Unsymmetrical unsaturated ketones from lactones and carboxylic acids in one step

Article abstract of DOI:10.1002/hlca.200490154

A one-step transformation of γ- and δ-(spiro)lactones into γ,δ- and δ,ε-unsaturated ketones in the presence of carboxylic acids in the vapor phase at 400° over a supported manganese catalyst is reported for the first time. The scope of this new transformation is exemplified with a series of lactones, and a mechanistic rationale is proposed.

Full text of DOI:10.1002/hlca.200490154

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Helvetica Chimica Acta Vol. 87 (2004)
Unsymmetrical Unsaturated Ketones from Lactones and Carboxylic
Acids in One Step
by Wolfgang Giersch* and Ferdinand Naef
Firmenich SA, Corporate R&D Division, P.O. Box 239, CH-1211 Geneva 8
(phone: ‡41227803605; fax: ‡41227803334; e-mail: wolfgang.giersch@firmenich.com)
Dedicated to G¸nther Ohloff on the occasion of his 80th birthday
A one-step transformation of g- and d-(spiro)lactones into g,d- and d,e-unsaturated ketones in the presence
of carboxylic acids in the vapor phase at 4008 over a supported manganese catalyst is reported for the first time.
The scope of this new transformation is exemplified with a series of lactones, and a mechanistic rationale is
proposed.
1. Introduction. In the preceding publication [1], we reported a new method for
making unsaturated aldehydes from five- and six-membered lactones by reacting them
in the gas phase with formic acid over a supported manganese(II) catalyst. We asked
ourselves what might happen if we replaced in this same reaction formic acid with
acetic acid or a higher homologue?
The thermolysis (300 4008) of carboxylic acid salts for the preparation of
symmetrical and unsymmetrical ketones is well-documented and, to the best of our
knowledge, was mentioned for the first time by Williamson in 1850 [2] who pyrolyzed
potassium acetate to isolate acetone, and pyrolyzed a mixture of sodium acetate and
potassium valerate (ˆ potassium pentanoate) to obtain hexan-2-one. The use of
dicarboxylic acids led to cyclic ketones [3], and Ruzicka and co-workers [4][5] used
this method to synthesize macrocyclic ketones, an important class of musk odorants [6].
The reaction was first rendered catalytic by Squibb [7] by means of supported catalysts
at 3508 in the gas phase (for a review, see [8]).
2. Results. When we passed lactone 1 (64 :36 mixture 1a/1b) [9] with an excess of
acetic acid (2) over a MnII catalyst supported on pumice at 4008, we obtained
unsaturated ketone 3 in 63% yield with the concomitant liberation of CO2 (Scheme 1).
We next explored the scope and limitations of this transformation by reacting
different lactones (see 1, 4, 9, and 12) with a series of carboxylic acids (see 2, 5, and 10;
Table). In general, the yields of the obtained ketones (see 3, 6 8, 11, and 13 17 in the
Table) were better than when aldehydes were made from lactones and formic acid [1],
mainly due to the increased thermal stability of ketones.
3. Discussion. As seen from the Table, the yields of the formed ketones seem to be
greatly influenced by the ease of ring opening of the lactones tested, whilst being
independent of the chain length of the carboxylic acid. Although the yields never

Helvetica Chimica Acta Vol. 87 (2004)
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Scheme 1
exceed ca. 50%, this one-step transformation is unique and difficult to achieve by other
synthetic methodology. Catalyst optimization is still needed, and a stepwise procedure
from the lactone via the unsaturated acid, and the mixed anhydride (as outlined below
for mechanistic studies) may be advantageous in certain cases, despite the two
additional steps.
Regarding the mechanism of this new transformation, the first step is almost
certainly lactone opening to give either an unsaturated acid or directly an unsaturated
mixed anhydride, as exemplified by 1 ‡ 2 ! 18 or 19 (Scheme 2). Both acids [2
5][7][8] and symmetric anhydrides [10 13] are known to give ketones. Koch and
Scheme 2

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Helvetica Chimica Acta Vol. 87 (2004)
Table. Thermal Reaction of Carboxylic Acids with Lactones at 4008
Entry
1
Starting materials
Catalyst
Product(s)
Yield
63%
MnII/pumice
2
MnII/ZnII/pumice
12%
50%
41%
3
4
5
MnII/ZnII/pumice
MnII/pumice
48%
MnII/pumice
ca. 30%
6
MnII/pumice
52%a);
68.7%b)
10.3%b)
9.6%b)
4.6%b)

Helvetica Chimica Acta Vol. 87 (2004)
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Table (cont.)
Entry Starting materials
Catalyst
Products
Yield
7
MnII/ZnII/pumice
5%
50%
a) Total yield of 13 16. b) Product composition by GC.
Leibnitz [11] showed that, in the case of carboxylic acids, the corresponding anhydrides
are intermediates, which then decompose to the ketones.
To establish that, in our case, anhydrides are also intermediates, we specifically
prepared the mixed anhydride 19 from carboxylic acid 18 and acetyl chloride
(Scheme 3) and subjected it to catalytic pyrolysis at 4508. Exclusively the asymmetric
ketone 3 was obtained as major product, besides cyclic ketone 20. Since it is known that
thermolysis of mixed anhydrides leads to disproportionation and the formation of
symmetric anhydrides [14], a first attempted preparation of the mixed anhydride 19 at
508 gave mainly the symmetric anhydride 21 (besides a small amount of 19), which
upon catalytic pyrolysis at 4508 led predominantly to the symmetric ketone 22.
Scheme 3

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Helvetica Chimica Acta Vol. 87 (2004)
Exactly what role the catalyst is playing in this anhydride decomposition is not
clear. However, in analogy to the closely related PiriaÀLimpricht reduction of
carboxylic acids and lactones [1], we propose complexation of the amphoteric MnII
salt (acid and base character) with the anhydride 19 as depicted in the polar
intermediate structure i (RˆMe) in Scheme 4. A 1,3 shift of the alkyl group R, driven
by CO2 formation and facilitated by the MnII salt, would then lead via intermediate ii to
ketone 3.
Scheme 4
4. Conclusions.
This surprising one-step transformation provides a simple
approach to a variety of ketones that, by other routes, are not easily accessible. Further
examples and improved catalysts will be needed to evaluate the preparative usefulness
of this reaction.
The authors are indebted to Mrs. V. Revillet and C. Bise for careful experimental work, to Prof. P. Vogel,
EPF-Lausanne, for helpful mechanistic discussions, to Mr. W. Thommen for having recorded the spectral data,
to Dr. O. Haefliger for LC/MS measurements, and to Dr. E. Walther for reference samples.
Experimental Part
1. General. See [1].
2. Thermolysis: General Procedure. See [1]. 2.1. (Æ)-4-[4-(tert-Butyl)cyclohex-1-en-1-yl]butan-2-one (3). A
soln. of 8-(tert-butyl)-1-oxaspiro[4.5]decan-2-one (1) (20 g, 95 mmol) in 2 (30 g, 0.5 mol) was introduced at the
top of the column filled with the catalyst Mn(OAc)2 on pumice1) at 4008. The crude pyrolysate was washed twice
1
with brine and then distilled at 1608/0.6 mbar (bath temp.): 14.0 g (ca. 63%) of 3 (90% purity). H-NMR: 0.85
(s, 9 H); 2.2 (s, 3 H); 5.4 (br. s, 1 H). 13C-NMR: 24.2 (t); 26.8 (t); 27.2 (t); 29.8 (q); 29.9 (t); 31.4 (t); 32.2 (s); 42.2
‡
(t); 44.1 (d); 121.6 (d); 136.1 (s); 208.9 (s). MS: 208 (17, M ), 190 (6), 175 (5), 150 (25), 134 (22), 109 (22), 94
(100), 79 (33), 57 (59), 43 (51).
1
)
For catalyst preparation, see [1].

Helvetica Chimica Acta Vol. 87 (2004)
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2.2. 1-(Cyclohex-1-en-1-yl)octan-3-one (6). A soln. of 1-oxaspiro[4.5]decan-2-one (4) [15] (5 g, 32 mmol)
and hexanoic acid (5; 3.8 g, 32 mmol) was thermolyzed over Mn(OAc)2/Zn(OAc)2 on pumice1) at 4508 and the
product distilled at 1258/0.25 mbar: 3.8 g of 6 (21%) and undecan-6-one2) (7; 50%) mainly.
‡
Data of 6: MS: 208 (10, M ), 190 (2), 165 (24), 152 (13), 137 (10), 119 (9), 99 (100), 79 (47), 71 (47), 43
(38).
‡
Data of 7: MS: 170 (6, M ), 127 (8), 114 (8), 99 (81), 71 (81), 58 (58), 43 (100).
2.3. 4-(Cyclohex-1-en-1-yl)butan-2-one/4-Cyclohexylidenebutan-2-one (8). A soln. of 4 (5 g, 32 mmol) in 2
(9.7 g, 160 mmol) was thermolyzed as described in 2.2. Distillation at 908/0.1 mbar gave 2.55 g (41.2%) of 8
‡
(80% purity). MS: 152 (37, M ), 137 (4), 134 (4), 109 (50), 94 (100), 79 (93), 67 (53), 43 (48).
The same reaction of octahydro-2H-1-benzopyran-2-one (9; Aldrich, mixture of cis/trans isomers) with 2
gave 8 in 48% yield.
2.4. 5-(Cyclohex-1-en-1-yl)pentan-3-one (11). A soln. of 9 (20 g, 132 mmol) in propanoic acid (10; 30 g,
0.4 mol) was thermolyzed over Mn(OAc)2 on pumice1) at 4508. Distillation at 1758/30 mbar gave 11 (28%) and
unreacted 9 (56%). Pure 11 was obtained with Girard reagent [16]. 1H-NMR: 1.05 (t, J ˆ 7, 3 H); 5.4 (br. s, 1 H).
‡
MS: 166 (47, M ), 137 (14), 119 (10), 109 (58), 94 (100), 79 (96), 67 (83), 57 (85), 41 (34).
2.5. (5E)-Dec-5-en-2-one (13). A soln. of (Æ)-nonano-4-lactone (12; 5 g, 32 mmol) in 2 (45 g, 0.75 mol) was
thermolyzed as described in 2.4. Distillation at 2008/40 mbar gave 3.6 g (52%) of 3 (68.7%), 14 (10.3%), 15
(9.6%), and 16 (4.6%).
Data of 13: 1H-NMR: 0.96 (t, J ˆ 7, 3 H); 1.33 (m, 4 H); 1.96 (m, 2 H); 2.09 (s, 3 H); 2.24 (m, 2 H); 2.49
(m, 2 H); 5.48 (m, 2 H). 13C-NMR: 13.9 (q); 22.2 (t); 26.9 (t); 30.0 (q); 31.7 (t); 32.2 (t); 43.6 (t); 128.2 (d); 131.6
‡
(d); 208.5 (s). MS: 154 (3, M ), 125 (3), 111 (4), 90 (18), 81 (21), 67 (12), 54 (21), 43 (100).
‡
Data of (3E)-Dec-3-en-2-one (14): MS: 154 (2, M ), 139 (37), 125 (7), 111 (11), 97 (32), 69 (53), 55 (97),
43 (100).
‡
Data of (5Z)-Dec-5-en-2-one (15): MS: 154 (3, M ), 125 (3), 111 (5), 96 (19), 81 (22), 67 (13), 54 (23), 43
(100).
‡
Data of (4E)-Dec-4-en-2-one (16): MS: 154 (4, M ), 139 (62), 125 (11), 111 (19), 97 (51), 69 (69), 55 (85),
43 (100).
2.6. (9E)-Tetradec-9-en-6-one (17). A soln. of 12 (5 g, 32 mmol) and hexanoic acid (5; 20 g, 172 mmol) was
thermolyzed at 4508 over Mn(OAc)2/Zn(OAc)2 on pumice1). Distillation at 708/0.6 mbar gave 14.6 g 12 (4.5%),
‡
17 (5.0%), and the Piria ketone from hexanoic acid, undecan-6-one (7; 90%). 17: MS: 210 (3, M ), 167 (9), 154
(10), 139 (16), 99 (100), 71 (47), 55 (43), 43 (51).
2.7. (Æ)-Acetic 3-[4-(tert-Butyl)cyclohex-1-en-1-yl]propanoic Anhydride (19). To a soln. of (Æ)-3-[4-(tert-
butyl)cyclohex-1-en-1-yl]propanoic acid (18; 1 g, 4.8 mmol) in N,N-dimethylaniline (5 ml) was added dropwise
at 08 with stirring acetyl chloride (0.33 ml, 4.8 mmol). After 3 h, now at r.t., ice was added to the mixture which
was then extracted with pentane. The org. layer was washed with ice-cold 10% HCl soln., ice-cold NaHCO3 soln.
and ice-cold brine, dried (Na2SO4), and evaporated at 208: 1.08 g (90%) of crude 19. 1H-NMR: 0.87 (s, 9 H); 1.2
(m, 2 H); 1.7 (m, 2 H); 2.0 (m, 3 H); 1.68 (s, 3 H); 2.22 (s, 3 H); 2.3 (m, 2 H); 2.55 (m, 2 H); 5.43 (br. s, 1 H).
13C-NMR: 22.2 (q); 24.1 (t); 26.8 (t); 27.6 (q); 29.7 (t); 31.7 (t); 32.2 (s); 33.8 (t); 44.0 (d); 122.5 (d); 135.0 (s);
166.5 (s); 169.1 (s).
2.8. 3-[4-(tert-Butyl)cyclohex-1-en-1-yl]propanoic Anhydride (21). As described in 2.7, but after 3 h at 08 !
r.t., the mixture was stirred at 508 for 5 h: 0.8 g (67%) of 21, containing some 19 (15%). 21: IR: 1750, 1815.
1H-NMR: 0.87 (s, 18 H); 5.45 (br. s, 2 H). 13C-NMR: 24.1 (t); 26.8 (t); 27.2 (q); 29.7 (t); 31.7 (t); 32.2 (s); 33.9 (t);
‡
44.0 (d); 122.5 (d); 135.1 (s); 169.3 (s). LC/MS: 402 (M ).
2.9. (Æ)-4-[4-(tert-Butyl)cyclohex-1-en-1-yl]butan-2-one (3). A soln. of 19 (850 mg) in THF (3.5 ml) was
passed over Mn(OAc)2/Zn(OAc)2 on pumice1) at 4508. The product was distilled at 2008/0.8 mbar: 210 mg of 3
(65%) and 20 (30%).
1
Data of 3: H-NMR: 0.85 (s, 9 H); 5.4 (br. s, 1 H). 13C-NMR: 24.2 (t); 26.8 (t); 27.2 (q); 29.9 (t); 31.4 (t);
‡
32.2 (s); 42.2 (t); 44.1 (d); 121.6 (d); 136.1 (s); 208.9 (s). MS: 208 (17, M ), 190 (6), 175 (5), 150 (26), 134 (22),
109 (22), 94 (100), 79 (33), 57 (59), 43 (52).
Data of 6-(tert-Butyl)-2,3,4,5,6,7-hexahydro-1H-inden-1-one (20): see [1].
2.10. 1,5-Bis[4-(tert-butyl)cyclohex-1-en-1-yl]pentan-3-one (22). The soln. of 21 (0.8 g) containing some 19
(15%) was thermolyzed as described in 2.9. After a pre-run, distillation at 2508/0.8 mbar) furnished 250 mg of
1
22. H-NMR: 0.87 (s, 18 H). 13C-NMR: 24.2 (t); 26.8 (t); 27.2 (q); 29.9 (t); 31.4 (t); 32.2 (s); 41.2 (t); 44.1 (d);
2
)
Piria reaction product of hexanoic acid.

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Helvetica Chimica Acta Vol. 87 (2004)
‡
121.5 (d); 136.2 (s); 210.9 (s). MS: 358 (97, M ), 340 (22), 325 (6), 301 (11), 283 (10), 259 (8), 221 (17), 206 (27),
193 (53), 175 (22), 149 (27), 137 (39), 119 (33), 109 (40), 93 (57), 57 (100), 41 (24).
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Received March 5, 2004