A C(aryl)-N(amine) bond atropisomeric aminophosphine: Preparation and use as a ligand in a catalytic asymmetric allylic alkylation

Article abstract of DOI:10.1016/S0957-4166(03)00545-7

The existence of 3 as a pair of stable atropisomers has been demonstrated analytically through chiral phase LC-CD investigations. Resolution of 3d was achieved by preparative chiral HPLC. Finally, the ability of the first C(aryl)-N(amine) axially chiral p

Full text of DOI:10.1016/S0957-4166(03)00545-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2503–2506
A C(aryl)ꢀN(amine) bond atropisomeric aminophosphine:
preparation and use as a ligand in a catalytic asymmetric allylic
alkylation
Takashi Mino,* Youichi Tanaka, Toshihiro Yabusaki, Daisuke Okumura, Masami Sakamoto and
Tsutomu Fujita
Department of Materials Technology, Faculty of Engineering, Chiba University, Inage-ku, Chiba 263-8522, Japan
Received 19 June 2003; accepted 9 July 2003
Abstract—The existence of 3 as a pair of stable atropisomers has been demonstrated analytically through chiral phase LC–CD
investigations. Resolution of 3d was achieved by preparative chiral HPLC. Finally, the ability of the first C(aryl)ꢀN(amine) axially
chiral phosphine ligand 3d is demonstrated in a catalytic asymmetric reaction.
© 2003 Elsevier Ltd. All rights reserved.
Asymmetric catalysis has been advanced in many areas
by the discovery and application of atropisomeric lig-
and BINAP.1 The chiral environment imposed by the
orthogonal naphthalene ring in addition to the chelat-
ing nature of this ligand has proven effective for induc-
ing high stereoselectivity in a variety of asymmetric
reactions.2 The binaphthylmono-phosphines (MOP’s)
and related ligands have also found use in catalytic
asymmetric reactions.3 More recently, C(aryl)ꢀC(aryl)
bond atropisomeric aminophosphine ligands such as
QUINAP4 and MAP5 were applied to transition-metal
catalyzed asymmetric reactions. The synthesis of new
axially chiral biaryls, however, remains a challenge due
to the difficulties in forming the central sterically hin-
dered C(aryl)ꢀC(aryl) bond.6 In the case of nonbiaryl
CꢀC bond atropisomeric ligands, C(aryl)ꢀC(amide car-
bonyl) bond atropisomeric phosphine ligands7 and
C(aryl)ꢀN bond atropisomeric phosphine ligands such
as N-arylimide type ligand 18 and quinazolinone-con-
taining N-anilide type ligand 29 have been reported.
However, C(aryl)ꢀN(amine) bond atropisomeric com-
pounds have been described only rarely, with examples
including, for N-aryl pyrroles,10 N,N-di(1-naphthyl)-
indolo[3,2-b]-carbazole,11 and murrastifoline-F.12 To
the best of our knowledge, C(aryl)ꢀN(amine) bond
atropisomeric amines have never been employed as
chiral ligands in catalytic asymmetric reactions, includ-
ing their use as substrates in asymmetric reactions. We
have applied them to the synthesis of pyrrolidinyl-con-
taining aminophosphines with the aim of exploiting the
less popular amines.13
Herein, we report the first synthesis and resolution of
C(aryl)ꢀN(amine) bond atropisomeric amines such as
aminophosphines 3 with a bulky substituent at R1 and
apply them to transition-metal catalyzed asymmetric
reactions, such as palladium-catalyzed asymmetric
allylic alkylation.
* Corresponding author. Tel.: +81-43-290-3385; fax: +81-43-290-3401;
e-mail: tmino@faculty.chiba-u.jp
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00545-7

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T. Mino et al. / Tetrahedron: Asymmetry 14 (2003) 2503–2506
attempts on 3a have been unsuccessful to date. The
ORTEP drawings of 3b–d are shown in Figure 1. In all
cases, C(aryl)ꢀN(amine) bonds were twisted between an
aryl ring with diphenylphosphine and an indoline or
tetrahydroquinoline ring.
We attempted to separate these isomers by using HPLC
on a chiral phase. We were able to obtain an almost-
resolved UV plot for aminophosphines 3, except 3c, in
addition to a pair of clear positive and negative CD
signals of an HPLC run at 254 nm on Chiralcel® OJ
(Fig. 2). In the case of 3c, although a pair of clear
positive and negative CD signals appeared, no UV plot
was obtained for the resolution peaks. This phe-
nomenon means that the C(aryl)ꢀN(amine) bond of 3c
was rotated slowly on the chiral column at room
temperature.
Scheme 1.
Aminophosphine ligands 3 were easily prepared in two
steps. A nucleophilic aromatic substitution (SNAr) reac-
tion of the corresponding phosphine oxides such as
We conducted a study on the thermal racemization of
chiral 3, except 3c, separated by HPLC on a chiral
phase by heating its toluene solution. A small portion
of the solution was taken out at regular intervals up to
4 h, and subsequently analyzed for enantiomeric excess
by chiral HPLC analysis. We conducted this experiment
at more than three different temperatures in each case.
For 3d, the half-life was found to be about 4.7×102 days
in toluene at 25°C, which corresponds to a rotational
barrier (DG‡) of 28.5 kcal/mol (Table 1).
1-methoxy-2-(diphenylphosphino)naphthalene
oxide
with the lithium salt of indoline gave the corresponding
aminophosphine oxide 4a. This aminophosphine oxide
was converted into the desired aminophosphine ligand
3a using trichlorosilane-triethylamine in good yield
(Scheme 1). The other ligands were easily prepared in
the same manner.
We successfully conducted X-ray crystallographic
analyses of racemic aminophosphines 3b–d: however,
Figure 1. The ORTEP drawing of 3b–d.

T. Mino et al. / Tetrahedron: Asymmetry 14 (2003) 2503–2506
2505
The chiral aminophosphine 3d was then applied as the
chiral ligand for the transition-metal catalyzed asym-
metric reaction such as a palladium-catalyzed asymmet-
ric allylic alkylation (AAA)14 of 1,3-diphenyl-2-
propenyl acetate 5 with dimethyl malonate 6. This
reaction was carried out in the presence of 5 mol% of
[Pd(h3-C3H5)Cl]2, 10 mol% of 3d, and a mixture of
N,O-bis(trimethylsilyl)acetamide (BSA) and 5 mol% of
LiOAc (Scheme 2 and Table 2).
Figure 2. HPLC-UV and -CD analysis of 3 using a chiral
phase.
Scheme 2.
Table 1. Racemization energies of 3a, 3b and 3d at 25°C
(+)- and (−)-3d were able to induce moderate enantiose-
lectivities in toluene at room temperature (entries 1 and
2). Next a reaction was carried out using (−)-3d at 0°C
(entry 3). Although the reaction rate decreased, the
enantioselectivity of (S)-7 was improved to 91% ee. We
further examined the effect of reaction solvents using
the chiral ligand 3d. A reaction carried out in CH2Cl2
improved the reaction yield to 88% with 87% ee (entry
4). Low reactivity was observed in THF as opposed to
other solvents (entry 5).
in toluene
3a
3b
3d
DG‡ (kcal/mol)
DH‡ (kcal/mol)
DS‡ (cal/mol·K)
Erac(kcal/mol)
27.6
29.9
7.92
30.5
3.95×10−8
102
24.5
27.3
9.25
28.5
25.4
−10.3
26.0
27.9
krac (s−1
t1/2 (day)
)
6.81×10−6
0.59
8.59×10−9
467
In summary, we have shown that the synthesis of
aminophosphines 3 could be achieved in good yields by
nucleophilic aromatic substitution (SNAr) followed by
silane reduction. The existence of 3 as a pair of stable
atropisomers was demonstrated analytically through
chiral phase LC–CD investigations. Resolution of 3d
was achieved by preparative chiral HPLC. Finally, the
ability of the first C(aryl)ꢀN(amine) axially chiral phos-
phine ligand 3d is demonstrated in catalytic asymmetric
reactions such as a palladium-catalyzed asymmetric
allylic alkylation.
In fact, the enantiopure 3d (>99% ee) racemized to 82%
ee after 130 days in toluene at room temperature. In the
case of an ethanol solution, the racemization of 3d was
slower, such as the 98% ee of 3d was decreased to 92%
ee after 130 days at room temperature. The half-lives of
3a and 3b were shorter than 3d. Optically active
atropisomeric aminophosphine 3d on a preparative
scale, such as a 100 mg scale, was obtained using a
semi-preparative chiral phase column (Chiralcel® OJ:
25 cm×1 cm i.d.).
Table 2. Pd-Catalyzed AAA reaction using chiral atropisomeric aminophosphine 3d
Entry
Ligand
Solv.
Temp. (°C)
Time (h)
Yielda (%)
Eeb (%)
Config.c
1
2
3
4
5
6
(+)-3d
(−)-3d
(−)-3d
(+)-3d
(−)-3d
(−)-3d
PhMe
PhMe
PhMe
DCM
THF
rt
rt
0
0
0
24
24
72
72
72
72
60
60
63
88
38
61
74
76
91
87
80
75
R
S
S
R
S
S
PhCF3
0
a Isolated yields.
b Enantiomeric excesses were determined by HPLC on Chiral phase (Chiralcel® OD-H).
c The absolute stereochemistry was determined by HPLC retention times.

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T. Mino et al. / Tetrahedron: Asymmetry 14 (2003) 2503–2506
(b) Dai, X.; Wong, A.; Virgil, S. C. J. Org. Chem. 1998,
References
63, 2597.
1. Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.;
Kumobayashi, H.; Taketomi, T.; Akutagawa, S.; Noyori,
R. J. Org. Chem. 1986, 51, 629.
2. Noyori, R. Asymmetric Catalysis in Organic Synthesis;
John Wiley & Sons: New York, 1994; Chapter 1.
3. (a) Hayashi, T.; Iwamura, H.; Uozumi, Y.; Matsumoto,
Y.; Ozawa, F. Synthesis 1994, 15, 526; (b) Uozumi, Y.;
Tanahashi, A.; Lee, S.-Y.; Hayashi, T. J. Org. Chem.
1993, 58, 1945; (c) Alcock, N. W.; Brown, J. M.; Hulmes,
D. I. Tetrahedron: Asymmetry 1993, 4, 743.
10. (a) Bock, L. H.; Adams, R. J. Am. Chem. Soc. 1931, 53,
374; (b) Adams, R.; Joyce, R. M., Jr. J. Am. Chem. Soc.
1938, 60, 1491; (c) Vorkapic-Furac, J.; Mintas, M.; Kast-
ner, F.; Mannschreck, A. J. Heterocycl. Chem. 1992, 29,
327.
11. Hu, N.-X.; Xie, S.; Popovic, Z.; Hor, A.-M. J. Am.
Chem. Soc. 1999, 121, 5097.
12. Bringmann, G.; Tasler, S.; Endress, H.; Kraus, J.;
Messer, K.; Wohlfarth, M.; Lobin, W. J. Am. Chem. Soc.
2001, 123, 2703.
13. (a) Mino, T.; Tanaka, Y.; Akita, K.; Sakamoto, M.;
Fujita, T. Heterocycles 2003, 60, 9; (b) Kondo, K.;
Kazuta, K.; Fujita, H.; Sakamoto, Y.; Murakami, Y.
Tetrahedron 2002, 58, 5209; (c) Mino, T.; Tanaka, Y.;
Akita, K.; Anada, K.; Sakamoto, M.; Fujita, T. Tetra-
hedron: Asymmetry 2001, 12, 1677; (d) Mino, T.; Tanaka,
Y.; Sakamoto, M.; Fujita, T. Tetrahedron: Asymmetry
2001, 12, 2435; (e) Mino, T.; Tanaka, Y.; Sakamoto, M.;
Fujita, T. Heterocycles 2000, 53, 1485; (f) Hattori, T.;
Komuro, Y.; Hashizaka, N.; Takahashi, H.; Miyano, S.
Enantiomer 1997, 2, 203.
4. (a) Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Tetrahedron
1994, 50, 4493; (b) Brown, J. M.; Hulmes, D. I.; Layzell,
T. P. J. Chem. Soc., Chem. Commun. 1993, 22, 1673; (c)
Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron:
Asymmetry 1993, 4, 743.
5. (a) Ding, K.; Wang, Y.; Yun, H.; Liu, J.; Wu, Y.;
Terada, M.; Okubo, Y.; Mikami, K. Chem. Eur. J. 1999,
5, 1734; (b) Vyskocil, S.; Smrcina, M.; Kocovsky, P.
Tetrahedron Lett. 1998, 39, 9289; (c) Vyskocil, S.;
Smrcina, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J.
Org. Chem. 1998, 63, 7738.
14. (a) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1; (b)
Trost, B. M.; Lee, C. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; VCH: New York, 2000; p. 893;
(c) Helmchen, G. J. Organomet. Chem. 1999, 576, 203; (d)
Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Eds.; Springer: Tokyo, 1999; Vol. 2, p. 833 and references
cited therein.
6. (a) Stanforth, S. Tetrahedron 1998, 54, 263; (b) Bring-
mann, G.; Walter, R.; Weirich Angew. Chem., Int. Ed.
Engl. 1990, 29, 977.
7. Dai, W.-M.; Yeung, K. K. Y.; Liu, J.-T.; Zhang, Y.;
Williams, I. D. Org. Lett. 2002, 4, 1615.
8. Chen, Y.; Smith, M. D.; Shimizu, K. D. Tetrahedron
Lett. 2001, 42, 7185.
9. (a) Dai, X.; Virgil, S. Tetrahedron Lett. 1999, 40, 1245;