Phenyliodine bis(trifluoroacetate) mediated intramolecular oxidative coupling of electron-rich N-phenyl benzamides

Article abstract of DOI:10.1055/s-0031-1290680

The intramolecular oxidative C-O coupling of N-(4-alkoxy-phenyl) and N-(4-acetamido-phenyl) benzamides was achieved under metal-free conditions by using phenyliodine bis(trifluoroacetate) as oxidant and TMSOTf as catalyst. The reactions afford benzoxazole

Full text of DOI:10.1055/s-0031-1290680

1534▌
LETTER
letter
Phenyliodine Bis(trifluoroacetate) Mediated Intramolecular Oxidative
Coupling of Electron-Rich N-Phenyl Benzamides
Zhengsen Yu, Lijuan Ma, Wei Yu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
E-mail: yuwei@lzu.edu.cn
Received: 15.02.2012; Accepted after revision: 03.04.2012
roacetoxylation at the para position of the N-phenyl ring,
while the electron-withdrawing group substituted coun-
terparts were converted into N-iodophenylation products
in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP)–TFA (10:1).
On the other hand, it was reported that when N-(3,4-dime-
thoxyphenyl)benzamide was subjected to PIFA in
CH2Cl2, the intermolecular C–C oxidative coupling took
place, giving rise to the dimerization product. The reac-
tion proceeded probably via a single-electron-transfer
mechanism.15 These studies indicate that the reactions of
N-arylamides with hypervalent iodine reagents are largely
influenced by the reaction conditions, the structural fea-
tures of the substrates and hypervalent iodine reagents.
We hoped that by choosing reaction conditions and sub-
strates, the hypervalent iodine reagent promoted transfor-
mation from N-arylamides to benzoxazoles could be
realized. Herein we wish to report our preliminary study
toward this goal.
Abstract: The intramolecular oxidative C–O coupling of N-(4-alk-
oxy-phenyl) and N-(4-acetamido-phenyl) benzamides was achieved
under metal-free conditions by using phenyliodine bis(trifluoroace-
tate) as oxidant and TMSOTf as catalyst. The reactions afford benz-
oxazole products in high yields.
Key words: hypervalent iodine, N-phenyl benzamides, cyclization,
oxidative coupling, benzoxazoles
PhI(OAc)2 (PIDA) and PhI(OCOCF3)2 (PIFA) are versa-
tile organic hypervalent iodine reagents which have found
wide applications in organic synthesis.1 One characteristic
property of PIDA and PIFA is that they are capable of pro-
moting the oxidative couplings involving electron-rich ar-
omatic compounds: for instances, the intra- and
intermolecular biaryl coupling,2,3 the C–C bond formation
between aryl rings and other groups,4 and the functional-
ization of aromatic rings.5 It is also possible to apply the
reactions to the synthesis of aromatic heterocycles via in-
tramoleluar CAr–H/X (X = N, O, S, etc.) coupling,6–8 but
studies toward this end are not fully explored.
Our investigation was initiated by treating N-phenyl benz-
amide 1a with PIFA in several non-nucleophilic solvents
such as CH2Cl2, trifluoroethanol (TFE), HFIP, and
MeCN. When CH2Cl2 was used as solvent, the reaction
did not take place, with the starting material being recov-
ered. Using Lewis acids such as BF3·OEt2 and TMSOTf
as catalyst resulted in the decomposition of 1a. When 3.0
equivalents of trifluoroacetic acid (TFA) were used in
combination with PIFA, the benzoxazole product 2a was
generated in 10% yield (Scheme 1). No improvement was
made when the reaction was performed in other solvents.
PIDA was ineffective to promote the desired reaction ei-
ther under various conditions.
Benzoxazoles have long been of interest to synthetic or-
ganic chemists due to their important applications in me-
dicinal chemistry.9 Recently, Ueda and Nagasawa
reported a very efficient synthesis of benzoxazoles from
anilides via Cu(OTf)2-catalyzed intramolecular oxidative
C–O coupling.10 We anticipated that this transformation
might also be achieved under metal-free conditions by us-
ing PIDA or PIFA as oxidant. However, the reactions of
anilides with hypervalent iodine(III) reagents were inves-
tigated before, but no benzoxazole products have been re-
ported in these works so far to our knowledge. In an early
study, Barlin and Riggs found that acetanilides having
electron-donating substituents at the para position reacted
with PIDA to afford meta-acetoxy-substituted products in
high yields.11 The reaction was later demonstrated to pro-
ceed via an ionic pathway by Nair et al.12 Recently, Gu re-
ported that the reaction between anilides and PIFA led to
the direct para acetoxylation and etherification of ani-
lides.13 Kikugawa et al. investigated the reaction between
N-arylamides and PIFA, and found that the composition
of the products depended on the electronic nature of ani-
lides and reaction conditions.14 The reaction of electron-
rich anilides in TFA (10 equiv)–CHCl3 led to the trifluo-
PIFA (1.2 equiv)
O
TFA (3.0 equiv)
CH2Cl2, r.t.
O
Ph
N
N
Ph
H
1a
2a 10%
Scheme 1
We speculated that the disappointing results with 1a
might be due to the lack of substituents to stabilize the cat-
ion species that was expected to generate during the reac-
tion. Therefore, N-(4-ethoxyphenyl)benzamide (1b) was
chosen next as the substrate and was subjected to the reac-
tion conditions previously used upon 1a. The results are
shown in Table 1.
SYNLETT 2012, 23, 1534–1540
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DOI: 10.1055/s-0031-1290680; Art ID: ST-2012-W0139-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxidative C–O Coupling of Electron-Rich N-Phenyl Benzamides
1535
PIDA (1.2 equiv)
TMSOTf (2.0 equiv)
O
EtO
PIDA (1.2 equiv)
O
O
2b
MeCN, r.t.
42%
MeCN, r.t.
21%
N
Ph
N
Ph
H
1b
4b
Scheme 2
When the reaction was carried out in CH2Cl2 with PIFA as Compounds shown in Figure 1 decomposed mostly under
oxidant in the absence of Lewis acid, benzoxazole 2b was the reaction conditions.
generated in only trace amount, and the major product was
found to be compound 3b (Table 1, entry 1). Using MeCN
Two different mechanisms might account for the forma-
tion of benzoxazole products (Scheme 3). One involves
as solvent raised the yield of 3b (81%, Table 1, entry 2).
the electrophilic activation of the N-phenyl ring in the
On the other hand, the reaction in TFE resulted in the de-
form of nitrenium ion, which is generated from the attack
composition of 1b (Table 1, entry 3). The desired 2b was
of PIFA on the amide moiety [Scheme 3, path (a)].14 In
this mechanism, compound 1b firstly reacts with PIFA to
generate intermediate A, which is converted into the nitre-
nium ion B by cleavage of the N–I bond. The formation of
B is largely favored by the presence of para alkoxy group.
In the next step, a nucleophilic attack at the phenyl ring by
formed in 12% yield when the reaction was conducted in
HFIP (Table 1, entry 4). In contrast to these results, when
TMSOTf was used in combination with PIFA, the expect-
ed reaction took place in CH2Cl2, MeCN, and TFE at
room temperature, giving rise to compound 2b in varying
yields. Using 2.0 equivalents of TMSOTf guaranteed a
complete conversion in five minutes. MeCN performed
the best among these three solvents (Table 1, entry 12).
The reaction also took place at low temperature (Table 1,
entry 8). Similar results were obtained with BF3·OEt2 as
the catalyst except in TFE (Table 1, entry 13). However,
when THF was used as solvent, the reaction proceeded
poorly, with 1b mostly decomposed (Table 1, entry 15).
Table 1 Screening of the Conditions for the Reaction of 1b with
PIFAa
Entry Solvent
Additive
(equiv)
Reaction Product Yield
time (min)
(%)b
1
2
CH2Cl2
MeCN
none
none
120
2b
3b
trace
47
N-(4-Ethoxyphenyl)benzamide (1b) can also react with
PIDA to afford 2b with the assistance of TMSOTf or
BF3·OEt2, but the yield was considerably lower (Scheme
2). In the absence of Lewis acid, on the other hand, the re-
action generated unexpectedly compound 4b in low yield.
120
2b
3b
trace
81
c
3
4
TFE
none
10
10
5
–
HFIP
none
2b
2b
2b
2b
2b
2b
2b
2b
2b
12
30
58
53
50d
55d
30
74
78
To further improve the yield of the benzoxazole product,
we performed the reaction in dilute solution (with concen-
tration of 1b at 0.01 M) under the conditions otherwise the
same as shown in Table 1, entry 12. As expected, the yield
of 2b was raised to 96%. These conditions were then ap-
plied to a variety of substituted anilides, and the results are
summarized in Table 2. The reaction proceeded very fast
for N-(4-alkyloxy-phenyl) benzamides, and the corre-
sponding benzoxazoles were generated in high yields (Ta-
ble 2, entries 1–9). Compound 1k and 1l were transformed
smoothly to 2k and 2l too in good yields (Table 2, entries
10 and 11). However, the expected reaction failed to take
place for compounds 1m–p (Table 2, entries 11–14).
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
MeCN
TFE
TMSOTf (1.0)
TMSOTf (2.0)
BF3·OEt2 (2.0)
TMSOTf (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (1.0)
BF3·OEt2 (2.0)
TMSOTf (2.0)
BF3·OEt2 (2.0)
TMSOTf (2.0)
TMSOTf (2.0)
6
5
7
5
8
5
9
5
10
11
12
13
14
15
5
5
5
c
5
–
TFE
5
2b
2b
41
5
TBSO
HO
Me
O
O
O
THF
5
N
N
N
Ph
Ph
Ph
OH
H
H
H
H
EtO
O
N
1q
1r
1s
N
Ph
Ph
O
O
O
EtO
R1
Ph
N
N
Ph
2b
3b
H
H
R2
a The reaction was carried out on 0.2 mmol scale in 2 mL solvent at
r.t. unless otherwise specified.
1t R1 = OMe, R2 = H
1u R1 = H, R2 = OMe
1v
b Isolated yield.
c The substrate decomposed under the conditions.
d The reaction was performed at –40 °C.
Figure 1 Compounds decomposed mostly under the reaction condi-
tions
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1534–1540

1536
Z. Yu et al.
LETTER
the carbonyl oxygen generates cyclization product C, tuted substrates were suitable for the reaction. For
from which 2b is formed after deprotonation. The other compounds less electronically rich and with higher oxida-
possible mechanism involves the single electron transfer tion potentials, such as 1a and 1s, other competitive path-
(SET) from 1b to PIFA [Scheme 3, path (b)]. This mech- ways would dominate. Compounds 1q, 1r, and 1u, despite
anism has been employed generally to rationalize the in- being electronically rich, were labile to decompose under
tra- and intermolecular oxidative coupling of electron- the reaction conditions. The failure of compounds 1m–p
rich aromatic compounds.2,3 Both mechanisms are consis- suggests that the nucleophilicity of the amido oxygen
tent with the fact that only electron-rich 4-alkoxy-substi- atom also has a large influence on the reaction.
Table 2 The Reactions of N-Phenyl Anilides with PIFAa,16,17
Entry
1
Substrate
Product
Yield (%)b
96
EtO
O
N
H
N
O
2b
EtO
1b
Me
EtO
O
N
2
3
4
5
97
98
93
90
H
N
Me
OMe
Br
O
O
2c
EtO
1c
OMe
EtO
O
N
H
N
2d
EtO
1d
Br
EtO
O
N
H
N
O
O
2e
EtO
1e
OTBS
EtO
O
N
H
N
OTBS
2f
EtO
1f
I
6
7
8
72
96
99
MeO
H
O
N
N
O
I
MeO
2g
1g
Me
H
N
MeO
O
N
Me
O
MeO
2h
1h
MeO
O
N
Me
H
N
O
Me
MeO
2i
1i
Synlett 2012, 23, 1534–1540
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxidative C–O Coupling of Electron-Rich N-Phenyl Benzamides
1537
Table 2 The Reactions of N-Phenyl Anilides with PIFAa,16,17 (continued)
Entry
9
Substrate
Product
Yield (%)b
88
MeO
O
N
H
N
I
I
O
MeO
2j
1j
MeO
O
O
N
O
10
74
H
N
O
O
MeO
2k
1k
MeO
H
N
O
N
Ph
11
12
76
–
Ph
MeO
2l
1l
NO2
n.r.c
H
N
O
EtO
1m
13
decomp.d
–
H
N
N
O
O
EtO
1n
H
N
14
15
n.r.c
–
–
Me
EtO
1o
H
decomp.d
Me
N
O
MeO
1p
a The reaction was performed at 0.01 M in MeCN.
b Isolated yield.
c No reaction took place after prolonged reaction time.
d The starting material decomposed.
As shown in Table 1, Lewis acids BF3·OEt2 and TMSOTf The unreactiveness of N-(4-ethoxy-phenyl) acetanilide
played a critical role in determining the reaction course. In (1o) towards PIFA suggested that if the acetamido group,
the absence of BF3·OEt2 or TMSOTf, compound 3b was an electron-donating group too, was attached to the para
obtained after workup when the reaction was carried out position of the N-phenyl ring of benzamide, selective C–
in MeCN and CH2Cl2 (Table 1, entries 1 and 2), whereas O coupling would be observed for the benzamido group.
in the presence of these Lewis acids, the intramolecular Indeed, when compounds 5a–f were treated with PIFA in
C–O coupling took place readily. It is well-known that ac- the presence of TMSOTf, 6a–f were obtained, respective-
ids can promote the hypervalent iodine reagent mediated ly, in satisfactory yields (Table 3, entries 1–6). In the case
electron transfer process as well as the geneation of inter- of 5c, deprotection product 6c′ was generated along with
mediates like B.2,3,14 As a result, the formation of benzox- 6c. Compound 5g can be converted into the symmetrical
azoles was facilitated by BF3·OEt2 or TMSOTf according benzodioxazole 6g if excessive amount of PIFA and
to the mechanisms shown in Scheme 3.
TMSOTf were used (Table 3, entry 7). It is worthy of note
that while TMSOTf was effective to catalyze the reac-
tions, using BF3·OEt2 as catalyst failed to convert 5a into
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1534–1540

1538
Z. Yu et al.
LETTER
EtO
O
EtO
EtO
H
O
O
+
+
N
Ph
– PhI
N
Ph
N
Ph
+I
PIFA,
Lewis acid
B
Ph
A
(a)
(b)
H
EtO
O
N
1b
Ph
2b
+
– H+
C
[O]
PIFA,
Lewis acid
H
N
Ph
N
Ph
+
•
– H+
O
O
EtO
EtO
H
D
E
Scheme 3
6a. On the other hand, the results were unsatisfactory the reaction to proceed. The reaction was very sensitive to
when the substrate was compound 5h or 5i. The majority the structure features of the substrates. While N-(4-alk-
of these two compounds decomposed under these reaction oxy-phenyl)benzamides could be converted into corre-
conditions (Table 3, entries 8 and 9).
sponding benzoxazoles in high yields, N-(4-alkoxy-
phenyl)acetanilde was unreactive under the same condi-
tions. Consequently, selective C–O coupling can be
achieved for N-(4-acetamido-phenyl)benzamides.
In summary, we found that PIFA could promote the intra-
molecular oxidative coupling of electron-rich N-phenyl
benzamides to generate benzoxazole products. The use of
Lewis acid such as BF3·OEt2 and TMSOTf was critical for
Table 3 The Selective C–O Coupling for Compounds 5a,16,17
Entry
1
Substrate
Product (s)
Yield (%)b
86
AcHN
AcHN
O
N
O
Ph
N
H
Ph
6a
5a
AcHN
AcHN
O
N
2
3
96
O
O
C6H4-4-OMe
N
H
C6H4-4-OMe
C6H4-4-OTBS
6b
5b
AcHN
AcHN
O
N
6c
C6H4-4-OTBS
55
6c′
23
N
H
6c
5c
AcHN
O
N
C6H4-4-OH
C6H4-3-Me
6c′
AcHN
AcHN
O
N
4
90
O
N
H
C6H4-3-Me
6d
5d
Synlett 2012, 23, 1534–1540
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxidative C–O Coupling of Electron-Rich N-Phenyl Benzamides
1539
Table 3 The Selective C–O Coupling for Compounds 5a,16,17 (continued)
Entry
5
Substrate
Product (s)
Yield (%)b
75
AcHN
AcHN
O
N
O
O
C6H4-2-Cl
C6H3-3,5-2Me
Ph
N
H
C6H4-2-Cl
6e
5e
AcHN
AcHN
O
N
6
7
99
N
H
C6H3-3,5-2Me
6f
5f
N
H
82c
O
N
N
Ph
Ph
O
O
O
N
Ph
H
6g
5g
BocHN
BocHN
37d
27d
O
8
9
O
Ph
N
N
Ph
H
6h
5h
BocHN
BocHN
O
N
O
C6H4-4-Br
N
H
C6H4-4-Br
6i
5i
a Conditions: 1.2 equiv of PIFA and 2.0 equiv of TMSOTf were used unless otherwise specified. The reaction time was 5 min at r.t.
b Isolated yield.
c Conditions: 3.0 equiv of PIFA and 4.0 equiv of TMSOTf were used.
d Conditions: 1.2 equiv of BF3·OEt2 was used as Lewis acid. Using TMSOTf resulted in lower yield of the desired product.
(3) For examples of intermolecular aryl–aryl coupling, please
Acknowledgment
see: (a) Dohi, T.; Morimoto, K.; Kiyono, Y.; Maruyama, A.;
Tohma, H.; Kita, Y. Chem. Commun. 2005, 2930. (b) Dohi,
T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett. 2006,
The authors thank the National Natural Science Foundation of
China (No. 20772053) for financial support.
8, 2007. (c) Dohi, T.; Ito, M.; Morimoto, K.; Iwata, M.; Kita,
Y. Angew. Chem. Int. Ed. 2008, 47, 1301. (d) Kita, Y.;
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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4272.
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(12) Kokil, P. B.; Patil, S. D.; Ravindranathan, T.; Nair, P. M.
Tetrahedron Lett. 1979, 20, 989.
(13) Liu, H.; Wang, X.; Gu, Y. Org. Biomol. Chem. 2011, 9,
1614.
(14) Itoh, N.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. J. Org.
Chem. 2002, 67, 7424.
(17) Typical Spectroscopic Data for the Products
6-Ethoxy-2-(4-bromophenyl)benzo[d]oxazole (2e)
White solid; mp 136–138 °C. 1H NMR (400 MHz, CDCl3):
δ = 1.46 (t, 3 H, J = 7.2 Hz, CH3CH2), 4.08 (q, 2 H, J = 7.2
Hz, OCH2), 6.95 (dd, 1 H, J = 8.8, 2.4 Hz, C5-H), 7.06 (d, 1
H, J = 2.4 Hz, C7-H), 7.61 (d, 1 H, J = 8.8 Hz, C4-H), 7.62
(d, 2 H, J = 8.4 Hz, 4-BrPhH), 8.04 (d, 2 H, J = 8.4 Hz, 4-
BrPhH). 13C NMR (100 MHz, CDCl3): δ = 14.8, 64.2, 96.0,
113.5, 120.0, 125.6, 126.3, 128.5, 132.1, 135.6, 151.6,
157.8, 161.2. MS (EI): m/z (rel. int., %) = 317 (71) [M+], 262
(7), 210 (10), 183 (21), 79 (54), 51 (100). ESI-HRMS: m/z
calcd for C15H12BrNO2 + H: 318.0124; found: 318.0134
N-{2-Phenylbenzo[d]oxazol-6-yl}acetamide (6a)
Light yellow solid; mp 176–177 °C. 1H NMR (400 MHz,
acetone-d6): δ = 2.13 (s, 3 H, CH3CO), 7.38 (dd, 1 H, J = 8.8,
1.6 Hz, C5-H), 7.59–7.61 (m, 3 H, PhH), 7.64 (d, 1 H, J = 8.8
Hz, C4-H), 8.21–8.24 (m, 2 H, PhH), 8.39 (d, 1 H, J = 1.6 Hz,
C7-H), 9.50 (br s, 1 H, NH). 13C NMR (100 MHz, acetone-
d6): δ = 24.4, 102.3, 117.2, 120.5, 128.1, 128.2, 130.0, 132.3,
138.6, 138.7, 152.0, 163.3, 169.2. MS (EI): m/z (rel. int., %)
= 252 (39) [M+], 210 (100), 149 (6). ESI-HRMS: m/z calcd
for C15H12N2O2 + H: 253.0972; found: 253.0973
N-{2-(4-Methoxyphenyl)benzo[d]oxazol-6-yl}acetamide
(6b)
Light yellow solid; mp 187–189 °C. 1H NMR (400 MHz,
DMSO-d6): δ = 2.09 (s, 3 H, CH3CO), 3.85 (s, 3 H, OCH3),
7.13 (d, 2 H, J = 8.4 Hz, 4-MeOPhH), 7.37 (d, 1 H, J = 8.4
Hz, C5-H), 7.65 (d, 1 H, J = 8.8 Hz, C4-H), 8.09 (d, 2 H, J =
8.8 Hz, 4-MeOPhH), 8.22 (s, 1 H, C7-H), 10.22 (br s, 1 H,
NH). 13C NMR (100 MHz, DMSO-d6): δ = 24.0, 55.5, 101.1,
114.7, 116.2, 118.9, 119.1, 128.8, 136.9, 137.1, 150.2,
161.9, 162.0, 168.4. MS (EI): m/z (rel. int., %) = 282 (15)
[M+], 240 (18), 225 (10), 178 (12), 149 (100). ESI-HRMS:
m/z calcd for C16H14N2O3 + H: 283.1077; found: 283.1080.
(15) Moreno, I.; Tellitu, I.; Etayo, J.; SanMartin, R.; Domínguez,
E. Tetrahedron 2001, 57, 5403.
(16) General Procedure for the Reactions of 1 (or 5)
To a stirred MeCN solution (40 mL) containing 1 (or 5, 0.5
mmol) and TMSOTf (1.0 mmol) was added dropwise PIFA
(0.6 mmol) in MeCN (10 mL). The stirring was continued at
r.t. for another 5 min. The mixture was then poured into a sat.
NaHCO3 solution (100 mL), and the product was extracted
Synlett 2012, 23, 1534–1540
© Georg Thieme Verlag Stuttgart · New York