Decarboxylative (4+1) Oxidative Annulation of Malonate Monoesters with 2-Vinylpyridine Derivatives

Article abstract of DOI:10.1002/adsc.201600506

A novel N-iodosuccinimide-mediated decarboxylative (4+1) oxidative annulation between 2-vinylpyridine derivatives and malonate monoesters was developed. It offers a new way to construct indolizine derivatives by utilizing malonate monoesters as a C₁unit. The alkyl 2,2-diiodoacetate was found to be the active reaction intermediate during the transformation. (Figure presented.).

Full text of DOI:10.1002/adsc.201600506

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DOI: 10.1002/adsc.201600506
Decarboxylative (4+1) Oxidative Annulation of Malonate
Monoesters with 2-Vinylpyridine Derivatives
Shan Tang,a Xinlong Gao,a and Aiwen Leia,b,*
a
College of Chemistry and Molecular Sciences, the Institute for Advanced Studies (IAS), Wuhan University, Wuhan
430072, Peopleꢀs Republic of China
Fax : (+86)-27-6875-4067; phone: (+86)-27-6875-4672; e-mail: aiwenlei@whu.edu.cn
National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, Peopleꢀs Republic of
b
China
Received: May 12, 2016; Revised: June 13, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600506.
Abstract: A novel N-iodosuccinimide-mediated de-
carboxylative (4+1) oxidative annulation between
2-vinylpyridine derivatives and malonate mono-
developed as powerful tools in the formation of
carbon-carbon and carbon-heteroatom bonds.[9] While
2
À
early studies focused on C(sp ) COOH functionaliza-
A
tion, recent attention has been paid to the decarboxy-
3
[10]
À
struct indolizine derivatives by utilizing malonate
monoesters as a C1 unit. The alkyl 2,2-diiodoacetate
was found to be the active reaction intermediate
during the transformation.
lative cross-coupling with C(sp ) COOH bonds.
Among these reports, the direct decarboxylative
cross-coupling of malonate monoester provided an ef-
fective approach to access synthetically useful a-sub-
stituted carboxylic compounds. In 2011, Liu and co-
workers developed a Pd-catalyzed decarboxylative
cross-coupling reaction for the synthesis of a-arylated
esters with malonate monoesters. Later on, Wan and
Keywords: C1 unit; decarbonylation; indolizines; N-
iodosuccinimide; oxidative annulation
co-workers utilized an iodine catalysis system for the
3
À
decarboxylative C(sp ) N coupling to access a-amino
esters.[10q] In this work, we would like to demonstrate
Heterocyclic compounds are among the most impor- that malonate monoesters could serve as a C1 unit for
tant structural motifs in numerous natural products, the synthesis of indolizines from 2-vinylpyridine de-
pharmaceuticals and materials.[1] Thus, continuous ef- rivatives through decarboxylative oxidative cross-cou-
forts have been devoted to their synthesis. The con- pling.
struction of five-membered nitrogen heterocycles is
2-Vinylpyridine (1a) and 3-ethoxy-3-oxopropanoic
among the most useful organic transformations. Gen- acid (2a) were chosen as model substrates to test the
erally, they were synthesized through the intramolecu- reaction conditions. Condition optimization is shown
lar (3+2) annulation with alkenes or alkynes.[2] Alter-
natively, intramolecular (4+1) annulation has recent-
ly been developed as a complementary method to the
former ones.[3] Carbon monoxide,[4] isocyanides,[5]
sulfur ylides[6] and diazo compounds[7] have been sub-
sequently utilized as one carbon units in (4+1) annu-
lation to construct five-membered nitrogen-containing
heterocycles (Scheme 1a). With a continuous interest
in oxidative annulation to synthesize five-membered
heterocycles,[8] we studied the (4+1) oxidative annu-
lation with malonate monoester and found that malo-
nate monoester could also serve as a C1 unit for the
synthesis of indolizines through the in situ formation
of
(Scheme 1b).
During the past decade, transition metal-catalyzed
decarboxylative cross-coupling reactions have been through (4+1) annulation.
an
alkyl
2,2-diiodoacetate
intermediate
Scheme 1. Synthesis of five-membered nitrogen heterocycles
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Table 1. Optimization of the reaction conditions.[a]
smoothly under the optimized conditions to afford
the corresponding products (Table 2, entries 2–4). Im-
portantly, benzylic, allylic and propargylic malonate
monoesters were all suitable in this transformation
and good to high yields were obtained under the stan-
dard conditions (Table 2, entries 5–7). To our delight,
when cyanoacetate was applied as substrate in this
transformation, the desired indolizine product could
be obtained in an excellent yield (Table 2, entry 8).
En- Oxidants
try
Base
Sol-
vent
Yield
[%][b]
1
2
3
4
5
6
7
8
9
3.5 equiv. I2
0.5 equiv. I2 +3 equiv. CHP
NaOAc MeCN n.d.
NaOAc MeCN 16
0.5 equiv. I2 +3 equiv. TBPB NaOAc MeCN n.d.
0.5 equiv I2 +3 equiv TBHP NaOAc MeCN 11
0.5 equiv. I2 +3 equiv. DTBP NaOAc MeCN 11
3.5 equiv. PhI(OAc)2
3.5 equiv NIS
Table 2. Substrate scope of the decarboxylative (4+1) oxi-
dative annulation of 1a with different malonate mono-
NaOAc MeCN n.d.
NaOAc MeCN 76
Na2CO3 MeCN 64
K3PO4 MeCN 67
esters.[a]
ACHTUNGTRENNUNG
3.5 equiv. NIS
3.5 equiv. NIS
10 3.5 equiv. NIS
11 3.5 equiv. NIS
11 3.5 equiv. NIS
13 3.5 equiv. NIS
14 3.5 equiv. NIS
15 3.5 equiv. NIS
16 2.5 equiv. NIS
17 1.5 equiv. NIS
Py
DBU
MeCN 37
MeCN 12
NaOAc DCE
NaOAc EtOAc 55
NaOAc PhCl 49
NaOAc DMSO 20
NaOAc MeCN 61
NaOAc MeCN 50
53
[a]
Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), oxi-
dants, base (0.60 mmol), solvent (2.0 mL), 1008C, 10 h.
CHP=cumene hydroperoxide, TBPB=tert-butyl peroxy-
benzoate, TBHP=tert-butyl hydroperoxide, DTBP=di-
tert-butyl peroxide, Py=pyridine, DBU=1,8-diazabicy-
clo[5.4.0]undec-7-ene, DCE=1,2-dichloroethane.
[b]
Yields are determined by GC analysis with biphenyl as
the internal standard. n.d.=not detected.
in Table 1. Without co-oxidants, molecular iodine (I2)
was unable to furnish the desired product (Table 1,
entry 1). Different peroxides were then added into
the reaction system and the decarboxylative oxidative
coupling product 3a was indeed observed when CHP,
TBHP and DTBP was applied (Table 1, entries 2–5).
However, these reactions proceeded in very low effi-
ciency by using the combination of I2 and co-oxidants.
Thus, oxidizing iodine reagents such as iodobenzene
diacetate and N-iodosuccinimide (NIS) were used in-
stead (Table 1, entries 6 and 7). Delightfully, NIS
showed a good result for the decarboxylative (4+1)
oxidative annulation reaction. Opimization of base
and solvent showed that NaOAc and MeCN were the
most suitable combination for this oxidative annula-
tion reaction (Table 1, entries 7–15). Moreover, at-
tempts on decreasing the amount of NIS in the reac-
tion were unsuccessful (Table 1, entries 16 and 17).
The formed indolizine product 3a was obtained in
74% isolated yield with 2a (Table 2, entry 1). To test
the applicability of this transformation, different mal-
onate monoesters were then applied in the synthesis
of indolizines. Various alkyl malonates reacted
[a]
[b]
Reaction conditions: The reactions were carried out with
1a (0.20 mmol), 2 (0.40 mmol), NIS (0.70 mmol), NaOAc
(0.60 mmol) in MeCN (2.0 mL) at 1008C for 10 h.
Isolated yields.
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To demonstrate the applicability of this methodolo- ing methyl or methoxy substituents gave the desired
gy, the substrate scope of the 2-vinylpyridine deriva- product in similar yields (Table 3, entries 3 and 4). Im-
tives was also explored. 2-(Prop-1-en-2-yl)pyridine portantly, halide substituents were well tolerated but
showed a good reactivity in this transformation, af- afforded the corresponding pyrrolo[1,2-a]quinolines
fording the desired product in a moderate yield in slightly decreased yields (Table 3, entries 5 and 6).
(Table 3, entry 1). Delightfully, 2-vinylquinoline was It was worthy of note that 2-vinylquinoxaline was also
also reactive in this (4+1) oxidative annulation reac- reactive in this transformation. It provided a novel
tion, which furnished a pyrrolo[1,2-a]quinolone ring strategy for the synthesis of substituted pyrrolo[1,2-
product 3j in a moderate yield (Table 3, entry 2). Af- a]quinoxaline (Table 3, entry 7).
terwards, the functional group tolerance was also ex-
To get some insight into the reaction mechanism,
plored for the synthesis of substituted pyrrolo[1,2- experiments for studying the reaction intermediates
a]quinolines. 2-Vinylquinoline bearing electron-donat- were conducted. In the presence of 2 equiv. of
NaOAc, the direct mixing of 3-ethoxy-3-oxopropanoic
acid with 2 equiv. of NIS at 1008C furnished ethyl 2,2-
Table 3. Substrate scope of the decarboxylative (4+1) oxi-
diiodoacetate (5) in 71% isolated yield (Scheme 2a).
dative annulation of 2-vinylpyridine derivatives with 2a.[a]
Only a trace amount of ethyl 2-iodoacetate (4) was
observed in the reaction mixture.[10q,11] Moreover, no
desired product could be observed when ethyl 2-io-
doacetate was applied to react with 2-vinylpyridine
(Scheme 2b). However, 2,2-diiodoacetates were able
to react with 2-vinylpyridine directly to afford indoli-
zine 3a in a good yield (Scheme 2c). To probe wheth-
er the reaction went through a radical reaction path-
way, radical inhibition experiments were carried out
by adding 1 equiv. of 2,2,6,6-tetramethylpiperidin-1-yl
oxyl (TEMPO) or butylated hydroxytoluene (BHT)
into the reaction system. Only trace amounts of the
oxidative annulation product could be observed in
both cases (Scheme 3).
Based on these experimental results and previous
reports,[8a,b] a plausible mechanism was put forward in
Scheme 4. In the first step, malonate monoester reacts
with NIS to generate ethyl 2,2-diiodoACTHNUGRTENUNGacetate with the
help of base. Then 2-vinylpyridine undergoes nucleo-
philic attack to the in situ generated ethyl 2,2-diiodoa-
[a]
[b]
Reaction conditions: 1 (0.20 mmol), 2a (0.40 mmol), NIS
(0.70 mmol), NaOAc (0.60 mmol) in MeCN (2.0 mL) at
1008C for 10 h.
Isolated yields.
Scheme 2. Study of the reaction intermediates.
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The tube was then charged with nitrogen. Acetonitrile
(MeCN, 2.0 mL) was injected into the tube via syringe. 3-
Ethoxy-3-oxopropanoic acid (2a, 0.40 mmol) and 2-vinylpyr-
idine (1a, 0.2 mmol) were subsequently injected into the re-
action tube. The reaction mixture was then stirred at 1008C
for 10 h. After completion, the reaction was quenched with
saturated NaHSO3 solution. Then the mixture was extracted
with diethyl ether (3ꢂ10 mL). The organic layers were com-
bined and dried over anhydrous Na2SO4. The pure product
was obtained by flash column chromatography on silica gel
(petroleum: ethyl acetate=20:1) as a colorless oil; yield:
28.0 mg (74%). 1H NMR (400 MHz, CDCl3): d=9.48–9.38
(m, 1H), 7.52 (d, J=4.5 Hz, 1H), 7.49 (d, J=8.9 Hz, 1H),
7.00 (ddd, J=8.8, 6.7, 1.0 Hz, 1H), 6.79 (td, J=7.0, 1.2 Hz,
1H), 6.47 (d, J=4.4 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 1.40
(t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=161.38,
138.02, 127.25, 121.60, 121.42, 118.78, 114.00, 112.56, 101.05,
59.68, 14.57.
Scheme 3. Radical inhibition experiments.
Acknowledgements
This work was supported by the 973 Program
(2012CB725302), the National Natural Science Foundation of
China (21390400, 21520102003, 21272180, 21302148), the
Hubei Province Natural Science Foundation of China
(2013CFA081), the Research Fund for the Doctoral Program
of Higher Education of China (20120141130002), and the
Ministry of Science and Technology of China
(2012YQ120060). The Program of Introducing Talents of
Discipline to Universities of China (111 Program) is also ap-
preciated.
Scheme 4. Proposed mechanism.
À
cetate to generate a pyridine cation. The C I bond of
this intermediate can undergo homolytic breaking to
generate a carbon radical. Subsequent intramolecular
radical addition to the C=C double bond generates
a dihydroindolizine radical. The dihydroindolizine
radical then couples with the in situ generated iodine
radical to afford an iodo-hydroindolizine. Subsequent
HI elimination and deprotonation of this intermediate
give the final product.[12]
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6 Decarboxylative (4+1) Oxidative Annulation of Malonate
Monoesters with 2-Vinylpyridine Derivatives
Adv. Synth. Catal. 2016, 358, 1 – 6
Shan Tang, Xinlong Gao, Aiwen Lei*
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