Cascade Access to Carboline Carboxylates from Indolyl Ketoximes and Acrylates via Palladium-Catalyzed C-H Bond Alkenylation/Annulation

Article abstract of DOI:10.1055/s-0040-1707192

An efficient palladium-catalyzed C-H bond alkenylation/annulation strategy to access carboline carboxylates from indolyl ketoximes and acrylates through C-C/C-N bond formation is reported. Indolyl ketoximes not only direct ortho -olefination with acrylate

Full text of DOI:10.1055/s-0040-1707192

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©
Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
letter
A
en
Synlett
X.-P. Fu et al.
Letter
Cascade Access to Carboline Carboxylates from Indolyl Ketoximes
and Acrylates via Palladium-Catalyzed C–H Bond Alkenylation/
Annulation
Xiao-Pan Fua
Lu Chena
Gao-Rong Wua
Hong-Wei Liua
N
N
O
Pd(TFA)2 (10 mol%)
COOR
R2
H
Ag2O (2.0 equiv)
R2
+
COOR
N
R1
N-Ac-Val-OH (1.0 equiv)
N
R1
AcOH–DCE (1:3; 3.0 mL), 90 °C
Cheng-Cai Xia*b
Ya-Fei Ji*a
3
7 examples, up to 75% yield
first reported cyclization of traceless directing group with simple acrylates
mild conditions and good functional group tolerance
a direct and efficient method for carboline carboxylate synthesis
a
Engineering Research Centre of Pharmaceutical Process
Chemistry, Ministry of Education; School of Pharmacy, East
China University of Science and Technology, 130 Meilong
Road, Shanghai 200237, P. R. of China
jyf@ecust.edu.cn
Pharmacy College, Shandong First Medical University and
b
Shandong Academy of Medical Sciences, 619 Changcheng
Road, Taian 271016, P. R. of China
xiachc@163.com
Received: 13.05.2020
Accepted after revision: 11.06.2020
Published online: 15.07.2020
In recent years, directing-group-assisted C–H bond
functionalization with transition-metal catalysts has
emerged as a powerful tool for generating C–C and C–X
bonds with high site selectivity in atom- and step-econom-
DOI: 10.1055/s-0040-1707192; Art ID: st-2020-u0286-l
Abstract An efficient palladium-catalyzed C–H bond alkenylation/an-
nulation strategy to access carboline carboxylates from indolyl ketoxim-
es and acrylates through C–C/C–N bond formation is reported. Indolyl
ketoximes not only direct ortho-olefination with acrylates, but also un-
dergo an intramolecular N–O bond cleavage/traceless annulation to
construct carboline carboxylates straightforwardly in this concise meth-
od.
4
ic modes. In particular, a variety of directing groups such
5
6
7
8
9
as ester, amide, carboxy, pyridyl, and others have been
successfully applied to ortho-olefination. In addition, the
groups of Sanford,1
0a,b,d
Che,
10c
Yu,
10e
and Shi have de-
10f
scribed oxime ethers that have excellent directing abilities
to assist in C–H functionalizations. Given the remarkable
2
properties of oxime ethers in the ortho-C(sp )–H alkenyla-
Key words carboline carboxylates, alkenylation, annulation, indolyl
ketoximes, C–H activation, palladium catalysis
tions reported by Ellman,1 Sun, and Jeganmohan and
their respective co-workers, an ingenious strategy has been
developed involving the design of oxime ethers to act as
traceless directing groups in building blocks for fused het-
erocycles.12
1a
11b
11c
Carboline carboxylates are outstanding structural mo-
tifs in a variety of natural products, pharmaceuticals, and
drug-like scaffolds (Figure 1). Over the past decades, classi-
cal methods have been reported for the syntheses of these
type of compounds, including the Pictet–Spengler reaction
and the Bischler–Napieralski reaction.2 However, these
transformations usually require high temperatures or an
excess of oxidants. Therefore, the search for efficient and
environmentally friendly methods for synthesizing carbo-
line carboxylates has attracted much attention.
1
In 2019, we reported a benzothienyl methyloxime-di-
rected tandem approach to benzothienopyridines from
substituted styrenes through Pd catalysis.1 Later, a similar
cascade formation of C–C and C–N bonds was reported for
substituted carbolines (Scheme 1A).1 However, these
methods were limited in that only intermolecular alkenyla-
tion products were isolated when acrylates were used.
Here, we reported a cascade access to carboline carboxyl-
ates from indolyl ketoximes and acrylates, in which acry-
lates were successfully employed as the coupling partners
to implement C–H bond olefination and annulation
(Scheme 1B).
3a
3b
3
HO
OH
O
N
O
N
O
OH
OH
O
O
O
N
H
N
Initially, the O-methyl oxime 1a and methyl acrylate
(2a) were chosen as starting materials for the reaction (Ta-
ble 1). To our delight, 31% of the alkenylation/cyclization
product 3a was obtained by using a Pd salt as the catalyst, a
N
Me
H
NH
N
H
O
O
HO
N
Mescengricin
Flazin HO
Hyrtiocarboline
Figure 1 Some bioactive carbolines containing a carboxy group
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
X.-P. Fu et al.
Letter
A) Previous work:13a,b
tected and N-Boc-protected O-methyl oxime indoles, but no
products were obtained under the standard conditions (3D
and 3E). When a 2-acetylindole O-methyl oxime and a ben-
zothieno O-methyl oxime reacted with methyl acrylate, ex-
cellent yields of the corresponding intermolecular alkenyla-
tion products 3F′ and 3G′ were obtained instead of the cy-
cloaddition product 3F and 3G. It is possible that the Pd(0)
species cannot insert into the oxime ether due to oxidative
addition failure, which keeps the reaction in the intermo-
lecular alkenylation stage.1
(
Ar
N
N
OMe
Pd catalyst
Pd catalyst
Ar
X
X
X = S, O
X = S, O
N
N
OMe
Ar
R
R
Ar
N
N
R1
R1
(
B) This work:
3a
N
N
OMe
COOR
R2
H
Pd catalyst
R2
COOR
Table 1 Optimization of the Reaction Conditionsa
N
R1
N
R1
N
Scheme 1 Pd-catalyzed annulations of ketoximes with alkenes
N
OMe
COOCH3
[Pd], oxidant, additive
H
+
COOCH3
N
solvent, 90 °C, 24 h
N
Ph 1a
2a
3a
Ph
Ag salt as the oxidant, an amino acid as the additive, and
DCE as the solvent at 90 °C (Table 1, entry 1). Other solvents
b
Entry
Catalyst
Oxidant
Additive
Yield
(%)
[
1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), 1,4-dioxane, and
AcOH] all gave unsatisfactory results (entries 2–4). When
:3 AcOH–DCE was used as the solvent, a satisfactory yield
1c
2d
3e
4f
5
Pd(OAc)
Pd(OAc)
Pd(OAc)
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgOAc
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
N-Ac-Val-OH
–
31
NR
NR
30
2
2
2
1
was obtained (entry 5). AcOH not only causes C–H bond
cleavage, but also plays an important role in the formation
of the C–N bond, which is necessary for this annula-
Pd(OAc)2
g
h
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
47 (41 , 21 )
13a,14
tion.
6
49
37
57
32
NR
39
54
57
When other oxidants were tested, Ag O showed the best
2
7
Ag
Ag
Ag
2
2
3
CO
3
activity, giving the product 3a in 57% yield (Table 1, entries
6
amined, Pd(TFA) was found to give the highest yield (en-
tries 10–14). Further optimization was carried out to in-
crease the yield of the product (entry 14). Amino acids have
been reported to promote C–H activation, and, as expect-
ed, N-Ac-Val-OH showed a better reactivity than other ad-
ditives (entries 15–20). The effect of an N atmosphere was
also examined (entry 21).
With the optimized conditions in hand, we examined
the scope of various substituents on the reactants oximes 1
(
3
3
line derivatives in moderate yields, generally accompanied
by byproducts from intermolecular alkenylation. Notably,
the N-(1-naphthyl) substrate also afforded the desired
product 3l in a good yield. It is worth mentioning that an N-
ethyl-protected indolyl O-methyloxime also reacted well to
deliver the cyclization product 3m in 51% yield. Additional-
ly, N-benzyl-protected substrates also underwent the reac-
tion to provide the corresponding products 3n–x. N-Benzyl
substituents carrying a variety of functional groups (OMe,
8
O
–9). When the performance of various catalysts was ex-
9
Pd(TFA)
[Cp*RhCl2]2
PdCl
Pd(PPh
Pd(MeCN)
Pd(TFA)
2
PO
4
2
10
2
Ag O
11
12
13
14
2
Ag
Ag
Ag
2
2
2
O
O
O
13a
3
)
2
Cl
2
2
Cl
2
2
i
j
2
Ag
2
O
O
O
O
O
O
O
63 (54, 60 )
trace
15
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
2
Ag
Ag
Ag
Ag
Ag
Ag
2
16
17
18
19
20
2
2
2
2
2
2
N-Ac-Gly
42
Scheme 2). A variety of electron-donating groups (3b, 3c,
g, and 3h) or electron-withdrawing groups (3d, 3e, 3f, and
i–k) were all transformed into the corresponding carbo-
2
2
2
2
glycine
trace
py
<10
Cu(OAc)
PivOH
2
48
37
46k
21
Pd(TFA)2
Ag O
2
N-Ac-Val-OH
a
Reaction conditions: 1a (0.3 mmol), 2a (1.5 mmol), catalyst (10 mol %),o
oxidant (2.0 equiv), additive (1.0 equiv), 1:3 AcOH–DCE (1:3, 3.0 mL), 90 C,
2
4 h.
b
Isolated yield of 3a; NR = no reaction.
c
d
e
f
In DCE.
In HFIP.
In 1,4-dioxane.
In AcOH.
In 1:1 AcOH–DCE.
In 1:3 AcOH–DCE.
At 100 °C.
At 110 °C.
Under N .
2
g
h
i
Me, i-Pr, F, Cl, Br, and CF ) were all well tolerated, as was an
3
N-(2-naphthylmethyl) group (3y). However, with F, Cl, and
Br substituents on the benzene ring of the indole, no reac-
tion occurred (3z and 3A–C). We also tested the N-unpro-
j
k
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
Synlett
X.-P. Fu et al.
Letter
N
N
Pd(TFA)2 (10 mol%)
Ag2O (2.0 equiv)
OMe
COOCH3
R2
H
R2
COOCH3
+
N
R1
N-Ac-Val-OH (1.0 equiv)
N
R1
2a
AcOH–DCE (1:3; 3.0 mL), 90 °C
1
3a–E
N
N
N
COOCH3
COOCH3
COOCH3
R1 = OMe, 3b, 46%
R1 = Me, 3c, 51%
R1 = F, 3d, 62%
R1 = OMe, 3g, 56%
N
N
N
R1 = Me, 3h, 50%
R1 = F,3i, 64%
1
R1
R1 = Cl, 3j, 58%
R1 = Br, 3k, 53%
3a, 63%
R
R
= Cl, 3e, 57%
= Br, 3f, 47%
1
R1
N
N
N
COOCH3
COOCH3
COOCH3
N
N
N
R1
F
X-ray structure of 3i
CCDC 1974231
R1 = Me, 3m, 51%
R1 = Ph, 3n, 48%
3i
3
l, 42%
N
1
R
R
R
R
R
= Me, 3o, 47%
= Pr, 3p, 51%
= F, 3q, 64%
= CF3, 3r, 57%
= Br, 3s, 56%
COOCH3
N
1
1
1
1
i
COOCH3
R1
N
R1 = OMe, 3t, 61%
R1 = Cl, 3u, 56%
N
R1
R
1
= Br, 3v, 49%
N
N
COOCH3
COOCH3
N
R1
COOCH3
N
N
R2
N
R2 = 4-F, 3z, NR
1
1
R
R
= Me, 3w, 49%
= F, 3x, 56%
2
2
2
R
R
R
= 4-Cl, 3A, NR
= 6-Br, 3B, NR
= 6-F, 3C, NR
3y, 63%
COOCH3
N
N
N
COOCH3
COOCH3
S
N
R1
N
1
1
R
R
= H, 3D, NR
= Boc, 3E, NR
Ph
3F, tracea
3G, 0%b
Scheme 2 Substrate scope of indole. Reagents and conditions: 1 (0.3 mmol), 2a (1.5 mmol), Pd(TFA) (10 mol%), Ag O (2.0 equiv), N-Ac-Val-OH (1.0
2
2
a
equiv), 1:3 AcOH–DCE (3.0 mL), 90 °C, 24 h. Isolated yields of 3 are reported (NR = no reaction). The intermolecular alkenylation product 3F′ was
b
obtained in 91% yield. The intermolecular alkenylation product 3G′ was obtained in 95% yield.
Next, we tested the substrate scope of the acrylate in the
process (Scheme 3). When ethyl, butyl, isobutyl, tert-butyl,
and benzyl acrylates were subjected to reaction with O-
methyl oxime 1a, the corresponding cyclization products
Next, a series of control experiments were performed.
First, an intermolecular competition experiment in which
methyl acrylate (2a) was treated with substrates with an
electron-rich (1c) and an electron-deficient (1e) substitu-
ent revealed that the latter was kinetically favored (Scheme
4). Furthermore, the scalability of the protocol was success-
fully tested by performing a gram-scale reaction (Scheme 5).
To obtain some further mechanistic insights, experi-
ments with isotopically labeled solvents15 and some control
experiments were conducted (Scheme 6). A deuterium-in-
4a–f were obtained in moderate yields. With phenyl acry-
late as the reaction partner, disappointingly only a trace of
the desired product 4e was detected. The reactions of vari-
ous acrylates with the methyl-protected indole O-methyl-
oxime fortunately gave the desired annulation products
4g–k. None of the desired product was detected when we
used nonactivated alkenes such as cyclohexyl acrylate,
hept-1-ene, or acrylonitrile (4l–n), possibly because Pd in-
termediates cannot interchange with these alkenes. More-
over, when ethyl vinyl sulfone and ethyl vinyl ketone were
examined as reactants, disappointedly the desired products
corporation study with AcOD showed that C–H activation is
the first step and is reversible;1
0,13,15
incorporation of deute-
rium in the methyl group of 3a probably occurs after the
first step of the reaction.13 In addition, the 3-acetylindole
oxime 1a failed to react with either electron-rich methyl
acrylate (2m) or with electron-deficient acrylonitrile (2n)
4o and 4p were not obtained, possibly because of electronic
effects on the alkenylation process.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
Synlett
X.-P. Fu et al.
Letter
N
N
Pd(TFA)2 (10 mol%)
Ag2O (2.0 equiv)
OMe
COOR
H
COOR
N
N-Ac-Val-OH (1.0 equiv)
N
R1
R1
AcOH–DCE (1:3; 3.0 mL), 90 °C
4
a–l
1
2
N
N
N
N
t
COOEt
COOBu
COOBu
i
COO Bu
N
N
N
N
4a, 51%
4b, 49%
4c, 47%
4d, 41%
N
N
COOPh
COOBn
N
N
COOCH3
COOEt
N
N
N
N
4e, trace
4f, 51%
4g, 48%
4h, 73%
N
N
N
N
N
N
N
N
i
t
COOBu
COOBu
COO Bu
COOCy
N
N
N
N
N
N
N
N
4i, 75%
4j, 61%
4k, 53%
4l, NR
O
O
O
4
CN
S
4m, NR
4n, NR
4o, NR
4p, NR
Scheme 3 Substrate scope of acrylate. Reagents and conditions: 1 (0.3 mmol), 2 (1.5 mmol), Pd(TFA) (10 mol %), Ag O (2.0 equiv), N-Ac-Val-OH (1.0
2
2
equiv), 1:3 AcOH–DCE (3.0 mL), 90 °C, 24 h. Isolated yields of 4 are reported (NR = no reaction).
N
N
N
COOCH3
COOCH3
N
OMe
Pd(TFA)2 (10 mol%)
Ag2O (2.0 equiv)
Pd(TFA)2 (10 mol%)
Ag2O (2.0 equiv)
COOCH3
H
N
N
COOCH3
N
1c/1e
2a
N-Ac-Val-OH (1.0 equiv)
N
N-Ac-Val-OH (1.0 equiv)
AcOH–DCE (1:3; 3.0 mL), 90 °C
AcOH–DCE (1:3; 3.0 mL), 90 °C
1
a, 1.32 g
2a, 5.0 equiv
3a, 0.77g (49%)
3c, 46%
Cl
3e, 41%
Scheme 5 Gram-scale reaction
Scheme 4 Intermolecular competition experiment
of the key alkenylpalladium(II) species E.13,16 Finally, C–N
bond formation and N–O bond cleavage provide intermedi-
ate F, which undergoes cyclization through -hydride elim-
under the standard conditions, showing that appropriate
electronegativity of the alkene is a key factor if it is to act as
a coupling partner in the cyclization reaction.13
17,18
ination.
Based on these mechanistic studies and on documented
In summary, an efficient route has been developed for
palladium(II)-catalyzed C–H activation/annulation of ke-
toximes with acrylates through C–C/C–N formation. This
approach provides a direct, concise, and convenient route
to a variety of carboline carboxylates that will be applied in
exploring for potential drugs in the future.
11,13
reports,
a plausible mechanism for this reaction is pro-
posed (Scheme 7). First, Pd(TFA) coordinates with the sub-
2
strate 1a by C–H activation to form intermediate A revers-
ibly, possibly through a concerted metalation–deprotona-
11b,13
tion pathway.
The endo-cyclopalladated intermediate A
then undergoes ligand exchange with the acrylate to afford
intermediate B. Intermediate D and a Pd(0) species are then
formed through a 1,2-migratory insertion, a -hydride
elimination, and a reductive elimination. Subsequently, oxi-
dative addition leads to N–O bond cleavage and formation
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
Synlett
X.-P. Fu et al.
Letter
(
33%)
D/H)3C
(
N
N
OMe
OMe
H/D
(16%)
Pd(TFA)2 (10 mol%)
Ag2O (2.0 equiv)
H
N
N
(A)
N-Ac-Val-OH (1.0 equiv)
AcOD–DCE (1:3; 3.0 mL), 90 °C
1
a-d
1a
(
68%)
(
D/H)3C
(D/H)3C
N
N
N
(
28%)
COOCH3
OMe
Pd(TFA)2 (10 mol%)
Ag2O (2.0 equiv)
OMe
H/D
12%)
H
2a
(B)
N
N
N
H/D
41%)
(
N-Ac-Val-OH (1.0 equiv)
(
AcOD–DCE (1:3; 3.0 mL), 90 °C
1a
1
a-d
3a-d
Scheme 6 Deuterium-incorporation studies
Gottfried, S.; Spiteller, M.; Spiteller, P. J. Nat. Prod. 2013, 76, 127.
d) Singh, D.; Hazra, C. K.; Malakar, C. C.; Pandey, S. K.; Kaith, B.
S.; Singh, V. ChemistrySelect 2018, 3, 4859.
N
(
COOR1
Ag2O
N
N
OCH3
(
2) (a) Wolf, G.; Zymalkowski, F. Arch. Pharm. (Weinheim, Ger.)
1976, 309, 279. (b) Love, B. E. Org. Prep. Proced. Int. 1996, 28, 1.
(c) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 9318.
(d) Litvinov, V. P.; Dotsenko, V. V.; Krivokolysko, S. G. Adv. Het-
erocycl. Chem. 2007, 93, 117.
Ph
H-Pd -OCH3
0
N
Pd(II)L2
Ph
N
Ag
COOR1
C–H activation
N
Pd II
Ph
(3) (a) Song, Y.; Wang, J.; Teng, S. F.; Kesuma, D.; Deng, Y.; Duan, J.;
Wang, J. H.; Qi, R. Z.; Sim, M. M. Bioorg. Med. Chem. Lett. 2002,
12, 1129. (b) Zhang, G.; Cao, R.; Guo, L.; Ma, Q.; Fan, W.; Chen,
X.; Li, J.; Shao, G.; Qiu, L.; Ren, Z. Eur. J. Med. Chem. 2013, 65, 21.
F
OCH3
N
PdII
L
OCH3
OCH3
Pd II
N
N
Ph
A
(c) Hung, T.; Dang, T.; Janke, J.; Villinger, A.; Langer, P. Org.
N
COOR1
COOR1
oxidative addition
Biomol. Chem. 2015, 13, 1375.
Ph
(4) (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
E
Pd (0)
(
b) Godula, K.; Sames, D. Science 2006, 312, 67. (c) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2009,
8, 5094. (d) Zhou, M.; Crabtree, R. H. Chem. Soc. Rev. 2011, 40,
N
PdII
OCH3
N
OCH3
COOR1
N
4
Ph
B
N
H-Pd-L
1875. (e) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588.
(f) Ackermann, L. Acc. Chem. Res. 2013, 47, 281.
COOR1
N
OCH3
Ph
D
N
(5) (a) Graczyk, K.; Ma, W.; Ackermann, L. Org. Lett. 2012, 14, 4110.
(b) Padala, K.; Pimparkar, S.; Madasamy, P.; Jeganmohan, M.
Chem. Commun. 2012, 48, 7140. (c) Hu, X.-H.; Zhang, J.; Yang, X.-
F.; Xu, Y.-H.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 3169. (d) Gao,
S.; Wu, Z.; Wu, F.; Lin, A.; Yao, H. Adv. Synth. Catal. 2016, 358,
COOR1
Ph
PdII
L
C
Scheme 7 Plausible reaction mechanism
4
129.
6) (a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010,
32, 6908; corrigendum: J. Am. Chem. Soc. 2012, 134, 18148.
b) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem.
(
1
(
Funding Information
Soc. 2011, 133, 2350. (c) Deb, A.; Bag, S.; Kancherla, R.; Maiti, D.
J. Am. Chem. Soc. 2014, 136, 13602. (d) Hyster, T. K.; Dalton, D.
M.; Rovis, T. Chem. Sci. 2015, 6, 254. (e) Semakul, N.; Jackson, K.
E.; Paton, R. S.; Rovis, T. Chem. Sci. 2017, 8, 1015. (f) Jaiswal, Y.;
Kumar, Y.; Kumar, A. J. Org. Chem. 2018, 83, 1223.
We gratefully thank the National Natural Science Foundation of China
(Project No. 21676088) for financial support.
N
ati
o
n
a
l Natural S
c
i
e
n
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Supporting Information
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7) (a) Shi, B.-F.; Zhang, Y.-H.; Lam, J.-K.; Wang, D.-H.; Yu, J.-Q.
J. Am. Chem. Soc. 2010, 132, 460. (b) Engle, K. M.; Wang, D.-H.;
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Supporting information for this article is available online at
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(
(17) CCDC 1974231 contains the supplementary crystallographic
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www.ccdc.cam.ac.uk/getstructures.
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trated in vacuo. H O (30 mL) and CH Cl (15 mL) were added,
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2
2
2
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and the aqueous layer was separated and extracted with CH Cl2
2
133, 6449. (b) Shi, Z.; Koester, D.; Boultadakis-Arapinis, M.;
(2 × 15 mL). The combined organic layer was dried (MgSO ) and
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concentrated in vacuo to provide a crude product that was
further purified by column chromatography [silica gel, PE–EtAc
(10:1)].
Methyl
1-Methyl-5-phenyl-5H-pyrido[4,3-b]indole-3-car-
(
boxylate (3a)
1
21, 3505. (b) Fu, X.-P.; Tang, S.-B.; Yang, J.-Y.; Zhang, L.-L.; Xia,
White solid; yield: 59.7 mg (84%); mp 191–192 °C. H NMR (400
C.-C.; Ji, Y.-F. Eur. J. Org. Chem. 2019, 5974.
MHz, CDCl ):  = 8.31 (d, J = 8.0 Hz, 1 H), 8.07 (s, 1 H), 7.68 (t, J =
3
(
(
14) Li, W.; Zhao, Y.; Mai, S.; Song, Q. Org. Lett. 2018, 20, 1162.
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7.2 Hz, 2 H), 7.61–7.57 (m, 2 H), 7.57–7.47 (m, 4 H), 4.05 (s, 3 H),
13
3.34 (s, 3 H). C NMR (100 MHz, CDCl ):  = 166.5, 153.6, 145.1,
3
(
b) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2014, 136, 2735.
142.5, 142.1, 135.9, 130.3 (2 C), 128.8, 127.6, 127.2 (2 C), 123.0,
121.9, 121.8, 120.3, 110.6, 106.2, 53.0, 24.1. HRMS (EI): m/z [M ]
+
(
16) (a) Hosokawa, T.; Shimo, N.; Maeda, K.; Sonoda, A.; Murahashi,
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calcd for C20H16N O : 316.1212; found: 316.1213.
2
2
1999, 28, 45. (c) Kitamura, M.; Narasaka, K. Chem. Rec. 2002, 2,
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–F