Assistant Professor of Chemistry
- 1993 Berea College, BA
- 2001 Virginia Polytechnic Institute & State University, Ph.D.
Hypervalent Halogen Amine Complexes
Over the past few decades, hypervalent halogen complexes such as the
Dess-Martin (DMP) and IBX reagents (Fig. 1) have been used in a wide
variety of applications. These include the conversion of alcohols,
imines, thioketals and benzylic methylenes (Ph-CH2-R) to ketones,
aldehydes, amines, imines, phenols to quinones, and the synthesis of
δ-lactams and cyclic urethanes. Although such reagents are desirable
because of their versatility, they are somewhat expensive
(approximately $300/mol), shock sensitive, and suffer from an
unfavorable atom economy in most applications. In an effort to find a
more attractive alternative to such reagents, we are exploring the uses
of hypervalent bromine (I) amine complexes first developed by Blair and
Quinuclidine and related compounds react with
molecular bromine to give hypervalent complexes such as
bis-quinuclidine bromine (I) bromide (BQBB) and polymeric DABCO-bromine
complex (PDB; Fig. 2). It has already been established that such
complexes are mild oxidants converting secondary and primary alcohols
to the corresponding ketone and aldehyde. These reagents are
chemoselective for the oxidation of secondary hydroxyls over primary.
Figure 1. Dess-Martin (DMP) and IBX reagents.
Figure 2. Hypervalent halogen amine complexes bis-quinuclidine bromine (I) bromide and polymeric DABCO bromine (PDB) complex.
Recently, we have discovered that these reagents, like the IBX and DMP
reagents, also exhibit a variety of reactivity and are a shelf-ready
source of electrophilic and free-radical bromine. For example, PDB is
capable of converting amines to imines, or ketones and/or aldehydes,
depending on the reaction conditions (Scheme 1). This complex is also a
high yielding para- selective brominating reagent for aromatic systems
with strong electron donating substituents (Scheme 2). It has also been
observed that PDB brominates aromatic hydrocarbons such as toluene,
ethyl benzene and cumene are converted to benzyl bromide,
(1-bromoethyl)benzene, and 2-bromo-2-phenylpropane, the latter of which
eliminates rapidly to α-methyl styrene under biphasic CH2Cl2/H2O
reaction conditions (Scheme 2). We hope to carefully study the scope
and limitations of these synthetic routes to provide an alternative to
the somewhat unattractive IBX and DMP reagents.
The Asymmetric Baylis-Hillman Reaction – Cyclodextrin as a Chiral Additive and Catalyst Support
The field of organocatalysis has grown dramatically over recent years.
The notion of mimicking enzymatic processes using relatively small and
inexpensive compounds is certainly an attractive one. By far,
nucleophilic, nitrogen- based compounds are the most popular.
Organocatalysts such as derivatives of proline, quinuclidine, indole,
imidazole, dimethylaminopyridine (DMAP), and various oligopeptides have
been used in a variety of applications including aldol, Mannich,
Michael, cycloaddition, cyclopropanation, Stetter, Baylis-Hillman,
epoxidation, and acyl transfer reactions.
reaction (Scheme 3) is of particular interest because it possesses
several attractive features found in the most useful organic
transformations. First, Baylis-Hillman adducts contain several
functional groups and a new chiral center; a hydroxyl group bound to a
chiral carbinol and an alkene in conjugation with an electron
withdrawing group, typically carbonyl, imidyl, thionyl or nitrile.
Baylis-Hillman adducts are, therefore, useful synthons for the
synthesis of more complex compounds. Second, the most widely used
catalyst is typically a derivative of quinuclidine; a bicyclic tertiary
amine found in the cinchona class of natural products and other chiral
reagents used in asymmetric catalytic processes (Fig. 3).
Lastly, the reaction generally features a favorable atom economy. This
reaction has its drawbacks however. Most notably, the reaction requires
long reaction times that are typically on the order of hours or days.
Slow reaction rates may be overcome by running the reaction at high
pressures and/or concentrations, using highly electron deficient
alkenes or aldehydes, or the use of hydrogen bonding solvents or
additives. Increased temperatures also enhance the rate although,
interestingly, there is at least one account of an increase in reaction
rate as temperature decreases.
Scheme 3 Figure
3. Baylis-Hillman catalysts: a) quinuclidine, b)
1,4-diazabicyclo[2.2.2]octane (DABCO), c) 3-hydroquinuclidine, d)
3-quinuclidone, e) C-2 symmetric 2,3-diphenyl DABCO (-R = -Ph) or
2,3-dialkoxy DABCO (-R = -OR), f) C-2 symmetric 2,5-dibenzyl DABCO (-R
= -CH2Ph), g) indolizine, h) imidazole, i) a chiral derivative, j)
quinidine (-R = -OMe) or cinchonine (-R = -H),
k) quinine (-R = -OMe) or cinchonidine (-R = -H), and l) β-isocupreidine.
The most widely accepted mechanism is shown in Scheme 4 (e. g. acrylic
ester and benzaldehyde). In the first step, the nucleophilic catalyst
adds in a Michael fashion to an activated (electron poor) alkene to
give a zwitter ionic enolate. The newly generated enolate is then
available to add in an aldol fashion to electrophiles such as aldehydes
and ketones. Subsequent proton transfer and catalyst regeneration steps
complete the cycle.
Hydrogen bonding has been shown to enhance the rate. Two to 10 fold
increases have been reported in the presence of hydrogen bond donors.
Hydrogen bonding solvents and additives may enhance the rate by 1)
activating the alkene further, and thus enhancing the addition of the
nucleophilic catalyst and/or stabilizing the resulting enolate (Scheme
5) or 2) activating the electrophile (aldehyde) making it more reactive
in the aldol step and stabilizing the alkoxide intermediate (Scheme 6),
or 3) a combination of these effects. Several investigators have made
compelling arguments supporting each rationale, but the effect of
hydrogen bonding is still unclear.
Electron demand also has
an effect on the reaction rate. Ethyl acrylate ( -EWG = -CO2Et; Scheme
3), for example, reacts with benzaldehyde slower than
2,2,2-trifluoroethyl acrylate (EWG = -CO2CH2CF3).
Over the past 15 years, efforts to develop an asymmetric Baylis-Hillman
reaction have been moderately successful. The majority of these
endeavors have taken advantage of two of the three major strategies for
stereocontrol: substrate control and asymmetric catalysis. Regarding
substrate controlled processes, the reaction is moderately Felkin-Ahn
selective (Scheme 7) usually giving product ratios ranging from 1.2 : 1
to 7 : 1 favoring the Felkin (syn-) product. Chiral auxiliary
approaches have demonstrated varying degrees of stereoselectivity (e.
g. eqs. 1 - 3) with auxiliary bound acrylates and acrylamides. However,
in order to obtain Baylis-Hillman adducts, such strategies require two
additional steps, the attachment and removal the auxiliary or an
additional modification, and are therefore not favorable in an atom
Asymmetric catalysts, like C-2 symmetric catalysts and the cinchona
alkaloids (Fig. 3, compounds e, f, j, and k), have exhibited low to
moderate stereoselectivities (0 – 47% ee) with acrylonitrile and methyl
vinyl ketone. Improvements were made with variety of alkenes and
electrophiles using a pyrrolizidine derivative (Fig. 3, compound i)
giving stereoselectivities of 30 – 75% ee. High selectivities (91 – 99%
ee) have been observed while using β-isocupreidine (Fig. 3, compound l)
at -55 oC with the highly reactive acrylate
1,1,1,3,3,3-trifluoroisopropyl acrylate (-R’ = -CH(CF3)2, Scheme 2).
At low temperatures, high selectivities are observed only for the
activated acrylate and, like chiral auxiliary approaches, the removal
of the trifluoroisopropyl group from the adduct is often required for
the synthesis of more complex compounds. The rationales for high
stereoselectivities when using both β-isocupreidine and the
pyrrolizidine derivative address the idea that both catalysts have
hydrogen bond donors (Figure 4) and act as bifunctional
nucleophilic/hydrogen bond donating organocatalysts.
4. Rationale of high stereoselectivity using β-isocupreidine and a
pyrrolizidine derivative showing possible bifunctional
nucleophilic/hydrogen bonding character of the catalyst. Both cases
argue that the orientation of the aldehyde such that the alkyl group is
directed away from the bulk of the intermediate/catalyst is the favored
orientation en route to the observed major stereoisomer.
We hope to develop a new method for an asymmetric Baylis-Hillman
reaction using DABCO as a catalyst and cyclodextrin or a cyclodextrin
derivative as a co-catalyst/chiral additive. Cyclodextrins are
macrocyclic oligomers composed of glucopyranose subunits (cyclic
oligosaccharides) and are commercially available as α-, β-, and γ-
cyclodextrins which contain six, seven, and eight subunits
respectively. These compounds are also available commercially as a
variety of derivatives (Fig. 5) and are widely used in chiral
There are a few recent
examples of their use as chiral supports for transition metals and
other reagents for asymmetric reductions and cyclopropanation
reactions. In much of the cyclodextrin literature, the structure is
often described as taking on a conical “lamp shade” shape with the
primary hydroxyls oriented near the narrow opening of the “lamp shade”
while the secondary hydroxyls are found on the opposite side (Fig. 6).
Cyclodextrins and their derivatives have been described as “artificial
enzymes” and are known to interact with organic compounds in a
host-guest manner such that their hydrophobic cavities tend to
encapsulate and release nonpolar compounds.
It has also been
suggested that, for compounds such as benzaldehyde, the aryl portion of
the aldehyde finds itself encapsulated within the hydrophobic cavity
while the carbonyl is held outside the cavity because of hydrogen
bonding. For Baylis-Hillman applications, restricted mobility of the
electrophile and/or the alkene within a bulky chiral template may lead
to high stereoselectivities. Furthermore, hydrogen bond donation of
cyclodextrin may also enhance the reaction rate.
5. Various commercially available cyclodextrins: a) α-cyclodextrin, b)
hepatkis (2,3-di-O-methyl)-β-cyclodextrin, and c) octakis
6. “Lamp shade” depiction of a a) cyclodextrin and b) hydrogen bonding
between bezaldehyde and cyclodextrin in which the aryl moiety of the
aldehyde is encapsulated within the hydrophobic cavity of the
We have conducted a preliminary study
using methyl acrylate, a variety of aldehydes, DABCO and α-cyclodextrin
as an additive/co-catalyst. Our data show that yields are slightly
higher when cyclodextrin is present compared to when it is absent over
the same time period. We have yet to determine the effect cyclodextrin
might have on the stereoselectivity of this reaction. Not surprisingly,
we have discovered that α-cyclodextrin is insoluble in a number of
However, in many small molecular
weight aldehydes (used in a 13 to 14 fold excess with respect to
acrylate), cyclodextrin is soluble at room temperature and, when no
solvent is used, we have observed that the rate enhancement is even
more pronounced compared to reactions in which solvents such as DMSO,
DMF, THF or CH2Cl2 are used. This is particularly encouraging from a
“green chemistry” standpoint. We hope to continue this study using
other large cyclic oligosaccharides as chiral additives/co-catalysts.
Expanding on the theme of bifunctional organocatalysts, it is hoped
that this project might be developed further by binding the
nucleophilic catalyst directly to the cyclodextrin macrocycle. Luckily,
there is a substantial amount of literature addressing the manipulation
and functionalization of cyclodextrins. To bind quinuclidine and other
nucleophilic catalysts to the primary face of cyclodextrins, we will
follow Yi’s well established protocol for primary face monoalkylation
which involves protection of the primary face, exhaustive methylation
of the secondary face, deprotection of the primary face and finally
monotosylation or mesylation of the primary face. Yi has shown that the
tosylate is easily displaced by SN2 reaction using alkoxides as
nucleophiles. In our case we will use the alkoxide of
3-hydroxyquinuclide (compound c, Fig. 3).
have also been used to modify the secondary face of cyclodextrins.
There are also examples in the literature of using imidazole (compound
h, Fig. 3) as a nucleophilic reagent to displace the tosylate
ultimately giving imidazole modified cyclodextrins. In short, we hope
to generate a cyclodextrin supported quinuclidine and imidazole
catalysts for use in the Baylis-Hillman reaction.
Figure 7. Quinuclidine (primary face) and imidazole (secondary face) modified cyclodextrin derivatives.