New Catalysts
for Reductive Amination－ Ver.4 －Cl IrNN

Fro m a carbo
Fromcarbonyl
ny l cocompound,m po u n d,Cl IrNNNON

Ir-PA2a priprimar
m ar y amamii n e,e , a secon
se co n dar y am ine
ine,a terte r titiar
ar y amamine
i n e are eeasilyasi l y anandd
ClNinpott syn
i n a o nen e -po
sy n th esi
e si sIr-PA1R'NO

Cl IrNOCF3NewNNO2

OCl IrNONewIr-PA5

NIr-QN2

New

secondary and tartiary amines synthesis

Ir catalyst
AcOH, solvent

Ir-PA3

Iridium catalysts
for reductive amination Cl Ir

Ir

Ir-PA4

primary amines synthesis

RON

Ir-QN1+ HCO2NH4Cl IrNNHNconveniently
co nve n i e n tl y synthesized
sy n th e si ze dO

NOO

NH2
R

R'R+R'HN

R1

Ir catalyst

R1R2

HCO2H, solvent

RN

R2
R'Amine compounds are useful compounds used in a wide range of applications such as pharmaceuticals,agricultural materials, functionalized materials, and starting materials for resins .Reductiveamination of carbonyl compounds is known as one of the eﬀective synthetic methods for amines.
We Kanto Chemical has developed and marketed a reductive amination catalyst (iridium catalyst)
excellent in practicality that can synthesize primary amines, secondary amines, and tertiary amines under mild conditions so far , We have received popularity from everyone. We have newly added 3 reductive amination catalysts with diﬀerent substrate coverage. Please use it for your productdevelopment and research.

High reactivity

High catalytic activity

1-Phenylethylamine can be synthesized fromacetophenone under the condition of S / C = 10,000.

Chemoselective reaction

Primary amines can be synthesized from acetophenone derivatives without impairing functional groups.

High diastereoselectivity

Primary amines can be synthesized diastereoselectively from cycloaliphatic ketones with substituents.

S i mp l e o pe ra t ion
Not necessar y
special equipment
Mild reaction conditions

Air- stabl e catal ysts

Since ammonium formate or formic acid is used as ahydrogen source, special equipment is not required.
Since this catalyst can be used under reﬂux
conditions from 60 ℃, it has high practicality.
Since this catalyst can be handled stably in the air, it
can be weighed with ordinary laboratory equipment

A list of reductive amination catalyst products is posted on the back cover

Kanto Chemical Co., Inc.

Kanto Chemical Co., Inc.
Primary amine synthesisOR

Ir catalyst+ HCO2NH4

AcOH, solvent

R'Cl Ir
NN

NH2
RR'

Cl Ir
NNHN

Cl Ir
NNO

O

O

Ir-PA1

Cl Ir
NNN

NN

Ir-PA3

Ir-PA5Cl Ir
NNOO

Ir-PA2

Ir-PA4NO2New

CF3New

Ir-PA1~Ir-PA5 catalysts which have picolin amide particles are suitable for primary aminesynthesis. The feature of each catalyst are described below.
Catalyst

Feature and use application

Ir-PA1

Ir-PA1 shows a wide range of substrate adaptability.
We recommend that you consider using this catalyst when you ﬁrst try.

Ir-PA2

Ir-PA2 has high activity, and it is also applicable to substances with high bulkinessnear the carbonyl group. If the by-product of the alcohol is less in the reaction of
Ir-PA1 catalyst, Ir-PA2 can be expected to reduce the amount of catalyst.

Ir-PA3We recommend using Ir-PA3 catalyst together with the Ir - PA 2 catalyst whenstudying the reaction of a substrate that is sterically bulky near the carbonyl group.

Ir-PA4
Ir-PA5

These catalysts are suitable for electron-deﬁcient substrates. In the reaction using
the Ir - PA1 catalyst or the Ir - PA2 catalyst, this catalyst may be eﬀective when theby - production of the alcohol is remarkable.

Reaction condition of catalyst
hydrogen source
amine source

Ammonium formate are used as hydrogen source in this reaction.
3 to 5 equivalents to the substrate are optimum.

solvent

Ethanol is optimum in terms of solubility and reactivity of ammonium formate.
Water can also be used in the case of water-soluble substrates.

temperature

It is suitable to reﬂux conditions from 60 ℃ (eg around 80 ℃ for methanol). Reﬂux
conditions are recommended in terms of reactivity, but when side reactions occur
concurrently, side reactions can be surpressed by lowering the reaction temperature.

additive

Add 1 equivalent of acetic acid to the substrate.
Increasing the amount of acetic acid added (eg 2 equivalents) toimprove reactivity can improve yield.

control ofby-productcautionAs the main by-product of the reaction, there are formyl, alcohol(reduced form ofketone) and overalkylated forms(A reductant of an imine formed by a condensation
reaction between a primary amine and a ketone substrate) of primary amines whichis the target product. Formyl compounds tend to increase with increasing reaction
time, so caution is necessary when extending the reaction time beyond necessity.
Alcohol may be observed conspicuously depending on the substrate, but asmentioned above, the use of Ir - PA 4 catalyst or Ir - PA 5 catalyst may make itpossible to suppress alcohol.
Carbon dioxide is released as this reaction progresses.
Avoid reacting in a closed system, for example connect it to a line of inert gas,or connect it to a highly gas-tight gas balloon and carry out the reaction while
releasing the generated carbon dioxide outside the system.

Kanto Chemical Co., Inc.
Secondary and tertiary amine synthesis

OR+HN

R'R1

Ir catalyst

R1

R2

HCO2H, solventR

Cl IrNOCl IrNNR2
R'NO

Cl IrNOIr-QN1

NIr-PA1

Cl IrNNNONIr-QN2

NewN

Ir-PA2For the synthesis of secondary amines and tertiary amines, an Ir - QN 1 ,and Ir - QN 2 witha quinolinol ligand are suitable. However, in the synthesis of secondary amines that are notsterically bulky like the reaction of aldehydes with primary amines, tertiary amine as a byproduct by overalkylation reaction is a concern. So in this case, secondary amines can beobtained highly selectively by using Ir - PA1 catalyst or Ir - PA2 catalyst with picolinamideligand. Please see the table below for the characteristics and proper use of each catalyst.
Catalyst

Feature and use application

Ir-QN1

Ir-QN1 shows a wide range of substrate adaptability. We recommend thatyou consider using this catalyst when you ﬁrst try.

Ir-QN2Ir-QN-2 is a catalyst with higher activity than Ir - QN1, and when thereaction result of Ir - QN1 catalyst is good, Ir-QN2 can be expected toreduce the amount of the catalyst.

Ir-PA1
Ir-PA2In the case of synthesis of secondary amines that are not sterically bulky when
the by-production of tertiary amines becomes a problem due to an overalkylation,
secondary amines can be obtained highly selectively

Reaction condition of catalyst
hydrogen source

Formic acid are used as hydrogen source in this reaction.
3 to 5 equivalents to the substrate are optimum.

solvent

Various solvents can be used in consideration of the solubility
and reactivity of the substrate.

temperature

In general it is recommended to perform at 40 ℃ to 60 ℃.

control ofby-productIf alcohol is produced as a by-product, yield can be expected to be improved bychanging reaction solvent and increasing amine equivalent..

cautionCarbon dioxide is released as this reaction progresses.
Avoid reacting in a closed system, for example connect it to a line of inert gas,or connect it to a highly gas-tight gas balloon and carry out the reaction while
releasing the generated carbon dioxide outside the system.

Kanto Chemical Co., Inc.
Primary amine synthesis
Reductive amination of functionalized substrate such as electron attracting group

Acetophenones substituted with nitro, cyano and halogen groups also give the corresponding primary amines in good yieldwith no loss of functional groups in the presence of Ir - PA1 catalyst.
NH2NH2X

NH2X

O+X

NH2Ir-PA1

HCO2NH43 eq.

AcOH (1 eq.)
MeOH, reflux, 4 h

S/C = 1,000X

X

X

OCH3BraNO2aCNaayield (%)
9799
94
96

X
OCH3ClNO2yield (%)
98
99
98

X
yield (%)
OCH392
CH335
F96
Cl
41Br
21Conditions: 60 °C

Reductive amination of bulky substrate

In the reaction of a substrate having a substituent at the ortho position as described above, the yield tends to decrease due tosteric hindrance. In that case, the yield can be expected to be improved by using Ir - PA 2 catalyst or Ir - PA 3 catalyst.
Even in relatively bulky substrates such as isopropyl phenyl ketone, the Ir - PA 2 catalyst and Ir - PA 3 catalyst show higher
reactivity than the Ir - PA 1 catalyst, giving the corresponding primary amines in high yield.

XO+

HCO2NH45 eq.

S/C = 2,000

Ir catX

NH2AcOH (2 eq.)
MeOH, reflux, 4 hO

Ir cat+ HCO2NH4NH2

S/C = 2,000X

Ir catyield (%)

123456ClClClBrBrBr

Ir-PA1
Ir-PA2Ir-PA3
Ir-PA1
Ir-PA2
Ir-PA3459086
186985

Ir catIr-PA1
Ir-PA2
Ir-PA3

AcOH (2 eq.)
MeOH, reflux, 4 h5 eq.

entryyield (%)
5397
97

Reduction of use of catalyst

In the reaction of acetophenone, Ir-PA2 catalyst shows the highest reactivity when comparing the catalytic performances ofIr-PA1, Ir-PA2, and Ir-PA3 catalyst under the condition of S / C (substrate / catalyst molar ratio) = 10,000 (Entry 2).

O+HCO2NH45 eq.

S/C = 10,000

Ir catNH2

AcOH (2 eq.)
MeOH, reflux, 4 hentry

Ir catyield (%)

123Ir-PA1
Ir-PA2
Ir-PA355
9031

Reductive amination of heteroaromatic ring compound.

Amines containing heteroaromatic rings are important compounds contained in pharmaceuticals, agricultural materials, andfunctionalized materials. In the presence of the Ir - PA1 catalyst, the reaction of the furan ring, the thiophene ring, andthe ketones having a pyrrole ring progresses smoothly, giving the corresponding primary amines in good yield.
OHeteroaryl+

HCO2NH43–5 eq.

NH2Ir-PA1
AcOH (1–2 eq.)
MeOH, 60–80 °C, 4–6 h

S/C = 1,000

Heteroaryl

Hetero aryl:yield (%)

NON

SN

72

92

NS

93

96

89

>99

94

Reaction control of a substrate on which an alcohol is easily by-produced

In the reaction of 2- (4-chlorobenzoyl) pyridine having a heteroaromatic ring in the molecule, use of Ir-PA 2 catalyst or Ir-PA 1
catalyst with high catalytic activity produces a negligible amount of alcohol form (Entries 1 and 2), Ir-PA4 catalyst or Ir-PA5
catalyst with controlled reducing power can greatly reduce alcohol by-product (Entries 3 and 4). Ir-PA4 catalyst and Ir-PA5
catalyst may work eﬀectively in reaction of electron-deﬁcient substrate.
yield (%)
ONH2OHamine alcohol
entry Ir cat
Ir catNN
N+ HCO2NH4134
Ir-PA254
AcOH (2 eq.)273
Ir-PA1153 eq.
ClMeOH, 60 °C, 4 hClCl
3
Ir-PA481
9S/C = 500
aminealcohol
4Ir-PA582
8

Reductive amination of cycloaromatic ketone

Amines derived from indanone, tetralone, and chromanone are important compounds contained in the basic skeleton ofpharmaceuticals. The reaction of such aromatic cyclic ketones also proceeds smoothly in the presence of the Ir - PA1 catalyst
and the corresponding primary amines are obtained.
NH2O
NH2NH2NH2Ir-PA1+HCO2NH4X
X
AcOH (1 eq.)
Br
3–5 eq.
MeOH, reflux, 4 hyield (%)
80
73
94
S/C = 1,000

NH2O

90

Kanto Chemical Co., Inc.
High diastereoselective and reductive amination of cycloaliphatic ketones

In the case of cycloaliphatic ketones with substituents, the reaction proceeds higher diastereoselectively than known
synthetic methods, giving the corresponding primary amines. In the reaction of 1,4-cyclohexanedione and ammonium
formate, the reaction proceeds smoothly in the presence of Ir-PA1 catalyst by using water as a reaction solvent, giving
1,4-cyclohexyldiamine with cis: trans = 98: 2 in good yield.
NH2O
NH2Ir-PA1
NH2NH2NH2+ HCO2NH4C 6H5
CO 2EtRR
AcOH (1 eq.)
3 eq.
MeOH, 60 °C
S/C = 500
81% yield
75% yield
54% yield
75% yield
cis:trans = 98:2 cis:trans = 94:6 cis:trans = 96:4 cis:trans = 4:96
NH2O+NH2

Ir-PA1HCO2NH48 eq.

NH2HAcOH (3 eq.)
H2O, 60 °C, 6 hO
S/C = 1,000

NH2NH2NH282% yield
cis:trans = 98:2

C6H597% yield
cis: > 99%

99% yield
79% yield
62% yield
cis:trans = 93:7 cis:trans = 90:10 exo:endo = 6:94

Synthesis of α-amino acid from α-ketoacid

α-Amino acids are major compounds as pharmaceutical raw materials. In the reaction of α-keto acid with ammonium formate
in the presence of Ir-PA 1 catalyst, giving the corresponding α-amino acid in high yield.

OOH+O

HCO2NH43 eq.

NH2Ir-PA1OHAcOH (1 eq.)
MeOH, 60 °C, 1.5 hO

S/C = 500

99% yield

Secondary and tertiary amine synthesis
Synthesis of secondary amines from ketones and primary amines

In the presence of Ir-QN1 catalyst, the reaction of ketones with primary amines proceeds smoothly, giving the corresponding
secondary amines in high yield.
Ir-QN1OHN+ H 2N
HCO2H (3.0 eq.)
RR
AcOEt, 40 °C, 16–24 h
R = n-Pr, C6H5
R = n-Pr (98% yield)
1.05 eq.
C6H5(90% yield)
S/C = 1,000

Reduction of use of catalyst

Comparing the catalytic performances of the Ir - QN1 catalyst and the Ir - QN2 catalyst in the reaction of 2 - pentanone
with benzylamine, the Ir - QN2 catalyst shows high reactivity (Entries 1 and 2). Furthermore, by optimizing the equivalenceof amine and the reaction temperature in the presence of the Ir - QN 2 catalyst, The reaction can be proceeded quantitatively
even under the condition of S / C = 15,000 (entry 3). The reaction progresses quantitatively (entry 3).
entry Ir cat
S/C Benzyl
Ir catamine (eq.) temp. (°C）yield (%)
OH2NHN+4063
1 Ir-QN1 3,000
1.05
HCO2H (3.0 eq.)
IPA,40-60°C,24hIr-QN24097
2
3,000
1.05
S/C = 3,000-15,000

Synthesis of tertiary amines from ketones and secondary amines

3Ir-QN2 15,000

1.260

99

Synthesis of tertiary amines by reaction of ketones with secondary amines is a reaction that is likely to cause reductive reactionsof ketones due to the diﬃculty of forming imines. To control side reactions, selection of reaction solvent and amount of amineused are important. In the reaction between acetophenone and pyrrolidine, the corresponding tertiary amine is given quantitatively
by using 1.5 equivalents of amine in THF in the presence of Ir - QN1 catalyst.

O+Ir-QN1N
H
1.5 eq.

NHCO2H (3.0 eq.)
THF, 40 °C, 20 h

S/C = 1,000

99% yield

Synthesis of secondary amines in high yield from aldehydes and primary amines

In the reaction of aldehydes with primary amines, the preparation of tertiary amines by overalkylation reaction can be suppressedby using the Ir-PA1 catalyst, and the corresponding secondary amines can be obtained in high yield.

OH
S/C = 1,000

Ir-PA1+ H2N1 eq.

HCO2H (3 eq.)
MeOH, 60 °C, 1.5 hN
H95% yieldKanto Chemical Co., Inc.
Standard procedure for primary amine synthesis

OR+ HCO2NH4

Ir catalyst
AcOH, solvent

R'NH2
R

R'Reaction

Puriﬁcation

Glass round-bottom ﬂask (dry)Remove MeOH under vacuum

HCO2NH4Degas and recharge with an inert gas (Ar or N2)
MeOH＊１、ketone substrate、acetic acid、Ir catalyst＊２
Stir until a reaction is ﬁnished＊３)

Cool to room temperature

aqueous KOH or aqueous NaOH＊４
Extract with CH2Cl2

Remove CH2Cl2 under vacuum

The amine can be obtained through thepriscribed reﬁning method＊５Standard procedure for secondary and tertiry amine synthesis

OR+R'HN

R1

Ir catalyst

R1

R2

HCO2H, solvent

RReaction
Glass round-bottom ﬂask (dry)Degas and recharge with an inert gas (Ar or N2)
solvent＊１、ketone substrate、amine
Cool below 10℃ in ice bath
HCO2H
Warm to room temperature
Ir catalyst＊２

NR2
R'Puriﬁcation

Remove solvent under vacuum
aqueous KOH or aqueous NaOH＊４
Extract with CH2Cl2Remove CH2Cl2 under vacuum

The amine can be obtained through thepriscribed reﬁning method＊５

Stir until a reaction is ﬁnished＊３)

Cool to room temperature＊１ ︓Anhydrous and degassed solvent is not necessarily needed.
＊２ ︓Ir cat can be handled in an open air.
＊３ ︓Do not conduct the reaction in a closed system, since carbon dioxide will be released.
For example, insert an inert gas line or attach an airtight balloon.
＊４ ︓For water soluble amines, the use of conc. KOH solution.
is more eﬀective to extract amine compounds from aqueous layer.
＊５ ︓The residual catalyst can be removed by ﬁltering the organic layer
through a short column of silica gel.

Kanto Chemical Co., Inc.
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List of products
Product
Chloro[N-[4-(dimethylamino)phenyl]-2-pyridinecarboxamidato](pentamethylcyclopentadienyl)iridium(III)abbreviation︓Cp*IrCl(Dap-picolinamidato)

CAS︓1364328-83-5

Cl IrNN(Ir-PA1)

FW︓603.18

N(CH3)2O

Chloro[4-(dimethylamino)-N-(dimethylamino)
pheny-2-pyridinecarboxamidato](pentamethylcyclopentadienyl)iridium(III)abbreviation︓Cp*IrCl(Dap-Da-picolinamidato)

CAS︓-(Ir-PA2)

FW︓646.25

Cl IrN
NN(CH3)2O

CAS︓-

Package07127-68

100 mg07127-95

500 mg07429-68

100 mg07429-95

500 mg07430-68

100 mg07430-95

500 mg07964-68

100 mg07964-95

500 mg07965-68

100 mg07965-95

500 mg07128-68

100 mg07128-95

500 mg07966-68

100 mg07966-95

500 mg(CH3)2N

Chloro[4-(dimethylamino)-2-pyridinecarboxamidato](pentamethylcyclopentadienyl)iridium(III)abbreviation︓Cp*IrCl(Da-picolinamidato)

Product No.

(Ir-PA3)

Cl Ir
N
NH

FW︓527.09

O(CH3)2N

Chloro(pentamethylcyclopentadienyl)(4-dimethylamino-8-quinolinolato)iridium(III)abbreviation︓Cp*IrCl(CF3-picolinamidato)

CAS︓-(Ir-PA4)

FW︓628.11

Cl Ir
N
N

CF3O

Chloro[N-(4-nitrophenyl)-2-pyridinecarboxamidato](pentamethylcyclopentadienyl)iridium(III)abbreviation︓Cp*IrCl(NO2-picolinamidato)

CAS︓1887154-21-3(Ir-PA5)

FW︓605.11

Cl Ir
N
NO

Chloro(pentamethylcyclopentadienyl)(8-quinolinolato)iridium(III)
Cl Ir
NO

abbreviation︓Cp*IrCl(quinolinolato)(Ir-QN1)

CAS︓1217487-22-3

FW︓507.05

Chloro(pentamethylcyclopentadienyl)(4-dimethylamino-8-quinolinolato)iridium(III)abbreviation︓Cp*IrCl(Da-8-quinolinolato)

CAS︓-

FW︓550.12

NO2(Ir-QN2)(CH3)2NCl IrNO

OFC-05-ENG (202012)