Aryloxide-Facilitated Catalyst Turnover in Enantioselective α,β-Unsaturated Acyl Ammonium Catalysis

Article abstract of DOI:10.1002/anie.201706402

A new general concept for α,β-unsaturated acyl ammonium catalysis is reported that uses p-nitrophenoxide release from an α,β-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to α,β-unsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79 % yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the α,β-unsaturated p-nitrophenyl ester, and a recently reported variable-time normalization kinetic analysis method was used to delineate the complex reaction kinetics.

Full text of DOI:10.1002/anie.201706402

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Accepted Article
Title: Aryloxide-Facilitated Catalyst Turnover in Enantioselective α,β-
Unsaturated Acyl Ammonium Catalysis
Authors: Anastassia Matviitsuk, Mark Greenhalgh, Diego Barrios
Antunez, Alexandra Slawin, and Andrew David Smith
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706402
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10.1002/anie.201706402
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Aryloxide-Facilitated Catalyst Turnover in Enantioselective ,-
Unsaturated Acyl Ammonium Catalysis
Anastassia Matviitsuk, Mark D. Greenhalgh, Diego-Javier Barrios Antúnez, Alexandra M. Z. Slawin and
Andrew D. Smith*
Abstract:
A
new general concept for ,-unsaturated acyl
In this manuscript we report the development of a new general
concept for ,-unsaturated acyl ammonium catalysis. Catalyst
turnover is not facilitated by the nucleophilic reaction partner, but
by an aryloxide counterion released in situ during the reaction by
using an ,-unsaturated aryl ester as the ,-unsaturated acyl
ammonium precursor (Scheme 1 c).[9-11] This allows the use of
simple nucleophiles as reaction partners, providing enhanced
potential for further advancement of the field. Mechanistic work
including kinetic analysis, catalyst labeling and crossover studies
are also reported to deliver a fundamental understanding of this
process.
ammonium catalysis is reported that uses p-nitrophenoxide release
from an ,-unsaturated p-nitrophenyl ester substrate to facilitate
catalyst turnover. This method was used for the enantioselective
isothiourea-catalyzed Michael addition of nitroalkanes to ,-
unsaturated p-nitrophenyl esters in generally good yield and with
excellent enantioselectivity (27 examples, up to 79% yield, 99:1 er).
Mechanistic studies identified rapid and reversible catalyst acylation
by the ,-unsaturated p-nitrophenyl ester, and a recently-reported
variable time normalization kinetic analysis method was used to
delineate the complex reaction kinetics.
Lewis base organocatalysis is a widely studied field due to the
diverse range of molecular frameworks that can be produced
with high levels of regio-, chemo- and stereocontrol.[1] At the
carboxylic acid oxidation level
a
variety of ammonium
intermediates with differing reactivity can be accessed from
readily available substrates using tertiary amine Lewis bases
(Scheme
1 a). Acyl ammonium and ammonium enolate
intermediates have been extensively studied and applied in
enantioselective acyl transfer processes and formal
cycloadditions, respectively.[2,3]
A less studied but equally
powerful reactivity mode is that of ,-unsaturated acyl
ammonium intermediates.[4] These species contain electrophilic
centres at the C1 and C3 positions, and a latent nucleophilic
centre at C2, providing new opportunities for reaction design to
target previously inaccessible product architectures.[5]
Seminal work by Fu first demonstrated the feasibility of this
concept in a formal [3+2] cycloaddition using ,-unsaturated
acyl fluorides as the ,-unsaturated acyl ammonium precursor
(Scheme 1b).[6] Recent studies from ourselves, Romo, and
Matsubara, has built on this precedent to achieve highly
enantioselective
Michael
addition-annulation,
formal
cycloaddition and complex cascade methodologies.[7] These
examples used ,-unsaturated acid anhydrides or halides as
the ,-unsaturated acyl ammonium precursors. In addition,
these methodologies require the reactive partner to contain two
distinct nucleophilic functionalities to i) undergo conjugate
addition to the ,-unsaturated acyl ammonium intermediate,
and ii) enable turnover of the Lewis base catalyst (Scheme 1 b).
This requirement inherently limits ,-unsaturated acyl
ammonium catalysis and must be overcome to allow more
diverse processes. In addition only preliminary experimental
mechanistic work has been undertaken, with no kinetic analysis
reported to date.[8]
Scheme 1. Nomenclature, reactivity and applications of ammonium
intermediates in catalysis
As initial proof of concept, the Michael addition of nitroalkanes to
,-unsaturated aryl esters using a Lewis basic isothiourea
catalyst was investigated.[12] Although the organocatalytic
enantioselective Michael addition of nitroalkanes to enones or
enals is well precedented,[13] Lewis base catalysis of this
process has not been demonstrated at the carboxylic acid
oxidation level.
Initial investigations focused on the reaction of a range of ,-
unsaturated aryl esters 1-4, bearing different aryl groups, with
excess nitromethane using HyperBTM 5 as catalyst (Table 1,
entries 1-4). The Michael addition products 6-9 were formed in
each case in moderate to excellent yield (48-81%) but with
uniformly high enantioselectivity (up to 96:4 er) and with
complete regioselectivity.[14] The highest yields were obtained
using p-nitrophenyl (PNP) and 3,5-bis(trifluoromethyl)phenyl
esters 1 and 4, with PNP ester 1 chosen for further studies due
to the higher enantioselectivity obtained. Mixed solvent systems
A. Matviitsuk, Dr M. D. Greenhalgh, D.-J. B. Antúnez, Prof. A. M. Z.
Slawin, Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews, North
Haugh, St Andrews, Fife, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
Homepage: http://ch-www.st-andrews.ac.uk/staff/ads/group/
Supporting information for this article is given via a link at the end of
the document.
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Table 2. Reaction scope: Variation of ,-unsaturated p-nitrophenyl ester and
proved ineffective, with lower yields obtained in the presence of
both THF and MeCN (entries 5-6). The addition of a base (2,6-
lutidine) did not prove beneficial (entry 7),[15] whilst heating the
reaction at 70 °C resulted in complete decomposition (entry 8).
Alternative isothiourea catalysts did not provide improved results,
and lower catalyst loadings resulted in incomplete conversion,
which complicated product isolation.[16]
nucleophilic quench[a]
Table 1. Reaction optimization.
Entry Substrate
Solvent
Additive (equiv.) Yield (%)[a] er[b]
1
1
2
3
4
1
1
1
1
neat
-
81 (55)
54 (41)
48 (33)
78 (45)
50
96:4
94:6
95:5
93:7
ND[c]
ND[c]
ND[c]
-
2
neat
-
3
neat
neat
-
4
-
5
MeNO2:THF (1:1)
MeNO2:MeCN (1:1)
neat
-
6
-
43
7
8[d]
2,6-lutidine (0.2)
-
63
neat
0
[a] Determined by 1H NMR spectroscopic analysis using 1,4-dinitrobenzene as
internal standard (isolated yields given in parentheses). [b] Determined by
chiral HPLC analysis. [c] ND = not determined. [d] Reaction performed at
70 °C.
[a] Isolated yields given; er determined by chiral HPLC analysis. [b] Excess
MeOH and DMAP (20 mol%) used in step ii).
The effect of olefin configuration was investigated using maleate
PNP ester derivative 25 (Scheme 2). Interestingly, the Michael
addition product 12 was obtained in the same enantiomeric form
(93:7 er) as when using the isomeric fumarate PNP ester 1 (95:5
er). Monitoring reaction progress by 1H NMR spectroscopy
revealed rapid isomerization of maleate 25 to fumarate PNP
ester 1 on a faster timescale than formation of product, with
control reactions in d6-DMSO indicating reversible aryloxide
The scope and limitations of the method was then investigated.
Given the moderate isolated yields of PNP ester products, the
addition of a suitable nucleophile at the end of the reaction was
used to give a range of readily isolable functionalized products
(Table 2). The use of primary and secondary amines gave
secondary and tertiary amides 10-14 in good yield, whilst
addition of methanol gave methyl ester 15. All amide and ester
products were obtained with high enantioselectivity indicating no
significant loss in enantiopurity during the derivatization process.
The scope of -substituted ,-unsaturated aryl esters
amenable to the process was then investigated. Methyl-,
isopropyl- and benzyl esters gave the addition products 16-18 in
good yield and with excellent enantioselectivity. The
incorporation of amides at the -position was also well tolerated,
giving unsymmetrical succinamide derivatives 19 and 20 in
equally high yield and levels of enantiocontrol. The absolute
configuration of 19 was confirmed by single crystal X-ray
analysis, with all other examples assigned by analogy.[17]
Limitations of this methodology include incompatibility of
substrates such as -keto ester derivative 22, which gave a
complex mixture of products, and cinnamic acid derivative 23,
which was completely unreactive. A derivative bearing -alkyl
substitution however gave product 21 with excellent
enantiocontrol, albeit in low yield. The synthesis of a quaternary
stereogenic carbon centre was also attempted, however
application of ,-disubstituted derivative 24 failed to give the
desired Michael addition product.
conjugate addition as
isomerization process.[16,18]
a
possible mechanism for this
Scheme 2. Michael addition using maleate derivative 25
Attention was next turned to the use of alternative nitroalkanes
and subsequent derivatization of the products. Nitroethane and
nitropropane were suitable nucleophiles giving addition products
26 and 27 in good yield. Although only minimal diastereocontrol
was observed, both diastereoisomers were obtained with
excellent enantioselectivity (99:1 er, Table 3). Pleasingly, the
use of 2-nitropropane and nitrocyclopentane was also
successful, giving amide and ester products 28-31 in moderate
yield but with excellent enantiocontrol.
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Table 3. Reaction scope: Nitroalkane variation[a]
reaction, the 19F chemical shift (F) of (2R,3S)-8F-HyperBTM 36
underwent a significant downfield drift (F = −122.68 → ~−119.6
ppm), indicative of an equilibrating mixture of protonated and
freebase isothiourea. Using an independently synthesized
sample of 36·HCl as a reference (F = −116.72 ppm), the
proportion of freebase isothiourea 36 in the reaction was
calculated as a function of its chemical shift (Figure 1b, ×).[16,21]
Low concentrations (≤ 0.4 mM) of proposed acyl isothiouronium
species 38 (○) and 39 (△) were also identified by the downfield
chemical shift of the isothiouronium fluorine label (F = −111.79
and −111.97 ppm) (Figure 1 a and b, inset).[10d] Addition of an
isolated ,-unsaturated acyl isothiouronium 38 (where X = Cl,
−111.81 ppm)[22] to a reaction in progress resulted in significant
enhancement of both signals, providing support for this
assignment. In addition, mixing (2R,3S)-8F-HyperBTM 36 and
Michael addition product 37 gave a minor species with F
=
[a] Isolated yields given; dr of crude product determined by 1H NMR
spectroscopic analysis (relative configurations not confirmed); er determined
by chiral HPLC analysis. [b] Isolated as a mixture of diastereoisomers. [c] er of
both diastereoisomers. [d] Diastereoisomers separated by column
chromatography [41% (major); 32% (minor)]. [e] Excess MeOH and DMAP (20
mol%) used in step ii).
−111.97 ppm, consistent with nucleophilic addition of 36 to 37 to
give the post-Michael addition acyl isothiouronium 39.[16] These
studies are consistent with speciation of the isothiourea catalyst
between at least four forms, with the dominant, resting state, the
freebase isothiourea 36.
Having established a method for quantifying the temporal
concentration of reaction components, determination of the
reaction order with respect to each component was sought. The
complex catalyst speciation, in addition to slow hydrolysis of
starting material over the reaction course, indicated that kinetic
analysis may be challenging. However, as the temporal
concentrations of each component were easily measured, the
innovative variable time normalization graphical analysis method
reported recently by Burés was applied.[23] Kinetic analysis was
performed for three reactions with different starting
concentrations of ,-unsaturated ester 35 and (2R,3S)-8F-
HyperBTM 36 (Figure 1 a), with the concentration of MeNO2
assumed to remain constant (pseudo-zero order in MeNO2). A
plot of concentration of product 37 against a normalized time
axis of [35][36]t (where  and  represent the respective
reaction orders of each component) allowed graphical
interrogation of the kinetic profiles. Systematically varying  and
 provided optimal overlay for  = 1.0 and = 1.0, indicating the
reaction is first order in both ester substrate and catalyst.[16]
Despite good overlay, the curvature of the plot suggested an
additional reaction variable had been omitted from the analysis.
Further studies showed that addition of product 37 (10 mM) at
the start of the reaction resulted in rate retardation, consistent
with product inhibition.[16] Incorporation of [37] into the
normalized time axis ([35][36][37]t) resulted in good overlay
and linearity at an arbitrary value of = 0.5 (Figure 1 c).
Reduction of -nitro methyl esters 15, 29 and 31 and
concommitant cyclization was achieved with no loss in
enantiopurity to give pyrrolidinone derivatives 32-34 in excellent
yield and highly enantioenriched form (Table 4).[19] The biological
importance of pyrrolidinones, and -aminobutryric acid (GABA)
derivatives in general, is well precedented.[20]
Table 4. Product derivatization: Synthesis of enantioenriched pyrrolidinones[a]
To provide greater insight into this methodology, the reaction
mechanism and kinetics were investigated to identify reaction
intermediates and determine the reaction order with respect to
each component. Quantitative reaction monitoring was achieved
by in situ 19F{1H} NMR spectroscopy using 19F-labeled PNP
ester 35 and (2R,3S)-8F-HyperBTM 36 in MeNO2 using PhF as
internal standard and a C6D6-filled capillary reference (Figure 1
a,b). Attempts to interrogate the kinetic data revealed a
substantial reduction in reaction rate over the course of the
reaction, suggesting deactivation of the catalyst. During the
Figure 1. Temporal concentration data and variable time normalization kinetic analysis (VTNKA) for Michael addition of nitromethane to 35 using (2R,3S)-8F-
HyperBTM 36. a) Reaction scheme. b) Typical reaction profile: initial conditions: 35 (100 mM), 36 (12 mmol) in MeNO2 (0.6 mL), PhF (100 mM), C6D6 capillary
reference, r.t.; Key: ● = 35; × = freebase 36 (calculated); ▲ = 37; inset:  = 38; △ = 39. c) VTNKA: x-axis normalization for [35], [36] and [37].
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A series of crossover reactions was used to investigate the
reversibility of the primary catalytic steps (Scheme 3). Treatment
of ,-unsaturated esters 40 and 41 bearing two distinct PNP
ester groups (2-fluoro and 3-fluoro) and two distinct -
substituents (amide and ester) under catalytic conditions was
monitored by in situ 19F{1H} NMR spectroscopy (Scheme 3 a).
Rapid equilibration gave a mixture of all four possible ,-
unsaturated esters 40-43 within 5 minutes, with subsequent
formation of the four corresponding Michael addition products
44-47.[24] A second crossover experiment between two Michael
addition products, 44 and 45, bearing distinct PNP ester groups
and -substituents, also resulted in rapid exchange (Scheme 3
b). These experiments show that the isothiourea undergoes
rapid and reversible acylation by both the ,-unsaturated PNP
ester and the reaction product. Competitive acylation of the
catalyst 5 by the product and starting material is consistent with
the observed product inhibition and partial negative order in
product.
isothiouronium 49 adopts an s-cis conformation, with a syn-
coplanar non-covalent 1,5-S···O interaction between the acyl O
and catalyst S providing a conformational lock.[7b,d,8,10d,27] The
stereochemical outcome of the process can therefore be
rationalized by Michael addition of nitronate to the ,-
unsaturated acyl isothiouronium 49 anti- to the stereodirecting
phenyl substituent of the isothiourea catalyst.
Scheme 4. Proposed mechanism
In conclusion, a new general concept for ,-unsaturated acyl
ammonium catalysis has been developed which exploits p-
nitrophenoxide release from an ,-unsaturated p-nitrophenyl
ester substrate to facilitate catalyst turnover. This method allows
the use of simple nucleophilic reaction partners for the first time.
The concept was demonstrated in an enantioselective Michael
addition of nitroalkanes to ,-unsaturated p-nitrophenyl esters
in generally good yield and with excellent enantioselectivity (27
examples, up to 79% yield, 99:1 er). Mechanistic studies
identified rapid and reversible catalyst acylation by the ,-
unsaturated p-nitrophenyl ester to give a key ,-unsaturated
acyl isothiouronium intermediate. Product inhibition and catalyst
deactivation by protonation were identified under the reaction
conditions, and application of a recently-reported variable time
normalization graphical analysis method was required to allow
the complex reaction kinetics to be probed. It is hoped that the
report of this new reaction paradigm in ,-unsaturated acyl
ammonium catalysis will enable and encourage further
advancement of this burgeoning field.[28]
Scheme 3. Crossover experiments monitored by in situ 19F{1H} NMR
spectroscopy
Based on these studies the following catalytic cycle is proposed
(Scheme 4). The process begins with rapid and reversible
catalyst acylation by the ,-unsaturated PNP ester 48 to give
,-unsaturated acyl isothiouronium 49, with the position of
equilibrium favoring the free catalyst 5 and ,-unsaturated PNP
ester 48. Michael addition of nitronate to ,-unsaturated acyl
isothiouronium 49, followed by protonation, gives acyl
isothiouronium 51.[25] It is conceivable that the p-nitrophenoxide
counterion released upon acylation may facilitate deprotonation
of nitromethane,[26] with subsquent protonation of the
isothiouronium enolate 50 facilitated by either nitromethane or p-
nitrophenol. Finally, catalyst turnover by p-nitrophenoxide gives
the Michael addition product 52 and regenerates isothiourea 5.
Based on kinetic studies and the rapid crossover between 19F-
labeled ,-unsaturated PNP esters 40 and 41 relative to the
overall rate of reaction, it is likely that Michael addition of
nitronate to ,-unsaturated acyl isothiouronium 49 is the
turnover rate-limiting step. Based on previous experimental and
computational studies it is believed the ,-unsaturated acyl
Acknowledgements
We thank the European Research Council under the European
Union's Seventh Framework Programme (FP7/2007-2013) ERC
grant agreement no. 279850 (A.D.S) and the EPSRC
(EP/J018139/1, A.M.) for funding. A.D.S. thanks the Royal
Society for a Wolfson Research Merit Award. We also thank the
EPSRC UK National Mass Spectrometry Facility at Swansea
University.
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10.1002/anie.201706402
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COMMUNICATION
Keywords: Lewis base catalysis • ,-unsaturated ammonium •
isothiourea • aryloxide catalyst turnover • kinetic and mechanistic
analysis
[20] a) S. Shorvon, Lancet 2001, 358, 1885-1892; b) M. Ordóñez, C.
Cativiela, Tetrahedron Asymm. 2007, 18, 3-99.
[21] T. Rodima, V. Maemets, I. Koppel, J. Chem. Soc. Perkin Trans. 1, 2000,
2000, 2637–2644.
[22] ,-Unsaturated acyl isothiouronium chloride 38 (where X = Cl) was
unreactive in MeNO2, however upon addition of tetrabutylammonium p-
nitrophenoxide (1 equiv.), product 37 and starting material 35 were
formed rapidly (<120 s), with subsequent full conversion to product 37
over time (~600 s). See the Supporting Information for full details.
[23] a) J. Burés, Angew. Chem. Int. Ed. 2016, 55, 16084-16087; Angew.
Chem. 2016, 128, 16318-16321; b) J. Burés, Angew. Chem. Int. Ed.
2016, 55, 2028-2031; Angew. Chem. 2016, 128, 2068-2071.
[1]
[2]
[3]
S. E. Denmark, G. L. Beutner, Angew. Chem. Int. Ed. 2008, 47, 1560-
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C. E. Müller, P. R. Schreiner, Angew. Chem. Int. Ed. 2011, 50, 6012-
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[4]
[5]
For a review see: S. Vellalath, D. Romo, Angew. Chem. Int. Ed. 2016,
55, 13934-13943; Angew. Chem. 2016, 128, 14138-14148.
For a recent review on the related area of ,-unsaturated acyl azolium
catalysis see: C. Zhang, J. F. Hooper, D. W. Lupton, ACS Catal. 2017,
7, 2583-2596.
[24] Michael addition products 44-47 were independently synthesised to
allow identification.
[25] In the crossover experiment between reaction products (Scheme 3b),
the formation of ,-unsaturated esters 40-43 was not observed. In
addition, whilst reaction of (2R,3S)-8F-HyperBTM 36 with Michael
addition product 37 gave post-Michael addition acyl isothiouronium 39,
the formation of ,-unsaturated acyl isothiouronium 38 or PNP ester
35 was not observed. Both of these experiments suggest that one or
both steps in the catalytic cycle between 49 and 51 may be essentially
irreversible under the reaction conditions (Scheme 4).
[6]
[7]
E. Bappert, P. Muller, G. C. Fu, Chem. Commun. 2006, 2604-2606.
For
a review see ref [4]. For selected examples see: a) S.
Pandiancherri, S. J. Ryan, D. W. Lupton, Org. Biomol. Chem. 2012, 10,
7903-7911; b) E. R. T. Robinson, C. Fallan, C. Simal, A. M. Z. Slawin,
A. D. Smith, Chem. Sci. 2013, 4, 2193-2200; c) G. Liu, M. E. Shirley, K.
N. Van, R. L. McFarlin, D. Romo, Nat. Chem. 2013, 5, 1049-1057; d) M.
E. Abbasov, B. M. Hudson, D. J. Tantillo, D. Romo, J. Am. Chem. Soc.
2014, 136, 4492-4495; e) Y. Fukata, K. Asano, S. Matsubara, J. Am.
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Cordes, A. M. Z. Slawin, A. D. Smith, Chem. Eur. J. 2016, 22, 17748-
17757.
[26] For examples in which deprotonation has been postulated to be
facilitated by a basic counter-anion of an acyl ammonium intermediate
see: a) S. Xu, I. Held, B. Kempf, H. Mayr, W. Steglich, H. Zipse, Chem.
Eur. J. 2005, 11, 4751-4757; b) K. Nakata, K. Gotoh, K. Ono, K. Futami,
I. Shiina, Org. Lett. 2013, 15, 1170-1173; c) L. C. Morrill, J. Douglas, T.
Lebl, A. M. Z. Slawin, D. J. Fox, A. D. Smith, Chem. Sci. 2013, 4, 4146-
4155.
[8]
[9]
For studies which have included computational mechanistic work see:
ref [7d] and; a) E. R. T. Robinson, D. M. Walden, C. Fallan, M. D.
Greenhalgh, P. H.-Y. Cheong, A. D. Smith, Chem. Sci. 2016, 7, 6919-
6927; b) M. E. Abbasov, B. M. Hudson, D. J. Tantillo, D. Romo, Chem.
Sci. 2017, 8, 1511-1524.
[27] Non-covalent S···O interactions have recognized importance in
medicinal chemistry: a) B. R. Beno, K.-S. Yeung, M. D. Bartberger, L. D.
Pennington, N. A. Meanwell, J. Med. Chem. 2015, 58, 4383-4438; b) X.
Zhang, Z. Gong, J. Li, T. Lu, J. Chem. Inf. Model. 2015, 55, 2138-2153;
For discussions of S···O interactions in isothiourea-catalyzed reactions:
c) V. B. Birman, X. Li, Z. Han, Org. Lett. 2007, 9, 37-40; d) P. Liu, X.
Yang, V. B. Birman, K. N. Houk, Org. Lett. 2012, 14, 3288-3291.
[28] The research data underpinning this publication can be found at DOI:
http://dx.doi.org/10.17630/421487e5-d537-4fc8-b067-b6dd664c20d3
For a review on aryloxide-assisted catalyst turnover in Lewis base
catalysis see: W.C. Hartley, T. J. C. O’Riordan, A. D. Smith, Synthesis,
2017, 49, 3303-3310.
[10] For examples of aryloxide-assisted catalyst turnover in ammonium
enolate catalysis see: a) T. H. West, D. S. B. Daniels, A. M. Z. Slawin,
A. D. Smith, J. Am. Chem. Soc. 2014, 136, 4476-4479; b) K. J.
Schwarz, J. L. Aoms, J. C. Klein, D. T. Do, T. N. Snaddon, J. Am.
Chem. Soc. 2016, 138, 5214-5217; c) X. Jiang, J. J. Beiger, J. F.
Hartwig, J. Am. Chem. Soc. 2017, 139, 87-90; d) T. H. West, D. M.
Walden, J. E. Taylor, A. C. Brueckner, R. C. Johnston, P. H.-Y. Cheong,
G. C. Lloyd-Jones, A. D. Smith, J. Am. Chem. Soc. 2017, 139, 4366-
4375.
[11] For examples of using aryl esters as azolium enolate and ,-
unsaturated acyl azolium precursors see: a) L. Hao, Y. Du, H. Lv, X.
Chen, H. Jiang, Y. Shao, Y. R. Chi, Org. Lett. 2012, 14, 2154-2157; b) J.
Cheng, Z. Huang, Y. R. Chi, Angew. Chem. Int. Ed. 2013, 52, 8592-
8596; Angew. Chem. 2013,125, 8754-8758; c) Z. Fu, X. Wu, Y. R. Chi,
Org. Chem. Front. 2016, 3, 145-149.
[12] For a recent review of isothiourea catalysis see: J. Merad, J.-M. Pons,
O. Chuzel, C. Bressy, Eur. J. Org. Chem. 2016, 2016, 5589-5610.
[13] a) L. S. Aitken, N. R. Arezki, A. Dell’Isola, A. J. A. Cobb, Synthesis
2013, 45, 2627-2648; b) R. Ballini, G. Bosica, D. Fiorini, A. Palmieri, M.
Petrini, Chem. Rev. 2005, 105, 933-971.
[14] Yields determined by 1H NMR spectroscopy using an internal standard.
Isolated yields were 13-33% lower, which was attributed to hydrolysis of
the PNP ester upon purification by flash silica column chromatography.
[15] Romo has reported a beneficial effect of using 2,6-lutidine in Diels-
Alder-lactonization organocascades, see refs 7c, 8b.
[16] See the Supporting Information for full details.
[17] CCDC 1554262 contains the supplementary crystallographic data for
19.
[18] For thiophenolate-catalyzed isomerization of maleate esters to
fumarate esters see: a) H. Yamashita, T. Mukaiyama, Chem. Lett. 1985,
14, 363-366; b) R. Kowalczyk, P. J. Boratyński, Adv. Synth. Catal. 2016,
358, 1289-1295.
[19] CCDC 1554261 contains the supplementary crystallographic data for
34.
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10.1002/anie.201706402
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Anastassia Matviitsuk, Mark D.
Greenhalgh, Diego-Javier Barrios
Antúnez, Alexandra M. Z. Slawin, and
Andrew D. Smith*
Page No. – Page No.
Aryloxide-Facilitated Catalyst
Turnover in Enantioselective ,-
Unsaturated Acyl Ammonium
Catalysis
A new concept in ,-unsaturated acyl ammonium catalysis is reported which uses
aryloxide release from an ,-unsaturated aryl ester substrate to facilitate catalyst
turnover. Enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to
,-unsaturated p-nitrophenyl esters was achieved in good yield and with excellent
enantioselectivity. Variable time normalization kinetic analysis was used to probe
reaction mechanism, with rapid and reversible catalyst acylation of starting material
and product identified through crossover reactions.
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