Synthesis and functional group transformations of tris(pyrazol-1-yl)methane (Tpm) and -ethane (Tpe) derivatives for the preparation of sterically hindered chelating macrobicycles

Article abstract of DOI:10.1055/s-0029-1216968

Tris(pyrazol-1-yl)methane (Tpm) and -ethane (Tpe) chelate derivatives bearing meta-benzonitrile groups in the position ortho to the coordinating nitrogen atom have been prepared from 3-(1H-pyrazol-3-yl)benzonitrile, and subjected to functional group trans

Full text of DOI:10.1055/s-0029-1216968

PAPER
3419
Synthesis and Functional Group Transformations of Tris(pyrazol-1-yl)meth-
ane (Tpm) and -ethane (Tpe) Derivatives for the Preparation of Sterically
Hindered Chelating Macrobicycles
S
ynthesis of Fu
e
nctionalize
y
o
o
l-1-yl)ethane
n
s
g Wang,1 Clément Michelin, Jean-Claude Chambron*
Institut de Chimie Moléculaire de l’Université de Bourgogne (ICMUB, UMR CNRS n° 5260), 9 avenue Alain Savary, BP 47870,
21078 Dijon cedex, France
Fax +33(3)80396117; E-mail: jean-claude.chambron@u-bourgogne.fr
Received 19 May 2009; revised 26 May 2009
Abstract: Tris(pyrazol-1-yl)methane (Tpm) and -ethane (Tpe) che-
S
S
late derivatives bearing meta-benzonitrile groups in the position
ortho to the coordinating nitrogen atom have been prepared from 3-
(1H-pyrazol-3-yl)benzonitrile, and subjected to functional group
transformations leading to the corresponding benzylthiol-substitut-
ed derivatives. The Tpe analogue was reacted with 1,3,5-tribro-
momethylbenzene in basic conditions to afford the Tpe-
incorporating macrobicycle 2 in 40% yield.
S
6
5
2
4
N
N
N
N
4'
N
N
5'
1 R = H
Key words: chelates, heterocycles, ligands, macrobicycles, pyra-
C
2 R = Me
zoles
R
Figure 1 Macrobicycles 1 and 2
Tris(pyrazol-1-yl)methane2 (Tpm) chelates derive from
analogous tris(pyrazol-1-yl)hydroborates3 (Tp) by substi-
tution of BH– by the isoelectronic methine (CH) connec-
tor. The coordination chemistry4 and applications5 of
these neutral nitrogen-based ligands are much less devel-
oped than those of negatively charged scorpionates, which
have been used notably in transition metal catalysis6 and
metalloenzyme mimicry.7 Such applications have re-
quired the development of a range of substituted scorpi-
onates in order to control the steric environment and the
coordination sphere of the metal cation.8
SR2
SR2
N
N
N
N
N
R1
N
3 R1 = H, R2 = Ac
4 R1 = Me, R2 = Ac
5 R1 = H, R2 = H
6 R1 = Me, R2 = H
R2S
Rather than using Tpm ligands bearing bulky substituents
ortho (position 3¢) to the coordinating nitrogen atoms, we
have developed a family of macrobicycles incorporating
the Tpm chelate (Figure 1).9 In these molecules, the [N3]
coordinating site is capped by a benzenic fragment that re-
stricts the space available for ancillary ligands, which
leads to unusual coordination properties of the Tpm che-
late. For example, reaction of 1 with [Cu(MeCN)4]+ in wet
acetone ultimately leads to the helical coordination poly-
mer [Cu(1)(H2O)]nn+, the water molecule of which is con-
tained inside the cavity of the macrobicycle subunits, and
simultaneously bound to Cu(I) and a pyrazole nitrogen.9b
The macrobicycles are prepared by tripod-tripod coupling
reaction between benzylthiol-substituted Tpm (5 for 1,
Figure 2), or tris(pyrazol-1-yl)ethane Tpe (6 for 2), and
1,3,5-tribromomethylbenzene in basic conditions.
Figure 2 Benzylthiol-functionalized Tpm 5 and Tpe 6, and their
respective benzylthioacetate precursors 3 and 4
earlier studies (see below),9 the tripodal framework is
elaborated at an early stage of the macrobicycle synthesis,
starting from the appropriate benzonitrile-substituted
pyrazole, the function of which is not sensitive to either
acidic or basic media (reaction conditions of Tpm synthe-
sis). The preparation of macrobicycle 2, which incorpo-
rates the rare tris(pyrazol-1-yl)ethane chelate, is presented
lastly.
Homoleptic tris(pyrazolyl)methane ligands built from
symmetrically-substituted pyrazoles are usually readily
prepared by heating a chloroform solution of the pyrazole
of interest in the presence of a base under either solid–
liquid10 or liquid–liquid11 phase-transfer catalysis (meth-
od A). For example, tris(pyrazol-1-yl)methane and
tris(3,5-dimethyl-1-pyrazolyl)methane were isolated in
63% and 65% yield, respectively, in the latter reaction
conditions. When unsymmetrically substituted pyrazoles
are involved (e.g., different substituents on the positions 3
and 5), a mixture of regioisomers is obtained, which can
This work reports a straightforward synthesis of the ben-
zylthiol-functionalized Tpm 5 and Tpe 6. By contrast to
SYNTHESIS 2009, No. 20, pp 3419–3426
x
x.
x
x
.
2
0
0
9
Advanced online publication: 28.08.2009
DOI: 10.1055/s-0029-1216968; Art ID: Z10209SS
© Georg Thieme Verlag Stuttgart · New York

3420
L. Wang et al.
PAPER
SH
SH
SAc
+
i. p-TSA
SH
N
N
N
N
N
N
N
H
N
H
N
toluene, reflux
10
+
N
N
N
N
N
N
ii. K2CO3, MeOH
iii. 5% aq HCl
N
N
N
N
NH
7
8
HS
5 42%
HS
9 15%
Scheme 1 One-pot formation of Tpm 59a
be converted to the less sterically hindered species by 14 (28%). Interestingly, 14 can be converted into 15 by re-
equilibration of the reaction mixture in refluxing toluene action with 10 (20 equiv) and p-TSA (1 equiv) in reflux-
containing catalytic amounts of p-TSA.11,12 Alternatively, ing toluene. The desired homoleptic Tpm 15 is obtained in
treatment of a prototypical tris(pyrazolyl)methane (1 53% yield after chromatographic separation. These exper-
equiv) with an excess (10 equiv) of the pyrazole of interest iments show that the metathesis reaction that was devel-
in the presence of p-TSA (1 equiv) in refluxing toluene oped for tris(pyrazol-1-yl)methanes13 also works in the
was shown to produce a mixture of heteroleptic and case of tris(pyrazol-1-yl)ethane.
homoleptic tris(pyrazolyl)methanes (method B).13
In earlier studies benzylthiol-substituted Tpm 5 was syn-
CN
thesized from pyrazole 7 bearing a benzylthioacetate
group in position 3¢ and tris(3,5-dimethyl-1-pyrazol-
i. aq Na2CO3
n-Bu4NBr
CN
yl)methane 8, under conditions B (Scheme 1).9a However,
the thioacetate function was cleaved to some extent even
in acidic medium (p-TSA in refluxing toluene), thus im-
peding the clean formation of the benzylthioacetate-
substituted Tpm intermediate 3. Instead, Tpm with mixed
CH2SAc and CH2SH functions were obtained.14 Meth-
anolysis of the crude reaction mixture in the presence of
K2CO3 followed by column chromatography afforded the
desired homoleptic 5, and heteroleptic 9 benzylthiol-
substituted Tpm in 42% and 15% yield, respectively.9a
N
N
N
H
NC
CHCl3, reflux
N
N
p-TSA
ii.
N
N
toluene, reflux
NH
19%
10
NC
11
Scheme 2 One-pot synthesis of Tpm 11
In the new synthetic strategy reported here, the chelate
skeletons of macrobicycles 1 and 2 were elaborated start-
ing from 3-(1H-pyrazol-3-yl)benzonitrile (10).15 At first
(conditions A, Scheme 2), heating 10 in a refluxing mix-
ture of CHCl3 and water for two days in the presence of
Na2CO3 and n-Bu4NBr produced a mixture of isomeric
tris(pyrazolyl)methanes, which were subsequently equili-
brated for 24 hours in refluxing toluene in the presence of
p-TSA. Product 11 was separated from the starting mate-
rial by chromatography and obtained in 19% yield. In con-
ditions B (Scheme 3), a mixture of 10 (10 equiv) and Tpm
8 (1 equiv) was heated in refluxing toluene in the presence
of p-TSA (1 equiv) for two days. Column chromatogra-
phy of the crude mixture allowed to separate the desired
homoleptic Tpm 11 (45%) from the heteroleptic Tpm 13
(24%). Whereas 11 can be prepared using either method
A or B, this is not the case with its tris(pyrazol-1-yl)ethane
homologue 15, which obviously cannot be formed from
CHCl3. Therefore, conditions B, using the known
tris(pyrazol-1-yl)ethane Tpe 1216 instead of Tpm 8 were
explored. In these conditions, Tpe derivative 15 was ob-
tained in 54% yield, alongside with heteroleptic derivative
The sequences of transformations leading to Tpm 5 (or
Tpe 6) are shown in Scheme 4. At first, reaction of 11 (15)
with DIBAL-H (3 equiv) in CH2Cl2 at –78 °C, followed
by acidic workup (1% HCl) afforded benzaldehyde-sub-
stituted Tpm 16 (Tpe 17) in 74% (82%) yield. The corre-
sponding benzyl alcohol derivative 18 (19) was obtained
in 99% (96%) yield, by NaBH4 reduction in MeOH–THF
at 0 °C. Subsequent treatment of 18 (19) with thioacetic
acid (6 equiv) in Mitsunobu reaction conditions17 (Ph3P,
DIAD, THF, 0 °C) afforded thioacetate 3 (4) in 83%
(93%) yield after chromatography. Finally, benzylthiol-
substituted Tpm 5 (Tpe 6) was produced in 76% (ca.
100%) yield by methanolysis of 3 (4) using K2CO3 as base
followed by acidic workup.
This sequence of functional group transformations has
notably allowed us to obtain in preparative yield benzyl-
thioacetate-substituted Tpm 3, which was previously iso-
lated in minor amounts from the metathesis reaction
between 7 and Tpm 8.9a
Synthesis 2009, No. 20, 3419–3426 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Tris(pyrazol-1-yl)ethanes
3421
CN
CN
R2
CN
N
N
N
N
N
R2
N
R2
N
N
N
NC
p-TSA
+
10
+
N
N
N
N
N
N
toluene, reflux
R2
R2
R1
R1
R1
N
N
N
N
R2
R2
NH
R2
10
8 R1 = H, R2 = Me
12 R1 = Me, R2 = H
NC
NC
13 R1 = H, R2 = Me, 24%
14 R1 = Me, R2 = H, 28%
11 R1 = H, 45%
15 R1 = Me, 54%
Scheme 3 Preparation of benzonitrile-functionalized Tpm 11 and Tpe 15 by metathesis reaction
CN
CHO
OH
i. DIBAL-H
OH
N
N
N
N
N
N
N
R
N
R
NaBH4
NC
OHC
CH2Cl2, –78 °C
N
N
N
N
N
N
N
MeOH–THF
0 °C
ii. 1% aq HCl
R
N
N
N
NC
HO
OHC
11 R = H
15 R = Me
16 R = H, 74%
17 R = Me, 82%
18 R = H, 99%
19 R = Me, 96%
SAc
SH
SAc
SH
N
N
N
N
N
R
i. K2CO3, MeOH–DMF
ii. 1% aq HCl
AcSH, DIAD, Ph3P
THF, 0 °C
N
N
N
N
N
R
N
N
AcS
HS
5 R = H, 76%
6 R = Me, 100%
3 R = H, 83%
4 R = Me, 93%
Scheme 4 Sequence of functional group transformations starting from Tpm 11 and Tpe 15, and leading to Tpm 5 and Tpe 6, respectively
Tpe-incorporating macrobicycle 2 was prepared in the The proton NMR spectra of macrobicycles 1 and 2 in
same conditions as 19a by tripod-tripod coupling reaction CD2Cl2 are shown in Figure 3. They were assigned using
1
between benzylthiol-functionalized Tpe 6 and 1,3,5-tri- 2D H/1H COSY and ROESY NMR spectroscopy. Con-
bromomethylbenzene (20) in the presence of K2CO3 as sistency of the attributions was checked by 2D 13C/1H
base in DMF at 60 °C under high dilution (1.68 mM), and HSQC and HMBC NMR spectroscopy. Comparison of
obtained in 40% yield after purification by column chro- these spectra shows interesting differences. Contrary to
matography (Scheme 5). Tpm macrobicycle 1 being iso- what is observed in the case of 1, the signals of protons H-
lated in 28% yield in these conditions, the higher yield of 2, H-4, H-5, and H-6 of 2 do not show first order splitting
macrobicycle 2 could attest to the increased rigidity/ patterns (respectively s, d, t, and d in the case of 1). In ad-
preorganization of the Tpe framework.
dition, the signals of the following protons are shifted up-
Synthesis 2009, No. 20, 3419–3426 © Thieme Stuttgart · New York

3422
L. Wang et al.
PAPER
SH
S
S
S
Br
SH
N
N
N
K2CO3
+
N
N
DMF, 60 °C
40%
Br
N
N
Me
N
N
N
N
Br
N
C
Me
HS
20
2
6
Scheme 5 Preparation of macrobicycle 2
Figure 3 Comparison of the 1H NMR spectra (600 MHz, CD2Cl2) of macrobicycles 2 (a) and 1 (b); the arrows show ROESY correlations in 2
field significantly: H-2 (–0.21), H-6 (–0.11), ArH (–0.16), basic Tpm precursor and a functionalized pyrazole, show-
and ArCH2S (–0.14 ppm), while those of peripheral H-4, ing that the Tpm skeleton tolerated a range of reaction
H-4¢, H-5, and H-5¢ are only slightly affected by changing types and conditions. In addition, this route could be
the methine proton in 1 to a methyl group in 2. Therefore, equally applied to a simple Tpe precursor, allowing to
this substitution induces conformational changes that af- synthesize a benzylthiol-functionalized Tpe from which,
fect mainly protons of the aryl cap or its vicinity, that is, for demonstration purposes, a Tpe-incorporating macro-
protons remote from the methine connector. Based on bicycle was prepared.
NOE correlations (e.g., H-4¢/H-4) the solution structure of
macrobicycle 1 is quite similar to its solid state structure,9b
Unless otherwise stated all reactions were performed under argon
in which the phenyl substituents are coplanar with the
pyrazole rings. The same NOE correlations are also ob-
served in the case of macrobicycle 2. This suggests that its
conformation is probably very close to that of 1.
using standard Schlenk techniques. DMF was filtered on alumina
and stored over molecular sieves; THF and toluene were distilled
over sodium/benzophenone, and CH2Cl2 over P2O5. All other chem-
icals were used as received. Silica gel for column chromatography
was from Merck (Kieselgel 60). NMR spectra were obtained using
Bruker Avance 300 and 600, and DRX 500 spectrometers. IR spec-
tra were recorded with a Bruker IFS 66v Fourier Transform IR spec-
There are quite few reports on the synthesis of functional-
ized Tpm and their functional group transformations. This
study has developed a straightforward and clean route for trophotometer. Mass spectra were obtained with a Bruker Daltonix
Proflex III spectrometer (MALDI-TOF, dithranol matrix). Melting
the preparation of a benzylthiol-substituted Tpm from a
points were measured with a Büchi Melting Point B-545 apparatus.
Synthesis 2009, No. 20, 3419–3426 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Tris(pyrazol-1-yl)ethanes
3423
Elemental analyses were run with an EA1108 CHNS Fisons Instru-
ment analyzer.
tioned between CH2Cl2 (50 mL) and 5% aq NaHCO3 (50 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 50 mL) and the com-
bined organic layers were dried (MgSO4). Column chromatography
of the crude product (silica gel, CH2Cl2) followed by flash column
chromatography (silica gel, 1% EtOAc in CH2Cl2) afforded 15
(0.483 g, 54%) and 14 (0.203 g, 28%) as colorless solids.
The following compounds were prepared according to the litera-
ture: Ethanethioic acid S-{[3-(1H-pyrazol-3-yl)phenyl]methyl} es-
ter (7),9b 3-(1H-pyrazol-3-yl)benzonitrile (10),15 1,1¢,1¢¢-
methylidynetris[3,5-dimethyl-1H-pyrazole] (8),11 1,1¢,1¢¢-ethyli-
dynetris[1H-pyrazole] (12),16 and 1,3,5-tribromomethylbenzene
(20).18
14
1H NMR (500 MHz, CDCl3): d = 3.08 (s, 3 H, CH3), 6.38 (t, J = 2.0
Hz, 1 H, H-4¢¢), 6.66 (d, J = 2.6 Hz, 2 H, H-4¢ or H-5¢), 6.95 (d,
J = 2.6 Hz, 2 H, H-5¢ or H-4¢), 7.05 (d, J = 2.0 Hz, 1 H, H-3¢¢ or H-
5¢¢), 7.51 (t, J = 7.8 Hz, 2 H, H-5), 7.61 (dt, J = 7.8, 1.4 Hz, 2 H, H-
6 or H-4), 7.73 (d, J = 2.0 Hz, 1 H, H-5¢¢ or H-3¢¢), 8.04 (dt,
J = 7.8, 1.4 Hz, 2 H, H-4 or H-6), 8.12 (t, J = 1.4 Hz, 2 H, H-2).
3,3¢,3¢¢-[Methylidynetris(1H-pyrazole-1,3-diyl)]tribenzonitrile
(11)
Method A: A mixture of 3-(1H-pyrazol-3-yl)benzonitrile (10; 3.384
g, 20.07 mmol), n-Bu4NBr (0.324 g, 1 mmol), and Na2CO3 (12.713
g, 120.12 mmol) in CHCl3 (10 mL) and H2O (40 mL) was heated at
reflux for 2 days. The aqueous layer was extracted with Et2O (2 ×
15 mL). The combined organic layers were washed with H2O until
pH <8, and dried. The residue was redissolved in toluene (50 mL),
and the mixture heated at reflux in the presence of p-TSA (0.060 g,
0.324 mmol) for 24 h in a Dean–Stark apparatus. The reaction mix-
ture was washed with 5% aq NaHCO3 (50 mL) and H2O (70 mL).
Flash column chromatography (silica gel, 0.5% MeOH in CH2Cl2)
afforded 11 as a colorless solid; yield: 0.665 g (19%).
15
Mp 110.6–111.3 °C.
IR (KBr): 2229.8 (C≡N) cm–1.
1H NMR (500 MHz, CDCl3): d = 3.14 (s, 3 H, CH3), 6.69 (d, J = 2.6
Hz, 3 H, H-4¢ or H-5¢), 7.06 (d, J = 2.6 Hz, 3 H, H-5¢ or H-4¢), 7.52
(t, J = 7.8 Hz, 3 H, H-5), 7.62 (dt, J = 7.8, 1.4 Hz, 3 H, H-6 or H-4),
8.05 (dt, J = 7.8, 1.4 Hz, 3 H, H-4 or H-6), 8.13 (t, J = 1.4 Hz, 3 H,
H-2).
13C NMR (125 MHz, CDCl3): d = 26.4, 91.2, 104.6, 113.1, 118.7,
129.6 (2 s), 130.2, 131.2, 131.8, 133.9, 151.4.
MS (MALDI-TOF): m/z = 362.30 [M + H – C10H7N3]+.
Method B: A solution of 8 (0.894 g, 3 mmol), 10 (7.5 g, 0.045 mol),
and p-TSA (0.57 g, 3 mmol) in toluene (100 mL) was refluxed for
48 h. The reaction mixture was subsequently washed with 10% aq
NaHCO3 (50 mL), H2O (3 × 50 mL), brine (50 mL), and dried
(MgSO4). Column chromatography (alumina, heptane 40% in
CH2Cl2) of the crude product from two reactions run on a total of
3.7 mmol of 8 allowed to separate 13 (0.400 g, 24%) from 11 (0.860
g, 45% yield).
Anal. Calcd for C32H21N9: C, 72.30; H, 3.98; N, 23.71. Found: C,
72.12; H, 4.46; N, 23.07.
Conversion of 14 into 15
11
A solution of 14 (0.203 g, 0.457 mmol), 10 (1.600 g, 9.54 mmol),
and p-TSA (0.090 g, 0.472 mmol) in toluene (8.5 mL) was refluxed
for 48 h using a Dean–Stark apparatus. The reaction mixture was di-
luted with CH2Cl2 (25 mL) and transferred into a separatory funnel.
The organic phase was washed with 5% aq NaHCO3 (50 mL), dried
(MgSO4), and the solvents evaporated. Column chromatography
(silica gel, 0.5–2% EtOAc in CH2Cl2) allowed the removal of ex-
cess of 10, unreacted 14, and released pyrazole. Flash column chro-
matography (silica gel, 1% EtOAc in CH2Cl2) afforded pure 15
(0.132 g, 53%).
IR (KBr): 2229 (C≡N) cm–1.
1H NMR (300 MHz, CDCl3): d = 6.74 (d, J = 2.6 Hz, 3 H, H-4¢),
7.51 (t, J = 7.8 Hz, 3 H, H-5), 7.62 (td, J = 7.8, 1.2 Hz, 3 H, H-6),
7.79 (d, J = 2.6 Hz, 3 H, H-5¢), 8.03 (td, J = 7.8, 1.2 Hz, 3 H, H-4),
8.12 (s, 3 H, H-2), 8.49 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 83.9 (CH), 105.2 (C-4¢), 113.0,
118.8 (CN), 129.6 (C-5), 129.7 (C-2), 130.2 (C-4), 131.6 (C-5¢),
131.9 (C-6), 133.7, 151.8.
MS (MALDI-TOF): m/z = 350.61 [M + H – C10H6N3]+.
3,3¢,3¢¢-[Methylidynetris(1H-pyrazole-1,3-diyl)]tribenzalde-
hyde (16)
Anal. Calcd for C31H19N9: C, 71.94; H, 3.70; N, 24.36. Found: C,
71.99; H, 3.76; N, 23.68.
A 1 M solution of DIBAL-H (5 mL, 5 mmol) in hexane was added
dropwise to a solution of 11 (0.695 g, 1.34 mmol) in CH2Cl2 (45
mL) at –78 °C. After stirring for 3 h at r.t., the reaction mixture was
quenched with 1% aq HCl (200 mL), and extracted with CH2Cl2 (5
× 100 mL). The combined organic layers were dried (MgSO4). Pu-
rification of the crude product by column chromatography (silica
gel, 5% EtOAc in CH2Cl2) afforded 16 (0.511 g, 74%) as a colorless
waxy solid.
13
IR (KBr): 2229 (C≡N) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.26 (s, 3 H, CH3), 2.46 (s, 3 H,
CH3), 5.97 (s, 1 H, H-4¢¢), 6.67 (d, J = 2.6 Hz, 3 H, H-4¢), 7.50 (t,
J = 7.8 Hz, 2 H, H-5), 7.60 (td, J = 7.8, 1.2 Hz, 2 H, H-6), 7.72 (d,
J = 2.6 Hz, 2 H, H-5¢), 8.03 (td, J = 7.8, 1.2 Hz, 2 H, H-4), 8.11 (t,
J = 1.2 Hz, 2 H, H-2), 8.36 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 11.0 (CH3), 14.0 (CH3), 81.0 (CH),
104.7 (C-4¢), 107.7 (C-4¢¢), 112.9, 118.8 (CN), 129.5 (2 s, C-2, C-
5), 130.1 (C-4), 131.4 (C-5¢), 131.8 (C-6), 134.2, 141.4, 150.8,
151.3.
IR (KBr): 1996.0 (C=O) cm–1.
1H NMR (500 MHz, CDCl3): d = 6.77 (d, J = 2.6 Hz, 3 H, H-4¢),
7.55 (t, J = 7.7 Hz, 3 H, H-5), 7.79 (d, J = 2.6 Hz, 3 H, H-5¢), 7.83
(dt, J = 7.7, 1.4 Hz, 3 H, H-6 or H-4), 8.09 (dt, J = 7.7, 1.4 Hz, 3 H,
H-4 or H-6), 8.30 (t, J = 1.4 Hz, 3 H, H-2), 8.55 (s, 1 H, CH), 10.05
(s, 3 H, CHO).
13C NMR (125 MHz, CDCl3): d = 83.9, 105.1, 127.1, 129.5, 129.7,
131.4, 131.8, 133.5, 136.9, 152.5, 192.3.
Anal. Calcd for C26H20N8·0.25 H2O: C, 69.55; H, 4.60; N, 25.00.
Found: C, 69.68; H, 4.72; N, 23.90.
3,3¢,3¢¢-[Ethylidynetris(1H-pyrazole-1,3-diyl)]tribenzonitrile
(15)
MS (MALDI-TOF): m/z = 354.62 [M + H – C10H8N2O]+.
A solution of 1,1¢,1¢¢-ethylidynetris[1H-pyrazole] (12; 0.386 g, 1.69
mmol), 3-(1H-pyrazol-3-yl)benzonitrile (10; 5.749 g, 0.034 mol),
and p-TSA (0.355 g, 1.87 mmol) in toluene (20 mL) was refluxed
for 2 h in a Dean–Stark apparatus. The reaction mixture was parti-
Anal. Calcd for C31H22N6O3·0.5 H2O: C, 69.52; H, 4.33; N, 15.69.
Found: C, 70.09; H, 4.36; N, 15.52.
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L. Wang et al.
PAPER
3,3¢,3¢¢-[Ethylidynetris(1H-pyrazole-1,3-diyl)]tribenzaldehyde
(17)
13C NMR (125 MHz, CD3OD): d = 25.9, 64.2, 91.2, 104.4, 124.6,
125.0, 127.1, 129.0, 131.4, 133.2, 142.3, 153.8.
A 1 M solution of DIBAL-H (17.50 mL, 17.50 mmol) in hexane
was added dropwise to a solution of 15 (2.267 g, 4.263 mmol) in
CH2Cl2 (140 mL) at –78 °C. After stirring for 3 h at r.t., the reaction
mixture was treated with 1% aq HCl (145 mL for quenching, 750
mL for washing) and extracted with CH2Cl2 (5 × 50 mL). The com-
bined organic layers were dried (MgSO4). Purification of the crude
product by flash column chromatography (silica gel, 2% EtOAc in
CH2Cl2) afforded 17 (1.896 g, 82%) as a colorless waxy solid.
MS (MALDI-TOF): m/z = 372.62 [M + H – C10H10N2O]+.
Anal. Calcd for C32H30N6O3: C, 70.31; H, 5.53; N, 15.37. Found: C,
69.85; H, 5.62; N, 15.19.
S,S¢,S¢¢-[Methylidynetris(1H-pyrazole-1,3-diyl-3,1-phenylene-
methylene)] Triethanethioate (3)
Method B: A solution of 7 (5.23 g, 0.0225 mol), 8 (0.671 g, 2.25
mmol), and p-TSA (0.387 g, 2.25 mmol) in toluene (60 mL) was re-
fluxed for 48 h. After cooling to r.t., the reaction mixture was dilut-
ed with CH2Cl2 (150 mL) and the organic layer washed with 2% aq
NaHCO3 (150 mL), H2O (3 × 50 mL), brine (50 mL), and dried
(MgSO4). Column chromatography of the residue (silica gel,
CH2Cl2–heptane) allowed the separation of the pure S-[3-(1-acetyl-
1H-pyrazol-3-yl)benzyl] ethanethioate (0.438 g, 7%)14 as a crystal-
line product (EtOH), and 3 (0.118 g, 7%) as a waxy solid.
IR (KBr): 1697.2 (C=O) cm–1.
1H NMR (500 MHz, CDCl3): d = 3.19 (s, 3 H, CH3), 6.73 (d, J = 2.9
Hz, 3 H, H-4¢ or H-5¢), 7.00 (d, J = 2.9 Hz, 3 H, H-5¢ or H-4¢), 7.86
(dt, J = 7.8, 1.5 Hz, 3 H, H-6 or H-4), 8.13 (dt, J = 7.8, 1.5 Hz, 3 H,
H-4 or H-6), 8.34 (t, J = 1.5 Hz, 3 H, H-2), 10.08 (s, 3 H, CHO).
13C NMR (125 MHz, CDCl3): d = 26.4, 91.4, 104.6, 127.1, 129.6,
129.8, 131.1, 131.9, 133.8, 137.0, 152.3, 192.4.
From 18: DIAD (0.433 mL, 2.183 mmol) was added to a solution
of Ph3P (0.572 g, 2.183 mmol) in THF (6 mL) at 0 °C. The resulting
suspension was further stirred for 0.5 h and warmed to r.t. It was
then reacted with a solution of 18 (0.310 g, 0.582 mmol) and thio-
acetic acid (0.248 mL, 3.492 mmol) in THF (2.5 mL) at 0 °C. After
stirring for 3 h at r.t., the solvent was removed in vacuo. Flash col-
umn chromatography (silica gel, 2% EtOAc in CH2Cl2) of the crude
mixture afforded 3 (0.342 g, 83%).
MS (MALDI-TOF): m/z = 368.17 [M + H – C10H8N2O]+.
Anal. Calcd for C32H24N6O3·0.25 C4H8O2: C, 70.45; H, 4.66; N,
14.94. Found: C, 70.73; H, 5.00; N, 14.99.
3,3¢,3¢¢-[Methylidynetris(1H-pyrazole-1,3-diyl)]tribenzene-
methanol (18)
NaBH4 granules (0.0371 g, 1 mmol) were added to a solution of 16
(0.330 g, 0.627 mmol) in a mixture of MeOH (44 mL) and THF (11
mL) at 0 °C. After stirring for 1 h, the reaction mixture was
quenched with 5% aq NaHCO3 (75 mL). The resulting suspension
was stirred for 1.5 h, diluted with H2O (300 mL), extracted with
CH2Cl2 (3 × 100 mL), and the combined organic extracts were dried
(MgSO4). Purification of the crude product by column chromatog-
raphy (silica gel, 4–7% MeOH in CH2Cl2) afforded 18 (0.330 g,
99%) as a colorless solid; mp 161.8–162.6 °C.
S-[3-(1-Acetyl-1H-pyrazol-3-yl)benzyl] Ethanethioate
Mp 76.1–78.4 °C.
IR (KBr): 1728 (NCO), 1688 (SCO) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 2.75 [s, 3 H,
NC(O)CH3], 4.16 (s, 2 H, CH2), 6.74 (d, 1 H, J = 2.9 Hz, H-4¢), 7.31
(d, J = 7.5 Hz, 1 H, H-6), 7.36 (t, J = 7.5 Hz, 1 H, H-5), 7.73 (br d,
J = 7.5 Hz, 1 H, H-4), 7.79 (s, 1 H, 2-H), 8.26 (d, 1 H, J = 2.9 Hz,
H-5¢).
13C NMR (75 MHz, CDCl3): d = 21.8 [NC(O)CH3], 30.4
[SC(O)CH3], 33.3 (CH2), 107.6 (4¢-C), 125.3 (4-C), 126.7 (2-C),
129.2 (5-C), 129.4 (5¢-C), 129.7 (6-C), 132.2, 138.4, 155.1, 169.7
(NCO), 195.0 (SCO).
IR (KBr): 3357.9 (OH) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.75 (br s, 3 H, OH), 4.74 (s, 6 H,
CH2), 6.69 (d, J = 2.6 Hz, 3 H, H-4¢), 7.34 (br d, J = 7.7 Hz, 3 H, H-
6 or H-4), 7.40 (t, J = 7.7 Hz, 3 H, H-5), 7.69 (d, J = 2.6 Hz, 3 H, H-
5¢), 7.74 (d, J = 7.7 Hz, 3 H, H-4 or H-6), 7.84 (br s, 3 H, H-2), 8.49
(s, 1 H, CH).
Anal. Calcd for C14H14N2O2S: C, 61.29; H, 5.14; N, 10.21; S, 11.69.
Found: C, 61.52; H, 5.31; N, 10.15; S, 11.10.
13C NMR (125 MHz, CDCl3): d = 64.2, 84.0, 104.7, 124.6, 125.0,
127.1, 128.8, 131.8, 133.0, 142.3, 154.0.
MS (MALDI-TOF): m/z = 554.62 [M + Na]+, 358.63 [M + H –
3
C10H10N2O]+.
IR (KBr): 1686 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 9 H, CH3), 4.17 (s, 6 H,
CH2), 6.69 (d, J = 2.6 Hz, 3 H, H-4¢), 7.28 (d, J = 7.7 Hz, 3 H, H-6),
7.35 (t, J = 7.7 Hz, 3 H, H-5), 7.69 (d, J = 2.6 Hz, 3 H, H-5¢), 7.71
(d, J = 7.7 Hz, 3 H, H-4), 7.76 (s, 3 H, H-2), 8.52 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 30.4 (CH3), 33.5 (CH2), 83.9 (CH),
104.8 (C-4¢), 125.1 (C-4), 126.5 (C-2), 128.9 (C-6), 129.1 (C-5),
130.9 (C-5¢), 132.9, 138.1, 153.3, 195.2 (C=O).
Anal. Calcd for C31H28N6O3·0.25 H2O: C, 69.32; H, 5.35; N, 15.65.
Found: C, 69.47; H, 5.62; N, 15.55.
3,3¢,3¢¢-[Ethylidynetris(1H-pyrazole-1,3-diyl)]tribenzene-
methanol (19)
NaBH4 granules (0.027 g, 0.713 mmol) were added to a solution of
17 (0.257 g, 0.475 mmol) in MeOH (40 mL) at 0 °C. After stirring
for 1 h, the reaction mixture was quenched with 5% aq NaHCO3 (50
mL). The resulting suspension was stirred for 1.5 h, extracted with
CH2Cl2 (4 × 50 mL) and the combined organic layers were dried
(MgSO4). Purification of the crude product by column chromatog-
raphy (silica gel, 7% MeOH in CH2Cl2) afforded 19 (0.330 g, 96%)
as a colorless solid; mp 141.7–143 °C.
Anal. Calcd for C37H34N6O3S3·H2O: C, 61.30; H, 5.00; N, 11.59; S,
13.27. Found: C, 61.31; H, 5.17; N, 11.45; S, 12.29.
S,S¢,S¢¢-[Ethylidynetris(1H-pyrazole-1,3-diyl-3,1-phenylene-
methylene)] Triethanethioate (4)
DIAD (0.6 mL, 3.05 mmol) was added to a solution of Ph3P (0.720
g, 2.745 mmol) in THF (10 mL) at 0 °C. The resulting suspension
was further stirred for 0.5 h and warmed to r.t. Next, it was reacted
with a solution of 19 (0.400 g, 0.732 mmol) and thioacetic acid
(0.40 mL, 5.60 mmol) in THF (3.5 mL) at 0 °C. After stirring over-
night at r.t., the solvent was removed in vacuo. Repeated flash col-
umn chromatography (silica gel, 0–1% EtOAc in CH2Cl2) of the
crude mixture afforded 4 (0.490 g, 93%) as a waxy solid.
IR (KBr): 3360.7 (OH) cm–1.
1H NMR (500 MHz, CDCl3): d = 2.47 (br s, 3 H, OH), 3.16 (s, 3 H,
CH3), 4.74 (s, 6 H, CH2), 6.63 (d, J = 2.6 Hz, 3 H, H-4¢ or H-5¢),
6.88 (d, J = 2.6 Hz, 3 H, H-5¢ or H-4¢), 7.34 (ddd, J = 7.6, 1.6, 1.3
Hz, 3 H, H-6 or H-4), 7.40 (t, J = 7.6 Hz, 3 H, H-5), 7.76 (ddd,
J = 7.6, 1.6, 1.3 Hz, 3 H, H-4 or H-6), 7.86 (br s, 3 H, 2-H).
Synthesis 2009, No. 20, 3419–3426 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Tris(pyrazol-1-yl)ethanes
3425
IR (KBr): 1689.8 (C=O) cm–1.
3,3¢,3¢¢-[Ethylidynetris(1H-pyrazole-1,3-diyl)]tribenzene-
methanethiol (6)
1H NMR (500 MHz, CDCl3): d = 2.35 [s, 9 H, C(O)CH3], 3.15 (s, 3
H, CH3), 4.16 (s, 6 H, CH2), 6.61 (d, J = 2.6 Hz, 3 H, H-4¢ or H-5¢),
6.85 (d, J = 2.6 Hz, 3 H, H-5¢ or H-4¢), 7.27 (dt, J = 7.5 Hz, 3 H, H-
6 or H-4), 7.34 (3 H, t, J = 7.5 Hz, 5-H), 7.71 (dt, J = 7.5, 1.5 Hz, 3
H, H-4 or H-6), 7.75 (t, J = 1.5 Hz, 3 H, 2-H).
13C NMR (125 MHz, CDCl3): d = 26.2, 30.4, 33.5, 91.3, 104.3,
125.1, 126.4, 128.9, 129.1, 130.7, 133.2, 138.1, 153.0, 195.2.
Solid K2CO3 (0.754 g, 5.455 mmol) was added to a solution of 4
(0.437 g, 0.606 mmol) in a mixture of DMF (14 mL) and MeOH (70
mL). After stirring for 4 h at r.t., the reaction mixture was quenched
with 1% aq HCl (60 mL) at 0 °C, diluted with H2O (100 mL), ex-
tracted with CH2Cl2 (3 × 100 mL), and dried (MgSO4). Evaporation
of the solvents afforded 6 (0.362 g; ca. 100%) as a colorless solid;
mp 138.4–139.4 °C.
MS (MALDI-TOF): m/z = 488.73 [M + H – C12H12N2OS]+.
IR (KBr): 2540.5 (SH) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.80 (t, J = 7.6 Hz, 3 H, SH), 3.17
(s, 3 H, CH3), 3.79 (d, J = 7.6 Hz, 6 H, CH2), 6.63 (d, J = 2.6 Hz, 3
H, H-4¢ or H-5¢), 6.87 (d, J = 2.6 Hz, 3 H, H-5¢ or H-4'), 7.31 (dt,
J = 7.7 Hz, J = 1.4 Hz, 3 H, H-6 or H-4), 7.36 (t, J = 7.7 Hz, 3 H, H-
5), 7.70 (dt, J = 7.7 Hz, J = 1.4 Hz, 3 H, H-4 or H-6), 7.80 (t, J = 1.4
Hz, 3 H, H-2).
13C NMR (125 MHz, CDCl3) d = 26.2, 29.0, 91.2, 104.3, 124.8,
125.6, 128.1, 129.1, 130.7, 133.2, 141.7, 153.1.
MS (MALDI-TOF): m/z = 404.93 [M + H – C10H10N2S]+.
Anal. Calcd for C38H36N6O3S3·0.25 C4H8O2: C, 63.05; H, 5.15; N,
11.31; S, 12.94. Found: C, 62.87; H, 5.38; N, 11.47; S, 12.49.
3,3¢,3¢¢-[Methylidynetris(1H-pyrazole-1,3-diyl)]tribenzene-
methanethiol (5)
From a Crude Mixture of Thioesters: Solid K2CO3 (3.53 g, 0.0256
mol) was added to the crude mixture of thioesters (obtained from
3.34 mmol of 7) in DMF (15 mL) and MeOH (450 mL). After stir-
ring for 4 h at r.t., the reaction mixture was quenched with 5% aq
HCl (35 mL). The resulting solution was concentrated on the rotary
evaporator, diluted with CH2Cl2 (200 mL), washed with H2O (3 ×
50 mL), brine (50 mL), and dried (MgSO4). Column chromatogra-
phy (silica gel, 10% heptane in CH2Cl2, then 1–4% EtOAc in tolu-
ene) afforded 9 (0.245 g, 15%) and 5 (0.819 g, 42%) as pale yellow
oils.
Anal. Calcd for C32H30N6S3: C, 64.62; H, 5.08; N, 14.13; S, 16.17.
Found: C, 64.32; H, 5.20; N, 14.17; S, 15.98.
Macrobicycle 2
A solution of 6 (0.100 g, 0.168 mmol) and 1,3,5-tribromomethyl-
benzene (20; 0.060 g, 0.168 mmol) in DMF (24 mL) was added
dropwise to a stirred suspension of K2CO3 (0.139 g, 1 mmol) in
DMF (75 mL) at 60 °C over 7 h. After stirring overnight, the solvent
was removed in vacuo and the residue partitioned between CH2Cl2
(100 mL) and H2O (100 mL). The organic phase was washed with
brine (50 mL) and dried (MgSO4). Purification of the crude product
by flash column chromatography (silica gel, 4% EtOAc in toluene,
then silica gel, CH2Cl2) afforded 2 (0.0474 g, 40%) as a colorless
solid.
1H NMR (600 MHz, CD2Cl2): d = 2.88 (s, 3 H, CH3), 3.53 (s, 6 H,
ArCH2S), 3.57 (s, 6 H, CH2S), 6.66 (d, J = 2.4 Hz, 3 H, H-4¢), 6.89
(s, 3 H, ArH), 7.30 (m, 6 H, H-5, H-6), 7.43 (m, 3 H, H-4), 7.46 (br
m, 3 H, H-2), 7.76 (d, J = 2.4 Hz, 3 H, H-5¢).
From Pure Thioester 3: Solid K2CO3 (1.138 g, 8.235 mmol) was
added to a solution of 3 (0.647 g, 0.915 mmol) in a mixture of DMF
(8 mL) and MeOH (400 mL). After stirring for 3 h at r.t., the reac-
tion mixture was quenched with 1% aq HCl (70 mL), extracted with
CH2Cl2 (5 × 100 mL), and dried (MgSO4). Purification of the crude
product by column chromatography (silica gel, 0.5% EtOAc in
CH2Cl2) afforded 5 (0.403 g, 76%) as a pale yellow oil.
9
IR (KBr): 2561 (SH) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.79 (t, J = 7.6 Hz, 2 H, SH), 2.24
(s, 3 H, CH3), 2.43 (s, 3 H, CH3), 3.77 (d, J = 7.6 Hz, 4 H, CH2),
5.93 (s, 1 H, CH), 6.64 (d, J = 2.6 Hz, 2 H, H-4¢), 7.29 (d, J = 7.7
Hz, 2 H, H-4 or H-6), 7.35 (t, J = 7.7 Hz, 2 H, H-5), 7.63 (d, J = 2.6
Hz, 2 H, H-5¢), 7.66 (d, J = 7.7 Hz, 2 H, H-4 or H-6), 7.78 (s, 1 H,
H-2), 8.35 (s, 1 H, CH).
13C NMR (150 MHz, CD2Cl2): d = 28.7 (CCH3), 36.1 (ArCH2S),
36.3 (CH2S), 89.1 (CCH3), 105.3 (C-4¢), 124.7 (C-4), 127.2 (C-2),
128.5 (CHarom, C-6), 129.3 (C-5), 130.1 (C-5¢), 133.9 (C-3), 139.1
(C-1), 139.3 (ArCCH2), 151.4 (C-3¢).
MS (MALDI-TOF): m/z = 296.38 [M + H – C10H9N2S]+, 390.45 [M
– C5H7N2]+.
MS (MALDI-TOF): m/z = 709.60 [M + H]+.
Anal. Calcd for C41H36N6S3·CH2Cl2: C, 63.54; H, 4.82; N, 10.59, S,
12.12. Found: C, 64.65; H, 4.81; N, 10.89; S, 12.21.
5
IR (KBr): 2560 (SH) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.80 (t, J = 7.6 Hz, 3 H, SH), 3.78
(d, J = 7.6 Hz, 6 H, CH2), 6.69 (d, J = 2.6 Hz, 3 H, H-4¢), 7.31 (d,
J = 7.7 Hz, J = 1.3 Hz, 3 H, H-6), 7.36 (t, J = 7.7 Hz, 3 H, H-5),
7.68 (d, J = 2.6 Hz, 3 H, H-5¢), 7.69 (d, J = 7.7 Hz, J = 1.3 Hz, 3 H,
H-4), 7.79 (s, 3 H, 2-H), 8.50 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 29.1 (CS), 84.0 (CH), 104.9 (C-4¢),
124.9 (C-4), 125.7 (C-2), 128.2 (C-6), 129.2 (C-5), 131.0 (C-5¢),
133.0, 141.8, 153.5.
References
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L. Wang et al.
PAPER
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Synthesis 2009, No. 20, 3419–3426 © Thieme Stuttgart · New York