Copper-catalyzed selective arylations of benzoxazoles with aryl iodides

Article abstract of DOI:10.1021/acs.joc.5b00019

A copper-catalyzed direct ring-opening double N-arylation of benzoxazoles with aryl iodides has been developed. The present system exhibits high selectivity despite competition from C-arylation. The selectivity between ring-opening N-arylation and C-arylation was controlled by the choice of reaction vessel. The nitrile bound bis(triphenylphosphine)copper cyanide was identified as the active catalytic species for both reactions, and when combined with a nitrile-containing solvent, enhanced the reaction efficiency.

Full text of DOI:10.1021/acs.joc.5b00019

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Note
Copper-Catalyzed Selective Arylations of Benzoxazoles with Aryl Iodides
Donghae Kim, Kwangho Yoo, Se Eun Kim, Hee Jin Cho, Junseong Lee, Youngjo Kim, and Min Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00019 • Publication Date (Web): 13 Mar 2015
Downloaded from http://pubs.acs.org on March 17, 2015
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Copper-Catalyzed Selective Arylations of Benzoxazoles with Aryl Iodides
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Donghae Kim,†,§ Kwangho Yoo,†,§ Se Eun Kim,† Hee Jin Cho,† Junseong Lee,‡ Youngjo Kim,*,† and Min Kim*,†
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†Department of Chemistry and BK21Plus Research Team, Chungbuk National University, 1 Chungdaeꢀro,
Seowonꢀgu, Cheongjuꢀsi, Chungbuk, 362ꢀ763, Republic of Korea
‡Department of Chemistry, Chonnam National University, Gwangju, 500ꢀ757, Republic of Korea
Eꢀmail: ykim@chungbuk.ac.kr & minkim@chungbuk.ac.kr
Abstract: A copperꢀcatalyzed direct ringꢀopening double Nꢀarylation of benzoxazoles with aryl iodides has been
developed. The present system exhibits high selectivity despite competition from Cꢀarylation. The selectivity
between ringꢀopening Nꢀarylation and Cꢀarylation was controlled by the choice of reaction vessel. The nitrile
bound bis(triphenylphosphine)copper cyanide was identified as the active catalytic species for both reactions,
and when combined with a nitrileꢀcontaining solvent, enhanced the reaction efficiency.
Benzoxazole derivatives are important heterocyclic organic molecules in pharmaceutical research.1 Various
functionalizations of benzoxazole have been studied. In particular, the most acidic CꢀH bond, between the
nitrogen and oxygen atom, can be easily activated allowing for the functionalization of the Cꢀ2 position.
Arylation of the Cꢀ2 position has been explored using aryl halides in combination with palladium, nickel or
copper catalysts.2ꢀ4 A stoichiometric amount of copper iodide was employed to functionalized the CꢀH bond in
the Cꢀ2 position using an arylation reaction by Miura et al.4a On the other hand, the Daugulis group developed a
copperꢀcatalyzed arylation of the benzoxazole Cꢀ2 position with lithium tertꢀbutoxide as the base.4b In addition
to carbonꢀcarbon bond formation at the Cꢀ2 position, carbonꢀnitrogen bond formation was also developed using
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transition metalꢀcatalyzed conditions.5
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Direct arylation of the Cꢀ2 position can be in competition with a ringꢀopening arylation reaction. In Miura’s
system, a small amount of triphenylamine derivative was detected which could be synthesized via a benzoxazole
ringꢀopening reaction followed by Nꢀarylation.4a Both the Ullmann and BuchwaldꢀHartwig aminations are well
known copperꢀcatalyzed crossꢀcoupling reactions between an aryl halide and an amine.6 These reactions
suggested that the benzoxazole was transformed into an aminophenol derivative first, followed by a Buchwaldꢀ
Hartwig type Nꢀarylation to form the triphenylamine product. In a complementary fashion, Han et al. also
applied the benzoxazole ringꢀopening reaction to Oꢀarylation reactions using copper nanoparticles.7 In the
proposed mechanism of this system, cesium carbonate was first employed to open the benzoxazole ring, and
then a copperꢀcatalyzed Oꢀarylation of the orthoꢀaminophenol intermediate took place. Very little is known
about the ringꢀopening Nꢀarylation as there are no catalytic studies on this system to date, hence no way to
optimize the transformation. Described herein is our study on the copperꢀcatalyzed selective ringꢀopening Nꢀ
arylation of benzoxazole with aryl iodides.
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Scheme 1. Carbonꢀcarbon, carbonꢀoxygen, and carbonꢀnitrogen bond formations of benzoxazole using
transition Cu catalysts.
Using benzoxazole (1a) and iodobenzene (2a) as starting materials, optimization of the ringꢀopening Nꢀarylation
was undertaken (Table 1). While the Cꢀ2 arylated product (4aa) was the major product using Miura’s
condition,4a changing the reaction vessel from a roundꢀbottomed flask to a screwꢀcapped reaction vial shifts the
preference from an arylation of the Cꢀ2 position to a ringꢀopening Nꢀarylation. Additionally, changing the
copper salt from copper(I) iodide to copper(I) cyanide increased catalytic efficiency of the ringꢀopening Nꢀ
arylation (entry 2). It turns out that the counter anion in the copper catalyst and the solvent displayed significant
effects on the catalytic activity as demonstrated in entry 3. Among the various polar solvent screening, the
nitrileꢀcontaining solvents displayed improved reactivity and solubility. To circumvent the low boiling point of
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o
many nitrile containing solvents, pivalonitrile (2,2,ꢀdimethylpropanenitrile, b.p. 105 C) was used for the ringꢀ
opening Nꢀarylation reaction. While the combination of both a nitrileꢀcontaining copper salt and solvent has
good reactivity, modulating the base had a pronounced effect. Using cesium carbonate as a base accelerated the
ringꢀopening Nꢀarylation to afford 2ꢀ(diphenylamino)phenol (3aa) in 98% isolated yield (entry 4). It has been
suggested that the cesium carbonate plays a key role in the ringꢀopening of benzoxazole. Han and coꢀworkers
proposed a cesium carbonateꢀmediated benzoxazole ringꢀopening route for the first step of their reaction
mechanism.7 In fact, switching to cesium carbonate, from sodium carbonate, decreased the amount of copper
salt required to obtain a similar yield (entry 5) from stoichiometric (1 equiv.) to catalytic (10 mol%) amounts.
However, the reaction time and quantity of phosphine ligand were inversely proportional. When the reaction
time decreased from 24 h to 18 h, the amount of phosphine required increased from 20 mol% to 30 mol% (entry
6). Entries 5ꢀ7 demonstrate that the amount of triphenylphosphine ligand has a significant effect on this
particular system. Interestingly, the monoꢀNꢀarylation product was not obtained as the major product under any
condition, even with only a single equivalent of aryl iodide present.
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Table 1. Screening of reaction conditions for copperꢀcatalyzed selective arylationsa
yield(%)b
entry
copper salt
PPh3
base
Solvent
temp
time
3aa
4aa
CuI
(1 equiv.)
CuCN
(1 equiv.)
CuCN
(1 equiv.)
CuCN
(1 equiv.)
CuCN
(10 mol%)
CuCN
1
2
3
4
5
6
7
8
9
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
30 mol %
ꢀ
Na2CO3
Na2CO3
DMF
DMF
160
160
140
140
120
120
120
120
120
24
24
24
24
24
18
18
18
24
33
10
28
ꢀ
ꢀ
14
ꢀ
Na2CO3 Pivalonitrile
Cs2CO3 Pivalonitrile
Cs2CO3 Pivalonitrile
Cs2CO3 Pivalonitrile
Cs2CO3 Pivalonitrile
Cs2CO3 Pivalonitrile
Cs2CO3 Pivalonitrile
98
92
90
44
94
96
ꢀ
ꢀ
(10 mol%)
CuCN
ꢀ
(10 mol%)
CuCN(PPh3)2
(10 mol%)
CuCN(PPh3)2
(10 mol%)
ꢀ
ꢀ
10 mol%
ꢀ
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CuCN(PPh3)2
(10 mol%)
CuCN(PPh3)2
(10 mol%)
106
reflux
10c
11
10 mol%
10 mol%
Cs2CO3 Pivalonitrile
Cs2CO3 DMF
24
24
ꢀ
85
16
150
59
aReaction condition: A mixture of benzoxazole (0.15 mmol), iodobenzene (0.45 mmol), copper salt, triphenylphosphine and base (0.45
mmol) in solvent (0.5 mL) was placed in screwꢀcapped vial, closed, and stirred for the indicated time and temperature.
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bIsolated yield of product reported as an average from at least two independent measurements.
cA mixture of benzoxazole (0.6 mmol), iodobenzene (1.8 mmol), copper salt (10 mol%), triphenylphosphine (10 mol%), cesium carbonate
(1.8 mmol) in pivalonitrile (2 mL) was placed in roundꢀbottomed flask and stirred for 24 h.
Since CuCl(PPh3)3 is a widely studied and common copper salt, the active catalytic species was expected to be
CuCN(PPh3)3 in our optimized reaction condition. However, bis(triphenylphosphine)copper cyanide was only
obtained and confirmed by the reaction of copper cyanide and triphenylphosphines.8 A hexameric PPh3ꢀbounded
copper cyanide species [CuCN(PPh3)2]6 (5) could be synthesized and isolated by following a previous report.8a
(Scheme 1) It was originally reported as a red crystal, however only colorless crystals were obtained and the
structure was confirmed by single crystal Xꢀray diffraction (Scheme 1 and Supporting Information for detail). In
the hexameric complex (5), the nitrile coordinates with two copper atoms by using each carbon and nitrogen
atom. A decade ago, the polymeric structure of CuCN was intensively studied, and it has a similar oligomeric
binding mode to CuCN(PPh3)2.9 Interestingly, the reaction yield was improved by exchanging copper cyanide
with the synthesized bis(triphenylphosphine)copper cyanide salt and reacting with external triphenylphosphines
(entries 5, 7, and 8). The best condition for the ringꢀopening double Nꢀarylation was achieved by using
bis(triphenylphosphine)copper cyanide (5) salt with additional triphenylphosphine ligands (entry 9).
Finally, perfect selectivity of arylation was revealed by a simple choice of reaction vessel. In the optimized
condition (entry 9 in Table 1), the reaction was performed in a screwꢀcapped vial, and formed the ringꢀopened
doubleꢀarylated product 3aa, as the sole product. However, by changing the reaction vessel from a closed, and
assuming pressured, screwꢀcapped vial to an open roundꢀbottomed flask, the Cꢀarylated product 4aa was the
major product and isolated in high yields (85%, entry 10). Interestingly, the selectivity of arylation was not
achieved using DMF as the solvent. Both 3aa (59%) and 4aa (16%) were obtained from condition B in DMF at
150 oC. Utilizing a nitrileꢀcontaining solvent and copper salt together can optimize this series of reactions to be
performed as a selective oneꢀpot synthesis (entry 11).
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Scheme 2. Synthesis of [CuCN(PPh3)2]6.
Under the optimized conditions using CuCN as a catalyst and PPh3 as a ligand, substrate scope was
subsequently investigated (Condition A, Table 2). In general, electronic variation on the aryl iodides, bearing
different types of substituents, displayed substantial effects on the reaction efficiency. Aryl iodides containing
electron donating groups showed moderate to good yields for all orthoꢀ, metaꢀ, and paraꢀ substituted substrates
(entries 1ꢀ7). However, certain electron withdrawing groups (i.e., 4ꢀnitroiodobenzene and methylꢀ4ꢀ
iodobenzoate) demonstrate poor reactivity in the Nꢀarylation reaction. The halides seemed to be exempt as 4ꢀ
fluoroiodobenzene and 4ꢀchloroiodobenzene showed moderate reactivity in condition A.
Table 2. Copperꢀcatalyzed ringꢀopening double Nꢀarylation of benzoxazole with aryl iodidesa
OH
Condition
A or B or C
O
N
O
N
N
R
I
+
+
R
R
R
1a
2b-2j
3ab-3aj
4ab-4aj
Condition A & B
: in a screw-capped vial for
3a
synthesis
4a
synthesis
Condition C
: in a round-bottomed flask for
Yield (%)b
entry
R
Condition A Condition B
Condition C
4ab, 96
1
2
3
4ꢀMe
3ꢀMe
2ꢀMe
3ab, 61
3ac, 82
3ad, 53
3ab, 79
ꢀ
4ac, 94
3ad, 79
4ad, 75
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4ꢀOMe
3ꢀOMe
2ꢀOMe
3,5ꢀdiMe
4ꢀF
3ae, 58
3af, 95
3ag, 65
3ah, 64
3ai, 71
3aj, 30
3ae, 80
ꢀ
4ae, 93
4af, 87
4ag, 89
4ah, 82
4ai, 86
4aj, 55
3ag, 78
3ah, 71
3ai, 77
3aj, 68
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4ꢀCl
aReaction condition A: A mixture of benzoxazole (0.15 mmol), aryl iodide (0.45 mmol), copper cyanide (0.015 mmol), triphenylphosphine
(0.045 mmol), and cesium carbonate (0.45 mmol) in pivalonitrile (0.5 mL) was placed in a screwꢀcapped vial and stirred for 18 hour at 120
oC. Reaction condition B: A mixture of benzoxazole (0.15 mmol), aryl iodide (0.45 mmol), bis(triphenylphosphine) copper cyanide (0.015
mmol), triphenylphosphine (0.015 mmol), and cesium carbonate (0.45 mmol) in pivalonitrile (0.5 mL) was placed in a screwꢀcapped vial
and stirred for 24 hour at 120 oC. Reaction condition C: A mixture of benzoxazole (0.3 mmol), aryl iodide (0.9 mmol),
bis(triphenylphosphine) copper cyanide (0.03 mmol), triphenylphosphine (0.03 mmol), and cesium carbonate (0.9 mmol) in pivalonitrile (1
mL) was placed in a roundꢀbottomed flask and stirred for 24 hour under reflux.
bIsolated yield of product reported as an average from at least two independent measurements.
Due to the fact that the preꢀsynthesized bis(triphenylphosphine)copper cyanide has better reactivity in the ringꢀ
opening double Nꢀarylation with iodobenzene (Table 1), we scrutinized the aryl iodide substrate scope again
using complex 5 instead of CuCN (Condition B, in Table 2). We were pleased to observe improved yields under
reaction condition
B which employed the bis(triphenylphosphine)copper cyanide and an external
triphenylphosphine. At the same time, the C arylated product 4a series was successfully synthesized using
condition C from same starting materials and catalysts.
Under the optimized condition B, we also explored the substrate scope of the benzoxazole component to the
ringꢀopening double Nꢀarylation using iodobenzene (Scheme 3). Benzoxazoles bearing substituents with diverse
electronic properties such as methyl (1bꢀ1d), phenyl (1e), and chloro(1f) groups all underwent reactions with
iodobenzene to provide the desired products in the moderate yields. In contrast to the effects seen when the
substrate is on the aryl halide, benzoxazoles bearing electronꢀwithdrawing group, such as a chloro group (1f),
showed the highest conversion in the reaction condition. The reaction with 4ꢀmethylbenzoxazole (1b) and 6ꢀ
methylbenzoxazole (1d) afforded the corresponding product with a diminished yield. Both benzothiazole and
benzimidazole exhibit no reactivity in the copperꢀcatalyzed ringꢀopening double Nꢀarylation even with elevated
temperature, suggesting that the present copper system could discriminate between these types of intermediates
and only perform the arylation on aminophenols.
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aReaction condition: A mixture of benzoxazole (0.15 mmol), aryl iodide (0.45 mmol), bis(triphenylphosphine) copper cyanide (0.015 mmol),
triphenylphosphine (0.015 mmol), and cesium carbonate (0.45 mmol) in pivalonitrile (0.5 mL) was placed in screwꢀcapped vial and stirred
for 24 hour at 120 oC. The yields of isolated products are reported as an average from at least two independent measurements.
Scheme 3. Ringꢀopening double Nꢀarylation with various benzoxazoles.a
Cs2CO3
t-BuCN
23%
OH
Ph
I
OH
CuCN(PPh3)2
O
N
CuCN(PPh3)2
PPh3
N
Isolation yield
of product from
2-aminophenol:
95%
PPh3
Cs2CO3
NH2
Cs2CO3
t-BuCN
t-BuCN
62%
Scheme 4. Teasing apart the order of reactions for the transformation of benzoxazole to 2ꢀ
(diphenylamino)phenol.
To obtain any mechanistic insight into the present ringꢀopening double Nꢀarylation, the reaction was performed
in separated systems (Scheme 4). As discussed in reference 7, benzoxazole rings can be opened by cesium
carbonate. By employing benzoxazole and cesium carbonate only, the ringꢀopened 2ꢀaminophenol was obtained
in 23% yield, with the remaining materials being unreacted benzoxazole. Interestingly, a mixture of copper salt,
triphenylphosphine, and base converted benzoxazole to 2ꢀaminophenol with higher yield (62%), indicating that
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the copper catalyst can also affect the ringꢀopening of benzoxazole. Using 2ꢀaminophenol as the starting
material for condition B, the final product was obtained in a 95% yield. Unsurprisingly, when the Cꢀ2 arylated
product (4aa) was used as a starting material, no further reaction (ringꢀopening or arylation) was observed.
These separated results led us to propose that the copperꢀcatalyzed ringꢀopening double Nꢀarylation as a
sequential set of reactions. Ringꢀopening of benzoxazole occurs first followed by the copperꢀcatalyzed Nꢀ
arylation to form the product.10
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In summary, we have presented a copperꢀcatalyzed direct arylation and ringꢀopening double Nꢀarylation of
benzoxazoles. Judicious choice of both the copper catalyst and reaction conditions was crucial for achieving
selectivity and preference for the catalytic activity to follow down a nonꢀtraditional route. The reaction pathway
between Cꢀarylation and ringꢀopening double Nꢀarylation was perfectly controlled by choice of the reaction
vessel with nitrileꢀcontaining solvent. A wide range of substituted starting materials was examined using the
developed copperꢀcatalyzed arylation of benzoxazoles. In this system the key parameters, such as the substituent
placement on either the aryl halide or the benzoxazole, and the electronics of the substituent, can be teased apart
leading to an improved understanding of the mechanism and optimization of the synthesis..
Experimental Section
All reagents were used as received unless otherwise noted. Flash column chromatography was performed on
silica gel (400ꢀ630 mesh) using the indicated solvent system. Proton nuclear magnetic resonance spectra (1H
NMR) were recorded at 400 MHz or 500 MHz. Chemical shifts were quoted in parts per million (ppm)
referenced to the appropriate solvent peak or 0 ppm for TMS. The following abbreviations were used to describe
peak patterns when appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet.
Coupling constants, J, were reported in Hertz unit (Hz). Carbon 13 nuclear magnetic resonance spectroscopy
(13C NMR) was recorded at 100 MHz or 125 MHz and was fully decoupled by broad band decoupling.
Chemical shifts were reported in ppm referenced to the center line of a triplet at 77.0 ppm of chloroformꢀd or the
appropriate solvent peak. Highꢀresolution mass spectra (HRMS) were acquired on a high resolution QꢀTOF
mass spectrometer (ionization mode: ESI).
CuCN(PPh3)2(5),8a 2ꢀ(diphenylamino)phenol (Table 1, 3aa),11 2ꢀphenylbenzoxazole (Table 1, 4aa),12 2ꢀ(diꢀpꢀ
tolylamino)phenol (Table 2, entry 1, 3ab)10b, 2ꢀ(pꢀtolyl)benzo[d]oxazole (Table 2, entry 1, 4ab)13a, 2ꢀ(mꢀ
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tolyl)benzo[d]oxazole (Table 2, entry 2, 4ac)13a, 2ꢀ(diꢀoꢀtolylamino)phenol (Table 2, entry 3, 3ad)10b, 2ꢀ(oꢀ
5
6
7
8
tolyl)benzo[d]oxazole (Table 2, entry 3, 4ad)4b, 2ꢀ(bis(4ꢀmethoxyphenyl)amino)phenol (Table 2, entry 4, 3ae)10b
2ꢀ(4ꢀmethoxyphenyl)benzo[d]oxazole (Table 2, entry 4, 4ae)4b, 2ꢀ(bis(3ꢀmethoxyphenyl)amino)phenol (Table 2,
3af)11, 4af)13a
2ꢀ(2ꢀ
,
9
entry
5,
2ꢀ(3ꢀmethoxyphenyl)benzo[d]oxazole
(Table
2,
entry
5,
,
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methoxyphenyl)benzo[d]oxazole (Table 2, entry 6, 4ag)13b, 2ꢀ(bis(3,5ꢀdimethylphenyl)amino)phenol (Table 2,
entry 7, 3ah)11, 2ꢀ(3,5ꢀdimethylphenyl)benzo[d]oxazole (Table 2, entry 7, 4ah)4b, 2ꢀ(4ꢀ
fluorophenyl)benzo[d]oxazole (Table 2, entry 8, 4ai)4b, 2ꢀ(4ꢀchlorophenyl)benzo[d]oxazole (Table 2, entry 9,
4aj)13a, 2ꢀ(diphenylamino)ꢀ4ꢀmethylphenol (Scheme 3, 3ca)10b, 4ꢀchloroꢀ2ꢀ(diphenylamino)phenol (Scheme 3,
3fa)10b are kwon compounds.
Preparation of CuCN(PPh3)2(Scheme 2).8a Copper(I) cyanide (250 mg, 2.8 mmol), triphenylphosphine(2.89 g,
11 mmol) and chloroform (40 mL) were added to round bottom flask. The mixture was vigorously stirred at
room temperature for 4 h. The colorless solid was separated by filtration and washed with 20 mL diethyl ether (4
times). After washing, the solid was recrystallized in hot methanol. The colorless powder was separated by
filtration again and solvent was removed in vacuo, the desired product was finally recrystallized in
dichloromethane (1.12 g, 65%).
General procedures for the copper-catalyzed ring-opening double N-arylation: Condition A (Table 1 and
2). Benzoxazole (18 mg, 0.15 mmol), aryl iodide (0.45 mmol), cesium carbonate (147 mg, 0.45 mmol), copper(I)
cyanide (1.3 mg, 0.015 mmol), triphenylphosphine (12 mg, 0.045 mmol) and pivalonitrile (0.5 mL) were added
o
to an ovenꢀdried screwꢀcapped vial. The mixture was vigorously stirred at 120 C for 18 h. After cooling to
room temperature, the mixture was diluted with ethyl acetate (1 mL). Solvent was removed in vacuo, and the
desired product was isolated by a silica gel column chromatography.
General procedures for the ring-opening double N-arylation: Condition B (Table 1, 2 and Scheme 3).
Benzoxazole (18 mg, 0.15 mmol), aryl iodide (0.45 mmol), cesium carbonate (147 mg, 0.45 mmol),
bis(triphenylphosphine)copper(I) cyanide (9 mg, 0.015 mmol), triphenylphosphine (4 mg, 0.015 mmol) and
pivalonitrile (0.5 mL) were added to an ovenꢀdried screwꢀcapped vial. The mixture was vigorously stirred at 120
oC for 24 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (1 mL). Solvent was
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Copper-catalyzed direct arylation of benzoxazole (Table 1, entry 10). Benzoxazole (71 mg, 0.6 mmol),
iodobenzene (0.20 mL, 1.8 mmol), cesium carbonate (586 mg, 1.8 mmol), bis(triphenylphosphine)copper(I)
cyanide(37 mg, 0.06 mmol), triphenylphosphine (16 mg, 0.06 mmol) and pivalonitrile (2.0 mL) were added to a
roundꢀbottomed flask. The mixture was vigorously stirred under reflux for 24 h. After cooling to room
temperature, the mixture was filtered through silica gel pad with ethyl acetate (10 mL) to remove insoluble
solids. Solvent was removed in vacuo, and the desired product was isolated by a silica gel column
chromatography.
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General procedures for the direct arylation of benzoxazole: Condition C (Table 2). Benzoxazole (36 mg,
0.3 mmol), aryl iodidie (0.9 mmol), cesium carbonate (293 mg, 0.9 mmol), bis(triphenylphosphine)copper(I)
cyanide(19 mg, 0.03 mmol), triphenylphosphine (8 mg, 0.03 mmol) and pivalonitrile (1 mL) were added to a
roundꢀbottomed flask. The mixture was vigorously stirred under reflux for 24 h. After cooling to room
temperature, the mixture was filtered through silica gel pad with ethyl acetate (10 mL) to remove insoluble
solids. Solvent was removed in vacuo, and the desired product was isolated by a silica gel column
chromatography.
2-(Diphenylamino)phenol(Table 1, 3aa).11 Condition A: iodobenzene (0.050 mL, 0.45 mmol) was used for the
preparation of the title compound, and it was purified by a silica gel column chromatography
(dichloromethane/nꢀhexane, 1:5) as a colorless solid (36 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 5.53 (s, 1H),
6.93ꢀ6.97 (m, 1H), 7.02ꢀ7.08 (m, 7H), 7.11ꢀ7.13 (q, 1H) 7.20ꢀ7.24(m, 1H), 7.26ꢀ7.31(m, 4H); 13C NMR (100
MHz, CDCl3) δ 116.6, 121.5, 121.8, 122.8, 127.7, 129.4, 133.1, 146.8, 152.4.
2-Phenylbenzoxazole (Table 1, 4aa).12 Iodobenzene (0.20 mL, 1.8 mmol) was used for the preparation of the
title compound, and it was purified by a silica gel column chromatography (ethyl acetate/nꢀhexane, 1:20) as a
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colorless solid (100 mg, 85%); H NMR(400 MHz, CDCl3) δ 7.35ꢀ7.39 (m, 2H), 7.51ꢀ7.56 (m, 3H), 7.57ꢀ7.62
(m, 1H), 7.77ꢀ7.82 (m, 1H), 8.26ꢀ8.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 110.6, 120.0, 124.7, 125.2, 127.0,
127.7, 129.0, 131.7, 141.8, 150.7, 163.1.
2-(Di-p-tolylamino)phenol (Table 2, entry 1, 3ab).10b Condition A and B: 4ꢀiodotoluene (98 mg, 0.45 mmol) was
used for the preparation of the title compound, and it was purified by a silica gel column chromatography
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(dichloromethane/nꢀhexane, 1:5) as a colorless solid (34.4mg, 79%);1H NMR (400 MHz, CDCl3) δ 2.32 (s, 6H),
5.57 (s, 1H), 6.89ꢀ6.95 (m, 5H), 7.01ꢀ7.10 (m, 6H), 7.15ꢀ7.19 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 20.7,
116.4, 121.3, 121.8, 127.3, 129.0, 130.0, 132.2, 133.6, 144.6, 152.2.
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2ꢀ(pꢀTolyl)benzo[d]oxazole (Table 2, entry 1, 4ab)13a Condition C: 4ꢀiodotoluene (196 mg, 0.90 mmol)was used
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for the preparation of the title compound, and it was purified by a silica gel column chromatography
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(dichloromethane/nꢀhexane, 1:5) as a colorless solid (60.3 mg, 96%); H NMR (400 MHz, CDCl3) δ 2.44 (s,
3H), 7.32ꢀ7.36 (m, 4H), 7.56ꢀ7.58 (m, 1H), 7.75ꢀ7.78 (m, 1H), 8.14ꢀ8.16 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 21.6, 110.4, 119.8, 124.3, 124.4, 124.8, 127.5, 129.6, 142.0, 142.1, 150.6, 163.2.
2-(Di-m-tolylamino)phenol(Table 2, entry 2, 3ac). Condition A: 3ꢀiodotoluene (0.058 mL, 0.45 mmol) was used
for the preparation of the title compound, and it was purified by a silica gel column chromatography
(dichloromethane/nꢀhexane, 1:5) as a colorless solid (35.7mg, 82%); 1H NMR (400 MHz, CDCl3) δ 5.30 (s, 1H),
6.82ꢀ6.84 (m, 6H), 6.89ꢀ6.93 (m, 1H), 7.01ꢀ7.04 (q, 1H), 7.08ꢀ7.20 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
29.7, 116.5, 121.5, 121.7, 122.7, 127.7, 129.4, 133.1, 146.7, 152.4; HRꢀESIꢀMS (QꢀTOF) m/z calcd. for
C20H19NO [M+H]+: 290.1545, found [M+H]+: 290.1545.
2ꢀ(mꢀTolyl)benzo[d]oxazole (Table 2, entry 2, 4ac)13a Condition C: 3ꢀiodotoluene (116 mL, 0.90 mmol)was used
for the preparation of the title compound, and it was purified by a silica gel column chromatography
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(dichloromethane/nꢀhexane, 1:5) as a yellow solid (59.1mg, 94%); H NMR (400 MHz, CDCl3) δ 2.45 (s, 3H),
7.32ꢀ7.35 (m, 3H), 7.38ꢀ7.42 (t, 1H, J = 7.6 Hz), 7.56ꢀ7.58 (m, 1H), 7.76ꢀ7.79 (m, 1H), 8.04ꢀ8.06 (d, 1H, J = 7.7
Hz), 8.10 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.2, 110.5, 119.9, 124.5, 124.7, 124.9, 126.9, 128.1, 128.7,
132.3, 138.6, 142.0, 150.7, 163.2.
2-(Di-o-tolylamino)phenol (Table 2, entry 3ad).10b Condition A and B: 2ꢀiodotoluene (0.057 mL, 0.45 mmol)
was used for the preparation of the title compound, and it was purified by a silica gel column chromatography
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(dichloromethane/nꢀhexane, 1:5) as a colorless solid (34.4 mg, 79%); H NMR (400 MHz, CDCl3) δ 1.96 (s,
6H), 5.19 (s, 1H), 6.77ꢀ6.86 (m, 4H), 6.95ꢀ6.97 (q, 1H), 7.05ꢀ7.14 (m, 5H), 7.18ꢀ7.20 (d, 2H); 13C NMR (100
MHz, CDCl3) δ 18.5, 100.0, 116.2, 120.9, 125.8, 126.2, 131.9, 134.8, 150.3.
2ꢀ(oꢀTolyl)benzo[d]oxazole (Table 2, entry 3, 4ad)4b Condition C: 2ꢀiodotoluene (115 mL, 0.90 mmol)was used
for the preparation of the title compound, and it was purified by a silica gel column chromatography
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(dichloromethane/nꢀhexane, 1:5) as a yellow solid (47.4 mg, 75%); H NMR (400 MHz, CDCl3) δ 2.83 (s, 3H),
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7.34ꢀ7.38 (m, 4H), 7.39ꢀ7.44 (m, 1H), 7.58ꢀ7.62(m, 1H), 7.81ꢀ7.83 (m, 1H), 8.18ꢀ8.20(m, 1H); 13C NMR (100
MHz, CDCl3) δ 22.2, 110.5, 120.1, 124.3, 125.0, 126.0, 126.2, 129.9, 130.9, 131.8, 138.8, 142.1, 150.3, 163.4.
2-(Bis(4-methoxyphenyl)amino)phenol (Table 2, entry 4, 3ae). 10b Condition A and B: 4ꢀiodoanisole (105 mg,
0.45 mmol) was used for the preparation of the title compound, and it was purified by a silica gel column
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chromatography (dichloromethane/nꢀhexane, 1:2) as a yellow solid (39.2 mg, 81%); H NMR (400 MHz,
CDCl3) δ 3.80 (s, 6H), 5.61 (s, 1H), 6.81ꢀ6.84 (m, 4H), 6.89ꢀ6.92 (m, 1H), 6.94ꢀ6.97 (m, 4H), 7.01ꢀ7.06 (m, 2H),
7.13ꢀ7.17 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 55.5, 114.7, 116.3, 121.1, 123.2, 126.8, 128.4,134.2, 140.8,
151.9, 155.3.
2ꢀ(4ꢀMethoxyphenyl)benzo[d]oxazole (Table 2, entry 4, 4ae)4b Condition C: 4ꢀiodoanisole (211 mg, 0.90
mmol)was used for the preparation of the title compound, and it was purified by a silica gel column
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chromatography (dichloromethane/nꢀhexane, 1:5) as a colorless solid s(62.7 mg, 93%); H NMR (400 MHz,
CDCl3) δ 3.90 (s, 3H), 7.02ꢀ7.05 (m, 2H), 7.30ꢀ7.35 (m, 2H), 7.55ꢀ7.57 (m, 1H), 7.73ꢀ7.76 (m, 1H), 8.19ꢀ8.22
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 55.4, 110.4, 114.4, 119.7, 119.8, 124.4, 124.6, 129.4, 142.3, 150.7,
162.4, 163.2.
2-(Bis(3-methoxyphenyl)amino)phenol(Table 2, entry 5, 3af).11 Condition A: 3ꢀiodoanisole (0.054 mL, 0.45
mmol) was used for the preparation of the title compound, and it was purified by a silica gel column
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chromatography (dichloromethane/nꢀhexane, 1:2) as a yellow solid (45.9 mg, 95%); H NMR (400 MHz,
CDCl3) δ 6.6ꢀ6.7 (m, 6H), 6.9 (m, 1H), 7.0 (q, 1H), 6.9 (m, 1H), 7.1ꢀ7.2 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ 55.3, 108.0, 108.1, 114.5, 116.7, 121.5, 127.9, 129.4, 130.1, 133.0, 147.9, 152.5, 160.6.
2ꢀ(3ꢀMethoxyphenyl)benzo[d]oxazole (Table 2, entry 5, 4af)13a Condition C: 3ꢀiodoanisole (107 mL, 0.90
mmol)was used for the preparation of the title compound, and it was purified by a silica gel column
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chromatography (dichloromethane/nꢀhexane, 1:5) as a colorless solid (58.8 mg, 87%); H NMR (400 MHz,
CDCl3) δ 3.92 (s, 3H), 7.07ꢀ7.10 (m, 1H), 7.34ꢀ7.38 (m, 2H), 7.41ꢀ7.44 (t, 1H, J = 6.4 Hz), 7.57ꢀ7.60 (m, 1H),
7.77ꢀ7.80 (m, 2H) 7.84ꢀ7.86 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 55.5, 110.6, 111.8, 118.3, 120.0, 120.1,
124.6, 125.1, 128.3, 130.0, 142.0, 150.7, 159.9, 162.9.
2-(Bis(2-methoxyphenyl)amino)phenol (Table 2, entry 6, 3ag) Condition A and B: 2ꢀiodoanisole (0.059 mL, 0.45
mmol) was used for the preparation of the title compound, and it was purified by a silica gel column
chromatography (dichloromethane/nꢀhexane, 1:2) as a yellow solid (37.7 mg, 78%); 1H NMR (400 MHz, CDCl3)
δ 3.62 (s, 6H), 6.80ꢀ6.98 (m, 8H), 7.05ꢀ7.13 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 55.9, 112.7, 115.4, 119.9,
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121.0, 124.7, 124.9, 126.8, 127.6, 135.2, 137.1, 153.2, 153.5; HRꢀESIꢀMS (QꢀTOF) m/z calcd. for C20H19NO3
[M+H]+: 322.1443, found [M+H]+: 322.1442.
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2ꢀ(2ꢀMethoxyphenyl)benzo[d]oxazole (Table 2, entry 6, 4ag)13b Condition C: 2ꢀiodoanisole (117 mL, 0.90
mmol)was used for the preparation of the title compound, and it was purified by a silica gel column
chromatography (dichloromethane/nꢀhexane, 1:5) as a yellow solid (60.3 mg, 89%); 1H NMR (400 MHz, CDCl3)
δ 4.01 (s, 3H), 7.07ꢀ7.11 (m, 2H), 7.32ꢀ7.35 (m, 2H), 7.48ꢀ7.51 (m, 1H), 7.57ꢀ7.60 (m, 1H), 7.81ꢀ7.84 (m, 1H),
8.13ꢀ8.15 (dd, 1H, J = 1.4, 6.2 Hz); 13C NMR (100 MHz, CDCl3) δ 56.1, 110.4, 112.0, 116.1, 120.2, 120.7,
124.2, 124.9, 131.3, 132.7, 142.1, 150.3, 158.4, 161.5.
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2-(Bis(3,5-dimethylphenyl)amino)phenol (Table 2, entry 7, 3ah).11 Condition A and B: 3,5ꢀdimethylꢀiodobenzene
(0.065 mL, 0.45 mmol) was used for the preparation of the title compound, and it was purified by a silica gel
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column chromatography (dichloromethane/nꢀhexane, 1:5) as a colorless solid (34.0 mg, 71%); H NMR (400
MHz, CDCl3) δ 2.23 (s, 12H), 5.56 (s, 1H), 5.65ꢀ5.67 (d, 6H), 6.90ꢀ6.94 (m, 1H), 7.02ꢀ7.04 (q, 1H), 7.08ꢀ7.11
(q, 1H), 7.16ꢀ7.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 21.3, 99.9, 116.3, 119.8, 121.2, 124.5, 127.3, 129.3,
133.5, 139.0, 146.9, 152.3
2ꢀ(3,5ꢀDimethylphenyl)benzo[d]oxazole (Table 2, entry 7, 4ah)4b Condition C: 3,5ꢀdimethyl iodobenzene (130
mL, 0.90 mmol)was used for the preparation of the title compound, and it was purified by a silica gel column
chromatography (dichloromethane/nꢀhexane, 1:5) as a yellow solid (54.8 mg, 82%); 1H NMR (400 MHz, CDCl3)
δ 2.41 (s, 6H), 7.15 (s, 1H), 7.32ꢀ7.37 (m, 2H), 7.55ꢀ7.58 (m, 1H), 7.76ꢀ7.78 (m, 1H), 7.89(s, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.2, 110.4, 119.8, 124.4, 124.9, 125.3, 126.8, 133.2, 138.5, 142.1, 150.6, 163.4.
2-(Bis(4-fluorophenyl)amino)phenol (Table 2, entry 8, 3ai). Condition A and B: 1ꢀfluoroꢀ4ꢀiodobenzene (0.052
mL, 0.45 mmol) was used for the preparation of the title compound, and it was purified by a silica gel column
chromatography (dichloromethane/nꢀhexane, 1:2) as a yellow solid (33.5 mg, 75%); 1H NMR (400 MHz, CDCl3)
δ 6.85ꢀ6.96 (m, 8H), 7.01ꢀ7.04 (m, 2H), 7.16ꢀ7.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 96.3, 118.1, 127.3,
129.1, 131.2, 133.5, 150.5; HRꢀESIꢀMS (QꢀTOF) m/z calcd. for C18H13F2NO [M+H]+:298.1043, found [M+H]+:
298.1039.
2ꢀ(4ꢀFluorophenyl)benzo[d]oxazole (Table 2, entry 8, 4ai)4b Condition C: 1ꢀfluoroꢀ4ꢀiodobenzene (104 mL, 0.90
mmol)was used for the preparation of the title compound, and it was purified by a silica gel column
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chromatography (dichloromethane/nꢀhexane, 1:5) as a colorless solid (55.0 mg, 86%); H NMR (400 MHz,
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CDCl3) δ 7.17ꢀ7.21 (t, 2H, J = 8.6 Hz), 7.33ꢀ7.35 (m, 2H), 7.54ꢀ7.56 (m, 1H), 7.74ꢀ7.76 (m, 1H), 8.22ꢀ8.25 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 110.5, 116.0, 116.2, 119.9, 123.4, 123.4, 124.6, 125.1, 129.7, 129.8, 142.0,
150.7, 162.1, 163.5, 166.0.
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2-(Bis(4-chlorophenyl)amino)phenol (Table 2, entry 9, 3aj). Condition A and B: 1ꢀchloroꢀ4ꢀiodobenzene (107
mg, 0.45 mmol) was used for the preparation of the title compound, and it was purified by a silica gel column
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chromatography (dichloromethane/nꢀhexane, 1:5) as a yellow solid (33.5 mg, 68%); H NMR (400 MHz,
CDCl3) δ 5.41(s, 1H), 6.92ꢀ6.97 (m, 5H), 7.02ꢀ7.06 (m, 2H), 7.19ꢀ7.23 (m, 5H);13C NMR (100 MHz, CDCl3) δ
117.0, 121.9, 122.9, 128.0, 128.3, 129.3, 132.4, 145.1, 152.2; HRꢀESIꢀMS (QꢀTOF) m/z calcd. for C18H13Cl2NO
[M+H]+: 330.0452, found [M+H]+: 330.0447.
2ꢀ(4ꢀChlorophenyl)benzo[d]oxazole (Table 2, entry 9, 4aj)13a Condition C: 1ꢀchloroꢀ4ꢀiodobenzene (214 mg,
0.90 mmol)was used for the preparation of the title compound, and it was purified by a silica gel column
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chromatography (dichloromethane/nꢀhexane, 1:5) as a colorless solid (38.0 mg, 55%); H NMR (400 MHz,
CDCl3) δ 7.35ꢀ7.38 (m, 2H), 7.49ꢀ7.51 (d, 2H, J = 8.6 Hz), 7.57ꢀ7.59 (m, 1H), 7.76ꢀ7.78 (m, 1H), 8.18ꢀ8.20 (d,
2H, J = 8.6 Hz); 13C NMR (100 MHz, CDCl3) δ 110.6, 120.1, 124.7, 125.3, 125.7, 128.8, 129.3, 137.8, 142.0,
150.8, 162.1.
Experimental procedures for ring-opening double N-arylation with various benzoxazoles (Scheme 3)
2-(Diphenylamino)-3-methylphenol (Scheme 3, 3ba). Condition B: 4ꢀmethylbenzoxazole (38.9 mg, 0.25
mmol)was used for the preparation of the title compound, and it was purified by a silica gel column
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chromatography (dichloromethane/nꢀhexane, 1:5) as a colorless solid (20.4 mg, 49%); H NMR (400 MHz,
CDCl3) δ 2.05 (s, 3H), 5.58 (s, 1H), 6.84ꢀ6.95 (m, 2H), 6.98ꢀ7.02 (m, 2H), 7.08ꢀ7.11 (m, 4H), 7.19ꢀ7.23 (t, 1H),
7.25ꢀ7.29 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 18.4, 113.9, 120.0, 122.1, 123.1, 128.5, 129.4, 130.6, 138.9,
145.3, 153.7; HRꢀESIꢀMS (QꢀTOF) m/z calcd. for C19H17NO [M+H]+: 275.1310, found [M+H]+: 275.1309.
2-(Diphenylamino)-4-methylphenol (Scheme 3, 3ca).10b Condition B: 5ꢀmethylbenzoxazole (20 mg,
0.15mmol)was used for the preparation of the title compound, and it was purified by a silica gel column
chromatography (dichloromethane/nꢀhexane, 1:5) as a yellow solid (20.4 mg, 49%);1H NMR (400 MHz, CDCl3)
δ 2.26 (s, 3H), 5.36 (s, 1H), 6.93ꢀ6.96 (m, 2H), 7.01ꢀ7.08 (m, 7H), 7.26ꢀ7.31 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 20.4, 117.4, 121.3, 121.5, 128.4, 129.2, 129.3, 131.1, 132.8, 147.6, 152.3.
2-(Diphenylamino)-5-methylphenol (Scheme 3, 3da). Condition B: 6ꢀmethylbenzoxazole (38.9 mg, 0.25
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chromatography (dichloromethane/nꢀhexane, 1:5) as a colorless solid (20.8 mg, 50%); H NMR (400 MHz,
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CDCl3) δ 2.37 (s, 1H), 5.50 (s, 1H), 6.76ꢀ6.78 (q, 1H), 6.89ꢀ6.90 (d, 1H), 7.00ꢀ7.08 (m, 7H), 7.26ꢀ7.29 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 21.3, 117.0, 121.6, 122.3, 122.6, 129.2, 129.4, 130.5, 138.1, 146.9, 152.2; HRꢀ
ESIꢀMS (QꢀTOF) m/z calcd. for C19H17NO [M+H]+: 275.1310, found [M+H]+: 275.1312
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3-(Diphenylamino)-[1,1'-biphenyl]-4-ol (Scheme 3, 3ea). Condition B: 5ꢀphenylbenzoxazole (38.9 mg, 0.25
mmol)was used for the preparation of the title compound, and it was purified by a silica gel column
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chromatography (dichloromethane/nꢀhexane, 1:5) as a yellow solid (24 mg, 47%); H NMR (400 MHz, CDCl3)
δ 5.54 (s, 1H), 7.03ꢀ7.07 (m, 2H), 7.10ꢀ7.14 (m, 5H), 7.28ꢀ7.32(m, 5H), 7.367.41 (m, 3H), 7.45ꢀ7.51(m, 3H);
13C NMR (100 MHz, CDCl3) δ 117.0, 121.8, 122.9, 126.3, 126.7, 126.9, 127.9, 128.7, 129.5, 133.4, 134.9,
140.3, 146.7, 151.8.HRꢀESIꢀMS (QꢀTOF) m/z calcd. for C24H19NO [M+H]+: 338.1545, found [M+H]+:
338.1539.
4ꢀChloroꢀ2ꢀ(diphenylamino)phenol (Scheme 3, 3fa).10b Condition B: 5ꢀchlorobenzoxazole(23 mg, 0.15mmol)
was used for the preparation of the title compound, and it was purified by a silica gel column chromatography
(dichloromethane/nꢀhexane, 1:5) as a yellow solid (41 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 5.48 (s,
1H),6.98ꢀ7.01 (d, 1H), 7.05ꢀ7.09 (m, 5H), 7.10ꢀ7.12 (m, 1H), 7.16ꢀ7.19 (m, 1H), 7.28ꢀ7.33 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 118.9, 121.7, 122.2, 123.2, 127.3, 129.5, 129.9, 134.6, 147.2, 153.6.
Experimental procedure for the synthesis of 2-aminophenol from benzoxazole (Scheme 4).
Benzoxazole (18 mg, 0.15 mmol), cesium carbonate (147 mg, 0.45 mmol), and pivalonitrile (0.5 mL) were
added to an ovenꢀdried screwꢀcapped vial. The mixture was vigorously stirred at 120 oC for 18 h. After cooling
to room temperature, the mixture was purified and isolated by a silica gel column chromatography (ethyl
acetate/nꢀhexane, 1:4) as a pale yellow solid (3.8 mg, 23%)
Experimental procedure for the synthesis of 2-(diphenylamino)phenol from 2-aminophenol (Scheme 4).
Condition B: 2ꢀaminophenol (16 mg, 0.15 mmol) was used for the preparation of 2ꢀ(diphenylamino)phenol, and
it was purified by a silica gel column chromatography (ethyl acetate/nꢀhexane, 1:10) as a colorless solid (40 mg,
97%).
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Supporting Information. H and 13C spectra for all obtained compounds. The CIF file for complex 5. This
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material is available free of charge via the Internet at http://pubs.acs.org.
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Author Information
Corresponding Author. Eꢀmail: ykim@chungbuk.ac.kr (Y.K.) and minkim@chungbuk.ac.kr (M.K.)
§
D. K. and K. Y. contributed equally to this work.
Notes. The authors declare no competing financial interest.
Acknowledgements
We thank Dr. Corinne A. Allen (University of California, San Diego, USA) and Hyojin Park (C.B.N.U) for
helpful discussions. This research was supported by Basic Science Research Program through the National
Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning
(2013R1A1A1061399) and the Creative Human Resource Training Project for Regional Innovation though NRF
funded by the Ministry of Education (2014H1C1A1066874).
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