One-pot access to 2-amino-3-arylbenzofurans: Direct entry to polyheterocyclic chemical space

Article abstract of DOI:10.1039/d0ob01715a

As a means to make new benzofuran-embedded polycyclic structures, we established two efficient one-pot sequential coupling routes to 2-amino-3-arylbenzofurans and 2-amino-3-arylnaphtho[2,1-b]furans. Further ring formation (six- and seven-membered rings) with the resulting amine moiety at the C2 position of benzofurans was realized, leading to further expansion of benzofuran-based chemical space.

Full text of DOI:10.1039/d0ob01715a

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One-pot Access to 2-Amino-3-arylbenzofurans: Direct Entry to
Polyheterocyclic Chemical Spaces
Sure Siva Prasad, Dirgha Raj Joshi, Jeong Hwa Lee, and Ikyon Kim*
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University
8
5 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea
*
Corresponding author. Tel.: +82 32 749 4515; fax: +82 32 749 4105; e-mail:
ikyonkim@yonsei.ac.kr
Table of Contents
Exploitation of one-pot sequential assembly reactions provides two efficient synthetic routes
to 2-amino-3-arylbenzofurans, versatile intermediates of novel polyheterocycles.
ArCHO
TMSCN
R
R
Ar
Ar
TMSCN
ArH
CHO
OAc
R
NH2
NH2
R
O
O
MeO
MeO
OH
-
direct approaches to 2-amino-3-
New Polyheterocyles
arylbenzofurans
-
formation of two C-C and one C-O bonds in
a one-pot mode
N
-
access to benzofuran-embedded polycyclic
chemical spaces
O
Abstract: As a means to make new benzofuran-embedded polycyclic structures, we
established two efficient one-pot sequential coupling routes to 2-amino-3-arylbenzofurans and
2
-amino-3-arylnaphtho[2,1-b]furans. Further ring formation (six- and seven-membered rings)
1

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with the resulting amine moiety at the C2 position of benzofurans was realized, leading to more
expansion of benzofuran-based chemical space.
Keywords: Benzofuran; One-pot Reaction; Polycyclic Heteroaromatics; Hybrid structure;
Chemical space; Diversity-oriented synthesis; Atom-economy
Introduction
In connection with a growing interest on polycyclic heteroaromatic systems1 in various
research fields such as medicinal and material chemistry, extension of polyaromatic chemical
space through design and synthesis of new chemical scaffolds is highly required. In particular,
it is desirable to assemble polyaromatic heterocycles by strategic use of one-pot coupling
2
reactions, thereby increasing the overall efficiency of the synthetic protocols. For example,
great advances have been made in the syntheses of polycyclic benzofurans along this line due
to their versatile properties including biological, electrochemical, and photochemical ones.3
Recently, we have recently communicated on one-pot three-component approaches to
4
5
diarylacetonitriles and diarylmethylphosphonates as versatile intermediates to get direct
access to polyaromatic systems (Scheme 1a).
Scheme 1. Synthetic Plans
2

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(a) one-pot three-component synthesis of
diarylacetonitriles and diarylmethylphosphonates (refs 4 and 5)
Ar'H
Nu
BF -OEt2
polycyclic
heteroaromatic
compounds
Ar'
ArCHO
Ar
G
3
1
2
(G = CN or PO(OR)2)
(b) 2-aminobenzofurans (this work)
R
Ar
Ar
OH
ArCHO
CN
R
R
NH2
TMSCN
O
OH
Lewis Acid
1
3
4
To extend these protocols, we envisioned that use of phenol as an electron-rich arene in
coupling with aldehyde 1 and TMSCN in the presence of Lewis acid would lead to 2-
aminobenzofuran 4 via further cyclization of intermediate 3 (Scheme 1b). Despite the
importance of these compounds and their derivatives in the fields of medicinal and material
6
science, synthetic methods to get access to highly functionalized 2-aminobenzofurans are
7
8
very limited. As part of our synthetic efforts to broaden benzofuran chemical spaces, here
we wish to describe one-pot syntheses of 2-amino-3-arylbenzofurans and 2-amino-3-
arylnaphtho[2,1-b]furans from commercially available starting materials.
Results and discussion
Reaction optimization was carried out with 3,4-dimethoxybenzaldehyde (1a), 3,4-
9
dimethoxyphenol, and TMSCN (Table 1). Two conditions (A and B) were examined. In
conditions A, 3,4-dimethoxyphenol was added to the premixed solution of aldehyde 1a,
TMSCN, and catalyst in appropriate solvent after 30 min. Unfortunately, the desired 4a was
not formed under various Lewis acid catalytic systems (entries 1-8). 3a was isolated in variable
3

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yields along with the recovered starting materials. When excess BF -OEt (1.2 equiv to 2 equiv)
3
2
was used, 2-aminobenzofuran 4a was obtained in 20-47% yields (entries 9-11). In conditions
B, cyanohydrin 1b or 1c was first formed by the action of ZnI (0.1 equiv) before 3,4-
2
dimethoxyphenol and additional catalyst were added.10 While catalytic amount of Bi(OTf)3,
Ag(OTf), or Cu(OTf) still gave 3a as a major product, BF -OEt (1.2 equiv) furnished 4a (40%)
2
3
2
and 3a (31%) (entries 12-15). When BF -OEt (2 equiv) was used, the best result was observed
3
2
(entries 16 and 17).
Table 1. Reaction Optimizationa
OMe
OMe
conditions A
TMSCN (1.5 equiv)
MeO
MeO
MeO
MeO
CHO
catalyst, solvent
+
rt, 30 min then
MeO
MeO
MeO
MeO
3,4-dimethoxyphenol (1 equiv)
CN
NH2
1a
O
OH
4
a
3a
TMSCN (1.5 equiv)
OR
ZnI (0.1 equiv)
2
conditions B
MeO
CN
CH Cl (4 mL)
3,4-dimethoxyphenol
catalyst
2
2
MeO
0
°C to rt, 30 min
1b (R = H)
0
°C to 30 °C
1c (R = TMS)
time
entry
catalyst (equiv)
solvent
yield (%)b
(h)
conditions A
1b
4a
3a
1
2
3
4
5
6
7
8
9
Bi(OTf) (0.2)
Ag(OTf) (0.2)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
48
48
48
48
48
48
24
48
24
24
48
10
30
20
32
10
41
-
80
-
-
-
-
-
-
-
51
42
38
10
20
trace
34
-
3
Cu(OTf) (0.2)
2
Yb(OTf) (0.2)
3
Sc(OTf) (0.2)
3
Zn(OTf) (0.2)
-
2
FeCl (0.2)
trace
-
20
31
47
3
ZnI (0.2)
2
BF -OEt (1.2)
31
32
15
3
2
1
0
1
BF -OEt (1.5)
3
2
1
BF -OEt (2.0)
-
3
2
conditions B
4

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1
1
1
1
1
1
2
3
4
5
6
7
Bi(OTf) (0.2)
Ag(OTf) (0.2)
DCM
DCM
DCM
DCM
DCM
DCM
24
24
24
24
24
14
-
-
-
-
-
-
trace
trace
-
40
52
57
68
54
31
34
10
3
Cu(OTf) (0.2)
2
BF -OEt (1.2)
3
2
BF -OEt (1.5)
3
2
BF -OEt (2.0)
78
3
2
a
A mixture of 1a (100 mg, 0.6 mmol, 1 equiv), TMSCN (1.5 equiv), 3,4-dimethoxyphenol (1
equiv), and catalyst in solvent (4 mL) was used. Isolated yield (%).
b
To see if the reaction proceeded via cyanohydrin, the isolated intermediate 1b was treated with
3
,4-dimethoxyphenol and BF -OEt (2 equiv) to afford 4a in 89% yield (Scheme 2).
3 2
Scheme 2. Conversion of 1b to 4a
OMe
NH2
MeO
OH
3
,4-dimethoxyphenol
MeO
MeO
CN
BF -OEt (2 equiv)
CH Cl , 0 °C to rt, 4 h
MeO
MeO
3
2
2
2
89%
O
1b
4a
With these optimized conditions in hand, the reaction scope was first examined with various
aldehydes and 3,4-dimethoxyphenol (Table 2). Overall, the corresponding 2-amino-3-
arylbenzofurans 4b-l were obtained in good to excellent yields. Uncyclized diarylacetontriles
3
were isolated as minor products in some cases (3c, 3e, and 3g). In case of N,N-dimethylaniline
as a nucleophile, 3i was obtained as a major product. Transformation of 3a to 4a was readily
achieved upon exposure of 3a to BF -OEt in CH Cl (Scheme 3). Thiophene-2-
3
2
2
2
carboxaldehyde was employed to give 2-aminobenzofuran 4l bearing a heterocycle at C3 site.
As noted in our previous work, aldehydes bearing electron-donating group(s) at ortho-, and/or
para-position(s) seemed to be crucial for successful three-component coupling process,
implying the importance of resonance stabilization of the reaction intermediates, cyanohydrins,
by alkoxyl and/or hydroxyl at ortho-, and/or para-position(s) under these conditions.11
5

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Table 2. Synthesis of 4 with 3,4-Dimethoxyphenola
MeO
MeO
TMSCN (1.5 equiv)
Ar
Ar
ZnI (0.1 equiv)
2
OH
MeO
MeO
MeO
MeO
ArCHO
+
CN
OH
NH2
CH Cl2
BF3-OEt2 (2 equiv)
0 °C to 30 °C, 14 h
2
O
0
°C to rt, 30 min
1
4
3
O
OMe
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
+
CN
NH2
NH2
O
O
OH
4
b (83%)b
4c (64%) + 3c (16%)
OMe
OMe
OMe
MeO
MeO
MeO
OMe
OMe
OMe
MeO
NH2
MeO
MeO
MeO
+
CN
OH
NH2
O
O
MeO
MeO
4
d (72%)
4e (80%) + 3e (9%)
OMe
OMe
OMe
MeO
MeO
MeO
Br
CN
OH
OMe
NH2
Br
MeO
MeO
MeO
MeO
MeO
+
NH2
O
O
MeO
4f (62%)
4g (74%) + 3g (7%)
N
OMe
O
O
HO
Br
MeO
MeO
MeO
MeO
MeO
MeO
CN
OH
NH2
NH2
O
O
4
h (44%)
3i (82%)
4j (61%)
6

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OH
MeO
S
MeO
MeO
MeO
NH2
NH2
O
MeO
O
4
k (54%)
4l (47%)
a
After a mixture of 1 (100 mg, 1 equiv), TMSCN (1.5 equiv), and ZnI (0.1 equiv) in DCM (4
2
mL) was stirred at rt for 30 min, 3,4-dimethoxyphenol (1 equiv) and BF -Et O (2 equiv) were
3
2
b
added at 0 °C. The reaction mixture was stirred at 30 °C for 14 h. Isolated yield (%).
Scheme 3. Conversion of 3a to 4a
OMe
OMe
NH2
MeO
MeO
BF -OEt (1.2 equiv)
3
2
CH Cl , 0 °C to rt
MeO
MeO
MeO
MeO
2
2
CN
3
h, 91%
O
OH
3a
4a
Next, this coupling was carried out with different phenols. As shown in Table 3, variously
substituted phenols were successfully employed as nucleophiles in this process to furnish the
corresponding 2-amino-3-arylbenzofurans. Alkoxyl, alkyl, aryl, or halogen substituent of the
phenol was well tolerated under these conditions. Use of 2-naphthol produced 2-amino-3-
arylnaphtho[2,1-b]furans 4u-x. When 3-methoxyphenol and 3-phenylphenol were used,
respectively, the desired 2-aminobenzofurans (4y and 4aa) were isolated as minor products.
The uncyclized adducts (4y’ and 4aa’) were obtained as major products as a consequence of
alternative nucleophilic attack of phenols to the intermediates, cyanohydrins. Surprisingly, 4-
bromophenol gave unwanted adduct 4z’ whereas 4-chlorophenol provided the desired 2-
aminobenzofuran 4r. Interestingly, the isomerized products (4ab’ and 4ac’) were mainly
observed from the reactions with 3,4,5-trimethoxyphenol. We believe that this isomerization
7

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may be caused to avoid the steric clash between methoxyl and aryl at the C3 site of benzofuran
3
(
Scheme 4). An sp carbon at the C3 position via isomerization would be expected to release
the steric strain.
Table 3. Synthesis of 4 with Different Phenols or 2-Naphthola
TMSCN (1.5 equiv)
R
Ar
ZnI (0.1 equiv)
2
OH
ArCHO
R
NH2
CH Cl2
BF3-OEt2 (2 equiv)
0 °C to 30 °C, 14 h
2
O
4
1
0
°C to rt, 30 min
OMe
OMe
OMe
MeO
MeO
MeO
MeO
BnO
O
O
NH2
NH2
NH2
O
O
O
4
m (78%)b
4n (70%)
4o (75%)
OMe
OMe
OMe
MeO
MeO
MeO
Ph
Cl
NH2
NH2
NH2
O
O
O
4
p (70%)
4q (71%)
4r (63%)
OMe
MeO
OMe
OMe
MeO
MeO
Br
Cl
NH2
NH2
NH2
O
O
O
Me
4
s (61%)
4t (60%)
4u (70%)
8

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OMe
OMe
OMe
HO
OH
MeO
MeO
NH2
NH2
O
NH2
O
O
4
v (63%)
4w (50%)
4x (47%)
OMe
OMe
OMe
NH2
MeO
MeO
MeO
+
HO
CN
CN
O
MeO
HO
OMe
Br
4
y (21%) + 4y’ (60%)
4z’ (58%)
OMe
OMe
MeO
MeO
+
CN
Ph
NH2
O
Ph
HO
4
aa (20%) + 4aa’ (63%)
OMe
OMe
R
R
OMe
OMe
+
MeO
MeO
MeO
MeO
NH2
NH
O
O
R = OMe: 4ab (4%) + 4ab’ (56%)
R = H: 4ac’ (51%)
a
After a mixture of 1 (100 mg, 1 equiv), TMSCN (1.5 equiv), and ZnI (0.1 equiv) in DCM (4
2
mL) was stirred at rt for 30 min, phenol or 2-naphthol (1 equiv) and BF -Et O (2 equiv) were
3
2
b
added at 0 °C. The reaction mixture was stirred at 30 °C for 14 h. Isolated yield (%).
Scheme 4. Rationale for the Formation of 4ab’ and 4ac’
9

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steric strain
OMe
NH2
OMe
R
R
OMe
OMe
sp3
MeO
MeO
MeO
MeO
NH
O
O
R = H or OMe
In the meantime, we also investigated the possibility that the corresponding 2-amino-3-
arylbenzofurans 5 would be formed by participation of the neighboring hydroxyl group when
salicylaldehydes such as 4-methoxy-2-hydroxybenzaldehyde were allowed to react with
TMSCN and arene(s) in the presence of Lewis acid (Table 4). Indeed, this combination
provided access to 2-amino-3-arylbenzofurans 5a-d albeit in modest yields. After some
optimization, however, we discovered that protection of the hydroxyl as an acetate improves
the efficiency of this process (Table 5). Although this protection did not allow direct cyclization
after three-component coupling event, the overall yields of this two-step procedure were much
better than the one-pot process shown in Table 4. Thus, 2-acetoxybenzaldehydes 6 were
employed to make diarylacetonitriles 7, which underwent base-mediated cyclization12 to
furnish 5.
Table 4. Synthesis of 5a-da
ZnI (0.1 equiv)
TMSCN (1.5 equiv)
2
OR
CN
Ar
CHO
ArH (1.2 equiv)
NH2
MeO
OH CH2Cl2
0 °C, 1 h
BF3-OEt2 (2 equiv)
30 °C, 14 h
O
MeO
MeO
OH
5
R = H or TMS
5
1
0

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OMe
OMe
OMe
MeO
MeO
MeO
MeO
OMe
NH2
NH2
NH2
O
O
O
MeO
MeO
MeO
5
a (38%)b
5b (40%)
5c (39%)
OMe
MeO
OMe
NH2
O
MeO
5
d (48%)
After a mixture of 2-hydroxy-4-methoxybenzaldehyde (100 mg, 0.66 mmol, 1 equiv),
TMSCN (1.5 equiv), and ZnI (0.1 equiv) in DCM (4 mL) was stirred at 50 °C for 1 h, ArH
a
2
(
°
1.2 equiv) and BF -Et O (2 equiv) were added at 0 °C. The reaction mixture was stirred at 30
C for 14 h. Isolated yield (%).
3 2
b
Table 5. Synthesis of 5e-5ja
R
TMSCN (1.5 equiv)
CHO ArH (1.2 equiv)
R
R
Ar
Ar
Et N (2 equiv)
3
CN
NH2
BF -OEt (2 equiv)
rt, 8 h
MeOH, rt, 7 h
MeO
OAc
3
2
O
MeO
MeO
OAc
6a (R = H)
7
5
6b (R = OMe)
OMe
OMe
OMe
MeO
MeO
OMe
Br
Br
NH2
CN
OAc
O
MeO
MeO
7
e (95%)b
5e (92%)
1
1

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OMe
OMe
NH2
CN
OAc
O
MeO
MeO
MeO
MeO
7
f (81%)
5f (87%)
S
S
Br
CN
OAc
Br
NH2
O
MeO
MeO
7
g (68%)
5g (89%)
O
O
CN
OAc
NH2
O
7
h (61%)c
5h (74%)
N
N
NO2
NO2
CN
NH2
O
MeO
MeO
OAc
7
i (60%)
5i (77%)
OMe
OMe
OMe
OMe
OMe
OMe
NH2
CN
OAc
O
MeO
MeO
7
j (84%)
5j (73%)
a
A mixture of 6 (100 mg, 1 equiv), ArH (1.2 equiv), TMSCN (1.5 equiv), and BF -Et O (2
3
2
equiv) in DCM (4 mL) was stirred at rt for 8 h. A mixture of 7 (50 mg, 1 equiv) and Et N (2
3
b
c
equiv) in MeOH (4-5 mL) was stirred at rt for 7 h. Isolated yield (%). Furan (2.5 equiv) was
used.
Next, further synthetic elaboration of the resulting 2-amino-3-arylbenzofurans was attempted.
As shown in Table 6, reaction conditions for oxidative Pictet-Spengler ring closure13 of 4a
1
2

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were optimized. While formation of imine 8a’ was so facile in the presence of TFA, DBSA,
BF -OEt , or FeCl , the desired ring cyclized product 8a was not observed in most cases
3
2
3
(
entries 1-8). Although reaction with Yb(OTf) (0.2 equiv) at rt gave an excellent yield of 8a’,
3
reaction at 90 °C provided a mixture of 8a (35) and 8a’ (51) (entries 9 and 10). Toluene as a
solvent rather resulted in inferior outcome (entry 11). Finally, Yb(OTf) -catalyzed reaction in
3
DCE at 130 °C delivered benzofuran-isoquinoline hybrid14,15 skeleton 8a in 89% yield (entry
1
2).
Table 6. Synthetic Application: Oxidative Pictet-Spengler Reactiona
OMe
NH2
OMe
OMe
MeO
MeO
MeO
PhCHO
+
MeO
Ph
MeO
MeO
reaction MeO
conditions
Ph
N
N
O
O
8a
O
MeO
MeO
4a
8a'
yield (%)b
entry
catalyst (equiv)
solvent
temperature (°C)
time (h)
8
a
8a’
1
2
3
4
5
6
7
8
9
TFA (0.2)
TFA (0.2)
DCM
DCM
THF
THF
THF
toluene
DCE
DCE
DCE
DCE
rt
60
60
60
60
120
80
80
rt
1.5
24
1
24
4
22
32
24
3
12
12
14
86
79
87
81
72
70
61
45
97
51
41
DBSA (0.1)
DBSA (0.1)
PTSA (0.2)
DBSA (0.2)
BF -OEt (1.2)
trace
16
3
2
FeCl (0.1)
3
Yb(OTf) (0.2)
3
1
0
1
2
Yb(OTf) (0.2)
90
130
130
35
15
89
3
1
1
Yb(OTf) (0.2)
toluene
DCE
3
Yb(OTf) (0.2)
3
a
To a mixture of 4a (50 mg, 0.15 mmol, 1 equiv) and benzaldehyde (0.3 mmol, 2 equiv) in
solvent (2 mL) was added catalyst at rt. The reaction mixture was stirred at the indicated
b
temperature for the indicated time. Isolated yield (%).
1
3

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Under these conditions, several 2-amino-3-arylbenzofurans were converted to the
corresponding fluorescent polycyclic products 8 (Table 7). Electron-rich as well as electron-
poor arylaldehydes were incorporated in the range of 30-94% yields. Use of trans-
cinnamaldehyde in this reaction provided 8h albeit in modest yield.
Table 7. Synthesis of 8a
R2
R2
ArCHO
Ar
R1
NH2
Yb(OTf)3
R1
N
DCE
O
4
O
8
130 °C
OMe
OMe
OMe
MeO
MeO
MeO
O
O
OMe
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
MeO
O
O
O
8
b (88%, 38 h)b
8c (91%, 27 h)
8d (30%, 50 h)
OMe
OMe
OMe
MeO
MeO
MeO
OMe
OMe
OMe
Me
Cl
MeO
MeO
MeO
MeO
MeO
MeO
N
N
O
N
O
O
8
e (30%, 40 h)
8f (52%, 27 h)
8g (56%, 14 h)
OMe
MeO
OMe
OMe
OMe
Ph
MeO
MeO
Cl
Ph
MeO
MeO
MeO
N
N
N
O
O
O
Me
8
8
h (35%, 21 h)
8i (86%, 23 h)
8j (56%, 12 h)
OMe
OMe
OMe
MeO
MeO
MeO
OMe
OMe
OMe
OMe
OMe
MeO
MeO
Ph
MeO
MeO
N
N
N
O
O
O
k (37%, 25 h)
8l (94%, 3 h)
8m (63%, 20 h)
a
To a mixture of 4 (50 mg, 1 equiv) and aldehyde (2 equiv) in DCE (2 mL) was added Yb(OTf)
0.2 equiv) at rt. The reaction mixture was stirred at 130 °C for the indicated time. Isolated
3
b
(
yield (%), reaction time (h).
1
4

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Oxidative Pictet-Spengler cyclization of 4ab’ with benzaldehyde also worked well to give 8n
Scheme 5).
(
Scheme 5. Oxidative Pictet-Spengler Reaction of 4ab’
OMe
OMe
MeO
MeO
OMe
PhCHO
Yb(OTf) (0.2 equiv)
3
OMe
Ph
MeO
MeO
DCE, 130 °C, 7 h
NH 71%
MeO
MeO
N
O
O
4ab'
8n
In addition, subsequent construction of 7-membered rings was successfully realized (Scheme
). Use of 3,4-dimethoxyphenylacetonitrile and methyl 3,4-dimethoxyphenylacetate as
6
nucleophiles in these three-component couplings with 6a and TMSCN afforded amidine 10
and lactam 13 through the intermediates 9 and 11, respectively. While base-mediated
cyclization of 11 at rt gave a mixture of 12 and 13, heating the reaction mixture at 80 °C cleanly
produced 13 in 91% yield. The resulting two novel tetracyclic ring systems may be useful
heterocyclic scaffolds for further biological study.
Scheme 6. Syntheses of 9-13
1
5

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MeO
MeO
CN
OMe
OMe
MeO
MeO
Et N (2 equiv)
3
TMSCN (1.5 equiv)
CN
6a
MeOH, rt, 10 h
BF -OEt (2 equiv)
rt, 8 h, 86%
3
2
CN
OAc
NH2
78%
N
O
MeO
MeO
9
10
MeO
MeO
CO Me
2
OMe
OMe
NH2
MeO
MeO
TMSCN (1.5 equiv)
Et N (2 equiv)
3
CO Me
2
6a
CO Me
2
BF -OEt (2 equiv)
MeOH, rt, 15 h
3
2
CN
OAc
rt, 10 h, 77%
O
MeO
12 (73%)
MeO
+
11
OMe
OMe
MeO
MeO
Et N (2 equiv)
3
11
o
MeOH, 80 C
O
O
NH
13 (16%)
3
h, 91%
NH
O
O
MeO
MeO
13
Conclusions
In summary, two highly efficient direct one-pot approaches to 2-amino-3-arylbenzofurans and
-amino-3-arylnaphtho[2,1-b]furans were accomplished via Lewis acid-mediated sequential
2
coupling reactions where multi-bond formation (two C-C and one C-O) took place. Versatility
of the resulting compounds was demonstrated through additional cyclizations leading to three
novel polyheterocyclic systems, benzofuro[2,3-c]isoquinoline, 5H-benzo[d]benzofuro[2,3-
b]azepin-6-amine, and 5,7-dihydro-6H-benzo[d]benzofuro[2,3-b]azepin-6-one, respectively.
We hope that our one-pot assembly protocols enabling rapid access to new benzofuran-based
chemical space would be useful for drug discovery research with unique molecular entities.
1
6

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Synthetic efforts to generate new heterocyclic chemical space via one-pot assembly of readily
available building blocks as well as biological application of the resulting products are being
continuously made.
Experimental Section
General Methods
Unless specified, all reagents and starting materials were purchased from commercial sources
and used as received without purification. “Concentrated” refers to the removal of volatile
solvents via distillation using a rotary evaporator. “Dried” refers to pouring onto, or passing
through, anhydrous magnesium sulfate followed by filtration. Flash chromatography was
performed using silica gel (230−400 mesh) with hexanes, ethyl acetate, and dichloromethane
as the eluents. All reactions were monitored by thin-layer chromatography on 0.25 mm silica
plates (F-254) visualized with UV light. Melting points were measured using a capillary
melting point apparatus. H and 13C NMR spectra were recorded on a 400 MHz NMR
spectrometer and were described as chemical shifts, multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet), coupling constant in hertz (Hz), and number of protons. HRMS was
measured with an electrospray ionization (ESI) and Q-TOF mass analyzer.
1
General Procedure for the Synthesis of 4:
To a stirred solution of 3,4-dimethoxybenzaldehyde 1a (100 mg, 0.6 mmol, 1 equiv) and
trimethylsilyl cyanide (112 µL, 0.9 mmol, 1.5 equiv) in CH Cl (4 mL) at 0 °C under N
2
2
2
atmosphere was added ZnI (19 mg, 0.06 mmol, 0.1 equiv). After being stirred at rt for 30 min,
2
the reaction mixture was cooled down to 0 °C and 3,4-dimethoxyphenol (92 mg, 0.6 mmol, 1
1
7

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equiv) was added at once, which was followed by dropwise addition of BF -OEt (112 µL, 1.2
3
2
mmol, 2.0 equiv) for a period of 2-3 min. The reaction mixture was allowed to stir at 30 °C for
4 h. After completion of reaction, indicated by TLC, the reaction mixture was diluted with
CH Cl (15-20 mL), washed with aq. NaHCO (5 mL x 2) and brine solution (5 mL). The
1
2
2
3
organic layer was dried over MgSO and concentrated in vacuo to yield the crude product.
4
Purification by flash chromatography on silica gel (15-20% EtOAc/hexanes) afforded 2-
aminobenzofuran 4a.
3
-(3,4-Dimethoxyphenyl)-5,6-dimethoxybenzofuran-2-amine(4a). Off-whitesolid(154mg,
1
7
8%); mp: 110-112 °C; R = 0.3 in 40% EtOAc in hexane; H
f
OMe
MeO
NMR (400 MHz, CDCl ) δ 7.04 (d, J = 8.0 Hz, 2H), 7.00 – 6.91
3
1
3
(
m, 3H), 4.16 (s, 2H), 3.91 (s, 6H), 3.89 (s, 3H), 3.87 (s, 3H); C
MeO
MeO
NH2
NMR (100 MHz, CDCl ) δ 152.5, 149.6, 147.5, 146.5, 145.3,
3
O
4a
1
43.9, 126.0, 122.2, 119.9, 112.1, 110.9, 100.4, 95.8, 94.9, 56.6,
+
5
3
6.6, 56.1, 56.1; HRMS (ESI-QTOF) m/z [M+H] calcd for C H NO 330.1336, found
1
8
20
5
30.1334.
2
-(3,4-Dimethoxyphenyl)-2-(2-hydroxy-4,5-dimethoxyphenyl)acetonitrile (3a). Colorless
1
viscous liquid (20 mg, 10%); R = 0.2 in 40% EtOAc; H NMR (400 MHz, CDCl ) δ 6.94 (d,
f
3
J = 8.2 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.74 (s,
H), 6.41 (s, 1H), 6.11 (s, 1H), 5.46 (s, 1H), 3.84 (s, 3H), 3.81
OMe
MeO
1
1
3
(
s, 3H), 3.76 (s, 3H), 3.71 (s, 3H); C NMR (100 MHz, CDCl )
3
MeO
MeO
CN
OH
δ 149.8, 149.3, 148.7, 147.2, 143.4, 128.1, 120.3, 119.8, 113.7,
12.2, 111.4, 110.8, 101.2, 56.8, 56.0, 56.0, 56.0, 35.6; HRMS
3a
1
1
8

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+
(
ESI-QTOF) m/z [M+H] calcd for C H NO 330.1336, found 330.1336.
18 20 5
5
,6-Dimethoxy-3-(4-methoxyphenyl)benzofuran-2-amine (4b). Light brown viscous liquid
1
(
181 mg, 83%); R = 0.3 in 30% EtOAc; H NMR (400 MHz, CDCl ) δ 7.44 (d, J = 8.6 Hz,
f
3
OMe
2H), 7.02 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 3.2 Hz, 2H), 4.12 (s,
1
3
2
H), 3.89 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H); C NMR (100 MHz,
MeO
MeO
CDCl ) δ 157.9, 152.4, 146.5, 145.2, 143.9, 128.7, 128.7, 125.7,
3
NH2
O
1
22.3, 114.8, 114.8, 100.4, 95.7, 94.8, 56.7, 56.7, 55.4; HRMS
4b
+
(
ESI-QTOF) m/z [M+H] calcd for C H NO 300.1230, found
1
7
18
4
3
00.1237.
3
-(Benzo[d][1,3]dioxol-5-yl)-5,6-dimethoxybenzofuran-2-
O
O
amine (4c). Light green solid (133 mg, 64%); mp: 145-147 °C;
1
R = 0.3 in 30% EtOAc; H NMR (400 MHz, CDCl ) δ 7.01 (s,
f
3
MeO
MeO
NH2
1
H), 6.97 – 6.86 (m, 4H), 5.98 (s, 2H), 4.16 (s, 2H), 3.88 (s, 6H);
O
4c
1
3
C NMR (100 MHz, CDCl ) δ 152.5, 148.3, 146.5, 145.8, 145.2,
3
1
43.8, 127.1, 122.0, 120.7, 109.1, 108.1, 101.1, 100.3, 95.7, 94.8, 56.6, 56.6; HRMS (ESI-
+
QTOF) m/z [M+H] calcd for C H NO 314.1023, found 314.1024.
1
7
16
5
2
-(Benzo[d][1,3]dioxol-5-yl)-2-(2-hydroxy-4,5-dimethoxyphenyl)acetonitrile (3c). Light
1
blue solid (33 mg, 16%); mp: 84-86 °C; R = 0.25 in 30% EtOAc in hexane; H NMR (400
f
MHz, CDCl ) δ 6.89 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 6.3 Hz,
3
O
O
1
9
MeO
MeO
CN
OH
3c

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2
H), 6.77 (d, J = 8.0 Hz, 1H), 6.40 (s, 1H), 5.95 (s, 2H), 5.41 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H);
1
3
C NMR (100 MHz, CDCl ) δ152.5, 148.3, 146.5, 145.8, 145.2, 143.8, 127.1, 122.0, 120.7,
3
+
1
09.1, 108.1, 101.1, 100.3, 95.7, 94.8, 56.6, 56.6; HRMS (ESI-QTOF) m/z [M+H] calcd for
C H NO 314.1023, found 314.1022.
1
7
16
5
5
,6-Dimethoxy-3-(3,4,5-trimethoxyphenyl)benzofuran-2-amine (4d). Off-white solid (132
1
mg, 72%); mp: 91-93 °C; R = 0.3 in 30% EtOAc in hexane; H NMR (400 MHz, CDCl ) δ
f
3
OMe
OMe
6.99 (s, 1H), 6.95 (s, 1H), 6.73 (s, 2H), 4.20 (s, 2H), 3.90 (s, 12H),
MeO
1
3
3
.88 (s, 3H); C NMR (100 MHz, CDCl ) δ 154.0, 154.0, 152.7,
3
MeO
MeO
1
46.6, 145.4, 144.0, 136.5, 129.1, 122.0, 104.8, 104.8, 100.5,
NH2
O
95.9, 95.1, 61.1, 56.7, 56.7, 56.4, 56.4; HRMS (ESI-QTOF) m/z
4d
+
[
M+H] calcd for C H NO 360.1442, found 360.1445.
1
9
22
6
5
,6-Dimethoxy-3-(2,4,5-trimethoxyphenyl)benzofuran-2-
OMe
MeO
amine (4e). Light brown liquid (146 mg, 80%); R = 0.3 in 30%
f
1
EtOAc in hexane; H NMR (400 MHz, CDCl ) δ 7.07 (s, 1H),
OMe
NH2
3
MeO
MeO
6
.92 (d, J = 6.1 Hz, 2H), 6.67 (s, 1H), 4.39 (s, 2H), 3.92 (s, 3H),
O
4e
13
3
.87 (s, 3H), 3.85 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H); C NMR
(
100 MHz, CDCl ) δ 153.2, 150.2, 148.3, 146.2, 144.9, 144.3, 143.9, 122.9, 113.7, 112.9, 100.5,
3
+
9
9.6, 95.8, 90.8, 57.4, 56.6, 56.5, 56.5, 56.2; HRMS (ESI-QTOF) m/z [M+H] calcd for
C H NO 360.1442, found 360.1446.
1
9
22
6
2
0

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2
-(2-Hydroxy-4,5-dimethoxyphenyl)-2-(2,4,5-trimethoxyphenyl)acetonitrile
(3e).
1
Colorless viscous liquid (16 mg, 9%); R = 0.2 in 30% EtOAc; H NMR (400 MHz, CDCl ) δ
f
3
OMe
6.92 (s, 2H), 6.53 (s, 1H), 6.43 (s, 1H), 6.14 (s, 1H), 5.58 (s, 1H),
.90 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H);
MeO
3
OMe
CN
OH
1
3
C NMR (100 MHz, CDCl ) δ 150.0, 149.9, 149.7, 147.2, 143.9,
MeO
MeO
3
1
5
43.5, 120.1, 115.1, 113.1, 112.3, 111.8, 101.8, 97.7, 56.9, 56.8,
3e
+
6.8, 56.3, 56.0, 30.7; HRMS (ESI-QTOF) m/z [M+H] calcd
for C H NO 360.1442, found 360.1447.
1
9
22
6
5
,6-Dimethoxy-3-(2,4,6-trimethoxyphenyl)benzofuran-2-amine (4f). Light brown liquid
1
(
113 mg, 62%); R = 0.3 in 30% EtOAc; H NMR (400 MHz,
f
OMe
CDCl ) δ 6.93 (s, 1H), 6.58 (s, 1H), 6.28 (s, 2H), 4.01 (s, 2H),
3
MeO
1
3
3
.88 (s, 6H), 3.82 (s, 3H), 3.81 (s, 6H); C NMR (100 MHz,
OMe
NH2
MeO
MeO
CDCl ) δ 160.8, 158.8, 158.8, 153.5, 145.9, 144.8, 144.2, 123.5,
3
O
4f
1
02.5, 102.2, 95.5, 91.4, 91.4, 88.3, 56.7, 56.6, 56.0, 56.0, 55.6;
+
HRMS (ESI-QTOF) m/z [M+H] calcd for C H NO 360.1442, found 360.1440.
1
9
22
6
3
-(2-Bromo-4,6-dimethoxyphenyl)-5,6-dimethoxybenzofuran-2-amine (4g). Light purple
solid (123 mg, 74%); mp: 116-118 °C; R = 0.3 in 30% EtOAc
f
OMe
1
in hexane; H NMR (400 MHz, CDCl ) δ 6.95 (s, 1H), 6.88 (s,
3
MeO
1
H), 6.55 (s, 1H), 6.53 (s, 1H), 3.91 (s, 2H), 3.89 (s, 3H), 3.86
Br
MeO
MeO
NH2
1
3
(s, 3H), 3.83 (s, 3H), 3.76 (s, 3H); C NMR (100 MHz, CDCl )
3
O
4g
δ 160.6, 159.7, 153.3, 146.2, 145.0, 143.9, 126.6, 122.9, 114.5,
2
1

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+
1
09.5, 101.7, 98.6, 95.7, 91.8, 56.7, 56.6, 56.2, 55.8; HRMS (ESI-QTOF) m/z [M+H] calcd
for C H BrNO 408.0441, found 408.0447.
1
8
19
5
2
-(2-Bromo-4,6-dimethoxyphenyl)-2-(2-hydroxy-4,5-dimethoxyphenyl)acetonitrile (3g).
Colorless viscous liquid (12 mg, 7%); R = 0.3 in 30% EtOAc in
f
OMe
1
hexane; H NMR (400 MHz, CDCl ) δ 6.98 (s, 1H), 6.78 (d, J =
3
MeO
Br
CN
OH
2
5
.3 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 6.39 (s, 1H), 5.89 (s, 1H),
.59 (s, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.80 (s, 3H);
MeO
MeO
3
g
13
C NMR (100 MHz, CDCl ) δ 161.0, 158.6, 149.8, 147.6, 142.9,
3
1
25.4, 118.7, 115.6, 113.6, 111.2, 110.6, 101.5, 99.4, 56.8, 56.5, 56.1, 55.8, 32.8; HRMS (ESI-
+
QTOF) m/z [M+H] calcd for C H BrNO 408.0441, found 408.0441.
1
8
19
5
3
-(6-Bromobenzo[d][1,3]dioxol-5-yl)-5,6-
O
O
dimethoxybenzofuran-2-amine (4h). Light brown viscous
1
liquid (76 mg, 44%); R = 0.3 in 30% EtOAc in hexane; H NMR
f
Br
MeO
MeO
NH2
(400 MHz, CDCl ) δ 7.14 (s, 1H), 6.93 (s, 1H), 6.89 (s, 1H), 6.65
3
O
4h
(s, 1H), 6.02 (d, J = 7.3 Hz, 2H), 4.01 (s, 2H), 3.88 (s, 3H), 3.84
1
3
(
s, 3H); C NMR (100 MHz, CDCl ) δ 152.62, 148.0, 147.8, 146.5, 145.3, 143.7, 126.4, 122.7,
3
1
15.0, 113.4, 111.4, 102.1, 100.7, 95.7, 95.4, 56.7, 56.6; HRMS (ESI-QTOF) m/z [M+H]+
calcd for C H BrNO 392.0128, found 392.0129.
1
7
15
5
2
-(4-(Dimethylamino)phenyl)-2-(2-hydroxy-4,5-
N
2
2
MeO
MeO
CN
OH
3i

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dimethoxyphenyl)acetonitrile (3i). Off-white solid (171 mg, 82%); mp:157-159 °C R = 0.3
f
1
in 50% EtOAc in hexane; H NMR (400 MHz, CDCl ) δ 7.22 (d, J = 8.3 Hz, 2H), 6.83 (s, 1H),
3
6
.69 (d, J = 8.4 Hz, 2H), 6.38 (s, 1H), 5.37 (s, 1H), 4.96 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 2.94
1
3
(
s, 6H); C NMR (100 MHz, CDCl ) δ 150.3, 149.7, 146.7, 143.7, 128.4, 128.4, 122.7, 120.5,
3
1
14.4, 112.9, 112.9, 112.3, 101.5, 56.8, 56.2, 40.6, 40.6, 35.7; HRMS (ESI-QTOF) m/z
+
[
M+H] calcd for C H N O 313.1547, found 313.1548.
1
8
21
2
3
5
-(2-Amino-5,6-dimethoxybenzofuran-3-yl)-2-methoxyphenol (4j). Off-white solid (127
mg, 61%); mp: 158-160 °C; R = 0.2 in 40% EtOAc in hexane;
f
OMe
HO
1
H NMR (400 MHz, CDCl ) δ 7.11 (s, 1H), 7.04 – 6.90 (m, 4H),
3
5
.77 (s, 1H), 4.16 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H);
MeO
MeO
NH2
13
C NMR (100 MHz, CDCl ) δ 152.5, 146.5, 146.3, 145.2, 144.9,
3
O
4j
1
43.9, 126.8, 122.1, 119.3, 113.8, 111.6, 100.5, 95.7, 94.7, 56.7,
+
5
6.7, 56.2; HRMS (ESI-QTOF) m/z [M+H] calcd for C H NO 316.1179, found 316.1179.
1
7
18
5
4
-(2-Amino-5,6-dimethoxybenzofuran-3-yl)-2-methoxyphenol (4k). Off-white viscous
1
liquid (112 mg, 54%); R = 0.2 in 40% EtOAc in hexane; H
f
OMe
HO
NMR (400 MHz, CDCl ) δ 7.05 – 6.98 (m, 3H), 6.95 (d, J = 3.1
3
Hz, 2H), 5.65 (s, 1H), 4.11 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H),
MeO
NH2
13
3
.88 (s, 3H); C NMR (100 MHz, CDCl ) δ 152.4, 147.2, 146.5,
3
O
MeO
4k
1
45.4, 144.2, 144.0, 125.3, 122.3, 120.8, 115.3, 110.4, 100.5,
+
9
5.8, 95.3, 56.7, 56.7, 56.1; HRMS (ESI-QTOF) m/z [M+H] calcd for C H NO 316.1179,
1
7
18
5
found 316.1174.
2
3

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5
,6-Dimethoxy-3-(thiophen-2-yl)benzofuran-2-amine (4l). Colorless viscous liquid (115 mg,
1
4
7%); R = 0.2 in 40% EtOAc in hexane; H NMR (400 MHz,
f
S
CDCl ) δ 7.27 (dd, J = 5.0, 4.0 Hz, 1H), 7.18 – 7.09 (m, 3H), 6.93
3
MeO
MeO
1
3
NH2
(s, 1H), 4.38 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H); C NMR (100
O
4l
MHz, CDCl ) δ 153.2, 146.7, 145.5, 143.8, 135.4, 127.8, 122.6,
3
+
1
22.5, 121.5, 100.9, 95.7, 89.8, 56.7, 56.7; HRMS (ESI-QTOF) m/z [M+H] calcd for
C H NO S 276.0689, found 276.0691.
1
4
14
3
3
-(3,4-Dimethoxyphenyl)-5-methoxybenzofuran-2-amine (4m).
OMe
NH2
MeO
Off-white solid (140 mg, 78%); mp: 180-182 °C; R = 0.3 in 40%
f
1
EtOAc in hexane; H NMR (400 MHz, CDCl ) δ 7.19 (d, J = 8.7
MeO
3
O
Hz, 1H), 7.09 – 7.01 (m, 2H), 7.01 – 6.94 (m, 2H), 6.66 (dd, J =
4m
8
.7, 2.5 Hz, 1H), 4.28 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.81 (s,
1
3
3
1
H); C NMR (100 MHz, CDCl ) δ 156.4, 154.2, 149.6, 147.5, 144.7, 131.0, 125.9, 119.9,
3
12.1, 111.0, 110.2, 107.8, 101.5, 94.5, 56.1, 56.1, 56.1; HRMS (ESI-QTOF) m/z [M+H]+
calcd for C H NO 300.1230, found 300.1237.
1
7
18
4
5
-(Benzyloxy)-3-(3,4-dimethoxyphenyl)benzofuran-2-amine (4n). Brown solid (157 mg,
1
7
0%); mp: 114-116 °C; R = 0.2 in 30% EtOAc in hexane; H
f
OMe
MeO
NMR (400 MHz, CDCl ) δ 7.44 (d, J = 7.3 Hz, 2H), 7.38 (t, J =
3
7
.4 Hz, 2H), 7.31 (dd, J = 8.3, 6.0 Hz, 1H), 7.19 (d, J = 8.7 Hz,
BnO
NH2
O
2
4
4n

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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01715A
1
4
1
1
3
H), 7.07 – 7.00 (m, 3H), 6.97 (d, J = 8.7 Hz, 1H), 6.74 (dd, J = 8.7, 2.5 Hz, 1H), 5.07 (s, 2H),
1
3
.28 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H); C NMR (100 MHz, CDCl ) δ 155.6, 154.2, 149.6,
3
47.5, 144.9, 137.6, 131.0, 128.6, 128.6, 127.9, 127.6, 127.5, 125.9, 119.9, 112.1, 110.9, 110.2,
+
08.8, 102.8, 94.5, 70.9, 56.1, 56.12; HRMS (ESI-QTOF) m/z [M+H] calcd for C H NO
2
3
22
4
76.1543, found 376.1538.
7
-(3,4-Dimethoxyphenyl)-[1,3]dioxolo[4,5-f]benzofuran-6-amine (4o). Pale yellow solid,
(
141 mg, 75%); mp: 186-188 °C; R = 0.3 in 30% EtOAc in hexane;
f
OMe
MeO
1
H NMR (400 MHz, CDCl ) δ 7.01 (d, J = 8.4 Hz, 2H), 6.95 (d, J
3
=
7.9 Hz, 1H), 6.90 (s, 1H), 6.87 (s, 1H), 5.92 (s, 2H), 4.13 (s, 2H),
O
O
NH2
13
3
.91 (s, 6H); C NMR (100 MHz, CDCl ) δ 152.7, 149.6, 147.5,
3
O
4o
1
44.3, 144.3, 143.2, 125.8, 123.4, 119.9, 112.0, 110.9, 100.9, 97.3,
+
9
3
5.5, 93.4, 56.1, 56.1; HRMS (ESI-QTOF) m/z [M+H] calcd for C H NO 314.1023, found
1
7
16
5
14.1025.
3
-(3,4-Dimethoxyphenyl)-5-isopropylbenzofuran-2-amine (4p). Light yellow solid (131 mg,
1
7
0%); mp: 135-137 °C; R = 0.3 in 30% EtOAc in hexane; H
f
OMe
MeO
NMR (400 MHz, CDCl ) δ 7.33 (d, J = 1.1 Hz, 1H), 7.23 (d, J =
3
8
2
6
.3 Hz, 1H), 7.13 – 7.06 (m, 2H), 7.00 – 6.96 (m, 2H), 4.28 (s,
NH2
H), 3.94 (s, 3H), 3.93 (s, 3H), 3.05 – 2.92 (m, 1H), 1.29 (d, J =
O
4p
1
3
.9 Hz, 6H); C NMR (100 MHz, CDCl ) δ 153.6, 149.5, 148.4,
3
1
2
47.4, 143.9, 130.2, 126.1, 120.0, 119.4, 114.6, 112.1, 111.1, 109.6, 94.2, 56.1, 56.1, 34.4, 24.7,
+
4.7; HRMS (ESI-QTOF) m/z [M+H] calcd for C H NO 312.1594, found 312.1591.
1
9
22
3
2
5

Organic & Biomolecular Chemistry
Page 26 of 52
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DOI: 10.1039/D0OB01715A
3
-(3,4-Dimethoxyphenyl)-5-phenylbenzofuran-2-amine (4q). Brown solid (147 mg, 71%);
1
mp: 111-113 °C; R = 0.25 in 30% EtOAc in hexane; H NMR (400
f
OMe
MeO
MHz, CDCl ) δ 7.67 (s, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.44 (t, J =
3
7
.4 Hz, 2H), 7.39 – 7.29 (m, 3H), 7.11 (d, J = 8.2 Hz, 2H), 7.00 (d,
Ph
NH2
13
J = 7.9 Hz, 1H), 4.34 (s, 2H), 3.94 (s, 3H), 3.93 (s, 3H); C NMR
O
4q
(
100 MHz, CDCl ) δ 153.9, 149.6, 149.6, 147.6, 142.2, 136.8, 130.8,
3
1
5
28.8, 128.8, 127.5, 127.5, 126.8, 125.8, 120.5, 120.2, 115.8, 112.1, 111.1, 110.0, 94.3, 56.1,
+
6.1; HRMS (ESI-QTOF) m/z [M+H] calcd for C H NO 346.1438, found 346.1435.
2
2
20
3
5
-Chloro-3-(3,4-dimethoxyphenyl)benzofuran-2-amine (4r).
OMe
NH2
MeO
Light yellow solid (114 mg, 63%); mp: 138-141 °C; R = 0.25 in
f
1
3
0% EtOAc in hexane; H NMR (400 MHz, CDCl ) δ 7.38 (d,
3
Cl
J = 2.1 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.06 – 6.95 (m, 4H),
O
4r
1
3
4
.35 (s, 2H), 3.93 (s, 6H); C NMR (100 MHz, CDCl ) δ 154.5,
3
1
5
49.7, 148.3, 147.8, 131.8, 128.8, 125.1, 120.7, 120.1, 116.8, 112.1, 110.9, 110.8, 93.9, 56.2,
+
6.1; HRMS (ESI-QTOF) m/z [M+H] calcd for C H ClNO 304.0735, found 304.0735.
1
6
15
3
5
-Chloro-3-(3,4-dimethoxyphenyl)-7-methylbenzofuran-2-amine (4s). Yellow solid (116
1
mg, 61%); mp: 148-150 °C; R = 0.3 in 25% EtOAc in hexane; H
f
OMe
MeO
NMR (400 MHz, CDCl ) δ 7.23 (d, J = 1.7 Hz, 1H), 7.02 (d, J =
3
6
.3 Hz, 2H), 6.97 (d, J = 8.7 Hz, 1H), 6.87 (s, 1H), 4.34 (s, 2H),
Cl
NH2
O
2
6
Me
4s

Page 27 of 52
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DOI: 10.1039/D0OB01715A
1
3
3
1
.92 (s, 6H), 2.42 (s, 3H); C NMR (100 MHz, CDCl ) δ 154.2, 149.7, 147.7, 147.1, 131.1,
3
28.5, 125.4, 122.0, 121.3, 120.1, 114.4, 112.1, 110.9, 94.2, 56.2, 56.1, 14.8; HRMS (ESI-
+
QTOF) m/z [M+H] calcd for C H ClNO 318.0891, found 318.0895.
1
7
17
3
5
-(4-Bromophenyl)-3-(3,4-dimethoxyphenyl)benzofuran-2-amine (4t). Brown solid (152
1
mg, 60%); mp: 144-146 °C; R = 0.3 in 30% EtOAc in hexane; H NMR (400 MHz, CDCl ) δ
f
3
7
.58 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.43 (d, J
OMe
MeO
=
8.4 Hz, 2H), 7.33 (d, J = 8.3 Hz, 1H), 7.26 – 7.19 (m, 1H),
Br
7
.07 (d, J = 6.2 Hz, 2H), 6.98 (d, J = 8.7 Hz, 1H), 4.33 (s,
1
3
NH2
2H), 3.92 (s, 3H), 3.90 (s, 3H); C NMR (100 MHz, CDCl )
3
O
4t
δ 154.1, 149.7, 149.6, 147.6, 141.1, 135.5, 131.8, 131.8,
1
30.9, 129.0, 129.0, 125.6, 120.9, 120.2, 120.2, 115.5, 112.1, 111.1, 110.1, 94.2, 56.1, 56.1;
+
HRMS (ESI-QTOF) m/z [M+H] calcd for C H BrNO 424.0543, found 424.0540.
2
2
19
3
1
-(3,4-Dimethoxyphenyl)naphtho[2,1-b]furan-2-amine (4u). Off-white solid (134 mg,
1
7
0%); mp: 84-86 °C; R = 0.3 in 30% EtOAc in hexane; H NMR (400 MHz, CDCl ) δ 7.87
f
3
(
d, J = 8.5 Hz, 2H), 7.53 (s, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.30 –
OMe
NH2
MeO
7
.23 (m, 1H), 7.12 – 7.04 (m, 2H), 7.00 (d, J = 7.9 Hz, 1H), 4.11
1
3
(s, 2H), 3.97 (s, 3H), 3.86 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
1
1
53.7, 153.7, 149.3, 148.4, 146.3, 131.1, 128.8, 127.1, 126.1,
O
4u
24.9, 124.0, 123.6, 122.7, 121.5, 113.8, 111.7, 111.4, 97.2, 56.1,
+
5
6.1; HRMS (ESI-QTOF) m/z [M+H] calcd for C H NO 320.1281, found 320.1283.
2
0
18
3
2
7

Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01715A
1
-(3,4,5-Trimethoxyphenyl)naphtho[2,1-b]furan-2-amine (4v). Light green solid (112 mg,
1
6
3%); mp: 116-118 °C; R = 0.3 in 30% EtOAc in hexane; H NMR (400 MHz, CDCl ) δ 7.95
f
3
OMe
OMe
(d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.55 (s, 2H), 7.48
MeO
–
7.27 (m, 2H), 6.78 (s, 2H), 4.18 (s, 2H), 3.98 (s, 3H), 3.87
1
3
(
s, 6H); C NMR (100 MHz, CDCl ) δ 153.8, 153.8, 153.8,
3
NH2
O
1
53.7, 146.4, 137.2, 131.2, 129.3, 128.9, 126.9, 125.1, 124.1,
4v
1
23.7, 121.6, 111.4, 107.5, 107.5, 97.3, 61.1, 56.3, 56.3; HRMS (ESI-QTOF) m/z [M+H]+
calcd for C H NO 350.1387, found 350.1387.
2
1
20
4
5
-(2-Aminonaphtho[2,1-b]furan-1-yl)-2-methoxyphenol(4w).
OMe
NH2
HO
Light purple viscous liquid (99 mg, 50%); R = 0.3 in 40% EtOAc
f
1
in hexane; H NMR (400 MHz, CDCl ) δ 7.91 (d, J = 8.3 Hz,
3
1
H), 7.87 (d, J = 8.2 Hz, 1H), 7.53 (s, 2H), 7.36 (t, J = 7.5 Hz,
H), 7.28 (d, J = 7.9 Hz, 1H), 7.13 (s, 1H), 7.07 – 6.98 (m, 2H),
O
4w
1
1
3
5
1
9
.74 (s, 1H), 4.09 (s, 2H), 3.99 (s, 3H); C NMR (100 MHz, CDCl ) δ 153.7, 146.3, 146.1,
3
46.0, 131.1, 128.8, 127.2, 126.8, 125.0, 123.9, 123.7, 122.5, 121.4, 116.7, 116.7, 111.4, 111.3,
+
7.2, 56.2; HRMS (ESI-QTOF) m/z [M+H] calcd for C H NO 306.1125, found 306.1124.
1
9
16
3
4
-(2-Aminonaphtho[2,1-b]furan-1-yl)-2-methoxyphenol (4x). Light purple viscous liquid
1
(
94 mg, 47%); R = 0.3 in 40% EtOAc in hexane; H NMR (400 MHz, CDCl ) δ 7.88 (d, J =
f
3
8
.3 Hz, 2H), 7.54 (s, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.9
OH
MeO
2
8
NH2
O
x
4

Page 29 of 52
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DOI: 10.1039/D0OB01715A
1
3
Hz, 1H), 7.10 – 7.00 (m, 3H), 5.75 (s, 1H), 4.10 (s, 2H), 3.89 (s, 3H); C NMR (100 MHz,
CDCl ) δ 153.7, 147.0, 146.3, 145.1, 131.1, 131.1, 128.9, 127.1, 125.4, 125.0, 124.0, 123.6,
3
+
1
23.6, 121.5, 115.1, 113.2, 111.4, 97.4, 56.2; HRMS (ESI-QTOF) m/z [M+H] calcd for
C H NO 306.1125, found 306.1124.
1
9
16
3
3
-(3,4-Dimethoxyphenyl)-6-methoxybenzofuran-2-amine (4y). Brown solid (38 mg, 21%);
1
mp: 103-105 °C; R = 0.3 in 30% EtOAc in hexane; H NMR (400 MHz, CDCl ) δ 7.35 (d, J
f
3
=
8.4 Hz, 1H), 7.10 – 7.02 (m, 2H), 6.96 (d, J = 8.1 Hz, 1H), 6.92
OMe
MeO
(d, J = 1.5 Hz, 1H), 6.82 (dd, J = 8.4, 1.4 Hz, 1H), 4.18 (s, 2H),
1
3
3
.92 (s, 6H), 3.83 (s, 3H); C NMR (100 MHz, CDCl ) δ 155.8,
3
NH2
O
MeO
152.4, 150.7, 149.6, 147.4, 126.1, 123.5, 119.8, 117.3, 112.0, 110.9,
10.4, 96.5, 94.3, 56.1, 56.1, 56.0; HRMS (ESI-QTOF) m/z
M+H] calcd for C H NO 300.1230, found 300.1229.
4y
1
+
[
1
7
18
4
2
-(3,4-Dimethoxyphenyl)-2-(4-hydroxy-2-methoxyphenyl)acetonitrile (4y’). Colorless
1
viscous liquid (107 mg, 60%); R = 0.3 in 30% EtOAc in hexane; H NMR (400 MHz, CDCl )
f
3
OMe
δ 7.04 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 9.3
MeO
Hz, 2H), 6.45 – 6.36 (m, 2H), 6.26 (s, 1H), 5.39 (s, 1H), 3.85 (s,
1
3
3
1
1
H), 3.83 (s, 3H), 3.76 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
CN
OMe
57.6, 157.3, 149.1, 148.6, 129.5, 128.2, 120.5, 120.1, 116.4, 111.4,
HO
4y'
10.9, 107.6, 99.4, 56.0, 56.0, 55.7, 35.5; HRMS (ESI-QTOF) m/z
+
[
M+Na] calcd for C H NO Na 322.1050, found 322.1053.
1
7
17
4
2
9