University of Groningen
Harnessing the reactivity of alkenyl heteroarenes through copper catalysis and Lewis acids
Lanza, Francesco
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Lanza, F. (2018). Harnessing the reactivity of alkenyl heteroarenes through copper catalysis and Lewis acids. University of Groningen.
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1
Harnessing the Reactivity of Alkenyl Heteroarenes Through
Copper Catalysis and Lewis Acids
2
The work described in this thesis was carried out at the Stratingh Institute for Chemistry, University of Groningen (The Netherlands).
This work was financially supported by NWO.
Printed by Ridderprint BV, Ridderkerk, The Netherlands. Cover picture by Emanuela Lanza.
ISBN: 978-94-034-0761-6 (Printed Book) ISBN: 978-94-034-0762-3 (Ebook)
3
Harnessing the reactivity of alkenyl
heteroarenes through copper
catalysis and Lewis acids
PhD thesis
to obtain the degree of PhD at the
University of Groningen
on the authority of the
Rector Magnificus Prof. E. Sterken
and in accordance with
the decision by the College of Deans.
This thesis will be defended in public on
Friday 15 June 2018 at 14.30 hours
by
Francesco Lanza
born on 19 August 1987
4 Supervisors Prof. S. Harutyunyan Prof. J.G. Roelfes Assessment Committee Prof. E. Otten Prof. F.J. Dekker Prof. A. Alonso
6
Table of Contents
List of abbreviations ... 9
Chapter 1 Synthesis and Functionalization of Aliphatic and Aromatic Heterocycles ... 11
1.1 Introduction ... 12
1.2 Pyridines ... 12
1.3 Benzoxazoles and Its Analogues ... 16
1.4 Conclusions ... 20
1.5 Outline of the Thesis ... 20
1.6 Bibliography ... 21
Chapter 2 Copper Catalysed Conjugate Addition of Grignard Reagent to Alkenyl Aromatic Heterocycles .. 25
2.1 Introduction ... 26
2.2 Results and Discussion ... 27
2.3 Conclusion ... 35
2.4 Experimental Section ... 37
2.4.1 General Information ... 37
2.4.2 Synthesis and Characterizations of Substrates ... 37
2.4.3 General Procedure A: Cu-Catalyzed Asymmetric Grignard Addition to N-Containing Aromatic Heterocycles ... 42
2.4.4 General Procedure B: Synthesis of Racemic Products ... 43
2.4.5 Catalytic Asymmetric Addition of EtMgBr to (E)-1i and (Z)-1i ... 58
2.4.6 Controlled Experiments ... 58
2.4.7 (E)/(Z) Photoisomerization Experiments ... 59
2.4.8 (E)/(Z) Isomerization Experiments of (Z)-10i ... 59
2.4.9 Determination of Absolute Configuration ... 59
2.5 Bibliography ... 61
Chapter 3 Hetero Aromatic Enolate Trapping Promoted by BF3⋅OEt2 ... 63
3.1 Introduction ... 64
3.2 Rseults and Discussion ... 65
3.3 Conclusion ... 74
3.4 Experimental Section ... 75
3.4.1 General Information ... 75
3.4.2 Synthesis and characterizations of substrates ... 75
3.4.3 General Procedure A: Enantioselective Conjugate Addition/Trapping Process ... 79
3.4.4 General Procedure B: Racemic Conjugate Addition/Trapping Process ... 80
3.4.5 Crystallographic Data ... 83
3.5 Bibliography ... 85
Chapter 4 Copper Catalysed Alkylation of β-Substituted 2- and 4-Alkenyl Pyridines ... 87
4.1 Introduction ... 88
7
4.3Conclusion ... 96
4.4 Experimental Section ... 97
4.4.1General information ... 97
4.4.2 Synthesis and Characterizations of Substrates ... 97
4.4.3General Procedure A: Cu-Catalyzed Asymmetric Grignard Addition to 4-Alkenyl Pyridines. ... 101
4.4.4General Procedure B: Cu-Catalyzed Asymmetric Grignard Addition to 2-Alkenyl Pyridines. ... 101
4.4.5 General Procedure C: synthesis of Racemic Products ... 102
4.4.6Synthesis and Characterizations of Products (13a-d, 15a-f, and 16a-j) ... 102
4.4.7Controlled Experiments ... 111
4.4.8Synthesis and Characterization of Functionalized Pyridines (17-21) ... 112
4.4.9Synthesis and Characterization of Cu-Complexes Derived From Ligand L7 and L8 ... 117
4.4.10Determination of Absolute Configuration by X-Ray Analysis of 2a’ ... 118
4.5 Bibliography ... 121
Chapter 5 On the Cu Catalysed Conjugated Addition of Grignard Reagent to Alkenyl Pyridine Derivatives: a Mechanistic Study ... 123
5.1 Introduction ... 124
5.2 Result and Discussion ... 126
5.3Conclusion ... 135
5.4 Experimental Section ... 136
5.4.1 General Information ... 136
5.4.2 Synthesis and Characterizations of Substrates 17 and 18 ... 136
5.4.3 Synthesis and Characterizations of Products 19 ... 137
5.4.4 Synthesis and characterizations of product 20 ... 138
5.4.5 (E)/(Z) Isomerization Studies ... 138
5.4.6NMR Studies ... 142
5.4.7 General Procedure for Preparation of Pyridine-LA and Pyridine-EtMgBr Complexes ... 142
5.5 Bibliography ... 143
Summary ... 145
Nederlandse Samenwatting ... 147
9
List of abbreviation
ACA: asymmetric conjugate addition API: active pharmaceutical ingredient CA: conjugate addition
ee: enantiomeric excess DCM: dichloromethane DHIQ: dihydroisoquinoline
DMPU: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon EWG: electron withdrawing group
HMPA: hexamethylphosphramide LA: Lewis acid
MTBE: Methyl-tert-butylether
NOESY: Nuclear Overhouser effect spectroscopy RDS: rate determining step
RI-NMR: Rapid Injection NMR
TBSOTf: tert-butyldimethylsilyl trifluoromethanesulfonate TBDPSOTf: tert-butyldiphenylsilyl trifluoromethanesulfonate TESCl: triethylsislyl chloride
TESOTf: triethylsilyl trifluoromethanesulfonate THF: tetrahydrofuran
THIQ: tetrahydroisoquinoline
TMSOTf: trimethylsilyl trifluoromethanesulfonate TMSBr: trimethylsilyl bromide
TMSCl: trimethylsilyl chloride
11
Chapter 1
12
1.1 Introduction
Heterocycles, both aliphatic and aromatic, are ubiquitous motives in nature, and they found application in several areas such as medicine,1 materials and dyes,2 and synthetic chemistry.3 Their immense importance is reflected by the massive presence of heterocyclic structures among the alkaloids. Alkaloids are well known for the many biological activities displayed by the members of this class of compounds.4 In the past, alkaloids were defined as nitrogen containing organic compound found in plants with strong bioactivity and basic character, while nowadays many molecules without basic properties are considered members of this family in virtue of their pronounced biological activity.5 The synthetic strategies to access chiral heterocyclic derivatives can be divided in two main classes: 1) cyclization reactions6 or 2) direct functionalization of a heterocyclic scaffold.7 In both approaches the chiral information can be introduced using an external source (i.e. catalyst, nucleophiles, electrophiles) or can be dictated by a chiral moiety already present in the substrates. Despite the first approach often relies on long multistep process, due to the major versatility it offers, it is the most commonly used one, while the second approach is an emerging field. Among the plethora of heterocyclic structures found in alkaloids and other biologically active compounds, only the heterocycles relevant for this thesis will be discussed in this chapter.
1.2 Pyridines
Being commonly found in bioactive compounds8 and functional materials,9 pyridines and their synthesis have always attracted the attention of organic chemists. This interest resulted in the appearance of a conspicuous amount of reports in literature on the topic.3d,6c,6d,7a,10,11 De novo construction of the pyridine ring, through both inter- and intramolecular processes, is one of the most exploited startegies, due to the high structural diversity that can be achieved.6c,6d,10 Forefather of this approach is the Hantzsch pyridine synthesis,12 a formal [2+2+1+1] multicomponent cyclization reaction between ammonia, formaldehyde and β-keto esters (Scheme 1).
Scheme 1: Hantzsch pyridine synthesis.
The growing knowledge on transition metal catalysed processes contributed significantly in the development of new synthetic routes to access pyridine derivatives. In 1998, Roesch and Larock reported one of the first example of formal [4+2] cycloaddition reaction between halovinyl imines and internal alkynes promoted by catalytic amount of Pd.13 Several multi-substituted pyridines and other heterocycles could be synthesized using this protocol (Scheme 2a). The proposed mechanism starts with oxidative addition of the halovinyl imine 34 on Pd(0) species affording organopalladium compound 37. Insertion of the latter on the acetylene generates intermediate 38, that upon reaction with the imine moiety forms 7-member palladacycle 39. Finally, in the reductive elimination step final product 36 is obtained and the Pd(0) species is regenerated (Scheme 2b).
13
Scheme 2: Pd-catalysed synthesis of substituted pyridines via annulation reaction.
Besides Pd,13,14 formal [4+2] cycloaddition reactions for the construction of the pyridine ring have been achieved using many others transition metals such as Fe,15 Rh,16 Au,17 Ru18 and Cu.19 Copper catalysis itself has been used by Liu and Liebeskind in one of the few examples of C-N cross coupling/electrocyclizzation cascade sequence.19 Simple α,β-unsaturated ketoxime O-pentafluorobezoates 40, derived by condensation of α,β-unsaturated ketone with hydroxylamine followed by acylation with perfluorinated benzoyl chloride, undergoes N-imination in presence of Cu(II) salt and alkenyl boronic acid 41 (Scheme 3).19,20
Scheme 3: Cu-catalysed C-N cross coupling/electrocyclizzation cascade sequence
The reaction is believed to be proceeding through formation of azatriene (E)-42 and azatriene (Z)-42 with the latter undergoing electrocyclization to afford a dihydropyridine intermediate that is oxidised to pyridine 43. This represents a straightforward way to access mono-, di-, and tri-substituted pyridine rings.
Cycloaddition reactions enabling the formation of pyridine derivatives are not limited to [4+2] strategies. Several [3+3] approaches have been reported as well as some [2+2+2] and [3+2+1] methodologies.6b,20 In a recent example, Chiba and co-workers developed an elegant formal [3+3] annulation using vinyl azides and cyclopropanols accessing a wide range of di- and tri-substituted pyridines in overall good yields.21 In this process, a Mn(III) salt oxidises cyclipropanol 44 via single electron transfer, generating the oxo-radical 45 that evolves in carbo-radical species 46 (Scheme 4).
14
Scheme 4: Formal [3+3] annulation of vinyl azides and cyclopropanols.
The newly formed radical undergoes conjugate addition to vinyl azide 47 affording iminyl radical 48 with consequent elimination of a molecule of N2. Intermediate 48 reacts with the Mn(II) species in order to form the iminyl metal species 49 that upon direct addition to the carbonyl moiety affords oxanion 50. Hydrolysis of the latter restores the Mn(III) catalyst and releases disubstituted tetrahydropyridine 51. Dehydration and oxidation of 51 finally produce the desired product 52. Another interesting [3+3] cycloaddition procedure has been developed by Manning and Davies.22 Isoxazole 53 reacts with diazovinyl compound 54 in presence of Rh(II) catalyst to deliver multisubstituted pyridines 55 (Scheme 5).
Scheme 5: Rh-catalysed cycloaddition of isoxazoles and diazovinyl compounds.
The reaction is believed to proceed via formation of a Rh-carbene and its insertion into the N-O bond of isoxazole 53 results in the formation of intermediate 56, that upon heating and oxidation forms pyridine 55. Main limitation of the approach is the necessity of high
15 temperature to promote the release of N2 from 54 and the presence of carbonyl moiety (ester or ketone) as R3- substituent on the diazo compound.
Due to the sp2-character of the carbons constituting the pyridine core, the synthesis of chiral pyridines requires the use of stoichiometric amount of chiral molecules that will be incorporated in the structure of the final product. To the best of our knowledge, only few examples have been reported of such transformation.23 A different approach for the synthesis of decorated pyridine rings is represented by the direct functionalization of the pyridine moiety itself through coupling reaction,24,25 α-metallation, or addition of strong nucleophiles to pyridinium analogues followed by oxidation.25 The latter is an established field with a plethora of highly yielding process covering a large spectrum of functionalities. Regioselectivity issues (1,2- vs 1,4-addition) can be circumvented by a careful choice of the nucleophile. As for common Michael acceptors, hard nucleophiles will be directed in 2-position, whereas soft nucleophiles will prefer the attack in 4-position (Scheme 6).
Scheme 6: Nucleophilic addition to pyridinium derivatives.
The lack of scientific reports in literature on the chiral version of such strategy is mainly due to the necessity of employing configurationally stable chiral nucleophiles. Synthesizing nucleophiles of this type is not always straightforward especially for small simple moieties. Moreover, use of stoichiometric amounts of chiral reagents to prepare the chiral nucleophile is often required, making this approach tedious and not practical. To achieve this goal, coupling chemistry could represent a more convenient approach.26 Aggarwal and co-workers recently developed a stereospecific coupling of boronic esters with activated pyridines (Scheme 7).7a
16
Secondary and tertiary enantioenriched boronic esters undergo transmetallation with ortho- and lithiated pyridines affording intermediate 59 shown in scheme 7 only for the para-lithiated substrate. Essential for the reaction to proceed, is the 2,2,2-trichloroethyl chloroformate (TrocCl) that at first promote the 1,2 migration of the alkyl group from the boron centre to the pyridine and later the hydrolysis/rearomatization process by increasing the electrophilicity of intermediates 60 and 61. NMR and React-IR studies confirmed the formation of all the postulated intermediates during the reaction, with the only exception of 60 due to an extremely fast reaction leading directly to compound 61 upon addition of TrocCl to the reaction mixture. The high yields and stereospecificities with which α-chiral pyridines can be accessed using this methodology partially compensate the necessity to use pre-formed chiral boronoic esters.
In spite of their importance, enantioselective catalytic methods are still rare.26d,27 Based on their previous studies on C-H bond addition of aromatic and heteroaromatic compounds to alkenes,28 Huo and co-workers explored the possibility to develop an asymmetric variant of this transformation (Scheme 8).26d Chiral half-sandwich Sc-complexes promoted the addition of 2-substituted pyridines to several terminal alkenes yielding chiral 2,6-di2-substituted pyridines with excellent results.
Scheme 8: Sc-catalysed addition of substituted pyridines to terminal alkenes.
1.3 Benzoxazoles and Its Analogues
Benzoxazoles and analogue scaffolds, such as oxazoles, thiazoles, imidazoles and their benzo-fused counterparts, found extensive application in medicinal chemistry.29 Therefore, development of new synthetic methodologies for the preparation and modification of this class of compounds is a continuous challenge in organic chemistry. As for the other heterocycles already discussed in this chapter, also in this case, typical strategies for their construction rely on cyclization reactions6b,30 or direct functionalization of the heterocycle scaffold.24b,31 In this section the focus will be on benzo-fused five member rings, namely benzoxazole and benzothiazole.
Cyclization reactions occur between ortho-substituted aniline and either aldehydes31f,31g,31h or carboxylic acid derivatives.31i,31l,31m In the first case the reaction proceed via formation of imine intermediate 67, that in turn reacts with the nucleophlilic substituent on the aniline moiety followed by oxidation/rearomatization process to afford final product 69 (Scheme 9).
17
Scheme 9: Intermolecular cyclization between ortho-substituted anilines and aldehydes.
An interesting variation on this methodology have been proposed by Punniyamurthy and co-workers.32 In place of ortho-substituted anilines, aryloxyamines were used, and condensation with arylaldehydes generates bisaryloxime ether33 70 (Scheme 10). According to their mechanistic studies, compound 70 undergoes chelation with the copper slat, forming intermediate 71. The latter rearranges to intermediate 72, that upon intramolecular cyclization affords copper species 73. Finally, a reductive elimination step delivers 2-arylbenzoxazole 74.
Scheme 10: Synthesis of 2-arylbenzoxazoles through Cu(II) catalysed bisaryloxime ethers rearrangement.
When carboxylic acid derivatives are taken into account, the first step is the formation of intermediate amide 76 (Scheme 11). Based on the nature of the X- substituent on the ortho-position, two different route are possible. If X- is a nucleophilic substituent, like alcohols, amines or thiols, then it will undergoes direct addition to the carbonyl moiety providing compound 77. Elimination of a molecule of water will lead to the formation of benzoxazole 69. The intramolecular cyclization requires harsh condition and/or the use of strong Lewis acids.34 When X- is a halogen, usually bromine, the final step towards product 69 is a cross-coupling reaction, most commonly catalysed by copper salts.35
18
In general, it can be concluded that cyclization reactions for the synthesis of substituted benzoxazoles often require high temperature and catalytic amount of metal catalyst (i.e. Pd, Cu, Sn, Zr), even though few metal-free strategies that rely instead on the use of microwave irradiation have been reported.31m,36
The continuous advances in transition metal catalysed chemistry and C-H activation, led to a flourishment of reports on the direct functionalization of heteroaromatic scaffolds.24b,32 These methodologies allow a straightforward and easy access to a broad spectrum of structures starting from simple reagents. Arylation of benozoxazoles and related structures have received significant attention due to wide application of 2-aryl azoles in pharma industry.37 Since the seminal work of Nakamura in the 80s,38 an increasing number of reports on arylation methodologies have appeared. The majority of them are based on a Pd(0)-Pd(II) catalytic system in combination with phosphine ligands.32,39 The general catalytic cycle derived from the studies of Miura and co-workers is depicted in scheme 12.40
Scheme 12: Catalytic cycle for Pd-catalysed arylation of azoles.
A Pd(0) species undergoes oxidative addition to aryl halide 78 and the subsequent nucleophilic addition of 80 to the newly formed Pd(II) species 79, affords adduct 81. Deprotonation of the latter leads to re-aromatised azole ring 82, that upon reductive elimination releases product 83 closing the cycle. Alternatively, Rh and Cu catalysts have been employed successfully in this transformation.24b,32b,32c,41 Recently, Gao et al. reported a simple copper catalysed direct arylation of benzoxazoles (Scheme 13).31c
19 Cheap copper salts and triphenyl phospine ligand promote the coupling of several aryl bromides affording the desired product in good to excellent yields. Moreover, other heteroaromatic scaffolds, such as pyridines and quinolines, can be coupled effectively.
In contrast, alkylation processes are less common, even rare when their asymmetric version is considered.31d,31m,31n,42 This is partially due to the tendency of metal-alkyl intermediates to undergo β-hydrate elimination, consuming the alkylating agent in an unproductive way.43 Filloux
et al. have recently disclosed a Rh(I)-catalysed asymmetric alkylation of benzoxazoles using
bidentate phosphine ligand 90 (Scheme 14).42b
Scheme 14: Rh-catalysed asymettric alkylation proposed by Filloux et al.
Moreover, they gained useful insight on the mechanism and on the origin of the enantioselectivity with a series of competition and deuterium labeling experiments. Based on the results obtained, the catalytic cycle depicted in scheme 15 is proposed. Rh-Complex 91 mediates the C-H activation of 92 and generates the Rh-heteroaryl complex 93. Rh-enolate 95 is formed upon migratory insertion on acrylate 94. β-hydride elimination process triggers isomerization to 97 via Rh-η2 complex 96. Hydrolysis mediated by acetic acid restores catalytically active species 91 and releases final product 98.
20
The labeling experiments suggest that the enantiodetermining step is the migratory insertion. Subsequent stereospecific β-hydride elimination/hydrorhodation leading to intermediate 97, prevents epimerization of the newly formed stereocentre.
1.4 Conclusion
Over the years, the extensive studies on the synthesis and functionalization of heterocyclic compounds led to the development of hundreds of reports, covering a significantly broad scope of catalytic systems, substrates and reaction partners. Despite this incredible production, effective asymmetric synthesis is still difficult to achieve. The continuous demand of new heteroaromatic structures with potential biological activity urges the scientific community to further improve the already existing methods and explore new ones. In the past decade, exploitation of heteroaromatic moiety as activating group, though a weak one, has arisen as new tool for synthetic chemists to install stereogenic centres in a remote position. Pioneering in this field has been the work of Lam and Lautens.44 In chapters 2 and 4 of this manuscript, the advances in the field and our contribution to it will be discussed in more details.
1.5 Outline of the Thesis
The aim of this thesis is the development of efficient methodologies for the modification of heterocyclic scaffolds in catalytic asymmetric fashion, using synthetic strategies involving metal catalysts. Moreover, for each transformation mechanistic studies have been conducted to gain a deeper understanding of the corresponding catalytic cycles.
In Chapter 2, the copper catalysed asymmetric conjugate addition of Grignard reagents to alkenyl heteroarenes is discussed. Main player of this chapter is boron based Lewis acid BF3∙OEt2, able to promote a process otherwise impossible. Linear Grignard reagents, as well as branched, functionalised and aromatic ones, can be added to a wide range of alkenyl aromatic heterocycles under cryogenic conditions. The desired addition products are obtained in high yields and excellent enantiomeric excesses. Interestingly, a side-reaction of this process made us realize that Lewis acids can be used, not only to activate electrophilic substrates, but also to gain control over the chemoselectivity of a given reaction.
The trapping process of the heteroaromatic enolate formed upon conjugate addition to alkenyl aromatic heterocycles using enoates is discussed in Chapter 3. The high chemoselectivity exhibited by the process has been studied by use of low temperature NMR spectroscopy.
Chapter 4 describes the development of a catalytic system for the conjugated addition of organometallic reagents to various alkenyl pyridine scaffolds. Combination of copper salts, diphosphine ligands and strong Lewis acid trimethylsilyl trifluorometanesulfonate (TMSOTf) enabled the conjugate addition of alkyl Grignard reagents to pyridine substrates usually considered poorly reactive. In presence of substrates bearing reactive functional groups, the process showed a remarkable functional group tolerance.
Finally, Chapter 5 presents the results of the mechanistic studies conducted on the catalytic system for the alkylation of alkenyl pyridines. Experimental studies revealed important insights on the role of the Lewis acid in the process as well as on the influence of the double bond geometry on the selectivity of the reaction. Additional information on the catalytic cycle have been acquired conducting low temperature NMR spectroscopy analysis of the reaction system.
21
1.6 Bibliography
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24
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Chapter 2
Copper Catalysed Conjugate Addition of Grignard Reagents to
Alkenyl Aromatic Heterocycles
In this chapter, the asymmetric copper catalysed addition of Grignard reagents to poorly reactive alkenyl aromatic heterocycles is described. Use of boron trifluoride etherate (BF3∙OEt2) was essential to unlock the reactivity of the substrates. The protocol can be applied to several aromatic heterocycles using a wide range of Grignard reagents affording the desired products in excellent yields and enantioselectivities.
Part of this chapter has been published:
26
2.1 Introduction
As already mentioned in the introduction of this thesis, heterocycles are key structures in pharmaceuticals and bioactive compound.1 The majority of all known active pharmaceutical ingredients (APIs) contains one or more aromatic heterocyclic moieties in their structure, with
N-containing aromatic heterocycles being the most common.2 Moreover, many bioactive compounds often exist as chiral molecules, and the two different enantiomers exhibit markedly different activities in the living organisms. These data make clear the reason why achieving high stereocontrol in the production of APIs is a requirement of fundamental importance. Developing synthetic strategies that allow the total control on the stereochemical outcome of a chemical transformation has been always one of the main challenges for organic chemistry. Among the different class of chemical transformations, direct asymmetric C-C bond formation reactions are most sought after.3 Conjugate addition (CA) of nucleophilic moieties to electron deficient alkenes (Michael acceptors) is an efficient and well-known method for the formation of new C-C bonds.4,5 In this context the enantioselective addition of carbon nucleophiles to conjugated alkenyl aromatic heterocycles is an intriguing approach to access chiral aromatic heterocycle derivatives in enantiopure form (Scheme 1).
Scheme 1: Enantioselective nucleophilic addition to conjugated alkenyl aromatic heterocycles.
While addition of carbon nucleophiles (both stabilised and non-stabilised) to vinyl heteroaromatic compounds is well known,6 there is only a handful of reports for β-substituted analogues, especially with organometallic nucleophiles. A first attempt to use conjugated alkenyl heteroaromatic compounds as Michael acceptors appeared in literature in 1998.7 In that work, a catalytic system based on a chiral Nickel complex was employed to promote the conjugate addition of aryl magnesium bromide to 4-substituted alkenyl pyridines. Despite the desired products were obtained with moderate to good yields, the process exhibited poor enantioselectivity with only 15% of enantiomeric excess as best result (Scheme 2).
Scheme 2: Ni catalysed conjugate addition of Grignard reagent to alkenyl pyridines.
Research in this field has been silent until 2010 when Lam and co-workers developed highly enantioselective addition of organoboronic acids to alkenyl substituted heteroaromatic compounds using Rh chiral complexes as catalyst (Scheme 3).8
27
Scheme 3: Rh-catalysed asymmetric conjugate addition of arylboronic acid to alkenyl heteroaromatic compounds.
Using this catalytic system it was possible to obtain the desired addition products in good to excellent yields and with enantiomeric excesses (ee’s) above 90% in most of the cases. Remarkably, several heteroarmatic compounds were compatible with this protocol, but unfortunately introduction of alkyl chains was not reported. Few years later, Lautens and co-workers developed a domino synthetic strategy for the synthesis of aza-dihydrodibenzoxepines with moderate yields and excellent ee’s (Scheme 4).9 This strategy exploited the reactivity of Rh catalyst to promote the formal conjugate addition of aryl-boronic ester to electron poor alkenyl pyridines, and Pd catalyst for the C-O coupling for the ring closure.
Scheme 4: Domino sequence for the synthesis of aza-dihydrodibenzoxepines catalysed by Rh and Pd.
While the asymmetric addition of different non stabilised-carbon nucleophiles, both aliphatic and aromatic, to common Michael acceptors is a well-established transformation,5 the conjugate addition to β-substituted alkenyl aromatic heterocycles is in an early stage. The scarce amount of reports on this topic is due to the poor reactivity of β-substituted alkenyl aromatic heterocycles. Compared with the typical electron withdrawing group used in Michael-type reaction to activate the conjugated double bond, such as carbonyl, nitriles, sulfonyl and nitro group, the aromatic heterocycle has a poor tendency to activate adjacent olefinic moieties. Moreover seems reasonable to assume that the reactivity of these uncommon Michael acceptors is strongly dependant on the ease with which the aromaticity of the heterocycles can be altered. To tackle the poor reactivity of these substrates we decide to exploit the high reactivity of Grignard reagent, while copper was choice as metal catalyst due to its well-known ability to direct preferentially the addition of non-stabilised carbon nucleophiles to the β-position of α,β-unsaturated carbonyl compounds as demonstrated by the plethora of reports appeared in literature after the seminal work of Kharash and Tawney.10
2.2 Results and Discussion
To test our hypothesis, 2-styrylbenzoxazole 10a was chosen as model compound. This molecule can be easily obtained in gram scale by simple condensation of benzaldehyde 9 with
28
Scheme 5: Synthesis of 2-styrylbenzoxazole 10a.
First, substrate 10a was subjected to different reaction conditions (Table 1) in which the effects of every components of the reaction were separately explored. As expected, no conversion towards product 14a was detected when Grignard reagents were added to 10a at low temperature in presence of catalytic amount of CuBr∙SMe2 (Table 1, entry 1). Addition of chiral diphosphine ligand L1-Cu complex to the reaction mixture, did not improve the outcome (Table 1, entry 2). These results highlighted again the marked low reactivity of alkenyl heteroaromatics and the necessity of a stronger activation of the substrate. We aimed to enhance the reactivity of aromatic heterocycles by combining our catalytic system, namely chiral diphosphine copper complexes and Grignard reagents, with strong Lewis acid (LA) additives commonly used to enhance the reactivity of various electrophiles.11 Based on a similar approach, Terada and co-workers recently proposed a methodology in which chiral phosphoric acid promote the addition of nitrogen based nucleophiles towards alkenyl benzimidazoles (Scheme 6).12
Scheme 6: Aza-Michael type addition to alkenyl benzimidazoles.
Addition of BF3⋅Et2O in the reaction mixture at -78 °C (Table 1, entry 3) disappointingly did not promote the desired reaction. To our great delight, the introduction of chiral diphosphine ligand L1 in the system led to the formation of desired product 14a in moderate yield and good enantioselectivity (Table 1, entry 4). An operational temperature below -50 °C is necessary since at higher temperatures the reaction between the BF3⋅Et2O and the Grignard reagent become predominant. Considering that no reaction is taking place in absence of the chiral catalyst, the stereocontrol of the process will be determined exclusively by the catalyst ability to transfer the chiral information.
29
Table 1: Preliminary studies on the addition of EtMgBr to compound 10a.
Entry L Solvent Additive (1.5 equiv) Temp. [˚C] Yield (%)[a] ee
(%)[b]
1 - tBuOMe - -25 Complex mix. -
2 L1 tBuOMe - -25 Complex mix. -
3 - Toluene BF3.OEt2 -78 0 -
4 L1 Toluene BF3.OEt2 -78 59 87
[a] Reported yields are for isolated products; [b] Determined by chiral HPLC.
Having found BF3⋅Et2O able to promote the reaction, the effect of different organic solvents and chiral ligands was assessed (Table 2). In almost every solvent tested, the desired addition product 14a was obtained with excellent levels of stereocontrol and good to excellent yields. The only exception was THF (Table 2, entry 4) that delivered the product in moderate enantioselectivity. Moreover, due to the large amount of side products formed, it was impossible to isolate compound 14a in a pure form. This outcome can be rationalised taking into account the different reactivity of Grignard reagents depending on their aggregation state in solution. Grignard reagents dissolved in non-coordinating solvents have high aggregation order, existing usually as dimers or trimers.13 Coordinating solvents, like THF, can break these aggregates forming monomers, that appear to be more reactive than in the aggregate state.13c This behaviour can explain the lower selectivity and higher amount of side products when the reaction was run in THF. To continue our investigation, Et2O was chosen as solvent for its superior performance compared to the other solvents tested in our catalytic protocol (Table 3, entry 5).
Table 2: Solvent screening
Entry Solvent Time [h] (%)Yield [a] (%)ee [b]
1 Tol 16 59 87
2 MTBE 18 55 94
3 DCM 18 67 94
4 THF 18 N.D. 50
5 Et2O 15 94 97
30
The effect of other LAs on the same transformation was studied next. Trimethylsilyl chloride (TMSCl), TiCl4, MgBr2 and trimethylsilyl trifluoromethansulfonate (TMSOTf) were examined but none of them gave superior results compared with BF3⋅Et2O (Table 3).
Table 3: Lewis acid screening.
Entry L.A. [Equiv.] Conv.[%]a Yield(%)[a] ee
(%)[b] 1 TiCl4 1.1 0 - - 2 TMSCl 1.1 0 - - 3 MgBr2 1.1 0 - - 4 TMSOTf[c] 2.0 25 - - 5 BF3.OEt2 1.1 100 94 97
[a] Reported yields are for isolated products; [b] Determined by chiral HPLC; [c] reaction with 1.2 equivalents of TMSOTf has been carried out in DCM showing only 50% conv. towards the desired product. Reaction condition: 0.1 mmol of 10a, CuBr⋅Et2O 5 mol%, L1 6 mol%, Lewis acid,
EtMgBr 1.5 equiv., Et2O 1ml, -78 °C.
For the optimization of the catalytic system, different phosphine ligands were studied. Binaphthyl bidentate ligand L4 and L5 delivered the product with enantioselectivity above 90% but with moderate yields (Table 4, entries 4 and 5). On the other hand, monodentate phosphoramidite ligands L6 and L7 failed in promoting the reaction and unreacted starting material was recovered (Table 4, entries 6 and 7). Ferrocenyl ligand L3, belonging to the Josiphos family, delivered product 14a with moderate yield and enantioselectivity (Table 4, entry 3). Ligand L2 did not catalysed the reaction probably due to the sterically demanding substituent. Several bidentate diphosphine ligands are able to promote the desired reaction, however due to the higher yield obtained, ligand L1 was selected as optimal ligand. Once the optimal reaction conditions were established (0.1 mmol of 10a, CuBr⋅SMe2 5 mol%, L1 6 mol%, BF3⋅OEt2 1.1 equiv, EtMgBr 1.5 equiv, Et2O 1ml, -78 °C), the effect of various substituents on the phenyl ring at the β-position of the double bond was investigated (Scheme 7). In all the cases, regardless the electronic properties of the substituent, the addition products 14b – 14h were obtained with high enantioselctivities. However, the reactivity of the substrates showed to be strongly dependent on the nature of the substituents. The corresponding addition products were obtained with a broad range of yields without a clear trend (Scheme 7). The aromatic β-substituent can be replaced by an alkyl chain furnishing the corresponding product in good yield and enantioselectivity (Scheme 7, compound 2h).
31
Table 4: Chiral ligand screening.
Entry Ligand Cat [%] Solvent Time [h] (%)Yield [a] (%)ee [b]
1 L1 5 Et2O 15 94 97 2 L2 10 Et2O 15 - - 3 L3 10 Et2O 15 35 53 4 L4 10 Tol[c] 19 36 91 5 L5 5 Tol[c] 18 45 92 6 L6 10 Tol[c] 19 - - 7 L7 10 Et2O 15 - -
[a] Reported yields are for isolated products; [b] Determined by chiral HPLC; [c] Toluene was used instead of Et2O
due to the insolubility of the ligand in ethereal solvent.
Scheme 7: Influence of different substituents at β-position. [a] Reported yields are for isolated products; [b]
Determined by chiral HPLC;[c] Absolute configuration was assigned by analogy with the literature.14
The substrate scope was investigated by evaluating the reactivity of other naturally occurring heteroaromatic moieties.1 For our delight not only benzoxazole, but also other heteroaromatic
32
substrates such as benzothiazoles (10i and 10j), oxazoles (10k and 10l), pyrimidines (10m and 10n), triazine (10o) and quinoline (10p), underwent conjugate addition of EtMgBr smoothly. The corresponding products were isolated with high yields and enantioselectivities (Scheme 8). When 4-styryl pyridine 10q was subjected to our protocol, no conversion to the corresponding addition product 14q was detected. Further studies that will be discussed in the next chapter will show that pyridine-based substrates require different reaction condition in order to undergo conjugated addition with high level of stereocontrol and yields.
Scheme 8: Aromatic heterocycles scope. [a] Reported yields are for isolated products; [b] Determined by chiral HPLC;
[c] 3 equiv of EtMgBr and 2.2 equiv of BF3⋅Et2O were used in this case.
This insensitivity to the nature of the hetero-aromatic moiety, which might be expected to interfere with the stability and activity of the chiral copper catalyst, makes the reaction remarkably general.
Next, the scope of the nucleophiles was assessed and for this purpose two different aromatic heterocycles, benzoxazole 10a and pyrimidine 10m, were selected. Aliphatic, both linear and branched, as well as cyclic, functionalized and aromatic Grignard reagents were studied as nucleophiles. In the case of compound 10a, all the corresponding addition products were isolated with enantioselectivities around 90% while the yields were from good to excellent, with only few exceptions in which the yields were moderate (Scheme 9, 15b, 15f, 15i, 15o). Chain length did not influenced strongly the process (Scheme 9, compound 14a vs 15a) while the system showed to be sensitive to the steric hindrance of the nucleophile. This trend is reflected in the isolated yields of compounds 15b to 15e: less hindered the nucleophile, higher the yield. Grignard reagents bearing a terminal olefin or trimethylsylyl moiety were also tolerated, delivering the product with moderate to good yields. Addition of PhMgBr led to the desired product in moderate yield but with excellent stereocontrol (Scheme 9, compound 3i). When substrate 10m was tested with the same nucleophiles, the process exhibited comparatively superior stereocontrol. In all the cases, the corresponding addition product was obtained with enantioselectivities above 97%. On the other hand, 10m has demonstrated to be more sensitive
33 to bulky nucleophiles. In this case, addition of sterically demanding α-branched Grignard reagents (i.e. c-pentyl-MgBr, PhMgBr) was not possible.
Scheme 9: Grignard reagents scope. [a] Reported yields are for isolated products; [b] Determined by chiral HPLC; [c] 3equiv of EtMgBr and 2 equiv of BF3⋅Et2O were used in this case; [d]solvent mixture Et2O/DCM (2:1) was
used in this case.
Substrate 10m was also subjected to a series of experiment to determine the feasibility of the scaling up of the reaction. Reducing the catalyst loading to 1mol% did not affect the reaction outcome as well as running the reaction in a larger 10-fold scale. In both cases, the product was obtained without any loss in terms of yield and enantioselectivity. Moreover, the copper catalyst recovered from the latter reaction can be reused in a new reaction maintaining its efficiency (Scheme 10).
34
Scheme 10: Scale up experiments.
It is known that in asymmetric reactions involving alkenes transformation, the configuration of the double bond has a substantial influence on the steriodetermination of the reaction product.13 In their mechanistic studies on ACA of Grignard reagents to enones and enoates, Harutyunyan et
al. showed that moving from trans to cis double bond configuration in the copper catalysed ACA
to enoates, led to the formation of the corresponding addition product with opposite absolute configuration and lower enantioselectivity.13 Further studies proved that under their reaction conditions, isomerization of the cis double bond towards the more stable trans took place explaining the loss in enantioselectivity. In order to investigate the influence of the geometry of the double bond over the stereoselectivity in our system, the addition of EtMgBr to (Z)-2-styrylbenzothioazole (Z)-10i was performed. Compound (Z)-10i was prepared in 90% purity by isomerization of (E)-10i using ultraviolet light irradiation. Similarly to the abovementioned results, subjecting (Z)-10i to our standard reaction conditions led to the formation of the corresponding addition product 14i with opposite absolute configuration but drastically lower enantioselectivity (40% ee vs 86% ee). Also in this case, the drop in the stereocontrol could be ascribed to partial isomerization of the substrates during the reaction promoted by the active catalyst. In order to confirm this hypothesis, the addition of EtMgBr to compound (Z)-10i in our standard condition was monitored by NMR spectroscopy. Unfortunately, the high rate of the reaction prevented the analysis of the reaction mixture in real time. The use of the less reactive MeMgBr, with which no addition to (Z)-10i occurs, allowed us to monitor the process via NMR spectroscopy. Several experiment with different combination of reaction components were carried out pointing that isomerization of the double bond indeed took place but only when CuBr⋅SMe2, L1, BF3⋅OEt2 and MeMgBr were present in the reaction media (Scheme 11).
Scheme 11: Isomerization experiments
Extensive NMR studies on the CA of stoichiometric amount of organocuprates to enones and enoates conducted by Ogle,15 have detected key intermediates in the process. Organocuprates form a Cu(I) π-complex with the C-C double bond of the substrates that evolve in a Cu(III) σ-complex upon oxidative addition (Scheme12).
35
Scheme 12: Reaction mechanism for the CA of organocuprates to enones and enoates.
Assuming that the mechanism depicted above could represent a single catalytic cycle, the double bond isomerization reaction observed for CA to enoates, suggests that the Cu(I) π-complex is in fast equilibrium with the Cu(III) σ-complex. Based on the analogies between the CA to enoates13,15 and our system, it is plausible that the latter follows a similar mechanism (Scheme 13).
Scheme 13: Tentative mechanism for the asymmetric copper catalysed CA of Grignard reagents to alkenyl aromatic
heterocycles.
The process starts with the formation of catalytically active species 17 upon transmetallation of Cu/diphosphine dimeric complex by a molecule of Grignard reagent. Complex 17 then will form π-complex 19 after reaction whit the activated substrate 18 (Scheme 13, step1). Oxidative addition process (Scheme 13, step 2) lead to the formation of σ-complex 20. Finally, reductive elimination (Scheme 13, step 3) affords product 21 and restores active species 17.
2.3 Conclusion
In summary, a simple methodology for remote functionalization of several aromatic heterocycles has been developed. Combination of highly reactive and readily available Grignard reagents, copper-diphosphine chiral complexes and boron based Lewis acid additives has shown to be an extremely efficient tool to overcame the low reactivity of the heteroaromatic substrates allowing the introduction of aliphatic substituents, that was not possible with the known methodologies.
36
Furthermore, this transformation can be carried out in the most common organic solvent, such as dichloromethane, diethyl ether, toluene and methyl tert-butyl ether with the latter two commonly used for industrial process. The necessity of using pricy ferrocenyl diphosphine ligands in our protocol it is compensated by the fact that the copper-diphosphine chiral complexes can be recovered without loss in the efficiency. Mechanistic studies aimed to clarify the role of the Lewis acid and achieve a deeper comprehension of the reaction mechanism are underway.
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2.4 Experimental Section
2.4.1 General Information
All reactions using oxygen- and/or moisture-sensitive materials were carried out with anhydrous solvents (vide infra) under a nitrogen atmosphere using oven dried glassware and standard Schlenk techniques. Reactions were monitored by 1H NMR. Purification of the products, when necessary, was performed by column chromatography using Merck 60 Å 230-400 mesh silica gel. NMR data was collected on Varian VXR230-400 (1H at 400.0 MHz; 13C at 100.58 MHz), equipped with a 5 mm z-gradient broadband probe. Chemical shifts are reported in parts per million (ppm) relative to residual solvent peak (CDCl3, 1H: 7.26 ppm; 13C: 77.00 ppm). Coupling constants are reported in Hertz. Multiplicity is reported with the usual abbreviations (s: singlet, bs: broad singlet, d: doublet, dd: doublet of doublets, ddd: doublet of doublet of doublets, t: triplet, td: triplet of doublets, q: quartet, dq: doublet of quartet, quin: quintet, sex: sextet, sep: septet, m: multiplet). Exact mass spectra were recorded on a LTQ Orbitrap XL apparatus with ESI ionization. Enantiomeric excesses were determined by Chiral HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector. E-Z photoisomerization experiments were performed using Spectroline model ENC-280C/FE lamp (λmax = 365 nm, ± 30nm). Unless otherwise indicated, reagents and substrates were purchased from commercial sources and used as received. Solvents not required to be dry were purchased as technical grade and used as received. Dry solvents were freshly collected from a dry solvent purification system prior to use. Inert atmosphere experiments were performed with standard Schlenk techniques with dried (P2O5) nitrogen gas. Grignard reagents were purchased from Sigma-Aldrich (EtMgBr, PhMgBr (3M in Et2O), ButMgBr, HexMgBr,
iPentMgBr, iButMgBr, cyclopentylMgBr (2M in Et2O). All other Grignard reagents were prepared from the corresponding alkyl bromides and Mg activated with I2 in Et2O. (iHexMgBr (1.5 M in Et2O), but-3-en-1-ylMgBr (1.2M in Et2O), pent-4-en-1-ylMgBr (1.5M in Et2O) and TMS(CH2)2MgBr (0.4 M in Et2O). Unless otherwise noted substrates were prepared by literature reported methods (vide infra). Chiral ligands (L1-L7) were purchased from Sigma Aldrich and Solvias. All reported compounds were characterized by 1H and 13C NMR and compared with literature data. All new compounds were fully characterized by 1H and 13C NMR and HRMS techniques. Absolute configuration of the chiral compounds were determined by analogy with literature report (vide infra).14
2.4.2 Synthesis and Characterizations of Substrates
(E)-2-styrylbenzoxazole (10a)16Compound 10a was prepared by literature procedure.7 The product was obtained as a white solid after crystallization in MeOH.
1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 16.3 Hz, 1H), 7.68-7.64 (m, 1H), 7.54 (m, 2H), 7.51-7.45
38
13C NMR (101 MHz, CDCl3): δ 162.8, 150.4, 142.1, 139.5, 135.1, 129.8, 129.0, 127.6, 125.2, 124.5,
119.8, 113.9, 110.3.
(E)-2-(4-methylstyryl)benzoxazole (10b)17
Compound 1b was prepared by literature procedure.3b The product was obtained as a white solid after crystallization in MeOH.
1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 16.3 Hz, 1H), 7.74 – 7.68 (m, 1H), 7.55 – 7.46 (m, 3H),
7.36 – 7.29 (m, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.03 (d, J = 16.3 Hz, 1H), 2.39 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 163.0, 150.4, 142.2, 140.2, 139.5, 132.4, 129.7, 127.5, 125.1, 124.4,
119.7, 112.8, 110.3, 21.5.
(E)-2-(4-isopropylstyryl)benzoxazole (10c)
Compound 1c was prepared by literature procedure.3b The product was obtained as a white solid after crystallization in MeOH. Yield = 45%.
1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 16.3 Hz, 1H), 7.67 (dt, J = 7.5, 3.7 Hz, 1H), 7.53 – 7.43 (m,
3H), 7.33 – 7.20 (m, 4H), 7.01 (d, J = 16.3 Hz, 1H), 2.90 (sep, J = 7.0 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H).
13C NMR (101 MHz, CDCl3): δ 163.0, 151.1, 150.4, 142.2, 139.5, 132.8, 127.7, 127.1, 125.1, 124.5,
124.1, 119.7, 112.9, 110.3, 34.1, 23.8.
HR-MS (EI): m/z calcd. for C18H17N1O1 ([M+H+]) 264.13829, found 264.13798.
(E)-2-(4-methoxystyryl)benzoxazole (10d)3c
Compound 1d was prepared by literature procedure.3b The product was obtained as a white solid after crystallization in MeOH.
1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 16.3 Hz, 1H), 7.82 – 7.77 (m, 1H), 7.68 – 7.58 (m, 3H),
7.45 – 7.39 (m, 2H), 7.08 – 7.00 (m, 3H), 3.95 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 163.1, 160.8, 150.2, 142.1, 139.0, 129.0, 127.8, 124.7 , 124.2, 119.5,
39 (E)-2-(3-methoxystyryl)benzoxazole (10e)3c
Compound 1e was prepared by literature procedure.3b The product was obtained as a yellow solid after silica gel flash-chromatography (CH2Cl2:Pentane, 2:1, v/v).
1H NMR (400 MHz, CDCl3): δ 7.77 – 7.67 (m, 2H), 7.53 – 7.46 (m, 1H), 7.34 – 7.27 (m, 3H), 7.19 – 7.14 (m, 1H), 7.09 (s, 1H), 7.04 (dd, J = 16.3, 0.9 Hz, 1H), 6.93 – 6.87 (m, 1H), 3.82 (d, J = 1.3 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 176.6, 160.0, 150.4, 142.2, 139.4, 136.5, 129.9, 125.2, 124.5, 120.2, 119.9, 115.6, 114.2, 112.5, 110.3, 55.3. (E)-4-(2-(benzoxazol-2-yl)vinyl)-N,N-dimethylaniline (10f)18
Compound 1f was prepared by literature procedure.3b The product was obtained as an orange solid after crystallization in MeOH.
1H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 16.2 Hz, 1H), 7.66 – 7.60 (m, 1H), 7.49 – 7.41 (m, 3H),
7.29 – 7.23 (m, 2H), 6.81 (d, J = 16.2, 1.7 Hz, 1H), 6.68 (d, J = 8.9 Hz, 2H), 2.99 (s, 6H).
13C NMR (101 MHz, CDCl3): δ 164.0, 150.3, 142.4, 139.9, 129.1, 124.4, 124.2, 119.3, 112.0, 110.0,
108.5, 40.2.
(E)-2-(4-chlorostyryl)benzoxazole (10g)3c
Compound 1g was prepared by literature procedure.3b The product was obtained as a white solid after crystallization in MeOH.
1H NMR (400 MHz, CDCl3): δ 7.70 – 7.61 (m, 2H), 7.48 – 7.39 (m, 3H), 7.34 – 7.29 (m, 2H), 7.29 –
7.23 (m, 2H), 6.96 (d, J = 16.3 Hz, 1H).
13C NMR (101 MHz, CDCl3): δ 162.4, 150.4, 142.1, 138.0, 135.6, 133.6, 129.2, 128.7, 125.4, 124.6,
119.9, 114.5, 110.3.
(E)-2-(prop-1-en-1-yl)benzoxazole (10h)19
Compound 1h was prepared by literature procedure.20 The product was obtained as a pale-yellow solid after silica gel chromatography (Pentane: EtOAC, 95:05, v/v).
