Synthesis of 13C1-pinonaldehyde

Article abstract of DOI:10.1002/jlcr.910

¹³C₁-pinonaldehyde is prepared in seven steps from cis-pinonic acid. In the key sequence, the introduction of labeled carbon is accomplished by Lieben degradation of a methyl ketone followed by treatment of the resultant carboxylic a

Full text of DOI:10.1002/jlcr.910

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 223–229.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.910
Note
13
Synthesis of C1-pinonaldehyde
Christopher W. Dicus, Dan Willenbring and Michael H. Nantz*
Department of Chemistry, University of California, Davis, CA 95616, USA
Summary
13C1-pinonaldehyde is prepared in seven steps from cis-pinonic acid. In the key
sequence, the introduction of labeled carbon is accomplished by Lieben degradation
of a methyl ketone followed by treatment of the resultant carboxylic acid with
13C-methyl lithium. Copyright # 2005 John Wiley & Sons, Ltd.
Key Words: pinonaldehyde; carbon-13; Lieben degradation
Introduction
It is well known that the oxidation products of biogenic monoterpenes play a
major role in tropospheric chemistry, as their atmospheric degradation by
ozone and hydroxyl and nitrate radicals leads to the formation of volatile
oxygenated compounds (VOCs), such as aldehydes, ketones, and carboxylic
acids.1 While this process contributes to the atmospheric accumulation of trace
gases such as formaldehyde, carbon dioxide, and acetone, it has been shown
that further secondary degradation of the larger oxidative products has more
impact on the atmospheric budget of VOCs than the primary oxidation steps
alone.2 The understanding of this process is crucial to elucidating its role in
atmospheric chemistry, however the quantification and identification of the
primary and secondary terpene oxidation products continues to present a
challenge.3
Much research efforts have focused on the ubiquitous terpene a-pinene and
its major primary oxidation product, cis-pinonaldehyde (1).4 Reported results
from simulated atmospheric oxidation of these compounds illustrate the
difficulty in the quantification and identification of the degradation products,
with yields of pinonaldehyde from a-pinene ranging from 28 to 87%.5 In
5
addition, work by Noziere et al. identifies formaldehyde as the primary
"
oxidation product of pinonaldehyde at 150%, along with a large amount of
*Correspondence to: M. H. Nantz, Department of Chemistry, University of California, One Shields Avenue,
Davis, CA 95616, USA. E-mail: mhnantz@ucdavis.edu
Copyright # 2005 John Wiley & Sons, Ltd.
Received 15 October 2004
Revised 5 November 2004
Accepted 9 November 2004

224
C. W. DICUS ET AL.
Figure 1. cis-Pinonaldehyde (1) and retrosynthetic analysis
unidentified carbonyls. This result was not, however, supported by theoretical
calculations of this oxidative process.6
Because isotope dilution mass spectrometry is recognized as the most
accurate method towards the quantification of low-molecular-weight VOCs,7
we believe that 13C-labeled pinonaldehyde (13C1-1) could be used as a mass
spectrometry standard to improve quantification accuracy. In addition, a
source of carbon-13 may also be beneficial in determining the mechanism by
which formaldehyde is produced from pinonaldehyde, as well as in the
structural determination of previously unidentified carbonyls arising from
secondary oxidation.
Results and discussion
Our retrosynthetic analysis (Figure 1) identifies O-protected carboxylic acid 2
as the proximal target. We envisioned 2 as the product of a Lieben
degradation, thus suggesting commercially available cis-pinonic acid (3) as
our starting material.8 Conversion of 2 to 13C1-1 would proceed according to
an established carboxylic acid-to-methyl ketone transformation, [for a recent
example of this transformation, see ref.]9 but using 13C-iodomethane as a
source of labeled methyl.
The borane reduction of cis-pinonic acid (3) (Scheme 1) proceeded smoothly
to give material that matched the reported NMR spectral data of diol 4.10, y
Selective protection of the primary hydroxyl group as a p-methoxybenzyl ether
(PMB) was followed by PCC oxidation to provide methyl ketone 6.z
Following the procedure of Moglioni et al. for Lieben degradation,8 ketone
6 was degraded to carboxylic acid 7. Subsequent transformation of 7 to methyl
ketone 8 was accomplished following the method of Jorgenson.9 The 13C-
MeLi required for this step was prepared in situ from 13C-MeI.11 The PMB
group was cleaved using Yonemitsu’s conditions,12 and the title compound
(13C1-1) was isolated following PCC oxidation of alcohol 9. Spectral analysis,
particularly the vicinal 1JC,C of the ketone carbonyl carbon and the JC,H of the
y During the course of this work, we prepared native pinonaldehyde by bis-oxidation of diol 4, constituting
an effective new route to this sensitive substrate. While the Swern oxidation of 4 gave a modest 46% yield,
we were gratified to find that PDC oxidation provided 1 in 74% yield.
z While traditional 18-selective protecting groups (TBS, BPS) provided yields of ꢀ95%, these compounds
were not sufficiently soluble in the aqueous conditions necessary for the Lieben degradation step.
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SYNTHESIS OF 13C1-PINONALDEHYDE
225
Scheme 1. Synthesis of 13C1-1. Conditions: (a) BH3 (2 eq), THF, 92%; (b)
PMB-Cl (1 eq), NaH, DMF, 63%; (c) PCC, NaOAc, CH2Cl2, 90%; (d)
aqueous NaOBr, 91%; (e) 13CH3-Li (2.2 eq), Et2O, 65%; (f) DDQ,
CH2Cl2:H2O, 20:1, 91%, (g) PCC, NaOAc, CH2Cl2, 90%
Figure 2. NMR overlays of pinonaldehyde (1) (top) and 13C1-1 (bottom)
methyl ketone protons (Figure 2), confirm the structural integrity of the
oxidation product.
Experimental
Ether and THF were distilled from sodium-benzophenone ketyl and CH2Cl2
was distilled from LiAlH4. All chemicals were obtained from the Aldrich
1
Chemical Company and used without further purification. H and 13C NMR
spectra were recorded in CDCl3 using a Varian Inova 400 spectrometer with
1H and 13C signals referenced to TMS and residual CHCl3.
1-[3-(2-hydroxyethyl)-2,2-dimethylcyclobutyl]ethanol (4)
A solution of cis-pinonic acid (3.57 g, 19.4 mmol) in THF (70 ml) at 08C was
treated with BH3 ꢁ THF (38.8 ml of a 1 M solution, 38.8 mmol). The reaction
mixture was stirred at room temperature (rt) for 6 h whereupon methanol
(20 ml) was added. After stirring an additional 12 h, the solvents were removed
in vacuo and the residue was dissolved in methanol and concentrated ( ꢂ 3).
Purification of the crude product by column chromatography (SiO2; pet.
ether:EtOAc, 1:1) provided diol 4 as a colorless oil (3.07 g, 92%); Rf=0.21
1
(pet. ether:EtOAc, 1:1); IR 3347, 2953, 1460 cmꢃ1, H NMR d 1.02 (s, 3H),
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1.05 (d, 2H, J=6.3 Hz), 1.12 (s, 3H), 1.08–1.12 (m, 1H), 1.38–1.49 (m, 1H),
1.58–2.00 (m, 4H), 3.57 (br t, 2H, J=6.3 Hz), 3.72 (br m, 1H); 13C NMR d
16.7, 21.2, 26.5, 31.3, 33.4, 38.4, 39.6, 50.4, 61.6, 69.3.
(3-acetyl-2,2-dimethylcyclobutyl)acetaldehyde (1)
To a solution of diol 4 (132 mg, 0.765 mmol) in CH2Cl2 (10 ml) at 08C was
added PDC (633 mg, 1.68 mmol). The reaction was warmed to rt and stirred
18 h, after which Florisil1 was added to adsorb the chromium salts. The
reaction mixture was stirred an additional 0.5 h and then filtered through a
short pad of Celite1. The retentate was washed with CH2Cl2 and the filtrates
were combined and concentrated in vacuo. The residue was purified by column
chromatography (SiO2; pet. ether:EtOAc, 8:2) to furnish cis-pinonaldehyde (1)
as a colorless oil (96 mg, 74%); Rf=0.50 (pet. ether:EtOAc, 1:1); IR 2950,
1
2908, 2818, 1720, 1703 cmꢃ1; H NMR d 0.85 (s, 3H), 1.34 (s, 3H), 1.90–2.05
(m, 2H), 2.05 (s, 3H), 2.36–2.53 (m, 3H), 2.93 (dd, 1H, J=10.0, 7.6 Hz), 9.74
(t, 1H, J=1.6 Hz); 13C NMR d 17.6, 22.7, 30.1, 30.3, 35.7, 43.2, 45.1, 54.3,
201.4, 207.4.
1-{3-[2-(4-methoxybenzyloxy)ethyl]-2,2-dimethylcyclobutyl}ethanol (5)
NaH (260 mg, 10.8 mmol) was added to a solution of diol 4 (930 mg,
5.40 mmol) in DMF (30 ml) at 08C. The resultant suspension was stirred
20 min at rt. After cooling to 08C, PMB-Cl (0.73 ml, 5.40 mmol) was added
and the mixture was warmed to 608C and stirred 3 h. The reaction mixture
then was quenched by pouring over sat. NaHCO3 and followed by extraction
with ether. The combined organics were washed successively with water, brine,
and dried (Na2SO4). The solvents were evaporated in vacuo and the residue
was purified by column chromatography (SiO2; pet. ether:EtOAc, 8:2) to
provide 5 as a colorless oil (955 mg, 63%); Rf=0.45 (pet. ether:EtOAc, 1:1); IR
1
3430, 2954, 2860, 1612, 1512 cmꢃ1; H NMR d 1.00 (s, 3H), 1.03 (d, 3H,
J=6.4 Hz), 1.10 (s, 3H), 1.05–1.15 (m, 1H), 1.46 (ddd, 1H, J = 13.6, 8.4,
6.8 Hz), 1.62–1.72 (m, 2H), 1.79–1.91 (m, 2H), 3.35 (t, 2H, J = 7.2 Hz), 3.70
(dq, 1H, J = 9.6, 6.4 Hz), 3.80 (s, 3H), 4.41 (s, 2H), 6.88 (m, 2H), 7.26 (m,2H);
13C NMR d 16.7, 21.2, 26.5, 30.4, 31.4, 38.8, 39.6, 50.4, 55.3, 68.7, 69.4, 72.6,
113.8, 129.2, 130.8, 159.1.
1-{3-[2-(4-methoxybenzyloxy)ethyl]-2,2-dimethycyclobutyl}ethanone (6)
To a solution of alcohol 5 (796 mg, 2.86 mmol) in CH2Cl2 (20 ml) at 08C was
added PCC (925 mg, 4.29 mmol) followed by NaOAc (352 mg, 4.29 mmol).
The reaction mixture was warmed to rt and stirred 2.5 h whereupon Florisil1
was added to adsorb the chromium salts. The reaction suspension was stirred
an additional 30 min and then filtered through a short pad of Celite1. The
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SYNTHESIS OF 13C1-PINONALDEHYDE
227
retentate was washed with CH2Cl2 and the filtrates were combined and
evaporated in vacuo. The residue was purified by column chromatography
(SiO2, pet. ether:EtOAc, 8:2) to give 6 as a colorless oil (710 mg, 90%);
1
Rf=0.31 (pet. ether:EtOAc, 8:2); IR 2950, 2860, 1702, 1612, 1512 cmꢃ1; H
NMR d 0.84 (s, 3H), 1.27 (s, 3H), 1.42–1.55 (m, 1H), 1.59–1.70 (m, 1H), 1.76–
2.10 (m, 3H), 2.03 (s, 3H), 2.81 (dd, 1H, J=9.9, 7.5 Hz), 3.36 (dt, 2H, J=6.9,
3.0 Hz), 3.80 (s, 3H), 4.41 (s, 2H), 6.87 (m, 2H), 7.25 (m, 2H); 13C NMR d 17.2,
23.0, 30.1, 30.4, 30.8, 38.9, 43.2, 54.3, 55.2, 68.2, 72.6, 113.7, 129.2, 130.6,
159.1, 208.0.
3-[2-(4-methoxybenzyloxy)ethyl]-2,2-dimethylcyclobutanecarboxylic acid (7)
To a solution of methyl ketone 6 (540 mg, 1.87 mmol) in dioxane (6 ml) at 08C
was added an aqueous solution of NaOBr, prepared by adding bromine
(0.35 ml, 6.83 mmol) and NaOH (1.00 g, 25.0 mmol) to water (25 ml) at 08C.
After complete addition, dioxane was added until the reaction mixture was
homogeneous. The reaction mixture was stirred at 08C for 2h, at rt for 6h, and
then extracted with CH2Cl2. The CH2Cl2 layer was extracted with 1N NaOH.
The aqueous layers were combined and acidified to pH 3 with conc. HCl
followed by addition of 40% aq. NaHSO3 and extraction with ether. The
combined ether extracts were dried (Na2SO4) and concentrated to provide 7
(500 mg, 1.71 mmol, 91%); which was used without further purification; IR
2960, 2864, 1700, 1612, 1512 cmꢃ1; 1H NMR d 0.98 (s, 3H), 1.19 (s, 3H), 1.48–
2.10 (m, 5H), 2.72 (dd, 1H, J=10.5, 7.5 Hz), 3.36 (dt, 2H, J=6.9, 1.5 Hz), 3.80
(s, 3H), 4.41 (s, 2H), 6.87 (m, 2H), 7.25 (m, 2H), 9.6 (b, 1H); 13C NMR d 17.4,
24.3, 30.1, 30.3, 39.2, 42.8, 46.0, 55.2, 68.2, 72.5, 113.7, 129.2, 130.4, 159.1,
178.5.
13C1-1-{3-[2-(4-methoxybenzyloxy)ethyl]-2,2-dimethylcyclobutyl}ethanone (8)
A solution of 13CH3I (0.25 ml, 3.9 mmol) in Et2O (10 ml) at ꢃ788C was treated
with t-BuLi (4.6 ml of a 1.7 M solution, 7.8 mmol). The reaction mixture was
stirred at ꢃ788C for 30 min and then at rt for 1 h to destroy any remaining
t-BuLi. The reaction mixture was cooled to ꢃ788C and added dropwise via
cannula into a solution of acid 7 (523 mg, 1.79 mmol) in THF (10 ml) at
ꢃ788C. On complete addition, the reaction mixture was stirred at ꢃ788C for
30 min and then at rt for 2 h. The reaction was quenched by first cooling to 08C
followed by dropwise transfer via cannula into a rapidly stirring solution of ice
cold sat. NH4Cl. The aqueous layer was extracted with ether and the combined
organics washed successively with water and brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column chromatography
(SiO2, pet. ether:EtOAc, 8:2) to provide 13C-methyl ketone 8 as a colorless oil
(340 mg, 1.17 mmol, 65%); Rf=0.31 (pet. ether:EtOAc, 8:2); IR 2953, 2860,
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C. W. DICUS ET AL.
1
1705, 1612, 1512 cmꢃ1; H NMR d 0.85 (s, 3H), 1.27 (s, 3H), 1.42–1.53 (m,
1H), 1.60–1.69 (m, 1H), 1.78–1.94 (m, 2H), 1.99–2.07 (m, 1H), 2.02 (d, 3H,
J
C,H=126.8 Hz), 2.81 (dd, 1H, J=10.0, 7.2 Hz), 3.32–3.41 (m, 2H), 3.80
(s, 3H), 4.41 (s, 2H), 6.87 (m, 2H), 7.25 (m, 2H); 13C NMR d 17.2, 23.0,
30.1, 30.4, 30.8, 38.9, 43.2, 54.3 (d, JC,C = 13.6 Hz), 55.2, 68.2, 72.5, 113.7,
2
1
129.2, 130.5, 159.1, 208.0 (d, JC,C=38.9 Hz); HRMS m/z calculated for
[13C1C17H26O3] 291.1916, found 291.1923.
13C1-1-[3-(2-hydroxyethyl)-2,2-dimethylcyclobutyl]ethanone (9)
To a solution of methyl ketone 8 (300 mg, 1.03 mmol) in a mixture of
CH2Cl2:H2O (20:1, 5 ml: 0.25 ml) was added DDQ (281 mg, 1.24 mmol). The
reaction was stirred for 1 h, then filtered through Celite. The retentate was
washed with CH2Cl2 and the filtrates were combined and washed with water
and brine, dried (Na2SO4), and concentrated in vacuo. Purification of the
residue by column chromatography (SiO2; pet. ether:EtOAc, 8:2) provided
alcohol 9 as a colorless oil (160 mg, 91%); Rf=0.40 (pet. ether:EtOAc, 1:1); IR
3404, 2949, 2912, 2853, 1703 cmꢃ1; 1H NMR d 0.87 (s, 3H), 1.30 (s, 3H), 1.42–
1.51 (m, 1H), 1.58–1.66 (m, 1H), 1.83–2.08 (m, 3H), 2.04 (d, 3H,
J
C,H=126.8 Hz), 2.84 (dd, 1H, J=10.0, 7.2 Hz), 3.53–3.63 (m, 2H); 13C
2
NMR d 17.2, 23.0, 30.1, 30.4, 33.0, 38.6, 43.2, 54.3 (d, JC,C=12.9 Hz), 61.1,
208.1 (d, JC,C=39.5 Hz), HRMS calculated for [13C1C9H18O2] 171.1340,
1
found 171.1341.
13C1-(3-acetyl-2,2-dimethylcyclobutyl)acetaldehyde (13C1-1)
To a solution of alcohol 9 (135 mg, 0.788 mmol) in CH2Cl2 (5 ml) were added
PCC (255 mg, 1.18 mmol) and NaOAc (97 mg, 1.18 mmol). The reaction
mixture was stirred at rt 2 h whereupon Florisil1 was added to adsorb the
chromium salts. The reaction suspension was filtered through a short pad of
Celite1, and the retentate was washed with CH2Cl2. The organic filtrates were
combined and concentrated in vacuo. The residue was purified by column
chromatography (SiO2, pet ether:EtOAc, 8:2) to afford 13C1-1 (120 mg, 90%)
as a colorless oil; Rf=0.50 (pet ether:EtOAc, 1:1); IR 2956, 2905, 2847, 1720,
1
1703 cmꢃ1; H NMR d 0.85 (s, 3H), 1.34 (s, 3H), 1.90–2.05 (m, 2H), 2.05 (d,
3H, JC,H=127.2 Hz), 2.38–2.53 (m, 3H), 2.93 (dd, 1H, J=10.0, 7.6 Hz), 9.74
(t, 1H, J=1.6 Hz); 13C NMR d 17.6, 22.8, 30.1, 30.3, 35.7, 43.2, 45.1, 54.3 (d,
1
2JC,C=12.9 Hz), 201.4, 207.4 (d, JC,C=38.7 Hz); HRMS calculated for
[13C1C9H16O2] 169.1184, found 169.1185.
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