Dynamic Covalent Organocatalysts Discovered from Catalytic Systems through Rapid Deconvolution Screening

Article abstract of DOI:10.1002/chem.201502088

The first example of a bifunctional organocatalyst assembled through dynamic covalent chemistry (DCC) is described. The catalyst is based on reversible imine chemistry and can catalyze the Morita-Baylis-Hillman (MBH) reaction of enones with aldehydes or N-tosyl imines. Furthermore, these dynamic catalysts were shown to be optimizable through a systemic screening approach, in which large mixtures of catalyst structures were generated, and the optimal catalyst could be directly identified by using dynamic deconvolution. This strategy allowed one-pot synthesis and in situ evaluation of several potential catalysts without the need to separate, characterize, and purify each individual structure. The systems were furthermore shown to catalyze and re-equilibrate their own formation through a previously unknown thiourea-catalyzed transimination process.

Full text of DOI:10.1002/chem.201502088

DOI: 10.1002/chem.201502088
Full Paper
&
Dynamic Chemistry
Dynamic Covalent Organocatalysts Discovered from Catalytic
Systems through Rapid Deconvolution Screening
Fredrik Schaufelberger and Olof Ramstrçm*[a]
Abstract: The first example of a bifunctional organocatalyst
assembled through dynamic covalent chemistry (DCC) is de-
scribed. The catalyst is based on reversible imine chemistry
and can catalyze the Morita–Baylis–Hillman (MBH) reaction
of enones with aldehydes or N-tosyl imines. Furthermore,
these dynamic catalysts were shown to be optimizable
through a systemic screening approach, in which large mix-
tures of catalyst structures were generated, and the optimal
catalyst could be directly identified by using dynamic decon-
volution. This strategy allowed one-pot synthesis and in situ
evaluation of several potential catalysts without the need to
separate, characterize, and purify each individual structure.
The systems were furthermore shown to catalyze and re-
equilibrate their own formation through a previously un-
known thiourea-catalyzed transimination process.
alysis[4] and organocatalysis,[5] providing quick and facile routes
to bifunctional catalyst scaffolds. Elegant studies by the Reek[6]
and Breit groups,[7] have also shown the potential for simplified
screening of such systems by deconvolution methods. Howev-
er, supramolecular assemblies lack the robustness of covalent
linkages. Dynamic covalent chemistry (DCC) uses reversible co-
valent bonds to mimic the adaptive nature of supramolecular
systems, while retaining the advantages of well-defined, stable
covalent compounds.[8] For example, DCC has been successful-
ly used for ligand/receptor identification,[9] molecular-interac-
tion analysis,[10] kinetic processes,[11] biopolymers,[12] and chemi-
cal reaction networks.[13]
Introduction
Synthesis of new catalysts is critical for modern synthetic
chemistry, but catalyst discovery is commonly based on time-
consuming and frustrating trial-and-error protocols. To address
this issue, many combinatorial approaches to accelerate the
process have been developed.[1,2} However, combinatorial cat-
alysis has been hampered by limited access to structurally di-
verse systems, in particular with bifunctional scaffolds. Non-
trivial synthetic operations are commonly required for their as-
sembly, which renders the systems unsuitable for automated
high-throughput synthesis. Furthermore, a significant draw-
back of most combinatorial catalytic protocols is the require-
ment for all candidates to be purified, characterized, and evalu-
ated individually, regardless of their activity. Therefore, collec-
tive catalyst screening is highly desirable, although only a few
pioneering reports have been described.[3]
Due to the high interest in developing tunable catalysts and
catalytic systems, we became interested in the possibility of
creating such a „dynamic“ catalyst and investigating its proper-
ties. There are furthermore no known bifunctional catalysts, in
which the two functional parts are connected by a reversible
covalent bond. The application of DCC for catalyst discovery
has otherwise been a long-standing goal.[14] Early examples
relied on adaptive host systems that re-equilibrate in the pres-
ence of a transition-state analogue (TSA), leading to amplifica-
tion of the host that in theory best stabilizes the transition
state.[15] However, this leads to a need for design and synthesis
of the TSA, and the screening process may result in a host that
only binds the TSA without possessing any actual catalytic ac-
tivity.
In recent years, substantial effort has been invested into the
design of modular and responsive catalysts, in which the activi-
ty can be controlled through secondary inputs. In particular,
highly successful self-assembled supramolecular catalysts with
tunable activity have been developed for transition-metal cat-
[a] F. Schaufelberger, Prof. O. Ramstrçm
Department of Chemistry
KTH - Royal Institute of Technology
Teknikringen 30, 10044 Stockholm (Sweden)
E-mail: ramstrom@kth.se
Because dynamic covalent chemistry is equipped with a de-
veloped framework for analysis of large mixtures, we imagined
a possibility to directly find an optimal dynamic catalyst for
a given reaction from a large adaptive system. Herein, we have
developed a method for the dynamic combinatorial synthesis
of systems of bifunctional catalysts, followed by in situ identifi-
cation of the optimal catalyst. The methodology was applied
to the challenging Morita–Baylis–Hillman (MBH) reaction, and
a selective bifunctional catalyst with interesting properties was
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502088. It contains additional experi-
mental procedures, control experiments, and compound-characterization
data.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of Creative Commons Attri-
bution NonCommercial-NoDerivs License, which permits use and distribu-
tion in any medium, provided the original work is properly cited, the use is
non-commercial and no modifications or adaptations are made.
Chem. Eur. J. 2015, 21, 12735 – 12740
12735 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
discovered.[16] This method circumvents previous issues with
DCC and catalysis by directly screening towards the actual
chemical transformation in a kinetic manner.
as donors are also hard to control, with polymerization and
side-reactions often diminishing the efficiency. Accurate cata-
lyst predictions for such a reaction would indicate that the dy-
namic screening methodology possessed a high level of gener-
ality.
Thus, a racemic catalyst system that incorporated a nucleo-
philic Lewis base, an H-bond donor and a dynamic imine bond
connecting the two components was designed as shown in
Scheme 1a. Acids and water render the imine bond labile, but
Results and Discussion
In bifunctional catalysis, two functional groups capable of acti-
vating substrates are mounted on one scaffold.[17] It was hy-
pothesized that if such a scaffold incorporated a reversible
bond as shown in Figure 1a, a dynamic combinatorial system
Figure 1. a) Principle of dynamic bifunctional organocatalysis. b) Removal of
a single-system component gives propagating effects, eliminating all possi-
ble linear combinations of the component.
Scheme 1. a) Direct bifunctional dynamic catalyst formation for use in an
MBH reaction. b) Catalyst preorganizes and activates the substrates towards
the MBH reaction.
of potential bifunctional catalysts could be generated. By al-
lowing the system to reach equilibrium, a predictable product
distribution dictated only by the relative thermodynamic stabil-
ity of the catalysts would be obtained. Thus, dynamic deconvo-
lution with selective component removal can be used to evalu-
ate the effect of each component (Figure 1b).[18] Note that the
thermodynamic nature of the key bond connection is essential
for the accuracy of the deconvolution approach. Performing
the same deconvolution on mixtures, in which the bifunctional
catalyst has been constructed under kinetic control is not a fea-
sible methodology. Such systems are highly vulnerable to ki-
netic traps, resulting in a risk of active catalysts being unex-
pressed in the mixture. For a dynamic system, as long as the
building blocks utilized for constructing the catalysts are rela-
tively uniform in terms of the dynamic covalent functional
group, all possible linear combinations should be expressed in
the system in predictable ratios.
removal of either component leads to a structurally robust
linkage. This „conditional reversibility“ is essential, because
a dynamic catalyst should be able to equilibrate under one set
of conditions and stay inert under another. As illustrated in
Scheme 1b, the catalyst should activate both the enone and
the aldehyde, and preorganize the substrates for conversion
towards the MBH adduct.
The initial strategy was to first form the imines, and then
allow the dynamic system to reach equilibrium in situ using an
equilibration catalyst. This approach was tested for the model
system shown in Scheme 2, using components A, B, 1, and 2
to form imines A1, A2, B1, and B2 quantitatively. Herein, only
component B2 fulfills the criteria for bifunctionality, because it
possesses both a nucleophilic tertiary amine moiety and an H-
bond donating thiourea group.
To utilize this DCC methodology for discovery of dynamic bi-
functional catalysts, we required a synthetically relevant model
transformation. The MBH reaction was chosen, because orga-
nocatalysis has proven to be highly successful for this transfor-
mation, and the importance of bifunctionality has been well in-
vestigated.[19] Furthermore, studies have found that optimal
catalyst architectures were difficult to predict through rational
design, which together with the often very long reaction times
highlighted a need for rapid catalyst screening methods.[19b,e]
Traditionally, MBH reactions utilizing a,b-unsaturated ketones
However, upon attempted re-equilibration by addition of
catalytic amounts of water and widely used transimination cat-
alysts, such as benzoic acid or Sc(OTf)3, it was noticed that the
component distribution in the imine system did not change.
Control experiments confirmed that the system had in fact al-
ready reached equilibrium during condensation (see the Sup-
porting Information). This result was surprising, because
amines and aldehydes in the absence of acid are known to
condensate irreversibly under kinetic control.
Chem. Eur. J. 2015, 21, 12735 – 12740
www.chemeurj.org
12736 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 2. Model-system formation with indirect re-equilibration route (top) and direct condensation route (bottom). THF=tetrahydrofuran, MS=molecular
sieves.
It is known that thiourea moieties form strong H bonds with
imines. It was thus hypothesized that the thiourea NÀH pro-
tons could act as general acid catalysts for the system and self-
catalyze the system synthesis, in which it takes part. Further
control experiments indicated that thioureas are indeed able
to induce equilibration of dynamic imine systems, as long as
water and/or amines are still present in the mixture (see the
Supporting Information). We also confirmed that transimina-
tion did not proceed at all in the absence of these species,
which supports a hydrolysis/condensation mechanism for the
re-equilibration. This effectively led to dynamic systems that
were „locked“ at equilibrium under dry conditions, because the
water necessary for re-equilibration was continuously removed
during the condensation phase. Furthermore, it was also con-
firmed that thiourea structures were capable of catalyzing the
exchange even in the absence of primary amines, indicating
that aliphatic amine transimination catalysis was not the sole
factor at play. To the best of our knowledge, this is the first
report of H-bond-catalyzed transimination outside of biological
systems. This finding greatly simplified our method, because
the re-equilibration step shown in Scheme 2 could be entirely
omitted. Furthermore, it added a further layer of complexity to
this potential catalyst class, because these dynamic thiourea-
imine catalysts are, in a sense, able to modify and catalyze
their own formation.
With equilibration conditions in hand, the system was next
expanded to four aldehydes and four amines, as shown in
Scheme 3, to increase the chances of finding an active catalyst.
Aldehydes 2, 3, and 4 comprise nucleophilic sites in the ortho
position to the imine linker, whereas amines B, C, and D incor-
porate H-bond donors. Cyclohexylamine A and benzaldehyde
1 were used as controls. A dynamic catalyst system composed
of 16 different imines was formed analogously to the model re-
action, and equilibrium was again attained during the conden-
sation phase. Next, ethyl vinyl ketone and p-nitrobenzaldehyde
were added directly to the system as shown in Figure 2a. The
MBH reaction proceeded readily, and 20–25% yield of the de-
sired adduct 5 was obtained after 24 h, as indicated by NMR
analysis. Thus, at least one of the 16 potential catalysts in the
mixture possessed MBH activity.
Figure 2. a) Model MBH reaction. b) Observed initial rate difference for MBH
reaction upon selective replacement of investigated components 2–4 or B-D
by equivalent amount of non-functionalized analogues 1 or A in the pre-
generated catalyst system. Conditions: 0.12 mmol p-nitrobenzaldehyde,
0.24 mmol ethyl vinyl ketone, 4 Š MS (300 mg), anhydrous THF (0.5 mL), pre-
generated imine catalyst system (0.075 mmol of each initial component A-D
and 1–4 except for the omitted building block and the replacement com-
pound A or 1 of which 0.15 mmol was added). Duplicate experiments; for
further experimental details and kinetic plots, see the Supporting Informa-
tion.
Scheme 3. Formation of dynamic 16-component imine system and „locking“
by water removal.
Chem. Eur. J. 2015, 21, 12735 – 12740
www.chemeurj.org
12737 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
To minimize the number of experiments required to identify
the active components in the mixture, a dynamic deconvolu-
tion scheme was devised, the results of which are shown in
Figure 2b. Equimolar amounts of the amine and aldehyde spe-
cies were generally required, because the formed imines were
inert under MBH conditions even in the presence of thioureas.
Hence, deconvolution could be efficiently accomplished
through selective replacement of the evaluated component by
an equivalent amount of a reference compound (A for amines,
1 for aldehydes). Initial rates were then measured to fully cor-
relate systemic catalytic activity with changes in system com-
position upon component replacement.[20] Replacement of po-
tentially active components by inactive species would lead to
retarded rates of the investigated reaction, compared with the
complete system with all functionalities present (the reference
bar in Figure 2b). Conversely, removal of a component that is
detrimental to catalytic activity should give enhanced initial
rates.
Figure 3. Yields of compound 5 in parallel catalyst-screening experiments.
Conditions: 0.1 mmol p-nitrobenzaldehyde, 0.3 mmol ethyl vinyl ketone,
0.02 mmol bifunctional catalyst, 0.5 mL THF, 200 mg 4 Š MS, 24 h, RT.
The relatively high catalytic ability of B3 was initially surpris-
ing, because the system experiments actually predicted the
compound to be detrimental to catalysis. However, subsequent
experiments showed that B3 was highly unselective, with for-
mation of large amounts of byproducts. Furthermore, product
5 was shown to be unstable in the presence of B3, and de-
composed over time. These effects are an example of why care
has to be taken in the collective screening of catalyst mixtures,
because simple determination of the yield of 5 upon complet-
ed reaction would not lead to accurate predictions of the opti-
mal catalyst activities. However, this study has showcased that
kinetic measurements of initial rates is a possible way to mea-
sure systemic activities of catalyst mixtures.
As can be seen from Figure 2b, replacement of the dimeth-
ylamino-containing component 2 gave a slight rate increase. A
potential explanation for this observation can be the systemic
effects of bifunctionality in the catalyst system. Assuming one
or more optimal combinations of nucleophile and H-bond
donor, a scenario, in which pairing of an inactive component
with a potentially active species would produce a bifunctional
catalyst that exhibits low activity, can be envisaged. If this pair-
ing would be thermodynamically more preferred than pairing
of two active components, then removal of the inactive com-
ponent would lead to re-equilibration in favor of the more
active catalyst combination and thus increased rates. This sce-
nario may be well applicable to the case of component 2.
However, removal of diphenylphosphine-containing aldehyde
3 led to complete loss of catalytic activity, implying that the
highly nucleophilic phosphine was the only nucleophile in the
system capable of catalyzing the reaction. In further support of
this observation, imidazole-based aldehyde 4 showed almost
no rate change when replaced.
Although C3 is by no means a state-of-the-art catalyst activi-
ty-wise, these results provide compelling evidence that the de-
convolution methodology has accurately predicted the most
active catalyst from a dynamic system. This protocol seems to
be highly suited for detecting components crucial for activity,
but it can also differentiate between less important functional
groups that still contribute to the catalysis in the system. The
method is simple and straightforward, and allows one-pot syn-
thesis and subsequent screening of well-defined, covalently
linked bifunctional organocatalysts without the need for sepa-
ration, purification, and characterization of each individual mol-
ecule. The small model system investigated in this study is
easily amenable to expansion, and the deconvolution protocol
would be expected to increase further in efficiency with larger
systems. Furthermore, considering the range of dynamic cova-
lent linkages developed in recent years, a wide range of poten-
tial dynamic catalysts architectures could be envisaged.
The results from the H-bond donor screen showed less pro-
nounced differences. Removal of the weaker H-bonding thiour-
ea C provided the largest systemic effect, with the product for-
mation rate decreasing by almost 30%. Replacement of the
stronger H-bond donor B instead led to a rate increase, sug-
gesting that B had deleterious effects on the catalysis.
To evaluate the accuracy of the deconvolution predictions,
a parallel screening test was subsequently performed. All linear
combinations of the catalysts were synthesized in situ by
direct condensation of the corresponding amine and aldehyde,
and tested in single experiments. Only the four reactions in-
volving the imines resulting from aldehyde 3 showed any
product formation after 24 h. These four catalysts were then
synthesized and purified, giving bench-stable compounds that
were subsequently tested in controlled single experiments.
The results are summarized in Figure 3 and are in accordance
with the dynamic deconvolution results. Compound C3 turned
out to be the most active catalyst, with a 19% yield of the
MBH product 5, compared to 15% for B3 and only 3% for A3
and D3.
Having shown that the dynamic covalent chemistry enabled
accelerated activity screening, we turned to investigating the
behavior of the dynamic bifunctional catalyst C3 in more
detail. When the MBH reaction was performed with 20% load-
ing of C3, a yield of 87% could be provided after an extended
reaction time (240 h). In comparison, a maximum of only 27%
yield could be obtained using B3. Also, C3 could efficiently cat-
alyze an aza-MBH reaction with highly electrophilic phenyl N-
tosyl imine 6 to give aza-MBH adduct 7 in a very good 85%
yield over 72 h (Scheme 4).[21]
Chem. Eur. J. 2015, 21, 12735 – 12740
www.chemeurj.org
12738 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
amine pair. These results indicate that the dynamic bifunctional
organocatalysts might be utilized as primitive switches, espe-
cially given the discovered self-modifying capabilities of this
class of catalysts.
The inclusion of a dynamic imine bond, as well as a transimi-
nation catalyst, into the same structure also opens further in-
teresting possibilities. For the catalyst screening, the dynamic
system was „locked“ during the entire catalytic event to main-
tain accuracy in reaction kinetics measurements. However, it is
also straightforward to „unlock“ the dynamic system and allow
living dynamic catalyst behavior, in which the catalyst structure
is continuously changing during the reaction. In theory, orga-
nocatalysts capable of in situ error correction of their own mo-
lecular architecture could then be envisaged.
Conclusion
A new class of dynamic bifunctional catalysts capable of cata-
lyzing modifications of their own constitution was developed,
and it was showcased how this property allows one-pot syn-
thesis and evaluation of large systems of catalysts. The meth-
odology uncovered a relatively effective catalyst for the
Morita–Baylis–Hillman reaction, and catalyst effectiveness
could be regulated through manipulations of the dynamic co-
valent bond. DCC is integral for the screening approach, be-
cause it enables a deconvolution strategy that rapidly identifies
the system components that contribute most to catalytic activ-
ity. The dynamic imine linkage allows proofreading of the dy-
namic system, with the reversibility ensuring a uniform catalyst
distribution. The methodology can be utilized for catalyst dis-
covery, and the obtained dynamic bifunctional scaffolds exhibit
the potential for use as adaptable organocatalysts. Further-
more, this also marks the first report of thiourea-catalyzed tran-
simination. Further investigations on the screening methodolo-
gy and the self-modifying ability of the dynamic catalysts are
currently in progress.
Scheme 4. Catalyst performance in MBH and aza-MBH reactions. Conditions:
0.2 mmol aldehyde/imine 6, 0.6 mmol ethyl vinyl ketone, 0.04 mmol C3, 4 Š
MS (100 mg), 1.0 mL THF, N2.
Table 1. Tunable catalytic activity for C3.[a]
Catalyst
Incubation time [h]
MBH activity[b]
C3
–
ON
C
3
–
–
24
–
24
OFF
OFF[e]
OFF
OFF[e]
ON
C3[c]
C+3
C+3[d]
[a] Conditions: 0.1 mmol p-nitrobenzaldehyde, 0.3 mmol ethyl vinyl
1
ketone, 0.02 mmol catalyst, 0.5 mL THF, N2. [b] Indicated by H NMR spec-
troscopy after 7 h. [c] With 0.2 mmol H2O. [d] With 4 Š MS (100 mg).
[e] Trace amounts.
Experimental Section
Experimental procedure for dynamic system generation
Aldehydes and amines (0.075 mmol each) were dissolved in anhy-
drous THF (0.5 mL) in an Eppendorf vial, and the solution was
transferred to a dry reaction vial containing pre-activated 4 Š MS
(300 mg) under N2. The mixture was stirred at room temperature
for 20 h after which time the equilibrated system was obtained.
Tests for thiourea system equilibration were performed (see the
Supporting Information), showing that the systems were at equilib-
rium after condensation.
Furthermore, we were interested in investigating if the dy-
namic covalent bond could be utilized to modulate the MBH
activity. Running the reaction with only amine C predictably
only led to imine formation with p-nitrobenzaldehyde, but
more surprisingly, utilizing aldehyde 3 as the sole catalyst led
to almost no product and quick decomposition (Table 1).
When adding C and 3 together, the MBH reaction proceeded
with very low selectivity and yield, with decomposition of the
aldehyde presumably occurring over MBH adduct formation.
However, when C and 3 were pre-stirred with 4 Š MS over-
night, C3 was formed in quantitative yield, and the corre-
sponding MBH reaction proceeded readily and selectively. Con-
versely, pre-stirring four equivalents of H2O with C3 followed
by reagent addition again produced almost no product forma-
tion, because the thiourea seemed to have catalyzed the par-
tial hydrolysis of the imine back to the unfavorable aldehyde–
Kinetic analysis of Morita-Baylis–Hillman reactions with dy-
namic systems catalysis
A dynamic system was generated according to the description
above. Afterwards, p-nitrobenzaldehyde (18.1 mg, 0.12 mmol) in
anhydrous THF (0.120 mL) was added under N2, followed by addi-
tion of ethyl vinyl ketone (23.9 mL, 20.8 mg, 0.24 mmol). The mix-
ture was stirred at room temperature under N2. An aliquot of the
reaction mixture (30.0 mL) was withdrawn and added to 0.550 mL
Chem. Eur. J. 2015, 21, 12735 – 12740
www.chemeurj.org
12739 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
W. He, X. Li, Z. Li, B. Chen, P. Ouyang, K. Guo, Bioorg. Med. Chem. Lett.
2013, 23, 5174–5177.
[10] a) A. G. Santana, E. JimØnez-Moreno, A. M. Gómez, F. Corzana, C. Gon-
zµlez, G. JimØnez-Oses, J. JimØnez-Barbero, J. L. Asensio, J. Am. Chem.
Soc. 2013, 135, 3347–3350; b) M. d. F. Capela, N. J. Mosey, L. Xing, R.
Wang, A. Petitjean, Chem. Eur. J. 2011, 17, 4598–4612.
[11] a) P. Vongvilai, M. Angelin, R. Larsson, O. Ramstrçm, Angew. Chem. Int.
Ed., 46, 948–950; Angew. Chem. 2007, 119, 966–968; Angew. Chem.
2007, 119, 966–968; b) M. Sakulsombat, Y. Zhang, O. Ramstrçm, Chem.
Eur. J. 2012, 18, 6129–6132; c) P. Vongvilai, O. Ramstrçm, J. Am. Chem.
Soc. 2009, 131, 14419–14425; d) R. Sundell, M. Turcu, L. Kanerva, Curr.
Org. Chem. 2013, 17, 672–681; e) L. Hu, O. Ramstrçm, Chem. Commun.
2014, 50, 3792–3794.
[12] a) L. Marin, B. Simionescu, M. Barboiu, Chem. Commun. 2012, 48, 8778–
8780; b) Y. Ruff, V. Garavini, N. Giuseppone, J. Am. Chem. Soc. 2014, 136,
6333–6339; c) A. K. H. Hirsch, E. Buhler, J.-M. Lehn, J. Am. Chem. Soc.
2012, 134, 4177–4183.
[13] a) Y. Zhang, L. Hu, O. Ramstrçm, Chem. Commun. 2013, 49, 1805–1807;
b) J. W. Sadownik, D. Philp, Angew. Chem. Int. Ed 2008, 47, 9965–9970;
Angew. Chem. 2008, 120, 10113–10118; c) Y. Zhang, O. Ramstrçm,
Chem. Eur. J. 2014, 20, 3288–3291.
[14] For reviews on DCC in catalysis, see: a) G. Gasparini, M. Dal Molin, L. J.
Prins, Eur. J. Org. Chem. 2010, 2429–2440; b) P. Dydio, P.-A. R. Breuil,
J. N. H. Reek, Isr. J. Chem. 2013, 53, 61–74.
[15] a) B. Brisig, J. K. M. Sanders, S. Otto, Angew. Chem. 2003, 115, 1308–
1311; Angew. Chem. Int. Ed. 2003, 42, 1270–1273; b) L. Vial, J. K. M.
Sanders, S. Otto, New J. Chem. 2005, 29, 1001–1003; c) G. Gasparini,
L. J. Prins, P. Scrimin, Angew. Chem. Int. Ed. 2008, 47, 2475–2479;
Angew. Chem. 2008, 120, 2509–2513; d) M. Matsumoto, D. Estes, K. M.
Nicholas, Eur. J. Inorg. Chem. 2010, 1847–1852.
CDCl3 in an NMR tube, with PhSiMe3 (0.020 mL/mL CDCl3) as inter-
nal standard. NMR measurements were performed within 5 min, al-
though control experiments indicated that the aliquot composition
was stable for several hours in anhydrous CDCl3. Product formation
was monitored by integrating the characteristic peaks at d=5.66
and 6.00 ppm and comparing to the internal standard.
Acknowledgements
This study was supported by the Swedish Research Council.
F.S. gratefully acknowledges financial support from the Royal
Institute of Technology Excellence Award.
Keywords: catalyst screening · dynamic covalent chemistry ·
organocatalysis · Schiff bases · transimination
[1] M. T. Reetz, Angew. Chem. Int. Ed. 2001, 40, 284–310; Angew. Chem.
2001, 113, 292–320.
[2] a) K. Ding, H. Du, Y. Yuan, J. Long, Chem. Eur. J. 2004, 10, 2872–2884;
b) S. Dahmen, S. Bräse, Synthesis 2001, 1431–1449; c) C. Gennari, U.
Piarulli, Chem. Rev. 2003, 103, 3071–3100.
[3] a) A. Teichert, A. Pfaltz, Angew. Chem. Int. Ed. 2008, 47, 3360–3362;
Angew. Chem. 2008, 120, 3408–3410; b) C. Hinderling, P. Chen, Angew.
Chem. Int. Ed. 1999, 38, 2253–2256; Angew. Chem. 1999, 111, 2393–
2396; c) C. Markert, A. Pfaltz, Angew. Chem. Int. Ed 2004, 43, 2498–
2500; Angew. Chem. 2004, 116, 2552–2554.
[16] For selected reviews on MBH reactions, see: a) Y. Wei, M. Shi, Chem. Rev.
2013, 113, 6659–6690; b) Y. Wei, M. Shi, Acc. Chem. Res. 2010, 43,
1005–1018; c) V. r. Declerck, J. Martinez, F. d. r. Lamaty, Chem. Rev. 2009,
109, 1–48; d) D. Basavaiah, B. S. Reddy, S. S. Badsara, Chem. Rev. 2010,
110, 5447–5674.
[17] For selected reviews on H-bonding catalysis, see: a) R. R. Knowles, E. N.
Jacobsen, Proc. Natl. Acad. Sci. USA 2010, 107, 20678–20685; b) A. G.
Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–5743; c) X. Yu, W.
Wang, Chem. Asian J. 2008, 3, 516–532.
[18] a) T. Bunyapaiboonsri, O. Ramstrçm, S. Lohmann, J.-M. Lehn, L. Peng, M.
Goeldner, ChemBioChem 2001, 2, 438–444; b) O. Ramstrçm, S. Loh-
mann, T. Bunyapaiboonsri, J.-M. Lehn, Chem. Eur. J. 2004, 10, 1711–
1715.
[4] a) M. Weis, C. Waloch, W. Seiche, B. Breit, J. Am. Chem. Soc. 2006, 128,
4188–4189; b) B. Breit, W. Seiche, J. Am. Chem. Soc. 2003, 125, 6608–
6609; c) V. F. Slagt, M. Rçder, P. C. J. Kamer, P. W. M. M. van Leeuwen,
J. N. H. Reek, J. Am. Chem. Soc. 2004, 126, 4056–4057; d) R. Bellini, S. H.
Chikkali, G. Berthon-Gelloz, J. N. H. Reek, Angew. Chem. Int. Ed. 2011, 50,
7342–7345; Angew. Chem. 2011, 123, 7480–7483.
[5] a) M. L. Clarke, J. A. Fuentes, Angew. Chem. Int. Ed. 2007, 46, 930–933;
Angew. Chem. 2007, 119, 948–951; b) T. Mandal, C.-G. Zhao, Angew.
Chem. Int. Ed. 2008, 47, 7714–7717; Angew. Chem. 2008, 120, 7828–
7831; c) Y. Yao, J.-L. Li, Q.-Q. Zhou, L. Dong, Y.-C. Chen, Chem. Eur. J.
2013, 19, 9447–9451.
[6] P. Dydio, C. Rubay, T. Gadzikwa, M. Lutz, J. N. H. Reek, J. Am. Chem. Soc.
2011, 133, 17176–17179.
[19] For selected reports, see: a) M. Shi, L.-H. Chen, C.-Q. Li, J. Am. Chem.
Soc. 2005, 127, 3790–3800; b) Y.-L. Shi, M. Shi, Adv. Synth. Catal. 2007,
349, 2129–2135; c) M. Shi, Y.-M. Xu, Angew. Chem. Int. Ed. 2002, 41,
4507–4510; Angew. Chem. 2002, 114, 4689–4692; d) J. Wang, H. Li, X.
Yu, L. Zu, W. Wang, Org. Lett. 2005, 7, 4293–4296; e) K. Matsui, S. Takiza-
wa, H. Sasai, J. Am. Chem. Soc. 2005, 127, 3680–3681; f) V. K. Aggarwal,
S. Y. Fulford, G. C. Lloyd-Jones, Angew. Chem. Int. Ed. 2005, 44, 1706–
1708; Angew. Chem. 2005, 117, 1734–1736; g) P. Buskens, J. Klanker-
mayer, W. Leitner, J. Am. Chem. Soc. 2005, 127, 16762–16763; h) C. E. S.
Jones, S. M. Turega, M. L. Clarke, D. Philp, Tetrahedron Lett. 2008, 49,
4666–4669.
[20] Collecting initial-rate data is the sole way to accurately relate catalytic
activity with systemic changes. However, simply determining the
1H NMR yield of 5 in each experiment after a relatively short time
period (ca. 5 h) gave activity results in line with the kinetic data. For
practical applications, this type of kinetic “snapshots” constitutes a sig-
nificantly faster method to perform the deconvolution screening, once
the accuracy of the initial rate kinetics has been verified.
[7] J. Wieland, B. Breit, Nat. Chem. 2010, 2, 832–837.
[8] For reviews on DCC, see: a) M. Barboiu, Constitutional Dynamic Chemis-
try, Springer, Berlin, Heidelberg, 2012; b) B. L. Miller, Dynamic Combina-
torial Chemistry: In Drug Discovery, Bioorganic Chemistry, and Materials
Science, Wiley, Hoboken, 2010; c) J. N. H. Reek, S. Otto, Dynamic Combi-
natorial Chemistry, Wiley-VCH, Weinheim, 2010; d) A. Herrmann, Chem.
Soc. Rev. 2014, 43, 1899–1933; e) Q. Ji, R. C. Lirag, O. S. Miljanic, Chem.
Soc. Rev. 2014, 43, 1873–1884; f) J.-M. Lehn, Angew. Chem. Int. Ed. 2013,
52, 2836–2850; Angew. Chem. 2013, 125, 2906–2921; g) E. Moulin, G.
Cormos, N. Giuseppone, Chem. Soc. Rev. 2012, 41, 1031–1049; h) J. Li, P.
Nowak, S. Otto, J. Am. Chem. Soc. 2013, 135, 9222–9239; i) Y. Jin, C. Yu,
R. J. Denman, W. Zhang, Chem. Soc. Rev. 2013, 42, 6634–6654; j) M. Sa-
kulsombat, Y. Zhang, O. Ramstrçm, Top. Curr. Chem. 2012, 322, 55–86.
[9] a) M. Demetriades, I. K. H. Leung, R. Chowdhury, M. C. Chan, M. A.
McDonough, K. K. Yeoh, Y.-M. Tian, T. D. W. Claridge, P. J. Ratcliffe, E. C. Y.
Woon, C. J. Schofield, Angew. Chem. Int. Ed. 2012, 51, 6672–6675;
Angew. Chem. 2012, 124, 6776–6779; b) A. J. Clipson, V. T. Bhat, I.
McNae, A. M. Caniard, D. J. Campopiano, M. F. Greaney, Chem. Eur. J.
2012, 18, 10562–10570; c) R. Caraballo, H. Dong, J. P. Ribeiro, J. JimØ-
nez-Barbero, O. Ramstrçm, Angew. Chem. Int. Ed. 2010, 49, 589–593;
Angew. Chem. 2010, 122, 599–603; d) M. Rauschenberg, S. Bomke, U.
Karst, B. J. Ravoo, Angew. Chem. Int. Ed. 2010, 49, 7340–7345; e) S.
Hamieh, V. Saggiomo, P. Nowak, E. Mattia, R. F. Ludlow, S. Otto, Angew.
Chem. Int. Ed. 2013, 52, 12368–12372; Angew. Chem. 2013, 125, 12594–
12598; f) M. K. Chung, C. M. Hebling, J. W. Jorgenson, K. Severin, S. J.
Lee, M. R. GagnØ, J. Am. Chem. Soc. 2008, 130, 11819–11827; g) Z. Fang,
[21] Unoptimized preliminary experiments with chiral versions of C3 have
also been performed with enantiomeric ratio of 5 in the range of 54:46
to 58:42.
Received: May 28, 2015
Published online on July 14, 2015
Chem. Eur. J. 2015, 21, 12735 – 12740
www.chemeurj.org
12740 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim