Comprehensive Organic Name Reactions and Reagents

2558 Pages·2009·46.1 MB·English

by  Zerong Wang

1
Abnormal Claisen
Rearrangement
A. GENERALDESCRIPTIONOFTHEREACTION
The first example of abnormal Claisen rearrangements was reported by Lauer and
Filbert in 1936.1 In contrast to the regular Claisen rearrangement ([3,3] (cid:1) migration),2
theabnormalClaisenrearrangement3usuallyoccursfortheallylaromaticethers.Asimilar
reactionalsooccursforthethermalrearrangementofcyclopropylketonestohomoallylic
ketones.4 The abnormal Claisen rearrangement is believed to proceed via two consecu-
tive processes, i.e., the normal ortho Claisen rearrangement of γ-alkylallyl aryl ether to
an o-(α-alkylallyl) phenol and the isomerization of the resulting phenol. In general, this
typeofabnormalClaisenrearrangementdoesnotoccursmoothly,exceptwheninthepres-
ence of Lewis acids FeCl , even though other Lewis acids (e.g., HfCl , GaCl , ZrCl )
3 4 3 4
havelimitedabilitytoacceleratesuchreaction.3a ItisreportedthattheabnormalClaisen
rearrangementcanbepreventedbytheapplicationof1,1,1,3,3,3-hexamethyldisilazaneand
N,O-bis(trimethylsilyl)acetamide.5
B. GENERALREACTIONSCHEME
O OH OH
[3,3]
R R R
Detectable Product Major Product
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Copyright©2010JohnWiley&Sons,Inc.
1
2 ABNORMALCLAISENREARRANGEMENT
C. PROPOSEDMECHANISMS
TwokindsofmechanismshavebeenproposedfortheabnormalClaisenrearrangement:
theconcertedprocess(Scheme1)6andthestepwiseprocessconsistingoftwoconsecutive
steps(Scheme2).4However,muchexperimentalevidenceisinconsistentwiththestepwise
mechanism.
SCHEME1.ConcertedmechanismforabnormalClaisenrearrangement.
SCHEME2.StepwisemechanismforabnormalClaisenrearrangement.
D. MODIFICATION
N/A
E. APPLICATIONS
Thisreactionhascertainapplicationsinorganicsynthesis.
F. RELATEDREACTIONS
ThisreactionisrelatedtotheClaisenRearrangement.
G. CITEDEXPERIMENTALEXAMPLES
OH
OH
O HO CHO
HO
HO CHO 160–170°C
+
CHO
1 2
Reference7.
CITEDEXPERIMENTALEXAMPLES 3
◦
Caution! The reaction becomes vigorous and exothermic when heated above 200 C,
especiallyonalargescale.Toa25-mLround-bottomedflaskequippedwithamagneticstir-
ringbarandanaircondenserwasadded5.06g3-hydroxy-2-(2-propenyloxy)benzaldehyde
(28.43mmol).TheflaskwasgentlyheatedtomeltthesolidandthenplacedinaWood’s
◦
metal bath at 165–170 C. After an induction period of a few minutes, the liquid in the
flaskdarkenedandevolvedagas.Whenthereactionwasfinished(detectedbyTLC)and
cooleddown,themixturewastriturated10timeswithboilinghexane.Thedark,granular
residuewasdissolvedinEtOAcandadsorbedon10silica.Themixturewasseparatedby
column chromatography using hexane/EtOAc/AcOH (65:35:1) as the eluent to give the
majornormalClaisenrearrangementproductandthefirstabnormalClaisenrearrangement
product,i.e.,2-allyl-3,4-dihydroxybenzaldehyde(1).Thehexaneextractswereevaporated
andchromatographedonsilicausinghexane/EtOAc/AcOH(80:20:1)aseluenttogivethe
secondabnormalClaisenrearrangementproduct,i.e.,2,3-dihydroxy-4-allylbenzaldehyde
(2)andotherminorproducts.
H
O SnCl4
O O
O
Ph
O CH Cl , –78°C
2 2 H
Reference3a.
GeneralProcedureforthePreparationofGeranylPhenylEther
To a stirred suspension of 176 mg sodium hydride (60% in oil, 4.4 mmol) in 20 mL
THFatroomtemperatureunderargonatmospherewasadded0.376gphenol(4.0mmol)
in portions followed by a catalytic amount of hydroquinone. The mixture was stirred for
0.5h.HMPA(2mL)and0.74mLgeranylchloride(4.0mmol)weresuccessivelyadded.
The whole mixture was stirred for 1 day. After decomposition of excess sodium hydride
with0.5mLmethanol,themixturewaspouredontoicewaterandextractedwithether.The
combinedorganiclayersweredried,concentrated,andpurifiedbycolumnchromatography
onsilicagel(hexane-dichloromethaneaseluent).
GeneralProcedurefortheEnantioselectiveCyclizationofGeranylPhenol
EtherPromotedbytheBINOL-SnCl Complex
4
To a solution of BINOL (0.22 mmol) in 4 mL distilled CH Cl was added 200 (cid:2)L
2 2
1.0MSnCl inCH Cl (0.2mmol)at−78◦Cunderargonatmosphere.Afterthemixture
4 2 2
was stirred for several minutes at the same temperature, 0.230 g geranyl phenyl ether
(0.1 mmol) was added dropwise at −78◦C. After the resulting mixture was stirred for
3 days at −78◦C, 16 (cid:2)L pyridine (0.2 mmol) was added. Then the mixture was poured
ontoasaturatedNaHCO solutionandextractedwithether.Thecombinedorganiclayers
3
were dried over anhydrous MgSO and concentrated. The residue was purified by silica
4
gel column chromatography using hexane/CH Cl (4:1) as the eluent to give 98% of the
2 2
rearrangementproductasdetectedbyGC.
4 ABNORMALCLAISENREARRANGEMENT
Other references related to the abnormal Claisen rearrangement can be found in the
literature.8
H. REFERENCES
1. Lauer,W.M.andFilbert,W.F.,J.Am.Chem.Soc.,1936,58,1388.
2. SeeClaisenRearrangementherein(P.649).
3. (a)Nakamura,S.;Ishihara,K.andYamamoto,H.,J.Am.Chem.Soc.,2000,122,8131.(b)Patel,
G.N.andTrivedi,K.N.,J.IndianChem.Soc.,1988,65,192.(c)Shah,R.R.andTrivedi,K.N.,
Curr.Sci.,1975,44,226.(d)Jain,A.C.andGupta,R.K.,Chem.Lett.,1974,1353.(e)Mahey,
S.; Seshadri, T. R. and Mukerjee, S. K., Indian J. Chem., 1973, 11, 1126. (f) Jain, A. C. and
Jain,S.M.,IndianJ.Chem.,1972,10,971.(g)Hansen,H.J.,Mech.Mol.Migr.,1971,3,177.
(h)Jefferson,A.andScheinmann,F.,J.Chem.Soc.,C,1969,243.(i)Marvell,E.N.andSchatz,
B.S.,TetrahedronLett.,1967,67.(j)Roberts,R.M.andLandolt,R.G.,J.Org.Chem.,1966,31,
2699.(k)Jefferson,A.andScheinmann,F.,Chem.Commun.(London),1966,239.(l)Marvell,
E.N.;Anderson,D.R.andOng,J.,J.Org.Chem.,1962,27,1109.(m)Habich,A.;Barner,R.;
Roberts,R.M.andSchmid,H.,Helv.Chim.Acta,1962,45,1943.
4. (a)Roberts,R.M.;Landolt,R.G.;Greene,R.N.andHeyer,E.W.J.Am.Chem.Soc.,1967,89,
1404.(b)Roberts,R.M.andLandolt,R.G.J.Am.Chem.Soc.,1965,87,2281.
5. Fukuyama,T.;Li,G.Q.andPeng,G.,TetrahedronLett.,1994,35,2145.
6. Lauer,W.M.;Doldouras,G.A.;Hileman,R.E.andLiepins,R.,J.Org.Chem.,1961,26,4785.
7. Kilenyi,S.N.;Mahaux,J.M.andVanDurme,E.,J.Org.Chem.,1991,56,2591.
8. (a)Puranik,R.;Rao,Y.J.andKrupadanam,G.L.D.,IndianJ.Chem.SectionB:Org.Chem.,
2002,41B,868.(b)Schobert,R.;Siegfried,S.;Gordon,G.;Mulholland,D.;Nieuwenhuyzen,M.,
TetrahedronLett.,2001,42,4561.(c)Ito,H.;Sato,A.andTaguchi,T.,TetrahedronLett.,1997,38,
4815.(d)Palani,N.andBalasubramanian,K.K.,TetrahedronLett.,1993,34,5001.(e)Grieco,P.
A.;Clark,J.D.andJagoe,C.T.,J.Am.Chem.Soc.,1991,113,5488.(f)Shah,R.R.andTrivedi,
K.N.,IndianJ.Chem.,SectionB:Org.Chem.,1981,20B,210.(g)Okely,H.M.andGrundon,
M.F.,J.Chem.Soc.,PerkinTrans.I,1981,897.(h)Yagodin,V.G.;Bunina-Krivorukova,L.I.
andBal’yan,K.V.,Zh.Org.Khim.,1970,6,2513.(i)Lauer,W.M.andJohnson,T.A.,J.Org.
Chem.,1963,28,2913.
2
Acetoacetic Ester
Condensation
(Claisen-Geuther Ester Condensation)
A. GENERALDESCRIPTIONOFTHEREACTION
This reaction was first reported by Geuther in 18631 and subsequently studied by
Claisen.2 It is a self-condensation of ester in the presence of alkali alkoxide in alcohol
to form β-keto esters (e.g. ethyl acetoacetate from ethyl acetate) and is generally known
as acetoacetic ester condensation.3 This reaction was extensively explored by McElvain
in 1930s.4 In general, it is carried out under basic conditions (e.g., NaOEt) to generate
β-keto-estersfromaliphaticcarboxylicacidesters.
B. GENERALREACTIONSCHEME
O O O
NaOEt
R R (R = H, alkyl, aryl)
O EtOH O
R
C. PROPOSEDMECHANISMS
Thegeneralmechanismforacetoaceticestercondensationshownhereusesethylacetate
asanexample.3f,4
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Copyright©2010JohnWiley&Sons,Inc.
5
6 ACETOACETICESTERCONDENSATION
O O
O O
NaOEt O
Na+ O O
O EtOH – O O –
Na+
O O– O O
O O O
NaOEt
D. MODIFICATION
Threeesters(ethylisovalerate,ethylt-butylacetate,andethylisobutyrate)donotundergo
thistypeofcondensationundernormalconditionswithsodiumethoxide,presumablydueto
thesterichindrance.However,theircondensationproceedsreadilywhenmesitylmagnesium
bromide is applied as the base.5 In addition, the acetoacetic ester condensation has been
improvedtogivehighyieldsusingsomequaternaryammoniumsaltsoflongaliphaticchains
asthephasetransfercatalystinbenzene.6
E. APPLICATIONS
Thisreactionisusefulforthesynthesisofaseriesofβ-ketoesters(bothbranchedand
unbranched).Inaddition,ethylacetoacetatecanbeappliedtothepreparationofγ-diketones
inreactionwithepoxidesfollowedbyoxidationanddecarboxylation.7
F. RELATEDREACTIONS
ThisreactionisrelatedtoAcetoaceticEsterSynthesis.
G. CITEDEXPERIMENTALEXAMPLES
Ph
Ph O NaOEt Ph O
O O O
55%
Reference3a.
Toa500-mLflaskequippedwithasealedstirrerandarefluxcondenserwereaddedfresh
NaOEt(preparedfrom4.6gsodium)and70.0gethylphenylacetate(0.42mol).Theflask
◦
washeatedwithstirringinasteambathatabout95 Cfor6h;however,thesolidmaterial
(NaOEt) in the reaction mixture completely disappeared after a few minutes of heating.
Thentheflaskwascooledtoroomtemperatureandtreatedcarefullywith15mLaceticacid
in 100 mL water. At this point, a considerable amount of ethyl α,γ-diphenylacetoacetate
precipitated. Ether (150 mL) was added to return this precipitate to solution, and the
REFERENCES 7
separatedaqueouslayerwasfurtherextractedwith50mLether.Thecombinedetherlayers
werewashedsufficientlywithsaturatedsodiumbicarbonatesolution.Aftertheremovalof
ether,theresiduewasallowedtocrystallize,andtheresultingcrystallinemasswasagain
◦
added to 20 mL alcohol and kept at 0 C. The precipitate was filtered off by suction and
driedoveraporousplate,and28gofmaterialwasobtained.Thefiltratewasthendistilled
from an oil bath to remove alcohol, and the unreacted ethyl phenylacetate was collected
◦
at 5 mmHg. The residue was dissolved in another 10 mL hot alcohol and cooled to 0 C.
Anadditional3gethylα,γ-diphenylacetoacetatewasrecovered.Theyieldwas55%onthe
basis of sodium ethoxide used, or 78% based on the ethyl phenylacetate recovered. The
◦
producthasanm.p.75–77 C.
R
O NaOEt O
R R
O O O
R = C H , n = 1, 2, ...12
n 2n+1
Reference3f.
Toa125mLClaisenflaskequippedwitha35-cm-longfractioningcolumnwereplaced
0.1molcorrespondingesterand0.05molNaOEt.Thefractioningcolumnwasattachedto
areceivingflask(withoutcooling)thatwasinturnattachedthroughasodalimetowerand
asafetybottletoamanometerandawaterpump.Theflaskwasthenheatedcarefullyinan
oilbathtoatemperatureandunderapressurethatcausedamoderate,butnottoovigorous,
evolutionofalcoholvapor,asshownbytheebullitionofthereactionmixture.Therequired
temperatureandpressurevariedwiththeboilingpointoftheesters;thelowerestersrequired
lowerreactiontemperaturesandhigherpressurestopreventthelossofester.Consequently,
the time necessary for the completion of the reaction in these cases was increased. After
thereactionhadproceededforsometime,thetemperaturesandpressurescouldberaised
andlowered,respectively,untilthereactionmassceasedebullition.Thereactionproduct
aftercoolingwastreatedwiththecalculatedquantityof30%aceticacidandshakenvig-
orouslyuntilthesodiumsalthadbeencompletelydecomposed.Theβ-ketoesterwasthen
extracted with 25 mL ether followed by the standard workup procedure. This procedure
wasquitesatisfactoryforalloftheestersexceptethylα-pelargonylpelargonateandethyl
α-caprylcaprate,bothofwhichsufferedasmallamountofpyrolysistothecorresponding
ketone.
Otherreferencesrelatedtoacetoaceticestercondensationarecitedintheliterature.8
H. REFERENCES
1. Geuther,A.,Arch.Pharm.,1863,106,97.
2. Claisen,R.L.andLowman,O.,Ber.,1887,20,651.
3. (a)Roberts,D.CandMcElvain,S.M.,J.Am.Chem.Soc.,1937,59,2007.(b)Meincke,E.R.
andMcElvain,S.M.,J.Am.Chem.Soc,1935,57,1443.(c)Cox,R.F.B.andMcElvain,S.M.,
J.Am.Chem.Soc.,1934,56,2459.(d)Fisher,N.andMcElvain,S.M.,J.Am.Chem.Soc.,1934,
56,1766.(e)Thomas,W.B.andMcElvain,S.M.,J.Am.Chem.Soc.,1934,56,1806.(f)Cox,
R.F.B.;Kroeker,E.H.andMcElvain,S.M.,J.Am.Chem.Soc.,1934,56,1173.(g)Briese,R.
8 ACETOACETICESTERCONDENSATION
R.andMcElvain,S.M.,J.Am.Chem.Soc.,1933,55,1697.(h)Prill,E.A.andMcElvain,S.M.,
J.Am.Chem.Soc.,1933,55,1233.(i)Snell,J.M.andMcElvain,S.M.,J.Am.Chem.Soc.,1933,
55,416.(j)Snell,J.M.andMcElvain,S.M.,J.Am.Chem.Soc.1931,53,2310.(k)Snell,J.M.
andMcElvain,S.M.,J.Am.Chem.Soc.,1931,53,750.(l)McElvain,S.M.,J.Am.Chem.Soc.,
1929,51,3124.
4. Frampton,O.D.andNobis,J.F.,Ind.Eng.Chem.,1953,45,404.
5. Spielman,M.A.andSchmidt,M.T.,J.Am.Chem.Soc.,1937,59,2009.
6. Durst,H.D.andLiebeskind,L.,J.Org.Chem.,1974,39,3271.
7. Adams,R.M.andVanderwerf,C.A.,J.Am.Chem.Soc.,1950,72,4368.
8. (a) Chandra, M. and Mehrotra, J. K., J. Indian Chem. Soc., 1970, 47, 46. (b) Colonge, J. and
Cayrel,J.-P.,Bull.Soc.Chim.Fr.,1965,3596.(c)Shivers,J.C.;Hudson,B.E.andHauser,C.R.,
J.Am.Chem.Soc.,1943,65,2051.(d)Hauser,C.R.andHudson,B.E.,Org.React.,1942,1,266.
(e)Roland,J.R.andMcElvain,S.M.,J.Am.Chem.Soc.,1937,59,132.(f)Adickes,F.,Ber.,
1932,65B,522.(g)Franklin,M.C.andShort,W.F.,J.Chem.Soc.,1928,591.(h)Scheibler,H.
andMarhenkel,E.,Ann.,1927,458,1.(i)Scheibler,H.,Angew.Chem.,1923,36,6.(j)Branch,
G.E.K.andBranch,H.E.H.,J.Am.Chem.Soc.,1918,40,1708.
3
Acetoacetic Ester Synthesis
A. GENERALDESCRIPTIONOFTHEREACTION
ThisreactionwasfirstreportedbySimonsenin1908;1 unfortunately,itwasnotnamed
afterthisinventor.Itisthesynthesisofα-substitutedaceticacidestersorsubstitutedacetones
from acetoacetic ester by treatment of ethyl acetoacetate with a strong base, followed by
alkylationandsubsequentdeacetylationordecarboxylation;itisknownasacetoaceticester
synthesis.2 Being adjacent to two electron-withdrawing groups (i.e., carbonyl and ester
groups),theα-methyleneprotonsinβ-ketoesters(e.g.,acetoaceticesters)areveryacidic;
the pKa of which could be as low as 10.3 Therefore, the α-methylene proton is readily
deprotonated,andtheresultingα-carbanioncanbealkylatedoracylated.Inaddition,the
acetoaceticesterscanalsobealkylatedinacidicconditionviatheformofenolintermediate,
althoughsomeunexpectedproductsmightform.4Thenewsubstitutedβ-ketoestersarethen
eithertreatedwithaconcentratedbase(normallystrongbase)togivesubstitutedestersor
arehydrolyzedundermildconditions(eitheracidicorbasic)togivesubstitutedacetones
throughdecarboxylation.5,6
B. GENERALREACTIONSCHEME
O O
O O O
Base R Dilute OH–
R O R′ + ROH
O R′-X or H+
R′
Conc. alcoholic
alkali
O
R′ R + AcO–
O
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Copyright©2010JohnWiley&Sons,Inc.
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10 ACETOACETICESTERSYNTHESIS
C. PROPOSEDMECHANISMS
Displayedhereisageneralmechanismforacetoaceticestersynthesisfromethylacety-
lacetate.
D. MODIFICATION
N/A
E. APPLICATIONS
Besidestheapplicationstosynthesizeketonesandesters,thisreactionhasbeenusedto
synthesize7-nitro-indolebymein1995,asshowninthefollowingreactionroute.
O MeI, NaOEt
O N2+Cl–
EtOH NO2
O O
O O
O
N N
N
NO OEt H
2 NO
2
F. RELATEDREACTIONS
ThisreactionisverycloselyrelatedtoAcetoaceticEsterCondensation;andmechanisti-
cally,thecleavageofβ-ketoestersunderstrongbaseconditionsissimilartotheRetro-Aldol
Addition.