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Synthesis of 2 4 6-trisubstituted naphthalenes via novel copper-promoted tandem coupling and intramolecular cyclization.

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Full Paper
Received: 3 May 2009
Revised: 15 June 2009
Accepted: 21 June 2009
Published online in Wiley Interscience: 24 July 2009
(www.interscience.com) DOI 10.1002/aoc.1531
Synthesis of 2,4,6-trisubstituted naphthalenes
via novel copper-promoted tandem coupling
and intramolecular cyclization
Yuguang Wanga , Bingchun Zhua,b∗ and Qin Zhua
An unprecedented copper-promoted tandem coupling and intramolecular cyclization reaction is disclosed. This strategy offers a
simple and promising method for accessing 2,4,6-trisubstituted naphthalenes. A reaction mechanism involving initial formation
c 2009 John Wiley &
of diynes followed by a 6-exo-dig cyclization and subsequent rearrangement is proposed. Copyright Sons, Ltd.
Keywords: intramalecular cyclization; coupling; tandem reaction; copper catalyst; naphthalenes
Introduction
Experimental
General Methods
398
New methods that produce complex, useful compounds from
simpler materials in a single reaction vessel are important
challenges in modern synthetic chemistry. Tandem catalysis,[1 – 3]
which utilizes a single catalyst to mediate more than one
transformation in a selective manner within the same medium
to produce a desired product, is becoming increasingly important
for the economic and environmental acceptability. Thus, there
have been many examples,[4 – 8] indicating that transition metalcatalyzed tandem reactions enhance the reactivity and economical
efficiency of the synthesis of complex organic molecules. The
homocoupling of terminal acetylenes is a classic method which
has been extensively investigated and is still widely used in modern
organic synthesis.[9 – 16] The intramolecular cyclization is also the
most powerful carbon–carbon forming reaction in synthetic
organic chemistry. Noble metal compounds such as Pd, Pt, Au and
Ru complex are the most frequently used catalysts in this type of
reactions.[17 – 23] Little attention has been paid to copper-catalyzed
cyclization reactions even though the inexpensive copper salts
are efficient catalysts in various transformations. To the best
of our knowledge, no examples of copper-promoted tandem
homocoupling and intramolecular cyclization process have been
reported.
On the other hand, the naphthalene ring system plays an
important role in both natural product[24 – 26] and medicinal
chemistry research.[27,28] As a result, new synthetic methods[29] for
the preparation of naphthalene are an active area of research. We
report here a very simple and efficient method for the synthesis
of 2,4,6-trisubstituted naphthalenes. By using copper catalyst,
terminal alkynes undergo a tandem coupling and intramolecular
cyclization to afford 2,4,6-trisubstituted naphthalenes in good
yields. This is an important strategy for the synthesis of natural
products consists of applying transition metal-catalyzed or mediated reactions to obtain multi-substituted compounds that
can be further functionalized.
Appl. Organometal. Chem. 2009 , 23, 398–402
Substituted alkynes were synthesized according to the
literatures.[30,31] Other starting materials were obtained from commercial suppliers. Unless otherwise noted, the reagents were
purchased from Shanghai Chemical Reagent Company and used
without further purification. 1 H NMR (400 MHz) and 13 C NMR
(100 MHz) spectra were recorded on a Bruker Avance spectrometer using CDCl3 as the solvent and TMS as the internal standard;
chemical shifts were quoted in ppm and J values were given in Hz.
Mass spectra (EI, 70 eV) were recorded on a HP5989B mass spectrometer. Elemental analyses were performed on a Flash EA1112
instrument. Infrared spectra in KBr were recorded on a Shimadzu
IR-408 spectrometer. Melting points are uncorrected.
General Synthetic Procedure
All experiments were operated according to the following general
procedure: a mixture of terminal alkyne (2 mmol), CuBr2 (2.2 mmol)
and TMEDA (2 mmol) in CH3 CN (10 ml) was stirred in air at 50 ◦ C
for 10 h. After completion of the reaction, as indicated by TLC, the
reaction mixture was concentrated in vaccuo and the residue was
purified by column chromatography (hexane–EtOAc mixtures)
to give the corresponding product. The analytical data to these
products are shown below.
∗
Correspondence to: Bingchun Zhu, Zhejiang Research Institute of Chemical
Industry, Hangzhou, Zhejiang, 310023, People’s Republic of China.
E-mail: zhumelta@gmail.com
a Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, People’s
Republic of China
b Zhejiang Research Institute of Chemical Industry, Hangzhou, Zhejiang, 310023,
People’s Republic of China
c 2009 John Wiley & Sons, Ltd.
Copyright Copper-promoted tandem coupling and intramolecular cyclization
4-(5-Ethoxycarbonyl-6-phenyl-hex-5-en-2-ynyl)-naphthalene-2carboxylic acid ethyl ester (2a)
Yield: 84%. Oil (found: C 78.66, H 6.43%; calcd for C28H26 O4 : C 78.85,
H 6.14%); 1 H NMR (CD3 Cl) δ 8.52 (s, 1H), 8.18 (s, 1H), 8.10–8.08
(d, J = 8.0 Hz, 1H), 7.97–7.95 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H),
7.63–7.59 (m, 1H), 7.56–7.50 (m, 3H), 7.34–7.31 (m, 3H), 4.45–4.40
(q, J = 7.2 Hz, 2H), 4.32–4.26 (q, J = 7.2 Hz, 2H), 4.00 (s, 2H),
3.42 (s, 2H), 1.44–1.41 (t, J = 7.2 Hz, 3H), 1.33–1.29 (t, J = 7.2 Hz,
3H); 13 C NMR (CD3 Cl) δ 167.1, 166.5 (carbonyl C), 139.9 (vinyl C),
134.9, 133.6, 133.5, 132.8, 130.3, 130.0, 129.5, 128.7, 128.4, 128.3,
128.2 (aryl C), 127.3 (vinyl C), 126.3, 124.8, 123.6 (aryl C), 80.8, 77.6
(alkynyl C), 61.0, 60.9 (OCH2 ), 23.3, 18.1 (CH2 ), 14.3, 14.1 (CH3 ). MS
m/z 426 (M+ ). IR νmax (cm−1 ) 3059, 2980, 2933, 1713, 1630, 1602,
1447, 1397, 1290, 1271, 1242, 1202, 1166, 1145, 1103, 1024, 940,
908, 779, 700, 593.
(t, J = 7.2 Hz, 3H); 13 C NMR (CD3 Cl) δ 168.0, 167.1 (carbonyl C),
150.6, 149.9 (aryl C), 140.7 (vinyl C), 135.4, 131.8, 131.7, 131.0, 130.2
(aryl C), 125.5 (vinyl C), 125.3, 123.1, 122.7, 122.6, 115.6, 111.6,
101.9 (aryl C), 80.8, 77.4 (alkynyl C), 60.6, 60.5 (OCH2 ), 40.2, 40.0
(N(CH3 )2 ), 23.8, 18.2 (CH2 ), 14.4, 14.3 (CH3 ); MS m/z 512 (M+ ); IR
νmax (cm−1 ) 3747, 3359, 2924, 1702, 1600, 1520, 1443, 1361, 1236,
1195, 1103, 1028, 947, 811, 765, 529.
EtOOC
COOEt
Catalyst,TMEDA
CH3CN
EtOOC
2a
1a
Scheme 1. Copper-promoted tandem coupling and intramolecular cyclization.
4-(5-Ethoxycarbonyl-6-p-tolyl-hex-5-en-2-ynyl)-6-methylnaphthalene-2-carboxylic acid ethyl ester (2b)
Yield: 85%. Oil (found: C 79.05, H 6.92%; calcd for C30H30 O4 : C 79.27,
H 6.65%). 1 H NMR (CD3 Cl) δ 8.48 (s, 1H), 8.16–8.15 (d, 1H), 7.88–7.85
(m, 2H), 7.74 (s, 1H), 7.43–7.41 (d, J = 8.0 Hz, 2H), 7.38–7.36 (m,
1H), 7.12–7.10 (d, J = 8.0 Hz, 2H), 4.45–4.40 (q, J = 7.2 Hz, 2H),
4.31–4.25 (q, J = 7.2 Hz, 2H), 3.98 (s, 2H), 3.43–3.42 (m, 2H), 2.51
(s, 3H), 2.35 (s, 3H), 1.44–1.41 (t, J = 7.2 Hz, 3H), 1.32–1.29 (t,
J = 7.2 Hz, 3H); 13 C NMR (CD3 Cl) δ 167.5, 166.8 (carbonyl C), 140.1
(vinyl C), 139.0, 138.6, 133.8, 133.0, 132.1, 131.1, 130.2, 129.9, 129.8,
129.2, 128.62 (aryl C), 127.5 (vinyl C), 126.5, 125.1, 123.02 (aryl C),
80.9, 77.7 (alkynyl C), 61.1, 61.0 (OCH2 ), 23.4 (CH2 ), 22.3, 21.4 (CH3 ),
18.3 (CH2 ), 14.4, 14.3 (CH3 ); MS m/z 454 (M+ ); IR νmax (cm−1 ) 3401,
2983, 2924, 1710, 1630, 1609, 1581, 1510, 1444, 1366, 1246, 1200,
1103, 1024, 950, 912, 845, 810, 757, 666, 504.
4-[5-Ethoxycarbonyl-6-(4-methoxy-phenyl)-hex-5-en-2-ynyl]-6methoxy-naphthalene-2-carboxylic acid ethyl ester (2c)
Yield: 87%. Oil (found: C 73.85, H 6.33%; calcd for C30 H30 O6 : C
74.06, H 6.21%). 1 H NMR (CD3 Cl) δ 8.43 (s, 1H), 8.114–8.112 (d, 1H),
7.85–7.83 (d, J = 9.0 Hz,1H), 7.68 (s, 1H), 7.46–7.44 (d, J = 8.8 Hz,
2H), 7.32–7.31 (d, 1H), 7.18–7.16 (d, J = 9.0 Hz, 1H), 6.79–6.77
(d, J = 8.8 Hz, 2H), 4.43–4.38 (q, J = 7.2 Hz, 2H), 4.29–4.23 (q,
J = 7.2 Hz, 2H), 3.92 (s, 2H), 3.87 (s, 3H), 3.78 (s, 3H), 3.42 (s, 2H),
1.43–1.40 (t, J = 7.2 Hz, 3H), 1.31–1.28 (t, J = 7.2 Hz, 3H); 13 C NMR
(CD3 Cl) δ 167.5, 166.7 (carbonyl C), 160.1, 159.52 (aryl C), 139.8
(vinyl C), 135.2, 132.3, 131.6, 131.5, 130.1, 128.12 (aryl C), 127.3
(vinyl C), 126.0, 125.7, 125.0, 119.0, 113.9, 102.52 (aryl C), 80.8, 77.5
(alkynyl C), 60.9, 60.8 (OCH2 ), 55.2, 55.1 (OCH3 ), 23.7, 18.1 (CH2 ),
14.4, 14.2 (CH3 ); MS m/z 486 (M+ ); IR νmax (cm−1 ) 3526, 2980, 2837,
1708, 1626, 1605, 1573, 1511, 1474, 1441, 1366, 1258, 1237, 1202,
1177, 1103, 1082, 1027, 950, 921, 827, 770, 555.
6-Dimethylamino-4-[6-(4-dimethylamino-phenyl)-5-ethoxycarbonyl-hex-5-en-2-ynyl]-naphthalene-2-carboxylic acid ethyl ester
(2d)
Appl. Organometal. Chem. 2009, 23, 398–402
Yield: 73%. Oil (found: C 68.05, H 4.76%; calcd for C28 H24 Cl2 O4 :
C 67.89, H 4.88%). 1 H NMR (CD3 Cl) δ 8.43 (s, 1H), 8.11 (s, 1H),
8.006–8.003 (d, 1H), 7.86–7.84 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H),
7.45–7.42 (d, J = 8.8 Hz, 1H), 7.37–7.35 (d, J = 8.4 Hz, 2H),
7.23–7.21 (d, J = 8.4 Hz, 2H), 4.41–4.36 (q, J = 7.2 Hz, 2H),
4.27–4.22 (q, J = 7.2 Hz, 2H), 3.89 (s, 2H), 3.33 (s, 2H), 1.40–1.36 (t,
J = 7.2 Hz, 3H), 1.28–1.25 (t, J = 7.2 Hz, 3H); 13 C NMR (CD3 Cl) δ
166.9, 166.2 (carbonyl C), 138.7 (vinyl C), 134.8, 134.5, 134.2, 133.3,
133.0, 131.5, 131.1, 130.8, 130.4, 130.1, 128.7, 128.62 (aryl C), 127.4
(vinyl C), 126.0, 122.92 (aryl C), 80.8, 77.4 (alkynyl C), 61.19, 61.17
(OCH2 ), 23.3, 18.1 (CH2 ), 14.3, 14.2 (CH3 ); MS m/z 494 (M+ ); IR νmax
(cm−1 ) 3444, 2980, 1715, 1627, 1590, 1491, 1448, 1420, 1403, 1372,
1305, 1283, 1266, 1241, 1217, 1190, 1087, 1029, 921, 766, 502.
2,9-Bis-(4-fluoro-benzylidene)-deca-4,6-diynedioic acid diethyl ester
(3f)
Yield: 79%. White solid, m.p.:109–111 ◦ C (found: C 72.66, H 5.32%;
calcd for C28 H24 F2 O4 : C 72.72, H 5.23%). 1 H NMR (CD3 Cl) δ 7.73
Table 1. Catalyst screening for the tandem coupling and intramolecular cyclization reactiona
Entry
Catalyst
Temperature
1
2
3
4
5
6
7
8
9
10
11
CuBr2
Cu(OAc)2
CuCl
CuCl
CuCl2
PdCl2
RhCl3
RuCl3
ZnCl2
AlCl3
FeCl3
50 ◦ C
50 ◦ C
50 ◦ C
50 ◦ C
50 ◦ C
50 ◦ C
50 ◦ C
70 ◦ C
70 ◦ C
70 ◦ C
70 ◦ C
Time
10
10
10
10
10
10
10
10
15
15
15
h
h
h
h
h
h
h
h
h
h
h
Yield (%)b
84
83
82
26c
76
57
60
0
0
0
0
a
Substituted alkyne 1a (2.0 mmol), TMEDA (2.0 mmol), CH3 CN (10 ml),
catalyst (2.2 mmol).
Isolated yields.
c Reaction was performed under a nitrogen atmosphere.
b
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
399
Yield: 78%. Oil (found: C 74.82, H 7.36, N 5.24%; calcd for
C32 H36 N2 O4 : C 74.97, H 7.08, N 5.46%). 1 H NMR (CD3 Cl) δ 8.37
(s, 1H), 8.06 (s, 1H), 7.81–7.79 (d, J = 9.2 Hz, 1H), 7.67 (s, 1H),
7.47–7.45 (d, J = 8.8 Hz, 2H), 7.14–7.11 (d, J = 9.2 Hz, 1H),
6.992–6.986 (d, 1H), 6.55–6.53 (d, J = 7.2 Hz, 2H), 4.41–4.36 (q,
J = 7.2 Hz, 2H), 4.28–4.23 (q, J = 7.2 Hz, 2H), 3.90 (s, 2H), 3.45 (s,
2H), 3.03 (s, 6H), 2.97 (s, 6H), 1.43–1.39 (t, J = 7.2 Hz, 3H), 1.32–1.29
6-Chloro-4-[6-(4-chloro-phenyl)-5-ethoxycarbonyl-hex-5-en-2-ynyl]naphthalene-2-carboxylic acid ethyl ester (2e)
Y. Wang, B. Zhu and Q. Zhu
Table 2. Tandem coupling and intramolecular cyclization of alkynesa
EtOOC
COOEt
R=
R1
R1=H, CH3, OCH3, Cl, N(CH3)2
R1
2
EtOOC
R1
R
EtOOC
1
R
R
R= p-FC6H4, o-CH3C6H4,
o-OCH3C6H4, m-CH3C6H4, naphthyl
COOEt
3
Entry
1
2
3
4
5
6
7
8
9
10
11
a
b
R
Substrate
Product
Yield (%)b
C6 H5
p-CH3 C6 H4
p-CH3 OC6 H4
p-N(CH3 )2 C6 H4
p-ClC6 H4
p-FC6 H4
o-CH3 C6 H4
o-CH3 OC6 H4
m-CH3 C6 H4
Naphthyl
p-NO2 C6 H4
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
2a
2b
2c
2d
2e
3f
3g
3h
3i
3j
No Reaction
84
85
87
78
73
79
78
80
81
75
–
Terminal alkyne (2.0 mmol), TMEDA (2.0 mmol), CH3 CN (10 ml), CuBr2 (2.2 mmol), at 50 ◦ C for 10 h.
Isolated yields from the average of two runs.
(s, 2H), 7.49–7.46 (m, 4H), 7.15–7.10 (m, 4H), 4.34–4.29 (q,
J = 7.2 Hz, 4H), 3.43 (s, 4H), 1.38–1.35 (t, J = 7.2 Hz, 6H); 13 C
NMR (CD3 Cl) δ 166.7 (carbonyl C), 163.0(J = 248.8 Hz, aryl C), 139.7
(vinyl C), 131.5 (J = 8.2 Hz, aryl C), 130.8 (J = 3.0 Hz, aryl C), 126.6
(vinyl C), 115.8 (J = 21.3 Hz, aryl C), 74.6, 65.8 (alkynyl C), 61.3
(OCH2 ), 18.5 (CH2 ), 14.2 (CH3 ); MS m/z 462(M+ ); IR νmax (cm−1 )
3446, 3059, 2983, 2956, 1697, 1638, 1600, 1509, 1461, 1420, 1372,
1313, 1294, 1265, 1228, 1198, 1164, 1102, 1084, 1016, 918, 844,
792, 754, 585, 534, 515.
2,9-Bis-(2-methyl-benzylidene)-deca-4,6-diynedioic acid diethyl ester
(3g)
◦
Yield: 78%. White solid, m.p.:97–99 C (found: C 79.48, H 6.51%;
calcd for C30 H30 O4 : C 79.27, H 6.65%). 1 H NMR (CD3 Cl) δ 7.84 (s,
2H), 7.39–7.36 (m, 2H), 7.27–7.19 (m, 6H), 4.36–4.30 (q, J = 7.2 Hz,
4H), 3.31 (s, 4H), 2.28 (s, 6H), 1.39–1.36 (t, J = 7.2 Hz, 6H); 13 C NMR
(CD3 Cl) δ 166.6 (carbonyl C), 140.0 (aryl C), 136.9 (vinyl C), 134.0,
130.1, 128.8, 128.6 (aryl C), 127.6 (vinyl C), 125.9 (aryl C), 74.9, 65.6
(alkynyl C), 61.1 (OCH2 ), 19.8 (CH3 ), 18.6 (CH2 ), 14.2 (CH3 ); MS m/z
454 (M+ ); IR νmax (cm−1 ) 3441, 2977, 2920, 1709, 1636, 1460, 1447,
1404, 1392, 1370, 1290, 1272, 1242, 1211, 1108, 1026, 928, 856,
794, 737, 675, 515.
2,9-Bis-(2-methoxy-benzylidene)-deca-4,6-diynedioic acid diethyl ester (3h)
400
Yield: 80%. White solid, m.p.:103–105 ◦ C (found: C 73.98, H 6.30%;
calcd for C30 H30 O6 : C 74.06, H 6.21%). 1 H NMR (CD3 Cl) δ 7.92
www.interscience.wiley.com/journal/aoc
(s, 2H), 7.49–7.47 (d, 2H), 7.35 (t, 2H), 7.02 (t, 2H), 6.91–6.89 (d, 2H),
4.34–4.28 (q, J = 7.2 Hz, 4H), 3.84 (s, 6H), 3.38 (s, 4H), 1.38–1.35 (t,
J = 7.2 Hz, 6H); 13 C NMR (CD3 Cl) δ 166.8 (carbonyl C), 157.6 (aryl
C), 136.8 (vinyl C), 130.7, 130.1 (aryl C), 126.8 (vinyl C), 123.8, 120.6,
110.5 (aryl C), 75.2, 65.7 (alkynyl C), 61.1 (OCH2 ), 55.4 (OCH3 ), 19.0
(CH2 ), 14.3 (CH3 ); MS m/z 486 (M+ ); IR νmax (cm−1 ) 3440, 2985,
2907, 2836, 1703, 1633, 1599, 1487, 1464, 1436, 1373, 1294, 1271,
1247, 1216, 1023, 943, 920, 785, 755, 598, 563, 503.
2,9-Bis-(3-methyl-benzylidene)-deca-4,6-diynedioic acid diethyl ester
(3i)
Yield: 81%. White solid, m.p.: 75–76 ◦ C (found: C 79.09, H 6.77%;
calcd for C30 H30 O4 : C 79.27, H 6.65%). 1 H NMR (CD3 Cl) δ 7.76 (s,
2H), 7.33–7.28 (m, 6H), 7.20–7.18 (m, 2H), 4.35–4.29 (q, J = 7.2 Hz,
4H), 3.45 (s, 4H), 2.39 (s, 6H), 1.39–1.36 (t, J = 7.2 Hz, 6H); 13 C NMR
(CD3 Cl) δ 166.9 (carbonyl C), 141.0 (aryl C), 138.3 (vinyl C), 134.7,
130.3, 129.9, 128.6 (aryl C), 126.7 (vinyl C), 126.5 (aryl C), 74.9, 65.7
(alkynyl C), 61.2 (OCH2 ), 21.4 (CH3 ), 18.7 (CH2 ), 14.3 (CH3 ); MS m/z
454(M+ ); IR νmax (cm−1 ) 3446, 2976, 2918, 1708, 1638, 1466, 1449,
1408, 1392, 1370, 1290, 1274, 1242, 1211, 1088, 1026, 926, 871,
790, 739, 703, 686, 590.
2,9-Bis-naphthalen-1-ylmethylene-deca-4,6-diynedioic acid diethyl
ester (3j)
Yield: 75%. Low melting point solid (found: C 82.00, H 5.90%; calcd
for C36 H30 O4 : C 82.11, H 5.74%). 1 H NMR (CD3 Cl) δ 8.31 (s, 2H),
7.89–7.81 (m, 6H), 7.59–7.57 (m, 2H), 7.50–7.20 (m, 6H), 4.40–4.34
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2009, 23, 398–402
Copper-promoted tandem coupling and intramolecular cyclization
CuBr2 EtOOC
CuBr2
2 EtOOC
R
EtOOC
a
b
R
3
1
R
EtOOC
EtOOC
BrCu
a
BrCu
+
EtOOC
R
- H+
+
EtOOC
R
R
4
R
5
EtOOC
EtOOC
H
BrCu
+H
+
- BrCu+
EtOOC
R
EtOOC
R
R
6
R
7
EtOOC
- BrEtOOC
R
2
6-exo
R
EtOOC
EtOOC
CuBr
b
R
EtOOC
+
EtOOC
R
R
R
8
9
7-endo
R=H, CH3, OCH3, Cl, N(CH3)2
Scheme 2. Proposed reaction mechanism.
(q, J = 7.2 Hz, 4H), 3.35 (s, 4H), 1.42–1.38 (t, J = 7.2 Hz, 6H); 13 C
NMR (CD3 Cl) δ 166.4 (carbonyl C), 139.1 (vinyl C), 133.3, 131.8,
131.3, 129.3, 128.9, 128.5 (aryl C), 126.7 (vinyl C), 126.5, 126.2,
125.3, 124.3 (aryl C), 75.0, 65.7 (alkynyl C), 61.2 (OCH2 ), 19.0 (CH2 ),
14.2 (CH3 ); MS m/z 526(M+ ); IR νmax (cm−1 ) 3436, 3053, 2980, 1709,
1634, 1506, 1449, 1408, 1368, 1340, 1280, 1254, 1206, 1090, 1018,
930, 864, 782, 602.
Results and Discussion
Appl. Organometal. Chem. 2009, 23, 398–402
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
401
We previously reported the CuAl-LDH (Layered double hydroxide)
catalyzed homocoupling of terminal alkynes.[32] In line with this, we
synthesized phenyl substituted alkyne 1a as substrate to enlarge
the substrate scope. Then 1a was subjected to homocoupling upon
the treatment with CuAl-LDH and TMEDA (N,N,N ,N -tetramethyl
ethylenediamine) in CH3 CN at room temperature. Surprisingly,
the obtained compound was not the expected diyne, instead,
complex 2,4-disubstituted naphthalene 2a was afforded in 83%
yield (Scheme 1). This compound would result from a one pot
coupling and intramolecular cyclization reaction.
In order to find whether other catalysts were effective on this
tandem coupling and intramolecular cyclization reaction, we then
examined the reaction of 1a with a series of metal reagents. The
results are described in Table 1. CuBr2 , Cu(OAc)2 and CuCl exhibited
the best activity leading to 2a in high isolated yield (entries 1–3,
Table 1). A lower reaction rate was observed when CuCl2 was
used as the catalyst (entry 5, Table 1). However, a poor result
was afforded when the reaction was performed under a nitrogen
atmosphere with CuCl as the catalyst (entry 4, Table 1). This result
indicates that the reaction is dependent on the presence of oxygen
and Cu(II) is effective catalyst.[33] Among the tested noble metal
catalysts, PdCl2 and RhCl3 led to the formation of 2a in moderate
yield (entries 6–7, Table 1), while RuCl3 was completely ineffective
even on increasing the reaction temperature (entry 8, Table 1). The
strong Lewis acids AlCl3 , FeCl3 and the mild Lewis acid ZnCl2 were
also ineffective in promoting the reaction even after a prolonged
reaction time or at elevated temperature (entries 9–11, Table 1).
To study the influence of the aromatic ring substitution, we
prepared several phenyl substituted terminal alkynes. These
substrates were then submitted to our previously optimized
conditions using CuBr2 as catalyst. The results are summarized
in Table 2.
As shown in Table 2, we found that different substituted groups
on the aryl moiety exerted different activities on the reaction. That
is, the intramolecular cyclization reaction was mainly influenced by
electron effect. Reaction of alkynes with electron-donating groups
Y. Wang, B. Zhu and Q. Zhu
on the para positions of aryl moiety afforded the corresponding
2,4,6-trisubstituted naphthalenes in good yields (entries 2–4,
Table 2). It is because of the activation of these electron-donating
groups on the benzene ring. However, for the alkynes with
halogen substituent in the para positions of benzene ring, the
corresponding products were obtained according to the different
halogen. Chloride substituent substrate provided cyclized product
(entry 5, Table 2) due to the p–π conjugative effect. However, the
p-fluoro substituent substrate 1f resulted in the coupled product
3f, instead of cyclized product. It might not be able to accomplish
further cyclization due to the strong electron-withdrawing effect
of fluorin (entry 6, Table 2). Moreover, alkynes with methyl and
methoxy groups attached at ortho or meta positions of benzene
rings also afforded coupled diynes as the only isolated product
in good yield (entries 7–9, Table 2). As a result of the steric
factor, reaction of naphthayl substituted alkyne compound 1j
led to the exclusive formation of diyne 3j (entry 10, Table 2).
Incorporation of a strong electron-withdrawing group on the aryl
nucleus completely suppressed the reaction, even the coupling
reaction did not take place at all (entry 11, Table 2).
The proposed reaction mechanism is shown in Scheme 2. It is
particularly noteworthy that substrates 1 usually give 2 by a 6-exodig pathway, instead of 9, the product of a 7-endo-dig cyclization.
The mechanism of Scheme 2 shows intermediates representative
based on a tandem coupling and intramolecular cyclization
reactions.[34] The reaction should proceed via homocoupling to
afford diyne intermediate 3, and then the alkenyl carbenium
ion 4 is formed by copper(II) activation of the triple bond. It is
then followed by an intramolecular attack of the arene to the
alkenyl carbenium ion to furnish intermediate 5. Whereafter, the
intermediate 6 is formed by the elimination of H+ , and BrCu+ is
replaced by H+ to furnish intermediate 7, which then rearranges
to the more stable product 2 (path a, Scheme 2). No trace of the
7- endo mode product (seven-membered ring product) such as 9
was detected (path b, Scheme 2).
Conclusions
In conclusion, we have developed a novel and efficient methodology for the synthesis of 2,4,6-trisubstituted naphthalenes. It is
the first time that the copper-promoted tandem coupling and
intramolecular cyclization reaction of substituted alkynes was
realized. Because of the advantages of simple operation, easily
available catalyst and good to high yields, this reaction will show
its utility in organic synthesis.
Acknowledgment
We are grateful for the financial support of the Education Office
Foundation of Zhejiang Province (project no. Y200803795) and the
Zhejiang Province Natural Science Foundation of China (project
no. Y2080303).
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synthesis, promote, intramolecular, naphthalene, couplings, cyclization, novem, tandem, coppel, trisubstituted, via
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