Synthesis of Optically Active Atropisomeric Anilide Derivatives through Diastereoselective N-Allylation with a Chiral Pd-π-Allyl Catalyst

Article abstract of DOI:10.1021/jo035305l

N-Allylation of o-tert-butyl anilides derived from o-tert-butyl aniline and (S)-lactic acid or (S)-mandelic acid proceeded with high diastereoselectivity in the presence of a (BINAP)Pd-π-allyl catalyst to give atropisomeric N-allyl o-tert-butyl anilide de

Full text of DOI:10.1021/jo035305l

are the first example of catalytic asymmetric synthesis
of atropisomeric compounds having a N-C chiral axis.7
Unfortunately, although various reaction conditions in-
volving a survey of many known chiral phosphine ligands
were investigated, high enantioselectivity could not be
achieved [maximum up to 44% ee (our reaction) and 53%
ee (Curran’s reaction)].8
Syn th esis of Op tica lly Active
Atr op isom er ic An ilid e Der iva tives th r ou gh
Dia ster eoselective N-Allyla tion w ith a
Ch ir a l P d -π-Allyl Ca ta lyst
Osamu Kitagawa, Masashi Takahashi,
Mitsuteru Kohriyama, and Takeo Taguchi*
Tokyo University of Pharmacy and Life Science, 1432-1
Horinouchi, Hachioji, Tokyo 192-0392, J apan
taguchi@ps.toyaku.ac.jp
Received September 4, 2003
Abstr a ct: N-Allylation of o-tert-butyl anilides derived from
o-tert-butyl aniline and (S)-lactic acid or (S)-mandelic acid
proceeded with high diastereoselectivity in the presence of
a (BINAP)Pd-π-allyl catalyst to give atropisomeric N-allyl
o-tert-butyl anilide derivatives.
On the other hand, not only the enantioselective
synthesis, but also diastereoselective construction of
optically active atropisomeric anilides has been so far
uncommon. For example, as the first synthesis of an
atropisomeric anilide with high optical purity and defi-
nite absolute configuration, we reported optical resolution
of diastereomeric atropisomeric lactamide prepared from
N-allyl-o-tert-butylaniline and (S)-O-acetyl lactic acid,
while the diastereoselectivity in the condensation reac-
tion was not high (50% de) (eq 2).4a,b If a highly diaste-
reoselective preparation of diastereomeric lactamides
which can be easily separated by column chromatography
can be achieved, it should provide a useful synthetic
method of optically active atropisomeric anilides. In this
paper, we report an efficient synthesis of atropisomeric
anilides with high optical purity (g97% ee) through
diastereoselective N-allylation of lactamide and man-
delamide using a (BINAP)Pd-π-allyl catalyst. Further-
more, a transition state model for the origin of the
diastereoselectivity is also proposed.
Since Curran’s report in 1994,1 N-substituted o-tert-
butyl anilide derivatives have received much attention
as new atropisomeric compounds2 and have also been
applied to several asymmetric reactions.3,4 Optically
active forms of such atropisomeric anilides have so far
been prepared through optical resolution by the forma-
tion of a diastereomeric derivative or HPLC separation
using a chiral column.3,4 Quite recently, we and Curran’s
group reported the synthesis of optically active atropi-
someric anilides through enantioselective N-allylation of
N-nonsubstituted o-tert-butyl anilide with a chiral Pd-
π-allyl complex (eq 1).5,6 As far as we know, these reports
* To whom correspondence should be addressed. Fax and Tel: +81-
426-76-3257. E-mail (O.K.): kitagawa@ps.toyaku.ac.jp.
(1) Curran, D. P.; Qi, H.; Geib, S. J .; DeMello, N. C. J . Am. Chem.
Soc. 1994, 116, 3131.
(2) Papers in relation to racemic or achiral atropisomeric anilides:
(a) Kishikawa, K.; Tsuru, I.; Kohomoto, S.; Yamamoto, M.; Yamada,
K. Chem. Lett. 1994, 1605. (b) Hughes, A. D.; Price, D. A.; Shishkin,
O.; Simpkins, N. S. Tetrahedron Lett. 1996, 37, 7607. (c) Curran, D.
P.; Hale, G. R.; Geib, S. J .; Balog, A.; Cass, Q. B.; Degani, A. L. G.;
Hernandes, M. Z.; Freitas, L. C. G. Tetrahedron: Asymmetry 1997, 8,
3955. (d) Bach, T.; Schro¨der, J .; Harms, K. Tetrahedron Lett. 1999,
40, 9003. (e) Dantale, S.; Reboul, V.; Metzner, P.; Philouze, C. Chem.
Eur. J . 2002, 8, 632.
(3) Papers in relation to optically active atropisomeric anilides (a)
Kawamoto, T.; Tomishima, M.; Yoneda, F.; Hayami, J . Tetrahedron
Lett. 1992, 33, 3169. (b) Hughes, A. D.; Simpkins, N. S. Synlett 1998,
967. (c) Hughes, A. D.; Price, D. A.; Simpkins, N. S. J . Chem. Soc.,
Perkin Trans. 1 1999, 1295. (d) Kondo, K.; Fujita, H.; Suzuki, T.;
Murakami, Y. Tetrahedron Lett. 1999, 40, 5577. (e) Curran, D. P.; Liu,
W.; Chen, C. H. J . Am. Chem. Soc. 1999, 121, 11012. (f) Shimizu, K.
D.; Freyer, H. O.; Adams, R. D. Tetrahedron Lett. 2000, 41, 5431. (g)
Kondo, K.; Iida, T.; Fujita, H.; Suzuki, T.; Yamaguchi, K.; Murakami,
Y. Tetrahedron 2000, 56, 8883. (h) Godfrey, C. R. A.; Simpkins, N. S.;
Walker, M. D. Synlett 2000, 388. (i) Ates, A.; Curran, D. P.; J . Am.
Chem. Soc. 2001, 123, 5130. (g) Sakamoto, M.; Iwamoto, T.; Nono, N.;
Ando, M.; Arai, W.; Mino, T,; Fujita, T. J . Org. Chem. 2003, 68, 942.
(4) Our papers in relation to optically active atropisomeric anil-
ides: (a) Kitagawa, O.; Izawa, H.; Taguchi, T.; Shiro, M. Tetrahedron
Lett. 1997, 38, 4447. (b) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi,
A.; Taguchi, T.; Shiro, M. J . Org. Chem. 1998, 63, 2634. (c) Fujita, M.;
Kitagawa, O.; Izawa, H.; Dobashi, A.; Fukaya, H.; Taguchi, T.
Tetrahedron Lett. 1999, 40, 1949; 2000, 41, 4997 (Corrigendum). (d)
Kitagawa, O.; Momose, S.; Fushimi, Y.; Taguchi, T. Tetrahedron Lett.
1999, 40, 8827. (e) Fujita, M.; Kitagawa, O.; Yamada, Y.; Izawa, H.;
Hasegawa, H.; Taguchi, T. J . Org. Chem. 2000, 65, 1108. (f) Kitagawa,
O.; Fujita, M.; Kohriyama, M.; Hasegawa, H.; Taguchi, T. Tetrahedron
Lett. 2000, 41, 8539.
We expected that asymmetric induction due to the
chirality of the substrate would be possible in N-allylation
of a chiral carboxamide such as N-o-tert-butylphenyl
lactamide with the Pd-π-allyl catalyst. As the substrates
for the diastereoselective N-allylation, lactamide and
(6) Terauchi, J .; Curran, D. P. Tetrahedron: Asymmetry 2003, 14,
587.
(7) A highly enantioselective synthesis of 2,6-disubstituted atropi-
someric anilides through enantiotopic selective lithiation of a prochiral
2,6-disubstituted arene chromium complex with stoichiometric chiral
base was recently reported by Uemura et al. However, this method
cannot be applied to the synthesis of atropisomeric o-tert-butylanilide
which can effectively work as a chiral molecule. (a) Hata, T.; Koide,
H.; Taniguchi, N.; Uemura, M. Org. Lett. 2000, 2, 1907. (b) Koide, H.;
Hata, T.; Uemura, H. J . Org. Chem. 2002, 67, 1929.
(8) For reviews on catalytic asymmetric allylation with a chiral
π-allylpalladium complex: (a) Hayashi, T. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1994; pp 325-
365. (b) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(c) Williams, J . M. Synlett 1996, 705.
(5) Kitagawa, O.; Kohriyama, M.; Taguchi, T. J . Org. Chem. 2002,
67, 8682.
10.1021/jo035305l CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/15/2003
J . Org. Chem. 2003, 68, 9851-9853
9851

TABLE 1. Dia ster eoselective N-Allyla tion of La cta m id e
or Ma n d ela m id e
by (R)-selectivity due to the chirality of both the substrate
and the catalyst. Indeed, the reaction with (R)-BINAP
gave 2a and 2a ′ with high diastereoselectity (2a /2a ′ )
15.9, entry 2), while the use of mismatched (S)-BINAP
resulted in a decrease in the diastereoselectivity (2a /2a ′
) 5.2, entry 3).
The increase in the diastereoselectivity by such double
stereodifferentiation was also observed in the reaction
of (S)-mandelamide 1b. That is, the N-allylation of 1b
with the matched (R)-BINAP-Pd catalyst gave the
products 2b and 2b′ with higher diastereoselectivity (2b/
2b′ ) 13.5, entry 5) than that in the reaction with an
achiral dppf-Pd catalyst (2b/2b′ ) 5.1, entry 4). The
reaction with mismatched (S)-BINAP gave 2b and 2b′
with lower diastereoselectivity (2b/2b′ ) 3.2, entry 6).
The (R)-configuration of the atropisomeric part of the
major isomer 2b was determined after conversion to
known ketoamide 4b4d (eq 4).
a
b
Isolated yield. The ratio was determined by 300 MHz 1H
NMR.
mandelamide which are prepared from o-tert-butylaniline
and cheap lactic acid or mandelic acid, were chosen (Table
1). Initially, N-allylation of the amide anion prepared
from (S)-O-methoxymethyl lactamide 1a and NaH was
conducted in the presence of allyl palladium chloride
dimer (2.2 mol %), dppf ligand (4.4 mol %), and allyl
acetate (1 equiv) in THF (Table 1, entry 1). The reaction
proceeded with moderate diastereoselectivity (2a /2a ′ )
6.8) to give diastereomeric atropisomeric N-allyl lacta-
mides 2a and 2a ′ in excellent yield (97%). The stereo-
chemistry of the atropisomerism part of the major isomer
2a was confirmed to be the (R)-configuration after the
conversion to known lactamide 3a 4a,b (eq 3). It should be
noted that the (R)-selectivity of this Pd-catalyzed N-
allylation is in contrast to (S)-selectivity in the case of
the amide-forming reaction shown in eq 2. For further
improvement of the diastereoselectivity, although a
survey of protective groups (Bn, Me, Ac, TBDPS) on the
R-oxygen atom, phosphine ligand (dppe), solvent (toluene,
CH2Cl2), and base (n-BuLi, KH) was performed, improve-
ment of the selectivity and yield compared to those in
entry 1 was not realized.
F IGURE 1. Transition-state model for the origin of the
diastereoselectivity.
We next attempted the improvement of the selectivity
on the basis of a double stereodifferentiation method.9
In our previous paper concerning enantioselective N-
allylation of achiral anilide,5 we reported that the use of
the (S)-BINAP-Pd catalyst always gives (S)-configurated
N-allyl anilide in 32-44% ee. Accordingly, the reaction
(R)-Selectivity on the basis of the substrate control may
be rationalized according to the transition-state model
shown in Figure 1. During N-allylation of the sodium
imino alcoholate intermediate, rotation of a coplanar tert-
butylphenyl group to the imine plane may simultane-
ously occur to produce the N-allyl anilide having a per-
pendicular tert-butylphenyl group to the amide plane.
The clockwise rotational transition state which gives 2′
having an (S)-configuration should result in steric repul-
sion between the R-substituent and the o-tert-butyl group.
Accordingly, the reaction may preferentially proceed
through the counterclockwise rotational transition state to
give (R)-atropisomeric N-allyl anilide 2 as a major isomer.
10
of (S)-lactamide 1a with an (R)-BINAP-Pd catalyst
may bring about an increase in the diastereoselectivity
(9) For a review in relation to double stereodifferentiation: Masam-
une, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew. Chem. 1985, 97, 1.
(10) (a) Noyori, Y.; Takaya, H. Acc. Chem. Res. 1990, 23, 345. (b)
Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.;
Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizuka, T.; Akutagawa, S.;
Takaya, H. J . Org. Chem. 1994, 59, 3064.
9852 J . Org. Chem., Vol. 68, No. 25, 2003

8.8, 14.1 Hz), 3.30 (3H, s), 1.40 (9H, s), 1.30 (3H, d, J ) 6.5 Hz);
13C NMR (CDCl3) δ 171.8, 146.3, 137.9, 132.2, 131.9, 130.3,
128.6, 126.2, 118.7, 94.7, 70.8, 55.7, 54.5, 36.5, 32.5, 18.8; MS
(m/z) 328 (M+ + Na); Anal. Calcd for C18H27NO3: C, 70.79; H,
8.91; N, 4.59. Found: C, 70.73; H, 8.95; N, 4.51. In the 1H and
13C NMR spectra of 2a , the minor signals on the basis of the
existence of the amide C-N rotamer were also observed in a
ratio of 15:1. 2a ′: white solid; [R]D ) +75.0 (c ) 1.0, CHCl3);
mp 59-60 °C; IR (KBr) 1667 cm-1; 1H NMR (CDCl3) δ 7.56 (1H,
dd, J ) 1.5, 8.2 Hz), 7.32 (1H, dt, J ) 1.8, 8.2 Hz), 7.18 (1H, dt,
J ) 1.5, 7.9 Hz), 7.12 (1H, dd, J ) 1.8, 7.9 Hz), 6.03 (1H, dddd,
J ) 5.0, 8.2, 10.0, 17.0 Hz), 5.17 (1H, d, J ) 10.0 Hz), 5.09 (1H,
dd, J ) 0.9, 17.0 Hz), 4.95 (1H, dd, J ) 5.0, 14.1 Hz), 4.48 (1H,
d, J ) 7.0 Hz), 4.19 (1H, d, J ) 7.0 Hz), 3.91 (1H, q, J ) 6.2 Hz),
3.33 (1H, dd, J ) 8.2, 14.1 Hz), 3.28 (3H, s), 1.37 (9H, s), 1.34
(3H, d, J ) 6.2 Hz); 13C NMR (CDCl3) δ 170.9, 146.1, 138.3,
132.4, 132.0, 129.8, 128.5, 126.2, 118.8, 96.3, 71.8, 55.8, 54.8,
As regards stereoselective synthesis of optically active
atropisomeric o-tert-butylanilide by other groups, only
one example has been reported by Curran’s group.3i,11
However, the ee of anilides obtained by their method
using crystallization-induced asymmetric transformation
is not sufficient for application to asymmetric reaction
(maximum 93% ee, 77% ee). On the other hand, by the
use of our method, anilides 3a (4a ) and 4b which are
already found to effectively work as chiral molecules4b,d
can be obtained in g97% ee.
In conclusion, we have succeeded in the diastereose-
lective synthesis of atropisomeric anilide derivatives with
high optical purity (g97% ee) through double stereodif-
ferentiative N-allylation of N-o-tert-butylphenyl lacta-
mide or -mandelamide using a (BINAP)Pd catalyst. In
addition, we also proposed plausible transition state
model for the origin of the diastereoselectivity based on
substrate control. The present reaction should provide
new and efficient methodology for the synthesis of
optically active atropisomeric anilide derivatives.
36.3, 32.6, 17.7; MS (m/z) 328 (M+ + Na). Anal. Calcd for C18H27
-
NO3: C, 70.79; H, 8.91; N, 4.59. Found: C, 70.62; H, 9.08; N,
4.59.
(S,R)- a n d (S,S)-N-Allyl-N-2-(ter t-bu tyl)p h en yl 2-Meth -
oxym eth oxyp h en yla ceta m id e (2b) a n d (2b′). 2b and 2b′
were prepared from 1b (164 mg, 0.5 mmol) in accordance with
the general procedure. Purification by column chromatography
(hexane/AcOEt ) 4) and subsequent MPLC (hexane/AcOEt )
5) gave 2b′ (less polar, 9 mg, 5%) and 2b (more polar, 162 mg,
88%). 2b: white solid; [R]D ) -2.0 (c ) 1.0, CHCl3); mp 58 °C;
Exp er im en ta l Section
Gen er a l p r oced u r e for d ia ster eoselective N-Allyla tion
w ith BINAP -P d Ca ta lyst. Under Ar atmosphere, to a suspen-
sion of NaH (20 mg, 0.5 mmol) in THF (2 mL) was added (S)-
lactamide 1a (133 mg, 0.5 mmol). After being stirred for 10 min
at room temperature, allylpalladium chloride dimer (4 mg, 0.011
mmol), (R)-BINAP (14 mg, 0.022 mmol), and allyl acetate (81
µL, 0.75 mmol) in THF (1 mL) were added to the mixture at
-78 °C, and then the reaction mixture was stirred for 15 h from
-78 to 0 °C. The mixture was poured into 2% HCl solution and
extracted with AcOEt. The AcOEt extracts were washed with
brine, dried over MgSO4, and evaporated to dryness. Purification
of the residue by column chromatography (hexane/AcOEt ) 12)
gave 2a ′ (less polar, 9 mg, 6%) and 2a (more polar, 137 mg, 90%).
(S,R)- a n d (S,S)-N-Allyl-N-2-(ter t-bu tyl)p h en yl 2-Meth -
oxym et h oxyp r op a n a m id e (2a ) a n d (2a ′). 2a : white solid;
[R]D ) -104.6 (c ) 1.0, CHCl3); mp 34-35 °C; IR (KBr) 1667
1
IR (KBr) 1670 cm-1; H NMR (CDCl3) δ 7.57 (1H, dd, J ) 1.5,
8.0 Hz), 7.20-7.29 (4H, m), 7.06 (2H, dd, J ) 1.5, 8.0 Hz), 6.89
(1H, dt, J ) 1.5, 8.0 Hz), 6.09 (1H, dd, J ) 1.5, 8.0 Hz), 5.83
(1H, dddd, J ) 5.0, 8.5, 10.1, 17.4 Hz), 5.04 (1H, d, J ) 10.1
Hz), 4.99 (1H, tdd, J ) 1.2, 5.0, 14.4 Hz), 4.96 (1H, dd, J ) 1.2,
17.4 Hz), 4.91 (1H, s), 4.55 (1H, d, J ) 7.0 Hz), 4.41 (1H, d, J )
7.0 Hz), 3.30 (1H, dd, J ) 8.5, 14.4 Hz), 3.26 (3H, s), 1.46 (9H,
s); 13C NMR (CDCl3) δ 169.4, 146.5, 137.6, 135.6, 133.6, 132.3,
129.9, 129.5, 128.7, 128.6, 128.2, 126.0, 118.6, 93.4, 75.8, 55.9,
54.3, 36.4, 32.4; MS (m/z) 390 (M+ + Na). Anal. Calcd for C23H29
-
NO3: C, 75.17; H, 7.95; N, 3.81. Found: C, 75.21; H, 7.93; N,
3.83. 2b′: colorless oil; [R]D ) +141.3 (c ) 1.0, CHCl3); IR (neat)
1667 cm-1 1H NMR (CDCl3) δ 7.56 (1H, dd, J ) 1.5, 8.0 Hz),
;
7.38 (1H, dt, J ) 1.8, 8.0 Hz), 7.23-7.29 (6H, m), 7.17 (1H, dd,
J ) 1.5, 8.0 Hz), 6.02 (1H, dddd, J ) 5.3, 8.2, 9.9, 17.2 Hz), 5.18
(1H, d, J ) 9.9 Hz), 5.09 (1H, dd, J ) 1.0, 17.2 Hz), 5.06 (1H, s),
5.03 (1H, tdd, J ) 1.0, 5.3, 14.0 Hz), 4.57 (1H, d, J ) 7.0 Hz),
4.50 (1H, d, J ) 7.0 Hz), 3.29 (3H, s), 3.26 (1H, dd, J ) 8.2, 14.0
Hz), 1.04 (9H, s); 13C NMR (CDCl3) δ 169.2, 146.9, 137.7, 135.4,
132.6, 131.7, 130.6, 129.2, 128.7, 128.7, 128.2, 126.4, 119.1, 94.7,
75.0, 55.7, 54.7, 35.9, 31.9; MS (m/z) 390 (M+ + Na). Anal. Calcd
for C23H29NO3: C, 75.17; H, 7.95; N, 3.81. Found: C, 74.99; H,
7.75; N, 3.85.
cm-1 1H NMR (CDCl3) δ 7.58 (1H, dd, J ) 1.2, 7.9 Hz), 7.33
;
(1H, dt, J ) 1.2, 7.3 Hz), 7.17 (1H, dt, J ) 1.2, 7.3 Hz), 6.93
(1H, dd, J ) 1.2, 7.9 Hz), 5.97 (1H, dddd, J ) 5.0, 8.8, 10.0, 17.0
Hz), 5.16 (1H, d, J ) 10.0 Hz), 5.08 (1H, dd, J ) 0.6, 17.0 Hz),
4.98 (1H, dd, J ) 5.0, 14.1 Hz), 4.60 (1H, d, J ) 7.0 Hz), 4.52
(1H, d, J ) 7.0 Hz), 4.04 (1H, q, J ) 6.5 Hz), 3.32 (1H, dd, J )
(11) N,N-Dialkyl 2,6-disubstituted aromatic amides are also known
to exist as stable nonbiaryl atropisomeric compounds at room temper-
ature. Recently, the stereoselective synthesis of optically active forms
of these compounds has been reported by several groups. (a) Th-
ayumanavan, S.; Beak, P.; Curran, D. P.; Tetrahedron Lett. 1996, 37,
2899. (b) Clayden, J .; Lai, L. W. Angew. Chem., Int. Ed. 1999, 38, 2556.
(c) Clayden, J .; J ohnson, P.; Pink, J . H. J . Chem. Soc., Perkin Trans.
1 2001, 371. (d) Clayden, J .; Mitjans, D.; Youssef, L. H. J . Am. Chem.
Soc. 2002, 124, 5266. (e) Rios, R.; J imeno, C.; Carrol, P. J .; Walsh, P.
J . J . Am. Chem. Soc. 2002, 124, 10272.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation and characterization data of 1a ,
1b, 3a , 3b, and 4b. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O035305L
J . Org. Chem, Vol. 68, No. 25, 2003 9853