DEAD-(cat)ZnBr2 an efficient system for the oxidation of alcohols to carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2009.01.080

The combination of diethyl azodicarboxylate (DEAD) and a catalytic amount of ZnBr₂ is an efficient system for the dehydrogenation of alcohols to the corresponding carbonyl compounds. The scope and limitations of this process have been studied.

Full text of DOI:10.1016/j.tetlet.2009.01.080

Tetrahedron Letters 50 (2009) 1493–1494
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
DEAD-(cat)ZnBr an efficient system for the oxidation of alcohols
2
to carbonyl compounds
Hai Thuong Cao, René Grée *
Université de Rennes 1, Laboratoire de Chimie et Photonique Moléculaires, CNRS UMR 6510, Avenue du Général Leclerc, 35042 Rennes-Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The combination of diethyl azodicarboxylate (DEAD) and a catalytic amount of ZnBr2 is an efficient sys-
tem for the dehydrogenation of alcohols to the corresponding carbonyl compounds. The scope and lim-
itations of this process have been studied.
Received 26 November 2008
Revised 12 January 2009
Accepted 14 January 2009
Available online 20 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Diethyl azodicarboxylate (DEAD) and its congeners are very
useful reagents in organic synthesis, especially regarding the Mits-
unobu reaction. It is known that DEAD alone can dehydrogenate
ketone in 90% and 84% yields, respectively. Of the different salts at-
tempted, ZnBr was found to be the most efficient and the most
convenient for the substrate alcohol chosen. With this latter salt,
the dehydrogenation of 1 is complete within 30 min.
The next step was to explore the possibility to use this mild Le-
wis acid salt in a catalytic manner. For that purpose, the same alco-
hol was used as a reference and the results are reported in Table 2.
2
1
various types of compounds (alcohols, thiols, hydroxylamines,
hydrazines for instance).2 The oxidation by DEAD, of alcohols to
carbonyl compounds, has been first reported on a limited number
3
of examples by the group of Yoneda. This is an interesting reaction
affording, as the only byproduct, diethyl hydrazodicarboxylate
(
2
DEADH ), which is easily separated by chromatography. Further-
more, this product could be recycled since reoxidation to DEAD
has also been reported.4 However, to the best of our knowledge,
this methodology has not been very often used in organic synthesis
until now. By analogy with the well-known Meerwein–Pondorf–
Verley/Oppenauer reactions,5 we can propose a simple pericyclic
mechanism for this reaction (Scheme 1): a six-membered cyclic
transition state could account for the transfer of the two hydrogen
EtO C
2
N
N
Δ
R1
O
H
O
EtO2C NH
R1
R2
CO Et
R2
2
+
HN CO2Et
H
EtO2C
H
N
Δ
R1
R2
EtO2C NH
HN CO2Et
N
+
R1
R2
CO2Et
O
6
atoms onto the azo molecule. Based on this tentative mechanism,
O H
LA
it appeared to us that this reaction could be catalyzed by an appro-
priate Lewis acid (LA). Complexation of the oxygen atom of the
alcohol should facilitate the cleavage of the OH bond and the
hydrogen transfer. This should contribute to have a faster reaction
occurring under milder conditions.
LA
Scheme 1. Postulated mechanism for the DEAD-mediated dehydrogenation and
our working hypothesis.
The purpose of this Letter is to demonstrate that the combina-
2
tion of DEAD with catalytic amounts of ZnBr indeed gives a simple
Table 1
and efficient process for the oxidation of various types of alcohols
under mild reaction conditions.
Screening of the salts used as mild Lewis acids
CO2Et
CO2Et
Salt
O
HN
NH
The first stage of this study was to validate this proposal and
perform a quick screening of the possible Lewis acids. This was
done by using phenyl-1-propanol 1 as a model. As indicated in Ta-
ble 1, various salts are indeed able to activate this reaction: in
refluxing toluene, the oxidation by DEAD alone is complete only
OH
C2H5
N
N
+
+
Ph
C2H5
Ph
EtO2C
EtO2C
Toluene, reflux
4
2
3
1
Entry
Salt (1 equiv)
—
Time (h)
Ketone 3 (yield) (%)
after 48 h, while in the presence of 1 equiv of MgBr
2
or CuBr
2
,
1
2
3
4
5
6
48
1
1
2
0.5
0.5
98
90
84
82
94
96
the reaction is finished after 1 h affording the corresponding
MgBr
CuBr
NiBr
2
2
2
InBr
3
*
Corresponding author. Tel.: +33 (0)2 23 23 57 15; fax: +33 (0)2 23 23 69 78.
ZnBr
2
E-mail address: rene.gree@univ-rennes1.fr (R. Grée).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.080

1
494
H. T. Cao, R. Grée / Tetrahedron Letters 50 (2009) 1493–1494
Table 2
ZnBr2 (0.1eq)
Toluene, reflux
O
OH
+
+
DEADH2
4'
Optimization of the amount of catalyst
DEAD
2'
Ph
C2H5
Ph
C2H5
Entry
ZnBr
2
(equiv)
Time (h)
Ketone 3 (yield) (%)
3
1
1
2
3
4
5
6
—
1
0.6
0.2
0.1
48
0.5
0.5
0.75
1
98
96
98
98
96
98
Scheme 2. Reaction with DEAD anchored on Merrifield’s resin.
a
–
At this stage, this reaction does not work with allylic or propar-
gylic alcohols since it leads to complex mixtures of products but
0.05
3
a
9
Under the same reaction conditions, diisopropyl azodicarboxylate (DIAD) gives
not to the desired carbonyl compounds.
the ketone 3 in 92% yield.
A final attractive possibility is to use DEAD anchored on a sup-
0
port 2 , since it would offer additional facility for the separation of
0
Table 3
the byproduct which will be the supported DEADH
2
4 (Scheme 2).
Extension to various types of alcohols
This reaction works indeed very well. By using 1 equiv of com-
mercially available DEAD supported on Merrifield resin, the reac-
tion is complete in 1.5 h affording the pure ketone 3 in 95% yield
CO2Et
CO2Et
ZnBr2 (0.1eq)
Toluene, reflux
O
HN
NH
OH
R2
N
N
+
+
10
R1
R2
after filtration and evaporation of the solvent.
R1
EtO2C
EtO2C
4
2
6
In conclusion, these preliminary results demonstrate that cata-
5
2
lytic amounts of ZnBr strongly catalyze the DEAD-mediated dehy-
drogenation of alcohols to carbonyl compounds. Extension of this
methodology is under active study in our group.
Entry
Alcohol 5
Time (h)
Carbonyl derivative 6
yield) (%)
(
1
2
3
4
PhCH
p-NO
2
OH
PhCH
1.5
1.5
1.5
2.5
90
91
92
90
2
2
OH
OH
Acknowledgments
p-MeOPhCH
t-BuCH OH
2
2
We thank CNRS and MESR for financial support. H.T.C. thanks
the Vietnamese government for a PhD thesis fellowship. We
acknowledge Dr. M. Capet, Professor V. Nair, Dr. A. T. Biju, and
Dr. S. Chandrasekhar for very fruitful discussions.
5
2.5
70
N
CH2OH
CH2OH
Cl
6
7
8
2
86
96
98
References and notes
N
Ph
2
CHOH
1.5
4
1. For recent reviews on Mitsunobu reaction see: (a) Dembinski, A. Eur. J. Org.
Chem. 2004, 2763–2772; (b) But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2, 1340–
1355 and references cited therein.
nC4H9
nC8H17
OH
2. Stoner, E. J. In Encyclopedia of Organic Reagents for Organic Synthesis; Paquette, L.
A., Ed.; John Wiley & Sons, 1995; pp 1790–1793.
3.
(a) Yoneda, F.; Suzuki, K.; Nitia, Y. J. Am. Chem. Soc. 1966, 88, 2328–2329; (b)
Yoneda, F.; Suzuki, K.; Nitia, Y. J. Org. Chem. 1967, 32, 727–729.
9
t Bu-cyclohexanol
OH
3.5
98
4. Moriarty, R. M.; Prakash, I.; Penmasta, R. Synth. Commun. 1987, 17, 409–413.
5.
Smith, M. B.; March, J. March’s Advanced Organic Chemistry Reactions,
Mechanisms, and Structure, 5th ed.; John Wiley & Sons, 2001.
6.
This tentative mechanism is based on the simple analogy of the p-system of the
azo group with a carbonyl group. Of course, alternative mechanisms could be
considered as well. For a new DEAD-mediated dehydrogenation of tertiary
amines, see: Xu, X.; Li, X.; Ma, L.; Ye, N.; Weng, B. J. Am. Chem. Soc. 2008, 130,
2
In fact ZnBr is an efficient catalyst since the oxidation of 1 is quan-
14048–14049.
titative even at the level of 5 mol % (entry 6). In the latter case, the
7
.
.
The reaction temperature is also important: by reacting 1 with 0.1 equiv of
ZnBr2 and 1 equiv of DEAD in toluene, the reaction is not complete after 2 days
at 80 °C and the isolated yield in ketone 3 is only 34%.
reaction duration is 3 h only.7
The next step was the extension of this reaction to other alco-
hols and to check its scope and limitations. For that purpose we se-
lected the following standard reaction conditions: DEAD (1 equiv)
8
Representative experimental procedure: To a solution of alcohol 1 (230 mg,
1
(
.7 mMol) in toluene (2.5 mL) are added DEAD 2 (294 mg, 1.7 mMol) and ZnBr
38 mg, 0.17 mMol). The solution is heated under reflux for 0.5 h. After removal
of the solvent under reduced pressure, SiO chromatography easily allows
separation of the ketone 3 (218 mg, 96% yield) and DEADH 4 (287 mg, 96%
yield). Compound 3: R ) d
= 0.57 (pentane/ether: 9:1). 1H NMR: (300 Hz, CDCl
ppm) 7.96–7.25 (m, 5H (HAr)), 3.00 (qd, J = 7.3 Hz, 2H (CH )), 1.21 (t, J = 7.3 Hz,
) d (ppm) 8.2, 31.7, 127.9, 128.5, 132.9, 136.9,
2
with ZnBr
in Table 3.
2
(10 mol %) in refluxing toluene. The results are reported
2
8
2
f
3
Several points are worthy of noted:
(
3
2
2
13
H(CH
3
)) C NMR: (75 Hz, CDCl
= 0.14 (pentane/ether: 9:1) H NMR (300 Hz, CDCl
)), 1.27 (t, J = 7.1 Hz, 6H (2CH
) d (ppm) 14.0, 61.9, 156.4. All other carbonyl derivatives
3
1
00.8. 4: R
f
3
) d (ppm) 6.62
)).
–
Excellent results are obtained with benzyl alcohol and substi-
tuted derivatives with electron-withdrawing, as well as elec-
tron-donating groups (entries 1–3). A very good yield is also
obtained with a sterically hindered alcohol (entry 4).
The reaction is compatible with heteroaromatic systems such as
pyridine or quinoline derivatives (entries 5 and 6).
It is possible to use it efficiently as well with diaryl- (entry 7) as
well as dialkyl-secondary alcohols (entry 8) or cyclohexyl deriv-
atives (entry 9).
(
br, 2H (2NH)), 4.20 (qd, J = 7.1 Hz, 4H (2CH
2
3
13
C NMR (75 Hz, CDCl
3
have spectral data in agreement with authentic samples and/or with literature
data.
9
.
It is well established that DEAD reacts in ene-type reactions with allylic
derivatives (see Ref. 2). Catalysis of this type of reaction by Lewis acids has
been also reported, see for instance: (a) Brimble, M. A.; Heathcock, C. H. J. Org.
Chem. 1993, 58, 5261–5263; (b) Aburel, P. S.; Zhuang, W.; Hazell, R. G.;
Jorgensen, K. A. Org. Biomol. Chem. 2005, 3, 2344–2349 and references cited
therein.
–
–
10. Another possibility would be the use of DEAD anchored on a fluorous support
since such reagents and their use have been reported recently. See for instance:
–
The reaction is slightly faster on the secondary alcohol 1 as com-
pared to corresponding primary benzyl alcohol: a competition
experiment using a 1:1 mixture of these two alcohols affords a
(
(
a) Dobbs, A. P.; McGregor-Johnson, C. Tetrahedron Lett. 2002, 43, 2807–2810;
b) Dandapani, S.; Curran, D. P. Tetrahedron 2002, 58, 3855–3864; (c) Chu, Q.;
Henry, C.; Curran, D. P. Org. Lett 2008, 10, 2453–2456. and references cited
1
.4:1 mixture of ketone 3 and benzaldehyde.
therein.