Palladium-catalysed Suzuki-Miyaura coupling reactions of Bromhexine and Ambroxol

Article abstract of DOI:10.1016/j.tet.2014.05.116

The Suzuki-Miyaura coupling reaction was applied for the synthesis of biologically relevant derivatives of known mucolytic agents Bromhexine and Ambroxol. Using commercially available electron-rich and electron-poor arylboronic acids the desired products

Full text of DOI:10.1016/j.tet.2014.05.116

Accepted Manuscript
Palladium–catalysed Suzuki–Miyaura Coupling Reactions of Bromhexine and
Ambroxol
Muhammad Sharif , Anahit Pews–Davtyan , Jan Lukas , Susann Pohlers , Arndt
Rolfs , Peter Langer , Matthias Beller
PII:
S0040-4020(14)00846-1
10.1016/j.tet.2014.05.116
TET 25665
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 February 2014
Revised Date: 30 May 2014
Accepted Date: 31 May 2014
Please cite this article as: Sharif M, Pews–Davtyan A, Lukas J, Pohlers S, Rolfs A, Langer P, Beller M,
Palladium–catalysed Suzuki–Miyaura Coupling Reactions of Bromhexine and Ambroxol, Tetrahedron
(2014), doi: 10.1016/j.tet.2014.05.116.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Leave this area blank for abstract info.
Palladium–catalysed Suzuki–Miyaura Coupling
Reactions of Bromhexine and Ambroxol
Muhammad Sharif,[a,c] Anahit Pews-Davtyan,[a] Jan Lukas,[b] Susann Pohlers,[b] Arndt Rolfs,*[b] Peter
Langer,[a,d] and Matthias Beller*[a]
aLeibniz-Institut für Katalyse an der Universität Rostock e.V. Albert-Einstein-Str. 29a, 18059 Rostock, Germany
bAlbrecht Kossel-Institute for Neuroregeneration, Medical University Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
cDepartment of Chemistry, COMSATS Institute of Information Technology, Abbottabad, Pakistan
dInstitut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
The Suzuki-Miyaura coupling reaction was applied for the synthesis of biologically relevant derivatives of known
mucolytic agents Bromhexine and Ambroxol. Using commercially available electron–rich and electron–poor arylboronic
acids the desired products are obtained in moderate to high yields (42-81%).

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Palladium–catalysed Suzuki–Miyaura Coupling Reactions of
Bromhexine and Ambroxol
Muhammad Sharif,[a,c] Anahit Pews–Davtyan,[a] Jan Lukas,[b] Susann Pohlers,[b] Arndt Rolfs,*[b]
[a]
Peter Langer,[a,d] and Matthias Beller
aLeibniz–Institut für Katalyse an der Universität Rostock e.V. Albert–Einstein–Str. 29a, 18059 Rostock, Germany, Tel.
bAlbrecht Kossel–Institute for Neuroregeneration, Medical University Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
cDepartment of Chemistry, COMSATS Institute of Information Technology, Abbottabad, Pakistan
dInstitut für Chemie, Universität Rostock, Albert–Einstein–Str. 3a, 18059 Rostock, Germany
Article history:
Received
Received in revised form
Accepted
Available online
Abstract: The Suzuki–Miyaura coupling
reaction was applied for the synthesis of biologically relevant derivatives of known
mucolytic agents Bromhexine and Ambroxol. Using commercially available electron–rich
and electron–poor arylboronic acids the desired products are obtained in moderate to high
yields (42–81%).
Keywords:
Catalysis
Palladium
Suzuki–Miyaura
Bromhexine
Ambroxol
Besides the secretolytic activity Ambroxol and Bromhexine exert
a wide range of other pharmacological activities, such as anti–
inflammatory, antioxidant, local anaesthetic effects through
1. Introduction
The well–known mucolytic agent Bromhexine (2,4–dibromo–6–
{[cyclohexyl(methyl)amino]methyl}aniline) constitutes
sodium channel blocking, and the recently detected effectiveness
in the treatment of chronic pancreatitis, etc.10 In addition, they
inhibit or scavenge oxidative and nitrosative stress11–13 and the
risk of viral infections can be reduced by clearing the bronchial
tree.14 Interestingly, it was also demonstrated that Ambroxol can
function as a chemical chaperone in Gaucher disease, a rare
condition of glycosphingolipid storage (OMIM #230800) by
stabilising mutant lysosomal glucocerebrosidase (beta–
glucosidase, GCase, EC 3.2.1.45)15.
In spite of the significant pharmacological importance of
Bromhexine and Ambroxol and extensive exploration of their
biology over decades, the synthetic chemistry of the title
compounds and their catalytic transformations were scarcely
investigated.
a
synthetic benzylamine derivative of the parent molecule vasicine,
an alkaloid that has been found in the plant Adhatoda vasica.1
Bromhexine as well as its metabolite Ambroxol (4–{[(2–amino–
3,5–dibromophenyl)methyl]amino}cyclohexan–1–ol) belong to
the group of expectorants with a long history and are frequently
used in the treatment of respiratory diseases, associated with
increased mucus production, like acute and chronic bronchitis.
Clinical studies of these drugs (as active ingredients in mucolytic
drugs Bisolvon Forte, Mucosolvan, Mucoangin etc.) have shown
that they significantly improve the coughing, promote mucus
clearance as well as production and transport of sputum of
patients.2–4 Additionally, Ambroxol is able to enhance production
of pulmonary surfactant,5–8 which is vitally important especially
for newborns.
Based on our interest in Pd–catalysed coupling reactions,16 and a
joint programme for the development of biologically active
compounds,16d,17 we became interested to explore the coupling
chemistry of Bromhexine and Ambroxol. In general, selective
catalytic coupling reactions should allow for the preparation of a
multitude of biologically interesting derivatives (Figure 1).
Among other ways of action these bioactive substances
decrease the viscosity of mucoid sputum by depolymerisation of
the high molecular weight mucopolysaccharide protein fibers.9
———
Corresponding author. Tel.: +49-381-1281-113; fax: +49-381-1281-51113; e-mail: Matthias.beller@catalysis.de

ACCEPTED MANUSCRIPT
2
Tetrahedron
entries 1, 3, 6, and 10). Notably, the conversion was complete in
coupling reactions
with Aryl-X, alkylation etc.
3–5 hours at 100 °C in the presence of the given solvents.
Table 1. Model coupling reaction using Pd(OAc)2 and different ligands.[a]
NH2
NH2
R´
HO
OH
N
Br
B
NH2
N
+
Br
N
Br
R
Pd-catalyzed
coupling reactions
with aryl boronic
acids, amines,
alcoholes, cyanides,
etc.
1
2a
3a
Br
Ligand (yield, %)[b]
R = CH3 , R´ = H (Bromhexine)
R = H ,
R´ = OH (Ambroxol)
Figure 1. Different possibilities for metal-catalyzed coupling reactions of Ambroxol and
Bromhexine.
I (32)
II (15)
III (78)
IV (15)
To the best of our knowledge, no general study on coupling
reactions of Ambroxol and Bromhexine has been reported to
date, except acylations of Ambroxol and Bromhexine18 and one
example of a Sonogashira coupling product with Bromhexine.19
Herein, we report our investigations on Suzuki–Miyaura coupling
reactions of Bromhexine and Ambroxol. The new synthesized
potentially bioactive products are not readily available by other
methods.
PPh2
PPh2
V (31)
VI (12)
VII (39)
VIII (14)
1. Results and Discussion
In recent years, numerous palladium catalysts for the cross–
coupling reactions of halogenated arenes and different
organoboron reagents (Suzuki–Miyaura reaction) have been
developed and the methodology has found widespread
application in the functionalization of different types of organic
molecules.20
IX (16)
X (24)
XI (12)
[a] Reaction conditions: Bromhexine 1 (1.0 mmol), phenylboronic acid 2a (3.0 mmol),
Pd(OAc)2 (5 mol%), ligand (10 mol%), solvent: 1,4–dioxane (3 mL), K2CO3 (1M,
2ml) in H2O, 100 °C, 10–12 h, conventional heating in pressure tube. [b] GC yields.
In order to identify suitable reaction conditions, in our study
initially model coupling reactions between Bromhexine (1) and
phenylboronic acid (2a) using different phosphine ligands and
solvents were performed. Selected results are presented in Tables
1 and 2, respectively. Low yields of the desired coupling product
3a were observed in the presence of 5 mol% of Pd(OAc)2 and
commercially available ligands II, IV, VI, VIII, IX and XI
(Table 1). However, in the presence of Buchwald´s ligand III (S–
Phos),21 a 78% yield of the dicoupled product was obtained in 12
hours using the 1,4–dioxane as a solvent.
Table 2. Model coupling reaction using Pd(OAc)2/S–Phos (ligand III) and
different solvents.[a]
Entry
Solvent
1,4–dioxane
Yield (%)[b]
1
2
3
4
78
24
76
CCl4
1,2–dichloroethane
1,2–dichlorobenzene
40
Next, we screened different solvents using ligand III.
Moreover, variation of reaction temperature (60–140 °C) and
monitoring of reaction time by TLC and GC analysis were
performed. More specifically, the model reaction was performed
at 140, 120, 100 °C. While at 120 and 140 °C the reaction is
completed in 6-8 hours, at 100 °C the reaction needed 10 hours to
achieve full conversion. Further lowering the temperature
reaction prolonged the reaction time to 16-20 hours. Best yields
(76–81%) of the coupling product were found in solvents 1,4–
dioxane, 1,2–dichloroethane, NMP, and acetonitrile (Table 2,
30[c]
5
THF
48
39[c]
6
7
8
NMP
DCM
77
47[c]
69[c]
Toluene

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3
Miyaura coupling reactions of Bromhexine (1) and Ambroxol
9
DMF
49[c]
81[c]
(4) with arylboronic acids afforded products 3a–r (Table 3) and
5a–b (Table 4) in moderate to high yields. To our delight, no
protection of the inherent reactive functional groups (amino and
hydroxyl function) is necessary. In addition to the basic starting
materials, also the corresponding hydrochlorides (commercially
available form of 1 and 4) can be used in the respective coupling
reactions, but typically the salt free ones give slightly higher
yields.
10
CH3CN
[a] Reaction conditions: Bromhexine 1 (1.0 mmol), phenylboronic acid 2a (3.0 mmol),
Pd(OAc)2 (5 mol%), S–Phos (ligand III, 10 mol%), K2CO3 (1M, 2ml) in H2O, 100 °C,
10–12 h, conventional heating in pressure tube. [b] GC yield. [c] Isolated yield.
Table 3. Suzuki–Miyaura coupling products of Bromhexine (3a–r)[a]
NH2
NH2
As shown in Table 3, a variety of mono– and disubstituted
electron–poor or electron–rich arylboronic acids gave the desired
arylated derivatives of Bromhexine. Apart from substituted
benzene compounds also heteroarylboronic acids led to the
desired coupling products (Table 3, entries 9, and 11). All the
new compounds could be easily isolated by standard column
chromatography and were fully characterized. The tolerance of
functional groups and the generality of the procedure were also
demonstrated in the coupling reactions of unprotected Ambroxol
(4) with two boronic acids (Table 4). Both coupling products
were obtained without any complication using our standard
procedure in high yields.
ArB(OH)2
Ar
Br
2.
N
N
2a-r
Ar
3a-r
Br
1
Entry
2
a
b
c
d
e
f
3
a
b
c
d
e
f
Ar
Yield of 3 (%)[b]
1
2
C6H5
81[c]
59
77
77
76
42
73
74
67
59
4–(MeO)C6H4
3
2,6–(MeO)2C6H3
2–MeC6H4
4
For the initial evaluation of potential biological activity of the
prepared compounds an inhibition test with recombinant wild
type GCase (active agent: Imiglucerase) was performed. As
shown in Figure 2, all compounds tested showed significant
inhibitory effects on the enzyme). Noteworthy, compared to the
parent molecule (closed circles), compounds 3i and 3j even
showed more potent inhibition. These initial biological tests of
the compounds suggest a putative medical application for
patients with Gaucher disease. In a somewhat counterintuitive
approach, enzyme inhibitors have been revealed to elevate
activity in the cellular context by stabilising the proteins’ mutant,
hence abolished, structure. Ambroxol functions as a potent
inhibitor for the GCase and mainly compounds 3i and 3j display
strong inhibitory effect towards the enzyme in vitro which makes
these substances likely candidates for pharmacological chaperone
testing in Gaucher disease.[22]
5
4–EtC6H4
6
4–VinylC6H4
4–AcetylC6H4
4–FC6H4
7
g
h
i
g
h
i
8
9
Thiophen–2–yl
3,5–(Me)2C6H3
10
11
j
j
6–(MeO)Pyridin–3–
yl
k
l
k
l
78
69
72
68
80
58
60
68
12
13
14
15
16
17
18
2–CF3C6H4
3–MeC6H4
Table 4: Suzuki–Miyaura coupling products of Ambroxol (5a–b)[a]
m
n
o
p
q
r
m
n
o
p
q
r
4–(EtO)C6H4
4–(n–Bu)C6H4
3,5–(MeO)2C6H3
3,5–(CF3)2C6H3
3,5–F2C6H3
OH
OH
NH2
NH2
ArB(OH)2
Ar
Br
N
H
N
H
2a,b
Ar
Br
5a-b
4
Entry
2
4
a
b
Ar
Yield of 5 (%)[b]
1
2
a
C6H5
70
73
[a] Reagents and conditions: Bromhexine 1 (1.0 mmol), 2a–r (3.0 mmol), K2CO3
(1M, 2mL) in H2O, Pd(OAc)2 (5 mol%), S–Phos (ligand III, 10 mol%), 1,4–dioxane,
100 °C, 3–4 h. [b] Isolated yields. [c] Solvent–acetonitrile.
b
4–(MeO)C6H4
[a] Reagents and conditions: Ambroxol 4 (1.0 mmol), 2a,b (3.0 mmol), K2CO3 (1M,
2ml) in H2O, Pd(OAc)2 (5 mol%), S–Phos (ligand III, 10 mol%), 1,4–dioxane, 120 °C,
4–6 h. [b] Isolated yields.
The optimized reaction conditions were used to demonstrate
the scope and limitations of this protocol. In fact, Suzuki–

ACCEPTED MANUSCRIPT
4
Tetrahedron
(CDCl3): δ = 25.9 (2CH2), 26.3 (CH2), 28.2 (2CH2), 36.3 (CH3), 58.3 (CH2), 61.9 (CH),
124.1 (C), 126.0 (CH), 126.2 (2CH), 127.7 (C), 128.2 (CH), 128.6 (2CH), 128.7 (2CH),
129.3 (2CH), 139.8, 141.7, 143.9 (C); GC–MS (EI, 70 eV): m/z (%) 370 (100) [M+];
HRMS (EI): Calc for C26H30N2: 370.24035; found: 370.240754; FTIR (ATR, cm–1):
2955, 2921, 2851, 1616, 1467, 1377, 1226, 1072, 1032, 966, 885, 835, 776, 741, 720,
698, 647, 600, 575, 561, 501.
4.1.2. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(4–methoxyphenyl)aniline (3b)
Yield: 108 mg (59%); yellow viscous oil; (from ethyl
acetate/hexane); Rf = 0.25 (solvent ethyl acetate/hexane/TEA
1:4); 1H NMR (300 MHz, CDCl3): δ = 1.01–1.42 (m, 5H),
MeO
NH2
N
1.65 (d, 1H, J = 12.3 Hz), 2.21 (s, 3H), 3.79 (s, 2H), 3.84 (s,
3H), 3.88 (s, 3H), 5.09 (s, 2H, NH2), 6.96 (dt, 2H, J = 8.90,
4.39 Hz), 7.01 (dt, 2H, J = 8.90, 4.40 Hz), 7.22 (d, 1H, J =
OMe
2.41 Hz), 7.30 (d, 2H, J = 2.41 Hz), 7.45 (dt, 2H, J = 8.92,
4.41 Hz), 7.51 (dt, 2H, J = 8.92, 4.41 Hz); 13C NMR (CDCl3): δ = 25.9 (2CH2), 26.2
(CH2), 28.1 (2CH2), 36.3 (CH3), 55.2 (2OCH3), 58.2 (CH2), 61.9 (CH), 114.0 (2CH),
114.1 (2CH), 127.2 (2CH), 127.6 (2CH), 129.7 (C), 134.4 (2CH), 131.9, 133.9, 143.4,
158.2, 158.6 (C); GC–MS (EI, 70 eV): m/z (%) 432 (100) [M+]; HRMS (ESI): Calc for
C28H34N2O2: 431.2693; found: 431.2692 (M+H); FTIR (ATR, cm–1): 3426, 3256, 2926,
2851, 1736, 1608, 1573, 1510, 1466, 1360, 1281, 1240, 1174, 1107, 1073, 1029, 965,
890, 826, 794, 726, 683, 636, 590, 545, 527, 464, 412.
Figure 2. Inhibition of recombinant GCase (Imiglucerase, Genzyme Corporation,
Cambridge, MA, USA) by Ambroxol and chosen compounds. The inhibitory curve for
Ambroxol at pH 6.7 showed diminishment of activity. Total reduction at 1 mM was
53.7%. Compounds 3d and 3e showed inhibition only at concentrations ≥100 µM.
Compounds 3i and 3j were more efficient at the tested concentrations than the lead
substance Ambroxol.
4.1.3. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(2,6–dimethoxyphenyl)aniline (3c)
OMe
NH2
Yield: 183 mg (77%); yellow viscous oil; (from ethyl
acetate/hexane); Rf = 0.51 (solvent ethyl acetate); 1H NMR (300
MHz, CDCl3): δ = 0.85–1.34 (m, 7H), 1.48–1.55 (m, 2H), 1.72 (t,
1H, J = 13.0 Hz), 1.96 (s, 1H), 2.21 (s, 3H), 2.44 (t, 1H, J = 11.0
Hz), 3.61 (s, 6H), 3.63 (s, 6H), 3.98 (t, 3H, J = 6.74 ), 6.54 (dd, 4H,
J = 10.2, 8.41 Hz), 6.96 (q, 2H, J = 4.20 Hz), 7.08 (t, 1H, J = 8.41
N
OMe
MeO
OMe
3. Conclusion
Hz), 7.18 (t, 1H, J = 8.31 Hz); 13C NMR (CDCl3): δ = 25.9 (2CH2), 26.3 (CH2), 28.0
(2CH2), 30.6 (CH), 36.3 (CH3), 55.9 (2OCH3), 56.0 (2CH3), 60.9 (CH), 64.2 (CH), 104.8
(CH), 104.9 (CH), 116.9, 119.2, 120.4, 121.3 (C), 127.3 (CH), 128.6 (CH), 132.3 (CH),
133.2 (CH), 144.2, 157.8, 158.4 (C); GC–MS (EI, 70 eV): m/z (%) 490 (12) [M+], 407
(100); HRMS (EI): Calc for C30H38N2O4: 490.2826; found: 490.2822 (M+H); FTIR
(ATR, cm–1): 3433, 3263, 2926, 2851, 1736, 1616, 1583, 1467, 1430, 1280, 1243, 1170,
1102, 1030, 966, 882, 779, 725, 607, 557.
In conclusion, palladium–catalysed Suzuki–Miyaura coupling
reactions of Bromhexine and Ambroxol with various aryl– and
heteroarylboronic acids are conveniently carried out using
a
commercially available palladium catalyst system. Twenty
potentially bioactive derivatives have been smoothly prepared in
moderate to high yields. Electronic and steric factors in the
arylboronic acid do not show a significant effect on the reactivity.
This synthetic procedure allows for a straightforward access to the
target compounds. Most of obtained products can be also considered
as functionalized meta–terphenyl derivatives, which are of interest
for other applications, too.23
4.1.4. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(2–methylphenyl)aniline (3d)
Yield: 148 mg (77%); yellow viscous oil; (from ethyl
acetate/hexane); Rf = 0.50 (solvent ethyl acetate/hexane 1:4); 1H
Me
NH2
N
NMR (300 MHz, CDCl3): δ = 0.98–1.53 (m, 6H), 1.72 (t, 4H, J =
13.8 Hz), 2.09 (s, 3H), 2.29 (s, 3H), 2.31 (s, 3H), 2.40 (t, 1H, J =
Me
11.7 Hz), 3.67 (s, 2H), 5.06 (s, 2H, NH2), 6.97 (d, 1H, J = 7.59 Hz),
7.06 (d, 1H, J = 6.70 Hz), 7.15–7.29 (m, 8H); 13C NMR (CDCl3): δ
= 21.4 (CH3), 21.5 (CH3), 25.9 (2CH2), 26.3 (CH2), 28.2 (2CH2), 36.3 (CH3), 58.3 (CH2),
61.9 (CH), 123.4 (CH), 123.9 (C), 126.3 (2CH), 126.8 (CH), 127.1 (CH), 127.8 (CH),
128.1 (CH), 128.5 (CH), 128.6 (CH), 130.0 (CH), 138.1, 138.3, 139.6, 141.2, 143.8 (C);
HRMS (ESI): Calc for C28H35N2: 399.27948; found: 399.28053 (M+H); HRMS (EI):
Calc for C28H34N2: 398.2716; found: 398.2721; FTIR (ATR, cm–1): 3430, 3255, 3026,
2924, 2851, 2787, 1665, 1604, 1468, 1448, 1378, 1338, 1293, 1260, 1203, 1159, 1093,
1033, 966, 878, 835, 780, 727, 701, 650, 630, 609, 589, 523, 466, 436.
4. Experimental Section
All reactions were carried out under argon atmosphere. Reactions were monitored by
TLC analysis (pre–coated silica gel plates with fluorescent indicator UV254, 0.2 mm) and
visualized with 254 nm UV light or iodine. Chemicals were purchased from Aldrich,
Fluka, Acros, AlfaAsar, Strem and unless otherwise noted were used without further
purification. All compounds were characterized by 1H NMR, 13C NMR, GC–MS, HRMS
and IR spectroscopy. 1H spectra were recorded on Bruker AV 300 and AV 400
spectrometers. 13C NMR spectra were recorded at 282 MHz. IR spectra were recorded on
FT–IR ALPHA (Bruker) with Platinum–ATR (Bruker). EI (70 eV) mass spectra were
recorded on MAT 95XP (Thermo ELECTRON CORPORATION). GC was performed
on Agilent 6890 chromatograph with a 30 m HP5 column. HRMS was performed on
MAT 95XP (EI) and Agilent 6210 Time–of–Flight LC/MS (ESI). GC–MS was
performed on Agilent 5973 chromatograph Mass Selective Detector. All yields reported
refer to isolated yields.
4.1.5. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(4–ethylphenyl)aniline (3e)
Et
Yield: 173 mg (76%); yellow viscous oil; (from ethyl
NH2
acetate/hexane); Rf = 0.50 (solvent ethyl acetate/hexane 1:4); 1
H
N
NMR (300 MHz, CDCl3): δ = 1.02–1.28 (m, 11H), 1.53 (d, 1H,
J = 12.8 Hz), 1.73 (t, 4H, J = 14.3 Hz), 2.09 (s, 3H), 2.41 (t, 1H,
J = 11.1 Hz), 2.53–2.65 (m, 4H), 3.67 (s, 2H), 5.05 (s, 2H, NH2),
7.11–7.18 (m, 4H), 7.21 (s, 1H), 7.24 (d, 1H, J = 2.27 Hz), 7.33
Et
(dt, 2H, J = 8.31, 4.13 Hz), 7.40 (dt, 2H, J = 8.31, 4.15 Hz); 13C NMR (CDCl3): δ = 15.5
(CH3), 15.6 (CH3), 25.9 (CH2), 26.3 (CH2), 28.2 (CH2), 28.4 (CH2), 28.6 (CH2), 36.3
(CH3), 58.3 (CH2), 61.9 (CH), 115.1, 123.8 (C), 126.2 (2CH), 127.7 (CH), 128.0 (CH),
128.2 (2CH), 128.2 (2CH), 129.3 (2CH), 137.0, 138.7 (C), 142.1 (2C), 143.1 (2C), 143.8
(2C); GC–MS (EI, 70 eV): m/z (%) 426 (100) [M+], 407 (100); HRMS (ESI): Calc for
C30H39N2: 427.3108; found: 427.3112 (M+H); FTIR (ATR, cm–1): 3431, 3257, 3021,
2961, 2925, 2851, 1662, 1612, 1510, 1468, 1450, 1409, 1375, 1336, 1293, 1257, 1203,
1182, 1158, 1114, 1048, 1020, 965, 891, 826, 785, 683, 590, 545, 517, 422.
4.1. General procedure of Suzuki couplings reactions (3a–r, 5a–b): The reaction was
carried out in an Ace–pressure tube. To a dioxane suspension (3 mL) of 1 (200 mg, 0.53
mmol), arylboronic acids (1.60 mmol), K2CO3 (1M in water, 2 ml), Pd(OAc)2 (5 mol%)
and ligand III (S–Phos, 10 mol%) were added under argon atmosphere. The pressure
tube was fitted with a Teflon cap and heated at 100 °C (TLC control). The mixture was
cooled to room temperature and diluted with ethyl acetate. The organic layer was washed
with water. After removal of the solvent in vacuum, the coupling products were isolated
by column chromatography in hexane/ethyl acetate.
4.1.6. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(4–ethenylphenyl)aniline (3f)
Yield: 96 mg (42%); yellow viscous oil; (from ethyl
acetate/hexane); Rf = 0.60 (solvent ethyl acetate/hexane 1:4);
1H NMR (300 MHz, CDCl3): δ = 0.99–1.43 (m, 6H), 1.65 (d,
NH2
N
4.1.1. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–diphenylaniline (3a)
1H, J = 12.7 Hz), 1.84 (t, 4H, J = 12.7 Hz), 2.20 (s, 3H), 2.51
(t, 1H, J = 11.7 Hz), 3.78 (s, 2H), 5.01–5.44 (m, 4H), 5.79 (t,
2H, J = 16.4 Hz), 6.73 (t, 1H, J = 11.1 Hz), 6.80 (t, 1H, J =
Yield: 145 mg (81%); yellow viscous oil; (from ethyl
NH2
acetate/hexane); Rf = 0.50 (solvent ethyl acetate/hexane 1:4); 1H
N
NMR (300 MHz, CDCl3): δ = 1.04–1.54 (m, 6H), 1.73 (t, 4H, J =
13.7 Hz), 2.09 (s, 3H), 2.04 (t, 1H, J = 10.3 Hz), 3.68 (s, 2H), 5.07
(s, 2H, NH2), 7.12–7.18 (m, 2H), 7.22–7.50 (m, 10H); 13C NMR
11.1 Hz), 7.28 (d, 1H, J = 2.15 Hz), 7.36 (d, 1H, J = 2.15 Hz),
7.42–7.58 (m, 8H); 13C NMR (CDCl3): δ = 26.0 (CH2), 26.4 (CH2), 28.3 (CH2), 36.4
(CH3), 58.4 (CH2), 62.1 (CH), 113.2 (CH2), 114.0 (CH2), 126.3 (2CH), 126.6 (2CH),

ACCEPTED MANUSCRIPT
5
126.7 (2CH), 127.6 (CH), 128.1 (CH), 129.5 (2CH), 135.5 (2C), 136.5 136.6 (C), 139.2,
140.6 (C), 144.1 (2C); HRMS (ESI): Calc for C30H35N2: 423.2794; found: 423.2806
[M+H]+; FTIR (ATR, cm–1): 3430, 3254, 3021, 2925, 2851, 1665, 1607, 1509, 1468,
1450, 1409, 1390, 1337, 1292, 1234, 1204, 1158, 1113, 1054, 1032, 987, 965, 892, 832,
786, 683, 610, 5422.
124.4 (C), 127.5 (CH), 128.1 (CH), 130.1 (CH), 136.9 (CH), 139.7 (CH), 144.2 (CH),
144.5 (C), 147.1 (CH), 162.9, 163.4 (C); HRMS (ESI): calc for C26H33N4O2 [M+H]+:
433.2598; found: 433.2597; FTIR (ATR, cm–1): 3427, 3257, 3012, 2926, 2851, 2789,
1601, 1562, 1492, 1464, 1423, 1358, 1278, 1174, 1124, 1076, 1022, 965, 885, 827, 756,
734, 690, 647, 626, 598, 566, 539, 476, 420.
4.1.7.
1–{4–[5–(4–Acetylphenyl)–2–amino–3–
4.1.12.
2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(2–
{[cyclohexyl(methyl)amino]methyl}phenyl]phenyl}ethan–1–one (3g)
(trifluoromethyl)phenyl)aniline (3l)
O
Yield: 143 mg (73%); yellow viscous oil; (from ethyl
acetate/hexane); Rf = 0.33 (solvent ethyl acetate/hexane3:7); 1
Yield: 184 mg (69%); yellow viscous oil; (from ethyl
acetate/hexane); Rf = 0.62 (solvent ethyl acetate/hexane 1:4); 1H
NMR (300 MHz, CDCl3): δ = 1.09–1.40 (m, 6H), 1.57–1.65 (m,
1H), 1.75–1.83 (m, 4H), 2.19 (s, 3H), 2.38–2.48 (m, 1H), 3.63 (d,
1H, J = 14.1 Hz), 3.84 (d, 1H, J = 14.1 Hz), 4.62 (s, 1H), 6.94 (s,
NH2
Me
NH2
H
N
CF3
N
NMR (300 MHz, CDCl3): δ = 1.08–1.45 (m, 7H), 1.55–1.75
(m, 2H), 1.76–1.96 (m, 4H), 2.11–2.32 (m, 3H), 2.62 (s, 3H),
2.66 (s, 3H), 3.81 (s, 2H), 7.34 (d, 1H, J = 3.00 Hz), 7.38 (s,
1H), 7.63 (t, 4H, J = 8.50 Hz), 7.98 (dt, 2H, J = 8.75, 3.38 Hz),
8.06 (dt, 2H, J = 8.75, 3.38 Hz); 13C NMR (CDCl3):δ = 25.9
CF3
1H), 7.03 (s, 1H), 7.36–7.62 (m, 6H), 7.71 (d, 1H, J = 7.92 Hz), 7.80 (d, 1H, J = 7.92
Hz); 13C NMR (CDCl3):δ = 25.9, 26.0, 27.1, 29.1, 30.8 (d, J = 13.4 Hz), 36.3, 57.9, 61.0,
64.4, 122.4 (d, J = 31.0 Hz), 122.7, 124.3, 126.0 (d, J = 5.20 Hz), 126.6, 127.8, 128.1,
128.7 (d, J = 29.6 Hz), 129.4, 129.9 (d, J = 29.6 Hz), 130.7 (d, J = 2.92 Hz), 131.1,
131.9, 132.4, 132.8, 139.6 (d, J = 271.9 Hz), 144.3; GC–MS (EI, 70 eV): m/z (%) 506
(7) [M+], 423 (100); HRMS (EI): calc for C28H28N2F6: 506.2151; found: 506.2156; FTIR
(ATR, cm–1): 3444, 3258, 3063, 3034, 2928, 2853, 2793, 2669, 1738, 1715, 1617, 1604,
1588, 1575, 1493, 1469, 1446, 1421, 1380, 1361, 1347, 1335, 1311, 1260, 1225, 1204,
1160, 1125, 1106, 1078, 1051, 1033, 988, 969, 957, 892, 860, 854, 835, 766, 756, 736,
691, 663, 653, 693, 611, 597, 567, 555, 543.
O
Me
(2CH2), 26.2 (CH2), 26.6 (CH3), 26.7 (CH3), 28.1 (CH2), 28.2 (CH2), 29.6 (CH2), 29.7
(CH2), 36.4 (CH3), 62.1 (CH), 126.1 (2CH), 129.0 (CH), 129.2 (C), 129.5 (CH), 134.5,
134.9, 135.9, 136.4, 145.0, 145.5 (C), 197.7 (CO); HRMS (ESI): calc for C30H35N2O2
[M+H]+: 455.2693; found: 455.2704. IR (ATR): ν = 3432, 3191, 2925, 2851, 2789,
1674, 1596, 1559, 1510, 1469, 1402, 1390, 1355, 1264, 1182, 1113, 1078, 1014, 955,
893, 830, 766, 731, 684, 589, 471, 397.
4.1.13. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(3–methylphenyl)aniline (3m)
4.1.8. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(4–fluorophenyl)aniline (3h)
Me
Yield: 151 mg (72%); yellow viscous oil; (from ethyl
acetate/hexane); Rf = 0.60 (solvent ethyl acetate/hexane 1:4); 1H
NH2
Yield: 160 mg (74%); yellow viscous oil; (from ethyl
F
N
NMR (300 MHz, CDCl3): δ = 0.99–1.33 (m, 6H), 1.55 (d, 1H, J =
11.6 Hz), 1.74 (t, 4H, J = 13.5 Hz), 2.10 (s, 3H), 2.31 (s, 6H), 2.33
(s, 3H), 2.37–2.45 (m, 1H), 3.68 (s, 2H), 5.04 (s, 2H), 6.97–7.30
(m, 10H); 13C NMR (CDCl3):δ = 21.4 (CH3), 21.5 (CH3), 25.9
acetate/hexane); Rf = 0.40 (solvent ethyl acetate/hexane 1:4); 1H
NMR (300 MHz, CDCl3): δ = 1.00–1.32 (m, 5H), 1.54 (d,1H, J
= 11.4 Hz), 1.74 (t, 4H, J = 12.5 Hz), 2.10 (s, 3H), 2.15 (t, 1H, J
= 11.4 Hz), 3.67 (s, 2H), 5.02 (s, 2H, NH2), 6.94–7.16 (m, 6H),
7.34–7.45 (m, 4H); 13C NMR (CDCl3):δ = 25.9 (2CH2), 26.4
(CH2), 28.3 (2CH2), 36.4 (CH3), 58.3 (CH2), 62.1 (CH), 115.6
NH2
N
Me
(2CH2), 26.3 (CH2), 28.2 (2CH2), 36.3 (CH3), 58.3 (CH2), 61.9 (CH), 123.4 (CH), 123.9
(C), 126.3 (CH), 127.1 (CH), 127.7 (CH), 128.5 (CH), 128.6 (CH), 129.9 (CH), 130.0,
138.1, 138.3, 139.6, 141.2, 143.7 (C); GC–MS (EI, 70 eV): m/z (%) 398 (16) [M+], 315
(100); HRMS (ESI): calc for C28H35N2 [M+H]+: 399.2794; found: 399.2797; FTIR
(ATR, cm–1): 3433, 3255, 3025, 2924, 2851, 2787, 1604, 1508, 1468, 1449, 1378, 1292,
1260, 1203, 1159, 1125, 1094, 1057, 1033, 966, 907, 879, 835, 812, 780, 727, 701, 648,
630, 609, 585, 556.
F
(CH), 124.2, 127.0 (C), 127.7 (2CH), 127.8 (2CH), 128.2 (2CH), 129.1 (C), 130.9
(2CH), 131.1 (2CH), 135.4, 137.2, 143.9 (C), 161.9 (dd, CF, J = 244.7, 18.0 Hz); GC–
MS (EI, 70 eV): m/z (%) 406 (17) [M+], 323 (100); HRMS (ESI): calc for C26H29F2N2
[M+H]+: 407.2293; found: 407.2301; FTIR (ATR, cm–1): 3433, 3254, 2926, 2852, 1614,
1508, 1468, 1403, 1381, 1293, 1218, 1156, 1125, 1094, 1073, 1032, 965, 891, 829, 812,
801, 767, 720, 683, 609, 585, 556, 527.
4.1.14. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(4–ethoxyphenyl)aniline (3n)
4.1.9. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(thiophen–2–yl)aniline (3i)
EtO
Yield: 165 mg (68%); yellow viscous oil; (from ethyl
NH2
acetate/hexane); Rf = 0.40 (solvent ethyl acetate/hexane
N
Yield: 135 mg (67%); yellow viscous oil; (from ethyl
1:4); 1H NMR (300 MHz, CDCl3): δ = 1.04–1.37 (m, 6H),
1.44 (q, 6H, J = 14.1 Hz), 1.64 (d, 1H, J = 13.8 Hz), 1.83 (t,
4H, J = 13.5 Hz), 2.19 (s, 3H), 2.44–2.53 (m, 1H), 3.75 (s,
NH2
acetate/hexane); Rf = 0.64 (solvent ethyl acetate/hexane 0.5:9.5);
S
N
1H NMR (300 MHz, CDCl3): δ = 0.99–1.29 (m, 5H), 1.54 (d,1H, J
= 13.1 Hz), 1.73 (t, 4H, J = 13.7 Hz), 2.09 (s, 3H), 2.39 (t, 1H, J =
11.1 Hz), 3.64 (s, 2H), 5.41 (s, 2H, NH2), 6.93 (d, 1H, J = 3.60 Hz),
S
OEt
2H), 4.03–4.28 (m, 5H), 6.82-6.93 (m, 4H), 7.12 (d, 1H, J =
2.29 Hz), 7.20 (d, 1H, J = 2.29 Hz), 7.31-7.43 (m, 4H); 13C NMR (CDCl3):δ = 14.9
(2CH3), 26.0 (2CH2), 26.4 (CH2), 28.3 (2CH2), 36.4 (CH3), 58.4 (CH2), 62.0 (CH), 63.5
(2CH2), 114.7 , 114.8, 115.4, 124.0, 127.3, 127.6, 127.6 (CH), 127.9 (2C), 128.9 (CH),
129.8 (2C), 130.5 (CH), 130.9 (CH), 133.8, 143.4, 157.7, 158.1 (C); HRMS (ESI): calc
for C30H39N2O2 [M+H]+: 459.3006; found: 459.3012; FTIR (ATR, cm–1): 3427, 3253,
3033, 2976, 2925, 2851, 1679, 1606, 1509, 1466, 1390, 1357, 1277, 1237, 1173, 1114,
1073, 1043, 964, 921, 890, 824, 802, 726, 686, 637, 611, 591, 561, 527, 411, 378.
7.02–7.08 (m, 3H), 7.10–716 (m, 2H); 13C NMR (CDCl3):δ = 25.8 (2CH2), 26.3 (CH2),
28.2 (2CH2), 36.3 (CH3), 58.1 (CH2), 61.9 (CH), 120.0 (C), 121.2 (CH), 123.0 (CH),
123.5 (2C), 124.1 (C), 125.3 (CH), 126.1 (CH), 127.5 (2CH), 127.8 (CH), 127.9 (CH),
140.7, 144.8 (C); GC–MS (EI, 70 eV): m/z (%) 382 (33) [M+], 299 (100); HRMS (ESI):
calc for C22H27S2N2 [M+H]+: 383.1610; found: 383.1621; FTIR (ATR, cm–1): 3423,
3218, 2924, 2850, 1735, 1613, 1472, 1449, 1427, 1345, 1321, 1298, 1229, 1180, 1124,
1080, 1026, 964, 883, 841, 816, 785, 686, 599, 565, 541, 489.
4.1.15. 2–4–Bis(4–butoxyphenyl)–6–{[cyclohexyl(methyl)amino]methyl}–aniline (3o)
4.1.10. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(3,5–dimethylphenyl)aniline (3j)
Yield: 218 mg (80%); yellow viscous oil; (from ethyl acetate/hexane); Rf = 0.30 (solvent
Me
Yield: 133 mg (59%); yellow viscous oil; (from ethyl
ethyl acetate/hexane 1:4); 1H NMR (300 MHz, CDCl3): δ =
acetate/hexane); Rf = 0.22 (solvent ethyl acetate/hexane 1:9); 1H
BuO
NH2
NH2
0.90 (t, 3H, J = 7.35 Hz), 0.92 (t, 3H, J = 7.35 Hz), 0.99–
Me
N
N
NMR (300 MHz, CDCl3): δ = 1.04–1.31 (m, 6H), 1.56 (d,1H, J
= 12.4 Hz), 1.75 (t, 4H, J = 13.5 Hz), 2.10 (s, 3H), 2.27 (s, 6H),
2.29 (s, 6H), 2.41 (s, 1H), 3.67 (s, 2H), 5.04 (s, 1H), 6.82 (s, 1H),
6.91 (s, 1H), 7.04 (s, 2H), 7.11 (s, 2H), 7.15 (d, 1H, J = 2.20 Hz),
1.31 (m, 5H), 1.43 (hept, 4H), 1.55 (d, J = 12.2 Hz), 1.64–
1.79 (m, 8H), 2.10 (s, 3H), 2.42 (t, 1H, J = 10.7 Hz), 3.67
(s, 2H), 3.91 (q, 4H, J = 6.60 Hz), 4.32 (s, 2H), 6.80- 6.90
Me
Me
OBu
(m, 4H), 7.10 (d, 1H, J = 2.23 Hz), 7.19 (d, 1H, J = 2.23
7.23 (s, 1H); 13C NMR (CDCl3):δ = 21.4 (2CH3), 21.5 (2CH3), 26.0 (2CH2), 26.4 (CH2),
28.3 (2CH2), 36.4 (CH3), 58.4 (CH2), 62.1 (CH), 124.3 (2CH), 125.1 (2CH), 127.1
(2CH), 127.8 (CH), 128.1 (CH), 128.3, 130.1 (C), 138.1 (2C), 138.3 (2C), 139.6, 141.5,
143.8, 151.9 (C); GC–MS (EI, 70 eV): m/z (%) 426 (19) [M+], 343 (100); HRMS (ESI):
calc for C30H39N2 [M+H]+: 427.3107; found: 427.3116; FTIR (ATR, cm–1): 3427, 3018,
2923, 1600, 1449, 1376, 1346, 1297, 1261, 1159, 1073, 1034, 965, 891, 844, 785, 756,
731, 702, 665, 634, 600, 536, 463, 432, 415, 397, 381.
Hz), 7.29-7.40 (m, 4H); 13C NMR (CDCl3):δ = 13.9 (2CH3), 19.9 (2CH2), 25.9 (2CH2),
26.4 (CH2), 28.3 (2CH2), 31.4 (2CH2), 36.4 (CH3), 58.2 (CH2), 62.0 (CH), 67.8 (2CH2),
114.7 (2CH), 114.8 (2CH), 123.8 (C), 127.3 (2CH), 127.6 (CH), 127.7 (CH), 127.9,
129.8 (C), 130.4 (2CH), 131.8, 133.8, 143.5, 157.9, 158.3 (C); GC–MS (EI, 70 eV): m/z
(%) 514 (24) [M+], 403 (100); HRMS (ESI): calc for C34H47N2O2 [M+H]+: 515.3632;
found: 515.3636; FTIR (ATR, cm–1): 3429, 3260, 3033, 2926, 2853, 1608, 1572, 1509,
1464, 1380, 1345, 1278, 1240, 1173, 1110, 1070, 1026, 1009, 968, 890, 826, 726, 685,
624, 594, 562, 528, 414.
4.1.11. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(6–methoxypyridin–3–yl)aniline
(3k)
4.1.16.
2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(3,5–dimethoxyphenyl)aniline
MeO
N
Yield: 133 mg (78%); yellow viscous oil; (from ethyl
acetate/hexane); Rf = 0.55 (solvent ethyl acetate/hexane 1:4);
1H NMR (300 MHz, CDCl3): δ = 1.04–1.78 (m, 6H), 1.56 (d,
1H, J = 11.4 Hz), 1.74 (t, 4H, J = 12.1 Hz), 2.11 (s, 3H), 2.40
(t, 1H, J = 11.4 Hz), 3.67 (s, 2H), 3.88 (s, 3H), 3.92 (s, 3H),
6.69 (d, 1H, J = 8.58 Hz), 6.76 (d, 1H, J = 8.58), 7.10 (s, 2H),
(3p)
NH2
N
OMe
Yield: 283 mg (58%); yellow viscous oil; (from ethyl
NH2
acetate/hexane); Rf = 0.61 (solvent ethyl acetate/Hexane 1:9); 1
H
MeO
N
NMR (300 MHz, CDCl3): δ = 1.13–1.33 (m, 5H), 1.45–1.58 (m,
1H), 1.72 (t, 4H, J = 13.0 Hz), 2.10 (s, 3H), 2.40 (t, 1H, J = 10.7
Hz), 3.67 (s, 2H), 3.73 (s, 6H), 3.74 (s, 6H), 6.30 (t, 1H, J = 2.36
Hz), 6.38 (t, 1H, J = 2.36 Hz), 6.56 (d, 2H, J = 2.25 Hz), 6.62 (d,
N
OMe
7.62–7.69(m, 2H); 13C NMR (CDCl3):δ = 25.9 (2CH2), 26.3 (CH2), 28.2 (2CH2), 36.4
MeO
OMe
(CH3), 53.5 (OCH3), 53.6 (OCH3), 58.3 (CH2), 61.9 (CH), 110.6 (CH), 110.9 (CH),

ACCEPTED MANUSCRIPT
6
Tetrahedron
2H, J = 2.25 Hz), 7.16 (d, 1H, J = 2.58 Hz), 7.26 (d, 1H, J = 2.58 Hz); 13C NMR
minutes in a 37°C water bath under slight agitation. The reaction was stopped using
glycine NaOH buffer (pH 10.5) and recorded with a fluorescent plate reader (Tecan,
Männedorf, Switzerland) at a wave length of 466 nm.
(CDCl3): δ = 26.0 (2CH2), 26.4 (CH2), 28.3 (2CH2), 36.4 (CH), (CH3), 55.4 (2OCH3),
55.5 (2CH3), 58.4 (CH), 98.3 (CH), 99.6 (CH), 104.6 (2CH), 107.2 (2CH), 123.9 (C),
127.5 (C), 127.7 (C), 128.4 (2CH), 129.7 (2C), 141.7 (C), 143.5 (C), 144.3 (C), 161.1 (d,
C, J = 4.75 Hz); HRMS (ESI): Calc for C30H39N2O4: 491.2904; found: 491.2902
(M+H)+; FTIR (ATR, cm–1): 3430, 3264, 2927, 2851, 1735, 1589, 1452, 1418, 1393,
1364, 1336, 1295, 1257, 1202, 1150, 1084, 1061, 991, 949, 892, 830, 755, 735, 695, 648,
537, 469, 421.
Acknowledgements
We thank the State of Mecklenburg–Western Pomerania, the
BMBF (Bundesministerium für Bildung und Forschung), the
Deutsche Forschungsgemeinschaft (Graduiertenkolleg 1213 and
Leibniz prize) and the Fonds der Chemischen Industrie for
financial support. We thank our analytical department for their
excellent technical and analytical support.
4.1.17. 2,4–Bis[3,5–bis(trifluoromethyl)phenyl]–6–{[cyclohexyl(methyl)amino]methyl}–
aniline (3q)
Yield: 389 mg (60%); yellow viscous oil; (from ethyl
CF3
acetate/hexane); Rf = 0.26 (solvent ethyl acetate/Hexane 1:4);
1H NMR (300 MHz, CDCl3): δ = 1.13–1.45 (m, 5H), 1.67 (d,
NH2
F3
C
N
1H, J = 12.9 Hz), 1.88 (t, 4H, J = 13.3 Hz), 2.24 (s, 3H), 2.54
(t, 1H, J = 12.1 Hz), 3.86 (s, 3H), 5.36 (s, 2H), 7.34 (q, 2H, J
= 12.6 Hz), 7.79 (s, 1H), 7.94 (s, 1H), 8.00 (d, 4H, J = 7.39
Hz); 13C NMR (CDCl3): δ = 25.9 (2CH2), 26.3 (CH2), 28.3
(2CH2), 36.4 (CH3), 58.2 (CH2), 62.3 (CH), 119.7–119.9 (m,
References and notes
F3C
CF3
1.
2.
Gent, M.; Knowlson, P.A.; Prime, F. J. Lancet 1969, 294, 1094–1096.
(a) Latli, B.; Hrapchak, M.; Switeck, H–K.; Retz, D. M.;
Krishnamurthy, D.; Senanayake, C. H. J. Label Compd. Radiopharm.
2010, 53, 15–23; (b) Lapenna, D.; Ciafani, G.; Pierdomenico, S. D.;
Neri, M.; Giamberardino, M. D.; Cuccurullo, F. Bio. Pharm. 2007, 74,
265–272.
CH), 121.3–121.5 (m, CH), 123.3 (d, J = 272.6 Hz, 2CF3), 123.5 (d, J = 272.6 Hz,
2CF3), 126.2 (d, J = 3.72 Hz, 2CH), 127.3 (CH), 127.8 (CH), 128.9 (d, J = 16.7 Hz, C),
129.3 (CH), 129.7 (d, J = 3.72 Hz, 2CH); GC–MS (EI, 70 eV): m/z (%) 642 (8) [M+],
571 (48), 560 (25), 559 (100), 530 (35), 112 (29); HRMS (EI): Calc for C30H36N2F12
:
642.1898; found: 642.1893 (M+H); FTIR (ATR, cm–1): 3456, 3271, 2934, 2859, 1492,
1453, 1366, 1272, 1224, 1126, 1070, 1048, 990, 965, 942, 900, 877, 844, 783, 755, 729,
709, 699, 681, 663, 605, 558, 541, 519, 472, 411, 393.
3.
4.
(a) Kopitar, Z.; Jauch, R.; Hankwitz, R.; Pelzer, H. Eur. J. Pharm.
1973, 21, 6–10; (b) Schraven, E.; Koss, F. W.; Keck, J.; Beisenherz, G.
Eur. J. Pharmacol. 1967, 1, 445–451.
Maegawa, G. H. B.; Tropak, M. B.; Buttner, J. D.; Rigat, B. A.; Fuller,
M.; Pandit, D.; Tang, L.; G. Kornhaber, J.; Hamuro, Y.; Clarke, J. T.
R.; Mahuran, D. J. J. Bio. Chem. 2009, 284, 23502–23516.
Gremmel, J.–F. J. Vet. Pharmacol. Therap. 2010, 27, 219–225.
Nobata, N.; Fujimura, M.; Ishiura, Y.; Nakao, S. J. Clin. Exp. Med.
2006, 6, 79–83.
4.1.18. 2–{[Cyclohexyl(methyl)amino]methyl}–4,6–bis(3,5–difluorophenyl)aniline (3r)
Yield: 300 mg (68%); yellow viscous oil; (from ethyl
F
acetate/hexane); Rf = 0.51 (solvent ethyl acetate/Hexane 1:4);
1H NMR (300 MHz, CDCl3): δ = 0.99–1.27 (m, 5H), 1.54 (d,
NH2
F
N
1H, J = 12.3 Hz), 1.73 (t, 4H, J = 12.3 Hz), 2.16 (s, 3H), 2.37
(t, 1H, J = 12.3 Hz), 3.65 (s, 2H), 5.26 (s, 2H), 6.53–6.61 (m,
1H), 6.66–6.74 (m, 1H), 6.68–6.99 (m, 4H), 7.13 (t, 4H, J =
2.30 Hz); 13C NMR (CDCl3): δ = 25.9 (2CH2), 26.4 (CH2),
5.
6.
F
F
28.3 (2CH2), 36.4 (CH3), 58.3 (CH2), 62.1 (CH), 101.3 (t, J = 25.5 Hz, CH), 102.8 (t, J =
25.5 Hz, CH), 108.8 (d, J = 25.4 Hz, CH), 108.9 (d, J = 9.90 Hz, CH), 112.2 (d, J = 25.5
Hz, CH), 112.3 (d, J = 9.90 Hz, CH), 124.4 (CH), 124.5 (C), 127.4 (t, J = 2.65, C), 128.7
(CH), 142.7 (d, J = 9.49 Hz, C), 144.3 (t, J = 9.49 Hz, C), 144.9 (2C), 163.3 (dd, J =
249.5, 6.18 Hz, 2CF), 163.4 (dd, J = 249.5, 6.18 Hz, 2CF), GC–MS (EI, 70 eV): m/z (%)
442 (13) [M+], 371 (41), 359 (100), 330 (58), 315 (40), 112 (28); HRMS (EI): Calc for
C26H26N2F4: 442.2026; found: 442.2022 (M+H); FTIR (ATR, cm–1): 3441, 3255, 2928,
2853, 1618, 1590, 1491, 1452, 1428, 1396, 1365, 1325, 1240, 1170, 1140, 1078, 1034,
986, 949, 893, 849, 783, 757, 702, 709, 640, 614, 568, 527, 509, 484.
7.
8.
Meijer, L. A.; Verstegen, J. C. M.; Bull, S.; Fink–Gremmels, J. J. Vet.
Pharmacol. Ther. 2004, 27, 219–225.
(a) Gibbs, B. F.; Schmutzler, W.; Vollrath, I. B.; Brosthardt, P.; Braam,
U.; Wolff, H. H.; Klarwasser, G. Z. Inflamm. Res. 1999, 48, 86–93; (b)
Heath, M. F.; Jacobson, W. Lungs 1985, 163, 337–344.
Langlands, J. H. M.; Lancet 1970, 295, 448–450.
9.
10. For reviews see: (a) Malerba, M.; Ragnoli, B. Expert Opinion on Drug
Metabolism & Toxicology 2008, 4, 1119–1129; (b) Beeh, K. M.; Beier,
J.; Esperaster, A.; Paul, L. D. Eur. J. Med. Res. 2008, 13, 557–562; (c)
Tsujimoto, T.; Kawaratani, H.; Yoshiji, H.; Uemura, M.; Fukui, H.
Current Drug Abuse Reviews 2008, 1, 197–202; (d) Weiser, T.; CNS
Neuroscience & Therapeutics 2008, 14, 17–24.
4.1.19. 4–{[(2–Amino–3,5–diphenyl)methyl]amino}cyclohexan–1–ol (5a)
Yield: 131 mg (70%); yellow viscous oil; (from ethyl
acetate/hexane); Rf = 0.39 (solvent ethyl acetate/hexane 1:4);
1H NMR (300 MHz, CDCl3): δ = 1.09–1.31 (m, 5H), 1.86–
OH
NH2
N
H
2.00 (m, 3H), 2.01 (s, 1H), 2.44–2.55 (m, 1H), 3.49–3.64 (s,
2H), 3.87 (s, 2H), 4.90 (s, 2H), 7.19–7.34 (m, 6H), 7.37–7.43
(m, 4H), 7.46–7.51 (m, 2H); 13C NMR (CDCl3):δ = 30.9
11. (a) Ulas, M. M.; Hizarci, M.; Kunt, A.; Ergun, K.; Kocabeyoglu, S. S.;
Korkmaz, K.; Lafci, G.; Gedik, S.; Cagli, K. J. Cardiovasc.
Pharmacol. 2008, 52, 518–523; (b) Gaida, W.; Klinder, K.; Arndt, K.;
Weiser, T. Neuropharm. 2005, 49, 1220–1227.
(CH2), 33.8 (2CH2), 50.8 (2CH2), 55.7 (CH), 70.3 (CH), 126.2 (CH), 126.3 (2CH), 127.2
(CH), 127.8 (CH), 128.2 (CH), 128.6 (2CH), 128.8 (2CH), 129.2 (2CH), 130.3, 139.4,
140.9 (C), 143.5 (C), 145.0 (C); GC–MS (EI, 70 eV): m/z (%) 372 (21) [M+], 273 (100);
HRMS (ESI): calc for C25H29N2O [M+H]+: 373.2591; found: 373.2597; FTIR (ATR, cm–
1): 3337, 3055, 3028, 2926, 2853, 1733, 1598, 1463, 1439, 1370, 1241, 1070, 964, 884,
807, 759, 696, 647, 606, 496.
12.
Felix, K.; Pairet, M.; Zimmermann, R. Life Sci. 1996, 59, 1141–1147.
13. Pfeifer, S.; Zissel, G.; Kienast, K. Eur. J. Med. Res. 1997, 2, 129–132.
14. Meijer, L. A.; Verstegen, J. C. M.; Bull, S.; Gremmel, J. F. J. Vet.
Pharmacol. Therap. 2010, 27, 219–225.
15. Maegawa, G. H. B.; Tropak, M. B.; Buttner, J. D.; Rigat, B. A.; Fuller,
M.; Pandit, D.; Tang, L.; Kornhaber, G. J.; Hamuro, Y.; Clarke, J. T.
R.; Mahuran, D. J. J. Biol. Chem. 2009, 284, 23502–23516.
4.1.20. 4–{[(2–Amino–3,5–bis(4–methoxyphenyl)phenyl]methyl}amino)cyclohexan–1–ol
(5b)
MeO
OH
Yield: 158 mg (73%); yellow viscous oil; (from ethyl
acetate/hexane); Rf = 0.30 (solvent ethyl acetate/hexane
1:4); 1H NMR (300 MHz, CDCl3): δ = 0.77–0.99 (m, 1H),
1.07–1.32 (m, 6H), 1.87–2.01 (m, 4H), 2.46–2.56 (m, 1H),
3.49–3.59 (m, 1H), 3.75 (s, 3H), 3.79 (s, 3H), 3.85 (s, 2H),
4.77 (s, 2H), 6.83–6.94 (m, 4H), 7.19–7.21 (m, 2H), 7.29–
7.43 (m, 4H); 13C NMR (CDCl3):δ = 30.1 (2CH2), 33.7
NH2
16. (a) Wu, X.–F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40,
4986–5009; (b) Wu, X.–F.; Neumann, H.; Beller, Angew. Chem. Int.
Ed. 2010, 49, 5284–5288; Angew. Chem. 2010, 122, 5412–5416; (c)
Mangu, N.; Spannenberg, A.; Beller, M.; Tse, M.–K. Synlett 2010, 2,
211–214; (d) Pews–Davtyan, A.; Tillack, A.; Ortinau, S.; Rolfs, A.;
Beller, M. Org. Biomol. Chem. 2008, 6, 992–997; (e) Schwarz, N.;
Pews–Davtyan, A.; Alex, K.; Tillack, A.; Beller, M. Synthesis 2007,
23, 3722–3730; (f) Zapf, A.; Beller, M. Chem. Commun. 2005, 431–
440; (g) Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees,
A.; Fuhrmann, C.; Shaikh, N.; Dingerdissen, U.; Beller, M. Chem.
Commun. 2004, 38–39; (h) Reimann, S.; Sharif, M.; Hein, M.;
Villinger, A.; Wittler, K.; Ludwig, R.; Langer, P. Eur. J. Org. Chem.
2012, 604; (i) Sharif, M.; Zeeshan, M.; Reimann, S.;Villinger, A.;
Langer, P. Tetrahedron Lett. 2010, 51, 2810; (j) Sharif, M.; Reimann,
S.; Villinger, A.; Langer, P. Synlett 2010, 913; (k) Munawar Hussain,
N
H
OMe
(2CH2), 55.4 (OCH3), 55.8 (CH), 70.5 (CH), 114.2 (2CH), 114.3 (2CH), 127.4 (2CH),
127.9 (C), 128.4 (CH), 128.9 (CH), 130.4 (2CH), 130.5, 131.6, 133.5, 143.1, 158.5,
158.9 (C); HRMS (ESI): calc for C27H33N2O3 [M+H]+: 433.2485; found: 433.4958; FTIR
(ATR, cm–1): 3331, 2922, 2852, 1608, 1512, 1460, 1400, 1282, 1244, 1177, 1109, 1077,
1031, 964, 901, 830, 795, 722, 592, 549, 527, 485.
Glucocerebrosidase inhibition assay
Forty units of recombinant Glucocerebrosidase (Cerezyme, Genzyme Corporation,
Cambridge, MA, USA) were dissolved in citrate phosphate puffer (pH 6.7) and mixed
with increasing compound concentrations. Reactions were started by the addition of
4MU–b–Glc (Sigma, 1 mM final concentration) and the mixture was incubated for 15

ACCEPTED MANUSCRIPT
7
Dhafer Saber Zinad, Ghazwan Ali Salman, Muhammad Sharif,
19
Duplais, Ch.; Forman, A. J.; B. Baker, A.; Lipshutz, B. H. Chem.
Eur. J. 2010, 16, 3366–3371.
Alexander Villinger, Peter Langer*, Synlett. 2010, 276; (l),
Muhammad Sharif, Sebastian Reimann, Kai Wittler, Leif R. Knöpke,
Annette-E. Surkus, Christian Roth, Alexander Villinger, Ralf Ludwig,*
Peter Langer*, Eur. J. Org. Chem. 2011, 5261; (m) Muhammad Sharif,
Aneela Maalik, Sebastian Reimann, Jamshed Iqbal, Tamás Patonay,
Alexander Villinger, Peter Langer*, J. Fluorine Chem. 2013, 146, 19;
(n) Shahzad Ahmed, Muhammad Sharif*, Khurram Shoaib, Sebastian
Reimann, Jamshed Iqbal, Anke Spannenberg, Peter Langer*,
Tetrahedron Lett. 2013, 54, 1669; (o) Muhammad Sharif, Anahit
Pews–Davtyan, Jan Lukas, Johannes Schrank, Peter Langer, Arndt
Rolfs* and Matthias Beller* Eur. J. Org. Chem. 2013, 2783; (p)
Sebastian Reimann, Kai Wittler, Stella Schmode, Muhammad Sharif,
Anke Spannenberg, Ralf Ludwig, and Peter Langer. Eur. J. Org.
Chem. 2013, 8115; (q) Muhammad Sharif, Aneela Maalik, Sebastian
Reimann, Jamshed Iqbal, Tamás Patonay, Alexander Villinger, Anke
Spannenberg, and Peter Langer*, Tetrahedron 2013, 69, 174.
20. For selected reviews in this area see: (a) Fortman, G. C.; Nolan, S. P.
Chem. Soc. Rev. 2011, 40, 5151–5169; (b) Balanta, A.; Godard, C.;
Claver, C. Chem. Soc. Rev. 2011, 40, 4973–4985; (c) Fihri, A.;
Bouhrara, M.; Nekoueishahraki, B.; Basset, J–M.; Polshettiwar, V.
Chem. Soc. Rev. 2011, 40, 5181–5203; (d) Mehtaa, V. P.; Van der
Eycken, E. V. Chem. Soc. Rev. 2011, 40, 4925–4936; (e) Doucet, H.
Eur. J. Org. Chem. 2008, 2013–2030; (f) Littke, A. F.; Fu, G. C. Angew.
Chem, Int. Ed. 2002, 41, 4176–4212; Angew. Chem. 2002, 114, 4350–
4386.
21. (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685–4696; (b) Walker, S. D.; Barder, T. E.;
Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43,
1871–1876; Angew. Chem. 2004, 116, 1907–1912.
22. Asano, N.; Ishii, S.; Kizu, H.; Ikeda, K.; Yasuda, K.; Kato, A.; Martin,
O.R.; Fan, J.–Q. Eur. J. Biochem. 2000, 267, 4179–4186.
17. (a) Pews–Davtyan, A.; Tillack, A.; Schmöle, A.–C.; Ortinau, S.; Frech,
M. J.; Rolfs, A.; Beller, M. Org. Biomol. Chem. 2010, 8, 1149–1153;
(b) Schmöle, A.–C.; Brennführer, A.; Karapetyan, G.; Jaster, R.;
Pews–Davtyan, A.; Hübner, R.; Ortinau, S.; Beller, M.; Rolfs, A.;
Frech, M. J. Bioorg. Med. Chem. 2010, 18, 6785–6795.
23. (a) Gasowska, J. S.; Cowling, S. J.; Cockett, M. C. R.; Hird, M.; Lewis,
R. A.; Raynes, E. P.; Goodby, J. W. J. Mater. Chem. 2010, 20, 299–
307; (b) Bahadir, M.; Pieper, A.; Vogt, R.; Wichmann, H.; Grunenberg,
J.; Hopf, H.; Chemosphere 2003, 50, 1151–1156.
18. (a) Yamada, T.; Takemura, Y.; Niisato, N.; Mitsuyama, E.; Iwasaki,
Y.; Marunaka, Y. Biochem. Biophys. Research Commun. 2009, 380,
586–590; (b) Goeber, B.; Liskowski, H.; Franke, P. Pharmazie 1988,
43, 23–26.
Supplementary Material
Scans of NMR spectra for all compounds are provided.

ACCEPTED MANUSCRIPT
SUPPORTING INFORMATION
Palladium–catalysed Suzuki–Miyaura Coupling Reactions of Bromhexine
and Ambroxol
Muhammad Sharif,[a,c] Anahit Pews-Davtyan,[a] Jan Lukas,[b] Susann Pohlers,[b] Arndt
Rolfs,*[b] Peter Langer,[a,d] and Matthias Beller*[a]
aLeibniz–Institut für Katalyse an der Universität Rostock e.V. Albert–Einstein–Str. 29a, 18059 Rostock, Germany
bAlbrecht Kossel–Institute for Neuroregeneration, Medical University Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
cDepartment of Chemistry, COMSATS Institute of Information Technology, Abbottabad, Pakistan
dInstitut für Chemie, Universität Rostock, Albert–Einstein–Str. 3a, 18059 Rostock, Germany
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-diphenylaniline (3a):
1H NMR
NH2
N
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
NH2
N
140
130
120
110
100
90
80
70
60
50
40
30
ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(4-methoxyphenyl)aniline (3b):
1H NMR
O
NH2
N
O
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
O
NH2
N
O
160
150
140
130
120
110
100
90
80
70
60
50
40
30
ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(2,6-dimethoxyphenyl)aniline (3c):
1H NMR
O
NH2
N
O
O
O
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
O
NH2
N
O
O
O
160
150
140
130
120
110
100
90
80
70
60
50
40
30 ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(2-methylphenyl)aniline (3d):
1H NMR
NH2
N
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
NH2
N
140
130
120
110
100
90
80
70
60
50
40
30
ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(4-ethylphenyl)aniline (3e):
1H NMR
NH2
N
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0 ppm
13C NMR
NH2
N
140
130
120
110
100
90
80
70
60
50
40
30
20
ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(4-ethenylphenyl)aniline (3f):
1HNMR
NH2
N
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
NH2
N
140
130
120
110
100
90
80
70
60
50
40
30
ppm

ACCEPTED MANUSCRIPT
1-{4-[5-(4-Acetylphenyl)-2-amino-3-
{[cyclohexyl(methyl)amino]methyl}phenyl]phenyl}ethan-1-one (3g):
1H NMR
O
NH2
N
O
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
O
NH2
N
O
200 190 180 170 160 150 140 130 120 110 100
90
80
70
60
50
40
30
20 ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(4-fluorophenyl)aniline (3h):
1H NMR
F
NH2
N
F
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
F
NH2
N
F
160
150
140
130
120
110
100
90
80
70
60
50
40
30 ppm

ACCEPTED MANUSCRIPT
2-((Cyclohexyl(methyl)amino)methyl)-4,6-di(thiophen-2-yl)aniline) (3i):
1H NMR
NH2
S
N
S
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
NH2
S
N
S
140
130
120
110
100
90
80
70
60
50
40
30
ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(3,5-dimethylphenyl)aniline (3j):
1H NMR
NH2
N
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
NH2
N
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20 ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(6-methoxypyridin-3-yl)aniline (3k):
1H NMR
O
N
NH2
N
N
O
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
O
N
NH2
N
N
O
160
150
140
130
120
110
100
90
80
70
60
50
40
30
ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(2-(trifluoromethyl)phenyl)aniline (3l):
1H NMR
NH2
N
F
F
F
F
F
F
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
NH2
N
F
F
F
F
F
F
150
140
130
120
110
100
90
80
70
60
50
40
30 ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(3-methylphenyl)aniline (3m):
1H NMR
NH2
N
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
NH2
N
140
130
120
110
100
90
80
70
60
50
40
30
ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(4-ethoxyphenyl)aniline (3n):
1H NMR
O
NH2
N
O
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
O
NH2
N
O
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20 ppm

ACCEPTED MANUSCRIPT
2-4-Bis(4-butoxyphenyl)-6-{[cyclohexyl(methyl)amino]methyl}-aniline (3o):
1H NMR
BuO
NH2
N
OBu
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0 ppm
13C NMR
BuO
NH2
N
OBu
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20 ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(3,5-dimethoxyphenyl)aniline (3p):
1H NMR
OMe
NH2
MeO
N
MeO
OMe
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
OMe
NH2
MeO
N
MeO
OMe
160
150
140
130
120
110
100
90
80
70
60
50
40
30 ppm

ACCEPTED MANUSCRIPT
2,4-Bis[3,5-bis(trifluoromethyl)phenyl]-6-{[cyclohexyl(methyl)amino]methyl}aniline
(3q):
1H NMR
CF3
NH2
F3C
N
F3C
CF3
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
CF3
NH2
F3C
N
F3C
CF3
160
150
140
130
120
110
100
90
80
70
60
50
40
30
ppm

ACCEPTED MANUSCRIPT
2-{[Cyclohexyl(methyl)amino]methyl}-4,6-bis(3,5-difluorophenyl)aniline (3r):
1H NMR
F
NH2
F
N
F
F
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
F
NH2
F
N
F
F
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30 ppm

ACCEPTED MANUSCRIPT
4-{[(2-Amino-3,5-diphenyl)methyl]amino}cyclohexan-1-ol (5a):
1H NMR
OH
NH2
N
H
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
ppm
13C NMR
OH
NH2
N
H
140
130
120
110
100
90
80
70
60
50
40
ppm

ACCEPTED MANUSCRIPT
4-{[(2-Amino-3,5-bis(4-methoxyphenyl)phenyl]methyl}amino)cyclohexan-1-ol (5b):
1H NMR
O
OH
NH2
N
H
O
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0 ppm
13C NMR
O
OH
NH2
N
H
O
160
150
140
130
120
110
100
90
80
70
60
50
40
ppm