TBAI/TBHP-Promoted Generation of Malonyl Radicals: Oxidative Coupling with Styrenes Leads to γ-Keto Diesters

Article abstract of DOI:10.1002/asia.201800992

A metal-free protocol for oxidative coupling of malonic esters with styrenes to form γ-keto diesters has been developed. Key to the success of this process is the generation of malonyl radicals from unfunctionalized malonic esters under organo-catalysis conditions with TBAI and TBHP. This process tolerates both terminal and internal olefins with diverse malonic esters. It provides a new green metal-free alternative to traditional metal mediated process for generation of malonyl radicals and there by γ-keto diesters.

Full text of DOI:10.1002/asia.201800992

CHEMISTRY
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Accepted Article
Title: TBAI/TBHP-Promoted Generation of Malonyl Radicals: Oxidative
Coupling with Styrenes Leads to γ-Keto Diesters
Authors: Soumitra Maity, Soumyadeep Roy Chowdhury, and Injamam
Ul Hoque
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TBAI/TBHP-Promoted Generation of Malonyl Radicals: Oxidative
Coupling with Styrenes Leads to -Keto Diesters
Soumyadeep Roy Chowdhury, [a] Injamam Ul Hoque, [a] and Soumitra Maity*[a]
Dedication ((optional))
Abstract: A metal-free protocol for oxidative coupling of malonic
esters with styrenes to form -keto diesters has been developed. Key
to the success of this process is the generation of malonyl radicals
from unfunctionalized malonic esters under organo-catalysis
conditions with TBAI and TBHP. This process tolerates both terminal
and internal olefins with diverse malonic esters. It provides a new
green metal-free alternative to traditional metal mediated process for
generation of malonyl radicals and there by -keto diesters.
compounds[10h-j] have been quite known, reports showing similar
coupling with malonic esters are scarce. Only one example to
date is reported in the literature by Nair,[11] where CAN was used
to activate the malonate-C-H bond and to install the keto
functionality into styrene. Additionally, the reaction is not
chemoselective, often furnish overoxidation products[12] and
limited to terminal styrenes only. Therefore development of
efficient methods with broad substrate scope for this
transformation is needed.
Malonyl radicals are valuable reactive intermediates that can be
used as a starter in radical cascade reactions[1] to synthesize
complex molecules relevant to natural products, drug discovery
and material science.[2] In addition, malonyl radicals are widely
used in -lactone synthesis.[3] However their generation in mild
reaction conditions has been challenging. Traditionally, malonyl
radicals are generated from prefuctionalized halo- or seleno-
malonates under relatively harsh reaction conditions like, UV light
irradiation and/or by using very toxic alkyltin reagents (Scheme
1a).[2a, 4] Recently, visible light mediated photoredox catalysis has
enabled malonyl radical generation under mild conditions,
however these methods require expensive heavy metal
photocatalysts.[1e, 5] Direct generation of malonyl radicals from
malonic esters are rare[6] and often characterized by using
stoichiometric amount of metal salts like, Ceric ammonium nitrate
(CAN),[7] Manganese acetate[8] and iron perchlorate[3a, 3c] in acidic
medium (Scheme 1b). Moreover, these radical initiators often lack
the chemoselectivity and functional group compatibility. To
explore the high synthetic value of malonyl radicals, a new
synthetic method is highly desirable that extends beyond the
existing route to access them.
Scheme 1. a, b) Generation of malonyl radicals. c) Metal free generation of
malonyl radicals and coupling with styrenes.
In the past decade, various synthetic methods have been
developed that utilize metal-free organo-iodides as a replacement
of metal catalysts to drive organic reactions in enviro-economic
conditions.[13] Along these lines, tetrabutylammonium iodide
(TBAI) in combination with tert-butyl hydroperoxide (TBHP) have
been used as a unique oxidation system to generate C-centre
radicals, where in situ generated tBuOO• radical served as the key
intermediate.[14] Herein, we report for the first time, TBAI/TBHP
mediated coupling of styrenes with unfunctionalized malonic
esters to give -keto diesters through oxidative generation of
malonyl radical in the absence of metal with broad substrate
scope (Scheme 1c). From the synthetic stand point, current
method is simple and unique to generate malonyl radicals and
their subsequent addition to olefins leading to a C-C single bond
and a C=O double bond in excellent regioselectivity.
-keto diesters themselves are important molecules in the
chemical, biochemical, and material sciences.[9] Conventional
routes to this class of molecules include the nucleophilic
substitution of malonate to -halogenated ketones.[9] Alternatively,
oxidative radical difunctionalization of cheap and readily available
alkenes[10] with simple malonates might provide a better route to
access them. While difunctionalization of styrenes with -
10g]
cyanoesters[10c]
,
-ketoesters[10d,
and 1,3-dicarbonyl
[a]
Soumyadeep Roy Chowdhury, Injamam Ul Hoque, Dr. Soumitra
Maity
We initially investigated the coupling reaction with 4-tert-butyl
styrene (1a) and dimethyl malonate (DMM) (2a) as the model
substrates (Table 1).[15] In the presence of TBAI, TBHP and
triethyl amine, the desired product -keto diester 3a was isolated
Department of Applied Chemistry
Indian Institute of Technology (ISM) Dhanbad
Dhanbad 826004, JH, India
E-mail:smaity@iitism.ac.in
o
in 15% yield within 3h at 120 C (entry 1). To improve the yield,
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
several other bases, including organic and inorganic, were
examined (entries 25).
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Table 1. Optimization of the reaction conditions. [a]
keto diesters in moderate to good yields. Styrenes having
electron-withdrawing substituents such as halogens (-F, -Cl, and
-Br) at the para-position afforded the desired products (3ce) in
good yields. However, when strong electron-withdrawing 4-
nitrostyrene (3f) was used as substrate, no desired product was
formed.
Entry
Catalyst
Oxidant[e]
base
Solvent
Yield (%) [b]
Scheme 2. Scope of styrenes [a]
1
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAB
I2
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
BPO
Et3N
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
15
20
7
2
3
Py
4
K2CO3
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
-
0
5
65
0
6
7
0
8
K2S2O8
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
-
0
9
trace
0
10
11
12
13
14
15[c]
16
17
18
19[d]
TBAI
TBAI
TBAI
TBAI
TBAI
-
30
20
0
THF
DMF
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
0
68
0
TBAI
TBAI
TBAI
0
TBHP
TBHP
0
TMEDA
5
[a] Unless otherwise noted, all reactions were carried out with: 1a (0.4 mmol),
2a (0.2 mmol), catalyst (20 mol%), oxidant (3.0 equiv), base (3.0 equiv) and
solvent (2 mL) in a pressure tube at 120 oC for 3 h under N2. [b] Isolated yield.
[c] 4Å Molecular sieves, dust (2 wt %). [d] in air. [e] TBHP 5.5 M in decane.
[a] Conditions: 1 (0.4 mmol), 2a (0.2 mmol), TBAI (20 mol%), TBHP (3.0 equiv),
TMEDA (3.0 equiv), 4Å Molecular sieves (2 wt %) and degassed CH3CN (2 mL)
in a pressure tube at 120 oC for 3 h under N2.
Gratifyingly, switching the organic base to TMEDA enhanced the
reaction efficiency to furnish 3a in 65% yield, but other bases,
particularly inorganic bases were completely ineffective.[16]
Subsequently, we examined the oxidants, finding that TBHP only
exhibited the requisite activity among other peroxides (entry 5 vs
entries 68). Further optimization by changing promoter and
Other halo-styrenes with substitution at the meta-position also
afforded the desired products (3gh). Styrenes having electron-
donating substituents such as -CH3 (3i and 3j) were also tolerated
under the reaction conditions. Unfortunately, when ortho-
substituted styrene (3k) or more congested 2-vinylmesitylene was
used as a substrate in the reaction, the yield was drastically
solvent did not improve the yield of 3a (entries 914). Interestingly, reduced to trace or even nil. We speculated that steric effect was
when 4Å molecular sieves were employed as the additive, a
decent 68% yield was observed (entry 15). Control studies
showed that the catalyst, oxidant, and base were all essential for
this transformation (entries 1618). The yield of 3a diminished
sharply when the reaction was performed in air, implying the
detrimental effect of aerial oxygen in this reaction (entry 19).
Additional optimization by changing reaction temperature and
reactants ratio didn’t add any improvement in yield (entries 18-21
and 26, Table S1).15
one of the crucial factor to this reaction. Interestingly, bulky 1-
vinylnaphthalene poses no difficulty and gave the desired product
3l, albeit lower yield. Moreover, the conjugated diene, 1-phenyl-
1,3-butadiene participated in the coupling, which occurred
regioselectively at the terminal double bond to provide -keto
diesters 3m. To test the positional compatibility of the styrene, we
applied the protocol to internal olefins which are a part of acyclic
or cyclic systems. Reaction with internal vinylarenes afforded -
keto diesters 3np in moderate yield, demonstrating the
compatibility of this oxidative coupling protocol with terminal as
well as internal styrenes. But the poor productivity of internal
olefins (3np) compared to the terminal one (3n vs 3i, 3o vs 3c)
With suitable conditions in hand, the substrate scope of the metal-
free coupling reaction was investigated. As shown in Scheme 2,
the transformation generally proceeded to produce the desired -
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could be due to steric reason. Unfortunately, no reaction occurred
when aliphatic alkenes were employed as the substrate in the
above transformation.
potential use of malonic esters as alkylacetate coupling
partners.[20]
In order to gain preliminary insights into the reaction mechanism,
few mechanistic studies were designed and performed (Scheme
5). When the reaction of 4-tert-butyl styrene 1a with dimethyl
malonate 2a was carried out under standard condition (Table 1,
entry 15) in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO, 2 equiv), the formation of 3a was completely inhibited.
Subsequently, the TEMPO-adduct 8 was detected by the GC/MS
analysis of the crude product (Scheme 5A), implying the
involvement of a carbon radical intermediate. To further validate
this radical intermediate, the radical clock experiment was
performed (Scheme 5B). It was found that the reaction of -
cyclopropyl-4-chlorostyrene 9 with DMM
Next, we focused on the scope of malonic esters. As exemplified
in Scheme 3, a range of structurally diverse malonates were
readily implementable with substituted styrenes to provide their
corresponding products (4aj) in moderate to good yields.
Importantly, -keto diester 4i, a product of mixed malonate, is
synthetically highly useful for chemoselective functionalization of
the ester groups.[17] In addition, sterically crowded tertiary
malonate (4j) was also successful in this protocol, allowing direct
access to desired product having a - quaternary carbonyl
substitution. Unfortunately, no product was formed when other
carbonyl compounds, such as ethyl acetoacetate, ethyl
cyanoacetate and acetylacetone were employed as substrate.
Scheme 3. Scope of malonic esters. [a]
Scheme 5. Mechanistic studies.
[a] Conditions: 1 (0.4 mmol), 2 (0.2 mmol), TBAI (20 mol%), TBHP (3.0 equiv),
TMEDA (3.0 equiv), 4Å Molecular sieves (2 wt %) and degassed CH3CN (2 mL)
in a pressure tube at 120 oC for 3 h under N2.
under
standard
reaction
conditions
provided
To further showcase the utility of the present oxidative-coupling
process, some valuable synthetic transformations were executed
using 3e (Scheme 4). Reduction of 3e with NaBH4 provided -
lactone 5 in excellent yield.[9e] When 3e was treated with
dehydronaphthalene 10, resulted from the ring-opening
cyclization of cyclopropylmethyl radical I at the phenyl ring.[21]
This reveals strong support for the participation of the manonyl
radical in this transformation. As the reaction inhibited under
aerobic conditions (Table 1, entry 19), suggesting the source
of keto-oxygen in the -keto diester is from the reagents. To
confirm this, a controlled reaction of -methylstyrene 11 with
2a was carried out under standard conditions with an idea to
interrupt the oxidative conversion to end keto product (Scheme
5C). As expected the -peroxydiester 12 was isolated in 34%
yield, confirming the dual roles of TBHP as the terminal oxidant
and source of the keto-oxygen incorporated into the product.
The present investigations coupled with the previous
e-f]
reports[10a,
collectively suggest a plausible reaction
mechanism as shown in Scheme 6. Initially, the catalytic cycle
of TBAI/TBHP promotes the decomposition of TBHP to tert-
butoxyl and/or tert-butylperoxyl radicals which abstract the -
H atom of malonic ester 2 to generate the malonyl radical 13.
Addition of the malonyl radical to the double bond of styrene
afforded a transient radical 14, which selectively couples with
tBuOO• (Ingold-Fischer “Persistent Radical Effect”[22]), to
generate peroxide intermediate 15. Meanwhile, the oxidation
of radical 14 followed by trapping of a benzylic carbocation by
TBHP under basic conditions to dialkylperoxide 15 could not
Scheme 4. Diversification of 3e.
hydrazine, imino-amidation followed by decarboxylative
cyclization afforded dihydropyridazinone 6. These scaffolds are of
great importance in medicinal chemistry but are challenging to
access synthetically.[18] Dealkoxycarbonylation[19] of malonate
ester 3e converted to -keto ester 7, which further expand the
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10.1002/asia.201800992
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be excluded. Finally, 15 in presence of base is converted
(Kornblum-DeLaMare rearrangement[23]) into the -keto diester
16. The beneficiary role of molecular sieves may scavenge the
water, which have been formed in TBAI/TBHP catalytic cycle.
Panjab University, CIF-BIT, Mesra and CSS-IACS, Kolkata for
providing NMR facilities.
Keywords: malonyl radical • oxidative coupling • ketodiester •
metal-free conditions • TBAI/TBHP
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Scheme 6. Plausible reaction mechanism.
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In conclusion, a simple and efficient approach to the
synthesis of -keto diester via oxidative coupling of styrenes
with malonic esters has been developed. A catalytic amount
of cost-effective TBAI in combination with TBHP efficiently
coupled a variety of malonic esters with styrenes in
moderate to good yields. The present coupling was
characterised by use of metal-free catalyst with excellent
levels of regioselectivity, particularly for internal and
conjugated styrenes. The utility of this -keto diester is
further showcased by its transformation to other
heterocyclic derivatives. Mechanistic studies supported
evidence for a radical mechanism with a facile Kornblum-
DeLaMare rearrangement.
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General procedure for metal free coupling of malonic esters with
styrenes: To an oven dried pressure tube equipped with a stir bar were
added 0.04 mmol of TBAI, 0.2 mmol of malonic ester 2, 0.4 mmol of
styrene 1, 0.6 mmol of TMEDA and 1 mL of dry degassed acetonitrile
solvent. The mixture was stirring for a while followed by the addition of 0.6
mmol of TBHP (5.5 M in decane), 4Å MS (2 wt %) and another 1 ml of dry
degassed acetonitrile. Then the mixture was purged with nitrogen for a few
minutes, capped with a teflon screw cap and heated at 120 oC for 3 h. After
the reaction was completed as shown by TLC, the mixture was cooled to
room temperature, quenched with Na2S2O3 and diluted with ethyl acetate.
The organic layer was separated and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were dried over Na2SO4,
filtered and concentrated under vacuum. The residue was purified by silica
gel column chromatography to afford the corresponding -keto diesters 3-
4.
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Acknowledgements
We are grateful to DST-INSPIRE (IFA 13-CH-90), SERB
(ECR/2016/000270) and IIT(ISM) for financial support. SRC & IH
thank IIT(ISM) Dhanbad and DST-INSPIRE for their research
fellowships respectively. The authors also acknowledge SAIF-
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Chemistry - An Asian Journal
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10.1002/asia.201800992
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Soumyadeep Roy Chowdhury, Injamam
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TBAI/TBHP-Promoted Generation of
Malonyl Radicals: Oxidative Coupling
with Styrenes Leads to Keto
Diesters
Metal-Free Malonyl: A Metal-free approach to the synthesis of -keto diester via
oxidative radical coupling of styrenes with malonic esters has been developed. Key
to the success of this process is the generation of malonyl radicals from malonic
esters under organo-catalysis conditions with TBAI and TBHP.
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