Tuning the oxidation properties of vanadium(V) through ligand stoichiometry

Article abstract of DOI:10.1016/j.tetlet.2006.06.051

Vanadium(V) (5 mol %) and hydroxamic acid ligand (45 mol %) were found to promote the selective tert-butyl hydroperoxide-mediated oxidation of allylic and propargylic alcohols to the corresponding aldehydes and ketones.

Full text of DOI:10.1016/j.tetlet.2006.06.051

Tetrahedron Letters 47 (2006) 5923–5926
Tuning the oxidation properties of vanadium(V) through
ligand stoichiometry
Wei Zeng, T. Eric Ballard and Christian Melander*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204, USA
Received 12 May 2006; revised 3 June 2006; accepted 8 June 2006
Available online 30 June 2006
Abstract—Vanadium(V) (5 mol %) and hydroxamic acid ligand (45 mol %) were found to promote the selective tert-butyl hydroper-
oxide-mediated oxidation of allylic and propargylic alcohols to the corresponding aldehydes and ketones.
Ó 2006 Elsevier Ltd. All rights reserved.
As an oxidation catalyst, vanadium mediates a wide
V(O-iPr)3 (5 mol%)
array of synthetic transformations, including the epoxid-
R1
OH
t
-BuOOH
R1
OH
O
O
ation of allylic alcohols, and the oxidation of activated
C–H bonds, sulfides, and primary/secondary alcohols.1
In each of these aforementioned cases, the scope of
the synthetic transformation (i.e., epoxidation vs oxida-
tion) has been dictated by the reaction conditions
and substrate identity. In this letter, we report an
alternative approach to controlling the reactivity of a
vanadium-based catalyst system through varying ligand
stoichiometry.
OH
R2
N
(7.5 mol%)
R3
R3
R2
O
V
O
O
R1
N
O
O
O
Scheme 1.
Allylic alcohols have been employed for decades as
model substrates for the investigation of novel epoxida-
tion catalysts. In this regard, a number of reports have
documented that vanadium(V), in combination with a
hydroxamic acid (HA) ligand (5.0 mol % metal and
7.5–15 mol % ligand) and tert-butyl hydroperoxide
(TBHP) will selectively catalyze the epoxidation of a
wide range of allylic alcohols into their corresponding
epoxy alcohols via the proposed peroxovanadium inter-
mediate2 depicted below (Scheme 1).3 We have discov-
ered that by increasing the stoichiometry of the HA
ligand, the course of this oxidation reaction can be fun-
damentally altered to produce metal complexes that no
longer perform epoxidation reactions but that selectively
oxidize4 allylic and propargylic alcohols to the corre-
sponding aldehydes and ketones with moderate yields
under mild conditions with a minimal quantity of the
metal catalyst.
Optimal conditions for this transformation were first
determined by studying the conversion of cinnamyl alco-
hol to cinnamyl aldehyde (Scheme 2). The yield of the
reaction was maximized by systematically investigating
the ligand/metal ratio, reaction solvent, reaction time,
reaction temperature, oxidant concentration, and cata-
lyst/substrate ratio. We found that we could achieve a
50% yield of cinnamyl aldehyde from cinnamyl alcohol
at room temperature in toluene by using 5 mol %
VO(O-iPr)3, 45 mol % N-hydroxy-N-methylbenzamide
1,5 and 150 mol % (1.5 equiv) of TBHP. In addition,
we observed that if the HA ligand, the TBHP, or the
vanadium(V) were omitted, no reaction occurred.
H
V(O-iPr)3 (5 mol%)
O
OH
t-BuOOH (1.5 eq)
O
OH
(1)
(45 mol%)
Ph
N
*
Corresponding author. Tel.: +1 919 513 2960; fax: +1 919 515
5079; e-mail: Christian_Melander@ncsu.edu
Scheme 2.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.051

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W. Zeng et al. / Tetrahedron Letters 47 (2006) 5923–5926
Table 1. The effect of ligand/metal ratio on vanadium-mediated
From these optimization experiments, we also deter-
mined the extent to which the ligand-to-metal ratio
(LMR) controlled the reactivity of this system. This data
is summarized in Table 1. At 7.5 mol % vanadium(V) and
11.3 mol % HA ligand 1 (LMR = 1.5), we achieved 65%
conversion to the epoxy alcohol (similar to the 70% yield
that was previously reported).3c With 7.5% vanadium(V)
and 22.5% we observed that the oxidation system started
to perform both allylic oxidation and epoxidation reac-
tions. The ratio of oxidation/epoxidation product in-
creased until the LMR reached 9, at which point only
oxidation was observable.
oxidation of cinnamyl alcohola
Entry Ligand/metal
ratio (mol/mol)
Yieldb (%)
H
OH
O
O
1
2
3
4
5
6
7
1.5
3.0
4.0
5.0
7.0
9.0
0
9
65 (70)c
32
21
13
<5
0
18
24
32
50
31
11
0
Next, the substrate scope of the reaction was established
by studying the oxidation of various primary and sec-
ondary alcohols to their corresponding aldehydes and
ketones. As can be seen from Table 2, this reagent com-
bination selectively oxidizes allylic and propargylic alco-
a Procedure identical to outlined in Ref. 9, only ligand concentration
was varied.
b Isolated yield after column chromatography.
c Yield in parenthesis is the previously reported yield.3c
Table 2. Catalytic oxidation of primary and secondary alcohols in the presence of vanadium/hydroxamic acid complex9
Entry
Substrate
Time (h)
Product
Yielda (%)
50
H
OH
1
48
O
O
2
3
4
72
48
24
28
0
OH
OH
H
H
O
O
OH
OH
46
N
N
H
5
6
48
48
44
41
O
H
OH
O
O
7
8
48
48
22
28
OH
O
O
H
H
H
OH
OH
O
O
9
24
48
14
66
N
N
H
OH
O
10
O2N
O2N
O
OH
11
72
67
H
a Isolated yield after column chromatography.

W. Zeng et al. / Tetrahedron Letters 47 (2006) 5923–5926
5925
hols to their corresponding aldehydes and ketones. No
epoxy alcohol could be detected under these reaction
conditions. We have compared the reactivity of primary
and secondary allylic alcohols (entries 1 and 2), and
have discovered that the primary alcohol is oxidized to
the corresponding aldehyde in higher yield in a shorter
time frame than the secondary alcohol (50% yield in
48 h vs 28% yield in 72 h). The vanadium/hydroxamic
acid complex does not oxidize primary alcohols that
are not allylic/propargylic (entry 3), and is tolerant to
pyridine functionality (entry 4). Propargylic substrates
(entry 11) or substrates with a conjugated electron with-
drawing substituent (entry 10) were oxidized in the high-
est yield. Analysis of the efficiency in which our
substrates are oxidized indicates that both steric and
electronic effects govern the oxidation system. Increas-
ing the steric hindrance of the allylic alcohol at Ca leads
to a substantial decrease in product yield (entries 1 and
2), while decreasing the steric hindrance of the substrate
at Ca leads to improved oxidation yield (entries 1 and
11). Electronic effects also play a key role in this catalyst
sytem, as increasing the electron density of the allylic
double bond leads to decreased product yield, while
electron deficient substrates enhance oxidation perfor-
mance (entries 1, 9, and 10).
alcohol to complex 2 with concomitant displacement of
the final isopropoxide ligand to provide the active com-
plex 3. Oxidation of the substrate mediated by tert-butyl
hydroperoxide via a 1eÀ process generates the desired
aldehyde and regenerates the catalyst for further oxida-
tion cycles. However, further mechanistic studies are
necessary to validate the proposed catalyst cycle.
In conclusion, we have shown that the course of a vana-
dium-based oxidation reaction can be controlled
through simple ligand stoichiometry. Since both steric
and electronic factors dictate product yield, current
efforts are centered on using modified hydroxamic acid
ligands to improve reaction yields and substrate scope.
We are also exploring the potential of alternative ligands
to allow the use of molecular oxygen as the oxidant, and
will report our studies in due course.
Acknowledgments
The authors would like to thank North Carolina State
University for funding, NMR, and mass spectrometry.
Mass spectra were obtained at the Mass Spectrometry
Laboratory for Biotechnology at North Carolina State
University. Partial funding for the NCSU Facility was
obtained from the North Carolina Biotechnology
Center and the NSF.
Based upon early observations that epoxidation is inhib-
ited by excess HA ligand,6 the elevated concentration of
the hydroxamic acid ligand most likely forces the vana-
dium to accommodate an additional HA ligand, leaving
only one site available for coordination (vs two coordi-
nation sites for the epoxidation catalyst) (Fig. 1).
Vanadium-based oxidations of alcohols to their corre-
sponding carbonyl derivatives typically proceed via a
1eÀ process,7 so a possible mechanism for this reaction
is outlined in Scheme 3. Initially, the HA ligands displace
the isopropoxide ligands to form complexes of type 2.
Given the well documented weak affinity of TBHP for
vanadium(V) complexes,8 we propose that the subse-
quent coordination occurs via addition of the allylic
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.06.051.
References and notes
1. For reviews on vanadium-mediated oxidations, see: (a)
Bortolini, O.; Conte, V. J. Inorg. Biochem. 2005, 99, 1549–
1557; (b) Bolm, C. Coord. Chem. Rev. 2003, 237, 245–256;
(c) Butler, A.; Clague, M. J.; Meister, G. E. Chem. Rev.
1994, 94, 625–638, and references cited therein.
O
V
R3
R2
Ph
O
O
O
O
O
O
O
N
N
V
OR
N
OR
Ph
OR
2. Bryliakov, K. P.; Talsi, E. P.; Kuhn, T.; Bolm, C. New J.
Chem. 2003, 27, 609–614.
Epoxidation
Catalyst
Oxidation
Catalyst
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epoxidations, see: (a) Michaelson, R. C.; Palermo, R. E.;
Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 1990–1992; (b)
Hoshino, Y.; Murase, N.; Oishi, M.; Yamamoto, H. Bull.
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Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamam-
oto, H. Angew. Chem., Int. Ed. 2005, 44, 4389–4391, and
references cited therein.
4. For examples of other vanadium-based oxidation systems,
see: (a) Velusamy, S.; Punniyamurthy, T. Org. Lett. 2004, 6,
217–219; (b) Maeda, Y.; Washitake, Y.; Nishimura, T.;
Iwai, K.; Yamauchi, T.; Uemura, S. Tetrahedron 2004, 60,
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Ochiai, Y.; Takizawa, S.; Takahata, H.; Nemoto, H. Chem.
Figure 1.
O
V
Ph
O
O
O
O
N
(2)
N
Ph
O
OR
X
t
X
OH
+
H2O
H
HOR
-ButylOOH
O
V
Ph
O
O
O
N
N
O
Ph
X
O
(3)
Scheme 3.

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W. Zeng et al. / Tetrahedron Letters 47 (2006) 5923–5926
Commun. 1999, 1387–1388; (f) Kaneda, K.; Kawanishi, Y.;
9. General experimental procedure for catalytic oxidation: To
a solution of the hydroxymate complex of vanadium readily
prepared from N-hydroxy-N-methylbenzamide (50 mg,
0.33 mmol) and VO(O-iPr)3 (38 lmol, 9 lL) in 6 mL of
dry toluene (25 °C, 1 h) were added cinnamyl alcohol
(104 mg, 0.776 mmol) and t-BuOOH (1.14 mmol, 228 lL,
5.0 M) at À20 °C under an Ar atmosphere. The solution
was stirred at À20 to 0 °C for 4 h, the solution allowed to
warm to 25 °C and stirred for 48 h. The reaction was
distilled to dryness in vacuum, and chromatography of the
residue on silica gel gave 51 mg cinnamyl aldehyde (50%
yield).
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