Catalytic enantioselective dibromination of allylic alcohols

Article abstract of DOI:10.1021/ja4083182

A new dibromination reaction involving the combination of dibromomalonate as the bromonium source and a titanium bromide species as the bromide source has been developed. Enantioselective catalysis has been achieved through apparent ligand acceleration by a tartaric acid-derived diol.

Full text of DOI:10.1021/ja4083182

Communication
pubs.acs.org/JACS
Catalytic Enantioselective Dibromination of Allylic Alcohols
Dennis X. Hu, Grant M. Shibuya, and Noah Z. Burns*
Department of Chemistry, Stanford University, Stanford, California 94305, United States
S
* Supporting Information
Scheme 1. Challenges for Asymmetric Dibromination and a
Strategy for Achieving Enantiocontrol
ABSTRACT: A new dibromination reaction involving the
combination of dibromomalonate as the bromonium
source and a titanium bromide species as the bromide
source has been developed. Enantioselective catalysis has
been achieved through apparent ligand acceleration by a
tartaric acid-derived diol.
lkene dibromination is a fundamental organic reaction that
A
is not easily amenable to enantioselective catalysis.1,2 The
power of achieving asymmetric dibromination would stem from
the versatility of alkyl bromides as building blocks in organic
synthesis and the myriad of derivatizations to enriched chiral
molecules that it could enable. Herein we report the
development of a unique dibromination reaction that has
been rendered enantioselective and catalytic in chiral diol
through apparent ligand acceleration.
The difficulty in controlling the absolute stereochemical
outcome of alkene dibromination may be attributed to a
number of mechanistic factors in addition to the capriciousness
of the reagents and intermediates involved (Scheme 1, top).
First, bromine and other common dibrominating reagents react
rapidly with alkenes, making the feat of achieving catalysis over
nonselective background bromination a challenge. While one
approach could involve enantioselective formation of the three-
membered bromonium intermediate, Denmark3 has shown that
enriched bromonium ions can rapidly racemize (Scheme 1A) in
the presence of alkene (i.e., the dibromination substrate).4
Finally, control over the regioselectivity during bromide
addition is crucial because regioisomeric chiral dibromides are
enantiomeric (Scheme 1B). A successful asymmetric alkene
dibromination must take into account the aforementioned
issues.
Our approach was to formally separate Br2 into electrophilic
and nucleophilic components that are unreactive on their own
but in combination would form an active dibrominating species,
1 (Scheme 1, bottom). In particular, we speculated that an α,α-
dibromocarbonyl and a Lewis acidic metal bromide could serve
this purpose and that this could allow for enantiocontrol with
an appropriate chiral ligand regardless of the identity of the
selectivity-determining step. We recognized that the regiose-
lectivity of bromide delivery could be controlled by 1, but as an
initial simplification, we investigated aryl-substituted alkenes 2
wherein delivery should occur at the benzylic carbon.
brominating phenol when the two are reacted neat at 100
°C;5c and (3) Yamamoto’s use of chiral dichloromalonates as
reagents for the ZrCl4-mediated enantioselective chlorination of
silyl enol ethers.6 To the best of our knowledge, 3 or similar
species have seen only a single use (in 1926) in the electrophilic
halogenation of unactivated alkenes.7
As desired, it was found that 3 alone is unreactive toward
alkenes. The addition of bromotitanium triisopropoxide,
however, resulted in alkene dibromination. This bromide
source was an ideal choice as the promoter because of its
trivial cost and ease of preparation8 and titanium’s privileged
history and amenability to ligand acceleration in enantiose-
lective catalysis.9,10 trans-1-Phenylbut-1-ene (4) reacted with
these two reagents in nitromethane solvent mixtures to give
racemic dibromide 5 in low conversion along with equimolar
diethyl bromomalonate as a byproduct (Table 1, entry 1).
With a new method for dibromination that appeared suitable
for modification, the effect of chiral ligands was next examined.
The TADDOL11 ligand class was found to be most compatible
Important precedents identifying reactivity and the potential
for activation of α,α-dibromodicarbonyls include the following:
(1) Trost’s5a use of commercially available diethyl dibromo-
malonate (3) (Table 1) as a reagent for the transfer alkylation
of dienolates;5b (2) Eames’ report that 3 is capable of
Received: June 29, 2013
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja4083182 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
tanium triisopropoxide caused a reduction in selectivity to 54%
ee in both cases (Table 1, entries 8 and 9), consistent with
bromide being involved in the selectivity-determining step.
trans-Phenylbutene 4 has no effect on the selectivity of the
bromination of cinnamyl alcohol 6, and no crossover
dibromophenylbutane 5 was observed (entry 10). These
observations indicate that bromonium transfer between alkenes
is either inoperative or irrelevant in this system4b and that these
conditions offer a chemoselective method for dibromination of
allylic alcohols. Excess cinnamyl alcohol greatly reduced the
selectivity of the reaction (entry 11), but the addition of an
equal amount of hydrocinnamyl alcohol had a similar effect
(entry 12), suggesting that excess free alcohol, not alkene,
negatively affects the selectivity, likely because of disruption of
the coordination chemistry that is crucial for selectivity. Similar
evidence was provided by the result that the use of more
coordinating acetonitrile [ε = 38.0, donor number (DN) = 14.1
kcal/mol] in place of nitromethane (ε = 35.9, DN = 2.7 kcal/
mol)13 provided racemic dibromide.
Table 1. Development of a Catalytic Enantioselective
Dibromination Reaction
Additionally, while diethyl dichloromalonate was found to be
unreactive, the use of chlorotitanium triisopropoxide as the
halide source gave a lower yield of a single bromochloride
product with 88% ee in which chloride was delivered at the
benzylic position.12 This confirmed the role of diethyl
dibromomalonate as the bromonium source and titanium
halide as the halide anion source.
The above results are consistent with the proposed catalytic
cycle shown in Scheme 2. Ligand exchange on titanium might
Scheme 2. Proposed Catalytic Cycle
a
Reactions were conducted on a 0.1 mmol scale; absolute stereo-
b
chemistry was determined by X-ray crystallography. Determined by
c
d
1H NMR analysis. Determined by chiral HPLC. Substrate and
e
BrTi(Oi-Pr)3 were added over 8 h. Yield based on BrTi(Oi-Pr)3.
with the reaction conditions, with BINOL and dialkyl tartrates
both inhibiting reactivity. While no selectivity was seen with
isolated olefin substrates (Table 1, entry 2), we suspected that
the introduction of polar functionality capable of binding to the
metal might lead to improvements in the reactivity, selectivity,
and product utility. Indeed, cinnamyl alcohol (6) was converted
to dibromide (−)-7 with 43% ee using (R,R)-TADDOL 8
(entry 3). Allylic ethers, amides, and sulfonamides were all less
reactive, and the products were racemic. Optimization12 of the
backbone and aryl groups on the diol led to the identification of
(R,R)-9 as the optimal diol, with 100 mol % loading leading to
the dibromination of cinnamyl alcohol with 87% ee (entry 4).
Clear indications that the diol acts as a catalyst for this reaction
were the observations that lowering its loading to 20 mol % led
to only an 11% decrease in ee (entry 5) and that the addition of
2.5 mol % diol still resulted in significant enantioinduction
(entry 6). Slow addition of substrate and titanium to a solution
of 3 and 9 was found to restore some selectivity under
substoichiometric conditions, delivering (−)-7 with 81% ee
(entry 7). It is of practical and mechanistic significance that the
diol was recoverable in nearly quantitative yield under all
conditions, further demonstrating its role as a catalyst even
when stoichiometric quantities are used.
lead to the combination of substrate, titanium bromide, 3, and
9 into a coordinatively saturated titanium complex (10) in
which 3, bromide, and substrate are arranged to allow for both
intramolecular bromonium delivery and intramolecular bro-
mide capture. In such a monomeric structure,14 the metal
should activate the malonate, promoting potentially reversible
intramolecular bromine atom transfer to form bromonium 11.
Charge separation within zwitterion 11 should increase the
nucleophilicity of the bromide, which could then add to the
bromonium through hypothetical transition state 12 wherein
the two bidentate ligands enforce an octahedral geometry.
A number of findings have informed our current mechanistic
thinking. Excess bromide in the form of anhydrous
tetrabutylammonium bromide (TBAB) or additional bromoti-
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dx.doi.org/10.1021/ja4083182 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Correspondingly, the replacement of 3 with other brominating
agents led to reduced enantioselectivity in the reaction
employing 100 mol % 9 (N-bromosuccinimide, 33% ee;
tetrabromocyclohexadienone, 69% ee; tetrabutylammonium
tribromide, 55% ee). Seebach11 and others15 have invoked
monomeric species akin to 10 in other Ti−TADDOL-mediated
transformations.
Experimental evidence thus far is most consistent with
bromide delivery being selectivity-determining (12). Such a
scenario may manifest itself through an effective dynamic
kinetic resolution of the reversibly formed transient bromonium
intermediate 11. Selectivity-determining bromonium formation
or a concerted dibromination step, however, cannot be
unequivocally ruled out at this time.
performance is intrinsic to such substrates or the instability of
the corresponding products. Electron-donating substitution at
the meta position, however, was tolerated (entry 10). While the
yields in most cases were moderate, diastereomeric dibromide
products were not observed; starting material and malonate−
alcohol transesterification products composed the majority of
the remaining material. In the case of a p-vinyl substrate (entry
11), dibromination at the terminal olefin was not observed,
although decomposition resulted in low mass balance. Multiply
substituted substrates, including a differentially protected
diphenol, were also viable (entries 7 and 12). Preliminary
results with alkyl allylic alcohols (55% ee) indicated that some
degree of regiocontrol and enantioselectivity is possible in the
absence of aromatic substitution. Under the current conditions,
homoallylic alcohols (75% ee) and cis-aryl-substituted allylic
alcohols (51% ee) were also modest but encouraging
substrates.12
Under the optimized conditions, we next examined the
reaction scalability and various substituted cinnamyl alcohols
using both 100 and 20 mol % diol (S,S)-9 (Table 2). With
The synthetic utility of enantioenriched dibromides relies
strongly on whether they can be stereospecifically transformed.
With newfound access to such species, an initial survey of
subsequent reactions of 7 was undertaken, and it revealed that
nearly perfect stereospecificity is possible in derivatizations
(Scheme 3). Silver salts allow for stereoretentive substitution at
Table 2. Reaction Scalability and Cinnamyl Alcohol Aryl
Substituent Effects
Scheme 3. Enriched Chiral Building Blocks Enabled by
a
Enantiospecific Derivatizations
a
See the Supporting Information for assignment of product relative
stereochemistries.
the benzylic position, presumably via a configurationally stable
bromonium. The nonbenzylic alkyl bromide can be selectively
functionalized as well by intramolecular displacement of the
pendant alcohol. Alcohol oxidation is also possible and
proceeds with only a slight erosion of enantioselectivity. The
present methodology thus enables the synthesis of chiral
building blocks that are now accessible in highly enantioen-
riched form.
In conclusion, we have described a catalytic enantioselective
dibromination of allylic alcohols. This reaction is enabled by a
unique combination of reagents constituting a new strategy for
alkene dihalogenation. Current efforts are underway to better
understand this reactivity and the origins of the selectivity, to
realize applications of the enabled products, and to find new
uses for this reagent combination in other enantioselective
halofunctionalization and olefin addition reactions.
a
Reactions were conducted on a 1.0 mmol scale; absolute
b
configurations were assigned by analogy to 7. Isolated yields.
c
d
Determined by chiral HPLC. Scale = 10.0 mmol (1.34 g of 6).
Reaction time = 60 h. Reaction time = 44 h. 2.0 equiv of 3.
e
f
g
parent substrate 6, a 100-fold increase in scale resulted in little
change in overall reaction performance (Table 2, entry 1 vs
Table 1, entries 4 and 7). The dibromination remained highly
selective with electron-poor substitution at the ortho and para
positions of the aromatic ring (entries 2−6 and 8) but was
slightly less selective with meta substitution (entry 9). Nitro
substitution resulted in poor conversion. Electron-donating
substituents at the ortho and para positions resulted in low
dibromide yields, but other dibromination methods on such
substrates are similarly low yielding, suggesting that the poor
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterizations, and spectral data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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S
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dx.doi.org/10.1021/ja4083182 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
K. B. J. Am. Chem. Soc. 1991, 113, 106. (c) Seebach, D.; Plattner, D. A.;
Beck, A. K.; Wang, Y. M.; Hunziker, D.; Petter, W. Helv. Chim. Acta
AUTHOR INFORMATION
Corresponding Author
nburns@stanford.edu
■
́
1992, 75, 2171. (d) Ramon, D. J.; Yus, M. Chem. Rev. 2006, 106, 2126.
(10) The pseudomicroscopic reverse, a Ti-catalyzed bromination of
β-ketoesters in 23% ee, has been reported. See: Hintermann, L.;
Togni, A. Helv. Chim. Acta 2000, 83, 2425.
Notes
The authors declare no competing financial interest.
(11) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001,
40, 92.
(12) See the Supporting Information for details.
ACKNOWLEDGMENTS
■
This work was supported by Stanford University and the NSF
(GRF to D.X.H., DGE-114747). We are grateful to Professors
Du Bois, Trost, Stack, and Kanan for helpful discussions and
Dr. Diego Solis-Ibarra and the Karunadasa group for X-ray
crystallographic analysis.
(13) Values from: Gutmann, V. Coord. Chem. Rev. 1976, 18, 225.
(14) Complex 10 is thought to be one of two potentially reactive
diastereomeric titanium species; no nonlinear effect was observed. See
the Supporting Information for details.
(15) (a) Haase, C.; Sarko, C. R.; DiMare, M. J. Org. Chem. 1995, 60,
1777. (b) For a related Ti−TADDOL-catalyzed iodocarbocyclization
of alkenyl malonates, see: Inoue, T.; Kitagawa, O.; Saito, A.; Taguchi,
T. J. Org. Chem. 1997, 62, 7384 and references therein. (c) Bertogg, A.;
Hintermann, L.; Huber, D. P.; Perseghini, M.; Sanna, M.; Togni, A.
Helv. Chim. Acta 2012, 95, 353.
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dx.doi.org/10.1021/ja4083182 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX