Cascade Reaction for the Synthesis of Carbolines from O-Methylketoximes and Styrenes via Palladium-Catalyzed C–H Activation and Sequential Annulation

Article abstract of DOI:10.1002/ejoc.201901035

A novel cascade reaction has been described for the synthesis of Carbolines via palladium-catalyzed successive C–C/C–N formation from O-methylketoximes and styrenes. The oxime ether auxiliary not only serves as a traceless directing group, but is also partly transformed into the value-added pharmacophore in a two-step, one-pot fashion.

Full text of DOI:10.1002/ejoc.201901035

A Journal of
Accepted Article
Title: Cascade Reaction to Synthesis of Carbolines from O-
Methylketoximes and Styrenes via Palladium-Catalyzed C–H
bond Activation and Sequential Annulation
Authors: Xiao-Pan Fu, Shi-Biao Tang, Jin-Yue Yang, Li-Li Zhang,
Cheng-Cai Xia, and Ya-Fei Ji
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901035
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901035
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10.1002/ejoc.201901035
European Journal of Organic Chemistry
SHORT COMMUNICATION
Cascade Reaction to Synthesis of Carbolines from O-
Methylketoximes and Styrenes via Palladium-Catalyzed C–H bond
Activation and Sequential Annulation
Xiao-Pan Fu,+a Shi-Biao Tang,+a Jin-Yue Yang, a Li-Li Zhang,a Cheng-Cai Xia*b and Ya-Fei Ji*a
functionalization assisted by DG (directing groups) has become an
efficient method for C-C and C-X bond formation.5 Especially in
recent years, the ortho alkenylation directed by DG provides an
atom- and step-economic fashion in contrast to the traditional
transformations, such as Heck reaction.6 Significant progress with
the help of various DG such as pyridine,7 ester,8 amide,9 carboxyl
10and others11 has been accomplished.
Abstract: A novel cascade reaction has been described for synthesis of
Carbolines via palladium-catalyzed successive C–C/C–N formation
from O-methylketoximes and styrenes. The oxime ether auxiliary not
only serve as a traceless directing group, but also be partly transformed
into the value-added pharmacophore in a two-step, one-pot fashion.
Oxime ethers as heteroatom-containing directing group, have a
superior directing ability to assist the C–H bond
functionalization.12 The oxime ethers directed ortho C(sp2)–H
Introduction
Carbolines are important structural motifs in numerous natural
products and bioactive molecules.1 Carboline derivatives have a
wide range of applications not only in the pharmaceutical
chemistry,2,3a-e but also in the materials.3f,3g (Figure 1) Therefore,
many methods have been established for synthesis of carbolines
derivatives, including Graebe-Ullmann, Fischer indolization,
Bischler-Napieralski, and Pictet-Spengler reactions. However, the
reactions are required to assemble the carboline frameworks.4
Therefore, the development of simple and efficient method for
construction of the carbolines has attracted significant attention.
Over the past few decades, transition-metal-catalyzed C–H bond
functionalization such as acyloxylation,13h,13d arylation,13a,13c
13g
hydroxylation
arylation,13a,13c which generally go through a
Scheme 1. O-Methyloxime Directed Oxidative Heck Reaction
Figure 1. Some Bioactive Compounds Containing Carboline
Structures
five-membered endo-palladacycle intermediate.13 Apart from these
reactions, Ellman,13e Sun13f and Jeganmohan13i groups respectively
reported the ortho olefination assisted by oxime ethers via different
catalysts There are several reports for metal-catalyzed annulation
reactions starting from oxime ethers.14 (Scheme 1A). Despite
tremendous efforts have been made, these reports are limited in the
intermolecular alkenylation.14 Therefore, oxime ethers serve as a
traceless directing group, go through a tandem, 2-fold C-H bond
functionalization in a one pot fashion with sole catalyst would be
of great significance.
To continue our interest,14h we here report the palladium-catalyzed
the protected Indol-O-methyloxime-directed 2-fold C−H bond
functionalization with substituted styrenes, providing carbolines in
good yields (Scheme 1B). The newly dual functionalization
strategy can not only make the step concise and efficient but also
could be applied in the synthesis of key functional units.
a Dr. Xiao-Pan Fu, Shi-Biao Tang, Jin-Yue Yang, Li-Li Zhang, Prof. Ya-Fei Ji
Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of
Education; School of Pharmacy, East China University of Science & Technology,
130 Meilong Road, Shanghai 200237, P. R. China.
Email: jyf@ecust.edu.cn.
URL: http://pharmacy.ecust.edu.cn/2008/1203/c2779a22276/page.htm
b Assoc. Prof. Cheng-Cai Xia
Institute of Pharmacology, Pharmacy College, Shandong First Medical
University & Shandong Academy of Medical Sciences, Tai’an 271016, China.
Email: xiachc@163.com.
+ Xiao-Pan Fu and Shi-Biao Tang contributed equally as the first authors
†Electronic Supplementary Information (ESI) available: Detailed experimental
Results and Discussion
procedures and analytical data. CCDC 1916781 for 4b
. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/x0xx00000x
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10.1002/ejoc.201901035
European Journal of Organic Chemistry
SHORT COMMUNICATION
At the outset of the experiment, a variety of reaction conditions
were examined. we initially tested the model substrate O-
methyloxime ether 1a and 4-fluorostyrene 2a using the catalyst
Pd(OAc)2 (10 mol %), the oxidant AgTFA (1.5 equiv), the base
pyridine (20.0 equiv) in AcOH at 110 oC under air (Table1). To our
delight, the product 3a was observed in the yield of 19%. Inspired
by that result, different solvents were tested, the yield was
improved significantly in HFIP (entries 1-4). Next, oxidants were
screened, Ag3PO4 gave a better yield than other Ag salts including
AgOAc, Ag2CO3 and Ag2O (entries 5-8). When we tested the
catalysts, Pd(OAc)2 holding the best transformation other than Pd
salts (entries 9-12). Base can improve the reaction15a,15b and the
pyridine evidently facilitate the transformation (entries 13-19).
Different amount of the pyridine was examined (entry 20). When
Table 2. Substrate scope of Styrenes.a,b
o
o
increasing the temperature to 120 C or decreasing to 100 C, we
observed that the yields were slightly decreased.
a Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), Pd(OAc)2 (10
mol%), Ag3PO4 (1.5 equiv), Pyridine (20.0 equiv), HFIP (3.0 mL),
110 oC, 20 h. b Isolated yields of 3.
Table 1 Optimization of reaction conditions a,b
Having the optimized reaction conditions, we continued to explore
the scope of substrates in this reaction. First, a remarkably broad of
the styrenes with 1-(1-phenyl-1H-indol-3-yl) ethan-1-one O-methyl
oxime (1a) was achieved. As shown in Table 2. The styrenes with
electron-withdrawing groups, such as F (3a), Cl (3b), Br (3c), CF3
(3d) on the para-position of the phenyl ring, could afford the
corresponding alkenylation-cyclization products in good yields.
Notably, the DG was directly removed under basic conditions.
Moreover, the introduced DG can not only assist the C–H bond
functionalization but also be transformed into Carboline units. The
electron-donating groups (3e, 3f) gave the satisfactory yield. It is
Entry
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
Oxidant
AgTFA
AgTFA
AgTFA
AgTFA
Ag3PO4
AgOAc
Ag2CO3
Ag2O
Additive
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
NaOAc
CsOAc
Cu(OAc)2
Et3N
Yield b(%)
19c
24d
12e
1
2
Table 3. Substrate scope of various indoles.a,b
3
4
57f(67)g
5
79
6
67
7
54
8
37
9
Ag3PO4
Ag3PO4
Ag3PO4
73
10
11
12
13
14
15
16
17
18
19
70
Pd(PPh3)2Cl2
68
Pd(CH3CN)2Cl2 Ag3PO4
61
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
<10
<5
NR
43
DBU
68
DABCO
/
trace
<10
20
21
Pd(OAc)2
Pd(OAc)2
Ag3PO4
Ag3PO4
Pyridine
Pyridine
54h(66)i(70)j
77k (76) l
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (10
mol %), oxidant (1.5 equiv), additive (20.0 equiv), HFIP (3.0 mL),
o
b
c
d
110 C, 20 h. Isolated yield of 3a. AcOH (3.0 mL). DCE (3.0
e
f
g
h
mL). Dioxane (3.0 mL). HFIP (3.0 mL). TFE (3.0 mL).
a Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), Pd(OAc)2 (10
mol%), Ag3PO4 (1.5 equiv), Pyridine (20.0 equiv), HFIP (3.0 mL),
110 oC, 20 h. b Isolated yields of 4.
i
j
Pyridine (5.0 equiv). Pyridine (10.0 equiv). Pyridine (30.0
equiv). k 100 oC. l 120 oC.
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10.1002/ejoc.201901035
European Journal of Organic Chemistry
SHORT COMMUNICATION
worth mentioning that electron-withdrawing groups on the para-
position provide higher yield than those electron-donating groups.
The substitution at the meta-position were also isolated (3g-3i).
The ortho-substituted styrenes were also transformed into the
cyclization products in good yields (3j-3l). In addition, 1-
vinylnaphthalene and 2-vinylnaphthalene could be also delivered
the desired product (3n, 3o).
of gram scale was also examined (Scheme 3).
Based on documented reports,13f,14h,15 a plausible reaction pathway
through CMD (concerted metalation-deprotonation) pathway13f,14,16
or an agnostic intermediate14h,17 was proposed in Schemes 4.
Firstly, the substrate 1a coordinates with Pd(OAc)2 reversible to
form endo-cyclopalladated (II) intermediate A. The ligand of the
endo-cyclopalladated A interchanges with alkene to provide B,
which followed by 1,2-migratory insertion, β-hydride elimination
and reductive elimination to form the product D and liberation of
Pd (0) species. After the oxidative addition, the N-O bond was
cleaved and an alkenylpalladium species (II) was generated the key
intermediate E.14h,15a-e Then C−N bond formation/N−O bond
cleavage and β-hydride elimination provide the product.
Next, we explored the substrates scope in the alkenylation-
cyclization reaction. To our delight, a various of substituted
substrates proved to be compatible in the transformation, obtaining
the desired products in moderate to good yields (Table 3). The
substrates with electron-donating groups (4a, 4b) gave better yield
than electron-withdrawing groups (4c, 4d) on the para-position of
the phenyl. Gratifyingly, the meta-substituted substrates (4e, 4f, 4g)
are tolerated under the standard reaction conditions. As we all
know, the Br group could be transformed into different functional
groups via cross-coupling reaction. Benzyl (4h), multiply-
substituted (4i, 4j), naphthalene (4k) were well reacted with 2a,
affording the desired products in good yields. The alkyl-protected
indole derivatives offered the moderate yield (4l, 4m).
Respectively, the phenyl protected indole is crucial for the
transformation. Then, substituted on the indol afforded a good
yield in 83% (4n). 2-Acetyl-indole was also obtained the
corresponding product (4o). Unfortunately, removable protecting
group such as N-Boc (4p) and the unprotecting group N-H (4q)
were not suitable for reaction. In addition, 3-aldoximine (4r) was
unable to afford any desired product.
Scheme 4. Postulated reaction mechanism
Additionally, we carried out the intermolecular competition
experiments to probe the electronic effect of the alkenylation-
cyclization reaction (Scheme 2). Firstly, different substituted
styrenes 2a and 2e (1:1 equiv) with substrate 1a was performed in
110 oC for 20 h. We isolated the products 3a and 3e with the ratio
of 3.1/1.0, revealing that the electron-deficient styrene kinetically
favored. In contrast, competition experiment between
electronically biased para-substituted substrates 1b and 1c (1:1
equiv) reacted with styrene 2a, showing the electron-rich substrate
(4b) reacted preferentially. These observations have agreement
with the mode of electrophilic activation.9a Moreover, the reaction
Conclusions
In conclusion, we have developed a novel method for synthesis of
carbolines via palladium-catalyzed dual C–C/C–N formation and
annulation with styrenes. This protocol provides a simple, direct,
efficient method to construct diversified carbolines for the
screening of the potential natural products and medicines.
Scheme 2. Intermolecular Competition Experiments.
Acknowledgements
We gratefully thank the National Natural Science Foundation of China
(Project Nos. 21676088 and 21476074) for financial support.
Scheme 3. Gram scale reaction.
Keywords: carbolines • dual C–C/C–N formation • annulation •
styrenes • palladium-catalyzed
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
COMMUNICATION
Layout 2:
COMMUNICATION
Styrenation Annulation
Xiao-Pan Fu,+a Shi-Biao Tang,+a Jin-Yue
Yang, a Li-Li Zhang,a Cheng-Cai Xia*b
and Ya-Fei Ji*a
Page No. – Page No.
Text for Table of Contents: Cascade reaction has been described for synthesis of
Carbolines via palladium-catalyzed dual C–C/C–N formation and annulation with
styrenes.
Title
Cascade Reaction to Synthesis of
Carbolines from O-Methylketoximes
and Styrenes via Palladium-Catalyzed
C–H bond Activation and Sequential
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