Two-carbons homologation of methyl ketones examplified for the synthesis of citral from 6-methyl-5-hepten-2-one

Article abstract of DOI:10.1081/SCC-120017196

New facile syntheses of 3,7-dimethyl-octadien-2,6-al (citral) from homologation of 6-methyl-5-hepten-2-one are reported.

Full text of DOI:10.1081/SCC-120017196

This article was downloaded by: [McGill University Library]
On: 03 January 2013, At: 12:52
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Two-Carbons Homologation of Methyl Ketones
Examplified for the Synthesis of Citral from 6-Methyl-5-
hepten-2-one
a
a
a
a
a
Alain Valla , Dominique Cartier , Alain Laurent , Benoist Valla , Roger Labia & Pierre
b
Potier
a
Chimie et Biologie des Substances Naturelles, Quimper, France
b
Institut de Chimie des Substances Naturelles, Gif-sur-Yvette Cedex, France
Version of record first published: 21 Aug 2006.
To cite this article: Alain Valla , Dominique Cartier , Alain Laurent , Benoist Valla , Roger Labia & Pierre Potier (2003): Two-
Carbons Homologation of Methyl Ketones Examplified for the Synthesis of Citral from 6-Methyl-5-hepten-2-one, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:7, 1195-1201
To link to this article: http://dx.doi.org/10.1081/SCC-120017196
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should
be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims,
proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in
connection with or arising out of the use of this material.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 7, pp. 1195–1201, 2003
Two-Carbons Homologation of Methyl Ketones
Examplified for the Synthesis of Citral from
6
-Methyl-5-hepten-2-one
1
,
1
1
Alain Valla, * Dominique Cartier, Alain Laurent,
1
1
Benoist Valla, Roger Labia, and Pierre Potier
2
1
Chimie et Biologie des Substances Naturelles,
Quimper, France
2
Institut de Chimie des Substances Naturelles,
Gif-sur-Yvette Cedex, France
ABSTRACT
New facile syntheses of 3,7-dimethyl-octadien-2,6-al (citral) from
homologation of 6-methyl-5-hepten-2-one are reported.
Key Words: Citral; Geranial; Neral; 6-Methyl-5-hepten-2-one.
*
Correspondence: Alain Valla, Chimie et Biologie des Substances Naturelles,
FRE 2125 CNRS 6, rue de l’Universite–29000 Quimper, France; E-mail: alain.
´
valla@univ-brest.fr.
1
195
DOI: 10.1081/SCC-120017196
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1
196
Valla et al.
The aldehyde ‘citral’ 1 is the most important of the acyclic mono-
[
terpenoids, occurring in many essential oils. Itwas firstisola te d in 1888
1]
[2]
by Bertram from the oil of Backhousia citriodora. Citral is the principal
[
3]
constituent (75–85%) of the oil of lemon grass, presentas a mix tu re of
two geometric isomers of 3,7-dimethyl-octadien-2,6-als (Sch. 1).
[
This aldehyde has been synthesised by different methods and is
4]
[
5]
therefore of current interest. Itis commonly used as an impor at nt
intermediate for the production of b-ionone, on which all industrial
syntheses of vitamin A, b-carotene and related compounds are based.
We report here new syntheses of citral 1 via 6-methyl-5-hepten-2-one
2
. Noteworthy is the fact that only a few examples of the preparation of
[
6]
[7]
[8]
this ketone from smaller synthons (C-4, C-5, C-7 ) have been
reported. We synthesised ketone 2 by a modification of the versatile
procedure of Esikova and Yufit in which ethyl acetoacetate is con-
densed with 1-bromo-3-methyl-but-2-ene (NaH/ether, 24 h, r.t.).
[
7]
Hydrolysis of the intermediate b-ketoester (NaOH/EtOH-H O, reflux,
2
[
9,10]
6
h) gave the 6-methyl-5-hepten-2-one 2 (Sch. 2).
We have developed four synthetic routes to citral 1 starting from this
synthon 2.
The first proceeds via compound 3 (3,7-dimethyl-2,6-octadieneni-
trile). This derivative has been previously synthesised by a Knoevenagel
Scheme 1.
Scheme 2.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3
,7-Dimethyl-octadien-2,6-al
1197
[
8]
condensation of cyanoacetic acid with 6-methyl-5-hepten-2-one or a
Horner-Emmons reaction with cyanomethylphosphonic acid diethyl
[7]
ester.
A more efficient synthesis was achieved by condensation of 2 and
[
acetonitrile in the presence of solid KOH (reflux, 4 h, 65%), affording
11]
the dienenitrile 3 (80%) as a mixture of E/Z isomers (80:20). Subsequent
ꢀ
reduction [1) DIBAL-H/toluene, 0 C 30 min 2) HCl 10%, 95%] led to
citral 1 (Sch. 3).
A second process consisted of a Horner–Emmons reaction of ketone
ꢀ
[12]
with triethyl phosphonoacetate [1) NaH/DME, 0 C then reflux, 4 h
2
2
) NH Cl, 85%]. Reduction of the ester 4 with DIBAL-H [1) DIBAL-
4
ꢀ
ꢀ
H/toluene, 0 C then 5 C, 2 h 2) H O, 90%], afforded the allylic alcohol 5,
2
which was oxidised with manganese dioxide (MnO /pentane, r.t. 12 h,
2
9
0%) to citral 1 (Sch. 4).
A third route was by way of a Wittig and Hesse synthesis using the
[
13]
allylic imine 6
ꢀ
BuLi/THF 0 C 15 min, 2/THF 0 C then r.t. 4 h 2) NH Cl]. Citral was
derived from N-ethylidenecyclohexylamine
ꢀ
[1)
4
obtained by smooth acid-catalysed hydrolysis of 6 (by column chroma-
tography (SiO /CH Cl , 95%) or (COOH) 2%, r.t. 12 h, 60% or
HCOOH/HCOONa/cyclohexane/H O, r.t. 12 h, 75%) (Sch. 5).
2
2
2
2
2
In the fourth synthesis, condensation of diethyl 2-cyclohexylamino-
[
vinylphosphonate (submitted by Nagata et al in Org. Synth. ) wit h
14]
ꢀ
ketone 2 [a) NaH, ether, 0 C, 15 min then r.t. 4 h. b) 1 M HCl], led
directly to citral (Sch. 6).
Scheme 3.
Scheme 4.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1
198
Valla et al.
Scheme 5.
Scheme 6.
EXPERIMENTAL
All reactions were carried out under an argon atmosphere. All the
compounds are known in the literature and gave satisfactory IR
1
13
(
recorded on a Bruker IFS 55 spectrometer), H NMR and C NMR
determined on a Bruker Avance DPX 400 spectrometer) spectral ana-
(
lyses.
[11,15]
[16]
The Chemical Abstracts nomenclature is used below.
-methyl-5-hepten-2-one (2). Ethyl acetoacetate (5 mM, 6.5 g) was
6
slowly added at0 C to a stirred suspension of NaH (5 mM, 2 g) in
ꢀ
ꢀ
ether (25 mL). After 15 min at 0 C, 4-bromo-2-methyl-1-buten (5 mM,
4.45 g) in ether (25 mL) was added and after stirring at room temperature
for 24 h, the reaction mixture was hydrolysed by a saturated solution of
NaCl. The reaction mixture was extracted with ether (2 Â 25 mL) and the
organic layer was washed with water (2 Â 25 mL) and dried over anhy-
drous Na SO . Solvent was evaporated and the oily product was rectified
2
4
under reduce pressure to provide the b-ketoester, as a colourless oil
82%). 2 g of the obtained b-ketoester and a solution of NaOH (8 mM,
(
3
.2 g) in water (50 mL) and ethanol (30 mL) were refluxed for 6 h. The
ꢀ
solution was acidified at 0 C by a solution of 20% HCl and extracted
with ether (2 Â 25 mL). The organic layer was washed with water and
dried over Na SO . The solventwas evapora et d and ht e crude product
2
4
was purified by column chromatography (SiO -CH Cl /MeOH: 97/3).
2
2
2
Colourless oil.–C H O (126.20): Calcd. C 76.14, H 11.18, O 12.68;
8
14
found C 75.99 H 11.24 O 12.77.
,7-dimethyl-2,6-octadienenitrile (3). 2 (8 mM, 10.08 g) in MeCN
3
(
(
100 mL) was slowly added to a stirred solution of powered KOH
8 mM, 5.5 g) in MeCN (100 mL) at reflux. After 4 h at this temperature,
1
50 mL of cold water was added and the crude mixture was extracted
with ether (2 Â 100 mL). The organic layer was washed with water
2 Â 50 mL) and dried over Na SO . The solventwas evapora et d and
(
2
4

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3
,7-Dimethyl-octadien-2,6-al
1199
the crude product, purified by column chromatography (column chroma-
tography (SiO -CH Cl ), yielded the 3,7-dimethyl-2,6-octadienenitrile, as
a mixture of isomers (E/Z: 80/20). Colourless oil (65%) C H N
2
2
2
1
0
15
(
149.12): Calcd. C 80.48, H 10.13, N 9.39; found C 80.31 H 10.22 O 9.47.
Citral (1) via 3. DIBAL-H (1 mM, 1.42 g) in toluene (as a 1 M sol)
ꢀ
was slowly added at0 C to a stirred solution of 3 (1 mM, 1.49 g) in
toluene (10 mL). After 30 min, the reaction mixture was slowly hydro-
lysed by a solution of 10% HCl (50 mL). The salts were filtered off and
washed with ether (2 Â 25 mL). The organic layer was washed with brine
and dried over Na SO . The solventwas evapora te d and th e crude prod-
2
4
uctwas purified by column chroma ot graphy (SiO /CH Cl ) to provide
2
2
2
citral, as a mixture of isomers (E/Z: 80/20). Yellow oil (65%).
Ethyl 3,7-dimethyl-2,6-octadienoate (4). Triethylphosphonoacetate
ꢀ
(
(
8 mM, 17.9 g) was slowly added at0 C to a stirred suspension of NaH
8 mM, 3.2 g, as a 60% dispersion in mineral oil) in DME (25 mL). After
ꢀ
15 min at0 C, 3 (8 mM, 10.1 g) in DME (10 mL) was slowly added and
the solution was refuxed for 4 h. The mixture was treated at 0 C by a
ꢀ
saturated solution of NH Cl (25 mL) and extracted with ether
4
(
Na SO . The solvent was evaporated and the crude product was purified
2 Â 25 mL). The organic layer was washed with water and dried over
2
4
by column chromatography (SiO -CH Cl /MeOH: 99/1). Yellow oil
2
2
2
ꢀ
E/15 125 C, 85%) C H O (196.29): Calcd. C 73.43, H 10.27,
12 20 2
(
O 16.30; found C 73.27 H 10.41 O 16.32.
3,7-dimethyl-2,6-octadien-1-ol (5). DIBAL-H (2 mM, 2.84 g) in
toluene (as a 1 M sol) was slowly added at 0 C to a stirred solution of
ꢀ
ꢀ
3
(1 mM, 1.96 g) in toluene (10 mL). After 2 h at 5 C, the reaction mixture
was slowly hydrolysed by a solution of 10% HCl (100 mL). The salts were
filtered off and washed with ether (2 Â 25 mL). The organic layer was
washed with brine and dried over Na SO . The solventwas evapora et d
2
4
and the crude product was purified by column chromatography (SiO2-
CH Cl /MeOH: 97/3). Yellow oil (90%) C H O (154.25): Calcd.
C 77.84, H 11.76, O 12.37; found C 77.78 H 11.93 O 10.29.
2
2
10 18
Citral (1) via 5. MnO (7.5 mM, 6.5 g) in suspension in pentane
2
(
30 mL) and 5 (1 mM, 1.54) were stirred at r.t. for 12 h. The crude mixture
was filtered off and the precipitated salt was washed with
pentane (30 mL). The citral was purified by column chromatography
(SiO -CH Cl /MeOH: 99/1) and obtained in 90% yield, as a mixture of
2 2 2
isomers (E/Z: 80/20, 90%).
Citral (1) via 6. BuLi (1 mM) in hexanes (as a 1.6 M sol) was slowly
ꢀ
added at0 C t o t he -N( 3,7-dimethyl-2,6-octadienylidene) cyclohexana-
mine 6 (1 mM) in THF (10 mL) (obtained by using the procedure of
[13]
Wittig and Hesse ). After 15 min, (2) (1 mM) in THF (10 mL) was

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1
200
Valla et al.
slowly added and the solution was stirring at r.t. for 4 h. The mixture was
quenched with a saturated solution of NH Cl (30 mL) and citral was
4
obtained by smooth acid-catalysed hydrolysis: by column chromatogra-
phy, (SiO /CH Cl , 95%), oxalic acid (with 10 eq. of a 2% solution, 60%)
atr.t for 12 h or formic acid (HCOOH/HCOONa/cyclohexane/H 2O,
2
2
2
1
5 eq., 75%) atr. t. for 12 h.
[
14]
Citral (1) via 2. Diethyl 2-cyclohexylaminovinylphosphonate
1 mM) in THF (20 mL) was added to a stirred suspension of NaH
(
(
ꢀ
1 mM, dispersed in oil), at0 C. After 15 min, 2 (1 mM) in
THF (20 mL) was added and the solution was stirred at r.t. for 4 h.
The mixture was quenched by a saturated solution of NH Cl (30 mL)
4
and extracted with ether (2 Â 25 mL). The organic layer was washed with
water (2 Â 25 mL) and dried over MgSO . The citral was purified
4
by column chromatography (SiO -CH Cl /MeOH: 99/1) and produced
2
2
2
with 85% yield.
ACKNOWLEDGMENTS
We are indebted to Dr. R. H. Dodd for helpful discussions.
REFERENCES
1
. For reviews: Simonsen, J.L. The terpenes 1947, vol. I, 83–100.
Guenther, E. The Essential Oils 1949, vol. II, 326–36.
. Bertram, J. Schimmel’s Report 1888, April, p. 17.
. Dodge, F.D. Am. Chem. J. 1890, 12, 553–64; Tiemann, F. Chem.
Ber. 1898, 31, 3278–96; Naves, Y.R. Chem. Zentralbl. 1931, 102,
2
3
3
1
1
2
29–330; Rutowski, B.N.; Winogradowa, I.W. Chem. Zentralbl.
930, 101, 3618–20; Hibber, H.; Cannon, L.T. J. Am. Chem. Soc.
924, 46, 119–30; Krishna, H.J.V.; Joshi, B.N. J. Org. Chem. 1957,
2, 224–26.
4. Witzeman, J.S.; Nottingham, W.D. J. Org. Chem. 1991, 56, 1713–18;
Ooi, T.; Maruoka, K.; Yamamoto, H. Tetrahedron 1994, 50,
6505–22; Sarma, B.K.; Barua, N.C. Indian J. Chem. Sect. B 1993,
32, 615–17; Sobenina, L.N.; Mikhaleva, A.I.; Petrova, O.V.;
Polovnikova, R.I.; Trofimov, B.A. Russ. J. Org. Chem. 1997, 33,
041–42; Harris, C.E.; Chrisman, W.; Bickford, S.; Lee, L.Y.;
Torreblanca, A.E.; Singaram, B. Tetrahedron Lett. 1997, 38,
81–84; Progrebnoi, S.I.; Kalyan, Y.B.; Krimer, M.Z.; Smit, W.;
Scheller, M.E.; Frei, B. Helv. Chim. Acta. 1992, 75, 69–78.
1
9

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3
,7-Dimethyl-octadien-2,6-al
1201
5. Shinada, T.; Yoshihara, K. Tetrahedron Lett. 1995, 36, 6701–04;
Wei, H.-X.; Schlosser, M. Chem. Europ. J. 1998, 4, 1738–43;
Kumar, R.; Pais, G.C.G.; Pandey, B.; Kumar, P. J. Chem. Soc.
Chem. Commun. 1995, 13, 1315–16; Neumann, R.; Juwiler, D.
Tetrahedron 1996, 52, 8781–88; Picquet, M.; Bruneau, C.;
Dixneuf, P. Chem. Commun. 1997, 13, 1201–02; Marko, I.E.;
Giles, P.R.; Tsukazaki, M.; Chelle-Regnault, I.; Urch, C.J.;
Brown, S.M. J. Am. Chem. Soc. 1997, 119, 12661–62; Bobbit,
J.M. J. Org. Chem. 1998, 9367–74.
6
7
. Boccara, N.; Maitte, P. Bull. Soc. Chim. Fr. 1972, 1448–62.
. Witzeman, J.S.; Nottingham, W.D. J. Org. Chem. 1991, 56,
1713–18; Esikova, I.; Yuffit, S.S.A. Bull. Acad. Sci. USSR Div.
Chem. Sci. 1980, 29, 328–35; Gebhard, R.; Courtin, J.M.L.;
Shadid, J.B.; van Haveren, J.; van Haeringen, C.J.; Lugtenburg, J.
Recl. Trav. Chim. Pays-Bas 1989, 108, 207–14; Sobenina, L.N.;
Mikhaleva, A.I.; Petrova, O.V.; Polovnikova, R.I.; Trofinov, B.A.
Russ. J. Org. Chem. 1997, 33, 1041–42.
8
9
. Sarycheva, I.K.; Shustorovitch, E.M.; Vorob’eva, G.A.;
Preobrazhenskii, N.A. Zh. Obshch. Khim. 1959, 29, 1189; Engl.
Ausg. 1159–62.
. Piva, O. Tetrahedron 1994, 50, 13687–96.
1
1
0. Cuvigny, T.; Julia, M. J. Organomet. 1987, 331, 121–38.
1. Andriamialisoa, Z.; Valla, A.; Zennache, S.; Giraud, M.; Potier, P.
Tetrahedron Lett. 1993, 34, 8091–92.
1
2. Inoue, S.; Tanaka, H.; Tani, K.; Otsuka, S.; Sato, T.; Noyori, R.
J. Am. Chem. Soc. 1990, 112, 4897–905; Zahn, T.J.; Ksebati, M.B.;
Gibbs, R. Tetrahedron 1998, 39, 3991–94.
1
1
1
3. Wittig, G.; Hesse, A. Org. Synth. Coll. (Wiley & Sons, Inc.) 1988, 6,
9
01–04.
4. Nagata, W.; Wakabayashi, T.; Hayase, Y. Org. Synth. Coll. (Wiley
Sons, Inc.) 1988, 6, 448–50.
&
1
5. H NMR: Yamase, T.; Usami, T. J. Chem. Soc. Dalton Trans. 1988,
83–90; Schneider, R.; Schaefer, H.J. Synthesis 1989, 10, 742–43;
1
Green, G.; Griffith, W.; Hollinshead, D.; Ley, S.; Schroeder, M.
J. Chem. Soc. Perkin Trans. 1984, 4, 183–90; IR: Yang, L.; Li, B.
Synth. Commun. 1991, 21, 1521–26.
16. IUPAC Commission on the nomenclature of Organic Chemistry,
Pure Appl. Chem. 1975, 41, 407.
Received in the USA May 15, 2002

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.