C. Wiles et al. / Tetrahedron Letters 47 (2006) 5261–5264
5263
ary results obtained for the selective oxidation of pri-
mary (and secondary) alcohols in a pressure-driven flow
reactor (Fig. 1).
Table 2. Summary of the results obtained for the oxidation of
secondary alcohols, using silica-supported Jones’ reagent 4, in a flow
reactor
a
b
Entry
Secondary alcohol
Conversion
(%)
Yield
(%)
As Scheme 1 illustrates, when a primary alcohol 1 is oxi-
dised, precautions must be taken to ensure that the de-
sired aldehyde 2 is not further oxidised to the
corresponding carboxylic acid 3. In practice, this can
be achieved by distillation of the aldehyde as it forms,
this technique is however restricted to molecules of
low molecular weight.
1
2
3
4
5
6
7
8
9
1-Phenylpropan-1-ol
1-Phenylethanol
1-(4-Aminophenyl)ethanol
Diphenylmethanol
1-(4-Iodophenyl)ethanol
1-(4-Nitrophenyl)ethanol
1-(4-Hydroxyphenyl)ethanol
1-Phenylbutan-1-ol
1-(4-Methylphenyl)ethanol
1-(4-Bromophenyl)ethanol
1,3-Diphenylpropan-1-ol
1-(4-Chlorophenyl)ethanol
Cyclopentanol
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
98.8
99.6
99.6
100
99.3
100
99.5
99.2
100
99.0
99.2
100
We therefore proposed that by conducting the reaction
in a continuous flow reactor, where the residence time
of a reagent can be carefully controlled, selective oxida-
tion of the primary alcohol could be achieved. In addi-
tion to the obvious advantage of enhanced product
selectivity, in the case of acidic oxidants, such as Jones’
reagent (H CrO ), the use of silica-supported analogues
1
1
1
0
1
2
13
14
15
Cyclohexanol
2-Methylcyclohexanol
99.7
2
4
a
proves advantageous as heavy metal contamination of
the product is avoided, as even in its reduced form,
n =P15.
b
À1
Flow reactor operated at 650 ll min
.
9
the chromium residues are retained by the support. Un-
like previous examples where EOF-based flow reactors
1
0
have been employed, due to solvent incompatibilities
with the supported oxidising agent 4, a simple pres-
sure-driven system was constructed.
lack of reaction control exhibited in the stirred, batch
reactor (Fig. 2a). However, by further reducing the flow
rate to 650 ll min (residence time = P126 s), quanti-
À1
tative conversion to the carboxylic acid 3 was observed
(Fig. 2c). Having demonstrated the ability to synthesise
selectively either benzaldehyde 2 or benzoic acid 3 in
excellent yield and purity (Table 1), the reaction was re-
peated using an array of substituted primary alcohols.
As illustrated in Table 1, excellent selectivity was ob-
tained for all primary alcohols investigated; impor-
tantly, no functional group incompatibilities were
observed.
In order to perform
0.150 mmol) of silica-supported Jones’ reagent 4 was
packed into a borosilicate glass flow reactor (0.3 cm
i.d.) · 3.0 cm (length)) and a solution of benzyl alcohol
(0.01 M in DCM) pumped through the reactor, using a
syringe pump (Harvard Apparatus), at the desired flow
rate. The reaction products were collected from the reac-
tor outlet at 1 min time intervals and analysed by GC–
MS (number of samples (n) = P15). After chromato-
graphic analysis, the reaction products were combined,
concentrated in vacuo, the ‘crude’ product dissolved in
a
flow reaction, 0.150 g
(
(
1
In order to demonstrate the versatility of the aforemen-
tioned methodology, a series of secondary alcohols was
subsequently oxidised within the flow reactor. As Table
2 illustrates, in all cases, quantitative conversion of the
alcohol to the respective ketone was observed, affording
all products in excellent yield and purity; again no sub-
strate dependancy was observed.
CDCl and analysed by NMR spectroscopy; all known
3
compounds prepared had spectroscopic data consistent
with the literature. In order to confirm product purity
and reagent 4 stability, the reaction products were also
À5
analysed by ICP-MS; whereby 66.9 · 10 % w/w Cr
was detected in all samples.
Finally, the oxidation of aliphatic primary alcohols (C2–
As Figure 2b illustrates, when operating the flow reactor
C ) was investigated; however, in all cases leaching of
8
À1
at 650 ll min , providing a reagent residence time of
oxidising agent from the silica support was observed
(indicated by colouration of the reaction products), an
observation that was attributed to an increase in the
polarity of the reactant stream, compared to that ob-
served for the primary aromatic alcohols. Consequently,
this particular supported oxidising agent is limited to the
oxidation of aromatic alcohols in a flowing system; this
could however be overcome by the use of covalently
bound oxidising agents.
1
1
9
.7 s, over-oxidation to benzoic acid 3 was successfully
prevented and quantitative conversion of benzyl alcohol
to benzaldehyde 2 was obtained.
1
Interestingly, when the reactor was operated at
À1
3
00 ll min (residence time = 21 s), the reaction prod-
ucts contained a mixture of unreacted starting material
, benzaldehyde 2 and benzoic acid 3, replicating the
1
Owing to the unique reaction conditions obtained as a
result of incorporating supported reagents into continu-
ous flow reactors, we have demonstrated the ability to
oxidise selectively an array of primary alcohols to their
respective aldehydes (residence time = 9.7 s) or carbox-
ylic acids (residence time = 126 s), depending on the
flow rate employed (Table 1).
When the flow reactions were performed using water, acetonitrile,
tetrahydrofuran or diethyl ether as the reaction solvent, chromium
release was observed (determined by a distinct orange colouration of
the product stream). In comparison, when performing the reaction in
dichloromethane, no colouration of the reaction products was
observed (confirmed by ICP-MS analysis of the product stream,
À7
6
6.9 · 10 % w/w Cr).