Organometallics in Synthesis - Startseite€¦ · 2 Organometallics in Synthesis, Fourth Manual Contents 1. Introduction 3 2. Click Chemistry: Just Add Copper 4 3. Cu-Catalyzed Aminations

Organometallics in Synthesis Fourth Manual

Organometallics in Synthesis Fourth Manual

Edited by

Bruce H. Lipshutz University of California, Santa Barbara, California, USA

Rh Ni Cu

Au

W I L E Y

Copyright © 2013 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data

Organometallics in synthesis : fourth manual / edited by Bruce H. Lipshutz, University of California, Santa Barbara, California, USA. — Fourth edition.

pages cm Includes bibliographical references and index.

ISBN 978-1-118-48882-9 (pbk.) 1. Organic compounds—Synthesis. 2. Organometallic compounds. I. Lipshutz, Bruce H. QD262.0745 2013b 547\05—dc23 2013009447

Printed in the United States of America.

10 9 8 7 6 5 4 3 2 1

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Contents

Contributors vii

Preface ix

Foreword xii Prof Dr. Reinhard W. Hoffmann

I Organocopper Chemistry 1 Bruce H Lipshutz

II Organorhodium Chemistry 135 Iwao Ojima. Alexandra A. Athan, Stephen J. Chaterpaul, Joseph J. Kaloko, and Yu-Han Gary Teng

III Organonickel Chemistry 317 John Montgomery

IV Organogold Chemistry 426 Norbert Krause

Index 547

v

Contributors

Chapter I

BRUCE H. LIPSHUTZ Department of Chemistry & Biochemistry, University of California, Santa Barbara, CA, USA

Chapter II

IWAO OJIMA ALEXANDRA A. ATHAN STEPHEN J. CHATERPAUL JOSEPH J. KALOKO YU-HAN GARY TENG Department of Chemistry, State University of New York, Stony Brook, NY, USA

Chapter III

JOHN MONTGOMERY Department of Chemistry, University of Michigan, Ann Arbor, MI, USA

Chapter IV

NORBERT KRAUSE Organic Chemistry, Dortmund University of Technology, Dortmund, Germany

vii

Preface

When the first edition of Organometallics in Synthesis, A Manual appeared back in 1994, it offered the community a rare, atypical source of experimental "inside information." It was a stand-alone resource of how to's and why's, written by card-carrying organic chemists with a heavy accent on organic synthesis where the C-C, C-H, and C-heteroatom bonds being made are mediated by metals that serve as either reagents or catalysts. The second edition, published in 2002, was expanded by four metals (from 7 to 11) and surpassed 1200 pages in length. And yet, it was essentially a new book. Now, more than a decade later, the third edition has just appeared. Increasing the length of this monograph, however, was no longer an option from a publishing perspective. So, to do justice to the evolving technologies associated with metals discussed in prior editions, as well as to add metals that had not been covered previously, the Manual was divided, as was the work associated with bringing each to fruition. Thus, in the third edition, Manfred Schlosser oversaw inclusion of chapters focused on organoalkali reagents, as well as those highlighting organo-silicon, -magnesium, -zinc, -iron, and -palladium chemistry, each written, again, by a "who's who" in these prominent areas.

With this fourth edition, the torch has been passed. Chapters can be found on organo-rhodium, -copper, -nickel, and -gold chemistry, where the theme is unquestionably on catalysis. And although this opus is equally split between two precious (Rh, Au) and two base (Ni, Cu) metals, the discussion is heavily, and at times exclusively, devoted to the use of each metal in catalytic quantities. Price is no longer the sole driving force; indeed, environmental considerations have become a major topic in the planning and execution of organic synthesis, regardless of the metal involved.

Three of the four contributing authors in this 4th edition are new to this series; hence, this is the first coverage in the Manual on rhodium, nickel, and gold chemistry. As for copper, this chapter has been completely redone; there is no redundancy whatsoever insofar as prior discussions in earlier editions are concerned. Thus, this monograph compliments the third edition beautifully. And although it may show a different name below as editor, it is likely to continue to be viewed as another worthy addition to the Schlosser Manuals.

BRUCE H. LIPSHUTZ May 2013

ix

Foreword

OMCOS Chemistry: What's the Value?

Analysis and synthesis define the main activities of chemistry that shape the material world around us. Synthesis is the only means to secure new substances and materials when non-natural products are to be studied and to be used. Present-day synthesis of complex organic chemicals is subject to challenging demands: It should be efficient and short, it should be safe and environmentally acceptable, and it should be resource efficient and proceed in high yield, being economically feasible. These concepts imply that the methods by which we do synthesis today need to be constantly challenged as to how well they meet these criteria.

Of the operations to be carried out in synthesis, those that construct the molecular skeleton are the most important and demanding. That is precisely where the development of new methods has brought substantial progress during the last 150 years, and it is in particular the application of organometallic reagents to synthesis that is indicative of the progress made. Imagine the state of synthetic methodology in which there were no organometallic reagents: You are left with certain variants of the Aldol- and Michael-additions, the alkylation of active methylene compounds, the Friedel-Crafts acylation, and the Diels-Alder addition to build the molecular skeleton of your target structures. This is hardly anything more than what nature uses in biosynthesis. Such a restricted arsenal of methods might fascinate some advocates of green chemistry, but it would not be sufficient to address the current practices and needs of medicinal chemistry. It is thus evident that adapting organometallic reagents to the needs of organic synthesis marked the progress in synthetic methodology over the last century; it enabled organic synthesis to fulfill most of the tasks in an acceptable manner, and it constitutes one of the major cultural achievements of chemistry.

Given that situation, one may hold that a Manual of organometallics in synthesis might be more of a historic exercise than an opus that meets the needs of today's chemists. The value of such a Manual, however, becomes evident when one takes the viewpoint of those that apply these methods in synthesis. Those doing actual synthesis of complex target molecules are focused on the synthesis and do not want to lose time or materials by applying methods with which they are not familiar; that is, in general, chemists doing synthesis are highly conservative regarding the methods they apply.

For instance, a survey of (arbitrarily chosen) 41 syntheses of complex natural products carried out in 1981 revealed that more than 70% of the skeleton bond-forming steps fell to enolate and Grignard reactions, the Wittig reaction and cuprate reactions, or what we would call classic organometallic reactions. In the late 1970s, a golden era of organometallics in organic synthesis started, providing the synthetic chemists with olefin metathesis; the Heck, Negishi, Suzuki, and Sonogashira reactions; and many related cross-couplings. Yet, when surveying 58 syntheses of complex natural products published in 2006, these new methods amounted to (already or merely!) 20% of the skeleton bond-forming reactions used, whereas the classic organometallic reactions men-

xi

Xli FOREWORD

tioned lost only 15% of their usage. This underscores the statement that synthetic chemists are slow in taking up new (and, hopefully, more advantageous) methods as long as the older, established ones do not do too badly . The motivation to apply any method (whether old or new) depends on the practitioner's level of confidence in the scope and reliability of the method. Although a time-consuming, thorough literature search could provide this information, chemists tend to get around this and to stick with the familiar methods as long as justifiable. It is clear that it is the work of a small number of daring chemists applying newly described methods in synthesis that provided the basis for a Manual in which scope, usefulness, and reliability of a method can be documented. The merit of such a Manual is invaluable as it gives the majority of synthetic chemists the information to make a reasonable judgment as to which method might best serve their immediate synthetic needs. As the present Manual covers the long established organometallic methods side by side with the methods of younger vintage, it allows the synthetic chemists to make objective choices regarding the methods to be applied. The availability of such a Manual should reduce the reluctance of chemists to apply methods with which they are not (yet) familiar. Therefore, the fourth edition of Organometallics in Synthesis, A Manual is timely and a well-taken endeavor.

PROF. DR. REINHARD W. HOFFMANN

Chapter One

Organocopper Chemistry

Bruce H. Lipshutz

Department of Chemistry & Biochemistry University of California, Santa Barbara, USA

11

Cu

2 Organometallics in Synthesis, Fourth Manual

Contents

1. Introduction 3

2. Click Chemistry: Just Add Copper 4

3. Cu-Catalyzed Aminations and Amidations 16 3.1 Aminations 16 3.2 Amidations 34

4. Cu-Catalyzed O- and 5-Arylations 38 4.1 Diaryl Ether Formation 39 4.2 Diaryl Thioether Formation 46

5. Asymmetric Cu-Catalyzed Borylations 49

6. Oxidations of Organocopper Complexes 58 6.1 Biaryl Syntheses 58 6.2 Aminations 63

7. 1,2-Additions to Imines 64

8. Cu-Catalyzed Asymmetric C-C Bond Formation 70 8.1 Copper Enolates 70 8.2 Conjugate Additions 71 8.3 Asymmetric Allylic Alkylations (AAA) 85

9. Copper Hydride Chemistry 94

10. Miscellaneous Processes 113 10.1 C-H Activation 113 10.2 Protodecarboxylation 115 10.3 Cu-Catalyzed Carbometallation 116

11. Conclusions and Outlook 118

12. Acknowledgments 118

13. References 119

Chapter 1: Organocopper Chemistry, by Bruce H. Lipshutz 3

1. Introduction

Synthetic Chemistry of Cu(I): Still in Focus and "Hot59

Catalysis. It was the buzzword in the 1990s, and certainly insofar as organocopper chemistry is concerned, there has been no letup on this front in the new millennium. Very good reasons exist for this emphasis, both in terms of development of new methodologies as well as in applications. The key driver is usually the cost of waste disposal; whether copper is contained in an aqueous workup mixture, or in amounts greater than the ppm level allowed in pharmaceuticals, it requires attention. Starting with as little copper as possible in a reaction just makes sense, notwithstanding its "base" metal status. So, whereas the accent in previous versions of the Manual was on reagents, this chapter is organized by reaction type and focuses heavily on processes that are catalytic in copper(I). Nonetheless, attention is also directed to traditional albeit stoichiometric copper chemistry, acknowledging the fundamentals that began with Henry Gilman more than 60 years ago[1] and still are very much valued by the synthetic community today.

Within the catalysis manifold, remarkable advances have been brought to light in both asymmetric as well as achiral synthesis. As already witnessed with precious metal-based technologies, such as asymmetric hydrogenations, the metal is important, but the ligands "rule." Research over the past decade has led to several mono- and (mostly) bidentate nonracemic ligands that possess, and translate, their extraordinary innate facial biases as their derived copper complexes to a host of substrate types. Several newly discovered species now present themselves to the practitioner, where enantioselectivities are routinely in excess of 90%. On the other hand, chiral upgrades often allow industrial chemists to realize the desired high levels of enantiometric excesses (ee's) needed in pharma, thereby dettaching any real significance to the "magic" barrier of 90% ee. Nonetheless, the challenges extended by nature to chemists to achieve as close to 100% stereocontrol have not in the past, nor are they likely in the future, to be ignored. Of course, stereocontrol is not the only element that counts in such catalysis; indeed, with up-front costs for copper essentially nonexistent from the perspective of economics, it is turnover number (TON) that may dictate usage. The gap between what academicians may see as "catalytic amounts" (usually 1-5 mol%) and the required low loadings for an industrial process can be hard to fill. Hopefully, some of the progress made as highlighted in this contribution will entice our industrial colleagues.

A wealth of achiral copper chemistry is also covered; in fact, it is still the lion's share of reports in this field. Whether copper(I) in the form of its salts (CuX), perhaps (in situ) derived organocopper species (RCu), or even a cuprate (R2Cu"M+), there is no denying the textbook status of this metal in organic synthesis. Nonetheless, both silver and especially gold chemistry are making astounding advances. But of the group 11 metals, copper still offers the widest variety of synthetically valued chemoselectivities. And while questions regarding mechanisms, aggregation state(s), and structure of organocopper complexes remain, tremendous progress has been


made on these fronts as well. The spirited debate throughout the 1990s on the existence, or not, of "higher order" cuprates provided new incentives for computational, structural, spectroscopic, and physical organic chemistry that has since appeared and has helped to advance the field.

As noted in earlier editions of this Manual, and as is true herein, this chapter is written for the practitioner who faces an ever expanding literature on organometallics. Notwithstanding the emphasis now squarely placed on catalysis, many of the same practical questions arise as highlighted previously, choices of copper salt, solvent, precursor reagent, stoichiometry, and additives, and today, there have been new variables that can play major roles, such as the choice of {e.g., nonracemic) ligand, potential for heterogeneous catalysis, and the option to employ microwave assistance. Thus, with additional insights from several colleagues who have shared their experiences in organocopper chemistry, many of the "secrets to success" are again revealed in this single source. Unfortunately, however, the field is too broad for this opus to be comprehensive; indeed, tough decisions had to be made as to coverage. Thus, there are entire areas even within Cu(I)-catalyzed chemistry that are not included {e.g., cyclopropanations, Diels-Alder constructions, etc.), and surely others that may cause the reader to wonder "What about ...?". The explanation is simple: Each author had a page limitation to his chapter, and it was recommended (mainly as a result of technical matters associated with binding) that the editor not violate his own rules!

2. Click Chemistry: Just Add Copper

Reviews. Diez-Gonzalez, S. Curr. Org. Chem. 2011,15, 2830; Diez-Gonzalez, S. Catal. Sci Technol. 2011, 1, 166; Cantillo, D.; Avalos, ML; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C. Org. Biomol. Chem. 2011, 9, 2952; Elchinger, P-H.; Faugeras, P-A.; Boens, B.; Brouillette, F.; Montplaisir, D.; Zerrouki, R.; Lucas, R. Polymers, 2011, 3, 1607; Becer, C. R.; Hoogenboom, R.; Schubert, U. S. Angew. Chem., Int. Ed. 2009, 48, 4900 {metal-free)', Meldal, M; Tornoe, C. W. Chem. Rev. 2008,108, 2952; Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018; Fokin, V. V.; Wu, P. Aldrichimica Acta 2007, 40, 7; Bock, B. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.


The 2002 papers by the groups of Sharpless[2] at Scripps (La Jolla, CA) and Meldal[3] at the Carlsberg Laboratory (Denmark) highlighting the remarkable acceleration of Huisgen cycloadditions between organic azides[4] and terminal alkynes by Cu(I) have led to an avalanche of renewed interest in, and usage of, copper(I) in synthesis. The facility with which these two relatively high-energy educts "click" to form heteroaromatic 1,2,3-triazoles is truly impressive, and the community at large is

R — H R'N3

Huisgen cycloaddition

Cu(I)-catalysis

S" R

1,4-triazole

t

X N - M N

J^ SN

FT

1,5-triazole

using this chemistry in both routine and highly innovative ways. Importantly, these otherwise thermally driven cycloadditions, which often lead to mixtures of 1,4- and 1,5-disubstituted triazoles,[5] are fully controlled in the presence of Cu(I) to afford only the 1,4-regioisomer[6] (while Ru leads to the corresponding l,5-isomer).[7]

Mechanistic details have not been fully elucidated, but significant progress has been made, most notably by Finn[8a] and Fokin,[8b] and more recently using density functional theory (DFT) calculations.[9] The data suggest involvement of copper(I) acetylides, shown to be associated within a dimeric array. Electron-withdrawing groups on the alkyne increase reactivity. A key point for the synthetic practitioner here is the acid/base chemistry that must ensue en route to the acetylide, implying strong potential influence of base in the medium. Indeed, it is now well accepted that selected bases can dramatically influence rates of click reactions.[6' 10] Curiously, however, the nature of the copper species selected can make a difference in the outcome, with the field narrowing in on two approaches: 1) the original Sharpless protocol using CuS04, a copper(II) salt that is readily reduced in aqueous /-butanol by excess sodium ascorbate {i.e., the inexpensive Na salt of vitamin C).[2] Usually, ca. 1% CuS04 is employed in the presence of excess ascorbate, and with unhindered partners, cycloadditions occur at ambient temperatures in high yields; 2) Cul in organic solvent. Each of these is represented by the two procedures below. A third alternative involving in situ oxidation of Cu(0) is also available[8b] and, although considered of equal efficiency, is less frequently used.

10% CuS04«5H20 sodium ascorbate

(94%)

Copper (I)-catalyzed synthesis of 1,4-disubstituted 1,2,3-triazoles; general procedure. 2 'S-l 7-[l-(2 ',3 '-Dihydroxypropyl)-lH-[l,2,3]-triazol-4-yl]-estradioft2^

17-Ethynyl estradiol (888 mg, 3 mmol) and (S)-3-azidopropane-l,2-diol (352 mg, 3 mmol) were suspended in 12 mL of a 1:1 water//-butanol mixture. Sodium ascorbate (0.3 mmol, 300 |iL of freshly prepared 1-M solution in water) was added, followed by


copper(II) sulfate pentahydrate (7.5 mg, 0.03 mmol, in 100 juL of water). The heterogeneous mixture was stirred vigorously overnight, at which point it cleared and thin layer chromatography (TLC) analysis indicated complete consumption of the reactants. The reaction mixture was diluted with 50 mL of water and cooled in ice, and the white precipitate was collected by filtration. After being washed with cold water (2 x 25 mL), the precipitate was dried under vacuum to afford 1.17 g (94%) of pure product as an off-white powder; mp 228-230 °C.

CuI-DIPEA-catalyzed click chemistry}x 1]

O A ^ P A C X A ^ P A C

A c ( jV ^ N H C 1 4 H 2 9 AGO/ o

Cul, DIPEA, PhMe, rt AcO

VlAr ^ N 3 UJI , DIPEA, PhMe, rt ^ A p - I N=N

(85%)

The azide (20 mg, 0.047 mmol), alkyne (12.7 mg, 0.047 mmol, 1 equiv), and Cul (0.9 mg, 0.004 mmol, 0.1 equiv) were dissolved in toluene (500 jiL) in a glass vial (15.5 x 50 mm). To this mixture was added diisopropylethylamine (8.3 jiL, 0.047 mmol, 1 equiv) and the vial was capped. After stirring for 18 h at room temperature (RT), the crude product was filtered over Celite (Sigma-Aldrich, St. Louis, MO) and purified by flash chromatography on silica gel using as eluent w-hexane/EtOAc (from 1:1 to 1:2). The product (28 mg) was isolated in 85% yield as a single 1,4-regioisomer as an amorphous solid; HR-MALDI-FTMS calcd. for CaaHsÔnNa [M + Na]+, 705.3681; found 705.3681.

Click chemistry with copper metal. 2,2-Bis((4-phenyl-lH-l,2,3-triazol-l-yl)-methyl)-propane-1 y 3-diofSb]

. INk Ph HO HOv I f ' V " ^ N 3 + M — p h

c o p p e r m e t a l , N = N ] N - ^ N3^Y " " H20/t-BuOH ' P h - V O S T 7

7 rt, 24 h 7 HO ( 9 8 % ) HO

Phenylacetylene (2.04 g, 20 mmol) and 2,2-Z>/s(azidomethyl)-propane-l,3-diol (1.86 g, 10 mmol) were dissolved in a 1:2 /-butyl alcohol/water mixture (50 mL). About 1 g of copper metal turnings was added, and the reaction mixture was stirred for 24 h; after which time, TLC analysis indicated complete consumption of starting materials. Copper was removed, and the white product was filtered off, washed with water, and dried to yield 3.85 g (98%) of pure Ws-triazole product; mp 211-212 °C; ESIMS m/z: 391.2 (M + H+) 413.2 (M + Na+).

Stabilized Cu(I) in the form of its N-heterocyclic carbene (NHC) complex, e.g., (SIMes)CuBr (SIMes = AÂr,-6/5(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene), and the cyclohexyl analog [(ICy)2Cu]PF6, catalyzes click reactions very well in aqueous /-butanol, and even better in water alone.[12] Low conversions were noted in nonaqueous solvents such as tetrahydrofuran (THF), /-BuOH, and dichloromethane (DCM). Starting from an alkyl bromide, triazoles could be smoothly generated by in situ conversion to the corresponding azide (aqueous NaN3) followed by copper-catalyzed cycloaddition. This is but one example of the potential for combining several steps in a single flask that culminates with a click reaction (vide infra). The


alternative use of CuBr(Ph3P)3 (0.5 mol%) in these 3-component couplings with NaN3 (1.3 equiv) at room temperature is also best carried out in water as solvent.[13]

NaN3(1.05equiv) ■ ^

5% (SIMes)CuBr ^ N ^ ^ fl—= water, rt, 30 min " N ' C7H15-A7

(92%) F

SIMes

In general, as suggested by the above examples, outstanding compatibility exists among azides, 1-alkynes, and copper(I) along with the product triazoles with a vast array of other functional groups that may be present in either educt. Steric factors do exert an effect on rates. In most situations, the beneficial impact of a trialkylamine base (e.g., /-Pr2NEt and l,4-diazabicyclo[2.2.2]octane [DABCO]) or others (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene [DBU] and 2,6-lutidine) is used to great advantage, in particular when less soluble Cul in toluene (or even CH3CN) is the catalyst. A recent study suggests that in the presence of catalytic amounts of HO Ac, together with i-Pr2NEt (1:1), rapid quenching of the intermediate copper species occurs leading to enhanced reaction rates.[14] The counterion in the Cu(I) salt (e.g., Br, I, and OAc), or the Cu(II) precursor to catalytically active Cu(I) (e.g., -OAc and -N03) can exert influence. Microwave assistance can reduce reaction times from hours to minutes, although yields are mostly unaffected by this mainly thermal phenomenon. Tandem events in one-pot include initial azide formation by halide substitution resulting in a net three-component coupling all under microwave irradiation (procedure below).

,NX ° / = \ _ . S 0 2 N 3 100/0 Cul U(-f~T\t~

y^ 2,6-lutidine CHCI3, 0 °C, 12 h // V

o

2 (90%)

Remarkable is the in situ conversion of amines into azides by Cu(II)-catalyzed diazo transfer in a mixed aqueous environment (using trifluoromethanesulfonylazide, TfN3), followed by click cyclization.[15] Ligands such as ^ra(benzyltriazolylmethyl)amine (TBTA) and clickphine (below) have been used to accelerate these copper-catalyzed cycloadditions.[16] Recently, conditions have been found that lead to 7V-sulfonyl-4-substituted-l,2,3-triazoles using sulfonylazides (e.g., 1 to 2), avoiding products from competing ring-opening oc-diazoimino tautomers.[17a] Reactions are best run in chloroform at 0 °C using catalytic Cul, giving yields in the moderate-to-high range. In a mixed aqueous solvent environment, or water alone, the corresponding 7V-tosylated amides are formed in good yields, rather than the corresponding triazoles.[17b] Sequential displacement of oc-tosyloxy ketones by azide ion and subsequent one-pot cyclization in a polyethylene glycol (PEG)/water mixture at room temperature leads to carbonyl-containing triazole derivatives.[18]

Organometallics in Synthesis, Fourth Manual

Phf N T \

l \ k M / \ N" "Ph

PPh?

9\ N

N

L ligand TBTA

// N

I M

clickphine ligand

Sequential one-pot process for diazo transfer and azide-alkyne cycloaddition using CuS04 and sodium ascorbate[l5]

NHFmoc

HOOCT

1. TfN3, 2% CuS04

NaHC03, rt, 30 min

2. 30% Na ascorbate 5% ligand, ^W 80 °C, 20 min

[ligand = TBTA]

NHFmoc

HOOC

(94%)

Triflyl azide (TfN3) was freshly prepared prior to each reaction. NaN3 (6 equiv per substrate amine) was dissolved in a minimum volume of water (solubility of NaN3 in water is approximately 0.4 g/mL). At 0 °C, an equal volume of DCM was added and triflic anhydride (Tf20; 3 equiv) was added dropwise to the vigorously stirred solution. After stirring for 2 h at 0 °C, the aqueous phase was once extracted with DCM. The combined organic phases were washed with sat. NaHC03 solution and used without further purification. The amine, Fmoc-Lys-OH (81 mg, 0.22 mmol), CuS04 (2 mol%), and NaHC03 (1 equiv) were dissolved/suspended in water (equal volume relative to DCM used for TfN3). The TfN3 solution was added, followed by addition of methanol until the mixture became homogeneous. The reaction was stirred at RT (ca. 30 min) until TLC showed complete consumption of the amine. Phenylacetylene (24 JLIL, 0.22 mmol) was added, then ligand TBTA (5 mol%), and then sodium ascorbate (30 mol%), and the reaction was heated to 80 °C in the microwave until complete loss of azide (<30 min). The reaction mixture was then diluted with water and the organics extracted. Solvents were removed under reduced pressure. After flash chromatography (CHCl3/MeOH/AcOH 96:3:1), the product (103 mg, 94%) was isolated as a white powder. ESIMS (MeOH): m/z calcd. for 495.2 [M-H]"; found 495.3.

General procedure for microwave-assisted, three-component coupling reactions. 4-Phenyl-1 - (3,4,5-trimethoxybenzyl)-lH-l, 2,3-triazole[ 19]

M e C T ^ f ^ + NaN3 + H-OMe

-Ph Cu(0), CuS04

» H20/t-BuOH, H W 15 min, 125 °C

(91%)

The benzylic halide (1.0 mmol), phenylacetylene (1.1 mmol), and sodium azide (1.1 mmol) were suspended in a 1:1 mixture of water and r-BuOH (1.5 mL each) in a 10-mL glass vial equipped with a small magnetic stirring bar. To this was added copper wire (50 mg) and copper sulfate solution (200 uL, 1 N), and the vial was tightly sealed with an aluminum/Teflon crimp top. The mixture was then irradiated using an irradiation power of 100 W (CEM Discover instrument; Matthews, NC). After completion of the reaction, the vial was cooled to 50 °C and then diluted with water (20 mL) and filtered.


The residue was washed with cold water (20 mL), 0.25-N HC1 (10 mL), and petroleum ether (50 mL) to furnish the product triazole in 91% yield; EIMS [M+]: 325 (100%).

Although aqueous /-butanol is commonly employed according to the original recipe, click cyclizations between 1-alkynes and aryl or aliphatic azides can be realized "on water" at room temperature.[20] Copper(I) bromide (5 mol%) in the presence of thioanisole (50 mol%) leads for most substrates within minutes (or hours with selected cases, such as with azidothymidine [AZT], below) to good isolated yields of triazoles. Good functional group tolerance is evident, especially given the "green" conditions used (i.e., water as the medium, and no additional energy input).

General procedure for copper-catalyzed cycloadditions of aliphatic and aryl azides with alkynes to triazoles "on water "[20]

O

Y NH ^ N " ^ 0 1 H ^ ^ N ^ O cat. CuBr L"°NJ

V "l0'"'5h J1 a r* N3 Boc.^N^pN

AZT H O (88%)

Water (1-2 mL), alkyne (0.6 mmol), azide (0.5 mmol), CuBr (0.05 mmol, 7.5 mg), and thioanisole (0.25 mmol, 31 mg) were added to a flask with a stir bar, and the mixture was stirred at RT without exclusion of air. After total consumption of the starting azide (by TLC), the resulting solution was poured into a water/EtOAc mixture. After extraction of the aqueous phase with EtOAc, the combined organic layers were dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by rotary evaporation, and the crude product was purified on a short silica gel column using EtOAc/petroleum ether (v/v, 10:1 to 1:1) as eluent to give the product triazole.

The potential for sequential copper-catalyzed processes can also be illustrated in the case of formation of fully substituted l,2,3-triazoles.[21] In this sequence, the same copper catalyst is promoting two distinct types of catalysis: [3+2]-cycloaddition and arylation via "C-H activation." Each reaction type tolerates both electron-rich and -poor substrates, as well as steric hindrance, adding noteworthy breadth to this scheme. A 4-component sequence using NaN3, rather than an alkyl azide, is shown below. The diamine DMEDA (N, N'-dimethylethylenediamine) is used to stabilize the copper catalyst.

P h — = + PhCH2N3

:-0-F M 1. cat. Cul, DMF, 60 °C

2. I-

LiO-t-Bu, DMF, 140 °C NN Bn

(79%)


Representative procedure; synthesis of a 1,4,5-trisubstituted-triazole^ 1]

f\ 1. cat. Cul , DMF, rt . ^ 1 DMEDA (15 mol %) B U \ / '

B u - ^ ^ + NaN3 + II I *- r=\ OMe r 2l ! H N \yy

MeO V ^ LiO-t-Bu, 140 °C, 20 h (81%)

To a suspension of Cul (19 mg, 0.10 mmol, 10 mol%) and NaN3(69 mg, 1.05 mmol) in AÂf-dimethylformamide (DMF) (3 mL) was added 1-hexyne (82 mg, 1.00 mmol), 3-iodotoluene (234 mg, 1.00 mmol), and AyV'-dimethylethylenediamine (13 mg, 0.15 mmol, 15 mol%), and the mixture was stirred under N2 at RT for 2 h. Then, LiO- -Bu (160 mg, 2.00 mmol), 2-iodoanisole (702 mg, 3.00 mmol), and DMF (2.0 mL) were added and the resulting suspension was stirred under N2 at 140 °C for 20 h. Upon cooling to RT, Et20 (50 mL) and H20 (50 mL) were added, and the separated aqueous layer was extracted with Et20 (2 x 75 mL). The combined organic layers were washed with sat. aq. NH4C1 (50 mL), H20 (50 mL), and brine (50 mL), and then they were dried over anhydrous Na2S04. Concentration in vacuo gave a residue that was purified by column chromatography on silica gel («-hexane/EtOAc 12/1 to 10/1) to yield the product as an off-white solid (260 mg, 81%).

Several heterogeneous catalysts have been shown to effect related multicomponent couplings. These include cross-linked polymeric ionic liquid material-supported copper (Cu-CPSIL), silica-dispersed CuO (CuO/Si02), and imidazolium-loaded Merrifield resin-supported copper (Cu-PSIL),[22] all of which can be used in water at room temperature to arrive at l,4-disubstituted-l,2,3-triazoles from alkyl halides, NaN3, and terminal alkynes. Each can be filtered and reused several times with minimal loss of efficacy. Multistep flow synthesis,[23] specifically including generation of underused vinyl azides and their subsequent click conversions to vinyl triazoles, has also been reported.[24]

Access to regio-defmed trisubstituted triazoles (i.e., with substituents at the 5-position), using an acetylenic halide (in particular, bromide), has been reported.[25]

The resulting derivative allows for subsequent manipulation, including metal-halogen exchange, assuming compatibility within the remaining portion(s) of the educt. Mechanistically, it remains unclear how the sequence proceeds, but in light of the exclusive isomer formed, a copper acetylide intermediate is likely.

OBn OBn N02 / = \ N 3 \ ^ 20% CuBr2 \ - IVU.M (?

0,N_/ V ^ + BnO-Ô .^-Br 2—+ BnO-^-0 J N ( U 2 N N^J/ B n O - w ^ ^ - ^ 20% Cu(OAc)2 BnO~**^^VN

OBn THF,50°C 0 B n [ Br

(99%)

AMJnsubstituted 1,2,3-triazoles are also readily prepared using trimethylsilylazide (TMS-N3) as a precursor to in situ generated HN3 in the presence of methanol (or water).[26] Using Cul and nonactivated terminal alkynes, high yields of 4-substituted products result, as shown below. Cu powder is also useful for these


cycloadditions, while other salts with group 11 metals (e.g., AuCl3 and AgCl) were totally ineffective, as was ZnCl2. Noteworthy is that bulky acetylenes (e.g., TIPS-acetylene) and conjugated networks (e.g., an enyne) clicked under standard conditions (DMF/MeOH, 9:1, 0.5 M, 100 °C, 10-24 h).

TIPSQ

TMS-N3

5% Cul

TIPSO DMF, MeOH 100 °C, 20 h

N

(84%)

Representative procedure for the synthesis ofN-unsubstituted 1,2,3-triazoles^

^ cat. Cul

+ TMS-N3

DMF/ MeOH (9:1)

100 °C, 12 h (83%)

Trimethylsilylazide (0.1 mL, 0.75 mmol) was added to a DMF and MeOH solution (1 mL, 9:1) of Cul (4.8 mg, 0.025 mmol) and /?-tolylacetylene (58 mg, 0.5 mmol) under Ar in a pressure vial. The reaction mixture was stirred at 100 °C for 12 h in a tightly capped 5-mL microvial. After completion, the mixture was cooled to RT and filtered through a short pad of Florisil and concentrated in vacuo. The residue was purified by silica gel column chromatography («-hexane/EtOAc 10:1 to 2:1) to afford 66 mg of 4-(p-tolyl)-lH-l,2,3-triazole (83%).

N-Allylated 1,2,3-triazoles, where the allyl moiety is positioned at either N-\ or N-2, can be generated regiospecifically by virtue of a Pd-Cu bimetallic-catalyzed, three-component coupling.[27] Terminal alkynes and in situ formed HN3 (see procedure above) undergo Huisgen cycloaddition, as expected when Cu(I) is present. However, with both catalytic Pd(0) and an allylic carbamate in the pot, TV-de-ally lation/re-allylation can afford either regioisomer (Scheme 1-1). The combination of Pd2(dba)3*CHCl3/CuCl(PPh3)/P(OPh)3 leads exclusively to 2-allylated products, while switching the copper/phosphine source to CuBr2/PPh3 inverts the product ratio entirely favoring N-\ allylated, 1,4-disubstituted triazoles. The presence of P(OPh)3 in the former cyclization is crucial for regiocontrol. Nonpolar solvents decreased yields, while more polar media gave mixtures. For the latter, the absence of phosphine led to no reaction (recovery of alkyne); other sources of copper (e.g., CuBr and CuCl2) produced a mixture of triazoles.

p h w H N

(83%)

2.5% Pd2(dba)3

10% CuCI(PPh3)3

20% P(OPh)3

EtOAc, 100 °C

2% Pd(OAc)2

2% CuBr2

8% PPh3

toluene, 80 °C

3 (88%)

Scheme 1-1

Representative procedure for the synthesis of 1-allyltriazoles (3)[27]

To a toluene solution (1 mL) of Pd(OAc)2 (2.3 mg. 0.01 mmol), PPh3 (10.5 mg, 0.04 mmol), and CuBr2 (2.2 mg, 0.01 mmol) were added phenylacetylene (55 fxL, 0.5 mmol),


allylmethylcarbonate (68 jiL, 0.6 mmol), and TMSN3 (80 jiL, 0.6 mmol) under an Ar atmosphere. The reaction mixture was stirred at 80 °C for 3 h in a tightly capped 5 mL microvial. After completion, the mixture was cooled to RT and filtered through a short pad of Florisil (U.S. Silica Co., Frederick, MD) with Et20 (-100 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc 20:1 to 2:1) to afford 81.3 mg of l-allyl-4-phenyl-lH-[l,2,3]-triazole

Applications of click chemistry are already far too numerous to acknowledge by even offering an example from each area herein. Some of these areas include dendrimers, polypeptides, polymeric materials, conformationally restricted macrocycles, new ligand designs, and carbohydrates. One representative procedure is provided below. A related study describes sugar-based silica gels for use as hydrophilic interaction chromatography (HILIC) for separation of monosaccharides.[28]

Heterogeneous polysaccharide click chemistry[29]

AcQ

HO-\ (S)-tartaric acid

(5 mol %)

5-hexynoic acid, neat, 110 °C, 6 h

w N 3

Cu(II), Na ascorbate H20:MeOH:EtOAc-l : l : l

highly fluorescent

Reactions were performed in dried glass tubes sealed with plugs that contain an activated drying agent. 5-Hexynoic acid (3.4 mmol) and tartaric acid (0.17 mmol) were mixed in glass vials, and known amounts of paper samples (17 mg) were introduced into the mixture. The vials were sealed with screw caps, and the reactions were run for 6 h at 110 °C. After cooling, the filter papers were Soxhlet extracted using DCM and water, respectively. The samples were dried prior to further analysis. The cellulose paper was added to Wang's probe 4 (25 mg, 0.1 mmol) in water/methanol/EtOAc (1:1:1, v/v, 5 mL). Next, a freshly prepared solution of sodium ascorbate (20 JLIL, 0.02 mmol, 1 M) in water and a 7.5% solution of copper(II) sulfate pentahydrate in water (17 JIL, 0.005 mmol) were added. The heterogeneous mixture was stirred vigorously overnight in the dark at RT. Finally, the cellulose paper was extensively washed with cold water and Soxhlet extracted using DCM and water. The synthesized probes were analyzed using !H and 13C nuclear magnetic resonance (NMR) spectroscopy. The cellulose samples were analyzed directly (Perkin-Elmer Spectrum One FT-IR; Waltham, MA). The fluorescence of the derivatized cellulose samples was analyzed using a Leica (Allendale, NJ) fluorescence microscope with an excitation/emission filter cub (filter cub A): excitation (kex) =340-380 nm and emission (êm) = >425 nm.

Solid-phase click chemistry in organic solvents (e.g., DMF and THF) works well, seemingly independent of the support. Resins such as polystyrene and polyethylene glycol (PEGA) attest to tolerance to both nonpolar and polar types. As outlined in the original Meldal et al papers,[3] novel triazole-containing polypeptides


are realizable based on heterogeneous 4-hydroxymethylbenzoic acid (HMBA)-PEGA8oo-bound acetylene substrates that "click" in THF with excess Cul/Hunig's base at room temperature.[3] Conversions were high (>95%), and all amino acids examined participated offering considerable prospects for synthesis of large libraries of novel products.

Solid phase click chemistry. General procedure to peptidotriazoles] ,[3]

oT r?\ ol AA?OÎ ,*> o\ fp\ ol

L J 2 THF, rt, 16 h A c Q

/ h 9 rphH ol

H H°6^PN=N [H J J 2 HO

NaOH

OH 2

H20

(>95%)

1 -(2-Deoxy-1 -thiophenyl-oc-D-galactopyranos-2-yl)- l//-[ 1,2,3]-triazol-4-ylcarbonyl-Phe-Gly-Phe-Gly-OH. DIPEA (50 equiv), Cul (2 equiv), and phenyl-3,4,6-tri-0-acetyl-2-azide-2-deoxy-l-thio-oc-D-galacto-pyranoside (2 equiv) were added to resin-bound alkyne (5 mg of resin, ca. 2 (imol swollen in 200 JIL of THF) and reacted for 16 h at 25 °C. The resin was then washed with THF, water, and THF again. A sample was cleaved using aqueous NaOH, and the product was analyzed by high-profile liquid chromatography (HPLC) and mass spectrometry (MS). Conversion was >95% with 75-99% purity. ESIMS: m/z calcd. for (MH+) Csv^NyOioS*: 776.3; found: 776.8.

Insofar as heterogeneous Cu(I)-catalyzed click chemistry is concerned, new catalysts continue to appear. Nanoparticles of copper can be generated and used in aqueous solution, from which crystalline products often precipitate. Inclusion of copper (as CuCl) into Lewis acidic zeolites, using in particular "Cu(I)-USY" (pore size 6-8 A), is one such catalyst employed in toluene.[30] Other solvents such as DCM, CH3OH, CH3CN, and benzene were not recommended, and yields of 1,4-disubstituted triazoles can be highly variable.

Nanoparticles of Cu(0) powder that undergo oxidation in the presence of an amine hydrochloride lead to active Cu(I).[31] The amine is presumed to play several roles: reduction of Cu(II) to Cu(I); stabilization of Cu(I) as ligand; and enhancement of solubility of copper in organic media. Nanosize clusters also catalyze click reactions, in this case in H20//-BuOH at 25 °C without salts.[32] A simplified route to copper nanoparticles (CuNPs) relies on CuCl2, lithium metal, and catalytic amounts of 4,4'-di-*-butylbiphenyl (DTBB) in THF at ambient temperatures.[33] They exist as a range of nanospheres mainly between 1 and 6 nm, as analyzed by transmission electron microscopy (TEM). Terminal alkynes and a variety of azides can be cyclized in THF (88-98% isolated yields) between room and refluxing temperatures. Cycloadditions take place within 10-30 minutes, and simple filtration suffices to remove the catalyst. Recycling of CuNPs, however, is not an option.


P h N ^ \ £°2Et 10% CuNPs \ \-J

Et02CCH2N3 + P h — ^ *• I W THF, Et3N, A, 30 min N

(88%)

An extensive study has been made on the catalyst "copper-in-charcoal" (Cu/C; Sigma-Aldrich #70910-7), where Cu(N03)2 has been impregnated into the pores of commercially available activated charcoal.[34] The solid support relies on readily available wood (and not coconut) charcoal (Aldrich, catalog #242276) of 100 mesh size. Larger size particles with less surface area do not lead to active catalyst, while finer grades (i.e., higher mesh sizes) are too difficult to handle to be practical. Only Cu(N03)2 can be used as the source of copper, where mounting, based on literature precedent (albeit at much higher temperatures), reportedly relies on loss of oxides of nitrogen [(NO)x] resulting in both Cu20 and CuO within the charcoal matrix. Other copper salts possessing alternative counterions (halides, acetate, etc.) are apparently readily washed out during processing to Cu/C. Nanoparticle distribution of copper aggregates are formed by simply mixing Cu(N03)2 and charcoal in water, followed by ultrasonication, distillation, and finally drying. The free-flowing charcoal, in general, is best stored away from light, air, and moisture, although its use as a catalyst specifically for click reactions requires no such precautions; i.e., it can be placed in a container (vial, bottle, etc.) on the shelf. More recently, a streamlined procedure has been developed that eliminates the distillation step. Thus, by mixing Cu(N03)2 + charcoal in water, ultrasonication of the mixture in a standard bath overnight, and filtration, the resulting (wet, or dried) Cu/C is active. The modified procedure for the preparation of Cu/C is as follows.

Simplified preparation of Cu/C} 41

1. H20, ultrasound Cu(N03)2*3H20 + charcoal *• "Cu/C"

2. drying

Darco KB-activated carbon (50.0 g, 100 mesh, 25% H20 content) was added to a 500-mL round-bottom flask containing a stir bar. A solution of Cu(N03)2

#3H20 (Acros Organics [Geel, Belgium], 11.114 g, 46.0 mmol) in deionized H20 (100 mL) was added to the flask and deionized H20 (100 mL) was further added to wash down the sides of the flask. The flask was loosely capped and stirred in air for 30 min, and then submerged in an ultrasonic bath for 7 h. Subsequent filtration and washing (H20, then toluene) followed by air drying (3 h) by vacuum suction yielded ca. 85 g of "wet" Cu/C. The catalyst can be used at this stage, or further dried in vacuo at 120 °C overnight, to yield 44 g of "dry" Cu/C.

Click reactions mediated by Cu/C require no special precautions with respect to handling; reaction partners can be weighed out in air, as can the catalyst. Without additives of any kind (e.g., reducing agents, base, ligands, etc.), mild heating to 60 °C is enough to complete the conversion into triazoles. Significant rate enhancements are to be expected when Et3N is present (only 1 equiv), used "out of the bottle," and most reactions with unhindered educts take place at ambient temperatures. Solvents ranging from nonpolar (e.g., toluene) to 100% water give similar results. Most examples to date, however, have been run in undistilled dioxane (although toluene is, in fact, the preferred solvent), open to air. Microwave heating to 150 °C reduces the


time requirements for typical cycloadditions in the absence of base from a few hours (at 60 °C) to <5 minutes with no loss in regioselectivity (i.e., only 1,4-triazoles are formed). Higher-than-average molecular weight products can be made using this catalyst (e.g., 7). Yields in almost all cases reported exceed 90%. Cu/C can be recovered by filtration and recycled several times without erosion of efficacy. Control experiments and ICP-AES (inductively coupled plasma-atomic emission spectroscopy) suggest that little bleeding of copper into solution is occurring.

Procedure for Cu/C-catalyzed "click" reaction^

MeCT^f^' 3 Cu/C, TEA, dioxane M e O ^ ^ ^ ^ OTs 6 0 ° c ' 30 min 0 T s

5 7; MW = 1029 (87%)

Cu/C (50 mg, 1.01 mmol/g, ca. 0.05 mmol) is added to a clean 10-mL flask fitted with a stir bar and septum. Dioxane (2 mL) is added slowly to the sidewalls of the flask, rinsing the catalyst down. While the heterogeneous mixture is stirred, triethylamine (0.153 mL, 1.1 mmol), azide 5 (0.377 g, 1.0 mmol), and alkyne 6 (0.783 g, 1.2 mmol) are added. The flask is stirred at 60 °C, and the reaction progress is monitored by TLC until complete consumption of azide has occurred. The mixture is filtered through a pad of Celite to remove the catalyst, and the filter cake is further washed with EtOAc to ensure complete transfer. The volatiles are removed in vacuo to give the crude triazole, which was further purified via flash chromatography with 5:1 hexanes/EtOAc as eluent yielding 0.891 g of colorless oil (87%).

Yet here is another approach that, in this case, avoids solvent altogether, and leads to rapid and ligand-free cycloaddition reactions run in a planetary ball mill (e.g., see http://www.fritsch-milling.com/products/milling/planetary-mills/pulverisette-7-classic-line/). High conversions and selectivities are to be expected using Cu(OAc)2 in catalytic amounts (5 mol%), with reaction times on the order of only 10 minutes.[35]

Bottom-line comments. Copper-catalyzed click chemistry is experimentally too easy and works too well in most cases not to be strongly considered as a means of "stitching" together just about any terminal alkyne and azide. The regiospecificity for 1,4-disubstituted heteroaromatic triazoles is complemented by the corresponding ruthenium-catalyzed cycloadditions to afford 1,5-adducts. And with options for heterogeneous processes, microwave-assisted thermal rate enhancements, and solvent-free conditions, click chemistry has become, and rightfully so, a tremendously powerful tool in synthesis.


3. Cu-Catalyzed Aminations and Amidations

Reviews. Zhang, M. Synthesis 2011, 3408; Sadig, J. E. R.; Willis, M. C. Synthesis 2011, 1; Rao, H; Fu, H. Synlett 2011, 745; Das, P.; Sharma, D.; Kumar, M ; Singh, B. Curr. Org. Chem. 2010, 14, 754; Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954; Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054; Ma, D.; Cai, Q. Ace. Chem. Res. 2008, 41, 1450; Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337.

3.1 Aminations

Modern amination reactions of both aromatic and heteroaromatic rings have become some of the most valuable tools in synthesis, especially to the medicinal chemist. Problems associated with traditional Ullmann-like couplings to form di- and tri-arylamines, such as stoichiometric levels of copper in solution, have been largely solved using more recent transition-metal-based catalysis. While palladium-catalyzed processes offer considerable promise and have been enthusiastically embraced by industry,[36] extensive efforts to update copper as an inexpensive, viable alternative have, indeed, led to significant advances. And as with palladium catalysis, much of the story is focused on associated ligands,[37] although the nature of the base, and/or the solvent, surely plays an important role. Many combinations of substrate/amine are possible; that is, educts can be aryl or heteroaryl halides or pseudohalides, while amines can be 1° or 2°, aryl, diaryl, alkyl, dialkyl, heteroaromatic, etc. In addition, derivatives of amines (e.g., amides) can also serve as nucleophilic partners. Akin to developments with palladium catalysis, studies on aryl halides as substrates began with iodides and have more recently concentrated on bromides. Some preliminary work on aryl chlorides using catalytic Cu20/NaO-/-Bu in hot iV-methyl-2-pyrrolidone (NMP) have led to reasonable yields of aniline products.[38] However, no general methodology yet exists for such aminations of aryl chlorides based on Cu(I), although this is likely to appear in the not-too-distant future. Preliminary work employing Cu nanoparticles that catalyze cross-couplings of activated chlorides with imidazoles looks especially promising.[39] Studies on the origin of copper(I) catalysis initiating from copper(II) precursors, using ultraviolet (UV)-vis spectroscopy and *H NMR analyses on phenanthroline complexes, have shown that reduction occurs in situ, with both the amine and the base being required for the proposed P-hydride elimination sequence.[40]

rf^V* / ^ c a t Cu(I) r x ^ r / N V R-4- T + H-N ► R-f- T f

Table 1-1 lists many of the more successful combinations involving aryl iodides or bromides, highlighting the variety of both (substituted) amines and recommended ligands. Some trends are clear: Usually, highly polar solvents are involved together with carbonate or phosphate bases. Ligands are both noticeably variable (e.g., among amino acids) and often structurally unrelated, and they can be

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Organometallics in Synthesis - Startseite€¦ · 2 Organometallics in Synthesis, Fourth Manual Contents 1. Introduction 3 2. Click Chemistry: Just Add Copper 4 3. Cu-Catalyzed Aminations