Catalytic hydrogenation of functionalized amides under basic and neutral conditions

Article abstract of DOI:10.1039/c4cy01227e

A new, base-free high turnover number (TON) catalyst for hydrogenation of simple and functionalized amides is prepared by reacting [Ru(η³-C₃H₅)(Ph₂P(CH₂)₂NH₂)₂]BF₄ and BH₄^- under hydrogen. The hydrogenation proceeds with C-N cleavage to form the corresponding amine and alcohol. The base-free and base-promoted hydrogenations tolerate alcohols, amines, aromatic bromides, chlorides and fluorides, ethers, certain olefins, and N-heterocyclic rings. The reaction was used to deprotect the amine groups in certain acetyl amides to form, for example, an N-heterocyclic amine containing an aryl bromide. The base-free system also selectively hydrogenates N-acyloxazolidinones without epimerization at the α-position, and reduced β-lactams to form the corresponding amino alcohols.

Full text of DOI:10.1039/c4cy01227e

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Catalytic hydrogenation of functionalized amides
under basic and neutral conditions†
Cite this: DOI: 10.1039/c4cy01227e
a
b
b
b
Jeremy M. John, Rasu Loorthuraja, Evan Antoniuk and Steven H. Bergens*
A new, base-free high turnover number (TON) catalyst for hydrogenation of simple and functionalized
3
3 5 2 2 2 2 2 4
4−
amides is prepared by reacting ijRuIJη -C H )IJPh PIJCH ) NH ) ]BF and BH under hydrogen. The hydroge-
nation proceeds with C–N cleavage to form the corresponding amine and alcohol. The base-free and
base-promoted hydrogenations tolerate alcohols, amines, aromatic bromides, chlorides and fluorides,
ethers, certain olefins, and N-heterocyclic rings. The reaction was used to deprotect the amine groups in
certain acetyl amides to form, for example, an N-heterocyclic amine containing an aryl bromide. The base-
free system also selectively hydrogenates N-acyloxazolidinones without epimerization at the α-position,
and reduced β-lactams to form the corresponding amino alcohols.
Received 19th September 2014,
Accepted 3rd November 2014
DOI: 10.1039/c4cy01227e
www.rsc.org/catalysis
structure of the amide and catalyst will also influence the
selectivity of the reduction.
Introduction
We report an active system for the hydrogenation of simple
and functionalized amides under neutral conditions with
high turnover numbers (TON). The reduction of amides pro-
duces alcohols and/or amines that have biological activity and
The heterogeneous amide hydrogenation catalysts favor
net C–O cleavage, and the more active systems use ~1 mole%
6
catalyst at T > 130 °C under 30–100 atm H . These systems
2
tolerate certain ether functionalities, amines, and alcohols.
Arene hydrogenation and bond hydrogenolysis can occur as
side reactions. Recently, Cole-Hamilton et al. reported that a
4% Pt–4% Re/TiO2 catalyst effects the hydrogenation of
1
,2
industrial applications. Amides are the least reactive of the
carboxylic acid derivatives, and their reduction requires force-
ful conditions or reducing agents that are oxophilic. Amide
reductions are typically carried out with stoichiometric
6
n
amides in flow reactors.
3
hydride reducing agents such as Al–H, B–H, or Si–H species.
The homogeneous amide hydrogenation catalysts are
classified into acid-promoted systems and into bifunctional-
type systems that operate under neutral and basic condi-
Recently, Procter et al. reported a stoichiometric reduction
2
with SmI (4–8 equiv.) as reducing agent to form the amine
4
and alcohol products of net C–N cleavage. The reduction of
tions. RuIJacac)3 (acacH = 2,4-pentanedione), 1,1,1-tris-
amides proceeds through hemiaminal or related intermedi-
ates (Scheme 1).
IJdiphenylphosphinomethyl)ethane, and methanesulphonic
acid form a catalyst that hydrogenates N-phenyl amides with pre-
dominantly C–O cleavage under acidic conditions with 1% cata-
5
Elimination of H O (C–O cleavage) forms the higher
2
7a–d
amine as net product (path A). The elimination of H O is pro-
lyst at T = 200–220 °C under 10–40 atm H2.
homogeneous precursors include Cp*RuClIJX–N) (X = N, P),
PNN-Ru pincer complexes (PNN = 2-IJdi-tert-butylphosphinomethyl)-
The bifunctional
2
7e–g
moted by acid, sieves, oxophilic reagents, the presence of
hydrogen on nitrogen, or by high temperatures to remove
water. The majority of stoichiometric amide reductions pro-
7
h
6-IJdiethylaminomethyl)pyridine, etc.), and RuCl IJY–N) com-
2
2
7k
ceed by C–O cleavage to form the higher amine. Elimination
plexes (e.g. Y–N = 2-IJIJdicyclohexylphosphino)methyl)pyridine.
2
of H NR (C–N cleavage) during amide reduction forms the
These systems operate under neutral conditions, typically in
2
corresponding lower amine and alcohol (path B). The net
2
elimination of H
2
NR from the hemiaminal is promoted by
basic conditions at low to moderate temperatures. The
a
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, USA
b
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2,
Canada. E-mail: steve.bergens@ualberta.ca
†
Electronic supplementary information (ESI) available: Experimental details
and spectroscopic data are given in the supporting information. See DOI:
0.1039/c4cy01227e
1
Scheme 1
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−
THF solvent at T = 80–200 °C with 1–10 mole% catalyst
reducing any ligands in these precursors with BH . It is
4
under 10–50 atm H . The major products are the alcohol
and amine resulting from C–N cleavage. The activity of
some of these catalysts is promoted under basic condi-
likely that the reduced activity of catalysts made from 5 and 6
results from inefficiencies inherent with utilizing two in situ
reactions to prepare the catalyst: the reaction with 7, followed
by reaction with NaBH4 and hydrogen. The relatively low
reactivity of the dichloride 3 perhaps illustrates the relative
ease by which the allyl group in 2 is removed by hydrogena-
tion relative to the reduction of the chloride ligands in 3 by
2
tions. In 2011, we reported that the cationic allyl precursor
3
ijRuIJη -C
H )IJPh PIJCH )
3 5 2 2 2
NH ) ]BF
2 2 4
(2) or the neutral dichloride
RuCl IJPh PIJCH ) NH ) (3) with base in THF hydrogenate
2
2
2 2
2 2
a wide variety of simple amides with C–N cleavage and with
remarkable TON's up to ~7000 (100 °C, 50 atm, 4–5 mol%
4
NaBH .
8
a
base, 24 h).
Table 2 shows the results for the base-free hydrogenations
of representative simple amides with 2 (0.1 mol%) and NaBH4
IJB/Ru = 2, 100 °C, 50 atm (rp), 24 h, THF). For comparison, we
include the yields reported previously for the same hydrogena-
There are no reports of a high TON (>300) neutral amide
hydrogenation catalyst, nor of an amide hydrogenation cata-
lyst that tolerates a wide variety of functional groups. We
now report such a neutral catalyst, and we demonstrate its
functional group tolerance under neutral and basic condi-
tions. We also illustrate the utility of the system as a rela-
tively mild, catalytic method to liberate amines by hydrogena-
tion of the corresponding acetyl amides.
8a
tions carried out with excess base (4 mol% KNijSiIJCH ) ] ).
3
3 2
The N-diphenyl (entry 1), N-phenyl-N-methyl (entry 2), and
N-phenyl acetamides (entry 3) were all hydrogenated in high
TON (800–1000) with both catalyst systems. Interestingly,
the 2° N-phenyl acetamide (entry 3) was slightly more reac-
tive with the base-free catalyst than with the base-
promoted catalyst. The same order of activity occurs with
N,N-diphenyl benzamide as substrate (entry 6). We believe
that under basic conditions, 2° amides are deprotonated at
Results and discussion
9
10a–e
Noyori and others
reported that catalysts containing
−
BH4 adducts are active for ketone hydrogenations under
base-free conditions. For this study, we found that the cat-
ionic allyl precursor ijRuIJη -C H )IJPh PIJCH ) NH ) ]BF (2) reacts
nitrogen to form strongly coordinating amidate anions that
11
−
partially hinder the catalyst. The hydrogenations with BH
4
3
are less susceptible to this type of inhibition. The morpholino
acetamide (8d) was smoothly hydrogenated under base-free
and basic conditions (entry 4), and the stable N,N-dimethyl-
acetamide (8e), was hydrogenated with appreciable TON (240,
entry 5) with the base-free catalyst. The base-promoted system
was more active (TON = 500). Taken together, the hydrogena-
tions of the N-phenyl, N-alkyl, and secondary acetamides in
Table 1 demonstrate that these hydrogenations offer a rela-
tively mild, efficient, and environmentally benign alternative
to the stoichiometric methods used to liberate amines that
3
5
2
2 2
2 2
4
with 2 equiv. of NaBH under H in THF (~2 atm, 60 °C, 30 min)
4
2
to form a base-free catalyst that hydrogenates N-phenylpyrrolidin-
-one (4) with C–N cleavage in high TON (910) (24 h, 50 atm
reaction pressure, rp), 100 °C, Table 1, entry 1). There was no
2
(
evidence of C–O cleavage, despite the neutral conditions for
this hydrogenation. Catalysts prepared by reacting the ruthe-
6
12
nium precursors ijRuIJIJ1-3;5-6-η)-C H )IJη -anthracene)]BF (5)
or ijRuIJη -C
8
11
4
3
3 5 2 4
H )IJCOD)IJMeCN) ]BF (COD = 1,5-cyclooctadiene)
(
6) in situ with Ph PIJCH ) NH (7, 2 equiv.), and then
2
2 2
2
1
4
with NaBH4 (5 equiv.) were somewhat less active (entries 2
and 3) than the catalyst prepared from 2. The dichloride
RuCl IJPh PIJCH ) NH ) (3) with NaBH was ~66% less active
were protected as acetamides.
Table 3 shows the results from the base-free and base-
promoted hydrogenations of functionalized amides. Gener-
ally, the system with added base was more active for these
2
2
2 2
2 2
4
(
entry 4). The ratio of Ru : BH was increased to 1 : 5 with 5, 6,
4
and 3 to accommodate any uncertainties in the amounts of
in situ catalyst formed, as well as any potential difficulties in
Table 2 Base-free hydrogenation of simple amidesa b
,
Table 1 Base-free hydrogenation of 4 by various Ru-precursors
1
2
3
c
Entry
Sub
R
R
R
% conv
TON
a
1
2
3
4
5
6
8a
8b
8c
8d
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Me
H
100(100)
93(100)
80(70)
96(100)
24(50)
1000
930
800
960
240
710
Entry
Catalyst
Ru : NaBH
4
% conv
TON
b
1
2
5
6
3
1 : 2
1 : 5
1 : 5
1 : 5
91
71
66
76
913
710
660
378
c
f
2
–C
Me
Ph
4
8
H O–
c
d
3
8e
Me
H
d
e
4
8f
71(50)
a
1
b
a
Determined by H NMR spectroscopy. 2 was reacted with NaBH
4
4 2
2 reacted with NaBH for 20 min under ~2 atm H at 60 °C. [8a–e] =
b
c
for 20 min under ~2 atm H
2
2
at 60 °C. 5 or 6 were reacted with
under ~2 atm H
for 20 min under
2.5 M in THF. In parenthesis are the results for the base-assisted
hydrogenation using 0.1 mol% and 4 dmol% KNijSiIJCH
Determined using H NMR spectroscopy. Anthracene used as
equiv. 7 (under Ar for 30 min), then with NaBH
4
2
2
3 3 2
) ] .
d
c
1
for 20 min at 60 °C. 3 was reacted with NaBH
2 atm H at 60 °C. rp = reaction pressure.
4
e
f
~
2
2 2 2 2
internal standard. [8f] = 2 M in THF. –CH CH OCH CH –.
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Table 3 Base-freea vs. base-assistedb hydrogenation of functionalized amides
%
conv
TON
c
Entry
1
Sub
t (t)
Base-free
34
Base-assisted
Base-free
34
Base-assisted
442
d
24(24)
89
e
2
3
4
24(21)
19(28)
nd(24)
0
50
0
50
500
100
f,g
69
nd
100
69
nd
100
d
5
6
7
16(24)
nd(24)
24(24)
32
nd
5
88
32
nd
5
438
500
86
d,g
100
86
8
24(24)
nd(24)
100
nd
100
100
100
nd
500
500
h
a
b
2
(1 mol%) reacted with NaBH
4
(2 mol%) for 20 min under ~2 atm H
2
at 60 °C. [amide] = 0.25 M in THF. nd = not determined. 2 (1 mol%)
c
d
reacted with KOt-Bu (4 mol%). [Amide] = 0.25 M in THF. Time for base-assisted hydrogenations denoted in parenthesis. Ru : KOt-Bu : amide
1
1
e
f
g
h
: 20 : 500. Ru : KOt-Bu : amide 1 : 5 : 100. Proceeded with 8% C–O cleavage. Ferrocene used as internal standard. Reaction performed at
0 atm H pressure.
2
substrates. The functional groups that tolerated the base-
promoted hydrogenation with good TON (400–500) include
arene rings, aromatic fluorides (entries 1 and 3), and bromides
N-Acyloxazolidinones are typically harder to reduce than
amides. We prepared the diastereomerically pure IJ2-benzyl)-
propanamide oxazolidinones 9a and 9b by benzylation of the
1
3
(entry 4). The halide can reside on the acyl group (entries 1 and 2),
parent enolates. Hydrogenation of 9a and 9b under base-
free conditions with 10 mol% Ru proceeded with quantitative
reduction of the endocyclic C–N bond to furnish only the
corresponding hydroxyl amides and methanol (Table 4) The
diastereomeric ratio of the product was (>99 : 1) for both
these hydrogenations, showing epimerization did not occur.
Steric crowding around the exocyclic amide bond likely drives
the preference for hydrogenation of the oxazolidinone
or in the amine of the amide (entries 3 and 4). Interestingly,
and for reasons unknown at this time, the base-assisted
hydrogenation of the N-IJ4-fluorophenyl)benzamide (entry 3)
proceeded quantitatively (TON = 500) with 92% net C–N cleav-
age and ~8% net C–O cleavage. The aromatic chloride (entry 2)
was less reactive than the fluorides and bromides. Impor-
tantly, furans are not hydrogenated and do not hinder catalysis
(entries 5 and 6, TON = 400–500), demonstrating that amides
can be selectively hydrogenated in the presence of furans.
Amides containing 2° N-heterocycles can also be hydrogenated,
albeit with lower, but useful TON (86, entry 7). The haloge-
nated heterocyclic amine 5-bromoindoline was deprotected by
the neutral and base-promoted hydrogenations of 1-acetyl-
Table 4 Base-free hydrogenation of N-acyloxazolidinones
1
2
3
a
a
5
-bromoindoline (entry 8). Significantly, the base-promoted
hydrogenation of this substrate (entry 8) was carried out under
0 atm reaction pressure to give 500 turnovers in 24 hours,
Entry
Sub
R
R
R
% conv
TON
b
1
9a
9b
Ph
H
Me
iPr
CMe(H)Bn
CMe(H)Bn
100
100
10
10
1
b
2
demonstrating that this catalytic system is active towards cer-
tain amides under lower pressures. The hydrogenation also
tolerates ethers (see Table 2, entry 4), as well as alcohols and
amines as these are the products of the hydrogenation.
a
1
b
Determined using H NMR spectroscopy. 2 (10 mol%) reacted
(20 mol%) for 10 min under ~2 atm H at 60 °C.
Reaction conditions: 50 atm H (rp) at 50 °C for 24 h. [9a or 9b] =
25 mM in THF. dr of 9a or 9b = 99 : 1.
with NaBH
4
2
2
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carbonyl. In contrast, the hydrogenation of 9a with 2 in the
presence of base (10 mol% 2, 20 mol% KOt-Bu) also occurred
with near exclusive endocyclic C–N cleavage, but the products
consisted of a mixture of diasteromeric hydroxyl amides resulting
from base-catalyzed epimerization of the IJ2-benzyl)propanamide
group. These results demonstrate that the base-free hydroge-
nation will preserve the stereochemistry at enolizable carbon
centers. Ikariya and coworkers reported that hydrogenation
Catalyst preparation
General procedure for base-assisted hydrogenations using
2
and KOt-Bu. 2 (6.80–13.8 mg, 10.0–20.0 μmol) and KOt-Bu
(
9.00–44.8 mg, 80.0–400 μmol, 4.00–5.00 mol%) were weighed
out into two respective NMR tubes in a glove box. Freshly dis-
tilled THF (1.0 mL) was then added by cannula under Ar
pressure into the tube containing 2. This yellow solution was
then cannulated into the NMR tube containing KOt-Bu under
of 9a using 3 mol% Cp*RuClIJPh
2 2 2 2
PIJCH ) NH ) and KOt-Bu
~
2 atm H pressure. It was then heated at 60 °C for 20 min
2
(
Ru : base = 1 : 1) under 30 atm H at 80 °C for 20 h in 2-PrOH
2
with occasional mixing. This mixture turned orange/red during
this time and was then used for the base-assisted amide hydro-
genations described in the next section (method A or B).
General procedure for base-free hydrogenations using 2 or
proceeding exclusively with exocyclic C–N cleavage resulting
7
e
from hydrogenation of the acyl carbonyl. We believe the
−
active catalyst generated from 2 and BH4 is more susceptible
to steric crowding than the catalyst Cp*RuHIJPh PIJCH ) NH )
2
2 2
2
3
and NaBH
respectively) and NaBH4 (1.50 mg, 2.00 equiv. based on 2,
0.0 μmol, or 3.80 mg, 5.00 equiv. based on 3, 100 μmol)
4
. 2 or 3 (13.8 mg 2 or 12.6 mg 3, 20.0 μmol
described by Ikariya and coworkers.
Control experiments were performed to investigate the
identity of the active catalyst. The use of Ru black as catalyst
resulted only in the hydrogenation of the arene ring in 5.
It is therefore unlikely that Ru nanoparticles are the active
catalyst in these amide hydrogenations. In control NMR
4
were weighed out into two respective NMR tubes in a glove
box. THF (1.0 mL) was then added by cannula under Ar pres-
sure into the NMR tube containing the Ru-precursor at room
temperature. This solution (or mixture) was then transferred
by cannula using ~2 atm H2 pressure into the NMR tube
experiments, we found that 2 reacts with 2 equiv. of NaBH
after 30 min at 60 °C under ~2 atm H to form in 95% yield
4
2
containing NaBH
then heated at 60 °C for 20 min under ~2 atm H
4
at room temperature. The mixture was
with peri-
trans-RuIJH)IJBH
4
)IJPh
2
PIJCH
2
)
2
NH
2
)
2
. Propylene and remaining
complex was
2
NaBH were also present. The trans-H–Ru–BH
4
4
1
odic mixing. The mixture turned orange/brown during this
time and was then used for the base-free amide hydrogena-
tions described in the next section (method A or B).
General procedure for base-free hydrogenations using
in situ prepared catalysts derived from 5 or 6, 2 equiv.
1
1
31
31
1
11
15
identified using H, H{ P}, P{ H}, B, H– N HSQC,
gTOCSY, and gCOSY NMR experiments. Based upon this obser-
vation, we propose that the catalyst generated under base-free
conditions is trans-RuIJH) IJPh PIJCH ) NH ) , made from
2
2
2 2
2 2
9
b
4 2 2 2 2 2
trans-RuIJH)IJBH )IJPh PIJCH ) NH ) .
Ph
2 2 2 2 4
PIJCH ) NH and 5 equiv. NaBH . 5 or 6 (8.4 mg, 20 μmol
5
or 9.7 mg, 20 μmol 6) and NaBH4 (3.8 mg, 0.10 mmol,
Conclusions
5.0 equiv. based on Ru) were weighed out into two respective
NMR tubes in a glove box. THF (1.0 mL) was then added by
cannula under Ar pressure to the NMR tube containing the
The new base-free catalyst system and the base-promoted
catalyst system hydrogenate a synthetically useful variety of
functionalized and heterocyclic amides. The absolute con-
figurations are preserved at stereogenic carbon centers in
groups attached to nitrogen, and in groups alpha to the car-
bonyl group under base-free conditions. Certain olefins tolerate
the hydrogenation, and the system is a catalytic, clean
method to deprotect amines from acetyl amides.
Ru-precursor at room temperature. Ph
2 2 2 2
PIJCH ) NH (7.8 μL,
40 μmol, 2.0 equiv. based on Ru) was then added to the THF
solution of Ru-precursors. The contents of the NMR tube
were then heated at 60 °C for 0.5 h under Ar with periodic
mixing. This solution was then transferred by cannula under
~
2 atm H pressure at room temperature into the NMR tube
2
4
containing the 5.0 equiv. NaBH . The mixture was then
heated at 60 °C for 20 min with periodic shaking. The mix-
ture turned orange/brown during this time and was then
used for the base-free amide hydrogenation described in the
next section (method A).
Experimental section
General procedures used to synthesize ruthenium precursors
3
ijRuIJη -C
3
H
5
)IJPh
2
PIJCH
2
)
2
NH
2
)
2
]BF
4
(2) was prepared according
8
a
31
1
to our original procedure.
P{ H} NMR – (201.643 MHz,
2
General procedures for hydrogenation
CD Cl , 27 °C): δ 48.5 (minor, s), 51.9 (major, d, J = 29.6 Hz),
2
2
P–P
2
6
9.9 (major, d, JP–P = 30.2 Hz).
RuCl IJPh PIJCH ) NH ) (3) was prepared according to a
Method A: solid amides. The amide (2.0–20 mmol,
100–1000 equiv.) was added to a stainless steel autoclave
equipped with a magnetic stir bar. The autoclave was then
purged with H for 10 min at room temperature. 4.0–5.0 mL
2
of THF was then added to the autoclave using a gas tight
2
2
2 2
2 2
1
5
procedure reported by Morris and coworkers.
3
1
1
P{ H} NMR – (161.839 MHz, CD
2
Cl
2
, 27 °C): δ 55.4
2
2
(
trans, d, J
= 32.0 Hz), 61.8 (cis, s), 66.8 (trans, d, JP–P
=
P–P
3
2.0 Hz).
ijRuIJIJ1-3;5-6-η)-C
syringe. The catalyst–NaBH4 or catalyst–base mixture, pre-
pared above, was then added by cannula under H pressure
2
6
16
8
H
11)IJη -anthracene)]BF
4
(5) was prepared
via a modification of a procedure reported by Komiya and
coworkers.
followed by a 2.0–4.0 mL THF wash. The autoclave was then
1
2
pressurized to 50 atm H . The reaction mixture was stirred at
2
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5
0–100 °C for 23 h. The autoclave was then allowed to
Notes and references
cool over the course of 1 h before venting at room tempera-
ture. The percent conversions were determined by H NMR
spectroscopy.
Method B: liquid amide or N-acyloxazolidinones (9a and 9b).
The atmosphere of a stainless steel autoclave was purged
1
1 P. D. Bailey, T. J. Mills, R. Pettecrew and R. A. Price, in
Comprehensive Organic Functional Group Transformations II:
5.06 – Amides, ed. A. R. Katritzky and R. J. K. Taylor, Elsevier,
Oxford, 2005, pp. 201–294.
with H for 10 min at room temperature. A solution of the
amide or N-acyloxazolidinone (0.2–20 mmol, 10–1000 equiv.)
in THF (1.0 mL), prepared under Ar, was then added by a
2 (a) Modern Amination Methods, ed. A. Ricci, Wiley-VCH, Weinheim,
2000; (b) Modern Reduction Methods, ed. P. G. Andersson
and I. J. Munslow, Wiley-VCH, Weinheim, 2008.
2
cannula under H pressure followed by a 4.0 mL THF wash.
3 J. Seyden-Penne, Reductions by the Aumino- and Borohydrides
in Organic Synthesis, Wiley, New York, 2nd edn, 1997.
4 M. Szostak, M. Spain, A. J. Eberhart and D. J. Procter, J. Am.
Chem. Soc., 2014, 136, 2268.
2
The catalyst–NaBH mixture, prepared above, was then added
4
2
by cannula under H pressure followed by a 2.0 mL THF
wash. The autoclave was then pressurized to 50 atm H . The
2
reaction mixture was stirred at 50–100 °C for 23–47 h. The
autoclave was then allowed to cool over the course of 1 h
before venting at room temperature. The percent conversions
5 P. A. Dub and T. Ikariya, ACS Catal., 2012, 2, 1718–1741.
6 Heterogeneous amide hydrogenation: (a) B. Wojcik and
H. Adkins, J. Am. Chem. Soc., 1934, 56, 2419–2424; (b)
J. C. Sauer and H. Adkins, J. Am. Chem. Soc., 1938, 60,
1
were determined by H NMR spectroscopy.
4
02–406; (c) F. Galinovsky and E. Stern, Ber. Dtsch. Chem.
Spectroscopic identification of products
Ges. A/B, 1943, 76, 1034–1038; (d) A. Guyer, A. Bieler and
G. Gerliczy, Helv. Chim. Acta, 1955, 38, 1649–1654; (e)
H. S. Broadbent and W. J. Bartley, J. Org. Chem., 1963, 28,
All hydrogenation products except 9a and 9b are known.
1
9
a: H NMR (599. 926 MHz, CDCl , 27 °C): δ 0.71 (3H, d,
3
2
345–2347; ( f ) I. D. Dobson, BP Chemicals Limited; Patent
J = 7.0 Hz, CH
.0 Hz, CH ), 1.73 (1H, m, CH), 2.53 (1H, m, CH), 2.70
1H, m, CH), 2.95 (1H, m, CH), 3.23 (1H, bs, OH), 3.60 (3H,
m, 3 CH), 5.72 (1H, bs, NH), 7.17–7.26 (5H, m, 5 aromatic
3 3
), 0.78 (3H, d, J = 6.5 Hz, CH ), 1.21 (3H, d, J =
EP0286280, 1988, p. 11; (g) C. Hirosawa, N. Wakasa and
T. Fuchikami, Tetrahedron Lett., 1996, 37, 6749–6752; (h)
A. A. Smith, P. Dani, P. D. Higginson and A. J. Pettman,
Avantium Internation B.V., Patent WO2005066112A1,
6
3
(
13
1
CH). C{ H} NMR (175.969 MHz, CDCl
8.5 (CH), 19.2 (CH), 28.6 (CH), 40.4 (CH), 43.9 (CHNH), 56.9
aromatic), 63.6 (CHOH), 126.2 (aromatic), 128.3 (aromatic),
3
, 27 °C): δ 17.9 (CH),
2
005, p. 34; (i) G. Beamson, A. J. Papworth, C. Phillips,
1
(
A. M. Smith and R. Whyman, Adv. Synth. Catal., 2010, 352,
869–883; ( j) G. Beamson, A. J. Papworth, C. Phillips,
A. M. Smith and R. Whyman, J. Catal., 2010, 269, 93–102; (k)
G. Beamson, A. J. Papworth, C. Phillips, A. M. Smith and
R. Whyman, J. Catal., 2011, 278, 228–238; (l) R. Burch,
C. Paun, X. M. Cao, P. Crawford, P. Goodrich, C. Hardacre,
P. Hu, L. McLaughlin, J. Sà and J. M. Thompson, J. Catal.,
1
15
1
28.8 (aromatic), 139.7 (aromatic), 176.5 (CO). H– N
+
HSQC (498.117 MHz, CDCl , 27 °C): δ 123. HRMS (ESI ) m/z
3
+
2
calculated for C15H24NO (M + H) : 250.18. Found: 250.1802.
Difference (ppm): 0.75. 9a is not stable for prolonged periods
in solution.
1
9
b: H NMR (599. 926 MHz, CDCl
3
, 27 °C): δ 0.79 (3H,
2
011, 283, 89–97; (m) M. Stein and B. Breit, Angew. Chem.,
d, J = 7.2 Hz, CH
3
), 1.21 (3H, d, J = 6.6 Hz, CH ), 2.43 (1H,
3
Int. Ed., 2013, 52, 2231–2234; (n) J. Coetzee, H. G. Manyar,
C. Hardacre and D. J. Cole-Hamilton, ChemCatChem,
sex, J = 6.6 Hz, CH), 2.70 (1H, dd, J = 6.6 Hz, CH), 2.93 (1H,
dd, J = 8.4 Hz, CH), 3.91 (1H, bs, OH), 4.19 (1H, m, CH), 4.75
2
013, 5, 2843–2847.
(
1
1H, bs, NH), 5.38 (1H, d, J = 7.8 Hz, CH), 7.15–7.33 (10H, m,
0 aromatic CH). C{ H} NMR (150.868 MHz, CDCl , 27 °C):
3
1
3
1
7 Homogeneous amide hydrogenation: (a) M. Kilner,
D. V. Tyers, S. P. Crabtree and M. A. Wood, Davy Process
Technology Limited, UK, Patent WO03093208A1, 2003, p. 23;
δ 14.5 (CH), 17.7 (CH), 40.5 (CH), 43.8 (CH), 50.9 (CHNH),
6.7 (CHOH), 126.3 (aromatic), 126.4 (aromatic), 127.4 (aromatic),
28.0 (aromatic), 128.4 (aromatic), 128.9 (aromatic), 139.7
7
1
(
b) A. A. N. Magro, G. R. Eastham and D. Cole-Hamilton,
1
15
Chem. Commun., 2007, 3154–3156 Amendment: D. L. Dodds
and D. J. Cole-Hamilton, Catalytic reduction of amides
avoiding the use of LiAlH and B2H6, in Sustainable
4
(aromatic), 140.7 (aromatic), 176.4 (CO). H– N HSQC
+
(
3
599.925 MHz, CDCl , 27 °C): δ 127. HRMS (ESI ) m/z calcu-
+
lated for C H NO (M + Na) : 320.1621. Found: 320.1621.
1
9
23
2
Catalysis: Challenges and Practices for the Pharmaceutical and
Fine Chemical Industries, ed. P. J. Dunn, K. K. Hii, M. J. Krische
and M. T. Williams, John Wiley & Sons, Inc., New York, 2013,
ch. 1, pp. 1–36(c) G. R. Eastham, D. J. Cole-Hamilton and
A. A. N. Magro, Lucite International UK Limited, UK, Patent
WO2008035123A2, 2008, p. 36; (d) J. Coetzee, D. L. Dodds,
J. Klankermayer, S. Brosinski, W. Leitner, A. M. Z. Slawin
Difference (ppm): 0.01.
Acknowledgements
This work was supported in part by the Natural Sciences
and Engineering Research Council of Canada (NSERC), the
GreenCentre Canada and the University of Alberta. We grate-
fully appreciate the assistance of Mark Miskolzie and Nupur
Dabral at the University of Alberta High Field NMR labora-
tory. We acknowledge the R.A. awarded to J. M. J. by the
University of Alberta Department of Chemistry.
and D. J. Cole-Hamilton, Chem.
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