Co/NHPI-mediated aerobic oxygenation of benzylic C-H bonds in pharmaceutically relevant molecules

Article abstract of DOI:10.1039/c6sc03831j

A simple cobalt(ii)/N-hydroxyphthalimide catalyst system has been identified for selective conversion of benzylic methylene groups in pharmaceutically relevant (hetero)arenes to the corresponding (hetero)aryl ketones. The radical reaction pathway tolerates electronically diverse benzylic C-H bonds, contrasting recent oxygenation reactions that are initiated by deprotonation of a benzylic C-H bond. The reactions proceed under practical reaction conditions (1 M substrate in BuOAc or EtOAc solvent, 12 h, 90-100 °C), and they tolerate common heterocycles, such as pyridines and imidazoles. A cobalt-free, electrochemical, NHPI-catalyzed oxygenation method overcomes challenges encountered with chelating substrates that inhibit the chemical reaction. The utility of the aerobic oxidation method is showcased in the multigram synthesis of a key intermediate towards a drug candidate (AMG 579) under process-relevant reaction conditions.

Full text of DOI:10.1039/c6sc03831j

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Page 1 of 6
Pleas Ce hꢀ d eo mꢀ ni oc ta ꢀ la dS jcu i se t nꢀ mc ea rginsꢀ
View Article Online
DOI: 10.1039/C6SC03831J
ChemicalꢀScienceꢀ
ꢀ
EDGEꢀARTICLEꢀ
Co/NHPI-mediatedꢀaerobicꢀoxygenationꢀofꢀbenzylicꢀC–HꢀBondsꢀinꢀ
pharmaceuticallyꢀrelevantꢀmolecules†ꢀ
Receivedꢀ00thꢀJanuaryꢀ20xx,ꢀ
Acceptedꢀ00thꢀJanuaryꢀ20xxꢀ
a
a
b
a ꢀ
DamianꢀP.ꢀHruszkewycz, ꢀKelseyꢀC.ꢀMiles, ꢀOliverꢀR.ꢀThiel ꢀandꢀShannonꢀS.ꢀStahl* ꢀ
DOI:ꢀ10.1039/x0xx00000xꢀ
Aꢀsimpleꢀcobalt(II)/N-hydroxypthalimideꢀcatalystꢀsystemꢀhasꢀbeenꢀidentifiedꢀforꢀselectiveꢀconversionꢀofꢀbenzylicꢀmethyleneꢀ
groupsꢀ inꢀ pharmaceuticallyꢀ relevantꢀ (hetero)arenesꢀ toꢀ theꢀ correspondingꢀ (hetero)arylꢀ ketones.ꢀ Theꢀ radicalꢀ reactionꢀ
pathwayꢀtoleratesꢀelectronicallyꢀdiverseꢀbenzylicꢀC–Hꢀbonds,ꢀcontrastingꢀrecentꢀoxygenationꢀreactionsꢀthatꢀareꢀinitiatedꢀbyꢀ
deprotonationꢀofꢀaꢀbenzylicꢀC–Hꢀbond.ꢀTheꢀreactionsꢀproceedꢀunderꢀpracticalꢀreactionꢀconditionsꢀ(1ꢀMꢀsubstrateꢀinꢀBuOAcꢀ
orꢀEtOAcꢀsolvent,ꢀ12ꢀhr,ꢀ90-100ꢀ°C),ꢀandꢀtheyꢀtolerateꢀcommonꢀheterocycles,ꢀsuchꢀasꢀpyridinesꢀandꢀimidazoles.ꢀAꢀcobalt-
free,ꢀelectrochemical,ꢀNHPI-catalyzedꢀoxygenationꢀmethodꢀovercomesꢀchallengesꢀencounteredꢀwithꢀchelatingꢀsubstratesꢀ
thatꢀinhibitꢀtheꢀchemicalꢀreaction.ꢀTheꢀutilityꢀofꢀtheꢀaerobicꢀoxidationꢀmethodꢀisꢀshowcasedꢀinꢀtheꢀmultigramꢀsynthesisꢀofꢀaꢀ
keyꢀintermediateꢀtowardsꢀaꢀdrugꢀcandidateꢀ(AMGꢀ579)ꢀunderꢀprocess-relevantꢀreactionꢀconditions.ꢀ
www.rsc.org/ꢀ
reactions,ꢀinꢀparticular,ꢀareꢀrarelyꢀusedꢀforꢀtheꢀproductionꢀofꢀ
pharmaceuticalsꢀorꢀrelatedꢀcomplexꢀmolecules.ꢀꢀ
Aꢀ numberꢀ ofꢀ groupsꢀ haveꢀ recentlyꢀ reportedꢀ methodsꢀ forꢀ
Introductionꢀ
Liquid-phaseꢀ radical-chainꢀ autoxidationꢀ reactionsꢀ areꢀ
amongstꢀ theꢀ largest-scaleꢀ oxidationꢀ reactionsꢀ performedꢀ inꢀ
1
industryꢀ (Schemeꢀ 1). ꢀ Prominentꢀ examplesꢀ includeꢀ theꢀ
5,6
aerobicꢀoxygenationꢀofꢀbenzylicꢀC–Hꢀbonds ꢀ(Schemeꢀ2A).ꢀTheꢀ
reactionsꢀ areꢀ oftenꢀ compatibleꢀ withꢀ heterocyclesꢀ andꢀ otherꢀ
heteroatom-containingꢀ functionalꢀ groups,ꢀ suggestingꢀ theyꢀ
couldꢀ beꢀ wellꢀ suitedꢀ forꢀ useꢀ inꢀ pharmaceuticalꢀ applications.ꢀ
Furtherꢀ studiesꢀ haveꢀ shownꢀ thatꢀ heterocyclesꢀ canꢀ playꢀ anꢀ
importantꢀ roleꢀ inꢀ promotingꢀ theꢀ reactionꢀ byꢀ facilitatingꢀ
formationꢀ ofꢀ anꢀ enamineꢀ orꢀ relatedꢀ tautomerꢀ thatꢀ isꢀ moreꢀ
Co/Mn/Br-catalyzedꢀoxidationꢀofꢀp-xyleneꢀtoꢀterephthalicꢀacidꢀ
2
inꢀ variationsꢀ ofꢀ theꢀ Mid-Centuryꢀ processꢀ (Schemeꢀ 1B), ꢀ
autoxidationꢀofꢀcumeneꢀenꢀrouteꢀtoꢀphenolꢀandꢀacetoneꢀinꢀtheꢀ
3
Hockꢀ processꢀ (Schemeꢀ 1C) ꢀ andꢀ radical-chainꢀ autoxidationꢀ ofꢀ
cyclohexaneꢀtoꢀaꢀmixtureꢀofꢀcyclohexanoneꢀandꢀcyclohexanolꢀ
4
"KAꢀoil",ꢀSchemeꢀ1D). ꢀInꢀcontrastꢀtoꢀtheseꢀprominentꢀlarge-ꢀ
(
7
susceptibleꢀ toꢀ aerobicꢀ oxygenationꢀ (Schemeꢀ 2B). ꢀ ꢀ Inꢀ aꢀ
scaleꢀapplications,ꢀaerobicꢀoxidationsꢀandꢀradicalꢀautoxidationꢀ
ꢀ
representativeꢀ example,ꢀ Maesꢀ andꢀ coworkersꢀ developedꢀ aꢀ
copper-catalysedꢀ oxygenationꢀ method,ꢀ inꢀ whichꢀ theyꢀ
contrastedꢀ successfulꢀ oxygenationꢀ inꢀ 2-ꢀ andꢀ 4-benzylpyridineꢀ
A) General mechanism of radical autoxidation:
O
H
X
X
H
O
6e
O2
oxygenated
product(s)
withꢀ theꢀ poorꢀ reactivityꢀ ofꢀ 3-benzylpyridine. ꢀ Aꢀ subsequentꢀ
mechanisticꢀ studyꢀ providedꢀ evidenceꢀ forꢀ aꢀ heterolyticꢀ C–Hꢀ
cleavageꢀpathwayꢀandꢀtheꢀinvolvementꢀofꢀtheꢀbenzylpyridineꢀ
R1
R2
R1
R2
R1
R2
B) Terephthalic acid synthesis (Mid-Century process):
O
6l
cat. Co(OAc)2/Mn(OAc)2
Me
enamineꢀtautomerꢀ(Schemeꢀ2B). ꢀꢀ
ꢀ
cat. HBr
OH
6
0 x 106 t/a
AcOH/H2O, 180-220 ˚C, HO
Me
A) Aerobic benzylic oxygenations
1
5-30 bar air
O
C) Cumene hydroperoxide synthesis:
O
Various catalysts
Me
OOH
Me
Me
(Het)Ar
R
(Het)Ar
R
Δ, O2
Me
initiator
7 x 106 t/a
1
1
00-140 ˚C, 6-7 bar air
B) Implications of heterolytic C–H cleavage pathway (cf. Maes, ref. 4e):
O
D) Cyclohexane oxidation to KA oil:
H
N
O
OH
N
cat. [Cu]
N
8
0%
Ph
Ph
Ph
cat. CoX2 or no catalyst
isolated
7 x 106 t/a
Δ, O2
+
1
50-180 ˚C, 10-20 bar air
ꢀ
2
-benzylpyridine: Imine-enamine tautomerization precedes oxygenation
Schemeꢀ1.ꢀSummaryꢀofꢀmajorꢀindustrialꢀradicalꢀautoxidationꢀprocesses.ꢀ
H
N
N
N
H
cat. [Cu]
0
%
Ph
Ph
Ph
Δ, O2
O
3-benzylpyridine: Tautomerization inaccessible
ꢀ
Schemeꢀ2.ꢀRecentꢀworkꢀonꢀaerobicꢀbenzylicꢀoxygenation.ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ1ꢀꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Pleas Ce hꢀ d eo mꢀ ni oc ta ꢀ la dS jcu i se t nꢀ mc ea rginsꢀ
Page 2 of 6
ARTICLEꢀ
Theꢀ "heterolytic"ꢀ C–Hꢀ oxygenationꢀ reactionsꢀ showꢀ broadꢀ
JournalꢀNameꢀ
a
Tableꢀ1.ꢀOptimizationꢀofꢀreactionꢀconditions. ꢀ
View Article Online
O
DOI: 10.1039/C6SC03831J
syntheticꢀ appeal,ꢀ butꢀ theꢀ mechanismꢀ limitsꢀ theirꢀ utilityꢀ toꢀ
substratesꢀ withꢀ relativelyꢀ acidicꢀ benzylicꢀ C–Hꢀ bonds.ꢀ Inꢀ thisꢀ
context,ꢀ weꢀ soughtꢀ anꢀ alternativeꢀ methodꢀ thatꢀ couldꢀ bypassꢀ
thisꢀ limitation,ꢀ andꢀ ourꢀ attentionꢀ wasꢀ drawnꢀ toꢀ theꢀ N-
1
mol% CoX2
Me
Me
2
0 mol% NHPI
N
1 M, 12 hr, solvent,
temp, 1 atm O2
N
1
a
2a
8
entry
CoX2
solvent
temp (˚C)
conv. (%)b yield (%)b
hydroxypthalimideꢀ (NHPI)-basedꢀ C–Hꢀ oxygenationꢀ reactions. ꢀ
1
2
3
4
5
6
7
8
9
Co(OAc)2•4H2O
--
EtOAc
EtOAc
MeCN
AcOH
70
70
70
70
70
70
70
70
80
90
60
<1
50
35
61
35
<1
14
95
99
59
<1
45
30
59
35
<1
14
89
94
Inꢀ theꢀ 1990s,ꢀ Ishiiꢀ andꢀ coworkersꢀ showedꢀ thatꢀ useꢀ ofꢀ redox-
activeꢀ metalꢀ salts,ꢀ suchꢀ asꢀ Co(OAc)2,ꢀ inꢀ combinationꢀ withꢀ O2ꢀ
enableꢀ efficientꢀ conversionꢀ ofꢀ NHPIꢀ intoꢀ theꢀ phthalimido-N-
Co(OAc)2•4H2O
Co(OAc)2•4H2O
Co(OAc)2•4H2O
Co(NO ) •6H O
9
oxylꢀ(PINO)ꢀradical. ꢀPINOꢀthenꢀmediatesꢀselectiveꢀabstractionꢀ
ofꢀweakꢀC–Hꢀbondsꢀ(Schemeꢀ3)ꢀtoꢀgenerateꢀanꢀorganicꢀradicalꢀ
BuOAc
BuOAc
BuOAc
BuOAc
BuOAc
BuOAc
3
2
2
1
0
thatꢀ canꢀ reactꢀ withꢀ O2ꢀ toꢀ affordꢀ theꢀ oxygenatedꢀ products. ꢀ
Thisꢀ methodologyꢀ hasꢀ beenꢀ demonstratedꢀ inꢀ numerousꢀ
Co(acac)2
Co(Cl)2 6H2O
8
oxidationꢀreactions,ꢀincludingꢀindustrialꢀapplications, ꢀbutꢀtheꢀ
Co(OAc)2•4H2O
1
0
Co(OAc)2•4H2O
vastꢀmajorityꢀofꢀstudiesꢀhaveꢀfocusedꢀonꢀsimpleꢀhydrocarbonꢀ
a
b
ꢀ
1
ꢀmmolꢀscale,ꢀorbitalꢀmixing.ꢀ ꢀGCꢀyieldsꢀwithꢀbenzonitrileꢀasꢀanꢀinternalꢀstandard.ꢀ
11
substrates. ꢀꢀ
ꢀ
[Co]/O2
a
Tableꢀ2.ꢀComparisonꢀofꢀcatalystꢀsystems. ꢀ
O
O
O
H
Me
Me
catalyst system
N
O
N O
N
1 atm O2
N
PINO
O
NHPI
O
1a
2a
H
O
R
conv. (%)b yield (%)b
O
O
O2
entry
catalyst system
ref.
(Het)Ar
R
(
Het)Ar
R
Co/Brc
Co/Mn/Brd
CuI, 1 eq AcOHe
FeCl2•4H2O, 1 eq AcOHf
13
51
20
5
19
<1
<1
<1
94
(
Het)Ar
(Het)Ar
R
1
2
3
4
5
ꢀ
13
6e
Schemeꢀ3.ꢀSimplifiedꢀmechanismꢀdepictingꢀC–Hꢀabstractionꢀbyꢀphthalimido-
N-oxylꢀ(PINO)ꢀandꢀradicalꢀoxygenationꢀbyꢀO .ꢀ
2
6e
7
ꢀ
12
Co/NHPIg
This work
99
Here,ꢀweꢀexploreꢀCo/NHPI-catalyzedꢀbenzylic ꢀoxygenationꢀ
reactionsꢀofꢀsubstratesꢀbearingꢀcommonꢀheterocycles,ꢀsuchꢀasꢀ
ꢀ
c
a
b
1
ꢀmmolꢀscale,ꢀorbitalꢀmixing.ꢀ ꢀGCꢀyieldsꢀwithꢀbenzonitrileꢀasꢀanꢀinternalꢀstandard.ꢀ 1ꢀ
d
mmolꢀ1a,ꢀ1ꢀmLꢀAcOH,ꢀ10ꢀmol%ꢀCo(OAc)
·4H O,ꢀ5ꢀmol%ꢀMn(OAc)
C.ꢀ 0.5ꢀmmolꢀ1a,ꢀ1ꢀmLꢀDMSO,ꢀ10ꢀmol%ꢀCuI,ꢀꢀ1ꢀeqꢀAcOH,ꢀ1ꢀatmꢀO
mmolꢀ1a,ꢀ1ꢀmLꢀDMSO,ꢀ10ꢀmol%ꢀFeCl ·4H O,ꢀꢀ1ꢀeqꢀAcOH,ꢀ24ꢀhr,ꢀ100ꢀ°C.ꢀ 1ꢀmmolꢀ1a,ꢀ1ꢀ
O,ꢀ20ꢀmol%ꢀNHPI,ꢀ12ꢀhr,ꢀ90ꢀ°C.ꢀ
2
·4H
2
O,ꢀ10ꢀmol%ꢀHBr,ꢀ12ꢀhr,ꢀ100ꢀ°C.ꢀ 1ꢀmmolꢀ1a,ꢀ
·4H O,ꢀ10ꢀmol%ꢀHBr,ꢀ12ꢀhr,ꢀ100ꢀ
pyridines,ꢀ benzimidazolesꢀ andꢀ thiophenes,ꢀ andꢀ benzylicꢀ 1ꢀmLꢀAcOH,ꢀ5ꢀmol%ꢀCo(OAc)
2
2
2
2
e
f
°
2
,ꢀ24 hr,ꢀ100ꢀ°C.ꢀ 0.5ꢀ
ꢀ
ketonesꢀareꢀoftenꢀobtainedꢀinꢀgood-to-excellentꢀyield.ꢀNotably,ꢀ
theꢀradicalꢀautoxidationꢀpathwayꢀenablesꢀoxygenationꢀofꢀnon-
acidicꢀsubstratesꢀthatꢀareꢀineffectiveꢀwithꢀcatalystꢀsystemsꢀthatꢀ
mediateꢀoxygenationꢀviaꢀaꢀ‘heterolytic’ꢀpathway.ꢀForꢀreactionsꢀ
thatꢀappearꢀtoꢀbeꢀinhibitedꢀbyꢀheterocycleꢀchelationꢀtoꢀtheꢀCoꢀ
co-catalyst,ꢀ weꢀ showꢀ thatꢀ aꢀ Co-free,ꢀ electrochemicalꢀ NHPI-
mediatedꢀ methodꢀ offersꢀ aꢀ promisingꢀ alternativeꢀ approach.ꢀ
Finally,ꢀweꢀdemonstrateꢀtheꢀpracticalityꢀandꢀscalabilityꢀofꢀtheꢀ
Co/NHPIꢀ catalyticꢀ conditionsꢀ inꢀ theꢀ multigramꢀ synthesisꢀ ofꢀ aꢀ
pharmaceuticalꢀintermediate.ꢀ
g
2
2
mLꢀBuOAc,ꢀ1ꢀmol%ꢀCo(OAc)
ꢀ
2 2
·4H
ꢀ
Aꢀ comparisonꢀ ofꢀ theꢀ optimizedꢀ Co/NHPIꢀ reactionꢀ
conditionsꢀ withꢀ previouslyꢀ reportedꢀ benzylicꢀ oxygenationꢀ
methodsꢀinꢀTableꢀ2ꢀhighlightsꢀtheꢀpotentialꢀutilityꢀofꢀtheꢀnewꢀ
conditions.ꢀPoorꢀyieldsꢀandꢀmassꢀbalancesꢀwereꢀobtainedꢀusingꢀ
twoꢀMid-Century-typeꢀradicalꢀautoxidationꢀmethodsꢀ(Entriesꢀ1-
1
4
2
theꢀ H-atomꢀ abstractionꢀ step.ꢀ Weꢀ alsoꢀ testedꢀ representativeꢀ
), ꢀinꢀwhichꢀaꢀbromineꢀradicalꢀisꢀproposedꢀtoꢀparticipateꢀinꢀ
6e
Resultsꢀandꢀdiscussionꢀ
catalystꢀ systems ꢀ forꢀ "heterolytic"ꢀ aerobicꢀ C–Hꢀ oxygenation,ꢀ
Weꢀbeganꢀourꢀstudiesꢀbyꢀevaluatingꢀtheꢀoxygenationꢀofꢀ3- correspondingꢀtoꢀtheꢀmethodsꢀnotedꢀinꢀSchemeꢀ2.ꢀAsꢀexpectedꢀ
ethylpyridineꢀ (1a)ꢀ toꢀ 3-acetylpyridineꢀ (2a)ꢀ (Tableꢀ 1).ꢀ Thisꢀ fromꢀ theꢀ precedents,ꢀ 3-ethylpyridineꢀ 1aꢀ isꢀ notꢀ aꢀ viableꢀ
1
5
reactionꢀ isꢀ expectedꢀ toꢀ beꢀ problematicꢀ forꢀ manyꢀ ofꢀ theꢀ substrateꢀwithꢀtheseꢀcatalystꢀsystemsꢀ(Entriesꢀ3-4). ꢀꢀ
recentlyꢀ reportedꢀ oxygenationꢀ methods.ꢀ First,ꢀ weꢀ usedꢀ
Theꢀ optimizedꢀ reactionꢀ conditionsꢀ wereꢀ thenꢀ testedꢀ forꢀ
Co(OAc)2ꢀ asꢀ theꢀ cobaltꢀ sourceꢀ andꢀ comparedꢀ solventsꢀ thatꢀ aerobicꢀoxygenationꢀofꢀaꢀnumberꢀofꢀpharmaceutically-relevantꢀ
1
6
haveꢀ beenꢀ consideredꢀ previouslyꢀ inꢀ Ishii-typeꢀ oxidationꢀ (hetero)areneꢀsubstratesꢀ(Tableꢀ3). ꢀInꢀgeneral,ꢀpyridinesꢀareꢀ
13
reactionsꢀ(entriesꢀ1-4). ꢀAꢀsuperiorꢀyieldꢀwasꢀobtainedꢀusingꢀ wellꢀ tolerated,ꢀ withꢀ good-to-excellentꢀ yieldsꢀ obtainedꢀ forꢀ
EtOAcꢀ (entryꢀ 1),ꢀ andꢀ aꢀ similarꢀ yieldꢀ wasꢀ obtainedꢀ withꢀ theꢀ productsꢀ 2a–f.ꢀ Thisꢀ collectionꢀ ofꢀ substratesꢀ includesꢀ 3-
higherꢀboilingꢀesterꢀsolvent,ꢀn-BuOAcꢀ(entryꢀ5).ꢀTheꢀidentityꢀofꢀ substitutedꢀ pyridineꢀ derivativesꢀ (1a,ꢀ 1c,ꢀ 1f),ꢀ whichꢀ areꢀ
theꢀcounterionꢀinꢀtheꢀCoX2ꢀco-catalystꢀhadꢀaꢀmarkedꢀeffectꢀonꢀ ineffectiveꢀwithꢀheterolyticꢀC–Hꢀoxygenationꢀmethods,ꢀasꢀwellꢀ
catalyticꢀ efficiencyꢀ (entriesꢀ 5-10).ꢀ Theꢀ bestꢀ yieldsꢀ wereꢀ asꢀ2-ꢀandꢀ4-substitutedꢀpyridines,ꢀwhichꢀareꢀcompatibleꢀwithꢀ
II
obtainedꢀwithꢀCo(OAc)2·4H2OꢀandꢀotherꢀCo -carboxylateꢀsaltsꢀ theꢀheterolyticꢀmethods.ꢀExcellentꢀyieldsꢀwereꢀobtainedꢀforꢀtheꢀ
(
seeꢀTablesꢀS1ꢀandꢀS2ꢀinꢀtheꢀESI†ꢀforꢀfullꢀscreeningꢀdata).ꢀUseꢀofꢀ benzimidazoleꢀderivativesꢀ1gꢀandꢀ1h.ꢀEthylbenzeneꢀderivativesꢀ
BuOAcꢀsolventꢀenabledꢀaccessꢀtoꢀhigherꢀreactionꢀtemperaturesꢀ bearingꢀ remoteꢀ heteroatom-containingꢀ functionalꢀ groups,ꢀ
entriesꢀ9-10),ꢀandꢀanꢀexcellentꢀyieldꢀofꢀ2aꢀwasꢀachievedꢀatꢀ90ꢀ includingꢀaꢀpyridyl,ꢀanꢀimidazoleꢀandꢀanꢀacetamideꢀgroupꢀ(1i,ꢀ
(
°
Cꢀ(94%,ꢀentryꢀ10).ꢀ
1j,ꢀandꢀ1k),ꢀalsoꢀunderwentꢀsuccessfulꢀoxygenation.ꢀꢀ
2
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
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Page 3 of 6
Pleas Ce hꢀ d eo mꢀ ni oc ta ꢀ la dS jcu i se t nꢀ mc ea rginsꢀ
JournalꢀNameꢀ
ꢀARTICLEꢀ
a
a
Tableꢀ3.ꢀOxygenationꢀofꢀpolarꢀ(hetero)arenes. ꢀ
Tableꢀ5.ꢀUseꢀofꢀpyridineꢀco-solventꢀforꢀimprovedꢀselectivity. ꢀ
View Article Online
DOI: 10.1039/C6SC03831J
1
mol% Co(OAc)2•4H2O
0 mol% NHPI
O
1 mol% Co(OAc)2•4H2O
O
2
20 mol% NHPI
(Het)Ar
R
(Het)Ar
R
(Het)Ar
R
(Het)Ar
R
1
M, BuOAc, 12 hr,
1 M, 7:3 BuOAc:pyr, 12 hr
90 ˚C, 1 atm O2
1
90-100 ˚C, 1 atm O2
2
1
2
O
O
O
O
O
O
S
2m 65% (65%)
2n 50% (48%)
w/o pyr 7%
Me
Ph
Ph
Ph
n-Pent
n-Pent
S
w/o pyr 3%
N
N
N
N
2
a 84%
2b 93%
O
2c 92%
2d 89%
O
Me
O
S
2o 72% (64%)
w/o pyr 31%
N
2p 94% (80%)
w/o pyr 58%
Ph
Ph
O
O
H
N
N
N
2g, R = H
94%
Me
n-Pr
2
h, R = OMe 92%
ꢀ
N
N
O
a
1
N
R
1ꢀmmolꢀscale.ꢀYieldsꢀwereꢀdeterminedꢀbyꢀ HꢀNMRꢀspectroscopy.ꢀIsolatedꢀyieldsꢀinꢀ
parentheses.ꢀ
2
e 56%
2f 60%
ꢀ
O
O
Theꢀ secondꢀ caseꢀ involvedꢀ 2-ethylpyridineꢀ (1q)ꢀ andꢀ 2-
ethylbenzimidazoleꢀ (1r),ꢀ inꢀ whichꢀ theꢀ benzylicꢀ C–Hꢀ bondsꢀ ofꢀ
theꢀ ethylꢀ substituentꢀ isꢀ directlyꢀ adjacentꢀ toꢀ aꢀ coordinatingꢀ
group.ꢀUnderꢀtheꢀstandardꢀconditions,ꢀtheꢀbenzylicꢀketonesꢀ2qꢀ
andꢀ2rꢀwereꢀobtainedꢀinꢀonlyꢀ48%ꢀandꢀ15%ꢀyields,ꢀrespectivelyꢀ
Me
Me
Me
Ac
N
N
N
H
N
2
i 87%
2j 66%
2k 74%
ꢀ
a
1
ꢀmmolꢀscale,ꢀisolatedꢀyields.ꢀ
ꢀ
ꢀ
(Schemeꢀ4A).ꢀThisꢀpoorꢀreactivityꢀcontrastsꢀtheꢀgoodꢀreactivityꢀ
observedꢀwithꢀanalogousꢀdoublyꢀbenzylicꢀsubstratesꢀ1b,ꢀ1gꢀandꢀ
Theꢀ standardꢀ reactionꢀ conditionsꢀ inꢀ Tableꢀ 3ꢀ provedꢀ toꢀ beꢀ
1
hꢀ inꢀ Tableꢀ 3.ꢀ Weꢀ hypothesizedꢀ that,ꢀ inꢀ theseꢀ reactions,ꢀ theꢀ
17
ineffectiveꢀ forꢀ certainꢀ substrates, ꢀ andꢀ twoꢀ differentꢀ
approachesꢀ wereꢀ identifiedꢀ toꢀ addressꢀ someꢀ ofꢀ theseꢀ
limitations.ꢀ Inꢀ theꢀ firstꢀ case,ꢀ theꢀ simpleꢀ hydrocarbon,ꢀ n-
butylbenzeneꢀ(1l)ꢀ(Tableꢀ4),ꢀasꢀwellꢀasꢀtheꢀsulphur-containingꢀ
heterocyclicꢀ substratesꢀ1m,ꢀ 1n,ꢀ andꢀ 1oꢀ (Tableꢀ 5)ꢀ ledꢀ toꢀ poorꢀ
resultsꢀ (42%,ꢀ 3%,ꢀ 7%,ꢀ andꢀ 31%ꢀ yields,ꢀ respectively).ꢀ Inꢀ theꢀ
reactionꢀ ofꢀ 1l,ꢀ benzoicꢀ acidꢀ wasꢀ observedꢀ asꢀ theꢀ majorꢀ sideꢀ
product,ꢀarisingꢀfromꢀcleavageꢀofꢀtheꢀalkylꢀchain.ꢀSubsequentꢀ
empiricalꢀstudiesꢀshowedꢀthatꢀuseꢀofꢀpyridineꢀasꢀaꢀco-solventꢀ
attenuatedꢀthisꢀalkylꢀchainꢀcleavageꢀandꢀenabledꢀhigherꢀyieldsꢀ
andꢀ massꢀ balanceꢀ inꢀ theꢀ oxygenationꢀ ofꢀ 1l.ꢀ Theꢀ optimalꢀ 7:3ꢀ
BuOAc:pyrꢀsolventꢀmixtureꢀ(77%ꢀyieldꢀofꢀ2l,ꢀentryꢀ4)ꢀprovedꢀtoꢀ
beꢀ similarlyꢀ beneficialꢀ forꢀ theꢀ oxygenationꢀ ofꢀ theꢀ sulphur-
heterocycleꢀsubstratesꢀ1m,ꢀ1n,ꢀandꢀ1oꢀandꢀtheꢀN-methylatedꢀ
productꢀcouldꢀchelateꢀtheꢀcobaltꢀco-catalystꢀandꢀinhibitꢀfurtherꢀ
productꢀformation.ꢀToꢀtestꢀthisꢀhypothesis,ꢀweꢀinvestigatedꢀtheꢀ
reactionꢀ ofꢀ anꢀ effectiveꢀ substrate,ꢀ 4-ethylpyridineꢀ 1e,ꢀ inꢀ theꢀ
presenceꢀ andꢀ absenceꢀ ofꢀ 4-acetylpyridineꢀ 2eꢀ orꢀ 2-
acetylpyridineꢀ2qꢀ(Schemeꢀ4B).ꢀTheꢀresultsꢀshowꢀthatꢀ2eꢀhasꢀ
minimalꢀ impactꢀ onꢀ theꢀ reactionꢀ (Schemeꢀ 4B,ꢀ entriesꢀ 1-3),ꢀ
whereasꢀtheꢀpresenceꢀofꢀ2qꢀsignificantlyꢀlowersꢀtheꢀyieldꢀinꢀtheꢀ
oxygenationꢀofꢀ1eꢀ(Schemeꢀ4B,ꢀentriesꢀ1ꢀandꢀ4-5).ꢀꢀ
ꢀ
A) Results under standard conditions (cf. Table 3)
O
O
H
N
Me
Me
N
N
2
q, 48%
2r, 15%
18
benzimidazoleꢀ1pꢀ(Tableꢀ5). ꢀTheꢀlatterꢀsubstratesꢀunderwentꢀ B) Product inhibition studies
O
oxygenationꢀ inꢀ 65%,ꢀ 50%,ꢀ 72%,ꢀ andꢀ 80%ꢀ yields,ꢀ respectively.ꢀ
Theꢀreactionsꢀwithꢀpyridineꢀco-solventꢀhaveꢀaꢀdarkꢀredꢀcolor,ꢀ
O
1
mol% Co(OAc)2•4H2O
20 mol% NHPI
Me
Me
Me
±
19
N
N
consistentꢀ withꢀ pyridineꢀ coordinationꢀ toꢀ cobalt. ꢀ Weꢀ
speculateꢀthatꢀthisꢀcoordinationꢀmightꢀattenuateꢀunproductiveꢀ
2e or 2q added, 12 hr,
00 °C, 1 atm O2
N
1
e
2q
2
e
1
1 M in BuOAc
cobalt-mediatedꢀsideꢀreactionsꢀinꢀtheseꢀsubstrates.ꢀ
ꢀ
ꢀ
conditionsa
conv. (%)b
yield 2e (%)b
entry
1
2
3
4
5
no additive
0.1 M 2e
0.25 M 2e
0.1 M 2q
82
79
74
11
3
66
63
57
7
Tableꢀ4.ꢀEnhancedꢀselectivityꢀforꢀformationꢀofꢀ2lꢀinꢀtheꢀpresenceꢀofꢀpyridineꢀ
a
cosolvent. ꢀ
1
mol% Co(OAc)2•4H2O
0 mol% NHPI
O
2
0.25 M 2q
1
ꢀ
Ph
Me
Ph
Me
a
b
1
2 h, 90 °C, 1 atm O2
1ꢀmmolꢀscale,ꢀorbitalꢀmixing.ꢀ ꢀGCꢀyieldsꢀwithꢀchlorobenzeneꢀasꢀanꢀinternalꢀstandard.ꢀ
1
l
2l
1
M
BuOAc:pyr (0-50 vol% pyr)
a
Schemeꢀ4.ꢀProduct-inhibitionꢀstudiesꢀinꢀCo/NHPI-catalyzedꢀoxygenation. ꢀꢀ
entry
vol% pyr
conv. (%)b
yield (%)b
ꢀ
Theꢀ observationsꢀ inꢀ Schemeꢀ 4ꢀ promptedꢀ usꢀ toꢀ considerꢀ
1
2
3
4
5
6
0
>99
98
95
90
84
74
42
74
76
77
73
66
10
20
30
40
cobalt-freeꢀ electrochemicalꢀ aerobicꢀ oxygenationꢀ reactions,ꢀ
20,21
originallyꢀreportedꢀbyꢀMasuiꢀandꢀcoworkersꢀinꢀtheꢀ1980s.
ꢀ
TheseꢀmethodsꢀgenerateꢀPINOꢀviaꢀelectrochemicalꢀoxidationꢀofꢀ
NHPIꢀ(i.e.,ꢀinꢀtheꢀabsenceꢀofꢀcobaltꢀions)ꢀand,ꢀtherefore,ꢀshouldꢀ
notꢀ beꢀ susceptibleꢀ toꢀ chelate-inhibitionꢀ byꢀ theꢀ product.ꢀ
Preliminaryꢀstudiesꢀvalidatedꢀthisꢀhypothesis.ꢀOptimizationꢀofꢀꢀ
ꢀ
50
ꢀ
a
b
1
ꢀmmolꢀscale,ꢀorbitalꢀmixing.ꢀ ꢀGCꢀyieldsꢀwithꢀbenzonitrileꢀasꢀanꢀinternalꢀstandard.ꢀ
ꢀ
ꢀ
ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ3ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Pleas Ce hꢀ d eo mꢀ ni oc ta ꢀ la dS jcu i se t nꢀ mc ea rginsꢀ
Page 4 of 6
ARTICLEꢀ
JournalꢀNameꢀ
1
mol% Co(OAc)2•4H2O
0 mol% NHPI
M, BuOAc, 12 hr,
ꢀ
View Article Online
DOI: 10.1039/C6SC03831J
2
Co/NHPI
A) Retrosynthesis of AMG 579
1
O
O
1
00 ˚C, 1 atm O2
H
N
N
O
(Het)Ar
R
(Het)Ar
R
H
N
N
N
1
20 mol% NHPI
2
O
2
0 mol% pyr
.1 M, 1:1 MeCN:Acetone,
.1 M TBAP, RVC|Pt,
N
NHPI/E-chem
F
0
AMG 579: Potent inhibitor of
Phosphodiesterase 10A for
the treatment of schizophrenia.
2
r
0
N
Ac
1
8 hr, 50 ˚C, 1 atm O2
O
O
H
N
Co/NHPI: 48%
Co/NHPI: 15%
Me
Me
B) Amgen process route to access the ketone 2r
NHPI/E-chem: 82%
NHPI/E-chem: 70%
N
N
2
q
2r
O
1
2
. CH(OEt)3, cat. HCl
. DIPA
H
N
N
Co
e-
O
3. 4-Fluorobenzonitrile, THF
4. LDA, THF, -25 ˚C
5. HCl/IPA
N
Co/NHPI:
product chelation
reaction inhibition
NHPI/E-chem:
no product
inhibition
NHPI
N
H
-
F
N
- e
Me
-
H+
2r 82%
PINO
ꢀ
C) Co/NHPI oxygenation route to 2r
ꢀ
NH2
Schemeꢀ5.ꢀOvercomingꢀaꢀlimitationꢀinꢀCo/NHPIꢀchemistryꢀthroughꢀtheꢀ
HO C
2
+
electrochemicalꢀgenerationꢀofꢀPINO.ꢀ
NH2
F
ꢀ
Δ
Masui'sꢀ reportedꢀ electrochemicalꢀ conditionsꢀ withꢀ 1qꢀ andꢀ 1rꢀ
enabledꢀ formationꢀ ofꢀ theꢀ ketoneꢀ productsꢀ 2qꢀ andꢀ 2rꢀ inꢀ 82%ꢀ
andꢀ 70%ꢀ yields,ꢀ respectively.ꢀ Theseꢀ resultsꢀ representꢀ
substantialꢀ improvementsꢀ overꢀ thoseꢀ obtainedꢀ withꢀ theꢀ
chemicalꢀconditionsꢀ(Schemeꢀ5).ꢀFurtherꢀstudiesꢀwillꢀbeꢀneededꢀ
toꢀexploreꢀtheꢀfullꢀscopeꢀandꢀlimitationsꢀofꢀtheꢀelectrochemicalꢀ
method.ꢀPreliminaryꢀstudiesꢀwithꢀotherꢀsubstratesꢀ(e.g.,ꢀwithꢀ
H
N
N
F
1
r
1
mol%
Co(OAc)2•4H2O
1 M, EtOAc
12 hr, 90 ˚C
9% O /N
2
2
2
0 mol% NHPI
(
500 psi)
1
bꢀ andꢀ 1g)ꢀ suggestꢀ thatꢀ theꢀ chemicalꢀ conditionsꢀ willꢀ beꢀ
superiorꢀ toꢀ theꢀ electrochemicalꢀ conditionsꢀ inꢀ otherꢀ cases.ꢀ
Theseꢀobservationsꢀtogetherꢀwithꢀtheꢀeaseꢀofꢀreactionꢀsetꢀupꢀ
andꢀperformanceꢀofꢀtheꢀCo/NHPI/O2ꢀoxygenationsꢀsuggestꢀthatꢀ
theꢀ aerobicꢀ reactionsꢀ willꢀ beꢀ advantageousꢀ inꢀ mostꢀ cases.ꢀ
Nonetheless,ꢀ theꢀ resultsꢀ withꢀ theꢀ oxygenationꢀ ofꢀ 1qꢀ andꢀ 1rꢀ
demonstrateꢀ thatꢀ electrochemicalꢀ NHPI-mediatedꢀ reactionsꢀ
couldꢀ beꢀ aꢀ valuableꢀ complementꢀ toꢀ Co/NHPIꢀ reactionsꢀ inꢀ
strategicꢀsituations.ꢀ
O
H
N
N
F
g scale
2r 95%
2
ꢀ
Schemeꢀ6.ꢀStreamlinedꢀsyntheticꢀrouteꢀtowardꢀAMGꢀ579ꢀviaꢀCo/NHPI-
catalyzedꢀbenzylicꢀoxygenation.ꢀꢀ
ꢀ
Thisꢀrouteꢀtoꢀ2sꢀincorporatesꢀaꢀnumberꢀestablishedꢀgreenꢀ
Theꢀ standardꢀ Co/NHPI/O2ꢀ conditionsꢀ developedꢀ hereꢀ
exhibitꢀaꢀnumberꢀofꢀfeaturesꢀthatꢀareꢀappealingꢀfromꢀaꢀprocessꢀ
chemistryꢀperspective,ꢀincludingꢀaꢀlowꢀcobaltꢀcatalystꢀloadingꢀ
andꢀ aꢀ highꢀ reactionꢀ concentration,ꢀ whichꢀ minimizesꢀ solventꢀ
volume.ꢀTheꢀrelativelyꢀhighꢀNHPIꢀloadingꢀ(20ꢀmol%)ꢀisꢀoffsetꢀbyꢀ
itsꢀextraordinarilyꢀlowꢀcostꢀ(<$5/kgꢀonꢀcommercialꢀscale).ꢀꢀInꢀanꢀ
effortꢀtoꢀdemonstrateꢀtheꢀpotentialꢀutilityꢀofꢀthisꢀmethodꢀforꢀ
larger-scaleꢀ applications,ꢀ weꢀ targetedꢀ aꢀ streamlinedꢀ routeꢀ toꢀ
theꢀ heterocyclicꢀ ketoneꢀ 2sꢀ (Schemeꢀ 6A),ꢀ anꢀ intermediateꢀ enꢀ
25
chemistryꢀ principles: ꢀ (i)ꢀ wasteꢀ preventionꢀ dueꢀ toꢀ highꢀ
volumetricꢀefficiency,ꢀ(ii)ꢀatomꢀeconomyꢀdueꢀtoꢀuseꢀofꢀO2ꢀasꢀ
bothꢀtheꢀterminalꢀoxidantꢀandꢀoxygenꢀatomꢀsource,ꢀ(iii)ꢀuseꢀofꢀ
26
anꢀenvironmentallyꢀbenignꢀesterꢀsolvent, ꢀ(iv)ꢀuseꢀofꢀanꢀearth-
abundantꢀ metalꢀ catalyst,ꢀ (v)ꢀ applicationꢀ ofꢀ practicalꢀ reactionꢀ
conditionsꢀwithꢀrespectꢀtoꢀtemperatureꢀandꢀpressure,ꢀasꢀwellꢀ
asꢀ(vi)ꢀapplicationꢀofꢀinherentlyꢀsafeꢀreactionꢀconditionsꢀ(i.e.,ꢀ
belowꢀ theꢀ LOCꢀ ofꢀ EtOAc).ꢀ Althoughꢀ moreꢀ thoroughꢀ analysisꢀ
wouldꢀbeꢀrequiredꢀtoꢀcompareꢀtheꢀoverallꢀprocessꢀviabilityꢀofꢀ
theꢀ twoꢀ routes,ꢀ theꢀ two-stepꢀ condensation/oxidationꢀ
sequenceꢀ inꢀ Schemeꢀ 6Cꢀ shouldꢀ haveꢀ aꢀ muchꢀ smallerꢀ
environmentalꢀfootprint,ꢀowingꢀtoꢀtheꢀformationꢀofꢀwaterꢀasꢀaꢀ
2
2
routeꢀ toꢀ AMGꢀ 579. ꢀ Theꢀ latterꢀ compoundꢀ isꢀ aꢀ clinicalꢀ
candidateꢀforꢀtheꢀtreatmentꢀofꢀneurologicalꢀconditionsꢀsuchꢀasꢀ
schizophreniaꢀ andꢀ Huntington’sꢀ disease.ꢀ Theꢀ reportedꢀ multi-
stepꢀrouteꢀtoꢀ2rꢀisꢀeffective,ꢀbutꢀitꢀisꢀoperationallyꢀcomplexꢀandꢀ
requiresꢀ carefulꢀ controlꢀ ofꢀ reactionꢀ temperatureꢀ duringꢀ theꢀ
2
7
onlyꢀstoichiometricꢀby-productꢀinꢀeachꢀofꢀtheꢀtwoꢀreactions. ꢀ
Reflectingꢀ thisꢀ feature,ꢀ theꢀ routeꢀ inꢀ Schemeꢀ 6Bꢀ hasꢀ anꢀ
estimatedꢀ E-factorꢀ ofꢀ >15,ꢀ whileꢀ theꢀ two-stepꢀ
2
3
deprotonationꢀandꢀadditionꢀ(Schemeꢀ6B). ꢀWeꢀenvisionedꢀanꢀ
alternative,ꢀ two-stepꢀ routeꢀ toꢀ 2s,ꢀ startingꢀ fromꢀ theꢀ
inexpensive,ꢀ commerciallyꢀ availableꢀ precursorsꢀ o-phenyleneꢀ
diamineꢀ andꢀ 4-fluorophenylaceticꢀ acidꢀ (Schemeꢀ 6C).ꢀ Theꢀ
Co/NHPI-catalyzedꢀoxygenationꢀofꢀ1sꢀwasꢀperformedꢀinꢀEtOAcꢀ
28
condensation/oxidationꢀsequenceꢀcanꢀbeꢀ<5. ꢀꢀ
Conclusionsꢀ
(
concentrationꢀ belowꢀ theꢀ limitingꢀ oxygenꢀ concentrationꢀ (LOC)ꢀ
1ꢀ M)ꢀ withꢀ 500ꢀ psiꢀ ofꢀ 9%ꢀ O2ꢀ inꢀ N2ꢀ toꢀ maintainꢀ theꢀ O2ꢀ
TheꢀresultsꢀdescribedꢀhereinꢀrepresentꢀshowꢀthatꢀCo/NHPI-
catalyzed,ꢀ radical-mediated,ꢀ benzylicꢀ aerobicꢀ oxygenationꢀ
reactionsꢀ areꢀ quiteꢀ effectiveꢀ withꢀ pharmaceuticallyꢀ relevantꢀ
2
4
ofꢀEtOAc. ꢀOperationꢀofꢀthisꢀreactionꢀonꢀ2ꢀgꢀscaleꢀresultedꢀinꢀ
nearꢀquantitativeꢀisolatedꢀyieldꢀofꢀ2rꢀ(95%).ꢀ
4
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
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Page 5 of 6
Pleas Ce hꢀ d eo mꢀ ni oc ta ꢀ la dS jcu i se t nꢀ mc ea rginsꢀ
JournalꢀNameꢀ
ꢀARTICLEꢀ
heterocyclicꢀsubstrates.ꢀTheꢀcomparativelyꢀnon-polarꢀnatureꢀofꢀ ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
View Article Online
DOI: 10.1039/C6SC03831J
theꢀH-atomꢀtransferꢀstepꢀmediatedꢀbyꢀPINOꢀplaysꢀanꢀimportantꢀ
roleꢀinꢀexpandingꢀtheꢀscopeꢀofꢀaerobicꢀbenzylicꢀoxygenationꢀtoꢀ
substratesꢀthatꢀareꢀineffectiveꢀwithꢀcomplementaryꢀheterolyticꢀ
Synthesis,ꢀ2013,ꢀ45,ꢀ1701;ꢀꢀ(i)ꢀY.ꢀJeong,ꢀY.ꢀMoonꢀandꢀS.ꢀHong,ꢀ
Org.ꢀLett.,ꢀ2015,ꢀ17,ꢀ3252;ꢀꢀ(j)ꢀJ.-W.ꢀYu,ꢀS.ꢀMaoꢀandꢀY.-Q.ꢀWang,ꢀ
TetrahedronꢀLett.,ꢀ2015,ꢀ56,ꢀ1575;ꢀꢀ(k)ꢀG.ꢀZheng,ꢀH.ꢀLiuꢀandꢀM.ꢀ
Wang,ꢀ Chin.ꢀ J.ꢀ Chem.,ꢀ 2016,ꢀ 34,ꢀ 519;ꢀ ꢀ (l)ꢀ H.ꢀ Sterckx,ꢀ J.ꢀ Deꢀ
Houwer,ꢀC.ꢀMensch,ꢀI.ꢀCaretti,ꢀK.ꢀA.ꢀTehrani,ꢀW.ꢀA.ꢀHerrebout,ꢀS.ꢀ
VanꢀDoorslaerꢀandꢀB.ꢀU.ꢀW.ꢀMaes,ꢀChem.ꢀSci.,ꢀ2016,ꢀ7,ꢀ346;ꢀꢀ(m)ꢀ
H.ꢀ Sterckx,ꢀ J.ꢀ Deꢀ Houwer,ꢀ C.ꢀ Mensch,ꢀ W.ꢀ Herrebout,ꢀ K.ꢀ A.ꢀ
Tehraniꢀ andꢀ B.ꢀ U.ꢀ W.ꢀ Maes,ꢀ Beilsteinꢀ J.ꢀ Org.ꢀ Chem.,ꢀ 2016,ꢀ 12,ꢀ
5,6
oxygenationꢀ methods. ꢀ Theꢀ chemistryꢀ andꢀ reactionꢀ
conditionsꢀidentifiedꢀhereinꢀareꢀsufficientlyꢀpracticalꢀthatꢀtheseꢀ
methodsꢀ couldꢀ beꢀ compellingꢀ forꢀ large-scaleꢀ application.ꢀ Inꢀ
additionꢀtoꢀtheꢀlowꢀE-factorsꢀassociatedꢀwithꢀtheseꢀreactions,ꢀ
theꢀ homogeneousꢀ reactionꢀ conditionsꢀ (i.e.,ꢀ lackingꢀ solidꢀ
reagentsꢀ orꢀ additives)ꢀ suggestꢀ thatꢀ theyꢀ areꢀ excellentꢀ
1
44;ꢀ(n)ꢀQ.ꢀLi,ꢀY.ꢀHuang,ꢀT.ꢀChen,ꢀY.ꢀZhou,ꢀQ.ꢀXu,ꢀS.-F.ꢀYinꢀandꢀL.-
B.ꢀHan,ꢀOrg.ꢀLett.,ꢀ2014,ꢀ16,ꢀ3672;ꢀ(o)ꢀY.ꢀHuang,ꢀT.ꢀChen,ꢀQ.ꢀLi,ꢀY.ꢀ
ZhouꢀandꢀS.-F.ꢀYin,ꢀOrg.ꢀBiomol.ꢀChem.,ꢀ2015,ꢀ13,ꢀ7289;ꢀ(p)ꢀM.ꢀ
Liu,ꢀT.ꢀChenꢀandꢀS.-F.ꢀYin,ꢀCatal.ꢀSci.ꢀTechnol.,ꢀ2016,ꢀ6,ꢀ690;ꢀ(q)ꢀH.ꢀ
Xie,ꢀY.ꢀLiao,ꢀS.ꢀChen,ꢀY.ꢀChenꢀandꢀG.-J.ꢀDeng,ꢀOrg.ꢀBiomol.ꢀChem.,ꢀ
2
9
candidatesꢀforꢀcontinuous-flowꢀapplications. ꢀThisꢀopportunityꢀ
warrantsꢀattentionꢀinꢀfutureꢀstudies.ꢀ
2
015,ꢀ13,ꢀ6944;ꢀ(r)ꢀC.ꢀZhang,ꢀZ.ꢀXu,ꢀL.ꢀZhangꢀandꢀN.ꢀJiao,ꢀAngew.ꢀ
Acknowledgementsꢀ
Chem.,ꢀInt.ꢀEd.,ꢀ2011,ꢀ50,ꢀ11088;ꢀ(s)ꢀZ.ꢀXu,ꢀC.ꢀZhangꢀandꢀN.ꢀJiao,ꢀ
Angew.ꢀChem.,ꢀInt.ꢀEd.,ꢀ2012,ꢀ51,ꢀ11367;ꢀ(t)ꢀC.ꢀZhang,ꢀL.ꢀZhangꢀ
andꢀN.ꢀJiao,ꢀAdv.ꢀSynth.ꢀCatal.,ꢀ2012,ꢀ354,ꢀ1293.ꢀ
ꢀꢀ Thisꢀ pathwayꢀ isꢀ analogousꢀ toꢀ aerobicꢀ oxygenationꢀ reactionsꢀ
adjacentꢀtoꢀcarbonylꢀgroups.ꢀForꢀexamples,ꢀsee:ꢀ(a)ꢀF.-T.ꢀDuꢀandꢀ
J.-X.ꢀJi,ꢀChem.ꢀSci.,ꢀ2012,ꢀ3,ꢀ460;ꢀ(b)ꢀX.ꢀXu,ꢀW.ꢀDing,ꢀY.ꢀLinꢀandꢀQ.ꢀ
Song,ꢀOrg.ꢀLett.,ꢀ2015,ꢀ17,ꢀ516;ꢀ(c)ꢀX.ꢀHuang,ꢀX.ꢀLi,ꢀM.ꢀZou,ꢀJ.ꢀPanꢀ
andꢀN.ꢀJiao,ꢀOrg.ꢀChem.ꢀFront.,ꢀ2015,ꢀ2,ꢀ354;ꢀ(d)ꢀH.ꢀChengꢀandꢀC.ꢀ
Bolm,ꢀSynlett,ꢀ2016,ꢀ27,ꢀ769.ꢀ
Financialꢀ supportꢀ wasꢀ providedꢀ byꢀ theꢀ NIHꢀ (F32GM113399,ꢀ
D.P.H.),ꢀ theꢀ DOEꢀ (DE-FG02-05ER15690,ꢀ S.S.S.),ꢀ andꢀ Merckꢀ
Researchꢀ Laboratories–Rahwayꢀ (K.C.M.,ꢀ electrochemicalꢀ
studies).ꢀ Spectroscopicꢀ instrumentationꢀ wasꢀ partiallyꢀ
supportedꢀ byꢀ theꢀ NIHꢀ (S10ꢀ OD020022)ꢀ andꢀ theꢀ NSFꢀ (CHE-
7
8
9
1
048642).ꢀ
ꢀꢀ (a)ꢀ Y.ꢀ Ishii,ꢀ S.ꢀ Sakaguchiꢀ andꢀ T.ꢀ Iwahama,ꢀ Adv.ꢀ Synth.ꢀ Catal.,ꢀ
2001,ꢀ343,ꢀ393;ꢀ(b)ꢀF.ꢀRecuperoꢀandꢀC.ꢀPunta,ꢀChem.ꢀRev.,ꢀ2007,ꢀ
Notesꢀandꢀreferencesꢀ
1
07,ꢀ3800;ꢀ(c)ꢀL.ꢀMeloneꢀandꢀC.ꢀPuntaꢀinꢀLiquidꢀPhaseꢀAerobicꢀ
ꢀ
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
Oxidationꢀ Catalysis:ꢀ Industrialꢀ Applicationsꢀ andꢀ Academicꢀ
Perspectives,ꢀ S.ꢀ S.ꢀ Stahlꢀ andꢀ P.ꢀ L.ꢀ Alsters,ꢀ Eds.,ꢀ Wiley-VCH:ꢀ
Weinheim,ꢀ2016,ꢀpp.ꢀ253-266.ꢀ
ꢀꢀ (a)ꢀ Y.ꢀ Ishii,ꢀ T.ꢀ Iwahama,ꢀ S.ꢀ Sakaguchi,ꢀ K.ꢀ Nakayamaꢀ andꢀ Y.ꢀ
Nishiyama,ꢀ J.ꢀ Org.ꢀ Chem.,ꢀ 1996,ꢀ 61,ꢀ 4520;ꢀ (b)ꢀ Y.ꢀ Yoshino,ꢀ Y.ꢀ
Hayashi,ꢀ T.ꢀ Iwahama,ꢀ S.ꢀ Sakaguchiꢀ andꢀ Y.ꢀ Ishii,ꢀ J.ꢀ Org.ꢀ Chem.,ꢀ
1
ꢀꢀ H.ꢀ J.ꢀ Teles,ꢀ I.ꢀ Hermans,ꢀ H.ꢀ G.ꢀ Franzꢀ andꢀ R.ꢀ A.ꢀ Sheldon,ꢀ
"
Oxidation"ꢀ inꢀ Ullmann'sꢀ Encyclopediaꢀ ofꢀ Industrialꢀ Chemistry,ꢀ
ElectronicꢀRelease,ꢀWiley-VCH:ꢀWeinheim,ꢀ2015.ꢀ
2
ꢀꢀ (a)ꢀ W.ꢀ Partenheimer,ꢀ Catal.ꢀ Today,ꢀ 1995,ꢀ 23,ꢀ 69;ꢀ (b)ꢀ R.ꢀ A.ꢀ F.ꢀ
Tomas,ꢀJ.ꢀC.ꢀM.ꢀBordadoꢀandꢀJ.ꢀF.ꢀP.ꢀGomes,ꢀChem.ꢀRev.,ꢀ2013,ꢀ
1
13,ꢀ 7421;ꢀ (c)ꢀ V.ꢀ A.ꢀ Adamianꢀ andꢀ W.ꢀ H.ꢀ Gongꢀ inꢀ Liquidꢀ Phaseꢀ
1
997,ꢀ62,ꢀ6810.ꢀ
Aerobicꢀ Oxidationꢀ Catalysis:ꢀ Industrialꢀ Applicationsꢀ andꢀ
AcademicꢀPerspectives,ꢀS.ꢀS.ꢀStahlꢀandꢀP.ꢀL.ꢀAlsters,ꢀEds.;ꢀWiley-
VCH:ꢀWeinheim,ꢀ2016,ꢀpp.ꢀ41-66.ꢀ
1
1
0ꢀꢀForꢀdetailedꢀdiscussionꢀofꢀtheꢀmechanismꢀofꢀaerobicꢀCo/NHPIꢀ
oxygenations,ꢀseeꢀrefꢀ8a.ꢀ
1ꢀꢀStudiesꢀ ofꢀ substratesꢀ potentiallyꢀ relevantꢀ toꢀ pharmaceuticalꢀ
applicationsꢀareꢀrareꢀandꢀhaveꢀmetꢀwithꢀlimitedꢀsuccess:ꢀ(a)ꢀA.ꢀ
Shibamoto,ꢀ S.ꢀ Sakaguchiꢀ andꢀ Y.ꢀ Ishii,ꢀ Org.ꢀ Processꢀ Res.ꢀ Dev.,ꢀ
3
4
5
ꢀꢀ M.ꢀ Weber,ꢀ M.ꢀ Weber,ꢀ M.ꢀ Kleine-Boymann,ꢀ "Phenol",ꢀ inꢀ
Ullmann'sꢀ Encyclopediaꢀ ofꢀ Industrialꢀ Chemistry,ꢀ Electronicꢀ
Release,ꢀWiley-VCH,ꢀ2004.ꢀ
ꢀꢀ M.ꢀT.ꢀMusser,ꢀ"CyclohexanolꢀandꢀCyclohexanone"ꢀinꢀUllmann'sꢀ
EncyclopediaꢀofꢀIndustrialꢀChemistry,ꢀElectronicꢀRelease,ꢀWiley-
VCH,ꢀ2011.ꢀ
ꢀꢀ For,ꢀ metal-freeꢀ conditions:ꢀ (a)ꢀ K.ꢀ K.ꢀ Park,ꢀ L.ꢀ K.ꢀ Tsouꢀ andꢀ A.ꢀ D.ꢀ
Hamilton,ꢀSynthesis,ꢀ2006,ꢀ3617;ꢀ(b)ꢀC.ꢀQi,ꢀH.ꢀJiang,ꢀL.ꢀHuang,ꢀZ.ꢀ
ChenꢀandꢀH.ꢀChen,ꢀSynthesis,ꢀ2011,ꢀ387;ꢀ(c)ꢀC.ꢀZhang,ꢀZ.ꢀXu,ꢀL.ꢀ
Zhangꢀ andꢀ N.ꢀ Jiao,ꢀ Tetrahedron,ꢀ 2012,ꢀ 68,ꢀ 5258;ꢀ (d)ꢀ A.ꢀ Dosꢀ
Santos,ꢀL.ꢀElꢀKaimꢀandꢀL.ꢀGrimaud,ꢀOrg.ꢀBiomol.ꢀChem.,ꢀ2013,ꢀ11,ꢀ
2
000,ꢀ4,ꢀ505;ꢀ(b)ꢀB.ꢀB.ꢀWentzel,ꢀM.ꢀP.ꢀJ.ꢀDonners,ꢀP.ꢀL.ꢀAlsters,ꢀM.ꢀ
C.ꢀFeitersꢀandꢀR.ꢀJ.ꢀM.ꢀNolte,ꢀTetrahedron,ꢀ2000,ꢀ56,ꢀ7797;ꢀ(c)ꢀS.ꢀ
Sakaguchi,ꢀ A.ꢀ Shibamotoꢀ andꢀ Y.ꢀ Ishii,ꢀ Chem.ꢀ Commun.,ꢀ 2002,ꢀ
1
80;ꢀ(d)ꢀL.ꢀSchmieder-vanꢀdeꢀVondervoort,ꢀS.ꢀBouttemy,ꢀF.ꢀHeu,ꢀ
K.ꢀWeissenbockꢀandꢀP.ꢀL.ꢀAlsters,ꢀEur.ꢀJ.ꢀOrg.ꢀChem.,ꢀ2003,ꢀ578.ꢀ
2ꢀ Forꢀsimplicity,ꢀtheꢀtermꢀ"benzylic"ꢀisꢀusedꢀforꢀsitesꢀadjacentꢀtoꢀ
bothꢀarylꢀandꢀheteroarylꢀrings.ꢀ
3ꢀ T.ꢀIwahama,ꢀY.ꢀYoshino,ꢀT.ꢀKeitoku,ꢀS.ꢀSakaguchiꢀandꢀY.ꢀIshii,ꢀJ.ꢀ
Org.ꢀChem.,ꢀ2000,ꢀ65,ꢀ6502.ꢀ
4ꢀ Forꢀ similarꢀ reactionꢀ conditionsꢀ forꢀ Midꢀ Century-typeꢀ
autoxidation,ꢀ see:ꢀ (a)ꢀ A.ꢀ S.ꢀ Hayꢀ andꢀ H.ꢀ S.ꢀ Blanchard,ꢀ Can.ꢀ J.ꢀ
Chem.,ꢀ 1965,ꢀ 43,ꢀ 1306;ꢀ (b)ꢀ B.ꢀ Gutmann,ꢀ P.ꢀ Elsner,ꢀ D.ꢀ Robergeꢀ
andꢀC.ꢀO.ꢀKappe,ꢀACSꢀCatal.,ꢀ2013,ꢀ3,ꢀ2669.ꢀ
5ꢀ Seeꢀalso:ꢀJ.ꢀLiu,ꢀX.ꢀZhang,ꢀH.ꢀYi,ꢀC.ꢀLiu,ꢀR.ꢀLiu,ꢀH.ꢀZhang,ꢀK.ꢀZhuoꢀ
andꢀA.ꢀLei,ꢀAngew.ꢀChem.,ꢀInt.ꢀEd.,ꢀ2015,ꢀ54,ꢀ1261.ꢀ
1
1
1
3
1
282;ꢀ(e)ꢀL.ꢀRen,ꢀL.ꢀWang,ꢀY.ꢀLv,ꢀG.ꢀLiꢀandꢀS.ꢀGao,ꢀOrg.ꢀLett.,ꢀ2015,ꢀ
7,ꢀ2078;ꢀ(f)ꢀK.ꢀBao,ꢀF.ꢀLi,ꢀH.ꢀLiu,ꢀZ.ꢀWang,ꢀQ.ꢀShen,ꢀJ.ꢀWangꢀandꢀ
W.ꢀZhang,ꢀSci.ꢀRep.,ꢀ2015,ꢀ5,ꢀ10360.ꢀ
6
ꢀꢀ Forꢀ metal-catalyzedꢀ examples:ꢀ (a)ꢀ F.ꢀ M.ꢀ Moghaddam,ꢀ Z.ꢀ
Mirjafary,ꢀH.ꢀSaeidianꢀandꢀM.ꢀJ.ꢀJavan,ꢀSynlett,ꢀ2008,ꢀ892;ꢀ(b)ꢀ X.ꢀ
Fan,ꢀY.ꢀHe,ꢀX.ꢀZhang,ꢀS.ꢀGuoꢀandꢀY.ꢀWang,ꢀTetrahedron,ꢀ2011,ꢀ67,ꢀ
1
1
6
369;ꢀ(c)ꢀX.-S.ꢀFan,ꢀY.ꢀHe,ꢀY.-Y.ꢀWang,ꢀZ.-K.ꢀXue,ꢀX.-Y.ꢀZhangꢀandꢀ
6ꢀ Pyridinesꢀimidazolesꢀareꢀamongstꢀtheꢀmostꢀcommonlyꢀoccurringꢀ
N-heterocyclesꢀ inꢀ F.D.A.-approvedꢀ pharmaceuticals.ꢀ See:ꢀ ꢀ E.ꢀ
Vitaku,ꢀD.ꢀT.ꢀSmithꢀandꢀJ.ꢀT.ꢀNjardarson,ꢀJ.ꢀMed.ꢀChem.,ꢀ2014,ꢀ57,ꢀ
J.-J.ꢀWang,ꢀTetrahedronꢀLett.,ꢀ2011,ꢀ52,ꢀ899;ꢀ(d)ꢀY.-F.ꢀWang,ꢀF.-L.ꢀ
ZhangꢀandꢀS.ꢀChiba,ꢀSynthesis,ꢀ2012,ꢀ44,ꢀ1526;ꢀꢀ(e)ꢀJ.ꢀDeꢀHouwer,ꢀ
K.ꢀ Abbaspourꢀ Tehraniꢀ andꢀ B.ꢀ U.ꢀ W.ꢀ Maes,ꢀ Angew.ꢀ Chem.,ꢀ Int.ꢀ
Ed.,ꢀ 2012,ꢀ 51,ꢀ 2745;ꢀ ꢀ (f)ꢀ C.ꢀ Menendez,ꢀ S.ꢀ Gau,ꢀ S.ꢀ Ladeira,ꢀ C.ꢀ
LherbetꢀandꢀM.ꢀBaltas,ꢀEur.ꢀJ.ꢀOrg.ꢀChem.,ꢀ2012,ꢀ2012,ꢀ409;ꢀꢀ(g)ꢀ
B.ꢀPieberꢀandꢀC.ꢀO.ꢀKappe,ꢀGreenꢀChem.,ꢀ2013,ꢀ15,ꢀ320;ꢀꢀ(h)ꢀS.ꢀ
Cacchi,ꢀG.ꢀFabrizi,ꢀA.ꢀGoggiamani,ꢀA.ꢀIazzettiꢀandꢀR.ꢀVerdiglione,ꢀ
1
0257.ꢀ
1
7ꢀ Aꢀ"robustnessꢀscreen"ꢀinꢀwhichꢀtheꢀreactionꢀofꢀ1aꢀwasꢀcarriedꢀ
outꢀinꢀtheꢀpresenceꢀofꢀadditivesꢀbearingꢀpotentiallyꢀinterestingꢀ
functionalꢀ groups,ꢀ togetherꢀ withꢀ independentꢀ reactionsꢀ ofꢀ 2-
propylfuran,ꢀ isobutylbenzene,ꢀ andꢀ 2-ethylacetanilide,ꢀ areꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ5ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Pleas Ce hꢀ d eo mꢀ ni oc ta ꢀ la dS jcu i se t nꢀ mc ea rginsꢀ
Page 6 of 6
ARTICLEꢀ
JournalꢀNameꢀ
ꢀ
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
View Article Online
DOI: 10.1039/C6SC03831J
presentedꢀinꢀtheꢀESI†.ꢀSeeꢀTablesꢀS4ꢀandꢀS5ꢀandꢀassociatedꢀtextꢀ
forꢀdetails.ꢀ
1
1
8ꢀ Forꢀaꢀreviewꢀonꢀthiophene-containingꢀpharmaceuticals,ꢀsee:ꢀD.ꢀ
Gramec,ꢀ L.ꢀ Peterlinꢀ Masicꢀ andꢀ M.ꢀ Sollnerꢀ Dolenc,ꢀ Chem.ꢀ Res.ꢀ
Toxicol.,ꢀ2014,ꢀ27,ꢀ1344.ꢀ
9ꢀ (a)ꢀH.ꢀHenschel,ꢀJ.-P.ꢀKloeckner,ꢀI.ꢀA.ꢀNichollsꢀandꢀM.ꢀH.ꢀProsenc,ꢀ
J.ꢀMol.ꢀStruct.,ꢀ2012,ꢀ1007,ꢀ45;ꢀ(b)ꢀA.ꢀB.ꢀP.ꢀLeverꢀandꢀD.ꢀOgden,ꢀJ.ꢀ
Chem.ꢀSoc.ꢀA,ꢀ1967,ꢀ2041.ꢀ
2
2
0ꢀ M.ꢀMasui,ꢀS.ꢀHara,ꢀT.ꢀUeshima,ꢀT.ꢀKawaguchiꢀandꢀS.ꢀOzaki,ꢀChem.ꢀ
Pharm.ꢀBull.,ꢀ1983,ꢀ31,ꢀ4209.ꢀ
1ꢀ Forꢀelectrochemical,ꢀPINO-mediatedꢀoxygenationꢀofꢀallylicꢀC–Hꢀ
bonds,ꢀsee:ꢀ(a)ꢀM.ꢀMasui,ꢀK.ꢀHosomi,ꢀK.ꢀTsuchidaꢀandꢀS.ꢀOzaki,ꢀ
Chem.ꢀPharm.ꢀBull.,ꢀ1985,ꢀ33,ꢀ4798;ꢀ(b)ꢀE.ꢀJ.ꢀHorn,ꢀB.ꢀR.ꢀRosen,ꢀY.ꢀ
Chen,ꢀJ.ꢀTang,ꢀK.ꢀChen,ꢀM.ꢀD.ꢀEastgateꢀandꢀP.ꢀS.ꢀBaran,ꢀNature,ꢀ
2
016,ꢀ533,ꢀ77.ꢀ
2
2ꢀ E.ꢀHu,ꢀN.ꢀChen,ꢀM.ꢀP.ꢀBourbeau,ꢀP.ꢀE.ꢀHarrington,ꢀK.ꢀBiswas,ꢀR.ꢀK.ꢀ
Kunz,ꢀK.ꢀL.ꢀAndrews,ꢀS.ꢀChmait,ꢀX.ꢀZhao,ꢀC.ꢀDavis,ꢀJ.ꢀMa,ꢀJ.ꢀShi,ꢀD.ꢀ
Lester-Zeiner,ꢀ J.ꢀ Danao,ꢀ J.ꢀ Able,ꢀ M.ꢀ Cueva,ꢀ S.ꢀ Talreja,ꢀ T.ꢀ
Kornecook,ꢀH.ꢀChen,ꢀA.ꢀPorter,ꢀR.ꢀHungate,ꢀJ.ꢀTreanorꢀandꢀJ.ꢀR.ꢀ
Allen,ꢀJ.ꢀMed.ꢀChem.,ꢀ2014,ꢀ57,ꢀ6632.ꢀ
2
2
3ꢀ O.ꢀR.ꢀThiel,ꢀJ.ꢀR.ꢀHuckins,ꢀD.ꢀB.ꢀBrown,ꢀE.ꢀA.ꢀBercot,ꢀJ.ꢀT.ꢀColyer,ꢀB.ꢀ
Riahi,ꢀR.ꢀR.ꢀMilburn,ꢀS.ꢀM.ꢀShawꢀandꢀJ.ꢀTomaskevitch,ꢀACSꢀSymp.ꢀ
Ser.,ꢀ2014,ꢀ1181,ꢀ269.ꢀ
4ꢀ TheꢀLOCꢀisꢀdefinedꢀasꢀtheꢀminimumꢀpartialꢀpressureꢀofꢀoxygenꢀ
thatꢀ supportsꢀ aꢀ combustibleꢀ mixture.ꢀ Belowꢀ theꢀ LOC,ꢀ
combustionꢀisꢀnotꢀpossible.ꢀP.ꢀM.ꢀOsterberg,ꢀJ.ꢀK.ꢀNiemeier,ꢀC.ꢀJ.ꢀ
Welch,ꢀJ.ꢀM.ꢀHawkins,ꢀJ.ꢀR.ꢀMartinelli,ꢀT.ꢀE.ꢀJohnson,ꢀT.ꢀW.ꢀRootꢀ
andꢀS.ꢀS.ꢀStahl,ꢀOrg.ꢀProcessꢀRes.ꢀDev.,ꢀ2015,ꢀ19,ꢀ1537.ꢀ
2
2
5ꢀ P.ꢀ T.ꢀ Anastasꢀ andꢀ J.ꢀ C.ꢀ Warner,ꢀ Greenꢀ Chemistry:ꢀ Theoryꢀ andꢀ
Practice,ꢀOxfordꢀUniversityꢀPress,ꢀOxford,ꢀ1998.ꢀ
6ꢀ (a)ꢀR.ꢀK.ꢀHenderson,ꢀC.ꢀJimenez-Gonzalez,ꢀD.ꢀJ.ꢀC.ꢀConstable,ꢀS.ꢀR.ꢀ
Alston,ꢀG.ꢀG.ꢀA.ꢀInglis,ꢀG.ꢀFisher,ꢀJ.ꢀSherwood,ꢀS.ꢀP.ꢀBinksꢀandꢀA.ꢀ
D.ꢀCurzons,ꢀGreenꢀChem.,ꢀ2011,ꢀ13,ꢀ854;ꢀ(b)ꢀD.ꢀPrat,ꢀO.ꢀPardigon,ꢀ
H.-W.ꢀFlemming,ꢀS.ꢀLetestu,ꢀV.ꢀDucandas,ꢀP.ꢀIsnard,ꢀE.ꢀGuntrum,ꢀ
T.ꢀSenac,ꢀS.ꢀRuisseau,ꢀP.ꢀCrucianiꢀandꢀP.ꢀHosek,ꢀOrg.ꢀProcessꢀRes.ꢀ
Dev.,ꢀ2013,ꢀ17,ꢀ1517;ꢀ(c)ꢀD.ꢀPrat,ꢀJ.ꢀHaylerꢀandꢀA.ꢀWells,ꢀGreenꢀ
Chem.,ꢀ2014,ꢀ16,ꢀ4546.ꢀ
2
2
7ꢀ AnotherꢀattractiveꢀfeatureꢀofꢀtheꢀreactionꢀisꢀthatꢀtheꢀNHPIꢀandꢀ
itsꢀ decompositionꢀ productsꢀ areꢀ readilyꢀ separatedꢀ fromꢀ theꢀ
reactionꢀmixtureꢀthroughꢀhydrolysisꢀwithꢀaqueousꢀNaOH.ꢀ
8ꢀ Theꢀ condensationꢀ stepꢀ wasꢀ notꢀ optimized,ꢀ butꢀ literatureꢀ
precedentsꢀ suggestꢀ theseꢀ reactionsꢀ canꢀ proceedꢀ inꢀ near-
quantitativeꢀ yieldꢀ underꢀ neatꢀ conditionsꢀ (seeꢀ ref.ꢀ 5d).ꢀ Forꢀ E-
factorꢀanalysis,ꢀseeꢀESI†.ꢀ
2
9ꢀ Forꢀ leadingꢀ referencesꢀ toꢀ continuous-flowꢀ aerobicꢀ oxidationꢀ
chemistry,ꢀseeꢀrefs.ꢀ6g,ꢀ14b,ꢀandꢀtheꢀfollowing:ꢀ(a)ꢀX.ꢀYe,ꢀM.ꢀD.ꢀ
Johnson,ꢀT.ꢀDiao,ꢀM.ꢀH.ꢀYatesꢀandꢀS.ꢀS.ꢀStahl,ꢀGreenꢀChem.,ꢀ2010,ꢀ
1
2,ꢀ1180;ꢀ(b)ꢀH.ꢀP.ꢀL.ꢀGemoets,ꢀV.ꢀHessel,ꢀT.ꢀNoel,ꢀinꢀLiquidꢀPhaseꢀ
Aerobicꢀ Oxidationꢀ Catalysis:ꢀ Industrialꢀ Applicationsꢀ andꢀ
AcademicꢀPerspectives,ꢀS.ꢀS.ꢀStahlꢀandꢀP.ꢀL.ꢀAlsters,ꢀEds.;ꢀWiley-
VCH:ꢀWeinheim,ꢀ2016,ꢀpp.ꢀ399–417.ꢀ
6
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
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