low-cost instant co generation at room temperature from ... · low-cost instant co generation at...

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Low-CostInstantCOGenerationatRoomTemperaturefromFormicAcid,MesylChlorideandTriethylamine

CedrickVeryser,aSegerVanMileghem,aBrechtEgle,PhilippeGillesandWimM.DeBorggraeve*

(a) Authorscontributedequally

DepartmentofChemistry,MolecularDesignandSynthesis,KULeuven,Celestijnenlaan200Fbox2404,3001Leuven,Belgium.

[email protected]

SupportingInformation

Electronic Supplementary Material (ESI) for Reaction Chemistry & Engineering.This journal is © The Royal Society of Chemistry 2016

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TableofContents

1.GENERALINFORMATION...........................................................................................................S31HNMRSPECTRA.................................................................................................................................S313CNMRSPECTRA................................................................................................................................S3CHROMATOGRAPHY...............................................................................................................................S3MATERIALS...........................................................................................................................................S3

2.13C-NMRSTUDYOFTHECOGENERATINGSYSTEM.....................................................................S4

3.INFLUENCEOFMESYLCHLORIDEANDACETICANHYDRIDEONTHEDECOMPOSITIONRATEOFFORMICACID–AVISUALEXPERIMENT.........................................................................................S6

4.PRICECOMPARISONOFRECENTLYPUBLISHEDCOGENERATINGSYSTEMS................................S84.1.LOW-COSTINSTANTCOGENERATIONATROOMTEMPERATUREFROMFORMICACID,MESYLCHLORIDEANDTRIETHYLAMINE.....................................................................................................................................S84.2.CHLOROFORMASACARBONMONOXIDEPRECURSOR:INOREXSITUGENERATION...................................S94.3.SILACARBOXYLICACIDSASEFFICIENTCARBONMONOXIDERELEASINGMOLECULES:SYNTHESISANDAPPLICATIONINPALLADIUM-CATALYZEDCARBONYLATIONREACTIONS...........................................................S94.5.EFFICIENTFLUORIDE-CATALYZEDCONVERSIONOFCO2TOCOATROOMTEMPERATURE..........................S10

5.PRICECOMPARISONOFCOMMERCIALLYAVAILABLE13COPRECURSORS..................................S11

6.PALLADIUM-CATALYSEDAMINOCARBONYLATION..................................................................S126.1.GENERALPROCEDURE....................................................................................................................S12

Aminocarbonylation....................................................................................................................S12Purification..................................................................................................................................S12

6.2.SYNTHESISOFBENZAMIDES............................................................................................................S136.3SYNTHESISOFWEINREBAMIDES......................................................................................................S166.4SYNTHESISOFC-12ANDC-13PHARMACEUTICALCOMPOUNDS............................................................S19

7.REFERENCES............................................................................................................................S66

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1.GeneralInformation

1HNMRspectra1H-NMRspectrawererecordedonBrukerAvance300(300MHz),BrukerAvance400(400MHz)andBrukerAvance II+ 600 (600MHz) spectrometers. Samplesweredissolved inCDCl3orDMSO-d6 andtetramethylsilanewasusedasinternalstandard.Theδ-valuesareexpressedinppm.

13CNMRspectra 13C-NMR spectra were recorded on Bruker Avance 300 (working at 75 MHz), Bruker Avance 400(working at 100 MHz) and Bruker Avance II+ 600 (working at 150 MHz) spectrometers. Thedeuteratedsolventswereusedasinternalstandard(CDCl3:77.16ppm,triplet;DMSO-d6:39.52ppm,quintet).Theδ-valuesareexpressedinppm.

Chromatography

TLCplates:pre-coatedTLC-platesSILG-25(withfluorescence-indicator254nm):layerthickness0.25mm;averageporediameter60Å;20x20cmglassplates

Silicagelforcolumnchromatography:MPSilica32-63,averageporediameter60Å,Ecochron

MPLCapparatus:BüchiSepacoreTMflashapparatus,consistingofaC-660Büchifractioncollector,C-615Pumpmanager,C-635UV-photometer,twoC-605pumpmodulesandaLinseisD120Splotter.

Materials

Allreagentswereobtainedfromcommerciallyavailablesourcesandwereusedaspurchasedwithoutfurtherpurification.Allmoisture-sensitivereactionswerecarriedoutunderargonatmosphereandinflame-driedglassware.Reactionsweremagneticallystirredandmonitoredbyusingpre-coatedsilicagel60F254(250µm)glass-supportedTLCplates.CompoundswerevisualizedbyUVirradiation(254nm). Flash column chromatography was performed on pre-packed silica gel (40-63 µm) columns.Solvents were evaporated with a rotavapor at a temperature of 40°C. Yields refer to isolatedcompoundsafterchromatography.

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2.13C-NMRstudyoftheCOgeneratingsystem

To gain insight in the steps involved in the decomposition mechanism of formic acid to carbonmonoxideinpresenceofmesylchlorideandtriethylamine,a13C-NMRstudywasconductedatroomtemperature(SchemeS2).Therecordedspectraweremeasuredinacetonitrile-d3.

- Spectrum[A]0.5mmolHCOOHin600µLCD3CN.

- Spectrum[B]0.5mmolMsClin600µLCD3CN.

- Spectrum[C]0.5mmolHCOOHand0.5mmolMsClin600µLCD3CN.

- Spectrum[D]0.5mmolHCOOH,0.5mmolMsCland1.0mmolEt3Nin600µLCD3CN.

- Spectrum[E]0.5mmolMsOHand1.0mmolEt3Nin600µLCD3CN.

Spectra [A], [B], [E] show the reference ppm-values of formic acid (HCOOH = 162.7 ppm), mesylchloride (MsCl = 53.3 ppm) and methanesulfonate (MsO- = 39.6 pppm). Upon addition of mesylchloridetoformicacid,nogasformationisobservedinthetube.ThisisconfirmedbyNMRwherenoshiftsinpeakswereobserved(spectrum[C]isthesumofspectra[A]and[B]).Apparentlynoreactionoccursbetweenthesereagentsintheabsenceofbase.

Upon dropwise addition of 1.0mmol Et3N to 0.5mmol HCOOH and 0.5mmolMsCl, vigorous gasdevelopmentoccurs for several seconds.Afterwards a 13C-NMR spectrumwas recorded (spectrum[D])andcompletedecompositionofHCOOHwasobservedasthecorrespondingpeakdisappeared.The peak of mesyl chloride shifted to lower ppm-values (from 53.3 to 39.6 ppm), indicating theformationoftriethylammoniummethanesulfonatesalt.

Theseresultsindicatethatoncetheformicacidisdeprotonated,itmostprobablyreactswithmesylchlorideandformsahighlyunstablemixedanhydrideintermediate.AseconddeprotonationleadstoinstantCOformation,asthemethanesulfonateisanexcellentleavinggroup(SchemeS1).

Scheme S1. Proposed decomposition mechanism of formic acid in presence of 1 equiv. mesyl chloride and 2 equiv.triethylamineleadingtoinstantCOgeneration.

H OH

O

H O

OS

O

OCOS Cl

O

O

1 equiv. Instant CO generationdue to highly unstable intermediate

2 equiv. Et3N

1 equiv.

+

S5

SchemeS2.13C-NMRstudyoftheCOprecursoratroomtemperature.[A]0.5mmolHCOOHin600µLCD3CN.[B]0.5mmolMsClin600µLCD3CN.[C]0.5mmolHCOOHand0.5mmolMsClin600µLCD3CN.[D]0.5mmolHCOOH,0.5mmolMsCland1.0mmolEt3Nin600µLCD3CN.[E]0.5mmolMsOHand1.0mmolEt3Nin600µLCD3CN.

HCOH

O

HCOH

O

CD3CN

CD3CN

H3C S

O

O

Cl

H3C S

O

O

Cl

H3C S

O

O

O

H3C S

O

O

O

Et3NH

Et3NH Et3NH

Et3NH

[B]

[E]

[D]

[C]

[A]

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3.InfluenceofMesylChlorideandAceticAnhydrideonthedecompositionrateofFormicAcid–AVisualExperiment

Recently theWu group reported that formic acid releases carbonmonoxide in presence of aceticanhydrideunderbasicconditions.1,2Unfortunately thisdecomposition isslow,while instantcarbonmonoxidegenerationisdesiredasitdirectlystabilisesthecatalyticsystemandshortensthereactiontime.3

Wehavediscoveredthatformicacidcanbeinstantlydecomposedtocarbonmonoxideinpresenceofmesylchlorideandtriethylamine.

Avisualexperimentwasconductedtocomparetheinfluenceofmesylchlorideandaceticanhydrideonthedecompositionrateofformicacidinpresenceoftriethylamine(FigureS1).Two10mLscrew-cappedvialswerefilledwith0.5mmolformicacidand2mLdrydegassedtoluene.Next0.5mmolofmesyl chloride and 0.5mmol acetic anhydridewere added to respectively the left and right tube.Thentwosyringeswereconnectedtothehead-spacethroughthesealedcap.Onesyringecontained1.0mmoltriethylamineandtheothersyringe(12mL)wasempty(FigureS1[A]).Aftertheadditionoftriethylamine instantexpansionof the leftsyringewasobserved.After10seconds, the leftsyringealreadycontained7mLofCO(FigureS1[C]).Ontheotherhandtheexpansionoftherightsyringe(containingaceticanhydride)onlystartedafter70seconds.UsingaceticanhydrideasadditiveresultsinamuchslowerCOgeneration,asthecorrespondingsyringeonlycontained4mLofCOafterthreeminutes(FigureS1[F]).

Remark:AvideoofthisvisualexperimentisavailableinSupportingInfo(MsCl_versus_AcOAc.mp4).

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Figure S1. Visual experiment about the influence of mesyl chloride (left tube) and acetic anhydride (right tube) on thedecompositionrateof formicacidtocarbonmonoxide inpresenceof triethylamine.Eachtubecontains0.5mmolHCOOHand0.5mmoladditivein2mLdrydegassedtoluene.1.0mmoltriethylaminewasaddedtodecomposetheformicacid.[A]Beforeadditionoftriethylamine.[B]Additionoftriethylamine.[C]10secondsaftertheadditionofEt3N.[D]1minuteaftertheadditionofEt3N.[E]2minutesaftertheadditionofEt3N.[F]3minutesaftertheadditionofEt3N.

[A] [B] [C]

[D] [E] [F]

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4.PricecomparisonofrecentlypublishedCOgeneratingsystems

RecentlyafewnewexcellentCOgeneratingsystemswerereported.4-7HoweversomeoftheseCO-precursors and/or additives are non-trivial chemicals and require one or more synthetic steps toproduce.5,6 In addition, the use of an expensive heterogeneous base or a transition metal issometimes necessary to decompose the precursor.4,7 Therefore it is advantageous if inexpensivecommoditiescanbeusedtoreleasecarbonmonoxide.

In this paper we report a state-of-the-art low-cost CO generation system based on the instantdecompositionofformicacidbyadditionofmesylchlorideandtriethylamineatroomtemperature.As shown in Table S1, this system is 30 to 140 timesmore cost efficient than the other reportedprecursors.ThedetailsofthesepricecalculationsarereportedinTableS2-TableS8.Notethatnocosts of solvent, work-up, purification and carbon dioxide were taken into account for thesecalculations.Alsonotethatthesepricecalculationsareonlyindicative,astheywillchangeovertime.Howeverthepricedifferenceissignificant(factor30–140).

TableS1.PricecomparisonofrecentlypublishedCOgeneratingsystems.aDetailedinformationseeTableS2-TableS8.bTheactualandrelativepriceareevenhigherasnocostsofwork-up,purificationandcarbondioxideweretakenintoaccount.

Method COgeneratingsystem Pricea Relativepricecomparedtomethod1

1

0.03euro 1

2 3.45euro 115

3

0.96eurob 32b

4

4.24euro 140

51.12eurob 37b

4.1.Low-CostInstantCOGenerationatRoomTemperaturefromFormicAcid,MesylChlorideandTriethylamine

OurreportedCOgeneratingsystemsconsistsof1.3equiv.formicacid,1.3equiv.mesylchlorideand2.6equiv.triethylamine.

Table S2. Price of our reported CO generating system. aEquivalents reported in the article. bCompared to 0.5mmol arylbromideaslimitingreagent.cCommercialpricebasedontheonlinecataloguesofSigma-Aldrich(dateofconsultation:the19thofDecember2015).

Chemicals Equivalentsa mmolb Commercialpricec Commercial pricepermmol

Price

Formicacid 1.3 0.65 43.50europer1L 0.002euro 0.001euroMesylchloride 1.3 0.65 24.10europer100mL 0.019euro 0.01euroTriethylamine 2.6 1.30 107.00europer1L 0.015euro 0.02euro

TotalPrice 0.03euro

H OH

OMsCl

Et3N+ CO

CHCl3CsOH.H2O

CO

Si OH

O

PhPh

F-CO

OCl

Cat. Pd0

CO

SiSi

PhPh

Cat. F-COPh

PhCO2+

S9

4.2.ChloroformasaCarbonMonoxidePrecursor:InorExSituGeneration.4

The CO generating system in this article consists of 3.0 equiv. chloroform and 10.0 equiv. ofcesiumhydroxidemonohydrate.

Table S3. Price of the reported CO generating system. aEquivalents reported in the article. bCompared to 0.5mmol arylbromideaslimitingreagent.cCommercialpricebasedontheonlinecataloguesofSigma-Aldrich(dateofconsultation:the19thofDecember2015).


Price

CHCl3 3.0 1.5 72.20europer1L 0.003euro 0.01euroCsOH.H2O 10.0 5.0 40.90europer10G 0.688euro 3.44euro

TotalPrice 3.45euro

4.3.SilacarboxylicAcidsasEfficientCarbonMonoxideReleasingMolecules:SynthesisandApplicationinPalladium-CatalyzedCarbonylationReactions.5

TheCOgeneratingsysteminthisarticleconsistsof1.5equiv.methyldiphenylsilacarboxylicacidand1.7 equiv. potassium fluoride. However the methyldiphenylsilacarboxylic acid is not commerciallyavailable,butcanbepreparedviaoneextrasynthesisstep.

Table S4. Price of themethyldiphenylsilacarboxylic acid synthesis. aEquivalents reported in the article. bCompared to 0.5mmolmethyldiphenylsilacarboxylic acid as limiting reagent. cCommercial price based on the online catalogues of Sigma-Aldrich(dateofconsultation:the19thofDecember2015).


Price

Lithium 4.5 2.25 83.90europer25G 0.023euro 0.05euroChlorodiphenyl(methyl)silane

1.0 0.5 91.50europer25G 0.855euro 0.43euro

Carbondioxide - - - - -

TotalPrice 0.48euro

Taken into account a reported yield of 77%, the total price to synthesise 0.5 mmolmethyldiphenylsilacarboxylic acid is 0.62 euro. However the actual price is higher as no costs ofwork-up,purificationandcarbondioxidewereconsidered.


Chemicals Equivalentsa mmolb Commercialpricec Commercialpricepermmol

Price

Methyldiphenylsilacarboxylicacid

1.5 0.75 - - 0.93euro

Potassiumfluoride 1.7 0.85 64.50europer100G 0.03euro 0.03euro

TotalPrice 0.96euro

4.4. Ex Situ Generation of Stoichiometric and Substoichiometric 12CO and 13CO and Its EfficientIncorporationinPalladiumCatalyzedAminocarbonylations.7

The CO generating system in this article consists of 1.0 equiv. 9-methyl-9H-fluorene-9-carbonylchloride,5mol%Pd(dba)2,5mol%P(tBu)3and1.5equiv.DIPEA.

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Price

9-methyl-9H-fluorene-9-carbonylchloride


Pd(dba)2 0.05 0.025 93.00europer2G 26.72euro 0.67euroP(tBu)3 0.05 0.025 79.50europer1G 16.09euro 0.40euroDIPEA 1.5 0.75 371europer1L 0.065euro 0.05euro

TotalPrice 4.24euro

4.5.EfficientFluoride-CatalyzedConversionofCO2toCOatRoomTemperature.6

TheCOgeneratingsysteminthisarticleconsistsof1.5equiv.tetraphenyldimethyldisilane,2.0equiv.carbondioxideand0.1equiv.ofcesiumfluoride.Howeverthetetraphenyldimethyldisilaneadditiveisnotcommerciallyavailable,butcanbepreparedviaoneextrasynthesisstep.

Table S7. Price of the tetraphenyldimethyldisilane synthesis. aEquivalents reported in thearticle. bCompared to 0.5mmoltetraphenyldimethyldisilaneaslimitingreagent.cCommercialpricebasedontheonlinecataloguesofSigma-Aldrich(dateofconsultation:the19thofDecember2015).


Price

Lithium 0.7 0.35 83.90europer25G 0.023euro 0.01euroChlorodiphenyl(methyl)silane


TotalPrice 0.44euro

Taken into account a reported yield of 60%, the total price to synthesise 0.5 mmoltetraphenyldimethyldisilaneacidis0.73euro.Howevertheactualpriceishigherasnocostsofwork-upandpurificationwereconsidered.


Chemicals Equivalentsa mmolb Commercialpricec Commercialpricepermmol

Price

Tetraphenyldimethyl-disilane

1.5 0.75 - - 1.10euro

Cesiumfluoride 0.1 0.05 63.00europer25G 0.38euro 0.02euroCarbondioxide 2.0 1.00 - - -

TotalPrice 1.12euro

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5.Pricecomparisonofcommerciallyavailable13COprecursors

Since 13C-formic acid is commercially available, our reported procedure also provides an obvioussourceof 13CO.Note that thisenrichedprecursor is at least9 times lessexpensivepermmol 13COthan any other reported commercial 13CO precursor (Table S9). Also note that these pricecalculations are only indicative, as they will change over time. However the price difference issignificant(factor9–11).

TableS9.Pricecomparisonofthecommercialavailable13COprecursors.aCommercialpriceisbasedontheonlinecataloguesof Sigma-Aldrich (date of consultation: the 19th of December 2015). bMethyldiphenylsilacarboxylic acid andtetraphenyldimethyldisilanearenotcommerciallyavailable.

Method COgeneratingsystem Commercialpricepergrama

Commercialpricepermmol13CO

Relativepricecomparedtomethod1

1

307euro 14euro 1

2 1056euro 126euro 9

3

-b - -

4

653euro 158euro 11

5

-b - -

H13C

OH

OMsCl

Et3N+ 13CO

13CHCl3CsOH.H2O 13CO

Si13C

OH

O

PhPh

F-13CO

13CO

ClCat. Pd0

13CO

SiSi

PhPh

Cat. F-13COPh

Ph13CO2+

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6.Palladium-catalysedAminocarbonylation

6.1.Generalprocedure

Aminocarbonylation

Chamber A of a flame-dried two-chamber reactor (Figure S2) was filled with 1 mg Palladium(II)acetate (5.00 µmol, 1mol%), 3mg Xantphos (5.00 µmol, 1mol%) and 159mg sodium carbonate(1.50 mmol, 3 equiv.). The reactor was brought under argon atmosphere by two consecutivevacuum-argon cycles. Next, chamber B was filled with 2 mL dry degassed toluene, 51 µL mesylchloride(0.65mmol,1.3equiv.)and25µLformicacid(0.65mmol,1.3equiv.). InchamberA,1mLdrydegassedtoluenewasadded,followedby0.5mmolarylbromide(1equiv.)and0.75mmolamine(1.5equiv.).Finally,181µLtriethylamine(1.3mmol,2.6equiv.)wasaddedbyinjectionthroughtheseptuminchamberBatroomtemperatureandinstantgasformationwasobserved.After2minutes,thereactorwasimmersedinanoil-bathat100°C.

AvideoofthelaststepisavailableinSupportingInfo(General_Procedure.mp4)

Remark:whenthearylbromideand/ortheaminearesolidsatroomtemperature,theywereaddedtoChamberAaftertheadditionofPalladium(II)acetateandXantphos.

Remark:fortheC-13labelledcompounds,25µLof13C-HCOOH(95wt.%inH2O)wasused.

Purification

After 2 hours, the reactor was brought to room temperature and excess CO was released byremovingoneofthecaps.Ascarbonmonoxideisahighlytoxicgas,thereactionwasleftstirringatroomtemperatureforanother15minutestoensurethatallcarbonmonoxidegaswasextractedoutof the fume hood.Next, the content of chamber Awas transferred to a 100mL round-bottomedflask.Thischamberwaswashed5timeswith2mLofEtOAc,thesefractionswereaddedtothesameflask.Aftertheadditionof1gramCelite®535,thesolventwasremovedunderreducedpressure.Thecrudeproductwaspurifiedbysolid-phaseflashcolumnchromatographyonsilicagel.

FigureS2.Representationofthetwo-chamberreactor.Innervolume=20mL.

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6.2.SynthesisofBenzamides

N-hexylbenzamide(compound3a)

Thegeneralprocedurewas followedusing53µLbromobenzene (0.5mmol,1equiv.)and99µLn-hexylamine (0.75 mmol, 1.5 equiv.). The crude mixture was purified by solid-phase flash columnchromatographyonsilicagel (85:15heptane/ethylacetate).Thetitlecompoundwasobtainedasacolourlessoil(101mg,98%).

1HNMR(300MHz,CDCl3)7.85–7.30(5H,m),6.65(1H,brd),3.39(2H,td,J7.2,5.9),1.65–1.50(2H,m),1.42–1.16(6H,m),0.86(3H,t,J6.7).

13CNMR(75MHz,CDCl3)167.68,134.89,131.25,128.48,126.97,40.19,31.56,29.65,26.73,22.61,14.07.

Thesedataareinagreementwithliteraturedata.8

N-methoxy-N-methylbenzamide(compound3b)

Thegeneralprocedurewasfollowedusing53µLbromobenzene(0.5mmol,1equiv.)and73mgN,O-dimethylhydroxylamine hydrochloride (0.75mmol, 1.5 equiv.). The crudemixture was purified bysolid-phase flash column chromatography on silica gel (80:20 heptane/ethyl acetate). The titlecompoundwasobtainedasacolourlessoil(73mg,89%).

1HNMR(300MHz,CDCl3)7.69–7.34(5H,m),3.54(3H,s),3.35(3H,s).

13CNMR(75MHz,CDCl3)170.06,134.22,130.65,128.22,128.11,61.12,33.88.


N-allyl-N-methylbenzamide(compound3c)

Thegeneralprocedurewas followedusing53µLbromobenzene(0.5mmol,1equiv.)and71µLN-methylprop-2-en-1-amine (0.75 mmol, 1.5 equiv.). The crude mixture was purified by solid-phaseflash column chromatographyon silica gel (80:20heptane/ethyl acetate). The title compoundwasobtainedasacolourlessoil(71mg,81%).

1HNMR(600MHz,DMSO-d6)7.47–7.35(5H,m),5.89–5.75(1H,m),5.24–5.15(2H,m),3.94(2H,s),2.90(3H,s).

13CNMR(151MHz,DMSO-d6)169.99,136.28,133.06,128.76,127.76,126.09,116.50,50.78,34.04.


N(H)-n-hexyl

O

O

NO

O

N

S14

N-butylbenzamide(compound3d)

Thegeneralprocedurewas followedusing53µLbromobenzene(0.5mmol,1equiv.)and74µLN-butylamine (0.75 mmol, 1.5 equiv.). The crude mixture was purified by solid-phase flash columnchromatographyonsilicagel (85:15heptane/ethylacetate).Thetitlecompoundwasobtainedasacolourlessoil(79mg,89%).

1HNMR(400MHz,DMSO-d6)8.42(1H,brd),7.48(5H,m),3.26(2H,dd,J12.8,6.9),1.57–1.45(2H,m),1.39–1.27(2H,m),0.90(3H,t,J7.3).

13CNMR(101MHz,DMSO-d6)166.07,134.75,130.90,128.16,127.09,38.85,31.25,19.65,13.69.


Phenyl(piperidin-1-yl)methanone(compound3e)

The general procedure was followed using 53 µL bromobenzene (0.5 mmol, 1 equiv.) and 74 µLpiperidine (0.75 mmol, 1.5 equiv.). The crude mixture was purified by solid-phase flash columnchromatographyonsilicagel (80:20heptane/ethylacetate).Thetitlecompoundwasobtainedasacolourlessoil(88mg,93%).

1HNMR(300MHz,CDCl3)7.36(5H,s),3.68(2H,s),3.31(2H,s),1.64(4H,s),1.49(2H,s).

13CNMR(75MHz,CDCl3)170.29,136.49,129.33,128.38,126.76,48.73,43.10,26.53,25.66,24.58.


Morpholino(phenyl)methanone(compound3f)

The general procedure was followed using 53 µL bromobenzene (0.5 mmol, 1 equiv.) and 66 µLmorpholine (0.75 mmol, 1.5 equiv.). The crude mixture was purified by solid-phase flash columnchromatographyonsilicagel (50:50heptane/ethylacetate).Thetitlecompoundwasobtainedasacolourlessoil(91mg,95%).

1HNMR(400MHz,CDCl3)7.38(5H,s),3.63(8H,brd).

13CNMR(101MHz,CDCl3)170.52,135.67,129.90,128.62,127.21,67.00,46.88(brd).


N-benzylbenzamide(compound3g)

N(H)-n-butyl

O

O

N

O

NO

S15

The general procedure was followed using 53 µL bromobenzene (0.5 mmol, 1 equiv.) and 82 µLphenylmethanamine (0.75mmol, 1.5 equiv.). The crudemixturewas purified by solid-phase flashcolumn chromatography on silica gel (85:15 heptane/ethyl acetate). The title compound wasobtainedasawhitesolid(96mg,91%).

1HNMR(400MHz,DMSO-d6)9.04(1H,brd),7.95–7.86(2H,m),7.58–7.43(3H,m),7.33(4H,d,J4.3),7.24(1H,dd,J8.6,4.4),4.49(2H,d,J6.0).

13C NMR (101 MHz, DMSO-d6) 166.19, 139.68, 134.34, 131.20, 128.29, 128.25, 127.22, 127.17,126.70,42.59,39.52.


Methyl2-benzamidoacetate(compound3h)

The general procedure was followed using 53 µL bromobenzene (0.5mmol, 1 equiv.) and 94mgmethyl glycinate hydrochloride (0.75 mmol, 1.5 equiv.). The crude mixture was purified by solid-phaseflashcolumnchromatographyonsilicagel(80:20heptane/ethylacetate).Thetitlecompoundwasobtainedasawhitesolid(93mg,96%).

1HNMR(300MHz,CDCl3)7.82–7.75(2H,m),7.52–7.34(3H,m),7.06(1H,brd),4.18(2H,d,J5.3),3.73(3H,s).

13CNMR(75MHz,CDCl3)170.18,167.28,133.18,131.39,128.15,126.72,52.01,41.29.


O

NH

O

NH

O

O

S16

6.3SynthesisofWeinrebAmides

4-isocyano-N-methoxy-N-methylbenzamide(compound4a)

Thegeneralprocedurewas followedusing91mg4-bromobenzonitrile (0.5mmol,1equiv.)and73mg N,O-dimethylhydroxylamine hydrochloride (0.75 mmol, 1.5 equiv.). The crude mixture waspurifiedbysolid-phaseflashcolumnchromatographyonsilicagel(60:40heptane/ethylacetate).Thetitlecompoundwasobtainedasalightyellowoil(87mg,92%).

1HNMR(300MHz,CDCl3)7.72(4H,dd,J20.6,8.5),3.50(3H,s),3.35(3H,s).

13CNMR(75MHz,CDCl3)167.95,138.33,131.92,128.88,118.24,114.15,61.40,33.26.


N-methoxy-N-methylthiophene-3-carboxamide(compound4b)

Thegeneralprocedurewasfollowedusing47µL3-bromothiophene(0.5mmol,1equiv.)and73mgN,O-dimethylhydroxylaminehydrochloride (0.75mmol,1.5equiv.). Thecrudemixturewaspurifiedby solid-phase flash column chromatography on silica gel (80:20 heptane/ethyl acetate). The titlecompoundwasobtainedasalightyellowoil(77mg,90%).

1HNMR(300MHz,CDCl3)8.06(1H,dd,J3.0,1.2),7.56(1H,dd,J5.1,1.2),7.27(1H,dd,J5.1,3.0),3.64(3H,s),3.35(3H,s).

13CNMR(75MHz,CDCl3)163.41,134.11,130.54,128.69,124.46,60.86,32.94.


4-chloro-N-methoxy-N-methylbenzamide(compound4c)

Thegeneralprocedurewasfollowedusing144mg1-bromo-4-chlorobenzene(0.75mmol,1.5equiv.)and 49mgN,O-dimethylhydroxylamine hydrochloride (0.50mmol, 1.0 equiv.). The crudemixturewaspurifiedbysolid-phaseflashcolumnchromatographyonsilicagel(80:20heptane/ethylacetate).Thetitlecompoundwasobtainedasacolourlessoil(83mg,83%).

1HNMR(300MHz,CDCl3)7.64(2H,d,J8.7),7.36(2H,d,J8.7),3.52(3H,s),3.34(3H,s).

13CNMR(75MHz,CDCl3)168.73,136.81,132.34,129.94,128.35,77.16,61.19,33.59.


N-methoxy-N-methyl-3-nitrobenzamide(compound4d)

N

O

NC

O

O

NO

Cl

S17

Thegeneralprocedurewasfollowedusing101mg1-bromo-3-nitrobenzene(0.5mmol,1equiv.)and73mgN,O-dimethylhydroxylamine hydrochloride (0.75mmol, 1.5 equiv.). The crudemixture waspurifiedbysolid-phaseflashcolumnchromatographyonsilicagel(75:25heptane/ethylacetate).Thetitlecompoundwasobtainedasalightyellowoil(90mg,86%).

1HNMR(300MHz,CDCl3)8.57–8.53(1H,m),8.34–8.27(1H,m),8.05–7.99(1H,m),7.60(1H,t,J8.0),3.54(3H,s),3.38(3H,s).

13CNMR(75MHz,CDCl3)167.26,147.85,135.58,134.44,129.30,125.36,123.61,61.45,33.33.


2-cyano-N-methoxy-N-methylbenzamide(compound4e)

Thegeneralprocedurewas followedusing92mg2-bromobenzonitrile (0.5mmol,1equiv.)and73mg N,O-dimethylhydroxylamine hydrochloride (0.75 mmol, 1.5 equiv.). The crude mixture waspurifiedbysolid-phaseflashcolumnchromatographyonsilicagel(70:30heptane/ethylacetate).Thetitlecompoundwasobtainedasacolourlessoil(85mg,89%).

1HNMR(400MHz,CDCl3)7.74–7.45(4H,m),3.52(3H,s),3.36(3H,s).

13CNMR(101MHz,CDCl3)166.92,139.14,132.85,132.49,129.92,127.95,116.94,110.93,61.46,


N,4-dimethoxy-N-methylbenzamide(compound4f)

Thegeneralprocedurewas followedusing63µL1-bromo-4-methoxybenzene (0.5mmol,1equiv.)and 73mgN,O-dimethylhydroxylamine hydrochloride (0.75mmol, 1.5 equiv.). The crudemixturewaspurifiedbysolid-phaseflashcolumnchromatographyonsilicagel(80:20heptane/ethylacetate).Thetitlecompoundwasobtainedasacolourlessoil(85mg,87%).

1HNMR(300MHz,CDCl3)7.70(2H,d,J8.9),6.87(2H,d,J8.9),3.81(3H,s),3.53(3H,s),3.32(3H,s).

13CNMR(75MHz,CDCl3)168.98,161.12,130.14,125.57,112.84,60.49,54.92,33.49.


N-methoxy-N-methyl-2-naphthamide(compound4g)

N

OOO2N

O

NO

CN

O

NO

O

S18

Thegeneralprocedurewasfollowedusing104mg2-bromonaphtalene(0.5mmol,1equiv.)and73mg N,O-dimethylhydroxylamine hydrochloride (0.75 mmol, 1.5 equiv.). The crude mixture waspurifiedbysolid-phaseflashcolumnchromatographyonsilicagel(85:15heptane/ethylacetate).Thetitlecompoundwasobtainedasacolourlessoil(94mg,88%).

1HNMR(300MHz,CDCl3)8.22(1H,s),7.92–7.73(4H,m),7.58–7.47(2H,m),3.55(3H,s),3.40(3H,s).

13CNMR (75MHz, CDCl3) 169.91, 134.23, 132.50, 131.42, 128.86, 128.69, 127.73, 127.66, 127.43,126.52,125.08,61.15,33.89.


N-methoxy-N,3,5-trimethylbenzamide(compound4h)

Thegeneralprocedurewasfollowedusing68µL1-bromo-3,5-dimethylbenzene(0.5mmol,1equiv.)and 73mgN,O-dimethylhydroxylamine hydrochloride (0.75mmol, 1.5 equiv.). The crudemixturewaspurifiedbysolid-phaseflashcolumnchromatographyonsilicagel(70:30heptane/ethylacetate).Thetitlecompoundwasobtainedasacolourlessoil(86mg,89%).

1HNMR(300MHz,CDCl3)7.22(2H,s),7.06(1H,s),3.56(3H,s),3.31(3H,s),2.32(6H,s).

13CNMR(75MHz,CDCl3)170.53,137.66,134.24,132.16,125.64,77.16,61.04,34.10,21.29.


O

NO

O

NO

S19

6.4SynthesisofC-12andC-13PharmaceuticalCompounds

(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)(piperidin-1-yl)methanoneorCX-546(compound5a)

The general procedure was followed using 67 µL 6-bromo-2,3-dihydrobenzo[b][1,4]dioxine (0.5mmol, 1 equiv.) and 74 µL piperidine (0.75mmol, 1.5 equiv.). The crudemixturewas purified bysolid-phaseflashcolumnchromatographyonsilicagel(80:20heptane/ethylacetate).Compound5awasobtainedasawhitesolid(111mg,90%).

1HNMR(600MHz,CDCl3)6.95–6.82(3H,m),4.25(4H,m),3.52(4H,m),1.68–1.64(2H,m),1.57(4H,m).

13C NMR (151 MHz, CDCl3) 169.99, 144.91, 143.56, 130.03, 120.65, 117.26, 116.70, 64.65, 64.52,45.98(brd),26.29,24.85.


Carbon-13 labelled (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)(piperidin-1-yl)methanone or CX-546(compound5b)

The general procedure was followed using 67 µL 6-bromo-2,3-dihydrobenzo[b][1,4]dioxine (0.5mmol, 1 equiv.) and 74 µL piperidine (0.75mmol, 1.5 equiv.). The crudemixturewas purified bysolid-phaseflashcolumnchromatographyonsilicagel(80:20heptane/ethylacetate).Compound5bwasobtainedasawhitesolid(124mg,94%).

Remark:fortheC-13labelledCX-546,25µLof13C-HCOOH(95wt.%inH2O)wasused.

1HNMR(600MHz,CDCl3)6.94–6.81(3H,m),4.26–4.20(4H,m),3.66–3.38(4H,m),1.68–1.62(2H,m),1.61–1.52(4H,m).

13CNMR(151MHz,CDCl3)169.94(s),144.87(s),143.51(s),129.95(d,J67.7),120.59(s),117.20(d,J4.9),116.64(d,J2.3),64.60(s),64.48(s),46.23(brd),26.24(s),24.80(s).

4-chloro-N-(2-morpholinoethyl)benzamideorMoclobemide(compound6a)

Thegeneralprocedurewasfollowedusing98mg1-bromo-4-chlorobenzene(0.5mmol,1equiv.)and99µL2-morpholinoethan-1-amine(0.75mmol,1.5equiv.).Thecrudemixturewaspurifiedbysolid-phase flash columnchromatographyon silica gel (96:4dichloromethane/methanol). Compound6awasobtainedasawhitesolid(130mg,97%).

1HNMR(300MHz,CDCl3)7.75–7.68(2H,m),7.45–7.37(2H,m),6.76(1H,brd),3.77–3.68(4H,m),3.57–3.48(2H,m),2.63–2.56(2H,m),2.54–2.43(4H,m).

N

OO

O

13CN

OO

O

NH

O

Cl

NO

S20

13CNMR(75MHz,CDCl3)166.44,137.75,133.08,128.95,128.47,67.11,56.90,53.43,36.18.


Carbon-13labelled4-chloro-N-(2-morpholinoethyl)benzamideorMoclobemide(compound6b)

Thegeneralprocedurewasfollowedusing98mg1-bromo-4-chlorobenzene(0.5mmol,1equiv.)and99µL2-morpholinoethan-1-amine(0.75mmol,1.5equiv.).Thecrudemixturewaspurifiedbysolid-phase flash columnchromatographyon silica gel (96:4dichloromethane/methanol).Compound6bwasobtainedasawhitesolid(126mg,94%).

Remark:fortheC-13labelledMoclobemide,25µLof13C-HCOOH(95wt.%inH2O)wasused.

1HNMR(300MHz,CDCl3)7.70(2H,m),7.39(2H,m),6.80(1H,brd),3.78–3.64(4H,m),3.59–3.48(2H,m),2.58(2H,m),2.54–2.41(4H,m).

13CNMR(75MHz,CDCl3)166.43(s),137.70(s),133.04(d,J65.2),128.91(d,J4.4),128.45(d,J2.5),67.08(s),56.89(s),53.41(s),36.18(s).


N,N-diethylnicotinamideorNikethamide(compound7a)

The general procedurewas followed using 49 µL 3-bromopyridine (0.5mmol, 1 equiv.) and 78 µLdiethylamine (0.75mmol, 1.5 equiv.). The crudemixturewas purified by solid-phase flash columnchromatography on silica gel (97:3 dichloromethane/methanol). Compound 7a was obtained as ayellowoil(68mg,76%).

1HNMR(300MHz,CDCl3)8.58(2H,m),7.71–7.62(1H,m),7.34–7.26(1H,m),3.36(4H,m),1.14(6H,m).

13CNMR(75MHz,CDCl3)168.59,150.29,147.19,134.28,133.00,123.43,43.45,39.57,14.30,12.87.


Carbon-13labelledN,N-diethylnicotinamideorNikethamide(compound7b)

The general procedurewas followed using 49 µL 3-bromopyridine (0.5mmol, 1 equiv.) and 78 µLdiethylamine (0.75mmol, 1.5 equiv.). The crudemixturewas purified by solid-phase flash columnchromatography on silica gel (97:3 dichloromethane/methanol). Compound 7b was obtained as ayellowoil(73mg,82%).

Remark:fortheC-13labelledNikethamide,25µLof13C-HCOOH(95wt.%inH2O)wasused.

13CNH

O

Cl

NO

N

N

O

N

13CN

O

S21

1HNMR(300MHz,CDCl3)8.60(2H,m),7.78–7.57(1H,m),7.38–7.26(1H,m),3.37(4H,m),1.15(6H,m).

13CNMR(75MHz,CDCl3)168.63(s),150.34(s),147.23(d,J3.0),134.30(d,J1.6),133.03(d,J66.7),123.48(s),43.47(s),39.60(s),14.32(s),12.91(s).

S22

6.5NMRspectraofthesynthesisedcompounds

S66

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