Regioselective Catalytic Dehydrogenation of Aldehydes and Ketones

Full text of DOI:10.1021/jo980112x

5640
J . Org. Chem. 1998, 63, 5640-5642
Our preliminary investigation of the scope of this
rection indicated that, while aldehydes and cycloal-
kanones are reactive, neither simple acyclic ketones, nor
esters, lactones, and nitriles were reactive in the above
reaction. This behavior may conceivably be related to
the higher acidity8 of the R-H atoms of aldehydes and
cycloalkanones relative to acyclic ketones, esters, and
nitriles, assuming that the enolization of the carbonyl
compound is associated with the rate-determining step
of the deydrogenation reaction. This assumption will be
checked in future mechanism studies. The presence of
triphenylphosphine did not affect the reaction. No black
Pd deposit could be observed during the reaction.
Regioselective Ca ta lytic Deh yd r ogen a tion
of Ald eh yd es a n d Keton es
Youval Shvo* and Anan Haj Ichia Arisha
School of Chemistry, Raymond and Beverly Sackler School
of Exact Sciences, Tel Aviv University,
Tel Aviv, 69978, Israel
Received J anuary 22, 1998
A simple one-step reaction inducing regioselective
introduction of a double bond into an aliphatic molecular
framework is a desirable synthetic tool.
Selective dehydrogenation is an important reaction in
organic chemistry as well as in biochemical processes,
with chloranil and DDQ being the classic and useful
stoichiometric dehydrogenation reagents in organic chem-
istry. Substitution reactions of the R-position of ketones
with halogens,1 sulfur,2 and selenium3 groups, with
subsequent elimination of these groups, are stoichiomet-
ric and cumbersome procedures for the preparation of
R,â-unsaturated ketones.
Certain transition metal complexes catalyze dehydro-
genation reactions of saturated ketones to R,â-unsatur-
ated ketones. Among those are the Pd(OAc)2/Cu(II)/O2
dehydrogenation system4 applied directly to ketones, and
Pd-phosphine complexes acting indirectly on the silyl
enol ethers of aldehydes and ketones in the presence of
allyl carbonate,5 and on allyl enol carbonates.6
We have discovered a new reaction condition whereby
aldehydes and cyclic ketones are directly transformed
into their R,â-unsaturated derivatives with moderate to
good yields, under mild conditions with no prior deriva-
tization and in the absence of oxygen. The reaction con-
sisted of heating a THF (or DMF) solution of the satu-
rated carbonyl compound, allyl diethyl phosphate (ADP),
and sodium carbonate (or sodium bicarbonate) in the
presence of 4 mol % Pd(OAc)2 to yield the desired product.
The progress of the reaction was monitored by GC. The
reaction products (known compounds) were identified by
NMR, IR, and MS, and by comparison with authentic
samples. The stoichiometry of the reaction, exemplified
with aldehyde and a ketone, is shown in Scheme 1.
Propylene was determined by trapping the evolved gas
in Br2/CCl4 solution.7 The stereochemistry of the conju-
gated double bond was established by 1H NMR spin
decoupling experiments. The results of various experi-
ments are presented in Table 1.
The formation of phenyl allyl ether as a byproduct in
expt 2 (Table 1) indicates that the primary product,
cyclohexenone, is being further dehydrogenated to give
phenol, which in the basic reaction solution is being
allylated by the ADP to give the phenyl allyl ether. This
was further demonstrated in expt 3 by prolonging the
reaction time, and in expt 6 where excess ADP and
prolonged reaction time generated the phenyl allyl ether
as the main reaction product, as shown in Scheme 2. All
of the above compounds were detected by GC during the
progress of the reaction. As formulated above, 3 mol of
ADP are required to obtain the final product. This has
been also demonstrated with R-tetralone (expt 8) using
a 2.7/1 molar ratio of ADP/R-tetralone, which resulted
in the formation of allyl 1-naphthyl ether with high
selectivity. It should be noted that ADP/sodium carbon-
ate ratio was always kept at least at a 1:1 ratio.
Thus, the above reaction provides a simple, catalytic,
good yield route for the conversion, under mild conditions,
of cyclohexanone, and substituted cyclohexanones, di-
rectly to phenyl allyl ethers.
The 2- and 4-methyl-substituted cyclohexanones were
also studied briefly (expts 4 and 5). The reaction with
2-methylcyclohexanone proved to be nonselective (expt
5), inasmuch as the two isomeric products were formed
in a ratio of ca. 1:2.
An additional interesting aspect of the above reaction
system is its capacity to catalytically oxidize alcohols to
ketones. Thus, cyclohexanol, with excess ADP, was also
transformed into phenyl allyl ether (expt 7). This
demonstrates that cyclohexanols can also be used as the
starting materials for the aromatic ethers.
In the same fashion, the 3-hydroxy group of cholesterol
was converted to the ketone under the standard reaction
conditions (Table 1, expt 9), followed by the introduction
of two double bonds, consequently forming cholesta-1,4,6-
trien-3-one in 75% isolated yield, as shown in Scheme 3.
A 3/1 ratio of ADP/cholesterol had to be used, since lower
ratios resulted in a mixture of products. The ready
dehydrogenation of the steroidal system is significant.
Both allyl diethyl phosphate (ADP) and sodium car-
bonate (or bicarbonate) were found, by control experi-
ments, to be essential for the above reaction. Noteworthy
are the findings that, neither allyl alcohol, nor allyl
acetate, carbonate, tosylate, and bromide induce the
above reaction in THF. Thus allyl phosphate is a critical
component of this new reaction.
Three saturated aldehydes were examined (expts 10-
12), all resulting in the formation of the corresponding
R,â-unsaturated aldehydes in 55-59% yield (THF). In
a larger scale experiment, 2-octenal, derived from octanal,
(1) Stotter, P. L.; Hill, K. A. J . Org. Chem. 1973, 38, 2576.
(2) Trost, B. M.; Salzmann, T. N.; Hirori, K. J . Am. Chem. Soc. 1976,
98, 4887.
(3) Reich, H. J .; Renga, J . M.; Reich, L. I. J . Org. Chem. 1974, 39,
2133.
(4) Theissen, R. J . J . Org. Chem. 1971, 36, 752.
(5) Minami, I.; Takahashi K.; Shimizu, I.; Kimura, T.; Tsuji, J .
Tetrahedron 1986, 42, 2971.
(8) March, J . Advanced Organic Chemistry, 4th ed.; Wiley-Inter-
science: New York, 1992; Chapter 8, p 250 and Streitwieser, A.;
Heathcock, C. H.; Kosower, E. M. Introduction to Organic Chemistry,
4th ed.; Macmillan: New York, 1992; Chapter 15, p 422.
(6) Shimizu, I.; Minami, I.; Tsuji, J . Tetrahedron Lett. 1983, 24, 1797.
(7) 1,2-dibromopropane was identified by 1H-NMR.
S0022-3263(98)00112-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/23/1998

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5641
Sch em e 1
Ta ble 1.a . Exp er im en ta l Da ta for Deh yd r ogen a tion Rea ction s w ith P d (OAc)2
time convb
expt
allyl/base (mmol)
substrate (mmol)
(h)
(%)
products (yield %)b
1
2
3
4
5
ADP (5) Na2CO3 (6)
ADP (5) Na2CO3 (6)
ADP (5) Na2CO3 (6)
ADP (5) Na2CO3 (6)
ADP (5) Na2CO3 (6)
cyclopentanone (5)
cyclohexanone (5)
cyclohexanone (5)
4-methylcyclohexanone (5) 21
2-methylcyclohexanone (5) 21
21
5
24
86 2-cyclopenten-1-one (63)
61 2-cyclohexen-1-one (71), allyl phenyl ether (3.3)
79 2-cyclohexen-1-one (59), phenol (4.3), allyl phenyl ether (5.6)
82 4-methyl-2-cyclohexen-1-one (73)
42 6-methyl-2-cyclohexen-1-one (53), 2-methyl-2-
cyclohexen-1-one (24)
6
7
8
ADP (10) Na2CO3 (12)
ADP (13.5) Na2CO3 (15) cyclohexanol (2.5)
ADP (13.5) Na2CO3 (13) R-tetralone (5)
ADP (5.85) Na2CO3 (7)
ADP (5) NaHCO3 (6)
ADP (5) NaHCO3 (6)
ADP (5) NaHCO3 (6)
cyclohexen-3-one (5)
21
43
16
40
19
16
16
23
5
79 allyl phenyl ether (67), phenol (6)
95 allyl phenyl ether (44), 2-cyclohexen-1-one (10), phenol (3.3)
97 allyl 1-naphthyl ether (59), 1-naphthol (1.7)
100 cholesta-1,4,6-trien-3-one (75)
97 2-octenal (59)
94 2-decenal (57)
9
cholesterol (1.67)
octanal (5)
decanal (5)
pentanal (5)
cyclohexanone (5)
octanal (5)
10
11
12
92 2-pentenal (55)
13a AMC (11) K2CO3 (13)
98 phenol (30), 2-cyclohexen-1-one (2.5), phenyl allyl ether (4.7)
85 2-octenal (42)
14a ADP (5) NaHCO3 (6)
15
ADP (5) NaHCO3 (6)
citral (5)
20
88c 3,7-dimethyl-2,4,6-heptatrienal (32)c
a
Reaction conditions: reactions 1-12 and 15 were carried out in THF (4 mL), and reactions 13 and 14 in DMF (4 mL). 4 mol % of
b
Pd(OAc)2 with respect to substrates was used in all experiments. All reactions were carried out at 86 °C under argon. Conversions and
yields were determined quantitatively by an internal standard method using gas chromatography and are accurate to (5%. The product
of expt 9 was isolated by column chromatography (see Experimental Section). c The conversion and yield of this experiment were estimated
from the appropriate GC peak areas.
Sch em e 2
Sch em e 3
was isolated in 50% yield after distillation (see Support-
ing Information). The main byproducts of these reactions
are the allyl esters of the respective acids of the alde-
hydes. Their mode of formation has not yet been
determined. The use of sodium bicarbonate rather than
carbonate with aldehydes gave better yields of the
dehydrogenated aldehydes.
F igu r e 1. Rates of formation of octen-2-al in THF and DMF
with allyl diethylphosphate.
No reaction could be observed with cyclohexanone by
replacing the allyl diethyl phosphate (ADP) with allyl
methyl carbonate (AMC) in THF. However, using AMC,
and also replacing the solvent THF by DMF, resulted in
the conversion of cyclohexanone to mainly phenol with
30% yield (expt 13). This solvent effect was further
investigated with octanal. In Figure 1, the rate of
dehydrogenation of octanal with ADP in the two solvents,
under identical conditions (see expt 10, Table 1), was
compared. Clearly the reaction is significantly faster in
DMF than in THF, where a reaction induction period was
noted. The above rate difference may be attributed to
the greater solubility of the carbonate salt in the more
polar DMF reaction solution. However, the observed
increase in the rate of formation of the allyl octanoate
byproduct in DMF resulted in a lower yield compared to
THF (expts 10 and 14, Table 1).

5642 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
Gen er a l P r oced u r e. A general procedure is exemplified
using experiment 1. To a 50 mL round-bottom flask equipped
with a condenser and magnetic stirrer under argon were added
sodium carbonate (0.64 g; 6 mmol), diethyl allyl phosphate (0.97
g; 5 mmol), THF (4 mL), cyclopentanone (0.42 g; 5 mmol), and
Pd(OAc)2 (0.045 g; 0.2 mmol). The flask was heated with stirring
under argon in an oil bath at 86 °C for 21 h. After cooling, the
reaction mixture was quantitatively analyzed by GC using
n-decane as internal standard to give unreacted cyclopentanone
(0.052 g; 86% conv) and 2-cyclopenten-1-one (0.188 g; 63% yield).
2-Cyclopenten-1-one was identified by repeating the above
experiment throughout and then adding methylene chloride (20
mL) to the final reaction mixture, washing the organic solution
with water (2 × 20 mL), drying over MgSO4, and evaporating
the solvents to give a residue. GC/MS: m/z, M+ (82). IR ν
Sch em e 4
The introduction of a double bond in the 6,7 position
of cholesterol implies that the present dehydrogenation
reaction system may also be reactive with carbon atoms
other than those R to a carbonyl group. This assumption
was tested and verified with citral as a substrate accord-
ing to reactions shown in Scheme 4. A rather complex
mixture (not separated) was obtained, in which the triene
(isomers), identified by GC-MS, was formed in 32% (GC
area).
No mechanism study for the dehydrogenation reaction
described herein has yet been conducted. However, in
any mechanism, a π-allyl palladium diethyl phosphate9
complex intermediate must be invoked. Indeed, a 1H
NMR experiment with an equimolar quantities of Pd-
(PPh3)4 and allyl diethyl phosphate in benzene-d6 indi-
cated the fast disappearance of the resonance lines of the
latter, and the appearance of new higher field signals.
The unique and unexpected feature of the present reac-
tion is that no allylation products of the carbonyl
compounds could be detected. Thus, if an R carbon atom
nucleophile is involved, it avoids reacting with the allyl
moiety, but attacks exclusively the Pd atom of the π-allyl
Pd complex.
In conclusion, the novel catalytic reaction described
herein results in the direct regioselective dehydrogena-
tion of aldehydes and cyclic ketones, in a straightforward
manner with moderate to good yields. No prior deriva-
tization5,6 of the substrates is necessary. The circumven-
tion of the use of oxygen4 is of particular importance for
the dehydrogenation of aldehydes which are susceptible
to oxygen, as well as for other oxygen-sensitive functional
groups which may be present in a carbonyl substrate.
No extensive parametrization has been carried out yet.
An effort will be made to apply this reaction to acylic
ketones as well.
(CCl4): 1716 cm-1
.
1H NMR (δ): 7.75 (dd, J ) 6 Hz, 2.8 Hz,
1H); 6.22 (dt, J ) 4 Hz, 2 Hz, 1H); 2.72 (m, 2H); 2.36 (m, 2H),
conforming to a published spectrum.11
The same procedure and quantities of reactants were used
with aldehydes, but sodium carbonate was replaced with sodium
bicarbonate.
E xp er im en t 9. To a 50 mL round-bottom flask equipped
with a condenser and magnetic stirrer under argon were added
sodium carbonate (0.742 g; 7 mmol), diethyl allyl phosphate (1.13
g; 5.85 mmol), Pd(OAc)2 (0.015 g; 0.07 mmol), THF (4 mL); and
cholesterol (0.644 g; 1.67 mmol). The flask was heated with
stirring under argon in an oil bath at 86 °C for 40 h. After
cooling, methylene chloride (20 mL) was added, and the organic
solution was washed with water (2 × 20 mL), dried over MgSO4,
and then evaporated to dryness. TLC of the residue indicated
total absence of the starting material and consisted of single spot.
The residue was chromatographed on silica using methylene
chloride:petroleum ether as eluent and increasing their ratio
from 1:1 to pure methylene chloride. The emerging yellow solid,
cholesta-1,4,6-trien-3-one, (0.47 g; 75% yield) gave a single spot
on TLC. Mp 80-82 °C (lit.12 82-83 °C). MS: m/z 380 (M+),
365, 267, 247, 173, 159, 133, 119, 107. IR ν (CCl4): 1659 cm-1
.
1H NMR (δ): 7.08(d, J ) 10 Hz, 1H); 6.14(m, 4H); 1.19(s, 3H);
0.78(s, 3H), conforming to a published spectrum.13
Exp er im en t 15. Workup of the reaction mixture according
to the general procedure described in expt 1 gave a liquid
mixture. GC/MS: m/z, M+ (150) and additional peaks. No
separaton was attempted; conversion (86%) and yield (32%) were
estimated from GC peak areas.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, GC, GC/
MS, and IR data are presented to support characterization of
products from experiments 4, 5, 10, 11, and 12, Table 1 (1
page). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Exp er im en ta l Section
J O980112X
Gen er a l. Data regarding the quantities of the reactants and
solvents, reaction temperature and duration, as well as percent
conversions and yields are given in Table 1 and its accompanied
footnotes.
(11) The Aldrich Library of NMR Spectra, 1st ed.; Vol. I, p 687A.
(12) Djerassi, C.; Rosenkranz, G.; Romo, J .; Kaufmann, S.; Patakai,
J . J . Am. Chem. Soc. 1950, 72, 4534.
Allyl diethyl phosphate (ADP) was prepared from the com-
mercially available diethyl chlorophosphate and allyl alcohol.10
The following experiments are numbered according to the
numbers in Table 1.
(13) Brown, F. J .; Djerassi, C. J . Org. Chem. 1981, 46, 954.
(14) Barieux, J . J .; Gore, J .; Richer, J . C. Bull. Soc. Chim. Fr. (Part
II) 1974, 1020.
(15) Reich, H. J .; Renga, J . M.; Reich, I. L., J . Am. Chem. Soc. 1975,
97, 5434. Purohit, P. C.; Sonawane, H. R. Tetrahedron 1981, 37, 873.
(16) Corey, E. J .; Erickson, B. W.; Noyori, R. J . Am. Chem. Soc. 1971,
93, 1724.
(9) Murahashi, S.-I.; Imada, Y.; Taniguchi, Y.; Higashiura, S. J . Org.
Chem. 1993, 58, 1538.
(10) Guijarro, D.; Manchefio, B.; Yus, M. Tetrahedron 1994, 50, 8551.
(17) The Aldrich Library of NMR Spectra, 1st ed.; Vol. I, p 739B.
(18) The Aldrich Library of NMR Spectra, 1st ed.; Vol. I, p 735C.