Pd(II) supramolecular cage-catalyzed successive oxidative coupling: One-pot and regioselective synthesis of functionalized carbazoles from indoles

Article abstract of DOI:10.1016/j.catcom.2019.02.023

Carbazole is an important compound in pharmaceuticals and functional materials. A new Pd(II) supramolecular cage-catalyzed protocol for the synthesis of multifunctional carbazoles from indoles is described through regioselective successive oxidative Heck reactions. This new protocol is highly efficient, with a low Pd (2.4 mol%) catalyst loading and good compatibility for both N-H free and N-protected indole substrates. Moreover, it can be used to synthesize carbazoles with various functional groups by a one-pot two-step procedure. The excellent catalytic activity can be attributed to the distinct properties of the supramolecular cage structure in uniformly distributive and well-defined Pd(II) active centers on the cage surfaces.

Full text of DOI:10.1016/j.catcom.2019.02.023

Accepted Manuscript
Pd(II) supramolecular cage-catalyzed successive oxidative
coupling: One-pot and regioselective synthesis of functionalized
carbazoles from indoles
Xi-Ren Wu, He-Long Peng, Lian-Qiang Wei, Li-Ping Li, Su-Yang
Yao, Bao-Hui Ye
PII:
S1566-7367(19)30057-3
DOI:
Reference:
https://doi.org/10.1016/j.catcom.2019.02.023
CATCOM 5634
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Catalysis Communications
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Accepted date:
26 December 2018
21 February 2019
22 February 2019
Please cite this article as: X.-R. Wu, H.-L. Peng, L.-Q. Wei, et al., Pd(II) supramolecular
cage-catalyzed successive oxidative coupling: One-pot and regioselective synthesis of
functionalized carbazoles from indoles, Catalysis Communications, https://doi.org/
10.1016/j.catcom.2019.02.023
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ACCEPTED MANUSCRIPT
Pd(II) supramolecular cage-catalyzed successive oxidative coupling:
one-pot and regioselective synthesis of functionalized carbazoles
from indoles
Xi-Ren Wu,†,‡ He-Long Peng,† Lian-Qiang Wei,† Li-Ping Li,† Su-Yang Yao† and
Bao-Hui Ye*,†
†MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun
Yat-sen University, Guangzhou 510275, China.
‡School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China.
E-mail:cesybh@mail.sysu.edu.cn.
ABSTRACT: Carbazole is an important compound in pharmaceuticals and functional materials. A new Pd(II)
supramolecular cage-catalyzed protocol for the synthesis of multifunctional carbazoles from indoles is described
through regioselective successive oxidative Heck reactions. This new protocol is highly efficient, with a low Pd
(2.4 mol%) catalyst loading and good compatibility for both N-H free and N-protected indole substrates. Moreover,
it can be used to synthesize carbazoles with various functional groups by a one-pot two-step procedure. The excel-
lent catalytic activity can be attributed to the distinct properties of the supramolecular cage structure in uniformly
distributive and well-defined Pd(II) active centers on the cage surfaces.
Keywords: Carbazole, Indole, Oxidative Heck reaction, Pd(II) supramolecular cage, C-H functionalization.
1. Introduction
Carbazole is an important compound in many bioactive natural products, pharmaceuticals, and functional materials
[1,2]. Thus, various synthetic protocols have been developed to construct functionalized carbazoles during the past
several decades [3-6]. Among the protocols, cyclization strategies of direct coupling of indoles with alkene mole-
cules are a great attraction because the parent compound indole is readily available. Indeed, [2+4] annulation of
indole with di-alkene or [2+2’+2’’] annulation of indole with ketone and alkene to produce a carbazole scaffold
has been reported using Brønsted acid and/or transition-metal as a catalyst [7-13]. However, most of the alkene
substrates need to be prefunctionalized. Alternatively, the oxidative coupling of arenes with alkene, discovered by

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Fujiwara and Moritani [14-16], is an oxidative Heck reaction and has been developed for regioselective alkenyla-
tion on indole [17,18]. The successive alkenylation on indole was successfully performed to prepare carbazole
with diverse functionalized groups [19-22]. The advantages of this protocol are step and atom economy, and the
substrates are commercially available. However, the present approaches contain some limitations such as a high
Pd(II) catalyst loading (10-20 mol%) and occasional use of phosphorus ligands. In addition to that, the indole sub-
strate also has high limitations; hence, either N-protected indoles [19,20,22] or N-H free indoles can be used as a
substrate (see Scheme 1) [21]. Therefore, a new catalytic reaction with a substrate that has high catalytic efficiency
and excellent compatibility (both N-H free and N-protected indoles) and an environmentally friendly solvent is
highly desirable. Moreover, different reaction mechanisms were proposed for indole-to-carbazole conversion de-
pending on the substrates and catalysts. Reactions of N-protected indoles with alkenes or its synthetic equivalent to
produce 1,3-disubstituted carbazoles using Pd-Cu-Ag trimetallic [19] or Pd-Cu bimetallic [20] catalysts were re-
ported to occur through a Diels−Alder reaction of 3-alkenyated indoles with alkenes. In contrast, N-H free indoles
reacted with alkenes to produce 1,3-disubstituted carbazoles through the successive oxidative Heck reactions using
Pd-Cu as catalysts in the presence of the PPh3 ligand [21]. Unlike the aforementioned reports, Laha and Dayal
demonstrated the formation of 2,3-disubstituted carbazoles from N-protected indoles and alkenes through two
sequentially oxidative Heck reactions at the C-3 and C-2 positions of indole in the presence of the Pd-Ag-K2S2O8
catalyst, followed by thermally intramolecular electrocyclization [22].
Scheme 1. Synthesis of carbazole through oxidative coupling of indole and alkene.
To develop a highly efficient catalyst for the oxidative Heck reaction, we pay attention to Pd(II) supramolecular
cage, which not only arranges the catalytic center Pd(II) in an isolated single site by coordinating with organic
ligands with a well-defined structure but also maximally exposes the active Pd(II) ions to the substrates because of

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the discrete structure. Moreover, the heterometallic catalyst, which exerts a synergistic effect between Pd(II) and
other metal ions through the ligand, has been demonstrated to have much increased catalytic activity [23,24]. Fol-
lowing these strategies,
a Pd(II)-Al(III) supramolecular cage [Al2Pd3L6Cl6] (Pd-Al) (where HL is
1-(4-(1H-imidazol-1-yl)phenyl)butane-1,3-dione) was synthesized in our laboratory [25]. In each cage, three
-diketone groups with chelating nature from three HL ligands bind to a hard Al(III) ion, and each Pd(II) ion coor-
dinates with two N-donors of imidazolate from two L ligands and two labile chlorides in a trans fashion as a po-
tential catalytic center (see Fig S1 in the Supporting Information). It should be pointed out that the long and rigid
rod-like ligand ensures the supramolecular cage possesses large windows, in which substrates could freely pass
through and the catalytic centers are located in the appropriate sites separately. The introduction of chloride as a
labile ligand is beneficial for catalysis because it is easily displaced by substrates. Moreover, the strong N-donors
of imidazolate effectively prevent Pd(II) ion leaching out from the cage. In this contribution, we present our recent
results on the successive oxidative coupling of indoles with alkenes to produce functional carbazoles using the
supramolecular cage Pd-Al as a catalyst in PEG–DMSO solvent (see Scheme 1e). The catalytic experiments
showed that the supramolecular cage Pd-Al is an efficient catalyst for the successive oxidative Heck reactions of
indole-to-carbazole with a high regioselectivity and a low Pd(II) catalyst loading as well as excellent compatibility
in both N-protected and N-H free indoles.
2. Experimental
2.1 General data
1
All chemicals were commercially available and used as purchased unless otherwise noted. H and 13C NMR
spectra were recorded with a Bruker AV 400 spectrometer using the solvent as an internal standard. Powder X-ray
diffraction patterns were recorded on a D8 ADVANCE diffractometer with Cu-Kα radiation (λ = 1.5409 Å) at a
scanning rate of 4° min−1, with 2θ ranging from 5 to 35°. The catalyst Pd-Al was prepared according to our previ-
ously published procedure [25]. The phase purity of the as-synthesized samples was confirmed by PXRD, com-
paring the patterns with the one simulated from single crystal data (see Fig. S2). The as-synthesized Pd-Al sample
was activated by heating at 110 °C under vacuum for 6 h.
2.2 General procedure for indole-to-carbazole reaction.
A mixture of indole (0.5 mmol), Pd-Al catalyst (0.8 mol%), Cu(OAc)2 (1.0 mmol), acrylate (1.5 mmol), and
pivalic acid (PivOH, 0.25 mmol) in PEG-300/DMSO (5:1, 2 mL) was stirred at 120 ºC for 20 h. The reaction mix-
ture was allowed to cool to room temperature and diluted with ethyl acetate (10 mL). The resulting solution was
filtered. The filtrate was washed with saturated brine solution three times (3×10 mL). The organic layer was dried
over Na2SO4, and then, the solvent was removed under reduced pressure. The residue was purified by column
chromatography using ethyl acetate/hexane (1:15-1:5) as an eluent to obtain the corresponding product, which
1
was identified by H and 13C NMR analyses (see the Supporting Information).

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3. Results and discussion
To identify the optimal reaction conditions for indole-to-carbazole conversion, we began our study with N-H
free indole 1a and methyl acrylate 2a as model substrates to screen the reaction conditions in the presence of 1.0
mol% Pd-Al as a catalyst and 1.5 equiv of Cu(OAc)2 as an oxidant in DMF-DMSO (v/v, 5:1, 2 mL) solution at
100 °C. To our delight, the mono-oxidative Heck product 3aa and 1,3-disubstituted carbazole 4aa were obtained in
yields of 66% and 23%, respectively (see entry 1 in Table 1). By increasing the amount of the oxidant Cu(OAc)2 to
2.0 equiv, the yield of carbazole improved to 37%, indicating that increasing the amount of oxidant is beneficial
for the formation of carbazole. However, continued increase of Cu(OAc)2 to 2.5 equiv had no significant effect on
the yield of carbazole (see entry 3 in Table 1). Thus, we turned to screen other oxidants such as O2, MnO2, K2S2O8,
Ag2CO3, BQ, and TBHP (see entries 4-9 in Table). Only trace product was observed when O2 was used as an oxi-
dant. Oxidants such as MnO2, K2S2O8, Ag2CO3, BQ, and TBHP were barely successful in the observed reaction
conditions. Then, we investigated the effect of solvent and found that the yield of carbazole sharply decreased to
11%, but the mono-oxidative Heck product 3aa increased to 81% when dioxane (Diox) was used as a co-solvent
with DMSO (v/v, 5:1). It seemed that Diox solvent is favorable for the formation of the regioselective
mono-oxidative Heck product 3aa rather than the successive oxidative coupling product 4aa (see entries 10 and 11)
[17]. In contrast, a significant improvement in the yield of 4aa to 48% was observed when PEG-300/DMSO (v/v,
5:1) was used as a co-solvent (see entry 12 in Table 1). However, the yield was still moderate. Therefore, the ratio
of PEG-DMSO was varied to 3:1 and 9:1 under identical conditions. We found the best ratio of PEG-DMSO as a
co-solvent was 5:1 for the formation of product 4aa. To screen the optimal conditions, we focused on reaction
temperature because high temperature would be beneficial for the successive oxidative Heck reaction. Indeed, the
reaction yield of the product 4aa was improved to 71% when reaction temperature was increased to 120 °C (see
entry 15 in Table 1). Inspired by the discovery that acid was beneficial for the alkenylation of indole [17,22],
PivOH was added to the reaction mixture as an additive. Surprisingly, the yield of the product 4aa was improved
to 83% when 0.5 equiv PivOH was used as an additive at 120 °C. Extending the reaction time to 24 h or increasing
the amount of PivOH to 0.7equiv had no significant effect on the reaction. Finally, catalyst loading tests were
performed to determine the efficiency of the catalyst. No significant change in the yield of the product 4aa was
observed when catalyst Pd-Al loading was decreased from 1.0 mol% to 0.8mol% (see entry 19 in Table 1). How-
ever, the yield was sharply decreased to 56% when the amount of catalyst was lowered to 0.5 mol%. Additionally,
the control experiments showed that Pd(II) ion was indispensable for the formation of the product 4aa. When 3
mol% PdCl2 was employed as a catalyst, the yield of theproduct 4aa was obtained as 36% (see entry 21 in Table1).
On addition of the ligand HL to the above reaction solution, the yield slightly increased to 41% (see entry 22 in
Table 1). Therefore, the formation of heterometallic supramolecular cage Pd-Al, which can effectively prevent
Pd(II) ion agglomeration and maintain Pd(II) ion as an isolated active site, helps to improve the stability of Pd

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species and catalytic activity.
Table 1.
Optimalconditions of oxidative coupling reaction.a
Catalyst
(mol%)
Oxidant
(equiv)
Additive
(equiv)
Temp (ºC) Yield(%)b
Entry
Solvent
/time (h)
3a4a
1
2
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (1.0)
Pd-Al (0.8)
Pd-Al (0.5)
PdCl2 (3.0)
PdCl2 + HL
Cu(OAc)2(1.5)
Cu(OAc)2 (2)
Cu(OAc)2(2.5)
DMF-DMSO(5:1)
DMF-DMSO (5:1)
DMF-DMSO (5:1)
DMF-DMSO (5:1)
DMF-DMSO (5:1)
DMF-DMSO (5:1)
DMF-DMSO (5:1)
DMF-DMSO (5:1)
DMF-DMSO (5:1)
Diox-DMSO (5:1)
Diox-DMSO (5:1)
PEG-DMSO (5:1)
PEG-DMSO (9:1)
PEG-DMSO (3:1)
PEG-DMSO (5:1)
PEG-DMSO (5:1)
PEG-DMSO (5:1)
PEG-DMSO (5:1)
PEG-DMSO (5:1)
PEG-DMSO (5:1)
PEG-DMSO (5:1)
PEG-DMSO (5:1)
100/20
100/20
100/20
100/20
100/20
100/20
100/20
100/20
100/20
100/20
100/8
66
23
37
38
49
3
48
c
4
O2
trace
N.D.d
N.D.
N.D.
N.D.
N.D.
81
5
MnO2(1.5)
6
K2S2O8 (1.5)
Ag2CO3 (1.5)
BQ (1.5)
7
8
9
TBHP (1.5)
10
11e
12
13
14
15
16
17
18
19
20
21
22f
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
11
95 N.D.
100/20
100/20
100/20
120/20
120/20
120/24
120/20
120/20
120/20
120/20
120/20
35
23
33
16
10
10
10
11
28
35
30
48
37
46
71
83
83
82
82
56
36
41
PivOH (0.5)
PivOH (0.5)
PivOH (0.7)
PivOH (0.5)
PivOH (0.5)
PivOH (0.5)
PivOH (0.5)
aReaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), catalyst, and oxidant in 2 mL of solvent.

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bIsolated yield based on indole.
cO2 balloon.
dN.D. = not detected.
e2a is 0.55 mmol.
f PdCl2 (3.0 mol%) + HL(6.0 mol%).
With the optimal reaction conditions in hand, the universality of this protocol for indole-to-carbazole conver-
sion was explored under reaction conditions. First, ethyl acrylate (2b) and butyl acrylate (2c), respectively, were
used instead of 2a to react with indole 1a under the identical conditions. Surprisingly, the corresponding carbazole
products 4ab and 4ac were obtained in good yields of 80% and 79%, respectively, as shown in Table 2. This also
encouraged us to extend the reaction to other indoles with various functional groups. Indeed, when 5-OCH3 indole
(1b) was used to react with acrylates 2a, 2b, and 2c, the reaction proceeded favorably to produce the correspond-
ing products4ba, 4bb, and 4bc in good yields of 85%, 82%, and 80%, respectively. Next, 5-Br indole (1c) with an
electron-withdrawing group was used to react with acrylates 2a, 2b, and 2c to examine the reaction universality of
this protocol. Although the reaction was slightly sluggish, good yields of 72%, 68%, and 65% were also obtained
for the products 4ca, 4cb, and 4cc, respectively. Despite the aryl bromide group being sensitive to metal catalysis
reaction, it remains intact in the reaction and provides opportunities for further functionalization of carbazole.
When 5-NO2 indole (1d), a substrate with stronger electron-withdrawing group, was used as a substrate to react
with acrylates 2a, 2b, and 2c, moderate yields of 53%, 48%, and 46% was obtained for 4da, 4db, and 4dc, respec-
tively, indicating that the electron-withdrawing effect on the indole ring is unfavorable for the formation of carba-
zole. This was consistent with the finding in the previous report by Verma and co-worker [21]. Finally, the sub-
strate was expanded to N-protected indole, which was demonstrated to be inapplicable to the approach developed
by Verma because of the uniquely directing function of free N-H in indole for the successive oxidative Heck reac-
tions [21]. We were pleased to find that N-methyl indole (1e) reacted with acrylates 2a, 2b, and 2c smoothly to
produce the corresponding carbazoles 4ea, 4eb, and4ec in good yields of 71%, 69%, and 68%, respectively. Fur-
thermore, to examine the applicability of this protocol for N-protected indole substrates, N-propyl indole (1f) and
N-benzoyl indole (1g) were used to react with acrylates 2a, 2b, and 2c; the corresponding products 4fa, 4fb, 4fc,
4ga, 4gb, and 4gc were obtained in moderate yields of 44-57% (see Table 2), indicating that our in-
dole-to-carbazole protocol processes good compatibility in substrate, i.e., not only N-H free but also N-protected
indoles are appropriate as starting materials. This protocol is different from the previous protocols suitable either
for N-H free indole [21] or for N-protected indole substrates [19,20,22]. Moreover, indoles bearing various func-
tional groups including electron-neutral, electron-rich, and electron-deficient substituents are suitable as substrates
for the preparation of carbazoles in moderate to good yields under the optimal conditions.

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Table 2.
Substrate scopefor the synthesis of carbazoles.a,b
Then, this protocol was applied to regioselectively synthesize multifunctional carbazole with diverse groups
through a one-pot two-step procedure. Indeed, when 1a reacted with 1.1 equiv of styrene (2d) in the presence of
1.2 mol% catalyst Pd-Al at 120 °C for 4 h to produce 5-methoxy-3-styryl-1H-indole (3ad), 1.5 equiv of 2a was
added to the reaction to produce the corresponding methyl 3-phenyl-9H-carbazole-1-carboxylate (4ada) in yield of
42% for 16 h (see Table 3). When 1b, 1c, and 1d were used instead of 1a to react with 2d, and then 2a, the corre-
sponding products 4bda, 4cda, and 4dda were obtained in yields of 45%, 41%, and 36%, respectively. Moreover,
the N-CH3 indole (1e) was also used as a substrate to react with 2d, and then 2a; the yield of the asymmetric
product 4eda was given as 44%, indicating that the asymmetrically multifunctional carbazoles can be really pre-

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pared using two kinds of alkenes in the one-pot two-step strategy. It should be pointed out that the low yields may
be related to the low reaction activity of styrene.
Table3
One-pot two-step synthesis of asymmetriccarbazoles.a
Gram-scale reaction was also conducted to evaluate the practicability of the indole-to-carbazole reaction.
When N-H free indole 1a (1.17 g, 10.0 mmol) was used to react with ethyl acrylate 2b (3.19 mL, 30 mmol) under
the optimal conditions, 4ab (2.33g) was obtained with the yield of 75% (see equation 1). A similar case was ob-
served in N-protected indole 1e, obtaining 4eb (2.18 g) with a yield of 67% (see equation 2).
Three different reaction mechanisms have been reported for the synthesis of indole-to-carbazole depending on the
substrates and catalysts. Diels−Alder reaction and thermally intramolecular electrocyclization were proposed for
the reaction of N-protected indoles and alkenes [19,20,22], while the successive oxidative Heck reactions were
demonstrated for the reaction of N-H free indoles with alkenes [21]. To probe the reaction mechanism, control
experiments were performed (see equations 3 and 4). The mono-Heck reaction product 3-substituted indole 3ab,
regarded as an intermediate in the synthesis of carbazole, was isolated and used as the starting material to react
with methyl acrylate 2a and butyl acrylate 2c. Asymmetrically 1,3-disubstituted carbazoles 4aba and 4abc were
obtained in yields of 83% and 79%, respectively, under the optimal reaction conditions. In contrast, no carbazole

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product was observed under the similar conditions but in the absence of Pd-Al catalyst. These observations were
consistent with Verma’s observations [21] and clearly indicated that the formation of carbazole from indole was
through the successive oxidative Heck reactions rather than the Diels−Alder reaction. Similarly, when 3eb, a
mono-Heck reaction product of N-methyl-indole, was used instead of 3ab under identical conditions, the corre-
sponding products 5eba and 5ebc were produced in yields of 73% and 70%, respectively. This result was different
from the results obtained by Verma [21]. Moreover, no 2,3-disubstitued indole product was observed in our reac-
tion. Thus, thethermal intramolecular cyclization procedure would be ruled out [22].
Although the real mechanism remains unclear, a plausible mechanism of the reaction of indole with alkyene to
produce carbazole using Pd-Al cage as a catalyst is outlined in Scheme 2 on the basis of the control experiments
and relative literature [21,22]. First, the3-alkenyl indole 3 was obtained by theregioselective oxidative Heck reac-
tion by means of the insertion reaction of acrylate 2 into C-3 Pd(II) intermediate (I) to produce intermediate (II),
followed by β-hydrideelimination [26]. During this period, the reduced Pd(0) complex was oxidized by Cu(OAc)2
to regenerate Pd(II), which further catalyzed the next catalyticcycle. Similarly, the intermediate 5 was produced
by the second oxidative coupling reaction through theformation of palladium complex intermediates III and IV
[21, 27]. Finally, a fast intramolecular oxidative Heck reaction occurred through theformation of intermediates V
and VI, leading to the carbazole formation. It is worth mentioning that the distinct coordination in the supramolec-
ular cage structureof Pd-Al could prevent Pd(0) agglomeration and prolong the catalyst lifetime.
Scheme 2. Plausible mechanism of the indole-to-carbazole reaction
4. Conclusions

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In summary, we have developed a new protocol for the synthesis of functionalized carbazoles from indoles
through the regioselective successive oxidative Heck reaction using Al2Pd3 supramolecular cage as a catalyst. Un-
like the previous reports, the new protocol described herein is highly efficient with a low Pd(II) catalyst loading
and good compatibility for both N-H free and N-protected indole substrates. Moreover, an extension of this ap-
proach to the synthesis of multifunctional carbazoles in a one-pot two-step procedure warranted a broad applica-
tion. The excellent catalytic activity can be attributed to the distinct properties of the supramolecular cage structure
in uniformly distributive and well-defined Pd(II) active centers on the cage surfaces. This provides a complemen-
tary strategy for designing a new catalyst for specific organic reactions.
Acknowledgment
This work was supported by theNationalNatural Science Foundation of China (No. 21571195).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/xxx.
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ACCEPTED MANUSCRIPT
Graphical abstract

ACCEPTED MANUSCRIPT
Highlights:
 A low Pd(II) catalyst loading for indole-to-carbazole synthesis.
 Both free N-H and N-protected indoles as suitable substrates.
 An effective Pd(II) supramolecular cage catalyst for oxidative Heck reaction.
 One-pot strategy was successful in providing asymmetrically substituted car-
bazole.