Y. Kohno et al. / Tetrahedron Letters 55 (2014) 1826–1828
1827
Table 1
BnO
O
Studies on Claisen rearrangement-cyclization cascade
Entry
Solvent
Additive
Tempa (°C)
Time (h)
Yieldb
N.R.
5a (R = MOM)
5b (R = TBS)
1
2
3
4
5
6
7
Toluene
o-Xylene
PEG-400
o-Xylene
DecalinÒ
PEG-400
PEG-400
—
—
—
PhNEt2
PhNEt2
PhNEt2
—
120
160
120–220
170
210
7
5
7
15
7
BnO
OR
Decomp.
2%c
N.R.
3%c
30%c
69%c
BnO
BnO
O
(HO)2B
BnO
230
270
1
0.25
+
Cl
OR
a
b
c
Bath temperature.
A (= 8)
Isolated yield as a mixture of 8 and 80.
B (= 11)
The ratio of 8:80 was around 5:2 in all cases.
(R = MOM or TBS)
O
Br
Cl
Br
Br
b or c
a
C (= 7)
Cl
HO
OH
BnO
OH
HO
OH
E (= 9)
10
9
BnO
OH
Br
BnO
(HO)2B
d
D (= 6)
Scheme 1. Synthetic plan for 5a and 5b.
OR
BnO
12a (R = MOM)
12b (R = TBS)
OR
11a (R = MOM)
11b (R = TBS)
BnO
OH
BnO
O
a
12b
8
conditions
12a
Cl
Cl
5a
5b
8
e
6
7
Cl
Scheme 3. Synthesis of 5a. Reagents and conditions: (a) BnBr, NaH, DMF (55%); (b)
MOMCl, iPr2NEt, CH2Cl2 (93%); (c) TBSCl, NaH, THF (91%); (d) n-BuLi, B(OMe)3, THF
(71% for 12a; 69% for 12b); (e) Pd(PPh3)4 (5 mol %), K2CO3, aq DMF, 80 °C (89%).
BnO
O
b
+
BnO
O
Table 1
Cl
8
8'
(undesired)
3). Thus, the desired chromene 8 was obtained as a mixture with
the regioisomer 80. However, the isolated yield of a mixture of 8
and 80 was only 2%. These results suggest the instability of 7 or
8/80 under thermal conditions. One probable reason for degrada-
tion may be the resulting HCl; therefore, we attempted to prevent
this degradation by adding PhNEt2 (1.0 equiv) as an acid scavenger.
Although PhNEt2 is recognized as being effective against degrada-
tion (entry 4), the yield of 8/80 was only 3%, even in refluxing dec-
alinÒ (entry 5). We then used PEG-400 and observed a dramatic
improvement in the yield (entry 6). However, we also found that
the addition of PhNEt2 made both the monitoring as well as the
purification of 8/80 significantly more difficult. Therefore, we tried
high-temperature short-time conditions without PhNEt2 (entry 7).
By using a preheated bath at 270 °C, the reaction proceeded rapidly
to give the desired 8/80 with a 69% yield in 15 min. We noted that
reactions using Lewis-acids,8 and aqueous solvents9 resulted in no
reaction. We also noted that a mixture of 8 and 80 was difficult to
separate by chromatography, but was easily separated by recrys-
tallization (from hexane), and the best yield of pure 8 was 49%.10
It is expected that there are two possible pathways in this cascade,
as described in Scheme 2. However, we are unable to discuss this
matter here, because we have no experimental evidence.
With the key intermediate 8 in hand, our next challenge was
Suzuki–Miyaura cross coupling. We prepared two boronic acids
from 4-bromocresol (9). Mono-protection of 9 was attempted with
moderate selectivity to give the corresponding mono-Bn ether 10
(55%; di-Bn ether 23%, regioisomer 4%).11 This was protected in
the usual manner to give 11a and 11b (93% and 91%, respectively),
which were then converted into the corresponding boronic acids
12a and 12b (71% and 69%, respectively). Suzuki–Miyaura cross
coupling between 8 and 12a was then studied. Fortunately, the
BnO
O
7
Cl
Claisen
Cl
Path A
Path B
-HCl
BnO
OH
Cl
BnO
O
Cl
Cl
electrocyclic
reaction
-HCl
SN'-type
8 and 8'
Scheme 2. Synthesis of 8. Reagents and conditions: (a) ClCH2CCl@CHCl, NaH, DMF
(91%); (b) PEG-400, 270 °C, 15 min (49% after recrystallization).
corresponding allylic ether 7 in 91%. This was an E/Z-mixture (E/
Z = ca. 2:1), because the commercially available 1,2,3-trichroro-1-
propene was also an E/Z-mixture. This mixture was subjected to
the next step, that is, Claisen rearrangement-cyclization cascade
reaction, without further purification. This reaction was examined
and summarized in Table 1. Thermal conditions in toluene resulted
in no reaction (entry 1), whereas that in o-xylene resulted in
decomposition (entry 2). We then used PEG-400 as a solvent. Reac-
tion temperature was gradually increased to 220 °C, because the
desired reaction did not appear to have begun at 120 °C, and the
heating was maintained until 7 had almost disappeared (entry