Enantioselective α-Chlorination Reactions of in Situ Generated C1 Ammonium Enolates under Base-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.1c02256

The asymmetric α-chlorination of activated aryl acetic acid esters can be carried out with high levels of enantioselectivities utilizing commercially available isothiourea catalysts under base-free conditions. The reaction, which proceeds via the in situ formation of chiral C1 ammonium enolates, is best carried out under cryogenic conditions combined with a direct trapping of the activated α-chlorinated ester derivative to prevent epimerization, thus allowing for enantioselectivities of up to e.r. 99:1.

Full text of DOI:10.1021/acs.orglett.1c02256

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Letter
Enantioselective α‑Chlorination Reactions of in Situ Generated C1
Ammonium Enolates under Base-Free Conditions
Lotte Stockhammer, David Weinzierl, Thomas Bögl, and Mario Waser*
Cite This: Org. Lett. 2021, 23, 6143−6147
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ABSTRACT: The asymmetric α-chlorination of activated aryl acetic acid esters can be
carried out with high levels of enantioselectivities utilizing commercially available
isothiourea catalysts under base-free conditions. The reaction, which proceeds via the in
situ formation of chiral C1 ammonium enolates, is best carried out under cryogenic
conditions combined with a direct trapping of the activated α-chlorinated ester
derivative to prevent epimerization, thus allowing for enantioselectivities of up to e.r.
99:1.
Scheme 1. Use of in Situ Generated C1 Ammonium
Enolates, Pioneering α-Halogenation Approaches, and the
Herein Investigated α-Chlorination
symmetric α-heterofunctionalization reactions, especially
α-halogenations, of prochiral enolate precursors and
A
analogues represent important transformations to access
valuable chiral building blocks suited for further manipulations
as well as potentially biologically active target molecules.1 Over
the last several decades, numerous asymmetric (organo)-
catalysis-based α-halogenation approaches for, for example,
amino acid derivatives,2 (cyclic) β-ketoesters,3 and oxindoles4
(to name a few), have been reported, and the introduction of
new concepts and methods is still a topic of considerable
interest. Whereas the asymmetric α-halogenation of cyclic
pronucleophiles has been very extensively developed,1−4 the
direct α-halogenation of acyclic enolate precursors, especially
simple carboxylic acid (ester)-based precursors, has been a
more challenging task. One conceptually very appealing
strategy to employ acyclic carboxylic acid equivalents in
asymmetric transformations relies on the use of chiral
nucleophilic organocatalysts (i.e., chiral amines, pyridine
derivatives, and isothioureas).5,6 These easily available catalysts
can react with ketenes or activated carboxylic acid derivatives
(esters, chlorides, or in situ generated anhydrides) to form
well-defined chiral C1 ammonium enolates (Scheme 1A).
These in situ generated species undergo various α-function-
alization reactions with high levels of stereoinduction, followed
by the release of the catalyst upon the addition of a nucleophile
(Nu).5−9 This attack may happen either in an intramolecular
fashion when the C1 ammonium enolate is reacted with a
suitable dipolar partner (resulting in formal (2 + n)
cyclizations)5,6 or in an intermolecular manner (e.g., the
ester group that is cleaved off during the ammonium enolate
formation is added again).7 This unique concept has over the
last several years shown its potential for a variety of asymmetric
C−C bond-forming reactions,5−7 even in a cooperative
manner with transition-metal catalysis.9
Received: July 6, 2021
Published: July 28, 2021
Surprisingly, however, asymmetric α-halogenation ap-
proaches have received less attention so far (Scheme 1B),
although early impressive reports by Lectka’s group demon-
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.orglett.1c02256
Org. Lett. 2021, 23, 6143−6147
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Letter
a
strated the potential of this concept to facilitate asymmetric α-
halogenations of acylhalides using Cinchona alkaloid catalysis.
(Turnover was achieved by the choice of the proper
electrophilic halide-transfer reagent or the addition of an
external nucleophile.)10,11 In addition, Smith’s and Fu’s groups
reported α-halogenations of ketene precursors using either
chiral N-heterocyclic carbenes (NHCs)12 or planar chiral
pyridine catalysts,13 underscoring the potential of this concept
to access valuable enantioenriched α-halogenated acyclic
carboxylic acid derivatives.
Table 1. Optimization of Reaction Conditions
t
conv.
b
3aOMe
c
d
entry Ar ITU (mol %) T (°C) (h)
(%)
(%)
e.r.
1
2
3
4
5
6
7
8
A
A
A
A
A
A
A
A
A
B
C
D
A
A
A
A
ITU1 (20%)
ITU2 (20%)
ITU3 (20%)
ITU1 (20%)
ITU1 (20%)
ITU1 (20%)
ITU1 (20%)
ITU1 (10%)
ITU1 (20%)
ITU1 (20%)
ITU1 (20%)
ITU1 (20%)
ITU1 (10%)
ITU1 (5%)
ITU1 (40%)
25
25
20
20
20
20
20
20
20
20
40
40
40
40
40
40
40
40
>95
95
90
>95
>95
80
45
40
>95
0
85
80
>95
45
>95
80
73
69
67
69
67
68
n.d.
n.d.
82
50:50
50:50
50:50
50:50
75:25
95:5
97:3
98:2
95:5
Our group recently became interested in asymmetric α-
chlorination reactions,14 and considering the value of α-
chlorinated carbonyl compounds15 and the unique potential of
C1 ammonium enolate chemistry to facilitate asymmetric α-
functionalizations of simple carboxylic acid derivatives, we
thought about developing the, to the best of our knowledge,
unprecedented α-chlorination of simple activated esters 1
(Scheme 1C). We reasoned that the use of well-established
isothioureas (i.e., the commercially available ITU1−3)6,16,17 in
combination with N-chlorosuccinimide (NCS, 2) would
hereby provide an entry to the α-chlorinated derivatives 3.
This reaction may be first steered toward the aryloxide-
rebound product 3Oar, which can then be converted into other
products by the addition of a nucleophile in a separate step, or
it may also be possible to carry out the reaction in the presence
of an external nucleophile, directly giving products 3Nu.
Furthermore, it should be possible to carry out the reaction
either totally in the absence of an external base,18 or at least
using only catalytic amounts of base, considering the fact that
the released succinimide should be capable of serving as the
base required for enolate formation. Encouragingly, during the
finalization of this manuscript, Zheng and coworkers reported
an elegant complementary approach for the α-fluorination of
free carboxylic acids (which are activated in situ upon the
addition of TsCl) in the presence of a newly designed
[2.2]paracyclophane-based isothiourea catalyst (Scheme
1B),19 thus underscoring the potential of this catalysis concept.
We started by carrying out the α-chlorination of the
pentafluorophenyl ester 1a. (Table 1 gives an overview of
the most significant screening results.) The first room-
temperature experiments in tetrahydrofuran (THF) showed
good conversion to the target 3aOAr in the absence of any
external base, substantiating our initial proposal. Unfortu-
nately, this product turned out to be rather unstable during the
work up and purification. Thus we changed our strategy in
such a way that we first carried out the ITU-catalyzed α-
chlorination (at the given temperature for the indicated time)
followed by the addition of MeOH to access the stable ester
3aOMe instead, which could easily be accessed and analyzed by
high-performance liquid chromatography (HPLC) using a
chiral stationary phase.20 Unfortunately, product 3aOMe was
isolated only in a racemic manner, independent of the used
ITU catalyst (entries 1−3). In addition, we also observed the
formation of small quantities of the dichlorinated product 4a
(usually <5% when using 2 equiv of NCS), and the amount of
4a significantly increased when a larger excess of NCS was
used.21
25
e
f
f
f
f
f
f
f
f
f
f
f
f
−40
−40
−60
−80
−80
−60
−60
−60
−60
−60
−60
−60
−60
9
10
11
12
13
14
15
16
66
61
79
n.d.
81
68
93:7
90:10
96:4
97:3
85:15
99:1
Se-ITU1
g
(10%)
f
17
18
19
20
A
A
A
A
ITU2 (10%)
ITU3 (10%)
ITU3 (10%)
ITU3 (10%)
−60
−60
−60
−60
40
40
63
63
70
75
>95
90
51
67
91
84
95:5
99:1
99:1
99:1
f
f
h
a
All reactions were carried out using 0.1 mmol 1 and 0.2 mmol 2 in
b
THF (0.1 M with respect to 1), unless otherwise stated. Conversion
c
of 1 judged by 1H NMR of the crude product. Isolated yields.
d
Determined by HPLC using a chiral stationary phase. Absolute
configuration of the major (R) enantiomer was assigned by the
comparison of the retention time order and its (−) rotation with
previous reports.20 MeOH added after warming the reaction mixture
e
f
to r.t. MeOH added at the cryogenic reaction temperature followed
g
by a slow warm up to r.t. over 8 h. Se-HyperBTM analogue was
recently introduced by Smith’s group.23 MeOH (2 equiv) present
h
during the whole reaction.
addition at low temperature (entry 5) resulted in notable levels
of enantioenrichment. Studies concerning the configurational
stability of product 3aOMe showed that this compound slowly
epimerized in the presence of external bases (e.g., Et3N),
whereas no loss of optical purity was observed after silica gel
column chromatography and upon prolonged dissolution in
nonbasic solvents. Thus the results reported in entries 4 and 5
can be rationalized by a rapid epimerization of 3aOAr in the
presence of the catalyst, most likely via the formation of the α-
chlorinated catalyst-bound intermediate II22 (Scheme 1C),
which shows increased acidity in the α-position (also
rationalizing the dichlorination toward 4). A quench at low
temperature, on the contrary, allows this epimerization to be
overcome by forming the more stable 3aOMe, which no longer
allows the formation of II. With these insights at hand, we
further lowered the temperature, resulting in good enantiose-
lectivities at −60 °C or lower (entries 6 and 7). Unfortunately,
the reaction significantly slowed down at −80 °C (entries 7
and 8), and we thus next carried out further optimizations at
−60 °C for 40 h (entries 9−19; all reactions were run in THF
because toluene and CH2Cl2 did not allow for any product
formation at all). Testing alternative esters 1a (entries 10−12)
Because ITU1 was found to be slightly more active
compared with ITU2 and ITU3 (entries 1−3), further testing
at lower temperatures was next done with ITU1. Interestingly,
when the chlorination was carried out at −40 °C followed by a
MeOH quench at room temperature (r.t.) (entry 4), product
3aOMe was still formed only as a racemate, whereas MeOH
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proved the crucial nature of the aryloxide. Whereas, as
expected, phenoxide (B) did not allow for any conversion,
the electron-poor aryl groups C and D allowed for good
conversion but with a slightly lower e.r. compared with the
initially used A. Changing the catalyst loading lead to a
surprising observation, as lower amounts of catalysts allowed
for slightly improved enantioselectivities (entries 13 and 14),
whereas a higher loading had a detrimental effect (entry 15).
Finally, we tested ITU2 and ITU3 as well as the recently
introduced HyperBTM isoselenourea (Se instead of S) Se-
ITU123 under the optimized conditions (entries 16−18).
Remarkably, whereas the selectivity of HBTM (ITU2) was
similar to that of ITU1 (compare entries 13 and 17),
isoselenourea Se-ITU1 and BTM (ITU3) both allowed for
significantly improved enantioselectivities of 99:1, albeit with
slightly lower conversions after 40 h reaction times (entries 16
and 18). In addition, in both cases, the formation of the
dichloro compound 4a was almost completely suppressed.
Gratifyingly, the slightly lower conversion with these catalysts
compared with ITU1 could easily be overcome by longer
reaction times (entry 19). Furthermore, we also tested whether
it may be possible to add MeOH right from the beginning, and
the outcome was very similar (entry 20); however, because
small amounts of methyl phenylacetate (formed via the
transesterification of 1a) were formed, too, we used the
stepwise protocol (entry 19) with the commercially available
ITU3 to investigate the application scope (Scheme 2).
Interestingly, the presence of electron-neutral organic
substituents and halides in different positions as well as
alternative aryl moieties primarily affected the conversion rate
but allowed for reasonable enantioselectivities in all cases
(3aOMe−3kOMe). Interesting observations were made when the
syntheses of the Br-substituted 3hOMe, the methoxy-containing
3mOMe and the nitro-derivative 3lOMe were attempted. Target
3hOMe was obtained with e.r. 98:2 after 40 h (complete
conversion) but with a slightly reduced selectivity of 95:5 after
63 h only,24 whereas the presence of the more electron-
donating methoxy group para to the reaction center resulted in
the formation of only racemic 3mOMe. These results may
primarily be attributed to the epimerization of the catalyst-
bound α-Cl intermediates II under the reaction conditions.
Whereas this process is not that strongly pronounced for
electron-neutral aryl substituents, the presence of more
electron-donating substituents (i.e., a methoxy group) para
to the benzylic chlorination site significantly increases the
epimerization rate. (The p-MeO group most likely triggers the
in situ cleavage of the Cl group via the formation of a quinone-
methide-type-stabilized benzylic carbocation followed by an
unselective readdition of the Cl.) It is noteworthy, this
epimerization could be mainly suppressed by the addition of
MeOH (2 equiv) right from the beginning (compare with
entry 20, Table 1), which allowed for a reasonably selective
direct synthesis of 3mOMe. In sharp contrast, the presence of
the NO2 group resulted in the quantitative formation of only
the dichloro product 4lOMe (the same was observed when
MeOH was added up front), which can be hereby rationalized
by the increased reactivity of the corresponding intermediate
II. (Using just 1 equiv of NCS gave 4lOMe in addition to
starting material 1l only!) Unfortunately, the α-alkylated ester
1n and the homologous phenylpropionic acid ester 1o were
not found to be reactive, which is in accordance with previous
observations for other C1 ammonium enolate applica-
tions.5−7,9,19
a
Scheme 2. Application Scope
Finally, we also carried out quenches with a few other
aliphatic alcohols and amines. The use of ethanol and i-PrOH
(products 3aOEt and 3aOiPr) resulted in slightly lower
enantioselectivities compared with the use of MeOH, which
can be rationalized by a slightly slower esterification with these
alcohols, thus allowing for some epimerization of intermediates
II. Unfortunately, the use of amines turned out to be much
more difficult, resulting in a significant loss of enantiopurity
(products 3aNHBn and 3aMorpholine). Considering the already
observed configurational lability of intermediates II, especially
under basic conditions, these results came as no big surprise,
and they underscore the need for the carefully optimized
reaction conditions developed herein.
In conclusion, it was possible to introduce a highly
enantioselective α-chlorination protocol of activated esters 1
under chiral isothiourea catalysis, but the reaction as such
requires carefully fine-tuned conditions to suppress the
epimerization of the reactive catalyst-bound intermediates.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02256.
a
All reactions were carried out using 0.1 mmol 1 and showed >95%
Experimental and analytic details (including copies of
HPLC traces) (PDF)
b
conversion unless otherwise stated. Repeated on a 1 mmol scale,
providing 3dOMe in 71% yield and with e.r. 99:1.
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Letter
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AUTHOR INFORMATION
■
Corresponding Author
Mario Waser − Institute of Organic Chemistry, Johannes
Kepler University Linz, 4040 Linz, Austria; orcid.org/
0000-0002-8421-8642; Email: mario.waser@jku.at
Authors
Lotte Stockhammer − Institute of Organic Chemistry,
Johannes Kepler University Linz, 4040 Linz, Austria
David Weinzierl − Institute of Organic Chemistry, Johannes
Kepler University Linz, 4040 Linz, Austria
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turnover: West, T. H.; Daniels, D. S. B.; Slawin, A. M. Z.; Smith, A. D.
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Thomas Bögl − Institute of Analytical Chemistry, Johannes
Kepler University Linz, 4040 Linz, Austria
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02256
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Austrian Science Funds
(FWF): project no. P31784.
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(24) This, together with the lower e.r. with higher catalyst loadings,
points against a process where a dynamic kinetic resolution (DKR) of
intermediate II may be dominant.
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Org. Lett. 2021, 23, 6143−6147