Mechanistically Guided Design of an Efficient and Enantioselective Aminocatalytic α-Chlorination of Aldehydes

Article abstract of DOI:10.1021/jacs.1c02997

The enantioselective aminocatalytic α-chlorination of aldehydes is a challenging reaction because of its tendency to proceed through neutral intermediates in unselective pathways. Herein we report the rational shift to a highly selective reaction pathway involving charged intermediates using hexafluoroisopropanol as solvent. This change in mechanism has enabled us to match and improve upon the yields and enantioselectivities displayed by previous methods while using cheaper aminocatalysts and chlorinating agents, 80-95% less amount of catalyst, convenient temperatures, and shorter reaction times.

Full text of DOI:10.1021/jacs.1c02997

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Mechanistically Guided Design of an Efficient and Enantioselective
Aminocatalytic α‑Chlorination of Aldehydes
George Hutchinson, Carla Alamillo-Ferrer, and Jordi Burés*
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ABSTRACT: The enantioselective aminocatalytic α-chlorination of aldehydes is a challenging reaction because of its tendency to
proceed through neutral intermediates in unselective pathways. Herein we report the rational shift to a highly selective reaction
pathway involving charged intermediates using hexafluoroisopropanol as solvent. This change in mechanism has enabled us to match
and improve upon the yields and enantioselectivities displayed by previous methods while using cheaper aminocatalysts and
chlorinating agents, 80−95% less amount of catalyst, convenient temperatures, and shorter reaction times.
Scheme 1. Key Steps That Determine the Enantioselectivity
of the Aminocatalytic α-Chlorination of Aldehydes
ver the past 20 years, many different enantioselective
aminocatalytic reactions have been developed to
O
functionalize carbonyl compounds.1−3 This field has expanded
rapidly because of its relevance and operational simplicity, but
emphasis has been placed on the discovery of diverse reactions
over their optimization. Consequently, the currently available
aminocatalytic reactions often require atypical reagents, high
catalyst loadings, low temperatures, and long reaction times.
For example, the asymmetric α-chlorination of aldehydes
requires nonideal reaction conditions to avoid several pathways
that erode the intrinsic stereoselectivity of the aminocatalyst
and reduce its turnover frequency.4−7
Mechanistic studies of aminocatalytic reactions have shown
the existence of unexpected reaction pathways involving
neutral diastereotopic downstream intermediates.4−7 Inves-
tigation into the α-chlorination reaction demonstrated that
although the facial selectivity of the enamine in the
chlorination step is almost perfect (Scheme 1), the final
enantioselectivity of the product is low due to a posterior
bifurcation of the reaction pathway. Catalytic intermediate 1 is
involved in fast equilibria with the diastereoisomeric 1,2-aminal
adducts syn-2 and anti-2 (Scheme 1).5 Under standard
reaction conditions, the 1,2-aminal adducts are the resting
state of the reaction because of their higher stability with
respect to the charged iminium salt (1 in Scheme 1). As a
consequence, the reaction proceeds through the pathways
involving 1,2-aminals (red pathways in Scheme 1), which are
intrinsically slower than the one through the direct hydrolysis
of the iminium ion (blue pathway in Scheme 1). In addition,
the stereospecific elimination of the diastereoisomeric 1,2-
aminals leads to diastereomeric enamines, Z-3 and E-3, which
ultimately form products with opposite stereochemistry at the
α-center to the carbonyl (R-4 and S-4). Pioneering
enantioselective aminocatalytic chlorinating methods solved
this problem by using aminocatalysts that favor one of the
diastereomeric 1,2-aminals,8 using chlorinating agents that
result in poorly coordinating counterions,9,10 using SOMO
catalysis (single occupied molecular orbital),11 or using a
combination of a very sterically hindered catalyst, N-chloro-4-
nitrophthalimide and a mixture of trifluoroacetic and acetic
acid.12 All these solutions led to highly enantio-enriched
products, but they require expensive or noncommercially
available aminocatalysts and chlorinating agents, high catalyst
Received: March 19, 2021
Published: April 30, 2021
https://doi.org/10.1021/jacs.1c02997
J. Am. Chem. Soc. 2021, 143, 6805−6809
© 2021 American Chemical Society
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loadings, and, in some cases, low temperatures (−30 °C) and
very long reaction times (48 h).13 Herein we report the use of
hexafluoroisopropanol (HFIP) to invert the standard stability
of aminocatalytic intermediates in organic solvents, which
enables the efficient and enantioselective aminocatalytic α-
chlorination of aldehydes.
Hexafluoroisopropanol is well-known to stabilize cations
because of its high dielectric constant and low nucleophil-
icity.14 Therefore, we envisioned that HFIP could stabilize
iminium ions with respect to neutral 1,2-aminal downstream
intermediates. To test this hypothesis, we mixed hydro-
cinnamaldehyde with the Jørgensen−Hayashi type catalyst 3a
in HFIP (Scheme 2). We observed, by 1H NMR spectroscopy,
Scheme 2. Enamine and Iminium Ion Stability in Different
Organic Solvents
quantitative conversion of the catalyst to the iminium ion of
the hydrocinnamaldehyde.13 The remarkable preference for
the iminium ion contrasts with the exclusive formation of the
corresponding enamine that we observed in all the other
solvents we tried: CD2Cl2, CDCl3, CD3CN, THF-d8, methyl
tert-butyl ether (MTBE), toluene-d8, DMSO-d6, CD3OD, and
even isopropanol.13
Encouraged by the capacity of HFIP to stabilize iminium
ions, we attempted the α-chlorination reaction in HFIP. We
initially obtained a disappointing 2.4% of the monochlorinated
product and 5.9% of dichlorinated product (71% of
dichlorination) in 12 h when using N-chlorosuccinimide
(NCS), 2.5 equiv of hydrocinnamaldehyde, and 2 mol % of
catalyst 3a (Figure 1). To understand the reasons for this
discouraging result and to improve the reaction yield, we
monitored the reaction by 1H NMR spectroscopy. The rate of
formation of dichlorinated product was not proportional to the
concentration of monochlorinated product (Figure 1a), which
suggested that the dichlorinated product was mainly generated
from the overchlorination of a catalytic intermediate instead of
the subsequent chlorination of the released monochlorinated
product. We reasoned that the addition of water should reduce
the percentage of dichlorination because water is involved in
the hydrolysis of the chlorinated iminium but not in its
equilibration with the chlorinated enamine and subsequent
dichlorination reaction. When we ran the reaction with 11.15
M of water, the percentage of dichlorinated product
satisfactorily decreased from 71% to 3% (Figure 1b). While
the addition of water solved the dichlorination problem, it
further reduced the overall yield to 3%. We attributed this even
lower yield to deactivation processes involving the free catalyst
because we observed that water shifted the iminium formation
equilibrium toward the free catalyst.13
Figure 1. Addition of water reduces the amount of dichlorinated
product, but it also decreases the overall yield after 12 h.
corresponding to the aldehyde chain. Consequently, we
investigated the potential deactivation pathways arising from
reaction of the free catalyst with the chlorinating agent. We
1
monitored, by H NMR spectroscopy, the reaction of four
different Jørgensen−Hayashi type catalysts (3a−3d, Scheme
3) with NCS in HFIP. We observed immediate chlorination of
all the catalysts, which led to a Grob-type fragmentation15,16 in
the case of the catalysts bearing two phenyl groups, 3c and 3d
(Scheme 3). We hypothesize that the 3,5-bis(trifluoromethyl)-
phenyl groups in catalysts 3a and 3b disfavor the required
Scheme 3. Reversible and Irreversible Deactivation
Processes of Jørgensen−Hayashi Type Catalysts
To better understand the deactivation processes, we focused
1
our attention on the H NMR signals of the catalytic species
observed during the reaction. The spectroscopic data acquired
during the reaction showed a quick and near-quantitative
formation of a catalytic intermediate without signals
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conformation for a Grob-type fragmentation, and as a
consequence, the corresponding chlorinated catalysts are
stable for more than 16 h.13 To the best of our knowledge,
this is the first Grob-type fragmentation described for
Jørgensen−Hayashi type catalysts and may also be relevant
for other aminocatalytic reactions.
As we found that the chlorination of the catalyst is
reversible,13 we tried to shift the chlorination equilibrium
toward the active catalyst by adding succinimide to the
reaction. Unfortunately, even running the reaction in HFIP
saturated with succinimide was not enough to accelerate the
reaction sufficiently (20% yield in 10 h with 0.3 M of
succinimide added).13
Finally, we attempted to mitigate the catalyst deactivation by
dosing the NCS slowly. This strategy was previously used by
Hein, Armstrong, and Blackmond to minimize the reversible
reaction of prolinate salts with diethyl azodicarboxylate.17 On
the basis of our newfound understanding of the reaction in
HFIP, we expected low concentrations of NCS to disfavor the
formation of inactive chlorinated catalyst and to reduce the
percentage of dichlorination. To monitor the progress of the
reaction during the slow addition of chlorinating agent, we
used an in situ FT-IR probe, which allowed us to continuously
measure the concentration of NCS and succinimide. The
instantaneous addition of NCS to a reaction containing 2.7 M
of water (Figure 2a) led to the quick chlorination of the
catalyst and the stagnation of the reaction at 9% yield with 14%
of the product being dichlorinated. Longer addition times (4
min, Figure 2b) led to a gradual accumulation of NCS, which
resulted in a 52% yield with 2% of dichlorination. When the
NCS was added sufficiently slowly (19 min, Figure 2c), the
generation of succinimide perfectly matched the addition of
NCS; the reaction was complete in just 19 min, and only 1% of
the product was dichlorinated. By dosing NCS at the adequate
rate, we increased the yield of the reaction from 9% to 100% and
decreased the percentage of dichlorination from 14% to 1%.13
We identified the concentration of water and rate of addition
of the chlorinating agent as key parameters to control the
overall yield of the reaction, the enantiomeric ratio of the
product, and the ratio of mono- and dichlorinated aldehyde.7
Higher concentrations of water decreased the percentage of
dichlorinated product and increased the chlorination of the
catalyst.13 Lower rates of addition reduced the percentage of
dichlorinated product and the chlorination of the catalyst, but
too-low rates allowed the racemization of the product by the
free catalyst.13 We also observed that higher percentages of
dichlorination usually correlated to slight increases in the final
enantiomeric ratio of the product, probably because of a
kinetic resolution analogous to the one described by Jørgensen
in the α,α-difluorination of aldehydes.18
Figure 2. Slow addition of the chlorinating agent enables the
completion of the reaction.
selective reaction pathway, which was shown to be quicker
when using NCS instead of NCP.5 Additionally, we achieved
similar enantioselectivities with the typically less selective
catalyst 3a by sacrificing some yield (Table 1, entry 3). We
were able to produce comparable results despite reducing the
amount of catalyst by half, to 1 mol %, through longer addition
times of the chlorinating agent and the addition of phthalimide
at the beginning of the reaction to reduce catalyst chlorination
(Table 1, entry 4). We achieved excellent results running the
reaction at room temperature, conditions under which the
reaction is complete in just 20 min (Table 1, entry 5). We
obtained remarkable results even using hydrocinnamaldehyde
as limiting reagent, by adding the chlorinating agent over 150
min (Table 1, entry 6). The longer addition time (150 min) is
The mechanistic understanding acquired during this study
enabled us to demonstrate excellent results under several
practical reaction conditions (Table 1). The amount of water
and rate of addition of the chlorinating agent were quickly
tuned for each set of reaction conditions following a standard
procedure detailed in the Supporting Information.13 For the
hydrocinnamaldehyde, we obtained excellent yields and
enantioselectivities in just 60 min, at 0 °C, using only 2 mol
% of catalyst 3b and standard N-chlorophthalimide (NCP) as
chlorinating agent (Table 1, entry 1). We also attained
exceptional results using NCS as the chlorinating agent (Table
1, entry 2). The slightly smaller enantioselectivity obtained
with NCS may be due to the partial competition of the less
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Table 1. Example of Optimized Reaction Conditions for the α-Chlorination of Aldehydes
a
b
entry
deviation from above
H2O (μL) time of addition of the chlorinating agent (min) yield (%)
er
1
2
3
none
35
35
10
35
30
40
75
65
70
100
48
70
20
60
50
60
150
20
150
60
60
75
75
25
85
84
70
85
91
68
77
76
66
78
80
80
68
99:1
97:3
98:2
98:2
97:3
97:3
99:1
99:1
99:1
98:2
99:1
98:2
99:1
NCS instead of NCP
catalyst 3a instead of 3b
1 mol % of 3b instead of 2 mol %
rt instead of 0 °C
0.76 mmol of hydrocinnamaldehyde instead of 1.88 mmol
dodecanal instead of hydrocinnamaldehyde
octanal instead of hydrocinnamaldehyde
pentanal instead of hydrocinnamaldehyde
propanal instead of hydrocinnamaldehyde
isovaleraldehyde instead of hydrocinnamaldehyde
5-bromopentanal instead of hydrocinnamaldehyde
δ-valerolactol instead of hydrocinnamaldehyde
c
4
5
6
d
7
8
9
10
11
12
13
e
75
1440
f
a
b
Yield of α-chloroaldehyde measured by standard addition with the ReactIR 15.19 Enantiomeric ratio determined after reduction of the α-
c
d
chloroaldehyde to the α-chloroalcohol. 0.76 mmol of phthalimide added at the beginning of the reaction. 0.90 mmol (1.2 equiv) of NCP infused
over the time of addition. Reaction run at room temperature and 80% of the scale. 5 mol % of catalyst 3b at 8 °C and yield measured by qNMR
with an internal standard.
e
f
required to avoid catalyst deactivation due to the higher
percentage of free catalyst present at lower concentrations of
aldehyde. To show the ease of tuning the amount of water and
rate of addition of chlorinating agent for new substrates, we
also chlorinated dodecanal (Table 1, entry 7), octanal (Table
1, entry 8), pentanal (Table 1, entry 9), propanal (Table 1,
entry 10), isovaleraldehyde (Table 1, entry 11), and 5-
bromopentanal (Table 1, entry 12) with excellent yields and
enantioselectivities. We were even able to chlorinate with good
yield and exquisite selectivity the δ-valerolactol (Table 1, entry
13), a poorly reactive substrate due to the predominance of its
hemiacetal form.
In conclusion, hexafluoroisopropanol switches the natural
reaction pathway of the α-aminocatalytic chlorination reaction
in organic solvents by stabilizing charged catalytic intermedi-
ates. Originally, this change in mechanism engendered enantio-
enriched products at the cost of high levels of dichlorination
and catalyst deactivation. Both these complications have been
mitigated by tuning the amount of water and the rate of
addition of the chlorinating agent. The resulting synthetic
methodology achieves better overall yields and enantioselec-
tivities than current methods while using more convenient
catalysts and cheaper chlorinating agents in shorter reaction
times and at milder temperatures.
AUTHOR INFORMATION
■
Corresponding Author
Jordi Burés − Department of Chemistry, The University of
Manchester, M13 9PL Manchester, U.K.; orcid.org/0000-
0002-7821-9307; Email: jordi.bures@manchester.ac.uk
Authors
George Hutchinson − Department of Chemistry, The
University of Manchester, M13 9PL Manchester, U.K.;
orcid.org/0000-0001-5477-9521
Carla Alamillo-Ferrer − Department of Chemistry, The
University of Manchester, M13 9PL Manchester, U.K.;
orcid.org/0000-0003-3607-846X
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c02997
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research leading to these results has received funding from
the EPSRC projects EP/S005315/1 and EP/R513131/1.
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