CeCl3/NaClO: A safe and efficient reagent for the allylic chlorination of terminal olefins

Article abstract of DOI:10.1016/S0040-4039(03)01630-7

The preparation of allylic chlorides by reaction of terminal olefins with sodium hypochlorite in the presence of cerium trichloride heptahydrate is described. The scope, limitations and synthetic perspectives of the reaction are discussed.

Full text of DOI:10.1016/S0040-4039(03)01630-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6691–6693
CeCl3/NaClO: a safe and efficient reagent
for the allylic chlorination of terminal olefins
F. Javier Moreno-Dorado, Francisco M. Guerra, Francisco L. Manzano, F. Javier Aladro,
Zacar´ıas D. Jorge and Guillermo M. Massanet*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Ca´diz, Apartado 40, 11510 Puerto Real, Ca´diz, Spain
Received 13 June 2003; revised 16 June 2003; accepted 30 June 2003
Abstract—The preparation of allylic chlorides by reaction of terminal olefins with sodium hypochlorite in the presence of cerium
trichloride heptahydrate is described. The scope, limitations and synthetic perspectives of the reaction are discussed.
© 2003 Elsevier Ltd. All rights reserved.
Many natural products bear an isopropenyl group as a
part of their structure.1 Very often this isopropenyl
group is the starting point to reach more complex
atomic arrangements.2
acetic acid limits the reaction to non-sensitive
substrates.
The replacement of acetic acid (a Brønsted acid) by
cerium trichloride (a Lewis acid) provides a milder
environment in which reaction takes place smoothly in
a two-phase system (dichloromethane/water) under vig-
orous stirring to ensure the homogeneus distribution of
the in situ generated electrophilic chlorine.
A convenient way to functionalize an isopropenyl
group is the allylic chlorination since further manipula-
tion on the chloride may afford several functional
groups.3 Although this procedure can be performed
directly by bubbling molecular chlorine through the
reaction medium, this is always tedious due to the
difficulty of handling chlorine gas. As an alternative, Li
and co-workers, in the synthesis of eudesmane acids
employed a combination of the Vilsmeier reagent and
H2O2 but the presence of POCl3 exclude the use of
acid-sensitive substrates.4
We first checked the reaction on dihydrocarvone 1 in
order to optimize the reaction conditions. The results
are summarized in Table 1.
The optimum solvent was found to be a biphasic
system of dichloromethane and water (entries 6–10).
From entries 1 and 12 can be deduced that the presence
of cerium trichloride is needed for the reaction to
proceed. The stoichiometry of the reaction is also a key
point. Loads of three equivalents of cerium trichloride
and sodium hypochlorite provide quantitative yields in
case of this particular substrate, although in simpler
substrates, the reaction proceeds better with two equiv-
alent of each reagent (vide infra).
In 1980, Wolinsky and co-workers, reported the prepa-
ration of allylic chlorides through a combination of
solid CO2 and calcium hypochlorite. This procedure
was effective for the preparation of allylic chlorides in
some highly hindered olefins.5
In the course of our research programme aimed at the
synthesis of natural sesquiterpenoids, we have had to
carry out this transformation. We have discovered a
more straightforward way to accomplish this reaction
by means of a combination of sodium hypochlorite and
cerium trichloride heptahydrate. The generation of
chlorine has been previously reported using sodium
hypochlorite and acetic acid,6 but the presence of the
In order to assess the scope and limitations of this
reaction, different substrates were studied (Table 2).
Entries 1–4 show, respectively, the almost quantitative
conversion of dihydrocarvone (entry 1), 7-epi-cyperone
(entry 2), 6b-hydroxy-7-epi-cyperone (entry 3), and 6-
oxo-7-epi-cyperone into their chlorinated derivatives.
This reaction also works well with carvone and other
related substrates. As a blank test, we ran the reactions
* Corresponding author. Tel.: 34-956-016405; fax: 34-956-6288;
e-mail: francisco.guerra@uca.es
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01630-7

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F. J. Moreno-Dorado et al. / Tetrahedron Letters 44 (2003) 6691–6693
Table 1. Allylic chlorination of dihydrocarvone 1
(1)
Entry
Equivalents of CeCl3
Equivalents of NaClO
Solvent
2 yield (%)
Recovered 1 (%)
1
2
3
4
5
6
7
8
0
1
3
5
3
1
3
5
2
1.1
2
3
2
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
CH2Cl2
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
0
9
27
100
54
33
Complex mixture
2
46
29
44
69
60
98
25
0
47
66
53
18
31
0
1.1
1.1
1.1
2
3
0.3
0
9
10
11
12
3
5
3
55
100
Simple alkenes show very high conversion, as in 2-
methylprop-1-ene (entry 5), in which the reaction takes
place very cleanly. The presence of hydroxyl groups is
tolerated (entry 3) as long as the hydroxyl group is not
allowed to interfere with the incipient carbocation.
When this is the case, a simple protection with TBDM-
SCl is enough to avoid this problem (entry 6).7
with these four substrates by bubbling chlorine gas
through the solution. The reaction took place
sluggishly.
Table 2. Allylic chlorination with CeCl3·7H2O and NaClO
Entry 7 shows the case in which the intermediate
carbocation is stabilized by a phenyl group. In this
case, along with the allylic chloride, a second addition
of chlorine is observed. This fact is also detected in
other substrates when more than three equivalents of
CeCl3/NaClO are added.
As previously pointed out, it is noteworthy to mention
that no reaction takes place in the absence of cerium
trichloride. The procedure is therefore based on the
mild generation of electrophilic chlorine. Chlorination
of the corresponding alkene and loss of a proton of the
cationic intermediate leads to formation of the chlori-
nated products. In order to shed some light on the
mechanism of this reaction, we ran an experiment using
camphene. This substrate is very prone to undergo
rearrangements and the same products described when
the camphene is treated with molecular chlorine were
obtained (Scheme 1).8
Camphene provides a complex mixture of products due
to the different possibilities of rearrangement and car-
bocation trapping by the nucleophile. But when this
possibility is constrained, the reaction can be syntheti-
cally useful as is the case of b-pinene in which a single
product is obtained in high yield (Scheme 2).
Different sources of cerium were checked to evaluate
the importance of the anion in this process, replacing in
Eq. (1), the CeCl3 by different cerium salts (Table 3).

F. J. Moreno-Dorado et al. / Tetrahedron Letters 44 (2003) 6691–6693
6693
with some transition metal chlorides. Investigation on
these results is being conducted at present and will be
reported in due course.
General procedure
1 mmol of the alkene is dissolved in CH2Cl2:H2O (1:1,
10 mL) and CeCl3·7H2O is added (2 equiv.). The mix-
ture is vigorously stirred and diluted NaClO (10–13%
available chlorine, 2 equiv.) is added dropwise for 5
min. After 30 min, saturated aqueous Na2SO3 is added
and the mixture is extracted with CH2Cl2 (3×20 mL).
The organic layer is dried over anhydrous sodium
sulfate. Removal of the solvent in vacuo afforded the
corresponding chloride.
Scheme 1.
Acknowledgements
We wish to thank the Spanish Ministerio de Ciencia y
Tecnolog´ıa (grant BQU2001-3076) and Junta de
Andaluc´ıa (PAI-2000) for the financial support. F.L.M
is grateful to the Junta de Andaluc´ıa for a fellowship.
We are also grateful to Professor M. J. Tenorio for his
helpful comments.
Scheme 2.
Table 3. Role of the cerium counterion (2 equiv. of metal
source)
Entry
Metal source
2 yield (%)
Recovered 1 (%)
References
1
2
3
Ce(NO3)3
Ce(SO4)2
CeO2
47
80
0
42
0
100
1. Fraga, B. Nat. Prod. Rep. 2002, 650 and references cited
therein.
2. (a) Bartel, S.; Bohlmann, F. Tetrahedron Lett. 1989, 30,
685; (b) Li, Y. L.; Chen, X.; Shao, S. C.; Li, T. S. Synth.
Commun. 1993, 23, 2457; (c) Kido, F.; Abiko, T.; Kato,
M. J. Chem. Soc., Perkin Trans. 1 1995, 23, 2989; (d)
Barrero, A. F.; Oltra, J. E.; Alvarez, M. Tetrahedron Lett.
2000, 41, 7639; (e) Barriault, L.; Denissova, I. Org. Lett.
2002, 4, 1371.
Ce(NO3)3 provides modest results, in part due to the
absence of the Cl− ions. Ce(IV) is observed to be also
effective when Ce(SO4)2 is used. CeO2 fails due to its
low solubility.
3. (a) Gruesorensen, G.; Nielsen, I. M.; Nielsen, C. K. J.
Med. Chem. 1988, 31, 1174; (b) Na´jera, C.; Sansano, J. M.
Tetrahedron 1992, 48, 5179; (c) Groesbeek, M.; Smith, S.
O. J. Org. Chem. 1997, 62, 3638; (d) Chen, Y. G.; Zhou,
G.; Liu, L. J.; Xiong, Z. M.; Li, Y. L. Synthesis 2001,
1305.
4. Xiong, Z. M.; Yang, J.; Li, Y. L. Tetrahedron: Asymmetry
1996, 9, 2607.
5. (a) Hegde, S. G.; Vogel, M. K.; Saddler, J.; Hrinyo, T.;
Rockwell, N.; Haynes, R.; Olever, M.; Wolinsky, J. Tetra-
hedron Lett. 1980, 21, 441; (b) Hegde, S. G.; Wolinsky, J.
J. Org. Chem. 1982, 47, 3148.
6. For a recent example, see: VanBrunt, M. P.; Ambenge, R.
O.; Weinreb, S. M. J. Org. Chem. 2003, 68, 3323.
7. Under the reaction conditions, 3-methylbut-3-en-1-ol
affords a complex mixture, in which the presence of the
corresponding oxetane derivative, formed from the trap-
ping of the cation by the hydroxyl group, is observed.
8. Erman, W. F. Chemistry of Monoterpenes: An Encyclope-
dic Handbook (part B); Marcel Dekker, Inc: New York,
1985; p. 1158.
We also wanted to know whether sodium hypochlorite
was the only source of chlorine or CeCl3 also con-
tributed to its supply. We thus checked different oxi-
dants instead of NaClO, some of them lacking chlorine
atoms. The reaction of dihydrocarvone 1 with the
organic peroxyacids MCPBA and MMPP (2 equiv. of
CeCl3·7H2O, 2 equiv. of oxidant) as oxidant under
similar conditions took place, although in low yields (20
and 11%, respectively). Consequently, the reaction is
possible in the absence of sodium hypochlorite. The
chlorine present in CeCl3 may play some role in the
process, although the major part seems to come from
the sodium hypochlorite. NaClO2 also provided the
allylic chloride in low yield (22%).
In summary, the main advantages of this method lie in
its technical simplicity, safety and high yields. The use
of protic acids is avoided, being replaced by cerium
trichloride, which effectively promotes the formation of
electrophilic chlorine. Some other metallic salts have
been checked and interesting results have been obtained