Multicomponent Synthesis of 2-Imidazolines

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Multicomponent synthesis of 2-imidazolines
Bon, RS; van Vliet, B.; Sprenkels, N.E.; Schmitz, R.F.; de Kanter, FJJ; Stevens, C.V.;
Swart, M; Bickelhaupt, FM; Groen, MB; Orru, RVA
published in
Journal of Organic Chemistry
2005
DOI (link to publisher)
10.1021/jo050132g
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citation for published version (APA)
Bon, RS., van Vliet, B., Sprenkels, N. E., Schmitz, R. F., de Kanter, FJJ., Stevens, C. V., Swart, M., Bickelhaupt,
FM., Groen, MB., & Orru, RVA. (2005). Multicomponent synthesis of 2-imidazolines. Journal of Organic
Chemistry, 70(9), 3542-3553. https://doi.org/10.1021/jo050132g
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Multicomponent Synthesis of 2-Imidazolines
Robin S. Bon,† Bart van Vliet,† Nanda E. Sprenkels,† Rob F. Schmitz,† Frans J. J. de Kanter,†
Christian V. Stevens,‡ Marcel Swart,§ F. Matthias Bickelhaupt,§ Marinus B. Groen,† and
Romano V. A. Orru*,†
DepartmentofChemistry,FacultyofSciences,VrijeUniversiteitAmsterdam,DeBoelelaan1083,1081
HV,Amsterdam,TheNetherlands,andDepartmentofOrganicChemistry,FacultyofAgriculturaland
AppliedBiologicalSciences,GhentUniversity,Coupurelinks653,9000Gent,Belgium
[email protected]
ReceivedJanuary21,2005
Amulticomponentreaction(MCR)betweenamines,aldehydes,andisocyanidesbearinganacidic
R-protongiveseasyaccesstoadiverserangeofhighlysubstituted2-imidazolines.Thelimitations
ofthemethodologyseemtobedeterminedbythereactivityoftheisocyanideandbythestericbulk
ontheinsitugeneratedimineratherthanbythepresenceofadditionalfunctionalgroupsonthe
imine.Lessreactiveisocyanides,forexamplep-nitrobenzylisocyanide25a,reactsuccessfullywith
amines and aldehydes, using a catalytic amount of silver(I) acetate. Some of the resulting
p-nitrophenyl-substituted 2-imidazolines undergo air oxidation to the corresponding imidazoles.
DifferencesinreactivityoftheemployedisocyanidesareexplainedwithuseofDFTcalculations.
Difficultreactionswithketonesinsteadofaldehydesastheoxo-compoundinthisMCRarepromoted
by silver(I) acetate as well.
Introduction with MDM2 to a high degree. The 2-imidazoline core
essentiallyactsasafairlyrigidreplacementofthehelical
In the past decades, 2-imidazoline derivatives have backbone of p53. Also, 2-imidazolines have been exam-
attracted considerable interest because of their wide inedfortheirhormonaleffectsduetoestrogenreceptor
variety of biological activities. Several 2-imidazolines modulation4 as well as for their interaction with R2-
haveahighaffinityforimidazolinebindingsites(IBS).1 adrenoceptors.5 Studies have been reported on the pos-
These IBS are being increasingly studied for their sible application of 2-imidazolines as, among others,
involvement in hypertension, regulation of blood pres- antihyperglycemic,6 antiinflammatory,7 antihyperten-
sure, insulin secretion control, and numerous human sive,5,8 and antihypercholesterolemic9 agents. Further-
brain disorders such as depression, neurodegeneration, more, 2-imidazolines are widely used as convenient
and opioid tolerance/dependence.2 Moreover, a series of building blocks for the synthesis of biologically active
highlysubstitutedcis-imidazolineanaloguescalledNut- moleculessuchasazapenams,(bis)dioxocyclams,diaza-
lins (Nutley inhibitors) has been successfully screened pinones,10 and 2,3-diamino acids.11
asinhibitorsofMDM2,aproteinthatnegativelymodu-
latesthetranscriptionalactivityandstabilityofthep53 (4)(a) Gust, R.; Keilitz, R.; Schmidt, K.; von Rauch, M. J. Med.
tumorsuppressorprotein.3Crystalstructuresshowthat Chem.2002,45,3356-3365.(b)vonRauch,M.;Schlenk,M.;Gust,R.
J.Med.Chem.2004,47,915-927.
the Nutlins mimic the interactions of the p53 peptide (5)Scha¨fer,U.;Burgdorf,C.;Engelhardt,A.;Kurz,T.;Richardt,G.
J.Pharmacol.Exp.Ther.2002,303,1163-1170.
(6)(a)Doyle,M.E.;Egan,J.M.Pharmacol.Rev.2003,55,105-
†VrijeUniversiteitAmsterdam,OrganicandInorganicChemistry. 131.(b)Rondu,F.;leBihan,G.;Wang,X.;Lamouri,A.;Touboul,E.;
‡GhentUniversity. Dive,G.;Bellahsene,T.;Pfeiffer,B.;Renard,P.;Guardiola-Lemaitre,
§VrijeUniversiteitAmsterdam,TheoreticalChemistry. B.; Manechez, D.; Penicaud, L.; Ktorza, A.; Godfroid, J.-J. J. Med.
(1)Bousquet,P.;Feldman,J.;Schwartz,J.J.Pharmacol.Exp.Ther. Chem.1997,40,3793-3803.
1984,230,232-236. (7)Ueno, M.; Imaizumi, K.; Sugita, T.; Takata, I.; Takeshita, M.
(2)Forarecentreviewaboutimidazolinebindingsitesandtheir Int.J.Immunopharmacol.1995,17,597-603.
ligands,see: Dardonville,C.;Rozas,I.Med.Res.Rev.2004,24,639- (8)Bousquet,P.;Feldman,J.Drugs1999,58,799-812.Touzeau,
661. F.;Arrault,A.;Guillaumet,G.;Scalbert,E.;Pfeiffer,B.;Rettori,M.-
(3)Vassilev,L.T.;Vu,B.T.;Graves,B.;Carvajal,D.;Podlaski,F.; C.;Renard,P.;Me´rour,J.-Y.J.Med.Chem.2003,46,1962-1979.
Filipovic,Z.;Kong,N.;Kammlott,U.;Lukacs,C.;Klein,C.;Fotouhi, (9)Li,H.-Y.;Drummond,S.;DeLucca,I.;Boswell,G.A.Tetrahedron
N.;Liu,E.A.Science2004,303,844-848. 1996,52,11153-11162.
10.1021/jo050132gCCC:$30.25 ©2005AmericanChemicalSociety
3542 J.Org.Chem.2005,70,3542-3553 PublishedonWeb03/30/2005
MulticomponentSynthesisof2-Imidazolines
In addition to their pharmaceutical relevance, 2-imi- SCHEME1. MulticomponentSynthesisof
dazolinesarebecomingincreasinglyimportantincataly- 2-Imidazolines
sis. They have been satisfyingly employed as chiral
ligandsinasymmetriccatalysis.12Moreimportant,how-
ever, is their growing application as precursors for
N-heterocyclic carbene (NHC) ligands.13 These remark-
ablystablecarbenesexhibitpropertiesstrikinglysimilar
and even superior to those of the electron-rich organo-
phosphanes PR .14 Therefore, phosphorus ligands have
3
oftenbeenadvantageouslyreplacedbyNHCsasligands
intransitionmetalcatalysis.15Nitrogenalkylationof2H-
2-imidazolines and subsequent deprotonation of the
correspondingsaltsisanestablishedandelegantwayto
generate saturated NHCs.16
Evidently, 2-imidazolines are interesting synthetic
targets. Both medicinal chemists and researchers in-
volved in catalysis will benefit from simple and flexible
extensivescopestudyaddressingthefollowingissues: (i)
2-imidazolinesyntheses,whichfacilitatefastandefficient
theinfluenceofstericallydemandingand/ormorefunc-
generation of diverse libraries of these compounds for
tionalized amines and aldehydes; (ii) further variation
high-throughput screening procedures. However, tradi-
oftheisocyanidecomponent;and(iii)theapplicationof
tionallinearsyntheticapproachestoward2-imidazolines
ketones instead of aldehydes as the oxo-components in
involvemultiplestepsandareratherlimitedinscope.17
the MCR.
Apowerfulalternativestrategyfortherapidintroduction
ofmoleculardiversityinvolvesmulticomponentreactions
Results and Discussion
(MCRs).18 Recently, we reported a versatile multicom-
ponentsynthesisof2H-2-imidazolines5fromamines1, Stericfactorswerebelievedtocausethedisappointing
aldehydes 2, and isocyanides 4 (Scheme 1).17 The MCR yields for MCRs with benzhydrylamine and isobutyral-
probablyinvolvesanaldol-typeadditionoftheisocyanide dehydeastheamineandaldehydecomponents,respec-
4totheinsitugeneratedimine3followedbyringclosure tively.Bulkygroupshinderthealdol-typeadditionofthe
ofintermediateA.19However,aconcertedcyclizationof isocyanide 4 to the in situ generated imine 3. To
3 and 4 to produce 5 cannot be excluded. investigateifthesefactorsindeeddeterminethelimita-
The compatibility of a range of structurally different tions of the MCR, a series of sterically more and less
aldehydes and amines in this MCR was demonstrated, demanding amines and aldehydes was tested in combi-
butthereactionseemstobecriticallydependentonthe nation with isocyanoacetate 4a (Table 1).
acidity of the isocyanide R-proton. So far, the method The application of bulky amines such as tert-butyl-
provedusefultoprepare4-disubstituted2-imidazolines. amine, 2,4,6-trimethylaniline, or benzhydrylamine re-
Also, the yield of the MCR decreased notably when the sults in diminished yields of 5 (5hmr, 5ins, and 5jot,
ratherbulkybenzhydrylaminewasusedasaminecom- respectively), unless a very small aldehyde like formal-
ponent1.Finally,ketoneswerenottestedyetastheoxo- dehyde is used (5c-e). On the other hand, sterically
component in the MCR. Here, we wish to report an demandingaldehydessuchaspivaldehydeandmesital-
dehydereactevenmoresluggishly.Notonlydotheygive
nodetectableformationof2-imidazolineincombination
(10)(a)Betschart,C.;Hegedus,L.S.J.Am.Chem.Soc.1992,114,
5010-5017.(b)Hsiao,Y.;Hegedus,L.S.J.Org.Chem.1997,62,3586- with the moderately bulky isopropylamine (5l and 5q),
3591. atert-butylgrouponthealdehydeevenslowsdownthe
(11)(a)Dunn.P.J.;Haner,R.;Rapoport,H.J.Org.Chem.1990,
55,5017-5025andreferencestherein.(b)Han,H.;Yoon,J.;Janda, reaction significantly when ammonia is used as the
K.D.J.Org.Chem.1998,63,2045-2048. aminecomponent(5k),althoughtheisolatedyieldof5k
(12)Menges,F.;Neuburger,M.;Pfaltz,A.Org.Lett.2002,4,4713- was still reasonable after prolonged stirring at room
4716.
temperature.Applicationofmesitaldehydetogetherwith
(13)Herrmann,W.A.;Weskamp,T.;Bo¨hm,V.P.W.Adv.Orga-
nomet.Chem.2001,48,1-69. ammoniaprovedtobesatisfying(5p).Itisunlikelythat
(14)Bourrissou,D.;Guerret,O.;Gabba¨ı,F.P.;Bertrand,G.Chem. lowyieldsareduetosluggishimineformation,because
Rev.2000,100,39-91.
in general, considerable amounts of imine could be
(15)(a) An example is the development of ruthenium-based me-
tathesiscatalysts.Forareviewonthissubject,see: Trnka,T.;Grubbs, recoveredafterthereaction.Thepresenceofoneortwo
R.H.Acc.Chem.Res.2001,34,18-29.(b)ForareviewonNHCligands moderatelybulkygroupsontheinsituformediminedoes
inhomogeneouscatalysis,see: Herrmann,W.A.Angew.Chem.,Int.
Ed.2002,41,1290-1309andreferencestherein. not hinder the aldol-type addition (5b, 5f, and 5g), but
(16)(a)Pytkowicz,J.;Roland,S.;Mangeney,P.J.Organomet.Chem. surprisingly, combination of ammonia, paraformalde-
2001, 631, 157-163. (b) Roland, S.; Auduoin, M.; Mangeney, P. hyde, and 4a furnished only the 2-oxazoline, resulting
Organometallics2004,23,3075-3078.
(17)Bon,R.S.;Hong,C.;Bouma,M.J.;Schmitz,R.F.;deKanter, fromareactionbetweentheinsitugeneratedformalde-
F.J.J.;Lutz,M.;Spek,A.L.;Orru,R.V.A.Org.Lett.2003,5,3759- hydeandisocyanoacetate4a.20Inconclusion,theresults
3762andreferencestherein. presented in Table 1 indicate that steric congestion
(18)(a)Orru,R.V.A.;deGreef,M.Synthesis2003,1471-1499.(b)
Do¨mling,A.;Ugi,I.Angew.Chem.,Int.Ed.2000,39,3168-3210.(c) aroundtheiminecarbonindeedinfluencesthealdol-type
Bienayme´,H.;Hulme,C.;Oddon,G.;Schmitt,P.Chem.Eur.J.2000, additionstepofthe2-imidazolineformation(towardthe
6,3321-3329.(d)Zhu,J.Eur.J.Org.Chem.2003,7,1133-1144.
(19)(a) Meyer, R.; Scho¨llkopf, U.; Bo¨hme, P.Liebigs Ann. Chem.
1977,1183-1193.(b)vanLeusen,A.M.;Wildeman,J.;Oldenziel,O. (20)Hoppe,D.;Scho¨llkopf,U.Angew.Chem.,Int.Ed.Engl.1970,
H.J.Org.Chem.1977,42,1153-1159. 9,300-301.
J.Org.Chem,Vol.70,No.9,2005 3543
Bonetal.
TABLE1. TheInfluenceofStericallyDemandingAmineandAldehydeSubstituentsa,b
R1)Hc R1)i-Pr R1)t-Bu R1)Mes R1)CHPh2
R2)Hd 5a,<5%e,f 5b,70% 5c,69% 5d,65% 5e,82%
R2)i-Pr 5f,76%(68:32) 5g,74%(75:25) 5h,21%(anti) 5i,<5%e 5j,13%(66:34)
R2)t-Bu 5k,56%g(78:22) 5l,<5%e 5m,<5%h 5n,<5%e 5o,<5%e
R2)Mes 5p,67%(anti) 5q,<5%e 5r,15%(anti) 5s,<5%e 5t,17%(74:26)
aIsolatedyieldsanddiastereomericratiosarereported,unlessstatedotherwise.bStructurescontainingasymmetriccarbonsrepresent
racemiccompounds.cAsolutionof2NNH3inMeOHwasused.dParaformaldehydewasused.eInthe1HNMRspectrumofthecrude
product,no2-imidazolinecouldbeobserved.fThecorresponding2-oxazolinewasisolatedinquantitativeyield.gYieldafterstirringfor
3days.Afterareactiontimeof18h,only20%of5kcouldbeisolated.hThecorresponding2-oxazolinewasisolatedin10%yield.
proposedintermediateAinScheme1).Furthermore,they TABLE2. Synthesisof2-Imidazolineswith
FunctionalizedAminesandAldehydesa
suggestthatonlyonestericallydemandinggrouponthe
in situ formed imine is allowed.
To synthesize 2-imidazolines susceptible to further
manipulation, amines and aldehydes containing ad-
ditionalfunctionalgroupsweretestedinourMCR(Table
2).AlthoughapplicationofanR,(cid:226)-unsaturatedaldehyde
provedsuccessfulbefore,17theuseofacrolein7resulted
inanunidentifiedmixtureofpolymers(entry1).Onthe
otherhand,allylamine9furnishedanimidazolinebear-
ingaterminalalkenesubstituentsuitablefor,e.g.,olefin
metathesisorrhodium-catalyzedringclosure(entry2).21
The ease with which unprotected alcohols in both the
amineandthealdehydecomponentcanbeaccommodated
is illustrated by entries 3-5. Because of insolubility of
the imine derived from amine 18 and aldehyde 16 in
DCM, the synthesis of 2-imidazoline 19 was performed
in methanol.
Manystudiesarededicatedtothepromisingabilities
of multivalent ligands and inhibitors for the manipula-
tion of polyvalent interactions between biological enti-
ties.22 It has been established that, in comparison with
their monomeric counterparts, dimeric molecules often
showhigherbiologicalactivity.Therefore,wedecidedto
investigatethepotentialofourMCRtoaccessproducts
containing multiple 2-imidazoline units connected by
varioustethers.Suchbis-imidazolineswouldbevaluable
precursorsforbidentateNHCligandsfortransitionmetal
catalysis as well. In Schemes 2 and 3, the synthesis of
twodifferentbis-imidazolinesisillustrated.Reactionof
hexane-1,6-diamine (20) with isobutyraldehyde (10) (2
equiv) and 9-isocyanofluorene (4b) (2 equiv) efficiently
provideshexane-tetheredbis-imidazoline21.Withboth
1Hand13CNMRmeasurements,nodistinctionbetween
thetwopossiblediastereomerscouldbemade.Reaction
of isophthalaldehyde (22) with isopropylamine (6) (2
equiv)and4b(2equiv)gavebis-imidazoline23contain-
ing a somewhat more rigid tether. Again, the diastere-
omericratiocouldnotbedeterminedfromtheNMRdata.
Becausefurthervariationoftheisocyanidecomponent
inthemulticomponentsynthesisof2-imidazolineswould
significantly increase the versatility of the reaction,
(21)Thefirstexampleofarhodium-catalyzeddirectC-Hinsertion
of4,4-dimethyl-2-imidazolineto3,3-dimethylbut-1-enewasreported a9-Isocyanofluorene4bwasusedastheisocyanidecomponent.
in: Wiedemann,S.H.;Bergman,R.G.;Ellman,J.A.Org.Lett.2004, Forstructure,seeref17.bIsolatedyieldsarereported.cReaction
6,1685-1687. was performed in methanol.dYield after flash column chroma-
(22)Mammen, M.; Choi, S.-K.; Whitesides, G. M. Angew. Chem.,
Int.Ed.1998,37,2754-2794andreferencestherein. tographyandcrystallization.
3544 J.Org.Chem.,Vol.70,No.9,2005
MulticomponentSynthesisof2-Imidazolines
SCHEME2. ABis-imidazolinefrom TABLE3. Synthesisof4-Monosubstituted2-Imidazoline
Hexane-1,6-diamine 28
SCHEME3. ABis-imidazolinefrom entry T,°C catalyst yield,a%
Isophthalaldehyde 1 20 none 0b
2 60 none 0b
3 20 AgOAcc 39(anti)d,e
aIsolatedyieldsarereported.bOnlyimineandisocyanide25a
wererecovered.c2mol%ofAgOAcwasused.dRelativestereo-
chemistrywasdeterminedfromthe1HNMRcouplingconstants
ofH-4andH-5.eAlsothecorrespondingimidazole29wasisolated
in27%yield.
additional isocyanides with acidic R-protons were con- SCHEME4. Synthesisofp-NitrobenzylIsocyanide
25aa
sideredaswell.Tosynthesize4-monosubstituted2-imi-
dazolines24,weexploredtheuseofisocyanideswiththe
general structure 25 (eq 1).
aReagentsandconditions: (a)aceticformicanhydride,DCM,
0°Ctort,1h;(b)POCl3,Et3N,THF,-78to0°C,1h.
SCHEME5. AirOxidationof
p-Nitrobenzyl isocyanide (25a) was envisioned as an p-Nitrophenyl-SubstitutedImidazolinessyn-28and
isocyanide of type 25 that still contains a fairly acidic anti-28
methyleneunit.Itwassynthesizedfromthecorrespond-
ingamine26,whichwaspreparedaccordingtoalitera-
ture procedure23 in two steps (overall yield 98%).
Thefirstattempttoallow25atoreactwiththeinsitu
generatedimineofisopropylamine(6)andisobutyralde-
hyde (10) did not result in the formation of the desired
product28(Table3,entry1).Onlyimineandisocyanide
25acouldbeisolated.Alsoperformingthereactionata group on the imine nitrogen.28 In 1999, Grigg et al.
highertemperaturewasunsuccessful(entry2).Instead describedtheefficientsilver(I)acetatecatalyzedcycload-
of using even higher temperatures to obtain the 2-imi- ditionofmethylisocyanoacetatetoMichaelacceptors.29
dazoline 28, another method was conceived. Several Weenvisionedsilver(I)acetateasasuitableLewisacid
studieshavebeenconductedontheincreasedacidityof to activate p-nitrobenzyl isocyanide (25a). Indeed, one-
R-protonsofisocyanidescoordinatedtometals.24Transi- potreactionof25awith6and10inthepresenceofonly
tionmetalcatalyzedcycloadditionsofvariousisocyanoac- 2mol%ofsilver(I)acetateprovided2-imidazolineanti-
etates,25 benzyl isocyanide,26 and allyl isocyanide27 to a 28in39%yieldasasinglediastereomer(Table3,entry
range of electron-poor olefins or aldehydes have been 3).
reported.Thecycloadditiontoimines,however,required
Besidesanti-28,anotherproductwasisolatedin27%
CdN bond activation by the introduction of a sulfonyl
yieldafterflashcolumnchromatography.30Thisproduct
was identified as imidazole 29 (Scheme 5). Apparently,
(23)Katayama, S.; Ae, N.; Kodo, T.; Masumoto, S.; Hourai, S.;
Tamamura,C.;Tanaka,H.;Nagata,R.J.Med.Chem.2003,46,691- some of the initially formed imidazoline had been oxi-
701. dizedduringthereactionorduringworkup/purification.31
(24)For examples see: (a) Fehlhammer, W. P.; Bartel, K.; Petri,
W.J.Organomet.Chem.1975,87,C34-C36.(b)Fehlhammer,W.P.;
Zinner,G.;Bakola-Christianopoulou,M.J.Organomet.Chem.1987, (28)Dai,L.-X.;Lin,Y.-R.;Hou,X.-L.;Zhou,Y.-G.PureAppl.Chem.
331,193-205. 1999,71,1033-1040andreferencestherein.
(25)Forexamplessee: Soloshonok,V.A.;Kacharov,A.D.;Avilov, (29)Grigg,R.;Lansdell,M.I.;Thornton-Pett,M.Tetrahedron1999,
D.V.;Ishikawa,K.;Nagashima,N.;Hayashi,T.J.Org.Chem.1997, 55,2025-2044.
62,3470-3479andreferencestherein. (30)Asecondbyproduct,isolatedinonly7%,wascharacterizedas
(26)Saegusa,T.;Ito,Y.;Kinoshita,H.;Tomita,S.J.Org.Chem. theoxazolineformedbyreactionof25aand10.
1971,36,3316-3323. (31)For a recent example of the air oxidation of imidazolines to
(27)Saegusa,T.;Murase,I.;Ito,Y.Bull.Chem.Soc.Jpn.1972,45, imidazolessee: Illgen,K.;Nerdinger,S.;Behnke,D.;Friedrich,C.Org.
830-833. Lett.2005,7,39-42.
J.Org.Chem,Vol.70,No.9,2005 3545
Bonetal.
SCHEME6. ProposedMechanismforthe TABLE4. CalculatedEnergyDifferencesbetweensyn-
Silver(I)-CatalyzedCycloadditionof25atoImines andanti-Imidazolines
31 entry compd ¢E(syn)-(anti),akcal/mol
1 28 4.0
2 36 2.0
3 37 4.7
aBP86/TZP.
SCHEME7. AttemptstowardtheSynthesisof
4-Vinyl-Substituted2-Imidazoline39a
CHART1. 4-Nitrophenyl-Substituted
2-Imidazolines aReagents and conditions: (a) Na2SO4, DCM, rt, 18 h; (b)
Na2SO4,AgOAc(2mol%),DCM,rt,18h.
37, both diastereomers anti-37 and syn-37 could be
detected in a 62:38 ratio. However, after flash column
chromatography only anti-37 and the corresponding
imidazole were isolated. Both diastereomers of 36 ap-
peared to be much more air-stable. Nevertheless, after
storing the mixture for months under air, both diaster-
eomers were oxidized to the imidazole.
The air oxidation of 2-imidazolines could proceed via
a radical stabilized by the p-nitrophenyl group. For the
Because complete diastereoselectivity had never been
oxidationofbothdiatereomers,similarradicalintermedi-
observedbeforeinourMCR,wereasonedthat29should
ates are expected. For the syn-diastereomers, the two
be formed from syn-28. To test this hypothesis, and to
substituentsatC-4andC-5moveawayfromeachother
examinethefactorscausingtheoxidation,boththeMCR
during this radical formation (this reduces the steric
andsubsequentworkupwereperformedunderexclusion
repulsion), whereas for the anti-diastereomers, these
ofoxygen.Indeed,inthecrudeproductamixtureofanti-
groupsmovetowardeachother(thisincreasesthesteric
28 and syn-28 could be observed in a ratio of 58:42
repulsion).Formationofthisradicalintermediateshould
according to 1H NMR. When this crude mixture was
be faster from the syn-diastereomers than for the anti-
subjectedtoair,syn-28wasrapidlyoxidizedto29,even
diastereomers. This is supported by density functional
intheabsenceoflight.Alsoanti-28isnotinfinitelyair-
theory(DFT)32calculationsthatshowtheanti-imidazo-
stable. After storing a purified sample for half a year
lines to be more stable than their syn counterparts by
underair,itcontainedabout75%oftheoxidizedproduct 2-5 kcal/mol (Table 4).
29.Inconclusion,29isaproductoftheairoxidationof
Encouraged by the good results in the silver(I) cata-
syn-28 (fast) and/or anti-28 (very slow) (Scheme 5). For
lyzed reactions of 25a, allyl isocyanide 25b was tested
this oxidation, neither silver(I) catalyst nor light is
tosynthesizemore2-imidazolinesoftype24.Combina-
needed.
tionofp-methoxybenzylamine(15),p-anisaldehyde(38),
The proposed mechanism for the silver(I) catalyzed
and25bwithoutcatalystdidnotresultinanyimidazo-
MCR with p-nitrobenzyl isocyanide (25a) is depicted in
line formation (Scheme 7). Addition of silver(I) acetate
Scheme6.Itisbelievedthattheactivatedisocyanide30
tothereactionmixturedidnotpromotethecycloaddition.
isdeprotonatedbyeithertheacetateanionoratraceof
Inbothcases,onlytheiminederivedfrom15and38was
aminepresentinthereactionmixture(actingasbaseB
isolated after evaporation of the solvent and unreacted
after in situ imine formation). Then, the imine 31 is
25b.Apparently,thereactivityofactivatedallylisocya-
attacked by the deprotonated complex 32 to give aldol
nide toward imines is considerably lower compared to
adduct33.Ringclosureofthesecondaryaminefollowed
that of 25a.
by exchange of the silver(I) cation by a proton would
To rationalize the differences in reactivity of the
provide the 2-imidazoline 35. The formation of 34 from
various isocyanides in our MCR, DFT (BP86/TZ2P)
31 and 32 may proceed via either a concerted cycload-
calculationsprovedhelpful.Theproposedmechanismfor
ditionorastepwisemechanism.Analternativepathway
thealdol-typeadditionprobablyinvolvesdeprotonation
wouldinvolvethealdol-typeadditiontoaniminiumion
of the isocyanide followed by attack of the anion to the
intermediate.
(protonated) imine. Three aspects are important for
Variationoftheamineandaldehydesubstituentsgave understandingthereactivity: theprotonaffinity(PA)of
two more 4-nitrophenyl-substituted 2-imidazolines 36 theisocyanide(whichcorrelatestotheacidity),theorbital
and37inreasonabletogoodyields(Chart1).According
toNOESYmeasurements,for2-imidazoline36,thesyn-
(32)Koch, W.; Holthausen, M. C. A Chemist’s Guide to Density
diastereomerwasformedinexcess.Inthecrudeproduct FunctionalTheory;Wiley-VCH: Weinheim,Germany,2000.
3546 J.Org.Chem.,Vol.70,No.9,2005
MulticomponentSynthesisof2-Imidazolines
TABLE5. ComputedProtonAffinities(kcal/mol)of TABLE6. MCRswithCyclohexanone40
IsocyanidesandOrbitalEnergiesoftheHOMOs(eV)and
Contributionsofpz-OrbitalsinHOMOs(%)ofTheir
Anionsa,b
Ag+ PA, (cid:15)HOMO,a
entry isocyanide coordinated kcal/mol eV %pz(Canion)
1 4a no 181.4 -3.63 27.4
2 4b no 180.3 -3.87 31.5
3 4c no 190.3 -3.91 47.6
4 25a no 181.9 -4.01 27.9
5 25a yes 170.2 -4.63 27.3
6 25b no 200.8 -3.01 36.9
7 25b yes 179.5 -4.31 26.1
aBP86/TZ2P.bIn all calculations, DCM was taken as the
solvent.
energyofthehighestoccupiedmolecularorbital(HOMO) entry isocyanide catalyst yield,%
of its carbanion, and the contribution of carbanion
1 4b none 0a
orbitals in the HOMO. The PA of a molecule BH is 2 4a none 7
definedasthesystem’senthalpychangeforthereaction 3 25a none 0a
BHfB-+H+,e.g.,asmallerPAcorrespondstoalarger 4 4b AgOAcb 20
concentration of the B- anion. The difference in energy 5 4a AgOAcb 55
6 25a AgOAcb 77
betweentheHOMOoftheattackingdeprotonatedcom-
plex and the lowest unoccupied orbital (LUMO) of the aOnlyimineandisocyanidewereisolated.b2mol%ofAgOAc
wasused.
imine (or the iminium ion) determines the interaction
betweenthetwo.Thus,thereactivityisgovernedbythe
[B-], the HOMO-LUMO gap, and the contribution of is ascribed to its HOMO being 0.4 eV lower in energy
carbanion orbitals in the HOMO. than that of 4a. The activation by silver(I) has mainly
The computational setup for calculating PAs was an effect on the PA of 25a, which is reduced by almost
validatedagainstaseriesoforganicandinorganicbases, 12 kcal/mol (entry 5). Consequently, the concentration
forwhichexperimentaldataareavailable.33Itwasshown of carbanion increases significantly, which apparently
thatDFTgivesbothqualitativelyandquantitativelygood compensates for the still rather poor (cid:15)HOMO and causes
resultsforprotonaffinities.34Solventeffects(DCM)are the reaction to proceed after activation. Based on the
properlytakenintoaccountbytheCOSMOmodel.35DFT HOMO orbital energy and the contribution of the car-
calculations were performed for five different isocya- banion pz-orbital in it, allyl isocyanide (25b) should be
nides: 4a,4b,25a,25b,andmethylisocyanoacetate4c, able to react with imines, were it not for its very high
which is also known to undergo cycloadditions with PA, which is, in fact, the highest of the series. Prelimi-
imines (Table 5).19a naryresultssuggestthatthePAofallylgroupsmayeven
Thetwoisocyanidesthatdisplaythehighestreactivity beunderestimatedbyourcomputationalsetupbyupto
in our MCR, 4a and 4b (entries 1 and 2), have similar 5kcal/mol.34Thismakesitunlikelythatanycarbanions
values for the PA (ca. 181 kcal/mol),36 HOMO orbital arepresent(entry6).Afteractivationbysilver(I),thePA
energy (ca. -3.7 eV), and contribution of carbanion (p) becomes comparable to that of 4a or 4b, which should
z
orbitalintheHOMO(ca.30%).Thesevaluescanbetaken be sufficient for reaction, but both the HOMO orbital
as reference values for the reactivity of isocyanides in energy and the contribution of the carbanion pz-orbital
our MCR. Methyl isocyanoacetate 4c (entry 3) has a intheHOMOdecreasedramatically,by1.3eVandfrom
larger contribution of carbanion orbitals in the HOMO, 37% to 26%, respectively (entry 7). As a result, the
in fact the largest of all isocyanides we studied, and a carbanionswillnotbereactivetowardimines.Further-
HOMO orbital energy that is comparable to that of 4b more, it was found that, for the anion of 25b, not the
(entry2).However,itsprotonaffinityisalmost10kcal/ isocyano group but the allyl group is the energetically
mollargerthanthatof4aand4b,whichwouldresultin favoredcoordinationsiteforsilver(I)(adifferenceofca.
a lower carbanion concentration and hence a lower 5 kcal/mol, see the Supporting Information for details).
reactivity.Thisisconsistentwithourpreviouslyreported This thermodynamically more stable complex has a
experiments.17 HOMO energy of -5.10 eV and a contribution of the
Although its PA and contribution of the carbanion carbanionpz-orbitalofonly22.9%.Therefore,nucleophilic
orbitalintheHOMOaresimilartothoseof4a(entry1), attack would be even more hampered.
p-nitrobenzyl isocyanide (25a) (entry 4) does not react Instead of aldehydes, ketones also could be imagined
withiminesintheabsenceofsilver(I).Itsnonreactivity astheoxo-componentsinthemulticomponentsynthesis
of 2-imidazolines. However, both steric and electronic
(33)Bickelhaupt, F. M.; Buisman, G. J. H.; de Koning, L. J.; effectsmightdecreasethereactivityoftheinsituformed
Nibbering,N.M.M.;Baerends,E.J.J.Am.Chem.Soc.1995,117, ketimines.Thefirstattemptstoapplycyclohexanone40
9889-9899.
in the MCR gave disappointing results (Table 6). With
(34)Swart,M.;Bickelhaupt,F.M.Unpublishedresults.
(35)(a)Klamt,A.;Schu¨u¨rmann,G.J.Chem.Soc.,PerkinTrans.2 either9-isocyanofluorene(4b)orp-nitrobenzylisocyanide
1993,799-805.(b)Pye,C.C.;Ziegler,T.Theor.Chem.Acc.1999,101, (25a),no2-imidazolinewasformedatall(entries1and
396-408.
3). Employing isocyanoacetate 4a as the isocyanide
(36)ThemeasuredpKaof4binDMSO(25°C)is12.3,see: Bordwell,
F.G.Acc.Chem.Res.1988,21,456-463. component gave the expected 5-disubstituted product,
J.Org.Chem,Vol.70,No.9,2005 3547
Bonetal.
CHART2. 2-ImidazolinesSynthesizedfrom Conclusions and Outlook
AcetonewithSilver(I)AcetateasCatalyst
The scope of the multicomponent synthesis of 2H-2-
imidazolines from isocyanides bearing acidic R-protons
and in situ generated imines has been studied exten-
sively.Threedifferentisocyanideswereusedincombina-
tion with aldehydes and amines containing a variety of
simpleandfunctionalizedsidechains.Themostimpor-
tantlimitationsarethestericbulkoftheiminesubstit-
uentsandthereactivityoftheisocyanide.Boththeease
with which the isocyanide is deprotonated and the
SCHEME8. Synthesisof49aand49b
reactivityoftheanionareimportant.Silver(I)catalysis
appeared to be an excellent method to promote both
difficultaldol-typeadditionstoketiminesandreactions
withp-nitrobenzylisocyanide.Theresultingp-nitrophe-
nyl-substituted2-imidazolinesarerelativelyunstableto
air.Bothdiastereomersareoxidizedunderairexposure
(although with different rates) to the corresponding
imidazoles. This MCR/oxidation procedure could be de-
velopedtowardausefulandflexibleimidazolesynthesis
additionaltoSisko’smethodology.39Fortheapplication
SCHEME9. Synthesisof50aand50b ofallylisocyanideintheMCR,probablystrongeractiva-
torsforeithertheisocyanideortheiminearerequired.
Currently, we are investigating the activation of iso-
cyanides with transition metals complexed to chiral
ligandsinordertoachievestereoselectivealdoladdition
to in situ formed imines. Finally, different mono- and
dimeric imidazolines are being used as precursors for
N-heterocycliccarbenescontainingtwodifferentC-back-
bone substituents.
albeit in only 7% yield (entry 2). Addition of a catalytic
amount of silver(I) acetate appeared to be sufficient to Theory
activatetheisocyanidestosuchanextentthatreaction
DFT(BP86)calculationswereperformedwiththeAmster-
withthelesselectrophilicketimines(ascomparedtothe
dam Density Functional (ADF) program.40 The MOs were
similar aldimines) is accelerated, which resulted in expandedinlargeuncontractedsetsofSlater-typeorbitals,41
significantly increased yields (entries 4-6). The some- whichareoftriple-œquality,augmentedbyone(TZP: 3don
what low yield for 42 is probably the result of steric C,N,O;2ponH)ortwosetsofpolarizationfunctions(TZ2P:
3dand4fonC,N,O;2pand3donH;5pand4fonAg);the1s
factors. This is supported by experiments that combine
coreshellofcarbon,nitrogen,oxygenandthe1s-3dcoreshells
acetone,benzylamine,andisocyanides(4a,4b,and25a)
ofsilverweretreatedbythefrozencore(FC)approximation.40b
in the silver(I) catalyzed MCR, which furnished 2-imi- Anauxiliarysetofs,p,d,f,andgSTOswasusedtofitthe
dazolines45-47(Chart2).Evenwith9-isocyanofluorene moleculardensityandtorepresenttheCoulombandexchange
(4b) a good yield was obtained now. potentials accurately in each SCF cycle. For the silver-
containingsystems,(scalar)relativisticeffectsweretakeninto
When 3-(chloromethyl)cyclobutanone (48)37 was ap-
account with use of the zeroth-order regular approximation
plied, no additional catalyst was needed to perform the
(ZORA).40b,42
MCR(Scheme8).Reactionof48,benzylamine(41),and Energiesandgradientswerecalculatedbyusingthelocal
9-isocyanofluorene(4b)provided2-imidazolines49aand density approximation (LDA; Slater exchange and VWN
49b, which contain a chloromethyl unit suitable for correlation)43 with nonlocal corrections due to Becke44 (ex-
further derivatization, as a mixture of isomers. The change) and Perdew45 (correlation) added self-consistently.
Thisxc-functionalisoneofthethreebestDFTfunctionalsfor
identityofthetrans-isomer49awasestablishedbyNOE
theaccuracyofgeometries,46withanestimatedunsignederror
measurements.Alsoisocyanoacetate4agavegoodresults
whenreactedwith48and41(Scheme9).38Again,NOE
(39)Sisko,J.;Kassick,A.J.;Mellinger,M.;Filan,J.J.;Allen,A.;
measurements were used for the identification of the Olsen,M.A.J.Org.Chem.2000,65,1516-1524.
trans-isomer50a.Therelativelyhighreactivityofimines (40)(a)teVelde,G.;Bickelhaupt,F.M.;Baerends,E.J.;Fonseca
Guerra, C.; van Gisbergen, S. J. A.; Snijders, J. G.; Ziegler, T. J.
derived from cyclobutanone compared to the other Comput.Chem.2001,22,931-967.(b)FonsecaGuerra,C.;Snijders,
ketimines can be accounted for by the release of ring J.G.;teVelde,G.;Baerends,E.J.Theor.Chem.Acc.1998,99,391-
strain, going from an sp2 ring carbon to an sp3 ring 403.(c)ADF2004.01;SCM,TheoreticalChemistry,VrijeUniversiteit,
Amsterdam,TheNetherlands,http://www.scm.com.
carbon. (41)vanLenthe,E.;Baerends,E.J.J.Comput.Chem.2003,24,
1142-1156.
(42)vanLenthe,E.;Baerends,E.J.;Snijders,J.G.J.Chem.Phys.
(37)(a)Stevens,C.V.;deKimpe,N.J.Org.Chem.1996,61,2174- 1993,99,4597-4610.
2178.(b)Rammeloo,T.;Stevens,C.V.;deKimpe,N.J.Org.Chem. (43)Vosko,S.H.;Wilk,L.;Nusair,M.Can.J.Phys.1980,58,1200-
2002,67,6509-6513. 1211.
(38)Applicationofthealmostpureiminefrom48and41(prepared (44)Becke,A.D.Phys.Rev.A1988,38,3098-3100.
withTiCl4,seeref36b)resultedinevenhigheryieldsfor50a(42%) (45)Perdew, J. P. Phys. Rev. B 1986, 33, 8822-8824. Erratum:
and50b(33%). Perdew,J.P.Phys.Rev.B1986,34,7406-7406.
3548 J.Org.Chem.,Vol.70,No.9,2005
MulticomponentSynthesisof2-Imidazolines
of0.009ÅincombinationwiththeTZ2Pbasisset.Geometries 1H),4.01(s,3H),3.81(d,J)9.8Hz,1H),2.52(s,3H),2.50-
wereoptimizedbyusinganalyticalgradienttechniquesuntil 2.29(brs,6H);13CNMR(63MHz,CDCl )(cid:228)(ppm)173.7(C),
3
the maximum gradient component was less than 1.0 (cid:2) 10-4 155.7(CH),143.2(2(cid:2)C),137.8(2(cid:2)C),133.3(C),129.3(2(cid:2)
atomicunits.Vibrationalfrequencieswereobtainedthrough CH), 128.6 (2 (cid:2) CH), 127.5 (CH), 125.5 (2 (cid:2) CH), 80.4 (C),
numericaldifferentiationoftheanalyticalgradients.40b 58.7(CH ),53.0(CH ),20.8(CH ),17.8(2(cid:2)CH );IR(neat)
2 3 3 3
2951(m),2923(m),1729(s),1600(s),1576(s),1488(s),1263
(s),1217(s)cm-1;HRMS(EI,70eV)calcdforC H NO (M+)
Experimental Section 20 22 2 2
322.1681,found322.1672.
For general experimental methods, see the Supporting Methyl1-Benzhydryl-4-phenyl-4,5-dihydro-1H-imida-
Information.Experimentaldetailsandcharacterizationdata zole-4-carboxylate(5e).AccordingtoGeneralProcedureI,
forcompounds5gand5jhavebeenreportedelsewhere.17 reaction between benzhydrylamine (366 mg, 2.0 mmol), p-
GeneralProcedureIfortheSynthesisof2-Imidazo- formaldehyde(60mg,2.0mmol),and4a(196mg,1.12mmol),
lines.Reactionswerecarriedoutataconcentrationof1Mof followed by flash column chromatography, afforded 5e (340
amine,1Mof aldehyde(orketone),and0.5Mofisocyanide mg,82%)asayellowoil.1HNMR(250MHz,CDCl3)(cid:228)(ppm)
in dry CH Cl , unless noted otherwise. Na SO and the 7.34-7.30 (m, 2H), 7.25-7.08 (m, 12H), 7.00-6.85 (m, 1H),
2 2 2 4
aldehyde were added, at room temperature, to a stirred 6.82 (s, 1H), 5.32 (s, 1H), 4.24 (d, J ) 9.8 Hz, 1H), 3.59 (s,
solutionoftheamine.Afterthemixturewasstirredfor2h, 3H), 3.19 (d, J ) 9.8 Hz, 1H); 13C NMR (63 MHz, CDCl3) (cid:228)
theisocyanidewasaddedandthereactionmixturewasstirred (ppm) 174.0 (C), 156.4 (CH), 142.8 (C), 139.8 (C), 139.8 (C),
at room temperature for an additional 18 h. The reaction 129.3 (2 (cid:2) CH), 129.0 (2 (cid:2) CH), 128.6 (CH), 128.44 (CH),
mixture was then filtered and concentrated in vacuo. The 128.40 (CH), 128.36 (2 (cid:2) CH), 128.3 (2 (cid:2) CH), 128.0 (CH),
crudeproductwaspurifiedbyflashcolumnchromatography 127.9 (CH), 126.0 (2 (cid:2) CH), 80.3 (C), 66.4 (CH), 58.6 (CH2),
(PE:EtOAc:Et3N)2:1:0.01,gradient,unlessstatedotherwise). 53.4 (CH3); IR (KBr) 3025 (m), 1721 (s), 1595 (m), 1258 (s),
Methyl4-Phenyl-4,5-dihydro-1H-imidazole-4-carboxy- 706 (s) cm-1; HRMS (EI, 70 eV) calcd for C24H22N2O2 (M+)
late(5a).AccordingtoGeneralProcedureI,reactionbetween 370.1681,found370.1691.
NH3 (2 M in MeOH, 2.3 mL, 4.6 mmol), p-formaldehyde (60 Methyl5-Isopropyl-4-phenyl-4,5-dihydro-1H-imidazole-
mg,2.0mmol),and4a(175mg,1.0mmol),followedbyflash 4-carboxylate(5f).AccordingtoGeneralProcedureI,reaction
columnchromatography(EtOAc:MeOH:Et3N)1:0:0.01,gra- betweenNH3(2MinMeOH,2.3mL,4.6mmol),isobutyral-
dient), did not afford 5a, but the corresponding 2-oxazoline dehyde (154 mg, 2.1 mmol), and 4a (192 mg, 1.1 mmol),
(235mg,quant)asayellowoil.1HNMR(250MHz,CDCl3)(cid:228) followedbyflashcolumnchromatography,afforded5f(206mg,
(ppm) 7.42-7.28 (m, 5H), 7.08 (s, 1H), 5.21 (d, J ) 8.9 Hz, 76%)asa68:32mixtureofdiastereomersasayellowoil.1H
1H),4.28(d,J)8.9Hz,1H),3.77(s,3H);13CNMR(63MHz, NMR (250 MHz, CDCl ) (cid:228) (ppm) 7.60-7.46 (m, 2H), 7.45-
3
CDCl3) (cid:228) (ppm) 171.4 (C), 161.0 (CH), 136.2 (C), 128.8 (2 (cid:2) 7.33 (m, 2H), 7.30-7.10 (m, 4H + 4H), 6.2 (br s, 1H + 1H),
CH), 128.5 (CH), 126.0 (2 (cid:2) CH), 67.8 (C), 64.7 (CH2), 53.5 4.53(d,J)3.2Hz,1H),4.09(d,J)2.2Hz,1H),3.64(s,3H),
(CH3);IR(neat)2956(s),1757(s),1257(s),1214(s)cm-1;MS 3.62(s,3H),2.45-2.35(m,1H),1.55-1.40(m,1H),1.01(d,J
(EI,70eV)m/z(%))205(0.5)[M]+,187(100),145(68). )6.9Hz,3H),0.84(d,J)6.9Hz,3H),0.71(d,J)6.6Hz,
Methyl1-Isopropyl-4-phenyl-4,5-dihydro-1H-imidazole- 3H), 0.35 (d, J ) 6.6 Hz, 3H); 13C NMR (63 MHz, CDCl ) (cid:228)
3
4-carboxylate(5b).AccordingtoGeneralProcedureI,reac- (ppm)175.1(C),172.8(C),154.1(CH),153.3(CH),144.1(C),
tionbetweenisopropylamine(118mg,2.0mmol),p-formalde- 136.9(C),128.7(CH),128.4(2(cid:2)CH),128.1(CH),128.0(CH),
hyde(60mg,2.0mmol),and4a(175mg,1.0mmol),followed 127.5(2(cid:2)CH),126.3(CH),78.7(C),78.6(CH),76.6(C),71.7
by flash column chromatography (EtOAc:MeOH:Et N ) 1:0: (CH),53.3(CH ),52.9(CH ),29.6(CH),29.1(CH),22.0(CH ),
3 3 3 3
0.01,gradient),afforded5b(173mg,70%)asayellowoil.1H 21.8 (CH ), 16.1 (CH ), 16.0 (CH ); IR (KBr) 3136 (m), 2938
3 3 3
NMR (250 MHz, CDCl ) (cid:228) (ppm) 7.40-7.19 (m, 5H), 6.98 (s, (m), 1728 (s), 1221 (s) cm-1; HRMS (EI, 70 eV) calcd for
3
1H),4.27(d,J)9.6Hz,1H),3.63(s,3H),3.53-3.42(m,1H), C H N O (M+)246.1368,found246.1352.
14 18 2 2
3.27(d,J)9.6Hz,1H),1.15(d,J)6.6Hz,3H),1.11(d,J) anti-Methyl 1-tert-Butyl-5-isopropyl-4-phenyl-4,5-di-
6.6Hz,3H);13CNMR(63MHz,CDCl3)(cid:228)(ppm)173.9(C),154.8 hydro-1H-imidazole-4-carboxylate(5h).AccordingtoGen-
(CH),143.1(C),128.4(2(cid:2)CH),127.3(CH),125.4(2(cid:2)CH), eral Procedure I, reaction between tert-butylamine (146 mg,
79.1(C),54.6(CH2),52.8(CH3),47.6(CH),21.14(CH3),21.09 2.0mmol),isobutyraldehyde(144mg,2.0mmol),and4a(190
(CH3);IR(neat)2970(s),1726(s),1593(s),1254(s),1214(s) mg, 1.09 mmol), followed by flash column chromatography,
cm-1;HRMS(EI,70eV)calcdforC14H18N2O2(M+)246.1368, affordedanti-5h(59mg,21%)asastickyyellowsolid.1HNMR
found246.1392. (250MHz,CDCl )(cid:228)(ppm)7.56-7.44(m,2H),7.31-7.17(m,
3
Methyl1-tert-Butyl-4-phenyl-4,5-dihydro-1H-imidazole- 4H),4.50(d,J)2.1Hz,1H),4.48(s,3H),1.58-1.49(m,1H),
4-carboxylate(5c).AccordingtoGeneralProcedureI,reac- 1.27(s,9H),0.74(d,J)7.2Hz,3H),0.40(d,J)6.9Hz,3H);
tionbetweentert-butylamine(88mg,1.2mmol),p-formalde- 13CNMR(63MHz,CDCl)(cid:228)(ppm)175.2(C),155.3(CH),137.5
3
hyde(36mg,1.2mmol),and4a(98mg,0.56mmol),followed (C),128.2(2(cid:2)CH),127.9(2(cid:2)CH),127.5(CH),83.8(C),66.7
byflashcolumnchromatography,afforded5c(100mg,69%) (CH), 53.4 (C), 52.7 (CH ), 30.7 (3 (cid:2) CH ), 29.7 (CH), 20.0
(ams,a2yHel)l,o7w.2o9i-l.71H.18N(MmR,3(H25),07M.1H0z(,sC,1DHC)l,3)4.(cid:228)31(p(pdm,J)7).399.-77H.3z5, ((Cs)H, 31)6,1677.0(s(C),H132);1I7R((sn)eactm3)-219;56H(RmM),S29(1E4I,(3m7)0,2e8V5)0(cmal)c,d17f4o5r
1H), 3.62 (s, 3H), 3.30 (d, J ) 9.7 Hz, 1H), 1.18 (s, 9H); 13C C H N O (M+)302.1994,found302.1998.
18 26 2 2
NMR(101MHz,CDCl )(cid:228)(ppm)174.1(C),153.6(CH),143.4
3 Methyl5-tert-Butyl-4-phenyl-4,5-dihydro-1H-imidazole-
(C),128.5(2(cid:2)CH),127.4(CH),125.6(2(cid:2)CH),79.2(C),54.3
4-carboxylate(5k).AccordingtoGeneralProcedureI,reac-
(CH ),52.9(CH ),52.5(C),29.1(3(cid:2)CH );IR(neat)2972(s),
2 3 3 tion between NH (2 M in MeOH, 2.0 mL, 4.0 mmol),
1726(s),1592(s),1258(s),1236(s),1201(s);HRMS(EI,70 3
pivaldehyde(172mg,2.0mmol),and4a(175mg,1.0mmol),
eV)calcdforC H N O (M+)286.1893,found286.1890.
15 20 2 2 followed by flash column chromatography, afforded 5k (146
Methyl1-Mesityl-4-phenyl-4,5-dihydro-1H-imidazole-
mg,56%)asa78:22mixtureofdiastereomersasawhitesolid.
4-carboxylate(5d).AccordingtoGeneralProcedureI,reac- 1HNMR(250MHz,CDCl )(cid:228)(ppm)7.61-7.56(m,2H),7.49-
3
tion between 2,4,6-trimethylaniline (270 mg, 2.0 mmol), 7.36 (m, 2H), 7.30-7.16 (m, 4H + 4H), 4.43 (d, J ) 0.9 Hz,
p-formaldehyde(60mg,2.0mmol),and4a(175mg,1.0mmol),
1H),4.02(s,1H),3.67(s,3H),3.65(s,3H),0.99(s,9H),0.60
followed by flash column chromatography, afforded 5d (209 (s, 9H); 13C NMR (63 MHz, CDCl ) (cid:228) (ppm) 174.8 (C), 172.7
mg,65%)asayellowoil.1HNMR(250MHz,CDCl3)(cid:228)(ppm) (C), 153.1 (CH), 151.9 (CH), 144.33(C), 136.3 (C), 128.3 (2 (cid:2)
7.76-7.50 (m, 6H), 7.15-7.11 (m, 2H), 4.94 (d, J ) 9.8 Hz, CH),128.00(2(cid:2)CH),127.97(2(cid:2)CH),127.8(2(cid:2)CH),127.4
(CH),126.8(CH),84.1(CH),78.5(C),74.9(CH),52.9(CH ),
3
(46)Swart,M.;Snijders,J.G.Theor.Chem.Acc.2003,110,34-41. 52.5(CH3),34.8(C),34.5(C),27.2(3(cid:2)CH3),27.1(3(cid:2)CH3)
J.Org.Chem,Vol.70,No.9,2005 3549
Bonetal.
(one-quarternaryCofminordiastereomerremainedundetect- 127.56(CH),127.4(CH),127.33(CH),127.30(CH+CH),127.1
able);IR(neat)3186(s,br),2954(s),1732(s),1597(s),1254 (CH),126.8(CH+CH),126.7(CH),126.0(CH),124.9(CH),
(s) cm-1; HRMS (EI, 70 eV) calcd for C H N O (M+) 84.4(C),84.0(C),67.4(CH),64.1(CH),63.7(CH),63.3(CH),
15 20 2 2
260.1525,found260.1523. 53.2(CH ),51.9(CH ),21.3(CH ),20.9(CH ),20.7(2(cid:2)CH ),
3 3 3 3 3
Methyl1,5-Di-tert-butyl-4-phenyl-4,5-dihydro-1H-imi- 20.7(CH3),20.4(CH3),theassignmentsoftheseveralsignals
dazole-4-carboxylate(5m).AccordingtoGeneralProcedure was confirmed by using gs-HMBC and gs-HMQC measure-
I, reaction between tert-butylamine (146 mg, 2.0 mmol), ments.Duetothecrowdedaromaticregion,notall34different
pivaldehyde(172mg,2.0mmol),and4a(175mg,1.0mmol), aromatic CH signals could be assigned (for the spectra, see
followedbyflashcolumnchromatography,didnotafford5m, the Supporting Information); IR (neat) 3029 (m), 2950 (m),
but the corresponding 2-oxazoline (26 mg, 10%) as a single 1726(s),1594(s),1576(s),1493(s),1452(s),1225(s),1179
diastereomer(anti)asayellowoil.1HNMR(250MHz,CDCl3) (s) cm-1; HRMS (EI, 70 eV) calcd for C33H32N2O2 (M+)
(cid:228) (ppm) 7.83 (d, J ) 7.2 Hz, 2H), 7.44-7.37 (m, 3H), 7.30- 488.2464,found488.2459.
7.25(m,1H),4.38(s,1H),4.07(s,3H),1.06(s,9H);13CNMR 2-Imidazoline11.AccordingtoGeneralProcedureI,reac-
(63MHz,CDCl)(cid:228)(ppm)154.4(C),131.1(C),129.1(CH),128.5 tion between allylamine (570 mg, 10.0 mmol), isobutyralde-
3
(2(cid:2)CH),126.5(CH),125.0(2(cid:2)CH),75.8(CH),60.4(C),60.1 hyde(720mg,10.0mmol),and4b(1.0g,5.24mmol),followed
(CH ),36.0(C),25.3(CH );IR(neat)2957(s),1741(s),1713 byflashcolumnchromatography,afforded11(1.439g,91%)
3 3
(s),1250(s),1079(s)cm-1;HRMS(EI,70eV)calcdforC H - asabrownoil.1HNMR(250MHz,CDCl )(cid:228)(ppm)7.60-7.55
15 19 3
NO (M+)261.1365,found261.1383. (m,2H),7.36-7.12(m,7H),5.97-5.84(m,1H),5.35-5.28(m,
3
anti-Methyl5-Mesityl-4-phenyl-4,5-dihydro-1H-imida- 2H), 3.96 (dd, J ) 15.5, 4.7 Hz, 1H), 3.71 (dd, J ) 15.5, 7.8
zole-4-carboxylate(5p).AccordingtoGeneralProcedureI, Hz, 1H), 3.56 (d, J ) 8.2 Hz, 1H), 0.79 (d, J ) 6.8 Hz, 3H),
reaction between NH3 (2 M in MeOH, 2.0 mL, 4.0 mmol), 0.19(d,J)6.7Hz,3H);13CNMR(63MHz,CDCl3)(cid:228)(ppm)
mesitaldehyde(296mg,2.0mmol),and4a(175mg,1.0mmol), 160.4 (CH), 150.9 (C), 145.7 (C), 140.6 (C), 140.5 (C), 133.3
followedbyprecipitationfromEt OandPE,affordedanti-5p (CH),128.3(2(cid:2)CH),127.7(CH),127.0(CH),126.4(CH),124.4
2
(216mg,67%)asawhitesolid.Mp222-225°C;1HNMR(250 (CH),119.8(CH),119.7(CH),119.4(CH2),83.6(C),73.6(CH),
6M.7H1z,(sC,D1CHl)3,)6(cid:228).3(5pp(ms,)17H.1)8,-6.73.409(s(,m1,H3)H,)3,.66.298(s-,63.H93),(m2.,583H(s),, 5(s1),.429(C27H(2m),)2,92.8969(C(Hm)),,12607.73((Cs)H,13)6,0199(.s9),(C14H439);(sI)Rcm(n-e1a;tH)R29M6S0
3H), 2.05 (s, 3H), 1.65 (s, 3H); 13C NMR (63 MHz, CDCl3) (cid:228) (EI,70eV)calcdforC21H22N2(M+)302.1783,found302.1779.
(ppm) 175.1 (C), 152.3 (CH), 138.4 (C), 137.8 (C), 137.7 (C), 2-Imidazoline14.AccordingtoGeneralProcedureI,reac-
137.0(C),131.5(C),130.8(CH),129.0(CH),127.0(2(cid:2)CH), tion between 2-aminoethanol (122 mg, 2.0 mmol), p-formal-
126.9(CH),126.8(2(cid:2)CH),81.0(C)*,64.5(CH)*,53.2(CH ), dehyde(60mg,2.0mmol),and4b(191mg,1.0mmol),followed
3
21.4 (CH ), 20.6 (CH ), 20.3 (CH ), The signals labeled with by flash column chromatography (EtOAc:MeOH:Et N ) 1:0:
3 3 3 3
anasteriskcouldonlybefoundusinggs-HMBCandgs-HMQC 0.01,gradient),afforded14(218mg,83%)asastickyyellow
measurements(forthespectra,seetheSupportingInforma- solid.1HNMR(250MHz,CDCl )(cid:228)(ppm)7.58-7.55(m,4H),
3
tion);IR(neat)3056(s,br),2949(s),2916(s),2853(m),1732 7.36-7.17(m,5H),3.51(s,2H),3.44-3.40(m,2H),3.36(brs,
(s),1597(s),1447(s),1232(s)cm-1;HRMS(EI,70eV)calcd 1H), 3.11 (t, J ) 5.4 Hz, 2H); 13C NMR (63 MHz, CDCl ) (cid:228)
3
forC H N O (M+)322.1681,found322.1666. (ppm) 158.8 (CH), 149.7 (2 (cid:2) C), 139.8 (2 (cid:2) C), 129.1 (2 (cid:2)
20 22 2 2
anti-Methyl 1-tert-Butyl-5-mesityl-4-phenyl-4,5-dihy- CH), 128.5 (2 (cid:2) CH), 124.0 (2 (cid:2) CH), 119.7 (2 (cid:2) CH), 79.2
dro-1H-imidazole-4-carboxylate(5r).AccordingtoGeneral (C),59.1(CH2),58.6(CH2),49.4(CH2);IR(neat)3177(s,br),
Procedure I, reaction between tert-butylamine (146 mg, 2.0 3044(m),2924(m),2854(m),1663(s),1590(s),1449(s),1067
mmol), mesitaldehyde (296 mg, 2.0 mmol), and 4a (175 mg, (s)cm-1;HRMS(EI,70eV)calcdforC17H16N2O(M+)264.1263,
1.0mmol),followedbyflashcolumnchromatography,afforded found264.1255.
anti-5r(58mg,15%)asasinglediastereomerasastickywhite 2-Imidazoline17.AccordingtoGeneralProcedureI,reac-
solid. 1H NMR (250 MHz, CDCl ) (cid:228) (ppm) 7.27 (s, 1H), 7.15 tion between p-methoxybenzylamine (274 mg, 2.0 mmol),
3
(d,J)5.9Hz,2H),7.01-6.95(m,3H),6.69(s,1H),6.32(s, p-hydroxybenzaldehyde(244mg,2.0mmol),and4b(191mg,
1H), 6.24 (br s, 1H), 3.66 (s, 3H), 2.63 (s, 3H), 2.08 (s, 3H), 1.0mmol),followedbyflashcolumnchromatography(EtOAc:
1.80(s,3H),1.18(s,9H);13CNMR(63MHz,CDCl )(cid:228)(ppm) MeOH:Et N)1:0:0.01,gradient),afforded14(294mg,68%)
3 3
175.0 (C), 153.9 (CH), 138.3 (C), 138.0 (C), 136.3 (C), 136.2 asayellowsolid.Precipitationfromethylacetategaveawhite
(C),133.6(C),130.7(CH),128.9(CH),126.7(2(cid:2)CH),126.5 powder. Mp 245-248 °C; 1H NMR (400 MHz, pyridine-d ) (cid:228)
5
(CH),125.7(2(cid:2)CH),85.5(C),61.4(CH),54.2(C),53.1(CH ), (ppm)11.28(brs,1H),8.10(s,1H),7.62-7.59(m,2H),7.54
3
29.2(3(cid:2)CH ),21.3(CH ),20.8(CH ),20.6(CH );IR(neat) (s, 1H), 7.47 (d, J ) 7.2 Hz, 1H), 7.36-7.29 (m, 4H), 7.17-
3 3 3 3
2974 (s), 1723 (s), 1597 (s), 1237 (s), 1212 (s), 1197 (s) cm-1; 7.08 (m, 2H), 7.03 (d, J ) 8.3 Hz, 2H), 6.95 (d, J ) 8.0 Hz,
HRMS(EI,70eV)calcdforC H N O (M+)378.2307,found 2H),6.85(d,J)8.2Hz,2H),5.10(s,1H),4.94(brs,1H),4.76
24 30 2 2
378.2319. (d,J)14.4Hz,1H),4.14(d,J)14.4Hz,1H),3.68(s,3H);
Methyl1-Benzhydryl-5-mesityl-4-phenyl-4,5-dihydro- 13C NMR (101 MHz, pyridine-d5) (cid:228) (ppm) 160.0 (CH), 159.8
1H-imidazole-4-carboxylate (5t). According to General (C),158.2(C),151.1(C),146.7(C),141.6(C),140.4(C),130.5
ProcedureI,reactionbetweenbenzhydrylamine(366mg,2.0 (2(cid:2)CH),128.8(2(cid:2)CH),128.7(CH),128.6(C),128.3(CH),
mmol),mesitaldehyde(296mg,2.0mmol),andisocyanoacetate 128.1 (CH), 127.2 (CH), 127.1 (CH), 125.8 (C), 125.0 (CH),
4a(180mg,1.03mmol),followedbyflashcolumnchromatog- 119.91 (CH), 119.86 (CH), 115.8 (2 (cid:2) CH), 114.6 (CH), 85.6
raphy, afforded 5t (84 mg, 17%) as a 74:26 mixture of (C),72.9(CH),55.2(CH3),49.8(CH2);IR(KBr)3438(s,br),
diastereomers as a yellow oil. 1H NMR (400 MHz, CDCl ) (cid:228) 3035(s),2997(s),2928(s),1609(s),1588(s),1506(s),1249
(ppm)7.65-7.63(m,2H),7.42-6.94(m,15H+13H),6.903(s, (s) cm-1; HRMS (EI, 70 eV) calcd for C29H24N2O2 (M+)
1H),6.83(s,1H),6.81(s,1H),6.74(s,1H),6.66(s,1H),6.48 432.1838,found432.1850.
(s, 1H), 6.20 (s, 1H), 5.33 (s, 1H), 4.99 (s, 1H), 4.94 (s, 1H), 2-Imidazoline19.AccordingtoGeneralProcedureI,reac-
3.67 (s, 3H), 3.33 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.14 (s, tion between 3-amino-1-propanol (150 mg, 2.0 mmol), 4-hy-
3H),1.92(s,3H),1.73(s,3H),1.71(s,3H);13CNMR(101MHz, droxybenzaldehyde(244mg,2.0mmol),and4b(191mg,1.0
CDCl )(cid:228)(ppm)174.9(C),171.5(C),153.1(CH),152.9(CH), mmol) in MeOH, followed by flash column chromatography
3
144.4(C),141.0(C),139.3(C),139.2(C),139.1(C),138.9(C), (EtOAc:Et N ) 1:0.01, EtOAc:MeOH:Et N ) 1:0.01:0.01,
3 3
138.7(C),138.4(C),138.3(C),138.2(C),137.3(C),137.20(C), gradient)andcrystallizationfromEtOAcandPE,afforded16
137.16(C),131.3(CH),130.6(CH),130.4(C),129.5(CH),129.4 (141mg,38%)asawhitesolid.Mp190-193°C;1HNMR(250
(CH+CH),129.2(CH),129.1(CH),128.90(CH),128.87(CH), MHz, DMSO-d ) (cid:228) (ppm) 9.12 (br s, 1H), 7.66 (s, 1H), 7.64-
6
128.86 (CH), 128.69 (CH), 128.67 (CH), 128.5 (CH), 128.30 7.63 (m, 1H), 7.56-7.49 (m, 2H), 7.40-7.32 (m, 2H), 7.12-
(CH),128.25(CH),127.9(CH+CH),127.8(CH),127.58(CH), 7.06(m,1H),7.01-6.96(m,2H),6.53(d,J)8.5Hz,2H),6.36
3550 J.Org.Chem.,Vol.70,No.9,2005