Differentiating alkyne reactivity in the post-Ugi transformations: Access to polycyclic indole-fused frameworks

Article abstract of DOI:10.1016/j.tetlet.2018.03.079

The Ugi adducts prepared from propiolic acids, propargylamines, indole-2-carbaldehydes, and isocyanides were utilized to assemble polycyclic indole-fused frameworks via two consecutive carbocyclizations involving triple bonds. First, the peptidyl position

Full text of DOI:10.1016/j.tetlet.2018.03.079

Accepted Manuscript
Differentiating Alkyne Reactivity in the Post-Ugi Transformations: Access to
Polycyclic Indole-Fused Frameworks
Chao Liu, Gaigai Wang, Yingchun Wang, Kristof Van Hecke, Olga P.
Pereshivko, Vsevolod A. Peshkov
PII:
S0040-4039(18)30406-4
https://doi.org/10.1016/j.tetlet.2018.03.079
TETL 49848
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 December 2017
21 March 2018
26 March 2018
Please cite this article as: Liu, C., Wang, G., Wang, Y., Van Hecke, K., Pereshivko, O.P., Peshkov, V.A.,
Differentiating Alkyne Reactivity in the Post-Ugi Transformations: Access to Polycyclic Indole-Fused Frameworks,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.03.079
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Differentiating Alkyne Reactivity in the Post-Ugi Transformations: Access to Polycyclic
Indole-Fused Frameworks
a#
a#
a
b
a,
a,
Chao Liu, Gaigai Wang, Yingchun Wang, Kristof Van Hecke, Olga P. Pereshivko, * Vsevolod A. Peshkov *
a
College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Dushu Lake Campus,
Suzhou, 215123, China
b
XStruct, Department of Chemistry, Ghent University, Krijgslaan 281-S3, B-9000, Ghent, Belgium
#
These authors contributed equally to this work
E-mails: olga@suda.edu.cn; vsevolod@suda.edu.cn
ABSTRACT: The Ugi adducts prepared from propiolic acids, propargylamines, indole-2-carbaldehydes, and
isocyanides were utilized to assemble polycyclic indole-fused frameworks via two consecutive
carbocyclizations involving triple bonds. First, the peptidyl position of Ugi adduct underwent potassium
carbonate-mediated cyclization onto the triple bond derived from propiolic acid. Then, the position 3 of
indole core engaged into gold-catalyzed cyclization onto the propargylamine-originated alkyne, completing
the construction of polycyclic core.
Many structurally interesting and biologically active natural products contain indole moiety imbedded into
1
complex polycyclic framework. In virtue of this, the development of practical strategies to synthesize
libraries of alkaloid-mimicking indole-annulated heterocyclic systems has become a popular research
2
,3,4,5,6,7,8,9,10
direction.
Following this trend, a number of diversity-oriented approaches towards this class of
11
compounds have been established relying on either intramolecular Ugi reaction or various post-Ugi
12
transformations.
The possibility to bring together virtually any kind of functional groups into a linear peptide-like precursor,
which can be readily transformed into heterocycle, placed a four-component Ugi reaction among the major
13
diversification tools. For example, the Ugi adducts bearing alkyne group and a suitable nucleophilic
14
15,16
reactive site can undergo a large variety of hetero- and carbocyclizations
with the aid of gold and silver
catalysis. It was also demonstrated that the propiolic acid-derived Ugi adducts could be readily transformed
17
18
into pyrrol-2-ones
and β-lactams,
exploiting the nucleophilicity of the peptidyl position via
enolization-triggered 5-endo-dig and 4-exo-dig cycloisomerizations, respectively.
In 2016, Van der Eycken and coworkers disclosed an interesting study towards imidazole-fused polycyclic
19
scaffolds 7 (Scheme 1a). Subjecting propiolic acid 1, propargylamine 2, 1H-imidazole-2-carbaldehyde (3)
and isocyanide 4 in the Ugi reaction led to the formation of adduct 5 that at the elevated temperature of
5
0°C underwent spontaneous cyclization into pyrrol-2-one 6, deploying peptidyl nucleophilic site and the
propiolic acid-originated triple bond. Next, the remaining alkyne group underwent a nucleophilic attack by an

imidazole moiety upon the activation by silver(I) hexafluoroantimonate catalyst, giving rise to the target
structure 7 via 6-exo-dig heterocyclization. We envisaged that the analogous approach based on the strategic
differentiation of the triple bond reactivity could be applied for the synthesis of polycyclic indole-fused
frameworks. Herein, we present the resulting three-step sequence for the synthesis of
indolizino[8,7-b]indol-3-ones 11 and pyrrolo[1',2':1,2]azepino[3,4-b]indoles 12 (Scheme 1b). The first step of
the strategy involved the four-component Ugi reaction of propiolic acid 1, propargylamine 2,
indole-2-carbaldehyde 8 and isocyanide 4 that worked best at the elevated temperature of 50°C. In the next
step, the resulting Ugi adduct 9 underwent cyclization into pyrrol-2-one 10 in the presence of potassium
carbonate in DMF at room temperature. Finally, the treatment of 10 with catalytic amount of gold(I)
triphenylphosphine chloride and silver(I) triflate in chloroform at room temperature produced desired
polycyclic scaffold 11 or 12. The results of the substrate scope investigation are summarized in Table 1.
Scheme 1 Strategies for sequential assembly of polycyclic frameworks based on post-Ugi transformations
At first, we have evaluated different propiolic acids 1 in combination with terminal propargylamine (2a),
indole-2-carbaldehyde (8a) and tert-butyl isocyanide (4a). In all cases, the overall sequence worked well
producing indolizino[8,7-b]indol-3-ones 11a-c with moderate to good efficiency per step (Table 1, entries 1-3).
The final alkyne hydroarylation step involved
propargylamine-originated terminal triple bond onto position 3 of indole that proceeded selectively in
-exo-dig fashion. In case of substrate 10c derived from phenyl propiolic acid, the formation of
a
cationic gold-catalyzed cyclization of
6
pyrrolo[2',1':3,4]pyrazino[1,2-a]indole 13 byproduct through the competing cyclization onto indole nitrogen
was observed (Table 1, entry 3). Next, we decided to explore a series of internal propargylamines 2b-f in
combination with 1a, 8a and 4a (Table 1, entries 4-8). Interestingly, in this case, the gold-catalyzed cyclization
of
pyrrol-2-ones
10d-h
proceeded
selectively
in
7-endo-dig
mode,
delivering
20
pyrrolo[1',2':1,2]azepino[3,4-b]indoles 12a-e as final products. Thus, the current methodology allows to
obtain both skeletal and substituent-based diversity. The final step of the sequence worked especially well
with the substrates 10d-g derived from the (hetero)aryl substituted propargylamines 2b-e, producing
polycyclic products 12a-d in up to 91% yield (Table 1, entries 4-7). This was slightly deteriorated by the fact
that the Ugi reaction of 3-(thiophen-2-yl)prop-2-yn-1-amine (2e) afforded Ugi adduct 9g in only poor yield of
3
1% (Table 1, entry 7). An introduction of chlorine atom into indole core of aldehyde 8b was well tolerated,
allowing to acquire indolizino[8,7-b]indol-3-one 11d over the standard three-step synthesis (Table 1, entry 9).
With respect to the isocyanide component, the methodology was extended to the use of n-butyl isocyanide
(
4b) and aromatic naphthalene-2-isocyanide (4c), with the latter showing decreased efficiency in the initial
Ugi step (Table 1, entries 10 and 11). The structures of representative indolizino[8,7-b]indol-3-one 11c,

pyrrolo[2',1':3,4]pyrazino[1,2-a]indole 13 and pyrrolo[1',2':1,2]azepino[3,4-b]indole 12a were established by
21
the X-ray crystallographic analysis (Figure 1).
Table 1 Scope of the strategy
Yield
Yield
Polycyclic product
Yield of
Entry
1
Ugi adduct 9
Pyrrol-2-one 10
a
a
a
of 9, %
of 10, %
11, 12 or 13
11, 12 or 13, %
83
76
81
69
59
2
83
6
1
8
1
3
80
72
4
5
75
78
79
77
85
85
6
7
73
31
83
74
91
90

8
66
46
62
9
1
76
79
83
86
61
82
0
1
1
44
74
62
a
Isolated yield.
Figure 1 X-ray crystallographic molecular structures of compounds 11c, 13 and 12a, showing thermal
displacement ellipsoids at the 50% probability level. The water molecules in the crystal packing of 12a are
not shown.
Additionally, in the course of this study, the intramolecular alkyne hydroarylation of pyrrol-2-one 10a into
indolizino[8,7-b]indol-3-one 11a has been briefly investigated (Table 2). The use of standard gold(I)
triphenylphosphine chloride / silver(I) triflate combination gave better results in chloroform as compared to
dichloromethane (Table 2, entry 1 versus entry 2). Gold(I) triphenylphosphine chloride / silver(I)
tetrafluoroborate combination and preformed cationic gold(I) complex bearing bulky phosphine ligand also
showed good performance when employed in chloroform as a solvent (Table 2, entries 3 and 4). Other tested
catalytic combinations could not provide a full conversion of substrate 10a under the same settings, with
gold(I) triphenylphophine chloride / silver(I) nitrate being absolutely inefficient (Table 2, entries 5-7). Not
surprisingly, gold(I) triphenylphophine chloride also completely failed to catalyze the conversion of 10a into
1
1a in the absence of silver(I) salt (Table 2, entry 8). Likewise, silver(I) triflate alone proved to be inefficient
catalyst, delivering desired 11a in only low yield of 30% (Table 2, entry 9).

a
Table 2 Screening of the parameters of the alkyne hydroarylation step
b
b
Entry
Catalyst
Solvent Time, h
Conversion of 10a, %
Yield of 11a, %
1
2
3
4
5
6
7
8
9
5 mol% AuPPh
5 mol% AuPPh
5 mol% AuPPh
3
3
3
Cl/AgOTf
CHCl
3
3
100
92
72
65
72
71
66
61
-
Cl/AgOTf
2
CH Cl
2
3
Cl/AgBF
4
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
3
3
3
3
3
3
3
3
100
100
85
5 mol% [Au(JohnPhos)(MeCN)]SbF
6
3
5 mol% AuPPh
5 mol% AuPPh
5 mol% AuPPh
5 mol% AuPPh
3
3
3
3
Cl/AgNTf
2
3
Cl/AgPF
4
3
84
Cl/AgNO
3
3
12
Cl
12
8
0
-
10 mol% AgOTf
59
30
a
b
1
The reactions were run on 0.2 mmol scale in 2 mL of solvent; Determined by H NMR using 3,4,5-trimethoxybenzaldehyde as internal
standard. JohnPhos = (2-biphenyl)di-tert-butylphosphine.
In conclusion, we have developed a concise and versatile strategy to access polycyclic indole derivatives. The
overall sequence relied on Ugi reaction followed by two consecutive carbocyclizations involving triple bonds.
In general, all the steps proceeded with moderate to good efficiency, allowing to attain a small set of target
products. Depending on the alkyne substitution pattern, two kinds of indole-fused heterocyclic frameworks
could be generated.
Acknowledgements
This work was supported by the start-up fund from Soochow University (grant Q410900714), National
Natural Science Foundation of China (grant 21650110445), Natural Science Foundation of Jiangsu Province of
China (grants BK20160310 and BK20150317), the Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD) and the project of scientific and technologic infrastructure of Suzhou (grant
SZS201708). K.V.H. thanks the Hercules Foundation (project AUGE/11/029 ‘3D-SPACE: 3D Structural Platform
Aiming for Chemical Excellence’) and the Special Research Fund (BOF) – UGent (project 01N03217) for
funding.

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20
Regarding the exo- to endo- regioselectivity switch when moving from terminal to internal alkynes, a similar
trend has been observed previously, see: S. T. Staben, J. J. Kennedy-Smith, D. Huang, B. K. Corkey, R. L. LaLonde, F.
4
h
16d
D. Toste Angew. Chem. Int. Ed. 2006, 45, 5991–5994 and references
and . A possible rationale for such
4
h
differentiation is given in reference .
21
CCDC 1588587 (for 11c), 1588588 (for 13), and 1588589 (for 12a) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.
Highlights




Functionalized Ugi adducts were utilized to assemble polycyclic indole derivatives
The strategic differentiation of the triple bond reactivity was applied
In general, each step of the sequence proceeded with moderate to good efficiency
Depending on the alkyne substitution pattern, two kinds of products were accessed