Facile synthesis of [1,2,3]-triazole-fused isoindolines, tetrahydroisoquinolines, benzoazepines and benzoazocines by palladium-copper catalysed heterocyclisation

Article abstract of DOI:10.1055/s-0032-1316839

An elegant method for the synthesis of 1,2,3-triazoles fused with five-, six-, seven- and eight-membered benzoheterocycles, including isoindoline, tetrahydroisoquinoline, benzoazepine and benzoazocine, has been developed via palladium-copper catalysed reactions in one-pot. The broad scope of this reaction was illustrated by effecting bis-heteroannulations, synthesis of uracil derivatives of biological interest, and employment of acetylene gas as an inexpensive substrate. The reactions are experimentally simple and utilise easily accessible substrates of different types. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316839

PAPER
▌545
paper
Facile Synthesis of [1,2,3]-Triazole-Fused Isoindolines, Tetrahydroisoquino-
lines, Benzoazepines and Benzoazocines by Palladium-Copper Catalysed
Heterocyclisation
Palladium-Copper Catalysed Heterocyclisation
Kaushik Brahma, Basudeb Achari, Chinmay Chowdhury*
Chemistry Division, Indian Institute of Chemical Biology (CSIR), 4, Raja S. C. Mullick Road, Kolkata 700032, India
Fax +91(33)24735971; E-mail: chinmay@iicb.res.in
Received: 05.11.2012; Accepted after revision: 06.12.2012
cycloaddition8 (IAAC), in which regioselectivity is usual-
Abstract: An elegant method for the synthesis of 1,2,3-triazoles
ly determined by the initial positions of the azide and
fused with five-, six-, seven- and eight-membered benzoheterocy-
alkyne groups present in the starting compounds, has
emerged as a possible solution to this problem.
cles, including isoindoline, tetrahydroisoquinoline, benzoazepine
and benzoazocine, has been developed via palladium-copper cata-
lysed reactions in one-pot. The broad scope of this reaction was il-
lustrated by effecting bis-heteroannulations, synthesis of uracil
derivatives of biological interest, and employment of acetylene gas
as an inexpensive substrate. The reactions are experimentally sim-
ple and utilise easily accessible substrates of different types.
On the other hand, benzo-fused aza-heterocycles (e.g.,
isoindoline,9 tetrahydroisoquinoline,10 benzoazepine,11
benzoazocine12) are considered as important scaffolds be-
cause of their presence as key structural units in various
drugs, bioactive compounds, and natural products. Nota-
bly, benzo-heterocycles fused with 1,2,3-triazoles have
been shown13 to mimic benzolactams that are difficult to
access, but which are known for effectively mimicking te-
leocidines.14 Therefore, fusion of the aforesaid heterocy-
cles with 1,2,3-triazole, resulting in the formation of
compounds 1–4 (Figure 1), could perhaps lead to potent
pharmacophores and/or important building blocks in
pharmaceutical research. Indeed, triazoles fused with oth-
er heterocycles have already proven to be important in
drug discovery programs due to their broad spectrum of
activities such as anxiolytic15a (e.g., alprazolam and es-
tazolam drugs), antidepressant (e.g., triazolam drug),15b
anti-allergic,15c glycosidase inhibitor,15d and 5-HT1A/B/D
receptor antagonist.15e In addition, compounds 516a and
616b are being considered as potent chemotherapeutic
agents (Figure 1). In view of the immense biological im-
portance of this class of compounds, interest in this area
has been growing in recent times.
Key words: 1,2,3-triazoles, nitrogen heterocycles, intramolecular
reactions, azide-alkyne cycloaddition, bis-heteroannulations
In recent years, novel nitrogen-containing heterocycles
have found widespread applications in drug development.
Notable among them are 1,2,3-triazoles, which have at-
tracted enormous interest due to their wide range of bio-
logical activities such as antiviral,1a antifungal,1b anti-
parasitic,1c antimicrobial,1d immunostimulant1e and oth-
ers.1f Additionally, these heterocycles have remarkable
metabolic stability and have proven to be important as
amide surrogates in various bioactive agents.2 Historical-
ly, the first straightforward synthesis of 1,4- and 1,5-sub-
stituted 1,2,3-triazoles as a regioisomeric mixture was
achieved by Huisgen3 during the 1960s. Later, regioselec-
tive synthesis of 1,4-substituted 1,2,3-triazoles was
established4 through copper-catalysed azide–alkyne cy-
cloaddition (CuAAC) under mild reaction conditions. In
the recent past, synthesis of 1,5-substituted 1,2,3-tri-
azoles, the other regioisomer, was achieved by Fokin,
who employed a catalytic amount of tetramethylammoni-
um hydroxide5a or [Cp*RuCl(PPh3)2].5b,c These catalysed
cycloadditions, popularly known as ‘click reactions’,
have found widespread applications in areas ranging from
medicinal chemistry6a,b,1f to materials science.6c–f Mostly
terminal alkynes have been used in these reactions, result-
ing in 1,4- or 1,5-substituted 1,2,3-triazoles. But an ele-
gant synthesis of fully 1,4,5-substituted 1,2,3-triazoles in
one pot7 employing azide and internal alkyne as substrates
is more challenging and remains to be developed. The em-
ployment of unsymmetrical internal alkynes in these reac-
tions often results in diminished reaction rates and poor
regioselectivity. However, intramolecular azide–alkyne
Me
Me
N
O
R
H
N
N
N
N
N
N
N
H
N
( )n
HN
N
5
N
6
1 n = 1
2 n = 2
3 n = 3
4 n = 4
(R = H, alkyl, aryl)
N
Figure 1 Important fused 1,2,3-triazoles
Literature reports indicate that fully 1,4,5-substituted
1,2,3-triazoles including fused derivatives can be synthe-
sised primarily by two strategic approaches. One involves
intermolecular regioselective dipolar cycloaddition be-
tween azide and terminal alkyne followed by metal-
catalysed arylation of the resulting 1,2,3-triazole.17 The
SYNTHESIS 2013, 45, 0545–0555
Advanced online publication: 04.01.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316839; Art ID: SS-2012-Z0863-OP
© Georg Thieme Verlag Stuttgart · New York

546
K. Brahma et al.
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alternative approach18 involves thermal or metal-cata- provided comparable yields of the products. Therefore,
lysed regioselective IAAC of the azido-alkyne substrates we modified the previous reaction conditions and elabo-
in which the acetylenic group is disubstituted. In a contin- rated the scope of this present reaction procedure by using
uation of our work on palladium-catalysed reactions, we substrates 7a–d as shown in Table 1. For substrates 7a–b,
followed the latter approach in which substrates having the reactions were found to be complete within a few
azide functionality tethered to acetylene underwent metal- hours (0.5–6 h) upon heating at 115 °C, but the reactions
catalysed C-arylation at the terminal acetylene and subse- with substrate 7c to afford the seven-membered ring-
quent intramolecular cycloaddition affording 1,2,3-tri- fused product 3 required 7–17 hours heating (Table 1, en-
azoles fused with morpholine,19a 1,4-benzoxazine,19b 1,4- tries 11–15). More significantly, the reaction did not pro-
benzodiazepin-5-one,19c 1,4-benzodiazocin-6-one,19c and ceed at all when compound 7d was employed as a
piperazine.19d We speculated that replacement of these reactant. Therefore, we were forced to increase the reac-
substrates by ortho-iodo-azides 7a–d and subsequent re- tion temperature to 150 °C (for 13–19 h) to achieve for-
action with terminal acetylenes 8 in the presence of a pal- mation of the desired eight-membered-ring analogues 4
ladium catalyst could allow access to 1,2,3-triazole-fused (Table 1, entries 16–18), albeit with moderate yields. Both
five-, six-, seven- and eight-membered benzo-heterocy- aryl and alkyl acetylenes having different functional
cles 1–4 in one pot. In this paper, we describe in detail the groups successfully participated in the reactions. Typical-
results achieved (Scheme 1).20 This straightforward syn- ly, aryl acetylenes having electron-withdrawing groups
thesis of tricyclic nitrogen-containing heterocycles consti- (EWGs) provided better yields than those with electron-
tutes an important alternative strategy to the reported two- donating groups (EDGs) as seen from Table 1 (entry 2 vs.
step route,17d as shown in Scheme 1.
3, entry 7 vs. 6, entry 13 vs. 12, and entry 17 vs. 18). A
sugar moiety with acetylene pendant was found to be
compatible in this reaction, affording the products 2e and
3e, respectively (Table 1, entries 9 and 15). However, use
of tosylated acetylene 8h led to the isolation of the unex-
pected product 2f (Table 1, entry 10), which is possibly
formed through elimination of p-TsOH from the initially
formed tosylated product under the reaction conditions.
R
n = 1–4; X = I
N
N
(this work)
X
R
N
+
Pd(PPh3)2Cl2, CuI
Et3N, DMF, heat
N3
( )n
( )n
8
1–4
7
Cu(OAc)2·H2O
H2O, 100 °C
n = 1, 2
X = I, Br
X
N
N
Pd(PPh3)2Cl2
In view of the immense importance of 5-substituted ura-
cils,22 and in continuation of our work on the synthesis of
biologically active compounds,23 we became interested in
the demethylation of 2,4-dimethoxypyrimidine deriva-
tives 2d and 3d (Table 1, entries 8 and 14). Accordingly,
when compounds 2d and 3d were successively treated
with chlorotrimethylsilane and sodium iodide in anhy-
drous acetonitrile at room temperature overnight, the ex-
pected uracil derivatives 11a,b24 were produced smoothly
in excellent yields (Scheme 3).
1, 2
R
N
n-Bu4NOAc
NMP, 100 °C
(ref. 17d)
( )n
9
Scheme 1 Synthesis of 1,2,3-triazole-fused heterocycles 1–4
The starting ortho-iodo-azides 7a–d (X = I, n = 1–4) re-
quired for this study were synthesised from their corre-
sponding precursor alcohols 10a–d. For this, the latter,
which were prepared in a few steps using reported proce-
dures,21 were subjected to mesylation followed by azida-
tion as shown in Scheme 2.
We then studied the applicability of the regioselective
IAAC reaction for bis-heteroannulations, employing 1,3-
diethynyl benzene 12 as reactant (Table 2). To our satis-
faction, bis-heteroannulated products (13a–d) were
formed readily when o-iodo-azides 7a–d were employed
as coupling partners (Table 2, entries 1–4). Thus, this
method is amenable to the synthesis of polyheteroannulat-
ed frameworks in one pot and under operationally simple
palladium-catalysed reaction conditions.
I
I
a n = 1
b n = 2
c n = 3
d n = 4
a, then
b or c
OH
N3
( )n
( )n
7a–d
10a–d
Scheme 2 Synthesis of starting substrates 7a–d. Reagents and con-
ditions: (a) MsCl, Et3N, CH2Cl2, 0–5 °C, 2 h; (b) NaN3, DMF, r.t.,
2 h, 94% (for 7a); (c) NaN3, DMF, 90 °C, 1 h, 90–92% (for 7b–d).
O
MeO
With substrates 7a–d in hand, we investigated the influ-
ence of catalyst, solvent, base and temperature on the for-
mation of the target products. These studies revealed that
bis(triphenylphosphine)palladium(II) chloride and cop-
per(I) iodide constitute the best catalytic system, whereas
DMF and Et3N prove to be the optimal solvent and base,
respectively. We also observed that carrying out the reac-
tions by immediate heating (115 °C for 7a–c, 150 °C for
7d) instead of initial stirring at r.t. (for 12 h) followed by
heating (at 115 °C for a few hours) as reported earlier20
NH
N
HN
N
O
OMe
N
N
N
Me3SiCl, NaI
MeCN, r.t., overnight
N
N
N
( )n
11a n = 2 (85%)
11b n = 3 (82%)
2d n = 2
3d n = 3
Scheme 3 Synthesis of uracil derivatives 11a and 11b
Synthesis 2013, 45, 545–555
© Georg Thieme Verlag Stuttgart · New York

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Palladium-Copper Catalysed Heterocyclisation
547
Table 1 Synthesis of Fused 1,2,3-Triazoles 1–4a
R
N
N
I
Pd(PPh3)2Cl2, CuI, Et3N
+ R
N
N3
DMF, 115–150 °C
( )n
7a–d
8
1–4
Entry
Azide 7
n
1
1
Alkyne 8
R
Temp (°C) Time (h)
Product
Yield (%)b
N
N
1
7a
8a
8b
115
2.0
70
N
1a
1b
CO2Me
OMe
2
7a
115
0.5
72
3
4
7a
7a
1
1
8c
115
115
2.5
5.5
1c
65
62
8d
n-Bu
1d
N
N
5
7b
2
8a
115
2.5
76
N
2a
2b
6
7
7b
7b
2
2
8c
8e
115
115
2.0
0.5
47
79
NO2
2c
N
N
OMe
8
9
7b
7b
2
2
8f
115
115
0.75
1.0
2d
68
54
MeO
O
O
O
O
8g
2e
H
O
O
N
N
10c
7b
7c
2
3
8h
8a
CH2CH2OTs
115
115
2.5
40
55
N
2f
N
N
11d
12.0
N
3a
3b
12d
13
7c
7c
7c
7c
3
3
3
3
8c
8e
8f
115
115
115
115
17.0
7.0
40
50
32
38
3c
3d
3e
14d
15d
15.0
12.0
8g
© Georg Thieme Verlag Stuttgart · New York
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548
K. Brahma et al.
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Table 1 Synthesis of Fused 1,2,3-Triazoles 1–4a (continued)
R
N
I
Pd(PPh3)2Cl2, CuI, Et3N
N
+ R
N
N3
DMF, 115–150 °C
( )n
7a–d
8
1–4
Entry
Azide 7
n
Alkyne 8
R
Temp (°C) Time (h)
Product
Yield (%)b
N
N
N
16d
7d
4
8a
150
13.0
40
4a
4b
17d
18d
7d
7d
4
4
8b
8c
150
150
13.0
19.0
43
38
4c
a Reaction conditions: azide 7 (1.0 mmol), alkyne 8 (1.25 mmol), [Pd(PPh3)2Cl2] (0.035 mmol), CuI (0.07 mmol), Et3N (5.0 mmol), anhydrous
DMF (5 mL), 115–150 °C, 0.5–19 h.
b Yield of chromatographically isolated pure products based on azide 7.
c Elimination of p-TsOH from the tosylated product under the reaction conditions leading to the formation of 2f.
d In addition to the expected product 3/4, the corresponding acyclic intermediate (internal alkyne), formed through coupling between terminal
alkyne and o-iodo-azide 7c/7d through the Sonogashira pathway, was also isolated (12–18%).
Table 2 Synthesis of Bis-heteroannulated Products 13a–da
these conditions did not furnish any desired product 2a′;
instead, triazole 14b (where n = 2) was isolated with 70%
N
N
N
( )n
yield. However, carrying out this reaction at higher tem-
perature (110 °C) succeeded in delivering the desired
product 2a′, albeit in only 23% yield. We then changed
this one-pot strategy and used two-step reactions as shown
in Scheme 4 (results in Table 3). Accordingly, cycloaddi-
tion of acetylene (gas) with the azido group of substrates
7b–d was first carried out at 60 °C in the presence of CuI
I
Pd(PPh3)2Cl2, CuI
+
N3
Et3N, DMF, 115–150 °C
( )n
7a–d
12
13a–d
N
N
N
( )n
Entry
Azide 7
n
Temp (°C) Time (h) Yield (%)b (3 mol%) and K2CO3 (2 equiv), affording the intermediate
1,2,3-triazoles 14b–d. These crude intermediates were
1
2
3
4
7a
7b
7c
7d
1
2
3
4
115
115
130
130
2
2
13a (54)
13b (50)
13c (47)
13d (27)
then directly submitted to palladium-catalysed cyclocon-
densation reaction, furnishing the target products 2a′–4a′
with moderate to good yields (Table 3, entries 2–4).
12
15
n = 1
N
I
acetylene, Pd(PPh3)2Cl2
N
N
a Reaction conditions: azide 7 (1.0 mmol), alkyne 12 (0.6 mmol),
[Pd(PPh3)2Cl2] (0.035 mmol), CuI (0.07 mmol), Et3N (5.0 mmol), an-
hydrous DMF (6 mL), 115–150 °C, 2–15 h.
N3
CuI, K2CO3, DMF, 60 °C, 4 h
( )n
7a–d
n = 2–4
1a'
b Yield of chromatographically isolated pure product based on azide 7.
N
N
conditions A
(for 14b,c )
or
I
N
acetylene
N
N
N
( )n
CuI, K2CO3
( )n
conditions B
(for 14d)
We also tested the feasibility of using acetylene gas as an
inexpensive substrate in place of substituted acetylenes 8
to gain access to fused triazoles 1–4 (R = H, see Figure 1)
in which 1,2,3-triazoles are 1,5-disubstituted rather than
fully substituted. Toward this objective, we first em-
ployed o-iodo-azide 7a as a synthon and heated the reac-
tion at 60 °C (4 h) under balloon pressure of acetylene in
the presence of [Pd(PPh3)2Cl2] (1.5 mol%), CuI (3 mol%)
and K2CO3 (2 equiv) in anhydrous DMF. Pleasingly, the
desired product 1a′ was formed with 60% yield along
with the acyclic 1,2,3-triazole derivative 14a (where
n = 1) with 24% yield (Scheme 4). With substrate 7b, on
the other hand, heating the reaction at 60 °C (4 h) under
2–4a'
DMF, 60 °C, 4 h
14 (crude)
(n = 2–4)
2a',14b n = 2
3a',14c n = 3
4a',14d n = 4
Scheme 4 Synthesis of fused 1,2,3-triazoles 1a′, 2a′, 3a′ and 4a′ by
employing acetylene (gas). Conditions A: [Pd(PPh3)2Cl2], K2CO3,
TBAB, DMF, 110–130 °C; Conditions B: Pd(OAc)2, NaHCO3,
TBAB, DMF, 130 °C.
The structures of products 1–4 were determined on the ba-
sis of their spectral (IH and 13C NMR, IR and mass) and
analytical data. In the 1H NMR spectra, signals for the N-
CH2 protons appeared at δ = 5.39 ppm as a singlet for 1a.
Synthesis 2013, 45, 545–555
© Georg Thieme Verlag Stuttgart · New York

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Palladium-Copper Catalysed Heterocyclisation
549
respectively.25 A variety of o-iodo-azides and acetylenic
substrates were found to react under the reaction condi-
tions, affording a diverse array of products with moderate
to good yields. The reaction protocol was successfully uti-
lised for the formation of one C–C and two C–N bonds in
a one-pot reaction. The broad scope of this reaction was il-
lustrated by effecting bis-heteroannulations, synthesis of
uracil derivatives of biological interest, and employment
of acetylene gas as an inexpensive substrate. We believe
that the reaction protocol can be used in library generation
based on diversity oriented synthesis for lead develop-
ment and, thus, would be of interest to the practitioners of
organic and medicinal chemistry.
Table 3 Synthesis of Fused 1,2,3-Triazoles 1a′–4a′
Entry
Substrate Reaction temp. of the crude
Yield
intermediate 14b–d (heating time) 1–4a′ (%)e
_
1
2
3
4
7aa
7bb
7cb
7db
1a′ (60)
110 °C (4 h for 14b)c
130 °C (4 h for 14c)c
130 °C (2.5 h for 14d)d
2a′ (82)
3a′ (52)
4a′ (42)
a Azide 7a was directly converted into product 1a′ as depicted in
Scheme 4.
b Reaction conditions: azide 7b–d (1.0 mmol), CuI (0.03 mmol),
K2CO3 (2.0 mmol), anhydrous DMF (5 mL), 60 °C, 4 h under balloon
pressure of acetylene; the resulting crude product 14b–d obtained
through standard work-up was then used for next step of the reaction.
c Heating was carried out under reaction conditions A (as described in
Scheme 4).
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were obtained with a JASCO FT/IR-4200 infra-
1
red spectrometer either neat or as KBr plates. H and 13C NMR
d Heating was carried out under reaction conditions B (as described in
Scheme 4).
spectra were recorded with Bruker-300, 500 or 600 MHz NMR
spectrometers and chemical shifts are reported relative to tetrameth-
ylsilane (TMS) as internal reference. Mass spectra were recorded in
ESI-TOF, EI or FAB ionization mode. HRMS were recorded with
a Q-Tof Micro or JEOL JMS-700 mass spectrometer. Crystallo-
graphic data were obtained with a Bruker Kappa Apex 2 instrument.
Column chromatography was performed using silica gel (60–120 or
100–200 mesh) [Merck, India]. Thin-layer chromatography (TLC)
was performed on silica gel 60 F254 aluminum sheets [Merck, Ger-
many] and visualization of the developed chromatogram was
achieved by UV absorbance. Petroleum ether (PE) refers to the frac-
tion boiling in the range 60–80 °C.
e Chromatographically isolated, pure product.
As expected, these signals shifted upfield in the products
with larger rings [XX′ part of AA′XX′ and AA′BB′XX′
systems at δ = 4.61 and 4.36 ppm, respectively, for 2a and
3a, and double doublets at δ = 4.81 (J = 14.1, 6.3 Hz) and
3.61 ppm (J = 14.1, 11.7 Hz) for 4a] as the protons are no
longer benzylic. The signals of the benzylic protons of 2a
and 3a also appeared as components of subspectra of type
AA′XX′ and AA′BB′XX′ at δ = 3.27 and 2.76 ppm, re-
spectively, whereas in 4a, one of the signals appeared as a
double doublet at δ = 2.95 ppm (dd, J = 13.8, 8.4 Hz) and
the second at around δ = 2.15 ppm, overlapped by peaks
for other protons. Additionally, unambiguous structural
confirmation also came from X-ray diffraction analysis of
the representative eight-membered-ring product 4a (Fig-
ure 2).
Preparations of starting materials 7a–d and their spectral data are
provided in the Supporting Information.
[1,2,3]-Triazole-Fused Products 1–4; General Procedure
The reagents [Pd(PPh3)2Cl2] (24.6 mg, 0.035 mmol), CuI (13.3 mg,
0.07 mmol) and Et3N (0.71 mL, 5.0 mmol) were sequentially added
to a solution of o-iodo-azide 7a–c (1.0 mmol) in anhydrous DMF (8
mL) and the mixture was stirred at r.t. under an argon atmosphere
for 20 min. Acetylenic compound 8 (1.25 mmol) dissolved in anhy-
drous DMF (1 mL) was added dropwise under argon. The reaction
mixture was then heated at 115 °C for the requisite time (0.5–17 h,
see Table 1). After completion of the reaction (TLC), the solvent
was removed in vacuo; the residue was mixed with H2O (30 mL)
and extracted with EtOAc (2 × 25 mL). The combined organic ex-
tracts were dried with anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The resulting residue was purified through
silica gel (100–200 mesh) column chromatography (EtOAc–PE,
15–20% v/v) to afford the corresponding product 1–3.
The same procedure was adopted for the synthesis of products 4
(employing o-iodo-azide 7d and acetylenic compound 8, see Table
1), the only difference being that the reaction mixture was heated at
150 °C instead of 115 °C and for 13–19 h.
3-Phenyl-8H-[1,2,3]triazolo[5,1-a]isoindole (1a)
Yield: 0.163 g (70%); light-brown solid; mp 152–154 °C (lit.17d
153–155 °C).
IR (KBr): 3056, 2963, 1607, 1444, 1362, 1172, 982, 762, 699 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 5.39 (s, 2 H), 7.39–7.56 (m, 6 H),
7.90–7.97 (m, 3 H).
Figure 2 ORTEP representation of 4a
13C NMR (CDCl3, 75 MHz): δ = 50.9, 121.2, 124.1, 126.9, 128.0,
128.1, 128.3, 128.7, 128.9, 131.2, 138.9, 139.2, 141.1.
MS (ESI): m/z = 234.04 [M + H]+.
HRMS (EI, 70 eV): m/z [M]+ calcd for C15H11N3: 233.0953; found:
233.0960.
In conclusion, we have described a straightforward palla-
dium-copper catalysed method for the synthesis of 1,2,3-
triazoles fused with five-, six-, seven- and eight-
membered benzoheterocycles, featuring isoindoline, tet-
rahydroisoquinoline, benzoazepine and benzo-azocine,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 545–555

550
K. Brahma et al.
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Methyl 4-(8H-[1,2,3]Triazolo[5,1-a]isoindol-3-yl)benzoate (1b)
MS (ESI): m/z = 300.20 [M + Na]+.
HRMS (EI, 70 eV): m/z [M]+ calcd for C17H15N3O: 277.1215;
Yield: 0.210 g (72%); white solid; mp 196–198 °C.
IR (KBr): 2951, 1710, 1609, 1437, 1283, 1110, 766, 703 cm–1.
found: 277.1212.
1H NMR (CDCl3, 300 MHz): δ = 3.97 (s, 3 H), 5.42 (s, 2 H), 7.44–
7.59 (m, 3 H), 7.93 (br d, J = 7.5 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 2 H),
8.21 (d, J = 8.4 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 51.0, 52.2, 121.4, 124.3, 126.7,
127.7, 128.8, 128.9, 129.5, 130.2, 135.7, 138.3, 139.8, 141.3, 166.7.
MS (ESI): m/z = 314.14 [M + Na]+.
HRMS (EI, 70 eV): m/z [M]+ calcd for C17H13N3O2: 291.1008;
1-(4-Nitrophenyl)-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquino-
line (2c)
Yield: 0.231 g (79%); yellow solid; mp 192–193 °C.
IR (KBr): 3064, 2949, 1601, 1508, 1340, 1184, 1104, 858, 768, 689
cm–1.
1H NMR (CDCl3, 300 MHz): δ = 3.30, 4.63 (2 H each, comprising
AA′XX′ system), 7.24–7.29 (m, 1 H), 7.34–7.42 (m, 2 H), 7.56 (d,
J = 7.8 Hz, 1 H), 7.97 (d, J = 8.7 Hz, 2 H), 8.34 (d, J = 8.7 Hz, 2 H).
found: 291.0999.
13C NMR (CDCl3, 75 MHz): δ = 29.2, 44.9, 124.0, 124.3, 124.4,
127.7, 128.8, 128.9, 129.9, 130.4, 133.2, 138.3, 140.6, 147.5.
MS (ESI): m/z = 315.02 [M + Na]+.
3-(4-Methoxyphenyl)-8H-[1,2,3]triazolo[5,1-a]isoindole (1c)
Yield: 0.171 g (65%); white solid; mp 146–148 °C (lit.17d 154–
156 °C).
IR (KBr): 3069, 2838, 1614, 1576, 1507, 1451, 1419, 1358, 1301,
1250, 1174, 1029, 982, 828, 773 cm–1.
HRMS (EI, 70 eV): m/z [M]+ calcd for C16H12N4O2: 292.0960;
found: 292.0962.
1H NMR (CDCl3, 300 MHz): δ = 3.89 (s, 3 H), 5.38 (s, 2 H), 7.07
(d, J = 8.4 Hz, 2 H), 7.39–7.56 (m, 3 H), 7.88 (app d, J = 8.1 Hz,
3 H).
13C NMR (CDCl3, 75 MHz): δ = 50.9, 55.3, 114.3, 120.9, 123.8,
124.1, 128.1, 128.2, 128.7, 138.3, 139.1, 140.9, 159.5.
MS (ESI): m/z = 264.05 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C16H13N3NaO: 286.0956;
1-(2,4-Dimethoxypyrimidin-5-yl)-5,6-dihydro[1,2,3]triazo-
lo[5,1-a]isoquinoline (2d)
Yield: 0.210 g (68%); white solid; mp 134–136 °C.
IR (KBr): 2953, 1619, 1563, 1490, 1468, 1399, 1358, 1282, 1191,
1078, 1013, 739 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 3.30, 4.65 (2 H each, comprising
AA′XX′ system), 3.89 (s, 3 H), 4.09 (s, 3 H), 7.14–7.24 (m, 2 H),
7.27–7.35 (m, 2 H), 8.49 (s, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 28.9, 44.9, 53.9, 54.9, 107.1, 124.5,
124.6, 127.3, 128.2, 129.1, 131.1, 132.3, 134.8, 159.4, 165.5, 168.4.
found: 286.0950.
3-Butyl-8H-[1,2,3]triazolo[5,1-a]isoindole (1d)
Yield: 0.132 g (62%); colourless solid; mp 76–78 °C.
MS (ESI): m/z = 332.06 [M + Na]+.
HRMS (EI, 70 eV): m/z [M]+ calcd for C16H15N5O2: 309.1226;
IR (KBr): 3067, 2926, 2860, 1448, 1302, 1163, 1006, 767, 724
cm–1.
1H NMR (CDCl3, 300 MHz): δ = 0.97 (t, J = 7.2 Hz, 3 H), 1.38–1.51
(m, 2 H), 1.75–1.85 (m, 2 H, overlapped by H2O signal), 2.95 (t,
J = 7.5 Hz, 2 H), 5.30 (s, 2 H), 7.34–7.40 (m, 1 H), 7.44–7.51 (m,
2 H), 7.61 (d, J = 7.5 Hz, 1 H).
found: 309.1222.
1-({(3aR,5R,6S,6aR)-5-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-
2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-yloxy}methyl)-
5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2e)
Yield: 0.240 g (54%); brown gum.
13C NMR (CDCl3, 75 MHz): δ = 13.7, 22.2, 25.5, 31.5, 50.8, 120.7,
124.0, 127.6, 128.4, 128.6, 139.1, 139.3, 140.5.
MS (ESI): m/z = 236.05 [M + Na]+.
IR (neat): 2986, 2935, 2099, 1639, 1377, 1215, 1162, 1074, 1022,
849, 758 cm–1.
1H NMR (CDCl3, 600 MHz): δ = 1.23 (s, 3 H), 1.32 (s, 3 H), 1.39
(s, 3 H), 1.50 (s, 3 H), 3.22–3.25 (m, 2 H), 3.97–4.03 (m, 2 H),
4.11–4.13 (m, 1 H), 4.17 (d, J = 3.0 Hz, 1 H), 4.29–4.31 (m, 1 H),
4.54–4.58 (m, 1 H), 4.61–4.66 (m, 1 H), 4.71 (d, J = 4.2 Hz, 1 H),
4.91 (d, J = 12 Hz, 1 H), 5.01 (d, J = 12 Hz, 1 H), 5.88 (d,
J = 3.6 Hz, 1 H), 7.33–7.39 (m, 3 H), 7.84–7.86 (m, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 25.0, 26.0, 26.6, 26.7, 28.8, 44.6,
63.3, 67.1, 72.1, 80.9, 81.0, 82.1, 105.1, 108.8, 111.6, 124.3, 125.6,
127.7, 128.2, 129.2, 132.1, 132.3, 138.6.
1-Phenyl-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2a)
Yield: 0.188 g (76%); yellow solid; mp 150–151 °C (lit.17d 154–
156 °C).
IR (KBr): 3049, 1496, 1440, 1360, 1195, 1153, 994, 759, 698 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 3.27, 4.61 (2 H each, comprising
AA′XX′ system), 7.19 (td, J = 1.1, 7.4 Hz, 1 H), 7.26–7.36 (m, 2 H),
7.39–7.50 (m, 3 H), 7.60 (d, J = 7.5 Hz, 1 H), 7.71–7.75 (m, 2 H).
13C NMR (CDCl3, 150 MHz): δ = 29.3, 45.0, 124.5, 125.1, 127.5,
128.42, 128.48, 128.5, 128.7, 129.1, 129.3, 131.7, 132.8, 143.0.
MS (ESI): m/z = 465.97 [M + Na]+.
HRMS (EI, 70 eV): m/z [M]+ calcd for C23H29N3O6: 443.2056;
found: 443.2049.
MS (ESI): m/z = 248.24 [M + H]+.
HRMS (EI, 70 eV): m/z [M]+ calcd for C16H13N3: 247.1109; found:
247.1108.
1-Vinyl-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2f)
Yield: 0.079 g (40%); yellow solid; mp 110–112 °C.
1-(4-Methoxyphenyl)-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquin-
oline (2b)
Yield: 0.130 g (47%); brown gum.
IR (KBr): 3062, 2930, 2836, 1450, 1300, 1158, 1002, 753 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 3.20, 4.56 (2 H each, comprising
AA′XX′ system), 5.49 (dd, J = 1.5, 11.1 Hz, 1 H), 6.31 (dd, J = 1.8,
17.4 Hz, 1 H), 6.98 (dd, J = 11.1, 17.4 Hz, 1 H), 7.33–7.41 (m,
3 H), 7.71 (d, J = 6.9 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 29.2, 44.6, 117.6, 124.7, 124.8,
125.1, 127.7, 128.5, 128.9, 132.9, 140.5.
IR (neat): 2934, 2839, 1614, 1513, 1465, 1364, 1297, 1250, 1180,
1031, 838 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 3.26, 4.59 (2 H each, comprising
AA′XX′ system), 3.88 (s, 3 H), 7.00 (d, J = 8.7 Hz, 2 H), 7.18–7.23
(m, 1 H), 7.29–7.35 (m, 2 H), 7.59–7.66 (m, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 29.1, 44.9, 55.2, 113.9, 123.9,
124.1, 125.0, 127.3, 128.3, 128.7, 128.8, 129.6, 132.6, 142.7, 159.6.
HRMS (EI, 70 eV): m/z [M]+ calcd for C12H11N3: 197.0953; found:
197.0944.
Synthesis 2013, 45, 545–555
© Georg Thieme Verlag Stuttgart · New York

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Palladium-Copper Catalysed Heterocyclisation
551
1-(Phenyl)-6,7-dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]aze-
pine (3a)
IR (neat): 2985, 2936, 2097, 1641, 1454, 1377, 1216, 1162, 1075,
1022, 849, 756 cm–1.
Yield: 0.144 g (55%); yellow solid; mp 101–103 °C.
1H NMR (CDCl3, 600 MHz): δ = 1.29 (s, 3 H), 1.31 (s, 3 H), 1.40
(s, 3 H), 1.50 (s, 3 H), 2.41–2.48 (m, 2 H), 2.62–2.68 (m, 2 H),
3.95–4.01 (m, 2 H), 4.12–4.15 (m, 2 H), 4.28–4.34 (m, 2 H), 4.41–
4.46 (m, 1 H), 4.67 (d, J = 3.6 Hz, 1 H), 4.72 (d, J = 11.4 Hz, 1 H),
4.83 (d, J = 11.4 Hz, 1 H), 5.87 (d, J = 3.6 Hz, 1 H), 7.35–7.43 (m,
3 H), 7.62 (dd, J = 1.5, 7.5 Hz, 1 H).
13C NMR (CDCl3, 150 MHz): δ = 25.3, 26.2, 26.8, 26.81, 30.3, 31.1,
46.0, 62.9, 67.2, 72.4, 81.2, 81.5, 82.3, 105.2, 108.9, 111.8, 126.9,
127.4, 129.1, 129.9, 129.91, 136.6, 138.7, 140.6.
IR (KBr): 3059, 2926, 2856, 1605, 1448, 1361, 991, 768 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 2.44, 2.76, 4.36 (2 H each, form-
ing AA′BB′XX′ system), 7.24–7.40 (m, 7 H), 7.71 (dd, J = 1.5,
7.8 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 30.2, 30.9, 45.8, 127.1, 127.8,
127.9, 128.5, 128.9, 129.7, 129.8, 131.0, 132.9, 138.9, 143.6.
MS (ESI): m/z = 284.12 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H15N3Na: 284.1164;
MS (ESI): m/z = 458.25 [M + H]+.
HRMS (EI, 70 eV): m/z [M]+ calcd for C24H31N3O6: 457.2213;
found: 284.1156.
1-(4-Methoxyphenyl)-6,7-dihydro-5H-benzo[c]-[1,2,3]triazo-
lo[1,5-a]azepine (3b)
found: 457.2221.
Yield: 0.117 g (40%); brown solid; mp 108–110 °C.
Phenyl-5,6,7,8-tetrahydrobenzo[c][1,2,3]triazolo[1,5-a]azocine
(4a)
IR (KBr): 2935, 1610, 1512, 1465, 1359, 1296, 1248, 1180, 1025,
837, 771 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 2.42, 2.75, 4.34 (2 H each, form-
ing AA′BB′XX′ system), 3.82 (s, 3 H), 6.89 (app d, J = 9.0 Hz,
2 H), 7.25–7.28 (m, 1 H), 7.33 (d, J = 7.2 Hz, 1 H), 7.37–7.39 (m,
2 H), 7.64 (app d, J = 9.0 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 30.3, 30.9, 45.9, 55.2, 113.9, 123.6,
127.2, 128.0, 128.5, 128.9, 129.6, 129.8, 132.3, 138.9, 143.5, 159.4.
MS (ESI): m/z = 292.23 [M + H]+.
Yield: 0.110 g (40%); white solid; mp 154–156 °C.
IR (KBr): 3059, 2933, 2859, 1603, 1445, 1353, 1253, 1218, 982,
768, 698 cm–1.
1H NMR (CDCl3, 600 MHz): δ = 1.53–1.61 (m, 1 H), 1.81–1.92 (m,
1 H), 2.13–2.17 (m, 2 H), 2.23–2.26 (m, 1 H), 2.95 (dd, J = 8.4,
13.8 Hz, 1 H), 3.61 (dd, J = 11.7, 14.1 Hz, 1 H), 4.81 (dd, J = 6.3,
14.1 Hz, 1 H), 7.21 (dd, J = 1.2, 7.8 Hz, 1 H), 7.23–7.29 (m, 4 H),
7.43 (br d, J = 7.2 Hz, 1 H), 7.47 (td, J = 1.6, 7.4 Hz, 1 H), 7.59–
7.62 (m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H17N3NaO: 314.1269;
found: 314.1261.
13C NMR (CDCl3, 150 MHz): δ = 29.1, 29.3, 32.6, 48.1, 126.60,
126.65, 126.7, 127.6, 128.4, 130.1, 130.4, 130.6, 131.1, 133.3,
143.6, 143.7.
MS (ESI): m/z = 298.16 [M + Na]+.
HRMS (ESI): m/z [M+ H]+ calcd for C18H18N3: 276.1501; found:
1-(4-Nitrophenyl)-6,7-dihydro-5H-benzo[c][1,2,3]triazolo[1,5-
a]azepine (3c)
Yield: 0.153 g (50%); yellow solid; mp 178–180 °C.
276.1504.
IR (KBr): 2939, 2860, 1601, 1512, 1349, 1251, 1112, 989, 858, 759
cm–1.
1-(4-Carbomethoxyphenyl)-5,6,7,8-tetrahydroben-
zo[c][1,2,3]triazolo[1,5-a]azocine (4b)
1H NMR (CDCl3, 600 MHz): δ = 2.47, 2.77, 4.38 (2 H each, form-
ing AA′BB′XX′ system), 7.31–7.35 (m, 2 H), 7.44–7.47 (m, 2 H),
7.94 (d, J = 8.4 Hz, 2 H), 8.21 (d, J = 9.0 Hz, 2 H).
Yield: 0.143 g (43%); white solid; mp 180–182 °C.
IR (KBr): 3061, 2944, 2858, 1717, 1609, 1437, 1278, 1109, 978,
862, 775 cm–1.
13C NMR (CDCl3, 150 MHz): δ = 30.1, 31.0, 46.0, 123.9, 126.9,
127.4, 127.5, 128.8, 130.2, 130.5, 134.6, 137.6, 139.1, 141.3, 147.1.
MS (ESI): m/z = 328.97 [M + Na]+.
HRMS (EI, 70 eV): m/z [M]+ calcd for C17H14N4O2: 306.1117;
found: 306.1121.
1H NMR (CDCl3, 600 MHz): δ = 1.54–1.61 (m, 1 H), 1.81–1.89 (m,
1 H), 2.12–2.19 (m, 2 H), 2.23–2.27 (m, 1 H), 2.98 (dd, J = 8.4,
13.8 Hz, 1 H), 3.62 (dd, J = 11.7, 14.1 Hz, 1 H), 3.89 (s, 3 H), 4.82
(dd, J = 6.3, 14.1 Hz, 1 H), 7.19 (dd, J = 0.6, 7.8 Hz, 1 H), 7.27 (td,
J = 1.2, 8.4 Hz, 1 H, overlapped by solvent peak), 7.45 (br d,
J = 7.2 Hz, 1 H), 7.50 (td, J = 1.2, 7.5 Hz, 1 H), 7.69 (app d,
J = 8.4 Hz, 2 H), 7.95 (app d, J = 9.0 Hz, 2 H).
13C NMR (CDCl3, 150 MHz): δ = 29.0, 29.2, 32.7, 48.2, 52.1, 126.2,
126.4, 126.8, 129.0, 129.8, 129.9, 130.5, 130.9, 134.3, 135.6, 142.7,
143.6, 166.9.
1-(2,4-Dimethoxypyrimidin-5-yl)-6,7-dihydro-5H-ben-
zo[c][1,2,3]triazolo[1,5-a]azepine (3d)
Yield: 0.104 g (32%); brown liquid.
IR (neat): 2949, 2867, 2097, 1693, 1616, 1559, 1484, 1393, 1354,
1281, 1196, 1075, 1020, 753 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 2.47, 2.74, 4.41 (2 H each, form-
ing AA′BB′XX′ system), 3.61 (s, 3 H), 4.03 (s, 3 H), 7.03 (d,
J = 7.5 Hz, 1 H), 7.19–7.28 (m, 1 H), 7.32–7.36 (m, 2 H), 8.53 (s,
1 H).
MS (ESI): m/z = 356.23 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C20H19N3NaO2: 356.1375;
found: 356.1382.
13C NMR (CDCl3, 75 MHz): δ = 30.1, 31.1, 46.1, 53.6, 54.9, 106.7,
126.9, 127.9, 128.1, 129.5, 135.3, 136.8, 138.1, 158.8, 165.2, 167.9.
MS (ESI): m/z = 346.23 [M + Na]+.
1-(4-Methoxyphenyl)-5,6,7,8-tetrahydrobenzo[c][1,2,3]triazo-
lo[1,5-a]azocine (4c)
Yield: 0.116 g (38%); yellow solid; mp 158–160 °C.
IR (KBr): 2926, 2851, 1614, 1516, 1471, 1356, 1297, 1251, 1179,
1108, 1010, 835, 759 cm–1.
Anal. Calcd for C17H17N5O2: C, 63.15; H, 5.30; N, 21.66. Found: C,
63.19; H, 5.27; N, 21.72.
1H NMR (CDCl3, 600 MHz): δ = 1.52–1.59 (m, 1 H), 1.79–1.87 (m,
1 H), 2.11–2.16 (m, 2 H), 2.21–2.25 (m, 1 H), 2.94 (dd, J = 8.4,
13.8 Hz, 1 H), 3.59 (dd, J = 11.4, 14.4 Hz, 1 H), 3.78 (s, 3 H), 4.78
(dd, J = 6.0, 13.8 Hz, 1 H), 6.82 (app d, J = 9.0 Hz, 2 H), 7.19 (dd,
J = 1.2, 7.8 Hz, 1 H), 7.25 (td, J = 1.2, 7.5 Hz, 1 H), 7.41 (br d,
J = 7.8 Hz, 1 H), 7.46 (td, J = 1.2, 7.5 Hz, 1 H), 7.53 (app d,
J = 9.0 Hz, 2 H).
1-({(3aR,5R,6S,6aR)-5-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-
2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-yl-oxy}meth-
yl)-6,7-dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepine (3e)
Yield: 0.174 g (38%); yellow liquid.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 545–555

552
K. Brahma et al.
PAPER
1,3-Bis(8H-[1,2,3]triazolo[5,1-a]isoindol-3-yl)benzene (13a)
Yield: 0.210 g (54%); greenish solid; mp 226–228 °C.
IR (KBr): 3398, 1664, 1616, 1343, 1179, 891, 767 cm–1.
13C NMR (CDCl3, 75 MHz): δ = 29.1, 29.2, 32.6, 48.1, 55.1, 113.8,
123.7, 126.6, 126.7, 127.9, 130.0, 130.3, 130.5, 132.5, 143.5, 143.6,
159.1.
MS (ESI): m/z = 306.28 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H19N3NaO: 328.1426;
1H NMR (CDCl3, 300 MHz): δ = 5.42 (s, 4 H), 7.41–7.57 (m, 6 H),
7.69 (t, J = 7.7 Hz, 1 H), 7.99–8.05 (m, 4 H), 8.59 (s, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 50.9, 121.7, 124.1, 125.5, 126.5,
found: 328.1425.
128.0, 128.5, 129.0, 129.5, 132.0, 139.0, 139.3, 141.1.
FAB-MS: m/z = 389.4 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C24H16N6Na: 411.1334;
found: 411.1339.
Synthesis of 5-(5,6-Dihydro[1,2,3]triazolo[5,1-a]isoquinolin-1-
yl)pyrimidine-2,4(1H,3H)-dione (11a); Typical Procedure
To a well-stirred solution of 2d (309 mg, 1.0 mmol) in anhydrous
MeCN (7.0 mL) was added anhydrous NaI (90 mg, 3.0 mmol) fol-
lowed by chlorotrimethylsilane (0.4 mL, 3.0 mmol) under an argon
atmosphere. The reaction mixture was then stirred at r.t. for 20 h.
The solvent was evaporated under reduced pressure and the residue
was triturated with aqueous sodium metabisulfite solution (3 mL)
and filtered, washed with H2O (3 mL) and dried to furnish the pure
product 11a.
1,3-Bis(5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinolin-1-yl)ben-
zene (13b)
Yield: 0.208 g (50%); yellow solid; mp 262–264 °C.
IR (KBr): 3052, 2928, 1732, 1610, 1347, 1241, 1190, 910, 770, 739
cm–1.
1H NMR (CDCl3, 300 MHz): δ = 3.26, 4.61 (4 H each, comprising
two identical AA′XX′ systems), 7.17 (t, J = 7.4 Hz, 2 H), 7.26–7.35
(m, 4 H), 7.57–7.65 (m, 3 H), 7.79 (d, J = 7.5 Hz, 2 H), 8.07 (s,
1 H).
The same procedure was adopted for the conversion of compound
3d into product 11b.
Yield: 0.239 g (85%); colourless solid; mp >300 °C.
IR (KBr): 3427, 3159, 3052, 2830, 1716, 1672, 1485, 1425, 1209,
1181, 993, 773, 637 cm–1.
13C NMR (CDCl3, 75 MHz): δ = 29.3, 44.9, 124.6, 124.9, 127.7,
1H NMR (DMSO-d6, 500 MHz): δ = 3.21, 4.56 (2 H each, compris-
ing AA′XX′ system), 7.26–7.34 (m, 3 H), 7.39 (br d, J = 7.5 Hz,
1 H), 7.69 (d, J = 6.0 Hz, 1 H), 11.24 (d, J = 4.5 Hz, 1 H), 11.35 (s,
1 H).
13C NMR (DMSO-d6, 75 MHz): δ = 28.3, 44.5, 104.6, 124.5, 125.0,
127.3, 128.3, 128.9, 130.9, 132.9, 134.6, 142.6, 151.2, 162.5.
128.4, 128.66, 128.7, 129.18, 129.2, 129.5, 132.3, 132.7, 142.6.
FAB-MS: m/z = 417.5 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H20N6Na: 439.1647;
found: 439.1649.
1,3-Bis(6,7-dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepin-1-
yl)benzene (13c)
Yield: 0.209 g (47%); yellow solid; mp 158–160 °C.
MS (ESI): m/z = 304.03 [M + Na]+.
IR (KBr): 2944, 2867, 2096, 1603, 1448, 1356, 1248, 768 cm–1.
Anal. Calcd for C14H11N5O2: C, 59.78; H, 3.94; N, 24.90. Found: C,
59.83; H, 3.91; N, 24.87.
1H NMR (CDCl3, 500 MHz): δ = 2.38, 2.61, 4.30 (4 H each, form-
ing two identical AA′BB′XX′ systems), 7.13–7.17 (m, 2 H), 7.23–
7.26 (m, 2 H), 7.29–7.30 (m, 4 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.77
(dd, J = 1.0, 7.5 Hz, 2 H), 7.93 (s, 1 H).
5-(6,7-Dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepine-1-
yl)pyrimidine-2,4(1H,3H)-dione (11b)
Yield: 0.242 g (82%); light-yellow solid; mp >300 °C.
13C NMR (CDCl3, 150 MHz): δ = 30.2, 30.9, 45.8, 125.5, 126.7,
127.0, 127.6, 128.9, 129.1, 129.5, 129.8, 131.3, 133.0, 138.6, 143.2.
IR (KBr): 3475, 3169, 3059, 2827, 1716, 1671, 1504, 1416, 1204,
1176, 990, 768, 638 cm–1.
1H NMR (DMSO-d6, 500 MHz): δ = 2.33, 2.59, 4.26 (2 H each,
forming AA′BB′XX′ system), 7.24 (d, J = 7.5 Hz, 1 H), 7.28 (t,
J = 7.5 Hz, 1 H), 7.34 (t, J = 7.3 Hz, 1 H), 7.39 (d, J = 7.5 Hz, 1 H),
7.62 (d, J = 6.0 Hz, 1 H), 11.13 (d, J = 5.0 Hz, 1 H), 11.19 (s, 1 H).
FAB-MS: m/z = 445.5 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C28H24N6Na: 467.1960;
found: 467.1982.
13C NMR (DMSO-d6, 75 MHz): δ = 29.6, 30.6, 45.7, 104.0, 126.9,
127.8, 129.2, 129.6, 135.3, 136.4, 138.4, 142.2, 151.1, 162.4.
MS (ESI): m/z = 318.06 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H13N5NaO2: 318.0967;
1,3-Bis(5,6,7,8-tetrahydrobenzo[c][1,2,3]triazolo[1,5-a]azocin-
1-yl)benzene (13d)
Yield: 0.128 g (27%); white solid; mp 240–242 °C.
IR (KBr): 3048, 2948, 2092, 1616, 1450, 1352, 1251, 889, 771
cm–1.
found: 318.0963.
1H NMR (CDCl3, 500 MHz): δ = 1.46–1.60 (m, 2 H), 1.73–1.83 (m,
3 H), 2.03–2.08 (m, 1 H), 2.11–2.22 (m, 4 H), 2.73 (dd, J = 8.3,
13.8 Hz, 1 H), 2.94 (dd, J = 8.5, 13.5 Hz, 1 H), 3.52–3.64 (m, 2 H),
4.72–4.82 (m, 2 H), 7.02 (d, J = 7.5 Hz, 1 H), 7.13 (t, J = 7.0 Hz,
2 H), 7.20 (br, 1 H), 7.30 (d, J = 7.5 Hz, 2 H), 7.39–7.51 (m, 4 H),
7.60 (br, 1 H), 7.87 (br, 1 H).
13C NMR (CDCl3, 150 MHz): δ = 28.9, 29.0, 29.1, 29.2, 30.9, 32.6,
48.4, 124.7, 125.9, 126.5, 126.7, 126.76, 126.82, 128.8, 129.3,
129.9, 130.1, 130.3, 130.37, 130.40, 130.6, 130.8, 143.0; additional
peaks are attributed to conformational equilibrium.
Synthesis of Bisheteroannulated Products 13a–d; General Pro-
cedure
To a well-stirred solution of o-iodo-azide 7a–d (1 mmol) in anhy-
drous DMF (8 mL) were added successively [Pd(PPh3)2Cl2] (24.6
mg, 0.035 mmol), CuI (13.3 mg, 0.07 mmol) and Et3N (0.71 mL,
5.0 mmol). The reaction mixture was then stirred under argon for 20
min. A solution of 1,3-diethynyl benzene 12 (0.6 mmol) dissolved
in anhydrous DMF (1 mL) was then added dropwise and the reac-
tion mixture was heated at 115 °C (except for 7d, for which heating
was carried out at 150 °C) for a few hours until consumption of the
starting materials was observed (TLC). Upon completion of the re-
action, the solvent was removed in vacuo, the residue was mixed
with H2O (30 mL) and then extracted with EtOAc (2 × 25 mL). The
combined organic extracts were dried over anhydrous Na2SO4, fil-
tered and concentrated under reduced pressure. The resulting resi-
due was purified through silica gel (100–200 mesh) column
chromatography (EtOAc–PE, 40–50% v/v) to afford the corre-
sponding product 13a–d.
MS (ESI): m/z = 495.32 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C30H28N6Na: 495.2273;
found: 495.2292.
Synthesis of 1a′
To a well-stirred solution of o-iodo-azide 7a (259 mg, 1 mmol) in
anhydrous DMF (6 mL) were added successively [Pd(PPh3)2Cl2]
(10.5 mg, 0.015 mmol), CuI (5.7 mg, 0.03 mmol) and K2CO3 (276
Synthesis 2013, 45, 545–555
© Georg Thieme Verlag Stuttgart · New York

PAPER
Palladium-Copper Catalysed Heterocyclisation
553
mg, 2.0 mmol), and the reaction mixture was heated at 60 °C for 4 h
under balloon pressure of acetylene gas. After completion of the re-
action (TLC), the solvent was removed in vacuo; the residue was
mixed with H2O (50 mL) and extracted with EtOAc (2 × 25 mL).
The combined organic extracts were dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The resulting res-
idue was purified through silica gel (100–200 mesh) column chro-
matography (EtOAc–PE, 20% v/v) to afford the product 1a′ (95 mg,
60%). The acyclic product 14a (n = 1) was also isolated (69 mg,
24%) from this reaction mixture.
5,6-Dihydro[1,2,3]triazolo[5,1-a]isoquinoline (2a′)
Yield: 0.070 g (82%); white solid; mp 94–96 °C.
IR (KBr): 3117, 3066, 3023, 2975, 1666, 1485, 1457, 1425, 1346,
1295, 1244, 1183, 1107, 960, 835, 773 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 3.25, 4.61 (2 H each, comprising
AA′XX′ system), 7.34–7.38 (m, 3 H), 7.58–7.59 (m, 1 H), 7.95 (s,
1 H).
13C NMR (CDCl3, 75 MHz): δ = 28.6, 44.4, 124.2, 124.5, 127.7,
128.35, 128.39, 129.2, 131.8, 133.7.
MS (ESI): m/z = 172.18 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C10H9N3Na: 194.0694;
8H-[1,2,3]Triazolo[5,1-a]isoindole (1a′)
Yield: 0.094 g (60%); black solid; mp 84–86 °C.
found: 194.0685.
IR (KBr): 3131, 2932, 1447, 1410, 1263, 1217, 1151, 1093, 974,
850, 772 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 5.35 (s, 2 H), 7.39–7.55 (m, 3 H),
7.66 (d, J = 7.2 Hz, 1 H), 7.84 (s, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 50.9, 121.5, 124.0, 127.4, 128.3,
128.7, 140.9, 142.7.
6,7-Dihydro-5H-benzo[c][1,2,3]triazolo[1,5-a]azepine (3a′)
Yield: 0.048 g (52%); pale-yellow liquid.
IR (neat): 3129, 3065, 2942, 2862, 1451, 1359, 1246, 1200, 1108,
1022, 981, 768 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 2.45, 2.72, 4.44 (2 H each, form-
ing AA′BB′XX′ system), 7.32–7.38 (m, 3 H), 7.39–7.47 (m, 1 H),
7.80 (s, 1 H).
MS (ESI): m/z = 158.14 [M + H]+.
HRMS (EI, 70 eV): m/z [M]+ calcd for C9H7N3: 157.064; found:
13C NMR (CDCl3, 75 MHz): δ = 30.3, 30.6, 46.3, 127.0, 127.2,
157.0646.
128.2, 129.6, 129.8, 131.4, 137.8, 138.3.
MS (ESI): m/z = 208.01 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C11H11N3Na: 208.0851;
found: 208.0844.
1-(2-Iodobenzyl)-1H-1,2,3-triazole (14a)
Yield: 0.068 g (24%); white solid; mp 63–64 °C.
IR (KBr): 3078, 1469, 1435, 1209, 1114, 1084, 1010, 736 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 5.66 (s, 2 H), 7.03–7.08 (m, 2 H),
7.34 (t, J = 7.5 Hz, 1 H), 7.60 (s, 1 H), 7.73 (s, 1 H), 7.90 (d,
J = 7.8 Hz, 1 H).
5,6,7,8-Tetrahydrobenzo[c][1,2,3]triazolo[1,5-a]azocine (4a′)
Yield: 0.042 g (42%); pale-yellow solid; mp 114–116 °C.
13C NMR (CDCl3, 75 MHz): δ = 58.2, 98.5, 123.7, 129.0, 129.5,
130.3, 134.1, 137.3, 139.8.
IR (KBr): 3132, 3012, 2939, 2854, 1440, 1354, 1237, 1202, 1104,
964, 855, 767 cm–1.
MS (ESI): m/z = 307.95 [M + Na]+.
1H NMR (CDCl3, 500 MHz): δ = 1.98 (br, 4 H), 2.45 (br, 2 H), 4.27
(br, 2 H), 7.29–7.32 (m, 2 H), 7.34 (d, J = 7.5 Hz, 1 H), 7.43–7.47
(m, 1 H), 7.68 (s, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 28.6, 28.9, 32.7, 48.4, 126.1, 126.3,
129.6, 130.2, 130.5, 132.4, 137.6, 142.8.
Anal. Calcd for C9H8IN3: C, 37.92; H, 2.83; N, 14.74. Found: C,
37.88; H, 2.81; N, 14.78.
Synthesis of products 2–4a′
To a well-stirred solution of o-iodo-azide 7b–d (0.5 mmol) in anhy-
drous DMF (6 mL) were added successively CuI (2.9 mg, 0.015
mmol) and K2CO3 (138 mg, 1.0 mmol), and the reaction mixture
was then heated at 60 °C for 4 h under balloon pressure of acetylene
gas. After completion of the reaction (TLC), the solvent was re-
moved in vacuo; the residue was mixed with H2O (30 mL) and ex-
tracted with EtOAc (2 × 25 mL). The combined organic extracts
were dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure to afford the corresponding crude product 14b–d,
which was used directly without further chromatographic purifica-
tion.
MS (ESI): m/z = 222.04 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H13N3Na: 222.1007;
found: 222.1003.
Acknowledgment
K.B. thanks CSIR, New Delhi, India for a fellowship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are the preparation and characterization data of 7a–d, X-ray crystal-
lographic data of 4a and copies of 1H and 13C NMR spectra of com-
To a well-stirred solution of crude intermediate 14b/14c in anhy-
drous DMF (5 mL) were added successively [Pd(PPh3)2Cl2] (17.5
mg, 0.025 mmol), K2CO3 (207 mg, 1.5 mmol) and TBAB (16 mg,
0.05 mmol). The reaction mixture was then heated (110 °C for 14b,
130 °C for 14c) for 4 h under an argon atmosphere. After comple-
tion of the reaction (TLC), the solvent was removed in vacuo; the
residue was mixed with H2O (30 mL) and then extracted with
EtOAc (2 × 25 mL). The combined organic extracts were dried over
anhydrous Na2SO4, filtered and concentrated under reduced pres-
sure. The resulting residue was purified through silica gel (100–200
mesh) column chromatography (EtOAc–PE, 10–20% v/v) to afford
the corresponding product 2a′/3a′.
pounds 7a–d, 1–4, 11a–b, 13a–d, 1a′–4a′, 14a. SnugIiofop
r
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 545–555

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Palladium-Copper Catalysed Heterocyclisation
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(24) Cytotoxicities of compounds 11a and 11b against various
cancer cell lines are currently under study.
intermediate o-alkynyl azide derivative, which is then
converted into products 1–4 through intramolecular [3+2]
cycloaddition between azide and alkyne moieties. An
alternative mechanism involving copper-assisted
regioselective [3+2] cycloaddition between acetylene and
azide groups of substrates 8 and 7, leading to the formation
of intermediate 1,4-substituted 1,2,3-triazoles 9 (X = I),
which may undergo intramolecular coupling with aryl iodide
through C–H bond activation to form the products 1–4, was
ruled out on the basis of control experiments.
(25) Based on control experiments and known features of
palladium chemistry, a plausible reaction mechanism can be
envisaged. Mechanistically, the active catalytic species
Pd(0) is generated in situ by dimerization, to a small extent,
of acetylenic compound 8. Next, coupling of 8 with iodide 7
takes place through the Sonogashira pathway, see:
Sonogashira, K.; Tohda, Y.; Haghihara, N. Tetrahedron
Lett. 1975, 50, 4467; leading to the formation of
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 545–555