Synthesis of tris(pyrazolyl)methanes of unprecedented complexity and functionality

Article abstract of DOI:10.1016/S0040-4039(00)01867-0

In this paper we show that simple tris(pyrazolyl)methane (Tpm) ligands can be equilibrated with substituted pyrazoles to form new 'mixed' tris(pyrazolyl)methanes. The product ratio depends on the nature of the starting tris(pyrazolyl)methane, the nature o

Full text of DOI:10.1016/S0040-4039(00)01867-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5–7
Synthesis of tris(pyrazolyl)methanes of unprecedented complexity
and functionality
M. Scott Goodman* and Margaret A. Bateman
Department of Chemistry, Buffalo State College, Buffalo, NY 14222, USA
Received 18 October 2000; revised 23 October 2000; accepted 24 October 2000
Abstract—In this paper we show that simple tris(pyrazolyl)methane (Tpm) ligands can be equilibrated with substituted pyrazoles
to form new ‘mixed’ tris(pyrazolyl)methanes. The product ratio depends on the nature of the starting tris(pyrazolyl)methane, the
nature of the substituted pyrazole, and the relative amounts of these two reagents. The method has been used to easily synthesize
several new asymmetric and functionalized Tpm ligands. © 2000 Elsevier Science Ltd. All rights reserved.
ligands contain a carbon in place of the boron and are
therefore neutral analogues of the Tp ligands.
R1
R2
R1
N
R2
N
N
N
N
N
The most ordinary Tp and Tpm ligands (1st generation)
R2
M+n
+n
are the unsubstituted parent ligands (Fig. 1, R =R =
H
N
1 2
Z
H
Z
M
L
N
H) and the 3,5-dimethyl derivatives (Fig. 1, R =R =
N
1
2
R1
R2
R2
R1
3
CH3). These simple ligands provide little steric
hindrance and are capable of forming octahedral 2:1
ligand/metal complexes with a variety of metal ions.
N
N
N
R2
R1
4
R1
However, introducing bulky substituents in the 3-posi-
tion (2nd generation) produces sterically hindered lig-
ands, which only reluctantly form (or are sometimes
−
Figure 1. The tris(pyrazolyl)borates (Z=B ) and -methanes
Z=C). R and R can be H, alkyl, or aryl.
(
1
2
5
incapable of forming) 2:1 ligand/metal complexes.
The tris(pyrazolyl)borates (Tp) are a versatile class of
nitrogen-donor ligands, first employed about 30 years
ago, that are still receiving considerable attention to-
Previous syntheses of 3- and 5-substituted Tpm ligands
produced a mixture of regioisomers, which were typi-
cally equilibrated under acidic conditions giving the
1
day. These anionic ligands consist of a tetrahedral
6
boron bonded to 3 pyrazoles, with the remaining group
most stable regioisomer. We reasoned that under simi-
−
on the boron usually being a hydride (Fig. 1, Z=B ).
lar conditions, substitution of the pyrazoles with other
nucleophiles would also be possible. In this paper we
show that simple tris(pyrazolyl)methanes 1 can be equi-
More recently, the tris(pyrazolyl)methanes (Tpm) have
2
been developed as ligands. (Fig. 1, Z=C). The Tpm
R '
2
R '
1
pyrazoles
R1
N
R '
1
R1
N
N
HN
N
H+
H
C
a R , R =H
1 2
HC
N
N
N
b R , R =CH
1 2 3
3
n
3-n
c R = Ph, R =CH
3
1
2
R2
R '
R2
2
d R =Ph, R =H
1
2
1
2
Scheme 1.
*
0
Corresponding author.
040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01867-0

6
M. S. Goodman, M. A. Bateman / Tetrahedron Letters 42 (2001) 5–7
Table 1. The results of equilibrating 1a and 1b with various pyrazoles
Experiment
Starting compound
Pyrazole
(R2)
Product distribution (%)
(
R )
1
(equiv.)
n=0
n=1
n=2
n=3
1
2
3
4
5
6
7
1a
b
c
Me
Me
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
H
3
10
1
3
10
3
24
12
67
32
10
14
3
59
32
29
54
47
37
15
16
41
4
13
35
35
41
1
14
0
1
8
d
c
14
41
H
10
8
9
0
1
2
3
1b
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
H
H
H
1
3
10
1
3
10
27
10
ꢀ0
10
ꢀ0
ꢀ0
46
36
15
38
17
23
39
42
45
56
33
4
14
43
7
27
67
1
1
1
1
d
ꢀ0
librated with substituted pyrazoles (a–d) to form new
mixed’ tris(pyrazolyl)methanes 2 (Scheme 1). The com-
position of the product depends on the nature of the
starting tris(pyrazolyl)methane, the nature of the substi-
tuted pyrazole, and the relative amount of these two
reagents.
mixture. Also for the compounds shown it is possible to
separate and purify the individual components of the
‘
8
mixture by flash chromatography. In each case, the
1
13
mixed components gave the expected H NMR,
C
NMR, and mass spectrum. To our knowledge, the
mixed compounds (2) have never been described before.
The results of our experiments are presented in Table 1.
In a typical experiment, a mixture of the tris(pyra-
zolyl)methane (1 equiv.), the substituted pyrazole (1, 3
or 10 equiv.), and p-toluenesulfonic acid (1 equiv.) were
mixed with toluene ([1]=0.033 M) and the reaction
The results reveal that disubstituted 1b is more reactive
than unsubstituted 1a towards substitution (exp. 3 ver-
sus 8). The increased lability of the 3,5-dimethylpyra-
zole groups in 1b is undoubtedly due to steric hindrance
arising from the substituent in the 5-position. Similarly,
it is also apparent that a substituent in the 5-position
7
was brought to reflux for 48 hours. The reaction
(
(
R ) of the pyrazole hinders the incoming pyrazole
exp. 8 versus 11). By careful consideration of the
mixture was then worked up with NaHCO (aq.), dried
2
3
and evaporated. The ratio of the products was deter-
1
reactivity of the starting tris(pyrazolyl)methane, the
nature of the pyrazole, and the relative amount of each
it is possible to maximize the yield of a particular
product. For example, the monosubstitution product is
favored when 1a is equilibrated with 3 equiv. of 3,5-
dimethylpyrazole (exp. 1), but with 10 equiv. the disub-
stituted product is favored. In the most favorable case
mined by the relative intensities of the H NMR singlet
from the methine CꢀH between 8.0 and 8.6 ppm. Small
amounts (<5%) of regioisomers were noted in experi-
ments 3–5.
The chemical shifts of the individual compounds are
shown in Table 2. Generally, the shift of the methine
CꢀH was quite sensitive to the substitution and
changed in a regular way with addition of each new
pyrazole. The exception is the reaction of 1a with c
(
exp. 13) it was possible to favor the formation of the
trisubstituted product, tris(3-phenylpyrazolyl)methane
d.
1
(
experiments 3–5). The two tris(pyrazolyl)methanes 1a
These results were then applied to the synthesis of a
Tpm ligand containing 3 different pyrazoles. (Scheme
and 1c have very similar chemical shifts; however, it
was still possible to resolve the H NMR signals in this
1
2
). Equilibration of 1b with c (3 equiv.) and d (1 equiv.)
Table 2. Chemical shifts of the methine CꢀH of 1 and 2
H C
3
CH3
H C
3
1H NMR chemical shift (l)
Reaction
c (3 eqs.)
d (1 eq.)
H+
N
N
N
N
N
N
n=0
n=1
n=2
n=3
H C
H C
N
N
1a+b
1a+c
1a+d
1b+c
1b+d
8.42 (1a)
8.42 (1a)
8.42 (1a)
8.07 (1b)
8.07 (1b)
8.27 (2a b) 8.19 (2ab2) 8.07 (1a)
8.40 (2a c) 8.44 (2ac2) 8.41 (1c)
8.45 (2a d) 8.47 (2ad2) 8.50 (1d)
8.18 (2b c) 8.29 (2ac2) 8.41 (1c)
H C
3
CH3
CH3
H C
3
CH3
2
N
N
N
N
2
H C
3
2
2
1
b
racemic-2bcd (~20%)
8.21 (2b d) 8.36 (2ad2) 8.50 (1d)
2
Scheme 2.

M. S. Goodman, M. A. Bateman / Tetrahedron Letters 42 (2001) 5–7
7
O
O
O
O
N
O
O
O
O
O
O
O
1
. DMF dimethyl acetal
. hydrazine/EtOH
N
H
H C
3
2
O
O
pyrazole e
Scheme 3.
leads to a mixture containing all ten possible Tpm
ligands, with the desired racemic-2bcd being present at
about 20% by NMR. Column chromatography lead to
5. (a) Rheingold, A. L.; Ostrander, R. L.; Haggerty, B. S.;
Trofimenko, S. Inorg. Chem. 1994, 33, 3666–3676. (b)
Ruf, M.; Vahrenkamp, H. Inorg. Chem. 1996, 35, 6571–
6578. (c) Fillebeen, T.; Hascall, T.; Parkin, G. Inorg.
Chem. 1997, 36, 3787–3790. (d) Chia, L. M. L.; Rado-
jevec, S.; Scowen, I. J.; McPartlin, M.; Halcrow, M. A. J.
Chem. Soc., Dalton Trans. 2000, 133–140.
9
the isolation of the pure ligand.
We next turned our attention to the synthesis of a
functionalized Tpm ligand. Benzo-18-crown-6-substi-
tuted pyrazole e was synthesized from the 4-acetyl
6. (a) Jameson, D. L.; Castellano, R. K. Inorg. Synth. 1998,
2, 51–63. (b) Reger, D. L.; Collins, J. E.; Jameson, D.
10,11
3
derivative as shown in Scheme 3.
Acid-catalyzed
L.; Castellano, R. K. Inorg. Synth. 1998, 32, 63–65.
. The reaction progress was checked periodically by work-
up of a small aliquot followed by NMR analysis. The
composition of the mixture stopped changing within 24
hours in most cases, and in all cases 48 hours was
sufficient to assure that equilibrium had been reached.
. Typically, separation was achieved on silica gel by gradu-
ally increasing the amount of CH OH (0–5%) in CH Cl .
equilibration of this pyrazole (1 equiv.) with 1c gave the
expected mixture of the mono-, di-, and tri-substituted
products, from which the monosubstituted compound
7
1
2
2c2e was isolated.
In summary, a number of new ligands have been pre-
pared and characterized by acid-catalyzed equilibration
of simple Tpm ligands with pyrazoles. We are currently
preparing metal complexes of the new ‘mixed’ ligands,
as well as exploring the potentially interesting host–
guest chemistry of metal complexes containing the
crown ether pyrazole.
8
9
3
2
2
The trisubstituted compounds elute with pure CH Cl ,
2
2
followed by the disubstituted compounds (1–2%
CH OH) and then the monosubstitution products (4–5%
3
CH OH).
3
1
. Characterization of 2bcd: H NMR (300 MHz in CDCl )
3
l=2.21 (s, 3H), 2.23 (s, 3H), 2.29 (s, 3H), 5.90 (s, 1H),
6.43 (s, 1H), 6.60 (d, J=2.6 Hz, 1H), 7.29–7.39 (m, 7H),
Acknowledgements
7.77 (d, J=8.1 Hz, 2H), 7.81 (d, J=8.1 Hz, 2H), 8.35 (s,
13
1
1
H). C NMR l=11.0, 11.1, 13.8, 81.1, 103.7, 104.8,
08.0, 125.8, 126.0, 128.0, 128.2, 128.5, 128.6, 131.3,
We thank the National Science Foundation (cNSF-
ILI 9751163) for partial funding of the 300 MHz NMR
used in this work. We also thank the SUNY Research
Foundation at Buffalo State College for financial sup-
port (Undergraduate Research Fellowship).
132.7, 133.0, 141.3, 141.5, 149.7, 151.8, 153.3. EIMS m/z:
+
+
+
408 (10, M ), 313 (30, M −b), 265 (30, M −d). 251 (100,
+
M −c). EI-HRMS: calc. for C25
08.2087.
H N 408.2062, found
24 6
4
1
1
0. Talma, A. G.; van Vossen, H.; Sudh o¨ lter, E. J. R.; van
Eerden, J.; Reinhoudt, D. N. Synthesis 1986, 680–683.
1. Lin, Y.; Lang, Jr., S. A. J. Heterocyclic Chem. 1977, 14,
1
3
45–347. Pyrazole e H NMR (300 MHz in CDCl3)
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