Organoselenium and DMAP co-catalysis: Regioselective synthesis of medium-sized halolactones and bromooxepanes from unactivated alkenes

Article abstract of DOI:10.1039/c5cc10245f

A catalytic system consisting of bis(4-methoxyphenyl)selenide and 4-(dimethylamino)pyridine (DMAP) has been developed for the regioselective synthesis of medium-sized bromo/iodo lactones and bromooxepanes possessing high transannular strain. ⁷⁷Se NMR, mass spectrometry and theoretical studies reveal that the reaction proceeds via a quaternary selenium intermediate.

Full text of DOI:10.1039/c5cc10245f

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DOI: 10.1039/C5CC10245F
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Organoselenium and DMAP Co-Catalysis: Regioselective Synthesis
of Medium-Sized Halolactones and Bromooxepanes from
Unactivated Alkenes†
Received 00th January 20xx,
Accepted 00th January 20xx
Ajay Verma,a Sadhan Jana,a Ch. Durga Prasad,a Abhimanyu Yadav,a and Sangit Kumara*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A catalytic system consisting of bis(4-methoxyphenyl)selenide and increases the enthalpy of activation in the formation of
4-(dimethylamino)pyridine (DMAP) has been developed for the medium-sized lactones.8 High thermodynamic barrier
regioselective synthesis of medium-sized bromo/iodo lactones diminishes the formation of seven to nine-membered lactones
and bromooxepanes possessing high transannular strain. 77Se by 104 to 106 times than that of six-membered analogues.8b,12a
NMR, mass spectrometry and theoretical studies reveal that the Synthesis of medium-sized lactones has been achieved under
dilution conditions, slow addition of reagents,9 using TM-
catalysts,10 and bifunctional substrates.11 Rousseau et al.
described the synthesis of iodolactones and iodooxepanes
reaction proceeds via quaternary selenium intermediate.
The applications of organoselenium reagents in the synthetic
chemistry have been well-established, and being explored for
various transformations.1 Organoseleniums used as efficient
catalysts for the oxidation, and electrophilic halogenation
reactions of alkenes,2,3 as selenium enhances the electrophilic
nature of halogen.3e
Medium-sized lactones have attracted considerable interest to
the researchers because of their difficulty in preparation,
interesting biological activities and structural diversity.4 In
contrast to the synthesis of five and six membered
halolactones,5 synthetic protocols for the medium-sized
halolactones, and oxepanes are rare, despite their potential
applications in the synthesis of biologically important natural
products (Fig 1).6,7
using
highly
activated
iodine
source
[bis(sym-
̅
collidine)iodine(I)]+PF6 under slow addition conditions.12 Lewis
acid-mediated ring expansion by the cycloaddition of alkyne to
the in-situ generated oxetenium species was also applied for
the construction of medium-sized lactones.13 Recently, Yeung
et al., have given a representative procedure for the synthesis
of bromolactones using sulfur-based zwitterion catalyst.14a The
report describes the synthesis of only one seven-membered
bromolactone from alkyl chain substrates and higher size
lactones were achieved by the incorporation of the
heteroatom, which lowers the transannular strain in the chain.
Moreover, cyclization of alkenols for the synthesis of medium-
sized bromooxepanes has not been accomplished under
catalytic conditions. In continuation of our work on
organoselenium chemistry,15 and synthesis of heterocyclic
compounds,16 herein we disclose a new method for the regio-
and stereo-selective construction of medium-sized bromo,
iodolactones, and bromooxepanes by using organoselenium
catalyst, DMAP co-catalyst and NBS/NIS as a halogenating
reagent and crystal structure study of several medium-sized
lactones has been reported for the first time.
Fig 1. Biologically important medium-sized lactones
The substrate with long alkyl chain possesses high degree of
conformational flexibility that brings a negative entropy
change in the intramolecular cyclization process,8b also
transannular strain is one of the dominant factors which
Optimization of reaction conditions were carried out on the 6-
heptenoic acid substrate by screening various organoselenides
1a-1g, co-catalysts 2a-2e, brominating reagents, additives, and
solvents (Scheme 1 and detailed study is presented in the
Table S1, ESI page S3-S5). Noteworthy, selenide 1e alone failed
to provide bromolactone 3, and also DMAP provided poor
yield of 3 from 6-heptenoic acid, and NBS. However, catalyst
1e together with co-catalyst DMAP gave 3 in 64% yield. After
extensive screening of various conditions, we have chosen
catalyst 1e (10 mol %), co-catalyst 2a (20 mol %), NaHCO3 (1
aDepartment of Chemistry, Indian Institute of Science Education and Research
(IISER) Bhopal, Bhopal By-pass Road, Bhauri, Bhopal, Madhya Pradesh, India-
462066. E-mail: sangitkumar@iiserb.ac.in.
Web address: https://home.iiserb.ac.in/~sangitkumar/
†
Experimental details, spectroscopic data, 1H, 13C, 135-DEPT, 77Se, 2D-NMR, mass
spectra and X-ray crystallographic data [CCDC No. 984340 (1e), 984339 (3),
1407583 (18), 984338 (33), 984341 (1eb)]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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equiv), and NBS (2 equiv) in chloroform at 0 oC to explore lactones 3 and 18 are depicted in Fig 2 (for detailsVsieeweArEtiSclIe pOanlginee
DOI: 10.1039/C5CC10245F
further substrate scope of the reaction, and results are S50-S61).
summarized in Scheme 2.
Fig 2. Crystal structures of bromolactones 3 and 18, respectively with 50% ellipsoidal
probability and hydrogen atoms are omitted for clarity.
Iodolactonization of selected alkenoic acids was also explored.
Indeed the use of N-iodosuccinimide under optimized
conditions, provided iodolactones 6, 8, 12, and 14 in 25-85%
yields.
Scheme 1. Various catalysts and co-catalysts screened. a,b,c Yields obtained using 1e, 2a,
and (1e+2a), respectively.
Scheme 3. Synthesis of eight to eleven-membered bromolactones. a,bYields obtained
using (1e+2a), and 2a (10 mol %), respectively.
Next, eight and higher-membered bromolactones were
explored (Scheme 3). Synthesis of eight and higher-membered
bromolactones has not been accomplished till date
presumably due to high transannular strain; whereas only
halolactones consisting of heteroatom such as oxygen, which
Scheme 2. Synthesis of seven-membered halolactones.
reduces the strain have been reported. Alkenoic acid
In the beginning, we have studied catalytic system for the
consisting only carbon atom in the chain provided novel eight-
synthesis of small-sized bromolactones. Indeed, quantitative
membered bromolactone 23 in 30% yield. Incorporation of the
yields of five- and six-membered bromolactones 4 and 5 were
heteroatom in the alkyl chain provided improved yields (46-
obtained under developed catalytic system. Next, synthesis of
55%) of eight-membered bromolactones 24-26. Nine-
various seven-membered bromolactones 6-22 (Scheme 2) was
membered bromolactone 27 having oxygen as heteroatom in
explored from respective alkenoic acids. Bromolactones 7-10
the ring was obtained as exo-isomer exclusively; on the other
having an oxygen heteroatom in the chain were obtained
hand bromolactone 28 lacking oxygen atom formed exo-
precedently in good (65-90%) yields, as heteroatom reduces
isomer as a major product and endo-isomer as minor
the transannular strain and also stabilizes bromiranium ion in
product.12c 10- and 11-Membered bromolactones 29, 30 and
transition state by nonbonded intermolecular interaction.12b
32 were also obtained via exo-trig ring closure in 40-65%
Bromolactone 11 consisting phenyl supported chain was
yields. Phoracantholide I (Fig 1) is a natural product consisting
isolated in quantitative yield (99%) within 3 h. Medium-sized
of 10-membered lactone moiety with defensive property in
lactone 13 containing phenyl as well as the heteroatom in the
beetles. Here, bromo-derivative 30 of phoracantholide I was
chain was obtained in moderate yields. Substitution on
synthesized in 40% yield from 9-decenoic acid. Oleic acid
benzene ring, enhanced the yield of bromolactones (15-18, 20-
having long alkyl chain provided both isomers 31a and 31b in
22). To our delight, medium-sized bromolactones 3, and 18
1:1 ratio. Synthesis of bromolactones 23-32 was also studied in
were isolated as crystalline solids, which were reported as
the presence of DMAP 2a alone, which failed to provide
semisolids or liquids earlier.12,14a The crystal structures of
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bromolactones 23-30, although, 10- and 11-membered downfield shifted as compared to selenide 1e (δV=iew3A8rt9iclepOpnmlin)e.
lactones 31 and 32 were obtained in poor yields 8 and 11% The addition of co-catalyst 2a to 1DeOaI: 1le0a.1d0s39/tCo5CCfu10rt2h4e5Fr
respectively.
Next, diastereoselectivity
downfield shift of the signal from
the seems to be hypervalent Se(IV) 1ec which could be in the
δ 712 to δ 851 ppm and
was
examined
in
halolactonization using selenide 1e and 2a catalytic system equilibrium with 1ec’ (Scheme 7) as the calculated energy
(Scheme 4). Indeed, (R)-(+)-citronellic acid gave bromolactone difference between 1ec and 1ec’ is low (10 kcal/mol) and also
33 diastereoselectively (98:2) under the reaction conditions. the interconversion energy for both isomer is found to be
Worth noting, bromolactone 33 was obtained with poor 14.86 kcal/mol.19
diastereoselectivity (80:20) when only 2a was used as a
catalyst. Similarly, (S)-(-)-citronellic acid also gave
diastereoselective bromolctone 35 (98:2). Iodolactonization in
(R)-(+)- and (S)-(-)-citronellic acids also offered excellent
diastereoselectivity for the synthesis of seven-membered
iodolactones 34 and 36. It seems that the formation of
diastereoselective product was driven by dimethyl substituted
carbon and an interaction with the catalytic intermediate (for
details, see ESI page S8). Stereochemistry was also confirmed
by the single crystal X-ray analysis of the bromolactone 33.17
Scheme 6. Mechanistic study by 77Se NMR and mass analysis.
77Se NMR study on the equimolar reaction mixture of selenide
1e, DMAP 2a, NBS and 6-heptenoic acid after 6 h, showed two
peaks for 1e (δ = 387 ppm) and 1ec (δ = 851 ppm) (ESI page
S346). Attempted isolation of 1ea and 1ec were unsuccessful
and instead, Se(IV)Br2 1eb was isolated. Selenium(IV)
dibromide 1eb alone and also with DMAP provided trace
amount of 3 under optimized reaction conditions. The catalytic
cycle for the construction of medium-sized bromolactones is
depicted in Scheme 7.
a
Scheme 4. Diastereoselective synthesis of halolactones.
Diastereomeric ratio
determined by 1H NMR; b DMAP alone used as a catalyst; c CHCl3 was used as a solvent;
d CH2Cl2 was used as a solvent.
With
the
optimized
condition
in
hand,
cyclo-
bromoetherification reaction of alkenols was studied for the
synthesis of seven-membered bromooxepanes (Scheme 5).
Alkenols underwent bromoetherification reaction smoothly
leading to various seven-membered bromooxepanes 37-39 in
58-66% yields. However, bromoetherification required
considerably longer time (24-54 h) compared to the
bromolactonization and could be due to slower deprotonation
of alcohol than the acid (vide infra).18 Bromooxepanes 40 and
41 were obtained with 64 and 65% yields as a racemic mixture
of both diastereomers.
Scheme 7. Proposed catalytic cycle for bromolactonization.
The reaction between 1e, 2a, and NBS provided intermediate
1ec which may be in equilibrium with 1ec’. Alkene and acid
terminals of alkenoic acid would bind with the intermediate
1ec’ and give 1ed’. Selenium-nitrogen coordination elongates
Scheme 5. Synthesis of bromooxepanes.
77Se NMR, mass spectrometry and theoretical calculations
were carried out to understand the co-operative effect of
selenide 1d and 1e with co-catalyst 2a in the
bromolactonization reaction (for details, see ESI, page S6-S7).
The reaction mixture of NBS and catalyst 1e showed a peak at
the Se–
Br bond20 and thus favours the facile generation of Br+.
The formation of bromiranium ion and interaction of
carboxylate ion with the ammonium ion in the same species
would favour the cyclization that lead to medium-sized
δ
712 ppm, attributed to 1ea (Scheme 6), which is significantly
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In an alternative pathway, reaction of alkenoic acid with 1ec
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bromolactones is currently under study in our laboratory.
SK thanks DST New Delhi (EMR/2015/000061) and IISER
Bhopal for generous funding and also Ms. Ruchi Shrivastava for
mass experiments. AV, DP, and AY acknowledge UGC, New
Delhi and SJ thanks IISER Bhopal for fellowship, respectively.
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