Catalytic Hydrogenation of Amides
2nd/Aug/2014 (Sat) Ozawa Jun (D1)O

R1cat., H2
J]\’ R3 i’N
R2R

1 /\l, R

3

N
R2

JOH

or
R1

, R3

+ HN
R2

1.

Introduction

p 1

2.

Hydrogenations with Heterogeneous Catalysts

2-1.

Early Development

p 4

2-2.

Recent Progress

p 6

3.

Hydrogenations with Homogeneous Catalysts

p 13

4.

Summaryp 20

1. Introduction
An amide, one of the most robust functional groups, is resistant to various chemical reactions
such as nucleophilic attacks, redox reactions and acidic or basic decomposition.
The reason is clear: the resonance depicted below.

9OO
R1 lL N »
R2

3

R

<i>

R1

J\\®' R3N
R2

The resonance results in
1. a lower positive charge on the carbon atom than that in other carbonyl compounds
lower electrophilicity
2. lower electron density on the nitrogen atom
low basicity and coordinating ability, and high resistance toward oxidation of the nitrogen3. planar nature due to the sp2 hybridized orbital of the nitrogen
There is an energy barrier to rotation of the C-N bond (formamide: 75 ~ 80 kJ/mol).
O

O

HB
HA
JL.<i>JL.
H
N
H
N
HA

80 kJ/mol- 1/20 -HBSpeaking of reduction of amides, LiAlH4 is the most practical and reliable choice:O

LiAlH4NH2

Ph

Ph

THF, r.t. ~ reflux

NH2> 90% yield

Other metal hydride agents (DIBAL, Red-Al, AlH3, BH3, LiEt3BH, ...) are also effective ones.
disadvantages:
1. coproduction of stoichiometric amounts of waste metal salts
complicated workup, poorly atom economical
2. incomplete chemoselectivity
Other functional groups such as ketones, nitro groups, some alkynes, will be reduced.
It's difficult to use such reagents at the late stage of the synthesis.

a promising alternative: catalytic hydrogenation
O
R1

N
R2

cat., H2

R3

H H
R1

N
R2

R3

+

H2O

1. Water is the sole stoichiometric waste.
2. It is possible to control the chemoselectivity by modifying the catalysts:

O

O

O

cat., H2

N
H

OH
not

N
H

N
H

cf. different catalyst system brings the different selectivity of hydrogenation
Pd/C, H2OH

Pd/C, H2, NH3
OBn

MeOH

OBn

MeOH

93%

93%
K. Hirota Tetrahedron 1998, 54, 13981-13996.

Fe cat.
H2 (3 atm)

OH

O

toluene, 25 C

H2 (10 bar)
[RhCl(cod)]2
Bu4NHSO4
buffer/scC2H6
36 C

88%

* scC2H6: supercritical ethane

C. P. Casey JACS 2007, 129, 5816-5817.

OH
OC
OC

Fe

97%

P. G. Jessop Chem. Commun. 2000, 941-942.

TMS
Fe cat. =

O

TMS
H

- 2/20 -other reduction reactions of amides
1. silane reduction
Stoichiometric silane reagents are needed, but metal catalysts are generally catalytic amount.
easier workup than when Al-H or B-H reagents are used
M. Beller JACS 2010, 132, 1770-1771.

Zn(OAc)2 (10 mol%)(EtO)3SiH (3 eq)

O
1

R

N
R2

R3

R1

THF, r.t. ~ 40 C

N
R2

R3

72 ~ 99%

Only tertiary amides are applicable.
Ketone, nitrile, nitro group, olefin, ester,diimide are tolerated.

2. metal-free reduction using Hantzsch ester (HEH)
A. B. Charette JACS 2008, 130, 18-19.

HEH (2.5 eq)
Tf2O (1.1 eq)

O
3

R1

N
R2

R

1

R

CH2Cl2, r.t.

N
R2

R3

EtO2C

CO2Et

HEH =
N
H

46 ~ 91%

Only tertiary amides are applicable.
Ketone, nitrile, conjugated olefin, alkyne, ester,
epoxide, are tolerated.
Sterically hindered amides are difficult to reduce.
O

O
i

Ph

N
i
Pr
< 5%

Pr

t

Bu

Bn
N
Bn
18%

Mild and chemoselective reduction of amides into amines has been achieved,
but the methods are still atom inefficient.

- 3/20 -2. Hydrogenations with Heterogeneous Catalysts
2-1. Early Development
pioneering work using Cu-Cr oxide catalysts by Adkins

H. Adkins JACS 1934, 56, 247.
H. Adkins Patent US 2143751
the preparation of the catalysts:
H. Adkins JACS 1932, 54, 1138-1145.

O
R1

N
R2

R3

Cu/Cr cat. (~ 15 mol%)H2 (200 ~ 300 bar)

C6H13

N
H

C6H13

NH2

39%

C11H23O
N
H

C11H23

58%

N
H
37%

Ph

Ph NH2

C11H23

29%

H
N

NH2

14%
N
H

C11H23

Ph

5%

Et

N
Et

C6H13

C11H23

2%

O
N
Et

C6H13

Ph
Ph

C6H13

R3

Products

O
NH2

N
R2

neat or 1,4-dioxane
250 C

Substrate (selected)

C6H13

R1

Et
N
H

C6H13

4%

Et

64%

C6H13

N
H

C6H13

25%

O
C6H13

N

C6H13

N

C6H13

92%

OH
5%

Extremely high H2 pressure (~ 300 bar) and reaction temperature (250 C) were required.
The target amines were obtained, but they were generally minor products.
The solvent 1,4-dioxane was thought to dilute the water and minimize the hydrolysis of amides.

Additives could improve the selectivity or reaction cocnditions
1. NH3 effectively suppressed the formation of secondary amines in the hydrogenation of primary amines:
Cu/Cr, H2

O
C7H15

NH2

NH2

C7H15

C7H15

+

300 atm, 300 C, w/o NH3: 9%
400 atm, 350 C, w/ NH3: 90%

N
H

C7H15

83%
10%
A. Guyer Helv. Chim. Acta 1955, 38, 1649-1654.

- 4/20 -the mechanism for the genaration of symmetric secondary amines
(a)

(b)

R. Whyman Chem. Rev. 2014, 114, 5477-5510.

(c)subject to nucleophilic attacks
the attack of the target amine
secondary amine
the attack of NH3
no change (primary amine)

2. A 4A zeolite enabled the hydrogenation as low as 140 bar and improved the selectivity.
O
C11H23

Me

N
Me

Cu/Cr
H2 (140 bar)

C11H23287 C
w/o MS4A:
w/ MS4A:

Me
N
Me

+

C11H23

17%
72%

N
H
9%
9%

C11H23 +C11H23

OH

+

1%
8%

rsm
53%
8%

R. M. King Patent US 4448998

Additives could reduce the H2 pressure, but the reaction temperature was still high (over 200 C).
The catalyst itself must be modified for higher catalytic property.

- 5/20 -2-2. Recent Progress
A landmark paper by T. Fuchikami (TL 1996, 37, 6749-6752.) says,"the bimetallic catalysts consisting of group 8 to 10, and group 6 or 7 metals show extremely potent reducing
abilities in the hydrogenation of amides".
(One year before he reported that the same kind of bimetalic catalysts were also effective for the hydrogenationof carboxylic acids to alcohols. (TL 1995, 36, 1059-1062.))

group
Cr
Cu

6
11

Rh
Ru
Re
Mo
W

9
8
7
6
6

further investigation of thesubstrate scope*Cat.1: Cat. 2 = 1:1, DME: 1,2-dimethoxyethane, bp 85 C

Monometallic catalysts were all ineffective (entry 1 to 5).
The hydrogenation proceeded at 100 atm of H2 at 160 C, much milder than the conditions mentioned above.
(see the next page)
Secondary and tertiary amides were hydrogenated smoothly to give the corresponding amines, and a primaryamide was reduced to the primary amine with the help of Et2NH that suppressed the formation of (C6H13)2NH.
Benzene rings were unfortunately hydrogenated into cyclohexane rings (entry 6 and 7).
*Rh(0) catalyzes benzene hydrogenation: R G. Finke JACS 1998, 120, 5653-5666.

- 6/20 -

O
1

R

N
R2

R3

Rh/Re
H2 (100 atm)

R1

DME

N
R2

R3

Bulky substituents didn't
hinder the hydrogenation.

aromatic rings hydrogenated!!

Et2NH needed to suppress
the generation of (C6H13)2NH.

Whyman researched the properties of the bimetallic catalysts.
R. Whyman J. Catal. 2010, 269, 93-102. (Rh/Mo)
R. Whyman Adv. Synth. Catal. 2010, 352, 869-883. (Ru/Mo)
R. Whyman J. Catal. 2011, 278, 228-238. (Ru/Re, Rh/Re)
Here only Rh/Mo catalyst system is put on the agenda.
Catalytic Procedures
Rh6(CO)16 (0.0165 g, 0.0930 mmol Rh), Mo(CO)6 (0.0135 g, 0.0511 mmol Mo) and CyCONH2 (0.235 g, 1.85 mmol)
were added to a glass liner containing DME (30 mL), and n-octane (0.100 g) as an internal standard for GC
analysis. The liner was placed in a ca. 300 mL capacity pressure vessel and the reaction mixture, underagitation, was purged (at 5 bar), 3 times with N2 followed by 3 times with H2. The autoclave was thenpressurized to 100 bar with H2 and heated to 160 C for 16 h. After cooling and depressurization, a darkcoloured colloidal suspension was recovered. This slowly settled to leave a colourless solution, and dark
residue (ca. 15 mg), which was separated by centrifugation (2000 rpm, 20 min), washed several times with
DME and dried as a fine black powder.

DME
n-octane

Rh6(CO)16
Mo(CO)6amide

N2 (5 bar)
3 times

H2 (5 bar)
3 timesH2 (100 bar)
160 C

cooling
depressurization
centrifugation(16 h)- 7/20 -The ratio of Mo:Rh is an essential factor of high selectivity and onversion.
Ocat., H2 (100 bar)Nthe highest when Mo/Rh = 0.67
NDME, 160 C, 16 h

The selectivity and conversion varied depending on the Mo:Rh ratio.
The best ratio of Mo:Rh varied dependig on the substrate.
Rh/Mo cat.
H2 (100 bar)

O
Cy

NH2

Cy
160 C, 16 h

NH2

Mo:Rh

Conversion(%)

CyCH2NH2(%)

CyCH2OH(%)(CyCH2)2NH
(%)

0
0.16
0.55
1.01
1.39
1.53
1.90
2.37
3.40
4.03

20
91
100
100
100
100
89
22
24
29

68
89
87
77
58
47
43
0
0
0

24
8
10
11
22
27
36
21
34
33

4
2
0
8
15
24
16
78
62
64

excellent selectivity for the primary amine
w/o additional NH3 or other amines!

no primary amine

Best result (conversion and primary amine selectivity) was obtained when Mo/Rh was around 0.6.
Significant decrease in the primary amine selectivity was observed at the ratio higher than 1.
Above a Mo:Rh ratio of 2, the conversion dramatically decreased, with the secondary amine formed as the only
amine product. (excess Mo is a catalyst poison?)- 8/20 -Low temperature and pressure of H2 resulted in low conversion and selectivity.
Rh/Mo cat.
H2 (?? bar)

O
NH2

Cy

NH2

Cy
?? C, 16 h

T ( C)

H2 (bar)Conversion(%)

CyCH2NH2(%)

CyCH2OH(%)(CyCH2)2NH
(%)

160
140
130
120
160
160
160

100
100
100
100
50
20
10

100
97
95
9
100
63
41

87
79
53
0
83
66
56

10
7
19
75
8
10
26

0
12
23
20
14
17
20

The conversion dramatically decreased below 130 C probably due to temperature dependentadsorption/desorption of reactants and products on the catalyst surface.

HP-FTIR analysis to monitor catalyst genesis during the N-acetyl piperidine hydrogenation

O
N

Mo(CO)6*Rh6(CO)16 is insoluble to DME.

[Rh13H3(CO)24]2-

Mo(CO)6-n(NAP)nRh6(CO)16 and Mo(CO)6 gradually change into the real catalyst in situ.
NAP starts to be consumed just after the absorption of COs has disappeared; the induction period is about 8 h.
2016 cm-1 and 1849 cm-1 are consistent with the reported peaks for [Rh13H3(CO)24]2-:(CO) in THF: 2020 and 1840 cm-1 (P. Chini Chim. Ind. (Milan) 1978, 60, 989-997.)- 9/20 -X-ray Photoelectron Spectroscopy (XPS) of Rh6(CO)16/Mo(CO)6 catalyst (Mo:Rh = 0.67)

Rh is present in the metallic state throughout.
Mo has various oxidation state ranging IV to VI; Mo(VI) is dominant on the catalyst surface, but Mo(IV) exists
inside the catalyst (entry 9 and 10).
After hydrogenation the catalyst surface is still covered with Mo(VI), but Mo(V) has generated inside, which
is a clear contrast with the catalyst derived from Rh and MoO3 (entry 11 to 15).

quantification of XPS profiles of the fresh Mo:Rh = 0.67 catalyst
Ar+ sputter etching time [min]Mo:Rh ratio

0
2.17

1
1.10

2
0.95

4
0.67

8
0.62

higher Mo content in the outer layer
At high Mo:Rh levels excess Mo has the effect of
coating the surface of Rh/Mo catalyst, blocking active
sites, and thus leading to the observed poisoning of
catalytic activity, and possibly influencing reaction
selectivity via longer residence times.

MoO2 has both acidic and metallic properties(J. W. Sobczak Surf . Interf ace Anal. 2002, 34, 225-229.)
The acidic Mo initially adsorbs the amide carbonylgroup, which could lead to the promotion of overall
rates of reduction at adjacent Rh centers.

R. Whyman Chem. Rev. 2014, 114, 5477-5510.

- 10/20 -Other aspects of the bimetallic catalysts
1. amide reduction reactivity ranking: Primary > Tertiary > Secondary (the position of Secondary is rather variable)
R. Whyman Adv. Synth. Catal. 2010, 352, 869-883.

O
Cy

N
R1

R2

Ru3(CO)12/Mo(CO)6 (1:2)
H2 (100 bar)Cy

DME, 160 C, 16 h

N
R1

R2

(R1, R2)

conv. [%]

yield [%]

(H, H)(H, Me)(Me, Me)

100
5
30

85
trace
22

a. Nitriles can be intermediates only for primary amides, which may be preferred to hydrogenation to hemiaminals.
O

OH
NH2

R

R

OH

H2
R

NH

- H2O

NH2

H2

R

NH

R

NH2

H2
- H2O
O
R

- H2O
NH2

R

N

H2

R

H2
NH

R

NH2

R. Whyman J. Catal. 2011, 278, 228-238.

* This is an idealistic representation of the reaction pathways because the free energy values don't take account of the effect of therequirement for adsorption of the reactants and intermediates on the catalyst surface.

b. For tertiary amides there is an alternative pathway to tertiary amines: direct cleavage of C=O bonds.
DFT calculation was performed to investigate the reaction mechanism of the cleavage of the carbonyl bond in
N,N-dimethylacetamide on both flat and stepped Ru surface.

P. Hu J. Phys. Chem. C 2012, 116, 18713-18721.

- 11/20 -In both cases direct C=O cleavage (DMA to DMAED) is preferred.
c. Hydrogenation using D2 (A. M. Smith Ph.D. Thesis, University of Liverpool, 2006.)
Ru/Mo cat.
D2 (20 bar)

O
NH2

Cy

O

nC8H18, 160 C, 20 h
OD

D2
Cy

NH2

Cy

H/D exchange was observed on Cy ring.
An H2O to DHO ratio was ca. 1:1.

?

D

NH2

D

+

DHO

+

DHO

NH

Cy
D

OH
NH

Cy

OH

D2
Cy

D

NH

Cy

NHD

1:1

D
+
Cy

H2O

ND

O
Cy

NH2

R

N

+

H2O

d. Substituent(s) on N may be a steric bulk during amide adsorption onto the catalyst surface.
e. Hydrogen-bonded oligomer may also be an inhibiting factor for the adsorption onto the catalyst surface.
2. the comparison among the catalysts of Ru/Mo, Rh/Mo, Ru/Re and Rh/Re
R. Whyman J. Catal. 2011, 278, 228-238.

It cannot be determined which combination is the best for the hydrogenation of amides, mainly
because there is no comprehensive data of substrate scope in the Whyman's papers.

- 12/20 -3. Hydrogenations with Homogeneous Catalysts
There was only one report of the homogeneous hydrogenation of an amide before Cole-Hamilton's report.

S. P. Crabtree WO03/093208A1 (2003)
Ru(acac)3
triphos
H2 (1000 psi)

O
NH2

Et

Et

N
H

Et

+

OH
Me

O

O

164 C, THF, 14 h

Et

+
NHPr

OPr

PPh2
PPh2
PPh2
triphos(yields not given)much milder reaction conditions than that of Cu-Cr catalyst system, but no primary amine detected...

Cole-Hamilton further researched the catalyst system.
D. J. Cole-Hamilton Chem. Commun. 2007, 3154-3156.
Ru(acac)3
triphos
H2 (40 bar)

O
C8H17

N
H

Ph

C8H17
164 C, THF, 14 h

N
H

Ph

+

C8H17

OH

No reaction occurred in the absence of Ru(acac)3 (entry 1 and 3).
Lower conversion was observed in the absence of triphos (entry 2 and 4).
Water was not essential for full conversion, but the catalyst was not stable in the absence of water (entry 5).
Lower temperature than 140 C resulted in lower conversion and secondary amine selectivity (entry 6 to 8).
Additional aniline unfortunately reduced the catalyst stability and decreased the selectivity (entry 9), which isa strong contrast with heterogeneous catalyst system discussed above.

- 13/20 -Hydrogenation of butanamide
Ru(acac)3
triphos
H2 (40 bar)

O
C3H7

NH2

NH2

C3H7

164 C, THF, 14 h

+

N
H

C3H7

O

C3H7

N

C3H7

C3H7
C3H7

O
+

C3H7

+

OBu

+
C3H7

NHBu

C3H7

OH

In this case addition of appropriate amount of NH3 had an critical effect on the improvement of primary amine
selectivity.
Excess liquid NH3 had a bad effect on conversion (entry 4)
Excess aqueous NH3 increased the concentration of water, leading to the hydrolysis and the alcohol production(entry 5 to 8).
In fact, the work proved irreproducible at 164 C; 200 C was necessary for good reproducibility.

Further development by Cole-Hamilton
D. J. Cole-Hamilton Chem. Eur. J. 2013, 19, 11039-11050.

MsOH as an additive enabled the hydrogenation at as low as 10 bar of H2, accelerated the reaction, and improved
the selectivity (entry 1 and 2).
Too much MsOH resulted in relatively complicated reaction (entry 4).
The reaction vessel had a strange effect on the reduction of the aromatic ring (entry 6).

- 14/20 -The appropriate amount of MsOH dramatically improved
the conversion and the selectivity in the hydrogenationof N-phenylacetamide.

NH3 was necessary for high primary amine selectivity (entry 1).
Conversion and/or selectivity were low if there was not any aryl group on N (entry 2, 14, 18, 20, 24).
N-Chorophenylamides yielded variable conv. and sel. depending on the position of Cl (entry 9 to 11).
The benzene ring and the NO2 group were reduced (entry 12).
The yields for the hydrogenation of tertiary amides were generally poor.

- 15/20 -Mechanistic insight
NMR studies showed that high temperature was required for the initial reduction of RuIII to RuII and triphos
coordination.
Ru(acac)3 (1 eq), triphos (2 eq) and MsOH (1.5 eq) were mixed and pressurised at 10 bar with H2 in THF-d 8
at 130 C (the max. probe temp.) : very little change on 1H and 31P NMR.
after exposed to the typical reaction conditions: a number of species, including oxidized triphos, detected
High temperature is also required for the turnover of the catalyst.
Triphos-coordinated RuII catalyst (7 ~ 10) were tested ifthey showed catalytic activity, and 9 and 10 did display it.

10 was generated after the hydrogenation catalyzed by 9.

In the presence of MsOH (> 1 eq.) 9 was converted to the mixture of 12 ~ 14, and 10 to 12, 16 ~ 18.

catalyticallyinactive

Cole-Hamilton proposed thatthe role of MsOH would not only be to generate the active catalytic species, but also to control the protonationdeprotonation sequences required for efficient catalytic turnover;the equilibrium mixture of 12 ~ 14 would act as a pool for the [(triphos)Ru]2+ fragment as the entry point into theactual catalytic cycle;
the generation of 18 would be an important deactivation pathway.

- 16/20 -Hydrogenation of amides to alcohols and amines ~C-N bond cleavage~
Milstein reported hydrogenation of amides with cleavage of the C-N bond.
D. Milstein JACS 2010, 132, 16756-16758.

Ru cat. 3
H2 (10 atm)

O
1

R

N
R2

R3

THF, 110 C

OH
R1

+

HN
R2

R3

N H Pt-Bu2

Ru cat. =
N

Ru
CO
3

Although C-N bond cleavages and the generation of alcohols were mentioned in the previous papers, they
were likely to be the result of hydrolysis of the amides to carboxylic acids, followed by hydrogenation.
The reaction above was anhydrous, so direct C-N bond cleavage surely occurred.
No hydrogenation on aromatic rings was observed (see the table below).

* No reaction occurred in the absence of base (entry 1, cat. 4).

N H Pt-Bu2
Et2N

Ru

N H Pt-Bu2
t-Bu2PRu

CO1

N H Pt-Bu2
NCO2- 17/20 -RuCO4(the precursor of 3)Clproposed mechanism by Milstein

Milstein postulated that key to the success of C-N
cleavage is that it does not involve intermediacyof free hemiaminal, avoiding water elimination to
give an imine.

Mhemiaminoxy
intermediate

O
R1

R1

NHR2

+

R1

NHR2

+

NHR2

M

O

OH
R

1

NHR2

easierOH

DFT analysis for the hydrogenation with Milstein's catalyst
D. Cantillo Eur. J. Inorg. Chem. 2011, 3008-3013.

*relative energies calculated at 298 K and 1 atm

highestbarrier(S)highestbarrier

Pathway of C-O cleavage*equilibrium constant between 4 and 4': K ~ 10-8 (H. Sigel, R. B. Martin Chem. Rev. 1982, 82, 385-426.)- 18/20 -There are two possible pathways from 5 to 6:

41.5 kcal/mol

Dearomative hydride transfer to thecarbonyl group cost higher energy.

(+23.2)Hydride must come from Ru-H species.
96.7 kcal/mol

Pathway of C-N cleavage

The highest energy barrier (39.5 kcal/mol) is lower
than those in the catalytic cycles A and A' (51.0 and
52.2 kcal/mol, respectively).

Pathway C is preferable during amide hydrogenation.

highestbarrier

Calculation at 110 C and 10 atm gave the same orderof the energy barriers for the pathway A, A' and C.
(R)- 19/20 -4. Summary
Various catalysts have been developed for hydrogenation of amides. Recent progress has enabled thehydrogenation under milder reaction conditions (160 C, 100 bar) than primitive ones (250 C, 300 bar),
but they are still far from practical temperature and H2 pressure (r.t. and 1 atm are ideal).

What revealed:
1. Multimetallic catalysts, composed of oxophilic metal(s) and typical metal(s), are more effective thanmonometallic catalysts.
2. Some homogeneous catalysts can directly cleave the C-N bond in the amide moiety to give the corresponding
alcohol and the amine.
3. DFT analysis by Cantillo discovered that hydride transfer to an amide or an iminol double bond had very highenergy barrier (40 ~ 50 kcal/mol), likely being the rate-determining step.

Remaining challenges:
1. mild reaction conditions
2. substrate scope expansion
3. product selectivities (primary amides to primary amines, secondary amides to secondary amines, tertiary
amides to tertiary amines)
4. functional group tolerance (aromatic rings must be tolerated; other carbonyl groups, unsaturated bonds,
epoxides etc. should be tolerated)
5. cheap metal catalyst center

reference:
R. Whyman Chem. Rev. 2014, 114, 5477-5510. and the references therein[EOF]- 20/20 -