Regioselective N-1 and C-2 diacylation of 3-substituted indoles with arylglyoxal hydrates for the synthesis of indolyl diketones

Article abstract of DOI:10.1039/c8ob01776j

A highly regioselective N-1 and C-2 diacylation of 3-substituted indoles with arylglyoxal hydrates to afford N-1 and C-2 indolyl diketones in moderate to good yields is described. Notably, the control of regioselectivity is achieved by small changes in the Cu catalyst, additive and solvent. Importantly, the intermediates for N-1 and C-2 diacylation were detected and two plausible pathways were also proposed.

Full text of DOI:10.1039/c8ob01776j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Regioselective N–1 and C–2 diacylation of 3-substituted indole
with arylglyoxal hydrates for the synthesis of indolyl diketones
Received 00th January 20xx,
Accepted 00th January 20xx
Dalong Pan,‡a Jinpeng Chu,‡a Xianrui Gao,a Cuiping Wang,*a,b Qingtao Meng,a Haijun Chi,a Yan
Dong,a Chunying Duanb and Zhiqiang Zhang*a
DOI: 10.1039/x0xx00000x
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A highly regioselective N–1 and C–2 diacylation of 3-substituted diketones and their application in the synthesis of a broad
indole with arylglyoxal hydrates to afford N–1 and C–2 indolyl range of indole derivatives.11 However, for the N–1 and C–2
diketones in moderate to good yields is described. Notably, the diacylation of indole, only three examples have been reported
control of regioselectivity is achieved by small changes in the Cu by using 3-substituted indole as a substrate to achieve the
catalyst, additive and solvent. Importantly, the intermediates for control of regioselectivity (Scheme 1a,b,c).10d,10e,12 But we
N–1 and C–2 diacylation were detected and two plausible found that the diacylation occurred on N–1 position not C–2
pathways were also proposed.
position of 3-substituted indole by NMR analysis of the
product in Li’s works (Scheme 1a and 1b).10d,10e The other
involved the reaction of 3-methylindole with 2-oxo-2-
phenylacetaldehyde hydrate to afford N–1 indolyl diketones in
only 33% yield by Ivonin group.12 Encouraged by these results,
we commenced our investigation on the regioselectivity of N–
1 and C–2 diacylation of 3-substituted indole. First, the
reaction of 3-methylindole with 2-(4-bromophenyl)-2-
oxoacetaldehyde hydrate was performed under our
established conditions (20 mol% of Cu(OAc)2·H2O,
Dioxane/HOAc (4.0/0.5, v/v), 100 oC, air). Interestingly, both
N–1 and C–2 indolyl diketones were obtained in 57% and 26%
yields, respectively (Scheme 1d).10f Inspired by the result,
herein, we report the regioselective transformation for the
construction of N–1 and C–2 indolyl diketones via the cross-
coupling of 3-substituted indole with arylglyoxal hydrates.
The indole nucleus is an important nitrogen-containing
heterocycle in organic chemistry and is considered to be a
“privileged” structure in medicinal chemistry.1 Indole
derivatives exhibit various pharmaceutical activities, such as
anticancer,2 antidiabetic,3 antipsychotic4 and anti-HIV.5
Transition-metal-catalyzed direct functionalization of
indoles has emerged as a powerful tool in organic synthesis
over the past decades.6 Generally, the substitution reaction on
indole ring occurs at C–3 position because of the intrinsic
reactivity of the indole system.7 The regiocomplementary C–2
functionalization was also achieved by introducing on the
nitrogen atom
a directing group such as 2-pyridyl, 2-
pyrimidinyl or other groups.8 For the past few years, some
regioselective functionalization of indoles were achieved
based on the suitable adjustment of the reactivity of the
substituted indoles and the different reaction conditions
avoiding the introduction of a directing group.9 Therefore, the
further development of the efficient and highly regioselective
methodologies of indoles controlled only by the changes in the
reaction conditions should be strongly pursued.
Previous Work
H3C
O
O
O
O
CuCl,TBHP
N
NHR3
(a)
CH3
Ph
Ph
Ph
Ph
CH2Cl2, rt
Ref. 10d
O
+
CH3
N
H
Ph
N
Pd(OAc)2, Cu(OAc)2
(b)
(c)
MeCN, HOAc, 80 o
C
N
H
Ref. 10e
O
In recent years, C–3 diacylation of indole has been widely
reported10 due to the various biologically activities of indolyl
H3C
O
Benzene,80 oC, 3 h
N
Ph
or Benzene,20 oC, 10 h
O
CH3
O
Ref. 12
O
Yield: 33%
O
+
Ph
CH3
H3C
H2O
N
H
H
O
Cu(OAc)2 H2O
N
(d)
+
Ph
dioxane/HOAc,100 o
C
N
Ph
O
H
O
Ref. 10f
Yield:26%
Yield: 57%
This Work
R1
R1
R1
Dioxane
HOAc
O
O
Cu(OAc)2 H2O
HOAc
O
O
H
R
N
R2
R2
+
R2
R
N
H
air, 100 o
C
H2O
Toluene
N
H
O
O
air, 100 o
C
R
C-2 diacylation
N-1 diacylation
Scheme 1 Diacylation of 3-substituted indole
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Table 1 Optimization of Reaction Conditionsa
Entry
1
Catalyst
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CuO
Additive
Solvent
Dioxane
Toluene
Temp. (oC)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
80
Yield of 3a
52/8
/
4a (%)b
—
—
2
77/1
3
HOAc (20 mol%)
HOAc (20 mol%)
TFA (20 mol%)
HOAc (30 mol%)
HOAc (10 mol%)
HOAc (5 mol%)
HOAc (5 mol%)
HOAc (5 mol%)
HOAc (5 mol%)
HOAc (5 mol%)
HOAc (5 mol%)
HOAc (5 mol%)
HOAc (5 mol%)
HOAc (5 mol%)
HOAc (5 mol%)
TFA (20 mol%)
—
Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
HOAc
69/2
4
80/2
5
46/20
75/3
6
7
82/1
8
9c
84/1
77/1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29e
30f
31
32
80/2
Cu2(OH)2CO3
Cu2O
55/2
47/3
CuCl2·2H2O
CuSO4·5H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
—
trace/trace
trace/trace
85/1
54/2
100
100
100
100
100
100
100
100
100
100
100
100
100
100
120
80
trace (58)d/trace
54/trace
0/55
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
—
—
TFA
trace/trace
0/40
—
HOAc
—
—
TFA
0/16
—
Dioxane (0.2 mL)
Dioxane (0.5 mL)
Dioxane (1.0 mL)
Toluene (0.5 mL)
DMSO (0.5 mL)
DMF (0.5 mL)
Dioxane (0.5 mL)
Dioxane (0.5 mL)
Dioxane (0.5 mL)
Dioxane (0.5 mL)
HOAc
1/57
—
HOAc
1/63
—
HOAc
1/60
—
HOAc
5/57
—
HOAc
1/43
—
HOAc
1/55
—
HOAc
1/81
—
HOAc
1/81
—
HOAc
1/80
—
HOAc
1/65
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (20 mol%), additive, solvent (4 mL), 100 oC, 7 h, under air atmosphere. b Isolated yields. c Cu(OAc)2·H2O (10
mol%) was used. d 1-(4-bromophenyl)-2-hydroxy-2-(3-methyl-1H-indol-1-yl)ethan-1-one 5a was obtained in 58% yield. e 2a (0.7 mmol) was used. f 2a (0.8 mmol) was
used.
First, the different reaction conditions including the catalyst, addition, the temperature was also examined. Unfortunately,
additive, solvent and temperature were examined. Our elevating or lowering the temperature did not improve the
investigation commenced with the reaction of 3-methylindole yield (entries 15 and 16). The reaction could also proceed in
1a and 2-(4-bromophenyl)-2-oxoacetaldehyde hydrate 2a. The the absence of a Cu catalyst and afforded the product 1-(4-
results indicated that the addition of Cu catalyst and a small bromophenyl)-2-hydroxy-2-(3-methyl-1H-indol-1-yl)ethan-1-
amount of weak acid HOAc was favorable for the production of one 5a in 58% yield (entry 17). Subsequently, the diacylation
N–1 diacylation product 3a; however, the addition of a big reaction was carried out in sole HOAc or TFA (entries 18–22).
amount of weak acid HOAc (0.5 mL, under standard The investigation showed that a big amount of HOAc solvent
conditions) or a small amount of strong acid additive TFA (20 was much more favorable for C–2 diacylation (entries 19 and
mol%) was much more favorable for the production of C–2 21). Inspiringly, the yield of 4a was enhanced to 57% in HOAc
diacylation product 4a (Table 1, entries 1–8). Different in the presence of Dioxane (0.2 mL) without Cu catalyst (entry
catalysts and the loading were then examined, but no further 23). The amount of Dioxane was also examined. A satisfactory
improvement of the yield was obtained (entries 9–14). In
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result was observed when the reaction was performed with substrates was explored in Table 2. We were pleased to find
Dioxane (0.5
that phenylglyoxal hydrates with electron-deficient groups,
such as 4-Br, 4-Cl, 4-F, 4-I, 4-NO2, 4-CF3, 4-COOCH3 and 3-Cl,
exhibited high reactivity and furnished the desired products
Table 2 N–1 diacylation of 3-substituted indole with arylglyoxal hydratesa
3a–3h in relatively high yields. Importantly, halogen
Table 3 C–2 diacylation of 3-substituted indole with arylglyoxal hydratesa
a
Conditions: 1 (0.5 mmol), 2 (0.6 mmol), Cu(OAc)2·H2O (20 mol%), HOAc (5
mol%), Toluene (4.0 mL), 100 oC, under air atmosphere; the isolated yields are
given.
a Conditions: 1 (0.5 mmol), 2 (0.6 mmol), Dioxane (0.5 mL), HOAc (4.0 mL), 100 oC,
mL) in HOAc solvent, which led to the formation of 4a in 63%
yield (entry 24). The screening of other additives such as
Toluene, DMSO and DMF was found to be less effective for this
transformation (entries 26–28). Based on the above results,
we found that the substrate 1a was not exhausted completely
after the reaction. Thus, the amount of 2a was increased. The
results indicated that the yield of 4a was improved to 81%
evidently when 2a (0.7 mmol) was used (entries 29 and 30).
Further investigation of the reaction temperature
demonstrated that elevating or lowering the temperature did
not improve the yield of 4a (entries 31 and 32).
b
under air atmosphere; the isolated yields are given. The structures of the
products 4s and 4t were detected by only HPLC/MS analysis (see SI) and were not
isolated.
substituents on the products remained intact, which could
potentially be used for further functionalization. Moreover,
phenylglyoxal hydrates with electron-rich groups, such as CH3
and OCH3, gave the corresponding products 3j–3m in good
yields. Meta-substituted or sterically hindered ortho-
substituted phenylglyoxal hydrates also provided the target
product 3h, 3k and 3l in 78%, 71% and 69 % yields,
respectively. It is worth noting that fused 2-(naphthalen-2-yl)-
With the optimized reaction conditions in hand, the scope of
the reaction using various arylglyoxal hydrates as the
2-oxoacetaldehyde hydrate also gave the product 3n in 61%
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yield. In addition, the effect of the substituted group on the
benzene ring of indole was also examined. The result showed
that 4-Br, 5-Br and 5-F substituted 3-methylindole afforded the
H3C
O
Cu(OAc)2 H2O (20 mol%)
N
HOAc (5 mol%)
Br
Toluene (10 mL), air, 100 o
C
O
O
CH3
3a
H
desired products 3o, 3p and 3q in 78%, 82% and 84 % yields,
1.23 g, 72% yield
H2O
+
O
CH3
O
N
respectively. Furthermore, C-3 substituted groups on indole
ring were also investigated. The result demonstrated that 3-
alkyl and 3-aryl substituted indoles were tolerated and
Br
H
Dioxane(1.25 mL)
HOAc (10 mL)
1a
5 mmol
2a
6 or 7 mmol
air, 100 o
C
N
Br
H
O
4a
provided the target products 3r
Notably, di(1 -indol-3-yl)methane 1u was also reacted with
two molar equivalents of 2a to afford the product 3u
Subsequently, a variety of arylglyoxals hydrates for C–2
–3w in relatively high yields.
1.10 g, 64% yield
H
.
Scheme 2 Gram-scale synthesis of 3a and 4a
diacylation of 3-substituted indole were also tested under the (A) Reprecentative LC-MS result for N–1 diacylation
H3
C
OH
optimal reaction conditions as shown in Table 3. The results
indicated that phenylglyoxal hydrates with electron-
withdrawing groups, such as 4-Br, 4-Cl, 4-F, 4-I, 4-NO2, 4-CF3, 4-
COOCH3 and 3-Cl, generated the corresponding C–2 diacylation
N
Br
O
CH3
O
5a
Cu(OAc)2 H2O
HOAc, Toluene
H3 C
O
H
+
N
H2O
Br
N
H
O
+
H3
C
O
Br
air, 100o
C
O
N
1a
2a
Br
3a
HO
products 4a
phenylglyoxal hydrates with electron-donating groups, such as
CH3 and OCH3, gave the desired products 4j 4n in 60-72%
–4h in 77-88% yields. On the other hand,
5b
+ESI TIC Scan Frag=160.0V SY6-2-1701101.d Smooth
5.2
6
x10
2
–
1.8
1.6
1.4
1.2
1
12.2
yields. Meanwhile, the ortho-effect was not abvious, 4l and 4m
were isolated in 71% yields. Additionally, fused 2-(naphthalen-
2-yl)-2-oxoacetal-dehyde hydrate also proceeded smoothly to
furnish 4o in 68% yield. Similarly, both the substituted group
on the benzene ring and C-3 substituted groups on indole ring
were also tested. The result indicated that the protocol was
compatible with 4-Br, 5-Br, 5-F substituted 3-methylindole and
3-aryl substituted indoles, and gave the corresponding
6.9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Counts vs. Acquisition Time (min)
products 4p–4r and 4u–4w in moderate to good yields.
Unfortunately, only <10% yields of 4s and 4t were detected
due to the steric effect of the substituents at C-3 position on
indole ring or the poor stability of the substrates under the
acid condition. Moreover, the structures of N–1 product 3e
and C–2 product 4a were confirmed by single crystal X-ray
data analysis (see Table S1 in SI).
B) Reprecentative LC-MS result for C–2 diacylation
CH3
OH
To highlight the practical usefulness of these syntheses, N–1
and C–2 diacylation reactions of 3-methylindole 1a (5 mmol)
with 2-(4-bromophenyl)-2-oxoacetaldehyde hydrate 2a (6
mmol or 7 mmol) were carried out on a gram scale under the
optimal conditions. The desired product 3a and 4a were
isolated in satisfactory 72% (1.23 g) and 64% (1.10 g) yields,
respectively (Scheme 2).
N
H
Br
+
O
6a
H+
Dioxane(0.5 mL)
HOAc (4.0 mL)
CH3
O
CH3
H
O
+
H2O
air, 100 o
C
CH3
N
H
O
N
Br
Br
H
O
O
1a
2a
4a
N
Br
H HO
6b
To gain further insight into the reaction mechanism,
representative LC-MS analyses were shown in Figure 1. It is
noteworthy that an intermediate 5a was detected in the
reaction process and was exhausted completely after the
reaction for N–1 diacylation (Figure 1A). Moreover, the
intermediate 5a was also isolated and determined by HRMS
and NMR analyses. Interestingly, another two isomeric
intermediates 6a (major) and 6b (minor) were detected in C–2
diacylation. However, the two isomeric intermediates 6a and
6b were not isolated successfully because of their coexistence
and easy oxidation to the desired product 4a (Figure 1B).
Based on the above results, two plausible paths for N–1 and
6b
[M-H]-=342.0074
Figure 1 (A) Reprecentative LC-MS result for N–1 diacylation. (B) Reprecentative LC-MS
result for C–2 diacylation.
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C–2 diacylation were proposed as shown in Scheme 3. First, it substrate scope, which provides a straightforward strategy for
is worth noting that the reasonable structure of the arylglyoxal the regioselective synthesis of N–1 and C–2 indolyl diketones.
hydrate 2a was confirmed as the structure of two hydroxyl Meanwhile, this method also provides an attractive guidance
groups on one carbon atom 2a-C with the intramolecular for the further development of the regioselective
hydrogen bond based on NMR and IR analyses (see SI) and the functionalization of indole derivatives. Further insight into the
reported literatures.13 Therefore, the arylglyoxal hydrates precise mechanism and further applications is underway in our
could be the major content under our reaction systems laboratory.
because the conversion or coexistence of dry arylglyoxals and
its hydrates were also detected through the combination or
removal of a molecule of H2O.14 For N–1 diacylation (path a),
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (21542017), Department of
education of Liaoning Province (2016TSPY01), Excellent Talents
in University of Science and Technology Liaoning (2015RC08).
Notes and references
1
2
3
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Scheme 3 Plausible reaction pathway
6
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firstly took place at the N–1 position of 1a in non-polar solvent
(Toluene) providing the intermediate 5a, which underwent
subsequent oxidation to afford the N–1 diacylation product 3a
and Cu2O (XRD, X-ray powder diffraction, see Figure S1 in SI) in
the presence of Cu(OAc)2·H2O and air. For C–2 diacylation
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path b), initially, the N–1 position of 3-methylindole 1a was
surrounded by lots of protons to form the unstable indole-
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7
8
I
(HOAc) because the actual protonation of indole easily took
place in strong acid medium.15 The subsequent electrophilic
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.
Conclusions
In conclusion, we have developed a highly regioselective N–1
and C–2 diacylation of 3-substituted indole with arylglyoxal
hydrates under air atmosphere. In particular, the
regioselectivity of the reaction appears to be controlled by the
suitable adjustment of the reaction conditions. The reaction
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exhibites
a good functional group tolerance and broad
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