Copper-Catalyzed Tandem O-Vinylation of Arylhydroxylamines/[3,3]-Rearrangement/Cyclization: Synthesis of Highly Substituted Indoles and Benzoindoles

Article abstract of DOI:10.1021/acscatal.9b00470

Herein, we developed a copper-catalyzed O-vinylation of arylhydroxylamine using vinyliodonium salts as vinylation reagents to generate a transient O-vinyl-N-arylhydroxylamine that rapidly undergoes a [3,3]-sigmatropic rearrangement and subsequent cyclizat

Full text of DOI:10.1021/acscatal.9b00470

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Article
Copper-Catalyzed Tandem O-Vinylation of Arylhydroxylamines/
[3,3]-Rearrangement/Cyclization: Synthesis of
Highly Substituted Indoles and Benzoindoles
Hairui Yuan, Lirong Guo, Fengting Liu, Zechen Miao, Lei Feng, and HONGYIN GAO
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 26 Mar 2019
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ACS Catalysis
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Copper-Catalyzed Tandem O-Vinylation of Arylhydroxylamines
/[3,3]-Rearrangement/Cyclization: Synthesis of Highly Substituted
Indoles and Benzoindoles
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Hairui Yuan,† Lirong Guo,† Fengting Liu,† Zechen Miao,† Lei Feng,† and Hongyin Gao*,†
†School of Chemistry and Chemical Engineering, Key Laboratory of Colloid and Interface Chemistry, Ministry of Education,
Shandong University, 27 South Shanda Road, Ji’nan 250100, Shandong (China)
KEYWORDS: copper, arylhydroxylamines, vinyliodonium salts, rearrangement, indoles
ABSTRACT: Herein, we developed a copper-catalyzed O-vinylation of arylhydroxylamine using vinyliodonium salts as vinylation
R2
Ar
R2
reagent to generate
arylhydroxylamine that rapidly undergoes a [3,3]-
sigmatropic rearrangement and subsequent
cyclization/rearomatization to form substituted
a transient O-vinyl, N-
I
R2
R1
ii. [3,3]-sigmatropic
rearrangement
OH
N
O
N
R1
X
58 examples
R
R1
PG
up to 99% yield
one-pot operation
PG
iii. cyclization
iv. rearomatization
R
Copper salts
N
R
i. O-vinylation
PG
indole. A wide range of highly substituted indoles and benzoindoles can be afforded in good yields. This approach is readily scalable
and the scope and application of this process are presented.
The indole nucleus is one of the most ubiquitous scaffold
because of its wide presence in a plethora of natural products,
pharmaceuticals, agrochemicals, as well as materials science.1
In particular, highly substituted indoles have been referred to as
“privileged structures” because of their capable of binding to a
variety of receptors with high affinity.2 In view of the
importance and abundance of the indole motif, it is not
surprising that significant efforts have been devoted to develop
new strategies for the generation of indole unit and numerous
methods have been reported1g,3 (for example, Fischer,4
Madelung,5 Hegedus,6 Bartoli,7 Larock,3c,8 and Buchwald9
indole synthesis and so on). However, via these methods, harsh
successful in a number of synthetic applications involving a
series of bioactive molecules.7e,10 While powerful, this method
is inherently limited to substrates which have to possess a
substituent ortho to the nitro group of the nitroarenes,
otherwise, the reaction gives low or no yield of the desired
indole product. In addition, the three equivalents of alkenyl
Grignard reagent and the harsh conditions of low temperature
(-78 to -20 oC) are necessary. The products of the Bartoli indole
synthesis are restricted to 7-substituted indoles and the yields
are usually moderate (less than 70%). If such a process could be
generalized for non-ortho-substituted nitroarene substrates, the
scope of the potential applications could be further expanded to
a broader range of transformations.
o
conditions [for example, high temperature (> 100 C), low
o
temperature (< -40 C)], specific starting material availability
and low functional-group tolerance often hamper the versatility
and utility of indole synthesis. Thus, the continuous
development of alternative approaches that may allow for the
straightforward construction of structurally diverse indoles (in
particular, 3-substituted indoles) is still a field of increasing
interest.
Scheme 1. Proposed indole synthesis inspired by the Bartoli
reaction
(a) The Bartoli indole synthesis: Restricted to 7-substituted indoles.
MgBr
O
NO2
(3 equiv)
N
N
MgBr
H
R
R
In 1989, Bartoli and co-workers described the reaction of
ortho-substituted nitroarenes 1 with excess (3 equivalents or
more) vinyl Grignard reagents at low temperature to generate 7-
R
1
2
3
(b) Proposed one-pot process to substituted indoles: Applicable to all substituted patterns.
R2
Ar
R2
I
R2
ii. [3,3]-sigmatropic
rearrangement
substituted indoles 3 upon aqueous work-up conditions.7c
A
O
N
OH
N
5
X
R1
presumably formed intermediate 2 from the addition of the
second equivalent of Grignard reagent to the corresponding
nitrosoarene, which was in situ generated by the addition of the
first equivalent of Grignard reagent to the oxygen of the nitro
group followed by the rapid elimination/decomposition of the
O-alkenylated intermediate, could undergo a facile [3,3]-
sigmatropic rearrangement, followed by an intramolecular
nucleophilic addition and rearomatization to furnish the final
indole products (Scheme 1 a). This approach has been proven
PG
R1
PG
iii. cyclization
iv. rearomatization
R1
Copper salts
N
i. O-vinylation
PG
4
6
7
Along this line and inspired by the Bartoli indole synthesis,
we surmised that the direct O-vinylation of arylhydroxylamines
4 would occur using highly reactive vinyliodonium salts 5 as
the vinylation reagent to form O-vinyl, N-arylhydroxylamines
6, which would rapidly undergo the similar [3,3]-rearrangement
/cyclization/rearomatization to afford indole products
7
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ACS Catalysis
b). This approach utilizes N-protected
Page 2 of 8
(Scheme
1
With the optimized conditions in hand, we next turned our
attention to assessing the scope and limitations of this
transformation. We were pleased to find that the copper-
1
2
3
4
5
6
7
8
arylhydroxylamines, which are readily prepared from
nitroarenes,11 as substrates would undergo a copper-catalyzed
cross-coupling reaction12 with vinyliodonium salts.
Vinyliodonium salts are an environmentally benign
electrophilic vinylation reagent with low toxicity, high
reactivity, moisture- and air-stability.13 However, compared to
the diverse utility of analogous diaryliodonium salts14 in organic
synthesis, vinyliodonium salts are much less explored.
Table 2. Substrate scope of arylhydroxylamines.a,b
Ph
CuBr (10 mol%)
Na2CO3 (1.2 equiv)
PG
N
OTf Me
I
+
R
OH
Ph
DCE, 25 o
N2, 24 h
C
R
N
PG
4
5b
7
Initially, we chose N-Boc-phenylhydroxylamine (4a) and
(E)-phenyl(styryl)iodonium trifluoromethanesulfonate (5a) as
model substrates to optimize the reaction conditions (selected
results are summarized in Table 1 and detailed optimization
results are summarized in the Supporting Information). Without
the employment of catalyst, the reaction did not occur (Table 1,
entries 1 and 2). The screening of copper salts catalysts revealed
that CuBr was an efficient catalyst to afford 50% yield of the
desired indole product in the presence of Na2CO3 (Table 1,
entries 3-7). Various bases (K2CO3, Cs2CO3, DTBP) were also
tested and no higher yields were provided (Table 1, entries 8-
10). To our delight, when (E)-styryl(o-tolyl)iodonium trifluoro-
methanesulfonate (5b) was used as the vinylation reagent,
higher yield was afforded (Table 1, entry 11). Further
optimization screening turned out that increasing the loading of
iodonium salt 5b had positive effect on the reaction (Table 1,
entries 12-13). The results revealed that 2.0 equivalents of 5b,
Ph
Ph
Ph
Ph
Ph
9
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
N
N
N
N
N
CO2Me
Boc
Ac
Cbz
Bz
(5) , 87%
7a
7b
(2) , 68%
c 7c
7d
(4) , 63%
7e
(1) , 78%
(3)
, 74%
Ph
Ph
Ph
Ph
Ph
F
Cl
Br
Ph
Me
N
N
N
N
N
Bz
, 71%
Bz
, 83%
Bz
, 55%
Bz
Bz
c 7f
c 7g
d 7h
e 7i
7j
(6)
(7)
(8)
(9)
, 50%
(10) , 71%
O
Ph
Ph
Ph
Ph
Me
Ph
Et
PhO
MeO
BnO
N
N
N
N
N
Bz
, 80%
Bz
Bz
Bz
Bz
c 7k
e 7l
7m
f 7n
e 7o
(11)
(12)
, 62%
Ph
(13)
, 44%
(14)
, 42%
Ph
(15)
, 60%
Ph
Br
Cl
Ph
Ph
S
N
N
N
N
N
Bz
Bz
Bz
Bz
Bz
F
Cl
c 7s
F
Cl
o
1.2 equivalents of Na2CO3, 10 mol% CuBr in DCE at 25 C
were optimal conditions (Table 1, entry 14).
c 7p
c 7q
f 7r
f 7t
(16)
, 47%
Ph
(17)
, 35%
Ph
(18) , 47%
(19)
, 73%
(20) , 52%
F
Ph
Ph
Ph
Table 1. Optimization of the reaction conditions.a
N
N
N
N
N
Ph
Catalyst
Base
OH
OTf
R
Bz
Bz
Bz
Bz
Bz
Br
Me
OMe
OMe
(25)
N
I
f 7u
7w
7x
c 7y
+
(21)
, 61%
, 61%
(23)
, 44%
(24) , 71%
, 33%
Ph
Boc
DCE, 25 o
N2, 24 h
C
N
Boc
Cl
Ph
Ph
Ph
Ph
Ph
Ph
4a
5a
5b
7a
, R = H
, R = Me
O
O
7a, yieldb
0
0
0
N
N
N
N
entry
1
2
3
4
5
6
7
8
5a/5b
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
base
catalyst
-
-
Cu(OTf)2
Cu(OAc)2
CuI
CuCl
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
N
Bz
Bz
Bz
Bz
7ad
(30) , 42%
Bz
OMe
(26)
OMe
Na2CO3
tBuOK
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
Cs2CO3
DTBP
f 7z
7aa
f 7ab
7ac
, 63%
(27)
, 56%
(28)
, 47%
(29)
, 44%
Ph
F
Me
Ph
Ph
Ph
Ph
N
0
N
N
N
N
F
Me
Bz
Bz
Bz
f,g 7af 7af'
Bz
Bz
trace
34
50
29
34
0
60
64
73
78
f,g 7ae 7ae'
f 7ag
, 84%
(31)
/
(1/0.8), 90%
(32)
/
(1/0.8), 92%
MeO
(33)
BnO
Ph
Ph
Ph
Ph
Ph
N
N
N
N
9
Bz
Bz
Bz
Bz
10
11
12c
13d
14e
(34)
OMe
, 73%
Ph
(35)
, 99%
, 1.63 g, 94%
(36)c
7
aj
, 75%
Ph
(37)
, 92%
Ph
e 7ah
f 7ai
c 7ak
CCDC: 1840956
5 mmol
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Ph
Ph
Ph
N
N
N
N
N
Bz
Bz
O
Bz
N
Bz
N
OMe
Bz
aUnless otherwise noted, all reactions were carried out under the
following conditions: 4a (0.2 mmol), 5a or 5b (1.1 equiv), base
(1.5 equiv), catalyst (10 mol%), DCE (1 mL) at 25 oC under N2
for 24 hours. bYields of isolated products. c1.5 equivalents of 5b
was employed. d2.0 equivalents of 5b was employed. e1.2
equivalents of base was employed. Boc = t-Butyloxy carbonyl;
DCE = 1,2-dichloroethane; DTBP = 2,6-di-tert-butylpyridine;
Tf = trifluoromethanesulfonyl; Ac = Acetyl.
f 7al
c 7am
f 7an
c 7ao
c 7ap
(42) , 0%
(38)
, 80%
(39)
, 69%
(40)
, 66%
(41)
, 0%
aReaction conditions: 4 (0.2 mmol), 5b (0.4 mmol), CuBr (10
mol%), Na2CO3 (0.24 mmol), DCE (1 mL) at 25 oC under N2 for
24 hours. bYields of isolated products. cAt 50 oC. dAt 70 oC. eAt
60 C. At 35 C. The regioselectivity was determined by H
NMR analysis of the crude reaction mixture; Combined yield of
the pure regioisomers. Cbz = benzoxycarbonyl; Bz = benzoyl.
o
f
o
g
1
catalyzed cascade O-vinylation15/rearrangement/cyclization
works across a broad range of arylhydroxylamines, providing
access to a diverse array of substituted indole motifs (Table 2).
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We first explored the scope of the protecting group onto the
Me
Cl
1
nitrogen atom and found that the benzoyl group is the best
option to give good yield of the desired indole product (Table
2, entries 1-5). The variation of different substituents on the
para position of the phenyl group was then examined. Both
electron-withdrawing groups and electron-donating groups can
be well tolerated in this transformation to afford the
corresponding indole products in moderate to good yields
(Table 2, entries 6-14). It is noteworthy that the acetyl and 2-
thiophenyl groups are compatible with this reaction system
(Table 2, entries 15-16). Meanwhile, various ortho-substituted
arylhydroxylamines were amenable to the optimized reaction
conditions to generate 7-substituted indoles (Table 2, entries
17-27). Notably, different disubstituted aromatic rings, in
particular, dihalides substituted substrates were also well
tolerated in this transformation (Table 2, entries 18, 20, 25-27).
Probably, the steric hindrance of the ortho-substituents has
negative effect on the efficiency of the reaction and resulted in
the relatively lower yields than the para-substituted substrates
(Table 2, entries 6 vs 17, 7 vs 19, 10 vs 23). To our delight, a
series of substrates with redox-sensitive moieties, such as
alkynes and olefins, can also be well tolerated (Table 2, entries
28-30). When meta-substituted arylhydroxylamines were used
as substrates, low regioselectivity but good yields was observed
(Table 2, entries 31 and 32). Furthermore, this methodology is
applicable in more complex aromatic rings, such as naphthalene
system (Table 2, entries 33-39) and dibenzofuran system
(Table 2, entry 40), especially noteworthy are the excellent
regioselectivity and high isolated yields of benzoindoles when
2-substituted naphthylhydroxylamines were employed as
substrates (Table 2, entries 35-39). The structure of the product
was unambiguously confirmed by the single crystal X-ray
diffraction of compound 7ai (Table 2, entry 35).16 However, this
method is not suitable to pyridine- and quinoline-containing
substrates due to the favored coordination of nitrogen atom to
copper prevented the formation of the highly electrophilic vinyl
copper complex which was in situ generated between
vinyliodonium salts and copper catalyst (Table 2, entries 41-
42).
2
3
4
5
6
7
8
9
Cl
N
N
N
N
N
Bz
Bz
Bz
Bz
, 61%
Bz
7aq
7ar
7as
c 7at
c 7au
(47)
(43)
, 78%
(44)
, 86%
(45)
, 78%
(46)
, 71%
Cl
Cl
Cl
Cl
OMe
MeO
C4H9
X
N
N
N
N
N
Bz
7aaa
, 94%
Bz
Bz
Bz
Bz
, 96% (53)
5 mmol
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
7av
7ax
7ay
7az
(48) X = H,
(49)d X = Cl,
, 88% (50)
, 88%
(51)
, 95%
(52)
OMe
, 1.47 g, 90%
7aw
, 61%
C4H9
Ph
Ph
Me
Cl
Ph
Ph
Ph
N
N
N
N
Bz
Bz
Bz
Bz
d 7aab
7aac
CCDC: 1880190
7aad
7aae
(57) , 35%
(55)
, 49%
(56)
, 40%
(54)
, 53%
aReaction conditions: 4 (0.2 mmol), 5 (0.4 mmol), CuBr (10
mol%), Na2CO3 (0.24 mmol), DCE (1 mL) at 35 C under N2 for
o
24 hours. bYields of isolated products. cAt 60 oC. dAt 50 oC.
Further investigation with respect to the scope of
vinyliodonium salts was conducted (Table 3). As shown in
Table 3, these optimized conditions are amenable to a wide
range of alkenyliodonium triflates. Both electron-rich and
electron-poor styrenes (Table 3, entries 43-45) as well as
alkylvinyl groups (Table 3, entries 46-54) are efficiently
transferred onto the indole motif with good to excellent yields.
Notably, 2,3-disubstituted benzoindole 7aac, 7aad and 7aae
can also be synthesized in moderate yields employing (2,2-
diphenylvinyl)(o-tolyl)-λ3-iodanyl trifluoromethanesulfonate 5i
and (2-methoxyphenyl)(2-phenylprop-1-en-1-yl)-λ3-iodanyl
trifluoromethanesulfonate 5j as electrophiles under standard
conditions (Table 3, entries 55-57). The structure of the product
7aac was also confirmed by the single crystal structure, which
is analysed by X-ray diffraction.16
To demonstrate the synthetic utility of this one-pot
(benzo)indole process on a multi-gram scale, we chose
naphthylhydroxylamine 4ai and vinyliodonium salt 5b and 5h
as substrates. We gratefully found that benzoindole 7ai and
7aaa were afforded in 94% and 90% isolated yield with
excellent regioselectivities, respectively (Table 2, entry 35 and
Table 3, entry 53). This methodology can also be applied to the
late-stage functionalization of pharmaceutically relevant and
structurally complex intermediates, such as an estradiol
derivative 7aaf (Scheme 2, Eq. (1)), a terpenoid derivative 7aag
(Scheme 2, Eq. (2)) and a cholesterol derivative 7aah (Scheme
2, Eq. (3)).
Table 3. Substrate scope of vinyliodonium salts.a,b
R1
Bz
N
R2 OTf
X
CuBr (10 mol%)
Na2CO3 (1.2 equiv)
I
R2
R1
+
R
OH
DCE, 35 o
N2, 24 h
C
R
N
Bz
X = Me, OMe
4
5c-5j
7
Scheme 2. Late-stage functionalization of pharmaceutically
relevant compounds.
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Page 4 of 8
O
O
Me
Me
Ph
5b
(2.0 equiv)
Ph
Ph
1
H
CuBr (10 mol%)
Na2CO3 (1.2 equiv)
H
O
O
Bu
N
Ph
NO2
2
H
H
(1)
N
H
H
OH
H
DCE, 35 oC,
N2, 24 h
N
Ph
13
, 85%
3
4
5
6
7
8
9
Br
4aaf
7aaf
, 55%
Bz
Bz
N
N
Me
Me
CN
Me
5b
(2.0 equiv)
Ph
, 90%
O
Ph
O
CuBr (10 mol%)
Na2CO3 (1.2 equiv)
12
14
, 88%
Ph
NO2
O
O
O
(2)
NC
DCE, 35 oC,
N2, 24 h
c
OH
Me
Me
N
N
Ph
b
NBdS
Me
Me
7aag
11
Ph
R1
Bz
Bz
O
4aag
, 76%
Ph
Ph
CO2Me
Ph
Me
Me
TMSCF3
Ph
9
Me
Me
Me
CF3
N
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
a
e
N
N
5b
(2.0 equiv)
Me
R
MeO2C
10
H
CuBr (10 mol%)
Na2CO3 (1.2 equiv)
8
H
DMF
Ph
15
, 41%
, 41%
,
POCl
H
H
(3)
Ph
Me
Me
H
Me
H
DCE, 50 oC,
N2, 12 h
Ph
3
O
O
h
f
Me
Me
PhOMe
Ph
g
PhOMe, HOTf
O
O
OH
N
N
Ph
Ph
Bz
Bz
CHO
4aah
7aah
, 60%
N
OMe
Bu
N
Me
Me
, 86%
To further expand the synthetic applications of our indole
18
16
, 68%
N
products, we wished to demonstrate that the products of this
reaction can be selectively manipulated to more complex
functional molecules17 (Scheme 3). For example, treatment of
3-phenyl-1H-indole 8a or 1-butyl-3H-benzo[e]indole 8aaa
with Cu(OTf)2 and methyl (E)-2-oxo-4-phenylbut-3-enoate 9 or
Ac
, 70%
17
a) 9, Cu(OTf)2, 1,4-Dioxane, 70 oC, 12 h. b) 11, Cu(OTf)2, CH3CN,
35 oC, 36 h. c) nitrostyrene, Zn(OTf)2, toluene, 80 oC, 12 h. d) NBS,
trifluorotoluene, 100 oC, 1 h. e) TMSCF3, PhI(OAc)2, BQ, K3PO4,
(E)-2-benzoyl-3-phenylacrylonitrile
11
led
to
o
9H‑pyrrolo[1,2‑a]indoles 1017a and 1217b in moderate to good
yields, respectively (Scheme 3, a and b). A Zn(OTf)2 catalyzed
Friedel−Crafts C2-alkylationreactions of 3-substituted indole
8ai with nitrostyrene as alkylating agents generated C2-
alkylated product 13 in 85% yield17c (Scheme 3, c). The C2-
position of our indole products can be also readily converted
into other important building blocks via various direct C2-
functionalization reactions, for instance, bromination,17d
trifluoromethylation17e and formylation17f reactions (Scheme 3,
d, e and f). A TfOH promoted umpolung hydroarylation
reactions of Indole 8aaa-Ac with anisole was successfully
accomplished to afford 17 in good yield of 70%17g (Scheme 3,
g). Additionally, a palladium-catalyzed dehydro-genative
annulation of 3-aryl substituted indole 8ai-Me with 1,2-
CH3CN, 85 C, 12 h. f) POCl3, DMF, toluene, reflux, 42 h. g)
anisole, TfOH, CH2Cl2, 25 oC, 1.5 h. h) 1,2-diphenylethyne,
o
Pd(OAc)2, TBAB, Cu(OAc)2, DMF, 100 C, 12 h. NBS = N-
Bromosuccinimide, BQ
=
benzoquinone, DMF
=
N,N-
dimethylformamide, TBAB = tetrabutylammonium bromide.
Based on our findings and the previous studies related to the
combination of copper catalysts and iodonium salts which have
been established by Gaunt,14a, 14c, 14e, 14g, 18 MacMillan14d, 14f, 14h
and others,13g, 19 we proposed a reaction pathway involving a
vinyl-CuIII species (Scheme 4). We postulated that CuBr will
undergo chemoselective oxidative addition into the vinyl-iodine
bond to form a highly electrophilic alkenyl-CuIII complex A
rather than aryl-CuIII complex A′ because of the ortho effect13n,
20 in the presence of vinyliodonium triflate 5. The complexation/
nucleophilic attack of arylhydroxylamine 4 to alkenyl-CuIII
complex A is expected to generate intermediate B, which, upon
diphenylethyne
was
conducted
to
produce
dibenzo[c,g]carbazole 18 in good yield17h (Scheme 3, h).
reductive elimination, will afford
a
O-vinyl, N-
Scheme 3. Synthetic applications of the indole products.
arylhydroxylamine C and reconstitute the active CuBr catalyst
to complete the catalytic cycle. O-vinyl, N-arylhydroxylamine
C will undergo a facile [3,3]-sigmatropic rearrangement
process, which is similar to the Bartoli indole synthesis,
followed by 1,3-proton migration/re-aromatization to furnish
intermediate E. The intramolecular condensation between
aldehyde and amide will occur to generate iminium
intermediate F and the final indole product 7 will be formed by
the 1,2-migration/dehydration/rearomatization of intermediate
F.
Scheme 4. Proposed mechanism of the one-pot process for
indole synthesis.
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X = Me, OMe
OTf
B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J., Methods
R2
X
for drug discovery: development of potent, selective, orally effective
cholecystokinin antagonists. J. Med. Chem. 1988, 31, 2235-2246. (b)
Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G. Q.;
Barluenga, S.; Mitchell, H. J., Natural Product-like Combinatorial
Libraries Based on Privileged Structures. 1. General Principles and
Solid-Phase Synthesis of Benzopyrans. J. Am. Chem. Soc. 2000, 122,
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Chem. Rev. 2003, 103, 893-930.
1
2
3
4
5
6
7
8
X
I
I
R1
X
5
Br
Cu
OTf
A'
R2
OTf
Cu
(III)
A
R1
CuBr
Br
PG
N
O
PG
9
Base
+
N
R
OH
Br
R2
PG
N
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
R
Cu
(III)
R1
PG
R1
C
O
4
R2
R
N
B
R1
R
[3,3]
PG
R2
7
PG
N
PG
N
- H
H
N
1,2-migration
H
R
R
R
- H2O
O
O
R2
R2
R2
R1
R1
R1
D
E
F
In summary, we have developed a highly efficient copper-
catalyzed tandem protocol for the synthesis of substituted
indoles and benzoindoles using readily available
arylhydroxylamines and vinyliodonium salts under mild
conditions. This transformation is tolerant to a broad range of
functional groups and provides ready access to a wide selection
of indole products in high yield and with excellent
regioselectivity. In addition, the indole products can be readily
converted into more complex functionalized indoles or
polycyclic heterocycles. We envision that this method will be
instrumental for the late-stage functionalization of bioactive
compounds and drug discovery. Further investigation and
synthetic applications are undergoing in our laboratory and will
be reported in due course.
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H.; Bang-Andersen, B.; Madsen, R.; Joergensen, M., Palladium-
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available
free of charge via the Internet at http://pubs.acs.org.
Experimental procedures, detailed optimization, compound
characterization and NMR spectra.
catalyzed aryl amination-Heck cyclization cascade:
a one-flask
approach to 3-substituted indoles. Angew. Chem., Int. Ed. 2008, 47,
888-890. (h) Bandini, M.; Eichholzer, A., Catalytic Functionalization
of Indoles in a New Dimension. Angew. Chem., Int. Ed. 2009, 48, 9608-
9644. (i) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S., Copper-
catalyzed C-C bond formation through C-H functionalization:
synthesis of multisubstituted indoles from N-aryl enaminones. Angew.
Chem., Int. Ed. 2009, 48, 8078-8081. (j) Barluenga, J.; Jimenez-
Aquino, A.; Aznar, F.; Valdes, C., Modular Synthesis of Indoles from
Imines and o-Dihaloarenes or o-Chlorosulfonates by a Pd-Catalyzed
Cascade Process. J. Am. Chem. Soc. 2009, 131, 4031-4041. (k) Stuart,
D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K., Rhodium(III)-Catalyzed
Arene and Alkene C-H Bond Functionalization Leading to Indoles and
Pyrroles. J. Am. Chem. Soc. 2010, 132, 18326-18339. (l) Wang, Y.-Z.;
Ye, L.-W.; Zhang, L.-M., Au-catalyzed synthesis of 2-alkylindoles
from N-arylhydroxylamines and terminal alkynes. Chem. Commun.
2011, 47, 7815-7817. (m) Wang, Y.; Liu, L.; Zhang, L., Combining Zn
ion catalysis with homogeneous gold catalysis: an efficient annulation
approach to N-protected indoles. Chem. Sci. 2013, 4, 739-746. (n)
Breazzano, S. P.; Poudel, Y. B.; Boger, D. L., A Pd(0)-Mediated Indole
(Macro)cyclization Reaction. J. Am. Chem. Soc. 2013, 135, 1600-1606.
(o) Ackermann, L., Carboxylate-Assisted Ruthenium-Catalyzed
Alkyne Annulations by C-H/Het-H Bond Functionalizations. Acc.
Chem. Res. 2014, 47, 281-295.
AUTHOR INFORMATION
Corresponding Author
* E-mail: hygao@sdu.edu.cn.
ORCID
Hongyin Gao: 0000-0003-4049-6832
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support of Shandong
University, the National Natural Science Foundation of China
(21702122) and the Natural Science Foundation of Shandong
Province (ZR2017MB002). We thank Prof. Di Sun at Shandong
University for the X-Ray diffraction and data analysis.
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