Iodine-promoted oxidative amidation of terminal alkenes - Synthesis of α-ketoamides, benzothiazoles, and quinazolines

Article abstract of DOI:10.1002/ejoc.201403547

A novel metal-free strategy for oxidative amidation of terminal alkenes by using I₂/DMSO for the synthesis of α- ketoamides has been developed. Intriguingly, the use of tertbutylhydroperoxide (TBHP) as co-oxidant can facilitate the synthesis of α-ketoamides at room temperature without any solvent, thereby making it a green protocol. The reaction with primary amines can be easily achieved by using SeO₂ as an oxidizing agent. Besides, the scope of the method was also extended to the synthesis of benzothiazolines and quinazolines.

Full text of DOI:10.1002/ejoc.201403547

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403547
Iodine-Promoted Oxidative Amidation of Terminal Alkenes – Synthesis of
α-Ketoamides, Benzothiazoles, and Quinazolines[‡]
Ramesh Deshidi,[a] Shekaraiah Devari,[a] and Bhahwal Ali Shah*[a]
Keywords: Alkenes / Iodine / α-Ketoamides / Benzothiazoles / Quinazolines / Green chemistry
A novel metal-free strategy for oxidative amidation of ter-
minal alkenes by using I2/DMSO for the synthesis of α-
ketoamides has been developed. Intriguingly, the use of tert-
butylhydroperoxide (TBHP) as co-oxidant can facilitate the
synthesis of α-ketoamides at room temperature without any
solvent, thereby making it a green protocol. The reaction
with primary amines can be easily achieved by using SeO2
as an oxidizing agent. Besides, the scope of the method was
also extended to the synthesis of benzothiazolines and quin-
azolines.
Introduction
α-Ketoamides are attractive for organic chemists, be-
cause they are characteristically present in a wide range of
biologically active molecules ranging from immunosup-
pressive drugs like FK506, FKBP12, and rapamycin to hu-
man cytosolic phospholipase A2 (GIVAPL2) cyclotheon-
amide, androgen, and estrogen receptors.[1,2] Their scope
also expands into the synthesis of non-immunosuppressive
compounds like V-10367 and GVI-1046, sodium channel
blocker GW-356194, homoprotoberberines, α-diones, 11
cis- and trans-isomers of β-lactam, oxazolidin-4-ones, and
5-HT6 binding ligands. In addition, they are intermediates
for a broad range of functional group transformations.[3,4]
In the recent past, tremendous amount of work has gone
into the development of newer synthetic approaches, each
enabling greater scope in terms of coupling partners and
milder reaction conditions (Figure 1).[5,6]
In this regard, terminal monosubstituted alkenes are
ideal prospective starting materials for organic synthesis,
because they are manufactured on very large scales and can
be functionalized by a broad range of chemical transforma-
tions.[7] Thus, as a part of our continued studies,[8] we were
interested in expanding the scope of these alkenes for the
synthesis of α-ketoamides. Herein, we report a metal-free
oxidative amidation protocol for the synthesis of α-keto-
amides from a range of terminal alkenes and amines by
using iodine and DMSO, which acts both as a solvent and
an oxidant. Interestingly, the use of tert-butylhydroperoxide
Figure 1. Synthesis of α-ketoamides.
(TBHP) as a co-oxidant facilitates the reaction at room
temperature without use of any solvent, thereby making it
a green protocol. α-Ketoamides could easily be synthesized
from primary amines by using SeO2 as oxidant. The
method was also successfully utilized for the synthesis of
benzothiazoles and quinazolines.
Results and Discussion
Our study commenced with the reaction of styrene (1a)
and pyrrolidine (2a) in the presence of iodine (0.5 equiv.)
and DMSO as solvent at 80 °C. As expected the reaction
afforded the desired product 3a in 56% yield (Table 1 entry
1). The increase of iodine loading to 1 equiv. improved the
yield of 3a to 72% (Table 1 entry 2). Further increase of
iodine loading to 1.5 equiv. had no significant impact on
the outcome of the reaction (Table 1 entry 3). We also
probed the effect of temperature on the reaction; decreasing
the temperature to room temperature resulted in almost no
product formation in 12 h (Table 1 entry 4). Furthermore,
to establish the role of iodine we performed the reaction
[‡] IIIM Communication No. IIIM/1763/2015
[a] Academy of Scientific and Innovative Research (AcSIR);
Natural Product Microbes
CSIR – Indian Institute of Integrative Medicine
Canal Road, Jammu-Tawi 180001, India
E-mail: bashah@iiim.res.in
http://www.iiim.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403547.
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R. Deshidi, S. Devari, B. A. Shah
SHORT COMMUNICATION
with N-iodosuccinimide (NIS) and tetrabutylamonium iod- theless, the reaction with TBHP led to product formation
ide (TBAI), while there was no product formation with with all secondary amines at room temperature in compara-
NIS, TBAI gave the product in trace amounts. The feasibil- tively better yields (Scheme 1). Importantly, the reaction
ity of reaction in other solvents, namely DMF, THF, dichlo- with primary amines did not yield the desired product
romethane (DCM), and toluene was also explored, only to either by route I or by route II. With the reasonable as-
find that no product was formed in these solvents (Table 1 sumption that TBHP is a better co-oxidant than DMSO,
entry 7–10). Thus, the optimization studies showed that the outcome of the reaction suggests that product forma-
1 equiv. of iodine at 80 °C in DMSO was found to be the tion at room temperature is probably due to the greater oxi-
reaction conditions of choice.
dizing strength of TBHP as compared to DMSO.
Table 1. Optimization studies for the oxidative coupling of styrene
and pyrrolidine.[a]
Entry Solvent Promoter Equivalents Temperature [°C] Yield [%][b]
1
2
3
4
5
6
7
8
9
10
DMSO I2
DMSO I2
DMSO I2
DMSO I2
DMSO NIS
DMSO TBAI
0.5
1
1.5
1
1
1
1
1
1
1
80
80
80
r.t.
80
80
80
40
80
80
56
72
75
Ͼ 10
–
trace
–
–
DMF
THF
DCM
I2
I2
I2
–
–
Toluene I2
[a] Reactants: 1 (1 mmol), 2 (1.5 mmol), air, 6 h. [b] Isolated yields.
To determine whether terminal alkenes can be used in
efficient synthesis of various α-ketoamides, the scope of the
reaction with different styrenes and pyrrolidine under the
optimized conditions was investigated. The reaction with a
range of styrenes gave the corresponding products in good
yields (Scheme 1). The results showed that the styrenes with
electron-donating functions, that is, p-methyl-, 2,4-di-
methyl-, and p-methoxystyrene, gave the corresponding
products 3b, 3c, and 3d in 74, 73, and 76% yield, respec-
tively. The halogen-substituted styrenes, that is, o-chloro-
Scheme 1. Generality of the reaction in terms of alkenes and sec-
ondary amines for constructing various α-ketoamides.
A possible explanation for the formation of α-keto-
and p-bromostyrene gave the corresponding products 3e amides from styrenes and amines is shown in Scheme 2. For
and 3f in 64 and 68% yields, respectively. Also the reaction route I, the reaction possibly proceeds via α-iodoaceto-
with naphthyl styrene proceeded efficiently to give product phenone (B),[9] which subsequently undergoes Kornblum
3g in 66% yield, which showed that steric hindrance had oxidation to give 2-oxoaldehyde (2-OA, C) with the release
no impact on the outcome of the reaction. The reaction of HI. The HI, in the presence of DMSO, regenerates iod-
also efficiently led to the synthesis of a variety of α-keto- ine,[8] which activates the aldehyde group of C followed by
amides with secondary amines like piperidine, morpholine, subsequent attack of the amine to generate the iminium ion
N-methyl piperazine, N-Boc-piperazine, and N,N-diethyl- (D) as the active intermediate required for further progress
amine to give the corresponding products 3h, 3i, 3j, 3k, and of the reaction. As we know, DMSO can acts as an oxygen
3l in 69, 64, 62, 60, and 58% yield, respectively. The results donor;[9] therefore, the more electrophilic carbon center of
show that the reaction is versatile as well as mild enough to the iminium ion makes the substrate available for nucleo-
encompass acid-sensitive and heterocyclic functionalities. philic attack by DMSO, which, on elimination of water and
To gain further insights into the special features of iodine- dimethyl sulfide (DMS), results in the formation of prod-
catalyzed synthesis of α-ketoamides, we performed a reac- ucts. For route II, the TBHP is decomposed to a tert-
tion in the presence of a co-oxidant like TBHP. To our de- butoxyl and a hydroxy radical in the presence of I2. The
light, the reaction of styrene with pyrrolidine resulted in the hydroxy radical in turn attacks on styrene to give a
formation of product 3a in 80% yield. The special feature phenacyl radical (A), which undergoes further oxidation
of this reaction is that it operates at room temperature and and iodination in presence of I2/TBHP to give α-iodoaceto-
requires no solvent; this makes it a green protocol. Never- phenone (B),[10] followed by nucleophilic substitution with
2
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Iodine-Promoted Oxidative Amidation of Terminal Alkenes
Scheme 2. Plausible mechanism.
amine to generate intermediate (E).[11] Finally, intermediate with secondary amines.[12] Thus, we placed a reaction of
E is oxidized by TBHP to form the desired product 3a. styrene with aniline, using I2/SeO2 in DMSO at 80 °C, to
To further generalize the method and make it applicable afford the corresponding product in 66% yield. We further
to primary amines as well, we envisaged the use of SeO2, as extended this method to a variety of primary amines having
it is known to provide α-ketoamides with 2-OA, but only both electron-withdrawing and electron-donating functions.
Scheme 3. (I) Generality of the reaction in terms of alkenes and primary amines for constructing various α-ketoamides; (II) plausible
mechanism.
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R. Deshidi, S. Devari, B. A. Shah
SHORT COMMUNICATION
The reaction proceeded efficiently and gave the correspond- center of the imine and make the nucleophilic attack more
ing products in good yields (Scheme 3). Mechanistically the feasible. From our previous work,[8] we knew that using
reaction probably proceeds by formation of 2-OA (C), as TMSOTf in conjunction with iodine can enhance the
shown in Scheme 2. The iodine activates the aldehyde nucleophilicity of the iminium ion to such an extent that
group; this is followed by the attack of aniline to generate DMSO undergoes addition to iminium center. Thus, follow-
α-hydroxyacetophenone (F). Intermediate F subsequently ing this rationale, we used TMSOTf in combination with
generates intermediate G upon reaction with SeO2 to conse- iodine, and to our delight the reaction gave product 5a in
quently afford the desired α-ketoamide, 3m, with release of 61% yield. The reaction also efficiently gave the corre-
selanediol (Scheme 3).[12]
sponding products 5b–c with p-methyl- and 3,4-methylene-
Prior studies of the mechanism suggest that the reaction dioxystyrene in 65 and 71% yields. As mentioned earlier,
possibly proceeds through the formation of imine with in we also extended the reaction for the construction of quin-
situ generated 2-OA (Scheme 2). We reasoned that the reac- azolines, a motif commonly encountered in numerous
tion with 2-aminobenzothiol and 2-aminobenzamide may bioactive natural and synthetic compounds.[15] Therefore,
lead to the synthesis of benzothiazoles and quinazolines the reaction of styrene with commercially available 2-
(Scheme 4).[13] Thus, we started with the synthesis of benzo- aminobenzamide in the presence of TMSOTf/I2 resulted in
thiazoles, as they represent a class of heterocyclic com- the synthesis of 2-benzolylquinazoline 7a in 55% yield. The
pounds commonly encountered in a large number of natu- reaction with p-methyl- and naphthylstyrene also gave
ral products having biological and medicinal importance.[14] products 7b and 7c in 58 and 51% yields, respectively. It
Under optimized reaction conditions (Table 1 entry 2), the would be pertinent to mention here that the present method
reaction of styrene with 2-aminobenzothiol gave the prod- gives access to benzothiazoles and quinazolines without use
uct in poor yields and lot of side products. Approaching of a metal and oxidant.
the reaction mechanistically, we thought of using an acid
that is known to enhance the electrophilicity of the carbon
Conclusion
In summary, we have developed an efficient metal-free
strategy for the synthesis of α-ketoamides from terminal
alkenes both at high temperatures and at room temperature.
Furthermore, the method efficiently leads to the synthesis
of benzothiazoles and quinazolines without use of a metal
or oxidant. A simple experimental procedure, low catalyst
loading, the stoichiometric quantity of the reactants, and
the wide substrate scope are some of the advantages of the
process.
Experimental Section
Synthesis of α-Ketoamides Form Secondary Amines
Route I: Iodine (1 mmol) was added to a solution of styrene 1
(1 mmol) in DMSO (2 mL) followed by the addition of
2
(1.5 mmol). The reaction mixture was then heated at 80 °C for 6 h,
and the product formation was monitored by TLC. After comple-
tion of the reaction, the reaction mixture was extracted with ethyl
acetate (3ϫ 50 mL). The combined organic layers were washed
with brine, concentrated in a rotary evaporator, and purified by
column chromatography using ethyl acetate and hexane to afford
3a in 72% yield.
Route II: To prepare α-ketoamides from primary amines and
benzothiazoles/quinazolines, TBHP, SeO2 and TMSOTf were used
in addition (please see the Supporting Information for detailed pro-
cedures).
Acknowledgments
We thank the Department of Science and Technology (DST), New
Delhi for financial assistance. R. D. and S. D. thank the University
Grants Commission (UGC) and the Council of Scientific and In-
dustrial Research (CSIR), New Delhi for the award of Senior Re-
search Fellowships.
Scheme 4. (I) Synthesis of benzothiazoles and quinazolines; (II)
plausible mechanism.
4
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Iodine-Promoted Oxidative Amidation of Terminal Alkenes
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Received: November 30, 2014
Published Online: ᭿
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R. Deshidi, S. Devari, B. A. Shah
SHORT COMMUNICATION
Oxidative Amidation
R. Deshidi, S. Devari,
B. A. Shah* ....................................... 1–6
Iodine-Promoted Oxidative Amidation of
Terminal Alkenes – Synthesis of α-Keto-
amides, Benzothiazoles, and Quinazolines
Keywords: Alkenes
amides / Benzothiazoles / Quinazolines /
Green chemistry
/ Iodine / α-Keto-
A novel metal-free strategy for oxidative
amidation of terminal alkenes using I2/
DMSO for the synthesis of α-ketoamides
has been developed. Intriguingly, the use of
tert-butylhydroperoxide (TBHP) as co-
oxidant can facilitate the synthesis of α-
ketoamides at room temperature without
any solvent, whereas for reaction with pri-
mary amines SeO2 is required as oxidizing
agent.
6
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