Name Reactions for Carbocyclic Ring Formations
Edited by Jie Jack Li
Bristol-Myers Squibb Company
Foreword by E. J. Corey Harvard University
WILEY A JOHN WILEY & SONS, INC., PUBLICATION This page intentionally left blank Name Reactions for Carbocyclic Ring Formations Wiley Series on Comprehensive Name Reactions Jie Jack Li, Series Editor
Name Reactions in Heterocyclic Chemistry Edited by Jie Jack Li
Name Reactions of Functional Group Transformations Edited by Jie Jack Li
Name Reactions for Homologation, Part 1 and Part 2 Edited by Jie Jack Li
Name Reactions for Carbocyclic Ring Formations Edited by Jie Jack Li Name Reactions for Carbocyclic Ring Formations
Edited by Jie Jack Li
Bristol-Myers Squibb Company
Foreword by E. J. Corey Harvard University
WILEY A JOHN WILEY & SONS, INC., PUBLICATION Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
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Library of Congress Cataloging-in-Publication Data:
Name reactions for carbocyclic ring formations / edited by Jie Jack Li ; foreword by E.J. Corey. p. cm. Includes index. ISBN 978-0-470-08506-6 (cloth) 1. Ring formation (Chemistry) I. Li, Jie Jack. QD281.R5N36 2010 547'.2—dc22 2010008429
Printed in the United States of America.
10 987654321 Dedicated to Professor Keith R. Fagnou
June 27,1971-November 11, 2009 This page intentionally left blank Contents foreword Preface xi Contributing Authors XV
Chapter 1 Three-Membered Carbocycles 1 1.1 Freund Reaction 2 1.2 Kishner Cyclopropane Synthesis 7 1.3 Kulinovich Cyclopropanol Synthesis 13 1.4 Simmons-Smith Cyclopropanation 25
Chapter 2 Four-Membered Carbocycles 45 2.1 Staudinger Ketene Cycloaddition 45
Chapter 3 Five-Membered Carbocycles 71 3.1 Danheiser Annulation 72 3.2 Dieckmann Condensation 93 3.3 Favorskii Rearrangement 109 3.4 Nazarov Cyclization 122 3.5 Pauson-Khand Reaction 147 3.6 Weiss-Cook Reaction 181
Chapter 4 Six-Membered Carbocycles 197 4.1 Bardhan-Sengupta Pheantherene Synthesis 198 4.2 Bergman Cyclization 209 4.3 Bogert-Cook Reaction 222 4.4 Bradsher Cycloaddition and Bradsher Reaction 236 4.5 Bradsher Reaction 251 4.6 Darzens Synthesis of Tetralin Derivatives 267 4.7 Diels-Alder Reaction 275 4.8 Dötz Benzannulation 309 4.9 Elbs Reaction 324 4.10 Fujimoto-Belleau Reaction 336 4.11 Haworth Reaction 342 4.12 Moore Cyclization 356 4.13 Myers-Saito Cyclization 369 4.14 Robinson Annulation 386 4.15 Scholl Reaction 409
VII Vili
Chapter 5 Large-Ring Carbocycles 423 5.1 Buchner Reaction 424 5.2 de Mayo Reaction 451 5.3 Ring-closing Metathesis (RCM) 489 5.4 Thorpe-Ziegler Reaction 578
Chapter 6 Transformations of Carbocycles 589 6.1 Blanc Chloromethylation Reaction 590 6.2 Asymmetric Friedel-Crafts Reactions: Past to Present 600 6.3 Houben-Hoesch Reaction 675 6.4 Kolbe-Schmitt Reaction 688 6.5 Vilsmeier-Haack Reaction 698 6.6 von Richter Reaction 710
Appendices
1, Contents Volume 1: 717 Name Reactions in Heterocyclic Chemistry 2, Contents Volume 2: 720 Name Reactions for Functional Group Transformations 3, Contents Volume 3: 722 Name Reactions for Homologations—Part I 4, Contents Volume 4: 724 Name Reactions for Homologations—Part II 5, Contents Volume 6: 726 Name Reactions in Heterocyclic Chemistry—Part II
Subject Index 729 Foreword
Part of the charm of synthetic organic chemistry derives from the vastness and multidimensionality of the intellectual landscape. First, there is the almost infinite variety and number of possible target structures that lurk in the darkness waiting to be made. Then there is the vast body of organic reactions that serve to transform one substance into another, now so large in number as to be beyond credibility to a nonchemist. There is the staggering range of reagents, reaction conditions, catalysts, elements, and techniques that must be mobilized in order to tame these reactions for synthetic purposes. Finally, it seems that new information is being added to that landscape at a rate that exceeds the ability of a normal person to keep up with it. In such a challenging setting, any author or group of authors must be regarded as heroic if through their efforts, the task of the synthetic chemist is eased. This volume on methods for formation of carbon rings brings to the attention of practicing synthetic chemists and students of chemistry a wide array of tools for the formation of such rings by synthesis. Since cyclic structures are among the most useful molecules, it is a valuable addition to the literature that will prove its merit for years to come. The new knowledge that arises with its help will prove to be of great benefit to humankind.
E. J. Corey February 1,2010
ix This page intentionally left blank Preface This book is the fifth volume of the series Comprehensive Name Reactions, an ambitious project conceived by Professor E. J. Corey of Harvard University in the summer of 2002. Volume 1, Name Reactions in Heterocyclic Chemistry, was published in 2005. Volume 2, Name Reactions for Functional Group Transformations was published in 2007. Volumes 3 and 4 on homologations were both published in 2009. They have been warmly received by the organic chemistry community. After this Volume 5, Name Reactions on Carbocyclic Ring Formations is out in 2010, we will roll out the final volume, Volume 6 on Name Reactions in Heterocyclic Chemistry—Part II, in 2011. Continuing the traditions of the first four volumes, each name reaction in Volume 5 is reviewed in seven sections: 1. Description, 2. Historical Perspective, 3. Mechanism, 4. Variations and Improvements, 5. Synthetic Utility, 6. Experimental, and 7. References. I also introduced a symbol [R] to highlight review articles, book chapters, and books dedicated to the respective name reactions. I have incurred many debts of gratitude to Professor E. J. Corey. What he once told me — "The desire to learn is the greatest gift from God" — has been a true inspiration. Furthermore, it has been my great privilege and a pleasure to work with a collection of stellar contributing authors from both academia and industry. Some of them are world-renowned scholars in the field, some of them have worked intimately with the name reactions that they have reviewed, some of them even discovered the name reactions that they authored in this series. As a consequence, this volume truly represents the state-of-the-art for Name Reactions for Carbocyclic Ring Formations. I welcome your critique.
Jack Li February 1,2010
xi This page intentionally left blank Jie Jack Li and E. J. Corey, circa 2002 This page intentionally left blank Contributing Authors:
Dr. Nadia M. Ahmad Dr. Paul Galatsis Takeda Cambridge Medicinal Chemistry 418 Cambridge Science Park Pfizer Global Research & Development Cambridge Eastern Point Road CB4 OPA Groton, CT 06340 United Kingdom Professor Brian Goess Dr. Jeffrey A. Campbell Department of Chemistry Department of Chemistry Furman University Lehigh University 3300 Poinsett Highway Bethlehem, PA 18015 Greenville, SC 29613
Dr. Louis S. Chupak Dr. Martin E. Hayes Discovery Chemistry Medicinal Chemistry Bristol-Myers Squibb Company Abbott Bioresearch Center 5 Research Parkway 381 Plantation Street Wallingford, CT 06492 Worcester, MA, 01605
Dr. Timothy T. Curran Professor Nessan Kerrigan Chemical Development Department of Chemistry Vertex Pharmaceuticals Oakland University 130 Waverly Street 2200 North Squirrel Road Cambridge, MA 02139 Rochester, MI
Professor Roman Dembinski Dr. Ewa Krawczyk Department of Chemistry Department of Heteroorganic Chemistry Oakland University Centre of Molecular & Macromolecular 2200 North Squirrel Road Studies Rochester, MI 48309 Polish Academy of Sciences Sienkiewicza 112 Dr. Matthew J. Fuchter 90-363 Lodz, Poland Department of Chemistry Imperial College London Dr. Jie Jack Li London SW7 2AZ Discovery Chemistry Bristol-Myers Squibb Company 5 Research Parkway Wallingford, CT 06492
XV XVI
Noha S. Maklad Professor Kevin M. Shea Medicinal Chemistry Department of Chemistry Pfizer Global Research & Development Clark Science Center Eastern Point Road Smith College Groton, CT 06340 Northampton, MA 01063
Professor Richard J. Mullins Professor Nicole L. Snyder Department of Chemistry Hamilton College Xavier University 198 College Hill Road 3800 Victory Parkway Clinton, NY 13323 Cincinnati, OH 45207-4221 Dr. Stephen W. Wright Dr. Kevin M. Peese Medicinal Chemistry Discovery Chemistry Pfizer Global Research & Development Bristol-Myers Squibb Company Eastern Point Road 5 Research Parkway Groton, CT 06340 Wallingford, CT 06492 Dr. Yong-Jin Wu Dr. Frank Rong Discovery Chemistry ChemPartner Bristol-Myers Squibb Company No. 2 Building, 998 Halei Road 5 Research Parkway Zhangjiang Hi-Tech Park, Pudong Wallingford, CT 06492 Shanghai, China 201203 Chapter 1 Three-Membered Carbocycles 1
1.1 Freund Reaction 2 1.2 Kishner Cyclopropane Synthesis 7 1.3 Kulinovich Cyclopropanol Synthesis 13 1.4 Simmons-Smith Cyclopropanation 24 Name Reactions Carbocyclic Ring Formations
1.1 Freund Reaction
Frank Rong
1.1.1 Description
The Freund reaction refers to the formation of alicyclic hydrocarbons by the reaction of sodium on open chain dihalo compounds.1
1.1.2 Historical Perspective
In 1882 Freund reported that treating trimethylene glycol with hydrobromic acid gave trimethylene dibromide, which was further treated with sodium in reflux temperature. As a result the sodium dissolved, the sodium bromide was precipited, and a gas from the reaction was collected. What is the gas? By treacting with bromine it went back to trimethylene dibromide. By treacting with hydriodic acid it gave iodopropane. Therefore, the gas was concluded to be cyclopropane for the first time.1 This reaction has been called the Freund reaction on occasion. However, reference to the original literature shows that although Freund was the first to make cyclopropane itself, he used an extension of the Wurtz reaction and therefore had no claim to the method of ring closure that employs zinc in the presence of protonic solvent. Gustavson published in 1887 a paper titled "Concerning a New Method of Preparation of Trimethylene."2 Gustavson and Popper extended this method to the preparation of substituted cyclopropanes; using zinc dust-treated trimethylene dibromide gave cyclopropane.2'3 In 1936 Hass reported addition of sodium iodide to the zinc dust and 1,3-dichloropropane reaction mixture, both the yield of cyclopropane and the conversion rate were changed singnificantly.
1.1.3 Mechanism
The mechanism of Freund reaction is more likely as same as the Wurtz reaction, a free-radical mechanism. In the presence of iodide ions, the pathways might be a combination of substitution (SNI or SN2) with a free- radical mechanism.3 Chapter 1 Three-Membered Carbocycles 3
Na Br' ~Br Δ
Δ
1.1.4 Variations and Improvements
Gustavson reported a new method in the preparation of cyclopropane.2 Treating trimethylene dibromide (10 g) with zinc dust (12 g) suspended in aqueous alcohol at 50-60 °C gave cyclopropane. He tried different ratios of alcohol to water and found without water the reaction was very slow and at least 2% water was needed. Hass has further modified the Gustavson reaction condition.4 By using a large excess of zinc dust and by raising the temperature of the reaction mixture with high-boiling solvents, the rate of conversion was increased materially. When sodium iodide was added to a refluxing mixture of zinc dust, ethanol, and 1,3-dichloropropane, a marked acceleration of the reaction rate occurred. For example, using 1 mole of anhydrous sodium carbonate for each mole of 1,3-dichloropropane, a 100% excess of zinc dust, and 1/6 mole of sodium iodide in a solvent consisting of 75% ethanol and 25% water, a 95% yield of crude cyclopropane was obtained in 12 h in the same apparatus as before. A better yield and purer product were obtained if both sodium carbonate and acetamide were employed. The 1,3- dichloropropane was prepared by the chlorination of propane obtained from natural gas. This is called as Hass cyclopropane process.
1.1.5 Synthetic Utility
The cyclopropane was an important anesthetic in 1930s. Galasso said: "The safest anesthetic agent—the one which presents all the good qualities and none of the objectional side effects of the agents we have on hand— cyclopane."5 This drug has been manufactured execusively by the following reaction sequence.
2HBr Br' ^Br + 2 H,0 (1) 4 Name Reactions Carbocyclic Ring Formations
Zn (or Mg) 2 - A + ZnBr2 (or MgBr2) ( )
The 1,3-propanediol (trimethylene glycol) was obtained as a by- product of the soap industry, where it exists as a minor impurity in the glycerol. However, both 1,3-propanediol and hydrobromiic acid are relatively expensive compared to propane and chlorine.4 Hass process made the production of cyclopropane more cost effective. Shortridge and co-workers reported an extension of the Gustavson method for the synthesis of cyclopropane and its derivatives. They successfully prepared spiranes containing a cyclopropane ring and provide an easy, straightforward way of producing this type of hydrocarbon in quantity and in a good state of purity. The corresponding dibromide 1 was cyclized by zinc in aqueous ethanol to give spirane 2 in excellent yield.
Br/>T^Br - R^ Ri R2 EtOH/H20 Δ
1
CHa HaC^V^^CH·, H3C CH,
Yield: 3:92% 4:94% 5:91% 6:89%
H0 CH3 OH ^ρΒ^ H3C CH3CH3 _Ξΐ „ H3C
HC/\^CH3 Br-^-^Br 0 °C to r.t. H3C^\7 n-PrOH / H20 7 8 9
The Freund reaction for the preparation of cyclopropane derivatives has in certain cases been unsatisfied due largely to the formation of olefins as the principal product. In general primary-primary 1,3-dibromides give high yields, primary-secondary dibromides give good yields. Secondary- secondary dibromides give fair yields, and all condensations involving a tertiary bromide give products containing an olefin as the principal or sole product. Bartleson and co-workers found that this problem can be solved at low terperature for the ring closure reaction.7 The 1,1,2- trimethylcyclopropane 9 was prepared from 2-methyl-2,4-dibromopentane 8 by the Freund reaction at low temperature. The yield of crude product was Chapter 1 Three-Membered Carbocycles 5
86% and the purity can reach 95% by fractional distillation in a high efficiency distilling column. The l,2-dimethyl-3-ethylcyclopropane 12 was similarly synthesized from 3-methyl-2,4-dibromohexane 11.7 A yield of 90% was obtained in the ring closure step. The secondary-tertiary and secondary-secondary 1,3- dibromides, 8 and 11, were prepared in 90% yields by the reaction of phosphorus tribromide with the diols, 7 and 10, at low temperature (-24 °C). The low temperature prevents the loss of hydrogen bromide from the reaction mixture.
CHa CH OH OH pBr3 CH3 { Zn
H3C" ^Υ ^" 3 Br"^Y^Br o°Ctor.t. x^^. ^CH, H C CH3 CH3 n-PrOH/H20 3 10 11 12
1.1.6 Experimental
Preparation of 1,1-dimethylcyclopropane (14)6
Zn Br" X" ^Br H3C CH3 EtOH/H20 H3CX CH3
13 14
In a 2 L three-necked flask equipped with a dropping funnel, mercury-sealed stirrer and reflux condenser (connected to a trap surrounded by a dry ice- acetone bath) were placed 900 mL 95% ethanol, 90 mL distilled water and 628 g (9.6 mol) zinc dust; it was necessary to maintain vigorous stirring at all times to prevent caking of the zinc. The mixture was brought to gentle reflux, and 562 g (2.4 mol) of l,3-dibromo-2,2-dimethyl-propane 13 was added dropwise at the temperature. Heating and stirring were continued for 24 h after the last of the dibromide had been added; the bulk of the hydrocarbon collected in the trap during this period. The remaining 1,1- dimethylcyclopropane (along with some alcohol) was then distilled from the reaction flask and was collected in the trap. The crude product 14 (162 g) was washed with ice water and dried. The product 12 was obtained in 96% yield (based on distilled dibromide) with these physical properties: b.p. 20.63 20 °C (760 mm) and « D 1.3668. 6 Name Reactions Carbocyclic Ring Formations
Preparation of 1,1,2-trimethylcyclopropane (9)7
The reaction was carried out in a 1 L, three-necked flask fitted with a reflux condenser, thermometer, dropping funnel and mercury sealed stirrer. To the flask was added 100 mL water, 300 mL «-propyl alcohol and 196 g oxygen- free zinc dust prepared from commercial-grade zinc dust. The flask was placed in an ice-bath and 244 g (1 mol) of freshly distilled 2-methyl-2,4- dibromopentane was added dropwise with efficient stirring over a period of about 90 min. The icebath was then removed and the mixture was stirred at room temperature for about 32 h. After about 10 h an immiscible layer of hydrocarbon had formed. At the end of the reaction the hydrocarbon product was separated by distillation. The crude product 9 was collected over a temperature range of 49-51 °C and weighed 78.1 g, a yield of 86%. The 20 refractive index of the crude product was « D 1.3847. The crude product was further purified by fractional distillation in a high-efficiency distilling column to give 95% pure product 9 with these physical properties: b.p. 52.1 °C (736 mm) and n2\ 1.3850.
1.1.7 References
1. Freund, A. Monatsh. 1882, 3, 625-635. 2. Gustavson, G. J. Prakt. Chem. (2) 1887, 36, 300-303. 3. Gustavson, G.; Popper; J. J. Prakt. Chem. (2) 1898, 58, 458. 4. Hass, H. B.; McBee E. T.; Hinds, G. E.; Gluesenkamp, E. W. Ind. Eng. Chem. 1936, 28, 1178-1181. 5. Galasso, Anesth. and Anaiges. 1936,15, 32. 6. Shortridge, R. W.; Craig, R. A.; Greenlee, K. W.; Derfer, J. M.; Boord, C. E. J. Am. Chem. Soc. 1948, 70, 946-949 7. Bartleson, J. D.; Burk, R. E.; Lankelma, H. P. J. Am. Chem. Soc. 1946, 68, 2513-2518. Chapter 1 Three-Membered Carbocycles
1.2 Kishner Cyclopropane Synthesis
Frank Rong
1.2.1 Description
Kishner cyclopropane synthesis refers to the formation of cyclopropane derivatives 3 by decomposition of pyrazolines 2 formed by reacting α,β- unsaturated ketones or aldehydes with hydrazine.1
1.2.2 Historical Perspective
In 1912 Kishner and Zavadovsku reported the synthesis of phenylcyclopropane by heating decomposition of 5-phenyl-3-pyrazoline.' The Kishner cyclopropane synthesis has become wellknown due to its unique and the smallest cyclic core structure.2
1.2.3 Mechanism
It is believable that the pyrazoline, 4 or 5, undergoes thermolytic decomposition and gives the diradicai 6 first. Then, the diradicai formed a bond quickly to give the cyclopropane 7. ' This could be a reversible reaction between the diradicai 6 and the cyclized product 7.
R ^ 2 R >v 22 R Rl^NCÌ _ Rl^/N^R . R.. XV , 2 R_ ^2 ^R 3 J J -NH N=N •R3
4 5
Stereochemical crossover in the pyrolysis of 3,5-disubstituted pyrazolines was proposed.3'4 The observation of a stereochemical crossover phenomenon stimulated a consideration of the mechanism from a different viewpoint. The loss of molecular nitrogen in the pyrolysis of a cis-3,5- disubstituted pyrazoline, cis-8, might be expected to give a trimethylene 8 Name Reactions Carbocyclic Ring Formations intermediate that could cyclized to a cw-disubstituted cyclopropane 10, if internal rotations were slow, or to a mixture of eis- and /raws-cyclopropanes, if internal rotations were fast. In the later case, the eis- and /raws-pyrazoline, 8 and 9, should give identical mixtures of cyclopropanes 10 and 11. The experimental facts, however, are inconsistent with either of these models since the stereochemistry of the cyclopropane product in each case is predominantly (3:1) opposite to that of the pyrazoline. Obviously, a stereorandomized trimethylene cannot be the sole intermediate. In fact, the stereochemistry of deazetation of pyrazolines is still not completely understood.
H H H CH3 X% H3C°\ /''CH3 H3C \ /'Ή 3 N=N J ó ISFN c/s-8 trans-9 major minor minor
HVVCH3 H3C CH3 H3CT^H
10 11
The research groups of McGreer5,6 and Crawford7-11 have done comprehensive investigation on the cyclic azo compounds thermal decomposition. Crawford's group investigated the stereochemistry problem in the thermal decomposition of eis- and ira«s-3,5-dimethylpyrazolines (12 and 13).7 The major products of these decompositions are the stereoisomeric dimethylcyclopropane, and the major pathway is apparent single inversion of stereochemistry in each case. Crawford and Mishra rationalized these observations by assuming that the pyrazolines decompose in the envelope conformation leading directly to 0,0 intermediates. Predominant conrotatory closure then leads to overall single inversion of stereochemistry.7
H/,VY.»CH3 + Η/..Λ..,Η
H3C H H3C CH3
12) R1 = R3 = CH3 and R2 = R4 = H frans- 66.1% eis- 33.2% 13) R-, = R4 = CH3 and R2 = R3 = H frans- 25.4% eis- 72.6% Chapter 1 Three-Membered Carbocycles 9
One of the most difficult mechanisms to rule out rigorously involves the possibility than only one C-N bond breaks initially, leading (in the case of trans-pyrazoline 14 or 15) to diradicai 16. If the radical center at C-2 is now required to carry out a backside displacement of N2 at C-4, a product of the correct stereochemistry is produced.12 However, Crawford and his co- workers have carried out a number of elegant studied that provide support for a mechanism that involves simultaneous cleavage of both C-N bonds.7"11
H Λ CH, un A „CH 3
" H3 C*lw ^ >H N-NH N=N " N2 14 15 16
H^/U H C*§ V"H 3 CH3 n3^ w" 'a H3C CH3
17 18 19
/. 2.4 Variations and Improvements
A couple of different approaches in the synthesis of pyrazolines were shown. Crawford and Ohno synthesized a 40:60 mixture of eis- and trans-3,5- divinyl-1-pyrazoline, 21 and 22, by adding a concentrated solution of vinyldiazomethane 20 in diethyl ether, purified by distillation, to a large excess of 1,3-butadiene maintained as a liquid in a pressure bottle at low temperature.8 The intermolecular 1,3-cycloaddition of the diazoalkane proceeded more rapidly than the intramolecular cyclization to pyrazole. The kinetic of the thermolysis of these compounds in diphenyl ether at 35-65 °C producing divinylcyclopropane 23 were studied by measuring the rate of nitrogen evolution. They concluded that both carbon-nitrogen bonds are being broken in the rate determining step.8
©Θ N=N N=N Ph20 N=N butadiene ^/ y* <^l \j, heat II H2° -80 °C 20 21 22 23
The eis- and fran,s-3-ethyl-5-vinyl-l-pyrazoline, 25 and 26, were similarly prepared by the cycloaddition of 1-diazopropane 24 to 1,3- butadiene. The mixture of cis-25 and trans-Id (18% eis, 82% trans, by NMR) was heated at 120 °C for 2 h. The product proportions were 10 Name Reactions Carbocyclic Ring Formations determined by GC to be 57% eis- and 43% ira«5-ethyl-2-vinylcyclopro-pane, 27 and 28, respectively.
ΘΘ butadiene N=N N=N =N=N + H,C- H3C. 1 V // H3CN Jt \n^
24 25 eis I trans =18/82 26
Ph20 ^ + f 120 °C, 2h CH3 CH3 27 28 eis I trans = 57/43
7.2.5 Synthetic Utility
A great attention has been paid on the cyclopropane derivatives after Kishner reported his discovery due to the similarities between olefins and cyclopropane with respect to both their chemical and physical properties. ' Cyclopropane resembles ethylene in some respects, and both systems can enter into conjugation with other unsaturated groups such as a carbonyl group, a phenyl group, or a pyridyl group. Smith and Rogier synthesized the 2-phenylbicyclopropyl by the Kishner method.13 The styryl cyclopropyl ketone 29 was converted to pyrazoline 30, which was decomposed at 220 °C to give the 2-phenylbicyclopropyl 31 in 74% yield. The physical and chemical properties of this compound were also studied. The results indicated that this compound does not exhibit any of the conjugative effect shown by phenylcyclopeopane.
29 30 31
Mishra and Crawford reported the synthesis of (3R,5R)-(+)-trans-3,5- dimethyl-1-pyrazoline 35 by different approach starting from alcohol 32.7 The pyrazoline 35 undergoes thermolysis, producing 25.6% of trans-1,2- dimethyl-cyclopropane 36, processing 23% optical purity, and having the SV·!) configuration. Chapter 1 Three-Membered Carbocycles 11
1)Hg(OAc) H PBr5 CH3 0H 2 Bf HO^^-CH3 ^ DN2H4 N=N _Nz Λ t Λ % M Π3H3C^\X'"CH υΠ33 " H»C3 ° ^CH< 3, Η,Ο^3 C 3 2) Na2C03 ° ^ ^ ^ ~''~' ^ ^ ^ 3)HgO 35 (3R:5R) 36 (1S:2S) 37(1R:2S) Crawford and Tokunaga synthesized 3,3,5,5-tetramethyl-4- methylene-1-pyrazoline 41 by a different approach.10 The tetramethyl-4- pyrazolidone 39 was prepared by the reaction of hydrazine with α,α'- dibromodiisopropylketone 38. Then oxidizing 39 by Mn02 gives intermediate 40, which was converted to 41 by following Mock's procedure.14 O o ° H3CX X fH3 N2H4 H3C U CH3 Mn02 HgC^J^CHa Η3 3 N_N CH3CH3 °ΗΝ-ΝΗ 38 39 40 CH2 Η Ph3PCH2 3<\ U CH3 3 ό N=N 41 They also studied the thermolysis of the compound 41.10 They found the thermolysis of 41 proceeds at 1/63 the rate of 4-methylene-l-pyrazoline. The 41 is undergoing thermolysis by a mechanism different from that for 4- methylene-1-pyrazoline. The 2,2,3,3-tetramethylmethylenecyclopropane 42 produced rapidly isomerizes under the reaction conditions to 2,2- dimethylisopropylidenecyclopropane 43. The four opposed methyl groups of 42 have created sufficient ground state destabilization as to cause its isomerization to be 147 times faster than the conversion of 2,2- dimethylmethylenecyclopropane 44 to isopropylidenecyclopropane 45. 12 Name Reactions Carbocyclic Ring Formations 41 / \ CH2 H3CVv/CH3 II Π 3 \J ^J_V*^ w Π 3 Ä-CH3 H3C CH3 CH3 42 43 H3C\^CH3 2 CH3 A 44 45 /. 2.6 Experimental Preparation of phenylcyclopropane 47.15 // \ /. heat HN'N -N2 46 47 A mixture of 118 g 5-phenyl-3-pyrazoline 46, prepared by published procedure; 30 g pulverized potassium hydroxide; and 2.5 g platinized asbestos was heated in a 1 L, three-necked flask equipped with a stirrer and a Claisen distillation head. The temperature was raised slowly and the heat was shut off at the first sign of reaction. When the exothermic reaction ceased the temperature was again raised and the product was distilled. Both the distillate and the residue were steam distilled and the steam distillate was taken up in ether and dried first with sodium sulfate and then with sodium and redistilled. The product 47 was collected at 60-63 °C (11 mm Hg) and was finally redistilled giving a colorless oil, 11.5 g (12%), b.p. 173.5 °C (740 mm Hg), 20 and « D 1.5320. Preparation of 2-phenylbicyclopropyl (31)13 Preparation of 3-cyclopropyl-5-phenyl-2-pyrazoline (30): Styryl cyclopropyl ketone 29 (42 g, 0.245 mol) was added to a solution of aqueous hydrazine (25 mL, 0.42 mol) in ethanol (95%, 70 mL); the mixture became Chapter 1 Three-Membered Carbocycles 13 warm and acquired a green color. It was allowed to stand for 45 min., then warmed on the steambath for 1 h, after which excess hydrazine and solvent were removed under reduced pressure. Distillation of the residue gave 30 as a light green liquid (37.8 g, 86%), which boiled at 164 °C (1 mm Hg). Preparation of 2-phenylbicyclopyl (31): Powdered potassium hydroxide (7.2 g) and platinized asbestos (3.2 g) were placed in a 100 mL round-bottomed flask arranged for distillation, and immersed in a metal bath. The bath was heated to 220 °C (thermometer in the bath), and the pyrazoline 30 (38.8 g, 0.2 mol) was slowly added. After the rapid evolution of nitrogen cased, the product 31 was distilled from the reaction mixture; it distilled at 92-96 °C (0.8 mm Hg), and weighed 22.5 g (74%). The products from several runs were combined and fractionated through a column (15 x 1.5 cm) packed with glass helices. A center cut was taken for analysis. This boiled at 57 °C (0.12 mm), and had n 90 D 1.5352, a 904 0.9587, and molar refraction 51.40. 1.2.7 References 1. Kishner, N. M.; Zavadovskii, A. J. Russ. Phys. Chem. Soc. 1912, 43, 1132. 2. [R] Berson, J. A. in Rearrangements in Ground and Excited Slates vol. 1, P. de Mayo, Academic Press, New York, 1980, pp 326-329. 3. [R] Bergmann, R. G. in Free Radicals, vol. 1, J. Kochi, Wiley, New York, 1973. Pp 191- 230. 4. Crawford, R. J.; Mishra, A. J. Am. Chem. Soc. 1965, 87, 3768. 5. McGreer, D. E.; Chiù, N. W. K.; Vinje, M. G.; Wong, K. C. K. Can. J. Chem. 1965, 43, 1407. 6. McGreer, D. E.; McDaniel, R. S.; Vinje, M. G. Can. J. Chem. 1965, 43, 1389-1397. 7. Mishra, A.; Crawford, R. J. Can. J. Chem. 1969, 47, 1515-1519. 8. Crawford, R. J.; Ohno, M. Can. J. Chem. 1974, 52, 3134-3139. 9. Crawford, R. J.; Erickson, G. L. J. Am. Chem. Soc. 1967, 89, 3907. 10. Crawford, R. J.; Tokunaga, H. Can. J. Chem. 1974, 52,4033-4039. 11. Crawford, R. J.; Mishra, A. J. Am. Chem. Soc. 1966, 55, 3963. 12. Roth, W. R.; Martin, M. Ann. 1967, 702, 1. 13. Smith, L. I.; Rogier, E. R. J. Am. Chem. Soc. 1951, 73, 3840-3842. 14. Mock, W. L. Ph.D. thesis, Harvard University, Cambridge, MA, 1964. 15. Hammond, G. S.; Todd, R. W. J. Am. Chem. Soc. 1954, 76,4081^1083. 14 Name Reactions Carbocyclic Ring Formations 1.3 Kulinkovich Cyclopropanol Synthesis Jie Jack Li 1.3.1 Description 0 2 equiv. EtMgBr X R 0.1eq.Ti(/-PrO)4 \7 1 THF/Et20(4:1) 2 Kulinkovich cyclopropanol synthesis, also known as Kulinkovich reaction or Kulinkovich cyclopropanation, is titanium-catalyzed transformation of esters 1 to its corresponding cyclopropanols 2.1 9 The EtMgBr/Ti(7-OPr)4 mixture resulting in bis-ethoxytitanacyclopropane is known as the Kulinkovich reagent, which is considered a synthetic equivalent of a two-carbon-1,2- e e dianion synthon ( CH2CH2 ). /. 3.2 Historical Perspective Professor Oleg Grigor'evich Kulinkovich,10 a student of I. G. Tischenko of the Tischenko reaction fame, discovered the titled reaction in 1989 at Belorussian State University.11^14 The unprecedented transformation has received great attention and utility, as testified by the references cited herein. 1.3.3 Mechanism Kulinkovich himself proposed that the dialkoxytitanacyclopropanes as the key intermediate in the Kulinkovich cyclopropanation.1 Extensive theoretical study on mechanism was published in 2001.15 Eisch also provided detailed exploration of the mechanism for the Kulinkovich reaction in 2003.16 In 2007, Kulinkovich proposed a modified "ate" complex mechanism for titanium-mediated cyclopropanation of carboxylic esters with Grignard reagents.17 Summing up the state-of-the-art understanding, the mechanism may be described as the following: When Ti(0/-Pr)4 was mixed with the ethyl Grignard reagent, they react to provide diethyl titanium intermediate 3, which immediately undergoes ß-elimination with formation of the titanacyclopropane 4 and with release of ethane gas. Next, a nucleophilic attack at the ester carbonyl furnishes the titanoxacyclopentane 5. Rearrangement to the homoenolate with concomitant activation of the carbonyl group allows for an intramolecular attack of the titanium-carbon Chapter 1 Three-Membered Carbocycles 15 bond to give the titanium cyclopropane alkoxide 6. Metal exchange reaction with excess of Grignard reagent liberates the product as the magnesium alkoxide 7 and regenerates the catalytically active species 3. H3C CH3 2EtMgBr /-PrOMgBr Ti(;-PrO)4 ► (R30)2Ti -CH3 3, R3 = /-Pr or R2 2 H+ Ri OMgBr + R3OH * „ „ 3, R =/-Pr or R + R OMgBr 3 2 2 EtMgBr 1.3.4 Variations and Improvements HQ H CH3 0.1 eq. CITi(i'-PrO)3, 2 eq. n-PrBr 4 eq. Mg, THF, 18-20 °C, 79% Initially, the ethyl Grignard reagent was successfully employed in the prototypical Kulinkovich reaction. In 1994, Corey demonstrated that when chlorotitanium(IV) triisopropoxide was better suited for higher substituted Grignard reagents, such as «-butylmagnesium bromide, can be used.18 As exemplified by transformation 8 to 9, the reaction was completely diastereoselective to give the cz's-1,2-dialkylated cyclopropanol 9. Furthermore, Corey also carried out the preliminary studies of an enantioselective version of the cyclopropanol synthesis with promising 16 Name Reactions Carbocyclic Ring Formations results. Employing a chiral TADDOL-based titanium reagent, 85:12 to 89:11 enantio-selectivity was achieved. The other significant variation of the prototypical Kulinkovich reaction is the so-called Kulinkovich-de Meijere reaction, where de Meijere extended the substrates from esters to amides.19'20 Other carboxylic acid derivatives including (cyclic) carbonate, imides, and nitriles also react with the key Kulinkovich intermediate. Szymoniak21 developed an efficient new synthesis of cyclopropanes via hydrozirconation of allylic ethers (e.g., using Cp2Zr(H)Cl) followed by addition of a Lewis acid (e.g., BF3»OEt2). Casey et al. further investigated the stereochemistry of this interesting cyclopropanation reaction using deuterated allylic ethers. 1. 2.5 eq. EtMgBr, 1 eq. Ti(/-PrO)4 9 2. -78 °C to 20 °C (THF) \7 FT^NBn2 Rr"NBn2 + 10 3. H30 11 1.3.5 Synthetic Utility 1.3.5.1 General Utility In general, esters, acid chlorides, and anhydrides are most reactive toward the Kulinkovich reagent. Carbonates and thioesters are of moderate reactivity, whereas carbonamides are least reactive. Case in point was made by chemoselective Kulinkovich reaction of succinic ester-amide 12. Cha observed that only the ester portion underwent the Kulinkovich reaction to afford cyclopropanol 13. Szymoniak24 demonstarted that nitriles are more reactive than ester and amides. ° Ù^ / c-C5H9MgCI HO I O "0' "-" ^f ^ 0.8 eq. (/-PrO)3TiCI 12 O *■ Γ 13 rt, 58% "\ ^-""^OTIPS I OTIPS Cha's group was among the earlier researchers to investigate and extend the utility of the Kulinkovich reaction. Employing 4-alkoxybutyyl Grignard reagents such as 15 (several other Grignard reagents such as 2- phenethylmagnesium bromide did not work) and chlorotitanium(IV) triiso- propoxide converted cyclopropanol 16 as a single diastereomer.25 Chapter 1 Three-Membered Carbocycles 17 HQ 15 ,MgCI C02Me TIPSO 14 16 (/-PrO)3TiCI, 60% OTIPS An important contribution from Sato and Cha was their successful extension of the Kulinkovich reaction to the intramolecular version. For instance, reductive coupling of carboxylic ester 17 with a terminal olefin provided bicyclo[3.1.0]hexan-l-ol (18) in 71% yield.27 Cha also extended the low-valent titanium-mediated cyclopropanation to vinylogous esters as substrates. An interesting application is an intramolecular version of the methodology that transformed vinylogous ester 19 with a pendent terminal olefin to tricycle 20. 28 OH n-BuMgCI, (/-PrO)3TiCI 18 17 ether, rt, 6.5 h, 71% H c-C5H9MgCI, Ti(0/-Pr)4 then F^B-EtoO OMe OMe 20 19 Cha also explored substrate directed asymmetric synthesis using the Kulinkovich reaction. Sequential treatment of homoallylic alcohol 21 with Ti(0/-Pr)4 and c-CsHgMgCl furnished the putative intermediate 22, which upon exposure to ethyl acetate produced trans-l,2dialkylcyclopropanol 23 in 12.2 : 1 dr.29 Ti (0/-Pr)4 c-C5H9MgCI tol., rt THF, rt 0/-Pr OEt -Ti-0 Ph 22 23, dr= 12.2: 1 18 Name Reactions Carbocyclic Ring Formations Sato and colleagues discovered a new titanium complex, (η - propene)Ti(0/-Pr)2 (24), generated in situ, by treatment of Ti(0/-Pr)4 with 2 equiv of z'-PrMgX. Compond 24 was proven to a versatile reagent in synthetic reactions involving alkynes. At the onset of the investigation, the Sato group soon discovered that use of /-PrMgX as the Grignard reagent was very important for generating a titanium compound that afforded alkyne- titanium complexes by the reaction with alkynes.30 When silyl alkyne 25 was treated with 24, the putative complex 26 was formed. Exposure of 26 to cyclopentyl aldehyde was followed by iodine to afford adduct 27 in 71% yield. An intramolecular version of the aforementioned transformation has been developed. Therefore, intramolecular coupling of diyne 28 provided [5,6]-bicyclic cyclopentadienol 29.31 SiMe 3 Me3Si 1 eq. Ti (0/-Pr)4 VT./rt.„N ». jj>Ti(0/-Pr)2 r u 2 eq. /-PrMgCI r J 25 26 Me3Si Lc-CsHnCHO C Hi 2. I, 6 equiv Ti (0/-Pr)4 2 equiv /-PrMgCI 85% 29 In addition, Sato et al. developed an interesting enantioselective synthesis of bicyclic cyclopropanols 31 from iV-acylcamphorsultam (the Oppolzer's chiral auxiliary) derivatives 30.32 HO, 2 eq. Ti (0/-Pr)4 31,c/r>92:8 ee > 98% 4 eq. /-PrMgCI 56-87% •ϋ Chapter 1 Three-Membered Carbocycles 19 EtMgBr HN' Ti(/-PrO)4 OH OTHP THF/Et20 OTHP 32 33 In the realm of medicinal chemistry, cyclopropanol provides a unique rigidity for the side chain. For instance, cyclopropanol 33, from ester 32, was incorporated into nucleoside 34, an analogue of acyclovir. 33 Similarly, ester 35 was converted to cyclopropanol 36, which was assembled onto guanine 37, an anti-HBV agent. 34 EtMgBr, 0.25 eq. Ti(0/-Pr)4 TBDPSO TBDPSO OH 35 THF, 0to25°C, 10 h, 80% 36 OH HPN^N^N 37 0=P-OH OH 1.3.5.2 Applications in the total synthesis of natural products Ollivier and co-workers used the Kulinkovich reaction in their total synthesis ofheliannuolsKandL.35,36 Thus, conversion of ester 38 with pendent olefin to cyclopropanol 39 was achieved using bromotitanium(IV) triisopropoxide and cyclohexyl Grignard reagent. Cyclopropanol 39 then underwent oxidation using FeCU and dechlorination to yield benzoxocinone 40, an intermediate for both heliannuols K (41) and L. c-CsHgMgCI, (/-PrO)3TiBr ^O. ■ ■ ■- ■■■ *· -OH THF, rt, 1 h, 43% 39 20 Name Reactions Carbocyclic Ring Formations Singh's group converted ester 42 to its corresponding cyclopropanol 43, which was treated with NBS and then Et3N to deliver enone 44 via the intermediacy of ß-bromoketone.37 Enone 44 was transformed to tarchonanthuslactone 45. TBSO EtMgBr, Ti(0;-Pr)4 TBSO Et3N, 95% Corey employed the Kulinkovich reaction in the total synthesis of ß- ananeosene (48)/3δ8 Ester 46 was converted to cyclopropanol 47, which served as the substrate to make cyclobutanone by treating 47 with Al(Me)3. EtMgCI, (/-PrO)3TiCI THF, 0 to 23 °C, 48 h, 60% Chapter 1 Three-Membered Carbocycles 21 1.3.5.3 Utility of the Kulinkovich-de Meijere reaction O c-C5H9MgCI, (;-PrO)3TiCI I-AN THF, 52% Joullié took advantage of the Kulinkovich-de Meijere reaction and synthesized a series of constrained jV.TV-dialkyl neurotransmitter analogues. For instance, indolylcyclopropylamine 50 was assembled from indole-olefin 49 and DMF in 52% yield. While intermolecular Kulinkovich-de Meijere reaction assembles cyclopropylamine, many have taken advantage of a pendent olefin at the substrates to synthesize bicycles. Cha converted olefinyl amide 51 to bicyclic amine 52 in excellent yields.40 Six and co-workers prepared eight bicyclic aminocyclopropanes including 54 (from substrate 53) with yields ranging from26to87%.41'42 R R 2-N' 3 OTIPS Ti(0/-Pr)4 c-C5H9MgCI 80-95% 1.5 eq. Ti(0/-Pr)4 4 eq. c-C5H9MgCI THF, 20 °C, 37% 1.3.6 Experimental 1.3.6.1 Intramolecular Kulinkovich cyclopropanation reaction of carboxylic ester with olefin: bicyclo[3.1.0]hexan-l-ol (2) 43 OH n-BuMgCI, (/-PrO)3TiCI )2Me 18 17 ether, rt, 6.5 h, 71% H 22 Name Reactions Carbocyclic Ring Formations To a 500-mL, round-bottomed flask, equipped with a magnetic stirring bar and rubber septum, is added at room temperature a mixture of 2.0 g (15.6 mmol) of methyl 5-hexenoate (17, 11.2 mL, 11.2 mmol) of a 1 M solution of chlorotitanium triisopropoxide in hexane, and 54 mL anhydrous ether under a nitrogen atmosphere. A 1 M solution of n-butylmagnesium chloride in ether (52 mL, 52 mmol) is added over a period of 6.5 hr via a syringe pump at room temperature. After the addition is complete, the resulting black reaction mixture is stirred for an additional 20 min. The mixture is cooled to 0 °C with an ice bath, diluted with 50 mL ether and then quenched by slow addition of water (14 mL). The resulting mixture is stirred for an additional 3 h at room temperature. The organic phase is separated and the aqueous phase is extracted with ether (3 x 100 mL). The combined organic extracts are washed with brine (2 χ 50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator. Purification of the crude product by column chromatography on 40 g silica gel using a gradient of 5% to 10% ether/pentane as the eluent provides 1.09 g (71%) of bicyclo[3.1.0]hexan-l-ol (18) as a colorless oil. 1.3.6.2 Inter molecular Kulinkovich cyclopropanation reaction of carboxylic ester with olefin: frans-2-benzyl-l-methylcyclopropan-l-ol (56)43 CH3C02Et CH3 _ Ph c-C5H9MgCI, (;-PrO)3TiCI HO—jL ^^ U> /Ph 55 ether, rt, 3 h, 80% 56 To a 500 mL, round-bottomed flask, equipped with a magnetic stirring bar and rubber septum, is added a mixture of 2.5 g (21 mmol) allylbenzene (55, 2 mL, 20 mmol) ethyl acetate, 20 mL of a 1 M solution of chlorotitanium triisopropoxide in hexane, and 160 mL anhydrous tetrahydrofuran (THF). After the mixture has been cooled to 0 °C with an ice bath under a nitrogen atmosphere, a 1 M solution of cyclopentylmagnesium chloride in ether (80 mL, 80 mmol) is added over a period of 2.5 h via a syringe pump. After the addition is complete, the resulting black reaction mixture is stirred for 30 min at 0 °C, then is quenched by the cautious addition of water (15 mL). The resulting mixture is stirred for an additional 1 h at room temperature and filtered through a pad of Celite, which is rinsed thoroughly with ether (4 χ 50 mL). The combined filtrate and rinsings are poured into a separatory funnel containing 50 mL water and shaken thoroughly. The organic phase is separated, washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator. Purification of the crude product (obtained as a pale yellow oil)