Methyl homologues of methyl jasmonate and methyl dihydrojasmonate (Hedione) from sorbyl alcohol

Article abstract of DOI:10.1002/hlca.200490147

Treatment of cycloalkanone dimethyl acetals 3-6 with sorbyl alcohol (=(2E,4E)-hexa-2,4-dien-1-ol; 1) in the presence of acids afforded the novel cycloalkenones 8, 9, 11, and 13 via a domino reaction (Claisen rearrangement with intramolecular ene reaction and retro-ene reaction). Cyclopentenone 8 was readily transformed into 14 and 15, methyl homologues of racemic methyl jasmonate (16) and methyl dihydrojasmonate (= Hedione; 17), respectively. The organoleptic properties of 14 and 15 are also discussed.

Full text of DOI:10.1002/hlca.200490147

Helvetica Chimica Acta Vol. 87 (2004)
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Methyl Homologues of Methyl Jasmonate and Methyl Dihydrojasmonate
¾
(Hedione ) from Sorbyl Alcohol
by Wolfgang Giersch and Iris Farris
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
Treatment of cycloalkanone dimethyl acetals 3 6 with sorbyl alcohol (ˆ(2E,4E)-hexa-2,4-dien-1-ol; 1) in
the presence of acids afforded the novel cycloalkenones 8, 9, 11, and 13 via a domino reaction (Claisen
rearrangement with intramolecular ene reaction and retro-ene reaction). Cyclopentenone 8 was readily
transformed into 14 and 15, methyl homologues of racemic methyl jasmonate (16) and methyl dihydrojasmonate
(ˆ Hedione¾; 17), respectively. The organoleptic properties of 14 and 15 are also discussed.
1. Introduction. As part of a screening program comprising the synthesis of new
odorant compounds, we decided to study the acid-catalyzed reaction of sorbyl alcohol1)
(1) with dimethyl acetals of general structure A, thus offering potential access to
dienones B via Claisen rearrangement2) (Scheme 1).
Scheme 1
2. Results and Discussion. 2.1. Acid-Catalyzed Reaction of 1 with 2 6. Dimethyl
acetals 2 6 (3 mol-equiv.), readily available from corresponding ketones by a standard
acetalization procedure [1], were heated individually with 1 (1 mol-equiv.) in the
presence of a catalytic amount of malonic acid (0.01 mol-equiv.)3) in an Inox autoclave
at 2008 during 48 h. Cooling of resulting product mixtures to room temperature was
followed by bulb-to-bulb distillation in vacuo, whereby the compounds 7 13 (see
1
)
)
)
Sorbyl alcohol is the trivial name for (2E,4E)-hexa-2,4-dien-1-ol.
For the same strategy applied to prop-2-en-1-ol, see [1].
Other Br˘nsted acids such as, e.g., citric acid, TsOH, and H2SO4 could also be employed as catalyst.
2
3

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Helvetica Chimica Acta Vol. 87 (2004)
Table) were isolated and spectroscopically characterized4). For Entries 4 and 5,
preparative GC was necessary to separate the mixtures 10/11 and 12/13.
Table. Acid-Catalyzed Reaction of Sorbyl Alcohol (1) with Dimethyl Acetals 2 6a)
Entry
1
Substrate
Product(s)
Yield [%]b)
47
2
3
4
73
68
83
5
68
a) Reaction conditions: substrate (3 mol-equiv.), 1 (1 mol-equiv.), malonic acid (0.01 mol-equiv.), 200 8, 48 h.
b) Isolated yield based on 1. c) 2 : 1 Diastereoisomer mixture.
As can be seen from the Table, the acyclic substrate 2 gave only the expected
Claisen rearrangement product 7, as a 2 :1 diastereoisomer mixture in 47% yield
(Entry 1)5). In contrast, the cyclic substrates 3 6 afforded cycloalkenone E, either
4
)
)
All chiral compounds reported in this work are racemic and were fully characterized, see Exper. Part.
Despite this only moderate yield, no other compound (>5%) was detected by GC in the crude product
mixture.
5

Helvetica Chimica Acta Vol. 87 (2004)
1603
exclusively or as one of the principal products. Thus, 3 and 4 afforded 8 and 9 in 73%
and 68% yield, respectively (Entries 2 and 3), whereas 5 and 6 afforded mixtures of the
dienone B and the corresponding cycloalkenone E, i.e., 10/11 1:1 and 12/13 2.4 :1 in
83% and 68% yield, respectively (Entries 4 and 5). As shown in Scheme 2, the
formation of the (Z)-configured E can be rationalized by invoking a domino reaction
[2] in which the enol tautomer C of the initially formed Claisen-rearrangement product
B undergoes an intramolecular ene reaction followed by a 1,5-H transfer (retro-ene
reaction) of the intermediate cyclopropyl ketone D6). It is important to note that the
stereoselectivity of the conversion of C to D and/or D' has no influence on the
formation of E, due to the known epimerization (D > D') of these systems [4]. The
difference in behavior between 2 and 3 6 is almost certainly due to the (Z)-
configuration of C, which favors the transition state of the subsequent ene reaction.
However, in contrast to Entries 2 and 3, the requisite transition-state geometry in
Scheme 2. Mechanistic Proposal for the Formation of E from A (via B)
6
)
For a literature precedent of an analogous domino reaction, see [3].

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Helvetica Chimica Acta Vol. 87 (2004)
Entries 4 and 5 is progressively harder to attain, due to the higher conformational strain
of the seven- and eight-membered rings.
2.2. Synthesis of 14 and 15 from 8. With 8 in hand, we now had ready access to 14
and 15, methyl homologues of (Æ)-methyl jasmonate (16)7) and (Æ)-methyl
dihydrojasmonate (ˆ Hedione8); 17) both well-known jasmine-type odorants [7].
Accordingly, treatment of 8 with dimethyl malonate under basic conditions
followed by decarboxylative saponification [8] and subsequent esterification afforded
14 (diastereoisomer mixture at C(1)) in 60% overall yield. Catalytic hydrogenation
then furnished 15 (diastereoisomer mixture at C(1)) in 96% yield, in a straightforward
manner (Scheme 3).
Scheme 3. Synthesis of 14 and 15 from 8. Compounds 14 and 15 contained ca. 5 10% of the corresponding cis
diastereoisomer.
a) NaOMe, dimethyl malonate, À 58, 5 d. b) NaOH, MeOH, then H2SO4, MeOH, reflux. c) 10% Pd/C,
MeOH, H2.
2.3. Organoleptic Evaluation of 14 and 15. The odor of 14 has a floral, jasminic note,
is more indolic than Hedione¾, and has a fruity-raspberry undertone. Compound 15
smells floral, Hedione¾-like, but with a citrus connotation. It is finer, not as powerful,
but more long-lasting than Hedione¾.
We thank Dr. Pierre-Alain Blanc for the organoleptic evaluation, Dr. Roger L. Snowden for help in the
preparation of the manuscript and Walter Thommen for the discussion of the NMR spectra.
Experimental Part
General. Flash chromatography (FC): Silica gel 60, 35 70 mm. Anal. GC: Varian STAR 3400; He as carrier
gas; fused-silica capillary columns SPB-1 and Supelcowax¾, each 30 m  0.25 mm i.d. with 0.25-mm film. Prep.
1
GC: JAS-2000 system, column HP-Wax, 10 m  0.1 mm, 50 2508, 308/min. H- and 13C-NMR Spectra: Bruker-
7
)
)
For the isolation of (À)-methyl jasmonate from jasmine oil, see [5]; for synthetic work, see [6].
Registered trade name of Firmenich SA.
8

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DPX-400 or AV-500 spectrometers; d in ppm downfield from SiMe4, J in Hz. GC-MS: Hewlett-Packard-5890 or
-6890 system equipped with a capillary column (30 m  0.25 mm i.d.), coupled with a Hewlett-Packard MSD-
5972 or -5973 quadrupole mass spectrometer; electron energy ca. 70 eV; in m/z (rel. int. in % of the base peak).
1. Dimethyl Acetals 2 6: General Procedure. To a stirred soln. of the ketone (2 mol), trimethyl
orthoformate (5 mol), and MeOH (700 ml), TsOH (500 mg) was added at r.t. After 4 days, the mixture was
poured onto ice, worked up with Et2O, and washed with sat. NaHCO3 soln. and brine, then distilled.
3,3-Dimethoxypentane (2) [9]: 115 g (63%). B.p. 120 1248. 1H-NMR: 0.82 (t, J ˆ 7.3, 6 H); 1.60 (q, J ˆ 7.3,
‡
4 H); 3.15 (s, 6 H). MS: 144 (<0.5, M ), 103 (100), 101 (60), 69 (11), 57 (43), 45 (28).
1,1-Dimethoxycyclopentane (3) [10]: 172 g (66%). B.p. 138 1408. 1H-NMR: 1.6 1.8 (m, 8 H); 3.2 (s, 6 H).
‡
MS: 130 (1, M ), 101 (100), 99 (48), 67 (42), 57 (22), 41 (10).
1,1-Dimethoxycyclohexane (4) [11]: 199 g (69.4%). B.p. 75 788/40 mbar. 1H-NMR: 1.35 1.7 (m, 10 H); 3.2
‡
(s, 6 H). MS: 144 (5, M ), 113 (45), 101 (100), 81 (31), 55 (13), 43 (11).
1,1-Dimethoxycycloheptane (5) [12]: 255 g (74%). B.p. 85 898/36 mbar. 1H-NMR: 1.55 (br. s, 8 H); 1.78
‡
(m, 4 H); 3.16 (s, 6 H). 13C-NMR: 21.7 (t); 29.2 (t); 36.1 (t); 47.8 (q); 104.4 (s). MS: 158 (8, M ), 127 (46), 115
(12), 101 (100), 95 (20), 55 (19).
1,1-Dimethoxycyclooctane (6) [13]: 254 g (74%). B.p. 85 898/36 mbar. H-NMR: 1.55 (s, 10 H); 1.76 (br.
s, 4 H); 3.14 (s, 6 H). 13C-NMR: 21.3 (t); 24.6 (t); 28.2 (t); 30.3 (t); 47.7 (q); 103.8 (s). MS: 172 (6, M ), 141 (48),
1
‡
101 (100), 88 (44), 67 (26), 55 (25), 41 (22).
2. Acid-Catalyzed Reaction of Sorbyl Alcohol (1) with the Dimethyl Acetals 2 6: General Procedure. A
mixture of 1 (1 mol-equiv.), acetal (3 mol-equiv.), and malonic acid (100 mg) was heated with stirring in an
autoclave (Bergauf; 100 ml, 100 mbar) to 2008 during 48 h. The mixture was then bulb-to-bulb distilled under
vacuum.
(Æ)-(6E)-5-Ethenyl-4-methyloct-6-en-3-one (7): 4 g ( 47%). B.p. 1280/14 mbar. 1H-NMR: 0.98 1.04
(m, 6 H); 1.58 1.69 (m, 3 H); 2.33 2.47 (m, 2 H); 2.55 (quint., J ˆ 8.2, 1 H); 2.9 (quint., J ˆ 8.2, 1 H); 4.94
5.07 (m, 2 H); 5.22 5.78 (m, 3 H). 13C-NMR: 7.49, 7.90 (2q); 14.49, 14.54 (2q); 18.00 (q); 35.59, 35.72 (2t); 49.95,
50.21 (2d); 50.30 (d); 115.07, 115.08 (2t); 126.49, 127.30 (2d); 130.82, 131.24 (2d); 138.58, 139.17 (2d); 214.40 (s).
‡
MS: 166 (2, M ), 151 (9), 137 (30), 109 (11), 81 (100), 67 (18), 57 (43), 41 (27), 29 (23).
(Æ)-2-[(2Z)-1-Methylpent-2-enyl]cyclopent-2-en-1-one (8): 6 g (73%). B.p. 988/16 mbar. 1H-NMR: 0.95
(t, J ˆ 7.5, 3 H); 1.14 (d, J ˆ 7.1, 3 H); 1.66 2.659 (m, 6 H); 3.5 (quint., J ˆ 7.1, 1 H); 5.31 (dd, J ˆ 10, 10, 1 H);
5.37 (dt, J ˆ 10, 7, 1 H ) ; 7.3 ( m, 1 H). 13C-NMR: 14.3 (q); 20.4 (q); 20.7 (t); 26.4 (t); 28.3 (d); 34.9 (t); 131.6 (d);
131.8 (d); 150.4 (s); 156.2 (d); 209.0 (s).
1
(Æ)-2-[(2Z)-1-Methylpent-2-enyl]cyclohex-2-en-1-one (9): 8.5 g (68%). B.p. 1088/13 mbar. H-NMR: 0.94
(t, J ˆ 7.5, 3 H); 1.07 (d, J ˆ 6.8, 3 H); 1.90 2.45 (m, 8 H); 3.7 (quint., J ˆ 7.5, 1 H); 5.25 (dd, J ˆ 10, 10, 1 H);
5.32 (dt, J ˆ 6.8, 10, 1 H); 6.73 (m, 1 H). 13C-NMR: 14.3 (q); 20.8 (t); 21.1 (q); 22.9 (t); 26.1 (t); 30.3 (d); 131.1
‡
(d); 133.0 (d); 143.5 (d); 144.2 (s); 198.6 (s). MS: 178 (16, M ), 163 (11), 149 (100), 135 (9), 121 (12), 107 (10),
93 (28), 79 (22), 67 (12), 55 (37), 41 (20).
(Æ)-2-[(2E)-1-Ethenylbut-2-enyl]cycloheptanone (10) and (Æ)-2-[(2Z)-1-Methylpent-2-enyl]cyclohept-2-
en-1-one (11): 1.60 g (83%). B.p. 130/13 mbar. Separation of the isomers was effected by prep. GC.
Data of 109): 1H-NMR: 4.95 5.05 (m, 2 H); 5.30 5.52 (m, 2 H); 5.65 5.80 (1 H). 13C-NMR: major
isomer: 18.0 (q); 24.8 (t); 28.3 (t); 28.4 (t); 29.5 (t); 43.5 (t); 49.3 (d); 56.8 (d); 114.8 (t); 127.4 (d); 130.2 (d); 139.8
(d); 215.7 (s); minor isomer: 18.0 (q); 24.8 (t); 28.3 (t); 28.4 (t); 29.5 (t); 43.5 (t); 49.5 (d); 56.8 (d); 115.8 (t);
‡
126.3 (d); 131.5 (d); 138.7 (d); 215.5 (s). MS: major isomer: 192 (8, M ); 177 (5), 163 (9), 149 (63), 81 (100), 55
‡
(24), 41 (36); minor isomer: 192 (8, M ), 177 (5), 193 (9), 149 (62), 81 (100), 55 (22), 41 (33).
1
Data of 11: H-NMR: 0.93 (t, J ˆ 7.3, 3 H); 1.06 (d, J ˆ 7.0, 3 H); 1.65 1.78 (m, 4 H); 2.05 (m, 2 H); 2.35
(m, 2 H); 2.54 (m, 2 H); 3.7 (m, 1 H); 5.2 (dd, J ˆ 9.5, 10.5, 1 H); 5.32 (dt, J ˆ 7.5, 10.5, 1 H); 6.36 (t, J ˆ 6.4,
1 H). 13C-NMR: 14.3 (q); 20.7 (t); 21.0 (q); 21.6 (t); 24.9 (t); 27.3 (t); 33.3 (d); 42.9 (t); 131.4 (d); 133.1 (d); 137.6
‡
(d); 206.0 (s). MS: 192 (<0.5, M ), 178 (1), 177 (5), 163 (100), 135 (19), 121 (15), 107 (19), 93 (35), 79 (37), 67
(25), 55 (32), 41 (35).
(Æ)-2-[(2E)-1-Ehenylbut-2-enyl]cyclooctanone (12) and (Æ)-2-[(2Z)-1-Methylpent-2-enyl]cyclooct-2-en-1-
one (13): 1.40 g (68%). B.p. 1458/13 mbar. Separation of the isomers was effected by prep. GC.
Data of 129): Major isomer: 1H-NMR: 5.00 5.07 (m, 2 H); 5.23 5.30 (m, 1 H); 5.32 5.42 (m, 1 H); 5.6
5.68 (m, 1 H). 13C-NMR: 18.1 (q); 24.8 (t); 25.0 (t); 25.8 (t); 27.8 (t); 31.3 (t); 43.8 (t); 50.5 (d); 54.2 (d); 115.8 (t);
‡
126.4 (d); 131.2 (d); 139.2 (d); 219.5 (s). MS: 206 (5, M ), 191 (2), 177 (5), 163 (10), 149 (29), 135 (5), 121 (5),
9
)
3:1-Mixture of diastereoisomers.

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1
107 (10), 93 (11), 81 (100), 67 (11), 55 (23), 41 (30). Minor isomer: H-NMR: 4.91 4.97 (m, 2 H); 5.22 5.30
(m, 1 H); 5.43 5.52 (m, 1 H); 5.60 5.68 (m, 1 H). 13C-NMR: 18.0 (q); 24.8 (t); 25.0 (t); 25.9 (t); 27.8 (t); 31.3
‡
(t); 43.8 (t); 50.5 (d); 54.5 (d); 114.9 (t); 127.3 (d); 131 (d); 139.4 (d); 219.6 (s). MS: 206 (7, M ), 191 (2), 177 (4),
163 (12), 149 (33), 135 (5), 121 (4), 107 (11), 98 (11), 81 (100), 55 (6), 41 (33).
Data of 13: 1H-NMR: 0.93 (t, J ˆ 7, 3 H); 1.09 (d, J ˆ 7, 3 H); 5.12 (br. dd, J ˆ 11, 11, 1 H); 5.36 (dt, J ˆ 7, 11,
1 H); 5.75 (dt, J ˆ 1.3, 7.4, 1 H). 13C-NMR: 14.3 (q); 20.0 (q); 20.4 (t); 22.1 (t); 22.8 (t); 28.9 (t); 29.4 (t); 36.3 (d);
‡
43.7 (t); 129.0 (d); 131.8 (d); 132.0 (d); 142.6 (s); 213.6 (s). MS: 206 (7, M ), 191 (8), 177 (100), 163 (28), 149
(20), 135 (19), 121 (22), 107 (32), 93 (53), 81 (58), 67 (42), 55 (71), 41 (67).
(Æ)-Methyl 2-[(2Z)-1-Methylpent-2-enyl]-3-oxocyclopentaneacetate (14). To a cooled (À158) mixture of
dimethyl malonate (50 g, 0.4 mol) and Na (0.17 g, 7 mmol) was added a soln. of 8 (10 g, 61 mmol), dimethyl
malonate (7 g), and MeOH (13 ml) with stirring under N2. After complete addition, the mixture was stirred at
À 58 for 5 days, then neutralized with AcOH (4 g, 20 mmol), diluted with Et2O, washed with H2O, and distilled
at 110 1208/0.4 mbar. The distillate (17.8 g, 98%) was then refluxed in H2O (200 ml) in the presence of KOH
(8 g, 143 mmol) for 5 h. After cooling, the mixture was washed with pentane (2 Â 100 ml), the aq. soln. acidified
with ice/H2SO4 and extracted with Et2O, the Et2O phase evaporated, and the residue esterified with MeOH
(150 ml) and conc. H2SO4 soln. (5 ml) at r.t. during 5 days. Then the MeOH was distilled off, the remaining
mixture diluted with Et2O, and the Et2O soln. washed with brine and distilled: 14 (8.6 g, 60%) as a
‡
diastereoisomer mixture. B.p. 1708/0.6 mbar. MS: 238 (25, M ), 220 (32), 165 (54), 149 (23), 147 (33), 135 (24),
123 (26), 109 (47), 107 (26), 95 (28), 93 (33), 83 (100), 82 (41), 67 (29), 55 (80), 41 (31); the MS of the isomers
are identical.
(Æ)-Methyl 2-(1-Methylpentyl)-3-oxocyclopentaneacetate (15). A mixture of 14 (3 g, 12 mmol), 10% Pd/C
(50 mg), and MeOH (50 ml) was hydrogenated at r.t. and 1 atm and then filtered. The filtrate was evaporated
and the residue purified by FC (heptane/AcOEt 95 :5): 15 (1.4 g, 46%) as an isomer mixture. B.p. 1508/0.6 mbar.
13C-NMR: isomer A: 14.1 (q); 16.6 (q); 22.8 (t); 27.4 (t); 30.1 (t); 32.7 (d); 34.2 (t); 36.2 (d); 39.0 (t); 39.5 (t); 51.6
(q); 58.5 (d); 172.6 (s); 220.0 (s); isomer B: 14.1 (q); 16.9 (q); 22.8 (t); 27.4 (t); 30.1 (t); 32.9 (d); 34.2 (t); 34.8 (d);
‡
38.6 (t); 39.9 (t); 51.6 (q); 58.5 (d); 172.7 (s); 219.3 (s). MS: 240 (2, M ), 209 (3), 183 (6), 167 (10), 156 (42), 109
(7), 96 (7), 83 (100), 55 (19), 41 (20); the MS of both isomers are identical.
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Received January 19, 2004