Electronic effects in the reaction of 1,3-diaryl-1,3-diketones with hydrazinopyridines

Article abstract of DOI:10.1016/j.tetlet.2008.07.104

The regioselectivity of the condensation of electronically unsymmetrical 1,3-diaryl-1,3-diketones with 2-hydrazinopyridine and 2,6-bis-hydrazinopyridine to form N-(2-pyridyl)-3,5-diarylpyrazoles was studied. Significant electronic effects on regioselectivities were observed, and regioselectivities were opposite to those exhibited by perfluoroalkyl/alkyl 1,3-diketones. The electronic effects correlate well to the difference between the Hammett σ⁺ coefficients of the para substituents on the aryl rings.

Full text of DOI:10.1016/j.tetlet.2008.07.104

Tetrahedron Letters 49 (2008) 5766–5769
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Electronic effects in the reaction of 1,3-diaryl-1,3-diketones with
hydrazinopyridines
*
Nathan C. Duncan, Charles M. Garner , Tim Nguyen, Fernando Hung, Kevin Klausmeyer
Department of Chemistry and Biochemistry, Baylor University, One Bear Place, #97348, Waco, TX 76798, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselectivity of the condensation of electronically unsymmetrical 1,3-diaryl-1,3-diketones with
2-hydrazinopyridine and 2,6-bis-hydrazinopyridine to form N-(2-pyridyl)-3,5-diarylpyrazoles was
studied. Significant electronic effects on regioselectivities were observed, and regioselectivities were
opposite to those exhibited by perfluoroalkyl/alkyl 1,3-diketones. The electronic effects correlate well
to the difference between the Hammett r+ coefficients of the para substituents on the aryl rings.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 2 July 2008
Revised 17 July 2008
Accepted 19 July 2008
Available online 24 July 2008
The pyrazole ring is an important component of many
biologically active compounds.1 2-Pyrazolylpyridines and 2,6-bis-
pyrazolylpyridines are also robust ligands for a wide variety of
transition metals.2 The most common synthesis of the pyrazole
ring involves the reaction of a 1,3-diketone with a hydrazine.
When a substituted hydrazine is reacted with an unsymmetrical
diketone, the problem of regioselectivity arises. The regioselec-
tivity of the reaction is determined by a combination of steric
and electronic factors. Studies of electronic and steric effects in
the regioselectivity of pyrazole synthesis have been reported;3–5
however, these previous studies did not entirely separate
electronic effects from steric factors. For example, studies of
unsymmetrical perfluoroalkyl/alkyl diketones have been
reported.4,5 However, these diketones are known to exist as single
enol tautomers, and thus regioselectivity is more a question of 1,2-
versus 1,4-addition and the hardness/softness of the hydrazine
used.5
R
5'
R
5'
N
N
N
N
N
HN
N
NH
H2N
NH2
3'
3'
R
R
1
2
Given that this new route allowed for aryl groups to be placed at
both the 30 and 50 positions, we set out to study the regioselectivity
of BHP in reactions with 1,3-diaryl-1,3-diketones in which the aryl
rings were electronically dissimilar but sterically identical by
virtue of para-substitution (e.g., 3, Scheme 1). Although 1,3-dia-
ryl-1,3-diketones are known to be nearly 100% enolic, they tauto-
merize between the two possible enol forms at an extremely
rapid rate through resonance-assisted hydrogen bonding.7 Indeed,
in crystal structures of these compounds, the enol systems are
symmetrical.7c Thus, products are determined by which of the
carbonyl (or enol) carbons is undergoing initial attack by the
hydrazine NH2 group, rather than whether 1,2- or 1,4-addition is
occurring. Because pyrazolylpyridines are chelating ligands, we
anticipated that electron-donating and electron-withdrawing
groups on the aryl rings are likely to influence metal binding
through direct resonance with the pyrazole rings, lending synthetic
as well as theoretical importance to such a study.
Eight of the requisite diaryl-1,3-diketones (3a–h) were readily
prepared8 in 60–100% yields by the condensation of the more
electron-rich acetophenones with the more electron-deficient
methylbenzoates (Scheme 1), followed by purification by recrystal-
lization from hot ethanol. We found that the alternate arrange-
ment led to poor yield or no reaction at all. In these diketones
and the derived pyrazolylpyridine products, RD represents the
more electron-donating of the two substituents, and RW represents
the more electron-withdrawing in any given diketone.
We recently developed6a a route to 2,6-bis-pyrazolylpyridines
(1), which, for the first time, allowed for groups larger than methyl
at the 50 positions. This route involves reaction of 2,6-bis-hydraz-
inopyridine (BHP, 2)6 with 1,3-diketones, and accommodates 50
groups as large as phenyl and even tert-butyl with no difficulty.
In contrast to the nucleophilic aromatic substitution reactions that
were previously used to make unsymmetrical 2,6-bis-pyrazolyl-
pyridines, BHP reacts quite selectively with sterically unsymmetri-
cal 1,3-diketones to place the larger group at the 50 position.
Electronically unsymmetrical (e.g., CF3 vs CH3) 1,3-diketones react
to selectively place the more electron-withdrawing group at the 50
positions.4
* Corresponding author. Tel.: +1 254 710 6862; fax: +1 254 710 2403.
E-mail address: Charles_Garner@baylor.edu (C. M. Garner).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.104

N. C. Duncan et al. / Tetrahedron Letters 49 (2008) 5766–5769
5767
RD
RW
O
O
H
H
a
b
c
d
e
f
CF3
CN
H
1. NaH, THF, heat
2. H3O+
OCH3
+
OMe
OMe
OMe
NMe2
NMe2
NMe2
RW
RD
CF3
CN
H
O
O
RD = more electron-donating group
RW = more electron-withdrawing group
g
h
CF3
CN
RD
RW
3a-h
Scheme 1. Synthesis of substituted 1,3-diaryl-1,3-diketones.
C6H4RD
5'
C6H4RW
C6H4RD
3a-h
N
N
N
N
N
+
N
NH
0.1 eq TFA
THF, reflux, 12 h
N
3'
NH2
C6H4RW
4
5a-h
(major)
6a-h
(minor)
Scheme 2. Reaction of 3a–h with 2-hydrazinopyridine (4).
The diketones 3a–h were first reacted with the simpler and
commercially available 2-hydrazinopyridine (4) and a catalytic
amount of trifluoroacetic acid in THF at reflux for 12 h (Scheme
2).9 This led to complete conversion to the 30,50-diarylpyrazolyl-
pyridines 5a–h and 6a–h. The isomer ratios (Table 1) were deter-
mined by gas chromatography on HP-5, and generally verified by
1H (and, in three cases, by 19F) NMR. The regioisomers were not
easily separable by TLC or column chromatography. However, in
three of the eight cases (b, e, and g), fractional crystallization pro-
vided X-ray quality crystals that proved the regiochemistry to be
that of isomer 5, and GC of the actual X-ray crystals showed this
to be the major isomer in each case. Thus, these reactions regio-
selectively place the more electron-donating aryl group (RDC6H4)
at the 50 position. It should be noted that all of these product
mixtures exhibited fluorescence when exposed to UV light at both
254 nm and 365 nm (Fig. 1), particularly those containing dimeth-
ylamino substituents.
Figure 1. Fluorescence in the mixtures of 5/6a–h at 365 nm.
The regioselectivity of the reaction of 2-hydrazinopyridine with
the eight diketones 3a–h showed a clear correlation with the elec-
tronic nature of the para substituents, and the electronic effects of
the two groups were additive. Thus, the log of the ratio of (5/6) is
linearly related to the difference (Dr
+) between the Hammett
coefficients r+ (RW) and r+ (RD) for the para substituents (Graph
1). Because r+ values for electron-donating groups are negative,
D
r+ is always a positive number.
The reaction of diketones 3a–h was repeated with 2,6-bis-
hydrazinopyridine (2) (Scheme 3) to prepare 2,6-bis-pyrazolylpyri-
dines 7–9. The reaction conditions were the same as before, but
these higher-boiling product mixtures required analysis on a
Graph 1. Log of (5/6) versus D .
rpþ
high-temperature carborane-based GC column. In two cases (3e
and 3h), the product mixtures were not separable by GC nor easily
analyzed by NMR. The remaining six diketones gave GC-analyzable
mixtures of products 7–9 (Table 2). In two of these cases (c and d),
fractional recrystallization gave X-ray quality crystals, and the
structures were shown to be that of 7c and 7d, with both of the
50 positions being occupied by electron-donating groups. Again,
GC of the crystals after X-ray showed that they belonged to the ma-
jor isomer in both cases. The mixtures of the three regioisomers
were again inseparable by silica chromatography, and the product
mixtures of 7–9 also exhibited fluorescence at both 254 nm and
Table 1
Product ratios from reaction of 3a–h with 4
3
RD
RW
(5/6)
a
b
c
d
e
f
H
H
CF3
CN
H
CF3
CN
H
1.88
2.10
2.35
4.43
4.87
6.48
10.56
13.58
OMe
OMe
OMe
Me2N
Me2N
Me2N
g
h
CF3
CN

5768
N. C. Duncan et al. / Tetrahedron Letters 49 (2008) 5766–5769
C6H4RD
5'
RDC6H4
3a-h (2 eq)
N
N
N
N
N
HN
H2N
N
NH
0.1 eq TFA
THF, reflux, 12 h
3'
NH2
2
RWC6H4
RWC6H4
7a-h
C6H4RW
(major)
C6H4RD
N
C6H4RW
C6H4RD
RWC6H4
+
N
N
N
N
N
+
N
N
N
N
RDC6H4
RDC6H4
C6H4RW
8a-h
9a-h
(minor)
Scheme 3. Reaction of 3a–h with 2,6-bis-hydrazinopyridine (2).
Table 2
Inherent selectivity in reactions of 3a–h with 2 calculated from product ratios
Graph 2. Log of inherent selectivity in reaction of 3a–h with 2 versus D .
rpþ
3
RD
RW
Ratio 7:8:9
Inherent selectivity
a
b
c
d
e
f
H
H
CF3
CN
H
CF3
CN
H
2.43:3.30:1
3.97:3.91:1
7.22:5.72:1
22.79:9.55:1
N/A
63.87:15.08:1
137.12:23.42:1
N/A
1.69
1.99
2.69
4.78
N/A
7.99
11.7
N/A
OMe
OMe
OMe
Me2N
Me2N
Me2N
H
F3C
H3C
H2N
O
O
N
N
N
N
N
H
g
h
CF3
CN
F3C
CH3
1,4-addn
H
O
O
365 nm (Fig. 2), particularly in cases where dimethylamino substit-
uents were present.
RD
RW
Given that reactions with BHP require two separate selective
reactions, we sought to determine the average selectivity of an
individual reaction. Thus, if X and Y represent the fractional prob-
abilities in the reaction of any one hydrazino group placing the
electron donating group in the 50 or 30 positions, respectively, the
fraction of product 7 should be X2, that of product 9 would be Y2,
and that of product 8 would be 2XY. This analysis revealed that
the selectivities observed for 2-hydrazinopyridine were very simi-
lar to those calculated for BHP (Table 3). Indeed, the Hammett plot
(Graph 2) for BHP reactions is nearly superimposable on that of 2-
hydrazinopyridine. Thus, the selectivity of the reaction of the first
3a-h
Scheme 4. Enolization in perfluoroalkyl/alkyl 1,3-diketones and in 1,3-diaryl-1,3-
diketones.
hydrazino group in BHP does not appear to significantly influence
the selectivity of the second one.
For both 2-hydrazinopyridine and BHP, the observed regio-
chemistry is consistent with initial reaction of the hydrazine NH2
group at the carbonyl (or enol) carbon closer to the more elec-
tron-withdrawing aryl group. This regiochemistry is opposite of
that observed for perfluoroalkyl/alkyl 1,3-diketones, where the
perfluoroalkyl groups occupy the pyrazole 50 positions. In these
cases, the reactions proceed by 1,4-addition to a single enol form
(Scheme 4). For 1,3-diaryl-1,3-diketones, the data suggest that
the regiochemistry of the reaction depends simply on the relative
electrophilicity of each carbonyl (or enol) carbon rather than on
the location of an enolic double bond or whether 1,2- or 1,4-addi-
tion occurs. This is consistent with the resonance-assisted hydro-
gen bonding model in that a high degree of delocalization makes
it impossible to distinguish between 1,2- versus 1,4-addition.
Figure 2. Fluorescence in the mixtures of 7/8/9a–h at 365 nm.
Acknowledgments
Table 3
We would like to thank the Robert A. Welch Foundation (Grant
AA-1395) for support of this work and the National Science Foun-
dation (Award #CHE-0420802) for funding of our 500 MHz NMR
spectrometer.
Comparison of selectivity in reactions of 3a–h with 4 and 2
3
RD
RW
From 4 (Ratio 5/6)
Selectivity from
reactions with 2
a
b
c
d
e
f
H
H
CF3
CN
H
CF3
CN
H
1.88
2.10
2.35
4.43
4.87
6.48
10.56
13.58
1.69
1.99
2.69
4.78
N/A
7.99
11.7
N/A
References and notes
OMe
OMe
OMe
Me2N
Me2N
Me2N
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5769
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cyano example is typical: to a flask under nitrogen atmosphere containing
470 mg of NaH (19.6 mmol, 1.06 equiv) in refluxing THF was added dropwise a
THF solution containing 3.05 g of 4-dimethylaminoacetophenone (18.4 mmol,
1.0 equiv) and 3.10 g of methyl 4-cyanobenzoate (18.6 mmol, 1.01 equiv). The
solution was allowed to reflux for 16 h, was cooled, acidified to pH 2 with 1 M
HCl and extracted three times with 50 mL of CH2Cl2. After concentration, the
crude solid was recrystallized from ethanol to give small fluorescent yellow
needles (5.27 g, 98%; lit. 35%), spectroscopically identical with known8
material.
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round-bottomed flask with 279 mg (1.00 mmol, 1 equiv) of 4-cyano-40-
methoxydibenzoylmethane, and was placed under nitrogen atmosphere. The
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8. The procedure used in all cases was a modification of Soto, Y.; Morimoto, M.;
Segawa, H.; Shimidzu, T. J. Phys. Chem 1995, 99, 35–39. The dimethylamino/
mixture was dissolved in 10 mL of THF, then
7 lL of trifluoroacetic acid
(0.094 mmol, 0.094 equiv) was added and the reaction was heated to reflux for
12 h. After cooling, the reaction mixture was added to 50 mL of 1 M NaOH and
extracted three times with 25 mL of CH2Cl2. The combined organic extracts were
washed with saturated NaCl (50 mL) and dried over MgSO4 and concentrated by
rotary evaporation to yield 306 mg (87%) of a mixture of two isomers. Major
isomer: N-(2-pyridyl)-3-(40-cyanophenyl)-5-(40-methyoxyphenyl)pyrazole. MS:
352 (M+), 351 (base), 337, 308, 280, 250, 224, 207, 176, 154, 127, 78, 51. Minor
isomer: N-(2-pyridyl)-3-(40-methyoxyphenyl)-5-(40-cyanophenyl)pyrazole. MS:
352 (M+), 351 (base), 337, 308, 280, 253, 230, 218, 192, 175, 154, 127, 102, 78,
51.