Optimization of the microwave-assisted ortho ester claisen rearrangement: Application to monoterpenols

Article abstract of DOI:10.1080/00397910902985515

Two monoterpenols, perillyl alcohol and nerol, have been converted into their,-unsaturated ester derivatives following a modified process of microwave-assisted ortho ester Claisen rearrangement. The yields obtained (90%) are better than those previously obtained. The optimized process needs less reaction time (5min), smaller amount of reagent, and no solvent.

Full text of DOI:10.1080/00397910902985515

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Optimization of the Microwave-Assisted
Ortho Ester Claisen Rearrangement:
Application to Monoterpenols
Florence Mehl a , Isabelle Bombarda a , Carine Franklin b & Emile M.
Gaydou a
a Paul Cezanne University, Faculty of Sciences and Technology
of Saint-Jérôme, Molecular Science Institute of Marseille,
Phytochemistry Group, Marseille, France
b Technological University Institute of Marseille, Chemistry
Department, Marseille, France
Published online: 06 Jan 2010.
To cite this article: Florence Mehl , Isabelle Bombarda , Carine Franklin & Emile M. Gaydou
(2010): Optimization of the Microwave-Assisted Ortho Ester Claisen Rearrangement: Application to
Monoterpenols, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:3, 462-468
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Synthetic Communications1, 40: 462–468, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902985515
OPTIMIZATION OF THE MICROWAVE-ASSISTED
ORTHO ESTER CLAISEN REARRANGEMENT:
APPLICATION TO MONOTERPENOLS
Florence Mehl,1 Isabelle Bombarda,1 Carine Franklin,2 and
Emile M. Gaydou1
1Paul Cezanne University, Faculty of Sciences and Technology of
´ ˆ
Saint-Jerome, Molecular Science Institute of Marseille, Phytochemistry
Group, Marseille, France
2Technological University Institute of Marseille, Chemistry Department,
Marseille, France
Two monoterpenols, perillyl alcohol and nerol, have been converted into their c,d-unsatu-
rated ester derivatives following a modified process of microwave-assisted ortho ester
Claisen rearrangement. The yields obtained (>90%) are better than those previously
obtained. The optimized process needs less reaction time (5 min), smaller amount of
reagent, and no solvent.
Keywords: Focused microwave; Johnson–Claisen; monoterpenol; ortho ester rearrangement
INTRODUCTION
In 1970, Johnson et al.[1] reported a variant of the original Claisen rearrange-
ment. Instead of the conventional method,[2] generating a c,d-unsaturated aldehyde
from allyl alcohols via the corresponding allyl vinyl ethers, Johnson and coworkers
developed a one-pot procedure for generating c,d-unsaturated esters from allyl alco-
hols. In this method, heating an allyl alcohol 1 in an excess of triethyl orthoacetate
(TEOA) in the presence of a trace amount of a weak acid furnishes the correspond-
ing c,d-unsaturated esters 4; this is now commonly referred as the ortho ester Claisen
rearrangement (Scheme 1). This is a very useful reaction in organic synthesis to
create a quaternary center in a one-pot reaction.
The use of microwave heating is attractive in organic synthesis.[3] Microwave
irradiation has been shown not only to reduce reaction times but to provide better
yields of the desired products than conventional heating methods.[4–7] The micro-
wave heating technique[8–10] was used to carry out the ortho ester Claisen rearrange-
ment. In 1995, Srikrishna et al.[8] described the application of the microwave heating
Received February 2, 2009.
Address correspondence to Isabelle Bombarda, Universite´ Paul Ce´zanne, Faculte´ des Sciences et
´ ˆ
Techniques de Saint-Jerome, UMR CNRS 6263, Institut des Sciences Moleculaires de Marseille,
AD2EM, LSCC, Groupe Phytochimie, Boıte 461, Avenue Escadrille Normandie Niemen, F-13397
´
ˆ
´
Marseille Cedex 20, France. E-mail: isabelle.bombarda@univ-cezanne.fr
462

MICROWAVE-ASSISTED ORTHO ESTER CLAISEN REARRANGEMENT
463
Scheme 1. Mechanism of the ortho ester Claisen rearrangement.
technique for rapid generation of c,d-unsaturated esters by acceleration of the ortho
ester Claisen rearrangement. To carry out this rearrangement using microwave
heating, a domestic microwave oven was employed. They experimented with differ-
ent conditions [no solvent, methanol, chloroforme, hexane, dimethylformamide
(DMF), in sealed tubes or in open vessels] and chose DMF as the best solvent
because of its high dielectric constant and boiling point, and therefore reactions were
carried out in open vessels.
In this work, the ortho ester Claisen rearrangement was carried out in sealed
tubes, without solvent, in a high-powered, focused microwave oven and with
magnetic stirring. In the case of our reaction, the microwave increased reaction rates
with thermal effect.[11] In fact, using microwave technology, products were heated
directly instead of by convection and conduction, and we could work at a controlled
temperature (190ꢀC). A Biotage focused microwave with its powerful 400-W
magnetron delivers precise heating control (measured by infrared, IR). Heating at
this temperature was not possible with an oil bath because the temperature was
limited by the boiling point of the reagent (138ꢀC). We have screened microwave
irradiation conditions (temperature and time), the molar ratio of terpenol=TEOA,
and the role of solvent to optimize the process.
RESULTS AND DISCUSSION
The microwave-assisted ortho ester Claisen rearrangement was investigated
with two monoterpenols: perillyl alcohol 5 and nerol 7. The corresponding c,d-
unsaturated esters 6 and 8 (Schemes 2 and 3) have already been obtained from
these two monoterpenols under classical conditions (heating 8 h at 140ꢀC with
7 eq of TEOA), and only ester 8 was synthesized under microwave irradiation
conditions.
Scheme 2. Synthesis of c,d-unsaturated esters 6 from perillyl alcohol 5.

464
F. MEHL ET AL.
Scheme 3. Synthesis of c,d-unsaturated esters 8 from nerol 7.
Under classical conditions, esters 6 and 8 (140ꢀC, 8 h, 7 eq) were obtained
with yields similar to those obtained previously,[12,13] 84% (81% in literature) and
42% (67% after saponification in literature), as shown in Tables 1 and 2 (entries a
and a0).
When nerol 7 was heated in a focused microwave oven at 190ꢀC for 15 min in
dry DMF (entry b0, Table 2), as described in the literature,[8] ester 8 was obtained
with a yield similar to that previously given.[8] This microwave-assisted synthesis
increased the yield of 8 from 42% up to 82% (entries a0 and b0).
The reaction can give better yield without the use of solvent. In fact, the ester 6
was obtained from perillyl alcohol 5 with 95% yield (entry b) using the same method
given for ester 8 in entry b0 but without solvent. TEOA possess a dielectric constant,
so it absorbs microwave energy, which is converted into warmth. Our process does
not need any solvent, in contrast to that of Srikrishna et al.[8]
As shown in entries b, c, and d, the best amount of TEOA was found to be 14
eq. This result was confirmed with nerol because we obtained 87% yield for 8 using
14 eq of TEOA and 82% using 27 eq.
Three reaction times were tested with 7 eq of TEOA, and the best result (75%)
was obtained after 5 min for 6 (entries d, e, and f). This optimized time was
confirmed for 8 because we obtained a better yield in 5 min (93%) than in 15 min
(87%, entries c0 and d0).
Table 1. Johnson–Claisen rearrangement from perillyl alcohol 5 using either classi-
cal or microwave heating
Entry Temperature (ꢀC) Time (min)
5:(EtO)3CMea
Product Yield (%)
a
b
c
d
e
f
140b
190c
190c
190c
190c
190c
190c
480
15
15
15
10
5
1:7
6
6
6
6
6
6
6
84
95
95
73
70
75
99
1:27
1:14
1:7
1:7
1:7
g
5
1:14
aMolecular ratio.
bIn oil bath.
cUnder microwaves.

MICROWAVE-ASSISTED ORTHO ESTER CLAISEN REARRANGEMENT
465
Table 2. Johnson–Claisen rearrangement from nerol 7 using either classical
or microwave heating
Entry Temperature (ꢀC) Time (min) 7:(EtO)3CMea Product Yield (%)
a0
b0
c0
140b
190c
190d
190d
480
15
15
5
1:7
8
8
8
8
42
82
87
93
1:27
1:14
1:14
d0
aMolecular ratio.
bIn oil bath.
cIn DMF.
dUnder microwaves.
With this study, we proved that the best conditions for the Claisen ortho ester
rearrangement is to heat the mixture of allyllic alcohol with 14 eq of TEOA in a
sealed tube for 5 min at 190ꢀC in a microwave oven. We obtained excellent yields
for 6 and 8 (99% and 93% respectively, entries g and d0). Unlike Srikrishna et al.,
we do not use any solvent other than the reagent, the reaction time is shorter
(5 min instead of 12), and the yield of 8 obtained from nerol is better (93% versus
87% for Srikrishna et al.).[8] Furthermore, the microwave oven used is high powered
and focused, and all reaction conditions (such as temperature, pressure, stirring) are
controllable, so the reaction carried out in this oven is repeatable.
CONCLUSION
We have optimized the ortho ester rearrangement process using focused
microwave oven heating. The significant features of this method include operational
simplicity, repeatability, high yields, and short reaction time. Unlike other methods,
no solvent is employed. Less energy is needed.
EXPERIMENTAL
The NMR spectra were recorded on a Bruker Avance DPX-300 (300-MHz)
instrument and a Bruker Avance DRX-500 (500-MHz) instrument. Triethyl
orthoacetate and perillyl alcohol were purchased from Sigma-Aldrich and nerol
was obtained from Fluka in high quality, and they were used without any further
purification.
Typical Procedure
A stirred mixture of allylic alcohol (0.231 g, 1.50 mmol), TEOA (4 mL,
22 mmol), and a catalytic amount of propionic acid (6 mL, 0.08 mmol) was heated
in a sealed tube at 190ꢀC in a microwave oven (Biotage, Initiator) for 5 min at an
inside pressure of the reaction vessel of less than 7 bar. The excess of TEOA was
hydrolyzed with HCl 1 N, and then the mixture was extracted with diethyl ether.
The combined extracts were washed with brine, dried over MgSO4, and evaporated

466
F. MEHL ET AL.
under reduced pressure. The yellow oil obtained was purified by column chromato-
graphy over silica gel using n-heptane=ethyl acetate (8:2, v=v) as eluent to give a
mixture of esters as oil.
Ethyl 2-((1R,5S)-2-Methylene-5-(prop-1-en-2-yl)cyclohexyl)acetate
(6a) and Ethyl 2-((1S,5S)-2-Methylene-5-(prop-1-en-2-yl)cyclohexyl)-
acetate (6b)
Esters 6a and 6b (80=20, GC relative percentage) were obtained quantitatively
as a colorless oil (0.347 g, 1.58 mmol) from (7S)-(–)-perillyl alcohol 5 (0.240 g,
1.58 mmol).
Ethyl 2-((1R,5S)-2-Methylene-5-(prop-1-en-2-yl)cyclohexyl)acetate
(6a)
1H NMR (500 MHz, CDCl3) d 1.26 (t, J ¼ 7.2 Hz, 3 H), 1.61 (ddd, J ¼ 13.0 Hz,
J ¼ 11.9 Hz, J ¼ 5.0 Hz, 1 H), 1.72 (s, 3 H), 1.72 (m, 1 H), 1.84 (m, 1 H), 2.25 (m, 3 H),
2.47 (dd, J ¼ 14.0 Hz, J ¼ 7.6 Hz, 1 H), 2.55 (dd, J ¼ 14.0 Hz, J ¼ 8.2 Hz, 1 H), 2.96
(m, 1 H), 4.13 (q, J ¼ 7.2 Hz, 2 H), 4.69 (m, 1 H), 4.73 (m, 3 H); 13C NMR
(100 MHz, CDCl3) d 14.34 (C-14), 21.00 (C-10), 30.96 (C-3), 32.88 (C-4), 36.77
Figure 1. Chiral HPLC of compound 8 on Chiralcel OD-H (Chiralcel OD-H (250 ꢁ 4.6 mm) column,
0.5 mL=min n-hexane, detection: UV220 nm and polarimeter, 25ꢀC).

MICROWAVE-ASSISTED ORTHO ESTER CLAISEN REARRANGEMENT
467
(C-6), 39.19 (C-5), 39.72 (C-1), 38.26 (C-11), 60.29 (C-13), 108.83 (C-7), 109.09 (C-9),
149.33 (C-8), 149.64 (C-2), 172.60 (C-12).
Ethyl 2-((1S,5S)-2-Methylene-5-(prop-1-en-2-yl)cyclohexyl)acetate (6b)
1H NMR (500 MHz, CDCl3) d 1.06 (q, J ¼ 12.3 Hz, 1 H), 1.27 (m, 1 H), 1.28 (q,
J ¼ 7.2 Hz, 3 H), 1.72 (s, 3 H), 1.90 (m, 2 H), 2.16 (m, 1 H), 2.23 (m, 1 H), 2.25 (m
1 H), 2.28 (dd, J ¼ 15.0 Hz, J ¼ 7.6 Hz, 1 H), 2.41 (dt, J ¼ 13.2 Hz, J ¼ 2.6 Hz, 1 H),
2.66 (dd, J ¼ 15.0 Hz, J ¼ 6.5 Hz, 1 H), 4.13 (q, J ¼ 7.2 Hz, 2 H), 4.54 (m, 1 H), 4.73
(m, 3 H); 13C NMR (100 MHz, CDCl3) d 14.30 (C-14), 20.85 (C-10), 33.47 (C-4),
36.49 (C-3), 38.08 (C-11), 39.19 (C-1), 39.48 (C-6), 45.30 (C-5), 60.36 (C-13),
104.80 (C-7), 108.83 (C-9), 149.50 (C-8), 151.17 (C-2), 173.15 (C-12).
Ethyl-3,7-dimethyl-3-vinyloct-6-enoate (8)
Ester 8 was obtained without enantioselectivity as a light yellow oil with 83%
isolated yield (1.113 g, 5 mmol) from nerol 7 (0.924 g, 6 mmol). The two enantiomers
were obtained without selectivity [Chiral HPLC on Chiralcel OD-H (250 ꢁ 4.6 mm)
column, 0.5 mL=min n-hexane, detection with UV220 nm and polarimeter, 25ꢀC]
20
(Fig. 1). ½aꢂD ¼ 0 (c ¼ 0.16; CH2Cl2).
1H NMR (300 MHz, CDCl3) d 1.06 (s, 3 H), 1.17 (t, J ¼ 7.1 Hz, 3 H), 1.32–1.37
(m, 2 H), 1.51 (s, 3 H), 1.60 (s, 3 H), 1.80–1.86 (m, 2 H), 2.24 (s, 2 H), 4.03
(q, J ¼ 7.1 Hz, 2 H), 4.92 (dd, Jgem ¼ 1.1 Hz, Jtrans ¼ 17.5 Hz, 1 H), 4.95 (dd,
Jgem ¼ 1.1 Hz, Jtrans ¼ 17.5 Hz, 1 H), 5.00 (m, 1 H), 5.75 (dd, Jcis ¼ 10.8 Hz,
Jtrans ¼ 17.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) d 14.52 (C-14), 17.79 (C-10),
23.09 (C-5), 23.45 (C-8), 25.88 (C-9), 39.39 (C-3), 40.85 (C-4), 45.17 (C-2), 60.19
(C-13), 112.27 (C-12), 124.67 (C-6), 131.59 (C-7), 145.76 (C-11), 171.97 (C-1).
REFERENCES
1. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T. T.; Faulkner,
D. J.; Petersen, M. R. A simple stereoselective version of the Claisen rearrangement
leading to trans-trisubstituted olefinic bonds: Synthesis of squalene. J. Am. Chem. Soc.
1970, 92, 741–743.
2. (a) Claisen, L. Rearrangement of phenyl allyl ethers in C-allylphenols. Chem. Ber. 1912,
45, 3157–3166; (b) Ziegler, F. E. The thermal, aliphatic Claisen rearrangement. Chem.
Rev. 1988, 88, 1423–1452.
3. Loupy, A. Microwaves in Organic Synthesis, 2nd ed.; Wiley-VCH: Weinheim, 2006.
4. Chemat-Djenni, Z.; Hamada, B.; Chemat, F. Atmospheric pressure microwave assisted
heterogeneous catalytic reactions. Molecules 2007, 12, 1399–1409.
5. Hedidi, M.; Hamdi, S. M.; Mazari, T.; Boutemeur, B.; Rabia, C.; Chemat, F.; Hamdi, M.
Microwave-assisted synthesis of calix[4]resorcinarenes. Tetrahedron 2006, 62, 5652–5655.
6. Roberts, B. A.; Strauss, C. R. Toward rapid, ‘‘green,’’ predictable microwave-assisted
synthesis. Acc. Chem. Res. 2005, 38, 653–661.
7. De la Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Microwaves in organic synthesis: Thermal and
non-thermal microwave effects. Chem. Soc. Rev. 2005, 34, 164–178.
8. Srikrishna, A.; Nagaraju, S.; Kondaiah, P. Application of microwave heating technique
for rapid synthesis of c,d-unsaturated esters. Tetrahedron 1995, 51, 1809–1816.

468
F. MEHL ET AL.
9. Abramovitch, R. A. Applications of microwave energy in organic chemistry: A review.
Org. Prep. Proc. Int. 1991, 23, 683–711.
10. Tymoshenko, D. O. Microwave-assisted Claisen and aza-Claisen rearrangements.
Mini-Rev. Org. Chem. 2008, 5, 85–95.
11. Herrero, M. A.; Kremsner, J. M.; Kappe, C. O. Nonthermal microwave effects revisited:
On the importance of internal temperature monitoring and agitation in microwave
chemistry. J. Org. Chem. 2008, 73, 36–47.
12. Paruch, E.; Ciunik, Z.; Nawrot, J.; Wawrzenczyk, C. Lactones, 9: Synthesis of terpenoid
lactones active insect antifeedants. J. Agric. Food Chem. 2000, 48, 4973–4977.
13. Gunther, H. J.; Guntrum, E.; Ja¨ger, V. Synthese von 4-Penten-4-oliden(c-Methylen-a-
¨
butyrolactonen) uber 4-Pentensa¨uren. Lieb. Ann. Chem. 1984, 15–30.
¨