Study on Palladium(II)-Catalyzed Mono-1-alkenylation of 9 H -Carbazoles

Article abstract of DOI:10.1055/a-1387-5435

A general and efficient method is reported for the direct mono-1-alkenylation of 9 H -carbazole molecules with divalent palladium as a catalyst and an N -(2-pyridyl)sulfanyl directing group. This method also provides an efficient synthetic route for the s

Full text of DOI:10.1055/a-1387-5435

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, 800–804
letter
800
en
D. Guo et al.
Letter
Synlett
Study on Palladium(II)-Catalyzed Mono-1-alkenylation of 9H-Car-
bazoles
Dongdong Guoa,b
Bin Lib
Wenmei Gaoa
Wuxia Zhanga
Yongqiang Wang*b
Jinzhong Zhao*a
Pd(OAc)2 (10 mol%)
TFA (2.0 equiv)
R2
R3
H
+
N
S
O
N
S
O
R2
R3
N
HFIP, O2 (1 atm)
60 °C, 14–16 h
R1
H
O
N
O
R1
R1 = H, Me, CO2Me
mono-1-alkenylated
10 examples
76–95%
R
R
2 = H, Ph
3 = EWG, Ph
a College of Arts and Sciences, Shanxi Agricultural University,
Taigu 030801, P. R. of China
zhaojz@sxau.edu.cn
b Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, P. R. of China
wangyq@nwu.edu.cn
Corresponding Authors
Received: 17.12.2020
(a) Known strategy: previous di-1-alkenylated
Accepted after revision: 09.02.2021
Published online: 09.02.2021
DOI: 10.1055/a-1387-5435; Art ID: st-2020-k0631-l
R2
R3
R3
R2
N
N
Abstract A general and efficient method is reported for the direct
mono-1-alkenylation of 9H-carbazole molecules with divalent palladium
as a catalyst and an N-(2-pyridyl)sulfanyl directing group. This method
also provides an efficient synthetic route for the synthesis of cross-di-
alkenylated carbazoles.
O
N
S
O
R1
R1
SO2Py
O
S
N
SO2Py =
O
(b) This work: mono-1-alkenylated
Key words alkenylation, palladium catalysis, C−H activation, carba-
zoles
N
R3
R2
N
O
N
S
O
SO2Py
R1
Carbazoles are an important group of nitrogen-contain-
ing heterocyclic compounds, as the carbazole ring is a
structural unit commonly found in many bioactive sub-
stances and pharmaceutical compounds.1,2 Carbazole deriv-
atives are also of great significance in materials science.3
The modification of carbazole rings has therefore long been
of great interest to organic chemists.4,5 Although template-
assisted methodologies have been widely employed for C–H
bond olefinations,6 further development is required for C–H
functionalization of carbazoles compared with that of other
heterocyclic compounds.7–9 Recently, some highly monose-
lective C–H functionalizations of carbazoles have been re-
ported.10 Carretero and co-workers proposed a Pd-cata-
lyzed alkenylation of carbazoles directed by an N-(2-pyr-
idyl)sulfonyl group, from which dialkenylated carbazoles
were the main products (Scheme 1a).11 The Song group re-
ported a Ru-catalyzed mono-1-alkenylation of carbazoles
directed by an N-dimethylcarbamoyl group.10f However,
there are few reports on metal-catalyzed monoalkenyla-
tions of carbazoles with high selectivity. We are pleased to
report that such a reaction (Scheme 1b) was achieved by
the method described below.
Scheme 1 Alkenylation of carbazoles with various alkenes
Initially, palladium(II) acetate [Pd(OAc)2] was selected as
the catalyst with trifluoroacetic acid (TFA) as an additive.
This combination was chosen on the basis that TFA inter-
acts with Pd(OAc)2 to produce a more active [Pd(II)O2CCF3]+
species that then forms a -carbazole–Pd complex. Com-
pared with [Pd(II)OAc]+, the complex has a higher activity
in electrophilic substitution of C–H bonds,12–14 which fur-
ther facilitates the reaction.
Because of the potential directing effect at the C-1 site
exerted by the carbazole N-protecting group, we first
screened various protecting groups for the reaction be-
tween carbazoles 1 and methyl acrylate (2a) at 60 °C (Table
1). The catalyst for the reaction was 10 mol% Pd(OAc)2 and
the additive was two equivalents of TFA. The reaction was
carried out in DCE with dioxygen (1 atm) as the oxidant.
With tosyl or acetate as the N-protecting group, only a trace
of the corresponding product 3 was obtained (<10%) (Table
1, entry 1). However, with a (2-pyridyl)sulfonyl15,16 as the
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 800–804
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

801
D. Guo et al.
Letter
Synlett
N-protecting group, the yield of the monoalkenylated prod-
uct 3 significantly increased to 76% (entry 2). We then in-
vestigated the effect of the catalyst and found that the reac-
tion did not proceed in the absence of a palladium catalyst
(entry 3), whereas both Pd(OAc)2 and Pd(TFA)2 were effec-
tive catalysts, giving similar yields (entry 2). However, be-
cause of its lower cost, Pd(OAc)2 was chosen as the catalyst
for subsequent reactions. By thorough solvent screening for
the reaction (entries 4 and 5), 1,1,1,3,3,3-hexafluoroisopro-
panol (HFIP) emerged as the optimal solvent, showing
promising results in terms of a high yield and a superior
mono- to disubstitution ratio. The use of three or four
equivalents of 2a under otherwise identical conditions gave
similar results to that obtained with two equivalents of 2a
(entry 5). Subsequently, the doses of TFA and Pd(OAc)2 were
tested. With two equivalents of TFA as the additive,
Pd(OAc)2 gave almost identical results to Pd(TFA)2 (entry 6),
but a smaller amount of TFA resulted in an incomplete reac-
tion (entry 7). In addition, when the dose of Pd(OAc)2 was
reduced to 5%, the conversion rate was significantly reduced
(entry 8). We also tried other potential directing groups,
such as 2-pyridyl (Py)10a–d and 2-pyrimidinyl (Pym),10e but
only a trace of product was obtained (entry 9). Pleasingly,
when we used an N-dimethylcarbamoyl (Dmc) group as the
directing group under the standard reaction conditions, the
monoalkenylation product 3 was isolated 62% yield (entry 10).
Having determined the optimal reaction conditions, we
tested various alkenes to examine the tolerance of the
method to various substituent groups. First, the effects of
electronic and structural variations in the alkene were in-
vestigated (Scheme 2). The reaction was found to tolerate a
range of alkenes. Monosubstituted alkenes, including both
electrophilic alkenes and more challenging nonactivated
styrene derivatives, reacted successfully with 1, producing
the corresponding C1-alkenylated products 3a–j in high
yields of 76–95%. Interestingly, the reactions of monosub-
stituted alkenes gave monoalkenylated products 3a–d con-
taining E-double bonds in yields of 91–95%. The molecular
structure of 3b was confirmed by X-ray crystallography
(see Supporting Information).17 Promisingly, 1,2-disubsti-
tuted alkenes successfully coupled to the carbazole at the
C(1) site to give the corresponding double-bond isomeriza-
tion products 3e–g in high yields.18 In addition, a 1,1-disub-
stituted alkene (1,1-diphenylethylene) also gave the corre-
sponding alkenylated carbazole 3h in 82% yield.
Application of this protocol was also successfully ex-
tended to the corresponding 3,6-di-tert-butyl-9H-carba-
zole, providing the desired products 3i in 76% yield. In addi-
tion, 9-(dimethylcarbamoyl)-9H-carbazole10f afforded the
corresponding mono-o-olefination product 3j in 62% yield.
Table 1 Optimization of Reaction Conditionsa
O
OMe
2a
+
catalyst (10 mol%)
N
N
N
O
2 (1 atm)
PG
PG
PG
MeO2C
CO2Me
TFA, solvent
MeO2C
1
3
3'
Entry
Catalyst
PG
Solvent
Mono/di
Yieldb (%) of 3
1
2
Pd(OAc)2
Pd(OAc)2
–
Ts or Ac
2-SO2Py
2-SO2Py
2-SO2Py
2-SO2Py
2-SO2Py
2-SO2Py
2-SO2Py
Py or Pym
Dmc
DCE
–
trace
76
c
DCE
<1:20
–
3
DCE
–
4
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
solventd
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
<1:20
>10:1
>10:1
>10:1
>10:1
–
<10
95
5e
6
96
7f
8g
9
65
55
trace
62
10
>10:1
a Reaction conditions: 1 (1.0 mmol), 2a (2.0 mmol), catalyst, O2 (1 atm), TFA (2.0 mmol), solvent (10 mL), 60 °C, 16 h.
b Isolated yield after purification by flash column chromatography.
c With Pd(TFA)2 as the catalyst, the result was almost identical.
d Solvent: toluene, AcOH, 1,4-dioxane, DMSO, MeOH, MeCN, THF, DMA, i-PrOH, t-BuOH, F3CCH2OH, or MeNO2.
e With three or four equivalents of 2a, the results were almost identical.
f TFA (1.0 mmol).
g 5 mol% Pd(OAc)2.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 800–804

802
D. Guo et al.
Letter
Synlett
Pd(OAc)2 (10 mol%)
TFA (2.0 equiv)
R2
R1
R2
R3
N
+
N
N
S
R3
N
zinc powder
HFIP, O2 (1 atm)
60 °C, 14–16 h
SO2Py
O
O
N
R1
H
SO2Py
MeO2C
MeO2C
aq NH4Cl/THF (1:1), rt
4a
1a
3a–j
3a
Scheme 4 Deprotection of the N-(2-pyridyl)sulfonyl group
N
N
CH
SO2Py
SO2Py
MeO2C
EtO2C
>99% H
3a, 95%
3b, 91%
X-ray
N
MeO2C
H/D
MeO2C
SO2Py
N
N
CO2Me
N
dimethyl maleate
Pd(OAc)2 (10 mol%)
TFA (2.0 equiv)
SO2Py
SO2Py
EtO
SO2Py
3e, 23% yield
P
CO2Me
Me2N
O
O
EtO
+
HFIP, O2 (1 atm)
D2O (5.0 equiv)
60 °C, 6 h
3c, 93%
N
3d, 94%
3e, 89%
from dimethyl maleate
>99% H
SO2Py
1a
N
N
D/H
H/D
N
N
SO2Py
SO2Py
MeO2C
SO2Py
SO2Py
Me
CO2Me
MeO2C
1a, 68% recovery
3f, 84%
3g, 87%
3h, 82%
Scheme 5 H/D exchange experiment
from dimethyl fumarate
from methyl (E)-crotonate
t-Bu
t-Bu
N
The N-(2-pyridyl)sulfonyl protecting/directing group of
product 3a was easily removed by treatment with zinc
powder in 1:1 THF–aq NH4Cl at room temperature, without
affecting the stereochemistry of the alkene (Scheme 4).
When the reaction of nondeuterated 1a with dimethyl
maleate was carried out under the standard conditions in
the presence of D2O (5.0 equiv) for six hours, product 3e
was isolated in 23% yield together with 68% of the recovered
N
Me
O
N
CO2Me
SO2Py
Me
CO2Me
3i, 76%
(E)-3j, 62%
Scheme 2 Mono-C(1)-alkenylation of carbazoles with various alkenes
Encouraged by the successful mono-1-olefination of
carbazoles, we investigated the synthesis of cross-dialke-
nylated carbazoles (Scheme 3), Under the optimized reac-
tion conditions, the mono-C(1)-alkenylated carbazoles 3a–
c reacted with a second alkene to produce cross-di-o-alke-
nylated carbazoles 3k–m in high yields.
1
starting material 1a (Scheme 5). H NMR analysis revealed
the presence of traces of -incorporation of deuterium in
compounds 1a and 3e, suggesting that the C–H activation
process is irreversible.19
A plausible reaction mechanism is shown in Scheme 6.
Treatment of Pd(OAc)2 with TFA produces a more active
Pd(O2CCF3)+ complex,20–22 and palladium attacks the sub-
strate to form the seven-membered palladium-containing
intermediate I.23–27 Subsequently, coordination of the
alkene to form intermediate II and insertion into its C=C
bond result in the formation of palladium(II) complex III.
Elimination of the -hydrogen atom gives the alkenylated
carbazole product 3 with release of zero-valent palladium,
which is reoxidized to Pd(O2CCF3)+ by O2 in the presence of
TFA to complete the catalytic cycle.28,29
Pd(OAc)2 (10 mol%)
R5
K2S2O8 (2.0 equiv)
R4
R2
R3
+
R2
R3
N
N
R5
R6
R6
DCE (2 mL)
90 °C, 24–26 h
SO2Py
R1
SO2Py
R1
R4
0.4mmol
0.2 mmol
N
N
CO2Me
SO2Py
MeO2C
SO2Py
EtO2C
MeO2C
NMe2
O
3k, 92%
3l, 88%
from dimethyl maleate
In conclusion, a simple and efficient palladium(II)-cata-
lyzed N-(2-pyridyl)sulfonyl group-directed approach for
mono-1-olefination of carbazoles has been developed.30
The directing group introduced into the reaction system is
easily removed after completion of the reaction. This ap-
proach has prospects for widespread application in the
fields of synthetic and medical chemistry. Further studies
N
CO2Me
SO2Py
MeO2C
O
NMe2
3m, 91%
from dimethyl maleate
Scheme 3 Synthesis of cross-dialkenylated carbazole derivatives
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 800–804

803
D. Guo et al.
Letter
Synlett
References and Notes
Pd(OAc)2
TFA
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N
F3CCO2PdII
SO2Py
III
I
R
N
O
O
F3CCO2
PdII
N
S
R
2
R
II
Scheme 6 Plausible mechanism for the transformation
on the detailed mechanism and extensions to similar reac-
tions of other organic molecules are in progress.
Conflict of Interest
The authors declare no conflict of interest.
Funding Information
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (NSFC-31800678), the Science and Technol-
ogy Research Project in Shanxi Province (Nos. 201801D221062), the
Shanxi Excellent Doctor Grant Award (No. SXYBKY201737, SXYB-
KY201706), the Science and Technology Innovation Project of Shanxi
Agricultural University (No. 2017YJ38, 2017YJ41, ZDPY201606, ZD-
PY201708, ZDPY201803), Shanxi Science and Technology Research
Project (201703d, 221008-4), and Science and Technology Innovation
Project of Shanxi (2019L0374).
N
ati
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na
l
N
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ura
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dati
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S
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C-3
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1)
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We also thank Dr. Leo Holroyd of the Liwen Bianji, Edanz Group China
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1387-5435.
S
u
p
p
orti
n
gI
n
f
orm
a
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S
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p
p
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Primary Data
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record/4633398 and can be cited using the following DOI:
10.5281/zenodo.4633398.
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Primary
D
ataPri
m
ary
D
a
t
a
1
0
.5
2
8
1
/
z
e
n
o
d
o
.
4
6
3
3
3
9
8
.
2
0
2
1-02-0
9
Z
a
h
l
e
n
1
C
he
m
i
str
y
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 800–804

804
D. Guo et al.
Letter
Synlett
(15) Fabry, D. C.; Ronge, M. A.; Zoller, J.; Rueping, M. Angew. Chem.
Int. Ed. 2015, 54, 2801.
(d, J = 7.8 Hz, 1 H), 7.43–7.37 (m, 2 H), 7.32–7.27 (m, 2 H), 6.46
(d, J = 15.8 Hz, 1 H), 3.83 (s, 3 H). 13C NMR (100 MHz, CDCl3):  =
167.5, 154.5, 149.8, 144.0, 140.6, 139.3, 137.6, 130.1, 127.4,
126.0, 125.4, 125.2, 122.8, 121.1, 119.8, 118.5, 117.1, 51.7.
HRMS (ESI): m/z [M + Na]+ calcd for C21H16N2NaO4S: 415.0723;
found: 415.0721.
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data for compound 3b. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/structures.
Unsymmetrical Dialkenylated Carbazoles 3k–m; General
Procedure
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Chem. Asian J. 2017, 12, 130.
A sealed tube was charged with the appropriate monoalke-
nylated carbazole 3 (0.2 mmol), Pd(OAc)2 (5.0 mg, 10 mol%), and
K2S2O8 (108.0 mg, 0.4 mmol). DCE (2 mL) and the appropriate
alkene (0.4 mmol) were added, and the mixture was heated to
90 °C for 24–26 h until the reaction was complete (TLC). The
mixture was allowed to cool to r.t., diluted with EtOAc (50 mL),
and washed with H2O (3 × 5 mL). The combined organic phase
was dried (Na2SO4) and concentrated under reduced pressure
and purified by flash chromatography.
Methyl (2E)-3-[8-[(1E)-3-(Dimethylamino)-3-oxoprop-1-en-
1-yl]-9-(pyridin-2-ylsulfonyl)-9H-carbazol-1-yl]acrylate (3k)
Purified by flash column chromatography [silica gel, PE–EtOAc
(3:1)] as an oil; yield: 44.9 mg (92%). IR (KBr): 3394, 3189, 2921,
2850, 1708, 1646, 1465, 1419, 1371, 1263, 1168, 1110, 869,
794, 727, 642, 572 cm–1. 1H NMR (400 MHz, CDCl3):  = 8.51 (d,
J = 16.0 Hz, 1 H), 8.22–8.19 (m, 2 H), 7.66–7.62 (m, 2 H), 7.60–
7.49 (m, 3 H), 7.38–7.30 (m, 3 H), 7.25–7.22 (m, 1 H), 7.05 (d, J =
15.6 Hz, 1 H), 6.54 (d, J = 16.0 Hz, 1 H), 3.88 (s, 3 H), 3.27 (s, 3 H),
3.11 (s, 3 H).
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13C NMR (100 MHz, CDCl3):  = 167.3, 152.6, 149.1, 141.9, 141.4,
138.8, 137.0, 132.0, 131.7, 129.3, 127.9, 127.1, 126.8, 126.5,
125.9, 123.3, 121.0, 120.2, 118.8, 118.1, 51.9, 37.8, 35.9. HRMS
(ESI): m/z [M + Na]+ calcd for C26H23N3NaO5S: 512.1251; found:
512.1252.
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(30) 1-Alkenyl-9H-carbazoles 3a–j; General Procedure
A sealed tube containing 9-(2-pyridylsulfonyl)-9H-carbazole
(1a; 0.2 mmol) and Pd(OAc)2 (5.0 mg, 10 mol%) was evacuated
and filled with O2 gas by using an O2-containing balloon. HFIP (2
mL), the appropriate alkene (0.4 mmol), and TFA (0.4 mmol)
were sequentially added from a syringe under O2, and the
mixture was heated at 60 °C for 14–16 h until the reaction was
complete (TLC). The mixture was then allowed to cool to r.t.,
concentrated under reduced pressure, diluted with EtOAc (30
mL), and washed with sat. aq NaHCO3 (3 × 2 mL). The combined
organic phase was (Na2SO4) and concentrated under reduced
pressure, and the residue was purified by flash chromatography.
Methyl (2E)-3-(9H-carbazol-1-yl)acrylate (4a); Typical Proce-
dure
A suspension of 3a (39 mg, 0.1 mmol) and nonactivated Zn
powder (325 mg, 5 mmol) in 1:1 THF–sat. aq NH4Cl (4 mL) was
stirred at 30 ℃ until the starting material was consumed (TLC).
The mixture was then filtered through a pad of Celite to remove
the Zn powder, and the filtrate was extracted with EtOAc (15
mL). The extracts were washed with sat. aq NH4Cl and brine,
and the combined organic phase was dried (Na2SO4) and con-
centrated. The residue was purified by flash chromatography
[silica gel, PE–EtOAc (4:1)] to give a light-yellow solid; yield:
24.1 mg (95%); mp 98–99 °C.
IR (KBr): 3355, 2123, 1707, 1325, 1173, 1028, 754, 602 cm–1. 1H
NMR (400 MHz, DMSO):  = 11.84 (s, 1 H), 8.31 (d, J = 16.0 Hz, 1
H), 8.20 (d, J = 7.6 Hz, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 7.85 (d, J =
7.5 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 7.51–7.40 (m, 1 H), 7.19–
7.21 (m, 1 H), 6.82 (d, J = 16.0 Hz, 1 H), 3.79 (s, 3 H). 13C NMR
(100 MHz, DMSO):  = 167.5, 140.8, 140.6, 139.0, 126.6, 124.8,
124.3, 123.2, 122.6, 120.8, 119.7, 119.4, 117.7, 111.8, 51.9.
HRMS (ESI): m/z [M + Na]+ calcd for C16H13NNaO2: 274.0838;
found: 274.0834.
Methyl
(2E)-3-[9-(Pyridin-2-ylsulfonyl)-9H-carbazol-1-
yl]acrylate (3a)
Purified by flash column chromatography [silica gel, PE–EtOAc
(3:1)] as a white solid; yield: 37.0 mg (95%); mp 171–172 °C. IR
(KBr): 3027, 2951, 1702, 1578, 1429, 1406, 1359, 1272, 1182,
1116, 1031, 956, 860, 752, 663, 586 cm–1 1H NMR (400 MHz,
.
CDCl3):  = 8.37 (d, J = 15.8 Hz, 1 H), 8.31 (d, J = 4.0 Hz, 1 H), 8.22
(d, J = 8.3 Hz, 1 H), 7.83–7.78 (m, 2 H), 7.74–7.70 (m, 2 H), 7.64
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 800–804