Investigation of the Reactivity of 1-Azido-3-iodobicyclo[1.1.1]pentane under click Reaction Conditions

Article abstract of DOI:10.1021/acs.joc.0c02432

The bicyclo[1.1.1]pentane (BCP) unit is under scrutiny as a bioisostere in drug molecules. We employed methodologies for the synthesis of different BCP triazole building blocks from one precursor, 1-azido-3-iodobicyclo[1.1.1]pentane, by click reactions and integrated cycloaddition-Sonogashira coupling reactions. Thereby, we accessed 1,4-disubstituted triazoles, 5-iodo-1,4,5-trisubstituted triazoles, and 5-alkynylated 1,4,5-trisubstituted triazoles. This gives entry to the synthesis of multiply substituted BCP triazoles on either a modular or a one-pot basis. These methodologies were further utilized for appending porphyrin moieties onto the BCP core.

Full text of DOI:10.1021/acs.joc.0c02432

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Investigation of the Reactivity of 1‑Azido-3-
iodobicyclo[1.1.1]pentane under “Click” Reaction Conditions
Elisabeth Sitte, Brendan Twamley, Nitika Grover, and Mathias O. Senge*
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ABSTRACT: The bicyclo[1.1.1]pentane (BCP) unit is under
scrutiny as a bioisostere in drug molecules. We employed
methodologies for the synthesis of different BCP triazole building
blocks from one precursor, 1-azido-3-iodobicyclo[1.1.1]pentane,
by “click” reactions and integrated cycloaddition−Sonogashira
coupling reactions. Thereby, we accessed 1,4-disubstituted
triazoles, 5-iodo-1,4,5-trisubstituted triazoles, and 5-alkynylated
1,4,5-trisubstituted triazoles. This gives entry to the synthesis of
multiply substituted BCP triazoles on either a modular or a one-
pot basis. These methodologies were further utilized for appending
porphyrin moieties onto the BCP core.
BCP derivatives, “click” reactions on BCP have been limited to
he development of synthetic routes toward
Tbicyclo[1.1.1]pentane (BCP) derivatives is a field of a rather narrow scope of small molecule substrates such as
growing interest.1 This rigid hydrocarbon scaffold has attracted
attention as a linear linker in electron donor−acceptor systems
methyl propiolate, ethoxyethyne, phenylacetylene, and
(azidomethyl)benzene.6
In this study, we focused our efforts on broadening the range
of accessible BCP-triazoles 2 to derivatives with more complex
chromophoric substituents. To investigate the substrate scope,
we also screened some smaller aromatic moieties. In doing so,
we came across more “click”-type reactions that yielded
functional BCP-triazole cores 3 and 4. This led us to study the
use of 1-azido-3-iodo-BCP as a precursor for three different
“click”-type reactions for the synthesis of 5-protio-1,2,3-
triazoles (2), 5-iodo-1,2,3-triazoles (3), and 5-alkynylated
1,2,3-triazoles (“tweezers”) (4). Such scaffolds have attracted
widespread attention as compounds for anion recognition and
in biomedical applications, among others.7
The syntheses of both 5-iodotriazoles (3) and of “tweezer”-
like triazole (4) compounds have been unexplored to date for
BCP scaffolds. The applied synthetic methods enabled us to
obtain the building blocks 2−4 from the same precursors in
single step one-pot reactions.
as well as in molecular rods and rotors. Future applications
require simple and robust synthetic methods for its
modification. BCP derivatives have promise as bioisosteres
for organic moieties, such as phenyl rings, tert-butyl groups,
and alkynes. The BCP moiety was found to favorably alter
different physicochemical and pharmacokinetic properties of
drug candidate molecules.1a,2
The synthesis of functionalized hydrocarbon cages that can
serve as building blocks and molecular tectons for possible
applications in medicinal and materials chemistry is an active
research interest of our group.3 We are especially interested in
appending BCP with chromophores for the construction of
donor−acceptor systems. Searching for versatile methods for
the synthesis of new BCP building blocks and BCP-
chromophore arrays, we reflected that the copper-catalyzed
azide−alkyne 1,3-dipolar cycloaddition (“click” reaction)4 can
be a very useful tool due to its broad substrate scope, its
efficiency, and easily available precursors.5 Although previously
described for 1-azido-3-iodo-BCP 1 (Figure 1) and a few other
To investigate the modification of BCP via 1,3-dipolar
cycloaddition reactions, 1-azido-3-iodo-BCP 1 was prepared
according to a literature procedure.8 Compound 1 was chosen
as a precursor for all transformations of the azide moiety due to
Received: October 14, 2020
Figure 1. 1-Azido-3-iodo-BCP 1 precursor and general structures of
the three triazole building blocks derived thereof.
https://dx.doi.org/10.1021/acs.joc.0c02432
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its easy preparation and relative stability.8b Intending to
append a chromophore on BCP, 1 was reacted with ethynyl-
substituted BODIPY 5 under “click” reaction conditions as
reported previously.6a,b Stirring a solution of BCP 1 in THF
with triethylamine (TEA) (1.5 equiv), CuI (0.1 equiv), and
BODIPY 5 (1 equiv) for 16 h yielded the 1,2,3-triazole
product 9 in 82% yield (Scheme 1). Interestingly, a small
respectively, where reactions under air showed higher yields
(Table 1). An increase in the amount of CuI (1.0 equiv) used
Table 1. Screening of Reaction Conditions for the
Formation of 5-Protio-1,2,3-triazole 9 and 5-Iodo-1,2,3-
a
triazole 10 from Precursors 1 and 5
b
c
c
conditions
atmosph.
argon
yield of 10
yield of 9
1
2
3
4
5
6
CuI (0.2 equiv),
TEA (1.5 equiv)
CuI (0.3 equiv),
TEA (1.5 equiv)
CuI (0.2 equiv),
TEA (1.5 equiv)
CuI (0.3 equiv),
TEA (1.5 equiv)
CuI (1.0 equiv),
TEA (3.8 equiv)
CuI (1.0 equiv),
DIPEA (1.0 equiv),
NBS (1.2 equiv)
11%
13%
15%
17%
33%
69%
80%
71%
54%
54%
22%
6%
Scheme 1. “Click” Reactions with 1-Azido-3-iodo-BCP 1
and Different Substrates
argon
air
air
air
argon
a
All reactions were carried out with 1 (28.7 μmol) and 5 (28.7 μmol)
b
in THF (0.67 mL) for 16 h. For reactions carried out under an argon
atmosphere, the solvent was deoxygenated by purging with argon for
15 min. Yield obtained from H NMR with an internal standard.
c
1
and carrying out the reaction under air led to an elevated yield
of 5-iodo-1,2,3-triazole 10 of 33% along with 22% of the 5-
protio-1,2,3-triazole 9. However, formation of a considerable
amount of a butadiyne-linked BODIPY dimer from a Glaser11
coupling reaction occurring under these conditions limited the
yield of 10. To enhance the formation of the new BCP-5-
iodotriazole building blocks, we applied a literature procedure
which uses CuI (1.0 equiv) in combination with an oxidant, N-
bromosuccinimide (NBS) (1.2 equiv), and a base, N,N-
diisopropylethylamine (DIPEA) (1.0 equiv).12 Compound 10
was formed in a good yield of 69% under these conditions
(Scheme 2).
fraction eluted just before 1,2,3-triazole 9. The 1H NMR
spectrum showed a characteristic singlet at 3.07 ppm
corresponding to the six BCP bridge protons. At the same
time, the signals of the BODIPY moiety could be found but no
proton signal for the 5-position of the triazole ring was
apparent, pointing toward a 1,4,5-substituted triazole. Mass
spectrometry gave evidence that 5-iodo-1,2,3-triazole 10 had
formed as a side product of the “click” reaction with a yield of
3%. Similar reactions of BCP 1 with other chromophoric
substrates, 1-ethynylpyrene 6 and alkynyl-porphyrin 7, also
gave the corresponding 5-iodo-1,2,3-triazoles 12 and 14 as
minor products in 3% and 7% yield, respectively, next to 5-
protio-1,2,3-triazoles 11 (10%) and 13 (79%). However, when
the reaction was carried out using phenylacetylene, only the 5-
protio-1,2,3-triazole product 15 was isolated (Scheme 1).
This demonstrated that the “click” reaction conditions
according to Scheme 1 are not only applicable for small
molecule acetylenes but mostly give good yields for larger
aromatic substrates as well. The most intriguing observation,
however, appeared to be the repeated formation of BCP 5-
iodo-1,2,3-triazoles as side products, and we aimed to
investigate this side reaction in more depth. A survey of the
literature revealed that the synthesis of 5-iodo-1,2,3-triazoles
via 1,3-dipolar cycloaddition reactions can be achieved by two
different routes. Either a terminal alkyne can be used in
combination with an electrophilic iodine species which is
added as such or generated in situ or an iodoalkyne is
employed as a starting material.9 In a few cases, the formation
of small amounts of 5-iodo-1,2,3-triazoles as side products in
“click” reactions was observed under conditions similar to the
ones employed by us.10
Scheme 2. Synthesis of 5-Iodo-1,2,3-triazoles from 1
These reaction conditions proved to be promising for the
synthesis of different BCP-5-iodo-1,2,3-triazoles in improved
yields and were applied to other substrates. While reaction
with 4-ethynylpyridine 17 proceeded in a good yield of 66%,
more electron-rich substrates such as 1-ethynylpyrene 6 and
phenylacetylene 8 gave low yields of 17% and 7%, respectively.
Possibly, this is due to side reactions such as Glaser couplings
The formation of 5-iodo-1,2,3-triazoles is likely affected by
the presence of residual oxygen in the reaction mixture which
facilitates oxidation of I− to an electrophilic iodine species.
This assumption was supported by the results of test reactions
carried out in argon-purged solvents and under air,
B
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occurring to a larger extent with these substrates. The reaction
with alkynyl-BODIPY 5 and porphyrin 7 yielded the 5-iodo-
1,2,3-triazoles 10 and 14 in 14% and 19% yield, respectively.
When the reaction with 4-ethynylpyridine was carried out on a
larger scale (1.5 mmol) compound 18 was isolated in 53%
yield, showcasing that the reaction is robust to scale-up.
The 5-iodo of the triazole ring is a useful synthetic handle
for subsequent functionalization with a second moiety yielding
tweezer-like 1,4,5-trisubstituted 1,2,3-triazoles. Such scaffolds
can likewise be synthesized by several single-step procedures
from the respective azide and different precursors such as
terminal alkynes.9b,13 1,4,5-Trisubstituted 1,2,3-triazoles have
been reported as compounds with promising biological
activities in various fields.7d,e Hence, we investigated the
reactivity of 1-azido-3-iodo-BCP to produce 1,4,5-trisubsti-
tuted 1,2,3-triazoles. 5-Alkynylated triazoles can be obtained in
one-pot reactions using only copper salts as catalysts in the
presence of oxygen or oxidants such as N-methylmorpholine-
N-oxide.9b,13,14 The reaction proceeds via a triazolide
intermediate with copper(I) bound in the 5-position of the
triazole ring that undergoes C−C bond formation with a free
terminal acetylene.13 Another approach to 5-alkynyl-1,2,3-
triazoles is the use of 5-halogenated precursors or their in situ
generation followed by Pd-catalyzed Sonogashira15 coupling
reaction.7e,16 Surprisingly, when we directly used 1-azido-3-
iodo-BCP in a Sonogashira reaction with 1-ethynylpyrene
using Pd(PPh3)2Cl2 (0.1 equiv) and CuI (0.2 equiv),
formation of the 1,4,5-trisubstituted triazole 20 in 7% yield
was observed (Scheme 3). Apparently, the reaction conditions
materials as a side product in Sonogashira coupling reactions
was reported in the literature, and it was proposed that the 5-
alkynylation reaction is copper-mediated.17 To investigate the
dependence of the 5-alkynylation reaction on Pd, we carried
out one reaction with 4-ethynylpyridine under the reported
conditions but without addition of a Pd catalyst. No formation
of product 23 was observed, indicating that Pd is required for
the 5-alkynylation reaction to take place.
For the two reaction procedures according to Schemes 2 and
3, the yields were found to be variable. This observation can be
explained by the electronic and steric effects of the substrates
used. The Glaser coupling side reaction reduces the availability
of all substrates for cycloaddition reactions. This seems to be
especially true for the electron-rich substrates 1-ethynylpyrene
and phenylacetylene. The reactivity of large aromatic systems
such as BODIPY, porphyrin, and pyrene with the azide moiety
is additionally lowered by the steric bulk of these compounds.
Due to the low yield for large chromophoric moieties in the
one-pot cycloaddition−coupling reaction, a sequential ap-
proach was tested. When 5-iodo-1,2,3-triazole 10 was reacted
with ethynyl-substituted BODIPY 5 under Sonogashira
coupling conditions, however, only the BODIPY dimer 25
was obtained along with unreacted starting material 10.
Preliminary results in our lab showed that Suzuki coupling
reactions are much more promising for the functionalization of
the 5-position of 5-iodotriazoles (see Supporting Information
(SI)). More detailed studies on Suzuki coupling reactions with
5-iodotriazoles are underway.
The structures of BODIPY 5 and BCP compounds 9, 12, 14,
15, 16, 18, 22, 23, and 24 (see SI Figures S3−S12) were
determined by single crystal X-ray diffraction analysis. We
focused on the identification of prominent noncovalent
interactions. Such interactions are of great importance in
nature, where they determine the 3D structure of biomacro-
molecules and mediate ligand−receptor interactions.18 Con-
sidering that the BCP moiety attracts growing interest as a
bioisostere in drug candidates,2 it is pivotal to study the effects
of the bioisosteric replacement on the weak interactions with
molecules in the surroundings. The engineering of crystals with
tuned noncovalent interactions is also of growing interest for
the design of functional materials.19 In the case of BCP-
triazoles some interesting noncovalent interactions were
observed for the different types of molecules. Halogen
bonding20 governs the molecular packing in several structures.
Prominent interactions that were identified are I···N,21 I···
I,21c,22 C−H···I,23 and C−H···N24 contacts resulting in the
arrangement of molecules in 2D sheets or 3D networks,
respectively (see SI Figures S13−S18).
In conclusion, we explored three different means to
synthesize new BCP-triazole building blocks using 1,3-dipolar
cycloaddition reactions. We obtained molecules that were
iodinated in the 5-position of the triazole ring in moderate to
good yields. Iodine in this position is a useful synthetic handle
for further functionalization as well as a site for molecular
interaction. We also produced BCP compounds substituted
with 5-alkynylated 1,2,3-triazoles in a one-step cycloaddition-
Pd-catalyzed coupling reaction to yield molecular tweezer
compounds. X-ray analysis revealed notable intermolecular
interactions of some of the synthesized derivatives in the solid
state. Particularly noteworthy are different noncovalent
interactions involving iodine moieties, indicating intermolec-
ular binding capabilities of this class of molecules. The
synthetic approaches presented herein are promising tools for
Scheme 3. One-Pot Procedure for the Synthesis of 1,4,5-
Trisubstituted 1,2,3-Triazoles from 1 and Terminal Alkynes
mediated the azide−alkyne 1,3-dipolar cycloaddition and C−C
bond formation reaction in the 5-position of the triazole ring in
a single step. The scope of this unprecedented reaction was
tested using different alkynyl substrates as reactants (Scheme
3). With phenylacetylene the 1,4,5-trisubstituted 1,2,3-triazole
product 22 was obtained in 10% yield while, using 4-
ethynylpyridine, 27% of the trisubstituted product 23 formed.
The 5-protio-1,2,3-triazole 24 was also formed in 31% yield.
We saw potential in using this reaction for the one-pot
synthesis of BCP-bound chromophore tweezers and reacted 1
with alkynyl-substituted BODIPY 5 and porphyrin 7. In both
cases, formation of complex mixtures of reaction products and
difficult purifications allowed only the isolation of trace
amounts of the respective 1,4,5-trisubstituted 1,2,3-triazoles
19 and 21. One such example of the formation of a 1,4,5-
trisubstituted 1,2,3-triazole from azide and alkyne starting
C
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residue was dry-loaded onto silica gel and purified by column
chromatography.
the generation of new BCP-triazole scaffolds. Notably, this
study presents the to date unexplored incorporation of the
BCP moiety in 1,4,5-trisubstituted triazoles. Since such units
are part of various drug candidates,7b−e and the BCP moiety is
known as a bioisostere for phenyl rings, tert-butyl groups, and
alkynes,1 this could give rise to new BCP-containing building
blocks for medicinal chemistry applications.25
General Procedure B for the Synthesis of 5-Iodo-1,2,3-
triazoles 10, 12, 14, 16, 18. A modified literature procedure was
used for the synthesis of 5-iodo-1,2,3-triazoles.12 A microwave vial
equipped with a rubber septum was evacuated and refilled with argon
(3×). 1-Azido-3-iodobicyclo[1.1.1]pentane (1) (1.0 equiv) dissolved
in anhydrous THF was added to the vial, followed by DIPEA (1.0
equiv). Argon was bubbled through the mixture for 10 min. CuI (1.0
equiv), the ethynyl substrate (1.0 equiv), and, at the end, NBS (1.2
equiv) were added, and argon was bubbled for another 5 min. The
reaction mixture was stirred under argon at room temperature in the
dark for 18 h. The solvent was removed under reduced pressure, and
the residue was dry-loaded onto silica gel and purified by column
chromatography.
General Procedure C for the Synthesis of 5-Alkynylated
1,2,3-Triazoles 19−23. An oven-dried Schlenk tube equipped with a
rubber septum was evacuated and refilled with argon (3×). 1-Azido-3-
iodobicyclo[1.1.1]pentane (1) (1.0 equiv) dissolved in anhydrous
THF was added to the tube, followed by the same amount of
anhydrous TEA. The ethynyl substrate (2.2−2.4 equiv) was added,
and argon was bubbled through the mixture for 15 min. CuI (0.2
equiv) and Pd(PPh3)2Cl2 (0.1 equiv) were added, and argon was
bubbled for another 5 min. The reaction mixture was stirred under
argon at room temperature in the dark for 18 h. The solvent was
removed under reduced pressure. The residue was dissolved in ethyl
acetate (EtOAc) or DCM and passed through a plug of silica gel.
Subsequently, the crude mixture was dry-loaded onto silica gel and
further purified by silica gel column chromatography.
EXPERIMENTAL SECTION
■
General Information. All reagents were obtained from
commercial sources and used as received unless otherwise stated.
All air- and/or water-sensitive materials were handled using standard
high vacuum procedures. Anhydrous THF and TEA were purchased
from Sigma-Aldrich, and anhydrous dichloromethane (DCM) was
obtained by distillation from P2O5 and stored over activated
molecular sieves. The precursors 1-azido-3-iodobicyclo[1.1.1]pentane
(1),8 8-(4-ethynylphenyl)-4,4-difluoro-1,3,5,7-tetramethyl-4-bora-
3a,4a-diaza-s-indacene (5),26 1-ethynylpyrene (6),27 and [5-(4-
ethynylphenyl)-10,20-bis(4-methylphenyl)-15-phenylporphyrinato)]-
zinc(II) (7)3c were synthesized according to literature procedures.
Phenylacetylene (8) and 1-ethynylpyridine (17) are commercially
available compounds and were purchased from Aldrich and
Fluorochem, respectively. For some reactions, a mixture of 1-azido-
3-iodobicyclo[1.1.1]pentane (1) and 1,3-diiodobicyclo[1.1.1]pentane
was used. To rule out the possibility that the use of this mixture as a
starting material for “click” reactions has an effect on the product
formation, a test “click” reaction with neat 1-azido-3-iodo-BCP 1 and
BODIPY 2 was performed under the conditions of general procedure
A. The 5-iodo-1,2,3-triazole product 7 was formed with a yield of 6%,
alongside the 5-protio-1,2,3-triazole product 6 with a yield of 71%.
This product distribution was comparable to the results obtained
when a mixture of 1-azido-3-iodobicyclo[1.1.1]pentane and 1,3-
diiodobicyclo[1.1.1]pentane was used, indicating that use of the
mixture had no influence on the product formation. Reactions at
elevated temperatures were carried out using a hot plate with an oil
bath as a heat source. Flash chromatography was carried out using
silica gel Florisil (200 mesh; Aldrich). Preparative thin layer
chromatography was performed on precoated preparative Uniplates
(silica, 2000 μm, 20 cm × 20 cm, Analtech). Analytical thin-layer
chromatography was carried out on precoated 60 F254 silica plates
(0.2 mm thick, 20 cm × 20 cm) and visualized by UV irradiation on a
Shimadzu Multispec-1501. Bruker DPX 400 and Agilent 400 were
Screening of Reaction Conditions for the Formation of 5-
Protio-1,2,3-triazole 9 and 5-Iodo-1,2,3-triazole 10. Five
reactions were carried out with 1 (6.7 mg, 28.7 μmol, 1.0 equiv)
and 5 (10.0 mg, 28.7 μmol, 1.0 equiv) and varying amounts of
reagents in 0.67 mL of anhydrous THF based on general procedure
A: (I) CuI (1.1 mg, 5.78 μmol, 0.2 equiv), TEA (6 μL, 43.0 μmol, 1.5
equiv), under an argon atmosphere according to general procedure A.
(II) CuI (1.6 mg, 8.4 μmol, 0.3 equiv), TEA (6 μL, 43.0 μmol, 1.5
equiv), under an argon atmosphere according to general procedure A.
(III) CuI (1.1 mg, 5.78 μmol, 0.2 equiv), TEA (6 μL, 43.0 μmol, 1.5
equiv); the solvent was not deoxygenated, and the reaction was
carried out under air. (IV) CuI (1.6 mg, 8.4 μmol, 0.3 equiv), TEA (6
μL, 43.0 μmol, 1.5 equiv); the solvent was not deoxygenated, and the
reaction was carried out under air. (V) CuI (5.5 mg, 28.9 μmol, 1.0
equiv), TEA (15 μL, 108 μmol, 3.8 equiv); the solvent was not
deoxygenated, and the reaction was carried out under air. One
reaction was carried out based on general procedure B with 1 (6.7 mg,
28.7 μmol, 1.0 equiv) and 5 (10.0 mg, 28.7 μmol, 1.0 equiv) in 0.67
mL of THF. (VI) CuI (5.5 mg, 28.9 μmol, 1.0 equiv), DIPEA (5 μL,
28.7 μmol, 1.0 equiv), NBS (6.1 mg, 34.2 μmol, 1.2 equiv) under an
argon atmosphere according to general procedure B. All reactions
were left to stir for 16 h in the dark, and the solvent was removed
under reduced pressure. For reactions I−IV the crude solids were
completely dissolved in CDCl3 (∼0.5 mL), the internal standard
1
used to obtain H (400.13 MHz), 13C{H} (100.61 MHz), 19F{H}
(376.60 MHz), and 11B (128.40 MHz) NMR spectra, and a Bruker
1
AV 600 was employed for H (600.13 MHz) and 13C{H} (150.90
MHz) NMR spectra. NMR spectroscopy was carried out at room
temperature using deuterated solvent, as indicated for each synthesis.
All melting points are uncorrected and determined with a Digital
Stuart SMP10 melting point apparatus. UV/vis spectra were recorded
in solutions using a Specord 250 spectrophotometer from Analytik
Jena (1 cm path length quartz cell). Mass spectrometry analysis
(HRMS) was performed with a Q-Tof Premier Waters quadrupole
time-of-flight (Q-TOF) mass spectrometer equipped with Z-spray
electrospray ionization (ESI) and matrix assisted laser desorption
ionization (MALDI) sources with trans-2-[3-(4-tert-butylphenyl)-2-
methyl-2-propenylidene]malononitrile as the matrix and with a
Bruker micrOTOF-Q-III with ESI and atmospheric pressure chemical
ionization (APCI) sources.
General Procedure A for the Synthesis of 1,2,3-Triazoles 9,
11, 13, 15. 1,2,3-Triazoles were synthesized by adapting a literature
procedure.6a,b A microwave vial equipped with a rubber septum was
evacuated and refilled with argon (3×). 1-Azido-3-iodobicyclo[1.1.1]-
pentane (1) (1.0 equiv) dissolved in anhydrous THF was added to
the vial, followed by TEA (1.5 equiv). Argon was bubbled through the
mixture for 10 min. CuI (0.1 equiv) and the ethynyl substrate (1.0
equiv) were added, and argon was bubbled for another 5 min. The
mixture was stirred under argon at room temperature in the dark for
16 h. The solvent was removed under reduced pressure, and the
1
dibromomethane (20 μL) was added, and H NMR spectra of the
four samples were recorded. For reactions V and VI, a lower solubility
was observed due to side product formation. Therefore, the crude
solids were dissolved in CHCl3 (1 mL), aliquots of this solution (30
μL) were mixed in NMR tubes with dibromomethane (10 μL) and
CDCl3 (∼0.5 mL), and the 1H NMR spectra were recorded. The total
amounts of compounds 9 and 10 in the reaction mixtures were
calculated based on the intensity of their BCP bridge proton signals at
2.87 and 3.07 ppm relative to the intensity of the signal of
dibromomethane at 4.93 ppm
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-(8-(4-phenyl)-4,4-di-
fluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene)-
1H-1,2,3-triazole (9). Compounds 1 (13.5 mg, 57.4 μmol), 5 (20
mg, 57.4 μmol), CuI (1.1 mg, 5.78 μmol), and TEA (12 μL, 86.1
μmol) were reacted in 0.7 mL of THF in accordance with general
procedure A. Silica gel column chromatography (hexane/EtOAc
gradient 20:1 to 5:1) afforded 9 as orange crystals (27.5 mg, 47.2
D
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μmol, 82%). Mp = 140−174 °C (decomposition (dec.)). Rf = 0.26
(hexane/EtOAc 5:1). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, 2H, J =
8.1 Hz), 7.80 (s, 1H), 7.36 (d, 2H, J = 8.1 Hz), 5.98 (s, 2H), 2.88 (s,
6H), 2.56 (s, 6H), 1.42 (s, 6H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 155.8, 147.1, 143.2, 141.2, 135.2, 131.5, 131.1, 128.8, 126.6,
121.5, 118.5, 62.0, 54.8, 14.7, −3.0 ppm. 19F{1H} NMR (376.6 MHz,
CDCl3) δ −146.29 (q, J = 32.7 Hz) ppm. 11B NMR (128.4 MHz,
CDCl3) δ 0.77 (t, J = 33.3 Hz) ppm. UV−vis (CH2Cl2) λmax (log ε) =
349 (3.89), 474 sh, 504 (4.96). HRMS (ESI): m/z calcd for
[C26H26BF2IN5] [M + H]+ 584.1293; found 584.1303.
(log ε) = 348 (4.08), 477 sh, 504 (5.10) nm. HRMS (ESI): m/z calcd
for [C26H23BF2I2N5] [M − H]− 708.0114; found 708.0097.
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-(1-pyrenyl)-5-iodo-
1H-1,2,3-triazole (12). Compounds 1 (11.2 mg, 47.8 μmol), 6 (11.8
mg, 47.8 μmol), CuI (9.1 mg, 47.8 μmol), NBS (10.2 mg, 57.3 μmol),
and DIPEA (9 μL, 51.7 μmol) were reacted in 2 mL of THF in
accordance with general procedure B. Silica gel column chromatog-
raphy (hexane/EtOAc gradient 200:1 to 40:1) and trituration with
hexane and toluene afforded 12 as a yellow solid (4.8 mg, 8.17 μmol,
17%). Mp = 196−201 °C (dec.). Rf = 0.24 (hexane/EtOAc 10:1). 1H
NMR (400 MHz, CDCl3) δ 8.27−8.20 (m, 3H), 8.17−8.10 (m, 2H),
8.09 (s, 2H), 8.07−8.02 (m, 2H), 3.15 (s, 6H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 152.3, 132.1, 131.4, 131.0, 129.9, 128.5, 128.4,
128.3, 127.5, 126.4, 125.7, 125.6, 125.3, 125.1, 124.7, 124.6, 124.2,
62.5, 56.9, 53.6, −1.5 ppm. UV−vis (CH2Cl2) λmax (log ε) = 271 sh,
281 (4.67), 336 sh, 348 (4.52) nm. HRMS (ESI): m/z calcd for
[C23H16I2N3] [M + H]+ 587.9428; found 587.9434.
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-(1-pyrenyl)-1H-1,2,3-
triazole (11). Compounds 1 (20.6 mg, 87.6 μmol), 6 (20 mg, 87.6
μmol), CuI (1.7 mg, 8.93 μmol), and TEA (19 μL, 0.138 mmol) were
reacted in 2 mL of THF in accordance with general procedure A.
Silica gel column chromatography (hexane/EtOAc gradient 50:1 to
10:1) afforded 11 as a white solid (4.2 mg, 9.10 μmol, 10%). Mp =
1
201−214 °C (dec.). Rf = 0.16 (hexane/EtOAc 10:1). H NMR (600
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-[5-(4-phenyl)-10,20-
(4-methylphenyl)-15-phenylporphyrinato]zinc(II)-5-iodo-1H-
1,2,3-triazole (14). Compounds 1 (8.4 mg, 35.6 μmol), 7 (26.0 mg,
35.6 μmol), CuI (6.8 mg, 35.7 μmol), NBS (7.6 mg, 42.7 μmol), and
DIPEA (5 μL, 28.7 μmol) were reacted in 1.4 mL of THF in
accordance with general procedure B. Silica gel column chromatog-
raphy (hexane/EtOAc gradient 20:1 to 10:1) afforded 14 as a purple
solid (7.5 mg, 6.87 μmol, 19%). 1H and 13C NMR spectra were
recorded of 14 with pyridine as the axial ligand to prevent
intermolecular interactions between porphyrins arising from zinc(II)
coordination. Mp = 262−282 °C (dec.). Rf = 0.32 (hexane/EtOAc
MHz, CDCl3) δ 8.65 (d, 1H, J = 9.2 Hz), 8.23−8.20 (m, 4H), 8.11
(m, 3H), 8.05−8.02 (t, 1H, J = 7.6 Hz), 7.90 (s, 1H), 2.97 (s, 6H)
ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 147.7, 131.6, 131.5, 131.0,
128.9, 128.5, 128.1, 127.5, 127.4, 126.3, 125.7, 125.4, 125.2, 125.0,
124.9, 124.9, 124.8, 121.2, 62.2, 54.9, 53.6, 29.9, −2.7 ppm. UV−vis
(CH2Cl2) λmax (log ε) = 273 sh, 283 (4.61), 353 (4.51). HRMS
(ESI): m/z calcd for [C23H17IN3] [M + H]+ 462.0462; found
462.0463.
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-[5-(4-phenyl)-10,20-
(4-methylphenyl)-15-phenylporphyrinato]zinc(II)-1H-1,2,3-tri-
azole (13). Compounds 1 (8.0 mg, 34.0 μmol), 7 (25 mg, 34.2
μmol), CuI (0.6 mg, 3.15 μmol), and TEA (6 μL, 43.0 μmol) were
reacted in 1.3 mL of THF in accordance with general procedure A.
Silica gel column chromatography (hexane/EtOAc gradient 20:1 to
10:1) afforded 13 as purple crystals (23.2 mg, 24.0 μmol, 79%). Mp
>300 °C. Rf = 0.22 (hexane/EtOAc 5:1). 1H NMR (600 MHz,
CDCl3) δ 9.00−8.97 (m, 6H), 8.95 (d, 2H, J = 4.6 Hz), 8.28 (d, 2H, J
= 8.0 Hz), 8.24−8.22 (m, 2H), 8.16 (d, 2H, J = 8.0 Hz), 8.11 (d, 4H,
J = 7.8 Hz), 7.96 (s, 1H), 7.79−7.73 (m, 3H), 7.56 (d, 4H, J = 7.7
Hz), 2.97 (s, 1H), 2.71 (s, 6H) ppm. 13C{1H} NMR (151 MHz,
CDCl3) δ 150.6, 150.5, 150.4, 150.1, 147.9, 143.2, 143.0, 140.0, 137.3,
135.1, 134.6, 134.5, 132.3, 132.2, 132.1, 131.8, 129.5, 127.6, 127.5,
126.7, 124.2, 121.5, 121.3, 120.4, 118.4, 62.1, 54.9, 21.7, −2.7 ppm.
UV−vis (CH2Cl2) λmax (log ε) = 406 sh, 423 (6.98), 551 (5.56), 592
(4.96) nm. HRMS (ESI): m/z calcd for [C53H39IN7Zn] [M + H]+
964.1598; found 964.1599.
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-phenyl-1H-1,2,3-tria-
zole (15). Compounds 1 (25 mg, 0.106 mmol), 8 (12 μL, 0.106
mmol), CuI (2.0 mg, 10.6 μmol), and TEA (22 μL, 0.159 mmol)
were reacted in 3 mL of THF in accordance with general procedure A.
Silica gel column chromatography (hexane/EtOAc gradient 200:1 to
10:1) afforded 15 as a white solid (26.5 mg, 78.6 μmol, 74%).
Characterization data in accordance with the literature.6a Rf = 0.24
(hexane/EtOAc 10:1). 1H NMR (600 MHz, CDCl3) δ 7.82−7.80 (m,
2H), 7.44−7.40 (m, 2H), 7.36−7.32 (m, 1H), 2.87 (s, 6H) ppm.
HRMS (ESI): m/z calcd for [C13H13IN3] [M + H]+ 338.0149; found
338.0150.
1
5:1). H NMR (600 MHz, CDCl3) δ 8.93−8.90 (m, 6H), 8.87 (d,
2H, J = 4.4 Hz), 8.30 (d, 2H, J = 7.8 Hz), 8.24 (d, 2H, J = 7.8 Hz),
8.20 (d, 2H, J = 7.1 Hz), 8.08 (d, 4H, J = 7.5 Hz), 7.75−7.70 (m,
3H), 7.53 (d, 4H, J = 7.4 Hz), 6.70 (t, 1H, J = 7.4 Hz), 6.01−5.96 (m,
2H), 4.17 (br s, 2H), 3.15 (s, 6H), 2.70 (s, 6H) ppm. 13C{1H} NMR
(151 MHz, CDCl3) δ 150.8, 150.6, 150.5, 150.3, 150.1, 143.7, 143.1,
140.0, 137.4, 137.3, 134.8, 134.6, 134.5, 132.3, 132.2, 132.0, 131.8,
131.1, 129.1, 129.0, 128.4, 127.6, 127.4, 126.7, 125.9, 121.4, 121.3,
120.3, 72.9, 62.5, 57.0, 54.0, 21.7, −1.4.ppm. UV−vis (CH2Cl2) λmax
(log ε) = 403 sh, 423 (5.73), 551 (4.31), 592 (3.73) nm. HRMS
(APCI): m/z calcd for [C53H38I2N7Zn] [M + H]+ 1090.0564; found
1090.0537.
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-phenyl-5-iodo-1H-
1,2,3-triazole (16). Compounds 1 (11.2 mg, 47.8 μmol), 8 (6 μL,
54.6 μmol), CuI (9.1 mg, 47.8 μmol), NBS (10.2 mg, 57.3 μmol), and
DIPEA (9 μL, 51.7 μmol) were reacted in 2 mL of THF in
accordance with general procedure B. Silica gel column chromatog-
raphy (hexane/EtOAc gradient 200:1 to 20:1) afforded 16 as an off-
white solid (1.5 mg, 3.24 μmol, 7%). Mp = 182 °C (dec.). Rf = 0.42
(hexane/EtOAc 10:1). 1H NMR (600 MHz, CDCl3) δ 7.86 (d, 2H, J
= 7.4 Hz), 7.46 (t, 2H, J = 7.6 Hz), 7.41 (t, 1H, J = 7.3 Hz), 3.06 (s,
6H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 150.8, 123.0, 128.9,
128.7, 127.9, 72.6, 62.4, 56.8, −1.4 ppm. HRMS (APCI): m/z calcd
for [C13H12I2N3] [M + H]+ 463.9115; found 463.9118.
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-(4-pyridinyl)-5-iodo-
1H-1,2,3-triazole (18). Compounds 1 (14.1 mg, 60.0 μmol), 17 (6.2
mg, 60.1 μmol), CuI (11.5 mg, 60.3 μmol), NBS (12.8 mg, 71.9
μmol), and DIPEA (8 μL, 45.9 μmol) were reacted in 2 mL of THF
in accordance with general procedure B. The crude product was
purified by silica gel column chromatography (hexane/EtOAc
gradient 5:1 to 2:1). The isolated product was dissolved in DCM
and washed with saturated aqueous NaHCO3 solution (2×) and H2O
(1×) to afford 18 as an off-white solid (18.3 mg, 38.8 μmol, 66%).
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-(8-(4-phenyl)-4,4-di-
fluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene)-5-
iodo-1H-1,2,3-triazole (10). Compounds 1 (6.8 mg, 28.7 μmol), 5
(10.0 mg, 28.7 μmol), CuI (5.5 mg, 28.9 μmol), NBS (6.1 mg, 34.3
μmol), and DIPEA (5 μL, 28.7 μmol) were reacted in 2 mL of THF
in accordance with general procedure B. Silica gel column
chromatography (hexane/DCM gradient 2:1 to 1:1) afforded 10 as
an orange solid (2.8 mg, 3.95 μmol, 14%). Mp = 212−236 °C (dec.).
1
Mp = 136−139 °C (dec.). Rf = 0.40 (hexane/EtOAc 1:1). H NMR
(600 MHz, CDCl3) δ 8.73 (br s, 2H), 7.89 (br d, 2H, J = 3.7 Hz),
3.07 (s, 6H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 150.4, 147.8,
137.6, 121.6, 73.6, 62.4, 56.8, −1.9 ppm. HRMS (ESI): m/z calcd for
[C12H11I2N4] [M + H]+ 464.9068; found 464.9069.
1
Rf = 0.33 (hexane/EtOAc 5:1). H NMR (600 MHz, CDCl3) δ 8.05
(d, 2H, J = 8.2 Hz), 7.39 (d, 2H, J = 8.2 Hz), 5.99 (s, 2H), 3.07 (s,
6H), 2.56 (s, 6H), 1.43 (s, 6H) ppm. 13C{1H} NMR (151 MHz,
CDCl3) δ 155.9, 149.9, 143.2, 141.1, 135.6, 131.5, 130.8, 128.5, 128.4,
121.5, 73.1, 62.4, 56.9, 14.8, 14.7, −1.7 ppm. 19F{1H} NMR (376.6
MHz, CDCl3) δ −146.28 (q, J = 33.0 Hz) ppm. 11B NMR (128.4
MHz, CDCl3) δ 0.78 (t, J = 33.3 Hz) ppm. UV−vis (CH2Cl2) λmax
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-(8-(4-phenyl)-4,4-di-
fluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene)-5-
(8-(4-phenylethynyl)-4,4-difluoro-1,3,5,7-tetramethyl-4-bora-
3a,4a-diaza-s-indacene)-1H-1,2,3-triazole (19). Compounds 1
(12.0 mg, 51.1 μmol), 5 (42.0 mg, 121 μmol), CuI (2.1 mg, 11.0
E
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
μmol), and Pd(PPh3)2Cl2 (3.9 mg, 5.56 μmol) were reacted in a
mixture of 1 mL of THF and 1 mL of TEA in accordance with general
procedure C. Silica gel column chromatography (1. chromatography
hexane/EtOAc gradient 10:1 to 5:1; 2. chromatography neat DCM
and DCM/EtOAc 100:1) afforded 19 as an orange solid (trace
Hz), 8.73 (dd, 2H, J = 4.6, 1.6 Hz), 8.00 (dd, 2H, J = 4.6, 1.6 Hz),
7.44 (dd, 2H, J = 4.4, 1.6 Hz), 3.02 (s, 6H) ppm. 13C{1H} NMR (101
MHz, CDCl3) δ 150.6, 146.6, 137.0, 128.7, 125.1, 120.7, 116.8, 100.5,
78.6, 62.3, 55.2, 29.8, −2.7 ppm. HRMS (APCI): m/z calcd for
[C19H15IN5] [M + H]+ 440.0367; found 440.0369.
1
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-(4-pyridinyl)-1H-
amount). H NMR (400 MHz, CDCl3) δ 8.32 (d, 2H, J = 8.4 Hz),
1,2,3-triazole 24. Mp = 216−222 °C (dec.). Rf = 0.33 (hexane/
7.67 (d, 2H, J = 8.1 Hz), 7.41 (dd, 4H, J = 8.0, 1.8 Hz), 6.00 (s, 2H),
5.97 (s, 2H), 3.04 (s, 6H), 2.55 (s, 6H), 2.54 (s, 6H), 1.43 (s, 6H),
1.43 (s, 6H) ppm. HRMS (MALDI): m/z calcd for [C47H42B2F4IN7]
[M]+ 929.2669; found 929.2646.
1
EtOAc 1:2). H NMR (600 MHz, CDCl3) δ 8.69 (s, 2H), 7.85 (s,
1H), 7.71 (br d, 2H, J = 3.7 Hz), 2.88 (s, 6H) ppm. 13C{1H} NMR
(151 MHz, CDCl3) δ 150.6, 145.4, 137.7, 120.2, 119.5, 62.0, 54.8,
−3.2 ppm. HRMS (APCI): m/z calcd for [C12H12IN4] [M + H]+
339.0101; found 339.0105.
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-(1-pyrenyl)-5-(1-pyre-
nylethynyl)-1H-1,2,3-triazole (20). Compounds 1 (25.0 mg, 0.106
mmol), 6 (57.5 mg, 0.254 mmol), CuI (4.0 mg, 21.2 μmol), and
Pd(PPh3)2Cl2 (7.4 mg, 10.6 μmol) were reacted in a mixture of 0.6
mL of THF and 0.6 mL of TEA in accordance with general procedure
C. Two silica gel column chromatographies (hexane/EtOAc 20:1 and
hexane/EtOAc 100:3) afforded 20 as a light yellow solid (5.4 mg,
7.88 μmol, 7%). Mp = 200−212 °C (dec.). Rf = 0.21 (hexane/EtOAc
10:1). 1H NMR (400 MHz, CDCl3) δ 8.68 (d, 1H, J = 9.3 Hz), 8.49
(d, 1H, J = 7.9 Hz), 8.34 (d, 1H, J = 7.9 Hz), 8.29 (d, 1H, J = 7.5 Hz),
8.23−8.15 (m, 5H), 8.12−7.96 (m, 7H), 7.77 (d, 1H, J = 9.1 Hz),
7.33 (d, 1H, J = 9.1 Hz), 3.24 (s, 6H) ppm. 13C{1H} NMR (151
MHz, CDCl3) δ 149.9, 132.4, 132.2, 132.2, 131.5, 131.3, 131.2, 130.8,
129.5, 129.2, 129.1, 128.9, 128.5, 128.1, 127.6, 127.2, 126.6, 126.4,
126.2, 125.7, 125.6, 125.6, 125.3, 124.9, 124.9, 124.7, 124.6, 124.4,
124.4, 124.1, 119.9, 115.2, 101.9, 80.3, 62.6, 55.5, −1.6 ppm. UV−vis
(CH2Cl2) λmax (log ε) = 282 (4.74), 297 sh, 352 (4.77), 374 sh, 398
sh. HRMS (APCI): m/z calcd for [C41H25IN3] [M + H]+ 686.1088;
found 686.1101.
Upscale Synthesis of Compound 18. Compounds 1 (353 mg,
1.5 mmol), 17 (155 mg, 1.5 mmol), CuI (288 mg, 1.5 mmol), NBS
(320 mg, 1.8 mmol), and DIPEA (0.20 mL, 1.5 mmol) were reacted
in 57 mL of THF in accordance with general procedure B. The crude
product was purified by silica gel column chromatography (hexane/
EtOAc gradient 2:1 to 2:3). The isolated product was dissolved in
DCM and washed with saturated aqueous NaHCO3 solution (2×).
The combined aqueous layers were extracted with DCM (5×). The
organic layers were combined and washed with H2O (1×) to afford
18 as an off-white solid (367 mg, 0.791 mmol, 53%).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02432.
Additional experimental data, X-ray crystallography data,
and NMR spectra (PDF)
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-[5-(4-phenyl)-10,20-
(4-methylphenyl)-15-phenylporphyrinato]zinc(II)-5-[5-(4-
phenylethynyl)-10,20-(4-methylphenyl)-15-phenyl-
porphyrinato]zinc(II)-1H-1,2,3-triazole (21). Compounds 1 (6.4
mg, 27.5 μmol), 7 (44.0 mg, 60.3 μmol), CuI (1.0 mg, 5.25 μmol)
and Pd(PPh3)2Cl2 (2.0 mg, 2.85 μmol) were reacted in a mixture of
0.5 mL of THF and 0.5 mL of TEA in accordance with general
procedure C. Silica gel column chromatography (DCM/hexane 3:7,
2:3, neat DCM, DCM/EtOAc 10:1) and preparative TLC (DCM/
Accession Codes
CCDC 2030937−2030944 and 2036122−2036123 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.
1
hexane 4:1) afforded 21 as a purple solid (trace amount). H NMR
(400 MHz, CDCl3) δ 9.05 (d, 2H, J = 4.7 Hz), 8.99 (d, 2H, J = 4.9
Hz), 8.96−8.89 (m, 12H), 8.69 (d, 2H, J = 8.3 Hz), 8.41 (d, 2H, J =
8.1 Hz), 8.28 (d, 2H, J = 8.4 Hz), 8.20−8.16 (m, 2H), 8.09−8.02 (m,
6H), 7.76−7.70 (m, 4H), 7.53−7.48 (m, 4H), 3.27 (s, 6H), 2.67 (s,
6H), 2.66 (s, 6H) ppm. HRMS (MALDI): m/z calcd for
[C101H68IN11Zn2] [M]+ 1689.3287; found 1689.3296.
AUTHOR INFORMATION
■
Corresponding Author
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-phenyl-5-phenyle-
thynyl-1H-1,2,3-triazole (22). Compounds 1 (20 mg, 85.1 μmol),
8 (20.9 mg, 0.205 mmol), CuI (3.2 mg, 16.8 μmol), and
Pd(PPh3)2Cl2 (6.0 mg, 8.55 μmol) were reacted in a mixture of 1
mL of THF and 1 mL of TEA in accordance with general procedure
C. Silica gel column chromatography (hexane/EtOAc 40:1) afforded
22 as a white solid (3.8 mg, 8.69 μmol, 10%). Mp = 173−176 °C. Rf =
Mathias O. Senge − School of Chemistry, SFI Tetrapyrrole
Laboratory, Trinity Biomedical Sciences Institute, Trinity
College Dublin, The University of Dublin, Dublin 2, Dublin,
Ireland; orcid.org/0000-0002-7467-1654;
Email: sengem@tcd.ie
1
Authors
0.62 (hexane/EtOAc 10:1). H NMR (600 MHz, CDCl3) δ 8.15 (d,
Elisabeth Sitte − School of Chemistry, SFI Tetrapyrrole
Laboratory, Trinity Biomedical Sciences Institute, Trinity
College Dublin, The University of Dublin, Dublin 2, Dublin,
Ireland
Brendan Twamley − School of Chemistry, Trinity College
Dublin, The University of Dublin, Dublin 2, Dublin, Ireland
Nitika Grover − School of Chemistry, SFI Tetrapyrrole
Laboratory, Trinity Biomedical Sciences Institute, Trinity
College Dublin, The University of Dublin, Dublin 2, Dublin,
Ireland
2H, J = 7.5 Hz), 7.59−7.55 (m, 2H), 7.50−7.43 (m, 5H), 7.38 (t, 1H,
J = 7.3 Hz), 3.03 (s, 6H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ
148.4, 131.6, 130.1, 130.1, 129.0, 128.9, 128.9, 126.5, 121.4, 116.3,
102.4, 75.6, 62.3, 55.2, −1.7 ppm. HRMS (ESI): m/z calcd for
[C21H17IN3] [M + H]+ 438.0462; found 438.0456.
1-(3-Iodobicyclo[1.1.1]pentan-1-yl)-4-(4-pyridinyl)-5-(4-pyr-
idinylethynyl)-1H-1,2,3-triazole (23) and 1-(3-Iodobicyclo-
[1.1.1]pentan-1-yl)-4-(4-pyridinyl)-1H-1,2,3-triazole (24). Com-
pounds 1 (20 mg, 85.0 μmol), 17 (21 mg, 204 μmol), CuI (3.2 mg,
17.2 μmol), and Pd(PPh3)2Cl2 (6.0 mg, 8.50 μmol) were reacted in a
mixture of 0.4 mL of THF and 0.4 mL of TEA in accordance with
general procedure C. Silica gel column chromatography (hexane/
EtOAc gradient 2:1, to 1:2) afforded 23 as a white solid (9.9 mg, 22.5
μmol, 27%) and 24 as a white solid (9.0 mg, 26.6 μmol, 31%). 1-(3-
Iodobicyclo[1.1.1]pentan-1-yl)-4-(4-pyridyl)-5-(4-pyridinylethynyl)-
1H-1,2,3-triazole (23): Mp = 159 °C (dec.). Rf = 0.19 (hexane/
EtOAc 1:2). 1H NMR (400 MHz, CDCl3) δ 8.77 (dd, 2H, J = 4.4, 1.6
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02432
Notes
The authors declare no competing financial interest.
F
https://dx.doi.org/10.1021/acs.joc.0c02432
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(c) Kokhan, S. O.; Valter, Y. B.; Tymtsunik, A. V.; Komarov, I. V.;
Grygorenko, O. O. Bicyclo[1.1.1]pentane-Derived Building Blocks for
Click Chemistry. Eur. J. Org. Chem. 2017, 2017, 6450−6456.
(7) Selected references: (a) Mullaney, B. R.; Thompson, A. L.; Beer,
P. D. An All-Halogen Bonding Rotaxane for Selective Sensing of
Halides in Aqueous Media. Angew. Chem. Int. Ed. 2014, 53, 11458−
62. (b) Morris, J. C.; Chiche, J.; Grellier, C.; Lopez, M.; Bornaghi, L.
ACKNOWLEDGMENTS
■
This work was supported by a grant from Science Foundation
Ireland (SFI IvP 13/IA/1894), the Sydney E. Auchinleck
Foundation, and Trinity College Dublin.
REFERENCES
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