Organic Process Research & Development
Article
Hz, 6H) ppm. 13C-NMR (400 MHz, CDCl3): δ = 141.0 (s),
137.2 (s), 132.0 (d), 131.7 (d), 128.3 (d), 122.0 (s), 44.7 (t),
30.1 (d), 22.9 (q), 22.3 (2q) ppm. GC-MS (EI, tR 3.93 min):
m/z (relative intensity): 228 (20), 226 (20, [M]+•), 186 (21),
185 (97), 184 (23), 183 (100), 105 (19), 104 (14), 103 (17),
77 (13).
reaction mass was quenched with saturated sodium carbonate
(500 mL). The resulting crude methoxy ethoxy acetals were
hydrolyzed with water (500 mL) containing hydrochloric acid
(37%, 50 g) at an internal temperature of 90 °C for 5 h. The
water layer was removed, and the organic layer was washed
with water and brine. The organic layer was dried over MgSO4,
and the volatiles were removed in vacuo. The above procedure
was repeated three times, and the combined intermediate 23
8.1.3. 4-Isobutyl-2-methylbenzaldehyde (19). Magnesium
turnings (180 g, 7.4 mol) were placed in a reactor and covered
with tetrahydrofuran (THF). A small amount (6 mL) of the
mixture of 13, 14, and 15 was added, and the reaction was
initiated by gentle heating. The remaining mixture of the
bromide (1684 g, 7.4 mol) was mixed with THF (3 L) and
added dropwise while maintaining a gentle reflux (70−85 °C)
without external heating. After the addition was complete, the
jacket temperature was increased to 85 °C and the mixture was
stirred at reflux for an additional hour. The reaction mixture
was cooled to an internal temperature of 10 °C, and
dimethylformamide (602 g, 8.1 mol) was added dropwise
over 1 h keeping the internal temperature below 30 °C. The
reaction mixture was stirred for 1 h and then quenched with
ice-cold HCl (2 M). The mixture was extracted with hexane;
the organic layers were combined and washed with water and
brine. The solution was dried over MgSO4 and concentrated in
vacuo. The above procedure was repeated 10 times to give a
mixture of 19 (70%) and 20 (30%) (6260 g, 48% yield). The
mixture was distilled over a 100 cm packed column (bp 105
1
was short-path-distilled at a 120 °C bath temperature. H-
NMR (400 MHz, CDCl3): δ = 9.87 (s, 1H), 7.78 (d, J = 15.89
Hz, 1H), 7.55 (d, J = 8.31, 1H), 7.06 (m, 1H), 6.96 (m, 1H),
6.68 (m, 1H), 2.50 (s, 2H), 2.49 (s, 3H), 1.88 (m, 1H), 0.94
(d, J = 6.60 Hz, 6H) ppm. 13C-NMR (400 MHz, CDCl3): δ =
194.0 (d), 150.4 (d), 145.5 (s), 137.8 (s), 131.9 (d), 130.3 (s),
128.7 (d), 127.5 (d), 126.7 (d), 45.3 (t), 30.1 (d), 22.40 (2q),
19.8 (q) ppm. GC-MS (EI, tR 3.93 min): m/z (relative
intensity): 202 (8, [M]+•), 187 (42), 159 (31), 145 (100), 141
(13), 131 (30), 129 (20), 128 (22), 116 (18), 115 (34).
8.1.6. 3-(4-Isobutyl-2-methylphenyl)propanal (4). The
distilled 23 was charged into an autoclave and mixed with
isopropanol (600 mL). The unsaturated aldehyde was
hydrogenated over palladium (5%) on carbon at a 0.5 bar
hydrogen pressure and room temperature. The catalyst was
removed by filtration, and the solution was concentrated in
vacuo. The crude product was purified by distillation over a 50
cm Sulzer column (bp 116 °C, 0.05 mbar) to provide
Nympheal (4, 3334 g, 80% yield based on 19). Odor: floral,
1
°C, 2.5 mbar) to give pure 19 (3631 g, 58% yield). H-NMR
1
aldehydic, green, rubbery, lilial, watery. H-NMR (400 MHz,
(400 MHz, CDCl3): δ = 10.22 (s, 1H), 7.71 (d, J = 7.82 Hz,
1H), 7.14 (d, J = 7.58 Hz, 1H), 7.04 (s, 1H), 2.65 (s, 3H), 2.50
(d, J = 7.34 Hz, 2H), 1.91 (m, 1H), 0.92 (d, J = 6.85 Hz, 6H)
ppm. 13C-NMR (400 MHz, CDCl3): δ = 192.3 (d), 148.2 (s),
140.5 (s), 132.6 (d), 132.3 (d), 132.2 (s), 127.1 (d), 45.4 (t),
30.1 (d), 22.4 (2q), 19.6 (q) ppm. GC-MS (EI, tR 3.93 min):
m/z (relative intensity): 176 (53, [M]+•), 134 (100), 133 (38),
106 (14), 105 (70), 103 (14), 91 (37), 77 (19), 43 (30), 41
(14).
CDCl3): δ = 9.88 (t, J = 1.5 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H),
7.0−6.95 (m, 2H), 2.98−2.93 (m, 2H), 2.79−2.74 (m, 2H),
2.46 (d, J = 7.1 Hz, 2H), 2.33 (s, 3H), 1.95−1.82 (m, 1H),
0.95 (d, J = 6.6 Hz, 6H) ppm. 13C-NMR (400 MHz, CDCl3):
δ = 202.2 (d), 140.2 (s), 136 (s), 135.9 (s), 131.6 (d), 128.6
(d), 127.3 (d), 45.4 (t), 44.6 (t), 30.6 (d), 25.5 (t), 22.9 (q),
19.7 (q) ppm. GC-MS (EI, tR 3.93 min): m/z (relative
intensity): 204 (23, [M]+•), 161 (100), 147 (26), 143 (49),
119 (84), 118 (34), 117 (33), 115 (33), 105 (59), 91 (36).
8.1.4. 1-Isobutyl-3-methylbenzene (11) Recycling from 2-
Isobutyl-4-methylbenzaldehyde (20). The experimental setup
illustrated in Figure 2 and used for the dehydrogenation of 10
was charged with a fresh catalyst (100 g, Merck, 5% Pd on
aluminum oxide, cylindrical pellets 3.2 mm, art. #205745). The
oven was heated to 200 °C, and the pressure was set to 20
mbar. Over a period of 8 h, previously distilled 20 (270 g, 1.5
mol) from the above experiment was added at a rate of 30 g/h.
The pressure increased from 20 mbar to 40 mbar as carbon
monoxide formed. 1-Isobutyl-3-methylbenzene (11) contain-
ing 20% of 20 (226 g, 78% yield) was recovered as a colorless
liquid. Adjustment of the addition rate and the temperature
would most likely result in higher selectivity of the decarbon-
ylation and close to complete recovery of 11.
8.1.5. (E)-3-(4-Isobutyl-2-methylphenyl)acrylaldehyde
(23). A reactor was charged with 19 (1.2 kg, 6.8 mol),
methanol (470 mL), and trimethyl orthoformate (1000 g, 9.4
mol). The reaction mixture was cooled to an internal
temperature of −10 °C, and aqueous hydrochloric acid
(37%, 1 g) was added. The reaction was exothermal, and the
temperature of the mixture increased to 25 °C, and stirring was
continued for 30 min. The reaction was quenched with sodium
acetate (20 g), and the volatiles were removed by distillation
under vacuum. The residual acetal was charged into a second
reactor, boron trifluoride etherate (1 g) was added, and ethyl
vinyl ether (649 g, 9.0 mol) was added dropwise over 4 h while
maintaining the internal temperature at 25−30 °C. The
AUTHOR INFORMATION
Corresponding Author
■
Martin A. Lovchik − Fragrance S&T, Givaudan Schweiz AG,
Authors
Chi-Lam Tse − Fragrance S&T, Givaudan Schweiz AG, 8310
Kemptthal, Switzerland
Simon Ellwood − Fragrance S&T, Givaudan Schweiz AG,
8310 Kemptthal, Switzerland
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
REFERENCES
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(1) Laue, H.; Kern, S.; Badertscher, R. P.; Natsch, A.; Ellis, G. p-
244−255.
(2) Goeke A, K. P. Discovery of Nympheal: The definite muguet
aldehyde. Perfum. Flavor. 2018, 43, 24−31.
H
Org. Process Res. Dev. XXXX, XXX, XXX−XXX