Reductive amination of ketonic compounds catalyzed by Cp*Ir(III) complexes bearing a picolinamidato ligand

Article abstract of DOI:10.1021/acs.joc.9b01565

Cp*Ir complexes bearing a 2-picolinamide moiety serve as effective catalysts for the direct reductive amination of ketonic compounds to give primary amines under transfer hydrogenation conditions using ammonium formate as both the nitrogen and hydrogen source. The clean and operationally simple transformation proceeds with a substrate to catalyst molar ratio (S/C) of up to 20,000 at relatively low temperature and exhibits excellent chemoselectivity toward primary amines.

Full text of DOI:10.1021/acs.joc.9b01565

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Article
Reductive Amination of Ketonic Compounds Catalyzed
by Cp*Ir(III) Complexes Bearing a Picolinamidato Ligand
Kouichi Tanaka, Takashi Miki, Kunihiko Murata, Ayumi Yamaguchi,
Yoshihito Kayaki, Shigeki Kuwata, Takao Ikariya, and Masahito Watanabe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01565 • Publication Date (Web): 30 Jul 2019
Downloaded from pubs.acs.org on July 31, 2019
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Reductive Amination of Ketonic Compounds Catalyzed by Cp*Ir(III) Complexes Bearing a
Picolinamidato Ligand
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Kouichi Tanaka,† Takashi Miki,† Kunihiko Murata,† Ayumi Yamaguchi,‡ Yoshihito Kayaki,‡
Shigeki Kuwata,*‡ Takao Ikariya,‡ and Masahito Watanabe*†
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†Central Research Laboratory, Technology & Development Division, Kanto Chemical Co., Inc. 7-1, Inari
1-chome, Souka-city, Saitama, 340-0003, Japan
‡Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo
Institute of Technology, 2-12-1-E4-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
O
NH2
R"
Ir cat.
+
HCO2NH4
R'
R"
R'
AcOH or HCO2H
CH3OH, reflux
up to S/C = 20,000
Ir cat.
- Transfer-hydrogenation conditions
- High activity and chemoselectivity
- Broad substrate scope
Cl Ir
N
N R2
O
R1
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ABSTRACT:
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Cp*Ir complexes bearing a 2-picolinamide moiety serve as effective catalysts for the direct reductive
amination of ketonic compounds to give primary amines under transfer hydrogenation conditions using
ammonium formate as both the nitrogen and hydrogen source. The clean and operationally simple
transformation proceeds with a substrate to catalyst molar ratio (S/C) of up to 20,000 at relatively low
temperature and exhibits excellent chemoselectivity towards primary amines.
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INTRODUCTION
The development of efficient methods for the synthesis of primary amines is important for providing
access to the requisite building blocks of pharmaceuticals, agrochemicals, functional materials, and food
additives.1 One of the most practical methods to obtain unprotected primary amines is direct reductive
amination (DRA),2 in which a mixture of carbonyl compounds and ammonia is subjected to a reducing
agent in a one-pot procedure.
atom-economical process that avoids problematic reaction wastes and careful workup stages in the
reduction with metal hydrides such as borohydrides.
In light of various heterogeneous3 and
DRA under pressurized molecular hydrogen is a well-studied
homogeneous4 hydrogenation catalysts employed to date in DRA, considerable effort has been devoted to
prevent the competitive reduction of the carbonyl group and the formation of secondary and tertiary amines
via overalkylation, thus alleviating the need for stringent reaction conditions. Formic acid and formate
salts have been utilized as viable hydrogen alternatives to control the chemoselectivity in DRA. In
addition to the classical noncatalytic Leuckart–Wallach reaction, which requires severe temperature
conditions,5 the homogeneous catalytic DRA, based on a hydrogen transfer reaction, has been explored
mainly by using Ru,6 Rh,7 and Ir8 complexes; however, reports of the selective synthesis of primary amines
have been limited.
Kitamura and coworkers reported that the use of ammonium formate instead of ammonia in transfer
hydrogenative DRA is a highly selective method for the preparation of primary amines in the presence of
catalytic amounts of [Cp*RhCl2]2.7 Although the alternative NH2 source possibly hindered the catalyst
deterioration arising from the inherent coordination of ammonia to form ammine complexes, the catalytic
activity remained at a lower level, compared to that of the transfer hydrogenation of ketones.9 Kadyrov
described the asymmetric DRA of aromatic ketones with ammonium formate catalyzed by chiral Ru
complexes with a diphosphine ligand, which resulted in the concomitant N-formylation of amines, a
relatively low catalytic activity, and a limited substrate scope.6a
Ogo and co-workers exploited a
water-soluble Cp*Ir catalyst with a 2,2’-bipyridyl group when synthesizing -amino acids from -keto
acids with a large excess (20 equiv) of ammonium formate in an aqueous solution.8a Xiao also developed
cyclometalated Ir complexes derived from ketimines as effective catalysts for DRA using ammonium
formate.8b,c The reaction of various ketones using 10 equiv of ammonium formate was completed even at
a low catalyst concentration with S/C = 1,000 at a comparatively mild temperature of 80 °C.
Since the formation of imine intermediates from ketones and amines and the subsequent reduction of
imines are generally facilitated under relatively acidic conditions, we propose that acid-tolerant hydrogen
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transfer catalysts are well suited for further improvements to their catalytic activity and chemoselectivity,
as well as to reduce the amount of ammonium formate required. In a series of chiral diamine-based
arene-Ru complexes,10 which have been recognized as excellent catalysts for the asymmetric transfer
hydrogenation of ketones and imines, however, the DRA of ketones with ammonium formate resulted in a
low selectivity for chiral primary amines.10b
The arene-Ru catalyst derived from
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N-sulfonyl-1,2-diphenylethylenediamine would be rather susceptible to ligand dissociation by protonolysis,
leading to the deterioration of catalyst performance.11 As easily accessible bidentate ligands that have
strong metal-nitrogen bonds rather than amine ligands, we studied the combination of pyridine with
carboxamides12,13 or sulfonamides14,15 for tunable candidate substructures.
Herein, we describe the
synthesis of Ir complexes with bidentate picolinamidato ligands and their catalytic applications to the
practical DRA of a range of ketones.
RESULTS AND DISCUSSION
The picolinamidato complexes 2a-f were smoothly synthesized by treatment of dimeric dichloridoiridium,
[Cp*IrCl2]2 (Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl), with 2-picolinamides 1a-f in CH2Cl2 at 30 °C
for 16 h, in the presence of 2 equiv of triethylamine, as shown in Scheme 1. Analogous reactions with
5-methylpyridine-2-sulfonamides led to the formation of the corresponding sulfonamidato complexes 3a
and 3b. These half-sandwich amidato complexes, characterized by NMR spectroscopy and combustion
analyses, were stable enough to handle in air. In addition, X-ray analysis of 2c confirmed the three-legged
piano-stool geometry around the Ir center with a five-membered chelation of the picolinamidato ligand and
a chloride ligand (see Experimental Section).
Scheme 1 Synthesis of Cp*Ir Complexes Bearing a Picolinamidato or 2-Pyridinesulfonamidato
Ligand
N
HN R2
O
1
2
Et3N
2a
2b
2c
2d
2e
; R = H, R = H
[Cp*IrCl2]2
Cl Ir
N
+
1
2
; R = N(CH3)2, R = H
N R2
O
CH2Cl2
R1
; R = H, R = 4-N(CH3)2C6H4
1
2
30 °C, 16 h
1
2
; R = N(CH3)2, R = 4-N(CH3)2C6H4
1a 1f
–
1
2
R1
; R = H, R = 4-CF3C6H4
2a 2f
–
1
2
2f
; R = H, R = 4-NO2C6H4
N
HN R
n-C4H9Li
Cl Ir
N
[Cp*IrCl2]2
S
+
O
N R
THF
O
3a
3b
; R = H
S
O
rt, 14 h
; R = CH3
O
The catalytic DRA of 2-acetonaphthone (4a) with the picolinamidato-Ir complexes 2a-f and the
sulfonamidato complexes 3a and 3b was examined with an S/C of 500, as shown in Table 1. Performing
the reaction of 4a and 3 equiv of ammonium formate in the presence of 1 equiv of AcOH in methanol at
60 °C for 4 h, 2-naphthylethylamine (5a) was obtained in 83–98% yields (entries 1–6) with no concomitant
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formation of alcohol 6a. Among the catalysts derived from picolinamide, complex 2d, which possesses
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two dimethylamino groups, showed the best performance for the DRA.
The reactions with the
sulfonamidato complexes 3a and 3b resulted in poor yields of 16% (entries 7 and 8), possibly due to
insufficient nucleophilicity of the hydridoiridium species with the sulfonamidato ligands compared to the
carboxamido ligands.
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Table 1 DRA of 2-Acetonaphthone Catalyzed by Cp*Ir Complexesa
O
NH2
OH
Ir cat (S/C = 500)
+
HCO2NH4
3.0 equiv
+
AcOH (1.0 equiv)
CH3OH, 60 °C, 4 h
4a
5a
6a
NMR yield (%)b
Entry
Ir cat
2a
Conv. (%)
88
5a
6a
1
2
3
4
5
6
7
8
83
94
98
98
95
90
16
16
0
0
0
0
0
0
5
7
2b
2c
100
100
100
97
2d
2e
2f
92
3a
34
3b
36
aReaction conditions: 4a (2.0 mmol), HCO2NH4 (6.0 mmol), Ir cat (4.0×10–3 mmol), AcOH (2.0 mmol),
and methanol (2.0 mL) were stirred at 60 °C (oil bath) in a Schlenk tube for 4 h. bDetermined by 1H NMR
using coumarin as an internal standard.
The reaction conditions were further optimized by performing the DRA of acetophenone (4b), with the
effective Ir complex 2d as the catalyst and with an S/C of 10,000. The product yield and selectivity were
found to be markedly influenced by the amount of ammonium formate, the use of acetic acid, and the
choice of solvent, as summarized in Table 2.
When the reaction was conducted with 5 equiv of
ammonium formate with 2 equiv of acetic acid in methanol under reflux condition for 4 h,
1-phenylethylamine (5b) and N-(1-phenylethyl)formamide (7b) were formed in 90% and 8% yields
respectively (entry 1). A control experiment without the catalyst under otherwise identical conditions did
not give the products. Lowering of the amount of ammonium formate to 3 equiv could suppress the
N-formylation and resulted in a slight increase in the selectivity of 5b (97% yield) and 7b (<3% yield)
(entry 2).
The reaction without the addition of acetic acid decreased the yield to 61% (entry 3).
Alcoholic solvents, such as methanol, ethanol, and 2-propanol, produced 5b in satisfactory yields of 90%,
87%, and 86% (entries 1, 4, and 5, respectively). The reactions in aprotic solvents of AcOEt and CH3CN
gave good yields of 78% and 80%, while DMF was less effective for the reaction, affording a modest yield
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of 16% along with the formation of 7b with a 38% yield (entries 6–8). The reaction in H2O produced a
34% yield of 5b and a 34% yield of 1-phenylethanol (entry 9), possibly because imine formation was
retarded due to the phase separation of the ketonic substrates and ammonium formate, thus resulting in the
facilitation of the reduction of ketones to alcohols. In fact, the single-phase reaction in a 1:1 mixed
solvent of H2O and methanol restored the yield to 86% (entry 10). Changing the additive acid from acetic
acid to formic acid improved the yield from 64% to 89%, even at the higher S/C of 20,000 (entries 11 and
12).
This DRA can be conducted in various solvents, and it proceeds with a reduced amount of
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ammonium formate, compared to that of the cyclometalated Ir catalyst system reported by Xiao’s group.8c
Table 2. Optimization of the DRA Conditions Catalyzed by 2da
CHO
O
NH2
HN
2d
Ir cat
(S/C = 10,000)
+
HCO2NH4
5.0 equiv
+
AcOH (2.0 equiv)
solvent, 80 oC, 4 h
4b
5b
7b
Yield (%)b
Entry
1
2c
Solvent
Conv. (%)b
>99
>99
82
5b
7b
8
methanol
methanol
methanol
ethanol
2-propanol
AcOEt
90
97
61
87
86
78
80
16
34
86
64
89
<3
2
3d
4
>99
>99
93
12
9
5
6
10
8
7
CH3CN
DMF
>99
>99
97
8
9e
10f
11g
12g,h
38
13
4
H2O
H2O/methanol (1:1)
methanol
>99
82
10
9
methanol
>99
aReaction conditions: 4b (20 mmol), HCO2NH4 (100 mmol), AcOH (40 mmol), 2d (2.0×10–3 mmol), and
b
1
the solvent (10 mL) were stirred at 80 °C (oil bath) in a Schlenk tube for 4 h. Determined by H NMR
c
d
using coumarin as an internal standard. Three equivalents of ammonium formate were used. In the
absence of AcOH. e1-Phenylethanol was obtained with a 34% yield. ,f1-Phenylethanol was obtained in 6%
yield. gS/C = 20,000, HCO2NH4 (3.0 equiv), 6 h. hHCO2H (2.0 equiv) was used instead of AcOH.
Table 3 summarizes the DRA of 2-acetonaphthone (4a) and the substituted acetophenones 4c-l catalyzed
by 2d. The amination of 4a to 1-(2-naphthylethyl)amine (5a) was amenable to a reduced amount of the
catalyst, even with an S/C of 20,000, which led to a yield of 90% (entry 1). The outcomes of the reactions
of substituted acetophenones were not strongly influenced by electron-donating or electron-withdrawing
substituents on the aromatic ring. Acetophenones having fluoro (4c), bromo (4d), nitro (4e), and cyano
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(4f) groups at the para position were converted to the corresponding primary amines in 73–88% yields
without deterioration of the functional groups. These compounds are appealing for the synthesis of
multifunctional compounds for pharmaceutical applications due to the tolerance of their
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nitrogen-containing functional groups (CN and NO2) under the catalytic conditions.
In addition to
meta-chloroacetophenone (4h), the acetophenone derivatives (4g, 4i, and 4j) having an electron-donating
methoxy group at the para-, meta-, or ortho-position were also feasible for the DRA, producing high yields
in a range of 89–95% (entries 6–9). The ortho-substituted acetophenones (4k and 4l) could be also
aminated effectively by using acetic acid as the acid promotor under the condition of S/C = 2,000 to give
the desired amines in 86% and 81% yields, respectively (entries 10 and 11). Excellent yields of the
primary amines were obtained from the alkylphenones other than the methyl ketones, as exemplified by the
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yield of 1-indanone (4m; 83%), 1-tetralone (4n; 92%), and propiophenone (4o; 93%) (entries 12–14).
A
more sterically congested substrate around the carbonyl group, 2-methyl-1-phenylpropan-1-one (4p), was
also transformed with a 93% yield, albeit with a slightly longer reaction time of 8 h (entry 15).
a
Table 3. Ir-Catalyzed DRA of Aromatic Ketones with HCO2NH4
O
NH2
R
2d 2a
or
Ir cat
+
HCO2NH4
R
Acid (2.0 equiv)
CH3OH, reflux, 4 h
X
X
3.0–5.0 equiv
4a, 4c p
5a, 5c p
–
–
Entry
Ketone
S/C
HCO2NH4
(equiv)
Acid
Amine
Yield (%)
O
NH2
NH2
1b
2
20,000
10,000
10,000
3
3
3
HCO2H
HCO2H
90
88
84
5a
4a
O
5c
NH2
4c
4d
F
F
O
3
HCO2H
HCO2H
HCO2H
5d
NH2
Br
Br
O
4
10,000
5,000
3
3
83
73
5e
NH2
4e
O2N
O2N
NC
O
5c
5f
4f
NC
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NH2
O
5
6
7
8
9
6
10,000
3
HCO2H
89
4g
5g
CH3O
Cl
CH3O
Cl
NH2
O
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7
8
10,000
10,000
10,000
2,000
3
3
3
5
HCO2H
HCO2H
HCO2H
AcOH
90
95
91
86
5h
4h
O
NH2
CH3O
CH3O
CH3O
CH3O
4i
5i
5j
O
NH2
9
4j
Cl
Br
O
O
Cl
NH2
10d
4k
5k
5l
Br NH2
11e
12c
13c
2,000
5,000
5,000
5
2
4
AcOH
HCO2H
HCO2H
80
83
92
4l
O
NH2
4m
5m
NH2
NH2
NH2
O
4n
5n
O
O
14
10,000
5,000
2
8
HCO2H
HCO2H
93
93
4o
4p
5o
5p
15c
aStandard reaction conditions: 4 (20 mmol), HCO2NH4 (60 mmol), HCO2H (40 mmol) or AcOH (40 mmol),
2d (2.0×10–3 mmol), and methanol (10 mL) were stirred at reflux (oil bath temperature of 80 °C) in a
Schlenk tube. 4a (40 mmol), HCO2NH4 (120 mmol), HCO2H (80 mmol), 2d (2.0×10–3 mmol), methanol
b
(20 mL) were used. 2d (4.0×10–3 mmol). 2d (1.0×10–2 mmol), methanol (20 mL). 2a (1.0×10–2 mmol),
c
d
e
methanol (20 mL).
As shown in Table 4, a range of heteroaromatic ketones was also found to be applicable to the DRA with
a comparatively reduced amount (3 equiv) of ammonium formate. At an S/C ratio of 10,000, the 2-furyl
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ketones (4q, 4r) were converted to primary furfurylamines with 70% and 84% yields. Thienyl (4s),
pyrrolyl (4t), and pyridyl (4u) ketones afforded the corresponding amines in 81–85% yields with S/C =
5,000. Changing the Ir catalyst to 2e with a CF3 group on the ligand, in addition to changing the acid
promotor to acetic acid, allowed the selective DRA of the sterically congested aryl heteroaryl ketone,
2-(4-chlorobenzoyl)pyridine (4v), but a rather high catalyst loading (S/C = 500) was required to obtain an
acceptable yield of 75%. In contrast, use of the regular catalyst 2d resulted in preferential formation of
-(4-chlorophenyl)-2-pyridinemethanol as the ketone reduction product in 54% yield, which was
accompanied by the target amine 5v in 34% yield.
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a
Table 4. DRA of Heteroaryl Ketones with HCO2NH4
O
NH2
R
2d
Ir cat
+
R
HCO2NH4
3.0 equiv
Hetero
aryl
Hetero
aryl
Acid (2.0 equiv)
CH3OH, reflux
4q v
5q v
–
–
Entry
Ketone
S/C
Acid
Time
(h)
Amine
Yield (%)
O
NH2
O
O
1b
2b
3
10,000
10,000
5,000
HCO2H
HCO2H
HCO2H
2
2
4
76
84
85
4q
5q
5r
O
NH2
O
O
4r
O
O
NH2
NH2
4s
4t
5s
S
S
4
5,000
AcOH
4
2
88
5t
N
N
O
NH2
5
5,000
500
HCO2H
AcOH
81
75
4u
5u
5v
Cl
N
N
O
NH2
4v
N
N
6c
4
Cl
aStandard reaction conditions: 4 (20 mmol), HCO2NH4 (60 mmol), HCO2H (40 mmol) or AcOH (40
mmol), 2d (4.0×10–3 mmol), and methanol (10 mL) were stirred at reflux (oil bath temperature of 80 °C) in
b
c
a Schlenk tube. 2d (2.0×10–3 mmol). A mixture of 4v (5.0 mmol), HCO2NH4 (15 mmol), AcOH (10
mmol), 2e (1.0×10–2 mmol), and methanol (5.0 mL) was stirred at 60 °C in a Schlenk tube.
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Compatibility with aliphatic ketones was also demonstrated under the optimal conditions using 3 equiv
of ammonium formate in the presence of 2 equiv of HCO2H, as summarized in Table 5. The reaction of
4-phenyl-2-butanone (4w) and 3-nonanone (4x) proceeded rapidly and the corresponding amines were
obtained with 92% and 84% yields (entries 1 and 2). The nonconjugated alkene moiety remained intact
after the reaction of 4y to give the amine 5y in 90% yield (entry 3). Cyclic ketones also reacted well,
providing high yields above 90% (entries 4 and 5), as shown by the results for cyclododecanone (4z) and
10
11
12
13
14
15
16
17
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19
20
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59
60
3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-one (4aa).
Notably, the spiroketal 4aa derived from
symmetrical cyclohexane-1,4-dione was successfully monoaminated without deprotection.
Table 5. DRA of Aliphatic Ketones and Cyclic Aliphatic Ketones with HCO2NH4
O
2d
NH2
Ir cat
(S/C = 10,000)
+
HCO2NH4
3.0 equiv
R1
R2
R1
5w z, 5aa
R2
HCO2H (2.0 equiv)
CH3OH, reflux
4w z, 4aa
–
–
Entrya
1
Ketone
Time (h)
Amine
Yield (%)
92
O
NH2
4
4w
5w
5x
O
NH2
NH2
4x
2
3
4
4
84
90
O
5y
5z
4y
O
NH2
4z
4
5
6
4
90
93
NH2
5aa
O
O
O
4aa
O
O
aReaction conditions: 4 (20 mmol), HCO2NH4 (60 mmol), HCO2H (40 mmol), 2d (2.0×10–3 mmol), and
methanol (10 mL) were stirred at reflux (oil bath temperature of 80 °C) in a Schlenk tube.
The versatility of this efficient catalytic system prompted us to validate the DRA for the
diastereoselective synthesis of substituted primary cyclohexylamines, and the results are summarized in
Table 6. The reaction of 2-phenylcyclohexan-1-one (4ab) was carried out at 60 °C for 4 h with Ir
complex 2d (S/C = 1,000), producing 1-amino-2-phenylcyclohexane (5ab) in 91% yield with a high
cis/trans ratio of 96/4 (entry 1). The diastereoselective formation of 4-substituted cyclohexylamines was
also achieved by using 2c for the DRA of 4-(tert-butyl)cyclohexan-1-one (4ac) and
4-phenylcyclohexan-1-one (4ad), leading to excellent cis/trans ratios of 99/1 and 93/7 (for entries 2 and 3,
respectively). The application of the competent Ir catalyst was extended to the double amination of
cyclohexane-1,4-dione (4ae), which was transformed into a potential monomer for poly(imide) synthesis,16
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cis-cyclohexane-1,4-diamine (5ae), in 65% yield with a diastereomeric ratio of 98/2, after the reaction was
conducted on a sub-kilogram scale in water using 8 equiv of ammonium formate (entry 4). The relative
cis-configuration of the major product was confirmed by single-crystal X-ray analysis of a bis-acetamide
derivative 5af, obtained by diacetylation of 5ae (see Experimental Section). Similar to diastereoselective
hydrogenation catalyzed by a catalyst combination of RuCl2(PPh3)3 and NH2(CH2)2NH2,17 the significant
cis-selectivity is consistent with the preferred approach of the sterically demanding hydrido-Ir species, thus
approaching on the less hindered equatorial side of the cyclic imine intermediate and adapting a chair-like
conformation with the substituent at an equatorial position.18
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Table 6. Diastereoselective DRA of Cyclic Ketones with HCO2NH4
O
NH2
R2
2c 2d
or
Ir cat
+
HCO2NH4
3.0 equiv
R1
R2
AcOH (2.0 equiv)
CH3OH, 60 oC
R1
5ab ae
4ab ae
–
–
Entry
1a
Ketone
S/C
Time
(h)
Amine
Yield (%)
Cis/transd
Ph
Ph
4ab
4ac
5ab
1,000
4
91
96:4
O
H2N
H2N
O
tBu
tBu
Ph
5ac
5ad
5ae
2b
3b
4c
2,000
2,000
1,000
4
4
6
83
76
65
99:1
93:7
98:2
4ad
4ae
O
O
Ph
H2N
H2N
O
NH2
a4ab (5.0 mmol), HCO2NH4 (15 mmol), AcOH (10 mmol), 2d (5.0×10–3 mmol), and methanol (5 mL) were
b
used. 4 (100 mmol), HCO2NH4 (300 mmol), AcOH (200 mmol), 2c (5.0×10–2 mmol), and methanol (25
c
mL) were used. 4ae (3.0 mol), HCO2NH4 (24 mol), AcOH (9.0 mol), 2c (3.0 mmol), and H2O (750 mL)
were stirred at 60 °C (oil bath) in a 5 L four-neck round bottom flask. dDetermined by 1H NMR.
The -keto acids 8a-g were also suitable for the synthesis of the -amino acids 9a-g by the DRA
reaction, as summarized in Table 7. By the reaction performed with 3 equiv of ammonium formate and 2
equiv of formic acid in the presence of 2d at a reduced catalyst loading of S/C = 10,000,
2-oxo-2-phenylacetic acid (8a) was converted into phenylglycine (9a) in 85% yield (entry 1). Other
phenylglycine derivatives 9b-e, regardless of their electron-donating and electron-withdrawing
substructures, were also produced in 79–94% yields within 0.5–1.5 h under the condition of S/C = 2,000
(entries 2–5). In particular, 2-(4-methoxyphenyl)-2-oxoacetic acid (8b), 2-(4-fluorophenyl)-2-oxoacetic
acid (8d), and 2-(naphthalen-2-yl)-2-oxoacetic acid (8e) were smoothly converted, even in the absence of
formic acid, possibly with the aid of the inherent acidity of the keto acid substrates. Heteroaromatic and
aliphatic bulky substituents on the ketoacids, as typified by 2-oxo-2-(thiophen-2-yl)acetic acid (8f) and
3,3-dimethyl-2-oxobutanoic acid (8g), were also compatible with the DRA, using the combination of
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ammonium formate and AcOH to give the corresponding -amino acids in 74% and 77% yields (entries 6
4
5
6
and 7, respectively).
7
8
9
Table 7. DRA of -Keto Acids with HCO2NH4
O
NH2
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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60
2d
Ir cat
OH
OH
+
HCO2NH4
3.0 equiv
R
R
Acid (2.0 equiv)
CH3OH, reflux
O
8a g
9a g
–
–
Entry
1a
-Keto acid
S/C
Acid
Time
(h)
Amine
Yield (%)
85
O
NH2
OH
OH
10,000 HCO2H
4
8a
9a
O
O
O
NH2
OH
OH
2b
2,000
—
1
94
8b
9b
O
O
CH3O
CH3O
CH3O
NH2
O
CH3O
OH
OH
3b
2,000 HCO2H 1.5
79
94
O
O
9c
8c
OCH3
NH2
OCH3
O
OH
9d
OH
8d
4b
2,000
—
0.5
O
O
F
F
NH2
O
OH
OH
8e
5b
6c
7b
2,000
5,000
2,000
—
1
4
2
91
74
77
9e
O
O
O
NH2
O
OH
OH
S
S
8f
9f
AcOH
AcOH
O
OH
O
NH2
OH
8g
9g
O
O
a8a (20 mmol), HCO2NH4 (60 mmol), HCO2H (40 mmol), 2d (2.0×10–3 mmol), and methanol (20 mL). b8
(2.0 mmol) HCO2NH4 (6.0 mmol), AcOH or HCO2H (4.0 mmol), 2d (1.0×10–3 mmol), and methanol (2.0
mL). c8f (5.0 mmol), HCO2NH4 (15 mmol), AcOH (10 mmol), 2d (1.0×10–3 mmol), and methanol (10 mL).
To obtain corroborative evidence of the active catalyst species in DRA, we attempted to verify whether a
hydridoiridium complex can be generated from formic acid under the acidic conditions. When the
chloridoiridium complex 3c was treated with 5 equiv of formic acid in the presence of 2 equiv of Et3N at
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40 °C, a new hydrido-Ir complex 10 was obtained quantitatively, as shown in Scheme 2. The presence of
1
the hydrido ligand in 10 was substantiated by the H NMR spectrum, which showed a characteristic
low-field resonance at δ –11.3 with a 1H intensity. Unlike the well-defined bifunctional hydrido-Ir
complexes bearing
a
protic amine chelate relevant to hydrogen transfer reactions,19 the
picolinamido-ligated complex 10 was stable in a solution containing formic acid. Catalyst tolerance under
acidic conditions is essential for the highly efficient catalytic DRA in the presence of acid additives, which
accelerate the formation of iminium intermediates from ketones and ammonium formate.
10
11
12
13
14
15
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17
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19
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Scheme 2 Synthesis of Hydrido-Iridium Complex 10 from 2c
Ir Cl
N
Ir
H
N
+
HCO2H
N
N
N
N
Et3N (2.0 equiv)
CH3OH, 40 oC, 2 h
5.0 equiv
O
O
2c
10
1H NMR in CD3OD
hydride peak: 11.3 ppm (s, 1H)
Based on the formation of 10 from 2c, a plausible catalytic cycle for the DRA involving the hydrido-Ir
intermediate is depicted in Scheme 3. The chlorido complex A reacts with ammonium formate, releasing
ammonium chloride to give the formato complex B, which is followed by spontaneous decarboxylation to
generate a hydrido-Ir bond in C.20 The reduction under acidic conditions facilitates the formation of the
iminium species, giving rise to the selective formation of amines in preference to alcoholic products by the
hydrogen transfer to ketones. After the hydrido ligand attaches to the C=N bond of the iminium salt via
an ionic mechanism,21 the resulting cationic complex D reacts with formate to regenerate the formato
complex B that carries the catalytic cycle.
Scheme 3 A Plausible Mechanism of Ir-Catalyzed DRA of Ketones
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O
CO2
+
NH3
R2
H
Ir
H
N R1
- H2O
N
7
8
9
O
C
NH2
10
11
12
13
14
15
16
17
18
19
20
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R2
O
Ir Cl
N R1
Ir
O
H
HCO2NH4
– NH4Cl
N
N
N R1
NH2
O
O
R2
A
B
Ir
N
N R1
O
D
HCO2
CONCLUSION
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This study demonstrates that Cp*Ir complexes with a picolinamide ligand serve as highly efficient
reductive amination catalysts that use ammonium formate as both of an amine source and a hydrogen donor.
The Ir catalysts provide for a practical preparative method for the primary amines from a variety of ketonic
substrates, including aromatic ketones, heteroaromatic ketones, aliphatic ketones, and -keto carboxylic
acids, with remarkable catalyst turnover numbers up to 18,000. The straightforward reaction tolerates
with carboxylic ester, halogen, and nitrogen-containing groups and exhibits excellent chemoselectivity,
impeding ketone hydrogenation.
In addition, 2- and 4-substituted cyclohexylamines and
Formation of a new
cis-cyclohexane-1,4-diamines can be obtained with high diastereoselectivity.
hydrido-Ir complex was confirmed by treatment of the catalyst precursor with excess formic acid, implying
that the acquired durability of Ir catalysts with a picolinamide ligand under acidic conditions contributes to
the high catalytic performance.
The versatility and simplicity of this protocol established it as a
convenient option to be utilized in a wide range of synthetic applications, especially on a large scale.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all the reactions were carried out under an argon
atmosphere.
All the reagents were commercially purchased and used without further purification.
Synthesis of Cp*Ir complexes and DRA were performed in commercial anhydrous solvents. The NMR
1
spectra were recorded on a JEOL ECX-400P NMR spectrometer, unless otherwise specified. The H
NMR spectra chemical shifts were referenced to an external tetramethylsilane signal (0.0 ppm) by using the
signals of the residual proton impurities in the deuterated solvents. Abbreviations for the NMR analyses
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9
are as follows: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, and br = broad.
The 13C NMR chemical shifts were referenced to the residual solvent peak (δ 77.0 ppm for CDCl3, 39.7
ppm for DMSO-d6 and 49.5 ppm for CH3OH). The IR spectra were recorded on a JASCO FT-IR 660 Plus
and are reported in frequency of absorption (cm-1). The high resolution mass spectra (HRMS) were
acquired with a Double Focusing Mass Spectrometer (JEOL JMS-700), Thermo high resolution Q Exactive
focus mass spectrometer (Thermo Fisher Scientific), or a Waters XevoTM G2-XS Q-TOF. The elemental
analyses were performed using a CE Instruments EA1112.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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Synthetic Procedure for the Picolinamide Ligands 1b. A mixture of 4-chloro-2-cyanopyridine (58 g,
419 mmol) and dimethylamine solution 40 wt% in H2O (550 mL, 4.19 mol) in a 2 L four-neck round
bottom flask was refluxed at 60 °C in an oil bath for 2 h. The resulting mixture was poured in a mixture of
CH2Cl2 and H2O (4:1, 2.9 L total) and stirred at room temperature for 10 min. The organic phase was
separated and the aqueous phase was extracted with CH2Cl2 (400 mL). The combined organic phase was
washed with H2O (580 mL) and dried over Na2SO4. After removal of the solvent under reduced pressure,
the crude product was purified by flash column chromatography with silica gel using CH2Cl2/AcOEt (1:1)
as eluent. The obtained solid product was mixed with 2-propanol (890 mL) and stirred at 80 °C for 1 h.
The mixture was cooled to room temperature and stirred further at 0 °C for 1 h. The precipitate was
collected by filtration and dried in vacuo to yield 1b (57.8 g, 81% yield)22 as a pale yellow solid. 1H NMR
(400 MHz, CDCl3) δ 8.17 (d, J = 5.5 Hz, 1H), 7.91 (bs, 1H), 7.47 (d, J = 2.7 Hz, 1H), 6.57 (dd, J = 5.5, 2.7
Hz, 1H), 5.56 (bs, 1H), 3.07 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.0 (NCOC), 155.1, 149.7,
148.4, 108.3, 105.3, 39.2 (N(CH3)2); HRMS (ESI) m/z: [M + H]+ Calcd for C8H12N3O 166.0975; Found
166.0986.
N
NH2
O
N
1b
General Procedure for the Preparation of Picolinamides 1c, 1e, and 1f.23 Ethyl chloroformate (12.4
mL, 130 mmol), and amine (130 mmol) was slowly added to a THF (640 mL) solution containing picolinic
acid (16.0 g, 130 mmol) and triethylamine (18.1 mL, 130 mmol) at 0 °C. The mixture was warmed to room
temperature and stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was
diluted with ethyl acetate (265 mL) and filtrated. After removal of the solvent under vacuum, the resulting
crude mixture was dissolved in dichloromethane (345 mL), washed with water (175 mL × 3), dried over
Na2SO4 and evaporated. After the residue was washed thoroughly with diisopropyl ether (170 mL),
followed by evaporation to dryness in vacuo, the picolinamide product 1 was obtained.
1
N-[4-(Dimethylamino)phenyl]picolinamide (1c):22 green solid (27.7 g, 88% yield); H NMR (400
MHz, CDCl3) δ 9.83 (bs, 1H), 8.63-8.58 (m, 1H), 8.32-8.27 (m, 1H), 7.93-7.85 (m, 1H), 7.69-7.62 (m, 2H),
7.49-7.42 (m, 1H), 6.81-6.74 (m, 2H), 2.95 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.4 (NCOC),
150.1, 147.8, 147.8 137.5, 127.7, 126.0, 122.1, 121.0, 113.0, 40.8 (N(CH3)2).
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N
HN
O
N
1c
N-[4-(Trifluoromethyl)phenyl]picolinamide (1e):24 white solid (32.7 g, 89% yield); H NMR (400
1
MHz, CDCl3) δ 10.2 (bs, 1H; NH), 8.63 (d, J = 4.6 Hz, 1H; C5H4N), 8.31 (d, J = 7.8 Hz, 1H; C5H4N),
10
11
12
13
14
15
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18
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7.99-7.88 (m, 3H; C6H4 and C5H4N), 7.65 (d, J = 8.7 Hz, 2H; C6H4), 7.56-7.49 (m, 1H; C5H4N); C{1H}
NMR (100 MHz, CDCl3) δ 162.3 (NCOC), 149.2, 148.0, 140.7, 137.8, 126.8, 126.5 (q, J = 3.8 Hz), 126.0
(q, J = 32.6 Hz), 124.1 (q, J = 272.2 Hz), 122.5, 119.3.
N
HN
O
CF3
1e
N-(4-Nitrophenyl)picolinamide (1f): white solid (9.98 g, 20% yield); 1H NMR (400 MHz, CDCl3) δ 10.4
(bs, 1H), 8.69-8.62 (m, 1H), 8.35-8.25 (m, 3H), 8.00-7.93 (m, 3H), 7.60-7.51 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 162.4 (NCOC), 148.8, 148.1, 143.6, 143.5, 138.0, 127.1, 125.2, 122.7, 119.2. HRMS (ESI)
m/z: [M – H]– Calcd for C12H8N3O3 242.0571; Found 242.0574.
N
HN
O
NO2
1f
Synthetic Procedure of 4-(Dimethylamino)-N-[4-(dimethylamino)phenyl]picolinamide (1d).22,23
Ethyl chloroformate (35.3 g, 325 mmol) and N,N-dimethyl-1,4-phenylenediamine (44.3 g, 325 mmol) were
slowly added into a THF (1.6 L) solution of 4-bromopicolinic acid (65.7 g, 325 mmol) and triethylamine
(45.3 mL, 325 mmol) at 0 °C. The mixture was warmed to room temperature and stirred at 80 °C in an oil
bath for 2 h. After the reaction mixture cooled to room temperature, ethyl acetate (1.95 L) was added. The
resulting mixture was filtrated and the solvent was removed under vacuum. Diisopropyl ether (650 mL)
was added, the resulting suspension was stirred at room temperature for 30 min. The precipitate was
filtered and washed again with diisopropyl ether (50 mL) and H2O (50 mL). The volatiles were removed in
vacuo to yield 4-bromo-N-[4-(dimethylamino)phenyl]picolinamide (62.4 g, 60% yield) as a green solid.
A mixture of 4-bromo-N-[4-(dimethylamino)phenyl]picolinamide (61 g, 191 mmol) and a
dimethylamine solution 40 wt% in H2O (251 mL, 1.95 mol) in a 2 L four-neck round bottom flask was
refluxed at 60 oC for 2 h. The reaction mixture was poured in a mixture of CH2Cl2 and H2O (2:1, 1.8 L
total) and stirred at room temperature for 10 min. The organic phase was washed with H2O (600 mL) and
dried over Na2SO4. After removal of the solvent under reduced pressure, the crude product was purified by
flash column chromatography with silica gel using CH2Cl2/AcOEt (v/v, 20/1 to 5/1) as eluent. The obtained
solid product was mixed with AcOEt (215 mL), the resulting suspension was stirred at 30 °C for 1 h. The
precipitate was collected by filtration and dried in vacuo to yield 1d (40.2 g, 74% yield) as a light green
solid. 1H NMR (400 MHz, CDCl3) δ 9.95 (bs, 1H), 8.19 (d, J = 5.5 Hz, 1H), 7.70-7.60 (m, 2H), 7.55 (d, J =
2.7 Hz, 1H), 6.81-6.73 (m, 2H), 6.60-6.53 (m, 1H), 3.08 (s, 6H), 2.94 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.4 (NCOC), 155.3, 150.3, 147.9, 147.6, 128.2, 120.9, 113.0, 107.9, 104.9, 40.9 (N(CH3)2),
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39.2 (N(CH3)2); HRMS (ESI) m/z: [M + H]+ Calcd for C16H21N4O 285.1710; Found 285.1724.
5
6
N
HN
N
7
8
9
O
N
1d
10
11
12
13
14
15
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17
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General Procedure for the Preparation of -Keto Acids 8.25 A solution of bromoarene (100 mmol) in
dry THF (48 mL) was added dropwise to Mg turnings (2.67 g, 110 mmol) with a crystal of iodine in dry
°
THF (76 mL) at 25–40 C over 1 h under Ar and then stirred further at 50 °C for 2 h. To the reaction
mixture, a solution of dimethyl oxalate (17.7 g, 150 mmol) in dry THF (350 mL) was added at -70 °C. After
°
stirring at -70 C for 1 h, the reaction mixture was warmed to room temperature and stirred for 2 h. The
reaction mixture was quenched with 10% HCl followed by extraction with tBuOCH3, and the organic layer
was dried over Na2SO4 and concentrated. Purification by silica gel column chromatography (hexane/EtOAc
= 9:1) afforded 14.4 g of methyl 2-(naphthalen-2-yl)-2-oxoacetate as a pale yellow oil (67% yield). An
aqueous solution (47 mL) of NaOH (5.9 g, 148 mmol) was added to the obtained ketoester dissolved in
THF (80 mL) at 0 °C. After stirring at the same temperature for 1 h, the reaction mixture was concentrated
on a rotary evaporator. An aqueous HCl solution (3 M) was added to the resulting residue and extracted
t
with BuOCH3. The organic phase was dried over Na2SO4 and concentrated. Purification by silica gel
column chromatography (CH2Cl2/methanol = 20/1) and recrystallization from a saturated solution of
hexane/diisopropylether = 2/1 gave the α-keto acid 8.
2-(4-Methoxyphenyl)-2-oxoaceticacid(8b): pale orange solid (4.2 g, 27% yield); 1H NMR (400 MHz,
13
CDCl3) δ 8.54-8.47 (m, 2H), 7.03-6.96 (m, 2H), 3.93 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 182.3,
165.7, 162.4, 134.2, 124.6, 114.4, 55.7 (OCH3); HRMS (ESI) m/z: [M – H]– Calcd for C9H7O4 179.0350;
Found 179.0352.
O
CO2H
CH3O
8b
1
2-(3,5-Dimethoxyphenyl)-2-oxoacetic acid (8c): pale green solid (9.8 g, 53% yield); H NMR (400
MHz, CDCl3) δ. 7.52 (d, J = 2.3 Hz, 2H), 6.79 (t, J = 2.3 Hz, 1H), 3.86 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ. 184.3, 163.3, 160.9, 133.2, 108.4, 108.4, 55.7 (OCH3); HRMS (ESI) m/z: [M – H]– Calcd for
C10H9O 209.0455; Found 209.0450.
O
CH3O
CO2H
OCH3
8c
1
2-(4-Fluorophenyl)-2-oxoacetic acid (8d):25 white solid (4.8 g, 29% yield); H NMR (400 MHz,
CDCl3) δ 8.53-8.45 (m, 2H), 7.28-7.18 (m, 2H);13C{1H} NMR (100 MHz, CDCl3) δ 183.0, 167.3 (d, J =
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259.8 Hz), 162.5, 134.2 (d, J = 10.5 Hz), 128.2 (d, J = 2.9 Hz), 116.4 (d, J = 22.0 Hz).
O
6
7
CO2H
8
9
F
8d
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2-(Naphthalen-2-yl)-2-oxoacetic acid (8e):25 yellow solid (9.2 g, 46% yield); H NMR (400 MHz,
CDCl3) δ 9.24 (s, 1H), 8.22 (dd, J = 8.7, 1.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97-7.88 (m, 2H),
7.73-7.58 (m, 2H); 13C{1H} NMR (400 MHz, CDCl3) δ 184.5, 162.9, 136.5, 135.3, 132.2, 130.4, 130.0,
129.0, 129.0, 127.8, 127.2, 124.5.
O
CO2H
8e
2-Oxo-2-(thiophen-2-yl)acetic acid (8f):26 brown solid (3.8 g, 28% yield); H NMR (400 MHz,
CDCl3) δ 8.57 (dd, J = 3.7, 0.9 Hz, 1H), 7.97 (dd, J = 5.0, 1.4 Hz, 1H), 7.28 (d, J = 4.1 Hz, 1H); 13C{1H}
1
NMR (100 MHz, CDCl3) δ 175.3, 159.6, 140.2, 139.9, 136.2, 129.3.
HRMS (ESI) m/z: [M – H]– Calcd for C6H3O3S 154.9808; Found 154.9806.
O
S
CO2H
8f
General Procedure for the Preparation of Picolinamidato Iridium Complexes 2a-f. Triethylamine
(365 µL, 2.62 mmol) was introduced into a CH2Cl2 (25 mL) solution containing [Cp*IrCl2]2 (1.01 g, 1.26
mmol) and picolinamide (2.62 mmol) in a Schlenk tube, and the resulting mixture was stirred for 15 h at
room temperature. The reaction mixture was washed with water (10 mL × 4), and dried under vacuum.
The resulting solid was washed with diisopropyl ether (25 mL), filtrated, and then dried in vacuo to yield
the desired picolinamidato-iridium complex. These DRA catalysts are commercially available from Kanto
Chemical Co., Inc.
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Cp*Ir[2-pyridinecarboxamidato]Cl (2a): light orange solid (1.02 g, 84% yield); H NMR (400 MHz,
CDCl3) δ 8.56 (d, J = 5.5 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.91 (td, J = 7.8, 1.8 Hz, 1H), 7.50-7.42 (m,
1H), 5.69 (bs, 1H), 1.72 (s, 15H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.4 (NCOC), 154.5, 150.1, 138.6,
127.3, 125.9, 85.9 (C5(CH3)5), 8.9 (C5(CH3)5); Anal. Calcd for C16H20ClIrN2O: C, 39.70; H, 4.17; N, 5.79.
Found: C, 39.33; H, 4.05; N, 5.66; IR (KBr, cm-1) 1639 (C=O).
Cl Ir
N
NH
O
2a
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Cp*Ir[4-(dimethylamino)-2-pyridinecarboxamidato]Cl (2b): light orange solid (152 mg from 0.163
mmol of [Cp*IrCl2]2, 88% yield); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 6.4 Hz, 1H), 7.25 (d, J = 5.0
Hz, 1H), 6.53 (dd, J = 6.9, 3.2 Hz, 1H), 5.64 (bs, 1H), 3.12 (s, 6H), 1.71 (s, 15H); 13C{1H} NMR (100 MHz,
CDCl3) δ 173.4 (NCOC), 155.1, 153.1, 149.0, 109.1, 108.0, 85.0 (C5(CH3)5), 39.4 (N(CH3)2), 8.9
(C5(CH3)5); Anal. Calcd for C18H25ClIrN3O: C, 41.02; H, 4.78; N, 7.97. Found: C, 40.89; H, 4.67; N, 7.90;
IR (KBr, cm-1) 1615 (C=O).
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Cl Ir
N
NH
O
N
2b
Cp*Ir[N-{4-(dimethylamino)phenyl}-2-pyridinecarboxamidato]Cl (2c): reddish brown solid (5.58 g
from 7.0 mmol of [Cp*IrCl2]2, 89% yield); 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.5 Hz, 1H), 8.14 (d,
J = 7.8 Hz, 1H), 7.89 (t, J = 7.3 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.45 (t, J = 6.0 Hz, 1H), 6.74 (d, J = 8.7
Hz, 2H), 2.92 (s, 6H), 1.42 (s, 15H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.5 (NCOC), 155.9, 149.4,
147.8, 138.5, 138.3, 127.1, 127.0, 126.1, 112.9, 86.5 (C5(CH3)5), 41.3 (N(CH3)2), 8.4 (C5(CH3)5); Anal.
Calcd for C24H29ClIrN3O: C, 47.79; H, 4.85; N, 6.97. Found: C, 47.72; H, 4.73; N, 6.85; IR (KBr, cm-1)
1620 (C=O).
Cl Ir
N
N
O
N
2c
Cp*Ir[4-(dimethylaminophenyl)-N-(dimethylamino)phenyl-2-pyridinecarboxamidato]Cl (2d): light
orange solid (192 mg from 0.167 mmol of [Cp*IrCl2]2, 89% yield); 1H NMR (400 MHz, CDCl3) δ 8.06 (d,
J = 6.9 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 2.7 Hz, 1H), 6.74 (d, J = 8.7 Hz, 2H), 6.55 (dd, J =
6.9, 3.2 Hz, 1H), 3.12 (s, 6H), 2.91 (s, 6H), 1.41 (s, 15H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.3
(NCOC), 154.9, 154.4, 148.4, 147.5, 139.3, 127.2, 112.9, 109.0, 108.0, 85.5 (C5(CH3)5), 41.4 (N(CH3)2),
39.3 (N(CH3)2), 8.4 (C5(CH3)5); Anal. Calcd for C26H34ClIrN4O: C, 48.32; H, 5.30; N, 8.67. Found: C,
47.96; H, 5.23; N, 8.53; IR (KBr, cm-1) 1595 (C=O).
Cl Ir
N
N
O
N
N
2d
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Cp*Ir[N-[4-(trifluoromethyl)phenyl]-2-pyridinecarboxamidato]Cl (2e): yellow solid (15.0 g from
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19.0 mmol of [Cp*IrCl2]2, 92% yield); H NMR (400 MHz, CDCl3) δ 8.60 (dd, J = 5.5, 0.9 Hz, 1H), 8.18
(dd, J = 7.8, 0.9 Hz, 1H), 7.96 (td, J = 7.3, 1.4 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H),
7.56-7.50 (m, 1H), 1.42 (s, 15H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.2 (NCOC), 154.3, 151.4, 149.6,
138.4, 127.6, 126.9, 125.8, 125.2 (q, J = 32.6 Hz; CCF3), 124.7 (q, J = 3.8 Hz; CHCCF3), 124.1 (q, J =
271.3 Hz; CF3), 86.3 (C5(CH3)5), 8.0 (C5(CH3)5); Anal. Calcd for C23H23ClF3IrN2O: C, 43.98; H, 3.69; N,
4.46. Found: C, 44.18; H, 3.72; N, 4.37; IR (KBr, cm-1) 1632 (C=O).
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Cl Ir
N
N
O
CF3
2e
Cp*Ir[N-(4-nitrophenyl)-2-pyridinecarboxamidato]Cl (2f):13h light orange solid (23.1 g from 20.1
1
mmol of [Cp*IrCl2]2, 95% yield); H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 5.5 Hz, 1H), 8.24-8.15 (m,
3H), 7.98 (td, J = 7.8, 1.4 Hz, 1H), 7.96-7.90 (m, 2H), 7.60-7.52 (m, 1H), 1.43 (s, 15H); 13C{1H} NMR
(100 MHz, CDCl3) δ 168.4 (NCOC), 155.0, 154.4, 149.9, 143.5, 138.9 128.0, 127.5, 126.5, 123.7, 86.7
(C5(CH3)5), 8.5 (C5(CH3)5); Anal. Calcd for C22H23ClIrN3O3: C, 43.67; H, 3.83; N, 6.94. Found: C, 43.90;
H, 3.74; N, 6.84; IR (KBr, cm-1) 1633 (C=O).
Cl Ir
N
N
O
NO2
2f
Synthetic Procedure of Cp*Ir[N-[4-(dimethylamino)phenyl]-2-pyridinecarboxamidato]H (10).
Triethylamine (46.3 µL, 0.332 mmol) and formic acid (31.3 µL, 0.829 mmol) were added via a syringe to a
methanol (3 mL) solution containing Ir complex 2c (100.0 mg, 0.166 mmol) in a Schlenk tube, and the
resulting mixture was stirred for 2 h at 40 °C in an oil bath. After AcOEt (12 mL) was added to the reaction
mixture, the resulting precipitate was washed with water (3×4 mL) and dried under vacuum to yield the
title compound as a light orange solid. Yield 86% (81 mg). 1H NMR (400 MHz, CD3OD) δ 8.84 (d, J = 5.5
Hz, 1H), 8.03-7.88 (m, 2H), 7.57-7.44 (m, 1H), 7.18 (d, J = 6.4 Hz, 2H), 6.87 (d, J = 6.4 Hz, 2H), 2.97 (s,
6H), 1.62 (s, 15H), –11.30 (s, 1H); 13C{1H} NMR (100 MHz, CD3OD) δ 169.8 (NCOC), 156.5, 153.2,
149.7, 140.5, 137.6, 128.1, 127.8, 126.6, 114.3, 89.6 (C5(CH3)5), 41.7 (N(CH3)2), 9.6 (C5(CH3)5).
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H Ir
N
N
O
N
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General Procedure for the Preparation of Sulfonamido Iridium Complexes 3. A mixture of
[Cp*IrCl2]2 (38.5 mg, 0.048 mmol) and pyridinesulfonamide (0.10 mmol) in THF (5 mL) was added to
n-buthyllithium (1.65 M hexane solution, 59 μL, 0.097 mmol) at –78 °C. The mixture was slowly
warmed to room temperature over 14 h. After removal of the solvent in vacuo, the residue was extracted
with dichloromethane (5 mL×3) and evaporated to dryness. Recrystallization form dichloromethane–
hexane (2 mL/18 mL) gave the title compounds as yellow crystals.
Cp*Ir[5-methylpyridine-2-sulfonamidato]Cl (3a): yellow crystals (35.6 mg, 69% yield); 1H NMR (400
MHz, CD2Cl2) δ 8.34 (s, 1H), 7.79, 7.68 (d, 3JHH = 7.8 Hz, 1H each), 3.59 (s, 1H), 2.44 (s, 3H), 1.64 (s,
15H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.5, 151.7, 140.7, 138.3, 121.4, 87.1 (C5(CH3)5), 18.4, 8.8
(C5(CH3)5); Anal. Calcd for C16H22ClIrN2O2S: C, 35.99; H, 4.15; N, 5.25. Found: C, 35.85; H, 4.08; N,
5.07.
Cl Ir
N
NH
O
S
O
3a
Cp*Ir[N-methyl-5-methylpyridine-2-sulfonamidato]Cl (3b): yellow crystals (40.4 mg, 74% yield); 1H
NMR (400 MHz, CD2Cl2) δ 8.31 (s, 1H), 7.75, 7.62 (d, 3JHH = 7.8 Hz, 1H each), 2.87 (s, 1H), 2.41 (s, 3H),
1.62 (s, 15H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.5, 151.7, 140.7, 138.3, 121.4, 87.1 (C5(CH3)5), 18.4,
8.8 (C5(CH3)5); Anal. Calcd for C17H24ClIrN2O2S: C, 37.25; H, 4.41; N, 5.11. Found: C, 36.97; H, 4.29; N,
4.98.
Cl Ir
N
N
S
O
O
3b
Typical Procedure for the DRA of Ketones. Formic acid (1.51 mL, 40 mmol) was introduced via a
syringe into a methanol (10 mL) solution containing ketone (20 mmol), 2d (1.29 mg, 2×10-3 mmol), and
ammonium formate (3.78 g, 60 mmol) in a Schlenk tube, and the resulting mixture was stirred 80 °C in an
oil bath for 4 h. After the mixture cooled to room temperature, the solvent was evaporated under vacuum.
An aqueous solution of NaOH (6.7 M) was added to the resulting residue and extracted with CH2Cl2 (15
mL × 2). The combined organic layers were dried over sodium sulfate and evaporated under reduced
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pressure. The crude product was purified by column chromatography on silica gel (CH2Cl2/methanol =
20/1).
1-(Naphthalen-2-yl)ethanamine (5a):8c white solid (6.16 g from 40 mmol of 4a, 90% yield); 1H NMR
(400 MHz, CDCl3) δ 7.84-7.76 (m, 4H), 7.52-7.40 (m, 3H), 4.29 (q, J = 6.9 Hz, 1H), 1.60 (bs, 2H), 1.47 (d,
J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.9, 133.2, 132.3, 127.8, 127.5, 127.3, 125.7, 125.1,
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124.2, 123.4, 51.0, 25.3.
NH2
5a
1-(4-Fluorophenyl)ethanamine (5c):8c colorless oil (2.45 g, 88% yield); 1H NMR (400 MHz, CDCl3) δ
7.36-7.27 (m, 2H), 7.05-6.96 (m, 2H), 4.12 (q, J = 6.4 Hz, 1H), 1.50 (bs, 2H), 1.36 (d, J = 6.4 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 161.5 (d, J = 244.4 Hz), 143.3 (d, J = 2.9 Hz), 127.1 (d, J = 7.7 Hz),
115.0 (d, J = 21.1 Hz), 50.5, 25.7.
NH2
F
5c
1-(4-Bromophenyl)ethanamine (5d):8c yellow oil (3.36 g, 84% yield); H NMR (400 MHz, CDCl3) δ
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7.48-7.41 (m, 2H), 7.26-7.20 (m, 2H), 4.10 (q, J = 6.4 Hz, 1H), 1.46 (bs, 2H), 1.36 (d, J = 6.4 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 146.4, 131.1, 127.3, 120.0, 50.4, 25.5.
NH2
Br
5d
1-(4-Nitrophenyl)ethanamine (5e):8c reddish oil (2.76 g, 83% yield); H NMR (400 MHz, CDCl3) δ
1
8.22-8.16 (m, 2H), 7.57-7.51 (m, 2H), 4.26 (q, J = 6.4 Hz, 1H), 1.52 (bs, 2H), 1.40 (d, J = 6.4 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 155.1, 146.2, 126.3, 123.2, 50.4, 25.3.
NH2
O2N
5e
1
1-(4-Cyanophenyl)ethanamine (5f): colorless oil (2.37 g, 81% yield); H NMR (400 MHz, CDCl3) δ
7.62 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.20 (q, J = 6.9 Hz, 1H), 1.50 (bs, 2H), 1.38 (d, J = 6.9
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.9, 132.0, 126.4, 118.7, 110.1, 50.8, 25.4; HRMS (ESI)
m/z: [M + H]+ Calcd for C9H11N2 147.0917; Found 147.0907.
NH2
NC
5f
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1-(4-Methoxyphenyl)ethanamine (5g):8c yellow oil (2.69 g, 89% yield); 1H NMR (400 MHz, CDCl3)
δ 7.30-7.24 (m, 2H), 6.90-6.84 (m, 2H), 4.08 (q, J = 6.9 Hz, 1H), 3.80 (s, 3H), 1.47 (bs, 2H), 1.36 (d, J =
6.9 Hz, 3H);13C{1H} NMR (100 MHz, CDCl3) δ 158.2, 139.8, 126.5, 113.6, 55.0, 50.5, 25.6.
NH2
9
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MeO
5g
1-(3-Chlorophenyl)ethanamine (5h):27 colorless oil (2.80 g, 90% yield); 1H NMR (400 MHz, CDCl3)
δ 7.38-7.32 (m, 1H), 7.29-7.17 (m, 3H), 4.09 (q, J = 6.4 Hz, 1H), 1.51 (bs, 2H), 1.36 (d, J = 6.4 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 149.8, 134.2, 129.7, 126.8, 125.9, 123.9, 50.9, 25.6.
NH2
Cl
5h
1-(3-Methoxyphenyl)ethanamine (5i):8c pale yellow oil (2.87 g, 95% yield); H NMR (400 MHz,
1
CDCl3) δ 7.27-7.20 (m, 1H), 6.94-6.89 (m, 2H), 6.79-6.74 (m, 1H), 4.07 (q, J = 6.4 Hz, 1H), 3.79 (s, 3H),
1.50 (bs, 2H), 1.37 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.6, 149.5, 129.3, 117.9,
111.9, 111.2, 55.0, 51.2, 25.5.
NH2
CH3O
5i
1-(2-Methoxyphenyl)ethanamine (5j):8c colorless oil (2.75 g, 91% yield); 1H NMR (400 MHz, CDCl3)
δ 7.32 (dd, J = 7.8, 1.4 Hz, 1H), 7.22 (ddd, J = 9.1, 7.3, 1.8 Hz, 1H), 6.94 (td, J = 7.3, 0.9 Hz, 1H), 6.86 (d,
J = 8.2 Hz, 1H), 4.35 (q, J = 6.4 Hz, 1H), 3.84 (s, 3H), 1.65 (brs, 2H), 1.39 (d, J = 6.4 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 156.6, 135.6, 127.5, 125.6, 120.5, 110.3, 55.1, 45.9, 23.1.
CH3O
NH2
5j
1-(2-Chlorophenyl)ethanamine (5k):28 colorless oil (2.68 g, 86% yield); 1H NMR (400 MHz, CDCl3)
δ 7.52 (dd, J = 7.8, 1.4 Hz, 1H), 7.33 (dd, J = 8.2, 1.4 Hz, 1H), 7.27 (t, J = 8.2, 1H), 7.16 (td, J = 7.8, 1.8
Hz, 1H), 4.54 (q, J = 6.9 Hz, 1H), 1.54 (bs, 2H), 1.39 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 144.6, 132.6, 129.5, 127.7, 127.1, 126.2, 47.5, 23.6; HRMS (ESI) m/z: [M + H]+ Calcd for
C8H11ClN 156.0575; Found 156.0563.
Cl
NH2
5k
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1-(2-Bromophenyl)ethanamine (5l):29 yellow oil (3.20 g, 80% yield); H NMR (400 MHz, CDCl3) δ
7.55-7.49 (m, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.08 (td, J = 8.2, 1.8 Hz, 1H), 4.50 (q, J = 6.9 Hz, 1H), 1.54 (bs,
2H), 1.38 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.1, 132.7, 128.1, 127.7, 126.4, 123.0,
7
8
9
49.9, 23.7.
Br NH2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5l
2,3-Dihydro-1H-indan-1-amine (5m):8c yellow oil (2.21 g, 83% yield); 1H NMR (400 MHz, CDCl3) δ
7.34-7.29 (m, 1H), 7.25-7.14 (m, 3H), 4.26 (t, J = 7.3 Hz, 1H), 2.98-2.89 (m, 1H), 2.85-2.75 (m, 1H),
2.54-2.44 (m, 1H), 1.73-1.61 (m, 1H), 1.59 (bs, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 147.4, 143.0,
127.0, 126.4, 124.5, 123.2, 57.2, 37.3, 30.0.
NH2
5m
1,2,3,4-Tetrahydronaphthalen-1-amine (5n):8c yellow oil (2.71 g, 92% yield); H NMR (400 MHz,
1
CDCl3) δ 7.38 (d, J = 7.3 Hz, 1H), 7.20-7.10 (m, 2H), 7.07 (d, J = 6.9 Hz, 1H), 3.96 (t, J = 5.5 Hz, 1H),
2.82-2.71 (m, 2H), 2.04-1.89 (m, 2H), 1.80-1.64 (m, 2H), 1.54 (bs, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ 140.9, 136.3, 128.7, 127.7, 126.2, 125.7, 49.1, 33.3, 29.3, 19.3.
NH2
5n
1-Phenylpropan-1-amine (5o):8c colorless oil (2.51 g, 93% yield); H NMR (400 MHz, CDCl3) δ
1
7.35-7.27 (m, 4H), 7.27-7.19 (m, 1H), 3.79 (t, J = 6.9 Hz, 1H), 1.75-1.61 (m, 2H), 1.53 (bs, 2H), 0.86 (t, J
= 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.3, 128.1, 126.6, 126.2, 57.6, 32.2, 10.8.
NH2
5o
2-Methyl-1-phenylpropan-1-amine (5p):8b colorless oil (2.78 g, 93% yield); H NMR (400 MHz,
1
CDCl3) δ 7.34-7.19 (m, 5H), 3.59 (d, J = 7.3 Hz, 1H), 1.92-1.77 (m, 1H), 1.48 (bs, 2H), 0.98 (d, J = 6.9 Hz,
3H), 0.77 (d, J = 6.9 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 145.4, 128.1, 127.0, 126.7, 62.4, 35.4,
13
19.8, 18.8.
NH2
5p
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1-(2-Furyl)ethanamine (5q):27 yellow oil (1.56 g, 70% yield); 1H NMR (400 MHz, CDCl3) δ 7.33 (t, J
= 0.9 Hz, 1H), 6.30 (dd, J = 3.2, 1.8 Hz, 1H), 6.10 (d, J = 3.2 Hz, 1H), 4.08 (q, J = 6.4 Hz, 1H), 1.58 (bs,
2H), 1.42 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.0, 140.9, 109.7, 103.0, 44.8, 21.8.
NH2
9
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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26
27
28
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41
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5q
1-(5-Methylfuran-2-yl)ethan-1-amine (5r):30 pale yellow oil (2.10 g, 84% yield); 1H NMR (400 MHz,
CDCl3) δ 5.95 (d, J = 2.7 Hz, 1H), 5.87-5.85 (m, 1H), 4.01 (q, J = 6.4 Hz, 1H), 2.27 (s, 3H), 1.56 (bs, 2H),
1.39 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.2, 150.4, 105.4, 103.6, 44.7, 21.7, 13.1;
HRMS (ESI) m/z: [M + Na]+ Calcd for C7H11NONa 148.0733; Found 148.0732.
NH2
O
5r
1-(Thiophen-2-yl)ethan-1-amine (5s):31 yellow oil (2.16 g, 85% yield); 1H NMR (400 MHz, CDCl3) δ
7.27 (dd, J = 4.6, 2.7 Hz, 1H), 7.12-7.10 (m, 2H), 4.18 (q, J = 6.4 Hz, 1H), 1.53 (bs, 2H), 1.40 (d, J = 6.4
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 149.2, 125.8, 125.7, 118.9, 47.1, 25.2; HRMS (ESI) m/z: [M
+ H]+ Calcd for C6H10NS 128.0528; Found 128.0532.
NH2
S
5s
1
1-(1-Methyl-1H-pyrrol-3-yl)ethan-1-amine (5t): orange oil (2.19 g, 88% yield); H NMR (400 MHz,
CDCl3) δ 6.53-6.48 (m, 2H), 6.09-6.05 (m, 1H), 4.03 (q, J = 6.4 Hz, 1H), 3.59 (s, 3H), 1.47 (bs, 2H), 1.36
(d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 131.3, 121.5, 117.5, 105.6, 44.5, 35.8, 25.4;
HRMS (ESI) m/z: [M + Na]+ Calcd for C7H12N2Na 147.0893; Found 147.0893.
NH2
N
5t
1-(Pyridin-4-yl)ethan-1-amine (5u):32 yellow oil (1.98 g, 81% yield); H NMR (400 MHz, CDCl3) δ
1
8.54 (dd, J = 4.6, 1.4 Hz, 2H), 7.28 (dd, J = 4.6, 1.4 Hz, 2H), 4.11 (q, J = 6.9 Hz, 1H), 1.60 (bs, 2H), 1.38
(d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.1, 150.0, 120.8, 50.1, 25.1; HRMS (ESI) m/z:
[M + H]+ Calcd for C7H11N2 123.0917; Found 123.0909.
NH2
N
5u
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(4-Chlorophenyl)(pyridin-2-yl)methanamine (5v): yellow oil (0.82 g from 5 mmol of 4v, 75% yield);
1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 4.6 Hz, 1H), 7.61 (td, J = 7.3, 1.8 Hz, 1H), 7.39-7.33 (m, 2H),
7.31-7.22 (m, 3H), 7.18-7.12 (m, 1H), 5.22 (s, 1H), 2.05 (bs, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
162.9, 149.1, 143.1, 136.6, 132.8, 128.6, 128.3, 122.0, 121.3, 60.3; HRMS (ESI) m/z: [M + H]+ Calcd for
C12H12ClN2 219.0684; Found 219.0667.
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11
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51
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53
54
55
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57
58
59
60
NH2
N
Cl
5v
4-Phenylbutan-2-amine (5w):8c white solid (2.75 g, 92% yield); H NMR (400 MHz, CDCl3) δ
1
7.30-7.24 (m, 2H), 7.21-7.14 (m, 3H), 2.90 (sext, J = 6.4 Hz, 1H), 2.72-2.56 (m, 2H), 1.72-1.57 (m, 2H),
1.23 (bs, 2H), 1.10 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.2, 128.2, 128.2, 125.6,
46.4, 41.7, 32.7, 23.9.
NH2
5w
Nonan-3-amine (5x):8c pale yellow oil (2.41 g, 84% yield); 1H NMR (400 MHz, CDCl3) δ 2.65-2.56 (m,
1H), 1.51-1.19 (m, 12H), 1.17 (brs, 2H), 0.95-0.85 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 52.5, 37.5,
31.7, 30.5, 29.3, 26.0, 22.4, 13.8, 10.2.
NH2
5x
6-Methylhept-5-en-2-amine (5y):8c pale yellow oil (2.29 g, 90% yield); 1H NMR (400 MHz, CDCl3) δ
5.11 (td, J = 7.3, 1.8 Hz, 1H), 2.92-2.83 (m, 1H), 2.16-1.89 (m, 2H), 1.69 (s, 3H), 1.62 (s, 3H), 1.43-1.28
(m, 2H), 1.21 (bs, 2H), 1.06 (dd, J = 4.6, 1.8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 131.0, 124.0,
13
46.3, 39.9, 25.3, 24.7, 23.6, 17.3.
NH2
5y
Cyclododecanamine (5z):8c yellow oil (3.30 g, 90% yield); 1H NMR (400 MHz, CDCl3) δ 2.89 (quin,
J = 6.0 Hz, 1H), 1.60-1.49 (m, 2H), 1.46-1.21 (m, 20H), 1.18 (bs, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
47.4, 33.1, 24.0, 23.5, 23.2, 23.2, 21.2.
NH2
5z
3,3-Dimethyl-1,5-dioxaspiro[5.5]undecan-9-amine (5aa):8c pale yellow oil (3.71 g, 93% yield); H
1
NMR (400 MHz, CDCl3) δ 3.51 (s, 2H), 3.48 (s, 2H), 2.81-2.69 (m, 1H), 2.23-2.16 (m, 2H), 1.77-1.69 (m,
2H), 1.49-1.28 (m, 6H), 0.96 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 96.8, 69.9, 69.5, 49.4, 31.9, 30.2,
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29.8, 22.4.
O
5
6
7
8
H2N
O
5aa
9
cis-2-Phenylcyclohexan-1-amine (5ab):33 pale yellow oil (0.80 g from 5 mmol of 4ab, 91% yield);
1H NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 2H), 7.24-7.17 (m, 3H), 3.25 (q, J = 3.2 Hz, 1H), 2.81 (dt, J =
12.8, 3.2 Hz, 1H), 2.02-1.94 (m, 1H), 1.91-1.80 (m, 2H), 1.78-1.68 (m, 1H), 1.68-1.47 (m, 3H0), 1.47-1.35
(m, 1H), 0.88 (bs, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.5, 128.1, 127.4, 125.8, 51.2, 47.3, 33.4,
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60
26.2, 23.4, 19.3; HRMS (ESI) m/z: [M + H]+ Calcd for C12H18N 176.1434; Found 176.1420.
NH2
5ab
cis-4-(tert-Butyl)cyclohexan-1-amine (5ac):34 colorless oil (12.9 g from 100 mmol of 4ac 83% yield);
1H NMR (400 MHz, CDCl3) δ 3.15 (quin, J = 3.2 Hz, 1H), 1.71-1.62 (m, 2H), 1.58-1.47 (m, 4H), 1.41-1.21
(m, 4H), 1.02-0.90 (m, 1H), 0.86 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 48.2, 45.0, 33.7, 32.4, 27.3,
20.5; HRMS (ESI) m/z: [M + H]+ Calcd for C10H22N 156.1747; Found 156.1735.
H2N
5ac
cis-4-Phenylcyclohexan-1-amine (5ad):35 colorless oil (13.3 g from 100 mmol of 4ad 76% yield); 1H
NMR (400 MHz, CDCl3) δ 7.33-7.14 (m, 5H), 3.25-3.20 (m, 1H), 2.60-2.51 (m, 1H), 1.91-1.79 (m, 2H),
1.76-1.64 (m, 6H), 1.39 (bs, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.9, 128.0, 126.6, 125.6, 45.1,
43.3, 33.1, 27.4; HRMS (ESI) m/z: [M + H]+ Calcd for C12H18N 176.1434; Found 176.1419.
H2N
5ad
Large scale preparation of cis-Cyclohexane-1,4-diamine (5ae).36 Acetic acid (515 mL, 9 mol) was
introduced via a syringe into a water (750 mL) solution containing 1,4-cyclohexanedione (336 g, 3 mol), 2c
(1.81 g, 3 mmol), and ammonium formate (1.51 kg, 24 mol) in a 5 L 4-necked flask, and the resulting
mixture was stirred 60 °C in an oil bath for 6 h. After the mixture cooled to room temperature, KOH
(2.12 kg, 37.8 mol) was added to the resulting residue and extracted with THF (1.5 L × 2). The combined
organic layers were evaporated under reduced pressure. Ethyl acetate (4.5 L) was added to the residue
and evaporated under reduced pressure. The crude product was distilled under reduced pressure to yield
the title compound as a colorless oil. 65% yield (221.9 g). 1H NMR (400 MHz, CDCl3) δ 2.92-2.84 (m,
13
2H), 1.66-1.44 (m, 8H), 1.17 (brs, 4H); C{1H} NMR (100 MHz, CDCl3) δ 47.2, 30.9; HRMS (ESI) m/z:
[M + H]+ Calcd for C6H15N2 115.1230; Found 115.1224.
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H2N
NH2
6
7
5ae
8
9
10
11
Derivatization of 5ae to cis-Cyclohexane-1,4-diacetamide (5af). A mixture of 5ae (0.50 g, 4.38
mmol) and Ac2O (0.5 g, 4.38 mmol) in a 20 mL Schlenk tube was refluxed at 150 °C in an oil bath for 2 h.
After removal of the volatiles under reduced pressure, diisopropyl ether (20 mL) was added to the residue,
and the resulting suspension was stirred at room temperature for 30 min. The precipitate was collected by
filtration and dried in vacuo to yield cis-cyclohexane-1,4-diacetamide (0.83 g, 96% yield)36a as a white
solid. 1H NMR (400 MHz, CDCl3) δ 5.43 (bs, 2H), 3.92 (bs, 2H), 1.98 (s, 6H), 1.86-1.74 (m, 4H),
1.61-1.49 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.3, 45.7, 28.2, 23.5; HRMS (ESI) m/z: [M +
12
13
14
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51
52
53
54
55
56
57
58
59
60
Na]+ Calcd for C10H18N2O2Na 221.1260; Found 221.1265.
O
HN
O
NH
5af
Typical Procedure for the DRA of α-Keto Acids. Formic acid (151 µL, 4 mmol) was introduced via
a syringe into a methanol (2 mL) solution containing α-keto acid (2 mmol), 2d (6.46 mg, 1×10-3 mmol),
and ammonium formate (378 mg, 6 mmol) in a Schlenk tube, and the resulting mixture was stirred at 80 °C
in an oil bath for 1.5 h. After the reaction mixture cooled to room temperature, methanol (1 mL) was
added and the resulting precipitate was filtered off and washed with methanol to give the α-amino acid 9.
1
2-Amino-2-phenylacetic acid (9a):8c white solid (2.56 g from 20 mmol of 8a, 85% yield); H NMR
(400 MHz, DMSO-d6 + HCl aq) δ 8.82 (bs, 3H), 7.60-7.35 (m, 5H), 5.01 (s, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6 + HCl aq) δ 170.4, 133.7, 130.5, 130.0, 128.9, 56.6.
NH2
CO2H
9a
2-Amino-2-(4-methoxyphenyl)acetic acid (9b):8c white solid (339 mg, 94% yield); 1H NMR (400
MHz, DMSO-d6 + HCl aq) δ 8.72 (bs, 3H), 7.36 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 4.94 (s, 1H),
3.73 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6 + HCl aq) δ 170.7, 160.7, 130.3, 125.6, 115.2, 56.1,
55.9.
NH2
CO2H
CH3O
9b
2-Amino-2-(3,5-dimethoxyphenyl)acetic acid (9c):37 white solid (332 mg, 79% yield); 1H NMR (400
MHz, D2O + HCl aq) δ 6.51 (brs, 2H), 6.48 (brs, 1H), 4.92 (s, 1H), 3.63 (s, 6H); 13C{1H} NMR (100 MHz,
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D2O + HCl aq and a drop of methanol as a reference) δ 171.1, 161.6, 134.4, 107.0, 102.4, 57.0, 56.2, 49.5
(methanol); HRMS (ESI) m/z: [M + H]+ Calcd for C10H14NO4 212.0917; Found 212.0902.
NH2
CH3O
CO2H
9
10
11
12
13
14
15
16
17
18
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22
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53
54
55
56
57
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59
60
OCH3
9c
2-Amino-2-(4-fluorophenyl)acetic acid (9d):38 white solid (319 mg, 94% yield); 1H NMR (400 MHz,
DMSO-d6 + HCl aq) δ 8.83 (bs, 3H), 7.65-7.45 (m, 2H), 7.40-7.20 (m, 2H), 5.09 (s, 1H); 13C{1H} NMR
(100 MHz, DMSO-d6 + HCl aq) δ 170.1, 163.0 (d, J = 246.3 Hz), 131.0 (d, J = 8.6 Hz), 129.9 (d, J = 2.9
Hz), 116.4 (d, J = 21.6 Hz), 55.3.
NH2
CO2H
F
9d
2-Amino-2-(naphthalen-2-yl)acetic acid (9e):8c white solid (365 mg, 91% yield); 1H NMR (400 MHz,
DMSO-d6 + HCl aq) δ 8.93 (bs, 3H), 8.10-7.85 (m, 4H), 7.70-7.48 (m, 3H), 5.20 (s, 1H); 13C{1H} NMR
(100 MHz, DMSO-d6 + HCl aq) δ 170.4, 133.7, 133.3, 131.1, 129.7, 128.8, 128.6, 128.5, 127.9, 125.7,
56.6.
NH2
CO2H
9e
2-Amino-2-(thiophen-2-yl)acetic acid (9f):8c white solid (583 mg from 5 mmol of 8f, 74% yield); H
1
NMR (400 MHz, DMSO-d6 + HCl aq) δ 8.89 (bs, 3H), 7.61 (dd, J = 5.5, 0.9 Hz, 1H), 7.27 (dd, J = 3.7, 0.9
Hz, 1H), 7.08 (dd, J = 5.5, 3.7 Hz, 1H), 5.39 (s, 1H); 13C{1H} NMR (100 MHz, DMSO-d6 + HCl aq) δ
169.7, 134.6, 129.7, 129.0, 128.3, 51.8.
NH2
S
CO2H
9f
2-Amino-3,3-dimethylbutanoic acid (9g):39 white solid (508 mg from 5 mmol of 8g, 77% yield); H
NMR (400 MHz, D2O) δ 3.30 (s, 1H), 0.92 (s, 9H). 13C{1H} NMR (100 MHz, D2O and a drop of methanol
1
as a reference) δ 174.1, 64.7, 49.5 (methanol), 32.6, 26.5.
NH2
CO2H
9g
X-ray Crystallographic Analysis of 2c and 5af. The single crystals of 2c and 5af were obtained by
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recrystallization from methanol and chloroform–hexane, respectively. Measurements were made on a
Rigaku Saturn CCD area detector with graphite monochromated Mo Kα radiation (λ = 0.71073 Å) under
nitrogen stream at 93 K. The single crystals were mounted on glass fibers. Intensity data were corrected
for Lorentz-polarization effects and for absorption. Structure solution and refinements were performed
with the CrystalStructure program package.40 The heavy-atom positions were determined by a direct
method program (SIR9741) and the remaining non-hydrogen atoms were found by subsequent Fourier
syntheses and refined by full-matrix least-squares techniques against F2 using the SHELXL-2014/7
program.42 The hydrogen atoms were placed at calculated positions and refined with a riding model.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
10.1021/acs.joc.xxxxx.
1H and 13C NMR spectra of all Ir complexes and products (PDF).
Crystallographic data (CIF).
AUTHOR INFORMATION
Corresponding Authors
*(S.K.) E-mail: skuwata@apc.titech.ac.jp
*(M.W.) E-mail: watanabe-masahito@gms.kanto.co.jp
ORCID
Yoshihito Kayaki: 0000-0002-4685-8833
Shigeki Kuwata: 0000-0002-3165-9882
Notes
The authors declare the following competing financial interest(s): JP Patent No.5,719,115, US Patent
No.8,481,735, and EP Patent No.2,228,377 by Kanto Chemical Co., Inc. contain intellectual property
described in this article.
ACKNOWLEDGMENTS
We thank Mr. Takaaki Yajima, Mr. Hiroshi Abe, Ms. Kana Nakashima, and Mr. Masahiro
Miyakawa of the Kanto Chemical and Suzukakedai Materials Analysis Division, Technical
Department, Tokyo Institute of Technology for the measurement of HRMS spectra, and Dr.
Tatsuro Toda of Tokyo Institute of Technology for helping preparation of the sulfonamidato
complexes. This work was partly supported by JSPS KAKENHI Grant number JP18K19070
(SK).
REFERENCES
(1) (a) Nugent, T. C.; Seemayer, R. An Efficient Enantiopure Synthesis of a Pivotal Precursor to Substance
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