Rhodium(III)-Catalyzed Regioselective Direct C4-Alkylation and C2-Annulation of Indoles: Straightforward Access to Indolopyridone

Article abstract of DOI:10.1002/ejoc.201701755

A straightforward Rh^III-catalyzed strategy was developed for the site-selective C4-alkylation and C2-annulation of indole by using electronically variable diazo esters. The transformation was accomplished with the assist of an oxime directing group at the C3 position of the indole core with wide scope and functional-group tolerance. The method directly provided an indolopyridone core. The selectivity was triggered by the reactivity of the diazo coupling partner.

Full text of DOI:10.1002/ejoc.201701755

A Journal of
Accepted Article
Title: Rhodium(III)-Catalyzed Regioselective Direct C4-Alkylation
and C2-Annulation of Indoles: Straightforward Access to
Indolopyridone
Authors: Aniruddha Biswas and Rajarshi Samanta
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701755
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701755
Supported by

10.1002/ejoc.201701755
European Journal of Organic Chemistry
FULL PAPER
Rhodium(III)-Catalyzed Regioselective Direct C4-Alkylation and
C2-Annulation
Indolopyridone
of
Indoles:
Straightforward
Access
to
Aniruddha Biswas[a] and Rajarshi Samanta*[a]
Abstract:
A
straightforward Rh(III)-catalyzed strategy was
compounds followed by migratory insertion.13, 14 Based on these
12,15
developed for the site selective C4-alkylation and C2-annulation of
indole using electronically variable diazo esters. The transformation
was accomplished with the assist of oxime directing group at the C3
position of indole core with wide scope and functional group
tolerance. The method directly provided indolopyridone core. The
selectivity was triggered by the reactivity of the diazo coupling
partner.
development and our own recent progress on this field
we
assumed that transition metal catalyzed C4-alkylation of indole
moiety might possible with the aid of suitably positioned
removable directing group. However, control on six membered
over five membered metallacycle is the key challenge to obtain
this C4 selectivity.8,16 During our manuscript preparation, very
recently Song and Li group revealed rhodium catalyzed site-
selective C4-alkylation versus C2-annulation on indole
scaffold.17 Herein, we independently disclose a removable oxime
group directed18 mild Rh(III)-catalyzed C4- selective alkylation
and C2-annulation of an indole derivative to provide
indolopyridone core using diazo esters (Scheme 1b).
Introduction
Indoles are one of the most prevalent structure in the bioactive
natural products and widely available heteroatomic in functional
materials and marketed pharmaceuticals.1 Hence, continuous
studies have been employed in recent past to introduce various
functional groups at the available inequivalent C-H bonds of
indole core especially at its C2 and C3- position under transition
metal catalysis.2 Comparably, regioselective functionalization at
the less accessible C-H bonds in the benzene core of indole
moiety remains a big challenge.3-6 Therefore, site-selective direct
introduction of functional groups at the sufficiently less
nucleophilic C4- position of indole moiety has been realized
recently (Scheme 1a).7, 8
Since the elegant development by Jia and co-workers in Pd-
catalyzed C4- olefination of tryptophan moieties or recently on
free indole derivatives via Rh catalysis,8a,d Prabhu’s group
elegantly showed Ru-catalyzed C4- olefination of 3-acyl and
formylindoles.8b,c In a recent significant work, You group showed
Rh catalyzed regioselective C-H bond activation/annulation of
indolyl aldehydes at the C4- position9a whereas Wang and co-
workers explored the oxidative annulation of 3-(1H-indol-3-yl)-3-
oxopropanenitriles and internal alkynes under Rh catalysis.9b
Importantly, Shi and co-workers very recently established C4-
arylation and fluoroalkylation of indoles under Pd catalyzed
conditions.4,10 Notably, Ir-catalyzed C4- amination of indole
derivatives was independently reported by Prabhu’s group and
You’s group.11 Very recently, our group also developed Rh-
catalyzed C4- thiolation and selenylation of indole derivatives
having removable oxime directing group at its C3- position.12
In recent past, many important transition metal catalysed highly
regioselective transformations were carried out by directed C–H
bond metallation, metal–carbene formation using diazo
Scheme 1. C4 Functionalization of Indoles.
Results and Discussion
Based on the above realization, we initiated our investigations
with methyl oxime derivative of N-benzyl-3-acetylindole (1a) and
diethyl 2-diazomalonate (2a) in the presence of [Cp*RhCl2]2
catalyst (Table 1). Initially, we did the transformation with Rh(III)
catalyst and AgOAc additive in methanol (Table 1, entry 1) at
40 °C. Gratifyingly, C4- alkylated product 3a was obtained in
77% yield without having any C2-alkylated product. When we
performed the same reaction conditions except the additive
AgSbF6, the yield of the desired product decreased to 37%
(Table 1, entry 2). Significantly, the yield of 3a was improved to
84% by using DCE solvent (Table 1, entry 3). To our delight,
introduction of AgNTf2 as silver additive marginally improved the
isolated yield upto 91% (table 1, entry 4). For further
development, other solvents with different polarity were tested
(Table 1, entries 5-7). But none of these solvents were found
suitable for this transformation. When diazo 2a reacted with
[a]
Department of Chemistry
Indian Institute of Technology Kharagpur
Kharagpur 721302, India
E-mail: rsamanta@chem.iitkgp.ernet.in
http://www.chemistry.iitkgp.ac.in/~rsamanta/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701755
European Journal of Organic Chemistry
FULL PAPER
oxime 1a at 100 °C, it provided product 3a (C4 alkylated
product) only with very high reaction rate.
directing groups including aldoxime and keto-oximes at the C3-
position of indole core also afforded desired products with good
yield (Scheme 2, 3u-3w). Additionally, benzyloxime derivative
also provided desired product with satisfying yield (Scheme 2,
3x). To increase its synthetic applicability, the reaction was
performed with 1a in 25 fold high amounts (Scheme 2, 3a)
having 83% isolated yield. Finally, the C4- selective alkylation
has been unequivocally established by single x-ray crystal
structure of compound 3r (CCDC no: 1584741; see supporting
information for details).
Further, the reaction of 1a with less reactive bis(2,2,2-
trifluoroethyl) 2-diazomalonate (2u) did not provide 3a or 4a
under the optimized conditions at 40 °C (Table 1, entry 8).
Incidentally, increase of reaction temperature up to 100 °C led to
provide the C2 annulated indolopyridone product 4a in satisfying
t
87% yield (Table 1, entry 9). Solvents like AmOH and 1,4-
dioxane provided very good to moderate yield (table 1, entries
10-11). Screening of other solvents was not turned out to be
effective (Table 1, entries 12-14). However, lowering of reaction
temperature to 80 °C decreased the isolated yield of 4a in
significant amount.
RO2C
CO2R
DG
DG
OMe
N2
Rh(III) [2 mol%]
N
+
DG =
Ag(I) [10 mol%]
DCE, 40 °C
RO2C
CO2R
N
R1
N
R1
2
3
1
Table 1. Optimization of Reaction Conditions
tBuO2C
CO2tBu
DG
EtO2C
CO2Et
DG
MeO2C
CO2Me iPrO2C
DG
CO2iPr
DG
N
Bn
N
Bn
N
Bn
N
3a, 91%
Bn
3d, 82%
EtO2C CO2Et
DG
3b, 87%
3c, 88%
(83%)b
EtO2C
CO2CH2CF3
DG
AllO2C
CO2All
BnO2C
CO2Bn
DG
DG
N
N
N
Bn
N
Bn
Mes
Bn
3f, 69%
EtO2C
3g, 76%
3h, 86%
3e, 83%
temp
(°C)
40
40
40
40
40
40
40
Yieldc
3a
77
37
84
91
42
trace
EtO2C
CO2Et
DG
EtO2C
CO2Et
DG
EtO2C
CO2Et
DG
CO2Et
DG
En.
1a
R
additive solvent
AgOAc MeOH
AgSbF6 MeOH
AgSbF6 DCE
4a
-
-
-
-
-
-
-
F
Et
Et
Et
Et
Et
Et
Et
2a
N
3a
N
N
N
Bn
Ph
PMB
3k, 88%
3j, 80%
4a
AgNTf2
AgNTf2
AgNTf2
AgNTf2
DCE
3i, 83%
3l, 79%
5a
dioxane
MeCN
DMF
EtO2C
CO2Et
EtO2C
CO2Et
DG
EtO2C
Cl
CO2Et
EtO2C
CO2Et
DG
6 a
7a
DG
DG
trace
8b
CH2CF3 AgNTf2
CH2CF3 AgNTf2
CH2CF3 AgNTf2
CH2CF3 AgNTf2
CH2CF3 AgNTf2
CH2CF3 AgNTf2
CH2CF3 AgNTf2
DCE
40
-
-
-
-
-
-
-
-
N
Bn
N
Bn
MeO
N
Bn
N
Bn
MeO2C
3p, 77%
F3C
9b
DCE
100
100
100
100
100
100
87
82
67
33
trace
trace
3m, 82%
3n, 85%
10b
11b
12b
13b
14b
tAmOH
dioxane
TFE
3o, 69%
EtO2C
CO2Et
DG
EtO2C
CO2Et
DG
EtO2C
CO2Et
DG
EtO2C
CO2Et
DG
DMF
toluene
Ph
N
Bn
N
N
N
Bn
aReaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), [Cp*RhCl2]2 (2
mol%), silver salt (10 mol%), 12 h, 0.1 M. bReaction conditions: 2u
(0.15 mmol), 12 h, 0.1 M. cIsolated yields.
Bn
Br
3q, 92%
Bn
3t, 93%
OBn
3r [xray]c
90%
3s, 84%
OMe
OMe
OMe
N
N
N
N
(EtO2C)2HC
Et
iPr (EtO2C)2HC
(EtO2C)2HC
H (EtO2C)2HC
With the established optimized conditions, initially we sought to
explore the indole substrate scope with various diazomalonates
for the C4- alkylation (Scheme 2). Gratifyingly, the reaction
proceeded smoothly with sterically and electronically variable
diazomalonates (Scheme 2, 3a-3f). Mixed diazo malonate like 1-
ethyl 3-(2,2,2-trifluoroethyl) 2-diazomalonate (2g) also reacted
successfully with 1a to provide desired C4- alkylated indole
product (Scheme 2, 3g). Moreover, protection of indole-NH with
versatile alkyl and phenyl groups did not influence the efficacy of
the reaction (Scheme 2, 3h-3k). Electron donating methoxy
group, halogen, and electron withdrawing groups like CF3 and
ester groups were also firmly tolerated at the C5- and C6-
position of indole core (Scheme 2, 3l-3p). Next, alkyl and
halogen substitutions at the C7- position of indole core did not
creat any trouble during the C4- alkylation with good to excellent
yield (Scheme 2, 3q-3r). More conjugated derivatives also
alkylated smoothly with admirable degree of regioselectivity to
provide desired products (Scheme 2, 3s-3t). Furthermore, other
N
N
N
Bn
N
Bn
3v, 73%
3w, 71%
Bn
Bn
3x, 69%
3u, 96%
Scheme 2. Scope of C4- alkylated indoles: Reaction conditions: 1 (0.1 mmol),
2 (0.12 mmol), [Cp*RhCl2]2 (2 mol%), AgNTf2 (10 mol%), 10-12 h, DCE (0.1
M); b1a in 2.5 mmol scale cCCDC no: 1584741
We explored the scope for C2- annulation of indole moiety
under developed conditions using less reactive bis(2,2,2-
trifluoroethyl) 2-diazomalonate (2u) as coupling partner. In
general, electronically and sterically variable functional groups at
different position of indole scaffold were well tolerated (Scheme
3). Electron donating alkyl and methoxy group at the C5-
position of indole afforded excellent yields of desired products
(Scheme 3, 4b-4d). Gratifyingly, various aryl groups and
heterocycles at the C5- position were survived under the
optimized conditions with excellent yields (Scheme 3, 4e-4h).
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10.1002/ejoc.201701755
European Journal of Organic Chemistry
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Subsequently, indoles containing halogens at C5- position were
firmly accommodated keeping the window open for further
modifications of the final indolopyridones (Scheme 3, 4i-4j). We
were delighted to see that substrates having electron
withdrawing groups at C5- position also provided desired
products in moderate to good yields (Scheme 3, 4k-4l). Halogen
at C6- position of indole core was firmly tolerated during the
transformation (Scheme 3, 4m). Notably, C7- methyl substituted
indole moiety also afforded desired product albeit in moderate
yield (Scheme 3, 4n). Substituted Indoles with N-methyl
protecting group afforded desired products with excellent yields
(Scheme 3, 4o-4r).
Scheme 4. Control experiments
Importantly, post operative removal of the directing group i.e. the
removal of ketoxime group from the compound 3a was
performed uninterruptedly in two consecutive steps or in single
step to provide C4-alkylated indole derivative 5 (Scheme
4i).4,10,12 Subsequently, benzyl group was also removed from the
keto-congener of 3a to provide compound 6 using anhydrous
AlCl3 (Scheme 4ii) conditions.19 Strikingly, indolopyridone
compound 7 was synthesized in one step using 1a, 2a and 2u in
one pot under standard reaction conditions (Scheme 4iii). The
control on site-selectivity was strategically realized with the help
of variable diazo compounds and reaction temperature.
Scheme 3. Scope of C2-annulated indoles: Indolopyridones: Reaction
Conditions: 1a (0.1 mmol), 2u (0.15 mmol), [Cp*RhCl2]2 (2 mol%), AgNTf2 (10
mol%), 12-16 h, DCE (0.1 M), 100 °C. b at 130 °C for 24 h
Importantly, benzo[g] indole derivative also provided highly
conjugated polyaromatic product (Scheme 3, 4s) with excellent
yield. Other alkyl or phenyl protecting group at indole NH did not
interfere in the desired transformation (Scheme 3, 4t-4v).
Furthermore, another indole ketoxime derivative provided the
desired product with very good yield (Scheme 3, 4w).
Benzyloxime derivative of indole also smoothly afforded desired
indolopyridone in 76% yield (Scheme 3, 4x).
Scheme 5. Mechanistic studies
Different control experiments were performed to shed light on
the plausible mechanism (Scheme 5). Treatment of indole 1a
with CD3OD as the co-solvent in presence or absence of 2a
offered very low H/D scrambling at C4- position (Scheme 5i). In
contrast, H/D exchanges were significantly observed at C4 and
C2- position of 1a in presence or absence of coupling partner 2u
(Scheme 5ii-iii) at elevated temperature. This outcome reveals
that more likely the formation of six membered rhodacycle for
C4- activation at lower temperature is kinetically controlled and
formation of five-membered rhodacycle for C2 activation is
thermodynamically controlled. Presumably, the selectivity
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10.1002/ejoc.201701755
European Journal of Organic Chemistry
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between C2 and C4 depends on the equilibrium between the
formation of corresponding 6-membered and 5-membered
rhodacycle. At lower temperature, 2a only provided desired C4
alkylated product whereas 2u did not react at all under the
developed conditions with 1a. But at higher temperature, 2a
reacted faster to provide the only C4 alkylated product where as
2u provided only C2- annulated product. These facts surely
indicate that the regioselectivity depends on the reactivity of the
corresponding diazo compounds. Hence, in presence of more
reactive 2a, the reaction favors kinetic controlled pathway to
provide product 3a formation and comparatively less reactive 2u
favors thermodynamic controlled pathway to furnish 4a.
Furthermore, C2-alkylation reaction did not provide the diazo
inserted 4-methoxyphenyl malonate derivative in presence of
anisole. This proves that the reaction proceeds through C-H
activation followed by metallocarbene generation (see
supporting information) and its subsequent migratory insertion.
Based on the preliminary mechanistic investigations and earlier
related literatures,13, 14, 20 a plausible mechanistic pathway was
proposed (Scheme 6) for the formation of compound 3a. The
active catalyst A is generated from [Cp*RhCl2]2 by halide
abstraction with AgNTf2. Next, the following formation of 6-
membered rhodacycle through oxime directed C4-H bond
cleavage provides intermediate B. Further, formation of metal
carbene species C occurs in presence of diazo malonate 2a via
nitrogen extrusion. Subsequent migratory insertion of Rh-C bond
provides intermediate D which will further undergo proto-
demetalation to furnish compound 3a with the regeneration of
active Rh(III) species. Now for the formation of C2-alkylated
product, the reaction proceeds via thermodynamically controlled
five membered rhodacycle. Finally, activation of ester group
The C2 annulation method provides a straightforward approach
to obtain indolopyridone core.
Experimental Section
All commercially available compounds were used without further
purification. Solvents for elution in column were distilled. Analytical thin
layer chromatography (TLC) was performed on pre- coated silica gel 60
F254. Visualization on TLC was achieved by the use of UV light (254 nm).
Column chromatography was undertaken on silica gel (230-400 mesh).
1H NMR was recorded on BRUKER ULTRA SHIELD (400 MHz, 500MHz
and 600 MHz). Chemical shifts were quoted in parts per million (ppm)
referenced to the appropriate solvent peak or 0.0 ppm for
tetramethylsilane. The following abbreviations were used to describe
peak splitting patterns when appropriate: br = broad, s = singlet, d =
doublet, t= triplet, q= quartet, dd = doublet of doublet, td = triplet of
doublet, m = multiplet. Coupling constants, J, were reported in hertz unit
(Hz). 13C NMR was recorded on BRUKER (150 MHz, 125 MHz, 100 MHz
and 50 Mhz) and was fully decoupled by broad band proton decoupling.
Chemical shifts were reported in ppm referenced to the centre of a triplet
at 77.16 ppm of chloroform-d, 19F NMR spectra were recorded on
BRUKER (376 MHz). Infrared (IR) spectra were recorded using Perkin–
Elmer FT-IR Spectrometer. Frequencies are given in reciprocal
centimetres (cm-1) and only selected absorbance peaks are reported.
High resolution mass spectra were obtained from waters XEVO-G2QTOF
by using TOF MS ESI+ method. Materials were obtained from
commercial suppliers or prepared according to standard procedures
unless otherwise noted.
General procedure for the synthesis of 3-acetyl indole derivatives:
To a stirred solution of indole derivative (1 equiv) in dry toluene, acid
chloride (2 equiv) was added. The reaction mixture was cooled to 0 oC
and stirred for 10 min. Next, stannic chloride (2 equiv) was added drop-
wise to the reaction mixture and stirred for 12 h. After completion of
reaction (as monitored by TLC), it was cooled to 0 0C, quenched by
saturated NaHCO3 solution and extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude product
was purified by silica gel column chromatography to provide desired
product
General procedure for preparation of N-substituted 3-acetyl indole:
To a stirred suspension of NaH (60 wt% in mineral oil, 1.5 equiv) in dry
THF, solution of 3-acetyl indole derivative (1 equiv) was added at 0 oC
and stirred for 15 min. Then corresponding alkyl halide (1.1 equiv) was
added dropwise to the reaction mixture and stirred overnight at rt. After
completion of the reaction (as monitored by TLC), it was cooled to 0 0C
and quenched by addition of water and extracted with ethyl acetate.
Combined organic layers were washed with water, brine, and dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography to obtain
desired N-alkylated 3-acetyl indole derivatives.
Figure 1. Proposed Mechanism
from C2 alkylated product by Rh(III) catalyst followed by
tautomerization and nucleophilic attack of O-methyl-
hydroxylamine moiety affords annulated product 4a.
Procedure for synthesis of N-phenyl 3-acetyl indole[21a]:. In a oven-
dried sealed tube, 3-acetyl indole (1 equiv) dissolved in CH2Cl2 (6 mL),
phenylboronic acid (2 equiv), anhydrous copper(II) acetate (2 equiv), and
triethylamine (2 equiv) were added. The mixture was stirred at room
temperature for 3 days, concentrated in vacuo, diluted with chloroform
and water. The organic layer was separated, washed with brine and dried
over anhydrous Na2SO4, concentrated in vacuo, and purified by column
chromatography (EtOAc/hexane) to obtain pure product.
Conclusions
In summary, we have successfully explored an efficient
regiocontrolled C4-alkylation and C2-annulation of indoles with
electronically variable diazo esters. Selectivity has been
achieved through the aid of removable oxime group. Reactivity
of diazo esters plays a crucial role in control of site-selectivity.
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10.1002/ejoc.201701755
European Journal of Organic Chemistry
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General procedure for preparation of ketoximes[21b]: Ketone (1 equiv)
organic layers were dried over anhydrous Na2SO4 and concentrated
under vaccum. The crude product was purified by silica gel column
chromatography to obtain pure product 8 (37.6 mg, 86%) as white solid.
Diethyl 2-(3-acetyl-1-benzyl-1H-indol-4-yl)malonate (3a’); brown solid
(90%);1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.39 – 7.31 (m, 3H),
7.31 – 7.24 (m, 2H), 7.16 (dd, J = 7.4, 1.9 Hz, 2H), 6.80 (s, 1H), 4.44 –
3.94 (m, 4H), 2.51 (s, 3H), 1.29 (t, J = 7.1 Hz, 6H). 13C NMR (125 MHz,
CDCl3) δ 192.52 , 169.87 , 138.48 , 137.96 , 135.50 , 129.24 , 128.46 ,
was taken in a 50 mL round bottom flask equipped with a stir bar.Then ,
R4ONH2 HCl (2.7 equiv), NaOAc (4.4 equiv), and EtOH:H2O (1:3) was
.
added to the reaction mixture. The reaction mixture was heated at 70 0C.
After completion of reaction (as monitored by TLC), it was cooled to rt
and EtOH was removed under vaccum. The mixture was extracted with
EtOAc. The combined organic layers were dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography to yield the desired
analytically pure ketoxime 1 in moderate to good yield.
128.21 , 127.13 , 125.82 , 124.11 , 123.74 , 118.43 , 110.30 , 61.49 ,
~
56.37 , 50.94 , 28.33 , 14.24; FT-IR:  = 2980, 1733,1705,1452, 1391,
1296, 1208, 1132 cm-1; M.p. 103-107 °C; HRMS (ESI): m/z calcd for:
[M+H]+ C24H26NO5:Exact Mass: 408.1805; found:408.1811
General procedure for preparation of diazo compounds: Malonates
(1 mmol) were dissolved in dry THF (10 mL), Cs2CO3 (1.1 mmol, 1.1
equiv.) followed by tosyl azide (1.1 mmol, 1.1 equiv.) were added at room
temperature. The reaction was allowed to stir for 24 h at the same
temperature. After completion of the reaction, solvent was evaporated
under reduced pressure. Then diazo malonates were purified by silica gel
column chromatography using hexane/ethyl acetate (80-90 % yield).
One step removal of oxime directing group: Compound 3a (86 mg,
0.2 mmol) in dry benzene was taken in a sealed tube. Next, ethylene
glycol (0.2 mL) and p-toluenesulfonic acid monohydrate (172 mg, 5
equiv) were added consecutively. The reaction mixture was heated at
120 0C for 5 h. The reaction mixture was cooled and saturated sodium
bicarbonate solution was added and extracted with ethyl acetate. The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography to obtain pure product 8 (37.9 mg,
52%) as white solid
General procedure for of C4-alkylation: To an oven-dried 10 mL screw
cap vial ketoxime 1 (0.1 mmol) was taken in dry DCE (0.1 M). Next,
[Cp*RhCl2]2 (2 mol%), AgNTf2 (10 mol%) and Diazo-malonate (0.12
mmol) were added to it and stirred at 40-50 0C for 8-12 h. After
completion of the reaction (as monitored by TLC), the solvent was
evaporated under reduced pressure. The crude reaction mixture was
directly loaded to column and purified by silica gel column
chromatography using EtOAc/hexane mixture (10%-20% v/v) as elluent
to obtain desired pure product.
Deprotection of benzyl group[19]: Compound 3a (86 mg, 0.2 mmol) was
added to a suspension of AlCl3 (5 equiv.) in dry benzene. Next, this
mixture was sonicated for 10 h at room temperature. Then reaction
mixture was quenched with 3 mL of saturated solution of (1:1) mixture of
sodium bicarbonate and potassium carbonate and sonicated for 10 min.
then 15 mL EtOAc was added to the mixture and sonicated for 5 min.
The organic layer was separated and dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography to obtain N-H free indole derivative 6
(37.9 mg, 60% brsm) as white solid.
General procedure for of C2-alkylation and annulation: To an oven-
dried 10 mL screw cap vial ketoxime 1 (0.1 mmol) was taken in dry DCE
(0.1 M). Next, [Cp*RhCl2]2 (2 mol%), AgNTf2 (10 mol%) and bis(2,2,2-
trifluoroethyl) 2-diazomalonate (0.15 mmol) were added to it and stirred
at 100 0C for 10-20 h. After completion of the reaction (as monitored by
TLC), the solvent was evaporated under reduced pressure. The crude
reaction mixture was directly loaded to column and purified by silica gel
column chromatography using EtOAc/hexane mixture (50%-90% v/v) as
elluent to obtain desired pure product.
Analytical data of C4 alkylated products:
(E)-Diethyl
2-(1-benzyl-3-(1-(methoxyimino)ethyl)-1H-indol-4-
yl)malonate (3a): White solid, 91%; 1H NMR (400 MHz, CDCl3) δ 7.37 –
7.21 (m, 7H), 7.13 (dd, J = 7.4, 1.8 Hz, 2H), 6.64 (s, 1H), 5.30 (s, 2H),
4.35 – 4.12 (m, 4H), 4.01 (s, 3H), 2.25 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H).
13C NMR (125 MHz, CDCl3) δ 169.44 , 152.03 , 137.80 , 136.59 , 130.51 ,
Large scale experiment: To an oven-dried 30 mL screw cap vial
ketoxime 1a (675 mg, 2.5 mmol) was taken in dry DCE (10 mL). Next,
[Cp*RhCl2]2 (15.4 mg, 1 mol%), AgNTf2 (48.5 mg, 5 mol%) and Diazo-
malonate (558 mg, 1.2equiv, 2a) were added to it and stirred at 50 0C for
24 h. After completion of the reaction (as monitored by TLC), the solvent
was evaporated under reduced pressure. The crude reaction mixture was
directly loaded to column and purified by silica gel column
chromatography using EtOAc/hexane mixture (10%-20% v/v) as elluent
to obtain desired pure product (83%, 904 mg, 3a).
128.99 , 128.02 , 127.06 , 126.91 , 124.56 , 122.86 , 121.87 , 113.99 ,
~
110.02 , 61.66 , 61.45 , 55.21 , 50.45 , 16.08 , 14.21; FT-IR:  = 2980,
2936, 1736, 1500, 1436, 1368, 1304, 1152 cm-1; M.p. 77–80 °C; HRMS
(ESI): m/z calcd for: [M+H]+: C25H29N2O5;Exact Mass: 437.2071; found:
437.2072
(E)-Dimethyl
2-(1-benzyl-3-(1-(methoxyimino)ethyl)-1H-indol-4-
Stepwise removal of directing group: O-Methyl oxime compound 3a
(87 mg, 0.2 mmol) was dissolved in 1,4-dioxane (4 mL) and stirred for 15
min, then 6N HCl (1.5 mL) was added. The reaction was heated at 80 0C
and stirred at the same temperature for 2 h. After completion, the
reaction mixture was quenched with saturated sodium bicarbonate and
extracted with EtOAc. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under vaccum. The crude product
was purified by silica gel column chromatography to obtain the
correspondin 3-acetyl indole derivative 3a’(81 mg, 90%) as yellow solid.
Next, to a stirred solution of compound 3-acetyl indole derivative (50 mg,
0.12 mmol, 3a’) in dry benezene (2 mL) was added ethylene glycol (0.1
mL) and p-toluenesulfonic acid monohydrate (35 mg, 1.1 equiv) and
heated under reflux condition for 2 h. After completion (as monitored by
TLC), the reaction mixture was cooled and saturated sodium bicarbonate
solution was added and extracted with ethyl acetate. The combined
yl)malonate (3b); Greenish solid, 87%; 1H NMR (400 MHz, CDCl3) δ
7.34 – 7.27 (m, 4H), 7.27 – 7.21 (m, 3H)., 7.13 (dd, J = 7.3, 1.9 Hz, 2H),
6.73 (s, 1H), 5.29 (s, 2H), 4.00 (s, 3H), 3.75 (s, 6H), 2.26 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 169.93 , 152.10 , 137.84 , 136.48 , 130.70 ,
128.99 , 128.03 , 127.04 , 126.62 , 124.49 , 122.91 , 121.98 , 113.88 ,
~
110.14 , 61.61 , 54.91 , 52.62 , 50.45 , 15.91; FT-IR:  = 2992, 2943,
1736, 1733, 1424, 1353, 1317, 1089 cm-1; M.p. 91–93 °C; HRMS (ESI):
m/z calcd for: [M+H]+: C23H25N2O5;Exact Mass: 409.1758; found:
409.1753
(E)-Diisopropyl
2-(1-benzyl-3-(1-(methoxyimino)ethyl)-1H-indol-4-
yl)malonate(3c); Colorless oil. 88%; 1H NMR (400 MHz, CDCl3) δ 7.35 –
7.28 (m, 4H), 7.25 (m, 3H), 7.13 (dd, J = 7.4, 1.8 Hz, 2H), 6.62 (s, 1H),
5.30 (s, 2H), 5.10 (hept, J = 6.3 Hz, 2H), 4.04 (s, 3H), 2.25 (s, 3H), 1.29
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701755
European Journal of Organic Chemistry
FULL PAPER
(d, J = 6.3 Hz, 6H), 1.26 (d, J = 6.3 Hz, 6H). 13C NMR (125 MHz,CDCl3) δ
168.86 , 151.88 , 137.74 , 136.64 , 130.34 , 128.97 , 127.98 , 127.14 ,
(E)-Diethyl
2-(3-(1-(methoxyimino)ethyl)-1-phenyl-1H-indol-4-
yl)malonate (3i); Colourless oil, 83%; 1H NMR (400 MHz, CDCl3) δ 7.53
(t, J = 7.8 Hz, 2H), 7.48 – 7.38 (m, 5H), 7.33 – 7.22 (m, 2H), 6.56 (s, 1H),
4.24 (m, 4H), 4.04 (s, 3H), 2.31 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 169.37 , 151.95 , 138.99 , 137.68 , 130.20 , 129.85 ,
127.03 , 124.59 , 122.77 , 121.74 , 114.03 , 109.90 , 68.86 , 61.69 ,
~
55.44 , 50.42 , 21.80, 21.71, 16.16; FT-IR:  = 2982, 2938, 1737, 1497,
1438, 1371, 1303, 1150 cm-1; HRMS (ESI): m/z calcd for: [M+H]+:
C27H33N2O5; Exact Mass: 465.2384; found: 465.2389
127.57 , 126.83 , 125.31 , 124.85 , 123.35 , 122.44 , 115.46 , 110.79 ,
~
61.76 , 61.54 , 55.11 , 16.24 , 14.22 ; FT-IR:  = 2990, 2941, 1742,1736,
1532, 1391, 1325, 1154 cm-1; HRMS (ESI): m/z calcd for: [M+H]+:
(E)-Di-tert-butyl
2-(1-benzyl-3-(1-(methoxyimino)ethyl)-1H-indol-4-
yl)malonate(3d);Colorless oil, 82%; 1H NMR (400 MHz,CDCl3) δ 7.33 –
7.21 (m, 7H), 7.14 (dd, J = 7.7, 1.8 Hz, 2H), 6.39 (s, 1H), 5.31 (s, 2H),
4.06 (s, 3H), 2.25 (s, 3H), 1.50 (s, 18H). 13C NMR (125 MHz, CDCl3) δ
168.52 , 151.88 , 137.73 , 136.70 , 130.19 , 128.97 , 127.97 , 127.63 ,
C24H27N2O5; Exact Mass: 423.1914; found: 423.1917.
(E)-Diethyl
2-(3-(1-(methoxyimino)ethyl)-1-methyl-1H-indol-4-
yl)malonate (3j); Yellow oil, 80%; 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J
= 4.5 Hz, 2H), 7.25 (m, 2H), 6.62 (s, 1H), 4.31 – 4.14 (m, 4H), 4.00 (s,
3H), 3.78 (s, 3H), 2.25 (s, 3H), 1.25 (t, J = 7.1 Hz, 6H). 13C NMR (125
MHz, CDCl3) δ 169.33 , 151.83 , 138.06 , 131.00 , 126.70 , 124.21 ,
127.08 , 124.62 , 122.74 , 121.42 , 114.18 , 109.75 , 81.33 , 61.71 ,
~
57.27 , 50.43 , 28.11 , 16.28; FT-IR:  = 2981, 2933, 1737, 1731, 1436,
1367, 1301, 1159 cm-1; HRMS (ESI): m/z calcd for: [M+H]+: C29H37N2O5;
Exact Mass: 493.2697; found:493.2701
122.56 , 121.53 , 113.15 , 109.38 , 61.50 , 61.29 , 55.05 , 33.17 , 15.86 ,
~
14.07 ; FT-IR:  = 2936, 1732, 1536, 1452, 1394, 1300, 1142 cm-1;
HRMS (ESI): m/z calcd for: [M+H]+: C19H25N2O5; Exact Mass: 361.1758;
(E)-Dibenzyl
2-(1-benzyl-3-(1-(methoxyimino)ethyl)-1H-indol-4-
yl)malonate (3e); Yellow solid, 83%; 1H NMR (400 MHz, CDCl3) δ 7.34 –
7.22 (m, 16H), 7.20 (d, J = 7.7 Hz, 1H), 7.12 (dd, J = 7.2, 1.9 Hz, 2H),
6.96 (s, 1H), 5.30 (s, 2H), 5.20 (s, 2H), 5.19 (s, 2H), 3.84 (s, 3H), 2.18 (s,
3H). 13C NMR (125 MHz, CDCl3) δ 169.15 , 151.98 , 137.88 , 136.57 ,
135.85 , 130.69 , 129.02 , 128.49 , 128.14 , 128.04 , 127.01 , 126.63 ,
found: 361.1783.
(E)-Diethyl
2-(1-(4-methoxybenzyl)-3-(1-(methoxyimino)ethyl)-1H-
indol-4-yl)malonate (3k); Brown liquid, 88%; 1H NMR (400 MHz, CDCl3)
δ 7.37 – 7.10 (m, 4H), 7.09 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H),
6.65 (s, 1H), 5.23 (s, 2H), 4.39 – 4.14 (m, 4H), 4.02 (s, 3H), 3.79 (s, 3H),
2.25 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ
169.43 , 159.40 , 152.05 , 137.73 , 130.32 , 128.56 , 128.45 , 126.83 ,
124.54 , 122.90 , 122.20 , 114.04 , 110.14 , 67.11 , 61.61 , 55.08 , 50.47 ,
~
15.84; FT-IR:  = 3032, 2983, 2935, 1740, 1502, 1433, 1365, 1301,
1153 cm-1; M.p. 111–114 °C; HRMS (ESI): m/z calcd for: [M+H]+:
C35H33N2O5; Exact Mass: 561.2384; found: 561.2377
124.56 , 122.75 , 121.80 , 114.34 , 113.77 , 110.00 , 61.62 , 61.42 ,
~
55.40 , 55.17 , 49.94 , 16.05 , 14.19; FT-IR:  = 2991, 2939, 1748, 1527,
1397,1373, 1258, 1152 cm-1; HRMS (ESI): m/z calcd for: [M+H]+:
(E)-Diallyl
2-(1-benzyl-3-(1-(methoxyimino)ethyl)-1H-indol-4-
yl)malonate(3f); Yellow solid, 69%; 1H NMR (400 MHz, CDCl3) δ 7.42 –
7.15 (m, 7H), 7.13 (dd, J = 7.4, 1.8 Hz, 2H), 6.84 (s, 1H), 5.90 (ddt, J =
17.4, 10.8, 5.6 Hz, 2H), 5.37 – 5.23 (m, 4H), 5.19 (dt, J = 10.5, 1.5 Hz,
2H), 4.80 – 4.53 (m, 4H), 3.99 (s, 3H), 2.25 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 168.90 , 151.91 , 137.74 , 136.41 , 131.86 , 130.54 , 128.89 ,
C26H31N2O6; Exact Mass: 467.2177; found: 467.2169.
(E)-Diethyl 2-(1-benzyl-5-fluoro-3-(1-(methoxyimino)ethyl)-1H-indol-
4-yl)malonate (3l); White solid, 79%; 1H NMR (400 MHz, CDCl3) δ 7.38
– 7.27 (m, 4H), 7.22 – 7.09 (m, 3H), 7.01 (ddd, J = 10.5, 8.8, 1.7 Hz, 1H),
6.89 (d, J = 3.1 Hz, 1H), 5.28 (s, 2H), 4.24 (q, J = 7.1 Hz, 4H), 4.00 (s,
3H), 2.24 (s, 3H), 1.26 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz,CDCl3) δ
168.68 , 157.64 (d, J = 238.4 Hz), 151.63 , 136.21 , 134.25 , 132.02 ,
129.08 , 128.19 , 127.04 , 125.21 (d, J = 6.0 Hz), 114.31 (d, J = 17.8 Hz),
127.92 , 126.91 , 126.51 , 124.43 , 122.78 , 121.98 , 118.13 , 113.88 ,
~
110.01 , 65.89 , 61.60 , 54.87 , 50.36 , 15.84; FT-IR:  = 2987, 2933,
1734, 1732, 1476, 1382, 1319, 1132 cm-1; M.p. 86-88 °C; HRMS (ESI):
m/z calcd for: [M+H]+: C27H29N2O5; Exact Mass: 461.2071; found:
461.2070
114.07 (d, J = 4.5 Hz), 111.75 (d, J = 27.9 Hz), 110.84 (d, J = 10.5 Hz),
~
61.73 , 61.52 , 51.54 , 50.71 , 15.79 , 14.20; FT-IR:  = 2980, 2937,
1733, 1731, 1442, 1378, 1299, 1144 cm-1; M.p. 98-100 °C; HRMS (ESI):
m/z calcd for: [M+H]+: C25H28FN2O5; Exact Mass: 455.1977; found:
455.1974.
(E)-1-Ethyl
3-(2,2,2-trifluoroethyl)
2-(1-benzyl-3-(1-
(methoxyimino)ethyl)-1H-indol-4-yl)malonate (3g); Colorless liquid,
76%; 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.33 – 7.23 (m, 6H), 7.16
– 7.08 (m, 3H), 5.30 (s, 2H), 4.59 (m, 1H), 4.49 (m, 1H), 4.34 – 4.16 (m,
2H), 4.02 (s, 3H), 2.26 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (125
MHz, CDCl3) δ 168.70 , 168.06 , 152.00 , 137.90 , 136.44 , 131.05 ,
129.01 , 128.05 , 126.96 , 125.93 , 124.38 , 122.96 (q, J =273.2 Hz),
(E)-Diethyl
2-(1-benzyl-6-methoxy-3-(1-(methoxyimino)ethyl)-1H-
indol-4-yl)malonate (3m): colourless oil, 82%; 1H NMR (400 MHz,
CDCl3) δ 7.36 – 7.27 (m, 3H), 7.20 (s, 1H), 7.12 (dd, J = 7.4, 1.7 Hz, 2H),
6.94 (d, J = 2.2 Hz, 1H), 6.73 (s, 1H), 6.67 (d, J = 2.3 Hz, 1H), 5.22 (s,
2H), 4.23 (p, J = 7.2 Hz, 4H), 4.00 (s, 3H), 3.77 (s, 3H), 2.22 (s, 3H), 1.27
(t, J = 7.1 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 169.26 , 156.50 ,
151.96 , 138.75 , 136.53 , 129.74 , 129.73 , 128.96 , 127.95 , 127.81 ,
122.93 , 122.01 , 113.84 , 110.44 , 61.83 , 61.58 , 60.94 (q, J = 36.7 Hz),
~
54.68 , 50.46 , 15.65 , 14.10 ; FT-IR:  = 2996, 2935, 1734, 1731, 1434,
1380, 1322, 1189 cm-1; HRMS (ESI): m/z calcd for: [M+H]+:
C25H26F3N2O5; Exact Mass: 491.1788; found: 491.1787.
127.00 , 119.06 , 113.97 , 111.39 , 93.71 , 61.58 , 61.44 , 55.66 , 55.19 ,
~
50.38 , 15.68 , 14.20; FT-IR: 
= 2926, 2853, 1727, 1619, 1537, 1454,
(E)-Diethyl 2-(3-(1-(methoxyimino)ethyl)-1-(2,4,6-trimethylbenzyl)-1H-
indol-4-yl)malonate (3h); White solid, 86%; 1H NMR (400 MHz, CDCl3)
δ 7.50 (dd, J = 7.9, 1.3 Hz, 1H), 7.40 – 7.18 (m, 2H), 6.97 (s, 2H), 6.73 (s,
1H), 6.63 (s, 1H), 5.19 (s, 2H), 4.49 – 4.12 (m, 4H), 3.98 (s, 3H), 2.35 (s,
3H), 2.23 (s, 6H), 2.11 (s, 3H), 1.28 (t, J = 7.1 Hz, 6H).13C NMR (100
MHz, CDCl3) δ 169.48 , 152.28 , 138.56 , 138.28 , 137.90 , 129.59 ,
1273, 1152 cm-1; HRMS (ESI): m/z calcd for: [M+H]+: C26H31N2O6; Exact
Mass: 467.2177; found: 467.2187.
(E)-Diethyl 2-(1-benzyl-6-chloro-3-(1-(methoxyimino)ethyl)-1H-indol-
4-yl)malonate (3n); White solid, 85%; 1H NMR (400 MHz,CDCl3) δ 7.49
– 7.30 (m, 3H), 7.29 – 7.23 (m, 3H), 7.12 (dd, J = 7.2, 1.8 Hz, 2H), 6.66
(s, 1H), 5.25 (s, 2H), 4.25 (m, 4H), 4.01 (s, 3H), 2.24 (s, 3H), 1.28 (t, J =
7.1 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 168.90 , 151.61 , 138.15 ,
136.00 , 131.11 , 129.12 , 128.85 , 128.23 , 128.22 , 126.98 , 123.30 ,
122.50 , 114.31 , 109.96 , 61.71 , 61.68 , 54.94 , 50.51 , 15.93 , 14.18;
FT-IR:  = 2977, 2936, 1735, 1503, 1437, 1370, 1305, 1152 cm-1; M.p.
127.98 , 127.94 , 126.76 , 124.72 , 122.56 , 121.87 , 113.29 , 109.51 ,
~
55.12 , 44.01 , 21.19 , 19.75 , 16.24 , 14.20 ; FT-IR:  = 2941, 1736,
1731, 1534, 1451, 1397, 1332, 1048 cm-1; M.p. 121-124 °C; HRMS
(ESI): m/z calcd for: [M+H]+: C28H35N2O5; Exact Mass: 479.2540;
found:479.2548.
~
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701755
European Journal of Organic Chemistry
FULL PAPER
81-83 °C; HRMS (ESI): m/z calcd for: [M+H]+: C25H28ClN2O5; Exact
Mass: 471.1681; found:471.1687.
– 7.98 (m, 1H), 7.96 – 7.83 (m, 1H), 7.63 (s, 1H), 7.43 – 7.20 (m, 6H),
7.14 – 7.07 (m, 2H), 6.41 (s, 1H), 5.79 (s, 2H), 4.37 – 4.12 (m, 4H), 4.04
(s, 3H), 2.29 (s, 3H), 1.29 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3)
δ 169.20 , 152.46 , 136.97 , 131.32 , 131.30 , 130.58 , 129.45 , 129.20 ,
(E)-Diethyl 2-(1-benzyl-3-(1-(methoxyimino)ethyl)-6-(trifluoromethyl)-
1H-indol-4-yl)malonate (3o): Colourless oil, 69%; 1H NMR (400 MHz,
CDCl3) δ 7.55 (s, 1H), 7.50 (d, J = 1.3 Hz, 1H), 7.40 (s, 1H), 7.38 – 7.27
(m, 3H), 7.13 (dd, J = 7.2, 1.9 Hz, 2H), 6.62 (s, 1H), 5.34 (s, 2H), 4.25
(qd, J = 7.2, 2.3 Hz, 4H), 4.01 (s, 3H), 2.24 (s, 3H), 1.27 (t, J = 7.1 Hz,
6H). 13C NMR (100 MHz, CDCl3) δ 168.77 , 151.43 , 136.85 , 135.76 ,
132.59 , 129.21 , 128.41 , 127.88 , 127.13 ,126.84, 124.93 (J = 32 Hz),
127.89 , 126.26 , 125.96 , 125.74 , 124.16 , 123.05 , 122.08 , 120.92,
~
115.05 , 61.77, 61.63, 55.13 , 54.15 , 17.14 , 14.24 ; FT-IR:  = 2986,
2940, 1744, 1700, 1530, 1394, 1322, 1096 cm-1; M.p. 117-119 °C; HRMS
(ESI): m/z calcd for: [M+H]+: C29H31N2O5; Exact Mass: 487.2227; found:
487.2233
124.82 (q, J = 272 Hz), 118.50 (q, J = 3.7 Hz), 114.58 , 107.36 (q, J = 4.0
(E)-Diethyl
2-(1-benzyl-3-((methoxyimino)methyl)-1H-indol-4-
~
yl)malonate (3u); Colorless oil, 96%; 1H NMR (400 MHz, CDCl3) δ 8.29
(s, 1H), 7.38 (s, 1H), 7.33 – 7.21 (m, 6H), 7.13 (d, J = 6.8 Hz, 2H), 6.54 (s,
Hz), 61.79 , 61.73 , 55.08 , 50.60 , 16.12 , 14.16; FT-IR: 
=2927, 2853,
1729, 1455, 1391, 1294, 1209, 1157 cm-1; HRMS (ESI): m/z calcd for:
[M+H]+: C26H28F3N2O5; Exact Mass: 505.1945; found: 505.1954.
1H), 5.28 (s, 2H), 4.25 (m, 4H), 3.96 (s, 3H), 1.28 (t, J = 7.2 Hz, 6H). 13
C
NMR (125 MHz, CDCl3) δ 169.33 , 144.44 , 138.28 , 136.20 , 132.66 ,
129.04 , 128.14 , 127.13 , 126.94 , 124.99 , 123.26 , 122.31 , 110.28 ,
(E)-Diethyl
2-(1-benzyl-6-(methoxycarbonyl)-3-(1-
~
109.06 , 61.67 , 61.62 , 55.71 , 50.53 , 14.19; FT-IR:  = 2993, 2946,
(methoxyimino)ethyl)-1H-indol-4-yl)malonate (3p): Colourless oil,
77%; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 1.4 Hz, 1H), 7.93 (d, J =
1.3 Hz, 1H), 7.40 (s, 1H), 7.36 – 7.27 (m, 3H), 7.13 (dd, J = 7.4, 1.9 Hz,
2H), 6.56 (s, 1H), 5.36 (s, 2H), 4.25 (m, 4H), 4.01 (s, 3H), 3.89 (s, 3H),
2.23 (s, 3H), 1.28 (t, J = 7.2 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
169.02 , 167.58 , 151.52 , 137.30 , 136.06 , 133.00 , 129.14 , 128.29 ,
1755, 1712, 1535, 1391, 1318, 1131 cm-1; HRMS (ESI): m/z calcd for:
[M+H]+: C24H27N2O5; Exact Mass: 423.1914; found: 423.1914.
(E)-Diethyl
2-(1-benzyl-3-(1-(methoxyimino)propyl)-1H-indol-4-
yl)malonate (3v); Colourless oil, 73%; 1H NMR (400 MHz, CDCl3) δ 7.38
– 7.16 (m, 7H), 7.13 (dd, J = 7.7, 1.7 Hz, 2H), 6.55 (s, 1H), 5.31 (s, 2H),
4.22 (qq, J = 10.8, 7.1 Hz, 4H), 4.00 (s, 3H), 2.72 (q, J = 7.6 Hz, 2H),
1.26 (t, J = 7.1 Hz, 6H), 1.11 (t, J = 7.6 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 169.37 , 157.36 , 137.73 , 136.61 , 130.08 , 128.98 , 127.99 ,
127.88 ,127.87,127.17 , 126.93 , 124.60 , 122.61 , 114.57 , 112.15 ,
~
61.77 , 61.64 , 55.19 , 52.18 , 50.48 , 16.17 , 14.20; FT-IR: 
=2983,
2936, 1715, 1615, 1434, 1388, 1226, 1152 cm-1; HRMS (ESI): m/z calcd
for: [M+H]+: C27H31N2O7; Exact Mass: 495.2126; found: 495.2137.
127.02 , 126.74 , 125.10 , 122.79 , 121.94 , 112.36 , 110.01 , 61.64 ,
~
61.46 , 54.74 , 50.45 , 23.75 , 14.19 , 11.42 ; FT-IR:  = 2938, 1741,
(E)-Diethyl 2-(1-benzyl-7-bromo-3-(1-(methoxyimino)ethyl)-1H-indol-
4-yl)malonate (3q): White solid (92%): 1H NMR (400 MHz, CDCl3) δ 7.41
(d, J = 8.1 Hz, 1H), 7.35 – 7.25 (m, 3H), 7.23 (s, 1H), 7.10 (d, J = 8.1 Hz,
1H), 7.07 – 6.98 (m, 2H), 6.33 (s, 1H), 5.84 (s, 2H), 4.23 (qd, J = 7.1, 5.3
Hz, 4H), 4.00 (s, 3H), 2.22 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 168.89 , 151.74 , 138.20 , 133.73 , 133.28 , 128.89 ,
1728, 1537, 1453, 1371, 1289, 1151 cm-1; HRMS (ESI): m/z calcd for:
[M+H]+: C26H31N2O5; Exact Mass: 451.2227; found: 451.2229
(E)-Diethyl
2-(1-benzyl-3-(1-(methoxyimino)-2-methylpropyl)-1H-
indol-4-yl)malonate (3w); Colourless oil, 71%;1H NMR (400 MHz,
CDCl3) δ 7.37 – 7.17 (m, 6H), 7.17 – 7.10 (m, 3H), 5.86 (s, 1H), 5.31 (s,
2H), 4.31 – 4.11 (m, 4H), 3.97 (s, 3H), 3.60 (hept, J = 7.0 Hz, 1H), 1.26 (t,
J = 7.1 Hz, 6H), 1.11 (d, J = 7.0 Hz, 6H).13C NMR (125 MHz, CDCl3) δ
169.04 , 161.18 , 136.87 , 136.80 , 128.99 , 128.70 , 127.97 , 127.05 ,
128.37 , 127.68 , 127.59 , 126.44 , 126.17 , 122.87 , 114.17 , 104.12 ,
~
61.78 , 61.66 , 54.52 , 52.05 , 16.82 , 14.18; FT-IR: 
= 2975, 2871,
1735, 1537, 1446, 1366, 1241, 1033 cm-1; M.p. 133-136 °C; HRMS
(ESI): m/z calcd for: [M+H]+: C25H2879BrN2O5; Exact Mass: 515.1176;
found: 515.1168.
126.15 , 125.88 , 122.50 , 121.68 , 109.91 , 109.40 , 61.76 , 61.63 ,
~
53.95 , 50.43 , 28.92 , 19.77 , 14.18; FT-IR:  = 2941, 1739,1537, 1462,
1377, 1309, 1148 cm-1; HRMS (ESI): m/z calcd for: [M+H]+: C27H33N2O5;
(E)-Diethyl 2-(1-benzyl-3-(1-(methoxyimino)ethyl)-7-methyl-1H-indol-
4-yl)malonate (3r); White solid, 90%; 1H NMR (400 MHz, CDCl3) δ 7.34
– 7.22 (m, 3H), 7.19 (s, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 7.2 Hz,
3H), 6.39 (s, 1H), 5.57 (s, 2H), 4.60 – 4.11 (m, 4H), 4.01 (s, 3H), 2.51 (s,
3H), 2.24 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ
169.44 , 152.26 , 138.79 , 136.32 , 132.29 , 129.07 , 127.68 , 126.00 ,
Exact Mass: 465.2384; found: 465.2370
(E)-Diethyl
2-(1-benzyl-3-((benzyloxyimino)ethyl)-1H-indol-4-
yl)malonate (3x); Yellow oil, 69%; 1H NMR (400 MHz, CDCl3) δ 7.48 –
7.43 (m, 2H), 7.41 – 7.27 (m, 7H), 7.24 (m, 3H), 7.13 (dd, J = 7.5, 1.8 Hz,
2H), 6.72 (s, 1H), 5.36 (s, 2H), 5.28 (s, 2H), 4.21 (qd, J = 7.1, 5.2 Hz, 4H),
2.30 (s, 3H), 1.25 (t, J = 7.1 Hz, 6H).13C NMR (100 MHz, CDCl3) δ
169.48 , 152.53 , 138.37 , 137.85 , 136.54 , 130.69 , 129.00 , 128.44 ,
128.18 , 128.04 , 127.76 , 127.08 , 126.24 , 124.59 , 122.87 , 121.92 ,
125.66 , 125.49 , 124.56 , 121.86 , 121.22 , 113.91 , 61.69 , 61.45 ,
~
54.82 , 52.73 , 19.79 , 16.73 , 14.23; FT-IR:  = 2967, 2939, 1736,
1728, 1443, 1378, 1306, 1130 cm-1; M.p. 92-93 °C; HRMS (ESI): m/z
calcd for: [M+H]+: C26H31N2O5; Exact Mass: 451.2227; found: 451.2228
113.95 , 110.00 , 75.89 , 61.44 , 55.20 , 50.47 , 16.38 , 14.23 ; FT-IR:
~
 = 2936, 1732, 1536, 1507, 1452, 1394, 1300, 1150 cm-1; HRMS
(E)-Diethyl 2-(1-benzyl-3-(1-(methoxyimino)ethyl)-2-phenyl-1H-indol-
4-yl)malonate (3s); Colourless oil, 84%; 1H NMR (400 MHz, CDCl3) δ
7.38 (s, 5H), 7.28 – 7.13 (m, 6H), 6.96 (dd, J = 7.4, 1.8 Hz, 2H), 5.98 (s,
1H), 5.27 (s, 2H), 4.35 – 4.15 (m, 4H), 4.02 (s, 3H), 1.78 (s, 3H), 1.28 (t,
J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 168.99 , 154.09 , 140.71 ,
137.49 , 137.11 , 131.25 , 130.57 , 128.89 , 128.78 , 128.63 , 127.41 ,
(ESI): m/z calcd for: [M+H]+: C31H33N2O5; Exact Mass: 513.2384;
found:513.2381
Analytical data for C-2 annulated products:
126.29 , 125.50 , 124.78 , 122.50 , 121.59 , 112.28 , 110.75 , 61.81 ,
2,2,2-Trifluoroethyl 5-benzyl-2-methoxy-1-methyl-3-oxo-3,5-dihydro-
2H-pyrido[4,3-b]indole-4-carboxylate(4a); Yellow solid, 87%; 1H NMR
(600 MHz, DMSO-d6) δ 8.00 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H),
7.37 (t, J = 7.6 Hz, 1H), 7.30 – 7.24 (m, 3H), 7.24 – 7.17 (m, 1H), 7.02 –
6.92 (m, 2H), 5.36 (s, 2H), 4.68 (q, J = 8.9, 2H), 4.04 (s, 3H), 2.95 (s, 3H).
13C NMR (150 MHz, DMSO-d6) δ 164.40 , 155.00 , 144.80 , 144.79 ,
142.84 , 135.76 , 128.55 , 127.27 , 126.29 , 125.97 , 123.21(q, J = 279
~
61.60 , 54.07 , 47.83 , 17.76 , 14.20 ; FT-IR:  = 2989, 2947, 1736,
1453, 1372, 1300, 1159 cm-1; HRMS (ESI): m/z calcd for: [M+H]+:
C31H33N2O5; Exact Mass: 513.2384; found: 513.2385
(E)-Diethyl 2-(1-benzyl-3-(1-(methoxyimino)ethyl)-1H-benzo[g]indol-
4-yl)malonate (3t); White solid, 93%; 1H NMR (400 MHz, CDCl3) δ 8.06
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10.1002/ejoc.201701755
European Journal of Organic Chemistry
FULL PAPER
Hz), 121.96 , 120.91 , 110.15 , 105.87 , 95.90 , 64.00 , 60.57 (q, J = 35.4
105.60 , 96.09 , 64.08 , 60.63 (q, J = 34.9 Hz), 46.58 , 14.55 ; FT-IR:
~
~
Hz), 46.44 , 14.33 ; 19F NMR (376 MHz, DMSO-d6) δ -71.82 FT-IR:  =
 = 2942, 1745, 1641, 1481, 1291, 1163, 1105, 782 cm-1; M.p. 182–
2954, 1744, 1648, 1572, 1472, 1280, 1156 cm-1; M.p. 143-149 °C; HRMS
(ESI): m/z calcd for: [M+H]+: C23H20F3N2O4; Exact Mass: 445.1370;
found: 445.1371.
186 °C; HRMS (ESI): m/z calcd for: [M+H]+: C27H22F3N2O4S: Exact Mass:
527.1247; found: 527.1253.
2,2,2-Trifluoroethyl 5-benzyl-2-methoxy-1-methyl-3-oxo-8-(thiophen-
3-yl)-3,5-dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4h); Yellow
solid, 92%; 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.93 (s, 1H),
7.72 (d, J = 8.4 Hz, 1H), 7.68 – 7.61 (m, 2H), 7.45 (d, J = 8.5 Hz, 1H),
7.25 (dt, J = 14.8, 6.9 Hz, 3H), 6.99 (d, J = 7.3 Hz, 2H), 5.37 (s, 2H), 4.68
(q, J = 8.8 Hz, 2H), 4.05 (s, 3H), 3.03 (s, 3H). 13C NMR (125 MHz,
DMSO-d6) δ 164.84 , 155.46 , 145.78 , 145.55 , 142.55 , 142.07 , 136.24 ,
130.09 , 129.08 , 127.80 , 127.36 , 127.11 , 126.49 , 125.26 , 123.71 (q,
2,2,2-Trifluoroethyl
5-benzyl-2-methoxy-1,6-dimethyl-3-oxo-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate(4n); Yellow solid, 59%;
1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 7.7 Hz, 1H), 7.29 – 7.19 (m,
3H), 7.19 – 7.08 (m, 2H), 6.91 – 6.81 (m, 2H), 5.47 (brs, 2H), 4.49 (brs,
2H), 4.01 (s, 3H), 2.94 (s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz, DMSO-
d6) δ 164.97 , 155.58 , 146.13 , 144.59 , 141.53 , 137.87 , 130.77 ,
129.17 , 127.63 , 125.44 , 123.59 (q, J = 279 Hz), 123.57 , 122.61 ,
121.22 , 119.71 , 106.47 , 96.75 , 64.51 , 61.01 (q, J = 35.1 Hz), 49.04 ,
J = 276.3 Hz) 123.10 , 120.88 , 118.86 , 110.99 , 106.32 , 96.46 , 64.53 ,
~
~
19.56 , 14.77; FT-IR:  = 2959, 2852, 1744, 1650, 1602, 1581, 1463,
61.08 (q, J = 35.2 Hz), 47.02 , 15.05 ; FT-IR:  =2937, 1742, 1641,
1271, 1155 cm-1; M.p. 166-169 °C; HRMS (ESI): m/z calcd for: [M+H]+:
1493, 1283, 1155, 1097 cm-1; M.p. 187-189 °C; HRMS (ESI): m/z calcd
C24H22F3N2O4; Exact Mass: 459.1526; found: 459.1531.
for: [M+H]+: C27H22F3N2O4S: Exact Mass: 527.1247; found: 527.1252.
2,2,2-Trifluoroethyl 5-benzyl-7-chloro-2-methoxy-1-methyl-3-oxo-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4m); Yellow solid,
90%; 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 8.3 Hz, 1H), 7.57 (d, J
= 1.9 Hz, 1H), 7.40 – 7.13 (m, 4H), 7.02 – 6.88 (m, 2H), 5.35 (s, 2H),
4.64 (q, J = 9.0 Hz, 2H), 4.01 (s, 3H), 2.92 (s, 3H). 13C NMR (100 MHz,
DMSO-d6) δ 164.14 , 154.94 , 145.37 , 145.12 , 143.87 , 135.47 , 130.84 ,
128.64 , 127.37 , 125.92 , 123.18 (q, J = 279.1 Hz), 122.09 , 121.89 ,
2,2,2-Trifluoroethyl 5-benzyl-8-(4-fluorophenyl)-2-methoxy-1-methyl-
3-oxo-3,5-dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4f); Yellow
solid, (89%): 1H NMR (600 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.79 (ddd, J =
8.5, 5.5, 2.5 Hz, 2H), 7.63 (dt, J = 8.3, 2.2 Hz, 1H), 7.48 (ddd, J = 7.9, 4.8,
1.9 Hz, 1H), 7.34 – 7.25 (m, 4H), 7.22 (t, J = 7.3 Hz, 1H), 7.00 (d, J = 7.5
Hz, 2H), 5.38 (s, 2H), 4.68 (q, J = 9.0 Hz, 2H), 4.05 (s, 3H), 3.03 (s, 2H).
13C NMR (150 MHz, DMSO-d6) δ 164.34 , 161.67 (d, J = 244.2 Hz),
155.01 , 145.32 , 145.13 , 136.86 , 135.72 , 133.47 , 128.90 (d, J = 8.2
Hz), 128.60 , 128.55 , 127.32 , 125.98 , 125.26 , 123.61 (d, J = 277.3 Hz),
122.73 , 119.08 , 115.60 (d, J = 21.2 Hz), 110.56 , 105.83 , 96.05 , 64.08 ,
120.96 , 110.34 , 105.21 , 96.41 , 64.07 , 60.66 (q, J = 35.3 Hz), 46.51 ,
~
14.44 ; FT-IR:  = 2967, 1741, 1632, 1571, 1475, 1279, 1151 cm-1; M.p.
167- 171°C; HRMS (ESI): m/z calcd for: [M+H]+: C23H1935ClF3N2O4; Exact
Mass: 479.0980; found:479.0976.
60.5 (d, J = 35.5 Hz), 46.58 , 14.50; 19F NMR (376 MHz, DMSO-d6) δ -
~
71.82 , -121.22; FT-IR:  = 2953, 1737, 1632, 1481, 1295, 1163, 1102
cm-1; M.p. 209–211 °C; HRMS (ESI): m/z calcd for: [M+H]+:
2,2,2-Trifluoroethyl 5-benzyl-8-bromo-2-methoxy-1-methyl-3-oxo-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4j); Yellow solid, 85 %;
1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H),
7.39 (d, J = 8.5 Hz, 1H), 7.34 – 7.18 (m, 3H), 6.96 (d, J = 7.0 Hz, 2H),
5.35 (s, 2H), 4.67 (q, J = 9.0 Hz, 2H), 4.03 (s, 3H), 2.95 (s, 3H). 13C NMR
(150 MHz, DMSO-d6) δ 164.14 , 154.96 , 146.08 , 144.95 , 141.85 ,
135.45 , 128.70 , 128.59 , 127.35 , 125.93 , 124.10 , 123.24 (q, J = 279.3
C29H23F4N2O4; Exact Mass: 539.1588; found: 539.1598.
2,2,2-Trifluoroethyl
5-benzyl-2-methoxy-8-(4-methoxyphenyl)-1-
methyl-3-oxo-3,5-dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4e);
Yellow solid, (88%): 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.68
(dd, J = 8.7, 2.0 Hz, 2H), 7.60 (dt, J = 8.8, 2.2 Hz, 1H), 7.45 (dd, J = 8.9,
4.2 Hz, 1H), 7.35 – 7.13 (m, 3H), 7.12 – 6.92 (m, 4H), 5.37 (s, 2H), 4.68
(q, J = 9.1 Hz, 2H), 4.04 (s, 3H), 3.80 (s, 3H), 3.02 (s, 3H). 13C NMR (125
MHz, DMSO-d6) δ 164.42 , 158.66 , 155.03 , 145.23 , 145.09 , 141.98 ,
135.80 , 134.30 , 132.84 , 128.64 , 128.06 , 127.35 , 126.03 , 124.92 ,
Hz), 123.13 , 114.20 , 112.06 , 104.83 , 95.97 , 64.12 , 60.61 (d, J = 35.4
~
Hz), 46.59 , 14.51; FT-IR:  = 2958, 1747, 1649, 1575, 1477, 1331,
1281, 1143 cm-1; M.p. 187-191 °C; HRMS (ESI): m/z calcd for: [M+H]+:
C23H1979BrF3N2O4; Exact Mass: 523.0475; found: 523.0477.
123.26 (q, J = 278.5 Hz) 122.71 , 118.64 , 114.36 , 110.54 , 105.95 ,
~
95.98 , 64.10 , 60.63 (q, J = 35.7 Hz), 55.19 , 46.58 , 14.53; FT-IR:  =
2,2,2-Trifluoroethyl
oxo-3,5-dihydro-2H-pyrido[4,3-b]indole-4-carboxylate(4c);
5-benzyl-8-cyclopropyl-2-methoxy-1-methyl-3-
White
2931, 1739, 164o, 1491, 1279, 1144, 1096 cm-1; M.p. 199-201 °C; HRMS
(ESI): m/z calcd for: [M+H]+: C30H26F3N2O5: Exact Mass: 551.1788;
found:551.1787.
solid, 91%; 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 1.7 Hz, 1H),
7.34 – 7.15 (m, 4H), 7.04 (dd, J = 8.5, 1.6 Hz, 1H), 6.95 (d, J = 7.2 Hz,
3H), 5.30 (s, 2H), 4.66 (q, J = 9.0 Hz, 2H), 4.02 (s, 3H), 2.95 (s, 3H), 2.07
(m, 1H), 1.01 – 0.86 (m, 2H), 0.78 – 0.60 (m, 2H). 13C NMR (125 MHz,
DMSO-d6) δ 164.48 , 155.01 , 144.92 , 144.81 , 141.10 , 137.44 , 135.88 ,
128.59 , 127.30 , 126.01 , 123.54 , 123.25 (d, J = 279.6 Hz), 122.09 ,
2,2,2-Trifluoroethyl
5-benzyl-2-methoxy-1,8-dimethyl-3-oxo-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4b); Yellow solid,
(93%): 1H NMR (600 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.30 (d, J = 8.3 Hz,
1H), 7.25 (t, J = 7.3 Hz, 2H), 7.19 (dd, J = 16.6, 7.9 Hz, 2H), 6.96 (d, J =
7.3 Hz, 2H), 5.32 (s, 2H), 4.66 (q, J = 9.0 Hz, 2H), 4.03 (s, 3H), 2.95 (s,
3H), 2.43 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 164.42 , 154.95 ,
144.89 , 144.68 , 141.03 , 135.83 , 131.09 , 128.51 , 127.22 , 127.14 ,
118.26 , 110.04 , 105.87 , 95.68 , 64.04 , 60.58 (d, J = 35.3 Hz), 46.49 ,
~
15.16 , 14.46 , 9.27 ; FT-IR:  = 2937, 1738, 1636, 1402, 1334, 1284,
1168 cm-1; M.p. 168–171 °C; HRMS (ESI): m/z calcd for: [M+H]+:
C26H24F3N2O4: Exact Mass: 485.1683; found: 485.1694.
125.96 , 123.2 (q, J = 281 Hz), 122.10 , 121.15 , 109.88 , 105.83 , 95.65 ,
~
63.98 , 60.52 (q, J = 35.2 Hz), 46.43 , 20.88 , 14.36; FT-IR:  = 2957,
2,2,2-Trifluoroethyl 5-benzyl-2-methoxy-1-methyl-3-oxo-8-(thiophen-
2-yl)-3,5-dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4g); Yellow
solid, 93%; 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.62 (d, J = 8.5
Hz, 1H), 7.56 (d, J = 3.3 Hz, 1H), 7.51 (d, J = 5.0 Hz, 1H), 7.43 (d, J = 8.5
Hz, 1H), 7.27 – 7.18 (m, 3H), 7.16 – 7.10 (m, 1H), 6.97 (d, J = 7.4 Hz,
2H), 5.35 (s, 2H), 4.66 (q, J = 9.1 Hz, 2H), 4.03 (s, 3H), 3.00 (s, 3H). 13C
NMR (125 MHz, DMSO-d6) δ 164.30 , 154.99 , 145.53 , 145.09 , 143.57 ,
142.38 , 135.67 , 128.62 , 128.46 , 128.13 , 127.35 , 125.99 , 125.13 ,
124.27 , 123.54 , 132.22 (q, J = 278.7 Hz), 122.79 , 117.69 , 110.75 ,
1755, 1639, 1571, 1399, 1277, 1184 cm-1; M.p. 182-187 °C; HRMS
(ESI): m/z calcd for: [M+H]+: C24H22F3N2O4: Exact Mass: 459.1526;
found:459.1523.
2,2,2-Trifluoroethyl
5-benzyl-2,8-dimethoxy-1-methyl-3-oxo-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4d); Yellow solid,
(87%): 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 2.4 Hz, 1H), 7.33 (d,
J = 8.8 Hz, 1H), 7.29 – 7.16 (m, 3H), 7.05 – 6.92 (m, 3H), 5.30 (s, 2H),
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10.1002/ejoc.201701755
European Journal of Organic Chemistry
FULL PAPER
4.66 (q, J = 9.0 Hz, 2H), 4.02 (s, 3H), 3.83 (s, 3H), 2.94 (s, 3H). 13C NMR
(150 MHz, DMSO-d6) δ 164.44 , 155.13 , 154.96 , 145.20 , 145.12 ,
137.25 , 135.90 , 128.56 , 127.27 , 126.02 , 123.24 (q, J = 280.1 Hz),
2.2 Hz, 1H), 7.23 – 7.28 (m, 5H), 7.18 (td, J = 6.5, 2.2 Hz, 1H), 5.04 (q, J
= 9.0 Hz, 2H), 4.02 (s, 3H), 3.45 (s, 3H), 3.06 – 2.97 (m, 2H), 2.97 – 2.90
(m, 2H), 2.88 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 164.22 , 154.90 ,
145.87, 144.62 , 141.66 , 141.55 , 135.14 , 128.50, 128.21 , 126.68 ,
125.81,123.64 (q, J = 278.7 Hz), 121.77, 120.59 , 109.47 , 105.61 ,
122.86 , 113.01 , 110.81 , 106.08 , 105.89 , 95.40 , 64.05 , 60.53 (q, J =
~
34.9 Hz), 55.78 , 46.55 , 14.36 ; FT-IR:  = 2934, 1758, 1640, 1567,
1382, 1298, 1181 cm-1; M.p. 175-177 °C; HRMS (ESI): m/z calcd for:
94.63 , 63.99 , 60.48 (q, J = 34.7 Hz), 37.76 , 37.01 , 31.24 , 14.38 ; FT-
~
[M+H]+: C24H22F3N2O5: Exact Mass: 475.1475: found: 475.1475.
IR:  = 2952 , 1751, 1712, 1683 , 1560, 1385, 1274,1085 cm-1; M.p.
156–158 °C; HRMS (ESI): m/z calcd for: [M+H]+: C25H24F3N2O4; Exact
Mass: 473.1683; found: 473.1681.
2,2,2-Trifluoroethyl 5-benzyl-8-cyano-2-methoxy-1-methyl-3-oxo-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4k); Yellow solid,
(43%): 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 1.5 Hz, 1H), 7.81 (dd,
J = 8.5, 1.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.33 – 7.16 (m, 3H), 6.97 (d,
J = 6.5 Hz, 2H), 5.41 (s, 2H), 4.67 (q, J = 9.0 Hz, 2H), 4.04 (s, 3H), 3.00
(s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 163.95 , 155.02 , 146.71 ,
2,2,2-Trifluoroethyl
2-methoxy-1,5-dimethyl-3-oxo-8-phenyl-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4q); Yellow solid,
(87%): 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 1.9 Hz, 1H), 7.74 (d,
J = 7.5 Hz, 2H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H),
7.47 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 5.04 (q, J = 9.1 Hz, 2H),
4.01 (s, 3H), 3.49 (s, 3H), 2.96 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ
164.15 , 154.92 , 146.02 , 145.15 , 142.72 , 140.39 , 134.12 , 128.89 ,
126.97 , 126.91 , 125.14 ,123.61 (q, J = 278.0 Hz) 122.47 , 118.81 ,
145.34
, 145.29 , 135.19 , 130.27 , 128.69 , 127.49 , 125.94 ,
124.90 ,123.15 (q, J = 276.1 Hz) 122.64 , 119.53 , 111.12 , 104.67 ,
~
104.16 , 96.83 , 64.20 , 60.75 (q, J = 35.4 Hz), 46.74 , 14.61; FT-IR:  =
2951, 2236, 1755, 1649, 1563, 1389, 1273,1151 cm-1; M.p.189–191 °C;
HRMS (ESI): m/z calcd for: [M+H]+: C24H19F3N3O4; Exact Mass:
470.1322; found: 470.1325.
110.15 , 105.56 , 94.98 , 64.05 , 60.53 (q, J = 35.0 Hz), 31.30 , 14.46 ;
~
FT-IR:  = 2954, 1756, 1682, 1566, 1392, 1268, 1182 cm-1; M.p. 184–
186 °C; HRMS (ESI): m/z calcd for: [M+H]+: C23H20F3N2O4; Exact Mass:
445.1370; found: 445.1377.
8-Methyl 4-(2,2,2-trifluoroethyl) 5-benzyl-2-methoxy-1-methyl-3-oxo-
3,5-dihydro-2H-pyrido[4,3-b]indole-4,8-dicarboxylate (4l); Yellow
solid, (77 %): 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 1.5 Hz, 1H),
7.97 (dd, J = 8.6, 1.4 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.24 (ddd, J =
13.1, 7.9, 6.2 Hz, 3H), 7.05 – 6.81 (m, 2H), 5.39 (s, 2H), 4.65 (q, J = 9.0
Hz, 2H), 4.03 (s, 3H), 3.87 (s, 3H), 2.97 (s, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 166.23 , 164.07 , 155.01 , 146.11 , 145.87 , 145.41 , 135.36 ,
128.70 , 127.74 , 127.47 , 125.94 , 123.39 (q, J = 278.4 Hz), 123.24 ,
2,2,2-Trifluoroethyl 8-methoxy-7,11-dimethyl-9-oxo-9,11-dihydro-8H-
benzo[g]pyrido[4,3-b]indole-10-carboxylate(4s); Yellow solid, (81%):
1H NMR (500 MHz, DMSO-d6) δ 8.51 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 9.0
Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.67 – 7.61 (m,
1H), 7.58 (t, J = 7.4 Hz, 1H), 5.08 (q, J = 9.2 Hz, 2H), 4.06 (s, 3H), 3.87
(s, 3H), 3.03 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 163.93 , 154.75 ,
148.68 , 146.08 , 138.54 , 132.67 , 129.10 , 126.25 , 125.42, 123.69 (q, J
122.20 , 121.75 , 110.25 , 105.24 , 96.84 , 64.17 , 60.74 (q, J = 35.3 Hz),
~
52.20 , 46.75 , 14.59; FT-IR:  = 2952, 1756, 1701, 1640, 1568, 1394,
= 278.2 Hz), 123.18 , 122.02 , 121.01 , 119.03 , 118.85 , 106.24 , 94.76 ,
~
1276, 1178 cm-1; M.p. 166-168 °C; HRMS (ESI): m/z calcd for: [M+H]+:
64.04, 60.20 (q, J = 34.9 Hz), 38.63 , 14.58; FT-IR:  = 2929, 1736,
C25H22F3N2O6; Exact Mass: 503.1424; found: 503.1431.
1641, 1421, 1357, 1281, 1165, 1032 cm-1; M.p. 157–160 °C; HRMS
(ESI): m/z calcd for [M+H]+: C21H17F3N2O4 :Exact Mass: 419.1213; found:
419.1217.
2,2,2-Trifluoroethyl 5-benzyl-8-fluoro-2-methoxy-1-methyl-3-oxo-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4i); Yellow solid,
(82 %): 1H NMR (400 MHz, DMSO-d6) δ 7.84 (dd, J = 9.5, 2.5 Hz, 1H),
7.43 (dd, J = 8.9, 4.3 Hz, 1H), 7.33 – 7.15 (m, 4H), 7.03 – 6.79 (m, 2H),
5.35 (s, 2H), 4.67 (q, J = 9.0 Hz, 2H), 4.03 (s, 2H), 2.94 (s, 3H). 13C NMR
(125 MHz, DMSO-d6) δ 164.27 , 158.16 (d, J = 236.3 Hz), 155.00 ,
146.06 , 145.44 , 139.21 , 135.66 , 128.64 , 127.38 , 126.03 , 123.24 (d,
J = 275.3 Hz), 123.03 (d, J = 9.9 Hz), 113.18 (d, J = 24.9 Hz), 111.19 (d,
J = 9.8 Hz), 107.65 (d, J = 26.6 Hz), 105.48 , 99.54 , 95.78 , 64.14 ,
2,2,2-Trifluoroethyl
2-methoxy-1,5-dimethyl-3-oxo-3,5-dihydro-2H-
pyrido[4,3-b]indole-4-carboxylate (4o); White solid, (95%): 1H NMR
(600 MHz, DMSO-d6) δ 7.93 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H),
7.45 – 7.38 (m, 1H), 7.25 (d, J = 7.8 Hz, 1H), 5.04 (q, J = 9.1 Hz, 2H),
4.02 (s, 3H), 3.47 (s, 3H), 2.90 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ
164.17 , 154.91 , 145.71 , 144.72 , 143.14 , 126.20 , 123.6 (d, J = 274.6
Hz) 121.72 , 121.69 , 120.69 , 109.72 , 105.55, 94.80 , 63.98 , 60.48 (d, J
~
60.62 (q, J = 35.3 Hz), 46.68 , 14.40; 19F NMR (376 MHz, DMSO-d6) δ -
= 34.8 Hz), 31.15 , 14.28 ; FT-IR:  = 2945, 1741, 1631, 1404, 1352,
~
71.80 , -121.23 . FT-IR:  = 2957, 1749, 1682, 1454, 1352, 1302 1283,
1283, 1149 cm-1; M.p. 176-179 °C; HRMS (ESI): m/z calcd for: [M+H]+:
1109, 1091 cm-1; M.p. 171–174 °C; HRMS (ESI): m/z calcd for: [M+H]+:
C17H16F3N2O4; Exact Mass: 369.1057; found: 369.1061
C23H19F4N2O4; Exact Mass: 463.1275; found: 463.1281.
2,2,2-Trifluoroethyl 2-methoxy-1-methyl-3-oxo-5-phenyl-3,5-dihydro-
2H-pyrido[4,3-b]indole-4-carboxylate (4t); Yellow solid, (83%): 1H
NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 7.5 Hz, 1H), 7.59 (dd, J = 11.9,
7.1 Hz, 3H), 7.40 (d, J = 7.3 Hz, 2H), 7.36 – 7.28 (m, 2H), 6.90 (d, J = 7.7
Hz, 1H), 4.05 (s, 3H), 3.92 (q, J = 8.9 Hz, 2H), 2.99 (s, 3H). 13C NMR
(125 MHz, DMSO-d6) δ 162.89 , 155.35 , 145.89 , 145.64 , 144.05 ,
136.14 , 130.48 , 129.59 , 128.15 , 126.94 ,123.56 (q, J = 279.7 Hz),
(E)-2,2,2-Trifluoroethyl
2-methoxy-1,5-dimethyl-3-oxo-8-styryl-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate(4r); White solid, (89%):
1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 1.5 Hz, 1H), 7.70 (dd, J =
8.5, 1.5 Hz, 1H), 7.65 – 7.57 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.43 –
7.34 (m, 3H), 7.32 – 7.20 (m, 2H), 5.03 (q, J = 9.1 Hz, 2H), 4.02 (s, 3H),
3.47 (s, 3H), 2.96 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 164.60 ,
155.38 , 146.45 , 146.43 , 143.28 , 137.87 , 131.53 , 129.20 , 129.15 ,
127.76 , 127.39 , 126.71 , 125.11 ,123.92 (q, J = 277.1 Hz), 122.73 ,
122.82 , 122.38 , 121.51 , 110.31 , 106.21 , 96.19 , 64.52 , 60.37 (q, J =
~
35.3 Hz), 14.94; FT-IR:  = 2928, 1737, 1641, 1410, 1356, 1285, 1171
119.50 , 110.46 , 105.93 , 95.50 , 64.49 , 61.00 (q, J = 35.1 Hz), 31.77 ,
cm-1; M.p. 191–192 °C; HRMS (ESI): m/z calcd for: [M+H]+:
~
14.94; FT-IR:  = 2948, 1756, 1669, 1565, 1378, 1277, 1176 cm-1; M.p.
C22H18F3N2O4; Exact Mass: 431.1213; found: 431.1218
189-192 °C; HRMS (ESI): m/z calcd for: [M+H]+: C25H22F3N2O4; Exact
Mass: 471.1526; found:471.1521.
2,2,2-Trifluoroethyl 2-methoxy-5-(4-methoxybenzyl)-1-methyl-3-oxo-
3,5-dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4u); Yellow solid,
(90%): 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 7.8 Hz, 1H), 7.43 (d,
J = 8.1 Hz, 1H), 7.40 – 7.32 (m, 1H), 7.28 – 7.19 (m, 1H), 6.94 – 6.88 (m,
2H), 6.84 – 6.75 (m, 2H), 5.26 (s, 2H), 4.72 (q, J = 9.0 Hz, 2H), 4.02 (s,
2,2,2-Trifluoroethyl 2-methoxy-1,5-dimethyl-3-oxo-8-phenethyl-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4p); Yellow solid,
(87%): 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.39 (dd, J = 8.4,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701755
European Journal of Organic Chemistry
FULL PAPER
3H), 3.65 (s, 3H), 2.93 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 164.42 ,
158.52 , 154.99 , 144.82 , 144.74 , 142.85 , 127.47 , 127.42 , 126.29,
123. 37 (q, J = 271 Hz), 122.01 , 121.93 , 120.93 , 114.01 , 110.29 ,
121.93 , 120.28 , 109.93 , 100.17 , 61.79 , 56.00 , 50.40 , 14.21; FT-IR:
~
 = 2955, 1731, 1412, 1353, 1301, 1139 cm-1; M.p. 101–103 °C; HRMS
(ESI): m/z calcd for: [M+H]+: C22H24NO4; Exact Mass: 366.1700; found:
105.89 , 95.86 , 64.01 , 60.64 (q, J = 35.2 Hz), 54.99 , 45.91 , 14.36; FT-
366.1716.
~
IR:  = 2951, 1747, 1649, 1575, 1477, 1281, 1152 cm-1; M.p. 182–
184 °C; HRMS (ESI): m/z calcd for: [M+H]+: C24H22F3N2O5; Exact Mass:
Diethyl 2-(3-acetyl-1H-indol-4-yl)malonate (6); White solid (60%): 1H
NMR (500 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.45 (s, 1H), 7.46 (d, J = 8.0
Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H),
4.28 – 3.96 (m, 4H), 2.49 (s, 3H), 1.16 (t, J = 7.0 Hz, 6H). 13C NMR (125
475.1475; found: 475.1477.
2,2,2-Trifluoroethyl
5-allyl-2-methoxy-1-methyl-3-oxo-3,5-dihydro-
2H-pyrido[4,3-b]indole-4-carboxylate (4v); Yellow solid, (78%): 1H
NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 7.8 Hz, 1H), 7.56 – 7.30 (m,
2H), 7.30 – 7.09 (m, 1H), 5.79 (m, 1H), 5.07 (dd, J = 10.5, 1.6 Hz, 1H),
4.96 (q, J = 9.1 Hz, 2H), 4.84 (dd, J = 17.3, 1.6 Hz, 1H), 4.73 – 4.63 (m,
2H), 4.01 (s, 3H), 2.91 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 164.62 ,
155.00 , 144.63 , 144.49 , 131.47 , 126.26 ,123.51(q, J = 278 Hz),
MHz, DMSO-d6) δ 169.42 , 138.49 , 137.94 , 126.96 , 124.90 , 123.47 ,
~
122.46 , 118.00 , 112.57 , 61.26 , 56.28 , 28.59 , 14.40; FT-IR:  = 3392,
2980, 2937, 1733, 1731, 1441, 1369, 1298, 1150 cm-1; M.p. 139–143 °C;
HRMS (ESI): m/z calcd for: [M+H]+: C17H20NO5; Exact Mass: 318.1336;
found:318.1342.
121.91 , 121.87 , 120.89 , 116.76 , 110.06 , 105.82 , 95.78 , 64.02 ,
~
60.71 (q, J = 35.1 Hz), 45.34 , 14.32; FT-IR:  = 2963, 1748, 1652,
Acknowledgements
1573, 1467, 1276, 1151 cm-1; M.p. 166-168 °C; HRMS (ESI): m/z calcd
for: [M+H]+: C19H18F3N2O4; Exact Mass: 395.1213; found: 395.1217.
This work is supported by the SERB-DST, India
(YSS/2014/000383 and SR/FST/CSII-026/2013 for 500 MHz
NMR facility). Fellowship received from CSIR, India (A.B.) is
gratefully acknowledged. We thank Mr. U. Karmakar and Mr. A.
Pal for some initial help.
2,2,2-Trifluoroethyl
5-benzyl-1-ethyl-2-methoxy-3-oxo-3,5-dihydro-
2H-pyrido[4,3-b]indole-4-carboxylate (4w); Yellow solid, (84%): 1H
NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.8 Hz, 1H), 7.40 (dt, J = 15.2,
8.0 Hz, 2H), 7.31 – 7.12 (m, 4H), 6.99 (d, J = 7.0 Hz, 2H), 5.35 (s, 2H),
4.66 (q, J = 9.0 Hz, 2H), 4.08 (s, 3H), 3.31 (q, J = 7.4 Hz, 2H), 1.38 (t, J =
7.5 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 164.40 , 155.08 , 149.46 ,
145.01 , 142.96 , 135.78 , 128.63 , 127.34 , 126.51 , 126.02 , 123.2 (q, J
Keywords: Indole • diazo • Regioselective C-H
= 275.3 Hz) 122.27 , 121.24 , 120.73 , 110.34 , 105.27 , 96.25 , 64.66 ,
Functionalization• metal carbene • Indolopyridone
~
60.65 (q, J = 35.3 Hz), 46.49 , 21.55 , 12.11; FT-IR:  = 2958,
1748,1649, 1569, 1476, 1278, 1131 cm-1; M.p. 159–162 °C; HRMS
(ESI): m/z calcd for: [M+H]+: C24H22F3N2O4; Exact Mass: 459.1526;
found: 459.1531.
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2,2,2-Trifluoroethyl
5-benzyl-2-(benzyloxy)-1-methyl-3-oxo-3,5-
dihydro-2H-pyrido[4,3-b]indole-4-carboxylate (4x): Yellow solid,
(76%): 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 7.8 Hz, 1H), 7.56 (dd,
J = 6.6, 2.8 Hz, 2H), 7.50 – 7.35 (m, 5H), 7.29 – 7.15 (m, 4H), 7.02 –
6.94 (m, 2H), 5.36 (s, 2H), 5.26 (s, 2H), 4.68 (q, J = 9.0 Hz, 2H), 2.89 (s,
3H). 13C NMR (125 MHz, DMSO-d6) δ 164.48 , 155.35 , 145.17 , 144.87 ,
142.89 , 135.79 , 133.88 , 129.86 , 129.24 , 128.62 , 127.34 , 126.39 ,
126.02 , 123.27 (q, J = 278.5 Hz), 122.07 , 121.98 , 120.97 , 110.27 ,
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521.1683; found: 521.1689.
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Diethyl
2-(5-benzyl-2-methoxy-1-methyl-3-oxo-4-((2,2,2-
trifluoroethoxy)carbonyl)-3,5-dihydro-2H-pyrido[4,3-b]indol-9-
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7.32 (m, 2H), 7.30 – 7.14 (m, 4H), 7.04 – 6.88 (m, 2H), 5.47 (s, 1H), 5.32
(s, 2H), 4.65 (q, J = 9.0 Hz, 2H), 4.17 (qt, J = 7.4, 3.8 Hz, 4H), 4.07 (s,
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δ 168.12 , 164.34 , 154.79 , 145.57 , 145.40 , 143.83 , 135.48 , 128.60 ,
127.35 , 126.88 , 126.08 , 125.98 , 123.91 , 123.22 (d, J = 277.6 Hz),
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121.54 , 109.73 , 106.93 , 95.33 , 64.16 , 61.70 , 60.63 (d, J = 35.3 Hz),
~
56.18 , 46.61 , 18.20 , 13.83 ; FT-IR:  = 2952, 2861, 1739, 1732, 1701,
166o, 1400, 1321, 1287, 1196 cm-1; HRMS (ESI): m/z calcd for: [M+H]+:
C30H30F3N2O8; Exact Mass: 603.1949; found: 603.1959.
Diethyl 2-(1-benzyl-1H-indol-4-yl)malonate (5); White solid (78%): 1H
NMR (400 MHz, CDCl3) δ 7.34 – 7.22 (m, 4H), 7.21 – 7.09 (m, 5H), 6.61
(d, J = 3.2 Hz, 1H), 5.31 (s, 2H), 5.07 (s, 1H), 4.24 (qd, J = 7.1, 4.1 Hz,
4H), 1.27 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 168.51 ,
137.38 , 136.62 , 128.90 , 128.63 , 128.36 , 127.81 , 127.04 , 125.11 ,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701755
European Journal of Organic Chemistry
FULL PAPER
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701755
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Regioselective indole
Functionalization
Aniruddha Biswas and Rajarshi
Samanta*
A straightforward Rh(III)-catalyzed strategy was developed for the site selective
C4-alkylation and C2-annulation of indole using variable diazo esters.
Page No. – Page No.
Rhodium(III)-Catalyzed
Regioselective Direct C4-Alkylation
and C2-Annulation of Indoles:
Straightforward Access to
Indolopyridone
This article is protected by copyright. All rights reserved.