Arene Amination Instead of Fluorination: Substitution Pattern Governs the Reactivity of Dialkoxybenzenes with Selectfluor

Article abstract of DOI:10.1021/acs.joc.1c00231

Arene substitution patterns are well-known to affect the regioselectivity of a given transformation but not necessarily the type of reactivity. Herein, we report that the substitution pattern of alkoxyarenes dictates whether a putative one-electron or two

Full text of DOI:10.1021/acs.joc.1c00231

pubs.acs.org/joc
Article
Arene Amination Instead of Fluorination: Substitution Pattern
Governs the Reactivity of Dialkoxybenzenes with Selectfluor
Joseph N. Capilato and Thomas Lectka*
Cite This: J. Org. Chem. 2021, 86, 5771−5777
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ABSTRACT: Arene substitution patterns are well-known to affect the
regioselectivity of a given transformation but not necessarily the type of
reactivity. Herein, we report that the substitution pattern of alkoxyarenes
dictates whether a putative one-electron or two-electron reaction
predominates in reactions with Selectfluor. A series of amination products
is presented, resulting from the single-electron oxidation of electron-rich
arenes followed by direct C−H to C−N bond formation. We demonstrate
the ability of this transformation to synthesize medicinally and biologically
relevant nitrogen heterocycles. Lastly, this unusual “mechanistic switch” is
probed with computational chemistry and competition experiments.
functionalize an unactivated carbon atom, as opposed to
substitution chemistry involving amines and alkyl, acyl, or aryl
halides, are particularly useful; however, they may suffer from a
lack of regioselectivity.6 Thus, the site-selective amination of
electron-rich arenes is of practical utility, especially given the
ubiquity of nitrogen-containing pharmaceuticals.7 Typically,
these valuable products are synthesized in a roundabout
fashion from the electron-rich arene via either a halogenation−
cross-coupling sequence or a nitration−reduction−substitution
sequence.8 Direct C−H to C−N bond formation between
arenes and nitrogen heterocycles is more rare, although a few
recent methods have been reported.9 In this article, we disclose
a remarkably simple and effective solution to this problem
using only the coupling partners (the nitrogen heterocycle and
electron-rich arene) and commercially available Selectfluor.
Moreover, we reveal a mechanistic switch that occurs based on
the substitution pattern of the electron-rich arene, allowing a
user to toggle between the amination and fluorination
products.
1. INTRODUCTION
Electron-rich aromatic compounds are typically best-known for
their ability to engage in electrophilic aromatic substitution
(EAS) reactions with strong electrophiles.1 This classic
reaction paradigm and the complementary topic of directing
group effects are fundamental concepts taught to every student
of organic chemistry. Less appreciated is the dual ability of
these electron-rich arenes to undergo single-electron oxidation
to the corresponding radical cations.2 Several groups have
recently demonstrated the synthetic utility of this approach en
route to compounds of biological or pharmaceutical interest.3
Our laboratory has found a class of electron-rich arenes that
can be predictably tuned to favor either an apparent two-
electron or a sequential one-electron reactivity (i.e., EAS vs
oxidation to the radical cation, respectively) under the same
conditions.
Using Selectfluor as the key reagent in our studies, we found
that dialkoxyarenes react based on their substitution patterns.
At the onset, we reasoned that Selectfluor would be ideal for
this study as it possesses the necessary dual reactivity; it is
widely employed as both an electrophilic fluorination reagent
and an oxidant.4 Surprisingly, upon the reaction with
Selectfluor, meta-dialkoxyarenes give exclusively the EAS
fluoride product whereas ortho- and para-dialkoxyarenes
predominantly form amination products, resulting from the
putative single-electron oxidation of the electron-rich arene.
We quickly recognized the potential of this divergent reactivity
to be useful as a synthetic method as well as a tool to better
understand these archetypal reactions.
2. RESULTS AND DISCUSSION
2.1. The Substitution Pattern Determines Amination
vs Fluorination. Our attention was drawn to this reactivity
upon treating Selectfluor with veratrole (1,2-dimethoxyben-
Received: January 29, 2021
Published: March 31, 2021
C−N bond-forming reactions are well-studied and widely
employed throughout synthetic chemistry.5 Methods that
https://doi.org/10.1021/acs.joc.1c00231
© 2021 American Chemical Society
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Article
zene) in acetonitrile at room temperature. Instead of the
expected EAS product 1-fluoro-3,4-dimethoxybenzene, we
isolated an amination product, an adduct of veratrole and
the Selectfluor-derived amine, in a nearly quantitative yield
(Figure 1, compound 7). This came as a surprise given our
Figure 2. Scope of nitrogen heterocycles.
providing compounds 1−4 in good yields. A dibrominated
imidazole and 2-methylphthalimidobenzimidazole provided
the desired aryl adducts in a higher yield than unsubstituted
imidazole and benzimidazole (compounds 5 and 6, respec-
tively), a notable result given the prevalence of imidazole- and
benzimidazole-containing pharmaceuticals that are substituted
at the 2-position.14
Figure 1. Divergent reactivity of dialkoxybenzenes with Selectfluor.
knowledge of similar products being prepared using a dual-
catalyst system, since no examples have been reported using
Selectfluor alone.10 Accordingly, several analogous arenes were
tested to determine the generality of the reaction. Anisole
afforded only the EAS fluorination product upon a reaction
with Selectfluor,11 suggesting the need for an increased
electron-rich character to accomplish the amination. That
idea, however, was contravened by the reaction of 1,3-
dimethoxybenzene with Selectfluor, which exclusively formed
the EAS aryl fluoride.12 Further complicating the situation, 1,4-
dimethoxybenzene predominately gave the amination product,
although in lower yield than veratrole. Given the trend
presented in Figure 1, it was not immediately obvious what
might be causing the reactivity switch between the fluorination
and amination reactions. From both a steric and an electronic
viewpoint, one would not predict a large difference between
the three isomers of dimethoxybenzene in regard to
fluorination versus amination.
2.2. Synthetic Utility and Product Examples. While the
aryl−Selectfluor adducts are not high-demand compounds
themselves, they can be easily transformed to medicinally
relevant aryl piperazines using a one-pot process developed by
the Ritter group (Figure 2, compounds 7 and 8).10 We found
that other types of adducts can be formed in a high yield by
performing the reaction in the presence of a variety of nitrogen
heterocycles, thereby greatly increasing the synthetic utility of
the reaction. As some veratrole−nitrogen heterocycle adducts
are known to be medicinally active, such as the drug
Domipizone,13 these products demonstrate the simple and
direct synthesis of pharmaceutically relevant veratrole adducts.
Screening was performed using veratrole as a model electron-
rich arene; many nitrogen heterocycles were found to be
competent in the reaction, although the use of Selectfluor
could be problematic with certain highly reactive heterocycles.
Nevertheless, benzimidazole, benzotriazole, 5-tBu-tetrazole,
and imidazole were found to work well in the reaction,
Having established some representative examples for the
substrate scope of the nitrogen heterocycles, we next shifted
our focus to examining the substrate scope of the electron-rich
arenes. Beyond 1,2-dialkoxybenzenes, we also demonstrate that
their 1,4-substituted analogues can undergo the amination,
albeit in slightly lower yields than their ortho-counterparts
(Figure 3, compound 9). Importantly, in this case we found
that the amination reaction with benzimidazole was higher
yielding than the amination without benzimidazole (to form
the aryl−Selectfluor adduct). Replacing one of the methoxy
groups in veratrole with either a thiomethyl or a
dimethylamino group proved to be detrimental to the desired
amination. On the other hand, adding a third alkoxy group at
the 3-position resulted in a productive reaction; the amination
with benzimidazole had a slightly higher yield than that of
veratrole (compound 10). This allowed for the expeditious
derivitization of 1,2,3-trialkoxybenzene compounds that are
common in biology and medicine.15 Along those lines, an alkyl
substituent was also tolerated at the 3-position, as an N-
benzylacetamide derivative underwent amination in a good
yield (compound 11). The phase-transfer catalyst dibenzo-18-
crown-6 was found to be similarly successful in the amination
(compound 12), allowing one-step access to new catalysts that
could be useful in specialty applications. As illustrated in Figure
3, each of these examples gives a small amount of an aryl
fluoride byproduct due to the use of Selectfluor; however, the
desired amination product is easily separated from the fluoride
impurity by column chromatography, as the aromatic amines
are significantly more polar than the fluorides.
The aptitude of other electron-rich arenes to participate in
the reaction proved difficult to predict, although we did find
that other species beyond the examples presented in Figure 3
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Figure 4. Application to medicinal chemistry.
2.4. Mechanistic Remarks. To understand the reaction
mechanism, we first sought to shed light on the divergent
reactivity of the dialkoxybenzene regioisomers. Why would the
ortho- and para-isomers undergo amination while the meta-
isomer undergoes fluorination instead? We turned to computa-
tional chemistry to address this question, calculating the energy
difference for the oxidation of the three dimethoxybenzene
isomers using DFT (B3LYP/6-311++G** (MeCN)). Con-
sistent with experimental results, the oxidation of the meta-
isomer was the most energetically uphill (7 kJ/mol higher than
the ortho-isomer and 35 kJ/mol higher than the para-isomer
(Figure 5)). This energy difference is significant and coincides
Figure 3. Substrate examples of alkoxyarenes.
can undergo the amination reaction. Carbazole, for instance,
can engage in the amination with Selectfluor, albeit in a
moderately low yield. This finding came as a surprise to us
given the large structural difference between carbazole and the
alkoxybenzenes; however, to further complicate the analysis,
the oxygen analogue of carbazole (dibenzofuran) was
unsuccessful in the reaction. This is consistent with our earlier
observation that the dimethylamino and thiomethyl analogues
of veratrole did not undergo the amination. Together, these
results demonstrate the discriminate nature of the reaction, as
certain electron-rich arenes are not competent in the amination
and instead undergo either fluorination or no reaction.
2.3. Application to Medicinal Chemistry. To demon-
strate the synthetic utility of this transformation, we propose
an improved synthesis of a medicinally relevant compound
(compound 13, Figure 4). This commercially available
benzodioxane derivative is employed as a precursor to
dopamine D4 receptor ligands (via the N-benzylation of the
piperazinyl secondary amine).16 Additionally, 13 represents an
analogue of eltoprazine, a drug useful for treating neuro-
degenerative disorders.17 Two distinct methods have been
utilized to synthesize 13 from 1,4-benzodioxane: (a) either a
halogenation−cross-coupling sequence or (b) a nitration−
reduction−substitution sequence, which provides the product
in three steps.18 On the other hand, using our method, 13 can
be accessed in two steps, both of which are operationally
simpler than the steps in the previous syntheses. Notably, our
approach avoids undesirable reactions from the previous
methods, such as the Buchwald−Hartwig cross coupling
amination or the nitration using concentrated nitric acid. As
demonstrated by this example, the direct C−H to C−N bond
formation featured in this reaction represents a powerful
strategy toward the expeditious synthesis of nitrogen hetero-
cycles that are of medicinal interest.
Figure 5. Energy of the arene oxidation calculated at B3LYP/6-311+
+G** (MeCN).
with the observation that in the present reaction the meta
isomer may not undergo oxidation to its radical cation and the
subsequent amination but could instead react with Selectfluor
in a putative electrophilic aromatic halogenation. The
oxidation of para-dialkoxy substrates is evidently more
favorable than those of the ortho-substrates; however, the
amination was higher-yielding for ortho-dialkoxyarenes. To
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rationalize this observation, we considered steric factors, which
favor the ortho-substrates.
nitrogen heterocycle. We ruled out this possibility by
performing an experiment in which the Selectfluor−veratrole
adduct was generated first and then benzimidazole was added
after the Selectfluor was fully consumed. In this reaction, we
observed no conversion of the Selectfluor−veratrole adduct to
the benzimidazole−veratrole adduct, thereby disproving the
nucleophilic aromatic substitution mechanism. An additional
subtle mechanistic difference involves the oxidation of the
radical produced from step two; in this case, the intermediate
loses a proton to rearomatize instead of losing a hydrogen
atom. Our group aims to investigate this distinction and
elucidate further mechanistic details in a forthcoming study.
Next, we became interested in probing the relative reaction
rates of the two competing reactionsamination vs fluorina-
tion. Thus, we subjected Selectfluor (1.0 equiv) to an
intermolecular competition experiment with equimolar
amounts of ortho- and meta-dimethoxybenzene (5.0 equiv
each). A ratio of 1.0:3.5 was observed for the amination and
fluoride products derived from the ortho- and meta-isomers,
respectively (Figure 6). From this experiment, it is apparent
3. CONCLUSION
The arene substitution pattern of dialkoxybenzenes was shown
to govern the divergent reactivity with Selectfluor. Ortho- and
para-isomers predominately give amination products, whereas
the meta-isomer exclusively gives fluoride products. The
amination pathway allows direct access to pharmaceutically
important nitrogen heterocycles using a simple yet efficient set
of conditions. DFT calculations illuminated details regarding
the mechanistic switch, as the meta-isomer was revealed to be
more difficult to oxidize. Finally, an initial mechanism was
proposed, involving oxidation, nucleophilic addition, hydrogen
atom transfer, and rearomatization.
Figure 6. An intermolecular competition experiment.
that the aryl fluorination is much faster than the amination.
This finding further demonstrates the unusual behavior of
ortho-dialkoxybenzenes, which undergo amination in high
yields despite the fact that fluorination is apparently faster.
Finally, we propose an initial mechanistic hypothesis for the
amination reaction, relying on literature precedents and our
own experience in working with Selectfluor. The reaction can
begin with the oxidation of the electron-rich dialkoxyarene by
Selectfluor to produce the corresponding arene radical cation,
the Selectfluor-radical dication (SRD), and fluoride (Figure 7).
4. EXPERIMENTAL SECTION
4.1. General Methods. Unless otherwise stated, all reactions were
carried out under strictly anhydrous conditions and a N2 atmosphere.
All solvents were dried and distilled by standard methods. Arene
substrates and nitrogen heteocycles were purchased from Sigma-
Aldrich and used directly in the reaction unless otherwise noted. All
1H spectra were acquired on a 400 MHz NMR spectrometer in
CDCl3, 19F spectra were acquired on a 300 MHz NMR spectrometer
in either CD3CN or CDCl3, and 13C NMR spectra were acquired on a
1
400 MHz NMR spectrometer in CDCl3. The H, 13C, and 19F NMR
chemical shifts are given in parts per million (δ) with respect to an
internal tetramethylsilane (TMS, δ 0.00 ppm) standard or 3-
chlorobenzotrifluoride (δ −64.2 ppm relative to CFCl3). NMR data
are reported in the following format: chemical shift (integration,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constants (Hz)).
4.2. General Amination Procedure. The arene substrate (1.0
mmol, 1.0 equiv) was added to an oven-dried round-bottom flask
equipped with a stir bar and then dissolved in anhydrous acetonitrile
(25 mL). The nitrogen heterocycle (2−4 equiv; yields reported with
3.5 equiv unless otherwise stated) was then added, and the solution
was stirred at room temperature. Selectfluor (1.2 mmol, 1.2 equiv)
was then added, and the reaction mixture was stirred for 3−6 h. The
1
reaction was monitored by H NMR (0.3 mL reaction aliquot + 0.2
mL of CD3CN). Yields for the aryl-fluoride byproducts were
determined by 19F NMR spectroscopy of the crude reaction mixture
via the integration of product signals relative to an internal standard.
The reaction can be driven further to completion by adding an
additional amount of Selectfluor relative to the amount of the
unreacted arene substrate and stirring for an additional 2−5 h. After
the reaction, most of the solvent was removed in vacuo, and the
mixture was diluted with 1 M NaOH. The mixture was extracted with
CH2Cl2 (×3); the combined organic layers were then washed with 2
M NaOH (to remove the excess nitrogen heterocycle), followed by
brine. The organic solution was finally dried over Na2SO4 and
concentrated to dryness. The residue was purified by gradient flash
chromatography on silica gel.
Figure 7. Proposed mechanism for arene amination.
The arene radical cation can be trapped by a nitrogen
heterocycle via a nucleophilic addition to the allylic cation to
form the 4-substituted adduct. This species could then
undergo hydrogen atom transfer (HAT) to form the product.
This HAT step is most likely accomplished with the SRD that
was produced during the course of the reaction, as the
Selectfluor-radical dication is known for its ability to abstract
hydrogen atoms from a variety of substrates.19 On the other
hand, an alternate mechanism might involve a nucleophilic
aromatic substitution of the Selectfluor−arene adduct with the
4.3. Characterization of Amination Products. 4.3.1. 1-(3,4-
Dimethoxyphenyl)-1H-benzo[d]imidazole (Compound 1). The
amination was run according to the general procedure using 1,2-
dimethoxybenzene as the arene substrate and benzimidazole as the
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nitrogen heterocycle. The product was isolated via gradient column
chromatography on silica gel with EtOAc/hexanes: white solid (173
mg, 68%); H NMR (400 MHz, CDCl3): δ 8.07 (1H, s), 7.91−7.85
Selectfluor byproducts, namely the DABCO monocation, as it was
also a BF4 salt and had similar properties. The H NMR spectrum
shows the product along with the Selectfluor-derived amine in a
1.0:1.1 ratio.
1
1
(1H, m), 7.50−7.45 (1H, m), 7.36−7.30 (2H, m), 7.07−6.99 (3H,
m), 3.97 (3H, s), 3.93 (3H, s); 13C{1H} NMR (100 MHz, CDCl3): δ
149.9, 148.9, 142.6, 129.3, 123.6, 122.6, 120.5, 116.7, 111.7, 110.3,
108.2, 56.2, 56.1; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
4.3.8. 1-(3,4-Dimethoxyphenyl)piperazine (Compound 8). The
amination was run according to the procedure for compound 7. The
DABCO adduct was reduced to a piperazine using a previously
reported procedure.10 After the amination had completed, a solution
of saturated aq Na2S2O3 (10.0 mL) was added to the mixture,
followed by H2O (10.0 mL). The mixture was stirred in the sealed
flask or tube at 100 °C for 12−24 h using a heating mantle with sand.
Upon cooling to room temperature, the reaction mixture was
transferred to a separatory funnel and diluted with DCM (20 mL).
Ethylene diamine (2 mL) was added, followed by 6 M NaOH (6 mL),
and the mixture was shaken. The resulting emulsion was treated with
brine (50 mL), and the organic layer was separated after shaking. The
aqueous layer was re-extracted with DCM (2 × 20 mL), then the
combined organic layers were extracted with 1 M HCl (2 × 20 mL).
Ethylene diamine (6 mL) was added to the combined HCl extracts,
followed by 6 M NaOH (10 mL). The basified aqueous mixture was
then extracted with DCM (3 × 20 mL), and the combined organic
layers were dried with Na2SO4, filtered, and concentrated: yellow oil
(157.8 mg, 71%); spectral data match the previously reported
characterization.23
+
C15H15N2O2 255.1128, found 255.1125.
4.3.2. 1-(3,4-Dimethoxyphenyl)-1H-benzo[d][1,2,3]triazole
(Compound 2). The amination was run according to the general
procedure using 1,2-dimethoxybenzene as the arene substrate and
benzotriazole as the nitrogen heterocycle. The product was isolated
via gradient column chromatography on silica gel with EtOAc/
hexanes: white solid (138 mg, 54%); spectral data match the
previously reported characterization.20
4.3.3. 5-(tert-Butyl)-2-(3,4-dimethoxyphenyl)-2H-tetrazole (Com-
pound 3, Major Isomer). The amination was run according to the
general procedure using 1,2-dimethoxybenzene as the arene substrate
and 5-tBu tetrazole as the nitrogen heterocycle. The product was
isolated via gradient column chromatography on silica gel with
EtOAc/hexanes: white solid (194 mg, 74% for both regioisomers); 1H
NMR (400 MHz, CDCl3): δ 7.65−7.58 (2H, m), 6.93 (1H, d, J = 8.6
Hz), 3.96 (3H, s), 3.92 (3H, s), 1.47 (9H, s); 13C{1H} NMR (100
MHz, CDCl3): δ 174.3, 149.7, 149.4, 130.6, 112.1, 111.0, 103.6, 56.2,
56.1, 31.6, 29.5; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
4.3.9. 1-(2,5-Dimethoxyphenyl)-1H-benzo[d]imidazole (Com-
pound 9). The amination was run according to the general procedure
using 1,4-dimethoxybenzene as the arene substrate and benzimidazole
as the nitrogen heterocycle. The product was isolated via gradient
column chromatography on silica gel with EtOAc/hexanes: white
+
C13H19N4O2 263.1503, found 263.1502.
4.3.4. 1-(3,4-Dimethoxyphenyl)-1H-imidazole (Compound 4).
The amination was run according to the general procedure using
1,2-dimethoxybenzene as the arene substrate and imidazole as the
nitrogen heterocycle using the following modifications: 4.0 equiv of
imidazole, 4.0 equiv NaHCO3, and 3.5 equiv of Selectfluor. The
product was isolated via gradient column chromatography on silica gel
with EtOAc/hexanes: white solid (84 mg, 41%); spectral data match
the previously reported characterization.21
1
solid (142 mg, 56%); H NMR (400 MHz, CDCl3): δ 8.09 (1H, s),
7.88−7.85 (1H, m), 7.37−7.29 (3H, m), 7.06 (1H, d, J = 8.9 Hz),
7.02−6.96 (2H, m), 3.82 (3H, s), 3.74 (3H, s); 13C{1H} NMR (100
MHz, CDCl3): δ 153.7, 148.0, 143.8, 143.3, 134.2, 125.3, 123.3,
122.4, 120.3, 114.2, 113.6, 113.1, 110.7, 56.3, 55.9; HRMS (ESI-
+
Orbitrap) m/z [M + H]+ calcd for C15H15N2O2 255.1128, found
4.3.5. 4,5-Dibromo-1-(3,4-dimethoxyphenyl)-2-methyl-1H-imi-
dazole (Compound 5). The amination was run according to the
general procedure using 1,2-dimethoxybenzene as the arene substrate
and 4,5-dibromo-2-methylimidazole as the nitrogen heterocycle. The
product was isolated via gradient column chromatography on silica gel
255.1129.
4.3.10. 1-(3,4,5-Triethoxyphenyl)-1H-benzo[d]imidazole (Com-
pound 10). The amination was run according to the general
procedure using 1,2,3-triethoxybenzene24 as the arene substrate and
benzimidazole as the nitrogen heterocycle. The product was isolated
via gradient column chromatography on silica gel with EtOAc/
hexanes: white solid (232 mg, 71%); 1H NMR (400 MHz, CDCl3): δ
8.07 (1H, s), 7.89−7.84 (1H, m), 7.55−7.50 (1H, m), 7.35−7.29
(2H, m), 6.67 (2H, s), 4.16−4.06 (6H, m), 1.46 (6H, t, J = 7.0 Hz),
1.41 (3H, t, J = 7.1 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 153.8,
143.9, 142.4, 137.6, 133.9, 131.6, 123.6, 122.7, 120.6, 110.5, 103.1,
69.1, 65.0, 15.6, 14.8; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
1
with EtOAc/hexanes: white solid (275 mg, 73%); H NMR (400
MHz, CDCl3): δ 6.96 (1H, d, J = 8.5 Hz), 6.82−6.77 (1H, m), 6.69
(1H, d, J = 2.4 Hz), 3.95 (3H, s), 3.89 (3H, s), 2.26 (3H, s); 13C{1H}
NMR (100 MHz, CDCl3): δ 150.0, 149.5, 146.6, 128.4, 120.0, 115.7,
111.0, 110.7, 104.2, 56.2, 56.1, 14.5; HRMS (ESI-Orbitrap) m/z [M
+
+ H]+ calcd for C12H13Br2N2O2 374.9338, found 374.9338.
4.3.6. 2-((1-(3,4-Dimethoxyphenyl)-1H-benzo[d]imidazol-2-yl)-
methyl)isoindoline-1,3-dione (Compound 6). The amination was
run according to the general procedure using 1,2-dimethoxybenzene
as the arene substrate and 2-methylphthalimidobenzimidazole22 as the
nitrogen heterocycle. The product was isolated via gradient column
chromatography on silica gel with EtOAc/hexanes: white solid (322
mg, 78%); 1H NMR (400 MHz, CDCl3): δ 7.85−7.81 (2H, m),
7.76−7.70 (3H, m), 7.28−7.19 (2H, m), 7.13−7.09 (1H, m), 7.06−
7.02 (1H, m), 7.00−6.93 (2H, m), 5.04 (2H, s), 3.93 (3H, s), 3.87
(3H, s); 13C{1H} NMR (100 MHz, CDCl3): δ 167.5, 149.8, 149.6,
148.6, 137.1, 134.1, 132.1, 127.8, 123.5, 123.2, 122.6, 119.8, 119.7,
111.4, 110.6, 110.1, 56.1, 56.1, 34.9; HRMS (ESI-Orbitrap) m/z [M
+
C19H23N2O3 327.1703, found 327.1703.
4.3.11. N-(5-(1H-Benzo[d]imidazol-1-yl)-2,3-dimethoxybenzyl)-
acetamide (Compound 11). The amination was run according to
the general procedure using N-(2,3-dimethoxybenzyl)acetamide as
the arene substrate and benzimidazole as the nitrogen heterocycle.
The product was isolated via gradient column chromatography on
1
silica gel with EtOAc/hexanes: white solid (195 mg, 60%); H NMR
(400 MHz, CDCl3): δ 8.02 (1H, s), 7.86−7.81 (1H, m), 7.50−7.46
(1H, m), 7.34−7.28 (2H, m), 7.03 (1H, d, J = 2.5 Hz), 6.95 (1H, d, J
= 2.5 Hz), 6.37−6.20 (1H, m), 4.51 (2H, d, J = 6.1 Hz), 3.94 (3H, s),
3.90 (3H, s), 2.00 (3H, s); 13C{1H} NMR (100 MHz, CDCl3): δ
170.1, 153.4, 146.5, 143.7, 142.1, 133.7, 133.6, 131.9, 123.6, 122.7,
120.3, 116.5, 110.4, 107.8, 60.7, 56.0, 38.5, 23.1; HRMS (ESI-
+
+ H]+ calcd for C24H20N3O4 414.1448, found 414.1440.
4.3.7. 1-(Chloromethyl)-4-(3,4-dimethoxyphenyl)-1,4-
diazabicyclo[2.2.2]octane-1,4-diium (Compound 7). The amination
was run according to the general procedure with the following
modification: no nitrogen heterocycle was added. The product was
precipitated with the addition of 50% EtOAc in hexane, filtered, and
washed with more EtOAc/hexane. The product was dissolved in
acetone and concentrated to dryness: white hygroscopic solid (448.8
mg, 95%); 1H NMR (400 MHz, CDCl3): δ 7.31−7.26 (2H, m),
7.13−7.09 (1H, m), 5.36 (2H, s), 4.42−4.36 (6H, t, J = 7.3 Hz),
4.16−4.10 (6H, t, J = 7.3 Hz), 3.92 (3H, s), 3.88 (3H, s); HRMS
+
Orbitrap) m/z [M + H]+ calcd for C18H20N3O3 326.1499, found
326.1499.
4.3.12. 1-(6,7,9,10,17,18,20,21-Octahydrodibenzo[b,k]-
[1,4,7,10,13,16]hexaoxacyclooctadecin-2-yl)-1H-benzo[d]-
imidazole (Compound 12). The amination was run according to the
general procedure using dibenzo-18-crown-6 as the arene substrate
and benzimidazole as the nitrogen heterocycle. The product was
isolated via gradient column chromatography on silica gel with DCM/
+
1
(ESI-Orbitrap) m/z [M − BF4]+ calcd for C15H23N2O2ClBF4
hexanes with 1.5% Et3N: white solid (305 mg, 64%); H NMR (400
385.1472, found 385.1465. The product was inseparable from the
MHz, CDCl3): δ 8.03 (1H, s), 7.88−7.84 (1H, m), 7.47−7.42 (1H,
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m), 7.34−7.27 (2H, m), 7.02−6.98 (3H, m), 6.91−6.86 (4H, m),
4.26−4.22 (2H, m), 4.21−4.15 (6H, m), 4.08−4.01 (8H, m);
13C{1H} NMR (100 MHz, CDCl3): δ 149.6, 148.7, 148.7, 148.6,
143.8, 142.5, 134.1, 129.5, 123.5, 122.5, 121.3, 121.3, 120.4, 117.0,
113.9, 113.6, 113.6, 110.3, 110.1, 70.0, 69.7, 69.6, 69.2, 69.1, 68.7,
REFERENCES
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4.4. Synthesis and Characterization of New Starting
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1
with EtOAc/hexanes: white solid (390 mg, 93%); H NMR (400
MHz, CDCl3): δ 7.02 (1H, t, J = 7.9 Hz), 6.91−6.85 (2H, m), 5.92
(1H, br. s), 4.44 (2H, d, J = 5.7 Hz), 3.87 (3H, s), 3.86 (3H, s), 1.97
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131.8, 124.2, 121.4, 111.9, 60.6, 55.7, 39.0, 23.2; HRMS (EI) m/z
+
[M]+· calcd for C11H15NO3 209.1052, found 209.1078.
COMPUTATIONAL METHODS
■
Density functional theory calculations were performed using the
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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.joc.1c00231.
■
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AUTHOR INFORMATION
Corresponding Author
Thomas Lectka − Department of Chemistry, Johns Hopkins
University, Baltimore, Maryland 21218, United States;
orcid.org/0000-0003-3088-6714; Email: lectka@
jhu.edu
■
Author
Joseph N. Capilato − Department of Chemistry, Johns
Hopkins University, Baltimore, Maryland 21218, United
States; orcid.org/0000-0001-5996-2456
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00231
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
T.L. thanks the National Science Foundation (CHE 1800510)
for support. The authors also thank the Mass Spectrometry
Facility at the University of Delaware.
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