Synthesis of Chromeno[4′,3′:4,5]pyrido[1,2- a ]pyrazines and -diazepines by the Reaction of Substituted 2-(3-Acetyl-2-oxo-2 H -chromen-4-yl)fumarates with 1, n -Diamines

Article abstract of DOI:10.1055/s-0036-1591550

A two-step sequence was developed for the synthesis of chromeno[4′,3′:4,5]pyrido[1,2- a ]pyrazine-13-carboxylates and -diazepine-14-carboxylates by the reaction of substituted dimethyl 2-(3-acetyl-2-oxo-2 H -chromen-4-yl)fumarates with 1, n -diamines at room temperature. Advantages of this protocol include ease of handling and the absence of a metal catalyst.

Full text of DOI:10.1055/s-0036-1591550

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
A. Alizadeh, P. Jamal
Letter
Synlett
Synthesis of Chromeno[4′,3′:4,5]pyrido[1,2-a]pyrazines and
-diazepines by the Reaction of Substituted 2-(3-Acetyl-2-oxo-2H-
chromen-4-yl)fumarates with 1,n-Diamines
Abdolali Alizadeh*
Parinaz Jamal
O
H
NH
MeO
O
H
OMe
O
n
MeO2C
H2N
H2N
O
O
N
CO2Me
O
R2
Department of Chemistry, Tarbiat Modares University,
P.O. Box 14115-175, Tehran, Iran
aalizadeh@modares.ac.ir
R2
n
R2
Ph3P
Me
Me
Me
+
CH2Cl2
CH2Cl2
O
O
O
abdol_alizad@yahoo.com
O
O
CO2Me
R1
R1 3 examples
R1
7 examples
92–96% yield
63–80% yield
Received: 15.12.2017
Accepted after revision: 11.02.2018
Published online: 04.04.2018
arophiles to give phosphorus- or nonphosphorus-contain-
ing products. For example, 2,5-dihydro-1,2-oxaphospholes
have been synthesized by the reaction of triphenylphos-
phine, alkynes, and ethyl 3-bromopyruvate.25 Additionally,
the three-component reactions of amines with diketene
and dibenzoylacetylene in the presence of triphenylphos-
phine yields functionalized furamide derivatives.26
The widespread use of polycyclic nitrogen heterocycles
in the discovery of novel bioactive compounds27 promoted
us to choose 1,n-diamines as ambidentate nucleophiles for
reaction with various dimethyl 2-(3-acetyl-2-oxo-2H-
chromen-4-yl)fumarate derivatives.
DOI: 10.1055/s-0036-1591550; Art ID: st-2017-d0904-l
Abstract A two-step sequence was developed for the synthesis of
chromeno[4′,3′:4,5]pyrido[1,2-a]pyrazine-13-carboxylates and -diaze-
pine-14-carboxylates by the reaction of substituted dimethyl 2-(3-ace-
tyl-2-oxo-2H-chromen-4-yl)fumarates with 1,n-diamines at room tem-
perature. Advantages of this protocol include ease of handling and the
absence of a metal catalyst.
Key words dimethyl acetyloxochromenfumarates, chromenopyrido-
pyrazinecarboxylates, chromenopyridodiazepinecarboxylates, cyclization,
polycyclic heterocycles
Initially, we explored the preparation of the dimethyl 2-
(3-acetyl-2-oxo-2H-chromen-4-yl)fumarates 3. A range of
3-acetylcoumarins were prepared by the reaction of the ap-
propriate salicylaldehydes with ethyl 3-oxobutanoate in
EtOH at room temperature in the presence of piperidine.
The resulting 3-acetylcoumarins 3 reacted with dimethyl
acetylenedicarboxylate in the presence of triphenylphos-
phine (100 mol%) in dichloromethane at room temperature
to afford the desired dimethyl 2-(3-acetyl-2-oxo-2H-
chromen-4-yl)fumarates 3 in 92–96% yields (Scheme 1).28
The synthesis of fused heterocyclic compounds has at-
tracted much attention, because such heterocycles have im-
portant roles in the biological profiles of drugs.1 Fused
heterocyclic derivatives have been obtained by combining
smaller heterocyclic compounds with one another, and
such combinations containing two biologically active moi-
eties can display synergistic effects, resulting in new biolog-
ical activities compared with the parent compounds.2–13
Coumarin is present as a structural framework in many
bioactive natural products.14 Derivatives have also been
found that demonstrate antitumor,15 antioxidant,16 or anti-
inflammatory properties17 or which act as nonpeptidic HIV
protease inhibitors,18 topoisomerase II inhibitors,19 tyrosine
kinase inhibitors,20 diuretics, or analgesics.21,22 Heterocycles
fused at the 3,4-position of coumarin have also attracted at-
tention.23
O
O
R2
CHO
R2
Me
piperidine
Me
+
EtOH, r.t., 3 h
OEt
OH
O
O
O
R1
2
1
R1
OMe
O
MeO
O
O
CO2Me
CO2Me
R2
Ph3P
Me
2
+
CH2Cl2, r.t., 3 h
Among the various synthetic methods that have been
developed for synthesis of heterocycles, zwitterion chemis-
try is one of the more interesting.24 Nucleophilic addition of
phosphorus at an unsaturated carbon of dialkyl acety-
lenedicarboxylates yields zwitterions that react with dipol-
O
O
R1
3
Scheme 1 Synthesis of dimethyl 2-(3-acetyl-2-oxo-2H-chromen-4-yl)
fumarates 3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
A. Alizadeh, P. Jamal
Letter
Synlett
The use of substoichiometric amounts of triphenylphos-
phine or the use of solvents other than dichloromethane
led to decreased yields. The scope of the reaction was fur-
ther explored with various 3-acetylcoumarins. All the prod-
ucts were isolated in good to high yields (Table 1).
Although no detailed mechanistic studies have been
carried out at this stage, a plausible mechanism for this
transformation is outlined in Scheme 2. On the basis of the
well-known chemistry of trivalent phosphorus nucleo-
philes,25–28 it is reasonable to assume that initial addition of
triphenylphosphine to the dimethyl acetylenedicarboxylate
and subsequent attack of the resulting zwitterion 4 on the
double bond of 3-acetylcoumarin 2 yields the intermediate
5, which is converted into intermediates 6 by a 1,2-proton
transfers. Subsequently, a 1,4-proton transfer converts 6′
into intermediate 7, which gives rise to product 3 by the
elimination of triphenylphosphine. Computational experi-
ments showed that, unlike a 1,2-hydride shift, a direct intra-
molecular 1,2-proton transfer is impossible because it re-
quires a high activation energy.30 Computational studies
and isotopic labelling have shown that 1,4- and 1,2-proton
transfers require an external proton source and that these
proton shifts should be corrected to a water-catalyzed 1,4-
or 1,2-proton transfers.31
Table 1 Synthetic Route to Dimethyl 2-(3-Acetyl-2-oxo-2H-chromen-
4-yl)fumarates 3
MeO
OMe
O
O
O
O
CO2Me
R2
R2
Ph3P
Me
Me
+
CH2Cl2, r.t., 3 h
O
O
O
O
CO2Me
R1
R1
2
3
Entry
R1
R2
Product
Yield (%)
1
2
3
H
H
3a
3b
3c
95
92
96
H
Br
H
MeO
CO2Me
MeO2C
PPh3
The structure of 3a was determined by IR, NMR spec-
troscopy, and single-crystal X-ray analysis. The mass spec-
trum of 3a showed a molecular-ion peak at m/z = 330, in
agreement with the proposed structure. In the IR spectrum
of 3a, the absorption band at 1720 cm–1 was ascribed to the
carbonyl stretching frequency. In the 1H NMR spectrum,
four singlets at δ = 7.09, 3.75, 3.55, and 2.55 ppm corre-
sponded to the vinylic hydrogen, two methoxy groups, and
the methyl group, respectively. In addition, the four aro-
matic hydrogen atoms gave rise to characteristic resonanc-
es in the aromatic region of the spectrum. Observation of
CO2Me
CO2Me
H
CO2Me
CO2Me
R2
COMe
Ph3P
Ph3P
+
4
O
1,2-proton transfer
O
O
R2
R1
Me
5
O
O
R1
2
CO2Me
CO2Me
PPh3
CO2Me
PPh3
MeO2C
MeO2C
MeO2C
PPh3
COMe
H
R2
R2
COMe
R2
COMe
H
H
O
O
O
O
O
1
17 distinct signals in the H-decoupled 13C NMR spectrum
R1
R1
6
R1
6''
6'
of 3a was also in agreement with the proposed structure. In
the 13C NMR spectrum of 3a, two methoxy groups and one
methyl group appeared at δ = 53.4, 52.3, and 30.9 ppm, re-
spectively. Signals at 198.1, 164.2, and 163.8 ppm were at-
tributed to the ketone carbonyl and two ester carbons. Final
confirmation of the structure of this product was derived
by an X-ray analysis (Figure 1).29
CO2Me
MeO
O
H
MeO2C
OMe
O
PPh3
O
R2
COMe
R2
1,4-proton transfer
Me
– Ph3P
O
O
O
O
R1
7
R1
3
Scheme 2 Proposed mechanism for the first step of the reaction
In continuation, we were interested in synthesizing the
polycyclic nitrogen heterocycle 8a from 3a and ethane-1,2-
diamine (7a), as shown in Scheme 3.
A solution of 3-acetylcoumarin (2a) and triphenylphos-
phine in anhydrous dichloromethane reacted with dimeth-
yl acetylenedicarboxylate to give dimethyl 2-(3-acetyl-2-
oxo-2H-chromen-4-yl)fumarate (3a). A solution of ethane-
1,2-diamine (7a; 1 mmol) was added to give the desired
methyl
7-methyl-6,12-dioxo-10,11,12,12a-tetrahydro-
6H,9H-chromeno[4′,3′:4,5]pyrido[1,2-a]pyrazine-13-carbo-
Figure 1 ORTEP diagram for compound 3a
xylate (8a).32
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
A. Alizadeh, P. Jamal
Letter
Synlett
Based on these results, a plausible mechanism for the
formation of 8 is proposed in Scheme 4. Formation of
imine 9 occurs through condensation of amine 7 with the
acyl group of intermediate 3. Imine 9 then undergoes a
6π electrocyclization to produce chromenopyridine 10. Fi-
nally, product 8 is produced through N-cyclization of
chromenopyridine 10 through attack on the C=O double
bond and loss of methanol.
H
N
O
MeO
O
H2N
MeO2C
OMe
O
N
O
O
H2N
7a
Me
Me
CH2Cl2, r.t., 2 h
O
O
O
8a
3a
Scheme 3 Approach to the synthesis of methyl 7-methyl-6,12-dioxo-
10,11,12,12a-tetrahydro-6H,9H-chromeno[4′,3′:4,5]pyrido[1,2-a]pyr-
azine-13-carboxylate (8a)
MeO
O
MeO
O
OMe
O
OMe
N
O
O
n
NH2
R2
R2
H2N
Me
Me
+
n
We then probed the scope of this annulation with vari-
ous substituted dimethyl 2-(3-acetyl-2-oxo-2H-chromen-
4-yl)fumarates 3 and 1,n-diamines 7 which gave a range of
chromeno[4′,3′:4,5]pyrido[1,2-a]pyrazine-13-carboxylates
or -diazepine-14-carboxylates 8 in good to excellent yields
(Table 2).
– H2O
H2N
O
O
O
O
R1
R1
3
7
9
OMe
O
O
NH
NH2
H
MeO2C
MeO2C
n
n
N
O
N
R2
R2
electrocyclization
Me
Me
– MeOH
O
O
O
Table 2 Synthesis of Chromeno[4′,3′:4,5]pyrido[1,2-a]pyrazine-13-
carboxylates or -diazepine-14-carboxylates 8
R1
R1
8
10
Scheme 4 Proposed mechanism for the second step of the reaction
O
NH
MeO
O
H2N
n
MeO2C
OMe
O
N
n
In conclusion, we have synthesized novel chrome-
no[4′,3′:4,5]pyrido[1,2-a]pyrazine-13-carboxylates and -di-
azepine-14-carboxylates by the reaction of substituted di-
methyl 2-(3-acetyl-2-oxo-2H-chromen-4-yl)fumarates with
1,n-diamines. Substrates for these transformations are read-
ily accessible by a sequential three-component reaction of
3-acetylcoumarin, dimethyl acetylenedicarboxylate, and
triphenylphosphine.
O
H2N
7
R2
R2
Me
Me
CH2Cl2, r.t., 2 h
O
O
O
O
R1
R1
8
3
Entry
R1
R2
Diamine 7
Product Yield (%)
1
2
3
4
5
6
7
H
H
H
H
H
H
H2N(CH2)2NH2
H2N(CH2)3NH2
Me2C(CH2NH2)2
H2N(CH2)2NH2
Me2C(CH2NH2)2
H2N(CH2)2NH2
Me2C(CH2NH2)2
8a
8b
8c
8d
8e
8f
63
65
65
60
70
80
80
H
H
Supporting Information
Br
Br
H
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591550.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
OMe
OMe
H
3g
References and Notes
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1685, and 1620 cm–1 were attributed to the NH, CO2Me, and
1
NHC=O stretching frequencies, respectively. In the H NMR
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1
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proposed structure.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
A. Alizadeh, P. Jamal
Letter
Synlett
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A solution of dimethyl acetylenedicarboxylate (1 mmol) in
CH2Cl2 (3 mL) was added dropwise over 15 min to a magneti-
cally stirred solution of the appropriate 3-acetylcoumarin (1
mmol) and Ph3P (1 mmol) in anhyd CH2Cl2 (3 mL) at r.t., and the
mixture was stirred for 4 h. When the reaction was complete,
the solvent was removed and the product was precipitated by
adding hexane, collected by filtration, and washed with EtOH.
Dimethyl
(2E)-2-(3-Acetyl-2-oxo-2H-chromen-4-yl)but-2-
enedioate (3a)
Cream powder; yield: 0.31 g (95%); mp 111–113 °C. IR (KBr):
1720 (C=O), 1598 and 1533 (Ar) cm–1 1H NMR (300.13 MHz,
.
CDCl3): δ = 2.56 (s, 3 H, CH3), 3.55 (s, 3 H, OCH3), 3.75 (s, 3 H,
OCH3), 7.09 (s, 1 H, CH3 of butenedioate), 7.23 (t, 3JHH = 8.6 Hz, 1
H, CH6), 7.33 (d, 3JHH = 7.8 Hz, 1 H, CH8), 7.35 (d, 3JHH = 7.8 Hz, 1
3
H, CH5), 7.57 (t, JHH = 7.7 Hz, 1 H, CH7). 13C NMR (75.46 MHz,
CDCl3) δ = 30.9 (CH3), 52.3 (OCH3), 53.42 (OCH3), 117.2 (C3),
118.4 (CH8), 123.7 (C4a), 125.1 (CH6), 126.9 (CH7), 128.3 (CH5),
133.8 (C2 of butenedioate), 141.3 (CH3 of butenedioate), 152.3
(C8a), 153.7 (C4), 158.8 (C2=O), 163.8 (CO2Me), 164.2 (CO2Me),
198.1 (C=O). MS (EI, 70 eV): m/z (%) = 331 [M + 1]+ (2), 330 [M]+
(1), 288 (14), 287 (71), 272 (46), 271 (100), 257 (16), 243 (15),
229 (11), 227 (12), 213 (12), 197 (23), 113 (18), 59 (17), 43 (30).
Anal. Calcd for C17H14O7 (330.07): C, 61.82; H, 4.27. Found: C,
61.79; H, 4.29.
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Crystal data for 3a (C17H14NO7): MW = 330.28, monoclinic,
P21/n, a = 13.8388(18) Å, b = 8.6354(8) Å, c = 14.095(2) Å, β =
113.541(17), V = 1544.2(3) Å3, Z = 4, Dc = 1.421 mg/m3, F (000) =
688; crystal dimensions, 0.45 × 0.40 × 0.38 mm; radiation, Mo
Kα (λ = 0.71073 Å). 2.84 ≤ 2 ≤ 25.09, intensity data were col-
lected at 293(2) K with a Bruker APEX area-detector diffractom-
eter by employing an ω/2θ scanning technique in the range –16
≤ h ≤ 13, –10 ≤ k ≤ 8, –16 ≤ l ≤ 15. The structure was solved by
direct methods; all nonhydrogen atoms were positioned, and
anisotropic thermal parameters were refined from 1699
observed reflections with R (into) = 0.1124 by a full-matrix
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least-squares technique, converging to R = 0.0754 and Raw
0.2308 [I > 2σ (I)].
Dimethyl (2E)-2-(3-Acetyl-6-bromo-2-oxo-2H-chromen-4-
yl)but-2-enedioate (3b)
=
Cream powder; yield: 0.37 g (92%); mp 135–137 °C. IR (KBr):
1722 (C=O), 1601 and 1530 (Ar) cm–1 1H NMR (300.13 MHz,
.
CDCl3): δ = 2.58 (s, 3 H, CH3), 3.64 (s, 3 H, OCH3), 3.82 (s, 3 H,
OCH3), 7.13 (s, 1 H, CH3 of butenedioate), 7.30 (d, 3JHH = 8.8 Hz, 1
4
3
H, CH8), 7.50 (d, JHH = 2.0 Hz, 1 H, CH5), 7.78 (dd, JHH = 8.8 Hz,
4JHH = 2.1 Hz, 1 H, CH7). 13C NMR (75.46 MHz, CDCl3): δ = 30.9
(CH3), 52.6 (OCH3), 53.6 (OCH3), 117.9 (C3), 119.0 (CH8), 120.0
(C-Br), 124.5 (C4a), 128.8 (CH7), 129.0 (CH5), 136.5 (C2 of
butenedioate), 140.8 (CH3 of butenedioate), 151.0 (C8a), 152.5
(C4), 158.2 (C2=O), 163.6 (CO2Me), 164.2 (CO2Me), 197.8 (C=O).
Anal. Calcd for C17H13BrO7 (409.19): C, 49.90; H, 3.20. Found: C,
49.87; H, 3.22.
(26) Alizadeh, A.; Zohreh, N.; Rostamnia, S. Tetrahedron 2007, 63,
8083.
(29) CCDC 1526737 contains the supplementary crystallographic
data for compound 3a. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

E
A. Alizadeh, P. Jamal
Letter
Synlett
(30) Wang, Y.; Cai, P.-J.; Yu, Z.-X. J. Org. Chem. 2017, 82, 4604.
(31) (a) Liang, Y.; Liu, S.; Xia, Y.; Li, Y.; Yu, Z.-X. Chem. Eur. J. 2008, 14,
4361. (b) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.;
Liu, S.; Li, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470.
139 (24), 128 (12), 127 (20), 126 (12), 115 (18), 77 (10), 70 (11),
63 (15), 59 (48), 56 (11), 44 (11), 43 (24), 42 (37), 41 (16). Anal.
Calcd for C18H16N2O5 (340.33): C, 63.53; H, 4.74; N, 8.23. Found:
C, 63.49; H, 4.75; N, 8.28.
(32) Polycyclic Heterocycles 8a–g; General Procedure
Methyl 7-Methyl-6,13-dioxo-9,10,11,12,13,13a-hexahydro-
6H-chromeno[4′,3′:4,5]pyrido[1,2-a][1,4]diazepine-14-
carboxylate (8b)
A solution of the appropriate diester 3 (1 mmol) and 1,n-
diamine 7 (1 mmol) in CH2Cl2 was magnetically stirred at r.t. for
2 h until the reaction was complete (TLC). The mixture was then
filtered, and the residue was purified by column chromatogra-
phy [silica gel (Merck 230–240 mesh), EtOAc].
Yellow powder; yield: 0.230 g (65%); mp 245 °C (dec.). IR (KBr):
3424 and 3351 (NH), 1661 (C=O), 1611 (NCO), 1514 and 1455
(Ar), 1245 and 1099 (C–O) cm–1. 1H NMR (500 MHz, DMSO-d6):
δ = 1.77–1.93 (m, 2 H, CH2), 2.55 (s, 3 H, Me), 3.30–3.32 (m, 1 H,
CH2N), 3.59–3.61 (m, 2 H, CH2NH), 3.60 (s, 3 H, OMe), 4.36–4.38
Methyl 7-Methyl-6,12-dioxo-10,11,12,12a-tetrahydro-6H,9H-
chromeno[4′,3′:4,5]pyrido[1,2-a]pyrazine-13-carboxylate (8a)
Yellow powder; yield: 0.214 g (63%); mp 170 °C (dec.). IR (KBr):
3425 (NH), 1686 (C=O), 1620 (NCO), 1527 and 1458 (Ar), 1221
(C–O) cm–1. 1H NMR (500 MHz, DMSO-d6): δ = 2.56 (s, 3 H, Me),
3.36–3.40 (m, 2 H, CH2NH), 3.61 (s, 3 H, OMe), 3.70–3.74 (m, 1
H, CH2N), 4.23–4.027 (m, 1 H, CH2N), 5.06 (s, 1 H, CH12a), 7.07 (d,
3
(m, 1 H, CH2N), 5.44 (s, 1 H, CH13a), 7.07 (d, JHH = 7.7 Hz, 1 H,
CH4 of chromene), 7.08 (t, 3JHH = 7.1 Hz, 1 H, CH2 of chromene),
3
3
7.37 (t, JHH = 7.3 Hz, 1 H, CH3 of chromene), 7.60 (d, JHH = 7.3
Hz, 1 H, CH1 of chromene), 7.70 (s, 1 H, NH). 13C NMR (125 MHz,
DMSO-d6): δ = 17.08 (Me), 30.59 (CH2), 41.11 (CH2NH), 52.07
(OMe), 53.65 (CH2N), 62.71 (CH13a), 96.93 (C6a of chromene),
106.11 (C14), 117.03 (CH4 of chromene), 118.75 (C14b of
chromene), 123.26 (CH2 of chromene), 129.81 (CH of
chromene1), 131.56 (CH3 of chromene), 136.43 (C14a of
chromene), 152.30 (C4a of chromene), 161.17 (C7), 162.90
(COOMe), 167.32 (COO), 171.93 (CONH). MS (EI, 70 eV): m/z (%) =
354 [M+] (3), 167 (11), 149 (53), 104 (13), 83 (15), 81 (10), 76
(10), 71 (26), 70 (24), 69 (28), 67 (12), 57 (93), 56 (20), 55 (57),
43 (100), 42 (18), 41 (92).Anal. Calcd for C19H18N2O5 (354.36): C,
64.40; H, 5.12; N, 7.91. Found: C, 66.50; H, 4.90; N, 6.92.
3
3JHH = 7.7 Hz, 1 H, CH4 of chromene), 7.08 (t, JHH = 7.1 Hz, 1 H,
CH2 of chromene), 7.23 (t, 3JHH = 7.3 Hz, 1 H, CH3 of chromene),
3
7.37 (d, JHH = 7.3 Hz, 1 H, CH1 of chromene), 8.16 (s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): δ = 21.92 (Me), 43.75 (CH2–NH),
50.26 (CH2–N), 56.90 (OMe), 66.10 (CH12a), 98.78 (C6a), 110.51
(C13), 122.04 (C13b of chromene), 123.01 (CH4 of chromene),
128.42 (CH2 of chromene), 132.76 (CH1 of chromene), 136.37
(CH3 of chromene), 137.20 (C13a of chromene), 157.15 (C4a of
chromene), 165.77 (C7), 169.31 (COOMe), 172.23 (COO), 173.5
(CONH). MS (EI, 70 eV): m/z (%) = 340 [M+] (58), 325 (11), 282
(20), 281 (100), 212 (15), 211 (12), 210 (20), 155 (12), 140 (21),
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E