Metal-free, Mild, and Selective Synthesis of Bis(pyrazolyl)alkanes by Nucleophile-Catalyzed Condensation

Article abstract of DOI:10.1021/acs.joc.0c02442

Bis(pyrazolyl)alkanes are a prolific class of ligands for catalysis, accessible by the condensation between bis(pyrazolyl)methanones and carbonyls. In this report, we describe a nucleophile-catalyzed innovation on this condensation that avoids the transition metals, high temperatures, reagent excess, and air-sensitive reagents common among the existing protocols. Significantly, this method accommodates sterically hindered and electronically diverse pyrazoles and aldehydes, applicable for systematic ligand optimization. Furthermore, our scope includes azoles and bridging functional groups previously unreported for this reaction, promising for new heteroscorpionate catalysts. We provide the first direct evidence for an elusive reaction intermediate and characterize the most complete mechanism for this condensation.

Full text of DOI:10.1021/acs.joc.0c02442

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Article
Metal-free, Mild, and Selective Synthesis of Bis(pyrazolyl)alkanes by
Nucleophile-Catalyzed Condensation
Maxym Tansky, Zipeng Gu, and Robert J. Comito*
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ABSTRACT: Bis(pyrazolyl)alkanes are a prolific class of ligands
for catalysis, accessible by the condensation between
bis(pyrazolyl)methanones and carbonyls. In this report, we
describe a nucleophile-catalyzed innovation on this condensation
that avoids the transition metals, high temperatures, reagent excess,
and air-sensitive reagents common among the existing protocols.
Significantly, this method accommodates sterically hindered and
electronically diverse pyrazoles and aldehydes, applicable for
systematic ligand optimization. Furthermore, our scope includes
azoles and bridging functional groups previously unreported for
this reaction, promising for new heteroscorpionate catalysts. We
provide the first direct evidence for an elusive reaction
intermediate and characterize the most complete mechanism for
this condensation.
moderate yields from a 1:1 ratio of bis(pyrazolyl)methanone
and carbonyl.13 Alternatively, other contributors reported the
in situ preparation and stoichiometric reaction of air-sensitive
sulfinyldipyrazoles with carbonyls in good yields.14 More
recently, the sulfinyldipyrazole-based protocol has been applied
to pyrazoles with 3-substituents larger than methyl.15 This
underexplored modification provides ligands with improved
steric tuning and site isolation, which seeks to avoid
deactivation by metal aggregation or homoleptic complex
formation. Also of ongoing interest, variation of the
coordinating groups’ basicity and geometry promises improved
electronic tuning within this ligand class. However, to our
knowledge, this condensation approach has not been applied
to heteroazoles other than pyrazoles and imidazoles.
Furthermore, the involvement of air-sensitive reagents and
intermediates, as well as residues of the transition-metal
catalyst in the product, remain practical disadvantages of the
existing condensation methods for bis(pyrazolyl)alkane syn-
thesis.
INTRODUCTION
■
Single-site metal−ligand complexes have revolutionized the
application and mechanistic understanding of organometallic
catalysis. Their primary role is to provide discrete kinetics and
structural modularity as the basis for the rational design,
analysis, and optimization of catalysts.1 In this effort, pyrazole-
based ligands are particularly useful because of the availability
of pyrazoles bearing sterically, functionally, and electronically
diverse substituents. In particular, bis(pyrazolyl)alkanes2 have
been fashioned into a diverse range of heteroscorpionate
ligands.3 Their transition4 and main group5 metal complexes
have been extensively studied as catalysts for a wide range of
reactions including ethylene trimerization,6 transfer hydro-
genation,7 and C−H amination (Scheme 1, top).8 Further-
more, their tripodal arrangement of weak field ligands
constitutes an enzyme-like coordination environment ideal
for biomimetic catalysis and modeling.9
Although simple bis(pyrazolyl)methane ligands are prepared
straightforwardly by nucleophilic substitution on dihaloal-
kanes,10 this strategy often fails for more elaborate
bis(pyrazolyl)alkanes because of either inefficient substitution
In this report, we describe a new method for the synthesis of
bis(pyrazolyl)alkanes based on the nucleophile-catalyzed
condensation between carbonyls and bis(pyrazolyl)-
́
or precursor synthesis. Addressing this limitation, The and
Peterson developed a metal-catalyzed condensation reaction
between carbonyls and either bis(pyrazolyl)methanones11 or
sulfinyldipyrazoles12 that deliver bis(pyrazolyl)alkanes substi-
tuted at the linking carbon (Scheme 1). Their method is atom-
economical and operationally simple, but requires an excess of
carbonyl substrate for high yields, restricting the synthesis to
ligands with simple bridging groups. Later, others showed that
solvent-free condensation gives simple bis(pyrazolyl)alkanes in
Received: October 14, 2020
https://dx.doi.org/10.1021/acs.joc.0c02442
© XXXX American Chemical Society
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A

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a
Scheme 1. Methods for Poly(pyrazolyl)alkane Synthesis
Table 1. Catalyst Evaluation and Optimization
b
loading
yield
entry
catalyst
(mol %)
solvent
THF
(%)
1
2
DMAP
DBU
10
10
10
10
10
10
10
10
89
80
85
85
76
72
63
54
31
38
59
28
54
23
52
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CHCl3
3
4
5
quinuclidine
potassium 2-pyridone
TBD
6
7
1-methylimidazole
DABCO
8
9
triphenylphosphine
none
10
11
12
13
14
15
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
5
20
10
10
10
10
acetonitrile
toluene
DMF
methanones (Scheme 1, bottom). The conditions are mild and
avoid both metal catalysts and air-sensitive reagents. We show
that this reaction accommodates both large 3-substituents on
the pyrazole and an electronically diverse set of heterocycles in
good to high yields using a 1:1 ratio of reagents. Finally, we
characterize a two-cycle catalytic mechanism involving a
carbamate intermediate, providing to our knowledge the
most complete mechanism proposed for carbonyl/
bis(pyrazolyl)methanone condensation.
a
Reactions were perfomed using 1:1 ratio of 1:2 at 0.5 mmol of 1 in 3
b
mL of anhydrous THF at 60 °C, unless noted otherwise. Yields
obtained by crude H NMR analysis with an internal standard.
1
(5) provided the highest yield of 3 (89%, entry 1).
Nevertheless, the neutral, nitrogen-based nucleophiles 1,8-
diazabicycloundec-7-ene (DBU) (6), quinuclidine, potassium
2-pyridone, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)
also performed well (entries 2−5), and we later found that
DBU was the optimal catalyst for certain substrates. Yield of 3
was higher at 10 mol % catalyst loading than at 5 or 20 mol %
(entries 10 and 11). Finally, higher yields were obtained in
THF than in any of the common solvents such as toluene,
acetonitrile, chloroform, and N,N-dimethylformamide at 60 °C
(entries 12−15).
Having identified effective catalytic conditions, we next
evaluated the synthesis of bis(azolyl)alkanes with 3-substituted
pyrazoles and other heterocycles by reaction with aldehyde 1
(Table 2). To our knowledge, bis(azolyl)alkanes have only
been prepared by condensation from pyrazoles, imidazole, and
benzimidazole.19 Promisingly, we could prepare all of the
corresponding bis(azolyl)methanone precursors in high yield
by acylation with triphosgene (Sections S1 and S2). Indeed,
both sterically hindered and unhindered pyrazoles react
successfully and in similar isolated yields (entries 1−6),
promising for the synthesis of sterically varied ligand libraries.
Among the other heterocycles, bis(azolyl)alkanes were
obtained in good yields not only with simple imidazole and
RESULTS AND DISCUSSION
■
́
Originally, The and Peterson had proposed a carbamate
intermediate formed through a metal-catalyzed acylation step
for their catalytic condensation (see below).16 Given the more
recent development of nucleophilic catalysis for acylation,17 we
speculated that a related metal-free method would be possible
using common nucleophiles instead. Along these lines, we
evaluated catalytic quantities of common Lewis bases and acids
to promote the 1:1 condensation of salicylaldehyde (1) and
bis(3,5-dimethylpyrazol-1-yl)methanone (2) in toluene at 110
°C (Table S4.1). Under these conditions, in the absence of the
catalyst, 3 was the minor product (27% yield, entry 1) and
carbamate 4 was the major product (33% yield).18 In contrast,
several nucleophilic catalysts considerably improved the yield
of 3 and selectivity over 4 (Table S4.1, entries 2−8), while the
use of catalytic acids all resulted in lower yields compared with
the catalyst-free control (entries 9−12).
We next evaluated several common solvents near their
boiling point, ultimately identifying dry tetrahydrofuran
(THF) at 60 °C as optimal. Under these conditions (Table
1), we found that 4-(N,N-dimethylamino)pyridine (DMAP)
B
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a
We next evaluated the aldehyde scope of the nucleophile-
catalyzed condensation using 2 as methanone. Under these
conditions, we obtained moderate to good yields of the
bis(pyrazolyl)alkane product for a range of phenyl, heteroaryl,
and alkyl aldehydes (Table 3). The series of para-substituted
benzaldehydes demonstrated the effectiveness of this method
within a wide electronic range (entries 1−6). Similarly, we
successfully prepared heteroscorpionate ligands with a range of
coordinating groups using heteroaryl and 2-
(diphenylphosphino)phenyl aldehydes, albeit in reduced yields
Table 2. Azole Scope under Catalytic Conditions
a
Table 3. Aldehyde Scope of Catalytic Condensation
a
b
Yields were obtained by isolation. Performed with 10 mol % DBU.
c
d
Performed with no catalyst. Performed with 10 mol % DMAP.
benzimidazole (entries 7 and 9) but also with 1,2,4-triazole and
2-methylimidazole (entries 8 & 10), heterocycles previously
unreported for this reaction. The reaction with imidazole
(entry 7) was scaled up to 10 mmol, resulting in an isolated
yield of 80% after workup by simple filtration. The
unsubstituted products are promising precursors for polytopic
N-heterocyclic carbene ligands,20 while the 2-substituted
imidazoles highlight the success of this method toward
sterically hindered substrates. In contrast, condensation with
pyrrole- or indole-based precursors did not result in
bis(pyrrolyl)alkanes. Presumably, nucleophilic catalysis re-
quires a good pKa match between the azolide leaving group
and the nucleophile, as has been well studied for nucleophile-
catalyzed acylation.21 Notably, catalyst omission experiments
show clear and consistent decreases in yields without the
nucleophile for all of the azoles evaluated, confirming DMAP’s
role in the reaction.
a
b
All yields were obtained by isolation. Performed with 10 mol %
c
DMAP as the catalyst. Performed with 10 mol % DBU.
d
Bis(pyrazolyl)methanone was used instead of bis(3,5-
e
f
dimethylpyrazolyl)methanone. Performed with no catalyst. Per-
formed at 22 °C with TBD as the catalyst.
C
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Scheme 2. (A) Intermediate Resubmission Experiment; (B) Crossover Experiment; (C) Carbamate Intermediate Proposed by
16
́
The and Peterson; (D) Proposed Bicyclic Mechanism for Nucleophile-Catalyzed Condensation of 1 and 2
for sterically hindered and electron-rich aldehydes (entries 7, 8,
9, 11, and 12). Furthermore, the protocol provides
bis(pyrazolyl)alkanes bearing vinyl, primary alkyl, secondary
alkyl, and tertiary alkyl substituents at the bridging carbon
(entries 10 and 13−16), providing an additional handle for
steric tuning and postsynthetic elaboration. For all of these
substrates, 5 or 6 were optimal as catalysts. In contrast,
although 2-formylpyridine was amenable to catalysis, we still
obtained the highest yield with this substrate without the
nucleophile in near-boiling toluene.
Fortuitously, under nucleophilic catalysis at ambient
temperature with 2-formylpyridine, we obtained carbamate 9
as the major product in good yield (Table 3, entry 16). This
product directly resembles the reaction intermediate 10
experiments between benzaldehyde and various 4-substituted
benzaldehydes, we obtained a Hammett ρ value of +2.04
(Section S5) consistent with a selectivity-determining reaction
of aldehyde with a nucleophile.
Based on these data, we propose a bicyclic catalytic
mechanism linked by this carbamate intermediate (Scheme
2D). First, the addition of nucleophile 5 into bis(pyrazolyl)-
methanone 7 generates ion pair 12 consisting of the acylated
catalyst and pyrazolate, consistent with our crossover results.
Then, selectivity-determining nucleophilic addition of the
pyrazolate into aldehyde 13, consistent with our Hammett
analysis, would generate ion pair 14. Then, acyl transfer would
regenerate 5 and furnish carbamate 16. In the second cycle,
nucleophilic addition into 16 would generate ion pair 17.
Nucleophilic addition along with loss of CO2 would then
regenerate catalyst 5 and furnish the product.
Interestingly, analogous results but lower yields were
obtained by these experiments in the absence of the catalyst:
9 was converted to 8 in 25% yield, 11 was formed from 2 and 7
in 33% yield, and a Hammett ρ value of +1.48 was obtained
under identical conditions without the nucleophile. We
interpret these results as evidence for an uncatalyzed
background reaction by a similar mechanism, albeit in reduced
selectivity and efficiency. Nevertheless, the fact that the catalyst
improves the yield and selectivity not only on the overall
reaction but also in both of these mechanistic experiments
supports our claim of catalyst involvement in both the
generation and conversion of carbamate 15.
́
(Scheme 2C), proposed but not isolated by The and
Peterson.16 We did not find any analogous carbamate from a
substructure search in SciFinder or Reaxys, however, and this
key finding formed the basis of our mechanistic analysis of this
reaction.
To confirm the role of this carbamate as an intermediate and
not a byproduct, we first submitted 9 to a range of nucleophiles
in THF at 60 °C (Scheme 2A). Indeed, carbamate 9 was
converted to bis(pyrazolyl)alkane 8 in 43% yield with
quinuclidine as the catalyst. Next, we sought to confirm
whether the nucleophile adds reversibly to the bis(pyrazolyl)-
methanone substrate as the first step in a nucleophile-catalyzed
acylation mechanism. Because crossover between labeled
bis(pyrazolyl)methanones would be predicted by this mecha-
nism, we submitted 2 and 7 to nucleophilic catalysis with 10
mol % DMAP in THF at 60 °C. Consistently, after 5 h, we
observed a statistical mixture of 2, 7, and crossover product 11
(Scheme 2B). Finally, we studied this reaction by Hammett
analysis to distinguish between a charge-building aldehyde-
activation step involving nucleophilic addition into the
carbonyl and a charge-depleting step involving electrophilic
acyl transfer. After performing a series of competition
CONCLUSIONS
■
In summary, our nucleophile-catalyzed condensation of
bis(azolyl)methanones and aldehydes provides a wide range
of bis(azolyl)alkanes in good to high yields. The method avoids
air-sensitive reagents, metal catalysts, reagent excess, and high
reaction temperatures. Sterically hindered azole and aldehyde
components both react efficiently, providing a modular handle
D
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stirring. This yellow solution was stirred for 2 h, and then ethanol was
removed using a rotary evaporator. The leftover residue was extracted
three times with dichloromethane. The combined organic layer was
washed twice with brine, dried over Na2SO4, filtered, and
concentrated in vacuo to give a red oil which crystallized upon
standing. The crude product was recrystallized from boiling toluene to
give an orange solid which was collected by vacuum filtration and
washed with cold toluene until the orange color disappears, leaving
for steric modification of metal−ligand complexes. Likewise,
nucleophilic condensation accommodates aldehydes and azoles
of varying electronics, from electron-rich to electron-poor.
These substrates are directly applicable to the synthesis of
polytopic N-heterocyclic carbenes and complex heteroscorpi-
onate ligands. We anticipate that this method will enable the
synthesis of more elaborate heteroscorpionate ligands for
catalysis, featuring more readily tailored substitution, geometry,
and electronics for catalyst fine-tuning.
1
behind the product as white crystals (2.49 g, 51% yield). H NMR
(400 MHz, CDCl3): δ 7.63 (s, 1H), 6.92 (s, 2H), 6.20 (s, 1H), 2.31
(s, 3H), 2.07 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 143.7,
1
138.4, 138.0, 136.8, 128.2, 128.1, 105.9, 21.2, 20.4. Our H and 13C
EXPERIMENTAL SECTION
NMR are consistent with those reported for this compound.28
General Procedure for Bis(pyrazolyl)methanones. An oven-
dried Schlenk flask was charged with pyrazole, anhydrous THF, and
triethylamine under nitrogen. The solution was allowed to stir for 30
min and then cooled to 0 °C. Triphosgene as a solution in anhydrous
THF was added dropwise over 10 min. The resulting pale-yellow and
inhomogeneous suspension was allowed to warm to room temper-
ature and stir for 4 h. The reaction was then filtered, the solids were
washed with THF, and the combined filtrate and washings were
concentrated in vacuo to yield a pale yellow solid which was purified
by recrystallization from the appropriate solvent or by column
chromatography. The bis(pyrazolyl)methanones slowly hydrolyze in air
and should be stored cold or in a desiccator.
■
General Information. Commercial reagents were purified prior
to use following the guidelines of Perrin and Armarego.22 All solvents
were purified according to the method of Grubbs.23 Organic solutions
were concentrated under reduced pressure on a Buchi rotary
̈
evaporator. Chromatographic purification of products was accom-
plished using force-flow chromatography on VWR silica gel according
to the method of Still.24 Thin-layer chromatography was performed
on Merck 250 μm silica gel plates. Compounds were visualized by
irradiation with UV light, treatment with a solution of potassium
permanganate followed by heating, or exposure to iodine. Yields refer
to pure compounds, unless otherwise indicated.
1H NMR and 13C NMR spectra were recorded on a JEOL (400
MHz) spectrometer and are internally referenced relative to residual
protio solvent signals (CDCl3) at δ 7.27 ppm (1H) or DMSO-d6 at δ
Bis(pyrazol-1-yl)methanone. It was prepared by the general
procedure with pyrazole (1.38 g, 20.2 mmol, 6 equiv), triethylamine
(3.1 mL, 22 mmol, 6.5 equiv), triphosgene (1.0 g, 3.4 mmol, 1 equiv),
and THF (75 mL). The crude product was recrystallized from
dichloromethane/hexanes by first dissolving the crude product in
boiling dichloromethane and then slowly adding boiling hexanes until
the solution turns turbid, followed by a minimal amount of boiling
dichloromethane until the solution just turns clear. After storage at
−20 °C overnight, the product was isolated as a white solid (1.27 g,
77% yield). 1H NMR (400 MHz, CDCl3): δ 8.69 (d, J = 2.7 Hz, 2H),
7.87 (s, 2H), 6.52 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ
145.5, 144.6, 134.2, 110.0. Our 1H and 13C NMR are consistent with
those reported for this compound.29
1
2.50 ppm (1H). Data for H NMR are reported as follows: chemical
shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, h = heptet, m = multiplet, and ap = apparent), integration,
and coupling constant (Hz). 13C spectra are referenced relative to
CDCl3 at δ 77.16 ppm or DMSO-d6 at δ 39.52 ppm. Data for 13C
NMR are reported in terms of chemical shift and multiplicity where
appropriate. IR spectra were recorded on a Thermo Fisher Nicolet
iS10 spectrometer with a Smart iTR diamond plate and are reported
in terms of wavenumber of absorption (cm−1). High-resolution mass
spectra were obtained from The University of Texas at Austin’s Mass
Spectrometry Facility.
Synthesis of Pyrazoles. 3,5-Diethyl-1H-pyrazole. 3,5-Heptane-
dione (1.35 mL, 10.0 mmol, 1.0 equiv) was mixed with 10 mL of
ethanol in a 50 mL round bottom flask, and hydrazine monohydrate
(0.58 mL, 12 mmol, 1.2 equiv) was added to it at room temperature.
After stirring overnight, all volatiles were removed under vacuum,
Bis(3,5-dimethylpyrazol-1-yl)methanone (2). It was prepared by
the general procedure with 3,5-dimethylpyrazole (19.4 g, 202 mmol, 6
equiv), triethylamine (30.5 mL, 219 mmol, 6.5 equiv), triphosgene
(10 g, 34 mmol, 1 equiv), and THF (300 mL). The crude product
was recrystallized from dichloromethane/hexanes by first dissolving
the crude product in boiling dichloromethane and then slowly adding
boiling hexanes until the solution turns turbid, followed by a minimal
amount of boiling dichloromethane until the solution just turns clear.
After storage at −20 °C overnight, the product was isolated as an ecru
1
giving the desired product as a yellow solid (1.16 g, 93% yield). H
NMR (400 MHz, CDCl3): δ 11.68 (s, 1H), 5.89 (s, 1H), 2.67 (q, J =
7.6 Hz, 4H), 1.26 (t, J = 7.8 Hz, 6H). 13C{1H} NMR (101 MHz,
CDCl3): δ 150.5, 100.7, 20.4, 13.8. Our 1H and 13C NMR are
consistent with those reported for this compound.25
1
solid (19.12 g, 86% yield). H NMR (400 MHz, CDCl3): δ 6.03 (s,
3-Isopropyl-1H-pyrazole. It was prepared according to a reported
2H), 2.46 (s, 6H), 2.26 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3):
literature procedure.26
1
δ 153.1, 148.0, 145.5, 111.5, 14.1, 13.2. Our H and 13C NMR are
3-tert-Butyl-1H-pyrazole. It was prepared according to a reported
literature procedure.27
consistent with those reported for this compound.29
Bis(3,5-diethylpyrazol-1-yl)methanone. It was prepared by the
general procedure with 3,5-diethylpyrazole (1.16 g, 9.33 mmol, 6
equiv), triethylamine (1.41 mL, 10.1 mmol, 6.5 equiv), triphosgene
(0.460 g, 1.55 mmol, 1.0 equiv), and THF (50 mL). The crude
product was recrystallized from hexanes to give a brown solid (1.20 g,
94% yield). 1H NMR (400 MHz, CDCl3): δ 6.06 (s, 1H), 2.80 (q, J =
7.4 Hz, 2H), 2.58 (q, J = 7.6 Hz, 2H), 1.14−1.21 (m, 6H). 13C{1H}
NMR (101 MHz, CDCl3): δ 158.3, 151.5, 148.2, 107.9, 21.7, 20.5,
13.2, 12.7. HRMS (ESI-TOF) m/z: [M + H]+, calcd for C15H23N4O,
275.1866; found, 275.1868, difference −0.75 ppm.
3-Mesityl-1H-pyrazole. It was prepared by a modification to a
reported literature procedure.28 Potassium tert-butoxide (4.38 g, 39.1
mmol, 1.3 equiv) was added in one portion to a stirring solution of
2′,4′,6′-trimethylacetophenone (5.0 mL, 30 mmol, 1 equiv), ethyl
formate (7.3 mL, 90 mmol, 3 equiv), and toluene (40 mL). Following
a brief and mild exothermic reaction, the initially homogenous
reaction became a yellow suspension. This mixture was stirred for
another hour at room temperature and then partitioned between ethyl
acetate and water, stirring until two homogeneous phases were
observed. The mixture was acidified to pH 4 by the addition of acetic
acid followed by extraction with ethyl acetate two times. The
combined organic layer was washed with saturated aqueous NaHCO3,
and the resultant aqueous layer was extracted once more with ethyl
acetate. The combined organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo to give the
intermediate mesityl α-hydroxymethyleneacetone as a yellow oil.
The crude intermediate was dissolved in ethanol (40 mL), and then,
hydrazine monohydrate (9.0 mL, 190 mmol) was added while
Bis(3-isopropylpyrazol-1-yl)methanone. It was prepared by the
general procedure with 3-isopropylpyrazole (2.23 g, 20.2 mmol, 6
equiv), triethylamine (3.1 mL, 22 mmol, 6.5 equiv), triphosgene (1.0
g, 3.4 mmol, 1 equiv), and THF (50 mL). The crude product was
purified by flash chromatography on silica using 8:1 hexanes/ethyl
1
acetate to give a colorless oil (2.44 g, 98%). H NMR (400 MHz,
CDCl3): δ 8.67 (s, 2H), 6.36 (s, 2H), 3.03−3.13 (m, 2H), 1.29 (d, J =
6.7 Hz, 12H). 13C{1H} NMR (101 MHz, CDCl3): δ 164.9, 134.8,
E
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1
107.8, 28.2, 22.7, 22.1. Our H and 13C NMR are consistent with
2-Bis(3,5-dimethylpyrazol-1-yl)methylphenol (3). The product
was prepared according to the general procedure with salicylaldehyde
(1, 0.104 mL, 1.00 mmol, 1.0 equiv), bis(3,5-dimethylpyrazol-1-
yl)methanone (2, 218 mg, 1.00 mmol, 1.0 equiv), DMAP (12.2 mg,
0.10 mmol, 0.1 equiv), and THF (3 mL). Volatiles were removed in
vacuo, and then, the remaining residue was purified by flash
chromatography on silica using 3:1 hexanes/ethyl acetate to obtain
those reported for this compound.30
Bis(3-tert-butylpyrazol-1-yl)methanone. It was prepared by the
general procedure with pyrazole (2.51 g, 20.1 mmol, 6 equiv),
triethylamine (3.1 mL, 22 mmol, 6.5 equiv), triphosgene (1.0 g, 3.4
mmol, 1 equiv), and THF (50 mL). The crude product was
recrystallized by dissolving in boiling hexanes and then storing at −20
°C overnight to obtain the product as an ecru solid (2.01 g, 73%). 1H
NMR (400 MHz, CDCl3): δ 8.68 (d, J = 2.7 Hz, 2H), 6.40 (d, J = 2.5
Hz, 2H), 1.35 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 167.5,
144.7, 134.7, 107.5, 30.5, 29.9. HRMS (ESI-TOF) m/z: [M + H]+,
calcd for C15H23N4O, 275.1866; found, 275.1868, difference −0.53
ppm.
1
the product as a white solid (251 mg, 85% yield). H NMR (400
MHz, DMSO-d6): δ 9.86 (s, 1H), 7.58 (s, 1H), 7.18 (t, J = 7.5 Hz,
1H), 6.83 (t, J = 9.0 Hz, 2H), 6.76 (t, J = 7.5 Hz, 1H), 5.87 (s, 2H),
2.07 (s, 6H), 2.04 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ
154.5, 146.3, 139.4, 129.7, 128.7, 122.8, 118.7, 115.1, 106.1, 68.4,
1
13.5, 10.8. Our H and 13C NMR are consistent with those reported
for this compound.29
Bis(3-phenylpyrazol-1-yl)methanone. It was prepared by the
general procedure with 3-phenylpyrazole (2.91 g, 20.2 mmol, 6
equiv), triethylamine (3.1 mL, 22 mmol, 6.5 equiv), triphosgene (1.0
g, 3.4 mmol, 1 equiv), and THF (100 mL). The crude product was
recrystallized by dissolving in boiling THF and then storing at −20 °C
2-Bis(pyrazol-1-yl)methylphenol (Table 2, Entry 1). The product
was prepared according to the general procedure with salicylaldehyde
(0.104 mL, 1.00 mmol, 1.0 equiv), bis(pyrazol-1-yl)methanone (162
mg, 1.00 mmol, 1.0 equiv), DBU (15.2 μL, 0.100 mmol, 0.1 equiv),
and THF (3 mL). Volatiles were removed in vacuo, and then, the
remaining residue was purified by flash chromatography on silica
using 3:1 hexanes/ethyl acetate to obtain the product as a white solid
1
overnight to obtain the product as a white solid (2.36 g, 74%). H
NMR (400 MHz, CDCl3): δ 8.89 (d, J = 1.4 Hz, 2H), 7.95 (d, J = 7.5
Hz, 4H), 7.41−7.49 (m, 6H), 6.89 (d, J = 1.4 Hz, 2H). 13C{1H}
NMR (101 MHz, CDCl3): δ 156.8, 144.5, 135.7, 131.3, 129.8, 129.0,
126.8, 107.9. Our 1H and 13C NMR are consistent with those
reported for this compound.31
Bis(3-mesitylpyrazol-1-yl)methanone. It was prepared by the
general procedure with 3-mesitylpyrazole (1.36 g, 7.30 mmol, 6
equiv), triethylamine (1.1 mL, 7.9 mmol, 6.5 equiv), triphosgene
(0.36 g, 1.2 mmol, 1 equiv), and THF (20 mL). The crude product
was purified by flash chromatography on silica using 4:1 hexanes/
ethyl acetate to give a white solid (1.16 g, 80%). 1H NMR (400 MHz,
CDCl3): δ 8.90 (d, J = 2.7 Hz, 2H), 6.94 (s, 4H), 6.45 (d, J = 2.5 Hz,
2H), 2.32 (s, 6H), 2.16 (s, 12H). 13C{1H} NMR (101 MHz, CDCl3):
δ 157.0, 144.5, 138.6, 137.3, 134.9, 129.0, 128.4, 111.9, 21.3, 20.6.
HRMS (ESI-TOF) m/z: [M + H]+, calcd for C25H27N4O, 399.2179;
found, 399.2181, difference −0.50 ppm.
1
(184 mg, 77% yield). H NMR (400 MHz, DMSO-d6): δ 10.07 (s,
1H), 7.96 (s, 1H), 7.67 (s, 2H), 7.56 (s, 2H), 7.24 (t, J = 7.6 Hz, 1H),
6.89 (t, J = 8.3 Hz, 2H), 6.80 (t, J = 7.5 Hz, 1H), 6.32 (s, 2H).
13C{1H} NMR (100 MHz, DMSO-d6): δ 154.7, 139.9, 130.4, 129.9,
1
127.8, 122.6, 118.9, 115.5, 105.8, 72.3. Our H and 13C NMR are
consistent with those reported for this compound.33
2-Bis(3,5-diethylpyrazol-1-yl)methylphenol (Table 2, Entry 2).
The product was prepared according to the general procedure with
salicylaldehyde (0.104 mL, 1.00 mmol, 1.0 equiv), bis(3,5-
diethylpyrazol-1-yl)methanone (274 mg, 1.00 mmol, 1.0 equiv),
DBU (15.2 μL, 0.100 mmol, 0.1 equiv), and THF (3 mL). Volatiles
were removed in vacuo, and then, the remaining residue was purified
by flash chromatography using 10:1 hexanes/ethyl acetate to obtain
1
the product as a white solid (205 mg, 58% yield). H NMR (400
MHz, CDCl3): δ 10.31 (s, 1H), 7.51 (s, 1H), 7.06 (t, J = 7.2 Hz, 1H),
6.87 (d, J = 6.7 Hz, 1H), 6.68−6.80 (m, J = 7.8 Hz, 2H), 5.91 (s, 2H),
2.56 (q, J = 7.4 Hz, 4H), 2.46 (q, J = 7.2 Hz, 4H), 1.17 (t, J = 7.5 Hz,
6H), 1.10 (t, J = 7.3 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ
155.4, 154.0, 146.7, 130.3, 129.2, 122.5, 119.3, 117.8, 103.2, 72.4,
21.5, 18.8, 13.8, 12.6. HRMS (ESI-TOF) m/z: [M + Na]+, calcd for
C21H28N4ONa, 375.2155; found, 375.2155, difference 0.14 ppm.
2-Bis(3-isopropylpyrazol-1-yl)methylphenol (Table 2, Entry 3).
The product was prepared according to the general procedure with
salicylaldehyde (0.104 mL, 1.00 mmol, 1.0 equiv), bis(3-isopropylpyr-
azol-1-yl)methanone (246 mg, 1.00 mmol, 1.0 equiv), DMAP (12.2
mg, 0.10 mmol, 0.1 equiv), and THF (3 mL). Volatiles were removed
in vacuo, and then, the remaining residue was purified by flash
chromatography on silica using 9:1−6:1 hexanes/ethyl acetate to
General Procedure for Bis(imidazolyl)methanones. An oven-
dried Schlenk flask was charged with triphosgene and anhydrous THF
under nitrogen. The solution was then cooled to 0 °C, and a solution
of imidazole in anhydrous THF was added to it via a syringe. The
reaction mixture was stirred for 24 h, and white crystalline imidazole
hydrochloride was removed by filtration, and the filtrate was
concentrated down on a rotary evaporator, resulting in a white
powder.
Bis(benzimidazol-1-yl)methanone. It was prepared by the general
procedure with 1,3-benzodiazole (1.47 g, 12.5 mmol, 12.5 equiv),
triphosgene (0.30 g, 1.0 mmol, 1.0 equiv), and THF (50 mL). The
crude product was recrystallized from hexanes to give a white solid
1
(0.754 g, 96% yield). H NMR (400 MHz, CDCl3): δ 8.36 (s, 2H),
7.89 (d, J = 17.7 Hz, 4H), 7.49 (t, J = 3.1 Hz, 4H). 13C{1H} NMR
(101 MHz, CDCl3): δ 144.9, 144.0, 141.3, 131.9, 126.4, 126.0, 121.5,
1
obtain the product as a white solid (210 mg, 65% yield). H NMR
1
114.2. Our H and 13C NMR are consistent with those reported for
(400 MHz, CDCl3): δ 11.73 (s, 1H), 7.63 (s, 1H), 7.40 (s, 2H), 7.09
(t, J = 7.7 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.71−6.77 (m, 2H), 6.07
(s, 2H), 2.92−3.02 (m, 2H), 1.23 (d, J = 7.1 Hz, 12H). 13C{1H}
NMR (101 MHz, CDCl3): δ 160.3, 155.5, 131.5, 130.7, 130.4, 121.7,
119.8, 119.2, 103.1, 77.4, 27.8, 22.7. Our 1H and 13C NMR are
consistent with those reported for this compound.33
this compound.32
Bis(2-methylbenzimidazol-1-yl)methanone. It was prepared by
the general procedure with 2-methylbenzimidazole (1.65 g, 12.5
mmol, 12.5 equiv), triphosgene (0.30 g, 1.0 mmol, 1.0 equiv), and
THF (50 mL). The crude product was recrystallized from hexanes to
give a white solid (820 mg, 94% yield). 1H NMR (400 MHz, CDCl3):
δ 7.35 (d, J = 7.8 Hz, 2H), 6.92 (t, J = 7.7 Hz, 2H), 6.73 (t, J = 7.7 Hz,
2H), 6.31 (d, J = 8.2 Hz, 2H), 2.31 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3): δ 152.1, 146.9, 142.4, 132.3, 125.1, 125.0, 120.2,
112.2, 16.1. HRMS (ESI-TOF) m/z: [M + H]+, calcd for C17H15N4O,
291.1240; found, 291.1244, difference −1.38 ppm.
General Procedure for Nucleophile-Catalyzed Condensa-
tion. Bis(pyrazolyl)methanone or bis(imidazolyl)methanone was
dissolved in THF with the aldehyde and catalyst. The headspace of
the vial or flask was purged with nitrogen. The reaction mixture was
stirred at 60 °C using an aluminum block for 24 h. After cooling down
to room temperature, all volatiles were removed under vacuum and
the reactants were purified by flash chromatography or other
methods.
2-Bis(3-tert-butylpyrazol-1-yl)methylphenol (Table 2, Entry 4).
The product was prepared according to the general procedure with
salicylaldehyde (0.104 mL, 1.00 mmol, 1.0 equiv), bis(3-tert-
butylpyrazol-1-yl)methanone (274 mg, 1.00 mmol, 1.0 equiv),
DMAP (12.2 mg, 0.10 mmol, 0.1 equiv), and THF (3 mL). Volatiles
were removed in vacuo, and then, the remaining residue was purified
by flash chromatography on silica using 5−10% ethyl acetate in
hexanes to obtain the product as a white solid (249 mg, 71% yield).
1H NMR (400 MHz, CDCl3): δ 7.71 (s, 2H), 7.31−7.35 (m, 2H),
7.08 (d, J = 7.9 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.09 (s, 2H), 1.25
(s, 18H). 13C{1H} NMR (101 MHz, CDCl3): δ 163.1, 155.7, 131.3,
130.5, 130.1, 121.9, 119.5, 118.6, 102.6, 77.5, 77.2, 76.9, 32.3, 30.6.
1
Our H and 13C NMR are consistent with those reported for this
compound.33
F
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2-Bis(3-phenylpyrazol-1-yl)methylphenol (Table 2, Entry 5). The
product was prepared according to the general procedure with
salicylaldehyde (0.104 mL, 1.00 mmol, 1.0 equiv), bis(3-phenyl-
pyrazol-1-yl)methanone (314 mg, 1.00 mmol, 1.0 equiv), DMAP
(12.2 mg, 0.10 mmol, 0.1 equiv), and THF (3 mL). Volatiles were
removed in vacuo, and then, the remaining residue was purified by
flash chromatography on silica using 3:1 hexanes/ethyl acetate to
d6): δ 10.37 (s, 1H), 8.46 (s, 1H), 8.26 (s, 2H), 7.72 (d, J = 7.6 Hz,
2H), 7.32 (d, J = 7.6 Hz, 3H), 7.16−7.24 (m, 4H), 7.02 (d, J = 7.9
Hz, 1H), 6.83 (t, J = 7.5 Hz, 2H). 13C{1H} NMR (151 MHz, DMSO-
d6): δ 155.8, 144.2, 143.5, 143.3, 133.4, 131.9, 127.8, 123.8, 123.0,
120.6, 120.5, 119.8, 116.6, 111.3. Our 1H and 13C NMR are
consistent with those reported for this compound.35
2-Bis(2-methyl-benzimidazol-1-yl)methylphenol (Table 2, Entry
10). The product was prepared according to the general procedure
with salicylaldehyde (0.104 mL, 1.00 mmol, 1.0 equiv), bis(2-methyl-
benzimidazol-1-yl)methanone (262 mg, 1.00 mmol, 1.0 equiv), DBU
(15.2 μL, 0.100 mmol, 0.1 equiv), and THF (3 mL). The product was
recrystallized from cold acetone and hexane, resulting in a white solid
1
obtain the product as a white solid (299 mg, 76% yield). H NMR
(400 MHz, CDCl3): δ 11.88 (s, 1H), 7.74−7.77 (m, 6H), 7.62 (s,
1H), 7.37 (t, J = 7.3 Hz, 4H), 7.19−7.32 (m, 4H), 6.95 (d, J = 8.0 Hz,
1H), 6.87 (t, J = 7.2 Hz, 1H), 6.59 (s, 2H). 13C{1H} NMR (101
MHz, CDCl3): δ 155.5, 152.8, 132.4, 132.2, 132.0, 131.0, 128.8,
1
1
128.4, 126.0, 121.0, 120.3, 119.8, 103.8, 78.7. Our H and 13C NMR
(169 mg, 46% yield). H NMR (400 MHz, DMSO-d6): δ 10.25 (s,
are consistent with those reported for this compound.33
1H), 7.99 (s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H),
7.09 (b, 2H), 6.90−6.95 (m, 2H), 6.82 (t, J = 7.3 Hz, 2H), 6.44 (d, J
= 7.6 Hz, 1H), 6.25 (d, J = 7.9 Hz, 2H), 2.04 (s, 6H). 13C{1H} NMR
(101 MHz, DMSO-d6): δ 156.1, 153.0, 152.0, 142.9, 135.6, 132.2,
127.4, 123.0, 120.3, 120.0, 119.7, 116.7, 111.0, 110.6, 14.9. HRMS
(ESI-TOF) m/z: [M + Na]+, calcd for C23H20N4ONa, 391.1529;
found, 391.1536, difference −1.70 ppm.
2-Bis(3-mesitylpyrazol-1-yl)methyl-phenol (Table 2, Entry 6).
The product was prepared according to the general procedure with
salicylaldehyde (0.104 mL, 1.00 mmol, 1.0 equiv), bis(3-mesitylpyr-
azol-1-yl)methanone (399 mg, 1.00 mmol, 1.0 equiv), DMAP (12.2
mg, 0.10 mmol, 0.1 equiv), and THF (3 mL). Volatiles were removed
in vacuo, and then, the remaining residue was purified by flash
chromatography on silica using 6:1 hexanes/ethyl acetate to obtain
Bis(3,5-dimethylpyrazol-1-yl)methylbenzene (Table 3, Entry 1).
The product was prepared according to the general procedure with
benzaldehyde (0.102 mL, 1.00 mmol, 1.0 equiv), bis(3,5-dimethylpyr-
azol-1-yl)methanone (218 mg, 1.00 mmol, 1.0 equiv), DMAP (12.2
mg, 0.10 mmol, 0.1 equiv), and THF (3 mL). Volatiles were removed
in vacuo, and then, the remaining residue was purified by flash
chromatography on silica using 4:1 hexanes/ethyl acetate to obtain
1
the product as a white solid (363 mg, 76% yield). H NMR (400
MHz, CDCl3): δ 7.90 (d, J = 1.8 Hz, 2H), 7.37−7.45 (m, 3H), 7.25
(s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 7.7 Hz, 1H), 6.87 (s,
4H), 6.16 (d, J = 2.1 Hz, 2H), 2.28 (s, 6H), 1.99 (s, 12H). 13C{1H}
NMR (101 MHz, CDCl3): δ 155.9, 152.0, 137.9, 137.5, 132.2, 131.8,
131.1, 129.9, 128.2, 120.6, 120.4, 120.1, 107.4, 79.4, 21.2, 20.5. Our
1H and 13C NMR are consistent with those reported for this
compound.33
1
the product as a white solid (170 mg, 61% yield). H NMR (400
MHz, CDCl3): δ 7.63 (s, 1H), 7.31 (s, 3H), 6.90 (d, J = 4.3 Hz, 2H),
5.85 (s, 2H), 2.21 (s, 6H), 2.19 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3): δ 148.4, 141.2, 136.9, 128.6, 128.5, 126.9, 106.9, 74.0, 13.9,
12.0. Our 1H and 13C NMR are consistent with those reported for this
compound.36
1-Bis(3,5-dimethylpyrazol-1-yl)methyl-4-methoxybenzene
(Table 3, Entry 2). The product was prepared according to the general
procedure with 4-methoxybenzaldehyde (0.122 mL, 1.00 mmol, 1.0
equiv), bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol,
1.0 equiv), DBU (15.2 μL, 0.100 mmol, 0.1 equiv), and THF (3 mL).
Volatiles were removed in vacuo, and then, the remaining residue was
purified by flash chromatography on silica using 9:1 hexanes/ethyl
acetate to obtain the product as a colorless oil (147 mg, 47% yield).
1H NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.83 (s, 4H), 5.83 (s,
2-Bis(imidazol-1-yl)methylphenol (Table 2, Entry 7). The product
was prepared according to the general procedure with salicylaldehyde
(0.104 mL, 1.00 mmol, 1.0 equiv), 1,1′-carbonyldiimidazole (162 mg,
1.00 mmol, 1.0 equiv), DBU (15.2 μL, 0.100 mmol, 0.1 equiv), and
THF (3 mL). The product precipitated out from the reaction mixture
and was collected by filtration, resulting in a white solid (198 mg, 83%
1
yield). H NMR (500 MHz, DMSO-d6): δ 10.24 (s, 1H), 7.92 (s,
1H), 7.70 (s, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.18 (s, 2H), 6.95 (s, 2H),
6.87 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.72 (d, J = 7.6 Hz,
1H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 155.2, 137.4, 131.3,
1
129.5, 127.2, 123.0, 119.7, 119.1, 116.2, 65.6. Our H and 13C NMR
are consistent with those reported for this compound.34
2-Bis(imidazol-1-yl)methylphenol (10 mmol Scale) (Table 2,
Entry 7). The product was prepared according to the general
procedure with salicylaldehyde (1.04 mL, 10.0 mmol, 1.0 equiv), 1,1′-
carbonyldiimidazole (1.62 g, 10.0 mmol, 1.0 equiv), DBU (15.2 μL,
0.100 mmol, 0.1 equiv), and THF (30 mL). The product precipitated
out from the reaction mixture and was collected by filtration and
washed with acetone, resulting in a white solid (1.91 g, 80% yield).
2-Bis(1,2,4-triazol-1-yl)methyl-phenol (Table 2, Entry 8). The
product was prepared according to the general procedure with
salicylaldehyde (0.104 mL, 1.00 mmol, 1.0 equiv), 1,1′-carbonyldi-
(1,2,4-triazole) (164 mg, 1.00 mmol, 1.0 equiv), DBU (15.2 μL, 0.100
mmol, 0.1 equiv), and THF (3 mL). Volatiles were removed in vacuo,
and then, the remaining residue was purified by flash chromatography
on silica using 10% methanol in dichloromethane to obtain the
2H), 3.77 (s, 3H), 2.19 (s, 6H), 2.18 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3): δ 159.6, 148.3, 141.1, 128.9, 128.2, 113.9, 106.9, 73.8,
55.3, 13.6, 11.9. HRMS (ESI-TOF) m/z: [M + Na]+, calcd for
C18H22N4ONa, 333.1686; found, 333.1690, difference −1.12 ppm.
1-Bis(3,5-dimethylpyrazol-1-yl)methyl-4-methylbenzene (Table
3, Entry 3). The product was prepared according to the general
procedure with 4-methylbenzaldehyde (0.118 mL, 1.00 mmol, 1.0
equiv), bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol,
1.0 equiv), DMAP (12.2 mg, 0.10 mmol, 0.1 equiv), and THF (3
mL). Volatiles were removed in vacuo, and then, the remaining
residue was purified by flash chromatography on silica using 9:1−4:1
hexanes/ethyl acetate to obtain the product as a white solid (154 mg,
52% yield). 1H NMR (400 MHz, CDCl3): δ 7.60 (s, 1H), 7.12 (d, J =
7.8 Hz, 2H), 6.80 (d, J = 7.8 Hz, 2H), 5.84 (s, 2H), 2.33 (s, 3H), 2.21
(s, 6H), 2.19 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 148.3,
141.1, 138.3, 133.9, 129.3, 126.8, 106.9, 74.0, 21.2, 13.9, 12.0. HRMS
(ESI-TOF) m/z: [M + Na]+, calcd for C18H22N4Na, 317.1737; found,
317.1741, difference −1.36 ppm.
4-Bis(3,5-dimethylpyrazol-1-yl)methyl-nitrobenzene (Table 3,
Entry 4). The product was prepared according to the general
procedure with p-nitrobenzaldehyde (151 mg, 1.00 mmol, 1.0 equiv),
bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol, 1.0
equiv), DMAP (12.2 mg, 0.10 mmol, 0.1 equiv), and THF (3 mL).
Volatiles were removed in vacuo, and then, the remaining residue was
purified by flash chromatography on silica using 3:1 hexanes/ethyl
acetate to obtain the product as a yellow solid (218 mg, 67% yield).
1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.9 Hz, 2H), 7.62 (s,
1
product as a yellow crystalline solid (146 mg, 60% yield). H NMR
(400 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.63 (s, 2H), 8.25 (s, 1H),
8.07 (s, 2H), 7.27 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.90
(d, J = 8.0 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H). 13C{1H} NMR (101
MHz, DMSO-d6): δ 155.3, 152.8, 145.1, 131.7, 128.4, 120.6, 119.8,
116.1, 68.7, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4. HRMS (ESI-TOF)
m/z: [M + Na]+, calcd for C11H10N6ONa, 265.0808; found,
265.0815, difference −2.45 ppm.
2-Bis(benzimidazol-1-yl)methylphenol (Table 2, Entry 9). The
product was prepared according to the general procedure with
salicylaldehyde (0.104 mL, 1.00 mmol, 1.0 equiv), bis(benzimidazol-
1-yl)methanone (262 mg, 1.00 mmol, 1.0 equiv), DBU (15.2 μL,
0.100 mmol, 0.1 equiv), and THF (3 mL). The product precipitated
out from the reaction mixture and was collected by filtration, resulting
1
in a white solid (208 mg, 61% yield). H NMR (400 MHz, DMSO-
1H), 7.11 (d, J = 8.3 Hz, 2H), 5.88 (s, 2H), 2.19 (s, 6H), 2.18 (s,
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6H). 13C{1H} NMR (101 MHz, CDCl3): δ 149.0, 147.9, 143.8, 141.1,
128.3, 123.8, 107.5, 73.2, 13.8, 11.8. HRMS (ESI-TOF) m/z: [M +
H]+, calcd for C17H20N5O2, 326.1612; found, 326.1612, difference
−0.29 ppm.
1.00 mmol, 1.0 equiv), DMAP (12.2 mg, 0.100 mmol, 0.1 equiv), and
THF (3 mL). Volatiles were removed in vacuo, and then, the
remaining residue was purified by flash chromatography on silica
using 5:1 hexanes/ethyl acetate to obtain the product as a white solid
(131 mg, 32% yield). 1H NMR (400 MHz, CDCl3): δ 7.83 (t, J = 3.4
Hz, 1H), 7.48 (s, 1H), 7.19−7.31 (m, 6H), 6.92 (t, 2H), 5.85 (s, 2H),
5.03 (s, 2H), 2.13 (s, 6H), 2.07 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3): δ 148.6, 147.7, 141.4, 136.8, 135.6, 128.9, 128.0, 126.6,
123.7, 122.4, 121.0, 110.1, 107.7, 13.7, 11.5. HRMS (ESI-TOF) m/z:
[M + H]+, calcd for C25H27N6, 411.2292; found, 411.2293, difference
−0.35 ppm.
(E)-3,3-Bis(3,5-dimethylpyrazol-1-yl)-1-phenylpropene (Table 3,
Entry 10). The product was prepared according to the general
procedure with trans-cinnamaldehyde (0.126 mL, 1.00 mmol, 1.0
equiv), bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol,
1.0 equiv), DMAP (12.2 mg, 0.100 mmol, 0.1 equiv), and THF (3
mL). Volatiles were removed in vacuo, and then, the remaining
residue was purified by flash chromatography on silica using 10:1
hexanes/ethyl acetate to obtain the product as a white solid (202 mg,
67% yield). 1H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 7.3 Hz, 2H),
7.20−7.32 (m, 3H), 7.05 (d, J = 21.4 Hz, 2H), 6.41 (d, J = 14.7 Hz,
1H), 5.82 (s, 2H), 2.22 (s, 6H), 2.20 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3): δ 147.9, 140.1, 135.9, 133.5, 128.6, 128.4, 127.2,
123.9, 107.1, 73.8, 13.8, 11.4. HRMS (ESI-TOF) m/z: [M + Na]+,
calcd for C19H22N4Na, 329.1737; found, 329.1740, difference −1.07
ppm.
4-Bis(3,5-dimethylpyrazol-1-yl)methyl-fluorobenzene (Table 3,
Entry 5). The product was prepared according to the general
procedure for the preparation of bis(pyrazolyl)alkanes with 4-
fluorobenzaldehyde (0.107 mL, 1.00 mmol, 1.0 equiv), bis(3,5-
dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol, 1.0 equiv),
DMAP (12.2 mg, 0.10 mmol, 0.1 equiv), and THF (3 mL). Volatiles
were removed in vacuo, and then, the remaining residue was purified
by flash chromatography on silica using 5:1 hexanes/ethyl acetate to
1
obtain the product as a white solid (245 mg, 82% yield). H NMR
(400 MHz, CDCl3): δ 7.58 (s, 1H), 7.01 (t, J = 8.6 Hz, 2H), 6.89−
6.92 (m, 2H), 5.94−5.74 (2H), 2.20 (d, J = 6.2 Hz, 12H). 13C{1H}
NMR (101 MHz, CDCl3): δ 148.6, 141.1, 128.9, 128.8, 115.7, 115.5,
107.1, 73.5, 13.8, 11.9. 19F NMR (376 MHz, CDCl3): δ −113.59.
HRMS (ESI-TOF) m/z: [M + Na]+, calcd for C17H19FN4Na,
321.1486; found, 321.1489, difference −0.84 ppm.
4-Bis(3,5-dimethylpyrazol-1-yl)methyl-chlorobenzene (Table 3,
Entry 6). The product was prepared according to the general
procedure with 4-chlorobenzaldehyde (141 mg, 1.00 mmol, 1.0
equiv), bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol,
1.0 equiv), DMAP (12.2 mg, 0.10 mmol, 0.1 equiv), and THF (3
mL). Volatiles were removed in vacuo, and then, the remaining
residue was purified by flash chromatography on silica using 10:1
hexanes/ethyl acetate to obtain the product as a white solid (259 mg,
82% yield). 1H NMR (400 MHz, CDCl3): δ 7.56 (s, 1H), 7.29 (d, J =
8.3 Hz, 2H), 6.85 (d, J = 7.6 Hz, 2H), 5.85 (s, 2H), 2.19 (s, 6H), 2.18
(s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 148.6, 141.1, 135.4,
134.5, 128.8, 128.5, 107.1, 73.5, 13.8, 11.9. HRMS (ESI-TOF) m/z:
[M + Na]+, calcd for C17H19ClN4Na, 337.1190; found, 337.1194,
difference −1.10 ppm.
2-Bis(pyrazol-1-yl)methyl-1-(diphenylphosphino)benzene (Table
3, Entry 7). The product was prepared according to the general
procedure with 2-(diphenylphosphino)benzaldehyde (290 mg, 1.00
mmol, 1.0 equiv), bis(pyrazol-1-yl)methanone (162 mg, 1.00 mmol,
1.0 equiv), DBU (15.2 μL, 0.100 mmol, 0.1 equiv), and THF (3 mL).
Volatiles were removed in vacuo, and then, the remaining residue was
purified by flash chromatography on silica using 2:1 hexanes/ethyl
acetate to obtain the product as a white solid (121 mg, 30% yield). 1H
NMR (400 MHz, CDCl3): δ 8.58 (d, J = 7.5 Hz, 1H), 7.47 (s, 2H),
7.37 (t, J = 7.5 Hz, 1H), 7.21−7.32 (m, 7H), 7.18 (d, J = 2.3 Hz, 2H),
7.06−7.12 (m, 5H), 6.94 (dd, J = 7.3, 4.3 Hz, 1H), 6.08 (s, 2H).
13C{1H} NMR (101 MHz, CDCl3): δ 140.9, 140.8 (d, J = 23.1 Hz),
136.4 (d, J = 18.3 Hz), 135.3 (d, J = 7.7 Hz), 135.0, 133.9 (d, J = 19.3
Hz), 129.9, 129.7, 129.5, 128.8, 128.5 (d, J = 7.7 Hz), 127.5 (d, J =
5.8 Hz), 106.3, 75.7 (d, J = 28.9 Hz). 31P NMR (162 MHz, CDCl3): δ
−18.04. HRMS (ESI-TOF) m/z: [M + H]+, calcd for C25H22N4P,
409.1577; found, 409.1576, difference 0.05 ppm.
1,1′-(Furan-2-ylmethylene)bis(3,5-dimethylpyrazole) (Table 3,
Entry 11). The product was prepared according to the general
procedure with 2-formylfuran (0.107 mL, 1.00 mmol, 1.0 equiv),
bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol, 1.0
equiv), DMAP (12.2 mg, 0.100 mmol, 0.1 equiv), and THF (3 mL).
Volatiles were removed in vacuo, and then, the remaining residue was
purified by flash chromatography on silica using 5:1 hexanes/ethyl
acetate to obtain the product as a white solid (200 mg, 74% yield). 1H
NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.45 (s, 1H), 6.38 (s, 1H),
6.22 (s, 1H), 5.83 (s, 2H), 2.21 (d, J = 7.6 Hz, 12H). 13C{1H} NMR
(101 MHz, CDCl3): δ 148.6, 148.4, 143.2, 140.9, 110.9, 110.8, 107.1,
1
69.3, 13.9, 11.3. Our H and 13C NMR are consistent with those
reported for this compound.37
Indole-2-bis(3,5-dimethylpyrazol-1-yl)methane (Table 3, Entry
12). The product was prepared according to the general procedure
with indole-2-carboxaldehyde (145 mg, 1.00 mmol, 1.0 equiv),
bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol, 1.0
equiv), DMAP (12.2 mg, 0.100 mmol, 0.1 equiv), and THF (3 mL).
Volatiles were removed in vacuo, and then, the remaining residue was
purified by flash chromatography on silica using 4:1 hexanes/ethyl
acetate to obtain the product as a white solid (100 mg, 31% yield). 1H
NMR (400 MHz, CDCl3): δ 9.92 (s, 1H), 7.72 (s, 1H), 7.56 (d, J =
7.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.09
(t, J = 7.4 Hz, 1H), 6.47 (s, 1H), 5.80 (s, 2H), 2.24 (s, 6H), 2.19 (s,
6H). 13C{1H} NMR (101 MHz, CDCl3): δ 148.8, 140.8, 136.2, 132.4,
127.8, 122.6, 121.0, 120.0, 111.7, 107.1, 103.1, 68.3, 13.8, 11.5.
HRMS (ESI-TOF) m/z: [M + Na]+, calcd for C19H21N5Na,
342.1689; found, 342.1692, difference −0.92 ppm.
N-Benzyl-2-bis(3,5-dimethylpyrazol-1-yl)methylimidazole (Table
3, Entry 8). The product was prepared according to the general
procedure with N-benzyl-2-formylimidazole (186 mg, 1.00 mmol, 1.0
equiv), bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol,
1.0 equiv), DMAP (12.2 mg, 0.100 mmol, 0.1 equiv), and THF (3
mL). Volatiles were removed in vacuo, and then, the remaining
residue was purified by flash chromatography on silica using ethyl
acetate to obtain the product mixed with pyrazole, which was then
sublimed off at 80 °C, and the desired product was obtained as a pale
1,1-Bis(3,5-dimethylpyrazol-1-yl)propane (Table 3, Entry 13).
The product was prepared according to the general procedure with
propionaldehyde (0.072 mL, 1.00 mmol, 1.0 equiv), bis(3,5-
dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol, 1.0 equiv),
DMAP (12.2 mg, 0.100 mmol, 0.1 equiv), and THF (3 mL). Volatiles
were removed in vacuo, and then, the remaining residue was purified
by flash chromatography on silica using 9:1 hexanes/ethyl acetate to
1
yellow solid (186 mg, 49% yield). H NMR (400 MHz, CDCl3): δ
7.28 (m, 4H), 7.07 (s, 1H), 6.99 (d, J = 5.8 Hz, 2H), 6.90 (s, 1H),
5.84 (s, 2H), 4.74 (s, 2H), 2.16 (s, 6H), 2.01 (s, 6H). 13C{1H} NMR
(101 MHz, CDCl3): δ 148.3, 141.3, 141.2, 135.5, 129.0, 128.3, 128.1,
127.6, 122.6, 107.6, 70.1, 50.5, 13.8, 11.3. HRMS (ESI-TOF) m/z:
[M + H]+, calcd for C21H25N6, 361.2135; found, 361.2137, difference
−0.42 ppm.
2-Bis(3,5-dimethylpyrazol-1-yl)methyl-N-benzyl-benzimidazole
(Table 3, Entry 9). The product was prepared according to the general
procedure with 2-formyl-N-benzylbenzimidazole (0.107 mL, 1.00
mmol, 1.0 equiv), bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg,
1
obtain the product as a white solid (168 mg, 72% yield). H NMR
(400 MHz, CDCl3): δ 6.12 (t, J = 7.7 Hz, 1H), 5.73 (s, 2H), 2.53−
2.61 (m, 2H), 2.16 (s, 6H), 2.15 (s, 6H), 0.88 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 147.3, 139.8, 106.8, 74.5, 26.4,
13.6, 11.2, 10.4. HRMS (ESI-TOF) m/z: [M + H]+, calcd for
C13H21N4, 233.1761; found, 233.1769, difference −3.34 ppm.
Bis(3-phenylpyrazol-1-yl)cyclohexylmethane (Table 3, Entry 14).
The product was prepared according to the general procedure with
cyclohexanecarboxaldehyde (0.112 mL, 1.00 mmol, 1.0 equiv), bis(3-
H
https://dx.doi.org/10.1021/acs.joc.0c02442
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
phenylpyrazol-1-yl)methanone (314 mg, 1.00 mmol, 1.0 equiv),
DMAP (12.2 mg, 0.100 mmol, 0.1 equiv), and THF (3 mL). Volatiles
were removed in vacuo, and then, the remaining residue was purified
by flash chromatography on silica using 10:1 hexanes/ethyl acetate to
+ Na]+, calcd for C17H19N5O2Na, 348.1431; found, 348.1431,
difference −0.07 ppm.
Resubmission of Carbamate (9) under DMAP Conditions. In
a vial, carbamate intermediate 9 (163 mg, 0.500 mmol, 1.0 equiv) and
quinuclidine (5.6 mg, 0.05 mmol, 0.1 equiv) were dissolved in THF,
the vial headspace was purged briefly with nitrogen, and then, it was
sealed and stirred at 60 °C using an aluminum block for 24 h. Then,
all volatiles were removed in vacuo, and the residue was analyzed in
DMSO-d6 with 1,4-dioxane as an internal reference standard.
Mechanistic Crossover Experiment between Methanones
2a and 2b. To one vial were added bis(3,5-dimethylpyrazol-1-
yl)methanone (2a) (109 mg, 0.500 mmol, 1 equiv), bis(pyrazol-1-
yl)methnaone (2b) (81 mg, 0.50 mmol, 1 equiv), DMAP (12.2 mg,
0.100 mmol, 0.2 equiv), and THF (3 mL). A second vial was charged
with the same reagents and amounts except with no DMAP added.
Both solutions were stirred at 60 °C using an aluminum block for 5 h
and then cooled to room temperature. All volatiles were evaporated;
then, the residues were redissolved in CDCl3 with 1,4-dioxane as an
internal reference standard.
1
obtain the product as a white solid (218 mg, 76% yield). H NMR
(400 MHz, CDCl3): δ 5.81 (d, J = 11.0 Hz, 1H), 5.73 (s, 2H), 3.00
(q, J = 11.2 Hz, 1H), 2.34 (s, 6H), 2.17 (s, 6H), 1.67 (d, J = 10.4 Hz,
3H), 1.09−1.38 (m, 5H), 0.87−0.95 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3): δ 147.6, 139.9, 106.3, 76.7, 39.6, 29.5, 26.3, 25.5, 13.7,
11.5. Our 1H and 13C NMR are consistent with those reported for this
compound.38
1-Bis(3,5-dimethylpyrazol-1-yl)methyladamantane (Table 3,
Entry 15). The product was prepared according to the general
procedure with 1-admantanal (164 mg, 1.00 mmol, 1.0 equiv),
bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol, 1.0
equiv), DMAP (12.2 mg, 0.100 mmol, 0.1 equiv), and THF (3 mL).
Volatiles were removed in vacuo, and then, the remaining residue was
purified by flash chromatography on silica using 9:1 hexanes/ethyl
acetate to obtain the product as a white solid (130 mg, 38% yield). 1H
NMR (400 MHz, CDCl3): δ 5.72 (s, 2H), 5.61 (s, 1H), 2.19 (d, J =
12.3 Hz, 12H), 1.96 (s, 3H), 1.83 (s, 6H), 1.63 (t, J = 14.3 Hz, 6H).
13C{1H} NMR (101 MHz, CDCl3): δ 147.4, 139.9, 105.6, 77.2, 40.6,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02442.
■
sı
39.0, 36.8, 28.4, 14.0, 11.9. HRMS (ESI-TOF) m/z: [M + H]+, calcd
for C21H31N4, 339.2543; found, 339.2546, difference −0.76 ppm.
1-Phenyl-2,2-bis(3,5-dimethylpyrazol-1-yl)ethane (Table 3, Entry
16). The product was prepared according to the general procedure
with freshly distilled phenylacetaldehyde (0.111 mL mg, 1.00 mmol,
1.0 equiv), bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00
mmol, 1.0 equiv), DMAP (12.2 mg, 0.100 mmol, 0.1 equiv), and THF
(3 mL). Volatiles were removed in vacuo, and then, the remaining
residue was purified by flash chromatography on silica using 6:1
hexanes/ethyl acetate to obtain the product as a white solid (168 mg,
Spectral characterization for all compounds, Hammett
analysis data plots, and crude NMRs for resubmission
experiments (PDF)
AUTHOR INFORMATION
Corresponding Author
■
1
57% yield). H NMR (400 MHz, CDCl3): δ 7.17−7.18 (m, 3H),
Robert J. Comito − The University of Houston, Houston,
Texas 77004, United States; orcid.org/0000-0003-1298-
2876; Email: rjcomito@central.uh.edu
6.95−6.97 (m, 2H), 6.21 (t, J = 7.2 Hz, 1H), 5.72 (s, 2H), 3.89 (d, J =
7.1 Hz, 2H), 2.21 (s, 6H), 2.03 (s, 6H). 13C NMR (101 MHz,
CDCl3): δ 148.0, 139.6, 136.7, 129.4, 128.5, 127.0, 106.4, 72.3, 40.1,
1
13.8, 11.1. Our H and 13C NMR are consistent with those reported
for this compound.39
Authors
Maxym Tansky − The University of Houston, Houston, Texas
77004, United States
Zipeng Gu − The University of Houston, Houston, Texas
77004, United States
2-Bis(3,5-dimethylpyrazol-1-yl)methylpyridine (8, Table 3, Entry
17). The product was prepared according to a modification of the
general procedure with 2-formylpyridine (0.096 mL, 1.00 mmol, 1.0
equiv), bis(3,5-dimethylpyrazol-1-yl)methanone (218 mg, 1.00 mmol,
1.0 equiv), and toluene (3 mL). The reaction mixture was stirred at
110 °C for 24 h. Volatiles were removed in vacuo, and then, the
remaining residue was purified by flash chromatography on silica
using 2:1−3:1 ethyl acetate/hexanes to obtain the product as an off-
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02442
1
white solid (227 mg, 81% yield). H NMR (400 MHz, CDCl3): δ
Author Contributions
The manuscript was written through contributions of all
authors.
8.62 (d, J = 4.1 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.55 (s, 1H), 7.22−
7.24 (m, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.86 (s, 2H), 2.18 (s, 6H),
2.16 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 155.7, 149.6,
1
Funding
148.7, 140.8, 137.0, 123.3, 122.4, 107.0, 74.7, 13.9, 11.5. Our H and
13C NMR are consistent with those reported for this compound.36
The authors gratefully acknowledge funding of this research
from the Welch Foundation (grant # E-1983-20190330) and
startup funding from the University of Houston.
1-(3,5-Dimethylpyrazol-1-yl)-(2-pyridinyl)methyl-3,5-dimethyl-
pyrazole-carboxylate (9, Table 3, Entry 18). The product was
prepared according to a modification of the general procedure with 2-
formylpyridine (0.44 mL, 4.6 mmol, 1.0 equiv), bis(3,5-dimethylpyr-
azol-1-yl)methanone (1.0 g, 4.6 mmol, 1.0 equiv), TBD (52 mg, 0.46
mmol, 0.1 equiv), and dichloromethane (10 mL). The reaction
mixture was stirred at 22 °C for 24 h. Volatiles were removed in
vacuo, and then, the remaining residue was purified by flash
chromatography on silica using ethyl acetate to obtain the product
as a light tan solid mixed with pyrazole. This was suspended in
hexanes, and dichloromethane was added until a clear homogenous
solution was observed; then, it was kept at −20 °C for a few days to
get the desired material as an off-white solid (1.12 g, 75%). 1H NMR
(400 MHz, CDCl3): δ 8.57 (d, J = 3.2 Hz, 1H), 7.76−7.83 (m, 3H),
7.26−7.29 (m, 2H), 5.97 (s, 1H), 5.83 (s, 1H), 2.51 (s, 3H), 2.46 (s,
3H), 2.25 (s, 3H), 2.16 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3):
δ 154.5, 153.5, 150.5, 149.4, 149.1, 145.1, 141.7, 137.2, 123.9, 122.0,
111.3, 106.8, 82.7, 14.4, 14.0, 13.9, 11.2. HRMS (ESI-TOF) m/z: [M
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
TBD, 1,5,7-triazabicyclodec-5-ene; DBU, 1,8-diazabicycloun-
dec-7-ene; THF, tetrahydrofuran; DMAP, 4-(N,N-
dimethylamino)pyridine
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Article
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