Halogen–Metal Exchange on Bromoheterocyclics with Substituents Containing an Acidic Proton

12 Pages·2017·7.49 MB·English

molecules
Article
Halogen–Metal Exchange on Bromoheterocyclics with
Substituents Containing an Acidic Proton via
Formation of a Magnesium Intermediate
QingqiangTian,SuqinShang,HuajunWang,GuoqiangShi,ZhiyaoLiandJianyongYuan*
PharmacyCollege,ChongqingMedicalUniversity,Chongqing400016,China;[email protected](Q.T.);
[email protected](S.S.);[email protected](H.W.);[email protected](G.S.);
[email protected](Z.L.)
* Correspondence:[email protected];Tel./Fax:[phone]
Received:18October2017;Accepted:9November2017;Published:11November2017
Abstract: A selective and practical bromine–metal exchange on bromoheterocyclics bearing
substituents with an acidic proton under non-cryogenic conditions was developed by a simple
modificationofanexistingprotocol. Ourprotocolofusingacombinationofi-PrMgClandn-BuLi
hasnotonlysolvedtheproblemofintermolecularquenchingthatoftenoccurredwhenusingalkyl
lithiumaloneasthereagentforhalogen–lithiumexchange,butalsoofferedahighlyselectivemethod
forperformingbromo–metalexchangeondibrominatedarenecompoundsthroughchelationeffect.
Keywords: acidicproton;non-cryogenic;arene;bromine–metalexchange
1. Introduction
Substitutedheterocyclicsareanimportantclassofheterocyclicbuildingblocksthatareroutinely
usedinthesynthesisofmedicinalandagrochemicalproducts[1]. Functionalizationofheterocyclics
viaorganometallicintermediateshasbeenoneofthemostfrequentlyusedmethodsforthesynthesis
of various heterocyclic derivatives. One of the strategies relies on the rapid bromine–lithium
exchangereactiononhalogenatedheterocyclicsundercryogenicconditionsatlowtemperature[2].
However, thereactivityandstabilityofthelithiatedspeciesunderthereactionconditionsusually
requirecryogenicconditionstominimizeundesiredside-reactions,suchasnucleophilicattackofthe
heterocyclicringbyalkyllithium(Scheme1)[3–10]. Theprotocolreportedbytheliteraturebasically
allowsforthelithiationofbromo-substitutedheterocyclesinthepresenceofN–HandO–Hacidic
protonssuchasindolesorphenols.Correspondingprotocolsareknown.Inthesepapers,astheauthors
didmorethantwoequivalentsoftheorgano-lithiumreagent(oranotherstrongbasesuchasKH)is
employed,andfirstdeprotonationoftheacidicprotonstakesplace,followedbythelithiation[11–14].
Alternatively, the preparation of the Grinard reagent via halogen–magnesium exchange typically
usesi-PrMgCl. Thesubsequentquenchingwithvariouselectrophileshasbeenproventobeahighly
usefulmethod forthesynthesis ofheterocyclic derivatives[15–21]. Inthismethod, the additional
functionalgroupscantoleratetheprocessofhalogen–metalexchange,whichconsiderablyenhancedits
syntheticutility. However,forthosesubstratesthatbearinganacidicproton(Compound1,Scheme1),
i-PrMgCl is generally not reactive enough to affect Br–Mg exchange. Under these circumstances,
the use of more reactive alkyl lithium reagents only made limited success because of nucleophilic
attackonthepyridineringbyn-BuLiaswellastheformationofcorrespondingprotonatedproducts
duetointermolecularquenching[22–25](Br–Liexchangeisusuallyfastenoughtocompetewiththe
removalofanacidicprotonbyn-BuLi).
Molecules2017,22,1952;doi:10.3390/molecules22111952 www.mdpi.com/journal/molecules
Molecules2017,22,1952 2of12
Molecules 2017, 22, 1952 2 of 12
previous works
EE+
R X R
Y RR11MMggXLi E+ X
KH, tBuLi/n-BuLi
or LITMP or
R RN' X (iX-P r=)2 IM, gBarL, iCCll R RN' EE+
Y = C , N
Y R, R' = Alkyl, Aryl, Ester, Cyan, etc X
This work
R1 Br R1 EE+
A H A H
X i-PrMgCl n-BuLi X
or or
R1 -20-0 ℃ E+ H2O R1 X EE+
X Br
X = C , N
N
N A = O, N H
H
R1 = Alkyl; Aryl, Halogen etc
1 3
ScShcehmemee1 1..M Meettaall hhaallooggeenn eexxcchhaannggee mmeeththoodd. .
TheTrheefroerfeo,rteh, etdhee vdeelovpemlopenmteonftn oefw nmewet hmoedtohloodgoielosgthieast cthaant acdadnr easdsdthreessse itshseusee siisssuheigs hilsy hdiegshirlyab le.
Intdheissirpaabplee. rI,nw tehiws ipsahpteor, rwepeo wrtisthh atto hraeploogret nth–amt ehtaalloegxench–manegtael oenxchheatnegreo coync lhicetseurobcsytcrlaitce ssubbesatrraintegs an
acidbeicarpinrog toann caacindibce pproertofonr mcaend beef fipceirefnortmlyetdh reoffuicgihenatlyco tmhrboiungehd au sceomofbii-nPerdM ugsCe loaf nid-PrnM-BguCLl iaunndd er
essnen-BtuiaLlliy unnodnerc reysosegnetniaicllyc onnodnictrioyongseannicd ctohnadtihtiiognhs raengdio tshealte chtiigvhit ryegcaionsebleecatcivhiiteyv ceadn obne haachloiegveend– mone tal
exchhaalnoggeeno–nmseutabls etrxactheawngieth otnw soubbsrtoramteo wgirtohu tpwsov biarocmhoel gartioounpes fvfeiac tc.helation effect.
2. R2.e Rsuelstuslatsn adnDd iDscisucsussisoinon
WeWstea rstteadrtewdi thwibtrho mbroopmyorpidyirnidei1nae t1haa ttshuabt sstuitbustteitdutwedit hwaitBho ca- pBrooct-epcrtoetdecatmedi naomgirnoou pgrtoouepx ptolo re
theexbpelsotrceo tnhde ibtieosnt ctoonedxiteicount etot hexeeBcur–teM thgee Bxrc–hMangg eexcinhatnhgee pinre tsheen cpereosfenacne aocf idanic accaidrbica mcaarbteamparotet on.
proton. When Compound 1a was treated with one to three equivalents of i-PrMgCl at room
When Compound 1a was treated with one to three equivalents of i-PrMgCl at room temperature,
temperature, no expected Br–Mg exchange took place (Table 1, entries 1–3). In addition, we used
noexpectedBr–Mgexchangetookplace(Table1,entries1–3). Inaddition,weusedthreeequivalentsof
i-PrtMhrgeeC el,qluoiwvaelreendtst hoef it-ePmrMpegrCalt,u lorewteore0d◦ tChea ntedminpcerreaatusered ttoh 0e °rCea acntido nintcirmeaes,ewd itthhen roeaecxtpioenc tteimdee,x wchitahn ge
no expected exchange results, resulting in a list of impurities (Table 1, entry 4). Subsequently, we
results,resultinginalistofimpurities(Table1,entry4). Subsequently,weusedthemoreactivelithium
used the more active lithium reagent to treat Compound 1a with one to three equivalents of n-BuLi
reagenttotreatCompound1awithonetothreeequivalentsofn-BuLiatlowtemperatureanddid
at low temperature and did not find the desired target product to obtain unwanted polymers (Table
notfindthedesiredtargetproducttoobtainunwantedpolymers(Table1,entries5–7). Inthiscase,
1, entries 5–7). In this case, we considered the combination of i-PrMgCl and n-BuLi. First, we
weconsideredthecombinationofi-PrMgClandn-BuLi. First, weexploredi-PrMgCl:n-BuLi=1:1
explored i-PrMgCl:n-BuLi = 1:1 equivalent and found no efficient exchange (Table 1, entry 8). Then,
equivalentandfoundnoefficientexchange(Table1,entry8). Then,whenweincreasedtheamount
when we increased the amount of i-PrMgCl to i-PrMgCl:n-BuLi = 1:2 equivalents, compound 1a was
ofit-rPeraMtedg Cslutcoceis-sPirvMelyg Cwl:inth-B ounLei =eq1u:2iveaqleunitv aolfe ni-tPsr,McogmClp oaut n0d °1Ca wanads ttrweoa teedqusiuvcacleenstssi voefl ynw-BiuthLio, ne
equgirvaatliefynitnogflyi- aP rcMleganC leaxtch0a◦nCgea ntodotkw polaecqeu ainvdal esnutbsseoqfune-nBtu qLui,egnrcahtiinfygi nogf ltyhea icnletearnmeexdcihaaten gweittho oDkMpFla ce
andgasvueb ase 9q0u%e nytieqldu eonf cthhein egxpoefcttheed ianltdeerhmyeddei patreodwuictth 3Da M(TFabglea1v,e enat9ry0 %9).y i eldoftheexpectedaldehyde
productA3caco(Trdabinlge 1to, eKnntroych9e)l. et al. [26], LiCl-mediated Br–Mg exchange reaction was used to prepare
fuAncctcioonrdaliinzgedt oarKyln coocmheploeutnadls. [f2r6o]m,L oirCgla-nmice dbriaotmedideBsr.– TMhgene xwceh gaunegseserdea tchteio rnolwe oafs luitsheidumto ipn rtehpea re
funscytsitoenma.l iWzeed uasreydl icnoomrgpaonuicn lditshifuromm caorrbgoannaitce barnodm liitdheius.mT chhelnorwidee ginusetesasedd oft hne-BruoLlei, oafnldit hfoiuunmd innot he
systtaermge.tW preoudsuecdt fionromrgataendi c(Tliatbhlieu m1, ecnatrrbieosn 1a0t eaanndd 11li)t.h Aiut mthec hsalomried teimines, tweaed uosefdn -pB-burLoim,aonpdhefnoouln ads no
raw material, to further explore the role of inorganic lithium chloride in the system and found no
targetproductformated(Table1,entries10and11). Atthesametime,weusedp-bromophenolas
p-hydroxybenzaldehyde but the starting material (Table 1, entry 12). Therefore, n-BuLi plays a
rawmaterial, tofurtherexploretheroleofinorganiclithiumchlorideinthesystemandfoundno
pivotal role in the reaction.
p-hydroxybenzaldehydebutthestartingmaterial(Table1,entry12). Therefore,n-BuLiplaysapivotal

roleinthereaction.
Molecules 2017, 22, 1952 3 of 12
Table 1. Tert-butyl (5-formylpyridin-2-yl) carbamate of metalating reagents prepared from
2-(N-BOC-amino)-5-bromopyridine.
Br metalating DMF OHC
BOC conditions BOC
N NH N NH
1a 3a
Molecules 2017, 22, 1952 3 of 12
Molecules2017,22,1952 3of12
Entry Metalating Reagent ReactionConditions Yield a of 3a (%)
1 i-PrMgCl (1.0 equiv.) THF, rt, 24h Trace
Table 1. Tert-butyl (5-formylpyridin-2-yl) carbamate of metalating reagents prepared from
2T able 1. i-PTreMrt-gbCutly (l2.(05 -efoqrumivyl.p) yridin-2-yl) TcaHrbFa, mrta, t2e4 ohf metalating reagents pTrreapcaer ed from
2-(N-BOC-amino)-5-bromopyridine.
32 -(N-BOCi--aPmriMnog)C-5l- b(r3o.m0 oepqyuriivd.i)n e. THF, rt, 24 h Trace
4 i-PrMgCl (3B.r0 equiv.) THF, 0°C, 36hOHC Trace
metalating DMF
5 n-BuLi (1.0 equiv.) BOC conTditHionsF, −78°C, 24h BOC Trace
N NH N NH
6 n-BuLi (2.0 equiv1a.) THF, −20 °C, 0.5 h 3a Trace
7 Entry n-BuLi (2.M0 eetqaulaitvin.)g Reagent THF, −20R °eCa,c t0i.o5n hC onditions YieTldraacoef 3a(%)
Entry Metia-PlarMtinggC lR +e na-gBeunLti ReactionConditions Yield a of 3a (%)
8 b 1 i-PrMgCl(1.0equiv.) THF, −20 °C, T0H.5F ,hr t,24h TraTrcaec e
1 i2-PrMg(1C.0l: 1(1.0. 0ie- PqeruqMiuvgi.Cv) l.)(2.0equiv.) THF, rt, 2T4HhF,rt,24h TTrarcaece
2 i3-PrMi-PgrCMl g(C2.l0i -+ Pe nrqM-uBgiuCvLl.)i( 3.0equiv.) THF, rt, 2T4H hF ,rt,24h TTrarcaece
3 9 c i4-PrMg(1C.0l: 2(3.0. 0ie- PqeruqMiuvgi.Cv) l.)( 3.0equiv.) THTFH, −F2,0 r t°,C T2, H40 .Fh5, 0h◦ C,36h 9T0Tr arcaece
5 n-BuLi(1.0equiv.) THF,−78◦C,24h Trace
4 10 i6-PrMi-PgrCMl g(3C.l0 + ne -LqBiuu2CLiviO(.2)3 .0equiv.) TTHHF,F −, 200° °TCCH,, F30,6.−5h 2h0 ◦C,0.5h TrTaTrcareca ece
5 7n-Bu(L1i. 0(:12..00 eenqq-uuBiuivvL..)i) ( 2.0equiv.) THF, −78T°HCF, ,2−42h0◦C,0.5h TTrarcaece
8b i-Pir-MPrMgCglC +l +LniC-Blu Li(1.0:1.0equiv.) THF,−20◦C,0.5h Trace
6 11 9cn-BuLii -(P2r.M0 geCqlu+inv-.B)u Li(1.0:2.0eTqTuHHivFF.),, −−2200 °°TCCH, ,F0 ,0.−5.5 2h 0h ◦ C,0.5h TraTc9re0a ce
(1.0:2.0 equiv.)
7 10n-BuLii- P(2rM.0g eCqlu+iLvi.)C O (1.0:2.0eTquHivF.), −20 °TCH,F ,0−.52 0h◦ C,0.5h TTrarcaece
12 d 11i-PrMi-PgrCiM-Plg r+MC nlg -C+B lLu+iLCL2iilC l3(1.0:2.0equTiHv.)F, −20 °TCH, F0,.−5 2h0 ◦C,0.5h TraTcrea cee
8 b 12d (1.0i-:2P.r0M egqCuli+vL.)i Cl(1.0:2.0eqTuiHv.)F, −20 °TCH,F ,0−.52 0h◦ C,0.5h TrTarcaecee
(1.0:1.0 equiv.)
a Yields were determined by HPLC; b reaction conditions: i-PrMgCl (1.0 equiv.), THF, at 0 °C, then
a Yieldsiw-PerreMdegteCrml i+n end-bByuHLPiL C; b reaction conditions: i-PrMgCl (1.0 equiv.), THF, at 0 ◦C, then n-BuLi
9 c n-(B2.u0Leqi u(2iv..0) aetq−u2i0v.◦)C a;tc −re2a0c t°ioCn; cco rnedaitciotinosn: i-cPornMTdgHiCtiloF(n1, .s0−: 2eiq-0Pu ri°vMC.),g,T C0Hl.F 5,(1 ah.t00 e◦Cqu,tihve.n), nT-BHuFL,i (a2t. 00e q°Cui,v .t)9ha0etn − n20-B◦uCL; i
(2d.0r aewqumivat.e) r(ai1atl .s−02f:o20r .°b0Cr oe; mdq orupaihwve n.m)o la;teesrtiaarltsin fgomr batreormialoopnhlye.nol; e starting material only.
i-PrMgCl + Li CO
2 3
10 WWe eeexxaamminineedd tthhee ssttaabbiilliittyy ooff tthheem meetatalalTatetHeddFs p,s ep−c2eic0eis e°asC na,d n0df.o5 uf ohnu dntdh atthtahte thinet einrmteerdmiaeTtderiawactaees wstaasb lsetaibnle
(1.0:2.0 equiv.)
inT THHFFa att− −2200 ◦°CC,, ggiivvee 33aa wwiitthha ay yiieellddo off9 900%%,,e evveenna aftfeterra aggininggf oforr0 0.5.5h hb befeoforeretr teraetaetdedw withithte tretr-bt-ubtuytlyl
i-PrMgCl + LiCl
(51(-51f-o fromrmylyplpyyrirdidinin-2-2-y-yl)l )ccaarrbbaammaattee ((TTaabbllee 22)).. THF, −20 °C, 0.5 h Trace
(1.0:2.0 equiv.)
TaTbalbel ei2-.2P S.rtSMatbabigliiCltiytly o+of fmLmieCetatlal alattiinngg rreeaaggeennttss pprreeppaarreedd ffrroomm2 2--((NN--BBOOCC-a-ammininoo)-)5--5b-rbormomopoypryidriidnien.e.
12 d THF, −20 °C, 0.5 h Trace e
(1.0:2.0 equiBvr .) Reaction conditions * DMF OHC
a Yields were determined by HPLC; bB OrCeactioagning ctimoenditions: i-PrMgCl (1.B0OC equiv.), THF, at 0 °C, then
N NH N NH
n-BuLi (2.0 equiv.) at −20 °C; c re1aaction co*n i-dPrMitgiCol n(1.s0 :e qiu-ivP); r 0M ℃gCl (1.0 3eaquiv.), THF, at 0 °C, then n-BuLi
(2.0 equiv.) at −20 °C; d raw materials for b r tohemn n-oBupLih (2e.0n eoquliv;) ; e- 2s0 t℃arting material only.
Aging TiAmgein (ghT)ime(h) Yielda Yielda
We examined the stability of the metalated species and found that the intermediate was stable
0.25 0.25 69 69
in THF at −20 °C, give 3a with a0 .y5 ield o0.f5 90%, even after aging9 0for 0.5 h9 b0 efore treated with tert-butyl
1 75
(5-formylpyridin-2-yl) carbamat1e (Table 2). 75
2 40
2 40
5 23
Table 2. Stability of metal5a ting reagents prepared from 2-(N-BOC-am23in o)-5-bromopyridine.
aYieldsweredeterminedbyHPLCanalysis.
a Yields were determined by HPLC analysis.
Br Reaction conditions * DMF OHC
CComompapraerded wwitihth ththee tytyppicicaall BBrr––LBLOiiC eexxcchhaaagnninggg teiem ewwiitthh aallkkyyll lliitthhiiuumm wwhhicichBhOCr ereqquuiriersest otob ebep eprefrofromrmeded
under cryogenic condition, tNhe cNuHrrent reaction could be performN edNHat about 0 ◦C. It was found
under cryogenic condition, the 1caurrent re*a ic-PtriMognCl c(1o.0u eqludiv) ;b 0e ℃ performed3a at about 0 °C. It was found that
twthoa teqtwuioveaqleunivtsa loefn tns-oBfunL-iB uwLeirwe enreecnesescae rs tyshea nrf noy-Bruf Loti hr (2et.0h eeequxievc)x;h -c2a0h n℃agneg etoto bbee ccoommppll eetteedd,, iinnddiiccaattininggt hthatatt htehe
bromine–metal exchange was probably affected by the action of an “ate” complex (2) (Scheme 2)
bromine–metal exchAanggine gw Tasi mpreo (bha)bly affected by the action of an “atYe”ie clodmaplex (2) formed from
formedfromoneequivalentofN-magnesiumsaltandtwoequivalentsofn-BuLi[27–29]. Similarly,
one equivalent of N-magnesium salt and two equivalents of n-BuLi [27–29]. Similarly, following the
0.25 69
following the same protocol, bromine–magnesium exchange could be performed successively on
same protocol, bromine–magnesium exchange could be performed successively on other
0.5 90
other bromopyridines bearing an acidic carbamate proton, then quenching of the organometallic
bromopyridines bearing an acidic carbamate proton, then quenching of the organometallic
intermediateswithDMFan1d otherelectrophilestoaffordahighyieldofthe75co rrespondingproducts
(Table3,entry1). 2 40
5 23

a Yields were determined by HPLC analysis.
Compared with the typical Br–Li exchange with alkyl lithium which requires to be performed
under cryogenic condition, the current reaction could be performed at about 0 °C. It was found that
two equivalents of n-BuLi were necessary for the exchange to be completed, indicating that the
bromine–metal exchange was probably affected by the action of an “ate” complex (2) formed from
one equivalent of N-magnesium salt and two equivalents of n-BuLi [27–29]. Similarly, following the
same protocol, bromine–magnesium exchange could be performed successively on other
bromopyridines bearing an acidic carbamate proton, then quenching of the organometallic
Molecules 2017, 22, 1952 4 of 12
intermMMoeoledleccuiualeltess e2 2s00 1w177, ,i2 t22h2, ,1 1D9955M22 F and other electrophiles to afford a high yield of the corresponding p44 or ofo f1 d122 u cts
MoleMcMuololeelscecu2ul0els1e s72 2,00211277,, ,21 2292,5 ,12 1995522 44 o of4 f1 o12f2 12
MMoloelceuculelse s2 2001177, ,2 222, ,1 1995522 44 o of f1 122
(TablMeM o3olel,ec ceuulnelests 2r 20y011 717, ,)2 .22 2, ,1 1995522 44 o off 1 122
MMoloelceuculelse s2 2001177, 2, 222, 1, 1995522 44 o of f1 122
iiMMMnniiMnnoottooltteeleleleeecerrcccurrmmuuummllelleeseeess ese dd2 2 2dd200ii001aaii111aa77tt77,ttee, , ,2ee 2 ss222ss2 22,ww, , ,ww1 1 119ii999ttii555tthh522hh22 DD DD MMMMFFFF aa aannnndddd oo ootttthhhheeeerrrr ee eelleelleeccccttttrrrroooopppphhhhiilliieelleessss tt ttoooo aa aaffffffffoooorrrrdddd aa aa hh hhiiggiigghhhh yy yyiieeiieellddlldd oo ooffff tt tthhhheeee cc ccoooorrrrrrrreeeessssppppoooonnnnddddiinniinngggg pp pprrrroooodd44dd44 uu o o uuoofccff f cc1 tt1 11ttss222ss2
ininteterrmmeeddiaiatetess w witihth D DMMFF a anndd o oththeerr e elelecctrtroopphhilieless t oto a afffoforrdd a a h higighh y yieieldld o of ft hthee c coorrrreessppoonnddiningg p prroodduucctsts
(i((i(iiniT(in(((TTniiTnnnTnTTTnttataaattettetaeaaaebbbebeeerrrbbbbrrlrllrmrlmmmeeellllmemmmeeee ee3e333 e eeee3333ddd,,,d,d d dd ,,,,eieee i iiaieeeeiaaiinannnaaaantnnnttttttttetteteerttttrrereeesssrrrrysyyyssss yy yy ww w w w1w11w1w 1111)i)))iiiti.))))i..tti.it t ht ....ththh h hhh DD D D DDDDMMMMMMMMFFFFFFFF aa a a aaaannnnnnnndddddddd oo o o oooottttthtththhhhhheeeeeeeerrrrrrrr ee e e eeeellllleleelleeeeecBccccccctttrttrttrtrrrrrroooooooopppppppphhhhhhhhiiiiililililelleelleeeeessssssss tt t t tottotoooooo aa a a aaaafffffffffffffoffofoooooorrrrrrrdrddddddd aa a a aaaa hh h h hhhhiiiigiiggiiggggghhhhhhhh yy y y yyyyiiiieiieeiieeeeelllldllddllddddd oo o o oooofffff fff tt t t thtththhhhhheeeeeeee cc c c ccccoooooooorrrrrrrrrrrrrrrereeeeeeessssssssppppppppoooooooonnnnnnnnddddddddiiiiniinniinnnnngggggggg pp p p pppprrrrrrrorooooooodddddddduuuuuuuucccccccctttttsttstssssss
((((T(T(TTTTaaaaaabbbbbblllleelleeee 3 3 3333,,, , ,, e e eeeennnnnnttttrtrtrrryryyyyy 1 1 1111)))).).). . .. BBBBBBrrrrrr A Mg(n-Bu)2 Li
BBrrN
ThTeh eabaobvoev-em-menentitoionneded eefffifiSccciSeihecneSnSShSmtSSSScccct ecccchhhhmemhmhhheeee2eeeemmmmeeemmmm.t etee2eMheeeehB B .B222B2 oB Brroe2222Ir....rrAr n d t....IdIII a AAAANNAAnNNNInnINIIt=AnN AANAAAANANNNnNn nnlN e t==t=t=f=t= fO= =eeet=hrt=tt== e== o o OOOOOOe,eee O r m rrrO OOOOaOO,,Nr,,,r,rrrrmmm, m , NN,,,,,NNl,NNmmmm N eNoNNNNNNppAAeAAAeeAeAd2AgAAAAeeAeeAd22dd22d22ee22dddd22i22e22iiiiMMraMMrMMaMaaniaiiiMMMMMMMfafataatggtgtggtggoeogeeetgtgttggegeg(((((((eeeenn nn (nn (r((( ((nxr““n““nn“nnn n -----m-m“-“““cBBaBB-BaaaB-a-----BBBBBBaaBaahBtuuttuututuueiueettttueuuuuieua))))))nee)ee”n22””22)2”2))))))2”n 2 ”2” ””222 22 LLg LLL L g cL cccg L LLLLLcLiiiiiccccioio oo i iiiieioi ooooh mmmhmmmmmmmaapppplppppplelollloeeelellltlgeeeexhxxexgxxxx.e..x.o e ....n . d n–.–mmeettaalle exxcchhaannggeeo onns usbusbtsrtartaetses
SSchcheemmee 2 2. .I nIntetermrmeeddiaiatete “ “aatete”” c coommpplelexx. .
bebaerainrign gcTTaTTchhrahhbeeree ab aamaaabbbbmooaoovvtavveeetee --e--mmgmmgreeoeernnonnutttutiipooiioop(nnnns(ees)eedd )ddw eeweeffaffffafsfiiccsii cciieSeeiSieSSeescnncsccnnhthtththatt eaee mmebmmbmmmmlleeeieeieeestt s 2 tthh 2h22hhh..oo .. eI eoo IInddIndndddnt tt.ete .ffe erffoorrTroommrrmTmrrh ee ppheedeppdddeeeinieeiarrinaaarr,ffttt ,ffooeteeooew rr“w “rr“mm“aammaeatettiiet eenniie”s”nns””gg o oc ggc c couou ohhomhhmmgmaagaapllhphppoolllolottlelggee eggxxeexttx.ee.oonn . . nn –– ––eemmmmxxeetteeettettaannaalld lld eeee xxtxxtcchhcchhehheaaaa nnsnnsaggaggmeemee ooeooennnnp pssrssuuoruubbocbbssecssttdettrrrrdaauaatturtteeeeessrss et oto
TThhee a abboovvee-m-meenntitoionneedd e efffifcicieiennt tm meeththoodd f oforr p peerrfoforrmminingg h haalologgeenn––mmeetatal le exxcchhaannggee o onn s suubbsstrtraatetess
bstbhawaTerareeqcrrrryaiTbfcsbhaeohiaooleooauubtdueoqarrefyyctmmhmmloionlcrybmabukttddve WtoimbsbsbtbhbtbhawaTeawaTemrarhcbsbtbhawaTerabsbtbhawaTerarbsbtbhawaTerbsbtbhawaTerashllbsbtbhawaTeraaiyooo bsbtbhawaTerirrrbsbtbhawaTerabsbtbhawaTerarbsbsbtbhbtbhawaTeawaTerararrabsbtbhawaTerreebsbtbhawaTerreeeeeee ieerqqepvteccrrrqqqcrrtcrrrrerereqccreyycrrrerrer3aarerrvyyrereqyaarcyrarrraerrereiiorttWeyeaeeiiioenaeqeieeceireleqppiiqqqicrerrrcrrqccrrrriiyiqaacrirerniarercooorrrererlliolayareryyyaoooeeoooooarerllaaayoaalyooeaooelooieaooiaaeooaaauueaiaaoiiliaaiigauuaaiaeuooaibbuittddmlo,bbttidadabittaiidobeelutidaiaeaaeoo3eoeoelooaoooolellaboeetooldecoomoeeoooolaeaooueoocaeaagaaaccuaaucacuuabamt ucdttcammmuchhebctttbdbbtmmmpmttdtyyddhehmmmmbtmttdhbmmlltud rrhmmmmecemmeellrrmm eltrmelrhrliimmllclccihirilenltcccwilmcccchrrlyycctna tmm,cttrmmrmmhyymmmmhtrihhykklmtrrltthyammmcmmohimmmmkkltrtlmmkll rrrtmmklrtryeliirvvileeiexikcvvitiiveeiililvcellic rcceyilbcl crirry rvrryaykyy etrTWWttyooriiyekhckWttWkkttottoTWitik aotiTWtkiotinnvheinnviihhiiTWtnvvvreoiillneaveehwhi aaavehlleeyyhflaar aaoooo ln ayyta aooTWtnooy oooioohy iifoolTWtWtoo oWWtt iiiaoxiooo iiTWtiaaoyno iTWiitioooiaanaehnnnalo nsinhanhhhh lnoylg hllaaooa haralaaaaccylaybnyyoo33aoococu oooovviyhcoo ys33coovov 3iyo ooi vbhii3agg ov hilttto iddgcgaaaaiigaattttt3(gay tvhaaiiattllaipppph ai llppgppl cppnntl ppll3aincnvthcccnll3ancel3lv33hppcvxlivv3gvh3teetivaahiiingaggigggleettaattigiiittettgagaigilemmtaigaaaappiih,,ii tgaoirmtnmlai,pp,lnmllppnppppe,emlaoeelpp,eeilgeppnneenneel mmleenllmsee,enldo m ndmel meaz micccgee eaeeiceeiccachaagiidiimiicge gga ,miiicc eyyyygai mgmy,mma yyyy,,,myyele,cm yy em, rreea m eeeeeeee erreyy meree mhh mmre mcwwhl hm hnncc wwcchcocrcc cc wn yyn nc w ccnnn c ( ceoo n yychnyy yyyy oo wyye oe yy ron ca ee rn rrrhe eoreicbbrw ehhlhhnrbrrrr boccwaah bwwwhbrrrrnsw ecanahe rrnn c waccoarrnd cafhrhn cmTob aoooh hh ao aarr aiioe hhaa hii aaheiaeeedffbni e ettfrrnfa bahbfbbaffftftibrrrrtarrrrbsaafcfaaxxt rr faiiiihtrreefhafxaxhhxoiiiihtatxa.iinnassiiiifhahhhhhnsoonisa iuaaggihnsxiioahhfhnsooiiiag gho bi gfhtuu of gfffss fnsuufbtytuttfbssahrr xfuotsgfy yddffddddiitsr r fxyxr fxxddbyyddiiir ruiiddxiiiinsddxysydiiyhiiionsygnsr nnssinthnsddohhhgteobnoosggghuoyaaeeghsmdobgeuaaeessuuubattser sussbaeyddusyttyyr str rr yddtc oddr ddddaooennbbr iddynn y[yyddeeoo nbnbytonn nbooyeoencnbaeonebbaeoennnd dooinbaenndndateaaeeennaendhhoddatetiiiitthhdtd ehoiiiidtnnbsihiidnll enii omm nbo ooinbln lnnbbonoennmlm nhbed3eeonmlrnbiioenmeneooalndvndnnmddooennnhdnonnnniio naannohdahnonnhhdnn iiddanaiinneeh iiiideelavnnh b ii dmaedet iieecloeb lnenllmvemcelmmlvnn accml-sm crceTecvrocrrssinee-nner isosrrabeoenoosnennco snn rrennnea nnnno earvaannn 0 ra nne edeaveeese eeebedd eveerecevddrrdffcmmdcccBssffccscrmm ierfrrcmbsseeeerfccmsr ds escovsse ttseeeeeeacs Beeereoosrttrrtieefemiitruuortseoorci ieuudeieeouo aiouatdo dddfem dtc sddidcuf mfoffom mmd deestfcs mdss cfcc , tmd iesbeecdeee iiseeeeco teeoiioonntivuttiieee dtt otieiinnitaieiubiintuiitmmuue oinoteeioousssstimmou emei oss ssemss id -noess tcr dur3a d- ddcmc3- dessb aidvoocycccaainaooict-acbbioaiiaciunoaiiiiniilcnnbmbtaittienbttnnssiiinbtmimnotmmneiaassceneeamss-ssssnefmssaaabiiemssa-tiai icac-inccmo-i o mrrca reea aorrboocooaecbreaccaioaavvmiercboaoebaacnbbi vavibiviiabnvaaarinunn1ei,noalambbiamnaattaavabbabnn btimitabtiirLlrbtbbnni rmsshbt nai ema.bn rssr rresbvtteee--rsteeeiirbnatbbttvae--oaavztvvee-iibLtbave-isrbveirbtabddalaattba-nddbeeeabidbbttbrtttdbbne ebnesnbbtnnbrreibtnemiibsnrsssdorrt-isibvveineeisrbr]teeBBi-itrttv-vtt--eeierevbtieeBB-iiebhrrbbvtttBe-iebtBmedieeirrebtrraaaheeedrevtdeeddeaBattedetaeidiereeaiittrrrrvtteiteerteeeebttivaitaeiiremeBbbtrirrtev tievnrvvebeBreeiibbrBv,BBt etvttteB eibeirbtBr iirrbeateibreeee oorta eo aeaa eooniaaenatibo v, nttatt o aaaantyyeacc att aatanttaaycycebt3aeybcoauueeabb tally ca enttibauaeunn llu te ttlibu aibt liiybbct iebaaan,o ib tt uaal aoadtot toov oa tt oaayctao aaeooa naaoycaaoaaaycuyyccggooaniilaatycaatagycogaouniiulgoauuuugnlitllgoutoollittmmdl uu5utlauoloeomltmttuotlmgomp rroail.mtathhaagtt..terarttttuhrhat..hrogolmtto.soohi.gotzzitLLrrrtagzozhgiouggoo.LzLiiirrgllLozolmitrgLouirutluuloltmloulmooll mmnzlruoiislmsLhtol tnmr .nttri iertrrhi nhrlt.hhrnnitrr.d..iihrep.ihnnrrzt.oini rLinrirmmtzisi6ztzzLidaaeeoLlrmmLLz rrrmLznanBraeremsLliiiaeelrlli aevvliiieeeli nmvv naai inneeviliiae evnrasai e nniaitoiianrnnnrnnirrivniiinmiireonuin ooryoaiaieiimioomoiommaooaiemniaeonnoaaoeemo s(oaevoineane i iiani-varienovevv ie eevoaeennnavaao ettan %nnnna nntnnoteii,,ntnoto nli,,ooindiio ,r ourooitt,n nlododiteeo oo ottodntoe benonn t, eTn e nn3bggnttdd gng neuueegnn dnnd t ,gt dppttn cuiuee dnnt ue,pttp u,ene,,p tgt ggb,p ssldedy, diiddgtg –uastesttgxeiisetgpee isteinegttridn gtstg9ugietggnssd sstdgnp dd uge dsus esuusveebdsp suep pps sutegeph slpooi eeeegbgseggtsososisseeddgioooiis georisddotoi deeo dveoat eeeeeottt sppesct eeellMt deppsos s epsssiessllps ls esrlss ouu e eyeeepouuhdo oooaalu e )ou dh((oaoadedd oeooa d((oae rdee(oue p eee(o reereele oeepea p cyppeereelnnovaeple((dll pe lan anelluln nndn srrldlu aeunlnuu trnlru (oornbabbnu a rdaaoTT. o(oabb( ((toalapbTTo(((nbTer(rTrrr(( ae(neideeo(nnbeTnieeliendnnnnnbbnnrrie e(dlnnlebblldaan xxneybnnlrorbrrbnlaatx xrTnan xoiiriaebmo xeaoobbbT (boTiibTTrtoibTtgssfri(aTn(x i((cvrssn(as (vves iinllibii nnnve nttlleeeaee bnlxbsbbetlt ebeeatxaTlbetaamtxxxivv eaaaxavlniexvvcciaariviiatsvecica cir escsrrss ssi v s vvyylovvar srss er s tcyy))lrse lyallhhd ri y)e)tlter)ttel ehhee)trsivheaeth eycoovievavvvaaa)toavo((cahcpovcc eaaaaaoaac((rsc(aoaaa vya( aa rsersaarrsstt o )y rbb sy yyehootrst a( y)(tbb )ttyaan))faeaotboh )ehobhht at)aohdht aoholtaitdvfb( oooiooa aorrata( fai(aao((taafarar( aa aantr( taar baaiieeoft tttbtaiiebeLbbtorieot oofftbrrr i etaoccbrrtattaa ttfofrr.t afcrcrdritfatafcrtrwwiecrfnfr twwhwvffrwrf llfttcrrmm rrt efr hltltvvimeeemr l3tmweltvvmeeiefiveoiiepeefrveiecgpri iet elftrmtoofttrffrrciric r fccrrrwvetoo feaacririoforrii crowawaywwifririaiiwoeeltrimawf riiioiiiefevlteimeiletllmttmmieieilativme[irivletvvmeeiveivvie etovviii 3ii ov aooorinnff sco) cayeiongfnafriddiaaerinefrriiasiiinfri,dvvdacii eriidciieiiieedvv)iiiie vfeiiiiinfe ttvi nncttittd aastn3nhtitvt hnvvtvvaa ntia c nfa tc n..ndfn n ftsnnff aattic.na..fsvd .ndf ddaactt.idavictiiv dvvat it veii n vthh.o t eae33ttteeantnhhti nt nntehtt33ippateenaht3aasgge n t3 pacp epag g . ipg ea heeaiigt 3.e .e ..eyyeiiat.paeitssaatt.eyygioa ty3asastetieeys0hs3e[[eeieeieeceeeheeh1ehhp[3ei[ye3tth33[eigee seh3[pept3tppegoe tegpgg tesccipg [go yscsceisseaicee,,siitsceyissysyy,e,iesses,yeesss1 ,ys[ehceeeseeeoe ssex33 e[ehht[se[[e,n sas3ii 3[ shnh3t [ tshtt3i iehctin T tipsc r s s sc 3 e ,ssccna hr scn,n s icw,sfss,e,, s,e shn, e n e see 3 h e e scci3 s ss3 h33 h hhscuc3fee aai shic3iin n hciea eafeeeia n 3 ea oo ee e 3n e cc 00no oe 33oeacc00 onl1130 be cc0i e ee1c1 1c ocoo eu1e e0 tooeace- ctocc c oc r 1eaeeaceeaa tss eea o t e eha eeeo sso0 o e s o3 ooes3c33 0ot10i00nn oc0nnececc1yn0ns1sso11hcnonn1ec nnppessee1nBoseeotaaooppase,,op1 neeffatoparbns,ab,eeef,tfahhs nnf,tsi sefessphahn neash B neashbnd nco, uunff fnsnuunnffenhnunfnnnp33sufnnsssaanp3s3b,ppp 3sfetap3ettueeafbaa,pm e ,h,,lfantftff,as t tfae,3eh met nheefhhnmnn etth--ne yhufantrrt -t-t dm- u lftr ur fuu-ff3nr u f]r u f3 3t33 - 3t rrm3 yysraanoo tchtyttmy aoao yt BBao ymta tao-hnm11 BB arraBarbbtbb1-t1rBtt- y--r1ran btab or bbr-1r ibtrr aa br- haab r b Bbbaras aaa 1 sa barb nr,abbycb naob yyaaoyyBaaoaaooyttabor1yBaorBBBbat btp–a1aaBto111rBttbrbrr1babbbbbra1bcbbbyyribdbabraataa–bddayb yaallabbybanbbabdyedla]]lbdlnnbdl]]dem]nobyeerrtss]rrnntucchhd9rlrssstrrntnrsttcrchnehr]stcrihnetaacdh5byyaiardsardbiinlgybacybbyyhebiydi]l,dbddliyllndien,,l]nnad]l]]roes,h,]rMne, c]hir,srrsnrrrssrrmncinnhrrcscchrllhh nt––rascrdoohnM,cttl lh ––alo to–aaacctitlto tii–datrroactc iii ddic riiriclr ,i ti–dmr oit) dd,smm,,,eeci,ddmmr b99,deem 6deiilm tt–99eoed9htiil t559–l ill– o––iidcwoimoitddloo t5–5ethrttl3o t5–iih ctdod95iichdcciutdriidiiddricrrd i c rihwoor d5cmMM eiiododMMm9oda1 dd mmm.eMmmoe dssieeMm 9mdmem999hmsesi59imsuiiuotti19sMhidi 5i5tt55i bh itdii5mhdddt5is di))c d o M)) t )gso% )66oMoomM MM os 6M6o m6Mom mm)s6sssmct3orogmsohh uus3a3iioct 6tohhtthhuu3itihu ccg hithh ) u yohicc haa11..ot)c t o)))cTha1a16.u.)ia1. )h a1 .6o6 66co 6bb6oa1. ibhbutliccb3o3th33brohuchcihhucuuoic%%ii hhuhchhihucb%a1hi% e. ccce%h ch% a1.cca1oo.aa11ogg..deea1.aaoooa1gog.%o gdbaaonogdrapyy abtcbtbbeettttyooyboTTgrdycbetetctyto%cco aeteTTtocetTtocd%f T% %% y% ooet%g dt oT rrao ogdoogoohoogg rraogradwfaaoygrdaetat oyeTxyeeyyeheeetrtyetgoeetttoTetteooyTeteeeTTetobetedrrTeteppo ye T arrwppr w puddrr ep e dd rddffdr rrdr rpddf f doordf duf eohoe d hh o eowee hteehedfreehpewwe yhep ebropwr rrp m ppdr r eepbbrh ddpdd yyd effeddddbbdedwwdye b y yde duufdo bdy fdddfw ffw ydfxwuuf o xdwu fhro ooe u btod hyofh hhowwhhhwwwiuuhhhh ehb..dpp yfe.mm.ebnweerrdppb.bbd yddueipof hy.m mbyydrerpwm bywrdwwfoum yueevruufowowu.eepnreuxxemeerhxixoxo xheoohehheiie . hroop hoi i mx.olri.pw..epi o pp.mnn crpcm.mmrt rri pomoennrmwinooirionxeoe eeoioeeeonxexeoxxoene xoexieees reeo o orrreoo eii eieeoiio ereroeiww e rnri cTT ccrr wwntxn wTTancecoonnwTittehciniiT crrnoltreocoornnuwoeTonencdeenehhgsseene rressnooeeeese eearewrs cc ronoerreTnnco errxxwcco oorwr nwwTcnhnlcxTsxwTTccntccomoxelltwTttnhhcorrx Tocol lnhdrrlcrhhlnnsrxnnnsohth nhenhslosrsse scorisontooyxhhheecoo cccnoxntdhinncheexoddlxxop hconehrooxhhnehhossdxd l lodttrll prhrrsdslppsrtrtlheeessrth hhhtiiaedehyy p aieh iiseyy ittootyirythettoot oe ihtedoephethhiee yhhesdipho edtddtaaodsiipshssdtpateatt s iimarr)stttiiayeti egr reet tiroeoityt ii ohyreyyt i aeeooiyloi thhoytttoeeooootwerhootol hte e))oo t ggo))h aeiooi) geegn)ogallooitnasraagiotiialolwwi llhhealr)itrrrtlwttw.lhlg htrwdt el hoiirowtl hhh hhileittnnoeoeei ooe()eitwnotn lhetno gne.. )tn i)o)) egi.r.)ee gl gge.o)nnogoo.tn g wlonn lhul pll onrnnr rlniw nlhw.lww lhnllnihheewi inlhhrwnl hetneriniieiin rrrreitn nntnittnn urnrr.rr tnTrnrn tnrnreg. .nn..Tg.o . n rgr nnnngnr gn e n TTenrggn i wnniii ggTnTergggTenee rrfrrgTgesigo gngeesg grr r fgrrrrrn fnTrmnnr ss iiooreenr,,ssmgngsiosioeey,s ,sfsioe,s sioe,mmsp T mg m gaggm gs iooTeg,smTTTfTgaagagggToag ggftgoamagg afgossattioefeo,sh daa ettsioe sio,sthsseiiooee,s ,,ssaaaetsioeoumr,shhsio hea,seea uu rra mh hhmmmaet euaurrme h hurmeaa huaro huaaauuaa aoaaearuhtruau hohh ua o utt hhttaa hththplwwehppuallhhuasraaas hwwpbaplelwuehprlaeelru hruuwrrp ahel hhure huooorru ahuaraawoptolnnanoua huo uunnurn u h uenih hh ohuuwpttlhue ee tbbu unetwtpbuwl we pewwltpprllbub ewtpbl ewpblrourppt.onmer eoooybp opponpeyonymynn dp sm n ooyn u to oo errpobeemuloutuur rt ertte eueb reuueebtebbu retggeb uueobuuggpgruddgmgregvv rpddnnmpppdldvvyu pydeenyyvnm vo pgnvmn essnel lloeroooedessollvserolsrnesurrelleergeeoorueuuuidWgsooudglggssouivigonondgssnndddddiisvieevdvvsnndndnsdnnvaondsenvnttdleeenndtriessttslessltrrllesndtlppsrrtlottrpper potaatitrsopoorete i o,,iatiip annsdoeras i ss,,ta ips,nde ndsnn,ddtatnd nd,aiiit t t,rtt cciiit piatrcicrtrrecp prrrc ppanc ioortiprrt tter ri p ,et eeoto ra i crarnoaatr c 3r ,noa i ,r,,a i xss o, r , r os snppoilrrs s pc p lwwlrrih ipiipss plwciwrrcccwirsssr cwrnoscersprw plern orr wweeoroowwrwr r rrenworr aawerwsen wow aassweeer aw aawe wa aaepe sdpasatess taesdwpdrlwepslppwllswpdeoowawruuwprwwarresaogowsrussuaiio,werusousiigwewcdi..giaweawo.w.eeuwwueewww.awewa.gaaaweeauiwaaellsaeeaaedalldeidd.lrteeouleeg.louiottessoooou uu eoglutstsiooo ui t.siiog tsiog eli.....eetseelo. o e teeouueeel le llteleuu etseol u pplueeetsiieeo ep aap eeee epoiiietspaoa ts uittosse eooa itssseoa tseoe sseddsp(uus eiesdd(a(upuWWeduuedee(ueeWWebeeh epW uu seueuuWuupeioua dhuttiuueuapuep pptWuti p haittiiasepaahtesi ee a i e ad(uud esu sssbhtnsTWdr(Wud(ddsu((uu dTTgg nu eessWdWuWWTgug ue seWsttg e sWehtg etsututuu hhtph tu tt tt u hhgh etsh ff ht h h t ff llee feflehleTleg TesTfleTTe esfg esgt sseggs eessastg esuutle sstg es htstt uau st uhahwwt hu hhfrr hww htuuswffttlearrfwffaaurhhuuftttrleaulefaleagt lleehhruatlheawaalhetrsaauueeutws aaashessseedd uesu uuauwesd dhua d r u wdw uwwit w r ewar heerrauwr turuultdatteiireuhauaathtehhruaaateiaihaala ieehlaieooieerr eedeooieereelro iss reo dedeeredd bsss d oesededbnnb vseo ett re bn nooliteernt e e tneesdl teeeoie ieeiieoeleiolnriehhiteoee oonoeddrooi hheesrerroheeddr oih dsinnr osssder nbesneexxbntbbsn ehon nxenxes nntdxt ttneo bx t neann e eetoll n n ieonnenllhxh hhnledoo l hl hhehhhhssood hlhnldnondd hnlsolccsd glesxdn onscnnhch cn xgxdocnxx g x n s x nl een snc gn iinnleehnxlnllettoiinleehi l htccthhcsioteeeeohloo ltccllhnco segeceesessttlo ceismcgectscctthtc gwt coeecgl e ee ssttee bbcciteeeettecteetbcbcieieleiibtic iiooecet bciteetteeeiiioe oeteeci ocdtcctietcco eeceeebcehh eceectcetttchh iillgtoche the llt et el oo ddebceec iilece te oodhdtettibciodebnnicsbbtyccieooceedtbtliceennbiceoinii oooenicodo hhii hoee c3eorrhh ccchnluuhthhhc33rhrbccheuttrulh3lurolln d iutttt looid htilodottntdiooooddni r tiinood utioodn 5ieecnnn tthnneehnoot oe lereooih huohh ff3ohr3hr33torruhdeufifnuuraafteeurot tfotturrnaaneteot o a teeo tttrnoor a etrn o f a,etr o y ,,he aoeeeeee o,ar3e rfeeo te oueoooossf eonntoos–os fafosqqeffnnt oo sf ene r–qaqmmf n ea aa– qe ee r aqmmrerr os am e rss mneoor – , sqes,,,ooso os iime o eee o s ieiww h nief –so siqnowoswqootssenwaons–nn awo mesq ddnneexx qqq–iiit nr–qmd edx x mqmmidi xwsi midoxfmi,wwssosso muuoownnwsi dxowsiuuxo wnn eeiwmuaa iniiuumu nieeao waswieuuwwadwneuawhd xuemuwvvnieqeewppdxvvdxdderimxxavie iipdupxvipdwxipfmusnnwowvwwmunnwnetupanuunwnnumutt nniemuaneuaeeuaattuuuetawooeuvtaiiupaooveioivvvioptv pdppivllip ceepaoo rrlelo tlieeonoorlrnennorwteoiir hueentiillttteeioeeeetoiribbeeateeeiuohheiiobbooieibiio hhiiibiohlie ih ivete ore l lp llbt te oerle eeohroorrhiletedvvioreddeo rvvi dleivnddii eehvdeb iieeddcderro iehetteeibebnddberrbbdvthteribhuuhhditdr iibhteinnuuhggio ur llr aaietnnudtrggtt nrtrgllea anvglead rl auvrrvlvved nd vdde grrdortrvdvii lratd rdirihhdddrttrriuttdttiirhhdteernrhsugtiuhuuyyleeaenuteingnnbuaagryeygglarnerrlyagllhhaaniaayglaaeeirladageeiei rtsaielluyrtrr aeirratldlhioortt i lii talrrillohot etteahddivdhhotrlrlhod tyerdldheleerdla aeydyyyeotd1ayraeeaatyrlaadeeaeippeileeiiuee aeaepp eleoetplg llae rp ddlrllllaetto tdalo toott dladlrrtrtlotrldlorrllt d optddlerddt rlrttoor rdlr rdttoonltdloetito rerpleeeehmmttle ptomepmtltppeleeemtpeedl tmet(l pi yeeeee rsdl tdle tddlltta 5eee dslms t rtetormdlrr t sses r hheit olaarssteottooshhtoalsahlelt o ah moot aleelohhaotomstimotmmettheerlcdhhoo maeth metehe euuee9m ee os feueeuse sss euehh ue a sdesgssh nntth ashheaeaash u onnpntn tahe net aeh nnnot eo noo te nhoeee)h hhd lotehnt ueetth r nttu uaauutee 5toftxxuauaee55rraxxnteseaxe5rhhtxrn oont aa r entnntteerhhononmtataeanhenn on4teae ehx unoea nher etpp.pheexoeastpetpatteeepenxtexpetaexes5artteaax5ee55xhxxaeeatthttarxoeaprtrrexxetttrhohtatthhroooaaateoheo eeattheolleah tt etccpl ltex l c clp ecxpoppe taeeffucpex tp --fexftl f eet% t-f-cttt-ii e ett- te t tttanii eft fci ee ttalllinat tti- eer tcpa cleld e lt lssclell ssilcl cccscsl fssscscscettss-ff sfloo f ff ehhssss fff-oos-rooa if--feshs 5heossfxtt s-e reehsooo-i hesiocteriit e olootai saftoaaiuceo oeooaeelhs lsollecleso ocleotl-ss ssshs ssssf ossonddshsoo..hpsfesaandndhoofssffoo.dhooos.st fhshhossa.ndoasofoha.sooooooaathtashtootttoouuotaadoeitoao.toouuooaa uol.uso tffho a fdfnnshu)lo aa of. fannndhcss anadnnddno.hao.ooww..ndassaaooaa.dsafwowa.r s fwuaotaownooaaaa-osumauo uusauowimmufa rr mdam nfmafa reffr AAmm mdd a rl fns ranf Amnn Amadaa ws Amns . a Asmsnmss aasws wrwws bbwuoaa Amwbsbf aobnnaShasbomaanniiorn m atnmiwimmf Amrbimrd arr aggdiu ddm aro Am A mddr AAmmngg Amg dd Amgi d bdnatbgbnttbbaunwadaabnnd--ttaibnwwo.ntann --atni w-winnii w- g i w oi da tmmg ngggu -dssgmmwdddgmdnssmAdsu snssggtbffoohn-m sseeg1gtwnstgttnososPPae-ge11to-oo--weeetow PwwP-e1oiPow- ee wsoP wgem o eeebo esuum eemmmPgeuusmotseessumussggsgoemsttglesgssggruoiPstgoedt1 oooes1geeetg11o AmPet oPPPo-eeo ooPeee oPee otue egeee5uee u euubg e 5u5eerii buesg 5 etngieioo t iii ddtita irrootiittodd eit rordit r dtisseer g s ttesPssed oetti ssste tdsterettess tt es 5ttties5 e55ees e tet iot itietteiitd ttsir so-ittuioooiidiihwtdoddritrddrrodrrt)sie rdtt ddMMrrre))sdhet.rsrrstessdeeMtMr)teshhtteMtrrsstteMttsresshhsttuutddsreshdrthhshutdudttM tttud hhut rdsuuhg t thh to attuue 1 dtur ud tuP hMdor.d)ebddr)rrr )) dMri. .huMdMM eerrrrM.rrhueMdeehrhheeeurhheudh ud uueddesh ueuhdtthh iued h e ttuoh u tuu tte sttu..f e uottpp .ot..tp pee.t.ee.pt.. peeoeetemme eee .elmmp e e me eeth m5 eMttee trreot t ttssttti rrt.tmo rtsoosrt pt rstonn tt.oi oso.o..duoteponnpr.tggppton. prenegpgeesm ugyye sgeokmyt yqnm mm y n tmtsy rmg eestnt ttrnu ere trryots e srtnssrr e iirsoooonrsrtnginirottnnuuioron egitntguyuggtugdSStruee)gyryyyniSSMeieytSeyr Snteue hn e ne eer ddrSuCCd essie eahddrCCssrditrruC isiidiirmChhs iuoommrt uddtiiiuttuuhyhSiomomteuhudddiomtC tushdomSeSdgSSeeeS. eiS heoomd e d Cst ss gff dCdmsddeCsCCssssuueeifdfllChssofmdCsdsueufeliltiuheiiluuomhhhuoemdlioomm dhddioumushdftoum s d.ueuel scseu sftcc euessffttl mfees ssfc cffsftcfutefleleullesfluutcee uflleftueyylelltu e lhul er uyuuyslc ysuftyeuslloaalns ll saylaCalugc af t ehbbssc aauceeyccft lemu lbfbt ffttecssaaeeabdemebbftycsae eb elfts ael ll eb byaaeeu lyb yylb eyaeabeddlsayae eaae dddl bldllsa aiduaal alaeobautsuanaaed nnu bsbaaaubbbseassaaaenb neeSs aae ssnbebsaean bebb s sbasedbae aaaee s aen ccdae rrddd ccddsss rrCcbds rc sddtsreasrrssbnsddibsahdrrcsasmaanrdrdsnsaynnrsanslllb nssssdlls rlsss sclr nn ss scscnrbnpcc s rrrnl cffdsrn cbsiissrsrsttftffsdsbidfiysddattrtubsteiflrsndrree sstidrtttslooerteaiisetuttfoeoliiilasffolltitteolitn ftafslstsefssnf sn nno sisfn sizzt uunt oo fffzzffi uhht uitzoiiof eut sttzoif ftuhhntetoiatohitttte tesheet tlteto tziii oufiooteiioytottittddiihoosofitifff dtidoofsqqdotfgdyolz((sqq uooaosqir((qzhot oulz(zz urod mmuuoo o(zoo ouhlzohm hhttumr qomt hb hhsamhrt( eittottt hhtdeehoibttttihiimteeidtoqdaeddoiooerredo(qohdoqrrrrdqqt r99ee(qto(nr((rqroemoor9e9(erot9ee(rom9emmmttrerhmtrrrtmrahuui9eherhhrntuutr hottururehtuenffueeuo rrtusue fufe r rfrr9errfurrrrr9err u dd9ec99eerrr9eee rf ddiia9e dsrre edirilaehuiettrziurss rrrsua t44rtuduufas tsur uu esuut4 4 uicsu 4f fff u4 laaf aatf sdidaas4ea uuid nad dd e uduaeieee uidiitettuisafaettmtteewwi4ttitttmtt atttstttteewsewtasstttt4 utewt4ts44tt tew ets 4 4 iiaot i mt ttdi ewitta iaaaufia t%%ea ttuu uu%%tu%itetuew%eettthhhhtttttt zhhtce ewettttttttewoheetwwhehhtt ttttth%hhewehthttthhewhtzzti h ztzc tie zi eiihhnntzhtimmtt%ii iin n tesmmntt itied%monzt% ii%%mtie%h%hqtheeneii(eehmhtthoihhhhethhtthhhiihezhthihhthimdzzzzenddzitmttiznnsiehdndoonoonnmdtntnimemmtndittniieovomoenontiomoeeeetieetoeeodeeeicceaeeerseeneaeeieecceioeoiciis9ecisi))eettedenn))ictts)dotdodd)nwitndnnroodnooooeuooeeneoo)tu ooceeeieseeeeeeeieeefeeeaeceecescceeecsc)st ) dt)))nt tt ) t o i) i t ttt vs4z iea t u tiitttewtninoo ye%eeccsehhthznmi.idnoeeeec)t
aarorommaatitcic h hyyddroroccaarbrboonn d deerirvivaatitviveess 3 3ee a anndd 3 3oo w witihth h higighh y yieieldld ( T(Taabblele 3 3, ,e enntrtireiess 5 5 a anndd 1 155).) .
aaaarrrroooommmmaaaatttitiiciccc h hhhyyyyddddrrrrooooccTTccTTaaaaaaraarbbrrbbbbbbllooeellooeen nn33n 33 .. d d..ddBB eBBeerrerrrr––rri––iMMivivMMvvaaggaaggtt tti((i iviLLv((vvLLeiieee))iiss ))ssee 3ee 3xx33xxeecceecc hh a hhaaaaanaannnnnnnddggddgg ee 3 3ee3 3ooo ooooonn nn w w wwbb bbirriitirrtootthhoohmmh mm h hhoohooiippigigppggyyhhyyhhrr rr ii y yddiiyyddiiiiieienniieennlleeldldeedssdss (bb ( ((TbbTeeTTeeaaaaaaaarrbbbrrbiilnniillelnneegge g g 3 33aa3 ,aa,nn, , enn ee eaan nnaanccttcctiitrrddirirididieiiieecceiisscc ss pp 5 pp55rr5 rroo a aaooattnnoottnnooddnnddnn 1aa 1 1..1aa5 5..55 ))))... .
EntryTabTlTTTeaa aab3bbbl.l elleBee 33 r33..–S ..BB MuBBrrbrr––g––MsM MMt(rLggagg i((t )L((Le LLeii)i)ix )) eec eexxhxxccacchhnhhaaagannnnegggg eeoee Eono oonnl nnbe bb c rbbrtorrroromooommmmpooohoopppippyyylyyerrrrriiiddididdiiinininnneeeeesssss b b bbbeeeeeaaaaarrrririniniinnPngggg rg aa oaa nnadnn naua aac ccacciitdidicddiiicdicicc pip cpprr roropoottrottoooonnntn oaa .aa.n ..Y ia.e ldb,%
EEnnttrryy TTaabblele 3 S3.S u.B uBbrb–rs–MstMtrrgaag t(te L(e Li )i )e exxcchhaannggeEe Eol olneenc bc tbrtrrorooompmphohopiiplyleyreirdidininees sb beeaarirniPngPgr aro anodn dau aucccicdtitdicic p prorototonn a .a . YYiieelldd b b, ,% %
EEnnttrryy TTaabbllee 3S3S..u BuBbrbr–s–sMtMtrraggat (te(LeL ii)) eexxcchhaannggeEeE ololennec cbtbtrrrroooopmmphohoippilyleyerriiddiinneess bbeeaarriinnPgPgr r oaaondnd uaaucccicitddtiicc pprroottoonn aa.. YYiieelldd b b, ,% %
EntryEEEE nnnnttrttrrryyyy TTaabSblBBuelBBrre rrb3S S3SS.s u.uB uutBbbrrbbr–sas–sMstttMrttrerrOagaO agat t(et teL(ee L i )i )e exxcchhaanngEgeEEle EEeol loellenceencct bcc trtbrttrrorrrooopooomppmpphhhohhoiipillipilyeelleyeerrididinineess b beOOOeOaHHaHHrCCrCCiniPnPgPPPgrr raro oraoondodndd audu auucccOuciccOtdtittcditcic p prroototonn a .a . YYYYiieiieeeYlldlldidd e bb bb,l, ,,d%% %% b, %
EEnntrtyry BBrrSSuubbsstrtOarOatete EElelecctrtoropphhiliele OOHHCCPProrodduucOcOtt YYieieldld b ,b ,% %
12 EEEEnnnn12121212121212t121212121212t1212 t tr r r ryyyy Br BBBBBBBrBNrrrrrrrSSS1S1uNNuNNNNbuNauNHNHNNNNNNNbb b b111111111111O1s1111111s11111111bbsbbaabsaaNHNHaaNHNHNHNHbNHNHNHNHNHaNHtNHbNHtbbabbbaNHabaaaNHaNHNHatNHNHONHNHNHNHNHNHNHNHtr r rOO OrO a O BaOBOBBOaOBOaBtBBBOOtOOOOrrtOrrrteOOeOOOOO rrerrBBBBeBBB B BBBBBB rr rrrrrr rr rr r r EEEElllleeeDecCcDDDDDDcDcCCCCDCtCDDDDDDDCtMCtCCCCCCtCrOrMMMMMMrMOOrOOOoOMOMoMMMMMMOOoOOOOOoOF2ppFF22FF22F2Fp2 F2p2F2 FFF2 FF222 F2 F 2h h h h iiiilllleeee OOOOOOOOOHHHHHHHHHCCCCCCCCCPPPPNNNNNrNNrNrNNNNNrNooN33333333o333333NHNHo3NHNHNH3NH3NH333333d333333NH3NHdNHNHNHbbbNHbNHbaababaaada3b3daCCCbNHCbabbbNHNHbabaaaNHNHaNHaNHuNH CCCC u NH b NHNHNHNHuNHa NHOu OOO NHcCCOOOOCCOOCOCOcCO c COcOCOCCCOCOOOCOOOOtOOOOtOtOOOOOOOtOOOOOOOOCOOOOOOOOOOOHHHOHOOOOOOOOOOOOOHHOHHHHHHHHHHHHHHHHO O H YYYYiiiiee98eell059988989898l9898ldd98989899889898dd00550505050505 050505005505 05 b b b b , ,98, , % %%05%
3 333333333333333 BBBBBBrrrrrr NH1111111111111Bbcccccbcccccc NHNH rNH NHNHNH NHNH NHNHNHNH NH NH BBBBBBrrrr r r CCCCCCCCCCCCCCCCOOOOOOOOOOOOOOOO2222222 222 2 222 2 2 HHHHHHOOOOOOOOOOOOCCCCCC333333NHNHNHNHNHNHNH33333NHNHNHNHNHcccNHcNHccCCCNHcccccC CCO O COOOOOOOOOOOHHHOHHH H 898888888888888899999999999999 89
6475 664477556475647564756475647564756475647566447755647564754567 BBOBrrrBBBBBBBBOOBBBOOOBBOBBBBBBBBBOBBBBOBrrBOrrOBOOrOrBOBrrBBBrBrrBrrrrr1rrrrrr1rr1r1rrrrrrrrrrrdecf 111111111111111111111111111111111111111111111111111111111111111dd1ggddeedggdHNgeegffeecffdfgfecfNHdgddedgddggcdeggedgfeeegfefefcfffNH NHNf B HNHNHNHNHNHNHNNHNHNHNHNHNH rHNNHHNHNHNHNNHNHNHNNHNHNHNNHNHNHNNHN NHNHNNHNHNNHNHNHNHNHNHNHNNHNHBNHNHNBB NHNHNBBNHNHNHNHNNHNNHNBNHNHNBNHNHNBBBrBBBBB rr r rr r r r BB rrrr BBr B r B B B rrBBBB Brr Br r r r rrrrrr DCCCDDDDDDDCCCCCCCCCCCCDCCCCCCDDDDDDDCCCMCCCCCCCCCCCCCCCCCCCCCCCCOOOMMMMMMMOOOOOOOOOOOOOOOOOOMOOOMMMMMMMOOOOOOOOOOOOOOOOOOOOOOOOF222FF222222FF222222F222F222 F222222F222 FFF222 FF222222222 F222 F 222 OOHOOOHOHOHBBBBBBOHOOOOHOBOHHOHBBBBBBBBHHHHHHOHrrOOrrrrOHrHHHHHHOOOHOrOOOOrOOrrrrOrOrOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOCCCCCCOOCCCCCCCCCCCCCCCCCC333333333333333333333333333333333333333333333333333333333333333dd3dggddgeegdgegdeegffefe3cffdHNHNfgf3HNHNeHN3HNc3fdgHNdedddggggcdegdfeeegefeHNfcfff HNfHNHNHN HN HN d e c f NHNH HN NHNH NH NH NHNHNHNHNHNH NHNH CC CCCCCCNHCCCCCCCCCCCCCNHNNHNNHNNHNHHNHNNHNHHHCHCNHNCCCCHCCNHNHNHNNHNNHNNHNOONHNHHNHNHHOOHOHONHNHNHNHONHNHNHOCOOOOOOOOOOONHONHNHNHNHONHNH NHN H OOOOOOO OOOOOOO O OOOOO OO NH HH H HH HO H H H HHH HOH H 688750018877886687868786878687868786878687868786887788668786878600110055010501050105010501050105010501050011005501050105 87860105

1g 3g
Molecules2017,22,1952 5of12
Table3.Cont.
MMMMoloooelllceeeucccuulueElllseee snss2 220t2r0010y117177,7 ,,2, 222222,2 ,,1, 11919959552522 2 Substrate Electrophile Product Yieldb,%555 5o oofo ff1f 112122 2
MMMMMooololloeeelclceceuucucluulleeelslsese s 2s22 020021011071771,7,,7 2,22, 22222,2,,2 1,11, 919915955925225 2 2 555 5 5ooo fofof f1f11 21221 2 2
MMooleleccuuleless 2 2001177, ,2 222, ,1 1995522 55 o of f1 122
MMMMMMooooololleeellleeccceciacuuuciaiaiaTaiaas uuus ss R ialsl al iaiaaiaTRiaRRRoRRiaeese lols oos o sls o111111RsR RReReRsRs111111s111111ee111111111111111111o111111R111111l89oeooeoeoeel89el89sl89os 89 89 111111l8989s111111111111401325a111111111111111111111111111111a111111e4013252a2e4013252111111a40132e5ae401325l8940132e5 ae401325e40132589a a 8 9fal89l89 a89al89ale89 89 l89 2 2 401325 t a4013252 4013 25401325a0401325ca0a4013254013250401325a245013aautata tafa ac401325 atc c c acce 00e0 ete1t1 1eu tct tt c c tc tcctctttt drce1i1ee1dee7d7id7iitdeitiittotttrtto7o7doio7ododi, id,id,iiid i h o p tnooo,oo,op,npnp22no2pnn n h p2n2npep2nr npnpn2n22pr nr r r 22coe2,,r ,croc orc or c r crc o r ,,o,co1c1d1cr oocooccoco o oood dcdod11i1o9no9 o9ooodonddnunoddnnnldu99uui9u555nnndlnnnnHuldndud5ucH5uduHddH5HHHH22uuc2ccclddHddHiddHd2Ht2HHH3Hc2di u citc iHtc3tciii33tt3333c.sCtt t .it.ttt. iCi3 iC. t 3iCii ti3CC3tCt3C333i it i ti3sit iitt.tt ott C.H.C.CO .HCCtCCoCoHo. HHiOoHHooOHCHiOHH HiHO HiOHrOi OHiH iHBHtHH HiHHoBBHonBHoOBoHHBOoBHHoBOOoHHOHHHOHHOnHOCHOBOHHnonHraHOnHHnnOHOOHHHCOOHOBOOCOOBBCOBBCOBCBOBCCOBHBOBHBOBBrBOOBOnOOOHnBHnsOHnrOnHnrBHaOnrHHBOCOBrBOrrCOBOrBOrCBOBOsBCBOBnHCsOBtsCOBCOBCOBOssOrsOrOrOHOCrOBrOHHOrrOHHHHrHHHHrBH:rBHHOrBHrBrrBsrOBBBesrH:ss:rstr:srsHNBr:OH: r:NOrHrOrHrrOrsHOrHOOrHHNHrNHrrHN NHNr NHN HNNHNHNNH N NNN:NNe:N:N:ONN:O:i:rO rO1OrOrOHNOr:HNr rNHNriNHNi HNN1i HNON111HN 1HNNi11 NNirNi 1NN1-1N1NHNN111NN 11N1NNt111111111111-1111111111-1 -1N111N1-i--11N111N11i11N11i11N1i11N1111N1mNiP1i1i1N111111h1111imN111P1hnk111m111N1N1P-om111Nt11PN111m1111NNm-111N1Pm1mNN-PN1P11N1N-NN11N1--hnk11N1-lij111hnko11N1111hnk11N1oH111N1hnko11N1hnk11N1hnkohnk-ooolijlij11N1HlijmNPlHijmlijNHNlijmhmlijNPNHmHNPNmHNHNPrNmNmPNNPmNPNNhnkN hnkohknhnkoohnkmoNNPhnkroehnkNNrhnkohnkNro oNNlijo N rlijNijlrN rHlij lijHhnk lij H olij Hlij lijHNH HN H NM N N lij N N HNr NM Nr MNr MN re NrN r M NrMM N N NrN N N N N N N N BN NM NB N NNN M M M B MMMeBBBBBBBBB BMBBBNNNNHNNNNgBBBBHrNBBHBeBBHgBrBBHBgBHgHBHBBgfrggrBBrrBBrrBr BrrrBBrBrBrBr BH BHB H gBBHB B HB gB CH HgBH grfB gBg rBgB B rrfBrrrHBrrCr BrrrBC grBC BrBr rC CB C rBr BrBB rrB Br rB BrB rB r rB B iB B B B Bfr rrC rr rrC Br Crr rrC rrC C C r r r rl r cC r rr irl rrr l rl r r rrlrlrlrrrrrr r r c l i l Bl l lll ( BlBBBB B(B(e ( ( ( ( i1 BBB1BrB1(B1BB(11(1(e((r(Brrrnrrr( .1111 1 11 .r . r. r.r1.r.0rrrnr000 0 00 .t . . .... . 000000 0 t 0 em ee e e ee qemeeeeeqeqqqqqeqquqeqqqquuquuuueuutuuiuuuuiiiiiivhtvvvivvviiiiiiihvv.vvvvvo..v...).)))))).o..,....,d.,),),),,) ))) ) DDDDD ,,d,,,DDDDD,,TDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD,CCC TT T T TTCCC CCCCCCCCCCCCDDDDDCCCCCC DDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDTfTDDDDDTTHCCCT TTCCCCCCCCCCCCCCCMMMMMCCCCCCTCCCHHHHCCCHMMMMMHMMMMMoOOOMMMMMMMMMMMMMMMMMMMMMMMMMfOOOOOOOOOOOOHOOOOOOOOOHHHMMMMMHHMMMMMHMMMMMMMMMMMMMMMMMMMMMMMMMoMMMMMMMMMMHOOOOOOOOOFMMMMMOOOOOOOOOrOOOOOOOOOFFFOOOFFFFFFFF222FFFFF222FFFFF222rFFFFFF 222FFFFFFFFFF222FFFFF222FFFFFF,222222FFFFF ,,F,222, ,, FFFFF 222FFFFFFFFFFb 222FFFFF 222 FFFFF 222FFFFF 222FFFFF FFFFF222 FFFFF222 222 FFFFF 222, , , , ,,0 , b , 00 0 0 0 0 r 0000000 ro 0 ° °° ° ° °° o Cm°C°C°C°°°C°CC°mCCCCCCC,C,,,,,, i ,,,,,,t,n,i tt t t t t h nhhththhthttttethhhehhhheheeeeee–neeeeeenenn–nnnemnHnn nnnnHH Hn HH mHH nHH HnHnH 3nH H Hn n n H33 3e3333nC-nnHnnnnCC3-C3-HCn3-CHHC3CH3--H3-3He3HHBHtHH3HHHHHCBCOBH-CBHHCH-CBHBH-CBHCH-CHHH--H-OHHHOOOCHOaOHO-OHHHtHHHOHOBOHOBHOBHOBOHHOOHBuBHBOHHHOOOOOOOOOBOOOHOuCHOOHOuOOHuOaOHOHOuOHOHuOuOOOOOCOOOCOlCOCOOCOCOCOOOOOHOOHOuOOHOHuOOHuOHOuLOHHOuOHOuHOHOu COHHOCOOOHCCHHCHHOHCuLHlCCLCHLOHHOLHLCHLHHOCOHCCHOOCHOCOHCCHHeHHNHHHH HHLHHOHNHLHNHLHNHOLHHNiCNHLHHNOHLCHHNCLHNHOHCOHOCCOHCOOHONOCOHCHCLOHHiONOCOiONiCNCCeONiCCNCHiNiCNHCNCCNCCNHN CCOxHNNNOHNNNOHNHNOHOHNHNOOHHNOH OH HO HHOiNOHN CO NO CiONCCiNiCCNNCiCNiNiCNCNCNCCONN(OCNCCNONONiNNOxHCOHONOCHO N3N(HNNHN( NN(HCHN NHNcN N(NON ( ( O33333H33C23C3 3C33OCCCOC333333O33332ON3333ONO2N3O(3332333NN33333333333NN(332HN3N2(2NN333N(NNN(333(N(3333c33333333333333333mCHN3hC3HN(CH33C3OHCHOHC333HCOC3333mO2.3333Ohknm33333OomO23333Om2m3333333m2C3333m3m2333322333.Ohkn333jli.o333hkn.333333hkno3hkn333oH3332.hkn333.hkno.Ho0hknhknoHooHhjliHjlHiH333jlHimijljlimjli0jlimjliN0m0mHmm0m00.ahkn ohknN.ohkn.Nmhkno.Nhkno..Nhkno.hknNhknoN oNjloi jli jli jl.i hkn jli 0 ojli jli jli0 0 0C 0 0 0 jl i N N NaN CN0 C N C NCN NN C NCn C NC N NCCNe NN C C C C CC C e C eC eC HCC Ce CCeN e CN C NC N CC NC HNCnNHNNCNHCNHHCN HCCHHNCNCqNCNCNeNCCeHCeCgHCOeCHCeCqeHeHqNHHqNCNqHqCNqOeNHNNNOHNOOHNHOONHHOCNOHNCNNCCCOHCCOHHOHNOqHOHOgNOHqHuNHqONqNqOqNqONHNONHOuOCeOOuOqCOOuOCNOCuHOuOCHuOHCOOCOHCOOHOHOOHH OOOOOBCHOOHOOHHOHH Hu B OBuO B uO BueHiOBuOBHuBuOHOOH HO HHOHOuiHOOiOHiOHOHO HiHiHi H H CHB v OB O B HB B HHrBHBBCHovHCOHHvCO vCOCiCBOvC OrvvOOirir ir iriri r HiHHCHvH CHO H CH OHvC O.oCv OvC rOC vC vOrOvOrHHr HrH . rrC Hr.vHO n.HH ..).r ) ) ) H) )H) H.H H O.H H. H . .n.. HO O .O ) O OO)O ) )))) −)O O−O−O −O O Ob−O − − O 2−−−−−−−2b2 2 2 −22 r 022222220000200ro 0000000 o 0 °m °° ° ° ° ° Cm°C°C°C°°°C°CC°CCCoCCCC;C;;;;;; o p ;;;;;;;b; b b b bpbb y b b b bbbbybyy y yyy y 99979888 ryyiyyyyyiiyi99889987iiirei99889987013949509988998799889987e998899879988998799889987e99889987eieeeiiiiidi99889987ii9988998799889987l3495010999889987e998899879988998799889987e99889987eeeel34950109el3495010999889987l3495010934950109l34950109ll3495010934950109edddddl34950109did34950109dl 3 4950 109l34950109l34950109l34950109l34950109l34950109 l34950109 d dnddd ddid on oo o e o o o ofooooooefffosfff 555 f f f fffsf 55f5 aooo oooafffn f ffn111 d111222d222
aaaararrereeRnennenTeTTiaiTiaeesTs iassieTTiToRTcso sosooosos Rsotoooo ooe o llli feafaol afla lf u abafuaauffufttntcfbubuteueteubctreutrrereecdddtieterartertrtdordidhohthaa t th otartppnphn hh hehrripenpeprer drrneirieeeirrr errcrooonn inrgrc ro oro otridddi igg iio gldd dlnlioliiiuuluinl l llll luuunudluululclccldlauuscucucsittutssasat:it.a.tn.ttssstt i st ..ts.nnrio ni rtr ttr-ttoarPrara rn ar antaaarttastaeeMtesttet:ataace ee:e e tcicitg tc t -ih dhtihitth-tPiCtdhdhhPdhehieeerlcei ireeeMi e (cce Mce e e 1 efee effg.eff0gffffffpfCfifiiffifppCcfepccirciiiliiqcccrciroi licreee iu(eoiioioiten(1eeenneinott1tvn.nnntoon0tto.nt. 0 t) tt tnnmtn,m m- m e mcm-Tm-em-mqcceocqeeHeuooeteeoentutethFihthnntthtnvtit,hhhhovhaootto.0to)aaoo.doaioddd),◦nid id,ddi dn Cn T nfif fT f no ii,HfoofifoffnnHonotorogorrrhFg grrg r r F rbe,bb b ,nbbbrb b0rrrso0rroro rnosrsuso °oomo-omumum°uCBbmmmmCmbbbuis,iiin ,snnsitLniisi tininntntethnteieetiihie–eeuete(–t–e–t2euu–m––nu–mm–em.nmm0meem nme enenenenentete-eetteq,ttta-Bt atatta,t,But,a l aaua llal iu l lllvweLle e e L .wwexweei)exxex eixxcxx −cxc(ece eh(c2ccchhhc 2 2h.hhhah0aa.0as0anaaa nsnsaens◦ ennnengenleeggCgqelglggqeglgee;eeuecee ueee b ec citoco o o vi et tyotovonoeonen.ndei)n.nnn dedn) d b lb b− b d −bbbrb2brrr2bor0roorororbb0oborom ofommm r°romrmimm°mCoosoomCoooommo;oompoop pl;poa pppbpypyoyotyb oiyey yyrynyriririydinnriririnridrdeiddidiiiddepiddlddodididilirnoondnoilniiioi nennlnelnl eedoeee eeoseeessefus sf ss s sca a aa a t anaaaaa.nnaannnnnnnndnndddddddddd dd
as4Icmtrtfbohhneuoroaeareeembnanmordbbah(vmctccngordbbah(vmctcordbbah(vmctcordbbh(vmctcorbbah(vmctcordbbah(vmctcordbbah(vmctcorbbah(vmctchesmedaooheordbbah(vmctcheorbbah(vmctchehordbbah(vmctcrheordbbah(vmctcheeordbbh(vmctchdheererrorbbah(vmctcordbbh(vmctceooordbbah(vmctcoeeooeboeeoeroofooroooordbbh(vmctcoerrrerorrrrerrrroreeorrrrerroerrrrrroeheeoeotehee.eheeheheehemeheTBeheeoeoeeooe.ogoooeeor.oecoo.rheemuooor.romrroe.oror.errm.eeermorrereeeetgrerrogmooreeremrroeemgsoomererroeeoaroeerrgeooeermlurreoeeoegeoooemruegooegmooumgooeesmutgmiumunrtmrrugstoglestgstg.letgtgl.sls.(l.lmale.mee.ec.me.nee emgeooeaemegeooemmege6ooemmutoeegeooemeu.geoowmugmcmooagnoonmug ooetcgimuanc temgmuaemusa etcmugaecnalt egcnc estnlapgn egaoo estgla.tmmgnaastglmmailmsummsalcilmmlaimmammammaptgii.psop.hl.ppi.phpr.c.nt. ecna ce,rgbnac eobhnca etoc aheconach her enmmaoa eh)aheormmahaoihorhhmma,rnbhmmahri,rmbmhcarth,ribmma epmmiat,rmmaab,rp.tbi,rs,braeip.btttpev.at Btnp.)p.npmemapen..eie.nlnenonhiio hBpoohhr Bo.h hBohv,h roBTohl ,rfhBThobre hB hBTl,rrbaeitlh,rhrbeoohtir,rlaboli,rtbelloe,retoib,rivhboi,trebsiivntoeetonvhtrenaeooe.vn(aoovaenvlavso,orenbaeaoonaain<tanosoa aiBoooaoosi ooaBTaeg icBTise Bilstil eBsnesl lBTe Bdu<lie lBeeeoi<llnoleel<iolaelolio<lv<oleio<e< voioBioovioadiaovoadbooovandalvoloavaa eaenvooaidaannioodsaaaiaoonaasnioiiaooonooaiaaosneaiooaaaosiieavdmlsiliaeai iselieilasani <aleeliaialeoe<nooelaliien l<doe8 llel<liin oeF alenid<iieontn<od<iim<iidodoiioeiioddnddld8andn8damonn<8taonsdod8nmat8iaaont8mn8aoina matooeatliaormt teimalormm ndinaemo lo isnamoeinlai niaminlen)saenilimsrnl mnd enliiemsey nmennsdrii nsenisid rieia iidrii eiid er rld 8erderedr8 ppn y8t 0 8tymii8iyotmss88tioymd8ytiomyytmotiepmitinommi0imgpsmon opmoo0sn8 m0ns pm, n0spse ttm0 nsrmdn0 em0fnm se drt sfoe os erefge er eogb r eege o erermneno gsreygs dog sygto dsdioiyoddyis sdyedisbrsd nydiydddbpyida d0ii tbtip0be pb0t%bi fp0to yfi0pt p0hteu0 t ui0 tare dhf gutoaeog aet mgo% ret apgoase%ietag0ooade%tsn ogiotdegtdms%gior%oddds%o%isdrddibdrisdmdissbdesddmdarbddddmgorhddbodtmoemomumd oteobmemmouotbesomutoo deootmoeod moetametm uthta aht gd e%hat oo d a%et hisod ha%tahiothad %tetd iorae%tdod od eie%od%oi%rgm dwiifrdomigardgmootodrmdogeormdgomro%egnmgrmooemoenomrmoi ooiewfomaoe omowooerdmeowmhemwhd wmeghnwowd eahnno d ohefnood ) hee hmdn fo hn ofd ened n lod feog fo f fgoaa rghagrmo)gd o)agoeoun ga)dlgraeaow)lo e)tawl)l)tteawealtelweallgwantwna owodnahw an fnd n ,nedf t (rna n fn tnd n afnno dtn faw t tf a fa ot faf tata oat),aoer)an,oeet)ol,eoe a)otlf,lee )ah, oealhh,e)e, )elaeh)ti t laeze ltdreal ltn a rdoan t ata n )t ordthtrn adrone rih et d aoln h z nt ia dton thidzoea ah ootz oahih tiohat zuait,t izoeaam zz ,oenh o,dyehno,oet to,eiet t,ae,eeht h,taeuettt thrteu tthetturt eo eth nr thtutt hron,ihuet thtt n toti hri w t norh zsnit oinih nti zi oi fth tiozioi ohihzo tohhezi iee iz zewnz whitawenoftihobewsfinthwio uoeftwtiwzhoeietothf ihefiotuonett foheftnueoeto,onh heuottannei hohhoesttun htasinehcuetntne ai nshnn tlhaiscttnhanhee asntatisel t(shisut cewetcnweicctwef iccowefc i c(wecooctfi e ewo(weifoc rw(cofi reon i o fi( r oefnlh(o fioo (ean(oh oeoanshoewealchsenahisnaohfgs haaohasl a eisos hl seaie l ct i ecl c witele hccicl laei gc ihc et sc rccg(ee ecc r cchce(ce cec h geeh(u e g chCg( gcr et ( eh eh t( ec h( h ht( tu c hte t ht ttcfe hu htCehtuh p lt(eitCu l Ceiu elu tCiet rueclCu hi Ctl Ccfi tlglc ihfilatc igpf t ec tgthpf cen fgcphfc tef hp vegnttp g l hi epigt pi h eh h ei tltht e hthhr hht tc t th aht ntheouh tth (nhteC uthhnh heC etuhtnhe iCtun oenuCihnteCu eauhtte C usfC oht aC(hftaoh mtphft(oeah ihfpta(ito aftiaopeliutio fl(oipfC i(itflp s iitptpish tipis–imiist htimir tshtmnstfh ass mnhdc(cmn hpmvhminh ne–y htnn– r nha–troha –a(rdhh(o–a ce le–hlr–voda( clrhelza(dolhi(rvc rnehoa(lviai(r ecu(daoe(co iivd(loce(vt(cs ii v(vei tsiemlitiesihemilistiamtmlisottremsuls(nmle screulolmrmeumi–rteuireu–reurreur–oLsrl–uhrd(u–clemiruvo–(c–er–dv(ocerertdl(vocrteed (avceoreeoL(vtodce(code(ovrctoLhvee–mlvroLthee)lrtroLheroLtlsnroLhroLrteluhdt bd(ahltcreh uv il arelu lreeuem reauu r)emare urae uuemat)reude)memel ebmoeum )eni )oe oer eue oe rooLo e d er ooLeh ooroLbhmroLnir.hbroLhnbigroLrhoLanim raboLehbhni oabdhnib niainnaiedm samdse )m r.amsdr emoLa dmr.g emad)ahedr.emmg) maermg )memmr. aem r.ai ng)r ga) gian g a i a pin –ein emi n ob ine )niabe niberenib e eb nis4e dnibssb rndbinimnidt r.mds idrmgadmr.dg mdbar.egtc nmr.i astm bgein mraturg.s einr.a e gts geina ga e s tdianese teissc i ntmesi tcnin r.etb t ceu g becae buebcee ubce ebc ucib tube usoreu cfeeps mts ett sbrser ss sadbear bts e vrtsb e ombpsret b bsrpet eistperstasrtcpt rabrpattctp upabtatce aubta mct enuetbaca mase buaacm aacoueb aabcsw eembuttumaseu mermaoes rrasc aibsnaaa c bs bnsrosbun rbeo a npbarno dnbaonpdr bor bcot rpiorsorpctarirpactriarrpatpcrapgicgtramricgbactiatimroatamaoaaaamaroaampoiemaomnmoauogtagnegparaga danagaogar nagrogn gmggnogr gegrnan otrnrercon ni arev–oc noiraoecnerinceareninc3nriarnccraieorci ttiaoottav–otatavav–ootavo–atrnto3gcv–togiv–og3av–rgv–a3gagrag3gr3agg3tr3goengagrneogg onegsranroeernaneoannaoeanonaoaenaentgnnaengntnae rt teasneet av–neset taav–ansneta nev–eanm nstne se3v–ram ctstv–sa3t( etve–v–3,ev–a t3ata t33o t3a thm3to tn tacmonv–ag(mcodna,o(meanmto(c,nomaee3maco,n( aecenecn(nee, (e(d,nseen, e,znesege nse gonaest rgnnsnne etgn bsee gstee stgs gdet nt tedo t t tna de t ne n dteem ei nds tncdm t dnb tn(emce b m,c(eee bom c(e,ee mbl1(m,eebedmc(eb,ebe teicee(,ede((i,e,ge,egiotmgi iotig1 e ogt (1 gedtto sn,g1en togt eedo1 tondtee1d t n1te 1d n ede one dbdnge ndebn sensetnbet e snebd eesne beedesbneibedsneebensn4ieslndedidd sitnotrs ttno ei1stb ntoi e1eehse ton hes1tn1o 4sehtns 1t7nen to eoe41a oe 4ee11 er1h4ee4 r44rsn 1rosnrn d1r1srn(n1dasnn1dsns1n disn1fsn1nsnn nd est ndhs t no e h s(tn t eisc tenl( sesntn( e4e ih estnst en4(esitn(e e4e (i t(e(e eer4eie4eeirtei4ii4re(4tes1trinee tern1t ee tcrnri1et eu t(ritn1etiie t(1n e)4 t(ne1 e 1d en1 t(n er t(n te( c r t( ce (a u c ( uuc1(i u nc( ic uy(rec ucina (u (ecu si( eic atiei iatet iaic e atbtec iece te asc ir(aawte t(aaatrseen ti t(atre eiis t(ae, xres t(rae ea t(rasrteas t(aa) t(sscst t(aa tutscaa usoactaea t uaacsttfa sucas usc at( ca c u c u) u c a)ci a)mch arl)a )ac)c ira)a uca aarsaaa arsdaar)aisaamr ahusa irtlmr s aai hr.amstlisaahhastaistlmsdiaialmhitsailmhimatlhn sahlai)altse aitfiareti)suiasa(e)sas)ue.a )hut)t) .c)hu)t).u)uah)tunt.au-).htsna.h)ta.)hn tha)tn n eaona n e,niam aeu hiamml euhi )e“mltui e ihetm liiuh nme ul ihiuimenulmihai )mhn,lihl )lun,aiine ),uin .enot) hu, t.),thiuht,m.),t)uhht)n.leu.thu t.tnuihttc.t.nafht.hftnlheaetFfnyae s)nhnaeu nuadeeua a e.r uehte euerne usl eFn ueyn u l es n,ueFc ly p nFs,yd lnms,lF ayerntdlFn,lsy Fnd Fsy tr,y sdsur,dtn,df,t rddrtfatpr rtatf npmtfaa ffm atap ,m dapanpampdesmaa maadmttexaaa deotd l edtdF yelitts Fetyle tstFe tdyealod stsFlyNrdFstxsylltidsrFsdlFytxytdFs ryssxdssref isx drssdf x pidrxxari iipmr ila piFm f iy iiapsdmi4d ia nimd dpdaimdapdrstmimdadimadtsibradidedstd d t stdsa4t tstns t 4tstm nnt4 aitsnx 4t s xb4nrdt 4nst4xnbrtns iixccbasc txiseibrsc xabrix tnt brxabri1 in iaitnd aa niaiiad inis ndc nsi n dxcisdgci siddi1c dscis14 c cnn1s o 4srcens 1 4 1n 41i1nc d b4r n c 4 br4 n 4nb rnasi brd ocaq rb nlaorb rrub n habrr a n4o rnoa nharioh onarcir nie ncd t nbcdalauc1dclcn6u1dalcaduc1 2hdcldh1 un lhul1 hl uhu1h 1 nah1ao hhshah c ahc6 hhat aaco62 tarca a6ao a 2raacaa16aoi2cer 6aceoic6ar26 ”oea e2rat 2oo2r rytoo ird tgo dolotuodoltudtldtuthlrtdhudlh duthlhluuhlhuaat uhohftxahacth6tth ahlaahchnd6ha2eaaeca6aaa)ael2cau6naaa2ca)a6aa2ca6oco 6eo2ocha6aho 2tao2 tlo 2not toal anotta)o atloan ngao tot) oco)alt6n aont)ltna ta)ln ntnloa2tat)tnn)aat)natanot)dan))n)tn)n)otologooetagttgtg,ttgtgtge.tt lottt tleott lt lnotte laolneat) l,loannnltae )lmtlo )a,entnno.n a e)lvo,ena)t anth.o)l acnlt,)ian n.)loo,ann)aan,y)da.,ao))an.)no.i)n.) o)gd7mnon tlg vlomnpnghtvmaang)ohttvmgyndnhmtotv)ngmeygvmdntohtngv lhyvdtdtohnhl teoyt dtdoyd ltontetmyddd tydtl te dlt,ne dg lna,dlec d.n,eln ,en e.te,e.,et.,de,v.e,ed.le.ad.Imenvdmdnhvmddnhov,moyndhmovn.ydvhmomn hnytvmdodvnIn heyvtdoi hgdyh d nI o ode yId on,yd d y dt)nId I m IdneI dnv d hnen -eeog y bdeedgeee,s gde e ee,ddgeeern ,g ede get gd ,e n,e dt-e,d,n d bf-nro e bp nn bn- Im n-nn bm--I7 bmnd b bInt iIfnI,n InfpIns If pec gfp 7fe gfepf ,e7p g en p 7e,pmg eI e 7,ge 7e ee,g7ego7e n, g -etc en, ,e b-ho o,cnm - ben mwn- bn ce enc bnn gn c- b ncen nmneo-r b n, bentn beennfnotne ftpoetn wn e fontenpwt f pot7wtf b opro f 7ow fpwf r)7 wpwp rn 7 p n7 tr .r7 oo7rth rc7 tbf c t c tp n)t ct n) 7nce) onoc e)h t n) ooe)hton)noehntooeowo ohtoooeheowoStoooehahwto tnrr wtoro tw.rn ovw rw aw reo te oder etoe rto aro t ro o taom orot a. woo)og t or tao.a) tar.a) aa rroo .) aarh.r)ofor.ah.)oao)hai)aoot hohuoo nohhooapehae ef)ra ehfai of oa mioosafuhe oaianfao fou afioan uo iroeaa i. oio u oraa eomn uo.a ooanurec auo.nanaaraem.ataaarec tn.emaerrrt.ma.r.aoma o mamsm mi am ma rc n .fm ra mc n afmardmcinf aricnaf ocurnincfarnc aunirafanrf uiefanf uiiean tu ti ade utuaneumdhnaaehadtmfaehentdmedimdfa d dmmt f uom mlfmht ym amttf o cefn mstt f rfcnmt n ttr p tcm nnm armcnnmftrcianoatneractnnctonnrctnranoora e eta oahmtodohotdttcdantrhddf ededptfd e ee ft eemfit d eefa tet e efn tee fatefdtn ott att nptaaoan paa naotp aiotndtonuo afpntiopdoad tpa itodp amo toiS oditodoidiatdoti ntoe oeda eoeq ovd ewoe trm d eSe d etmeSaa emdeSd eaua eemdeSd remaaeiSmmSpaSavonawi proavaaw pviradwp r ievxdepo wvriwvdp vrpwoiwirpd r iode iciudoid idoi oii oipoed o dm Sidi md Sdacdu mndSdamc udSdmcacdouSnd mavcSmevuSmamcwu Srvceuca u bwarevaw vre nwev rd wenevrcvmiwS evwnrruwc irnnacni nn nci ocn cnc invnwdi rc ed oecube-cuwdplecue cte ueec uedcu cuecuo e noe( h wno bece nwenoc o nwnocufco dwn bc nw dnwc n w nd ic cen( h cdn b adn (hed bd(h e b d(he e bbs(h be(h(hcbBbbenibeeoibeb bobci io ip biwoi wo e o w m o wdo “now docw wf d wfc(db hl bfc d (hb bc d db(hcobmd ecr(hcbb“ nbmb(h wbb mb( hb“n(hblbi(h“bm bmetib“nmhdm“nbi “n“enbi b btv (hib ni l e l at f l eb tf a elec tl o eicleotlbetecfoetetbtce sebcema ebcic“nmbacam“abnuhbamba“naamhao“natmaa“m)am“nytac“a“ntigbitir thlitat hlehimt aiohle“hita )mmiohleeh tsha)ltheena thh )lgaehla te.ohl)whegtees)tee)t)aegegaemagga s3malnyamaaestnwamtasnamba.amwetmnsawatntdisarnntwriswtshrswiwastshtsihsatasihhsa)bihtas.ihsash)ibs.hassh)bghhh.saha)sgbhsta.yh)b.hgb)t.be).g)im twr Lghmhtgnamhthnmwtysnrm)twtnsrmytemwnmys uewn sn ywesneyrs wyz ewyssh seswsse e hobs bmes ..h s s b .hnss hsb.sshh bw.sessb z.siebd .bz.oe b.z et eeszetezeeztzsNteyebt.eryieetetyotiea y i e y iebdy ohi yeb iyiN hbe ee tehN eNh o ha eN n oNhehaeNyo Nh zadeees eeozaedeo eea ozedioe a i az ”ee dzdeteehdzdenzezeneiseneefei eIsbninreisbn”enoiiesze”iisese”NisibiiieN”ie”ieNn”o”eaN oNeao NemadNdioN erado eas edo eoaado a d dnrdNh r dnmr desinedm edosnrs amidne sn ”s aimnedsnm dd”enismddmdas ”eis ess ei”sso s ”ii ed”ir” e”dnr and r 3eadsaradavrd driarar ”aaear aa oeea (rla ae aee m rd 3ueee md3eecs eomed3oe s me do3 ms d3m3s od(3m d md( s u ( ds rucd ( d(r ca(d(urc m dduar ucoaduarcr dacoadrcrd aoarteee aadoaeexo aa ed oe oeaqoiade 3ae oed de3rrdheeede3d.mreeat3oere3txir a(t3ert3 xqr3( retux q(ttoeetuxcqt( oxeeun (.cxqetx u qe(ce(.qq3(ci.ocuc.ioumc.icimo.c.omboid iotoo(diiogoodoodorodcodriddtdrbit rxlioo bertgex qi onrteir xgqo tirbeigtxb ,q dtoeb txbo gq.t ed ogxoq xg. eligxdme qeqi.oldmuqre.ildn.dieldto.ndt.ieml.noixlte ileoienltiqyenieoIntnooutmtootaou(.ioioruibolu oiiobuogo ui−uobIi gbopo,i gImio igIbosmdi giemb oImo dgiIogeImlgdiImedmlimndiiedlin,idateldnd l,etosnemg,ltlnselet,amenntoi,enutmw,ens,ottusetmdodstemausee momdeuoelduenoeoudnuoIdaunetdIditmanittItimaniitItm ainItatnmto aiInnuatmIntt iItmdrnmit tmn,t ii ni,isnm,ninsn,Imeies,memnsi,ri,msei,idmisetdmesmtmdeieondeonivdatlentnt,datnndettrtdzaennitrmtea nnetrateen t nenratennlatnn rtntannonrt rvpdittint otvno i vzn oinvs2zonvoia nnzotvb vi zitz piziiztin aipii nt pin iltpiitpieinpi ipiinerrti entr enaree nt raietnt rer aeeonivnrranoiriva roaieavziroviziorv nezotoroovtvt zrnoesrvtrzerr ttpitieze tzpyi tiz tttpiit tt ttpittit topvnioo pii pnis po ii zntos eln(a0s oon euoia nasnioeos a tsilse poaieiaerooeiaoaoriaeliroiooeirtuilao totorltuiatotrtcrtliaerttoltta uoliattltutoiao uitiatutiat ttttt.tntt toa– nreso n as–o ren–os,n–esotsTlnitenosoineo.srosees. oeee.oeea.oleo.asonsul.iaoea.flooseolussiaietaooel lsauiaetotilealoauiasoietllsialolse tolisuialoiilateuiiasieot–tefets–esf ttfesl csottn–f sgiafs tf ftt .t yt.tee . eoxa e .e ea.ceseam.ltlwe.c eemmse.aicleemeesaeueielec◦saecaeeil saccleeioxs psilesloxs.a eilioexfl si eeeoxfes l oxua tofxsl o x r ustf ls uyfsle tl sp l sfliut fe upftee u (up tt e etp e m 4epelene pm fpecse efcecuem etececeeceo x4c lnc ox4 l neo sx4el l o x 4 l lonx 4u lnle4f o4xln ou xl ncl o x uCe l p ule nl pul eeos upyue eesupeoex sp fle erpe spebfespel s fes n rf ufnyffan ye4pnlny nr14lnn y n4r ylna y4rylnr 4lr 4rr4lanrl 4rr lne at tr aereresra eaeq snae a(e4s lf enes hf e s fe t str e snfes tt efn yt fq onfyttf(nqttyotntrq(ttn.yhen(sarnqynhq r,(yqsyhr(qprye(f(rhraeherrhrheae,erroannerneoaar elryneeaor,an saoaea0, on asr.on,a os nan ,,ae ttsta, s n, r,t,tes sg tnetttaq n ,ttet( ,qeeten,e,(nqettehtncn(qtte hq(eh(qteqeheu q(e(eh (heh tohen -yeeoiaun eoq e,anse o( a,nnosuvan,f ohs oua-n, ont,s eu an, astn ,aeyu,re,siau,ns e,ayus u,ine yat eiennoy,nvweeinynen,iy-neaeyvnihnin,ve-s)dner-nvnvearne- vtev-rt- e-rAwn nrr wrntB w nd e. w un dw[n wudnwnBat 0ud ad tuy did uty iu tuya tui nty tivi[ynii-vByd[nyi-ivy[Bnir-vnB,[uv-r[n Bn[-v[rBnviolBdvs-Bir-,liw-nryliiiwrdnritiwrenddiwinnddiwivn3iididw-niiwdtinddwdinditdtdriidtddi[ldctidvitiidiiidtidw t[3nitwB3[3B[3dtBv[l 3td[ 3Blct3B[ v3[tc[tBivBc tBiltvwitc duicviw cdveuichivv vdii dw[dvi iw eiiBddwviidwiidditridvdbidvidvddvilidddeiiurd<3iieiiud3idiiiedudi 3deue tr3etu2eeu 3eutrte 3ctrtv ◦3irc3trtdi3vtr ctrtrvtrwctr tvcwt rv2crwc v rvcrv w2 d.3vv 2 de v )w 2dhvw 2tidv 22 dv ho cv devevuddyeu e .eue.eeuh.troeud7vhter.ueeud.hetur.e.rtrhyhetr Lr heheytrLr tryetre reorey2uere27 ye eaxoe 2r yxry7 o r2e x–7 eoc2 eoL7 terC 2o ,7o 72L 72 82L r Lea L .L eaL –.ah.–uea2eah.– ea .eahx–e.–h.–y.e–h yehh xyhee eeoxyue 7oyeoee ub7ey. oyue yx7)oe ou 7hoLue aec7uobeu Lo 7o7 L e7e L o eaye L oe ea L L–o )eae eLn e–ooea )c –ecoe7ac– 3)o oiccea– a) c–ea ))–c)–L c– cic0n unpa3uni 3u ni– 3nu ,oi npuns3 i3uui33 uiei rocpe s oe pc oep) c , eoa )pu c,oepe ) fp,coe pco ) oc, ) ,c s ,),)tcl ) smcc n s cheam7h n so r3ahsfn i s a3snfi )3na5 rf ia3 nac nf3ia3nfi fd3f3ima7i3 pim7 tpm%7 p 5,rnm7 pme7 u,5mr7pem735 ,ripdep,5pard5,r fs5arhd5r,rh, asha,ndt dsa ada dsa p aasfh eas rfsr ase,f aerfo a afe tra e f remf7ete f mrt7s srmr7rt )rotm 57rrt tam7 5rr m7 mf57rr]md7ra5raeradr5raaeds5r5a5raehdt)5rsad e)ame7dd)esaedoa s])aes)sa ])ed5)r x]era ht]e rt]abedoht] r]at aehte rtoearhtatrihtoar,athtrdhtor rctatrdo taoord obo,eoredeea brd rdaebs rdso r e)bs,tbe)bs,bem)s,eoe)],e,ro)se,]),o,)s,)]es,) aon]hton,s a] o,oehnts, a]e,ne]htes]eaon sht ] assoht )e aadoht htahtod −oe d b]togdo nbod bnd da bnchdte , b n e,bnob−ne ,b hnoeo ,,td−e onte ee,−,teodene ,el,s,,t−o fe,−e,soet− −e,betieosnot ,toos,n i e,so e tsos , ,sto l otf oloo o ti,t ntilt lnis l elne i in e il nwi g−e negon e−teng e eo −o t2ebo e−eetee−oteo −to−omheoel−wnotet ltwo e l ewto eo e2l obtw lle woo 2lt wb nl− lwoeoee2t ob i elte oot e2 eboli 2e t bow t2ooebi2tbeleoegiligioin iountgitonononoeonegninoeolowqoeolwoeel oiwe ooelec2oew bi leoew2 ib l eoewtlt 2woe0bi l ewone i2 eb eioee i2neb e n eoe 2onrw b2 obee2ebenceenelnwcsnnnat0n rtc 0nhoc2tbnc0nceratnoen0tr0ntnoent0cr0nsnoe rnoesrnnrioesrefoeiioeesoesiensisiencihelni ceieince oetnefec cnceefecc cncene fitcn o0 e fcitieielu0f ieftenf 0l crti 0nlcittroe0iniltntrt0ln0stlrm0lnohsrtn nnstronret tsroe soe tssoot s0o csoo c on rc no teefco e ocoee f °e scee cfeiede tce eof ieeoh tel fee ieoteeef leef ieeeef tleiettnelteiettci l°itt l l°oetal °ehoefe e °toeh ° to°h e° i roonhm ohooln h o hon aon onae lnoeonasoe ooei eaert oame eeca traeem eroteCem ee treeee ermtioerlmeedrte mspdt°meelt s°le s c°hl el°s eoch elCs°le csh s ° Ce°tn ch °CdcwhpnncgcCndhnhpCanahCnpCoyadnpdvan apdt°ndpnapram-rhabameraacmro( myarnlmoarysdrtmolrmya smatlotayas- octalyosoey l-cytCst l-enclts Ctlsercn-s mdC- c ep- -Ce dccepCectdn pC Cdt pC ltps dpt pdtpBtctno aCtoayooaeynt. pt.oaoyt oaryB-po tay aneBo-at z oyo dey Bot e-qyh o tB-etoBt- et.BBo -eo -o t.-reao teoo t.oe yrotnt. r rt.tdont qt.ot.trdnorotqdr-rn qtntedtnqdnqddq qhee a (b tBb bB o B o o B o eB t.o B eoB ot.B(resoot. no(reoAo nt.e(urot.de-n eqor(t.o0dt.n(prqolt.(oBdoon(roqorndodrqoodnosnqodndqAoisuqdobuqst.Abuo0AsprTruso0As spAu0bnAu pAdu0uq p0pi0 u0epp iued i u(reT siu(erTiuei(urTiuse(eeroTe(rBTorT(rrT bt(ro(dcbreosdocdsApoeuosAdouds0Adp(dusA0ptusAs0cbusp At0AucbpAtuo0oupcipu0t0ptitcbupp0tLcbptipucfbrTcbsliuyprTipAupurT piurimurTiuo 0rrpT ouriTrTo LdrT roi dLs oy LdoiuoaoydLoyLdoLLrdTydyuidt yycbuitcbuit cabputaiuci btpuiaceud irtptacbrt cpc ab p ar w ap apv po hu o ht c orL c oo Lr oyo Lg pr oyoLaoyvLorhyLvrLyiuriLhhvryrhuiyh vyyvui°hhtiov hgvuiaohhh uihgahLu ihguiabui gfay gagrl g amy a°ri m aoiyrm° iyui °ri roy °r ibyrr° i fyny° ib°ri alf br -efvlbrohblfvbfhbhov lrf flhohvrllhvoh ohgvhovuohvghh.rhhgahahCgmaoi gmrnge gyer°gvi Lhyr°mi( yrh. °ir ry a°i.abryCra°irf.airyarbiegy°Ciaa°fli.yaribe°Ci.arfali.barP.aeCroaafblaCiaaea fraCloiblaCbaifeilobrfefyloe°leiliiemoieloieb iefl iedi elliem o l l m l. rlel lme a.a rlCa .airalmCua.amrailloetCm.aramlecaiCel.oanarla.riC.aoearaiaaC asaeCoaaieCioeaiotooeeieiioeleeolgtiex.eoercelietnadaeecleCieta lneicieblt nllieetceiel etcn lloieteicin eclnonm ilxol iml lxo llmiofxiolmoieiriexloxlm xoxmll o ll ooceo ol neafol on heoeflttefoecelletnfeec letfenefceelftencelcteoenlecolcltlintecllcoetclniecnltxoclnicelo xtcil lcp otlxlifll olxcotipil ottxpi etcotx pnx x edaM fo fiep f 4ce f o xfec fod fce foof fece dffcecffccfeocdelce oloedeolcotledoltcedledcldetodpl lctodtcflpt lc dltloello t ldood ot ptd dtto t dt o c thol to lft ho ttoc ft t tt cf o tcf ot cf t e tdo cf feo dcfc3edciohroedohoedlydhnoey dedod oheydfh dohcheo drt3iosdoo ioo rtod3 o diod3 rterdo or t 3o roi 3ot topr i3o f3rottiooioro roottortis dttor oistor ois tt nrt isar isr yoishrfisety ahf hf htfy -h ef fnhf h3hn ioareh3 ior3)no gion3r snioon3r -o eh3or 3io- 3oroerrio-isireooaris-ore(-rra eisod)-o-erareois s)rais3a )oarsfis rr isao ars) isf ) s)m f ) s ofsP( s f (n f f (ar isfn (an (t a,(n( tadyanP-a eawnfdeP-nreaP-reaP-eePt -a,Pe)Po-rat-ne,)est-tae,)saiw t di,)tas aaw, it) dta,s w,a ) s) ea(w ) -s d wCse o ed (alws n w dae ed o( a a an oe(aa ne(h oe ae on)( ( oadn o(nsta nP a aP a P fP Ph(tm , Pi dtPh ,dPi hta,de wthd,rht aw,h idhtf wta, d,stoew,afgP dewoeafn nwaewodf wnafedoar fanfero t,neore o nbedor oonrgon rwnorngg roargn doong oedgho ongt gohno bn n nh odb hbb hgo bhofhgbo ohe obgbfea o tMgfogttfgogftosofrotfhtlfu rtrteroegreMorgenheioMergnreiMofrgseeinoeeMgeeiinresMoeeogMongsMobgnonsbnsotbrsgsobgbologobetgobrotgeboengrt1eeogrotegeogettrreoeorteeoetrretlbetettetletiMrndettneigtuM tetnaloeMelbeosetlMreleteiisMetteetr(eesMeMresMerrsetrer esu rrsrsru eu aererrMeu ernrru7 eeu nru eesrrtc eeerrneten eerlrrete enraatelrt mertlat ernr etal tnententtanndnrealteenranalneert1tnnetrnnnneennrrnmetroenu rmenrgrnru mnrdtru metyrmud mermu dreru geedu treeud reededraeg eeucr gearyg erira ngyu rarg niey nrgtag ennyatytnnn aytaytcn)nan ntncnntnmnrcntnt tn mtnci c mn -cnidcmlaneiedmee niemdmienmdioiedtetedgndetdetn-gettnnyg-tm tgt -ytetgtty- totg-yg dC-gsto-eyhs o tyc sy h tyo c.not oc oat n trcigt ncBo innCcc niy hcnC napi hC i hCtir iCtawhti Ct hCa hth ctB -a t tB-att apBt - at(s a itB-p ttosBt -tp BtwnBo -p- wo-p sp wop now wontowtwo n -nC n whCd no nhC n hC o C haa t ehCaC e hCBh a t eh Bnwa apB w aBpaw dB a1p ewCwB awBpnhwBw p wa wgpl tp wpu atw a aa at eoawawa twB1t tt1 p 1 l1ttu1tl w11luo url oilulo wlu uowuo t wot to tw tta wttt awtaw iittwtaandttt tia tttmtt ts itt m aiat 1iat i iw1t t1 t 0i l 1n hh huil1 nvi 1ul1o 1luionilnutninoilun lnnsolu0duo)uhhtteoa0ohto1aai0thovthhLtthhtt0vht0ttihhvl0tth0hhtthihtuhvhhhttvhttitvtttovtiCoaiawoa Litiaoai Ltaioat Lntoattait oaatnLoatnai LtatnLnti Lt tnii ttitinni0ndhh0eh.hh0v)hh h0hvh0hhiovhh0h0hv0hhivhhhhhhvhdeevoaeevadoa)hLtaoa)Lhtsa0dnsaoaod)thdLtahdhoadhord)tLathdtoav)oahoLtta)oaha)eheLtaoteLetoLtteeoeeoeteteetsesieteeeesoaeeeesreeeaesees,Ltroassrssstssrsurrrididdi)h,dd)ih,dios)hi,i–o)hd,d1)ho,d,i)eeho,)hee)ohee ee o eeoeeoseeseeeeosesereeeseese)eheereseesrssion r s ss srs s r i r re eie e i , i ,sis,iir,iv,t,,,vi,t m L 2t i 3dhoaeec)i,.
ddddeeeessssiiirrirreeeedddd pp pprrrroooodddduuuuccccttt t(( (d(ddd))).). .. BBBBBBBBrBBBBBrBBrBrrrrrBrrrNrrrrrANNrNNNNNAAAAAAANNNNNN NNAAAAANASA A = A======= = = = c=O == = = O=AOOOOOOA A A AA A A hOO OOOOOOA A A OA ,A A A A,A,N,,,,, N eN NH N N NN,H ,H,H,H,H,H,H,NN,NNNNNNmHHNHiHHHHHiiHi-iiii----P---iiPiPiPiiPiPiPP--i--r----SePr-PErPrSPrPSrMPrSPrPEEEPEMEEEMMMMMMrrrSrrrrrSEcSESEErMEMEEMESNMcgMcMMcME3NgNMdNggNNgNNggghdCddcddddhchcChcNCgNCgNCCgNCNCgcgNN.NgggddNdgdddlddhCCChedChClhCClClllllheeCeMllllllmBelleelemBAmBmBBBeBBAAAAAAArmBBBBmBrBmBrmBrArrArrAAmBAAAAeeArrrNrererrerHaNNrNNNNNHatHaHaHaHaHaHae eeNe N N NNeNN3NHaaHaHaHaHaNHaHaHa333Ha .3l333...3 AHP..AH.AHh.AHPAHPAHPAHAH. 2AHAH AHPAHAHAHAH2AHPr22PP2222AHOaPrrrOMOOOOO2O22Mo22MM222MMMrMoo2orOrOrOlOOOOOrMMMOMgMMMMopogoMgooggggpgppoCCCCggCCgCCggpgggpogppglCpoCoCoCClCClClEllllCEEEEEEoEsloelololllsllssoEElE2EEEEEN2e2E22N2s22NNneNNesNcNesessccec2e2cec2cece2Ne2eN22dN2qeNNNNN2edeeqddqNcqceqqceeqqcececceceueeceuduuqequuquudq qddqqqid q iumiuviuiiuiuiuuumvmAmvxvuvv vvA i AiA iAAiAiAiii m v v i v m vvmmvv v AnA mAc vAAAAAn n ne nAn n n e e e M - nhn M n MnMnMnnM-nMM-c-e--B--necee c cB B BM eMB BM BBMg-MM-MM- ----h-EgaMuggcgg-BggBhcEBhcEuBhcEBuBE(uBEBEuEuuucB(gL(g(g(n(g(g(gghgELEunLEuLnaEuhLEngLuhnELEuLhEnuununna(hEa(-au(i(((((L-L-iLn-i(Ln-iL-nL-iBL-niLniinnnnaLBgBnaBaaBnBBBnn--i-ai-i-i--i-iiiuL-BiBBuBnBuLuBBLBuLuiuLunLLLnnBe)iniii)u)u)LsuL)2i)uL)u)iLiuuLuiLLiLiis2ss2ui2L2222iL)ii)))i)i)m)Lii)NLiLiiLisLi2LL)2mm2smN22mNsis2N22NNNNis2LLLiLLiiLLLimiiNiNNmLNNmmNNNmNiiiii.iii.i..e b .bbb.b.b.bbAt. A A A AbAAbAbb bbbbhbAAAAAAAAAMoMMMMMMMMMMMgMdMMMgMgggggg((((gg((g(n(ggggg.nngnnnnn(((-(((((--(-nn--n-B-nnnnnBBnBBBBB--------u-BBBuBBuuBBBuuuuB))u)u)u)2)u)u)uuu22u22222L)))))))L)LLLLL2L)2222222i2LLiLiLiLLi LiLiiL iiiiiiii i
SScchheemmee 3 3. .P Prrooppoosseedd m meecchhaannisismm. .
33. .M Maateterriaialsls a anndd M Meeththooddss SScchheemmee 3 3. .P Prrooppoosseedd m meecchhaannisismm. .
33.. MMaatteerriiaallss aanndd MMeetthhooddss SScchheemmee 3 3. .P Prrooppoosseedd m meecchhaannisismm. .
3333.3.. .M.MM MMaaaatatteteetererririiraiaaialallsslsl ss aaa anannnnddddd MMM MMeeeetetththhthhoooododdddsss ss SScchheemmee 3 3. .P Prrooppoosseedd m meecchhaannisismm. .
33. .M Maatteerriiaallss a anndd M Meetthhooddss
33. .M Maatteerriiaallss a anndd M Meetthhooddss
33 . .M Maatteerriiaalsls a anndd M Meetthhooddss
33 . .M Maatteerriiaallss a anndd M Meetthhooddss
Molecules2017,22,1952 6of12
3. MaterialsandMethods
Generalremarks:AllreagentswereobtainedfromAladdinReagentShanghaiCo.,Ltd. (Shanghai,
China),LagewellTechnologyCo.,Ltd.,MeyerReagentShanghaiCo.,Ltd.,MacklinReagentShanghai
Co.,Ltd.,ChongqingChuandongChemicalCo.,Ltd. etc. withoutfurtherpurificationunlessotherwise
noted.Highresolutionmassspectra(SouthChinaAgriculturalUniversity,Guangzhou)weremeasured
oncommercialinstruments. NMRspectrawererecordedoncommercialinstruments(Brukercompany,
Karlsruhe,Germany)andoperatedat600MHzfor1H-NMRand151MHzfor13C-NMR.Chemical
shiftswerereportedinppmfromtetramethylsilanewiththesolventresonanceastheinternalstandard
((CD ) SO,δ=2.50,δ=3.33)in1H-NMRspectraandchemicalshiftswerereportedinppmfromthe
3 2
tetramethylsilanewiththesolventresonanceasinternalstandard((CD ) SO,δ=39.5)in13C-NMR
3 2
spectra. Spectraarereportedasfollows: chemicalshift(δppm),multiplicity(s=singlet,d=doublet,
t=triplet,q=quartet,m=multiplet),couplingconstants(Hz),integrationandassignment.
(5-Formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (3a): To a solution of (5-Bromo-pyridin-2-yl)-
carbamicacidtert-butylester(1.0g,3.7mmol,1.0equiv.) indryTHF(12mL)at0◦Cwasaddeda
2Msolutionofi-PrMgClinTHF(1.85mL,3.7mmol,1.0equiv.) during5min. Theclearsolutionwas
stirredatthattemperatureforanadditional5min,anda2.5Msolutionofn-BuLiinhexanes(3mL,
7.5mmol,2.0equiv.) wasaddeddropwiseduring5min,whilemaintainingthetemperaturebelow
−20◦C.Theresultingmixturewasstirredatthattemperaturefor0.5h,dryDMF(0.27g,3.7mmol,
1.0equiv.) indryTHF(5mL)wasaddeddropwiseduring10min. Theresultingmixturewaswarmed
to−20◦Cin0.5handquenchedwithwater(6mL).Afterstirringthemixturebelow−20◦Cfor10min,
thephaseswereseparatedandthewaterphasewasextractedoneadditionaltimewithethylacetate.
Theresultingsuspensionwasallowedtoreachroomtemperatureandfiteredthrougha0.5×1cm
padofsilicagelelutedwith10mLofethylacetate. Thefiltratewasconcentratedandtheresiduewas
purifiedbyflashchromatographyonsilicagel(eluent: petroleumether/ethylacetate=10:1)toafford
product3aaswhitesolid,0.73g(yield: 90%). 1H-NMR(600MHz,DMSO)δ10.42(s,1H),9.94(s,1H),
8.93–8.60(m,1H),8.17(dd,J=8.8,2.3Hz,1H),7.99(d,J=8.8Hz,1H),1.48(s,9H).13C-NMR(151MHz,
DMSO)δ191.18,157.08,152.82,152.40,138.23,127.30,112.23,80.97,28.37.
1H-Indole-2-carboxylicacid(3b): Toasolutionof2-Bromo-1H-indole(1.0g,5mmol,1.0equiv.) indry
THF(20mL)at0◦Cwasaddeda2Msolutionofi-PrMgClinTHF(2.5mL,5mmol,1.0equiv.) during
5min. Theclearsolutionwasstirredatthattemperatureforanadditional5min,anda2.5Msolution
ofnBuLiinhexanes(4mL,10mmol,2.0equiv.) wasaddeddropwiseduring5min,whilemaintaining
thetemperaturebelow−20◦C.Theresultingmixturewasstirredatthattemperaturefor0.5h,dryCO
2
(0.22g,5mmol,1.0equiv.) wasaddedto−20◦C.Theresultingmixturewaswarmedto−20◦Cin0.5h
andquenchedwithwater(6mL).Afterstirringthemixturebelow−20◦Cfor10min,thephaseswere
separatedandthewaterphasewasextractedoneadditionaltimewithethylacetate. Theresulting
suspensionwasallowedtoreachroomtemperatureandfiteredthrougha0.5 × 1cmpadofsilica
gelelutedwith10mLofethylacetate. Thefiltratewasconcentratedandtheresiduewaspurified
byflashchromatographyonsilicagel(eluent: petroleumether/ethylacetate=3:1)toaffordproduct
3baswhitesolid,0.7g(yield: 85%),m.p.: 203–204◦C.1H-NMR(600MHz,DMSO)δ12.94(s,1H),
11.76(s,1H),7.79–6.89(m,5H).13C-NMR(151MHz,DMSO)δ163.29,137.71,128.88,127.34,124.73,
122.40,120.41,112.95,107.77.
1H-Indole-3-carboxylicacid(3c): Toasolutionof3-Bromo-1H-indole(0.86g,4.4mmol,1.0equiv.) indry
THF(20mL)at0◦Cwasaddeda2Msolutionofi-PrMgClinTHF(2.2mL,4.4mmol1.0equiv.) during
5min.Theclearsolutionwasstirredatthattemperatureforanadditional5min,anda2.5Msolutionof
n-BuLiinhexanes(3.5mL,8.8mmol,2.0equiv.) wasaddeddropwiseduring5min,whilemaintaining
thetemperaturebelow−20◦C.Theresultingmixturewasstirredatthattemperaturefor0.5h,dryCO
2
(0.2g,4.4mmol,1.0equiv.) wasaddedto−20◦C.Theresultingmixturewaswarmedto−20◦Cin
0.5handquenchedwithwater(6mL).Afterstirringthemixturebelow−20◦Cfor10min,thephases
Molecules2017,22,1952 7of12
wereseparatedandthewaterphasewasextractedoneadditionaltimewithethylacetate. Theresulting
suspensionwasallowedtoreachroomtemperatureandfiteredthrougha0.5 × 1cmpadofsilica
gelelutedwith10mLofethylacetate. Thefiltratewasconcentratedandtheresiduewaspurifiedby
flashchromatographyonsilicagel(eluent: petroleumether/ethylacetate=3:1)toaffordproduct3c
asoff-whitesolid,0.63g(yield: 89%),m.p.: 193–196◦C.1H-NMR(600MHz,DMSO)δ11.82(s,1H),
8.02(t,J=5.7Hz,2H),7.47(d,J=7.6Hz,1H),7.32–6.99(m,2H).13C-NMR(151MHz,DMSO)δ166.43,
136.89,132.71,126.48,122.58,121.42,121.05,112.65,107.87.
1H-Indole-5-carboxylicacid(3d): Toasolutionof5-Bromo-1H-indole(0.86g,4.4mmol,1.0equiv.) indry
THF(20mL)at0◦Cwasaddeda2Msolutionofi-PrMgClinTHF(2.2mL,4.4mmol,1equiv.) during
5 min.Theclearsolutionwasstirredatthattemperatureforanadditional5min,anda2.5Msolutionof
n-BuLiinhexanes(3.5mL,8.8mmol,2.0equiv.) wasaddeddropwiseduring5min,whilemaintaining
thetemperaturebelow−20◦C.Theresultingmixturewasstirredatthattemperaturefor0.5h,dryCO
2
(0.2g,4.4mmol,1.0equiv.) wasaddedto−20◦C. Theresultingmixturewaswarmedto−20◦Cin
0.5handquenchedwithwater(6mL).Afterstirringthemixturebelow for10min,thephaseswere
separatedandthewaterphasewasextractedoneadditionaltimewithethylacetate. Theresulting
suspension was allowed to reach room temperature and fitered through a 0.5×1cm pad of silica
gelelutedwith10mLofethylacetate. Thefiltratewasconcentratedandtheresiduewaspurifiedby
flashchromatographyonsilicagel(eluent: petroleumether/ethylacetate=3:1)toaffordproduct3d
asoff-whitesolid,0.46g(yield: 65%),m.p.: 210–214◦C.1H-NMR(600MHz,DMSO)δ12.39(s,1H),
11.46(s,1H), 8.25 (s, 1H), 7.72 (dd, J = 8.5, 1.5 Hz, 1H), 7.45 (dd, J = 8.4, 5.7 Hz, 2H), 6.57 (s, 1H).
13C-NMR(151MHz,DMSO)δ168.90,138.80,127.64,127.35,123.28,122.67,121.87,111.57,102.93.
5-Bromo-1H-indole-3-carbaldehyde (3e): To a solution of 3,5-dibromo-1H-indole (1.2 g, 4.4 mmol,
1.0 equiv.) in dry THF (20 mL) at 0 ◦C was added a 2 M solution of iPrMgCl in THF (2.2 mL,
4.4mmol,1.0equiv.) during5min. Theclearsolutionwasstirredatthattemperatureforanadditional
5min,anda2.5Msolutionofn-BuLiinhexanes(3.5mL,8.8mmol,2.0equiv.) wasaddeddropwise
during5min,whilemaintainingthetemperaturebelow−20◦C.Theresultingmixturewasstirredat
thattemperaturefor0.5h,dryDMF(0.32g,4.4mmol,1.0equiv.) wasaddedto−20◦C.Theresulting
mixturewaswarmedto−20◦Cin0.5handquenchedwithwater(6mL).Afterstirringthemixture
below−20◦Cfor10min,thephaseswereseparatedandthewaterphasewasextractedoneadditional
timewithethylacetate. Theresultingsuspensionwasallowedtoreachroomtemperatureandfitered
througha0.5×1cmpadofsilicagelelutedwith10mLofethylacetate. Thefiltratewasconcentrated
andtheresiduewaspurifiedbyflashchromatographyonsilicagel(eluent: petroleumether/ethyl
acetate=3:1)toaffordproduct3easyellowsolid, 0.78g(yield: 80%), m.p.: 192–194 ◦C.1H-NMR
(600MHz,DMSO)δ12.35(s,1H),9.93(s,1H),8.47–8.05(m,2H),7.57–7.21(m,2H).13C-NMR(151MHz,
DMSO)δ185.57,139.67,136.23,126.49,126.36,123.39,117.90,115.27,115.01.
5-Methoxy-1H-indole-2-carboxylic acid (3f): To a solution of 2-Bromo-5-methoxy-1H-indole (1.0 g,
4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 ◦C was added a 2 M solution of i-PrMgCl in THF
(2.2mL,4.4mmol,1.0equiv.) during5min. Theclearsolutionwasstirredatthattemperatureforan
additional5min,anda2.5Msolutionofn-BuLiinhexanes(3.5mL,8.8mmol,2.0equiv.) wasadded
dropwiseduring5min,whilemaintainingthetemperaturebelow−20◦C.Theresultingmixturewas
stirredatthattemperaturefor0.5h,dryCO (0.20g,1.0equiv.) wasaddedto−20◦C.Theresulting
2
mixturewaswarmedto−20◦Cin0.5handquenchedwithwater(6mL).Afterstirringthemixture
below−20◦Cfor10min,thephaseswereseparatedandthewaterphasewasextractedoneadditional
timewithethylacetate. Theresultingsuspensionwasallowedtoreachroomtemperatureandfitered
througha0.5×1cmpadofsilicagelelutedwith10mLofethylacetate. Thefiltratewasconcentrated
andtheresiduewaspurifiedbyflashchromatographyonsilicagel(eluent: petroleumether/ethyl
acetate = 3:1) to afford product 3f as brown solid, 0.68 g (yield: 80%), m.p.: 199–201 ◦C. 1H-NMR
(600MHz,DMSO)δ7.36(d,J=8.9Hz,1H),7.06(d,J=23.6Hz,2H),6.90(d,J=8.8Hz,1H),3.73(s,3H).
13C-NMR(151MHz,DMSO)δ163.25,154.31,133.07,129.10,127.65,116.28,113.83,107.47,102.44,55.61.
Molecules2017,22,1952 8of12
1H-Benzoimidazole-5-carboxylicacid(3g): Toasolutionof5-Bromo-1H-benzimidazole(0.87g,4.4mmol,
1.0 equiv.) in dry THF (20 mL) at 0 ◦C was added a 2 M solution of i-PrMgCl in THF (2.2 mL,
1equiv.) during5min. Theclearsolutionwasstirredatthattemperatureforanadditional5min,
anda2.5Msolutionofn-BuLiinhexanes(3.5mL,8.8mmol,2.0equiv.) wasaddeddropwiseduring
5min,whilemaintainingthetemperaturebelow−20◦C.Theresultingmixturewasstirredatthat
temperature for 0.5 h, dry CO (0.20 g, 4.4mmol, 1.0 equiv.) was added to −20 ◦C. The resulting
2
mixturewaswarmedto−20◦Cin0.5handquenchedwithwater(6mL).Afterstirringthemixture
below−20◦Cfor10min,thephaseswereseparatedandthewaterphasewasextractedoneadditional
timewithethylacetate. Theresultingsuspensionwasallowedtoreachroomtemperatureandfitered
througha0.5×1cmpadofsilicagelelutedwith10mLofethylacetate. Thefiltratewasconcentrated
andtheresiduewaspurifiedbyflashchromatographyonsilicagel(eluent:petroleumether/ethyl
acetate=3:1)toaffordproduct3gasbrownsolid,0.5g(yield: 71%). 1H-NMR(600MHz,DMSO)δ
8.43(s,1H),8.26(s,1H),7.87(d,J=8.4Hz,1H),7.67(d,J=8.4Hz,1H).13C-NMR(151MHz,DMSO)δ
168.47,144.83,125.10,123.74,118.13,115.12.
4-Hydroxy-benzaldehyde(3h): Toasolutionof4-Bromo-phenol(1.5g,8.7mmol,1equiv.) indryTHF
(25mL)at0◦Cwasaddeda2Msolutionofi-PrMgClinTHF(4.3mL,8.7mmol,1.0equiv.) during
5min.Theclearsolutionwasstirredatthattemperatureforanadditional5min,anda2.5Msolutionof
n-BuLiinhexanes(7.0mL,17.4mmol,2.0equiv.)wasaddeddropwiseduring5min,whilemaintaining
thetemperaturebelow−20◦C.Theresultingmixturewasstirredatthattemperaturefor0.5h,dryDMF
(0.63g,8.7mmol,1.0equiv.) indryTHF(5mL)wasaddeddropwiseduring10min. Theresulting
mixturewaswarmedto−20◦Cin0.5handquenchedwithwater(6mL).Afterstirringthemixture
below−20◦Cfor10min,thephaseswereseparatedandthewaterphasewasextractedoneadditional
timewithethylacetate. Theresultingsuspensionwasallowedtoreachroomtemperatureandfitered
througha0.5×1cmpadofsilicagelelutedwith10mLofethylacetate. Thefiltratewasconcentrated
andtheresiduewaspurifiedbyflashchromatographyonsilicagel(eluent:petroleumether/ethyl
acetate = 5:1) to afford product 3h as white solid, 0.94 g (yield: 90%), m.p.: 114–116 ◦C. 1H-NMR
(600MHz,DMSO)δ10.59(s,1H),9.78(s,1H),7.75(d,J=8.6Hz,2H),6.93(d,J=8.6Hz,2H).13C-NMR
(151MHz,DMSO)δ191.35,191.33,163.76,132.53,128.89,116.29.
N-(4-Formyl-phenyl)-acetamide(3i): Toasolutionof4-Bromo-phenN-(4-Formyl-phenyl)-acetamide
(1.5g,7.0mmol,1.0equiv.) indryTHF(25mL)at0◦Cwasaddeda2MsolutionofiPrMgClinTHF
(3.5mL,7.0mmol,1.0equiv.) during5min. Theclearsolutionwasstirredatthattemperatureforan
additional5min,anda2.5Msolutionofn-BuLiinhexanes(5.6mL,14.0mmol,2.0equiv.) wasadded
dropwiseduring5min,whilemaintainingthetemperaturebelow−20◦C.Theresultingmixturewas
stirredatthattemperaturefor0.5h,dryDMF(0.5g,1.0equiv.) indryTHF(5mL)wasaddeddropwise
during10min. Theresultingmixturewaswarmedto−20◦Cin0.5handquenchedwithwater(6mL).
Afterstirringthemixturebelow−20◦Cfor10min,thephaseswereseparatedandthewaterphase
wasextractedoneadditionaltimewithethylacetate. Theresultingsuspensionwasallowedtoreach
roomtemperatureandfiteredthrougha0.5×1cmpadofsilicagelelutedwith10mLofethylacetate.
The filtrate was concentrated and the residue was purified by flash chromatography on silica gel
(eluent: petroleumether/ethylacetate=10:1)toaffordproduct3iaswhitesolid,1.0g(yield: 94%),
m.p.: 157–158◦C.1H-NMR(600MHz,DMSO)δ10.35(s,1H),9.86(s,1H),7.81(dd,J=32.9,8.6Hz,
4H),2.10(s,3H).13C-NMR(151MHz,DMSO)δ191.92,169.55,145.29,131.56,131.27,119.01,24.68.
1H-Pyrrole-2-carbaldehyde (3j): To a solution of 2-Bromo-1H-pyrrole (0.5 g, 3.4 mmol, 1.0 equiv.) in
dryTHF(15mL)at0◦Cwasaddeda2Msolutionofi-PrMgClinTHF(1.7mL,3.4mmol,1.0equiv.)
during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a
2.5 M solution of n-BuLi in hexanes (2.7 mL, 6.8 mmol, 2.0 equiv.) was added dropwise during
5min,whilemaintainingthetemperaturebelow−20◦C.Theresultingmixturewasstirredatthat
temperaturefor0.5h,dryDMF(0.25g,1.0equiv.) indryTHF(5mL)wasaddeddropwiseduring
10 min. The resulting mixture was warmed to −20 ◦C in 0.5 h and quenched with water (6 mL).
Molecules2017,22,1952 9of12
After stirringthemixturebelow−20◦Cfor10min,thephaseswereseparatedandthewaterphase
wasextractedoneadditionaltimewithethylacetate. Theresultingsuspensionwasallowedtoreach
roomtemperatureandfiteredthrougha0.5×1cmpadofsilicagelelutedwith10mLofethylacetate.
The filtrate was concentrated and the residue was purified by flash chromatography on silica gel
(eluent:petroleumether/ethylacetate=10:1)toaffordproduct3jaswhitesolid,0.29g(yield: 89%),
m.p.: 42–44◦C.1H-NMR(600MHz,DMSO)δ12.19(s,1H),11.69(s,1H),7.04–6.85(m,1H),6.72(dd,
J=4.2,2.9Hz,1H),6.12(dd,J=5.8,2.4Hz,1H).13C-NMR(151MHz,DMSO)δ162.31,123.82,123.35,
115.11,109.73.
1H-Imidazole-2-carbaldehyde(3k): Toasolutionof2-bromo-1H-imidazole(0.65g,4.4mmol,1.0equiv.)
in dry THF (20 mL) at 0 ◦C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol,
1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional
5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added
dropwise during 5 min, while maintaining the temperature below −20◦C. The resulting mixture
was stirred at that temperature for 0.5 h, dry DMF (0.32 g, 4.4 mmol, 1.0 equiv.) was added to
−20◦C. The resulting mixture was warmed to −20 ◦C in 0.5 h and quenched with water (6 mL).
Afterstirringthemixturebelow−20◦Cfor10min,thephaseswereseparatedandthewaterphase
wasextractedoneadditionaltimewithethylacetate. Theresultingsuspensionwasallowedtoreach
roomtemperatureandfiteredthrougha0.5×1cmpadofsilicagelelutedwith10mLofethylacetate.
The filtrate was concentrated and the residue was purified by flash chromatography on silica gel
(eluent: petroleumether/ethylacetate=10:1)toaffordproduct3kaspaleyellowsolid,0.38g(yield:
91%),m.p.: 205–206◦C.1H-NMR(600MHz,DMSO)δ13.60(s,1H),9.64(s,1H),7.42(s,2H).13C-NMR
(151MHz,DMSO)δ181.66,146.09.
1H-Imidazole-4-carbaldehyde(3l): Toasolutionof4-bromo-1H-imidazole(0.65g,4.4mmol,1.0equiv.) in
dryTHF(20mL)at0◦Cwasaddeda2Msolutionofi-PrMgClinTHF(2.2mL,4.4mmol,1.0 equiv.)
during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a
2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during
5min,whilemaintainingthetemperaturebelow−20◦C.Theresultingmixturewasstirredatthat
temperaturefor0.5h, dryDMF(0.32g, 4.4mmol, 1.0equiv.) wasaddedto −20 ◦C.Theresulting
mixturewaswarmedto−20◦Cin0.5handquenchedwithwater(6mL).Afterstirringthemixture
below−20◦Cfor10min,thephaseswereseparatedandthewaterphasewasextractedoneadditional
timewithethylacetate. Theresultingsuspensionwasallowedtoreachroomtemperatureandfitered
througha0.5×1cmpadofsilicagelelutedwith10mLofethylacetate. Thefiltratewasconcentrated
andtheresiduewaspurifiedbyflashchromatographyonsilicagel(eluent:petroleumether/ethyl
acetate=10:1)toaffordproduct3lasoff-whitesolid,0.36g(yield: 85%),m.p.: 175–177◦C.1H-NMR
(600MHz,DMSO)δ9.74(s,1H),7.99(s,1H),7.94(s,1H).13C-NMR(151MHz,DMSO)δ184.46,139.44,
134.9,129.5.
6-Hydroxy-pyridine-2-carboxylicacid(3m):Toasolutionof2-bromo-6-hydroxypyridine(0.76g,4.4mmol,
1.0 equiv.) in dry THF (20 mL) at 0 ◦C was added a 2 M solution of -PrMgCl in THF (2.2 mL,
4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an
additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was
added dropwise during 5min, while maintaining the temperature below −20◦C. The resulting
mixture was stirred at that temperature for 0.5 h, dry CO (0.20 g, 1.0 equiv.) was added to
2
−20◦C. The resulting mixture was warmed to −20 ◦C in 0.5 h and quenched with water (6 mL).
Afterstirringthemixturebelow−20◦Cfor10min,thephaseswereseparatedandthewaterphase
wasextractedoneadditionaltimewithethylacetate. Theresultingsuspensionwasallowedtoreach
roomtemperatureandfiteredthroughambox0.5×1cmpadofsilicagelelutedwith10mLofethyl
acetate. Thefiltratewasconcentratedandtheresiduewaspurifiedbyflashchromatographyonsilica
gel(eluent: petroleumether/ethylacetate=10:1)toaffordproduct3masoff-whitesolid,0.56g(yield:
Molecules2017,22,1952 10of12
93%),m.p.: 275–277◦C.1H-NMR(600MHz,DMSO)δ7.56(dd,J=8.9,7.0Hz,1H),6.97(d,J=6.8Hz,
1H),6.65(d,J=9.0Hz,1H).13C-NMR(151MHz,DMSO)δ163.28,162.67,140.51,137.97,123.88,110.42.
2-Hydroxy-nicotinicacid(3n): Toasolutionof3-bromo-2-hydroxypyridine(0.76g,4.4mmol,1.0equiv.)
indryTHF(20mL)at0◦Cwasaddeda2Msolutionofi-PrMgClinTHF(2.2mL,4.4mmol,1.0equiv.)
during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a
2.5Msolutionofn-BuLiinhexanes(3.5mL,8.8mmol,2.0equiv.) wasaddeddropwiseduring5min,
whilemaintainingthetemperaturebelow−20◦C.Theresultingmixturewasstirredatthattemperature
for0.5h,dryCO (0.20g,1.0equiv.) wasaddedto−20◦C.Theresultingmixturewaswarmedto
2
−20◦Cin0.5handquenchedwithwater(6mL).Afterstirringthemixturebelow−20◦Cfor10min,
thephaseswereseparatedandthewaterphasewasextractedoneadditionaltimewithethylacetate.
Theresultingsuspensionwasallowedtoreachroomtemperatureandfiteredthrougha0.5×1cm
padofsilicagelelutedwith10mLofethylacetate. Thefiltratewasconcentratedandtheresiduewas
purifiedbyflashchromatographyonsilicagel(eluent: petroleumether/ethylacetate=10:1)toafford
product3nasoff-whitesolid,0.48g(yield: 79%),m.p.: 255–257◦C.1H-NMR(600MHz,DMSO)δ
14.76(s,1H),13.38(s,1H),8.38(dd,J=7.2,2.0Hz,1H),7.95(dd,J=6.3,2.0Hz,1H),6.68(t,J=6.7Hz,
1H).13C-NMR(151MHz,DMSO)δ165.46,165.04,146.61,141.95,117.12,109.09.
5-Bromo-3-hydroxyethynyl-pyridin-2-ol (3o): To a solution of 3,5-dibromo-2-hydroxypyridine (1.1 g,
4.4mmol,1.0equiv.) indryTHF(20mL)at0◦Cwasaddeda2Msolutionofi-PrMgClinTHF(2.2mL,
4.4mmol,1.0equiv.) during5min. Theclearsolutionwasstirredatthattemperatureforanadditional
5min,anda2.5Msolutionofn-BuLiinhexanes(3.5mL,8.8mmol,2.0equiv.) wasaddeddropwise
during5min,whilemaintainingthetemperaturebelow−20◦C.Theresultingmixturewasstirredat
thattemperaturefor0.5h,dryCO (0.20g,4.4mmol,1.0equiv.) wasaddedto−20◦C.Theresulting
2
mixturewaswarmedto−20◦Cin0.5handquenchedwithwater(6mL).Afterstirringthemixture
below−20◦Cfor10min,thephaseswereseparatedandthewaterphasewasextractedoneadditional
timewithethylacetate. Theresultingsuspensionwasallowedtoreachroomtemperatureandfitered
througha0.5×1cmpadofsilicagelelutedwith10mLofethylacetate. Thefiltratewasconcentrated
andtheresiduewaspurifiedbyflashchromatographyonsilicagel(eluent: petroleumether/ethyl
acetate=10:1)toaffordproduct3oasOff-whitesolid,1.0g(yield: 80%),m.p.: 245–247◦C.1H-NMR
(600MHz,DMSO)δ13.82(s,2H),8.31(d,J=2.8Hz,1H),8.23(d,J=2.8Hz,1H).13C-NMR(151MHz,
DMSO)δ164.43,163.72,147.95,142.51,118.49,99.96.
Experimentalproceduresandanalyticaldataofallcompounds(1H-and13C-NMR),copyofthe
1H,13CanddataareavailableintheSupplementaryMaterials.
4. Conclusions
Insummary,wehavedevelopedanefficientmethodforperformingbromine–metalexchange
process under non-cryogenic conditions on bromopyridines and arenes bearing an acidic
proton-containing substituent. The use of a combination of i-PrMgCl and n-BuLi in this method
has solved the problem of intermolecular quenching that is often encountered when using alkyl
lithium. Moreover,themethodisparticularlysuitableforarylbromidesofpoorreactivity.
SupplementaryMaterials:Thefollowingareavailableonline,generalprocedureforHalogen-metalexchange
reactionand1Hand13CNMRspectraofallproducts.
Acknowledgments: We are grateful for the generous financial support by the conversion of outstanding
achievementsincollegesanduniversitiesinChongqingofChina(KJZH14204).
Author Contributions: Guoqiang Shi and Jianyong Yuan conceived and designed the experiments;
QingqiangTianperformedtheexperiments;QingqiangTianandSuqinShanganalyzedthedata;HuajunWang
andZhiyaoLicontributedreagents/materials/analysistools;QingqiangTianwrotethepaper.
ConflictsofInterest:Theauthorsdeclarenoconflictsofinterest.