Short cut to 1,2,3-triazole-based p38 MAP kinase inhibitors via [3+2]-cycloaddition chemistry

Article abstract of DOI:10.1039/b818909a

A series of 4,5-substituted 1,2,3-triazoles was synthesised via Cu(i)-catalysed azide-alkyne 1,3-dipolar [2+3]-cycloaddition reactions followed by a Suzuki coupling. The 1,2,3-triazoles were evaluated as inhibitors of the p38α MAP kinase, showing IC₅

Full text of DOI:10.1039/b818909a

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Short cut to 1,2,3-triazole-based p38 MAP kinase inhibitors
via [3+2]-cycloaddition chemistryw
Peter Diner,a Terese Andersson,a Jimmy Kjellen,b Karin Elbing,b Stefan Hohmannb
and Morten Grøtli*a
Received (in Montpellier, France) 24th October 2008, Accepted 31st October 2008
First published as an Advance Article on the web 16th December 2008
DOI: 10.1039/b818909a
A series of 4,5-substituted 1,2,3-triazoles was synthesised via Cu(I)-catalysed azide–alkyne
1,3-dipolar [2+3]-cycloaddition reactions followed by a Suzuki coupling. The 1,2,3-triazoles
were evaluated as inhibitors of the p38a MAP kinase, showing IC50 values in the high
nanomolar range.
Introduction
The mitogen-activated protein (MAP) kinases participate in
important cellular processes and are potential targets in treat-
ments of inflammation, cancer, and other diseases. The MAP
kinase p38 responds to environmental stress (e.g. UV radia-
tion, osmotic shock and mechanical stress) and is involved in
the production of cytokines (IL-1 and TNFa), both of
which are implicated in chronic inflammatory diseases.1
Consequently, inhibition of the p38 MAP kinase with small
organic molecules could provide an effective therapy for the
treatment of these chronic autoimmune diseases and, there-
fore, major efforts have been made in order to synthesise and
evaluate different inhibitors of p38 kinase.2–5
Fig. 1 Examples of the known p38 kinase inhibitors SB203580
(R1: 4-Ph-SOCH3; R2: H), SB216995 (R1: H; R2: cyclopropylmethyl),
and SB220025.
One class of compounds that have been developed as
selective p38 inhibitors are the pyridinylimidazole-based
compounds (SB, SmithKline Beecham). Several of these
compounds have been shown to be highly potent and to
inhibit the p38 kinase at nanomolar concentration (Fig. 1).6,7
In our search for new scaffolds that could be used in the
development of kinase inhibitors we became interested in
4- and 5-substituted 1,2,3-triazoles. The key step in forming
this five-membered ring system would be the Cu(I)-catalysed
azide–alkyne 1,3-dipolar [2+3]-cycloaddition reaction.8,9
With the high reaction yield and simple reaction and
purification conditions of the ‘‘click chemistry’’, 1,3-dipolar
[2+3]-cycloaddition has found its use in applications in
organic synthesis and drug discovery.10–13
Scheme
1
Retrosynthetic strategy for 4- and 5-substituted
1,2,3-triazoles.
cycloaddition (and in situ iodination) and followed by the
substitution of the iodine for the pyridinyl ring via a Suzuki
coupling (Scheme 1).
In this paper we wish to present the design, synthesis and
biological evaluation of 4,5-substituted 1,2,3-triazoles. The
results show that these compounds are potential inhibitors
of p38a MAP kinase.
The structural similarities between 4- and 5-substituted
1,2,3-triazoles and the pyridinylimidazole-based inhibitors
suggest a possible similarity in binding mode to the p38
MAP kinase.
Results and discussion
With this strategy, the desired inhibitors could easily be
obtained in only two steps, starting with the conversion of
the azide into the 4-aryl substituted 5-iodo-1,2,3-triazole via
Design
The design of the inhibitors is based on the docking (Glide, XP
mode) of different 1,2,3-triazole based inhibitors into the p38a
MAP kinase having the SB220025 inhibitor in the active site
(pdb-1BL7).14–16
a Department of Chemistry, University of Gothenburg, Kemivagen 10,
¨
41296 Gothenburg, Sweden. E-mail: grotli@chem.gu.se;
Fax: +46 31 7723840; Tel: +46 31 7722905
The docking was used in order to evaluate if the triazole-
based compounds can mimic the binding modes of the
pyridine ring to the hinge region and the 4-fluorophenyl group
to the hydrophobic pocket I, as seen for the SB inhibitors
b Department of Cell and Molecular Biology/Microbiology, University
of Gothenburg, Medicinaregatan 9E, 41390 Gothenburg, Sweden
w Electronic supplementary information (ESI) available: Docking
results; biological results. See DOI: 10.1039/b818909a
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In order to explore the binding interaction between hydro-
phobic region I and the aromatic substituent in the 4-position
of the triazole ring, the fluorine in 5a was substituted with
chlorine (5b), bromine (5c) or a hydrogen (5d). The substitu-
tion generates compounds that also dock into the ‘‘preferred’’
binding mode.
Synthesis
With these promising docking results in hand, we turned to
our synthesis route in order to obtain the desired 1,2,3-triazole
compounds 5a–h. The benzyl azide 2a was easily prepared
from benzyl bromide and sodium azide in acetone in good
yield (75%) (Fig. 4).17 For the synthesis of the azido alcohols
2f–g, the corresponding amino acid derivative was converted
to the azide in moderate to good yields (32–84%) using triflyl
azide and DMAP in DCM.18 The L-tryptophan ethyl ester was
converted to the corresponding azide 2h in 51% isolated yield,
using triflyl azide, DIPEA, CuSO4ꢁ5H2O and methanol at
room temperature for 18 h.19 The azides 2a and 2f–h were
converted to the 4-aryl substituted 5-iodo-1,2,3-triazoles (4a–d
and 4f–h) via the Cu(I)-catalysed [3+2] cycloaddition with
4-halogenated ethynylbenzene in THF–DCM and simulta-
neous iodination with ICl.20 The reactions proceeded
smoothly overnight in good yields (41–67%) considering
this is a one-pot two-step reaction with no intermediate
purifications.
Fig. 2 (A) Important interactions of inhibitor SB220025 in p38a
MAP kinase. (B) Superposition of 4,5-substituted 1,2,3-compounds
5a–h docked into p38a kinase (SB220025: purple; 5a–h: yellow).
(Fig. 2). Furthermore, the docking was used to guide the
design of new compounds in which the R-group interacts with
the hydrophobic region II of the ATP binding site (Fig. 3). The
docking results show that triazole compound 5a docks into the
ATP binding site in an almost identical way to the SB220025
ligand, i.e. the pyridine nitrogen hydrogen bonds to the hinge
region and the 4-fluorophenyl group is positioned in the
hydrophobic pocket I. The docking results also show
that the benzyl group in compound 5a is positioned in the
hydrophobic region II below the pyridine ring.
Compound 5e was used in order to directly compare the
binding of the 1,2,3-triazole scaffold and the imidazole based
inhibitor SB216995 to p38a kinase. The only difference
between 5e and SB216995 is that the carbon atom in the
2-position of the imidazole ring has been replaced with
a nitrogen atom in the triazole ring of compound 5e
(cf. SB216995, Fig. 1). The docking results suggest a binding
mode for compound 5e similar to that for compound 5a.
Another set of compounds that was found to mimic the
binding mode of the SB220025 inhibitor, i.e. binds to the hinge
region and hydrophobic region I (Fig. 2B), was compounds
5f–h which are derived from azides of the corresponding
amino acid derivatives (such as L-tryptophan, L-phenylalaninol,
and L-valinol). The docking of these compounds into the ATP
binding site of p38 suggests that the heteroatoms could form
hydrogen bonds to the entrance of the ATP pocket and thus
bind more strongly to the active site of the kinase.
The syntheses of 4- and 5-substituted 1,2,3-triazole inhibi-
tors 5a–h were completed via a palladium-catalysed Suzuki
coupling reaction between the halogenated 4-aryl substituted
5-iodo-1,2,3-triazoles (4a–d and 4f–h) and 4-pyridineboronic
acid in the presence of Pd(PPh3)4 2 mol% and K2CO3 at
150 1C in a microwave reactor. The triazole compounds 5a–d
having a benzyl substituent were obtained in good yields
(63–85%) and the amino acid derivatives 5f–h were obtained
in moderate to good yields (35–85%). The lower yield of the
tryptophan compound 5h (35%) could be explained by the fact
that the ester functionality was hydrolysed in situ to the
Fig. 4 Synthesis of 4- and 5-substituted 1,2,3-triazoles as potential
p38a inhibitors. (i) Amino acid derivatives, TfN3, CH2Cl2–methanol,
r.t. or benzyl bromide, NaN3, acetone–H2O, r.t., 2 h. (ii) Compounds
2a–d, CuI, triethylamine (1.2 equiv.), ICl, THF, r.t., overnight.
(iii) Compounds 4, 4-pyridineboronic acid (1.5 equiv.), K2CO3
(3 equiv.), Pd(PPh3)4 (2%), dioxane–H2O, MW (150 1C, 30 min).
Fig. 3 Potential 4- and 5-substituted 1,2,3-triazoles as inhibitors of
p38 MAP kinase.
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Table 1 IC50 values for synthesised compounds 5a–h in p38a MAP
kinase inhibition
Compound
IC50/nMa
SB203580
SB220025
SB216995
110 (80)
19
160
5a
5b
5c
5d
5e
5f
807
404
509
2020
961
83 454
3977
4100 000
5g
5h
a
Titration curves for the IC50 determinations are available in the
ESI.w
that introducing a cyclopropylmethyl group in the 1-position
(5e) leads to a similar inhibition as seen for compound 5a
(cf. 961 nM to 807 nM, respectively).
Fig. 5 Synthesis of inhibitor 5e. (i) TfN3, CuSO4ꢁ5H2O, NaHCO3,
DCM–MeOH–H2O, 30 min, r.t. (ii) 1-Ethynyl-4-fluorobenzene,
TBTA, Na ascorbate, 80 1C, MW, 1 h. (iii) n-BuLi, THF, ꢂ78 1C,
20 min, then add I2, 2 h. (iv) Compound 4e, 4-pyridineboronic acid
(1.5 equiv.), K2CO3 (3 equiv.), Pd(PPh3)4 (2%), dioxane–H2O, MW
(150 1C, 30 min).
The conclusion is that the 4,5-substituted 1,2,3-triazole ring
can be used as a scaffold for synthesising inhibitors of the
p38a MAP kinase. However, the results also suggest that
the 1,2,3-triazole scaffold binds five times more weakly to
the active site of p38a kinase than the imidazole-based scaffold
(compound 5e (807 nM) compared to SB216995 (160 nM)),
despite the structural similarity of the scaffolds.
carboxylic acid, thus making it difficult to purify by silica gel
chromatography.
Due to the volatility of the cyclopropyl azide, 1,2,3-triazole
4H-e was formed from the reaction between cyclopropyl azide
(prepared in situ) and subsequent reaction of the azide with
1-ethynyl-4-fluorobenzene (79% isolated yield) (Fig. 5). The
iodine was introduced in the 5-position via a deprotonation of
the triazole with n-butyllithium at ꢂ78 1C, followed by addi-
tion of iodine. The final compound 5e was obtained by the
Suzuki coupling in 78% yield using the same conditions as
previously described.
As seen from the binding mode of SB220025 (Fig. 2A), a
lysine residue (Lys53) hydrogen bonds to one of the nitrogens
in the five-membered ring. A comparison of the pKAH of the
protonated nitrogen in the imidazole and in the 1,2,3-triazole
(pKAH = 6.95 and pKAH = 1.2, respectively) suggests that the
more basic imidazole is a better hydrogen bond acceptor to
the lysine than triazole. In order to further investigate the
hydrogen bond acceptor capability of imidazole and triazole,
we performed a computational study of the electrostatic
potential of compound 5e and the SB216995 inhibitor at the
B3LYP/6-31G(d) level of theory.21–25
Biology
The inhibitory potencies of the compounds 5a–h were
evaluated using a commercial radiometric p38 assay.z The
obtained IC50 values for compounds 5a–h are shown in
Table 1. The best inhibition is seen for compounds 5a–c
having a benzyl group in the 1-position of the triazole ring
and a fluorine, a chlorine, or a bromine atom in the
para-position of the phenyl group in the 4-position of the
1,2,3-triazole ring. Surprisingly, p-chlorophenyl (5b) and
p-bromophenyl (5c) gave a two-fold increase in inhibition
compared to the p-fluorophenyl derivative 5a, while the inhibition
of compound 5d (having a phenyl group in the 4-position)
decreases two-fold.
The calculation shows a higher negative potential around
the imidazole nitrogen, indicating that the imidazole nitrogen
is a better hydrogen acceptor than 1,2,3-triazole (Fig. 6).
In order to quantify the difference in strength of the
hydrogen bond to imidazole and 1,2,3-triazole, we optimised
the structures of 1-methylimidazole and 1-methyl-1,2,3-triazole
in water (continuum model) at the B3LYP/6-31G(d) level
of theory. Further we also optimised the 1-methylimidazole
and 1-methyl-1,2,3-triazole hydrogen bonded to an ammonium
ion in water (continuum model) at the same level of theory.
From the the energies of the optimised molecules, the iso-
desmic reaction energy was calculated to be ꢂ1.1 kcal molꢂ1
(Fig. 6) in favour of hydrogen bonding to 1-methylimidazole.
An isodesmic reaction energy difference of 1.1 kcal molꢂ1
corresponds to a 6.2 times stronger binding of the ammonium
ion to 1-methylimidazole compared to 1-methyl-1,2,3-triazole.
The isodesmic energy for this reaction was also calculated
using explicit solvation of water on the nitrogen in 1-methyl-
1,2,3-triazole and 1-methylimidazole and the energy difference
of 0.73 kcal molꢂ1 corresponds to a 3.5 times stronger binding
of the ammonium ion to 1-methylimidazole compared to
1-methyl-1,2,3-triazole at the same level of theory. These
Introducing more bulky substituents in the 1-position, such
as in compounds 5f–h, resulted in a reduced inhibitory effect.
The decrease in activity was most dramatic for compounds 5h
and 5f, having a 1H-indol-3-ylpropanoic acid group and a
phenylpropan-1-ol group in the 1-position, respectively, where
the IC50 value dropped by a factor of more than a hundred
compared to compound 5b. Furthermore, the results showed
z Millipore’s KinaseProfilerTM service and protocols available
at http://www.millipore.com/drugdiscovery/dd3/KinaseProfiler
http://www.millipore.com/drugdiscovery/dd3/brochure
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The 1,2,3-triazole scaffold gives lower inhibition than can be
seen for the imidazole scaffold and the explanation for the
lower inhibition is the weaker hydrogen bonding ability of
the nitrogen in the 1,2,3-triazole ring. In order to improve the
triazole-based inhibitors, future work will focus on investigating
the substitution in the 1-, 4-, and 5-position of the scaffold in
order to improve potency.
Experimental
General
1H (400 MHz) and 13C (100 MHz) NMR spectra were
obtained using a JEOL JNM-EX 400 spectrometer. Column
chromatography was performed by manual flash chromato-
graphy (wet packed silica, 0.04–0.063 mm) or by automated
column chromatography on Biotage SP-4 using pre-packed
columns. Microwave reactions were performed in a Biotage
Initiator reactor with fixed hold time. IR spectra were
recorded on a Perkin-Elmer 16 PC spectrometer. Separation
of CH2Cl2 and H2O was performed by a phase separator. All
azides were prepared according to the literature and products
were in accordance with the literature. All comparative kinase
assays were conducted using Millipore’s KinaseProfilerTM
service according to the standard protocols.z
Fig. 6 Electrostatic potential for optimised compounds SB216995
and 5e at the B3LYP/6-31G(d) level of theory. Isodesmic energy for
the hydrogen bonded ammonium ion to 1-methylimidazole in water
compared to hydrogen bonded ammonium ion to 1-methyl-1,2,3-triazole
in water at the B3LYP/6-31G(d) level of theory.
results are in good agreement with the results obtained experi-
mentally (five times stronger binding). The result suggests that
the weaker hydrogen bonding ability of the nitrogen in the
1,2,3-triazole ring is the major reason for the difference in
inhibition between 5e and SB216995.
Computational details
Docking. X-ray structures with inhibitors were used as the
starting point for all dockings. The p38 kinase was prepared
according to the standard procedure in the Schrodinger
¨
package. Docking was performed by using Glide (Schrodinger)
¨
Conclusions
with extraprecision (XP) settings and standard parameters for
ligand docking.
In summary, we report a fast and efficient synthesis of
4,5-substituted 1,2,3-triazoles using Cu(I)-catalysed azide–
alkyne 1,3-dipolar [2+3]-cycloadditions and Suzuki coupling
chemistry. The obtained compounds show activity as inhibi-
tors of p38a MAP kinase in the high nanomolar range. The
best inhibition is seen for compound 5b, having a benzyl group
in the 1-position of the triazole ring and a p-chlorophenyl
group in the 4-position of the 1,2,3-triazole ring. From the
docking results, the benzyl group is suggested to interact with
the hydrophobic region II in the active site of p38a MAP
kinase (Fig. 7).
Quantum chemical calculations. Compounds 5e and
SB216995 were optimised at the B3LYP/6-31G(d) level of
theory using Jaguar26 from Schrodinger Inc. 1-Methylimidazole,
+
1-methylimidazole*NH4 , 1-methyl-1,2,3-triazole, 1-methyl-
¨
+
1,2,3-triazole*NH4 were optimised at the B3LYP/6-31G(d)
level of theory using a continuum model in water.
Synthesis
General procedure A for preparation of triazoles. Azide
(1 equiv.), alkyne (1 equiv.), Et3N (1.2 equiv.), dry THF
(10 ml), ICl dissolved in CH2Cl2 (1 equiv.) and CuI (1 equiv.)
were added in that order. The reaction mixture was stirred at
room temperature under a nitrogen atmosphere for 18 h and
concentrated under reduced pressure. The crude product was
purified by flash chromatography on a silica gel column using
hexane–ethyl acetate as eluent.
1-Benzyl-4-(4-fluorophenyl)-5-iodo-1H-1,2,3-triazole
(4a).
The title compound was prepared according to the general
procedure A and was obtained by flash chromatography
eluting with hexane–ethyl acetate (11 : 1) to yield a yellow
solid (314 mg, 41%). 1H NMR (CDCl3): d 7.93–7.90 (m, 2H),
7.39–7.13 (m, 7H), 5.67 (s, 2H); 13C NMR (CDCl3): d 163.3
(d, C–F, J = 247.0), 149.8, 134.6, 129.7 (d, C–F, J = 7.7 Hz),
129.3, 128.9, 128.2, 126.7, 115.9 (d, C–F, J = 22.2 Hz), 76.6,
Fig. 7 Suggested binding mode of compound 5b from Glide docking
in XP mode. Compound 5b hydrogen bonds to Met109 (hinge region)
and to Lys53.
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54.8; IR (KBr, cmꢂ1): 3429, 3031, 2924, 1609, 1542, 1479,
1236, 836, 723. EA(C15H11FIN3): Required: 47.51 (C); 2.92
(H); 11.08 (N); Found: 47.43 (C), 2.92 (H), 10.28 (N).
J = 245.5 Hz), 146.7, 127.3 (d, C–F, J = 8.4 Hz), 127.0
(d, C–F, J = 3.1 Hz), 118.8, 115.6 (d, C–F, J = 21.4 Hz), 55.0,
10.9, 4.1; IR (KBr, cmꢂ1): 3444, 3100, 1493, 1226, 1067, 829.
EA(C12H12FN3): Required: 66.34 (C); 5.57 (H); 19.34 (N);
Found: 66.07 (C), 6.43 (H), 19.29 (N).
1-Benzyl-4-(4-chlorophenyl)-5-iodo-1H-1,2,3-triazole (4b).
The title compound was prepared according to the general
procedure A and was obtained by flash chromatography
eluting with hexane–ethyl acetate (11 : 1) to yield a yellow
solid (396 mg, 50%). 1H NMR (CDCl3): d 7.90 (d, J = 8.8 Hz,
2H), 7.44–7.30 (m, 7H), 5.67 (s, 2H); 13C NMR (CDCl3):
d 149.5, 134.9, 134.5, 129.3, 129.1, 129.0, 129.0, 128.9, 128.2,
76.8, 54.8; IR (KBr, cmꢂ1): 3429, 3030, 2919, 2359, 1463, 1231,
1091, 831, 718. EA(C15H11ClIN3): Required: 45.54 (C); 2.80
(H); 10.62 (N); Found: 45.16 (C), 2,62 (H), 10.34 (N).
1-(Cyclopropylmethyl)-4-(4-fluorophenyl)-5-iodo-1H-1,2,3-triazole
(4e). n-BuLi (616 ml, 1.4 M in hexane, 0.58 mmol) was added to
a 0.1 M solution of 1-(cyclopropylmethyl)-4-(4-fluorophenyl)-
1H-1,2,3-triazole (125 mg, 0.58 mmol) in dry THF (5.8 ml)
under nitrogen atmosphere at ꢂ78 1C. After 20 min a solution
of I2 (292 mg, 1.15 mmol) in dry THF (1.3 ml) was added and
the reaction mixture was allowed to stir at ꢂ78 1C for 1 h and
was then stirred an additional hour at room temperature. The
reaction mixture was quenched with saturated NH4Cl solution
and extracted with CH2Cl2. The organic and aqueous layers
were separated with a phase separator. The organic layer was
concentrated under reduced pressure and the target compound
was obtained by flash chromatography eluting with hexane–
ethyl acetate (4 : 1) to yield a yellow solid (101 mg, 51%).
1H NMR (CDCl3): d 7.91 (m, 2H), 7.15 (m, 2H), 4.31 (d, J =
7.0 Hz, 2H), 1.44 (m, 1H), 0.65 (m, 2H), 0.54 (m, 2H);
13C NMR (CDCl3): d 162.8 (d, C–F, J = 248.3 Hz), 148.9,
129.3 (d, C–F, J = 8.5 Hz), 126.5 (d, C–F, J = 3.1 Hz), 115.5
(d, C–F, J = 22.2 Hz), 75.8, 55.3, 11.2, 4.3; IR (KBr, cmꢂ1):
3433, 2997, 1610, 1479, 1226, 836. EA(C12H11FIN3):
Required: 42.00 (C); 3.23 (H); 12.25 (N); Found: 41.36 (C),
3.30 (H), 11.90 (N).
1-Benzyl-4-(4-bromophenyl)-5-iodo-1H-1,2,3-triazole (4c).
The title compound was prepared according to the general
procedure A and was obtained by flash chromatography
eluting with hexane–ethyl acetate (12 : 1) to yield a yellow
solid (588 mg, 67%). 1H NMR (CDCl3): d 8.84 (d, J = 8.4 Hz,
2H), 7.59 (d, J = 8.4 Hz, 2H), 7.39–7.30 (m, 5H), 5.67 (s, 2H);
13C NMR (CDCl3): d 149.5, 134.5, 132.1, 129.5, 129.3, 129.2,
128.8, 128.2, 123.1, 76.8, 54.8; IR (KBr, cmꢂ1): 3433, 2919,
1454, 1225, 1066, 977, 825, 70. EA(C15H11BrIN3): Required:
40.94 (C); 2.52 (H); 9.55 (N); Found: 41.39 (C), 2.41 (H),
9.30 (N).
1-Benzyl-5-iodo-4-phenyl-1H-1,2,3-triazole (4d). The title
compound was prepared according to the general procedure
A and was obtained by flash chromatography eluting with
hexane–ethyl acetate (7 : 1) to yield a white solid (408 mg,
57%). 1H NMR (CDCl3): d 7.94 (d, J = 7.0 Hz, 2H),
7.48–7.41 (m, 8H), 5.68 (s, 2H); 13C NMR (CDCl3): d 150.5,
134.7, 130.5, 129.2, 128.9, 128.9, 128.8, 128.1, 127.8, 76.7, 54.7;
IR (KBr, cmꢂ1): 3423, 3030, 2927, 1606, 1445, 1224, 697.
EA(C15H12IN3): Required: 49.88 (C); 3.35 (H); 11.63 (N);
Found: 49.63 (C), 2.93 (H), 11,27 (N).
2-(4-(4-Fluorophenyl)-5-iodo-1H-1,2,3-triazol-1-yl)-3-phenyl-
propan-1-ol (4f). The title compound was prepared according
to the general procedure A and was obtained by flash chromato-
graphy eluting with hexane–ethyl acetate (2 : 1) to yield a
yellow solid (409 mg, 64%). 1H NMR (CDCl3): d 7.60
(m, 2H), 7.22–7.03 (m, 7H), 4.88 (m, 1H), 4.74 (s, 1H), 4.47
(m, 1H), 4.11(m, 1H), 3.25 (m, 2H); 13C NMR (CDCl3):
d 162.8 (d, C–F, J = 248.3 Hz), 147.3, 136.1, 129.1 (d, C–F,
J = 8.5 Hz), 129.0, 128.5, 127.0, 125.6 (d, C–F, J = 3.1 Hz),
115.4 (d, C–F, J = 21.5 Hz), 79.1, 65.8, 64.3, 37.8; IR
(KBr, cmꢂ1): 3295, 2933, 1607, 1473, 1232, 1041, 835.
EA(C17H15FIN3O): Required: 48.24 (C); 3.57 (H); 9.93 (N);
Found: 48.21 (C), 3.61 (H), 9.83 (N).
1-(Cyclopropylmethyl)-4-(4-fluorophenyl)-1H-1,2,3-triazole
(4H-e). Cyclopropanemethylamine (129 ml, 1.5 mmol), CuSO4ꢁ
5H2O (7.5 mg, 30 mmol) and NaHCO3 (126 mg, 1.5 mmol)
were placed in a microvial and dissolved in H2O (3 ml).
Freshly prepared triflyl azide was added, followed by addition
of methanol until the solution became homogenous. The
reaction mixture was stirred at room temperature until com-
pletion of the reaction according to TLC (30 min). 1-Ethynyl-
4-fluorobenzene (180 mg, 1.5 mmol), TBTA (40 mg, 75 mmol)
and sodium ascorbate (30 mg, 0.15 mmol) were added to the
solution and the reaction mixture was heated in the microwave
reactor at 80 1C for 1 h. The solvents were removed under
reduced pressure and the resulting slurry was extracted with
CH2Cl2 (3 ꢃ 10 ml). The combined organic phases were
washed with brine (10 ml) and H2O (10 ml), the organic and
aqueous layers were separated with a phase separator and
concentrated under reduced pressure. The title compound was
obtained by flash chromatography eluting with hexane–ethyl
acetate (4 : 1 v/v) to yield a white solid (258 mg, 79%).
1H NMR (CDCl3): d 7.83 (s, 1H), 7.77 (m, 2H), 7.09–7.03
(m, 2H), 4.20 (d, J = 7.3 Hz, 2H), 1.29 (m, 1H), 0.67 (m, 2H),
2-(4-(4-Fluorophenyl)-5-iodo-1H-1,2,3-triazol-1-yl)-3-methyl-
butan-1-ol (4g). The title compound was prepared according to
the general procedure A and was obtained by flash chromato-
graphy eluting with hexane–ethyl acetate (2 : 1) to yield a
yellow solid (236 mg, 47%). 1H NMR (CDCl3): d 7.82
(m, 2H), 7.13 (m, 2H), 4.39 (m, 2H), 4.06 (m, 1H), 2.53
(m, 1H), 1.12 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 7.0 Hz);
13C NMR (CDCl3): d 162.9 (d, C–F, J = 248.3 Hz), 147.7,
129.4 (d, C–F, J = 8.5 Hz), 126.0 (d, C–F, J = 3.1 Hz), 115.5
(d, C–F, J = 21.5 Hz), 79.3, 69.7, 63.1, 30.6, 19.5, 19.4;
IR (KBr, cmꢂ1): 3416, 2865, 1608, 1475, 1228, 1076, 834;
[a]2D5 = ꢂ5.6 (c = 0.5 in CH2Cl2). [M + 1]+ calcd for
C13H15N3OFI: 376.0317; found 376.0327.
Ethyl 2-(4-(4-fluorophenyl)-5-iodo-1H-1,2,3-triazol-1-yl)-3-
(1H-indol-3-yl)propanoate (4h). The title compound was
prepared according to the general procedure A and was
0.42 (m, 2H); 13C NMR (CDCl3):
d 163.1 (d, C–F,
ꢀc
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obtained by flash chromatography eluting with hexane–ethyl
1
acetate (4 : 1) to yield a yellow oil (217 mg, 62%). H NMR
(KBr, cmꢂ1): 3433, 3030, 1600, 1472, 836, 714. EA(C20H15BrN4):
Required: 61.39 (C); 3.86 (H); 14.32 (N); Found: 61.41 (C),
3.72 (H), 14.38 (N).
(CDCl3): d 8.22 (bs, 1H), 7.82 (m, 2H), 7.59 (d, J = 7.7 Hz,
1H), 7.31 (d, J = 8.1 Hz, 1H), 7.20–7.09 (m, 4H), 6.85 (s, 1H),
5.52 (app. t, J = 7.3, 8.1 Hz, 1H), 4.29 (q, J = 7.0, 7.3 Hz,
2H), 3.96 (d, J = 7.7 Hz, 2H), 1.27 (t, J = 7.0, 7.3 Hz, 3H);
13C NMR (CDCl3): d 167.6, 162.8 (d, C–F, J = 247.8 Hz),
148.5, 136.0, 129.4 (d, C–F, J = 7.6 Hz), 126.9, 126.1 (d, C–F,
J = 3.1 Hz), 123.7, 122.1, 119.6, 118.0, 115.5 (d, C–F, J =
21.4 Hz), 111.3, 109.4, 79.0, 63.8, 62.5, 27.4, 14.0; IR (KBr,
cmꢂ1): 3408, 2927, 1741, 1480, 1230. [M + 1]+ calcd for
C21H18N4O3FI: 505.0531; found 505.0531.
1-Benzyl-4-phenyl-5-(pyridin-4-yl)-1H-1,2,3-triazole
(5d).
The title compound was prepared according to the general
procedure B and was obtained by flash chromatography
eluting with hexane–ethyl acetate (1 : 1) to yield a white solid
(30 mg, 85%). 1H NMR (CDCl3): d 8.6 (s, 2H), 7.50–7.46
(m, 2H), 7.28–7.24 (m, 6H), 7.06–6.99 (m, 4H), 5.45 (s, 2H);
13C NMR (CDCl3): d 150.0, 145.7, 136.8, 135.1, 131.4, 130.4,
129.2, 129.0, 128.8, 128.6, 127.6, 127.3, 124.8, 52.8; IR (KBr,
cmꢂ1): 3416, 3035, 1602, 1219, 835, 751. EA(C20H16N4):
Required: 76.90 (C); 4.96 (H); 17.94 (N); Found: 76.46 (C),
4.96 (H), 17.73 (N).
General procedure for B Suzuki coupling reactions
Triazole (1 equiv.) was dissolved in dioxane–H2O (3 : 1) and
boronic acid (1.5 equiv.) and K2CO3 (3 equiv.) were added.
Nitrogen was bubbled through the reaction mixture for five
minutes before Pd(PPh3)4 (0.02 equiv.) was added. The reac-
tion mixture was irradiated with microwaves for 30 min at
150 1C. The resulting solution was concentrated under reduced
pressure and the residue was dissolved in CH2Cl2 (3 ml) and
filtered through Celite (2 cm). The filtrate was concentrated
under reduced pressure and the crude product was purified
by flash chromatography on a silica gel column with hexane–
ethyl acetate as eluent.
1-(Cyclopropylmethyl)-4-(4-fluorophenyl)-5-(pyridin-4-yl)-1H-
1,2,3-triazole (5e). The title compound was prepared according
to the general procedure B and was obtained by flash
chromatography eluting with hexane–ethyl acetate (1 : 1) to
1
yield a white solid (85 mg, 78%). H NMR (CDCl3): d 8.76
(d, J = 5.1 Hz, 2H), 7.42 (m, 2H), 7.28 (m, 2H), 6.94 (m, 2H),
4.09 (d, J = 7.3 Hz, 2H), 1.07 (m, 1H), 0.51 (m, 2H), 0.22
(m, 2H); 13C NMR (CDCl3): d 162.8 (d, C–F, J = 246.2 Hz),
151.2, 144.4, 136.9, 130.8, 129.1 (d, C–F, J = 7.6 Hz), 126.7
(d, C–F, J = 3.1 Hz), 124.7, 115.9 (d, C–F, J = 21.4 Hz), 53.6,
11.7, 4.6; IR (KBr, cmꢂ1): 3432, 3068, 3002, 1602, 1503, 1209,
838. EA(C17H15FN4): Required: 69.37 (C); 5.14 (H); 19.04
(N); Found: 69.18 (C), 5.08 (H), 18.83 (N).
1-Benzyl-4-(4-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazole
(5a). The title compound was prepared according to the
general procedure B and was obtained by flash chromato-
graphy eluting with hexane–ethyl acetate (2 : 1) to yield a
yellow solid (145 mg, 80%). 1H NMR (CDCl3): d 8.67 (d, J =
5.7 Hz, 2H), 7.46 (m, 2H), 7.25 (m, 3H), 7.06–6.94 (m, 6H),
5.45 (s, 2H); 13C NMR (CDCl3): d 163.0 (d, C–F, J = 246.8
Hz), 151.1, 144.8, 136.5, 135.0, 131.2, 129.2, 129.1 (d, C–F,
J = 7.7 Hz), 128.8, 127.6, 126.3 (d, C–F, J = 3.1 Hz), 124.7,
116.0 (d, C–F, J = 21.5 Hz), 52.8; IR (KBr, cmꢂ1): 3439, 3054,
1606, 1506, 1220, 833, 721. EA(C20H15FN4): Required:
72.71 (C); 4.58 (H); 16.96 (N); Found: 72.38 (C), 4.40 (H),
16.89 (N).
2-(4-(4-Fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)-
3-phenylpropan-1-ol (5f). The title compound was prepared
according to the general procedure B and was obtained by
flash chromatography eluting with hexane–ethyl acetate (1 : 2)
to yield a white solid (143 mg, 85%). 1H NMR (CDCl3): d 8.36
(s, 2H), 7.11–6.98 (m, 5H), 6.82 (m, 2H), 6.64 (m, 2H), 6.28
(m, 2H), 5.82 (bs, 1H), 4.70 (m, 1H), 4.22 (m, 1H), 4.08
(m, 1H), 3.24 (m, 1H), 2.98 (m, 1H); 13C NMR (CDCl3):
d 162.4 (d, C–F, J = 249.1 Hz), 150.0, 142.2, 136.4, 135.1,
133.0, 128.7, 128.6, 128.8 (d, C–F, J = 7.4 Hz), 126.8, 125.5
(d, C–F, J = 3.1 Hz), 124.6, 115.5 (d, C–F, J = 21.5 Hz),
65.0, 64.7, 38.2; [a]2D5 = ꢂ106.1 (c = 0.5 in CH2Cl2); IR
(KBr, cmꢂ1): 3400, 3168, 2859, 1609, 1510, 1222, 1063, 833.
[M + 1]+ calcd for C22H19N4OF: 375.1616; found 375.1630.
1-Benzyl-4-(4-chlorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazole
(5b). The title compound was prepared according to the
general procedure B and was obtained by flash chromato-
graphy eluting with hexane–ethyl acetate (2 : 1) to yield a
yellow solid (133 mg, 63%). 1H NMR (CDCl3): d 8.66 (d, J =
5.5 Hz, 2H), 7.41 (d, J = 8.42, 2H), 7.26–7.22 (m, 4H),
7.05–6.98 (m, 5H), 5.43 (s, 2H); 13C NMR (CDCl3): d 151.1,
144.6, 136.4, 135.0, 134.5, 131.5, 129.3, 129.2, 128.9, 128.8,
128.5, 127.6, 124.7, 52.8; IR (KBr, cmꢂ1): 3440, 3033, 1603,
1494, 836, 720. [M + 1]+ calcd for C20H15N4Cl: 347.1058;
found 347.1061.
2-(4-(4-Fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)-
3-methylbutan-1-ol (5g). The title compound was prepared
according to the general procedure B and was obtained by
flash chromatography eluting with hexane–ethyl acetate (1 : 2)
to yield a white solid (85 mg, 53%). 1H NMR (CDCl3): d 8.64
(d, J = 5.86 Hz, 2H), 7.15 (m, 2H), 7.09 (d, J = 5.86 Hz), 6.89
(m, 2H), 4.98 (bs, 1H), 4.50 (m, 1H), 4.10 (m, 1H), 3.82
(m, 1H), 2.35 (m, 1H), 0.92 (d, J = 6.59 Hz, 3H), 0.57
(d, J = 6.59 Hz, 3H); 13C NMR (CDCl3): d 162.5 (d, C–F,
J = 249.1 Hz), 150.5, 142.3, 135.8, 133.0, 128.6 (d, C–F, J =
8.4 Hz), 125.6 (d, C–F, J = 3.1 Hz), 125.1, 115.5 (d, C–F, J =
21.5 Hz), 68.2, 63.6, 30.7, 19.7, 19.6; [a]2D5 = ꢂ29.3 (c = 0.32
in CH2Cl2); IR (in CDCl3, cmꢂ1): 3298, 2968, 2878, 2240,
1608, 1230, 1058, 910, 733. [M + 1]+ calcd for C13H15N3OFI:
327.1616; found 327.1627.
1-Benzyl-4-(4-bromophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazole
(5c). The title compound was prepared according to the
general procedure B and was obtained by flash chromato-
graphy eluting with hexane–ethyl acetate (1 : 1) to yield a
yellow solid (145 mg, 53%). 1H NMR (CDCl3): d 8.68 (bs,
2H), 7.42–7.24 (m, 7H), 7.05–6.99 (m, 4H), 5.45 (s, 2H);
13C NMR (CDCl3): d 151.1, 144.7, 136.4, 135.0, 132.2,
131.6, 129.4, 129.3, 128.9, 128.7, 127.6, 124.7, 122.8, 52.9; IR
ꢀc
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2-(4-(4-Fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)-
3-(1H-indol-3-yl)propanoic acid (5h). The title compound was
prepared according to the general procedure B and was
obtained by flash chromatography eluting with ethyl acetate–
methanol (4 : 1) to yield a yellow solid (85 mg, 35%). 1H NMR
(DMSO6): d 8.45 (d, 2H), 7.34–7.10 (m, 6H), 7.01 (app. t, 1H),
6.86–6.83 (m, 3H), 6.64 (d, 1H), 4.64 (dd, J = 2.93, 11.72 Hz,
1H), 3.71 (dd, J = 2.93, 15.01 Hz, 1H), 3.53 (dd, J = 11.72,
15.01 Hz, 1H); 13C NMR (MeOD): d 174.8, 163.9 (d, C–F,
J = 246.8 Hz), 150.4, 144.1, 137.9, 137.8, 134.6, 130.2 (d, C–F,
J = 8.5 Hz), 128.2, 127.7 (d, C–F, J = 3.1 Hz), 126.1, 124.2
122.4, 119.9, 118.7, 116.4 (d, C–F, J = 22.3 Hz), 112.3, 111.6,
66.2, 30.2 (CHCH2C); [a]2D5 = ꢂ27.7 (c = 0.5 in MeOH); IR
(KBr, cmꢂ1): 3404, 1616, 1397, 1227, 832, 744. [M + 1]+ calcd
for C24H18N5O2F: 428.1517; found 428.1503.
7 P. R. Young, M. M. McLaughlin, S. Kumar, S. Kassis,
M. L. Doyle, D. McNulty, T. F. Gallagher, S. Fisher,
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Acknowledgements
This work was financed within the CELLCOMPUTE project.
P. D. thanks Dr Ola Engkvist and Pr. Per-Ola Norrby for
discussions about the computational work.
15 Macromodel [9.1], Schrodinger, LLC., New York, 2007.
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ꢀc
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1016 | New J. Chem., 2009, 33, 1010–1016