Binuclear complexes for aerobic oxidation of primary alcohols and carbohydrates

Article abstract of DOI:10.1016/j.tet.2010.07.077

The influence of electron-donating and electron-accepting properties of three pentadentate ligands was determined in connection with the aerobic oxidation ability of the corresponding binuclear copper(II) complexes for benzyl and allyl alcohols; additionally, the catalytic performance of their palladium and platinum analogs was characterized under comparable conditions. Quantitative aerobic oxidation of benzyl alcohol at 40 °C was achieved with a binuclear copper(II) complex - TEMPO catalyst in 2.5 h, while the regioselective aerobic oxidation of underivatized methyl-β-d-glucopyranoside was accomplished in about 35% yield at 60 °C after 24 h.

Full text of DOI:10.1016/j.tet.2010.07.077

Tetrahedron 66 (2010) 7927e7932
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Binuclear complexes for aerobic oxidation of primary alcohols and carbohydrates
*
Susanne Striegler , Natasha A. Dunaway, Moses G. Gichinga, Lisa K. Milton
Department of Chemistry and Biochemistry, 179 Chemistry Building, Auburn University, Auburn AL 36849, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 June 2010
Received in revised form 26 July 2010
Accepted 27 July 2010
Available online 3 August 2010
The influence of electron-donating and electron-accepting properties of three pentadentate ligands was
determined in connection with the aerobic oxidation ability of the corresponding binuclear copper(II)
complexes for benzyl and allyl alcohols; additionally, the catalytic performance of their palladium and
platinum analogs was characterized under comparable conditions. Quantitative aerobic oxidation of
benzyl alcohol at 40 ꢀC was achieved with a binuclear copper(II) complexdTEMPO catalyst in 2.5 h,
while the regioselective aerobic oxidation of underivatized methyl-
b-D-glucopyranoside was accom-
plished in about 35% yield at 60 ꢀC after 24 h.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
oxidation of the primary alcohols to carboxylic acids7,10 or limited
catalyst stability during the reaction11 currently reduce the appli-
cability of these methods for the synthesis of hexose-6-aldehydes.
Toovercomethis shortcoming, wepreviouslyproposeda catalytic
system for the regioselective aerobic oxidation of primary alcohols
consisting of the binuclear copper(II) complex N, N0-{bis (2-pyr-
A major obstacle to advances in glycobiology is the lack of pure
and structurally well-defined oligosaccharides and glyco-
conjugates.1 This shortage is particularly cumbersome for the
potential use of unnatural sugars as food components with a low
calorie value to fight obesity. Of particular interest in this regard are
5-C-hydroxymethylglycosides derived from sugar-6-carbaldehydes
that cannot be digested by mammalian enzymes or intestinal
bacteria.2 Enzymatic approaches towards synthesizing the pre-
requisite sugar-6-carbaldehydes are compromised by the specific-
ity of galactose oxidase for the transformation of substrates with
galacto-configuration, its moderate thermal stability, narrow pH
profile and comparably low reaction yields.3 Galactose oxidase is
the only enzyme known today to oxidize the primary alcohol group
of carbohydrates. Conventional multi-step syntheses on the other
hand typically involve numerous protection, deprotection and
activation steps prior to the regioselective oxidation of the primary
alcohol group of a carbohydrate, which somewhat diminishes the
value of established synthetic methods.4
The development of a protocol for the catalytic and regio-
selective oxidation of primary alcohols in underivatized carbohy-
drates is thus a long-term goal for the work in this laboratory. The
oxidation of the primary alcohol group in carbohydrates is con-
ventionally achieved using stoichiometric amounts of two-electron
oxidants, such as iodosylbenzene,5 amine N-oxides,6e8 peroxides,9
or transition metal complexes.10 These entities can be used in
catalytic amounts when re-oxidation by molecular oxygen, sodium
hypochlorite or other oxidants are provided.7 However, unselective
oxidation of both primary and secondary hydroxyl groups, over-
idylmethyl)-1,3-diaminopropan-2-ol}ato dicopper(II)
(m-acetato)
diperchlorate, Cu2(bpdpo) (1),12e14 and 2,2,6,6-tetramethyl-
piperidine-1-oxyl, TEMPO (2), in alkaline aqueous acetonitrile solu-
tion.12 This earlier study disclosed a sugar-discriminating binuclear
complex 113 promoting the aerobic oxidation of benzyl alcohol (3)
into benzaldehyde (4) in the presence of 2 and a base, while pre-
venting over-oxidation to carboxylic acids.12 Mononuclear com-
plexes derived from the same or similar backbone ligands were
inactive under comparable conditions.12 The constitution of the
catalytically active species was deduced from isothermal titration
calorimetryand kinetic experiments.12 A mechanismfor the catalytic
cycle for the oxidation of benzyl alcohols was proposed.12 The 1e2
catalyst regioselectively oxidizes primary over secondary alcohols.
Similar findings are reported for related catalysts for aerobic oxida-
tionsofprimaryalcoholswithcopper(II)complexesandTEMPO.15e24
Preliminary data furthermore suggested the catalytic oxidation
of
a-D-methylglucopyranoside (5) into the corresponding sugar
6-carbaldehyde 6 employing the 1e2 catalyst (Scheme 1).25
A
qualitative proof for the presence of 6 was obtained after treatment
of the reaction product with excess formaldehyde solution yielding
5-C-hydroxymethyl-a-D
-methylglucopyranoside 7,2 and the obser-
vation of its sodium adduct by ESI mass spectrometry (M7-
¼247.1). The mass peak of the sodium adduct of 7 gives evidence
Naþ
for the oxidation of 5 into 6 as a prerequisite for the formation of
7.25 In our previous attempts, 6 and 7 were isolated in less than 10%
from the solution. Full characterization data for 6 and 7 are pro-
vided by Mazur and Hiler previously.2
* Corresponding author. Tel.: þ1 334 844 6954; fax: þ1 334 844 6959; e-mail
address: Susanne.Striegler@auburn.edu (S. Striegler).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.077

7928
S. Striegler et al. / Tetrahedron 66 (2010) 7927e7932
N
N
O
OH
HO
Cu
O
Cu
O
OH
OH
N
O
N
O
O
O
excess
HCHO(aq)
HO
HO
HO
HO
N
H
N
H
HO
HO
OH
OH
HO
7
OH
5
6
O2, r.t.
OMe
OMe
OMe
Scheme 1. Aerobic oxidation of underivatized
a
-D-methylglucopyranoside (5) into a-D-methylglucopyranosyl-6-carbaldehyde (6) with a binuclear copper(II) catalyst derived from
Cu2(bpdpo) (1) and TEMPO (2), and successive reaction of 6 with excess formaldehyde yielding 5-C-hydroxymethyl-a-D-methylglucopyranoside (7).
Efforts by other researchers to apply the good selectivity of
OH
OH
OH
OH
TEMPO-mediated oxidations without any copper(II) salt towards
carbohydrates resulted in over-oxidation to the corresponding
uronate carboxylicacids.26e30 Optimizationof thesystem bystopping
F
F
3
10a
10b
10c
the reaction at the aldehyde level allowed the preparation of the
F
carbohydrate 6-aldehydes in 63% yield.31 However, a reaction time of
D
110 h, a minor amount of over-oxidation to undesirable uronate car-
OH
OH
OH
D
OH
boxylic acids, the use of DMF as solvent, and a tedious experimental
work-up hadtobeacceptedinreturn.31 Similartoourpreviousresults
though, a maximum aldehyde concentration of about 10% was
observed in aqueous carbonate-buffered solution.31,28
MeO
MeO
11a
11b
11c
3a
OMe
With the goal to improve the yield for the oxidation of glycosides
at the primary hydroxyl group, we hypothesized that the electron-
donating and the electron-accepting properties of the ligand back-
bone determine the oxidation ability of the corresponding
complexes. Along these lines, the catalytic performance of 1 was
characterized in more detail with selected benzyl and allyl alcohols,
and subsequently compared with the performance of an unsym-
metric analog N,N0-{bis(2-pyridylmethyl)-1,4-diaminobutan-2-ol}
OH
OH
12b
OH
12a
12c
OH
13
OH
12d
Figure 2. Selected benzyl and allyl alcohol substrates.
ato dicopper(II) (
symmetric salicylaldehyde-based complex N,N0-{1,3-bis[{2-
hydroxy-4-[2-(2-methoxyethoxy)-ethoxy]-ethoxy}benzylidene-
m-acetato) diperchlorate, Cu2(bpdbo) (8), and
a
The oxidation of all substrates 3, 10e12 follows classical satu-
ration kinetics; the product formation was followed and quantified
by gas chromatography. The product identity was established by
comparison of the retention times with commercial samples. The
data obtained were fitted using non-linear regression to determine
the turnover rate (kcat) and the substrate affinity (KM) with the
MichaeliseMenten model (Table 1). The initial rate of the oxidation
of all substrates depends linearly on the catalyst concentration. The
use of water-soluble 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-
oxyl, 4-OH-TEMPO (2a), instead of 2 was intended to provide
a water-soluble catalytic system that might improve the oxidation
of biomolecules in aqueous solution; however, the observed cata-
lytic oxidation of 3 by a 1e2a catalyst (Table 1, entry 2) was 3-fold
slower than with the 1e2 catalyst (Table 1, entry 1). Other catalytic
amino]-propan-2-ol}ato dicopper(II) (m-acetato), Cu2(TEGbsdpo)
(9), (Fig. 1).14,32 We furthermore optimized the conditions for the
carbohydrate oxidation and quantified the reaction yields in
dependence of the reaction temperature and the catalyst
amount. The recent results and insights are summarized below.
OH2
O
O
O
O
N
Cu
Cu
Cu
Cu
N
O
N
2ClO4
N
O
NH
2ClO4
N
H
N
H
N
H
1
8
O
O
Cu
Cu
Table 1
Catalytic oxidation of benzylic and allylic alcohols
RO
O
O
OR
O
a
Entry
1b
2
3
4
5
6
7
8
Catalyst
Substrate
kcat [minꢁ1
]
KM [M]a
N
N
R = -(CH2CH2O)3-Me
1e2
1e2a
1e2
1e2
1e2
1e2
1e2
1e2
1e2
1e2
1e2
1e2
1e2
1e2
3
3
3a
0.64ꢂ0.06
0.18ꢂ0.04
0.02ꢂ0.01
0.04ꢂ0.01
0.48ꢂ0.17
0.21ꢂ0.04
0.42ꢂ0.06
0.48ꢂ0.18
0.41ꢂ0.10
0.02ꢂ0.01
0.05ꢂ0.01
0.25ꢂ0.09
0.02ꢂ0.01
n.d.c
0.340ꢂ0.054
0.594ꢂ0.182
0.385ꢂ0.103
0.031ꢂ0.001
0.895ꢂ0.404
0.581ꢂ0.190
0.442ꢂ0.108
0.953ꢂ0.469
0.780ꢂ0.284
0.158ꢂ0.016
0.364ꢂ0.128
0.569ꢂ0.279
0.357ꢂ0.051
n.d.c
9
Figure 1. Structures of binuclear copper(II) complexes 1, 8, and 9.
10a
10b
10c
11a
11b
11c
12a
12b
12c
12d
13
2. Oxidation of benzylic and allylic alcohols by
a Cu2bpdpoeTEMPO catalyst
Prior to modifying the structure of the binuclear catalyst 1, its
substrate scope suitable for aerobic oxidation in alkaline solution at
ambient temperature was characterized in some more detail. Towards
this end, the oxidation of selected o-, m-, and p-substituted benzyl al-
cohols with electron-withdrawing fluoro (10) and electron-donating
methoxy substituents (11) were explored. Subsequently, the oxidation
abilityof the 1eTEMPO catalysttowardsallylicalcoholsincludingcis-2-
hexenol (12a), trans-2-hexenol (12b), geraniol (12c), cinnamyl alcohol
(12d), and trans-3-hexenol (13) was characterized (Fig. 2).
9
10
11
12
13
14
a
Each experiment was conducted in triplicate or more under aerobic oxidation
conditions at ambient temperature.
b
Values were taken from Ref. 12.
n.d.¼not determined; oxidation not observed.
c

S. Striegler et al. / Tetrahedron 66 (2010) 7927e7932
7929
systems derived from 2a were therefore not explored. A mono-
nuclear complex derived from N,N0-1,3-bis[(pyridin-2-ylmethyl)
amino]propan-2-ol, bpdpo (14), and equimolar amounts of Cu(II)
ions is not catalytically active.12 The use of deuterated benzyl
alcohol 3a instead of 3 showed a very large primary isotope effect
(kH/kD) of 33 (Table 1, entry 3), suggesting the abstraction of one
benzylic hydrogen atom as the rate-determining step as previously
proposed.12
The catalytic oxidation of 3 was initially studied using catalytic
systems derived from the binuclear copper(II) complexes 1, 8, and 9
and TEMPO (2) under the conditions described above. Sub-
sequently, the study was extended to derive catalytic systems from
the ligands 14 and 15, and Pd(II) and Pt(II) ions. Over-oxidation of 3
to benzoic acid (17) was not detected at any time; corresponding
carbonyl carbon atoms in the 13C NMR spectra at w170 ppm, as
typically observed in carboxylic acids, are absent; instead, a signal
for the aldehyde carbonyl carbon at 194 ppm is observed for the
formation of benzaldehyde (4).
The kinetic parameters for the oxidation of 3 with the 8e2 and
the 1e2 catalyst are similar (Table 1, entry 1 for the oxidation of 3
with 1e2; kcat(8e2)¼0.59ꢂ0.02 minꢁ1; KM(8e2)¼0.427ꢂ0.042 M).
Thus, the distortion of complex 8 and the accompanying shortening
of the intramolecular Cu/Cu distance in comparison to 2 has only
a minor effect on the ability of 8 to oxidize 3 in the presence of
TEMPO.
At ambient temperature, the yield of 4 is less than 30%, when
oxidizing 3 with the 1e2 catalyst (Table 2). The use of binuclear
copper(II) complex 1 is nevertheless favorable over the use of
complexes derived from the same backbone ligand and Pd(II) or Pt
(II) ions. In-situ formed binuclear Pd(II) and Pt(II) catalysts did not
promote any significant oxidation of 3 under comparable condi-
tions. Surprisingly, the use of the symmetric ligand 14 as backbone
ligand for the binuclear metal complexes provides slightly higher
reaction yields than the use of unsymmetric 15. All oxidation re-
actions of 3 with catalysts derived from backbone ligand 16 and Cu
(II), Pd(II) or Pt(II) ions yielded 4 in less than 1%. Ligand 16 was
therefore not considered any further.
All substrates with fluoro substituents 10aec are oxidized
slower than 3, which is in agreement with the general pattern
expected for oxidation of benzylic alcohols derivatized with elec-
tron-withdrawing substituents.30 The oxidation of fluorinated
benzyl alcohols is slowest for the fluoro substituent in o-position.
The effect is not as pronounced, when the electron-withdrawing
group is in p-position and smallest when in m-position (Table 1,
entries 4e6). A similar trend is observed for benzyl alcohols 11aec
substituted with an electron-donating methoxy-group (Table 1,
entries 7e9). While the turnover rate remains on average higher for
11aec than for 10aec, it is overall slower than for the oxidation of 3.
This finding suggests contributions of steric effects in addition to
electronic effects of the substituents to the overall rate of the oxi-
dation. Over-oxidation of the substituted benzylic alcohols to the
corresponding acids was not observed in contrast to reports about
other catalysts based on copper(II) complexes and TEMPO.30
The oxidation of the allylic alcohols 12aed is more than one
order of magnitude, i.e., about 30-fold, slower than the oxidation of
3 (Table 1, entries 10e13) The 1e2 catalyst oxidizes an allylic al-
cohol with a trans-substituted double bond twice as fast as corre-
sponding analogs with a cis-double bond. However, the turnover
rate for the allylic alcohols 12aed is not faster than 3 hꢁ1. The
substitution of the E-double bond with an electron-donating
methyl group, as given in geraniol (12c) (Table 1, entry 12), accel-
erates the oxidation about one order of magnitude compared to the
rate determined for all other allylic alcohol substrates studied. The
oxidation of geraniol (12c) is only about 3-fold slower than
the oxidation of 3 and comparable in its turnover rate to the oxi-
dation of 10c. The oxidation of trans-3-hexenol (13) was un-
successful; corresponding oxidation products were not detected.
While the aerobic oxidation of selected benzylic and allylic alcohols
is feasible with the 1e2 catalyst in alkaline, aqueous acetonitrile
solution, alterations of the ligand backbone structure might allow
the transformation of less activated primary alcohols in sufficient
quantities and turnover rates. Subsequent experiments and results
along these lines are summarized below.
Table 2
Aerobic oxidation of 3 into 4 with catalytic systems derived from backbone ligand 14
and 15, the metal ions Cu(II), Pd(II) and Pt(II), and TEMPO (2) at ambient
temperaturea
Entry
L
MA
MB
Molar ratio
L:MA:MB
Yield [%]b
1c
2
2
3
4
5
6
7
8
14
14
14
14
14
14
14
15
15
15
15
15
15
Cu
Cu
Pd
Pt
Cu
Cu
Pd
Cu
Pd
Pt
d
d
d
d
Pd
Pt
Pt
d
d
d
Pd
Pt
Pt
1:2
1:1
1:2
1:2
1:1:1
1:1:1
1:1:1
1:2
1:2
1:2
29.0
d
ꢁ
1.5
d
ꢁ
23.1
10.3
dd
17.5
dd
dd
9
10
11
12
Cu
Cu
Pd
1:1:1
1:1:1
1:1:1
17.0
8.8
3. Alternation of the ligand backbone and of the metal ion in
the catalytic system
dd
a
Each experiment was conducted in triplicate or more.
Determined by gas chromatography after a reaction time of 24 h.
Values taken from Ref. 12.
b
c
The backbone ligands of 1, N,N0-1,3-bis[(pyridin-2-ylmethyl)
amino]propan-2-ol, bpdpo (14) and of 8, N,N0-bis(2-pyr-
idylmethyl)-1,4-diaminobutan-2-ol, bpdbo (15), differ only in one
methylene group causing a slight distortion of 8 in comparison to
1 (Fig. 1); in turn, this distortion causes a small decrease of the
d
Not detectable or less than 1%.
33
ꢀ
Subsequently, the reaction temperature was raised in an at-
intermetallic Cu/Cu distance from 1 to 8 by about 0.1 A.
A
tempt to improve the reaction yields for aerobic oxidations with the
1e2 catalyst in alkaline, aqueous acetonitrile. The transformation of
3 into 4 was consequently conducted at 30, 40, 50, 60, and 70 ꢀC,
and the product formation quantified by using GC analysis. At 70 ꢀC,
the catalytic system changes its color from dark green to brown
even before substrate addition indicating catalyst decomposition.
Consequently, reactions at 70 ꢀC were not considered further. In-
creasing the catalyst amount from 1.5 mol % (4.57 mmol) to 5 mol %
(15.2 mmol) allows quantitative formation of 4 from 3 within 2.5 h
at 40e60 ꢀC (see Supplementary data). This result is comparable to
the performance of other copper(II) catalysts for aerobic oxidations
of primary alcohols.20,19
detailed discussion on the structural comparison of both com-
plexes was recently disclosed.33 However, the H-bond donating
functionality at both N-atoms in 14 and 15, and their overall
electron-donating ability in the corresponding binuclear copper
(II) complexes 1 and 8 remains similar. The performance of
a
complex 9 derived from backbone ligand N,N0-1,3-bis[{2-
hydroxy-4-[2-(2-methoxyethoxy)-ethoxy]-ethoxy}benzylidenea-
mino]-propan-2-ol, TEG(bsdpo) (16), is therefore contrasted to
the oxidation ability of 1 and 8. Ligand 16 has a H-bond accepting
function at the N-atoms, causing electron-withdrawing proper-
ties of the backbone ligand on the metal ions in 9. The in-
termetallic distances between 1 and 9 are comparable.33

7930
S. Striegler et al. / Tetrahedron 66 (2010) 7927e7932
4. Oxidation of methyl-b-D-glucopyranoside
a
Subsequently, the oxidation of methyl-b-D-glucopyranoside (18)
into methyl- -glucopyranoside-6-carbaldehyde (19) was explored
b-D
at 30, 40, 50, and 60 ꢀC with the 1e2 catalyst in alkaline acetonitrile
over a 24 h time period. The catalyst was then decomposed by pre-
cipitating the copper(II) ions as sulfides. The supernatant remaining
after centrifugation was treated with excess of aqueous formalde-
hyde to capture the primary oxidation product 19 as 5-C-hydroxy-
methyl derivative 20 as described for the oxidation of 6 (see above,
Scheme 1). The oxidation of 18 was performed under comparable
conditions with catalyst concentrations of 1.5 and 5 mol %.
Evidence for the oxidation of 18 into 19 was obtained by ob-
serving the sodium adduct of 5-C-hydroxymethyl-methyl-b-D-
glucopyranoside (20) using ESI mass spectrometry (Fig. 3). Side
products, including over-oxidation of 19 to glucuronic acid, were
not detected at any time. The reaction yield of 20 was determined
by quantitative HPLC and remains constant at about 28% for the use
of 1.5 mol % catalyst for the aerobic oxidations between 30 and
60 ꢀC (Fig. 4a and b). A slight increase in the formation of 20 from
29 to 35% is observed, when 5 mol % of catalyst are used under
otherwise identical reaction conditions. While the yield of the ox-
idation reaction follows general trends observed for increased re-
action temperatures and catalyst amounts, the effect is not as
pronounced in the current system.
b
34
32
30
28
26
In summary, we have explored and compared three structurally
related binuclear Cu(II) complexes for their ability to oxidize pri-
mary allylic and benzylic alcohols. The catalytic system derived from
30
40
50
60
T [°C]
Figure 4. (a) Typical HPLC chromatogram (blue line) used for quantitative analysis of
the oxidation of -D-methylglucopyranoside (black line); the solvent (green line) and
formaldehyde (red line) are given for comparison. (b) Yield of 5-C-hydroxymethyl-
methyl- -D-glucopyranoside (20) in dependence of the reaction temperature with
1.5 mol % catalyst (black square) and 5 mol % (red circle) catalyst in aqueous alkaline
acetonitrile; the reactions were conducted in triplicate.
247.0765
1.5x105
b
OH
OH
O
+
Na
1.2x105
9.0x104
6.0x104
Na+
b
HO
HO
O
HO
HO
(18-Na+)
OH
HO
OMe
OH
(20-Na+)
OMe
217.0680
5. Experimental section
3.0x104
0.0
5.1. Typical procedure for oxidation of benzyl and allyl
alcohols
200
220
240
260
The procedure was previously described.12 In short: 50 mL
round bottom flasks were charged with the dinuclear copper(II)
complexes 1, 8 or 9 (4.57 mmol) dissolved in 9 mL of alkaline
aqueous acetonitrile each (CH3CN/H2O¼2/1; NaOH 22 mM). Alter-
natively, the flasks were charged with the ligands 14, 15 or 16 and
appropriate amounts of Pt(II), Pd(II) and Cu(II) ions. The solutions
turned from dark blue to yellow-green after vigorous stirring at
m/z
Figure 3. Evidence for the formation of 19 from 18 captured as sodium adduct of 5-C-
hydroxymethyl-methyl-b-D-glucopyranoside (20) by ESI mass spectrometry; reaction
at 30 ꢀC, 1.5 mol % catalyst in aqueous alkaline acetonitrile.
the symmetric complex Cu2(bpdpo) (1) and TEMPO (2) is superior
during the oxidation of such substrates. The reaction is quantitative
at 40 ꢀC within 2.5 h for the oxidation of benzyl alcohol. Remarkably,
the regioselective oxidation of an underivatized, non-activated
carbohydrate 18 at its primary alcohol function is also accom-
plished. Most interesting in that regard is the fact that 18 is not
a substrate to galactose oxidase, which is the only enzyme known
today to promote the same reaction on underivatized sugars. Thus,
a new promising biomimetic system with galactose-oxidase like
ability has been developed that will be explored further in future
studies. The current results nevertheless also provide a first prom-
ising step towards the synthesis of sugar-6-carbaldehydes as pre-
requisites for the syntheses of unnatural sugars in the fight against
obesity. Optimization of the catalytic system to avoid the necessity
of a fairly alkaline solution should allow to improve the reaction
yields while avoiding side reactions of the primary oxidation
product. This might be accomplished by re-designing the binuclear
catalyst employing manganese ions and a pentadentate ligand with
oxygen donor atoms. Corresponding work is topic of current in-
vestigations and will be reported in due course.
ambient temperature for 45 min. Subsequently, 30 mL aliquots of
a TEMPO stock solution in acetonitrile were added to adjust the
total TEMPO concentration in the final reaction mixtures to 22 mM.
The solutions were stirred for another 30 min to allow formation of
catalytically active species. Darkening of the yellow-green solutions
to dark green is observed. Varying amounts of substrate are then
added to each flask, and the total volume of each solution is ad-
justed with the solvent mixture to a final volume of 10 mL. The final
substrate concentrations typically range from 50 to 450 mM.
Sample aliquots (200
60 s intervals, diluted with 10
and 100 L acetonitrile, centrifuged to remove precipitated CuS and
mL) of the reaction mixtures were taken in
m
L of a 1 M aqueous Na2S solution
m
filtered. The supernatant was subjected to GC analysis.
5.2. General procedure for temperature- and catalyst
amount-dependent oxidation reactions in microscale
The procedures followed the general description of the oxida-
tion of benzyl and allyl alcohols given above in microscale. The

S. Striegler et al. / Tetrahedron 66 (2010) 7927e7932
7931
reactions were allowed proceed in open vials with mechanical
stirring at 30, 40, 50, 60 or 70ꢂ0.1 ꢀC for 24 h. All reactions were
performed in triplicate by varying the stock solution of complex 1.
injection (1/100 split) at 200 ꢀC and flame ionization detection at
220 ꢀC. The compound identity of the aldehydes was confirmed by
comparison to commercially available samples.
5.3. Typical procedure for reactions with 1.5 mol % catalyst
5.4.3. ESI mass spectrometry experiments. Electrospray Ionization
(ESI) Mass spectrometric experiments were performed on a Q-ToF
An alkaline, aqueous acetonitrile solution was prepared by di-
luting 5 mL of an aqueous sodium hydroxide solution (48.53 mg,
1.21 mmol) into a 50 mL measuring flask by addition of a solution of
CH3CN/H2O (2:1, v/v). Complex 1 (19.88 mg, 0.03 mmol) was dis-
solved in 6 mL of alkaline, aqueous acetonitrile (see above) to
prepare a 5.04 mM stock solution. Subsequently, 1 mL from this
stock solution were transferred to 7 mL vials and stirred for 90 min.
Premier (Waters) in positive ion mode by injecting a 5 mL sample
aliquotof thereactionmixturesafterwork-up(seeabove)directlyinto
the ion source and scanning the masses between 100 and 500 m/z.
5.4.4. HPLC analysis. The HPLC analysis of the sample aliquots for
the carbohydrate oxidation was conducted with a Shimadzu HPLC
system employing an amino phase (PhenomenexÒ Luna 5
m
, NH2,
ꢀ
Then, 3
mL of a 8.09 M TEMPO (252.77 mg, 1.62 mmol in 200
mL of
250ꢃ4.60 mm, 100 A) and 70% acetonitrile isocratic at 1 mL/min as
CH3CN) solution in acetonitrile was added to each vessel, and
stirring continued for another 45 min at ambient temperature.
eluent at ambient temperature; 5
followed by refractive index detection at ambient temperature. The
retention of the -methyl 5-C-hydroxymethyl- -glycopyrano-
sides allows baseline separation from the corresponding
methyl-
-glycopyranosides under these conditions (e.g., Rf (19)¼
4.1 min; Rf (18)¼4.9 min).
mL injection. The analysis was
a/b
D
5.4. Typical procedure for reactions with 5.0 mol % catalyst
a/b-
D
An alkaline, aqueous acetonitrile solution was prepared by di-
luting 10 mL of an aqueous sodium hydroxide solution (323.53 mg,
8.09 mmol) into a 100 mL measuring flask by addition of a solution
of CH3CN/H2O (2:1, v/v). Complex 1 (66.27 mg, 0.10 mmol) was
dissolved in 6 mL of alkaline, aqueous acetonitrile (see above) to
prepare a 16.80 mM stock solution. Subsequently, 1 mL from this
stock solution were transferred to 7 mL vials and stirred for 90 min.
5.4.5. NMR experiments. 1H and 13C NMR spectra were recorded on
a Bruker AV400 (400.2 MHz for 1H, and 100.6 MHz for 13C).
Chemical shifts (d
) in 1H NMR are expressed in ppm and coupling
constants (J) in hertz. Signal multiplicities are denoted as s (singlet),
d (doublet), t (triplet), q (quartet) and m (multiplet). Deuterated
DMSO was used as solvent, and chemical shift values are reported
Then, 3 mL of a 26.96 M TEMPO (842.57 mg, 5.39 mmol in 200 mL of
CH3CN) solution in acetonitrile was added to each vessel, and
stirring continued for another 45 min at ambient temperature.
relative to the residual signals of this solvent (DMSO-d6:
d¼2.59 for
1H and
d
¼39.5 for 13C).
5.4.1. Benzyl alcohol as the substrate. After formation of the cata-
5.4.6. 5-C-Hydroxymethyl-methyl-b-D-glucopyranoside (20). The syn-
lytically active species via addition of TEMPO, 100
mL of 3.31 M
thesis of the title compound was carried out using methyl-b-D
-glu-
benzyl alcohol (1.25 g, 11.58 mmol in 3.50 mL of 67% aqueous ace-
tonitrile) solution was added, and the reaction was allowed to pro-
ceed at its corresponding reaction temperature. Sample aliquots
copyranoside as the substrate and the 1e2 catalyst as described
above. After precipitation of the copper(II) ions as copper(II) sulfide,
all volatile compounds were evaporated to obtain a colorless residue.
The residue was dried in vacuum for 4 h and subsequently extracted
with DMSO. After filtration, the title compound was obtained as
colorless oil (22 mg, 34%) dH 4.73 (d,1H, 6.88, H-1), 4.11 (d,1H, 7.77, H-
4), 3.37 (s, 2H, eCH2e), 3.34 (s, 2H, eCH2e), 3.30 (s, 3H, eCH3), 3.12
(1H, t, 8.86, H-2), 3.02 (1H, t, 8.08, H-3); dC 103.8 (C-1), 73.3 (C-5), 72.3
(C-2), 72.2 (C-3), 70.2 (C-4), 66.6 (C-6), 61.0 (C-7), 55.9 (Me); HRMS,
ESI-TOFþ, calcd for C8H16NaO7 (MþNa)þ: 247.0794; found: 247.0765.
(100
tervals for a total reaction time of 3.75 h. To facilitate the subsequent
analysis, 200 L of 67% aqueous acetonitrile solvent was added to the
reaction vessel prior to sample collection. The catalyst was then
decomposed by addition of 200 L (300 L) of 0.02 M (0.06 M)
mL) were collected from each reaction mixture at 45 min in-
m
m
m
aqueous sodium sulfide solution for a catalyst concentration of
1.5 mol % (5.0 mol %). The supernatant for each sample aliquot was
separated by centrifugation and subjected to GC analysis.
Acknowledgements
5.4.2. Methyl-
of the catalytically active species via addition of TEMPO, 100
3.31 M aqueous methyl- -glucopyranoside solution was added,
and the reaction was allowed to proceed at its corresponding re-
action temperature for 24 h. To facilitate the subsequent analysis,
b
-
D
-glucopyranoside as the substrate. After formation
mL of
A CAREER award from the National Science Foundation (CHE-
0746635) and a supplemental award (CHE-0938791) to S.S. for
partial support of this work are gratefully acknowledged; the help
of Ms Hae-In Kim during early stages of the project is highly
appreciated.
b-D
300
action vials. The catalyst was then decomposed by addition of
200 L (300 L) of 0.09 M (0.26 M) aqueous sodium sulfide solution
mL of 67% aqueous acetonitrile solvent was added to the re-
Supplementary data
m
m
for a catalyst concentration of 1.5 mol % (5.0 mol %). The superna-
tant of each sample was separated by centrifugation. Lastly, an
equal amount of 37% aqueous formaldehyde solution was added to
the centrifuged supernatant, and the resulting solution subjected to
analysis by ESI mass spectroscopy in positive ion mode, quantita-
tive HPLC on an amino column, and 1H and 13 C NMR spectroscopy.
GC analysis. The GC experiments were conducted as described
previously.12 In short, all oxidation experiments with allyl and
benzyl alcohols were monitored on a A14 gas chromatograph
(Shimadzu) with AOC-20 autoinjector and flame ionization de-
tector. Helium was used as a carrier gas, a Rtx-1 capillary column
Representative GC, HPLC, and mass spectrometric traces and
chromatograms observed during substrate oxidation. Supplemen-
tary data associated with this article can be found in online version
at doi:10.1016/j.tet.2010.07.077. This data include MOL files and
InChiKeys of the most important compound described in this
article.
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