Base-free Enantioselective C(1)-Ammonium Enolate Catalysis Exploiting Aryloxides: A Synthetic and Mechanistic Study

Article abstract of DOI:10.1002/anie.201908627

An isothiourea-catalyzed enantioselective Michael addition of aryl ester pronucleophiles to vinyl bis-sulfones via C(1)-ammonium enolate intermediates has been developed. This operationally simple method allows the base-free functionalization of aryl esters to form α-functionalized products containing two contiguous tertiary stereogenic centres in excellent yield and stereoselectivity (all ≥99:1 er). Key to the success of this methodology is the multifunctional role of the aryloxide, which operates as a leaving group, Br?nsted base, Br?nsted acid and Lewis base within the catalytic cycle. Comprehensive mechanistic studies, including variable time normalization analysis (VTNA) and isotopologue competition experiments, have been carried out. These studies have identified (i) orders of all reactants; (ii) a turnover-limiting Michael addition step, (iii) product inhibition, (iv) the catalyst resting state and (v) catalyst deactivation through protonation.

Full text of DOI:10.1002/anie.201908627

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Base-free Enantioselective C(1)-Ammonium Enolate Catalysis
Exploiting Aryloxides: A Synthetic and Mechanistic Study
Authors: Calum McLaughlin, Alexandra M. Z. Slawin, and Andrew
David Smith
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201908627
Angew. Chem. 10.1002/ange.201908627
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http://dx.doi.org/10.1002/ange.201908627

10.1002/anie.201908627
Angewandte Chemie International Edition
RESEARCH ARTICLE
Base-free Enantioselective C(1)-Ammonium Enolate Catalysis
Exploiting Aryloxides: A Synthetic and Mechanistic Study
Calum McLaughlin, Alexandra M. Z. Slawin and Andrew D. Smith*
Dedication ((optional))
Previous work: Enantioselective Michael addition-lactonization
Abstract: An isothiourea-catalyzed enantioselective Michael
I
via :
O
addition of aryl ester pronucleophiles to vinyl bis-sulfones via C(1)-
ammonium enolate intermediates has been developed. This
operationally simple method allows the base-free functionalization of
aryl esters to form α-functionalized products containing two
contiguous tertiary stereogenic centres in excellent yield and
i-Pr
N
Ph
O
NR3
CF3
O
S
Ph
N
Ph
Ph
Ph
Ph
OH
O
Ph
O
HyperBTM (5 mol%)
+
t-BuCOCl (1.5 equiv)
CF3 i-Pr2NEt (4.0 equiv)
O
CF3
“intramolecular”
turnover
stereoselectivity (all
≥ 99:1 er). Key to the success of this
95:5 dr, 97:3 er
CH2Cl2, –78 °C

ammonium enolate reactivity deprotonation turnover limiting

excess activating agent and auxiliary base required
methodology is the multifunctional role of the aryloxide, which
operates as a leaving group, Brønsted base, Brønsted acid and
Lewis base within the catalytic cycle. Comprehensive mechanistic
studies, including variable-time normalization analysis (VTNA) and
isotopologue competition experiments, have been carried out. These
studies have identified (i) orders of all reactants; (ii) a turnover-
limiting Michael addition step, (iii) product inhibition, (iv) the catalyst
resting state and (v) catalyst deactivation through protonation.
electrophile requires latent nucleophile for catalyst turnover via I
Scheme 1. Intramolecular catalyst turnover in ammonium enolate catalysis.
catalysis.[8] In our previous work this strategy was first applied to
the enantioselective [2,3]-rearrangement of allylic ammonium
ylides to form stereodefined α-amino acid derivatives (Scheme
2a).[9] In this case, aryloxide released upon addition of the Lewis
base catalyst to a para-nitrophenyl ester substrate was used to
attack the post-rearrangement acyl ammonium intermediate II
(or its HOBt ester equivalent) and regenerate the free catalyst.[10]
Building upon this approach, Snaddon and co-workers have
developed elegant α-allylation and α-benzylation protocols of
pentafluorophenyl esters in union with palladium catalysis
(Scheme 2b),[11] while Hartwig and co-workers developed a co-
operative isothiourea/iridium-catalyzed allylation.[12] In previous
work we reported the enantioselective addition of C(1)-
ammonium enolates, generated from para-nitrophenyl esters, to
iminium ion electrophiles, however stoichiometric tetra-n-butyl
ammonium para-nitrophenoxide was also required as an
Introduction
C(1)-Ammonium enolates[1] have emerged as powerful
catalytically-generated
synthetic
intermediates
for
enantioselective C-C and C-X bond formation. Traditionally
generated from Lewis basic tertiary amine catalysts[2] and
ketenes,[3] recent advances have sought to access C(1)-
ammonium enolates directly from either carboxylic acids[1b,4] or
activated aryl esters.[5] When using carboxylic acid starting
materials, the most common approach involves in situ
derivatization to an anhydride prior to preparation of the C(1)-
ammonium enolate. Although powerful in concept, this strategy
is limited in terms of sustainability and atom economy. As
exemplified in Scheme 1, treatment of phenylacetic acid with
excess activating agent (such as t-BuCOCl, 1.5 equiv.) is
necessary to generate a reactive anhydride in situ prior to C(1)-
ammonium enolate formation, while excess auxiliary base (such
as i-Pr2NEt, 4.0 equiv.) is required for effective catalysis.[6]
These methodologies generally require the use of an
electrophile that contains a latent nucleophilic site (such as an
enone), in order for catalyst turnover to be achieved through
intramolecular cyclization to give formal cycloaddition products
(Scheme 1, inset).
Recent advances: aryloxide promoted “intermolecular” catalyst turnover
(a) Enantioselective [2,3]-rearrangement of allylic ammonium ylides
O
II
Br
via
:
O
Ph
N
O
Ph
Ph
Ph
ArO
Me2N
N
S
R3N
ArO
(R)-BTM (20 mol%)
NMe2
NMe2
OAr
HOBt (20 mol%)
i-Pr2NEt (1.4 equiv)
MeCN, –20 °C, 24 h
Ar: 4-NO2C6H4
> 95:5 dr
> 99:1 er
“intermolecular”
turnover
(b) Enantioselective Pd-catalyzed allylation/benzylation
O
(R)-BTM (20 mol%)
XantPhosPd (4 mol%)
O
Ph
OAr
+
Ph
X
OAr
Ar = C6F5
i-Pr2NEt (1.25 equiv)
THF, 23 C, 12 h
°
Building upon Lectka’s pioneering work using halogenated
quinones as electrophiles for the in situ generation of
aryloxides,[7] recent work has focused on using electron-deficient
aryl esters as C(1)-ammonium enolate precursors in isothiourea
99:1 er
(c) Enantioselective addition to iminium ions
N
O
Ph
Br
•HCl
Ph
O
N
S
OAr
+
NR
(S)-TM•HCl (5 mol%)
Ph
OAr
NR
NBu4OAr (1 equiv)
i-Pr2NEt (1.5 equiv)
THF, –10 °C, 24 h
Ar = 4-NO2C6H4
~75:25 dr, 95:5 er

aryloxide promoted catalyst turnover broadens reaction scope
[a]
Mr C. McLaughlin, Prof. A. M. Z. Slawin, Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews,
North Haugh, Fife, Scotland, UK. KY16 9ST
E-mail: ads10@st-andrews.ac.uk
Supporting information for this article is given via a link at the end of
the document.
high catalyst loadings common (20 mol%)  no mechanistic analysis
 stoichiometric auxiliary base or additive required for optimal reactivity
Scheme 2. Aryloxide promoted intermolecular catalyst turnover in
enantioselective ammonium enolate catalysis. (HOBt: hydroxybenzotriazole).
This article is protected by copyright. All rights reserved.

10.1002/anie.201908627
Angewandte Chemie International Edition
RESEARCH ARTICLE
additive for optimal reactivity (Scheme 2c).[13] While these
impressive strategies broaden the compatibility of C(1)-
ammonium enolate intermediates in dual catalytic processes
and with alternative electrophilic components, all typically
employ high catalyst loadings of the Lewis base (commonly 20
mol%) as well as excess auxiliary base. Furthermore, these
latter processes (Scheme 2b,c) are not well–understood
mechanistically in terms of identification of reaction
intermediates, reaction orders with respect to components, and
turnover-limiting step.
Proof-of-principle studies commenced using para-nitrophenyl
ester 1, 1.1 equivalents of vinyl bis-sulfone
2
and
tetramisole•HCl 3 (20 mol%) in dichloromethane at room
temperature for 24 hours (Table 1, entry 1). Whilst the product
ester could be isolated following chromatographic purification, it
proved unstable to HPLC analysis and so all further products
were isolated as the corresponding benzyl amide following
addition of benzylamine at the end of the reaction.
Encouragingly, amide 4 was formed in good yield (67%) with
high
diastereoselectivity
(88:12
dr)
and
excellent
Given this background, we envisaged an alternative base-
free and proton neutral Lewis base-catalyzed strategy for the
catalytic enantioselective functionalization of electron-deficient
aryl esters. Addition of an isothiourea Lewis base to an aryl ester
would initially generate an acyl ammonium aryloxide ion pair,
with deprotonation of the acyl ammonium by the aryloxide
enantioselectivity (> 99:1 er). The use of various isothiourea
catalysts was next investigated. Benzotetramisole (BTM) 5 gave
the product in improved yield (78%, entry 2), whilst maintaining
high dr (86:14) and er (> 99:1). Using HyperBTM 6 as catalyst
gave amide 4 in a lower yield of 60% yield, although excellent
stereoselectivity was still observed (entry 3). Notably, consistent
with our mechanistic hypothesis (Scheme 3), the use of an
external base was not necessary for effective catalysis. The
catalyst loading of BTM 5 could be reduced to 5 mol% whilst
maintaining high diastereo- and enantioselectivity, however 4
was obtained in lower yield (54%, entry 4). Reversing the
stoichiometry and increasing the ester equivalents (1.5 equiv.)
and concentration (0.5 M) provided amide 4 in improved yield
(entry 5). The use of alternative, industrially preferable solvents
(dimethylcarbonate, iso-propyl acetate)[14] provided amide 4 in
comparable yields and stereoselectivity with the exception of 2-
methyl THF which led to reduced yields and dr (entries 6-8).
generating
the
reactive
C(1)-ammonium
enolate.
Enantioselective Michael addition to
a
suitable acceptor,
followed by proton transfer from the in situ generated phenol,
and subsequent aryloxide turnover would deliver α-alkylated
products containing two tertiary stereogenic centres (Scheme 3).
This approach would circumvent the previous necessity for the
addition of an auxiliary base but would require the aryloxide to
fulfill the role of proton shuttle within the catalytic cycle. In this
manuscript, this concept is demonstrated through the
isothiourea-catalyzed Michael addition of ester pronucleophiles
to bis-sulfone Michael acceptors, where the sulfone groups
present within the reaction product provide functional handles for
further derivatization. Mechanistic investigations have been
carried out to analyze the temporal concentrations of the
reaction components, with variable time normalization analysis
(VTNA) used to determine their respective orders. Catalyst
deactivation and product inhibition effects were also found to be
significant over the reaction course. Measurement of a kinetic
isotope effect (KIE) was used to identify the turnover-limiting
step of the catalytic process.
Table 1. Reaction optimization.
O
O
catalyst (X mol%)
p-tol
PhO2S
SO2Ph
NHBn
Ph
p-tol
Ph
OAr
solvent (0.2 M)
RT, 24 h then
BnNH2 (5 equiv)
RT, 24 h
SO2Ph
PhO2S
1
2
4
Ar: 4-NO2C6H4
(1.1 equiv)
i-Pr
N
N
N
N
Ph
Ph
N
S
N
S
S
Ph
•HCl
This work: base-free functionalization of esters
OAr
3
5
6
(2S,3R)-HyperBTM ( )
(S)-TM•HCl ( )
(R)-BTM ( )
NR3
O
O
O
Yielda
(%)
R1
R1
R1
Entry
Catalyst (mol%)
Solvent
drb
erc
NR3
NR3
R2
OAr
OAr
H
OAr
leaving
group
Brønsted
base
EWG
EWG
1d
2
(S)-TM•HCl (20)
(R)-BTM (20)
CH2Cl2
CH2Cl2
67
78
88:12
86:14
< 1:99
> 99:1
Lewis
base
Brønsted
acid
O
O
O
H
OAr
R1
R1
R1
(2S,3R)-HyperBTM
OAr
OAr
NR3
NR3
3
CH2Cl2
60
80:20
98:2
(20)
EWG
EWG
EWG
EWG
R2
R2
R2
NR3
OAr
4
(R)-BTM (5)
(R)-BTM (5)
(R)-BTM (5)
(R)-BTM (5)
(R)-BTM (5)
CH2Cl2
CH2Cl2
DMC
54
86 (75)
85
89:11
89:11
89:11
89:11
79:21
> 99:1
> 99:1
98:2
EWG
aryloxide as leaving group, Brønsted base, Brønsted acid, Lewis base
base-free low catalyst loadings (5 mol%) Inverse secondary KIE
19F{1H} NMR temporal analysis
kinetic analysis (VTNA)
EWG


5e
6e
7e
8e




Scheme 3 This work: base-free enantioselective ammonium enolate catalysis.
i-PrOAc
2-MeTHF
89
> 99:1
> 99:1
(EWG: electron-withdrawing group).
63
[a] Combined yield of major and minor diastereomers. Determined by 1H NMR
analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene internal
standard. Isolated yield of major diastereoisomer in parenthesis. [b]
Determined by 1H NMR analysis of the crude reaction mixture. [c] Determined
by chiral HPLC analysis. [d] 1.0 equiv. i-Pr2NEt added. [e] 1.5 equiv. 1, 1.0
equiv. 2, 0.5 M concentration. (DMC: dimethylcarbonate).
Results and Discussion
1. Optimization Studies
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10.1002/anie.201908627
Angewandte Chemie International Edition
RESEARCH ARTICLE
Key to this strategy is the multiple roles of the aryloxide
within the catalytic cycle. It is required to be an effective leaving
group for N-acylation, to act as a Brønsted base and a Brønsted
acid (as the corresponding phenol), before acting as a Lewis
base. The steric and electronic effects of the aryloxide leaving
group were examined to gain insight into the subtle effects that
could alter its nucleophilicity, nucleofugality and basicity (Table
2).15 Using para-nitrophenyl ester 7 allowed ester 13 to be
isolated in high yield, dr and er (entry 1, 84%, 84:16 dr, > 99:1
er). Reaction of pentafluorophenyl ester 8 gave product 14 in
lower yield (39%), although excellent stereocontrol was
maintained (entry 2). The use of tetrafluorophenyl ester 9 gave
product 15 in 56% yield (entry 3), whilst 3,5-bis(trifluoromethyl)
ester 10 gave product 16 in 44% yield (entry 4). Interestingly, the
reaction of both 2,4,6-trichlorophenyl ester 11 and the parent
phenyl ester 12 showed no reactivity (entries 5 and 6).
Correlation of the observed reactivity with variation in pKa of the
phenol can be identified. para-Nitrophenol (pKa 7.1 in H2O)[16] is
an efficient leaving group but is capable of the desired
amphoteric behavior and promoting catalyst turnover.
Pentafluorophenol (pKa 5.53) and tetrafluorophenol (pKa 6.0)
have lower pKa values,[17] with the corresponding aryloxides less
Brønsted basic and less nucleophilic, presumably resulting in
lower concentrations of the reactive ammonium enolate. Despite
2. Scope and Limitations
The generality of the Michael addition protocol was next
investigated by exploring the scope of the ester component
(Table 3). Dichloromethane proved the most general solvent for
effective catalysis upon extension to alternative substrates (see
SI for further details).[19] The diastereoisomers were separable
by column chromatography and the quoted yield in Table 3
refers to the isolated yield of the major diastereoisomer. Firstly,
a range of substituted arylacetic para-nitrophenyl esters with
different steric and electronic properties was explored. Electron-
neutral phenyl, 4-biphenyl and 2-naphthyl groups provided the
corresponding amide products 38, 39 and 40 in high yield and
diastereoselectivity, with exceptional enantiocontrol (all ≥ 99:1
er). Electron-donating aryl substituents (such as 4-tolyl, 4-
methoxyphenyl
and
4-dimethylaminophenyl)
gave
the
corresponding amide products 4, 41-44 in good yield and with
high diastereoselectivity (~ 90:10 dr). The relative and absolute
configuration of the major (2R,3S)-diastereoisomer
4 was
determined by single crystal X-ray crystallography with all other
products assigned by analogy.[20] Halogen-substituted aryl rings
gave amides 45-47 in good yield and er, although in reduced dr
(~ 80:20 dr). Introduction of the electron-withdrawing 4-
trifluoromethylphenyl group gave product 48 in diminished
diastereoselectivity (76:24 dr), albeit still in high yield and
enantiopurity for both diastereoisomers. Epimerization studies
were undertaken to probe the low diastereoselectivity (see SI);
no product epimerization under the reaction conditions was
observed, indicating the diastereoselectivity is derived from the
orientation of the electrophile on approach.[21] Having
demonstrated a range of substituted aryl rings were compatible
with the optimized conditions, attention was turned to other
classes of ester. Pleasingly, alkenyl substituents were tolerated,
with amide 49 obtained in 66% yield and with good
stereoselectivity. Heteroaryl esters were also compatible, with 2-
thiophenyl amide 50 obtained in high yield and dr; both
diastereoisomers were obtained in > 99:1 er. The relative and
absolute configuration within the minor (2R,3R)-diastereoisomer
50 was also determined by single crystal X-ray
crystallography.[22] This is consistent with high enantiocontrol at
C(2) for both diastereoisomers, which are epimeric at C(3).
Unfortunately, alkyl, α,α-disubstituted and benzyloxy esters were
unreactive in this protocol, only returning starting materials,[23]
whilst ortho-substitution gave product in diminished yield and
lower diastereoselectivity (see SI).
2,4,6-trichlorophenol having
a comparable pKa (5.99) to
tetrafluorophenol, the lack of reactivity is presumably due to the
steric demands of the ortho-substituents attenuating its
nucleophilicity.[18] The ester derived from phenol is less
electrophilic and does not acylate the catalyst. A careful balance
of leaving group ability, amphoteric behaviour and steric effects
within this series indicates that para-nitrophenol is the most
effective aryloxide for this application.
Table 2. Aryloxide study.
O
O
5
(R)-BTM (5 mol%)
Ph
PhO2S
SO2Ph
SO2Ph
OAr
Ph
Ph
Ph
OAr
CH2Cl2 (0.5
RT, 24 h
M)
PhO2S
13-18
7-12
(1.5 equiv)
2
F
F
CF3
CF3
Ar:
NO2
F
Cl
F
F
Cl
F
F
F
8
14
F
9
15
Cl
11
17
substrate
7
10
16
12
18
product 13
The scope of the developed process was further tested by
variation of the electrophile component (Table 3). Firstly, the
effect of the β-substituent was examined: the use of an
electrophile bearing a 4-fluorophenyl substituent gave amide 51
in excellent yield, dr and er. However, substitution with an
electron-donating 4-methoxyphenyl gave amide 52 in lower yield.
Entry
Substrate
Yielda (%)
drb
erc
1d
2
7
84
39
56
44
0
84:16
84:16
82:18
80:20
-
> 99:1
> 99:1
> 99:1
> 99:1
-
8
3
9
Using
the
commercially
available
unsubstituted
single
4
10
11
12
bis(phenylsulfonyl)ethylene electrophile provided
a
enantiomer of amide 53 in high yield (78%). The scope of the
electrophile was extended to alkyl sulfone groups, with methyl
sulfone giving amide 54 in acceptable yield (55%). The use of a
cyclic bis-sulfone allowed access to amide 55 in excellent yield,
dr and er but required acetonitrile as the reaction solvent due to
5
6
0
-
-
[a] Isolated yield of major diastereoisomer. [b] Determined by 1H NMR analysis
of the crude reaction mixture. [c] Determined by chiral HPLC analysis after
conversion to the corresponding benzyl amide. [d] isolated as 95:5 dr.
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10.1002/anie.201908627
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 3. Reaction scope.
O
R1
O
SO2R3
SO2R3
2, 31-37
Nuc
(R)-BTM 5 (5 mol%), CH2Cl2 (0.5 ), RT, 24 h
M
R2
R1
R3O2S
R3O2S
R2
OAr
then Nuc-H (5 equiv), RT, 24 h
1,7, 19-30
(1.5 equiv), Ar: 4-NO2C6H4
4, 38-57
Me
Ph
Me
O
O
O
O
O
NHBn
NHBn
NHBn
NHBn
NHBn
PhO2S
PhO2S
PhO2S
PhO2S
PhO2S
PhO2S
Ph
Ph
Ph
Ph
Ph
PhO2S
38
PhO2S
39
PhO2S
40
PhO2S
41
4
4
maj
; 80%
; 81%
; 83%
; 75%
(2R,3S)-
; 57%
88:12 dr; > 99:1 er
81:19 dr; 99:1 er
88:12 dr; > 99:1 er
90:10 dr; > 99:1 er
85:15 dr; > 99:1 er
OMe
MeO
MeO
Me2N
F
Cl
Br
O
O
O
O
O
O
NHBn
Ph
NHBn
NHBn
NHBn
Ph
NHBn
NHBn
PhO2S
PhO2S
PhO2S
PhO2S
PhO2S
PhO2S
PhO2S
Ph
Ph
Ph
Ph
PhO2S
42
PhO2S
PhO2S
44
PhO2S
45
PhO2S
43
46
47
; 61%
88:12 dr; > 99:1 er
; 72%
; 57%
; 58%
85:15 dr; > 99:1 er
; 78%
80:20 dr; > 99:1 er
; 68%
90:10 dr; > 99:1 er
89:11 dr; > 99:1 er
82:18 dr; > 99:1 er
F3C
S
S
O
O
O
O
O
Me
PhO2S
Ph
NHBn
NHBn
NHBn
NHBn
Ph
NHBn
PhO2S
PhO2S
PhO2S
PhO2S
Ph
Ph
Ph
PhO2S
48
PhO2S
49
PhO2S
(2R,3S)-
PhO2S
PhO2S
F
b
50
50
50
min
51
, 80%
88:12 dr; > 99:1 er
; 76%
; 66%
(2R,3R)-
78%;c 88:12 dr
(2R,3R)-
maj
min
80:20 dr; > 99:1 er
76:24 dr
99:1 ermaj; 99:1 ermin
> 99:1 ermaj; > 99:1 ermin
O
O
O
O
O
unsuccessful examples
Ph
Ph
Ph
MeO2S
MeO2S
54
Ph
Ph
PhO2S
PhO2S
SO2Ph
CF3
NHBn
NHBn
NHBn
O2
NHBn
Nuc
PhO2S
PhO2S
PhO2S
S
36
Ph
Ph
SO2Me
PhO2S
SO2
Ph
OMe
CO2Et
37
55 f
; 84%
e
52
53
; 27%
86:14 dr; > 99:1 er
; 78%
56
; Nuc = pyrrolidinyl
; 55%
> 99:1 er
84:16 dr
99:1 er
80:20 dr
75% (1.12 g); > 99:1 er
57; Nuc = OMe
99:1 ermaj; > 99:1 ermin
82%; 99:1 erd
[a] dr determined by 1H NMR analysis of the crude reaction mixture; isolated yield of a single major diastereoisomer; er determined by chiral HPLC analysis. [b]
isolated > 95:5 dr. [c] combined yield of separable diastereoisomers. [d] er determined after reduction to corresponding alcohol (58). [e] isolated 80:20 dr. [f]
MeCN as solvent.
the insolubility of the electrophile in dichloromethane.
Unfortunately, Michael acceptors bearing a single sulfone group
(36, 37) were unreactive, presumably due to the lower
electrophilicity of these acceptors. To further exemplify product
diversity, the addition of alternative nucleophiles to give isolable
products at the end of the reaction was investigated. Using
unsubstituted bis-sulfone 33, addition of pyrrolidine gave tertiary
substituted amide gave anti-product 59 in good yield (57%),
whilst maintaining stereointegrity (> 95:5 dr, 99:1 er).
Desulfonylation of pyrrolidinyl and benzyl-amides containing a
single stereogenic centre was also successful, providing amides
60 and 61 in improved yield (63% and 77%). Desulfonylation of
4-fluorophenyl amide 51 and thiophenyl amide 50 proved
amenable to the unmasking conditions, allowing access to single
amide 56 in high yield and er (75%, > 99:1 er) on a 3 mmol scale, enantiomers of products 62 and 63 in moderate yield.
allowing the formation of 1.12 g of product. Addition of methanol
provided ester 57 in excellent yield and er.
Alternatively, the pro-nucleophilic nature of the bis-sulfone
moiety could be exploited to allow further functionalization
(Scheme 4b). Treatment of 56 with either methyl vinyl ketone
(MVK) or benzyl bromide under basic conditions gave chain
extended amides 64 and 65 respectively in good yield whilst
maintaining enantiopurity.
Having demonstrated the scope and limitations of this
protocol, it was proposed that the sulfone functional handle in
the product could be exploited to carry out further manipulations
to access complex, valuable products. Following a procedure
developed by Williams and co-workers,[24] initial studies focused
on desulfonylation using magnesium turnings in methanol at
room temperature (Scheme 4a). Desulfonylation of 2,3-diphenyl
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10.1002/anie.201908627
Angewandte Chemie International Edition
RESEARCH ARTICLE
(a) Desulfonylation
the course of the reaction (Figure 1b) and giving product 68 in
82% yield, 88:12 dr and > 99:1 er.[25] During the course of the
reaction, both diastereoisomeric reaction products, each
containing two distinct 19F-environments, were observed and
were distinguishable from the starting components. Monitoring
the reaction over time revealed the 19F chemical shift of 19F-BTM
67 underwent a downfield shift (F −122.26 to F −121.99 ppm)
during the reaction, indicative of partial protonation, and hence
deactivation, of the catalyst.[26] To account for this observation
within the kinetic analysis, 19F-BTM•HCl was synthesized as a
standard (F −115.64 ppm), allowing the concentration of free
catalyst to be calculated as a function of F (See SI).[27] These
studies are consistent with the dominant catalyst resting state
being the free catalyst throughout the reaction protocol. The acyl
ammonium salt of the starting ester was synthesized as both the
chloride (F −115.52) and 2-fluoro-4-nitrophenoxide (F −111.70)
counterions as potential intermediates (see SI). However, no
long-lived intermediates corresponding to > 1% of the reaction
mixture were observed during the reaction.[28] A similar approach
was attempted to form the acyl ammonium of the product (see
SI); catalyst 67 was added to product 68, however no acyl
ammonium was observed.[29] Whilst no significant quantities of
other intermediates were detected during the analysis of this
reaction, an alternative intramolecular catalyst turnover event to
form a reactive, short-lived intermediate which is intercepted by
the aryloxide to form acyl ammonium product cannot be ruled
out. Such mechanistic alternatives could involve cyclisation
O
O
R1
R1
Me
Mg (40 equiv)
Nuc
Nuc
PhO2S
R2
MeOH (0.05 M)
RT, 6 h
R2
PhO2S
4, 50maj, 51, 53, 56
59-63
Me
O
NHBn
Me
O
NHBn
Me
O
N
Me
59
60
61
; 57%; 99:1 er
; 63%; > 99:1 er
; 77%; > 99:1 er
S
O
O
NHBn
NHBn
Me
Me
F
62; 45%; > 99:1 er
63; 51%; > 99:1 er
(b) Alkylation
O
O
O
MVK (1.3 equiv)
K2CO3
BnBr (1 equiv)
Ph
Ph
K2CO3
N
N
56
> 99:1 er
PhO2S
PhO2S
PhO2S
PhO2S
MeCN
MeCN
reflux, 24 h
reflux, 24 h
Me
Ph
65
; 43%; > 99:1 er
64
; 56%; 99:1 er
Scheme 4. Product derivatization through (a) desulfonylation and (b)
alkylation. (MVK: methyl vinyl ketone).
through the sulfone oxygen,[6] or via
a
cyclobutanone
3. Mechanistic Studies
intermediate.[30]
3.1 Quantitative 19F{1H} NMR Reaction Monitoring
3.2 Kinetic Analysis
Having demonstrated the reaction scope, further studies sought
to provide mechanistic insight into this developed methodology
through kinetic analysis. Primary studies set out to identify the
catalyst resting state and any potential reaction intermediates,
as well as determining the reaction order with respect to each
component. Quantitative reaction monitoring was achieved by in
situ 19F{1H} NMR spectroscopy using 19F-labelled ester 66 (F
−123.36), 19F-labelled electrophile 31 (F −107.64) and 19F-BTM
67 (F −122.26) in CD2Cl2 [0.1 M] using 1,3-difluorobenzene (F
−110.73) as an internal standard (Figure 1a). Under these
conditions, the reaction time (3 h) was substantially shorter than
the standard conditions (24 h) enabling facile NMR analysis over
Having determined the temporal concentration of the reaction
components, information concerning their reaction orders was
sought. The inventive variable time normalization analysis
(VTNA) reported by Burés was employed, which allows facile,
rapid elucidation of reaction orders by using temporal
concentration data.[31] Kinetic analysis was carried out by
performing seven different reactions, each with varying
concentrations of ester 66 (120-180 mM), electrophile 31 (80-
120 mM) and catalyst 19F-67 (16-24 mM). Visual analysis of the
data was achieved by plotting the concentration of product 68
(sum of both diastereoisomers) against a time normalized axis of
[66]α[31]β[67]γt. Subsequent variation of α, β and γ was
F
NO2
PhO2S
PhO2S
(a)
(b) Reaction profile
(c) VTNA
O
+
Ph
66
O
F
31
(120-180 mM), F –123.36
(80-120 mM), F –107.64
67
(R)-F-BTM
1,3-F2C6H4 (50 mM)
F
N
(16-24 mM)
F –122.26
F
–110.73
CD2Cl2, RT
Ph
N
S
F
NO2
F NO2
O
O
reaction 66 (mM) 31 (mM) 67 (mM)
1
2
3
4
5
6
7
150
180
150
150
120
150
150
100
100
120
100
100
80
20
20
20
24
20
20
16
Ph
Ph
O
O
PhO2S
PhO2S
PhO2S
PhO2S
F
F
100
68maj
68min
F –113.88, –123.47
F –114.58, –122.90
82%; 88:12 dr; > 99:1 ermaj
Figure 1. Mechanistic studies: (a) 19F{1H} NMR Spectroscopy for reaction mechanism analysis; (b) reaction profile using 150 mM 66, 100 mM 31 and 20 mM 67;
(c) variable time normalization analysis, α = 1, β = 1, and γ = 1.
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10.1002/anie.201908627
Angewandte Chemie International Edition
RESEARCH ARTICLE
carried out to achieve best overlay. Variation of α, β and γ at
integer and half-integer values from 0 to 2 (see SI) showed best
overlay when each component was set to 1. This is consistent
with the reaction being first order in each of the three
components, and indicates with the turnover-limiting step is
likely to be either Michael addition or catalyst turnover (Figure
1c). Significantly, this mechanistic information contrasts our
previous work regarding enantioselective Michael addition-
lactonizations that utilized intramolecular catalyst turnover in
ammonium enolate catalysis (Scheme 1).[6] In this previous work,
the process was found to be zero order in electrophile, with
deprotonation of the acyl ammonium ion identified as the
turnover-limiting step through a significant primary KIE. This is
consistent with two mechanistically distinct scenarios being
operative in these reactions.
the magnitude of kobs was calculated to be 0.86 the magnitude of
kobs of the standard reaction (see SI). It was proposed the cause
of the product inhibition could be the acidic proton adjacent to
the bis-sulfone functionality. Consistent with this hypothesis, the
addition of 20 mM of the saturated bis-sulfone 69 at the start of
the reaction resulted in a similar retardation of the reaction rate.
Using an identical protocol to that above, the magnitude of kobs
was calculated to be 0.80 the magnitude of kobs of the standard
reaction. Based on these results, it is postulated that the product
may inhibit the reaction by protonating either the C(1)-
ammonium enolate or aryloxide, thus retarding the rate of
catalyst turnover.
3.4 Inverse Secondary Kinetic Isotope Effect
To further probe the reaction mechanism the leverage of a
secondary kinetic isotope effect was investigated. The change in
hybridization of an sp2-hybridized Michael acceptor to an sp3-
hybridized product has previously been used to probe the
turnover limiting step of Michael addition reactions through the
observation of an inverse secondary kinetic isotope effect.[32,33]
We sought to generate this information through a direct
competition experiment between enantioselective addition of
ester 66 to a 50:50 ratio of isotopologues C(2)-H 31 (F −107.64)
and C(2)-D 70 (F −107.51) in solution. Monitoring the relative
rates of consumption of C(2)-H 31 and C(2)-D 70 in triplicate
gave a kinetic isotope effect kH/kD = 0.88 (Scheme 5). For
comparison, a similar effect (kH/kD = 0.89) was observed in
separate independent parallel kinetic experiments using C(2)-H
31 and C(2)-D 70 (see SI). This information is consistent with
the Michael addition being kinetically significant in this protocol
and contrasts the intramolecular catalyst turnover approach in
formal [4+2] cycloadditions, in which acyl ammonium
deprotonation was observed to be turnover-limiting.[6]
3.3 Product Inhibition
Although reasonable overlay had been achieved, the observed
curvature in Figure 1c indicates an additional variable, which has
an effect of reducing the reaction rate over time, remained
unaccounted for. As catalyst deactivation through protonation
had already been included in the kinetic analysis, the potential
for product inhibition was considered. Consistent with this
hypothesis, incorporation of the product concentration into the
time normalization approach [66]1[31]1[67]1[68]δ∆t, and
arbitrarily setting δ = −0.2 improved the linearity of the plot (see
SI). A series of control reactions were therefore untaken and
compared to the standard reaction profile (Figure 2). Reactions
with 20 mM product 68 added at the start of the reaction were
carried out in triplicate, with the displayed profile an average of
these three runs. It is clearly noticeable that the observed rate of
vinyl bis-sulfone consumption is reduced in comparison to the
standard reaction. Using the VTNA approach to estimate kobs
,
F
NO2
O
H
NO2
H
Ph
PhO2S
O
F
O
N
PhO2S
PhO2S
31 (50 mM)
Ph
Ph
F
NO2
O
O
N
S
F
66
Ester
(150 mM)
67
Ph
F
F
PhO2S
(R)-F-BTM 67 (20 mM)
O
F
66
(150 mM)
(R)-F-BTM
(20 mM)
PhO2S
68
additive (20 mM)
1,3-F2C6H4 (50 mM)
CD2Cl2

F –107.64
PhO2S
PhO2S
31
1,3-F2C6H4 (50 mM)
D
PhO2S
F
NO2
F
O
D
CD2Cl2
RT
PhO2S
PhO2S
F
RT
Ph
PhO2S
PhO2S
O
68
(100 mM)
kH/kD = 0.88
70

(50 mM)
F –107.51
F
71
Scheme 5. Inverse secondary kinetic isotope effect.
3.5 Proposed Mechanism
Taking all the mechanistic information into account, the following
mechanism is proposed (Scheme 6). The catalytic cycle starts
by reversible N-acylation of free base BTM catalyst I with ester II
to form acyl ammonium ion pair III. Reversible deprotonation of
the acyl ammonium by the aryloxide counteranion affords the
nucleophilic ammonium enolate IV and releases para-
nitrophenol. It is proposed that
(characterized as nO to σ*C-S
[34] lowers the rotational freedom of
this intermediate, with the stereodirecting phenyl group forced to
a 1,5-OS interaction
)
Figure 2. Product inhibition study.
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10.1002/anie.201908627
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RESEARCH ARTICLE
adopt a pseudo-axial position to minimize 1,2-strain, and hence
blocking the Si face of the enolate intermediate. Turnover rate-
limiting Michael addition to the electrophile V on the Re face of
the enolate leads to intermediate VI. Protonation by the para-
nitrophenol released in step two gives acyl ammonium ion-pair
VII. Addition of the aryloxide anion forms the product VIII and
regenerates catalyst I, which is in equilibrium with the
catalytically inactive protonated-BTM IX. Critical to the success
of this protocol is the aryloxides ability to act as the leaving
group, Brønsted base, Brønsted acid and nucleophile to
turnover the catalyst, enabling the reaction to be carried out in
the absence of auxiliary base. The observed diastereoselectivity
can be rationalized tentatively by a favoured open pre-transition
state assembly TS-I where gauche interactions are minimized
about the forming C–C bond[35] while allowing a potentially
favourable -cation interaction[36] between the β-substituent of
the bis-sulfone electrophile and the isothiouronium cation
(Scheme 6). Interestingly, the relative configuration within the
major diastereoisomer obtained using these bis-sulfone
electrophiles is opposite to that observed in previous isothiourea
catalysis employing intramolecular catalyst turnover processes
(Scheme 1) and in the intermolecular addition to iminium ions
(Scheme 2c). This difference can presumably be rationalized
due to the two highly sterically demanding sulfone groups of this
series of electrophile.
environmentally benign solvents, allows formation of α-alkylated
products in excellent yield and with excellent diastereo- and
enantioselectivity using low catalyst loadings (26 examples, up
to 90:10 dr and ≥ 99:1 er). Notably, no auxiliary base is required
for this Michael addition process, with the key role of the
aryloxide to act firstly as a leaving group, then a Brønsted base,
a Brønsted acid and finally a Lewis base to promote catalyst
turnover. The functional products can be deprotected upon
treatment with Mg in MeOH to form -alkylated amides without
loss of stereointegrity. Mechanistic investigations using 19F{1H}
NMR spectroscopy have enabled detailed investigation of the
speciation within the reaction, with a variable time normalization
analysis and an inverse secondary KIE indicative of Michael
addition being the turnover-limiting step. Catalyst protonation,
alongside product inhibition were also identified during this
analysis. It is hoped that this mechanistic study will aid future
reaction design in enantioselective ammonium enolate catalysis,
and we are actively exploring these possibilities in our
laboratory.[37]
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/M508214/1, C.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. We thank Dr Siobhan Smith for assistance with
manual NMR experiments.
N
Ph
N
H
S
product
inhibition
observed
X
O
IX
O
R1
R1
OAr
OAr
R3O2S
R3O2S
R2
II
N
1st Order
Ph
VIII
N
S
Keywords: isothiourea catalysis • enantioselective Michael
addition • base free / proton neutral • mechanistic analysis •
VTNA • inverse secondary kinetic isotope effect
5. Catalyst
turnover
1. N-acylation
I
1st Order
R2
O
S
O
S
R1
R3O2S
R3O2S
N
N
N
N
R1
ArO
Ph
[1]
[2]
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III
Ph
VII
ArO
4. Protonation
2. Deprotonation
H
OAr
ArO
H
R2
O
O
S
S
R3O2S
R3O2S
R1
N
N
N
N
R1
VI
3. Michael
addition
(turnover-
IV
Ph
Ph
SO2R3
[3]
S•••O interaction
R2
limiting)
SO2R3
V
O
S
H
R1
Inverse
secondary
KIE observed
PhO2S
N
N
1st Order
H
PhO2S
Ph
cation interaction
TS-1 stereochemical rationale
Scheme 6. Proposed Mechanism.
[4]
a) G. S. Cortez, R. L. Tennyson, D. Romo, J. Am. Chem. Soc. 2001,
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Conclusion
In conclusion, a base-free and proton neutral enantioselective
Michael addition of ester pronucleophiles to vinyl bis-sulfones
has been developed. This protocol, which can be carried out in
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10.1002/anie.201908627
Angewandte Chemie International Edition
RESEARCH ARTICLE
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isothiourea catalysts. For examples see reference 5, and a) A.
Matviitsuk, J. E. Taylor, D. B. Cordes, A. M. Z. Slawin, A. D. Smith,
Chem. Eur. J. 2016, 22, 17748-17757; b) M. D. Greenhalgh, S. Qu, A.
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[19] It is envisaged the use of green solvents in combination with higher
catalyst loadings could be applied to achieve similarly high yields.
[20] CCDC 1939040 (4maj) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[21] Epimerization of the post-Michael addition acyl ammonium ion cannot
be ruled out.
[22] CCDC 1939041 (50min) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[23] This current limitation is proposed to be due to the lower acidity of the
proton in the α-position.
[24] L. Acemoglu, J. M. J. Williams, J. Mol. Cat. A: Chemical 2003, 196, 3-
11.
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[25] The reaction time is considerably shorter (3 h) because 20 mol%
catalyst was used compared to 5 mol% under the optimized conditions
(24 h).
[6]
[7]
[26] It is proposed that slow partial hydrolysis of ester 66 to phenylacetic
acid and 2-fluoro-4-nitrophenol during the reaction could be the source
of catalyst protonation. Consistent with this hypothesis, a small quantity
of 2-fluoro-4-nitrophenol was observed to form over the reaction course
(< 5%).
a) H. Wack, A. E. Taggi, A. M. Hafez, W. J. Drury, III, T. Lectka, J. Am.
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[28] Two small, unknown peaks were detected: 0.24-0.38 mM at −111.36
ppm and 0.16-0.84 mM at 112.14 ppm. Both could not be identified as
any reaction intermediates.
[8]
[9]
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[29] This suggests that the catalyst turnover step is irreversible, an
observation found in previous work concerning the 2,3-rearrangement
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RESEARCH ARTICLE
The base-free functionalization of aryl
esters to form α-alkylated ester
Calum McLaughlin, Alexandra M. Z.
Slawin and Andrew D. Smith*
products in excellent enantioselectivity
(>20 examples, all ≥ 99:1 er) is
Page No. – Page No.
developed using isothiourea catalysis.
Key is the multifunctional role of the
aryloxide, which operates as a leaving
group, Brønsted base, Brønsted acid
and Lewis base within the catalytic
cycle. Mechanistic studies, including
variable time normalization analysis
and a kinetic isotope effect, were used
to probe the reaction mechanism.
Base-free Enantioselective C(1)-
Ammonium Enolate Catalysis
Exploiting Aryloxides: A Synthetic
and Mechanistic Study
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