Ruthenium-catalyzed oxidation of alcohols into amides

Article abstract of DOI:10.1021/ol900723v

The synthesis of secondary amides from primary alcohols and amines has been developed using commercially available [Ru(p-cymene)CI₂]₂ with bis(diphenylphosphino)butane (dppb) as the catalyst.

Full text of DOI:10.1021/ol900723v

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2667-2670
Ruthenium-Catalyzed Oxidation of
Alcohols into Amides
Andrew J. A. Watson,† Aoife C. Maxwell,‡ and Jonathan M. J. Williams*,†
Department of Chemistry, UniVersity of Bath, ClaVerton Down, Bath, BA2 7AY, U.K.,
and GlaxoSmithKline Research and DeVelopment, Gunnels Wood Road,
SteVenage, SG1 2NY, U.K.
j.m.j.williams@bath.ac.uk
Received April 6, 2009
ABSTRACT
The synthesis of secondary amides from primary alcohols and amines has been developed using commercially available [Ru(p-cymene)Cl2]2
with bis(diphenylphosphino)butane (dppb) as the catalyst.
The synthesis of secondary amides has traditionally relied
on the use of carboxylic acids and amines requiring sto-
ichiometric amounts of coupling reagents such as HOAt.1
These systems use reagents where the oxidation state of the
materials is already at the required level for the product, and
while giving good results, they lack atom efficiency. More
recent approaches have considered the use of oxidative
couplings from aldehydes,2 and while the results are good,
long-term storage and use of aldehydes can be troublesome
due to their inherent reactivity.
to form amides using a commercially available ruthenium-
based catalyst with a ketone as the oxidant (Scheme 1).
Scheme 1
.
Oxidative Coupling of Alcohols and Amines Using
Hydrogen Transfer Catalysis
Recently, several groups3 have reported catalytic amide
formation from alcohols, using transition metal catalysts to
oxidize the alcohol to the aldehyde in situ and then further
oxidize the hemiaminal to the desired amide via the loss of
2 equiv of H2. Alcohols have also been used as starting
materials in catalytic oxidative reactions leading to nitriles,4
acetals,5 esters,6 lactams,7 and benzazoles.8
We wish to report that our own research into this area
has led to the oxidative coupling of an alcohol with an amine
† University of Bath.
During our recent work on the use of alcohols as alkylating
agents for amines using borrowing hydrogen methodol-
ogy,9,10 we noticed that the formation of amides was
observed in specific cases, sometimes as a significant
‡ GlaxoSmithKline Research and Development.
(1) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. For a review,
see: Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447.
(2) (a) Suto, Y.; Yamagiwa, N.; Torisawa, Y. Tetrahedron Lett. 2008,
49, 5732. (b) Gao, J.; Wang, G.-U. J. Org. Chem. 2008, 73, 2955. (c) Yoo,
W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 13064.
(3) (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
790. (b) Zweifel, T.; Naubron, J.-V.; Gru¨tzmacher, H. Angew. Chem., Int.
Ed. 2008, 48, 559. (c) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem.
Soc. 2008, 130, 17672.
(4) Oishi, T.; Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2009,
DOI:1002/anie.200900418.
(5) Gunanathan, C.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc.
2009, 131, 3146
.
10.1021/ol900723v CCC: $40.75
Published on Web 05/15/2009
 2009 American Chemical Society

byproduct (as much as 30%).11 The coupling of an alcohol
1 with an amine 2 is expected to proceed via oxidation of
the alcohol to an aldehyde and formation of an intermediate
hemiaminal. Further oxidation of the hemiaminal would lead
to the amide 3, while elimination of water and return of
hydrogen would provide amine 4 (Scheme 2). The balance
Table 1. Optimization of Ligand, Hydrogen Acceptor, and
Solvent for the Formation of Amide 7a
entry
ligand
ketone
solvent convn (%)b amide (%)b
1
2
3
4
5
6
7
8
9
dppb
MeCOMe tBuOH
EtCOMe tBuOH
90
89
78
91
88
95
93
92
95
91
77
72
85
88
41
56
88
95
95
91
91
98
80
82
68
85
79
90
80
89
80
85
25
69
75
78
36
41
57
86
90
86
82
95
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
tBuCOMe tBuOH
iPrCOMe tBuOH
c-hexanone tBuOH
PhCOMe tBuOH
PhCOMec tBuOH
PhCOMe DME
Scheme 2
.
Amine/Alcohol Coupling Pathways to Either the
Amide or Amine Product
PhCOMe 2-MeTHF
PhCOMe dioxane
PhCOMe toluene
10 dppb
11 dppb
12 dppb
13 2 × PPh3 PhCOMe tBuOH
14 DPEphos PhCOMe tBuOH
15 Xantphos PhCOMe tBuOH
16 dppm
17 dppe
18 dppp
19 dppb
20 dpppe
21 dppf
noned
tBuOH
PhCOMe tBuOH
PhCOMe tBuOH
PhCOMe tBuOH
PhCOMe tBuOH
PhCOMe tBuOH
PhCOMe tBuOH
between these pathways may be expected to favor amide
formation in the presence of an oxidant or when the
hemiaminal is stabilized. Generally, hemiaminals have low
stability, either reverting to carbonyl compound and amine
or undergoing dehydration. However, there are examples of
isolated hemiaminals.12,13
22 (S,S)-DIOP PhCOMe tBuOH
a Conditions: 3-phenyl-1-propanol (1.0 mmol), benzylamine (1.1 mmol),
oxidant (2.5 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol %), phosphine (5 mol
%), Cs2CO3 (10 mol %), solvent (1 mL); reflux; 24 h. b Conversions
1
determined by H NMR; formation of Ph(CH2)3NHCH2Ph as a byproduct
accounts for the difference in conversion vs amide formation. c 20 mol %
water added. d The reaction was performed with a steady stream of N2 over
the reaction mixture.
We chose to examine the coupling of 3-phenylpropan-1-ol
5 with benzylamine 6 as a model reaction (Scheme 3). In an
lower conversions, as did the use of Na2CO3. However, the
use of Cs2CO3 led to 67% amide 7, and this base was selected
for further optimization reactions. In the absence of base,
no conversion into the amide was observed. Similarly, the
use of triethylamine as base also led to no conversion.
Preliminary screening reactions established that bis(diphe-
nylphosphino)butane (dppb) was an effective ligand, provid-
ing 80% amide formation under these conditions.
Scheme 3. Model Reaction for Oxidative Amide Formation
The choice of hydrogen acceptor was then examined. The
use of a ketone as the hydrogen acceptor also leads to the
potential complication of reaction with the substrate amine
to form an imine. We believe that under these reaction
conditions, although some ketimine formation was observed
at early stages in the reaction, this process is reversible due
to the relative lack of stability of ketimines.15 We did not
detect any isopropylamine derivatives which could have
arisen through reduction of ketimine derived from acetone
initial attempt using acetone as the hydrogen acceptor with
tBuOH as the solvent, the desired amide 7 was formed
with 57% conversion. The combination of [Ru(p-cymene)Cl2]2
with bis(2-diphenylphosphinophenyl)ether (DPEphos) was cho-
sen since it is known to be a competent catalyst for nonoxidative
alcohol and amine coupling.11
The choice of base was chosen as a starting point for the
optimization, since base activates ruthenium chloride com-
plexes to the catalytically active dihydride species.14 Re-
placement of K2CO3 with KHCO3, KOH, or KOtBu led to
Scheme 4
.
Conditions Used for the Formation of Amides
(6) (a) Ichikawa, N.; Sato, S.; Takahashi, R.; Sodesawa, T.; Inui, K. J.
Mol. Catal., A: Chem. 2004, 212, 197. (b) Zhang, J.; Leitus, G.; Ben-David,
Y.; Milstein, D. J. Am. Chem. Soc. 2005, 127, 10840. (c) Zhao, J.; Hartwig,
J. F. Organometallics 2005, 24, 2441.
(7) Naota, T.; Murahashi, S.-I. Synlett 1991, 693.
(8) Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.; Saidi, O.;
Williams, J. M. J. Org. Lett. 2009, 11, 2039.
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Org. Lett., Vol. 11, No. 12, 2009

Table 2. Oxidative Coupling of Alcohols with Amines to Give Amidesa
a Conditions: alcohol (3.0 mmol), amine (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 (3 mL); reflux; 24 h. b Isolated yields after column chromatography and/or recrystallization.
and benzylamine. Simple alkenes, including dodec-1-ene,
styrene, and cyclohexene, did not act as hydrogen acceptors
for this reaction, nor did hex-1-yne.
Replacement of acetone with alternative ketones was found
to be successful, as shown in Table 1. 2-Butanone (entry 2)
and cyclohexanone (entry 5) gave very similar results, while
pinacolone (entry 3) gave a reduced conversion, presumably
for steric reasons. The use of 3-methylbutan-2-one (entry 4)
or acetophenone (entry 6) gave improvements in both
conversion and selectivity toward amide over amine, with
only 6% and 5% secondary amine byproduct. The addition
of water to the reaction mixture, which was hoped may help
to disfavor elimination from the intermediate hemiaminal,
led to a lower conversion and more amine byproduct (entry
7). The use of nonhydroxylic polar solvents afforded
comparable results (entries 8-10), although the use of
toluene (entry 11) led to the formation of secondary amine
Ph(CH2)3NHCH2Ph as the major product, with only a modest
Org. Lett., Vol. 11, No. 12, 2009
2669

formation of amide. Interestingly, oxidation to give amide
was reasonably successful even in the absence of an oxidant;
a flow of nitrogen was employed to remove any hydrogen
gas which was formed (entry 12).
formation. In the case of morpholine (entry 14), a moderate
yield of the tertiary amide product was obtained.
In summary, we have identified a new catalytic system
for the convesion of primary alcohols into amides in good
yields. The process uses a commercially available catalyst
and is operationally straightforward.16
An investigation into the use of other ligands demonstrated
that other phosphines were also effective in providing a
catalytic system. Even triphenylphosphine generated a
reasonably effective catalyst (entry 13). 4,5-Bis(diphe-
nylphosphino)-9,9-dimethylxanthene (Xantphos) (entry 15)
was found to be significantly less effective than DPEphos
(entry 14), despite their structural similarity. The use of a
series of simple bidentate phosphines, Ph2P(CH2)nPPh2
(n ) 1-5, entries 16-20) confirmed that bis(diphenylphos-
phino)butane (dppb) was a good ligand in this process. In
fact, the use of (S,S)-DIOP {(4S,5S)-(+)-O-isopropylidene-
2,3-dihydroxy-1,4-bis(diphenylphosphino)butane} (entry 22),
with the same tether length as dppb, was found to be even
more effective.
Acknowledgment. We thank the EPSRC and Glaxo-
SmithKline for providing funding for a studentship (to
A. J. A. W.) through the collaborative EPSRC-Pharma
Synthesis Programme.
Supporting Information Available: Details of experi-
mental procedures and characterization data are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL900723V
(9) For reviews on borrowing hydrogen, see: (a) Guillena, G.; Ramo´n,
D. J.; Yus, M. Angew. Chem., Int. Ed. 2007, 46, 2358. (b) Hamid,
M. H. S. A.; Slatford, P. A.; Williams, J. M. J. AdV. Synth. Catal. 2007,
349, 1555. (c) Lamb, G. W.; Williams, J. M. J. Chim. Oggi 2008, 26, 17.
(d) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J. Dalton Trans. 2009,
753.
Although DIOP performed better than dppb, we chose to
use the latter as a simple, cheap, and effective ligand for the
process. In addition, even though acetophenone was found
to be a particularly good hydrogen acceptor in these reactions,
we anticipated potential problems for the isolation of amides
from any unreacted acetophenone and its reduction product
1-phenylethanol. We therefore selected 3-methyl-2-butanone
as the hydrogen acceptor. Although it is not quite as effective
as acetophenone, it is volatile (bp. 95 °C) as is the alcohol
derived from it (bp. 112 °C).
With the catalytic system chosen (Scheme 4), the reaction
was applied to the synthesis of a range of amides (Table 2)
with good isolated yields. We were interested to note that
introduction of a methoxy group into the molecule (entries
4, 5, and 12) reduced the formation of secondary amine
significantly, and in most cases the byproduct was neglible
only accounting for approximately 1% of the starting alcohol.
(10) (a) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.;
Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc.
2009, 131, 1766. (b) Hamid, M. H. S. A.; Williams, J. M. J. Tetrahedron
Lett. 2007, 8263.
(11) Hamid, M. H. S. A.; Williams, J. M. J. Chem. Commun. 2007,
725.
(12) (a) Heine, A.; DeSantis, G.; Luz, J. G.; Mitchell, M.; Wong, C. H.;
Wilson, I. A. Science 2001, 294, 369. (b) Evans, D. A.; Borg, G.; Scheidt,
K. A. Angew. Chem., Int. Ed. 2002, 41, 3188.
(13) Suni, V.; Kurup, M. R. P.; Nethaji, M. J. Mol. Struct. 2005, 749,
177.
(14) Aranyos, A.; Csjernyik, G.; Szabo´, K. J.; Ba¨ckvall, J.-E. Chem
Commun. 1999, 351.
(15) Godoy-Alca´ntar, C.; Yatsimirsky, A. K.; Lehn, J.-M. J. Phys. Org.
Chem. 2005, 18, 979.
(16) Procedure for the formation of amides from alcohols. To an
oven-dried, nitrogen-purged Schlenk tube containing [Ru(p-cymene)Cl2]2
(46.9 mg, 0.075 mmol), dppb (64.0 mg, 0.15 mmol), and Cs2CO3 (97.7
mg, 0.30 mmol) was added alcohol (3 mmol), amine (3.33 mmol), 3-methyl-
2-butanone (0.8 mL, 7.5 mmol), and tBuOH (3 mL), and the reaction was
heated at reflux for 24 h. On completion, the reaction was allowed to cool
to room temperature before the solvent was removed in vacuo. The crude
product was purified by column chromatography (Et2O/petroleum ether as
eluent) before recrystallization (from dichloromethane/hexane), to afford
the corresponding amide in good yield.
The use of the indole-containing substrate (entry 13) gave
a lower yield than anticipated. Secondary amines are poor
substrates in this reaction, showing very little product
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Org. Lett., Vol. 11, No. 12, 2009