A fast and selective decarboxylative difunctionalization and cyclization for easy access to gem-dihalo alcohol, ether, ester and bromo-1,4-dioxane

Article abstract of DOI:10.1039/c1cc16126a

A general strategy for fast decarboxylative difunctionalization to gem-dihalohydrin, gem-dihaloether, gem-dibromoester and cyclized bromo-1,4-dioxane synthons with outstanding regio- and stereoselectivity is demonstrated. The Royal Society of Chemistry 20

Full text of DOI:10.1039/c1cc16126a

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COMMUNICATION
A fast and selective decarboxylative difunctionalization and cyclization for
easy access to gem-dihalo alcohol, ether, ester and bromo-1,4-dioxanew
Saikat Khamarui, Deblina Sarkar, Palash Pandit and Dilip K. Maiti*
Received 1st October 2011, Accepted 21st October 2011
DOI: 10.1039/c1cc16126a
A general strategy for fast decarboxylative difunctionalization
to gem-dihalohydrin, gem-dihaloether, gem-dibromoester and
cyclized bromo-1,4-dioxane synthons with outstanding regio-
and stereoselectivity is demonstrated.
Halogenated organic molecules are the precursors of Heck,
Suzuki and other fundamental transformations and used as
key intermediates, bioactive natural products, agrochemicals,
pharmaceuticals and semiconductors.1 Hunsdiecker reaction
of a,b-unsaturated carboxylic acids with molecular bromine–
metal catalysts2 and in situ generation of bromine by metal halides
and oxidants (KBr-H2O2-Na2MoO4 and LiCl/LiBr-CAN),
Scheme 1 Decarboxylative dibromohydroxylation in a nanoreactor.
NBS-MnCl2 and HBr-O2-NaNO2 are utilized to access
bromoalkenes.3 However, utilization of functionalized gem-
KBr as the direct source of Br. We have envisioned that upon
dihalogenated building blocks in organic synthesis suffers the
hypervalent iodane12 inside a surfactant-assembled lipophilic
lack of a robust process which can selectively install two halogen
activation, a p-bond bearing carboxylic acid (1) with a
atoms.1f,4 In particular, substituted a,a-dibromohydrins (2)
andtheir ether analogues are available in natural products.5
They are key intermediates for synthesis of terminal alkynes6
and a-methoxy phenyl acetic acid which are used as chiral
resolution agents for amines,7 apoptosis inhibitors,8c plant
growth regulators8b and calcium antagonists.8a In general, it
is very difficult to obtain a,a-dibromohydrins (2) due to the
formation of a number of possible products (Scheme 1). One
short method has been pioneered by Chowdhury and Roy3a using
Mn(OAc)2 catalyst and expensive NBS (2 mol) in CH3CN–water
to provide 2 (yield: 37–98%) in 16 h. Two other methods require
the use of a Grignard reagent at low temperature9a or hydride
reduction of the dibromoketone precursor.9b To the best of our
knowledge, till now, no efficient 1,2-difunctionalization10 method
has been devised for decarboxylative gem-dihalogenation of
a,b-unsaturated carboxylic acids with simultaneous installation
of a hydroxyl/alkoxy/carboxylate group and a cyclization process.
Being most abundant, cheap and environmentally safe,
water11 is the solvent of our choice for development of a
cleaner and more benign dibromohydroxylation reaction using
nanoreactor13 can regioselectively accept BrÀ from an aqueous
surrounding (Scheme 1). Subsequent decarboxylation, selective
installation of BrÀ and solvolysis will furnish the new synthons.
Upon treatment of our model substrate trans-cinnamic acid
(1a, entry 1, Table 1) with p-bond activator PhI(OAc)2, cationic
surfactant CTAB and KBr at room temperature in aqueous
medium, BrÀ is transferred very rapidly (25 min) to afford
a,a-(dibromomethyl)phenylmethanol (2a, entry 1, Scheme 2).
Anionic (SDS) and neutral Tween 80 could not transfer BrÀ
(entries 2 and 3). Polymeric PhIO14 is inactive (entry 4) and the
use of the ‘‘TEAB/IBD’’ protocol does not produce the desired
product 4a (entry 5).15 Under the reaction conditions synthon 2a
is obtained in 63% yield. Gratifyingly, the gem-dibromination
with addition of a methoxy group is observed simply by changing
the solvent from water to methanol (entry 6, Table 1).
Table 1 Development and optimization of the reaction
Reagent and reaction
Entry conditionsa,b
t/min Conversion (%) Yield (%)
1
2
3
4
5
6
7
PhI(OAc)2, CTAB, H2O
PhI(OAc)2, SDS, H2O
25 100
2a, 88
2a, ndc
2a, nd
2a, nd
4ad, nd
6a, 90
5a, 76
300
PhI(OAc)2, Tween 80, H2O 300
0
0
0
PhIO, CTAB, H2O
PhI(OAc)2, TBAB, H2O
PhI(OAc)2, CTAB, MeOH 25 100
PhI(OAc)2, CTAB, DCMe 45 100
300
Department of Chemistry, University of Calcutta,
University College of Science, 92, A. P. C. Road, Kolkata-700009,
India. E-mail: dkmchem@caluniv.ac.in; Fax: +91-33-2351-9755;
Tel: +91-33-2350-9937
40 100
a
b
g3-Hypervalent iodanes (2.0 mol). Surfactant (10 mol%).
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data and NMR spectra. See DOI:
10.1039/c1cc16126a
c
d
Not detected. 2a (63%). Dichloromethane.
e
c
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Chem. Commun., 2011, 47, 12667–12669 12667

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a,a-(Dibromomethyl)phenylmethylmethyl ether (6a, entry 1,
Scheme 2) is obtained in excellent yield (90%). Other possible
regioisomer 7a is not found in the post-reaction mixture. In
contrast to the commonly used Hunsdiecker reaction of 1a to
form a-bromostyrene (4a), it has furnished only the tribromo-
product 5a upon the use of a polar aprotic solvent (entry 7).
The scope for synthesis of functionalized vicinal dibromohydrins
is demonstrated using various a,b-unsaturated carboxylic acids
(1b–r, Scheme 2, entries 2–18) toward rapidly (20–60 min) accessed
synthons (2b–r) with moderate to excellent yield (61–92%).
Aromatic precursors possessing electron donating substituents
(1g–k, entries 7–11) undergo the reaction at a faster rate and
give better yields (85–92%) compared to the precursors with
electron withdrawing substituents (72–83%, 1b–f,p,q entries
2–6, 16, 17). a,b-Unsaturated carboxylic acids bearing hetero-
cyclic rings (1l,m entries 12 and 13), naphthyl (1n, entry 14)
and a-methyl substituents (entry 18) are tolerated in this
innovative protocol. Other than water, methanol is utilized
as a solvent for direct addition of new bonds toward rapidly
(15–60 min) accessed a,a-dibromomethylmethylmethylether
(6b–r, entries 2–18) with high yield (60–92%) and complete
regioselectivity. It is applicable to the substrates having
unactivated, activated and heterocyclic aromatic rings and
many sensitive functionalities like 31-amine, methoxy, allyl,
propargyl etc. and also a-methyl substituent. However, the
reaction is unsuccessful with aliphatic a,b-unsaturated acids.
Surprisingly, in the case of precursor 3-[4-(2-carboxyvinyl)-
phenyl] acrylic acid (entry 15) one unsaturated moiety with
a carboxylic acid group remains intact with the reagent. This
approach is also compatible for synthesis of gem-dichloro-
hydrin (8a) and gem-dichloroether (8b) in the presence of CPC
(entry 19). The metal-free reaction has great synthetic value
since treatment of easily available a,b-unsaturated carboxylic
acids16 and nonhazardous KBr leads to synthesis of rare types of
halogenated building blocks with very fast reaction convergence,
outstanding selectivities and excellent yield.
Transfer of bromide from the homogeneous aqueous
solution is expected at the interface (Stern layer) between the
surface of the cationic surfactant-assembled nanoreactor1f and
water (eqn (1), Scheme 2). Activation of the double bond by
Scheme 2 Substrate scope toward a,a-dihalohydrin and a,a-dihaloether, possible reaction path (eqn (1)–(3)) and ESI-MS spectra.
c
12668 Chem. Commun., 2011, 47, 12667–12669
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is confirmed by means of a DLS experiment (ESIw) of the reaction
mixture in water (R = 333.5 nm), methanol (R = 383.5 nm) and
ethylene glycol (R = 666.6 nm).
In summary, the present study reveals an efficient decarboxy-
lative vicinal heterodifunctionalization of a,b-unsaturated
carboxylic acids to afford a series of functionalized halogenated
synthons. It is simple in execution, rapid, high yielding and
completely regio- and diastereoselective. The metal-free mild
reaction conditions with no environmental hazard highlight
the importance of our strategy which puts into another
frontier to the Hunsdiecker halo-decarboxylation reaction.
Financial support from DST (SR/NM/NS-29/2010 and SR/
S1/OC-22/2006), CRNN and research fellowships (JRF and
SRF) from CSIR, India, are gratefully acknowledged.
Scheme 3 Reaction with activated hydroxyl group (R–OH).
PhI(OAc)2 and subsequent transfer of BrÀ is expected to
involve a five membered cyclic transition state (I) with a
carboxylic acid bound ammonium head group. Simultaneous
addition of another BrÀ (II), reductive elimination of
g3-hypervalent iodine, decarboxylation and removal of the I
(III) moiety at the most bulky center by water lead to
formation of 2. Replacement of AcOÀ with surrounding
BrÀ regenerates CTAB (eqn (2), Scheme 2). Involvement of
water is established by using H218O (eqn (3), Scheme 2) and
subsequent analysis of both the products. For clarity, only the
characteristic peaks of the EI-MS spectra (16O-2a and 18O-2a)
are displayed in Scheme 2.
Notes and references
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Surprisingly, the valuable ether-forming reaction in ethanol
and other higher alcohols remains unsuccessful. However,
activated hydroxyl group containing propargyl alcohol, acetic
acid and L-lactic acid are successfully converted to corresponding
gem-dibromopropargyl ether (9, Scheme 3), gem-dibromoacetate
(10a) and chiral gem-dibromolactate (10b).
We are curious to determine whether this approach could be
extended to construct a novel 1,4-dioxane framework in one
step. In fact, ethylene glycol responds well to react rapidly
(15–30 min) with an a,b-unsaturated carboxylic acid (1) and
KBr at room temperature to provide 1,2-bromoaryl-1,4-dioxane
(11a–f, Scheme 4) in excellent yield (85–92%). We are surprised
to see the complete diastereoselectivity during the cyclization
process. To our knowledge, this decarboxylative halogenation
with cyclization is unprecedented and the first report toward
synthesis of the new synthons. Phenyl, activated aryl, naphthyl,
heterocyclic aromatic rings, halogen and triple bonds are
tolerated in this approach. Unfortunately, the reaction of 1f
possessing NO2 remains unsuccessful. It is expected that two
hypervalent residues in the intermediate II (Scheme 2) are
simultaneously removed by ethylene glycol. Formation of a
surfactant-assembled nanoreactor during the chemical process
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Scheme 4 Decarboxylative cyclization with ethylene glycol.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12667–12669 12669