Ni-Catalyzed C-H Arylation of Oxazoles and Benzoxazoles Using Pharmaceutically Relevant Aryl Chlorides and Bromides

Article abstract of DOI:10.1021/acs.joc.9b02094

This manuscript details the development of the nickel-catalyzed arylation of oxazoles and benzoxazoles with aryl halides. A series of aryl, heteroaryl, and druglike electrophiles relevant to pharmaceutical applications were surveyed. The desired arylated products were obtained in synthetically useful yields using electronically and structurally varied aryl halides. The use of microscale high-throughput experimentation was essential for both the rapid identification of optimal reaction parameters and the investigation of the aryl halide scope.

Full text of DOI:10.1021/acs.joc.9b02094

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pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Ni-Catalyzed C−H Arylation of Oxazoles and Benzoxazoles Using
Pharmaceutically Relevant Aryl Chlorides and Bromides
Helen Larson,† Danielle Schultz,*,‡ and Dipannita Kalyani*,†,§
†Department of Chemistry, St. Olaf College, 1520 St. Olaf Avenue, Northfield, Minnesota 55057, United States
‡Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
§Discovery Chemistry, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States
S
* Supporting Information
ABSTRACT: This manuscript details the development of the
nickel-catalyzed arylation of oxazoles and benzoxazoles with aryl
halides. A series of aryl, heteroaryl, and druglike electrophiles
relevant to pharmaceutical applications were surveyed. The
desired arylated products were obtained in synthetically useful
yields using electronically and structurally varied aryl halides. The
use of microscale high-throughput experimentation was essential for both the rapid identification of optimal reaction parameters
and the investigation of the aryl halide scope.
Scheme 1. Precedent for Ni-Catalyzed Azole Direct
Arylations Using Aryl Halides
INTRODUCTION
■
Azole-containing biaryls are prevalent in pharmaceuticals,
including flunoxaprofen and ensulizole (Figure 1).1 Hence,
Figure 1. Examples of bioactive biaryl azoles.
numerous methods have been developed to access such
motifs.1g Among these, transition-metal-catalyzed C−H
arylation of azoles with aryl halides has emerged as a powerful
method to enable rapid access to structurally diverse arylated
azoles.2,3
While the vast majority of reported direct arylations employ
precious metals (Pd, Rh, etc.),2,3 there has been increasing
interest in the use of first-row, earth-abundant metals for the
development of C−H arylations.4,5 In this context, a few
reports have detailed nickel-catalyzed C−H arylations of
heteroarenes using aryl halides.5−8 These include C−H
arylation of benzothiazoles (Scheme 1A),6a−c imidazoles
(Scheme 1B),6e imidazopyridines (Scheme 1C),6d and
oxazoles.6a,b Importantly, most illustrated examples for these
arylations require the use of aryl iodides as reacting partners,
while the scope with their more synthetically desirable ArBr
and ArCl counterparts has remained underexplored. Further-
more, a common feature of these reports is the limited number
of arylation examples using densely functionalized aryl/
heteroaryl halides as substrates, thereby lending inadequate
confidence for the applicability of these arylations in the
Special Issue: C-H Bond Functionalization
Received: July 30, 2019
© XXXX American Chemical Society
A
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a
context of late-stage functionalization of pharmaceutical
targets.9
Scheme 4. Optimization for 5-Phenyloxazole Arylation
Herein, we address this limitation by leveraging high-
throughput experimentation (HTE)10 for the development of
Ni-catalyzed oxazole arylations,1g,11 using diverse ArX (X = Cl,
Br), with specific emphasis on the use of electrophiles relevant
to pharmaceutical functionalizations.1
RESULTS AND DISCUSSION
■
Our investigations began with the high-throughput screen of
conditions for the Ni-catalyzed coupling of 5-methylbenzox-
azole (1) with 4-chloro anisole, an electron-rich aryl chloride
that is traditionally a challenging cross-coupling partner. This
screen revealed that using K3PO4 as base and tert-amyl alcohol
as solvent, along with bidentate ligands such as dcype and
dppb,6e,8d,12,13 affords the desired product 1a in good yield as
determined by UPLC analysis of the crude reaction mixtures
against 1,3,5-trimethoxybenzene as the standard (Scheme 2).
Scheme 2. Arylation of 5-Methylbenzoxazole
a
Calibrated UPLC yields against 1,3,5-trimethoxybenzene as the
standard.
bases that revealed that the use of stronger bases (e.g., LiOtBu,
NaOtBu, phosphazene base P2Et) is essential to obtain
product 2a in good yields. In general, P2Et is the most
effective base, while dcype or N-XantPhos are the best ligands:
product 2a was obtained in 87% yield using N-XantPhos/P2Et
as the ligand/base combination.14
Other electronically varied phenyloxazole derivatives also
participated in these arylations using the optimal conditions for
the formation of compound 2a (Scheme 5).
The optimal conditions for the formation of 1a were
successfully applied for the arylation of 5-methylbenzoxazole
with a series of simple, electronically varied aryl chlorides
(Scheme 3).
Interestingly, the use of these conditions for arylation of the
less acidic 5-phenyloxazole (2) with 4-chloroanisole provided
only a 38% yield of the corresponding arylated product 2a
(Scheme 4). This result led to a subsequent screen of ligands/
a
Scheme 5. Arylations Using Electronically Varied Oxazoles
Scheme 3. Scope of ArCl for Arylation of 5-
a
Methylbenzoxazole
a
b
Isolated yields, Ar = 4-OMeC6H4. ArBr used instead of ArCl.
c
dcype (12 mol %) used instead of N-XantPhos.
We next embarked on the use of structurally diverse
heteroaryl chlorides and bromides for the arylation of 5-
methylbenzoxazole. A broad survey of halides bearing
pharmaceutically relevant heterocyclic rings such as pyridines,
pyrimidines, triazoles, pyrazoles, piperidines, thiazoles, quino-
lines, quinoxalines, indoles, indazoles, and triazolopyridines
was conducted. Importantly, these halides contain function-
alities prevalent in medicinal targets (e.g., nitriles, trifluor-
omethyl group, alkyl sulfonyl, Boc, aryl chloride, and ethers),
rendering them representative surrogates for the highly
functionalized molecules targeted for late-stage functionaliza-
tion of drug-discovery targets.
a
Isolated yields.
B
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a
Scheme 6. Survey of Heteroaryl Halides for the Arylation of 5-Methylbenzoxazole.
a
Numbers in each box represent the experimental LCAP with isolated yields in parentheses. Reaction success was determined by LCAP (LC area
%) of the desired product from the crude reaction mixture. Conditional formatting was applied to highlight the range of product LCAP detected
b
c
d
(see the key above). Reaction run at 130 °C. Reaction run with tert-amyl alcohol as the solvent. Decomposition of heteroaryl halide observed.
e
f
No conversion, with heteroaryl halide remaining. Des-boc product isolated.
a
As shown in Scheme 6, several of these halides led to the
Scheme 7. Scope of Azoles for Arylation Using Halide I
desired arylated product. In general, aryl bromides were more
effective coupling partners than aryl chlorides. The use of
electrophiles (e.g., P and W) containing both a chloride and a
bromide led to selective functionalization at the C−Br bond
(indicated by the blue arrow). Pyridine (H−K, P), quinoline
(O), quinoxaline (U−W), triazolopyridine (X), indazole (Z),
and indole (AA) containing-halides reacted to afford
significant amounts of the desired arylated products. The
efficiency of the arylations is dependent on the substituents on
the heteroaryl halide. For example, triazolopyridine X reacted
to form the corresponding arylated product, while no product
was observed in the attempted arylation using the analogous
heteroaryl bromide Y containing a CF3 functionality in place of
the methyl group at the 3-position. Heteroaryl halide I was
selected for the arylation of electronically varied azoles to
afford the corresponding products in good to excellent yields
(Scheme 7).
The encouraging results with the heteroaryl halides in
Schemes 6 and 7 set the stage to screen a series of complex
druglike aryl halides for arylation of 5-methylbenzoxazole. In
2016, a report coined a set of druglike halides as “informers”
(Figure 2).15 Since this publication, the informer set has been
used as a benchmark to assess the robustness of cross-coupling
reactions.16 These reports revealed that different reaction
conditions are often optimal for cross-coupling of various
halides in this informer set. As such, we utilized HTE to
evaluate five different reaction conditions (A−E) for the
coupling of each informer halide (10 μmol) with 5-
methylbenzoxazole (10 μmol) (Figure 3).17a Consistent with
previous reports, the optimal reaction parameters varied with
the identity of the informers.17 While a number of informers
(e.g., X1, X2, X6, X12, and X15) reacted to form the
corresponding arylated products using several different
reaction conditions, halides X3, X10, X13, and X18 provide
significant desired product using one specific reaction
condition. The differential reactivity of the informers
exemplifies the importance of HTE to rapidly identify the
scope and limitations of the transformations with respect to the
a
b
Isolated yields. dcype (12 mol %) used instead of N-XantPhos.
substrates. Overall, a 50% hit rate was observed for the
formation of the desired products with >20 LC area %.
To assess the scalability of these transformations, couplings
with selected informer halides were conducted on a 0.25 mmol
scale under the optimal reaction conditions. As shown in
Figure 4, the reactions proved scalable, and the products were
obtained in modest yields. Remarkably, halides X12, X13,17b
and X15, containing free NH or OH bonds, reacted to form
the desired products in modest yields. Analogous to the results
in Scheme 6, informer X6, containing both an aryl bromide
and an aryl chloride, reacted to form the product obtained via
preferential functionalization at the C−Br bond.18 While the
informer aryl chlorides X16−X18 were ineffective reacting
partners, other druglike aryl chlorides did react to afford the
desired products (1af, 1ag, and 1ah) in modest yields. Overall,
while the hit rate with respect to arylation using druglike
C
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Figure 2. Structures of informer halides.
Figure 3. Screen of reaction conditions for coupling of 5-methylbenzoxazole with informer halides.
1000 μL). 1,2-Bis(dicyclohexylphosphino)ethane (dcype), N-Xant-
phos, DPEPhos, dppbz, dppb, and 5-methylbenzoxazole were
obtained from Aldrich and used as received. 5-Phenyloxazole was
obtained from Combi Blocks and used as received. Ni(COD)2 was
obtained from Strem Chemical or Aldrich and used as received.
Anhydrous cesium carbonate (Acros or Aldrich), anhydrous
K3PO4(Acros or Aldrich), LiOtBu (Aldrich), NaOtBu (Aldrich),
and P2Et (Aldrich) were obtained from commercial sources and used
as received. 5-Methoxybenzoxazole and 4-fluorobenzoxazole sub-
strates were obtained from Frontier Scientific.1 Aryloxazole substrates
except 5-phenyl-1,3-oxazole for Schemes 4, 5, and 7 were prepared
using literature procedures.19 Aryl halides were obtained from Aldrich,
Frontier Scientific, or Merck’s internal building block collection and
used as received. Anhydrous tert-amyl alcohol and diglyme were
obtained from Aldrich and used as received. Other solvents were
obtained from Fisher Chemical or VWR Chemical and used without
further purification. Flash chromatography was performed on EM
Science silica gel 60 (0.040−0.063 mm particle size, 230−400 mesh)
or using prepacked RediSep gold Rf silica gel columns on a Teledyne
Isco CombiFlash Rf automated chromatography system. Thin layer
chromatography was performed on TLC plates precoated with silica
halides is encouraging, further optimization is needed to
address the limitations presented in Figure 3.
In summary, this manuscript details the development of the
Ni-catalyzed direct arylation of oxazoles and benzoxazoles
using diverse aryl and heteroaryl aryl chlorides and bromides.
The use of parallel microscale HTE was essential for the rapid
survey of reaction parameters and the scope of aryl
electrophiles. A series of simple aryl and heteroaryl halides,
as well as druglike electrophiles, reacted to afford the desired
products in modest to good yields using a readily accessible Ni
catalyst and ligands. Particularly impressive is the compatibility
of the arylation with electrophiles bearing free NH and OH
groups. To the best of our knowledge, this manuscript
discloses the broadest survey and scope of aryl halides relevant
to pharmaceutical applications in the context of Ni-catalyzed
direct arylations using ArX (X = Cl, Br).
EXPERIMENTAL METHODS
■
Materials and Methods. Unless otherwise noted, all reactions
were performed in an MBraun glovebox operating with a constant N2
purge (oxygen typically <5 ppm). Reactions run in HTE format were
performed in 1 mL glass vials using aluminum reaction blocks
purchased from Analytical Sales and Services. Liquid handling was
done using single and multichannel Eppendorf pipettors (10, 100, and
1
gel 60 F254. Compounds were analyzed by H, 13C, and 19F NMR,
where appropriate, on 400, 500, or 600 mHz NMR spectrometers at
1
ambient temperature (unless otherwise noted). H NMR chemical
shifts are reported in parts per million (ppm) relative to TMS or to
residual protium in the NMR solvent. Multiplicities are reported as
D
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Figure 4. Isolated yields of products from the coupling of 5-methylbenzoxazole with informer and informer-like halides (letters in parentheses
indicate the reaction condition from Figure 3): (a) 1.5 equiv of aryl chloride; (b) diglyme used as solvent at 130 °C; (c) diglyme used as solvent at
105 °C.
follows: singlet (s), doublet (d), doublet of doublets (dd), multiplet
(m). LCMS samples were run on an a Waters Acquity UPLC with
Synapt G1 Q-ToF MS instrument in ESI+(electrospray) ionization
mode.
using an IKA heating plate for the indicated time. The reaction
mixture was cooled to room temperature and filtered through a 1.0 in.
plug of silica gel, eluting with EtOAc (150 mL). The filtrate was
concentrated and chromatographed on a silica gel column to afford
the product.
General Procedures for Ni-Catalyzed Arylations. General
Procedure A for C−H Arylations. Ni(COD)2, ligand (dppb, dcype or
N-Xantphos), K3PO4, aryl halide (if solid), and azole were weighed
into a scintillation vial in a glovebox. tert-Amyl alcohol was added
(liquid halides was added after addition of tert-amyl alcohol). The vial
was sealed with a Teflon-lined cap and taken out of the glovebox, and
the reaction vial (placed in an aluminum block) was allowed to stir at
the indicated temperature using an IKA heating plate for the indicated
time. The reaction mixture was cooled to room temperature and
filtered through a 1.0 in. plug of silica gel, eluting with Et2O (150
mL). The filtrate was concentrated and chromatographed on a silica
gel column to afford the product.
General Procedure B for C−H Arylations. Ni(COD)2, ligand
(dppb, dcype or N-Xantphos), and azole were weighed into a
scintillation vial in the glovebox. tert-Amyl alcohol, P2Et, and 4-
chloroanisole were added sequentially. The vial was sealed with a
Teflon-lined cap and taken out of the glovebox, and the vial (placed in
an aluminum block) was allowed to stir at the indicated temperature
using an IKA heating plate for the indicated time. The reaction
mixture was cooled to room temperature and filtered through a 1.0 in.
plug of silica gel, eluting with Et2O (150 mL). The filtrate was
concentrated and chromatographed on a silica gel column to afford
the product.
General Procedure C for C−H Arylations. Ni(COD)2, ligand
(dppb, dcype or N-Xantphos), aryl halide, and azole were weighed
into a scintillation vial in the glovebox. tert-Amyl alcohol and P2Et
were added sequentially. The vial was sealed with a Teflon-lined cap
and taken out of the glovebox, and the reaction vial (placed in an
aluminum block) was allowed to stir at the indicated temperature
using an IKA heating plate for the indicated time. The reaction
mixture was cooled to room temperature and chromatographed on a
silica gel column to afford the product.
General Procedure D for C−H Arylations. Ni(COD)2, ligand
(dppb, dcype or N-Xantphos), aryl halide, and azole were weighed
into a scintillation vial in the glovebox. tert-Amyl alcohol and P2Et
were added sequentially. The vial was sealed with a Teflon-lined cap
and taken out of the glovebox, and the reaction vial (placed in an
aluminum block) was allowed to stir at the indicated temperature
Procedures and Spectral Characterization of Arylation
Products (Scheme 3). 2-(4-Methoxyphenyl)-5-methyl-1,3-benzox-
azole (1a). Following general procedure A, 4-chloroanisole (53.5 mg,
0.375 mmol, 1.5 equiv), 5-methylbenzoxazole (33 mg, 0.25 mmol, 1.0
equiv), Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10 equiv), dppb (13 mg,
0.03 mmol, 0.12 equiv), K3PO4(80.0 mg, 0.375 mmol, 1.5 equiv), and
anhydrous tert-amyl alcohol (1.0 mL) were combined in a 4 mL
scintillation vial. The reaction mixture was allowed to stir at 110 °C
for 15 h. Chromatography on a silica gel column using 95/5 hexanes/
EtOAc (Rf = 0.15 in 95% hexanes/5% ethyl acetate) yielded product
1a as a white solid (52 mg, 86% yield). 1H NMR (500 MHz, CDCl3):
δ 8.18 (d, J = 8.9 Hz, 2H), 7.51 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.12
(dd, J = 8.3, 1.6 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 2.48
(s, 3H). The spectroscopic data is consistent with that previously
reported in the literature.11a
5-Methyl-2-(pyridin-3-yl)benzo[d]oxazole (1b). Following general
procedure A, 3-chloropyridine (42.6 mg, 0.375 mmol, 1.5 equiv), 5-
methylbenzoxazole (33 mg, 0.25 mmol, 1.0 equiv), Ni(COD)2 (6.88
mg, 0.025 mmol, 0.10 equiv), dppb (13 mg, 0.03 mmol, 0.12 equiv),
K3PO4 (80.0 mg, 0.375 mmol, 1.5 equiv), and anhydrous tert-amyl
alcohol (1.0 mL) were combined in a 4 mL scintillation vial. The
reaction mixture was allowed to stir at 110 °C for 18 h.
Chromatography on a silica gel column using 75/25 hexanes/
EtOAc (Rf = 0.26 in 75% hexanes/25% ethyl acetate) yielded product
1b as a white solid (35 mg, 67% yield). 1H NMR (400 MHz, CDCl3):
δ 9.47 (s, 1H), 8.76 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.58
(s, 1H), 7.49−7.45 (multiple peaks, 2H), 7.21 (d, J = 8.3 Hz, 1H),
2.50 (s, 3H). The spectroscopic data is consistent with that previously
reported in the literature.11b
2-(4-Cyanophenyl)-5-methyl-1,3-benzoxazole (1c). Following
general procedure A, 4-chlorobenzonitrile (51.6 mg, 0.375 mmol,
1.5 equiv), 5-methylbenzoxazole (33 mg, 0.25 mmol, 1.0 equiv),
Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10 equiv), dppb (13 mg, 0.03
mmol, 0.12 equiv), K3PO4 (80.0 mg, 0.375 mmol, 1.5 equiv), and
anhydrous tert-amyl alcohol (1.0 mL) were combined in a 4 mL
scintillation vial. The reaction mixture was allowed to stir at 110 °C
for 18 h. Chromatography on a silica gel column using 93/7 hexanes/
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EtOAc (Rf = 0.35 in 90% hexanes/10% ethyl acetate) yielded product
1c as a white solid (56 mg, 96% yield). 1H NMR (400 MHz, CDCl3):
δ 8.34 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 7.49
(d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 2.51 (s, 3H). The
spectroscopic data is consistent with that previously reported in the
literature.11b
2-(3-Trifluoromethylphenyl)-5-methyl-1,3-benzoxazole (1d). Fol-
lowing general procedure A, 3-chlorobenzotrifluoride (70.0 mg, 0.375
mmol, 1.5 equiv), 5-methylbenzoxazole (33 mg, 0.25 mmol, 1.0
equiv), Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10 equiv), dppb (13 mg,
0.03 mmol, 0.12 equiv), K3PO4 (80.0 mg, 0.375 mmol, 1.5 equiv),
and anhydrous tert-amyl alcohol (1.0 mL) were combined in a 4 mL
scintillation vial. The reaction mixture was allowed to stir at 110 °C
for 18 h. Chromatography on a silica gel column using 97/3 hexanes/
EtOAc (Rf = 0.58 in 95% hexanes/5% ethyl acetate) yielded product
1d as a white solid (52 mg, 75% yield). 1H NMR (400 MHz, CDCl3):
δ 8.52 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.66
(t, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.21 (d, J =
8.3 Hz, 1H), 2.50 (s, 3H). The spectroscopic data is consistent with
that previously reported in the literature.20
2-(4-Fluorophenyl)-5-methyl-1,3-benzoxazole (1e). Following
general procedure A, 1-chloro-4-fluorobenzene (49.0 mg, 0.375
mmol, 1.5 equiv), 5-methylbenzoxazole (33 mg, 0.25 mmol, 1.0
equiv), Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10 equiv), dppb (13 mg,
0.03 mmol, 0.12 equiv), K3PO4 (80.0 mg, 0.375 mmol, 1.5 equiv),
and anhydrous tert-amyl alcohol (1.0 mL) were combined in a 4 mL
scintillation vial. The reaction mixture was allowed to stir at 110 °C
for 20 h. Chromatography on a silica gel column using 95/5 hexanes/
EtOAc (Rf = 0.34 in 95% hexanes/5% ethyl acetate) yielded product
1e as a white solid (36 mg, 63% yield). 1H NMR (400 MHz, CDCl3):
8.26−8.23 (m, 2H), 7.54 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.26−7.15
(multiple peaks, 3H), 2.49 (s, 3H). The spectroscopic data is
consistent with that previously reported in the literature.21
(33 mg, 0.06 mmol, 0.12 equiv), phosphazene base P2Et (255 mg,
0.75 mmol, 1.5 equiv), and anhydrous tert-amyl alcohol (2.0 mL)
were combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 105 °C for 20 h. Chromatography on a silica gel
column using a gradient 100/0 to 70/30 hexanes/EtOAc (Rf = 0.75 in
70% hexanes/30% ethyl acetate) using the Teledyne Isco CombiFlash
purification system yielded product 2a as a light-yellow solid (101 mg,
80% yield). 1H NMR (500 MHz, CDCl3): δ 8.06 (d, J = 8.8 Hz, 2H),
7.71 (d, J = 7.4 Hz, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.41 (s, 1H), 7.33
(t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H). 13C{1H}
NMR (CDCl3): δ 161.3, 161.2, 150.6, 128.8, 128.1, 128.0, 127.9,
124.0, 123.2, 120.2, 114.2, 55.3. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C16H14NO2 252.1024, found 252.1031.
5-(4-Fluorophenyl)-2-(4-methoxyphenyl)-1,3-oxazole (3a). Fol-
lowing general procedure B, 1-chloro-4-methoxybenzene (107 mg,
0.75 mmol, 1.5 equiv), 5-(4-fluorophenyl)oxazole (82 mg, 0.50 mmol,
1.0 equiv), Ni(COD)2 (14 mg, 0.05 mmol, 0.10 equiv), N-Xantphos
(33 mg, 0.06 mmol, 0.12 equiv), phosphazene base P2Et (255 mg,
0.75 mmol, 1.5 equiv), and anhydrous tert-amyl alcohol (2.0 mL)
were combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 105 °C for 20 h. Chromatography on a silica gel
column using a gradient 100/0 to 70/30 hexanes/EtOAc (Rf = 0.70 in
70% hexanes/30% ethyl acetate) using the Teledyne Isco CombiFlash
purification system yielded product 3a as a white solid (113 mg, 83%
1
yield). H NMR (500 MHz, CDCl3): δ 8.06 (d, J = 8.8 Hz, 2H),
7.70−7.67 (m, 2H), 7.36 (s, 1H), 7.14 (t, J = 8.7 Hz, 2H), 7.00 (d, J =
8.8 Hz, 2H), 3.88 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ
162.4 (d, J = 262 Hz), 161.5, 161.2, 149.8, 127.9, 125.8 (d, J = 8.1
Hz), 124.4 (d, J = 3.3 Hz), 122.8, 120.0, 116.0 (d, J = 22 Hz), 114.2,
55.3. 19F NMR (470 MHz, CDCl3): δ −112.5 (m). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C16H13FNO2 270.0930, found
270.0936.
5-(3-Methoxyphenyl)-2-(4-methoxyphenyl)-1,3-oxazole (4a).
Following general procedure B, 1-chloro-4-methoxybenzene (107
mg, 0.75 mmol, 1.5 equiv), 5-(3-methoxyphenyl)oxazole (88 mg, 0.50
mmol, 1.0 equiv), Ni(COD)2 (14 mg, 0.05 mmol, 0.10 equiv), dcype
(25 mg, 0.06 mmol, 0.12 equiv), phosphazene base P2Et (255 mg,
0.75 mmol, 1.5 equiv), and anhydrous tert-amyl alcohol (2.0 mL)
were combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 105 °C for 20 h. Chromatography on a silica gel
column using a gradient 100/0 to 70/30 hexanes/EtOAc (Rf = 0.67 in
70% hexanes/30% ethyl acetate) using the Isco flash purification
Ethyl 4-(5-Methyl-1,3-benzoxazol-2-yl)benzoate (1f). Following
general procedure A, ethyl 4-chlorobenzoate (69.2 mg, 0.375 mmol,
1.5 equiv), 5-methylbenzoxazole (33 mg, 0.25 mmol, 1.0 equiv),
Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10 equiv), dppb (13 mg, 0.03
mmol, 0.12 equiv), K3PO4 (80.0 mg, 0.375 mmol, 1.5 equiv), and
anhydrous tert-amyl alcohol (1.0 mL) were combined in a 4 mL
scintillation vial. The reaction mixture was allowed to stir at 110 °C
for 15 h. Chromatography on a silica gel column using 95/5 hexanes/
EtOAc (Rf = 0.23 in 95% hexanes/5% ethyl acetate) yielded product
1f as a white solid (70 mg, > 99% yield). The isolated product
1
system yielded product 4a as a white solid (124 mg, 88% yield). H
1
NMR (500 MHz, CDCl3): δ 8.08 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H),
7.36 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.23 (t, J = 2.2 Hz,
1H), 7.01 (d, J = 8.9 Hz, 2H), 6.89 (dd, J = 8.1, 2.4 Hz, 1H) 3.89 (s,
6H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.3, 161.2, 160.0, 150.5,
130.0, 129.3, 127.9, 123.4, 120.1, 116.5, 114.2, 113.7, 109.5, 55.33,
55.30. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H16NO3
282.1130, found 282.1125.
contained ∼10% of an impurity related to the aryl halide. H NMR
(500 MHz, CDCl3): δ 8.31 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 8.4 Hz,
2H), 7.58 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.20 (dd, J = 8.3, 1.3 Hz,
1H), 4.42 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H).
The spectroscopic data is consistent with that previously reported in
the literature.12c
5-Methyl-2-(quinoxalin-6-yl)benzo[d]oxazole (1g). Following
general procedure A, 6-chloroquinoxaline (61.7 mg, 0.375 mmol,
1.5 equiv), 5-methylbenzoxazole (33 mg, 0.25 mmol, 1.0 equiv),
Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10 equiv), dppb (13 mg, 0.03
mmol, 0.12 equiv), K3PO4 (80.0 mg, 0.375 mmol, 1.5 equiv), and
anhydrous tert-amyl alcohol (1.0 mL) were combined in a 4 mL
scintillation vial. The reaction mixture was allowed to stir at 110 °C
for 20 h. Chromatography on a silica gel column using 80/20
hexanes/EtOAc (Rf = 0.24 in 80% hexanes/20% ethyl acetate) yielded
product 1g as a white solid (64 mg, 97% yield). 1H NMR (400 MHz,
CDCl3): δ 8.97−8.91 (multiple peaks, 3H), 8.66 (d, J = 8.0 Hz, 1H),
8.25 (d, J = 7.0 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.24
(m, 1H), 2.52 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.6,
149.2, 145.89, 145.85, 144.2, 142.8, 142.1, 134.7, 130.3, 128.8, 128.6,
128.3, 126.9, 120.2, 110.1, 21.5. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C16H12N3O 262.0980, found 262.0993.
Heteroaryl Halide Scope (Scheme 6). In a nitrogen-filled
glovebox, stock solutions of the electrophiles examined were dosed
into 1 mL vials equipped with magnetic stir bars (20.0 μL dosed, 0.25
M solution in MeCN (5.0 μmol, 1.5 equiv)). The plate was then
concentrated to dryness on the GenVac. To these vials were then
added 5-methylbenzo[d]oxazole (15.0 μL, 0.22 M solution in diglyme
(3.3 μmol)) and phosphazene base P2Et (15.0 μL, 0.33 M solution in
diglyme (5.0 μmol)). To this was added 33 μL of a stock solution of
precomplexed Ni-N-XantPhos* (0.01 M solution in diglyme (0.33
μmol, 10 mol %)). The reaction block was sealed, removed from the
glovebox, placed on a tumble stirrer, and heated to 105 °C for 16 h.
The reaction mixtures were sampled, diluted with 90:10 MeCN/
water, and analyzed by LCMS. *Prep of 0.01 M stock solution of Ni-
N-XantPhos complex: In a nitrogen-filled glovebox, a 4 mL vial
(equipped with a stir bar) was charged with Ni(COD)2 (10 mg, 36
mmol) and Ni-N-XantPhos (20 mg, 36 mmol) in 3.63 mL of diglyme.
This solution was aged for 10 min (resulting in a dark orange slurry)
before being dosed to the reaction plate.
Procedures and Spectral Characterization of Arylation
Products (Scheme 5). 5-Phenyl-2-(4-methoxyphenyl)-1,3-oxazole
(2a). Following general procedure B, 1-chloro-4-methoxybenzene
(107 mg, 0.75 mmol, 1.5 equiv), 5-phenyloxazole (73 mg, 0.50 mmol,
1.0 equiv), Ni(COD)2 (14 mg, 0.05 mmol, 0.10 equiv), N-Xantphos
Procedures and Spectral Characterization of Isolated
Arylation Products (Scheme 6). 2-(6-(Ethylsulfonyl)pyridin-3-
F
DOI: 10.1021/acs.joc.9b02094
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The Journal of Organic Chemistry
Article
yl)-5-methylbenzo[d]oxazole (1h). Following general procedure D
(except using diglyme as the solvent), 5-chloro-2-(ethylsulfonyl)-
pyridine (158 mg, 0.75 mmol, 1.5 equiv), 5-methylbenzo[d]oxazole
(68 mg, 0.50 mmol, 1.0 equiv), Ni(COD)2 (14 mg, 0.05 mmol, 0.10
equiv), N-Xantphos (33 mg, 0.06 mmol, 0.12 equiv), phosphazene
base P2Et (255 mg, 0.75 mmol, 1.5 equiv), and anhydrous diglyme
(2.0 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was allowed to stir at 105 °C for 20 h. Purification using the
Teledyne Isco CombiFlash purification system (eluting with EtOAc/
hexanes) yielded product 1h as a light tan solid (37 mg, 24% yield).
1H (500 MHz, CDCl3); δ 9.56 (dd, J = 2.1, 0.8 Hz, 1H), 8.76 (dd, J =
8.2, 2.1 Hz, 1H), 8.26 (dd, J = 8.2, 0.8 Hz, 1H), 7.63 (dt, J = 1.7, 0.8
Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.30−7.27 (m, 2H), 3.51 (q, J =
7.5 Hz, 2H), 2.53 (s, 3H), 1.37 (t, J = 7.5 Hz, 3H). 13C{1H} NMR
(126 MHz, CDCl3): δ 158.9, 158.2, 149.2, 148.9, 141.9, 136.5, 135.4,
127.9, 126.9, 122.4, 120.6, 110.4, 46.5, 21.5, 6.9. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C15H15N2O3S 303.0803, found 303.0805.
5-Methyl-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)benzo[d]oxazole (1i).
Following general procedure D (except using diglyme as the solvent),
4-bromo-2-(pyrrolidin-1-yl)pyridine (170 mg, 0.75 mmol, 1.5 equiv),
5-methylbenzo[d]oxazole (68 mg, 0.50 mmol, 1.0 equiv), Ni(COD)2
(14 mg, 0.05 mmol, 0.10 equiv), N-Xantphos (33 mg, 0.06 mmol,
0.12 equiv), phosphazene base P2Et (255 mg, 0.75 mmol, 1.5 equiv),
and anhydrous diglyme (2.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 130 °C
for 20 h. Purification using the Teledyne Isco CombiFlash purification
system (eluting with EtOAc/hexanes) yielded product 1i as a white
solid (110 mg, 79% yield). 1H (500 MHz, CDCl3): δ 8.33 (d, J = 5.3
Hz, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.30 (dd,
J = 5.3, 1.4 Hz, 1H), 7.23 (dd, J = 8.3, 1.7 Hz, 1H), 7.19 (d, J = 1.4
Hz, 1H), 3.71−3.46 (m, 5H), 2.52 (s, 3H), 2.20−2.01 (m, 4H).
13C{1H} NMR (126 MHz, CDCl3): δ 161.9, 149.0, 148.8, 142.0,
80.0, 45.1, 43.6, 28.4, 28.4, 21.5. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C22H27N4O3 395.2083, found 395.2086.
5-Methyl-2-(4-methylquinolin-2-yl)benzo[d]oxazole (1o). Fol-
lowing general procedure D (except using diglyme as the solvent),
2-chloro-4-methylquinoline (136 mg, 0.75 mmol, 1.5 equiv), 5-
methylbenzo[d]oxazole (68 mg, 0.50 mmol, 1.0 equiv), Ni(COD)2
(14 mg, 0.05 mmol, 0.10 equiv), N-Xantphos (33 mg, 0.06 mmol,
0.12 equiv), phosphazene base P2Et (255 mg, 0.75 mmol, 1.5 equiv),
and anhydrous diglyme (2.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 105 °C
for 20 h. Purification using the Teledyne Isco CombiFlash purification
system (eluting with EtOAc/hexanes) yielded product 1o as a light
tan solid (110 mg, 79% yield). 1H (500 MHz, CDCl3): δ 8.44 (dt, J =
8.6, 0.8 Hz, 1H), 8.36 (d, J = 1.1 Hz, 1H), 8.09 (dd, J = 8.4, 1.4 Hz,
1H), 7.83 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.71−7.67 (m, 2H), 7.64 (d,
J = 8.3 Hz, 1H), 7.26−7.19 (m, 1H), 2.86 (d, J = 0.9 Hz, 3H), 2.54 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.6, 149.6, 147.6, 146.3,
145.4, 142.0, 134.9, 130.7, 130.2, 128.8, 127.9, 127.6, 123.8, 120.8,
120.5, 110.9, 21.6, 18.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H15N2O 275.1184, found 275.1193.
5-Methyl-2-(2-methylbenzo[d]thiazol-5-yl)benzo[d]oxazole (1s).
Following general procedure D, 5-chloro-2-methylbenzo[d]thiazole
(141 mg, 0.75 mmol, 1.5 equiv), 5-methylbenzo[d]oxazole (68 mg,
0.50 mmol, 1.0 equiv), Ni(COD)2 (14 mg, 0.05 mmol, 0.10 equiv),
N-Xantphos (33 mg, 0.06 mmol, 0.12 equiv), phosphazene base P2Et
(255 mg, 0.75 mmol, 1.5 equiv), and anhydrous tert-amyl alcohol (2.0
mL) were combined in a 20 mL scintillation vial. The reaction
mixture was allowed to stir at 105 °C for 20 h. Purification using the
Teledyne Isco CombiFlash purification (eluting with EtOAc/
hexanes) system yielded product 1s as a yellow solid (90 mg, 63%
yield). 1H (500 MHz, CDCl3); δ 8.80 (d, J = 1.6 Hz, 1H), 8.28 (dd, J
= 8.4, 1.7 Hz, 1H), 7.97 (dd, J = 8.4, 0.6 Hz, 1H), 7.60 (dt, J = 1.6, 0.8
Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.20 (ddd, J = 8.3, 1.7, 0.7 Hz,
1H), 2.91 (s, 3H), 2.52 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3):
δ 168.6, 162.9, 153.5, 149.1, 142.3, 138.8, 134.5, 126.4, 125.5, 123.8,
121.9, 121.5, 119.9, 110.0, 21.5, 20.3. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C16H13N2OS 281.0748, found 281.0754.
2-(7-Methoxyquinoxalin-2-yl)-5-methylbenzo[d]oxazole (1v).
Following general procedure D (except using diglyme as the solvent),
2-chloro-7-methoxyquinoxaline (149 mg, 0.75 mmol, 1.5 equiv), 5-
methylbenzo[d]oxazole (68 mg, 0.50 mmol, 1.0 equiv), Ni(COD)2
(14 mg, 0.05 mmol, 0.10 equiv), N-Xantphos (33 mg, 0.06 mmol,
0.12 equiv), phosphazene base P2Et (255 mg, 0.75 mmol, 1.5 equiv),
and anhydrous diglyme (2.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 105 °C
for 20 h. Purification using the Teledyne Isco CombiFlash purification
system (eluting with EtOAc/hexanes) yielded product 1v as a light
tan solid (26 mg, 17% yield). 1H (500 MHz, CDCl3): δ 9.71 (s, 1H),
8.09 (d, J = 9.2 Hz, 1H), 7.71 (s, 1H), 7.64 (dd, J = 5.6, 2.8 Hz, 2H),
7.53 (dd, J = 9.2, 2.7 Hz, 1H), 7.31 (dd, J = 8.5, 1.7 Hz, 1H), 4.03 (s,
3H), 2.55 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.7,
160.0, 149.5, 143.7, 141.9, 141.6, 140.9, 139.2, 135.4, 130.2, 128.1,
125.2, 120.8, 110.8, 107.1, 56.0, 21.6. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C17H14N3O2 292.1086, found 292.1097.
135.3, 134.8, 127.1, 120.3, 110.2, 108.4, 104.3, 47.0, 25.6, 21.5 (one
carbon signal is absent due to incidental equivalence). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C17H18N3O 280.1450, found
280.1458.
2-(2-(2H-1,2,3-Triazol-2-yl)pyridin-4-yl)-5-methylbenzo[d]-
oxazole (1j). Following general procedure D (except using diglyme as
the solvent), 4-bromo-2-(2H-1,2,3-triazol-2-yl)pyridine (169 mg, 0.75
mmol, 1.5 equiv), 5-methylbenzo[d]oxazole (68 mg, 0.50 mmol, 1.0
equiv), Ni(COD)2 (14 mg, 0.05 mmol, 0.10 equiv), N-Xantphos (33
mg, 0.06 mmol, 0.12 equiv), phosphazene base P2Et (255 mg, 0.75
mmol, 1.5 equiv), and anhydrous diglyme (2.0 mL) were combined in
a 20 mL scintillation vial. The reaction mixture was allowed to stir at
105 °C for 20 h. Purification using the Teledyne Isco CombiFlash
purification system (eluting with EtOAc/hexanes) yielded product 1j
as a white solid (58 mg, 42% yield). The isolated product has trace
1
protodehalogenated halide. H (500 MHz, CDCl3): δ 8.88 (s, 1H),
8.77 (d, J = 5.1 Hz, 1H), 8.12 (d, J = 5.1 Hz, 1H), 7.96 (s, 2H), 7.64
(s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 2.52 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3): δ 159.8, 151.6, 149.8, 149.2,
141.9, 137.6, 136.9, 135.3, 127.9, 120.6, 120.2, 111.4, 110.4, 21.5.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H12N5O 278.1042,
found 278.1048.
2-(4-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-
methylbenzo[d]oxazole (1z). Following general procedure D (except
using diglyme as the solvent), 3-bromo-4-fluoro-1-(tetrahydro-2H-
pyran-2-yl)-1H-indazole (224 mg, 0.75 mmol, 1.5 equiv), 5-
methylbenzo[d]oxazole (68 mg, 0.50 mmol, 1.0 equiv), Ni(COD)2
(14 mg, 0.05 mmol, 0.10 equiv), N-Xantphos (33 mg, 0.06 mmol,
0.12 equiv), phosphazene base P2Et (255 mg, 0.75 mmol, 1.5 equiv),
and anhydrous diglyme (2.0 mL) were combined in a 20 mL
scintillation vial. The reaction mixture was allowed to stir at 105 °C
for 20 h. Purification using the Teledyne Isco CombiFlash purification
system (eluting with EtOAc/hexanes) yielded product 1z as a white
solid (11 mg, 6% yield). 1H (500 MHz, CDCl3): δ 7.68 (s, 1H), 7.54
(dd, J = 8.4, 2.1 Hz, 2H), 7.45−7.41 (m, 1H), 7.21 (dd, J = 8.4, 1.2
Hz, 1H), 7.04−7.00 (m, 1H), 5.89 (dd, J = 9.4, 2.8 Hz, 1H), 4.10−
4.03 (m, 1H), 3.81−3.76 (m, 1H), 2.69−2.59 (m, 1H), 2.50 (s, 3H),
2.25−2.14 (multiple peaks, 2H), 1.85−1.60 (multiple peaks, 3H).
tert-Butyl 4-(4-(5-Methylbenzo[d]oxazol-2-yl)pyridin-2-yl)-
piperazine-1-carboxylate (1k). Following general procedure D, tert-
butyl 4-(4-bromopyridin-2-yl)piperazine-1-carboxylate (262 mg, 0.75
mmol, 1.5 equiv), 5-methylbenzo[d]oxazole (68 mg, 0.50 mmol, 1.0
equiv), Ni(COD)2 (14 mg, 0.05 mmol, 0.10 equiv), N-Xantphos (33
mg, 0.06 mmol, 0.12 equiv), phosphazene base P2Et (255 mg, 0.75
mmol, 1.5 equiv), and anhydrous tert-amyl alcohol (2.0 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 105 °C for 20 h. Purification using the Teledyne Isco
CombiFlash purification system (eluting with EtOAc/hexanes)
1
yielded product 1k as a white solid (131 mg, 65% yield). H (500
MHz, CDCl3): δ 8.37 (dd, J = 5.2, 0.8 Hz, 1H), 7.62−7.58 (m, 1H),
7.52−7.46 (m, 2H), 7.41 (dd, J = 5.2, 1.2 Hz, 1H), 7.24 (dd, J = 8.2,
1.7 Hz, 1H), 3.72−3.66 (m, 4H), 3.64−3.56 (m, 4H), 2.52 (s, 3H),
1.52 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.6, 159.6,
154.8, 149.0, 141.9, 136.0, 134.9, 127.2, 120.3, 110.8, 110.2, 104.6,
G
DOI: 10.1021/acs.joc.9b02094
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The Journal of Organic Chemistry
Article
13C{1H} NMR (126 MHz, CDCl3): δ 157.0 (d, J = 119 Hz), 154.5,
alcohol (1.0 mL) were combined in a 4 mL scintillation vial. The
reaction mixture was allowed to stir at 105 °C for 20 h.
Chromatography on a silica gel column using a gradient 100/0 to
30/70 hexanes/EtOAc (Rf = 0.63 in 70% hexanes/30% ethyl acetate)
using the Teledyne Isco CombiFlash purification system yielded
product 5i as a yellow solid (45.1 mg, 59% yield). 1H NMR (CDCl3):
δ 8.28 (d, J = 5.5 Hz, 1H), 7.87 (td, J = 7.6, 1.7 Hz, 1H), 7.64 (d, J =
3.8 Hz, 1H), 7.38−7.34 (m, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.22−7.18
(multiple peaks, 2H), 7.11 (s, 1H), 3.62 (m, 4H), 2.08 (m, 4H).
13C{1H} NMR (126 MHz, CDCl3): δ 158.9 (J = 252 Hz), 159.7,
157.5, 148.9, 146.4, 134.9, 129.8 (J = 8.3 Hz), 127.9 (J = 13 Hz),
126.1 (J = 2.8 Hz), 124.6 (J = 3.5 Hz), 116.3, 116.1 (J = 21 Hz),
107.6, 102.9, 46.9, 25.5. 19F NMR (470 MHz, CDCl3): δ −111.5.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H17FN3O 310.1355,
found 310.1361.
148.9, 143.1 (d, J = 7.8 Hz), 142.1, 134.4, 131.6 (d, J = 3.7 Hz), 128.4
(d, J = 7.6 Hz), 126.6, 120.4, 112.8 (d, J = 22 Hz), 110.2, 108.1 (d, J =
20 Hz), 107.2 (d, J = 4.7 Hz), 86.9, 67.6, 29.3, 24.9, 22.2, 21.5. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C20H19FN3O2 352.1461, found
352.1477.
2-(1H-Indol-5-yl)-5-methylbenzo[d]oxazole (1aa). Following gen-
eral procedure D, tert-butyl 5-bromo-1H-indole-1-carboxylate (227
mg, 0.75 mmol, 1.5 equiv), 5-methylbenzo[d]oxazole (68 mg, 0.50
mmol, 1.0 equiv), Ni(COD)2 (14 mg, 0.05 mmol, 0.10 equiv), N-
Xantphos (33 mg, 0.06 mmol, 0.12 equiv), phosphazene base P2Et
(255 mg, 0.75 mmol, 1.5 equiv), and anhydrous tert-amyl alcohol (2.0
mL) were combined in a 20 mL scintillation vial. The reaction
mixture was allowed to stir at 105 °C for 20 h. Purification using the
Teledyne Isco CombiFlash purification system (eluting with EtOAc/
hexanes) yielded product des Boc-1aa as a light-yellow solid (74 mg,
58% yield). Characterization data for des-Boc product (product was
contaminated with 5% residualtert-amyl alcohol). 1H (500 MHz,
DMSO-d6): δ 11.50 (s, 1H), 8.44 (d, J = 1.6 Hz, 1H), 7.95 (dd, J =
8.5, 1.7 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H),
7.57−7.54 (m, 1H), 7.50 (t, J = 2.7 Hz, 1H), 7.19 (dd, J = 8.3, 1.7 Hz,
1H), 6.63 (ddd, J = 3.0, 1.8, 0.8 Hz, 1H), 2.45 (s, 3H). 13C{1H} NMR
(126 MHz, DMSO-d6): δ 164.7, 148.9, 142.6, 138.2, 134.3, 128.3,
127.7, 125.9, 120.7, 120.7, 119.6, 117.8, 112.7, 110.4, 102.9, 21.5.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H13N2O 249.1028,
found 249.1034.
5-(4-Fluorophenyl)-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)oxazole (3i).
Following general procedure D, 4-bromo-2-(pyrrolidine-1-yl)pyridine
(85 mg, 0.375 mmol, 1.5 equiv), 5-(4-fluorophenyl)oxazole (41 mg,
0.25 mmol, 1.0 equiv), Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10
equiv), dcype (13 mg, 0.03 mmol, 0.12 equiv), phosphazene base
P2Et (127 mg, 0.375 mmol, 1.5 equiv), and anhydrous tert-amyl
alcohol (1.0 mL) were combined in a 4 mL scintillation vial. The
reaction mixture was allowed to stir at 105 °C for 20 h.
Chromatography on a silica gel column using a gradient 100/0 to
30/70 hexanes/EtOAc (Rf = 0.50 in 70% hexanes/30% ethyl acetate)
using the Teledyne Isco CombiFlash purification system yielded
1
product 3i as a light-orange solid (62.9 mg, 81% yield). H NMR
1-(5-(5-Methylbenzo[d]oxazol-2-yl)pyridin-2-yl)cyclopentane-1-
carbonitrile (1ad). Following general procedure D (except using
diglyme as the solvent), 1-(5-chloropyridin-2-yl)cyclopentane-1-
carbonitrile (158 mg, 0.75 mmol, 1.5 equiv), 5-methylbenzo[d]-
oxazole (68 mg, 0.50 mmol, 1.0 equiv), Ni(COD)2 (14 mg, 0.05
mmol, 0.10 equiv), N-Xantphos (33 mg, 0.06 mmol, 0.12 equiv),
phosphazene base P2Et (255 mg, 0.75 mmol, 1.5 equiv), and
anhydrous diglyme (2.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 105 °C for 20 h.
Purification using the Teledyne Isco CombiFlash purification system
(eluting with EtOAc/hexanes) yielded product 1ad as a light pink
solid (48 mg, 31% yield). 1H (500 MHz, CDCl3): δ 9.43 (dd, J = 2.3,
0.9 Hz, 1H), 8.54 (dd, J = 8.2, 2.3 Hz, 1H), 7.83 (dd, J = 8.3, 0.9 Hz,
1H), 7.64−7.58 (m, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.24 (ddd, J = 8.3,
1.7, 0.7 Hz, 1H), 2.53 (s, 3H), 2.50−2.43 (m, 4H), 2.13−2.02 (m,
4H). 13C{1H} NMR (126 MHz, CDCl3): δ 160.9, 160.3, 149.0, 148.5,
141.9, 135.8, 134.9, 127.0, 123.8, 122.8, 121.1, 120.2, 110.2, 50.1,
40.3, 25.1, 21.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C19H18N3O 304.1450, found 304.1454.
(500 MHz, CDCl3): δ 8.27 (d, J = 5.4 Hz, 1H), 7.72−7.69 (multiple
peaks, 2H), 7.42 (s, 1H), 7.17−7.14 (multiple peaks, 3H), 7.02 (s,
1H), 3.57 (m, 4H), 2.06 (m, 4H). 13C{1H} NMR (126 MHz,
CDCl3): δ 162.8 (J = 250 Hz), 159.9, 157.5, 151.0, 148.9, 134.9,
126.3 (J = 8.3 Hz), 124.0 (J = 3.4 Hz), 123.2 (J = 1.3 Hz), 116.1 (J =
22 Hz), 107.5, 102.7, 46.9, 25.5. 19F NMR (470 MHz, CDCl3): δ
−111.5 (m). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H17FN3O 310.1355, found 310.1360.
5-(4-Methoxyphenyl)-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)oxazole
(6i). Following general procedure D, 4-bromo-2-(pyrrolidine-1-
yl)pyridine (85 mg, 0.375 mmol, 1.5 equiv), 5-(4-methoxyphenyl)-
oxazole (44 mg, 0.25 mmol, 1.0 equiv), Ni(COD)2 (6.88 mg, 0.025
mmol, 0.10 equiv), dcype (13 mg, 0.03 mmol, 0.12 equiv),
phosphazene base P2Et (127 mg, 0.375 mmol, 1.5 equiv), and
anhydrous tert-amyl alcohol (1.0 mL) were combined in a 4 mL
scintillation vial. The reaction mixture was allowed to stir at 105 °C
for 20 h. Chromatography on a silica gel column using a gradient
100/0 to 30/70 hexanes/EtOAc (Rf = 0.38 in 70% hexanes/30% ethyl
acetate) using the Teledyne Isco CombiFlash purification system
yielded product 6i as an orange solid (50.2 mg, 63% yield). 1H NMR
(500 MHz, CDCl3): δ 8.26 (d, J = 5.7 Hz, 1H), 7.66 (d, J = 8.8 Hz,
2H), 7.39 (s, 1H), 7.21 (d, J = 4.9 Hz, 1H), 7.09 (s, 1H), 6.99 (d, J =
8.8 Hz, 2H), 3.87 (s, 3H), 3.63 (m, 4H), 2.08 (m, 4H). 13C{1H}
NMR (126 MHz, CDCl3): δ 160.0, 159.3, 157.5, 152.0, 148.9, 135.1,
125.9, 122.1, 120.4, 114.4, 107.5, 102.6, 55.3, 46.8, 25.5. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C19H20N3O2 322.1555, found
322.1559.
5-(3-Fluorophenyl)-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)oxazole (7i).
Following general procedure D, 4-bromo-2-(pyrrolidine-1-yl)pyridine
(43 mg, 0.19 mmol, 1.5 equiv), 5-(3-fluorophenyl)oxazole (20 mg,
0.125 mmol, 1.0 equiv), Ni(COD)2 (3.44 mg, 0.013 mmol, 0.10
equiv), N-XantPhos (8.2 mg, 0.02 mmol, 0.12 equiv), phosphazene
base P2Et (64 mg, 0.19 mmol, 1.5 equiv), and anhydrous tert-amyl
alcohol (0.5 mL) were combined in a 4 mL scintillation vial. The
reaction mixture was allowed to stir at 105 °C for 20 h.
Chromatography on a silica gel column using a gradient 100/0 to
30/70 hexanes/EtOAc (Rf = 0.52 in 70% hexanes/30% ethyl acetate)
using the Teledyne Isco CombiFlash purification system yielded
product 7i as a yellow solid (38 mg, 98% yield). 1H NMR (500 MHz,
CDCl3): δ 8.28 (d, J = 5.4 Hz, 1H), 7.52−7.51 (multiple peaks, 2H),
7.45−7.42 (multiple peaks, 2H), 7.17 (d, J = 5.2 Hz, 1H), 7.09−7.05
(multiple peaks, 2H), 3.59 (m, 4H), 2.06 (m, 4H). 13C{1H} NMR
(126 MHz, CDCl3): δ 163.1 (J = 247 Hz), 160.3, 157.8, 150.7 (J =
Procedures and Spectral Characterization of Arylation
Products (Scheme 7). 5-Phenyl-2-(2-(pyrrolidin-1-yl)pyridin-4-
yl)oxazole (2i). Following general procedure D, 4-bromo-2-
(pyrrolidine-1-yl)pyridine (85 mg, 0.375 mmol, 1.5 equiv), 5-
phenyloxazole (36 mg, 0.25 mmol, 1.0 equiv), Ni(COD)2 (6.88
mg, 0.025 mmol, 0.10 equiv), N-Xantphos (16.6 mg, 0.03 mmol, 0.12
equiv), P2Et (127 mg, 0.375 mmol, 1.5 equiv), and anhydrous tert-
amyl alcohol (1.0 mL) were combined in a 4 mL scintillation vial. The
reaction mixture was allowed to stir at 105 °C for 20 h.
Chromatography on a silica gel column using a gradient 100/0 to
30/70 hexanes/EtOAc (Rf = 0.52 in 70% hexanes/30% ethyl acetate)
using the Isco flash purification system yielded product 2i as a light
1
yellow solid (63.3 mg, 87% yield). H NMR (500 MHz, CDCl3): δ
8.27 (d, J = 5.4 Hz, 1H), 7.74 (d, J = 7.5 Hz, 2H), 7.49 (s, 1H), 7.47
(t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.19 (d, J = 5.3 Hz, 1H),
7.05 (s, 1H), 3.59 (m, 4H), 2.07 (m, 4H). 13C{1H}NMR (126 MHz,
CDCl3): δ 160.0, 157.6, 151.9, 148.9, 134.9, 128.9, 128.8, 127.6,
124.4, 123.6, 107.5, 102.8, 46.8, 25.5. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C18H18N3O 292.1450, found 292.1454.
5-(2-Fluorophenyl)-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)oxazole (5i).
Following general procedure D, 4-bromo-2-(pyrrolidine-1-yl)pyridine
(85 mg, 0.375 mmol, 1.5 equiv), 5-(2-fluorophenyl)oxazole (41 mg,
0.25 mmol, 1.0 equiv), Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10
equiv), dcype (13 mg, 0.03 mmol, 0.12 equiv), phosphazene base
P2Et (127 mg, 0.375 mmol, 1.5 equiv), and anhydrous tert-amyl
H
DOI: 10.1021/acs.joc.9b02094
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Article
2.9 Hz), 148.9, 134.7, 130.7 (J = 8.5 Hz), 129.6 (J = 8.6 Hz), 124.5,
120.0 (J = 3.0 Hz), 115.6 (J = 21 Hz), 111.3 (J = 24 Hz), 107.5,
102.9, 46.9, 25.5. 19F NMR (470 MHz, CDCl3): δ −111.9 (m).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H17FN3O 310.1355,
found 310.1362.
temperature and concentrated using the Genevac. The reactions were
diluted with 500 μL of DMSO, and a 5 μL aliquot of the reaction
mixtures was analyzed by LCMS. *Preparation of stock solution of
Ni−ligand complex: In a nitrogen-filled glovebox, a 4 mL vial
(equipped with a stir bar) was charged with Ni(COD)2 (41 mg, 0.15
mmol) and ligand (0.18 mmol) in 1.5 mL of tert-amyl alcohol. This
solution was stirred at room temperature for 10 min before being
dosed to the reaction plate.
Procedures and Spectral Characterization of Arylation
Products (Figure 4). Ethyl 5-Methyl-8-(5-methylbenzo[d]oxazol-
2-yl)-6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-
3-carboxylate (1-X2). Following general procedure C, X2 (91 mg,
0.25 mmol, 1.0 equiv), 5-methylbenzoxazole (33 mg, 0.25 mmol, 1.0
equiv), Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10 equiv), dcype (13 mg,
0.03 mmol, 0.12 equiv), phosphazene base P2Et (127 mg, 0.375
mmol, 1.5 equiv), and anhydrous tert-amyl alcohol (1.0 mL) were
combined in a 4 mL scintillation vial. The reaction mixture was
allowed to stir at 105 °C for 20 h. Chromatography on a silica gel
column using a gradient 100/0 to 0/100 hexanes/EtOAc (Rf = 0.55 in
100% ethyl acetate) using the Teledyne Isco CombiFlash purification
system yielded product 1-X2 as a yellow solid (32.9 mg, 32% yield).
1H NMR (500 MHz, CDCl3): δ 8.93 (d, J = 1.6 Hz, 1H), 8.52 (d, J =
5-(3-Methoxyphenyl)-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)oxazole
(4i). Following general procedure D, 4-bromo-2-(pyrrolidine-1-
yl)pyridine (85 mg, 0.375 mmol, 1.5 equiv), 5-(3-methoxyphenyl)-
oxazole (44 mg, 0.25 mmol, 1.0 equiv), Ni(COD)2 (6.88 mg, 0.025
mmol, 0.10 equiv), dcype (13 mg, 0.03 mmol, 0.12 equiv),
phosphazene base P2Et (127 mg, 0.375 mmol, 1.5 equiv), and
anhydrous tert-amyl alcohol (1.0 mL) were combined in a 4 mL
scintillation vial. The reaction mixture was allowed to stir at 105 °C
for 20 h. Chromatography on a silica gel column using a gradient
100/0 to 30/70 hexanes/EtOAc (Rf = 0.44 in 70% hexanes/30% ethyl
acetate) using the Teledyne Isco CombiFlash purification system
1
yielded product 4i as a orange solid (68.7 mg, 86% yield). H NMR
(500 MHz, CDCl3): δ 8.28 (d, J = 5.5 Hz, 1H), 7.48 (s, 1H), 7.38 (t,
J = 7.8 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.25 (m, 1H), 7.17 (d, J =
5.2 Hz, 1H), 7.05 (s, 1H), 6.92 (dd, J = 8.0, 2.4 Hz, 1H), 3.89 (s,
3H), 3.58 (m, 4H), 2.06 (m, 4H). 13C{1H}NMR (126 MHz, CDCl3):
δ 160.0, 159.9, 157.5, 151.7, 148.9, 135.0, 130.1, 128.8, 123.9, 116.1,
114.2, 110.0, 107.5, 102.8, 55.4, 46.9, 25.5. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C19H20N3O2 322.1555, found 322.1560.
8.3 Hz, 1H), 8.05 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.49
(d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 5.30 (br s, 1H), 4.46 (m,
3H), 3.30 (s, 3H), 2.51 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (126 MHz, CDCl3): δ 165.6, 162.8, 160.8, 149.1, 142.0, 135.4,
134.9, 133.6, 131.8, 131.3, 129.7, 128.9, 127.8, 127.1, 122.5, 120.2
110.2, 61.1, 42.3, 36.0, 21.5, 14.3. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C23H21N4O4 417.1563, found 417.1567.
5-Methoxy-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)benzo[d]oxazole
(8i). Following general procedure D, 4-bromo-2-(pyrrolidine-1-
yl)pyridine (43 mg, 0.19 mmol, 1.5 equiv), 5-methoxybenzoxazole
(18.6 mg, 0.125 mmol, 1.0 equiv), Ni(COD)2 (3.44 mg, 0.013 mmol,
0.10 equiv), dcype (6.3 mg, 0.015 mmol, 0.12 equiv), phosphazene
base P2Et (64 mg, 0.188 mmol, 1.5 equiv), and anhydrous tert-amyl
alcohol (0.5 mL) were combined in a 4 mL scintillation vial. The
reaction mixture was allowed to stir at 105 °C for 20 h.
Chromatography on a silica gel column using a gradient 100/0 to
85/15 hexanes/EtOAc (Rf = 0.18 in 85% hexanes/15% ethyl acetate)
using the Teledyne Isco CombiFlash purification system yielded
Ethyl 4-(8-Chloro-3-(5-methylbenzo[d]oxazol-2-yl)-5,6-dihydro-
11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-
carboxylate (1-X6). Following general procedure D, X6 (115 mg,
0.25 mmol, 1.0 equiv), 5-methylbenzoxazole (33 mg, 0.25 mmol, 1.0
equiv), Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10 equiv), N-Xantphos
(17 mg, 0.03 mmol, 0.12 equiv), phosphazene base P2Et (127 mg,
0.375 mmol, 1.5 equiv), and anhydrous tert-amyl alcohol (1.0 mL)
were combined in a 4 mL scintillation vial. The reaction mixture was
allowed to stir at 105 °C for 20 h. Chromatography on a silica gel
column using a gradient 100/0 to 75/25 hexanes/EtOAc (Rf = 0.33 in
70% hexanes/30% ethyl acetate) using the Teledyne Isco CombiFlash
purification system yielded product 1-X6 as a yellow solid (53.5 mg,
42% yield). 1H NMR (500 MHz, CDCl3): δ 9.23 (d, J = 1.8 Hz, 1H),
8.31 (s, 1H), 7.55 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.21−7.17
(multiple peaks, 4H), 4.14 (q, J = 7.1 Hz, 2H), 3.92−3.76 (multiple
peaks, 2H), 3.50−3.40 (multiple peaks, 2H), 3.22−3.14 (multiple
peaks, 2H), 3.05−2.94 (m, 1H), 2.89−2.83 (m, 1H), 2.62−2.52 (m,
1H), 2.49 (s, 3H), 2.46−2.31 (multiple peaks, 3H), 1.26 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 160.7, 159.3, 155.4,
148.9, 145.4, 141.9, 139.4, 138.9, 137.1, 136.2, 134.8, 133.8, 133.5,
133.3, 130.6, 129.0, 126.8, 126.4, 122.2, 120.0, 110.1, 61.3, 44.7, 44.6,
31.5, 31.4, 30.8, 30.7, 21.5, 14.7. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C30H29ClN3O3 514.1897, found 514.1914.
1
product 8i as a yellow solid (34.8 mg, 94% yield). H NMR (500
MHz, CDCl3): δ 8.31 (d, J = 5.4 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H),
7.28−7.26 (multiple peaks, 2H), 7.16 (s, 1H), 7.00 (dd, J = 8.9, 2.6
Hz, 1H), 3.87 (s, 3H), 3.58 (m, 4H), 2.06 (m, 4H). 13C{1H} NMR
(126 MHz, CDCl3): δ 162.5, 157.5, 157.5, 149.0, 145.4, 142.6, 135.1,
114.7, 110.9, 108.3, 104.1, 102.9, 55.9, 46.9, 25.5. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H18N3O2 296.1399, found 296.1405.
4-Fluoro-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)benzo[d]oxazole (9i).
Following general procedure D, 4-bromo-2-(pyrrolidine-1-yl)pyridine
(43 mg, 0.19 mmol, 1.0 equiv), 4-fluorobenzoxazole (17.1 mg, 0.125
mmol, 1.0 equiv), Ni(COD)2 (3.44 mg, 0.013 mmol, 0.10 equiv),
dcype (6.3 mg, 0.015 mmol, 0.12 equiv), phosphazene base P2Et (64
mg, 0.188 mmol, 1.5 equiv), and anhydrous tert-amyl alcohol (0.5
mL) were combined in a 4 mL scintillation vial. The reaction mixture
was allowed to stir at 105 °C for 20 h. Chromatography on a silica gel
column using a gradient 100/0 to 85/15 hexanes/EtOAc (Rf = 0.42 in
80% hexanes/20% ethyl acetate) using the Teledyne Isco CombiFlash
purification system yielded product 9i as a yellow solid (36.4 mg, >
99% yield). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J = 5.4 Hz, 1H),
7.44−7.31 (multiple peaks, 3H), 7.24 (m, 1H), 7.12 (t, J = 9.2 Hz,
1H), 3.60 (m, 4H), 2.08 (m, 4H). 13C{1H} NMR (126 MHz,
CDCl3): δ 162.1, 157.6, 153.6 (J = 255 Hz), 152.7 (J = 7.1 Hz),
149.3, 134.3, 130.6 (J = 16.6 Hz), 126.1 (J = 7.1 Hz), 110.9 (J = 17.5
Hz), 108.3, 106.9 (J = 4.5 Hz), 104.3, 46.9, 25.5. 19F NMR (470
MHz, CDCl3): δ −124.9 (m). HRMS (ESI-TOF) m/z: [M + H]+
calcd for C16H15FN3O 284.1199, found 284.1202.
1-Ethyl-8-(((1R,2R)-2-hydroxycyclopentyl)amino)-3-(2-hydrox-
yethyl)-7-(4-methoxy-3-(5-methylbenzo[d]oxazol-2-yl)benzyl)-3,7-
dihydro-1H-purine-2,6-dione (1-X12). Following general procedure
C, X12 (131 mg, 0.25 mmol, 1.0 equiv), 5-methylbenzoxazole (33
mg, 0.25 mmol, 1.0 equiv), Ni(COD)2 (6.88 mg, 0.025 mmol, 0.10
equiv), dcype (13 mg, 0.03 mmol, 0.12 equiv), phosphazene base
P2Et (127 mg, 0.375 mmol, 1.5 equiv), and anhydrous tert-amyl
alcohol (1.0 mL) were combined in a 4 mL scintillation vial. The
reaction mixture was allowed to stir at 105 °C for 20 h.
Chromatography on a silica gel column using a gradient 100/0 to
0/100 hexanes/EtOAc (Rf = 0.33 in 100% ethyl acetate) using the
Teledyne Isco CombiFlash purification system yielded product 1-X12
as an off-white solid (50.0 mg, 35% yield). Isolated product was
Procedure for Informer Screen (Figure 3). In a nitrogen-filled
glovebox, stock solutions of the electrophiles examined were dosed
into 1 mL vials equipped with magnetic stir bars (10.0 μmol dosed).
The plate was then concentrated to dryness on the GenVac. To these
vials were then added 5-methylbenzo[d]oxazole (20.0 μL, 0.5 M
solution in tert-amyl alcohol (10 μmol)), precomplexed Ni−ligand,*
and base (25.0 μL, 0.6 M solution in tert-amyl alcohol (15 μmol)).
The reaction block was sealed, placed on a tumble stirrer, and heated
to 105 °C for 24 h. The reaction mixtures were cooled to room
1
contaminated with ∼5% of X12. H NMR (500 MHz, DMSO-d6): δ
8.13 (d, J = 2.3 Hz, 1H), 7.64−7.61 (multiple peaks, 2H), 7.53 (dd, J
= 8.7, 2.3 Hz, 1H), 7.28−7.26 (multiple peaks, 2H), 7.12 (d, J = 6.7
Hz, 1H), 5.40 (s, 2H), 4.03−3.90 (multiple peaks, 11H), 3.66 (t, J =
6.4 Hz, 2H), 2.48 (s, 3H), 2.13−2.06 (m, 1H), 1.92−1.87 (m, 1H),
I
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1.72−1.63 (multiple peaks, 2H), 1.59−1.47 (multiple peaks, 2H),
1.13 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3/CD3OD):
δ 161.2, 157.8, 153.4, 151.1, 148.1, 148.0, 141.1, 134.4, 132.1, 132.0,
129.9, 128.2, 126.3, 119.2, 115.5, 112.3, 109.7, 102.5, 78.5, 62.2, 59.7,
55.7, 45.5, 45.2, 36.1, 31.9, 30.0, 21.1, 20.7, 12.9. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C30H35N6O6 575.2618, found 575.2645.
tert-Pentyl (S,Z)-(1,4-Dimethyl-4-(4-(5-methylbenzo[d]oxazol-2-
yl)thiophen-2-yl)-6-oxotetrahydropyrimidin-2(1H)-ylidene)-
carbamate (1-X13). Following general procedure A (except that the
crude reaction mixture was filtered through a bed of silica gel eluting
with ethyl acetate), X13 (101 mg, 0.25 mmol, 1.0 equiv), 5-
methylbenzoxazole (33 mg, 0.25 mmol, 1.0 equiv), Ni(COD)2 (6.88
mg, 0.025 mmol, 0.10 equiv), dcype (13 mg, 0.03 mmol, 0.12 equiv),
K3PO4 (80.0 mg, 0.375 mmol, 1.5 equiv), and anhydrous tert-amyl
alcohol (1.0 mL) were combined in a 4 mL scintillation vial. The
reaction mixture was allowed to stir at 105 °C for 20 h.
Chromatography on a silica gel column using a gradient 100/0 to
80/20 hexanes/EtOAc (Rf = 0.18 in 80% hexanes/20% ethyl acetate)
using the Isco flash purification system yielded product 1-X13 as a
carbon signal is absent due to incidental equivalence). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C28H28NO5 458.1967, found
458.1984.
Methyl (1S,2S)-1-((tert-Butoxycarbonyl)amino)-2-(3-(5-
methylbenzo[d]oxazol-2-yl)phenyl)cyclopropane-1-carboxylate
(1ag). Following general procedure E (except using diglyme as the
solvent), methyl (1S,2S)-1-((tert-butoxycarbonyl)amino)-2-(3-
chlorophenyl)cyclopropane-1-carboxylate (250 mg, 0.75 mmol, 1.5
equiv), 5-methylbenzo[d]oxazole (68 mg, 0.50 mmol, 1.0 equiv),
Ni(COD)2 (14 mg, 0.05 mmol, 0.10 equiv), N-Xantphos (33 mg,
0.06 mmol, 0.12 equiv), phosphazene base P2Et (255 mg, 0.75 mmol,
1.5 equiv), and anhydrous diglyme (2.0 mL) were combined in a 20
mL scintillation vial. The reaction mixture was allowed to stir at 105
°C for 20 h. Purification using the Teledyne Isco CombiFlash
purification system yielded product 1ag as a light tan solid (87 mg,
1
40% yield). Rotamers observed in both H and 13C NMR. Product was
contaminated with 3% residual diglyme. 1H (600 MHz, CDCl3, 270 K):
δ 8.16−8.13 (m, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.57 (s, 1H), 7.51−
7.45 (m, 2H), 7.37 (dd, J = 20.4, 7.8 Hz, 1H), 7.20 (d, J = 8.3, 1.7 Hz,
1H), 4.81 (bs, 1H), 3.80 (s, 3H), 3.10 (t, J = 8.8 Hz, 1H), 2.51 (s,
3H), 2.19 (dd, J = 11.0, 5.1 Hz, 1H), 1.93 (t, J = 7.1 Hz, 1H), 1.33 (s,
9H). 13C{1H} NMR (151 MHz, CDCl3, 270 K): δ 172.8, 162.8,
155.9, 148.8, 141.9, 135.7, 134.7, 132.2, 128.9, 127.6, 127.0, 126.5,
126.4, 119.8, 110.1, 80.2, 52.9, 52.8, 40.0, 32.4, 28.2, 21.7. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C24H27N2O5 423.1920, found
423.1926.
1
yellow solid (46 mg, 39% yield). H NMR (CDCl3): δ 10.5 (s, 1H),
8.06 (d, I = 1.3 Hz, 1H), 7.62 (d, J = 1.4 Hz, 1H), 7.51 (s, 1H), 7.42
(d, J = 8.3 Hz, 1H), 7.16 (dd, J = 8.4, 1.2 Hz, 1H), 3.30 (s, 3H), 3.21
(d, J = 16 Hz, 1H), 2.98 (d, J = 16 Hz, 1H), 2.48 (s, 3H), 1.89 (q, J =
7.5 Hz, 2H), 1.84 (s, 3H), 1.51 (s, 6H), 0.96 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (CDCl3): δ 166.9, 163.7, 158.9, 157.3, 149.8, 148.5,
141.8, 134.6, 129.5, 127.0, 126.4, 123.1, 119.8, 109.8, 82.8, 53.2, 45.6,
33.3, 30.1, 28.7, 25.7, 25.6, 21.5, 8.5. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C24H29N4O4S 469.1909, found 469.1911.
tert-Butyl 5-Methyl-6-(5-methylbenzo[d]oxazol-2-yl)-3-oxo-2,3-
dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (1ah). Follow-
ing general procedure E (except using diglyme as the solvent), tert-
butyl 6-chloro-5-methyl-3-oxo-2,3-dihydrospiro[indene-1,4′-piperi-
dine]-1′-carboxylate (268 mg, 0.75 mmol, 1.5 equiv), 5-methylbenzo-
[d]oxazole (68 mg, 0.50 mmol, 1.0 equiv), Ni(COD)2 (14 mg, 0.05
mmol, 0.10 equiv), N-Xantphos (33 mg, 0.06 mmol, 0.12 equiv),
phosphazene base P2Et (255 mg, 0.75 mmol, 1.5 equiv), and
anhydrous diglyme (2.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 105 °C for 20 h.
Purification using the Teledyne Isco CombiFlash purification system
yielded product 1ah as a light tan solid (64 mg, 28% yield). Rotamers
N-tert-Butyl-4′-((6-(5-methylbenzo[d]oxazol-2-yl)-4-oxo-2-pro-
pylquinazolin-3(4H)-yl)methyl)-[1,1′-biphenyl]-2-sulfonamide (1-
X15). Following general procedure A (except that the crude reaction
mixture was filtered through a bed of silica gel eluting with ethyl
acetate), X15 (154 mg, 0.25 mmol, 1.0 equiv), 5-methylbenzoxazole
(33 mg, 0.25 mmol, 1.0 equiv), Ni(COD)2 (6.88 mg, 0.025 mmol,
0.10 equiv), dppb (13 mg, 0.03 mmol, 0.12 equiv), K3PO4 (80.0 mg,
0.375 mmol, 1.5 equiv), and anhydrous tert-amyl alcohol (1.0 mL)
were combined in a 4 mL scintillation vial. The reaction mixture was
allowed to stir at 105 °C for 20 h. Chromatography on a silica gel
column using a gradient 100/0 to 70/30 hexanes/EtOAc (Rf = 0.36 in
70% hexanes/30% ethyl acetate) using the Isco flash purification
system yielded product 1-X15 as a white solid (31 mg, 20% yield). 1H
NMR (500 MHz, CDCl3): δ 9.14 (d, J = 2.0 Hz, 1H), 8.63 (dd, J =
8.6, 2.0 Hz, 1H), 8.16 (dd, J = 7.9, 1.2 Hz, 1H), 7.82 (d, J = 8.6 Hz,
1H), 7.58−7.46 (multiple peaks, 6H), 7.31−7.27 (multiple peaks,
3H), 7.19 (dd, J = 8.4, 1.3 Hz), 5.50 (s, 2H), 3.52 (s, 1H), 2.81 (t, J =
7.6 Hz, 2H), 2.50 (s, 3H), 1.91−1.87 (m, 2H), 1.06, (t, J = 7.4 Hz,
3H), 0.98 (s, 9 H). 13C{1H} NMR (126 MHz, CDCl3): δ 162.0,
161.9, 158.6, 149.2, 142.4, 142.0, 139.2, 139.1, 136.0, 134.7, 133.0,
132.3, 131.8, 130.5, 128.3, 128.0, 127.8, 126.7, 126.6, 126.1, 125.6,
120.6, 120.1, 110.1, 54.4, 46.4, 37.1, 29.8, 21.5, 20.6, 13.9, one carbon
resonance is coincidentally overlapping. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C36H37N4O4S 621.2535, found 621.2547.
1
observed in both H and 13C NMR. 1H (500 MHz, CDCl3); δ 8.32 (s,
1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.24 (dd, J =
8.3, 1.7 Hz, 1H), 4.28 (bs, 2H), 2.89 (bs, 2H), 2.87 (s, 3H), 2.71 (s,
2H), 2.53 (s, 3H), 2.12 (td, J = 13.2, 4.6 Hz, 2H), 1.57 (d, J = 13.8
Hz, 2H), 1.53 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3): δ 204.2,
162.3, 159.3, 154.7, 148.7, 142.1, 138.9, 136.9, 134.7, 132.6, 127.0,
126.4, 125.5, 120.4, 110.0, 79.9, 47.3, 41.7, 41.5, 37.7, 28.5, 22.4, 21.5.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H31N2O4 447.2284,
found 447.2282.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
Isopropyl 2-Methyl-2-(4-(4-(5-methylbenzo[d]oxazol-2-yl)-
benzoyl)phenoxy)propanoate (1af). Following general procedure E
(except using diglyme as the solvent), isopropyl 2-(4-(4-
chlorobenzoyl)phenoxy)-2-methylpropanoate (fenofibrate) (271 mg,
0.75 mmol, 1.5 equiv), 5-methylbenzo[d]oxazole (68 mg, 0.50 mmol,
1.0 equiv), Ni(COD)2 (14 mg, 0.05 mmol, 0.10 equiv), N-Xantphos
(33 mg, 0.06 mmol, 0.12 equiv), phosphazene base P2Et (255 mg,
0.75 mmol, 1.5 equiv), and anhydrous diglyme (2.0 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
allowed to stir at 130 °C for 20 h. Purification using the Teledyne Isco
CombiFlash purification system yielded product 1af as a white solid
ACS Publications website at DOI: 10.1021/acs.joc.9b02094.
Spectra for isolated products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: danielle.schultz@merck.com
*Tel: 507 786 3740. E-mail: kalyani@stolaf.edu, dipannita.
kalyani@merck.com.
1
(108 mg, 47% yield). H (500 MHz, CDCl3): δ 8.36 (d, J = 8.4 Hz,
ORCID
2H), 7.91 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 9.0 Hz, 2H), 7.63−7.59
(m, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.23 (dd, J = 8.3, 1.8 Hz, 1H), 6.91
(d, J = 8.9 Hz, 2H), 5.17−5.07 (m, 1H), 2.52 (s, 3H), 1.69 (s, 6H),
1.23 (d, J = 6.3 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 194.6,
173.1, 162.1, 159.9, 149.2, 142.2, 140.4, 134.8, 132.1, 130.2, 130.2,
130.2, 127.3, 126.9, 120.2, 117.3, 110.1, 79.5, 69.4, 25.4, 21.5 (one
Danielle Schultz: 0000-0002-4811-2218
Dipannita Kalyani: 0000-0003-4349-8016
Notes
The authors declare no competing financial interest.
J
DOI: 10.1021/acs.joc.9b02094
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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ACKNOWLEDGMENTS
■
This work was supported by the NSF (CHE-1554630),
Dreyfus Foundation, St. Olaf College, and Merck & Co., Inc.
The authors are grateful for the support from Rebecca T. Ruck
and Shane W. Krska for enabling this collaboration. The
authors acknowledge Spencer D. Dreher for scientific
discussions and for providing the informer kits for microscale
HTE shown in Figure 3. The authors are grateful to Qi Gao for
the structure conformation for 1-X12.
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L
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