Oxone-KI Induced Lactonization and Etherification of Unsaturated Acids and Alcohols: A Formal Synthesis of Mintlactone

Article abstract of DOI:10.1055/s-2003-45009

Unsaturated acids and alcohols interact with Oxone and KI in acetonitrile-H₂O and undergo iodolactonization and iodoetherification in short times with good yields. The reaction has been used for the formal synthesis of mintlactone starting from isopulegol.

Full text of DOI:10.1055/s-2003-45009

368
LETTER
Oxone®-KI Induced Lactonization and Etherification of Unsaturated Acids
and Alcohols: A Formal Synthesis of Mintlactone
A
F
ormal Synthesis of
a
Mintlacton
s
e
simo Curini, Francesco Epifano, M. Carla Marcotullio,* Francesca Montanari
Dipartimento di Chimica e Tecnologia del Farmaco-Sez. Di Chimica Organica, Università degli Studi, via del Liceo 1, 06123 Perugia, Italy
Fax +39(075)5855116; E-mail: marcotu@unipg.it
Received 11 November 2003
Na2S2O8,9 to perform iodocyclizations. These procedures
Abstract: Unsaturated acids and alcohols interact with Oxone® and
have several disadvantages including the use of potential-
KI in acetonitrile–H2O and undergo iodolactonization and iodo-
ly dangerous and/or expensive products. Hydrogen per-
etherification in short times with good yields. The reaction has been
oxide needs to be activated by catalysts,10 and Na2S2O8
used for the formal synthesis of mintlactone starting from iso-
pulegol.
has been used only to perform lactonizations.
Key words: Oxone®, cyclizations, iodolactonizations, iodoetherifi-
cations, mintlactone
We have already shown the capability of Oxone® to oxi-
dize the iodide ion to iodine/hypoiodide in heterogenous
conditions.11
We wish to report here a highly efficient iodolactonization
and iodoetherification procedure using the Oxone®–KI
system in a CH3CN–H2O medium.
Lactones and tetrahydrofurans are very important moi-
eties both as synthons in organic synthesis and as key fea-
tures in natural products chemistry. Among different
procedures to obtain oxygenated five- or six-membered
rings, iodolactonization and iodoetherification are proba-
bly the most used methodologies.1
In a preliminary experiment, (E)-styryl acetic acid (1) in 2
mL of CH3CN was added to a solution of 2 equivalents of
Oxone® and 4 equivalents of KI in a 4:1 mixture of H2O–
CH3CN (5 mL) producing in 1 hour 4-iodo-5-phenyl-di-
hydrofuran-2-(3H)-one (2)12 in 90% yield (Table 1) as the
only diasteroisomer.
The first example of iodolactonization was reported by
Bougault (KI, I2, NaHCO3)2 at the begining of the last
century, and this procedure, with slight modifications, is
still used altough it often requires long reaction times.3
Since transport, handling and storage of halogens may
create environmental problems,4 in recent years, halogens
have been produced in situ by the oxidation of halides.
Different oxidants have been used in the presence of
Scheme 1 Proposed pathway leading to lactonization
8
iodide salts, such as Pb(IV),5 MCPBA,6 FeCl3,7 H2O2 and
Table 1 Results of Iodolactonizations
Acid
Product
Time (min)
60
Yield (%)
90
Reported yields (%)
939
1
3
213,14
49,15
50
96
929
5
7
610
30
60
97
87
969
969
89,16
9
1017
50
83
SYNLETT 2004, No. 2, pp 0368–0370
0
2.
0
2.
2
0
0
4
Advanced online publication: 19.12.2003
DOI: 10.1055/s-2003-45009; Art ID: G30603ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Formal Synthesis of Mintlactone
369
The trans relationship of the phenyl group and the iodine,
established by the coupling constant value (J = 7.5 Hz)
between H-4 and H-5, and confirmed by NOE measure-
ment, is consistent with a reaction pathway involving a
cyclic iodonium cation intermediate (Scheme 1).
It should be noted that the reaction is effective both for
five- and six-membered ring formation.
Figure 1
The same reaction conditions, applied to several alkenols,
led to tetrahydrofurans and tetrahydropyrans in short reac-
tion times and in good yields (Table 2).
Our retrosynthetic analysis is shown in Scheme 2.
It is interesting to compare the results of the reactions of
compounds 11 and 17. In both cases we have a 1,4-rela-
tionship between the hydroxyl group and the double bond,
but, in the first case, we achieve a 5-exo-trig process while
in the second, the product is generated by a 6-endo-trig
cyclization. Both processes follow Baldwin’s rules, indi-
cating that they are electrophile-driven reactions.
In recent years it has been reported that 5-endo-trig iodo-
etherification of homoallylic alcohols contravenes Bald-
win’s rules.18 After the first reaction, reported by
Bartlett,19 few other examples of this cyclization mode
have been described.3,6,20 In all cases, it is possible to
achieve cyclization only under anhydrous conditions, so
as to avoid the formation of iodohydrins by the preferred
intermolecular addition of water.
Scheme 2 Retrosynthetic analysis for the preparation of mint-
lactone from isopulegol
Commercial (–)-isopulegol (23) was treated according
our protocol and after only 30 minutes the reaction mix-
ture was complete with the formation of an inseparable
1:1 mixture of diastereoisomeric alcohols 25.26
The formation of 25 in our opinion could be due to an
addition–substitution process as shown in Scheme 3.
Following our procedure, no addition products were de-
tected and the cyclization of alcohols led to tetrahydro-
furans in excellent yields.
Despite, the difficulty that exists for the endo-cyclization
of homoallylic alcohols such as 19, we tried to extend this
methodology to a short synthesis of mintlactone (20), a
component of the essential oil of various Mentha spe-
cies.24 Several syntheses of this compound and of its iso-
mer [iso-mintlactone [21), Figure 1] have been reported,25
and (–)-isopulegol (23) is one of the most common start-
ing materials, but none of these syntheses utilizes a cy-
clization induced by iodonium ions on the isopropenyl
side chain.
Scheme 3
Table 2 Results of Iodolactonizations
Alcohol
Product
Time (min)
20
Yield (%)
88
Reported yields (%)
6510
11
13
1210
143
30
97
933
15
166,21
30
40
88
85
756
1722
1823
19
Complex mixture
Synlett 2004, No. 2, 368–370 © Thieme Stuttgart · New York

370
M. Curini et al.
LETTER
(15) 13C NMR (50.1 MHz, CDCl3): d = 9.7, 14.0, 25.7, 41.1, 90.3,
173.8.
The formation of 2527 could be due to the tendency of
the hindered iodo derivative to give spontaneously in-
tramolecular nucleophilic substitution.
(16) 13C NMR (50.1 MHz, CDCl3): d = 29.3, 32.1, 34.6, 36.0,
36.1, 92.4, 175.9.
(17) Yellow oil. IR(neat): 1727 cm–1. 1H NMR (200 MHz,
CDCl3;): d = 2.50–1.80 (m, 1 H), 1.80–2.10 (m, 2 H), 2.20
(m, 1 H), 2.30–2.70 (m, 2 H), 3.29 (dd, 1 H, J = 4.5, 10 Hz),
3.42 (dd, 1 H, J = 4.8, 10 Hz), 4.20–4.30 (m, 1 H). 13C NMR
(50.1 MHz, CDCl3): d = 7.5, 18.2, 28.0, 29.2, 78.8, 170.0.
(18) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(19) Bartlett, P. A.; Myerson, J. J. Am. Chem. Soc. 1978, 100,
3951.
Even though we obtained compound 25 instead of 22, our
procedure represents a short formal synthesis of mintlac-
tone (20).
Acknowledgment
The authors thank Università degli Studi-Perugia for financial
support.
(20) Okimoto, Y.; Kikuchi, D.; Sagakuchi, S.; Ishii, Y.
Tetrahedron Lett. 2000, 10223.
(21) Oil. 1H NMR (200 MHz, CDCl3): d = 1.00–1.70 (m, 4 H),
1.70–2.10 (m, 2 H), 3.00–3.70 (m, 4 H), 4.00–4.10 (m, 1 H).
13C NMR (50.1 MHz, CDCl3): d = 10.1, 23.1, 25.6, 31.7,
68.8, 77.0.
References
(1) Harding, K. E.; Tiner, T. H. In Comprehensive Organic
Synthesis, Vol. 4; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991, 363.
(2) Bougault, M. J. Ann. Chim. Phys. 1908, 14, 145.
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(12) General Procedure for the Iolactonization and the
Iodoetherification: To a stirred solution of 2 mmol of
Oxone® in 5 mL of a 4:1 H2O–CH3CN mixture, 4 mmol of
KI were added. After 10 min to the deep purple solution 1
mmol of the alkenoic acid (or the alkenol) in 2 mL of CH3CN
was added. The reaction was followed by TLC. After the
appropriate time (see Table 1 and Table 2) the reaction
mixture was diluted with H2O (10 mL), washed with a sat.
solution of Na2S2O3 and extracted with CH2Cl2 (3 × 10 mL).
The combined organic layers were dried and evaporated at
reduced pressure. All the products resulted pure by 1H and
13C NMR.
(22) To a stirred solution of 6-methyl-5-hepten-2-one (Aldrich)
(2 mmol) in 21 mL EtOH a solution of 40 mg (1 mmol) of
NaBH4 in 2 mL of H2O was added. The reaction was
monitored by TLC. At the end 10 mL of acetone were added
and the mixture was evaporated at reduced pressure. The
crude product was diluted with H2O (20 mL), acidified to pH
4 with a 4% solution of HCl and extracted with EtOAc
(3 × 10 mL). The combined organic layers were washed with
brine, dried and evaporated. The residue was purified by
column chromatography. Elution with CH2C12–MeOH 5%
gave 210 mg (93%) of alcohol 17. Oil. 1H NMR (200 MHz,
CDCl3): d = 1.23 (d, 3 H, J = 6 Hz), 1.40–1.60 (m, 2 H), 1.66
(s, 3 H), 1.73 (s, 3 H), 2.11 (m, 2 H), 3.84 (m, 1 H), 5.17 (m,
1 H). 13C NMR (50.1 MHz, CDCl3): d = 17.7, 23.4, 24.5,
25.7, 39.1, 67.9, 124.0, 132.4.
(23) Yellow oil. 1H NMR: d = 1.10 (d, 3 H, J = 6.0 Hz), 1.30–1.50
(m, 2 H), 1.41 (s, 3 H), 1.50 (s, 3 H), 2.31 (m, 2 H), 3.82 (m,
1 H), 4.12 (dd, 1 H, J = 5.0, 12.0 Hz). 13C NMR: d = 19.5,
22.2, 3 1.2, 34.5, 37.3, 38.5, 66.3.
(24) Takahashi, K.; Someya, T.; Muraki, S.; Yoshida, T. Agric.
Biol. Chem. 1980, 44, 1935.
(25) Ferraz, H. M. C.; Longo, L. S. Jr.; Grazini, M. V. Synthesis
2002, 2155.
(26) Compound 25 has been already reported as an intermediate
in a short synthesis of (–)-mintlactone by thallium(III)-
mediated cyclization of (–)-isopulegol: Ferraz, H. M. C.;
Grazini, M. V. A.; Ribeiro, C. M. R.; Brocksom, U.;
Brocksom, T. J. J. Org. Chem. 2000, 65, 2606.
(27) 3,6-Dimethyl-octahydro-1-benzofuran-3-ol(25). Oil. 1:1
Mixture of diastereoisomers. Yield 80%. 1H NMR: d = 0.90–
2.10 (m, 6 H), 0.97 (d, 3 H, J = 6.5 Hz), 1.25 (s, 3 H), 1.34
(s, 3 H), 3.20 (dd, 1 H, J = 4.0, 10.0 Hz), 3.26 (dd, 1 H,
J = 4.0, 10.0 Hz), 3.67 (d, 1 H, J = 9.0 Hz), 3.79 (d, 1 H,
J = 10.0 Hz), 3.86 (d, 1 H, J = 10.0 Hz), 3.87 (d, 1 H, J = 9.0
Hz). 13C NMR: d = 21.4, 22.0, 22.0, 22.7, 22.8, 24.0, 31.0,
31.0, 34.2, 34.3, 40.2, 40.3, 54.8, 56.4, 77.4, 77.8, 81.2, 81.2,
82.3, 82.3.
(13) Cambie, R. C.; Hayward, R. C.; Roberts, J. L.; Rutledge, P.
S. J. Chem. Soc., Perkin Trans. 1 1974, 1864.
(14) 13C NMR (50.1 MHz, CDCl3): d = 17.8, 41.0, 89.5, 126.0,
129.0, 129.4, 135.6, 173.7.
Synlett 2004, No. 2, 368–370 © Thieme Stuttgart · New York