Cyclopropyl methyl bromide-mediated gem-diallylation: Total synthesis of (±)-α-cuparenone

Article abstract of DOI:10.1080/00397911.2010.494812

The total synthesis of (±)-α-cuparenone, an aromatic sesquiterpene, has been described using the radical mediated gem-diallylation of substituted cyclopropyl methylbromide followed by ring-closing metathesis approach.

Full text of DOI:10.1080/00397911.2010.494812

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Cyclopropyl Methyl Bromide–Mediated
Gem-Diallylation: Total Synthesis of
(±)-α-Cuparenone
I. Shivakumar a , Ganesh B. Salunke a & Suneel Kumar a
a Division of Organic Chemistry, National Chemical Laboratory ,
Pune, India
Published online: 02 May 2011.
To cite this article: I. Shivakumar , Ganesh B. Salunke & Suneel Kumar (2011) Cyclopropyl Methyl
Bromide–Mediated Gem-Diallylation: Total Synthesis of (±)-α-Cuparenone, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:13, 1952-1957,
DOI: 10.1080/00397911.2010.494812
To link to this article: http://dx.doi.org/10.1080/00397911.2010.494812
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Synthetic Communications1, 41: 1952–1957, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.494812
CYCLOPROPYL METHYL BROMIDE–MEDIATED
GEM-DIALLYLATION: TOTAL SYNTHESIS OF
(ꢀ)-a-CUPARENONE
I. Shivakumar, Ganesh B. Salunke, and Suneel Kumar
Division of Organic Chemistry, National Chemical Laboratory, Pune, India
GRAPHICAL ABSTRACT
Abstract The total synthesis of (ꢀ)-a-cuparenone, an aromatic sesquiterpene, has been
described using the radical mediated gem-diallylation of substituted cyclopropyl methylbro-
mide followed by ring-closing metathesis approach.
Keywords Aromatic sesquiterpene; gem-diallylation; ring-closing metathesis
INTRODUCTION
Cuparene (1) was first isolated from Chaamaecyparis thyoides and later from
Biota orientalis,[1] whereas the ketones a- and b-cuparenones (2 and 3) were isolated
from the essential oil of Thuja orientalis,[2] and subsequently their presence was
detected in a number of other essential oils. Owing to its structural framework with
two contiguous quaternary centers, the synthesis of cuparene and its analogs has
fascinated organic chemists worldwide.
Received December 22, 2009.
Address correspondence to I. Shivakumar, Division of Organic Chemistry, National Chemical
Laboratory, Pune, India. E-mail: i.shivakumar@ncl.res.in
1952

(ꢀ)-a-CUPARENONE
1953
Scheme 1. Retrosynthetic analysis of (ꢀ)-a-cuparenone.
Several approaches the synthesis of cuparenones either in racemic or opti-
cally active forms have been reported.[3,4] We envisaged the synthesis of 2 owing
to our long-standing interest in exploiting the ring-closing metathesis of gem-
diallyl functionality created from cyclopropyl methylbromide via free radical
allylation.[5]
The retrosynthetic analysis of 2 (Scheme 1) revealed that cyclopentene moiety 4
could be obtained from suitably substituted gem-diallyl compound 5, which in turn
was envisioned from cyclopropyl methylbromide derivative 6. The compound 6 can
be realized from p-methyl acetophenone utilizing Wittig olefination and cyclopropa-
nation as key steps.
Scheme 2. Reagents and conditions: (a) NaH, (EtO)2P(O)CH2COOEt, THF, reflux, 86%; (b) LiAlH4,
Et2O; (c) Et2Zn, CH2I2, CH2Cl2; (d) PPh3, Py, CBr4, CH2Cl2; (e) allyltributyltin, AIBN, PhCH3; (f)
Grubbs’ first-gen. catalyst, CH2Cl2, rt; (g) i, BH3 ꢁ DMS, NaOH, H2O2; ii, IBX, DMSO; and (h) LiHMDS,
HMPA, MeI, DME, rt.

1954
I. SHIVAKUMAR, G. B. SALUNKE, AND S. KUMAR
RESULTS AND DISCUSSION
The synthetic strategy started by subjecting p-methyl acetophenone (7) to
two-carbon Wittig homologation to get the a-b-unsaturated ester 8. Reduction of
ester 8 by LiAlH4 in diethyl ether produced the allyl alcohol 9, which was subse-
quently cyclopropanated using diethyl zinc and diiodomethane in CH2Cl2. The
primary alcohol 10 was converted to bromide derivative 6 by treating with CBr4
and PPh3, which is an essential precursor for the gem-diallyl moiety.
The unstable compound 6 was subsequently subjected to crucial radical-mediated
opening of the cyclopropyl ring using allyltributyltin and azobisisobutyronitrile
1
(AIBN) in refluxing toluene to obtain the desired diallyl derivative 5. The H NMR
spectrum of compound 5 showed the presence of gem-diallyl functionality as corre-
sponding resonances were identified at d 4.91–5.03 and 5.44–5.65 ppm as multiplets.
The ring-closing metathesis was carried out on gem-diallyl substrate 5 using Grubbs’
first-generation catalyst to yield cyclopentene derivative 4. Further, the hydroboration
and oxidation of compound 4 resulted in the formation of ketone 11. Dimethylation of
ketone 11 was carried out by using MeI in presence of LiHMDS and hexamethyldisi-
lazane (HMPA) to give (ꢀ) a-cuparenone (2). The analytical and spectral data
obtained for a-cuparenone were in complete agreement with those reported.[6,7]
In conclusion, (ꢀ)-a-cuparenone was obtained in an overall yield of 15% over
eight steps starting from commercially available p-methyl acetophenone employing a
simple reaction sequence.
EXPERIMENTAL
All solvents were distilled prior to use. Dry solvents were prepared according to
the standard procedures. All reactions were monitored by thin-layer chromato-
graphy (TLC) on silica gel (60–120 mesh, Merck). Infrared (IR) spectra were
recorded on a Perkin-Elmer 1615 Fourier transform (FT)–IR spectrophotometer.
1H (200-MHz) and 13C (50-MHz) NMR spectra were recorded on a Bruker
AC-200 spectrometer. The carbon resonances were recognized by the use of
distortionless enhancement by polarization transfer (DEPT) experiments.
(E)-Ethyl-3-(4-methylphenyl)-but-2-enoate (8)
Triethylphosphonoacetate (56.0 g, 0.25 mol) was added dropwise to a stirred
suspension of sodium hydride (13.2 g, 60% dispersion in mineral oil, 0.33 mol) in
anhydrous tetrahydrofuran (THF) (300 mL) under a nitrogen atmosphere at 0 ꢂC.
The mixture was stirred for 30 min at room temperature, and then p-methylacetophe-
none (33.5 g, 0.25 mol) was added dropwise. The mixture was refluxed for 5 h,
poured into cold water, and extracted with ethyl acetate (3 ꢃ 300 mL). The combined
organic layer was dried (Na2SO4) and concentrated. The residue was purified on sil-
1
ica gel using ethyl acetate=light petroleum ether to give 8 (44.0 g, 86%) as an oil. H
NMR (200 MHz, CDCl3): d 1.31 (t, J ¼ 7.1 Hz, 3H), 2.35 (s, 3H), 2.57, (d, J ¼ 1.2 Hz,
3H), 4.20 (q, J ¼ 7.1 Hz, 2H), 6.13 (q, J ¼ 1.2 Hz, 1H), 7.16 (d, J ¼ 8.1 Hz, 2H), 7.38
(d, J ¼ 8.1 Hz, 2H); 13C NMR (50 MHz, CDCl3): d 14.3, 17.7, 21.1, 59.7, 116.2,
126.1, 129.1, 137.4, 139.1, 155.4, 166.9.

(ꢀ)-a-CUPARENONE
1955
(E)-3-(4-Methylphenyl)-but-2-en-1-ol (9)
LiAlH4 (0.892 g, 23.50 mmol) was added to the solution of compound 8 (4.05 g,
19.62 mmol) and anhydrous diethyl ether (20 mL) at 0 ꢂC. The temperature of the
reaction was allowed to attain room temperature and stirred further for 30 min.
Then a saturated solution of Na2SO4 (8 mL) was slowly poured into the reaction
mixture at 0 ꢂC. The solid separated was filtered off, and the filtrate was extracted
with ethyl acetate (2 ꢃ 40 mL). The combined organic layer was dried (Na2SO4)
and concentrated. The residue was purified on silica-gel chromatography using ethyl
acetate=light petroleum ether to give 9 (2.5 g, 79%) as thick oil. 1H NMR (200 MHz,
CDCl3): d 2.03 (s, 3H), 2.32 (s, 3H), 4.31 (d, J ¼ 6.6 Hz, 2H), 5.93 (m, 1H), 7.11 (d,
J ¼ 8.1 Hz, 2H), 7.29 (d, J ¼ 8.1 Hz, 2H); 13C NMR (50 MHz, CDCl3): d 15.8, 20.9,
59.7, 125.5, 127.5, 128.8, 136.8, 137.3, 139.8.
(2-Methyl-2-p-tolylcyclopropyl)methanol (10)
A 1 M solution of diethyl zinc in hexanes (18.5 mL, 18.5 mmol) and CH2I2
(2.5 ml, 30.84 mmol) was added dropwise to solution of compound 9 (1.0 g,
6.21 mmol) in anhydrous dichloromethane (8 mL) at ꢄ20 ꢂC under an N2 atmos-
phere, and stirred further for 12 h at the same temperature. The reaction mixture
was quenched with slow addition of saturated NH4Cl and warmed to rt. The layers
were separated, and aqueous layer was once again extracted with dichloromethane
(15 mL). The combined organic layer was washed with water, dried (Na2SO4), and
concentrated. The residue was purified on silica gel using ethyl acetate=light pet-
1
roleum as an eluent to furnish cyclopropyl derivative 10 (0.69 g, 64%) as a oil. H
NMR (200 MHz, CDCl3): d 0.61 (dd, J ¼ 5.3 Hz, 1H), 1.14 (dd, J ¼ 5.3 Hz, 1H),
1.40–1.49 (m, 1H), 1.48 (s, 3H), 2.37 (s, 3H), 3.73 (m, 1H), 3.92 (m, 1H), 7.16 (d,
J ¼ 7.9 Hz, 2H), 7.22 (d, J ¼ 7.9 Hz, 2H); 13C NMR (50 MHz, CDCl3): d 18.5,
20.5, 20.9, 24.4, 27.5, 63.4, 127.1, 128.9, 135.2, 144.6.
(2-Methyl-2-p-tolylcyclopropyl)methyl Bromide (6)
A solution of compound 10 (0.25 g, 1.42 mmol), PPh3 (0.744 g, 2.84 mmol), and
pyridine (0.5 mL), CBr4 (0.517 g, 1.56 mmol) in anhydrous dichloromethane (10 mL)
was taken in a round-bottomed flask. The reaction mixture was stirred for 1 h at
ambient temperature, and volatiles were evaporated. Chromatographic purification
of the resulting residue over silica gel afforded cyclopropyl bromide 6 (0.31 g, 91%).
1H NMR (200 MHz, CDCl3): d 0.55 (m, 1H), 1.19 (m, 1H), 1.35–1.47 (m, 1H), 1.44
(s, 3H), 2.36 (s, 3H), 3.30 (m, 1H), 3.35 (m, 1H), 7.16 (d, J ¼ 8.2 Hz, 2H), 7.22 (d,
J ¼ 8.2 Hz, 2H); 13C NMR (50 MHz, CDCl3): d 19.6, 20.9, 21.3, 26.5, 27.8, 39.0,
126.5, 129.0, 134.9, 144.2.
4-Methyl-4-(4-methylphenyl)-hepta-1,6-diene (5)
A solution of 6 (0.40 g, 1.67 mmol), allyltri-n-butyltin (1.11 g, 3.35 mmol), and
AIBN (10 mg) in anhydrous benzene (10 ml) was degassed with argon for 30 min.
The mixture was heated under reflux for 12 h and concentrated. The resulting residue

1956
I. SHIVAKUMAR, G. B. SALUNKE, AND S. KUMAR
was dissolved in diethyl ether (15 mL), and a saturated solution of KF (6 mL) was
added. After 1 h, the solid was filtered; the filtrate was dried (Na2SO4) and concen-
trated. The crude gem-diallyl compound was purified on silica gel using ethyl acet-
ate=light petroleum ether (1:30) to afford 5 (0.24 g, 72%) as an oil. 1H NMR
(200 MHz, CDCl3): d 1.26 (s, 3H), 2.32 (s, 3H), 2.22–2.32 (m, 2H), 2.40–2.51 (m,
2H), 4.85–4.97 (m, 4H), 5.38–5.54 (m, 2H), 7.16 (d, J ¼ 8.2 Hz, 2H), 7.29 (d,
J ¼ 8.2 Hz, 2H); 13C NMR (50 MHz, CDCl3): d 20.9, 24.2, 40.2, 46.9, 117.1, 126.3,
128.7, 135.0, 135.2, 144.1.
4-Methyl-4-(4-methylphenyl)-cyclopent-1-ene (4)
A degassed solution of 5 (0.1 g, 0.49 mmol) and Grubbs’ first-generation
catalyst (4 mg, 0.005 mmol) in benzene (15 mL) was heated under reflux. After 3 h,
reaction mixture was concentrated, and the residue was purified on silica gel using
ethyl acetate=light petroleum ether (1:19) as an eluent to obtain 4 (0.078 g, 91%)
as a colorless liquid. IR (neat): 816, 1216, 1650, 2926, 3022 cmꢄ1 1H NMR
;
(200 MHz, CDCl3): d 1.32 (s, 3H), 2.29 (s, 3H), 2.42 (d, J ¼ 14.9, 2H), 2.70 (d,
J ¼ 14.9, 2H), 5.70 (s, 2H), 7.06–7.19 (m, 4H); 13C NMR (50 MHz, CDCl3): d 20.8,
31.3, 45.6, 47.6, 125.8, 128.8, 129.2, 134.7, 148.6.
3-Methyl-3-(4-methylphenyl)-cyclopentanone (11)
BH3 ꢁ DMS reagent (1.39 mL, 14.63 mmol) was added to a solution of alkene 4
(1.40 g, 8.13 mmol) in anhydrous THF (10 mL) at 0 ꢂC. The mixture was stirred for 4 h
at the same temperature. It was then treated with aqueous NaOH (5 mL, 3 M) and
30% H2O2 (5 mL), gradually allowed to warm to rt, and further stirred for 3 h. Then
the reaction mixture was extracted with CH2C12. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated under vacuum. Purification by column
chromatography using ethyl acetate=light petroleum ether as an eluent afforded the
secondary alcohol (1.44 g, 93%). 1H NMR (200 MHz, CDCl3): d 1.29 (s, 3H),
1.68–2.31 (m, 6H), 2.28 (s, 3H), 4.32–4.51 (m, 1H), 7.09–7.21 (m, 4H); 13C NMR
(50 MHz, CDCl3): d 20.8, 30.9, 34.6, 38.2, 45.8, 49.6, 73.3, 125.6, 128.8, 134.8, 147.9.
IBX (2.94 g, 10.51 mmol) was added to a stirred solution of alcohol (1.0 g,
5.26 mmol) in anhydrous DMSO (10 mL), and the mixture was stirred at ambient
temperature for 4 h. After completion of reaction, the mixture was diluted with
ice-cold water (30 mL) and extracted with Et2O (2 ꢃ 20 mL). The combined organic
layer was then washed with water and brine, dried (Na2SO4), and concentrated. The
residue was purified on silica gel using ethyl acetate=light petroleum ether to give 11
1
(0.89 g, 90%) as a white solid. IR (CHCl3): 1245, 1614, 1722, 3021 cmꢄ1; H NMR
(200 MHz, CDCl3): d 1.36 (s, 3H), 2.19–2.67 (m, 6H), 2.33 (s, 3H), 7.15–7.28 (m,
4H); 13C NMR (50 MHz, CDCl3): d 20.7, 29.2, 36.1, 43.3, 52.5, 125.2, 129.0,
135.6, 145.3, 218.5.
(ꢀ)-a-Cuparenone (2)
LiHMDS (0.69 mL, 1.7 M, 1.17 mmol) and HMPA (0.01 mL, 0.06 mmol)
were added to the solution of compound 11 (0.10 g, 0.53 mmol) and anhydrous

(ꢀ)-a-CUPARENONE
1957
tetrahydrofuran (5 ml) cooled to ꢄ78 ꢂC. The reaction mixture was stirred for 2 h at
the same temperature, and then MeI (0.17 mL, 2.66 mmol) was added. The mixture
was further stirred for 5 h at the same temperature, and a saturated solution of
NH4Cl (2 mL) was added slowly. The mixture was extracted with ethyl acetate
(3 ꢃ 10 mL); the combined organic extracts were dried over Na2SO4 and concen-
trated. The residue was purified on silica gel using ethyl acetate=light petroleum ether
to give 2 (0.075 g, 65%) as a colorless oil. IR (neat): 1460, 1511, 1736, 2962 cmꢄ1; 1H
NMR (200 MHz, CDCl3): d 0.61 (s, 3H), 1.17 (s, 3H), 1.26 (s, 3H), 1.92 (m, 1H), 2.34
(s, 3H), 2.51 (m, 2H), 2.61 (m, 1H), 7.18–7.28 (m, 4H). 13C NMR (50 MHz, CDCl3):
d 18.3, 20.7, 21.9, 25.7, 29.7, 33.7, 48.2, 53.2, 126.4, 128.8, 135.6, 141.9, 222.7.
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