ZrCl4-promoted facile synthesis of indole derivatives

Article abstract of DOI:10.1039/c4ra02158d

Zirconium(iv) chloride effectively activates nitrogen (N₂) extrusion from aryl azidoacrylates followed by annulation to provide the desired indole products in moderate to good yields. The reaction proceeds at low temperature and in short reaction time and is applicable to a variety of substrates.

Full text of DOI:10.1039/c4ra02158d

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ZrCl4-promoted facile synthesis of indole
derivatives†
Cite this: RSC Adv., 2014, 4, 20048
J. Tummatorn, M. P. Gleeson,b S. Krajangsri,a C. Thongsornkleebac
a
*
and S. Ruchirawatac
Received 12th March 2014
Accepted 17th April 2014
DOI: 10.1039/c4ra02158d
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Zirconium(IV) chloride effectively activates nitrogen (N2) extrusion AlCl3, In(OTf)3, Yb(OTf)3, HfCl4 and ZrCl4. We found that only
from aryl azidoacrylates followed by annulation to provide the desired ZrCl4 and HfCl4 were promising as the reactions went to
indole products in moderate to good yields. The reaction proceeds at completion within a few minutes at room temperature and
low temperature and in short reaction time and is applicable to a provided the desired product (2a) in acceptable yields (entries
variety of substrates.
2–3, Table 1). Among metal catalysts reported to effect such a
transformation, ZrCl4 is much less expensive, hence more
economically advantageous. We then decided to select ZrCl4 as
the reagent for this transformation.6 In our optimization
process, we encountered a competitive reaction which resulted
in the formation of by-product 3a in a signicant amount. To
reduce the formation of by-product 3a, a lower temperature
(0 ꢀC, entry 4) was employed and found to improve the yield to
46%. Due to the polymeric structure with octahedral coordi-
nation geometry around the metal centers,7 ZrCl4 and HfCl4
could not be dissolved in DCE and, as a result, the corre-
sponding reactions were heterogeneous. To improve the effi-
ciency of ZrCl4, we envisioned that breaking up the polymeric
structure of ZrCl4 might enhance the efficiency of this trans-
formation. As reported in the literature8 that AgNO3 could
remove the chloride ligand from a metal center complex, we
thought that the silver salt could abstract chloride ligand from
ZrCl4 resulting in depolymerization of its polymeric structure
into short chains thereby increasing the reactivity of ZrCl4 in the
reaction. Therefore 0.1 equivalent of AgNO3 was added to the
reaction mixture (Table 1, entry 5). Unfortunately, the result was
an incomplete reaction aer 20 min as monitored by TLC.
When this reaction was allowed to proceed longer (60 min), side
reactions were observed and we obtained only 28% yield of the
desired indole. Then we attempted to enhance the conversion
by increasing the amount of ZrCl4 to 1.4 equivalents and we
found the reaction went to completion within 20 min at 0 ꢀC to
provide the desired product in 70% yield (entry 6). However,
when 1.0 equivalent of AgNO3 was employed, the reaction
provided a complex mixture (entry 7). In this entry, we initially
observed the formation of the desired product by TLC but this
product gradually disappeared from the decomposition under
the reaction conditions. We believed this was due to the
increased amount of AgNO3 which led to the excess amount of
Methodologies for the synthesis of indole derivatives have been
continuously developed over the past several decades due to
both naturally-occurring and synthetic indoles exhibiting a
broad range of biological activities.1 Several strategies for indole
construction have been reported including the synthesis of
indole-2-carboxylate derivatives2 of which aryl azidoacrylates
have been among the best precursors. Typically, the aryl azi-
doacrylate derivatives can be converted into indole-2-carboxyl-
ates using the Hemetsberger reaction which requires high
temperature.3 Recently, Driver has developed a new catalyst,
rhodium(II) peruorobutyrate, which can activate aryl azidoa-
crylates for the formation of indole-2-carboxylates via C–H
amination at relatively low temperatures (room temperature to
60 ꢀC).4 Subsequently, commercially available iron(II) triate
was also reported as an effective catalyst for this transformation
at 80 ꢀC.5 However, both catalysts still require high reaction
temperatures and long reaction times. Herein, we report for the
rst time that ZrCl4 is an effective reagent for such trans-
formation at room temperature or lower in less than 30
minutes. We commenced the investigation using the unac-
tivated phenyl azidoacrylate (1a) as a screening substrate and
started our study with several Lewis acids including BF3$OEt2,
aChulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210,
Thailand. E-mail: jumreang@cri.or.th; Fax: +66 2 5538545
bDepartment of Chemistry, Faculty of Science, Kasetsart University, 50 Phahonyothin
Road, Bangkok, Thailand 10900
cProgram on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence
on Environmental Health and Toxicology, CHE, Ministry of Education, 54
Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra02158d
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Table 1 Optimization of the synthesis of indole-2-carboxylate
Entry
Reagent/additive (eq.)
Solvent
Time (min)
Temp (ꢀC)
Yield of 2a (%)a
b
b
1
2
3
4
5
6
7
8
Lewis acids
HfCl4 (1.0)
ZrCl4 (1.1)
ZrCl4 (1.1)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
DCM
PhCH3
THF
—
1
1
5
—
0–14
42
40
46
28
70
—
Trace
—
—
rt
rt
0
0
0
0
0
0
0
0
rt
0
0
0
0
ZrCl4/AgNO3 (1.1 : 0.1)
ZrCl4/AgNO3 (1.4 : 0.1)
ZrCl4/AgNO3 (1.4 : 1.0)
ZrCl4/AgNO3 (0.1 : 0.2)
ZrCl4/Ag2O (1.4 : 0.1)
ZrCl4/KOAc (1.4 : 0.1)
ZrCl4/K2CO3 (1.4 : 0.1)
AgNO3 (1.0 eq.)
ZrCl4/AgNO3 (1.4 : 0.1)
ZrCl4/AgNO3 (1.4 : 0.1)
ZrCl4/AgNO3 (1.4 : 0.1)
ZrCl4/AgNO3 (1.4 : 0.1)
60
20
10
30
20
30
30
30
25
25
25
25
9
10
11
12
13
14
15
16
—
NR
NR
NR
NR
NR
a
Isolated yield. b 1 eq. of BF3$OEt2 ¼ NR (rt, 6 h), 1 eq. of AlCl3 ¼ complex mixture (rt, 30 min), 10 mol% of In(OTf)3 ¼ 14% (reux, O/N), 20 mol% of
Yb(OTf)3 ¼ trace (reux, O/N).
short chain ZrCl4 species from the depolymerization resulting which induced the nucleophilic attack by a chlorine atom
in disintegration of the indole product. Furthermore, we also from the zirconium complex. a-Naphthyl azidoacrylate was
examined the reaction using a catalytic amount of ZrCl4 successfully converted to indole 2f in 80% yield, whereas b-
(0.1 equivalent) and AgNO3 (0.2 equivalent) (entry 8). Only trace naphthyl azidoacrylate gave product 2g in lower yield (48%)
amount of indole product 2a was observed attributing to as the only isolable regioisomer. In the latter case, we
incomplete conversion of the azidoacrylate precursor 1a. In observed a purple-colored reaction which we suspected was a
addition, no conversion of compound 1a was obtained when sign of decomposition. p-Halogen-substituted phenyl azi-
ZrCl4 was excluded in the reaction mixture (entry 9). Therefore, doacrylates (entries 8–10) were effectively transformed to
stoichiometric amount of ZrCl4 was needed for this trans- indole products in good efficiency. By contrast, when a
formation.9 Additionally, the use of different additives such as substrate containing an electron-withdrawing nitro group
Ag2O, KOAc, and K2CO3 (entries 10–12) were also explored. (entry 11) was attempted, a low conversion was observed and
Unfortunately, these proved detrimental to the reactions, the corresponding product was obtained in low yield. This
providing only mixtures of unidentiable by-products. We also could be attributed to the strong electron-withdrawing effect
investigated the effect of solvents and found DCE to be well- of the p-nitro group which prevented the nitrogen extrusion.
suited for this transformation while there was no reaction in Subsequently, o-halogen-substituted phenyl azidoacrylates
CH3CN, DCM, toluene or THF (entries 13–16). We therefore (entries 12–13) were examined and found to provide the
used 1.4 equivalent of ZrCl4 and 0.1 equivalent of AgNO3 in DCE corresponding indoles in good yields. In the cases of m-
as our optimal conditions.
chlorophenyl azidoacrylate and m-uoro-p-tolyl azidoacrylate
To study the scope of this reaction, we then applied the (entries 14–15), we obtained a mixture of regioisomeric
optimal conditions to a variety of aryl azidoacrylate deriva- products in moderate to good overall yields. The products
tives and the results are summarized in Table 2. o-Tolyl azi- were obtained in approximately a 1 : 1 ratio for the chloro-
doacrylate and o-ethylphenyl azidoacrylate (entries 2–3) substituted indoles whereas in the uoro-substituted case,
provided the desired products in good yields. The reaction of the desired products were obtained in a 2 : 1 ratio. Interest-
p-tert-butylphenyl azidoacrylate (1d, entry 4) also proceeded ingly, m-methoxyphenyl azidoacrylate (entry 16) provided a
well under these conditions and furnished the corresponding single regioisomeric product. In this entry, the purple-
indole in 69% yield. Unfortunately, when p-biphenyl azi- colored reaction mixture was also observed and the reaction
doacrylate was subjected to this transformation, the yield produced the desired product in moderate yield. The reaction
dropped to 44% and we observed the formation of by-product of polysubstituted phenyl azidoacrylate (entry 17) proceeded
3e in a signicant amount (42%). The results implied that the well, affording the indole product in excellent yield. From
p-phenyl substituent increased the electrophilicity of the these results, we can draw a trend that aryl azidoacrylates
benzylic position of carbocation intermediate 5 (Scheme 1) p-substituted with electron-withdrawing groups such as
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Table 2 Scope of aryl azidoacrylates
Entry
1
Substrate
Product
Temp/Time
Yielda (%)
70
0 ꢀC (20 min)
2
3
15 ꢀC (3 min)
15 ꢀC (10 min)
75
69
4
5
6
15 ꢀC (10 min)
0 ꢀC / rt (5 min)
0 ꢀC (15 min)
69
44
80
7
0 ꢀC / rt (5 min)
48
8b
0 ꢀC / rt (10 min)
0 ꢀC (10 min)
0 ꢀC (10 min)
rt (30 min)
79
71
65
22
9
10
11
12
13
0 ꢀC / rt (30 min)
0 ꢀC / rt (10 min)
63
63
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Table 2 (Contd.)
Entry
14
Substrate
Product
Temp/Time
Yielda (%)
0 ꢀC / rt (10 min)
61b
15
16
15 ꢀC (20 min)
56b
0 ꢀC (10 min)
15 ꢀC (1 min)
54
88
17
a
Isolated yield. b Combined yield of separable regioisomeric products; 2nX ¼ 31%, 2nY ¼ 30%, 2oX ¼ 38%, and 2oY ¼ 18%.
highly oxophilic which can form a stable metal–oxygen
complex7,10 and also have a good chelation with the nitrogen
donor11 thus the coordinations of ZrCl4 with the nitrogen
and carbonyl group of the aryl azidoacrylate occurred in the
initial step to generate the hexacoordinate zirconium
complex 4.12 This complex subsequently undergoes a slight
rearrangement of bonds and a nitrogen extrusion to provide
zirconium complex 5. This is the important key intermediate
which could undergo two competing reaction pathways to
form the indole product 2a (pathway a) or chlorinated-
product 3a (pathway b). In pathway a, an intramolecular
nucleophilic aromatic substitution-type reaction of complex
5 provides the cyclization intermediate complex 6 which
rearomatizes and hydrolyzes upon workup to the desired
indole 2a. For the formation of chlorinated-product 3a,
the carbocation complex 5 could undergo an intramolecular
chlorine atom transfer (pathway b) to form the pentacoordi-
nate zirconium complex 8.13 This complex is then further
hydrolyzed during workup to give by-product 3a.14 DFT
calculations were performed to understand the reaction
Scheme 1 Proposed mechanism for the formation of indole 2 and by-
product 3.
phenyl and nitro groups (entries 5 and 11), led to the pathways of these transformation as shown in Fig. 1.
formation of the indole product in low yields whereas The conversion of intermediate 5 to indole 2a is thermody-
substrates containing electron-donating substituents in the namically more favorable (pathway a) than the conversion to
para-position (t-Bu, Br, and OCH3; entries 4, 8, and 17, compound 3a via the chlorine atom transfer (pathway b)
respectively) could provide the desired indole products in (Fig. 1). In addition, the activation energies of pathway
higher yields.
b is signicantly larger than pathway a (TS4–TS2 ¼ 6.2
The proposed mechanism for the formation of the indole kcal molꢁ1), which explains the exclusive formation of
2a and by-product 3a is shown in Scheme 1. Since Zr(IV) are indole 2a.
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the synthesis of indole derivatives which is applicable to a
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Acknowledgements
This research work was supported in part by grants from Center
of Excellence on Environmental Health and Toxicology, Science
& Technology Postgraduate Education and Research Develop-
ment Office (PERDO), Ministry of Education, and Chulabhorn
Research Institute.
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using the results from frequency calculations. Minima
showed positive frequencies while transitions states
showed a single negative frequency corresponding to the
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