Benzofuran and indole synthesis via Cu(i)-catalyzed coupling of N-tosylhydrazone and o-hydroxy or o-amino phenylacetylene

Article abstract of DOI:10.1039/c2ob26867a

A general and practical method to synthesize 2-substituted benzofurans and indoles is described. This method employs easily accessible N-tosylhydrazones and o-hydroxy or o-amino phenylacetylenes as substrates. The reaction proceeds through a CuBr-catalyzed coupling-allenylation-cyclization sequence under ligand-free conditions.

Full text of DOI:10.1039/c2ob26867a

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Benzofuran and indole synthesis via Cu(I)-catalyzed
coupling of N-tosylhydrazone and o-hydroxy or
o-amino phenylacetylene†
Cite this: DOI: 10.1039/c2ob26867a
Tiebo Xiao,a Xichang Donga and Lei Zhou*a,b
Received 22nd September 2012,
Accepted 30th October 2012
A general and practical method to synthesize 2-substituted benzofurans and indoles is described. This
method employs easily accessible N-tosylhydrazones and o-hydroxy or o-amino phenylacetylenes as sub-
strates. The reaction proceeds through a CuBr-catalyzed coupling–allenylation–cyclization sequence
under ligand-free conditions.
DOI: 10.1039/c2ob26867a
www.rsc.org/obc
1. Introduction
Benzofurans and indoles are important structural motifs of a
wide range of natural substances, compounds of pharma-
ceutical interest and commodity chemicals.1,2 We have pre-
viously communicated a new method for the synthesis of
benzofurans by a ligand-free CuBr-catalyzed sequential coup-
ling–allenylation–cyclization of salicyl N-tosylhydrazones and
terminal alkynes.3 In this reaction, a di-substituted allene
intermediate is formed via the migratory insertion of a copper
carbene species,4,5 which smoothly undergoes copper-cata-
lyzed intramolecular cyclization to afford 2-substituted benzo-
furans and indoles (Scheme 1, path a).6
Scheme 1 CuBr-catalyzed 2-substituted benzofurans and indoles synthesis.
However, the substituents on the benzofurans generated
from the salicyl N-tosylhydrazones and terminal alkynes are
limited to primary benzyl or alkyl groups at the 2-position,
which significantly restricts the application of this method in
organic synthesis. We note that similar di-substituted or tri-
substituted allene intermediates could be formed from
o-hydroxy or o-amino phenylacetylene with various N-tosylhy-
drazones (Scheme 1, path b). In this paper, we report the exten-
sion of our study along this line, which in combination
2. Results and discussion
In our preliminary communication, salicyl N-tosylhydrazones,
which are easily available from the corresponding aldehydes,
are reacted with a series of terminal alkynes with CuBr as the
catalyst in the presence of Cs2CO3 as the base (eqn (1)). A wide
range of functional groups are found to tolerate the reaction
conditions and 2-substituted benzofurans and indoles can be
obtained in good yields. In view of the advantages of this
transformation over the previous methods for benzofuran and
indole synthesis, we decided to further expand this reaction by
employing o-hydroxy or o-amino phenylacetylene and various
N-tosylhydrazones as substrates.
with the previous communication constitutes
a general
and synthetically useful procedure for the synthesis of benzo-
furans and indoles under copper-catalyzed ligand-free
conditions.7,8
ð1Þ
aSchool of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135
Xingang West Road, Guangzhou 510275, China. E-mail: zhoul39@mail.sysu.edu.cn;
Tel: +86 20 84110217
The initial studies have been carried out using phenyl
N-tosylhydrazone 1a and o-hydroxy phenylacetylene 2a as the
substrates in the presence of CuBr (10 mol%) and Cs2CO3 (3
equiv.) in MeCN at 100 °C (Scheme 2). This is the optimized
bBeijing National Laboratory of Molecular Sciences (BNLMS), College of Chemistry,
Peking University, Beijing 100871, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c2ob26867a
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Moreover, cyclic N-tosylhydrazone 4h, which is derived from
4-chromanone, also undergoes smooth reaction with 2a to
afford the corresponding benzofuran 5h in 76% yield (Table 2,
entry 8). This catalytic system has also been applied to the
reaction of 2a with N-tosylhydrazones derived from aliphatic
ketones 4j and 4k. To our delight, the corresponding products
5j and 5k could be obtained in 73% and 62% yields using
DMSO as the solvent at 120 °C (Table 2, entries 10 and 11).
Finally, we checked the possibility of assembling 2-substituted
indoles using our process. When Ac protected 2-aminophenyl-
acetylene 2b was reacted with N-tosylhydrazone 4a, a depro-
tected indole 5l was obtained in a yield of 71% (Table 2, entry
12). In another case, treatment of Ts protected 2-aminophenyl-
acetylene 2c with N-tosylhydrazone 4c yielded protected indole
5m in 85% (Table 2, entry 13).
Scheme 2 Fine-tuning of the reaction conditions.
reaction conditions for our previous synthesis of benzofurans.
Under such conditions, the desired product 3a was obtained
in 57% yield. Further fine-tuning of the reaction conditions
has revealed that tBuOLi is more effective than other inorganic
t
bases, such as K2CO3, NaOAc and BuOK. In contrast to the
previous observations on the CuBr-catalyzed coupling of salicyl
N-tosylhydrazones and terminal alkynes, the non-polar solvent
toluene was found to be favourable at 80 °C. Under the new
reaction conditions, the isolated yield of 3a could be improved
to 89%.
As shown in Scheme 1, the key step in this Cu-catalyzed
transformation has been proposed as the migratory insertion
of Cu carbene species, followed by protonation to afford the
allene intermediate. However, transition metal-catalyzed cycli-
zation of 2-ynlphenol or 2-ynlaniline to give benzofuran or
indole is a well-established process.10 Therefore, an alternative
mechanism, which involves Cu-catalyzed cyclization followed
by a direct Cu carbene insertion into the C–H bond of hetero-
cycles, cannot be strictly eliminated.11
To gain insight into the mechanism of this reaction, two
control experiments have been performed as shown in eqn (2)
and (3). First, 2a was heated under standard condition for 20 h
in the absence of N-tosylhydrazone. No benzofuran could be
observed and 90% of 2a was recovered (eqn (2)). Next, benzo-
furan and N-tosylhydrazone 1a were treated under standard
conditions for 4 h. This experiment resulted in a complex
mixture, and only a trace amount of the desired product 3a
could be detected by GC-MS (eqn (3)). These results indicate
that the pathway involving cyclization–Cu carbene insertion
seems less likely for the CuBr-catalyzed reaction described in
this paper.
The optimized conditions were then applied to a series of
N-tosylhydrazones 1a–i derived from aldehydes with different
electronic properties (Table 1). In all cases, the expected benzo-
furans were isolated in good to excellent yields. The N-tosylhy-
drazones bearing ortho-, para-, and meta-substituents on the
phenyl ring all worked well in this reaction. The electronic
properties of the substituents do not affect the efficacy of the
reaction (Table 1, entries 1–8). It is noteworthy that alkyl N-
tosylhydrazone 1i is also effective, affording the desired benzo-
furan 3i in 78% (Table 1, entry 9). In this case, the reaction
was carried out at 120 °C by using DMSO as the solvent
because of the sluggish reaction under the standard con-
ditions. The reaction proceeded equally well with Ts protected
2-aminophenylacetylene, which gave indole 3j in a yield of
78% (Table 1, entry 10). In another case, when Ac protected
2-aminophenylacetylene 2b was employed as the substrate, a
deprotected indole 3k was isolated in 81% yield (Table 1, entry 11).
Next, we proceeded to extend this methodology to the con-
struction of secondary alkyl substituted benzofurans and
indoles, which are more challenging compounds to synthesize
via transition metal-catalyzed cross-coupling reactions.9 Our
initial studies using o-hydroxy phenylacetylene 2a and N-tosyl-
hydrazone 4a have shown that the same catalytic system
employed in Table 1 only affords the desired benzofuran 5a in
51% yield (Table 2, entry 1). A slight modification of the reac-
tion conditions revealed MeCN was a better solvent than
toluene, in which the desired product 5a was generated in a
yield of 79%. This reaction also proceeded smoothly with
other substituted N-tosylhydrazones 4b, 4c and 4d. The reac-
tion is not affected by the substituents on the phenyl ring of
N-tosylhydrazones (Table 2, entries 2 and 4), while a slightly
diminished yield was observed when an electron-donating
group OMe was introduced (Table 2, entry 3). N-Tosylhydra-
zones derived from butyrophenone, cyclopropyl phenyl ketone
and 1,2-diphenylethanone are effective, affording the desired
benzofurans 5e–g in good yields (Table 2, entries 5–7).
ð2Þ
ð3Þ
The mechanism for this reaction is proposed in
Scheme 3.12 First, in situ generated diazo compound B from
N-tosylhydrazone is dediazonized by copper acetylide A,
leading to the formation of the copper carbene species C.
Migratory insertion of the carbenic carbon to the alkynyl
group affords intermediate D. The allene E is then formed by
protonation of intermediate D, followed by the copper pro-
moted intramolecular cyclization to give intermediate G.
Finally, protonation of intermediate G gives the benzofuran or
indole product and regenerated Cu(I) catalyst.
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Table 1 CuBr-catalyzed reactions of o-hydroxy or o-amino phenylacetylene 2 with N-tosylhydrazones derived from aldehydesa
Entry
1
Hydrazone
Alkyne
Product
Yieldb (%)
89
2a
2
2a
84
3
4
2a
2a
92
77
5
2a
95
6
7
2a
2a
87
81
8
2a
88
9c
2a
2c
78
78
10
11
2b
81
t
a Reaction conditions: N-tosylhydrazone 1 (0.33 mmol), alkyne 2 (0.3 mmol), CuBr (10 mol%), BuOLi (0.9 mmol), toluene (2 mL), 80 °C, 8 h.
b Isolated yield. c The reaction was carried out by using DMSO as the solvent at 120 °C for 12 h.
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Table 2 CuBr-catalyzed reactions of 2a–c with N-tosylhydrazones derived from ketonesa
Entry
1
Hydrazone
Alkyne
Product
Yieldb (%)
79(51c)
2a
2
2a
2a
82
3
62
4
2a
85
5
6
2a
2a
74
77
7
8
2a
2a
82
76
9
2a
2a
88
73
10d
11d
12
2a
2b
62
71
13
2c
85
t
a Reaction conditions: N-tosylhydrazone 4 (0.33 mmol), alkyne 2 (0.3 mmol), CuBr (10 mol%), BuOLi (0.9 mmol), MeCN (2 mL), 80 °C, 8 h.
b Isolated yield. c Toluene was used as the solvent. d The reaction was carried out by using DMSO as the solvent at 120 °C for 12 h.
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6H), 7.40–7.49 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 21.5, 35.0,
103.5, 111.5, 120.6, 122.7, 123.5, 128.9, 129.0, 129.5, 134.3,
136.5, 155.1, 158.3. MS (70 eV): m/z (%): 222 (100) [M]+, 207
(68), 178 (26), 131 (27).
2-(2-METHYLBENZYL)BENZOFURAN (3C). IR (film) 743.6, 1174.0,
1252.6, 1374.5, 1454.0, 1511.1, 2853.3, 2925.6 cm−1 1H NMR
;
(300 MHz, CDCl3) δ 2.38 (s, 3H), 4.12 (s, 2H), 6.26 (s, 1H),
7.21–7.30 (m, 6H), 7.42–7.50 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 19.8, 33.1, 103.5, 111.1, 120.5, 122.5, 123.5, 126.7,
127.3, 129.0, 130.0, 130.6, 135.6, 136.8, 155.0, 157.7; EI-MS
(m/z, relative intensity): 222 (M+, 100), 207 (35), 178 (35), 131
(37), 107 (85); HRMS (ESI) calcd for C16H15O (M + H+)
223.1117, found: 223.1109.
2-(3,4-DIMETHOXYBENZYL)BENZOFURAN (3D). IR (film) 669.4, 746.3,
1
806.0, 1029.3, 1141.2, 1256.3, 1454.3, 1514.1, 2924.5 cm−1; H
NMR (300 MHz, CDCl3) δ 3.88 (s, 6H), 4.07 (s, 2H), 6.38 (s,
1H), 6.84 (m, 3H), 7.20–7.26 (m, 2H), 7.41–7.49 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 35.0, 56.2, 103.4, 111.1, 111.5, 112.4,
120.6, 121.2, 122.7, 123.6, 129.0, 129.9, 148.0, 149.2, 155.1,
158.2; EI-MS (m/z, relative intensity): 268 (M+, 100), 253 (24),
237 (68), 221 (27), 181 (10), 165 (12), 149 (11), 131 (13); HRMS
(ESI) calcd for C17H17O3 (M + H+) 269.1173, found: 267.1175.
2-(4-CHLOROBENZYL)BENZOFURAN (3E). IR (film) 749.6, 797.4,
1016.1, 1091.9, 1225.4, 1454.1, 1491.4, 1513.8, 2924.4 cm−1; 1H
NMR (300 MHz, CDCl3) δ 4.09 (s, 2H), 6.39 (s, 1H), 7.20–7.36
(m, 5H), 7.40–7.50 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 34.7,
103.8, 111.2, 120.7, 122.8, 123.8, 128.9, 130.1, 130.4, 132.8,
135.9, 155.1, 157.2; EI-MS (m/z, relative intensity): 242 (M+,
100) (Cl35), 244 (M+, 34) (Cl37) 207 (48), 178 (58), 131 (46), 103
(12), 89 (37); HRMS (EI) calcd for C15H11ClO (M+) 242.0493,
found: 242.0491.
Scheme 3 Mechanistic studies.
3. Conclusions
In conclusion, we have further developed the method for the
synthesis of 2-substituted benzofurans and indoles via the
CuBr-catalyzed coupling–allenylation–cyclization of ortho-
hydroxy or amino phenylacetylene with N-tosylhydrazones. A
variety of secondary alkyl substituted benzofurans, which are
unable to access by our previously reported copper-catalyzed
coupling from salicyl N-tosylhydrazones and terminal alkyne,
can be obtained in good to excellent yields.
2-(3-CHLOROBENZYL)BENZOFURAN (3F). IR (film) 749.8, 799.1,
1015.9, 1091.9, 1254.5, 1454.0, 1593.0, 2924.5 cm−1 1H NMR
;
(300 MHz, CDCl3) δ 4.10 (s, 2H), 6.43 (s, 1H), 7.20–7.31 (m,
5H), 7.39–7.51 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 35.0,
104.0, 111.2, 1120.0, 120.7, 128.9, 129.2, 130.0, 134.6, 139.4,
155.2, 156.8; EI-MS (m/z, relative intensity): 242 (M+, 100)
(Cl35), 244 (M+, 31) (Cl37), 207 (36), 178 (48), 152 (8), 131 (62),
4. Experimental section
General procedure for the CuBr-catalyzed synthesis of
2-substituted benzofurans and indoles
t
CuBr (4.2 mg, 10 mol%), BuOLi (0.9 mmol, 72 mg) and N- 103 (9), 89 (24); HRMS (EI) calcd for C15H11ClO (M+) 242.0493,
tosylhydrazone (0.33 mmol) were suspended in toluene (2 mL) found: 242.0492.
in a 10 mL Schlenk tube under nitrogen. Then, 2-ethynylphe-
2-(2,6-DICHLOROBENZYL)BENZOFURAN (3G). IR (film) 748.3, 763.4,
nol (0.3 mmol) was added. The solution was stirred at 80 °C 953.4, 1089.4, 1167.8, 1254.4, 1436.6, 1563.0, 2925.4 cm−1; H
for 8 h. After cooling to room temperature, the resulting NMR (300 MHz, CDCl3) δ 4.47 (s, 2H), 6.26 (s, 1H), 7.14–7.24
mixture was filtered through a short path of silica gel, eluting (m, 3H), 7.34–7.45 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 31.0,
with hexane and CH2Cl2. The volatile compounds were 103.5, 111.2, 120.6, 122.7, 123.7, 128.5, 128.9, 133.5, 136.3,
removed in vacuo and the crude residue was purified by 154.9; EI-MS (m/z, relative intensity): 276 (M+, 100) (Cl35, Cl35),
1
column chromatography (SiO2, hexane).
278 (M+, 62) (Cl35, Cl37), 280 (M+, 12) (Cl37, Cl37), 279 (16), 280
The following known compounds were characterized by (12), 241 (25), 205 (12), 178 (17), 151 (8), 131 (29), 102 (4);
1
comparing their H NMR and 13C NMR to the reported values: HRMS (ESI) calcd for C20H17O2 (M + H+) 289.1223, found:
3a,3 3b,3 3i,3 3k,3 5a,13 5b,14 5c,15 5i,3 5j,16 5l.17
289.1217. HRMS (ESI) calcd for C15H11Cl2O (M + H+) 277.0182,
2-BENZYLBENZOFURAN (3A). 1H NMR (300 MHz, CDCl3) δ 4.12 (s, found: 277.0187.
2H), 6.38 (s, 1H), 7.18–7.34 (m, 7H), 7.38–7.48 (m, 2H); 13C
4-(BENZOFURAN-2-YLMETHYL)BENZONITRILE (3H). IR (film) 749.9,
NMR (75 MHz, CDCl3) δ 35.4, 103.6, 111.2, 120.6, 122.7, 123.7, 811.8, 951.4, 1095.2, 1253.2, 1454.0, 1607.0, 2228.8 cm−1 1H
;
127.0, 128.7, 128.9, 129.1, 137.4, 155.1, 158.0.
NMR (300 MHz, CDCl3) δ 4.17 (s, 2H), 6.46 (s, 1H), 7.19–7.27
2-(4-METHYLBENZYL)BENZOFURAN (3B). 1H NMR (300 MHz, (m, 2H), 7.31–7.43 (m, 3H), 7.48–7.52 (m, 1H), 7.57–7.62 (m,
CDCl3) δ 2.37 (s, 3H), 4.09 (s, 2H), 6.38 (s, 1H), 7.06–7.26 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 35.4, 104.4, 111.2, 111.9,
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119.8, 120.9, 123.0, 124.1, 129.6, 129.8, 132.6, 142.9, 155.2, CDCl3) δ 0.97 (t, J = 6.9 Hz, 3H), 1.93–2.05 (m, 1H), 2.17–2.28
155.8; EI-MS (m/z, relative intensity): 233 (M+, 100), 204 (27), (m, 1H), 4.08 (t, J = 7.2 Hz 1H), 6.46 (s, 1H), 7.18–7.31 (m, 7H),
176 (9), 149 (34), 131 (73), 116 (5), 102 (9); HRMS (ESI) calcd 7.39–7.50 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 14.3, 21.2, 37.0,
for C16H12NO (M + H+) 234.0916, found: 234.0913.
102.5, 111.2, 120.6, 122.6, 122.6, 123.5, 126.9, 128.2, 128.7,
2-(3-PHENYLPROPYL)BENZOFURAN (3I). 1H NMR (300 MHz, CDCl3) 128.9, 142.3, 154.9, 161.5; EI-MS (m/z, relative intensity): 250
δ 2.10–2.16 (m, 2H), 2.73–2.85 (m, 4H), 6.41 (s, 1H), 7.21–7.31 (M+, 27), 207 (100), 178 (37), 152 (5); HRMS (EI) calcd for
(m, 7H), 7.42–7.51 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 28.3, C18H18O [M]+ 250.1352, found: 250.1355.
29.7, 35.6, 102.4, 110.9, 120.4, 122.6, 123.3, 126.1, 128.6, 128.7,
129.1, 141.9, 154.8, 159.2.
2-(CYCLOPROPYL(PHENYL)METHYL)BENZOFURAN (5F). IR (film) 698.4,
740.9, 798.0, 1019.9, 1169.5, 1254.9, 1453.9, 2924.4 cm−1 1H
;
2-BENZYL-1-TOSYL-1H-INDOLE (3J). IR (film) 675.3, 748.3, 811.6, NMR (300 MHz, CDCl3) δ 0.40–0.48 (m, 2H), 0.67–0.70 (m, 1H),
1091.1, 1174.9, 1255.9, 1371.2, 1453.4, 2924.0 cm−1 1H NMR 0.75–0.78 (m, 1H), 1.47–1.53 (m, 1H), 3.43 (d, J = 9.3 Hz, 1H),
;
(300 MHz, CDCl3) δ 2.34 (s, 3H), 4.36 (s, 2H), 6.1 (s, 1H), 6.65 (s, 1H), 7.20–7.23 (m, 2H), 7.27–7.35 (m, 5H), 7.39–7.42
7.12–7.15 (m, 2H), 7.18–7.30 (m, 6H), 7.34–7.38 (m, 2H), (m, 1H), 7.53–7.56 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 5.0,
7.51–7.55 (m, 2H), 8.14–8.16 (d, J = 8.4 Hz, 1H); 13C NMR 5.7, 16.1, 50.5, 103.2, 111.3, 120.7, 122.7, 123.6, 127.1, 128.2,
(75 MHz, CDCl3) δ 21.9, 35.6, 111.1, 114.9, 120.5, 123.7, 124.2, 128.7, 128.9, 141.9, 155.1, 161.1; EI-MS (m/z, relative intensity):
126.6, 126.8, 128.7, 128.9, 129.6, 129.9, 136.3, 137.4, 138.2, 248 (M+, 68), 220 (100), 207 (40), 191(19), 178 (52), 152 (13),
141.2, 144.8; EI-MS (m/z, relative intensity): 361 (M+, 86), 205 144 (92), 115 (15); HRMS (ESI) calcd for C18H17O (M+H+)
(100), 178 (11), 91 (17); HRMS (ESI) calcd for C22H20NO2S 249.1274, found: 249.1277.
(M + H+) 362.1209, found: 362.1218.
2-(1,2-DIPHENYLETHYL)BENZOFURAN (5G). IR (film) 297.6, 749.3,
2-BENZYL-1H-INDOLE (3K). 1H NMR (300 MHz, CDCl3) δ 4.15 (s, 802.5, 1255.1, 1453.7, 1494.7, 2924.0 cm−1; 1H NMR (300 MHz,
2H), 6.34 (s, 1H), 7.07–7.16 (m, 2H), 7.24–7.37 (m, 6H), CDCl3) δ 3.29–3.36 (m, 1H), 3.62–3.69 (m, 1H), 4.43 (t, J =
7.55–7.58 (m, 1H), 7.78 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 7.5 Hz, 1H), 6.51 (s, 1H), 7.10–7.13 (m, 2H), 7.19–7.33 (m,
35.1, 101.3, 110.7, 119.9, 120.2, 126.9, 128.9, 129.0, 136.5, 10H), 7.47–7.54 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 41.4,
138.0, 138.7.
48.2, 103.4, 111.3, 120.8, 122.8, 123.7, 126.5, 126.8, 127.1,
2-(1-PHENYLETHYL)BENZOFURAN (5A). 1H NMR (300 MHz, CDCl3) 128.4, 128.5, 128.7, 129.3, 139.6, 141.5, 154.9, 160.3; EI-MS
δ 1.72 (d, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 1H), 6.44 (s, 1H), (m/z, relative intensity): 298 (M+, 5), 207 (100), 178 (33), 152 (6),
7.17–7.40 (m, 8H), 7.47–7.51 (m, 1H); 13C NMR (75 MHz, 105 (8); HRMS (ESI) calcd for C22H19O (M + H+) 299.1431,
CDCl3) δ 20.8, 40.1, 102.4, 111.3, 120.7, 122.7, 123.7, 126.9, found: 299.1433.
127.7, 128.8, 129.8, 143.5, 155.0, 162.3; MS (70 eV): m/z (%):
4-(BENZOFURAN-2-YL)CHROMAN (5H). IR (film) 698.7, 750.6, 801.7,
1017.5, 1256.5, 1453.5, 2853.9, 2927.8 cm−1 1H NMR
222 (39) [M]+, 207 (100), 194 (17), 165 (18), 118 (9).
;
2-(1-P-TOLYLETHYL)BENZOFURAN (5B). 1H NMR (300 MHz, CDCl3) (300 MHz, CDCl3) δ 2.31–2.49 (m, 2H), 4.16–4.31 (m, 2H), 4.37
δ 1.70 (d, J = 7.2 Hz, 3H), 4.23 (q, J = 7.2 Hz, 1H), 6.44 (s, 1H), (t, J = 5.1 Hz, 1H), 6.30 (s, 1H), 6.88–6.94 (m, 2H), 7.15–7.29
7.13–7.20 (m, 6H), 7.38–7.50 (m, 2H); 13C NMR (75 MHz, (m, 4H), 7.44–7.50 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 27.6,
CDCl3) δ 20.8, 21.5, 39.6, 102.2, 111.2, 120.6, 122.6, 123.6, 35.2, 63.6, 105.2, 111.3, 117.47, 120.9, 121.2, 122.9, 123.9,
127.6, 128.9, 129.5, 136.5, 140.5, 154.9, 162.5. MS (70 eV): m/z 124.6, 128.7, 128.8, 130.8, 155.1, 160.9; EI-MS (m/z, relative
(%): 236 (33) [M]+, 221 (100), 205 (4), 178 (23), 115 (9).
(5C). 1H
intensity): 250 (M+, 100), 235 (9), 221 (45), 165 (11), 131 (15);
2-(1-(4-METHOXYPHENYL)ETHYL)BENZOFURAN
NMR HRMS (ESI) calcd for C17H15O2 (M + H+) 251.1067, found:
(300 MHz, CDCl3) δ 1.70 (d, J = 7.2 Hz, 3H), 3.81 (s, 3H), 251.1065.
4.19–4.24 (m, 1H), 6.42 (s, 1H), 6.86–6.89 (m, 2H), 7.16–7.23
2-BENZHYDRYLBENZOFURAN (5I). 1H NMR (300 MHz, CDCl3) δ
(m, 4H), 7.38–7.50 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 20.8, 5.62 (s, 1H), 6.30 (s, 1H), 7.18–7.37 (m, 12H), 7.42–7.50 (m,
39.2, 55.6, 102.1, 111.2, 114.8, 120.6, 122.6, 123.6, 128.6, 128.9, 2H); 13C NMR (75 MHz, CDCl3) δ 51.7, 105.9, 111.4, 120.9,
135.6, 154.9, 158.5, 162.6; MS (70 eV): m/z (%): 252 (27) [M]+, 122.8, 123.9, 127.2, 128.7, 128.8, 129.1, 141.2, 155.3, 160.0; MS
237 (100), 222 (7), 194 (18), 165 (18), 118 (9).
2-(1-(3,4-DICHLOROPHENYL)ETHYL)BENZOFURAN
(70 eV): m/z (%): 284 (45) [M]+, 207 (100), 178 (33).
(5D). IR
(film)
2-CYCLOHEXYLBENZOFURAN (5J). 1H NMR (300 MHz, CDCl3) δ
726.3, 747.6, 804.1, 1030.6, 1091.8, 1256.4, 1453.4, 1467.0, 1.29–1.59 (m, 4H), 1.76–1.89 (m, 4H), 2.14–1.17 (m, 1H), 6.36
1
2924.3 cm−1; H NMR (300 MHz, CDCl3) δ 1.70 (d, J = 6.9 Hz, (s, 1H), 7.16–7.29 (m, 2H), 7.38–7.52 (m, 2H); 13C NMR
3H), 4.23 (q, J = 6.9 Hz, 1H), 6.49 (s, 1H), 7.11–7.14 (m, 1H), (75 MHz, CDCl3) δ 26.3, 26.5, 31.7, 37.9, 100.0, 110.9, 120.5,
7.19–7.29 (m, 2H), 7.38–7.42 (m, 3H), 7.52–7.55 (m, 1H); 13C 122.5, 123.2, 129.1, 154.5, 164.2; MS (70 eV): m/z (%): 200 (58)
NMR (75 MHz, CDCl3) δ 20.5, 30.1, 102.8, 111.3, 120.9, 122.9, [M]+, 185 (5), 171 (13), 157 (100), 144 (33), 131 (35), 115 (14).
124.0, 127.2, 128.6, 129.7, 130.7, 131.0, 132.8, 143.7, 155.0,
2-(PENTAN-3-YL)BENZOFURAN (5K). IR (film) 740.7, 749.9, 797.4,
160.7; EI-MS (m/z, relative intensity): 290 (M+, 36) (Cl35), 293 1008.3, 1251.4, 1454.5, 2853.9, 2927.8 cm−1
;
1H NMR
(M+, 98) [M]+(Cl37), 292 (20), 277 (55), 275 (100), 205 (12), 176 (300 MHz, CDCl3) δ 0.91 (t, J = 6.6 Hz, 6H), 1.73–1.78 (m, 4H),
+
(11), 145 (10); HRMS (EI) calcd for C16H12Cl2O (M ) 290.0260, 2.65 (t, J = 6.1 Hz, 1H), 6.39 (s, 1H), 7.18–7.26 (m, 2H),
found: 290.0259.
7.41–7.48 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 12.2, 26.8, 43.2,
2-(1-PHENYLBUTYL)BENZOFURAN (5E). IR (film) 745.0, 750.2, 102.5, 111.0, 120.6, 122.5, 123.1, 129.1, 154.7, 162.2; EI-MS
771.0, 1253.8, 1454.3, 2929.8, 2937.8 cm−1; 1H NMR (300 MHz, (m/z, relative intensity): 188 (M+, 24), 159 (100), 144 (12), 131
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(43), 115 (12), 91 (7); HRMS (EI) calcd for C13H16O [M]+
188.1196, found: 188.1192.
4 For recent examples on the migratory insertion of copper
carbene, see: (a) Q. Xiao, Y. Xia, H. Li, Y. Zhang and
J. Wang, Angew. Chem., Int. Ed., 2011, 50, 1114; (b) X. Zhao,
G. Wu, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2011, 133,
3296; (c) F. Ye, Y. Shi, L. Zhou, Q. Xiao, Y. Zhang and
J. Wang, Org. Lett., 2011, 13, 5020; (d) F. Ye, X. Ma, Q. Xiao,
H. Li, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2012, 134,
5742.
2-(1-PHENYLETHYL)-1H-INDOLE (5L). 1H NMR (300 MHz, CDCl3)
δ 1.75 (d, J = 6.6 Hz, 3H), 4.26 (q, J = 6.9 Hz, 1H), 6.45 (s, 1H),
7.11–7.37 (m, 8H), 7.35–7.70 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 21.7, 39.6, 99.8, 110.7, 119.9, 120.3, 121.6, 127.0,
127.8, 128.7, 128.9, 136.4, 143.2, 144.8; MS (70 eV): m/z (%):
221 (58) [M]+, 206 (100), 179 (15), 144 (10), 102 (13).
2-(1-(4-METHOXYPHENYL)ETHYL)-1-TOSYL-1H-INDOLE (5M). IR (film)
671.3, 749.3, 809.3, 1034.0, 1090.9, 1173.1, 1245.8, 1369.9,
5 For reviews on the migratory insertion of palladium
carbene, see: (a) Y. Zhang and J. Wang, Eur. J. Org. Chem.,
2011, 1015; (b) J. Barluenga and C. Valdés, Angew. Chem.,
Int. Ed., 2011, 50, 7486; (c) Z. Shao and H. Zhang, Chem.
Soc. Rev., 2012, 41, 560.
1
1510.8, 2924.3 cm−1; H NMR (75 MHz, CDCl3) δ 1.68 (d, J =
6.9 Hz, 3H), 2.30 (s, 3H), 3.79 (s, 3H), 4.98 (q, J = 7.2 Hz, 8H),
6.55–6.79 (m, 2H), 7.02–7.11 (m, 4H), 7.23–7.36 (m, 4H),
7.45–7.48 (m, 1H), 8.17 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 21.9, 24.2, 30.1, 55.6, 109.5, 113.9, 115.4, 120.6, 123.7,
124.3, 026.5, 128.9, 129.7, 129.9, 136.3, 136.9, 137.6, 144.4,
146.7, 158.3; EI-MS (m/z, relative intensity): 405 (M+, 50),
390 (17), 271 (39), 249 (73), 234 (100), 149 (60); HRMS (ESI)
calcd for C24H24NO3S (M + H+) 406.1471, found: 406.1474.
6 For the examples of ring-closing reaction of allenes, see:
(a) C. Mukai, H. Yamashita and S. Kitagaki, Org. Lett.,
2001, 3, 3385; (b) C. Mukai, M. Ohta, H. Yamashita and
S. Kitagaki, J. Org. Chem., 2004, 69, 6867; (c) H. Ohno,
H. Hamaguchi, M. Ohata, S. Kosaka and T. Tanaka, J. Am.
Chem. Soc., 2004, 126, 8744; (d) X. Yu, S.-Y. Seo and
T. J. Marks, J. Am. Chem. Soc., 2007, 129, 7244;
(e) S. Kitagaki, T. Kawamura, D. Shibata and C. Mukai,
Tetrahedron, 2008, 64, 11086; (f) S. Inuki, Y. Yoshimitsu,
S. Oishi, N. Fujii and H. Ohno, Org. Lett., 2009, 11,
4478; (g) R. W. Bates and M. R. Dewey, Org. Lett., 2009,
11, 3706; (h) R. W. Bates and Y. Lu, Org. Lett., 2010, 12,
3938.
Acknowledgements
Financial support from NSFC (Grand no. J1103305), the Sun
Yat-Sen University and the Beijing National Laboratory of Mo-
lecular Sciences (BNLMS) is gratefully acknowledged. The
author Lei Zhou thanks his postdoctoral supervisor Prof.
Jianbo Wang of Peking University for proofreading the
manuscript.
7 For a recent review on Cu-catalyzed synthesis of indoles
and benzofurans, see: S. Cacchi, G. Fabrizi and
A. Goggiamani, Org. Biomol. Chem., 2011, 9, 641.
8 For selected examples of copper-catalyzed synthesis of ben-
zofurans and indoles, see: (a) K. Okuro, M. Furuune,
M. Enna, M. Miura and M. Nomura, J. Org. Chem., 1993,
58, 4716; (b) C. G. Bates, P. Saejueng, J. M. Murphy and
D. Venkataraman, Org. Lett., 2002, 4, 4727; (c) P. Saejueng,
C. G. Bates and D. Venkataraman, Synthesis, 2005, 1706;
(d) J. H. Li, J. L. Li, D. P. Wang, S. F. Pi, Y. X. Xie,
M. B. Zhang and X. C. Hu, J. Org. Chem., 2007, 72, 2053;
(e) F. Liu and D. Ma, J. Org. Chem., 2007, 72, 4844;
(f) M. Wu, J. Mao, J. Guo and S. Ji, Eur. J. Org. Chem., 2008,
4050; (g) E. A. Jaseer, D. J. C. Prasad and G. Sekar, Tetra-
hedron, 2010, 66, 2077.
9 For recent examples of the synthesis of secondary alkyl sub-
stituted benzofurans and indoles, see: (a) L. Y. Chan,
S. Kim, W. T. Chung, C. Long and S. Kim, Synlett, 2011,
415; (b) Y. Nakao, N. Kashihara, K. S. Kanyiva and
T. Hiyama, Angew. Chem., Int. Ed., 2010, 49, 4451;
(c) G. A. Molander, O. A. Argintaru, I. Aron and
S. D. Dreher, Org. Lett., 2010, 12, 5783; (d) M. Bera and
S. Roy, J. Org. Chem., 2010, 75, 4402.
Notes and references
1 For selected reviews on benzofurans and indoles, see:
(a) B. A. Keay and P. W. Dibble, in Comprehensive Hetero-
cyclic Chemistry II, ed. A. R. Katritzky, C. W. Rees and
E. F. V. Scriven, Pergamon Press, Oxford, UK, 1996, vol. 2,
p. 395; (b) G. W. Gribble, in Comprehensive Heterocyclic
Chemistry II, ed. A. R. Katritzky, C. W. Rees and E. F. V.
Scriven, Pergamon Press, Oxford, UK, 1996, vol. 2, p. 207;
(c) X.-L. Hou, Z. Yang and H. N. C. Wong, Furans and ben-
zofurans, in Progress in Heterocyclic Chemistry, ed.
G. W. Gribble and T. L. Gilchrist, Pergamon, Oxford,
England, 2002, vol. 14, pp. 139–179; (d) T. Kawasaki and
K. Higuchi, Nat. Prod. Rep., 2007, 24, 843.
2 For selected reviews on the synthesis of benzofurans and
indoles, see: (a) D. A. Horton, G. T. Bourne and
M. L. Smythe, Chem. Rev., 2003, 103, 893; (b) F. Alonso,
I. P. Beletskaya and M. Yus, Chem. Rev., 2004, 104, 3079;
(c) R. E. Ziegert, J. Torang, K. Knepper and S. Brase, 10 For recent examples, see: (a) R. N. Nair, P. J. Lee,
J. Comb. Chem., 2005, 7, 147; (d) S. Cacchi and G. Fabrizi,
Chem. Rev., 2005, 105, 2873; (e) G. Zeni and R. C. Larock,
Chem. Rev., 2006, 106, 4644; (f) N. T. Patil and
Y. Yamamoto, Chem. Rev., 2008, 108, 3395.
3 L. Zhou, Y. Shi, Q. Xiao, Y. Liu, F. Ye, Y. Zhang and J. Wang,
Org. Lett., 2011, 13, 968.
A. L. Rheingold and D. B. Grotjahn, Chem.–Eur. J., 2010, 16,
7992; (b) A. Varela-Fernandez, J. A. Varela and C. Saa, Adv.
Synth. Catal., 2011, 353, 1933; (c) X. Li, J.-Y. Wang, W. Yu
and L.-M. Wu, Tetrahedron, 2009, 65, 1140; (d) H. Sakai,
K. Tsutsumi, T. Morimoto and K. Kakiuchi, Adv. Synth.
Catal., 2008, 350, 2498.
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Organic & Biomolecular Chemistry
11 For
a
review on Cu carbene C–H insertion, see:
(d) A. Suarez and G. C. Fu, Angew. Chem., Int. Ed., 2004,
43, 3580.
(a) M. M. Díaz-Requejo and P. Pérez, Chem. Rev., 2008,
108, 3379. For an example, see:
(b) J. M. Fraile, 13 L. Y. Chan, S. Kim, W. T. Chung, C. Long and S. Kim,
J. I. García, J. A. Mayoral and M. Roldán, Org. Lett., 2007,
9, 731.
Synlett, 2011, 415.
14 D.-H. Lee, K.-H. Kwon and C. S. Yi, Science, 2011, 333,
12 For the Cu-catalyzed reactions of terminal alkynes with
1613.
diazo
N. Jayaprakash and G. Balakishan, Org. Biomol. Chem., 16 R. Cano, M. Yus and D. J. Ramon, Tetrahedron, 2012, 68,
2011, 9, 7913; (b) M. Hassink, X. Liu and J. M. Fox, 1393.
Org. Lett., 2011, 13, 2388; (c) L. Zhou, J. Ma, Y. Zhang 17 P. Shukla, M. K. Choudhary and S. K. Nayak, Synlett, 2011,
compounds
see:
(a)
G.
Kumaraswamy, 15 J. Le Bras and J. Muzart, Tetrahedron, 2007, 63, 7942.
and J. Wang, Tetrahedron Lett., 2011, 52, 5484;
1585.
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