Synthesis of benzidine derivatives via FeCl3·6H 2O-promoted oxidative coupling of anilines

Article abstract of DOI:10.1021/jo4002504

Under open-flask conditions in the presence of commercially available FeCl₃·6H₂O, N,N-disubstituted anilines can be converted into diversely functionalized benzidines with yields of up to 99%. Oxidative coupling was extended to N-monosubstituted anilines, and the method was applied to the efficient preparation of 6,6′-biquinoline. Mechanistic investigations have also been performed to explain the observed reactivities.

Full text of DOI:10.1021/jo4002504

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Article
Synthesis of Benzidine Derivatives via FeCl3•6H2O-
Promoted Oxidative Coupling of Anilines
Xuege Ling, Yan Xiong, Ruofeng Huang, Xiaohui Zhang, Shuting Zhang, and Changguo Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4002504 • Publication Date (Web): 15 May 2013
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Synthesis of Benzidine Derivatives via
FeCl3·6H2O-Promoted Oxidative Coupling of Anilines
Xuege Ling, Yan Xiong,* Ruofeng Huang, Xiaohui Zhang, Shuting Zhang, and
Changguo Chen*
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School of Chemistry and Chemical Engineering, Chongqing University, Chongqing
400044, China, and State Key Laboratory of Elementoꢀorganic Chemistry, Nankai
University, Tianjin 300071, China
*Email: xiong@cqu.edu.cn; cgchen@cqu.edu.cn
R3
R3
R3
R1
N
R2
R1
N
R2
R1
FeCl3•6H2O
O
O
N
Toluene, 85 oC
R2
O
R1 = Alkyl, Benzyl, Oxa-alkyl
R2 = H, Alkyl, Benzyl, Oxa-alkyl
R3 = H, Alkyl, Alkoxyl, Halo-
32 examples
up to 99% yield
-NBn2
=
Trimerization in 52% yield
Abstract
Under openꢀflask conditions, in the presence of commercially available FeCl3ꢁ6H2O,
N,Nꢀdisubstituted anilines can be converted into diversely functionalized benzidines
with yields of up to 99%. Oxidative coupling was extended to Nꢀmonosubstituted
anilines and the method was applied to the efficient preparation of 6,6'ꢀbiquinoline.
Mechanistic investigations have also been performed to explain the observed
reactivities.
Introduction
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The development of efficient synthetic methodologies to prepare structurally
diverse benzidine derivatives has received increasing attention in recent years due to
their applicability in a wide variety of domains. For instance, they have found
applications as building blocks to construct functionalized heterocycles.1 The
chemical and physical properties of benzidineꢀbased compounds have enabled their
use in the manufacture of azodyes2 and in cell biology as staining reagents.3
Furthermore, they are important units for the implementation of molecular machines4
and construction of functionalized organic materials.5, 6
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The synthesis of benzidines is based on two major synthetic strategies: 1)
rearrangement of hydrazobenzenes; and 2) direct selfꢀcoupling of anilines. Generally,
the rearrangement of hydrazobenzenes suffers from low yields because of the
formation of byꢀproducts.7 In an important contribution to the field, the group of Cho
disclosed that aryl hydrazides with substituent(s) at the ortho or meta position could
suppress the formation of byꢀproducts.8 However, access is limited to orthoꢀ and/or
metaꢀsubstituted benzidines which lowers the synthetic appeal of this transformation.
Besides rearrangement of hydrazobenzenes, oxidative coupling of arylamines
represents a straightforward approach to prepare functionalized benzidines. Metal salt
oxidants such as TiCl4, cerium(IV) ammonium nitrate (CAN), CuBr/H2O2 and
Cu(ClO4)2 were employed for this reaction.9 Organic oxidant could also be used and
to this aim, 1,8ꢀbis(diphenylmethylium)naphthalenediyl dications were synthesized by
Ichikawa et al. and they were successfully applied to the selfꢀcoupling of
N,Nꢀdisubstituted anilines.10 The combination of anhydrous FeCl3 and oxygen was
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also employed to investigate the transformation of N,Nꢀdimethylaniline, which tended
to form Nꢀmethylaniline and 4,4'ꢀmethylenebis(N,Nꢀdimethylaniline) through iminum
cation intermediate.11 Utilizing anhydrous FeCl3/K2CO3, coupling products of
naphthylamines were obtained through a possible naphthyl iron intermediate reported
by Yang’s group.12 Although extensive efforts have been devoted to devise more
general and higherꢀyielding transformations, the preparation of diversely
functionalized benzidines remains an important synthetic challenge. We report herein
the successful implementation of an oxidative coupling of N,Nꢀdisubstituted and
Nꢀmonosubstituted anilines to prepare benzidines using FeCl3ꢁ6H2O as an efficient
oxidant. In the past decade, synthetic methodologies based on iron has underwent an
explosive growth due to the readily accessibility, favorable safety profile and low cost
of iron derivatives.13
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Results and Discussion
Oxidative coupling of N,Nꢀdimethylaniline 1a under air in toluene at 85°C was
used as a model reaction to optimize the conditions (Table 1). A set of different iron
sources was investigated and iron(III) chloride gave the best results (entries 1ꢀ6). The
reaction of 1a in the presence of 2.5 equiv of anhydrous FeCl3 gave rise to a mixture
of benzidine 2a and 4,4'ꢀmethylenebis(N,Nꢀdimethylaniline) 3a in 28% and 24%
yields, respectively (entry 4). The formation of 3a has already been observed under
similar reaction conditions through oxidation of the methyl groups in 1a.11
Interestingly, the use of FeCl3ꢁ6H2O suppressed the formation of 3a and under these
conditions, benzidine 2a was obtained in 88% yield (entry 5). The difference between
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FeCl3ꢁ6H2O and FeCl3 prompted us to investigate the effect of water in the system.
When 15.0 equiv water was added to anhydrous FeCl3, the coupling reaction
proceeded smoothly and 2a was obtained in 80% yield (entry 6). Subsequently, the
amount of FeCl3ꢁ6H2O was investigated. Addition of 1.0 equiv of FeCl3ꢁ6H2O led to
formation of product 2a in a very low yield of 2% along with byꢀproduct 3a as the
major product while large excess of FeCl3ꢁ6H2O gave rise selectively to 2a in
unimproved yields (entries 7ꢀ9). After screening the temperature, oxidative coupling
of 2a at 85°C using 2.5 equiv of FeCl3ꢁ6H2O turned out to be the best reaction
conditions (entries 5, 10 and 11). In iron(III)ꢀpromoted oxidative coupling of
naphthylamines, Yang et al. reported that reaction was facilitated by addition of a
base.12 Addition of Et3N or K2CO3 to the system was investigated in the selfꢀcoupling
of 2a (entries 12 and 13). Dimerization of anilines in the presence of Et3N gave only
byꢀproduct 3a in 68% yield while the use of K2CO3 furnished a mixture of 2a and 3a
in a ratio of about 1:2. Formation of 3a is supposed to proceed through oxidation of
the methyl groups and as a result, we envisioned that the use of N,Nꢀdibenzylaniline
would lead selectively to the corresponding benzidine. The reaction of 1b in the
presence of FeCl3ꢁ6H2O gave selfꢀcoupling product 2b in an excellent yield of 96%
(entry 14). It is worthwhile noting that reaction of 1b in the presence of anhydrous
FeCl3 or FeCl3ꢁ6H2O/K2CO3 afforded only compound 2b in diminished yield while
3a was the major compound for the selfꢀcoupling of 1a under indentical conditions
(entries 15 and 16).
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Table 1. Initial screening resultsa
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Entry
1
1
Iron salt / Additive (eq)
FeCl2ꢁ4H2O (2.5)
T oC
Yield %b
4
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1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
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120
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2
Fe2(SO4)3 (2.5)
n.pc
n.pc
28(24)d
88
3
Fe(NO3)3ꢁ9H2O (2.5)
FeCl3 (2.5)
4
5
FeCl3·6H2O (2.5)
6
FeCl3 (2.5) / H2O (15.0)
FeCl3ꢁ6H2O (1.0)
80
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2(33)d
83
8
FeCl3ꢁ6H2O (4.0)
9
FeCl3ꢁ6H2O (10.0)
FeCl3ꢁ6H2O (2.5)
67
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FeCl3ꢁ6H2O (2.5)
83
FeCl3ꢁ6H2O (2.5)/Et3N (1.0)
FeCl3ꢁ6H2O (2.5)/K2CO3 (1.0)
FeCl3·6H2O (2.5)
0(68)d
23(45)d
96e
FeCl3 (2.5)
42
FeCl3ꢁ6H2O (2.5)/K2CO3 (1.0)
36
a Reaction conditions: Anilines (0.4 mmol), iron sources and additives (specified amounts) in
b
c
d
2.0 mL of toluene for
2
h.
Isolated yields.
No product.
e
Yield of
4,4'ꢀmethylenebis(N,Nꢀdimethylaniline) 3a presented in parenthesis. Yield of 91% was obtained
in distilled toluene under N2.
With the optimal reaction conditions in hand (FeCl3ꢁ6H2O, toluene, 85°C, 2 h),
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the reaction scope was investigated focusing on the influence of nitrogen substitution
on the reaction (Table 2). Oxidative coupling of 1ꢀphenylpyrrolidine and
N,Nꢀdiethylaniline afforded 2c and 2d in moderate yields while
NꢀbenzylꢀNꢀmethylanilines underwent selfꢀcoupling in good yields. Oxaꢀalkyl
substituted aniline gave the coupling product 2f in a yield of 54%. The substitution
pattern of the benzyl group showed a dramatic influence on the reactivity. Methyl
substituent was wellꢀtolerated with the formation of 2h in 70% yield while starting
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materials were recovered with methoxyꢀ and cyanoꢀcontaining substrates.
Table 2. Influence of the nitrogen protecting groupa
2a, 88%
2b, 96%
2c, 42%
2d, 30%
2e, 77%
2f, 54%
2g, 73%
2h, 70%
2i, 0%
2j, 0%
a Reaction conditions: anilines (0.4 mmol), FeCl3ꢁ6H2O (1.0 mmol), toluene (2.0 mL), 85 oC, 2 h;
isolated yields.
Amongst all the nitrogen protecting group tested, the benzyl group gave the best
result. In addition, the benzyl group can be easily introduced and requires mild
conditions (H2, Pd/C) to be cleaved. As a result, the benzyl moiety was selected as a
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nitrogen protecting group to explore the influence of the aromatic substitution pattern
of anilines (Table 3). Oxidative coupling of anilines bearing metaꢀalkyl substitutent
gave the corresponding benzidines 2k-n in moderateꢀtoꢀgood yields. Naphthylamine
is a suitable substrate and selfꢀcoupling product 2o was obtained in 85% yield.
Electronꢀdonating groups such as methoxy and ethoxy impinge on the reaction
outcome. While 2p was obtained in 53% yield, benzidine 2q was obtained in 18%
yield along with trimer product 2z in 29% yield. Extending the reaction time of 1q to
24 h gave rise to trimer 2z in an improved yield of 52% and only trace of benzidine
2q was observed (Scheme 1). The reaction also worked well by using halogenated
anilines. N,Nꢀdibenzylꢀ3ꢀbromoaniline and N,Nꢀdibenzylꢀ3ꢀiodoaniline gave the
corresponding products 2t and 2u in excellent yields of 97% and 98%, respectively.
However, the coupling reactions did not proceed with N,Nꢀdibenzylanilines
containing fluoro, nitro, or acetyl group at metaꢀposition and only starting materials
were recovered. 1ꢀBenzylꢀ1,2,3,4ꢀtetrahydroquinoline was effectively transformed
into 2y in 61% yield and we were pleased to get crystals suitable for Xꢀray analysis.
Anilines bearing only ortho substitution(s) proved to be unreactive towards oxidative
croupling reaction (2r, 2vꢀx).
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Table 3. Selfꢀcoupling reactions of functionalized N,Nꢀdibenzyl anilinesa
2b, 96%
2k, 44%
2l, 92%
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2m, 95%
2n, 99%
2o, 85%
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2p, 53%
2s, 46%b
2v, 0%
2q, 18%
2t, 97%
2w, 0%
2r, 0%
2u, 98%b
2x, 0%
2y, 61%
a Reaction conditions: anilines (0.4 mmol), FeCl3ꢁ6H2O (1.0 mmol), toluene (2.0 mL), 85 oC, 2
h; isolated yields. b 8 h.
Scheme 1. Trimerization of N,Nꢀdibenzylꢀ3ꢀethoxyaniline (1q)
1q
2z, 52%
The lack of reactivities in selfꢀcoupling of 2r and 2vꢀx might be explained by
steric repulsions between the ortho methyl or alkoxyl group(s) of the benzene ring
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and the benzyl groups borne by the nitrogen. As a result, the rotations of aromatic
carbonꢀnitrogen bonds break the coplanar pꢀπ conjugation and this decreases the
ability of anilines to be oxidised. In this context, we surmised that oxidative coupling
of Nꢀbenzylanilines should be facilitated due to lower steric shielding around the
nitrogen. Unlike N,Nꢀdibenzyl anilines, Nꢀmonobenzylanilines underwent
selfꢀcoupling to provide corresponding benzidines (Table 4). Alkyl substitutions at the
ortho or meta position of the aromatic ring were tolerated, providing desired products
in 28% to 86% yields (4aꢀg). It is worthwhile noting that benzidine 4b can be readily
transformed through a simple debenzylation step into 3,3',5,5'ꢀtetramethylbenzidine
(TMB), an important and safe staining agent.3 orthoꢀAlkoxy substituted anilines
generated the corresponding selfꢀcoupling products 4h and 4i in moderate yields.
Haloꢀsubstitutions at the meta position of the mother benzene ring could afford
coupling product 4jꢀl while coupling reaction did not proceed using anilines bearing
ortho haloꢀsubstitutions. Commercially available 1,2,3,4ꢀtetrahydroquinoline gave
directly benzidine 4m in 59% yield.
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Table 4. Selfꢀcoupling reactions of functionalized Nꢀbenzylanilinesa
4a, 28%
4d, 66%
4b, 37%
4e, 86%
4c, 55%
4f, 44%
H
Bn
H
N
N
Bn
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4g, 33%
4j, 19%b
4h, 35%
4i, 30%
4l, 42%b
4k, 42%b
4m, 59%
a Reaction conditions: anilines (0.4 mmol), FeCl3ꢁ6H2O (1.0 mmol), toluene (2.0 mL), 85 oC, 2 h;
isolated yields. b 8 h.
In order to prepare orthoꢀsubstituted N,Nꢀdibenzylaninlines 2v-x, we investigated
the synthetic route composed of two steps: 1) selfꢀcoupling of orthoꢀmethyl
substituted Nꢀbenzylanilines under optimized conditions; and 2) Nꢀbenzylation with
benzyl bromide (Scheme 2). Following this strategy, benzidines 2v-x were obtained in
moderateꢀtoꢀgood overall yields over the two steps. In addition, the oxidative
coupling of Nꢀbenzyl aniline was applied to the preparation of 6,6'ꢀbisquinoline 5
which was found to be a potential photoactive materials (Scheme 3).14 Benzidine 4m
was obtained through oxidative coupling of the corresponding aniline and underwent
diisopropyl azodicarboxylate (DIAD)ꢀmediated dehydrogenation to afford 5 in 61%
yield.15
Scheme 2. Synthesis of oꢀmethyl substituted benzidines
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2v, 81%
2w, 22%
2x, 25%
Scheme 3. Synthesis of 6,6'ꢀbiquinoline
4m, 59%
5, 61%
Analysis of ultraviolet–visible (UVꢀVis) spectroscopy on selected coupling
products (2a, 2b, 2m, 2p, 2t and 4k) is shown in Figure 1. Compared to dimethyl
substituent 2a (λmax = 313 nm), the wavelengths of maximum absorption (λmax) for
N,N,N',N'ꢀtetrabenzylic substituent 2b and N,N,N',N'ꢀtetrabenzylic 2,5ꢀmethoxyl
substituent 2p redshift to 316 and 319 nm, which indicates that πꢀelectrons in 2b and
2p are more easily excited to higher antiꢀbonding molecular orbital. Different
substitutions on anilines lead to larger blueshifts of the wavelengths of maximum
absorption from 313 nm. N,N,N',N'ꢀTetrabenzylic bromoꢀsubstituent 2t,
N,N'ꢀdibenzylic bromoꢀsubstituent 4k, and N,N,N',N'ꢀtetrabenzylic ethylꢀsubstitution
2m give the wavelengths of maximum absorption at 278, 268 and 269 nm, which
shows that the substitutions on the benzene ring have a stronger impact on the energy
gap between the HOMO and the LUMO.
Figure 1. UVꢀVis spectra of 2a, 2b, 2m, 2p, 2t and 4k (2.5 × 10ꢀ5 M) in
dichloromethane
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compound
λmax, nm
313
є, Mꢀ1 cmꢀ1 (log є)
2a
2b
2m
2p
2t
39200 (4.59)
39000 (4.59)
32920 (4.51)
27720 (4.44)
41040 (4.61)
31480 (4.50)
316
269
319
278
4k
268
In efforts to glean insights into the mechanism, the selfꢀcoupling of 1b was
investigated by mass spectrometry in an attempt to trap iron intermediates. Under the
optimal conditions, iron intermediates were not detected during the course of the
reaction and only aniline 1b and product 2b were observed. A control experiment for
the FeCl3ꢁ6H2Oꢀpromoted oxidative coupling of N,Nꢀdibenzylaniline 1b in the
presence of the radical scavenger 2,2,6,6ꢀtetramethylpiperidinyloxy (TEMPO) was
performed and under these conditions, the reaction was blocked, contrary to Yang’s
report,12 and benzidine 2b could not be detected by LCꢀMS. Based on these results, a
possible radical mechanism for the oxidative selfꢀcoupling reaction was proposed
(Figure 2). Anilines 1a firstly coordinates with Fe3+ to generate iron(III) complex A,
in which methyl group on nitrogen and the paraꢀposition on aniline are both activated.
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With anhydrous FeCl3, radical B and F are formed from active transition state TS1
and give rise to benzidine 2a and 4,4'ꢀmethylenebis(N,Nꢀdimethylaniline) 3a,
respectively (Table 1, entry 4). It is worthwhile noting that an effective hydrogen bond
interaction between chlorine anion and one hydrogen of the methyl group leads to
formation of only 3a. The existence of crystal water decreases the basicity of chlorine
anion through hydrogen bonding interaction with water, and suppresses Clꢀꢀassisted
deprotonation of the methy group to formation of 3a. Thus paraꢀposition on the
aniline is relatively more reactive than methyl group. When hydrated FeCl2 is released
from transition state TS2, a free radical cation F is formed via a SET process. Free
radical cation F reacts with aniline 1a to generate coupling free radical cation G.
Followed by deprotonation and another SETꢀdeprotonation process, the selfꢀcoupling
product 2a is produced. The addition of an extra base such as Et3N and K2CO3 favors
the formation of 3a which lends further credence to hydrogen absorption of Cl (Table
1, entries 12 and 13).
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Figure 2. Proposed mechanism
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Me
Me
N
5
+
FeCl3•nH2O (n = 0 or 6)
6
7
8
1a
CH3
CH3
9
Me
N
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H
N
m
m = 0
Me
Me
H C
H
N
Cl
Cl
Fe Cl
O H
Cl
Cl
Cl
Cl
Cl Fe
Cl Fe
TS1
O
H
m
H
H
m
SET
TS2
A
SET
- FeCl2 mH2O
- FeCl2
.
- (FeCl2 + HCl)
F
H2C
N
N
H3C
F
B
C
2a
1a
SET
H2C
N
H
H
H3C
N
N
G
1a - H+
- H+
N
N
H
N
N
N
N
D
H
Fe3+
SET
- H+
1a
H
N
3a +
2a
E
Conclusions
In summary, we have developed a novel and effective selfꢀcoupling
transformation for the preparation of diversely functionalized benzidine derivatives
from N,Nꢀdialkylanilines and Nꢀmonoalkylanilines utilizing commercially available
FeCl3ꢁ6H2O as an oxidant. This methodology was applied to the preparations of
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valuable safe staining precursors and 6,6'ꢀbiquinoline. Trimeriztion product is
obtained by oneꢀstep synthesis, which possesses potential application in new ligand
design of metal complex catalysis. From our performances, a radical mechanism has
been suggested to account for the formation of benzidines.
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Experimental Section
General information: NMR spectra were recorded on a 500 spectrometer (500 MHz
for 1H, 125 MHz for 13C) with deuterated chloroform (CDCl3) as a solvent at 20ꢀ25 oC.
1H NMR spectra were reported in parts per million using TMS (δ = 0.00 ppm) as an
internal standard. 13C NMR spectra were reported in parts per million using solvent
CDCl3 (δ = 77.2 ppm) as an internal standard. Highꢀresolution mass spectra (HRMS)
were obtained with a QꢀToF MS spectrometer. UVꢀVisible spectroscopy experiments
were performed with CH2Cl2 as solvent at ambient temperature. Unless otherwise
specified, all reagents were purchased from commercial suppliers and used as
received and all experiments were conducted in the atmosphere. Column
chromatography and thinꢀlayer chromatography (TLC) which was used to monitor the
reactions were performed on silica gel.
General Procedure for the oxidative self-coupling reactions: To a stirred mixture
of FeCl3ꢁ6H2O (270.3 mg, 1.0 mmol) and 2.0 mL toluene was added
N,Nꢀdimethylaniline 1a (48.4 mg, 0.4 mmol) at room temperature. The reaction was
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stirred at 85 C for 2 h in atmosphere. After it was cooled to room temperature, the
reaction mixture was quenched by aqueous ammonia solution (mass fraction:
25%ꢀ28%, 10 mL) and extracted with dichloromethane (10 mL per time) until no
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product was observed in the extract, monitored by TLC. The combined extract was
washed with water (10 mL×3) followed by saturated NaCl solution (10 mL×1). The
organic layer was dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure to give crude product, which was chromatographed on silica gel
column using 1:80 (v/v) EtOAcꢀpetroleum ether solution as eluent to afford isolated
product 2a.
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Procedure for LC-MS experiments: To a stirred mixture of FeCl3ꢁ6H2O (270.3 mg,
1.0 mmol) and 2.0 mL toluene was added N,Nꢀdibenzylaniline (109.3 mg, 0.4 mmol)
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at room temperature. The reaction was stirred at 85 C for 40 min or 120 min in
atmosphere. After it was cooled to room temperature, the reaction mixture was
concentrated under reduced pressure to give dark red solid. The solid was dissolved in
acetonitrile for LCꢀMS analysis, the results of which demonstrated that only starting
material 1b and coupling product 2b was detected after 40 min and only coupling
product 2b was observed after 120 min, respectively. See supporting information for
LCꢀMS spectra.
Procedure for control experiment utilizing 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO): To a stirred mixture of FeCl3ꢁ6H2O (270.3 mg, 1 mmol) in 2.0 mL toluene
was added N,Nꢀdibenzylaniline
1b (109.3 mg, 0.4 mmol) and
2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀoxyl (125.0 mg, 0.8 mmol) successively at room
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temperature. The reaction mixture was stirred at 85 C for 2 h in atmosphere. After it
was cooled to room temperature, the reaction mixture was quenched by aqueous
ammonia solution (mass fraction: 25%ꢀ28%, 10 mL). After extraction, no desired
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coupling product 2b was examined by TLC and LCꢀMS which indicated that the
selfꢀcoupling of N,Nꢀdibenzylaniline was prohibited by TEMPO, therefore the
selfꢀcoupling reaction might undergo a radical pathway.
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N,N,N',N'-tetramethyl-[1,1'-biphenyl]-4,4'-diamine (2a):9a White solid; yield 88%,
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42.3 mg; mp: 190ꢀ192 C; H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 9.0 Hz, 4H),
6.80 (d, J = 8.5 Hz, 4H), 2.97 (s, 12H); 13C NMR (125 MHz, CDCl3) δ 149.4, 130.0,
127.1, 113.2, 41.0; HRMS (ESI) calcd. for C16H21N2 (M+H)+ 241.1705, found
241.1704.
N,N,N',N'-tetrabenzyl-[1,1'-biphenyl]-4,4'-diamine (2b): White solid; yield 96%,
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1
104.6 mg; mp: 196ꢀ197 C; H NMR (500 MHz, CDCl3) δ 7.34ꢀ7.31 (m, 12H),
7.27ꢀ7.23 (m, 12H), 6.75 (d, J = 9.0 Hz, 4H), 4.66 (s, 8H); 13C NMR (125 MHz,
CDCl3) δ 147.9, 138.8, 129.9, 128.8, 127.2, 127.0, 126.8, 112.9, 54.4; HRMS (ESI)
calcd. for C40H37N2 (M+H)+ 545.2957, found 545.2948.
4,4'-di(pyrrolidin-1-yl)-1,1'-biphenyl (2c): White solid; yield 42%, 24.6 mg; mp:
o
1
208 C; H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 7.5 Hz, 4H), 6.61 (d, J = 7.5 Hz,
4H), 3.31 (s, 8H), 2.00 (s, 8H); 13C NMR (125 MHz, CDCl3) δ 146.7, 129.1, 127.1,
112.1, 47.9, 25.6; HRMS (ESI) calcd. for C20H25N2 (M+H)+ 293.2018, found
293.2007.
N,N,N',N'-tetraethyl-[1,1'-biphenyl]-4,4'-diamine (2d):9a White solid; yield 30%,
17.8 mg; mp: 87ꢀ88 oC; 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 8.5 Hz, 4H), 6.72
(d, J = 8.0 Hz, 4H), 3.37 (s, 8H), 1.18 (t, J = 7.0 Hz, 12H); 13C NMR (125 MHz,
CDCl3) δ 146.4, 129.0, 127.3, 112.3, 44.6, 12.9; HRMS (ESI) calcd. for C20H29N2
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(M+H)+ 297.2331, found 297.2327.
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N4,N4'-dibenzyl-N4,N4'-dimethyl-[1,1'-biphenyl]-4,4'-diamine (2e): White solid;
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9
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yield 77%, 60.4 mg; mp: 146ꢀ147 C; 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 8.5
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Hz, 4H), 7.32ꢀ7.30 (m, 4H), 7.26ꢀ7.24 (m, 6H), 6.78 (d, J = 8.5Hz, 4H), 4.54 (s, 4H),
3.03 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 148.5, 139.3, 129.8, 128.7, 127.2, 127.0,
126.9, 112.9, 56.9, 38.8; HRMS (ESI) calcd. for C28H29N2 (M+H)+ 393.2331, found
393.2331.
N4,N4,N4',N4'-tetrakis(2-methoxyethyl)-[1,1'-biphenyl]-4,4'-diamine (2f): White
o
solid; yield 54%, 43.3 mg; mp: 49ꢀ51 C; 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J =
8.5 Hz, 4H), 6.75 (d, J = 9.0 Hz, 4H), 3.59ꢀ3.56 (m, 16H), 3.37 (s, 12H); 13C NMR
(125 MHz, CDCl3) δ 146.5, 129.4, 127.3, 112.2, 70.3, 59.2, 51.2; HRMS (ESI) calcd.
for C24H37N2O4 (M+H)+ 417.2753, found 417.2763.
N4,N4'-dibenzyl-N4,N4',2,2',6,6'-hexamethyl-[1,1'-biphenyl]-4,4'-diamine
(2g):
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White solid; yield 73%, 65.5 mg; mp: 96ꢀ97 C; H NMR (500 MHz, CDCl3) δ
7.35ꢀ7.29 (m, 8H), 7.25ꢀ7.24 (m, 2H), 6.55 (s, 4H), 4.51 (s, 4H), 2.96 (s, 6H), 1.87 (s,
12H); 13C NMR (125 MHz, CDCl3) δ 148.9, 139.9, 137.3, 129.5, 128.6, 127.3, 126.9,
111.8, 57.2, 38.3, 20.8; HRMS (ESI) calcd. for C32H37N2 (M+H)+ 449.2957, found
449.2959.
N4,N4'-dibenzyl-N4,N4'-bis(4-methylbenzyl)-[1,1'-biphenyl]-4,4'-diamine
(2h):
o
1
White solid; yield 70%, 80.1 mg; mp: 200ꢀ201 C; H NMR (500 MHz, CDCl3) δ
7.37ꢀ7.33 (m, 8H), 7.29ꢀ7.28 (m, 6H), 7.19ꢀ7.15 (m, 8H), 6.78 (d, J = 8.5 Hz, 4H),
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4.67 (s, 4H), 4.65 (s, 4H), 2.36 (s, 6H); C NMR (125 MHz, CDCl3) δ 148.0, 138.9,
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136.6, 135.7, 129.9, 129.5, 128.8, 127.2, 127.0, 126.9, 112.9, 54.3, 54.2, 21.3; HRMS
(ESI) calcd. for C42H41N2 (M+H)+ 573.3270, found 573.3271.
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N,N,N',N'-tetrabenzyl-2,2'-dimethyl-[1,1'-biphenyl]-4,4'-diamine (2k): White
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solid; yield 44%, 50.4 mg; mp: 169ꢀ170 C; 1H NMR (500 MHz, CDCl3) δ 7.34ꢀ7.31
(m, 8H), 7.28ꢀ7.23 (m, 12H), 6.90 (d, J = 8.5 Hz, 2H), 6.64 (d, J = 2.5 Hz, 2H), 6.57
(dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 2H), 4.63 (s, 8H), 1.99 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 148.4, 139.1, 137.4, 131.1, 130.7, 128.8, 127.0, 127.0, 113.5, 109.9, 54.2,
20.9; HRMS (ESI) calcd. for C42H41N2 (M+H)+ 573.3270, found 573.3260.
N4,N4,N4',N4'-tetrabenzyl-2,2',6,6'-tetramethyl-[1,1'-biphenyl]-4,4'-diamine
(2l):10a White solid; yield 92%, 110.5 mg; mp: 189ꢀ190 C; H NMR (500 MHz,
CDCl3) δ 7.33ꢀ7.21 (m, 20H), 6.53 (s, 4H), 4.59 (s, 8H), 1.82 (s, 12H); 13C NMR (125
MHz, CDCl3) δ 148.3, 139.4, 137.2, 129.5, 128.7, 127.2, 126.9, 111.7, 53.9, 20.8;
HRMS (ESI) calcd. for C44H45N2 (M+H)+ 601.3583, found 601.3565.
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N4,N4,N4',N4'-tetrabenzyl-2,2'-diethyl-[1,1'-biphenyl]-4,4'-diamine (2m): White
solid; yield 95%, 114.0 mg; mp: 138ꢀ139 oC; 1H NMR (500 MHz, CDCl3) δ 7.34ꢀ7.29
(m, 16H), 7.26ꢀ7.23 (m, 4H), 6.89 (d, J = 8.5 Hz, 2H), 6.67 (d, J = 2.0 Hz, 2H), 6.57
(dd, J1 = 8.5 Hz, J2= 2.5 Hz, 2H), 4.64 (s, 8H), 2.29 (dq, J1 = 7.5 Hz, J2= 2.5 Hz, 4H),
0.92 (t, J = 7.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 148.7, 143.5, 139.3, 131.4,
129.9, 128.7, 127.1, 127.0, 112.3, 109.9, 54.4, 26.8, 15.5; HRMS (ESI) calcd. for
C44H45N2 (M+H)+ 601.3583, found 601.3572.
N4,N4,N4',N4'-tetrabenzyl-2,2'-diisopropyl-[1,1'-biphenyl]-4,4'-diamine
(2n):
o
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White solid; yield 99%, 124.5 mg; mp: 58ꢀ59 C; H NMR (500 MHz, CDCl3) δ
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7.32ꢀ7.25 (m, 20H), 6.86 (d, J = 7.5 Hz, 2H), 6.69 (s, 2H), 6.56 (d, J = 7.5 Hz, 2H),
4.64 (s, 8H), 2.72(quat, J = 6.0 Hz, 1H), 2.71 (quat, J = 6.0 Hz, 1H), 0.95 (d, J = 6.5
Hz, 6H), 0.94 (d, J = 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 148.8, 148.1, 139.3,
131.3, 129.4, 128.7, 127.1, 127.0, 110.0, 109.7, 54.7, 30.0, 24.9, 23.5; HRMS (ESI)
calcd. for C46H49N2 (M+H)+ 629.3896, found 629.3896.
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N,N,N',N'-tetrabenzyl-[1,1'-binaphthalene]-4,4'-diamine (2o): White solid; yield
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85%, 109.6 mg; mp: 170ꢀ171 C; H NMR (500 MHz, CDCl3) δ 8.64 (d, J = 8.0 Hz,
2H), 7.53ꢀ7.50 (m, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.34ꢀ7.27 (m, 19H), 7.25ꢀ7.18 (m,
5H), 7.00 (d, J = 7.5 Hz, 2H), 4.36 (s, 8H); 13C NMR (125 MHz, CDCl3) δ 147.4,
138.4, 134.6, 134.1, 129.7, 128.8, 128.4, 127.9, 127.5, 127.2, 125.9, 125.5, 124.1,
118.1, 57.3; HRMS (ESI) calcd. for C48H41N2 (M+H)+ 645.3270, found 645.3261.
N4,N4,N4',N4'-tetrabenzyl-2,2',5,5'-tetramethoxy-[1,1'-biphenyl]-4,4'-diamine (2p):
o
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White solid; yield 53%, 70.5 mg; mp: 156ꢀ157 C; H NMR (500 MHz, CDCl3) δ
7.34ꢀ7.25 (m, 16H), 7.22ꢀ7.18 (m, 4H), 6.85 (s, 2H), 6.45 (s, 2H), 4.30 (s, 8H), 3.85 (s,
6H), 3.51 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 151.1, 146.7, 139.8, 139.3, 128.6,
128.3, 126.9, 120.4, 116.3, 106.9, 56.8, 56.6, 55.8; HRMS (ESI) calcd. for C44H45N2
O4(M+H)+ 665.3379, found 665.3359.
N4,N4,N4',N4'-tetrabenzyl-2,2'-diethoxy-[1,1'-biphenyl]-4,4'-diamine (2q): Slightly
o
1
yellow solid; yield 18%, 22.8 mg; mp: 63ꢀ64 C; H NMR (500 MHz, CDCl3) δ
7.32ꢀ7.24 (m, 20H), 7.06 (d, J = 8.0 Hz, 2H), 6.36 (d, J = 7.5 Hz, 2H), 6.31 (s, 2H),
4.63 (s, 8H), 3.78 (quat, J = 6.5 Hz, 4H), 1.13 (t, J = 6.0 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 157.3, 149.5, 139.2, 132.4, 128.7, 127.0, 127.0, 117.3, 105.0, 98.4,
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63.8, 54.6, 14.9; HRMS (ESI) calcd. for C44H45N2O2 (M+H)+ 633.3481, found
633.3470.
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N4,N4,N4',N4'-tetrabenzyl-2,2'-dichloro-[1,1'-biphenyl]-4,4'-diamine (2s): White
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solid; yield 46%, 56.1 mg; mp: 202ꢀ203 C; 1H NMR (500 MHz, CDCl3) δ 7.35ꢀ7.32
(m, 8H), 7.28ꢀ7.24 (m, 12H), 7.03 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 2.5 Hz, 2H), 6.63
(dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 2H), 4.64 (s, 8H); 13C NMR (125 MHz, CDCl3) δ 149.7,
138.1, 134.9, 132.5, 128.9, 127.3, 126.8, 126.7, 112.6, 110.7, 54.2; HRMS (ESI) calcd.
for C40H35Cl2N2 (M+H)+ 613.2177, found 613.2120.
N4,N4,N4',N4'-tetrabenzyl-2,2'-dibromo-[1,1'-biphenyl]-4,4'-diamine (2t): White
solid; yield 97%, 136.4 mg; mp: 203ꢀ204 oC; 1H NMR (500 MHz, CDCl3) δ 7.35ꢀ7.32
(m, 8H), 7.28ꢀ7.24 (m, 12H), 7.02 (d, J = 2.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.66
(dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 2H), 4.63 (s, 8H); 13C NMR (125 MHz, CDCl3) δ 149.7,
138.1, 132.3, 130.5, 128.9, 127.3, 126.9, 125.4, 115.6, 111.2, 54.1; HRMS (ESI) calcd.
for C40H35Br2N2 (M+H)+ 701.1167, found 701.1217.
N4,N4,N4',N4'-tetrabenzyl-2,2'-diiodo-[1,1'-biphenyl]-4,4'-diamine (2u): White
solid; yield 98%, 156.0 mg; mp: 185ꢀ186 oC; 1H NMR (500 MHz, CDCl3) δ 7.36ꢀ7.33
(m, 8H), 7.30 (d, J = 2.5 Hz, 2H), 7.28ꢀ7.24 (m, 12H), 6.94 (d, J = 8.5 Hz, 2H), 6.71
(dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 2H), 4.62 (s, 8H); 13C NMR (125 MHz, CDCl3) δ 149.5,
138.1, 137.8, 130.9, 128.9, 127.3, 126.9, 121.8, 112.1, 102.5, 54.0; HRMS (ESI) calcd.
for C40H35I2N2 (M+H)+ 797.0890, found 797.0878.
N4,N4,N4',N4'-tetrabenzyl-2,2',3,3'-tetramethyl-[1,1'-biphenyl]-4,4'-diamine (2v):
A mixture of isolated 4e of standard condition (72.3 mg, 0.17 mmol), benzylic
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bromide (65.0 mg, 0.38 mmol) and K2CO3 (95.1 mg, 0.69 mmol) in 2.0 mL
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acetonitrile was stirred at 100 C for 4 h in atmosphere. After it was cooled to room
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temperature, the reaction mixture was concentrated under reduced pressure to afford
crude product, which was chromatographed on silica gel column using 1:70 (v/v)
EtOAcꢀpetroleum ether solution as eluent to afford product 2v. Slight yellow gum;
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overall yield 81%, 97.3 mg; H NMR (500 MHz, CDCl3) δ 7.29ꢀ7.27 (m, 4H),
7.26ꢀ7.23 (m, 13H), 7.22ꢀ7.20 (m, 3H), 6.80 (d, J = 3.0 Hz, 4H), 4.06 (s, 8H), 2.42 (s,
6H) 1.94 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 148.7, 138.7, 138.2, 136.0, 132.3,
129.1, 128.2, 127.1, 127.0, 119.7, 57.2, 17.6, 15.0; HRMS (ESI) calcd. for C44H45N2
(M+H)+ 601.3583, found 601.3577.
N4,N4,N4',N4'-tetrabenzyl-3,3'-dimethyl-[1,1'-biphenyl]-4,4'-diamine
(2w):
A
mixture of isolated 4a of standard condition (22.1 mg, 0.056 mmol), benzylic
bromide (21.1 mg, 0.12 mmol) and K2CO3 (30.9 mg, 0.22 mmol) in 2.0 mL
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acetonitrile was stirred at 100 C for 4 h in atmosphere. After it was cooled to room
temperature, the reaction mixture was concentrated under reduced pressure to afford
crude product, which was chromatographed on silica gel column using 1:70 (v/v)
EtOAcꢀpetroleum ether solution as eluent to afford product 2s. White solid; overall
o
yield 22%, 25.2 mg; mp: 145ꢀ146 C; 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 1.5
Hz, 2H), 7.28ꢀ7.26 (m, 17H), 7.25ꢀ7.21 (m, 5H), 6.95 (d, J = 8.5 Hz, 2H), 4.10 (s, 8H),
2.49 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 149.0, 138.7, 135.9, 134.0, 129.6, 128.9,
128.3, 127.1, 124.5, 122.8, 57.0, 18.9; HRMS (ESI) calcd. for C42H41N2 (M+H)+
573.3270, found 573.3257.
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N4,N4,N4',N4'-tetrabenzyl-3,3',5,5'-tetramethyl-[1,1'-biphenyl]-4,4'-diamine (2x):
A mixture of isolated 4b of standard condition (31.1 mg, 0.074 mmol), benzylic
bromide (27.8 mg, 0.16 mmol) and K2CO3 (40.9 mg, 0.30 mmol) in 2.0 mL
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acetonitrile was stirred at 100 C for 4 h in atmosphere. After it was cooled to room
temperature, the reaction mixture was concentrated under reduced pressure to afford
crude product, which was chromatographed on silica gel column using 1:70 (v/v)
EtOAcꢀpetroleum ether solution as eluent to afford product 2t. white solid; overall
yield 25%, 30.0 mg; mp: 94ꢀ95 oC; 1H NMR (500 MHz, CDCl3) δ 7.30ꢀ7.27 (m, 8H),
7.25ꢀ7.24 (m, 8H), 7.23ꢀ7.21 (m, 8H), 4.11 (s, 8H), 2.21 (s, 12H); 13C NMR (125
MHz, CDCl3) δ 147.4, 139.7, 137.2, 137.1, 129.4, 128.3, 127.7, 127.1, 56.5, 20.2;
HRMS (ESI) calcd. for C44H45N2 (M+H)+ 601.3583, found 601.3561.
1,1'-dibenzyl-1,1',2,2',3,3',4,4'-octahydro-6,6'-biquinoline (2y): Slight yellow solid;
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yield 61%, 54.2 mg; mp: 179ꢀ180 C; yield 61%, 54.2 mg; H NMR (500 MHz,
CDCl3) δ 7.33ꢀ7.28 (m, 8H), 7.24ꢀ7.22 (m, 2H), 7.14ꢀ7.12 (m, 4H), 6.52 (d, J = 8.0
Hz, 2H), 4.48 (s, 4H), 3.36 (s, 4H), 2.85 (t, J = 6.0 Hz, 4H), 2.03 (quint, J = 6.0 Hz,
4H); 13C NMR (125 MHz, CDCl3) δ 144.3, 139.3, 129.5, 128.7, 127.2, 126.9, 126.8,
125.1, 122.5, 111.5, 55.5, 50.1, 28.5, 22.7; HRMS (ESI) calcd. for C32H33N2 (M+H)+
445.2643, found 445.2646.
N4,N4,N4',N4',N4'',N4''-hexabenzyl-2,2'',6'-triethoxy-[1,1':3',1''-terphenyl]-4,4',4''-t
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riamine (2z): White solid; yield 52%, 65.7 mg; mp: 60ꢀ61 C; H NMR (500 MHz,
CDCl3) δ 7.33ꢀ7.27 (m, 16H), 7.25ꢀ7.22 (m, 4H), 7.20ꢀ7.14 (m, 6H), 7.13ꢀ7.11 (m,
5H), 7.08ꢀ7.06 (m, 2H), 6.43 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 1H), 6.41 (s, 1H), 6.37 (dd,
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J1 = 8.5 Hz, J2 = 2.5 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 6.29 (d, J = 2.0 Hz, 1H), 4.64
(s, 4H), 4.62 (s, 4H), 3.94 (s, 4H), 3.82 (quat, J = 7.0 Hz, 2H), 3.73 (quat, J = 7.0 Hz,
2H), 3.71 (quat, J = 7.0 Hz, 2H), 1.15 (t, J = 7.0 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H),
1.03 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 157.6, 157.2, 155.3, 149.7,
149.2, 139.1, 139.1, 135.8, 132.7, 132.3, 129.1, 128.8, 128.7, 128.0, 127.1, 127.0,
126.6, 126.0, 122.2, 119.8, 117.9, 106.9, 105.4, 105.0, 99.2, 98.2, 64.4, 64.0, 63.6,
56.3, 54.6, 54.5, 15.0, 14.9; HRMS (ESI) calcd. for C66H66N3O3 (M+H)+ 948.5104,
found 948.5117.
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4,4'-methylenebis(N,N-dimethylaniline) (3a): To a stirred mixture of FeCl3ꢁ6H2O
(270.3 mg, 1.0 mmol), triethylamine (40.5 mg, 0.4 mmol) and 2.0 mL toluene was
added N,Nꢀdimethylaniline 1a (48.4 mg, 0.4 mmol) at room temperature. The
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reaction was stirred at 85 C for 2 h in atmosphere. After it was cooled to room
temperature, the reaction mixture was quenched by aqueous ammonia solution (mass
fraction: 25%ꢀ28%, 10 mL) and extracted with dichloromethane (10 mL per time)
until no product was observed in the extract, monitored by TLC. The combined
extract was washed with water (10 mL×3) followed by saturated NaCl solution (10
mL×1). The organic layer was dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure to give crude product, which was chromatographed on silica
gel column using 1:70 (v/v) EtOAcꢀpetroleum ether solution as eluent to afford
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isolated product 3a. white solid; yield 68%, 23.0 mg; mp: 90ꢀ91 C; H NMR (500
MHz, CDCl3) δ 7.05 (d, J = 9.0 Hz, 4H), 6.68 (d, J = 8.5 Hz, 4H), 3.80 (s, 2H), 2.89
(s, 12H); 13C NMR (125 MHz, CDCl3) δ 149.3, 130.5, 129.6, 113.2, 41.1, 40.1;
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HRMS (ESI) calcd. for C17H23N2 (M+H)+ 255.1861, found 255.1863.
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N4,N4'-dibenzyl-3,3'-dimethyl-[1,1'-biphenyl]-4,4'-diamine (4a): White solid; yield
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28%, 22.1 mg; mp: 167ꢀ168 C; H NMR (500 MHz, CDCl3) δ 7.43ꢀ7.41 (m, 4H),
7.39ꢀ7.36 (m, 4H), 7.32ꢀ7.28 (m, 6H), 6.66 (d, J = 8.5 Hz, 2H), 4.41 (s, 4H), 3.86 (s,
2H), 2.23 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 144.8, 139.8, 130.9, 128.8, 128.6,
127.7, 127.4, 125.2, 122.4, 110.5, 48.7, 17.9; HRMS (ESI) calcd. for C28H29N2
(M+H)+ 393.2331, found 393.2325.
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N4,N4'-dibenzyl-3,3',5,5'-tetramethyl-[1,1'-biphenyl]-4,4'-diamine (4b): white
solid; yield 37%, 31.1 mg; mp: 90ꢀ91 oC; 1H NMR (500 MHz, CDCl3) δ 7.39ꢀ7.38 (m,
4H), 7.36ꢀ7.33 (m, 4H), 7.30ꢀ7.27 (m, 2H), 7.22 (s, 4H), 4.14 (s, 4H), 3.21 (br, 2H),
2.32 (s, 12H); 13C NMR (125 MHz, CDCl3) δ 145.0, 140.7, 135.1, 130.1, 128.8, 128.2,
127.5, 127.4, 53.2, 18.9; HRMS (ESI) calcd. for C30H33N2 (M+H)+ 421.2644, found
421.2642.
N4,N4'-dibenzyl-2,2'-dimethyl-[1,1'-biphenyl]-4,4'-diamine (4c): White solid; yield
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55%, 43.2 mg; mp: 144ꢀ145 C; H NMR (500 MHz, CDCl3) δ 7.44ꢀ7.42 (m, 4H),
7.40ꢀ7.37 (m, 4H), 7.32ꢀ7.30 (m, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 2.0 Hz,
2H), 6.52 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 2H), 4.36 (s, 4H), 3.95 (s, 2H), 2.03 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 147.2, 139.8, 137.6, 131.6, 131.1, 128.8, 127.9, 127.4,
114.2, 110.1, 48.8, 20.5; HRMS (ESI) calcd. for C28H29N2 (M+H)+ 393.2331, found
393.2332.
N4,N4'-dibenzyl-2,2',6,6'-tetramethyl-[1,1'-biphenyl]-4,4'-diamine (4d): White
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gum; yield 66%, 55.5 mg; H NMR (500 MHz, CDCl3) δ 7.40ꢀ7.39 (m, 4H),
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7.36ꢀ7.33 (m, 4H), 7.29ꢀ7.26 (m, 2H), 6.43 (s, 4H), 4.29 (s, 4H), 3.78 (br, 2H), 1.84 (s,
12H); 13C NMR (125 MHz, CDCl3) δ 146.9, 139.9, 137.4, 130.2, 128.7, 128.0, 127.4,
112.0, 48.9, 20.4; HRMS (ESI) calcd. for C30H33N2 (M+H)+ 421.2644, found
421.2643.
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N4,N4'-dibenzyl-2,2',3,3'-tetramethyl-[1,1'-biphenyl]-4,4'-diamine (4e): white solid;
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yield 86%, 72.3 mg; mp: 138ꢀ140 C; H NMR (500 MHz, CDCl3) δ 7.44ꢀ7.42 (m,
4H), 7.38ꢀ7.35 (m, 4H), 7.31ꢀ7.26 (m, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.57 (d, J = 8.5
Hz, 2H), 4.38 (s, 4H), 3.81 (s, 2H), 2.13 (s, 6H), 2.01 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 144.9, 140.0, 135.4, 133.2, 128.8, 128.4, 128.0, 127.4, 120.4, 107.9, 49.0,
17.7, 13.4. HRMS (ESI) calcd. for C30H33N2 (M+H)+ 421.2644; found 421.2636.
N4,N4'-dibenzyl-2,2'-diethyl-[1,1'-biphenyl]-4,4'-diamine (4f): White gum; yield
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44%, 37.0 mg; H NMR (500 MHz, CDCl3) δ 7.46ꢀ7.45 (m, 4H), 7.42ꢀ7.39 (m, 4H),
7.34ꢀ7.32 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.63 (d, J = 2.5 Hz, 2H), 6.54 (dd, J1 =
8.0 Hz, J2 = 2.0 Hz, 2H), 4.38 (s, 4H), 3.98 (s, 2H), 2.41ꢀ2.33 (m, 4H), 1.06 (t, J = 7.5
Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 147.4, 143.7, 139.8, 131.5, 130.8, 128.8,
127.9, 127.4, 112.7, 109.9, 48.9, 26.6, 15.3; HRMS (ESI) calcd. for C30H33N2 (M+H)+
421.2644, found 421.2639.
N4,N4'-dibenzyl-2,2'-diisopropyl-[1,1'-biphenyl]-4,4'-diamine (4g): Slight yellow
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gum; yield 33%, 29.7 mg; H NMR (500 MHz, CDCl3) δ 7.42ꢀ7.41 (m, 4H),
7.37ꢀ7.34 (m, 4H), 7.30ꢀ7.27 (m, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.63 (d, J = 2.5 Hz,
2H), 6.48 (dd, J1 = 8.0 Hz, J2 = 2.5 Hz, 2H), 4.33 (s, 4H), 3.90 (br, 2H), 2.73 (heptet,
J = 7.0 Hz, 2H), 1.09ꢀ1.04 (m, 12H); 13C NMR (125 MHz, CDCl3) δ 148.5, 147.5,
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139.8, 131.4, 130.3, 128.8, 128.0, 127.4, 109.8, 49.0, 30.0, 24.9, 23.3; HRMS (ESI)
calcd. for C32H37N2 (M+H)+ 449.2957, found 449.2960.
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N4,N4'-dibenzyl-3,3'-diethoxy-[1,1'-biphenyl]-4,4'-diamine (4h): light gray solid;
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yield 35%, 31.6 mg; mp: 140ꢀ141 C; H NMR (500 MHz, CDCl3) δ 7.42ꢀ7.41 (m,
4H), 7.38ꢀ7.35 (m, 4H), 7.30ꢀ7.27 (m, 2H), 6.99 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 2H),
6.97 (s, 2H), 6.61 (d, J = 8.0 Hz, 2H), 4.68 (s, 2H), 4.41 (s, 4H), 4.14 (quat, J = 7.0
Hz, 4H), 1.45 (t, J = 7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 146.5, 140.0, 137.1,
131.0, 128.7, 127.6, 127.2, 119.3, 110.5, 109.6, 64.1, 48.3, 15.2; HRMS (ESI) calcd.
for C30H33N2O2 (M+H)+ 453.2542, found 453.2533.
N4,N4'-dibenzyl-2,2',5,5'-tetramethoxy-[1,1'-biphenyl]-4,4'-diamine (4i): White
solid; yield 30%, 29.2 mg; mp: 179ꢀ180 C; 1H NMR (500 MHz, CDCl3) δ 7.45ꢀ7.43
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(m, 4H), 7.39ꢀ7.36 (m, 4H), 7.31ꢀ7.28 (m, 2H), 6.75 (s, 2H), 6.32 (s, 2H), 4.67 (s, 2H),
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4.39 (s, 4H), 3.81 (s, 6H), 3.65 (s, 6H); C NMR (125 MHz, CDCl3) δ 152.0, 140.9,
139.8, 138.1, 128.8, 127.8, 127.3, 115.3, 113.8, 96.9, 56.9, 56.2, 48.5; HRMS (ESI)
calcd. for C30H33N2O4 (M+H)+ 485.2440, found 485.2435.
N4,N4'-dibenzyl-2,2'-dichloro-[1,1'-biphenyl]-4,4'-diamine (4j): Slight yellow solid;
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yield 19%, 16.0 mg; mp: 153ꢀ154 C; H NMR (500 MHz, CDCl3) δ 7.37ꢀ7.35 (m,
8H), 7.31ꢀ7.28 (m, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 2.5 Hz, 2H), 6.54 (dd, J1
= 8.0 Hz, J2 = 2.5 Hz, 2H), 4.32 (s, 4H), 4.13 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
148.5, 139.0, 134.9, 132.5, 128.9, 127.7, 127.6, 127.5, 112.9, 111.3, 48.4; HRMS (ESI)
calcd. for C26H23Cl2N2 (M+H)+ 433.1238, found 433.1239.
N4,N4'-dibenzyl-2,2'-dibromo-[1,1'-biphenyl]-4,4'-diamine (4k): White solid; yield
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42%, 44.0 mg; mp: 173ꢀ174 C; H NMR (500 MHz, CDCl3) δ 7.37ꢀ7.30 (m, 10H),
7.01 (d, J = 8.5 Hz, 2H), 6.92 (s, 2H), 6.58 (d, J = 8.5 Hz, 2H), 4.32 (s, 4H), 4.10 (s,
2H); 13C NMR (125 MHz, CDCl3) δ 148.6, 138.9, 132.3, 131.3, 128.9, 127.8, 127.7,
125.3, 115.9, 111.7, 48.4; HRMS (ESI) calcd. for C26H23Br2N2 (M+H)+ 521.0228,
found 521.0246.
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N4,N4'-dibenzyl-2,2'-diiodo-[1,1'-biphenyl]-4,4'-diamine (4l): White solid; yield
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42%, 52.0 mg; mp: 152ꢀ153 C; H NMR (500 MHz, CDCl3) δ 7.37ꢀ7.34 (m, 8H),
7.32ꢀ7.28 (m, 2H), 7.19 (d, J = 2.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.61 (dd, J1 =
8.5 Hz, J2 = 2.5 Hz, 2H), 4.30 (s, 4H), 4.04 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
148.3, 138.9, 138.6, 130.9, 128.9, 127.8, 127.7, 122.1, 112.5, 102.3, 48.4; HRMS
(ESI) calcd. for C26H23I2N2 (M+H)+ 616.9951, found 616.9971.
1,1',2,2',3,3',4,4'-octahydro-6,6'-biquinoline (4m):16 White solid; yield 59%, 31.1
mg; mp: 126ꢀ127 oC; 1H NMR (500 MHz, CDCl3) δ 7.16 (d, J = 7.5 Hz, 2H),7.14 (s,
2H), 6.51 (d, J = 7.5 Hz, 2H), 3.80 (s, 2H), 3.32 (s, 4H), 2.82 (s, 4H), 1.98 (s, 4H); 13C
NMR (125 MHz, CDCl3) δ 143.4, 130.9, 127.6, 125.0, 121.7, 114.7, 42.3, 27.3, 22.5;
HRMS (ESI) calcd. for C18H21N2 (M+H)+ 265.1705, found 265.1699.
6,6'-biquinoline (5):15 A solution of isolated 4m (132 mg, 0.5 mmol) and diisopropyl
azodicarboxylate (DIAD; 485.3 mg, 2.4 mmol) in 1.5 mL acetonitrile was stirred at
room temperature for 1 h in atmosphere. Then the reaction mixture was concentrated
under reduced pressure to afford crude product, which was chromatographed on silica
gel column using 1:1 (v/v) EtOAcꢀpetroleum ether solution as eluent to give
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6,6'ꢀbiquinoline 5. white solid; mp: 179ꢀ181 C; yield 61%, 81 mg; H NMR (500
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MHz, CDCl3) δ 8.95 (s, 2H), 8.26ꢀ8.23 (m 4H), 8.14ꢀ8.10 (m, 4H), 7.47 (s, 2H); C
NMR (125 MHz, CDCl3) δ 150.9, 148.0, 138.6, 136.5, 130.4, 129.4, 128.7, 126.3,
121.9; HRMS (ESI) calcd. for C18H12N2 (M+H)+ 257.1079, found 257.1068.
Acknowledgments
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We thank faithfully scientific research fundings of the Scientific Research Foundation
for the Returned Overseas Chinese Scholars, State Education Ministry, Partenariats
Hubert Curien Xu Guangqi 2012 (No. 27967RE), Fundamental Reseach Funds for the
Central Universities (No. CDJRC10220004 and No. CDJZR11220005), State Key
Laboratory of Elementoꢀorganic Chemistry, Nankai University (No. 201201) and the
National Natural Science Foundation of China (No. 21273292) for financial support
and Dr. Vincent Coeffard (CNRS) for constructive suggestions and discussions.
Supporting Information.
Experimental procedures, solvent optimization, Xꢀray structure of 2y, LCꢀMS spectra,
1H and 13C NMR spectra for all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) (a) Feiring, A. E.; Auman, B. C.; Wonchoba, E. R. Macromolecules. 1993, 26,
2779. (b) Chen, R.ꢀF.; Fan, Q.ꢀL.; Zheng, C.; Huang, W. Org. Lett. 2006, 8, 203.
(2) Vogel, A. I. Practical Organic Chemistry, 5th ed.; Longman: London, 1991; p 49.
(3) (a) Holland, V. R.; Saunders, B. C.; Rose, F. L.; Walpole, A. L. Tetrahedron. 1974,
30, 3299. (b) Liu, L.ꢀF.; Zhang, Y.ꢀL.; Qian, X.ꢀH. Dyes Pigments. 2004, 60, 17.
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