Drastic Deprotonation Reactivity Difference of 3- and 5-Alkylpyrazole Isomers, Their I2-Catalyzed Thermal Isomerization, and Telescoping Synthesis of 3,5-Dialkylpyrazoles: The Adjacent Lone Pair Effect Demystified

Article abstract of DOI:10.1021/acs.joc.5b02746

N-Protected 3-alkylpyrazoles are easily deprotonated by ⁿBuLi at the 5-position of the aromatic ring, while the 5-alkyl isomers are completely unreactive under the same conditions. Using computational analysis, we reveal that electron pair repulsion within the deprotonated anion is not the reason behind the lack of reactivity of 5-alkylpyrazoles. Instead, diminished π-resonance and attractive electrostatic interactions within the pyrazole ring are responsible for the observed effect. A greener, telescoping alternative to the synthesis of 3,5-dialkylpyrazoles is presented. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02746

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Note
Drastic deprotonation reactivity difference of 3- and 5-alkylpyrazole
isomers, their I2-catalyzed thermal isomerization, and telescoping synthesis
of 3,5-dialkylpyrazoles: the “adjacent lone pair effect” demystified
Basil Mohammed Ahmed, Huaiyu Zhang, Yirong Mo, and Gellert Mezei
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02746 • Publication Date (Web): 27 Jan 2016
Downloaded from http://pubs.acs.org on January 29, 2016
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Drastic deprotonation reactivity difference of 3- and 5-alkylpyrazole isomers,
their I -catalyzed thermal isomerization, and telescoping synthesis of 3,5-
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dialkylpyrazoles: the “adjacent lone pair effect” demystified
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*
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Basil M. Ahmed, Huaiyu Zhang, Yirong Mo and Gellert Mezei
Department of Chemistry, Western Michigan University, Kalamazoo, Michigan, USA
ABSTRACT
n
Nꢀprotected 3ꢀalkylꢀpyrazoles are easily deprotonated by BuLi at the 5ꢀposition of the aromatic
ring, while the 5ꢀalkyl isomers are completely unreactive under the same conditions. We reveal,
using computational analysis, that electron pair repulsion within the deprotonated anion is not the
reason behind the lack of reactivity of 5ꢀalkylꢀpyrazoles. Instead, diminished πꢀresonance and
attractive electrostatic interactions within the pyrazole ring are responsible for the observed
effect. A greener, telescoping alternative to the synthesis of 3,5ꢀdialkylpyrazoles is also
presented.
Pyrazole derivatives are employed in various applications, including a wide variety of
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pharmaceuticals, insecticides, fungicides, herbicides and dyes. Owing to its ability to bridge
metal centers together, the pyrazole moiety has also been exploited extensively for the
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construction of diverse multiꢀmetallic complexes, such as macrocycles, grids, clusters,
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nanocages and 3Dꢀframeworks. Uses of the resulting materials include H ꢀstorage, isomer
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separation, anion extraction and singleꢀmolecule magnets. Despite the broad interest and
widespread use, certain intrinsic properties of the pyrazole ring are still not fully understood. For
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instance, we have just recently revealed that the reason behind the preferred deprotonation of 3ꢀ
methylꢀ1ꢀRꢀpyrazole (R = Nꢀprotecting group) at an endocyclic carbon instead of the exocyclic
methyl group is a subtle combination of diminished πꢀconjugation, smaller bond angles and
strengthened induction of Csp
2
versus Csp , as compared to the sixꢀmembered analog, 3ꢀ
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methylpyridazine, which is preferentially deprotonated at the exocyclic methyl group (known as
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the “benzylic” position).
Furthermore, while 3ꢀmethylꢀ1ꢀTHPꢀpyrazole (THP
=
n
tetrahydropyranꢀ2ꢀyl) is easily deprotonated by BuLi at −78 °C, the 5ꢀmethylꢀ1ꢀTHPꢀpyrazole
isomer is completely resistant to deprotonation under the same experimental conditions (Fig. 1).
Herein we unveil that this intriguing property is not the result of the repulsion between the lone
pairs of the deprotonated anion and the adjacent Nꢀatom, as previously believed and referred to
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as to the “adjacent lone pair (ALP) effect”. We also discovered that the thermal isomerization of
the 5ꢀmethylꢀ to the 3ꢀmethylꢀ1ꢀTHPꢀpyrazole isomer is catalyzed by trace amounts of iodine,
and developed a convenient oneꢀpot, telescopic synthesis of unsymmetrical 3,5ꢀdialkylpyrazoles.
Figure 1. Deprotonation of 3ꢀmethylꢀ1ꢀRꢀpyrazole (A1) and 5ꢀmethylꢀ1ꢀRꢀpyrazole (A2) isomers. R =
methyl (computations) or tetrahydropyranꢀ2ꢀyl (synthesis).
As the aromatic rings of the 1,3ꢀdimethylpyrazole (A1) and 1,5ꢀdimethylpyrazole (A2)
isomers, as well as of their deprotonated products B1 and B2 (Fig. 1) are nearly but not perfectly
planar, all aromatic rings were restrained to a plane in quantum mechanical computations to
allow for the differentiation of σ and π interactions. Planarity requires an energy of less than 0.4
kcal/mol at the MP2/6ꢀ311+G(d,p) level.
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Table 1. Relative energies of A2 vs. A1 and B2 vs. B1, along with their inherent electron delocalization
energies (DEs) for σ and π electrons (kcal/mol)*
A1
0.00
A2
0.12
B1
0.00
B2
18.21
21.53
128.93
40.90
88.38
ꢀ
E(MP2)
E(HF)
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ꢀ
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0.82
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DE(total)
DE(σ)
140.37
36.62
104.96
139.70
36.71
104.26
141.87
39.91
102.87
DE(π)
*
Geometries are optimized at the MP2/6ꢀ311+G(d,p) level.
As expected, the 1,3ꢀdimethylpyrazole (A1) and 1,5ꢀdimethylpyrazole (A2) isomers are
essentially isoenergetic at the HF or MP2 theoretical levels. However, their deprotonated
products have very different energies: B1 is much more stable than B2. The conventional
explanation is the adjacent lone pair (ALP) effect, which suggests that the repulsion between the
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two lone pairs on the adjacent carbon and nitrogen atoms destabilizes B2. Our calculations
based on the pairwise Coulomb interaction (Eq. 1) show that there is indeed a slight increase (2.2
kcal/mol) from the repulsion between the two lone pairs in B2 to the repulsion between one lone
pair with the σCN bond in B1 (Fig. 2). This amount, however, is small and is correlated to the
structural change, i.e., the CN bond in these two species.
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RE = φiφi
φjφj
(1)
r1 − r
2
Figure 2. Adjacent pairꢀpair Coulomb interactions in B1 and B2 (a.u.).
This prompts further investigations of the electron delocalization effect in these
9−12
systems. Table 1 compiles the major results, where DE(total) is the energy change between a
fully delocalized and a fully localized Lewis state (i.e., the most stable resonance structure), and
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DE(π) and DE(σ) refer to the energy change by localizing π and σ electrons, respectively. The
sum of DE(π) and DE(σ) is very close to DE(total), suggesting negligible coupling between the
delocalizations of σ and π electrons.
It is interesting that from A to B, there is little change for the σ electron delocalization in
isomers (A1 vs. A2 and B1 vs. B2). However, the πꢀconjugation in B2 is less stabilizing than in
B1 by 13 kcal/mol, which accounts for 60% of the energy gap between B1 and B2. With all
electron pairs localized on either two atoms (bonds) or individual atoms (lone pairs), B1 is still
more stable than B2 by 8 kcal/mol, which most likely is a consequence of electrostatic
interactions: there are two H nuclei around the negatively charged carbon in B1 but only one in
B2 (Fig. 2). To verify our hypothesis, we examined the model system methylamine in different
conformations, as shown in Fig. 3. The deprotonation of the eclipsed conformation (A3) results
in two adjacent lone pairs, while the deprotonation of the staggered conformation (A4) does not.
Although A3 does have a higher deprotonation energy than A4, the difference is only 7.5 or 7.1
kcal/mol at the MP2 or HF levels, respectively (with geometries optimized at the MP2/6ꢀ
311+G(d,p) level). This amount is in excellent agreement with the energy difference between
electronꢀlocalized B1 and B2 (8 kcal/mol). Using Eq. 1, we also evaluated the repulsion between
the lone pairs in B3 (see Fig. 3), which turns out to be even less than the repulsion between the
lone pair and the C−H bond in B4. Therefore, we conclude that it is not the repulsion between
adjacent lone pairs of electrons (ALP effect) that leads to the drastic difference between the
deprotonation energies of the two isomers, but rather reduced πꢀresonance (62% or 13 kcal/mol)
and attractive electrostatic interactions (38% or 8 kcal/mol).
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As the deprotonation of A1 (R = THP) is an orthoꢀmetalation reaction, it can be argued
that the tetrahydropyranꢀ2ꢀyl group promotes orthoꢀdeprotonation, as its Oꢀatom can potentially
coordinate to the lithium countercation. While this scenario certainly contributes to the stability
of anion B1 compared to B2 (R = THP) in practice, our gasꢀphase calculations on the analogs
which lack the stabilizing Oꢀatom (R = CH ), also lead to the same conclusion that B1 is much
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more stable than B2. Therefore, the computational results clearly establish that the metalation of
the 5ꢀposition in A1 is not directed, but rather assisted by the THP group in practice, which
offers additional stability to the resulting anion B1.
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Figure 3. Deprotonation of eclipsed (A3) and staggered (A4) methylamine conformers, with values of
adjacent pairꢀpair Coulomb interactions shown for B3 and B4 (a.u.).
Aiming at greener preparative methods, we developed a telescopic synthesis of 3,5ꢀ
dialkylpyrazoles (53% overall yield based on 1Hꢀpyrazole), by combining five synthetic steps
into a oneꢀpot method (Fig. 4). Crucial to the value of this method are the solventꢀ and catalystꢀ
free, quantitative step of pyrazole protection, and the also solventꢀfree isomerization step of the
unreactive 5ꢀalkylꢀ1ꢀTHPꢀpyrazole to the reactive 3ꢀalkylꢀ1ꢀTHPꢀpyrazole isomer. Such
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protective group switching is usually accomplished by an acidꢀcatalyzed, sequential or direct
deprotectionꢀreprotection route. Our method significantly reduces the consumption of organic
solvents and additional reagents, and eliminates the use of highly toxic or explosive starting
materials and reagents (such as hydrazine, diazomethane and derivatives, often employed for the
synthesis of pyrazole derivatives). As the oneꢀpot method requires no purification of the
intermediates, losses are eliminated and waste production is greatly diminished.
Figure 4. Telescoping synthesis of 3,5ꢀdialkylpyrazoles from pyrazole (DHP = 3,4ꢀdihydroꢀ2Hꢀpyran; R
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nꢀhexyl or nꢀheptyl; R′ = nꢀbutyl), with % conversions (based on HꢀNMR)
.
Although the isomerization step of 5ꢀalkylꢀ to 3ꢀalkylꢀ1ꢀTHPꢀpyrazole can be
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accomplished by simple heating, a catalytic amount of iodine (I ) greatly reduces the reaction
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time needed to reach equilibrium. This discovery is rooted in our observation that when 5ꢀhexylꢀ
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ꢀTHPꢀpyrazole is prepared from 1ꢀiodohexane, it undergoes isomerization much faster than
when it is prepared from 1ꢀbromohexane, under the same conditions. Indeed, addition of 0.08
mol% I to 5ꢀhexylꢀ1ꢀTHPꢀpyrazole prepared from 1ꢀbromohexane reduces the isomerization
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time at 125 °C from 8 days to 24 hours, confirming our hypothesis that trace amounts of iodine
originating from 1ꢀiodohexane catalyze the isomerization. The mechanism of isomerization is
likely similar to the one proposed for the 2ꢀ(trimethylsilyl)ethoxymethyl chloride (SEMꢀCl)
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catalyzed SEM group transposition in SEMꢀprotected pyrazoles, as well as the N,Nꢀ
dimethylaminosulfonyl (DMAS), benzyl (Bn), methoxymethyl (MOM) and SEM protecting
group switching in Nꢀprotected imidazoles catalyzed by DMASꢀCl, BnBr, MOMꢀCl or SEMꢀCl,
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respectively. All the above protecting agents are alkylating agents, which, upon alkylation of
the free N2ꢀatom of the N1ꢀprotected diazole, induce the elimination of the protecting group and
render the N1ꢀatom free. The liberated protecting group alkylates the next substrate and
propagates the reaction. In our case (Figure 5), the alkylating agent is presumed to be 2ꢀ
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iodotetrahydropyran, which initially forms from the reaction of 3,4ꢀdihydroꢀ2Hꢀpyran (formed
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in trace amounts as a result of partial deprotection of the substrate upon heating ) with HI
2
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(formed from the reaction of I with the pyrazole ring, leading to 4ꢀiodopyrazole ).
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Alternatively, I2 can react directly with 3,4ꢀdihydroꢀ2Hꢀpyran to produce 2,3ꢀ
diiodotetrahydropyran, which can react similarly to 2ꢀiodotetrahydropyran as the initial
alkylating agent.
Figure 5. Proposed mechanism of the I ꢀcatalyzed thermal isomerization of 5ꢀalkylꢀ to 3ꢀalkylꢀ1ꢀTHPꢀ
2
pyrazoles (R = alkyl).
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Improved overall yields of 3,5ꢀdialkylpyrazoles (60% based on 1Hꢀpyrazole) are
obtained if the THPꢀprotected 3,5ꢀdialkylpyrazoles are purified before deprotection, as column
chromatographic separation is more efficient on the protected pyrazoles than the deprotected
products. Pure 3,5ꢀdialkylpyrazoles are obtained after deprotection with HCl and removal of the
solvent in vacuum.
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In summary, we have shown that the drastic deprotonation reactivity difference between
Nꢀprotected 3ꢀalkylꢀ and 5ꢀalkylpyrazole isomers is not the result of repulsion between adjacent
lone pairs (ALP effect), as previously thought, but is rather due to reduced πꢀresonance and
weaker stabilizing attractive electrostatic interactions within the 5ꢀalkylpyrazole isomer. The
thermal isomerization of the unreactive 5ꢀmethylꢀ to the reactive 3ꢀmethylꢀ1ꢀTHPꢀpyrazole
isomer is greatly accelerated by small amounts of elemental iodine. By combining five synthetic
steps into one pot, we developed a greener, telescoping synthesis of 3,5ꢀdialkylpyrazoles. This
new methodology could also be applied for the synthesis of various other 3,5ꢀdisubstituted
pyrazoles (e.g., alkyl, halogen, hydroxyl, amino, azido, carbonyl, organoꢀelement substituents),
both symmetrical and unsymmetrical, by employing the appropriate electrophiles.
EXPERIMENTAL SECTION
General methods. Tetrahydrofuran is dried with Na/benzophenone and freshly distilled under
1
nitrogen prior to use. All other commercial reagents and solvents are used as received. H and
1
3
C NMR spectra are recorded at room temperature, and peak assignments are confirmed by
1
1
H− H COSY experiments. Highꢀresolution mass spectra are obtained using an electrospray
ionization source (negative mode for pyrazoles, positive mode for THPꢀprotected pyrazoles).
Telescopic synthesis of 3(5)-butyl-5(3)-hexylpyrazole. The following steps are carried out in a
500 mL pressure flask (oneꢀpot). The contents are protected from atmospheric moisture between
steps by using an N blanket.
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a) Protection of 1H-pyrazole. THPꢀprotection of 1Hꢀpyrazole is accomplished according to our
1
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green method described previously, by heating 1.200 g (17.62 mmol) 1Hꢀpyrazole and 2.00 mL
(1.85 g, 22.0 mmol) of 3,4ꢀdihydroꢀ2Hꢀpyran for 24 h at 125 °C. After removing the slight
excess of DHP in vacuum, 2.68 g (100 %) pure 1ꢀ(tetrahydropyranꢀ2ꢀyl)pyrazole is obtained.
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b) Synthesis of 5-hexyl-1-(tetrahydropyran-2-yl)pyrazole. The flask containing the THPꢀ
protected pyrazole is evacuated and purged with N , then anhydrous THF (40 mL) is added via
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N ꢀpurged syringe. The solution is chilled to −78 °C, stirred for 30 minutes, then BuLi solution
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(1.6 M in hexanes, 11.0 mL, 17.6 mmol) is added dropwise over 10 minutes. After stirring at −78
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C for 30 minutes, 1ꢀbromohexane (2.72 mL, 3.20 g, 19.3 mmol) is added, the solution is stirred
at −78 °C for 90 minutes, then it is left to warm up to room temperature overnight under stirring.
The flask is then connected to vacuum (0.005 mmHg) and the excess bromohexane and
1
unreacted 1ꢀTHPꢀpyrazole are both removed by gently heating in a water bath at 55 °C. H NMR
shows a 96% conversion.
c) Isomerization to 3-hexyl-1-(tetrahydropyran-2-yl)pyrazole. To the 5ꢀhexylꢀ1ꢀTHPꢀ
pyrazole obtained from 1ꢀbromohexane is added a solution of I (7.0 mg, 28 ꢁmol) in DHP (2
2
ml) under an N atmosphere. The flask is closed and set in an oven at 125 °C for 24 hours. After
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cooling to room temperature, H NMR of the product shows an isomeric mixture of 85% 3ꢀ
hexylꢀ1ꢀTHPꢀpyrazole and 15% 5ꢀhexylꢀ1ꢀTHPꢀpyrazole. In the absence of I , it takes 8 days to
2
reach the 85/15 equilibrium mixture of isomers at 125 °C. If 5ꢀhexylꢀ1ꢀTHPꢀpyrazole is prepared
using 1ꢀiodohexane instead of 1ꢀbromohexane, traces of residual iodine in the product have the
same catalytic effect.
d) Synthesis of 5-butyl-3-hexyl-1-(tetrahydropyran-2-yl)pyrazole. The flask containing the
mixture described above, is evacuated and purged with N . Anhydrous THF (70 mL) is added
2
n
and the mixture is chilled to −78 °C for 30 minutes. BuLi (1.6 M in hexanes, 10.0 mL, 16.0
mmol) is added dropwise over 10 minutes and is stirred for 30 minutes, then 1ꢀbromobutane
(1.90 mL, 2.42 g, 17.6 mmol) is added. After stirring for 3 hours at −78 °C, the solution is left to
warm up to room temperature overnight under stirring, 1 mL water is added and the THF is
1
removed under vacuum. HꢀNMR shows an 89% conversion of 3ꢀhexylꢀ1ꢀ(tetrahydropyranꢀ2ꢀ
yl)pyrazole to 5ꢀbutylꢀ3ꢀhexylꢀ1ꢀTHPꢀpyrazole, along with traces of unreacted 5ꢀhexylꢀ and 3ꢀ
hexylꢀ1ꢀTHPꢀpyrazole.
e) Deprotection to 3(5)-butyl-5(3)-hexylpyrazole. To the material obtained above is added 200
1
mL ethanol and 50 mL HCl (37% in H O). After stirring for 8 hours ( H NMR shows complete
2
deprotection), the solvent is removed under vacuum. 5 mL of water is added to the residue, and
the pH is adjusted to 8 with a saturated NaHCO solution. The mixture is extracted with diethyl
3
ether (3 × 80 mL) and the combined organic layers are dried over MgSO overnight. The solid
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material is filtered out and the solvent is removed under vacuum to give crude 3(5)ꢀbutylꢀ5(3)ꢀ
1
hexylpyrazole (3.760 g) as dark redꢀbrown oil. H NMR shows a small amount of 3(5)ꢀhexylꢀ
1Hꢀpyrazole impurity. If 1ꢀiodobutane is used instead of 1ꢀbromobutane in the previous step,
3(5)ꢀbutylꢀ5(3)ꢀhexylꢀ4ꢀiodopyrazole byproduct is also identified by ESIꢀMS.
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f) Purification of 3(5)-butyl-5(3)-hexylpyrazole. The crude material is purified by column
chromatography using hexane:ethyl acetate (2:1) as eluent. The main product, 3(5)ꢀbutylꢀ5(3)ꢀ
hexylpyrazole is obtained as a yellow oil (1.941 g, 53% overall yield based on 1Hꢀpyrazole) with
R = 45%. If 1ꢀiodobutane is used instead of 1ꢀbromobutane in step d), the yield of the product
f
drops to 46% (1.671 g), and 0.649 g of 3(5)ꢀbutylꢀ5(3)ꢀhexylꢀ4ꢀiodopyrazole is also isolated as a
byproduct.
Alternative general method of preparation of 3,5-dialkyl-1-(tetrahydropyran-2-
yl)pyrazoles. 1ꢀTHPꢀpyrazole, 5ꢀalkylꢀ1ꢀTHPꢀpyrazoles and 3,5ꢀdialkylꢀ1ꢀTHPꢀpyrazoles are
prepared as described above (steps a through d). The protected 3,5ꢀdialkylꢀpyrazoles are
extracted from the crude residues obtained after quenching with water and removal of the THF
(d), using 4 mL water and three portions of 4 mL diethyl ether (per mmol of substrate). The
combined organic layers are washed with 60 mL brine and dried over MgSO . After evaporation
4
of the solvent, the crude products are purified by column chromatography using
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13
dichloromethane:ethyl acetate (4:1) as eluent, and are obtained pure (by H NMR, C NMR and
ESIꢀMS) as yellow oils (R = 87% for 3(5)ꢀR ꢀ5(3)ꢀR pyrazole, where R = nꢀbutyl and R = nꢀ
f
1
2
1
2
hexyl or nꢀheptyl).
5-butyl-3-hexyl-1-(tetrahydropyran-2-yl)pyrazole. Yield: 1.515 g (61% based on 1Hꢀ
1
3
3
pyrazole). H NMR (400 MHz, CDCl ): 5.84 (s, 1H, 4ꢀHꢀpz), 5.14 (dd, 1H, J = 10.4 Hz, J =
3
2
.4 Hz, CH–THP), 4.02–4.06 (m, 1H, CH O–THP), 3.57–3.63 (m, 1H, CH O–THP), 2.53–2.67
2
2
(m, 4H, CH (CH ) CH and CH (CH ) CH ), 2.41–2.52 (m, 1H, CH –THP), 2.05–2.08 (m, 1H,
2
2 4
3
2
2 2
3
2
CH –THP), 1.84–1.91 (m, 1H, CH –THP), 1.50–1.8 (m, 7H, CH –THP, CH CH (CH ) CH and
2
2
2
2
2
2 3
3
2
CH CH CH CH ), 1.20–1.44 (m, 8H, (CH ) (CH ) CH and (CH ) CH CH ), 0.93 (t, 3H, J =
2
2
2
3
2 2
2 3
3
2 2
2
3
2
13
7
.32 Hz (CH ) CH ), 0.86 (t, 3H, J = 6.6 Hz (CH ) CH ). CꢀNMR (101 MHz, CDCl ): 153.2,
2 3 3 2 5 3 3
144.5, 103.6, 84.2, 68.1, 31.8, 30.8, 29.9, 29.8, 29.4, 28.6, 25.10, 25.06, 23.3, 22.7, 22.5, 14.2
+
and 14.0. HRMS (ESIꢀTOF) m/z: [M+Na] calcd for C H N NaO 315.2412; found 315.2415.
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5
-butyl-3-heptyl-1-(tetrahydropyran-2-yl)pyrazole. Yield: 3.137 g (62% based on 1Hꢀ
1
3
3
pyrazole). HꢀNMR (400MHz, CDCl ): 5.84 (s, 1H, 4ꢀHꢀpz), 5.14 (dd, 1H, J = 10.4 Hz, J = 2.4
3
Hz, CH–THP), 4.02–4.06 (m, 1H, CH O–THP), 3.57–3.63 (m, 1H, CH O–THP), 2.53–2.67 (m,
2
2
4H, CH (CH ) CH and CH (CH ) CH ), 2.41–2.51 (m, 1H, CH –THP), 2.05–2.08 (m, 1H,
2 2 5 3 2 2 2 3 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
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3
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7
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CH –THP), 1.85–1.89 (m, 1H, CH –THP), 1.51–1.77 (m, 7H, CH –THP, CH CH (CH ) CH
3
2
2
2
2
2
2 4
and CH CH CH CH ), 1.21–1.44 (m, 10H, (CH ) (CH ) CH and (CH ) CH CH ), 0.93 (t, 3H,
2
2
2
3
2 2
2 4
3
2 2
2
3
2
2
13
J = 7.6 Hz (CH ) CH ), 0.85 (t, 3H, J = 6.8 Hz (CH ) CH ). CꢀNMR (101 MHz, CDCl ):
2
3
3
2 5
3
3
153.2, 144.5, 103.6, 84.2, 68.1, 31.9, 30.8, 29.9, 29.8, 29.7, 29.2, 28.6, 25.09, 25.06, 23.3, 22.7,
+
22.5, 14.2 and 14.0. HRMS (ESIꢀTOF) m/z: [M+Na] calcd for C H N NaO 329.2568; found
1
9
34
2
329.2559.
Alternative general method of preparation of 3,5-dialkylpyrazoles. 3,5ꢀDialkylꢀ1ꢀ
tetrahydropyranꢀ2ꢀyl)pyrazoles are deprotected as described above (e), using 8 mL ethanol and
mL HCl (37% in H O) per mmol of substrate for 8 hours. After removal of the solvent,
(
2
2
addition of 0.4 ml H O, neutralization and extraction with 3 × 6 mL diethyl ether (per mmol
2
substrate), followed by drying with MgSO and removal of the solvent in high vacuum, pure
4
1
13
products are obtained (based on H NMR, C NMR and ESIꢀMS).
3(5)-butyl-5(3)-hexylpyrazole. Yield: 1.061 g (99% based on 3(5)ꢀbutylꢀ5(3)ꢀhexylꢀ1ꢀTHPꢀ
1
pyrazole). HꢀNMR (400MHz, CDCl ): 5.83 (s, 1H, 4ꢀHꢀpz), 2.56–2.60 (m, 4H, CH (CH ) CH
3
2
2 4
3
and CH (CH ) CH ), 1.56–1.65 (m, 4H, CH CH (CH ) CH and CH CH CH CH ), 1.26–1.41
2
2 2
3
2
2
2 3
3
2
2
2
3
2
(m, 8H, (CH ) (CH ) CH and (CH ) CH CH ), 0.91 (t, 3H, J = 7.60 Hz (CH ) CH ), 0.86 (t,
2
2
2 3
3
2 2
2
3
2 3
3
2
13
3
2
2
H, J = 6.8 Hz (CH ) CH ). CꢀNMR (101 MHz, CDCl ): 149.5, 102.1, 31.7, 31.6, 29.4, 29.1,
2 5 3 3
+
7.2, 26.8, 22.7, 22.5, 14.1 and 13.9. HRMS (ESIꢀTOF) m/z: [M+H] calcd for C H N
2
1
3
25
09.2017; found 209.2023.
3(5)-butyl-5(3)-heptylpyrazole. Yield: 2.133 g (94% based on 3(5)ꢀbutylꢀ5(3)ꢀheptylꢀ1ꢀTHPꢀ
1
pyrazole). HꢀNMR (400MHz, CDCl ): 5.84 (s, 1H, 4ꢀHꢀpz), 2.55–2.60 (m, 4H, CH (CH ) CH
3
2
2 5
3
and CH (CH ) CH ), 1.56–1.65 (m, 4H, CH CH (CH ) CH and CH CH CH CH ), 1.26–1.42
2
2 2
3
2
2
2 3
3
2
2
2
3
2
(m, 10H, (CH ) (CH ) CH and (CH ) CH CH ), 0.91 (t, 3H, J = 7.20 Hz (CH ) CH ), 0.86 (t,
2 2 2 4 3 2 2 2 3 2 3 3
2
13
3H, J = 6.8 Hz (CH ) CH ). CꢀNMR (101 MHz, CDCl ): 149.4, 102.0, 31.9, 31.6, 29.5, 29.4,
2
5
3
3
+
2
9.2, 27.2, 26.9, 22.7, 22.5, 14.2 and 13.9. HRMS (ESIꢀTOF) m/z: [M+H] calcd for C H N
14 27 2
223.2174; found 223.2197.
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Computational method. The computations of resonance energies were performed with the
general blockꢀlocalized wavefunction (BLW) method, which is the simplest variant of ab initio
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valence bond (VB) theory.
In the BLW method, each blockꢀlocalized orbital is expanded only
in a subgroup of basis functions and orbitals of different blocks are nonꢀorthogonal, and the wave
function is expressed with a Slater determinant composed of doubly occupied orbitals.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1
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1
1
1
0.1021/xxxxxx. H, C and H− H COSY NMR spectra of all new compounds, computational
data (PDF).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: gellert.mezei@wmich.edu; yirong.mo@wmich.edu.
ACKNOWLEDGMENTS
G. M. acknowledges the support of the U. S. National Science Foundation under Grant No.
CHEꢀ1404730. H. Z. acknowledges the financial support from the China Scholarship Council
(CSC).
REFERENCES
1) (a) Keter, F. K.; Darkwa, J. Biometals 2012, 25, 9−21. (b) Schmidt, A.; Dreger, A. Curr. Org.
Chem. 2011, 15, 1423−1463.
. (a) Miras, H. N.; Chakraborty, I.; Raptis, R. G. Chem. Commun. 2010, 46, 2569–2571. (b) Li,
H.ꢀX.; Wu, H.ꢀZ.; Zhang, W.ꢀH.; Ren, Z.ꢀG.; Zhang, Y.; Lang J.ꢀP. Chem. Commun. 2007,
052–5054. (c) Puerta, D. T.; Cohen, S. M. Chem. Commun. 2003, 1278–1279. (d) Ardizzoia, G.
(
2
5
A.; Angaroni, M. A.; La Monica, G.; Cariati, F.; Cenini, S.; Moret, M.; Masciocchi, N. Inorg.
Chem. 1991, 30, 4347−4353.
3. (a) Sato, H.; Miya, L.; Mitsumoto, K.; Matsumoto, T.; Shiga, T.; Newton, G. N.; Oshio, H.
Inorg. Chem. 2013, 52, 9714−9716. (b) Newton, G. N.; Onuki, T.; Shiga, T.; Noguchi, M.;
Matsumoto, T.; Mathieson, J. S.; Nihei, M.; Nakano, M.; Cronin, L.; Oshio, H. Angew. Chem.
Int. Ed. 2011, 50, 4844–4848.
1
1
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The Journal of Organic Chemistry
Page 12 of 13
1
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5
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7
8
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1
1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
. (a) Stasch, A. Angew. Chem. Int. Ed. 2014, 53, 1338 –1341. (b) Song, H.ꢀB.; Xu, G.ꢀF.; Qiao,
X.; Yan, S.ꢀP.; Liao, D.ꢀZ.; Journaux, Y.; Cano, J. Chem. Commun. 2012, 48, 1015–1017. (c)
Baran, P.; Boča, R.; Chakraborty, I.; Giapintzakis, J.; Herchel, R.; Huang, Q.; McGrady, J. E.;
Raptis, R. G.; Sanakis, Y.; Simopoulos, A. Inorg. Chem. 2008, 47, 645−655. (d) Xu, J.ꢀY.; Xu,
J.ꢀY.; Qiao, X.; Song, H.ꢀB.; Yan, S.ꢀP.; Liao, D.ꢀZ.; Gao, S.; Journaux, Y.; Cano, J. Chem.
Commun. 2008, 6414–6416.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5. (a) Mezei, G. Chem. Commun. 2015, 51, 10341−10344. (b) Grzywa, M.; Bredenkötter, B.;
Denysenko, D.; Spirkl, S.; Nitek, W.; Volkmer, D. Z. Anorg. Allg. Chem. 2013, 639, 1461–1471.
(c) Fernando, I. R.; Surmann, S. A.; Urech, A. A.; Poulsen, A. M.; Mezei, G. Chem. Commun.
2012, 48, 6860–6862. (d) Duriska, M. B.; Neville, S. M.; Lu, J.; Iremonger, S. S.; Boas, J. F.;
Kepert, C. J.; Batten, S. R. Angew. Chem. Int. Ed. 2009, 48, 8919–8922.
6. (a) Cao, X.ꢀY.; Hubbard, J. W.; GuerreroꢀMedina, J.; HernándezꢀMaldonado, A. J.;
Mathivathanan, L.; Rinaldi, C; Sanakis, Y.; Raptis, R. G. Dalton Trans. 2015, 44, 3399–3409. (b)
Herm, Z. R.; Wiers, B. M.; Mason, J. A.; van Baten, J. M.; Hudson, M. R.; Zajdel, P.; Brown, C.
M.; Masciocchi, N.; Krishna, R.; Long, J. R. Science 2013, 340, 960−964. (c) Padial, N. M.;
QuartapelleꢀProcopio, E.; Montoro, C.; López, E.; Oltra, J. E.; Colombo, V.; Maspero, A.;
Masciocchi, N.; Galli, S.; Senkovska, I.; Kaskel, S.; Barea, E.; Navarro, J. A. R. Angew. Chem.
Int. Ed. 2013, 52, 8290–8294. (d) Montoro, C.; Linares, F.; QuartapelleꢀProcopio, E.; Senkovska,
I.; Kaskel, S.; Galli, S; Masciocchi, N.; Barea, E.; Navarro, J. A. R. J. Am. Chem. Soc. 2011, 133,
11888–11891. (e) Colombo, V.; Galli, S.; Choi, H. J.; Han, G. D.; Maspero, A.; Palmisano, G.;
Masciocchi, N; Long, J. R. Chem. Sci. 2011, 2, 1311–1319. (f) Zhang, J.ꢀP.; Kitagawa, S. J. Am.
Chem. Soc. 2008, 130, 907–917. (g) Choi, H. J.; Dincă, M.; Long, J. R. J. Am. Chem. Soc. 2008,
130, 7848–7850. (h) Zhang, J.ꢀP.; Horike, S.; Kitagawa, S. Angew. Chem. Int. Ed. 2007, 46,
889–892.
7. Mo, Y.; Ahmed, B. M.; Guan, L.; Karty, J.; Mezei, G. Org. Lett. 2014, 16, 4680−4683.
. (a) Roy, S.; Roy, S.; Gribble, G. W. Top. Heterocycl. Chem. 2012, 29, 155–260. (b) Takeuchi,
8
Y.; Yeh, H. J. C.; Kirk, K. L.; Cohen, L. A. J. Org. Chem. 1978, 43, 3565−3570. (c) Takeuchi,
Y.; Kirk, K. L.; Cohen, L. A. J. Org. Chem. 1978, 43, 3570−3578.
9
. Mo, Y. Nat. Chem. 2010, 2, 666−671.
10. Wu, W.; Su, P.; Shaik, S.; Hiberty, P. C. Chem. Rev. 2011, 111, 7557−7593.
1. Mo, Y.; Song, L.; Lin, Y. J. Phys. Chem. A 2007, 111, 8291−8301.
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2. Song, L.; Chen, Z.; Ying, F.; Song, J.; Chen, X.; Su, P.; Mo, Y.; Zhang, Q.; Wu, W. XMVB
.0: An ab initio Nonꢀorthogonal Valence Bond Program (Xiamen University, Xiamen 361005,
2
China, 2012).
1
3. (a) Snieckus, V. Chem. Rev. 1990, 90, 879−933. (b) Snieckus, V. Pure & Appl. Chem. 1990,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
2, 2047−2056. (c) MartínezꢀMartínez, A. J.; Kennedy, A. R.; Mulvey, R. E.; O’Hara, C. T.
Science 2014, 346, 834−837.
14. Velankar, A. D.; Quintini, G.; Prabhu, A.; Weber, A.; Hunaeus, G.; Voland, B.; Wuest, M.;
Orjeda, C.; Harel, D.; Varghese, S.; Gore, V.; Patil, M.; Gayke, D.; Herdemann, M.; Heit, I.;
Zaliani, A. Bioorg. Med. Chem. 2010, 18, 4547–4559.
15. McLaughlin, M.; Marcantonio, K.; Chen, C.ꢀY.; Davies, I. W. J. Org. Chem. 2008, 73,
4309–4312.
16. Ahmed, B. M.; Mezei, G. RSC Adv. 2015, 5, 24081–24093.
17. Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009, 131, 3042–3048.
18. (a) He, Y.; Chen, Y.; Du, H.; Schmid, L. A.; Lovely, C. J. Tetrahedron Lett. 2004, 45, 5529–
5532. (b) Bhagavatula, L.; Premchandran, R. H.; Plata, D. J.; King, S. A.; Morton, H. E.
Heterocycles, 2000, 53, 729−732.
19. Anderson, C. B.; Sepp, D. T. J. Org. Chem. 1967, 32, 607−611.
20. (a) Hüttel, R.; Schäfer, O.; Jochum, P. Justus Liebigs Ann. Chem. 1955, 593, 200−207. (b)
Vaughan, J. D.; Lambert, D. G.; Vaughan, V. L. J. Am. Chem. Soc. 1964, 86, 2857–2861.
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