2
Tetrahedron Letters
As an important class of polycyclic compounds, 9,10-
diversity was successfully accomplished and reported herein (eq
5).
dihydrophenanthrene derivatives, existing in many synthetic and
natural products,1 have shown various biological activities, such
At the outset, the assumption was tested by reaction of [1,1'-
biphenyl]-2,2'-dicarbaldehyde 1a with trans-4-hydroxy-L-proline
50 2a in N,N-dimethylformamide (DMF) at 150 ℃. Gratifyingly, the
expected product 10-(1H-pyrrol-1-yl)-9,10-dihydrophenanthren-
9-ol 3aa was obtained in 85% yield (Table 1, entry 1). Inspired
by this result, we started to optimize the reaction conditions to
improve the reaction efficiency. Among the solvents screened,
5 as antitumour,2 antifungal,3
antimicrobial,4
antialgal,5
antimalarial,6 cytotoxic activities,7 and so on. They are also useful
building blocks in material science.8 Therefore, the development
of efficient methods for the synthesis of 9,10-
dihydrophenanthrenes is of high interests. Hall and Turner9
10 reported the synthesis of 9,10-dihydrophenanthrene through the
reaction of 2,2’-di-(bromomethtl)diphenyl with lithium phenyl 55 dimethyl sulfoxide (DMSO) was found to be the most efficient
(eq 1). Suzuki10 and Uemura11 independently developed a SmI2
solvent with a desired product yield of 91% (Table 1, entry 2).
catalyzed intramolecular pinacol coupling strategy to obtain the
Xylenes was inferior and produced the product in 40% yield
trans-9,10-dihydrophenanthrene-9,10-diol from 2,2'-dicarbonyl-
(Table 1, entry 3). Other solvents, such as toluene, 1,2-
15 1,1'-biphenyls.(eq 2). You and coworkers12 modified the process
dichloroethane (DCE), acetonitrile, and ethanol, gave only trace
into a one-pot cascade reaction. Sato and coworkers13 reported a
60 of products (Table 1, entries 3-7). Furthermore, no desired
nickel-catalyzed [2+2+2] cycloaddition of arynes and alkenes (eq
product was detected in the solvent of 1,4-dioxane,
3). Ray and coworkers14 developed a palladium-assisted 6π
tetrahedronfuran (THF) and water (Table 1, entries 8-10). By
electrocyclic reaction to obtain 9,10-dihydrophenanthrenes (eq
increasing the amount of 2a (0.90 mmol), no considerable
20 4). Although the reported methods are somehow effective to the
improvement was observed (Table 1, entry 11), whereas
construction of a 9,10-dihydrophenanthrene skeleton, they suffer
65 decreasing the amount of 2a (0.60 mmol) lowered the yield
from some drawbacks, such as the starting materials were not
obviously (Table 1, entry 12). In addition, by increasing or
commercially available, transition metal catalysts were
decreasing the reaction time did not show any further
unavoidable in many cases, and limited substrate scopes. To the
improvement in the product yield (Table 1, entries 13-14).
25 best of our knowledge, the direct synthesis of pyrrolyl or indolyl
Further investigation indicated that 140 ℃ was the optimal
substituted 9,10-dihydrophenanthren-9-ols has not yet been
70 reaction temperature at which the product was obtained in a yield
reported. Thus, the development of a novel and efficient
of 92% (Table 1, entries 15-17). Thus, the optimized condition
approach to the direct construction of pyrrolyl or indolyl
was determined as follows: [1,1'-biphenyl]-2,2'-dicarbaldehyde
substituted 9,10-dihydrophenanthren-9-ol analogues is highly
1a (0.5 mmol), trans-4-hydroxy-L-proline 2a
30 desirable.
Table 1 Optimization of the reaction conditionsa
Previous work:
CHO
HO
N
OH
Br
Br
solvent
T, time
PhLi
SmI2
COOH
N
CHO
(1)
(2)
H
1a
2a
HO
OH
CHO
3aa
75
Entry
2a
Solvent
T (oC)
Time (min)
Yieldb
(mmol)
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
(%)[dr]c
OHC
1
2
3
4
5
6
7
8
DMF
DMSO
Xylenes
Toluene
DCE
150
150
150
150
150
150
150
30
30
30
30
30
30
30
85[87:13]
91[87:13]
40[86:14]
trace
trace
trace
E
Ni(cod)2
ligand, base
TMS
TfO
E
E
(3)
(4)
E
E = COOMe
MeCN
EtOH
Br
O
Pd(OAc)2,
ligand, base
trace
1,4-
R
R
150
30
0
Dioxane
THF
9
0.75
0.75
0.90
0.60
0.75
0.75
0.75
0.75
0.75
150
150
150
150
150
150
160
140
130
30
30
30
30
20
40
30
30
30
0
0
This work:
10
11
12
13
14
15
16
17
a
H2O
HO
N
OH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
90[87:13]
78[87:13]
88[87:13]
84[87:13]
87[87:13]
92[87:13]
72[87:13]
COOH
N
R'
R
R'
H
CHO
X
(5)
X
R
CHO
N
OH
COOH
N
H
X = nil, O or S
Reaction conditions: [1,1'-biphenyl]-2,2'-dicarbaldehyde 1a (0.5 mmol)
and trans-4-hydroxy-L-proline in 1.5 mL solvent were stirred in a 10 mL-
glass tube sealed with a cap in an oil bath at indicated temperature for 20-40
min.
R
R'
X
In our previous work, we reported the synthesis of N-β-
hydroxyethyl pyrroles and indoles from the reaction of aldehyde
35 with trans-4-hydroxy-L-proline or indoline-2-carboxylic acid via 80 b Isolated yields based on 1a.
a domino [3+2] cycloaddition and ring-opening aromatization
process.15 However, the transformation was not applicable to the
aromatic aldehydes bearing an electron-donating or a weak
electron-withdrawing group due to the low reactivity between
40 aldehydes and azomethineylides in the intermolecular [3+2]
cycloaddition. Fortunately, by replacing the two molecules of the
aldehyde with a dialdehyde molecule participated in the
intramolecular [3+2] cycloaddition, a novel methodology for the
direct synthesis of pyrrolyl or indolyl substituted 9,10-
45 dihydrophenanthren-9-ol analogues with wide substituent
c Determined by 1H-NMR.
(0.75 mmol), DMSO (1.5 mL) as solvent, and a 30-min reaction
time at 140 ℃.
With the optimized conditions in hand, the generality of the
85 reaction was evaluated by altering the diadldehydes and cyclic
amino acids. At first, the symmetrical dialdehyde compounds
were allowed to react with trans-4-hydroxy-L-proline 2a or
indoline-2-carboxylic acid 2b. As shown in Table 2, the
symmetrical [1,1'-biphenyl]-2,2'-dicarbaldehydes 1a-1g afforded
Song, Gonghua
