An atom-economical protocol for direct conversion of Baylis-Hillman alcohols to β-chloro aldehydes in water

Article abstract of DOI:10.1039/c7gc01483j

This paper describes an atom-economical strategy for the direct conversion of Baylis-Hillman alcohols to β-chloro aldehydes under metal free conditions with excellent functional group tolerance. The use of stable-nontoxic Oxone as a terminal oxidant along with an inexpensive salt (sodium chloride) as a halogen source and water as the reaction medium makes this chemical synthetic process more viable and environmentally benign contributing towards green chemistry.

Full text of DOI:10.1039/c7gc01483j

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An Eco-Economical Protocol for Direct Conversion of Baylis
Hillman Alcohols to β Chloro Aldehydes in water
Received 00th January 20xx,
Accepted 00th January 20xx
Raktani Bikshapathi, Sai Prathima Parvathaneni*and Vaidya Jayathirtha Rao*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: This paper describes an atom-economical strategy terms of its stability, solubility (water soluble nature),
for the direct conversion of Baylis Hillman Alcohols to β- manipulative simplicity and that of being non-toxic and cost-
chloro aldehydes under metal free conditions with excellent effective reagent.7
functional group tolerance. The use of stable-nontoxic The Morita-Baylis–Hillman (MBH) adducts are densely
oxone as terminal oxidant along with an inexpensive salt functionalized molecules which are generally used as
(sodium chloride) as halogen source and water as the advanced synthetic intermediates for construction of a
reaction medium makes this chemical synthetic process plethora of natural products, and drug molecules.8 In
more viable and environmentally benign contributing general, β-halo carbonyl compounds can be synthesized via
towards green chemistry.
halogenation of the corresponding carbonyls or oxidation
and subsequent β-halogenation of alcohols in a two-step
sequence.9 In terms of economy, one-pot oxidation with
subsequent halogenation would be more appropriate. In this
scenario, the conversion of alcohols to the corresponding α-
chloro carbonyl derivatives has been reported using
trichloroisocyanuric acid (TCCA)10. In the literature, very few
reports exists for preparation of β-halo aldehydes compared
to ketones as they are proved to be unstable.11
Oxone and sodium chloride supported on wet alumina have
been reported for the preparation of N-chloroamides.12 To
the best of our knowledge, the use of a stoichiometric
amount of oxone together with NaCl has been explored for
the first time for MBH derived alcohols. In an attempt to
develop sustainable chemical process,13 we have built up an
efficient protocol by employing NaCl/Oxone14 that’s largely
suitable for an aqueous system. Apart from bringing
experimental simplicity and efficiency, this method
significantly eliminates the organic wastes from
solvents/reagents.
Introduction
Halogenated carbonyl compounds are versatile synthons to
generate more complex organic architectures and multitude
of heterocyclic compounds.1 The most expedient methods
for the synthesis of β-halo carbonyl compounds are
conjugate addition of a hydrogen halide to an enone and the
electrophilic addition of an acyl chloride to an olefin. They
serve as reactive intermediates for late-stage function
alization of pharmaceutically important drugs
2
.
Traditional
methods for electrophilic chlorination usually involve the use
of molecular chlorine with a metal catalyst under relatively
harsh conditions.3 Significant progress was achieved to
replace environmentally hazardous molecular chlorine
through alternative N-chlorosuccinimide (NCS) for
electrophilic chlorination in organic synthesis.4 In terms of
green chemistry perspective several environmentally benign
protocols involving direct oxidative chlorination with chloride
anions (HCl, KCl, NaCl etc.) in the presence of an oxidant has
been developed to access halogenated carbonyl compounds
and to surpass the existing literature.5 Oxone is an effective
oxidizing agent with a large scope of synthetic applications.6
Over the years, oxone has become a versatile reagent in
As part of the continuing efforts in our laboratory toward the
development of metal-free oxidative transformations,15 we
have focused on realizing the synthetic potential of MBH
OH
Cl
CO2Me
Cl
CO2Me
CO2Me
O
NaCl, KHSO5
H2O, rt, 2h
A
2a
1a
Expected
B. Das et al.
Unexpected
present work
Crop Protection Chemicals, Organic Division II,
Indian Institute of Chemical Technology, Uppal Road Tarnaka,
Hyderabad-500 607, India. Fax: (+)91 40 27193382; Tel: (+) 91 40 27193933;
e-mail: saiprathimaiict@gmail.com; vaidya.opv@gmail.com
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1 One-pot synthesis of β Chloro Aldehydes
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chemistry.15c To our surprise the reaction of 1a with aqueous yield. Even though amount of halide source was decreased
NaCl/Oxone was finished in 2 hour, thus affording an to 2 equiv, the reaction resulted in 80% of the functionalized
unexpected product 2a with 100% conversion than the product (entry 4) in DCE compared to other solvents (entries
expected Das et al. accomplished product A as represented
Table 2 Substrate scope for MBH functionalizationa,b
in Scheme 1.16 These results inspired us to examine the
reaction of the MBH alcohol 1a with NaCl and oxone at room
temperature in water.
Herein we report one-pot synthesis of β chloro aldehydes
from MBH adducts using sodium chloride as chloro source
and oxone (potassium monopersulfate) as an oxidant. This
process not only represents a novel cascade transformation
but provides direct access to potential β chloro aldehydes in
good to excellent yields with high selectivity.
Results and discussion
Table 1 Optimization of reaction conditionsa
aAll the reactions were carried out in the presence of 1.0 equiv of 1,
1.2 equiv of oxone, 2 equiv of NaCl, in 2 mL of H2O at room
temperature for 2h. bIsolated yields.
2, 3 & 5). As our laboratory is involved in on-water catalysis12
we have performed the reaction in water by employing NaCl
(2 equiv) and oxone (1.2 equiv) and observed increase in the
product yield (entry 6). Notably there was decline in the yield
of the product with decrease in amounts of both NaCl and
oxone (entry 7). The addition of water improved both the
conversion and the reaction yield (entry 6). Furthermore the
combination of water with (1:1) mixture of organic solvents
with 1 equiv of halide source didn’t have considerable effect
on the product yields (entries 8-11). We have observed NaBr
and KBr as halo source were ineffective in affording the
desired bromo product 3a in low yields (entry 12 & 13).
Whereas LiBr is not suitable for this system (entry 14). The
reaction did not proceed in absence of oxone as well as NaCl
indicating the combination in aqueous phase is required for
the generation of the desired product 2a (entry 15 and 16).
aReaction conditions: Substrate 1a (1.0 equiv) in H2O
(2 mL) for 2 h at room temperature. bIsolated yields.
In accordance with MBH oxidation reports,14a our research
laboratory has focused on investigating oxone for selective
oxidations. The Morita–Baylis–Hillman (MBH) alcohol 1a
were chosen as the model substrate for selective oxidation
with oxone (1.2 equiv) and NaCl (4 equiv) as chlorine source
in acetonitrile system (Table 1, entry 1). To our surprise, we
have found unexpected 2a as the sole product with 95%
To investigate the generality of the oxidation of MBH
alcohols with oxone, various structurally diverse alcohols
were prepared from acrylates and were tested as substrates
under optimized conditions. All the MBH adducts (1a–1x)
gave corresponding β chloro aldehyde derivatives (2a–2x)
with good to excellent yields (Table 2). The reactions with
different electron-donating and electron-withdrawing
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substituents on the aryl ring of the MBH alcohols were In addition we have extended the scope of the developed
tolerated leading to high yields of the selective oxidized protocol to MBH adducts derived from aliphatic aldehydes to
products. The use of MBH alcohol 1a as model substrate accomplish valuable β chloro aldehyde products (Table 3).
proved to be effective in the formation of aldehyde 2a in However this method was ineffective for aliphatic substrates,
98% yield. There is no change in the reaction yields for ethyl as alkyl migration was not observed to provide desired
acrylate derived MBH alcohol in producing the corresponding products 4a, 4b, 4c and 4d (Table 3, entries 1-4). To
aldehyde 2b. Substrates bearing electron-withdrawing understand the feasibility of the reaction without ester
substituent (F, Cl and Br) at para position were successfully group we have performed with aliphatic allylic alcohols and
oxidised to produce the corresponding products 2c (96%) 2d desired product was not formed (Table 3, entries 6 & 7).
(92%) 2e (92%) 2f (91%) and 2g (85%) respectively. In case of Pleasingly, under the optimized conditions cyclohexenone
ortho and meta halo substituted at phenyl ring also derived MBH adduct gave good yield (82%) of the desired
underwent the reaction smoothly to give the corresponding product 4e (Table 3, entry 5). A similar result was achieved
products (2h-2p) in low yields (80-84%) when compared to with 1-phenylprop-2-en-1-ol substrate affording the product
para substituted MBH alcohols. However electron-donating 4h (Table 3, entry 8).
substituted MBH adducts also gave good yields (2q-2x). The
more sterically hindered para isopropyl-substituted
substrates was transformed into 2u and 2v (96%) at high
yields.
We then studied the selectivity of oxidative chlorination with
NaCl/Oxone system in which the anti-isomer 2v
predominated over the syn-isomer 2v1 by upto 9:1 was
observed from NMR spectra analysis of the crude product as
shown in scheme 2 (see supporting information).
Table 3 Substrate scope for allylic alcohol functionalizationa,b
Scheme 2. Oxidative chlorination of 1v
In order to expand insights into the reaction mechanism of
this oxidative transformation, a control experiment was
carried out by using radical-trapping reagent 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO). This showed the
variation in the reaction yield of the desired product 2a
(scheme 3). These results indicated that the present reaction
may not proceed via a radical pathway.
Scheme 3. Control Experiment
We have proposed a possible reaction pathway for the
oxidation of MBH alcohols with oxone as represented in
Scheme 4. In general allylic alcohols and their derivatives
undergo semipinacol rearrangement to give synthetically
useful β-halo carbonyl compounds induced by highly
electrophilic Halonium ions.17 Generally, electrophiles such
as halogeniums, can be generated by addition of C=C bond
and initiate rearrangements.18 The umpouling-based
oxidative transformation of halides into halonium ions takes
place in presence of oxidants. In the present reaction Oxone
aReaction conditions: Substrate (1.0 equiv) in H2O (2 mL) for 2 h at
room temperature. Isolated yields. Quantative Yield analysed by
Crude NMR.
b
c
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as the oxidant couples with inorganic halide salt (NaCl) to by CSIR-Senior Research Associateship (Scientist’s Pool
generate an active transient [Cl+] species as shown in scheme Scheme) and UGC-SRF Govt. of India, New Delhi. The authors
4. This undergoes electrophilic addition with MBH derived acknowledge S. Sunder for providing the HRMS data. We also
allylic alcohol 1a on the electrophilic carbon centre from the acknowledge Director IICT for providing infrastructural
sterically less hindered side to produce the intermediate A. facilities.
This trigger the aryl migration and follows semipinacol type
rearrangement to provide key chloro aldehyde 2a.
Notes and references
As shown in transition state models, model I is more
favoured. The steric effect of II is more due to proximity of Ar
and –CO2R as shown in Scheme 5. Having a sufficiently larger
group like CO2R is crucial for favourable attack of chloronium
ion from the least hindered side and produces anti-isomer as
major product.
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Scheme 6. Gram-scale synthesis of 2a
Conclusions
In summary, we have developed a mild, synthetically useful
transformation of various MBH alcohols into corresponding
β chloro aldehydes. Notably the NaCl/Oxone system serves
as an attractive alternative with oxone as oxidant and NaCl as
Cl donar. Moreover, the method is safe, inexpensive,
operationally simple and compatible with substrates bearing
diverse functional groups. This represents an atom-
economical and environmentally benign approach for
construction of β chloro aldehydes in aqueous conditions.
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Acknowledgements
The authors are grateful to the financial assistance provided
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