Gold(i) and platinum(ii) switch: A post-Ugi intramolecular hydroarylation to pyrrolopyridinones and pyrroloazepinones

Article abstract of DOI:10.1039/c2cc35900f

A regioselective approach for the synthesis of pyrrolopyridinones and pyrroloazepinones is reported employing an Ugi reaction followed by a gold(i) or platinum(ii) catalyzed intramolecular hydroarylation.

Full text of DOI:10.1039/c2cc35900f

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Gold(I) and platinum(II) switch: a post-Ugi intramolecular hydroarylation
to pyrrolopyridinones and pyrroloazepinonesw
a
Sachin G. Modha,z Amit Kumar,ab Dipak D. Vachhani,a Sunil K. Sharma,b
Virinder S. Parmarb and Erik V. Van der Eycken*a
Received 15th August 2012, Accepted 17th September 2012
DOI: 10.1039/c2cc35900f
A regioselective approach for the synthesis of pyrrolopyridinones
and pyrroloazepinones is reported employing an Ugi reaction
followed by a gold(I) or platinum(II) catalyzed intramolecular
hydroarylation.
conversion respectively, while no reaction was observed with
Au(PPh3)Cl (Table 1, entries 1–3). Use of cationic gold
Au(PPh3)OTf (5 mol%) at rt furnished 47% of pyrrolopyr-
idinone 6a, while heating at 50 1C it gave 100% conversion,
with an isolated yield of 93% (Table 1, entries 4 and 5). The
switch of selectivity for the formation of 6a or 7a depending on
the use of cationic gold(I) (Table 1, entry 5) or a AuCl/AuCl3-
catalyst (Table 1, entries 1 and 2) encouraged us to further
optimize the conditions.
Transition metal-catalyzed carbocyclizations and heteroannulations
of aromatic and heteroaromatic compounds with alkynes have
attracted much attention in the last couple of decades.1 In the vast
literature about intramolecular alkyne cyclizations for the synthesis
of biologically interesting carbo- and hetero-cycles, gold- and
platinum-catalyses2,3 have been on the front seat. Recently Beller
and co-workers have reported a mechanistically interesting
platinum-catalyzed intramolecular cyclization of alkynes on
the pyrrole and the indole core.4 Many elegant approaches
involving gold-catalyzed alkyne cyclizations are also reported for
the generation of various fused heterocycles.5 Intermolecular
gold-catalyzed reactions of pyrroles usually lack selectivity6 and
a less pronounced selectivity switch was observed in the related
furan cyclizations with gold- and platinum-catalysis.7 We have
recently reported a post-Ugi gold(I)-catalyzed intramolecular
hydroarylation approach to the synthesis of indoloazocines8
and spiroindolines.9 Inspired by this work and as a result of
our interest in the application of transition metal-catalysis10
and multicomponent reactions11 for the synthesis of diversely
substituted heterocycles, we here report a post-Ugi intramolecular
hydroarylation to pyrrolopyridinones and pyrroloazepinones.12
Ugi 4-CR13 of 2-formyl-N-methylpyrrole (1a), p-methoxy-
benzylamine (2a), 2-butynoic acid (3a) and t-Bu isonitrile (4a)
in methanol at 50 1C furnishes the corresponding Ugi-adduct
5a in 83% yield. This was further used for investigating the
intramolecular hydroarylation.
The application of Au(PPh3)SbF6 (5 mol%) at rt produced
only 30% of 6a, while employing solely AgOTf (5 mol%) at rt
Table 1 Optimization of the intramolecular hydroarylationa
Catalyst
Entry (mol%)
Time Temp Conversionb
Solvent
(h)
(1C) (%) (6a/7a)
1
2
3
4
5
6
7
8
AuCl (5)
AuCl3 (5)
Au(PPh3)Cl (5)
Au(PPh3)OTf (5) CDCl3
Au(PPh3)OTf (5) CDCl3
Au(PPh3)SbF6 (5) CDCl3
AgOTf (5)
AgOTf (5)
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)
H2PtCl6ꢀ6H2O (5) CDCl3
H2PtCl6ꢀ6H2O (5) CDCl3
Au(PPh3)OTf (5) ACN-d3
Au(PPh3)OTf (5) THF-d8
CDCl3
CDCl3
CDCl3
24
24
24
24
3
24
24
24
24
14
24
6
50
50
50
rt
50
rt
rt
50
rt
50
35
80
120
rt
50
50
50
50
50
50
50
50
50
25 (0/25)
35 (0/35)
0 (0/0)
47 (47/0)
100 (93/0)c
30 (30/0)
0 (0/0)
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
50 (0/50)
0 (0/0)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
100 (10/82)c
10 (0/10)
100 (25/75)
100 (35/75)
0 (0/0)
4
The application of 5 mol% of AuCl or AuCl3 as catalyst in
CDCl3 produced only pyrroloazepinone 7a in 25% and 35%
24
24
24
24
Traces (0/traces)
100 (60/0)c,d
100 (45/0)c,d
47 (47/0)
0 (0/0)
Au(PPh3)OTf (5) Toluene-d8 24
a Laboratory for Organic & Microwave-Assisted Chemistry
(LOMAC), Department of Chemistry, KU Leuven,
Celestijnenlaan 200F, B-3001, Leuven, Belgium.
E-mail: erik.vandereycken@chem.kuleuven.be
b Bioorganic Laboratory, Department of Chemistry,
University of Delhi, Delhi-110 007, India
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral data. See DOI: 10.1039/c2cc35900f
z Present address: ‘‘Mani Bhuvan’’, Nr Lohana Mahajan Vadi,
Chhaya-360 578, Porbandar, Gujarat, India.
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)
Au(PPh3)OTf (2) CDCl3
PtCl2 (2) CDCl3
ACN-d3
THF-d8
Toluene-d8 24
24
24
5 (0/5)
15 (0/15)
40 (40/0)
50 (10/40)
24
48
a
All reactions were run on a 0.1 mmol scale of 5a in a screw capped
b
vial. Conversion and ratio based on 1H NMR analysis. Isolated
d
yields. Unidentified byproducts formed. PMB = p-methoxybenzyl.
c
c
10916 Chem. Commun., 2012, 48, 10916–10918
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Table 2 Scope of the regioselective hydroarylation process
Entry Ugi adduct 5
Pyrrolopyridinone 6 Pyrroloazepinone 7
1
2
3
4
Scheme 1 Plausible mechanism for the intramolecular regioselective
hydroarylation.
did not give any conversion. Interestingly upon heating at 50 1C
AgOTf gave 50% of 7a as the sole product in 24 h (Table 1,
entries 6–8). PtCl2 (5 mol%) did not show any conversion at rt,
while upon heating at 50 1C 100% conversion was obtained in
14 h with 7a being the major product in 82% isolated yield
(Table 1, entries 9 and 10). To check the influence of the
temperature on the selectivity, the reactions were carried out
at 35 1C, 80 1C and 120 1C with PtCl2, but no amelioration was
observed (Table 1, entries 11–13). No conversion could be
obtained when H2PtCl6ꢀ6H2O (5 mol%) was used at rt or
under heating (Table 1, entries 14 and 15). In the case of
cationic gold catalysis, a change of the solvent decreased the
yield while for the platinum catalyst the conversion was strongly
reduced (Table 1, entries 16–21). Diminishing the catalyst
loading to 2 mol% resulted in a decreased conversion in both
cases (Table 1, entries 22 and 23).
5
6
A plausible mechanism2,8,9 is depicted in Scheme 1. Coordination
of the metal with the alkyne in 5a generates intermediate A. In
the case of cationic gold the nucleophilic attack of the pyrrole
on the activated alkyne occurs in an exo-dig fashion generating
intermediate B. This is followed by a 1,2-shift to furnish inter-
mediate C, which upon deprotonation and protodeauration forms
pyrrolopyridinone 6a. When platinum is used, the nucleophilic
attack of the pyrrole on the activated alkyne occurs in an endo-dig
fashion generating intermediate B0. After 1,2-shift, deprotonation
and protodeplatination pyrroloazepinone 7a is formed.
7
8
Having optimized the conditions for this intramolecular
hydroarylation, diversely substituted Ugi-adducts 5b–i were
synthesized and subjected to the protocol. Mostly the exo-dig
cyclization proceeds smoothly when cationic gold was used
giving pyrrolopyridinones 6b–i in good yields. Various substituents
on the isonitrile, the amine, the alkyne and the pyrrole are well
tolerated (Table 2). A bulky substituent like a p-methoxyphenyl on
a
b
25% of 6b was formed. 30% of 6e was formed after 24 h and rest of
c
the starting 5e was recovered. Unidentified byproducts were formed.
d
e
f
20% of 6f was formed. 46% of 6g was formed. No product was
formed even after 48 h; only starting 5i was recovered.
c
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the alkyne or a thiophene fused with the pyrrole ring is also well
tolerated delivering 6e and 6h respectively. However, when
N-p-tolyl pyrrole was subjected to reaction conditions, the
corresponding pyrrolopyridinone 6f was obtained in a moderate
yield of 35%, probably due to steric factors. Surprisingly applica-
tion of a tosyl protected pyrrole did not affect the nucleophilicity
of the ring and 6i was obtained in 72% yield.
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Chem. Soc., 2005, 127, 15024; (h) G. Zhang, V. J. Catalano and
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N. K. Pahadi, I. D. Gridnev and Y. Yamamoto, J. Org. Chem., 2006,
71, 6204.
The same Ugi-adducts 5b–i were subjected to endo-dig
cyclization by reaction with catalytic PtCl2. Gratifyingly,
most of the reactions proceed well and the corresponding
pyrroloazepinones 7 were isolated in good yields (Table 2).
Upon using p-methoxyphenyl substituted alkyne, only 30% of
exo-dig cyclized product 6e could be observed after 24 h and
no endo-dig cyclized product formed. This could be rationalized
by the fact that exo-dig cyclization is sterically unaffected by the
p-methoxyphenyl group, while the endo-dig cyclization is
strongly hampered and hence no 7e could be formed. When
the thiophene fused pyrrole was used the corresponding tricyclic-
azepinone 7h was formed in 79% yield. Surprisingly, in contrast
to the exo-dig cyclization (6i) a tosyl protected pyrrole did not
undergo endo-dig cyclization.
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In summary, we have developed a diversity-oriented regio-
selective intramolecular hydroarylation for the synthesis of
pyrrolopyridinones and pyrroloazepinones employing gold(I)-
and platinum(II)-catalysis respectively. The method allows the
selective formation of 6 and 7 membered pyrrole fused hetero-
cycles from easily available starting materials employing mild
reaction conditions. The use of this strategy for different
heterocycles is under current investigation.
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Support was provided by the research fund of the KU
Leuven and the FWO (Fund for Scientific Research – Flanders
(Belgium)). AK is thankful to EMA2experts (Erasmus Mundus
Action 2, Lot 11 Asia: Experts) for providing a doctoral
exchange scholarship and DDV is thankful to EMECW, lot
13 (Erasmus Mundus External Cooperation Window, Lot-13)
for providing a doctoral scholarship. The authors thank Ir. B.
Demarsin for HRMS measurements.
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c
10918 Chem. Commun., 2012, 48, 10916–10918
This journal is The Royal Society of Chemistry 2012