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Fluorine-Containing Synthons g acs.orw001 bs.1.f u1 p9 p://5-0 htt00 9 | k-2 0b er 22, 2010.1021/ ctobdoi: 6 on O2005 | 131, 34.y 2 3.ul 6J 89.1ate: y D d bon deati ac wnloPubli o D In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. g acs.orw001 bs.1.f u1 p9 p://5-0 htt00 9 | k-2 0b er 22, 2010.1021/ ctobdoi: 6 on O2005 | 131, 34.y 2 3.ul 6J 89.1ate: y D d bon deati ac wnloPubli o D In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. ACS SYMPOSIUM SERIES 911 Fluorine-Containing Synthons g acs.orw001 bs.1.f pu91 Vadim A. Soloshonok, Editor http://005-0 The University of Oklahoma 9 | k-2 0b er 22, 2010.1021/ ctobdoi: 6 on O2005 | 131, 34.y 2 3.ul 6J 89.1ate: y D d bon deati ac wnloPubli o D Sponsored by the ACS Divisions of Fluorine Chemistry, Medicinal Chemistry, and Organic Chemistry American Chemical Society, Washington, DC In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. Library of Congress Cataloging-in-Publication Data Fluorine-Containing Synthons / Vadim A. Soloshonok, editor, p. cm.—(ACS symposium series ; 911) Includes bibliographical references and index. ISBN 0-8412-3911-8 (alk. paper) g bs.acs.or1.fw001 C1on. gOrregssaensi.c compounds—Synthesis—Congresses. 2. Fluorine compounds— u1 p9 p://5-0 I. Soloshonok, V. Α. II. American Chemical Society. Divisions of Fluorine htt00 Chemistry, Medicinal Chemistry, and Organic Chemistry. III. Series. 9 | k-2 0b QD262. F584 2005 ctober 22, 20doi: 10.1021/ TN54ha7tei'.o 2np—aapld eScrt2a 2nud seadrd info rt hIinsf oprmubaltiicoanti oSnc iemnceeest—s Ptheerm maniennimceu mof r Peqapueirre m2fo0e0rn 5tP0sr4 ino1t1fe 9Ad4 m Leibrircaarny 136 on O1, 2005 | MCoapteyrriiaglhst, A©N 2S0I0 Z53 A9.m48e-r1ic9a8n4 C. hemical Society 34.y 2 Distributed by Oxford University Press 3.ul 6J 89.1ate: The cover art is reproduced from Scheme 3.2 in Chapter 31. y D d bon All Rights Reserved. Reprographic copying beyond that permitted by Sections 107 or deati 108 of the U.S. Copyright Act is allowed for internal use only, provided that a per ac wnloPubli -2c2h2a pRteors efeweo oofd $ D30ri.v0e0, Dplaunsv $e0rs.7, 5M pAe r0 1p9ag23e, iUs SpAai.d R teop tuhbel iCcaotpioynri gohrt r Cepleroardaunccteio Cn efnoter rs,a Ilnec ., o D of pages in this book is permitted only under license from ACS. Direct these and other permission requests to ACS Copyright Office, Publications Division, 1155 16th Street, N.W., Washington, DC 20036. The citation of trade names and/or names of manufacturers in this publication is not to be construed as an endorsement or as approval by ACS of the commercial products or services referenced herein; nor should the mere reference herein to any drawing, spec ification, chemical process, or other data be regarded as a license or as a conveyance of any right or permission to the holder, reader, or any other person or corporation, to manufacture, reproduce, use, or sell any patented invention or copyrighted work that may in any way be related thereto. Registered names, trademarks, etc., used in this publi cation, even without specific indication thereof, are not to be considered unprotected by law. PRINTED IN THE UNITED STATES OF AMERICA In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. Foreword The ACS Symposium Series was first published in 1974 to pro vide a mechanism for publishing symposia quickly in book form. The purpose of the series is to publish timely, comprehensive books devel oped from ACS sponsored symposia based on current scientific re search. Occasionally, books are developed from symposia sponsored by g bs.acs.or1.fw001 oauthdeire nocreg.a nizations when the topic is of keen interest to the chemistry pu91 Before agreeing to publish a book, the proposed table of con p://5-0 tents is reviewed for appropriate and comprehensive coverage and for htt00 9 | k-2 interest to the audience. Some papers may be excluded to better focus 0b er 22, 2010.1021/ tachphepa prbotoeporrsika ;at eroe, t hopevereesr r-mvrieaevywi e bwoer e adid npdtrreoidod rut octo top rrfyion vacil dhaeac pcctoeerpmst apnarercehe e anodsrid vreeedjn.e ecsDtsir.o anWf,t sha neondf ctobdoi: manuscripts are prepared in camera-ready format. 6 on O2005 | As a rule, only original research papers and original review 131, papers are included in the volumes. Verbatim reproductions of previ 34.y 2 ously published papers are not accepted. 3.ul 6J 89.1ate: y D d bon ACS Books Department deati ac wnloPubli o D In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. Preface Recent years have witnessed a spectacular growth of interest in selectively fluorinated chemicals and their utilization in the rational design g or1 of new compounds with desired properties. Thus, it becomes customary to 9 | http://pubs.acs.k-2005-0911.pr00 t(cshleoieeqn utsaaittdir nu licecntargusy rtso etro agonlafse ,nm ifcfalo unmroy ro ienlnxeeecaw umalltyepo slmde, e) f.soo igurI nntt edridi fse l uxaigtonrrretooemcmrheeeselyttmih nryigacl raegltslroy,o udinpnrou ngtienas tc,u otarhrnepad,ot hrmaaftvlaeuetdo e rnriiionnaweltso- ctober 22, 200doi: 10.1021/b bcpgoiaaomirnltoipecgdoui ulctanhardel,l s y s ftohararet usle stvh foauenf e tlp cerhdcive ominmleeopwg-oe, uddnr eesdvtgsrei.u olco-Ttp uhmareane ldn g ftresso atwteiunrire neosgssy enidlnteeh cmtehttieaivc ne dd em ifnenototrhrv ooodfd luoudcloeotsrigiiongynan, t eoiondff 6 on O2005 | fluorine into organic compounds. One of the most promising developments 131, in this area is the effective exploitation of a building-block, or synthon, 34.y 2 approach. In this strategy, incorporation of low molecular weight 3.ul by 89.16n Date: J psyonlythfuenticct iosnchale mfleu. orDinuee- ctoon ttahine insgy nsthyenttihco nvse rbseactiolimtye sa sas okcieayt edp arwt iothf tthhee wnloaded Publicatio sosyuf cntcthheiosss nr eianspe caporrcmohap cophur,o nmtdh pidste evadre eltohap eom Afe CrneSts. eDTarhicvehi s riahopanis d o bpfe rFeolngu roeersnisnj oeay nCidnh gteh mee xisitmrtarypo ortdroti ananascrkye o D Vadim Soloshonok and Vyacheslav Petrov to organize a symposium entitled "Fluorinated Synthons" at the 226th ACS Meeting in New York City (September 7-11, 2003). Vadim Soloshonok and Vyacheslav Petrov are very grateful for the support of this symposium from the ACS Division of Medicinal Chemistry, Asahi Glass Company, Central Glass Company, IM&T Research Company and Dupont Company. This ACS Symposium Series book, Fluorine-Containing Synthons, is based largely on the topics presented at the symposium. However, to give the readers more complete overview of the current activity in the field, have included in the book several invited chapters written by eminent xiii In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. scientists who recently contributed important new results in synthetic methodology of fluoro-organic chemistry. Therefore, the book is designed to be a comprehensive "snap-shot" of the current state-of-the-art of fluoro- organic methodology and to be useful to practitioners, in both academic and industrial laboratories, working in various areas of chemistry, such as fluorine, organic, bio-organic, medicinal, biochemistry, crystal engineering and material science. As an organizer of the symposium and the editor of this book, I take this opportunity to gratefully acknowledge the truly outstanding contributions from 30 speakers at the symposium and 35 authors of the book. Their efforts have made this project a very enjoyable task, as well as professionally highly rewarding. g or1 09 | http://pubs.acs.bk-2005-0911.pr00 ADVThesaespo daUcritinmmaitvee en ArPts r.ioot fySf e Cooshfsl oeoOmrs khilsaothryno maonakd Biochemistry ctober 22, 20doi: 10.1021/ NP62ho0or mnPeaa: rnr(,i 4nO0gK5to) -n73 32O051v-9a8l-2,3 7R095o 1o m 208 6 on O2005 | Fe-amx:a i(l:4 v05ad)[email protected] u 131, 34.y 2 http://cheminfo.chem.ou.edu/faculty/vas.html 3.ul 6J by 89.1n Date: wnloaded Publicatio o D xiv In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. Chapter 1 Recent Advances in Perfluoroalkylation Methodology Teruo Umemoto IM&T Research, Inc., 6860 North Broadway, Suite B, Denver, CO 80221 g bs.acs.or1.ch001 u1 p9 p://5-0 9 | httk-200 0b er 22, 2010.1021/ RTheceeyn t ardee vcellaospsmifeiendts anind pdeirsfslcuuosreoda lkiynl atthioen sf oalrloew rienvgi etwhreede. ctobdoi: categories: electrophilic, nucleophilic, and free radical 6 on O2005 | peleercflturooprohaillkicly laatinodn s. nucGleroeapth ialidcv antrcieflsu ohroamvee thbyeleant iomn adaere ains 131, involving the generation and synthetic application of CF3+ and 34.y 2 of CF- which had both long been desired because of their 63.Jul expect3ed broad application. 89.1ate: by n D ded atio wnloaPublic o D Introduction The unique behavior of fluorinaled compounds is attributed to the high electronegativity of fluorine (4.0), which is the highest of all elements, combined with its size, close to that of hydrogen (van der Waal's radii; F, 1.47A; H, 1.2 A). Perfluoroalkyl groups, RFCF +i, regarded as a gathering of fluorine n 2n atoms, have strong effects such as high electronegativity, stability, and lipophilicity (7,2). In addtion, long perfluoroalkyl groups of six or more carbons have high water- and oil-resistance. Therefore, the introduction of a perfluoroalkyl group into an organic compound can bring about remarkable changes in the physical, chemical, and biological properties that may result in new chemicals or materials for various applications {1-4). Among the 2 © 2005 American Chemical Society In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. 3 perfluoroalkyl groups, the introduction of the trifluoromethyl group has received much interest in medicinal and agricultural chemistry because it is expected to bring positive changes in biochemical activity (3,4). This review covers the development of perfluoroalkylation methodology in the last one or two decades. The perfluoroalkylations are classified and discussed in the following three categories: electrophilic (Rf4), nucleophilic (Rf), and free radical (Rf ) perfluoroalkylations. Some of this content may overlap with the chapters written by other authors in this book and readers are directed to the chapters written by Prof. Prakash and Prof. Langlois, with regards to CF- 3SiMe3, CF3H, and other nucleophilic trifluoromethylating agents. 1. Electrophilic Perfluoroalkylation g bs.acs.or1.ch001 chloInro p1h9e8y4l), (2Y,4a-gduimpoeltshkyili- et aandl. r/e?p-moretethdo xtyhpeh esnyynlt)h(tersifilsu oarnodm ereeiaycl)tisvuiltfyo noiufm (p - u1 9 | http://pk-2005-09 rxseayalltcestn e2ed aawnndidt h 3 a s(noSidsciohulemem e/a7 n-1dn) i trr(eo5pt)h.o irotTpehhdee nytoh lsaayttn et thhteeoss iezge ivdtre if 2ltu riaofnlrudoom 3roe bmthyey tlth reysalu tli/nfMogni iitu1rm owp hitsehan lymtsl - er 22, 20010.1021/b nsuoltfiicdeed, fbourt s odmide n toimt ere baeccta wusiteh o Λf Γth,Λe Γlo-dwim reetahcytliavniitliyn eo.f sTuhlfios nrieupmo rsta hltasd. not been ctobdoi: Scheme 1 6 on O2005 | 131, 3.34.uly 2 1 by 89.16n Date: J Scheme 2 23 RR,p=ROM2=Me, eR 2=H ded atio wnloaPublic 666bab;;; RRR£Ff==CCCFFF333,,,AAA===SSS,,,RRRiii===RHR2,2==RHH=,,MXX==eO,BXTF=4f O Tf o 2 D 6c; R=CF,A=S,Ri=ï-Bu,R=H,X=OTf f 3 2 6d; RpCFj,A=Se,Ri =R=H,X=OTf 2 6e; Rf=CF,A=Te,R|=R2=H,X=OTf 3 X=OTf, BF4 etc- 7a; Rf=CFA=S 3> ^N02 77bc;; RRpFCCFF,A3,A==TSee Rf=CF3, H-C3F7, «-CFn 3 etc. 8 A=S, Se, Te Rf=H, /-Bu R 2=H, Me The author recognized the importance of Yagupolskii*s report. In 1990, he and his coworkers reported a new system of heterocyclic chalcogenium salts, S, In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. 4 Se, and re-(perfluoroa!kyl)dibenzothio-, -seleno-, and -tellurophenium salts 6 and 7 as power-variable electrophilic perfluoroalkylating agents (Scheme 2) (6- 8). 2-RfS(0)- or RfSe(0)-biphenyl underwent easy intramolecular cyclization to give the S and Se-Rf-dibenzothio- and -selenophenium salts 6 in high yields. 6 were also prepared by direct fluorination in the presence of triflic acid (TfDH) or HBF(or BF). 2-RTe-biphenyl was treated with DMSO and Tf0 to give 4 3 f 2 Fe-Rrdibenzotellurophenium salts 6 (A=Te) in high yields. These triflates were nitrated with HN0/Tf0 to give 7. 6a and 6b were prepared on a large scale by 3 2 counteranion-exchange reaction of 6 (X=HSC>4) with NaOTf and NaBF4, respectively (8). The reactivity increases in the order of Te<Se<S and the ring substituents alkyl<H<N02. More powerful perfluoroaflcylating agents react wift less bs.acs.org 1.ch001 mrreeaoaccrteti v werei tahnc utmicvoleed oepnrahuticelleleyso prwehaiiltcehtsi v heiwg nihtu hcy lhieeiolgpdhhs ,i lyeaisne dlad lssle.o s wsM iptoohdw heeirgrafhtue yll yier elpdaosgw.e neTrthfsur erl eear secaatlg twse nitths u1 p9 6d, 6a, and 7a were chosen as useful power-variable trifluoromethylating p://5-0 reagents. The power order is 6d<6a<7a, where 7a is the most powerful reagent. 9 | httk-200 0b Scheme 3 er 22, 2010.1021/ 66ad;; AA==SS, eR, R=H=H ctobdoi: 7a; A=S, R=N02 6 on O2005 | Scheme 4 CF3 υ if Power order 6d < 6a < 7a 131, 34.y 2 3.ul 6J 89.1ate: by n D ded atio wnloaPublic o D OH 61% By means of the combination rule, the power-variable trifluoromethylating agents, 6d, 6a, and 7a, made it possible to trifluoromethylate a wide range of nucleophiles such as carbanbns, silyl enol ethers, phenols, anilines, phosphines, thiolates, and halides as shown in Scheme 4. In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.