Base-mediated intramolecular cyclization of (2-propargyl ether) arylimines: An approach to 3-amino-benzofurans

Article abstract of DOI:10.1016/j.tet.2014.04.053

We present here a practical synthesis of functional 3-amino-benzofurans through base-promoted intramolecular cyclization of (2-propargyl ether) arylimines. A systematic study of the cyclization system revealed that the presence and the amount of base play

Full text of DOI:10.1016/j.tet.2014.04.053

Tetrahedron 70 (2014) 3751e3756
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Base-mediated intramolecular cyclization of (2-propargyl ether)
arylimines: an approach to 3-amino-benzofurans
,
Rafaela Gai a, Thaís Prochnow a, Davi F. Back b, Gilson Zeni a
*
a
ꢀ
~
ꢀ
ꢀ
^
Laboratorio de Síntese, Reatividade, Avaliac¸ ao Farmacologica e Toxicologica de Organocalcogenios, CCNE, UFSM, Santa Maria, Rio Grande do Sul
97105-900, Brazil
b
ꢀ
^
Laboratorio de Materiais Inorganicos, CCNE, UFSM, Santa Maria, Rio Grande do Sul 97105-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
We present here a practical synthesis of functional 3-amino-benzofurans through base-promoted in-
tramolecular cyclization of (2-propargyl ether) arylimines. A systematic study of the cyclization system
revealed that the presence and the amount of base played an essential role in this reaction. The results
showed that the cyclization proceeded cleanly and smoothly under mild reaction conditions, employing
potassium tert-butoxide as base, THF as solvent, at room temperature in a short reaction time (1 h). The
generality of this reaction has been established with (2-propargyl ether) arylimines having both
electron-withdrawing and electron-donating groups.
Received 14 March 2014
Received in revised form 15 April 2014
Accepted 16 April 2014
Available online 25 April 2014
Keywords:
Cyclization
Benzofurans
Heterocycles
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
intramolecular cyclization (Scheme 1). Although, much attention
has been paid to the synthesis of carbocycles and heterocycles
Propargyl ethers are versatile building blocks for a variety of
important compounds, many of which are pharmaceutically sig-
nificant.1 They have also proven to be efficient starting materials to
a wide range of interesting transformations, such as Claisen rear-
rangement,2 transition-metal-catalyzed isomerization,3 Csp3eH
bond activation4 and propargylation reactions.5 In addition,
a number of synthetic protocols have been reported to date for the
synthesis of carbocycles and heterocycles, which are based on the
intramolecular cyclization of propargyl ethers.6 In this regard, the
transition-metal-catalyzed cyclization reactions represent a very
attractive alternative since simple substrates can be transformed in
more elaborated structures in a stepwise manner. Usually, transi-
tion-metals, such as Au,7 Fe,8 Pd,9 In,10 Ni,11 and Pt12 are used to
promote these cyclization reactions. Nevertheless, new alternative
strategies to intramolecular cyclization of propargyl ethers through
simplified routes are always desired. In this context, the carba-
nionic cyclization method for both carbocycles and heterocycles
formation has emerged as a powerful tool in organic synthesis.13 It
is known that propargyl ethers react with bases to give the corre-
sponding carbanions. The generation of such carbanions could re-
sult in the intermediates allenyl anions II and III and with two
carbons having nucleophilic character, which may undergo
applying carbanion intramolecular attack to an activated carbon-
ecarbon bond from alkynes and alkenes,14 the use of imines as
electrophilic center in an intramolecular cyclization was un-
precedented. Therefore, in this study we explored the behavior of
imines, as electrophilic center, on the base-promoted cyclization
reaction of (2-propargyl ether) arylimines 1 to the preparation of 3-
amino-benzofuran derivatives 2 (Scheme 1).
Scheme 1.
2. Results and discussion
The (2-propargyl ether) arylimines 1 were prepared by reacting
the corresponding salicylaldehyde with propargyl bromides in the
presence of K2CO3 in acetonitrile at 80 ꢀC for 4 h.15 After that, to the
introduction of N-tert-butylimine group, we reacted (2-propargyl
ether) benzaldehyde with tert-butylamine (10 equiv), without
* Corresponding author. Tel.: þ55 55 3220 9612; e-mail addresses: gzeni@pq.
ufsm.br, gzeni@ufsm.br (G. Zeni).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.053

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R. Gai et al. / Tetrahedron 70 (2014) 3751e3756
solvent, at room temperature for 24 h.16 (2-Propargyl ether) aryli-
mines 1 were very sensitive to hydrolysis and were used without
further purification. We prepared a number of (2-propargyl ether)
arylimines 1 and the generality and scope of the reaction are
summarized in the Supplementary data. To explore the optimal
reaction condition to the base-promoted cyclization, we began our
study with the reaction between substrate 1a and t-BuOK
(2.5 equiv) in DMF at room temperature (Table 1, entry 1). In this
first condition, the starting material was completely consumed
after 1 h and two products were observed in the TLC, as two spots,
which have very close Rf. 3-Amino-benzofuran 2a was isolated by
flash chromatography, followed by crystallization in 50% yield. Its
structure was determined by NMR spectroscopy and confirmed by
X-ray diffraction analysis (Fig. 1).17 The 1H NMR showed two dou-
blets, which resonate at 7.24 and 7.12 ppm, respectively, with
a coupling constant of 16 Hz. The second compound was isolated in
5% yield by column chromatography as oil. This compound showed
two doublets in 6.60 and 6.52 ppm with a coupling constant of
12 Hz, which indicates a cis-stereochemistry for vinylic hydrogens.
Other NMR experiments and, in particular, the data extracted from
the two dimensional experiments (HMQC) confirmed the assign-
ment of the Z isomer. We next proceeded to examine the optimi-
zation of this cyclization in order to improve the reaction yield
obtained in the first experiment (Table 1, entry 1). The influence of
solvent in the cyclization of (2-propargyl ether) arylimine 1a was
then evaluated, and the results are shown in Table 1, entries 2e10.
The best result was obtained by using THF, which gave the desired
3-amino-benzofuran 2a in 81% yield in a mixture of E and Z isomers
with a higher proportion of E isomers (Table 1, entry 10). The
amount of base was also optimized; the cyclization was not be
significantly improved by either increasing the t-BuOK amount to
3 equiv or decreasing until to the catalytic amount (Table 1, entries
11e15). However, when the reaction was carried out using 2 equiv
of t-BuOK the desired 3-amino-benzofuran 2a was obtained in 75%
Fig. 1. ORTEP view of the 3-amino-benzofurans 2a (right) and 2h (left).
yield after purification by column chromatography, in the complete
absence of Z isomer (Table 1, entry 12). We noticed that the use of
other bases, such as K2CO3, NaH, KOH, Cs2CO, and Et3N demon-
strated to be stagnant to this reaction (Table 1, entries 17e21). In
the case of temperature study, the change from 0 ꢀC to reflux did
not improve the reaction results. At various interval times, during
the optimization reactions, samples of the reaction mixture were
analyzed by TLC, which showed that 1 h was the reaction time
necessary to the complete consume of starting material. On the
basis of the above investigation, the optimal conditions for this
intramolecular cyclization reaction are the use of (2-propargyl
ether) arylimine 1a (0.25 mmol), t-BuOK (2 equiv), THF (3 mL) as
solvent, at room temperature for 1 h.
In order to test the utility of the optimized reaction conditions,
the reaction described in Table 1, entry 12, was applied in a some-
what more complex (2-propargyl ether) arylimines 1 (Table 2). At
the beginning, we studied the effect of the substituent on the aryl
bonded to alkyne. On the one hand, the reaction yields do not seem
to be strongly influenced by the electronic effects of the sub-
stituents since different aryl groups bearing neutral, electron-
withdrawing, and electron-donating groups in the aromatic rings
were compatible with the reaction conditions and yielded the
corresponding 3-amino-benzofurans in very similar yields (Table 2,
entries 1e5). On the other hand, the results shown in Table 2
revealed that the stereoselectivity was influenced by the elec-
tronic effect of the substituent in the aromatic rings, where the
strong electron-withdrawing, fluorine group, exerted significant
negative effects (Table 2, entry 6). Furthermore, the heteroaryl
thiophene, directly bonded to the alkyne, was also a suitable re-
actant in this cyclization conditions, giving 3-amino-benzofuran 2i
in 57% yield (Table 2, entry 7). The results in Table 2 showed that
only moderated amount of product was obtained for the cyclization
of (2-propargyl ether) arylimines having naphthyl group, where the
steric hindrance may exert significant negative effects (Table 2,
entry 8). We also examined the cyclization of starting materials
having a substituent on the central aromatic ring. With substrates
having both electron-withdrawing and electron-donating groups at
this position, the cyclization proceeded in almost comparable
yields, with the exception of the nitro group, that afforded 40% yield
of an inseparable mixture of E and Z isomer (3.5:1) (Table 2, entries
9e16). Particularly interesting was the cyclization reaction of 1q,
which has a terminal alkyne instead of an aromatic group, that
proceeded smoothly, giving the corresponding 3-amino-benzofu-
ran 2q with a terminal olefin moiety intact. One limitation of our
methodology was that extending the optimized conditions to (2-
propargyl ether) arylimine 1r, having an alkyl group directly
bonded to alkyne, the reaction did not afford the expected product
2r (Table 2, entry 18).
Table 1
Effect of reaction conditions on the cyclization of (2-propargyl ether) arylimine 1aa
#
Base (equiv)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
t-BuOK (2.5)
t-BuOK (2.5)
t-BuOK (2.5)
t-BuOK(2.5)
t-BuOK(2.5)
t-BuOK (2.5)
t-BuOK (2.5)
t-BuOK (2.5)
t-BuOK (2.5)
t-BuOK(2.5)
t-BuOK (3.0)
t-BuOK (2.0)
t-BuOK (1.0)
t-BuOK (0.5)
t-BuOK (0.2)
t-BuOK (2.0)
K2CO3 (2.0)
NaH (2.0)
DMF
DMSO
Dioxane
t-BuOH
MeOH
H2O
CH2Cl2
Hexane
Toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
50
60 (10:1)c
0
0
0
0
0
0
0
9
10
11
12
13
14
15
16
17
18
19
20
21
81 (6.6:1)c
85 (4:1)c
75
63
69 (6.5:1)c
59 (5.7:1)c
73 (12:1)c,d
0
0
0
0
0
KOH (2.0)
Cs2CO3 (2.0)
Et3N (2.0)
THF
THF
THF
Based on these results, we propose the reaction mechanism for
potassium tert-butoxide cyclization of (2-propargyl ether) aryli-
mines as illustrated in Scheme 2. The formation of Z-benzofuran
derivatives 2 could involve the abstraction of proton from 1 by t-
BuOK generating the progargyl carbanion I in equilibrium with the
allenes intermediated II and III.18 Deprotonation of the carbon
a
The reaction was performed in the presence of 1a (0.25 mmol), base, solvent
(3 mL), under argon atmosphere for 1 h at room temperature.
b
Yield of isolated compounds by column chromatography.
c
E/Z ratio was determined by 1H NMR spectra.
d
The reaction was continued for 24 h.
atom
a to the nitrogen, followed by the aromatization of cyclic

R. Gai et al. / Tetrahedron 70 (2014) 3751e3756
3753
Table 2
Table 2 (continued )
Synthesis of 3-amino-benzofuran derivatives 2a
#
Substrate 1
Product 2 yieldb (%)
11
#
1
Substrate 1
Product 2 yieldb (%)
12
13
2
3
4
14
15
16
5
6
7
17
18
a
The reaction was performed in the presence of (2-propargyl ether) arylimines 1
(0.25 mmol), t-BuOK (2.0 equiv) in THF (3 mL), under argon atmosphere for 1 h at
room temperature.
8
b
Isolated yields after column chromatography.
c
E/Z ratio was determined by 1H NMR spectra.
d
The reaction was carried out at the reflux temperature.
e
No product was obtained.
adduct leads to vinyl carbanion V, which affords benzofuran de-
rivatives 2. Since isomerization of E to Z isomers can potentially
occur through vinyl anions,19 we assume that the trace amount
obtained for the Z isomers may be formed via isomerization of vi-
nylic carbanion V (Scheme 2).
9
3. Conclusion
10
In conclusion, we found that t-BuOK is a valuable cyclization
promoter of (2-propargyl ether) arylimines to prepare 3-amino-

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R. Gai et al. / Tetrahedron 70 (2014) 3751e3756
intensity) m/z: 291 (58), 235 (100), 206 (31), 178 (17), 120 (48), 102
(35), 77 (25), 57 (24). HRMS calcd for C20H21NNaO: 314.1521. Found:
314.1525.
4.2.2. (E)-N-tert-Butyl-2-(4-methylstyryl)benzofuran-3-amine
(2b). Isolated as a yellow oil. Yield: 0.093 g (62%). 1H NMR (CDCl3,
400 MHz):
d
7.47 (d, J¼7.6 Hz, 1H), 7.43e7.34 (m, 3H), 7.25e7.10 (m,
5H), 7.06 (d, J¼16.1 Hz,1H), 2.58 (sl,1H), 2.32 (s, 3H),1.24 (s, 9H). 13
C
NMR (CDCl3, 100 MHz):
d 153.6, 149.5, 137.6, 134.5, 129.4, 129.3,
128.2, 126.5, 124.5, 124.2, 122.3, 119.6, 113.7, 110.9, 54.4, 30.6, 21.2.
MS (relative intensity) m/z: 305 (73), 249 (100), 233 (17), 220 (26),
178 (12), 130 (24), 120 (27), 57 (18). HRMS calcd for C21H24NO:
306.1858. Found: 306.1861.
Scheme 2.
4.2.3. (E)-N-tert-Butyl-2-(3-methylstyryl)benzofuran-3-amine
(2c). Isolated as a yellow oil. Yield: 0.096 g (63%). 1H NMR (CDCl3,
400 MHz):
d
7.49 (d, J¼7.6 Hz, 1H), 7.39 (d, J¼8.0 Hz, 1H), 7.36e7.30
benzofurans. The main advantages of this methodology are based
on the easy assembly of the starting materials from readily available
precursors, the incorporation of two different useful functionalities
in the structure and the mild reaction conditions. Another im-
provement of this protocol is the high regioselectivity regarding to
a possible nucleophilic competition between the five and seven
heterocycle formation. We believe that this approach to 3-amino-
benzofurans should prove quite useful in synthesis, particularly
when one considers that there are many ways to transform the
resulting alkene and amine functionalities into other substituents.
(m, 2H), 7.28e7.15 (m, 4H), 7.10 (d, J¼16.1 Hz, 1H), 7.06 (d, J¼7.3 Hz,
1H), 2.60 (sl, 1H), 2.36 (s, 3H), 1.26 (s, 9H). 13C NMR (CDCl3,
100 MHz):
d 153.7, 149.4, 138.2, 137.2, 129.3, 128.6, 128.5, 128.3,
127.3, 124.6, 124.5, 123.7, 122.3, 119.6, 114.4, 111.0, 54.4, 30.6, 21.3.
MS (relative intensity) m/z: 305 (76), 249 (100), 233 (18), 220 (20),
130 (29), 120 (32), 57 (18). HRMS calcd for C21H24NO: 306.1858.
Found: 306.1865.
4.2.4. (E)-N-tert-Butyl-2-(4-methoxystyryl)benzofuran-3-amine
(2d). Isolated as a yellow oil. Yield: 0.107 g (67%). 1H NMR (CDCl3,
400 MHz):
3H), 6.98 (d, J¼16.1 Hz, 1H), 6.89 (d, J¼8.8 Hz, 2H), 3.80 (s, 3H), 2.40
(sl,1H),1.25 (s, 9H). 13C NMR (CDCl3, 100 MHz):
159.5,153.5,149.6,
130.0,129.3,127.8,127.7,124.3,123.6,122.3,119.5,114.2,112.6,110.8,
55.3, 54.5, 30.5. MS (relative intensity) m/z: 321 (88), 265 (100), 250
(43), 221 (17),165 (12),146 (11), 57 (10). HRMS calcd for C21H24NO2:
322.1807. Found: 322.1811.
d
7.52e7.43 (m, 3H), 7.39 (d, J¼7.9 Hz, 1H), 7.27e7.14 (m,
4. Experimental section
4.1. General
d
Proton nuclear magnetic resonance spectra (1H NMR) were
obtained at 200 MHz or at 400 MHz spectrometer. Spectra were
recorded in CDCl3 solutions. Carbon-13 nuclear magnetic resonance
spectra (13C NMR) were obtained either at 50 MHz or at 100 MHz
spectrometer. Spectra were recorded in CDCl3 solutions. Mass
spectra were recorded on a spectrometer using EI at 70 eV. High
resolution mass spectra were recorded on an LCeMS-IT-TOF. Col-
umn chromatography was performed using Silica Gel (230e400
mesh). Thin layer chromatography (TLC) was performed using Silica
Gel GF254, 0.25 mm thickness. For visualization, TLC plates were
either placed under ultraviolet light, or stained with iodine vapor,
or acidic vanillin. Most reactions were monitored by TLC for dis-
appearance of starting material.
4.2.5. (E)-N-tert-Butyl-2-(4-chlorostyryl)benzofuran-3-amine
(2e). Isolated as a yellow oil. Yield: 0.097 g (60%). 1H NMR (CDCl3,
200 MHz):
d
7.49 (d, J¼7.6 Hz, 1H), 7.45e7.37 (m, 3H), 7.30 (d,
J¼8.3 Hz, 2H), 7.28e7.21 (m, 1H), 7.20e7.12 (m, 2H), 7.07 (d,
J¼15.9 Hz, 1H), 2.62 (sl, 1H), 1.25 (s, 9H). 13C NMR (CDCl3, 100 MHz):
d
153.6, 148.9, 135.7, 133.2, 129.1, 128.9, 127.6, 126.6, 124.8, 122.4,
119.7, 115.1, 111.0, 54.5, 30.6. MS (relative intensity) m/z: 325 (51),
269 (100), 233 (31), 204 (14), 178 (10), 120 (55), 57 (17). HRMS calcd
for C20H21ClNO: 326.1312. Found: 326.1317.
4.2.6. (E)-N-tert-Butyl-2-(4-fluorostyryl)benzofuran-3-amine
(2f). Isolated as a yellow oil. Yield: 0.111 g (72%). 1H NMR (CDCl3,
400 MHz): d 7.53e7.34 (m, 5.5H), 7.28e7.11 (m, 4.7H), 7.07e6.92 (m,
4.2. General procedure for the synthesis of 3-amino-benzo-
furans 2
4.2H), 6.53 (d, J¼12.7 Hz, 0.5H, Z isomer), 6.49 (d, J¼12.5 Hz, 0.5H, Z
To a solution of (2-propargyl ether) arylimines 1 (0.5 mmol) in
dry THF (3 mL) was added t-BuOK (2.0 equiv). The resulting solu-
tion was stirred at room temperature under an argon atmosphere
until complete consumption of the starting material (1 h). The
progress of the reaction was monitored by TLC. The residue was
dissolved in ethyl acetate, and the solution was washed with sat-
urated NH4Cl, dried (MgSO4), and concentrated in vacuo. The res-
idue was purified by column chromatography over silica gel to
provide benzofurans 2. Column chromatography was carried out
using hexane/ethyl acetate (8:2) as eluent.
isomer), 2.54 (sl, 1H), 1.26 (s, 9H), 1.21 (s, 4.5H, Z isomer). 13C NMR
(CDCl3, 100 MHz):
d
162.4 (d, J¼248.0 Hz), 162.1 (d, J¼247.0 Hz, Z
isomer), 153.6, 153.3, 149.1, 147.4, 133.4 (d, J¼3.0 Hz), 133.3 (d,
J¼3.0 Hz), 130.8 (d, J¼8.0 Hz, Z isomer), 129.2, 128.3, 128.1, 128.0 (d,
J¼8.0 Hz), 126.9, 126.1, 124.8, 124.7, 124.5, 124.4, 122.3, 119.9, 119.6,
115.7 (d, J¼21.1 Hz),115.6 (d, J¼1.5 Hz, Z isomer),114.8 (d, J¼22.0 Hz,
Z isomer), 114.4 (d, J¼2.2 Hz), 111.2 (Z isomer), 111.0, 54.7, 54.5, 30.6,
30.5 (Z isomer). MS (relative intensity) m/z: 309 (51), 253 (100), 224
(24), 120 (38), 57 (13). HRMS calcd for C20H20FNNaO: 332.1427.
Found: 332.1430.
4.2.1. (E)-N-tert-Butyl-2-styrylbenzofuran-3-amine (2a). Isolated as
a yellow solid. Yield: 0.109 g (75%), mp: 80e83 ꢀC. 1H NMR (CDCl3,
4.2.7. (E)-N-tert-Butyl-2-(2-(thiophen-3-yl)vinyl)benzofuran-3-
amine (2g). Isolated as a yellow solid. Yield: 0.084 g (57%), mp:
400 MHz):
d
7.56e7.47 (m, 3H), 7.43e7.31 (m, 3H), 7.30e7.15 (m,
103e105 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
7.48 (d, J¼7.6 Hz, 1H), 7.38
(d, J¼7.9 Hz, 1H), 7.36e7.14 (m, 6H), 6.95 (d, J¼16.0 Hz, 1H), 2.45 (sl,
1H), 1.25 (s, 9H). 13C NMR (CDCl3, 100 MHz):
153.6, 149.1, 140.0,
129.3, 126.2, 124.8, 124.5, 124.2, 122.7, 122.4, 122.3, 119.5, 114.7,
4H), 7.12 (d, J¼16.1 Hz, 1H), 2.49 (sl, 1H), 1.26 (s, 9H). 13C NMR
(CDCl3, 100 MHz):
d
153.7, 149.3, 137.3, 129.2, 128.7, 128.2, 127.7,
d
126.5, 124.7, 124.6, 122.4, 119.7, 114.7, 111.0, 54.5, 30.6. MS (relative

R. Gai et al. / Tetrahedron 70 (2014) 3751e3756
3755
110.9, 54.5, 30.6. MS (relative intensity) m/z: 297 (97), 241 (65), 226
(100), 208 (50), 152 (13), 120 (21), 77 (15), 57 (17). HRMS calcd for
(sl, 1H), 1.29 (s, 9H), 1.19 (s, 2.7H, Z isomer). 13C NMR (CDCl3,
100 MHz): 156.3, 156.1 (Z isomer), 152.3, 150.6 (Z isomer), 144.1,
d
C
18H20NOS: 298.1266. Found: 298.1274.
143.9 (Z isomer), 136.9 (Z isomer), 136.5, 132.0, 130.4, 129.9, 129.1 (Z
isomer), 128.8, 128.7, 128.4, 128.2, 128.0 (Z isomer), 126.8, 126.6 (Z
isomer), 124.5, 120.3, 120.2 (Z isomer), 116.6 (Z isomer), 116.0, 115.2
(Z isomer), 113.5, 111.5 (Z isomer), 111.2, 54.8 (Z isomer), 54.7, 30.5,
30.4 (Z isomer). MS (relative intensity) m/z: 336 (40), 280 (100), 234
(23), 204 (22), 165 (15), 116 (26), 57 (40). HRMS calcd for
4.2.8. (E)-N-tert-Butyl-2-(2-(naphthalen-2-yl)vinyl)benzofuran-3-
amine (2h). Isolated as a yellow solid. Yield: 0.102 g (60%), mp:
113e116 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
7.84 (s, 1H), 7.81e7.68 (m,
4H), 7.53e7.35 (m, 5H), 7.27e7.14 (m, 3H), 2.60 (sl, 1H), 1.27 (s, 9H).
13C NMR (CDCl3, 100 MHz):
153.7, 149.3, 134.7, 133.7, 133.1, 129.2,
d
C20H21N2O3: 337.1552. Found: 337.1560.
128.3, 128.2, 128.0, 127.7, 126.8, 126.3, 126.0, 124.7, 123.3, 122.4,
119.7, 114.8, 111.0, 54.5, 30.6. MS (relative intensity) m/z: 341 (75),
285 (73), 256 (20), 166 (100), 120 (36), 57 (16). HRMS calcd for
4.2.13. (E)-N-tert-Butyl-2-(4-methoxystyryl)-5-methylbenzofuran-3-
amine (2m). Isolated as a yellow solid. Yield: 0.107 g (64%), mp:
C
24H24NO: 342.1858. Found: 342.1862.
137e139 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
7.44 (d, J¼8.7 Hz, 2H),
7.30e7.22 (m, 2H), 7.16 (d, J¼16.1 Hz,1H), 7.02 (d, J¼8.5 Hz,1H), 6.96
4.2.9. (E)-N-tert-Butyl-5-methyl-2-styrylbenzofuran-3-amine
(d, J¼16.1 Hz, 1H), 6.88 (d, J¼8.7 Hz, 2H), 3.79 (s, 3H), 2.42 (s, 4H),
(2i). Isolated as a yellow solid. Yield: 0.114 g (75%), mp: 89e111 ꢀC.
1.26 (s, 9H). 13C NMR (CDCl3, 100 MHz):
d 159.5, 152.0, 149.8, 131.7,
1H NMR (CDCl3, 400 MHz):
0.4H, Z isomer), 7.41e7.17 (m, 6.2H), 7.16e6.98 (m, 2H), 6.57 (d,
J¼12.6 Hz, 0.1H, Z isomer), 6.50 (d, J¼12.6 Hz, 0.1H, Z isomer),
2.61e2.24 (m, 4.6H), 1.26 (s, 9H), 1.19 (s, 1.7H, Z isomer). 13C NMR
d
7.51 (d, J¼7.0 Hz, 2H), 7.45 (d, J¼7.3 Hz,
130.2, 129.5, 127.7, 127.6, 125.6, 123.6, 119.3, 114.3, 112.9, 110.4, 55.3,
54.4, 30.6, 21.3. MS (relative intensity) m/z: 335 (93), 278 (100), 264
(40), 250 (24), 207 (11), 146 (9), 57 (17). HRMS calcd for
C22H25NNaO2: 358.1783. Found: 358.1790.
(CDCl3, 100 MHz): d 152.1, 151.8 (Z isomer), 149.4, 137.3, 131.8, 129.3,
128.9, 128.7, 128.5 (Z isomer), 128.3 (Z isomer), 128.0, 127.8, 127.6,
127.4, 126.5, 126.0, 125.9, 125.7 (Z isomer), 124.4 (Z isomer), 119.7 (Z
isomer), 119.4, 116.1 (Z isomer), 114.7, 110.7 (Z isomer), 110.5, 54.6 (Z
isomer), 54.5, 30.6, 30.4 (Z isomer), 21.4 (2C). MS (relative intensity)
m/z: 305 (68), 249 (100), 220 (17), 178 (10), 134 (35), 116 (18), 57
(16). HRMS calcd for C21H23NNaO: 328.1677. Found: 328.1681.
4.2.14. (E)-N-tert-Butyl-2-(4-chlorostyryl)-5-methylbenzofuran-3-
amine (2n). Isolated as a yellow solid. Yield: 0.130 g (77%). 1H NMR
(CDCl3, 400 MHz):
d 7.45e7.37 (m, 2.8H), 7.31e7.24 (m, 5.0H),
7.17e7.00 (m, 3.8H), 6.51 (d, J¼12.7 Hz, 0.3H, Z isomer), 6.47 (d,
J¼12.5 Hz, 0.3H, Z isomer), 4.70 (sl, 0.2H, Z isomer), 2.45e2.40 (m,
3.8H), 2.20 (sl, 1H), 1.25 (s, 9H), 1.21 (s, 2.7H, Z isomer). 13C NMR
(CDCl3, 100 MHz):
d 152.1, 151.8 (Z isomer), 149.1, 147.5 (Z isomer),
4.2.10. (E)-N-tert-Butyl-5-methoxy-2-styrylbenzofuran-3-amine
135.8, 135.7 (Z isomer), 133.1, 133.0 (Z isomer), 131.8 (2C), 130.4,
129.1, 128.8, 128.2, 128.0, 127.6, 127.4, 126.4, 126.2 (2C), 126.1, 124.8,
119.6 (Z isomer), 119.4, 116.2 (Z isomer), 115.2, 110.8 (Z isomer),
110.5, 54.7 (Z isomer), 54.5, 30.6, 30.5 (Z isomer), 21.3 (2C). MS
(relative intensity) m/z: 339 (47), 283 (100), 247 (29), 207 (12), 134
(60), 115 (19), 57 (33). HRMS calcd for C21H23ClNO: 340.1468.
Found: 340.1475.
(2j). Isolated as
a
yellow solid. Yield: 0.117
g (73%), mp:
115.3e118.7 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
7.51 (d, J¼7.6 Hz, 2H),
7.45 (d, J¼7.3 Hz, 0.5H, Z isomer), 7.39e7.18 (m, 5.3H), 7.15 (d,
J¼8.8 Hz, 0.2H, Z isomer), 7.09 (d, J¼16.1 Hz, 1H), 6.99e6.93 (m,
1.1H), 6.89e6.80 (m, 1H), 6.59 (d, J¼12.6 Hz, 0.1H, Z isomer), 6.49 (d,
J¼12.6 Hz, 0.1H, Z isomer), 3.83 (s, 3H), 3.81 (s, 0.7H, Z isomer), 2.50
(sl, 1H), 1.26 (s, 9H), 1.18 (s, 2.5H, Z isomer). 13C NMR (CDCl3,
100 MHz):
d
155.8, 155.7 (Z isomer), 150.2, 148.6, 148.5 (Z isomer),
4.2.15. (E)-5-Bromo-N-tert-butyl-2-(3-methoxystyryl)benzofuran-3-
148.4 (Z isomer), 137.3 (Z isomer), 137.2, 129.7, 129.5, 129.0, 128.9,
128.7, 128.1, 127.7, 127.5, 126.5, 125.9, 124.7, 116.1 (Z isomer), 114.6,
113.4 (Z isomer),113.1,111.6 (Z isomer),111.4,102.6 (Z isomer),102.5,
55.9 (2C), 54.8 (Z isomer), 54.6, 30.6, 30.4 (Z isomer). MS (relative
intensity) m/z: 321 (77), 265 (100), 221 (16), 167 (15), 150 (34), 116
(16), 57 (20). HRMS calcd for C21H23NNaO2: 344.1626. Found:
344.1630.
amine (2o). Isolated as a yellow solid. Yield: 0.124 g (62%), mp:
106e112 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
7.61 (d, J¼1.9 Hz, 0.1H, Z
isomer), 7.59 (d, J¼1.7 Hz, 1H), 7.31 (dd, J¼1.9 Hz, J¼8.6 Hz, 1H),
7.29e7.16 (m, 3H), 7.11 (d, J¼7.6 Hz, 1H), 7.08e6.97 (m, 2.1H), 6.81
(dd, J¼1.9 Hz, J¼8.3 Hz, 1H), 6.59 (d, J¼12.5 Hz, 0.1H, Z isomer), 6.47
(d, J¼12.5 Hz, 0.1H, Z isomer), 3.81 (s, 3H), 3.73 (s, 0.2H, Z isomer),
2.48 (sl, 1H), 1.23 (s, 9H), 1.16 (s, 0.6H, Z isomer). 13C NMR (CDCl3,
100 MHz):
d 159.9, 159.3 (Z isomer), 152.3, 150.4, 148.8 (Z isomer),
4.2.11. (E)-5-Bromo-N-tert-butyl-2-styrylbenzofuran-3-amine
138.3, 131.3, 130.4 (Z isomer), 129.7, 129.0 (Z isomer), 128.9, 127.4 (Z
isomer), 127.3, 125.2 (Z isomer), 123.8, 122.6 (Z isomer), 122.2, 121.6
(Z isomer), 119.3, 115.7 (Z isomer), 115.6, 115.5 (Z isomer), 114.4,
113.9 (Z isomer), 113.8 (Z isomer), 113.4, 112.6 (Z isomer), 112.4,
112.1, 55.1 (2C), 54.6 (Z isomer), 54.5, 30.5, 30.3 (Z isomer). MS
(relative intensity) m/z: 401 (48), 343 (64), 263 (14), 198 (13), 146
(100), 131 (32), 57 (27). HRMS calcd for C21H23BrNO2: 400.0912.
Found: 400.0913.
(2k). Isolated as
a
yellow solid. Yield: 0.137
g (74%), mp:
61.3e64.7 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
7.65e7.56 (m, 1.2H), 7.50
(d, J¼7.3 Hz, 2H), 7.45e7.16 (m, 6.6H), 7.07 (d, J¼16.1 Hz, 1H), 6.63
(d, J¼12.6 Hz, 0.1H, Z isomer), 6.48 (d, J¼12.6 Hz, 0.1H, Z isomer),
2.45 (sl, 1H), 1.24 (s, 9H), 1.16 (s, 2H, Z isomer). 13C NMR (CDCl3,
100 MHz): d 152.3, 152.0 (Z isomer), 150.6, 148.9 (Z isomer), 137.0 (Z
isomer), 136.9, 131.3, 130.6, 130.5 (Z isomer), 129.1, 128.9, 128.7,
128.1, 127.9, 127.7, 127.3, 126.6, 125.0 (Z isomer), 123.7, 122.6 (Z
isomer), 122.3, 115.6, 115.5 (Z isomer), 114.1, 112.7 (Z isomer), 112.4,
54.7 (Z isomer), 54.5, 30.5, 30.4 (Z isomer). MS (relative intensity)
m/z: 371 (51), 313 (100), 233 (29), 204 (30), 178 (13), 116 (44), 57
(45). HRMS calcd for C20H20BrNNaO: 392.0626. Found: 392.0630.
4.2.16. (E)-5-Bromo-N-tert-butyl-2-(4-chlorostyryl)benzofuran-3-
amine (2p). Isolated as a yellow solid. Yield: 0.171 g (85%), mp:
149e162 ꢀC. 1H NMR (CDCl3, 400 MHz):
d 7.63e7.54 (m, 1.2H),
7.44e7.19 (m, 7.2H), 7.14 (d, J¼16.1 Hz, 1H), 7.09 (d, J¼8.7 Hz, 0.2H, Z
isomer), 7.02 (d, J¼16.1 Hz, 1H), 6.53 (d, J¼12.6 Hz, 0.1H, Z isomer),
6.47 (d, J¼12.6 Hz, 0.1H, Z isomer), 2.48 (sl, 1H), 1.23 (s, 9H), 1.19 (s,
4.2.12. (E)-N-tert-Butyl-5-nitro-2-styrylbenzofuran-3-amine
(2l). Isolated as an orange solid. Yield: 0.067 g (40%), mp:
2.5H, Z isomer). 13C NMR (CDCl3, 100 MHz):
d 152.3, 152.0 (Z iso-
105e126 ꢀC. 1H NMR (CDCl3, 400 MHz):
d
8.44 (d, J¼2.4 Hz, 0.3H, Z
mer), 150.3, 148.7 (Z isomer), 135.5 (Z isomer), 135.4, 133.5, 133.3 (Z
isomer), 131.2, 130.3, 130.2 (Z isomer), 128.9, 128.7 (Z isomer), 128.0,
127.7, 127.6, 127.5, 125.6 (Z isomer), 124.1 (Z isomer), 122.5 (Z iso-
mer), 122.3, 115.7, 114.6, 112.7 (Z isomer), 112.4, 54.7 (Z isomer),
54.5, 30.5, 30.4 (Z isomer). MS (relative intensity) m/z: 405 (42), 349
isomer), 8.42 (d, J¼2.2 Hz,1H), 8.18 (dd, J¼8.8 Hz, J¼2.2 Hz,1H), 8.13
(dd, J¼8.8 Hz, J¼2.2 Hz, 0.3H, Z isomer), 7.54 (d, J¼7.3 Hz, 2H), 7.47
(d, J¼8.8 Hz, 1H), 7.43e7.27 (m, 6.1H), 7.10 (d, J¼16.4 Hz, 1H),6.74 (d,
J¼12.5 Hz, 0.3H, Z isomer), 6.52 (d, J¼12.5 Hz, 0.3H, Z isomer), 2.50

3756
R. Gai et al. / Tetrahedron 70 (2014) 3751e3756
4. (a) Xiea, Y.; Yua, M.; Zhang, Y. Synthesis 2011, 2803; (b) Liu, L.; Floreancig, P. E.
Angew. Chem., Int. Ed. 2010, 49, 3069; (c) Yoshikai, N.; Mieczkowski, A.; Mat-
sumoto, A.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2010, 132, 5568.
(100), 311 (11), 198 (23), 150 (11), 115 (16), 57 (38). HRMS calcd for
20H20BrClNO: 404.0417. Found: 404.0420.
C
5. (a) Ding, C.-H.; Hou, X.-L. Chem. Rev. 2011, 111, 1914; (b) Aridoss, G.; Sarca, V. D.;
Ponder, J. F., Jr.; Crowe, J.; Laal, K. K. Org. Biomol. Chem. 2011, 9, 2518.
4.2.17. N-tert-Butyl-2-vinylbenzofuran-3-amine (2q). Isolated as
brown oil. Yield: 0.09 g (84%). 1H NMR (CDCl3, 400 MHz):
7.49 (d,
6. (a) Grimaldi, T. B.; Back, D. F.; Zeni, G. J. Org. Chem. 2013, 78, 11017; (b) Palmes, J.
A.; Aponick, A. Synthesis 2012, 44, 3699; (c) Lee, S. I.; Chatani, N. Chem. Commun.
2009, 371; (d) Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132; (e)
Arcadi, A. Chem. Rev. 2008, 108, 3266; (f) Crone, B.; Kirsch, S. F. Chem.dEur. J.
2008, 14, 3514; (g) Duschek, A. A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2008, 47,
d
J¼7.6 Hz, 1H), 7.37 (d, J¼8.0 Hz, 1H), 7.23 (t, J¼7.3 Hz, 1H), 7.16 (t,
J¼7.6 Hz, 1H), 6.75 (dd, J¼17.3 Hz, J¼11.2 Hz, 1H), 5.87 (dd,
J¼17.4 Hz, J¼1.5 Hz, 1H), 5.29 (dd, J¼11.2 Hz, J¼1.5 Hz, 1H), 1.46 (sl,
€
5703; (h) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410; (i)
1H), 1.22 (s, 9H). 13C NMR (CDCl3, 100 MHz):
d 153.5, 148.7, 129.0,
Tsuge, O.; Ueno, K.; Oe, A. K. Chem. Lett. 1981, 135.
ꢀ
ꢀ~
124.6, 124.0, 123.2, 122.3, 119.9, 113.4, 111.1, 54.4, 30.5. MS (relative
intensity) m/z: 215 (29), 200 (5), 159 (100), 130 (57), 115 (4), 103 (8),
57 (8). HRMS calcd for C14H17NNaO: 238.1208. Found: 238.1212.
7. Jimenez-Nunez, E.; Raducan, M.; Lauterbach, T.; Molawi, K.; Solorio, C. R.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2009, 48, 6152.
8. Pearson, A. J.; Dubbert, R. A. Organometallics 1994, 13, 1656.
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10. Nagase, Y.; Shirai, H.; Kaneko, M.; Shirakawa, E.; Tsuchimoto, T. Org. Biomol.
Chem. 2013, 11, 1456.
Acknowledgements
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The financial support by Universidade Federal de Santa Maria,
~
Coordenac¸ ao de Aperfeic¸ oamento de Pessoal de Nível Superior,
FAPERGS (PRONEX research grant # 10/0005-1), and Conselho
ꢀ
Nacional de Desenvolvimento Científico e Tecnologico (INCT-cat-
alise) is gratefully acknowledged. We thank CNPq for fellowships.
Supplementary data
Experimental procedures, characterization data, and copies of
the 1H NMR and 13C NMR spectra for the products. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2014.04.053.
15. Bera, K.; Sarkar, S.; Biswas, S.; Maiti, S.; Jana, U. J. Org. Chem. 2011, 76, 3539.
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H. Tetrahedron 2008, 64, 10924.
17. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication (CCDC 943274 and 946591). Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk).
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References and notes
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€
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