Regioselective boron trichloride-mediated aromatic Claisen rearrangement of resorcinol allyl ethers

Article abstract of DOI:10.1016/j.tetlet.2005.09.028

The regioselective Claisen rearrangement of resorcinol allyl ethers with boron trichloride was achieved with good selectivity (ca. 13:1) to afford the 6-isomer as major product.

Full text of DOI:10.1016/j.tetlet.2005.09.028

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7765–7767
Regioselective boron trichloride-mediated aromatic
Claisen rearrangement of resorcinol allyl ethers
Fumihiro Ito, Takuya Kumamoto* and Tsutomu Ishikawa
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi, Inage, Chiba 263-8522, Japan
Received 16 July 2005; revised 29 August 2005; accepted 7 September 2005
Available online 22 September 2005
Abstract—The regioselective Claisen rearrangement of resorcinol allyl ethers with boron trichloride was achieved with good selec-
tivity (ca. 13:1) to afford the 6-isomer as major product.
Ó 2005 Elsevier Ltd. All rights reserved.
Claisen rearrangement (CR)1 is one of versatile carbon–
HO
O
H
RO
OH
carbon bond forming reactions and its aromatic version
is most useful for the preparation of 2-allylphenols.
However, the non-selective introduction of carbon unit
is usually encountered when the resorcinol derivatives
1 are used as substrates for the rearrangement (Scheme
1).2 Syamaia and Ramamurthy 3 reported the regioselec-
tive photo-CR of 1–a-cyclodextrin complex to 6-isomer
2, but this system is not suitable for gram-scale prepara-
tion. In this letter, we report the regioselective boron tri-
chloride (BCl3)-mediated aromatic CR of resorcinol
allyl ethers.
O
X
H
A
H
OH
6
OH
O
4 (X = OH): (+)-miroestrol
5 (X = H): (+)-deoxymiroestrol
CR
10
RO
O
H
H
8
O
O
7
As a part of our chemical approaches to Thai miracle
herb Ôkwao keurÕ (Pueraria mirifica),4 we have started
the synthetic studies toward strong phytoestrogens
(+)-miroestrol (4)5 and (+)-deoxymiroestrol (5), in
which regioselective aromatic CR of resorcinol allyl
ethers 7 is the key step for the introduction of the A ring
at the 10-position of (R)-carvone (8) (Scheme 2).
Scheme 2.
Starting resorcinol ally ethers 7 were prepared as fol-
lows: direct displacement of the chlorine atom of 10-
chlorocarvone (10)6 with methyl 9b and benzoyl resor-
cinol 9d afforded the corresponding allyl ethers 7b and
7d, respectively; however, in the latter case partial
hydrolysis to phenol 7a was observed during reaction
course. Thus, the allyl ether 7a was prepared in 70%
yield from 10 by reaction with 9d followed by hydroly-
sis. 2-Propyl 7c and tert-butyldiphenylsilyl (TBDPS)
ether 7e were obtained by alkylation or silylation of 7a
(Scheme 3).7
H3CO
O
H3CO
OH
OH
hν
+
6
2
OCH3
1
2
3
Scheme 1.
At first, we tried thermal CR (Table 1). Heating the
methyl ether 7b in N,N-diethylaniline (PhNEt2) afforded
the rearranged products 6b and 11b in moderate total
yield and poor selectivity, the ratio was 1.2:1 with 6b
as a major product (run 1). Reaction proceeded much
Keywords: Claisen rearrangement; Regioselectivity; Boron trichloride;
Resorcinol allyl ether.
*
Corresponding author. Tel./fax: +81 43 290 2911; e-mail: tkuma@
p.chiba-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.028

7766
F. Ito et al. / Tetrahedron Letters 46 (2005) 7765–7767
a
Cl
7b
7d
RO
OH
H
(from 9b)
b
a : R = H
b : R = CH3
+
(from 9d)
c
c : R = 2-propyl
d : R = benzoyl
e : R = TBDPS
9
d
e
O
7a
7c
7e
(from 9d)
10
Scheme 3. Reagents and conditions: (a) K2CO3, DMF, 70 °C, 9 h (77% from 10); (b) K2CO3, DMF, 60 °C, 6 h (40% from 10 as isolated); (c) (1)
K2CO3, DMF, 60 °C, 6 h; (2) KOH, CH3OH, 0 °C, 30 min (70% from 10); (d) 2-bromopropane, K2CO3, DMF, 50 °C, 4 h (85%); (e) TBDPSCl,
imidazole, DMF, rt, 4 h.
Table 1. CR of the resorcinol ally ethers 7
RO
O
RO
OH
OH
H3CO
O
H
H
Y =
+
Et
Cl
Y
Y
Y
6
2
Y
+
OR
O
10
Conditions
7
6
11
12
O
Run
R in 7
Additive
Solvent
Yield (%)a
6
11
10
1
2
3
4
5
6
7
7b: CH3
7b: CH3
7a: H
7c: 2-Propyl
7d: Benzoyl
7e: TBDPS
7b: CH3
None
None
None
None
None
None
BCl3
PhNEt2
PhNEt2
PhNEt2
PhNEt2
PhNEt2
PhNEt2
CH2Cl2
140–220 °C, 9.5 h
27
44
38
34
28
42b
54
22
34
28
18
28
24b
10
0
0
0
0
0
Microwave, 250 °C, 40 min
Microwave, 200 °C, 45 min
Microwave, 250 °C, 30 min
Microwave, 250 °C, 50 min
Microwave, 250 °C, 40 min
À50 to À20 °C, 3 h
0
19
a Isolated yields from corresponding 7 unless otherwise noted.
b Isolated yields from 7a in two steps.
Table 2. BCl3-mediated CR of the resolcinol allyl ethers 7
faster under microwave condition and afforded better
chemical yields,8 but regioselectivity was not improved
(run 2). Reactions with varying electronic and steric
factors on the meta substituents showed the same kind
of regioselectivities in the range of 1:1 to 2:1 (runs
3–6). Next, we examined the rearrangement of the
methyl ether 7b in the presence of additives. No reaction
occurred in the presence of montmorillonite K10
(MK10)4c,d in refluxing benzene. The reaction with
diethylaluminum chloride9 in dichloromethane (CH2Cl2)
gave an ethyl-inserted product 12 in 47% yield as a 2.3:1
mixture of diastereomers in place of rearranged prod-
ucts. The reaction with aluminum trichloride in CH2Cl2
gave 6b in only 33% yield.10 So we next turned to the
utilization of BCl3, which had been reported as a good
Lewis acid for regioselective CR of 4-allyloxy-2-meth-
oxycinnamate.11 A mixture of 7b and BCl3 in CH2Cl2
was stirred at À50 to À20 °C for 3 h. The rearranged
products 6b and 11b were smoothly obtained and the de-
sired 6-isomer 6b was formed as the major isomer in a
ratio of ca. 5:1, albeit the concomitant production of a
cleaved product 10 (run 7). Thus, it was found that
BCl3 could effectively control the CR of the allyl ether
7b.
Run
R in 7
Conditions
Yield (%)a
6
11
10
1b
2
3
4
7b: CH3
7a: H
7d: Benzoyl
7c: 2-Propyl
7e: TBDPS
À50 to À20 °C, 3 h
À50 °C, 3 h
54
51
23
10
19
8
33
17
0
9
9
À50 °C, 1 h
À50 °C, 1 h
5c
5
À50 °C, 1 h
76d
6d
a Isolated yields from corresponding 7 unless otherwise noted.
b The data from run 7 in Table 1.
c A 4:1 mixture of 6c and 11c.
d Isolated yields from 7a in two steps.
allyl ether 7d (run 3). 2-Propyl ether 7c gave a complex
mixture containing small amount of 6c, 11c, and 10
because of lability of 2-propyl group in acidic condition
(run 4). Fortunately, it was found that the yield and the
regioselectivity were improved (6e/11e = 13:1, 76%
yield for 6e) when TBDPS ether 7e was used (run 5).
Regioselectivity of the BCl3-mediated CR using resor-
cinol methyl ether 1 was estimated by ab initio calcula-
tion based on B3LYP hybrid functional together with
the 6-31+G(d) basis set using Gaussian 98 (Fig. 1).
Two stable transition structures for each regioisomer
were obtained and it was calculated that the transition
structure (HOMO) for the 6-isomer was more stable
than that for the 2-isomer in about 3 kcal/mol.12 These
The BCl3-mediated CR was further examined (Table 2).
Nearly the same results were obtained when compound
7a was used as substrate (run 2) while the selectivity
was lowered in the reaction with benzoyloxy-substituted

F. Ito et al. / Tetrahedron Letters 46 (2005) 7765–7767
7767
2. Gozzo, F. C.; Fernandes, S. A.; Rodorigues, D. C.;
Eberlin, M. N.; Marsaioli, A. J. J. Org. Chem. 2003, 68,
5493–5499.
3. Syamaia, M. S.; Ramamurthy, V. Tetrahedron 1988, 44,
7223–7233.
4. (a) Chansakaow, S.; Ishikawa, T.; Seki, H.; Sekine, K.;
Okada, M.; Chaichantipyuth, C. J. Nat. Prod. 2000, 63,
173–175; (b) Chansakaow, S.; Ishikawa, T.; Sekine, K.;
Okada, M.; Higuchi, Y.; Kudo, M.; Chaichantipyuth, C.
Planta Med. 2000, 66, 572–575; (c) Iwasaki, M.; Wata-
nabe, T.; Ishikawa, T.; Chansakaouw, S.; Higuchi, Y.;
Tahara, S. Heterocycles 2004, 63, 1375–1392; (d) Ito, F.;
Iwasaki, M.; Watanabe, T.; Ishikawa, T.; Higuchi, Y. Org.
Biomol. Chem. 2005, 3, 674–681.
Figure 1. Calculated HOMO of transition structures of BCl3-mediated
CR of 1; left: rearrangement at the 6-position, right: rearrangement at
the 2-position.
5. Total synthesis of (+)-miroestrol: Corey, E. J.; Wu, L. I. J.
Am. Chem. Soc. 1993, 115, 9327–9328.
6. Weinges, K.; Schwarz, G. Liebigs Ann. Chem. 1993, 811–
814.
7. Compound 7e was obtained as a mixture of side product
derived from TPDPSCl.
8. Sonnenberg, F. M. J. Org. Chem. 1970, 35, 3166–3167.
9. Microwave reaction apparatus: CEM Discover. Condi-
tions: 300 W, 100 psi.
10. The generation of 11b was not observed in this reaction.
11. Cairns, N.; Harwood, L. M.; Astles, D. P.; Orr, A. J.
Chem. Soc., Perkin Trans. 1 1994, 3095–3100.
12. It has been reported that there is no difference between
two transition-state energy levels for both reaction path-
ways from 1 to 2 and 3 in thermal condition: see Ref. 2.
13. Compound 6b has been converted to methoxyethoxy-
methyl (MEM) ether 13 (Bn: benzyl) in seven steps. The
details will be reported elsewhere.
results could suggest the origin of this regioselectivity
observed in the BCl3-mediated CR. Although the reason
of the improved regioselectivity on the TBDPS ether 7e
is not clear, the electron density of the 2-position of
benzene ring would be more diminished by siloxy group
than by methoxy group.
In conclusion, it was found that the regioselectivity of
CR of resorcinol allyl ethers 7, especially the TBDPS
ether 7e, could be controlled by BCl3. Further mechanis-
tic approaches for the CR and the synthetic studies
toward miroestrols are under investigation.13
OBn
TBDPSO
OMEM
H
References and notes
O
1. Recent review: Martin Castro, A. M. Chem. Rev. 2004,
104, 2939–3002.
13
O