Harnessing Additional Capability from in Water Reaction Conditions: Aldol versus Knoevenagel Chemoselectivity

Article abstract of DOI:10.1002/adsc.202100301

Aldol reaction chemoselectivity, racemic or enantioselective, has not been previously demonstrated in the presence of Knoevenagel active functional groups. Here, we show that unhindered β-diketones remain unreacted while a ketone moiety undergoes a highly

Full text of DOI:10.1002/adsc.202100301

Title: Harnessing Additional Capability from in Water Reaction
Conditions: Aldol versus Knoevenagel Chemoselectivity
Authors: Thomas Nugent, Falguni Goswami, Samarpita Debnath,
Ishtiaq Hussain, Hussein Ali El Damrany Hussein, Alka Karn,
and Srinuvasu Nakka
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10.1002/adsc.202100301
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Harnessing Additional Capability from in Water Reaction
Conditions: Aldol versus Knoevenagel Chemoselectivity
Thomas C. Nugent,*,a Falguni Goswami,a Samarpita Debnath,a Ishtiaq Hussain,b
Hussein Ali El Damrany Hussein,a Alka Karn,a Srinuvasu Nakkaa
a
Department of Life Sciences and Chemistry, Jacobs University Bremen, 28759 Bremen, Germany,
Phone: (+49) 421 200-3232, E-mail: t.nugent@jacobs-university.de
Department of Pharmacy, Abbottabad University of Science and Technology, Havelian Abbottabad, 22010 Pakistan.
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Aldol reaction chemoselectivity, racemic or
enantioselective, has not been previously demonstrated in the
presence of Knoevenagel active functional groups. Here, we
show that unhindered -diketones remain unreacted while a
ketone moiety undergoes a highly enantioselective aldol
desymmetrization resulting in three new stereogenic centers
using in water reaction conditions. A mechanistic hypothesis
for the chemoselective formation of either aldol or
Knoevenagel products is presented. It elucidates how these
amino acid catalyzed reactions completely suppress formation
of the expected Knoevenagel product under heterogenous in
water reaction conditions, but not when homogeneous in
water reaction conditions are used. The concept permitting
this new type of chemoselectivity is detailed here and expands
the role of water at an organic-water interface.
Keywords: chemoselectivity; Knoevenagel condensation;
aldol; organic-water interface; in water; desymmetrization
exploitation of this fact could permit a new type of
chemoselectivity to be identified.
Introduction
Organic chemists rely on inventive reaction
sequences to efficiently tackle and tame complex
molecular architectures, but strategic creativity can be
no greater than the scope of available reactions. To
that end, the expansion of methods based on enantio-,
diastereo-, regio-, or chemoselectivity drive the
tactical advantages that permit more efficient
syntheses.[1]
Results and Discussion
Initial Reaction Development. The literature teaches
us that Knoevenagel reactions are faster and higher
yielding than aldol reactions under very similar
reaction conditions. For example, under (S)-proline
or (S)-tryptophan catalysis in DMSO or neat,
acetylacetone[5,6] reacts faster than cyclohexanone[7-
10] with benzaldehyde. It was therefore unremarkable
that treatment of triketone 1a and benzaldehyde (2a)
under amino acid catalysis, resulted in ~10:1
chemoselectivity for the Knoevenagel condensation
product (KCP) 4 over aldol 5a (Scheme 1). This was
possible in good yield using (S)-proline (conditions A,
69% yield) or (S)-tryptophan (conditions B, 80%
yield), respectively in the reaction media EtOH or
DMSO.
Aldol and Knoevenagel condensation reactions share
a common electrophile: aldehydes, and due to the
lower acidity of Knoevenagel nucleophiles, e.g., -
diketones, malonate esters, etc., precedent exists for
Knoevenagel product formation in the presence of a
ketone, but not vice versa.[2] Both of these reactions
can be catalyzed by amino acids, however the
catalytic role of the amine in each reaction is
different.[3,4] We consequently hypothesized that
1
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10.1002/adsc.202100301
Advanced Synthesis & Catalysis
Scheme 1. A chemoselective switch: Knoevenagel condensation (4) or aldol (5a) product formation using triketone 1a. [a]
Isolated yield of product 4, as a mixture of E and Z geometric isomers (~2:1). [b] Isolated yield of single diastereomer.
Figure 1. Aldol products from in water reaction conditions.[a]
[a]
All reactions performed neat with added H2O (4.0 equiv) and catalyst 3c (2 mol%) unless otherwise noted. Isolated
yields represent the major diastereomer. [b] Triketone (1.5 equiv) and aldehyde (1.0 equiv). [c] Catalyst 3d (2 mol%, Figure
2) was used. Catalyst 3d (5 mol%, Figure 2) was used. Triketone (1.0 equiv) and aldehyde (3.0 equiv). Two step
overall yield: bromination performed after the aldol reaction for characterization purposes. Acetic acid (5 mol%) was
[d]
[e]
[f]
[g]
added.
however, work-up at 36 h only resulted in recovery of
With the dominance of the Knoevenagel reaction
established for triketone 1a, the focus shifted to the
possibility of a chemoselective switch to the aldol
product. Thus, in water (heterogeneous) reaction
conditions[11] were explored to undermine the
Knoevenagel catalytic cycle, while continuing to
promote the aldol reaction catalytic cycle. The well-
established in water aldol criteria,[12,13,14a] Kobayashi
category type IIIc,[11c] were satisfied by combining
triketone 1a (1.0 equiv), benzaldehyde 2a (3.0 equiv),
and (S)-proline (5 mol%) in the presence of water
(4.0 equiv). A biphasic mixture, with solid catalyst
fully dissolved, was established within minutes,
triketone
1a (92% yield). Addition of more L-proline resulted
in incomplete dissolution and this catalyst was
abandoned. In a revelatory experiment, the in water
aldol reaction parameters were maintained, but now 5
mol% of the Gruttadauria[14] aldol catalyst (3c) was
employed (Scheme 1). This resulted in an
enantioselective desymmetrization of 1a with >48:1
chemoselectivity for aldol product 5a over
Knoevenagel condensation product 4 (Scheme 1).
Despite the mediocre yield of 5a (single diastereomer
in 48% yield, 98% ee) and significant triketone (1a)
2
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10.1002/adsc.202100301
Advanced Synthesis & Catalysis
recovery (30%),[15] these findings validated the
Catalyst Optimization. Before large quantities of
triketone 1a were in hand, we pre-emptively began
catalyst screening. To that end, cyclohexanone and
then a 4-substituted diketone (8), containing a linear
tether approximating that found in 1a, were examined
(Scheme 2). The examined catalysts (3c–p) are
shown in Figure 2. Summarizing for the
cyclohexanone reaction, 3c and 3d provided the
best product profile with an optimized catalyst
loading of 1 mol%. For these two catalysts, there was
no discernible difference in reaction time (12 h), dr
(> 20:1), ee (99%), and isolated yield of 7 (> 90%).
Further details are found in the Supporting
Information (Section 8, Table S1).
premise
that
aldol
over
Knoevenagel
chemoselectivity can be achieved.
Aldol product scope and profile. The high
chemoselectivity for aldol product formation
encouraged us to examine alternative aldehyde
substrates with triketone 1a and to examine triketones
1b-d (Figure 1). The product results are summarized
in Figure 1 and characterized by: no Knoevenagel by-
product formation, a lowered catalyst loading (2
mol% of 3c), high ee, and improved yield over the
first example with benzaldehyde (Scheme 1).
Furthermore, the yields for 5a-g and 6h-k (Scheme 1
and Figure 1) represent those of single diastereomeric
products.[15] For -hydroxyketones 6h-k (Figure 1), a
two-step overall yield is shown: aldol, followed by
bromination (NBS). The latter reaction was required
for characterization purposes, i.e., at the aldol stage
the minor and major diastereomers of 5h-k, not
shown, could not be separated. The 5a-k drs ranged
from 1.3:1 to 8.8:1 and represent the anti-major (4-
substituent up) and anti-minor (4-substituent down)
products.[16] The protocol also flexibly permitted
either starting material to be the limiting reagent
(Figure 1, see footnotes [b] and [e]). We speculate
that the Figure 1 yields might be raised if Bolm's ball-
mill technique, devised for chiral-amine-catalyzed
aldol reactions, were applied.[9] The technique is both
relevant to our work and appealing because we often
recovered starting material.[15]
Scheme 2. Catalyst screening prior to triketones 1a-d.
Gong was the first to report enamine based
desymmetrizations of 4-substituted cyclohexanones
exemplified by 1a–d.[17–19] But, our demonstrations
are the first to move beyond simple 4-alkyl- or 4-
phenyl
substituted
cyclohexanones,
and
so should increase the application utility. Remarkably,
aldol product formation supersedes Knoevenagel and
enaminone formation. The latter reaction occurs
when amines (here our catalysts) are combined with
-diketones, and have been reported when using
water as a solvent.[20]
Finally, presumably due to its lower pKa (~5),
triketone 1d defined a substrate limit. Preliminary 1H
NMR analysis of crude and semi-purified products
allow us to speculate that four equally represented
diastereomers
formed.
Furthermore,
an
intramolecular reaction product of 1d, representing
ring closure from cyclohexanone onto a carbonyl unit
of the 1,3-diketone, may have formed. Addition of 5
mol% AcOH significantly improved the aldol product
diastereoselectivity for 1d, permitting isolation of the
major diastereomer, albeit in poor yield and 63% ee
(Figure 1, compound 6k). The reduced ee was
apparently due to the presence of acetic acid, whose
increased loading (100 mol%) resulted in 44% ee.
Figure 2. Sixteen catalysts examined (Section 8,
Supporting Information gives details).
Uncertain if this trend would continue for a triketone
like 1a, we screened diketone 8 with many of the
same catalysts (Scheme 2). During that study, 8 was
reacted with 4-nitrobenzaldehyde and benzaldehyde
(Supporting Information, Section 8, Tables S2 and
S3). Interestingly, the same catalyst trend noted for
3
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10.1002/adsc.202100301
Advanced Synthesis & Catalysis
cyclohexanone was again noted, albeit catalyst 3c
facilitated small yield increases over the use of
catalyst 3d. Increased yield was also noted when
using catalyst 3c with triketone 1a (Figure 1, see
product 5b yield examples).
Table 1. Knoevenagel versus aldol chemoselectivity: Effect of heterogeneous and homogeneous water conditions.[a]
entry description[b]
catalyst mol%[c]
solvent
EtOH
M[d]
time
(h)
4
/
5a[e]
4
(% yield) 5a (% yield) 1a (%)[f]
1[g]
2[g]
3[22]
4
homogeneous[h]
homogeneous[h]
homogeneous[h]
homogeneous[h]
3a
3b
3c
3d
25
30
5
0.30 21
0.50 30
0.30 21
0.30 21
9.9:1.0
10:1.0
2.5:1.0
3.6:1.0
69
80
10
36
7
18
7
DMSO
EtOH
EtOH
8
4
79
36
25
10
5
homogeneous[h]
homogeneous
3d
3d
30
30
DMSO
DMSO +
H2O (4 equiv)
DMSO +
H2O (16 equiv)
neat
0.50 30
0.50 30
15:1.0
2.8:1.0
59
37
4
35
46
13[i]
6
homogeneous
3d
30
0.50 30
1.1:1.0
37
35[i]
28
7
homogeneous[h]
heterogeneous
3c
3c
5
5
-
-
36
36
1.0:1.3
21
<1
28[i]
48[i]
36
30
8
9[g]
neat +
(4 equiv H2O)
1.0:>48
[a]
[b]
Entries 1-7, 1a/2a stoichiometry = 1.0:1.5; entries 8 and 9, 1a/2a stoichiometry = 1.0:3.0.
All solid reactants and
catalysts were fully dissolved, see Supporting Information Section 7. [c] Catalyst mol%. [d] Molarity of EtOH or DMSO.
Knoevenagel to aldol product chemoselectivity. Recovered triketone. Scheme 1 result. No intentional addition of
H2O. [i] Entries 6 and 7 represent the isolated yield of the major and minor aldol diastereomers, entries 8 and 9 only
represent the isolated yield of the major aldol diastereomer.[15]
[e]
[f]
[g]
[h]
In total, the screening studies revealed dual H-bond
donor containing catalysts 3f,[13] g,[17] and h[21] to be
inferior to single H-bond containing catalysts 3c,[14]
d,[12] and e.[12] Thus, the latter set mediated product
formation with higher dr and ee. Using catalyst 3c we
also synthesized a derivative of 9, and subjected it to
X-ray crystallographic analysis. By this means, the
relative and absolute stereochemistry of the products
were established (Supporting Information, Sections 9
and 10).
selectivity (4/5a), respectively in EtOH and DMSO
(Table 1, entries 4 and 5). Those results compare
favorably with the natural amino acids examined in
the same solvents (Table 1, entries 1 and 2).
Those findings established the importance of the
reaction media. But what role, if any, was water
fulfilling when the in water reaction conditions
(Scheme 1 and Figure 1) provided exclusive aldol
chemoselectivity (Table 1, entry 9). To probe this, the
Knoevenagel chemoselective reaction with 3d in
DMSO (entry 5, 4/5a, 15:1) was repeated, albeit now
with 4 and 16 equiv of added H2O. In the event, the
former resulted in eroded Knoevenagel selectivity
(entry 6, 4/5a, 2.8:1), while the latter provided no
selectivity (entry 7, 4/5a, 1.1:1). Clearly, aqueous
solutions of DMSO increase the aldol product content.
However, even 16 equiv of water could not suppress
formation of the Knoevenagel product (37% yield),
and the aldol yield was low (35%) at high catalyst
loading (30 mol%), see Table 1 (entry 7 and footnote
i).
The role of water. To clarify the origin of the
chemoselectivity, i.e., to differentiate the role of the
medium from the influence of catalyst structure,
additional reactions were performed (Table 1). Thus,
the optimal in water catalysts, 3c and 3d, which
provide no Knoevenagel product, were subjected to
the Knoevenagel-favored reaction conditions. Those
reactions were shown earlier with (S)-proline and (S)-
tryptophan, respectively in EtOH and DMSO
(Scheme 1 and summarized in Table 1 as entries 1
and 2). Unfortunately, catalyst 3c was only sparingly
soluble in either EtOH or DMSO, ruling out its
examination at the required catalyst loading (Table 1,
entry 3).[22] However, catalyst 3d was highly soluble
and provided 3.6:1 and 15:1 Knoevenagel-over-aldol
To further examine the role of water, the highly
chemoselective aldol reaction, entry 9, was repeated,
albeit now without added water. Revealingly, these
4
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10.1002/adsc.202100301
Advanced Synthesis & Catalysis
neat reaction conditions produced significant
quantities of the Knoevenagel product (21% yield),
but did show a chemoselective preference for the
aldol product (28% yield), see Table 1 (entry 8). This
finding again reinforces the need in water reaction
conditions.
Scheme 3. Amino acid catalytic cycles for Knoevenagel (blue) and aldol (red) product formation.
Summarizing,
Table 1 shows
high aldol-
over-
Knoevenagel c
hemoselectivit
y
requires
an organic-
water interface.
Attempts
to
replicate the in
water
(heterogeneou
s) result (entry
9),
by
employing
homogeneous
solutions with
water
cosolvents
(entries 6 and
7) or neat
reaction
MeOH. Three rate influencing steps (iminium cation
formation, enolate addition to iminium cation, and
elimination) were identified.[25] For our amino acid
catalyzed reaction, the analogous reaction steps with
zwitterionic and salt intermediates 10, 11, 12, and 13,
would be favorably solvated in the EtOH and DMSO
media we performed these reactions in. It is
simultaneously the case that formation of iminium
carboxylate 14 (Scheme 3, left panel, aldol
background reaction pathway) is expected, however,
14 is not rate determining for aldol product
formation.[29]
conditions (entry 8), failed. Thus, the major factor
controlling chemoselectivity is the reaction medium
and whether added water results in heterogeneous or
homogeneous reaction conditions.
Catalytic cycles and preliminary mechanistic
conclusions. Mechanistically, the Knoevenagel
nucleophile is always described as the carbanion form
of the active methylene partner, but the electrophile
varies.[3,23] For example, secondary amine catalysis is
widely employed and the intermediacy of an iminium
cation, derived from the aldehydic partner, is
invoked.[24,25] It is noteworthy that Knoevenagel
correctly rationalized the catalytic role of primary or
secondary amines in 1898.[26] The amino acid
catalyzed variant was first demonstrated by Dakin in
1909, and later by Prout.[27]
On switching to the in water reaction conditions, it is
assumed that solvation of the same intermediates
would only be favorable at the organic-water
interface. However, the enforced proximity to water
would also undermine intermediates vulnerable to
hydrolysis. Thus, zwitterion 19 likely forms (Scheme
3, right panel), but rapid hydrolysis reverts it back to
starting materials. Zwitterion 16 also forms and
suffers from a similar hydrolysis fate. But,
infrequently 16 will instead lose a proton. In doing so,
it forms the enamine carboxylic acid found within
pre-transition state 17. Relative to 16, 18, or 19, the
enamine carboxylic acid is stable at the phase
boundary. In fact, pre-transition state 17 has been
The Knoevenagel catalytic cycle for the (S)-proline
(3a) catalyzed reaction of triketone 1a (Table 1, entry
1) is highlighted in Scheme 3 (blue arrows), and is
consistent with modern interpretations of this
reaction.[3,25,28] The closest reported mechanistic study
involves the reaction of acetylacetone with
benzaldehyde under piperidine catalysis (10 mol%) in
5
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10.1002/adsc.202100301
Advanced Synthesis & Catalysis
Experimental Section
described as optimally activated via a water based H-
bond donor capability that is unique to water at an
organic-water interface.[14a] Importantly, this catalysis
influences the rate determining step for enamine
based aldol reactions, i.e., carbon-carbon bond
formation.[29]
Two hundred and thirty-seven pages of experimental
details, spectral and chromatographic data, and XRD
crystallographic data are provided.
Generic procedure for aldol product (5) formation.
Method A: To a dry screw cap V-shaped reaction vessel
(2.0 mL or 5.0 mL, based on the reaction scale) containing
a pyrimidal-shaped magnetic stir bar were added the
catalyst (2.0 or 5.0 mol %), triketone (1.5 equiv), aldehyde
(1.0 equiv), and then water (4.0 equiv) was gently added
and slow stirring was administered.
Several important points follow for the reactions
studied here: (i) good to high Knoevenagel-over-aldol
chemoselectivity is expected in polar media with low
or no water content, (ii) excellent aldol-over-
Knoevenagel chemoselectivity is afforded in water,
but not when dissolved water is present, and (iii) high
enantioselectivity is imparted on the aldol product by
the in water reaction conditions.
Method B: Same as method A, except triketone (1.0
equiv) and aldehyde (3.0 equiv).
Reaction monitoring: TLC analysis was unreliable.
Instead, the reaction time was determined by setting up
two reactions and performing the work-up at 18 h and the
other at 24 h. If the 24 h time did not provide sufficient
consumption of the limiting reagent, two more reactions
were set up and work-up was performed at 30 h and 36 h.
The maximum reaction time was 36 h. A reaction was
considered complete when there was <10% of the limiting
Conclusion
New examples of chemoselectivity are less often
noted, arguably because they are the oldest type of
selectivity studied. Here we report a new example,
aldol over Knoevenagel chemoselectivity. In total,
these findings re-enforce and expand the unique role
of water at an organic-water interface. Unanswered,
is how this previously untapped capability manifests
itself. Thus, at the water interface, is meaningful H-
bonding available and coupled with solvation and
rapid hydrolysis for iminium cations. If so, it might
explain why amino acid catalyzed aldol reactions are
subordinate to Knoevenagel reactions in solutions
with little or no water, while in water reaction
1
reagent, based on H NMR integration, or if any two
worked-up reactions (18, 24, 30, or 36 h) provided the
same starting material to product ratio (1H NMR).
Work-up: The reaction was diluted with dichloromethane
(2 mL for the common reaction scale of 0.33- 0.50 mmol
of limiting reagent) and stirred for 2-3 min at room
temperature. This solution was transferred into a separating
funnel already containing water (20 mL). The reaction vial
was further rinsed with dichloromethane (2.0 mL x 3) and
then water (2.0 mL x 2) and transferred to the separating
funnel. The biphasic solution layers were separated, and
the
conditions allow
chemoselectivity.
a
complete reversal in
aqueous layer was further extracted with dichloromethane
(2 x 10 mL). We advise the use of dichloromethane
because the rotary evaporator bath temperature should not
exceed 28 °C, or risk epimerizing the aldol product under
heating. The combined organic layers were dried
(Na2SO4), filtered, and concentrated under rotary
evaporation (rotary evaporator - bath temperature never
above 28 °C) to obtain a crude gummy product.
General Purification: Column chromatography was
performed using either mixtures of EtOAc/petroleum ether
or iPrOH/CH2Cl2. See the Supporting Information for
further details.
In short, Knoevenagel reactions rely on the
persistence of iminium cations (rate determining step),
with turnover only coming after elimination of the
amine catalyst (Scheme 3, intermediate 13). The aldol
reaction also requires iminium cation formation, but
it is not rate determining, and turnover relies on
iminium cation hydrolysis (Scheme 3, intermediate
18). It is this distinction that may be allowing the
observed chemoselectivity.
Acknowledgements
The practical outcome, of this report, is access to
aldol products with three stereogenic centers in high
ee, with broadened spectator functionality (-
diketones). By extension, other Knoevenagel
functional groups are expected to be compatible, e.g.,
-ketoesters, malonate esters, dinitriles, etc.
Application of these findings: to enamine, imine, or
iminium-based reactions, to amine catalyzed cascade
reactions, or as expanded tactics for complex
molecule synthesis are anticipated.
This research was generously supported by the Deutsche
Forschungsgemeinschaft (award no. NU235/6-2) and by Jacobs
University Bremen. We are thankful for low- and high-resolution
mass spectrometry measurements provided by Professor Nikolai
Kuhnert. We also thank Professor Stephen Connon (Trinity
College Dublin) for insightful comments during the preparation
of this manuscript.
References
6
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10.1002/adsc.202100301
Advanced Synthesis & Catalysis
[1] T. Hudlicky and J. W. Reed in The Way of Synthesis:
Evolution of Design and Methods for Natural Products,
Wiley-VCH, Weinheim, Germany 2007.
[15] All yield data in this manuscript represents isolated
yields. No re-calculated yields, based on recovered
limiting reagent, are given. Recovered triketone is
sometimes shown to demonstrate that by-product
formation is minimal or not occurring.
[2] a) See the conversion of 4 to 6 within: G. S.
Gadaginamath, A. G. Kamat, Proc. Indian Acad. Sci.
(Chem. Sci.) 1994, 106, 857-862; b) See the conversion
of 8 to 13 within: R. M. Mohareb, F. O. Al Farouk, S.
M. Sherif, K. Karaghiosoff, Med. Chem. Res. 2014, 23,
3165-3177; c) See Scheme 2 for two examples within:
H. Tan, X. Chen, H.Chen, H. Liu, S. Qiu, Eur. J. Org.
Chem. 2015, 4956-4963; d) See the conversion of 9 to
10 within: J. Gomes, C. Daeppen, R. Liffert, J.
Roesslein, E. Kaufmann, A. Heikinheimo, M.
Neuburger, K. Gademann, J. Org. Chem. 2016, 81,
11017-11034.
1
[16] The dr information was determined by H NMR for
crude products 5, and is noted for 5a-k in the
Supporting Information.
[17] J. Jiang, L. He, S. W. Luo, L. F. Cun, L.-Z. Gong,
Chem. Commun. 2007, 736-738.
[18] For additional selected examples of 4-substituted
cyclohexanone aldol desymmetrizations, albeit without a
1,3-diketone moiety, under chiral amine catalysis, see
references 9, 14a and: a) S. Li, C. Wu, X. Fu, Q. Miao, Ind.
Eng. Chem. Res. 2011, 50, 13711-13716; b) S. Li, C. Wu,
X. Long, X. Fu, G. Chen, Z. Liu, Catal. Sci. Technol. 2012,
2, 1068-1071; c) T. C. Nugent, F. T. Najafian, H. A. E. D.
Hussein, I. Hussain, Chem. Eur. J. 2016, 22, 14342-14348;
d) T. C. Nugent, P. Spiteller, I. Hussain, H. A. E. D.
Hussein, F. T. Najafian, Adv. Synth. Catal. 2016, 358,
3706-3713.
[3] For a review on Knoevenagel condensations, see: L. F.
Tietze, U. Beifuss, in Comprehensive Organic
Synthesis, Vol. 2 (Ed.: B. M. Trost), Pergamon, Oxford,
UK, 1991, p. 341–394.
[4] For an aldol reaction review, see: B. M. Trost, C. S.
Brindle, Chem. Soc. Rev. 2010, 39, 1600-1632.
[5] See Table 4 within: P. Goswami, B. Das, Tetrahedron
Lett. 2009, 50, 897-900.
[19] For an enzymatic example of diketone
desymmetrization, see: T. Peschke, P. Bitterwolf, S.
Gallus, Y. Hu, C. Oelschlaeger, N. Willenbacher, K. S.
Rabe, C. M. Niemeyer, Angew. Chem. Int. Ed. 2018, 57,
17028-17032.
[6] See Table 1 and 4 within: Y. Hu, Y.-H. He, Z. Guan,
Catal. Commun. 2010, 11, 656-659.
[7] See page S2 of the Supporting Information within: S.
Bahmanyar, K. N. Houk, H. J. Martin, B. List, J. Am.
Chem. Soc. 2003, 125, 2475-2479.
[20] a) H. A. Stefani, I. M. Costa, D. de O. Silva, Synthesis
2000, 1526-1528; b) A.-I Tsai, C.-P. Chuang,
Tetrahedron 2008, 64, 5098-5102.
[8] See Table 2 within: Z. Jiang, Z. Liang, X. Wu, Y. Lu,
[21] This catalyst is reported for the first time and its
synthesis is found in the Supporting Information
(Section 2).
Chem. Commun. 2006, 2801-2803.
[9] a) B. Rodríguez, T. Rantanen, C. Bolm, Angew. Chem.
Int. Ed. 2006, 45, 6924-6926; (b) See Table 5 within: B.
Rodríguez, A. Bruckmann, C. Bolm, Chem. Eur. J.
2007, 13, 4710-4722.
[22] For completeness, entry 3 (Table 1) is included with
catalyst 3c at a 5 mol% loading, but it is not noteworthy.
Note: Catalyst 3c is only sparingly soluble in EtOH.
Thus, at the required reaction concentration (0.30 M
solution of 1a in EtOH) for direct comparison with
entry 1 (Table 1), 3c was not capable of dissolving at a
25 mol% loading. 3c was significantly more soluble in
DMSO. But, at the required reaction concentration (0.5
M solution of 1a in DMSO) for direct comparison with
entry 2 (Table 1), 3c was not capable of dissolving at a
30 mol% loading.
[10] See Table 4 within: A. Karmakar, T. Maji, S.
Wittmann, O. Reiser, Chem. Eur. J. 2011, 17, 11024-
11029.
[11] a) Y. Jung, R. A. Marcus, J. Am. Chem. Soc., 2007,
129, 5492-5502; b) R. N. Butler, A. G. Coyne, Org.
Biomol. Chem. 2016, 14, 9945-9960; c) T. Kitanosono,
S. Kobayashi, Chem. Eur. J. 2020, 26, 9408-9429; d)
M. Cortes-Clerget, J. Yu, J. R. A. Kincaid, P. Walde, F.
Gallou, B. H. Lipshutz, Chem. Sci. 2021, 12, 4237-
4266.
[23] Tertiary amine (sp3 hybridized) catalysis is also
possible, however Hann and Lapworth described it as
proceeding less rapidly than under primary or
secondary amine catalysis, presumably because the
aldehyde is not activated. This may explain the lack of
tertiary amine catalyst applications in modern times,
see: A. C. O. Hann, A. Lapworth, J. Chem. Soc. 1904,
85, 46-56.
[12] a) Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T.
Urushima, M. Shoji, Angew. Chem. Int. Ed. 2006, 45,
958-961; b) S. Aratake, T. Itoh, T. Okano, N. Nagae, T.
Sumiya, M. Shoji, Y. Hayashi, Chem. Eur. J. 2007, 13,
10246-10256; c) Y. Hayashi, Angew. Chem. Int. Ed.
2006, 45, 8103–8104.
[24] See page 343 of reference 3.
[13] J.-F. Zhao, L. He, J. Jiang, Z. Tang, L.-F. Cun, L.-Z.
[25] E. V. Dalessandro, H. P. Collin, L. G. L. Guimarꢀes,
M. S. Valle, J. R. Pliego Jr., J. Phys. Chem. B 2017,
121, 5300-5307.
Gong, Tetrahedron Lett. 2008, 49, 3372-3375.
[14] a) F. Giacalone, M. Gruttadauria, P. L. Meo, S. Riela,
R. Noto, Adv. Synth. Catal. 2008, 350, 2747–2760; b) F.
Giacalone, M. Gruttadauria, P. Agrigento, P. L. Meo, R.
Noto, Eur. J. Org. Chem. 2010, 5696-5704.
[26] E. Knoevenagel, Ber. Dtsch. Chem. Ges. 1898, 31,
2596-2619.
7
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Advanced Synthesis & Catalysis
[27] a) H. D. Dakin, J. Biol. Chem. 1909, 7, 49-55; b)
Prout hailed the use of -aminocaproic acid, see: F. S.
Prout, J. Org. Chem. 1953, 18, 928-933.
15101; b) D. Seebach, A. K. Beck, D. M. Badine, M.
Limbach, A. Eschenmoser, A. M. Treasurywala, R.
Hobi, Helv. Chim. Acta 2007, 90, 425-471.
[28] A. Lee, A. Michrowska, S. Sulzer-Mosse, B. List,
Angew. Chem. Int. Ed. 2011, 50, 1707-1710.
[29] a) N. Zotova, A. Franzke, A. Armstrong, D. G.
Blackmond, J. Am. Chem. Soc. 2007, 129, 15100-
8
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Advanced Synthesis & Catalysis
FULL PAPER
Harnessing additional capability from in water
reaction conditions: Aldol versus Knoevenagel
chemoselectivity
Adv. Synth. Catal. 2021, 363, Page – Page
Thomas C. Nugent,* Falguni Goswami,
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Alka Karn, Srinuvasu Nakka
9
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