The use of mixtures of ligands in the Ir-catalyzed asymmetric reductive amination of 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one

Article abstract of DOI:10.1007/s11172-015-1046-8

A comparative testing of complex catalysts with homo and hetero combinations of chiral and achiral monodentate phosphite- and phosphine-type ligands in the Ir-catalyzed asymmet- ric direct reductive amination of 2,3,4,9-tetrahydro-1H-carbozol-1-ones was carried out. A positive effect of the use in the reaction of a mixture of chiral and achiral ligands was demonstrated. This approach makes feasible a one-pot synthesis of valuable biologically active compounds of (tetrahydro-1H-carbazol-1-yl)amine series.

Full text of DOI:10.1007/s11172-015-1046-8

Russian Chemical Bulletin, International Edition, Vol. 64, No. 7, pp. 1591—1594, July, 2015
1591
The use of mixtures of ligands
in the Irꢀcatalyzed asymmetric reductive amination
of 6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ1ꢀone
S. E. Lyubimov,a D. V. Ozolin,a A. A. Pavlov,a P. Yu. Ivanov,a K. B. Mayorov,b V. S. Velezheva,a
V. A. Davankov,a and B. V. Nikonenkob
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: lssp452@mail.ru
bCentral Tuberculosis Research Institute
2 Yauzskaya alleya, 107564 Moscow, Russian Federation.
Fax: +7 (499) 785 9154. Eꢀmail: majorov@list.ru
A comparative testing of complex catalysts with homo and hetero combinations of chiral
and achiral monodentate phosphiteꢀ and phosphineꢀtype ligands in the Irꢀcatalyzed asymmetꢀ
ric direct reductive amination of 2,3,4,9ꢀtetrahydroꢀ1Hꢀсarbozolꢀ1ꢀones was carried out.
A positive effect of the use in the reaction of a mixture of chiral and achiral ligands was
demonstrated. This approach makes feasible a oneꢀpot synthesis of valuable biologically active
compounds of (tetrahydroꢀ1Hꢀcarbazolꢀ1ꢀyl)amine series.
Key words: asymmetric direct reductive amination, iridium, phosphoramidite, biologically
active compounds, mixture of ligands.
(Tetrahydroꢀ1Hꢀcarbazolꢀ1ꢀyl)amines are an imporꢀ
tant class of organic compounds known for their biologiꢀ
cal activity. For example, these compounds exhibit activiꢀ
ty in the inhibition of tuberculosis mycobacteria, prevenꢀ
tion of hepatitis C, as well as in the treatment of atypical
pneumonia.1,2 There are a number of other compounds
with similar structure, exhibiting high biological activity.3
Note that until recently these compounds were used as
racemic mixtures, which is considerably less efficient than
the use of enantiomerically pure compounds, since the
enantiomer possessing no required biological activity can
have a negative effect on the patient conditions.4 One of
the promising approaches to the preparation of chiral
(tetrahydroꢀ1Hꢀcarbazolꢀ1ꢀyl)amines is a oneꢀstep asymꢀ
metric metal complex reductive amination of correspondꢀ
ing ketones.5 In this case, there is no necessity in the
synthesis of scaled amounts of prochiral imines by a proꢀ
longed reflux of corresponding ketones with primary
amines, recrystallization of the reaction products suscepꢀ
tible to hydrolysis with their subsequent asymmetric reꢀ
duction.1 Recently, we reported a first successful applicaꢀ
tion of synthetically available phosphiteꢀtype ligands in
the reductive amination reaction of acetophenones with
up to 71% ee, however, the use of this group of ligands in
the reaction with substituted 2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbꢀ
azolꢀ1ꢀones gave only 34% enantioselectivity.6 In the
present work, we report the results of the use of the phosꢀ
phiteꢀtype ligands in the direct enantioselective reductive
amination reaction of 2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ1ꢀ
ones and a positive effect of the use of a mixture of chiral
and achiral ligands in this catalytic reaction, which gave a
considerable increase in enantioselectivity.
Results and Discussion
The phosphiteꢀtype ligands L1—L3 were initially testꢀ
ed in the asymmetric reductive amination reaction of
6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ1ꢀone (1) with
benzylamine (Scheme 1) in benzene at 50 C, using
[Ir(COD)Cl]2 as an iridium precursor and Ti(OPri)4 as
a waterꢀbinding agent (Table 1, entries 1—3).
Both the conversion and the selectivity in these experꢀ
iments turned out to be low. Taking into account a known
positive effect from the presence of iodine in the hydrogeꢀ
nation reaction of imines and heterocyclic compounds, we
added iodine to the catalyst (see Table 1, entries 4—6).7,8
And in fact, we observed a considerable increase in the
enantiomeric excess in the case of ligand L2 (see Table 1,
entry 5). Ligand L2, which gave the highest enantiomeric
excess in benzene, was tested in the reductive amination
of 6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ1ꢀone (1) in
other solvents: CH2Cl2, ethyl acetate, and THF. However,
these changes gave either comparable, or somewhat lower
values of conversion and enantioselectivity. The use of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1591—1594, July, 2015.
1066ꢀ5285/15/6407ꢀ1591 © 2015 Springer Science+Business Media, Inc.

1592
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Lyubimov et al.
Scheme 1
n = 1 (2a), 2 (2b)
molecular sieves 3 Å as a waterꢀbinding agent, which are
successfully used in the reductive amination with involveꢀ
ment of phosphine ligands,5 did not lead to the expected
reaction product (see Table 1, entry 10). An increase in
the reaction temperature to 60 C with Ti(OPri)4 as
a waterꢀbinding agent led to a slight increase in the conꢀ
version, however, the enantiomeric excess decreased (see
Table 1, entries 11 and 12). Further increase in the temꢀ
perature to 70 C led to a suppression of the process selecꢀ
tivity (see Table 1, entries 13 and 14).
catalyzed hydrogenation and in a number of cases makes
it possible to increase both the conversion and the enantioꢀ
selectivity.9 Apart from that, a successful example of the
use of hetero combination of two different monodentate
ligands in the Irꢀcatalyzed asymmetric hydrogenation of
quinolines is known.10,11 In fact, the coꢀuse of monodenꢀ
tate ligands L1—L3 with bulky triphenylphosphine made
it possible to considerably increase the enantioselectivity
(up to 78% ee) when the reaction was carried out in
benzene at 50 C (Table 2, entries 1—3). Interestingly, the
combination of "mixed" catalysts with the addition of
iodine led to considerably lower values of conversion and
enantioselectivity (see Table 2, entries 4—6). Besides, in
all the cases the addition of triphenylphosphine led to the
To check a possibility of optimization of the results of
this reaction, we tested an idea of the combination of two
different ligands at the central metal atom in the complexꢀ
catalyst. This approach is well known in the rhodiumꢀ
Table 1. IrꢀCatalyzed direct asymmetric reductive amination of 6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ
1ꢀone (1) with benzylamine (90 atm H2, 8 h)
Entry
Catalyst
Medium
Additive
T/C
Conversion (%) eea (%)
1
2
3
4
5
6
7
8
[Ir(COD)Cl]2/4L1
[Ir(COD)Cl]2/4L2
[Ir(COD)Cl]2/4L3
[Ir(COD)Cl]2/4L1
[Ir(COD)Cl]2/4L2
[Ir(COD)Cl]2/4L3
[Ir(COD)Cl]2/4L2
[Ir(COD)Cl]2/4L2
[Ir(COD)Cl]2/4L2
[Ir(COD)Cl]2/4L2
[Ir(COD)Cl]2/4L2
[Ir(COD)Cl]2/4L2
[Ir(COD)Cl]2/4L2
[Ir(COD)Cl]2/4L2
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
CH2Cl2
EtOAc
Ti(O—Pri)4
Ti(O—Pri)4
50
50
50
50
50
50
50
50
50
50
60
60
70
70
21
35
32
14
18
15
17
16
20
10
40
36
48
42
12 (+)
17 (+)
26 (+)
17 (+)
40 (+)
—
19 (+)
36 (+)
38 (+)
—
Ti(O—Pri)4
Ti(O—Pri)4, I2
Ti(O—Pri)4, I2
Ti(O—Pri)4, I2
Ti(O—Pri)4, I2
Ti(O—Pri)4, I2
Ti(O—Pri)4, I2
9
THF
10
11
12
13
14
Benzene Molecular sieves 3 Åb
Benzene
Benzene
Benzene
Benzene
Ti(O—Pri)4
Ti(O—Pri)4, I2
Ti(O—Pri)4
15 (+)
25 (+)
0
Ti(O—Pri)4, I2
14 (+)
a The sign of optical rotation of the product is given in parentheses.
b 200 mg.

Reductive amination
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 7, July, 2015
1593
inversion of the absolute configuration in the reaction
product. Most likely, this fact can be explained by the
changes in the structure of metal complex because of the
conversion of catalytic species IrI to IrIII in the reaction
with iodine, which is characteristic of the catalysts with
phosphine ligands.8 The use of THF instead of benzene
practically does not affect the enantioselectivity, whereas
the addition of iodine decreases both the conversion and
the enantioselectivity (see Table 2, entries 7 and 8). An
increase in the reaction temperature from 50 to 70 C led
to a slight increase in the conversion, however, the selecꢀ
tivity of the process decreased (see Table 2, entries 9
and 10). We also tested the equimolar additives of other
achiral ligands: triphenylphosphite and triethylphosphite
in a mixture with ligand L1. It is interesting, but in this
case the products were obtained either as racemates, or
with extremely low enantioselectivity (see Table 1, entries
11 and 12). The use of the complexes containing a combiꢀ
nation of two different chiral phosphoramidites (L1—L2)
in the composition of one catalyst led to considerably lowꢀ
er results as compared to those obtained on the complexes
with each of two ligands separately (cf. entry 13 in Table 2
and entries 1 and 2 in Table 1). The increase in the reacꢀ
tion time from 8 to 24 h using a hetero combination of L1
and triphenylphosphine in benzene at 50 C led to the
unexpected result: the enantioselectivity increased from
78 to 90% ee with a simultaneous increase in the converꢀ
sion (see Table 2, entry 14). It is possible that this is due to
the dynamic changes in the structure of the catalytic speꢀ
cies in the course of the reaction, for example, the coordiꢀ
nation of the forming reaction product, which is an
Nꢀligand.
We also carried out a reductive amination of 6ꢀmethꢀ
ylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ1ꢀone 1 with 2ꢀpheꢀ
nylethylamine in benzene. In this case, the reaction proꢀ
ceeded with high enantiomeric excess and good converꢀ
sion (Table 3, entry 1). The use of THF instead of benzene
gave similar values of conversion and enantioselectivity
(see Table 3, entry 2).
In conclusion, we for the first time showed a possibꢀ
ility of the efficient use of a mixture of phosphiteꢀtype
chiral ligands in the combination with triphenylphosꢀ
phine in the Irꢀcatalyzed reductive amination reaction.
Such a hetero combination of ligands in the complex proꢀ
vides a considerable increase in the enantiomeric excess
of the reaction product as compared to the use of individꢀ
ual chiral ligands, as well as makes feasible a oneꢀstep
preparation of valuable biologically active (tetrahydroꢀ1Hꢀ
carbazolꢀ1ꢀyl)amines with essential enantiomeric enꢀ
richment.
Table 2. IrꢀCatalyzed direct reductive amination of 6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ1ꢀone (1) with benzylꢀ
amine using mixed catalysts (90 atm H2)
Entry
Catalyst
Medium
Additive
T/C
/h Conversion (%) ee* (%)
1
2
3
4
5
6
7
8
[Ir(COD)Cl]2/2L1, 2PPh3
[Ir(COD)Cl]2/2L2, 2PPh3
[Ir(COD)Cl]2/2L3, 2PPh3
[Ir(COD)Cl]2/2L1, 2PPh3
[Ir(COD)Cl]2/2L2, 2PPh3
[Ir(COD)Cl]2/2L3, 2PPh3
[Ir(COD)Cl]2/2L1, 2PPh3
[Ir(COD)Cl]2/2L1, 2PPh3
[Ir(COD)Cl]2/2L1, 2PPh3
[Ir(COD)Cl]2/2L1, 2PPh3
[Ir(COD)Cl]2/2L1, 2P(OPh)3
[Ir(COD)Cl]2/2L1, 2P(OEt)3
[Ir(COD)Cl]2/2L1, 2L2
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
THF
Ti(O—Pri)4
Ti(O—Pri)4
50
50
50
50
50
50
50
50
70
70
50
50
50
50
18
18
18
18
18
18
18
18
18
18
18
18
18
24
45
32
30
16
24
28
35
22
55
49
30
15
17
75
78 (–)
58 (–)
63 (–)
10 (+)
29 (+)
15 (+)
78 (–)
16 (–)
70 (–)
14 (–)
0
Ti(O—Pri)4
Ti(O—Pri)4, I2
Ti(O—Pri)4, I2
Ti(O—Pri)4, I2
Ti(O—Pri)4
THF
Ti(O—Pri)4, I2
Ti(O—Pri)4
9
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
10
11
12
13
14
Ti(O—Pri)4, I2
Ti(O—Pri)4
Ti(O—Pri)4
15 (+)
0
90 (–)
Ti(O—Pri)4
[Ir(COD)Cl]2/2L1, 2PPh3
Ti(O—Pri)4
* The sign of optical rotation of the product is given in parentheses.
Table 3. IrꢀCatalyzed direct reductive amination of 6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ1ꢀone (1)
with 2ꢀphenylethylamine (50 C, 90 atm H2, 24 h)
Entry
Catalyst
Medium
Additive
Conversion (%)
ee* (%)
1
2
[Ir(COD)Cl]2/2L1, 2PPh3
[Ir(COD)Cl]2/2L1, 2PPh3
Benzene
THF
Ti(O—Pri)4
Ti(O—Pri)4
55
50
81 (–)
79 (–)
* The sign of optical rotation of the product is given in parentheses.

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Lyubimov et al.
2.79—2.85 (m, 1 H, Ha, CH2); 2.90—2.95 (m, 1 H, Hb, CH2);
2.97—3.03 (m, 2 H, N—CH2); 4.03—4.07 (m, 1 H, N—CH);
6.94 (d, 1 H, H(6); indole, JH,H = 8.0 Hz); 7.14 (d, 1 H, H(7),
indole, JH,H = 8.0 Hz); 7.21—7.25 (m, 3 H, oꢀH, pꢀH); 7.26
(s, 1 H, H(4), indole); 7.31 (t, 2 H, mꢀH, JH,H = 7.4 Hz); 8.28
(s, 1 H, NH). 13C{1H} NMR (CDCl3), : 21.00 (C(4), cyclohexyl);
21.60 (Me); 21.85 (C(3), cyclohexyl); 29.76 (C(2), cyclohexyl);
36.56 CH2); 46.92 (N—CH2); 52.42 (N—CH); 110.71 (C(7),
indole); 111.48 (C(3), indole); 118.14 (C(4), indole); 123.26
(C(6), indole); 126.48 (mꢀC); 127.65 (C); 128.37 (C(5), indole);
128.65 (oꢀC); 128.96 (pꢀC); 134.22 (N—C); 139.79 (ipsoꢀC);
140.70 (C(2), indole). Found (%): C, 82.94; H, 7.88; N, 9.11.
C21H24N2. Calculated (%): C, 82.85; H, 7.95; N, 9.20.
Experimental
NMR spectra were recorded on a Bruker Avance 600 spectroꢀ
meter (600.15 MHz). Chemical shifts in 1H and 13C spectra were
determined relative to the residual signals of chloroformꢀd. 2D
homonuclear correlation spectra COSY were recorded to obtain
information about homonuclear protonꢀproton interaction. Diꢀ
rect protonꢀcarbon correlations were recorded using a pulse proꢀ
cedure HSQC. Remote protonꢀcarbon interactions were regisꢀ
tered using a pulse procedure HMBC. Optical rotation for the
catalysis products was measured on a Perkin—Elmer 341 polaꢀ
rimeter. Hydrogenation was carried out in 10ꢀmL stainless steel
autoclaves. (Sa)ꢀ2ꢀ(Diethylamino)dinaphtho[2,1ꢀd:1´,2´ꢀf]ꢀ
[1,3,2]dioxaphosphepine (L1),12 (Sa)ꢀ2ꢀ(morpholino)dinaphꢀ
tho[2,1ꢀd:1´,2´ꢀf][1,3,2]dioxaphosphepine (L2),12 (Sa)ꢀ2ꢀ(phenꢀ
oxy)dinaphtho[2,1ꢀd:1´,2´ꢀf][1,3,2]dioxaphosphepine (L3),13
[Ir(COD)Cl]2,14 6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ1ꢀ
one (1)15 were obtained according to the procedures described
in the literature. Conversion was measured using 1H NMR data.
Spectral characteristics of 1ꢀbenzylaminoꢀ6ꢀmethylꢀ2,3,4,9ꢀ
tetrahydroꢀ1Hꢀcarbazole (2a) agree with the literature data.6
Optical yields were determined by HPLC on an Agilent HPꢀ1100
chromatograph. Compound 2a was isolated under the following
conditions: a Chiralcel ASꢀH column (UV,  = 219 nm, hexꢀ
ane—isopropyl alcohol—diethylamine = 98 : 2 : 0.1, 1 mL min–1).
The retention times for enantiomers of 2a are 10.0 min for
(+)ꢀisomer and 11.0 min for (–)ꢀisomer. Compound 2b was
isolated under the following conditions: a Chiralcel ODꢀH colꢀ
umn (UV,  = 219 nm, hexane—isopropyl alcohol—diethylꢀ
amine = 90 : 10 : 0.1, 1 mL min–1). The retention times for enanꢀ
tiomers of 2b are 9.4 min ((+)ꢀisomer) and 11.0 min ((–)ꢀisomer).
Asymmetric direct reductive amination of 6ꢀmethylꢀ2,3,4,9ꢀ
tetrahydroꢀ1Hꢀcarbazolꢀ1ꢀone (general procedure). Dimeric
[Ir(COD)Cl]2 (2.5 mg, 0.0037 mmol) and a corresponding ligand
(0.0149 mmol) (see Table 1) or two ligands (0.0074 mmol each)
(see Tables 2 and 3) were dissolved in CH2Cl2 (0.4 mL) and the
mixture was magnetically stirred for 5 min in an autoclave
(10 mL). If necessary (see Tables), I2 (19 mg, 0.074 mmol) was
added, and the mixture was stirred for another 10 min. The
solvent was evaporated in vacuo, 6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ
1Hꢀcarbazolꢀ1ꢀone (1) (147 mg, 0.74 mmol), amine (0.89 mol),
Ti(O—Pri)4 (0.33 mL, 1.11 mmol), and a corresponding solvent
(3 mL) (see Tables 1—3) were added to the catalyst obtained.
The reaction mixture was stirred in an autoclave filled with hyꢀ
drogen, at the pressure and the temperature listed in Tables 1—3.
The reaction mixture was diluted with ethyl acetate (3 mL),
followed by the addition of water (4 mL) and centrifuging the
precipitate of titanium oxide at the rate of 3000 rpm for 15 min.
The organic phase was passed through a short layer of silica gel
with subsequent evaporation of the solvent in vacuo. The comꢀ
position of the reductive amination products were analyzed by
1H NMR and HPLC.
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1ꢀ(2ꢀPhenylethylamino)ꢀ6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀ
carbazole (2b). 1H NMR (CDCl3), : 1.64—1.71 (m, 1 H, Ha(2),
cyclohexyl); 1.71—1.80 (m, 1 H, Ha(3), cyclohexyl); 1.97—2.03
(m, 1 H, Hb(3), cyclohexyl); 2.15—2.21 (m, 1 H, Hb(2), cycloꢀ
hexyl); 2.42 (s, 3 H, Me); 2.62—2.68 (m, 2 H, H(4), cyclohexyl);
Received April 10, 2015;
in revised form May 13, 2015