A short microwave-assisted synthesis of tetrahydroisoquinolin- pyrrolopyridinones by a triple process: Ugi-3CR-aza Diels-Alder/S-oxidation/ Pummerer

Article abstract of DOI:10.1016/j.tetlet.2011.07.134

A series of tetrahydroisoquinolin-pyrrolopyridinones were prepared from an easily accessible aldehyde, a commercially available amine, a readily isolable isonitrile, and maleic anhydride via a triple process: Ugi-3CR-aza Diels-Alder/S-oxidation/Pummerer.

Full text of DOI:10.1016/j.tetlet.2011.07.134

Tetrahedron Letters 52 (2011) 5245–5248
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A short microwave-assisted synthesis of tetrahydroisoquinolin-
pyrrolopyridinones by a triple process: Ugi-3CR–aza
Diels–Alder/S-oxidation/Pummerer
Alejandro Islas-Jácome a, Eduardo González-Zamora a, , Rocío Gámez-Montaño b,
⇑
⇑
a Departamento de Química, División de Ciencias Básicas e Ingeniería, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina Iztapalapa,
C.P. 09340, México D.F., Mexico
b Departamento de Química, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, C.P. 36050, Guanajuato, Gto., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of tetrahydroisoquinolin-pyrrolopyridinones were prepared from an easily accessible aldehyde, a
commercially available amine, a readily isolable isonitrile, and maleic anhydride via a triple process: Ugi-
3CR–aza Diels–Alder/S-oxidation/Pummerer. The combination of a multicomponent Ugi-type reaction
with other post-functionalization processes provides a powerful tool for the preparation of fused polyhet-
erocyclic compounds.
Received 10 June 2011
Revised 28 July 2011
Accepted 28 July 2011
Available online 5 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted synthesis
Tetrahydroisoquinolin-pyrrolopyridinones
Ugi-3CR
Aza Diels–Alder cycloaddition
S-oxidation
Pummerer cyclization
The chemistry of heterocyclic compounds has assumed an
important role in recent years.1 Nitrogenated heterocyclic com-
pounds are an integral part of numerous drugs and natural prod-
ucts,2 and the majority of these latter exhibit biological activity.3
For these reasons, several synthetic methodologies have been
developed for preparing natural products.4 Synthetic methodolo-
gies, such as multicomponent reactions (MCR’s) have been used
to achieve advanced intermediates for the synthesis of compounds
with biological activity.5 In this context, a combination of multi-
component reactions6 and an efficient post-transformation, typi-
cally involving a ring-forming process, has provided a powerful
tool to the synthesis of highly functionalized heterocyclic com-
pounds.7 Indeed, multicomponent reactions that combine three
or more reactants together during a single ordered event offer
not only molecular complexity and diversity in each step, they also
enable the matching of functionalities that are suitable for further
transformations. The reaction times and yields of MCR’s can greatly
benefit from the use of microwave (MW) irradiation.8
Recently, we focused on the preparation of compound libraries
using multicomponent processes, such as Ugi-type reactions
combined with other post-functionalization techniques, such as
free-radical cyclizations.15 We also focused on the preparation of
synthetically nitrogenated analogs of important natural products
in medicinal chemistry. In this context, one of our goals has been
to develop synthetic routes to compounds with the tetrahydroiso-
quinolin-pyrrolopyridinone skeleton, which is an aza-analog of the
tetrahydroisoquinolin-isoindolinone skeleton that may exhibit
biological activity. The preparation of these compounds presents
an attractive challenge.16
In 1997, Grigg and co-workers17 reported the synthesis of the
tetrahydroisoquinolin-pyrrolopyridinone
1 using a palladium-
catalyzed cascade cyclization–Friedel–Crafts alkylation approach
in 71% yield Figure 1.
In 2002, Gámez-Montaño and Zhu18 reported a three-step
synthesis of the tetrahydroisoquinolin-pyrrolopyridine 2 using a
combination of multicomponent reactions and Pummerer cycliza-
tion in good overall yield. This sequence provided the first syn-
thetic approach to tetrahydroisoquinolin-pyrrolopyridinones
without a carbonyl in the pyrrole ring of the linear polyheterocyclic
system, Figure 1.
Several post-transformations of Ugi products have been re-
ported, including cyclocondensations,9 radical cyclizations,10
SNAr’s,11 SN2’s,12 cycloadditions,13 and metathesis reactions.14
In this Letter, we describe the synthesis of the new compounds
3a–c (Fig. 1) containing the aza-tetracyclic skeleton of tetrahydro-
isoquinolin-pyrrolopyridinones via a combined multicomponent
Ugi-type reaction, aza Diels–Alder cycloaddition, and Pummer
⇑
Corresponding authors. Tel.: +52 55 58044913; fax: +52 55 58044666 (E.G.);
tel.: +52 473 7320006x8191; fax: +52 473 7320006x8168 (R.G.).
E-mail addresses: egz@xanum.uam.mx (E. González-Zamora), rociogm@quijote.
ugto.mx (R. Gámez-Montaño).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.134

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A. Islas-Jácome et al. / Tetrahedron Letters 52 (2011) 5245–5248
Table 1
Zhu et al.
Grigg et al.
Effect of the catalyst and the solvent in the synthesis of pyrrolo[3,4-b]pyridin-5-ones
9a–c.
COOEt
N
O
N
MeO
MeO
N
Yielda (%)
Product
O
Entry
Solvent
Additive or catalyst
N
SPh
N
Bn
1
2
3
4
5
6
7
PhMe
PhMe
PhMe
PhMe
PhH
LiBr 1.1 equiv
32
45
48
82
62
75
72
9a
9a
9a
9a
9a
9b
9c
NH4Cl 1.2 equiv
Yb(OTf)3 3 mol %
Sc(OTf)3 3 mol %
Sc(OTf)3 3 mol %
Sc(OTf)3 3 mol %
Sc(OTf)3 3 mol %
2
83%
1
71%
Our targets
O
R1
R2
N
PhMe
PhMe
N
O
N
S
a
Bn
After purification by silica gel column chromatography.
Ph
3a, R1, R2= -O-CH2-O-
3b, R1= -H, R2= -OMe
3c, R1=R2=-H
entries 6 and 7). Notably, the use of benzene in place of toluene
decreased the yield (Table 1, entry 5).
The pyrrolo[3,4-b]pyridin-5-one 9a was quantitatively S-
Figure 1. Compounds with the tetrahydroisoquinolin-pyrrolopyridinone skeleton.
oxidized26 using m-CPBA to the corresponding sulfoxide
compound 10a (Scheme 2).
A diastereomeric mixture was
expected as a consequence of the creation of an axial chiral center
at the sulfoxide axis, and the desired compound 10a was obtained
as a mixture in a 5:2 ratio of the inseparable diastereomers by
silica gel column chromatography. In the present work, the two
sulfoxide diastereoisomers (10a) did not need to be isolated and
were used as a mixture in the next step.
Closure of the diastereomeric mixture of the sulfoxide
compounds 10a, by a SEAr Pummerer-type cyclization27 using the
Hunig’s base and TMSOTf as a sulfoxide activator18 afforded the
desired tetrahydroisoquinolin-pyrrolopyridinone 3a in low yield
(Table 2, entry 1) as a single diastereoisomer. The optimal conditions
included DIEA (6.0 equiv), TMSOTf (6.0 equiv), and dichlorometh-
ane as the solvent, with incubation at 0 °C for 16 h to give the
polyheterocycle 3a in 72% yield (Table 2, entry 2), Scheme 2.
er-type cyclization as a post-functionalization reaction performed
under MW-irradiation.
Recently, our group developed a new methodology for preparing
the pyrrolopyridinone skeleton using a four-component reaction.15a
Following this methodology, the easily accessible aldehyde 4,19 the
commercially available piperonylamine (5a), and the readily
isolable isonitrile20 6 were sequentially combined in an Ugi-3CR in
toluene using MW as a heat source to give, after 45 min, the corre-
sponding 5-amino-oxazole 7a.21 Next, maleic anhydride (8)22 was
added to afford, after 15 min, the expected pyrrolo[3,4-b]pyridin-
5-one 9a via an aza-Diels–Alder cycloaddition23 (Scheme 1).
In the first attempt to obtain the pyrrolo[3,4-b]pyridin-5-one
9a, we used LiBr as an additive24 to facilitate the imine formation,
however, the desired compound was obtained in low yield (32%),
probably due to the hygroscopic properties of this salt (Table 1,
entry 1). The use of NH4Cl to generate the iminium ion, which
was expected to be more reactive than the imine in the Ugi reac-
tion, as reported by Zhu and co-workers,23 provided a better yield
(Table 1, entry 2). The use of metallic triflates as a catalyst25 pro-
moted this transformation (Table 1, entries 3 and 4) by activating
the imine prior to the isonitrile nucleophilic attack. The use of
Sc(OTf)3, in particular, gave the highest yield. Once the conditions
were optimized, including the reaction parameters associated with
the MW conditions, two pyrrolo[3,4-b]pyridin-5-ones 9b and 9c
were prepared in good yield within 60 min in a single step through
the use of two amines 5b and 5c as starting materials (Table 1,
O
O
N
N
m-CPBA
N
O
R1
R2
9a-c
CH2Cl2
0 °C
~ 100%
2h
S
10a-c
CH2Cl2
0 °C
DIEA
TMSOTf
72%
16h
28'
27
27'
O
28
O
4
O
26
R2
N
5
3
2
6
S
R1
N
H
Sc(OTf)3
24
25
7
11
12
10
N
1
4
9
22
3a, R1, R2= -O-CH2-O-
3b, R1= -H, R2= -OMe
3c, R1=R2=-H
23
PhMe
MW (68 oC)
~ 100%
13'
14'
13
14
R1
S
8
+
21
16
17'
NH
R2
17
15
R1
R2
S
18'
NH2
O
45 min
O
18
19
N
O
C
N
+
N
N
7a-c
Scheme 2. Preparation of the tetrahydroisoquinolin-pyrrolopyridinones 3a–c.
O
5a, R1, R2= -O-CH2-O-
5b, R1= -H, R2= -OMe
5c, R1=R2=-H
6
14'
Table 2
13'
+
O
O
Optimization of the Pummerer-type cyclyzation for the synthesis of final products
3a–c.
4
29
28
N
3
14
5
20
13
O
N
22
6
21
2
8
Entry
Conditionsa
Time (h)
Yieldb (%)
Product
N
7
23
O
1
15
9
26
PhMe
R1
27
10
11
10'
24
MW (68 oC)
82%
S
1
2
3
4
(1.0), (1.0)
(6.0), (6.0)
(6.0), (6.0)
(6.0), (6.0)
16
16
34
48
16
72
62
38
3a
3a
3b
3c
25
16
O
R2
11'
17
18
17'
12
15 min
8
18'
9a-c
19
a
Dichloromethane, DIEA, TMSOTf (equiv) at 0 °C.
After purification by silica gel column chromatography.
Scheme 1. Synthesis of the pyrrolo[3,4-b]pyridin-5-ones 9a-c based on a multi-
component reaction.
b

A. Islas-Jácome et al. / Tetrahedron Letters 52 (2011) 5245–5248
5247
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one-pot process. Under the conditions established previously for
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In summary, the multicomponent domino process used in the
present work, which involved a combination of Ugi-3CR, aza
Diels–Alder cycloaddition, S-oxidation, and Pummerer-type cycli-
zation under microwave-assistance, produced three fused rings
by creating seven new chemical bonds via the simple loss of water
and CO2. The obtained polyheterocycles containing the tetrahydro-
isoquinolin-pyrrolopyridinone system were produced in good
yields, considering the molecular complexity of the final com-
pounds. The operational simplicity of this synthesis is highly
attractive for a range of diversity-oriented synthetic approaches.
Acknowledgments
Financial support by the Consejo Nacional de Ciencia y Tec-
nología (CONACyT, project 51346-Q and J-50922) and a scholar-
ship awarded to A.I.-J. (227423) are gratefully acknowledged.
E.G.-Z. thanks A. Gutiérrez-Carrillo for NMR spectra and Professors
J. Tamariz-Mascarúa and A. Benavides-Macias for their fruitful
comments.
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All compounds were characterized by 1H NMR, 13C NMR, DEPT-135, COSY,
HSQC, HMBC, IR, and HRMS. The melting points are reported as the average
values from three tests.
silica-gel preparative plate (20 Â 20 cm) with a mixture of hexane and AcOEt
1:1 as the mobile phase to afford mixture of two inseparable
diastereoisomers 10a (in a 5:2 ratio) in quantitative yield. The NMR signals
of 10a were found to be duplicated.
a
Procedure for obtaining pyrrolo[3,4-b]pyridin-5-ones (See Ref. 15a).
Procedure for obtaining the tetrahydroisoquinolin-pyrrolopyridinones. Selected
compound 3a. To a stirred solution of compound 10a (0.103 mmol, 1.0 equiv) in
CH2Cl2 at 0 °C, TMSOTf (0.620 mmol, 6.0 equiv) and DIEA (0.620 mmol,
6.0 equiv) were sequentially added. After 16 h, the solvent was removed
under reduced pressure. The crude product was primarily treated with
3 Â 15 mL NaHCO3 (aq), followed by treatment with excess brine. The crude
Selected
compound
6-((benzo[d][1,3]dioxol-6-yl)methyl)-2-benzyl-6,7-
pyridin-5-one
dihydro-3-morpholino-7-((phenylthio)methyl)pyrrolo[3,4-b]
9a, yield 82%. Pale yellow powder, mp: 58 °C, Rf = 0.35 (Hexane/AcOEt 1:1).
Selected spectral data for compound 9a 1H NMR (500 MHz, CDCl3, 298 K) d: 7.83
(s, 1H, H-4), 7.23–7.12 (m, 10H, Harom), 6.72 (dd, 1H, J = 11.1, 0.8 Hz, H-26), 6.72
(d, 1H, J = 11.1 Hz, H-25), 6.70 (d, 1H, J = 0.8 Hz, H-22), 5.90 (d, 1H, J = 4.6 Hz, H-
27), 5.88 (d, 1H, J = 4.6 Hz, H-27), 5.21 (d, 1H, J = 15.1 Hz, H-20), 4.60 (m, 1H, H-
7), 4.28 (d, 1H, J = 14.2 Hz, H-8), 4.12 (d, 1H, J = 14.2 Hz, H-8), 3.84–3.79 (m, 5H,
H-14, H-20), 3.69 (dd, 1H, J = 14.1, 3.2 Hz, H-15), 3.56 (dd, 1H, J = 14.1, 4.1 Hz,
H-15), 2.83–2.79 (m, 4H, H-13). 13C NMR (125 MHz, CDCl3, 298 K) d: 167.0 (C-
5), 161.3 (C-2), 158.3 (C-28), 148.1 (C-23), 147.7 (C-3), 147.1 (C-24), 139.2 (C-
9), 135.2 (C-16), 131.1 (C-10), 130.4 (C-21), 128.8 (C-11), 128.7 (C-17), 128.2
(C-18), 126.7 (C-12), 126.1 (C-19), 125.1 (C-29), 123.5 (C-4), 121.5 (C-26),
108.6 (C-25), 108.2 (C-22), 101.0 (C-27), 67.1 (C-14), 59.0 (C-7), 52.9 (C-13),
43.6 (C-20), 39.8 (C-8), 35.4 (C-15). FT-IR (film in CH2Cl2): 1692 cmÀ1 (C@O).
HRMS calcd for C33H31N3O4S: 565.2035, found: 565.2029.
Procedure for obtaining 6-((benzo[d][1,3]dioxol-6-yl)methyl)-2-benzyl-6,7-
dihydro-3-morpholino-7-((phenylsulfinyl)methyl)pyrrolo[3,4-b]pyridin-5-one
10a: to a stirred solution of compound 9a (0.033 mmol, 1.0 equiv) in CH2Cl2 at
0 °C, m-CPBA (0.0462 mmol, 1.4 equiv) was added. After 2 h, the solvent was
removed under reduced pressure. The crude product was purified by silica gel
chromatography (hexane/AcOEt 1:1). Finally, the product was re-purified on a
product was immediately purified on
a silica-gel preparative plate
(20 Â 20 cm) using a mixture of hexane and AcOEt 3:1 as the mobile phase
to afford the desired compound 3a in 72% yield. White solid, mp: 72 °C.
Rf = 0.20 (Hexane/AcOEt 1:1). Selected spectral data for compound 3a, 1H NMR
(500 MHz, CDCl3, 298 K) d: 7.79 (s, 1H, H-4), 7.47–7.45 (m, 2H, H-13), 7.40–
7.38 (m, 2H, H-17), 7.28–7.18 (m, 7H, Harom), 6.63 (s, 1H, H-8), 5.98 (d, 1H,
J = 1.4 Hz, H-20), 5.93 (s, 1H, J = 1.4 Hz, H-20), 5.14 (d, 1H, J = 16.4 Hz, H-6), 4.66
(d, 1H, J = 7.8 Hz, H-10), 4.43 (d, 1H, J = 13.9 Hz, H-11), 4.34 (d, 1H, J = 7.8 Hz, H-
9), 4.33 (d, 1H, J = 13.9 Hz, H-11), 4.20 (d, 1H, J = 16.4 Hz, H-6), 3.85–3.83 (m,
4H, H-28), 2.86–2.82 (m, 4H, H-27). 13C NMR (125 MHz, CDCl3, 298 K) d: 165.8
(C-5), 165.4 (C-2), 159.3 (C-25), 147.8 (C-3), 147.2 (C-21), 147.0 (C-22), 139.4
(C-12), 133.2 (C-13), 132.9 (C-16), 129.2 (C-14), 128.9 (C-17), 128.7 (C-18),
127.8 (C-15), 127.5 (C-25), 127.2 (C-24), 126.2 (C-19), 124.5 (C-26), 123.3 (C-
4), 109.6 (C-7), 106.1 (C-8), 101.3 (C-20), 67.1 (C-28), 59.9 (C-10), 52.9 (C-27),
48.7 (C-9), 41.2 (C-6), 40.0 (C-11). FT-IR (film in CH2Cl2): 1696 cmÀ1 (C@O).
HRMS calcd. for C33H29N3O4S: 563.1879, found: 563.1881.