university of groningen dynamic transfer of chirality in ......was achieved via switchable iminium...

University of Groningen

Dynamic transfer of chirality in photoresponsive systemsPizzolato, Stefano Fabrizio

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Citation for published version (APA):Pizzolato, S. F. (2017). Dynamic transfer of chirality in photoresponsive systems: Applications of molecularphotoswitches in catalysis. University of Groningen.

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Chapter 4 Chapter 4

Studies towards a Trifunctionalized Molecular

Switch for Light-assisted Tandem Catalytic

Processes

This chapter describes the study towards a trifunctionalized molecular photoswitch based on an

overcrowded alkene for light–assisted tandem catalytic processes. We proposed a two-step sequence of

Morita–Baylis–Hillman (MBH) reaction and enamine catalyzed aldol reaction by merging two pairs of

orthogonal bifunctional catalytic groups. Alternative designs, compared to those described in chapter 3,

aimed to improve the catalytic activity in the MBH reaction and related attempted syntheses, are presented.

Finally, screening of other transformations that could be mediated by the initially proposed

photoswitchable catalysts design is reported.

Chapter 4

120

4.1 Introduction

Catalysis is unarguably the most powerful tool to efficiently and effectively transform readily available

building blocks into highly complex molecules and materials. Research focused for decades on the

development of highly selective catalysts to fulfill any possible synthetic task via careful optimization to

achieve high conversions and selectivities. While new synthetic methodologies are still under investigation,

the novel field of switchable catalysis has recently emerged as a promising platform to further extend our

control via more complex catalytic systems.1–6

Inspired by Nature, chemists are now crafting dynamically

responsive catalysts whose activity and selectivity can be tuned or reversed by an external stimulus.

Potential applications include the ability to control ‗one-pot‘ multi-component and multi-step synthetic

processes, thus providing access to a variety of valuable products from a pool of building blocks depending

on the order and type of stimuli provided. A brief selection of the most relevant systems for

photoswitchable catalysis has already been presented in Chapter 3. For a comprehensive view of the field,

the reader may refer to the recent reviews.1–6

Many systems have been demonstrated to achieve reversible control of the catalytic activity by external

input, either by altering the reaction rate or by effectively switching ON/OFF the substrate conversion.7–15

More limited in number and variety are the examples through which dynamic chemoselectivity11,15–17

or

stereoselectivity18–22

were accomplished. Our group largely established the potential of molecular motors23–

26 as versatile light-responsive central units for dynamic stereoselective catalysts,

19,22,27,28 harnessing their

unique tunable stereochemistry. Indeed, stimuli-responsive control of the activity and enantioselectivity

displayed by chiral catalysts was achieved via dynamic conformational changes of a first generation

molecular motor core equipped with two functional groups able to cooperatively accelerate a reaction. Such

responsive organocatalysts (ROC1 and ROC2) and coordination ligands (RCL) were successfully applied,

respectively, in the 1,4-addition of thiols to enones (Scheme 4.1a),19

the Henry reaction20

(Scheme 4.1b),

and palladium-catalyzed enantioselective allylic substitution (Scheme 4.1c).22

Leigh and co-workers reported a multi-tasking rotaxane catalyst RC1 featuring a concealable secondary

amine unit with which catalytic activity in an organocatalyzed reaction can be controlled by changes in pH

(Scheme 4.2a).29

Effective control of the rate of 1,4-addition of an aliphatic thiol to trans-cinnamaldehyde

was achieved via switchable iminium organocatalysis (Scheme 4.2b). Notably, further application of the

same catalyst was accomplished due to the versatility of secondary amines in organocatalysis through other

activation pathways, of which the non-protonated rotaxane (‗ON-state‘) displayed higher catalytic activity

as a general trend.15

Effective β-functionalization of carbonyl compounds with S-nucleophiles (Scheme

4.2b) or C-nucleophiles (Scheme 4.2c) were reported through iminium activation and nucleophilic addition

while substitution reactions were achieved via enamine catalysis (Scheme 4.2d). The rotaxane catalyst is

even able to promote tandem iminium-enamine reaction sequences (Scheme 4.2e) and the Diels–Alder

reaction of a dienal through a trienamine activation pathway (Scheme 4.2f). This concept of switchable

catalyst was further extended to an asymmetric organocatalytic rotaxane that features an acyclic chiral

secondary amine housed within a rotaxane framework.30

This system was able to control the rate of

catalyzed asymmetric Michael addition of 1,3-diphenylpropan-1,3-dione to aliphatic α,β-unsaturated

aldehydes. Good enantioselectivities (up to 93:7 er) were reported, however no dual stereocontrol could be

afforded due to the fixed stereoinduction provided by the catalytic center.

Studies towards a Trifunctionalized Molecular Switch for Light-assisted Tandem Catalytic Processes

121

Scheme 4.1. Stimuli-responsive control of catalytic activity and enantioselectivity achieved by dynamic

conformational changes of a bifunctional first generation molecular motor derivatives in organo- and metal-

catalyzed transformations: a) 1,4-addition of thiol,19

b) Henry reaction20

, c) palladium-catalyzed

enantioselective allylic substitution.22

Chapter 4

122

Scheme 4.2. Activation mode and scope of switchable rotaxane organocatalyst RC1 developed by Leigh

and co-workers.15,29


123

Noteworthy, Leigh and co-workers also developed a switchable rotaxane system featuring two different

organocatalytic sites: a squaramide moiety and a dibenzylamine group (Scheme 4.3a).11

When the rotaxane

is protonated, the macrocycle preferentially interacts with the ammonium unit revealing the squaramide

unit, which can promote the conjugated addition of 1,3-diphenylpropan-1,3-dione to trans-β-nitrostyrene

through hydrogen bonding catalysis (75% conversion after 18 h). In basic media, the macrocycle

preferentially resides over the squaramide, revealing the secondary amine which promotes the Michael

addition of 1,3-diphenylpropan-1,3-dione to crotonaldehyde via iminium ion catalysis (40% conversion

after 40 h). In this way, the catalyst state controls which building blocks react together and which product is

formed from a mixture of reactants (Scheme 4.3b).

Scheme 4.3. Activation mode and substrate-selective switchable rotaxane organocatalyst RC2 developed

by Leigh and co-workers.11

Despite the numerous approaches reported which are extensively reviewed in the literature,1–6

an artificial

system based on a multitasking switchable catalyst or combination of multiple switchable catalysts able to

control sequences of transformations has not yet been reported. The future impact and possible application

of such challenging quest are definitely not easy to predict, as it may lead to the development of highly

complex synthetic methodologies in a biomimetic-like fashion. An atom-efficient scenario achieved by

performing several consecutive reactions in a ‗one-pot‘ (single reactor) is an attractive target. Greater

economy of time and energy maximize resources and overall process simplicity, as well as decreasing

materials loss from multiple iterations of reaction, workup and purification.31–35

Moreover, the use of light

as a non-invasive external input allows for precise frequency, spatial and temporal control over functional

groups response and chemical transformations, providing an artificial alternative to the feedback loops and

trigger-induced effects typical of enzyme activity modulation.36

Chapter 4

124

In this context, we engaged in the challenge of developing a prototype for a dynamically responsive

multitasking catalyst,37–41

based on a second generation molecular motor core (Scheme 4.4). An interesting

aspect of such a motor scaffold is the possibility of functionalizing the otherwise symmetrical lower half

with two different catalytically active moieties (depicted as A and B, respectively), which could

dynamically cooperate with the single functionality (C) located on the upper half in a trifunctionalized

responsive core. Through this design two distinct bifunctional catalytic pairs could be alternatively

activated, thus selectively and orthogonally promoting a two-step transformation sequence upon external

input.

X

Y

C

BA

h1

(P)-[AC]

THI THI

h2

(M)-[BC]

R

R S

aryl

X

Y

C

A B

X

Y

C

BA

(M)-[AC] (P)-[BC]

aryl

X

Y

C

A B

aryl

aryl

R

S R

h1

h2

Scheme 4.4. Proposed design of a trifunctionalized light- and heat-responsive organocatalyst for diastereo-

and enantioselective ‗one-pot‘ assisted tandem catalysis. The catalyst is envisioned to be switchable

between four different states, each displaying a different combination of active cooperative catalytic pair

(AC or BC) and helicity (P or M). In the scheme are displayed only two of the four possible products

accessible by combining three starting components (depicted as different shapes) in a chemo- and

enantioselective fashion (suggested handedness of the newly generated stereogenic centers indicated on the

connecting bond). By triggering the proper catalyst states, both enantiomers of each diastereoisomer could

be accessed.

Notably, each of these two cooperative catalytic pairs could also be selectively addressed in two pseudo-

enantiomeric conformations (i.e. (P)-(AC) and (M)-(AC), (P)-(BC) and (M)-(BC), respectively) upon

triggering the correct light and thermally induced isomerization processes. Indeed, the 4-step isomerization

cycle featured by molecular motors provides access to two distinct catalyst configurations (E or Z), each of

them displaying opposite helical chirality (P or M). Hence, we envision such a design as a feasible future

route for developing the first responsive multi-tasking catalytic system capable of mediating ‗one-pot‘

multi-component transformations in a diastereo- and enantio-selective fashion. The complexity of the ideal

target system is clearly grasped by listing the various critical requirements for such a design (Scheme 4.4).

a) The two catalytic steps must be promoted by two orthogonal distinct bifunctional catalytic pairs

(AC and BC).

b) The shared catalytic moiety of the rotor (C) must be active in both bifunctional pockets.

c) The product of the first catalytic step must be an active substrate for the second step.


125

d) The rate of the intermolecular cooperative catalysis, via interaction of two molecules of catalyst,

should be negligible compared with the intramolecular cooperative mechanism, to efficiently

suppress the undesired catalytic event.

e) In order to avoid further complexity of the catalyst design and restrict the provided stereoinduction

to the sole dynamic chirality of the switch core, the catalytic moieties should not comprise

additional stereogenic centers. The presence of additional chiral elements would in fact increase

the number of possible diastereoisomeric forms of the catalyst, otherwise limited to the four

isomers depicted in Scheme 4.4. Moreover, matched-mismatched effects caused by the different

interaction between the distinct chirality of the switch core and the chirality of the functional

groups A-B-C could be expected, thus further complicating the tandem catalysis development.

f) The two steps of the tandem process should be performed in the same reaction conditions (solvent,

temperature, concentration, catalyst loading, etc.) in order to truly satisfy the requirements for

‗one-pot‘ multi-component transformation; alternatively, the modification of the conditions should

not interfere with the system‘s performance.

g) The catalytic switch should be switched efficiently, reversibly and robustly, i.e. featuring high PSS

ratios towards either the stable and metastable isomer, while displaying limited switching fatigue

or decomposition.

h) The photo-generated metastable state should be highly thermally stable, i.e. feature a long half-life,

thus retaining the desired configuration for extended time intervals (up to days) and non-cryogenic

temperatures (up to 50 °C and above). This feature would ensure a limited variation of the catalyst

mixture composition (ratio of stable vs. metastable) throughout the entire catalytic reaction, open

the application to catalyzed processes characterized by long reaction times and allow higher

working temperatures.

i) Substrates and products of the catalytic cycle should not be affected by photo-induced

decomposition, nor interfere with the switching process of the catalyst, for instance via their own

distinct light absorption or via quenching of the switch‘s excited state by intermolecular energy

transfer.

j) The catalyst inhibition caused by substrates or products should be negligible.

k) The catalyst must be chemically stable at the working catalysis conditions.

l) The synthesis of the trifunctionalized catalyst must be practically feasible and viable on a

reasonably large laboratory scale, to eventually allow for proper screening of the catalysis

conditions and optimization of the ultimate light-triggered tandem process.

m) If the product of the tandem catalyzed synthesis features newly formed stereogenic center(s), the

catalyzed tandem sequence could be performed in an enantioselective fashion by use of a non-

racemic catalyst mixture. Thanks to the inherent and dynamic helicity of the molecular motor

design, asymmetric induction may be achieved with both stable and metastable isomers of the

catalyst. However, asymmetric synthesis or resolution of the photoresponsive catalyst would be

required.

n) The assisted tandem transformation may be composed of two processes generating distinct

stereogenic centers. Noteworthy, the configuration of the secondly generated stereogenic center

may be subject to stereospecific substrate control exerted by the previously generated stereogenic

center rather than by stereoselective induction from the chiral catalyst.

Since the final goal of the project was to develop a catalytic molecular switch able to orthogonally mediate

two distinct catalyzed transformations, we undertook a careful investigation of precedent literature for

recent developments in catalyzed multicomponent ‗one-pot‘ reactions. ‗One-pot‘ reaction types include, but

are not limited to: cascade (domino) processes;42

tandem catalysis (catalysts performing sequential

transformations);43

multifunctional catalysts having more than one active site;44

dual catalyst systems where

one catalyst enhances or alters the properties of the other catalytic cycle;45

and ‗one-pot‘ reactions

involving isolated catalytic cycles, for example where a second catalyst is added after the first has

Chapter 4

126

completed its transformation, or where the first catalyst is selectively deactivated later by addition of a

second reagent.46

Mechanistically distinct from cascade or domino catalysis, in which a single catalytic

transformation occurs sequentially, orthogonal tandem catalysis47

is a ‗one-pot‘ reaction in which

sequential catalytic processes occur through two or more functionally distinct, and preferably non-

interfering, catalytic cycles. Tandem catalysis has also been subcategorized into auto- and assisted-tandem

catalytic cycles.43

Auto-tandem catalysis uses a single precatalyst to effect two or more mechanistically

distinct catalytic cycles, typically by cooperative interaction between the various species in the system. In

contrast, assisted tandem catalysis requires deliberate intervention in the system to switch between one

catalytic cycle and another. Several examples of multi-catalyst promoted tandem or cascade reactions have

been already described in literature,35

showcasing systems based on multiple metal-catalyzed

transformations,43

organocatalytic domino reactions,48

and the combination of metal catalysts and

organocatalysts.49,50

Marks and Lohr recently reported a perspective on orthogonal tandem catalysis, with

particular focus on recent strategies to address catalyst incompatibility.51

They also highlighted the concept

of thermodynamic leveraging by coupling multiple catalyst cycles to effect challenging transformations not

observed in single-step processes, encouraging application of this technique to energetically unfavorable or

demanding reactions. Noteworthy, this perspective mainly describes systems based on metal-catalyzed

reactions, either using homogeneous or heterogeneous catalysts. Reviewed systems include examples

applied to hydrocarbon upgrading via metal catalyzed olefin isomerization/metathesis, metal-catalyzed

tandem arylation/heterocoupling, and enzyme- and acid-catalyzed glucose conversion to

hydroxymethylfurfural. However, no examples of orthogonal tandem organocatalytically promoted

transformations were described.

4.2 Results and discussion

4.2.1 Design

The design of a switchable trifunctionalized catalytic system proposed hereto entails the reversible

formation and activation of two distinctive catalytic pockets. It is worth mentioning that the ability to retain

the switching properties should not be affected by individual electronic properties nor the cooperative

interactions between the catalytic moieties. Despite the wide variety and solid background of metal-

catalyzed processes, the formation of a metal-complex by cooperation of two ligating moieties (e.g.

phosphines, amines, heterocycles) might have dramatic influence on the switching properties of molecular

motor or switch. A preformed bidentate complex might be too stable to accommodate the isomerization of

the overcrowded alkene bond, especially if each of the two ligating moieties was located on one half of the

motor scaffold. It should be noted that previously reported examples of switchable coordination ligands

based on first generation molecular motor for palladium-catalyzed transformation were changed upon

irradiation of the responsive ligand not in presence of the metal source.22

However, in the case of labile

metal-complexes the reversible coordination of the bidentate ligand may still permit the isomerization of

mono- or non-coordinated species upon irradiation even in presence of the metal source, as demonstrated

subsequently for an analogous responsive core displaying dynamic control of chirality and self-assembly of

double-stranded helicates.28

On the other hand, a different molecular switch design based on a photo-

responsive core of which one half fully contains a flexible bidentate ligand unit may constitute a promising

approach (see Chapters 6 and 8).

We decided to focus our attention on the fast-growing field of organocatalysis (i.e. the catalysis with small

organic molecules in the absence of metals or metal ions) with the prospect of designing the first molecular

motor-based multi-catalyst based purely on organocatalyzed processes. A plethora of organocatalyzed

transformations have been developed in the last decades,52

which witnessed the rise of numerous catalytic

systems based for instance on enamine53

or iminium54

activated intermediates, phosphoric acids, N-

heterocyclic carbenes55

or H-bond donors in asymmetric catalysis.56

We envisioned that small molecule H-

bond donors in combination with Lewis-acid/base mediated catalysis could be implemented in our target

system, while preserving its switching properties. This is also supported by our precedent successful


127

applications of first generation molecular motor based smart systems to achieve reversible stimuli-

controlled catalytic transformation and anion binding.19,20,27

The Aldol reactions,57

conjugated additions,58

cycloadditions,59

Strecker reactions,60

Morita–Baylis–Hillman reactions,61

Mannich reactions,49

Henry

reactions62

and nucleophilic additions to nitroolefins63

are only a few of the organocatalyzed

transformations successfully developed so far.64

Several privileged catalytically active functional groups

have been harnessed in effective organocatalysts, ranging from amines to phosphines, alcohols, thioureas,

guanidines, amides, thiols, carboxylic acids, carbenes, the well-established proline and its related

derivatives. While all these topics support our expectations to find multiple reactions which might be

catalyzed by our goal multi-catalytic switches, it also generated doubts about their plausible selectivity and

specificity.62

It may go without mentioning that all the reported organocatalyzed transformations harness

the reactivity of particularly susceptible functional groups (e.g. imine, aldehyde, indole, α,β-unsaturated

carbonyl group, keto-esters, etc.) already at mild reaction conditions, as opposed for example to more

robust functional groups (e.g. aromatic halides, non-activated alkenes, non-activated allylic groups, etc.)

converted via harsher metal-catalyzed processes. Conversion of a substrate into a product inherently entails

a decrease in functional group reactivity (e.g. secondary amine, secondary alcohol, substituted heterocycles,

non-activated carbonyl group, etc.). Subsequent derivatization would often be required to increase the

intermediate reactivity towards a consecutive organocatalyzed process, unless a proper tandem or domino

sequence is applied. However, it should be noted that most of the reported ‗one-pot‘ tandem

organocatalyzed transformations in fact rely on an auto-tandem catalysis mechanism.43

Hannedouche and

co-workers recently reported the first use of a multitask chiral ligand in an asymmetric assisted tandem

catalysis protocol that successively combines a metal-catalyzed alkyne hydroamination followed by an

asymmetric organocatalyzed Friedel–Crafts alkylation.65

To the best of our knowledge, no examples of

fully organocatalyzed assisted tandem transformations have been reported to date.

In this context, we selected the Morita–Baylis–Hillman reaction (or MBH reaction, Scheme 4.5) as a

starting point for the development of our multi-catalytic system. The classical MBH reaction is a carbon-

carbon bond forming reaction yielding α-methylene-β-hydroxycarbonyl compounds by addition of α,β-

unsaturated carbonyl compounds to aldehydes.

Scheme 4.5. General scheme of Morita–Baylis–Hillman reaction.

Instead of aldehydes, imines can also participate in the reaction if they are appropriately activated: such

process is commonly referred to as the aza-Morita−Baylis−Hillman (aza-MBH) reaction. In either case, this

reaction provides a densely functionalized product, yielding a carbonyl-derived allylic alcohol or secondary

allylic amine upon addition to an aldehyde or an imine, respectively. Such characteristics had a strong

influence during the design of our proposed tandem process, as it retains a potentially reactive α,β-

unsaturated carbonyl motif in the product. Therefore, further functionalization could potentially be

conducted via a second organocatalyzed process in a ‗one-pot‘ fashion. Most effective catalysts for MBH

reactions are nucleophilic unhindered tertiary amines, such as DABCO and quinuclidine, or tertiary

phosphines like tributylphosphine.66–68

In particular the specificity of tertiary amines as catalysts in the

MBH reaction held good promise for our studies, as such functions may provide the orthogonality required

for an efficient assisted tandem catalysis process achieved by a switchable multiple organocatalyst.

Reaction conditions are often mild (temperature ranging from -20 °C to 40 °C), however reaction rates are

notoriously low (reaction times from hours to weeks). The catalytic cycle consists of three steps: 1)

Chapter 4

128

conjugate addition of the nucleophilic trigger catalyst to the β-position of the activated alkene motif; 2)

nucleophilic addition of the α-position of the resultant zwitterionic adduct to the carbonyl or imine

functionality of the electrophilic partner, also referred to the electrophilic quench; 3) proton transfer and

elimination of the catalyst, thus restoring the α,β-unsaturated carbonyl functional group.69

According to the

commonly established mechanism, the electrophilic quench is the rate determining step (second order in

aldehyde and first order in nucleophilic catalyst and enone).70,71

Rate enhancement can be achieved by

stabilizing the zwitterionic intermediate or by activating the aldehyde, for instance by a H-donor co-

catalyst.72

In more elaborate designs, the reported catalyst system comprises both catalytic partners linked

by a rigid chiral scaffold. The bifunctional catalysts based on the popular Cinchona alkaloid scaffold are a

clear example.69

In summary, the MBH reaction features critical advantages for the current study: (i) the

MBH products are flexible and multi-functionalized, retaining an inherent reactivity potentially exploitable

in a tandem sequence; (ii) the recently reported methodologies often involve the use of a bifunctional

organocatalytic systems; (iii) the MBH reaction is usually conducted under mild reaction conditions, which

well suit the very slow thermal relaxation process displayed at room temperature by our chosen switch

scaffolds (six-membered ring thiopyranyl upper half, five-membered ring fluorenyl lower half, see Chapter

2 and 3).

Recently, urea/thiourea-based bifunctional catalysts have emerged as powerful catalysts in a wide range of

asymmetric transformations. 39,73–78

Their high activities as well as their selectivities were attributed to their

ability of activating both electrophilic and nucleophilic centers of the reacting partners.40

Wang and co-

workers reported the use of a chiral binaphthyl-derived amine-thiourea catalyst 1 for asymmetric MBH

reaction (Scheme 4.6), proposing a synergy between the nucleophilic activation of the 2-cyclohexen-1-one

via reversible conjugated addition of the tertiary amine and the dual H-bond stabilization of the generated

enolate anion by the thiourea moiety.38,79

Scheme 4.6. Binaphthyl amine-thiourea catalyst 1 for enantioselective MBH reactions by Wang and co-

workers.79

Previously introduced, photoresponsive stereoselective catalysts based on a first generation molecular

motor ROC1 and ROC2 feature the combination of DMAP and thiourea functional moieties (Figure 4.1).7

These precedents indicate that a thiourea group and an aromatic amine conjugated to the motor core may be

well tolerated by our target trifunctionalized switch. Similarly, a tertiary aromatic amine substituent was

successfully implemented in a nitro-amine disubstituted chiroptical molecular switch 2, which displayed

efficient reversible photoswitching by use of UV and visible light (Figure 4.1).26

Inspired by these

preceding results, we opted for a thiourea substituent as a hydrogen-donor moiety in the upper half and a

basic dimethyl amine group in the lower half of molecular switches 3 and 4 to design the first bifunctional

cooperative catalytic pair (see Chapter 3).


129

Figure 4.1. DMAP-thiourea substituted molecular motor ROC1-2 and nitro-amine substituted chiroptical

switch 2 previously developed in our group. Proposed design of bifunctional molecular switches 3-4

described in Chapter 3.

The second active site of our photoswitchable trifunctionalized catalyst was proposed to harness the

cooperation of the shared thiourea moiety, linked to the upper half, together with a primary or secondary

aliphatic amine, linked to the lower half. In the general mechanism, amine catalysts activate carbonyls by

the formation of either an enamine or an iminium ion intermediate. Enamine formation raises the HOMO

energy, increases nucleophilicity, and facilitates nucleophilic addition and substitutions reactions (Scheme

4.7a).53,80

Conversely, iminium ion formation increases the electrophilicity of the carbonyl carbon and

lowers the LUMO energy.54

This allows access to pericyclic reactions and electrophilic addition reactions,

particularly conjugate additions (Scheme 4.7b).

Scheme 4.7. Enamine and iminium ion activation of saturated and α,β-unsaturated carbonyls.

The obtained bifunctional cooperative catalyst could then be employed, for instance, in an aldol-type

reaction with electrophiles (Scheme 4.8a) by activation of the carbonyl partner via enamine catalysis and

hydrogen-bond activation of the electrophile provided by the upper thiourea substituent.38,39,53,58,81

Alternatively, the α,β-unsaturated carbonyl motif could also be activated via iminium catalysis for

cycloaddition or nucleophilic 1,4-addition reactions (Scheme 4.8b).54

A cyclic aliphatic amine substituent could be considered a promising option in terms of catalytic activity

and versatility for the design of a catalyst for aldol-type reactions. Scheme 4.8c illustrates the proposed

design for bifunctional catalyst 5 featuring an imidazoline or imidazolidinone substituent directly attached

by one of the nitrogen atoms to the fluorenyl lower-half. MacMillan and co-workers developed an efficient

imidazolidinone-based catalyst for enantioselective aldol methodology.40

Chapter 4

130

Scheme 4.8. a) General scheme of an enamine-mediated aldol condensation. b) General scheme of an

enamine-mediated conjugated addition of ketones to activated olefins.

Inspired by their work, we considered such a structure as a solid starting point for our bifunctional catalyst.

First, such imidazolidin(on)e groups could simplify the synthesis through a straightforward Buchwald-

Hartwig coupling with a halogen-substituted fluorenyl lower half. Second, it would also avoid the

complication of generating a stereocenter within the bridging unit (vide supra). An alternative cyclic

pyrrolidine/pyrrolidinone substituent would in fact be connected to the switch lower half by a chiral tertiary

carbon, thus potentially resulting in a diastereomeric mixture of the target catalyst.

The concept design of a trifunctionalized photo-responsive organocatalyst for ‗one-pot‘ multi-step synthesis

via Morita–Baylis–Hillman and subsequent enamine mediated aldol condensation is presented in Scheme

4.9. Merged together, the two catalysts 3 or 4 and 5 would constitute the first multi-catalytic molecular

switch, able to perform a MBH-aldol reactions sequence in a ‗one pot‘ orthogonal tandem process upon

light-assisted isomerization of the catalyst. When the catalyst is switched to the E-isomer, the cooperative

activation by thiourea and tertiary amine groups is envisioned to promote the organocatalytic MBH reaction

of enones and aldehydes to generate the intermediate MBH adducts. Upon photoisomerization, the catalyst

could be switched to the Z-isomer, allowing the conversion of the MBH adduct to more complex final

products, e.g. via thiourea and primary/secondary amine cooperative catalyzed aldol-type transformation or

Michael 1,4-addition via iminium catalysis (not shown in scheme) upon activation of the second catalytic

pair.

S

N

HN

S

NH

N

organocatalyticBaylis-Hillman

reaction

O

R'

OH

organocatalyticenamine alkylation reaction

O

R'El

OH

h1

h2

El

NH

NH

S

CF3

F3C

S

NH

CF3

CF3

O

NR3

H

O

NR3

H

R'

O

H H

H

R' H

O

N

R'

OHR R

N

R'

OHR R

Etertiary amine

+ thiourea catalysis

secondary aliphatic amine

+ thiourea catalysis

O

ThioureaThiourea

HH

Thiourea

aryl aryl

E-isomer Z-isomer

RHN R

Scheme 4.9. Proposed design of a trifunctional photo-responsive organocatalyst for ‗one-pot‘ light-assisted

tandem catalysis via MBH reaction (E-isomer, thiourea + tertiary amine) and subsequent enamine mediated

aldol condensation (Z-isomer, thiourea + primary/secondary aliphatic amine).


131

4.2.2 Preliminary testing of bifunctional overcrowded alkenes as switchable catalysts

Morita–Baylis–Hillman reaction

Before starting the challenging synthesis of a multicatalytic molecular switch, we engaged a more

systematic approach by testing the basic concept of a photo-activated reversible ‗ON/OFF‘ catalyst on a

simpler prototype. The trifunctionalized catalytic switch design was split into the two corresponding

catalytic bifunctional components. Therefore, we suggested two initial designs 3 and 4 for a catalytic

molecular switch for MBH reactions (Figure 4.1). They feature a thiourea substituent as hydrogen-donor

moiety in the upper half and a basic aromatic dimethylamine group in the lower half. In our previous study

we showed that the combination of a 5-membered ring in the lower half (fluorene) with a sulphur

containing 6-membered ring in the upper half (5,8-dimethylthiochromene and benzo[f]thiochromene)

resulted in distinctive high energy activation barriers for the thermal relaxation step in the rotary cycle of

the second generation molecular motors and consequently long half-lives of the corresponding metastable

species. Moreover, by comparison of two structurally different upper halves we envisioned to investigate

the influence of the distance between the two cooperative catalytic functionalities on the catalytic

performance. Despite the literature claims by Wang and co-workers,79

our attempts to catalyze the model

reaction between 2-cyclohexen-1-one and 3-phenylpropionaldehyde by either (E)-3, (Z)-3, (E)-4, (Z)-4 or

the original literature catalyst 1 did not lead to any conversion to the desired MBH adduct as determined by

GC-MS and 1H NMR spectroscopy analysis (Scheme 4.10).

Scheme 4.10. Attempted catalysis of the MBH reaction between 2-cyclohexen-1-one and 3-

phenylpropionaldehyde using 1, stable isomers (E)-3, (Z)-3, (E)-4 or (Z)-4 as catalyst; no conversion to the

desired Michael adduct was observed by 1H NMR. Conditions according to literature.

79. Conversion

monitored by GC-MS and 1H NMR spectroscopy analysis of crude mixture.

We postulate that these disappointing results are due to the limited catalytic activity of the dimethylaniline

moiety, both in terms of the low nucleophilicity of the aryl amine and the structurally constrained nature of

the tertiary amine within the catalyst‘s structure. In order to sustain our hypothesis, the influence of both

nucleophilic and H-bond donor partners as separate co-catalyst units was addressed (Table 4.1). Notably,

no conversion to the MBH product was observed upon use of DABCO (1,4-diazabicyclo[2.2.2]octane) or 6

in neat conditions (entries 1-2). When the two components were combined, only the reaction conducted

without addition of solvent provided a moderate conversion to the expected product (entries 3-4), as proven

by comparison with precedent reported 1H NMR spectral data. To further support the hypothesis of lower

reactivity of the aromatic dimethylamine substituent, N,N‘-dimethylaniline (DMA) was tested alone and in

combination with thiourea 6 resulting in no conversion in either cases (entries 5-6).

Chapter 4

132

Table 4.1. Influence of Lewis-base (co-catalyst A) and thiourea 6 (co-catalyst B) in the MBH reaction

between 2-cyclohexen-1-one and 3-phenylpropionaldehyde.

Conjugated addition of 2,4-pentadione to trans-β-nitrostyrene

Compound 1 was also reported to catalyze the conjugated addition of 2,4-pentadione to trans-β-

nitrostyrene.82

Similar to the original study on catalyst for MBH reaction by Wang,79

the proposed

mechanism entails the acid-base cooperative activation by the bifunctional chiral catalyst of both reaction

partners. 2,4-pentadione is coordinated in its nucleophilc enolic form by the dimethylamine group. The

Michael acceptor trans-β-nitrostyrene is coordinated and activated by the thiourea group via double H-bond

donation. Wang‘s catalyst 1 and switches (E)-3, (Z)-3, (E)-4 and (Z)-4 were eventually tested in such

transformation by following the reported procedure. Similarly to the test results for the MBH reaction, no

conversion towards the Michael addition product was detected in any of the cases as determined by GC-MS

and 1H NMR spectroscopy analysis (Scheme 4.11).

Scheme 4.11. Literature reported82

and tested results for conjugated addition of 2,4-pentadione to trans-β-

nitrostyrene using Wang‘s catalyst and bifunctional switches (E)-3, (Z)-3, (E)-4 and (Z)-4. Conversion

monitored by GC-MS and 1H NMR spectroscopy analysis of crude mixture.

4.2.3 Attempted synthesis of alternative bifunctionalized switches

The initially proposed and subsequent alternative designs of a bifunctional switchable catalyst for MBH

reaction are presented in Figure 4.1. In accordance to more commonly encountered functional groups

featured by previously reported catalysts for MBH reactions, a small selection of alternative Lewis base

motifs was proposed (Figure 4.2). The stronger nucleophilic character of aliphatic tertiary amines featured

by 7, 8 and 9 and tertiary phosphines featured in 10 should ensure the desired higher catalytic activity.

Entrya Co-catalyst A (mol%) Co-catalyst B (mol%) Neat - Solvent Conversion (%)

b

1 DABCO (20) / neat No conversion

2 / 6 (20) neat No conversion

3 DABCO (20) 6 (20) neat 60

4 DABCO (10) 6 (10) acetonitrile No conversion

5 DMA (20) / neat No conversion

6 DMA (20) 6 (20) neat No conversion

[a] Conditions: 2-cyclohexen-1-one (0.75 mmol, 3 equiv), 3-phenylpropionaldehyde (0.25 mmol, 1 equiv), neat or in acetonitrile (1 mL) as specified, room temperature, 4 d. [b] Conversion monitored by GC-MS and

1H NMR

spectroscopy analysis of crude mixture.


133

Figure 4.2. Initial and alternative proposed designs of bifunctional switchable catalyst.

Scheme 4.12 illustrates the proposed retrosynthetic analysis of catalysts C and D. Similarly to 3 and 4, the

more sensitive thiourea motif in the upper half is to be installed after the construction of the tetrasubstituted

alkene and amination of the upper half via a Buchwald-Hartwig coupling.

Scheme 4.12. Retrosynthetic analysis of 7 and 8 starting from bromo-substituted diazospecies 12 and

tertiary amine-substituted thioketone 13.

The lower half coupling partner was synthesized from commercially available 2-carboxaldehyde-fluorene

14 (Scheme 4.13). Reductive amination of the carboxaldehyde moiety was conducted with a commercial

solution of dimethylamine (2M in MeOH) in presence of titanium(IV) isopropoxide and sodium

borohydride to afford 15 (87%). Oxidation of the fluorene core to ketone 16 (83%) was then achieved

under an atmosphere of air using the trialkyl ammonium salt Triton B as a phase transfer catalyst in

pyridine. The conversion of fluorenone 16 into the reactive thioketone 17 was subsequently unveiled to be

the weak link of the proposed synthetic route. Reaction with either P4S10 (Scheme 4.13a) or Lawesson‘s

reagent (Scheme 4.13b) resulted in rapid conversion of substrate 16, as observed by TLC analysis of the

reaction mixture with disappearance of any spot other than at the baseline already after few minutes.

However, no fraction resembling neither the substrate nor the product was collected upon flash column

chromatography of the residual crude. By comparison with the synthesis of 2-(dimethylamino)-9H-

fluorene-9-thione, the thionation of 16 appears to be detrimentally affected by the stronger

basicity/nucleophilicity of the aliphatic tertiary amine substituent. TLC analysis of the reaction mixture

showed a byproduct‘s spot (Rf < 0.05) at a very low elution speed in various mixtures of dichloromethane,

ethyl acetate and methanol. This may suggest the formation of a stable nitrogen-phosphorus adduct or salt

rapidly generated in the tested conditions, thus preventing the conversion towards the desired thioketone. In

a study conducted by Bergman and co-workers, the alternative thionating reagent P4S10·Py4 complex was

studied and employed for thionations of carbonyl functional groups in polar solvents such as acetonitrile

and dimethyl sulfone, displaying excellent selectivity and substrate versatility.83

Its properties have been

compared with the established Lawesson‘s reagent. Particularly interesting are the results from thionations

in dimethyl sulfone at high temperatures (∼165–175 °C), at which Lawesson‘s reagent is inefficient due to

rapid decomposition. The reported methodologies were successfully applied to a large variety of aliphatic

and aromatic ketones, amides and ketamines, containing scaffolds such as lactams, nicotinamides,

quinolones, indoles and oxindoles, to afford the corresponding thioketones and thioamides. Notably, no

Chapter 4

134

aliphatic amine was included in the procedure scope, with the exception of glycine which afforded 2,5-

piperazinedithione upon dimerization. Despite the lack of precedence, the thionation of 2-

((dimethylamino)methyl)-9H-fluoren-9-one 16 with P4S10·Py4 complex in acetonitrile (Scheme 4.13c) and

dimethyl sulfone (Scheme 4.13d) were both attempted by following reported procedures. In either case, no

trace of product was detected upon NMR analysis of the reaction crude. While the reaction in acetonitrile

gave no visible conversion, reacting in dimethyl sulfone caused a sudden change from yellow to vivid

purple color, a common indication of the presence of successfully thionated fluorenones. However, the

reported workup step involves the use of boiling water to hydrolyze the excess of P4S10·Py4 complex, which

in our case rapidly caused the mixture to turn brown and may have also decomposed the expected product.

When the procedure was subsequently repeated without the addition of water but using direct flash column

chromatography of the solidified melted, no purple fraction was isolated. Eventually the herein proposed

synthetic route towards 7, 8 and 9 via thionation of amine-substituted fluorenones and subsequent Barton-

Kellogg coupling with diazo compound 12 was abandoned in favor of an alternative approach.

Scheme 4.13. Attempted synthetic route to tertiary aliphatic amine-substituted thioketone 17.

An alternative retrosynthetic analysis was proposed, as illustrated in Scheme 4.14. Secondary amine-

substituted switches 7, 8 and 9 could potentially be obtained from a common dihalogenated intermediate

21, synthesized from the corresponding coupling partner bromo-diazochromane 12 and iodofluorenthione

22. Due to the expected higher reactivity of the iodo-substituted fluorenyl lower half, a plausible

chemoselectivity was envisioned upon lithiation and subsequent quenching with DMF to afford

carboxaldehyde intermediate 20, or upon phosphination to yield phosphine intermediate 19, respectively.

Similarly, quinuclidine-derived switch 18 may be obtained from intermediate 20 via condensation with 3-

quinuclidone and subsequent reduction of the carbonyl group (for instance via a Wolff–Kishner-type

reduction). Derivatization via Buchwald-Hartwig amination and subsequent introduction of the thiourea

substituent would afford the target compounds 7, 8, 9 and 10.


135

Scheme 4.14. Retrosynthetic analysis of switches 7-10 starting from bromo-substituted diazothiopyran 12

and iodo-substituted thioketone 22.

The attempted synthesis of bromo-iodo-substituted alkenes 25 and 27 started with the generation of 2-

iodofluoren-9-thione 22 upon reaction with Lawesson‘s reagent (Scheme 4.15). The unstable thioketone 22

was rapidly reacted in a Barton–Kellogg coupling with hydrazones 10 and 22 upon generation of the

corresponding highly reactive diazo compounds with PIFA at low temperature. However, after sulfur

extrusion with PPh3 or HMPT only small amounts of alkenes 25 and 27 were obtained by flash column

chromatography as inseparable mixtures of E- and Z-isomers. Separation of the stereoisomers could be

achieved in a later stage of the synthesis. However, due to the discouraging results from these Barton

Kellogg couplings and high catalyst loading often required in common organocatalytic transformations for

final application of the target compounds as catalysts, the synthesis of 7-10 along this path was

discontinued.

Scheme 4.15. Attempted synthesis of bromo-iodo-substituted overcrowded alkene 25 and 27 as precursors

of proposed catalysts 7-10.

Chapter 4

136

4.2.4 Investigation of catalytic performance in alternative organocatalyzed transformations

The project was eventually redirected to a different approach in order to optimize the time left. As

compounds 3 and 4 were already fully characterized, alternative reactions were tested to investigate their

catalyst performance in different types of transformations other than the MBH. The proposed applications

would harness either the basic and nucleophilic character of the dimethylamine substituent or its steric

hindrance in combination with the hydrogen-bond donor nature of the thiourea motif. It should be noted

that due to the very small quantities of 3 and 4 obtained, the screening tests described herein were

performed by using Wang‘s catalyst 1 as a model. Due to its inherent similarity with Z-isomers of 3 and 4,

the latter would have been tested once the successful reaction conditions were unveiled.

Alkylation of α-carboxypiperidones ethyl esters

The first investigated reaction was the synthesis of benzomorphan analogues by intramolecular Buchwald–

Hartwig cyclization developed by Khartulyari and co-workers.84

In their study, the key bond formation was

based on an intramolecular Buchwald–Hartwig enolate arylation reaction, to provide tricyclic

benzomorphan derivatives. Thus, alkylation of α-carboxypiperidones ethyl esters with ortho-bromobenzyl

bromides provides the necessary substrates. N-benzyl substituted piperidones were alkylated directly with

substituted benzyl bromides (Scheme 4.16a). N-methyl substituted piperidone required alkylation via

benzyl transfer by a pre-formed ammonium intermediate due to higher nucleophilicity of the nitrogen atom

in the piperidone ring (Scheme 4.16b). Despite the elegant synthetic approach to pharmaceutically valuable

targets, the described methodology provides only racemic products.

Scheme 4.16. Synthesis of benzomorphan analogues by intramolecular Buchwald–Hartwig cyclization

developed by Khartulyari and co-workers: a) N-benzyl protected piperidones directly alkylated with

substituted benzyl bromides; b) N-methyl protected piperidone required alkylation via benzyl transfer from

a pre-formed ammonium intermediate.84

It should be noted that the stereoselective event is the formation of the quaternary carbon via benzyl

transfer to the enolate intermediate of the starting piperidones. Upon intramolecular Buchwald–Hartwig

enolate arylation reaction, the tricyclic benzomorphane derivatives are subsequently constructed in a

stereospecific fashion. We envisioned that a chiral inductor able to coordinate via hydrogen-bonding the

prochiral enolate intermediate would give access to the corresponding enantioselective benzylation.

Scheme 4.17 illustrates the proposed mechanism mediated by chiral benzyl ammonium derivatives of 1 in

stoichiometric quantities. Similarly, using 3 or 4 as alkylating agents could allow achieving activity control

upon photoswitching. The E-isomers would in fact characterized by a less efficient intramolecular transfer


137

due to the larger distance between the functional group compared with Z-isomers, possibly resulting in a

lower alkylation rate. In alternative, a combination of activity and stereoselectivity control could be

expected in the case of enantioenriched 3 or 4. Similarly to the dynamic control of stereoselectivity reported

for catalyst ROC1 by Wang and co-workers,19

different enantioselectivity and reaction rate could be

expected between the distinct of E- and Z-isomers of 3 or 4 as benzyl ammonium salts.

Scheme 4.17. Proposed asymmetric synthesis of benzomorphan analogues via asymmetric alkylation of N-

protected piperidones with a pre-formed benzyl ammonium chiral intermediate (derivatives of 1 and

bifunctional switches 3 and 4) in stoichiometric quantities and subsequent palladium-catalyzed cyclization.

The initial investigation was approached by using 1 as model compound. The tertiary amine moiety of 1

was successfully converted upon reaction with benzyl bromide to the corresponding ammonium salt 28

(Scheme 4.18a). Surprisingly, 28 was found to be particularly unreactive in the benzyl transfer to

piperidone 29, despite the screening in toluene of temperatures from 50 °C up to reflux (Scheme 4.18b).

Upon careful monitoring of the reaction by 1H NMR spectroscopy analysis over time, compound 28 was

found to be slowly degraded to 1 and benzyl alcohol, as confirmed upon subsequent spiking of the sample

with commercial benzyl alcohol for reference. The reaction was repeated according to the literature using

the ammonium salt of dimethylaniline and benzyl bromide 31, which successfully yielded the expected

alkylated piperidone 30 already at 50°C (Scheme 4.18c). While the aromatic dimethylamine substituent of

1 displayed the required nucleophilic character to generate the alkyl ammonium salt, 28 was found too

unreactive towards the alkyl transfer. It could be hypothesized the nucleophilicity of the naphthalenyl

amine is higher than aniline, causing a greater stability of the corresponding ammonium salt. Alternatively,

the high steric hindrance caused by the thiourea group may prevent instead the efficient approach of the

piperidone enolate, thus impeding the alkylation. The bifunctional catalyst 1 was found again inactive

under the tested conditions and our proposed enantioselective approach of the reported synthesis of

benzomorphans derivatives was r unsuccessful.

Chapter 4

138

Scheme 4.18. Preliminary test with 1. a) Synthesis of chiral benzyl transfer intermediate 28. b) Attempted

asymmetric alkylation of piperidone 30 by stoichiometric benzyl transfer with 29. c) Repeating literature

procedure with dimethylamine-derived benzyl ammonium bromide.

Decarboxylative protonation of α-aminomalonates

Due to the unsatisfactory nucleophilic properties of the amine substituent of 1 and switches 3 and 4, we

decided to test their catalytic performance as a Brønsted base. Asymmetric decarboxylative protonation of

substituted aminomalonates in the presence of a chiral base is a synthetically convenient and

straightforward route to synthesize a variety of natural and unnatural optically pure α-aminoacids. This

synthetic methodology is based on the more general malonic acid synthesis where the chirality of the

product can be generated during the enolate protonation step (Scheme 4.19a). Thiourea derived cinchona

alkaloids promote the asymmetric decarboxylative protonation of cyclic, acyclic, or bicyclic α-

aminomalonate hemiesters under mild and metal-free conditions to afford enantioenriched aminoesters in

high yields and enantioselectivities. In particular, Rouden and co-workers reported the synthesis of both

enantiomers of the aminoesters starting from racemic substrates using cinchona alkaloid 32 and its

pseudoenantiomer derived from quinine (Scheme 4.19b).85]

However, it requires stoichiometric amount of

base (1 equiv) and long reaction times (7 d). In the proposed mechanism, the amine function could act as a

chiral proton shuttle whereas the urea/thiourea group, a strong hydrogen-bond donor, would anchor the

substrate to bring the chiral protonating agent in a close proximity to the prochiral enolate. An alternative

mechanism may involve the interaction of carboxylate anion with thiourea that facilitates the

decarboxylation step whereby protonation preferably occurs in a stereocontrolled fashion with the

ammonium moiety of promoter 32. Despite the difference in basicity between an aliphatic amine featured

by the cinchona alkaloids and the aromatic amine of 1, 3 and 4, we did envision the deprotonation process

of aminomalonates not to be largely affected. Indeed, the subsequent decarboxylation could be triggered by

the basic aniline motif, providing the target chiral amino-esters. Photoisomerization of switches 3 and 4

could give access to external control of activity or enantioselectivity depending on the selected catalyst

isomer.


139

Scheme 4.19. a) Proposed mechanism of enantioselective decarboxylative protonation of α-

aminomalonates. b) Enantioselective decarboxylative protonation of α-aminomalonates mediated by

thiourea cinchona alkaloid 32 developed by Rouden and co-workers.85

Preliminary tests on the decarboxylative protonation of 1-acetyl-2-(ethoxycarbonyl)piperidine-2-carboxylic

acid 33 to ethyl 1-acetylpiperidine-2-carboxylate 34 are presented in Table 4.2. The tested conditions are

according to the literature precedent.85

Both in absence or presence of DMA, conversion of the substrate

was observed only at temperature above room temperature (entries 1-4). Upon addition of a

substoichiometric amount of DMA, full conversion was still obtained only at higher temperature (entries 5-

6). The use of the more basic DABCO as base gave full conversion already at rt (entries 7-8).

Table 4.2. Influence of temperature, base and thiourea catalyst in the decarboxylative protonation of 1-

acetyl-2-(ethoxycarbonyl)piperidine-2-carboxylic acid.

Entrya Catalyst (mol%) Temperature (°C) Time (d) Conversion (%)

b

1 / rt 4 No conversion

2 / 40 2 60

3 DMA (110) rt 4 No conversion

4 DMA (110) 40 2 Full conversion

5 DMA (20) rt 4 No conversion

6 DMA (20) 40 2 Full conversion

7 DABCO (110) rt 1 Full conversion

8 DABCO (110) 40 1 Full conversion

9 DMA (20) + 6 (20) rt 1 No conversion

10 DMA (20) + 6 (20) 40 1 25

11 1 (50) rt 4 No conversion

12c 1 (50) 40 1 45

(racemic)

[a] Conditions: 33 (0.09 mmol) in THF (0.5 mL), catalyst loading, temperature and time as reported. [b] Conversion monitored by GC-MS and

1H NMR spectroscopy analysis of crude mixture. [c] Product was obtained as a racemic mixture as determined by

chiral HPLC analysis (OB-H, hept:2-propanol = 95:5, flow 0.5 mL/min, 40 °C, Rt 21.2 min and 26.0 min).

Chapter 4

140

Compound 6 was then used in combination with DMA in substoichiometric amounts, to investigate the

possibility of synergistic effects. Contrary to our expectations, low conversion was observed also at higher

temperature (entries 9-10). Eventually, 1 was tested affording similar results to the blank reactions (entries

11-12). No enantiomeric excess was observed for the isolated product. Compared with the higher activity of

DABCO, the large difference in pKb between the aliphatic amine in the cinchona alkaloid 32 and the

aromatic amine of 1 might be the cause of lack of catalytic activity of the latter. Alternatively the acidity of

the thiourea protons86

and the close proximity to the amine group might be responsible for its low basicity

and poor catalyst activity, as suggested by the control experiment using DMA in presence of 6.

Alcoholysis of styrene oxides

Finally, we tested the binding properties of our thiourea-substituted switches. Numerous studies have been

conducted on the supramolecular recognition of anions with ureas and thioureas derivatives.87

The success

of this class of systems lies in their hydrogen bonding ability to a variety of reactants and intermediates in

close similarity to those found in the active sites of enzymes. After the seminal reports by Wilcox88

and

Hamilton,89,90

appropriate incorporation of the (thio)urea motif in acyclic, cyclic or polycyclic frameworks

has become one of the prevailing strategies in the design of synthetic anion receptors.91

Recent advances in

supramolecular recognition allowed chemists to design a wide range of synthetic receptors matching the

requirements for inorganic and organic anion binding, such as halide anions, oxyanion, cyanide, nitronate,

enolate anions and nitro-groups, with remarkable application as powerful organocatalysts.92,93

In particular,

thiourea derivatives have been shown to effectively bind Y-shaped oxoanions such as carboxylates in polar

solvents,94

achieving selective recognition of amino acids95

and synergistic effect in catalysis.85,93,96

Schreiner and co-workers reported a method for mild and regioselective alcoholysis of styrene oxides via

cooperative Brønsted acid-type organocatalytic system comprised of mandelic acid 37 and N,N′-bis-[3,5-

bis-(trifluoromethyl)phenyl]-thiourea 38 (Scheme 4.20a).97

Scheme 4.20. a) Method for mild and regioselective alcoholysis of styrene oxides via cooperative Brønsted

acid-type organocatalytic system comprising mandelic acid 37 and N,N′-bis-[3,5-bis-

p(trifluoromethyl)phenyl]-thiourea 38 developed by Schreiner and co-workers.97

b) Reported Proposed

mechanism.


141

Various styrene oxides 35 are readily transformed upon addition of alcohols 36 into their corresponding β-

alkoxy alcohols 39 in good to excellent yields. Simple aliphatic and sterically demanding, as well as

unsaturated and acid-sensitive alcohols can be employed. The experimental findings suggested an H-

bonding-mediated cooperative Brønsted-acid catalysis mechanism (Scheme 4.20b). It is likely that co-

catalyst 38 coordinates to the acid 37 through double H-bonding, stabilizes the latter in the chelate-like cis-

hydroxy conformation, and acidifies the secondary alcoholic proton via an additional intramolecular H-

bond. The epoxide then is activated by a single-point hydrogen bond that facilitates regioselective

nucleophilic attack of the alcohol at the benzylic position. The incipient oxonium ion reprotonates the

mandelate ion and affords the β-alkoxy alcohol product. In this context, we envisioned switches 3 and 4 to

potentially exhibit selective reversible cooperative effects with mandelic acid 37 upon photoisomerization.

While E-isomers would provide effective binding of the acid and subsequent efficient catalytic activity, Z-

isomers were expected to display either lower activity or strong asymmetric preference due to the steric

hindrance generated by the amine substituent. Thioureas 1 and 6 were then tested beforehand to establish

such potential. More precisely, 1 was used as always to mimic the Z-isomers of 3 and 4, while 6 might have

provided insights on the use of E-isomers of 3 and 4, due to a reduce steric hindrance from the aromatic

tertiary amine envisioned for the latter. The influence of thiourea and Lewis-base catalyst in the alcoholysis

of styrene oxide 40 in presence of ethanol was investigated under conditions similar to those given for the

work of Schreiner as presented in Table 4.3.

Table 4.3. Influence of thiourea and base in the catalyzed alcoholysis of styrene oxide.

Entry

a Catalyst (mol%) Conversion (%)

b Comment

1 /

Chapter 4

142

Surprisingly, no conversion to the expected product 41 was observed in any case. The blank reaction gave

conversions to hydrolysed product 42 in traces (entry 1). The use of mandelic acid 37 alone only provided a

higher conversion to 42 (entry 2). Notably, the addition of co-catalyst 6 resulted in no significant variation

(entry 5). In any test where DMA was added, no conversion of 40 was detected (entries 3,4,6). It appears

that an additional base suppresses the hydrolysis to sideproduct 42. The use of 1 in combination with either

enantiomer of 37 resulted in conversion towards 42 to different extents. Noteworthy, Schreiner and co-

workers reported that parallel reference experiments without 38, as well as experiments using 38 without

acid co-catalyst 37 under identical reaction conditions, which showed no conversion to products 39.97

As

opposed to 38, thioureas 1 and 6 feature a single 1,3-bis(trifluoromethyl)benzyl substituent. From the

experimental evidence it appears that such structural difference causes a detrimental decrease in catalytic

activity, possibly due to the large difference in acidity of and non-covalent interaction provided by the

thiourea derivatives (compound, pKa in DMSO: 38, 8.5±0.1; 6, 12.1±0.1; 1, 10.72±0.02). Indeed, Schreiner

and co-workers reported a study on the acidities of popular (thio)urea organocatalysts in DMSO, which

showed the incremental effect of trifluoromethyl groups (-CF3) on acidic strength as associated to

established catalytic activity in noncovalent organocatalysis.98

Due to complete lack of effective catalytic

activity of 1 and 6 in such transformation, the investigation of the current project was eventually interrupted

without testing 3 and 4. Eventually compounds (E)-3 and (Z)-3 were found to provide successful control of

catalytic activity in the Michael addition reaction between (E)-3-bromo-β-nitrostyrene and 2,4-

pentanedione upon irradiation of the stable isomers towards the corresponding metastable forms (see

Chapter 3). Due to the insurmountable complications encountered during the development of an effective

switchable organocatalyst based on a reversibly photo-responsive bifunctional overcrowded alkene, the

venture of designing a switchable trifunctional catalyst for dynamic control of light-assisted tandem

synthetic transformations was interrupted in favor of more practicable research proposals.

4.3 Conclusions

This chapter describes the study towards a trifunctionalized molecular photoswitch based on an

overcrowded alkene for ‗one-pot‘ multi-catalytic systems. A detailed analysis of the requirements implied

by such complex design is given. We proposed a two-step sequence of Morita-Baylis Hillman reaction and

enamine catalyzed aldol or conjugated addition reaction catalyzed by merging two orthogonal bifunctional

catalytic group pairs. As a preliminary investigation, we have presented the design and attempted synthesis

of various photoresponsive bifunctionalized catalysts 7-10 for MBH reaction featuring combinations of

thiourea and tertiary amine or phosphines groups. As opposed to compounds 3 and 4, the synthesis of

compounds 7 failed due to incompatibility of the aliphatic tertiary amine with the thionation step required

to obtain one of the coupling partners for the Barton-Kellogg reaction. An alternative route towards 7-10

from a common dihalogenated intermediate 27 was proposed. However, it was affected by particularly low

yielding Barton–Kellogg couplings, after which the availability of small quantities of product would have

complicated the subsequent stages of the study. Eventually, alternative reactions were tested to investigate

the performance of 3 and 4 in mediating different types of transformations other than the MBH. More

precisely, we explored their application in: conjugated addition of 2,4-pentadione to trans-β-nitrostyrene;

alkylation of α-carboxypiperidones ethyl esters via benzyl transfer by a pre-formed ammonium

intermediate; decarboxylative protonation of α-aminomalonates; and alcoholysis of styrene oxides. In all

instances, the screening tests described herein were performed by using compound 1 as a model catalyst,

due to its inherent similarity with the Z-isomers of 3 and 4. As opposed to our initial assumption, no activity

was observed in any case. As demonstrated in this work, an aromatic amine substituent was shown to be a

poorly active catalytic moiety. These studies provide valuable insight into the requirements for the design

of more effective and complex trifunctionalized molecular switches, which may allow the photocontrol of

catalyst activity and selectivity in multicomponent reactions. Key to the successful development of these

future catalysts will be a deeper understanding of the compatibility of ancillary functional groups with the

overcrowded alkene syntheses and the introduction of more active catalytic groups to ensure higher catalyst

performance.


143

4.4 Acknowledgements

The author would like to thank Dr. B. S. L. Collins for her fundamental contribution to this work.

4.5 Experimental section

4.5.1 General methods

General experimental details can be found in Chapter 3. Wang‘s catalyst 1 was synthesized starting from

(R)-BINAM according to the reported procedure.79

P4S10·Py483

, N-benzyl-N,N-dimethylbenzenaminium

bromide84

, piperidones 2984

and 1-acetyl-2-(ethoxycarbonyl)piperidine-2-carboxylic acid 3399

were

synthesized according the reported procedures. 2-iodo-9H-fluoren-9-one 23 was synthesized by Jort

Robertus.100

4.5.2 Synthetic procedures

1-(9H-fluoren-2-yl)-N,N-dimethylmethanamine (15)

Compound 15 was prepared from commercially available fluorene-2-

carboxaldehyde by a modified procedure previously reported.101

Titanium(IV) isopropoxide (2.65 mL, 10.30 mmol) was added dropwise to a

commercially available 2M solution of dimethylamine in methanol (8.3 mL,

16.5 mmol, 3.2 equiv) followed by the addition of fluorene-2-carboxaldehyde 14 (1.0 g, 5.15 mmol). The

reaction mixture was stirred at ambient temperature for 4 h, after which sodium borohydride (200 mg, 5.15

mmol, 1.0 equiv) was added and the resulting mixture was further stirred for another period of 1.5 h. The

reaction was then quenched by the addition of water (3 mL), the resulting inorganic precipitate was filtered,

washed with diethyl ether (20 mL) and the aqueous filtrate was extracted with diethyl ether (20 mL x 2).

The combined organic extracts were dried on K2CO3, filtered and concentrated under reduced pressure. The

solid residue was recrystallized form EtOH : toluene (~10 mL) to yield 15 (1.10 g, 4.92 mmol, 95%) as

light brown solid. m.p. 182-184 °C. 1H NMR (200 MHz, CDCl3) δ 7.76 (t, J = 7.9 Hz, 1H), 7.62–7.47 (m,

1H), 7.43–7.21 (m, 2H), 3.90 (s, 1H), 3.51 (s, 1H), 2.29 (s, 3H). 13

C NMR (50 MHz, CDCl3) δ 143.4,

143.3, 141.6, 140.8, 137.5, 127.8, 126.7, 126.5, 125.8, 125.0, 119.8, 119.5, 64.6, 45.4, 36.8. HRMS (ESI,

m/z): calcd for C16H18N [M+H]+: 224.1434, found: 224.1434.

2-((dimethylamino)methyl)-9H-fluoren-9-one (16)

A 100 mL two-necked round bottom flask fitted with a reflux condenser was

charged successively with 1-(9H-fluoren-2-yl)-N,N-dimethylmethanamine 15

(970 mg, 4.34 mmol), pyridine (50 mL) and benzyltrimethylammonium

hydroxide (40 wt% solution in EtOH, 0.20 mL, 0.1 equiv). An air inlet was

then introduced through the septum and a stream of air was allowed to pass

through the reaction mixture. The reaction mixture was then allowed to stir at rt for 3 h under this set-up.

After this time the pyridine was removed under reduced pressure. The residue was then dissolved in CH2Cl2

(30 mL) and washed with water (3 x 30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated

under reduced pressure. The crude reaction mixture was then purified by flash column chromatography

(SiO2, NEt3 in pentane, gradient 10–25%) to provided the title compound 2-((dimethylamino)methyl)-9H-

fluoren-9-one 16 (860 mg, 3.62 mmol, 83%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.66 (dt, J = 7.3,

0.9 Hz, 1H), 7.61 (t, J = 1.1 Hz, 1H), 7.54–7.45 (m, 4H), 7.29 (td, J = 7.0, 1.6 Hz, 1H), 3.45 (s, 2H), 2.28

(s, 7H). 13

C NMR (100 MHz, CDCl3) δ 193.9, 144.4, 143.4, 140.4, 135.3, 134.6, 134.4, 134.3, 128.9, 125.1,

124.3, 120.2, 120.2, 63.8, 45.3. 13

C NMR (100 MHz, CDCl3) δ 195.0, 151.2, 145.9, 135.7, 134.8, 134.2,

126.8, 124.1, 121.2, 118.9, 116.6, 108.4, 40.7. HRMS (ESI, m/z): calcd for C16H16NO [M+H]+: 238.1226,

found: 238.1228.

Chapter 4

144

2-((dimethylamino)methyl)-9H-fluorene-9-thione (17)

Synthesis of compound 17 was attempted by following the procedure

described for 2-(dimethylamino)-9H-fluorene-9-thione (a, see Chapter 3) and

other previously reported procedures (b)102

, (c-d).83

(a) A 25 mL two-necked round bottom flask fitted with a reflux condenser and

nitrogen inlet was charged with 2-((dimethylamino)methyl)-9H-fluoren-9-one

16 (300 mg, 1.265 mmol), dry toluene (8 mL) and phosphorus pentasulfide (422 mg, 1.90 mmol, 1.5 equiv)

under nitrogen. The reaction mixture was then stirred at 110 °C for approximately 2 h, while the conversion

was monitored by TLC (EtOAc in pentane, 50%). The mixture was concentrated under reduced pressure

and the residue was filtrated by quick column chromatography (Al2O3, EtOAc in pentane, 50%). Analysis

by 1H NMR spectroscopy indicated that none of the collected fractions contained the desired product.

(b) A 25 mL two-necked round bottom flask fitted with a reflux condenser and nitrogen inlet was charged

with 2-((dimethylamino)methyl)-9H-fluoren-9-one 16 (200 mg, 0.843 mmol), dry toluene (8 mL) and

Lawesson‘s reagent (510 mg, 12.65 mmol, 1.5 equiv) under nitrogen. The reaction mixture was then stirred

at 80 °C for approximately 30 min, at which point TLC (EtOAc in pentane, 20%) showed complete

disappearance of the substrate. The mixture was concentrated under reduced pressure and the residue was

filtrated by quick column chromatography (SiO2, MeOH in CH2Cl2, 10%). As analyzed by 1H NMR

spectroscopy, none of the collected fractions contained the desired product.

(c) A Schlenk tube was charged with 2-((dimethylamino)methyl)-9H-fluoren-9-one 16 (250 mg, 1.05

mmol), P4S10 · Py4 (240 mg, 0.32 mmol, 0.3 equiv) and acetonitrile (5 mL). The reaction mixture was

heated at reflux for 2 h and then allowed to cool down to room temperature. The two-phase system was

concentrated under reduced pressure to ca. 2 mL and water (5 mL) was added. A solid was quickly formed

which was filtered and washed with water. As analyzed by 1H NMR spectroscopy, the obtained crude

residue did not contain the desired product.

(d) A Schlenk tube was charged with 2-((dimethylamino)methyl)-9H-fluoren-9-one 16 (250 mg, 1.05

mmol), P4S10·Py4 (240 mg, 0.32 mmol, 0.3 equiv) and dimethyl sulfone (1.0 g). The solid mixture was

heated at 170-175 °C for 15 min until changed to a vivid purple color. After cooling, boiling water (4 mL)

was added to the solidified melt. The color of the mixture rapidly changed to brown. Analysis by 1H NMR

spectroscopy indicated that the obtained crude residue did not contain the desired product.

(E/Z)-6-bromo-4-(2-iodo-9H-fluoren-9-ylidene)-3,5,8-trimethylthiochromene (25)

Synthesis of compounds 25 was attempted by following the

procedure described for compound 3 (see Chapter 3).

A 25 mL two-necked round bottom flask fitted with a reflux

condenser and nitrogen inlet was charged with 2-iodo-9H-

fluoren-9-one 23 (306 mg g, 1.0 mmol), dry toluene (10 mL)

and Lawesson‘s reagent (600 mg, 1.5 mmol, 1.5 equiv). The

mixture was then heated at 95 ºC for approximately 6 h, until

TLC (CH2Cl2 in pentane, 15%) started showing degradation. The mixture was diluted with a 1:1 solution of

pentane:CH2Cl2 (70 mL) to precipitate most of the Lawesson‘s reagent and filtered. The liquid fraction was

concentrated under reduced pressure and the residue was purified by a quick column chromatography

(SiO2, CH2Cl2 in pentane, 15%). The early yellow fraction was concentrated under reduced pressure to

yield 2-iodo-9H-fluorene-9-thione as a brown residue, which was used directly in the following step. A

Schlenk tube was charged with a solution of (E)-(6-bromo-3,5,8-trimethylthiochroman-4-

ylidene)hydrazone 24 (50 mg, 0.167 mmol) in N,N-dimethylformamide (3 mL) under nitrogen and cooled

to –40 °C. A solution of [bis(trifluoroacetoxy)iodo]benzene (80 mg, 0.18 mmol, 1.1 equiv) in N,N-

dimethylformamide (1 mL) was then added at this temperature via syringe. The resulting solution was

stirred for approximately 1 min followed by the addition of a solution 2-iodo-9H-fluorene-9-thione 22

(70 mg, 0.217 mmol, 1.3 equiv) in N,N-dimethylformamide (1.5 mL) and CH2Cl2 (1.5 mL) via syringe. The


145

resulting solution was stirred for 16 h while allowed to warm slowly to rt. After this time the reaction

mixture was diluted with EtOAc (15 mL) and washed sequentially with sat. aq. NH4Cl (10 mL), water (2 x

10 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated under

reduced pressure. Analysis of the crude residue by TLC (SiO2, CH2Cl2 in pentane, 10%) and 1H NMR

spectroscopy confirmed the presence of episulfide intermediate. The residue was transferred to a 10 mL

round bottom flask, dissolved in toluene (3 mL) and treated with tri(dimethylamino)phosphine (0.07 g, 0.06

mL, 0.33 mmol, 2.0 equiv). The resulting solution was heated at 70 °C and allowed to stir at this

temperature for 2 d. After this time the reaction mixture was cooled to rt and the solvent was removed

under reduced pressure. The crude reaction mixture was then purified by flash column chromatography

(SiO2, CH2Cl2 in pentane, 4%) to provide in the early fraction an inseparable (E/Z)-mixture of compound 6-

bromo-4-(2-iodo-9H-fluoren-9-ylidene)-3,5,8-trimethylthiochromene 25 (13 mg, 0.025 mmol, 15%) as a

red solid. 1H NMR (300 MHz, CDCl3, mixture of E and Z isomers) δ 8.67 (d, J = 5.5 Hz, 1H), 8.32 (dd, J =

19.6, 7.8 Hz, 1H), 7.82 (s, 2H), 7.69 (t, J = 8.4 Hz, 4H), 7.57 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 7.8 Hz, 4H),

7.33 (d, J = 9.4 Hz, 3H), 7.13 (t, J = 7.6 Hz, 1H), 6.73 (t, J = 7.6 Hz, 1H), 5.83 (d, J = 7.8 Hz, 1H), 3.46 –

3.22 (m, 3H), 2.75–2.65 (m, 7H), 2.22 (dd, J = 12.5, 6.8 Hz, 2H), 1.89 (d, J = 9.2 Hz, 6H), 1.40–1.32 (m,

2H), 0.92–0.80 (m, 6H).

(E/Z)-8-bromo-1-(2-iodo-9H-fluoren-9-ylidene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromene (27).

Synthesis of compounds 27 was attempted by

following the procedure described for compound 25,

starting from hydrazone 26 (160 mg, 0.5 mmol). The

crude reaction mixture was then purified by flash

column chromatography (SiO2, CH2Cl2 in pentane,

5%) to provide in the early fraction a complex

mixture mainly composed of bis-fluorenyl by-products as an orange residue. 1H NMR spectroscopy of the

residue showed diagnostic peaks of a mixture of the title compound (E/Z)-8-bromo-1-(2-iodo-9H-fluoren-9-

ylidene)-2-methyl-2,3-dihydro-1H-benzo[f]thiochromene 27 as minor component (traces). 1H NMR (300

MHz, CDCl3, mixture of E and Z isomers) δ 10.10 (s, 1H), 9.76–9.61 (m, 1H), 7.99 (d, J = 7.7 Hz, 1H),

7.93 (d, J = 7.4 Hz, 1H), 6.85–6.65 (m, 1H), 6.41 (s, 1H), 6.17 (d, J = 7.9 Hz, 1H), 6.06 (d, J = 8.0 Hz, 1H),

3.59–3.44 (m, 1H), 2.82–2.65 (m, 1H), 2.46–2.23 (m, 1H), 0.92–0.83 (m, 6H).

(R)-N-benzyl-2'-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,N-dimethyl-[1,1'-binaphthalen]-2-

aminium bromide (28)

A 10 mL round-bottom flask equipped with a stir bar and rubber septum

was charged with a solution of 1 in dry benzene (1.5 mL) under nitrogen. A

2 mL vial equipped with a septa screw-cap was charged with benzyl

bromide (35 mg, 24 µL, 0.205 mmol, 1.2 equiv) and attached to vacuum-

nitrogen inlet with a needle. Three cycles of vacuum and nitrogen were

applied. Dry benzene (0.5 mL) was added and the obtained solution was

transferred to the solution of A. The reaction mixture was stirred at room

temperature over a period of 24 h. Heptane (4 mL) was added to the

mixture, causing the precipitation of the desired ammonium adduct. The slurry was filtered on a P4 fritted

glass funnel under reduced pressure and the solid was washed with a mixture of pentane:Et2O 3:1 (4 mL)

and pentane (4 mL) to yield the title compound (R)-N-benzyl-2'-(3-(3,5-

bis(trifluoromethyl)phenyl)thioureido)-N,N-dimethyl-[1,1'-binaphthalen]-2-aminium bromide 28 (65 mg,

0.086 mmol, 51%) as pink/yellow powder. The product was stored under inert atmosphere in a desiccator

due to its high hygroscopicity and air sensitivity. 1H NMR (400 MHz, CDCl3) δ 11.17 (br s, 1H), 10.86 (br

s, 1H), 8.53 (br s, 2H), 8.29 (br d, J = 7.9 Hz, 1H), 8.23 (d, J = 9.0 Hz, 1H), 8.07 (br d, J = 7.9 Hz, 1H),

8.02 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.71 (d, J = 9.1 Hz, 2H), 7.62 (s, 1H), 7.52 (ddd, J = 8.2,

Chapter 4

146

6.9, 1.1 Hz, 1H), 7.48 (br s, 1H) 7.31 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.77 (br s,

1H), 3, 3.39 (br s, 1H), 3.10 (br s, 1H). 13

C NMR (100 MHz, CDCl3) δ 179.9, 133.5, 132.5, 131.7, 131.3,

129.4, 128.8, 128.2, 126.8, 124.5, 123.8, 121.8, 118.5, 48.7, 48.0, 42.0. 19

F NMR (400 MHz, CDCl3) δ -

62.83. HRMS (ESI, m/z): calcd for C38H30F6N3S [M-Br]+: 674.2059, found: 674.2056.

4.5.3 General procedure for screening of conditions for Morita–Baylis–Hillman reactions (Table

4.1)

A 4 mL vial was charged with catalyst (see reported equivalents in Table 4.1), followed by the addition of

MeCN (1 mL, when reported) and 2-cyclohexen-1-one (0.75 mmol, 3 equiv). The reaction mixture was

then stirred vigorously for 10 min at rt, prior to the addition of 3-phenylpropionaldehyde (0.25 mmol, 1

equiv) via syringe. The reaction mixture was then allowed to stir at rt for 4 d, after which it was

concentrated under reduced pressure and analyzed by GC-MS and 1H NMR spectroscopy (CDCl3) to

determine the conversion. No evidence of the desired MBH adduct was observed, as compared with

previously reported physical data.103

Product: 1H NMR (CDCl3) δ 7.29–7.15 (m, 5H), 6.85 (t, J = 4.0 Hz,

1H), 4.32 (1 H, dt, J = 7.0, 5.0 Hz, 1H), 3.04 (d, J = 7.0 Hz, 1H), 3.04 (d, J = 7.0 Hz, 1H), 2.85–2.77 (m,

1H), 2.69–2.62 (m, 1H), 2.43–2.36 (m, 4H), 2.03–1.89 (m, 4H).

4.5.4 General procedure for screening of conditions for conjugated additions of 2,4-pentadione to

trans-β-nitrostyrene (Scheme 4.11)

A 4 mL vial was charged with catalyst (see reported equivalents in Scheme 4.11), followed by the addition

of 2,4-pentadione (0.34 mmol, 2 equiv) and trans-β-nitrostyrene (0.17 mmol, 1 equiv) in Et2O (1 mL) at

room temperature. After 28 h of stirring, the reaction mixture was concentrated in vacuo. The residue was

analyzed by GC-MS and 1H NMR spectroscopy (CDCl3) to determine the conversion. No evidence of the

desired Michael adduct was observed, as compared with previously reported physical data.104

Product: 1H

NMR (CDCl3) δ 7.35–7.26 (m, 3H), 7.21–7.16 (m, 2H), 4.68–4.59 (m, 2H), 4.38 (d, J = 10.5 Hz, 1H),

4.28–4.21 (m, 1H), 2.30 (s, 3H), 1.95 (s, 3H).

4.5.5 General procedure for asymmetric alkylation of N-benzyl-oxopiperidine-3-carboxylate via

benzyl transfer with quaternary ammonium bromides (Scheme 4.18)

A dried Schlenk tube equipped with a stirring bar and rubber septa under nitrogen was charged with NaH

(0.2 mmol, 1.0 equiv, 60 % in mineral oil). A solution of N-benzyl-oxopiperidine-3-carboxylate (0.2 mmol)

in toluene (1.5 mL) was added. The stirred mixture was then kept at 80 °C for 1 h. Then, quaternary

ammonium bromide 28 or 31 (0.22 mmol, 1.1 equiv) was added in one portion to the suspension of the

sodium salt at room temperature. The reaction mixture was subsequently heated at the reported temperature

for the reported time (see Scheme 4.). After cooling, the mixture was poured carefully into water (2 mL).

The organic layer was separated, washed with brine (2 x 2 mL), dried with Na2SO4, filtered, and

concentrated to give an oily residue. The crude product was analyzed by GC-MS and 1H NMR

spectroscopy (CDCl3) to determine the conversion. Substrate: 1H NMR (300 MHz, CDCl3) δ 7.43–7.22

(m, 5H), 4.31–4.11 (m, 2H), 3.64 (s, 3H), 3.21 (t, J = 1.8 Hz, 2H), 2.61 (t, J = 5.9 Hz, 1H), 2.44-2.34 (m,

2H), 1.27 (t, 3H). Product: 1H NMR (300 MHz, CDCl3) δ 7.27–7.05 (m, 8H), 6.71–6.62 (m, 2H), 4.04–

3.94 (m, 2H), 3.49 (d, J = 5.1 Hz, 1H), 3.35 (dd, J = 11.5, 2.6 Hz, 2H), 3.14 (d, J = 13.7 Hz, 1H), 2.86 (s,

2H), 2.80-2.65 (m, 1H), 2.43–2.18 (m, 3H), 1.03 (t, J = 7.1 Hz, 3H).

4.5.6 General procedure for decarboxylative protonation of 1-acetyl-2-(ethoxycarbonyl)piperidine-

2-carboxylic acid (

4.5.7 Table 4.2)

A 4 mL vial was charged with catalyst (see reported equivalents in Table 4.2) and 1-acetyl-2-

(ethoxycarbonyl)piperidine-2-carboxylic acid 33 (0.09 mmol), followed by the addition of THF (0.5 mL).

The reaction mixture was then stirred vigorously (see reported time and temperature). The reaction mixture

was then concentrated under reduced pressure and analyzed by GC-MS and 1H NMR spectroscopy (CDCl3)


147

to determine the conversion. The crude product was purified by flash chromatography (SiO2, MeOH in

CH2Cl2, 1%) and the ee was determined by chiral HPLC analysis (Chiralcel OB-H, hept:2-propanol = 95:5,

flow 0.5 mL/min, 40 °C, Rt (1st) 21.2 min

university of groningen dynamic transfer of chirality in ......was achieved via switchable iminium...

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