Pd(II)-catalyzed intramolecular oxidative Heck dearomative reaction: Approach to thiazole-fused pyrrolidinones with a C2-azaquarternary center

Article abstract of DOI:10.1039/c5ob01970b

A Pd(ii)-catalyzed intramolecular oxidative Heck dearomative reaction for the construction of thiazole-fused pyrrolidinones with a C2-azaquarternary center and C3-exo-double bond has been achieved for the first time. The reaction exhibited good functional group tolerance and gram-scale capacity.

Full text of DOI:10.1039/c5ob01970b

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DOI: 10.1039/C5OB01970B
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Pd(II)-Catalyzed Intramolecular Oxidative Heck Dearomative
Reaction: Approach to Thiazloes Fused Pyrrolidinones with a C2-
Azaquarternary Center
Received 00th January 20xx,
Accepted 00th January 20xx
Shang Gaoa, Chi Yanga, Yue Huanga, Lei Zhaoa, Xiaoming Wua, Hequan Yaoa* and Aijun Lina*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Pd(II)-catalyzed intramolecular oxidative Heck dearomative
reaction to the construction of thiazloes fused pyrrolidinones with
a C2-azaquarternary center and C3 exo-double bond has been
achieved for the first time. The reaction exhibited good functional
group tolerance and gram-scale capacity.
As one of the most important transitional metal catalyzed
reactions, oxidative Heck reaction has drawn widely interests
since 1970s.1 Intermolecular oxidative Heck reaction2 was
applied to construct a variety of compounds containing
carbon-carbon double bond,3 while the intramolecular variant
was frequently utilized to the construction of sundry cyclic
structures.4 On the other hand, as a powerful method for the
construction of fused or spiro polycycles structures,
transitional metal catalyzed dearomative reaction has been
invested popularly.5 Combining oxidative Heck reaction and
dearomative reaction together could deliver interesting and
complex ring motifs more efficiently.
In 2011, Greaney and coworkers reported an intramolecular
oxidative C-H coupling reaction of C3-substituted indoles and
heteroarenes for medium-ring synthesis [eqn (1)].6 Electron-
withdrawing groups in C3 position were necessary to ensure
the transformations. In 2012, we reported an approach to the
construction of isoindolinones fused indolines with a newly
formed C2-azaquarternary center and C3-exo double bond via
intramolecular Heck reaction7 and dearomative process [eqn
(2)]. Recently, Jia’s group reported Pd-catalyzed intramolecular
asymmetric reductive Heck reaction to construct
isoindolinones fused indolines with a chiral C2-azaquarternary
center [eqn (3)].8 Lautens’s group developed the first Pd-
catalyzed indole bisfunctionalization via a diastereoselective
arylcyanation [eqn (4)].9 As is well-known, both thiazole
moieties,10 indoline moieties and pyrrolidinones are prevalent
scaffolds found in numerous natural products11 and
pharmacophores,12 many of them possess remarkable
bioactivities. In continuation of our persistent focus on the
oxidative Heck reaction and heterocyclic chemistry, herein, we
reported our work on Pd(II)-catalyzed intramolecular oxidative
Heck dearomative reaction, leading to the formation of
thiazoles fused pyrrolidinones with a C2-azaquarternary center
and C3-exo double bond [eqn (5)].
Our initial investigation focused on the intramolecular
oxidative Heck reaction of N-(2-phenylthiazole-4-carbonyl)-2,3-
dimethylindole (1a) as summarized in Table 1. At the outset,
we probed the representative protocol for oxidative Heck
a.State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal
Chemistry, School of Pharmacy China Pharmaceutical University, Nanjing, 210009
(P. R. China)
E-mail: ajlin@cpu.edu.cn. hyao@cpu.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Organic & Bioorganic Chemistry
Table 2. Substrate scope a, b
Table 1. Screening of reaction conditionsa
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DOI: 10.1039/C5OB01970B
Entry
Catalyst
Oxidant
Solvent
Yield (%)b
(10 mol %)
(2 equiv)
(2 mL)
(2a/3)
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Ag2CO3
AgOAc
Ag2O
DMF
DMF
41/24
55/21
5/60
3
DMF
4
Cu(OAc)2
p-BQ
DMF
20/0
5
DMF
5/0
6
K2S2O8
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
DMF
0/0
7c
8d
9
DMF
53/21
55/20
70/6
DMF
CH3CN
10
11
12
13
14
15
16
17
18
19
1,4-dioxane
32/10
31/24
0/0
toluene
tBuOH
NMP
55/0
DMSO
14/75
77/8
CH3CN/DMSOe
CH3CN/DMSOe
CH3CN/DMSOe
CH3CN/DMSOe
CH3CN/DMSOf
40/4
Pd(TFA)2
PdCl2(CH3CN)2
Pd(OAc)2
60/32
67/30
86(84g) /7
a Reaction conditions: 1a (0.5 mmol), catalyst (10 mol %), oxidant in solvent (2 mL)
at 130 oC for 15 h under air. b 1H NMR yields using dibromomethane (δ = 4.80) as
c
d
e
an internal standard. 140 oC. PivOH (2 equiv) was used. CH3CN/DMSO (1.98
mL / 0.02 mL). f CH3CN/DMSO (3.96 mL / 0.04 mL). g Isolated yields.
reaction with Pd(OAc)2 as catalyst and Ag2CO3 as oxidant in
o
DMF at 130 C for 15 h, offering the corresponding product 2a
in 41% yield with a homocoupling byproduct
3 in 24% yield
(entry 1). The characteristic peaks at 5.20 and 5.63 ppm in the
1H NMR spectrum and 72.5 ppm in the 13C NMR spectrum of
compound 2a should be assigned as the two hydrogens of the
terminal double bond and azaquarternary carbon respectively,
which indicated the formation of C3-exo double bonds and the
C2-azaquarternary center.13 A screen of oxidants revealed
AgOAc to be ideal, providing 2a in 55% yield (entry 2). The use
of Ag2O or other oxidants, such as p-BQ, Cu(OAc)2 or K2S2O8
failed to afford the desired product 2a in ideal yields (entries
3-6). Unexpectedly, neither higher temperature nor using the
PivOH as an additive could enhance the yield of 2a (entries 7-
8). Solvents screening (entries 10-14) indicated that the yield
of 2a could be improved to 70% when CH3CN was used as the
solvent (entry 9). It was noteworthy that most of 1a was
a
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (10 mol %), AgOAc (1 mmol) in
converted to 2a
/3
when DMSO was used as the solvent (entry CH3CN/DMSO (3.96 mL / 0.04 mL) at 130 oC under air for 15 h. b Isolated Yields. c
The yield was determined by 1H NMR with dibromomethane as internal standard.
14). This result suggested that DMSO might play a vital role in
stabilizing the Pd(0) intermediate by inhibiting its aggregation
into Pd(0) black and promoting the reoxidation of Pd(0) to
Pd(II) by oxidants to process the catalytic cycle.14 And we were
pleased to see that the yield of 2a was further improved to 77%
using CH3CN and DMSO as the co-solvent. Screening the ratios
of CH3CN/DMSO15 revealed that ideal yield could be obtained
when the ratio was set to 99:1 (v/v) (entry 15). Replacing
d 50% starting material (1m) was recovered. e The Z/E ratio was determined by 1H
NMR. f The Z/E ratio was determined according to the isolated yields. g 20 mol %
Cy3P was added. h No reaction and 90% substrate was recovered.
Pd(OAc)2 with other palladium catalysts such as PdCl2,
Pd(TFA)2 and PdCl2(CH3CN)2 offered 2a in lower yields (entries
2 | J. Name., 2012, 00, 1-3
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16-18). When the concentration was reduced to 0.125 M, 2a
could be obtained in 84% isolated yield (entry 19).
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DOI: 10.1039/C5OB01970B
Scheme 1. The large scale experiment
With the optimized catalytic system in hand, we then
embarked on the investigation of the substrate scope. Firstly,
we explored the effect of substituents on the benzene ring of
the indole part as shown in Table 2. To our delight, for
substrates containing various electron-donating groups, such
as methyl, ethyl, n-butyl and methoxyl, the reactions
proceeded well under the optimized reaction conditions and
afforded the desired products 2b-2e in good yields from 70%
to 82%. The substrates bearing electron-withdrawing groups, Scheme 2. Proposed reaction mechanism for intramolecular
such as fluoro and trifluoromethyl afforded 2f and 2i in 78%
and 50% yields. The substrates with chloro or bromo group
reacted smoothly to give 2g in 59% yield and 2h in 45% yield.
Then, we investigated the substituent effect at the C2- and C3-
position of indole derivatives. The substrates bearing ethyl
group at the C2-position afforded 2j in 77% yield and N-acyl
tetrahydrocarbazole gave the pentacyclic compound 2k in 56%
yield. Indole with phenyl at C2 position delivered the oxidative
Heck dearomative product 2l in 29% yield with some
intramolecular cross dehydronative coupling byproduct and
oxidative Heck dearomative process
homocoupling byproduct.16 When N-acyl 2-methyl indole (1m
,
R2 = H) was used, an oxidative Heck product 2m was obtained
in 19% yield. When C3 position was substituted with isopropyl,
2n was obtained in 67% yield. The substrates with ethyl or
benzyl on C3 position offered 2o in 82% yield (Z/E = 1.3:1) and
2p in 68% yield (Z/E = 1.1:1), respectively. The reaction
In conclusion, we have developed the first palladium
conditions were next applied to substrates with various catalyzed intramolecular oxidative Heck dearomative reaction
substituted thiazole core. The substrates with electron- for the synthesis of thiazoles fused pyrrolidinones with an C2
donating groups on the benzene ring of the thiazole afforded azaquarternary center and C3 exo-double bond in moderate to
2q
or halogen groups such as fluoro, chloro and trifluoromethyl tolerance and gram-scale capacity. Research on the detailed
gave the corresponding products 2t 2u and 2v in 62%, 74% reaction mechanism and extension to other heteroaromatic
and 68% yields with some incomplete consumption starting substrates are currently undergoing in our laboratory.
materials recovered. The substrate bearing a methyl group at
Generous financial support from the National Natural
-2s in 68%-73% yields. The ones with electron-withdrawing good yields. The reaction exhibited good functional group
,
the C2 position of the thiazole provided 2w in 50% yield Science Foundation of China (NSFC21572272 and
accompany with partially homocoupling product produced. NSFC21502232), the Natural Science Foundation of Jiangsu
Replacement of the thizaole group with the thiophene group Province (BK20140655 and BK20130645) and the Foundation
led to the cyclization product 4 in 20% yield with large number of State Key Laboratory of Natural Medicines (ZZJQ201306) is
of starting material recovered. The oxazole substrate could not gratefully acknowledged.
offer the intramolecular oxidative Heck product
optimized conditions.
5 under the
To test the practicality of our reaction, a gram-scale
evaluation was carried out (Scheme 1). The intramolecular
oxidative Heck dearomative reaction of 1e in a 6.0 mmol scale
gave the desired product 2e (1.55 g) in 72% yield under
standard condition. Compound 2e could also be obtained in
1.16 g (54% yield) with 5 mol % Pd(OAc)2 as the catalyst by
prolonging the reaction time to 24 h.
Notes and references
1
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,
On the basis of previous reports,17 a plausible catalytic cycle
was proposed as outlined in Scheme 2. Firstly, palladation of
634-642. For selected examples on oxidative Heck reaction,
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J.-Q. Yu, Nature 2012, 486, 518-522; (i) L. Meng, C. Liu, W.
the thiazole at C5 position formed palladium intermediate A,
which was followed by intramolecular coordination of the
palladium center to the olefin of the indole and migratory
insertion provided intermediate
B. Since no hydrogen existed
on the C2 position of intermediate
B
, the desired product 2a
Zhang, C. Zhou and A. Lei, Chem. Commun. 2014, 50, 1110; (j)
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was generated through β-H elimination of the C3 methyl group.
Finally, Pd(0) was reoxidized by Ag(I) in the reaction system to
give Pd(II) to complete the catalytic cycle. Intermediate
A
2
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could also couple with another molecule 1a through C-H bond
activation at C5 of thiazole ring and following reductive
elimination gave the homocoupling byproduct 3 17
.
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13 See Supporting Information for H NMR and 13C NMR spectra
of 2a
.
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15 See Table S1 in the Supporting Information for details.
16 Although we tried various methods, such as preparative high
performance liquid chromatography and recrystallization,
the compound 2l was inseparable with the intramolecular
1
cross dehydrogenative coupling byproduct. The H NMR and
13
NMR spectra of 2l was the mixture of 2l and the
dehydrogenative coupling byproduct with the ratio of 5:1.
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