Ru-Catalyzed C-H Hydroxylation of Tyrosine-Containing Di- and Tripeptides toward the Assembly of L-DOPA Derivatives

Ru-Ca alyzed CH Hyd oxyla ion o Ty osine-Con aining Di- and
T ipep ides owa d he Assembly o L-DOPA De i a i es
Paula And ade-Samped o,a, b Jon M. Ma xain,b, c and A kai z Co eaa,*
a
Uni e si y o he Basque Coun y (UPV/EHU), Depa men o O ganic Chemis y I, Joxe Ma i Ko a R&D Cen e , A da. Tolosa
72, 20018 Donos ia-San Sebas ián (Spain)
E-mail: [email p o ec ed]
b
Donos ia In e na ional Physics Cen e (DIPC), Paseo Manuel de La dizabal 4, 20018 Donos ia-San Sebas ián (Spain)
c
Polime o e a Ma e ial Au e a uak: Fisika, Kimika e a Teknologia Saila, Kimika Fakul a ea, Euskal He iko Unibe si a ea
(UPV/EHU), Paseo Manuel de La dizabal 3, 20018 Donos ia-San Sebas ián (Spain)
Manusc ip ecei ed: Ma ch 3, 2022; Re ised manusc ip ecei ed: Ap il 13, 2022;
Ve sion o eco d online: May 17, 2022
Suppo ing in o ma ion o his a icle is a ailable on he WWW unde h ps://doi.o g/10.1002/adsc.202200234
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e ms o he C ea i e Commons A ibu ion Non-Comme cial NoDe i s License, which pe mi s use and dis ibu ion in any
medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-comme cial and no modi ica ions o adap a ions a e made.
Abs ac : The de elopmen o ca aly ic ools o
he la e-s age modi ica ion o amino acids wi hin a
pep ide amewo k is a challenging ask o capi al
impo ance. He ein, we epo a Ru-ca alyzed C-
(sp2)H hyd oxyla ion o a collec ion o Ty -
con aining di- and ipep ides ea u ing he use o a
ca bama e as a emo able di ec ing g oup and
PhI(OCOCF3)2(PIFA) as oxidan . This ai -compa -
ible agging echnique is eliable, scalable and
p o ides access o L-DOPA (L-3,4-dihyd oxypheny-
lalanine) pep idomime ics in a acemiza ion- ee
ashion. Densi y Func ional Theo y calcula ions
suppo a Ru(II)/Ru(IV) ca aly ic cycle.
Keywo ds: hyd oxyla ion; y osine; u henium ca al-
ysis; pep ides; CH unc ionaliza ion
In oduc ion
The ins alla ion o small chemical en i ies such as
i luo ome hyl, me hyl o hyd oxyl g oups in a gi en
bioac i e molecule o en ushe s in highe binding
a ini y, di e en me abolism and imp o ed pha maco-
kine ic p ope ies o he esul ing compound.[1] As a
esul , he appendance o hose unc ional g oups in a
la e-s age ashion ep esen s a p essing goal o pa a-
moun chemical signi icance because i enables apid
lead di e si ica ion in he ealm o d ug disco e y.[2]
Hyd oxyla ed a oma ic compounds a e ubiqui ous in
Na u e and s and ou as aluable eeds ock in he
chemical indus y.[3] Among he exis ing phenol syn-
heses, he me al-ca alyzed C(sp2)H hyd oxyla ion o
a enes upon chela ion assis ance poses he mos
s eamlined and s aigh o wa d a enue (Scheme 1,
ou e a).[4] In his espec , a a ie y o di ec ing g oups
(DGs) ha e been epo ed o aid he p ac ical oxida ion
o simple a enes in he p esence o palladium,[5]
hodium,[6] u henium[7] o i on[8] ca alys s, among
o he s. Howe e , despi e he ad ances ealized, he
cu en syn he ic oolbox emains essen ially unex-
plo ed in mo e challenging se ings such as amino
acids and pep ides. In 2016, he Whi e g oup accom-
plished he si e-selec i e and p edic able C(sp3)H
hyd oxyla ion o alipha ic amino acids such as p oline,
leucine o aline in he p esence o a s a egically
designed i on ca alys which esembled o an enzyme-
ype eac i i y (Scheme 1, ou e b).[9] Mo e ecen ly, as
pa o hei s udies on he Pd-ca alyzed o ho-
hyd oxyla ion o benzoic acids, Yu and co-wo ke s
disclosed he hyd oxyla ion o a Ty de i a i e in a
emo e posi ion ea u ing a ca boxylic acid as a weak
DG.[10] Fu he mo e, he las yea s ha e wi nessed he
upsu ge o a shee numbe o bioca aly ic echniques o
pe o m CH oxida ion eac ions in in ica e sca olds
including amino acids.[11] Howe e , he challenging
si e-selec i e CH hyd oxyla ion o y osine (Ty )
compounds upon me al ca alysis emains elusi e.
Ty is he na u al p ecu so o L-DOPA (L-3,4-
dihyd oxyphenylalanine), which is a po en d ug o
he clinical ea men o Pa kinson’s disease and can be
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ans o med in o a wide ange o neu o ansmi e s
h ough biosyn he ic pa hways. Despi e i s emendous
medicinal ele ance, he e is cu en ly no gene al
me hod a ailable o di ec ly assemble L-DOPA om
he co esponding amino acid in a p ac ical ashion.
Indeed, he mos well-known p o ocols encompass Rh-
ca alyzed asymme ic hyd ogena ion eac ions o en-
amides de eloped by Knowles[12] o leng hy ou es
om L-Ty in ol ing a classical F iedel-C a s ace yla-
ion en ailing co osi e ace yl chlo ide ollowed by
subsequen educ ion s eps.[13] Likewise, hose me hods
ha e no been es ed in pep ides o p oduce L-DOPA
pep idomime ics. Despi e he comme cial a ailabili y
o L-DOPA o i s N-p o ec ed de i a i es, hey a e
a he expensi e and o en esul in low yields o he
co esponding pep ide de i a i es..[14] Acco dingly,
a ge ing a me al-ca alyzed CH hyd oxyla ion o Ty -
con aining compounds would a guably p o ide an
excellen s aigh o wa d app oach o o ge L-DOPA
de i a i es, while expanding ou chemical oolbox o
di e si y Ty -con aining pep ides[15,16] and comple-
men ing enzyma ic echniques.[17]
Al hough CH hyd oxyla ions wi hin simple a enes
ha e been well explo ed,[3–8] hey a ely include
subs a es housing amides as unc ional g oups. The e-
o e, hei ansla ion o he e e -g owing ield o
bioconjuga ion is no a i ial ask and poses se e al
challenges: a) u ilize a DG wi h supe io coo dina ing
abili y o ha o he pep ide backbone, and b) selec a
ca alys wi h high ole ance o amides wi hin pep ide
se ings. Inspi ed by he a ac i e ea u es o cos -
e ec i e u henium ca alysis in he hyd oxyla ions o
simple a enes,[18] we en isaged ha he phenol ing
wi hin Ty could be easily ans o med in o a weak
coo dina ing g oup[19] o u he assis he co espond-
ing hyd oxyla ion upon he o ma ion o a 6-membe ed
u henacycle (Scheme 1, ou e c). He ein we desc ibe a
eliable Ru-ca alyzed hyd oxyla ion me hod upon
assis ance o a ca bama e as emo able DG,[18g] hus
p o iding a gene al and less expensi e me hod o he
assembly o L-DOPA de i a i es in a simple ye
inno a i e manne .
Resul s and Discussion
Building on p eceden s epo ed by Acke mann abou
he supe io coo dina ing abili y o amides o ha o
ca bama es,[18 ,g] we selec ed simple Ty de i a i e 1a
de oid o a seconda y amide as a model subs a e o
e alua e he easibili y o ou hypo hesis.
A e sys ema ic op imiza ion,[20] we ound ha a
combina ion o [RuCl2(p-cymene)]2as ca alys and
hype alen iodine eagen PhI(OCOCF3)2(PIFA) as
oxidan enabled he selec i e and apid o ho-hyd ox-
yla ion o Ty compound 1a, he eby a o ding
exclusi ely mono-hyd oxyla ed p oduc 2a in 73%
yield a e 3.5 hou s (Table 1, en y 1). In line wi h ou
expec a ions, con ol expe imen s unde pinned he
c ucial ole o bo h he ca alys and oxidan in he
hyd oxyla ion eac ion (en ies 2 and 3). Likewise, he
Scheme 1. Me al-ca alyzed CH hyd oxyla ion eac ions.
Table 1. Ru-ca alyzed CH hyd oxyla ion o 1 a.[a]
[a] Reac ion condi ions: 1a (0.15 mmol), PIFA (0.45 mmol),
[RuCl2(p-cymene)]2(5 mol%) in a mix u e o DCE/TFA
(1:1, 2 mL) a 60°C o 3.5 h unde ai .
[b] Yield o isola ed p oduc a e column ch oma og aphy.
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addi ion o TFA was key o ensu e high yields
(en y 4). Impo an ly, he eac ion did no equi e an
ine a mosphe e and could be conduc ed unde ai
(en y 5), which cons i u es an addi ional bonus in
e ms o ope a ional simplici y. The sc eening o
oxidan s e ealed bo h he highe ac i i y o PIFA, in
compa ison o o he candida es such as K2S2O8o
oxone,[20] and he equi emen o adding 2 equi alen s
(en y 6). Closely ela ed PhI(OAc)2(PIDA) could be
also u ilized, albei 2a was ob ained in lowe yields
(en y 7). The pe o mance o he p ocess a lowe
empe a u e han 60°C was ound de imen al (en-
y 8), and deg ada ion o he s a ing ma e ial was
obse ed a highe empe a u es.[20] The use o
[RuCl2(p-cymene)]2as ca alys ushe ed in highe yields
han o he u henium ca alys s, which deli e ed 2 a in
compa a i ely lowe yields (en ies 9–12). The usage
o highe amoun o TFA (en y 13) o mo e dilu ed
solu ions (en y 14) did no imp o e he ca alys
pe o mance, hus showing he sub le ies o ou
sys em. Impo an ly, he dihyd oxyla ion eac ion was
ne e obse ed. Once he e iciency o u ilizing a
ca bama e as DG in a ully p o ec ed compound was
demons a ed, o he Ty compounds housing seconda y
amides we e es ed o e alua e he obus ness o he
me hod. As expec ed, Boc-p o ec ed Ty compound
(1aa) decomposed unde he op imized condi ions
in ol ing TFA, which is commonly used o e ec he
dep o ec ion o Boc-amine de i a i es. O he p o ec -
ing g oups such as benzyloxyca bonyl (1 ab) and nosyl
(1ac) could be employed, albei he hyd oxyla ion
eac ion occu ed in 43% and 37% yields, espec i ely.
Wi h hese esul s in hand, we nex ackled he
hyd oxyla ion eac ion in mo e complex pep ide
se ings o illus a e he gene ali y o his pla o m o
deli e L-DOPA de i a i es in a simple ashion. As
shown in Table 2, a wide numbe o p e iously
inaccessible hyd oxyla ed dipep ides could be as-
sembled in mode a e o excellen yields (up o 74%). A
sho amily o Ty -con aining dipep ides inco po a ing
Val (2b), Leu (2 c), Ile (2 d), P o (2 ), Phe (2g), Glu
(2h), Ty (2i) and Ala (2 j) esidues unde wen he
o ho-hyd oxyla ion eac ion in a si e-selec i e manne
unde sligh ly modi ied condi ions ea u ing he use o
lowe amoun o TFA and longe eac ion imes han
hose used wi h he single Ty compound 1a.[20] These
esul s clea ly indica ed ha he o ho-hyd oxyla ion o
a Ty esidue can be e icien ly di ec ed by he weak
coo dina ion o he ca bama e g oup in he p esence o
o he compe ing O-chela ing si es such as hose amides
o he pep ide backbone.[18 ] Encou aged by hese
p omising esul s wi h dipep ide de i a i es, we
syn hesized a a ie y o ipep ide compounds o
e alua e ou C(sp2)H hyd oxyla ion mani old. No a-
bly, he desi ed chemical modi ica ion o he Ty uni
could be achie ed ega dless o he posi ion o he Ty
esidue wi hin he pep ide sequence. Al hough he
hyd oxyla ed p oduc s we e ob ained in low o mode -
a e yields in ce ain cases (up o 56%), i is wo h
no ing ha ull con e sion was no always achie ed
and un eac i e s a ing ma e ial was some imes ob-
se ed. Owing o he use o a highly oxidizing sys em,
esidues bea ing po en ially oxidizable hyd oxyl
g oups wi hin Ty [21] (2i), Th (2 m) and Se (2n) as
well as amino g oups in Lys (2k) we e p o ec ed o
chemoselec i ely pe o m he co esponding CH
hyd oxyla ion. Con e sely, a dipep ide housing a
me hionine esidue wi h a hioe he mo i esul ed in
he p e e en ial oxida ion o he sul u a om. Likewise,
he use o pep ides bea ing he e ocyclic-con aining
amino acids such as his idine and yp ophan esul ed
in he en i e inhibi ion o he p ocess.[20] Impo an ly,
biologically ele an depsipep ides 2e and 2o could be
also hyd oxyla ed in good yields.
The s uc u e o 2 was unambiguously assigned
by X- ay di ac ion and suppo ed he appendance o
he hyd oxyl g oup a he o ho posi ion o he Ty
uni .[22] Un o una ely, despi e o ou nume ous a -
emp s, he p o ocol could no be applied in e a- o
hexapep ides (Table S5 and Table S7).[20] We hypo he-
sized ha he high numbe o amide bonds in
e apep ides could deeply comp omise he equi ed
coo dina ion o he Ru ca alys wi h he ca bama e,
hus ou compe ing wi h he ca bama e as weak O-
coo dina ing g oups. In ac , pep ides ha e been used
in Ru-ca alyzed ans o ma ions as e ec i e endoge-
nous and exogenous ligands.[23] In his espec , we
pe o med u he s udies o de e mine whe he o he
DGs could be used in hese endea o s o o e come
his syn he ic limi a ion.
As depic ed on Table 3, a simple Ty uni housing
o he DGs wi h ca bonyl mo i s as O-coo dina ing
g oups such as ace a e (2ag), ca bona es (2ah,2 ai) o
ca bama es (2aj,2ak and 2al) ei he inhibi ed he
eac ion o a o ded hyd oxyla ed compounds in much
lowe yields. Con e sely, among he es ed s ong
chela ing he e oa ene g oups py imidine a o ded a
ema kable 50% yield o he co esponding o ho-
hyd oxyla ed p oduc 2ae unde he s anda d condi-
ions. Acco dingly, we p epa ed he co esponding
e apep ide inco po a ing a py imidine uni e he ed
wi h he oxygen a om o he phenol ing; howe e ,
a e a wide a ie y o expe imen s wi h Ru and Pd
ca alys s (Table S6), we only ob ained 15% yield o
he desi ed p oduc 2 b when using Pd(OAc)2as
ca alys .[20] The e o e, he hyd oxyla ion o pep ides
wi h mo e han h ee amino acid esidues s ill poses a
daun ing challenge and ep esen s a ask which
dese es u he analysis.
The obus ness and syn he ic u ili y was demon-
s a ed by he pe o mance o he hyd oxyla ion o
amino es e 1a and dipep ide 1b in highe scale
(Scheme 2). Al hough he ca bama e clea age can be
pe o med unde a a ie y o condi ions in simple
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phenols,[24] i s emo al wi hin a pep ide amewo k is
no a i ial ask; ce ain eagen s such as LiAlH4o
NaOH canno be used wi hou a ec ing he pep ide
s uc u e and o he s such as hyd azine o he Schwa z
eagen did no wo k. A e a numbe o a emp s, he
clea age o he ca bama e in p oduc 2 a was achie ed
Table 2. Ru-ca alyzed CH hyd oxyla ion o Ty -con aining pep ides and depsipep ides.[a,b]
[a] As o Table 1, en y 1.
[b] Yield o isola ed p oduc a e column ch oma og aphy, a e age o a leas wo independen uns wi h a a iable yield by no
mo e han 5% be ween uns.
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upon ea men wi h sul u ic acid in MeOH, which
u nished he co esponding L-DOPA analog 3in 81%
yield. Rema kably, HPLC analysis o compound 3
e i ied ha no acemiza ion occu ed nei he along
he hyd oxyla ion no he clea age s ep.[20] Un o u-
na ely, when dipep ide 2b was submi ed o hose
condi ions compound 3was o med, which esul ed
om a dep o ec ion and amidolysis sequence.
Al hough i seems a limi a ion a i s sigh , he access
o ully deco a ed pep ides housing a ca bama e uni
could o e in e es ing possibili ies wi hin d ug
disco e y.[25]
In o de o unde s and he eac ion pa hway as well
as some o he obse ed expe imen al nuances, we
u he pe o med DFT s udies. In pa icula , we
ocused ou s udies on he CH hyd oxyla ion o Ty
de i a i e 1a and 1ad bea ing a ca bama e and a
py idine as DG, espec i ely, which expe imen ally
exhibi ed an en i ely dis inc eac i i y p o ile. Assum-
ing a simila eac ion pa hway o ha desc ibed o he
Ru-ca alyzed C(sp2)H hyd oxyla ion o a enes upon
weak chela ion assis ance o seconda y amides,[18b] we
p oposed he plausible mechanism depic ed in
Scheme 3. The eac ion would s a by complexa ion
o he Ru ca alys and he Ty compound assis ed by
TFA o deli e In -A. The la e would likely unde go
he o ho-CH me ala ion aided by he i luo oace a e
anion o p o ide he 6-membe ed u henacycle In -B.
Then, oxida i e addi ion o PIFA would esul in he
o ma ion o highly eac i e Ru(IV) In -C, p one o
Table 3. In luence o he di ec ing g oup.[a]
[a] Yield o isola ed p oduc a e column ch oma og aphy,
a e age o a leas wo independen uns wi h a a iable yield
by no mo e han 5% be ween uns.
[b] Reac ion ca ied ou wi h Pd(OAc)2(10 mol%), PIFA
(0.30 mmol) and DCE (2 mL) a 80°C unde ai .
[c] Ra io o mono- and dihyd oxyla ed p oduc .
[d] Reac ion ca ied ou wi h DCE (0.9 mL) and TFA (0.1 mL).
Scheme 2. High scale syn hesis and DG clea age o o ge L-
DOPA de i a i es. Scheme 3. P oposed eac ion pa hway o he Ru-ca alyzed
CH hyd oxyla ion o Ty compounds.
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unde go subsequen educ i e elimina ion o deli e
In -D, which would e en ually lead o hyd oxyla ed
p oduc 2a. As commen ed abo e, expe imen al
s udies e idenced he p o ound e ec o he na u e o
he DG in he eac ion ou come: whe eas subs a e 1a
bea ing a ca bama e as DG led o he a ge p oduc in
73% yield, subs a e 1ad wi h a s ong py idine DG
emained un eac i e.
Mo eo e , he lack o eac i i y o e apep ides
wi h mul iple amide bonds also indica ed ha he
na u e o DG was o u mos impo ance wi hin he
hyd oxyla ion o pep ide de i a i es. Acco dingly,
DFT calcula ions we e unde aken wi h 1a and 1ad as
model subs a es o analyze he in luence o using
weak s s ongly coo dina ing g oups in he h ee
undamen al s eps o he mechanism (Figu e 1, black
and blue eac ion pa hway, espec i ely). Wi h he
ene gy alues in hand,[20] we can conclude ha whe eas
bo h he CH ac i a ion and he oxida i e addi ion a e
ende gonic e en s, he educ i e elimina ion is exe -
gonic o bo h subs a es. As depic ed in Figu e 1, he
highe s abili y o he ensuing o ho-hyd oxyla ed
compound 2a sugges ed ha i s o ma ion may be he
d i ing o ce o ende he p oposed mechanis ic
scena io he modynamically a o ed. Indeed, all unda-
men al s eps a e he modynamically and kine ically
easible unde he op imized eac ion condi ions. The
i s s ep would consis o a CH ac i a ion e en o
he y osine de i a i e, leading o he o ma ion o In -
B h ough a CMD pa hway wi h an ene gy penal y o
14.74 Kcal/mol.
The op imized s uc u e o TS1 e eals an elonga-
ion o he CH bond o 0.3 Å and he app oxima ion
o he C a om o he me al cen e is e i ied by he
alue o he dis ance o he CRu bond, which
dec eased om 2.68 Å o 2.23 Å. The oxida i e
addi ion o PIFA o In -B he eby deli e ing Ru(IV)
species In -C would no occu in a s aigh o wa d
manne . As shown in Figu e 1, he ini ial coo dina ion
o PIFA o In -B upon a ligand exchange would
deli e In -B’, which would nex unde go a o mal
oxida i e addi ion h ough a conce ed pa hway lead-
ing o In -C’ wi h an ene gy ba ie o 13.62 kcal/mol.
This s ep could easily occu h ough a ansi ion s a e
(TS2) whe ein a IO bond is clea ed wi h he
simul aneous o ma ion o a new RuI bond. In ac ,
he IO dis ance is leng hened om 2.28 Å o 3.03 Å,
whe eas he RuI dis ance is sho ened om 3.76 Å o
2.98 Å. The so- o med In -C’ would u nish In -C
upon elease o PhI and TFA. The la e could unde go
a educ i e elimina ion s ep wi h an ene gy ba ie o
27.10 kcal/mol h ough a conce ed ansi ion s a e
(TS3), in which he RuO dis ance is leng hened om
2.03 Å o 3.61 Å and he CO dis ance is sho ened
om 2.64 Å o 1.38 Å. To ou su p ise, in sha p
con as wi h ou expe imen al s udies, he eac ion
pa hway o subs a e 1ad was shown also ene ge i-
cally easible; whe eas he CH ac i a ion and he
educ i e elimina ion s eps we e sligh ly mo e a o ed
han o subs a e 1 a, he oxida i e addi ion o PIFA
was shown mo e likely o happen wi h a subs a e
housing a weak coo dina ing g oup. Al hough me ely
specula i e, we hypo hesized ha he ansien u hena-
Figu e 1. Compa ison o he eac ion ene ge ics (ΔG in kcal/mol) o 1a and 1 ad.
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cycle species wi h a s ong py idine uni as suppo ing
ligand may be much mo e s able han he pa en
species ea u ing a conside ably weak coo dina ion
mode, he eby esul ing in he en i e inhibi ion o he
p ocess and likely e ol ing in o dime s o unp oduc-
i e eac ion pa hways.[26] In ac , a con ol expe imen
wi h an equimolecula mix u e o 1a and 1ad unde
he s anda d condi ions exclusi ely deli e ed 2a in
41% yield, hus e idencing a pa ial inhibi ion o he
p ocess in he p esence o a py idine uni . Fu he
s udies a e de ini ely equi ed o conclude why
e apep ides do no unde go he de eloped hyd oxyla-
ion eac ion.
Conclusion
In summa y, we ha e de eloped a hyd oxyla ion
eac ion o he modi ica ion o Ty -con aining pep-
ides ea u ing he use o cos -e ec i e and ai -
insensi i e u henium ca alysis. Unlike he me hods
a ailable o he assembly o L-DOPA, his p o ocol
enables he apid ins alla ion o hyd oxyl g oups wi hin
exis ing pep ides in a la e-s age ashion. As a esul ,
his labelling pla o m ep esen s a eliable, ye
scalable, means o he di e si ica ion o Ty -con ain-
ing compounds, hus p o iding access o L-DOPA
pep idomime ics. Salien ea u es o his unique s a -
egy a e he use o a ca bama e as a weak O-
coo dina ing g oup, mild eac ion condi ions, ope a-
ional simplici y and e en ion o he chi al in eg i y o
he exis ing s e eocen e s wi hin he pep ide ame-
wo k. Compu a ional s udies suppo ed a Ru(II)/Ru-
(IV) egime occu ing upon he in e mediacy o a
challenging 6-membe ed u henacycle.
Expe imen al Sec ion
Gene al p ocedu e o he Ru-ca alyzed hyd oxyla ion o
1a: A eac ion ube con aining a s i ing ba was cha ged wi h
y osine de i a i e 1a (0.25 mmol, 106 mg), PIFA (0.50 mmol)
and [RuCl2(p-cymene)]2(5 mol%). Then, anhyd ous 1,2-di-
chlo oe hane (1.0 mL) and TFA (1.0 mL) we e added by
sy inge. The eac ion ube was nex wa med up o 60°C in a
hea ing block and s i ed o 3.5 hou s. The mix u e was hen
allowed o wa m o oom empe a u e, he sol en was
e apo a ed and he esul ing c ude was washed up wi h an
aqueous solu ion o NaHCO3(20 mL). The aqueous laye was
ex ac ed wi h E OAc (3×20 mL), d ied o e MgSO4and
e apo a ed unde acuum. The esul ing c ude was hen pu i ied
by column ch oma og aphy o a o d 2a as a whi e solid
(80 mg, 73% yield). Mp 70–71°C. 1H NMR (400 MHz, CDCl3)
δ 7.82 (dd, J=5.5, 3.1 Hz, 2H), 7.72 (dd, J=5.5, 3.1 Hz, 2H),
7.04–6.80 (m, 2H), 6.74 (dd, J=8.2, 2.1 Hz, 1H), 5.16 (dd, J=
10.7, 5.7 Hz, 1H), 3.80 (s, 3H), 3.73–3.49 (m, 2H), 3.46–3.31
(m, 4H), 1.23 (d , J=21.9, 7.1 Hz, 6H). 13C NMR (101 MHz,
CDCl3) δ 169.2, 167.4, 154.5, 147.6, 139.0, 135.3, 134.1, 131.5,
123.5, 122.0, 120.9, 119.8, 53.0, 52.8, 42.5, 42.2, 33.9, 14.0,
13.1. IR (cm1): 3373, 2968, 1995, 1709, 1427, 1386, 1236,
1113, 716, 439. HRMS calcd. o (C23H24N2O7): 440.1584,
ound 440.1595. This eac ion was also pe o med in a highe
scale: he use o 1a (1.18 mmol, 500 mg), PIFA (2.36 mmol,
1.01 g) in a mix u e o DCE (8 mL) and TFA (1 mL) p o ided
305 mg (58% yield) o 2a as a whi e solid.
Acknowledgemen s
We a e g a e ul o Minis e io de Ciencia e Inno ación
(RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and Basque
Go e nmen (IT1033-16 and IT1254-19) o inancial suppo .
We hank o echnical and human suppo p o ided by SGIke
o UPV/EHU and Eu opean unding (ERDF and ESF). P. A.-S.
hanks DIPC o he esea ch con ac .
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UPDATES asc.wiley- ch.de
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published by Wiley-VCH GmbH
2079
Wiley VCH Donne s ag, 09.06.2022
2212 / 249781 [S. 2079/2079] 1