Copper(II) triflate-catalyzed and tosyl isocyanate-mediated three-step tandem synthesis of 9-arylfluorenes

Article abstract of DOI:10.1016/j.molcata.2016.06.015

A Cu(OTf)₂-catalyzed and TsNCO-mediated three-step tandem synthesis of 9-arylfluorenes were developed from biphenyls and aryl aldehydes, by which the electron-poor 9-aryl substituted fluorenes were synthesized smoothly. Its success is mainly at

Full text of DOI:10.1016/j.molcata.2016.06.015

Accepted Manuscript
Title: Copper(II) Triflate-Catalyzed and Tosyl
Isocyanate-Mediated Three-Step Tandem Synthesis of
9-Arylfluorenes
Author: Dayun Huang Xuesong Wang Xingyong Wang
Jianlan Zhang Xinyan Wang Yuefei Hu
PII:
S1381-1169(16)30228-X
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.06.015
MOLCAA 9921
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
6-5-2016
8-6-2016
17-6-2016
Please cite this article as: Dayun Huang, Xuesong Wang, Xingyong Wang, Jianlan
Zhang, Xinyan Wang, Yuefei Hu, Copper(II) Triflate-Catalyzed and Tosyl Isocyanate-
Mediated Three-Step Tandem Synthesis of 9-Arylfluorenes, Journal of Molecular
Catalysis A: Chemical http://dx.doi.org/10.1016/j.molcata.2016.06.015
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Copper(II) Triflate-Catalyzed and Tosyl Isocyanate-Mediated
Three-Step Tandem Synthesis of 9-Arylfluorenes
Dayun Huang, Xuesong Wang, Xingyong Wang, Jianlan Zhang, Xinyan Wang*
wangxinyan@mail.tsinghua.edu.cn, Yuefei Hu* yfh@mail.tsinghua.edu.cn
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China.
*Corresponding author. Tel.: +86-10-62795380; fax: +86-10-62771149.

Graphic Abstract

Abstract
A Cu(OTf)2-catalyzed and TsNCO-mediated three-step tandem synthesis of
9-arylfluorenes was developed from biphenyls and aryl aldehydes, by which the
electron-poor 9-aryl substituted fluorenes were synthesized smoothly. Its success is
mainly attributed to use an anhydrous synthesis of N-tosyl arylaldimines as a key step,
which was achieved in situ from the reaction of TsNCO and aryl aldehydes.
Keywords: Lewis Acid; Catalysis; N-Tosylimines; Tandem Synthesis;
9-Arylfluorenes.

1. Introduction
Since the fluorene molecule has a nearly planar tricyclic structure, its derivatives
usually exhibit unique properties. Many 9-arylfluorenes 1 and the synthetic
compounds containing the structural unit of 1 have been found creative material
applications [1,2]. As shown in Figure 1, the polycyclic compound 2 served as a
precursor to produce open-shell polyradicals with fascinating photoelectric properties
[2a]. Recently, these compounds also were found novel biological applications. For
example, the polymethoxylated compounds 3 showed unprecedented inhibitory
activities against tubulin polymerization [3].
Many methods have been developed for the synthesis of 9-arylfluorenes 1 in
literature. As shown in Scheme 1, they can be divided into three major methods: (a)
direct arylation at C9 of fluorene derivatives 4 [4]; (b) coupling of alkyne/alkyne or
alkyne/alkene [5]; (c) annulation of 2-substituted biphenyls 5-7 [6-8]. Although each
method has their own advantages, the multi-step synthesis of starting materials
remains a common and serious challenge. Therefore, it is necessary to develop new
methods to use the accessible starting materials and to increase the structural diversity
of products 1.
Herein, we would like to report a novel tandem synthesis of 9-arylfluorenes 1
from biphenyls 8 and aryl aldehydes 9. The method was efficiently catalyzed by
Cu(OTf)2 and mediated by TsNCO, by which a series of structurally novel
9-arylfluorenes 1 were synthesized conveniently.

2. Experimental
2.1. General. All melting points were determined on a Yanaco melting point
apparatus and are uncorrected. IR spectra were recorded as KBr pellets on a Nicolet
1
13
FT-IR 5DX spectrometer. The H NMR (300 or 400 MHz) and C NMR (75 or 100
MHz) spectra were recorded on JEOL JNM-ECA spectrometers 300 or 400 in CDCl3
or DMSO-d6. TMS was used as an internal reference and J values are given in Hz.
HRMS were obtained on a Bruker micrOTOF-Q II spectrometer. The biphenyls (8a-d)
were prepared by reported procedures in literature [15].
2.2.
A
Typical Procedure for the Preparation of 1,2,3-Trimethoxy-9-
(4-chlorophenyl)fluorene (1a). To a suspension of 3,4,5-trimethoxy-biphenyl (8a, 122
mg, 0.5 mmol) and 4-chlorobenzaldehyde (9a, 84 mg, 0.6 mmol), Cu(OTf)2 (18 mg,
0.05 mmol) in DCE (2 mL) was added tosyl isocyanate (118 mg, 0.6 mmol) in a
Schlenk tube under a balloon pressure of N2. The resultant mixture was stirred at 80
oC for 15 h. It was directly subjected to flash chromatography [silica gel, 5% EtOAc
o
in petroleum ether (60−90 C)] to give 170 mg (93%) of product 1a as colorless oil;
IR (KBr)3062, 2846, 1581, 1100 cm-1; 1H NMR (300 MHz)7.67 (d, J = 7.6 Hz,
1H), 7.35−7.32 (m, 1H), 7.20−7.18 (m, 4H), 7.10 (s, 1H), 7.03−7.00 (m, 2H), 5.02 (s,
13
1H), 3.97 (s, 3H), 3.86 (s, 3H), 3.44 (s, 3H); C NMR (75 MHz)154.5, 150.6,
148.3, 141.9, 140.8, 140.4, 136.8, 132.3, 132.1, 129.5 (2C), 128.5 (2C), 127.3, 126.9,
125.1, 119.3, 99.0, 60.9, 60.0, 56.3, 51.8; HRMS (ESI-TOF) (m/z): calcd for
C22H19ClO3, [M+H]+ 367.1095; found 367.1100.

The products 1b−1w were prepared by the similar procedure.
2.2.1. 1,2,3-Trimethoxy-9-(3-chlorophenyl)fluorene (1b). Yellow oil; IR (KBr) 2938,
2827, 1581, 1112 cm-1; 1H NMR (400 MHz)7.68 (d, J = 7.8 Hz, 1H), 7.37−7.33 (m,
1H), 7.24−7.20 (m, 2H), 7.17−7.15 (m, 2H), 7.11 (s, 1H), 7.06 (s, 1H), 7.00−6.97 (m,
1H), 5.02 (s, 1H), 3.98 (s, 3H), 3.86 (s, 3H), 3.45 (s, 3H); 13C NMR (100 MHz)
154.6, 150.5, 148.0, 143.9, 141.9, 140.8, 136.9, 134.0, 132.0, 129.6, 128.2, 127.4,
127.0, 126.7, 126.4, 125.1, 119.4, 99.1, 60.9, 60.0, 56.3, 52.0; HRMS (ESI-TOF)
(m/z): calcd for C22H19ClO3, [M+H]+ 367.1095; found 367.1092.
2.2.2. 1,2,3-Trimethoxy-9-(2-chlorophenyl)fluorene (1c). White solid, 111−112 oC; IR
1
(KBr) 2962, 2930, 2828, 1579, 1109 cm-1; H NMR (400 MHz) 7.67 (d, J = 7.8
Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.34−7.31 (m, 2H), 7.19−7.15 (m, 1H), 7.11−7.07
(m, 2H), 6.94−6.90 (m, 1H), 6.45−6.43 (m, 1H), 5.78 (s, 1H), 3.97 (s, 3H), 3.85 (s,
13
3H), 3.50 (s, 3H); C NMR (100 MHz) 154.4, 150.3, 148.3, 141.9, 140.7, 139.4,
137.2, 134.3, 132.2, 129.3, 128.3, 127.7, 127.2, 126.9, 126.8, 125.0, 119.3, 98.9, 60.9,
59.9, 56.2, 48.0; HRMS (ESI-TOF) (m/z): calcd for C22H19ClO3, [M+H]+ 367.1095;
found 367.1089.
2.2.3. 1,2,3-Trimethoxy-9-(4-fluorophenyl)fluorene (1d). Yellow oil; IR (KBr) 2831,
1636, 1113 cm-1; 1H NMR (400 MHz) 7.67 (d, J = 7.6 Hz, 1H), 7.35−7.31 (m, 1H),
7.20−7.19 (m, 2H), 7.11 (s, 1H), 7.06−7.02 (m, 2H), 6.93−6.89 (m, 2H), 5.04 (s, 1H),
3.97 (s, 3H), 3.86 (s, 3H), 3.42 (s, 3H); 13C NMR (100 MHz) 161.6 (d, J = 243.1 Hz,
1C), 154.4, 150.6, 148.6, 141.9, 140.7, 137.4, 136.7, 132.5, 129.5 (d, J = 7.6 Hz, 2C),

127.0 (d, J = 35.3 Hz, 2C), 125.0, 119.3, 115.2, 115.0, 99.0, 60.9, 60.0, 56.2, 51.7;
HRMS (ESI-TOF) (m/z): calcd for C22H19FO3, [M+H]+ 351.1391; found 351.1390.
2.2.4. 1,2,3-Trimethoxy-9-(4-bromophenyl)fluorene (1e). Yellowish oil; IR (KBr)
1
2825, 1583, 1110 cm-1; H NMR (400 MHz) 7.67 (d, J = 7.2 Hz, 1H), 7.36−7.32
(m, 3H), 7.20 (d, J = 4.4 Hz, 2H), 7.11 (s, 1H), 6.96 (d, J = 8.8 Hz, 2H), 5.01 (s, 1H),
13
3.98 (s, 3H), 3.85 (s, 3H), 3.44 (s, 3H); C NMR (100 MHz) 154.5, 150.5, 148.3,
141.9, 140.9, 140.7, 136.9, 132.2, 131.4 (2C), 129.9 (2C), 127.3, 126.9, 125.1, 120.2,
119.4, 99.0, 60.9, 60.1, 56.3, 51.9; HRMS (ESI-TOF) (m/z): calcd for C22H19BrO3,
[M+H]+ 411.0590; found 411.0590.
2.2.5. 1,2,3-Trimethoxy-9-(2-bromophenyl)fluorene (1f). White solid, mp 115−116
oC; IR (KBr)2837, 1595, 1103 cm-1; 1H NMR (400 MHz) 7.66 (t, J = 7.3 Hz, 2H),
7.35−7.31 (m, 2H), 7.19−7.15 (m, 1H), 7.11 (s, 1H), 7.02−6.93 (m, 2H), 6.43−6.41
13
(m, 1H), 5.78 (s, 1H), 3.97 (s, 3H), 3.85 (s, 3H), 3.50 (s, 3H); C NMR (100 MHz)
154.4, 150.3, 148.3, 141.9, 141.2, 140.6, 137.1, 132.6, 132.3, 128.4, 128.0, 127.5,
127.2, 126.9, 125.1, 124.9, 119.3, 98.8, 60.9, 59.9, 56.2, 50.8; HRMS (ESI-TOF)
(m/z): calcd for C22H19BrO3, [M+H]+ 411.0590; found 411.0593.
2.2.6. 1,2,3-Trimethoxy-9-phenylfluorene (1g). Colorless oil; IR (KBr)2834, 1461,
1
1109 cm-1; H NMR (400 MHz) 7.67 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H),
7.23−7.16 (m, 5H), 7.11−7.07 (m, 3H), 5.06 (s, 1H), 3.96 (s, 3H), 3.85 (s, 3H), 3.37 (s,
13
3H); C NMR (100 MHz) 154.3, 150.6, 148.8, 141.9, 141.7, 140.7, 136.9, 132.9,

128.3 (2C), 128.1 (2C), 127.1, 126.8, 126.5, 125.1, 119.2, 99.0, 60.8, 59.9, 56.2, 52.5;
HRMS (ESI-TOF) (m/z): calcd for C20H20O3, [M+H]+ 333.1485; found 333.1480.
2.2.7. 1,2,3-Trimethoxy-9-(4-methylphenyl)fluorene (1h). Colorless oil; IR (KBr)
2934, 2850, 1461, 1110 cm-1; 1H NMR (400 MHz) 7.66 (d, J = 7.2 Hz, 1H), 7.31
(t, J = 7.6 Hz, 1H), 7.23−7.15 (m, 2H), 7.11 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.97 (d,
J = 8.0 Hz, 2H), 5.04 (s, 1H), 3.97 (s, 3H), 3.86 (s, 3H), 3.41 (s, 3H), 2.28 (s, 3H); 13C
NMR (100 MHz)154.2, 150.6, 149.0, 141.9, 140.7, 138.5, 136.9, 136.0, 132.9,
129.0 (2C), 127.9 (2C), 127.0, 126.8, 125.1, 119.2, 99.0, 60.9, 60.0, 56.3, 52.2, 21.1;
HRMS (ESI-TOF) (m/z): calcd for C23H22O3, [M+H]+ 347.1642; found 347.1637.
2.2.8. 1,2,3-Trimethoxy-9-(3,4,5-trimethoxyphenyl)fluorene (1i). White solid, mp
181−182 oC; IR (KBr)2933, 2836, 1588, 1117 cm-1; 1H NMR (400 MHz)7.67 (d,
J = 7.8 Hz, 1H), 7.36−7.26 (m, 2H), 7.23−7.19 (m, 1H), 7.12 (s, 1H), 6.32 (s, 2H),
13
5.00 (s, 1H), 3.99 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.74 (s, 6H), 3.48 (s, 3H); C
NMR (100 MHz) 167.6, 154.3, 153.0, 150.6, 148.4, 141.9, 140.5, 137.2, 136.9,
136.6, 132.2, 127.2, 126.8, 125.0, 119.2, 105.0 (2C), 98.9, 60.9, 60.8, 60.1, 56.2, 56.0
(2C), 52.8; HRMS (ESI-TOF) (m/z): calcd for C25H26O6, [M+Na]+ 445.1622; found
445.1618.
o
2.2.9. 1,2,3-Trimethoxy-9-(4-nitrophenyl)fluorene (1j). White solid, mp 113−114 C;
1
IR (KBr) 2939, 2837, 1595, 1346 cm-1; H NMR (400 MHz) 8.09 (d, J = 8.0 Hz,
2H), 7.71 (d, J = 7.6 Hz, 1H), 7.39−7.35 (m, 1H), 7.24−7.17 (m, 4H), 7.13 (s, 1H),
13
5.13 (s, 1H), 3.99 (s, 3H), 3.85 (s, 3H), 3.48 (s, 3H); C NMR (75 MHz) 154.9,

150.3, 150.0, 147.3, 146.7, 141.7, 140.8, 136.8, 131.2, 128.9 (2C), 127.7, 127.0, 125.0,
123.6 (2C), 119.6, 99.0, 60.9, 59.9, 56.2, 51.9; HRMS (ESI-TOF) (m/z): calcd for
C22H19NO5, [M+H]+ 378.1336; found 378.1338.
2.2.10. 1,2,3-Trimethoxy-9-(3-nitrophenyl)fluorene (1k). Yellow oil; IR (KBr) 3000,
2840, 1524, 1353, 1106 cm-1; 1H NMR (300 MHz) 8.08−8.04 (m, 1H), 8.00 (s, 1H),
7.71 (d, J = 7.8 Hz, 1H), 7.40−7.35 (m, 3H), 7.22−7.20 (m, 2H), 7.13 (s, 1H), 5.14 (s,
13
1H), 3.99 (s, 3H), 3.85 (s, 3H), 3.48 (s, 3H); C NMR (75 MHz) 154.9, 150.4,
148.3, 147.3, 144.1, 141.8, 140.9, 136.8, 134.3, 131.2, 129.2, 127.7, 127.1, 125.0,
123.1, 121.7, 119.0, 99.1, 60.9, 60.0, 56.2, 51.8; HRMS (ESI-TOF) (m/z): calcd for
C22H19NO5, [M+H]+ 378.1336; found 378.1332.
2.2.11. 1,2,3-Trimethoxy-9-(4-cyanophenyl)fluorene (1l). Colorless oil; IR (KBr)
2870, 2223, 1543, 1110 cm-1. 1H NMR (400 MHz) 7.70 (d, J = 7.8 Hz, 1H), 7.53
(d, J = 8.3 Hz, 2H), 7.39−7.35 (m, 1H), 7.23−7.17 (m, 4H), 7.12 (s, 1H), 5.08 (s, 1H),
13
3.99 (s, 3H), 3.85 (s, 3H), 3.45 (s, 3H); C NMR (100 MHz) 154.8, 150.4, 147.8,
147.4, 141.8, 140.9, 136.9, 132.2 (2C), 131.4, 128.9 (2C), 127.6, 127.1, 125.0, 119.5,
118.9, 110.3, 90.0, 60.9, 60.0, 56.3, 52.2; HRMS (ESI-TOF) (m/z): calcd for
C23H19NO3, [M+H]+ 358.1438; found 358.1437.
2.2.12. 1,2,3-Trimethoxy-9-(4-methoxycarbonylphenyl)fluorene (1m). Colorless oil.
IR (KBr) 2992, 1724, 1590, 1108 cm-1. 1H NMR (400 MHz) 7.92 (d, J = 8.7 Hz,
2H), 7.69 (d, J = 7.8 Hz, 1H), 7.37−7.33 (m, 1H), 7.19 (d, J = 4.1 Hz, 2H), 7.16 (d, J
= 8.2 Hz, 2H), 7.12 (s, 1H), 5.10 (s, 1H), 3.98 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.39

(s, 3H),; 13C NMR (100 MHz) 166.9, 154.6, 150.5, 148.0, 147.5, 141.8, 140.8,
136.9, 132.0, 129.7 (2C), 128.5 (2C), 128.2, 127.4, 126.9, 125.1, 119.4, 99.0, 60.9,
59.9, 56.2, 52.3, 51.9. HRMS (ESI-TOF) (m/z): calcd for C24H22O5, [M+H]+
391.1540; found 391.1539.
2.2.13. 1,2,3-Trimethoxy-9-(4-trifluoromethylphenyl)fluorene (1n). Colorless oil. IR
(KBr) 2933, 2839, 1568, 1116 cm-1. 1H NMR (400 MHz) 7.69 (d, J = 7.8 Hz, 1H),
7.48 (d, J = 8.2 Hz, 2H), 7.36−7.32 (m, 1H), 7.20−7.18 (m, 4H), 7.12 (s, 1H), 5.09 (s,
13
1H), 3.97 (s, 3H), 3.85 (s, 3H), 3.43 (s, 3H); C NMR (100 MHz) 154.6, 150.5,
147.9, 146.1, 141.8, 140.8, 136.9, 131.9, 128.7 (q, J = 32.4 Hz), 128.4 (2C), 127.4,
126.9, 125.2 (q, J = 3.8 Hz, 2C), 125.0, 124.2 (q, J = 270.8 Hz, CF3), 119.4, 99.0,
60.9, 59.9, 56.2, 52.1; HRMS (ESI-TOF) (m/z): calcd for C23H19F3O3, [M+H]+
401.1359; found 401.1362.
2.2.14. 1,2,3-Trimethoxy-9-(4-formylphenyl)fluorene (1o). Yellow oil; IR (KBr)
3055, 2931, 2838, 1698, 1105 cm-1; 1H NMR (400 MHz) 9.94 (s, 1H), 7.76 (d, J =
7.8 Hz, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.38−7.34 (m, 1H), 7.26−7.13 (m, 4H), 5.12 (s,
13
1H), 3.98 (s, 3H), 3.85 (s, 3H), 3.43 (s, 3H); C NMR (100 MHz) 191.8, 154.7,
150.4, 149.4, 147.7, 141.8, 140.8, 136.9, 135.0, 131.8, 129.9 (2C), 128.8 (2C), 127.5,
127.0, 125.0, 119.4, 99.0, 60.9, 59.9, 56.2, 52.4; HRMS (ESI-TOF) (m/z): calcd for
C23H20O4, [M+H]+ 361.1434; found 361.1435.
2.2.15. 1,2,3-Trimethoxy-9-(2-bromo-4-chlorophenyl)fluorene (1p). Yellow oil; IR
1
(KBr) 2937, 2840, 1579, 1118 cm-1; H NMR (400 MHz) 7.66−7.63 (m, 2H),

7.31−7.27 (m, 2H), 7.15−7.10 (m, 1H), 7.09 (s, 1H), 6.93−6.90 (m, 1H), 6.34 (d, J =
13
8.2 Hz, 1H), 5.68 (s, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.56 (s, 3H); C NMR (100
MHz) 154.4, 150.1, 147.6, 141.7, 140.4, 139.9, 136.9, 132.4, 131.9, 131.6, 129.0,
127.7, 127.3, 126.8, 125.1, 124.7, 119.3, 98.7, 60.8, 59.9, 56.1, 50.1; HRMS
(ESI-TOF) (m/z): calcd for C22H18BrClO3, [M+H]+ 445.0201; found 445.0202.
2.2.16. 1,2,3-Trimethoxy-9-(2-bromo-4-methoxyphenyl)fluorene (1q). White solid, mp
o
1
107−108 C; IR (KBr) 3044, 2935, 2846, 1571, 1119 cm-1; H NMR (400 MHz)
7.66 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.37−7.30 (m, 2H), 7.18−7.15 (m,
1H), 7.10 (s, 1H), 6.61−6.58 (m, 1H), 5.97 (d, J = 2.8 Hz, 1H), 5.72 (s, 1H), 3.97 (s,
13
3H), 3.86 (s, 3H), 3.57 (s, 3H), 3.47 (s, 3H); C NMR (100 MHz) 158.7, 154.4,
150.3, 148.1, 142.3, 141.8, 140.5, 137.2, 133.0, 131.9, 127.2, 126.8, 124.8, 119.3,
115.6, 113.8, 113.7, 99.9, 60.9, 60.0, 56.2, 55.1, 51.0; HRMS (ESI-TOF) (m/z): calcd
for C23H21BrO4, [M+H]+ 441.0696; found 441.0688.
2.2.17 1,2,3-Trimethoxy-9-(2-bromo-5-nitrophenyl)fluorene (1r). Yellow solid, mp
o
1
140−141 C; IR (KBr) 2997, 2842, 1524, 1359 cm-1; H NMR (400 MHz)
7.89−7.83 (m, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.30−7.17 (m,
3H), 7.14 (s, 1H), 5.77 (s, 1H), 4.01 (s, 3H), 3.85 (s, 3H), 3.60 (s, 3H); 13C NMR (100
MHz) 155.0, 150.0, 147.3, 146.8, 143.8, 141.8, 140.8, 137.1, 133.6, 132.2, 130.6,
127.9, 127.0, 124.6, 123.3, 122.4, 119.8, 99.2, 61.0, 60.1, 56.2, 50.6; HRMS
(ESI-TOF) (m/z): calcd for C22H18BrNO5, [M+Na]+ 478.0261; found 478.0270.

2.2.18 1,2,3-Trimethoxy-7-methyl-9-(4-chlorophenyl)fluorene (1s). White solid, mp
112−113 oC; IR (KBr)2928, 2840, 1460, 1108 cm-1; 1H NMR (300 MHz)7.55 (d,
J = 7.9 Hz, 1H), 7.21−7.12 (m, 3H), 7.06−7.00 (m, 4H), 4.97 (s, 1H), 3.95 (s, 3H),
13
3.84 (s, 3H), 3.43 (s, 3H), 2.30 (s, 3H); C NMR (75 MHz)154.4, 150.5, 148.5,
141.5, 140.6, 138.1, 137.0, 136.8, 132.0, 131.9, 129.4 (2C), 128.5 (2C), 128.1, 125.7,
119.0, 98.8, 60.9, 60.0, 56.2, 51.6, 21.5; HRMS (ESI-TOF) (m/z): calcd for
C23H21ClO3, [M+H]+ 381.1252; found 381.1254.
2.2.19. 1,2,3-Trimethoxy-5-methyl-9-(4-chlorophenyl)fluorene (1t). White solid, mp
137−138 oC; IR (KBr)2930, 2840, 1465, 1100 cm-1; 1H NMR (300 MHz)7.28 (s,
1H), 7.19 (d, J = 8.4 Hz, 2H), 7.10−7.08 (m, 2H), 7.06−6.98 (m, 3H), 4.99 (s, 1H),
13
3.97 (s, 3H), 3.86 (s, 3H), 3.42 (s, 3H) , 2.72 (s, 3H); C NMR (75 MHz)154.0,
150.2, 148.8, 141.4, 140.8, 138.7, 137.9, 132.9, 132.1, 132.0, 129.6, 129.5 (2C), 128.4
(2C), 126.7, 122.7, 102.9, 60.8, 60.0, 56.3, 51.6, 20.7; HRMS (ESI-TOF) (m/z): calcd
for C23H21ClO3, [M+H]+ 381.1252; found 381.1250.
2.2.20. 1,2,3,6,7,8-Hexamethoxy-9-(4-chlorophenyl)fluorene (1u). White solid, mp
139−140 oC; IR (KBr)2933, 2833, 1405, 1121 cm-1; 1H NMR (400 MHz)7.18 (d,
J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.00 (s, 2H), 5.07 (s, 1H), 3.97 (s, 6H), 3.84
13
(s, 6H), 3.39 (s, 6H); C NMR (100 MHz)154.4 (2C), 150.2 (2C), 141.5 (2C),
140.4, 136.5 (2C), 133.3 (2C), 131.7, 129.5 (2C), 128.1 (2C), 98.6 (2C), 60.8 (2C),
59.9 (2C), 56.2 (2C), 49.7; HRMS (ESI-TOF) (m/z): calcd for C25H25ClO6, [M+H]+
457.1412; found 457.1406.

2.2.21. 1,2,3,6,7,8-Hexamethoxy-9-(4-nitrophenyl)fluorene (1v). Yellow solid, mp
o
1
152−154 C; IR (KBr)2832, 1599, 1342, 828 cm-1; H NMR (300 MHz)8.10 (d,
J = 7.9 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.04 (s, 2H), 5.17 (s, 1H), 4.00 (s, 6H), 3.83
13
(s, 6H), 3.43 (s, 6H); C NMR (75 MHz)154.7 (2C), 150.4, 150.1 (2C), 146.4,
141.4 (2C), 136.7 (2C), 132.3 (2C), 128.9 (2C), 123.3 (2C), 98.7 (2C), 60.8 (2C), 59.9
(2C), 56.2 (2C), 49.8; HRMS (ESI-TOF) (m/z): calcd for C25H25NO8, [M+H]+
468.1653; found 468.1656.
2.2.22. 1,2,3,6,7,8-Hexamethoxy-9-(3-nitrophenyl)fluorene (1w). Yellow solid, mp
o
1
135−136 C; IR (KBr)2940, 2834, 1580, 1347 cm-1; H NMR (300 MHz)
8.06−8.03 (m, 1H), 7.99−7.97 (m, 1H), 7.46−7.37 (m, 2H), 7.02 (s, 2H), 5.18 (s, 1H),
4.00 (s, 6H), 3.84 (s, 6H), 3.43 (s, 6H); 13C NMR (75 MHz)154.8 (2C), 150.2 (2C),
148.1, 144.3, 141.5 (2C), 136.7 (2C), 134.5, 132.2 (2C), 128.8, 123.1, 121.5, 98.8
(2C), 60.9 (2C), 59.9 (2C), 56.3 (2C), 49.8; HRMS (ESI-TOF) (m/z): calcd for
C25H25NO8, [M+H]+ 468.1653; found 468.1654.
2.2.23. Ethyl
2-(4-methylphenylsulfonamido)-2-(3,4,5-trimethoxy-[1,1'-biphenyl]
o
-2-yl)acetate (12). White solid, mp 108−109 C; IR (KBr)2936, 2846, 1731, 1346,
1
1113 cm-1; H NMR (400 MHz)7.42−7.41 (m, 3H), 7.34−7.32 (m, 2H), 7.29−7.26
(m, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.51 (s, 1H), 5.93 (d, J = 8.4 Hz, 1H), 4.97 (d, J =
8.4 Hz, 1H), 4.12-4.06 (m, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H) , 2.35 (s, 3H),
13
1.14 (t, J = 7.2 Hz, 3H); C NMR (100 MHz)170.7, 153.2, 151.4, 142.8, 140.8,
140.1, 137.9, 136.9, 129.7 (2C), 129.2 (2C), 128.2, 127.4 (2C), 127.0 (2C), 121.6,

108.5, 62.0, 60.6, 60.5, 55.9, 54.3, 21.4, 13.9; HRMS (ESI-TOF) (m/z): calcd for
C26H29NO7S, [M+Na]+ 522.1557; found 522.1562.
3. Results and Discussion
During our investigation, the method starting from 2-formyl biphenyls 6 has
attracted our attention [7]. As shown in Scheme 2, it actually is a two-step tandem
reaction to convert 6 into 1 in one-pot. Its pathway indicated that Ar3 is introduced
first by a nucleophilic addition of aldehyde of 6. The intermediate 7 then carries out a
Friedel-Crafts reaction to give 1. Since the aldehyde has low electrophilicity, a highly
electron-rich Ar3H is required to initialize this tandem reaction (such as indoles,
thiophenes and polyalkyl or polyalkoxy benzenes, etc). Thus, we proposed that the
product 1 may be synthesized by a tandem reaction from an electron-rich biphenyl 8
and an aryl aldehyde 9, wherein two advantages may be expected: (a) the substrates
are much more accessible because the preparation of 8 is much easier than 6; (b) the
products 1 bearing electron-poor Ar3 can be synthesized because EWG-substituted
aryl aldehydes have higher electrophilicity.
As shown in Scheme 3, we disappointingly observed that no reaction occurred
when the mixture of 3,4,5-trimethoxybiphenyl (8a) and 4-chlorobenzaldehyde (9a)
were treated by various Lewis acids including FeCl3. This result must be caused by
the fact that the aldehyde group in 9a has a low electrophilicity. It is well-known that
N-tosyl benzaldimines are significantly more electrophilic than the corresponding
benzaldehydes (for example: E = –19.92 for PhCHO, E = –11.50 for PhCH=NTs) [9]

and they can efficiently undergo further Lewis acid-catalyzed aza-Friedel-Crafts
reactions [10]. Thus, a FeCl3-catalyzed reaction between 8a and N-tosyl
4-chlorobenzaldimine (10a) was tested. To our delight, the expected product 1a was
obtained in 64% yield, but the expected intermediate 11a was not isolated at all.
These results indicated that the intermolecular aza-Friedel-Crafts between 8a and 10a
was a rate-determining step, while the intramolecular Friedel-Crafts of the
intermediate 11a was a fast step.
Since 10a was pre-made by a FeCl3-catalyzed dehydration between 9a and
TsNH2 [11]. we were encouraged to develop a three-step tandem synthesis of 1a
starting from 9a as shown in Scheme 4. Unfortunately, when the mixture of 8a, 9a
and TsNH2 was treated by FeCl3, 1a and 10a were isolated in 19% and 47% yields,
respectively. This result may be caused by the fact that one molecule of H2O was
formed in situ from step 1 and it then functioned as a Lewis base to strongly
coordinate with FeCl3, by which the catalytic activity of FeCl3 was reduced
significantly. This hypothesis was proved by adding one molecule of H2O into the
reaction described in Scheme 3. As a result, the yield of 1a was decreased from 64%
to 13%.
Therefore, our attention was directed to the anhydrous methods for the synthesis
of N-tosylimines. Based on the well understanding the pathway of two methods
reported by Weinreb [12] and Trost [13], respectively, we recently developed a
practical method to convert aryl aldehyde 9 into N-tosyl arylaldimines 10 without the

formation of H2O [14]. As shown in Scheme 5, the reaction was achieved
conveniently by heating the mixture of an aryl aldehyde 9 and TsNCO in a solvent or
in neat form. Thus, we realized that it is very suitable for our tandem reaction and a
group of experiments were tested under the similar conditions. As was expected, the
desired product 10a was obtained in 83% yield when the mixture of 9a and TsNCO
o
was heated at 80 C for 2 h. In the presence of FeCl3, the same reaction could be
finished within 1 h, that indicated that this reaction can be catalyzed by FeCl3 also. To
our delight, the target product 1a was obtained in 61% yield by heating the mixture of
8a, 9a, TsNCO and FeCl3 at 80 oC for 15 h.
Next, the conditions for the tandem synthesis of 1a were optimized by using
different catalysts. As shown in Table 1, many Lewis acids proved to be unsuitable
catalysts (entries 2-6). But, Sc(OTf)3 gave a higher yield of 1a compared to FeCl3
(entry 7). To our delight, Cu(OTf)2 showed the best catalytic activity to give the
highest yield of 1a (entry 8). The yield of 1a was not improved by using different
ratios of Cu(OTf)2 and different temperatures (entries 9-11). Thus, the entry 8 was
assigned as the standard conditions.
As shown in Scheme 6, a Cu(OTf)2-catalyzed three-step tandem reaction for
efficient synthesis of 1a was established thus far, which includes an anhydrous
preparation of N-tosylimine, an aza-Friedel-Crafts reaction and a normal
Friedel-Crafts reaction. It also is a TsNCO-mediated tandem reaction because TsNCO
involved in each steps but it did not appeared in molecule of 1a. In step 1, an
anhydrous preparation of 10a was established by using it as a substrate. In step 2, the

imine group of 10a was activated by its tosyl group. In step 3, TsNH2 served as a
neutral and low nucleophilic leaving group.
Finally, the scope of our tandem method was tested. As shown in Scheme 7, all
tested products were obtained smoothly under the standard conditions. The
ortho-substituted benzaldehydes gave the products (1c, 1f, 1p-1r, and 1t) in relatively
lower yields caused by steric effect. EDG-substituted benzaldehydes gave the
products (1h and 1i) in relatively lower yields caused by electronic effects. But, their
yields were elevated significantly by using two equivalents of aldehydes and TsNCO.
As was expected, EWG-substituted benzaldehydes gave the corresponding
9-arylfluorenes (1j-1n) in excellent yields because the in situ produced imine group
was activated by both tosyl group and EWG-substituent. The importance of our
method was enhanced greatly by his result because it is a rare method[5e] to synthesize
the electron-poor Ar3 substituted 9-arylflurenes. Almost quantitative yields of 1u-1w
were obtained from the substrates bearing trimethoxy-substituted Ar2. Under the
standard conditions, 1a was prepared in 92% yield on a 5-gram scale.
Like the existed methods in literature, still there are limitations to our method.
For example, 4-methoxy-biphenyl (8e) or 3,4,5-tirmethylbiphenyl (8f) did not carry
out the reaction possibly caused by their lower nucleophilicity compared to 8a.
Although 4-nitro- and 3-nitro-benzaldehydes (9j and 9k) were excellent substrates,
2-nitro-benzaldehyde (9s) did not carry out the reaction possibly caused by its steric
structure. As shown in Scheme 8, the reaction between 8a and ethyl glyoxylate (9t)
gave an only partial reaction product 12 in 98% yield. This result gave a strong

support to our hypothesis that 11a (see: Schemes 3, 4 and 6) was an intermediate in
our method.
Conclusions
In conclusion, three works have been made in this article. First, a novel strategy
to use aldehyde and biphenyl as substrates for the synthesis of 9-arylfluorenes was
proposed. Second, the proposed strategy was realized by using an anhydrous
preparation of N-tosyl arylaldimines as a key step. Third, a Cu(OTf)2-catalyzed and
TsNCO-mediated three-step tandem synthesis of 9-arylfluorenes was developed, by
which a series of structurally novel 9-arylfluorenes, especially electron-poor 9-aryl
substituted fluorenes, were synthesized conveniently by using much more accessible
starting materials. The method is a valuable addition and choice to the synthesis of
9-arylfluorenes.
Acknowledgements
This work was financially supported by the National Natural Science Foundation
of China (Nos. 21372142 and 21472107).

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Figure Captions
Figure 1. Some important compounds containing the structural unit of 1.
Scheme 1. Three major methods for the preparation of 1.
Scheme 2. A proposed strategy for the synthesis of 1 from 8 and 9.
Scheme 3. Two-step tandem synthesis of 1a from 8a and 10a.
Scheme 4. A failed three-step tandem synthesis from 8a, 9a and TsNH2.
Scheme 5. Conditional tests for tandem synthesis of 1a.
Scheme 6. Proposed pathway for our tandem reaction.
Scheme 7. The scope of our tandem method.
Scheme 8. An indirect evidence for the intermediate 11a.

Tables
Table 1. Optimization of the reaction conditions a
MeO
C6H4-4-Cl
MeO
9a, TsNCO, Lewis acid
MeO
MeO
MeO
MeO
DCE, temp, time
65-98%
Ph
8a
1a
Lewis acid
temp
(oC)
80
time
(h)
15
15
15
15
15
15
15
15
15
15
24
Yield of 1a
Entry
(mol%)
(%)[b]
64
0
1
2
FeCl3 (10)
Ce(OTf)3 (10)
Zn(OTf)2 (10)
FeBr3 (10)
80
3
80
14
23
25
27
75
93
90
73
61
4
80
5
Yb(OTf)3 (10)
Bi(OTf)3 (10)
Sc(OTf)3 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (20)
Cu(OTf)2 (5)
Cu(OTf)2 (10)
80
6
80
7
80
8
80
9
80
10
11
80
70
a
The mixture of 8a (0.5 mmol), 9a (0.6 mmol) and TsNCO (0.6 mmol)
in DCE (2 mL) was heated in the presence of a Lewis acid for 15 h.
Isolated yields were obtained.
b