Exploiting the Imidazolium Effect in Base-free Ammonium Enolate Generation: Synthetic and Mechanistic Studies

Article abstract of DOI:10.1002/anie.201608046

N-Acyl imidazoles and catalytic isothiourea hydrochloride salts function as ammonium enolate precursors in the absence of base. Enantioselective Michael addition–cyclization reactions using different α,β-unsaturated Michael acceptors have been performed to form dihydropyranones and dihydropyridinones with high stereoselectivity. Detailed mechanistic studies using RPKA have revealed the importance of the “imidazolium” effect in ammonium enolate formation and have highlighted key differences with traditional base-mediated processes.

Full text of DOI:10.1002/anie.201608046

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201608046
German Edition: DOI: 10.1002/ange.201608046
Organocatalysis
Exploiting the Imidazolium Effect in Base-free Ammonium Enolate
Generation: Synthetic and Mechanistic Studies
Claire M. Young, Daniel G. Stark, Thomas H. West, James E. Taylor, and Andrew D. Smith*
Abstract: N-Acyl imidazoles and catalytic isothiourea hydro-
chloride salts function as ammonium enolate precursors in the
absence of base. Enantioselective Michael addition–cyclization
reactions using different a,b-unsaturated Michael acceptors
have been performed to form dihydropyranones and dihydro-
pyridinones with high stereoselectivity. Detailed mechanistic
studies using RPKA have revealed the importance of the
“imidazolium” effect in ammonium enolate formation and
have highlighted key differences with traditional base-medi-
ated processes.
nucleophilic addition by suitable Lewis base catalysts to form
acyl ammonium intermediates that can be deprotonated
under basic conditions to form the required ammonium
enolate. Carboxylic acids can also be used as ammonium
enolate precursors, but require stoichiometric in situ func-
tionalization into either mixed anhydrides or activated esters
prior to the addition of the Lewis base catalyst.[5] All of these
procedures typically use an excess of reagents and organic
bases, and generate by-products that can be difficult to
chromatographically separate from the desired products.
In this manuscript, the development of a new, mild
method of catalytically generating ammonium enolates from
bench-stable N-acyl imidazole precursors that avoids the use
of stoichiometric additives and external base, and instead uses
isothiourea hydrochloride salts as catalysts, is reported. Key
to the process developed is the exploitation of the reactivity
underpinning the “imidazolium effect”—the recognized rate
enhancement for acylations using N-acyl imidazoliums com-
pared with N-acyl imidazoles (Scheme 1b).[6] For example,
Batey has developed N-methyl-N’-carbamoyl imidazolium
salts as efficient carbamoyl transfer agents,[7] while Gilday
used N-acyl imidazoles and stoichiometric imidazole hydro-
chloride for the challenging acylation of anilines.[8] Sarpong
has reported the dual Brønsted acid and Lewis base activation
of N-acyl imidazoles using stoichiometric pyridinium salts for
the acylation of alcohols and amines as well as for the
esterification of carboxylic acids.[9] Although powerful, to
date, this “imidazolium effect” has not been exploited in
either a catalytic fashion or for the generation of ammonium
enolate intermediates.[10] Furthermore, the expected imid-
azole by-product is both non-toxic and water soluble and
should be readily removed from reaction mixtures.
Ammonium enolates generated from tertiary amine-based
Lewis base catalysts are versatile intermediates that can be
utilized in a range of stereoselective processes.[1] Traditionally
accessed directly through nucleophilic attack of tertiary
amine catalysts onto ketenes,[1c] the practical challenges
associated with ketene preparation and their use has
prompted a number of alternative ammonium enolate
precursors to be developed (Scheme 1a). An early approach
generated ketenes in situ from the corresponding acid chlo-
ride using an organic base.[2] Alternatively, homoanhydrides[3]
and electron-deficient phenolate esters[4] can undergo direct
To the best of our knowledge, N-acyl imidazoles have not
been investigated as ammonium enolate precursors. How-
ever, Scheidt and co-workers have previously used N-acyl
imidazoles as azolium enolate precursors under basic reaction
conditions using N-heterocyclic carbene catalysis to form
dihydroquinolones and dihydrocoumarines with good enan-
tioselectivity.[11,12] The protocol developed herein represents
a new paradigm in ammonium enolate generation without the
addition of external base (Scheme 1c).[13] A range of enan-
tioselective Michael addition-cyclization processes with a,b-
unsaturated enones and ketimines to form substituted dihy-
dropyranones and dihydropyridinones have been explored.
Scheme 1. Ammonium enolate precursors at carboxylic acid oxidation
level.
[*] C. M. Young, Dr. D. G. Stark, T. H. West, Dr. J. E. Taylor,
Prof. A. D. Smith
Furthermore,
a detailed mechanistic investigation has
EaStCHEM, School of Chemistry, University of St Andrews
North Haugh, St Andrews, Fife, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
revealed key differences between this new process and
analogous reactions using carboxylic acids under basic con-
ditions.
Homepage: http://ch-www.st-andrews.ac.uk/staff/ads/group/
Investigations began with the Michael addition–lactoni-
zation reaction between N-phenacyl imidazole 1 (readily
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608046.
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 1: Reaction optimization.[a]
Table 2: Variation of the N-acyl imidazole with trifluoromethylenone 2.
Entry
R
Yield [%][a]
d.r.[b]
e.r.[c]
1
2
3
4
5
6
7
8
4-MeOC6H4
4-Me2NC6H4
3-MeC6H4
4-F3CC6H4
4-FC6H4
7
8
9
10
11
12
13
14
56
38
66
60
70
63
50
66
87:13
89:11
91:9
97:3
99:1
96:4
93:7
97:3
76:24
92:8
99:1
Entry Cat.
(mol%)
Solvent (m)
T
Yield d.r.[c]
[8C] [%][b]
e.r.[d]
91:9
89:11
88:12
83:17
72:28
2-ClC6H4
3-Thiophenyl
1
3 (20)
3 (20)
3 (20)
5 (20)
6 (20)
5 (20)
5 (10)
CH2Cl2 (0.2) rt
CH2Cl2 (0.2) rt
18
39
49
63
20
68[g]
65
84:16 76:24 (ent)
87:13
90:10 93:7 (ent)
88:12 95:5
85:15 88:12
2[e]
3
51:49
=
(E)-MeCH CH
MeCN (0.1)
MeCN (0.1)
MeCN (0.1)
MeCN (0.1)
MeCN (0.1)
rt
rt
rt
0
4
5
[a] Isolated yields as a mixture of diastereoisomers. [b] Determined by
1H NMR analysis of the crude material. [c] Determined by HPLC analysis.
6[f]
7[f]
91:9
92:8
97:3
91:9
0
although the latter was obtained with reduced diastereocon-
trol (Table 2, entries 7 and 8).
[a] Reactions performed on a 0.1 mmol scale. [b] Determined by 1H NMR
using 1,4-dinitrobenzene as internal standard. [c] Determined by
1H NMR spectroscopic analysis of the crude material. [d] Determined by
HPLC analysis. [e] Reaction with i-Pr2NEt (2.5 equiv). [f] Reaction using
1.5 equiv 1 for 16 h. [g] Isolated yield.
To assess whether the protocol was applicable across
a range of Michael acceptors, the reaction between N-
phenacyl imidazole 1 and a,b-unsaturated g-ketimine ester
15 to form dihydropyridinone 16 was studied. (À)-TM·HCl 3
(20 mol%) was the optimal catalyst, with the addition of
acetic acid (1.1 equiv) necessary to obtain product 16 in 67%
yield[17] with excellent 92:8 d.r. and 94:6 e.r. (Table 3,
prepared from phenylacetic acid and CDI) and trifluorome-
thylenone 2 (Table 1).[14] Encouragingly, the reaction using
(À)-tetramisole (TM) hydrochloride 3 (20 mol%) in CH2Cl2
at rt led to formation of dihydropyranone 4 in 84:16 d.r. and
promising 76:24 e.r. for the major anti-diastereoisomer, albeit
in only 18% yield (Table 1, entry 1). Notably, the same
reaction performed in the presence of i-Pr2NEt (2.5 equiv)
also gave 4, but as a racemate (Table 1, entry 2), consistent
with the addition of external base being detrimental to the
enantioselectivity of the process.[15] Changing the solvent to
MeCN led to an improvement in both reactivity and
enantioselectivity (Table 1, entry 3). A screen of alternative
isothiourea catalysts identified (+)-benzotetramisole (BTM)
hydrochloride 5 as the most effective, leading to higher yields
and improved stereoselectivity (Table 1, entries 4 and 5).
Decreasing the reaction temperature to 08C and using
1.5 equiv 1 led to the isolation of anti-4 in 68% yield with
excellent 91:9 d.r. and 97:3 e.r. (Table 1, entry 6).[16] Successive
aqueous acid-base work-up allowed imidazole removal and
catalyst recovery (88% yield). Reducing the catalyst loading
to 10 mol% led to slightly reduced conversion and enantio-
selectivity (Table 1, entry 7).
The scope of this process was assessed through variation
of the N-acyl imidazole (Table 2). Aryl groups bearing
electron-donating substituents were tolerated, forming anti-
dihydropyranones 7 and 8 with high enantioselectivity,
although a reduction in yield was observed (Table 2, entries 1
and 2). The presence of electron-withdrawing and halogen
aryl substituents (10 and 11) gave comparable results with
shorter reaction times, although the presence of an o-chloro
substituent led to reduced enantioselectivity for anti-12
(Table 2, entries 4–6). Heteroaromatic and alkenyl substitu-
ents were also successfully incorporated within 13 and 14,
Table 3: Variation of the N-acyl imidazole with ketimine 15.
Entry
R
Yield [%][a]
d.r.[b]
92:8
87:13
>95:5
92:8
92:8
89:11
92:8
e.r.[c]
1
2
3
4
5
6
7
Ph
16
17
18
19
20
21
22
67
51
42
47
55
68
66
94:6
94:6
97:3
97:3
78:22
92:8
97:3
4-MeOC6H4
4-Me2NC6H4
3-MeC6H4
4-F3CC6H4
4-FC6H4
2-ClC6H4
[a] Isolated yields as a mixture of diastereoisomers. [b] Determined by
1H NMR analysis of the crude material. [c] Determined by HPLC analysis.
entry 1).[18] The reactions of a,b-unsaturated g-ketimine
ester 15 with various N-acyl imidazoles displayed similar
trends to those observed with trifluoromethylenone 2. The
presence of electron-rich aryl substituents generally led to
lower yield, but high enantioselectivity (17–19) whereas
dihydropyridinone 20 containing an electron-deficient aryl
ring gave decreased enantiocontrol (Table 3, entries 2–5).
Notably, o-chloro substitution within 22 gave high stereocon-
trol (Table 3, entry 7).
Finally, the use of a,b-unsaturated saccharin derivatives as
Michael acceptors was investigated, with (+)-BTM·HCl 5
(10 mol%) in EtOAc at rt proving optimal, forming fused
dihydropyridinone 23 in 84% yield with 89:11 d.r. and 93:7
2
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 4: Reaction scope with a,b-unsaturated saccharin derivatives.
Entry
R
Ar
Yield [%][a] d.r.[b] e.r.[c]
1
2
3
4
5
6
7
8
Ph
3-MeC6H4
4-F3CC6H4
Ph
Ph
Ph
23 84
24 66
25 83
26 42
27 80
28 92
29 98
89:11 93:7
88:12 93:7
88:12 90:10
76:24 91:9
88:12 93:7
88:12 94:6
=
(E)-MeCH CH Ph
Ph
Ph
Ph
Ph
4-MeOC6H4
4-F3CC6H4
4-BrC6H4
94:6
91:9
3-Thiophenyl 30 82
86:14 92:8
[a] Isolated yields as a mixture of diastereoisomers. [b] Determined by
1H NMR analysis of the crude material. [c] Determined by HPLC analysis.
Scheme 2. a) Equilibrium between N-acyl imidazole 1 and acyl ammo-
nium 32. b) Crossover experiment. c) Use of alternative precatalysts.
e.r. (Table 4, entry 1).[17,19] The reaction scope was further
assessed through variation of both the N-acyl imidazole and
a,b-unsaturated saccharin. Electron-rich and electron-defi-
cient aryl substituents within the N-acyl imidazole were
tolerated, forming 24 and 25 with good yields and high
stereoselectivity (Table 4, entries 2 and 3). Alkenyl substitu-
tion led to a reduction in yield and diastereoselectivity for 26,
although enantioselectivity remained high (Table 4, entry 4).
A range of electron-rich, electron-poor and halogen-substi-
tuted aryl rings as well as a heteroaryl substituent was
tolerated within the saccharin component, forming dihydro-
pyridinones 27–30 in high yield with good stereocontrol in all
cases (Table 4, entries 5–8).
Having assessed the reaction scope, the role of the
“imidazolium effect” in N-acyl ammonium formation, as
well as the mechanism and reaction kinetics of this process
was investigated. The importance of using the isothiourea
hydrochloride salt was probed by studying the initial equilib-
rium between the catalyst and N-phenacyl imidazole 1. An
equimolar mixture of 1 and free-base (+)-BTM 31 in CD3CN
showed no evidence of catalyst acylation by 1H NMR. In
contrast, an equivalent mixture of (+)-BTM·HCl 5 and 1 led
to rapid equilibration with the corresponding N-acyl ammo-
nium 32 and free imidazole 33, with Kexp = 0.59 (Sche-
me 2a).[20] The position of this equilibrium is not the only
contributing factor to reactivity, as using N-acyl triazoles
instead of N-acyl imidazoles gave higher equilibrium con-
stants but displayed lower overall reactivity in reactions to
form 4.[21] Furthermore, a 1:1 mixture of N-acyl ammonium 32
and N-acyl imidazole 34 showed significant cross-over after
4 h (Scheme 2b), adding to the complexity of the initial
equilibrium.[22] The nature of the non-participating counter-
ion was not important for overall reactivity, with a range of
(+)-BTM·HX salts giving comparable results in the reaction
to form 4.[21] Isolated N-acyl ammonium 32 and imidazole 33,
or acyl imidazolium ion 36 and (+)-BTM 31 (20 mol%), are
competent precatalysts, reacting with 1 and 2 to form
dihydropyranone 4 in high e.r. (Scheme 2c). A 1:1 mixture
of N-acyl ammonium 32 and enone 2 did not lead to product
formation indicating the presence of either imidazole or N-
acyl imidazole is essential for reactivity.
The reaction kinetics were then assessed using the
reaction progress kinetic analysis (RPKA) technique pio-
neered by Blackmond.[23] The reaction between N-acyl
imidazole 34 (75 mm) and trifluoromethyl enone 2 (50 mm)
using (+)-BTM·HCl 5 (10 mm) in CD3CN at rt that forms
dihydropyranone 11 in 71% yield, 85:15 d.r. and 95:5 e.r. was
chosen as standard as the concentrations of all fluorine
containing species can be effectively monitored over time by
in situ 19F NMR spectroscopy using a,a,a-trifluorotoluene as
an internal standard (Figure 1). The decreasing concentra-
tions of both reactants and the formation of both diastereo-
isomers of product 11, as well as the concentration of N-acyl
ammonium 35, could be observed over a suitable reaction
time.
Figure 1. Reaction profile; initial conditions: 34 (75 mm), 2 (50 mm),
(+)-BTM·HCl 5 (10 mm) in CD3CN.
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
The corresponding reaction profile obtained using free-
base (+)-BTM 31 as the catalyst showed a slower initial rate
of consumption of the reactants and no measurable formation
of N-acyl ammonium 35.[24] This provides strong evidence of
a beneficial “imidazolium effect” that promotes formation of
N-acyl ammonium 35 and increases the overall reaction rate.
The reaction order in (+)-BTM·HCl 5 was assessed using
the graphical normalized time scale method recently reported
by Burꢀs.[25] Full reaction profiles at different catalyst
concentrations were obtained and plotting the concentration
of N-acyl imidazole 34 against a normalized time scale, t[5]n,
where n represents the order with respect to catalyst, showed
that n = 1 (first-order) gave the best graphical overlay (Fig-
ure 2a).[26,27] Next, a same excess experiment was performed
in which two different starting concentrations of 34 were used,
but with the same excess ([34]À[2] = 25 mm) with respect to
enone 2 (Figure 2b).[26] The time adjusted reaction profile
(&), in which the starting concentrations of 2 are aligned,
Scheme 3. Secondary kinetic isotope effect measurement.
limiting and the reaction is zero order with respect to enone
2.[14]
Finally, the catalyst resting state was probed by using
a fluorinated catalyst, (+)-F-BTM·HCl, and tracking the
concentrations of the catalyst-derived species. During the
reaction, the concentration of the corresponding N-acyl
ammonium decreases over time, while the concentration of
free (+)-F-BTM increases.[26] This suggests that the overall
process may follow a complex kinetic equation as a conse-
quence of the catalyst having no definitive resting state.[29]
This is plausible given the observed equilibrium between
(+)-BTM·HCl 5, N-acyl imidazole 1 and N-acyl ammonium
32, the position of which will vary as the concentration of
imidazole 33 increases throughout the reaction.
The above evidence allows the following catalytic cycle to
be proposed (Scheme 4). Initial equilibration between
(+)-BTM·HCl 5, N-acyl imidazole 1 and N-acyl ammonium
32 is likely to be facilitated by transient formation of N-acyl
imidazolium 36. The reaction displays a negative kinetic order
in released imidazole 33 as its concentration affects the
position of the initial equilibrium. Furthermore, as the
reaction displays no definitive catalyst resting state the
overall reaction kinetics are complex. Deprotonation of N-
acyl ammonium 32 using either imidazole 33 or another N-
acyl imidazole 1 forms (Z)-ammonium enolate 39, which can
undergo turnover-limiting stereoselective Michael addition
into enone 2. The conformation of 39 is thought to be
stabilized by a non-bonding nO to s*C-S interaction,[30] allowing
the stereoselective Michael addition to occur on the opposite
face to the stereodirecting phenyl substituent on the iso-
thiourea. Finally, lactonization releases the catalyst and forms
the dihydropyranone product 4.
*
displays poor overlap with the standard profile ( ). However,
by adding the expected imidazole 33 (25 mm) by-product the
~
time-adjusted profile ( ) displayed better visual correla-
tion.[28] This suggests that release of free imidazole 33
throughout the reaction inhibits the reaction rate.
The reaction orders with respect to both N-acyl imidazole
34 and enone 2 were then assessed by means of a graphical
rate equation by obtaining reaction profiles at different
reaction excesses in the presence of added imidazole 33
(Figure 2c). A plot of rate/[34]x versus [2]y, where x and
y represent the respective reaction orders, showed good
graphical overlap and linearity when both components are
first order (x = y = 1).[26] The reaction kinetics show that the
rate is positively dependent on the concentration of enone 2,
indicating that Michael addition into 2 may be turnover-rate
limiting. To further support this, an inverse secondary kinetic
isotope effect (kH/kD = 0.75) was observed through independ-
ent initial rate measurements of the reactions using enone
isotopologues 2 and 37-d (Scheme 3). These studies indicate
that the mechanism of this base-free process is distinct to that
of ammonium enolate generation from arylacetic acids under
traditional basic conditions, where deprotonation is turnover-
Figure 2. a) Determination of catalyst order using a time-normalized profile; initial conditions: 34 (75 mm), 2 (50 mm), (+)-BTM·HCl 5 (2.5–
20 mm) in CD3CN. b) Same excess experiments with time adjusted profiles. c) Graphical rate equation obtained using varying excesses of 34 and
2 with (+)-BTM·HCl 5 (10 mm) in CD3CN.
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Rev. 2007, 107, 5596 – 5605; c) D. H. Paull, A. Weatherwax, T.
Lectka, Tetrahedron 2009, 65, 6771 – 6803; d) L. C. Morrill, A. D.
Smith, Chem. Soc. Rev. 2014, 43, 6214 – 6226.
[2] For seminal examples, see: a) R. Tennyson, D. Romo, J. Org.
Chem. 2000, 65, 7248 – 7252; b) A. E. Taggi, A. M. Hafez, H.
Wack, B. Young, D. Ferraris, T. Lectka, J. Am. Chem. Soc. 2002,
124, 6626 – 6635; c) C. Zhu, X. Shen, S. G. Nelson, J. Am. Chem.
Soc. 2004, 126, 5352 – 5353.
[3] L. C. Morrill, L. A. Ledingham, J.-P. Couturier, J. Bickel, A. D.
Harper, C. Fallan, A. D. Smith, Org. Biomol. Chem. 2014, 12,
624 – 636.
[4] 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.
Amos, J. C. Klein, D. T. Do, T. N. Snaddon, J. Am. Chem. Soc.
2016, 138, 5214 – 5217.
[5] For seminal examples, see: a) G. S. Cortez, R. L. Tennyson, D.
Romo, J. Am. Chem. Soc. 2001, 123, 7945 – 7946; b) S. H. Oh,
G. S. Cortez, D. Romo, J. Org. Chem. 2005, 70, 2835 – 2838; c) H.
Henry-Riyad, C. Lee, V. C. Purohit, D. Romo, Org. Lett. 2006, 8,
4363 – 4366; d) C. A. Leverett, V. C. Purohit, D. Romo, Angew.
Chem. Int. Ed. 2010, 49, 9479 – 9483; Angew. Chem. 2010, 122,
9669 – 9673; e) D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z.
Slawin, A. D. Smith, J. Am. Chem. Soc. 2011, 133, 2714 – 2720.
[6] For seminal work, see: a) R. Wolfenden, W. P. Jencks, J. Am.
Chem. Soc. 1961, 83, 4390 – 4393; b) W. P. Jencks, D. G. Oaken-
full, K. Salvesen, J. Am. Chem. Soc. 1971, 93, 188 – 194.
[7] J. A. Grzyb, M. Shen, C. Yoshina-Ishii, W. Chi, R. S. Brown,
R. A. Batey, Tetrahedron 2005, 61, 7153 – 7175.
Scheme 4. Proposed reaction mechanism.
In conclusion, bench-stable N-acyl imidazoles are ammo-
nium enolate precursors under mild, base-free conditions in
the presence of catalytic isothiourea hydrochloride salts. The
ammonium enolates undergo highly stereoselective Michael
addition-lactonization/ lactamization processes in the pres-
ence of various a,b-unsaturated Michael acceptors. Mecha-
nistic studies have revealed the importance of the “imidazo-
lium effect” to promote reactivity, which represents a new
paradigm in ammonium enolate formation. The use of
Reaction Progress Kinetic Analysis has allowed the complex
reaction kinetics to be probed, identifying the Michael
addition step as turnover-rate limiting and the imidazole by-
product as a source of product inhibition. Further studies
within this laboratory are focused on the development and
mechanistic understanding of Lewis-base catalysed process-
es.[31]
[8] E. K. Woodman, J. G. K. Chaffey, P. A. Hopes, D. R. J. Hose, J. P.
Gilday, Org. Process Res. Dev. 2009, 13, 106 – 113.
[9] S. T. Heller, T. Fu, R. Sarpong, Org. Lett. 2012, 14, 1970 – 1973.
[10] DMAP salts effectively catalyse acylations via N-acyl ammoni-
um intermediate formation under base-free conditions, see:
a) A. Sakakura, K. Kawajiri, T. Ohkubo, Y. Kosugi, K. Ishihara,
J. Am. Chem. Soc. 2007, 129, 14775 – 14779; b) D. Vuluga, J.
Legros, B. Crousse, D. Bonnet-Delpon, Chem. Eur. J. 2010, 16,
1776 – 1779; c) Z. Liu, Q. Ma, Y. Liu, Q. Wang, Org. Lett. 2014,
16, 236 – 239.
[11] a) A. Lee, A. Younai, C. K. Price, J. Izquierdo, R. K. Mishra,
K. A. Scheidt, J. Am. Chem. Soc. 2014, 136, 10589 – 10592; b) A.
Lee, K. A. Scheidt, Chem. Commun. 2015, 51, 3407 – 3410.
[12] Enders has reported the use of a,b-unsaturated N-acyltriazoles
as a,b-unsaturated acyl azolium precursors for annulations with
1,3-dicarbonyls under basic conditions, see: Q. Ni, J. Xiong, X.
Song, G. Raabe, D. Enders, Chem. Commun. 2015, 51, 14628 –
14631.
Acknowledgements
We thank Dr Paul Dingwall for his insightful discussions
regarding RPKA. We thank the European Research Council
under the European Unionꢁs Seventh Framework Pro-
gramme (FP7/2007-2013) ERC Grant Agreement no.
279850 (C.M.Y., T.H.W., J.E.T.). A.D.S. thanks the Royal
Society for a Wolfson Merit Award. We also thank the
EPSRC UK National Mass Spectrometry Facility at Swansea
University.
[13] For reviews on isothioureas as Lewis base catalysts, see: a) J. E.
Taylor, S. D. Bull, J. M. J. Williams, Chem. Soc. Rev. 2012, 41,
2109 – 2121; b) J. Merad, J.-M. Pons, O. Chuzel, C. Bressy, Eur. J.
Org. Chem. 2016, DOI: 10.1002/ejoc.201600399; c) L. C. Morrill,
A. D. Smith, Chem. Soc. Rev. 2014, 43, 6214 – 6226.
[14] For the corresponding reaction under basic conditions starting
from arylacetic acids, see: L. C. Morrill, J. Douglas, T. Lebl,
A. M. Z. Slawin, D. J. Fox, A. D. Smith, Chem. Sci. 2013, 4,
4146 – 4155.
[15] A control experiment in the absence of tetramisole·HCl 3 led to
the formation of (Æ)-4 in 28% yield, suggesting a base-promoted
background process is responsible for the observed reactivity.
[16] The absolute and relative configuration of the product was
confirmed by comparison of its specific rotation and spectral
data with the literature, Ref. [14].
Keywords: imidazolium effect · isothiourea catalysis ·
mechanistic study · Michael addition · N-acyl imidazoles
[17] For a complete reaction optimization table, see the Supporting
Information.
[18] The absolute and relative configuration of the product was
confirmed by comparison of its specific rotation and spectral
data with the literature: P.-P. Yeh, D. S. B. Daniels, C. Fallan, E.
[1] For reviews on the generation and use of ammonium enolates,
see: a) S. France, D. J. Guerin, S. J. Miller, T. Lectka, Chem. Rev.
2003, 103, 2985 – 3012; b) M. J. Gaunt, C. C. C. Johansson, Chem.
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Gould, C. Simal, J. E. Taylor, A. M. Z. Slawin, A. D. Smith, Org.
Biomol. Chem. 2015, 13, 2177 – 2191.
[27] The same order in catalyst could also be obtained by initial rate
analysis. See the Supporting Information for more details.
[28] The remaining minor discrepancy between the time-adjusted
same-excess profile containing imidazole 33 and the original
data may be due to either experimental error or minimal catalyst
deactivation.
[29] For other examples of complex reaction kinetics due at least in
part to no definitive catalyst resting state, see: a) S. Y. Lee, J. M.
Murphy, A. Ukai, G. C. Fu, J. Am. Chem. Soc. 2012, 134, 15149 –
15153; b) L. Mesas-Sꢂnchez, P. Dinꢀr, Chem. Eur. J. 2015, 21,
5623 – 5631.
[30] a) V. B. Birman, X. Li, Z. Han, Org. Lett. 2007, 9, 37 – 40; b) P.
Liu, X. Yang, V. B. Birman, K. N. Houk, Org. Lett. 2012, 14,
3288 – 3291.
[31] The research data underpinning this publication can be found
at DOI: http://dx.doi.org/10.17630/346a5fe8-a636-46e8-9933-
71db82f0083a.
[19] The absolute and relative configuration of the product were
assigned by analogy to the other series reported.
[20] The same equilibrium position was obtained starting from
a mixture of N-acyl ammonium 32, obtained from the reaction of
(+)-BTM 5 with phenacyl chloride, and imidazole 33.
[21] See the Supporting Information for more details.
[22] The observed cross-over may occur via an intermediate N,N’-
diacyl imidazolium species, although no direct evidence for this
could be obtained. Alternatively, the in situ formation of
a ketene intermediate is another possible pathway.
[23] For reviews on this technique, see: a) D. G. Blackmond, Angew.
Chem. Int. Ed. 2005, 44, 4302 – 4320; Angew. Chem. 2005, 117,
4374 – 4393; b) D. G. Blackmond, J. Am. Chem. Soc. 2015, 137,
10852 – 10866.
[24] Synthetically, this gave product 11 in 70% NMR yield, 86:14 d.r.
and 81:19 e.r.
[25] J. Burꢀs, Angew. Chem. Int. Ed. 2016, 55, 2028 – 2031; Angew.
Chem. 2016, 128, 2068 – 2071.
Received: August 17, 2016
[26] See the Supporting Information for full reaction profiles and
analysis.
Revised: September 22, 2016
Published online: && &&, &&&&
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Organocatalysis
C. M. Young, D. G. Stark, T. H. West,
J. E. Taylor, A. D. Smith*
&&&& — &&&&
Exploiting the Imidazolium Effect in Base-
free Ammonium Enolate Generation:
Synthetic and Mechanistic Studies
Drop the Base: N-Acyl imidazoles act as
ammonium enolate precursors in the
presence of catalytic isothiourea hydro-
chloride salts in the absence of base.
Subsequent reactions with various
Michael acceptors proceed with high
stereoselectivity. Mechanistic investiga-
tions have revealed the importance of the
“imidazolium effect” during enolate for-
mation and highlight key differences with
traditional base-mediated processes.
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!