Efficient synthesis of optically active atropisomeric anilides through catalytic asymmetric N-arylation reaction

Article abstract of DOI:10.1021/ja042216x

In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)² catalyst, N-arylation of ortho-tert-butyl-NH-anilides with 4-nitroiodobenzene proceeds with high enantioselectivity (89-95% ee) to give optically active atropisomeric anilides possessing N-C chiral a

Full text of DOI:10.1021/ja042216x

Published on Web 02/23/2005
Efficient Synthesis of Optically Active Atropisomeric Anilides through
Catalytic Asymmetric N-Arylation Reaction
Osamu Kitagawa, Masashi Takahashi, Masatoshi Yoshikawa, and Takeo Taguchi*
Tokyo UniVersity of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received December 27, 2004; E-mail: taguchi@ps.toyaku.ac.jp
Table 1. Catalytic Asymmetric Aromatic Amination of Various NH
Anilides
Since Curran’s report in 1994, N-substituted ortho-tert-butyl-
anilide derivatives have received much attention as novel atrop-
isomeric compounds possessing an N-C chiral axis.1 On the other
hand, the utility of these anilides in asymmetric reaction is limited
by the lack of efficient methods for their preparation in high optical
purity.1 To date, although syntheses of several optically active
atropisomeric anilides through a multistep sequence from a chiral
pool precursor or HPLC separation using a chiral stationary phase
have been reported by several groups, including by us,2 some
problems remain in these methods with regard to generality and
efficiency.
Recently, we and Curran’s group reported the first catalytic
asymmetric synthesis of atropisomeric anilides through enantio-
selective N-allylation of achiral ortho-tert-butyl-NH-anilide (eq 1).3,4
However, in this methodology using a chiral π-allyl Pd catalyst,
high enantioselectivity could not be achieved (30-53% ee). In this
communication, we report a new and efficient catalytic asymmetric
synthesis of atropisomeric anilides through enantioselective inter-
and intramolecular N-arylation mediated by a chiral Pd catalyst.
The present reaction proceeds with high enantioselectivity to give
various optically active atropisomeric amides and lactams in good
yields. Moreover, this study should be also noted as a rare example
of catalytic asymmetric N-arylation.5
entry
1
R1
R2
2
yield (%)a
ee (%)b
abs config
1
2
3
4
5
6
7
1a C2H5
1b C2H5
H
2a
84
81
75
84
68
40
40
93
95
90
94
89
94
89
S
c
t-Bu 2b
-
S
S
1c
CH3
H
H
H
H
H
2c
2d
2e
2f
1d PhCH2CH2
c
1e
1f
cyclohexyl
PhCHdCH
-
c
-
c
1g CH3CHdCH
2g
-
a Isolated yield. b The ee was determined by HPLC analysis using chiral
column. c The absolute configuration was not determined.
in this case, racemic anilide 2a was obtained in 79% yield.
Subsequently, asymmetric N-arylation of 1a with various chiral
phosphine ligands was examined under the above conditions.7 The
reaction using (S)-BINAP gave 2a in relatively good chemical yield
(78%) and enantioselectivity (77% ee). With (R)-DTBM-SEG-
PHOS,8 the product 2a was obtained with high enantioselectivity
(89% ee), while considerable decrease in the chemical yield was
observed (28%). Improvement of both chemical yield and enantio-
selectivity was achieved by a survey of the base. That is, in the
reaction with (R)-DTBM-SEGPHOS, the use of t-BuOK instead
of Cs2CO3 led to the formation of 2a in excellent enantioselectivity
(93% ee) and high yield (84%) (Table 1, entry 1).
Under the optimized conditions [p-nitroiodobenzene (1.1 equiv),
(R)-DTBM-SEGPHOS (5.0 mol %), Pd(OAc)2 (3.3 mol %), and
t-BuOK (1.4 equiv) in toluene at 80 °C], catalytic asymmetric
N-arylation with various NH anilides 1b-1g was further examined
(Table 1). Similar to mono-tert-butylphenyl derivative 1a, the
reaction with N-(2,5-bis-tert-butyl)phenyl propanamide 1b also
proceeded with high enantioselectivity (95% ee) to give atropiso-
meric product 2b in 81% yield (entry 2). In the reaction with other
carboxamides such as acetamide 1c, phenylpropanamide 1d, and
cyclohexanecarboxamide 1e, similar high enantioselectivities were
also observed (89-94% ee, entries 3-5). Although the reaction of
R,â-unsaturated amides 1f and 1g brought about a decrease in the
chemical yield (40% yield), the products 2f and 2g were obtained
in high enantioselectivity (94 and 89% ee, entries 6 and 7).
The high enantioselectivities observed in these reactions may
indicate that no racemization of the products 2 occurs under the
above reaction conditions (heating for 2-6 h at 80 °C). Indeed,
when isolated propanamide 2a (93% ee) was heated for 6 h at 80
°C, no appreciable change in the ee was detected. In addition, the
absolute stereochemistries of major enantiomers of anilide products
2a, 2c, and 2d obtained by the use of (R)-DTBM-SEGPHOS were
In N-allylation with an asymmetric π-allyl Pd catalyst, since a
soft nucleophile such as anilide anion attacks the π-allyl carbon
from the opposite side of the Pd atom, asymmetric induction at the
anilide part by a chiral phosphine ligand may be difficult (eq 1).
Meanwhile, in the Pd-catalyzed asymmetric N-C coupling, it was
expected that high enantioselectivity may be achieved through attack
of an anilide nucleophile to the Pd atom followed by reductive
elimination of the resulting palladium amide complex (II), because
in such reaction, N-C bond formation should occur near the chiral
ligand (eq 2).
We chose an aromatic amination reaction that proceeds via such
a mechanism (eq 2).6 Initially, the N-arylation of propanamide 1a
(R1 ) Et) with racemic BINAP-Pd(OAc)2 catalyst was investigated
in the presence of various aryl halides and bases. The best result
was observed in the reaction using p-nitroiodobenzene as an aryl
halide and Cs2CO3 (1.4 equiv) as a base [in toluene (80 °C, 10 h)];
9
3676
J. AM. CHEM. SOC. 2005, 127, 3676-3677
10.1021/ja042216x CCC: $30.25 © 2005 American Chemical Society

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
of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc.
1994, 116, 3131. (b) Tetrahedron Symposium-in-print on Axially Chiral
Amides; Clayden, J., Ed.; Tetrahedron 2004, 60, 4325-4558.
(2) Representative papers: (a) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi,
A.; Taguchi, T.; Shiro, M. J. Org. Chem. 1998, 63, 2634. (b) Hughes, A.
D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1999,
1295. (c) Kondo, K.; Fujita, H.; Suzuki, T.; Murakami, Y. Tetrahedron
Lett. 1999, 40, 5577. (d) Ates, A.; Curran, D. P. J. Am. Chem. Soc. 2001,
123, 5130.
(3) Asymmetric syntheses of atropisomeric anilides through enantiotopic
selective deprotonation with a stoichiometric chiral base have been reported
by two groups. However, Uemura’s method (ref 3a) cannot be applied to
the synthesis of ortho-mono-tert-butylanilide, which can effectively work
as a chiral molecule. On the other hand, in Simpkins’ method (ref 3b),
improvement of the chemical yield (40-56%) and application to other
substrates except for N-ortho-tert-butylphenyl maleimide are problems
for future study. (a) Hata, T.; Koide, H.; Taniguchi, N.; Uemura, M. Org.
Lett. 2000, 2, 1907. (b) Bennett, D. J.; Pickering, P. L.; Simpkins, N. S.
Chem. Commun. 2004, 1392.
(4) (a) Kitagawa, O.; Kohriyama, M.; Taguchi, T. J. Org. Chem. 2002, 67,
8682. (b) Terauchi, J.; Curran, D. P. Tetrahedron: Asymmetry 2003, 14,
587.
(5) Kinetic resolution of racemic dibromoparacyclophane through PHANE-
PHOS-Pd-catalyzed amination has been reported (only one example), while
to the best of our knowledge, there has been no paper in relation to catalytic
asymmetric aromatic amination with achiral substrates. Rossen, K.; Pye,
P. J.; Maliakal, A.; Volante, R. P. J. Org. Chem. 1997, 62, 6462.
(6) (a) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927. (b)
Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1348. (c) Hartwig, J. F.; Loue, J. Tetrahedron Lett. 1995,
36, 3609. (d) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (e)
Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002,
58, 2041.
(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.;
Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
JA042216X
9
J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005 3677