Oxidative route to pyrroloisoquinoline-2,3-dione

Article abstract of DOI:10.24820/ark.5550190.p010.433

We herein report an efficient constructive method for synthesis of structurally important Pyrroloisoquinoline-2,3-dione from dihydroisoquinoline through oxidative cyclisation. Process is optimised to give best efficiency at gram scale and laborious purification techniques such as column chromatography or recrystallisation were avoided in all steps further featuring uniqueness of this method as compared to the available literature.

Full text of DOI:10.24820/ark.5550190.p010.433

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Arkivoc 2018, part iii, 184-190
Organic Chemistry
Oxidative Route to Pyrroloisoquinoline-2,3-dione
a
b
Hari K. Kadam * and Santosh G. Tilve
a
Department of Chemistry, St. Xavier’s College, Mapusa, Goa – 403507 India .
b
Department of Chemistry, Goa University, Taleigao plateau, Goa – 403206 India
Email: harikadam05@gmail.com
Received 12-12-2017
Accepted 01-28-2018
Published on line 02-25-2018
Abstract
We herein report an efficient constructive method for synthesis of structurally important Pyrroloisoquinoline-
,3-dione from dihydroisoquinoline through oxidative cyclisation. Process is optimised to give best efficiency
2
at gram scale and laborious purification techniques such as column chromatography or recrystallisation were
avoided in all steps further featuring uniqueness of this method as compared to the available literature.
Keywords: Isoquinoline, pyrrole, aerobic oxidation, synthesis, green chemistry, dione
©
DOI: https://doi.org/10.24820/ark.5550190.p010.433
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Introduction
Multiannular heterocycles are frequently encountered in several anticancer, antiviral, antibacterial
1
-4
compounds and naturally occurring microbial or marine metabolites or phytochemicals.
OMe
MeO
MeO
MeO
MeO
HO
N
O
N
O
N
O
MeO
MeO
O
O
O
Laurodionine
Telisatin A
O
Telisatin B
O
OH
N
O
N
O
O
O
MeO
O
O
Lettowianthine,
Annonbraine
11-Methoxylettowianthine
MeO
N
O
MeO
MeO
O
OMe
Dihydropyrrolo[2,1-a]isoquinoline-2,3-dione
Figure 1. Naturally occurring pyrroloquinoline-1,2-diones and pyrroloisoquinoline-2,3-dione under study.
5
-13
Pyrroloquinoline-1,2-diones are observed in natural compounds such as telisatin A and B, laurodionine,
annonbraine, methoxylettowianthine as depicted in Figure 1.
1
4-16
During our studies towards medicinally important organic heterocycles,
we encountered a route for
which are structurally similar to pyrroloquinoline-1,2-diones. In
this paper we describe an efficient, gram scale, purification free method for synthesis of pyrroloisoquinoline-
,3-dione 1 from dihydroisoquinoline 2 through oxidative cyclisation.
1
7-19
synthesis of Pyrroloisoquinoline-2,3-dione
2
Results and Discussion
We began by preparing secondary amide 3 of homoveratric acid and homoveratryl amine by two alternate
2
0
methods via acid chloride and via DCC coupling as described in scheme 1.
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COOH
MeO
MeO
MeO
MeO
NH2
DCC
DMAP
CH Cl
SOCl2
reflux, 2 h
2
2
8
1 %
COCl
MeO
MeO
MeO
MeO
MeO
MeO
K CO
2
O
3
NH
NH2 CH Cl
2
2
0
°C
overall yield: 76 %
MeO
3
OMe
Scheme 1. Synthesis of secondary amide 3.
Dihydroisoquinoline 2 was prepared by Bischler-Napieralski reaction
2
0-25
(Scheme 2) on amide 3. Ethyl
bromoacetate with dihydroisoquinoline 2 gave the corresponding salt which was in situ treated with
triethylamine in aerobic refluxing condition. The overall product obtained was identified to be
pyrroloisoquinoline-2,3-dione 1. With process optimisation to give best efficiency, (Scheme 3) laborious
purification techniques such as column chromatography or recrystallisation were avoided in all steps further
featuring uniqueness of this method as compared to the available literature.
MeO
MeO
1
) POCl3,
O
toluene
NH
N
reflux, 4 h
MeO
MeO
MeO
MeO
2
) aq. NaOH
1 %
7
3
OMe
2
OMe
Scheme 2. Preparation of dihydroisoquinoline 2.
MeO
MeO
MeO
1
) Ethyl bromoacetate,
Toluene, r.t. 6 h
N
O
N
MeO
MeO
2
) Et N, reflux, air,
3
1
2 h, 85 %
O
MeO
OMe
OMe 2
1
Scheme 3. Preparation of pyrroloisoquinoline-2,3-dione 1.
On successful method development, we also propose herein a probable mechanistic pathway as described
in scheme 4 for this constructive transformation. Dihydroisoquinoline 2 reacts with ethyl bromoacetate to
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form the quaternary ammonium salt. Addition of base gives enamine ester which undergoes intramolecular
cyclisation to give pyrroloisoquinoline.
Further presence of base gives azomethine which undergoes aerobic oxidation to directly give
pyrroloisoquinoline-2,3-dione 1.
MeO
MeO
MeO
MeO
MeO
MeO
Br
N
N
H
Br
N
COOEt Et
N
COOEt
3
EtO
O
MeO
MeO
MeO
OMe 2
OMe
OMe
MeO
MeO
MeO
MeO
MeO
EtO
O
N
O
[O]
N
N
Et N
3
MeO
MeO
O
O
MeO
MeO
OMe
OMe
OMe
1
Scheme 4. Probable mechanism for transformation of dihydroisoquinoline to pyrroloisoquinoline-2,3-dione.
Conclusions
In conclusion, we have developed an efficient constructive method for synthesis of structurally important
Pyrroloisoquinoline-2,3-dione from dihydroisoquinoline through oxidative cyclisation at gram scale. Laborious
purification techniques such as column chromatography or recrystallisation were avoided in all steps further
featuring uniqueness of this method.
Experimental Section
General. Reagents were purchased from Sigma-Aldrich and were used without further purification. IR spectra
1
13
were recorded with Shimadzu FTIR instrument. H & C NMR spectra were recorded in DMSO-d with Bruker
6
AVANCE 400 MHz NMR Spectrometer. LCMS were recorded with Shimadzu LCMS instrument. HRMS were
recorded with a MicroMass ESQTOF.
N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)acetamide (3). (a) SOCl method: Homoveratric acid (5
2
g, 25.5 mmol) was added to freshly distilled thionyl chloride (15 mL) and refluxed at 100 °C for 3 h. Excess
thionyl chloride was removed from reaction mixture by distillation and dry CHCl (10 mL) was added. This
3
solution of acid chloride was added dropwise with stirring to an ice cold solution of homoveratryl amine (4.16
g, 23.0 mmol) and K CO (5.53 g 40 mmol) in dry CHCl (20 mL). This mixture was stirred for 12 h from 0 °C to
2
3
3
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r.t. Solvent was removed under vacuum and distilled water (50 mL) was added. The solid thus obtained was
filtered and washed with water (20 mL X 3) and dried under vacuum. Analytically pure product 3 was obtained
as white amorphous solid in 76% (6.28 g) yield without any further purification. White amorphous solid, mp:
2
0
-1 1
1
24-125 °C. [lit. mp 124-125 °C] IR (KBr): ν
3325, 2960, 1641, 1589, 1517, 1028 cm . H NMR (400 MHz,
max
CDCl ): δ 2.60 (t, J 6.8 Hz, 2H), 3.36 (m, 2H), 3.41 (s, 2H), 3.75 (s, 3H), 3.76 (s, 3H), 3.79 (s, 3H), 3.81 (s, 3H), 5.37
3
1
3
(
br s, 1H), 6.45 (dd, J 8.4, 1.6 Hz, 1H), 6.54 (d, J 1.6 Hz, 1H), 6.62 (m, 3H), 6.73 (m, 1H) ppm. C NMR & DEPT
100 MHz, CDCl ): δ 34.97 (CH ), 40.71 (CH ), 43.42 (CH ), 55.81 (CH ), 55.84 (2x CH ), 55.89 (CH ), 111.08 (CH),
(
3
2
2
2
3
3
3
1
11.39 (CH), 111.64 (CH), 112.36 (CH), 120.56 (CH), 121.59 (CH), 127.14 (Cq), 131.00 (Cq), 147.61 (Cq), 148.27
(Cq), 148.91 (Cq), 149.22 (Cq), 171.30 (Cq) ppm.
(b) DCC coupling method: Homoveratric acid (5 g, 25.5 mmol), homoveratryl amine (4.62 g, 25.5 mmol) and
DMAP (0.05 g) were added in dry CH Cl (25 mL) and cooled to 0 °C. To this mixture, DCC (6.19 g, 30 mmol)
2
2
was added and stirred from 0 °C to r.t. for 24 h. Water (1 mL) and dioxane (2 mL) was added to this and stirred
for 2 h. Solvent was removed under vacuum, CH Cl (25 mL) was added, cooled to 0 °C and filtered. The filtrate
2
2
was again cooled to 0 °C and filtered. The solvent was removed under vacuum and product 3 was obtained as
white solid in 81% (7.41 g) yield without any further purification.
1
-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline (2). Amide 3 (7.18 g, 20 mmol) was
dissolved in dry toluene (10 mL) and freshly distilled POCl (5 mL) was added slowly and refluxed for 4 h. The
3
reaction mixture was then poured in ice and basified by cooled aq. NaOH solution (10 N) until pH 14.
Dihydroisoquinoline 2 was then extracted in CH Cl (20 mL X 2), dried by passing through anhy. Na SO and
2
2
2
4
2
0 1
concentrated under vacuum to give 71% (4.84 g) yield without any further purification. Viscous oil. H NMR
(
400 MHz, CDCl ): δ 1.89 (m, 2H), 2.76 (t, J 8.0 Hz, 2H), 3.74 (s, 3H), 3.76 (s, 3H), 3.79 (s, 3H), 3.86 (s, 3H), 4.20
3
1
3
(s, 2H), 6.64 (s, 1H), 6.69 (d, J 8.4 Hz, 1H), 6.78 (m, 1H), 6.95 (s, 1H) , 7.09 (s, 1H) ppm. C NMR & DEPT (100
MHz, CDCl ): δ 24.95 (CH ), 33.20 (CH ), 49.11 (CH ), 55.89 (CH ), 56.04 (CH ), 56.05 (CH ), 56.12 (CH ), 110.02
3
2
2
2
3
3
3
3
(CH), 112.20 (CH), 112.04 (CH), 121.16 (CH), 126.64 (CH), 131.09 (Cq), 133.89 (Cq), 147.66 (Cq), 149.68 (Cq),
1
51.71 (Cq), 154.19 (Cq), 156.13 (Cq), 164.69 (Cq) ppm.
1
-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2,3-dione (1).
Dihydroisoquinoline 2 (1.1 g, 3.22 mmol) in dry toluene (25 mL) was cooled to 0 °C and Ethyl bromoacetate
0.6 g, 3.4 mmol) in dry toluene (5 mL) was added and stirred from 0 °C to r.t. for 6 h. Further mixture was
(
cooled to 0 °C and insoluble salt was isolated by decanting. To this salt, triethylamine (10 mL) was added and
refluxed in air for 12 h. Finally excess triethylamine was removed under vacuum and ice cold distilled water
(50 mL) was added. The solid product thus obtained was filtered and washed with water (20 mL X 3) and dried
under vacuum. Analytically pure pyrroloisoquinoline 1 was obtained as wine red solid in 85 % (1.08 g) yield
without any further purification. Wine red solid, mp: 176-178 °C, IR (KBr): ν 3021, 1728, 1705, 1624, 1445
max
-
1 1
cm . H NMR (400 MHz, DMSO-d ): δ 3.06 (t, J 6.0 Hz, 2H), 3.25 (s, 3H), 3.68 (s, 3H), 3.70 (t, J 6.4 Hz, 2H), 3.77
6
1
3
(
(
(
s, 3H), 3.86 (s, 3H), 6.83 (m, 1H), 6.85 (s, 1H), 6.92 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H) ppm. C NMR
100 MHz, DMSO-d ): δ 27.55 (CH ), 35.90 (CH ), 54.62 (CH ), 55.53 (CH ), 55.61 (CH ), 55.94 (CH ), 107.24
6
2
2
3
3
3
3
Cq), 111.45 (CH), 112.02 (CH), 112.16 (CH), 113.49 (CH), 115.97 (Cq), 122.56 (CH), 122.94 (Cq), 133.84 (Cq),
46.98 (Cq), 148.37 (Cq), 148.82 (Cq), 153.14 (Cq), 157.05 (Cq), 158.00 (Cq), 182.85 (Cq) ppm. LCMS (m/z):
1
+
+
[
M+H] 395.9. HRMS (m/z): calculated for C H NO Na [M+Na] : 418.1267; found : 418.1289.
2
2
21
6
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Acknowledgements
Authors thank Science & Engineering Research Board (SERB), Department of Science & Technology, New Delhi
for funding. Authors acknowledge Indian Institute of Science (IISc), Bangalore for HRMS analysis.
Supplementary Material
1
13
Supplementary data ( H NMR, C NMR and DEPT spectra of all the products) associated with this article can
be found, in the online version.
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