Isoquinolone derivatives via a furan recyclization reaction

Article abstract of DOI:10.1016/j.tet.2007.06.114

A new approach to the synthesis of isoquinolone derivatives has been developed. It is based on the protolytic recyclization of amides of 2-carboxybenzylfurans. It was shown that the reaction proceeds via formation of allylic alcohols of isoquinolone serie

Full text of DOI:10.1016/j.tet.2007.06.114

Tetrahedron 63 (2007) 9437–9447
Isoquinolone derivatives via a furan recyclization reaction
Artem S. Dmitriev,a Vladimir T. Abaev,b Wolfgang Benderc and Alexander V. Butina,
*
aResearch Institute of Heterocyclic Compounds Chemistry, Kuban State University of Technology, Moskovskaya St. 2,
Krasnodar 350072, Russian Federation
bNorth-Ossetian State University, Vatutina 46, Vladikavkaz 362025, Russian Federation
cBayer HealthCare AG, D-51368 Leverkusen, Germany
Received 22 March 2007; revised 8 June 2007; accepted 28 June 2007
Available online 10 July 2007
Abstract—A new approach to the synthesis of isoquinolone derivatives has been developed. It is based on the protolytic recyclization of
amides of 2-carboxybenzylfurans. It was shown that the reaction proceeds via formation of allylic alcohols of isoquinolone series, which
under acidic conditions undergo isomerization into the corresponding ketones. A new condensed heterocyclic system of furo[20,30:3,4]cyclo-
hepta[1,2-c]isoquinolin-8(6H)-one has been synthesized.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
The methods of generation of intermediates A can be differ-
ent. In particular, the syntheses of the isoquinolone frame-
work via lithiation of N-substituted 2-alkylbenzamides and
subsequent treatment with DMF or other N,N-disubstituted
amides was disclosed in the literature.5 As an intermediate
product amidol B had been isolated. Its formation can be ra-
tionalized as the result of spontaneous intramolecular cycli-
zation of compound A, which was registered by spectral
methods in one case.5c The amidol B isolation confirms
the intermediacy of compound A in the synthesis of isoqui-
nolone derivatives upon treatment of primary or secondary
ortho-halobenzamides with ketone enolates under UV irra-
diation.6 It is obvious that the acidic hydrolysis of 2-(2-oxo-
alkyl)benzonitriles resulting in isoquinolone framework
formation also proceeds via intermediate A.7
The development of new effective methods for the synthesis
of the isoquinolone ring system is an important research area
for synthetic as well as for medicinal chemistry. Consider-
able interest from the synthetic community to this class of
heterocycles is stipulated by the fact that 1(2H)-isoquino-
lone skeleton constitutes the framework of large variety of
plant alkaloids1 and synthetic compounds with a wide range
of biological activity.2 Isoquinolones are also attractive from
the synthetic point of view since they can be used as a starting
material in the total synthesis of natural alkaloids.3
By now, sufficiently vast information about construction of
isoquinolone skeleton has been accumulated.4 Among a
great number of synthetic approaches, our attention was at-
tracted by the methods based on the spontaneous cyclization
of amides of ortho-carboxybenzylcarbonyl compounds A
formed during the reaction (Fig. 1).
It is well known that furan ring can serve as a latent 1,4-
dicarbonyl compound.8 This prerequisite underlies our
successfully developed general method of construction of
benzannelated heterocyclic compounds via the acid-cata-
lyzed recyclization of ortho-substituted benzylfurans serv-
ing as equivalents of ortho-substituted benzylcarbonyl
compounds. Varying the ortho-substituent allowed us to
obtain heterocycles such as benzofurans,9 indoles,10 iso-
chromones,11 and isochromenes12 (Scheme 1).
O
R3
R2
O
O
R3
R2
N
O
R3
R2
N
N
R
R
R
OH
R1
R1
R1
In this article, we propose a new synthetic method leading to
isoquinolone ring system that is based upon previously re-
ported single example13 and report in full details concerning
the study of recyclization of amides of 2-carboxybenzylfur-
ans into isoquinolone derivatives. The isolation of the corre-
sponding allylic alcohols allowed us to specify the possible
mechanism of the reaction.
B
A
Figure 1. Retrosynthetic analysis of isoquinolone ring system synthesis
from ortho-carboxybenzylcarbonyl compounds.
Keywords: Furan; Recyclization; Isoquinolone.
* Corresponding author. Tel.: +7 861 2559556; fax: +7 861 2596592;
e-mail: alexander_butin@mail.ru
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.114

9438
A. S. Dmitriev et al. / Tetrahedron 63 (2007) 9437–9447
R3
NH
XH
O
XH
O
H+
H
R1
OH
R1
+
O
O
R2
a
R'
R'
R2
R'
R
X
O
R
O
- H+
O
O
R2
R2
X
H+
- H3O+
1a-i
2a-i
O
O
R1
R'
O
Cl
R
R3-NH2
R2
O
O
O
for R =
X = O, NTs, COO, CH2O
R2
3a-i
Scheme 1.
Scheme 2. (a) DCC, R3–NH2, CH2Cl2, rt.
2. Results and discussion
Table 1. Synthesis of the amides 2a–i
R1
R2
R3
Product
Yield (%)
2.1. Synthesis of starting amides
Entry
a
b
c
d
e
f
g
h
i
H
Me
Me
Me
Me
Me
Me
Me
Me
t-Bu
t-Bu
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
33
35
32
30
36
34
32
35
33
34
The starting compounds for the synthesis of isoquinolone
derivatives in our approach were 2-carboxybenzylfuran
amides 2, which were obtained from the readily available
2-carboxyaryldifurylmethanes 1.11c The method of amide 2h
synthesis via refluxing acid 1h in benzylamine13 mentioned
in preliminary communication is not suitable for the synthe-
sis of amides derived from low-boiling amines. Therefore,
we had tested other synthetic ways to the required amides.
Cl
Br
H
H
H
H
H
H
Br
Me
Me
Me
Et
i-Pr
t-Bu
Bn
Me
Me
j
2j
It is known that acid chlorides are common precursors for the
synthesis of the corresponding amides. However, we were
not successful in obtaining acid chlorides 3, probably as
a consequence of furan ring susceptibility to acids and
high mobility of the hydrogen atom attached to the methyne
carbon atom. The interaction of acids 1 with PCl5, SOCl2, or
oxalyl chloride14 resulted only in the resinification of the
reaction mixture. The same result was obtained when the
a,a-dichloromethylmethyl ester was used.15 The acceptable
result was obtained only by generation of acid chloride in
situ in the system of PPh3–CCl4 with the subsequent reflux-
ing in the presence of amine.16 However, the amide 2h was
obtained by this method in yield not exceeding 30%. Under
such conditions many side-products were formed in the
reaction mixture, which made difficulties in the chromato-
graphical isolation of the desired product.
the isoquinolone derivative 4h was obtained upon treatment
of 2h with boiling ethanol saturated with hydrogen chloride.
However, further study had demonstrated that these con-
ditions were not optimal. In many cases the reaction was
accompanied with the formation of hardly separable side-
products that eventually lead to the reduced yields of the
desired products. We connected this fact with the possibility
of hydrolysis or alcoholysis of amides under such con-
ditions. The strong support for this assumption is an obser-
vation by TLC method of isocoumarine derivatives that
were obtained earlier upon recyclization of acids 1 under
the same conditions.11c
Attempting the search for the optimal conditions of this
reaction, we have found that refluxing amides 2a–h within
25 min in 16% solution of p-TsOH in benzene led to tetra-
cyclic isoquinolones 4a–h in moderate yields of 45–57%
(Scheme 3, Table 2) that were fully characterized by spectral
methods. For unambiguous proof of structure, X-ray analy-
sis was performed for 4h (Fig. 2).19
Finally, the amides 2 were obtained in satisfactory yields
(30–36%) with the use of dicyclohexylcarbodiimide17
(Scheme 2, Table 1). This method is optimal from the
preparative point of view. Despite comparatively low yields
the reaction proceeds clean enough and only two side-
products were formed in the reaction mixture. The first
one is dicyclohexylurea, which can be easily separated by
filtration, and the second product is amide of dicyclohexyl-
urea, which can be easily separated by column chromato-
graphy. The formation of the dicyclohexylurea amides
causes low yields of amides.18
O
R1
R3
N
p-TsOH, 2.8 equiv.
PhH, reflux
2a-h
O
4a-h
2.2. Recyclization reaction of amides
Scheme 3.
The amides 2 obtained were used in the further study of re-
cyclization reaction. In our earlier work,13 we reported that
The exception is the amide 2g, which did not give the corre-
sponding isoquinolone 4g, the fact that we explain by steric

A. S. Dmitriev et al. / Tetrahedron 63 (2007) 9437–9447
Table 2. Synthesis of tetracyclic isoquinolones 4a–h
9439
hindrance at the nitrogen atom of the amide group caused by
bulky tert-butyl substituent. In this case the reaction was
accompanied with the strong resinification. In other cases
along with the major product 4 we observed by TLC method
initially formed intermediates that are present in the reaction
mixture in minor amounts and expended during the reaction.
Entry
R1
R3
Product
Yield (%)
a
b
c
d
e
f
H
Cl
Br
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
54
57
57
55
55
45
0
Me
Me
Me
Et
i-Pr
t-Bu
Bn
It is known that the reducing of acid concentration in the
recyclization of 2-carboxyaryldifurylmethanes 1 into the
tetracyclic isochromone derivatives allows raising the selec-
tivity of intermediate ketones’ formation.11c This prerequi-
site was used in the synthesis of the corresponding ketones
of the isoquinolone series. To our surprise by reflux-
ing amides 2b–d in 3% benzene solution of p-TsOH, the
a,b-unsaturated alcohols 6b–d were isolated from the reac-
tion mixture along with the expected products 4b–d and
5b–d (Scheme 4). It should be noted that the formation of
allylic alcohols during the recyclizations of ortho-substituted
benzylfurans was observed for the first time.
g
h
4g
4h
55
To our knowledge, the a,b-unsaturated alcohols’ formation
resulting from intramolecular acid-catalyzed recyclization
of furan derivatives was already described in literature, al-
though this type of recyclization products is not common.20
These results and our own experimental data prompted us to
specify the possible mechanism of our reaction, which
earlier seemed to be similar to the mechanism cited for the
recyclization of furans into thiophenes and selenophenes21
(Scheme 5).
According to this scheme, due to preferential furan ring pro-
tonation at the a-position with subsequent ortho-nucleophilic
Figure 2. ORTEP diagram of 4h.
O
O
R1
R1
HO
N
N
p-TsOH, 0.8 equiv.
PhH, reflux
2b-d
4b-d
+
+
O
O
O
5b-d
6b-d
Yield (%)
5
Entry
R1
4
6
b
c
d
Cl
Br
H
17
14
15
29
32
31
27
26
25
Scheme 4.
XH
XH
X
H
H+
+
- H+
H
O
O
O
R'
R'
R'
R
R
R
X
X
R
OH
O
R'
X = O, NTs, COO, CH2O
R'
R
Scheme 5.

9440
A. S. Dmitriev et al. / Tetrahedron 63 (2007) 9437–9447
attack on electrophilic carbon eventually leading to recyc-
lization product, one can expect the formation of allylic
alcohols as the main products. Surprisingly, it is not the
case as in most of the reactions of this type corresponding
saturated ketones are major products. However, acid-
catalyzed isomerizations of allylic alcohols into the corre-
sponding saturated ketones were known for a long time.22
Assuming that alcohols 6 can be intermediate compounds
of the transformation of amides 2 into ketones 5 and in
order to study the facility of this process, the compounds
6b–d were treated with boiling 3% benzene solution of
p-TsOH. However, only tetracyclic compounds 4b–d were
isolated from the reaction mixture. To avoid intramolecular
cyclization and to confirm our assumption, we tried to
synthesize alcohol 7 as a model compound.
recyclization of the amides 2i,j similar intermediate was ob-
served in the reaction mixture (TLC monitoring), which
again had slight difference in Rf with the major product.
However, in this case we were lucky and the alcohol 6i
was isolated in minor amount by column chromatography.
The treatment of compound 6i with boiling solution of
p-TsOH in benzene smoothly led to ketone 5i.
O
O
R1
R1
N
HO
N
p-TsOH,
0.8 equiv.
+
2i,j
PhH, reflux
O
O
O
6i
5i
5i,j
p-TsOH, 0.8 equiv.
PhH, reflux
O
Yield (%)
Entry
R1
Conditions
HO
N
5
6
i
j
i
H
Br
H
2.8 equiv. p-TsOH
2.8 equiv. p-TsOH
0.8 equiv. p-TsOH
50
52
32
0
0
19
7
We started with 2-furylphthalide 823,11c that was reduced into
the corresponding 2-carboxybenzylfuran 924, which, in turn,
was transformed into amide 10 by interaction with MeNH2 in
the presence of DCC. The treatment of 10 with boiling 16%
benzene solution of p-TsOH, as itwas expected, smoothly led
to ketone 11 in 68% yield (Scheme 6). The lowering of the
concentration of p-TsOH to 3% rendered the conversion of
amide 10 sluggish, but nevertheless the alcohol 7 was not iso-
lated. In the reaction mixture one intermediate was observed
by TLC method in negligible amount that rapidly expended
during the reaction. Low concentration and the close proxim-
ity of Rf of this compound and isoquinolone 11 did not allow
us to isolate it for the structural determination.
Scheme 7.
Thus, we determined that the recyclization of the amides
of 2-carboxybenzylfurans 2 into isoquinolone ketones 5
proceeds via formation of intermediate a,b-unsaturated
alcohols 6 and the mechanism of the reaction could be spec-
ified (Scheme 8). The reaction starts with the protonation at
position 5 of the furan cycle of benzylfuran with subsequent
nucleophilic attack of ortho-substituent onto furanium cat-
ion leading to spiro-structure C. The subsequent attack of
a proton at the oxygen atom of dihydrofuran ring leads to
a,b-unsaturated alcohol formation, which eventually iso-
merizes into the corresponding ketones 5 and 11 (Scheme 8,
compare with Scheme 5). In turn the formation of tetracyclic
isoquinolones 4 from ketones 5 proceeds via intramolecular
electrophilic cyclization of 3-oxoalkyl substituent at b-posi-
tion of the furan ring. One cannot exclude from the consid-
eration the cyclization of allyl alcohol into the tetracyclic
derivatives. However, the fact that only one isomer, namely
tetracyclic isoquinolone 4 with positioning of double bond in
the seven-membered ring corresponding to the cyclization of
ketone, is an indirect evidence that isomerization of allylic
alcohol into saturated ketone precede the cyclization step.
O
O
OH
(a)
O
O
9
8
O
(b)
O
O
NHMe
O
N
(c) or (d)
It is obvious that in the case of benzylfurans bearing the
other ortho-nucleophiles the recyclization reaction also pro-
ceeds via the formation of unsaturated alcohols, which were
not observed previously because of their rapid isomerization
and consequently the low concentration in the reaction mix-
ture or because of Rf coincidence of the mentioned alcohols
with the corresponding ketones.
O
11
10
Scheme 6. (a) Zn, NH4OH, reflux; (b) DCC, MeNH2, CH2Cl2, rt; (c)
p-TsOH (2.8 equiv), PhH, reflux; (d) p-TsOH (0.8 equiv), PhH, reflux.
From our previous work,11c it is known that recyclization
of 2-carboxyaryldifurylmethanes with tert-butyl groups at
position 5 of furan rings stops at the corresponding
isochromone ketone formation. The second intramolecular
cyclization with the participation of 3-oxoalkyl fragments
of these ketones is not possible due to the bulky tert-butyl
substituent at carbonyl group.11b,c With this in mind, we
have studied the recyclization of amides 2i,j. Refluxing these
amides in 16% benzene solution of p-TsOH led to the
ketones 5i,j in 50–52% yields (Scheme 7). Like in the case
of amide 10 with reduced p-TsOH concentration during
2.3. Synthesis of tetracyclic isoquinolones
from isochromones
As a result of recyclization of 2-carboxyaryldifurylmethane
amides 2, we synthesized a new tetracyclic condensed sys-
tem 4 incorporating isoquinolone nucleus. To the best of
our knowledge, a limited number of synthetic works are
devoted to the synthesis of isoquinolones conjugated with

A. S. Dmitriev et al. / Tetrahedron 63 (2007) 9437–9447
9441
R3
NH
R3
NH
O
O
O
R1
R1
R1
R3
H+
N
H+
R2
H
R2
- H+
+
O
R2
H
O
N
O
R
R
R
2, 10
C
O
R
O
O
R
R1
R3
N
R1
R3
HO
R1
R3
H+
- H3O+
N
H+
R2
- H+
R2
H
R2
O
H
H+
O
R
6, 7
5, 11
O
R1
R3
N
O
for R =
O
4
Scheme 8.
seven-membered carbocycle.25 Obviously, the tetracyclic
system 4 is attractive for the medicinal chemists since it
includes two pharmacophoric fragments—isoquinolone
nucleus and seven-membered carbocycle. Therefore, in our
work special attention was paid to the synthesis of tetra-
cyclic isoquinolones unsubstituted at the nitrogen atom
meaning the possibility of their further modification.
Table 3. Synthesis of isoquinolones 4a, 13b–f from isochromones 12a–f
Entry
R1
R2
Compound
Product
Yield (%)
a
b
c
d
e
f
H
Cl
Br
I
OMe
OMe
H
H
H
H
H
OMe
12a
12b
12c
12d
12e
12f
4a
85
83
86
87
81
81
13b
13c
13d
13e
13f
One of the convenient methods of synthesis of isoquinolone
derivativesistransformationofisochromonesunderthe action
of amines. In particular, the isoquinolones unsubstituted at the
nitrogen atom can be obtained upon treatment ofisochromone
derivatives with ammonia.26 The tetracyclic isochromone de-
rivatives 12, which were obtained by previously developed
method in 65–75% yields,11c had been used as the starting
compounds for the synthesis of isoquinolones 13. However,
known protocols26 for the replacement of oxygen for nitrogen
in our case appeared inefficient.
3. Conclusion
We have developed a new approach to the synthesis of iso-
quinolone derivatives based on the recyclization of amides
of the 2-carboxybenzylfurans in the presence of acid cata-
lyst. The scope and limitations of the reaction have been
demonstrated. It has been shown that steric hindrance at
the nitrogen atom caused by bulky substituents prevents
recyclization reaction. We were able to isolate intermediate
product of this transformation—the corresponding allylic
alcohols. Facile isomerization of such allylic alcohols into
the corresponding saturated ketones allowed us to add miss-
ing step and specify the mechanism of the recyclization. It is
obvious now that the recyclization of other ortho-substituted
benzylfurans into benzannelated heterocycles, reported
previously,9–12 also proceeds via a,b-unsaturated alcohols
formation.
We have found that the heating of isochromones 12 in form-
amide for 25–60 min afforded the corresponding isoquino-
lones 4a and 13 in good yields (Scheme 9, Table 3). The use
of the formamide in the reactions of the transformation of iso-
chromone cycle is not precedented in the literature. The trans-
formation of phthalic anhydride into phthalimide by refluxing
in formamide can serve as the close analog of this reaction.27 It
should be mentioned that such route to the tetracyclic iso-
quinolones 4a and 13 is more preferable than the recyclization
of the corresponding amides since the recyclization of amide
2a gave product 4a in only 54% yield.
It has been shown that the recyclization of amides of 2-car-
boxyaryldifurylmethanes can be accompanied with the
second intramolecular cyclization, which leads to the new
tetracyclic system—furo[20,30:3,4]cyclohepta[1,2-c]isoqui-
nolin-8(6H)-one. The presence of tert-butyl group at posi-
tion 5 of furan cycles precludes this cyclization for steric
reasons. The tetracyclic isoquinolone derivatives were
obtained also by the alternative synthesis starting with the
corresponding isochromones by refluxing them in form-
amide. Such method of transformation of isochromones
into isoquinolones was not described in literature.
O
O
R1
R2
R1
R2
O
NH
HCONH2
reflux
O
O
12a-f
4a, 13b-f
Scheme 9.

9442
A. S. Dmitriev et al. / Tetrahedron 63 (2007) 9437–9447
4. Experimental
779, 717 cmꢁ1; dH (250 MHz, CDCl3) 7.23–7.43 (4H, m,
HAr), 5.91 (2H, d, J 3.1 Hz, 3-Hfur), 5.89 (2H, d, J 3.1 Hz,
4-Hfur), 5.88 (1H, s, CH), 5.80 (1H, br s, NH), 2.92 (3H, d,
J 4.9 Hz, NHMe), 2.25 (6H, s, Me).
4.1. General
Melting points are uncorrected. H and 13C NMR spectra
were recorded in CDCl3 and in DMSO-d6 on a Bruker AC
200, Bruker WM 250, and Bruker AM 300 spectrometers.
Chemical shifts are reported in parts per million relative to
tetramethylsilane as an internal standard and coupling
constants (J) are given as absolute values in hertz to the near-
est 0.1 Hz. Mass spectra were recorded on a Kratos MS-30
instrument with 70 eV electron impact ionization at
200 ꢀC. IR spectra were measured as KBr plates on Infra-
LUM FT-02 and InfraLUM FT-801 instruments. Column
chromatography was carried out using silica gel KSK
(5–40 mm) manufactured by LTD Sorbpolymer.
1
4.2.5. N-Ethyl-2-bis(5-methyl-2-furyl)methylbenzamide
(2e). Yield 1.16 g, 36% as a colorless crystals, mp 131–
132 ꢀC (from hexane–AcOEt). [Found: C, 74.20; H, 6.63.
C20H21NO3 requires: C, 74.28; H, 6.55%.] nmax (KBr)
3264, 1632, 1559, 1439, 1320, 1214, 1024, 783, 730 cmꢁ1
;
dH (250 MHz, CDCl3) 7.25–7.44 (4H, m, HAr), 5.93 (1H,
s, CH), 5.88 (4H, s, Hfur), 5.75 (1H, br s, NH), 3.42 (2H,
dq, J 4.9, 7.2 Hz, CH2Me), 2.24 (6H, s, Me), 1.14 (3H, t,
J 7.2 Hz, CH2Me).
4.2.6. N-Isopropyl-2-bis(5-methyl-2-furyl)methylbenz-
amide (2f). Yield 1.15 g, 34% as a colorless crystals, mp
116–117 ꢀC (from hexane–AcOEt). [Found: C, 74.64; H,
6.88. C21H23NO3 requires: C, 74.75; H, 6.87%.] nmax
(KBr) 3244, 1624, 1558, 1216, 1021, 778, 731 cmꢁ1; dH
(300 MHz, CDCl3) 7.43–7.46 (1H, m, HAr), 7.29–7.35
(3H, m, HAr), 5.88 (4H, s, Hfur), 5.86 (1H, s, CH), 5.61
(1H, br s, NH), 4.19–4.26 (1H, m, CH(Me)2), 2.24 (6H, s,
Me), 1.16 (6H, d, J 7.2 Hz, CH(Me)2).
4.2. General procedure for the synthesis of amides 2a–j
The mixture of acid 1 (0.01 mol), DCC (2.27 g, 0.011 mol),
and CH2Cl2 (90 cm3) was stirred for 10 min at room temper-
ature. Then amine (0.015 mol) or its concentrated aqueous
solution was added. Then stirring was continued for 20–
30 min and after it the mixture was filtered off from the
dicyclohexylurea. The filtrate was evaporated. The amide
2a–i was isolated from the mixture by column chromato-
graphy (silica gel, eluent: hexane–AcOEt, 4:1).
4.2.7. N-(tert-Butyl)-2-bis(5-methyl-2-furyl)methylbenz-
amide (2g). Yield 1.12 g, 32% as a colorless crystals, mp
102–103 ꢀC (from hexane–AcOEt). [Found: C, 75.29; H,
7.24. C22H25NO3 requires: C, 75.19; H, 7.17%.] nmax
(KBr) 3335, 1641, 1525, 1450, 1365, 1310, 1221, 1021,
780, 745 cmꢁ1; dH (300 MHz, CDCl3) 7.41–7.44 (1H, m,
HAr), 7.24–7.33 (3H, m, HAr), 5.85–5.87 (5H, m, Hfur+CH),
5.52 (1H, br s, NH), 2.25 (6H, s, Me), 1.38 (9H, s, t-Bu).
4.2.1. 2-Bis(5-methyl-2-furyl)methylbenzamide (2a).
Yield 0.97 g, 33% as a colorless crystals, mp 148–149 ꢀC
(from hexane–AcOEt). [Found: C, 73.12; H, 5.75.
C18H17NO3 requires: C, 73.20; H, 5.80%.] nmax (KBr)
3332, 3171, 1650, 1619, 779, 744 cmꢁ1; dH (250 MHz,
CDCl3) 7.51–7.54 (1H, m, HAr), 7.30–7.45 (3H, m, HAr),
6.04 (1H, s, CH), 5.89 (2H, d, J 3.1 Hz, 3-Hfur), 5.88 (2H,
d, J 3.1 Hz, 4-Hfur), 5.80 (2H, br s, NH2), 2.24 (6H, s, Me).
4.2.8. N-Benzyl-2-bis(5-methyl-2-furyl)methylbenz-
amide (2h). Yield 1.35 g, 35% as a colorless crystals, mp
88–89 ꢀC (from hexane–AcOEt). [Found: C, 77.81; H,
6.09. C25H23NO3 requires: C, 77.90; H, 6.01%.] nmax
(KBr) 3213, 1629, 1600, 1558, 1318, 1216, 1022, 780,
733, 699; dH (300 MHz, CDCl3) 7.46–7.48 (1H, m, HAr),
7.26–7.38 (8H, m, HAr), 6.10 (1H, br s, NH), 5.97 (1H, s,
CH), 5.86 (4H, s, Hfur), 4.58 (2H, d, J 5.4 Hz, CH2), 2.20
(6H, s, Me).
4.2.2. 5-Chloro-N-methyl-2-bis(5-methyl-2-furyl)methyl-
benzamide (2b). Yield 1.20 g, 35% as a colorless crystals,
mp 147–148 ꢀC (from hexane–AcOEt). [Found: C, 66.44;
H, 5.21. C19H18ClNO3 requires: C, 66.38; H, 5.28%.] nmax
(KBr) 3299, 1638, 1555, 1319, 782, 768 cmꢁ1; dH
(250 MHz, CDCl3) 7.32 (1H, dd, J 2.0, 8.5 Hz, HAr), 7.24
(1H, d, J 8.5 Hz, HAr), 5.91 (2H, d, J 3.1 Hz, 3-Hfur), 5.88
(2H, d, J 3.1 Hz, 4-Hfur), 5.81 (1H, br s, NH), 5.83 (1H, s,
CH), 2.92 (3H, d, J 4.9 Hz, NHMe), 2.23 (6H, s, Me).
4.2.9. N-Methyl-2-bis(5-(tert-butyl)-2-furyl)methylbenz-
amide (2i). Yield 1.30 g, 33% as a colorless crystals, mp
141–142 ꢀC (from hexane–AcOEt). [Found: C, 76.43; H,
7.85. C25H31NO3 requires: C, 76.30; H, 7.94%.]; nmax
(KBr) 3346, 1648, 1554, 1477, 1300, 1191, 1126, 1010,
772, 728, 681 cmꢁ1; dH (300 MHz, CDCl3) 7.42–7.44 (1H,
m, HAr), 7.26–7.33 (4H, m, HAr), 5.86 (5H, s, Hfur+CH),
5.65 (1H, br s, NH), 2.92 (3H, d, J 4.9 Hz, Me), 1.23
(18H, s, t-Bu).
4.2.3. 5-Bromo-N-methyl-2-bis(5-methyl-2-furyl)methyl-
benzamide (2c). Yield 1.24 g, 32% as a colorless crystals,
mp 150–151 ꢀC (from hexane–AcOEt). [Found: C, 58.85;
H, 4.60. C19H18BrNO3 requires: C, 58.78; H, 4.67%.] nmax
(KBr) 3296, 1636, 1587, 1552, 1408, 1317, 1217, 1022,
867, 782, 706, 688 cmꢁ1; dH (250 MHz, CDCl3) 7.55 (1H,
d, J 2.0 Hz, HAr), 7.47 (1H, dd, J 2.0, 8.3 Hz, HAr), 7.18
(1H, d, J 8.3 Hz, HAr), 5.91 (2H, d, J 3.1 Hz, 3-Hfur), 5.88
(2H, d, J 3.1 Hz, 4-Hfur), 5.82 (1H, s, CH), 5.77 (1H, br s,
NH), 2.92 (3H, d, J 4.9 Hz, NHMe), 2.23 (6H, s, Me).
4.2.10. 5-Bromo-N-methyl-2-bis(5-(tert-butyl)-2-furyl)-
methylbenzamide (2j). Yield 1.60 g, 34% as a yellow oil.
[Found: C, 63.69; H, 6.30. C25H30BrNO3 requires: C,
63.56; H, 6.40%.] nmax (KBr) 3296, 1639, 1558, 1318,
1195, 1013, 777; dH (300 MHz, CDCl3) 7.58 (1H, d,
J 2.1 Hz, HAr), 7.45 (1H, dd, J 2.1, 8.3 Hz, HAr), 7.15 (1H,
d, J 8.3 Hz, HAr), 5.86 (4H, s, Hfur), 5.80 (1H, br s, NH),
5.79 (1H, s, CH), 2.92 (3H, d, J 4.9 Hz, Me), 1.23 (18H, s,
t-Bu).
4.2.4. N-Methyl-2-bis(5-methyl-2-furyl)methylbenz-
amide (2d). Yield 0.93 g, 30% as a colorless crystals, mp
120–121 ꢀC (from hexane–AcOEt). [Found: C, 73.88; H,
6.10. C19H19NO3 requires: C, 73.77; H, 6.19%.] nmax
(KBr) 3278, 1646, 1543, 1406, 1316, 1216, 1022, 948,

A. S. Dmitriev et al. / Tetrahedron 63 (2007) 9437–9447
9443
4.3. General procedure for the synthesis of compounds
4a–h
nmax (KBr) 1650, 1581, 1550, 1484, 1413, 1334, 832, 773,
691 cmꢁ1; dH (300 MHz, DMSO) 8.37–8.40 (1H, m, HAr),
8.29–8.32 (1H, m, HAr), 7.71–7.76 (1H, m, HAr), 7.47–
7.52 (1H, m, HAr), 6.51 (1H, s, Hfur), 5.55 (1H, t, J 7.0 Hz,
]CH), 3.74 (3H, s, Me), 2.49 (2H, d, J 7.0 Hz, CH2), 2.48
(3H, s, Me), 2.01 (3H, s, Me); dC (50 MHz, DMSO) 161.5,
150.1, 148.1, 135.1, 133.4, 132.4, 131.2, 127.6, 126.1,
125.8, 123.8, 123.3, 114.9, 105.4, 104.6, 32.1, 29.5, 19.4,
13.3; MS: m/z (%) 292 (M++1, 27), 291 (M+, 100), 290
(46), 277 (22), 276 (99), 248 (24), 247 (18), 246 (23), 232
(15), 219 (13), 204 (14).
Amide 2 (0.01 mol) was refluxed within 25 min in 16% so-
lution of anhydrous p-TsOH in benzene (30 cm3), prepared
by azeotropic removal of water from a solution of p-TsOH
in benzene. The reaction mixture was poured into excess
of water and extracted with CH2Cl2. Extract was evaporated
to dryness and the residue separated by column chromato-
graphy (silica gel, eluent: hexane–AcOEt, 4:1).
4.3.1. 2,4-Dimethylfuro[20,30:3,4]cyclohepta[1,2-c]iso-
quinolin-8(6H)-one (4a). Yield 1.50 g, 54% as a yellowish
crystals, mp >310 ꢀC (decomp.) [from EtOH–1,4-dioxane).
[Found: C, 77.90; H, 5.36. C18H15NO2 requires: C, 77.96; H,
4.3.5. 7-Ethyl-2,4-dimethylfuro[20,30:3,4]cyclohepta[1,2-
c]isoquinolin-8(6H)-one (4e). Yield 1.68 g, 55% as a yel-
lowish crystals, mp 146–147 ꢀC (from hexane–AcOEt).
[Found: C, 78.67; H, 6.20. C20H19NO2 requires: C, 78.66;
H, 6.27%.] nmax (KBr) 1645, 1606, 1550, 1483, 1446,
1340, 1171, 852, 777 cmꢁ1; dH (300 MHz, DMSO) 8.34–
8.37 (1H, m, HAr), 8.29–8.31 (1H, m, HAr), 7.70–7.75 (1H,
m, HAr), 7.47–7.52 (1H, m, HAr), 6.50 (1H, s, Hfur), 5.51–
5.56 (1H, m, ]CH), 4.20–4.48 (2H, br m, CH2Me), 3.55–
3.75 (1H, br m, CH2), 2.48 (3H, s, Me), 2.20–2.40 (1H,
br m, CH2), 2.00 (3H, s, Me), 1.30–1.35 (3H, m, CH2Me);
dC (50 MHz, DMSO) 161.1, 150.3, 148.2, 135.3, 133.6,
132.7, 131.3, 127.7, 126.1 (2C), 124.0, 123.4, 116.2, 105.5,
104.9, 39.8, 29.3, 19.5, 14.0, 13.5; MS: m/z (%) 306
(M++1, 25), 305 (M+, 100), 304 (29), 291 (21), 290 (91),
277 (32), 276 (59), 262 (59), 260 (14), 247 (19), 246 (24),
232 (26).
5.45%.] nmax (KBr) 1656, 1612, 1472, 911, 829, 773 cmꢁ1
;
dH (300 MHz, DMSO) 11.61 (1H, s, NH), 8.36–8.38 (1H, m,
HAr), 8.25–8.27 (1H, m, HAr), 7.72–7.77 (1H, m, HAr), 7.47–
7.52 (1H, m, HAr), 6.45 (1H, s, Hfur), 5.36 (1H, t, J 6.7 Hz,
]CH), 2.92 (2H, d, J 6.7 Hz, CH2), 2.46 (3H, s, Me), 1.98
(3H, s, Me); dC (75 MHz, DMSO, 65 ꢀC) 161.4, 149.5,
147.5, 134.7, 134.6, 132.1, 130.8, 126.7, 125.1, 124.8,
124.1, 123.7, 115.5, 105.1, 103.1, 30.1, 19.3, 12.8; MS:
m/z (%) 278 (M++1, 19), 277 (M+, 100), 276 (32), 263
(17), 262 (87), 232 (6), 204 (6).
4.3.2. 10-Chloro-2,4,7-trimethylfuro[20,30:3,4]cyclo-
hepta[1,2-c]isoquinolin-8(6H)-one (4b). Yield 1.85 g,
57% as a yellowish crystals, mp 216–217 ꢀC (from hexane–
AcOEt). [Found: C, 70.10; H, 4.83. C19H16ClNO2 requires:
C, 70.05; H, 4.95%.] nmax (KBr) 1655, 1605, 1473, 899,
819 cmꢁ1; dH (300 MHz, DMSO) 8.39 (1H, d, J 9.0 Hz,
HAr), 8.22 (1H, d, J 2.3 Hz, HAr), 7.75 (1H, dd, J 2.3, 9.0 Hz,
HAr), 6.51 (1H, s, Hfur), 5.55 (1H, t, J 6.8 Hz, ]CH),
3.73 (3H, s, Me), 2.49 (2H, d, J 6.8 Hz, CH2), 2.48 (3H,
s, Me), 2.01 (3H, s, Me); dC (50 MHz, DMSO, 60 ꢀC)
160.4, 150.3, 147.4, 135.4, 132.3, 131.2, 130.4, 128.3,
126.3, 126.1, 124.5, 119.3, 114.7, 105.3, 104.1, 32.2, 29.4,
19.2, 13.1; MS: m/z (%) 328/326 (M++1, 7/24), 327/
325 (M+, 35/100), 313 (12), 312/310 (24/71), 282 (15),
280 (19).
4.3.6. 7-Isopropyl-2,4-dimethylfuro[20,30:3,4]cyclo-
hepta[1,2-c]isoquinolin-8(6H)-one (4f). Yield 1.44 g,
45% as a yellowish crystals, mp 166–167 ꢀC (from hexane–
AcOEt). [Found: C, 78.91; H, 6.68. C21H21NO2 requires: C,
78.97; H, 6.63%.] nmax (KBr) 1640, 1603, 1546, 1451, 1361,
1325, 1176, 1083, 1037, 956, 853, 774, 694 cmꢁ1; dH
(300 MHz, DMSO) 8.27–8.29 (2H, m, HAr), 7.68–7.73
(1H, m, HAr), 7.45–7.50 (1H, m, HAr), 6.50 (1H, s, Hfur),
5.53–5.58 (1H, m, ]CH), 5.07–5.22 (1H, br m, CH(Me)2),
3.62–3.78 (1H, br m, CH2), 2.47 (3H, s, Me), 2.16–
2.32 (1H, br m, CH2), 2.03 (3H, s, Me), 1.52–1.71 (6H,
br m, CH(Me)2); dC (75 MHz, DMSO) 161.6, 150.2,
148.3, 135.2, 133.3, 132.4, 131.2, 127.4, 126.4, 126.0,
124.4, 123.8, 116.4, 105.5 (2C), 50.5, 29.8, 20.1, 19.5,
13.5 (2C); MS: m/z (%) 320 (M++1, 9), 319 (M+, 58), 278
(36), 277 (100), 276 (63), 262 (20), 261 (100), 246 (17),
234 (15).
4.3.3. 10-Bromo-2,4,7-trimethylfuro[20,30:3,4]cyclo-
hepta[1,2-c]isoquinolin-8(6H)-one (4c). Yield 2.11 g,
57% as a yellowish crystals, mp 255–256 ꢀC (from hexane–
AcOEt). [Found: C, 61.58; H, 4.40. C19H16BrNO2 requires:
C, 61.64; H, 4.36%.] nmax (KBr) 1643, 1577, 1478, 1412,
915, 824, 798 cmꢁ1; dH (300 MHz, DMSO) 8.38 (1H, d, J
2.2 Hz, HAr), 8.33 (1H, d, J 8.9 Hz, HAr), 7.87 (1H, dd, J
2.2, 8.9 Hz, HAr), 6.51 (1H, s, Hfur), 5.55 (1H, t, J 6.9 Hz,
]CH), 3.73 (3H, s, Me), 2.49 (2H, d, J 6.9 Hz, CH2), 2.48
(3H, s, Me), 2.01 (3H, s, Me); dC (50 MHz, DMSO, 50 ꢀC)
160.3, 150.4, 147.5, 135.7, 135.1, 132.3, 131.3, 129.6,
126.3 (2C), 124.9, 118.7, 114.8, 105.4, 104.2, 32.3, 29.5,
19.3, 13.2; MS: m/z (%) 372/370 (M++1, 24/28), 371/
369 (M+, 96/100), 368 (18), 357 (17), 356 (86), 355 (12),
354 (94), 328 (21), 326 (20), 252(16), 247 (20), 246 (14),
219 (19).
4.3.7. 7-Benzyl-2,4-dimethylfuro[20,30:3,4]cyclo-
hepta[1,2-c]isoquinolin-8(6H)-one (4h). Yield 2.02 g,
55% as a yellowish crystals, mp 197–198 ꢀC (from hexane–
AcOEt). [Found: C, 81.53; H, 5.89. C25H21NO2 requires: C,
81.72; H, 5.76%.] nmax (KBr) 1651, 1602, 1481, 1394, 1163,
778, 740, 706 cmꢁ1; dH (300 MHz, DMSO) 8.36–8.42 (2H,
m, HAr), 7.76–7.81 (1H, m, HAr), 7.53–7.58 (1H, m, HAr),
7.21–7.39 (5H, m, Ph), 6.47 (1H, s, Hfur), 5.61 (2H, br s,
CH2Ph), 4.90–5.01 (1H, m, ]CH), 3.41–3.60 (1H, br m,
CH2), 2.47 (3H, s, Me), 2.12–2.31 (1H, br m, CH2), 1.90
(3H, s, Me); dC (75 MHz, DMSO) 161.9, 150.4, 147.9,
137.1, 135.3, 133.8, 133.1, 130.9, 128.7 (2C), 128.0,
127.1, 126.4 (4C), 124.1, 123.4, 115.7, 105.6, 105.2, 47.3,
29.9, 19.5, 13.5; MS: m/z (%) 368 (M++1, 16), 367 (M+,
76), 277 (20), 276 (100), 91 (22).
4.3.4. 2,4,7-Trimethylfuro[20,30:3,4]cyclohepta[1,2-c]iso-
quinolin-8(6H)-one (4d). Yield 1.60 g, 55% as a yellowish
crystals, mp 183–184 ꢀC (from hexane–AcOEt). [Found: C,
78.28; H, 5.95. C19H17NO2 requires: C, 78.33; H, 5.88%.]

9444
A. S. Dmitriev et al. / Tetrahedron 63 (2007) 9437–9447
4.4. General procedure for the synthesis of compounds
5b–d,i and 6b–d,i
0.93 g, 27% as a yellowish crystals, mp 144–145 ꢀC (from
hexane–AcOEt). [Found: C, 66.31; H, 5.22. C19H18ClNO3
requires: C, 66.38; H, 5.28%.] nmax (KBr) 3395, 2924,
1627, 1588, 1481, 1343, 1054, 968, 906, 823, 794,
594 cmꢁ1; dH (300 MHz, CDCl3) 8.40 (1H, d, J 1.7 Hz,
HAr), 7.51 (1H, dd, J 1.7, 8.7 Hz, HAr), 7.36 (1H, d,
J 8.7 Hz, HAr), 6.24 (1H, d, J 3.0 Hz, 3-Hfur), 6.18 (1H, d,
J 11.3 Hz, ]CH), 6.12 (1H, d, J 3.0 Hz, 4-Hfur), 5.76 (1H,
dd, J 9.0, 11.3 Hz, ]CH), 4.26–4.31 (1H, m, CH), 3.57
(3H, s, Me), 2.36 (3H, s, Me), 1.65 (1H, br s, OH), 1.12
(3H, d, J 6.2 Hz, Me); dC (50 MHz, CDCl3) 161.6, 152.5,
146.7, 140.1 (2C), 135.0, 132.9, 127.2, 126.5, 125.5, 122.2
(2C), 108.2. 112.3, 107.1, 64.6, 33.1, 21.9, 13.7; MS: m/z
(%) 345/343 (M+, 10/30), 301 (28), 300 (44), 299 (72),
298 (100), 286 (17), 284 (33), 282 (32), 271 (17), 270
(22), 257 (15), 256 (23), 186 (24).
Amide 3 (0.01 mol) was refluxed within 25 min in 3% solution
of anhydrous p-TsOH in benzene (60 cm3), prepared by azeo-
tropic removal of water from a solution of p-TsOH in benzene.
The reaction mixture was poured into excess of water and
extracted with CH2Cl2. Extract was evaporated to dryness
and the residue separated by column chromatography (silica
gel, eluent: hexane–AcOEt, 4:1) giving compounds 4–6.
4.4.1. 7-Chloro-2-methyl-4-(5-methyl-2-furyl)-3-(3-oxo-
butyl)isoquinolin-1(2H)-one (5b). Yield 1.00 g, 29% as
a yellowish crystals, mp 120–122 ꢀC (from hexane–AcOEt).
[Found: C, 66.32; H, 5.35. C19H18ClNO3 requires: C, 66.38;
H, 5.28%.] nmax (KBr) 1708, 1658, 1480, 1169, 1038, 1018,
910, 826, 787 cmꢁ1; dH (300 MHz, CDCl3) 8.39 (1H, d, J
2.1 Hz, HAr), 7.48 (1H, dd, J 2.1, 8.7 Hz, HAr), 7.21 (1H,
d, J 8.7 Hz, HAr), 6.27 (1H, d, J 3.0 Hz, 3-Hfur), 6.12 (1H,
d, J 3.0 Hz, 4-Hfur), 3.65 (3H, s, Me), 2.88–2.94 (2H, m,
CH2), 2.70–2.75 (2H, m, CH2), 2.34 (3H, s, Me), 2.16 (3H,
s, Me); dC (50 MHz, CDCl3) 208.8, 162.0, 152.5, 146.5,
144.2, 135.5, 132.7, 132.4, 127.1, 126.3, 125.0, 112.3,
108.2, 107.0, 42.7, 31.7, 30.0, 25.5, 13.7; MS: m/z (%)
346/344 (M++1, 7/23), 345/343 (M+, 38/100), 302 (22),
300 (57), 288 (14), 286 (39), 285 (14), 258 (35), 256 (14),
244 (17), 243 (18), 223 (14).
4.4.5. 7-Bromo-3-((Z)-3-hydroxy-1-butenyl)-2-methyl-
4-(5-methyl-2-furyl)isoquinolin-1(2H)-one (6c). Yield
1.01 g, 26% as a yellowish crystals, mp 144–145 ꢀC (from
hexane–AcOEt). [Found: C, 58.72; H, 4.73. C19H18BrNO3
requires: C, 58.78; H, 4.67%.] nmax (KBr) 3417, 2923,
1626, 1584, 1477, 1341, 1223, 1126, 1055, 967, 902, 794,
748, 594; dH (300 MHz, CDCl3) 8.59 (1H, d, J 1.8 Hz,
HAr), 7.66 (1H, dd, J 1.8, 8.7 Hz, HAr), 7.30 (1H, d,
J 8.7 Hz, HAr), 6.24 (1H, d, J 3.0 Hz, 3-Hfur), 6.17 (1H, d,
J 11.3 Hz, ]CH), 6.12 (1H, d, J 3.0 Hz, 4-Hfur), 5.76 (1H,
dd, J 9.0, 11.3 Hz, ]CH), 4.26–4.31 (1H, m, CH), 3.58
(3H, s, Me), 2.36 (3H, s, Me), 1.56 (1H, br s, OH), 1.13
(3H, d, J 6.2 Hz, Me); dC (50 MHz, CDCl3) 161.4, 152.5,
146.6, 140.3, 140.1, 135.6, 135.3, 130.4, 126.6, 125.8,
122.2, 120.8, 112.3, 108.0, 107.1, 64.6, 33.2, 21.9, 13.7;
MS: m/z (%) 389/387 (M+, 6/6), 346 (10), 345 (48), 344
(99), 343 (42), 342 (100), 330 (15), 328 (25), 326 (18),
262 (20), 220 (16).
4.4.2. 7-Bromo-2-methyl-4-(5-methyl-2-furyl)-3-(3-oxo-
butyl)isoquinolin-1(2H)-one (5c). Yield 1.24 g, 32% as a
yellowish crystals, mp 125–127 ꢀC (from hexane–AcOEt).
[Found: C, 58.72; H, 4.61. C19H18BrNO3 requires: C,
58.78; H, 4.67%.] nmax (KBr) 1712, 1651, 1590, 1474,
1367, 1315, 1215, 1022, 961, 829 cmꢁ1; dH (300 MHz,
CDCl3) 8.55 (1H, d, J 2.1 Hz, HAr), 7.62 (1H, dd, J 2.1,
8.7 Hz, HAr), 7.14 (1H, d, J 8.7 Hz, HAr), 6.27 (1H, d, J
3.0 Hz, 3-Hfur), 6.12 (1H, d, J 3.0 Hz, 4-Hfur), 3.65 (3H, s,
Me), 2.87–2.93 (2H, m, CH2), 2.71–2.76 (2H, m, CH2),
2.34 (3H, s, Me), 2.17 (3H, s, Me); dC (50 MHz, CDCl3)
205.8, 161.9, 152.5, 146.4, 144.5, 135.9, 135.5, 130.3,
126.4, 125.3, 120.3, 112.4, 108.3, 107.0, 42.7, 31.7, 29.9,
25.5, 13.8; MS: m/z (%) 390/388 (M++1, 9/10), 389/387
(M+, 41/41), 346/344 (22/22), 143 (23), 99 (43), 98 (25).
4.4.6. 3-((Z)-3-Hydroxy-1-butenyl)-2-methyl-4-(5-meth-
yl-2-furyl)isoquinolin-1(2H)-one (6d). Yield 0.77 g, 25%
as a yellowish crystals, mp 170–171 ꢀC (from hexane–
AcOEt). [Found: C, 73.84; H, 6.11. C19H19NO3 requires:
C, 73.77; H, 6.19%.] nmax (KBr) 3409, 2964, 1631, 1557,
1340, 1217, 1122, 1056, 1023, 801, 694 cmꢁ1; dH
(300 MHz, CDCl3) 8.45–8.48 (1H, m, HAr), 7.58–7.63
(1H, m, HAr), 7.41–7.51 (2H, m, HAr), 6.25 (1H, d, J
3.0 Hz, 3-Hfur), 6.20 (1H, d, J 11.3 Hz, ]CH), 6.12 (1H,
d, J 3.0 Hz, 4-Hfur), 5.75 (1H, dd, J 9.0, 11.3 Hz, ]CH),
4.26–4.33 (1H, m, CH), 3.59 (3H, s, Me), 2.36 (3H, s,
Me), 1.60 (1H, s, OH), 1.12 (3H, d, J 6.2 Hz, Me); dC
(50 MHz, CDCl3) 162.6, 152.2, 147.2, 139.9, 139.8, 136.6,
132.4, 127.8, 126.9, 124.7, 124.4, 122.3, 112.1, 108.1,
107.0, 64.6, 33.0, 21.9, 13.7; MS: m/z (%) 309 (M+, 15),
264 (61), 263 (100), 250 (33), 249 (14), 248 (56), 236
(22), 223 (25), 222 (34), 220 (15), 192 (18).
4.4.3. 2-Methyl-4-(5-methyl-2-furyl)-3-(3-oxobutyl)iso-
quinolin-1(2H)-one (5d). Yield 0.96 g, 31% as a yellowish
crystals, mp 136–137 ꢀC (from hexane–AcOEt). [Found: C,
73.70; H, 6.13. C19H19NO3 requires: C, 73.77; H, 6.19%.]
nmax (KBr) 1710, 1651, 1591, 1547, 1481, 1419, 1370,
1324, 1168, 1024, 801, 767, 698 cmꢁ1; dH (300 MHz,
CDCl3) 8.41–8.43 (1H, m, HAr), 7.53–7.55 (1H, m, HAr),
7.41–7.46 (1H, m, HAr), 7.25–7.27 (1H, m, HAr), 6.28 (1H,
d, J 3.0 Hz, 3-Hfur), 6.12 (1H, d, J 3.0 Hz, 4-Hfur), 3.66
(3H, s, Me), 2.89–2.94 (2H, m, CH2), 2.71–2.76 (2H, m,
CH2), 2.35 (3H, s, Me), 2.16 (3H, s, Me); dC (50 MHz,
CDCl3) 206.0, 163.2, 152.3, 147.0, 143.8, 137.2, 132.4,
127.8, 126.5, 124.4, 124.0, 112.1, 108.7, 106.9, 42.9, 31.5,
29.9, 25.5, 13.8; MS: m/z (%) 310 (M++1, 24), 309 (M+,
100), 265 (77), 252 (40), 248 (22), 233 (16), 224 (52), 223
(25), 222 (18), 210 (15), 209 (31), 99 (15).
4.4.7. 4-(5-(tert-Butyl)-2-furyl)-3-(4,4-dimethyl-3-oxo-
pentyl)-2-methylisoquinolin-1(2H)-one (5i). Ketone 5i was
obtained analogous to 4a–h within 10 min. Yield 1.97 g,
50% as a yellowish crystals, mp 115–116 ꢀC (from hexane–
AcOEt). [Found: C, 76.38; H, 7.99. C25H31NO3 requires: C,
76.30; H, 7.94%.] nmax (KBr) 1698, 1654, 1586, 1548,
1476, 1365, 1080, 1024, 971, 768, 698 cmꢁ1; dH (300 MHz,
DMSO) 8.24–8.27 (1H, m, HAr), 7.61–7.69 (1H, m, HAr),
7.43–7.51 (1H, m, HAr), 7.09–7.12 (1H, m, HAr), 6.41 (1H,
4.4.4. 7-Chloro-3-((Z)-3-hydroxy-1-butenyl)-2-methyl-
4-(5-methyl-2-furyl)isoquinolin-1(2H)-one (6b). Yield

A. S. Dmitriev et al. / Tetrahedron 63 (2007) 9437–9447
9445
d, J 3.1 Hz, 3-Hfur), 6.21 (1H, d, J 3.1 Hz, 4-Hfur), 3.60 (3H, s,
Me), 2.81–2.84 (4H, m, CH2CH2), 1.27 (9H, s, t-Bu), 1.07
(9H, s, t-Bu); dC (50 MHz, DMSO) 213.3, 163.5, 161.7,
146.5, 145.2, 136.7, 132.5, 127.2, 126.3, 123.8, 123.2,
111.4, 106.9, 103.3, 43.4, 35.6, 32.3, 31.0, 28.8 (3C), 26.0
(3C), 25.7; MS: m/z (%) 394 (M++1, 20), 393 (M+, 100),
378 (33), 308 (13), 222 (11), 57 (22).
m, CH2), 1.17 (9H, s, t-Bu); dC (75 MHz, CDCl3) 213.4,
163.5, 142.4, 136.4, 132.1, 127.8, 126.1, 125.2, 124.3, 104.8,
44.3, 35.1, 30.7, 27.7, 26.4 (3C); MS: m/z (%) 272 (M++1,
6), 271 (M+, 23), 187 (25), 186 (100), 172 (22), 142 (11),
89 (24).
4.7. General procedure for the synthesis of compounds
4a, 13b–f from 12a–f
4.4.8. 7-Bromo-4-(5-(tert-butyl)-2-furyl)-3-(4,4-dimethyl-
3-oxopentyl)-2-methylisoquinolin-1(2H)-one (5j). Ketone
5j was obtained analogous to 4a–h within 10 min. Yield
2.45 g, 52% as a yellowish crystals, mp 185–186 ꢀC (from
hexane–AcOEt). [Found: C, 63.50; H, 6.47. C25H30BrNO3
requires: C, 63.56; H, 6.40%.] nmax (KBr) 1700, 1640,
1540, 1477, 1364, 1188, 1080, 986, 820, 784 cmꢁ1; dH
(300 MHz, CDCl3) 8.53 (1H, d, J 2.1 Hz, HAr), 7.60 (1H,
dd, J 2.1, 8.7 Hz, HAr), 7.06 (1H, d, J 8.7 Hz, HAr), 6.25
(1H, d, J 3.0 Hz, 3-Hfur), 6.09 (1H, d, J 3.0 Hz, 4-Hfur),
3.64 (3H, s, Me), 2.88–2.93 (2H, m, CH2), 2.71–2.76 (2H,
m, CH2), 1.29 (9H, s, t-Bu), 1.11 (9H, s, t-Bu); dC
(50 MHz, CDCl3) 213.4, 164.7, 162.0, 146.3, 144.7, 136.1,
135.5, 130.2, 126.4, 125.3, 120.2, 111.7, 108.4, 103.2,
44.1, 36.0, 32.7, 31.6, 29.1 (3C), 26.4 (3C), 26.0; MS: m/z
(%) 474/472 (M++1, 15/16), 473/471 (M+, 100/100), 458
(20), 456 (20), 388 (23), 386 (23), 358 (15), 356 (15), 302
(28), 300 (28), 57 (81).
A mixture of isochromones 12a–f (0.01 mol) and formamide
(45 cm3) was refluxed until disappearance of the starting
compound (25–60 min). Resulted solution was poured into
water. The precipitate was filtered off and recrystallized
from the mixture of EtOH–1,4-dioxane (1:5). We failed to
display 13C NMR spectra of compounds 13b–d due to their
low solubility.
4.7.1. 2,4-Dimethylfuro[20,30:3,4]cyclohepta[1,2-c]isoqui-
nolin-8(6H)-one (4a). Yield 2.35 g, 85%, physical and spec-
tral properties were identical to compound synthesized by
amide 2a recyclization.
4.7.2. 10-Chloro-2,4-dimethylfuro[20,30:3,4]cyclo-
hepta[1,2-c]isoquinolin-8(6H)-one (13b). Yield 2.59 g,
83.3% as a colorless powder, mp >310 ꢀC (decomp.)
(from EtOH–1,4-dioxane). [Found: C, 69.40; H, 4.50.
C18H14ClNO2 requires: C, 69.35; H, 4.53%.] nmax (KBr)
1656, 1603, 1472, 1342, 899, 819; dH (300 MHz, DMSO)
11.72 (1H, s, NH), 8.38 (1H, d, J 8.9 Hz, HAr), 8.18 (1H,
d, J 2.2 Hz, HAr), 7.77 (1H, dd, J 2.2, 8.9 Hz, HAr), 6.47
(1H, s, Hfur), 5.35 (1H, t, J 6.5 Hz, ]CH), 2.91 (2H, d,
J 6.5 Hz, CH2), 2.45 (3H, s, Me), 1.98 (3H, s, Me); MS:
m/z (%) 313/311 (M+, 34/100), 310 (30), 298 (29), 297
(17), 296 (86).
4.4.9. 4-(5-(tert-Butyl)-2-furyl)-3-((Z)-3-hydroxy-4,4-di-
methyl-1-pentenyl)-2-methylisoquinolin-1(2H)-one (6i).
Alcohol 6i was prepared analogous to 6b–d as a white solid
1
with 90% purity and characterized by H NMR only. dH
(300 MHz, CDCl3) 8.48–8.50 (1H, m, HAr), 7.60–7.65
(1H, m, HAr), 7.48–7.55 (2H, m, HAr), 6.37 (1H, d,
J 11.5 Hz, ]CH), 6.29 (1H, d, J 3.0 Hz, 3-Hfur), 6.12 (1H,
d, J 3.0 Hz, 4-Hfur), 5.79 (1H, dd, J 9.1, 11.5 Hz, ]CH),
3.61–3.66 (1H, m, CH), 3.61 (3H, s, Me), 1.71 (1H, br s,
OH), 1.34 (9H, s, t-Bu), 0.79 (9H, s, t-Bu).
4.7.3. 10-Bromo-2,4-dimethylfuro[20,30:3,4]cyclo-
hepta[1,2-c]isoquinolin-8(6H)-one (13c). Yield 3.05 g,
85.6% as a colorless powder, mp >310 ꢀC (decomp.)
(from EtOH–1,4-dioxane). [Found: C, 65.59; H, 3.42.
C18H14BrNO2 requires: C, 60.69; H, 3.96%.] nmax (KBr)
1654, 1601, 1469, 1342, 902, 818 cmꢁ1; dH (300 MHz,
DMSO) 11.78 (1H, s, NH), 8.33 (1H, d, J 2.3 Hz, HAr),
8.31 (1H, d, J 8.9 Hz, HAr), 7.88 (1H, dd, J 2.3, 8.9 Hz,
HAr), 6.47 (1H, s, Hfur), 5.35 (1H, t, J 6.4 Hz, ]CH), 2.91
(2H, d, J 6.4 Hz, CH2), 2.45 (3H, s, Me), 1.98 (3H, s, Me);
MS: m/z (%) 357/355 (M+, 100/100), 356 (48), 354 (28),
343 (16), 342(74), 341 (17), 340 (73).
4.5. N-Methyl-2-(5-(tert-butyl)-2-furyl)methylbenz-
amide (10)
Amide 10 was obtained analogous to compounds 2a–j. Yield
0.95 g, 35% as a yellowish crystals, mp 94–95 ꢀC (from hex-
ane–AcOEt). [Found: C, 75.18; H, 7.87. C17H21NO2 re-
quires: C, 75.25; H, 7.80%.] nmax (KBr) 3286, 1643, 1569,
1460, 1410, 1360, 1172, 1126, 1011, 778, 716, 692 cmꢁ1
;
dH (300 MHz, CDCl3) 7.39–7.41 (1H, m, HAr), 7.30–7.33
(1H, m, HAr), 7.22–7.25 (2H, m, HAr), 6.37 (1H, br s,
NH), 5.85 (1H, d, J 3.0 Hz, 3-Hfur), 5.83 (1H, d, J 3.0 Hz,
4-Hfur), 4.08 (2H, s, CH2), 2.93 (3H, d, J 4.8 Hz, Me), 1.23
(9H, s, t-Bu).
4.7.4. 10-Iodo-2,4-dimethylfuro[20,30:3,4]cyclohepta[1,2-
c]isoquinolin-8(6H)-one (13d). Yield 3.52 g, 87.4% as
a colorless powder, mp >310 ꢀC (decomp.) (from EtOH–
1,4-dioxane). [Found: C, 53.55; H, 3.47. C18H14INO2 re-
quires: C, 53.62; H, 3.50%.] nmax (KBr) 3419, 2911, 1650,
1611, 1468, 818, 729, 651 cmꢁ1; dH (200 MHz, DMSO)
11.74 (1H, s, NH), 8.53 (1H, d, J 1.8 Hz, HAr), 8.15 (1H,
d, J 8.7 Hz, HAr), 8.02 (1H, dd, J 1.8, 8.7 Hz, HAr), 6.45
(1H, s, Hfur), 5.35 (1H, t, J 6.5 Hz, ]CH), 2.90 (2H, d,
J 6.5 Hz, CH2), 2.45 (3H, s, Me), 1.98 (3H, s, Me); MS:
m/z (%) 404 (M++1, 20), 403 (M+, 100), 402 (14), 389
(10), 388 (49).
4.6. 3-(4,4-Dimethyl-3-oxopentyl)-2-methylisoquinolin-
1(2H)-one (11)
Isoquinolone 11 was obtained analogous to 4a–h within
10 min. Yield 1.84 g, 68% as a yellowish crystals, mp 98–
99 ꢀC (from hexane–AcOEt). [Found: C, 75.31; H, 7.88.
C17H21NO2 requires: C, 75.25; H, 7.80%.] nmax (KBr)
2954, 1708, 1647, 1596, 1079, 993, 822, 756, 691 cmꢁ1
;
dH (300 MHz, CDCl3) 8.34–8.37 (1H, m, HAr), 7.54–7.59
(1H, m, HAr), 7.37–7.41 (2H, m, HAr), 6.29 (1H, s, ]CH),
3.60 (3H, s, Me), 2.92–2.97 (2H, m, CH2), 2.83–2.88 (2H,
4.7.5. 10-Methoxy-2,4-dimethylfuro[20,30:3,4]cyclo-
hepta[1,2-c]isoquinolin-8(6H)-one (13e). Yield 2.50 g,

9446
A. S. Dmitriev et al. / Tetrahedron 63 (2007) 9437–9447
81.3% as a colorless powder, mp >310 ꢀC (decomp.) (from
EtOH–1,4-dioxane). [Found: C, 74.34; H, 5.51. C19H17NO3
requires: C, 74.25; H, 5.58%.] nmax (KBr) 1651, 1542, 1486,
3860–3873; (e) Cushman, M.; Jayaraman, M.; Vroman, J. A.;
Fukunaga, A. K.; Fox, B. M.; Kohlhagen, G.; Strumberg, D.;
Pommier, Y. J. Med. Chem. 2000, 43, 3688–3698; (f) Ukita,
T.; Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Moritani, Y.;
Saruta, K.; Higashijima, T.; Kotera, J.; Takagi, M.; Kikkawa,
K.; Omori, K. J. Med. Chem. 2001, 44, 2204–2218; (g)
Snow, R. J.; Cardozo, M. G.; Morwick, T. M.; Busacca,
C. A.; Dong, Y.; Eckner, R. J.; Jacober, S.; Jakes, S.;
Kapadia, S.; Lukas, S.; Panzenbeck, M.; Peet, G. W.;
Peterson, J. D.; Prokopowicz, A. S., III; Sellati, R.; Tolbert,
R. M.; Tschantz, M. A.; Moss, N. J. Med. Chem. 2002, 45,
3394–3405; (h) Nagarajan, M.; Morrell, A.; Fort, B. C.;
Meckley, M. R.; Antony, S.; Kohlhagen, G.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2004, 47, 5651–5661; (i)
Ruchelman, A. L.; Houghton, P. J.; Zhou, N.; Liu, A.; Liu,
L. F.; LaVoie, E. J. J. Med. Chem. 2005, 48, 792–804.
3. (a) Couture, A.; Denian, E.; Lebrum, S.; Grandclaudon, P.
J. Chem. Soc., Perkin Trans. 1 1999, 789–794; (b) Treus, M.;
Estevez, J. C.; Castedo, L.; Estevez, R. J. Tetrahedron Lett.
2002, 43, 5323–5325; (c) Le, T. N.; Gang, S. G.; Cho, W.-J.
J. Org. Chem. 2004, 69, 2768–2772; (d) Le, T. N.; Cho, W.-J.
Chem. Pharm. Bull. 2005, 53, 118–120.
1439, 1357, 1287, 1237, 1200, 1102, 1036, 912, 827 cmꢁ1
;
dH (200 MHz, DMSO) 11.55 (1H, s, NH), 8.32 (1H, d,
J 9.1 Hz, HAr), 7.69 (1H, d, J 2.9 Hz, HAr), 7.37 (1H, dd, J
2.9, 9.1 Hz, HAr), 6.44 (1H, s, Hfur), 5.35 (1H, t, J 6.6 Hz,
]CH), 3.87 (3H, s, OMe), 2.90 (2H, d, J 6.6 Hz, CH2),
2.45 (3H, s, Me), 1.97 (3H, s, Me); dC (75 MHz, DMSO,
50 ꢀC) 161.3, 157.1, 149.6, 147.7, 132.3, 130.8, 128.7,
125.7, 125.5, 124.8, 121.7, 115.7, 107.7, 105.4, 103.3,
55.0, 30.0, 19.6, 13.0; MS: m/z (%) 308 (M++1, 21), 307
(M+, 100), 306 (26), 293 (17), 292 (79).
4.7.6. 10,11-Dimethoxy-2,4-dimethylfuro[20,30:3,4]cyclo-
hepta[1,2-c]isoquinolin-8(6H)-one (13f). Yield 2.71 g,
80.5% as a colorless powder, mp >310 ꢀC (decomp.)
(from EtOH–1,4-dioxane). [Found: C, 71.17; H, 5.60.
C20H19NO4 requires: C, 71.20; H, 5.68%.] nmax (KBr)
1665, 1616, 1511, 1380, 1263, 1216, 1171, 1105, 872,
786 cmꢁ1; dH (200 MHz, DMSO) 11.48 (1H, s, NH), 7.87
(1H, s, HAr), 7.64 (1H, s, HAr), 6.45 (1H, s, Hfur), 5.34 (1H,
t, J 6.7 Hz, ]CH), 3.91 (3H, s, OMe), 3.87 (3H, s, OMe),
2.89 (2H, d, J 6,7 Hz, CH2), 2.45 (3H, s, Me), 1.98 (3H, s,
Me); dC (75 MHz, DMSO, 50 ꢀC) 160.9, 152.9, 149.4,
147.7, 133.1, 130.8, 130.1, 124.6, 118.1, 115.6, 107.4,
105.3, 105.1 (2C), 103.1, 55.2, 55.1, 30.1, 19.6, 12.9; MS:
m/z (%) 338 (M++1, 23), 337 (M+, 100), 336 (22), 323
(15), 322 (64).
4. For review, see: Glushkov, V. A.; Shklyaev, Y. V. Khim.
Geterotsikl. Soedin. 2001, 723–747.
5. (a) Mali, R. S.; Kulkarni, B. K.; Shankaran, K. Synthesis 1982,
329–330; (b) Gore, V. G.; Narasimhan, N. S. J. Chem. Soc.,
Perkin Trans. 1 1988, 481–483; (c) Fisher, L. E.; Muchowaki,
J. M.; Clark, R. D. J. Org. Chem. 1992, 57, 2700–2705.
6. Beugelmans, R.; Bois-Choussy, M. Synthesis 1981, 729–731.
7. Snow, R. J.; Butz, T.; Hammach, A.; Kapadia, S.; Morwik,
T. M.; Prokopowicz, A. S., III; Takahashi, H.; Tan, J. D.;
Tschantz, M. A.; Wang, X.-J. Tetrahedron Lett. 2002, 43,
7553–7556.
8. See the following reviews: (a) Dean, F. M. Adv. Heterocycl.
Chem. 1982, 30, 167–238; (b) Dean, F. M. Adv. Heterocycl.
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Acknowledgements
Financial support was provided by Bayer HealthCare AG
and the Russian Foundation of Basic Research (grants
03-03-32759 and 07-03-00352). The authors would like to
emphasize their special thanks to Dr. Valery E. Zavodnik
for X-ray analysis and to Dr. Alexander S. Shashkov for
allylic alcohols’ structural determination.
9. (a) Butin, A. V.; Krapivin, G. D.; Zavodnik, V. E.; Kul’nevich,
V. G. Khim. Geterotsikl. Soedin. 1993, 616–626; (b) Abaev,
V. T.; Gutnov, A. V.; Butin, A. V. Khim. Geterotsikl. Soedin.
1998, 603–607; (c) Butin, A. V.; Gutnov, A. V.; Abaev, V. T.;
Krapivin, G. D. Khim. Geterotsikl. Soedin. 1998, 883–892;
(d) Gutnov, A. V.; Butin, A. V.; Abaev, V. T.; Krapivin,
G. D.; Zavodnik, V. E. Molecules 1999, 4, 204–218.
10. (a) Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin,
G. D. Tetrahedron Lett. 2001, 42, 2031–2033; (b) Butin,
A. V.; Smirnov, S. K.; Stroganova, T. A. J. Heterocycl.
Chem. 2006, 43, 623–628; (c) Butin, A. V.; Smirnov, S. K.;
Stroganova, T. A.; Bender, W.; Krapivin, G. D. Tetrahedron
2007, 63, 474–491.
11. (a) Gutnov, A. V.; Abaev, V. T.; Butin, A. V.; Dmitriev, A. S.
J. Org. Chem. 2001, 66, 8685–8686; (b) Dmitriev, A. S.;
Podelyakin, S. A.; Abaev, V. T.; Butin, A. V. Khim. Geterotsikl.
Soedin. 2005, 1400–1402; (c) Abaev, V. T.; Dmitriev, A. S.;
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c; a¼15.123(3), b¼5.952(1), c¼21.231(4) A, a¼90 , b¼
97.34(3) , g¼90 , V¼1895.4(6) A , Z¼4, Dcalcd¼1.288 g/cm3,
m(Mo Ka)¼0.081 mmꢁ1, 3750 reflections measured, 3618
unique (Rint¼0.0321), which were used in all calculations.
The final wR(F2) was 0.0718 (all data). Crystallographic data
(excluding structural factors) for the structure in this article
have been deposited at the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 632893.
Copies of the data can be obtained, free of charge, on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uc].
Each request should be accompanied by the complete citation
of this paper.
3
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20. (a) Faragher, R.; Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1
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