Polymer-supported N-methylmorpholine N-oxide as an efficient and readily recyclable co-oxidant in the TPAP oxidation of alcohols

Article abstract of DOI:10.1055/s-2001-16046

A readily available, polymer supported amine N-oxide has been prepared and shown to be a practicable, efficient, selective, and readily recyclable co-oxidant in the TPAP oxidation of alcohols.

Full text of DOI:10.1055/s-2001-16046

LETTER
1257
Polymer-Supported N-Methylmorpholine N-Oxide as an Efficient and Readily
Recyclable Co-oxidant in the TPAP Oxidation of Alcohols
Dearg S. Brown,b William J. Kerr,a* David M. Lindsay,a Kurt G. Pike,b Paul D. Ratcliffea
aDepartment of Pure and Applied Chemistry, University of Strathclyde, Glasgow, G1 1XL, Scotland, UK
bAstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, England, UK
Fax +44 141 548 4246; E-mail: w.kerr@strath.ac.uk
Received 2 June 2001
in the presence of amine by-products (from the 1.0 1.5
Abstract: A readily available, polymer supported amine N-oxide
equivalents of the requisite co-oxidant) which require to
be removed and are normally discarded. On consideration
has been prepared and shown to be a practicable, efficient, selective,
and readily recyclable co-oxidant in the TPAP oxidation of alco-
of these issues, it was envisaged that our recently estab-
lished poly-N-methylmorpholine N-oxide (PNMO) re-
agent could be applied as a co-oxidant within the TPAP
oxidation of alcohols in an efficient and potentially recy-
clable fashion.6
hols.
Key words: alcohols, oxidations, polymer-supported, ruthenium,
solid-phase synthesis
To initiate our studies, preparation of the requisite poly-
mer supported amine N-oxide was attempted using the
commercially available polymer supported morpholine
based resin 1. This was readily achieved by either utilising
the N-phenylsulfonyloxaziridine of Davis3a,b,7 or, impor-
tantly, using the commercially available oxidant MCPBA.
As shown in Scheme 1, this oxidation process provided
the required polymer supported morpholine N-oxide 2
with high theoretical loading.
As the chemical community comes under continued pres-
sure to develop production methods based on cleaner
technologies, attempts to establish more industrially ap-
plicable methodology are on the increase. Among other
factors, these developing methods should combine effi-
ciency, cost reduction, and more environmentally accept-
able advances.1 In attempts to satisfy, at least, some of
these set criteria and in a drive to prepare a library of spe-
cific solid phase reagents, we have recently reported a
flexible and novel synthesis of a polymer-supported
amine N-oxide.2 Moreover, this Argogel based resin was
found to be a highly efficient promoter of the Pauson-
Khand (P-K) annulation process, giving good to excellent
yields of cyclopentenones in remarkably fast times under
very mild reaction conditions. In an effort to enhance the
overall efficacy and wider applicability of the supported
N-oxide, a higher loading polymer bound reagent, based
a or b
O
N
N
1
2
O
O
loading 3.5 mmol g-1
loading 2.86 mmol g-1
on the readily available morpholinomethyl polystyrene Scheme 1 Reagents and conditions: (a) N-(phenylsulfonyl)pheny-
(Merrifield-type) resin, was prepared.3 Likewise, this was
also found to be an excellent promoter of the P-K cyclisa-
loxaziridine (4 equiv.), CH2Cl2, r.t., 4 h. (b) MCPBA (3 equiv.),
CH2Cl2, r.t., 4 h.
tion.
In terms of highly desirable processes for more environ-
mentally benign oxidation of alcohols, the efficient and
selective methods developed by Griffith and Ley, which
employ only catalytic quantities of tetrapropylammonium
perruthenate (TPAP),4 along with a stoichiometric co-ox-
idant, appear to offer an attractive and readily utilisable
technique for employment on small to large scales. More
recently, to enhance the applicability of this general oxi-
dative strategy, Ley and co-workers have modified the
TPAP protocol and developed the polymer supported per-
ruthenate (PSP) technique.5 Specifically, the PSP reagent
can be used in both stoichiometric quantities or, like the
solution phase reaction, in catalytic amounts when used in
tandem with a co-oxidant such as trimethylamine N-oxide
(TMANO) or N-methylmorpholine N-oxide (NMO) in the
presence of molecular sieves. With regards to the latter
approach, whilst only sub-stoichiometric quantities of the
ruthenium-based reagent are used, the process still results
With the required polymer supported N-oxide 2 in hand,
we turned our attention to the application of this resin
bound reagent as a co-oxidant in the TPAP oxidation of
alcohols. Initially, we found that these oxidations were re-
ally rather sluggish. For example, with benzyl alcohol 3,
only a 49% yield of benzaldehyde 4 was obtained after 24
hours, with the mass balance being made up by starting al-
cohol. Importantly however, although the initial oxida-
tions were not proceeding to completion, they did at least
demonstrate that the PNMO resin was acting as a co-oxi-
dant within the TPAP reaction mixture. To further probe
the preliminary oxidative processes, the conversion of E-
cinnamyl alcohol 5 to E-cinnamaldehyde 6 was followed
by GC. Perhaps unsurprisingly based on previous stud-
ies,4-6 it was observed that conversion of the alcohol to the
aldehyde initially occurs rapidly and up to 40% within 15
minutes. However, after a further 48 hours only a 60%
conversion was achieved.
Synlett 2001, No. 8, 1257–1259 ISSN 0936-5214 © Thieme Stuttgart · New York

1258
D. S. Brown et al.
LETTER
Table 1 TPAP Oxidations of a Range of Alcohols with Solid Phase
N-Oxide 2 as the Co-oxidant.
In most solution and solid phase TPAP processes, it is
necessary and, indeed, standard practice to introduce acti-
vated molecular sieves in order to achieve optimal rates
and efficiencies of oxidation; the sieves act as a general
dehydrating agent as water has a retarding effect upon the
reaction rate.4-6 Despite this, it was envisaged that the hy-
drophobic nature of the polystyrene-based resin would
discourage hydration of the key ruthenium species thus
negating any requirement for molecular sieves.8 Never-
theless, on addition of activated 4Å molecular sieves to
the reaction mixture, prior to introduction of the TPAP,
the desired oxidation processes proceeded much more ef-
ficiently. Using the conditions illustrated in Scheme 2, a
range of alcohols were tested and the results are presented
in Table 1. As can be seen, the oxidation of activated al-
cohols (Entries 1-4) proceed exceedingly well9 and even
the secondary alcohols 11 and 13 (Entries 5 & 6) gave the
ketones 12 and 14 in reasonable to good yields. The oxi-
dation of non-activated primary alcohols proceeds some-
what less efficiently.
O
N
OH
O
2
O
R1
R2
R1
R2
TPAP (20 mol%)
Activated 4Å Mol. Sieves
DCM, r.t., 24 h
Scheme 2
Having established that this solid supported co-oxidant is
particularly effective in the TPAP oxidation of benzylic
and allylic alcohols, we next investigated whether any se-
lectivity would occur in the reactions of activated and un-
activated alcohols. Pleasingly, using our developed
protocol, reaction of 1 equivalent of para-methoxybenzyl
alcohol 7 in the presence of 1 equivalent of 1-decanol 15
delivered a 71% yield of para-methoxybenzaldehyde 8
compared to only 13% yield of decanal 16 (with an 84%
yield of returned starting material, 1-decanol 15), after
only 30 minutes (Scheme 3).
First of all, it should be noted that during the series of ox-
idations already described, on completion of reaction and
following filtration, the spent amine resin is admixed with
the used molecular sieves. Furthermore, re-activated
sieves would be required for each successive oxidation
process. Since the resin was unlikely to be stable to the
vigorous conditions used for dehydration of the sieves, re-
With an efficacious and selective oxidative protocol in
hand, to exploit the recoverable nature of the supported
amine and establish the full efficiency of this methodolo-
gy, the recycling of the solid phase species was explored.
O
O
O
H
N
8
71%
OH
H3CO
2
7
+
+
H3CO
+
OH
TPAP (20 mol%)
Activated 4Å Mol. Sieves
DCM, r.t, 30 min
15
84%
13%
OH
15
H
O
16
Scheme 3
Synlett 2001, No. 8, 1257–1259 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Polymer-Supported N-Methylmorpholine N-Oxide
1259
EPSRC Mass Spectrometry Service, University of Wales, Swansea,
for analyses.
cycling of the resin/sieve mixture did not seem to be prac-
ticable. To circumvent these practical issues, a reaction
system was devised whereby the amine N-oxide resin 2
and the molecular sieves were separated from the outset
by an additional porous frit. More specifically, the N-ox-
ide resin is placed in a fritted filter tube and this is then
capped (leaving sufficient head space) with the second po-
rous frit. In turn, the resin is swollen with DCM and, sub-
sequently, the molecular sieves are introduced. On
completion of the alcohol oxidation with TPAP, draining
of the product mixture and washing of the resin is fol-
lowed by simple removal of the spent molecular sieves. In
due course, the amine resin is ready for re-oxidation and
further use within the same double fritted reaction vessel.
Using this technique with E-cinnamyl alcohol 5 as the
substrate, the excellent yield of the corresponding alde-
hyde 6 was maintained through five cycles (Table 2). It is
also worth noting that resin oxidised with either Davis’ re-
agent or MCPBA were effective throughout this recycling
study.10
References and Notes
(1) Green Chemistry: Frontiers in Benign Chemical Syntheses
and Processes; Anastas, P. T.; Williamson, T. C., Ed.; Oxford
University Press: Oxford, 1998.
(2) Kerr, W. J.; Lindsay, D. M.; Watson, S. P. Chem. Commun.
1999, 2551.
(3) (a) Brown, D. S.; Campbell, E.; Kerr, W. J.; Lindsay, D. M.;
Morrison, A. J.; Pike, K. G.; Watson, S. P. Synlett 2000, 1573.
(b) 2% DVB crosslinked morpholinomethyl polystyrene resin
was purchased from NovaBiochem with a nitrogen loading of
3.5 mmol g-1. (c) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85,
2149.
(4) (a) Griffith, W. P.; Ley, S. V.; Whitcomb, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1981, 1625. (b) Griffith, W.
P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13. (c) Ley, S. V.;
Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(5) Hinzen, B.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1997,
1907.
(6) It should be noted that both Markó and Ley have developed
techniques for the TPAP oxidation of alcohols where oxygen
has been employed as the co-oxidant. In these protocols
elevated temperatures (70–85 °C in toluene) are more usually
required: (a) Markó, I. E.; Giles, P. R.; Tsukazaki, M.; Chellé-
Regnaut, I.; Urch, C. J.; Brown, S. M. J. Am. Chem. Soc. 1997,
119, 12661. (b) Lenz, R.; Ley, S. V. J. Chem. Soc., Perkin
Trans. 1 1997, 3291. (c) Hinzen, B.; Lenz, R.; Ley, S. V.
Synthesis 1998, 977.
Table 2 TPAP Oxidations of a E-Cinnamyl Alcohol 5 with Re-
cycled Resin 2 as the Co-oxidant.
O
H
N
2
O
Ph
OH
Ph
O
TPAP (20 mol%)
Activated 4Å Mol. Sieves
DCM, r.t., 24 h
5
6
(7) Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S.;
Reddy, T. J. Org. Chem. 1988, 53, 2087.
(8) Dörwald, F. Z. Organic Synthesis on Solid Phase; Wiley-
VCH: Weinheim, 2000.
(9) Representative experimental procedure: PNMO resin 2
(2.86 mmol g-1 based on microanalysis, 150 mg, 0.43 mmol)
was weighed into an Alltech fritted filter tube. This was then
swollen in DCM (2 mL) for 30 minutes before addition of
activated 4Å molecular sieves (225 mg). The reaction vessel
was then shaken for a further 30 minutes followed by addition
of p-methoxybenzyl alcohol 7 (29.7 mg, 0.215 mmol), as a
solution in DCM (2 mL), and TPAP (15.1 mg, 0.043 mmol).
The reaction vessel was then shaken for 24 hours before
draining and washing of the resin with DCM (10 2mL),
filtration through a silica pad, and evaporation to dryness.
Purification by silica gel column chromatography gave p-
methoxybenzaldeyde 8 (28.0 mg, 95% Yield). IR (DCM):
1683, 1600, 1511, 1315, 1264, 1160, 1018, 828 cm–1; 1H NMR
(400 MHz, CDCl3): 9.89 (s, 1H), 7.84 (d, 2H, J = 9.5 Hz), 7.01
(d, 2H, J = 9.5 Hz), 3.89 (s, 3H) ppm.
(10) Initially, it had been anticipated that the PNMO resin might
sequester the catalytic quantity of TPAP introduced, which
would, in turn, allow this transition metal loaded polymer
species to be recycled for use in further catalytic oxidative
processes. However, it was apparent that, on draining the
reaction mixture, quantities of the TPAP residues were being
leached from the resin. Furthermore, after re-oxidation of the
spent resin, reaction with benzyl alcohol with no additional
TPAP failed to give any oxidised organic product after 24
hours.
aO-PNMO refers to oxaziridine (Davis’ reagent) oxidised resin.
bM-PNMO refers to MCPBA oxidised resin.
In conclusion, a readily accessible, high loading polymer
supported amine N-oxide 2 has been prepared, in one sim-
ple step from two commercially available reagents, the
morpholinomethyl polystyrene resin and MCPBA, or the
same resin and the routinely prepared Davis oxaziridine.
In turn, protocols have been developed which allow this
N-oxide resin to be utilised as an efficient co-oxidant in
the TPAP oxidation of alcohols. It was found that the resin
gave rise to high product yields in the oxidation of allylic
and benzylic alcohols and showed good chemoselectivity
for activated alcohol systems in competitive reactions.
Importantly, both the Davis reagent and MCPBA oxidised
resins could be readily recycled without loss in activity.
Acknowledgement
We thank AstraZeneca Pharmaceuticals for studentship support
(P.D.R) and Strategic Research Funding (W.J.K.) and the Universi-
ty of Strathclyde for financial support. We are also indebted to the
Article Identifier:
1437-2096,E;2001,0,08,1257,1259,ftx,en;D11801ST.pdf
Synlett 2001, No. 8, 1257–1259 ISSN 0936-5214 © Thieme Stuttgart · New York