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Page 1: Chapter 1 Hydroamination: A General Introductionshodhganga.inflibnet.ac.in/bitstream/10603/13646/9/09_chapter 1.pdf · Chapter 1 Hydroamination: A General Introduction 3 In 2005,

Chapter 1 Hydroamination: A General Introduction

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1.1 INTRODUCTION A variety of amines found in many natural and synthetic compounds possess interesting physiological and biological activities, and the development of synthetic methodologies for such molecules and their transformation is a persistent research topic in organic and pharmaceutical chemistry.1 Classical methods for their synthesis, either in laboratory or industrial scale, include transformations of alcohols or alkyl halides into amines, reductive amination of carbonyl compounds, aminoalkylation, reduction of amides, nitriles, azides or nitro compounds and last but not least the Ritter reaction.2 All these methods either require expensive starting materials which are difficult to synthesize or unsafe to handle. The inter- or intramolecular hydroamination reaction, on the other hand, is a 100% atom-economical, waste free process of fundamental simplicity in which an amine is added to an unsaturated substrate (Scheme 1.1).3

Scheme 1.1. Hydroamination of alkenes and alkynes

1.1.1 Hydroamination of multiple bonds – A convenient route to amine synthesis The addition of an N-H bond across the C=C or C≡C bonds of an alkene or alkyne is commonly known as hydroamination reaction. This process represents an attractive strategy for the construction of nitrogen-containing compounds that almost prevents the formation of by-products in the creation of a C-N linkage. The amines and the alkynes being both inexpensive and readily available have largely contributed to the rising popularity of this reaction in recent times.

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1.1.2 Applications based on various fields As countless examples of nitrogen-containing organic molecules can be found in pharmaceutical, agricultural and industrial areas, the synthesis of carbon-nitrogen bonds is of fundamental interest in organic chemistry. Hydroamination is distinctly superior to the other available methods like imination of ketones or the aminomercuration/ demercuration of alkynes that involve the stoichiometric use of toxic mercury reagents.2

Not only this, hydroamination of alkene, alkynes and other unsaturated substrates have been successfully employed as key steps in a variety of total syntheses of target molecules, substituted indoles, pyrroles, imidazoles and other heterocycles. 1.1.2.1 Synthesis of natural products A comprehensive literature search revealed that there are many processes which utilize hydroamination as a trigger for accessing heterocycles and natural products. In 2005, Yamamoto and co-workers introduced the diastereoselective synthesis of indolizidine (–)-209D II, a noncompetitive blocker of neuromuscular transmission, via the intramolecular hydroamination of ε-amino alkyne I (Scheme 1.2).4 This developed intramolecular hydroamination protocol utilized palladium(0)/benzoic acid and can also be used for the synthesis of other complex naturally occurring alkaloids.

Scheme 1.2. Total synthesis of indolizidine (–)-209D II

A similar kind of approach was utilized by Trost et al. for the synthesis of Pseudodistomin D III (Figure 1.1). The natural alkaloids of this group are known to exhibit calmodulin antagonistic activity and potent cytotoxicity against both murine leukemia and human epidermoid carcinoma KB cells.5

Figure 1.1. Pseudodistomin D III, a potent calmodulin antagonist

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In 2005, after the successful development of a titanium catalyzed methodology for the hydroamination of alkynes, Doye and co-workers has reported a new pathway for the enantioselective synthesis of benzylisoquinoline alkaloids (+)-(S)-laudanosine X and (–)-(S)-xylopinine XI (Scheme 1.3).6 The key steps of the synthesis involved

1. Sonogashira coupling of IV and V that builds up the C1–C8 bond of the benzylisoquinoline skeleton

2. Intramolecular Ti-catalyzed hydroamination of an aminoalkyne VII to yield VIII, and

3. Subsequent enantioselective imine reduction according to Noyori’s protocol to give X and XI.

Scheme1.3. Total synthesis of (+)-(S)-laudanosine X and (–)-(S)-xylopinine XI by Doye and co-workers.

HN OCF3

H3CO

H3CO

OCH3OCH3

I+

HN OCF3

H3CO

H3CO

OCH3OCH3

84%

NH2H3CO

H3CO

OCH3OCH3

N

OCH3OCH3

98% 90%

H3CO

H3CONH

OCH3OCH3

H3CO

H3CO

N

OCH3OCH3

H3CO

H3CO CH3N

OCH3OCH3

H3CO

H3CO

92%93% ee

99% 82%

Pd(PPh3)2Cl2PPh3, CuI

iPr2NH, 25 C, 16 h

(+)-(S)-laudanosine (-)-(S)-xylopinine

KOHMeOH, H2O

10 mol% Cp2TiMe2toluene

110 C, 16 h

IVV

VI

VIIVIIIIX

X XI

The regioselective titanium promoted intramolecular addition of amines to alkynes has also been applied to the total synthesis of the antifungal agent (+)-preussin (XIV), which contains a central pyrrolidine ring (Scheme 1.4).7 The key step of the synthesis is the cyclization of a 1-amino-4-alkyne XII. XII was cyclized in the

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presence of a stoichiometric amount of CpTiMe2Cl. Subsequently, the octyl side chain was introduced by quenching the intermediate aza-titanacyclobutene with octanoyl cyanide to yield XIII. Two further steps led to (+)-preussin (XIV) in 33–44% in overall yield.

Scheme 1.4. Total synthesis of (+)-preussin XIV

In 2004, a novel addition of amine to spiroketal enol ether XV by Yin et al. enabled the distereoselective synthesis of analogues of an antifeedant of certain plants and vegetables, Tonghaosu XVII.8

Figure 1.2. Tonghaosu XVII, 2-(2,4-hexadiynylidene)- 1,6-dioxaspiro[4.4]-non-3-ene

This hydroamination reaction proceeded in a highly regio- and diastereoselective fashion at -78 °C. (Scheme 1.5). The process was catalyzed with nBuLi, affording the product in good yield for secondary amines, such as morpholine, pyrrolidine, and piperidine. However, primary amines, such as N-butylamine, gave much lower yields, and aromatic amines did not react.

Scheme 1.5. Total synthesis of analogues of Tonghaosu XVII

OAr O

OAr OnBuLi, TMEDA

HNR1R2 XVI, THF-78 °C

NR1R2

XV XVII At a higher temperature, -40 °C, the presence of free amine was found to be critical for the reaction to take place and instead of XVII, an intermediate (E)-1-(benzo[d][1,3]dioxol-5-yl)-4-(4,5-dihydrofuran-2-yl)but-3-en-2-one XVIII was found to be formed.

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OO

OO

Figure 1.3. (E)-1-(benzo[d][1,3]dioxol-5-yl)-4-(4,5-dihydrofuran-2-yl)but-3-en-2-one XVIII

Recently, Iska et al. has reported an efficient silver-catalyzed desymmetrization of amino diynes via hydroamination for the synthesis of variety of functionalized 1-pyrroline derivatives in 73 to 88% yields.9 They reported the application of this method for a short and efficient synthesis of (±)-Monomorine XXIII (Scheme 1.6).

Scheme 1.6. Total synthesis of (±)-Monomorine XXIII

TBS

NH2

TBS

N

TBS

10 mol % Ag(Phen)OTfCH3CN, 50 C, 8 h

nBuLi, nPrBr

83 %

95 %

N Bu

TBS

a) DIBALHb) CbzCl, Et3N

c) TBAFN Bu

TBSCbz

NMe

Bu

26%(±)-Monomorine

XIXXX

XXI XXII

XXIII

1.1.2.2 Synthesis of substituted indoles Substituted indoles represent one of the most important structural classes in drug discovery and also possess multiple biological activities.10 Due to this prevalence of indoles in biologically active compounds, as well as natural products, there is a strong demand for the development of an efficient protocol for their synthesis.11

Despite the development of a variety of effective strategies, the synthesis of indole derivatives featuring substituents at positions other than C5 remains a challenge. Therefore, metal-catalyzed reactions for the construction of the indole backbone were developed.3,12 Still, examination of the literature leave a constant scope for the improvement of the existing procedures. In this regard, hydroamination of alkynes has emerged as an important tool for synthesizing diversely substituted indoles.13

A mild methodology for the synthesis of 2-substituted indoles was developed by Knochel and group in 2000.14 They reported the use of potassium and cesium salts for

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the intramolecular 5-endo-dig cyclization of ortho-arylethynylanilines to yield the corresponding indoles in good to excellent yields (Scheme 1.7).

Scheme 1.7. Intramolecular 5-endo-dig cyclization of ortho-arylethynylanilines to synthesize indoles

In recent years, a lot of literature is available for tandem synthesis of indoles via hydroamination. Ackermann et al. also used various metal catalysts for the inter- or intramolecular hydroamination of alkynes (Scheme 1.8).15

Scheme 1.8. Tandem synthesis of indoles via hydroamination

A highly efficient double-hydroamination reaction of o-alkynylanilines XXIX with terminal alkynes leading to N- alkenylindoles XXX was developed by using gold(III) by Zhang et al. in 2005 (Scheme 1.9).16

Scheme 1.9. Synthesis of N- alkenylindoles

1.1.2.3 Synthesis of other heterocycles Recently, Zheng et al.17 reported an inter- and intramolecular double hydroamination of primary amines with 1,3-Butadiynes XXXI in the presence of CuCl at 100 °C to afford 1,2,5-trisubsituted pyrroles XXXII in good yields (Scheme 1.10). The advantages of this procedure were readily available starting materials, mild reaction conditions, an inexpensive catalyst, and the high product yields.

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Scheme 1.10. Copper-catalyzed synthesis of 1,2,5-trisubstituted pyrroles

Substituted pyrrolidines are known to exist in numerous natural products and pharmaceutical agents, and display a broad spectrum of biological activities.18 An intramolecular hydroamination of conjugated enyne XXXIII was developed by Tang and group using commercially available nBuLi as a precatalyst (Scheme 1.11).19

Scheme 1.11. Base-catalyzed hydroamination of enynes

HN

R1R2

nBuLi (20 mol %)NR2

R1XXXIII

THF, -78 C, 1h N7R3

R1 = n-pentylR2 = Me

R3 = H, irniine XXXIVaR3 = OMe, irnidine XXXIVb

3 steps

This hydroamination reaction led to products with allene and pyrrolidine functional groups which can be successfully converted to natural products irniine XXXIVa and irnidine XXXIVb in three steps.

A gold-catalyzed cascade cyclization of diynes has been developed recently by Hirano et al. for the generation of fused indoles (Scheme 1.12).20 The reaction was successfully used for the synthesis of aryl-annulated[a]carbazoles, dihydrobenzo[g]indoles, and azepino- or oxepinoindole derivatives XXXVI in good to excellent yields, through an intramolecular cascade 5-endo-dig hydroamination followed by a 6-endo-dig cycloisomerization, without formation of any byproduct.

Scheme 1.12. Synthesis of Aryl-Annulated[a]Carbazoles

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Similarly, pyridines were also successfully synthesized in the literature by the hydroamination of flourine substituted enynes XXXVII and various benzylamines XXXVIII through a cascade process based on anionical C-F bond activation (Scheme 1.13).21

Scheme 1.13. Synthesis of highly substituted pyridines

Liu and group has reported an efficient tandem process of hydroamination and hydroarylation reactions between pyrrole-substituted anilines XL and alkynes XLI using a gold catalyst in toluene at 80 °C over a reaction time of 1–6 h to prepare substituted pyrrolo[1,2-a]quinoxalines XLII in moderate to excellent yields (Scheme 1.14).22

Scheme 1.14. Gold catalyzed synthesis of indolo- and pyrrolo[1,2-a]quinoxalines

Thus, hydroamination triggered cyclizations has become a powerful tool in synthetic organic chemistry and that will probably be used, for an efficient synthesis of numerous N-containing heterocyclic scaffolds, during the next few years.23 Despite the great achievements already accomplished, a number of challenges still remain in the addition of amines onto unsaturated substrates. 1.2 VARIOUS MECHANISTIC APPROACHES FOR HYDROAMINATION

The direct formation of a new C-N bond is thermodynamically feasible under normal conditions but there is a high reaction barrier which is usually avoided by making use

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of catalysts. Nucleophilic addition of amines to non-activated olefins and alkynes is found to be unfavorable due to some thermodynamic and kinetic aspects: 24

� The nucleophilic attack of the amine nitrogen, bearing the lone pair, on the electron-rich nonactivated multiple bonds leads to electrostatic repulsion.

� The high energy difference between Π (C=C) and σ (N-H) orbitals forbids a thermal [2+2] cycloaddition of the N-H bond and the alkene.

� The hydroamination reaction is only slightly exothermic or even thermoneutral. � Because of the highly negative reaction entropy, the reaction is not favored at

high temperatures.

Because of these limitations observed in hydroamination reaction, it was concluded that this efficient reaction can be promoted if:

� C-C multiple bonds were activated towards hydroamination by late transition metals.

� The amine can be activated by oxidative addition to a late transition metal, which allows insertion of the alkene into the M-N or M-H bond, thereby promoting the hydroamination catalytically.

� Strong bases or strongly electropositive metals like alkali, alkaline earth, or the lanthanide group elements, can deprotonate amines to give more nucleophilic amides, which can undergo addition to certain olefins.

� The amine can be activated by being converted into the coordinated imide M=NR using early transition metal complexes or actinides and the reaction of C-C multiple bonds with the M-N bond can then occur.

Most commonly, hydroamination reactions proceeds either by the activation of unsaturated substrate (by coordination to a late-transition-metal center) or by amine activation which utilizes alkali metals to generate highly nucleophilic amido species which are able to attack the unsaturated substrate directly (Scheme 1.15).

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Scheme 1.15.

An alternative amine activation route uses N-H oxidative addition to electron-rich, late transition-metal centers. Recent advances in catalytic aminations are based on the chemistry of early transition-metal and F-element, use of chiral lanthanide complexes for stereospecific cyclizations and shows a considerable symmetric induction potential.3 Furthermore, the alkyne hydroamination is more facile compared to the alkene hydroamination as they are sterically less demanding and their π-bond is about 70 kJ/mol weaker than that in alkenes. 1.3 CONCEPTUAL BASIS AND BACKGROUND OF THE WORK The outline of the present work was prepared after considering importance and various advantages of metal-catalyzed coupling reaction. We have planned to extend the scope of the benzotriazole methodology reported by our group for N-arylation of indoles, imidazoles and other heterocyclic amines.25 Many research groups have used inter- or intramolecular hydroamination of alkynes as an important tool for the synthesis of nitrogen containing diversely substituted heterocycles. In our recent report on copper-catalyzed tandem synthesis of indolo- and pyrrolo[2,1-a] isoquinolines XLVI, the reaction was proposed to undergo via formation of a hydroaminated intermediate XLV (Scheme 1.16).26

Scheme 1.16. Copper catalyzed tandem synthesis of indolo- and pyrrolo[2,1-a] isoquinolines

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With these successful reports on the synthesis of biologically important molecules via hydroamination and strong demand for the development of general, flexible, and regioselective methodologies motivated us to explore the addition of heterocyclic amines onto alkynes. 1.3.1 Addition of heterocyclic amines onto alkynes Among the number of intermolecular hydroamination reactions reported to date, the significant progress has been done on the addition of primary amines to alkenes and alkynes.27 But, very few reports on the addition of secondary and heterocyclic amines onto unsaturated substrates are given in the literature.

In a recent work by Brinkmann et al. the intermolecular hydroamination catalysis of vinylarenes with a variety of primary, secondary and N-heterocyclic amines like piperidine using Ca, Sr, Ba complexes has been reported.28 Nucleophilic addition to an electron-deficient carbon–carbon multiple bond is one of the most fundamental reactions in organic chemistry. While various potential electron-withdrawing groups (EWGs) adjacent to olefin or acetylene are utilized for this process.

In a recent report on the addition of imidazolines to 1-halo-1-alkynes by Urabe and co-workers, a variety of (Z)-(1-Bromo-2-alkenyl)imidazolines XLIX have been prepared in good to excellent yields using DMF (Scheme 1.17).29 These reaction conditions were also found valid for the similar addition of imidazoles.

Scheme 1.17. Preparation of various (Z)-(1-Bromo-2-alkenyl)imidazolines

A cationic Ir(I)-C3-TUNEPHOS complex has also been reported for an intermolecular hydroamination of styrene derivatives with various heteroaromatic amines (Scheme 1.18).30 The reported reaction conditions provided Markovnikov products with perfect regioselectivity and good enantioselectivity under solvent-free conditions.

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Scheme 1.18. Iridium-catalyzed hydroamination of various styrenes

In 2011, the use of a P, N-ligand to support a gold complex as a precatalyst for the stereoselective hydroamination of internal aryl alkynes with dialkylamines to afford E-enamine products has been reported by Stradiotto and co-workers (Scheme 1.19).31 Substrates featuring a diverse range of functional groups on both the amine and alkyne were found to be accommodated with synthetically useful regioselectivity by this methodology.

Scheme 1.19. Gold-catalyzed hydroamination of internal alkynes with dialkylamines

An intense review of literature suggested that there were very few reports on the hydroamination of N-heterocycles. In 1999, the first base catalyzed addition of amines and alcohols onto alkynes was given by Knochel using CsOH.H2O in NMP (Scheme 1.20).32

Scheme 1.20. Cesium hydroxide catalyzed nucleophilic addition onto phenylacetylene

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The addition of alcohols to phenylacetylene yielded cis:trans mixtures due to high reaction temperature and substituted anilines like diphenylamine or N-methylaniline and heterocyclic amines provided the enamine derivatives in 65–79% yield. Some of these substrates yielded selectively the cis-enamine products.

Later, in 2004, a phosphazene base t-Bu-P4 was used for the addition of pyrrole and other nucleophiles onto phenyl- and diphenylacetylene by Kondo and co-workers (Scheme 1.21).33 Apart from O-nucleophiles, diphenylamine also reacted smoothly with diphenylacetylene under the same reaction conditions to give the enamine in quantitative yield. N-Methylacetamide and pyrrole also reacted with the alkyne to give the corresponding enamine product in satisfactory yields.

Scheme 1.21. Phosphazene-catalyzed nucleophilic addition onto phenyl- or diphenylacetylene

With this limited work on the addition of N-heterocycles onto alkynes and as a part of our ongoing research on alkyne chemistry,13 this thesis work reports a novel study on the base-mediated regio- and stereoselective hydroamination of terminal and internal alkynes for the confirmation of the mechanistic pathway of tandem synthesis of [2,1-a]isoquinolines.26

1.4 SCOPE AND OBJECTIVE OF THE WORK DONE

The hydroamination of alkynes is a paradigmatic example of modern, sustainable organic reaction since it is catalytic and occurs with 100% atom economy. This reaction allows the preparation of important nitrogen- containing compounds such as imines, enamines and hydrazones. However, there is not yet a simple method to

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achieve this transformation in a selective, efficient and environmental friendly manner. Among the various classes of catalysts, Ti-complexes have impressively proven to be versatile new tools in organic chemistry that can be used for the addition of all classes of primary amines to all classes of alkynes. While typical Ti-catalyzed intermolecular hydroaminations of alkynes are performed at elevated temperature for several hours, certain catalysts possess improved activities and even offer the possibility to perform selected reactions at room temperature.

Great progress has also been made in controlling the regioselectivity for the hydroamination of terminal alkynes towards the Markovnikov and the anti-Markovnikov product by changing the ligands at the titanium center. Not surprisingly, the combination of the broad scope of the method with the reactivity of the imine products has additionally led to the development of original and efficient new strategies for the synthesis of many interesting classes of compounds such as amino acids, pyrroles, indoles, tryptamines, etc. or even natural products. Late transition metal catalysts like ruthenium and platinum complexes have widely been used for additions of amines to terminal alkynes partly in combination with subsequent C–H activation processes or C–C bond cleavages to give unexpected products in high yields. While Pd- and Au catalysts can also be used for high yielding additions of amines to terminal and internal alkynes. Simple hydroaminations of alkynes can also be performed in liquid–solid and liquid–liquid heterogeneous systems using immobilized Cu-catalysts. While the scope and limitations of corresponding processes are not yet well documented, the major advantage of this approach is the possibility to recover and reuse the catalysts.

In this regard, hydroamination of alkynes has become a very active area of research due to both the synthetic interest of the obtained products (enamines or imines) as well as the theoretical study of their mechanisms. While the intramolecular version of this transformation is well established, the intermolecular counterpart still remains relatively under developed. Thus, most methodologies rely on the use of transition metal-based catalysts. From a

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synthetical point of view, the stereocontrolled synthesis of enamines with a given configuration at the double bond represents an interesting challenge. The present report deals with all of the listed issues: a stereocontrolled intermolecular hydroamination mediated by simple and economical bases.

In continuation of our work in designing of novel ligands for various coupling reactions, we explored the scope of previous approaches for the nucleophilic addition of heterocyclic amines onto alkynes and successfully designed a base mediated selective methodology.14 Present thesis work and reported procedure were proved to be efficient for the synthesis of a wide variety of styryl- and vinyl enamines and enaminone derivatives (Scheme 1.22).

Scheme 1.22. Base mediated selective hydroamination of alkynes

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1.5 THESIS ORGANIZATION In extension of our ongoing work on the ligand designing and synthesis of novel heterocycles by electrophilic cyclization of alkynes, this thesis work consists of four chapters including introduction (first chapter).

Chapter 2: Base-mediated hydroamination of internal alkynes

PART A. Addition of N-heterocycles onto Symmetrical Internal alkynes

PART B. Addition of N-heterocycles onto Unsymmetrical Internal alkynes

Chapter 3: Base-catalyzed hydroamination of terminal alkynes

Chapter 4: Preferential addition of N-heterocycles onto halo-arylalkynes over N- arylation

The chapter wise content is described briefly in the following pages:

CHAPTER 2 Base-mediated hydroamination of internal alkynes

The second chapter is hydroamination of internal alkynes and it is divided into part A and part B (Scheme 1.23). Part A of second chapter shows the addition of various N-heterocycles onto symmetrical internal alkynes. This part also consists of optimization of reaction conditions by varying bases, solvents and temperatures. The regio- and stereoselective addition of N-heterocycles to alkynes using KOH was done and the formation of (Z)-isomers and their conversion to (E)- products were found to be dependent upon time as well as the choice of base. The stereochemistry of the products was established by X-ray crystallographic studies and NOESY data.14a

Scheme 1.23. Hydroamination of internal alkynes

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Part B of the chapter includes the extension of the methodology for the hydroamination of unsymmetrical internal alkynes.14 Selective attack of N-heterocycles on a more electrophilic alkynyl carbon was supported by DFT calculations, and intramolecular cyclization of ortho-haloalkynes in indolo-[2,1-a] isoquinolines.

CHAPTER 3

Base-catalyzed hydroamination of terminal alkynes In the third chapter, the scope of the utility of base KOH have been extended to the regio- and stereoselective addition of heterocycles onto variety of terminal alkynes, which furnished diversely substituted styryl enamines (Scheme 1.24).14

Scheme 1.24. Hydroamination of terminal alkynes

This chapter also includes the hydroamination of 1,3- and 1,4-diethynylbenzenes selectively at one alkynyl carbon and chemoselective addition of N-heterocycles onto various alkynes in the presence of KOH only (Scheme 1.25).

Scheme 1.25. Hydroamination of dialkynes

CHAPTER 4 Preferential addition of N-heterocycles onto halo-arylalkynes over N-arylation The fourth chapter describes the preferential addition of N-heterocycles onto halo-arylalkyne over N-arylation under catalytic conditions (Scheme 1.26).

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Scheme 1.26. Preferential addition of N-heterocycles onto haloarylalkynes over N-arylation

For the first time, a reaction of various N-heterocycles and halo-substituted arylalkynes was performed, and it was observed that under catalytic conditions also, hydroamination is preferred over amination of aryl halide. The results of this study suggested that the mechanism of the copper-catalyzed tandem synthesis of indolo- and pyrrolo[2,1-a]isoquinolines proceeds via generation of intermediate Q through hydroamination followed by oxidative addition to the key intermediate R and not vice versa (Scheme 1.27).14b

Scheme 1.27. Proposed mechanism for the synthesis of [2,1-a]isoquinolines

In summary, we have described a versatile and efficient regio- and stereoselective synthetic method to produce a broad range of functionalized vinyl- and styryl enamines which are useful and versatile synthetic intermediates for the synthesis of biologically active compounds. This metal and ligand free methodology utilizes a simple and economical base KOH and Cs2CO3 for the addition of N-

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heterocycles not only onto terminal and internal alkynes but also for 1,3- and 1,4-dialkynes. Addition of heterocyclic nucleophile onto alkynones has also been reported under mild conditions. Selective attack of N-heterocycles on more electrophilic alkynyl carbon was supported by DFT calculations and stereochemistry of the products was established by X-ray crystallographic studies and intramolecular cyclization of ortho-haloalkynes in to indolo-[2,1-a]isoquinolines.

Current work also supports and confirms the mechanistic pathway for the copper-catalyzed tandem synthesis of indolo- and pyrrolo[2,1-a]isoquinolines via formation of Z-stereoisomer by hydroamination of ortho-haloarylalkyne followed by oxidative addition in the presence of metal and ligand.

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1.6 REFERENCES

1. (a) Lawrence, S. A. in Amines: Synthesis, Properties, and Applications, Cambridge University Press, New York, 2004. (b) Brossi, A. in The Alkaloids: Chemistry and Pharmacology, Vol. 43 (Eds: G. A. Cordell), Academic Press, San Diego, 1993, pp. 119. (c) Daly, J. W.; Garraffo, H. M.; Spande, T. F. in The Alkaloids: Chemistry and Pharmacology, Vol. 43 (Eds: G. A. Cordell), Academic Press, San Diego, 1993, pp. 185.

2. Eller, K.; Henkes, E.; Rossbacher, R.; Höke, H. "Amines, Aliphatic" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2005.

3. For recent Reviews: (a) Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1407. (b) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104. (c) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. and references cited therein.

4. Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett. 2005, 46, 2101. 5. Trost, B. M.; Fandrick, D. R. Org. Lett. 2005, 7, 823. 6. Mujahidin, D.; Doye, S. Eur. J. Org. Chem. 2005, 2689. 7. (a) McGrane, P. L.; Livinghouse, T. J. Am. Chem. Soc. 1993, 115, 11485. (b)

McGrane, P. L.; Livinghouse, T. J. Org. Chem. 1992, 57, 1323. 8. Yin, B. L.; Hu, T. S.; Wu, Y. L. Tetrahedron Lett. 2004, 45, 2017. 9. Iska, V. B. R.; Verdolino, V.; Wiest, O.; Helquist, P. J. Org. Chem. 2010, 75,

1325. 10. (a) Sundberg, R. J. in The Chemistry of Indoles, Academic Press, New York,

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11. Joule, J. A. in Science of Synthesis (Houben-Weyl Methods of Molecular Transformations), 2000, Vol. 10 (Ed.: E. J. Thomas).

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14. (a) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40, 6193. (b) Rodriguez, A.; Koradin, C.; Dohle, W.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2488. (c) Koradin, C.; Dohle, W.; Rodriguez, A.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571.

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