Catalytic asymmetric intermolecular stetter reaction of enals with nitroalkenes: Enhancement of catalytic efficiency through bifunctional additives

Article abstract of DOI:10.1021/ja203810b

An asymmetric intermolecular Stetter reaction of enals with nitroalkenes catalyzed by chiral N-heterocyclic carbenes has been developed. The reaction rate and efficiency are profoundly impacted by the presence of catechol. The reaction proceeds with high selectivities and affords good yields of the Stetter product. Internal redox products were not observed despite of the protic conditions. The impact of catechol has been found to be general, facilitating far lower catalyst loadings than were previously achievable.

Full text of DOI:10.1021/ja203810b

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Catalytic Asymmetric Intermolecular Stetter Reaction of Enals
with Nitroalkenes: Enhancement of Catalytic Efficiency through
Bifunctional Additives
Daniel A. DiRocco and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S Supporting Information
b
Chart 1. Effect of Brønsted Acid Additivesa
ABSTRACT: An asymmetric intermolecular Stetter reac-
tion of enals with nitroalkenes catalyzed by chiral N-hetero-
cyclic carbenes has been developed. The reaction rate and
efficiency are profoundly impacted by the presence of
catechol. The reaction proceeds with high selectivities and
affords good yields of the Stetter product. Internal redox
products were not observed despite of the protic conditions.
The impact of catechol has been found to be general,
facilitating far lower catalyst loadings than were previously
achievable.
he use of N-heterocyclic carbenes as organocatalysts has led
to the development of a variety of enantioselective CÀC
T
bond-forming reactions.1 We recently reported a highly asym-
metric intermolecular Stetter reaction2 of heterocyclic aldehydes
and nitroalkenes using novel fluorinated triazolium salt 4 as a
precatalyst.3,4 We found that this reaction requires the presence
of a proximal heteroatom for reactivity and were intrigued by its
role in both the reactivity and enantioselectivity, given that
elucidation could lead to further advancement of this methodol-
ogy. Because of the invariance in reactivity and enantioselectivity
across a range of electronically diverse substrates,5 it seems un-
likely that the heteroatom lone pair acts as a Lewis base, leaving
the possibility that its impact is due to sterics.6 We reasoned that
enals would be electronically similar to aryl aldehydes but far less
sterically demanding and lacking a proximal Lewis base. To test
this hypothesis, cinnamaldehyde (1a) and β-cyclohexylnitroalk-
ene (2a) were subjected to our established conditions (1.0 equiv
of i-Pr2NEt, MeOH, 0 °C) in the presence of precatalyst 4
(Chart 1, entry 1). Although only a trace amount of product was
obtained from this reaction, it was isolated in a promising 93% ee.
This experiment demonstrates that a β-heteroatom is not
required for high enantioselectivity.
aReactions were conducted with 1 equiv of 1a and 1.5 equiv of 2a. bYields
refer to isolated yields after chromatography. cEnantiomeric excess was
determined by HPLC analysis on a chiral stationary phase.
shows a remarkable increase in reactivity and isolated yield
(Chart 1, entry 4). We note that products of redox esterification,9
a common pathway for enals under similar conditions,7 are not
formed in appreciable amounts. We speculated that the special
reactivity was due to the proximal nature of the phenolic protons.
Indeed, hydroquinone, which contains distal biprotic function-
ality and is electronically similar to catechol, showed only a slight
improvement in yield (Chart 1, entry 3). In order to isolate the
effects of electronics from the biprotic functionality, guaiacol
was also investigated and found to provide little benefit relative
to phenol (Chart 1, entry 5). These experiments strongly sug-
gest the participation of both functional groups in the rate-
accelerating event.
After identifying enals as potential substrates, we began to op-
timize the reaction in hopes of creating a more efficient process.
During previous optimization studies, it was established that
protic solvents are required for the desired reactivity. Phenols
have previously been shown to be compatible with NHC-cat-
alyzed processes,7 which led us to investigate them as potential
additives in the context of our work. Among those surveyed,
bisphenols were the most effective at increasing catalyst turnover.
Addition of 1 equiv of phenol to the reaction mixture afforded
very little improvement, but addition of 1 equiv of catechol8
Although the origin of its influence on the reactivity is not
rigorously understood, we speculate that catechol assists in pro-
ton transfer to generate crucial acyl anion equivalent II. Under
Received: May 5, 2011
Published: June 16, 2011
r
2011 American Chemical Society
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Chart 4. Reaction Scope a,b,c
Figure 1. Proposed mode of activation.
Chart 2. Variation of the Catechol Additivea,b
aReactions were conducted with 1 equiv of 1a and 1.5 equiv of 2a.
c
bExperiments were quenched after 30 min. Yields are isolated yields
after chromatography. dEnantiomeric excess was determined by HPLC
analysis on a chiral stationary phase.
Chart 3. Examination of Precatalystsa,b,c
aReactions were conducted with 1 equiv of 1 and 1.5 equiv of 2.
bEnantiomeric excess was determined by HPLC analysis on a chiral
stationary phase. cAbsolute stereochemistries were determined by X-ray
analysis of 3e (see the Supporting Information). dThe product crystal-
lized from the reaction mixture. e4-(Ethoxycarbonyl)catechol (Chart 2,
entry 4) was used.
absence of any bulky stereodirecting groups (Chart 3). For
comparison, desfluoro precatalyst 6 provided the product in
86% ee, only a modest improvement over precatalyst 5.
With the advent of this efficient dual catalytic system, we
investigated the scope of this transformation (Chart 4). Aryl
substitution on the enal results in product formation in good
yields (57À97%) and excellent enantioselectivities (93À98% ee).
Likewise, dienals may be incorporated with uniformly high
selectivity, while alkyl substitution on the enal produces some-
what reduced enantioselectivities. Secondary alkyl substitution of
the nitroalkene is well-tolerated, providing a variety of carbocyclic
and heterocyclic products. Under these conditions, primary-
alkyl-substituted nitroalkenes lead mainly to decomposition
products; however, the use of a more acidic ester-substituted
catechol derivative (Chart 2, entry 4) leads to high yields of the
nitroketone product, albeit with diminished enantioselectivity.
More sterically demanding electrophiles such as 1-nitrocyclohex-
ene do not participate (Chart 4).11
The somewhat disappointing results obtained with primary-
alkyl-substituted nitroalkenes prompted us to investigate the
effect of including larger electron-deficient N-aryl substituents on
the catalyst scaffold, in anticipation that these might increase the
selectivity. When aminoindanol-derived precatalyst 7 containing
a C6F5 substituent is subjected to the conditions developed for
primary-alkyl nitroalkenes, a modest yield of product 3n is
a,bSee Chart 1. cThe catalyst counterion (BF4À) has been omitted for clarity.
our basic reaction conditions, catechol monoanion (catecholate)
is likely the catalytically relevant species. Because direct 1,2-hydrogen
shifts are symmetry-forbidden,10 catecholate could aid in gen-
erating the acyl anion by facilitating proton transfer through a syn-
chronous transition state (I), reminiscent of the familiar car-
boxylic acid dimer (Figure 1).
A variety of catechol derivatives were examined to determine
their effect on the reactivity (Chart 2). We chose to use catechol
as the additive of choice in the remainder of our investigation
because of its high reactivity and wide availability.
With the identification of a suitably reactive catalyst system,
we began to investigate the effect of the catalyst structure on the
enantioselectivity. In our previous studies of the asymmetric inter-
molecular Stetter reaction, we showed that fluorination of the
catalyst backbone has a dramatic impact on the enantioselectivity.3
To probe the effect of backbone fluorination on the selectivity,
we screened both desfluoro analogue 6 and precatalyst 5, whose
chirality is dictated solely by its fluorine substituent. Remarkably,
precatalyst 5 displays high enantioselectivity (81% ee) in the
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Chart 5. Influence of the N-Aryl Substituent on the
Selectivity
the intramolecular Stetter reaction has recently provided signi-
ficant evidence for the conclusion that the turnover-limiting step
is initial proton transfer.12 Exposure of aldehyde 7 to 0.1 mol %
triazolium salt 9 and 0.2 mol % i-Pr2NEt in toluene provides low
yield (34%) of the cyclized product (Scheme 1). However,
introduction of only 0.2 mol % of catechol to the reaction results
in a dramatic increase in reactivity and an excellent isolated yield
(99%). Thus, it stands to reason that catechol is intimately in-
volved in facilitating proton transfer in this system, which may be
closely related to its action in the intermolecular reaction.
2
To test this hypothesis, we conducted a H kinetic isotope
effect study using 1a and its deuterated isotopologue (CDO) in
methanol or methanol-d4. The value of kH/kD was found to be
2.7 when the reaction was conducted in methanol and 4.2 when
conducted in methanol-d4 (Chart 6). These data suggest that
initial proton transfer to form acyl anion equivalent II is also
turnover-limiting in this transformation. Furthermore, we ob-
aThe opposite enantiomer was obtained.
1
served a kH/kD = 1.8 when H-aldehyde 1a was subjected to
Scheme 1. Effect of Catechol in the Intramolecular Stetter
Reaction
identical reaction conditions in methanol-d4, suggesting the par-
ticipation of the phenolic proton of catechol in the turnover-
limiting step.13
In summary, we have developed a highly efficient and en-
antioselective intermolecular Stetter reaction of enals and ni-
troalkenes. The incorporation of enals in the asymmetric Stetter
reaction not only significantly expands a scope previously limited
to heteroaryl aldehydes but also complements the homoenolate
reactivity commonly observed in NHC-catalyzed reactions of
enals. High selectivity has been achieved through the use of
fluorinated triazolium salt precatalysts. Furthermore, we have
shown that bifunctional Brønsted acids such as catechol significantly
enhance the reactivity and chemical yield in the Stetter reaction, and
their mechanism of action was probed through a series of kinetic
isotope effect studies, which provides convincing evidence that the
turnover-limiting step is initial proton transfer. This observation was
crucial in the development of this methodology and may have long-
lasting implications for other NHC-catalyzed processes.
2
Chart 6. H Kinetic Isotope Effect Studiesa
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization data, H/13C NMR spectra, and crystallographic
1
data (CIF) for 3e. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
rovis@lamar.colostate.edu
’ ACKNOWLEDGMENT
We thank NIGMS (GM72586) for support, Kevin Oberg and
Derek Dalton for X-ray analysis of 3e, and Amgen and Roche for
unrestricted support. D.A.D. thanks Roche for an Excellence in
Chemistry Award.
aSee the Supporting Information for complete experimental details.
obtained with very low enantioselectivity. We were pleased to
find that replacing the C6F5 substituent with the larger 2,4,6-Cl3-
3,5-F2 substituent on the same catalyst scaffold results in a
significant improvement in the selectivity. (Chart 5). We antici-
pate that future catalyst design will lead to a more general
solution for difficult substrates.
In an attempt to elucidate further the role of catechol in this
transformation, we investigated its effect on the well-studied
intramolecular Stetter reaction. A detailed mechanistic study of
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