Nickel-catalyzed C?H arylation of benzoxazoles and oxazoles: Benchmarking the influence of electronic, steric and leaving group variations in phenolic electrophiles

Article abstract of DOI:10.1016/j.tet.2017.02.021

Electronic, steric and leaving group effects for Ni-catalyzed direct arylations using C?O electrophiles were benchmarked. The scope of arylations with pivalates was general with respect to both the electronics on the electrophile and the azoles. Furthermore, the arylation of azoles with tosylates, mesylates and carbamates with varying electronics was explored, and showed electronic trends similar to those of the pivalate reactions. Finally, the relative rate of arylation of 5-methyl benzoxazole with two electronically-similar electrophiles bearing different leaving groups was established. The results from these studies implicate the following order of relative reactivity: mesylates>pivalates>carbamates.

Full text of DOI:10.1016/j.tet.2017.02.021

Accepted Manuscript
Nickel-catalyzed C−H arylation of benzoxazoles and oxazoles: Benchmarking the
influence of electronic, steric and leaving group variations in phenolic electrophiles
Deborah F. Steinberg, Morgan C. Turk, Dipannita Kalyani
PII:
S0040-4020(17)30146-1
10.1016/j.tet.2017.02.021
TET 28462
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 October 2016
Revised Date: 29 January 2017
Accepted Date: 8 February 2017
Please cite this article as: Steinberg DF, Turk MC, Kalyani D, Nickel-catalyzed C−H arylation of
benzoxazoles and oxazoles: Benchmarking the influence of electronic, steric and leaving group
variations in phenolic electrophiles, Tetrahedron (2017), doi: 10.1016/j.tet.2017.02.021.
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ACCEPTED MANUSCRIPT
Nickel-Catalyzed C−H Arylation of Benzoxazoles and Oxazoles:
Benchmarking the Influence of Electronic, Steric and Leaving Group
Variations in Phenolic Electrophiles
Deborah F. Steinberg, Morgan C. Turk, and Dipannita Kalyani*
Department of Chemistry, St. Olaf College, 1520 St. Olaf Avenue, Northfield, Minnesota 55057,
USA
e-mail: kalyani@stolaf.edu, Tel no. 1-011-507-786-3740
Graphical Abstract:
Key words: homogeneous catalysis, nickel, arylation, C−H activation, azoles, pivalates, sulfonates,
carbamates.
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Nickel-Catalyzed C−H Arylation of Benzoxazoles and Oxazoles:
Benchmarking the Influence of Electronic, Steric and Leaving Group
Variations in Phenolic Electrophiles
Deborah F. Steinberg, Morgan C. Turk, and Dipannita Kalyani*
Department of Chemistry, St. Olaf College, 1520 St. Olaf Avenue, Northfield, Minnesota 55057,
USA
1. Introduction
1.1 Significance. Transition metal-catalyzed direct arylation is an established method for the
construction of biaryl bonds.1 The vast majority of currently known direct arylations use aryl
halides as electrophiles.1-3 Recently, there has been an increasing interest to employ phenolic
electrophiles in place of aryl halides for several reasons.4-5 First, unlike aryl halides, the phenol
precursors to phenolic electrophiles can be obtained from natural sources. Second, the synthesis
of phenol derivatives often requires less harsh conditions than for aryl halides. Third, several
ortho-substituted phenol derivatives can be accessed via directed ortho-lithiation strategies.
Finally, phenolic electrophiles might exhibit complementary reactivity to aryl halides, thereby
enabling the selective functionalization of these electrophiles at different stages of complex
molecule synthesis.4-5 In light of these advantages several reports on transition metal catalyzed
direct arylation using C−O electrophiles have been published.4-5 Among these, nickel-catalyzed
direct arylations exhibit the broadest scope of electrophiles.6-8 For example, Pd-catalyzed
transformations are limited to the use of sulfonates and phosphates.9-11 In contrast, nickel-
catalyzed direct arylations are known with sulfonates, carboxylates, carbamates, sulfamates and
carbonates.6 This advantage of Ni-catalysis can be harnessed to its fullest potential for synthetic
applications once a comprehensive understanding of the relative reactivity and scope of the
various phenolic electrophiles is realized. To this end, this manuscript details the first systematic
investigation of the Ni-catalyzed arylation of oxazoles with electronically and sterically diverse
pivalates, tosylates, mesylates and carbamates. The following sections detail the state-of-the-art
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for Ni-catalyzed arylations using C−O electrophiles and present the important questions that this
manuscript seeks to address.
1.2 Background. The Itami group published the first report on Ni-catalyzed C−H
arylation of azoles using phenolic electrophiles in 2012.6a The reaction of benzoxazole with 2-
naphthyl sulfonate, pivalate, carbonate, sulfamate and carbamate affords the desired product in
excellent yields using the Ni(COD)2/dcype catalyst system (Scheme 1a). The reaction of
benzoxazole was explored with electronically varied phenyl triflates (Scheme 1b). While the
reaction with phenyl triflate leads to the phenylated product in good yield (75%), the yields with
electron-rich and electron-deficient triflates are significantly lower (55% and 52%). The use of
electronically varied, aryl pivalates, tosylates, mesylates, carbamates and carbonates is not
reported.
Scheme 1. Literature Precedent for Azole Arylation
The reaction of azoles with pivalates bearing extended π-systems affords the products in good
yields (Scheme 2a). Interestingly, however, the reaction with phenyl pivalate leads to the product
in only 11% yield (Scheme 2b). In 2015, one example for the coupling of benzoxazole with aryl
pivalate was reported in the context of sequential Suzuki coupling/decarbonylative C−H
arylation (Scheme 2c).6c The higher efficiency of C−H arylation using biphenyl pivalate (Scheme
2c) versus phenyl pivalate (Scheme 2b) may be due to the difference in the ligands employed for
these reactions (dcype vs dcypt).
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Scheme 2. Literature Precedent for Azole Arylation Using Pivalates
Recently, a more general example for the arylation of imidazoles with carbamates was
published.6b The reaction of N-methyl benzimidazole with electronically varied carbamates leads
to products in modest to good yields (Scheme 3a). Three examples for the arylation of oxazoles
were also reported with either phenyl carbamate or biphenyl carbamate to afford the products in
modest yields (Scheme 3b).
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Scheme 3. Literature Precedent for Azole Arylation Using Carbamates
As part of our program on Pd- and Ni-catalyzed reactions using C−O electrophiles,12 we
published the first report on the Ni-catalyzed intramolecular arylation of non-heteroaromatic
C−H bonds using pivalate electrophiles (Scheme 4).12b Our results are consistent with the reports
by the Itami group with respect to the electronic effect of the aryl electrophile (Scheme 1b vs.
Scheme 4). The reactions of electron-rich and electron-deficient pivalate-bearing substrates
afford the corresponding dibenzofuran products in lower yields than obtained with their
unsubstituted counterpart. Furthermore, these reactions are most effective using pivalates. The
use of carbamates, sulfonates and carbonates afford the product in lower yields.
Scheme 4. Literature Precedent for Intramolecular C−H Arylation
1.3 Challenges and goals. The results detailed in Schemes 1-4 above are significant
contributions to the field of Ni-catalyzed C−H arylations using C−O electrophiles. However,
these reports also provoke several important unanswered questions that are detailed below:
(1) The arylations presented in Schemes 1-2 are to date the only reported examples for Ni-
catalyzed coupling of azoles with aryl tosylates, mesylates, pivalates and carbonates. The use of
electronically and sterically varied aryl tosylates and mesylates remains elusive. Furthermore, the
scope of aryl pivalates for these arylations is limited primarily to the use of electrophiles bearing
extended π-systems (Scheme 2a). While Scheme 2 illustrates the two published examples for the
efficient use of aryl pivalates lacking extended π-systems (3-pyridyl and biphenyl pivalate), it is
ambiguous whether these reaction conditions can be extended to the use of other electronically
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varied aryl pivalates. Hence, a systematic investigation of Ni-catalyzed arylations with respect to
electronic and steric perturbations on the C−O electrophiles is necessary to delineate the scope of
these transformations.
(2) A systematic study exploring the electronic influence of the C−H substrate on the efficiency
of Ni-catalyzed azole arylations using various aryl electrophiles is hitherto unknown.
(3) A comparative study benchmarking the relative performance and scope of various C−O
electrophiles for Ni-catalyzed arylations is not reported. Such investigations are necessary to
understand the similarities and differences in the reaction parameters to accomplish arylations
using various phenolic electrophiles.
(4) Finally, the relative rates of Ni-catalyzed azole arylations using electrophiles bearing
different leaving groups remains unknown. The knowledge of relative rates is critical to
judiciously engage the various C−O electrophiles selectively at different stages in the synthesis
of complex molecules.
As part of our program on transition metal catalyzed arylations using C−O
electrophiles,12 this manuscript systematically addresses the aforementioned unanswered
questions. Importantly, the results described herein will inform future mechanistic and synthetic
investigations in the field of Ni-catalyzed C−H arylations.
2. Results and Discussion
2.1 Optimization of arylation using pivalates. Our studies commenced with the optimization of
Ni-catalyzed direct arylation of 5-methyl benzoxazole (1) with para-methoxyphenyl pivalate (A-
OPiv). As shown in Table 1, the original reaction parameters reported by the Itami group affords
product 1a, albeit in low yield (entry 1).6a The use of xylene instead of dioxane affords
comparable yields of 1a (entries 1 and 2). The most significant increase in reaction efficiency
was achieved using more equivalents of the pivalate electrophile leading to 1a in 83% yield
(entry 4). The use of K3PO4 (vs Cs2CO3, entries 4 and 5) or higher temperatures (entries 4 and 6)
afford 1a in similar yields. The use of Ni(OTf)2 as the catalyst also affords product 1a, albeit in
lower yield than that obtained using Ni(COD)2 (entries 6-7).6b Interestingly, the use of dcypt6,13
instead of dcype affords 1a in excellent yields even with 1.5 equiv of the pivalate (entries 6 and
8). No product is obtained in the absence of Ni(COD)2 or the ligand (entries 9-10). These
optimization results suggest that high yields of 1a can be obtained either using dcype (with 3.0
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equiv of pivalate, entry 6) or dcypt (with 1.5 equiv of pivalate, entry 8). Our further
investigations mainly focussed on the use of dcype conditions since this ligand is commercially
available. However, dcypt was used in instances where product yields were particularly low with
dcype.
Table 1. Optimization of Arylation Using Pivalates
[a]
General conditions: azole (1.0 equiv), pivalate (1.5 equiv), Ni(COD)2 (0.1 equiv), dcype (0.2 equiv),
base (1.5 equiv), p-xylene, 120 °C. [b] Calibrated GC yields against hexadecane as the internal standard.
[c]
3.0 equiv of pivalate used. [d] General conditions but with 3.0 equiv of pivalate using Ni(OTf)2 as the
catalyst. [e] General conditions but with 3.0 equiv of pivalate in the absence of Ni(COD)2.
2.2 Scope of pivalates for arylation of 5-methylbenzoxazole. The coupling of 5-methyl
benzoxazole (1) with electronically and sterically varied pivalates was explored. As depicted in
Scheme 5, electron-rich, electron-neutral, and electron-deficient pivalates participate in these
reactions to afford the products in good to excellent yields. However, small variations in reaction
conditions are needed for efficient reactions with electron-rich versus electron-deficient
pivalates. For example, relatively electron-neutral and electron-rich pivalates perform well under
the optimal conditions for the reaction of p-methoxyphenyl pivalate (Scheme 5, products 1a-1d).
However, electron-deficient pivalates afford the corresponding products 1f-1g in good yields
with 1.5 equivalents of the electrophile at 140 °C. Furthermore, dcypt is more effective than
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dcype for arylations using these electron-deficient electrophiles. Finally, ester-substituted aryl
pivalates lead to products (1h and 1i) in higher yields with K3PO4 than Cs2CO3. Interestingly,
sterically hindered ortho-methylphenyl pivalate affords product 1j in low yield.
Scheme 5. Scope of Pivalates for C–H Arylationa,b
[a]
General conditions: azole (1.0 equiv), pivalate (3.0 equiv), Ni(COD)2 (0.1 equiv), dcype (0.2 equiv), Cs2CO3
[b]
[c]
[d]
(1.5 equiv), p-xylene, 140 °C.
Isolated yields.
General conditions but with dcypt (0.2 equiv).
General
[e]
conditions but with dcypt (0.2 equiv), pivalate (1.5 equiv). General conditions but with pivalate (1.5 equiv) and
K3PO4 (1.5 equiv). [f] General conditions but with pivalate (1.5 equiv) and K3PO4 (2.0 equiv). [g] General conditions
but with dcypt (0.2 equiv), and K3PO4 (3.0 equiv).
2.3 Scope of azoles in reactions with pivalates. The reaction of pivalates with diverse azole
substrates was explored next (Scheme 6). These transformations are compatible with ethers,
fluorine, trifluoromethyl and benzylic alkyl groups. Benzoxazoles are generally more effective
than phenyl oxazoles (cf. 2c-6c vs. 8c-10c). Analogous to 5-methylbenzoxazole reactions, the
scope of phenyl oxazole arylation is also general with respect to the electronics on the pivalate
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electrophile (8c and 8f). Additionally, there is a noticeable electronic effect with respect to the
C−H substrate for these arylations. Electron-rich and electron-neutral substrates 8 and 9
participate in these reactions to afford the products (8c and 9c) in lower yields (57% and 63%)
than the electron-deficient oxazole 10 under identical reaction conditions (86% yield of 10c).14
Similarly product 4c is obtained in lower yield than 3c under the same conditions (68% versus
91% for 4c and 3c respectively). The lower yields of 8c, 9c and 4c compared to 10c and 3c,
could partly be due to the diminished acidity of the azole C−H bond undergoing
functionalization. The yield of 4c is enhanced (90% yield), however, using dcypt as the ligand.
Scheme 6. Scope of Azoles for Arylation Using Pivalatesa,b
[a] General conditions: azole (1.0 equiv), pivalate (3.0 equiv), Ni(COD)2 (0.1 equiv), dcype (0.2 equiv), Cs2CO3 (1.5
equiv), p-xylene, 140 °C. [b] Isolated yields. [c] General conditions with dcypt (0.2 equiv). [d] General conditions with
dcypt (0.2 equiv), and K3PO4 (3.0 equiv). [e] General conditions with dcypt (0.2 equiv), and pivalate (1.5 equiv). [f]
General conditions at 120 °C.
2.4 Arylation using sulfonates. We next explored reaction conditions for coupling of azoles with
tosylates and mesylates (Scheme 7). This is an advance over the previously published report,6a
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which primarily focused on the use of the more expensive and less bench-stable triflates (Scheme
1).
Scheme 7. Arylation of Oxazoles Using Sulfonatesa,b
[a]
General conditions: azole (1.0 equiv), sulfonate (1.5 equiv), Ni(COD)2 (0.1 equiv), dcype (0.2 equiv), Cs2CO3
[c]
[d]
(1.5 equiv), p-xylene, 120 °C. [b] Isolated yields. General conditions at 100 °C.
General conditions with dcypt
[e]
(0.2 equiv). General conditions at 140 °C. [f] General conditions with sulfonate (3.0 equiv) at 140 °C. [g] General
[h]
conditions with dcypt (0.2 equiv) at 140 °C. General conditions with dcypt (0.2 equiv), sulfonate (3.0 equiv) at
140 °C. [i] General conditions with dcypt (0.2 equiv), and K3PO4 (3.0 equiv) at 140 °C.
The couplings of 5-methyl benzoxazole with electronically varied tosylates results in lower
yields of products compared to reactions of the corresponding pivalates (Scheme 7a vs Scheme
5). Improved yields are obtained with the more atom-economical mesylates (Scheme 7b). Similar
to our observation with pivalates (Scheme 5), an ortho-substituted mesylate affords the product
(1j) in lower yields than para- and meta-substituted mesylates. Finally, the trends for couplings
using electronically varied azoles are comparable to those observed using pivalates (Scheme 7c).
2.5 Arylation using carbamates. The scope of the arylations with carbamates is shown in
Scheme 8. These reactions are more effective with K3PO4 instead of Cs2CO3.6b Under the
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optimal conditions the scope of these reactions are similar to that of pivalates and mesylates
described above.
Scheme 8. Arylation of Oxazoles Using Carbamatesa,b
[a] General conditions: azole (1.0 equiv), carbamate (1.5 equiv), Ni(COD)2 (0.1 equiv), dcypt (0.2 equiv), K3PO4 (3.0
equiv), p-xylene, 140 °C. [b] Isolated yields. [c] General conditions with carbamate (3.0 equiv). [d] Calibrated GC yield
against hexadecane as the internal standard.
2.6 Competition studies. As mentioned in the introduction, to date Ni-catalysis exhibits the
broadest scope of phenolic electrophiles (bearing different leaving groups) for direct arylations.6
This broad scope can be synthetically useful if one electrophile can be selectively engaged in
direct arylations in the presence of other electrophiles. To this end, we conducted systematic
competition studies to evaluate the relative reactivity of various electrophiles. The reaction of 5-
methyl benzoxazole with equimolar amounts of two electronically similar electrophiles with
different leaving groups was explored (Table 2). The relative amounts of products 1c and 1b
obtained from these competition reactions reflect the relative rates of the reaction of the two
electrophiles in the reaction vessel. For example, the reaction of equimolar amounts of PhOPiv
(1.5 equiv) and p-MeC6H4OCONEt2 (1.5 equiv) with 5-methylbenzoxazole (1.0 equiv) affords
1c and 1b in 71% and 16% yields respectively (entry 1). These results (see also entry 4) suggest
that the pivalate outcompetes the carbamate in these arylations, which is consistent with the
better leaving group ability of pivalates. Similarly, and as expected, the mesylate undergoes
arylation at a faster rate than the carbamate (entries 3 and 6). Interestingly, the vastly different
leaving group abilities of mesylate versus pivalate translate into a small difference in the relative
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rates for the direct arylation using these electrophiles (entries 2 and 5). These results imply the
following order for the relative rates of arylation: mesylate > pivalate > carbamate.
Table 2. Competition Studies
[a] Calibrated GC yield against hexadecane as the internal standard.
Importantly, the reactivity order in these studies is the same regardless of which electrophile has
phenyl or p-tolyl group (cf. entries 1-3 vs. 4-6). Overall, the results in entries 1-6 suggest that the
highest difference in relative rates exists between mesylates and carbamates. Furthermore, the
degree of selectivity between two leaving groups can be altered with different ligands. When
competition studies were done using dcype instead of dcypt (entries 7-9), the differences in
relative reaction rates decreased for all three combinations of leaving groups. The comparison
between the results in entries 1-3 vs. 7-9 exemplifies the potential for further ligand
optimizations to enhance the selectivity between electrophiles bearing different leaving groups.
As detailed above the highest difference in relative rates of arylation is exhibited in the
competition between the mesylate and the carbamate electrophiles (Table 2, entries 3, 6 and 9).
Consistent with this observation the reaction of 5-methyl benzoxazole with the electrophile
bearing both the mesylate and the carbamate groups affords the product (A) resulting from the
selective functionalization of the mesylate group (Scheme 9). Product B obtained via diarylation
of 1 is also observed. Importantly, however, product (C) resulting from the selective
functionalization of the carbamate is not observed.15 These results lend credence to the
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applicability of the competition studies detailed in Table 2 to the selective functionalization of
leaving groups at different stages in the context of multi-step syntheses.
Scheme 9. Intramolecular Competition Study
3. Conclusion
This manuscript details the first systematic elucidation of the electronic and steric influences of
diverse azoles and phenolic electrophiles in Ni-catalyzed direct arylations. The first general
report on the direct arylation of azoles with pivalates is described. The reaction of azoles with
aryl tosylates, mesylates, and carbamates are also presented. Four variables critical to the
optimization of these reactions are: base (Cs2CO3 or K3PO4), electrophile equivalents (1.5 or 3.0
equiv), ligands (dcype to dcypt), and temperature (100-140 °C). Establishing the general scope of
these Ni-catalyzed arylations set the stage for investigating the relative rates of arylations with
electrophiles bearing different leaving groups. Competition studies reveal the following order for
relative rates of arylation: mesylates > pivalates > carbamates. Furthermore, these studies
demonstrate the important role of ligand optimization in further enhancing the selectivity
between electrophiles. Detailed mechanistic investigations to elucidate the differences in optimal
reaction parameters for various combinations of azoles/electrophiles are underway and will be
reported in due course. Such studies are pivotal to further broadening the scope and selectivity
for these Ni-catalyzed arylations.
4. Experimental
4.1 General
1
NMR spectra were obtained on a Bruker 400 (399.96 MHz for H; 100.57 MHz for 13C)
1
spectrometer. H NMR chemical shifts are reported in parts per million (ppm) relative to TMS,
with the residual solvent peak used as an internal reference. Multiplicities are reported as
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follows: singlet (s), doublet (d), doublet of doublets (dd), triplet of doublets (td), triplet (t),
quartet (q), doublet of triplets (dt), triplet of triplets (tt), multiplet (m), and broad resonance (br).
IR spectra were obtained on a Thermo scientific Nicolet iS5 iD5 ATR spectrometer. Melting
points were obtained on a Thomas Hoover melting point apparatus.
4.2 Materials
1,2-Bis(dicyclohexylphosphino)ethane (dcype) and 5-methylbenzoxazole were obtained from
Aldrich and used as received. Benzoxazole was obtained from TCI America and used as
received. Ni(COD)2 and Ni(OTf)2 were obtained from Strem chemical and used as received.
Cesium carbonate, TosMic (Tosylmethylisocyanide) and K3PO4 were obtained from Acros and
used as received. Benzoxazole substrates (4, 5 and 6) were prepared using literature procedures.
Phenyl oxazole substrates 8-10 were prepared using literature procedures.17 The pivalates,
16
tosylates, mesylates and carbamates were prepared using literature procedures.18 2-Fluoro-4-
methoxy benzaldehyde, and 2-fluoro-5-methyl benzaldehyde were obtained from Matrix
Scientific and used as received. 2-Fluoro-5-(trifluoromethyl) benzaldehyde was obtained from
Alfa Aesar and used as received. K2CO3 was obtained from JT Baker and used as received. 3,4-
Bis-(dicyclohexylphosphino)thiophene (dcypt) was prepared using a literature procedure.19
Anhydrous p-xylene and 1,4-dioxane 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) and thin layer chromatography was performed on Analtech
TLC plates pre-coated with silica gel 60 F254.
4.3 Synthesis and Characterization of Substrates
4.3.1. 5-(2-fluoro-4-methoxyphenyl)-1,3-oxazole (11).
To an oven dried 20 mL scintillation vial under ambient atmosphere, was added 2-fluoro-4-
methoxy benzaldehyde (617 mg, 4.00 mmol, 1.0 equiv), TosMic (929 mg, 4.76 mmol, 1.2
equiv), K2CO3 (1.82 g, 13.2 mmol, 3.3 equiv) and MeOH (8.5 mL). The vial was sealed with a
Teflon lined cap and stirred at 70 °C for 2 h. Two of these same reactions were set up and
combined for purification. At the end of the reaction the reaction vials were cooled to room
temperature and the reaction mixture was filtered to remove the solid residues. The filtrate was
concentrated and chromatographed on a silica gel column using 80/20 hexanes/EtOAc (Rf = 0.30
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in 80% hexanes/20% ethyl acetate) yielded product 11 as a light yellow solid (1.27 g, 82%
yield). mp = 63-64 °C. IR (neat): 1628, 1574, 1509, 1486, 1465, 1332, 1308, 1268, 1245, 1192,
1160, 1098, 1040, 1019, 951, 915, 834, 640, 629, 569 cm-1. 1H NMR (CDCl3): δ 7.90 (s, 1H),
7.66 (t, J = 8.6 Hz, 1H), 7.37 (d, J = 3.8 Hz, 1H), 6.79 (dd, J = 8.4, 2.5 Hz, 1H), 6.72 (dd, J =
13
12.6, 2.5 Hz, 1H), 3.84 (s, 3H). C NMR (CDCl3): δ 160.8 (d, J = 10.7 Hz), 159.6 (d, J = 251
Hz), 149.5, 146.0 (d, J = 3.0 Hz), 126.8 (d, J = 5.0 Hz), 123.7 (d, J = 11.6 Hz), 110.5 (d, J = 2.9
Hz), 108.9 (d, J = 13.7 Hz), 102.0 (d, J = 24.3 Hz), 55.6. HRMS Calcd for C10H8FNO2
193.0539; Found: 193.0538.
4.3.2. 5-(2-fluoro-5-methylphenyl)-1,3-oxazole (12).
To an oven dried 20 mL scintillation vial under ambient atmosphere, was added 2-fluoro-5-
methyl benzaldehyde (552 mg, 4.00 mmol, 1.0 equiv), TosMic (929 mg, 4.76 mmol, 1.2 equiv),
K2CO3 (1.82 g, 13.2 mmol, 3.3 equiv) and MeOH (8.5 mL). The vial was sealed with a Teflon
lined cap and stirred at 70 °C for 2 h. Two of these same reactions were set up and combined for
purification. At the end of the reaction the reaction vials were cooled to room temperature and
the reaction mixture was filtered to remove the solid residues. The filtrate was concentrated and
chromatographed on a silica gel column using 80/20 hexanes/EtOAc (Rf = 0.46 in 80%
hexanes/20% ethyl acetate) yielded product 12 as a light yellow solid (1.42 g, 100% yield). mp =
73-74 °C. IR (neat): 1500, 1215, 1112, 1093, 1044, 954, 814, 757, 642 cm-1. 1H NMR (CDCl3): δ
7.94 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 3.9 Hz, 1H), 7.12-7.02 (multiple peaks, 2H),
2.38 (s, 3H). 13C NMR (CDCl3): δ 157.0 (d, J = 247 Hz), 150.0, 146.0 (d, J = 3.0 Hz), 133.9 (d, J
= 3.6 Hz), 130.1 (d, J = 8.0 Hz), 126.3 (d, J = 2.9 Hz), 125.5 (d, J = 12.4 Hz), 115.55 (d, J = 20.5
Hz), 115.58 (d, J = 14.5 Hz), 20.6. HRMS Calcd for C10H8FNO 177.0590; Found: 177.0587.
4.3.3. 5-[2-fluoro-5-(trifluoromethyl)phenyl]-1,3-oxazole (13).
To an oven dried 20 mL scintillation vial under ambient atmosphere, was added 2-fluoro-5-
trifluoromethyl benzaldehyde (768 mg, 4.00 mmol, 1.0 equiv), TosMic (929 mg, 4.76 mmol, 1.2
equiv), K2CO3 (1.82 g, 13.2 mmol, 3.3 equiv) and MeOH (8.5 mL). The vial was sealed with a
Teflon lined cap and stirred at 70 °C for 2 h. Two of these same reactions were set up and
combined for purification. At the end of the reaction the reaction vials were cooled to room
temperature and the reaction mixture was filtered to remove the solid residues. The filtrate was
concentrated and chromatographed on a silica gel column using the Biotage flash purification
system (Rf = 0.50 in 90% hexanes/10% ethyl acetate) yielded product 13 as a pale yellow solid
(778 mg, 42% yield). mp = 43-44 °C. IR (neat): 1509, 1342, 1319, 1265, 1233, 1165, 1141,
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1072, 1041, 949, 899, 891, 847, 826, 682, 640, 619, 585 cm-1. 1H NMR (CDCl3): δ 8.07 (dd, J =
6.5, 2.2 Hz, 1H), 8.00 (s, 1H), 7.62-7.58 (m, 1H), 7.59 (d, J = 4.1 Hz, 1H), 7.30 (t, J = 9.5 Hz,
1H). 13C NMR (CDCl3): δ 160.2 (d, J = 256 Hz), 150.7, 144.5 (d, J = 3.3 Hz), 127.5 (qd, J = 33,
3.6 Hz), 126.9 (d, J = 13.0 Hz), 126.7 (dq, J = 9.5, 3.6 Hz), 123.7 (m), 123.4 (q, J = 270 Hz),
117.0 (d, J = 14.5 Hz), 116.7 (d, J = 22.4 Hz). HRMS Calcd for C10H5F4NO 231.0307; Found:
231.0312.
4.3.4. (3-methanesulfonylphenyl) N,N-diethyl carbamate (electrophile in Scheme 9).
To an oven dried 100 mL Schlenk flask was added NaH (70.1 mg, 2.92 mmol, 1.1 equiv) and
anhydrous THF (2.3 mL) in the glove box. The flask was secured with a septum, taken out of the
glove box and cooled to 0 C. A solution of (3-hydroxyphenyl)methanesulfonate (500 mg, 2.66
mmol, 1.0 equiv) in THF (2.3 mL) was added dropwise to the NaH solution at 0 °C. The
resulting mixture was stirred for 1 h at 0 °C. To the resulting mixture was added N,N-
diethylcarbamoyl chloride dropwise at 0 °C. The reaction mixture was allowed to warm to room
temperature and was stirred at room temperature overnight. The solution was then cooled to 0 °C
and quenched with water. The solution was transferred to a separatory funnel, diluted with
EtOAc (20 mL) and washed with NaCl (20 mL). The aqueous and organic layers were separated
and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were
washed with brine (20 mL), dried over MgSO4 and concentrated under vacuum. The crude
product was purified using chromatography on silica gel (Rf = 0.30 in 70% hexanes/30% ethyl
acetate) to yield product as a light yellow, viscous oil (492 mg, 64% yield). IR (neat): 2976,
1714, 1472, 1417, 1364, 1265, 1239, 1219, 1181, 1152, 1114, 1078, 965, 924, 878, 818, 778,
752, 709, 683 cm-1. 1H NMR (CDCl3): δ 7.42-7.37 (m, 1H), 7.15-7.12 (multiple peaks, 3H),
3.46-3.36 (multiplet, 4H), 3.15 (s, 3H), 1.27-1.19 (multiplet, 6H). 13C NMR (CDCl3): δ 153.4,
152.3, 149.3, 130.0, 120.8, 118.5, 116.0, 42.3, 41.9, 37.3, 14.2, 13.3.
4.4 C–H Arylation of Aryl Pivalates
General Procedure (A) for C–H Arylations for solid electrophiles:
Ni(COD)2, ligand (dcype or dcypt), base (Cs2CO3 or K3PO4), aryl electrophile (pivalates,
mesylates or carbamates) and azole were weighed into in an oven dried 20 mL scintillation vial
in the glove box. Xylene was added, the vial was sealed with a Teflon lined cap, taken out of the
glove box and the reaction mixture was allowed to stir at the indicated temperature for the
indicated time. The reaction mixture was cooled to room temperature and filtered through a 1.0
16

ACCEPTED MANUSCRIPT
inch plug of silica gel, eluting with Et2O (125 mL). The filtrate was concentrated and
chromatographed on a silica gel column to afford the product.
General Procedure (B) for C–H Arylations for solid electrophiles:
Tosylate was weighed into an oven dried 20 mL scintillation vial. The vial was taken into the
glove box and Ni(COD)2, ligand (dcype or dcypt), base (Cs2CO3 or K3PO4), and azole were
added to it. Xylene was added, the vial was sealed with a Teflon lined cap, taken out of the glove
box and the reaction mixture was allowed to stir at the indicated temperature for the indicated
time. The reaction mixture was cooled to room temperature and filtered through a 1.0 inch plug
of silica gel, eluting with Et2O (125 mL). The filtrate was concentrated and chromatographed on
a silica gel column to afford the product.
General Procedure (C) for C–H Arylations for liquid electrophiles:
Ni(COD)2, ligand (dcype or dcypt), base (Cs2CO3 or K3PO4), and azole were weighed into in an
oven dried 20 mL scintillation vial in the glove box. A xylene solution of the aryl electrophile
(pivalates, mesylates or carbamates) was added to the reaction mixture. The reaction vial was
sealed with a Teflon lined cap, taken out of the glove box and the reaction mixture was allowed
to stir at the indicated temperature for the indicated time. The reaction mixture was cooled to
room temperature and filtered through a 1.0 inch plug of silica gel, eluting with Et2O (125 mL).
The filtrate was concentrated and chromatographed on a silica gel column to afford the product.
General Procedure (D) for C–H Arylations for liquid electrophiles and liquid azoles:
Ni(COD)2, ligand (dcype or dcypt), and base (Cs2CO3 or K3PO4) were weighed into in an oven
dried 20 mL scintillation vial in the glove box. A xylene (1.0 mL) solution of the pivalate and a
xylene (1.0 mL) solution of the azole was added to the reaction mixture. The reaction vial was
sealed with a Teflon lined cap, taken out of the glove box and the reaction mixture was allowed
to stir at the indicated temperature for the indicated time. The reaction mixture was cooled to
room temperature and filtered through a 1.0 inch plug of silica gel, eluting with Et2O (125 mL).
The filtrate was concentrated and chromatographed on a silica gel column to afford the product.
4.4.1 Procedures and spectral characterization of arylation products using pivalates
(Scheme 5)
4.4.1.1. 2-(4-methoxyphenyl)-5-methyl-1,3-benzoxazole (1a).
17

ACCEPTED MANUSCRIPT
Following general procedure C, 4-methoxy phenyl pivalate (312 mg, 1.50 mmol, 3.0 equiv), 5-
methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column using 90/10
hexanes/EtOAc (Rf = 0.30 in 90% hexanes/10% ethyl acetate) yielded product 1a as a white
solid (106 mg, 89% yield). mp = 109-110 °C. The spectroscopic data is identical to that
previously reported in the literature.12c
4.4.1.2. 2-(4-methylphenyl)-5-methyl-1,3-benzoxazole (1b).
Following general procedure A, 4-methyl phenyl pivalate (288 mg, 1.50 mmol, 3.0 equiv), 5-
methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column using 95/5
hexanes/EtOAc (Rf = 0.30 in 95% hexanes/5% ethyl acetate) yielded product 1b as a white solid
(105 mg, 94% yield). mp = 135-136 °C. The spectroscopic data is identical to that previously
reported in the literature.10c
4.4.1.3. 2-phenyl-5-methyl-1,3-benzoxazole (1c).
Following general procedure C, phenyl pivalate (134 mg, 0.75 mmol, 3.0 equiv), 5-
methylbenzoxazole (33.3 mg, 0.250 mmol, 1.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10
equiv), dcype (21.1 mg, 0.05 mmol, 0.20 equiv), Cs2CO3 (122 mg, 0.375 mmol, 1.5 equiv), and
anhydrous xylene (1.0 mL) were combined in a 4 mL scintillation vial. The reaction mixture was
allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column using 95/5
hexanes/EtOAc (Rf = 0.39 in 95% hexanes/5% ethyl acetate) yielded product 1c as a white solid
(49.0 mg, 94% yield). mp = 104-106 °C. The spectroscopic data is identical to that previously
reported in the literature.20
4.4.1.4. 2-(3-methoxyphenyl)-5-methyl-1,3-benzoxazole (1d).
Following general procedure C, meta-methoxy phenyl pivalate (312 mg, 1.50 mmol, 3.0 equiv),
5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column using 90/10
18

ACCEPTED MANUSCRIPT
hexanes/EtOAc (Rf = 0.34 in 90% hexanes/10% ethyl acetate) yielded product 1d as a white
solid (106 mg, 89% yield). mp = 107-110 °C. The spectroscopic data is identical to that
previously reported in the literature.10c
4.4.1.5. 2-(4-fluorophenyl)-5-methyl-1,3-benzoxazole (1e).
Following general procedure C, para-fluoro phenyl pivalate (294 mg, 1.50 mmol, 3.0 equiv), 5-
methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 24 h. Chromatography on a silica gel column using 95/5
hexanes/EtOAc (Rf = 0.4 in 95% hexanes/5% ethyl acetate) yielded product 1e as a white solid
(106 mg, 93% yield). mp = 132-134 °C. The spectroscopic data is identical to that previously
reported in the literature.21
4.4.1.6. 2-[3-(trifluoromethyl)phenyl]-5-methyl-1,3-benzoxazole (1f).
Following general procedure C, meta-trifluoromethyl phenyl pivalate (185 mg, 0.750 mmol, 1.5
equiv), 5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol,
0.10 equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv),
and anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column using
95/5 hexanes/EtOAc (Rf = 0.42 in 95% hexanes/5% ethyl acetate) yielded product 1f as a white
solid (118 mg, 85% yield). mp = 115-117 °C. The spectroscopic data is identical to that
previously reported in the literature.22
4.4.1.7. 2-[4-(trifluoromethyl)phenyl]-5-methyl-1,3-benzoxazole (1g).
Following general procedure A, para-trifluoromethyl phenyl pivalate (185 mg, 0.750 mmol, 1.5
equiv), 5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol,
0.10 equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv),
and anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column using
95/5 hexanes/EtOAc (Rf = 0.41 in 95% hexanes/5% ethyl acetate) yielded product 1g as a white
solid (70.4 mg, 51% yield). mp = 127-130 °C. The spectroscopic data is identical to that
previously reported in the literature.23
4.4.1.8. ethyl 3-(5-methyl-1,3-benzoxazol-2-yl)benzoate (1h)
.
19

ACCEPTED MANUSCRIPT
Following general procedure C, 3-(2,2-dimethyl-1-oxopropoxy)-ethyl ester benzoic acid (188
mg, 0.750 mmol, 1.5 equiv), 5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2
(13.8 mg, 0.05 mmol, 0.10 equiv), dcype (42.3 mg, 0.01 mmol, 0.20 equiv), K3PO4 (159 mg,
0.750 mmol, 1.5 equiv), and anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel
column using 90/10 hexanes/EtOAc (Rf = 0.40 in 90% hexanes/10% ethyl acetate) yielded
product 1h as a white solid (106 mg, 76% yield). mp = 97-98 °C. 1H NMR (CDCl3): δ 8.89 (t, J
= 1.7 Hz, 1H), 8.43 (dt, J = 7.8, 1.5 Hz, 1H), 8.21 (dt, J = 7.8, 1.5 Hz, 1H), 7.61 (t, J = 7.8 Hz,
1H), 7.58 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H),
2.50 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3): δ 165.7, 162.1, 149.0, 142.1, 134.5,
132.1, 131.45, 131.37, 129.0, 128.4, 127.7, 126.5, 120.0, 110.0, 61.3, 21.5, 14.3. IR (neat): 1716,
1455, 1423, 1311, 1285, 1247, 1195, 1123, 1109, 1056, 1021, 948, 921, 889, 823, 804, 765, 756,
710, 677, 614, 597 cm-1. HRMS Calcd for C17H15NO3 281.1052; Found: 281.1061.
4.4.1.9. ethyl 4-(5-methyl-1,3-benzoxazol-2-yl)benzoate (1i).
Following general procedure A, 4-(2,2-dimethyl-1-oxopropoxy)-ethyl ester benzoic acid (188
mg, 0.750 mmol, 1.5 equiv), 5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2
(13.8 mg, 0.05 mmol, 0.10 equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), K3PO4 (212 mg,
1.00 mmol, 2.0 equiv), and anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation
vial. The reaction mixture was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel
column using 90/10 hexanes/EtOAc (Rf = 0.40 in 90% hexanes/10% ethyl acetate) yielded
1
product 1i as a white solid (101 mg, 72% yield). mp = 153-154 °C. H NMR (CDCl3): δ 8.31 (d,
J = 8.3 Hz, 2H), 8.19 (d, J = 8.3 Hz, 2H), 7.58 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.4
13
Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). C NMR (CDCl3): δ
165.8, 161.9, 149.0, 142.1, 134.6, 132.6, 131.0, 129.9, 127.2, 126.8, 120.1, 110.0, 61.2, 21.4,
14.2. IR (neat): 1715, 1407, 1267, 1250, 1101, 1055, 1012, 804, 777, 714 cm-1. HRMS Calcd for
C17H15NO3 281.1052; Found: 281.1058.
4.4.1.10. 2-(2-methylphenyl)-5-methyl-1,3-benzoxazole (1j).
Following general procedure C, ortho-methyl phenyl pivalate (288 mg, 1.50 mmol, 3.0 equiv),
5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcypt (47.7 mg, 0.1 mmol, 0.20 equiv), K3PO4 (318 mg, 1.50 mmol, 3.0 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 24 h. Chromatography on a silica gel column using 50/50
20

ACCEPTED MANUSCRIPT
CH2Cl2/hexanes (Rf = 0.30 in 50% CH2Cl2/50% hexanes) yielded product 1j as a white solid
(48.3 mg, 44% yield). mp = 75-77 °C. The spectroscopic data is identical to that previously
reported in the literature.
4.4.2 Procedures and Spectral Characterization of Arylation products using pivalates
(Scheme 6)
4.4.2.1. 2-phenyl-1,3-benzoxazole (2c).
Following general procedure D, phenyl pivalate (267 mg, 1.50 mmol, 3.0 equiv), benzoxazole
(59.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10 equiv), dcype (42.3 mg,
0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and anhydrous xylene (2.0
mL) were combined in a 20 mL scintillation vial. The reaction mixture was allowed to stir at 140
°C for 22 h. Chromatography on a silica gel column using 95/5 hexanes/EtOAc (Rf = 0.25 in
95% hexanes/5% ethyl acetate) yielded product 2c as a white solid (88.6 mg, 91% yield). mp =
101-103 °C. The spectroscopic data is identical to that previously reported in the literature.10c
4.4.2.2. 2-phenyl-5-methoxy-1,3-benzoxazole (3c).
Following general procedure C, phenyl pivalate (134 mg, 0.75 mmol, 3.0 equiv), 5-
methoxybenzoxazole (37.3 mg, 0.250 mmol, 1.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10
equiv), dcype (21.1 mg, 0.05 mmol, 0.20 equiv), Cs2CO3 (122 mg, 0.375 mmol, 1.5 equiv), and
anhydrous xylene (1.0 mL) were combined in a 4 mL scintillation vial. The reaction mixture was
allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column using 90/10
hexanes/EtOAc (Rf = 0.42 in 90% hexanes/10% ethyl acetate) yielded product 3c as a white solid
(51.4 mg, 91% yield). mp = 75-78 °C. The spectroscopic data is identical to that previously
reported in the literature.24
4.4.2.3. 2-phenyl-6-methoxy-1,3-benzoxazole (4c).
Using dcype: Following general procedure C, phenyl pivalate (134 mg, 0.75 mmol, 3.0 equiv),
6-methoxybenzoxazole (37.3 mg, 0.250 mmol, 1.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol,
0.10 equiv), dcype (21.1 mg, 0.05 mmol, 0.20 equiv), Cs2CO3 (122 mg, 0.375 mmol, 1.5 equiv),
and anhydrous xylene (1.0 mL) were combined in a 4 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 18 h. Chromatography on a silica gel column using 90/10
hexanes/EtOAc (Rf = 0.34 in 90% hexanes/10% ethyl acetate) yielded product 4c as a white solid
(38.2 mg, 68% yield).
Using dcypt: Following general procedure C, phenyl pivalate (267 mg, 1.50 mmol, 3.0 equiv), 6-
methoxybenzoxazole (74.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
21

ACCEPTED MANUSCRIPT
equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 18 h. Chromatography on a silica gel column using 90/10
hexanes/EtOAc (Rf = 0.34 in 90% hexanes/10% ethyl acetate) yielded product 4c as a white solid
(115 mg, 90% yield). mp = 64-67 °C. The spectroscopic data is identical to that previously
reported in the literature.25
4.4.2.4. 2-phenyl-6-methyl-1,3-benzoxazole (5c).
Following general procedure C, phenyl pivalate (267 mg, 1.50 mmol, 3.0 equiv), 6-
methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 20 h. Chromatography on a silica gel column using 95/5
hexanes/EtOAc (Rf = 0.39 in 95% hexanes/5% ethyl acetate) yielded product 5c as a white solid
(98.7 mg, 94% yield). mp = 92-94 °C. The spectroscopic data is identical to that previously
reported in the literature.21
4.4.2.5. 2-phenyl-4-methyl-1,3-benzoxazole (6c).
Following general procedure D, phenyl pivalate (267 mg, 1.50 mmol, 3.0 equiv), 4-
methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 18 h. Chromatography on a silica gel column using 95/5
hexanes/EtOAc (Rf = 0.40 in 95% hexanes/5% ethyl acetate) yielded product 6c as a white solid
(95.2 mg, 91% yield). mp = 91-93 °C. The spectroscopic data is identical to that previously
reported in the literature.26
4.4.2.6. 2-phenyl-1,3-benzothiazole (7c).
Following general procedure C, phenyl pivalate (267 mg, 1.50 mmol, 3.0 equiv), benzothiazole
(67.9 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10 equiv), dcypt (47.7 mg,
0.10 mmol, 0.20 equiv), K3PO4 (318 mg, 1.50 mmol, 3.0 equiv), and anhydrous xylene (2.0 mL)
were combined in a 20 mL scintillation vial. The reaction mixture was allowed to stir at 140 °C
for 19 h. Chromatography on a silica gel column using 95/5 hexanes/EtOAc (Rf = 0.30 in 95%
hexanes/5% ethyl acetate) yielded product 7c as a white solid (64.4 mg, 61% yield). mp = 112-
114 °C. The spectroscopic data is identical to that previously reported in the literature.21
22

ACCEPTED MANUSCRIPT
4.4.2.7. 2,5-diphenyl-1,3-oxazole (8c).
Following general procedure C, phenyl pivalate (214 mg, 1.20 mmol, 3.0 equiv), phenyl oxazole
(58.1 mg, 0.400 mmol, 1.0 equiv), Ni(COD)2 (11.0 mg, 0.04 mmol, 0.10 equiv), dcype (33.8 mg,
0.08 mmol, 0.20 equiv), Cs2CO3 (195 mg, 0.6 mmol, 1.5 equiv), and anhydrous xylene (1.6 mL)
were combined in a 20 mL scintillation vial. The reaction mixture was allowed to stir at 140 °C
for 21 h. Chromatography on a silica gel column using 95/5 hexanes/EtOAc (Rf = 0.30 in 95%
hexanes/5% ethyl acetate) yielded product 8c as a white solid (50.2 mg, 57% yield). mp = 72-74
°C. The spectroscopic data is identical to that previously reported in the literature.27
4.4.2.8. 5-(4-methoxyphenyl)-2-phenyl-1,3-oxazole (9c).
Following general procedure C, phenyl pivalate (134 mg, 0.75 mmol, 3.0 equiv), 5-(4-
methoxyphenyl)-1,3-oxazole (43.8 mg, 0.250 mmol, 1.0 equiv), Ni(COD)2 (6.90 mg, 0.025
mmol, 0.10 equiv), dcype (21.1 mg, 0.05 mmol, 0.20 equiv), Cs2CO3 (122 mg, 0.375 mmol, 1.5
equiv), and anhydrous xylene (1.0 mL) were combined in a 4 mL scintillation vial. The reaction
mixture was allowed to stir at 140 °C for 21 h. Chromatography on a silica gel column using
95/5 hexanes/EtOAc (Rf = 0.29 in 95% hexanes/5% ethyl acetate) yielded product 9c as a white
solid (39.4 mg, 63% yield). mp = 80-82 °C. The spectroscopic data is identical to that previously
reported in the literature.28
4.4.2.9. 5-[4-(trifluoromethyl)phenyl]-2-phenyl-1,3-oxazole (10c).
Following general procedure C, phenyl pivalate (134 mg, 0.75 mmol, 3.0 equiv), 5-[4-
(trifluoromethyl)phenyl]-1,3-oxazole (53.3 mg, 0.250 mmol, 1.0 equiv), Ni(COD)2 (6.90 mg,
0.025 mmol, 0.10 equiv), dcype (21.1 mg, 0.05 mmol, 0.20 equiv), Cs2CO3 (122 mg, 0.375
mmol, 1.5 equiv), and anhydrous xylene (1.0 mL) were combined in a 4 mL scintillation vial.
The reaction mixture was allowed to stir at 140 °C for 21 h. Chromatography on a silica gel
column using 95/5 hexanes/EtOAc (Rf = 0.32 in 95% hexanes/5% ethyl acetate) yielded product
10c as a white solid (61.9 mg, 86% yield). mp = 106-108 °C. The spectroscopic data is identical
to that previously reported in the literature.29
4.4.2.10. 5-phenyl-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole (8f).
Following general procedure C, meta-trifluoromethylphenyl pivalate (185 mg, 0.75 mmol, 1.5
equiv), phenyloxazole (72.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column using 90/10
23

ACCEPTED MANUSCRIPT
hexanes/EtOAc (Rf = 0.36 in 90% hexanes/10% ethyl acetate) yielded product 8f as a white solid
(68.0 mg, 47% yield). mp = 127-129 °C. The spectroscopic data is identical to that previously
reported in the literature.30
4.4.2.11. 5-phenyl-2-[2-methylphenyl]-1,3-oxazole (8j).
Following general procedure C, ortho-methylphenyl pivalate (230 mg, 1.20 mmol, 3.0 equiv),
phenyloxazole (58.1 mg, 0.400 mmol, 1.0 equiv), Ni(COD)2 (11.0 mg, 0.04 mmol, 0.10 equiv),
dcype (33.8 mg, 0.08 mmol, 0.20 equiv), Cs2CO3 (195 mg, 0.600 mmol, 1.5 equiv), and
anhydrous xylene (1.6 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 120 °C for 22 h. Chromatography on a silica gel column using 95/5
hexanes/EtOAc (Rf = 0.30 in 95% hexanes/5% ethyl acetate) yielded product 8j as a white solid
(54.0 mg, 57% yield). mp = 87-89 °C. The spectroscopic data is identical to that previously
reported in the literature.10b
4.4.2.12. 5-(2-fluoro-4-methoxyphenyl)-2-phenyl-1,3-oxazole (11c).
Following general procedure C, phenyl pivalate (267 mg, 1.5 mmol, 3.0 equiv), 5-(2-fluoro-4-
methoxyphenyl)-oxazole (96.7 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol,
0.10 equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.75 mmol, 1.5 equiv),
and anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was allowed to stir at 140 °C for 20 h. Chromatography on a silica gel column using
90/10 hexanes/EtOAc (Rf = 0.27 in 90% hexanes/10% ethyl acetate) yielded product 11c as a
white solid (105 mg, 78% yield). mp = 93-95 °C. 1H NMR (CDCl3): δ 8.11 (dd, J = 8.0, 1.8 Hz,
2H), 7.77 (t, J = 8.6 Hz, 1H), 7.50-7.45 (multiple peaks, 4H), 6.82 (dd, J = 8.8, 2.6 Hz, 1H), 6.75
(dd, J = 12, 2.5 Hz, 1H), 3.86 (s, 3H). 13C NMR (CDCl3): δ 159.7 (d, J = 249 Hz), 160.7 (d, J =
10.9 Hz), 160.2, 145.8 (d, J = 3.5 Hz), 130.3, 128.8, 127.3, 126.6, 126.2, 125.7 (d, J = 11.7 Hz),
110.5 (d, J = 2.9 Hz), 109.2 (d, J = 13.4 Hz), 102.1 (d, J = 24.6 Hz), 55.7. IR (neat): 1628, 1499,
1480, 1464, 1443, 1325, 1308, 1286, 1269, 1192, 1116, 1021, 961, 955, 837, 814, 779, 706, 688,
633, 618, 579 cm-1. HRMS Calcd for C16H12FNO2 269.0852; Found: 269.0842.
4.4.2.13. 5-(2-fluoro-5-methylphenyl)-2-phenyl-1,3-oxazole (12c).
Following general procedure C, phenyl pivalate (267 mg, 1.5 mmol, 3.0 equiv), 5-(2-fluoro-5-
methylphenyl)-oxazole (88.8 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.75 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
24

ACCEPTED MANUSCRIPT
was allowed to stir at 140 °C for 20 h. Chromatography on a silica gel column using 95/5
hexanes/EtOAc (Rf = 0.30 in 95% hexanes/5% ethyl acetate) yielded product 12c as a white solid
1
(96.2 mg, 76% yield). mp = 86-87 °C. H NMR (CDCl3): δ 8.15-8.13 (multiple peaks, 2H), 7.65
(d, J = 7.0 Hz, 1H), 7.57 (d, J = 3.9 Hz, 1H), 7.53-7.47 (multiple peaks, 3H), 7.12-7.04 (multiple
peaks, 2H), 2.42 (s, 3H). 13C NMR (CDCl3): δ 160.7, 157.1 (d, J = 247 Hz), 145.7 (d, J = 3.6
Hz), 133.9 (d, J = 3.6 Hz), 130.4, 129.8 (d, J = 8.0 Hz), 128.7, 127.6 (d, J = 12.8 Hz), 127.2,
126.3, 126.0 (d, J = 2.9 Hz), 115.9 (d, J = 13.1 Hz), 115.6 (d, J = 20.9 Hz), 20.7. IR (neat): 1504,
1478, 1448, 1382, 1238, 1216, 1135, 1070, 1054, 967, 881, 861, 831, 814, 778, 757, 706, 691,
670, 659, 555 cm-1. HRMS Calcd for C16H12FNO 253.0903; Found: 253.0897.
4.4.2.14. 5-[2-fluoro-5-(trifluoromethyl)phenyl]-2-phenyl-1,3-oxazole (13c).
Following general procedure C, phenyl pivalate (134 mg, 0.75 mmol, 3.0 equiv), 5-(2-fluoro-5-
trifluoromethylphenyl)-oxazole (57.8 mg, 0.250 mmol, 1.0 equiv), Ni(COD)2 (6.9 mg, 0.025
mmol, 0.10 equiv), dcypt (23.8 mg, 0.05 mmol, 0.20 equiv), Cs2CO3 (122 mg, 0.375 mmol, 1.5
equiv), and anhydrous xylene (1.0 mL) were combined in a 4 mL scintillation vial. The reaction
mixture was allowed to stir at 140 °C for 20 h. Chromatography on a silica gel column using
93/7 hexanes/EtOAc (Rf = 0.26 in 93% hexanes/7% ethyl acetate) yielded product 13c as a white
1
solid (70.4 mg, 91% yield). mp = 143-144 °C. H NMR (CDCl3): δ 8.17-8.12 (multiple peaks,
3H), 7.67 (d, J = 4.0 Hz, 1H), 7.61-7.50 (multiple peaks, 4H), 7.31 (t, J = 9.5 Hz, 1H). 13C NMR
(CDCl3): δ 161.6, 160.2 (d, J = 255 Hz), 144.2 (d, J = 3.1 Hz), 130.9, 129.1, 128.9, 127.5 (qd, J
= 33.1, 3.5 Hz), 126.8, 126.6, 126.3 (m), 123.5 (q, J = 270 Hz), 123.3 (m), 117.4 (d, J = 14.4
Hz), 116.7 (d, J = 22.0 Hz). IR (neat): 1509, 1350, 1335, 1316, 1234, 1179, 1116, 1076, 1054,
900, 845, 780, 712, 699, 692, 682, 676, 588 cm-1. HRMS Calcd for C16H9F4NO 307.0620;
Found: 307.0626.
4.4.3 Procedures and spectral characterization of arylation products using tosylates
(Scheme 7a)
4.4.3.1. 2-phenyl-5-methyl-1,3-benzoxazole (1c).
Following general procedure B, phenyl tosylate (186 mg, 0.750 mmol, 1.5 equiv), 5-
methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 100 °C for 22 h. Chromatography on a silica gel column using 95/5
hexanes/EtOAc (Rf = 0.26 in 95% hexanes/5% ethyl acetate) yielded product 1c as a white solid
25

ACCEPTED MANUSCRIPT
(63.2 mg, 60% yield). The spectroscopic data is identical to that obtained using phenyl pivalate
(vide supra).
4.4.3.2. 2-(4-methoxyphenyl)-5-methyl-1,3-benzoxazole (1a)
.
Following general procedure B, 4-methoxy phenyl tosylate (209 mg, 0.750 mmol, 1.5 equiv), 5-
methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 100 °C for 20 h. Chromatography on a silica gel column using 90/10
hexanes/EtOAc (Rf = 0.40 in 90% hexanes/10% ethyl acetate) yielded product 1a as a white
solid (83.3 mg, 70% yield). The spectroscopic data is identical to that obtained using para-
methoxyphenyl pivalate (vide supra).
4.4.3.3. 2-(3-methoxyphenyl)-5-methyl-1,3-benzoxazole (1d).
Following general procedure B, meta-methoxy phenyl tosylate (209 mg, 0.750 mmol, 1.5 equiv),
5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 120 °C for 18 h. Chromatography on a silica gel column using 90/10
hexanes/EtOAc (Rf = 0.31 in 90% hexanes/10% ethyl acetate) yielded product 1d as a white
solid (52.7 mg, 44% yield). The spectroscopic data is identical to that obtained using meta-
methoxyphenyl pivalate (vide supra).
4.4.3.4. 2-[3-(trifluoromethyl)phenyl]-5-methyl-1,3-benzoxazole (1f).
Following general procedure B, meta-trifluoromethyl phenyl tosylate (237 mg, 0.750 mmol, 1.5
equiv), 5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol,
0.10 equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv),
and anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was allowed to stir at 120 °C for 22 h. Chromatography on a silica gel column using
95/5 hexanes/EtOAc (Rf = 0.42 in 95% hexanes/5% ethyl acetate) yielded product 1f as a white
solid (37.3 mg, 27% yield). The spectroscopic data is identical to that obtained using meta-
trifluoromethylphenyl pivalate (vide supra).
4.4.4 Procedures and spectral characterization of arylation products using mesylates
(Schemes 7b and 7c)
4.4.4.1. 2-phenyl-5-methyl-1,3-benzoxazole (1c).
26

ACCEPTED MANUSCRIPT
Following general procedure A, phenyl mesylate (129 mg, 0.750 mmol, 1.5 equiv), 5-
methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 120 °C for 22 h. Chromatography on a silica gel column using 96/4
hexanes/EtOAc (Rf = 0.28 in 96% hexanes/4% ethyl acetate) yielded product 1c as a white solid
(86.2 mg, 82% yield). The spectroscopic data is identical to that obtained using phenyl pivalate
(vide supra).
4.4.4.2. 2-(4-methylphenyl)-5-methyl-1,3-benzoxazole (1b).
Following general procedure A, 4-methyl phenyl mesylate (140 mg, 0.750 mmol, 1.5 equiv), 5-
methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column using 94/6
hexanes/EtOAc (Rf = 0.45 in 94% hexanes/6% ethyl acetate) yielded product 1b as a white solid
(69.8 mg, 62% yield). The spectroscopic data is identical to that obtained using para-
methylphenyl pivalate (vide supra).
4.4.4.3. 2-(4-methoxyphenyl)-5-methyl-1,3-benzoxazole (1a).
Following general procedure A, 4-methoxy phenyl mesylate (151 mg, 0.750 mmol, 1.5 equiv), 5-
methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 120 °C for 22 h. Chromatography on a silica gel column using 90/10
hexanes/EtOAc (Rf = 0.25 in 90% hexanes/10% ethyl acetate) yielded product 1a as a white
solid (94.4 mg, 79% yield). The spectroscopic data is identical to that obtained using para-
methoxyphenyl pivalate (vide supra).
4.4.4.4. 2-(3-methoxyphenyl)-5-methyl-1,3-benzoxazole (1d).
Following general procedure C, meta-methoxy phenyl mesylate (303 mg, 1.50 mmol, 3.0 equiv),
5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
27

ACCEPTED MANUSCRIPT
was allowed to stir at 140 °C for 18 h. Chromatography on a silica gel column using 91/9
hexanes/EtOAc (Rf = 0.31 in 91% hexanes/9% ethyl acetate) yielded product 1d as a white solid
(92.1 mg, 77% yield). The spectroscopic data is identical to that obtained using meta-
methoxyphenyl pivalate (vide supra).
4.4.4.5. 2-[3-(trifluoromethyl)phenyl]-5-methyl-1,3-benzoxazole (1f).
Following general procedure C, meta-trifluoromethyl phenyl mesylate (144 mg, 0.600 mmol, 1.5
equiv), 5-methylbenzoxazole (53.3 mg, 0.400 mmol, 1.0 equiv), Ni(COD)2 (11.0 mg, 0.04 mmol,
0.10 equiv), dcypt (38.1 mg, 0.08 mmol, 0.20 equiv), Cs2CO3 (195 mg, 0.600 mmol, 1.5 equiv),
and anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was allowed to stir at 140 °C for 21 h. Chromatography on a silica gel column using
94/6 hexanes/EtOAc (Rf = 0.29 in 94% hexanes/6% ethyl acetate) yielded product 1f as a white
solid (62.5 mg, 56% yield). The spectroscopic data is identical to that obtained using meta-
trifluoromethylphenyl pivalate (vide supra).
4.4.4.6. 2-(2-methylphenyl)-5-methyl-1,3-benzoxazole (1j).
Following general procedure C, ortho-methyl phenyl mesylate (279 mg, 1.50 mmol, 3.0 equiv),
5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcype (42.3 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol, 1.5 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column using 97/3
hexanes/EtOAc (Rf = 0.34 in 97% hexanes/3% ethyl acetate) yielded product 1j as a white solid
(32.9 mg, 30% yield). The spectroscopic data is identical to that previously reported in the
literature.27
4.4.4.7. 2,5-diphenyl-1,3-oxazole (8c).
Following general procedure A, phenyl mesylate (258 mg, 1.50 mmol, 3.0 equiv), phenyl
oxazole (72.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10 equiv), dcypt
(47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.75 mmol, 1.5 equiv), and anhydrous
xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture was allowed
to stir at 140 °C for 22 h. Chromatography on a silica gel column using 95/5 hexanes/EtOAc (Rf
= 0.40 in 95% hexanes/5% ethyl acetate) yielded product 8c as a white solid (63.7 mg, 58%
yield). The spectroscopic data is identical to that obtained using phenyl pivalate (vide supra).
4.4.4.8. 5-(4-methoxyphenyl)-2-phenyl-1,3-oxazole (9c).
28

ACCEPTED MANUSCRIPT
Using dcypt and Cs2CO3 : Following general procedure A, phenyl mesylate (258 mg, 1.50 mmol,
3.0 equiv), 5-(4-methoxyphenyl)-1,3-oxazole (87.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8
mg, 0.05 mmol, 0.10 equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750
mmol, 1.5 equiv), and anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial.
The reaction mixture was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel
column using 90/10 hexanes/EtOAc (Rf = 0.40 in 90% hexanes/10% ethyl acetate) yielded
product 9c as a white solid (44.6 mg, 35% yield). The spectroscopic data is identical to that
obtained using phenyl pivalate (vide supra).
Using dcypt and K3PO4: Following general procedure A in a 4 mL scintillation vial, phenyl
mesylate (64.6 mg, 0.375 mmol, 1.5 equiv), 5-(4-methoxyphenyl)-1,3-oxazole (43.8 mg, 0.250
mmol, 1.0 equiv), Ni(COD)2 (6.9 mg, 0.025 mmol, 0.10 equiv), dcypt (23.8 mg, 0.05 mmol, 0.20
equiv), K3PO4 (159 mg, 0.750 mmol, 3.0 equiv), and anhydrous xylene (1.0 mL) were combined.
The reaction mixture was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel
column using 90/10 hexanes/EtOAc (Rf = 0.40 in 90% hexanes/10% ethyl acetate) yielded
product 9c as a white solid (32.1 mg, 52% yield). The spectroscopic data is identical to that
obtained using phenyl pivalate (vide supra).
4.4.4.9. 5-[4-(trifluoromethyl)phenyl]-2-phenyl-1,3-oxazole (10c).
Following general procedure A, phenyl mesylate (258 mg, 1.50 mmol, 3.0 equiv), 5-[4-
(trifluoromethyl)phenyl]-1,3-oxazole (107 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg,
0.05 mmol, 0.10 equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), Cs2CO3 (244 mg, 0.750 mmol,
1.5 equiv), and anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The
reaction mixture was allowed to stir at 140 °C for 22 h. Chromatography on a silica gel column
using 95/5 hexanes/EtOAc (Rf = 0.32 in 95% hexanes/5% ethyl acetate) yielded product 10c as a
white solid (111 mg, 77% yield). The spectroscopic data is identical to that obtained using
phenyl pivalate (vide supra).
4.4.5 Procedures and spectral characterization of arylation products using carbamates
(Scheme 8)
4.4.5.1. 2-phenyl-5-methyl-1,3-benzoxazole (1c).
Following general procedure C, N,N-diethyl-phenyl carbamate (145 mg, 0.750 mmol, 1.5 equiv),
5-methylbenzoxazole (66.6 mg, 0.500 mmol, 1.0 equiv), Ni(COD)2 (13.8 mg, 0.05 mmol, 0.10
equiv), dcypt (47.7 mg, 0.10 mmol, 0.20 equiv), K3PO4 (318 mg, 1.50 mmol, 3.0 equiv), and
anhydrous xylene (2.0 mL) were combined in a 20 mL scintillation vial. The reaction mixture
29