N,N,N′,N′-Tetramethylenediamine dioxide (TMEDAO2) facilitates atom economical/open atmosphere Ley-Griffith (TPAP) tandem oxidation-Wittig reactions

Article abstract of DOI:10.1039/c5gc01346a

N,N,N′,N′-Tetramethylethylenediamine dioxide (TMEDAO₂) was explored as a more atom economical co-oxidant for the Ley-Griffith oxidation of alcohols to aldehydes. TMEDAO₂ was found to selectivity oxidise benzylic and allylic alcohols in comparable yields to that of the standard Ley-Griffith co-oxidant (NMO). Importantly TMEDAO₂ facilitated tandem Ley-Griffith-Wittig reactions with stabilised ylides, in good to excellent yields, without the requirement of anhydrous conditions.

Full text of DOI:10.1039/c5gc01346a

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N,N,N’,N’-Tetramethylenediamine dioxide
(TMEDAO2) facilitates atom economical/open
atmosphere Ley–Griffith (TPAP) tandem
oxidation-Wittig reactions†
Cite this: DOI: 10.1039/c5gc01346a
Received 16th June 2015,
Accepted 27th July 2015
DOI: 10.1039/c5gc01346a
www.rsc.org/greenchem
Christopher D. G. Read, Peter W. Moore and Craig M. Williams*
N,N,N’,N’-Tetramethylethylenediamine dioxide (TMEDAO2) was
explored as a more atom economical co-oxidant for the Ley–
Griffith oxidation of alcohols to aldehydes. TMEDAO2 was found to
selectivity oxidise benzylic and allylic alcohols in comparable
yields to that of the standard Ley–Griffith co-oxidant (NMO).
Importantly TMEDAO2 facilitated tandem Ley–Griffith-Wittig reac-
tions with stabilised ylides, in good to excellent yields, without the
requirement of anhydrous conditions.
Alcohol (1) to aldehyde (2) (Scheme 1) oxidation is an immen-
sely popular functional group transformation utilised by
chemical synthesis practitioners to access versatile building
blocks.1 Although, a staggering number of methods and
reagents are available to perform this transformation,2,3 three
main method types continue to command a high profile.4
These include sulfur activation protocols (e.g., Swern oxi-
dation5), hypervalent iodides [e.g., 2-iodoxybenzoic acid (IBX)6]
and the Ley–Griffith oxidation,7 which is underpinned by the
TPAP reagent {3, tetra-n-propylammonium perruthenate,
(nPr4N)+[RuO4]−} and the co-oxidant N-methylmorpholine
N-oxide (4, NMO) (Scheme 1). Subsequent to the discovery
of TPAP (3) a number of sustainability innovations have been
reported, for example, the use of a polymer-supported co-
oxidant,8 molecular oxygen,9 hydrogen peroxide10 and flow
applications.11 However, these innovative modifications seem
not to have been widely adopted, and thus the standard Ley–
Griffith oxidation continues to be routinely employed.
Recently, we reported a variation on the Ley–Griffith oxidation
using a non-hygroscopic version of the co-oxidant NMO,
NMO·TPB (5) (Scheme 1), which was found to selectively
oxidise benzylic and allylic alcohols without the requirement
of anhydrous conditions (i.e. no dry solvent or 4 Å molecular
sieves required).12 Although, this selectivity modification
Scheme 1 The oxidation of an alcohol (1) to an aldehyde (2) promoted
by a Ley–Griffith oxidation; TPAP (3), NMO (4), NMO·TPB (5) for selective
benzylic or allylic oxidation, and TMEDAO2 (6).
alleviated the use of anhydrous conditions, which produced
both energy and atom economy savings, we sought further
efficiencies on the atom economy front, results of which are
reported herein.
A
literature search identified N,N,N′,N′-tetramethyl-
ethylenediamine dioxide (6, TMEDAO2) (Scheme 1) as a poten-
tial substitute for the NMO·TPB (5) salt. Although, TMEDAO2
(6) has received only very little attention in synthesis,13 it can
potentially deliver twice the oxidation capacity of NMO (4)
using only 27% more molecular mass. On the other hand 6 is
substantially more atom economical than the NMO·TPB (5)
salt, albeit potentially offering the same co-oxidation capacity
(i.e. two N-oxides). Three synthetic procedures for 6 have been
reported,13 however, they involve a mix of solvents, extended
reaction times and/or purifications steps, not to mention
reagents to decompose excess peroxide. In the view that hydro-
School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane,
4072, Australia. E-mail: c.williams3@uq.edu.au
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data and copies of 1H and 13C NMR spectra. See DOI:
10.1039/c5gc01346a
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gen peroxide can be decomposed safely at slightly elevated anhydrous conditions were trialled using 7b, a lower yield of
temperature under vacuum,14 we firstly developed a simple 69% was observed for 8b, as compared to 90% using
synthesis of TMEDAO2 (6) by briefly treating neat N,N,N′,N′- TMEDAO2 (6) under anhydrous conditions. Surprisingly,
tetramethylethylenediamine (TMEDA) with a hydrogen per- however, when the stabilised phosphorane (9) was introduced
oxide solution at 0 °C, and subsequently removing water. The and the reaction allowed to run for 24 h a yield of 83% was
resulting white solid, TMEDAO2·xH2O, was found to contain obtained for the α,β-unsaturated ester 10c (Table 2) compared
3–4 waters of hydration, and absorb water at a much slower to the oxidation step alone, which gave a yield of 88% for alde-
rate as compared to NMO (4) facilitating slightly easier hand- hyde 8a (Table 1). Inspired by this observation a series of
ling. [Note: decreasing the number of waters of hydration is examples were explored to determine reaction scope (Table 2).
reportedly achieved via heating to 100 °C in the presence of
phosphorous pentoxide,13 however, this measure was not both electron withdrawing and electron donating substituted
deployed for this study.] α,β-unsaturated esters 10a–m were obtained in good to excel-
Under these one-pot tandem oxidation-Wittig conditions
TMEDAO2 (6) was then evaluated as a co-oxidant using stan- lent yields (63–95%). More remarkable, however, was the
dard Ley–Griffith oxidation conditions against a range of acti- observation that the E-isomer selectivity of 16 : 1, in the case of
vated primary and secondary alcohols (Table 1).
10a, was almost twice that reported for NMO, in addition, to a
In general similar or better yields for activated alcohols (i.e. significant increase in yield (i.e. 68 to 89%) (Table 2). Interest-
benzylic and allylic alcohols 8a–k, Table 1) were observed, for ingly, the reaction displays a synergic effect whereby reaction
example, 8a was obtained in 68% yield using NMO (4),7a without the addition of co-oxidant 6 provided a yield of 10c
whereas TMEDAO2 (6) afforded the product in 88% yield. (Table 2) in the order of 25%, significantly greater than the
However, unactivated alcohols afforded much lower conversion 5 mol% catalyst loading. Furthermore, molecular oxygen is
and significantly reduced yields (e.g. 8I, Table 1), as was the reported to drive the Ley–Griffith oxidation9 but requires
case previously observed with NMO·TPB (5).12
higher temperatures (i.e. 80 °C), which is absent in our system
With these results in hand we explored the possibility of (Table 2). Therefore triphenylphosphine oxide or the phospor-
amalgamating atom economy with step economy,15 via ane (e.g. 9) could be acting in a synergistic manner.
tandem16 (domino17) reactions. Although, Ley elegantly
demonstrated that his namesake oxidation was amenable to
tandem processes, involving the Wittig reaction of both non-
Table 2 One-pot synthesis of α,β-unsaturated estersa,b
stabilised and stabilised phosphoranes,18 we wished to avoid
the use of anhydrous conditions.
Initially disappointing results were obtained with the tran-
sition of TMEDAO2 (6) to non-anhydrous conditions (i.e. wet
solvent and no 4 Å molecular sieves). For example, when non-
Table 1 Ley–Griffith oxidation using TMEDAO2 (6) under anhydrous
conditionsa,e
a Isolated yields. b Literature TPAP yield 68%.7a c Literature TPAP yield
a Isolated yields using method A. b Values in [ ] represent E : Z isomer
75%.7a d Literature TPAP yield 91%.7a e The use of acetonitrile as
solvent gave lower yields.
ratios. c Literature TPAP/ sequential yield 68% [>9 : 1].18
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alcohol oxidation, but high consumption of aryl and allylic
alcohols. This promoted a competition experiment to be per-
formed with bi-functional diol 15 to further explore the
observed selectivity (Scheme 2). Pleasingly, the oxidation-
Wittig protocol showed a high degree of selectivity for the
benzylic position producing the mono ester 16 with only small
amounts of di-ester 17 and aliphatic ethyl ester 18. These
results are similar to our previous observations with diol 15
using NMO·TPB (5).
Table 3 Application of tandem oxidation-Wittig protocol using
different phosphoranesa,b
Conclusions
Application of a new co-oxidant, N,N,N′,N′-tetramethylethylene
diamine dioxide (6, TMEDAO2), to oxidise activated alcohols
under a standard Ley–Griffith oxidation displayed good oxi-
dation potential for activated alcohols. Use of TMEDAO2 (6) in
a tandem TPAP (3) catalysed oxidation Wittig protocol, open to
atmospheric conditions, provided a range of α,β-unsaturated
esters 10a–o and variations (e.g. 14a–f) in excellent overall
yields. It was found that benzylic and allylic alcohols react
selectively over primary and secondary alcohols. Application of
this observation in oxidising diol 15 to substituted ethyl cinna-
mate 16 highlights that this methodology could be amenable
to protecting group free oxidation/Wittig chemistry. Lastly, of
the tandem oxidation Wittig protocols currently available19 the
TMEDAO2 method reported herein is highly competitive in
terms of overall yield, low toxicity, and atom economy.
a Isolated yields using methods B and C. b Values in [ ] represent E : Z
isomer ratios. c One-pot, 1.1 eq. of phosphorane, refluxing. d r.t.
oxidation reaction (8 h) then reflux with 2 eq. of phosphorane. e r.t.
oxidation (8 h) then addition of 2 eq. of phosphorane, reflux (16 h)
followed by an additional 2 eq. of phosphorane and continued reflux
(8 h).
Further scope was investigated with a variety of stabilised
phosphoranes (11–13) (Table 3). For phosphoranes 11–13, only
low yields were obtained using the procedure developed for
products listed in Table 2. Although upon refluxing (40 °C) an
improvement was seen in the Wittig component, it effected
the oxidation reaction, in that, residual starting alcohol was
observed. This aspect was eventually solved by adopting a
sequential addition protocol, whereby the oxidation was run
for 8 h before addition of 2 equivalents of the phosphorane
and refluxing (40 °C) for 16 h.
Acknowledgements
We thank the University of Queensland (UQ) for financial
support. C. M. W acknowledges the Australian Research
Council for
a Future Fellowship award (FT110100851).
C. D. G. R. and P. W. M. are grateful for Australian Post-gradu-
ate Awards.
The reagent combination displayed in Table 2 showed
much less reactivity towards saturated primary and secondary
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