Asymmetric Hydrogenation of Azaindoles: Chemo- and Enantioselective Reduction of Fused Aromatic Ring Systems Consisting of Two Heteroarenes

Article abstract of DOI:10.1002/anie.201606083

High enantioselectivity was achieved for the hydrogenation of azaindoles by using the chiral catalyst, which was prepared from [Ru(η³-methallyl)₂(cod)] and a trans-chelating bis(phosphine) ligand (PhTRAP). The dearomative reaction exclusively occurred on the five-membered ring, thus giving the corresponding azaindolines with up to 97:3 enantiomer ratio.

Full text of DOI:10.1002/anie.201606083

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International Edition: DOI: 10.1002/anie.201606083
German Edition: DOI: 10.1002/ange.201606083
Asymmetric Catalysis
Asymmetric Hydrogenation of Azaindoles: Chemo- and
Enantioselective Reduction of Fused Aromatic Ring Systems
Consisting of Two Heteroarenes
Yusuke Makida, Masahiro Saita, Takahiro Kuramoto, Kentaro Ishizuka, and Ryoichi Kuwano*
Abstract: High enantioselectivity was achieved for the hydro-
genation of azaindoles by using the chiral catalyst, which was
prepared from [Ru(h3-methallyl)2(cod)] and a trans-chelating
bis(phosphine) ligand (PhTRAP). The dearomative reaction
exclusively occurred on the five-membered ring, thus giving the
corresponding azaindolines with up to 97:3 enantiomer ratio.
A
symmetric hydrogenation of heteroarenes is a promising
method for organic synthesis. The reaction directly transforms
heteroaromatic substrates into chiral heterocycles, which are
often seen in useful organic molecules.[1] In the last decade,
much effort has been devoted to developing the asymmetric
transformation. Various heteroarenes have been hydrogen-
ated to the corresponding heterocycles in high enantioselec-
tivity through asymmetric catalysis.[2–8] Meanwhile, asymmet-
ric hydrogenation of fused aromatic rings consisting of two (or
more) heteroarenes is still severely limited in scope because
of the complexity arising from chemoselectivity. The asym-
metric hydrogenations of indolizines[9] and pyrrolo[1,2-a]pyr-
azinium salts[10] have been reported. In these works, the
reductions selectively took place on the six-membered rings.
Fan and co-workers successfully developed the highly enan-
tioselective hydrogenation of 2,6-disubstituted 1,5-naphthyr-
idines.[11,12] Moderate to low site selectivities, however, were
observed when naphthyridines were unsymmetrically substi-
tuted with small electronic biases.
Scheme 1. Supposed pathways for the hydrogenation of azaindoles.
selectively on the pyrrole ring to afford azaindolines with up
to 97:3 enantiomer ratio (e.r.).
Initial attempts on the catalytic asymmetric hydrogena-
tion of azaindoles were performed using the 2-methyl-7-
azaindole 1aa as the benchmark substrate (Table 1). Exclu-
sive reduction of the pyrrole ring was observed in the
hydrogenation using
a
[Rh(nbd)2]+/PhTRAP catalyst
(Figure 1), which is useful for the asymmetric hydrogenation
of indoles (Table 1, entry 1).[2a,b] However, the azaindoline
We focused on the asymmetric hydrogenation of pyrido-
fused pyrroles, azaindoles. To develop the hydrogenation, two
possible reaction pathways, paths A and B, should be
considered (Scheme 1). Path A starts from the addition of
À
H2 to the C2 C3 double bond, thus leading to the formation
of an azaindoline. In path B, the pyridine ring is preferentially
reduced to give 4,5,6,7-tetrahydroazaindoles. Moreover, these
two possible products may be further hydrogenated to give
octahydroazaindoles. The fully saturated products as well as
the partially reduced azaindoles are important as biologically
active compounds,[13a–c] ligands in metal complexes,[13d] etc.[13e]
Herein, we describe the ruthenium-catalyzed asymmetric
hydrogenation of azaindoles. The hydrogenation occurred
Figure 1. Chiral ligands and catalysts used in Table 1.
[*] Dr. Y. Makida, M. Saita, T. Kuramoto, Dr. K. Ishizuka,
Prof. Dr. R. Kuwano
2aa was obtained in low yield and its e.r. value was moderate.
Use of a [Ru(h3-methallyl)2(cod)]/PhTRAP catalyst[2c] led to
the remarkable improvement of the yield as well as the
enantioselectivity (entry 2).[14] However, the hydrogenation
competed with the solvolysis of the Boc group of 1aa. The
undesired reaction caused a significant decrease in the yield
of 2aa. Furthermore, the hydrogenation was attempted with
some other chiral catalysts, which have been employed for the
Department of Chemistry, Faculty of Science, and International
Research Center for Molecular Systems (IRCMS), Kyushu University
744 Motooka, Nishi-ku, Fukuoka 819-0395 (Japan)
E-mail: rkuwano@chem.kyushu-univ.jp
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201606083.
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Table 1: Optimization study.[a]
Table 2: Enantioselective hydrogenation of 7-azaindoles.[a]
Entry PG
Conditions
Solvent Conv. Yield e.r.[d]
Entry R1
R2
R3
1
2
Conv. Yield e.r.[d]
[%][b]
[%][c]
5[b,f]
[%][b]
[%][c]
1
Boc
[Rh]/PhTRAP
iPrOH
MeOH
CH2Cl2
10
81:19
1[e]
2
3
Me
nHex
iBu
H
H
H
H
H
H
H
H
H
Me
F
H
H
H
H
H
H
H
H
H
H
H
H
1aa 2aa 100
98
98
71
–
10
77
59
56
96
81
93
79
85
94:6
88:12
77:23
–
96:4
97:3
97:3
91:9
97:3
91:9
84:16
81:19
93:7
[e]
(1aa) Cs2CO3
1b
1c
1d
1e
1e
1 f
1g
1h
1i
2b
2c
2d
2e
2e
2 f
2g
2h
2i
100
80
<5
17
2
Boc
[Ru]/PhTRAP
100
47[h]
–
93:7
[g]
(1aa) Cs2CO3
Boc
(1aa)
Boc
4
5
cHex
Ph
3[i]
4
Ir complex (A)[j]
<5
–
6[f,g]
7[f]
8[f]
9[e]
10[e]
11[e]
12[e]
13[e]
Ph
84
67
[j,k]
[Ir]/B, I2
toluene <5
THF <5
toluene <5
–
–
4-MeOC6H4
4-CF3C6H4
CO2Et
Me
Me
Me
(1aa)
Boc
60
100
87
5
[Ir]/C
–
–
[j,l]
(1aa) ClCO2Me/Li2CO3
Boc Ru complex (D)
(1aa) KOtBu[j,m]
6
–
–
1j
1k
2j
2k
2l
100
88
100
CF3
H
7
Boc
(1aa)
Ts
[Ru]/PhTRAP[n]
EtOAc
EtOAc
EtOAc
EtOAc
100
100
<5
<5
98
86
–
94:6
77:23
–
Me
Me 1l
8
[Ru]/PhTRAP[n]
[Ru]/PhTRAP[n]
[Ru]/PhTRAP[n]
[a] Unless otherwise noted, reactions were conducted on a 0.20 mmol
scale in 1.0 mL of EtOAc under 5.0 MPa of H2 at 608C for 4 h.
[b] Determined by 1H NMR analysis of the crude reaction mixture.
[c] Yield of the isolated product 2. [d] Determined by HPLC analysis.
[e] Without Et3N. [f] In toluene at 408C for 48 h. [g] 10.0 MPa of H2.
(1ab)
Me
9
(1ac)
H
10
–
–
(1ad)
[a] Unless otherwise noted, reactions were conducted on a 0.20 mmol
scale with 2.5 mol% catalyst loading in 1.0 mL of solvent under 5.0 MPa
of H2 at 608C for 4 h. [b] Determined by 1H NMR analysis of the crude
reaction mixture. [c] Yield of the isolated product 2. [d] Determined by
HPLC analysis. [e] [Rh(nbd)2]SbF6/PhTRAP/Cs2CO3 =1.0:1.1:10. [f] 1ad
was formed in 5% yield (1H NMR). [g] [Ru(h3-methallyl)2(cod)]/PhTRAP/
Cs2CO3 =1.0:1.1:10. [h] 1ad was formed in 50% yield (1H NMR).
[i] Under 7.5 MPa of H2 at RT for 24 h. [j] With 1.0% catalyst loading.
[k] [{IrCl(cod)}2]/B/I2 =0.5:1.1:10. [l] [{IrCl(cod)}2]/B/ClCO2Me/
Li2CO3 =0.5:1.1:110:120. [m] D/KOtBu=1.0:4.5. [n] [Ru(h3-methallyl)2-
(cod)]/PhTRAP=1.0:1.1. Boc=tert-butoxycarbonyl, cod=1,5-cyclo-
octadiene, nbd=norbornadiene, PG=protecting group, THF=tetra-
hydrofuran, Ts=4-toluenesulfonyl.
the ruthenium catalysis (entry 4). At 608C in EtOAc, the
reaction of the 2-phenyl-7-azaindole 1e led to 2e with high
stereoselectivity, but the yield of 2e was low (entry 5).
Prolonging the reaction time failed to improve the reaction
(19% for 72 h). In the early stage of the hydrogenation, trace
amounts of 1e decomposed into its free azaindole (less than
10%), which might inhibit the ruthenium catalysis. To avoid
the decomposition, the hydrogenation of 1e was carried out in
toluene at lower temperature. The mild reaction conditions
allowed the hydrogenation to produce 2-aryl-7-azaindolines
with high e.r. values in moderate yields (entries 6–8). The
electron-donating group on the aryl substituent was prefera-
ble to the electron-withdrawing one. The azaindolecarbox-
ylate 1h was quantitatively transformed into 2h with 97:3 e.r.
(entry 9). To our surprise, the enantioselectivity was signifi-
cantly affected by the electronic properties of the 5-substitu-
ent, even though it was located far from the reaction site
(entries 10–12). The position of the substituent scarcely
influenced the asymmetric catalysis as compared with the
electronic effect (entries 10 and 13).
A series of 6-, 5-, and 4-azaindoles were also transformed
into azaindolines by the PhTRAP/ruthenium catalyst
(Table 3). The position of the nitrogen atom modestly
affected the enantioselectivity in the reactions of 2-methyl-
azaindoles (entries 1, 4, and 7). In the case of 2-phenyl-
azaindoles, the reaction of 6- and 5-azaindoles, 3b and 5b,
proceeded with stereoselectivities comparable to that of 1e
(entries 2 and 5). However, 7e was reduced with moderate
e.r. values (entry 11). As with 2-phenylazaindoles, the 4-
azaindole-2-carboxylate 7 f was hydrogenated with lower
enantioselectivity than 3c and 5c (entries 3, 6, and 12). The
correlation between the e.r. value and the size of the 2-
substituent in the 4-azaindoles 7 is similar to that observed for
the 7-azaindoles 1 (entries 7–10).
enantioselective hydrogenation of indoles[2d] and benzo-fused
azines,[4a,b,6e] but reduction of neither the five- nor six-
membered ring was observed (entries 3–6). The undesired
solvolysis was completely suppressed by use of aprotic EtOAc
solvent, which led to the quantitative formation of 2aa
(entry 7). The N-substituent of the azaindole 1 remarkably
impacted the stereoselectivity as well as the reactivity
(entries 8–10). The PhTRAP/ruthenium catalyst could pro-
duce the N-tosylazaindoline 2ab in high yield, but its
e.r. value was moderate (entry 8). The methyl-substituted
and nonsubstituted azaindoles, 1ac and 1ad, did not react
under the ruthenium-catalyzed hydrogenation conditions
(entries 9 and 10).
Various 2-substituted 7-azaindoles (1) were transformed
into the chiral azaindolines 2 in good to high enantioselectiv-
ities (Table 2). The PhTRAP/ruthenium catalyst hydrogen-
ated the azaindoles bearing a primary alkyl (R1; entries 2 and
3). However, the bulkiness of R1 significantly affected the
enantioselectivity as well as the reaction rate. The products 2b
and 2c were obtained with 88:12 and 77:23 e.r. values,
respectively. The larger cyclohexyl group of 1d hampered
2
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Table 3: Enantioselective hydrogenation of 6-, 5-, and 4-azaindoles.[a]
Entry
Subst-
rate
Product
Conv.
[%][b]
Yield
[%][c]
e.r.[d]
Scheme 2. Deuterium-labeling experiment.
1[e]
2[f]
3
3a
3b
3c
4a
4b
4c
100
90
98
86
90
91:9
94:6
91:9
À
involving the hydrogenation of the C N double bond in the
iminium tautomer of the azaindole.[2e,g] To our surprise, the
deuteration of 3c gave [D2]-4c in a yield comparable to that of
the corresponding hydrogenation. The small kinetic isotope
À
effect (1.0–1.2) may indicate that the insertion of C2 C3
double bond into Ru H bond is the turnover-limiting step. A
100
À
similar kinetic isotope effect had been reported in the
rhodium-catalyzed hydrogenation of a-acetamidoacrylates.[16]
Finally, we explored the stereoselective hydrogenation of
the remaining pyridine rings in the chiral azaindoline
products. The octahydroazaindoles with an all-cis configura-
tion were selectively obtained by using a Pt/C catalyst in the
presence of Boc2O. Starting from the 5-azaindoline (À)-6b
with 92:8 e.r., the reduction proceeded to provide (À)-9 with
no loss of the enantiopurity [Eq. (1)]. Under the same
reaction conditions, the 6-azaindoline (À)-4c was selectively
converted into (À)-10 [Eq. (2)], which may be a useful
synthetic intermediate for a specific class of IAP inhibi-
tors.[13b,c]
4
5a
6a
100
94
95:5
5[f]
6
5b
5c
7a
6b
6c
8a
87
81
82
99
92:8
92:8
93:7
100
100
7[e]
8
7b
7c
7d
7e
7 f
8b
8c
8d
8e
8 f
100
100
<5
75
99
89
–
79:21
77:23
–
9
10
11[f]
12[g]
68[b]
85
83:17
75:25
100
[a] Unless otherwise noted, reactions were conducted on a 0.20 mmol
scale in 1.0 mL of EtOAc under 5.0 MPa of H2 at 608C for 4 h.
[b] Determined by 1H NMR analysis of the crude reaction mixture.
[c] Yield of isolated product. [d] Determined by HPLC analysis. [e] With-
out Et3N. [f] In toluene at 408C for 48 h. [g] At 1008C.
In summary, we found that the hydrogenation of azain-
doles selectively took place on the five-membered ring by
using the PhTRAP/ruthenium catalyst. The chiral catalyst
allows the hydrogenation to produce optically active azaindo-
lines with up to 97:3 e.r. Use of the trans-chelating bis(phos-
phine) ligand is crucial for the high enantioselectivity as well
as the chemoselectivity. Moreover, the azaindoline products
are further saturated to the cis-octahydroazaindoles without
formation of their diastereomers and loss of the enantiopur-
ities.
To shed light on the mechanism of the hydrogenation of
azaindoles, the deuteration of 3c was carried out under
2.0 MPa of D2 (Scheme 2). The deuterium atoms were
incorporated into the azaindoline product [D2]-4c through
a syn-addition.[15] This observation suggests that the hydro-
genation proceeds through the following mechanism: the
À
addition of a ruthenium hydride species to the C2 C3 moiety
of azaindole with either subsequent reductive elimination or
the s-bond metathesis with H2 to form the azaindoline.
Furthermore, the labelling experiment ruled out the isomer-
ization of a alkylruthenium intermediate and the pathway
Acknowledgements
This work was partly supported by the JSPS KAKENHI
Grant Numbers 15K13698, 15KT0066, and 16H04149. We
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hydrogenation · ruthenium
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Received: June 22, 2016
Published online: && &&, &&&&
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
Y. Makida, M. Saita, T. Kuramoto,
K. Ishizuka, R. Kuwano*
&&&& — &&&&
Asymmetric Hydrogenation of
Azaindoles: Chemo- and Enantioselective
Reduction of Fused Aromatic Ring
Systems Consisting of Two Heteroarenes
Caught in a TRAP: Chemo- and enantio-
selective hydrogenation of azaindoles
were achieved, affording optically active
7-, 6-, 5-, and 4-azaindolines with up to
97:3 e.r. This reaction was catalyzed by
a chiral ruthenium catalyst derived from
[Ru(h3-methallyl)2(cod)] and the trans-
chelating chiral bis(phosphine) ligand,
PhTRAP. Treatment of the reduction
products with Pt/C under hydrogen gave
the corresponding octahydroazaindoles
with all-cis stereochemistry.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!