Synthesis of chromeno[2′,3′:4,5]imidazo[2,1-a]isoquinolines via a novel domino reaction of isoquinoline-derived immonium salts. Scope and limitations

Article abstract of DOI:10.1016/j.tet.2012.04.087

A one-pot protocol towards chromeno[2′,2′:4,5]imidazo[2,1-a] isoquinoline derivatives via a domino reaction of isoquinoline-derived immonium salts and α-hydroxy aromatic aldehydes is elaborated. The scope and limitations of this reaction is discussed.

Full text of DOI:10.1016/j.tet.2012.04.087

Tetrahedron 68 (2012) 5498e5504
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
0
0
Synthesis of chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinolines via a novel domino
reaction of isoquinoline-derived immonium salts. Scope and limitations
*
Leonid G. Voskressensky , Alexey A. Festa, Ekaterina A. Sokolova, Alexey V. Varlamov
Organic Chemistry Department of the Russian Peoples’ Friendship University, 6, Miklukho-Maklaia St., Moscow 117198, Russia
a r t i c l e i n f o
a b s t r a c t
0 0
A one-pot protocol towards chromeno[2 ,2 :4,5]imidazo[2,1-a]isoquinoline derivatives via a domino re-
Article history:
Received 14 February 2012
Received in revised form 31 March 2012
Accepted 23 April 2012
action of isoquinoline-derived immonium salts and
scope and limitations of this reaction is discussed.
a
-hydroxy aromatic aldehydes is elaborated. The
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 30 April 2012
Keywords:
Domino reaction
Isoquinoline
Chromene
Salicylic aldehyde
Multi component reaction
1. Introduction
R
H
OH
In modern-day organic chemistry, a growing tendency towards
green and sustainable synthesis has been well illustrated by dom-
ino reactions, which allow the direct synthesis of complex mole-
K
2
CO
3
+
O
N
DMF\H O
1
2
Cl
A
cules in a highly efficient way. The synthesis of complex organic
substances needs to rely on methods that provide maximum effi-
ciency in research chemistry. Organic reactions are traditionally
viewed as linear and stepwise processes, in which isolation and
purification of key intermediates often lead to low yields. Domino
reactions, on the other hand, allow access to complex molecules in
N
R
N
2
an effective, atom-economical manner.
N
O
In the course of our studies on the development of new domino
B
3
reactions for creation of molecular complexity and diversity whilst
(24-55%)
combining economic aspects with environmental ones we have
recently reported preliminary results on a new synthetic protocol
Scheme 1.
0
0
towards previously unknown chromeno[2 ,3 :4,5]imidazo[2,1-a]
isoquinolines.4
The target compounds B were obtained in moderate yields by
the base-catalyzed reaction of isoquinolinium salts A with salicylic
aldehyde in a DMF\water mixture (Scheme 1).
2. Results and discussion
Herein we report our investigations of this reaction optimiza-
tion as well as its scope and limitations.
We presume that compound B is the product of an anionic
domino reaction, starting with the Kr o€ hnke condensation of sali-
cylic aldehyde and isoquinolinium salt A to produce the styryl de-
rivative C. The base-catalyzed deprotonation of the phenol OH
yields zwitterion D. This then undergoes two consecutive nucleo-
philic cyclizations, followed by a [1,4]dproton shift to yield the
pentacycle B (Scheme 2).
*
Corresponding author. E-mail address: lvoskressensky@sci.pfu.edu.ru (L.G.
Voskressensky).
0
040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.087

L.G. Voskressensky et al. / Tetrahedron 68 (2012) 5498e5504
5499
tarring and made it necessary to use column chromatography for
the isolation of the target products, thus significantly diminishing
the main benefit of any domino reactiondthe ease of isolation. In
R
OH
+
Cl
A
6
a paper published by Proen c¸ a et al. it was later reported, that in the
N
O
case of pyridinium salts this reaction could be effectively carried
out in water, but our attempts to follow this protocol all failed,
mainly due to the low solubility of the starting isoquinolinium salts
in water. After several experiments, we found, that the best yields
C
O
H
N
OH
2
0 0
R
R
of the chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinolines are achieved
H O
in a methanol/water mixture in the presence of 20% Na
2
3
CO .
(Scheme 4) (Table 1).
N
N
D
R4
R3
N
R2
1-5
N
O
O
+
R1
CHO
R7
N
R5
Na CO (20%)
2 3
HO
R
N
R
MeOH\H O
2
R8
R6
O
R5
R6
7-35
H
N
R8
N
O
[1,4]-shift
N
R7
N
Scheme 4.
O
B
Table 1
Scheme 2.
0 0
Chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinolines 7e35
#
R1
R2
R3
R4
R5
R6
R7
R8
%
Based on the obtained data we could presume that this anionic
domino reaction is influenced by different factors: (a) the electronic
and spatial effects of the substituents both on the isoquinoline ring
and on the salicylic aldehyde molecule (b) the nature of the solvent.
The quaternary isoquinolinium salts 1e4 were obtained by re-
actions of the commercially available isoquinolines with chloro or
iodoacetonitrile in acetonitrile. Due to poor solubility of 5- and 6-
hydroxyisoquinolines in acetonitrile, compounds 5,6 were
obtained by the same procedure in DMF. 2-(Cyanomethyl)-5,5-
dimethyl-10-oxo-5,10-dihydro[1]benzosilino[3,2-c]pyridin-2-ium
chloride (6) was obtained from the appropriate benzosilino[3,2-c]
7
H
H
H
H
H
H
H
H
36
8
H
H
H
H
H
H
34
9
H
H
H
H
H
H
H
H
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OEt
H
H
H
H
15
51
32
12
56
13
1
1
0
1
NO
Br
H
Br
H
2
12
13
14
Me
H
5
pyridine and chloroacetonitrile (Scheme 3).
15
Me
H
H
H
H
H
21
In preliminary experiments we used a DMF\water mixture at
reflux as a solvent for this reaction. However, it caused significant
1
1
1
19
20
21
6
7
8
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
OEt
H
H
Cl
Cl
H
28
25
29
52
65
59
NO
Br
H
Cl
H
2
R3 R2
R3 R2
R4
R1
R4
R1
2
XCH CN
N
N
2
2
H
H
H
OH
H
H
OMe
H
H
H
H
H
H
48
1
-5
X
1
4
1
2
3
4
5
R -R = H; X = Cl (72%)
N
1
3
4
2
23
2
2
26
27
2
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
H
H
H
H
H
H
OEt
H
H
37
3
R ,R ,R = H; R = Br, X = I (75%)
4
5
1
2
4
R = Me, R -R = H; X = I (74%)
NO
Br
H
Cl
H
2
49
51
76
48
34
1
3
4
R -R = H; R = OH; X = Cl (74%)
H
1
2
4
3
R ,R ,R = H; R = OH, X = Cl (47%)
Cl
Cl
H
8
9
Si
O
ClCH CN
Si
O
30
H
H
OH
H
H
H
51
2
Cl
N
N
N
31
H
H
H
H
H
H
H
H
H
H
OH
OH
OH
OH
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OEt
H
H
Cl
Cl
12
31
38
41
67
32
NO
Br
H
2
3
3
3
3
4
5
6
(23%)
Cl
Scheme 3.

5500
L.G. Voskressensky et al. / Tetrahedron 68 (2012) 5498e5504
In a typical experiment, a mixture of the isoquinolinium salt and
salicylic aldehyde is dissolved in methanol/water and solid Na CO
electron withdrawing groups. We have demonstrated the possi-
2
3
bility of the target products synthesis in the MCR mode, however
very low yields caused by side reactions complicate its further us-
age. Further work aimed in using 1,3-azolium salts in this reaction
is underway and will be reported in due course.
is then added, followed by intensive stirring at reflux. In most cases,
the precipitation of the target product starts in 5 min and the re-
action takes 1e2 h to complete (TLC monitoring). The products thus
0
0
formed are the target chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquino-
lines (90e95% purity as judged by NMR spectroscopic analysis). The
addition of water to methanol is mandatory to achieve homoge-
neity of the reaction mixture. The use of other bases, i.e., TEA, H u€ nig
4. Experimental section
4.1. General
base, pyridine or KOH in all cases led to the formation of by-
products, thus complicating the product isolation procedure.
The experiments demonstrate that the best results are achieved
when the molecule of salicylic aldehyde bears electron withdraw-
ing substituents (Table 1, entries 10, 13, 19, 20, 22, 25e28, 30, 35).
We presume, that electron withdrawing groups increase the acidity
of the phenolic OH, thus facilitating the formation of the zwitter-
ionic intermediate D (Scheme 2) and subsequent nucleophilic cy-
clizations. This assumption is indirectly proved by low-to-moderate
yields of the target products in the case of OMe or OEt substituted
aldehydes (Table 1, entries 9, 16, 24, 31). In all cases the only
products isolated were obtained by cyclization onto the C-1 atom of
the isoquinolines ring.
All solvents were distilled and dried before use, chloroacetoni-
trile and iodoacetonitrile were purchased from ACROS ORGANICS
and were used without any additional purification. H and C NMR
1
13
spectra were recorded in CDCl
25 C, using a 400 or 600 MHz NMR spectrometer, peak positions
3
, DMSO-d
6
, HMPA-d18 solutions, at
ꢀ
are given in parts per million (d) with tetramethylsilane used as the
internal standard. Mass-spectra were registered using ESI or EI
techniques, peaks of molecular ions of halogen-containing com-
3
5
79
pounds are indicated for Cl and Br. Melting points were de-
termined in a capillary tube and are uncorrected.
4.2. General procedure for the synthesis of isoquinolinium
We have also tried to work out the MCR variant of this reaction.
Thus, simply mixing the equimolar amounts of isoquinoline,
chloroacetonitrile, salicylic aldehyde and H u€ nig base in methanol
and benzosilinopyridinium salts 1e3, 6
Chloroacetonitrile (9.2 mmol) or iodoacetonitrile (9.2 mmol)
was added to a stirred solution of isoquinoline (7.7 mmol) or ben-
zosilinopyridine (7.7 mmol) in acetonitrile (5 mL). The reaction
mixture was heated at reflux for 3e18 h (TLC monitoring). The
target salt was filtered, washed with acetonitrile and dried in vacuo.
resulted in precipitation of the target 7 in 6% yield (Scheme 5).
i-Pr EtN/MeOH
2
N
reflux
N
4
.2.1. 2-(Cyanomethyl)isoquinolinium chloride 1. Yield 1.15 g (72%);
O
ꢀ
+
ClCH CN
as beige solid; mp 204e205 C (dec); [Found: C, 64.72; H, 4.31; N,
13.85. C11H ClN requires C, 64.56; H, 4.43; N, 13.69%]; d
9 2 H
2
N
7
(6%)
O
(
8
400 MHz, DMSO-d
.28 (t, J¼8.0 Hz, 1H, H-6), 8.38 (d, J¼8.0 Hz, 1H, H-5), 8.56 (d,
J¼8.0 Hz, 1H, H-8), 8.69 (d, J¼6.8 Hz, 1H, H-4), 8.97 (d, J¼6.8 Hz, 1H,
H-3), 10.44 (s, 1H, H-1); (100 MHz, DMSO-d ): 47.9, 115.0, 126.8,
6
) 6.37 (s, 2H, CH
2
), 8.07 (t, J¼8.0 Hz, 1H, H-7),
HO
Scheme 5.
d
C
6
1
27.6, 128.0, 131.5, 132.2, 135.2, 138.0, 138.5, 152.2; m/z (%)¼170
To further explore this reaction scope, we investigated the re-
action of 2-(cyanomethyl)-5,5-dimethyl-10-oxo-5,10-dihydro[1]
benzosilino[3,2-c]pyridin-2-ium chloride (6) with salicylic alde-
hyde. The target hexacyclic product was isolated in only 10% yield
þ
(
(
(
20), 169 (70) [MꢁCl] , 130 (27), 129 (100), 128 (24), 115(12), 103
22), 102 (13), 101 (30), 77 (17), 76 (12), 75 (13), 63 (16), 59 (17), 51
37), 50 (22), 48 (22), 43 (59), 42 (51).
(Scheme 6).
4
.2.2. 4-Bromo-2-(cyanomethyl)isoquinolinium iodide 2. Yield 2.17 g
ꢀ
(75%); asyellow solid; mp 184e185 C (dec);[Found: C, 35.43; H, 2.19;
N, 7.58. C11
DMSO-d ) 5.18 (s, 2H, CH
J¼8.3 Hz, 1H, H-7), 7.61 (td, J¼7.0, 1.3 Hz, 1H, H-5), 7.81 (d, J¼8.3 Hz,
H, H-8), 8.49 (d, J¼1.3 Hz, 1H, H-1), 9.42 (s, 1H, H-3); (100 MHz,
DMSO-d ): 47.9, 114.4, 122.3, 126.6, 127.6, 132.8, 133.0, 136.3, 136.8,
H
8
BrIN
2
requires C, 35.23; H, 2.15; N, 7.47%];
H
d (400 MHz,
6
2
), 7.34 (t, J¼7.0 Hz, 1O, O-6), 7.54 (d,
O
1
d
C
6
N
6
Na
2 3
CO
þ
N
140.3, 152.0; m/z (%)¼248 (2) [NeI] , 210(16), 209 (100), 208 (15),
+
36(10%)
207 (99), 129 (12), 128 (43), 127 (11), 101 (17), 50 (14), 43 (23).
MeOH\H
2
O
O
Si
O
4
.2.3. 2-(Cyanomethyl)-3-methylisoquinolinium iodide 3. Yield 1.77 g
HO
ꢀ
(74%); as orange solid; mp 197e198 C (dec); [Found: C, 46.43; H,
3
(
(
.44; N, 9.15. C12
400 MHz, DMSO-d
m, 1O, O-6), 8.24e8.31 (m, 2O, O-5, O-7), 8.52e8.56 (m, 2O, O-4,
(150.9 MHz, DMSO-d ) 19.5, 45.9, 114.2,
H
11IN
2
requires C, 46.47; H, 3.58; N, 9.03%];
d
H
6
) 2.95 (s, 3O, SO ), 6.13 (s, 2O, SO ), 8.02e8.06
3
2
Scheme 6.
O-8), 10.15 (s, 1O, O-1);
d
C
6
1
26.5, 126.9, 127.0, 131.1, 131.4, 138.6, 139.0, 144.5, 152.9; m/z (%)¼183
þ
3
. Conclusion
We have elaborated and optimized a new method for the syn-
(15) [MꢁI] , 167 (46), 144 (15), 143 (100), 142 (15), 129 (19), 128 (25),
127 (67), 116 (31), 115 (37), 101 (15), 79 (10), 63 (14), 59 (14), 55 (11),
51 (14).
0
0
thesis of polycyclic chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinolines
derivatives based on a new anionic domino reaction of cyclo-
immonium salts with o-hydroxybenzaldehydes. This reaction is
especially effective in the case of salicylic aldehydes bearing
4.2.4. 2-(Cyanomethyl)-5,5-dimethyl-10-oxo-5,10-dihydro[1]benzo-
silino[3,2-c]pyridin-2-ium chloride 6. Analytical sample was
recrystallyzed from CH CN. Yield 560 mg (23%); as beige solid; mp
3

L.G. Voskressensky et al. / Tetrahedron 68 (2012) 5498e5504
5501
ꢀ
1
70e171 C (dec); [Found: C, 60.81; H, 4.95; N, 8.77. C16
requires C, 61.04; H, 4.80; N, 8.90%]; (400 MHz, DMSO-d
H, (CH Si), 6.19 (s, 2H, CH
H
15ClN
2
OSi
J¼7.2 Hz, 3H, PSO
2
SO
3
), 4.16 (q, J¼7.2 Hz, 2H, PSO
2
SO
3
), 4.29 (s,
d
H
6
) 0.61 (s,
2H, O-8), 6.87 (d, J¼7.5 Hz, 2H, O-9, O-11), 7.00 (t, J¼7.5, 1H, O-10),
7.12 (d, J¼7.5 Hz, 1H, O-5), 7.53 (t, J¼7.5 Hz, 1H, O-2), 7.62 (t,
J¼7.5 Hz, 1H, O-3), 7.67e7.71(m, 2H, O-4, O-6), 8.61 (d, J¼7.5 Hz,
6
3
)
2
2
), 7.73 (t, J¼7.7 Hz, 1O, O-8), 7.81 (t,
J¼7.7 Hz, 1H, H-7), 7.61 (d, J¼7.7 Hz, 1H, H-6), 8.34 (d, J¼7.7 Hz, 1H,
H-9), 8.84 (d, J¼6.1 Hz, 1H, H-4), 9.42 (d, J¼6.1 Hz, 1H, H-3), 9.82 (s,
C 3
1H, O-1); d (100 MHz, CDCl ): 15.1, 23.4, 65.0, 99.3, 112.4, 112.6,
114.4, 116.8, 118.7, 120.3, 121.8, 123.0, 123.1, 125.0, 127.0, 127.6, 128.1,
1
1
H, H-1);
d
C
(100 MHz, DMSO-d
6
) ꢁ2.2(2C), 48.5, 114.6, 129.6, 131.5,
þ
33.6, 134.2, 135.0, 138.2, 139.0, 139.6, 144.6, 145.8, 163.0, 183.6; IR
129.0, 148.6, 150.5; m/z (%)¼317 (14), 316 (100) [M] , 315 (54), 301
ꢁ
1
þ
(
KBr),
n
: 1658 (C¼O) cm ; m/z (%)¼279 (5) [MꢁCl] , 239 (29), 225
(15), 287 (16), 144 (11), 58 (16), 43 (20).
(
18), 224 (100), 59 (10), 48 (13), 43 (34).
0 0
.4.4. 10-Nitro-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinoline
4
4
.3. General procedure for the synthesis of isoquinolinium
10. A¼7 mL, B¼0.7 mL. Analytical sample was recrystallyzed from
salts 4,5
i-PrOH/DMF. Yield 150 mg (51%); as light-yellow solid; mp
ꢀ
2
39e240 C (dec); [Found: C, 68.03; H, 3.55; N, 13.37. C18
H
11
N
3
O
3
Chloroacetonitrile (7.6 mmol) was added to a stirred solution of
- or 6-hydroxyisoquinoline (6.9 mmol) in DMF (7 mL). The re-
action mixture was heated at reflux for 4 h (TLC monitoring). The
H 6
requires C, 68.14; H, 3.49; N, 13.24%]; d (400 MHz, DMSO-d ) 4.49
(s, 2O, H-8), 7.38e7.44 (m, 2O, H-5, H-12), 7.59e7.67 (m, 2O, H-9,
H-11), 7.87e7.93 (m, 2H, H-2, H-3), 8.15e8.18 (m, 1O, H-6),
5
target salt was filtered, washedsubsequently with DMF and CHCl
and dried in vacuo.
3
8.30e8.38 (m, 2H, H-1, H-4);
101.9, 115.7, 117.9, 118.6, 118.8, 119.3, 121.6, 124.5, 126.2, 128.0, 130.6,
d
C
(100 MHz, CF
3
COOHþCDCl
3
): 20.8,
1
(NO
31.6, 132.6, 133.5, 140.2, 144.1, 154.1; IR (KBr),
n
: 1521 (NO
2
), 1336
ꢁ1
þ
4
.3.1. 2-(Cyanomethyl)-6-hydroxyisoquinolinium chloride 4. Yield
2
) cm ; m/z (%)¼318 (32), 317 (100) [M] , 316 (23), 287 (12),
ꢀ
1.12 g (74%); as grey solid; mp 234e235 C (dec); [Found: C, 60.02;
286 (44), 271 (42), 270 (20), 209 (31), 207 (14), 142 (17), 135 (13),
129 (35), 128 (25), 127 (16), 102 (30), 101 (16), 89 (17), 81 (10), 77
(21), 76 (22), 75 (30), 73 (32), 59 (19), 57 (13), 51 (19), 50 (11), 45
(17), 43 (15).
H, 4.14; N, 12.56. C11
H
9
ClN
2
O requires C, 59.88; H, 4.11; N, 12.70%];
), 7.52 (d, J¼2.1 Hz,1H, H-5),
d
H
(400 MHz, DMSO-d
6
) 5.99 (s, 2H, CH
2
7
.63 (dd, J¼8.0, 2.1 Hz, 1H, H-7), 8.26 (d, J¼8.0 Hz, 1H, H-8), 8.37 (d,
J¼8.1 Hz, 1H, H-4), 8.58 (dd, J¼8.1, 1.3 Hz, 1H, H-3), 9.85 (bs, 1H, H-
0
0
1
), 12.60 (bs, 1H, OH);
d
C
(100 MHz, DMSO-d
6
): 46.8, 109.3, 115.0,
4.4.5. 10-Bromo-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinoline
1
21.8, 123.8, 125.0, 134.2, 134.5, 140.8, 149.2, 167.5; m/z (%)¼186
11. A¼7 mL, B¼0.7 mL. Analytical sample was recrystallyzed from
þ
ꢀ
(
14), 185 (37) [MꢁCl] , 145 (100), 90 (16), 63 (16), 59 (14), 44 (10),
i-PrOH/DMF. Yield 100 mg (32%); as beige solid; mp 225e226
C
4
3 (62), 42 (19).
(dec); [Found: C, 61.61; H, 3.17; N, 8.04. C18
2
H11BrN O requires C,
6
1.56; H, 3.16; N, 7.98%]; (400 MHz, DMSO-d
d
H
6
) 4.33 (s, 2O, O-8),
4
.3.2. 2-(Cyanomethyl)-5-hydroxyisoquinolinium chloride 5. Yield
7.13 (d, J¼8.7 Hz, 1O, O-12), 7.31 (d, J¼7.3 Hz, 1O, O-5), 7.43 (dd,
J¼8.8, 2.1 Hz, 1O, O-11), 7.54e7.65 (m, 3O, O-2, H-3, H-9), 7.84 (d,
J¼7.3, 1O, O-6), 8.07 (d, J¼6.9 Hz, 1H, H-4), 8.34 (d, J¼7.8 Hz, 1O,
ꢀ
710 mg (47%); as yellow solid; mp 239e240 C (dec); [Found: C,
5
9.95; H, 4.15; N, 12.45. C11
9
H ClN
2
O requires C, 59.88; H, 4.11; N,
1
1
8
2.70%]; (400 MHz, DMSO-d
d
H
6
) 6.15 (s, 2H, CH
2
), 7.69 (d, J¼7.7 Hz,
O-1);
d
C
(100 MHz, CF
3
COOHþCDCl
3
): 21.1, 102.3, 116.4, 118.0, 118.7,
O, O-6), 7.91e7.99 (m, 2O, O-7, O-8), 8.64 (d, J¼7.1 Hz, 1H, O-4),
.75 (dd, J¼7.1, 1.1 Hz, 1O, O-3), 10.16 (bs, 1O, O-1), 11.92 (s, 1O,
119.2, 119.4, 119.8, 122.1, 128.6, 131.1, 131.9, 132.6, 132.9, 133.2, 133.4,
þ
141.4, 149.0; LC/MS m/z (%)¼353 (90), 351 (100) [M] .
C 6
PO); d (150.9 MHz, DMSO-d ) 47.9, 114.9, 120.0, 121.2, 121.9, 128.6,
0
0
1
28.9, 133.4, 133.8, 151.6, 153.9; m/z (%)¼186 (26), 185 (100)
4.4.6. 5-Bromo-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinoline
þ
[MꢁCl] , 146 (19), 145 (91), 117 (21), 91 (17), 89 (15), 59 (14), 57
12. A¼10 mL, B¼1 mL. Yield 30 mg (12%); as light-brown solid; mp
ꢀ
(
14).
218 C (dec); [Found: C, 61.64; H, 3.19; N, 7.95. C18
H11BrN
2
O requires
H 3
C, 61.56; H, 3.16; N, 7.98%]; d (600 MHz, CDCl ) 4.35 (s, 2H, H-8),
4
.4. General procedure for the synthesis of chromeno
7.14 (td, J¼7.5, 1.2 Hz, 1H, H-10), 7.22e7.24 (m, 1H, H-12), 7.28e7.33
0
0
[2 ,3 :4,5]imidazo[2,1-a]isoquinolines 7e35
(m, 2H, H-9, H-11), 7.69e7.78 (m, 2H, H-2, H-3), 8.07e8.11 (m, 2H,
H-4, H-6), 8.87 (d, J¼7.5 Hz, 1H, H-1);
C 6
d (100 MHz, DMSO-d ): 23.2,
101.1, 107.0, 118.1, 118.9, 123.0, 123.1, 124.0, 124.2, 126.8, 127.6, 128.7,
To a stirred solution of isoquinolinium salt (1 mmol) 1e5 and
aldehyde (0.9 mmol) in a mixture of of methanol (A mL) and water
B mL), solid Na CO (0.2 mmol) was added at reflux. The reaction
129.2, 129.5, 131.1, 136.8, 150.3, 151.7; m/z (%)¼353 (19), 352 (100),
þ
(
2
3
351 (50), 350 (99) [M] , 349 (33), 271 (13), 209 (17), 207 (15), 129
mixture was heated at reflux for 1e2 h (TLC monitoring). After
cooling, the precipitate was filtered-off, washed with water (3x)
and with methanol once to give the target chromeno[2 ,3 :4,5]
(14), 128 (43), 127 (15), 79 (15).
0
0
0
0
4.4.7. 5,10-Dibromo-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquino-
imidazo[2,1-a]isoquinolines 7e35.
line 13. A¼10 mL, B¼1 mL. Yield 220 mg (56%); as beige solid; mp
ꢀ
2
31e232 C (dec); [Found: C, 50.12; H, 2.35; N, 6.62. C18
2
H10Br N
2
O
0
0
4
.4.1. 8H-Chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinoline
H 6
requires C, 50.27; H, 2.34; N, 6.51%]; d (400 MHz, DMSO-d ) 4.40 (s,
7
. A¼2.5 mL, B¼2.5 mL. Yield 0.09 g (36%). The physical charac-
2O, O-8), 7.18 (d, J¼8.6 Hz, 1O, O-12), 7.47 (dd, J¼8.6, 2.2 Hz, 1O,
teristics and spectroscopic data were in good agreement with those
O-11), 7.56e7.60 (m, 1H, H-9), 7.73e7.78 (m, 2O, H-2, H-3),
reported earlier.4b
8.04e8.07 (m,1O, H-4), 8.44e8.49 (m,1H, H-1), 8.56 (s,1O, O-6);
d
C
(
100 MHz, CF ): 20.8, 102.0, 115.2, 116.3, 117.5, 118.6,
3
COOHþCDCl
3
0
0
0
0
4
8
.4.2. 16H-Benzo[5 ,6 ]chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinoline
119.2, 120.6, 122.5, 128.2, 130.7, 131.8, 132.5, 132.6, 132.9, 133.5,
þ
. A¼2.5 mL, B¼2.5 mL. Yield 0.10 g (34%). The physical charac-
141.5, 148.7; m/z (%)¼429 (100), 428 (41) [M] , 427 (54), 350 (16),
teristics and spectroscopic data were in good agreement with
348 (16), 176 (22), 174 (23), 135 (25), 127 (17).
reported earlier.4b
0 0
.4.8. 6-Methyl-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinoline
4
0
0
4
9
.4.3. 12-Ethoxy-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinoline
14. A¼4.5 mL, B¼4.5 mL. Yield 30 mg (13%); as white solid; mp
ꢀ
. A¼1.3 mL, B¼1.3 mL. Yield 40 mg (15%); as light-brown solid;
176e177 C (dec); [Found: C, 79.73; H, 4.90; N, 9.87. C19
14
H N
2
O
ꢀ
mp 108e109 C (dec); [Found: C, 75.85; H, 5.16; N, 8.64. C20
H
16
N
2
O
2
requires C, 79.70; H, 4.93; N, 9.78%];
H 6
d (400 MHz, DMSO-d ) 2.87
requires C, 75.93; H, 5.10; N, 8.86%];
d
H
(400 MHz, CDCl
3
) 1.50 (t,
(s, 3O, SO ), 4.82 (s, 2O, O-8), 7.02 (s, 1O, O-5), 7.12e7.17 (m, 2O,
3

5502
L.G. Voskressensky et al. / Tetrahedron 68 (2012) 5498e5504
þ
O-10, O-12), 7.28e7.32 (m, 1O, O-11), 7.35 (d, J¼7.6 Hz, 1O, O-4),
.52e7.58 (m, 2O, O-2, O-3), 7.71e7.73 (m, 1O, O-9), 8.30e8.32 (m,
O, O-1); (100 MHz, DMSO-d ): 18.7, 26.2, 100.9, 111.4, 117.2,
18.9, 121.3, 122.2, 123.5, 126.2, 127.1, 127.9, 128.1, 129.2, 130.5,133.6,
140.9, 144.4; m/z (%)¼322 (20), 321 (43), 320 (63) [M] , 319 (100),
7
1
1
142 (27).
d
C
6
0
0
4.4.14. 10,12-Dichloro-6-Methyl-8H-chromeno[2 ,3 :4,5]imidazo[2,1-
þ
133.9, 149.8, 150.6; m/z (%)¼287 (11), 286 (60) [M] , 285 (100), 284
a]isoquinoline 20. A¼7 mL, B¼4.5 mL. Yield 210 mg (65%); as white
ꢀ
(
11), 143 (14), 142 (12).
solid; mp 252e253 C (dec); [Found: C, 64.15; H, 3.35; N, 7.97.
C
CF
19
H
12Cl
2
N
2
O requires C, 64.24; H, 3.41; N, 7.89%];
COOHþCDCl ) 2.87 (s, 3H, Me), 4.66 (s, 2H, H-8), 7.09 (d,
J¼2.3 Hz, 1H, H-9), 7.20 (d, J¼2.3 Hz, 1H, H-11), 7.63e7.77 (m, 4H, H-
2, H-3, H-4, H-5), 8.18 (d, J¼8.2 Hz, 1H, H-1); (100 MHz,
CF ): 17.6, 21.6, 102.8, 114.7, 118.0, 119.1, 121.5, 123.8,
H
d (400 MHz,
0
0
0
0
4
.4.9. 14-Methyl-16H-benzo[5 ,6 ]chromeno[2 ,3 :4,5]imidazo[2,1-a]-
3
3
isoquinoline 15. A¼7 mL, B¼4.5 mL. Yield 60 mg (21%); as yellow
ꢀ
solid; mp 200e202 C (dec); [Found: C, 82.01; H, 4.84; N, 8.26.
d
C
C
H
23 16
N
2
O requires C, 82.12; H, 4.79; N, 8.33%];
) 2.92 (s, 3O, SO ), 4.85 (s, 2O, O-8), 6.70 (s, 1O, O-5), 7.33
d
H
(400 MHz,
3
COOHþCDCl
3
DMSO-d
(
7
2
6
3
127.0, 127.7, 129.6, 129.8, 130.9, 131.9, 132.8, 133.1, 134.6, 140.9,
þ
d, J¼8.7 Hz, 1O, O-14), 7.41e7.49 (m, 4O, O-9, O-10, O-11, O-12),
143.5; m/z (%)¼357 (16), 356 (39), 355 (71), 354 (65) [M] , 353
.55e7.59 (m, 1O, O-4), 7.72 (d, J¼8.7 Hz, 1O, O-13), 7.77e7.81 (m,
(100), 159 (15).
O, O-2, O-3), 8.50 (d, J¼7.8 Hz, 1O, O-1);
C 6
d (100 MHz, DMSO-d ):
0
0
1
9.6, 25.4, 100.8, 110.5, 112.4, 118.8, 122.3, 123.2, 124.5, 125.9, 127.0,
4.4.15. 3-Hydroxy-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinoline
1
27.3, 127.9, 128.6, 129.0, 129.6, 130.4, 130.8, 132.3, 132.9, 137.3,
21. A¼10 mL, B¼1 mL. Yield 150 mg (59%); as light-yellow solid;
þ
ꢀ
139.5, 148.9; LC/MS m/z (%)¼337 (100) [MþH] .
mp 231e232 C (dec); [Found: C, 74.94; H, 4.16; N, 9.80. C18
12
H N
2
O
2
H 6
requires C, 74.99; H, 4.20; N, 9.72%]; d (400 MHz, DMSO-d ) 4.29 (s,
0
0
4
.4.10. 12-Ethoxy-6-methyl-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
2O, O-8), 7.10e7.18 (m, 5O, O-2, O-4, O-5, O-11, O-12), 7.28 (t,
J¼8.5 Hz, 1O, O-10), 7.35 (d, J¼8.5 Hz, 1O, O-9), 8.03 (d, J¼6.2 Hz,
isoquinoline 16. A¼4.5 mL, B¼4.5 mL. Yield 80 mg (28%); as yellow
ꢀ
solid; mp 168e169 C (dec); [Found: C, 76.52; H, 5.20; N, 8.26.
C
1O, O-6), 8.17e8.19 (m, 1O, O-1), 10.00 (s, 1O, PO); d (100 MHz,
C
CDCl
21
H
18
N
2
O
2
requires C, 76.34; H, 5.49; N, 8.48%];
) 1.50 (t, J¼6.9 Hz, 3O, PSO SO ), 2.83 (s, 3O, S
SO ), 4.73 (s, 2O, O-8), 6.72 (s, 1O, O-5),
.78e6.83 (m, 2O, O-9, O-10), 6.94e6.98 (m, 1O, O-11), 7.44e7.55
(100 MHz,
): 15.0, 19.4, 23.5, 65.4, 112.4, 114.1, 114.5, 115.7, 120.4, 120.8,
d
H
(400 MHz,
6
DMSO-d ): 23.1, 99.1, 111.1, 112.0, 116.2, 118.0, 118.9, 119.1, 122.6,
3
2
3
6
-SO ), 4.13
3
124.0, 124.5, 128.5, 131.2, 131.4, 138.2, 150.1, 152.0, 157.8; m/z (%)¼
þ
(
6
q, J¼6.9 Hz, 2O, PSO
2
3
289 (16), 288 (100) [M] , 287 (64), 144 (10), 43 (11).
0
0
0
0
(
m, 3O, O-2, O-3, O-4), 8.55 (d, J¼7.8 Hz, 1O, O-1);
d
C
4.4.16. 11-Hydroxy-16H-benzo[5 ,6 ]chromeno[2 ,3 :4,5]imidazo[2,1-
CDCl
3
a]isoquinoline 22. A¼10 mL, B¼1 mL. Yield 150 mg (48%); as light-
ꢀ
121.8, 124.1, 125.4, 125.7, 125.9, 127.0, 127.2, 127.7 (2C), 128.0, 131.0;
brown solid; mp 248e250 C (dec); [Found: C, 77.91; H, 4.25; N,
þ
m/z (%)¼331 (16), 330 (73) [M] , 329 (100), 301 (40), 300 (14), 272
8.04. C22H N O
14 2 2
requires C, 78.09; H, 4.17; N, 8.28%];
H
d (400 MHz,
(
15), 151 (11), 142 (10), 115 (12).
6
DMSO-d ) 4.63 (s, 2O, O-16), 7.17e7.23 (m, 2O, O-10, O-12), 7.28 (d,
J¼7.2 Hz, 1O, O-13), 7.45 (d, J¼8.8 Hz, 1O, O-5), 7.54e7.58 (m, 1O,
O-3), 7.69e7.78 (m, 1O, O-2), 7.95e8.04 (m, 3O, O-4, O-6, O-9),
0 0
.4.11. 6-Methyl-10-nitro-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]iso-
4
quinoline 17. A¼7 mL, B¼4.5 mL. Yield 80 mg (25%); as orange
8.25e8.27 (m, 2O, O-1, O-14),10.09 (s,1O, PO);
C
d (100 MHz, DMSO-
ꢀ
solid; mp 236e237 C (dec); [Found: C, 68.93; H, 3.99; N, 12.72.
6
d ): 21.2, 99.8, 111.1, 111.7, 112.2, 116.2, 119.0, 119.1, 122.8, 123.5, 124.6,
C
19
H
13
N
3
O
3
requires C, 68.88; H, 3.95; N, 12.68%];
) 2.80 (s, 3O, SO ), 4.82 (s, 2O, O-8), 6.93 (s, 1O, O-5), 7.28
d, J¼9.5 Hz, 1O, O-12), 7.46e7.52 (m, 2O, O-3, O-4), 7.63 (d,
J¼7.6 Hz, 1O, O-2), 8.04 (dd, J¼9.5, 2.2 Hz, 1O, O-11), 8.18 (s, 1O,
O-9), 8.24 (d, J¼7.6 Hz, 1O, O-1); (100 MHz, CF COODþCDCl ):
7.4, 25.4, 102.2, 114.6, 118.1, 118.3, 121.4, 124.6, 126.0, 126.9 (2C),
29.7, 131.9, 132.8, 133.0, 134.8, 140.5, 144.0, 153.3; IR (KBr), : 1526
d
H
(400 MHz,
125.3, 127.6, 128.8, 129.3, 130.5, 131.5, 132.8, 138.3, 149.4, 149.6, 157.8;
m/z (%)¼338 (100) [M] , 337 (57), 144 (18), 115 (11), 43 (32).
þ
DMSO-d
(
6
3
0
0
4.4.17. 12-Ethoxy-3-hydroxy-8-H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
d
C
3
3
isoquinoline 23. A¼10 mL, B¼1 mL. Yield 110 mg (37%); as light-
ꢀ
1
1
yellow solid; mp 232e233 C (dec); [Found: C, 72.14; H, 4.92; N,
n
þ
8.21. C20
DMSO-d
OCH CH
O-9, O-10), 6.83 (s, 1O, O-4), 6.90 (d, J¼8.9 Hz, 1O, O-2), 7.42 (d,
J¼6.9 Hz, 1O, O-1), 8.09 (d, J¼8.9 Hz, 1O, O-1), 9.12 (s, 1O, PO);
(100 MHz, DMSO-d ): 15.3, 23.3, 65.0, 99.1, 111.1, 112.0, 112.9, 116.3,
H
16
N
2
O
3
requires C, 72.28; H, 4.85; N, 8.43%];
) 1.20 (t, J¼6.7 Hz, 3O, OCH CH ), 3.87 (q, J¼6.7 Hz, 2O,
3
), 4.02 (s, 2O, O-8), 6.60 (m, 2O, O-5, O-11), 6.73 (m, 2O,
H
d (400 MHz,
ꢁ1
(
NO
2
), 1342 (NO
2
) cm ; m/z (%)¼332 (17), 331 (83) [M] , 330
6
2
3
(
100), 285 (19), 284 (72), 283 (11), 142 (20), 115 (14).
2
0
0
4
.4.12. 10-Bromo-6-methyl-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
d
C
isoquinoline 18. A¼7 mL, B¼4.5 mL. Yield 100 mg (29%); as white
6
ꢀ
solid; mp 208 C (dec); [Found: C, 62.55; H, 3.65; N, 7.81.
118.9, 119.8, 122.4, 122.6, 123.6, 124.5, 131.3, 138.2, 142.1, 148.4,
þ
C
19
H13BrN
2
O requires C, 62.48; H, 3.59; N, 7.67%];
d
H
(400 MHz,
150.0, 157.8; m/z (%)¼333 (9), 332 (100) [M] , 331 (43), 303 (19),
DMSO-d ) 2.82 (s, 3O, SO
6
3
), 4.71 (s, 2O, O-8), 6.74 (s, 1O, O-5), 7.05
288 (30), 287 (28), 151 (22), 144 (13), 43 (28).
(
3
d, J¼8.5 Hz, 1O, O-12), 7.32e7.36 (m, 2O, O-3, O-4), 7.47e7.56 (m,
0
0
O, O-1, O-2, O-9), 8.50 (d, J¼8.5 Hz, 1O, O-11);
d
C
(100 MHz,
4.4.18. 3-Hydroxy-11-methoxy-8H-chromeno[2 ,3 :4,5]imidazo[2,1-
DMSO-d
1
(
2
6
): 19.5, 27.4, 99.5, 112.5, 114.4, 115.5, 119.6, 120.5, 122.2,
a]isoquinoline 24. A¼10 mL, B¼1 mL. Yield 10.0 mg (3%); as brown
ꢀ
23.2, 126.0, 129.6, 129.8, 127.4, 127.9, 128.1, 131.1, 132.6, 150.5; m/z
solid; mp>300 C (dec); [Found: C, 71.55; H, 4.61; N, 8.69.
þ
%)¼367 (15), 366 (64), 365 (95), 364 (61) [M] , 363 (100), 285 (24),
C
19
H
14
N
2
O
3
requires C, 71.69; H, 4.43; N, 8.80%];
) 3.75 (s, 3O, OCH ), 4.20 (s, 2O, H-8), 6.71e6.74 (m, 2O,
H
d (400 MHz,
02 (13), 142 (27), 115 (28), 79 (14), 43 (22).
DMSO-d
6
3
O-10, H-12), 7.10e7.13 (m, 2O, O-4, O-9), 7.16 (d, J¼7.1, 1O, O-5),
0
0
4
.4.13. 12-Chloro-6-methyl-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
7.25 (m, 1O, O-2), 8.02 (d, J¼7.1 Hz, 1O, O-6), 8.15e8.20 (m, 1O,
isoquinoline 19. A¼7 mL, B¼4.5 mL. Yield 150 mg (52%); as white
C 6
O-1), 9.96 (s, 1O, OH); d (100 MHz, DMSO-d ): 21.6, 55.2, 98.6,
ꢀ
solid; mp 229e230 C (dec); [Found: C, 71.01; H, 4.14; N, 8.64.
102.2, 110.0, 110.1, 110.3, 111.2, 115.4, 118.1, 121.7, 123.7, 130.6, 130.8,
þ
C
19
H
13ClN
HMPA-d18) 2.99 (s, 3O, SO
O-10), 7.25 (s, 1O, O-5), 7.37e7.44 (m, 2O, O-4, O-9), 7.52e7.64 (m,
O, O-2, O-3), 7.77e7.79 (m, 1O, O-11), 8.30e8.32 (m, 1O, O-1);
100 MHz, CF ): 18.0, 25.6, 102.9, 114.6, 117.6, 117.8,
COOHþCDCl
17.9, 121.1, 122.7, 125.4, 127.0, 127.9, 129.7, 131.6, 132.6, 133.0, 134.1,
2
O requires C, 71.14; H, 4.08; N, 8.73%];
d
H
(400 MHz,
137.3, 149.2, 151.9, 157.0, 158.8; m/z (%)¼319 (10), 318 (46) [M] , 317
3
), 5.04 (s, 2O, O-8), 7.15e7.19 (m, 1O,
(100), 274 (12).
0
0
2
(
1
d
C
4.4.19. 3-Hydroxy-10-nitro-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
3
3
isoquinoline 25. A¼10 mL, B¼1 mL. Yield 140 mg (49%); as green-
ꢀ
yellow solid; mp 209e211 C (dec); [Found: C, 64.74; H, 3.19; N,

L.G. Voskressensky et al. / Tetrahedron 68 (2012) 5498e5504
5503
12.51. C18
11
H N
3
O
4
requires C, 64.86; H, 3.33; N, 12.61%];
d
H
PO);
d
C
(100 MHz, DMSO-d
6
): 20.7, 100.5, 106.6, 111.0, 111.6, 112.7,
(
400 MHz, DMSO-d
6
): 4.46 (s, 2O, O-8), 7.14e7.21 (m, 2O, O-4,
118.5, 118.7, 120.6, 123.0, 123.6, 124.8, 127.1, 128.2, 128.7, 128.8,
O-12), 7.25 (d, J¼7.3 Hz,1O, O-5), 7.43 (d, J¼8.7 Hz,1O, O-2), 8.07 (d,
129.9, 132.2, 136.9, 148.7, 149.1, 153.3; m/z (%)¼339 (12), 338 (54)
þ
J¼7.3 Hz, 1O, O-6), 8.16e8.22 (m, 2O, O-1, O-11), 8.33 (d, J¼2.3 Hz,
[M] , 337 (100), 225 (17), 224 (22), 187 (12), 169 (21), 167 (18), 146
1
O, O-9), 10.09 (s, 1O, PO);
d
C
(100 MHz, CF
3
COOHþCDCl
3
): 21.7,
(11), 144 (16), 143 (20), 142 (33), 128 (20), 127 (30), 115 (27), 106
(14), 105 (18), 103 (11), 101 (16), 98 (17), 92 (12), 91 (30), 84 (12),
83 (18), 82 (10), 80 (12), 79 (13), 78 (11), 73 (29), 72 (12), 69 (12),
64 (70), 63 (14), 59 (19), 56 (36), 55 (44), 53 (13), 52 (18), 48 (69),
1
03.0,115.6,118.2,119.9,120.3,120.6,122.2,124.0,124.8,125.5,126.1,
27.6, 133.4, 133.6, 141.5, 145.1, 152.4; IR (KBr), : 1520 (NO ), 1334
) cm ; m/z (%)¼333 (4) [M] , 101 (30), 43 (100).
1
n
2
ꢁ
1
þ
(
NO
2
45 (40), 43 (19).
0 0
.4.20. 10-Bromo-3-hydroxy-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
4
0
0
isoquinoline 26. A¼10 mL, B¼1 mL. Yield 170 mg (51%); as light-
4.4.25. 12-Ethoxy-4-hydroxy-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
ꢀ
yellow solid; mp>300 C (dec); [Found: C, 58.93; H, 3.16; N, 7.70.
isoquinoline 31. A¼7.5 mL, B¼0.75 mL. Yield 40 mg (12%); as beige
ꢀ
C
18
H
11BrN
DMSO-d ): 4.31 (s, 2H, H-8), 7.11e7.20 (m, 4H, H-2, H-4, H-5, H-12),
.45 (dd, J¼8.7, 2.3 Hz, 1H, H-11), 7.57 (d, J¼2.3 Hz, 1H, H-9), 8.02 (d,
J¼6.9 Hz, 1H, H-1), 8.16e8.20 (m, 1H, H-6), 10.00 (s, 1H, OH);
100 MHz, DMSO-d ): 22.2, 98.0, 110.3, 111.4, 114.5, 115.4, 118.1,
19.3, 121.0, 121.7, 123.7, 130.5, 130.6, 132.7, 137.6, 149.0, 150.6, 157.0;
2
O
2
requires C, 58.88; H, 3.02; N, 7.63%];
d
H
(400 MHz,
solid; mp 189e191 C (dec); [Found: C, 72.16; H, 4.89; N, 8.32.
6
C
20
H
16
N
2
O
3
requires C, 72.28; H, 4.85; N, 8.43%];
) 1.42 (t, J¼6.9 Hz, 3H, OCH CH ), 4.12 (q, J¼6.9 Hz, 2H,
), 4.36 (s, 2O, O-8), 6.93 (d, J¼7.8 Hz, 1O, O-3), 6.98e7.09
(m, 3O, O-9, O-10, O-11), 7.44e7.50 (m, 2O, O-1, O-2), 7.82 (d,
J¼7.8 Hz, 1O, O-5), 8.09 (d, J¼7.8 Hz, 1O, O-6), 10.38 (s, 1O, PO);
(100 MHz, DMSO-d ): 15.3, 23.3, 64.8, 100.3, 107.0, 112.2, 112.7,
H
d (400 MHz,
7
DMSO-d
OCH CH
3
6
2
3
d
C
2
(
1
6
d
C
þ
m/z (%)¼369 (19), 368 (99), 367 (58), 366 (100) [M] , 365 (46), 286
6
(
10), 144 (23), 143 (39), 43 (12).
113.2,119.3,119.7, 121.0, 122.4, 123.7, 124.2, 129.2, 137.4, 142.0, 148.3,
þ
1
50.2, 154.0; m/z (%)¼333 (16), 332 (78) [M] , 331 (100), 303 (45),
0
0
4
.4.21. 12-Chloro-3-hydroxy-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
302 (15), 274 (21), 152 (16), 116 (12), 89 (13).
isoquinoline 27. A¼10 mL, B¼1 mL. Yield 220 mg (76%); as
ꢀ
0
0
brown solid; mp 215e216 C (dec); [Found: C, 66.64; H, 3.51; N,
4.4.26. 4-Hydroxy-10-nitro-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
8
(
.59. C18
400 MHz, DMSO-d
H-4, H-5, H-10), 7.34 (d, J¼8.2 Hz, 1H, H-11), 7.44 (d, J¼8.2 Hz,
H, H-9), 8.05 (d, J¼7.3 Hz, 1H, H-1), 8.20 (d, J¼9.2 Hz, 1H, H-6),
0.03 (s, 1H, OH); (100 MHz, CF ): 20.6,
COOHþDMSO-d
02.3, 113.1, 113.2, 116.0, 116.7, 117.4, 118.3, 121.6, 122.7, 125.3,
H
11ClN
2
O
2
requires C, 66.99; H, 3.44; N, 8.68%];
): 4.36 (s, 2H, H-8), 7.09e7.46 (m, 4H, H-2,
d
H
isoquinoline 32. A¼7.5 mL, B¼0.75 mL. Yield 90 mg (31%); as
ꢀ
6
light-grey solid; mp 186e187 C (dec); [Found: C, 64.70; H, 3.42;
N, 12.49. C18
11 3 4 H
H N O requires C, 64.86; H, 3.33; N, 12.61%]; d
1
1
1
(400 MHz, DMSO-d
6
) 4.46 (s, 2O, O-8), 6.99 (d, J¼8.9 Hz, 1O,
d
C
3
6
O-12), 7.39e7.43 (m, 1O, O-3), 7.49 (d, J¼7.3 Hz, 1O, O-5), 7.78
(d, J¼8.9 Hz, 1O, O-11), 8.05 (d, J¼7.3 Hz, 1H, O-6), 8.13e8.19 (m,
128.2, 129.5, 131.3, 132.5, 140.5, 145.2, 152.3; m/z (%)¼324 (42),
3
2O, O-1, O-2), 8.30 (d, J¼2.7 Hz, 1O, O-9), 10.38 (s, 1O, PO);
d
C
þ
22 (100) [M] , 161 (10), 144 (15), 143 (12), 116 (12), 89 (16), 73
(100 MHz, CF
3
COOHþCDCl
3
): 21.2, 102.2, 113.8, 113.9, 116.8, 117.1,
(
38), 43 (22).
118.2, 118.4, 119.0, 122.2, 124.9, 126.6, 132.0, 133.5, 140.6, 144.5,
ꢁ
1
152.7, 154.5; IR (KBr), : 1516 (NO
n
þ
2
), 1332 (NO
2
) cm ; m/z (%)¼
0
0
4
.4.22. 10,12-Dichloro-3-hydroxy-8H-chromeno[2 ,3 :4,5]imidazo
334 (18), 333 (91) [M] , 332 (100), 287 (23), 286 (87), 116 (12),
89 (13).
[
2,1-a]isoquinoline 28. A¼10 mL, B¼1 mL. Yield 150 mg (48%); as
ꢀ
yellow solid; mp 221e223 C (dec); [Found: C, 60.32; H, 2.71; N,
0
0
7.61. C18
H10Cl
2
N
2
O
2
requires C, 60.53; H, 2.82; N, 7.84%];
d
H
4.4.27. 10-Bromo-4-hydroxy-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
(
400 MHz, DMSO-d
6
) 4.40 (s, 2O, O-8), 7.16e7.26 (m, 3O, O-2, O-4,
isoquinoline 33. A¼7.5 mL, B¼0.75 mL. Yield 170 mg (51%); as
ꢀ
O-5), 7.50 (d, J¼2.3 Hz, 1O, O-11), 7.66 (d, J¼2.3 Hz, 1O, O-9), 8.07
brown solid; mp 208e210 C (dec); [Found: C, 58.96; H, 3.12; N,
(
(
1
d, J¼6.9 Hz, 1O, O-6), 8.21e8.24 (m, 1O, O-1), 10.09 (s, 1O, PO);
100 MHz, CF ): 20.8, 101.3, 111.6, 111.8, 114.9,
COOHþDMSO-d
16.0, 117.7, 119.8, 120.9, 121.9, 123.9, 127.9, 129.4, 133.6, 134.1, 140.1,
d
C
7.80. C18
2 2 H
H11BrN O requires C, 58.88; H, 3.02; N, 7.63%]; d
3
6
(400 MHz, DMSO-d
6
) 4.36 (s, 2O, O-8), 7.01 (d, J¼7.8 Hz, 1O, O-3),
7.18 (d, J¼8.7 Hz, 1O, O-12), 7.43e7.50 (m, 3O, O-1, O-2, O-5), 7.60
(bs, 1O, O-9), 7.81 (d, J¼8.3 Hz, 1O, O-11), 8.05 (d, J¼7.3 Hz, 1O,
þ
1
(
44.3, 158.8; m/z (%)¼358 (13), 357 (5), 356 (21) [M] , 160 (10), 64
12), 58 (23), 43 (100), 42 (21).
C 6
O-6), 10.38 (s, 1O, PO); d (100 MHz, DMSO-d ): 22.4, 99.4, 106.6,
1
11.6, 112.6, 114.9, 118.7, 119.6, 120.4, 121.1, 123.5, 128.7, 130.8, 133.0,
0
0
4
2
1
.4.23. 4-Hydroxy-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]isoquinoline
136.9,149.3,150.6,153.3; m/z (%)¼369 (12), 368 (64), 367 (100), 366
þ
9. A¼7.5 mL, B¼0.75 mL. Yield 90 mg (34%); as brown solid; mp
(70) [M] , 365 (96), 287 (10), 286 (28), 145 (10), 143 (33), 116 (13),
ꢀ
70e171 C (dec); [Found: C, 74.85; H, 4.13; N, 9.67. C18
H
12
N
2
O
2
115 (15), 89 (14).
H 6
requires C, 74.99; H, 4.20; N, 9.72%]; d (400 MHz, DMSO-d ) 4.33 (s,
0
0
2
H, H-8), 6.99 (d, J¼8.0 Hz, 1O, O-12), 7.11e7.19 (m, 2O, O-2, O-3),
.27e7.31 (m, 1O, O-1), 7.36e7.47 (m, 3O, O-9, O-10, O-11), 7.79 (d,
J¼7.7 Hz, 1O, O-5), 8.06 (d, J¼7.7 Hz, 1O, O-6), 10.36 (s, 1O, PO);
100 MHz, CF ): 20.8, 102.5, 113.4, 113.8, 115.4, 116.4,
COOHþCDCl
17.2, 117.5, 118.5, 121.8, 125.8, 129.2, 130.1, 131.7, 132.5, 141.4, 149.6,
4.4.28. 12-Chloro-4-hydroxy-8H-chromeno[2 ,3 :4,5]imidazo[2,1-a]-
7
isoquinoline 34. A¼7.5 mL, B¼0.75 mL. Yield 120 mg (41%); as light
ꢀ
d
C
beige solid; mp 228e230 C (dec); [Found: C, 66.85; H, 3.51; N, 8.53.
(
3
3
C
18
H11ClN
2 2 H
O requires C, 66.99; H, 3.44; N, 8.68%]; d (400 MHz,
1
DMSO-d
6
) 4.43 (s, 2O, O-8), 7.03 (d, J¼7.8 Hz, 1O, O-3), 7.15e7.19
þ
152.5; m/z (%)¼289 (11), 288 (61) [M] , 287 (100), 258 (12), 143
(m, 1O, O-2), 7.39 (d, J¼7.8 Hz, 1O, O-1), 7.46e7.52 (m, 3O, O-5,
O-9, O-10), 7.84 (d, J¼8.2 Hz, 1O, O-11), 8.11 (d, J¼7.3 Hz, 1O, O-6),
(
12), 89 (12).
1
C 6
0.38 (s, 1O, PO); d (100 MHz, DMSO-d ): 69.7, 99.9, 106.7, 109.6,
0
0
0
0
4
.4.24. 12-Hydroxy-16H-benzo[5 ,6 ]chromeno[2 ,3 :4,5]imidazo[2,1-
111.7, 112.6, 114.5,118.7, 120.6, 120.8, 123.5, 123.9, 128.7, 128.8, 129.6,
129.9, 133.5, 153.3; m/z (%)¼324 (20), 323 (41), 322 (63) [M] , 321
þ
a]isoquinoline 30. A¼7.5 mL, B¼0.75 mL. Yield 160 mg (51%); as
ꢀ
brown solid; mp 214e215 C (dec); [Found: C, 78.16; H, 4.13; N,
(100), 144 (18), 73 (13), 44 (12).
8
(
.37.
400 MHz, DMSO-d
O-6), 7.46e7.50 (m, 2O, O-10, O-11), 7.55e7.59 (m, 2O, O-2, O-3),
.70e7.74 (m, 1O, O-4), 7.86 (d, J¼7.8 Hz, 1O, O-5), 7.96e8.06 (m,
O, O-1, O-9, O-13), 8.29 (d, J¼7.3 Hz, 1O, O-14), 10.41 (s, 1O,
C
22
H
14
N
2
O
2
requires C, 78.09; H, 4.17; N, 8.28%];
d
H
0
0
6
) 4.68 (s, 2O, O-16), 7.04 (d, J¼7.8 Hz, 1O,
4.4.29. 10,12-Dichloro-4-Hydroxy-8H-chromeno[2 ,3 :4,5]imidazo
[2,1-a]isoquinoline 35. A¼7.5 mL, B¼0.75 mL. Yield 220 mg (67%);
ꢀ
7
3
as light beige solid; mp>300 C (dec); [Found: C, 60.41; H, 2.74; N,
2 2 2 H
7.81. C18H10Cl N O requires C, 60.53; H, 2.82; N, 7.84%]; d

5504
L.G. Voskressensky et al. / Tetrahedron 68 (2012) 5498e5504
(
7
400 MHz, DMSO-d
.40e7.47 (m, 2O, O-9, O-5), 7.52 (d, J¼7.3 Hz, 1O, O-6), 7.62 (d,
J¼2.2 Hz,1O, O-11), 7.76 (d, J¼7.8 Hz,1O, O-2), 8.29 (d, J¼7.8 Hz,1O,
O-1), 11.50 (s, 1O, PO); (100 MHz, CF ): 20.5,
COOHþDMSO-d
01.8, 113.2, 113.3, 116.2, 116.6, 117.9, 118.4, 121.6, 123.8, 127.7, 129.3,
30.9, 131.3, 132.8, 140.4, 144.0, 152.1; m/z (%)¼359 (18), 358 (41),
6
): 4.57 (s, 2O, O-8), 7.10 (d, J¼7.8 Hz, 1O, O-3),
Acknowledgements
The financial support of the Russian Foundation for Basic Re-
search (grant # 12-03-93000-Viet_a) is gratefully acknowledged.
d
C
3
6
1
1
3
(
þ
57 (71), 356 (63) [M] , 355 (100), 160 (33), 143 (35), 85 (15), 84
Supplementary data
32), 43 (25).
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.087. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
0
0
4
.5. Multi component synthesis of 8H-Chromeno[2 ,3 :4,5]
imidazo[2,1-a]isoquinoline 7
A solution of isoquinoline (715 mg, 5.55 mmol), o-hydroxy-
benzaldehyde (610 mg, 5 mmol), chloroacetonitrile (0.88 mL,
2
13.9 mmol) and i-Pr NEt (1.65 mL, 10 mmol) in methanol (10 mL)
was heated at reflux for 9 h. The precipitate was filtered, washed
with ethanol. The crude product was recrystallysed from ethanol to
give 80 mg (6%) compound 7 as light beige solid.
References and notes
1. (a) Tietze, L. F.; Beifuss, U. Angew. Chem. 1993, 105, 137e170; (b) Tietze, L. F.;
Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, 2006, pp 160e185; (c) Tietze, L. F. Chem. Rev. 1996, 96, 115e136.
. For selected recent publications on domino-reactions see f.i. (a) Ghandi, M.;
Mohammadimehr, E.; Sadeghzadeh, M.; Bozcheloei, A. H. Tetrahedron 2011, 67,
2
4
.6. 8,8-Dimethyl-8,16-dihydro-13H-[1]benzosilano[2,3-d]
0
0
chromeno[2 ,3 :4,5]imidazo[1,2-a]-pyridin-13-on 36
8484e8491; (b) Yang, Y.; Gao, M.; Wu, L.-M.; Deng, C.; Zhang, D.-X.; Gao, Y.; Zhu,
T.-P.; Wu, A.-X. Tetrahedron 2011, 67, 5142e5149; (c) Bryhas, A. O.; Horak, Y. I.;
Ostapiuk, Y. V.; Obushak, M. D.; Matiychuk, V. S. Tetrahedron Lett. 2011, 52,
The procedure was the same as for preparation of compounds
2324e2326; (d) Devi Bala, B.; Balamurugan, K.; Perumal, S. Tetrahedron Lett.
7
e35 (A¼8 mL, B¼1.5 mL). Yield 30 mg (10%); as light-brown
2011, 52, 4562e4566.
ꢀ
solid; mp 250e251 C (dec); [Found: C, 72.32; H, 4.66; N, 7.28.
3. (a) Voskressensky, L. G.; Borisova, T. N.; Kulikova, L. N.; Varlamov, A. V.; Catto, M.;
Altomare, C.; Carotti, A. Eur. J. Org. Chem. 2004, 3128e3135; (b) Voskressensky, L.
G.; Listratova, A. V.; Borisova, T. N.; Kovaleva, S. A.; Borisov, R. S.; Varlamov, A. V.
Tetrahedron 2008, 64, 10443e10452; (c) Voskressensky, L. G.; Borisova, T. N.;
Kulikova, L. N.; Varlamov, A. V. Chem. Heterocycl. Compd. 2007, 43, 913e918; (d)
Voskressensky, L. G.; Vorobiev, I. V.; Borisova, T. N.; Varlamov, A. V. J. Org. Chem.
C
H
23 18
N
2
O
2
Si requires C, 72.22; H, 4.74; N, 7.32%];
H
d (400 MHz,
DMSO-d
6
) 0.56 (s, 6O, Si(CH
3 2
)
), 4.35 (s, 2O, O-16), 7.14 (td, J¼7.5,
1
1
1
(
1
1
(
1
.4 Hz, 1O, O-2), 7.22e7.31 (m, 2O, O-3, O-4), 7.35 (d, J¼7.5 Hz,
O, O-1), 7.58e7.66 (m, 2O, O-10, O-11), 7.72 (dd, J¼6.9, 1.8 Hz,
O, O-12), 7.84 (d, 1O, O-7), 8.45 (dd, J¼7.8, 1.4 Hz, 1O, O-9), 8.99
2008, 73, 4596e4601.
4
. (a) Safarov, S.; Voskressensky, L. G.; Bizhko, O. V.; Kulikova, L. N.; Khrustalev, V.
N. Acta Crystallogr. 2010, E-66, o710; (b) Voskressensky, L. G.; Kulikova, L. N.;
Listratova, A. V.; Borisov, R. S.; Kukaniel, M. M.; Varlamov, A. V. Tetrahedron Lett.
s, 1O, O-14);
d
C
(100 MHz, DMSO-d
6
): ꢁ0.9(2C), 22.8, 100.7, 118.1,
18.9, 120.6, 124.5, 125.0, 127.9, 128.8, 129.3, 130.8, 131.3, 132.1,
33.0, 134.5, 139.6, 140.3, 140.6, 151.5, 153.3, 186.1; IR (KBr), : 1656
C¼O) cm ; m/z (%)¼383 (19), 382 (64) [M] , 381 (100), 323 (10),
83 (22).
2010, 50, 2269e2270.
n
5
. Prostakov, N. S.; Saxen, N.; Varlamov, A. V.; Klochkov, A. M. Chem. Heterocycl.
Compd. 1981, 17, 176e180.
6. Proen c¸ a, M. F.; Costa, M. Tetrahedron 2010, 66, 4542e4550.
ꢁ1
þ