New synthetic method for benzofurans from 2-(cyanomethyl)phenyl derivatives

Article abstract of DOI:10.1016/j.tet.2012.03.088

A convenient and mild synthetic method of synthesizing benzofuran from various 2-(cyanomethyl)phenyl carbonyl compounds under reduced oxygen conditions is reported. Nine C-2 substituted benzofurans were synthesized at 52-89%.

Full text of DOI:10.1016/j.tet.2012.03.088

Tetrahedron 68 (2012) 3942e3947
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New synthetic method for benzofurans from 2-(cyanomethyl)phenyl derivatives
Hee Jun Kim a, Jai Woong Seo a, Min Hyung Lee b, Dong Seok Shin b, Hyeong Baik Kim b, Hyeongjin Cho a,
,
Byoung Se Lee c, Dae Yoon Chi b
*
a Department of Chemistry, Inha University, 253 Yonghyundong Namgu, Inchon 402-751, Republic of Korea
b Department of Chemistry, Sogang University, 35 Baekbeomro Mapogu, Seoul 121-742, Republic of Korea
c Research Institute of Labeling, FutureChem Co. Ltd, 388-1 Pungnap-2-dong Songpagu, Seoul 138-736, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and mild synthetic method of synthesizing benzofuran from various 2-(cyanomethyl)
phenyl carbonyl compounds under reduced oxygen conditions is reported. Nine C-2 substituted ben-
zofurans were synthesized at 52e89%.
Received 10 December 2011
Received in revised form 19 March 2012
Accepted 21 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 30 March 2012
Keywords:
Benzofuran
C2-substituted benzofuran
C3-carboxylated benzofuran
Benzyl cyanide
Intramolecular cyclization
1. Introduction
produce benzofurans, is required to benzylidene phosphonium
salts. During a pyrolysis study of O-(2-cyanomethylphenyl)-N,N-
Active natural and synthetic benzofurans have been attracted
because of their pharmaceutical utilities.1,2 Accordingly, several
synthetic strategies, such as acid-catalyzed cyclization of carbonyl
containing compounds by dehydration (A type),2 palladium3 or
platinum4-catalyzed cyclization (B type),1c ring closure via an
intramolecular Wittig reaction5 or o-(acyloxy)benzyl anions6
(C type), Dieckmann condensation of activated methylene1d,7 or
ketene intermediate involved cyclization8 (D type), acid-catalyzed
dimethyl thiocarbamate (1), a couple of benzofuran derivatives
were isolated. Here, we describe a novel method of synthesizing
benzofuran and provide a plausible mechanism.
ring formation of
a
-aryloxycarbonyls9 or intramolecular
-phe-
FriedeleCrafts reaction10 (E type), photolytic cyclization of
a
nylketones11 (F type), and gold(III)-catalyzed tandem reaction of O-
arylhydroxylamines with 1,3-dicarbonyl compounds12 (G type)
have been developed to produce benzofurans (Fig. 1). In addition,
Youn reported one-pot procedures for the conversion of allyl aryl
ethers to 2-methylbenzofurans (via sequential Claisen rearrange-
ment and oxidative cyclization).13 Ohe also reported the synthesis
of 3-acyl-2-aminobenzofurans from 2-(cycanomethyl)phenyl esters
using catalytic amount of Pd(OAc)2, PCy3, and Zn.14
Most strategies devised to synthesize benzofurans resemble the
well known indole reactions, such as, those utilized during Leim-
grubereBatcho, Reissert, Madelung, Bischler, and Fisher indole
synthesis.15 Of these, Wittig-type ring formation,5a which is used to
* Corresponding author. E-mail address: dychi@sogang.ac.kr (D.Y. Chi).
Fig. 1. Synthetic strategies used to synthesize benzofuran.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.088

H.J. Kim et al. / Tetrahedron 68 (2012) 3942e3947
3943
2. Results and discussion
As shown in Scheme 1, a cyano functionality at the benzyl carbon
was selected because not only this allowed the straightforward
preparation of the starting material, but also the doubly activated
hydrogen at benzylic position by cyano and phenyl groups would
easily be deprotonated. Thiocarbamate 1, synthesized from 2-
hydroxybenzyl cyanide and dimethylamino thiocarbamoyl chloride,
was treated with t-BuOKunder THFrefluxfor 3 h. Subsequently, 2-(2-
hydroxyphenyl)-N,N-dimethyl-2-oxoethanethioamide (2) and 2-
dimethylamino-3-thoicarbamoylbenzofuran (3) were isolated as
major products.
Scheme 2.
Two-dimensional TLC17 and NMR of crude mixtures showed
that the phenolic intermediate 4a was present in the reaction
mixture. When we developed the mixture of 4a and 6 on silica gel
TLC plate, compound 4a appeared as the more polar spot. When
this TLC gel plate was developed again after 90ꢀ rotation, the low
spot of 4a was split into two spots, which are corresponding to 6
and 4a. Such evidence means that compound 4a can be trans-
formed to the desired benzofuran 6 on silica gel.
Scheme 1.
In particular, we noticed that acidic work up processing and
silica gel chromatography improved the conversion of intermediate
4a to 2-dimethylaminobenzofuran 6. From a mechanistic point of
view, we believe that intermediates II was converted to benzofuran
6 via by deprotonation in the presence of base. Furthermore, we
believe that intermediate II could form several intermediates,
which were observed in reaction mixtures to varying extents, and
that these intermediates loose the benzylic proton to form the re-
spective benzofurans (Fig. 3). Thus compound 4a is probably a re-
action intermediate, which can become the product under acidic
conditions like on silica gel.
2-Oxothioacetamide 2 could be generated by the oxidative
decyanation of benzyl cyanide in a manner similar to that reported
by Kulp and Rabjohn et al.16 after rearrangement of thiocarbamoyl
group as shown in Fig. 2. To proceed with the research, we changed
the starting material to carbamate 4 from thiocarbamate 1 due to
high viscosity of the latter.
Fig. 2. Oxidative decyanation mechanism after rearrangement of thiocarbamoyl
group.
To produce 5 and 6, carbamate 4 was treated with t-BuOK under
two different conditions: (i) with air bubbled through the reaction
mixture, and (ii) under oxygen-free conditions (achieved using
a Schlenk flask connected to vacuum and an Ar gas blanket to ex-
clude oxygen-involving side reactions (Scheme 2)). As was expec-
ted, while the former condition produced 2-(2-hydroxyphenyl)-
N,N-dimethyl-2-oxoacetamide (5) at a yield of 75% within 1 h at
room temperature, under oxygen depleted free conditions 2-
dimethylamino-3-amidobenzofuran (6) was produced at a yield
of 75%. This marked difference was presumed to have been caused
by the presence of singlet oxygen. Thus, we considered that the
formation of benzofuran 6 might proceed via a mechanism unlike
that of oxidative decyanation.
Fig. 3. Plausible mechanism from compound 4.
To optimize conditions, the reaction was performed under var-
ious temperature using various solvents and bases (Table 1). First,
the reaction mixture was treated with from 1 to 3 equiv of t-BuOK
at room temperature for 1 h. 1 equiv of base gave only 11% of the 3-
carboxyamidobenzofuran 6, but 2 or 3 equiv increased the yield to
60 and 75%, respectively. However, when the reaction was per-
formed using 3 equiv of base at ꢁ78 ꢀC, the desired product was
obtained at a yield of only 10% after 1 h. Further optimization was

3944
H.J. Kim et al. / Tetrahedron 68 (2012) 3942e3947
Table 1
Table 2
Optimization of the reactiona
Synthesis of various C2-substituted benzofuransa
Reactant
X
S
R
Product
Yieldb (%)
89
Entry
X
Base
Equiv
Solvent
Temp (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
9
O
O
O
O
O
O
O
O
S
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaH
1
2
3
3
3
3
3
3
3
THF
THF
THF
THF
DMF
Dioxane
THF
MeOH
THF
rt
rt
rt
11
60
75
10
66
65
50
d
1
3
ꢁ78
7
O
7p
69
rt
rt
rt
rt
rt
NaOMe
t-BuOK
8
9
O
O
8p
9p
81
66
75
a
All reactions were carried out at the 1.0 mmol scale in 15 mL of solvent under
argon.
b
Isolated yields.
performed using several solvents and bases (Table 1, entries 5 and
6). Reactions containing 3 equiv of t-BuOK in DMF or dioxane were
complete within 1 h at room temperature, yielding 66% and 65% of
product 6, respectively. The optimal reaction condition required for
the synthesis of benzofuran was practically unaffected by solvent
changes. Treatment with sodium hydride in THF produced benzo-
furan 6 at a yield of 50%, but reaction with sodium methoxide in
MeOH failed to produce 6. The use of thiocarbamate 1 as a substrate
also successfully provided the thioamide 3 as the major product at
a yield of 75% (Table 1, entry 9).
10
11
O
O
10p
11p
67
79
12
13
O
O
12p
13p
52
54
A comparison of our method of producing benzofurans with the
well known acid-catalyzed cyclization (A type in Fig. 1) and with
intramolecular Wittig ring closure (C type in Fig. 1), suggests that
our synthetic method is more convenient for producing diverse
benzofurans when the two main molecular building blocks, that is,
2-hydroxybenzyl cyanide and acid chloride or anhydride, are used
as starting materials.
14
O
14p
70
a
All reactions were carried out in 0.5 mmol scale at the condition of entry 3 of
Table 1 (see Supplementary data for detail procedure).
b
Isolated yields.
Synthesis of benzofuran from carbamate 7 (Fig. 3) using our
optimized condition (the same condition at entry 3, Table 1) pro-
duced only a mixture of benzofuran 7p and intermediate 7a
(structurally similar to intermediate 4a), which could not be isolated
in pure form. However, our aim was to produce benzofurans using
a straightforward method. As we mentioned two-dimensional TLC
results, compound 7a was transformed to the desired benzofuran 7p
on silica gel TLC plate. The extracted organic layer of reaction mix-
ture (0.5 mmol reaction scale) was washed with brine (5 mLꢂ3) and
dried over sodium sulfate. Silica gel (2.0 g) was poured into solution
and solvent was evaporated under reduced pressure. Silica gel was
dried in a high vacuum for 30 min and the residue was irradiated
under microwave (30 sꢂ3, 620 W). After the silica gel was sus-
pended in EtOAc, silica gel was filtered the solvent was removed
under reduced pressure to obtain 7p (80 mg, 69%) as yellow solid.
Using this microwave technique, several carbonyl starting com-
pounds (thiocarbamate (1), carbamates (7e11), carbonates (12 and
13), and the ester (14)) were used to produce benzofurans (Table 2).
Nine starting molecules were readily prepared by simply acylating 2-
hydroxybenzyl cyanide with corresponding carbonyl chlorides at
yields of 70e99%. Carbamates (7e11) produced the 2-
aminobenzofurans (7pe11p) in yields ranging from 66 to 81%. In
the case of carbonates, methyl 12 and allyl carbonate 13 afforded 2-
methoxybenzofuran 12p at 52% and 2-allyloxy benzofuran 13p at
54%, respectively. In addition, the benzoate 14 with a para-methoxy
group produced 2-(4-methoxy)phenyl benzofuran 14p at a yield
of 70%.
In conclusion, we described a convenient means of synthesizing
C2-substituted benzofurans. In situ two-step reactions using t-
BuOK in the absence of oxygen and microwave/silica gel treatment
provided several C2-derivatize benzofurans in yields of 52e89%.
Furthermore, straightforward purification of final product by fil-
tration from silica gel eliminated the need for column chromatog-
raphy. This described method is quite convenient as shown at Fig. 1,
because various starting compounds could be easily prepared from
commercially available carbonyl chlorides, such as, carbamoyl
chloride, thiocarbamoyl chloride, chloroformate, and acid chloride,
and because further derivatization of benzofurans at the C3 posi-
tion can be used to search biologically active benzofurans.
3. Experimental section
3.1. 2-Hydroxybenzyl cyanide
2-Hydroxybenzylalcohol (5.0 g, 40.3 mmol) and potassium cy-
anide (3.0 g, 61.2 mmol) were dissolved in DMF (80 mL) and the
solution was heated to 130 ꢀC with stirring. After 8 h, the mixture
was quenched with saturated aqueous NH4Cl (200 mL), which was
extracted with EtOAc (100 mLꢂ3). The combined organic layer was
washed with saturated aqueous NH4Cl (50 mLꢂ3), dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (40% EtOAc/n-hexane) to
obtain 2-hydroxybenzyl cyanide (2.5 g, 47%) as brown solid: mp

H.J. Kim et al. / Tetrahedron 68 (2012) 3942e3947
3945
113e114 ꢀC (116e118 ꢀC in literature18); 1H NMR (400 MHz, CDCl3)
3.73 (s, 2H), 5.54 (s, 1H, OH), 6.80 (dd, J¼8.0, 0.8 Hz, 1H), 6.95 (td,
J¼7.2, 0.8 Hz, 1H), 7.20 (td, J¼8.0, 1.6 Hz, 1H), 7.34 (dd, J¼7.2, 1.6 Hz,
149.1, 152.3; FT-IR (KBr) 747, 1023, 1130, 1220, 1264, 1408, 1702 cmꢁ1
;
d
MS (EI) m/z 244 (Mþ), 133, 112 (100), 69. HRMS (EI) calcd for
C14H16N2O2, 244.1212; found, 244.1216.
1H); 13C NMR (100 MHz, CDCl3)
d 18.5, 115.3, 116.8, 118.0, 121.2,
129.48, 129.57, 153.1; MS (EI) m/z 133 (Mþ, 100). Registry No.:
3.2.6. 2-(Cyanomethyl)phenyl 1-pyrrolidinecarboxylate (10). 1-
14714-50-2.
Pyrrolidinecarbonyl chloride (370
sired product 10 (511 mg, 74%) was obtained as pale yellow solid:
mp 74e75 ꢀC; 1H NMR (400 MHz, CDCl3)
1.89e2.02 (m, 4H), 3.48
mL, 3.3 mmol) was used and de-
3.2. General procedure for carbamate
d
(t, J¼6.4 Hz, 2H), 3.61 (t, J¼6.4 Hz, 2H), 3.69 (s, 2H), 7.20 (td, J¼7.4,
3.2.1. O-(2-Cyanomethylphenyl)-N,N-dimethyl thiocarbamate (1). To
1.6 Hz, 1H), 7.22 (d, J¼7.8 Hz, 1H), 7.34 (td, J¼7.8, 1.6 Hz, 1H), 7.39
a
THF solution (5 mL) of 2-hydroxybenzyl cyanide (400 mg,
(dd. J¼8.4, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 19.2, 24.8, 25.7,
3.0 mmol) was added t-BuOK (500 mg, 4.5 mmol) THF solution
(10 mL) at 0 ꢀC. After stirring for 5 min, dimethylthiocarbamoyl
chloride (3.6 mmol) was added and stirred at 90 ꢀC. After 2 h, the
reaction was quenched with water (30 mL), and then organic phase
was extracted with EtOAc (20 mLꢂ3). The combined organic layer
was washed with brine (10 mLꢂ3) and dried over Na2SO4. After
removal of the solvent under reduced pressure, the residue was
purified by flash column chromatography (30% EtOAc/n-hexane) to
obtain 1 (463 mg, 70%) as yellow oil: 1H NMR (400 MHz, CDCl3)
46.38, 46.51, 117.0, 122.48, 122.62, 125.6, 129.10, 129.13, 149.0, 151.7;
FT-IR (KBr) 770, 1065, 1096, 1168, 1220, 1399, 1707 cmꢁ1; MS (EI) m/
z 230 (Mþ), 98 (100), 55. HRMS (EI) calcd for C13H14O2N2, 230.1055;
found, 230.1058.
3.2.7. 2-(Cyanomethyl)phenyl 4-morpholinecarboxylate (11). 4-
Morpholinecarbonyl chloride (380
desired product 11 (700 mg, 94%) was obtained as yellow solid:
mp 88e89 ꢀC; 1H NMR (400 MHz, CDCl3)
3.58 (br s, 4H), 3.65 (s,
mL, 3.3 mmol) was used and
d
d
3.40 (s, 3H), 3.45 (s, 3H), 7.06 (d, J¼8.0 Hz,1H), 7.29 (t, J¼7.6 Hz,1H),
2H), 3.77 (br s, 4H), 7.18 (dd, J¼8.0, 1.2 Hz, 1H), 7.23 (td, J¼7.6,
7.39 (t, J¼8.0 Hz, 1H), 7.43 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
1.2 Hz, 1H), 7.36 (td, J¼8.0, 1.6 Hz, 1H), 7.38 (d, J¼7.6 Hz, 1H); 13C
CDCl3)
d
19.4, 38.8, 43.4,117.1,126.7,123.7,126.7,129.40,129.43,151.7,
NMR (100 MHz, CDCl3) d 19.3, 44.2, 44.9, 66.3, 66.4, 116.9, 122.6,
185.9; FT-IR (KBr) 750, 960, 1096, 1151, 1217, 1273, 1417, 1713 cmꢁ1
;
122.7, 126.0, 129.35, 129.40, 148.9, 152.3; MS (EI) m/z 246 (Mþ), 114
(100), 70. HRMS (EI) calcd for C13H14N2O3, 246.1004; found,
246.1003.
MS (EI) m/z 220 (Mþ), 133, 88 (100), 72. HRMS (EI) calcd for
C11H12N2OS, 220.0670; found, 220.0670.
3.2.2. O-(2-Cyanomethylphenyl)-N,N-dimethyl carbamate (4). Dimet-
hylcarbamoyl chloride (303
m
L, 3.3 mmol) was used and desired
3.3. General procedure for carbonate
product 4 (557 mg, 91%) was obtained as pale yellow oil: 1H NMR
(400 MHz, CDCl3)
d
3.01 (s, 3H), 3.14 (s, 3H), 7.17 (d, J¼8.0 Hz, 1H), 7.22
3.3.1. 2-(Cyanomethyl)phenyl methyl carbonate (12). To a solution
of 2-hydroxybenzyl cyanide (400 mg, 3.0 mmol) and methyl
(t, J¼7.6 Hz, 1H), 7.34 (t, J¼8.0 Hz, 1H), 7.39 (d, J¼8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d
19.1, 36.4, 36.7, 117.1, 122.67, 122.77, 125.9, 129.26,
chloroformate (254
m
L, 3.3 mmol) in CH2Cl2 (10 mL) was added
129.32, 149.2, 153.7; FT-IR (KBr) 753, 1163, 1225, 1391, 1489, 1686,
1725 cmꢁ1; MS (EI) m/z 204 (Mþ), 72 (100). HRMS (EI) calcd for
C11H12N2O2, 204.0899; found, 204.0895.
triethylamine (460
m
L, 3.3 mmol) at 0 ꢀC. After 5 min, removed the
ice bath and stirred at room temperature. After 1 h, the mixture
was quenched with water (30 mL), and then organic phase was
extracted with CH2Cl2 (20 mLꢂ3). The combined organic layer was
washed with brine (20 mLꢂ3) and dried over Na2SO4. After re-
moval of the solvent under reduced pressure, the residue was
purified by flash column chromatography (20% EtOAc/n-hexane)
to obtain 12 (520 mg, 91%) as yellow oil: 1H NMR (400 MHz,
3.2.3. O-(2-Cyanomethylphenyl)-N,N-diethyl carbamate (7). Diethylc-
arbamoyl chloride (418
mL, 3.3 mmol) was used and desired product 7
(550 mg, 79%) was obtained as yellow oil: 1H NMR (400 MHz, CDCl3)
d
1.21 (t, J¼7.2 Hz, 3H), 1.28 (t, J¼7.2 Hz, 3H), 3.39 (q, J¼7.2 Hz, 2H),
3.49 (q, J¼7.2 Hz, 2H), 3.67 (s, 2H), 7.16 (dd, J¼8.0, 0.8 Hz, 1H), 7.21 (td,
CDCl3)
d
3.70 (s, 2H), 3.91 (s, 3H), 7.24 (dd, J¼8.0, 1.2 Hz, 1H), 7.27
J¼7.6, 0.8 Hz,1H), 7.34 (td, J¼7.6, 1.2 Hz, 1H), 7.41 (d, J¼7.2 Hz, 1H); 13C
(td, J¼8.0, 1.2 Hz, 1H), 7.37 (td, J¼8.0, 1.6 Hz, 1H), 7.46 (dd, J¼7.6,
NMR (100 MHz, CDCl3)
d
13.3, 14.3, 19.2, 42.0, 42.3, 117.0, 122.61,
1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 18.5, 55.5, 116.6, 121.8,
122.73, 125.7, 129.15, 129.19, 149.1, 152.9; MS (EI) m/z 232 (Mþ), 100
(100), 72, 61. HRMS (EI) calcd for C13H16N2O2, 232.1212; found,
232.1215.
122.1, 126.4, 129.18, 129.21, 148.4, 153.0; MS (EI) m/z 191 (Mþ), 147,
132 (100), 104, 77. HRMS (EI) calcd for C10H9NO3, 191.0582; found,
191.0585.
3.2.4. O-(2-Cyanomethylphenyl)-N,N-diphenylcarbamate(8). Diphen-
3.3.2. Allyl 2-(cyanomethyl)phenyl carbonate (13). Allyl chlor-
ylcarbamoyl chloride (765 mg, 3.3 mmol) was used and desired
oformate (360
(654 mg, 99%) was obtained as yellow oil: 1H NMR (400 MHz,
CDCl3)
mL, 3.3 mmol) was used and desired product 13
product 8 (807 mg, 82%) was obtained as off-white solid: mp
1
98e100 ꢀC; H NMR (400 MHz, CDCl3)
d
3.45 (s, 2H), 7.16 (td, J¼7.2,
d
3.70 (s, 2H), 4.75 (dt, J¼6.0, 1.2 Hz, 2H), 5.34 (dd, J¼10.6,
1.6 Hz, 1H), 7.25 (br s, 2H), 7.31 (br s, 1H), 7.33 (d, J¼1.2 Hz, 2H),
1.2 Hz,1H), 5.43 (dd, J¼17.6, 1.2 Hz,1H), 5.94e6.04 (m, 1H), 7.25 (dd,
7.351e7.402 (m, 8H); 13C NMR (100 MHz, CDCl3)
d
18.9, 116.9, 122.2,
J¼8.0, 1.2 Hz, 1H), 7.27 (td, J¼7.6, 1.2 Hz, 1H), 7.37 (td, J¼8.0, 1.6 Hz,
125.9, 126.7, 129.02, 129.11, 129.13, 141.6, 148.7, 151.6; FT-IR (KBr) 835,
1032, 1147, 1255, 1464, 1510, 1701 cmꢁ1; MS (EI) m/z 328 (Mþ), 196
(100), 168, 77. HRMS (EI) calcd for C21H16N2O2, 328.1212; found,
328.1209.
1H), 7.46 (dd, J¼7.6, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 18.8,
69.5, 116.6, 119.7, 121.97, 122.13, 126.6, 129.31. 129.40, 130.6, 148.5,
152.4; MS (FAB) m/z 218 (Mþ, 100), 154, 137, 107. HRMS (FAB) calcd
for C12H12NO3 ([MþH]þ), 218.0812; found, 218.0820.
3.2.5. 2-(Cyanomethyl)phenyl 1-piperidinecarboxylate (9). 1-Piperid-
3.3.3. 2-(Cyanomethyl)phenyl 4-methoxybenzoate (14). 4-Methoxy-
benzoyl chloride (563 mg, 3.3 mmol) was used and desired product
14 (603 mg, 75%) was obtained as light yellow solid: mp 94e95 ꢀC; 1H
inecarbonyl chloride (413
uct 9 (671 mg, 91%) was obtained as off-white solid: mp 68e69 ꢀC; 1H
NMR (400 MHz, CDCl3) 1.65 (br s, 6H), 3.51 (br s, 2H), 3.66 (br s, 4H),
mL, 3.3 mmol) was used and desired prod-
d
NMR (400 MHz, CDCl3)
d
3.69 (s, 2H), 3.91 (s, 3H), 7.01 (d, J¼8.0 Hz,
7.15 (dd, J¼8.0, 1.2 Hz, 1H), 7.21 (td, J¼7.6, 1.2 Hz, 1H), 7.34 (td, J¼7.6,
2H), 7.26 (d, J¼8.0 Hz, 1H), 7.31 (t, J¼7.6 Hz, 1H), 7.43 (t, J¼8.0 Hz,1H),
2.0 Hz, 1H), 7.39 (dd, J¼7.6, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
7.51 (d, J¼8.0 Hz, 1H), 8.18 (d, J¼8.0 Hz, 2H); 13C NMR (100 MHz,
d
19.1, 24.1, 25.4, 25.9, 45.2, 45.6, 117.0, 122.7, 125.7, 129.12, 129.18,
CDCl3) d 19.2, 55.6, 114.1, 117.0, 120.8, 122.76, 122.93, 126.6, 129.51,

3946
H.J. Kim et al. / Tetrahedron 68 (2012) 3942e3947
129.60, 132.5, 148.8, 164.13, 164.27; MS (EI) m/z 267 (Mþ), 135 (100),
107, 92, 77. HRMS (EI) calcd for C16H13O3N, 267.0895; found, 267.0899.
(Mþ), 160 (100), 133, 104. HRMS (EI) calcd for C11H12O2N2,
204.0899; found, 204.0896.
3.6. General procedure for Table 2
3.4. Procedure of Scheme 1
3.6.1. 3-Carboxamido-2-diethylaminobenzofuran (7p). Compound 7
(116 mg, 0.5 mmol) and t-BuOK (170 mg,1.5 mmol) were dried under
high vacuum for 30 min and charged with argon gas. After 5 min,
freshly distilled THF (10 mL) under nitrogen was added and stirred at
room temperature for 1 h. The reaction was quenched by saturated
aqueous NH4Cl (20 mL), and then organic phase was extracted with
EtOAc (15 mLꢂ3). Thecombinedorganiclayer waswashed withbrine
(5 mLꢂ3) and dried over Na2SO4. Silica gel (2.0 g) was poured into
solution and solvent was evaporated under reduced pressure. Silica
gel was dried in a high vacuum for 30 min and the residue was irra-
diated under Microwave (30 sꢂ3, 620 W). After the silica gel was
suspended in EtOAc, silica gel was filtered the solvent was removed
under reduced pressure to obtain 7p (80 mg, 69%) as yellow solid: mp
To a THF solution (5 mL) of compound 1 (220 mg, 1.0 mmol)
were added NaH (120 mg, 3.0 mmol), THF solution (5 mL) and
stirred at 90 ꢀC. After 3 h, reaction was quenched with saturated
aqueous NH4Cl (20 mL), and then organic phase was extracted with
EtOAc (10 mLꢂ3). The combined organic layer was washed with
brine (5 mLꢂ3) and dried over Na2SO4. After removal of the solvent,
the residue was purified by flash column chromatography (5%
EtOAc/45% DCM/n-hexane) to obtain 2 and 3, respectively.
3.4.1. 2-(2-Hydroxyphenyl)-N,N-dimethyl-2-oxoethanethioamide
(2). Yellow gum: 1H NMR (400 MHz, CDCl3)
d 3.25 (s, 3H), 3.54 (s,
3H), 6.88 (td, J¼8.0, 0.8 Hz, 1H), 7.00 (dd, J¼8.4, 0.8 Hz, 1H), 7.50 (dt,
J¼7.6, 0.8 Hz, 1H), 7.52 (dd, J¼8.0, 0.8 Hz, 1H); 13C NMR (100 MHz,
115e117 ꢀC; 1H NMR (400 MHz, CDCl3)
d
1.20 (t, J¼7.2 Hz, 6H), 3.56 (q,
CDCl3) d 40.3, 42.5,116.1,118.6,119.5,131.9,137.4,163.5,193.3,193.5;
J¼7.2 Hz, 4H), 5.58 (br s, 2H, NH), 7.04 (t, J¼6.8 Hz, 1H), 7.15 (d,
MS (EI) m/z 209 (Mþ), 176, 121, 88 (100). HRMS (FABþ) calcd for
C10H12NO2S ([MþH]þ), 210.0583; found, 210.0587.
J¼8.0 Hz, 1H), 7.18 (t, J¼6.8 Hz, 1H), 7.23 (d, J¼8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d 13.7, 40.5, 88.1, 109.9, 118.0, 120.6, 123.3, 127.4,
148.6, 163.0, 167.7; MS (EI) m/z 232 (Mþ), 160 (100), 133, 104, 72.
3.4.2. 2-Dimethylamino-3-thiocarboxamidobenzofuran
(3). Yield
HRMS (EI) calcd for C13H16O2N2, 232.1212; found, 232.1215.
98 mg (89%) yellow solid: mp 135e136 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
3.40 (s, 6H), 6.15 (br s, 2H, NH2), 7.04 (t, J¼8.0 Hz, 1H), 7.07
3 . 6 . 2 . 3 - C a r b o x a m i d o - 2 - d i p h e n y l a m i n o b e n z o f u r a n
(8p). Compound 8 (164 mg, 0.5 mmol) was used and desired
product was obtained 8p (133 mg, 81%) as pale yellow solid: mp
(d, J¼8.0 Hz, 1H), 7.17 (t, J¼8.0 Hz, 1H), 7.23 (d, J¼8.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3)
d 43.7, 95.0, 109.8, 118.6, 121.0, 123.4, 126.3,
147.9, 162.8, 192.4; FT-IR (KBr) 750, 972, 1125, 1385, 1454,
1605 cmꢁ1; MS (EI) m/z 220 (Mþ, 100), 176, 144, 115. HRMS (EI)
calcd for C11H12N2OS, 220.0670; found, 220.0672.
163e165 ꢀC; 1H NMR (400 MHz, CDCl3)
d
6.27 (d, J¼8.0 Hz,1H), 6.28
(br s, 2H, NH2), 6.71 (td, J¼7.8,1.2 Hz,1H), 6.88 (td, J¼7.8,1.2 Hz,1H),
7.13 (d, J¼7.6 Hz, 1H), 7.16 (td, J¼7.6, 1.6 Hz, 2H), 7.20 (dd, J¼7.2,
1.2 Hz, 4H), 7.29 (t, J¼7.6 Hz, 4H); 13C NMR (100 MHz, CDCl3)
d 88.0,
3.5. Procedure of Scheme 2
109.2, 118.9, 120.7, 122.9, 125.3, 125.6, 126.8, 129.0, 144.1, 148.4,
166.0, 168.0; FT-IR (KBr) 693, 704, 745, 1017, 1249, 1350, 1409, 1493,
1627 cmꢁ1; MS (EI) m/z 328 (Mþ), 169 (100). HRMS (FABþ) calcd for
C21H17N2O2, 329.1285; found, 329.1290.
3.5.1. 2-(2-Hydroxyphenyl)-N,N-dimethyl-2-oxoacetamide (5). To
a THF (5 mL) solution of SM (204 mg, 1.0 mmol) and t-BuOK
(336 mg, 3.0 mmol) was bubbled air and stirred at room tempera-
ture. After 1 h, the reaction was quenched with saturated aqueous
NH4Cl (20 mL), and then organic phase was extracted with EtOAc
(10 mLꢂ3). The combined organic layer was washed with brine
(5 mLꢂ3) and dried over Na2SO4. After removal of the solvent un-
der reduced pressure, the residue was purified by flash column
chromatography (40% EtOAc/n-hexane) to obtain 5 (145 mg, 75%)
3.6.3. 3-Carboxamido-2-(piperidin-1-yl)benzofuran (9p). Compound
9 (122 mg, 0.5 mmol) was used and desired product was obtained 9p
(80 mg, 66%) as yellow solid: mp 157e159 ꢀC; 1H NMR (400 MHz,
CDCl3)
d 1.61e1.70 (m, 6H), 3.51e3.61 (m, 4H), 5.73 (br s, 2H, NH2),
7.03 (td, J¼7.8, 1.2 Hz, 1H), 7.16 (td, J¼7.6, 0.8 Hz, 1H), 7.21 (dd, J¼7.6,
1.6 Hz, 1H), 7.23 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.7,
as yellow viscose liquid: 1H NMR (400 MHz, CDCl3)
d
2.98 (s, 3H),
26.4, 46.3, 87.4, 109.8, 118.1, 120.6, 123.3, 127.2, 148.5,163.6, 167.6; FT-
IR (KBr) 753, 993, 1187, 1242, 1486, 1518, 1591, 1637 cmꢁ1; MS (EI) m/
z 244 (Mþ, 100), 160, 133, 104, 84. HRMS (EI) calcd for C14H16N2O2,
244.1212; found, 244.1208.
3.12 (s, 3H), 6.94 (t, J¼8.0 Hz, 1H), 7.24 (d, J¼8.4 Hz, 1H), 7.52 (t,
J¼8.0 Hz, 1H), 7.55 (d, J¼8.2 Hz, 1H), 11.32 (s, 1H, OH); 13C NMR
(100 MHz, CDCl3)
d 34.0, 37.1, 116.6, 118.5, 119.8, 132.0, 137.9, 163.2,
165.0, 196.7; MS (EI) m/z 193 (Mþ), 121 (100), 72. HRMS (FABþ)
calcd for C10H12NO3 ([MþH]þ), 194.0812; found, 194.0817.
3. 6. 4. 3 -Ca rboxa mido -2-(pyr rolidin -1-yl)benzo furan
(10p). Compound 10 (115 mg, 0.5 mmol) was used and desired
product was obtained 10p (77 mg, 67%) as yellow solid: mp
3.5.2. 3-Carboxamido-2-dimethylaminobenzofuran (6). Compound
4 (204 mg, 1.0 mmol) and t-BuOK (336 mg, 3.0 mmol) were dried
under high vacuum for 30 min and then purged with argon gas.
After 5 min, freshly distilled THF (15 mL) under nitrogen was added
and the reaction mixture was stirred for 1 h at room temperature.
The reaction was quenched with saturated aqueous NH4Cl (20 mL),
and then organic phase was extracted with EtOAc (15 mLꢂ3). The
combined organic layer was washed with brine (5 mLꢂ3) and dried
over Na2SO4. After removal of the solvent under reduced pressure,
the residue was purified by flash column chromatography (40%
EtOAc/CH2Cl2) to obtain 6 (77 mg, 75%) as off-white solid: mp
122e124 ꢀC; 1H NMR (400 MHz, CDCl3)
d 1.91 (br s, 4H), 3.63 (br s,
4H), 5.74 (br s, 2H, NH2), 7.03 (t, J¼7.6 Hz, 1H), 7.16 (t, J¼7.6 Hz, 1H),
7.37 (t, J¼8.4 Hz, 1H), 7.26 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 25.4, 47.4, 88.5, 109.9, 118.8, 120.5, 123.2, 127.1, 148.9, 162.8,
166.8; FT-IR (KBr) 753, 1024, 1177, 1389, 1438, 1582, 1633 cmꢁ1; MS
(EI) m/z 230 (Mþ), 160 (100), 133, 104, 70. HRMS (EI) calcd for
C13H14N2O2, 230.1055; found, 230.1055.
3. 6. 5. 3 -C arboxamido-2-(morp holin-4-yl)benzo furan
(11p). Compound 11 (123 mg, 0.5 mmol) was used and desired
product was obtained 11 (97 mg, 79%) as yellow solid: mp
112e113 ꢀC; 1H NMR (400 MHz, CDCl3)
d 3.09 (s, 6H), 5.66 (br s, 2H,
NH2), 7.04 (t, J¼8.0 Hz, 1H), 7.17 (t, J¼7.6 Hz, 1H), 7.23 (d, J¼7.8 Hz,
172e174 ꢀC; 1H NMR (400 MHz, CDCl3)
d
3.64 (t, J¼4.8 Hz, 2H), 3.77
1H), 7.24 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
37.5, 87.3,
(t, J¼4.8 Hz, 2H), 5.82 (br s, 2H, NH2), 7.05 (t, J¼7.2 Hz, 1H), 7.17 (d,
109.9, 118.6, 120.6, 123.4, 127.2, 148.7, 163.3, 168.6; FT-IR (KBr) 744,
J¼5.2 Hz, 1H), 7.19 (t, J¼6.8 Hz, 1H), 7.24 (d, J¼8.4 Hz, 1H); 13C NMR
1033, 1242, 1385, 1455, 1502, 1595, 1629 cmꢁ1; MS (EI) m/z 204
(100 MHz, CDCl3) d 45.9, 67.1, 86.6, 110.0, 118.0, 121.0, 123.6, 126.6,

H.J. Kim et al. / Tetrahedron 68 (2012) 3942e3947
3947
148.6, 164.2, 168.1; MS (EI) m/z 246 (Mþ), 160 (100), 132, 104, 86.
Supplementary data
HRMS (EI) calcd for C13H14N2O3, 246.1004; found, 246.1000.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.03.088. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
3.6.6. 3-Carboxamido-2-methoxybenzofuran (12p). Compound 12
(96 mg, 0.5 mmol) was used and desired product was obtained 12p
(50 mg, 52%) as yellow solid: mp 56e57 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
3.91 (s, 3H), 5.98 (br s, 2H, NH2), 7.07 (td, J¼8.0, 1.2 Hz, 1H),
7.20 (td, J¼7.6, 1.2 Hz, 1H), 7.22 (d, J¼7.6 Hz, 1H), 7.65 (d, J¼7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 51.0, 84.6, 109.6. 115.2, 119.3,
References and notes
121.5,124.0,126.6,149.0,164.4; MS (EI) m/z 191 (Mþ),159 (100),131,
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Heterocyclic Chemistry; Academic: New York, NY, 1975; Vol. 18, p 337; (b) Keay,
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prehensive Heterocyclic Chemistry II; Pergamon: Oxford, UK, 1996; Vol. 2, p 423;
(c) Jiang, X. Z.; Liu, W. L.; Zhang, W.; Jiang, F. Q.; Gao, Z.; Zhuang, H.; Fu, L. Eur. J.
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Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61,
103. HRMS (EI) calcd for C10H9NO3, 191.0582; found, 191.0582.
3.6.7. 2-Allyloxy-3-carboxamidobenzofuran (13p). Compound 13
(109 mg, 0.5 mmol) was used and desired product was obtained
13p (59 mg, 54%) as yellow solid: mp 134e135 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
4.84 (dt, J¼5.6, 1.6 Hz, 2H), 5.28 (dd, J¼10.6,
1.6 Hz, 1H), 5.42 (dd, J¼17.2, 1.6 Hz, 1H), 6.02 (br s, 2H, NH2),
6.020e6.117 (m, 1H), 7.06 (td, J¼7.8, 1.6 Hz, 1H), 7.20 (td, J¼7.6,
1.2 Hz, 1H), 7.21 (dd, J¼7.6, 1.2 Hz, 1H), 7.67 (d, J¼8.0 Hz, 1H); 13C
9280.
NMR (100 MHz, CDCl3)
d 64.3, 84.4, 109.6, 117.6, 119.3, 121.4, 124.0,
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126.6, 132.7, 149.0, 164.5; MS (FAB) m/z 217 (Mþ, 100), 159, 132, 104.
HRMS (EI) calcd for C12H11NO3, 217.0739; found, 217.0741.
3.6.8. 3-Carboxamido-2-(4-methoxyphenyl)benzofuran
(14p). Compound 14 (133 mg, 0.5 mmol) was used and desired
product was obtained 14p (93 mg, 70%) as yellow solid: mp
113e114 ꢀC; 1H NMR (400 MHz, CDCl3)
d 3.88 (s, 3H), 6.98 (d,
J¼8.8 Hz, 2H), 7.02 (br s, 2H, NH2), 7.020e7.073 (m, 3H),
7.217e7.241 (m, 1H), 7.74 (d, J¼8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3)
d 55.4, 94.2, 109.9, 113.4, 119.0, 121.6, 123.5, 126.4, 129.7,
133.2, 149.0, 161.8, 166.3, 189.8; MS (EI) m/z 267 (Mþ, 100), 266, 159,
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135. HRMS (EI) calcd for C16H13NO3, 267.0895; found, 267.0894.
Acknowledgements
17. See Supplementary data.
This research was supported by the Converging Research Pro-
gram (2011K00705) through the Ministry of Education, Science and
Technology.
18. Dong, C.-Z.; Ahamada-Himidi, A.; Plocki, S.; Aoun, D.; Touaibia, M.; Habich, N.
M.-B.; Huet, J.; Redeuilh, C.; Ombetta, J. E.; Godfrold, J. J.; Massicot, F.; Heymans,
F. Bioorg. Med. Chem. 2005, 13, 1989.