Catalytic enantioselective synthesis of atropisomeric indoles with an N-C chiral axis

Article abstract of DOI:10.1002/chem.201000243

(Chemical Equation Presented) A pivotal role: In the presence of (R)-(-)-5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4, 4′-bi-1,3-benzodioxole-PdCl₂ [(R)-SEGPHOS-PdCl₂], 5-endo-hydroaminocyclization of achiral ortho-alkynylanilines proceeds in an enantioselective manner to give optically active, axially chiral indoles (see scheme).

Full text of DOI:10.1002/chem.201000243

DOI: 10.1002/chem.201000243
À
Catalytic Enantioselective Synthesis of Atropisomeric Indoles with an N C
Chiral Axis
Nobutaka Ototake,[a] Yudai Morimoto,[a] Ayano Mokuya,[a] Haruhiko Fukaya,[b]
Yasuo Shida,[b] and Osamu Kitagawa*[a]
À
Atropisomeric compounds, owing to rotation restriction
Several N C axially chiral compounds with non-amide
skeletons have also been found.[1a,6] For example, Uemura
and Kamikawa recently reported that indole derivatives pos-
sessing a 2,6-disubstituted phenyl group on the nitrogen
atom (C) have a high rotational energy barrier around the
À
around an N C bond, have received much attention recent-
ly as novel chiral molecules.[1] ortho-tert-Butylanilide deriva-
tives are typical examples of such atropisomeric com-
pounds.[2] In 2005, we succeeded in the highly enantioselec-
tive synthesis of atropisomeric ortho-tert-butylanilides A and
N-(ortho-tert-butylphenyl)lactams B through chiral, Pd-cata-
À
N Ar bond; however, in their synthesis of the optically
active form, a stoichiometric chiral source is required.[6c] We
predicted that similar to indoles C, N-(ortho-tert-butylphenyl)-
indoles 1, also have stable atropisomeric structures.
In this paper, we report the catalytic, enantioselective syn-
thesis of axially chiral indoles 1 (non-amide compounds with
II
À
N C axial chirality) through the chiral, Pd -catalyzed, 5-
endo-hydroaminocyclization of ortho-alkynylanilines. Fur-
thermore, the stereochemical assignment of the axial chirali-
ty in indole products 1 is described.
For a catalytic, asymmetric synthetic method for atropiso-
meric N-(ortho-tert-butylphenyl)indole derivative 1, we
chose 5-endo-hydroaminocyclization of ortho-alkynylani-
lines. This reaction, which proceeds in the presence of a
transition-metal catalyst or basic reagent, has been investi-
gated by many groups as an efficient synthetic method of
creating an indole skeleton,[7] but, to the best of our knowl-
edge, its application to an asymmetric reaction has not been
reported to date. We expected that optically active atropiso-
meric indoles 1 could be obtained through chiral, transi-
tion-metal-catalyzed (ML*) 5-endo-hydroaminocycliztion of
lyzed, inter- and intramolecular N-arylation of achiral NH-
anilides.[3] These reactions were the first practical, catalytic,
À
asymmetric synthesis of compounds with N C axial chirali-
ty.[4]
After the publication of that work,[3a] catalytic, asymmet-
À
ric syntheses of similar compounds with N C axial chirality
were reported by several other groups, all of which are of
amide-type compounds, such as anilides, imides, and ureas.[5]
On the other hand, the catalytic, asymmetric synthesis of
À
non-amide compounds with N C axial chirality has not
been reported so far.
achiral
N-(ortho-tert-butylphenyl)-2-alkynylanilines
2
(Scheme 1).
[a] N. Ototake, Y. Morimoto, A. Mokuya, Prof. Dr. O. Kitagawa
Department of Applied Chemistry
Shibaura Institute of Technology
3-7-5 Toyosu, Koto-ku, Tokyo 135-8548 (Japan)
Fax : (+81)3-5859-8161
E-mail: kitagawa@shibaura-it.ac.jp
[b] H. Fukaya, Dr. Y. Shida
School of Pharmacy
Tokyo University of Pharmacy and Life Sciences
1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000243.
Scheme 1. Catalytic enantioselective synthesis of atropisomeric indoles.
6752
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Chem. Eur. J. 2010, 16, 6752 – 6755

COMMUNICATION
Table 2. Catalytic enantioselective 5-exo-aminocyclization with various
ortho-alkynylanilines 2.
Before the asymmetric reaction was attempted, the opti-
mization of the reaction conditions (transition metal and
solvent) was investigated by using N-(ortho-tert-butylphen-
yl)-2-(phenylethynyl)aniline (2a) as the substrate. It was
found that when the reaction was performed in EtOH, in
the presence of PdCl2 (5 mol%), for 4 h, at 808C the 5-
endo-cyclization product, 1a, was obtained in excellent yield
(99%).
Subsequently, under these optimized conditions, a survey
of various chiral ligands was performed (Table 1). The best
result was obtained by the use of (R)-SEGPHOS as the
Entry
2
R
Time [h]
1
Yield [%][a] ee [%][b]
1
2a C6H5
2b nC4H9
4
24
7
9
7
12
24
13
23
1a 93
1b 84
1c 89
1d 95
1e 71
1 f 90
1g 67
1h 85
1i 90
60
35
49
67
77
80
82
83
83
2[c]
3
2c 4-MeC6H4
2d 2-MeC6H4
2e 2-MOMOCH2C6H4
2 f 2-iPrC6H4
2g 2-NO2C6H4
2h 2-ClC6H4
2i 2-BrC6H4
4
5
6
[d]
Table 1. Survey of chiral ligands for the catalytic, enantioselective 5-exo-
aminocyclization of 2a.
7[c]
8
9
[a] Isolated yield. [b] The ee was determined by HPLC analysis using a
chiral column. [c] 5 mol% of Ag(OTf) was added. [d] MOMO=methoxy-
methoxy.
Entry
Ligand[a]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
(R)-BINAP
(R)-MOP
82
69
trace
14
0
2
–
3
0
PHOS–PdCl2 catalyst (Table 2). In contrast to 2a, the reac-
tion of 2b, which has an aliphatic substituent, in this case an
nBu group, barely proceeded under the optimized condi-
tions. In the reaction of such less reactive substrates the ad-
dition of AgOTf (5 mol%), which leads to the generation of
a more reactive cationic-Pd species, was effective. In this
case, indole product 1b was obtained in a good yield (84%),
although a decrease in the enantioselectivity was observed
in comparison with that of phenyl derivative 2a (35% ee,
Table 2, entries 1 and 2). The reaction of para-methylphenyl
derivative 2c also resulted in a decrease in the enantioselec-
tivity (49% ee, Table 2, entries 1 and 3). On the other hand,
with ortho-methylphenyl derivative 2d, a slight increase in
the enantioselectivity was observed (67% ee, Table 2, en-
tries 1 and 4). These results may indicate that the presence
of an ortho-substituent is important for improving the enan-
tioselectivity.
A
(R)-(S)-BPPFA
(R)-DTBM-SEGPHOS
P,N-ligand
8
trace
85
89
99
93
–
A
11
26
55
60
(R)-DIFLUOROPHOS
(R)-SYNPHOS
(R)-SEGPHOS
10
[a] BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl;
(R)-MOP=
(R)-2-(diarylphosphino)-1,1’-binaphthalene; (S,S)-Trost Ligand=2-diphe-
nylphosphanyl-N-[(1S,2S)-2-[(2-diphenylphosphanylbenzoyl)amino]cyclo-
hexyl]benzamide; (R)-(S)-BPPFA=(R)-N,N-dimethyl-1-[(S)-1’,2-bis(di-
phenylphosphino)ferrocenyl]ethylamine; (R)-DTBM-SEGPHOS=(R)-
(À)-5,5’-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4’-bi-1,3-
benzodioxole; P,N-ligand=(S)-(À)-2-[2-(diphenylphosphino)phenyl]-4-
(1-methylethyl)-4,5-dihydrooxazole; (R,R)-tBu-BOX=(R,R)-2,2’-methyl-
enebis(4-tert-butyl-2-oxazoline); (R)-DIFLUOROPHOS=(R)-(À)-5,5’-
bis(diphenylphosphino)-2,2,2’,2’-tetrafluoro-4,4’-bi-1,3-benzodioxole; (R)-
SYNPHOS=[(5,6),ACHTUNGTRENNUNG(5’,6’)-bis(ethylenedioxy)biphenyl-2,2’-diyl]bis(diphe-
Subsequently, the reactions with substrates 2e–2i, contain-
ing various ortho-substituents were examined (Table 1, en-
tries 5–9). The bulkier ortho-substituents were found to
bring about a further increase in the enantioselectivity. For
example, the reactions of ortho-methoxymethoxymethyl de-
rivative 2e and ortho-isopropyl derivative 2 f gave the
indole products 1e and 1 f in 77 and 80% ee, respectively
(Table 2, entries 5 and 6). In the reactions of 2g, 2h, and 2i,
containing either a nitro group or a halogen atom as the
ortho-substituent, the best enantioselectivities were ob-
served (82–83% ee, Table 2, entries 7–9). For the less reac-
tive ortho-nitro derivative 2g, the addition of AgOTf was re-
quired to obtain 1g in a good yield.
nylphosphine); SEGPHOS=5,5’-bis(diphenylphosphino)-4,4’-bi-1,3-ben-
zodioxole. [b] Isolated yield. [c] The ee was determined by HPLC analysis
using a chiral column.
ligand.[8] In this case, atropisomeric indole 1a, containing a
À
chiral N C axis, was obtained in 60% ee (Table 1, entry 10).
In general, the reaction in the presence of a chiral ligand re-
quired a longer reaction time in comparison with that of the
ligand-free reaction.
The chiral axis of indole 1a was confirmed to have a high
rotational-energy barrier. That is, even when the isolated 1a
was heated in EtOH for 24 h at 808C, no appreciable
change in the ee was detected.[9] Thus, it is evident that the
racemization of indole product 1a does not occur under the
reaction conditions.
The increase in the enantioselectivity caused by ortho-
substitution may be due to the dynamic axial chirality gener-
À
ated around the Calkynyl Cphenyl bond (Figure 1). That is, in
À
The reactions of various ortho-alkynylanilines (2b–2i)
were then investigated in the presence of the (R)-SEG-
the present reaction, the construction of the N C axial chir-
À
ality occurs in the N C bond-forming step; direct enantio-
Chem. Eur. J. 2010, 16, 6752 – 6755
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6753

O. Kitagawa et al.
Figure 1. Possible mechanism for the increase in the enantioselectivity
caused by the ortho-substituent.
control by the chiral ligand on the Pd atom would be diffi-
cult, because the chiral ligand is relatively far way from the
À
N C axis being constructed. In the reaction of substrates
containing a bulky ortho substituent, chiral information
from (R)-SEGPHOS may be effectively transferred to the
À
À
N C bond through the axially chiral Calkynyl
namic axial chirality).
Cphenyl bond (dy-
The absolute configuration of the enantiomers in atropiso-
meric indole product 1g (82% ee) were determined in ac-
cordance with Scheme 2; reduction of the nitro group and
Figure 2. X-ray crystal structure of 4g’.
Scheme 3. Stereochemical assignment of the major enantiomer in 1h;
dppf=1,1’-bis(diphenylphosphanyl)ferrocene.
endo-hydroaminocyclization of achiral ortho-alkynylACHTUNGTRENNUNGanilines
(up to 83% ee). The present reaction is the first asymmetric
version of indole synthesis through 5-endo-hydroaminocycli-
zation of ortho-alkynylanilines, as well as the first example
Scheme 2. Stereochemical assignment of the major enantiomer in 1g.
À
of the catalytic, enantioselective synthesis of non-amide N
C axially chiral compounds.
subsequent condensation with (S)-acetoxypropionyl chloride
gave diastereomeric amides 4g and 4g’. By MPLC separa-
tion of 4g and 4g’, followed by X-ray crystallographic analy-
sis of the minor diastereomer (4g’) (Figure 2),[10] the major
enantiomer in 1g was determined to be the S configuration.
The major enantiomer in ortho-bromo derivative 1h was
also confirmed to be the S configuration on the basis of cor-
relation with benzylamino phenyl derivative 5, which can be
formed from both 1h (84% ee) and 1g (82% ee) in accord-
ance with Scheme 3.
Experimental Section
N-(ortho-tert-Butylphenyl)-2-(2-nitrophenyl)-1H-indole (1g): A solution
of PdCl2 (6.8 mg, 0.038 mmol) and (R)-SEGPHOS (32.8 mg, 0.054 mmol)
in EtOH (2.5 mL) was stirred for 10 min at RT and then AgOTf
(10.0 mg, 0.038 mmol) was added to the reaction mixture. After being
stirred for a further 10 min at 808C, 2g (285 mg, 0.77 mmol) in EtOH
(5.0 mL) was added and the mixture was stirred for 24 h at 808C. The sol-
vent was evaporated to dryness. Purification by column chromatography
(hexane/AcOEt=50:1) and subsequent MPLC (hexane/AcOEt=150:1)
gave 1g (192 mg, 67%). The ee (82%) of 1g was determined by HPLC
In conclusion, we succeeded in the enantioselective syn-
À
thesis of atropisomeric indole derivatives with an N C
chiral axis through the (R)-SEGPHOS–PdCl2-catalyzed 5-
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Atropisomers
COMMUNICATION
analysis using a CHIRALCEL OD-3 column [25 cm x 0.46 cm i.d.; 1.0%
iPrOH in hexane; flow rate: 1.5 mLminÀ1; (+)-1g (major); tR =6.1 min,
(À)-1g (minor); tR =6.9 min]. 1g: pale yellow solid; m.p. 103–1048C;
[a]2D5 =+107.7 (c=1.2, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d=
[2] Typical papers on atropisomeric ortho-tert-butylanilides: a) D. P.
Curran, H. Qi, S. J. Geib, N. C. DeMello, J. Am. Chem. Soc. 1994,
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Chem. Soc. Perkin Trans. 1 1999, 1295–1304; e) T. Bach, J. Schrçder,
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7.54–7.50 (m, 2H), 7.39 (dd, J=1.2, 8.2 Hz, 1H), 7.27–7.17ACTHNUTRGENUG(N m, 4H), 7.09–
6.98 (m, 4H), 6.74 (d, J=8.0 Hz, 1H), 6.61 (d, J=0.6 Hz, 1H), 0.81 ppm
(s, 9H,); 13C NMR (100 MHz, CDCl3, TMS): d=150.1, 148.5, 140.9,
135.7, 133.8, 132.7, 132.6, 131.4, 130.0, 128.9, 128.6, 127.5, 126.94, 126.90,
124.0, 122.9, 120.8, 120.3, 111.6, 104.7, 36.0, 31.5 ppm; IR (KBr): n˜ =
3057 cmÀ1; MS: m/z: 371 [M+H]+; HRMS: m/z calcd for C24H23N2O2:
371.1760 [M+H]+; found: 371.1744.
N-(ortho-tert-Butylphenyl)-2-(2-bromophenyl)-1H-indole (1i): A solution
of PdCl2 (2.7 mg, 0.015 mmol) and (R)-SEGPHOS (12.8 mg, 0.021 mmol)
in EtOH (2 mL) was stirred for 5 min at RT and then 2i (121 mg,
0.30 mmol) in EtOH (2 mL) was added to the reaction mixture. After
being stirred for 23 h at 808C, the EtOH was evaporated to dryness. Pu-
rification by column chromatography (hexane only) and subsequent
MPLC (hexane/AcOEt=100:1) gave 1i (109 mg, 90%). The ee (83%) of
1i was determined by HPLC analysis using
a CHIRALCEL OD-3
column [25 cm x 0.46 cm i.d.; hexane only; flow rate: 1.5 mLminÀ1; (+)-
1i (minor); tR =11.8 min, (À)-1i (major); tR =18.1 min]. 1i: pale yellow
solid; m.p. 51–528C; [a]D25 =À75.0 (c=1.0, CHCl3); 1H NMR (400 MHz,
CDCl3, TMS): d=7.76–7.72 (m, 1H), 7.69–7.65 (m, 1H), 7.56 (d, J=
8.4 Hz, 1H), 7.41–7.35 (m, 1H), 7.27–7.24 (m, 2H), 7.23–7.18 (m, 3H),
7.10–7.04 (m, 2H), 6.99 (t, J=0.8 Hz, 1H), 6.94–6.90 (m, 1H), 1.04 ppm
(s, 9H); 13C NMR (100 MHz, CDCl3, TMS): d=148.7, 140.2, 138.7, 134.8,
133.6, 133.3, 133.1, 132.0, 129.9, 128.9, 128.7, 127.0, 126.32, 126.31, 124.8,
[4] Although the enantioselectivity is not high (30–50% ee), the first
À
catalytic, asymmetric synthesis of N C axially chiral compounds
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122.4, 120.6, 120.1, 111.7, 106.2, 36.1, 31.5 ppm; IR (KBr): n˜ =3059 cmÀ1
;
MS: m/z: 404 [M+H, 79Br]+, 406 [M+H, 81Br]+; elemental analysis calcd
(%) for C24H22NBr: C 71.29, H 5.48, N 3.46; found: C 71.27, H 5.48, N
3.49.
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Acknowledgements
This work was partly supported by a Grant-in-Aid for Scientific Research
(C22590015) and the Ministry of Education, Science, Sports and Culture
of Japan. We gratefully acknowledge Takasago International Corporation
for supplying the (R)-SEGPHOS.
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Keywords: atropisomerism · enantioselectivity · indoles ·
palladium · phosphane ligands
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À
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À
[9] A high rotational barrier around the N C chiral axis of the atropiso-
meric indole was also confirmed by using 1g (83% ee). That is, no
appreciable change in the ee was detected even after heating 1g in
EtOH for 24 h, at 808C.
[10] CCDC-763524 (4g’) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Received: January 28, 2010
Published online: May 12, 2010
Chem. Eur. J. 2010, 16, 6752 – 6755
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6755