Hypervalent iodine/TEMPO-mediated oxidation in flow systems: A fast and efficient protocol for alcohol oxidation

Article abstract of DOI:10.3762/bjoc.9.162

Hypervalent iodine(III)/TEMPO-mediated oxidation of various aliphatic, aromatic and allylic alcohols to their corresponding carbonyl compounds was successfully achieved by using microreactor technology. This method can be used as an alternative for the oxidation of various alcohols achieving excellent yields and selectivities in significantly shortened reaction times.

Full text of DOI:10.3762/bjoc.9.162

Hypervalent iodine/TEMPO-mediated oxidation in
flow systems: a fast and efficient protocol
for alcohol oxidation
Nida Ambreen, Ravi Kumar and Thomas Wirth*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1437–1442.
Cardiff University, School of Chemistry, Park Place, Cardiff CF10
doi:10.3762/bjoc.9.162
3AT, UK
Received: 17 May 2013
Accepted: 28 June 2013
Published: 17 July 2013
Email:
Thomas Wirth* - wirth@cf.ac.uk
*
Corresponding author
This article is part of the Thematic Series "Chemistry in flow systems III".
Guest Editor: A. Kirschning
Keywords:
alcohols; carbonyl compounds; flow chemistry; microreactor; oxidation
©
2013 Ambreen et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Hypervalent iodine(III)/TEMPO-mediated oxidation of various aliphatic, aromatic and allylic alcohols to their corresponding car-
bonyl compounds was successfully achieved by using microreactor technology. This method can be used as an alternative for the
oxidation of various alcohols achieving excellent yields and selectivities in significantly shortened reaction times.
Introduction
Oxidation of alcohols to carbonyl compounds plays an radical TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) as a
important role in organic chemistry. The transformation is tradi- catalyst in the oxidation of alcohols has gained much attention
tionally achieved by using chromium-based reagents such in recent years [10-12]. The redox cycle involves beside
as the Collins reagent, activated manganese dioxide, or pro- TEMPO also the corresponding hydroxylamine and the oxoam-
cedures known as the Swern [1], Pfitzner–Moffatt [2] or monium cation, which oxidizes the alcohol and is converted to
Parikh–Doering oxidation [3]. In synthetic chemistry, selective TEMPO–H [13]. Hypervalent iodine(III) reagents in combina-
methods for the oxidation of alcohols are highly sought after, tion with a catalytic amount of TEMPO have already been
and methods with the ability to differentiate between various reported in highly selective oxidations of alcohols to carbonyl
functional groups are desired. The use of hypervalent iodine compounds [14].
reagents in organic chemistry has increased during recent years
[
4-6]. Hypervalent iodine compounds in general have emerged The development of efficient flow-reactor systems for
as versatile oxidizing agents with compounds such as DMP molecular transformations is an important area in organic syn-
Dess–Martin periodinane) and IBX finding regular utility as thesis. The introduction of more general platforms to perform
highly selective oxidizing agents [7-9]. The use of the nitroxyl reactions under continuous flow rather than in batch mode has
(
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Beilstein J. Org. Chem. 2013, 9, 1437–1442.
led to improvements regarding safety and sustainability. tion started by combining this mixture with the solvent stream
Microreactor technology can be beneficial over classical of a second syringe containing the catalyst TEMPO.
approaches in a variety of chemical reactions. Many reactions
can benefit from the properties of microreactors. Enhanced
mass- and heat transfer and short diffusion distances can lead to
better yields within shorter reaction times [15]. Herein, we
describe the development of continuous-flow systems using
hypervalent iodine reagents in the TEMPO-mediated oxidation
of alcohols with the advantage of significantly shortened reac-
tion times. Several other oxidative processes have already been
reported in flow chemistry [16].
Figure 1: Flow setup for alcohol oxidations.
Results and Discussion
Benzyl alcohol was chosen as a substrate in order to examine
the efficiency of the reaction and the microreactor flow system. The reactions have been performed at 35 °C. With a residence
In a batch reaction, the mixture of benzyl alcohol (1a) and time of 30 s the conversion to benzaldehyde was determined by
(
diacetoxyiodo)benzene (2) did not show any reaction after stir- GC to be 52%. Increasing the residence time to 1 min, 2 min
ring for 12 h in dichloromethane at 35 °C. The addition of a and 4.5 min led to conversions of 65%, 79% and 95%, respect-
catalytic amount TEMPO to the reaction mixture led to a rapid ively. The reaction is incomplete if performed with amounts
conversion to benzaldehyde (3a). For initial investigations of a below 5 mol % of TEMPO (1 mol % TEMPO: 67% conversion,
flow system, a simple setup consisting of two syringes driven 2 mol % TEMPO: 81% conversion). Therefore all experiments
by a syringe pump, a T-connector and a tubing reactor (PTFE were performed with at least 5 mol % TEMPO catalyst.
tubing, length: 4 m, internal diameter: 0.75 mm) was used for
the oxidation of benzyl alcohol to benzaldehyde. The tubing To extend the substrate scope, various benzylic, aliphatic and
reactor was inserted in a water bath at constant temperature as allylic alcohols were investigated. Good yields at short reaction
shown in Figure 1. In all flow experiments, the alcohol sub- times and a high selectivity towards the oxidized products were
strate 1 and oxidant 2 were mixed in one syringe, and the reac- observed as shown in Table 1. Over-oxidation to the corres-
Table 1: Products and yields in the oxidation of alcohols performed in a tubing reactor at a total flow rate of 0.4 mL/min (residence time: 4.5 min)
at 35 °C.
Entry
1
Alcohol
Product
Referencea Conversion (%)b Yield (%)c
[17]
[18]
100
99
49
79
2
3
4
[19]
[17]
100
99
95
82
5
[20]
96
51
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Beilstein J. Org. Chem. 2013, 9, 1437–1442.
Table 1: Products and yields in the oxidation of alcohols performed in a tubing reactor at a total flow rate of 0.4 mL/min (residence time: 4.5 min)
at 35 °C. (continued)
6
[21]
97
75
7
8
9
[17]
[22]
[17]
80
89
96
48
61
76
1
0
1
2
[17]
[23]
[24]
97
89
97
87
–
1
1
100
1
3
4
[25]
[26]
56
87
–
–
1
15
[27]
100
–
16
17
18
[28]
[19]
[29]
87
88
91
–
–
–
1
9
0
[30]
[31]
77
–
–
2
95
21
[32]
100
–
2
2
3
[33]
[33]
n.d.
n.d.
52
40
2
aSpectral properties consistent with literature data. bConversions determined by GC. n.d.: not determined. cIsolated yields.
ponding carboxylic acids was not detected and high selectiv- of 4.5 min was then used to convert also a larger amount of
ities were obtained.
benzyl alcohol (15 mmol) to benzaldehyde, which was isolated
as the reaction product in 49% yield. These results provide
In larger scale reactions (0.5 g), the conversion monitored by further evidence that this flow process is effective for oxidation
GC was nearly quantitative. Isolated yields were lower than methods initially discovered and developed under batch condi-
those indicated by GC and largely reflect losses from isolation tions. The substrate scope of the catalytic method in this flow
procedures for individual products. The optimized reaction time process reflects that of the method originally developed in
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Beilstein J. Org. Chem. 2013, 9, 1437–1442.
General procedure for the alcohol oxidation
batch. N-Boc protected (S)-phenylalaninol [34] (Table 1,
entry 22) was oxidized to the corresponding aldehyde [35] in flow
without loss of optical purity as determined by the optical rota- Solutions of (diacetoxyiodo)benzene (1.1 equiv) and the alcohol
tions of starting material and product [36]. N-Boc protected (S)- (50 mg) in CH2Cl2 (1.5 mL) and 2,2,6,6-tetramethyl-1-
phenylglycinol [37] (Table 1, entry 23) suffered from some piperidinyloxyl (TEMPO) (5–10 mg, 10–20 mol %) in CH2Cl2
optical degradation probably during the work-up [38]. Alde- (1.5 mL) were loaded in two syringes. Both syringes were
hydes are rarely target molecules of pharmaceutical synthesis. placed in a syringe pump (Fusion 100) and connected via a
These functional groups rather represent highly useful inter- T-piece to a tubing reactor (PTFE, length: 4 m, internal
mediates for subsequent reactions. The addition of 1,2- diameter: 0.75 mm). The tubing reactor was immersed in a ther-
diaminobenzene to the crude oxidation product of 2,3-butane- mocontrolled water bath at 35 °C. The total flow rate was
diol (Table 1, entry 19) allowed the direct and almost quantitat- adjusted to 0.4 mL min–1 resulting in a residence time of
ive synthesis of 2,3-dimethylquinoxaline with para-toluenesulf- 4.5 min. The reaction mixture exiting the flow reactor was
onic acid as catalyst in the subsequent condensation reaction quenched with water and, after completion of the reaction,
performed in a batch system (Scheme 1) [39] The extracted with CH2Cl2. The combined organic layers were dried
oxidation–condensation sequence described here generates over magnesium sulfate and the solvents were removed in
almost no byproducts except iodobenzene which can be vacuo. Direct analysis with GC allowed the determination of the
removed very easily during the chromatographic purification of conversion by comparison of the product peak with the peak of
the product and should enable direct progression to the the starting alcohol.
subsequent synthetic steps, without the need for isolation or
Large scale oxidation of benzyl alcohol in
purification of the intermediate aldehyde or ketone.
flow
Conclusion
The reaction was performed with the Vapourtec E-Series using
In conclusion, a highly efficient and selective continuous-flow a PFA tubing reactor. Benzyl alcohol (2 g, 18.5 mmol) and
reaction for the oxidation of different alcohols was developed. (diacetoxyiodo)benzene (6.3 g 19.5 mmol) were dissolved in
Apart from short reaction times, high conversions and CH2Cl2 (120 mL). 2,2,6,6-Tetramethyl-1-piperidinyloxyl
excellent selectivities were obtained. These features, together (TEMPO) (160 mg, 1 mmol) was dissolved in CH2Cl2
with the low toxicity of the reagents, make the process (120 mL). Both solutions (flow rates: 2 mL min–1 each) were
attractive compared to the batch reaction. The economical and mixed in a T-piece before entering the tubing reactor (volume:
benign oxidation is broadly applicable to a wide range of alco- 10 mL) resulting in a residence time of 5 min. After constant
hols.
flow had been achieved, 200 mL of the reaction solution was
collected in a flask containing water (20 mL) as a quenching
agent. After completion of the reaction, the organic phase was
Experimental
General: 1H NMR and 13C NMR spectra were recorded on a removed and the aqueous phase was extracted with CH2Cl2
AV-400 Bruker spectrometer by using the solvents indicated (3 × 20 mL). The combined organic layers were dried over
with 400 and 100 MHz, respectively. All reactions were magnesium sulfate, and the solvents were removed in vacuo.
monitored by thin-layer chromatography that was performed on The crude reaction mixture was purified by flash chromatog-
precoated sheets of silica gel 60. GC analyses were performed raphy on silica using hexane/ethyl acetate (9:1) as eluent. Some
on a GC-FID (Varian 3900) chromatograph. All purchased benzaldehyde was lost during the drying processes and 0.8 g
chemicals were used without further purification.
(7.5 mmol, 49%) was isolated.
Scheme 1: Oxidation–condensation sequence in the synthesis of 2,3-dimethylquinoxaline.
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Beilstein J. Org. Chem. 2013, 9, 1437–1442.
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