Copper-Catalyzed Inter- and Intramolecular C-N Bond Formation: Synthesis of Benzimidazole-Fused Heterocycles

Article abstract of DOI:10.1021/acs.joc.5b01396

A Cu (II)-catalyzed, inter/intramolecular C-N bond formation for the synthesis of various benzimidazole-fused heterocycles in a concise manner has been reported. The robustness of this reaction is demonstrated by the synthesis of a series of benzimidazole-fused heteroaromatics (e.g., pyrido[1,2-a] benzimidazole, benzimidazo[1,2-a]quinolines, benzimidazo [1,2-a]pyrazine, benzo[4,5] imidazo[2,1-b]thiazoles) directly from 2-aminoheteroarenens and 2-iodoarylboronic acids in one-pot. The novel cascade protocol for C-N bond formation operates via unique combination of Chan-Lam type coupling followed by Ullmann-type reaction.

Full text of DOI:10.1021/acs.joc.5b01396

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Note
Copper-Catalyzed Inter-and Intramolecular C-N Bond
Formation: Synthesis of Benzimidazole-Fused Heterocycles
Sk Rasheed, D Nageswar Rao, and Parthasarathi Das
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01396 • Publication Date (Web): 31 Aug 2015
Downloaded from http://pubs.acs.org on August 31, 2015
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The Journal of Organic Chemistry
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CopperꢀCatalyzed Interꢀand Intramolecular CꢀN Bond
Formation: Synthesis of BenzimidazoleꢀFused
Heterocycles
Sk. Rasheed,a,b D. Nageswar Rao,a,b and Parthasarathi Das a,b,
*
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a Academy of Scientific and Innovative Research (AcSIR), JammuꢀCampus, Jammu 180001, India
b Medicinal Chemistry Division, Indian Institute of Integrative Medicine(CSIR), Jammu 180001, India
Eꢀmail: partha@iiim.ac.in
TOC Graphic
I
N
Cu(OAc)2 (20 mol%)
+
Ar
Het
Het
N
Cs2CO3 ( 3 equiv)
DMF, 120 oC, 24 h
N
Ar
(HO)2B
NH2
Het = 2-aminopyridine
2-aminoquinoline
1-aminoisoquinoline
2-aminopyrazine
6-aminopurine
28 examples
yield up to 91%
No external oxidant
No ligand
'Open-flask chemistry'
2-aminobenzothiazole
2-aminothiazole
ABSTRACT
A Cu (II)ꢀcatalyzed, inter/intramolecular CꢀN bond formation for the synthesis of various
benzimidazoleꢀfused heterocycles in a concise manner has been reported. The robustness of this reaction
is demonstrated by the synthesis of a series of benzimidazoleꢀfused heteroaromatics (e.g. pyrido[1,2ꢀa]
benzimidazole, benzimidazo[1,2ꢀa]quinolines, benzimidazo [1,2ꢀa]pyrazine, benzo[4,5] imidazo[2,1ꢀ
b]thiazoles) directly from 2ꢀaminoheteroarenens and 2ꢀiodoarylboronic acids in oneꢀpot. The novel
cascade protocol for CꢀN bond formation operates via unique combination of ChanꢀLam type coupling
followed by Ullmannꢀtype reaction.
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Transitionꢀmetal catalyzed CꢀN bond coupling has been established as a useful tool in modern organic
synthesis.1 Numerous protocols for the C–N bond formations have been developed, and most of these
methods involve the catalytic use of Pd complexes or Cuꢀsalts with the help of ligand and base.2,3 Since
the initial reports in 1998 independently by Chan, Lam and Evans the Cuꢀpromoted coupling reaction
for N/Oꢀarylation with arylboronic acids has emerged as a powerful and useful synthetic tool for
medicinal, cropꢀprotection and material chemists.4 The reason behind its popularity is the mild reaction
conditions needed, i.e. room temperature, weak base, and ambient atmosphere (“openꢀflask” chemistry).
Over the years, various research groups5 including our group6 made considerable progress in expanding
the scope of this methodology. Although the Cuꢀcatalyzed and boronic acid promoted the CꢀN bond
crossꢀcoupling would provide an efficient means in providing the valuable Nꢀarylated heterocycles, but
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the use of ChanꢀLam type of coupling in constructing heteroaromatic systems remain limited.7
N
S
N
N
N
HN
CH2COOH
N
N
N
CN
CN
CF3
Cl
Benzimidazo[1,2-a]quinoline Benzo[d]imidazo[2,1-b]thiazole
(anticancer)10b (anti-inflammatory agent )23a
Pyrido[1, 2-a]benzimidazole
(antimalarial)8b
Figure 1
. Medicinal interest with benzimidazole-fused heterocycles
The pyrido[1,2ꢀa]benzimidazole core (Figure 1) is one of the most important heterocyclic system since
it has not only found widespread applications in pharmaceutical chemistry8 but also broadly used in
material science.9 Similarly, benzimidazo[1,2ꢀa]quinoline and benzimidazo[2,1ꢀa]isoquinolines are
another important pharmacophore prevalent in a large number of biologically active molecules.10 The
wide range of biological properties shown by pyrido[1,2ꢀa]benzimidazoles inspired organic chemists to
pursue their synthesis in recent years. For the synthesis of pyrido[1,2ꢀa]benzimidazole, transitionꢀmetal
and metal free catalyzed methods are reported, where mostly Nꢀarylated aminoꢀheterocycles are used as
substrates (Scheme 1). Zhu and coꢀworkers reported an elegant Cu/Fe coꢀcatalyzed direct C–H
amination of 2ꢀ(arylamino)pyridines for the synthesis of pyrido[1,2ꢀa]benzimidazoles under an oxygen
atmosphere.11 The Maes group independently reported the direct C–H amination of 2ꢀ
(arylamino)pyridines to access pyrido[1,2ꢀa]benzimidazoles by using catalytic amount of copper(II)
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acetate.12 The metalꢀfree synthesis of pyrido[1,2ꢀa]benzimidazoles and other benzimidazole fused
heterocycles promoted by hypervalent iodine(III) were independently reported by Zhu13 and our
group.14 In another report Rossi and Cuny, demonstrated a photo stimulation procedure for
intramolecular C–N bond in 2ꢀ(2ꢀhalophenylamino) pyridines in the presence of potassium tertꢀbutoxide
in liquid ammonia, which gives fused imidazo[1,2ꢀa]pyridines by an SRN1 reaction.15 Wu et al. reported
Cuꢀcatalyzed and ligand assisted cascade method for CꢀN coupling in the synthesis of azaꢀfused
benzimidazoles.16 In most of these protocols requires couple of steps for the synthesis of fusedꢀ
benzimidazole derivatives, including the preparation of Nꢀarylated compounds from 2ꢀaminoꢀNꢀ
heterocycles. Moreover, the methods developed so far suffer from harsh conditions, narrow functional
group tolerance, expensive catalysts and ligands were required. Further, all the above reported protocols
are limited only to pyrido[1,2ꢀa]benzimidazoles. Thus finding a general/alternative protocol in
synthesizing these important heterocycles will be highly desirable. Here, we report a conceptually new
cascade reaction, for the synthesis of pyrido[1,2ꢀa]benzimidazoles and other azaꢀfused heterocycles
catalyzed by Cu(OAc)2 under ligand free conditions (Scheme 1). This cascade reaction involves
sequential intermolecular CꢀN bond formation (ChanꢀLam coupling) and intramolecular cyclization via
Ullmannꢀtype reaction.
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Scheme 1. Synthesis of pyrido[1,2ꢀa]benzimidazoles
Previous Work
N
N
Cu/Fe or
Cu/PivOH
H
N
N
H
ref 11, 12
N
N
ref 15
Cu/ligand
+
Br
X
N
N
H
H2N
N
I
This work
I
N
Cu(OAc)2 (20 mol%)
Ar
Het
Het
N
+
N
Cs2CO3 ( 3 equiv)
DMF, 120 oC, 24 h
Ar
NH2 (HO)2B
To find an optimized protocol for synthesis of pyrido [1,2ꢀa] benzimidazole we started our experiment
between 2ꢀaminopyridine (1a) and 2ꢀbromophenylboronic acid (1.1 equiv) in presence of Cu(OAc)2
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(0.2equiv) in methanol at rt and we observed only 15% product formation (entry 1, Table 1). Next we
performed the reaction with 2ꢀiodophenylboronic acid and the desired product was isolated in 25% yield
(entry 2, Table 1). When Et3N was added as base, the pyrido [1,2ꢀa] benzimidazole was isolated in
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moderate yield 35% (entry 3, Table 1).
9
a
Table1
. Optimization of reaction conditions for the formation of pyrido[1,2-a]benzimidazole
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X
N
Cu salt
+
reaction
conditions
N
(HO)2B
N
NH2
1a
2a
entry
catalyst
X
base
solvent
temp
time (h)
yieldb
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18c
19d
20e
21f
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
Br
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
Br
I
ꢀ
ꢀ
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
DMF
DCE
DME
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
rt
rt
rt
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15
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35
45
60
70
72
88
n.r.
n.r.
40
70
55
n.r
n.r.
60
65
40
75
85
20
Et3N
Et3N
80 oC
80 oC
80 oC
80 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
120 oC
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsOPiV
Py
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cu2O
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
I
I
I
aReaction conditions: 2ꢀaminopyridine (1.0 equiv), 2ꢀhalophenylboronic acid (1.1 equiv), copperꢀsalt (20 mol%), Cs2CO3 (3.0 equiv)
DMF (2 mL), 120 oC, 24 h, air; bIsolated yields; c 10 mol% Cu(OAc)2 was used; dCs2CO3 ( 2.0 equiv) was used; e reaction performed under
O2; f reaction performed under N2 atmosphere; n.r.= no reaction
Encouraged by these findings, various base/solvent combination at different temperature/time were
screened (entries 4ꢀ13, Table 1) and it was found that Cu(OAc)2 (20 mol%), Cs2CO3 (3 equiv) in DMF
o
at 120 C gave the best result (88%) in 24 h (entry 8, Table 1). Further screening of different Cuꢀsalts
such as CuI (entry 14, Table 1) and Cu2O (entry 15, Table 1) failed to produce any coupled product.
Whereas Cu(OTf)2 afforded 2a in moderate yield 60% (entry 16, Table 1). When we changed the
coupling partner from 2ꢀiodophenylboronic acid to 2ꢀbromophenylboronic acid under the same
optimized conditions the desired product isolated in 65% yield (entry 17, Table 1). Reducing the amount
of Cuꢀsalt to 10 mol% has negative impact on the isolated yield (40%) (entry18, Table 1). Further,
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changing the amount of base from 3 to 2 equiv gave a moderate drop in yield (75%) (entry19, Table 1).
Reaction under O2 (1atm) atmosphere did not show any further improvement in the yield (85%) (entry
20, Table 1), while incomplete conversion and poor yield was observed under N2 atmosphere (entry 21,
Table 1).
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Equipped with a set of optimized conditions, we evaluated the reactivity of various 2ꢀaminoꢀNꢀ
heterocycles with electronically diverse phenylboronic acids (Scheme 2). Gratifyingly, the reactions of
2ꢀaminopyridine with various arylboronic acids proved to be of wide scope and furnished the desired
products 2aꢀr in up to a 91% yield (Scheme 2). Electronic nature or the substitution pattern did not have
much effect on the crossꢀcoupling reactions.4c As an example when the reaction carried out with simple
2ꢀaminopyridine with phenylboronic acids bearing electronꢀdonating (2b-c, 2f) or electronꢀwithdrawing
group (2d-e) the desired product isolated in excellent yields (75ꢀ91%). Bicyclic boronic acid was also
investigated successfully as a example benzo[d][1,3]dioxolꢀ5ꢀylboronic acid gave the novel tetracyclic
moiety (2g) in good yield (76%). Then the effect of the substituent attached on the pyridine ring was
examined. Pleasingly, all the substituted 2ꢀaminopryridines underwent clean conversion with these
optimized conditions and afforded the desired product (2h-r) in excellent yields (75ꢀ89%). Interestingly,
steric congestion did not play major role as 2ꢀaminoꢀ6ꢀmethylpyridine derivative furnished the imidazo
pyridine (2l-o) in good yield (78ꢀ84%). Both bromo (2q) and cyano (2r) group were well tolerated
under these conditions and amenable to further functional group transformation. Next, we turned our
attention in synthesizing another important heterocyclic benzimidazo [1,2ꢀa]pyrazine.17 Under the
optimized reaction conditions 2ꢀaminopyrazine reacted smoothly with methoxy substituted boronic acid
and afforded product 8ꢀmethoxybenzo [4,5]imidazo[1,2ꢀa]pyrazine (2s, 80%). Further to establish the
generality of this protocol, we focused in synthesizing another two important heterocyclic frameworks
benzimidazo[2,1ꢀa]quinolines and benzimidazo[2,1ꢀa]isoquinolines.18 Benzimidazo[2,1ꢀa]quinolines
are previleged azaꢀfused heteroaromatics recently reported as topoisomeraseꢀII inhibitors.19 Reactivity
studies with different boronic acids were performed with 2ꢀamino quinoline and 1ꢀaminoisoquinoline
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under the optimized conditions. Both electronꢀdonating and electronꢀwithdrawing groups afforded the
crossꢀcoupled products (2t-w) in good yields (70ꢀ76%). Nꢀarylation of DNA/RNA nucleobases at the
nitrogen atom normally attached to the sugar moiety in DNA or RNA has been developed under Chanꢀ
Lam conditions.20 Whereas arylation of nitrogen at CꢀNH2 (e.g. purine) position reported rarely.21 Thus
we applied this optimized protocol for Nꢀarylation of 9ꢀethyl purinꢀ6ꢀamine, the corresponding purineꢀ
fused polcyclics product (2x), isolated in good yield (70%).22
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Scheme 2. Synthesis of pyrido[1,2-a]benzimidazoles and derivativesa
I
N
Cu(OAc)2 (20 mol%)
Ar
Het
Het
N
+
N
Cs2CO3 ( 3 equiv)
DMF, 120 oC, 24 h
Ar
N
(HO)2B
NH2
2a-x
N
N
N
N
N
N
N
R
O
OMe
Cl
2a
R = H; , 88%
O
MeO
2g
, 76%
F
R = Me, 2b, 90%
2e,
2f, 84%
75%
R = OMe, 2c, 91%
2d
R = Cl, , 78%
N
N
N
N
N
N
N
N
R
OMe
Me
OMe
Me
Me
R
Me
OMe
MeO
R = H, 2l, 82%
2m
R = H, 2h, 86%
R = OMe, 2i, 89%
R = Cl, 2j, 82%
R = F,
, 78%
2n, 84%
2k
, 86%
NC
N
N
N
N
N
N
N
N
Br
Me
F
Cl
O
Me
2o, 82%
2q, 78%
2r, 75%
2p, 78%
O
N
N
N
N
N
N
N
N
Cl
N
Cl
OMe
F
2u, 73%
OMe
2t, 76%
2s, 80%
2v, 70%
N
N
N
N
N
N
N
Et
Cl
2w, 73%
2x
, 70%
aReaction conditions: aminoꢀN-heterocycles (1.0 equiv), 2ꢀiodoarylboronic acid (1.1 equiv)
Cu(OAc)2 (20 mol%), Cs2CO3 (3.0 equiv), DMF (2 mL), 120 oC , 24 h, air.
Both benzo[d]thiazolo[3,2ꢀa]imidazoles and benzo[d]imidazo[2,1ꢀb]thiazoles are important heterocyclic
class of compounds known for their interesting biological properties.23 Despite their medicinal
importance, synthesis of this heterocyclic moiety is limited.24 To our delight this optimized protocol
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successfully applied in synthesizing benzo[d]thiazolo[3,2ꢀa]imidazoles (3a-b) and benzo[d]imidazo
[2,1ꢀb]thiazole derivatives (3c-d) in excellent yields (75ꢀ80%)(Scheme 3).
Scheme 3. Synthesis of benzo[d]thiazolo[3,2-a]imidazole and benzo[4,5]imidazo[2,1-b]thiazoles a
1
2
3
4
5
6
7
8
I
S
N
S
N
Cu(OAc)2 (20 mol%)
+
NH2
N
Cs2CO3 ( 3 equiv)
DMF, 120 oC, 24 h
(HO)2B
9
3a-d
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S
N
Me
S
S
S
N
N
N
N
N
N
N
Cl
3d, 75%
3c, 80%
3a
, 78%
3b
, 79%
aReaction conditions: 2ꢀamino thiazole (1.0 equiv), 2ꢀiodophenylboronic acid (1.1 equiv),
Cu(OAc)2 (20 mol%), Cs2CO3 (3.0 equiv), DMF (2 mL), 120 oC , 24 h, air.
Based on previous studies on ChanꢀLam type coupling25 and our experimental results a plausible
catalytic cycle was outlined in Scheme 4. In ChanꢀLam type of coupling the very first step involves the
rapid coordination of Cu(II) complex with 2ꢀaminopyridine (1a) forming A that subsequently undergoes
transmetallation with phenylboronic acid to afford complex B. Then the Cu(II) complex (B) undergoes
air oxidation (O2) to provide the higher oxidation Cu(III) complex C, facilitating the smooth reductive
elimination to furnish Nꢀarylated product (Intermediate-I).
Scheme 4
. Plausible reaction mechanism
CuI(OAc)
H
N
OMe
N
I
H
HOAc
III
Cu
OAc
I
N
Intermediate I
(confirmed by 1HNMR)
N
H+
N
OMe
MeO
O2
AcOH
N
C
I
Cu
D
OMe
NHII
Cu
B
N
I
N
OMe
Cha
OAc
n-Lam typ
Cu(II)/Cu(III)/Cu(I)
e
Ullm
ann type
N III
Cu
E
B(OH)2
OMe
I
I
H
II
Cu
N
N
A
AcOH
AcOH
HI
OMe
N
NH2
CuII(OAc)2
N
III
Cu
N
1a
F
AcO
CuI(OAc)
O2
H+
AcOH
N
OMe
N
2c
Now in Ullmannꢀtype coupling the first step involves the smooth coordination of Intermediate-I with
Cu(I) to form complex D which intramolecular oxidative addition with aryl halide furnished complex E
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and subsequently converted to complex F. As far as the oxidation state of the copper is concerned, these
types of reactions are thus supposed to proceed via Cu(I) and Cu(III) intermediates. 1a,b,e Now Cu(III)
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2
3
4
5
6
complex F on smooth
reductive elimination furnished cyclized product 7ꢀmethoxybenzo
7
8
[4,5]imidazo[1,2ꢀa]pyridine (2c) with concurrent formation of Cu(I). Finally, Cu(II) is generated by O2
9
(air) oxidation to complete the catalytic cycle.
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In conclusion, we have developed a ligand free Cu (II)ꢀcatalyzed oneꢀpot synthesis of benzimidazoleꢀ
fusedꢀheterocycles. This protocol is an example of unique combination of ChanꢀLam and Ullmann type
coupling, successfully utilized sequentially in CꢀN bond formation in delivering azaꢀfused
heteroaromatics. The described ‘openꢀflask’ cascade chemistry is general and the low cost of the
catalytic system made this process a valuable alternative compared to previously reported methods and
may find useful application in medicinal chemistry.
Experimental section
General Information:
Analytical thin layer chromatography (TLC) was performed on preꢀcoated silica gel plates. TLC plates
were visualized by exposing UV light or by iodine vapours or immersion in ninhydrin followed by
heating on hot plate. 1H and 13C NMR spectra were recorded at 500 and 400 MHz. HRMS spectra were
recorded with LCMSꢀQTOF (UHD) instrument. Melting points were measured in open capillary tubes
and are uncorrected. Unless otherwise indicated, chemicals and solvents were purchased from
commercial suppliers.
General procedure for the synthesis of copper-catalyzed benzimidazole-fused heterocycles with 2-
iodophenylboronic acids:
A oven dried round bottom flask charged with 2ꢀamino pyridine (1 equiv), 2ꢀiodophenylboronic acid
(1.1 equiv), copper acetate (20 mol%), cesium carbonate (3 equiv) and anhydrous DMF (2 mL), stirred
o
the reaction mixture at 120 C, for 24 h. The reaction was monitered by checking the TLC and after
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completion of the reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate (3
x 15 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The
crude product was purified by column chromatography (hexane/EtOAc) to provide the desired product
(2a-x, 3a-d).
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Benzo[4,5]imidazo[1,2-a]pyridine (2a):14 Eluent: Petroleum ether/ethyl acetate (4:1). Yield: 79 mg
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(88%). White solid, m.p. 180ꢀ182 oC; H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 6.7 Hz, 1H), 7.86 (dd,
J = 16.8, 8.2 Hz, 2H), 7.67 (d, J = 9.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.38 (m, 1H), 7.32 (t, J = 7.6
Hz, 1H), 6.81 (t, J = 6.7 Hz, 1H); 13C NMR (125 MHz, DMSOꢀd6) δ 172.0, 162.2, 143.8, 130.1, 126.9,
125.3, 120.5, 118.9, 116.9, 111.8, 110.2; HRMS (ESI): m/z calcd. for C11H9N2[M+H]+ :169.0760;
found: 169.0752.
7-Methylbenzo[4,5]imidazo[1,2-a]pyridine (2b):11 Eluent: Petroleum ether/ethyl acetate (4:1). Yield:
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87 mg (90%). White solid, m.p. 150ꢀ152 C; H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 7.0 Hz, 1H),
8.35 (d, J = 6.8 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.62 (m, 2H), 7.34 (ddd, J = 7.9, 7.0, 5.0 Hz, 2H),
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2.50(s, 3H); C NMR (125 MHz, CDCl3) δ 147.5, 142.7, 129.6, 128.0, 126.1, 125.3, 121.3, 117.8,
110.7, 107.9, 17.2; HRMS (ESI): m/z calcd. for C12H11N2[M+H]+ : 183.0917; found: 183.0904.
7-Methoxybenzo[4,5]imidazo[1,2-a]pyridine (2c):14 Eluent: Petroleum ether/ethyl acetate (4:1). Yield:
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95 mg (91%). White solid, m.p. 148ꢀ149 C; H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 6.8 Hz, 1H),
7.76 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.41(m, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.00 (dd, J =
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8.9, 2.2 Hz, 1H), 6.86 (t, J = 6.8 Hz, 1H), 3.92 (s, 3H); C NMR (125 MHz, CDCl3) δ 159.0, 148.1,
144.2, 129.4, 125.0, 122.8, 117.0, 112.4, 111.1, 111.0, 100.2, 55.8; HRMS (ESI): m/z calcd. for
C12H11N2O[M+H]+ :199.0866; found: 199.0864.
7-Chlorobenzo[4,5]imidazo[1,2-a]pyridine (2d):14 Eluent: Petroleum ether/ethyl acetate (4:1). Yield:
o
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83 mg (78%). White solid, m.p. 208ꢀ209 C; H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 6.8 Hz, 1H),
7.90 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 9.3 Hz, 1H), 7.47 (m, 1H), 7.33 (dd, J =
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8.7, 1.7 Hz, 1H), 6.90 (t, J = 6.6 Hz, 1H); C NMR (125 MHz, Acetoneꢀd6) δ 150.3, 146.3, 131.3,
128.6, 127.5, 121.6, 119.5, 118.2, 113.6, 113.5, 111.7; HRMS (ESI): m/z calcd. for C11H8ClN2[M+H]+
:203.0371; found: 203.0366.
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7-Chloro-8-fluorobenzo[4,5]imidazo[1,2-a]pyridine (2e):14 Eluent: Petroleum ether/ethyl acetate
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(4:1). Yield: 87 mg (75%). Brown solid, m.p. 222ꢀ224 C; H NMR (400 MHz, CDCl3) δ 8.25 (d, J =
6.7 Hz, 1H), 8.02 (s, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.60 (dd, J = 8.4, 4.6 Hz, 1H), 7.38 (m, 1H), 6.82 (t,
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J = 6.7 Hz, 1H); C NMR (100 MHz, CDCl3) δ 151.6, 147.3, 138.6, 129.5 (d, J = 13.4 Hz), 127.1,
119.6, 118.5 (d, J = 8.7 Hz), 118.0, 114.7, 114.4 (d, J = 7.0 Hz), 110.7; HRMS (ESI): m/z calcd. for
C11H7ClFN2[M+H]+ :221.0277; found: 221.0269.
7,9-Dimethoxybenzo[4,5]imidazo[1,2-a]pyridine (2f): Eluent: Petroleum ether/ethyl acetate (4:1).
Yield: 101 mg (84%). White solid, m.p. 142ꢀ144 oC; 1H NMR (400 MHz, Acetoneꢀd6) δ 9.03 (d, J = 6.9
Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 6.7, 1.3 Hz, 1H), 6.90 (t, J = 6.2 Hz, 1H), 6.85 (d, J =
13
6.1 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 4.10 (s, 3H), 3.89 (s, 3H); C NMR (125 MHz, CDCl3) δ 159.2,
149.2, 148.4, 129.2, 129.0, 128.5, 116.2, 110.4, 110.2, 93.8, 92.1, 55.8, 55.7; HRMS (ESI): m/z calcd.
for C13H13N2O2[M+H]+ :229.0972; found: 229.0965.
[1,3]Dioxolo[4'',5'':4',5']benzo[1',2':4,5]imidazo[1,2-a]pyridine (2g):14 Eluent: Petroleum ether/ethyl
acetate (4:1). Yield: 85 mg (76%). White solid, m.p. 235ꢀ237 oC; 1H NMR (400 MHz, CDCl3) δ 8.27 (d,
J = 6.8 Hz, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.30 (dd, J = 15.3, 10.0 Hz, 3H), 6.82 (t, J = 6.6 Hz, 1H), 6.07
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(s, 2H); C NMR (100 MHz, CDCl3) δ 147.8, 146.8, 126.9, 126.7, 123.1, 116.2, 110.2, 110.0, 100.6,
97.4, 89.5, 59.3; HRMS (ESI): m/z calcd. for C12H9N2O2[M+H]+ :213.0659; found: 213.0686.
2-Methylbenzo[4,5]imidazo[1,2-a]pyridine (2h):11 Eluent: Petroleum ether/ethyl acetate (4:1). Yield:
72 mg (86%). White solid, m.p. 152ꢀ154 oC; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.88 (d, J = 8.8
Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 9.3 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.22 (dd, J = 8.8,
2.0 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.0, 145.0, 133.2,
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128.0, 125.4, 122.6, 120.7, 120.0, 117.2, 103.8, 21.2; HRMS (ESI): m/z calcd. for C12H11N2[M+H]+
:183.0917; found: 183.0943.
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(4:1). Yield: 87 mg (89%). White solid, m.p. 143ꢀ144 C; H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H),
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7.72 (d, J = 8.9 Hz, 1H), 7.58 (d, J = 9.3 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.26 (s, 1H), 6.98 (dd, J =
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8.9, 2.3 Hz, 1H), 3.92 (s, 3H), 2.40 (s, 3H); C NMR (125 MHz, CDCl3) δ 158.4, 148.0, 145.7, 131.9,
123.2, 122.5, 119.9, 116.7, 111.7, 110.8, 100.6, 55.7, 18.1; HRMS (ESI): m/z calcd. for
C13H13N2O[M+H]+ :213.1023; found: 213.1020.
7-Chloro-2-methylbenzo[4,5]imidazo[1,2-a]pyridine (2j): Eluent: Petroleum ether/ethyl acetate (4:1).
Yield: 82 mg (82%). White solid, m.p. 156ꢀ159 oC; 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 7.59 (d,
J = 9.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.29 (s, 1H), 6.76 (d, J = 7.8 Hz, 1H),
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2.41 (s, 3H); C NMR (125 MHz, CDCl3) δ 152.6, 149.3, 143.0, 138.9, 134.6, 130.1, 127.9, 127.4,
126.0, 121.1, 117.0, 17.9; HRMS (ESI): m/z calcd. for C12H10ClN2[M+H]+ :217.0527; found: 217.0530.
7,9-Dimethoxy-2-methylbenzo[4,5]imidazo[1,2-a]pyridine (2k): Eluent: Petroleum ether/ethyl acetate
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(4:1). Yield: 96 mg (86%). White solid, m.p. 157ꢀ159 C; H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H),
7.60 (d, J = 9.3 Hz, 1H), 7.24 (d, J = 1.2 Hz, 1H), 6.91 (d, J = 1.7 Hz, 1H), 6.41 (d, J = 1.7 Hz, 1H),
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4.05 (s, 3H), 3.90 (s, 3H), 2.39 (s, 3H); C NMR (125 MHz, CDCl3) δ 158.9, 149.1, 147.7, 146.5,
131.5, 126.1, 119.6, 115.6, 113.5, 93.6, 92.2, 55.7, 18.2; HRMS (ESI): m/z calcd. for C14H15N2O2
[M+H]+ :243.1128; found: 243.1118.
1-Methylbenzo[4,5]imidazo[1,2-a]pyridine (2l):13b Eluent: Petroleum ether/ethyl acetate (4:1). Yield:
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69 mg (82%). White solid, m.p. 106ꢀ108 C; H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 1H),
7.97 (d, J = 8.2 Hz, 1H), 7.60 (m, 1H), 7.53 (m, 1H), 7.37 (m, 2H), 7.07 (dd, J = 8.5, 5.2 Hz, 1H), 3.04
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.4, 143.0, 138.2, 131.9, 128.4, 124.5, 121.6, 118.6, 116.2,
113.0, 109.3, 17.1; HRMS (ESI): m/z calcd. for C12H11N2[M+H]+ :183.0917; found: 183.0917.
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7-Fluoro-1-methylbenzo[4,5]imidazo[1,2-a]pyridine (2m): Eluent: Petroleum ether/ethyl acetate
(4:1). Yield: 72 mg (78%). Brown solid, m.p. 140ꢀ142 oC; 1H NMR (400 MHz, CDCl3) δ 8.04 (t, J = 8.2
Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 7.41 (m, 1H), 7.05 (t, J = 8.9 Hz, 1H), 6.68
(d, J = 6.7 Hz, 1H), 2.99 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 158.6, 154.4, 147.8, 139.3, 138.6 (d, J
= 6.2 Hz), 130.7, 126.2 (d, J = 8.7 Hz), 123.3, 121.8 (d, J = 8.3 Hz), 114.9, 112.5, 24.0; HRMS (ESI):
m/z calcd. for C12H10N2F[M+H]+ : 201.0823; found: 201.0818.
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7,8-Dimethoxy-1-methylbenzo[4,5]imidazo[1,2-a]pyridine (2n): Eluent: Petroleum ether/ethyl acetate
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(4:1). Yield: 94 mg (84%). White solid, m.p. 265ꢀ267 C; H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H),
7.64 (d, J = 9.3 Hz, 1H), 7.35 (s, 1H), 7.27 (t, J = 3.7 Hz, 2H), 4.02 (s, 3H), 4.01 (s, 3H), 2.42 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 149.4, 146.3, 137.9, 130.7, 129.4, 121.8 , 121.4, 120.2, 116.4, 100.2,
92.5, 56.4, 56.2, 18.2; HRMS (ESI): m/z calcd. for C14H15N2O2[M+H]+ :243.1128; found: 243.1114.
9-Methyl-[1,3]dioxolo[4'',5'':4',5']benzo[1',2':4,5]imidazo[1,2-a]pyridine (2o): Eluent: Petroleum
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ether/ethyl acetate (4:1). Yield: 85 mg (82%). White solid, m.p. 193ꢀ195 C; H NMR (400 MHz,
CDCl3) δ 7.52 (d, J = 5.1 Hz, 2H), 7.21 (d, J = 13.4 Hz, 2H), 6.53 (d, J = 6.5 Hz, 1H), 6.01 (s, 2H), 2.91
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(s, 3H); C NMR (100 MHz, CDCl3) δ 146.8, 143.9, 140.3, 137.5, 129.4, 127.4, 114.9, 111.1, 101.4,
98.2, 94.7, 67.7, 21.1; HRMS (ESI): m/z calcd. for C13H11N2O2[M+H]+ : 227.0815; found: 227.0810.
7-Chloro-2-fluorobenzo[4,5]imidazo[1,2-a]pyridine (2p): Eluent: Petroleum ether/ethyl acetate (4:1).
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Yield: 76 mg (78%). Brown solid, m.p. 140ꢀ141 C; 1H NMR (400 MHz, CDCl3) δ 9.33 (d, J = 6.2 Hz,
1H), 8.37 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.76 (m, 1H), 7.49 (m, 1H), 7.37 (dd, J = 8.0, 4.4 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 151.4, 149.1, 125.1, 121.8 (d, J = 6.8 Hz), 121.4 (d, J = 7.5 Hz), 118.6,
117.7, 117.1 (d, J = 8.4 Hz), 113.6, 113.1, 110.4; HRMS (ESI): m/z calcd. for C11H7ClFN2[M+H]+
:221.0277; found: 221.0269.
2-Bromo-7-methylbenzo[4,5]imidazo[1,2-a]pyridine (2q): Eluent: Petroleum ether/ethyl acetate (4:1).
Yield: 58 mg (78%). Brown solid, m.p. 142ꢀ145 oC; 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.55 (s,
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1H), 7.73 (m, 1H), 7.60 (dd, J = 12.6, 9.8 Hz, 1H), 7.44 (dd, J = 12.9, 5.4 Hz, 1H), 7.14 (d, J = 7.2 Hz,
1H), 2.57 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 136.5, 132.3, 132.0, 129.5, 127.5, 124.1, 123.3, 119.5,
118.6, 117.8, 109.9, 22.0; HRMS (ESI): m/z calcd. for C12H10N2Br[M+H]+ :261.0022; found: 261.0015.
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Yield: 61 mg (75%). White solid, m.p. 235ꢀ237 C; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 7.1 Hz,
1H), 8.14 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.52 (t, J =
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7.7 Hz, 1H), 6.99 (dd, J = 7.1, 1.3 Hz, 1H); C NMR (100 MHz, Acetoneꢀd6) δ 166.1, 135.2, 130.3,
128.8, 127.3, 125.2, 123.6, 121.2, 118.1, 113.0, 112.8, 110.4; HRMS (ESI): m/z calcd. for
C12H8N3[M+H]+ :194.0713; found: 194.0708.
8-Methoxybenzo[4,5]imidazo[1,2-a]pyrazine (2s): Eluent: Petroleum ether/ethyl acetate (3:1). Yield:
92 mg (80%). Brown solid, m.p. 138ꢀ140 C; 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.19 (s, 1H),
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7.87 (m, 2H), 7.24 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 5.3, 2.5 Hz, 1H), 3.90 (s, 3H); 13C NMR (125 MHz,
Acetoneꢀd6) δ 157.7, 145.8, 142.7, 139.8, 133.4, 127.4, 122.5, 119.5, 119.4, 94.3, 56.3; HRMS (ESI):
m/z calcd. for C11H10N3O[M+H]+ :200.0819; found: 200.0812.
9-Methyl-[1,3]dioxolo[4'',5'':4',5']benzo[1',2':4,5]imidazo[1,2-a]pyridine (2t):14 Eluent: Petroleum
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ether/ethyl acetate (3:1). Yield: 65 mg (76%). Brown solid, m.p. 120ꢀ123 C; H NMR (400 MHz,
CDCl3) δ 8.53 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.76 (t, J = 7.8 Hz,
1H), 7.69 (d, J = 9.5 Hz, 1H), 7.62 (d, J = 9.4 Hz, 1H), 7.48 (dd, J = 15.0, 7.3 Hz, 2H), 7.12 (d, J = 7.7
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Hz, 1H), 3.95 (s, 3H); C NMR (125 MHz, CDCl3) δ 157.4, 148.5, 135.3, 130.8, 129.7, 129.5, 125.3,
124.1, 123.3, 123.2, 117.3, 115.0, 114.5, 112.9, 101.5, 55.7; HRMS (ESI): m/z calcd. for
C16H13N2O[M+H]+ :249.1023; found: 249.1013.
9-Chlorobenzo[4,5]imidazo[1,2-a]quinoline (2u):14 Eluent: Petroleum ether/ethyl acetate (3:1). Yield:
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64 mg (73%). Yellow solid, m.p. 174ꢀ175 C; H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.5 Hz, 1H),
8.31 (d, J = 8.9 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.77 (dd, J = 20.0, 8.9 Hz,
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2H), 7.63 (d, J = 9.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.46 (dd, J = 8.7, 1.7 Hz, 1H); C NMR (100
MHz, CDCl3) δ 149.2, 145.6, 135.3, 131.8, 130.1, 129.9, 129.7, 124.5, 123.4, 123.2, 122.9, 120.0,
117.5, 115.1, 114.6; HRMS (ESI): calcd. For C15H10ClN2 [M+H]+, 253.0527; found: 253.0524.
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9-Chloro-10-fluorobenzo[4,5]imidazo[1,2-a]quinoline (2v):14 Eluent: Petroleum ether/ethyl acetate
(3:1). Yield: 65 mg (70%). Pale yellow solid, m.p. 204ꢀ206 oC; 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J
= 8.4 Hz, 1H), 8.16 (d, J = 9.7 Hz, 1H), 8.00 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.78 (t, J =
7.7 Hz, 1H), 7.71 (d, J = 9.5 Hz, 1H), 7.55 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 155.0, 153.1, 149.5
(d, J = 2.6 Hz), 141.2, 135.0, 131.8, 129.9 (d, J = 21.9 Hz), 124.8, 123.4, 121.0, 117.5, 114.7, 101.8 (d,
J = 28.9 Hz); HRMS (ESI): calcd. For C15H9ClFN2 [M+H]+, 271.0433; found: 271.0428.
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10-Chlorobenzo[4,5]imidazo[2,1-a]isoquinoline (2w):14 Eluent: Petroleum ether/ethyl acetate (3:1).
o
1
Yield: 64 mg (73%). Brown solid, m.p. 149ꢀ150 C; H NMR (400 MHz, CDCl3) δ 8.72 (t, J = 7.2 Hz
1H), 8.07 (d, J = 7.2 Hz, 1H), 7.91 (s, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.64 (m, 2H), 7.30 (dd, J = 8.6, 1.5
13
Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H); C NMR (100 MHz, CDCl3) δ 147.1, 143.3, 130.6, 129.4, 129.3,
127.4, 126.1, 124.1, 124.0, 121.3, 120.1, 118.5, 118.1, 111.0, 109.5; HRMS (ESI): calcd. For
C15H10ClN2 [M+H]+, 253.0527; found: 253.0526.
3-Ethyl-3H-benzo[4,5]imidazo[2,1-i]purine (2x):22 Eluent: Petroleum ether/ethyl acetate (1:1). Yield:
51 mg (70%). Brown solid, m.p. 219ꢀ221 oC; 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.99 (m, 3H),
7.58 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 4.41 (q, J = 7.3 Hz, 2H), 1.62 (t, J = 7.3 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 142.9, 138.3, 133.3, 132.4, 127.7, 125.7, 124.7, 121.0, 120.5, 118.6, 108.4,
37.8, 14.1; HRMS (ESI): m/z calcd. for C13H11N5[M+H]+ :238.1087; found: 238.1079.
Benzo[4,5]imidazo[2,1-b]thiazole (3a): (Cas Number. 247ꢀ83ꢀ6) Eluent: Petroleum ether/ethyl acetate
(9:1). Yield: 68 mg (78%). White solid, m.p. 142ꢀ143 oC; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0
Hz, 1H), 7.61 (dd, J = 13.9, 6.2 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 6.75 (d, J =
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4.4 Hz, 1H); C NMR (125 MHz, CDCl3) δ 155.4, 146.2, 130.9, 127.5, 124.3, 121.9, 120.7, 119.5,
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110.5; HRMS (ESI): m/z calcd. for C9H7N2S[M+H]+:175.0325; found: 175.0318.
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2-Methylbenzo[4,5]imidazo[2,1-b]thiazole (3b): (Cas Number. 16458ꢀ73ꢀ4) Eluent: Petroleum
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ether/ethyl acetate (9:1). Yield: 65 mg (79%). White solid, m.p. 156ꢀ159 C; H NMR (400 MHz,
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CDCl3) δ 7.73 (d, J = 8.1 Hz, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 6.28 (s, 1H), 2.67
13
(s, 3H); C NMR (125 MHz, CDCl3) δ 156.3, 143.4, 135.2, 130.0, 128.6, 122.0, 119.4, 117.9, 109.2,
21.4; HRMS (ESI): m/z calcd. for C10H9N2S[M+H]+ :189.0481; found:189.0472.
Benzo[d]benzo[4,5]imidazo[2,1-b]thiazole (3c):24 Eluent: Petroleum ether/ethyl acetate (9:1). Yield:
1
59 mg (80%). White solid , m.p. 138–140 °C; H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.76 (d, J =
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7.7 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.31 (m, 3H); C NMR (125 MHz,
CDCl3) δ 155.4, 148.2, 133.1, 128.9, 126.6, 124.3, 124.3, 123.5, 121.9, 119.5, 112.3, 110.5; HRMS
(ESI): m/z calcd. for C13H9N2S[M+H]+ :225.0481; found: 225.0474.
2-Chlorobenzo[d]benzo[4,5]imidazo[2,1-b]thiazole (3d):24 Eluent: Petroleum ether/ethyl acetate
1
(9:1). Yield: 52 mg (75%). White solid, m.p. 234–235 °C; H NMR (400 MHz, CDCl3) δ 7.87 (d, J =
6.0 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 15.0, 7.4 Hz, 2H), 7.31 (dd,
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J = 7.5, 5.9 Hz, 1H); C NMR (100 MHz, CDCl3) δ 155.5, 148.0, 135.9, 132.8, 131.7, 126.3, 123.9,
123.5, 122.9, 121.2, 118.7, 111.7, 109.5; HRMS (ESI): calcd. For C13H8ClN2S [M+H]+ :259.0091;
found: 259.0094.
N-(2-Iodo-5-methoxyphenyl)pyridin-2-amine (Intermediate-I): A oven dried round bottom flask
charged with 2ꢀamino pyridine (1 equiv), (2ꢀiodoꢀ5ꢀmethoxyphenyl)boronic acid (1.1 equiv), copper
acetate (20 mol%), cesium carbonate (3 equiv) and anhydrous DMF (2 mL), stirred the reaction mixture
o
at 120 C, after 6 h cool the reaction mixture to rt and passed through the small silica gel pad. Eluent:
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Petroleum ether/ethyl acetate (9:1). Colorless liquid; H NMR (400 MHz, Acetoneꢀd6) δ 7.90 (s, 1H),
7.68 (s, 1H), 7.22 (m, 2H), 7.01 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.35 (d, J =
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8.0 Hz, 1H), 3.66 (s, 3H); C NMR (100 MHz, CDCl3) δ 160.5, 153.8, 147.8, 142.4, 138.6, 129.9,
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124.1, 112.0, 108.6, 107.5, 105.4, 55.2; HRMS (ESI): calcd. for C12H12IN2O[M+H]+ :326.9988; found:
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326.9990.
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Acknowledgements:
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Sk. R. and D. N. R. thank CSIR and UGCꢀNew Delhi for research fellowship, respectively. We would
like to thank P.Y. S. Lam for helpful discussions. This research work financially supported by CSIRꢀ
New Delhi (BSC 0108). IIIM communication No IIIM/1807/2015.
Supporting Information Available: Copies of 1H and 13C NMR spectra.
This material is available free of charge via the Internet at http://pubs.acs.org.
Notes and References:
(1)
(2)
(3)
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(a) Chan, D. M. T.; Monaco, K. L.; Wang, R.ꢀP.; Winters, M. P. Tetrahedron Lett. 1998, 39,
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