Synthesis in fluorous phase: A convenient synthesis of isolongifolene epoxide and its rearrangement to ketone

Article abstract of DOI:10.1016/S0022-1139(99)00243-2

Aerobic epoxidation of isolongifolene 1 with pivalaldehyde/oxygen in perfluoro-2-butyltetrahydrofuran (FC-75) in the presence of Mn(OAc)₃·2H₂O as catalyst yielded isolongifolene-epoxide 3 in good yield. The rearrangement of isolongifolene-β-epoxide to ketone 4 was achieved.

Full text of DOI:10.1016/S0022-1139(99)00243-2

Journal of Fluorine Chemistry 102 (2000) 51±53
Synthesis in ¯uorous phase: a convenient synthesis of isolongifolene
epoxide and its rearrangement to ketone
*
K.S. Ravikumar, Jean-Pierre B e gu e , Dani eÁ le Bonnet-Delpon, Mich eÁ le Our e vitch
Laboratoire BIOCIS associ e au CNRS, Centre d'Etudes Pharmaceutiques, Rue J.B. Cl e ment, 92296 Ch aà tenay-Malabry, France
Received 22 May 1999; received in revised form 18 June 1999; accepted 7 July 1999
Dedicated to Professor Paul Tarrant on the occasion of his 85th birthday
Abstract
Aerobic epoxidation of isolongifolene 1 with pivalaldehyde/oxygen in per¯uoro-2-butyltetrahydrofuran (FC-75) in the presence of
Mn(OAc) Á2H O as catalyst yielded isolongifolene-epoxide 3 in good yield. The rearrangement of isolongifolene-b-epoxide to ketone 4
3
2
was achieved. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Fluorous phase; Epoxidation; Terpenes; Aerobic oxidation; Manganese catalyst
1
. Introduction
nalized ole®ns in a ¯uorous solvent afforded epoxides in
very high yield [6]. These new neutral epoxidation condi-
tions appeared to be well adapted to the acid sensitive
isolongifolene system.
Longifolene 1 and its derivatives ®nd a major role in
fragrance industry. It is reported that the rearrangement of
longifolene performed with BF ÁOEt affords isolongifolene
Isolongifolene 2 (1 equivalent) was allowed to react with
oxygen/pivalaldehyde (3 equivalent) in per¯uoro-2-butylte-
trahydrofuran (FC-75) in the presence of Mn(OAc) Á2H O
3
2
2
[1,2,3]. However, this reaction occurs with a high rate of
racemization (ee 14%) [2]. We have observed that this
racemization could be greatly limited if the reaction was
performed in dichloromethane as solvent. Treatment of
longifolene 1 with BF ÁOEt in CH Cl at 358C for 8 h
3
2
(4 mol%) as catalyst and provided isolongifolene b-epoxide
1
3 (H-7: H NMR d ˆ 3.15, dd, J ˆ 2.2, 2.9 Hz) as the only
product in 64% yield (Scheme 1).
Treatment of longifolene 1 under the same aerobic oxida-
tion conditions led only to recovered ole®n 1. These results
3
2
2
2
afforded isolongifolene 2 in very good yield (91%) with an
optical rotation ([a]
D
ˆ � 66.68). The highest optical rotation
reported for isolongifolene 2 is ([a] ˆ 828) [3], when the
D
reaction is performed in AcOH/H SO medium, and after a
2
4
several step puri®cation [3].
Peracetic acid [4] and perbenzoic acid [1,3,5] oxidation of
isolongifolene 2 generally led to a mixture of compounds
such as epoxide, alcohol, ketone, and lactone, since the
longifolene system is prone to undergo acid catalyzed
rearrangement or overoxidation. Consequently, isolongifo-
lene epoxide 3 was isolated in poor yields after a laborious
separation protocol [3].
The use of the ``¯uorous phase'' has been shown to
present several advantages for oxidations in organic synth-
eses [6±12]. We have recently shown that the
Mn(OAc) Á2H O catalyzed aerobic oxidation of unfunctio-
3
2
*
Corresponding author. Tel.: 33-1-46-83-57-38; fax: 33-1-46-83-57-40.
E-mail address: jean-pierre.begue@cep.u-psud.fr (J.-P. B e gu e ).
Scheme 1.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 4 3 - 2

5
2
K.S. Ravikumar et al. / Journal of Fluorine Chemistry 102 (2000) 51±53
2
.2. Isolongifolene b-epoxide 3
To a stirred solution of isolongifolene (2.04 g, 10 mmol)
in FC-75 (5 ml) and toluene (5 ml) at 258C was added
Mn(OAc) Á2H O (0.11 g, 4 mol%). To this heterogeneous
3
2
biphasic solution, pivalaldehyde (3.2 ml, 30 mmol) was
added under an atmosphere of oxygen (bubbling throughout
the experiment). The reaction was followed by GC. After
complete disappearance of ole®n, a solution of 5% aqueous
K CO was added and the three phase system was stirred for
Fig. 1. nOe effects in ketones 4 and 5.
2
3
an additional 15 min (258C). The ¯uorous phase was
removed by phase separation. The reaction mixture was
extracted with ether (2 Â 10 ml) and it was washed with
con®rm that our reagent system does not effect terminal
double bonds, even 1,1 disubstituted ones, and that the
reaction conditions are mild enough to avoid any rearrange-
ment.
brine and dried (MgSO ). The solvent was evaporated and
4
the residue was dissolved in pentane (5 ml) and ®ltered
through a short silicagel column. Removal of solvent
afforded isolongifolene-b-epoxide 3 as a colorless oil
Surprisingly, we observed by NMR that the longifolene
epoxide 3 rearranged slowly in a solution of CDCl , in the
3
presence of tetramethylsilane, into the ketone 4 as the only
product. From a preparative point of view, the isomerisation
(1.4 g, 64%). [a]
n 1372, 1392, 1245, 922, 800 cm ; H NMR (CDCl ) d
D
ˆ � 11.68 (c ˆ 3.36, CHCl ); IR (neat)
3
�
1 1
3
to ketone 4 was faster when performed in CHCl with one
3
equivalent of TMS. Isomerisation of this ketone 4 under
basic conditions provided the ketone 5 [3].
0.75 (s, 3 H), 0.81 (s, 6 H), 0.89 (s, 3 H), 1.0±1.3 (m, 5 H),
1.3±1.6 (m, 2 H), 1.60±1.90 (m, 4 H), 3.15 (dd, J ˆ 2.15,
1
3
2.93 Hz, 1 H); C NMR (CDCl ) 20.8, 22.2, 24.5, 25.0,
3
Contradictory NMR data for ketones 4 and 5 have been
clari®ed [13], and the con®guration of these ketones has
been determined without ambiguity with the complete
assignment of H and C NMR spectrum and nOe experi-
ments (Fig. 1). In ketone 4, nOe effects were observed on
Me-11a and Me-12a by irradiation of H-7, while in ketone 5
irradiation of H-7 was accompanied by nOe effects to Me-
25.3, 26.6, 27.2, 30.2, 32.9, 36.6, 39.3, 46.6, 52.3, 57.0,
72.6.
1
13
2.3. Ketone 4
A solution of isolongifolene epoxide 3 (200 mg) in
CHCl (3 ml) was kept at room temperature in the presence
3
1
1b and Me-12b.
In conclusion, we have reported an improved method for
of TMS (100 mg) for 16 h. Evaporation of solvents provided
1
the pure ketone 4 [3]. (196 mg, 98%); H NMR (CDCl ) d
3
the preparation of isolongifolene 2 and the clean preparation
of pure isolongifolene-b-epoxide 3 in good yield. Finally
the quantitative conversion of b-epoxide 3 into the ketone 4
was achieved under smooth conditions.
0.85 (s, 3 H, CH -11b), 0.9 (s, 3 H, CH -12a), 0.92 (m, 1 H,
H-4b), 1.00 (s, 3 H, CH -11a), 1.02 (dd, J
3
3
ˆ 1.6 Hz,
3
1a-2
J1a-1b ˆ 9.7 Hz, 1 H, H-1b), 1.19 (ddd, J
ˆ 12.4 Hz,
5a-5b
J5b-4a ˆ 3.7 Hz, J
ˆ 6.7 Hz, 1 H, H-5b), 1.26 (s, 3 H,
5b-4b
CH -12b), 1.29 (ddd, J
3
ˆ 2.3 Hz, J
ˆ 6.5 Hz,
1a-7 1a-2
10b-9b
10b-9a
J10b-10a ˆ 13.6 Hz, 1 H, H-10b), 1.38 (J
ˆ J
ˆ
2
. Experimental section
J1a-5b ˆ 2.8 Hz, J
H-4a), 1.55 (m, J1
H-2), 2.01 (ddd,
ˆ 9.7 Hz, 1 H, H-1a), 1.4 (m, 1 H,
ˆ 5.5 Hz, 1 H, H-10a), 1.56 (m, 1 H,
1a-1b
0a-9a
2
.1. Isolongifolene 2
J
9
ˆ 5.5 Hz,
J
ˆ 2.3 Hz,
ˆ 1.1 Hz,
b-10a
9b-10b
9a-10a
J9b-9a ˆ 15.4 Hz, 1 H, H-9b), 2.08 (ddd, J
To a stirred solution of longifolene (20.4 g, 0.1 mol) in
dry CH Cl (20 ml), was added BF ÁOEt (0.5 ml) and the
J9a-10b ˆ 6.5 Hz, J
ˆ 15.4 Hz, 1 H, H-9a), 2.13 (d,
9a-9b
13
J9-7'a ˆ 2.8 Hz, 1 H, H-7); C NMR (CDCl ) d 23.1
2
2
3
2
3
reaction was stirred for a further 8 h at 358C. The crude
(CH -11a), 23.4 (CH -12b), 23.6 (C-5), 25.4 (CH -11b),
3
3
3
product was poured into aqueous NaHCO solution and
extracted with CH Cl (2 Â 25 ml), washed with brine and
26.5 (C-4), 32.7 (CH -12a), 33.5 (C-11), 36.7 (C-1), 37.8
3
3
(C-10), 38.3 (C-12), 40.1 (C-9), 49.0 (C-2), 59.9 (C-6), 60.5
(C-7), 211.3 (C=O).
2
2
dried (MgSO ). Removal of solvent followed by bulb-to-
4
bulb distillation afforded isolongifolene 2 as a colourless oil
(
[
(
(
18.6 g, 91%). bp 82±838C/0.4 mm (lit. 105±1068C/6 mm
2.4. Ketone 5
2]) ; [a]
D
ˆ � 66.68 [(c ˆ 3.56, CHCl , lit. [a] ˆ � 74.88
D
3
�
1 1
CHCl )] [2]; IR (neat): n 1363, 1378, 820 cm ; H NMR
A suspension of ketone 4 (40 mg) and alumina (2 g) in
petrol ether (4 ml) was stirred for 22 h at room temperature,
®ltration from the alumina provided pure ketone 5 (39 mg)
3
CDCl ) d 0.85 (s, 3 H), 0.94 (s, 3 H), 0.96 (s, 3 H), 1.05 (s, 3
3
H), 1.16±1.24 (m, 2 H), 1.32±1.52 (m, 3 H), 1.6±1.8 (m, 4
13
1
H), 1.88±2.0 (m, 2 H), 5.14 (t, J ˆ 3.3 Hz, 1 H); C NMR
[3]. H NMR (CDCl ) d 0.90 (s, 3 H, CH -11a), 0.91 (s, 3 H,
3
3
(
CDCl ): d 22.9, 24.2, 24.9, 25.7, 26.6, 29.0, 31.2, 33.9,
CH -12a), 0.97 (s, 3 H, CH -11b), (m, 1 H, H-4b), 1.06 (dd,
J1b-2 ˆ 6.1 Hz, J1b-1a ˆ 12.0 Hz, 1 H, H-1b), 1.17 (s, 3 H,
3
3 3
3
6.8, 42.0, 46.7, 56.0, 110.67, 155.54.

K.S. Ravikumar et al. / Journal of Fluorine Chemistry 102 (2000) 51±53
53
CH -12b), 1.23 (m, 1 H, H-5a), 1.48 (ddd, J4a-5b ˆ 7.7 Hz,
3
J4a-4b ˆ 13.8 Hz, J
ˆ 2.6 Hz, 1 H, H-4a), 1.60 (J
ˆ
4a-5a
1a-2
6
1
8
0
.1 Hz, J ˆ 12.3 Hz, 1 H, H-1a), 1.72 (m, 1 H, H-5b),
.73 (m, 1 H, H-7), 1.80 (m, 1 H, H-2), 1.93 (dddq, J
1
a-1b
ˆ
ˆ
1
0a-9b
.1 Hz, J10a-9a ˆ 11.1 Hz, J
ˆ 19.2 Hz, J
9b-10a
10a-10b
10a-11
.5 Hz,
1
H, H-10a), 2.27 (ddd,
J
ˆ 8.0 Hz,
J9b-10b ˆ 2.7 Hz, J
ˆ 19.4 Hz, 1 H, H-9b), 2.36 (dddd,
References
9b-9a
J9a-10a ˆ 11.1 Hz,
J
ˆ 7.7 Hz,
J
ˆ 19.4 Hz,
3
9a-10b
9a-9b
1
3
J9a-2 ˆ 1.3 Hz, 1 H, H-9a); C NMR (CDCl ) d 23.2
[1] U.R. Nayak, S. Dev, Tetrahedron 8 (1960) 42±48.
[
[
2] R.E. Beyler, G. Ourisson, J. Org. Chem. 30 (1965) 2838±2839.
3] R. Ranganathan, U.R. Nayak, T.S. Santhanakrishnan, Dev Sukh,
Tetrahedron 26 (1970) 621±630.
(
CH -11a), 24.5 (C-5), 25.9 (CH -11b), 26.0 (CH -12a),
3 3 3
2
8.1 (CH -12b), 30.9 (C-5), 31.6 (C-7), 34.9 (C-10), 37.1
3
(
(
C-9), 37.9 (C-1), 44.1 (C-3), 48.4 (C-2), 56.3 (C-6), 63.9
C-7), 214.5 (C=O).
[
4] L.K. Lala, J.B. Hall, J. Org. Chem. 35 (1965) 1172±1173.
[5] T.S. Santhanakrishnan, U.R. Nayak, Dev Sukh, Tetrahedron 26
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(
[
[
[
6] K.S. Ravikumar, F. Barbier, J.P. B e gu e , D. Bonnet-Delpon,
Tetrahedron 54 (1998) 7447±7464.
7] R.D. Chambers, G. Sandford, A. Shah, Synth. Commun. 26 (1996)
Acknowledgements
1
861±1866.
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47±452.
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One of the authors, K.S. Ravikumar thanks CEFIPRA and
CNRS for associate researcher position.
(
4
[
[
[
[
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Appendix A.
Epoxidation of isolongifolene could be realized cleanly
and selectively under aerobic conditions using a ¯uorous
phase.
(
1998) 3141±3144.
13] E.H. Eschinasi, G.W. Shaffer, A.P. Bartela, Tetrahedron Lett. (1970)
3523±3526.