Full text of DOI:10.1002/adsc.201800206

Title: CuI-Catalyzed Selective 3-Alkylation of Indoles with N-
Tosylhydrazones and the I2-Mediated Further Cyclization to
Chromeno[2,3-b]indoles
Authors: Chun-Bao Miao, Yan-Fang Sun, He Wu, Xiaoqiang Sun, and
Haitao Yang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800206
Link to VoR: http://dx.doi.org/10.1002/adsc.201800206

10.1002/adsc.201800206
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
CuI-Catalyzed Selective 3-Alkylation of Indoles with N-
Tosylhydrazones and the I2-Mediated Further Cyclization to
Chromeno[2,3-b]indoles
Chun-Bao Miao,* Yan-Fang Sun, He Wu, Xiao-Qiang Sun, Hai-Tao Yang
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Advanced Catalysis and Green Manufacturing
Collaborative Innovation Center, School of Petrochemical Engineering, Changzhou University, Changzhou 213164,
China.
E-mail: estally@yahoo.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
of indoles. Zhang et al reported the copper-catalyzed
ortho-/para- reductive cross coupling of N-tosylhydrazones with
Abstract. The CuI-catalyzed reaction of indoles with N-
tosylhydrazones derived from the
hydroxybenzaldhydes affords selectively the C-3 alkylated
products rather than the N-alkylated products. In addition,
the I2-mediated cyclization of the generated C-3 alkylated
products allows the concise synthesis of chromeno[2,3-
b]indole derivatives.
nonprotected indoles and the N-alkylated products
were obtained exclusively through carbene insertion
into N-H bond.[3e] Thus, the selective 3-alkylation of
indoles with carbenes remains a great challenge.
It could be seen from the previously reported
transformation of N-tosylhydrazones, they were easy
to couple with various nucleophiles. As we know, the
C-3 position of indoles also exhibited strong
nucleophilicity, we wondered whether the
regioselectivity of the reaction between indoles and
N-tosylhydrazones could be reversed through the
changes of the catalytic system or subtle structural
tuning of the N-tosylhydrazones. When a hydroxyl
group was introduced to the ortho-position of
benzaldehyde-derived N-tosylhydrazone, to our
delight, the reaction of 1a with 2a in the presence of
catalytic amount of CuI (20 mol %) with K2CO3 (1.5
equiv) as the base under nitrogen atmosphere
afforded the C-3 alkylated product 3a selectively in
38% yield (Table 1, entry 1). There were many
unreacted 1a remaining in the reaction due to the
considerable consumption of 2a through its self-
reaction. The 2a could react with K2CO3 (or Cs2CO3)
in the presence of CuI to give a complex mixture
Keywords: indole; N-tosylhydrazone; CuI; iodine;
chromeno[2,3-b]indole
N-tosylhydrazones, which can be easily prepared
from aldehydes or ketones, have been widely used as
the precursors of diazo compounds or carbenes. They
have been used as versatile synthons in organic
synthesis and various useful transformations through
the transitionmetal-catalyzed or metal-free reactions
of N-tosylhydrazones have been reported.[1] Carbene
insertion into Y-H (Y = C,[2] N,[3] O,[4] S,[5] P,[6] B,[7]
Si,[8] Sn[9]) bonds as one of the most important
transformation in N-tosylhydrazone chemistry has
widespread application in the construction of
different types of C-Y bonds.
The indole core is a key building block found in
various biologically active natural compounds and
clinical drugs, which has attracted increasing
attention in the direct functionalization of indoles for
the synthesis of active indole derivatives.[10]
Generally, the direct alkylation of indoles with
alkyl/aryl halides always take place selectively at the
N-position. The reaction of indoles with ester group
stabilized carbene catalyzed by copper or rhodium
catalyst can give N1, C2, or C3 substituted indoles
depending on the substitution pattern of the original
substrate.[11] The amide group stabilized carbene
reacted with indoles catalyzed by rhodium only
furnish the N–H insertion product.[12] Most recently,
the non-stablized carbene generated from N-
tosylhydrazones has also been used in the alkylation
including
salicylaldehyde,
4-
methylbenzenesulfonamide, sulfone 3a',[13] and other
unidentified products (See supporting information).
Using Cs2CO3 instead of K2CO3 improved the yield
to 49%, albeit still with many leftovers of 1a (Table 1,
entry 2). Pleasingly, when 1.6 equiv of 2a and 2
equiv of Cs2CO3 were employed, full conversion of
indole 1a was observed, giving 72% yield of 3a
(Table 1, entry 3). Under air conditions, no desired
product was formed (Table 1, entry 4). The influence
of different solvents and copper salts were also
examined. Using toluene and acetonitrile as the
solvent gave very poor yield (Table 1, entries 5 and
6). DMSO gave comparative yield with that of 1,4-
dioxane while DMF gave a slightly lower yield
1
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10.1002/adsc.201800206
Advanced Synthesis & Catalysis
(Table 1, entries 7 and 8). Other copper salts such as
Cu(MeCN)4BF4, Cu(OAc)2, CuCl2, Cu(acac)2, and
Cu(ClO4)2 exhibited a very low catalytic activity and
CuX (X = Cl, Br) was inferior to the CuI (Table 1,
entries 9-15). Using t-BuOLi, DBU, or DMAP as the
base led to no formation of the desired product 3a
(Table 1, entries 16-18). When the amount of CuI
was reduced to 0.1 or 0.05 equiv, a longer reaction
time was needed and some indole 1a remained, thus
leading to a lower yield. In view of the operability,
1,4-dioxane was selected as the final solvent because
it had a lower boiling point compared with DMSO.
ring of hydrazone (2g) led to dramatic descend of the
yield (3g, 10%) due to the competitive self-reaction
of 2g to form sulfone 3g' (37%).[13] No desired
product was detected for the N-tosylhydrazone
derived
from
5-nitrosalicylaldehyde.
N-
Tosylhydrazone 2h derived from 2-hydroxy-1-
naphthaldehyde also delivered 56% yield of product
3h. Differently substituted indoles with either
electron-withdrawing or electron-donating group on
the phenyl ring were well tolerated in the reaction to
provide desired C-alkylated products 3i-o. 2-Methyl
or ester group substituted indole was also applicable
to the reaction, providing the desired products 3p or
3q in 74% or 71% yield, respectively. Unfortunately,
when the substrate was extended to the N-
tosylhydrazone derived from 2-hydroxyacetophenone,
no reaction occurred probably due to the steric
hindrance. Moreover, it should be noted that the N-
hydrogen atom of the indoles was essential to the
present reaction and no desired product was obtained
when it was replaced by a methyl, acetyl, or tosyl
group.
Table 1. Surveying of the Reaction Conditions.[a]
NNHTs
Ts
conditions
+
N
OH
3a'
N
HO
3a
HO
H
H
1a
2a
Time
(h)
6
Yield
(%)
38
Entry
[Cu], Base
CuI, K2CO3
Solvent
1[b]
2[b]
3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
CuI, Cs2CO3
CuI, Cs2CO3
CuI, Cs2CO3
CuI, Cs2CO3
CuI, Cs2CO3
CuI, Cs2CO3
CuI, Cs2CO3
CuCl, Cs2CO3
CuBr, Cs2CO3
6
6
49
72
0
4 [c]
6
Table 2. Substrate Scope for the CuI-Catalyzed Reaction
of N-Tosylhydrazones with Indoles.[a]
5
12
12
8
16
12
72
65
55
61
17
6[d]
7
CH3CN
NNHTs
CuI (0.2 equiv)
DMSO
Cs2CO3 (2 equiv)
+
dixoane, 100 oC, N2
N
8
DMF
8
N
H
HO
HO
R1
(0.5 mmol)
R1
R2
H
R2
2 (1.6 equiv)
1
9
1,4-dioxane
1,4-dioxane
1,4-dioxane
8
3
Me
Cl
10
11
8
OMe
Cu(MeCN)4BF4,
Cs2CO3
12
N
HO
N
HO
N
HO
3c
(3 h, 63%)
H
H
H
3b (4 h, 68%)
3a
(6 h, 72%)
12
13
Cu(OAc)2, Cs2CO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
18
18
18
12
12
12
12
10
10
18
10
21
23
0
Br
CuCl2, Cs2CO3
Cu(acac)2, Cs2CO3
Cu(ClO4)2, Cs2CO3
CuI, t-BuOLi
CuI, DBU
N
HO
N
HO
N
HO
H
14
H
H
OMe
3f
3d (2 h, 77%)
3e
(4 h, 52%)
(4 h, 72%)
15
CO2Et
16
CO2Et
Ts
HO
17
0
N
HO
N
HO
H
H
18
19[e]
20[f]
CuI, DMAP
0
3g (6 h, 10%)
3h
3g'
, 37%
(6 h, 56%)
CuI, Cs2CO3
53
49
MeO
Cl
CuI, Cs2CO3
N
H
HO
N
HO
N
H
HO
[a]
H
Unless otherwise indication, the reaction was performed with
0.5 mmol of 1a, 1.6 equiv of 2a, 0.2 equiv of copper salt, 2 equiv
of base, and 5 mL of solvent at 100 °C under nitrogen atmosphere.
3i (9 h, 40%)
3j (6 h, 68%)
3k
(3 h, 70%)
Br
NO2
[b]
[c]
2a (1 equiv), base (1.5 equiv).
Carried out under air
Cl
N
N
HO
N
HO
(6 h, 41%)
OH
N
HO
3n (11 h, 62%)
OH
H
H
H
condition. [d] Reacted at 80 °C. [e] 0.1 equiv of CuI was used.
0.05 equiv of CuI was used.
[f]
3m
3l
(6 h, 61%)
N
H
N
N
HO
CO2Et
3q (9 h, 71%)
H
H
Next, the general applicability of the CuI-catalyzed
C-3 alkylation was assessed with respect to different
substituted indoles 1 and N-tosylhyazones 2 (Table 2).
As can be seen from table 2, this transformation
displayed good functional group compatibility. For
the hydrazones, most of the substrates gave moderate
to good yield (3a−f). All the reactions of methyl-,
methoxy-, chloro-, and bromosubstituted substrates 2
with indole 1a yielded the corresponding products
3a−f in 52%−77% yields. A strong electronic effect
of the substituent was observed for substrates 2. A
moderate electron-withdrawing group on the phenyl
3p (5 h, 74%)
3o
(8 h, 52%)
To ascertain the significance of the hydroxyl group,
other hydrazones 2r-t derived from benzaldehyde, 2-
nitrobenzaldehyde, or 2-methoxybenzaldehyde were
introduced to the reaction and no desired product was
obtained (Scheme 1). The influence of the substituted
position of the hydroxyl group was also evaluated.
When the hydroxyl group was located at the meta-
position, no anticipated product 3u was formed.
2
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10.1002/adsc.201800206
Advanced Synthesis & Catalysis
However, the N-tosylhydrazones 2v and 2w
generated from 4-hydroxybenzaldehyde and 4-
hydroxy-3-methoxybenzaldehyde could react with
indole 1a to afford 3-alkylated products 3v and 3w,
respectively, albeit in a lower yield (Scheme 1).
These results clearly demonstrated that the hydroxyl
group and its location was critical to the present
reaction.
3
4
5
6
7
8
9
K2CO3 CH3CN 1:2.5:2.5
K2CO3 CH2Cl2 1:2.5:2.5
K2CO3 DMSO 1:2.5:2.5
2
2
2
2
2
2
2
2
88
74
63
77
87
59
80
86
trace
trace
trace
trace
trace
trace
trace
trace
K2CO3 DMF
K2CO3 EtOH
K2CO3 THF
1:2.5:2.5
1:2.5:2.5
1:2.5:2.5
DBU
CH3CN 1:2.5:2.5
10 DMAP CH3CN 1:2.5:2.5
[a] All the reactions were carried out with 0.2 mmol of 3a in 4 mL
[b]
NNHTs
of solvent at room temperature for the designated time.
CuI, Cs2CO3
3a/I2/additive.
+

N
H
dioxane, N2, 100 oC, 8 h
R
N
R
1a
2
H
2r
2s
2t
3 (0%)
, R = H; , R = 2-MeO; , R = 2-NO2
Chromeno[2,3-b]indole is the core skeleton in the
NNHTs
hyrtiazepine alkaloids hyrtimomine
A
and
CuI, Cs2CO3
hyrtimomine B.[15] Until now, there are few reports
on the synthesis of the chromeno[2,3-b]indole
derivatives. The first report of the preparation came
from the decomposition of the diazonium sulfate
+

dioxane, N2, 100 oC, 8 h
N
H
N
H
1a
1a
1a
2u
OH
OH
3u
(0%)
NNHTs
CuI, Cs2CO3
prepared
from
3-ortho-aminobenzylidene-7-
+
+
dioxane, N2, 100 oC, 8 h
N
H
OH
N
H
3v
OH
methyloxindole, affording 7-methylchromeno[2,3-b]
indole as a byproduct.[16] Intramolecular cyclizations
of the Knoevenagel adducts of oxindoles with 2-
hydroxyacetophenones gave a very low yield of
product.[17] The synthesis from 3-indolecarboxylates
and phenols needed 3 step- reaction.[18] Liu and Zhu
developed an efficient method for the synthesis of
chromeno[2,3-b]indoles through the Pd-catalyzed
2v
(8 h, 25%)
NNHTs
OMe
OH
OMe
dioxane, N2, 100 oC, 8 h
CuI, Cs2CO3
N
H
N
H
OH
2w
3w (6 h, 32%)
Scheme 1. Reaction of 1a with Different N-
Tosylhydrazones.
cascade
reaction
of
2-bromoindoles
with
salicylaldehydes.[19] Nevertheless, the 2-bromoindoles
were not easily available reagents. Most recently,
DDQ-mediated oxidative cyclization of 2,2-
bisindolylmethylphenols was reported;[20] however,
the use of excessive DDQ led to the formation of
many organic wastes. Owing to the limited synthetic
methods toward this nuclear, the biological character
has been rarely investigated except the high
antiproliferative activity against MV4-11, A549, and
Previously, we have focused on developing the I2-
mediated transformations.[14] In a continuous of our
interesting in this area, we wondered whether the
indole derivatives 3 could undergo a cycliazaiton
triggered by iodine. Initially, the product 3a was
chosen to try the possibility (Table 3). The reaction of
3a with 1 equiv of molecular iodine in the presence
of 1 equiv of K2CO3 in acetonitrile proceeded
smoothly at room temperature. Interestingly, two
cyclization products chromeno[2,3-b]indole 4a and
6,11-dihydrochromeno[2,3-b]indole 5a were obtained
in 36% and 19% yields, respectively, accompanied by
a large amount of raw material surplus. Increasing the
amount of iodine and K2CO3 to 2.5 equiv improved
the yield of 4a to 88% and only the traces of 5a were
observed (entry 3). Notably, treating 5a with 1.2
equiv of I2 and 1.2 equiv of K2CO3 resulted in the full
conversion to 4a in 90% yield. Other commonly used
bases and solvents were also effective in this
transformation (entries 4-10).
HCT116 cell lines.[18,21]
Herein, a simple and
efficient I2-mediated cyclization of 3-(2-hydroxyl)-
benzylindole for the synthesis of chromeno[2,3-
b]indoles under mild conditions was developed.
Various chromeno[2,3-b]indoles could be constructed
in moderate to good yields under standard conditions
(Table 4).
Table 4 Substrate Scope for the I2-Mediated Cyclization of
3.
I2 (2.5 equiv), K2CO3 (2.5 equiv)
CH3CN, rt.
N
H
HO
N
O
R1
R2
R1
R2
3
4
Table 3. Screening of the Cyclization Conditions.[a]
I2
+
conditions
N
HO
N
O
N
O
H
H
4a
5a
3a
I2, K2CO3
CH3CN, rt, 1 h, 90%
Yield (%)
Time
(h)
2
2
Entry Base
Solvent
Ratiob
4a
5a
19
7
1
2
K2CO3 CH3CN 1:1:1
K2CO3 CH3CN 1:2:2
36
73
3
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10.1002/adsc.201800206
Advanced Synthesis & Catalysis
OMe
Br
C-H insertion to Cu(I) carbene (like 8) would take
place. Maybe this could explain the relative low yield
for the reaction of indole 1a with 2v or 2w. 3a
reacted with I2 to generate the iodonium 16, which
underwent intramolecular attack by the hydroxyl
group followed by dehydroiodination to give 5.
Further iodination of 5 via iodonium 18 provided 19,
which eliminated the hydrogen iodide under basic
condition to afford chromeno[2,3-b] indole 4a.
O
O
N
O
N
N
4c, 5 h, 57%
4a, 2 h, 88%
4b
, 4 h, 80%
Cl
O
O
N
4f
, 5 h, 86%
O
N
OCH3
N
4d
4e, 4 h, 87%
, 6 h, 49%
O
O
N
O
N
O
N
4i, 5 h, 81%
4j, 3 h, 90%
4h, 5 h, 61%
N
Br
1a
H
Cl
N
CuI
Cs2CO3
NNHTs
N2
Cl
N2
O
O
N
O
N
4k, 7 h, 78%
O
N
-Ts-
path A
4m
, 2 h, 71%
4l
, 5 h, 81%
or
N
Cs2CO3
HO
HO
O
2
10
6
Cu
7
9
O
N
4o, 6 h, 69%
path B CuI
1a
3
6
N
Cu
O
H
1a
N
H
O
3
product
8
Cs2CO3
Cu
12
The possible reaction mechanism for the C-3
alkylation of indole with N-tosylhydrazone was
shown in Scheme 2. First, decomposition of the N-
tosylhydrazone 2 in the presence of base generated
the diazo compound 6 or 7, which might react with
CuI to give Cu(I) carbene complex 8 or produce o-
quinone methide intermediate 9. Indole 1a reacted
with CuI to generate complex 10, which coordinated
with 9 followed by intramolecular C-C bond
formation to generate 11 (it was equal to 12). Indole
1a reacted with 12 to afford product 3 and regenerate
complex 10 (path A). To confirm whether o-quinone
methide 9 was generated in the transformation,
several control experiments were performed (Scheme
3). TBS-protected 2-bromomethylphenol I has been
usually used as a precursor of o-quinone methide via
fluoride-induced desilylation.[22] However, the
reaction of indole 1a with 1.5 equiv of I, 1.5 equiv of
TBAF, and 1.5 equiv of Cs2CO3 did not afford
product 3a. When 0.2 equiv of CuI was added, 3a
was obtained in 51% yield.[23] This demonstrated that
o-quinone methide might be involved in the
transformation. To further prove this, the reaction of
2a with styrene (15 equiv) using Cs2CO3 as the base
was carried out. However, no anticipated [4+2]
product II was generated whether the CuI was added
or not. This result contradicted with the formation of
o-quinone methide because it was reported to react
with styrene easily to form II.[24] Therefore, we
proposed another possible reaction pathway (path B).
Under the basic condition, indole was deprotonated to
generate 13 (which was equal to 14). The reaction of
14 with 8 gave 15 and the subsequent abstraction of
proton afforded 11 (12). 12 reacted with 6 to give
product 3 and regenerate Cu(I) cabene complex 8.
The Cs2CO3 gave a better result than the K2CO3
probably owing to the stronger basicity which is
beneficial to the deprotonation of indoles. If the
hydroxyl group was located at the para-position, the
carbene complex 8 could not be formed and the direct
N
N
13
14
O
Cu
H+
N
O
N
15
Cu
11
I
I
B-
B-
I2
3a
-HI
N
H
O
N
H
O
N
O
H
5
H
17
16
I
I
B-
-HI
B-
-HI
I2
N
O
N
O
N
O
4a
H
19
18
Scheme 2. Proposed Mechanism.
conditions
dioxane, N2, 100 o
+
(1)
C
N
N
HO
O
H
H
1a
3a
Br
O
TBS
I
(1.5 equiv)
Bu4NF•3H2O (1.5 equiv), Cs2CO3 (1.5 equiv), 2 h
0%
Bu4NF•3H2O (1.5 equiv), Cs2CO3 (1.5 equiv), CuI (0.2 equiv), 2 h
51%
NNHTs
conditions
dioxane, N2, 100 o
+
(2)
C
OH
Ph
O
15 equiv
2a
II
Cs2CO3 (1.5 equiv), 12 h
Cs2CO3 (1.5 equiv), CuI, 12 h
0%
0%
Scheme 3 Control Experiments.
In summary, the CuI-catalyzed reaction of indoles
with N-tosylhydrazones for the selective C-3
4
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10.1002/adsc.201800206
Advanced Synthesis & Catalysis
alkylation was developed. Gratifyingly, there was no
N-alkylated product being observed in the reaction.
The ortho- or para- hydroxyl group was crucial to the
reaction. In addition, we developed a simple method
to synthesize the chromeno[2,3-b]indole derivatives
through an I2-mediated cyclization of the generated 3-
(2-hydroxybenzyl)-indoles. This discovery might be
of great importance on the selective construction of
other polycyclic indole structures. A possible reaction
mechanism for the two transformations was proposed.
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J. Wang, Angew. Chem. Int. Ed. 2015, 54,
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General information
1H, 13C NMR were recorded on 300 MHz (75 MHz for 13
C
NMR) spectrometer. Melting points were determined on a
micromelting point apparatus without corrections. Flash
column chromatography was performed over silica gel
(200−300 mesh). HRMS were obtained on an Thermo
Scientific LTQ Orbitrap XL equipped with an ESI source
(positive mode).
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Valdés, Angew. Chem. Int. Ed. 2010, 49, 4993–4996;
b) A.-H. García-Muñoz, M. Tomás-Gamasa, M. C.
Pérez-Aguilar, E. Cuevas-Yañez, C. Valdés, Eur. J.
Org. Chem. 2012, 3925–3928.
General Procedure for the Preparation of 3 through the
CuI-Catalyzed Reaction of Indole with N-
Tosylhydrazones
A test tube (Ø18 × 150 mm) was charged with indoles 1
(0.5 mmol), N-tosylhydrazones 2 (0.8 mmol), CuI (19.0
mg, 0.1 mmol), Cs2CO3 (325 mg, 1 mmol), and 1,4-
dioxane (5 mL). The reaction tube was evacuated and
backfilled with N2 (3 times, balloon). The reaction mixture
was stirred at 100 °C (oil bath temperature) under a N2
balloon. After completion of the reaction as determined by
TLC, the mixture was cooled to room temperature, diluted
with dichloromethane, and quenched with NH3∙H2O. The
reaction mixture was extracted with CH2Cl2 (20 mL × 3)
and washed with brine. The organic phase was dried over
anhydrous Na2SO4 and concentrated in vacuo, and the
residue was purified by column chromatography on silica
gel eluted with ethyl acetate-petroleum ether to provide the
corresponding products 3.
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The reaction of 3 with I2 for the synthesis of 4
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A test tube (Ø18 × 150 mm) was charged with 3 (0.2
mmol), I2 (0.5 mmol), K2CO3 (0.5 mmol), and acetonitrile
(4 mL). The reaction mixture was stirred at room
temperature until the completion of the reaction as
determined by TLC. The reaction mixture was quenched
with 2 aqueous solution of Na2S2O3 (100 mg / mL,), and
then extracted with CH2Cl2 (20 mL × 3). The organic layer
was dried over anhydrous Na2SO4, and then concentrated
under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with ethyl
acetate-toluene to provide 4.
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Acknowledgments
We are grateful for financial support from the Jiangsu Key
Laboratory of Advanced Catalytic Materials and Technology
(BM2012110) and Advanced Catalysis and Green Manufacturing
Collaborative Innovation Center.
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10.1002/adsc.201800206
Advanced Synthesis & Catalysis
COMMUNICATION
CuI-Catalyzed Selective 3-Alkylation of Indoles
with N-Tosylhydrazones and the I2-Mediated
Further Cyclization to Chromeno[2,3-b]indoles
Adv. Synth. Catal. Year, Volume, Page – Page
Chun-Bao Miao,* Yan-Fang Sun, He Wu, Xiao-
Qiang Sun, Hai-Tao Yang
7
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