S. He et al. / Tetrahedron Letters 55 (2014) 2212–2216
2213
O
O
EtO
EtO
CO2Et
O
O
Br
CHO
OH
Br
CO2Et
a
b
c
Br
a
b
Br
F
O
F
F
O
O
O2N
2
3
4
13
14
15
18
CO2Y
CO2Et
Br
Br
c
e
HN
EtO
HO
O
O
F
O
F
Ms
f
d
e
Br
H2N
O
Br
H2N
Br
O
N
X
H
5
6
X= NO2
X= NH2
7 Y= Et
8 Y= H
O
O
O
d
f
H2N
16
17
O
O
NH
NH
H
H
N
H
N
N
g
h
Br
Br
O
O
I
O
F
F
Br
Br
Br
h
X
g
O
O
HN
N
Ms
Ms
Ms
O
O
O
N
N
Ms
Ms
N
H
9
1a
19
12
10
Scheme 1. Synthesis of compound 1a. Reagents and conditions: (a) diethyl
carbonate (1.0 equiv), NaH (1.2 equiv), THF, 70 °C, 3 h, 95%; (b) 4-bromophenol
(3.0 equiv), FeCl3Á6H2O (0.15 equiv), (t-BuO)2 (2.2 equiv), reflux, 6 h, 14%; (c) fuming
HNO3 (8.1 equiv), CHCl3, À15 °C, 30 min, 66%; (d) Iron filings (3.0 equiv), NH4Cl
(6.0 equiv), MeOH–THF–H2O (2:2:1), reflux, 3 h, 82%; (e) MsCl (3.0 equiv), pyridine/
CH2Cl2 (1:5), 0 °C to 25 °C, 82%; (f) LiOHÁH2O (5.1 equiv), dioxane–H2O (5:1), 100 °C,
3 h, 96%; (g) HOBt (1.5 equiv), EDC (1.5 equiv), DMF, 25 °C, 2 h, Et3N (4.7 equiv),
CH3NH2ÁHCl (3.0 equiv), 94%; (h) MeI (3.0 equiv), K2CO3 (2.5 equiv), KI (0.02 equiv),
DMF, 80–90 °C, overnight, 94%.
Scheme 2. Preparation of compound 12. Reagents and conditions: (a) ethyl
diazoacetate (1.43 equiv), HBF4ÁEt2O (0.1 equiv), CH2Cl2, <38 °C; then H2SO4 (concd,
1.3 equiv), followed by Na2CO3 (aq), 75%; (b) fuming HNO3 (12.1 equiv), CHCl3,
À20 °C to 0 °C; 85%; (c) Fe filing (3.0 equiv), NH4Cl (6.0 equiv), MeOH–THF–H2O
(2:2:1), 68%; (d) LiOH H2O (5.0 equiv), dioxane–H2O (5.6:1), reflux, 97%; (e) EDC
(1.5 equiv), HOBt (1.5 equiv), DMF, 25 °C, 2 h; Et3N (3.0 equiv), MeNH2ÁHCl
(3.0 equiv), 25 °C, 2 h, 71%; (f) MsCl (2.0 equiv), pyridine (3.0 equiv), CH2Cl2, 0 °C
to 25 °C, 16 h, 70%; (g) K2CO3 (3.0 equiv), MeI (2.0 equiv), DMF, 80 °C, 3 h, 90%; (h)
LDA (5.0 equiv), I2 (6.0 equiv), THF, À78 °C, no required product was observed.
H
H
N
H
N
N
H
N
H
N
HN
O
O
O
O
O
O
Br
Br
Br
Br
Br
Br
a
b
I
B(OH)2
I
B(OH)2
or
O
N
Ms
O
O
O
H2N
O
N
N
Ms
O
H2N
H2N
Ms
18
20
21
10
11
12
H
N
H
N
O
Figure 2. Possible precursors for installing C2 groups: 10 and 11.
O
c
d
Br
Br
I
I
Ms
Ms
O
O
N
to install substituents at the C2-position.12 However, for conve-
nience, we desired a stable intermediate (such as 10), which could
be prepared and stored in bulk, to avoid preparing the organome-
tallic species from 12 separately for each C2 substituent.
Preparation of C2 iodobenzofuran from C2 unsubstituted
benzofuran has been well documented in the literature (Fig. 3).
For example, the Larock group demonstrated that quenching of
the lithium species derived from benzofuran with iodine provides
the 2-iodobenzofuran in high yield.7 In an example closely related
to our work, Presidio scientists reported the preparation of a
2-iodobenzofuran compound with a carboethoxy group at C3
position and a methoxy group at C5 position.13
N
H
22
10
Scheme 3. Preparation of compounds 20 and 10. Reagents and conditions: (a) LDA
(4.2 equiv), THF,1 h; B(OMe)3 (4.0 equiv), À78 °C, 1 h; 71%; (b) NIS(1.0 equiv),
MeCN, 0 °C to 25 °C, 79%; (c) MsCl (2.0 equiv), pyridine, 0 °C to 25 °C, 1.5 h,
LiOHÁH2O (7.9 equiv), 25 °C, 30 min, 59%; (d) K2CO3 (3.0 equiv), MeI (2.0 equiv),
DMF, 0 °C, then 80 °C, 1 h, 91%.
procedure described in the literature,13 the reaction failed to pro-
duce the required C2-iodo product 10.
We suspected that the sulfonamide may have interfered with
the metallation of 12. To test this hypothesis, we decided to try
the metallation on compound 18, an intermediate without the sul-
fonamide group (Scheme 3). Unfortunately, treatment of amine 18
with LDA, followed by quenching with iodine produced many
unidentified by-products and a poor yield of the required C2-iodide
21 (ꢀ6% after purification). On the other hand, when the lithium
species was quenched with trimethylborate followed by hydrolysis
of the boronate intermediate, boronic acid 20 was isolated in good
yield.14 Attempts to convert intermediate 20 to compound 11 were
unsuccessful probably due to the limited stability of the boronic
acid moiety. Instead, iododeboronation of boronic acid 20 with
N-iodosucciimide afforded iodide 21 in good yield.15 The methyl
sulfonamide group was then installed according to the chemistry
described above to provide the key intermediate 10.
We set out to prepare the C2 unsubstituted substrate (12) for
iodination/borylation (Scheme 2). The chemistry was similar to
the preparation of compound 1a (Scheme 1). However, when com-
pound 12 was treated with LDA followed by I2 according to the
t-BuLi, -78 o
C
I
ref. 8
O
O
I2
95%
EtO
EtO
O
O
MeO
MeO
LDA (3.5 eq.) -78 oC
I2
ref. 13
I
O
O
Once precursor 10 became available, a variety of substituents at
C2 were installed via Suzuki coupling with the required boronic
acids or boronates to afford compounds 1b–1n (Table 1). Substi-
tuted phenylboronic acids participated well in the Suzuki coupling
83%
Figure 3. Representative examples known for the preparation of C2-iodo benzo-
furan ring system.