Substituent electronic effects govern direct intramolecular C-N cyclization of N -(biphenyl)pyridin-2-amines induced by hypervalent iodine(III) reagents

Article abstract of DOI:10.1021/jo501822m

The hypervalent iodine(III) reagent-induced the direct intramolecular C-N cyclization of N-(biphenyl)pyridin-2-amines to 6-arylbenzimidazoles and N-pyridinyl-9H-carbazoles is presented. The substituent electronic effects governing the formation of benzimi

Full text of DOI:10.1021/jo501822m

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Article
Substituent Electronic Effects Govern Direct Intramolecular C-N Cyclization
of N-(Biphenyl)pyridin-2-amines Induced by Hypervalent Iodine(III) Reagents
Jean-Ho Chu, Wen-Ting Hsu, Yi-Hua Wu, Meng-Fan
Chiang, Nan-Hai Hsu, Hao-Ping Huang, and Ming-Jung Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501822m • Publication Date (Web): 04 Nov 2014
Downloaded from http://pubs.acs.org on November 11, 2014
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Substituent Electronic Effects Govern Direct Intramolecular
C-N Cyclization of N-(Biphenyl)pyridin-2-amines Induced by
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Hypervalent Iodine(III) Reagents
§
§
Jean-Ho Chu,* Wen-Ting Hsu, Yi-Hua Wu, Meng-Fan Chiang, Nan-Hai Hsu, Hao-Ping Huang,
and Ming-Jung Wu*
Department of Chemistry, National Sun Yat-sen University, Kaohsiung, Taiwan 804
E-mail: j_hchu@yahoo.com.tw; mijuwu@faculty.nsysu.edu.tw
ABSTRACT: The hypervalent iodine(III) reagents induced the direct intramolecular C-N
cyclization of N-(biphenyl)pyridin-2-amines to establish a variety of 6-arylbenzimidazoles and
N-pyridinyl-9H-carbazoles is presented. The substituent electronic effects govern the formation of
benzimidazoles and carbazoles from the reaction of N-(biphenyl)pyridin-2-amines with hypervalent
iodine(III) reagents is investigated. Radical trapping and UV-Vis spectroscopic experiments on the
detection of the cation radical are carried out. Rational mechanisms for these reactions are presented.
The selective intramolecular C-N and C-O cyclization of N-(biphenyl)acetamides based on the
substituent electronic effects is also presented.
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INTRODUCTION
The aromatic C-N bond formation is of great importance in synthetic chemistry on constructing
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many natural products, pharmaceuticals, and optoelectronics. Among various notable C-N
2
coupling reactions, the Buchwald-Hartwig amination remains outstanding due to the provided mild
reaction conditions, extensive substrate scope, high functional group compatibility, and further
3
,4
applications. Significant advances have been made on conventional C(Ar)-N coupling reactions,
however, these methodologies used to employ prefunctionalized materials (e.g., aryl halides) with
2
amines or amides. The direct C-N coupling without using prefunctionalized materials therefore
5
reveals its merit in organic synthesis.
The direct intramolecular C-N coupling via C-H activation has been recognized as a very
powerful and efficient method to establish various nitrogen heteroarenes, such as carbazoles,
6
benzimidazoles, indoles and phenathridines. A pioneering work on the direct intramolecular C-N
cyclization of N-(biphenyl)acetamides to N-acetyl-9H-carbazoles via palladium(II)-catalyzed C-H
6a
6b
6c
6d
activation had been reported by the Buchwald group in 2005. Gaunt, Driver, Youn, and Chu
6
e,f
and Wu
subsequently presented the direct intramolecular C-N cyclization of
2-azido-1,1’-biphenyl, N-(tosyl)biphenyl-2-amines, and
N-(benzyl)biphenyl-2-amines,
N-(biphenyl)pyridin-2-amines to N-benzyl-9H-carbazoles, 9H-carbazoles, N-tosyl-9H-carbazoles,
and N-pyridinyl-9H-carbazoles, respectively, which were carried out by the palladium(II) and
rhodium(II) catalysts. Very recently, the use of copper(II) catalyst for the direct intramolecular C-N
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coupling of N-(biphenyl)picolinamides to 9H-carbazoles via the direct oxidation/coupling of C-H
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and N-H bonds was reported by Hirano and Miura. On the other hand, the Chang and
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Antonchick groups employed PhI(OAc) as the oxidant into the direct intramolecular C-N
cyclization of N-(biphenyl)benzenesulfonamides and N-biphenyl-4-methylbenzenesulfonamides to
form N-phenylsulfonyl-9H-carbazoles and N-tosyl-9H-carbazoles, respectively. Moreover, Chang
2
and co-workers found that the addition of Cu(OTf) can facilitate the reaction, whereas the
Antonchick group carried out the reaction by using a catalytic amount of PhI(OAc)
in the presence of 2,2’-diiodo-4,4’,6,6’-tetramethylbiphenyl and peracetic acid.
2
as the catalyst
6
j
6k
6l-o
6p
In addition to carbazoles formation, Kutsumura and Saito, Maes, Zhu, Punniyamurthy,
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q
6r
Das,
and Antonchick presented the synthesis of benzimidazoles direct from either
N-(phenyl)pyridin-2-amines or amidines via the intramolecular C-N bond formation using a
2
stoichiometric amount of hypervalent iodine(III) reagents and a catalytic amount of Cu(OAc) ,
respectively. Kutsumura and Saito also used N-dihydrothiazin-2-yl and N-oxazin-2-yl anilines as
the starting substrates. In the Maes group, they used the catalytic amount of Cu(OAc)
2
H
2
O with
3
,4,5-trifluorobenzoic acid as a superior additive to achieve the synthesis of benzimidazoles in good
product yields. Zhu and co-workers combined Fe(NO
3
)
3
2 2
9H O with Cu(OAc) to generate an active
copper(III) species to catalyze the synthesis of benzimidazoles via an electrophilic aromatic
substitution pathway. Furthermore, an in situ preparation of the hypervalent iodine(III) reagent was
developed by the same group and able to catalyze the C-H cycloamination of
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N-aryl-2-aminopyridines and N-arylamidines. They additionally utilized that PhI(OPiv)
2
in
1
2
,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and PhI(OAc)
2 2 3
combining Cs CO as an additive in
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,2,2-trifluoroethanol (TFE) to perform the synthesis of benzimidazoles through the
demethylenation/C-H cycloamination of N-benzyl-2-aminopyridines and the direct C-H imidation
of N-arylamidines, respectively. On the other hand, the Punniyamurthy group used iodobenzene as a
precatalyst to furnish the synthesis of benzimidazoles in the presence of mCPBA through the C-H
amination of N-subsituted amidines. Das and co-workers also reported the synthesis of
2
benzimidazoles catalyzed by PhI(OAc) in water. Recently, the Antonchick group achieved the
2
PhI(OAc) -catalyzed the annulation of arenes with 2-aminopyridines in HFIP to produce various
benzimidazoles within a methyl group as a traceless non-chelating directing group.
6e,f
From the above reports and our previous work, we were interested in a direct intramolecular
C-N bond formation of the starting substrates bearing two feasible C-N coupling sites. Which
coupling pathway does it prefer to take place in the situation? N-(Biphenyl)pyridin-2-amines were
thus chosen as model molecules to investigate the site selectivity under the hypervalent iodine(III)
reagent conditions, and we especially focused on the influence of the substituent electronic effects.
Radical trapping and UV-Vis spectroscopic experiments were also applied to elucidate whether a
cation radical intermediate was generated in the course of the reaction. Finally, the selective
intramolecular C-N and C-O cyclization of N-(biphenyl)acetamides was studied based on the
substituent electronic effects.
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RESULTS AND DISCUSSION
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Optimization for the Direct Intramolecular C-N Cyclization of N-(Biphenyl)pyridin-2-amines:
First, starting substrates 1 for the presented study were prepared by the reaction of
N-phenylpyridin-2-amines (8) with a series of arylborane reagents 9 and 10 via
palladium(II)-catalyzed direct C-H activation and arylation using copper(II) acetate and
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e,f
p-benzoquinone (BQ) as the oxidant and promotor, respectively, in tert-butyl alcohol (the detail
synthetic procedure, please see the Experimental Section). Subsequently, the direct intramolecular
C-N cyclization of N-(biphenyl)pyridin-2-amines
1
to 6-arylbenzimidazoles
by the reaction
2
and
of
N-pyridinyl-9H-carbazoles was examined
3
2
N-([1,1'-biphenyl]-2-yl)pyridin-2-amine (1a) with iodobenzene diacetate (PhI(OAc) ) and
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iodobenzene bis(trifluoroacetate) (PhI(OTFA)
2
), respectively, in dichloromethane. These
o
experimental results are summarized in Table 1. First, the reaction was carried out at 0 C to room
temperature and traced by Thin-Layer Chromatography (TLC) and we found that substrate 1a was
2 2
almost consumed within 1-2 hours using either PhI(OAc) or PhI(OTFA) as the oxidant. In these
two cases, 6-phenylbenzimidazole 2a was generated as the major product (48% yield for both of
PhI(OAc) and PhI(OTFA) ) while N-pyridinyl-9H-carbazole 3a as the minor product (6% yield for
2
2
PhI(OAc)
2
2
and 8% for PhI(OTFA) ) (entry 1 and 5, Table 1). Herein, an additional product,
2
8-acetoxy-6-phenylbenzimidazole (2’a) was isolated in 11% yield by the use of PhI(OAc) ,
2
however, none of such product (i.e., 2’a) was obtained when PhI(OAc) was replaced by
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PhI(OTFA)
2
in the reaction. In order to examine the influence of the reaction temperature, the
o
reaction was subsequently proceeding at room temperature, 40-50, and 60-70 C. According to
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experimental results, substrate 1a was again consumed within 1-2, 0.5 hours, and 10 minutes,
2 2
respectively, at these reaction temperatures and whatever PhI(OAc) or PhI(OTFA) was used
(entries 2-4 and 6-8, Table 1). Although a higher reaction temperature can efficiently reduce the
reaction time, the product yields and ratios of 2a, 2’a, and 3a do not have much difference at these
reaction temperatures (see Table 1). We therefore chose room temperature as the optimal reaction
temperature for the direct intramolecular C-N cyclization of 1.
Table 1. Optimization for the Direct Transformation of 1a to 2a, 2’a and 3a
product
o
total yield
entry iodine(III)
T ( C)
t (h)
ratio
b
a
(%)
(2a:2’a:3a)
1
2
0-rt
rt
2
2
74:17:9
71:18:11
69:19:12
62:28:10
85:0:15
94:0:6
65
88
88
89
56
80
85
89
PhI(OAc)
2
3
4
5
6
7
8
40-50
0.5
60-70 10 min
0-rt
rt
1
1
PhI(OTFA)
2
40-50
0.5
93:0:7
60-70 10 min
93:0:7
a
b
Product ratio was determined by GC-FID for three runs. Product yield was obtained as an average for three runs by
GC-FID (using n-octadecane as the internal standard).
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Substrate Scope: With the optimal reaction conditions in hand (1.5 equivalents of iodine(III)
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2 2
reagents in CH Cl at room temperature for 1-2 hours), we subsequently carried out the reaction of
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2 2
with either PhI(OAc) or PhI(OTFA) to give these following C-N coupling products,
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-arylbenzimidazoles 2, 8-acetoxy-6-arylbenzimidazoles 2’ and N-pyridinyl-9H-carbazoles 3 in
modest to excellent total yields (30-99%, Table 2). Substrates 1a-c bearing a hydrogen, methyl, and
tert-butyl substituent, respectively, by the treatment of PhI(OAc) afforded 6-arylbenzimidazoles
2
2a-c as major products (45-57% yields) and both of 8-acetoxy-6-arylbenzimidazoles 2’a-c and
N-pyridinyl-9H-carbazoles 3a-c as minor products (43-55% yields) (entries 1-3, Table 2). Product
ratios of 2a-c, 2’a-c, and 3a-c were determined by GC-FID to be 71:18:11, 60:26:14, and 56:28:16,
respectively. The reaction of 1d bearing a naphthyl group with PhI(OAc)
2
produced
8
N-pyridinyl-9H-carbazole 3d
(65% yield) with two concomitant minor products,
6
-naphthylbenzimidazole 2d (13% yield) and 8-acetoxy-6-naphthylbenzimidazole 2’d (7% yield)
(
entry 4, Table 2). Furthermore, substrates 1e-h bearing a halogen group (F-, Cl, Br-, and I-) were
also introduced into the reaction to give a mixture of benzimidazoles 2e-g and 8-acetoxy-substituted
benzimidazoles 2’e-g in product ratios 2e:2’e = 88:12, 2f:2’f = 85:15, and 2g:2’g = 72:28 by
GC-FID with 87-90% total yields and none of N-pyridinyl-9H-carbazoles 3e-g was isolated (entries
5
-7, Table 2). However, only a single product, benzimidazole 2h (80% yield) was isolated in the
case of 1h (entry 8, Table 2). In addition, we isolated benzimidazoles 2i-m as a single product in
2
70-96% yields from the reaction of 1i-m with PhI(OAc) (entries 9-13, Table 2). In these cases of 1i
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and 1j, the electron-withdrawing group (-CHO and -NO ) might disfavor the acetoxylation on the
N-phenyl ring that eventually resulted in none of products 2’i-j formed. On the other hand, the
halogen substituent (F-, Cl-, and Br-) tagged at the para position of the N-phenyl ring in substrates
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2 2 2
k-m prevented the acetoxylation by PhI(OAc) . In addition to PhI(OAc) , PhI(OTFA) was also
employed to substrates 1 under the aforementioned reaction conditions that eventually generated the
alternative of benzimidazole 2 and carbazole 3 where none of acetoxylated products 2’ was formed
-
(see Table 2). This might be due to the poor reactivity of the trifluoroacetate anion ( OTFA). Other
2 2
than that, the reaction of 1a-m with PhI(OTFA) showed similar results with that of PhI(OAc) in
terms of chemical yields and product ratios. These structures of benzimidazoles 2f and 2’f were
9
finally secured by X-ray crystallography (see Figure S2, Supporting Information).
Table 2. Direct Intramolecular C-N Cyclization of 1 to 2, 2’, and 3 Induced by Either of
PhI(OAc)
2
and PhI(OTFA)
2
a
b
entry
1
substrate 1
product ratio (2:2’:3)
total yield (%)
80 (75), 74 (70)
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1:18:11 (97:0:3)
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82 (83), 76 (75)
75 (84), 70 (79)
30 (38), 24 (32)
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6:28:16 (90:0:10)
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60:26:14 (97:0:3)
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5:8:77 (43:0:57)
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87 (88), 83 (85)
88 (89), 85 (85)
80 (54), 74 (50)
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8:12
8
5:15
72:28
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6
8
80 (90), 73 (85)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
70 (80), 65 (76)
1
0
1
2
3
96 (99), 91 (95)
70 (79), 64 (74)
79 (73), 75 (70)
71 (74), 65 (70)
N
N
N
HN
1
1
1
F
F
1k
2k
N
N
N
HN
Cl
Cl
1l
2l
N
N
N
HN
Br
Br
1m
2m
a
Product ratio was determined by GC-FID for three runs and the ratio in the parentheses is from the treatment of
b
PhI(OTFA) . Product yield was determined as an average by GC-FID for three runs (using n-octadecane as the internal
2
standard) and the value in the parentheses is from the treatment of PhI(OTFA) . The isolated yield was reported after the
2
1
0
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2
3
4
2 2
comma for both of PhI(OAc) and PhI(OTFA) .
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Based on the above experimental results, we found that the substituent electronic effects seem to
play as an important factor for the formation of benzimidazole 2 and carbazole 3 in the direct
intramolecular C-N cyclization of N-(biphenyl)pyridin-2-amines 1.
Substituent Electronic Effects in the Direct Intramolecular C-N Cyclization of 1: In order to
verify the influence of the substituent electronic effects in the direct intramolecular C-N cyclization
of 1, we employed substrates 1n-u bearing the alternative of methoxy (-OMe, a strong
2
electron-donating substituent) and nitro group (-NO , a strong electron-withdrawing substituent) to
investigate the site selectivity of the direct intramolecular C-N cyclization of 1. These experimental
results are summarized in Table 3. We found that the reaction of substrates 1n-u with PhI(OTFA)
2
only produced a single product, 6-arylbenzimidazole 2 or N-pyridinyl-9H-carbazole 3 (see Table
10
3
). First, substrate 1n (R
1
= OMe/R
2
= H) was transformed to carbazole 3n in 95% yield (entry 1,
1 2 2
Table 3). By contrast, substrate 1o (R = H/R = OMe) by the treatment of PhI(OTFA) generated
benzimidazole 2o in 82% yield (entry 2, Table 3). We subsequently carried out the reaction of 1p
R = NO /R = H) and 1q (R = H/R = NO ) with PhI(OTFA) and found the anticipated
(
1
2
2
1
2
2
2
benzimidazole 2p and carbazole 3q were produced in 90% and 80% yields, respectively (entry 3
11
and 4, Table 3). On the basis of the above experimental results, the formation of benzimidazole 2
2
and carbazole 3 in the reaction of 1 with PhIX (X = OAc and OTFA) can indeed selectively be
11
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
controlled not only by a strong electron-donating substituent (e.g., -OMe) but also a strong
2
electron-withdrawing substituent (e.g., -NO ). In addition to 1n-q bearing a methoxy or -nitro
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
substituent, substrates 1r-u bearing a pair of methoxy and nitro substituents were also examined
1 2 2 1 2 2
under the same reaction conditions. As expected, 1r (R = OMe/R = NO ) and 1s (R = NO /R =
OMe) were definitely transformed to carbazole 3r and benzimidazole 2s in 68% and 58% yields,
respectively (entry 5 and 6, Table 3). Finally, a competitive experiment for the direct intramolecular
C-N cyclization of 1 was carried out by the employment of di-methoxy and di-nitro substituted
1 2 1 2 2 2
substrates 1t (R = OMe/R = OMe) and 1u (R = NO /R = NO ). From the reaction of 1t with
2
PhI(OTFA) , only benzimidazole 2t was isolated in 68% yield and none of carbazole 3t was
obtained (entry 7, Table 3). This might indicate that the amino group of 1t also plays as an
electron-donating role and thus prefer to generate benzimidazole 2t as the single product. However,
we did not observe any anticipated benzimidazole 2u or carbazole 3u was generated in the reaction
2
of 1u with PhI(OTFA) , and only recovered a large amount of starting material (entry 8, Table 3).
2
This implies that a strong electron-withdrawing group (e.g., -NO ) tagged on the certain aryl ring
could deactivate the aryl rings and then prevents the intramolecular C-N bond coupling. Herein, the
competitive experiment again elucidates that the substituent electronic effects govern the direct
intramolecular C-N cyclization of 1.
1
2
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2
3
4
Table 3. The Influence of the Substituent Electronic Effects on PhI(OTFA)
2
-Induced the
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Direct Intramolecular C-N Cylcyization of 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
yield
yield
entry
substrate 1
product 2 or 3
a
entry
substrate 1
product 2 or 3
a
(
%)
(%)
N
N
N
HN
MeO
1
95 (90)
82 (80)
90 (86)
80 (75)
5
58 (55)
NO2
OMe
OMe
MeO
O2N
MeO
3r
NO2
1r
N
N
N
N
HN
N
N
HN
2
3
6
7
8
OMe 68 (62)
OMe
2s
OMe
O N
1
s
2
2o
1o
N
N
N
HN
OMe
68 (64)
MeO
1t
2t
N
N
HN
N
4
--
0
NO2
NO2
3
q
1q
a
Product yield was determined as an average by GC-FID using n-octadecane as the internal standard and the isolated
yield was reported in the parenthesis.
1
3
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The Cation Radical Detection and Radical Trapping Experiments: In the direct intramolecular
2 2
C-N cyclization of 1 with both of PhI(OAc) and PhI(OTFA) , we initially recognized the cation
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
radical is the only key intermediate based on the Kita’s pioneering work in 1994. In their studies,
UV-Vis and ESR spectroscopic technologies were employed to detect the cation radical. In view of
this, we also attempted to detect the cation radical arose from the reaction of 1o with either of
2 2 3 2
PhI(OTFA) and PhI(OAc) in 1,1,1,3,3,3-hexafluoro-2-propanol ((CF ) CHOH) by the UV-Vis
spectroscopy (see Figure S3, Supporting Information). In the solution of 1o with PhI(OTFA)
2
, we
observed that a broaden absorption band between 400 and 550 nm was arose (Figure S3a,

+
Supporting Information) and that is suggested to be the characteristic of the cation radical (1o )
1
2
according to Kita’s studies. However, none of additional absorption bands was observed in the
case of 1o with PhI(OAc)
2
and its UV-Vis spectrum is almost the same with that of free substrate 1o
(
Figure S3b, Supporting Information). This indicates that none of the cation radical is generated in
2
the reaction of 1o with PhI(OAc) .
In addition to UV-Vis spectroscopic experiments, we also carried out radical trapping
experiments by using 1,1-diphenylethylene (DPE) and 2,6-di-tert-butyl-4-methylphenol (BHT) as
radical scavengers into the reaction of 1a with PhI(OAc) or PhI(OTFA) . These experimental
2
2
results are summarized in Table 4. The total yield for the reaction of 1a with PhI(OAc)
2
is slightly
down to 65% and 45% from 80% (none of radical scavengers, entry 1, Table 4) by the addition of
2
DPE and BHT (entry 3 and 5, Table 4). However, the total yield for the case of PhI(OTFA) is
1
4
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2
3
4
dramatically decreased to 15% and 6% from 75% (none of radical scavengers, entry 2, Table 4) in
the presence of DPE and BHT (entry 4 and 6, Table 4). These experimental results are consistent
with that of the cation radical detection of 1o by UV-Vis spectroscopy (see Figure S3, Supporting
Information).
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
Table 4. The Influence of Radical Scavengers on the Reaction of 1 with PhI(OAc) and/or
PhI(OTFA)
2
total
radical
product ratio
a
entry
iodine(III)
yield
scavenger
(2a:2’a:3a)
b
(
%)
80
75
65
15
45
6
1
2
3
4
5
6
--
--
PhI(OAc)
PhI(OTFA)
PhI(OAc)
PhI(OTFA)
PhI(OAc)
2
71:18:11
97:0:3
2
2
2
2
80:12:8
91:0:9
c
DPE
2
87:0:13
100:0:0
c
BHT
PhI(OTFA)
a
b
Product ratio was determined by GC-FID for three runs. Product yield was determined as an average by GC-FID for
c
three runs using n-octadecane as the internal standard. DPE
2,6-di-tert-butyl-4-methylphenol.
=
1,1-diphenylethylene; BHT
=
1
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Based on these UV-Vis spectroscopic and radical trapping experimental results, we believe that
+
the cation radical (i.e., 1 ) is the key intermediate in the direct intramolecular C-N cyclization of 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with PhI(OTFA)
2
, but does not form in the case of PhI(OAc)
2
. By contrast, the nitrenium ion
+
13
(
R
2
N ) is suggested to be the key intermediate in the reaction of 1 with PhI(OAc)
2
.
Proposed Mechanisms: Based on our studies, two possible reaction mechanisms via the cation
radical and nitrenium ion for the direct intramolecular C-N cyclization of
2
N-(biphenyl)pyridine-2-amines 1 to benzimidazoles 2 and carbazoles 3 by PhI(OTFA) and
2 2
PhI(OAc) are presented in Scheme 1. In Scheme 1a, the binding of 1 with PhI(OTFA) generates

-complex I (and/or I’) on the electron-richer phenyl ring. The -complex I (and/or I’) is then
transformed to the cation radical II (and/or II’) via one-electron abstraction by PhI(OTFA)
2
.
Subsequently, the cation radical II (and/or II’) is converted to a radical intermediate III (and/or III’)
through the intramolecular C-N coupling. Finally, benzimidazole 2 and carbazole 3 are given
through the re-aromatization of III and III’. In Scheme 1b, the amine nitrogen of 1 first attacks the
2
iodine(III) center of PhI(OAc) to generate the iodonium intermediate IV and subsequently
converted to intermediate V by a release of iodobenzene. The intermediate V is then divided into
1
4a
14b
the alternative of intermediates VI and VI’ via the electron transfer process. Furthermore, the
pyridinyl nitrogen of VI attacks the carbon cation to generate a C-N bond and undergoes the
electron transfer process to give intermediate VII. On the other hand, the intermediate VI’ is
transformed to VII’ via the electrocyclic ring closure and that eventually constructs a new C-N
1
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1
2
3
4
5
6
7
8
9
(a)
PhI + OTFA
N
Ph OTFA
+ OTFA
N
OTFA HOTFA
N
H
I
OTFA
HN
HN
N
R2
R2
R2
R1
R1
R1
III
-
complex I
cation radical II
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OTFA
PhI(OTFA)2
HOTFA
N
N
R1 = strong EWG ; R2 = H
or
R1 = H; R2
=
strong EDG
R2
R1
2
N
HN
R2
R1
1
N
N
R1 = strong EDG; R2 = H
or
R1
R1 = H; R2
=
strong EWG
HOTFA
R2
3
PhI(OTFA)2
OTFA
N
PhI + OTFA
+ OTFA
N
TFAO
HN
HN
N
OTFA HOTFA
OTFA
I
H
N
Ph
R2
R2
R1
R1
R1
cation radical II'
R2
III'
-complex I'
Scheme 1. Proposed mechanism for the formation of benzimidazole 2 and carbazole 3 by the
2 2
reaction of 1 with (a) PhI(OTFA) and (b) PhI(OAc) .
1
7
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
bond. Finally, both of benzimidazole 2 and carbazole 3 are given by the re-aromatization of VII and
VII’.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Regarding the formation of 8-acetoxy-6-arylbenzimidazole 2’, we initially suspected that it is
derived from the reaction of 6-arylbenzimidazole 2 with PhI(OAc)
2
. To verify the hypothesis, we
independently carried out the reaction of 2a with PhI(OAc)
2
(1.5 equivalents) under the
1
aforementioned reaction conditions, but none of anticipated product 2’a was detected by H NMR
spectroscopy and GC-FID. In the reaction, only starting material (i.e., 2a) was recovered even the
reaction time was prolonged. Thus, we suppose the acetoxylation might first take place on starting
substrate 1 and then undergo the direct intramolecular C-N coupling to give the acetoxylated
product 2’. A proposed mechanism for the formation of acetoxylated benzimidazole 2’ from 1 by
the employment of PhI(OAc) is presented in Sc heme 2. Initially, the nitrenium ion V is generated
2
2
through the ligand exchange between 1 and PhI(OAc) and the subsequent nitrogen-iodine bond
cleavage of intermediate IV by a release of iodobenzene. Furthermore, the charge delocalized
intermediate V’ is attacked by the acetate anion to afford intermediate VIII. Then intermediate VIII
2
is fast converted to IV’ via re-aromatization process promoted by PhI(OAc) . The acetoxylated
benzimidazole 2’ is eventually formed through the direct intramolecular C-N cyclization of IV’.
1
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1
2
3
4
5
6
7
8
9
N
PhI(OAc)2 HOAc
N
N
N
PhI
N
AcO
N
HN
AcO
Ph
N
I
AcO
R
IV
R
R
1
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
V
V'
N
OAc PhI(OAc)2
N
N
N
AcO
Ph
N
N
I
-
H
H
OAc
OAc
OAc
R
2'
R
R
VIII
IV'
Scheme 2. Proposed mechanism for the formation of acetoxylated benzimidazole 2’ from 1 by the
employment of PhI(OAc)
2
.
The Selective Intramolecular C-N and C-O Cyclization of N-(Biphenyl)acetamides Governed
by the Substituent Electronic Effects: In addition to N-(biphenyl)pyridin-2-amines 1, we also
2
introduced N-(biphenyl)acetamide 4 into the reaction by the treatment of PhI(OTFA) and
2
PhI(OAc) , respectively. These experimental results are summarized in Table 5. Herein, compounds
1
5
4
a and 4b were chose as model substrates (the detail synthetic procedure, please see the
Experimental Section). Both of them were subsequently treated with PhI(OTFA)2 in
16
dichloromethane at room temperature, however, only 15% yield of carbazole 5b was isolated from
2
the reaction of 4a with PhI(OTFA) (entry 1, Table 5), and none of anticipated benzoxazole 6 was
obtained in the case of 4b (entry 2, Table 5). However, 86% yield of carbazole 5a and 90% yield of
benzoxazole 6 were given when acetonitrile was used as the solvent in the reaction of 4a and 4b
1
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 5. Direct Intramolecular C-N and C-O Cyclization of 4 in the Presence of PhI(OAc)
2
and/or PhI(OTFA)
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
entry
substrate
4a
oxidant
additive
solvent
product
yield (%)
14 (10)
0
1
2
3
4
5
6
7
8
9
PhI(OTFA)
PhI(OTFA)
PhI(OTFA)
PhI(OTFA)
PhI(OTFA)
PhI(OTFA)
2
2
2
2
2
2
--
CH
CH
2
2
Cl
2
2
5b
6
4b
--
Cl
4a
--
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
5a
6
86 (80)
90 (85)
0
4b
--
b
b
4a
TMSOTf
5a
6
4b
TMSOTf
53 (47)
47 (41)
10 (6)
89 (85)
10 (5)
0
4a
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
2
2
2
2
2
2
--
CH
CH
2
2
Cl
2
2
5a
7
4b
--
--
Cl
4a
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
5a
7
1
1
1
0
1
2
4b
--
b
b
4a
TMSOTf
TMSOTf
5a
6
4b
42 (35)
a
Product yield was determined as an average by GC-FID for three runs using n-octadecane as the internal standard and
2
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b
the isolated yield was reported in the parenthesis. 2 equivalents of TMSOTf was added.
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with PhI(OTFA)
2
(entry 3 and 4, Table 5). In 2012, Yu and co-workers reported that
2
PhI(OTFA) -mediated intramolecular C-O coupling of electron-richer N-(phenyl)benzamides to
17
establish a variety of benzoxazoles. Under their optimal reaction conditions (1.2 equiv
2
PhI(OTFA) and 2 equiv TMSOTf at room temperature in acetonitrile), a N-(biphenyl)acetamide
analogue, N-(phenyl)acetamide was unable to afford 2-methylbenzo[d]oxazole. Based on their
2
reaction conditions, TMSOTf was added into the reaction of 4a,b with PhIX (X = OTFA and OAc),
but none of anticipated carbazole 5a was generated (entry 5 and 11, Table 5) and concurrently the
product yield of benzoxazole 6 was not obviously improved (42-53%, entry 6 and 12, Table 5).
2
Finally, carbazole 5a was generated in 47-89% yields from the reaction of 4a with PhI(OAc) in
both of dichloromethane and acetonitrile (entry 7 and 9, Table 5).
2
On the other hand, the reaction of 4b with PhI(OAc) in dichoromethane or acetonitrile did not
give the desired benzoxazole 6 (entry 8 and 10, Table 5), by contrast, approximate 10% yield of
18
benzoquinoneimine 7 was isolated from the reaction. A possible mechanism for the formation of 7
2 2
from 4b by PhI(OAc) is proposed in Scheme 3. The ligand exchange between 4b and PhI(OAc)
produces intermediate IX which is subsequently converted to the nitrenium ion X by a release of
N
iodobenzene. Compound 7 is then generated via the nucleophilic substitution (S 2) of methoxy
group and the electron transfer of intermediate X. Based on the finding of benzoquinoneimine 7, it
2
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
again strongly support the proposal of nitrenium ion as a key intermediate in the reaction of 1 (even
) with PhI(OAc) (see Scheme 1b). In addition, we did not isolate benzimidazole 6 in the reaction
4
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
of 4b with PhI(OAc) , and this might be due to the poor nucleophilicity of the acetamide group (see
Scheme 3).
2
On the basis of the above studies, we found that PhI(OTFA) can selectively induce the direct
intramolecular C-N and C-O cyclization of N-(biphenyl)acetamides 4 based on the substituent
electronic effects to afford the alternative of carbazole 5 and benzoxazole 6 in good yields (86-90%)
in acetonitrile.
Nu-Me
+
AcO
Me
O
Nu-
poor
nucleophilicity
N
Me
AcO
O
Me
HN
O
Me
AcO
O
O
Ph-I
PhI(OAc)2
OMe
HOAc
N
7
N
I
Ph
OMe
Me
OMe
O
N
4b
X
IX
OMe
6
Scheme 3
CONCLUSION
We have demonstrated the direct intramolecular C-N cyclization of N-(biphenyl)pyridin-2-amines
governed by the substituent electronic effects to form either benzimidazoles or carbazoles with
hypervalent iodine(III) reagents. Rational reaction mechanisms in the study were presented based
on controlled experiments, radical intermediate detection, and the formation of the key product, in
2
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2
which the cation radical was suggested to be the key intermediate for the reaction by PhI(OTFA) ,
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
whereas another intermediate is believed to be the nitrenium ion when PhI(OAc) is used. In
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
addition, the selective intramolecular C-N and C-O cyclization of N-(biphenyl)acetamides was
achieved based on the substituent electronic effects. Finally, we believe our observation and
investigation can provide an insight into related carbon-heteroatom coupling reactions via the cation
radical or nitrenium ion and as a useful synthetic strategy in organic synthesis.
EXPERIMENTAL SECTION
General: Solvents and reagents were purchased from commercial suppliers and used without
1
purification. H NMR spectra were measured on 300 and 500 MHz NMR spectrometers. Natural
13
abundance C NMR spectra were measured by using 300 and 500 MHz NMR spectrometers
operating at 75 and 125 MHz, respectively. Chemical shifts are given in parts per million (ppm) and
3
coupling constant J in hertz (Hz) for both nuclei, with the solvent (usually CDCl ) peak as an
1
13
internal standard. The reference peak for H is  7.26 of chloroform, and for C it is the central
peak at  77.0. Low- and high-resolution mass spectrometry was obtained by the following
ionization method and mass analyzer type: EI-magnetic sector. Melting points were measured by
using open capillary tubes and uncorrected.
2
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
General Procedure for the Synthesis of Starting Substrate 1:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The synthesis of substrates 1a-c, e-g, i-j, n, p had been reported, please see ref. 6e. A well-stirred
solution of N-phenylpyridin-2-amines 8 (8a, R = H: 90 mg, 0.53 mmol for 1d and 1h; 8k, R = F:
1
00 mg, 0.532 mmol for 1k; 8l, R = Cl: 109 mg, 0.534 mmol for 1l; 8m, R = Br: 132 mg, 0.530
2
mmol for 1m; 8o, R = OMe: 106 mg, 0.530 mmol for 1o; 8q, R = NO : 114 mg, 0.530 mmol for 1q)
with 2-naphthylboronic acid (9) (138 mg, 0.802 mmol for 1d), potassium
p-iodophenyltrifluoroborate (10b) (123 mg, 0.398 mmol for 1h), potassium phenyltrifluoroborates
(
10a) (147 mg, 0.799 mmol for 1k-m, o, q), potassium p-methoxyphenyltrifluoroborates (10c) (171
mg, 0.799 mmol for 1r and 1t), potassium p-nitrophenyltrifluoroborates (10d) (182 mg, 0.795
mmol for 1s and 1u), 10 mol % Pd(OAc)
2
(12 mg, 0.054 mmol), Cu(OAc)
2
(193 mg, 1.06 mmol),
o
BQ (57 mg, 0.53 mmol) in tert-butyl alcohol (10 mL) was heated to 80-90 C, and stirred at this
temperature for 4 hours. After cooling down to room temperature, the solution was filtered through
a pad of celite and then the filtrate was added to water (15 mL). The solution was further extracted
with ethyl acetate (10 mL x 2). Finally, organic layers were combined, dried over MgSO , filtered,
4
and evaporated in vacuum. The residue was purified by silica gel chromatography using
n-hexane/ethyl acetate (60/1 to 10/1) as the eluent to give a series of compounds 1. All product
yields were determined by GC-FID using n-octadecane as the internal standard and shown as
2
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follows: 1d: 58% (92 mg, 0.31 mmol); 1h: 22% (45 mg, 0.12 mmol); 1k: 40% (55 mg, 0.21 mmol),
l: 46% (67 mg, 0.24 mmol); 1m: 41% (72 mg, 0.22 mmol), 1o: 62% (91 mg, 0.33 mmol); 1q: 38%
49 mg, 0.17 mmol); 1r: 22% (39 mg, 0.12 mmol); 1s: 24% (42 mg, 0.13 mmol); 1t: 18% (29 mg,
.095 mmol); 1u: 20% (37 mg, 0.11 mmol).
General Procedure for the Synthesis of Compounds 2, 2’, and 3: A well-stirred solution of 1
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
0
2 2
with either of PhI(OAc) (35 mg, 0.11 mmol) and PhI(OTFA) (47 mg, 0.11 mmol) in
dichloromethane (5 mL) was held at room temperature for 1-2 hours. The reaction solution was then
washed by water (5 mL) and the aqueous layer was extracted by dichloromethane (5 mL x 2).
4
Organic layers were combined, dried over MgSO , filtered, and evaporated in vacuum. The residue
was purified by silica gel chromatography using n-hexane/ethyl acetate (5/1 to 1/1) as the eluent to
give products 2, 2’, and 3. The amounts of substrates 1 are listed as follows: 1a: 18 mg, 0.072 mmol;
1b: 19 mg, 0.072 mmol; 1c: 22 mg, 0.072 mmol; 1d: 21 mg, 0.072 mmol; 1e: 19 mg, 0.072 mmol;
1f: 20 mg, 0.072 mmol; 1g: 23 mg, 0.072 mmol; 1h: 27 mg, 0.072 mmol; 1i: 20 mg, 0.072 mmol;
1j: 21 mg, 0.072 mmol; 1k: 19 mg, 0.072 mmol; 1l: 20 mg, 0.072 mmol; 1m: 23 mg, 0.072 mmol;
1n: 20 mg, 0.072 mmol; 1o: 20 mg, 0.072 mmol; 1p: 21 mg, 0.072 mmol; 1q: 21 mg, 0.072 mmol;
1r: 23 mg, 0.072 mmol; 1s: 23 mg, 0.072 mmol; 1t: 22 mg, 0.072 mmol; 1u: 24 mg, 0.072 mmol.
All product yields were determined by GC-FID using n-octadecane as the internal standard and
shown as follows: 2a: 57% (10 mg, 0.041 mmol); 2b: 46% (9 mg, 0 033 mmol); 2c: 45% (10 mg,
0.032 mmol); 2d: 5% (1 mg, 0.004 mmol); 2e: 77% (15 mg, 0.055 mmol); 2f: 75% (15 mg, 0.054
2
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mmol); 2g: 58% (13 mg, 0.042 mmol); 2h: 80% (21 mg, 0.058 mmol); 2i: 70% (14 mg, 0.050
mmol); 2j: 96% (20 mg, 0.069 mmol); 2k: 70% (13 mg, 0.050 mmol); 2l: 79% (16 mg, 0.057
mmol); 2m: 71% (17 mg, 0.051 mmol); 2o: 82% (16 mg, 0.059 mmol); 2p: 90% (19 mg, 0.065
mmol); 2s: 68% (16 mg, 0.049 mmol); 2t: 68% (15 mg, 0.049 mmol); 2’a: 14% (3 mg, 0.01 mmol);
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
’b: 23% (5 mg, 0.017 mmol); 2’c: 20% (5 mg, 0.014 mmol); 2’d: 2% (0.4 mg, 0.001 mmol); 2’e:
10% (2 mg, 0.007 mmol); 2’f: 13% (3 mg, 0.009 mmol); 2’g: 22% (6 mg, 0.02 mmol); 3a: 9% (2
mg, 0.006 mmol); 3b: 13% (2 mg, 0.009 mmol); 3c: 11% (2 mg, 0.008 mmol); 3d: 23% (5 mg,
0.017 mmol); 3n: 95% (19 mg, 0.068 mmol); 3q: 80% (17 mg, 0.058 mmol); 3r: 58% (13 mg,
0.042 mmol).
Synthetic Procedure of Substrate 4:
A well-stirred solution of 8 (8a: 93 mg, 0.69 mmol for 4a; 8b: 114 mg, 0.691 mmol for 4b) with
boronic acid 9 (9a: 210 mg, 1.38 mmol for 4a; 9b: 168 mg, 1.38 mmol for 4b), 5 mol % Pd(OAc)
2
2 2
(8 mg, 0.09 mmol), Cu(OTf) (250 mg, 0.694 mmol), Ag O (160 mg, 0.693 mmol) in toluene (10
o
mL) was heated at 110-120 C for 24 hours. After cooling down to room temperature, the reaction
solution was filtered through a pad of celite. The filtrate was washed with water (20 mL) and the
aqueous layer was extracted with ethyl acetate (15 mL x 3). Organic layers were combined, dried
2
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3
4
over MgSO
4
, filtered, and evaporated in vacuum. The residue was purified by silica gel
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
chromatography using n-hexane/ethyl acetate (10/1 to 5/1) as the eluent to give product 4a (25%, 41
mg, 0.17 mmol) and 4b (66%, 109 mg, 0.452 mmol).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of Compounds 5-7: The synthetic procedure is the same with that of 2, 2’, and 3. The
amounts of reaction reagents are listed as follows: 4a and 4b (50 mg, 0.21 mmol); PhI(OTFA)
2
(
3
133 mg, 0.309 mmol); CH CN (5 mL); eluent (hexane/ethyl acetate = 30/1 to 10/1) to give
carbazole 5a (86%, 43 mg, 0.18 mmol) and benzoxazole 6 (90%, 45 mg, 0.19 mmol). PhI(OAc)
2
2
(100 mg, 0.311 mmol) instead of PhI(OTFA) gave carbazole 5a (89%, 45 mg, 0.19 mmol) and
2 2
benzoquinoneimine 7 (10%, 5 mg, 0.021 mmol). The reaction was carried out in CH Cl (5 mL,
3
instead of CH CN) to give carbazole 5b (14%, 8 mg, 0.029 mmol).
General Procedure for the Reaction of N-([1,1'-Biphenyl]-2-yl)pyridin-2-amine (1a) with
PhIX (X = OAc and OTFA) by the Addition of Radical Scavengers (DPE and BHT): A
2
2
well-stirred solution of 1a (15 mg, 0.061 mmol) with either of PhI(OAc) (30 mg, 0.092 mmol) and
2
PhI(OTFA) (40 mg, 0.092 mmol) in dichloromethane (5 mL) was added by 1,1-diphenylethylene
(
DPE) (11 mg, 0.061 mmol) and 2,6-di-tert-butyl-4-methylphenol (BHT) (13 mg, 0.061 mmol),
respectively, and kept at room temperature for 1 hour. The reaction solution was then washed by
water (5 mL) and the aqueous layer was extracted by dichloromethane (5 mL x 2). Organic layers
were combined, dried over MgSO , filtered, and evaporated in vacuum. Finally, the product ratio
4
and yield of 2a, 2’a, and 3a were determined by GC-FID (using n-octadecane as the internal
2
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2
3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
standard).
General Procedure for the Reaction of N-(Biphenyl)acetamides (4a and 4b) with PhIX
OTFA and OAc) by the Addition of Lewis Acid (TMSOTf): A well-stirred solution of 4a (50 mg,
.21 mmol) and 4b (50 mg, 0.21 mmol) with either of PhI(OTFA) (107 mg, 0.250 mmol) and
2
(X =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
2
PhI(OAc)
2
(80 mg, 0.25 mmol) in acetonitrile (5 mL) was added by trimethylsilyl
trifluoromethanesulfonate (TMSOTf) (92 mg, 0.42 mmol) and kept at room temperature for 3-4
hours. The reaction solution was then washed by water (5 mL) and the aqueous layer was extracted
4
by dichloromethane (5 mL x 2). Organic layers were combined, dried over MgSO , filtered, and
evaporated in vacuum to give carbazole 5 in 0% and benzoxazole 6 in 53% (26 mg, 0.11 mmol for
2 2
PhI(OTFA) ) and 42% (20 mg, 0.090 mmol for PhI(OAc) ), respectively, in which the product yield
was determined by GC-FID (using n-octadecane as the internal standard).
Characterization Data of Compounds 1-7:
Characterization data of compounds 3a-c and 3n, please see ref. 6e.
o
f
N-(2-(Naphthalen-2-yl)phenyl)pyridin-2-amine (1d): Pale-yellow solid; mp 120-121 C; R =
1
0
5
7
.61 (n-hexane/ethyl acetate = 3/1); H NMR (500 MHz, CDCl )  6.47 (bs, 1 H), 6.71 (dd, J = 7.0,
3
.5 Hz, 1 H), 6.79 (d, J = 8.5 Hz, 1 H), 7.16 (ddd, J = 7.5, 7.5, 1.0 Hz, 1 H), 7.37-7.41 (m, 2 H),
.46 (ddd, J = 7.5, 7.5, 2.0 Hz, 1 H), 7.50-7.53 (m, 3 H), 7.83-7.89 (m, 5 H), 8.15 (d, J = 4.5 Hz, 1
1
3
H); C NMR (125 MHz, CDCl
3
)  108.8 (CH), 115.1 (CH), 120.7 (CH), 123.0 (CH), 126.2 (CH),
126.3 (CH), 127.3 (CH), 127.7 (CH), 128.0 (CH), 128.3 (CH), 128.4 (CH x 2), 131.0 (CH), 132.6
2
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3
4
(
Cq), 133.3 (Cq), 133.6 (Cq), 136.3 (Cq), 137.6 (Cq), 137.7 (CH), 148.2 (CH), 155.8 (Cq); MS (EI,
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
16 2
m/z) 296 (M , 100), 295 (100), 169 (87); HRMS (EI-magnetic sector) m/z: [M ] Calcd for C21H N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
96.1313; Found 296.1314.
o
f
N-(4'-Iodo-[1,1'-biphenyl]-2-yl)pyridin-2-amine (1h): Pale-yellow solid; mp 145-146 C; R =
1
0
5
.69 (n-Hexane/ethyl acetate = 4/1); H NMR (500 MHz, CDCl
3
)  6.32 (bs, 1 H), 6.73 (dd, J = 5.0,
.0 Hz, 1 H), 6.79 (d, J = 8.5 Hz, 1 H), 7.12-7.16 (m, 3 H), 7.27 (dd, J = 8.0, 1.0 Hz, 1 H), 7.36
(ddd, J = 8.3, 8.3, 1.5 Hz, 1 H), 7.47 (ddd, J = 7.8, 7.8, 1.5 Hz, 1 H), 7.34-7.76 (m, 3 H), 8.16 (d, J
1
3
= 4.5 Hz, 1 H); C NMR (125 MHz, CDCl )  93.4 (Cq), 108.5 (CH), 115.2 (CH), 121.3 (CH),
3
123.4 (CH), 128.6 (CH), 130.5 (CH), 131.2 (CH x 2), 132.5 (Cq), 137.2 (Cq), 137.8 (CH), 137.9
+
(
(
CH x 2), 138.3 (Cq), 148.3 (CH), 155.8 (Cq); MS (EI, m/z) 372 (M , 100), 371 (55), 244 (32), 169
+
99), 71 (25); HRMS (EI-magnetic sector) m/z: [M ] Calcd for C17
H
13IN
2
372.0124; Found
3
72.0124.
f
N-(5-Fluoro-[1,1'-biphenyl]-2-yl)pyridin-2-amine (1k): Pale-yellow viscous liquid; R = 0.48
1
(
n-hexane/ethyl acetate = 3/1); H NMR (300 MHz, CDCl )  6.21 (bs, 1 H), 6.65 (d, J = 8.4 Hz, 1
3
H), 6.70 (dd, J = 6.2, 6.2 Hz, 1 H), 7.03-7.09 (m, 2 H), 7.36-7.47 (m, 6 H), 7.72-7.77 (m, 1 H), 8.15
1
3
(
3
d, J = 4.5 Hz, 1 H); C NMR (125 MHz, CDCl )  108.5 (CH), 114.7 (CH), 114.9 (d, JC-F = 21.9
Hz, CH), 117.3 (d, JC-F = 22.8 Hz, CH), 124.3 (d, JC-F = 8.3 Hz, CH), 128.0 (CH), 128.9 (CH x 2),
129.0 (CH x 2), 132.8 (Cq), 136.5 (d, JC-F = 7.8 Hz, Cq), 137.7 (Cq), 138.3 (CH), 146.9 (CH), 156.0
+
(Cq), 159.2 (d, JC-F = 242.5 Hz, Cq); MS (EI, m/z) 264 (M , 100), 263 (91), 248 (29), 187 (54), 71
2
9
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