Organocatalysis as a safe practical method for the stereospecific dibromination of unsaturated compounds

Article abstract of DOI:10.1021/ol300456x

Organocatalytic stereospecific dibromination of a wide variety of functionalized alkenes was achieved using a stable, inexpensive halogen source, 1,3-dibromo 5,5-dimethylhydantoin, and a simple thiourea catalyst at room temperature. The presence of a tertiary amine enhanced the rate of the dibromination reaction, and yields were good in various solvents, including aqueous solvents. The procedure was extended to alkynes and aromatic rings and to dichlorination reactions by using the 1,3-dichloro hydantoin derivative.

Full text of DOI:10.1021/ol300456x

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1858–1861
Organocatalysis as a Safe Practical
Method for the Stereospecific
Dibromination of Unsaturated
Compounds
Gloria Hernandez-Torres,†,‡ Bin Tan,† and Carlos F. Barbas III*,†
ꢀ
The Skaggs Institute for Chemical Biology and Departments of Chemistry and
Molecular Biology, The Scripps Research Institute, 10550 Torrey Pines Road, La Jolla,
´
ꢀ
California 92037, United States, and Departamento de Quımica Organica, Universidad
ꢀ
Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
carlos@scripps.edu
Received February 23, 2012
ABSTRACT
Organocatalytic stereospecific dibromination of a wide variety of functionalized alkenes was achieved using a stable, inexpensive halogen
source, 1,3-dibromo 5,5-dimethylhydantoin, and a simple thiourea catalyst at room temperature. The presence of a tertiary amine enhanced the
rate of the dibromination reaction, and yields were good in various solvents, including aqueous solvents. The procedure was extended to alkynes
and aromatic rings and to dichlorination reactions by using the 1,3-dichloro hydantoin derivative.
Halogenated compounds are important intermediates in
syntheses of many natural product derivatives.1 Many
halogenated marine natural products are of pharmacolo-
gical interest, and organic halides are useful synthons for
chemical transformations such as substitutions and cross-
coupling reactions. Certain organic halides are intermedi-
ates in the industrial-scale manufacture of pharmaceuti-
cals, agrochemicals, and fine chemicals. Bromination of
unsaturated CꢀC bonds has been primarily performed by
using molecular bromine as a reagent, mainly in chlori-
nated solvents and under harsh reaction conditions.2
During the past 10 years, several dibromination methods
have been developed using more environmentally benign
bromination reagents.3 In these alternative protocols,
other problematic substances are often used, however.4
The most general methods for electrophilic bromination of
alkenes employ a carrying agent supporting bromine5 or
in situ bromine generation that usually requires metal
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† The Scripps Research Institute.
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‡
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Universidad Autonoma de Madrid.
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Koukabi, N.; Soltani, H.; Bayani, L. S. Synth. Commun. 2010, 40, 2954–
2962. (l) Yonehara, K.; Kamata, K.; Yamaguchi, K.; Mizuno, N. Chem.
Commun. 2011, 47, 1692–1694. (m) Adimurthy, S.; Ghosh, S.; Patoliya,
P. U.; Ramachandraiah, G.; Agrawal, M.; Gandhi, M. R.; Upadhyay,
S. C.; Ghosh, P. K.; Ranu, B. C. Green Chem. 2008, 10, 232–237.
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10.1021/ol300456x
Published on Web 03/23/2012
2012 American Chemical Society

catalysts.3k,l,6 Dibromination products are usually obtained
as byproducts during halofunctionalization processes when
N-bromosuccinimide (NBS) is used as a brominated
agent.7 Dibromination reactions using NBS usually re-
quire the presence of inorganic bromide salts such as LiBr.8
Most organocatalytic halogenation procedures recently
described are based on organocatalytic monohalogenation
reactions, mainly asymmetric halolactonization processes,
where the organocatalyst directs the chirality-determining
step.9 To the best of our knowledge, only one organoca-
talyzed dibromination of alkenes has been described;10 this
procedure uses pyrrolidine as a catalyst and a combination
of NBS and succinimide. Halogenated solvent (CHCl3)
and high temperatures (60 °C) were required, and moder-
ate to good yields of the anti-dibrominated product were
obtained. The enantioselective version of this reaction
using chiral pyrrolidine was unsuccessful. Asymmetric
olefin dihalogenation remains a challenge. Nicolaou et al.
developed a pioneering enantioselective dichlorination11
of allylic alcohols catalyzed by a dimeric cinchona alkaloid
to yield enantio-enriched trans-dichlorinated product.12
The method requires preparation of aryl iododichlorides
from PhI and hazardous Cl2 gas. The ee’s obtained were
moderate.
Table 1. Dibromination Catalyst Screena
a Reactions were carried out using 1 (0.2 mmol) and DBDMH 2 (0.4
mmol) in DCM (2 mL) with 20 mol % of catalyst at rt. b Determined by
1H NMR of crude product. c Isolated yields.
Herein we report a new synthetic technique for dibro-
mination of unsaturated CꢀC bonds founded on the
unusual properties of hydantoin derivatives13 when com-
bined with a thiourea-functionalized catalyst. Mild conditions
and no hazardous reaction components were used, and
only inert byproducts were generated.
Initial experiments were performed in dichloromethane
(DCM) atrtusing chalcone 1 asa modelsubstrate with1,3-
dibromo-5,5-dimethylhydantoin (DBDMH) as a bromine
source. The anti-selective dibromination reaction took
place with excellent diastereoselectivity using 2 equiv of
DBDMH and 20 mol % of a broad selection of thiourea
derivatives as catalysts (Table 1). With simple thiourea I,
the trans-brominated compounds were formed with good
yields (86%) but moderate diastereoselectivity (10:1 dr).
Using methyl and aryl substituted thiourea catalysts (II,
III, VI and VII), the trans-brominated compounds were
formed but low conversion rates were observed even with
extended reaction times. Of these substituted catalysts,
only the symmetric N,N0-dimethylthiourea catalyst II gave
the product with excellent diastereoselectivity (>25:1 dr).
No product was obtained in the presence of urea derivative
IV. As nucleophilic organocatalysts can substantially
accelerate the transfer of electrophilic bromine from NBS
to alkenes,14,9b we focused our study on thiourea derivatives
containing tertiary amine moieties in their structure. Using
thiourea catalyst (VIIIꢀX), the trans-brominated com-
pounds were formed with high diastereoselectivity
(up >25:1 dr) and excellent yields (89 to 94%). Thiourea
catalyst V lacking the ethylenedimethylamine moiety but
containing instead a free amine gave the dibrominated
product in excellent yields but with lower diastereoselec-
tivity (up to 12:1). It is noteworthy that, in the absence of
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Org. Lett., Vol. 14, No. 7, 2012
1859

Table 2. Dibromination Solvent Screena
Scheme 1. Generality of the Dibromination Reactiona,b,c
entry
solvent
toluene
time (h) yield 3 (%)b dr of 3c yield 4b
1
2
3
4
5
6
7
8
12
3
95
94
93
90
79
ꢀ
>25:1
>25:1
>25:1
12:1
>25:1
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
81
ꢀ
ꢀ
DCM
CHCl3
1.5
2
EtOAc
1,4-dioxane
acetone
2
0.5
1
MeCN
55
82
7:1
H2O/DCM (3:1)
1
9:1
a Reactions were carried out using 1 (0.2 mmol) and DBDMH 2 (0.4
mmol) in solvent (2 mL) with 20 mol % of catalyst VIII at rt. b Isolated
yields. c Determined by crude 1H NMR.
any catalyst, no reaction occurs and that the use of other
common bromonium sources, such as NBS, with catalyst
VIII gave the dibrominated product with less than 20%
conversion. Since we observed increased reactivity with
thiourea catalysts containing a tertiary amine, we evalu-
ated how an external amine affected the reaction. When
combined with a thiourea catalyst, Et3N significantly
enhanced the reaction rate. Dibromination of chalcone 1
with catalyst X in the presence of 20 mol % of Et3N was
complete in only 30 min vs the 10 h needed without the
additive (entry 11). However, Et3N did not influence the
diastereoselectivity. Optimal results were obtained in the
reaction performed in presence of catalyst II and Et3N;
total conversion and 94% yield were obtained in just
30 min with excellent diastereoselectivity (entry 12). We
then studied the generality of the dibromination reactions
using the bifunctional catalystVIII and the combination of
thiourea II and Et3N. Both systems yielded the desired
products in reactions with nonfunctionalized olefins, but
better results were obtained with catalyst VIII when other
functional groups were present. Therefore, we further
optimized conditions for use of catalyst VIII.
We first evaluated the solvent effect. The dibrominated
product 3 was obtained in high yields and dr with short re-
action times with the solvents tested except acetone (Table 2).
In this case, hydroxylic attack at the reactive bromonium
intermediate presumably occurred more rapidly than the bro-
mine attack, and trans-bromo hydroxylated compound 4 was
isolated as the major product. Long reaction times were
necessary for completion of the reaction in solvents with
low polarity indices such as toluene (Table 2, entry 1). More
polar solvents as MeCN (entry 7) required shorter reaction
times. Of those tested, halogenated solvents DCM and CHCl3
proved to be the best with respect to catalytic activity and
selectivity, but toluene, 1,4-dioxane, EtOAc, and water/
DCM were acceptable. Nonhalogenated solvents ren-
der that methodology more environmentally benign.
Encouraged by these results, we evaluated the efficacy of
dibromination of different functionalized olefins containing
a Unless otherwise specified, all reactions were carried out using
olefins 1bꢀr (1 equiv) and DBDMH 2 (2 equiv) in DCM (0.1 M) with
20 mol % of catalyst VIII at rt. b1.5 equiv. cEt2O was used as solvent.
electron-withdrawing groups as shown in Scheme 1. The use of
1.5 equiv of DBHDM and 20 mol % of thiourea catalyst VIII
in DCM at rt resulted in compete reaction of the starting
material. Under these conditions, reaction of terminal and
substituted deactivated olefins containing esters, ketones,
and nitro functionalities with aryl and alkyl substituents
(1bꢀj) provided dibrominated products 3bꢀj with ex-
cellent yields and diastereoselectivities (Scheme 1).
The R,β-unsaturated aldehydes are interesting substrates.
The dibromination of trans-cinnamaldehyde occurred to
form 3l with good yield and excellent diastereselectivity after
12 h of stirring at rt using 2 equiv of DBDMH (Scheme 1).
R,β-Unsaturated aldehydes with chlorine on the aromatic
moiety, alkyl substituents, or R-substituted enals were also
acceptable reactants, and the corresponding dibrominated
aldehydes 3mꢀo were obtained in good yields. Finally, we
evaluated different methyleneindolinones. Oxindole motifs
are widely present in natural products and bioactive
molecules;15 in particular oxindole compounds bearing a
quaternary stereogenic center at the 3-position are extre-
mely useful. The dibrominated products 3pꢀ3r containing
different substitutions in the aromatic moiety or different
N-protecting groups were formed in high yields, although
without total stereocontrol. For these compounds, a slight
improvement in the diasteroselection was observed
when Et2O was used as solvent; dr’s of up to 17:1 were
obtained (Scheme 1). The anti stereochemistry of com-
pound 3p was established by X-ray analysis (see Sup-
porting Information).
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Org. Lett., Vol. 14, No. 7, 2012

Table 3. Dibromination of Organic Substratesa
Scheme 3. Control Experiments in Support of Mechanism
a Reaction carried out in an amber vial covered by aluminum foil in
the dark for 3 h.
and allow fast in situ generation of bromine which subse-
quently reacts with the unsaturated compounds. The color-
less solution of olefin and DBDMH in DCM turns dark red
when catalyst VIII is added, suggesting that Br2 is generated.
The solution loses color as the reaction proceeds. Sulfur
containing compounds show a complex free-radical chem-
istry, and radical reactions, where the sulfur atom of
different thioureas is involved, are known.17 Control ex-
periments showed no reaction of 1p using the usual
conditions but in the absence of ambient light or in the
presence of TEMPO (Scheme 3), which could act as a
radical inhibitor. We propose that the sulfur atom of
the thiourea catalyst is involved in a radical reaction
and might generate the bromide anion required to react
with the DBDMH and form the Br2 observed in the
reaction media.18 Additional interactions between the
in situ formed Br2, substrate, and catalyst may also
occur.
In summary, the organocatalytic and selective character
of the reported process and the nonhazardous reaction
components, mild conditions used, and short times re-
quired for completion render this dihalogenation method
an extremely practical and safe method for the bromina-
tion and chlorination of unsaturated compounds. A broad
substrate scope was demonstrated: both acyclic and cyclic
alkenes, alkynes, and activated aromatic rings are good
substrates for the halogenation reaction catalyzed by VIII
in the presence of DBDMH. This methodology holds
promise for the synthesis of enantioenriched dihaloge-
nated products starting from achiral unsaturated com-
pounds. Efforts to achieve enantioselectivity are
underway in our laboratory.
a Unless otherwise specified, all reactions were carried out using
compounds 5aꢀe (1 equiv) and DBDMH 2 (1.5 equiv) in DCM (0.1 M)
with 20 mol % of catalyst VIII at rt. b Isolated yields. c Determined by
crude 1H NMR d Reaction carried out using 2 equiv of DBDMH.
e Reaction carried out using 1 equiv of DBDMH.
Various alkenes, compounds with acetylenic function-
ality, and aromatic compounds were successfully subjected
to the bromination conditions as shown in Table 3.
With these results in hand, the applicability of this
organocatalyzed methodology to dichlorination pro-
cesses9 was evaluated. The commercially available analo-
gue 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) 7 was
used as a chlorine source. Treatment of cyclohexene 5a
with 1.5 equiv of DCDMH in DCM at rt gave rise to the
desired dichlorinated product in excellent yield and dia-
stereoselectivity (Scheme 2).
Scheme 2. Dichlorination Reaction
Since the chloronium anion intermediates that give rise
to the dichlorinated compounds show higher configura-
tional stability than their bromonium analogues,16 this
dichlorination process should be evaluated in asymmetric
dihalogenations.
Although the mechanism of this reaction has not been
completely elucidated, we believe that the thiourea and
amine groups of the catalyst VIII activate the DBDMH
Acknowledgment. Research support from the Skaggs
Institute for Chemical Biology is gratefully acknowledged.
We also thank Dr. A. L. Rheingold and Dr. C. E. Moore
(UC San Diego) for X-ray crystallographic analysis. G.H.-T.
ꢀ
also thanks Universidad Autonoma de Madrid for financial
support.
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Supporting Information Available. Experimental pro-
cedures, characterization of compounds, and X-ray data
(CIF file) of 3p. This material is available free of charge
via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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