Gold-catalysed cyclisation of N-propargylic β-enaminones to form 3-methylene-1-pyrroline derivatives

Article abstract of DOI:10.1039/c3ob42513d

A gold(i) catalysed reaction between N-propargylic β-enaminones and arynes was developed to access 3-methylene-1-pyrrolines. The title compounds were obtained in 57-78% yields. This reaction is useful for the generation of substituted 1-pyrrolines exhibiting significant molecular complexity. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ob42513d

Organic &
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Gold-catalysed cyclisation of N-propargylic
β-enaminones to form 3-methylene-1-pyrroline
Cite this: Org. Biomol. Chem., 2014,
12, 2869
derivatives†‡
Received 16th December 2013,
Accepted 13th February 2014
Kommuru Goutham,a,b N. S. V. M. Rao Mangina,a,b Surisetti Suresh,c
Pallepogu Raghavaiah§d and Galla V. Karunakar*a,b
DOI: 10.1039/c3ob42513d
www.rsc.org/obc
A gold(I) catalysed reaction between N-propargylic β-enaminones
and arynes was developed to access 3-methylene-1-pyrrolines.
The title compounds were obtained in 57–78% yields. This reaction
is useful for the generation of substituted 1-pyrrolines exhibiting
significant molecular complexity.
Heterocyclic molecules have received much attention in
organic synthesis.1 Among various heterocycles, nitrogen-con-
taining heterocycles are considered to be the most important.2
They are also useful in different applications in various fields
such as crop protection, human health care and functional
materials.3 1-Pyrrolines (3,4-dihydro-2H-pyrrolines) have
received considerable attention—they exhibit important roles
in several applications such as semiochemicals,4a flavouring
agents for various food products,4b natural products,4c alka-
loids,4d high-affinity radioligands,4e and therapeutic com-
pounds (Fig. 1).5
Fig. 1 Selected examples of important molecules containing 1-pyrro-
line core skeletons and their applications.
More significantly, 1-pyrrolines were used as building
blocks for the synthesis of several pharmaceutically active
molecules.6 For example 1-pyrrolines were used for the syn-
thesis of (i) β-lactam derivatives, which show inhibitory activity
against Mycobacterium tuberculosis,7 (ii) diarylpyrrolizine acetic
acid derivatives, which show anti-inflammatory and anti-
platelet activities,8 (iii) cyclic enaminone esters, which have
been investigated in mice for anticonvulsant activity,9 (iv)
fluoroquinolone analogs which have exhibited antibacterial
activity,10 and (v) pyrrolidino enaminone carboxylic derivatives
which were investigated for inhibition of the cyclooxygenase
enzyme.11
The search for versatile building blocks, new synthetic strat-
egies and the exploration of new methods to construct nitro-
gen heterocyclic compounds are limitless frontiers.
Enaminones are known as potential intermediates in synthetic
organic chemistry because they exhibit both nucleophilic char-
acter and electrophilic character exerted by the enamine and
the enone functional groups, respectively.12 We have under-
taken efforts to study the reactivity of N-propargylic β-enami-
nones 1, which are diversified chemical substrates with several
distinct functional groups such as alkyne, alkene, enamine,
enone, enaminone and propargylamine.
aCrop Protection Chemicals Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad, 500007, India. E-mail: gallavk@iict.res.in
bAcademy of Scientific and Innovative Research, New Delhi, 110001, India
cOrganic and Biomolecular Chemistry Division, CSIR-Indian Institute of
Chemical Technology, Hyderabad, 500007, India
As part of our current research program, we were driven to
investigate the reactivity of N-propargylic β-enaminones 1 with
alkynes. Despite their interesting structure, studies aimed
towards the synthetic applications of N-propargylic β-enami-
nones 1 have received much less attention.13 Recently, Ramto-
hul et al. reported that β-enaminone esters react with arynes to
produce the corresponding C-arylated β-enaminone derivatives.13c
dSchool of Chemistry, University of Hyderabad, Hyderabad, 500046, India
†Dedicated to Professor Mariappan Periasamy, on the occasion of his
60th birthday.
‡Electronic supplementary information (ESI) available. CCDC 932648. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob42513d
§Present Address: Department of Chemistry, Dr. Harisingh Gour University,
Sagar (M.P.), 470003, India.
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Table 1 Optimization of the reaction conditionsa
Tb
Time Yieldc
Entry Catalyst (mol%)
Solvent
(°C) (h)
(%)
Scheme 1 Strategies for the conversion of N-propargylic β-enaminone
1a to 1-pyrroline 3/3a via gold catalysis.
1
2
3
4
5
6
7
8
AuCl3/AgSbF6 (5/15)
No catalyst
AuCl3/AgSbF6 (5/15)
AuCl3/AgSbF6 (5/15)
AuCl3 (10)
AgBF4 (10)
CuI (10)
CH3CN
CH3CN
DMF
80
80
100
90
80
70
60
70
70
80
80
60
80
80
80
80
80
80
80
80
80
80
80
80
18
24
20
15
18
12
15
10
12
18
30
18
30
15
15
15
24
24
36
36
36
30
30
36
32
nr
nr
nr
16
nr
nr
57
26
nr
10
54
nr
32
78
48
53
nr
21
6
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Hashmi et al. have reported gold catalyzed formal 1,6-acyloxy
migrations utilizing suitably substituted homopropargylic
enaminones.14
Zn(OTf)2 (10)
9
Zn(OTf)2/AgBF4 (10/15)
Sm(OTf)3 (10)
Sc(OTf)3 (10)
Yb(OTf)3 (10)
Eu(OTf)3 (10)
AuClPEt3 (10)
AuClPEt3/AgSbF6(10/15)
AuClPEt3/Zn(OTf)2 (10/15) Toluene
AuClPEt3/Zn(OTf)2 (10/15) CH3CN
AgSbF6 (10)
AuClPEt3/AgSbF6 (5/7.5)
AuClPEt3/AgOTf (10/15)
AuClPPh3/AgOTf (10/15)
AuClPPh3/AgSbF6 (10/15)
AuClPPh3/AgBF4 (10/15)
IPrAuNTf2/AgOTf (10/15)
We envisaged the synthesis of 1-pyrroline 3 through gold
catalyzed15 cyclisation of 1a (Scheme 1a). Accordingly, we per-
formed a reaction to convert 1a to 2,4-dihydro pyrrole 3 in the
presence of AuCl3/AgSbF6 (10 : 15 mol%). However, this reac-
tion did not yield the desired product and instead N-pro-
pargylic β-enaminone 1a was recovered. We also performed a
few more reactions using AuClPEt3 and AuClPEt3/CsF for this
transformation. None of these reactions were successful. The
reasons may be attributed to the poor nucleophilicity of the
enaminone or the weak electrophilic character of the pro-
pargylic functionality under gold catalysis.
Hence we considered tuning the nucleophilicity of the
enaminone moiety or employing a reactive external alkyne sub-
strate like an aryne16 to enable the cyclisation, as depicted in
Scheme 1b. We then conducted experiments by reacting 1a
with benzyne, generated in situ by the reaction of 2-(trimethyl-
silyl)phenyl trifluoromethanesulfonate 2a (1 equiv.) and CsF
(3 equiv.), in the presence of the gold catalyst AuCl3/AgSbF6
(5/15 mol%). To our delight we have observed the formation of
3-methylene-3,4-dihydro-2H-pyrrole 3a in 32% yield (Table 1,
entry 1). The structure of product 3a was further confirmed by
X-ray crystal structure analysis (Fig. 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
19
8
5
17
a Reaction conditions: 1a (0.4 mmol), 2a (0.4 mmol), CsF (1.2 mmol),
solvent (3 mL); b Oil bath temperature. c Isolated yields; nr: no
reaction. All reactions were conducted under a nitrogen atmosphere.
It was revealed from X-ray crystal structure analysis that
mono substitution took place on the benzyne intermediate
and product 3a was formed with a quaternary stereocenter and
an exocyclic double bond.
With this result to hand, we have screened different cata-
lysts, catalyst combinations and reaction conditions to improve
the yield of 3a (Table 1). It is noteworthy that this trans-
formation did not occur in the absence of a catalyst (Table 1,
entry 2).
When the above reaction was performed in the presence of
Zn(OTf)2 and Yb(OTf)3, moderate yields of 3a (57% and 54%
respectively) were obtained (Table 1, entries 8 and 12). In
Fig. 2 ORTEP representation of 3-methylene-3,4-dihydro-2H-pyrrole
3a [CCDC 932648].
the case of AuClPEt3 only 32% of 3a was observed (Table 1, acetonitrile (Table 1, entries 16 and 17) that gave 3a in 48%
entry 14).
An impressive yield (78%) of 3a was obtained while utilizing
and 53% yields, respectively.
When the reaction was performed using only 10 mol% of
the combination of AuClPEt3 (10 mol%) and AgSbF6 (15 mol%) AgSbF6, the starting material remained intact (Table 1, entry
in CH3CN at 80 °C (Table 1, entry 15). Two experiments 18). This clearly indicates that AgSbF6 alone did not have any
were conducted utilizing AuClPEt3/Zn(OTf)2 in toluene and effect on this reaction.
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Table 2 Scope of the synthesis of 3-methylene-3,4-dihydro-2H-
pyrrolesa
Table 2 (Contd.)
Entry
9
Substrate
Product
Yield (%)
55
Entry
1
Substrate
Product
Yield (%)
78
a Reaction conditions: 1 (0.4 mmol), 2a (0.4 mmol), CsF (1.2 mmol),
CH3CN (3 mL); AuClPEt3/AgSbF6 (10/15 mol%); yields are for isolated
products. All of the reactions were carried out under a nitrogen
atmosphere.
2
3
4
5
58
66
67
64
We also conducted a reaction with 5 mol% of AuClPEt3 and
7.5 mol% of AgSbF6, in which only 21% of product 3a was iso-
lated (Table 1, entry 19). We screened the combinations of
AuClPPh3 with different silver catalysts such as AgOTf, AgSbF6
and AgBF4 for this transformation. However, only low yields of
product 3a were observed under these reaction conditions
(Table 1, entries 21–23). Another experiment was conducted
using a combination of IPrAuNTf2/AgOTf for this transform-
ation and 17% of product 3a was isolated (Table 1, entry 24).
Based on the best optimized reaction conditions (Table 1,
entry 15), the generality of this reaction and the scope of
the substrates were studied using different substituted
N-propargylic β-enaminones 1a–i with benzyne precursor 2a
(Table 2).
Electron withdrawing substituted N-propargylic β-enami-
nones like 1b reacted with 2a to yield 58% of product 3b.
When substrate 1d reacted with 2a, a 67% yield of product 3d
was isolated. N-Propargylic β-enaminones with electron donat-
ing groups like 1c, 1e, 1f and 1h reacted with 2a to give yields
of 66%, 64%, 67% and 72% of 3c, 3e, 3f and 3h, respectively.
Substrates with both electron withdrawing and electron donat-
ing groups like 1g and 1i reacted with 2a to give yields of 57%
and 55% of 3g and 3i, respectively. These results indicate that
the nucleophilicity of the enaminone has considerable effect
on the yield of the cyclisation product (Table 3).
When the reaction was performed with 1a and 1i with
benzyne precursor 2b, it gave 66% and 60% yields of 3j and
3k, respectively. Reaction of 1a and 1d with benzyne precursor
2c gave 64% and 68% yields of the inseparable mixtures of pro-
ducts 3l : 3l′ and 3m : 3m′, respectively. The 1H NMR spectral
data suggest that these mixtures were formed in a 1 : 1 ratio of
the m-Me and p-Me isomers.17
6
7
8
67
57
72
In conclusion, we have developed a straightforward one
pot synthesis of 3-methylene-1-pyrrolines with quaternary
stereocenters and exocyclic double bonds from the reaction of
N-propargylic β-enaminones and arynes under gold(I) catalysis.
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Acknowledgements
We thank CSIR-IICT for providing a start-up grant, the Depart-
ment of Science and Technology (DST) India for a Fast track
grant, and CSIR, New Delhi for financial support as part of XII
Five Year plan under title ORIGIN (CSC-0108). We also thank
Dr GS for his support. KG thanks CSIR, NSVMRM thanks UGC
for Junior Research Fellowship and also gives thanks to AcSIR.
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