Asymmetric Hydrogenation of Unprotected Indoles Catalyzed by η6-Arene/N-Me-sulfonyldiamine-Ru(II) Complexes

Article abstract of DOI:10.1021/jacs.6b06295

Protecting-group-free transformation is a challenging and important issue in atom-economical organic synthesis. The η⁶-arene/N-Me-sulfonyldiamine-Ru(II)-BF₄ complex-catalyzed asymmetric hydrogenation of 2-substituted unprotected indoles in weakly acidic hexafluoroisopropanol gives optically active indoline compounds with up to >99% ee. Under mild reaction media, halogen atoms and synthetically important protecting groups (e.g., silyl ether, acetal, benzyl ether, and ester) on indoles are maintained, which is advantageous for the synthesis of further complex indoline molecules.

Full text of DOI:10.1021/jacs.6b06295

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Article
Asymmetric Hydrogenation of Unprotected Indoles Catalyzed
by #6-Arene/N-Me-sulfonyldiamine-Ru(II) Complexes
Taichiro Touge, and Takayoshi Arai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b06295 • Publication Date (Web): 10 Aug 2016
Downloaded from http://pubs.acs.org on August 10, 2016
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Asymmetric Hydrogenation of Unprotected Indoles Catalyzed by η
Arene/ N-Me-sulfonyldiamine-Ru(II) Complexes
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Taichiro Touge*†‡and Takayoshi Arai*†
†Molecular Chirality Research Center, Department of Chemistry, Graduate School of Science, Chiba University 1ꢀ33 Yayoi,
InageꢀKu, Chiba 263ꢀ8522, Japan
‡Corporate Research & Development Division, Takasago International Corporation, 1ꢀ4ꢀ11 Nishiꢀyawata, Hiratsuka City,
Kanagawa 254ꢀ0073, Japan
KEYWORDS: Asymmetric Hydrogenation
•Indole •Indoline •Ru Complexes •N-Me-sulfonyldiamine Ligand •Halogen
Atom Protecting Groups Derivatization of chiral indolines
•
•
ABSTRACT: Protecting groupꢀfree transformation is a challenging and important issue in atomꢀeconomical organic synthesis. The
η6ꢀarene/NꢀMeꢀsulfonyldiamineꢀRu(II)ꢀBF4 complexꢀcatalyzed asymmetric hydrogenation of 2ꢀsubstituted unprotected indoles in
weakly acidic hexafluoroisopropanol gives optically active indoline compounds with up to >99% ee. Under mild reaction media,
halogen atoms and synthetically important protecting groups (e.g. silyl ether, acetal, benzyl ether, and ester) on indoles are mainꢀ
tained, which is advantageous for the synthesis of further complex indoline molecules.
substituted indoles is the simplest, most practical and atomꢀ
efficient.3
INTRODUCTION
The η6ꢀarene/sulfonyldiamineꢀRu(II) complexes pioneered by
Chiral indolines are important structural motifs in naturally
Noyori and Ikariya4 have been shown to exhibit excellent cataꢀ
1ꢀ3
occurring alkaloids and numerous bioactive compounds.
lytic activity in a wide range of asymmetric transfer hydrogenꢀ
For example, the antitumor agent SARꢀ260301 (1) 1hꢀi is an Nꢀ
ations of ketones or imines (Figure 2). Ohkuma reported the
amide of (S)ꢀ2ꢀmethylindoline, and the antiꢀinflammatory
cationic Ru(OTf)(TsDPEN)(pꢀcymene) complex (5a), which
agent 21j and antitumor agent 31k also contain the chiral indoꢀ
works efficiently in methanol for the catalytic asymmetric
line skeleton (Figure 1).
hydrogenation of ketonic substrates.5 The BF4 analog ((R,R)ꢀ
5b) has also been shown to exhibit similar catalytic activity.6a
FIGURE 1. Examples of Chiral IndolineꢀContaining Biologiꢀ
cally Active Compounds
FIGURE 2. η6ꢀArene/sulfonyldiamineꢀRu(II) Complexes
F3C
O
N
N
O
O
O
H
N
N
N
F3C
OH
N
H
N
O
2
1
(SAR-260301)
F
HO
O
H
N
H
S
O2
N
N
Through the use of η6ꢀarene/sulfonyldiamineꢀRu(II) complexꢀ
es, transfer hydrogenation and H2ꢀhydrogenation of prochiral
ketones,4,5 imines, quinolones, and quinoxalines have been
widely investigated, as summarized in Scheme 1.6 For examꢀ
ple, 2ꢀmethylquinoline and 2ꢀmethylquinoxaline can be sucꢀ
3
Among the various methods that are available for the synthesis
of chiral indolines,2 the direct asymmetric hydrogenation of 2ꢀ
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cessfully reduced by (R,R)ꢀ4 with formic acid as the hydrogen
acid (e.g., camphorsulfonic acid) was required as an activator
(Scheme 2, eq. (2)).
source [Method A].6h In the reduction of an imine substrate,
2,3,3ꢀtrimethylindolenine is smoothly obtained by (R,R)ꢀ5b in
methanol with hydrogen gas as a hydrogen source [Method B].
1
2
3
4
SCHEME 2. Classification of the Asymmetric Hydrogenation
of Indoles.
6b, d, e, g, j, k
However, the reduction of indoles is difficult to
achieve with Ru complexes under these conditions.
5
6
7
8
9
SCHEME 1. Asymmetric Reduction of NꢀHetero Aromatic
Compounds with η6ꢀArene/sulfonyldiamineꢀRu(II) Complexꢀ
es7
10
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There has been limited success in the catalytic asymmetric
reduction of unprotected indoles, and there is no previous reꢀ
port on the Ruꢀcatalyzed reduction of unprotected indoles. We
report here the first chiral Ru(II) complexꢀcatalyzed hydroꢀ
genation of unprotected indoles under mild reaction conditions
in protic solvent.
RESULTS AND DISCUSSION
Initial Screening of Asymmetric Hydrogenation of 2ꢀ
Methylindole.
Based on the work of Zhang and Zhou, we considered that the
iminium intermediate is a key point for the reduction of indole
derivatives with the use of η6ꢀarene/sulfonyldiamineꢀRu(II)ꢀ
type complexes. Based on these pioneering works,9aꢀb η 6ꢀ
arene/sulfonyldiamineꢀRu(II) complexes were applied to the
asymmetric hydrogenation of unprotected 2ꢀmethylindole (6a)
(Table 1). For the reaction with a substrate/catalyst molar ratio
(S/C) = 500 under H2 (5.0MPa) at 30 °C, although neither the
RuCl complex (R,R)ꢀ4 nor the RuBF4 complex (R,R)ꢀ5b proꢀ
moted the hydrogenation of 6a in MeOH, toluene or THF,
(R,R)ꢀ5b catalyzed the reaction in 2,2,2ꢀtrifluoroethanol (TFE)
to give the 2ꢀmethylindoline (7a) in 32% yield with 88% ee
(entry 6). The use of 1,1,1,3,3,3ꢀhexafluoroisopropanol (HFIP)
as a fluorinated solvent further improved the catalytic perforꢀ
mance of (R,R)ꢀ5b to give 7a in 65% yield with a higher steꢀ
reoselectivity of 94% ee (entry 7).
TABLE 1. Initial Screening for the Asymmetric Hydrogenaꢀ
tion of 2ꢀMethylindole
Kuwano and Ito reported the first hydrogenation of the olefinꢀ
portion of Nꢀprotected indoles using Rh and a Ru/PhTRAP
complex under basic conditions.8aꢀd Feringa8e and Pfaltz8f also
reported the asymmetric hydrogenation of Nꢀprotected indoles
with the use of Rh and Ir/N,P catalysts (Scheme 2, eq. (1)). In
contrast, the hydrogenation of unprotected indoles is still an
unsolved challenge. Zhang, Zhou and coꢀworkers approached
this problem by changing the reduction of the olefinꢀportion of
indole9aꢀb (a) to the reduction of an iminium ion intermediate
(b), which is generated with the assistance of a Brφnsted acid.
While the chiral diphosphineꢀPd catalyst reduced the iminium
ion intermediate, a stoichiometric amount of a strong Brφnsted
entry
catalyst
(R,R)-4
(R,R)-4
(R,R)-5b
solvent[a]
MeOH
yield (%)[b]
<0.1
ee (%)[c]
1
2
3
-
-
-
Toluene
MeOH
<0.1
<1
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(R,R)-5b
(R,R)-5b
(R,R)-5b
(R,R)-5b
Toluene
THF
1
<1
32
65
-
1
2
3
4
NꢀMethylated TsDPEN ligand (14) was prepared by the treatꢀ
ment of (R,R)ꢀTsDPEN (11) with methyl chloroformate (12)
under SchottenꢀBaumann reaction conditions (i) and subseꢀ
quent reduction using Vitride® (ii) in 64% yield in two steps.
Complexation of ligand (14) with [RuCl2(pꢀcymene)]2 (15)
easily afforded the parent RuCl complex ((R,R)ꢀ8-Cl) (iii) and
cationic RuBF4 complex ((R,R)ꢀ8) was prepared by the anion
exchange reaction using AgBF4 in quantitative yield (iv).
5
6
7
-
TFE[d]
HFIP[e]
88(R)
94.1(R)
5
6
7
8
9
[a] 0.7mL/100mg substrate of solvent was used. [b] GC yield.
[c] Determined by HPLC analysis. [d] 2,2,2ꢀTrifluoroethanol
[e] 1,1,1,3,3,3ꢀHexafluoroisopropanol
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Synthesis of New Cationic η6ꢀArene/NꢀMeꢀsulfonyldiamineꢀ
Ru(II) Complexes and Its Application for Asymmetric Hydroꢀ
genation of 2ꢀMethylindole.
TABLE 2. Catalyst Development for the Asymmetric Hydroꢀ
genation of 2ꢀMethylindole[a]
Ikariya and Wills reported that the catalytic activity of η6ꢀ
arene/sulfonyldiamineꢀRu(II) complexes could be enhanced
with the use of a secondary amino analogue.10 Based on a
consideration of the ease of preparation and the practical utiliꢀ
ty of related cationic complexes, we newly prepared a series of
Nꢀmethylated RuBF4 complexes (8ꢀ10) (Figure 3).
entry
catalyst
H2
(MPa)
temp
(ºC)
yield
ee
(%)[b]
(%)[c]
1
(R,R)-5b
(R,R)-8
(R,R)-9
(S,S)-10
(R,R)-8
(R,R)-8
(R,R)-8
(R,R)-8
(R,R)-8
(R,R)-8
(R,R)-8
5.0
5.0
5.0
5.0
5.0
5.0
5.0
3.0
1.0
5.0
5.0
30
30
30
30
20
10
0
65
>99
92
94.1(R)
95.6(R)
91.7(R)
95.4(S)
96.0(R)
96.2(R)
96.4(R)
96.0(R)
95.9(R)
96.2(R)
90.0(R)
FIGURE 3. New Cationic η6ꢀArene/NꢀMeꢀsulfonyldiamineꢀ
Ru(II) Complexes
2
3
4
>99
>99
98
5
6
7
96
8
10
10
10
10
96
9
96
10[d]
11[f]
>99[e]
93
SCHEME 3. Preparation of New Cationic η6ꢀArene/NꢀMeꢀ
sulfonyldiamineꢀRu(II) Complexes (R,R)ꢀ8
[a] 0.7mL/100mg substrate of solvent was used. [b] GC yield.
[c] Determined by HPLC analysis. [d] S/C = 1 000, 30 h. [e]
Isolated yield was 99%. [f] S/C=100, HFIP (1.0 eq. to 6a),
without the other solvent, 18 h.
The Nꢀmethylated RuBF4 complexes (R,R)ꢀ8 and (S,S)ꢀ10
furnished the full conversion of 6a to give (R)ꢀ7a with 95.6%
ee and (S)ꢀ7a with 95.4% ee, respectively. For the (R,R)ꢀ8ꢀ
catalyzed hydrogenation, the reaction carried out at 0 ºC gave
7a in up to 96.4 % ee, and the reaction could be conducted
under a lower hydrogen pressure (3 or 1 MPa), which would
be particularly important for industrial application. Finally,
the catalyst loading could be successfully reduced to S/C = 1
000 for full conversion while maintaining the enantiomeric
excess of 7a (96.2% ee), though the reaction time was proꢀ
longed (entry 10). When the amount of HFIP was reduced to 1
eq. to 6a, 7a was obtained in 93% yield with 90% ee (entry
11).
Asymmetric Hydrogenation of Various Unprotected Indoles.
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With the ruthenium catalysts (R,R)ꢀ8, 9, and (S,S)ꢀ10, the genꢀ Under the optimized conditions, 2ꢀalkylated indoles were
1
2
3
4
5
6
7
8
erality of the asymmetric hydrogenation of indoles was examꢀ
ined, and the results with the use of appropriate catalysts for
particular substrates are summarized in Table 3.
smoothly hydrogenated to give the corresponding indolines in
high conversion with high to excellent ees (entries 1,2). The
cyclopropyl ring remained intact in (R,R)ꢀ8ꢀcatalysis to give
7d with 83% ee. The (1Hꢀindolꢀ2ꢀyl)methanol (6g) was also
smoothly hydrogenated for the first time to directly access the
chiral 2ꢀhydroxymethtyl indoline (7g) with 73% ee. For methꢀ
oxy ethylꢀsubstituted 6e, (R,R)ꢀ8 gave 7e with 74% ee, though
(S,S)ꢀ10 gave better results for 7e with 83% ee. 2ꢀ
Phenylindole (6h) was slowly converted to 7h with moderate
ee (entry 7). For 2ꢀmethylindoles with substituents at the 5ꢀ
position, typically, (S,S)ꢀ10 showed better results than (R,R)ꢀ8
(entries 8,9). Ringꢀfused substrates (6kꢀm) that were connectꢀ
ed between the 2ꢀ and 3ꢀpositions of indole were sufficient for
the rutheniumꢀcatalyzed asymmetric hydrogenation. The hyꢀ
drogenation of 5ꢀmembered ringꢀfused substrate (6k) was
smoothly catalyzed by (R,R)ꢀ9 even with a catalyst loading of
S/C = 2 000 (entry 10). The 8ꢀmembered system to give 6m
achieved >99% ee with (R,R)ꢀ8 (entry 12). Although only cisꢀ
isomers were obtained for these ringꢀfused substrates, when
2,3ꢀdimethylindole was subjected to hydrogenation, the transꢀ
isomer was detected (cis: trans = 92 : 8), and both isomers
showed a very high enantiomeric excess (97% ee for cis and
99% ee for trans) (entry 13). Interestingly, a substrate bearing
a phenolic hydroxyl group at the 4ꢀposition of 2ꢀmethylindole
was reduced by (R,R)ꢀ8 with high yield and excellent ee (99%
ee) (entry 14).
TABLE 3. Asymmetric Hydrogenation of Unprotected Inꢀ
doles[a]
9
10
11
12
13
14
15
16
17
18
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22
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Asymmetric Hydrogenation of Halogenated Indoles.
entry
sub-
strat
e
catalyst
S/C
temp
(ºC)
time
(h)
yield[
ee[c]
(%)
b]
TABLE 4. Asymmetric Hydrogenation of Halogenated Inꢀ
doles [a]
(%)
1
6b
6c
6d
6e
6f
(R,R)-8
(R,R)-8
(R,R)-8
(S,S)-10
(R,R)-8
(R,R)-8
(S,S)-10
(S,S)-10
(S,S)-10
(R,R)-9
(R,R)-8
(R,R)-8
(R,R)-8
(R,R)-8
100
250
100
100
100
100
100
500
500
0
30
>99
96
97(R)
2
10
0
27
7
97(R)
83(S)
3
93
4
30
10
10
60
10
10
0
30
25
30
20
7
99
83(-)
5
84
86(+)
6
6g
6h
6i
98
73(S)
7
38
42(+)
8
>99
>99
97
96(S)
9
6j
7
95(+)
10[d]
11[d]
12[d]
13[e]
14
6k
6l
2 000
250
30
31
27
23
28
91(R,R)
96(R,R)
>99(+)
97 (R,R)
99(+)
30
30
10
10
96
6m
6n
6o
100
59
100
92
250
>99
[a] 0.7 mL/100 mg substrate of solvent was used. [b] The reꢀ
sults by using (R,R)-8 catalyst were shown in Supporting In-
formation (Table S2).
[a] 0.7mL/100mg substrate of solvent was used. [b] Isolated
yield. [c] Determined by GC or HPLC analysis. [d] Only cisꢀ
form products (7k-7m) were obtained. [e] Major product was
the cis isomer (7n) (84.0% de (cis), and the ee of the trans
isomer was 99% ee.)
The (S,S)ꢀ10ꢀcatalyzed asymmetric hydrogenation is also useꢀ
ful for the reduction of indoles having electronꢀwithdrawing
substituents. The 5ꢀfluoroꢀ2ꢀmethylindole was successfully
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R2
R2
converted to the 5ꢀfluoroꢀ2ꢀmethylindoline with 94% ee. Furꢀ
thermore, the reduction of chloroꢀ or bromoꢀsubstituted inꢀ
Catalyst (S/C = 100)
HFIP, conditions
1
2
R1 + H2
(5.0 MPa)
R1
*
N
H
N
H
doles was fascinating, since various lateꢀtransition metalꢀ
mediated reduction caused dehalogenation as a side reaction.
5ꢀChloroꢀ and 5ꢀbromoꢀ2ꢀmethylindole were converted to the
corresponding indolines 7q and 7s in almost quantitative
yields and with high enantioselectivities (95% ee and 96% ee,
respectively), while retaining the halogen atoms. In these reacꢀ
tions, dehalogenated products were not observed, and the reacꢀ
tion could be carried out on a 3 g scale to give 7q.
3
6t - 6y
7t - 7y
4
5
6
7
8
9
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Derivatization of (S)ꢀ5ꢀChloroꢀ2ꢀmethylindoline.
The synthetic utility of the chiral (S)ꢀ5ꢀchloroꢀ2ꢀ
methylindoline (7q) is shown in Scheme 4. The coupling reacꢀ
tions of 7q with potassium vinyltrifluoroborate (15) and 3ꢀ
formylphenylboronic acid (17) were catalyzed by a PdꢀCyꢀ
cBRIDP complex11 to afford the corresponding coupling prodꢀ
ucts 16 and 18 in high yields and without a loss of enantioseꢀ
[a] 0.7 mL/100 mg substrate of solvent was used.
lectivity. The successful introduction
a hydrogenationꢀ
sensitive vinyl group or formyl group demonstrates the adꢀ
vantage of the current halogenꢀtolerant catalytic asymmetric
reduction.
In weakly acidic HFIP reaction media (pH = 4–5), the acidꢀ
sensitive tertꢀbutyldimethylsilyl (TBS) protecting group of a
primary alcohol and ethylene acetal of an aliphatic aldehyde
were tolerated in the (S,S)ꢀ10ꢀcatalyzed hydrogenation to give
7t in 94% yield with 92% ee and 7u in 90% yield with 90%
ee, respectively. Both benzyl ethers of primary alcohol and
phenolic alcohol survived in the (R,R)ꢀ8ꢀcatalyzed hydrogenaꢀ
tion. Ethyl ester was also compatible with the hydrogenation
to give 7x in 95% yield with 91% ee. Since the previously
reported H8ꢀBINAPꢀPd catalysis in CSA9a,b did not give 7t or
7u at all, these results demonstrate the advantages of the curꢀ
rent ruthenium catalysis directed toward the synthesis of furꢀ
ther complex indolineꢀderived compounds (see details in the
Supporting Information).
SCHEME 4. Derivatizations of (S)ꢀ5ꢀchloroꢀ2ꢀmethylindoline
to 2ꢀmethylꢀ5ꢀvinylindoline and (S)ꢀ5ꢀ(3ꢀformylphenyl)ꢀ2ꢀ
methylindoline.
Pd(OAc)2 (2 mol %)
Cy-cBRIDP (4 mol %)
Cl
K2CO3 (4 eq)
+
BF3K
(1)
N
N
2-Methyl-2-butanol
reflux, 9 h
H
H
7q
(95% ee)
15
16
75% yield, 95% ee
Derivatization of Chiral Indoline to Tetrahydroꢀ1Hꢀ
pyrroloindole.
A oneꢀpot derivatization of acetalꢀprotected chiral indoline
(7u) to chiral tetrahydro 1Hꢀpyrroindole (21) is shown in
Scheme 5. After the deprotection of acetal 7u with trifluoroaꢀ
cetic acid, subsequent reduction of the intermediary tetrahydro
pyrroloindolium salt using sodium cyanoborohydride gave 21
in high yield and with almost no loss of enantioselectivity.
As shown in Figure 1, chiral tetrahydroꢀ1Hꢀpyrroloindole
skeletons are found in some biologically active compounds,
which have been prepared in multistep syntheses that include
optical resolution. This is the first and practical example of the
catalytic asymmetric synthesis of tetrahydroꢀ1Hꢀpyrroloindole.
Asymmetric Hydrogenation of Indoles with Protecting Groups.
SCHEME 5. Derivatization of Chiral Indoline to Tetrahydroꢀ
1Hꢀpyrroloindole
Furthermore, the results using indoles with synthetically imꢀ
portant protecting groups are fascinating, as shown in Table 5.
TABLE 5. Asymmetric Hydrogenation of Indoles with Proꢀ
tecting Groups[a]
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Reuse of HFIP Solvent for Asymmetric Hydrogenation.
From the perspective of green chemistry and industrial proꢀ
duction, the reuse of solvent is very important. Since the curꢀ
rent reaction system of asymmetric hydrogenation does not
require the use of coꢀsolvents or additives, the solvent can be
easily recovered by simple distillation after the reaction is
complete. The HFIP solvent was recovered quantitatively after
hydrogenation of 2ꢀmethylindole, and the recovered HFIP was
reused in the next hydrogenation to give 2ꢀmethylindole withꢀ
out a loss of yield or enantioselectivity (Scheme 6).
In contrast, when hydrogenation was performed with D2 and
HFIP, the incorporation of deuterium was observed only at the
2ꢀposition and the amine of the indoline (eq. 4, Scheme 7).
These experimental results prove that unprotected indoles are
activated in the weakly acidic HFIP solvent to form an iminiꢀ
um intermediate, and the η 6ꢀarene/NꢀMeꢀsulfonyldiamineꢀ
Ru(II)ꢀBF4 complexes hydrogenate the iminium intermediate
quite effectively to provide asymmetric indoline synthesis.
This highly efficient asymmetric hydrogenation is believed to
occur through cooperation between rutheniumꢀhydride and
amineꢀNH in the concerto catalysis.12 The moderate isotropic
labeling at 2ꢀposition in eq. 4 was discussed in the Supporting
Information, and was improved by carrying out the reaction
using both D2 and d2ꢀHFIP (eq. 5).
SCHEME 6. Reuse of the HFIP Solvent for Asymmetric Hyꢀ
drogenation of 2ꢀMethylindole
.
Proposed Transition State.
In the reaction of ketonic or imine substrates with η 6ꢀ
arene/sulfonyldiamineꢀRu(II) complexes, a CH/
π interaction
Mechanistic Study by Using Isotopic Labeling Experiments.
between a hydrogen atom on the η6ꢀarene and the aromatic
ring of a substrate has been proposed.10cꢀd,13 Furthermore, hyꢀ
drogenꢀbonding interaction between the substrates with NHꢀ
proton of ligand is believed to facilitate the enantioface selecꢀ
tion.13 With these interactions, acetophenone is reduced to (R)ꢀ
2ꢀphenylethanol by (R,R)ꢀRu catalyst. Because (R)ꢀenriched
indoline was obtained using (R,R)ꢀ8, the reaction would proꢀ
ceed via a similar transition state (Figure 4). For the reduction
of iminium intermediate, the cationic intermediate would seem
to be difficult to receive the assistance of hydrogenꢀbonding.
However, with including πꢀelectron of C=N double bond of
the iminium intermediate, the hydrogenꢀbonding network is
workable for constructing the 6ꢀmembered transition state.10d
If the proton is dissociated from the iminium intermediate, the
hydrogenꢀbonding interaction using imine would strongly
stabilize the 6ꢀmembered transition state. (See further discusꢀ
sion about the other possible transition states in the Supporting
Information (Figure S4)).
To elucidate the reaction mechanism, the negligible asymmetꢀ
ric transfer hydrogenation (ATH) reaction in this HFIP solvent
system was firstly confirmed (see details in the Supporting
Information). When asymmetric hydrogenation was run in d2ꢀ
1
HFIP and H2, HꢀNMR analysis showed that two deuterium
atoms were introduced at the 3ꢀposition, and deuteration at the
2ꢀposition was not observed (eq. 3, Scheme 7).
SCHEME 7. Isotopic Labeling Experiments Using D2 and d2ꢀ
HFIP
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taichiro_touge@takasago.com
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FIGURE 4. Proposed Transition State
Author Contributions
Both authors helped to write the manuscript. Both authors have
approved the final version of the manuscript. These authors conꢀ
tributed equally.
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8
Notes
The authors declare no competing financial interests.
9
ACKNOWLEDGMENT
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We thank Messrs. Yoshihiro Yaguchi, Akihiro Kawaraya,
Kazuhiko Sakaguchi, Jun Kurabe, Hiroaki Izumi, Kenichi Tomiꢀ
yama, Mses. Hisae Kasuga, Kyoko Zaizen, Chikako Kawata and
Noriko Yamamoto at Takasago International Corporation for the
measurement of NMR and mass spectra, and their assistance with
the experiments. We also thank Prof. Takeshi Nakai and Prof.
Masahiro Terada for helpful discussions. This research is supportꢀ
ed by JSPS KAKENHI Grant Number JP16H01004 in Precisely
Designed Catalysts with Customized Scaffolding.
CONCLUSION
In conclusion, various unprotected indole compounds were
efficiently hydrogenated by η6ꢀarene/NꢀMeꢀsulfonyldiamineꢀ
Ru(II)ꢀBF4 catalysts under mildly acidic HFIP, which showed
advantages for the synthesis of further complex molecules.
The 5ꢀhaloꢀ2ꢀmethylindoles were converted to the correspondꢀ
ing indolines with retaining the halogen atoms. From the 5ꢀ
haloꢀ2ꢀmethylindoles, cross coupling reactions were accomꢀ
plished. Some acidꢀsensitive protective groups were also tolerꢀ
ant under the mild η6ꢀarene/NꢀMeꢀsulfonyldiamineꢀRu(II)ꢀBF4
catalyses. With these fascinating and powerful hydrogenation,
further applications toward the synthesis of advanced indoline
molecules are now being examined by our group.
ABBREVIATIONS
TsDPEN, (Nꢀ(pꢀToluenesulfonyl)ꢀ1,2ꢀdiphenylethylenediamine
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EXPERIMENTAL DETAILS
General procedure for Asymmetric Hydrogenation of Indoles
Using η6-Arene/N-Me-sulfonyldiamine-Ru(II) complexes un-
der the conditions of S/C = 500, 10 °C for 7 h.
Indole (1.5 mmol) and Ru catalyst (0.003 mmol) were placed
in a 100 mL stainless steel autoclave equipped with a glass
inner tube. The atmosphere was replaced with argon gas, and
solvent (1.4 mL) was added to this mixture. Hydrogen was
initially introduced into the autoclave at a pressure of 1.0 MPa,
before being reduced to 0.1 MPa. This procedure was repeated
three times. Then the autoclave was pressurized with H2 gas
(5.0 MPa), and the solution was stirred vigorously at 10 ºC for
7 h. The product was obtained by silica gel chromatography.
Optical purities of the products were determined by ChiralꢀGC
or HPLC analysis.
ASSOCIATED CONTENT
Supporting Information
Methods for preparing Ru complexes and indoles, experimental
procedures for asymmetric hydrogenation, NMR, MS, chiralꢀGC
and chiralꢀHPLC data, [α]D values of products,. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
tarai@faculty.chibaꢀu.jp
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