Regioselective synthesis and slow-release suzuki-miyaura cross-coupling of MIDA boronate-functionalized isoxazoles and triazoles

Article abstract of DOI:10.1021/jo201973t

The efficient preparation of heterocycles with a range of substitutions ortho to heteroatoms remains as a challenge in organic synthesis, particularly relevant to the construction of druglike molecules due to the ubiquitous presence of such moieties in th

Full text of DOI:10.1021/jo201973t

Article
pubs.acs.org/joc
Regioselective Synthesis and Slow-Release Suzuki−Miyaura Cross-
Coupling of MIDA Boronate-Functionalized Isoxazoles and Triazoles
Jonathan E. Grob,* Jill Nunez, Michael A. Dechantsreiter, and Lawrence G. Hamann
Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: The efficient preparation of heterocycles with a
range of substitutions ortho to heteroatoms remains as a
challenge in organic synthesis, particularly relevant to the
construction of druglike molecules due to the ubiquitous
presence of such moieties in that chemical space. Modular
installation of heterocyclic building blocks using Suzuki−
Miyaura cross-coupling is a conceptually useful strategy to
address this challenge, though this has historically been met with technical difficulty due to issues of inaccessibility and instability
of the requisite heterocyclic boronates. Herein we report a mild and highly regioselective cycloaddition approach which affords
convenient access to stable MIDA boronate-functionalized isoxazoles and triazoles and their subsequent efficient Suzuki−
Miyaura cross-coupling. This methodology is then further applied to a set of druglike compounds in an efficient one-pot
telescoped sequence in line with green chemistry principles.
preparation has primarily been through direct derivatization
of a free boronic acid or its lithium alkoxide adduct.8 We
reasoned that by building certain 2-heterocyclic boronates from
smaller prefunctionalized fragments that the aforementioned
limitations might be avoided, and this powerful methodology
could thereby be extended to enable a streamlined construction
of heterocycle containing molecules.
INTRODUCTION
■
Heterocyclic frameworks find ubiquitous representation in
pharmaceutically active agents and other biologically relevant
molecules, and methods for their synthesis and functionaliza-
tion have been areas of intensive study for more than a
century.1 A more modular strategy, whereby preconstructed
heterocycles are introduced to build larger molecules,
constitutes a complementary synthetic approach with inher-
ently wide versatility as well as adaptability to parallel synthesis
approaches. One of the most general methods for introducing
such preconstructed heterocyclic building blocks is the Suzuki−
Miyaura (SM) cross-coupling.2 However, many such hetero-
cyclic boronic acids/esters, particularly those where boron is
attached to a carbon center adjacent to the ring heteroatom, are
often difficult to prepare,3 are unstable, and are poor substrates
in SM cross-couplings.4 In particular, there have not been any
reported methods for conveniently accessing 5-boronyl
isoxazoles or 4-boronyl triazoles in such a way as to enable
subsequent efficient cross-coupling chemistry. One practical
solution to the more general problem of efficient utilization of
unstable boronic acids, which was successfully applied to other
heterocycles (most notably 2-pyridyl boronates), has been to
introduce the boronic acid functionality in a masked form
which can subsequently be liberated in a controlled release
fashion into the SM reaction solution, resulting in efficient
couplings.5 This conceptual approach has been shown to be
somewhat general with the use of N-methyliminodiacetic acid
(MIDA) masked boronic acids,6 and a number of historically
difficult boronic acid cross-couplings have been successfully
demonstrated with their use.7 A remaining limitation to a
broader application of this approach has been the lack of
availability of convenient methods for the synthesis of
heterocyclic boronic acid MIDA esters. To date, their
RESULTS AND DISCUSSION
We chose to investigate the potential of [3 + 2] cycloadditions
of ethynyl boronic acid MIDA ester 1 (Figure 1, path A), as this
■
Figure 1. Two paths to the preparation of isoxazole MIDA boronates.
commercially available synthon has shown tremendous
versatility as a precursor to more complex intermediates with
Received: September 28, 2011
Published: November 2, 2011
© 2011 American Chemical Society
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a preinstalled functional handle.7c,9 We anticipated that this
method might offer a practical alternative to intercepting a
metalated heterocycle with a borate ester and a subsequent
requisite masking step (Figure 1, path B).
Cycloadditions of alkynyl boronates have been demonstrated
by Harrity and co-workers to provide convenient access to a
wide range of 5- and 6-membered ring heterocyclic
boronates.10,11 This includes precedent for [3 + 2] cyclo-
addition of alkynylpinacol boronate esters at elevated temper-
atures, giving rise to borylated isoxazoles in moderate yields and
with varying degrees of regioselectivity, depending on the
nature of the substitution at both the alkyne terminus and the
oxime carbon. However, while Suzuki−Miyaura cross-couplings
of 4-boronyl isoxazoles have found wide use in the literature,
the complementary Suzuki−Miyaura cross-couplings of the
whether the observed regioselectivity was an intrinsic property
of the reacting partners or merely an artifact of the lowered
reaction temperature, we tested the cycloaddition reaction at 40
°C, and still none of the 4-boronyl isoxazole was observed. We
therefore hypothesize that the complete regioselectivity in the
case of the MIDA ester examples stems from the presence of
the sp3-hybridized boron center which imparts a more
significant steric demand in the case of the MIDA boronates
relative to the sp2-hybridized boron of the pinacol esters.
With conditions for effective cycloaddition in hand, we
focused on the utilization of these new heterocyclic MIDA
boronates in the SM cross-coupling. As a starting point for our
optimization efforts, we turned to the conditions developed by
the Burke group for unstable 2-pyridylboronic acids.7a Applying
these conditions to the SM cross-coupling of 3-phenylisoxazole
MIDA boronate 3a with 4-chlorobenzonitrile afforded the
desired cross-coupling product 5 in low yield (Table 2, entry
1), as protodeboronation of the heterocyclic boronate was a
significant side product. We reasoned that an increase in the
overall rate of the SM cross-coupling would lead to improve-
ments in the observed level of selectivity for the SM cross-
coupling relative to the competing protodeboronation pathway.
This was investigated by replacing the aryl chloride (Table 2,
entry 1) with the analogous aryl bromide 4 (Table 2, entry 2).
An improvement was noted both in the yield and in the ratio of
desired product 5 relative to the reduced heterocycle 6. The
selectivity of the reaction was further improved by employing
Buchwald’s palladacyclic precatalyst.12 These precatalysts are
known to generate a highly active Pd0 species capable of
extremely rapid uptake of the aryl halide coupling partner via
oxidative addition and in this application, afforded for the first
time, synthetically useful yields of SM cross-coupling product
(Table 2, entry 4). In the complementary approach, we
investigated the role of base and alcohol cosolvent in an
attempt to modulate the rate of solvolysis of the MIDA
boronate and thereby improve the performance of SM cross-
coupling. In this context, reactions with weaker bases (e.g.,
Na2CO3) and more sterically hindered cosolvents (e.g., tert-
butyl alcohol) failed to react to completion due to extremely
slow solvolysis. This left only the reaction solvent as a potential
variable to positively influence the efficiency of the reaction. We
speculated that less polar solvents would impede the solvolysis
of the isoxazole MIDA boronate as well and afford improved
Figure 2. Divergent reactivity of boronyl isoxazoles.
unstable 5-boronyl isoxazoles are virtually unreported (Figure
2).
Our initial results from the reaction between ethynylboronic
acid MIDA ester 1 and the in situ generated phenyl nitrile oxide
derived from chlorooxime 2 (Table 1, entry 1) demonstrated
that under this protocol cycloaddition proceeded at room
temperature, in high yield, and with complete regioselectivity.
This transformation appears to be rather general in scope,
proving to be effective on a range of aryl substituted nitrile
oxides as well as heteroaryl, halogen, and carboxylate
substituted nitrile oxides. In contrast to reported findings
using the corresponding pinacol esters, all of the isoxazole
MIDA boronates prepared in this manner were obtained as
single regioisomers and were purified by silica gel chromatog-
raphy with no evidence of decomposition. In order to evaluate
a
Table 1. Cycloadditions with Ethynylboronic Acid MIDA Ester 1
b
entry
R
base
solvent
yield (%)
1
2
3
4
5
6
7
8
Ph−
Br−
K3PO4
K3PO4
KHCO3
Et3N
MeCN
MeCN
DCM
DCM
DCM
DCM
DCM
DCM
3a 90
3b 95
3c 73
3d 90
3e 72
3f 89
3g 75
3h 90
c
d
−CO2Et
4-F-Ph−
2-pyridyl−
4-MeO-Ph−
4-Cl-Ph−
Et3N
Et3N
Et3N
2-CF3Ph−
Et3N
a
Unless otherwise noted, ethynylboronic acid MIDA ester 1 (1 equiv), chlorooxime 2 (2 equiv), and base (2 equiv) were allowed to react at room
b
c
d
temperature for 18 h. Isolated yield. Dibromoformaldoxime was used. The reaction was carried out with excess (3 equiv) chlorooxime and base.
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Table 2. Optimization of Suzuki−Miyaura Cross-Couplings on Isoxazole Boronic Acid MIDA Esters
a
b
entry
Pd source
Pd2dba3
solvent
5:6
yield (%)
c
1
DMF
5:1
32
49
0
2
Pd2dba3
DMF
9:1
d
3
Pd2dba3
DMF
−
4
5
6
7
8
9
precatalyst 1
precatalyst 1
precatalyst 1
precatalyst 2
precatalyst 1
DMF
7:1
59
28
59
55
63
69
MeCN
MeCN
MeCN
MeCN
MeCN
6:1
e
16:1
29:1
14:1
15:1
ef
,
f
precatalyst 2
a
b
c
d
Assessed by UV-HPLC at 254 nm. Isolated yield. 4-Chlorobenzonitrile was used. Reaction was performed without the Cu(OAc)2 additive.
e
f
With preactivation by KOt-Bu (0.05 equiv) at room temperature. Reaction was carried out in a microwave at 120 °C for 20 min.
Table 3. Suzuki−Miyaura Cross-Couplings of Isoxazole Boronic Acid MIDA Esters
b
a
entry
method
R (boronate)
Ar
yield (%)
b
1
B
B
B
A
A
A
A
A
3a Ph−
3a Ph−
3a Ph−
3c −CO2Et
3d 4-F-Ph−
3f 4-MeO-Ph−
3g 4-Cl-Ph−
3h 2-CF3-Ph−
4-MeO-Ph−
4-SO2Me-Ph−
3-Py−
4-CN-Ph−
4-CN-Ph−
4-CN-Ph−
4-CN-Ph−
4-CN-Ph−
7a 72
7b 76
7c 73
7d 75
7e 73
7f 69
7g 59
7h 56
2
3
4
5
6
7
8
a
b
Isolated yield. Method A utilized first generation X-Phos precatalyst (5 mol %) with preactivation by KOt-Bu (5 mol %). Method B utilized second
generation X-Phos precatalyst (5 mol %) with no preactivation.
levels of selectivity for the desired cross-coupling reaction.
Initially, this approach appeared to fail as exchanging
acetonitrile for DMF (Table 2, entry 5) led to a diminished
yield and moderate selectivity for the desired cross-coupling.
However, upon close analysis of the crude reaction mixture the
presence of unactivated precatalyst was observed. This was not
entirely unexpected given that precatalyst activation occurs at
temperatures above 80 °C with carbonate bases. We chose to
address this issue in two ways: (1) by carrying out catalyst
preactivation with potassium tert-butoxide at room temperature
in the presence of the aryl halide coupling partner13 and (2) by
investigating the second generation 2-aminobiphenyl derived
precatalyst14 which is activated at ambient temperature by
carbonate bases. Both of these approaches proved effective
(Table 2, entries 6 and 7) and were utilized in further
optimization and evaluation of the reaction scope. We also
evaluated the performance of the reaction under microwave
heating and observed a further improvement in reaction
efficiency for both the preactivation approach applied to the
first generation precatalyst (entry 8) as well as for the second
generation precatalyst with no preactivation (entry 9).
We next investigated the generality of these optimized
conditions by screening substituents on the isoxazole as well as
a range of aryl halide coupling partners. We observed moderate
to high yields in substrates with varied electronic properties
(Table 3).
Having developed the isoxazole chemistry to where it
appeared to be of sufficient generality so as to be suitable for
analogue synthesis in a drug discovery environment, we were
also quite interested to explore whether other heterocycles
might be prepared and derivatized in a similar fashion.
Considering the vast precedent for [3 + 2] azide acetylene
cycloaddition (AAC) reactions between alkynes and azides,15
and encouraged by recent literature reports16,17 on a thermal
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a
Table 4. Investigation of “Cu” and Additives on the AAC of Ethynyl MIDA Boronate 1 with Benzyl Azide 8
b
entry
“Cu”
CuCl
additive
yield (%)
1
2
3
4
5
6
−
−
0
0
CuOAc
Cu(SO4)2
Cu(OAc)2
Cu(OAc)2
CuI
Na-ascorbate
TBTA (10%)
−
0
c
c
78
78
60
DIPEA
a
b
c
All reactions were run with equimolar amounts of alkyne and azide, 50 mol % “Cu” at 0.2 M unless otherwise indicated. Isolated yield. Reaction
was run with 10 mol % Cu(OAc)2.
cycloaddition approach to 5-boronyl triazoles and their
subsequent SM cross-coupling reactions, we set out to develop
a procedure that would afford ready access to triazole MIDA
boronates.
Scheme 1. Slow Release SM Cross-Coupling of 4-
Boronyltriazole 9 with Aryl-/Heteroaryl Halides
We initially surveyed some standard conditions18 for Cu-
catalyzed AAC and found three sets of conditions that provided
access to triazole MIDA boronates in synthetically useful yields
(Table 4). The optimal conditions were 10 mol % of
Cu(OAc)2-H2O and equimolar amounts of the reaction
partners heated to 60 °C for 18 h. These simple conditions
enable rapid accesss to the expected and previously unreported
4-boronyl triazoles 9 as their MIDA conjugates. These air stable
boronic acid surrogates are prepared with no trace of the
corresponding 5-boronyl regioisomers, are isolable by standard
silica gel chromatography, and for the first time enable the
investigation of SM cross-coupling of these interesting
heterocyclic building blocks.
In order to assess the viability of these new boronyl
heterocycles as coupling partners in the SM cross-coupling, we
applied the conditions developed for the 5-boronyl isoxazoles
and observed an equally efficient reaction between benzyl-
triazole MIDA boronate 9 and 4-bromobenzonitrile 4 as
compared with the corresponding isoxazole MIDA boronate
example 5. The cross-coupling was tolerant of both electron-
rich and electron-poor coupling partners and proceeded in
good yields in all cases (Scheme 1).
Scheme 2. CuAAC and SM Cross-Coupling with Druglike
Azides 11
As we ultimately sought to demonstrate the utility of this
method in a medicinal chemistry context, we next wished to
ascertain whether this reaction might be readily applicable to
the construction of a number of motifs commonly found in
biologically relevant small molecules. We envisioned that this
would enable a cycloaddition-SM cross-coupling sequence
providing access to complex triazole products in a streamlined
synthetic sequence. We selected three azide motifs for this
study: a protected hydroxamic acid 11a, a sulfonyl proline
derivative 11b, and an N-aryl oxazolidinone 11c. We evaluated
the performance of the CuAAC and the subsequent SM cross-
coupling without modification of either protocol (Scheme 2).
All three motifs participated in the CuAAC in high yields to
afford a somewhat diverse range of complex triazole MIDA
boronates 12a−c illustrative of the scope of this method. The
resultant boronates performed only moderately well in the
subsequent SM cross-coupling however. Yields could be
improved by applying a one-pot procedure for this two-step
sequence, improving the overall unoptimized yield to 49% as
compared to 39% for the two-step process (13a). This one-pot
approach while accessing the target compounds in higher yield
also has the advantage of reduced waste generation by avoiding
the work-up and purification of the intermediate boronyl
triazole and is thus a greener and more efficient process.
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min before being added to a second reaction vessel containing
heterocyclic MIDA boronate (1 equiv), potassium carbonate (7
equiv), copper(II) acetate monohydrate (0.5 equiv), and acetonitrile
(1 mL). 2-Propanol was then added (in sufficient quantity to achieve a
4:1 ratio of acetonitrile:2-propanol), and the reaction was subjected to
microwave irradiation at 120 °C for 20 min. The reaction solvent was
removed in vacuo, and the residue was dissolved in dichloromethane
and was purified by flash chromatography (heptanes/ethyl acetate).
General Procedure B for the SM-Cross-Coupling of Heterocyclic
MIDA Boronates. To a microwave vial containing 2-aminobiphenyl
derived X-Phos palladacycle precatalyst-2 (0.05 equiv), aryl halide
(1.25 equiv), heterocyclic MIDA boronate (1 equiv), potassium
carbonate (7 equiv), and copper(II) acetate monohydrate (0.5 equiv)
was added acetonitrile and 2-propanol (4:1, 0.1 M), and the reaction
was subjected to microwave irradiation at 120 °C for 20 min. The
reaction solvent was removed in vacuo, and the residue was dissolved
in dichloromethane and was purified by flash chromatography
(heptanes/ethyl acetate).
CONCLUSION
■
We have developed synthetic routes useful for accessing two
important classes of heterocyclic MIDA boronates5-isoxazole
and 4-triazole MIDA boronates, respectivelyand demon-
strated their utility in SM cross-coupling reactions. The [3 + 2]
cycloaddition reactions reported herein all proceed with
exceptionally high levels of regioselectivity. In the isoxazole
case this is due to the relatively large steric footprint of the
MIDA boronate. While in the triazole case the regioselectivity
arises both from the aforementioned steric bulk as well as the
reagent tolerance imparted by the MIDA boronate which
enables the use of Cu catalysis, a hallmark for reliable access to
the 1,4-disubstituted heterocycle. To our knowledge, this work
is the first systematic study of the SM cross-couplings of 5-
boronyl isoxazoles as well as the only report of the isolation,
characterization, and SM cross-coupling of 4-boronyl triazoles.
These cross-couplings were enabled by the stability of the
MIDA boronates and the predictable slow release achieved in
the course of the SM cross-coupling reactions. Further, this
methodology enabled rapid access to a number of druglike
molecules in a one-pot telescoped sequence. Additional
ongoing investigations into synthesis and reactivity of other
boronyl-functionalized heterocycles will be the subject of
forthcoming communications.
3-Phenylisoxazol-5-ylboronic Acid MIDA Ester (3a). A general
procedure was followed using ethynyl MIDA boronate (381 mg, 2.1
mmol) and N-hydroxybenzimidoyl chloride (421 mg, 2.2 mmol) and
tripotassium phosphate (993 mg, 4.5 mmol), affording desired product
as an off-white powder (560 mg, 90% yield). Melting point: 158−159
1
°C. H NMR (acetonitrile-d3, 400 MHz): δ = 7.85−7.95 (m, 2 H),
7.47−7.58 (m, 3 H), 7.09 (s, 1 H), 4.17 (d, J = 17.6 Hz, 2 H), 4.01 (d,
J = 18.1 Hz, 2 H), 2.78 ppm (s, 3 H). 13C NMR (acetonitrile-d3, 101
MHz): δ = 169.2, 162.6, 131.3, 130.42, 130.40, 128.1, 111.5, 63.1, 48.7
ppm. HRMS (ESI-TOF) [M + H]+ calculated for C14H13BN2O5:
301.0990; found: 301.1000.
EXPERIMENTAL SECTION
■
3-Bromoisoxazol-5-ylboronic Acid MIDA Ester (3b). A general
procedure was followed using ethynyl MIDA boronate (423 mg, 2.3
mmol), dibromoformaldoxime (726 mg, 3.4 mmol), and tripotassium
phosphate (1.1 g, 5 mmol), affording desired product as an off-white
powder (626 mg, 90% yield). Melting point: 177−178 °C
General Experimental Procedures. Unless otherwise stated, all
reagents were used as received from commercial vendors. Ethynyl
MIDA boronate was triturated with ether prior to use to remove
residual DMSO. Organic solutions were concentrated via rotary
evaporation under reduced pressure with a bath temperature of 35−40
°C or using a centrifugal evaporator system. Reactions were monitored
by analytical HPLC-MS (electrospray ionization) using a C-18, 3 μm,
4.6 × 50 mm column with either of two eluent systems: acidic (A:
water + 0.1% TFA; B: MeCN; flow rate: 2.1 mL/min gradient: 95% A
to 95% B over 5 min) or basic (A: 5 mM aqueous NH4OH; B: MeCN;
1
decomposed. H NMR (acetonitrile-d3, 400 MHz): δ = 6.81 (s, 1
H), 4.15 (d, J = 17.1 Hz, 2 H), 3.98 (d, J = 18.1 Hz, 2 H), 2.75 ppm (s,
3 H). 13C NMR (acetonitrile-d3, 101 MHz): δ = 168.9, 140.9, 116.8,
63.3, 48.8 ppm. HRMS (ESI-TOF) [M + H]+ calculated for
C8H8BBrN2O5: 302.9782; found: 302.9788.
(3-(Ethoxycarbonyl)isoxazol-5-yl)boronic Acid MIDA Ester (3c).
A general procedure was followed using ethynyl MIDA boronate (3.1
g, 17.1 mmol) and ethyl 2-chloro-2-(hydroxyimino) acetate (7.8 g,
51.4 mmol) and potassium bicarbonate (5.15 g, 51.4 mmol) in 300 mL
of acetonitrile (0.06 M), affording desired product as an off-white
1
flow rate: 2.1 mL/min gradient: 95% A to 95% B over 5 min). H and
13C NMR analyses were acquired on a 400 MHz spectrometer and
referenced either to tetramethylsilane or the residual peak of solvent.
Microwave reactions were carried out in 2−5 mL thick-walled glass
vessels and irradiated in a variable voltage microwave instrument.
Temperature was measured using an external IR sensor. All melting
points are uncorrected.
Synthetic Procedures. Synthesis of Isoxazole MIDA Boronates
via [3 + 2] Cycloaddition. General Procedures for the Synthesis of
Isoxazole MIDA Boronates. To a reaction vessel containing ethynyl
MIDA boronate 1 (1 equiv) and chlorooxime 2 (2 equiv) in
dichloromethane or acetonitrile (0.1 M) was added triethylamine or
tripotassium phosphate (2 equiv). The reaction was allowed to stir at
ambient temperature for 18 h, at which time the reaction solvent was
removed in vacuo, and the residue was purified by flash
chromatography (ethyl acetate isocratic or dichloromethane−acetoni-
trile).
Synthesis of Triazole MIDA Boronates via CuAAC. General
Procedure for the Synthesis of Triazole MIDA Boronates. To a
reaction vessel containing ethynyl MIDA boronate 1 (1 equiv), azide
(1 equiv), and copper(II) acetate monohydrate (0.1 equiv) was added
acetonitrile (0.1 M). The reaction was heated at 60 °C for 18 h, at
which time the reaction solvent was removed in vacuo and the residue
was purified by flash chromatography (ethyl acetate isocratic or
dichloromethane−acetonitrile).
MIDA Boronates Suzuki Coupling. General Procedure A for the
SM Cross-Coupling of Heterocyclic MIDA Boronates. To a reaction
vessel containing phenethylamine derived X-Phos palladacycle
precatalyst-1 (0.05 equiv), aryl halide (1.25 equiv), and dry acetonitrile
(0.75 mL) was added potassium tert-butoxide (0.1 M in THF, 0.05
equiv); this mixture was allowed to stir at ambient temperature for 5
1
powder (3.75 g, 73% yield). Melting point: 159−162 °C. H NMR
(acetonitrile-d3, 400 MHz): δ = 7.02 (s, 1 H), 4.42 (d, J = 7.1 Hz, 2
H), 4.20 (d, J = 18.2 Hz, 2 H), 4.04 (d, J = 16.2 Hz, 2 H), 2.75 (s, 3
H), 1.38 ppm (t, J = 7.3 Hz, 3 H). 13C NMR (DMSO-d6, 101 MHz): δ
= 168.6, 159.5, 155.0, 112.0, 61.8, 61.6, 47.4, 13.8 ppm. HRMS (ESI-
TOF) [M + H]+ calculated for C11H13BN2O7: 297.0889; found:
297.0892.
(3-(4-Fluorophenyl)isoxazol-5-yl)boronic Acid MIDA Ester (3d).
General procedure A was followed using ethynyl MIDA boronate (543
mg, 3 mmol) and 4-fluoro-N-hydroxybenzimidoyl chloride (1.04 g, 6
mmol) and triethylamine (607 mg, 6 mmol), affording desired product
as an off-white powder (940 mg, 99% yield). Melting point: 139−141
°C. 1H NMR (DMSO-d6, 400 MHz): δ = 7.98 (dd, J = 8.5, 5.5 Hz, 2
H), 7.35 (t, J = 9.0 Hz, 2 H), 7.24 (s, 1 H), 4.46 (d, J = 17.1 Hz, 2 H),
4.23 (d, J = 17.1 Hz, 2 H), 2.74 ppm (s, 3 H). 13C NMR (101 MHz,
DMSO-d6): δ =168.7, 161.8 (d, J = 247.0 Hz), 159.8, 129.1 (d, J = 8.4
Hz), 125.2 (d, J = 2.9 Hz), 116.1 (d, J = 21.6 Hz), 110.0, 61.7, 47.4
ppm. HRMS (ESI-TOF) [M + H]+ calculated for C14H12BFN2O5:
319.0896; found: 319.0905.
(3-(Pyridin-2-yl)isoxazol-5-yl)boronic Acid MIDA Ester (3e). A
general procedure was followed using ethynyl MIDA boronate (63 mg,
0.35 mmol) and N-hydroxypicolinimidoyl chloride (0.35 mmol) and
triethylamine (106 mg, 1.05 mmol), affording desired product as a
white powder which was an inseparable admixture with ethynyl MIDA
1
boronate (100 mg, 72% yield, purity 85%). H NMR (acetonitrile-d3,
400 MHz): δ = 8.61−8.71 (m, 1 H), 8.00−8.11 (m, 1 H), 7.87 (td, J =
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7.8, 2.0 Hz, 8 H), 7.36−7.48 (m, 1 H), 7.19 (s, 1 H), 4.18 (d, J = 17.1
Hz, 2 H), 4.03 (d, J = 17.1 Hz, 2 H), 2.77 ppm (s, 3 H). 13C NMR
(acetonitrile-d3, 101 MHz): δ = 168.7, 163.2, 150.8, 149.2, 138.1,
125.5, 122.6, 111.5, 62.8, 48.3 ppm. HRMS (ESI-TOF) [M + H]+
calculated for C13H12BN3O5: 302.0943; found: 302.0954.
3-Phenyl-5-(pyridin-3-yl)isoxazole (7c). General procedure B was
followed using 3a (65 mg, 0.22 mmol) and 3-bromopyridine (26 μL,
0.27 mmol), affording desired product as a yellow powder (35 mg,
1
73% yield). Melting point: 133−136 °C. H NMR (methanol-d4, 400
MHz): δ = 9.04−9.18 (m, 1 H), 8.65 (dd, J = 4.8, 1.3 Hz, 1 H), 8.34
(dt, J = 8.1, 2.0 Hz, 1 H), 7.86−7.99 (m, 2 H), 7.61 (dd, J = 8.1, 5.6
Hz, 1 H), 7.47−7.57 (m, 3 H), 7.45 ppm (s, 1 H). 13C NMR
(methanol-d4, 101 MHz): δ = 168.7, 164.7, 151.6, 147.4, 135.0, 131.5,
130.2, 130.0, 127.9, 125.7, 125.6, 100.5 ppm. HRMS (ESI-TOF) [M +
H]+ calculated for C14H10N2O: 223.0866; found: 223.0874.
(3-(4-Methoxyphenyl)isoxazol-5-yl)boronic Acid MIDA Ester
(3f). A general procedure was followed using ethynyl MIDA boronate
(50 mg, 0.276 mmol) and N-hydroxy-4-methoxybenzimidoyl chloride
(51 mg, 0.276 mmol) and triethylamine (28 mg, 0.276 mmol),
1
affording desired product as white foam (81 mg, 89% yield). H NMR
(DMSO-d6, 400 MHz): δ = 7.85 (d, J = 9.0 Hz, 2 H), 7.15 (s, 1 H),
7.05 (d, J = 8.5 Hz, 2 H), 4.44 (d, J = 17.1 Hz, 2 H), 4.21 (d, J = 19.1
Hz, 2 H), 3.81 (s, 3 H), 2.74 ppm (s, 3 H). 13C NMR (DMSO-d6, 101
MHz): δ = 168.8, 160.5, 160.2, 128.2, 121.0, 114.4, 109.7, 61.7, 55.2,
47.4 ppm. HRMS (ESI-TOF) [M + H]+ calculated for C15H15BN2O6:
331.1096; found: 331.1100.
(3-(4-Chlorophenyl)isoxazol-5-yl)boronic Acid MIDA Ester (3g).
A general procedure was followed using ethynyl MIDA boronate (50
mg, 0.276 mmol) and N-hydroxy-4-chlorobenzimidoyl chloride (53
mg, 0.276 mmol) and triethylamine (28 mg, 0.276 mmol), affording
desired product as an off-white powder (69 mg, 75% yield). Melting
point: 194−195 °C. 1H NMR (DMSO-d6, 400 MHz): δ = 7.95 (d, J =
8.5 Hz, 2 H), 7.58 (d, J = 8.5 Hz, 2 H), 7.27 (s, 1 H), 4.44 (d, J = 16.1
Hz, 2 H), 4.18−4.27 (m, 2 H), 2.74 ppm (s, 3 H). 13C NMR (DMSO-
d6, 101 MHz): δ = 168.7, 168.6, 159.8, 134.6, 129.2, 128.5, 127.5,
110.1, 61.7, 47.4 ppm. HRMS (ESI-TOF) [M + H]+ calculated for
C14H12BClN2O5: 335.0601; found: 335.0605.
Ethyl 5-(4-Cyanophenyl)isoxazole-3-carboxylate (7d). General
procedure A was followed using 3c (64 mg, 0.22 mmol) and 4-
bromobenzonitrile (49 mg, 0.27 mmol), affording desired product as a
brownish powder (39 mg, 75% yield). Melting point: 170−173 °C. 1H
NMR (chloroform-d, 400 MHz): δ = 7.93 (d, J = 8.6 Hz, 2 H), 7.80
(d, J = 8.6 Hz, 2 H), 7.04 (s, 1 H), 4.50 (q, J = 7.1 Hz, 2 H), 1.46 ppm
(t, J = 7.1 Hz, 3 H). 13C NMR (chloroform-d, 101 MHz): δ = 169.4,
159.6, 157.2, 133.0, 130.3, 126.4, 118.0, 114.3, 102.1, 62.6, 14.2 ppm.
HRMS (ESI-TOF) [M + H]+ calculated for C13H10N2O3: 243.0764;
found: 243.0775.
4-(3-(4-Fluorophenyl)isoxazol-5-yl)benzonitrile (7e). General pro-
cedure A was followed using 3f (63 mg, 0.19 mmol) and 4-
bromobenzonitrile (45 mg, 0.25 mmol), affording desired product as
an off-white solid (40 mg, 72% yield). Melting point: 160−161 °C. 1H
NMR (chloroform-d, 400 MHz): δ = 7.95 (d, J = 7.5 Hz, 2 H), 7.86
(dd, J = 8.8, 5.3 Hz, 2 H), 7.80 (d, J = 8.5 Hz, 2 H), 7.20 (t, J = 8.8 Hz,
2 H), 6.94 ppm (s, 1 H). 13C NMR (101 MHz, chloroform-d): δ ppm
168.3, 164.0 (d, J = 250.5 Hz), 162.4, 132.9, 131.0, 128.8 (d, J = 8.4
Hz), 126.3, 124.7 (d, J = 3.3 Hz), 118.2, 116.3 (d, J = 22.0 Hz), 113.7,
99.5. HRMS (ESI-TOF) [M + H]+ calculated for C16H9FN2O:
265.0783; found: 265.0772.
4-(3-(4-Methoxyphenyl)isoxazol-5-yl)benzonitrile (7f). General
procedure A was followed using 3f (62 mg, 0.19 mmol) and 4-
bromobenzonitrile (41 mg, 0.23 mmol), affording desired product as a
yellowish powder (36 mg, 69% yield). Melting point: 163−164 °C. 1H
NMR (MeOD, 400 MHz): δ = 8.07 (d, J = 8.0 Hz, 2 H), 7.90 (d, J =
9.0 Hz, 2 H), 7.85 (d, J = 9.0 Hz, 2 H), 7.40 (s, 1 H), 7.06 (d, J = 9.0
Hz, 2 H), 3.86 ppm (s, 3 H). 13C NMR (MeOD, 101 MHz): δ =
169.5, 164.5, 163.0, 134.2, 132.7, 129.4, 127.5, 122.2, 119.2, 115.5,
114.7, 101.1, 55.9 ppm. HRMS (ESI-TOF) [M + H]+ calculated for
C17H12N2O2: 277.0972; found: 277.0983.
(3-(2-Trifluoromethylphenyl)isoxazol-5-yl)boronic Acid MIDA
Ester (3h). A general procedure was followed using ethynyl MIDA
boronate (153 mg, 0.85 mmol) and 2-trifluoromethyl-N-hydroxyben-
zimidoyl chloride (378 mg, 1.69 mmol) and triethylamine (171 mg,
1.69 mmol), affording desired product as an off-white powder (280
1
mg, 90% yield). Melting point: 144−145 °C. H NMR (DMSO-d6,
400 MHz): δ = 7.93 (d, J = 7.5 Hz, 1 H), 7.81 (d, J = 7.5 Hz, 1 H),
7.72−7.78 (m, 1 H), 7.68 (d, J = 7.5 Hz, 1 H), 6.86 (s, 1 H), 4.45 (d, J
= 17.6 Hz, 2 H), 4.25 (d, J = 18.1 Hz, 2 H), 2.75 ppm (s, 3 H). 13C
NMR (DMSO-d6, 101 MHz): δ = 168.7, 159.7, 132.7, 131.8, 130.2,
128.0−126.4 (m), 125.1, 122.3, 112.7, 61.9, 47.4 ppm. HRMS (ESI-
TOF) [M + H]+ calculated for C15H12BF3N2O5: 369.0864; found:
369.0880.
4-(3-Phenylisoxazol-5-yl)benzonitrile (5). General procedure B
was followed using 3a (60 mg, 0.20 mmol) and 4-bromobenzonitrile
(45 mg, 0.25 mmol), affording desired product (34 mg, 69% yield).
Melting point: 166−167 °C. 1H NMR (chloroform-d, 400 MHz): δ =
7.96 (d, J = 8.5 Hz, 2 H), 7.87 (dd, J = 6.3, 3.3 Hz, 2 H), 7.80 (d, J =
8.5 Hz, 2 H), 7.44−7.56 (m, 3 H), 6.98 ppm (s, 1 H). 13C NMR
(chloroform-d, 101 MHz): δ = 168.1, 163.3, 132.9, 132.2, 131.1, 130.4,
129.1, 128.5, 128.0, 126.8, 126.3, 118.2, 113.6, 99.7 ppm. HRMS (ESI-
TOF) [M + H]+ calculated for C16H10N2O: 247.0866; found:
247.0876.
4-(3-(4-Chlorophenyl)isoxazol-5-yl)benzonitrile (7g). General
procedure A was followed using 3g (53 mg, 0.158 mmol) and 4-
bromobenzonitrile (35 mg, 0.19 mmol), affording desired product as a
yellowish powder (26 mg, 59% yield). Melting point: 158−161 °C. 1H
NMR (chloroform-d, 400 MHz): δ = 7.96 (d, J=8.0 Hz, 2 H), 7.77−
7.86 (m, 4 H), 7.49 (d, J = 8.5 Hz, 2 H), 6.95 ppm (s, 1 H). 13C NMR
(chloroform-d, 101 MHz): δ = 168.5, 162.3, 136.5, 132.9, 131.0, 129.4,
128.1, 127.0, 126.3, 118.2, 113.8, 99.5 ppm. HRMS (ESI-TOF) [M +
H]+ calculated for C16H9ClN2O: 281.0476; found: 281.0466.
4-(3-(4-(Trifluoromethyl)phenyl)isoxazol-5-yl)benzonitrile (7h).
General procedure B was followed using 3h (59 mg, 0.16 mmol)
and 4-bromobenzonitrile (35 mg, 0.19 mmol), affording desired
product as an off white solid (28 mg, 56% yield). Melting point: 154−
155 °C. 1H NMR (chloroform-d, 400 MHz): δ = 7.97 (d, J = 9.0 Hz, 2
H), 7.85 (d, J = 7.5 Hz, 1 H), 7.81 (d, J = 8.5 Hz, 2 H), 7.61−7.74 (m,
3 H), 6.87 ppm (s, 1 H). 13C NMR (101 MHz, chloroform-d): δ ppm
167.7, 162.3, 132.9, 132.1, 131.8, 131.0, 130.1, 128.9 (q, J = 31.2 Hz),
128.0, 127.7 (d, J = 2.2 Hz), 126.6 (q, J = 5.5 Hz), 126.4, 123.7 (q, J =
273.6 Hz), 118.2, 113.8, 103.0 (q, J = 3.3 Hz). HRMS (ESI-TOF) [M
+ H]+ calculated for C17H9F3N2O: 315.0740; found: 315.0739.
(1-Benzyl-1H-1,2,3-triazol-4-yl)boronic Acid MIDA Ester (9). A
general procedure was followed using ethynyl MIDA boronate (55 mg,
0.3 mmol) and benzylazide (40 mg, 0.3 mmol) and copper(II) acetate
monohydrate (6 mg, 0.03 mmol), affording desired product as an off-
5-(4-Methoxyphenyl)-3-phenylisoxazole (7a). General procedure
B was followed using 3a (65 mg, 0.22 mmol) and 4-bromoanisole (51
mg, 0.27 mmol), affording desired product as an off-white powder (39
1
mg, 72% yield). Melting point: 127−128 °C. H NMR (methanol-d4,
400 MHz): δ = 7.85−7.93 (m, 2 H), 7.79−7.85 (m, 2 H), 7.46−7.53
(m, 3 H), 7.02−7.11 (m, 3 H), 3.86 ppm (s, 3 H). 13C NMR
(methanol-d4, 101 MHz): δ = 172.0, 164.5, 163.0, 131.2, 130.4, 130.1,
128.5, 127.8, 121.4, 115.6, 97.4, 55.9 ppm. HRMS (ESI-TOF) [M +
H]+ calculated for C16H13NO2: 252.1019; found: 252.1026.
5-(4-(Methylsulfonyl)phenyl)-3-phenylisoxazole (7b). General
procedure B was followed using 3a (65 mg, 0.22 mmol) and 1-
bromo-4-(methylsulfonyl)benzene (64 mg, 0.27 mmol), affording
desired product as a yellow powder (49 mg, 76% yield). Melting point:
1
200−201 °C. H NMR (DMSO-d6, 400 MHz): δ = 8.16−8.23 (m, 2
H), 8.09−8.16 (m, 2 H), 7.91−7.98 (m, 2 H), 7.87 (s, 1 H), 7.52−7.62
(m, 3 H), 3.31 ppm (s, 3 H). 13C NMR (DMSO-d6, 101 MHz): δ =
168.0, 162.9, 142.0, 131.0, 130.5, 129.2, 128.2, 128.0, 126.6, 126.4,
100.9, 43.3 ppm. HRMS (ESI-TOF) [M + H]+ calculated for
C16H13NO3S: 300.0689; found: 300.0691.
1
white powder (74 mg, 78% yield). Melting point: 222−225 °C. H
NMR (DMSO-d6, 400 MHz): δ = 8.10 (s, 1 H), 7.23−7.42 (m, 5 H),
5.61 (s, 2 H), 4.33 (d, J = 17.7 Hz, 2 H), 4.07 (d, J = 17.7 Hz, 2 H),
2.60 ppm (s, 3 H). 13C NMR (DMSO-d6, 101 MHz): δ = 169.0, 136.3,
10246
dx.doi.org/10.1021/jo201973t | J. Org. Chem. 2011, 76, 10241−10248

The Journal of Organic Chemistry
Article
129.7, 128.7, 128.0, 127.8, 61.5, 52.2, 47.4 ppm. HRMS (ESI-TOF)
[M + H]+ calculated for C14H15BN4O4: 315.1259; found: 315.1271.
4-(1-Benzyl-1H-1,2,3-triazol-4-yl)benzonitrile (10a). General pro-
cedure B was followed using 9 (65 mg, 0.21 mmol) and 4-
bromobenzonitrile (47 mg, 0.26 mmol), affording desired product as
a yellowish powder (36 mg, 67% yield). Melting point: 139−140 °C.
1H NMR (DMSO-d6, 400 MHz): δ = 8.86 (s, 1 H), 8.05 (d, J = 8.5
Hz, 2 H), 7.92 (d, J = 8.5 Hz, 2 H), 7.32−7.50 (m, 5 H), 5.68 ppm (s,
2 H). 13C NMR (DMSO-d6, 101 MHz): δ = 145.1, 135.7, 135.1, 133.0,
128.8, 128.2, 127.9, 125.7, 123.3, 118.8, 110.1, 53.1 ppm. HRMS (ESI-
TOF) [M + H]+ calculated for C16H12N4: 261.1135; found: 261.1148.
5-(1-Benzyl-1H-1,2,3-triazol-4-yl)picolinonitrile (10b). General
procedure B was followed using 9 (65 mg, 0.21 mmol) and 5-
bromopicolinonitrile (47 mg, 0.26 mmol). The crude product was
purified by RP-HPLC (1−100% acetonitrile water with 3% 1-propanol
as a modifier), affording desired product as a white solid (41 mg, 76%
yield). Melting point: 163−164 °C. 1H NMR (methanol-d4, 400
MHz): δ = 9.16 (dd, J = 2.0, 1.0 Hz, 1 H), 8.60 (s, 1 H), 8.40 (dd, J =
8.1, 2.0 Hz, 1 H), 7.92 (dd, J = 8.1, 1.0 Hz, 1 H), 7.30−7.47 (m, 5 H),
5.68 ppm (s, 2 H). 13C NMR (methanol-d4, 101 MHz): δ = 149.2,
136.5, 134.9, 131.7, 130.1, 130.1, 129.7, 129.7, 129.2, 129.2, 124.2,
118.2, 55.3 ppm. HRMS (ESI-TOF) [M + H]+ calculated for
C15H11N5: 262.1082; found: 262.1094.
1-Benzyl-4-(4-(methylsulfonyl)phenyl)-1H-1,2,3-triazole (10c).
General procedure B was followed using 9 (65 mg, 0.21 mmol) and
1-bromo-4-(methylsulfonyl)benzene (60.8 mg, 0.259 mmol), affording
desired product as an off-white powder (48 mg, 74% yield). Melting
point: 177−179 °C. 1H NMR (methanol-d4, 400 MHz): δ = 8.50 (s, 1
H), 8.04−8.12 (m, 2 H), 7.95−8.04 (m, 2 H), 7.35−7.44 (m, 5 H),
5.67 (s, 2 H), 3.14 ppm (s, 3 H). 13C NMR (DMSO-d6, 101 MHz): δ
= 145.1, 135.7, 135.4, 128.8, 128.2, 128.0, 127.7, 125.7, 123.1, 66.7,
53.2, 43.5 ppm. HRMS (ESI-TOF) [M + H]+ calculated for
C16H15N3O2S 314.0958; observed: 314.0968.
followed using ethynyl MIDA boronate (50 mg 0.28 mmol) and
(2S,4S)-methyl 4-azido-1-tosylpyrrolidine-2-carboxylate (90 mg, 0.28
mmol) and copper(II) acetate monohydrate (5.5 mg, 0.028 mmol),
1
affording desired product as a white foam (123 mg 88% yield). H
NMR (acetonitrile-d3, 400 MHz): δ = 7.93 (s, 1 H), 7.78−7.83 (m, 2
H), 7.47 (d, J = 8.0 Hz, 2 H), 4.90−4.99 (m, 1 H), 4.42 (dd, J = 9.3,
5.3 Hz, 1 H), 4.12 (d, J = 17.6 Hz, 2 H), 3.90−3.98 (m, 2 H), 3.85 (d,
J = 5.5 Hz, 2 H), 3.66 (s, 3 H), 2.72−2.85 (m, 1 H), 2.56−2.65 (m, 1
H), 2.61 (s, 3 H), 2.47 ppm (s, 3 H). 13C NMR (acetonitrile-d3, 101
MHz): δ = 172.7, 169.6, 146.0, 135.4, 131.3, 129.6, 129.0, 62.8, 60.6,
58.7, 54.3, 53.5, 48.6, 37.2, 21.9 ppm. HRMS (ESI-TOF) [M + H]+
calculated for C20H24BN5O8S: 506.1511; found: 506.1511.
(R)-(1-((3-3-4-Fluorophenyl)-2-oxooxazolidin-5-yl)methyl)-1H-
1,2,3-triazol-4-yl)boronic Acid MIDA Ester (12c). A general proce-
dure was followed using ethynyl MIDA boronate (50 mg, 0.28 mmol)
and (R)-5-(azidomethyl)-3-(4-fluorophenyl)oxazolidin-2-one (65 mg,
0.28 mmol) and copper(II) acetate monohydrate (5.5 mg, 0.028
mmol), affording desired product as a white foam (99 mg, 86% yield).
1H NMR (acetonitrile-d3, 400 MHz): δ = 7.91 (s, 6 H), 7.31−7.41 (m,
2 H), 7.19 (dd, J = 8.8, 1.8 Hz, 1 H), 6.83−6.92 (m, 1 H), 5.09 (dd, J
= 9.3, 4.3 Hz, 1 H), 4.76 (dd, J = 4.3, 2.3 Hz, 2 H), 4.17 (t, J = 9.5 Hz,
1 H), 4.04 (d, J = 3.5 Hz, 1 H), 4.09 (d, J = 3.5 Hz, 1 H), 3.82−3.94
(m, 3 H), 2.46 ppm (s, 3 H). 13C NMR (acetonitrile-d3, 101 MHz): δ
= 169.5, 169.5, 165.3, 162.9, 155.1, 141.3, 141.2, 131.9, 131.8, 131.7,
114.9, 114.8, 111.7, 111.4, 106.6, 106.3, 72.1, 62.8, 53.1, 48.4 ppm.
HRMS (ESI-TOF) [M + H]+ calculated for C17H17BFN5O6:
418.1329; found: 418.1335.
N-(Benzyloxy)-4-(4-(4-cyanophenyl)-1H-1,2,3-triazol-1-yl)-
benzamide (13a). General procedure B was followed using 12a (105
mg, 0.23 mmol) and 4-bromobenzonitrile (52 mg, 0.28 mmol),
affording desired product as an off-white powder (44 mg, 47% yield).
1
tert-Butyl (3-(1-Benzyl-1H-1,2,3-triazol-4-yl)phenyl)carbamate
(10d). General procedure B was followed using 9 (65 mg, 0.21
mmol) and tert-butyl 3-bromophenylcarbamate (70.4 mg, 0.259
mmol), affording desired product as an off-white powder (49 mg,
Melting point: 193−195 °C. H NMR (DMSO-d6, 400 MHz): δ =
11.81 (s, 1 H), 8.87 (s, 1 H), 8.05 (d, J = 8.5 Hz, 2 H), 7.92 (d, J = 8.5
Hz, 2 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.29−7.52 (m, 7 H), 5.75 (s, 2 H),
4.91 ppm (s, 2 H). 13C NMR (DMSO-d6, 101 MHz): δ = 163.7, 145.0,
139.1, 135.7, 134.9, 132.9, 132.0, 128.9, 128.2, 127.9, 127.5, 125.6,
123.3, 118.7, 110.0, 76.9, 52.6, 38.7 ppm. HRMS (ESI-TOF) [M +
H]+ calculated for C24H19N5O2: 410.1612; found: 410.1618.
1
68% yield). Melting point: 155−156 °C. H NMR (methanol-d4, 400
MHz): δ = 8.26 (s, 1 H), 7.79−7.86 (m, 1 H), 7.27−7.48 (m, 8 H),
5.63 (s, 2 H), 1.52 ppm (s, 9 H). 13C NMR (methanol-d4, 101 MHz):
δ = 155.3, 149.2, 141.3, 136.8, 132.2, 130.4, 130.1, 129.6, 129.1, 122.3,
120.9, 119.6, 116.8, 81.0, 55.1, 28.7 ppm. HRMS (ESI-TOF) [M +
H]+ calculated for C20H22N4O2 351.1816; found: 351.1823.
(2S,4S)-Methyl 4-(4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl)-1-to-
sylpyrrolidine-2-carboxylate (13b). General procedure B was
followed using 12b (101 mg, 0.20 mmol) and 4-bromobenzonitrile
(46 mg, 0.25 mmol), affording desired product as a yellowish powder
3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1-tosyl-1H-indole (10e). Gener-
al procedure B was followed using 9 (65 mg, 0.21 mmol) and 3-
bromo-1-(phenylsulfonyl)-1H-indole (87 mg, 0.259 mmol), affording
desired product as an off-white powder (66 mg, 77% yield). Melting
point: 212−213 °C. 1H NMR (methanol-d4, 400 MHz): δ = 8.41 (s, 1
H), 8.09 (s, 1 H), 8.03 (d, J = 8.6 Hz, 1 H), 7.93−8.00 (m, 3 H),
7.57−7.64 (m, 1 H), 7.46−7.56 (m, 2 H), 7.28−7.44 (m, 7 H), 5.67
ppm (s, 2 H). 13C NMR (methanol-d4, 101 MHz): δ = 141.4, 139.5,
138.6, 137.5, 137.2, 132.6, 131.5, 130.9, 130.8, 130.5, 129.4, 128.1,
126.7, 126.0, 124.8, 124.5, 116.0, 96.6, 55.8 ppm. HRMS (ESI-TOF)
[M + H]+ calculated for C23H18N4O2S: 415.1223; found: 415.1226.
(1-(4-((Benzyloxy)carbamoyl)phenyl)-1H-1,2,3-triazol-4-yl)-
boronic Acid MIDA Ester (12a). A general procedure was followed
using ethynyl MIDA boronate (57 mg, 0.32 mmol) and 4-
(azidomethyl)-N-(benzyloxy)benzamide (89 mg, 0.32 mmol) and
copper(II) acetate monohydrate (6.3 mg, 0.032 mmol), affording
desired product as an off-white powder (121 mg, 83% yield). Melting
point: 158−160 °C. 1H NMR (acetonitrile-d3, 400 MHz): δ = 9.87 (br
s, 1 H), 7.91 (s, 1 H), 7.69 (d, J = 8.0 Hz, 2 H), 7.45−7.51 (m, 2 H),
7.36−7.45 (m, 3 H), 7.32 (d, J = 8.0 Hz, 2 H), 5.64 (s, 2 H), 4.96 (s, 2
H), 4.10 (d, J = 16.6 Hz, 2 H), 3.93 (d, J = 18.1 Hz, 2 H), 2.64 ppm (s,
3 H). 13C NMR (acetonitrile-d3, 101 MHz): δ = 169.6, 166.1, 141.3,
137.2, 133.6, 130.9, 130.6, 129.8, 129.7, 129.1, 128.9, 79.0, 62.9, 53.7,
48.6 ppm. HRMS (ESI-TOF) [M + H]+ calculated for C22H22BN5O6:
464.1736; found: 464.1745.
1
(37 mg, 41% yield). Melting point: 184−186 °C. H NMR (DMSO-
d6, 400 MHz): δ = 8.89 (s, 1 H), 7.98−8.03 (m, 2 H), 7.92−7.96 (m, 2
H), 7.81 (d, J = 8.0 Hz, 2 H), 7.49 (d, J = 8.0 Hz, 2 H), 5.04 (t, J = 6.3
Hz, 1 H), 4.48 (dd, J = 9.0, 5.5 Hz, 1 H), 3.86 (t, J = 6.3 Hz, 2 H), 3.59
(s, 3 H), 2.78 (dd, J = 6.8, 2.3 Hz, 1 H), 2.58−2.71 (m, 1 H), 2.43
ppm (s, 3 H). 13C NMR (DMSO-d6, 101 MHz): δ = 171.0, 144.8,
144.1, 134.9, 133.7, 133.1, 130.1, 127.5, 125.6, 122.4, 118.8, 110.2,
59.0, 57.7, 52.5, 52.3, 35.3, 21.0 ppm. HRMS (ESI-TOF) [M + H]+
calculated for C22H21N5O4S: 452.1387; found: 452.1389.
(R)-4-(1-((3-(3-Fluorophenyl)-2-oxooxazolidin-5-yl)methyl)-1H-
1,2,3-triazol-4-yl)benzonitrile (13c). General procedure B was
followed using 12c (83 mg, 0.20 mmol) and 4-bromobenzonitrile
(46 mg, 0.25 mmol), affording desired product as a yellowish powder
1
(26 mg, 36% yield). Melting point: 216−217 °C. H NMR (DMSO-
d6, 400 MHz): δ = 8.86 (s, 1 H), 8.06 (d, J = 8.0 Hz, 2 H), 7.94 (d, J =
8.5 Hz, 2 H), 7.37−7.48 (m, 2 H), 7.27 (dd, J = 7.5, 2.0 Hz, 1 H), 6.97
(td, J = 8.3, 2.0 Hz, 1 H), 5.20 (dd, J = 8.5, 5.5 Hz, 1 H), 4.91 (d, J =
5.5 Hz, 2 H), 4.29 (t, J = 9.0 Hz, 1 H), 3.96 ppm (dd, J = 9.5, 6.0 Hz, 1
H). 13C NMR (DMSO-d6, 101 MHz): δ = 163.3, 160.9, 153.3, 144.7,
139.7, 139.6, 134.8, 132.9, 130.6, 130.5, 125.7, 124.0, 118.7, 113.6,
110.2, 110.1, 110.0, 105.1, 104.8, 70.8, 52.1, 47.0, 38.7 ppm. HRMS
(ESI-TOF) [M + H]+ calculated for C19H14FN5O2: 364.1204; found:
364.1211.
(1-((3S,5S)-5-(Methoxycarbonyl)-1-tosylpyrrolidin-3-yl)-1H-1,2,3-
triazol-4-yl)boronic Acid MIDA Ester (12b). A general procedure was
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The Journal of Organic Chemistry
Article
(17) Examples of CuAAC in the presence of boronic acid derivatives:
(a) Mothana, S.; Grassot, J. M.; Hall, D. G. Angew. Chem., Int. Ed.
2010, 49, 2883−2887. (b) Molander, G. A.; Ham, J. Org. Lett. 2006, 8,
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(18) CuAAC using Cu(II): (a) Kuang, G.-C.; Michaels, H. A.;
Simmons, J. T.; Clark, R. J.; Zhu, L. J. Org. Chem. 2010, 75, 6540−
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DIPEA: (c) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952−
3015.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jonathan.grob@novartis.com.
ACKNOWLEDGMENTS
■
The authors acknowledge Michael McKinnon and Guangxiang
Wu for carrying out high resolution mass spectrometry and Dr.
Srinivasan Rajan for NMR support.
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