Iodine in dichloromethane - A simple method for selective cleavage of prenyl ethers

Article abstract of DOI:10.1055/s-2001-18765

Treatment of prenyl (Pre) ethers of simple alcohols, carbohydrates, steroids, with I₂ in CH₂Cl₂ in the presence of 3? molecular sieves, constitutes an effective method for their deprotection. This method tolerates other etheral functionalities such as acetals, allyl, t-butyldiphenylsilyl or benzyl groups as well as base labile groups such as acetates. This method applied to a prenyl aryl ether gave rise to a 2,2-dimethylchroman derivative in an acceptable yield.

Full text of DOI:10.1055/s-2001-18765

LETTER
1989
Iodine in Dichloromethane – A Simple Method for Selective Cleavage of Prenyl
Ethers
A
Simple
eMethod for
a
S
elective
C
n
leavage of
P
-
renyl Et
M
hers ichel Vatèle*
Laboratoire de Chimie Organique 1, UMR 5622 CNRS, domaine scientifique de la Doua, CPE, 3 rue Victor Grignard, 69616 Villeurbanne
Cedex, France
Fax +33(4724)31214; E-mail: vatele@univ-lyon1.fr
Received 30 August 2001
We decided to study the applicability of this protocol to
Abstract: Treatment of prenyl (Pre) ethers of simple alcohols, car-
the removal of prenyl protecting groups. We first exam-
bohydrates, steroids, with I2 in CH2Cl2 in the presence of 3Å molec-
ular sieves, constitutes an effective method for their deprotection.
This method tolerates other etheral functionalities such as acetals,
ined the reactivity of iodine towards 3-O-prenyl diacetone
glucose 1a under various experimental conditions.8 As
allyl, t-butyldiphenylsilyl or benzyl groups as well as base labile seen in the Scheme, the products obtained are very depen-
groups such as acetates. This method applied to a prenyl aryl ether
dent on the solvent used.
gave rise to a 2,2-dimethylchroman derivative in an acceptable
yield.
HO
Key words: chromans, iodine, prenyl ethers, protecting groups
HO
O
O
O
O
O
O
Selective protection and, more importantly, deprotection
of functional groups play a central role in organic synthe-
sis as shown by the number of monographs and reviews
dedicated to this topic.1,2 Because hydroxyl groups are
present in a large number of compounds of biological and
synthetic interest (carbohydrates, macrolides, polyethers,
prostaglandins, etc.), a plethora of hydroxyl protecting
groups has been developed. However, because only very
few of them have found wide applications, the develop-
ment of new protecting groups and the improvement of
existing methods of deprotection continue to be the sub-
ject of intensive research.
3
O
O
O
O
O
OH
O
O
O
I , CH Cl , 3 MS
Å
2
2
2
5h, RT
61%
1a
O
2a
O
I
O
O
O
O
O
OH
4
In connection with an ongoing program directed to the de-
velopment of a new generation of safety-catch protecting
groups,3 we needed a hydroxyl protecting group stable un-
der both acidic and basic conditions and cleaved under
neutral conditions.
Scheme
The cleavage of the prenyl ether of diacetone glucose pro-
ceeded best by using 1.5 equivalent of iodine in dichlo-
romethane, at room temperature, in the presence of
powdered 3Å molecular sieves. Without sieves, at room
temperature, only polar compounds were observed. In
methanol, in the presence of 20 mol% of I2, selective
cleavage of the 5,6-O-isopropylidene ketal of 1a oc-
curred.9 In aqueous THF, the iodohydrin 4 was obtained
in good yield. This new protocol for cleavage of prenyl
ethers was successfully applied to various substrates and
the results are listed in the Table.10
The allyl group, one of the most frequently used protec-
1b,2b
tive group in carbohydrate chemistry,
does fulfill
acid-base requirements but none of the numerous methods
of deprotection reported for this protecting group was sat-
isfactory for our purpose.1b,4 Indeed, most of them use
drastic conditions, are capricious5 or not suitable for large
scale preparations. The allyl group being dismissed, we
focussed our attention to a related allyl group: the prenyl
(3-methylbut-2-enyl) group. Only, three methods of
cleavage of prenyl ethers have been described6 but still
none of them meet our requirements.
With substrates containing acid-labile protecting groups
(entries 1–3, 9, 10), 3Å molecular sieves were added to
the reaction mixture in order to trap HI, which is presum-
ably formed during the reaction. Interestingly, treatment
with 1.2 equivalent of I2 of compound 1c, containing a pri-
mary and a secondary prenyl ether, cleaved only the pre-
nyl group attached to the secondary group functionality in
an acceptable yield. The applicability of this method was
successfully tested in the presence of acetonides (entries 1
In 1994, Cossy and coworkers, published a simple and
mild method for the deprotection of prenyl esters using io-
dine in cyclohexane as a reagent.7
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1989,1991,ftx,en;G19001ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1990
J.-M. Vatèle
LETTER
Table Selective Cleavage of Prenyl Ethers with Iodine in CH2Cl2
Entry
1
Substrate
I2 (equiv)
1.5
Time (h)
8
Product
Isolated yield (%)
72
OPre
O
OH
O
O
O
O
O
O
O
O
O
2b
1b
2
3
1.2
3
2
3
54
50
R
PreO
PreO
2c1
R=Pre
HO
O
OBn
O
OBn
2c2
R=H
O
O
O
O
1c
4
5
1.5a
1
92
79
OPre
OH
1d
2d
3a
3b
OPre
OH
O
O
1e
2e
1e
6
1.5a
1b
75
OPre
OH
1f
2f
7
8
3a,c
1.5a
1.5
2
1.5b
1
80
77
22
70
56
HO
OAll
PreO
OAll
2g
1g
PreO
OAc
HO
OAc
1h
2h
9
4
PreO
OTBS
HO
OTBS
1i
2i
10
11
3
PreO
OTBDPS
OPre
HO
OTBDPS
1j
2j
1.5a
1
PreO
O
OH
1k
I
2k
a No molecular sieves was added.
b Reaction carried out at 10 °C for entries 5 and 7 and at 0 °C for entry 6.
c The mixture of the two products obtained (2g and the corresponding vic-diiodo compound) was treated by zinc in ethanol at 60 °C.
Synlett 2001, No. 12, 1989–1991 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Iodine in Dichloromethane – A Simple Method for Selective Cleavage of Prenyl Ethers
1991
Chem. Soc., Perkin Trans. 1 1999, 1589. (e) Jarowicki, K.;
Kocienski, P. J. J. Chem. Soc., Perkin Trans. 1 2000, 2495.
(3) (a) Rudinger, J. Pure Appl. Chem. 1963, 7, 335. (b) Patek,
M. Int. J. Pept. Protein Res. 1993, 42, 97.
(4) (a) Rao, G. V.; Reddy, D. S.; Mohan, G. H.; Iyengar, D. S.
Synth. Commun. 2000, 30, 3565. (b) Kamal, A.; Laxman,
E.; Rao, N. V. Tetrahedron Lett. 1999, 40, 371; and
references cited therein.
(5) See for examples: (a) Nakayama, K.; Uoto, K.; Higashi, K.;
Soga, T.; Kusama, T. Chem. Pharm. Bull. 1992, 40, 1718.
(b) Lüning, J.; Möller, U.; Debski, N.; Welzel, P.
Tetrahedron Lett. 1993, 34, 5871.
(6) (a) Gigg, R. J. Chem. Soc., Perkin Trans. 1 1980, 738;
(t-BuOK, DMSO, 50 °C). (b) Sharma, G. V. M.; Ilangovan,
A.; Mahalingam, A. K. J. Org. Chem. 1998, 63, 9103;
(Yb(OTf)3 cat., CH3NO2, r. t.). (c) Tsuritani, T.; Shinokubo,
H.; Oshima, K. Tetrahedron Lett. 1999, 40, 8121; (TiCl4, n-
Bu4NI).
and 2), benzyl (entry 2), acetate (entry 8), t-butyldiphenyl-
silyl (entry 10) groups and a conjugated ketone (entry 5).
Unfortunately, even in the presence of sieves, the O-pre-
nyl group could not be removed selectively in the pres-
ence of a t-butyldimethlysilyl group (entry 9). In the case
of compound 1g, containing an allyl group, the desired
compound 2g was obtained along with the product of ad-
dition of iodine to the double bond of the allyl group (ratio
1/3 in favor of the vic-diiodo compound). Anyhow, treat-
ment of a mixture of these two compounds with zinc in hot
ethanol gave exclusively 2g in good yield (entry 7).
Another interesting feature of this method is that reaction
of iodine to the aryl prenyl ether 1k led to the 3-iodo chro-
man derivative 2k in moderate yield. Mechanistic aspects
of this transformation have not been investigated yet but a
plausible pathway may start by a [1,3]-sigmatropic rear-
rangement with formation of an o-prenyl phenol11 fol-
lowed by an electrophilic cyclization. 3-Iodo-2,2-
dimethylchroman derivatives are precursor of 2,2-dimeth-
ylchromenes, a very common structural motif in fla-
vanoids.12
(7) Cossy, J.; Albouy, A.; Scheloske, M.; Gomez Pardo, D.
Tetrahedron Lett. 1994, 35, 1539.
(8) Prenyl ethers were prepared according to the procedure
described by Gigg in ref.6a.
(9) I2 in methanol is known as a good reagent for selective
cleavage of acetals. See:Szarek, W. A.; Zamojski, A.;
Tiwari, K. N.; Ison, E. R. Tetrahedron Lett. 1986, 27, 3827.
(10) General Experimental Procedure. For entries 4–8, 11: To
a stirred solution of the prenyl ether (0.5 mmol) in
dichloromethane (5 mL), cooled to 10 °C for entries 5 and 7
and 0 °C for entry 6, was added iodine [(0.19 g, 1.5 equiv),
(0.38 g for entry 5)]. The progress of the reaction was
monitored by TLC. Upon consumption of the prenyl ether,
the solution was diluted with dichloromethane, washed
successively with 20% Na2S2O3 solution, sat. NaHCO3
solution, water, dried (Na2SO4), concentrated in vacuo and
purified by flash column chromatography on silica gel to
yield the desired product which gave satisfactory
spectroscopic and analytical data consistent with its
structure. For entries 1–3, 9–10: To a stirred solution of the
prenyl ether (0.5 mmol) in dichloromethane (6 mL) were
successively added 3Å powdered molecular sieves (0.15 g),
iodine (0.19 g, 1.5 equiv), (0.38 g for entry 3). After
consumption of the prenyl ether, the reaction mixture was
treated as in the first experimental procedure to give the pure
desired compound.
In conclusion, the use of iodine in dichloromethane pro-
vides a mild and efficient means of removing prenyl
ethers in the presence of a number of other functionalities.
Studies of the mechanism of this cleavage of prenyl ethers
as well as of other cleavage techniques are currently un-
derway.
References
(1) Monographs: (a) Kocienski, P. J. Protecting Groups;
Thieme: Stuttgart, 1994. (b) Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 3rd ed.; John
Wiley: New York, 1999. (c) Hanson, J. R. Protecting
Groups in Organic Synthesis; Sheffield Academic Press:
Sheffield, 1999.
(2) Reviews: (a) Kunz, H.; Waldmann, H. Protecting Groups,
In Comprehensive Organic Synthesis, Vol. 6; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991, 631. (b) Ziegler, T.
Protecting Group Strategies for Carbohydrates, In
Carbohydrate Chemistry; Booms, G. J., Ed.; Blackie
Academic and Professional: Glasgow, 1998, 21.
(c) Jarowicki, K.; Kocienski, P. J. J. Chem. Soc., Perkin
Trans. 1 1998, 4005. (d) Jarowicki, K.; Kocienski, P. J. J.
(11) For an example of such a rearrangement see: Dauben, W. G.;
Cogen, J. M.; Behar, V. Tetrahedron Lett. 1990, 31, 3241.
(12) The Handbook of Natural flavanoids, Vol. 1 and 2;
Harborne, J. B.; Baxter, B., Eds.; John Wiley and Sons:
England, 1991.
Synlett 2001, No. 12, 1989–1991 ISSN 0936-5214 © Thieme Stuttgart · New York