Ruthenium-catalysed oxidation of alcohols to amides using a hydrogen acceptor

Article abstract of DOI:10.1016/j.tet.2014.04.017

A wider investigation into the synthesis of secondary amides from primary alcohols using a hydrogen acceptor using commercially available [Ru(p-cymene)Cl₂]₂ with bis(diphenylphosphino)butane (dppb) as the catalyst. The report looks at over 50 examples with varying functionality and steric bulk, whilst also covering the first reported results using microwave heating to effect the transformation.

Full text of DOI:10.1016/j.tet.2014.04.017

Tetrahedron 70 (2014) 3683e3690
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Tetrahedron
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Ruthenium-catalysed oxidation of alcohols to amides using
a hydrogen acceptor
,
b
c
Andrew J.A. Watson a , Russell J. Wakeham , Aoife C. Maxwell ,
*
Jonathan M.J. Williams b
a Department of Chemistry, University of Canterbury, 20 Kirkwood Avenue, Ilam, Christchurch 8041, New Zealand
b Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom
c GlaxoSmithKline Research and Development, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A wider investigation into the synthesis of secondary amides from primary alcohols using a hydrogen
acceptor using commercially available [Ru(p-cymene)Cl2]2 with bis(diphenylphosphino)butane (dppb) as
the catalyst. The report looks at over 50 examples with varying functionality and steric bulk, whilst also
covering the first reported results using microwave heating to effect the transformation.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 6 February 2014
Received in revised form 23 March 2014
Accepted 7 April 2014
Available online 13 April 2014
Keywords:
Ruthenium
Oxidation
Amide
Alcohol
1. Introduction
Amides are present in many molecules throughout the chemical
industry, appearing in polymers, pharmaceuticals, agrochemicals,
fragrances and dyes. However, the synthesis of these important
functional groups often relies on stoichiometric activation of car-
boxylic acids, generating large amounts of waste material and
solvent, making them expensive to produce.1 An alternative is to
use pre-activated carboxylic acid derivatives such as acid chlorides,
however, these are often not available and have to be synthesised
by the user. To illustrate how important this bond formation is,
a recent poll on green chemistry in the pharmaceutical industry
voted that amide formation avoiding poor atom economy was the
highest priority area of research.1
Scheme 1. Examples of ruthenium-catalysed tandem oxidative reactions.
Our previous work has investigated ruthenium-catalysed oxi-
dations in tandem processes (Scheme 1). We have developed routes
to access heterocyclic scaffolds from alcohols,2 and developed
a tandem oxidation/CeH activation protocol.3
Many recent publications have focused on a wide range of
metal-catalysed amide formations.4 One such metal-catalysed ap-
proach that has seen significant research in the past 6 years has
been the oxidation of alcohols to amides using ruthenium
catalysts.5 Since Milstein’s early work, demonstrating that a ruthe-
nium catalyst was capable of oxidising an alcohol to an amide by
removing two molecules of dihydrogen,6 the area of ruthenium-
catalysed amide formation from alcohols has seen considerable
research activity with publications from Madsen,7 ourselves,8
Hong9 and more recent contributions from Crabtree,10 Milstein11
and others12 continuing to expand the applications of the original
work.
* Corresponding author. E-mail address: a.watson@canterbury.ac.nz (A.J.A.
Watson).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.017

3684
A.J.A. Watson et al. / Tetrahedron 70 (2014) 3683e3690
Table 1
In this article we wish to present the full extent of our work
showing how the catalytic system was developed and highlighting
its substrate scope and limitations.
Selected catalyst optimisation results
Entrya
Ru Source
Ligand
Oxidant
Solvent
Amideb (4) (%)
1c
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R2
R3
R4
R5
R6
R7
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
d
d
L2
L3
L4
L5
L6
L7
L8
L5
L5
L5
L5
L5
L5
O1
O1
O1
O1
O1
O1
O1
O1
O2
O3
O4
O5
O6
O7
O8
O8
O8
O8
O8
O8
O8
O8
O8
O8
O8
O8
O8
O8
O1
O3
O4
O5
O5
O5
S1
S1
S1
S2
S3
S4
S5
S6
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
57
0
2d
3
2. Results/discussion
67
45
50
47
47
66
45
62
69
63
39
55
80
74
64
42
62
69
56
79
43
86
93
86
83
20
80
82
79
85
72
85
4
5
6
7
8
9
Amide formation was initially observed as a by-product in the
borrowing hydrogen13 reaction of 3-phenyl-1-propanol (1) and
benzylamine (2).14 The formation of this product was unexpected,
and it was later determined that the reaction had been contami-
nated with acetone, which led to the formation of the amide via
oxidation of the hemi-aminal. The same amide (4) was formed
again in the absence of acetone when screening different solvents
for the same reaction, with the largest amount formed when using
10
11
12
13
14
15
16
17
18
19
20
21
22e
23
24
25
26
27
28
29
30
31
32
33f
34g
t
tBuOH. Considering that the addition of both acetone and BuOH
favoured amide formation, the combination of both was trialled in
one reaction (Scheme 2) and led to an increased conversion to
amide.
a
Reaction conditions: 3-phenyl-1-propanol (1 mmol), benzylamine (1.1 mmol),
oxidant (2.5 mmol), [Ru] (5 mol % in Ru), ligand (5 mol %), Cs2CO3 (10 mol %), solvent
(1 mL), 125 ꢀC, 24 h.
Scheme 2. Initial results.
In this case the amide was the major product, with 57% con-
version. This result led to us proposing the following mechanism
for formation of the amide (Scheme 3).
b
Determined by 1H NMR.
c
K2CO3 used as the base.
No base.
Ligand of 15 mol % added.
H2O of 20 mol % added.
d
e
f
g
Acetophenone of 10 mol % added.
Variation of the activating base showed carbonates to be supe-
rior over hydroxide, phosphate, hydrogen carbonate and tert-but-
oxide, with caesium carbonate being the most effective (entry 3,
Table 1). In the presence of weak organic bases such as triethyl-
amine the reaction did not proceed and the use of a group 2 base
(MgCO3) was also less efficient (neither shown in the table). It
should also be noted that with no base, the reaction did not proceed
(entry 2, Table 1). Hong and co-workers9f have recently shown that
for sterically demanding amines, their catalyst works better in the
presence of an activating base as it proceeds via the ester, which
then acylates the amide. However, throughout this work, the ester
was never isolated or seen in any crude reaction mixture, even in
the case of sterically hindered amines, thus it can be speculated that
this is not the case here.
Scheme 3. Proposed mechanism.
The alcohol (5) is initially oxidised to the aldehyde (6) via
hydrogen transfer to acetone (7) forming 2-propanol (8). The
aldehyde is then intercepted by an amine (9) forming a hemi-
aminal (10). Before the hemi-aminal can dehydrate to the im-
ine, the catalyst oxidises it to the amide (11), again via hydro-
gen transfer to acetone. Whilst the first two steps are at
equilibrium, the second oxidation step from the hemi-aminal to
the secondary amide is effectively irreversible and drives the
reaction.
t
As previously mentioned, using BuOH (entry 3, Table 1) as the
solvent gave the highest conversion (67%) of the solvents screened
(entries 3e8, Table 1), with 2-methyltetrahydrofuran (entry 8,
Table 1) also giving a similarly high conversion (66%) the high
conversion using these solvents may be due to the stabilisation of
the intermediate hemi-aminal via hydrogen bonding. A wide vari-
ety of hydrogen acceptors was screened (entries 9e15, Table 1)
with acetophenone (entry 15, Table 1) working over 10% better than
the next best choice cyclohexanone (entry 11, Table 1). Alkenes
would be a more desirable oxidant, as the reduction would be
To improve further upon the initial results (Scheme 2), and
make the reaction more viable as a synthetic method a screen of the
reaction conditions was undertaken (Table 1, Scheme 4).

A.J.A. Watson et al. / Tetrahedron 70 (2014) 3683e3690
3685
(entry 34, Table 1) to aid in the hydrogen transfer15 did little to
improve the conversion.
A range of alcohols was then screened (Table 2). Butanol (entry
1, Table 2) gave a disappointing result with only 42% yield, however,
on extending the chain length, thus increasing the boiling point of
the alcohol, the yield rose, to 70% and 71% in the cases of hexanol
(entry 2, Table 2) and nonanol (entry 3, Table 2), respectively.
Phenyl-substituted aliphatic alcohols also gave good results (en-
tries 4e6, Table 2) although a drop in yield was obtained with 3-
phenyl-1-butanol (entry 7, Table 2). This was not due to steric
reasons, as the corresponding 3,3-diphenyl-1-propanol (entry 8,
Table 2) gave a similar result to the unsubstituted examples men-
tioned earlier with 72% yield. Introduction of steric bulk at the b-
position did have a small effect, with 2-methyl-1-butanol (entry 9,
Table 2) returning a slightly lower yield.
Phenethyl alcohols also worked in this reaction, but showed
a larger variation in yields. Both electron rich (entries 12e14, Table
2) and electron poor (Table 2, entry 16) analogues gave similar
results to that obtained with phenethyl alcohol (Table 2, entry 10).
However, the use of the 4-chloro-substituted variant (entry 15,
Table 2) gave a lower yield than expected. As before, the in-
troduction of steric hindrance at the b-position led to a low yield
(entry 11, Table 2). However, it was pleasing to see that the un-
protected tryptophol (entry 17, Table 2) was tolerated, although the
pyridyl variant (not shown) led to a far lower conversion (11%),
presumably due to catalyst inhibition by complexation to the pyr-
idine. In all these cases an average 10% drop in yield was observed
compared with the previous aliphatic alcohols, which can be at-
tributed to the increased steric demands on the catalyst.
In the case of benzylic examples (rntry 18, Table 2), the yields
were significantly lower (20e40%).16 Whilst there is again an in-
creased steric demand, in these cases a by-product was present in
the reaction mixture accounting for another 20e50% of the alcohol.
Isolation and characterisation of an example showed it to be the
reduced aldol product from the reaction of the intermediate alde-
hyde and the ketone oxidant (Scheme 5). This transformation is
already known under Borrowing Hydrogen conditions,17 however,
it was unexpected here.
Scheme 4. Materials present in Table 1.
Once the alcohol is oxidised to the aldehyde, it is expected to
react with the amine to form the hemi-aminal and proceed to the
amide. However, in the case of benzylic alcohols, the aldehyde also
reacts with the enolate of the ketone forming a by-product. It
should be noted that it is only observed for benzylic alcohols.
This is probably due to several factors. The benzylic hemi-aminal
is severely sterically hindered, thus the rate of oxidation would be
low, allowing for the elimination back to the aldehyde, which can
then undergo the aldol reaction. The aldol reaction could be oc-
curring reversibly in all the reactions. If this is the case then the by-
product is only observed in these cases due to the aldol product
irreversible, however, significantly lower conversions were ob-
tained when tested (entry 9, Table 1).
The choice of ruthenium pre-catalyst was also analysed (entries
15e21, Table 1) indicating that [Ru(p-cymene)Cl2]2 was the best
option, over other similar choices such as [Ru(benzene)Cl2]2, and
[Ru(p-cymene)I2]2. Analysis of the phosphine ligand (entries
22e28, Table 1) indicated that the use of simple triphenylphos-
phine (entry 22, Table 1) in at least threefold excess (15 mol %) was
just as effective as the original DPEphos. By tethering two phos-
phines together with a three carbon linker (dppp, entry 24, Table 1)
it was possible to obtain the same result, without the higher
loading of ligand, and by extending the linker to four carbons, as in
dppb (entry 25, Table 1), a greater conversion was achieved. Other
ligands with longer chains (entry 26, Table 1), or other functionality
separating the phosphines (entry 27, Table 1) gave lower
conversions.
Consideration of the improved catalytic system suggested that
the use of acetophenone may not be considered atom efficient. As
such, a variety of ketones were re-screened under the reaction
conditions (entries 29e32, Table 1). 3-Methyl-2-butanone (entry
32, Table 1) was the next most effective, and can be considered
slightly more atom economic than acetophenone.
eliminating water to form the thermodynamically favourable a,b-
unsaturated ketone, which forms an extended conjugated system
with the aromatic ring. This can then be reduced either by direct
reduction of the double bond18 or via reduction of the ketone and
isomerisation of the double bond,19 both of which result in the
same product.
A series of alcohols with functionality attached to the b-atom
was also trialled (entries 19e24, Table 2). The use of ethers such as
methoxy (entry 19, Table 2) and benzoxy (entry 20, Table 2) both
gave good results, however, the use of a phenoxy ether resulted in
no conversion. The use of amino-substituted alcohols gave varying
results. Secondary amine results depended upon how electron rich
the nitrogen atom was, with electron rich methylamine (entry 22,
Table 2) giving poor results, and the electron poor phenylamine
(entry 23, Table 2) returning almost twice the yield. Tertiary
amines, such as the dimethylamine (entry 24, Table 2) also worked
well.
Final screening of further additives such as water to re-hydrate
the imine (entry 33, Table 1) or a catalytic amount of acetophenone

Table 2
Alcohol variation
Entrya
1
Amide
Isolated yield (%)
42
Entry
14
Amide
Isolated yield (%)
57
2
3
70
71
15
16
49
60
4
5
6
68
67
72
17
18
19
36
24
73
7
8
62
72
20
21
81
40
9
65
58
22
23
37
63
10
11
12
45
24
63
57
52
25
26
49
63
13
a
Reaction conditions: alcohol (3 mmol), benzylamine (3.3 mmol), 3-methyl-2-butanone (7.5 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol %), dppb (5 mol %), Cs2CO3 (10 mol %),
tBuOH (1 mL), 125 ꢀC, 24 h.

A.J.A. Watson et al. / Tetrahedron 70 (2014) 3683e3690
3687
Table 3) and 3-picolylamine (entry 10, Table 3) returning 54% and
93% isolated yields, respectively. However, the use of 2-
picolylamine gave no product. This was attributed to the sub-
strate binding to the catalyst preventing reaction. Considering the
wide variation in results obtained with both 3- and 2-picolylamine
from 93% isolated yield to 0%, 4-picolylamine was tested, and whilst
returning a good conversion (78%), the isolation proved difficult.
Having observed the effect of substitution on the benzylic
amines, aliphatic amines were studied next (entries 11e15, Table 3).
These generally gave good results, except in the cases of tryptamine
and cyclohexylamine, the latter being due to the steric bulk around
the nitrogen atom.
The use of acyclic examples such as diethylamine and diben-
zylamine led to no product being formed under the reaction con-
ditions. Even N-methyl-benzylamine (entry 16, Table 3), which is
very similar to the benzylic amines previously used, was not suc-
cessful in returning any product. However, cyclic secondary amines
(entries 17e20, Table 3), where the lone pair is more exposed due to
the alkyl chains being tied back, did form amides although in low
yields (20e30%). Both pyrrolidine and piperidine formed the ter-
tiary amide (entries 17 and 18, Table 3) and the scope could also be
expanded to include heterocycles such as morpholine and N-
methylpiperazine (entries 19 and 20, Table 3).
Scheme 5. Benzyl alcohol aldol product.
Amino alcohols were also tolerated as substrates with both
five- and six-membered lactams being formed in fair yields
(entries 25 and 26, Table 2), with the lower yield of the five-
membered ring being due to its lower boiling point during iso-
lation. However, the use of 2-aminophenethylalcohol under the
reaction conditions, did not form the oxindole and only the in-
dole was isolated (Scheme 6).
Recently published work by us, demonstrated the use of micro-
wave heating to achieve CeN bond formation using Borrowing Hy-
drogen methodology.22 The oxidation of alcohols we to amides using
a ruthenium catalyst under microwave conditions has not to the best
of our knowledge been reported, so proceeded to examine this fur-
ther with our system. Initial work focused on replicating the thermal
conditions used previously in this article (entry 19, Table 1). After
60 min 41% conversion to products was obtained of which 39% was
amide, indicating that the reaction was working. The other 2% was
the secondary amine. Extending the reaction to 90 min (entry 2,
Table 4) did not lead to any further conversion and analysis of the
reaction revealed that after 60 min no amine was left to continue the
reaction, despite a slight excess being present (1.1 equiv). This is due
to the benzylamine self-condensing to form dibenzylamine with
release of ammonia, which is well reported in the literature.23 As
such, additional benzylamine was added (1.4 equiv) and the reaction
repeated with an identical result obtained after 60 min and an im-
proved conversion of 52% with 50% amide obtained after 90 min
(entry 2, Table 4). Further extended heating to 120 and 180 min
showed no further improvement, and in both cases sufficient pri-
mary amine was left in solution to push the reaction further.
Believing the catalyst to be decomposing under the conditions,
the reaction was pulsed, heating to 125 ꢀC for 30 min before allowing
the reaction to cool and then repeating (entry 3, Table 4), again this
led to no significant gain in conversion. Reducing the temperature
and increasing the time (entry 5, Table 4) did improve the conver-
sion, however, again further extension of the reaction time beyond
240 min did not improve the conversion further. Increased heating
also improved the conversion (entry 6, Table 4), but again only to
a point. Further increases in reaction time or temperature (entry 7,
Table 4) did not further improve the conversion. Other options such
as increasing the amount of oxidant (entry 8, Table 4) or increasing
the amount of catalyst (entry 10, Table 4) did not improve upon
previous results. As expected, removing the oxidant (entry 9, Table 4)
led to a significantly lower conversion. The final result (entry 11,
Table 4) did provide some insight into why the reaction was not
proceeding further. After the first 90 min an extra portion of catalyst,
ligand and base was added under N2 before the reaction mixture was
heated for a further 90 min. As no further reaction occurred, it can
therefore be assumed that a material is being formed during the
reaction that is inhibiting the reaction.
Scheme 6. Indole formation.
In this case, the alcohol is oxidised to the aldehyde, which then
undergoes rapid cyclisation to form the cyclic hemi-aminal, at
which point, as discussed previously, it can be further oxidised to
the amide, in this case oxindole, or it can eliminate to form the
cyclic imine. Whilst Yamaguchi and co-workers have reported the
synthesis of similar cyclic oxindoles using a rhodium catalyst,20
under these conditions the elimination to the cyclic imine was
clearly the favoured pathway, before isomerisation to form the
indole occurred, as no trace of the oxindole was present in the 1H
NMR of the reaction mixture. Again, this transformation has been
reported by Grigg and co-workers21 (Scheme 7).
Scheme 7. Possible routes for 2-aminophenethyl alcohol.
Having screened a series of alcohols, variation of the amine
component was investigated (Table 3). Starting with a selection of
benzylic amines, electron rich aromatics (entries 2e4, Table 3)
generally gave good results, except for piperonylamine (entry 4,
Table 3), whilst electron poor aromatics also gave reasonable re-
sults (entries 5e7, Table 3) except for the trifluoromethyl example
(entry 7, Table 3). The structurally similar cyclohexyl example
(entry 9, Table 3) also worked, although returning a low yield (44%).
Heterocyclic amines were also tolerated with furfuryl (entry 9,
The major difference between the catalyst system reported here,
and others present in the literature is the requirement for an

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A.J.A. Watson et al. / Tetrahedron 70 (2014) 3683e3690
Table 3
Amine variation
Entrya
1
Amide
Isolated yield (%)
68
Entry
11
Amide
Isolated yield (%)
69
2
3
76
66
12
13
67
24b
4
5
45
51
14
15
68
33b
6
7
63
43
16
17
0b
23
8
44
18
35b
9
54
93
19
20
31
22
10
a
Reaction conditions: alcohol (3 mmol), benzylamine (3.3 mmol), 3-methyl-2-butanone (7.5 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol %), dppb (5 mol %), Cs2CO3 (10 mol %),
tBuOH (1 mL), 125 ꢀC, 24 h.
b
Conversion determined by 1H NMR.
oxidant. Most other systems rely on using a flow of inert gas to
remove the hydrogen formed. This approach also works for this
catalyst system with both nitrogen and argon (Scheme 8). However,
this method suffers from several issues making it less easy to repeat
including flow rate of the gas, reaction vessel shape and size, stir-
ring rate and whether the gas is bubbled through the solution or
passed over the top. To this end, the use of oxidant-free amide
formation was not pursued further.
investigation. Attempts to form ortho-metallated ruthenium com-
plexes with the picolylamine similar to those already reported in the
literature24 were unsuccessful. Similarly discounted was the pico-
lylamine acting as a bi-dentate ligand similar to the catalyst used by
Crabtree,10 due to the large degree of separation between the two
nitrogen atoms. Inclusion of pyridine as an organocatalyst or ligand
similar to Madsen7 also of had little effect. Whilst the reaction still
continued in the presence of a catalytic amount of pyridine (73%
conversion), it did not improve upon previous results. An alternative
idea as to why 3-picolylamine gave such a good result would follow
on from a similar effect observed in the Borrowing Hydrogen
Of the results obtained and reported in this paper, the reaction
between 3-picolylamine and 3-phenyl-1-propanol (entry 10, Table
3), gave the highest yield (93%). This prompted further

A.J.A. Watson et al. / Tetrahedron 70 (2014) 3683e3690
3689
Table 4
Microwave heating results
Entrya
Amine (equiv)
Temp (ꢀC)
Time (min)
Conversionb (%)
Amidec (%)
1
1.1
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
125
125
125
115
115
150
175
125
125
125
125
90
90
41
52
53
41
60
63
36
45
13
54
57
39
50
51
39
57
58
24
44
11
52
54
2
3d
4
3Â30
90
5
6
7
240
90
90
90
90
90
2Â90
8e
9f
10g
11h
a
Reaction conditions: 3-phenyl-1-propanol (1 mmol), benzylamine, 3-methyl-2-butanone (2.5 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol %), dppb (5 mol %), Cs2CO3 (10 mol %),
tBuOH (1 mL).
b
c
Conversion of the alcohol determined by 1H NMR.
Determined by 1H NMR.
d
e
f
Reaction heated to 125 ꢀC for 30 min, allowed to cool then re-heated.
3-Methyl-2-butanone (4 equiv).
No oxidant used.
g
h
[Ru(p-cymene)Cl2]2 (5 mol %), dppb (10 mol %), Cs2CO3 (20 mol %).
After 90 min the reaction mixture was allowed to cool to room temperature before another equivalent of catalyst, ligand and base were added.
reaction of 2-phenylethanol of 2-aminopyridine.25 The amine might
be involved in either stabilising the intermediate through hydrogen
bonding or aiding in the deprotonation of the hemi-aminal at the
catalyst to increase the rate of oxidation.
A screen of alcohols (Table 5) highlighted that when poor results
had been obtained previously (entry 2, Table 5) the yield was in-
creased when 3-picolylamine was used, with benzyl alcohol dou-
bling in isolated yield. This was encouraging suggesting that whilst
the effect might be specific to the 3-picolylamine, it could be
exploited advantageously with other alcohols. However, when
Scheme 8. Amide formation via dehydrogenation.
Table 5
Comparison of 3-picolylamine
Entrya
Alcohol
Amide
Isolated yield (%)
68
Amide
Isolated yield (%)
93
1
2
3
24
58
48
53
4
5
6
72
62
45
52
70
71
48
45
7
a
Reaction conditions: alcohol (3 mmol), benzylamine (3.3 mmol), 3-methyl-2-butanone (7.5 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol %), dppb (5 mol %), Cs2CO3 (10 mol %),
tBuOH (1 mL), 125 ꢀC, 24 h.

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7. (a) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130,
17672e17673; (b) Dam, J. H.; Osztrovszky, G.; Nordstrøm, L. U.; Madsen, R.
Chem.dEur. J. 2010, 16, 6820e6827.
higher yields were obtained with benzylamine, the yields were not
as good with the 3-picolylamine (entries 4e7, Table 5).
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3. Conclusion
To conclude, the discovery, optimisation, evaluation and further
development of a ruthenium-catalysed formation of amides from
alcohols has been reported and discussed. Whilst the isolated yields
vary, this can generally be explained by the relative steric bulk
causing crowding around the catalytic centre. The reaction success
also hinges upon the fine balance between the primary alcohol,
ketone, and resulting aldehyde and secondary alcohol presence of
the amine as a nucleophile, the irreversible oxidation to the amide
drives the reaction. In summary this article expands upon our
original report8 of an operationally straightforward process using
commercially available materials.
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Acknowledgements
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ꢀ
Martínez, R.; Brand, G. J.; Ramon, D. J.; Yus, M. Tetrahedron Lett. 2005, 46,
The authors would like to thank GSK and the Engineering and
Physical Sciences Research Council for providing funding for
A.J.A.W. through the Pharma-Synthesis Network. We would also
like to thank Dr. Anneke Lubben for mass spectrometry support and
Dr. John Lowe for NMR support.
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Supplementary data
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6, 2785e2788.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.04.017.
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