Synthesis of Symmetric Bis(N-alkylaniline)triarylmethanes via Friedel-Crafts-Catalyzed Reaction between Secondary Anilines and Aldehydes

Article abstract of DOI:10.1021/acs.joc.5b01875

The first general protocol for the preparation of symmetric triarylmethanes bearing secondary anilines by ytterbium-catalyzed Friedel-Crafts reaction of hetero(aryl) aldehydes and secondary anilines is reported. Mechanistic studies indicated that the imin

Full text of DOI:10.1021/acs.joc.5b01875

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Note
Synthesis of symmetric bis(N-alkylaniline)triarylmethanes via Friedel-
Crafts catalyzed reaction between secondary anilines and aldehydes
Rafael F.A. Gomes, Jaime A. S. Coelho, Raquel F.M. Frade, Alexandre F. Trindade, and Carlos A. M. Afonso
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Sep 2015
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Synthesis of symmetric bis(Nꢀalkylaniline)triarylmethanes via FriedelꢀCrafts catalyzed reaction
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between secondary anilines and aldehydes
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Rafael F. A. Gomes, Jaime A. S. Coelho*, Raquel F. M. Frade, Alexandre F. Trindade, Carlos A. M. Afonso*
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Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Prof.
Gama Pinto, 1649ꢀ003 Lisboa, Portugal
ABSTRACT: The first general protocol for the preparation of symmetric triarylmethanes bearing secondary
anilines by Ytterbiumꢀcatalyzed FriedelꢀCrafts reaction of hetero(aryl) aldehydes and secondary anilines is
reported. Mechanistic studies indicated that iminium ion intermediate is the electrophilic partner. The reaction is
greatly accelerated by highꢀpressure (9 kbar) and showed a broad substrate scope on hetero(aryl) aldehyde. The
new triarylmethanes exhibited activity against HTꢀ29 cancer cell lines with the best result scoring an IC50 of 1.74
µM.
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Triarylmethanes (TRAM) and related structures are important synthetic targets as they are a common motif in
many dyes,1 fluorescent probes,2 biologically active molecules,3 and natural products4 (Figure 1).
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N
OAc
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Cl
N
N
N
N
AcO
Malachite green
Bisacodyl
Clotrimazole
laxative
dye
antifungal
Figure 1. Selected examples of triarylmethanes
Within this family, anilineꢀbased triarylmethanes are typically obtained via FriedelꢀCraft reactions between
aromatic aldehydes and electronꢀrich tertiary anilines in the presence of Lewis or Bronsted acids under harsh
conditions (reflux in solvents with high boiling points, solventꢀfree under heating).1a,5 As a consequence, acidꢀ
labile functional groups or protection units are not expected to be tolerated under the current stateꢀofꢀart methods.
In fact, we found that TBDMSꢀprotected 5ꢀhydroxymethyl furfural 1, which incorporates an Oꢀsilyl protection
group and an acid labile furfural unit, delivered a very complex mixture of products when heated under
microwave in presence aniline hydrochloride salt as catalyst – conditions reported by MartinezꢀPalou and coꢀ
workers (Scheme 1a)5h. In this way, besides the obvious need to develop milder methods to access
triarylmethanes, there is also no current strategy available to directly access anilineꢀbased triarylmethanes from
secondary anilines.6 Motivated by this literature void, we explored a novel method to access new triarylmethanes
and related structures from secondary anilines and incorporating acidꢀsensitive functional groups, findings from
which are presented herein (Scheme 1b). Based on its peculiar reactivity,7 we envisioned that TBDMSꢀprotected
5ꢀhydroxymethyl furfural 1 constitutes the ideal test aldehyde substrate in combination with Nꢀmethylaniline to
achieve our goals.
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Scheme 1. Synthesis of TRAM bearing anilines
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The initial screening with protected 5ꢀhydroxymethyl furfural 1, Nꢀmethylaniline and diverse acid catalysts at 40
ºC for 48 h revealed that Yb(OTf)3, LaCl3ꢁ7H2O and AlCl3 are the most suitable catalysts for this transformation,
giving up to 82% yield of TRAM 2 and full conversion of 1 (Table 1, entries 1ꢀ7). Under the same reaction
conditions, the protic acid PTSA only provided 33% yield of 2 whereas no product was found in absence of
catalysts (Table 1, entries 1 and 2). From the initial catalyst hits, Yb(OTf)3 was selected for furthers studies as
LaCl3ꢁ7H2O and AlCl3 provided irreproducible yields after three test reactions (Table 1, entries 5 and 6). Further
optimization, namely temperature, time and concentration, led us to find that carrying the reaction at 40 ºC in 0.1
M acetonitrile for 34 h gives the desired TRAM 2 in quantitative yield (Table 1, entry 11). For longer reaction
time or higher temperatures, TBDMS deprotection of the TRAM 2 can be detected, highlighting the importance
of control of reaction conditions in the synthesis of acidꢀsensitive triarylmethanes.
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Table 1. Reaction condition optimization for TRAM formationa
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EntryCatalyst
t (h)T (ºC) Conv. Yield 2 (%)b
(%)b
50
1
None
48 40
48 40
ꢀc
33
2
3
PTSA
67
See footnoted48 40
up to 91< 50
4
5
6
ZrCl4
48 40
82
52
LaCl3ꢁ7H2Oe 48 40
100
94
100
53
100
83
100
70
72
82
e
AlCl3
48 40
48 40
24 40
24 50
32 40
34 40
27 40
30 40
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9
10
11
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
61 (60f)g
53
45g
81
100 (98f)
57
12h Yb(OTf)3
13i Yb(OTf)3
80
62
aReaction conditions: 1 (0.125 mmol), Nꢀmethylaniline (3
molar equiv.), catalyst (10 mol%) were reacted in
acetonitrile at desired temperature and time. Determined
by HPLC analysis of crude reaction mixture. Product 2
was not observed. FeCl3ꢁ6H2O, RuCl3ꢁxH2O, NiCl2, ZnI2,
b
c
d
AgOTf,
CeCl3,
ZrCl4,
CoCl2ꢁ6H2O,
Cu(OTf)2,
GdCl3ꢁ6H2O, BaCl2, Ti(OiPr). Not reproducible. Isolated
e
f
g
yield after column chromatography. Deprotected product
3 was also detected by TLC analysis of crude reaction
mixture. hReaction performed in a concentration of 0.05 M
of 1. iReaction performed in a concentration of 0.2 M of 1.
Reaction of unprotected 5ꢀhydroxymethyl furfural (4, HMF – an important bioderived raw material)8 with Nꢀ
methylaniline catalyzed by Yb(OTf)3 also smoothly produced the corresponding TRAM 3 in 91% yield after 28h
(Figure 2). As summarized in Figure 2, 5ꢀsubstituted hydroxymethyl furfurals bearing the hydroxyl protection
groups like acetyl, benzyl and benzoyl were also well tolerated under the reaction conditions, providing the
respective TRAM generally in good yields (Figure 2, compounds 5ꢀ7, condition A). After achieving this
important goal, we were pleased to find that benzaldehydes also produced the corresponding TRAM, despite of
generally requiring longer reaction times to achieve high conversions of the starting aldehydes (Figure 2,
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compounds 12ꢀ24, condition A). Despite a direct correlation between the electronic nature of the substituents with
the product yield was not observed, paraꢀnitro substitution resulted in the highest yield (Figure 2, compound 15).
Perhaps more importantly, these mild reaction conditions tolerated orthoꢀsubtitution in the benzaldehyde (Table 2,
compounds 16, 22 and 23, condition A). On the other hand, the reaction appears to be quite sensitive to increase
of steric bulkiness around the aniline nitrogen atom, as Nꢀbenzyl and Nꢀ(cylohexyl)methyl anilines presented
much lower conversion compared with Nꢀmethyl anilines (Figure 2, compounds 8ꢀ9, condition A). Tertiary N,Nꢀ
dimethyl anilines were virtually unreactive under our reaction conditions (Figure 2, compounds 10ꢀ11, condition
A), while aniline resulted in the formation of the equivalent imine in 63% isolated yield.
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Figure 2. Substrate scope of Yb(OTf)3ꢀcatalyzed reaction of aldehydes and anilines for TRAM formation.
Condition A: Reaction performed at normal pressure and 40 ºC; and Condition B: Reaction performed at
8970 atm. and room temperature. For experimental details see experimental section. The yields correspond
to the isolated yield after column chromatography.
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Dialdehydes like 2,5ꢀdiformylfuran and terephthalaldehyde, were also studied as aldehydes for TRAM formation.
The first reacted smoothly to give selectively the monoꢀTRAM 25, even when 6 molar equivalents of Nꢀ
methylaniline was used. Further extension of the reaction time to 2 days led to a very complex mixture with only
traces of the product, suggesting decomposition. In opposite, when terephthalaldehyde was subjected to the same
reaction conditions using 6 equivalents of Nꢀmethylaniline, both the corresponding TRAM 26 and the bisꢀTRAM
27 were obtained in a mixture of 1:1 and an overall isolated yield of 95% (Scheme 2), showing the superior
stability of these products.
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Scheme 2. Ytterbiumꢀcatalyzed FriedelꢀCrafts reaction between (hetero)aromatic aldehydes with Nꢀmethylaniline
The novel synthetic methodology to produce secondaryꢀaniline based triarylmethanes reported herein is
hypothesized to take place through a FriedelꢀCrafts type mechanism. This type of reaction is characterized by
displaying a negative volume of activation9 and thus is accelerated by pressure.10 Since pressures in the range of
1ꢀ20 kbar can strongly influence the rate and the chemical equilibria of reactions,11 we anticipated that our novel
methodology could also be accelerated by applying high pressure technology.12 The Yb(OTf)3ꢀcatalyzed reaction
of HMF (4) with Nꢀmethylaniline was extremely accelerated at 8970 bar, yielding the desired product in 86%
after only 30 minutes at room temperature (Figure 2, compound 3, condition B). For the sake of comparison, the
same reaction performed under conditions A provided only traces of product after 30 minutes.
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The reaction with other (hetero)aryl aldehydes was also greatly accelerated under highꢀpressure conditions as
summarized in Figure 2. As was observed at atmospheric pressure, several alcohol protecting groups of HMF are
well tolerated offering the corresponding TRAM in 79 to 90% yield (Figure 2, compounds 5ꢀ7). Substituted
benzaldehydes also reacted smoothly to yield the corresponding products in up to 94% yield (Figure 2, entries 12ꢀ
21, condition B). Finally, secondary anilines Nꢀbenzylaniline and Nꢀcyclohexylmethylaniline gave the increased
yields of the corresponding TRAM 8 and 9 of 84% and 31%, respectively.
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The current limitation of this methodology lies in the limited range of anilines that can be successfully employed,
which appears to have a negative correlation with the increase of sterics around the aniline nitrogen atom. Also,
the substitution degree in the aniline nitrogen impacted negatively the reaction success, since at normal pressure,
the more Cꢀnucleophilic tertiary anilines failed to react. These results are rather puzzling suggesting that a more
complex reaction mechanism leads to a formal FriedelꢀCrafts product. In addition we found that a competitive
reaction between Nꢀmethylaniline and N,Nꢀdimethylaniline delivered a mixture of three triarylmethanes, 2, 10 and
28 (Scheme 3).
Scheme 3. Competition reaction between tertiary and secondary anilines
Based on these results, we hypothesized that the FriedelꢀCrafts reaction proceeds via addition of the aniline
derivative to a transient iminium ion,13 formed by the ytterbiumꢀcatalyzed reaction of secondary aniline and the
aldehyde (Scheme 4). In order to further elucidate this hypothesis, conditions A between 1 and Nꢀmethylaniline in
deuterated acetonitrile were studied by NMR. Upon, addition of the catalyst to the reaction mixture, plausible
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iminiumꢀion and tertiary aniline intermediates were detected by H NMR analysis.14 Unfortunately, further
characterization of these intermediates was not possible since they were neither stable to silica nor detectable by
GCꢀMS analysis.
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Kinetic isotope effect (KIE) study was conducted by submitting a 1:1 mixture of Nꢀmethylaniline and Nꢀ
methylanilineꢀ2,4,6ꢀd3 to intermolecular competition experiment with HMF (4). The observed absence of an
isotope effect (KIE = 1.0) shows that CꢀH bond cleavage does not occur during the rateꢀdetermining step (RLS).15
Density Functional Theory (DFT) calculations showed that the reaction of HMF (4) and N-methylaniline has the
biggest energy barrier (RLS) for the FriedelꢀCrafts addition of the Nꢀmethylaniline to the iminiumꢀion A, and the
lowest energies for the proton abstraction steps (Scheme 4). Furthermore, the calculations indicate that the second
FriedelꢀCrafts alkylation occurs by a nonꢀconcerted fashion (the addition most probably occurs to the secondary
carbocation originated by aniline disconnection rather than to the tertiary aniline C).16
The great acceleration of the reaction under extreme highꢀpressure could be attributed to the fact that the RLS
occurs with a considerable negative activation volume (Scheme 4). Based on all the data gathered, we believe that
under extreme highꢀpressure the reaction can also proceed via direct addition of aniline derivative to the aldehyde,
as reaction with tertiary anilines under highꢀpressure gave the corresponding TRAM (Figure 2, compounds 12 and
13, condition B).
Scheme 4. Proposed mechanism for TRAM formation from aldehydes and secondary anilines (See supporting
information for further details on DFT results)
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Finally, some of the newly synthesized TRAMs were evaluated for their antiproliferative activity towards human
cancer cell lines from colon (HTꢀ29), lung (NCIꢀH460) and breast (MCFꢀ7) origin (Table 2). Interestingly,
compound 12 (Ar = Ph) induced an important cancer cell growth inhibition in contrast to compound 3 (Ar = 2ꢀ
furylꢀ5ꢀCH2OH) (Table 2, entries 1ꢀ2). This activity is exclusive against HTꢀ29 cell line (determined
concentration of 12 to reduce 50% of HTꢀ29 cell viability (IC50) was 5.1 µM whereas for the other cell lines tested
were greater than 20 µM)17. Thus, the IC50 of several TRAM bearing substituted benzaldehydes were determined,
leading to the paraꢀmethyl substitution in benzaldehyde (TRAM 13) as the most promising compound, with an
IC50 of 1.74 µM against HTꢀ29 cell line (Table 2, entry 3). A subclone of the parental CHO cell line, which was
derived from the ovary of an adult Chinese hamster (CHOK1) was also used to test toxicity of TRAM and data
demonstrates that larger doses of these compounds are required to attain the IC50 in this model.
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Table 2. Biological activity of the new TRAM derivatives
EntryTRAMIC50(HTꢀ29, µM) IC50(CHOK1, µM)
1
2
3
4
>20
ND
>20
14.55 ± 1.06
>20
3
5.1 ± 3.3
1.74 ± 2.32
7.97 ± 3.13
12
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15
ND = Not determined
In conclusion, the first direct and general method for the synthesis of symmetric triarylmethane derivatives
bearing secondary anilines is described. The protocol uses Yb(OTf)3 as catalyst under mild reaction conditions,
being compatible with protecting groups and furans. Experimental observations and DFT calculations indicate an
iminiumꢀion catalysis, explaining the distinct reactivity of secondary anilines. Further reaction conditions
investigation showed that the reaction is highly accelerated by extreme highꢀpressure (9 kbar). Finally, the new
synthesized TRAM exhibited important antiproliferative activity against HTꢀ29 cells and TRAM 13 present
interesting biological activity.
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EXPERIMENTAL SECTION
General Experimental Details
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All solvents were freshly dried and distilled before use. All reactions were performed in flame dried glassware
under argon atmosphere otherwise notice. Commercially available reagents were used as received without further
purification otherwise notice. Flash column chromatography was carried out on silica gel 60M using an
automated apparatus. Reaction mixtures were analyzed by TLC using silica gel 60, and visualization by UV and
phosphomolybdic acid stain. NMR spectra were recorded at room temperature in a 300 or 400 MHz apparatus
using CDCl3 as solvent and (CH3)4Si(1H) as internal standard. All coupling constants are expressed in Hz.
Elemental analysis was performed in a CHNSꢀO analyzer. HPLC analysis was performed using diode array
detector and normal phase silica column (pore size: 110 Å; 5 µm), manual injector with 20 ꢂL loop. Mobile phase
gradient hexane/2ꢀpropanol from 99:1 to 98:2 for 10 min, flow 0.7 to 1 mL/min for 10 min. HRMS was
performed using a LTQ Orbitrap XL mass spectrometer controlled by LTQ Tune Plus 2.5.5 and Xcalibur 2.1.0.
The capillary voltage of the electrospray ionization (ESI) was set to 3000 V. The capillary temperature was
275ºC. The sheath gas flow rate (nitrogen) was set to 5 (arbitrary unit as provided by the software seetings). The
capillary voltage was 36 V and the tube lens voltage 110 V. High pressure reactions were performed in a 4 mL
Teflon ampoules in a Liquid pressure vessel LV 30/16 coupled to a laboratory hydraulic press. The pressure
inside the vessel (Pv) is related to the pressure from the press according to the following expression: Pv [MPa] =
3.9 × Pp [bar]. 5ꢀHydroxymethylfurfural (HMF, 4) was prepared from Fructose or Glucose according to our
reported protocols.18 OꢀProtected derivatives of HMF were prepared using known protocols as recently reported
by us.19
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General procedure for reaction conditions optimization (Table 1). To a solution of 1 (30 mg, 0.125 mmol) in
anhydrous acetonitrile (1.3 mL, 0.1 M), Nꢀmethylaniline (40 µL, 3 equiv.) was added via gasꢀtight syringe. The
catalyst was added in one portion and the mixture was allowed to stir at the mentioned temperature and time
under argon atmosphere. The solvent was then evaporated and the crude reaction mixture was filtered through a
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small pad of silica gel. The solvent was evaporated and hexane/2ꢀpropanol was used to dilute the mixture to the
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appropriate concentration for HPLC analysis. Rt (1) = 6.2 min, λmax=275 nm; Rt (2) = 16.2 min, λmax=252 nm.
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General procedure for the synthesis of triarylmethanes at atmospheric pressure (Table 2, Condition A). To
a solution of aldehyde in anhydrous acetonitrile (0.1 M), desired aniline (3 molar equiv.) was added followed by
the addition of Yb(OTf)3 (10 mol%) in one portion. The reaction mixture was allowed to stir at the desired
temperature and time described in Table 2 under argon atmosphere. The solvent was then evaporated and the
product purified by column chromatography.
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General procedure for the synthesis of triarylmethanes under highꢀpressure (Table 2, Condition B). To a
proper Teflon vessel, the corresponding aldehyde, aniline (3 molar equiv.), anhydrous acetonitrile (1 mL) and
Yb(OTf)3 (10 mol%) were added (without argon atmosphere). Next the reactor was filled to the top with
acetonitrile (approximate total volume of 2.4 mL). The reactor was introduced in the highꢀpressure apparatus at
8970 bar and kept for the time described in Table 2. The solvent was then evaporated and the product purified by
column chromatography.
Procedure for amine competition experiment. N,NꢀDimethylaniline (50 µL, 0.39 mmol, 3 equiv.), Nꢀ
methylaniline (42 µL, 0.39 mmol, 3 equiv.) and Yb(OTf)3 (8 mg, 0.013 mmol, 10 mol%) were sequentially added
to a solution of 1 (30 mg, 0.13 mmol, 1 equiv.) in anhydrous acetonitrile (1.3 mL, 0.1 M). The reaction mixture
was allowed to stir for 89 h at 40 ºC under argon atmosphere. The solvent was evaporated and the crude mixture
was purified by column chromatography to yield the products 2 (6% yield), 10 (4% yield) and 28 (11% yield).
4,4'-((5-(((tert-butyldimethylsilyl)oxy)methyl)furan-2-yl)methylene)bis(N-methylaniline) (2). General procedure
for reaction conditions optimization (Table 1, entry 11) using 1 (0.13 mmol). Purification by column
chromatography (Hexane/EtOAc 8:2, Rf = 0.41) afforded the product as a brown viscous liquid (54 mg, 98%). 1H
NMR (300 MHz, CDCl3) δ 0.03 (s, 6H), 0.87 (s, 9H), 2.81 (s, 6H), 4.57 (s, 2H), 5.22 (s, 1H), 5.79 (d, J = 2.76 Hz,
1H), 6.12 (d, J = 2.68 Hz, 1H), 6.55 (d, J = 8.1 Hz, 4H), 6.98 (d, J = 8.3 Hz, 4H).13C NMR (100 MHz, CDCl3) δ
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5.2, 18.4, 25.9, 31.1, 49.3, 58.4, 107.7, 108.2, 112.5, 129.5, 131.7, 147.5, 153.3, 157.7. CHN calculated for
C26H36N2O2Si: C: 71.51; H: 8.31; N: 6.42, found: C: 71.12; H: 8.44; N: 6.69.
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(5-(bis(4-(methylamino)phenyl)methyl)furan-2-yl)methanol (3). General procedure
A
or
B
using
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5ꢀhydroxymethylfurfural 4 (A, 0.26 mmol; B, 0.26 mmol). Purification by column chromatography
(Hexane/EtOAc 4:6, Rf = 0.54) afforded the product as a dark green viscous oil (A, 76 mg, 91%; B, 72 mg, 86%).
1H NMR (300 MHz, CDCl3) δ 2.81 (s, 6H), 4.53 (s, 2H), 5.23 (s, 1H), 5.80 (d, J = 3.1 Hz, 1H), 6.18 (d, J = 2.9
Hz, 1H), 6.54 (d, J = 8.6 Hz, 4H), 6.97 (d, J = 8.3 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 30.9, 49.4, 57.6, 108.3,
108.5, 112.5, 129.4, 131.2, 147.9, 153.2, 158.5. HRMS (ESI): m/z calculated for C20H23N2O2 [M+H+] 323.17540,
found 323.17497.
(5-(bis(4-(methylamino)phenyl)methyl)furan-2-yl)methyl acetate (5). General procedure A or B using
(5ꢀformylfuranꢀ2ꢀyl)methyl acetate (A, 0.13 mmol; B, 0.26 mmol). Purification by column chromatography
(Hexane/EtOAc 8:2, Rf = 0.12) afforded the product as a light green viscous oil (A, 43 mg, 91%; B, 77 mg, 86%).
1H NMR (300 MHz, CDCl3) δ 2.06 (s, 3H), 2.82 (s, 6H), 4.99 (s, 2H), 5.25 (s, 1H), 5.84 (d, J = 3.1 Hz, 1H), 6.30
(d, J = 3.1 Hz, 1H), 6.56 (d, J = 8.5 Hz, 4H), 6.98 (d, J = 8.4 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 21.3, 31.3,
49.7, 58.8, 109.2, 111.6, 112.8, 129.8, 131.5, 148.2, 148.7, 159.7, 171.1. HRMS (ESI): m/z calculated for
C44H49N4O6 [2M+H+] 729.36466, found 729.36384, m/z calculated for C20H21N2O [(M – CH3COO)+] 305.16484,
found 305.16423.
(5-(bis(4-(methylamino)phenyl)methyl)furan-2-yl)methyl benzoate (6). General procedure A or B using (5ꢀ
formylfuranꢀ2ꢀyl)methyl benzoate (A, 0.14 mmol; B, 0.29 mmol). Purification by column chromatography
(Hexane/EtOAc 8:2, Rf = 0.18) afforded the product as a green viscous oil (A, 48 mg, 80%; B, 110 mg, 90%). 1H
NMR (300 MHz, CDCl3) δ 2.82 (s, 6H), 5.28 (s, 2H), 5.29 (s, 1H), 5.90 (d, J = 3.1 Hz, 1H), 6.41 (d, J = 3.1 Hz,
1H), 6.56 (d, J = 8.6 Hz, 4H), 7.03 (d, J = 8.4 Hz, 4H), 7.44 (t, J = 7.5 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 8.07 (d, J
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= 7.0 Hz, 2H). C NMR (100 MHz, CDCl3) δ 30.9, 49.4, 59.0, 108.9, 111.5, 112.4, 128.4, 129.5, 129.8, 130.1,
131.1, 133.0, 148.0, 148.4, 159.4, 166.3. HRMS (ESI): m/z calculated for C54H53N4O6 [2M+H+] 853.39596, found
853.39176, m/z calculated for C20H21N2O [(M – PhCOO)+] 305.16484, found 305.16341.
4,4'-((5-((benzyloxy)methyl)furan-2-yl)methylene)bis(N-methylaniline) (7). General procedure A or B using 5ꢀ
((benzyloxy)methyl)furanꢀ2ꢀcarbaldehyde (A, 0.13 mmol; B, 0.26 mmol). Purification by column
chromatography (Hexane/EtOAc 8:2, Rf = 0.12) afforded the product as a green viscous oil (A, 30 mg, 56%; B,
92 mg, 86%). 1H NMR (300 MHz, CDCl3) δ 2.81 (s, 6H), 4.44 (s, 2H), 4.51 (s, 2H), 5.26 (s, 1H), 5.83 (d, J = 3.1
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Hz, 1H), 6.24 (d, J = 3.1 Hz, 1H), 6.54 (d, J = 8.6 Hz, 4H), 6.99 (d, J = 8.3 Hz, 4H), 7.31 (m, 5H). 13C NMR (100
MHz, CDCl3) δ 30.9, 49.3, 64.0, 71.6, 108.5, 110.1, 112.4, 127.6, 128.0, 128.3, 129.5, 131.3, 138.1, 147.9, 150.7,
158.8. HRMS (ESI): m/z calculated for C27H29N2O2 [M+H+] 413.22235, found 413.22170.
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(5-(bis(4-(benzylamino)phenyl)methyl)furan-2-yl)methanol (8). General procedure
A
or
B
using 5ꢀ
5ꢀhydroxymethylfurfural 4 (A, 0.13 mmol; B, 0.26 mmol). Purification by column chromatography
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(Hexane/EtOAc 4:6, Rf = 0.85) afforded the product as a green oil (A, 12 mg, 20%; B, 104 mg, 84%). H NMR
(300 MHz, CDCl3) δ 4.18 (s, 4H), 4.37 (s, 2H), 5.13 (s, 1H), 5.72 (d, J = 3.1 Hz, 1H), 6.06 (d, J = 3.1 Hz, 1H),
6.46 (d, J = 8.6 Hz, 4H), 6.87 (d, J = 8.5 Hz, 4H), 7.13 ꢀ 7.28 (m, 10H) 13C NMR (100 MHz, CDCl3) δ 48.4, 49.3,
57.5, 108.6, 108.9, 113.2, 127.7, 128.0, 129.1, 129.9, 131.9, 140.0, 147.3, 153.7, 159.0. HRMS (ESI): m/z
calculated for C32H31N2O2 [M+H+] 475.23800, found 475.23707.
(5-(bis(4-((cyclohexylmethyl)amino)phenyl)methyl)furan-2-yl)methanol (9). General procedure A or B using 5ꢀ
(hydroxymethyl)furanꢀ2ꢀcarbaldehyde (A, 0.26 mmol; B, 0.26 mmol). Purification by column chromatography
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(Hexane/EtOAc 4:6, Rf = 0.49) afforded the product as a green oil (A, 18 mg, 14%; B, 39 mg, 31%). H NMR
(300 MHz, CDCl3) δ 0.87 ꢀ 1.82 (m, 22H), 2.92 (d, J = 6.6 Hz, 4H), 4.52 (s, 2H), 5.21 (s, 1H), 5.80 (d, J = 3.1 Hz,
1H), 6.17 (d, J = 3.1 Hz, 1H), 6.51 (d, J = 8.6 Hz, 4H), 6.94 (d, J = 8.4 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ
26.1, 26.7, 31.4, 37.7, 49.4, 50.9, 57.8, 108.4, 108.6, 112.6, 129.5, 130.9, 147.3, 153.1, 158.8. HRMS (ESI): m/z
calculated for C32H43N2O2 [M+H+] 487.33191, found 487.33104.
(5-(bis(4-(dimethylamino)phenyl)methyl)furan-2-yl)methanol
(10).
General
procedure
B
using
5ꢀhydroxymethylfurfural 4 (0.26 mmol). Purification by column chromatography (Hexane/EtOAc 4:6, Rf = 0.69)
afforded the product as a brown oil (38 mg, 42%). 1H NMR (300 MHz, CDCl3) δ 2.91 (s, 12H), 4.53 (s, 2H), 5.27
(s, 1H), 5.82 (d, J = 3.1 Hz, 1H), 6.18 (d, J = 3.1, Hz, 1H), 6.68 (d, J = 8.8 Hz, 4H), 7.03 (d, J = 8.7 Hz, 4H). 13C
NMR (100 MHz, CDCl3) δ 40.9, 49.2, 57.8, 108.4, 108.7, 112.8, 129.4, 130.6, 149.4, 153.1, 158.7. HRMS (ESI):
m/z calculated for C22H27N2O2 [M+H+] 351.20670, found 351.20656.
4,4'-((5-(((tert-butyldimethylsilyl)oxy)methyl)furan-2-yl)methylene)bis(N,N-dimethylaniline)
(11).
General
procedure B using 5ꢀ(((tertꢀbutyldimethylsilyl)oxy)methyl)furanꢀ2ꢀcarbaldehyde 1 (0.26 mmol) Purification by
column chromatography (Hexane/EtOAc 8:2, Rf = 0.68) afforded the product as a brown viscous oil (18 mg,
15%). 1H NMR (300 MHz, CDCl3) δ 0.09 (s, 6H), 0.93 (s, 9H), 2.94 (s, 12H), 4.63 (s, 2H), 5.30 (s, 1H), 5.85 (d, J
= 3.1 Hz, 1H), 6.17 (d, J = 3.1 Hz, 1H), 6.71 (d, J = 8.8 Hz, 4H), 7.08 (d, J = 8.6 Hz, 4H). 13C NMR (100 MHz,
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CDCl3) δ ꢀ5.5, 18.1, 25.6, 40.5, 48.8, 58.0, 107.4, 107.9, 112.3, 129.0, 130.5, 148.9, 152.9, 157.5. HRMS (ESI):
m/z calculated for C28H41N2O2Si [M+H+] 465.29318, found 465.29190.
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4,4'-(phenylmethylene)bis(N-methylaniline) (12). General procedure A or B using benzaldehyde (A, 0.26 mmol;
B, 0.26 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.31) afforded the product as a
blue viscous oil (A, 53 mg, 68%; B, 39 mg, 50%). The NMR data is in accordance to the literature.20 1H NMR
(300 MHz, CDCl3) δ 2.84 (s, 6H), 5.39 (s, 1H), 6.57 (d, J = 8.6 Hz, 4H), 6.97 (d, J = 8.3 Hz, 4H), 7.15 ꢀ 7.32 (m,
5H). 13C NMR (100 MHz, CDCl3) δ 31.0, 55.3, 112.4, 125.9, 128.2, 129.5, 130.2, 133.6, 145.6, 147.6.
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4,4'-(p-tolylmethylene)bis(N-methylaniline) (13). General procedure A or B using 4ꢀmethylbenzaldehyde (A, 0.12
mmol; B, 0.26 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.43) afforded the
product as a green oil (A, 27 mg, 65%; B, 73 mg, 88%). 1H NMR (300 MHz, CDCl3) δ 2.31 (s,3H), 2.82 (s, 6H),
5.32 (s, 1H), 6.57 (d, J = 8.6 Hz, 4H), 6.94 (d, J = 8.2 Hz, 4H), 7.01 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H).
13C NMR (100 MHz, CDCl3) δ 21.6, 31.7, 55.4, 113.2, 129.4, 129.8, 130.7, 134.7, 135.8, 142.9, 147.6. HRMS
(ESI): m/z calculated for C22H25N2 [M+H+] 317.20123, found 317.20069.
4,4'-((4-methoxyphenyl)methylene)bis(N-methylaniline) (14). General procedure
A
or
B
using 4ꢀ
methoxybenzaldehyde (A, 0.13 mmol; B, 0.26 mmol). Purification by column chromatography (Hexane/EtOAc
8:2, Rf = 0.32) afforded the product as a green oil (A, 28 mg, 65%; B, 69 mg, 80%). 1H NMR (300 MHz, CDCl3)
δ 2.82 (s, 6H), 3.78 (s, 3H), 5.31 (s, 1H), 6.54 (d, J = 8.6 Hz, 4H), 6.81 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.5 Hz,
4H), 7.05 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 30.9, 54.4, 55.2, 112.3, 113.5, 130.0, 130.2, 133.9,
137.7, 147.5, 157.7. CHN calculated for (C22H24N2O): C: 79.48; H: 7.28; N: 8.43, found: C: 79.40; H: 7.55; N:
8.67.
4,4'-((4-nitrophenyl)methylene)bis(N-methylaniline) (15). General procedure A or B using 4ꢀnitrobenzaldehyde
(A, 0.13 mmol; B, 0.26 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.25) afforded
the product as a yellow oil (A, 44 mg, 97%; B, 87 mg, 94%). 1H NMR (300 MHz, CDCl3) δ 2.82 (s, 6H, s), 5.43
13
(s, 1H), 6.55 (d, J = 8.6 Hz, 4H), 6.90 (d, J = 8.5, 4H), 7.29 (d, J = 8.6 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H). C
NMR (100 MHz, CDCl3) δ 30.9, 55.2, 112.5, 123.5, 130.1, 130.2, 131.8, 146.3, 148.1, 153.6. HRMS (ESI): m/z
calculated for C21H22N3O2 [M+H+] 348.17065, found 348.17012.
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2-(bis(4-(methylamino)phenyl)methyl)phenol (16). General procedure A or B using 2ꢀhydroxybenzaldehyde (A,
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6
7
0.13 mmol; B, 0.25 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.38) afforded the
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product as a green viscous oil that crystalizes in the freezer (A, 12 mg, 30%; B, 62 mg, 78%). H NMR (300
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9
MHz, CDCl3) δ 2.83 (s, 6H), 5.44 (s, 1H), 6.59 (d, J = 8.6 Hz, 4H), 6.83ꢀ6.85 (m, 3H), 6.99 (d, J = 8.4 Hz, 4H),
13
7.12ꢀ7.14 (m, 1H). C NMR (100 MHz, CDCl3) δ 31.2, 50.1, 113.0, 116.5, 120.7, 127.9, 130.3, 130.6, 131.6,
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131.7, 148.2, 154.1. HRMS (ESI): m/z calculated for C21H23N2O [M+H+] 319.18049, found 319.18032.
4,4'-(pyridin-2-ylmethylene)bis(N-methylaniline) (17). General procedure A or B using picolinaldehyde (A, 0.13
mmol; B, 0.26 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.15) afforded the
product as a green oil (A, 32 mg, 80%; B, 60 mg, 76%). 1H NMR (300 MHz, CDCl3) δ 2.80 (s, 6H), 5.35 (s, 1H),
6.54 (d, J = 8.6 Hz, 4H), 6.92 (d, J = 8.7 Hz, 4H), 7.17 (ddd, J = 0.7, 4.8, 7.8 Hz, 1H), 7.42 (dddd, J = 0.6, 1.7,
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2.3, 7.9 Hz, 1H), 8.43 (dd, J = 1.6, 4.8 Hz, 1H), 8.44ꢀ8.45 (m, 1H). C NMR (100 MHz, CDCl3) δ 30.5, 52.6,
112.6, 123.4, 130.3, 132.5, 137.1, 141.3, 147.7, 148.3, 151.3. HRMS (ESI): m/z calculated for C20H22N3 [M+H+]
304.18082, found 304.18042.
4,4'-(p-tolylmethylene)bis(N-benzylaniline) (18). General procedure A or B using 4ꢀmethylbenzaldehyde (A, 0.13
mmol; B, 0.26 mmol).Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.82) afforded the
1
product as a green oil (A, 2 mg, 3%; B, 55 mg, 45%). H NMR (300 MHz, CDCl3) δ 2.22 (s, 3H), 4.19 (s, 4H),
5.22 (s, 1H), 6.46 (d, J = 8.5 Hz, 4H), 6.83 (d, J = 8.5 Hz, 4H), 6.91ꢀ7.29 (m, 14H). 13C NMR (100 MHz, CDCl3)
δ 21.1, 48.7, 54.9, 112.8, 127.3, 127.7, 128.8, 129.3, 129.4, 130.2, 134.1, 135.4, 139.7, 142.4, 146.4. HRMS
(ESI): m/z calculated for C34H33N2 [M+H+] 469.26383, found 469.26257.
4,4'-((4-fluorophenyl)methylene)bis(N-methylaniline) (19). General procedure A or B using 4ꢀfluorobenzaldehyde
(A, 0.13 mmol; B, 0.26 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.33) afforded
1
the product as a green viscous oil (A, 5 mg, 12%; B, 62 mg, 75%). H NMR (300 MHz, CDCl3) δ 2.83 (s, 6H),
5.36 (s, 1H), 6.57 (d, J = 8.6 Hz, 4H), 6.95 (d, J = 8.5 Hz, 4H), 7.00ꢀ7.13 (m, 4H). 13C NMR (100 MHz, CDCl3) δ
31.5, 55.0, 112.9, 115.2, 115.5, 130.6, 131.2, 131.3, 133.9, 141.8, 148.2, 160.2, 163.4. HRMS (ESI): m/z
calculated for C21H22N2F [M+H+] 321.17615, found 321.17572.
4,4'-((4-chlorophenyl)methylene)bis(N-methylaniline) (20). General procedure
A
or
B
using 4ꢀ
chlorobenzaldehyde (A, 0.13 mmol; B, 0.26 mmol). Purification by column chromatography (Hexane/EtOAc 8:2,
Rf = 0.36) afforded the product as green viscous oil that crystalizes in the freezer (A, 7 mg, 16%; B, 61 mg, 70%).
1H NMR (300 MHz, CDCl3) δ 2.70 (s, 6H), 5.22 (s, 1H), 6.44 (d, J = 8.6 Hz, 4H), 6.81 (d, J = 8.3 Hz, 4H), 6.96
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(d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H). C NMR (100 MHz, CDCl3) δ 31.4, 55.1, 112.9, 128.8, 130.6,
131.3, 132.1, 133.5, 144.7, 148.3. HRMS (ESI): m/z calculated for C21H22ClN2 [M+H+] 337.14660, found
337.14647.
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4,4'-((4-(trifluoromethyl)phenyl)methylene)bis(N-methylaniline) (21). General procedure A or B using 4ꢀ
(trifluoromethyl)benzaldehyde (A, 0.13 mmol; B, 0.25 mmol). Purification by column chromatography
(Hexane/EtOAc 8:2, Rf = 0.41) afforded the product as green oil (A, 26 mg, 53%; B, 80 mg, 87%). 1H NMR (300
MHz, CDCl3) δ 2.71 (s, 6H), 5.30 (s, 1H), 6.45 (d, J = 8.6 Hz, 4H), 6.82 (d, J = 8.3 Hz, 4H), 7.15 (d, J = 8.8 Hz,
2H), 7.41 (d, J = 8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 30.9, 55.1, 112.4, 122.6, 125.0, 125.1, 129.7, 130.1,
132.5, 147.8, 149.7. HRMS (ESI): m/z calculated for C22H22N2F3 [M+H+] 371.17296, found 371.17228.
4,4'-((3-chloro-2-fluorophenyl)methylene)bis(N-methylaniline) (22). General procedure A using 3ꢀchloroꢀ2ꢀ
fluorobenzaldehyde (0.26 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.62)
afforded the product as green oil (66 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 2.49 (s, 6H), 5.33 (s, 1H), 6.23 (d,
13
J = 8.6 Hz, 4H), 6.53ꢀ6.68 (m, 6H), 6.92 (ddd, J = 2.6, 6.1, 7.8 Hz, 1H). C NMR (100 MHz, CDCl3) δ 30.6,
47.8, 112.6, 121.2 (d), 124.3 (d), 128.6, 129.6 (d), 130.3, 131.8, 134.9 (d), 148.4, 155.0, 158.3. HRMS (ESI): m/z
calculated for C21H21ClFN2 [M+H+] 355.13718 and 357.13423, found 355.13669 and 357.13349
4,4'-((2,4-dichlorophenyl)methylene)bis(N-methylaniline)
(23).
General
procedure
A
using
2,4ꢀ
dichlorobenzaldehyde (0.26 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.68)
afforded the product as green oil (53 mg, 55%). 1H NMR (300 MHz, CDCl3) δ 2.82 (s, 6H), 5.70 (s, 1H), 6.55 (d,
J = 8.6 Hz, 4H), 6.88 (d, J = 8.3 Hz, 4H), 6.94 (d, J = 8.4 Hz, 1H), 7.13 (dd, J = 2.2, 8.4 Hz, 1H) 7.38 (d, J = 2.2
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 31.0, 51.7, 113.1, 127.5, 130.1, 131.0, 132.3, 132.8, 133.0, 135.9, 142.7,
148.7. HRMS (ESI): m/z calculated for C21H21Cl2N2 [M+H+] 371.10763 and 373.10468 found 371.10748 and
373.10422.
4,4'-((3-bromophenyl)methylene)bis(N-methylaniline) (24). General procedure A using 3ꢀbromobenzaldehyde
(0.26 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.68) afforded the product as
1
green oil (64 mg, 65%). H NMR (300 MHz, CDCl3) δ 2.83 (s, 6H), 5.34 (s, 1H), 6.56 (d, J = 8.6 Hz, 4H), 6.94
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(d, J = 8.7 Hz, 4H), 7.11 (m, 2H), 7.33 (m, 2H). C NMR (100 MHz, CDCl3) δ 31.1, 55.3, 113.1, 123.2, 128.9,
129.8, 130.5, 130.9, 133.1, 133.4, 148.7, 149.0. HRMS (ESI): m/z calculated for C21H22BrN2 [M+H+] 381.09609
and 383.09404, found 381.09590 and 383.09337.
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5-(bis(4-(methylamino)phenyl)methyl)furan-2-carbaldehyde (25). General procedure A using furanꢀ2,5ꢀ
dicarbaldehyde (0.18 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.53) afforded the
product as a black oil (30 mg, 52%). 1H NMR (300 MHz, CDCl3) δ 2.80 (s, 6H), 5.33 (s, 1H), 6.13 (d, J = 3.5 Hz,
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1H), 6.54 (d, J = 8.5 Hz, 4H), 6.96 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 3.5 Hz, 1H), 9.54 (s, 1H). C NMR (100
MHz, CDCl3) δ 30.9, 49.7, 111.2, 112.6, 129.5, 129.7, 132.8, 148.3, 152.3, 165.9, 177.8. HRMS (ESI): m/z
calculated for C20H21N2O2 [M+H+] 321.15975, found 321.15900.
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4-(bis(4-(methylamino)phenyl)methyl)benzaldehyde (26). General procedure A using terephthalaldehyde (0.24
mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.77) afforded the product as a green
oil (39 mg, 49%). 1H NMR (300 MHz, CDCl3) δ 2.82 (s, 6H), 5.41 (s, 1H), 6.55 (d, J = 8.6 Hz, 4H), 6.92 (d, J =
8.3 Hz, 4H), 7.31 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 9.97 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 30.8,
55.5, 112.4, 129.7, 130.0, 130.1, 132.2, 134.4, 147.8, 153.0, 192.1. HRMS (ESI): m/z calculated for C22H23N2O
[M+H+] 331.18049, found 331.17986.
4,4',4'',4'''-(1,4-phenylenebis(methanetriyl))tetrakis(N-methylaniline) (27). General procedure
A
using
terephthalaldehyde (0.24 mmol). Purification by column chromatography (Hexane/EtOAc 8:2, Rf = 0.58) afforded
the product as blue viscous oil that crystalizes in the freezer (63 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 2.81 (s,
12H), 5.31 (s, 2H), 6.54 (d, J = 8.6, 8H), 6.95 (d, J = 8.4 Hz, 8H), 7.03 (s, 4H). 13C NMR (100 MHz, CDCl3) δ
30.9, 54.9, 112.3, 129.0, 130.1, 133.9, 142.7, 147.5. CHN calculated for (C36H38N4): C: 82.09; H: 7.27; N: 10.64,
found: C: 82.38; H: 7.30; N: 10.43.
4-((5-(((tert-butyldimethylsilyl)oxy)methyl)furan-2-yl)(4-(methylamino)phenyl)methyl)-N,N-dimethylaniline (28).
Procedure for amine competition experiment using 5ꢀ(((tertꢀbutyldimethylsilyl)oxy)methyl)furanꢀ2ꢀcarbaldehyde
1 (0.26 mmol). Isolated from the competion reaction. Purification by column chromatography (Hexane/EtOAc
8:2, Rf = 0.51) afforded the product as a brown viscous oil (13 mg, 11%). 1H NMR (300 MHz, CDCl3) δ 0.08 (s,
6H), 0.92 (s, 9H), 2.83 (s, 3H), 2.94 (s, 6H), 4.62 (s, 2H), 5.28 (s, 1H), 5.84 (d, J = 3.1 Hz, 1H), 6.16 (d, J = 3.1
Hz, 1H), 6.56 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ ꢀ5.1, 18.5, 26.0, 31.0, 40.9, 49.3, 58.4, 107.8, 108.3, 112.4, 112.7, 113.1, 129.4, 129.6,
129.6, 130.9, 131.5, 147.9, 149.3, 153.4, 157.9. HRMS (ESI): m/z calculated for C27H39N2O2Si [M+H+]
451.27753, found 451.27723.
N-((5-(((tert-butyldimethylsilyl)oxy)methyl)furan-2-yl)methylene)aniline. General procedure A using 5ꢀ(((tertꢀ
butyldimethylsilyl)oxy)methyl)furanꢀ2ꢀcarbaldehyde 1 (0.12 mmol). Purification by column chromatography
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(Hexane/EtOAc 8:2) afforded the product as a brown oil (26 mg, 68%). H NMR (300 MHz, CDCl3) δ 0.11 (s,
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6H), 0.93 (s, 9H), 4.77 (s, 2H), 6.42 (d, J = 3.4 Hz, 1H), 6.92 (d, J = 3.4 Hz, 1H), 7.22 (m, 3H), 7.37 (m, 2H), 8.23
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(s, 1H). C NMR (100 MHz, CDCl3) δ ꢀ4.8, 18.9, 26.4, 59.3, 109.6, 117.9, 121.6, 126.6, 129.7, 148.5, 151.9,
152.2, 159.3. HRMS (ESI): m/z calculated for C18H26NO2Si [M+H+] 316.17273, found 316.17259.
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Procedure for determination of the antiꢀproliferative activity. Cell lines were cultivated in media RPMIꢀ1640
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with Lꢀ glutamine, and supplemented with 10% fetal bovine serum (FBS) and antibiotics, and kept in a
humidified atmosphere with 5% CO2 and at 37ºC. For determination of the antiꢀproliferative activity, cells were
seeded in 96ꢀwell plates at a low density (0.5ꢀ1,5x105 cell/ml) and maintained in the incubator for approximately
24 hours. Stock solutions of the compounds to be tested were prepared in a way that the percentage of organic
solvent in contact with the cells was inferior to 1%. In this situation, it is not detected any solventꢀinduced
cytotoxicity in the used cell models. Samples were diluted in the cell culture medium with only 0.5% FBS in
order to attain the desired tested concentrations ranging in the interval [0ꢀ20] µM. Incubation lasted for 48 hours
to allow cells to duplicate in the presence of the compounds. At the end of the incubation period, viability was
determined using neutral red and as previously explained.21 Experimental points are an average of three repliques
and IC50 were determined using GraphPad Prism 5.
ASSOCIATED CONTENT
Supporting Information
DFT details and atomic coordinates of all optimized species; complete biological activity data and NMR and
HRMS spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: carlosafonso@ff.ulisboa.pt, jaimeacoelho@ff.ulisboa.pt
ACKNOWLEDGMENT
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We thank the Fundação para a Ciência e a Tecnologia (SFRH/BPD/73932/2010, SFRH/BPD/73822/2010,
SFRH/BPD/100433/2014, PTDC/QUIꢀQUI/119823/2010 and UID/DTP/04138/2013), and Fundação Calouste
Gulbenkian (Prémio de Estimulo à Investigação 2012) for financial support and REDE/1518/REM/2005 and the
Portuguese NMR Network (ISTꢀUTL Center) for providing access to the MS and NMR facilities.
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(6) To the best of our knowledge, a general methodology for the direct reaction of an aromatic aldehydes and the
corresponding secondary aniline is not described in the literature. However there are few examples of the
preparation of triarylmethanes via this reaction: a) Microwaveꢀassisted reaction of Nꢀmethylaniline and 4ꢀ
fluorobenzaldehyde or 4ꢀmethoxybenzaldehyde5h and; b) Reaction of Nꢀphenylnaphthalenꢀ1ꢀamine and 3ꢀ
chlorobenzaldehyde or 4ꢀnitrobenzaldehyde using a stoichiometric amount of iron(III) chloride (Li, XꢀL, Huang,
JꢀH, Yang, LꢀM, Org. Lett., 2011, 13, 4950).
(7) As recently described by us, in contrast to furfural derivatives that undergo furanꢀring opening reactions by
addition of nucleophiles to C5, 5ꢀhydroxymethylfurfural derivatives undergo εꢀfunctionalization under similiar
conditions. For further details on the peculiar reactivity of this class of compounds see Coelho, J. A. S.; Trindade,
A. F.; Andre, V.; Teresa Duarte, M.; Veiros, L. F.; Afonso, C. A. M. Org. Biom. Chem., 2014, 12, 9324.
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Putten, R.ꢀJ.; van der Waal, J. C.; de Jong, E.; Rasrendra, C. B.; Heeres, H. J.; de Vries, J. G. Chem. Rev. 2013,
113, 1499.
(9) Volume of activation (ꢃV≠) is defined as the difference between the partial molar volume occupied by the
transition state and that occupied by the reactants (ꢃV≠ = VTS – VR).
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(11) (a) Holzapfel, W. B.; Isaacs, N. S. High-pressure techniques in chemsitry and physics: A practical
approach; Oxford University Press, 1997 (b) Hugelshofer, C. L.; Magauer, T. Synthesis-Stuttgart 2014, 46, 1279.
(12) For the theory of the effect of highꢀpressure on organic reactions see a) Holzapfel, W. B.; Isaacs, N. S.
Highꢀpressure techniques in chemsitry and physics: A practical approach; Oxford University Press, 1997; b)
Eldik, R. v.; Hubbard, C. D. Chemistry under extreme or nonꢀclassical conditions; John Wiley & Sons Inc, 1996.
(13) (a) Grumbach, H. J.; Arend, M.; Risch, N. Synthesis-Stuttgart 1996, 883 (b) Rajesh, U. C.; Kholiya, R.;
Pavan, V. S.; Rawat, D. S. Tetrahedron Lett. 2014, 55, 2977.
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(14) Chemical shifts identified in the NMR of crude reaction mixture are similar to those reported in literature
for iminiumꢀion (Kaupp, G.; Schmeyers, J.; Boy, J., J. prakt. Chem, 2000, 342, 269.) and tertiary anilines (Murali,
A.; Puppala, M.; Varghese, B.; Baskaran, S., Eur. J. Org. Chem., 2011, 5297). See Supporting Information
material for further details.
(15) See supporting information for details on the determination of the KIE.
(16) See Supporting Information material for the complete energy diagram of the proposed reaction mechanism
(17) For complete details on biological activity of the sinthesized TRAM see supporting information.
(18) (a) Simeonov, S. P.; Coelho, J. A. S.; Afonso, C. A. M. Chemsuschem 2012, 5, 1388 (b) Simeonov, S. P.;
Coelho, J. A. S.; Afonso, C. A. M. Chemsuschem 2013, 6, 997.
(19) Coelho, J. A. S.; Trindade, A. F.; Andre, V.; Teresa Duarte, M.; Veiros, L. F.; Afonso, C. A. M. Org.
Biomol. Chem. 2014, 12, 9324.
(20) Sugasawa, T.; Toyoda, T.; Adachi, M.; Sasakura, K. J. Am. Chem. Soc. 1978, 100, 4842.
(21) Frade, R. F. M.; Coelho, J. A. S.; Simeonov, S. P.; Afonso, C. A. M. Toxicol Res. 2014, 3, 311.
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