Microwave assisted synthesis of the fragrant compound Calone 1951

Article abstract of DOI:10.1016/j.tetlet.2004.11.045

Microwave irradiation has been utilised in a three-step synthetic route to the fragrant compound, 7-methyl-benzo[b][1,4]dioxepin-3-one, commercially known as Calone 1951. The use of a microwave reactor increases the simplicity and efficiency of the overall synthesis. Calone 1951, 7-methyl-benzo[b][1,4]dioxepin-3-one, possesses a strong marine, ozone note with floral nuances and is synthesised via a three-step procedure using microwave irradiation. High yields were obtained, and reaction times reduced to a few minutes, allowing for an efficient and inexpensive synthesis of Calone 1951.

Full text of DOI:10.1016/j.tetlet.2004.11.045

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 39–41
Microwave assisted synthesis of the fragrant compound
Calone 1951â
Britta Drevermann, Anthony Lingham, Helmut Hugel* and Philip Marriott
¨
Department of Applied Chemistry, RMIT University GPO Box 2476V Melbourne, Victoria 3001, Australia
Received 28 May 2004; revised 3 November 2004; accepted 8 November 2004
Abstract—Calone 1951ꢀ, 7-methyl-benzo[b][1,4]dioxepin-3-one, possesses a strong marine, ozone note with floral nuances and is
synthesised via a three-step procedure using microwave irradiation. High yields were obtained, and reaction times reduced to a
few minutes, allowing for an efficient and inexpensive synthesis of Calone 1951ꢀ.
ꢁ 2004 Published by Elsevier Ltd.
Calone 1951ꢀ was discovered by Beereboom, Cameron
and Stephens at Pfizer, and is a member of a family of
benzodioxepinones, which share similarities in odour.
Furthermore it is the only one of this group to have been
commercially exploited (C.A.L. SA, Grasse, France)
in perfumery.1 An efficient synthesis of Calone 1951ꢀ
was required by our group for further research into
structure–odour–activity-relationships of fragrance
compounds.
We have found that microwave assisted Williamson
ether synthesis of phenols,7–9 is also applicable to
catechols (1 ! 2). Short reaction times gave impressive
,
10
yields of the dietherified product (90–97%).
With
conventional heating,11 it was found that the lengthy
time required at an elevated temperature favours the
formation of by-products due to the facile oxidation of
1. Alkylation using phase-transfer catalysis showed little
success under both classical heating and microwave irra-
diation. Solvent-free conditions were also unsuccess-
ful.12,13 Favourable conditions for the dialkylation of 1
involved K2CO3 (3equiv) in a dipolar aprotic solvent
and an excess of the alkylating agent added portionwise
prior to irradiation periods (2 · 2min). DMF and
DMSO both gave similar results (89–97%) on a small
The utilisation of microwave irradiation in organic syn-
theses is becoming increasingly popular.2 In many cases
product purity and reaction times are improved when
compared to conventional methods, with improvements
often being attributed to reduction in latent heating
times, superheating of solvents and more recently,
implementation of microwave specific effects.3,4 Current
microwave protocol involves either pressure sealed ves-
sels5 or irradiation in open vessels under a reflux con-
denser, generally at atmospheric pressure. The latter
method has been used for the current work.6
Synthesis of (2-methoxycarbonylmethoxy-4-methyl-phenoxy)-acetic
acid methyl ester (2): Ground, oven-dried K2CO3 (9.0g, 65.22mmol)
and methyl bromoacetate (6.0mL, 64.71mmol) were added sequen-
tially to a solution of 1 (2.0g, 16.13mmol) in anhydrous DMF
(100mL). The solution was irradiated under nitrogen (2min, 200W)
with vigorous stirring. After ambient cooling (15min), methyl
bromoacetate (2.0mL) was added and the solution irradiated a final
time (2min, 200W). Upon cooling (15min), the solution was added to
H2O (200mL) and extracted with CH2Cl2 (3 · 100mL). The organic
portion was washed with 5% aqueous NaOH (2 · 50mL) followed by
distilled water (2 · 50mL). Drying over MgSO4 and concentration in
vacuo resulted in a yellow oil (3.80g), consisting of 89% 2 according
to NMR and GC–MS data. The crude material was purified by
vacuum column chromatography through a short silica gel column,
initially washed with pentane then eluted with ethyl acetate/pentane
using a 1:9–3:7 gradient. Evaporation followed by Kugelrohr
distillation, (210ꢂC/1.0mmHg) gave 2 as a low melting pale yellow
solid (3.60g, 83%).
In this study, a known route has been significantly
improved by utilising microwave irradiation, to provide
a relatively fast and high yielding path to 7-methyl-
benzo[b][1,4]dioxepin-3-one (4) from 4-methyl catechol
(1) (Scheme 1).
Keywords: Calone 1951ꢀ; Fragrant compound; Microwave irradiation.
*
Corresponding author. Tel.: +61 3 9925 2626; fax: +61 3 9639
1321; e-mail: helmut.hugel@rmit.edu.au
0040-4039/$ - see front matter ꢁ 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.11.045

40
B. Drevermann et al. / Tetrahedron Letters 46 (2005) 39–41
O
O
O
OH
OH
O
i)
O
O
O
O
O
O
8
9
O
O
1
O
O
O
O
2
O
O
2
ii)
Scheme 2. 6/7-Methyl-benzo[1,4]dioxin-2-one (8 and 9).
R1
O
O
O
iii)
Dieckmann cyclisation (2 ! 3) using conventional
methods14 proved superior to microwave heating, giving
the desired product in 94% and 68% yields, respec-
tively,à,15 which were obtained as a mixture of regioiso-
mers (3a and 3b) in approximately 1:1 proportions.
Successful protocol involved the use of KOtBu in THF
under dry conditions, with sodamide giving comparable
yields. Temperatures above 70ꢂC encouraged the forma-
tion of by-products 8 and 9 (Scheme 2), indicated by the
development of a deep red colour. These were also iso-
lated as a 1:1 mixture of regioisomers and had a ten-
dency to polymerise.
O
O
O
R2
4
3a and 3b
R1=H, R2=COOCH3,
R1=COOCH3, R2=H
Scheme 1. Reagents and conditions: (i) methyl bromoacetate (5equiv),
K2CO3 (3equiv), DMF, 89–97%; (ii) KOtBu (2equiv), anhydrous
THF, 94–100%; (iii) 10% ethanolic/6M HCl, 92–95%.
scale (P2.0g), however DMSO proved superior to
DMF upon scale-up (10g). The results of the scale-up
gave 2 in 75% and 50% yields for DMSO and DMF,
respectively. These solvents are known to heat efficiently
by dipole interactions under microwave irradiation, with
small additional ionic heating contributed by the
K2CO3. An excess of methyl bromoacetate was neces-
sary, and an efficient condenser was required to prevent
loss of the alkylating agent. After irradiation, cooling
times exceeding 15min encouraged decomposition,
which was more prominent in DMSO than DMF.
Residual DMF and alkylating agent were easily re-
moved by flushing with pentane through a short silica
column prior to bulb-to-bulb distillation. The column
may not be required if the DMF and alkylating agent
can be removed under sufficient reduced pressure. Com-
pound 5 was found to be the major impurity (2–10%)
(Fig. 1), with by-products 6 and 7 also present in trace
amounts.
Hydrolysis of 3 in LiCl/H2O/DMSO16 followed by
decarboxylation under acidic conditions provided 4 in
low yield. The hydrolysis and decarboxylation were per-
formed in a one-pot microwave reaction in ethanolic
HCl, affording 4 in 93% yield.§, The decarboxylation
17
was performed promptly following work-up, or directly
following purification by column chromatography or
distillation, as 3 undergoes decomposition upon storage.
Comparable yields were obtained by conventional heat-
ing, although reaction times were significantly longer.
In conclusion, the promising synthetic methodology
proposed for the fragrant compound Calone 1951ꢀ
has been achieved by performing a microwave assisted
reaction sequence, improving reaction times and yields.
à Synthesis of 7-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]dioxepine-
2/4-carboxylic acid methyl esters (3a and 3b): Under an inert
atmosphere, a solution of 2 (3.72g, 13.88mmol) in anhydrous THF
(35mL) was added over 5min to KOtBu (3.11g, 27.76mmol) in
anhydrous THF (35mL) cooled in an ice/H2O bath. The reaction
flask was transferred to an oil bath at 70ꢂC for 30min, after which
time the caramel coloured solution was poured into HCl/ice (200mL,
pH2.0) and extracted with CH2Cl2 (3 · 100mL). Concentration in
vacuo gave a viscous light brown oil (3.00g), consisting of 94% 3a and
3b according to NMR and GC–MS data. When required, further
purification involved column chromatography on silica gel (hexane/
ethyl acetate, 1:1).
§ Synthesis of 7-methyl-benzo[b][1,4]dioxepin-3-one (4): Immediately
following work-up or purification of the cyclised mixture, 3 (1.00g,
4.24mmol) was dissolved in EtOH (10mL). 6M HCl (100mL) was
added and the solution irradiated with stirring (4min, 200W). The
reaction mixture was quenched with ice/H2O (100mL) and extracted
with CH2Cl2 (3 · 100mL). The product was dried over MgSO4 and
concentrated in vacuo to give a yellow resin (0.73g) exhibiting an
intense marine odour. NMR and GC–MS analysis confirmed yields
of 4 ranging from 92% to 95%. The product was purified further
(97–98%) by elution with Et2O using dry column vacuum
chromatography.
O
O
O
O
O
O
O
O
O
O
O
OH
O
O
5
6
O
O
O
OH
7
Figure 1. (2-Methoxycarbonylmethoxycarbonylmethoxy-4-methyl-
phenoxy)-acetic acid methyl ester (5), (2-methoxycarbonylmethoxy-5-
methyl-phenoxy)-acetic acid (6), (2-hydroxy-4-methyl-phenoxy)-acetic
acid methyl ester (7).

B. Drevermann et al. / Tetrahedron Letters 46 (2005) 39–41
41
4.71 (s, 2H), 4.69 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 2.26 (s,
3H); 13C NMR (50MHz, CDCl3): d (in ppm): 169.4, 169.2,
147.5, 145.5, 132.2, 122.5, 116.0, 115.5, 66.6, 66.2, 51.8,
51.8, 20.6; EIMS parent ion 268 m/z.
Acknowledgements
Financial support (B.D.) from the Faculty of Applied
Science, RMIT University, is acknowledged. We also
thank Michael Malcmann (Warlock Engineering) and
Raymond Lingham for technical assistance and provi-
sion of microwave apparatus.
11. Loupy, A.; Monteux, D.; Petit, A.; Aizpurua, J. M.;
Dominguez, E.; Palomo, C. Tetrahedron Lett. 1996, 37,
8177–8180.
12. Rechsteiner, B.; Texier-Boullet, F.; Hamelin, J. Tetrahe-
dron Lett. 1993, 34, 5071–5074.
13. Varma, R. S.; Kumar, D. Org. Lett. 1999, 1, 697–
700.
References and notes
14. Beereboom, J. J.; Lyme, O.; Cameron, D. P.; Stephens, C.
R. U.S. Patent 3, 517, 031, June 23, 1970; Chem. Abstr.
1970, 73, 56143.
1. Gaudin, J. U.S. Patent 5, 990, 076, Nov 23, 1999; Chem.
Abstr. 1999, 130, 227560.
2. (a) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225–9283; (b) Strauss, C. R.;
Trainor, R. W. Aust. J. Chem. 1995, 48, 1665–1692.
3. Perreux, L.; Loupy, A. Tetrahedron 2001, 44, 9199–9223.
4. Thanh, G. V.; Loupy, A. Tetrahedron Lett. 2003, 44,
9091–9094.
15. A regioselective outcome was not required since subse-
quent decarboxylation of both isomers led to 4. Hence,
separation of regioisomers 3a and 3b was not pursued.
Assignment of methylene protons was achieved through
COSY and HMQC correlations.
Spectroscopic data: 3a and 3b (isomeric mixture) viscous
1
5. Raner, K. D.; Strauss, C. R.; Trainor, R. W.; Thorn, J. S.
J. Org. Chem. 1995, 60, 2456–2460.
light brown oil; H NMR (200MHz, CDCl3): d (in ppm):
7.00–6.69 (m, 3H), 7.00–6.69 (m, 3H), 5.32 (s, 1H), 5.31 (s,
1H), [3a: 4.77–4.71 (d, J = 16.7Hz, 1H), 4.54–4.49 (d,
J = 16.6Hz, 1H)], [3b: 4.74–4.68 (d, J = 16.9Hz, 1H),
4.52–4.47 (d, J = 17.0Hz, 1H)], 3.84 (s, 3H), 3.84 (s, 3H),
2.27 (s, 3H), 2.26 (s, 3H); 13C NMR (50MHz, CDCl3): d
(in ppm): 199.7, 199.6, 165.5, 165.5, 147.0, 146.6, 145.0,
144.8, 135.1, 133.7, 125.6, 124.2, 121.7, 121.2, 120.7, 120.3,
82.1, 81.8, 77.0, 76.6, 52.9, 52.9, 20.7, 20.6; EIMS parent
ion 236 m/z.
6. Microwave experiments were performed in a prototype
microwave applicator ÔMDV2.4Õ and 0–700W variable
power microwave source (2m172) provided on trial by
Warlock Engineering: www.warlock.com.au/chemreactor.
htm.
7. Bogdal, D.; Pielichowski, J.; Jascot, K. Org. Prep. Proced.
Int. 1998, 30, 427–432.
8. Bogdal, D.; Pielichowski, J.; Boron, A. First International
Electronic Conference on Synthetic Organic Chemistry
(ECSOC-1) September 1–30, 1997.
16. Paquette, L. A.; Wang, H. J. Org. Chem. 1996, 61, 5352–
5356.
9. Li, F.; Wang, Q.; Ding, Z.; Tao, F. Org. Lett. 2003, 5,
2169–2171.
17. Spectroscopic data:
4
yellow resin; 1H NMR
(200MHz, CDCl3): d (in ppm): 6.93–6.71 (m, 3H),
4.72 (s, 2H), 4.67 (s, 2H), 2.29 (s, 3H); 13C NMR
(50MHz, CDCl3): (in ppm): 204.9, 147.9, 145.9,
133.7, 124.3, 121.1, 120.6, 75.7, 75.4, 20.5; EIMS parent
ion 178 m/z.
10. The structure of each compound was confirmed by 1H,
13C, DEPT135, COSY and HMQC NMR data.
1
Spectroscopic data: 2 pale yellow solid mp 39–41ꢂC; H
NMR (200MHz, CDCl3): d (in ppm): 6.82–6.67 (m, 3H),