Copper- and palladium-cocatalyzed intramolecular C-H functionalization/C-N bond formation: A route to the synthesis of indoloisoquinoline derivatives

Article abstract of DOI:10.1002/ejoc.201301699

A Cu and Pd bi-catalytic system is found to be very effective for the indole C2-H functionalization/C-N bond formation process.This is a unique reaction in which isoquinoline systems were synthesized from aldoximes rather than from ketoximes. During the reaction Cu(OTf)₂ converts the aldoximes into the corresponding cyanides and indoloisoquinolines, but introduction of Pd(OAc)₂ changes the outcome of the reaction significantly, by suppressing the formation of cyano products, thus giving exclusively indoloisoquinolines. A range of substituted indoloisoquinolines and aza-indoloisoquinolines are prepared in good to very good yields under air. A new approach to the synthesis of indoloisoquinoline derivatives is described. The activation of the indole C2-H bond is accomplished here by using a Pd(OAc)₂ and Cu(OTf)₂ bi-catalytic system. In this reaction aldoximes are converted into the corresponding isoquinolines in open atmosphere under mild reaction condition. Copyright

Full text of DOI:10.1002/ejoc.201301699

Job/Unit: O31699
/KAP1
Date: 27-02-14 17:21:31
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201301699
Copper- and Palladium-Cocatalyzed Intramolecular C–H Functionalization/C–N
Bond Formation: A Route to the Synthesis of Indoloisoquinoline Derivatives
Somjit Hazra,[a] Biplab Mondal,[a] Habibur Rahaman,[b] and Brindaban Roy*[a]
Keywords: Homogeneous catalysis / C–H activation / C–N bond formation / Nitrogen heterocycles / Copper / Palladium
A Cu and Pd bi-catalytic system is found to be very effective
for the indole C2–H functionalization/C–N bond formation
process.This is a unique reaction in which isoquinoline sys-
tems were synthesized from aldoximes rather than from ke-
toximes. During the reaction Cu(OTf)2 converts the aldox-
imes into the corresponding cyanides and indoloisoquinol-
ines, but introduction of Pd(OAc)2 changes the outcome of
the reaction significantly, by suppressing the formation of
cyano products, thus giving exclusively indoloisoquinolines.
A range of substituted indoloisoquinolines and aza-indoloiso-
quinolines are prepared in good to very good yields under
air.
Development of efficient methods to construct function-
alized indoloisoquinoline systems is thus essential for drug
discovery, as well as for organic optoelectronic devices.
Methods for the preparation of the patent indoloisoquin-
oline compounds include heating of 5-chloro-3-(2-
fluorophenyl)-2-isocyanatoindole at 240–260 °C or sequen-
tial heating of 5-chloro-1-methyl-3-phenylindole-2-carbox-
azide in DMF.[2a,2b] Another approach involves thermal cy-
clization of 2,3-disubstituted indoles with PhNCO.[3c] Al-
though these approaches provide access to indoloisoquinol-
ines, none of them involves metal-catalyzed environmentally
benign reaction conditions. Over the past years transition-
metal-catalyzed direct C–H functionalization/C–C or C-
heteroatom bond formation has become attractive due to
its versatility and low toxicity.[5] Recent studies have re-
vealed that copper-catalyzed C–H functionalization/C–N or
C–O bond formation is useful for the construction of the
heterocyclic architectures, with the synthesis of dibenzo-
furans,[6] 2-arylbenzoxazoles,[7] benzimidazoles,[8] benz-
oxazoles,[9] 4-aryl-2-quinolones,[10] carbazoles,[11] and quin-
azoline[12] and indolo[1,2-c]quinazoline derivatives[13] being
particularly important among them. Many of these reac-
tions were aided by directing groups, and therefore we rea-
soned that the oxime ether system might well serve as the
directing group with an appropriate catalytic system. There
are a few methods for obtaining isoquinoline derivatives
from oxime ether groups in the literature, but all of them
involve ketoximes, because aldoximes always tend to pro-
duce cyano byproducts and thereby reduce the efficiency of
the reaction.[14] We disclose here a new Cu(OTf)2/Pd-
(OAc)2-catalyzed synthesis of indoloisoquinolines from
suitably substituted indole derivatives directed by the aldox-
ime ether group through a C–H functionalization/C–N
bond-forming process.
Introduction
Indoloisoquinoline derivatives are important polyhetero-
cyclic compounds and have been successfully studied as
drug candidates (Figure 1). Compound A showed 51.8% in-
hibition of Lewis lung cancer cells implanted in mice (at
50 mgkg–1).[1] Compounds B and C exhibit potent antitu-
mor activity.[2] Other substituted indoloisoquinolines act as
anticancer agents and as neoplasm inhibitors and show
bactericidal and fungicidal activity.[3] In addition to their
use in medicinal chemistry, substituted indoloisoquinolines
are recognized as electroluminescent host hole transport de-
vices and as electroluminescent materials or electric materi-
als for organic optoelectronic devices.[4]
Figure 1. Bioactive indoloisoquinoline.
[a] Department of Chemistry, University of Kalyani,
Kalyani, Nadia, W.B. 741235, India
E-mail: broybsku@gmail.com
broybsku@rediffmail.com
http://www.klyuniv.ac.in/
[b] Department of Chemistry,Ranaghat College,
Ranaghat, Nadia, W.B. 741201, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301699.
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S. Hazra, B. Mondal, H. Rahaman, B. Roy
FULL PAPER
Lewis acidic behavior of Cu(OTf)2, we used other triflate
salts, namely AgOTf and Bi(OTf)3 (Table 1, Entries 19 and
20), but the starting substrate decomposed on both oc-
casions. The reaction was also found to be equally efficient
in air and under inert atmosphere.
Results and Discussion
We started our investigation by pursuing a synthetic
route for the conversion of indole 1a into C3-arylated in-
dole 3a. Our initial plan was to couple 2-bromobenz-
aldehyde with 1a at its 3-position and then to convert this
C3-arylated aldehyde into an aldoxime by a known pro-
cedure. Various palladium-catalyzed C2/C3 arylations of in-
dole are well known in the literature,[15] but we failed to
obtain our desired product by those procedures, instead no-
ticing the formation of different product mixtures. We
therefore changed our plan and decided to explore C3-aryl-
ation with aldoxime 2 instead of the 2-bromobenzaldehyde.
We were fortunate enough to isolate the C3-arylated indole
derivative 3a in 80% yield under Pd-catalyzed cross-cou-
pling reaction conditions in the presence of Ph3P and
K2CO3 at 115 °C in DMF (Scheme 1).
Table 1. Optimization of the catalytic cyclization of 3-substituted
indole derivative 3a.
Entry Cat. [mol-%]
Additive Solvent
[equiv.]
Yield [%][a,b]
4a
5a
1
2
3
4
5
6
7
8
Cu(OTf)2 [10]
Cu(OTf)2 [10]
Cu(OTf)2 [10]
Cu(OTf)2 [10]
Cu(OTf)2 [10]
Cu(OTf)2 [20]
Cu(OTf)2 [20]
Cu(OTf)2 [20]
CuBr2 [20]
–
DMF[c]
dioxane[c]
THF[c]
n.r.
n.r.
n.r.
toluene[d]
20
15
20
25
18
o-xylene[d] 30
o-xylene
45
25
K2CO3 [2] o-xylene
K3PO4 [2] o-xylene
o-xylene
n.r.
dec.
n.r.
n.r
9
Scheme 1. Synthesis of C3-arylated indoles.
10
11
12
13
14
CuCl2·H2O [20]
Cu(OAc)2·H2O [20]
CuBr [20]
o-xylene
o-xylene
o-xylene
o-xylene
To develop our idea of C–H functionalization of 3a, we
started a study of conversion of 3a into indoloisoquinoline
4a. Preliminary screening with 10 mol-% Cu(OTf)2 failed to
provide any product when DMF, dioxane, and THF were 15
used as solvents (Table 1, Entries 1–3). We then turned our
n.r.
Pd(OAc)2 [5]
5
5
12
10
66[e]
74[f]
0
0
0
0
0
0
Pd(OAc)2 [10]
Pd(OAc)2 [10]
Pd(OAc)2 [10]
Pd(OAc)2, Cu(OTf)2
Pd(OAc)2, Cu(OTf)2
Pd(OAc)2, AgOTf[g]
o-xylene
K2S2O8 [1] o-xylene
AgOAc [1] o-xylene
o-xylene
16
17
18
19
20
[g]
[g]
attention to nonpolar solvents. To our delight, with toluene
o-xylene
o-xylene
o-xylene
as solvent we obtained our desired product in 20% yield
along with the cyano derivative 5a (Table 1, Entry 4). o-Xyl-
ene proved to be even more fruitful than toluene for the
reaction (Table 1, Entry 5). Increasing the catalyst amount
to 20 mol-% resulted in further improvement in the yield of
the reaction (Table 1, Entry 6). Addition of base (K2CO3,
K3PO4), on the contrary, failed to show any encouraging
sign over the initial results. In fact, with K3PO4 decomposi-
tion of the starting precursor was observed (Entries 7 and
8). We subsequently tested other copper(II) salts but no
catalytic activity was noticed (Table 1, Entries 9–11). A CuI
salt was also found to be ineffective and the starting sub-
dec.
dec.
[g]
Pd(OAc)2, Bi(OTf)3
[a] Yields of the isolated compounds; n.r.: no reaction, dec: decom-
position. [b] All the reactions were monitored for 10 h unless the
substrate was consumed within the time period. [c] Reaction was
conducted at 110 °C, 100 °C, and 67 °C for DMF, dioxane, and
THF, respectively. [d] Reaction was performed at 110 °C. [e] Reac-
tion also conducted in DMSO, DMF, and THF. [f] Reaction time
= 2 h. [g] 10 mol-% of Pd(OAc)2 and 20 mol-% of the other triflate
salt were used and the reaction was performed both in air and
under inert atmosphere.
Using the optimized reaction conditions, we next ex-
strate remained intact (Table 1, Entry 12). The reaction pro- plored the scope and limitations of the substrates and
ceeded very slowly and the conversion was very poor when achieved substituent diversity of the reaction (Table 2). A
Pd(OAc)2 was employed as a catalyst (Table 1, Entries 13 number of substituted indole derivatives were tested under
and 14). External oxidants such as K2S2O8 and AgOAc the optimized reaction conditions and very good yields
(Entries 15 and 16) also did not improve the situation. The were observed (Table 2, Entries 1–10).The reaction went
first real breakthrough came along when we decided to use smoothly with various N-alkylindole derivatives. The pres-
Pd(OAc)2 simultaneously with Cu(OTf)2. This combined ence of electron-donating groups (OMe) in the benzene ring
catalytic system not only improved the yield but also sup- of the aldoxime resulted in a very good yield of the prod-
pressed the formation of cyano derivative 5a. We also tried ucts (Table 2, Entries 4–6). The presence of an OMe group
this bi-catalytic system [Pd(OAc)2 and Cu(OTf)2] in other in the 5-position of the indole ring produced better yields
solvents, but o-xylene proved to be the best for optimum (Table 2, Entries 7 and 8) than were obtained with 5-cyano-
conversion (Table 1, Entry 17). A slight increase in the yield indole derivatives (Table 2, Entries 9 and 10), in which the
was observed when the amount of Pd(OAc)2 was raised to reactions took longer times for completion and also the
10 mol-% (Table 1, Entry 18). To observe the effect of the yields were slightly diminished.
2
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Cu- and Pd-Cocatalyzed C–H Functionalization/C–N Formation
Table 2. Synthesis of substituted indoloisoquinolines.
altogether rather than merely converting the cyano deriva-
tive into compound 4a (Scheme 2).
Scheme 2. Reactions with cyanide adduct.
Based on the literature precedent, related reactions, and
our probe reactions with the cyano derivative 5a, the pos-
sible pathways for the formation of indoloisoquinoline 4 are
outlined in Scheme 3. The initial N–O bond scission of 3 in
the presence of Cu(OTf)2 presumably leads to the iminyl-
Cu species 8[8a,16] with the copper either in oxidation state
II or III.[16c,17] Now the formation of both the product 4
and 5 in the presence only of Cu(OTf)2 indicates that most
probably species 8 affords these products by two simulta-
neously operative different pathways (pathways “a” and
“b”), because the isolated cyano derivative 5 cannot be con-
verted into compound 4 (step “d”) in a separate reaction.
We think that in pathway “a” demetallation of the iminyl-
Cu species gave the cyano derivative 5, whereas in a dif-
ferent pathway, compound 4 was obtained from 8 through
the intermediacy of metallacycle 9. Earlier reports revealed
that an adduct of type 8 can be cyclized similarly, variously
through electrophilic aromatic substitution, via a metallacy-
cle, or by electrocyclic ring closure.[18] However, in the pres-
ence only of Cu(OTf)2, the slower reaction rate and lower
yield of the product 4, and the formation of significant
amounts of cyano derivative 5, indicate that electrophilic
metallation pathway (path “b”) is the most reasonable one.
We assumed that the instability and difficulty of formation
of the seven-membered copper metallacycle intermediate 9
is responsible for the low yield of 4 in the presence only of
Cu(OTf)2 as catalyst. We are not entirely sure about the role
of Pd(OAc)2, but we found that it suppresses the formation
of cyanide adduct in the reaction. We hypothesize that it
most probably undergoes a transmetallation reaction[16c]
with iminyl-Cu species 8, followed by C–H activation (path
“c”), to give the seven-membered palladacycle 10. Subse-
quent C–N bond formation and reductive elimination pro-
vide 4 in good to very good yields. The failure to obtain 4
from 5 in the presence of any catalytic combination of
Pd(OAc)2 and Cu(OTf)2 under the same reaction condition
excludes the possibilities of formation of 4 via the cyano
intermediate. Because other metal triflates and CuI and
CuII salts were found to be ill-suited for the reaction, we
concluded that Cu(OTf)2 is most probably not acting here
as a Lewis acid. Also, the sluggishness of the reaction in
the absence of Cu(OTf)2 led us to believe that the iminyl-
Cu species must be involved in the reaction. The equal effi-
ciency of the reaction both in air and under inert atmo-
sphere also suggests that Cu(OTf)2 most probably helps to
maintain the catalytic cycle here.
[a] Yields of isolated products. [b] Reaction time: 4 h. [c] Reaction
time: 5 h with 10% substrate recovery. [d] Reaction time: 6 h.
We extended this method to the preparation of aza-
indoloisoquinoline derivatives 7 (Table 3, Entries 1 and 2).
Here the presence of an additional nitrogen atom in the
aza-indole ring system did not seem to hinder the reaction
flow at all and after 4 h reaction time high yields of the
products were obtained.
Initially we hypothesized that the cyano derivative 5a was
involved in the reaction pathway. To probe its validity we
treated 5a with Cu(OTf)2 in o-xylene but we failed to obtain
any product (Scheme 2). We tried this reaction with
Pd(OAc)2, and also with the Pd(OAc)2/Cu(OTf)2 bi-cata-
lytic system, but the cyano derivative remained intact. This
led to our conclusion that a common intermediate is proba-
bly giving these two products by two different pathways in
the case of Cu(OTf)2 alone. Pd(OAc)2, on the other hand,
actually suppresses the formation of the cyano derivative
Table 3. Synthesis of substituted aza-indoloisoquinolines.
Entry
Substrate
R
Product
Yield (%)
1
2
6a
6b
ethyl
isopropyl
7a
7b
75
72
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S. Hazra, B. Mondal, H. Rahaman, B. Roy
FULL PAPER
Scheme 3. Proposed mechanism for the indoloisoquinoline formation.
of the reaction mixture were monitored by TLC analysis. After
completion (monitored by TLC), the reaction mixture was cooled
and water (10 mL) was added. The mixture was then extracted with
EtOAc (10 mLϫ3). The EtOAc extract was washed with water
(10 mLϫ4) followed by brine (10 mL). The organic layer was dried
(Na2SO4). Evaporation of EtOAc under reduced pressure furnished
a crude mass, which was purified by column chromatography over
silica gel. Elution of the column with pet. ether afforded the 3-
arylated indole.
Conclusions
We have developed a new Pd/Cu-catalyzed intramolecu-
lar C–N bond-formation reaction which involves activation
of the indole C2–H bond for the synthesis of indoloisoquin-
oline and aza-indoloisoquinoline derivatives. This reaction
features mild reaction conditions and extreme operational
simplicity. Our approach provides easy access to organo-
electric and medicinally important heterocyclic compounds.
Further studies on the development of this methodology in
constructing new heterocycles, especially regarding indole
C3–H bond activation, are ongoing.
(E)-2-(1-Ethyl-1H-indol-3-yl)benzaldehyde O-Methyl Oxime (3a):
Yield 80%; yellow solid, m.p. 71–72 °C. 1H NMR (400 MHz,
CDCl3): δH = 1.50 (t, J = 7.2 Hz, 3 H), 3.93 (s, 3 H, NCH3), 4.21
(q, J = 7.2 Hz, 2 H), 7.07 (s, 1 H, indole C2-H), 7.14 (t, J = 7.6 Hz,
1 H), 7.22–7.28 (m, 1 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.38–7.44 (m,
2 H), 7.51 (d, J = 7.6 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.99 (d,
J = 8.0 Hz, 1 H), 8.19 (s, 1 H, oxime C–H) ppm. 13C NMR
(100 MHz, CDCl3): δC = 15.5, 41.1, 61.9, 109.5, 113.8, 120.0, 120.0,
122.1, 126.3, 126.7, 127.0, 127.7, 129.6, 130.4, 131.0, 135.2, 135.9,
Experimental Section
General: Melting points were determined in open capillaries and
are uncorrected. IR spectra (ν
in cm–1) were recorded with a
˜
max
148.8 ppm. IR (KBr): ν = 1457, 1540, 1608, 2813, 2889, 2931 cm–1.
˜
Perkin–Elmer L 120–000A spectrometer on KBr disks. 1H NMR
and 13C NMR spectra were recorded with a Bruker DPX 400 spec-
trometer in CDCl3 with TMS as internal standard (chemical shift
in δ). Chemical shifts of common trace PMR impurities (CDCl3,
ppm) in some samples: H2O 1.56; solvent impurities 1.26, 0.86;
CHCl3 7.26. In some low-polar samples a 13C peak corresponding
to solvent greasy impurities was observed at 29.7 (δC). CHN was
recorded with a Perkin–Elmer 2400 series II CHN analyzer. MS
were recorded with a Q-TOF microTm instrument at the Indian
Institute of Chemical Biology, Kolkata. In addition, some MS were
measured at the Indian Association of Cultivation of Science, Kol-
kata, and the Indian Institute of Technology, Kharagpur. Silica gel
(60–120, 230–400 mesh, Rankem, India) was used for chromato-
graphic separation. Silica gel G (CDH, India) was used for TLC.
Petroleum ether (Pet. ether) refers to the fraction boiling between
60 °C and 80 °C.
HRMS (TOF, ES+): calcd. for C18H18N2O + H [M + H]+ 279.1497;
found 279.1483.
(E)-2-(1-Methyl-1H-indol-3-yl)benzaldehyde O-Methyl Oxime (3b):
Yield 78%; yellow solid, m.p. 61–62 °C. 1H NMR (400 MHz,
CDCl3): δH = 3.86 (s, 3 H), 3.94 (s, 3 H), 7.02 (s, 1 H, indole C2-
H), 7.15 (t, J = 7.6 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 1 H), 7.34–7.38
(m, 2 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.51 (d, J = 7.6 Hz, 1 H), 7.56
(d, J = 7.6 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 8.20 (s, 1 H, oxime
C–H) ppm. 13C NMR (100 MHz, CDCl3): δC = 33.0, 61.9, 109.5,
113.7, 119.9, 120.1, 122.3, 126.4, 126.8, 127.6, 128.7, 129.7, 130.4,
131.1, 135.1, 136.9, 148.8 ppm. IR (KBr): ν = 1481, 1545, 1613,
˜
2816, 2934 cm–1. C17H16N2O (264.33): calcd. C 77.25, H 6.10, N
10.60; found C 77.08, H 6.25, N 10.69.
(E)-2-(1-Isopropyl-1H-indol-3-yl)benzaldehyde O-Methyl Oxime
1
(3c): Yield 72%; yellow gum. H NMR (400 MHz, CDCl3): δH
=
General Procedure for the Preparation of C3-Arylated Indoles: The
N-alkylated indole (1 mmol), Pd(OAc)2 (10 mol-%, 0.1 mmol),
K2CO3 (3 mmol), TBAB (0.2 mmol), and triphenylphosphine
(0.1 mmol) were placed in an oven-dried reaction vessel. The reac-
tion vessel was fitted with a silicon septum, evacuated, and back-
filled with argon. DMF (10 mL) and the 2-brominated aryl oxime
(1.2 mmol) were then added successively under argon at room tem-
perature. The resulting mixture was heated under argon for 6 h to
12 h at 115 °C. The progress of the reaction and the composition
1.58 (d, J = 6.8 Hz, 6 H), 3.93 (s, 3 H, OCH3), 4.71–4.75 (m, 1 H),
7.14 (t, J = 7.6 Hz, 1 H), 7.18 (s, 1 H, indole C2-H), 7.24–7.28 (m,
1 H), 7.34 (t, J = 7.6 Hz, 1 H), 7.40–7.45 (m, 2 H), 7.51 (d, J =
7.6 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H),
8.17 (s, 1 H, oxime C–H) ppm. 13C NMR (100 MHz, CDCl3): δC
= 22.9, 47.3, 61.9, 109.8, 113.9, 120.0, 120.1, 122.0, 123.7, 126.3,
126.8, 127.7, 129.7, 130.4, 131.1, 135.4, 135.8, 148.9 ppm. IR
(neat): ν = 1462, 1543, 1610, 2816, 2932 cm–1. C H N O (292.38):
˜
19 20
2
calcd. C 78.05, H 6.89, N 9.58; found C 78.29, H 6.78, N 9.71.
4
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Cu- and Pd-Cocatalyzed C–H Functionalization/C–N Formation
(E)-4,5-Dimethoxy-2-(1-methyl-1H-indol-3-yl)benzaldehyde O- (E)-1-Ethyl-3-{2-[(methoxyimino)methyl]phenyl}-1H-indole-5-
1
Methyl Oxime (3d): Yield 72%; yellow solid, m.p. 105–106 °C. H
NMR (400 MHz, CDCl3): δH = 3.85 (s, 3 H, CH3), 3.90 (s, 3 H, NMR (400 MHz, CDCl3): δH = 1.53 (t, J = 7.2 Hz, 3 H), 3.95 (s,
carbonitrile (3i): Yield 64%; brown solid, m.p. 110–111 °C. 1H
CH3), 3.92 (s, 3 H, CH3), 4.0 (s, 3 H, CH3), 6.97 (s, 1 H), 7.0 (s, 1
H), 7.16 (t, J = 7.6 Hz, 1 H), 7.28 (t, J = 7.6 Hz, 1 H), 7.37 (d, J
3 H, OCH3), 4.25 (q, J = 7.2 Hz, 2 H), 7.21 (s, 1 H, indole C2-H),
7.38–7.48 (m, 5 H), 7.87 (s, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 8.07
= 8.4 Hz, 1 H), 7.50 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 8.14 (s, 1 (s, 1 H, oxime C–H) ppm. 13C NMR (100 MHz, CDCl3): δC = 15.5,
H, oxime C–H) ppm. 13C NMR (100 MHz, CDCl3): δC = 32.9, 41.5, 62.0, 103.1, 110.5, 115.0, 120.6, 125.0, 125.7, 126.5, 127.6,
55.9, 56.0, 61.8, 107.8, 109.5, 113.3, 113.4, 119.7, 120.0, 122.2,
122.9, 127.7, 128.5, 128.7, 136.8, 148.0, 148.5, 150.3 ppm. IR
127.6, 128.8, 129.8, 130.6, 131.0, 133.4, 137.4, 147.9 ppm. IR
(KBr): ν = 1465, 1542, 1611, 2217, 2932 cm–1. C H N O (303.36):
˜
19 17
3
(KBr): ν = 1508, 1549, 1594, 1612, 2934 cm–1. C19H20N2O3 calcd. C 75.23, H 5.65, N 13.85; found C 75.07, H 5.53, N 13.93.
˜
(324.38): calcd. C 70.35, H 6.21, N 8.64; found C 70.21, H 6.37, N
8.42.
(E)-1-Isopropyl-3-{2-[(methoxyimino)methyl]phenyl}-1H-indole-
5-carbonitrile (3j): Yield 61%; brown solid, m.p. 146–147 °C 1H
NMR (400 MHz, CDCl3): δH = 1.58 (d, J = 6.8 Hz, 6 H), 3.95 (s,
3 H, OCH3), 4.71–4.78 (m,1 H), 7.32 (s, 1 H, indole C2-H), 7.35–
(E)-2-(1-Ethyl-1H-indol-3-yl)-4,5-dimethoxybenzaldehyde O-Methyl
Oxime (3e): Yield 68%; yellow solid, m.p. 115–116 °C. 1H NMR
7.49 (m, 5 H), 7.86 (s, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 8.06 (s, 1 H,
(400 MHz, CDCl3): δH = 1.52 (t, J = 7.2 Hz, 3 H), 3.90 (s, 3 H),
oxime C–H) ppm. 13C NMR (100 MHz, CDCl3): δC = 22.8, 47.9,
3.92 (s, 3 H), 4.0 (s, 3 H), 4.24 (q, J = 7.2 Hz, 2 H), 6.98 (s, 1 H),
7.06 (s, 1 H), 7.15 (t, J = 7.6 Hz, 1 H), 7.25–7.29 (m, 1 H), 7.40 (d,
62.0, 103.1, 110.7, 115.1, 120.7, 124.8, 125.6, 125.7, 126.5, 127.6,
129.8, 130.7, 131.0, 133.6, 137.2, 148.0 (one signal not re-
J = 8.0 Hz, 1 H), 7.51 (s, 1 H), 7.55 (d, J = 7.6 Hz, 1 H), 8.13 (s,
solved) ppm. IR (KBr): ν = 1458, 1545, 1613, 2218, 2929,
˜
1 H, oxime C–H) ppm. 13C NMR (100 MHz, CDCl3): δC = 15.5,
41.1, 56.0, 56.0, 61.8, 107.8, 109.5, 113.3, 113.5, 119.8, 120.0, 122.0,
122.9, 126.8, 127.9, 128.9, 135.8, 148.0, 148.5, 150.3 ppm. IR
2975 cm–1. C20H19N3O (317.39): calcd. C 75.69, H 6.03, N 13.24;
found C 75.61, H 6.17, N 13.35.
(KBr): ν = 1505, 1549, 1594, 1611, 2931 cm–1. C20H22N2O3
˜
(E)-2-(1-Ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzaldehyde O-Meth-
yl Oxime (6a): Yield 65 %; yellow gum; 1H NMR (400 MHz,
CDCl3): δH = 1.54 (t, J = 7.2 Hz, 3 H), 3.95 (s, 3 H, OCH3), 4.42
(q, J = 7.2 Hz,2 H), 7.10 (dd, J = 7.6, 4.4 Hz, 1 H), 7.23 (s, 1 H,
indole C2-H), 7.36 (t, J = 7.2 Hz, 1 H), 7.44–7.46 (m, 2 H), 7.84
(d, J = 8.0 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 8.16 (s, 1 H, oxime
C–H), 8.38 (d, J = 4.4 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δC = 15.8, 39.5, 61.9, 112.2, 116.3, 120.1, 126.5, 126.8,
127.1, 128.0, 129.8, 130.3, 130.8, 134.4, 143.4, 147.2, 148.3 ppm.
(338.41): calcd. C 70.99, H 6.55, N 8.28; found C 71.16, H 6.69, N
8.12.
(E)-2-(1-Isopropyl-1H-indol-3-yl)-4,5-dimethoxybenzaldehyde O-
Methyl Oxime (3f): Yield 66%; pale yellow solid, m.p. 130–131 °C.
1H NMR (400 MHz, CDCl3): δH = 1.58 (d, J = 6.8 Hz, 6 H), 3.90
(s, 3 H), 3.91 (s, 3 H), 4.0 (s, 3 H), 4.71–4.76 (m,1 H), 6.97 (s, 1
H), 7.14 (t, J = 7.6 Hz, 1 H), 7.15 (s, 1 H), 7.23–7.27 (m, 1 H), 7.42
(d, J = 8.4 Hz, 1 H), 7.51 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 8.11
(s, 1 H, oxime C–H) ppm. 13C NMR (100 MHz, CDCl3): δC = 22.9,
47.3, 56.0, 56.0, 61.7, 107.8, 109.7, 113.3, 113.7, 119.8, 120.0, 121.9,
123.0, 123.4, 127.9, 129.1, 135.6, 148.0, 148.5, 150.3 ppm. IR
IR (neat): ν = 1429, 1537, 1595, 1609, 2935, 2974 cm–1. MS (EI):
˜
m/z = 280.2 [M + H]+, 248.1. C17H17N3O (279.34): calcd. C 73.10,
H 6.13, N 15.04; found C 73.29, H 6.02, N 14.94.
(E)-2-(1-Isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzaldehyde O-
(KBr): ν = 1506, 1548, 1593, 1610, 2932 cm–1. C21H24N2O3
˜
1
Methyl Oxime (6b): Yield 62%; yellow gum. H NMR (400 MHz,
(352.43): calcd. C 71.57, H 6.86, N 7.95; found C 71.35, H 6.98, N
7.84.
CDCl3): δH = 1.58 (d, J = 6.8 Hz, 6 H), 3.94 (s, 3 H, OCH3), 5.25–
5.29 (m,1 H), 7.09 (dd, J = 7.6, 4.8 Hz, 1 H), 7.30 (s, 1 H, indole
C2-H), 7.33–7.37 (m, 1 H), 7.42–7.47 (m, 2 H), 7.83 (dd, J = 8.0,
1.6 Hz, 1 H), 8.0 (d, J = 7.6 Hz, 1 H), 8.14 (s, 1 H, oxime C–H),
8.37 (dd, J = 4.4, 1.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δC = 23.0, 45.6, 61.9, 112.4, 116.4, 120.2, 123.7, 126.4, 127.0, 128.0,
(E)-2-(1-Ethyl-5-methoxy-1H-indol-3-yl)benzaldehyde O-Methyl
Oxime (3g): Yield 76%; yellow solid, m.p. 97–98 °C. 1H NMR
(400 MHz, CDCl3): δH = 1.47 (t, J = 7.6 Hz, 3 H), 3.78 (s, 3 H,
OCH3), 3.93 (s, 3 H, NCH3), 4.15 (q, J = 7.6 Hz, 2 H), 6.91 (dd,
J = 8.8, 2.0 Hz, 1 H), 6.98 (d, J = 2.0 Hz, 1 H), 7.04 (s, 1 H, indole
C2-H), 7.26 (d, J = 8.8 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.42 (t,
J = 7.6 Hz, 1 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1
H), 8.19 (s, 1 H, oxime C–H) ppm. 13C NMR (100 MHz, CDCl3):
δC = 15.6, 41.3, 55.9, 61.9, 101.2, 110.4, 112.7, 113.4, 126.4, 126.7,
127.3, 128.0, 129.8, 130.3, 130.9, 131.2, 135.4, 149.0, 154.7 ppm.
129.7, 130.4, 130.8, 134.6, 143.2, 147.0, 148.4 ppm. IR (neat): ν =
˜
1428, 1537, 1594, 1609, 2933, 2975 cm–1. C18H19N3O (293.37):
calcd. C 73.69, H 6.53, N 14.32; found C 73.82, H 6.67, N 14.08.
General Procedure for the Synthesis of Indoloisoquinolines: A 3-aryl-
ated indole oxime (0.5 mmol), Pd(OAc)2 (10 mol-%, 0.05 mmol),
and Cu(OTf)2 (20 mol-%, 0.1 mmol) were placed in an oven-dried
reaction vessel. o-Xylene (5 mL) was subsequently added, and the
mixture was then heated (110 °C) while open to the atmosphere.
After the completion of the reaction (monitored by TLC), water
(5 mL) was added, and the mixture was extracted with EtOAc
(10 mLϫ3). The organic layer was washed with water (10 mL) and
brine (10 mL) and dried (Na2SO4). The solvent was evaporated un-
der reduced pressure to furnish a crude mass, which was purified
by column chromatography over silica gel (60–120 mesh) with pet.
ether as eluent to afford an indoloisoquinoline product.
IR (KBr): ν = 1488, 1541, 1608, 2932, 2956 cm–1. C19H20N2O2
˜
(308.38): calcd. C 74.00, H 6.54, N 9.08; found C 74.14, H 6.71, N
8.95.
(E)-2-(1-Isopropyl-5-methoxy-1H-indol-3-yl)benzaldehyde O-Methyl
Oxime (3h): Yield 73%; yellow solid, m.p. 80–81 °C. 1H NMR
(400 MHz, CDCl3): δH = 1.55 (d, J = 6.8 Hz, 6 H), 3.79 (s, 3 H,
OCH3), 3.93 (s, 3 H, NCH3), 4.64–4.67 (m, 1 H), 6.91 (dd, J = 8.8,
2.4 Hz, 1 H), 6.97 (d, J = 2.0 Hz, 1 H), 7.15 (s, 1 H, indole C2-H),
7.29–7.35 (m, 2 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.49 (d, J = 7.6 Hz,
1 H), 7.98 (d, J = 7.6 Hz, 1 H), 8.17 (s, 1 H, oxime C–H) ppm. 13
C
7-Ethyl-7H-indolo[2,3-c]isoquinoline (4a): Yield 74%; yellow solid,
NMR (100 MHz, CDCl3): δC = 22.9, 47.5, 55.9, 61.8, 101.2, 110.5, m.p. 70–71 °C. 1H NMR (400 MHz, CDCl3): δH = 1.52 (t, J =
112.5, 113.6, 124.0, 126.3, 126.6, 127.9, 129.7, 130.4, 130.9, 131.0,
7.2 Hz, 3 H), 4.71 (q, J = 7.2 Hz, 2 H), 7.41 (t, J = 7.6 Hz, 1 H),
7.49–7.56 (m, 2 H), 7.63 (d, J = 8.0 Hz, 1 H),7.84 (t, J = 8.0 Hz, 1
H), 8.12 (d, J = 8.0 Hz, 1 H), 8.50 (d, J = 8.0 Hz, 1 H), 8.63 (d, J
= 8.4 Hz, 1 H), 9.14 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
135.6, 149.0, 154.6 ppm. IR (KBr): ν = 1489, 1543, 1610, 2934,
˜
2958 cm–1. C20H22N2O2 (322.41): calcd. C 74.51, H 6.88, N 8.69;
found C 74.68, H 6.73, N 8.78.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O31699
/KAP1
Date: 27-02-14 17:21:31
Pages: 8
S. Hazra, B. Mondal, H. Rahaman, B. Roy
δC = 14.6, 36.6, 106.2, 109.6, 120.1, 121.4, 122.5, 122.5, 123.4, J = 8.4 Hz, 1 H), 9.12 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
FULL PAPER
124.6, 124.8, 129.3, 130.9, 132.8, 137.5, 147.1, 150.2 ppm. IR
δC = 14.7, 36.6, 56.3, 105.4, 106.0, 110.3, 114.0, 121.6, 122.2, 123.2,
(KBr): ν = 1566, 1623, 2854, 2926, 2968, 3039 cm–1. HRMS (TOF,
124.4, 129.4, 130.9, 132.6, 132.8, 147.4, 150.2, 154.3 ppm. IR
˜
ES+): calcd. for C17H14N2 + H [M + H]+ 247.124; found 247.1233.
(KBr): ν = 1568, 1623, 2831, 2933, 2973 cm–1. C H N O (276.34):
˜
18 16 2
calcd. C 78.24, H 5.84, N 10.14; found C 78.12, H 5.70, N 10.21.
7-Methyl-7H-indolo[2,3-c]isoquinoline (4b): Yield 70%; yellow solid,
m.p. 96–97 °C. 1H NMR (400 MHz, CDCl3): δH = 4.14 (s, 3 H),
7.42 (t, J = 7.6 Hz, 1 H), 7.51–7.58 (m, 2 H), 7.62 (d, J = 8.0 Hz,
7-Isopropyl-10-methoxy-7H-indolo[2,3-c]isoquinoline (4h): Yield
73%; brown solid, m.p. 107–108 °C. 1H NMR (400 MHz, CDCl3):
1 H), 7.84–7.88 (m, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 8.50 (d, J = δH = 1.78 (d, J = 7.2 Hz, 6 H), 4.02 (s, 3 H, OCH3), 5.66–5.68 (m,
7.6 Hz, 1 H), 8.65 (d, J = 8.4 Hz, 1 H), 9.15 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δC = 28.0, 106.2, 109.5, 120.2, 121.2,
122.3, 122.5, 123.4, 124.6, 124.9, 129.3, 130.9, 132.7, 138.6, 147.8,
1 H), 7.18 (dd, J = 9.2, 2.4 Hz, 1 H), 7.49–7.52 (m, 1 H), 7.68 (d,
J = 8.8 Hz, 1 H), 7.83–7.87 (m, 1 H), 7.98 (d, J = 2.0 Hz, 1 H),
8.11 (d, J = 8.0 Hz, 1 H), 8.59 (d, J = 8.4 Hz, 1 H), 9.10 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δC = 22.9, 47.7, 56.0, 101.4,
110.6, 110.8, 112.0, 112.3, 119.7, 124.8, 125.7, 126.7, 129.5, 131.3,
150.2 ppm. IR (KBr): ν = 1566, 1622, 2854, 2924, 3045 cm–1. MS
˜
(EI): m/z = 233.1 [M + H]+, 234.1. C16H12N2 (232.28): calcd. C
82.73, H 5.21, N 12.06; found C 82.84, H 5.05, N 12.15.
132.7, 134.1, 139.5, 154.9 ppm. IR (KBr): ν = 1571, 1625, 2832,
˜
2935, 2974 cm–1. C19H18N2O (290.36): calcd. C 78.59, H 6.25, N
9.65; found C 78.75, H 6.39, N 9.41.
7-Isopropyl-7H-indolo[2,3-c]isoquinoline (4c): Yield 68 %; yellow
gum. 1H NMR (400 MHz, CDCl3): δH = 1.81 (d, J = 6.8 Hz, 6 H),
5.67–5.72 (m,1 H), 7.39 (t, J = 7.2 Hz, 1 H), 7.49–7.53 (m, 2 H),
7-Ethyl-7H-indolo[2,3-c]isoquinoline-10-carbonitrile (4i): Yield 62%;
1
7.77 (d, J = 8.0 Hz, 1 H), 7.82–7.86 (m, 1 H), 8.12 (d, J = 8.0 Hz, brown solid, m.p. 164–165 °C. H NMR (400 MHz, CDCl3): δH
=
1 H), 8.53 (d, J = 7.6 Hz, 1 H), 8.66 (d, J = 8.4 Hz, 1 H), 9.12 (s,
1.52 (t, J = 7.2 Hz, 3 H), 4.70 (q, J = 7.2 Hz, 2 H), 7.57–7.64 (m,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δC = 21.2, 45.7, 106.1, 2 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.90 (t, J = 7.6 Hz, 1 H), 8.14 (d,
111.4, 119.7, 121.8, 122.5, 122.5, 123.4, 124.4, 129.3, 130.8, 132.7,
J = 8.0 Hz, 1 H), 8.51 (d, J = 8.4 Hz, 1 H), 8.73 (s, 1 H), 9.17 (s,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δC = 14.6, 37.0, 102.9,
136.9, 147.3, 149.7. (one signal not resolved) ppm. IR (neat): ν =
˜
1566, 1624, 2929, 2971, 3052 cm–1. HRMS (TOF, ES+): calcd. for 105.9, 110.3, 120.6, 121.4, 122.2, 124.4, 125.0, 127.3, 127.7, 129.6,
C18H16N2+ H [M + H]+ 261.139; found 261.1386.
131.8, 132.4, 139.1, 147.9, 151.8 ppm. IR (KBr): ν = 1561, 1624,
˜
2217, 2853, 2924, 2955 cm–1. C18H13N3 (271.32): calcd. C 79.68, H
4.83, N 15.49; found C 79.84, H 4.72, N 15.64.
2,3-Dimethoxy-7-methyl-7H-indolo[2,3-c]isoquinoline (4d): Yield
78 %; pale yellow solid, m.p. 180–181 °C. 1H NMR (400 MHz,
CDCl3): δH = 4.06 (s, 3 H, CH3), 4.08 (s, 3 H, CH3), 4.19 (s, 3 H, 7-Isopropyl-7H-indolo[2,3-c]isoquinoline-10-carbonitrile (4j): Yield
CH3), 7.37–7.41 (m, 2 H), 7.52–7.59 (m, 2 H), 7.81 (s, 1 H), 8.34
(d, J = 7.6 Hz, 1 H), 8.93 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δC = 27.9, 56.0, 56.1, 101.4, 106.1, 107.4, 109.4, 119.8,
120.0, 121.0, 121.8, 124.7, 129.3, 138.7, 147.4, 147.5, 153.6 (one
65%; brown solid, m.p. 151–152 °C. 1H NMR (400 MHz, CDCl3):
δH = 1.81 (d, J = 6.8 Hz, 6 H), 5.65–5.69 (m,1 H), 7.60 (t, J =
8.0 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.80 (d, J = 8.8 Hz, 1 H),
7.93 (t, J = 8.0 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 8.58 (d, J =
8.4 Hz, 1 H), 8.83 (s, 1 H), 9.19 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δC = 21.1, 46.3, 102.5, 105.9, 111.8, 120.6, 121.8, 122.2,
124.4, 124.9, 127.2, 127.3, 129.5, 131.7, 132.4, 138.6, 148.1,
signal not resolved) ppm. IR (KBr): ν = 1579, 1629, 2847, 2931,
˜
3011 cm–1. HRMS (TOF, ES+): calcd. for C18H16N2O2 + H [M +
H]+ 293.129; found 293.1285.
151.4 ppm. IR (KBr): ν = 1562, 1626, 2217, 2852, 2927, 2954 cm–1.
˜
7-Ethyl-2,3-dimethoxy-7H-indolo[2,3-c]isoquinoline (4e): Yield 72%;
HRMS (TOF, ES+): [M + H]+ calcd. for C17H16N2O + H 286.135,;
found 286.1337.
1
yellow solid, m.p. 154–155 °C. H NMR (400 MHz, CDCl3): δH
=
1.52 (t, J = 7.2 Hz, 3 H), 4.06 (s, 3 H, CH3), 4.20 (s, 3 H, CH3),
4.68 (q, J = 7.2 Hz, 2 H), 7.37–7.40 (m, 2 H), 7.53 (t, J = 8.0 Hz,1
H),7.61 (d, J = 8.0 Hz, 1 H), 7.85 (s, 1 H), 8.37 (d, J = 8.0 Hz, 1
Compound 7a: Yield 75%; yellow solid, m.p. 55–56 °C. 1H NMR
(400 MHz, CDCl3): δH = 1.55 (t, J = 6.8 Hz, 3 H), 4.78 (q, J =
H), 8.94 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δC = 14.5, 6.8 Hz, 2 H), 7.27 (dd, J = 8.0, 4.8 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 1
36.5, 56.0, 56.1, 101.4, 106.1, 107.4, 109.5, 119.6, 120.0, 121.2,
121.9, 124.6, 129.3, 137.6, 146.9, 147.4, 147.5, 153.6 ppm. IR
H), 7.79 (t, J = 7.6 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 8.39 (d, J
= 8.4 Hz, 1 H), 8.57–8.59 (m, 2 H), 9.12 (s, 1 H) ppm. 13C NMR
(KBr): ν = 1583, 1603, 2852, 2919, 3052 cm–1. C19H18N2O2 (100 MHz, CDCl3): δC = 14.9, 35.7, 104.5, 114.6, 116.0, 122.2,
˜
(306.36): calcd. C 74.49, H 5.92, N 9.14; found C 74.32, H 5.78, N
9.21.
123.8, 124.8, 129.5, 129.8, 131.2, 132.7, 145.2, 146.8, 148.8,
151.0 ppm. IR (KBr): ν = 1564, 1600, 1624, 2850, 2923, 2967,
˜
3038 cm–1. HRMS (TOF, ES+): calcd. for C16H13N3 + H [M +
H]+ 248.119; found 248.1182.
7-Isopropyl-2,3-dimethoxy-7H-indolo[2,3-c]isoquinoline (4f): Yield
75 %; pale yellow solid, m.p. 147–148 °C. 1H NMR (400 MHz,
CDCl3): δH = 1.79 (d, J = 6.8 Hz, 6 H), 4.07 (s, 3 H, CH3), 4.21 Compound 7b: Yield 72%; brown solid, m.p. 62–63 °C. 1H NMR
(s, 3 H, CH3), 5.64–5.70 (m,1 H), 7.36–7.40 (m, 2 H), 7.50 (t, J = (400 MHz, CDCl3): δH = 1.88 (d, J = 6.8 Hz, 6 H), 5.78–5.81 (m,1
7.6 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.89 (s, 1 H), 8.31 (d, J =
7.6 Hz, 1 H), 8.94 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δC
= 21.1, 45.5, 56.0, 56.1, 101.5, 106.0, 107.4, 111.3, 119.3, 119.9,
121.6, 122.0, 124.2, 129.2, 137.0, 147.2, 147.4, 153.6 (one signal not
H), 7.32 (dd, J = 8.0, 4.8 Hz, 1 H), 7.54 (t, J = 8.0 Hz, 1 H), 7.83–
7.87 (m, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 8.53 (d, J = 8.4 Hz, 1 H),
8.58–8.60 (m, 1 H), 8.69–8.71 (m, 1 H), 9.18 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δC = 21.0, 45.6, 104.6, 114.7, 115.8,
122.3, 123.8, 124.6, 129.5, 129.8, 131.1, 132.8, 144.9, 147.2, 149.0,
resolved) ppm. IR (KBr): ν = 1592, 1628, 2853, 2924 cm–1
.
˜
C20H20N2O2 (320.39): calcd. C 74.98, H 6.29, N 8.74; found C
75.13, H 6.47, N 8.57.
150.6 ppm. IR (KBr): ν = 1564, 1600, 1624, 2872, 2926, 2968,
˜
3038 cm–1. C17H15N3 (261.33): calcd. C 78.13, H 5.79, N 16.08;
found C 78.24, H 5.66, N 16.31.
7-Ethyl-10-methoxy-7H-indolo[2,3-c]isoquinoline (4g): Yield 71%;
1
yellow solid, m.p. 118–119 °C. H NMR (400 MHz, CDCl3): δH
=
2-(1-Ethyl-1H-indol-3-yl)benzonitrile (5a): Yield 30%; reddish white
1
1.53 (t, J = 6.8 Hz, 3 H), 4.03 (s, 3 H, OCH3), 4.70 (q, J = 6.8 Hz, solid, m.p. 75–76 °C. H NMR (400 MHz, CDCl3): δH = 1.52 (t, J
2 H), 7.21 (dd, J = 8.8, 2.4 Hz, 1 H), 7.50–7.59 (m, 2 H), 7.86 (t,
J = 8.0 Hz, 1 H), 7.97 (s, 1 H), 8.13 (d, J = 8.4 Hz, 1 H), 8.58 (d,
= 7.2 Hz, 3 H), 4.25 (q, J = 7.2 Hz, 2 H), 7.18–7.23 (m, 1 H), 7.27–
7.33 (m, 2 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H),
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31699
/KAP1
Date: 27-02-14 17:21:31
Pages: 8
Cu- and Pd-Cocatalyzed C–H Functionalization/C–N Formation
Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174;
7.64 (s, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.76–7.79 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δC = 15.5, 41.3, 109.9, 110.6, 112.4,
119.5, 119.7, 120.5, 122.3, 125.9, 126.5, 127.4, 129.8, 132.7, 134.1,
g) K. Godula, D. Sames, Science 2006, 312, 67; h) F. Kakiuchi,
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136.2, 139.2 ppm. IR (KBr): ν = 1598, 1609, 2217, 2854, 2924,
˜
2984, 3078, 3111 cm–1. C17H14N2 (246.31): calcd. C 82.90, H 5.73,
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The authors thank the Department of Science and Technology
(DST), New Delhi for financial assistance through the DST
PURSE program and DST fast track scheme. S. H. and B. M. are
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Received: November 12, 2013
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O31699
/KAP1
Date: 27-02-14 17:21:31
Pages: 8
S. Hazra, B. Mondal, H. Rahaman, B. Roy
FULL PAPER
C–H Functionalization/Cyclization
S. Hazra, B. Mondal, H. Rahaman,
B. Roy* ............................................. 1–8
Copper- and Palladium-Cocatalyzed Intra-
molecular C–H Functionalization/C–N
Bond Formation: A Route to the Synthesis
of Indoloisoquinoline Derivatives
A new approach to the synthesis of indolo-
isoquinoline derivatives is described. The
activation of the indole C2–H bond is ac-
complished here by using a Pd(OAc)2 and
Cu(OTf)2 bi-catalytic system. In this reac-
tion aldoximes are converted into the cor-
responding isoquinolines in open atmos-
phere under mild reaction condition.
Keywords: Homogeneous catalysis / C–H
activation / C–N bond formation / Nitro-
gen heterocycles / Copper / Palladium
8
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Eur. J. Org. Chem. 0000, 0–0