ) CH2, R )
t-Bu) led to a remarkable increase in the enantioselectivity; in this
case, atropisomeric lactam 4b of 96% ee was obtained in good
yield (95%). The reactions of other 2,5-bis-tert-butylanilides 3c
(X ) NBn, Y ) CH2) and 3d (X ) CH2, Y ) NBn) also proceeded
with excellent enantioselectivity (94 and 95% ee) to give the cyclic
urea 4c and piperazinone 4d in good yields (82 and 71%),
respectively.
chirality of 4b was determined as (S)-configuration by comparing
with an authentic sample (S,S)-5b prepared from (S)-3-(2-iodo-
pheny)-2-methylpropanoate (see Supporting Information).
In conclusion, we have succeeded in the synthesis of optically
active atropisomeric anilide derivatives through a catalytic asym-
metric inter- and intramolecular N-arylation reaction. The present
reaction should provide new and efficient methodology for the
preparation of various atropisomeric anilides with high optical
purity. Furthermore, this study should attract the interest of many
chemists as the first example of practical catalytic asymmetric
aromatic amination with achiral substrates.
Acknowledgment. We gratefully acknowledge Takasago In-
ternational Corporation for the supply of chiral phosphine ligands
[(R)-(-)-DTBM-SEGPHOS].
Supporting Information Available: Experimental procedures and
characterization data for compounds 2a-2g, 3a-3d, 4a-4d, and 5b;
X-ray structural data and reaction scheme for the determination of
absolute configuration of 2a, 2c, 2d, and 4b; and a list of chiral
phosphine ligands examined (CIF, PDF). This material is available free
References
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the synthesis of ortho-mono-tert-butylanilide, which can effectively work
as a chiral molecule. On the other hand, in Simpkins’ method (ref 3b),
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substrates except for N-ortho-tert-butylphenyl maleimide are problems
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(5) Kinetic resolution of racemic dibromoparacyclophane through PHANE-
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(7) Results with other chiral phosphine ligands (see Supporting Informa-
tion): Trost ligand (0%), CHIRAPHOS (0%), PHANEPHOS (0%),
BPPFOAc (0%), DIOP (20%, 9% ee), Me-DuPhos (16%, 15% ee), Et-
FerroTANE (12%, 33% ee), MOP (18%, 52% ee), tol-BINAP (48%, 53%
ee), xyl-BINAP (56%, 78% ee).
Although these lactamizations required prolonged heating
(6-22 h at 80 °C) in comparison with intermolecular N-arylation,
no racemization of lactams 4a-4d was observed under the present
conditions.
Equation 4 is an application of a lactam product to stereoselective
reaction. The reaction of lactam enolate from 4b with MeI
proceeded with high diastereoselectivity (13:1) to give (S,S)-5b as
a major diastereomer. The absolute stereochemistry of the axial
(8) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.;
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