A room temperature alternative of the Claisen rearrangement route to ortho allylated phenols: Unique reactivity pattern of allylindium reagents

Article abstract of DOI:10.1016/j.tetlet.2005.01.152

Quinol ethers and quinone monoketals are shown to undergo formal anti-Michael addition reactions with allylindium reagents at room temperature to give only ortho allylated phenols in good yields.

Full text of DOI:10.1016/j.tetlet.2005.01.152

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2097–2100
A room temperature alternative of the Claisen
rearrangement route to ortho allylated phenols:
unique reactivity pattern of allylindium reagents
Dipakranjan Mal,* Pallab Pahari and Bidyut K. Senapati
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 4 December 2004; revised 20 January 2005; accepted 25 January 2005
Abstract—Quinol ethers and quinone monoketals are shown to undergo formal anti-Michael addition reactions with allylindium
reagents at room temperature to give only ortho allylated phenols in good yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The Claisen rearrangement,1 viewed as a [3,3] sigma-
tropic thermal isomerization, is a very useful carbon–
carbon bond forming reaction. It has been widely used
in the total synthesis of natural products.2 Since the ori-
ginal report3 by Claisen in 1912, the reaction has
witnessed numerous variants such as Caroll, Ireland,
Bellus, etc., which are all related to the aliphatic version
of the rearrangement.1 Surprisingly, there is no litera-
ture report on the alternatives of the aromatic Claisen
rearrangement route to allylated products. The Claisen
route to ortho allylated phenols traditionally entails
two steps: o-allylation of phenols and thermal isomeriz-
ation of the o-allyl derivatives. The rearrangement is typi-
cally carried out at 150–300 ꢁC. Although the products
of rearrangement are usually ortho isomers, para allyl-
ated phenols and benzofurans are often formed as side
products. The rearrangement can be performed at room
temperature only when alkylaluminium halides are used
as catalysts.4 However, the requirement for a large
excess of highly acidic catalysts restricts the practical
uses of this variant. Herein, we report an ambient tem-
perature alternative of the Claisen rearrangement route
to o-allylated phenols from the same set of starting
materials as used in the Claisen route. This is based
upon oxidative dearomatization of phenols to quinol
ethers or quinone monoketals followed by their
formal anti-Michael addition reaction with allylindium
reagents. The two-step conversion can be carried out
in one operation, by avoiding isolation and purification
of the substrates from the crude reaction mixtures if they
are prepared by oxidation of the corresponding phenols
with phenyliodonium diacetate (PIDA).
In connection with our ongoing programme5 on the
total synthesis of angucyclines, we planned to prepare 5-
allyl-4-methoxy-2-cyclohexenones (e.g., 5) from quinol
derivatives,6 which are accessible via a variety of routes.
Since there is no literature report on 1,4-addition of
allylmetal reagents to quinol ethers,7 we envisaged the
preparation of compound 5 in two steps (Scheme 1),
namely 1,2-addition of an allylmetal reagent to com-
pound 2 and oxy-Cope rearrangement of the resulting
product 4. The proposed tandem methodology is well
documented for acyclic systems and quinones.8 In view
of increasing interest in the use of allylindium reagents9
and the operational simplicity associated with them, we
decided to examine the Barbier type reactivity of the
parent allylindium reagent 3 towards quinol ether 2 in
order to obtain compound 4.
When compound 2,10 prepared by oxidation of p-cresol
with phenyliodonium diacetate in methanol, was reacted
in DMF with the allylindium reagent derived from allyl
bromide, a colourless liquid was isolated as the sole
product after work-up of the mixture and purification
of the crude product by chromatography. It was found
to be 2-allyl-4-methylphenol 6, contrary to the expected
product 4 or 5 (Scheme 1). Since both 2-allyl and 3-allyl
Keywords: Claisen rearrangement; Quinol ethers; Allylindium; Anti-
Michael.
*
Corresponding author. Tel.: +91 3222 283318; fax: +91 3222
282252; e-mail: dmal@chem.iitkgp.ernet.in
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.152

2098
D. Mal et al. / Tetrahedron Letters 46 (2005) 2097–2100
L
OMe
OMe
OMe
In
oxy-Cope
L
3
OH
OH
O
O
4
5
2
1
Scheme 1. The proposed route for the preparation of cyclohexenone 5.
1
derivatives of 4-methylphenol 1 have very similar H
ditions. The results are summarized in Table 1. When
the indium reagent derived from 2-methylallyl bromide
was examined with quinol ether 2, the ortho allylated
phenol 712 was obtained as the sole product in 78%
yield. The result with quinol ether 95a was different as
expected. The allyl derivative 10 was formed in 65%
yield along with its regioisomer 11 in 14% yield. Though
NMR spectra, the structure of compound 6 was con-
firmed by spectroscopic comparison with an authentic
sample prepared from p-cresol in two steps by the pub-
lished method.11 This unusual reactivity of quinol ether
2 prompted us to look into the scope of the reaction and
thus several substrates were examined under similar con-
Table 1. Allylation of quinol ethers and quinone ketals with allylindium reagents18
Entry
Phenol
Enone
Metal, allyl bromide
Product (% yield)a
OH
O
OH
Br
1
In,
Me OMe
O
2
Me
OH
(70%)
6
Me
OH
(45%)b
2
3
Br
In,
(78%)
7
Me OMe
O
2
Me
Me
OH
OH
OH
+
+
Br
In,
OMe
9
8
(65%)
OH
10
(14%)
11
O
OH
OH
4
Br
In,
OMe
9
(10%)
13
(70%)
12
Me
OH
O
OH
Me
Me
Br
5
6
7
In,
MeO OMe
15
OMe
OH
14
(60%)
+
16
19
O
O
O
OH
Br
In,
MeO OMe
OMe
17
OH
(10%)
20
(67%)
OMe
18
O
OH
OMe
OMe
OMe
Br
In,
(38%)b
22
21
23
a Yields are unoptimized and refer to the allylation step.
bYields refer to a one-pot process.

D. Mal et al. / Tetrahedron Letters 46 (2005) 2097–2100
2099
L
Me
Me OMe
Me OMe
Me
In
1,2- shift
L
H
1,2 addition
O
In
L
O
O
25
OH
L
2
24
6
Scheme 2. Mechanistic proposal for the formation of o-allylphenol from quinol ethers.
not separable by chromatography, their structures could
be ascertained from the H NMR spectrum of the mix-
larity can be found in the reaction of allylmagnesium
bromide with quinone monoketal derivatives as
reported by Swenton and co-workers.15 To account for
the unusual formation of 2-allyl-4-methylphenol 6, we
were initially tempted to invoke intermolecular SN20 dis-
placement16 of the methoxy group in 2 by an allylmetal
nucleophile. However, considering the high propensity9d
for 1,2-addition of allylindium reagents to carbonyl
compounds, we propose an anionic vinylogous semipin-
acol17 type rearrangement (Scheme 2) of the initially
formed 1,2-adduct 24 to 25. The indium salts formed
during the reaction, being acidic in nature, probably
trigger displacement of the methoxy group with con-
comitant migration of the allyl group. Attempts to iso-
late the 1,2-adduct 24 and thereby substantiate the
proposed mechanism were of no avail.
1
ture. The observed regioselectivity with ether 9 can be
explained in terms of a hyperconjugative effect of the
alkyl chain of the cyclopentane ring. A similar result
was obtained with the 2-methylallylindium reagent and
quinol ether 9 (entry 4).
Several quinone monoketals were next examined to
broaden the scope of the reaction. The monoketal
15,13 when submitted to the reaction with allylindium re-
agent 3 at room temperature, provided compound 16 as
the only product. 1,4-Naphthoquinone monoketal 18
yielded methoxy-substituted allylnaphthol 19 together
with 2-allyl-1,4-naphthoquinone 20. The latter might
have been formed by aerial oxidation of 19 during
work-up of the reaction. It should be noted that par-
tially protected naphthols are useful intermediates for
the synthesis of pyranonaphthoquinone antibiotics.14
The only example of an ortho quinone monoketal stud-
ied was compound 22. This was prepared from eugenol
21 in accordance with the reported procedure10 and was
treated with allylindium reagent 3 to furnish a complex
mixture of products. Though the formation of the
desired product 23 was revealed by examination of the
1H NMR spectrum of the mixture, it was too complex
for further investigation.
In conclusion, this study has revealed a formal anti-
Michael addition mode for the reactivity of quinol
ethers and quinone monoketals towards allylindium
intermediates, and has increased their synthetic utility.
It has also established the possibility of further develop-
ing the more convenient alternative of the aromatic
Claisen rearrangement. Resolution of the obvious ques-
tions generated by this initial finding with respect to
substrate specificity and reaction mechanism is under
investigation.
The unanticipated result with eugenol 21 and the excep-
tional stability of allylindium reagents to protic solvents
led us to explore the possibility of abbreviating the two-
step preparation of allylated phenols to a single-step
operation, thus adding synthetic usefulness to the meth-
od. The reaction mixture resulting from addition of
PIDA to a methanolic solution of p-cresol 1 was treated
as such with a solution of the allylindium reagent pre-
pared as previously described. Work-up of the reaction
mixture followed by purification of the crude product
provided compound 6 in 45% yield. The superiority of
the one-step version was remarkable for the preparation
of allyleugenol 23. When quinol derivative 22 was di-
rectly used for allylation without isolation, the expected
allyl derivative 23 was obtained in 38% overall yield,
which was better than that observed in the two-step
sequence. This higher yield may be a consequence of
avoidance of dimerization of the unstable quinol ether
22 during chromatographic purification.
Acknowledgements
This work was financially supported by CSIR and DST,
New Delhi. P.P. and B.S. gratefully acknowledge the
receipt of their Senior Research Fellowships from the
CSIR, New Delhi.
References and notes
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18. Typical procedure: to a stirred solution of In metal
(191.7 mg, 1.67 mmol) and NaI (250 mg, 1.67 mmol) in
DMF at room temperature, was added dropwise allyl
bromide (0.21 mL, 2.47 mmol). When the indium had
completely dissolved to form a homogeneous solution, a
solution of quinol ether or quinone monoketal
(1.59 mmol) in DMF (1.5 mL) was added. The resulting
mixture was stirred at ambient temperature until complete
consumption of the substrate (usually 12–24 h) and was
then quenched by addition of 3 N HCl (5 mL). It was then
extracted with ether (3 · 20 mL) and the combined organic
extracts were washed with aqueous sodium thiosulfate,
brine, dried and concentrated. Chromatographic (silica
gel) purification (1:10 mixture of ethyl acetate and
petroleum ether) of the resulting residue furnished the
product.
Selected data: compound 12 (oil): dH (CDCl3): 6.93 (1H,
s), 6.71 (1H, s), 4.92 (1H, s), 4.86 (1H, s), 3.34 (2H, s),
2.70–3.00 (4H, m), 1.95–2.15 (2H, m), 1.75 (3H, s);
HRESIMS (m/z): 187.1118, calcd for C13H15O ([MꢀH]+):
187.1123. Compound 19 (oil): dH (CDCl3): 8.00–8.25 (2H,
m), 7.35–7.60 (2H, m), 6.56 (1H, s), 5.95–6.20 (1H, m),
5.10–5.35 (2H, m), 3.96 (3H, s), 3.50–3.60 (2H, m).
Compound 23 (oil): dH (CDCl3): 6.73 (1H, s), 6.63 (1H,
s), 5.75–6.05 (2H, m), 5.42 (1H, br s), 4.85–5.15 (4H, m),
3.85 (3H, s), 3.20–3.35 (4H, m).