Rhodium-catalyzed asymmetric synthesis of β-branched esters from allylic amines

Article abstract of DOI:10.1039/c8cc02612b

Allylic amines are converted to chiral, β-branched esters under rhodium catalysis in the presence of alcohol nucleophiles. Allylic amines with aliphatic and aromatic vinylic substituents are converted to ester products with excellent enantioselectivities in all cases. Several alcohol nucleophiles have been utilized in the reaction including 1° and 2° derivatives.

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Rhodium-Catalyzed Asymmetric Synthesis of β-Branched Esters
from Allylic Amines
Summer D. Laffoon,a Zhao Wu a and Kami L. Hull *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Allylic amines are converted to chiral, β-branched esters under well as via strong acid catalysis (Fischer esterification). Though
rhodium catalysis in the presence of alcohol nucleophiles. Allylic these approaches generally proceed with high conversion, the
amines with aliphatic and aromatic vinylic substituents are conditions required to generate acyl halides or strongly acidic
converted to ester products with excellent enantioselectivities in conditions are not amenable to sensitive functionalities.
all cases. Several alcohol nucleophiles have been utilized in the Stoichiometric coupling reagents generate high molecular
reaction including 1° and 2° derivatives.
weight byproducts that can be challenging to separate from the
desired product. Early reports of catalytic esterification, such as
the Tishchenko reaction, generate simple homocoupled
products (Scheme 1a).3 In recent years, the catalytic
esterification of aldehydes via transfer hydrogenation has
emerged as a meaningful alternative to stoichiometric coupling
reactions; however, many of these reactions require solvent
quantities of the alcohol nucleophile and are generally sterically
limited such that β-branched esters as products are difficult to
obtain in synthetically useful yields.4–6
The installation of esters into complex molecular scaffolds has
been the subject of much investigation in recent years.1 Chiral,
β-branched esters are prevalent moieties in pharmaceuticals,
fragrances, materials, and agrochemicals (Figure 1), and esters
themselves serve as versatile synthetic handles for further
functionalization.2 In an effort to diversify the pool of β-
branched esters that are rapidly accessible, we report herein a
method that sets the β-stereocenter while also constructing the
ester in the same chemical operation through an
isomerization/oxidation manifold.
Much of the work in generating chiral, β-branched esters
has focused on asymmetric conjugate reduction7 and
Traditionally, esters are generated through reactive
intermediates, such as acyl halides, or carboxylic acids paired
with stoichiometric coupling reagents (Steglich esterification) as
Figure 1 Biologically active β-branched esters.
a.Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S.
Mathews Ave. Urbana, IL 61801, United States
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 1 Precedent for the catalytic synthesis of chiral, β-branched esters.
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enantioselective conjugate addition (ECA)8 to α,β-unsaturated amine byproduct
esters (Scheme 1b). The major limitation of such strategies is product 3a, consistent with our earlier hypotheses (Table 1). We
poor substrate scope for individual catalysts. Changes to the found that the identity of the solvent played a key role in
substitution pattern of the substrate can require a different improving the chemoselectivity of the reaction. Changing the
Journal Name
4
was observed along with the desired ester
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DOI: 10.1039/C8CC02612B
metal/ligand scaffold meaning in the context of a synthesis, solvent from THF to DME limited the formation of
4 to trace
extensive screening may be required.9 These methods often quantities. Further modification of the reaction conditions
rely on significant steric differentiation between the identified Na3PO4 as an effective base (Table 1, entry 4) with
substituents at the β-position or are dependent on olefin styrene as a sufficient hydrogen acceptor necessary for catalyst
geometry to achieve high stereoselectivity.7a,c,e,f
turnover (see Supporting Information).
To overcome the limitations of previous reports, we drew
After optimizing the reaction conditions, we investigated
inspiration from the asymmetric isomerization of allylic amines the nucleophile scope of the reaction (Table 2). A variety of 1°
to optically pure enamines, developed by Noyori and Otsuka.10 alcohol nucleophiles including 1-hexanol (3a), ethanol (3b), and
Because the enantioselectivity of the isomerization of the allylic methanol (3c) are well-suited for the reaction providing esters
amine proceeds via a suprafacial 1,3-hydride shift and the initial in good yields. Nucleophiles containing heterocycles such as a
binding of the substrate to the catalyst is facially selective,10e pendant morpholino group (3e) are well-tolerated under the
steric differentiation between the substituents at the prochiral reaction conditions despite the ability of 3° amines to strongly
center is not required to achieve enantiopurity. This coordinate to many transition metal catalysts. Benzyl alcohol
isomerization approach could pave the way for a critical and its derivatives demonstrate the effect of electronic
advance in the asymmetric synthesis of β-branched esters. We variation on the yield of the reaction; electron neutral and
envisioned the resulting enantioenriched enamines undergoing slightly electron deficient alcohols are most efficient (3f-3j).
a dehydrogenative coupling with alcohol nucleophiles in the More hindered nucleophiles give slightly diminished yields,
presence of water to produce esters (Scheme 1a, c). demonstrating some sensitivity to steric hinderance (3k-3m).
Furthermore, allylic amines are compelling substrates as they Unfortunately, phenols are not competent nucleophiles under
can be readily accessed in a diastereomerically pure fashion the current reaction conditions. This may be attributed to the
through a variety of methods (Scheme 2).
competitive binding of the phenol to the cationic Rh(I) species.12
We were pleased to discover that the reaction is amenable
Our group has published a similar transformation for the
formation of amides from allylic amines and amine to a broad range of substitution patterns on the allylic amine
nucleophiles.11 During those investigations, we discovered that (Table 3). Several β,β-dialkyl esters, such as those containing
a Rh-BINAP complex with NaBArF4 in ethereal solvents were the silyl ethers (3n)‡ or distal arenes (3o
, 3p), can be accessed from
ideal conditions for the clean conversion of allylic amines to the corresponding allylic amines with excellent enantiomeric
amides. To modify this method for the synthesis of esters, we excess in all cases. Even when the substituents on the starting
believed we could replace amine nucleophiles with alcohols; alkene are sterically similar, the catalyst maintains high
however, there are some inherent challenges with such an enantiocontrol (3q). 3,3-diaryl allylic amines show good
approach. Alcohols are less nucleophilic than amines, reactivity and enantioselectivity; however, increased catalyst
disfavoring the formation of the hemiacetal intermediate loading and temperature are necessary to establish good
necessary for the final dehydrogenation.6 For this reason, we conversion of starting material to product. Electron-rich furyl
were particularly concerned with identifying conditions for the
selective synthesis of esters over other byproducts such as
alcohol nucleophile homocoupling, aldol condensation, or
deleterious reduction pathways in the presence of a Rh–H
species.
When our catalytic amidation conditions were employed
with 1-hexanol as a nucleophile instead of an amine, a tertiary
Table 1 Optimization of reaction conditions.
Entry
Base
Solvent
THF
DME
THF
DME
DME
DME
DME
X
3
3
3
3
2
1.5
1
3a yield (%)b
4 yield (%)b
1
2
3
4
5
6
7
Cs2CO3
Cs2CO3
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
52
56
79
91
82
71
49
12
<5
17
<5
13
10.5
17
a[Rh(cod)Cl]2 (2 mol %), (±)-BINAP (4 mol %), NaBArF4 (4 mol %), 1 (0.12 mmol), 2
(1–3 equiv), styrene (3.0 equiv), base (50 mol %), solvent (0.100 mL), H2O (1.5
equiv), 80 °C, 24 h. bIn situ yield determined by gas chromatography with
comparison to diphenyl methane (10 μL) as an internal standard.
Scheme 2 Synthesis of diastereomerically pure allylic amines. See Supporting
Information for details of substrate synthesis.
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Table 3 Scope of allylic amines for asymmetric oxidative esterification. a [Rh(cod)Cl]2 (2
mol %), (R)-BINAP (4 mol %), NaBArF4 (4 mol %), Na3PO4 (50 mol %), allylic amine (0.12
mmol), alcohol nucleophile (3 equiv), styrene (3.0 equiv), H2O (1.5 equiv), DME (1.2 M),
80 °C, 24 h. b from the Z isomer of 1 (91.7 : 8.3 Z/E) c with 2.0 equiv nucleophile. d 68%
and 5.5 : 94.5 d.r. with S-BINAP e with 5.0 equiv nucleophile. f at 100 °C. g with (S)-BINAP.
h at 100 °C for 48 h with 8 mol % catalyst.
Table 2 Scope of 1° and 2° alcohols for the esterification of allylic amines. a [Rh(cod)Cl]2
(2 mol %), (R)-BINAP (4 mol %), NaBArF4 (4 mol %), Na3PO4 (50 mol %), allylic amine (0.12
mmol), alcohol nucleophile (3.0 equiv), styrene (3.0 equiv), H2O (1.5 equiv), DME (1.2 M),
80 °C, 24 h. b with 5.0 equiv nucleophile. c with 2.0 equiv nucleophile. d at 100 °C.
enamine II can participate in several equilibrium-controlled
processes with in situ H2O and nucleophile to form a Rh-alkoxide
rings are well-tolerated under the reaction conditions (3r).
Excitingly, we have found that substrates containing exocyclic
alkenes, a substrate class rarely demonstrated for asymmetric
synthesis of β-substituted carbonyl compounds,7g are reactive
leading to good yields and enantioselectivities (3v-3w). Allylic
amines with π-functionality are not only limited to aryl
substituents. When a substrate containing an enyne is
subjected to the reaction conditions, no hydrogenation of the
alkyne is observed (3x). Finally, the absolute stereochemistry
has previously been unambiguously determined by X-ray
crystallography.11a
To probe the chemoselectivity of the transformation, we
subjected allylic amine 1a to the reaction conditions with a 1:1
ratio of 1° alcohol 1-hexanol to a variety of 2° alcohols (Scheme
3). Primary alcohols were preferentially incorporated, with
selectivities ranging from 5.3:1 for the least sterically hindered
cyclopentanol to 16.7:1 for the most sterically hindered α-
hydroxyethylbenzene. In an intramolecular competition study
between a 1° and 3° alcohol, the 1° alcohol was exclusively
incorporated (see Supporting Information).
species III 13
This intermediate can then undergo a β-hydride
.
elimination to form the final ester product IV and a Rh–H
species. Styrene acts as a hydrogen acceptor to regenerate the
active catalyst. Though we believe this process to be redox
neutral, a Rh(I)/(III) cycle for the oxidation of intermediate III
cannot be ruled out. Furthermore, when citronellal was
employed as the substrate under standard reaction conditions,
the yield of the reaction diminished (Scheme 4b). While no
definitive mechanistic conclusion can be drawn by this data
alone, it suggests that the reaction does not proceed through
build-up of large quantities of a discrete aldehyde intermediate.
In fact, crude NMR reveals evidence of aldehyde decomposition
under standard conditions (see Supporting Information).
Instead, the catalytically formed aldehyde may immediately
react with the alcohol to yield the final product, or the
Our current mechanistic hypothesis draws inspiration from
the work of Noyori, Otsuka, and Tani (Scheme 4a).10 Cationic
Rh(I)-BINAP complexes are known to facilitate an isomerization
of allylic amines to form optically pure enamines. The initial β-
hydride elimination to form II is the enantiodetermining
step.10c,e Under our reaction conditions, the intermediate
Scheme
determined by 1H NMR of the crude reaction mixture.
3
aGeneral reaction conditions: see Table 2. bChemoselectivity
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3
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Transfer hydrogenative esterification: (a) Owston, N. A.;
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7
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proceeding through the aldehyde.
7
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Conclusions
In conclusion, we have disclosed a method by which chiral, β-
branched esters can be synthesized in one pot with a broad
scope of nucleophiles and substrates. Utilizing an isomerization
strategy has enabled enantioinduction that is not limited by the
steric differentiation of the substituents at the prochiral center.
This method has been demonstrated for the asymmetric
synthesis of β,β-dialkyl-, β,β-diaryl-, and β-alkyl-β-aryl-
substituted esters, a breadth of substrate scope not commonly
observed in methods for the synthesis of similar compounds.
Primary and secondary alcohols are competent reaction
partners without need for solvent quantities of nucleophile.
This method performs similarly under a variety of steric
environments, giving good to excellent yields with excellent
enantioselectivities in all cases.
8
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Conflicts of interest
There are no conflicts to declare.
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β-Substituted chiral esters are synthesized in excellent yields and enantioselectivities from
allylic amines using [(BINAP)Rh]BArF as the chiral catalyst.
4

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