Conversion of primary alcohols and aldehydes into methyl esters by ruthenium-catalysed hydrogen transfer reactions

Article abstract of DOI:10.1055/s-0028-1088026

Alcohols and aldehydes are oxidised to the corresponding methyl esters by reaction with methanol in the presence of crotononitrile as a hydrogen acceptor using a catalyst combination of Ru(PPh₃)₃(CO)H₂ with xantphos. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088026

1578
PRACTICAL SYNTHETIC PROCEDURES
Conversion of Primary Alcohols and Aldehydes into Methyl Esters by
Ruthenium-Catalysed Hydrogen Transfer Reactions
M
ethyl Esters by H
a
ydrogen T
t
ransferhan A. Owston,a Tracy D. Nixon,a Alexandra J. Parker,b Michael K. Whittlesey,a Jonathan M. J. Williams*a
a
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
Fax +44(1225)386231; E-mail: j.m.j.williams@bath.ac.uk
b
AstraZeneca, Global Process R&D, Avlon Works, Severn Road, Hallen, Bristol, BS10 7ZE, UK
PSP
Received 5 December 2008; revised 19 December 2008
No157
Abstract: Alcohols and aldehydes are oxidised to the corresponding methyl esters by reaction with methanol in the presence of crotono-
nitrile as a hydrogen acceptor using a catalyst combination of Ru(PPh3)3(CO)H2 with xantphos.
Key words: alcohols, esters, ruthenium, catalysis, hydrogen transfer
Me
O
CN
(2.5 equiv)
Bn
OH
Bn
O
Bn
[Ru] (5 mol%)
3 (5 mol%)
1
2
PhMe, reflux
24 h, 85% conversion
PPh3
OC
H
[Ru] =
Ru
Ph3P
H
O
PPh3
Ph2P
PPh2
3
Scheme 1 Oxidative dimerisation of 2-phenylethanol
Catalysed hydrogen transfer reactions have been widely alkenes were examined as the hydrogen acceptor, but
used for the interconversion of alcohols and carbonyl proved to be less successful.9
compounds.1 In the presence of a suitable hydrogen ac-
A more general formation of esters from two differing al-
ceptor, primary alcohols can be oxidised to the corre-
cohols is an appealing prospect, but suffers from the prob-
sponding aldehydes.2 However, the aldehyde can undergo
lem that since either alcohol could be oxidised, a mixture
further reaction to form a dimeric ester via an intermediate
of products would be expected. However, by choosing an
hemiacetal. The overall transformation of RCH2OH into
alcohol which either cannot be oxidised or is reluctant to
RCO2CH2R has been reported with various catalysts and
be oxidised, the preparation of ‘non-dimeric’ esters be-
oxidants.3 Milstein and co-workers have developed a ru-
comes realistic. We, therefore, decided to investigate the
thenium pincer complex capable of effecting this transfor-
conversion of alcohols into their methyl esters according
mation without the need for an oxidant.4 The oxidative
to Scheme 2. Selective oxidation of a primary alcohol
cyclisation of diols to give lactones has also been report-
rather than methanol is expected to take place due to the
relative stability of most aldehydes with respect to form-
ed.5
We have recently developed the combination of the ruthe- aldehyde. The intermediate aldehyde will then be in equi-
nium complex Ru(PPh3)3(CO)H2 with xantphos [4,5- librium with the corresponding hemiacetal which upon
bis(diphenylphosphino)-9,9-dimethylxanthene, 3]6 for further oxidation provides the methyl ester. Alternative
hydrogen transfer reactions between alcohols and alk- approaches to the conversion of alcohols into methyl
enes/alkynes.7 In a preliminary experiment, we observed esters have been reported using manganese dioxide10 and
dimerisation of alcohol 1 into the ester 2 using crotononi- iodosobenzene as the oxidants.11 Recently, the use of het-
trile as the hydrogen acceptor (Scheme 1). Crotononitrile erogeneous gold catalysts has also been reported for relat-
is a particularly good hydrogen acceptor using the ed transformations.12
Ru(PPh3)3(CO)H2/xantphos catalyst and has also been
Preliminary experiments demonstrated that the
used as the oxidant in the conversion of alcohols into al-
Ru(PPh3)3(CO)H2/xantphos catalyst was capable of ef-
dehydes with in situ conversion into alkenes.8 Alternative
fecting the conversion of primary alcohols into methyl es-
ters under the conditions identified in Table 1. The
reactions were also effective in the absence of water as an
additive, although when water was added, this minimised
SYNTHESIS 2009, No. 9, pp 1578–1581
Advanced online publication: 14.04.2009
DOI: 10.1055/s-0028-1088026; Art ID: Z27108SS
x
x
.
x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Methyl Esters by Hydrogen Transfer
1579
O
and 2-[4-(dimethylamino)phenyl]ethanol was converted
into methyl 2-[4-(dimethylamino)phenyl]acetate (4g)
with 74% isolated yield rather than the 87% isolated yield
observed on a smaller scale.
R
OH
R
OMe
[O]
OH
OMe
[O]
We were interested to examine whether nucleophiles oth-
er than methanol could be used to intercept the aldehyde,
and chose to perform the reaction in the presence of water
with tert-butylamine (Scheme 3). The reaction led to the
formation of the carboxylate salt 5 in good isolated yield,
with no evidence of amide formation under these reaction
conditions.13 Even in the absence of water, no amide was
formed, although the use of the more nucleophilic O-tert-
butylhydroxylamine led to the formation of the hydrox-
amic ester 6 along with oxime ether 7. In the absence of
water, the oxime ether 7 was formed as the exclusive
product. We have previously reported that oxime ethers
can undergo elimination to the corresponding nitrile,14 al-
though it would appear that for the tert-butyl ether, that
this elimination is not occurring.
MeOH
R
O
R
Scheme 2 Oxidation of alcohols to methyl esters
the formation of the byproduct arising from the conjugate
addition of methanol to crotononitrile. The addition of
larger amounts of water was found to be detrimental, as
was the addition of a catalytic amount (5 mol%) of either
propionic acid or 4-toluenesulfonic acid, which it was
hoped may have assisted with hemiacetal formation.
The reaction conditions were applied to a range of prima-
ry alcohols, which were successfully oxidised to the cor-
responding methyl esters 4a–j (Table 1).
O
Ru(PPh3)3(CO)H2 (2.5 mol%)
Xantphos (3) (2.5 mol%)
Table 1 Methyl Esters Formed from Primary Alcohols
Ru(PPh3)3(CO)H2 (5 mol%)
Bn
O–
O
Bn
OH
t-BuNH2 (1.2 equiv)
H2O (3 equiv)
crotononitrile (2.5 equiv)
PhMe, reflux, 4 h
+
Xantphos (3) (5 mol%)
t-BuNH3
5
83% yield
R
OH
R
OMe
H2O (2 equiv)
crotononitrile (3 equiv)
PhMe–MeOH (1:1)
reflux, 24–48 h
O
Ot-Bu
Ph
N
R
Time
(h)
Product
Isolatedyielda
(%)
H
Ru(PPh3)3(CO)H2 (2.5 mol%)
Xantphos (3) (2.5 mol%)
6
Ph
OH
71% yield
n-C7H15
n-C15H31
Cy
24
36
24
48
4a
4b
4c
4d
4e
4f
86
84
t-BuONH2 (1.1 equiv)
H2O (2 equiv)
crotononitrile (2.5 equiv)
PhMe, reflux, 24 h
+
Ot-Bu
N
(76)
83
Ph
Ph
H
6:7 74:26
7
Bn
inden-3-ylmethyl
4-HOC6H4CH2
4-Me2NC6H4CH2
(E)-CH=CHPh
Ph
24
24
24
24
24
24
79
Ru(PPh3)3(CO)H2 (2.5 mol%)
Xantphos (3) (2.5 mol%)
Ot-Bu
H
N
Ph
OH
84
t-BuONH2 (1.1 equiv)
molecular sieves
crotononitrile (1.5 equiv)
PhMe, reflux, 24 h
4g
4h
4i
87
7
96% conversion
76
Scheme 3 Oxidation of alcohols in the presence of amine and
(70)
74
hydroxylamine
4-O2NC6H4
4j
a Reactions run on a 2 mmol scale in toluene (2 mL) and MeOH (2
mL). Figures in parentheses indicate conversions.
Since aldehydes are assumed to be intermediates in the
conversion of primary alcohols into methyl esters
(Scheme 2), we considered the possibility of converting
aldehydes into methyl esters under similar reaction condi-
tions. In some cases, aldehydes are known to undergo de-
carbonylation with ruthenium complexes, which could
lead to catalyst deactivation.15 However, we were pleased
to find that a range of aldehydes could be converted into
methyl esters 4a,i–n by treatment with 1.5 equivalents of
crotononitrile and the Ru(PPh3)3(CO)H2/xantphos combi-
nation (Table 2). These reactions required a shorter reac-
tion time than for the alcohol oxidation and were complete
after four hours in most cases.
All of the reactions went to completion after the time in-
dicated in Table 1, except for cyclohexylmethanol, benzyl
alcohol, and 4-nitrobenzyl alcohol. We assume that in the
case of cyclohexylmethanol, the reaction is slower for
steric reasons. For the benzylic alcohols, it is less clear
why these substrates should be slower, since the initial ox-
idation to aldehyde is expected to be faster. Typical reac-
tions were run on a 2 mmol scale, although on a larger
scale (12 mmol), the oxidation also proved to be success-
ful. However, the isolated yield was somewhat reduced,
Synthesis 2009, No. 9, 1578–1581 © Thieme Stuttgart · New York

1580
N. A. Owston et al.
PRACTICAL SYNTHETIC PROCEDURES
resultant deep-red soln was added 2-[4-(dimethylamino)phe-
nyl]ethanol (1.98 g, 12 mmol), crotononitrile (2.42 g, 2.95 mL, 36
mmol), degassed anhyd MeOH (12 mL), and H2O (0.43 mL, 24
mmol) and the resultant yellow soln was heated at 110 °C for 24 h.
On completion the reaction was allowed to cool to r.t., diluted with
CH2Cl2, and the solvent removed in vacuo. The crude product was
purified by column chromatography (silica gel, Et2O–hexane), pro-
viding 4g (1.72 g, 74%) as a colourless solid; mp 54–56 °C;
Rf = 0.19 (hexanes–Et2O, 65:35), Rf = 0.41 (hexanes–EtOAc,
60:30), Rf = 0.16 (hexanes–Et2O, 80:20).
1H NMR (300 MHz, CDCl3, 25 °C): d = 2.94 (s, 6 H, Me2N), 3.57
(s, 2 H, CH2), 3.70 (s, 3 H, OMe), 6.77 (d, J = 8.4 Hz, 2 H), 7.14 (d,
J = 8.4 Hz, 2 H).
13C NMR (75.5 MHz, CDCl3, 25 °C): d = 40.7, 41.1, 52.3, 113.2,
122.2, 130.3, 150.2, 173.1.
Table 2 Methyl Esters Formed from Aldehydes
O
Ru(PPh3)3(CO)H2 (5 mol%)
Xantphos (3) (5 mol%)
R
R
OMe
O
H2O (1 equiv)
crotononitrile (1.5 equiv)
PhMe–MeOH (1:1)
reflux, 4 h
4
R
Product
4a
Isolated yielda (%)
n-C7H15
(95)
95
n-C10H21
Ph
4k
4i
(100)
(95)
(98)
83
2-MeC6H4
4-MeC6H4
4-O2NC6H4
4-O2NC6H4
4-pyridyl
4l
These data are consistent with the literature.16
4m
4j
Methyl 4-Nitrobenzoate (4j); Typical Procedure from Alde-
hydes
To an oven-dried, argon-purged 150-mL ampoule, fitted with a
PTFE Young’s Tap, charged with Ru(PPh3)3(CO)H2 (552 mg, 0.6
mmol) and xantphos (3, 347 mg, 0.6 mmol) was added degassed an-
hyd toluene (12 mL) and the mixture heated at 110 °C for 1 h then
allowed to cool to r.t. To the resultant deep-red soln was added 4-
nitrobenzaldehyde (1.81 g, 12 mmol), crotononitrile (1.21 g, 1.48
mL, 18 mmol), degassed anhyd MeOH (12 mL), and H2O (0.43 mL,
24 mmol) and the resultant yellow soln was heated at 110 °C for 4
h. On completion the reaction was allowed to cool to r.t., diluted
with CH2Cl2, and the solvent removed in vacuo. The crude product
was purified by column chromatography (silica gel, EtOAc–hex-
ane), providing 4j (1.89 g, 87%) as a pale yellow solid; mp 91–93
°C; Rf = 0.16 (hexanes–Et2O, 19:1), Rf = 0.28 (hexanes–EtOAc,
9:1).
4j
87b
4n
79
a Reactions performed on a 1 mmol scale. Figures in parentheses are
conversions as determined from the NMR spectra.
b Reaction performed on a 12 mmol scale.
The aldehyde oxidation was successful for aliphatic sub-
strates as well as benzylic substrates, including the oxida-
tion of a pyridine-containing substrate.
In summary, methyl esters 4 can be formed from either
primary alcohols or aldehydes by a ruthenium-catalysed
hydrogen transfer reaction involving crotononitrile as the
hydrogen acceptor.
1H NMR (300 MHz, CDCl3, 25 °C): d = 3.98 (s, 3 H, OMe), 8.22
(d, J = 8.8 Hz, 2 H), 8.29 (d, J = 8.8 Hz, 2 H).
13C NMR (75.5 MHz, CDCl3, 25 °C): d = 53.0, 123.7, 130.9, 135.7,
150.8, 165.5.
Reactions required the use of anhydrous, inert atmosphere tech-
niques and were carried out using standard Schlenk techniques. In
all cases, solvents were obtained by passing through anhydrous alu-
mina columns using an Innovative Technology Inc. PS-400-7 sol-
vent purification system. TLC using aluminium-backed plates
precoated with Macherey-Nagel Sil G/UV254nm neutral silica were
used to monitor reactions where appropriate. Visualisation of these
plates was by 254 nm UV light or KMnO4 dip followed by gentle
warming. Flash column chromatography was carried out using
Davisil LC 60 Å silica gel (35–70 micron) purchased from Fluoro-
chem. NMR spectra were run in CDCl3 on a Bruker Avance 300
spectrometer and recorded at 300 MHz (1H) and 75.5 MHz (13C).
Chemical shifts are reported relative to the residual solvent peak
where possible or alternatively to SiMe4 (d = 0.00 ppm) as internal
standard. Coupling constants (J) are given in Hz and multiplicities
denoted as singlet (s), doublet (d), triplet (t), quartet (q), pentet
(pent), septet (sept), unresolved multiplet (m) or broad (br). Melting
points were carried out on a Gallenkamp MF-370 hot stage melting
point apparatus and are uncorrected. All of the reported compounds
are known, and spectrocopic data correspond to the literature val-
ues.
These data are consistent with the literature.17
Acknowledgment
We thank AstraZeneca and the EPSRC for funding.
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To an oven-dried, argon-purged 150-mL Schlenk flask charged
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Synthesis 2009, No. 9, 1578–1581 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Methyl Esters by Hydrogen Transfer
1581
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