Regiocontrolled Coupling of Alkynes and Dipolar Reagents: Iron-Mediated [3 + 2] Cycloadditions Revisited

Article abstract of DOI:10.1021/acs.organomet.1c00032

Cyclopentadienyliron dicarbonyl based allenyliron complexes were prepared, and their formal [3 + 2] cycloaddition with a number of dipolar reagents was investigated as a means of preparing heterocyclic compounds in a regiocontrolled manner. In addition, the mechanism of the isomerization of an allenyliron complex to its propargyliron tautomer was investigated. Results in support of both radical and two-electron mechanisms for isomerization are presented.

Full text of DOI:10.1021/acs.organomet.1c00032

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Article
Regiocontrolled Coupling of Alkynes and Dipolar Reagents: Iron-
Mediated [3 + 2] Cycloadditions Revisited
Jin Zhu,† Austin C. Durham,† Yidong Wang, James C. Corcoran, Xiao-Dong Zuo, Steven J. Geib,
and Yi-Ming Wang*
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ABSTRACT: Cyclopentadienyliron dicarbonyl based allenyliron
complexes were prepared, and their formal [3 + 2] cycloaddition
with a number of dipolar reagents was investigated as a means of
preparing heterocyclic compounds in a regiocontrolled manner. In
addition, the mechanism of the isomerization of an allenyliron
complex to its propargyliron tautomer was investigated. Results in
support of both radical and two-electron mechanisms for
isomerization are presented.
the use of fluorinated and trifluoromethylated targets in
medicinal chemistry necessitates the continued development of
methods to produce synthetically challenging fluorine-contain-
ing five-membered heterocycles.6
INTRODUCTION
■
In recent decades, the synthesis and functionalization of
heterocycles have continued to be core areas of organic
synthesis research due to their central role in the development
of bioactive and therapeutic molecules.1 Among these species,
nitrogen-containing five-membered heterocycles have raised
particular interest. N-Arylpyrazoles, for example, constitute key
substructures in a range of molecules of pharmaceutical and
agricultural interest,2 including cyclooxygenase-2 (COX-2)
inhibitors such as celecoxib, mavacoxib, and rimonabant, as
well as insecticides/acaricides such as fipronil and ethiprole
(Scheme 1, top).3 Routes to access dihydropyrrole derivatives
are particularly valuable within the context of recent efforts to
incorporate saturated4 and partially saturated N-heterocycles5
into the toolkit of medicinal chemistry. Additionally, they are
also valuable as intermediates in synthesis and are observed in
numerous natural products and synthetic biologically active
compounds (Scheme 1, bottom). Similarly, a modern surge in
Although classical strategies for the preparation of these
compounds often suffice, these approaches sometimes result in
the formation of regioisomeric mixtures. Thus, the develop-
ment of regioselective routes to substituted five-membered
heterocycles has received particular attention.7 Generally, the
regiochemistry can be controlled by utilizing prefunctionalized
substrates,7a,b by multicomponent processes,7c or through
various transition-metal-catalyzed reactions.7d Among the
approaches utilizing transition metals, methods using Co,8a
Cu,8b Au,8c Ru,8d and Rh8e have been extensively investigated
and successfully put into practice.
The formal cycloaddition of dipolar reagents (Eδ+Nuδ−)
to unsaturated transition-metal complexes is a versatile route
for the synthesis of heterocycles.9 In many cases, transition-
metal complexes, especially metal carbonyl complexes,10 are
easily handled and are useful in organic synthesis, given their
straightforward preparation and good stability to air and
moisture. In particular, due to their regiospecific reactivity as
nucleophiles (via SE2′ addition) and latent reactivity as
precursors to electrophilic cationic π-complexes, propargyl
and allenyl derivatives of cyclopentadienyliron dicarbonyl
complexes are particularly versatile, functioning as all-carbon
Scheme 1. N-Containing or Fluorinated Five-Membered
Heterocycles in Therapeutics and Natural Products
Special Issue: Organometallic Solutions to Challenges
in Cross-Coupling
Received: January 18, 2021
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1,3-dipoles that can be used for the synthesis of five-membered
sulfonyl isocyanates,18 giving [3 + 2] cycloaddition products
isomeric with those derived from the tautomeric propargyliron
species (Scheme 2b).
carbo- and heterocycles (Scheme 2a,b; FpR = CpRFe(CO)2,
Recently, our group developed an iron-catalyzed α-
functionalization reaction of alkynes and alkenes with activated
electrophiles.21 By drastically increasing the acidity of the
propargylic/allylic C−H bond (Scheme 2c),22 formation of a
π-complex with the cationic iron fragment allows for the
deprotonation of the alkene or alkyne at the α-position using a
weak amine base. The resultant σ-allyliron or σ-allenyliron
complex subsequently undergoes reaction with the electrophile
to give the functionalized product. The key allenyliron
intermediate of the catalytic process was successfully isolated
in stoichiometric experiments23,24 and crystallographically
characterized.24
Scheme 2. Synthetic Applications of Propargyl- and
Allenyliron Species
On the basis of the numerous precedents for [3 + 2]
cycloaddition processes and this general approach for
preparing allenyliron complexes, we hypothesized that simple
alkynes and dipolar reagents could be coupled in a
regioselective manner by way of allenyliron species prepared
via deprotonation of cationic iron alkyne complexes. Moreover,
we expected this strategy to allow for the regioselective
formation of products complementary to those derived from
the tautomeric propargyliron complexes.25c Demetalation of
the product cycloadduct would furthermore provide access to a
number of highly substituted heterocycles from simple starting
materials. Indeed, a variety of conditions have been reported
for the elaboration of vinyliron species,9c including proto-
demetalation,13g halodemetalation, carbonylative demetalation
using single-electron oxidants,25a,b and nonoxidative function-
alization processes using Gilman or alkyllithium reagents.25c,d
Given the limited data on the fundamental reactivity of
allenyliron complexes and the synthetic interest in regiose-
lective syntheses of five-membered heterocycles using readily
accessed alkynes as starting materials, we explored the
stoichiometric reactivity of these organometallic complexes
with a number of electrophilic reagents. In this report, we
disclose the synthesis of a collection of five-membered
heterocycles resulting from these studies. In addition, during
the course of these investigations, we observed the isomer-
ization of an allenyliron complex to the tautomeric
propargyliron species. We report studies in relation to the
rate and mechanism of this process and consider its
implications for the regioselectivity of the formal [3 + 2]
cycloaddition.
CpR = substituted cyclopentadienyl ligand). The recently
reported cycloaddition reactions of alkynes and iron-coordi-
nated 1,3-dipolar organic fragments represents an interesting
variant of this strategy.8f,g
Dating back to the 1970s, the first [3 + 2] cycloaddition
reactions of propargyliron complexes were reported by
Wojcicki and co-workers, who extended their earlier work on
SO2 insertion11 into allylmanganese pentacarbonyl to prop-
argyliron complexes to afford crystallographically characterized
[3 + 2] cycloadducts.12 Subsequently, the cycloadditions of
transition-metal 2-alkynyl complexes with S-centered dipolar
reagents, including sulfur oxides (SO2, SO3, masked S2O)13a
and N-sulfinylamines and N-sulfinylamides,13c as well as C-
centered dipolar reagents, including isothiocyanates,13b iso-
cyanates,13d,e electron-deficient alkenes, alkynes, and kete-
nes,13f−h were disclosed (Scheme 2a). Owing to the activation
by the coordinated metal, cationic η2-allene complexes, arising
from SE2′ electrophilic attack of the acetylenic position, were
proposed to undergo annulation by attack of a pendant
nucleophilic moiety to deliver the observed [3 + 2]
cycloadduct.14 Detailed investigations into the mechanism
have been carried out by analyzing the stereochemical outcome
of the reaction with tetrasubstituted alkenes and through
kinetic studies with a series of substituted isocyanate
reagents.13e
Metal allenyl complexes are metallotropic tautomers of
propargylmetal complexes.15 The interconversion of propargyl-
and allenylmetal species via a formal 1,3-sigmatropic rearrange-
ment has been well-documented for main-group elements and
a number of transition metals.16 However, this transformation
has not yet been directly observed for organoiron species,
although observations made by Rosenblum and co-workers
suggested this possibility.17 In comparison with the convenient
preparation of propargyliron complexes from versatile
propargyl halides, the application of allenyliron species has
been much less documented, presumably due to the limited
number of methods for preparing these reagents. Reported
allenyliron species could only be accessed by SN2′ displace-
ment of terminal propargylic (pseudo)halides18,19 or those
with alkoxy substituents at the β-position19 with [CpFe-
(CO)2]− as the nucleophile. The allenyliron complexes were
subjected to electrophiles such as tetracyanoethylene20 and
RESULTS AND DISCUSSION
■
Carbonyl Derivatives as Cycloaddends. We first
examined the reactivity of pentamethylcyclopentadienyliron
dicarbonyl derived allenyliron 1a with ethyl trifluoropyruvate
(2) as a coupling partner, given the current interest in the
preparation of trifluoromethylated heterocycles6d and the
potential for downstream elaboration of the installed ethyl
ester function. As anticipated, allenyliron 1a and 2 underwent
[3 + 2] cycloaddition under mild conditions to afford the
vinyliron complex 3 as a single regioisomer (≥20:1 rr by NMR
analysis of the crude material) in 48% yield. Complex 3 could
also be prepared in slightly higher yield directly from 1-phenyl-
1-propyne (1) by combining it with 2 and [Fp*(thf)]+BF4
−
(Fp* = Cp*Fe(CO)2) in the presence of 2,2,6,6-tetramethyl-
piperidine (TMPH) as base, via the in situ generation of 1a
(Scheme 3, top and middle). Complex 3 could be recrystal-
lized from CH2Cl2/hexanes for characterization by single-
B
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Scheme 3. Vinyliron Dihydrofuran Synthesis and Divergent
Transformations
Scheme 4. Synthesis of Tautotomeric Dihydropyrrolone
Vinyliron Complexes
a
−
Conditions: 4 (2.0 equiv), 5 (1.1 equiv), [Fp*(thf)]+BF4 (1.0
equiv), BF3·Et2O (2.0 equiv), TMPH (3.0 equiv), DCE, 80 °C.
b
Conditions: 7a (1.0 equiv), 5 (1.1 equiv), DCE, 24 °C, 1 h.
a
c
Conditions: 1a (1.0 equiv), 2 (1.5 equiv), CH2Cl2, 24 °C.
Conditions: 7a (1.0 equiv), 5 (1.1 equiv), CH2Cl2, 40 °C, 16 h.
b
−
Conditions: 1 (2.0 equiv), 2 (1.0 equiv), [Fp*(thf)]+BF4 (1.0
d
Conditions: 6 (1.3 equiv), I2 (1.0 equiv), CH2Cl2/CHCl3, 0−24 °C.
equiv), BF3·Et2O (2.0 equiv), TMPH (3.0 equiv), DCE, 80 °C.
c
Conditions: 3 (1.0 equiv), N-bromosuccinimide (1.0 equiv),
crystallized from CH2Cl2/hexanes for characterization by
single-crystal X-ray diffraction (Figure 2). In comparison to
d
CH2Cl2, 24 °C. Conditions: 3 (1.0 equiv), (NH4)2Ce(NO3)6 (1.9
e
equiv), K2CO3 (2.9 equiv), EtOH/CH2Cl2, 24 °C. Conditions: 3
f
(1.0 equiv), I2(1.0 equiv), CH2Cl2, 0−24 °C. Conditions: 3 (1.0
equiv), TFA (2.0 equiv), wet CH2Cl2, 24 °C.
crystal X-ray diffraction (Figure 1). As a demonstration of
synthetic versatility, 3 was subjected to a series of demetalation
conditions to furnish functionalized organic products (Scheme
3, bottom).
Figure 2. ORTEP (thermal ellipsoids at 50% probability) plot of the
molecular structure of 6. Hydrogen atoms are omitted for clarity.
the C(sp2)−Fe bond in 3 (2.002 Å), which is situated at the
electron-rich β-position of an enol ether, the C(sp2)−Fe bond
in iron complex 6, located at an electron-poor position, is
shorter (1.977 Å).
Diazonium and Azo Compounds as Cycloaddends.
We next turned to diazonium and azo compounds to
investigate the possibility of C−N bond formation using
alkyne-derived allenyliron complexes. We were particularly
interested in the use of arenediazonium salts, by virtue of their
simple preparation and versatile reactivity as electrophilic
nitrogen sources.26 On the basis of our previous results, we
expected the [3 + 2] cycloaddition of arenediazonium
tetrafluoroborates with allenyliron complexes to furnish a
convenient and regioselective route to N-arylpyrazoles.
Previously, diazonium salts have been applied to the synthesis
of a number of heterocyclic scaffolds.27 In particular, pyrazoles
have previously been prepared by formal cycloaddition of
diazonium salts with 1,3-enones,28a 1,4-enones,28b and cyclo-
propanols.28c
Figure 1. ORTEP (thermal ellipsoids at 50% probability) plot of the
molecular structure of 3. Hydrogen atoms are omitted for clarity.
We also investigated the synthesis of a densely substituted
1,5-dihydro-2H-pyrrol-2-one derivative by coupling 1-phenyl-
1-butyne (4) with p-toluenesulfonyl isocyanate (5). Thus, in
the presence of TMPH and BF3·Et2O, 4 and 5 reacted to give
the 1,5-dihydropyrrolone-derived vinyliron complex 6
(Scheme 4, top). We also investigated the preparation of 6
from the isolated allenyliron intermediate 7a. As was observed
by Rosenblum and co-workers,17 the initially formed [3 + 2]
cycloadduct after short reaction times (1 h) was vinyliron
species 6′, derived from 1,3-dihydro-2H-pyrrol-2-one, which
could be isomerized to 6 by treatment with Et3N or by
allowing 5 and 7a to react at higher temperature and longer
reaction times (Scheme 4, middle). In the presence of I2, 6 was
transformed into 6a in moderate yield, with Fp*I being
recovered (Scheme 4, bottom). Vinyliron complex 6 could be
When vinyliron complex 7b was reacted with the series of 4-
substituted arenediazonium tetrafluoroborates 9a−d, organic
products identified as pyrazoles could be isolated in modest
yields (27−36%, Scheme 5, top). However, upon comparison
C
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CH2CCCH3) and an azodicarboxylate ester.13c We found,
however, that when 7b and 13 were reacted in the presence of
BF3·OEt2 as an additive, [3 + 2] cycloaddition took place with
concomitant dealkoxycarbonylation to afford a moderate yield
(36%) of N-acylpyrazole 14 as a single regioisomer (Scheme
6).32
Scheme 5. Pyrazole Synthesis Using Cyclopentadienyl-
Allenyliron Cycloaddition to Aryldiazonium Salts
a
Scheme 6. Pyrazole Synthesis Using Cyclopentadienyl-
Allenyliron Cycloaddition to Diisopropyl Azodicarboxylate
a
a
Conditions: 7b (1.0 equiv), 13 (1.5 equiv), BF3·Et2O (1.5 equiv),
CH2Cl2, 60 °C.
a
Conditions: 7a, 7b, or 11 (1.0 equiv), 9 (1.5 equiv), CH2Cl2, 60 °C.
Regioisomeric ratios reported are those of the crude material.
Allenyliron to Propargyliron Isomerization. During the
course of our investigations, it was found that the purity and
stability of the Fp*-based allenyliron species 1a derived from 1-
phenyl-1-propyne varied greatly depending on the exact
conditions of its synthesis and purification. The reaction of
1-phenyl-1-propyne with Fp*I/AgBF4 followed by deprotona-
tion with Et3N gave a crude product mixture, consisting mainly
of the expected product 1a and a trace amount (<1%) to ca.
70% of a second iron complex, depending on the batch. A
with literature characterization data of substituted pyrazoles,29
we noticed that the regiochemical outcome was unexpected.
The assigned connectivity was further confirmed by X-ray
diffraction (see the Supporting Information). Regardless of the
electronic nature of the substituents on the arenediazonium
salt, only one regioisomer of the pyrazole was observed in the
1H NMR spectrum of the crude material. Finally, we found
that the dialkyl-substituted allenyliron species 11 derived from
3-hexyne also participated in the [3 + 2] cycloaddition.
Notably, this route gave rise to the 3,5-dialkyl-substituted
pyrazole 12 that would be challenging to prepare with good
regioselectivity by conventional methods (Scheme 5, middle).
Notably, while the condensation of a hydrazine and a 3-alkyn-
1-one has been optimized to give a similar pyrazole in a
moderate regioisomeric ratio (up to 6.8:1 rr),30 the approach
presented here provides a route to achieve a better
regioselectivity from the alkyne and diazonium salt as readily
available starting materials (9.0:1 rr).
1
comparison of the H NMR spectrum of this side product (δ
1.60 ppm, C6D6) with data reported by Welker and co-
workers19 and the 13C{1H} (δ −12.2 ppm, C6D6) NMR
spectrum with other reported data15a for related propargylme-
tal complexes allowed its identification as propargyliron
complex 1a′. Moreover, it was found that, upon standing as
a solid or a solution in CD2Cl2 or C6D6, the allenyliron
complex 1a in the crude material isomerized to propargyliron
complex 1a′ to give a mixture in which the propargyliron
species was predominant (propargyliron:allenyliron ≈ 92:8),
suggesting equilibration between the two species.
Postulating that it would act as a more nucleophilic
substrate, we investigated an Fp*-derived allenyl complex as
the starting material. Indeed, a slight increase in yield was
observed when the reaction was conducted under the same
reaction conditions, but the change in ligand from Fp to Fp*
also resulted in a sharp decrease in regioselectivity (from
>100:1 to 1.5:1 rr for the reaction of 7a with 9c). The initially
expected pyrazole regioisomer was observed in considerably
larger quantities, albeit still as the minor isomer. It was found
that the regioselectivity diminished as the temperature
increased (Scheme 5, bottom). We posited that the
unexpected regiochemistry could be explained by interconver-
sion of allenyliron and propargyliron isomers, with the favored
regioisomer arising from a Curtin−Hammett scenario. Though
we were unable to definitively observe the propargyliron
tautomer of 7a or 7b, suggesting an unfavorable equilibrium
for tautomerization, we were able to directly study the allenyl
to propargyl isomerization of the related complex 1a (vide
infra).
Previously, Rosenblum and co-workers observed that
cyclopentadienyliron η1-allyl complexes bearing deuterium
labels or alkyl substituents on the allyl ligand underwent 1,3-
migration of the iron center to give label-scrambled or
rearranged products under mild conditions (0−60 °C).33 On
the basis of a crossover experiment and the observation that
label scrambling was accelerated by irradiation in the presence
of substoichiometric cyclopentadienyliron dicarbonyl dimer, a
source of Fp•, a radical chain mechanism involving homolytic
allylic substitution (SH2′) was proposed. A similar process for
the isomerization of propargyl/allenyliron systems by 1,3-
migration of the iron center was proposed but not observed or
investigated directly.17
Given the relevance of the isomerization to the unexpected
regiochemistry of the [3 + 2] cycloaddition of iron complexes
with diazonium salts described in the previous section, we set
out to investigate the rate and mechanism of the observed
allenyl to propargyl isomerization. First, a reliable procedure
for the preparation of allenyliron complex 1a in high chemical
and isomeric purity was developed (>98% purity and >100:1
allenyliron:propargyliron by 1H NMR; see the Supporting
Information). When a solution of carefully purified 1a in
CD2Cl2 or C6D6 was prepared and monitored with the
rigorous exclusion of light and oxygen at 24 °C, isomerization
To further explore the scope of N-centered dipolar reagents
that could be employed, we investigated the reaction with
azodicarboxylate ester 13, a slightly less reactive electrophile in
comparison to diazonium ions.31 Notably, Wojcicki and co-
workers noted that no reaction was observed between Fp(η1-
D
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to 1a′ proceeded slowly, with <10% conversion taking place
after 24 h (Figure 3).
observed, consistent with interruption of a radical chain
process through interception of the proposed chain carrier,
Fp*•.
To further examine the possibility of Fp*• acting as a radical
chain carrier, the allenyliron complex was also exposed to
substoichiometric Fp*2 in the presence of light (CFL or blue
LED), as previously reported by Rosenblum. Although rate
acceleration was observed in these cases, the interpretation of
these results was complicated by the formation of Cp*Fe-
(CO)(η3-1-phenylallen-1-yl) (1a″),35 which was the main
product of the reaction, along with the propargyliron complex
as a minor product, regardless of the light source and
luminosity. Exposure of 1a to light in the absence of Fp*2
afforded 1a″ cleanly at low concentration, without formation
of the propargyliron species. Complex 1a″ was characterized as
1
a solution in CD2Cl2 and C6D6 by H NMR, 13C NMR (with
1
and without H decoupling), and IR spectroscopy (Scheme 8,
Scheme 8. Irradiation of 1a and Key Spectral Properties of
Figure 3. Fraction of η1-propargyliron 1a′ vs time for 1a → 1a′.
1a″a
We initially hypothesized two pathways for the allenyl to
propargyl isomerization: a radical (SH2′) mechanism analo-
gous to Rosenblum’s proposal for the isomerization of allyliron
species and an electrophilic (SE2′) pathway, on the basis of
previously reported mixed η1,η2 neutral/cationic bimetallic
allyliron complexes, for the isomerization of 1a to 1a′ (Scheme
7, pathways I and III).34 To examine the likelihood of the
Scheme 7. Plausible Mechanisms for Allenyl to Propargyl
Isomerization of Fp*-Iron Complexes
a
Conditions: 1a (0.03 mmol), C6D6 (0.5 mL), 85 W CFL, 15 min.
Fp*2 (1 mol %).
b
top). As shown in Scheme 7, pathway II, this observation
suggests an alternate η1−η3−η1 isomerization mechanism
mediated by decarbonylation and recarbonylation. To examine
this possibility, a solution of 1a″ in C6D6 (>95% purity) was
subjected to bubbling of CO in an NMR tube or was stirred
under a CO atmosphere in a reaction vial, either in the dark or
under irradiation by a CFL. Under all conditions examined, no
conversion to propargyliron complex 1a′ was observed, making
pathway II unlikely to be operative in the facile isomerization
of 1a to 1a′ (Scheme 8, bottom).
radical pathway I, 1a was heated in the presence of a variety of
radical traps (Table 1). In each case (entry 1 vs entries 2 and 3
and entry 4 vs entries 5 and 6), a decrease in yield was
Table 1. Radical Scavenger Effect on the η1-Allenyliron to
η1-Propargyliron Isomerization
Finally, we examined the possibility that isomerization could
be promoted by electrophilic species through two-electron
pathways (Scheme 7, pathway III). To test the possibility that
(Fp*)+ could promote isomerization, [Fp*(thf)]+[BF4]− (15
mol %) was added to a solution of 1a in CD2Cl2 and the
1
c
reaction progress was monitored by H NMR spectroscopy at
entry
radical scavenger
conversion (%)
24 °C. As shown in Figure 3, a strong rate acceleration was
observed in comparison to the background, with the reaction
taking place at a ca. 30 times faster rate in comparison to the
uncatalyzed process, as determined by the initial rate kinetics.
Given measurements of the acidity of cationic alkyne-Fp*
complexes,22 Et3NH+ should be acidic enough to protonate 1a
to generate equilibrium concentrations of [Fp*(η2-PhC
CMe)]+, the dissociation of which would generate (Fp*)+.
Accordingly, a solution of 1a in CD2Cl2 was treated with
[Et3NH]+[BF4]− (100 mol %). A significant rate acceleration
was also observed in this case, though it was less dramatic than
a
1
2
3
4
5
6
none
85
64
65
60
7
a
O2 purged
BzOOBz 20%
none
TEMPO 5%
DHA 50%
a
b
b
b
44
a
b
c
Conditions: 1a (0.0125 mmol), C6D6 (0.5 mL), 51.0 °C, 1 h.
Conditions: 1a (0.01 mmol), C6D6 (0.5 mL), 45.0 °C, 1 h.
Abbreviations: TEMPO = 2,2,6,6-tetramethylpiperidine-1-oxyl, DHA
= 9,10-dihydroanthracene.
E
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what was observed when [Fp*(thf)]+[BF4]− was employed
resolution mass spectra were obtained on a Bruker Daltonics, Inc.
APEXIII 7.0 TESLA FTMS instrument (ESI) or Waters Micromass
GCT Premier instrument (EI). IR spectra were recorded on a
Thermo Scientific Nicolet iS5 spectrometer (iD5 ATR, diamond) and
are reported in terms of the frequency of the absorption (cm−1).
Elemental analyses were performed by Atlantic Microlabs Inc.,
Norcross, GA.
(Figure 3).
−
Control experiments showed that Et3N, BF4 sources, Ag
powder, and AgI did not promote the allenyl to propargyl
isomerization (see the Supporting Information). Therefore, it
is likely that small amounts of cationic Fp* species in the crude
product and/or prolonged exposure to [Et3NH]+[BF4]−
during the synthesis of the allenyliron complex 1a are
responsible for the generation of variable quantities of the
propargyliron complex as a side product before we re-
examined our synthetic procedure.
Under a variety of conditions, no significant allenyl to
propargyl isomerization was observed for allenyliron complexes
derived from 1-phenyl-1-butyne or 3-hexyne. However, the
regioselectivity of the coupling of allenyliron complex 7a and
diazonium salts suggests that the propargyliron complex is
present in equilibrium, though the equilibrium constant for
allenyl to propargyl isomerization appears to be unfavorable.36
In our previously reported catalytic C−H functionalization
chemistry,21,22 no sign of isomerization of the postulated
allenyliron intermediate was observed, presumably due to the
high electrophilicity of the oxocarbenium and iminium
intermediates, which intercept the catalytic allenyliron species
as soon as it forms.
One-Pot Synthesis of Iron Complex 3. In an argon-filled
glovebox, a threaded reaction tube (5 mL) equipped with a magnetic
−
stir bar was charged with [Fp*(thf)]+BF4 (203 mg, 0.50 mmol, 1.0
equiv), 1-phenyl-1-propyne (125 μL, 1.0 mmol, 2.0 equiv), ethyl
trifluoropyruvate (66 μL, 0.50 mmol, 1.0 equiv), and DCE (1 mL).
Subsequently, BF3·OEt2 (123 μL, 1.0 mmol, 2.0 equiv) and distilled
TMPH (235 μL, 1.5 mmol, 3.0 equiv) were added in rapid succession
and the reaction tube was fitted with a septum cap and removed from
the glovebox. The reaction mixture was stirred for 12 h at 80 °C, and
the crude material was loaded directly onto a silica gel column packed
with hexanes and purified by chromatography (hexanes/EtOAc 9/1
to 4/1) to give the product 3 as an oily yellow solid that crystallized
upon storage under nitrogen. Yield: 135 mg, 51%.
Alternative Synthesis of Iron Complex 3 Starting from η1-
Allenyl Pentamethylcyclopentadienyliron Dicarbonyl Com-
plex 1a. In an argon-filled glovebox, a threaded reaction tube (5 mL)
equipped with a magnetic stir bar was charged with ethyl
trifluoropyruvate (99 μL, 0.75 mmol, 1.5 equiv). A solution of freshly
prepared allenyliron complex 1a (182 mg, 0.50 mmol, 1.0 equiv) in
CH2Cl2 (0.5 mL) was then added, and the reaction tube was fitted
with a septum cap and removed from the glovebox. The reaction
mixture was then stirred at room temperature (24 °C) for 2.5 h. The
crude mixture was concentrated in vacuo and purified by flash column
chromatography on neutral aluminum oxide (hexanes/CH2Cl2 1/0 to
10/1 to 0/1) and subsequent recrystallization to provide the desired
product 3 as a bright yellow solid. A crystal suitable for X-ray
diffraction was obtained by carefully laying hexanes onto a CH2Cl2
CONCLUSION
■
In summary, we investigated the [3 + 2] cycloaddition of
alkyne-derived allenyliron species with a series of dipolar
reagents as a means of preparing heterocyclic compounds in a
regiocontrolled manner. Using this approach, we prepared a
number of heterocyclic scaffolds of general interest, including
dihydrofurans, dihydropyrrolones, and pyrazoles. In the case of
pyrazoles, the observed regiochemical outcome differed from
our initial expectations, a result that could be rationalized by
isomerization of allenyliron species to their propargyliron
counterparts. We investigated this process through a series of
mechanistic experiments. Further synthetic applications and
investigations of ligand effects are ongoing in our laboratory
and will be reported in due course.
1
solution of the corresponding compound. Yield: 128 mg, 48%. H
NMR (500 MHz, CD2Cl2): δ 7.61 (d, J = 7.0 Hz, 2H), 7.35 (t, J = 7.0
Hz, 2H), 7.30−7.27 (m, 1H), 4.31 (q, J = 7.0 Hz, 2H), 3.25−3.15 (m,
2H), 1.70 (s, 15H), 1.34 (t, J = 7.0 Hz, 3H). 19F NMR (470 Hz,
CD2Cl2): −75.9. 13C NMR (125 MHz, CD2Cl2): δ 217.0, 216.8,
169.2, 151.4, 134.7, 129.1, 127.6, 127.4, 124.3 (q, J = 281 Hz), 108.0,
96.5, 83.4 (q, J = 23 Hz), 62.2, 52.7, 13.8, 9.4. IR (ATR): ν(CO)
1993, 1931, 1753 cm−1. HRMS (ESI): calcd for C26H28F3FeO5 [M +
H]+ 533.1233, found 533.1232. Anal. Calcd for C26H27F3FeO5: C,
58.66; H, 5.11. Found: C, 58.74; H, 5.14.
One-Pot Synthesis of Iron Complex 6. In a septum-capped,
EXPERIMENTAL SECTION
argon-filled reaction tube (5 mL) equipped with a magnetic stir bar
■
−
and charged with [Fp*(thf)]+BF4 (203 mg, 0.50 mmol, 1.0 equiv)
General Information. Anhydrous solvents were purchased from
Acros (AcroSeal packaging), Sigma-Aldrich (Sure/Seal packaging),
and Frontier Scientific (J&KSeal packaging), respectively, and were
transferred into an argon-filled glovebox and used as received. All
reagents were purchased from Oakwood, Acros, Alfa Aesar, or Sigma-
Aldrich and used as received. Compounds were purified by flash
column chromatography using SiliCycle SiliaFlash F60 silica gel,
unless otherwise indicated. Thin-layer chromatography (TLC) was
performed on Silicycle 250 μm (analytical) or 1000 μm (preparative)
silica gel plates. Compounds were visualized by irradiation with UV
light or by staining with iodine/silica gel, potassium permanganate, or
phosphomolybdic acid (PMA). Yields refer to isolated compounds,
unless otherwise indicated. 1H NMR spectra were recorded on a
Bruker 400, 500, or 600 MHz spectrometer and are referenced
relative to residual CDCl3 proton signals at δ 7.26 ppm, CD2Cl2 at δ
were placed 1-phenyl-1-propyne (125 μL, 1.0 mmol, 2.0 equiv), tosyl
isocyanate (82 μL, 0.54 mmol, 1.1 equiv), and DCE (1 mL). Then, in
rapid succession, BF3·OEt2 (123 μL, 1.0 mmol, 2.0 equiv) and
distilled TMPH (235 μL, 1.5 mmol, 3.0 equiv) were added. After it
was stirred for 12 h at 80 °C, the crude reaction mixture was purified
directly by chromatography (CH2Cl2/EtOAc 1/0 to 49/1) to give the
product 6 as an oily yellow solid that crystallized upon storage under
nitrogen. A crystal suitable for X-ray diffraction was obtained by
slowly cooling a solution in hot CH2Cl2/hexanes (1/20 v/v). Yield:
126 mg, 44%.
Alternative Synthesis of Iron Complex 6 Starting from η1-
Allenyl Pentamethylcyclopentadienyliron Dicarbonyl Com-
plex 7a. In an argon-filled glovebox, a threaded reaction tube (5 mL)
equipped with a magnetic stir bar was charged with TsNCO (37 μL,
0.22 mmol, 1.1 equiv). A solution of freshly prepared allenyliron
complex 7a (75 mg, 0.20 mmol, 1.0 equiv) in CH2Cl2 (0.6 mL) was
then added. The reaction tube was fitted with a septum cap and
removed from the glovebox. The reaction mixture was then stirred at
40 °C for 16 h. Subsequently, the reaction mixture was concentrated
in vacuo, and the crude material was purified by flash column
chromatography on neutral aluminum oxide (hexanes/CH2Cl2 1/0 to
10/1 to 0/1) and subsequent recrystallization from hexanes/CH2Cl2
(10/1 v/v) to provide the desired product 6 as a bright yellow solid.
5.33 ppm, and C6D6 at δ 7.15 ppm. Data for H and 19F NMR are
1
reported as follows: chemical shift (δ, ppm), multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, ap = apparent),
integration, and coupling constant (Hz). 13C NMR spectra were
recorded on a Bruker 400, 500, or 600 MHz spectrometer and are
referenced to CDCl3 at δ 77.16 ppm, CD2Cl2 at δ 53.84 ppm, and
C6D6 at δ 128.39 ppm. Unless stated otherwise, the 13C NMR spectra
were obtained with 1H decoupling. Data for 13C NMR are reported in
terms of chemical shift and multiplicity where appropriate. High-
F
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Yield: 86 mg, 75%. 1H NMR (400 MHz, CD2Cl2): δ 7.57 (br s, 1H),
7.41−7.40 (m, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.21−7.19 (m, 2H),
7.04−7.02 (m, 2H), 6.98 (brs, 1H), 6.40 (brs, 1H), 5.37 (s, 1H), 2.32
(s, 3H), 2.00 (s, 3H), 1.73 (s, 15H). 13C NMR (100 MHz, CD2Cl2):
δ 216.1, 213.7, 167.4, 143.7, 139.3, 137.9, 136.8, 129.0, 128.7, 128.22,
128.16, 127.4, 125.2, 96.8, 75.8, 21.2, 14.0, 9.5. IR (ATR): ν(CO)
1993, 1940, 1730 cm−1. HRMS (ESI) Calcd for C30H32FeNO5S [M +
H]+: 574.1345. Found: 574.1340. Anal. Calcd for C30H31FeNO5S: C,
62.83; H, 5.45. Found: C, 62.57; H, 5.41.
NMR (376 MHz, CDCl3): δ −78.8. 13C NMR (100 MHz, CDCl3): δ
166.2, 153.5, 129.9, 128.8, 128.2, 127.9, 122.8 (q, J = 282 Hz), 84.8
(q, J = 31 Hz), 63.2, 51.8, 47.1, 14.0.
Ethyl 2-Hydroxy-5-oxo-5-phenyl-2-(trifluoromethyl)-
pentanoate (3d). To a solution of recently chromatographed iron
complex 3 (37 mg, 69 μmol) in CH2Cl2 (0.5 mL, stored in air on the
benchtop) was added trifluoroacetic acid (10.7 μL, 0.14 mmol, 2.0
equiv). The reaction mixture was stirred overnight (12 h) under air.
The purplish mixture was filtered through a short plug of basic
aluminum oxide and washed with CH2Cl2 and the filtrate
concentrated in vacuo to give the crude residue, which was purified
by preparatory plate chromatography (SiO2, hexanes/EtOAc 85/15)
to afford 3d. Yield: 21 mg, 98%. 1H NMR (400 MHz, CDCl3): δ 7.95
(d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H),
4.46−4.31 (m, 2H), 4.00 (s, 1H), 3.28−3.19 (m, 1H), 2.95−2.87 (m,
1H), 2.53−2.46 (m, 1H), 2.43−2.36 (m, 1H), 1.35 (t, J = 7.1 Hz,
3H). 19F NMR (376 MHz, CDCl3): δ −78.3. 13C NMR (100 MHz,
CDCl3): δ 198.2, 169.8, 136.4, 133.4, 128.7, 128.1, 123.5 (q, J = 285
Hz), 64.1, 31.9, 26.2, 13.9 (the quaternary carbon was not observed).
4-Iodo-3-methyl-5-phenyl-1-tosyl-1,5-dihydro-2H-pyrrol-2-
one (6a). To a solution of recrystallized iron complex 6 (33 mg, 58
μmol, 1.0 equiv) in dry CH2Cl2 (0.5 mL) at 0 °C was added dropwise
a solution of iodine (0.1 M in CHCl3, 460 μL, 0.80 equiv) over 15
min. The mixture was stirred at 0 °C for 30 min and then at room
temperature for another 2 h. The solution was chromatographed
directly (hexanes/EtOAc 95/5 to the desired product and 85/15 to
4/1 to Fp*I) to afford 6a. Yield: 12 mg, 59%. Additionally, Fp*I was
recovered (9.2 mg, 53%). The yield of 6a was much lower (7.2 mg,
Synthesis of Iron Complex 6′ Starting from η1-Allenyl
Pentamethylcyclopentadienyliron Dicarbonyl Complex 7a. In
an argon-filled glovebox, a threaded reaction tube (5 mL) equipped
with a magnetic stir bar was charged with a solution of 7a (98 mg,
0.26 mmol, 1.0 equiv) in dry DCE (2 mL). Tosyl isocyanate (45 μL,
0.29 mmol, 1.1 equiv) was added. The reaction tube was then fitted
with a septum cap and removed from the glovebox, whereupon the
reaction mixture was stirred at room temperature for 1 h. The
reaction mixture was loaded directly onto a column equilibrated with
hexanes/CH2Cl2 (1/1 v/v) and quickly purified by chromatography
(hexanes/CH2Cl2/EtOAc 9/1/0 to 1/1/0 to 0/49/1) to afford a
bright yellow amorphous solid 6′ that dried to a foam under high
1
vacuum. Yield: 64 mg, 43%. H NMR (400 MHz, CDCl3): δ 7.61−
7.59 (d, J = 8.3 Hz, 2H), 7.354−7.348 (m, 3H), 7.29−7.27 (m, 4H),
2.74 (q, J = 7.6 Hz, 1H), 2.42 (s, 3H), 1.62 (s, 15H), 1.21 (d, J = 7.6
Hz, 3H). 13C NMR (100 Hz): 217.3, 215.8, 183.2, 144.3, 138.1,
137.3, 137.0, 136.6, 129.7, 129.2, 127.7, 127.6, 127.3, 126.3, 96.4,
21.4, 18.0, 9.3.
Ethyl 4-Bromo-5-phenyl-2-(trifluoromethyl)-2,3-dihydrofur-
an-2-carboxylate (3a). To a solution of recently chromatographed
iron complex 3 (13 mg, 23 μmol, 1.0 equiv) in dry CH2Cl2 (0.5 mL)
was added NBS (4.2 mg, 23 μmol, 1.0 equiv). The mixture was stirred
at 24 °C under air and monitored by thin-layer chromatography until
the disappearance of the starting material (1 h) and concentrated in
vacuo, and the crude residue was purified by preparatory thin-layer
chromatography (SiO2, hexanes/EtOAc 85/15) to give 3a. Yield: 4.6
mg, 54%. Alternatively, 3a could be obtained using stoichiometric Br2
in place of NBS, though side product formation was apparent and a
reduced yield of the desired product was observed. Yield: 1.3 mg,
15%. 1H NMR (400 MHz, CDCl3): δ 7.92−7.90 (m, 2H), 7.42−7.40
(m, 3H), 4.36 (q, J = 7.2 Hz, 2H), 3.54 (s, 2H), 1.35 (t, J = 7.2 Hz,
3H). 19F NMR (376 MHz, CDCl3) δ −78.9. 13C NMR (100 MHz,
CDCl3): δ 166.1, 149.7, 129.7, 128.3, 128.1, 127.3, 122.7 (q, J = 282
Hz), 86.5, 83.5 (q, J = 31 Hz), 63.3, 43.4, 13.9. HRMS (ESI) Calcd
for C14H13O3BrF3 [M + H]+: 364.9995. Found: 364.9998.
Diethyl 5-Phenyl-2-(trifluoromethyl)-2,3-dihydrofuran-2,4-
dicarboxylate (3b). To a solution of recently chromatographed 3
(29.2 mg, 54.9 μmol) in dry CH2Cl2 (0.3 mL) were added solid
K2CO3 (22.2 mg, 161 μmol, 2.9 equiv), EtOH (1.0 mL), and ceric
ammonium nitrate (CAN) (57.4 mg, 105 μmol, 1.9 equiv). The
mixture was stirred in air at 24 °C until the disappearance of the
starting material (2 h). The mixture was then filtered through a plug
of silica, concentrated in vacuo, and purified by preparatory plate
chromatography (SiO2, hexanes/EtOAc 85/15) to give 3b. Yield: 8.5
mg, 43%. 1H NMR (600 MHz, CDCl3): δ 7.86−7.85 (m, 2H), 7.47−
7.45 (m, 1H), 7.43−7.40 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 4.18−
4.15 (m, 2H), 3.60−3.53 (m, 2H), 1.36 (t, J = 7.2 Hz, 3H), 1.24 (t, J
= 7.2 Hz, 3H). 19F NMR (282 MHz, CDCl3): δ −78.6. 13C NMR
(151 MHz, CDCl3): δ 165.9, 163.5, 163.3, 131.1, 129.5, 128.1, 127.8,
122.7 (q, J = 283 Hz), 101.9, 84.6 (q, J = 31 Hz), 63.3, 60.5, 37.4,
14.2, 14.0.
1
31%) when 1.0 equiv each of 6a and I2 were used instead. H NMR
(400 MHz, CDCl3): δ 7.39−7.37 (m, 3H), 7.32−7.28 (m, 2H), 7.10
(d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 5.53 (s, 1H), 2.36 (s,
3H), 1.93 (s, 3H). 13C NMR (400 MHz, CDCl3): δ 165.8, 144.8,
139.6, 135.5, 134.0, 129.3, 129.2, 128.8, 128.4, 128.0, 118.9, 71.5,
21.7, 13.4.
General Procedure for the Synthesis of N-Arylpyrazoles. In
an argon-filled glovebox, a sealed reaction tube equipped with a
magnetic stir bar was charged with diazonium tetrafluoroborate (0.30
mmol, 1.5 equiv). A solution of freshly prepared allenyliron complex
(0.20 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) was added in rapid
succession. The reaction tube was sealed and moved from the
glovebox. The reaction tube was placed in an oil bath, which was
preheated to 60 °C. After completion of the reaction (typically 12 h),
the reaction mixture was cooled to room temperature. The crude
mixture was concentrated in vacuo and purified by flash column
chromatography to provide the desired product.
5-Methyl-1,3-diphenyl-1H-pyrazole (10a). This compound was
prepared following the general procedure using iron complex 7b (59
mg, 0.19 mmol, 1.0 equiv) and phenyldiazonium tetrafluoroborate
(56 mg, 0.29 mmol, 1.5 equiv). The reaction mixture was stirred at 60
°C for 12 h, and the crude residue was purified by flash column
chromatography (hexanes/EtOAc 30/1 to 10/1). The desired
product 10a was obtained as a white solid. The regioisomeric ratio
1
(>100:1 rr) was determined by H NMR of the crude residue. Yield:
1
12 mg, 27%. H NMR (400 MHz, CDCl3): δ 7.87−7.85 (m, 2H),
7.54−7.47 (m, 4H), 7.42−7.37 (m, 3H), 7.33−7.30 (m, 1H), 6.53 (s,
1H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 151.5, 140.2,
140.0, 133.4, 129.1, 128.6, 127.8, 127.6, 125.7, 125.0, 104.4, 12.6.
1-(4-Methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazole (10b).
This compound was prepared following the general procedure using
iron complex 7b (53 mg, 0.17 mmol, 1.0 equiv) and 4-
methoxybenzenediazonium tetrafluoroborate (56 mg, 0.25 mmol,
1.5 equiv). The reaction mixture was stirred at 60 °C for 12 h, and the
crude residue was purified by flash column chromatography
(hexanes/EtOAc 30/1 to 5/1). The desired product 10b was
obtained as a pale yellow solid. The regioisomeric ratio (>100:1 rr)
was determined by 1H NMR of the crude residue. Yield: 16 mg, 36%.
1H NMR (500 MHz, CDCl3): δ 7.86−7.84 (m, 2H), 7.43−7.38 (m,
4H), 7.31−7.28 (m, 1H), 7.00−6.99 (m, 2H), 6.50 (s, 1H), 3.86 (s,
3H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 159.1, 151.1,
Ethyl 4-Iodo-5-phenyl-2-(trifluoromethyl)-2,3-dihydrofur-
an-2-carboxylate (3c). To a solution of recently chromatographed
iron complex 3 (77.8 mg, 0.15 mmol, 1.0 equiv) in dry CH2Cl2 (0.5
mL) was added I2 (0.1 M in CH2Cl2, 1.5 mL, 1.0 equiv) at 0 °C. The
reaction mixture was stirred at 24 °C for 2 h and concentrated in
vacuo, and the crude residue was purified by flash column
chromatography (hexanes/EtOAc85/15) to give 3c. Yield: 25 mg,
42%. Additionally, Fp*I was recovered (34 mg, 63%). 1H NMR (400
MHz, CDCl3): δ 7.62−7.59 (m, 2H), 7.37−7.35 (m, 3H), 4.34 (q, J =
7.2 Hz, 2H), 3.31 (d, J = 2.4 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). 19F
G
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Article
140.3, 133.5, 133.1, 128.5, 127.6, 126.6, 125.7, 114.3, 103.8, 55.6,
12.4.
Accession Codes
CCDC 2054882, 2059006, and 2059267 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
5-Methyl-1-(4-nitrophenyl)-3-phenyl-1H-pyrazole (10c). This
compound was prepared following the general procedure using iron
complex 7b (59 mg, 0.19 mmol, 1.0 equiv) and 4-nitrobenzenedia-
zonium tetrafluoroborate (70 mg, 0.29 mmol, 1.5 equiv). The
reaction mixture was stirred at 60 °C for 12 h, and the crude residue
was purified by flash column chromatography (hexanes/EtOAc 30/1
to 10/1). The desired product 10c was obtained as a white solid. The
1
regioisomeric ratio (>100:1 rr) was determined by H NMR of the
1
crude residue. Yield: 18 mg, 35%. H NMR (400 MHz, CDCl3): δ
AUTHOR INFORMATION
Corresponding Author
■
8.38−8.35 (m, 2H), 7.87−7.85 (m, 2H), 7.81−7.77 (m, 2H), 7.45−
7.41 (m, 2H), 7.38−7.34 (m, 1H), 6.61 (d, J = 0.8 Hz, 1H), 2.52 (d, J
= 0.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 153.0, 145.9, 145.0,
140.6, 132.5, 128.7, 128.4, 125.8, 124.8, 123.9, 106.6, 13.4.
Yi-Ming Wang − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States;
orcid.org/0000-0001-6414-0908; Email: ym.wang@
pitt.edu
Methyl 4-(5-Methyl-3-phenyl-1H-pyrazol-1-yl)benzoate (10d).
This compound was prepared following the general procedure using
iron complex 7b (53 mg, 0.17 mmol, 1.0 equiv) and 4-
(methoxycarbonyl)benzenediazonium tetrafluoroborate (64 mg, 0.25
mmol, 1.5 equiv). The reaction mixture was stirred at 60 °C for 12 h,
and the crude residue was purified by flash column chromatography
(hexanes/EtOAc 30/1 to 10/1). The desired product 10d was
obtained as a white solid. The regioisomeric ratio (>100:1 rr) was
Authors
Jin Zhu − Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260, United States
Austin C. Durham − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
Yidong Wang − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
James C. Corcoran − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
Xiao-Dong Zuo − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
Steven J. Geib − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States;
orcid.org/0000-0002-9160-7857
1
1
determined by H NMR of the crude residue. Yield: 17 mg, 35%. H
NMR (500 MHz, CDCl3): δ 8.17−8.16 (m, 2H), 7.87−7.85 (m, 2H),
7.65 (d, J = 8.5 Hz, 2H), 7.43−7.40 (m, 2H), 7.35−7.32 (m, 1H),
6.57 (s, 1H), 3.96 (s, 3H), 2.46 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 166.4, 152.2, 143.6, 140.3, 133.0, 130.6, 128.7, 128.6,
128.1, 125.8, 123.9, 105.6, 52.3, 13.1.
3-Ethyl-5-methyl-1-(4-nitrophenyl)-1H-pyrazole (12). This com-
pound was prepared following the general procedure using iron
complex 11 (49 mg, 0.19 mmol, 1.0 equiv) and 4-nitrobenzenedia-
zonium tetrafluoroborate (70 mg, 0.29 mmol, 1.5 equiv). The
reaction mixture was stirred at 60 °C for 12 h, and the crude residue
was purified by flash column chromatography (hexanes/EtOAc 30/1
to 10/1). The desired product 12 was obtained as a yellow oil. The
regioisomeric ratio (9.0:1 rr) was determined by GCMS. Yield: 17
mg, 40%. 1H NMR (400 MHz, CDCl3): δ 8.34−8.30 (m, 2H), 7.70−
7.67 (m, 2H), 6.11 (s, 1H), 2.68 (q, J = 7.6 Hz, 2H), 2.44 (d, J = 0.3
Hz, 3H), 1.28 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
156.8, 145.6, 145.1, 139.8, 124.7, 123.6, 107.9, 21.5, 13.7, 13.3.
HRMS (ESI) Calcd for C12H14N3O2 [M + H]+: 232.1081. Found:
232.1084. The connectivity was assigned by nuclear Overhauser effect
spectroscopy.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00032
Author Contributions
†J.Z. and A.C.D. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Synthesis of Isopropyl 5-Methyl-3-phenyl-1H-pyrazole-1-
carboxylate (14). In a glovebox, diisopropyl azodicarboxylate (60
μL, 0.31 mmol, 1.6 equiv) and BF3·OEt2 (38 μL, 0.31 mmol, 1.6
equiv) were dissolved in CH2Cl2 (0.25 mL) in a reaction tube
equipped with a magnetic stir bar. A solution of allenyliron complex
7b (59 mg, 0.19 mmol, 1.0 equiv) in CH2Cl2 (0.25 mL) was added in
rapid succession. The reaction mixture was stirred at 60 °C for 12 h,
and the crude residue was purified by flash column chromatography
(hexanes/EtOAc 30/1 to 5/1). The desired product 14 was obtained
as a brown oil. The regioisomeric ratio (>20:1 rr) was determined by
We gratefully acknowledge the University of Pittsburgh for
startup support and a Central Research Development Fund
grant (FY 2019, No. 1214).
REFERENCES
■
(1) For selected reviews on heterocycles, see: (a) Gomtsyan, A.
Heterocycles in drugs and drug discovery. Chem. Heterocycl. Compd.
2012, 48 (1), 7−10. (b) Godoi, B.; Schumacher, R. F.; Zeni, G.
Synthesis of Heterocycles via Electrophilic Cyclization of Alkynes
Containing Heteroatom. Chem. Rev. 2011, 111 (4), 2937−2980.
(c) Murray, C. W.; Rees, D. C. Opportunity Knocks: Organic
Chemistry for Fragment-Based Drug Discovery (FBDD). Angew.
Chem., Int. Ed. 2016, 55 (2), 488−492. (d) Ritchie, T. J.; Macdonald,
S. J. The impact of aromatic ring count on compound developability–
are too many aromatic rings a liability in drug design? Drug Discovery
Today 2009, 14 (21−22), 1011−20.
1
1H NMR of the crude residue. Yield: 17 mg, 36%. H NMR (400
MHz, CDCl3): δ 7.87−7.85 (m, 2H), 7.43−7.34 (m, 3H), 6.48 (s,
1H), 5.29−5.23 (m, 1H), 2.59 (s, 3H), 1.48 (d, J = 6.4 Hz, 6H). 13C
NMR (125 MHz, CDCl3): δ 153.9, 150.2, 145.1, 132.0, 128.9, 128.6,
126.5, 107.7, 72.6, 21.8, 14.7. HRMS (ESI) Calcd for C14H17N2O2
[M + H]+: 245.1285. Found: 245.1285. The connectivity was verified
by an independent synthesis of the pyrazole following literature
reports (see the Supporting Information).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00032.
■
sı
Experimental procedures, kinetic data, and spectroscopic
data for iron complexes and organic products (PDF)
(3) Palomer, A.; Cabré, F.; Pascual, J.; Campos, J.; Trujillo, M. A.;
Entrena, A.; Gallo, M. A.; García, L.; Mauleón, D.; Espinosa, A.
H
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