Metal–ligand cooperation and synergistic palladium catalysis for the dual ligand system [2,2′-bipyridin]-6(1H)–one/PCy3: milder conditions for the undirected C–H arylation of arenes

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RESEARCH ARTICLE
Ci e his: O g. Chem. F on ., 2025,
12, 467
Recei ed 6 h Oc obe 2024,
Accep ed 30 h Oc obe 2024
DOI: 10.1039/d4qo01877j
sc.li/ on ie s-o ganic
Me al–ligand coope a ion and syne gis ic
palladium ca alysis o he dual ligand sys em
[2,2’-bipy idin]-6(1H)–one/PCy
3
: milde condi ions
o he undi ec ed C–H a yla ion o a enes†
Cin ya Pinilla, Ma io Ga cía-Za za and Ana C. Albéniz *
The use o Pd(OAc)
2
and a mix u e o he coope a ing ligand [2,2’-bipy idin]-6(1H)–one (bipy-6-OH) and
PCy
3
in an op imal mol a io o Pd/bipy-6-OH/PCy
3
= 1 : 0.5 : 1 leads o a mo e ac i e sys em o he non-
chela e-assis ed di ec a yla ion o simple a enes. The sys em ope a es a a empe a u e 30 °C lowe han
ha o he Pd/bipy-6-OH sys em, and i is ac i e o a yl chlo ides as a yla ing pa ne s. Mechanis ic
expe imen s suppo he ope a ion o a bime allic pa hway ia wo connec ed ca aly ic cycles: a Pd/PCy
3
sys em esponsible o he oxida i e addi ion and educ i e elimina ion s eps and a Pd/bipy-6-OH sys em
ha enables C–H ac i a ion. Bo h cycles a e connec ed by a ansme ala ion s ep. The phosphine ligand
is no di ec ly in ol ed in he C–H ac i a ion, bu compa ed o he monoligand sys em, he occu ence o
he bime allic ou e changes he na u e o he key in e media e species in he C–H ac i a ion, a o ing
his u no e limi ing s ep and he o e all eac ion a e.
In oduc ion
The di ec use o a enes as coupling pa ne s in me al-ca a-
lyzed C–C bond- o ming eac ions is a sus ainable al e na i e
o he con en ional c oss-coupling p ocesses.
1
These eac ions
elimina e he need o use ei he he main g oup o gano-
me allic eac an o he o ganic halide (sul ona e)—o e en
bo h eagen s, sa ing he p e ious eac ion s eps equi ed o
hei p epa a ion. The di ec a yla ion o a enes is a s aigh -
o wa d example, whe e he o ganome allic eac an is subs i-
u ed by an a ene ha is con e ed in a bia yl de i a i e wi h
an a yl halide as a eac ion pa ne .
2
Howe e , s ong eac ion
condi ions a e gene ally equi ed because a C–H ac i a ion
s ep is needed, and i in ol es he coo dina ion o he a ene o
he me al and he clea age o he sluggish C–H bond. This
difficul y is mo e p onounced o non-chela e-assis ed (undi -
ec ed) unc ionaliza ion o simple a enes,
3
whe e he in e -
ac ion o he a ene wi h he me al is no acili a ed by he p es-
ence o a coo dina ing unc ional g oup, he di ec ing g oup,
ha ancho s he subs a e and allows an easie app oach o
he C–H bond o he me al cen e . The in oduc ion o
di ec ing g oups has many ad an ages in e ms o inc eased
eac i i y and selec i i y.
4
Howe e , he p e unc ionaliza ion o
he subs a e a ene wi h hese g oups e odes he s ep economy
and he sus ainabili y o he whole eac ion. Recen ad ances
in he use o ansien di ec ing g oups ha can be ins alled
and de ached in si u can alle ia e his d awback.
5
In any case,
mo e ac i e ca aly ic sys ems ha unc ionalize simple a enes
a e needed o b ing he undi ec ed C–H unc ionaliza ion
close o he mild condi ions o he con en ional c oss
couplings.
6
The unc ionaliza ion o simple a enes o en elies on he
use o me al–ligand coope a ion o enable he C–H ac i a ion
s ep.
7,8
Ligands con aining a basic g oup ha can pa icipa e
in he conce ed me ala ion dep o ona ion mechanism ha e
p o ed use ul: N-monop o ec ed amino acids (MPPA)
9
and py -
idone de i a i es, bo h mono-
10
and biden a e,
11
a e he mos
impo an , and a ew examples a e p esen ed in Scheme 1.
E en wi h he use o some o hese ligands, he palladium-
ca alyzed di ec a yla ion o simple a enes equi es long eac-
ion imes and empe a u es abo e 120 °C,
12
excep o some
speci ic ac i a ed subs a es, such as highly luo ina ed
a enes
13
o py idine oxide,
14
which ha e been ca ied ou a
abou 110 °C.
The use o a palladium p ecu so and wo diffe en
ligands, a so-called dual ligand sys em, has been used in C–H
unc ionaliza ion eac ions, leading o mo e efficien ca aly ic
sys ems in some cases.
15
In addi ion o he coope a ing
ligand, i.e., a MPAA o a py idone de i a i e ha enables C–H
†Elec onic supplemen a y in o ma ion (ESI) a ailable: Expe imen al de ails,
cha ac e iza ion and kine ic da a, selec ed spec a, compu a ional de ails and
absolu e ene gies o all he op imized s uc u es (PDF). Ca esian coo dina es
(xyz ile). See DOI: h ps://doi.o g/10.1039/d4qo01877j
IU CINQUIMA/Química Ino gánica, Uni e sidad de Valladolid, 47071 Valladolid,
Spain. E-mail: [email p o ec ed]
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ac i a ion, a second monoden a e ligand is added o he
mix u e. In all he epo ed cases, he C–H ac i a ion s ep has
been p oposed o occu in an in e media e complex wi h bo h
ligands coo dina ed o he me al (Scheme 2). Thus, an
Gemme en e al. used a combina ion o an N-monop o ec ed
amino acid and an N-dono he e ocyclic ligand, usually a py -
idine (Scheme 2a), o mo e efficien C–H unc ionaliza ion
eac ions o simple a enes,
16
such as ole ina ion,
17
cyana-
ion,
18
and alkynyla ion p ocesses.
19
Yu e al. used a simila
app oach in di ec ed C(sp
3
)–H unc ionaliza ion eac ions,
20
and a mix u e o a chela ing py idone and a monoden a e
py idine was employed o he ole ina ion o py idine
(Scheme 2a).
21
The ole ina ion o a enes using a mix u e o a
MPAA and a hioe he as ligands,
22
and he chalcogena ion o
a enes o he a yla ion o luo oole ins wi h a MPAAs/mono-
den a e py idine, ha e also been epo ed.
23
De Vos’sg oup
de eloped he a yla ion o he e ocycles using a mix u e o a
py idone and a phosphine (Scheme 2a). As in all he abo e-
men ioned examples, he au ho s p oposed ha bo h ligands
a e coo dina ed o he me al in he key s eps o he eac ion,
and hey p o ided expe imen al MS e idence o he occu -
ence o palladium species wi h bo h ligands a ached o he
me al.
24
We epo he e a palladium ca aly ic sys em ha uses a
combina ion o a bipy idone and a phosphine ligand and
shows highe ac i i y han he coope a ing monoligand sys em
(bipy idone). A a iance wi h he examples epo ed in he li -
e a u e, he sys em equi es a speci ic me al- o-ligand a io
ha poin s o a syne gis ic bime allic palladium ou e wi h wo
connec ed ca aly ic cycles. Each ligand is in ol ed in one ca a-
ly ic cycle, and hey a e no simul aneously coo dina ed o he
me al (Scheme 2b).
In con as o o he he e ome al combina ions, syne gis ic
Pd–Pd ca alysis is a e, and only a ew examples ha e been
epo ed,
25
e en ewe in he ealm o C–H ac i a ion. S udying
he di ec a yla ion o py idine oxide wi h he mix u e o Pd
(OAc)
2
and P
Bu
3
as ca alys sys em, Ha wig e al. epo ed a
bime allic mechanism whe e he me ala ion o P
Bu
3
led o a
palladacycle esponsible o he C–H ac i a ion s ep, whe eas
he oxida i e addi ion o he a yl halide akes place in a palla-
dium–phosphino complex (Scheme 3a).
26
Hong e al. obse ed
a simila p ocess using a diimine palladium complex, whe e
he chela ing ni ogen-dono ligand is no in ol ed in he C–H
ac i a ion s ep; his occu s in he absence o ligand ia a CMD
mechanism assis ed by he ca boxyla e used as a base
(Scheme 3b).
27
A bime allic pa hway has also been obse ed by
S ahl e al. in he oxida i e coupling o wo a enes o gi e
bia yl de i a i es.
28
The di ec a yla ion eac ions in Scheme 3
s ill equi ed high empe a u es and long eac ion imes. The
combina ion o a coope a ing chela ing bypi idone and a phos-
phine shown he e affo ds, by op imiza ion o each ligand ole,
a mo e ac i e ca alys sys em ha allows a shi o milde eac-
ion condi ions.
Resul s and discussion
Reac ion op imiza ion and a yla ion examples
The di ec a yla ion o oluene wi h a yl iodides can be ca ied
ou using a Pd-ca alys wi h [2,2′-bipy idin]-6(1H)–one (bipy-6-
OH) as he only ligand a 130 °C, as has been shown
p e iously.
11a,29
The effec o he addi ion o a phosphine
ligand was es ed using he coupling be ween oluene and
Scheme 2 Dual-ligand app oach in C–H unc ionaliza ion: (a) wo
ligands/one complex in he C–H ac i a ion s ep; (b) wo ligands/ wo
complexes wo king syne gis ically ( his wo k).
Scheme 3 Ca alys s o he di ec a yla ion o a enes ha ope a e by a
bime allic mechanism.
Scheme 1 Some examples o coope a ing ligands in C–H ac i a ion.
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p-CF
3
C
6
H
4
X (an a yl ha allows he easy moni o ing o he
eac ion by
19
F NMR) as a model eac ion (eqn (1)). Wi h
oluene as a eac an and sol en a 130 °C and using bipy-6-
OH as he only ligand, he bia yl de i a i e is o med in 20%
yield a e 6 h (Table 1, en y 1; 91% a e 24 h, see he ESI†).
The use o a combina ion o he bipy idone ligand and
icyclohexylphosphine has a bene icial effec on he eac ion,
and he mix u e o Pd(OAc)
2
(5 mol%)/bipy-6-OH (2.5 mol%)/
PCy
3
(5 mol%) accele a ed he eac ion, which was comple e in
6 h (90% yield s. 22% in he absence o PCy
3
, Table 1, en ies
1 and 2). This effec is also obse ed o he co esponding
and less expensi e b omoa yl, and a espec able 59% o he
coupling p oduc was ob ained a e 6 h, s. 16% in absence o
PCy
3
(en ies 3 and 4, Table 1).
O he phosphines such as PPh
3
and P
Bu
3
we e also es ed
unde hese condi ions, as well as o he Pd p ecu so s, bu
PCy
3
and Pd(OAc)
2
ga e he bes esul s (see Table S1, ESI†).
The use o a cosol en such as DMA o pinacolone accele a es
his ype o eac ion, and his has been shown and s udied
be o e.
29
Thus, he use o a oluene/DMA mix u e allowed he lowe -
ing o empe a u e o 100 °C and he eac ion o comple e in
3 h (en y 6, Table 1). Excellen yields we e ob ained a 90 °C
a e 24 h, (96% yield), bu he con e sion is oo low a 80 °C
(en ies 7 and 8, Table 1). A lowe excess o oluene (mol a io
oluene/A X = 10 : 1) led o a s ong dec ease in he yield (29%
a e 24 h). The a e o he eac ion and yield a e no affec ed
by he way he p eca alys mix u e is p epa ed. The eac ions in
Table 1 we e ca ied ou by mixing Pd(OAc)
2
and bo h ligands
in he eac ion lask. Unde he same condi ions, he p e ious
independen mix u es (in sepa a e lasks o Pd(OAc)
2
/PCy
3
on
he one hand and Pd(OAc)
2
/bipy-6-OH on he o he hand),
be o e addi ion o he solu ion o he eac an s, ga e he same
esul s shown in en y 6, Table 1.
Unde he op imum condi ions o sol en and empe a u e
(d y DMA as co-sol en and 100 °C, eqn (2)), o he ligands and
ligand a ios we e es ed, and he esul s a e p esen ed in
Table 2. The absence o PCy
3
o bipy-6-OH esul s in no C–C
c oss-coupling p oduc , and a yl b omide is mainly con e ed
in o he dehalogena ed A H de i a i e, so bo h ligands a e
necessa y unde hose condi ions (en ies 1–3, Table 2). The
C–H unc ionaliza ion was no obse ed o analogous ligands
o bipy-6-OH ha canno be in ol ed in me al–ligand
coope a ion because o he lack o a coope a ing py idone
moie y (i.e. bipy) o because, upon coo dina ion, he py idone
oxygen is a om he me al (i.e. bipy-4-OH, eqn (2)) (en ies 4
and 5, Table 2).
Modi ica ions in he bipy scaffold esul ed in a loss o
ac i i y (en y 6, Table 2). MPAA- ype ligands and he monoden-
a e 2-py idone we e also ied, bu hey ga e no coupling
p oduc (en ies 7 and 8, Table 2). Diffe en phosphines we e
es ed: PPh
3
and P
Bu
3
led o mode a e o low yields; howe e ,
XPhos p oduced simila esul s o PCy
3
bu in longe eac ion
imes (en ies 9–11, Table 2). Thus, bulky and elec on-dona ing
phosphines a e adequa e o his dual sys em; he inabili y o
P
Bu
3
o accele a e he eac ion migh be ela ed o i s known
abili y o o m P–C palladacycles, which a e no ac i e unde he
eac ion condi ions used he e.
26
T icyclohexylphosphonium
e a luo obo a e, less sensi i e han PCy
3
and easily dep o o-
na ed unde he eac ion condi ions, also ga e excellen yields
(en y 12, Table 2). Diffe en ligand concen a ions we e also
es ed: a 5 mol% o bipy-6-OH has a small effec on he eac ion
a e and yield; howe e , inc easing o dec easing he mola a io
o PCy
3
esul s in lowe a es (en ies 13–16, Table 2). In hese
cases, he eac ions need longe imes o comple ion, bu good
yields (80–90%) we e ob ained a e 24 h.
We decided o es he eac ion using p e o med palladium
complexes wi h coo dina ed PCy
3
. Thus, he mix u e Pd(OAc)
2
+ bipy-6-OH was combined wi h he co esponding palladium
phosphino complex. These complexes could be o med unde
ca aly ic condi ions and e en be in ol ed as eac ion in e -
media es. The Pd(0) de i a i e [Pd(PCy
3
)], as well as he Pd(II)
complex 1, led o excellen yields o he a yla ed oluene bu in
longe eac ion imes han he analogous expe imen using
he ee phosphine (6 h, en ies 17 and 18 s. 3 h o en y 1,
Table 2). The dime ic palladium complex 2was also es ed. In
his case, only one PCy
3
is coo dina ed o each palladium, and
he effec i e amoun o phosphine added is hal ha in he
expe imen s abo e (en y 19, Table 2). Longe eac ion imes
(24 h) a e needed o ge ull con e sion and good yield (87%).
A ine uning o he amoun o phosphine p esen along wi h
he p e o med complex 2 o a inal effec i e a io Pd/bipy-6-
OH/PCy
3
= 1 : 0.5 : 0.75, as shown in en y 20, Table 2, es o ed
he a e and yield obse ed unde he bes condi ions o en y
1, Table 2.
Table 1 A yla ion o oluene wi h p-CF
3
C
6
H
4
X acco ding o eqn (1)
using diffe en eac ion condi ions
a
En y L1
b
(mol %) L2
b
(mol %) X Sol en T
(°C) C ude yield, %,
(Con ., %), 6 h
c
1
d
5—I Toluene 130 20 (22)
2 2.5 5 I Toluene 130 90 (100)
35 —B Toluene 130 16 (16)
4 2.5 5 B Toluene 130 59 (65)
5 2.5 5 B Toluene 100 25 (28)
6 2.5 5 B Toluene/DMA
e
100 90 (94)
7 2.5 5 B Toluene/DMA
e
90 42 (44)
g
8 2.5 5 B Toluene/DMA
e
80 15 (15)
h
a
Reac ion condi ions: p-CF
3
C
6
H
4
X (0.34 mmol), Cs
2
CO
3
(0.68 mmol),
o al olume 3 mL.
b
L1 = bipy-6-OH; L2 = PCy
3
.
c
C ude yields de e -
mined by
19
F NMR o he eac ion mix u e. The educ ion o he a yl-
b omide (A H) and he homocoupling (A –A ) a e he obse ed byp o-
duc s.
d
Da a om he li e a u e ( e . 29).
e
1/1 olume a io (mol a io
oluene/A X = 40 : 1).
Reac ion ime 3 h.
g
96% yield a e 24 h.
h
33%
yield a e 24 h.
O ganic Chemis y F on ie s Resea ch A icle
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The di ec a yla ion o oluene using his ca alys sys em
can be ex ended o o he a yl b omides as coupling pa ne s
(Scheme 4). Elec on-dona ing o elec on-wi hd awing unc-
ional g oups can be p esen in he a yl halide (3aa–3ae,
Scheme 4). Longe eac ion imes we e used o ensu e he
comple e con e sion o he eac an s when he eac ion
could no be ollowed by NMR o he c ude mix u e. The
a yla ion o oluene is no egioselec i e, and a mix u e o
h ee isome s (o ho,me a and pa a) was ob ained in all
cases, wi h no s ong p e e ence o any posi ion a e con-
side ing he s a is ical ac o . p-B omobenzoni ile and
p-b omobenzoic acid we e also es ed, bu hey did no
lead o he c oss-coupling p oduc . Al hough elec onically
simila o o he a yl b omides es ed, he coo dina ion
abili y o he subs i uen , specially he ca boxyla e moie y
expec ed unde ca aly ic condi ions, may in luence he eac-
ion ou come. The o ho subs i u ion in a yl b omide dis a-
o ed he eac ion, and only 25% o a mix u e o isome ic
coupling p oduc s was ob ained when o-CF
3
C
6
H
4
B was
eac ed wi h oluene.
In e es ingly, he eac ion also wo ks o a yl chlo ides,
which bea bo h elec on-dona ing and elec on-wi hd awing
g oups (Scheme 4). This is ema kable since a yl chlo ides a e
a ely ac i e in di ec a yla ion eac ions o simple a enes wi h
no di ec ing g oups.
12a,30
As a esul , he eac ion o p-b omo-
chlo obenzene wi h oluene as a ene ga e a mix u e o mono-
and di olyl p oduc s.
Diffe en a enes we e also es ed. E hyl benzoa e, i luo o-
oluene, and N,N-dime hylaniline ga e mode a e o good yields
o he bia yl, he me a isome being he majo p oduc (3ca,
3e ,3ha, Scheme 4). The eac ion is comple ely me a egio-
selec i e o py idine (3ka). On he o he hand, when anisole
and luo obenzene we e eac ed, he o ho bia yl p oduc was
p e e ed (3da,3ga). The e is no clea co ela ion be ween he
elec onic p ope ies o he a ene and he egioselec i i y o
he eac ion. The p e e ence o py idine o a yla ion in he
me a posi ion has been obse ed be o e,
11a,31
as well as he
Table 2 Ca alys sc eening o he a yla ion o oluene wi h
p-CF
3
C
6
H
4
B acco ding o eqn (2)
a
En y Pd(OAc)
2
(mol %) L1 (mol %) L2 (mol %)
C ude yield,
%, (Con ., %),
6h
b
1 5 Bipy-6-OH (2.5) PCy
3
(5) 90 (94)
c
2 5 Bipy-6-OH (5) —0 (100)
35 —PCy
3
(10) 0 (100)
4 5 Bipy (2.5) PCy
3
(5) 0 (22)
5 5 Bipy-4-OH (2.5) PCy
3
(5) 0 (0)
6 5 BipyCH
2
-6-OH (2.5) PCy
3
(5) 3 (10)
75 N-Ac-Gly (2.5) PCy
3
(5) 0 (5)
8 5 2-Py idone (2.5) PCy
3
(5) 3 (12)
9 5 Bipy-6-OH (2.5) PPh
3
(5) 38 (45)
10 5 Bipy-6-OH (2.5) P
Bu
3
(5) 4 (9)
11 5 Bipy-6-OH (2.5) XPhos (5) 80 (85)
12 5 Bipy-6-OH (2.5) (PCy
3
H)BF
4
(5) 93 (97)
c
13 5 Bipy-6-OH (5) PCy
3
(5) 78 (84)
c
14 5 Bipy-6-OH (5) PCy
3
(10) 31 (40)
d
15 5 Bipy-6-OH (2.5) PCy
3
(7.5) 46 (54)
d
16 5 Bipy-6-OH (2.5) PCy
3
(2.5) 35 (38)
d
17 2.5 Bipy-6-OH (2.5) [Pd(PCy
3
)
2
] (2.5) 92 (95)
18 2.5 Bipy-6-OH (2.5) 1(2.5) 72 (75)
19 2.5 Bipy-6-OH (2.5) 2(1.25) 27 (35)
d
20 2.5 Bipy-6-OH (2.5) 2(1.25)
(PCy
3
H)BF
4
(1.25) 98 (98)
c
a
Reac ion condi ions: p-CF
3
C
6
H
4
B (0.34 mmol), Cs
2
CO
3
(0.68 mmol),
d y oluene (1.5 mL), d y DMA (1.5 mL), 100 °C.
b
C ude yields de e -
mined by
19
F NMR o he eac ion mix u e. The educ ion o he a ylb o-
mide (A H) and he homocoupling (A –A ) a e he obse ed byp oduc s.
c
A e 3 h.
d
80–90% yield a e 24 h (see ESI†).
Scheme 4 Di ec a yla ion o diffe en a enes wi h he Pd(OAc)
2
/bipy-
6-OH/PCy
3
ca alys sys em.
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o ho subs i u ion o luo ina ed a enes.
32
In a ew cases,
good esul s we e ob ained using jus 10 equi alen s o he
a ene (anisole, py idine).
The C–H a yla ion did no ake place wi h aniline as he
a ene, and he compe i i e C–N coupling p oduc was ob ained
as he only p oduc (amina ion eac ion), in sha p con as
wi h he ca aly ic sys em wi h bipy-6-OH as he only ligand,
which is capable o selec i ely p oducing o ho-a yla ed unp o-
ec ed anilines.
33
Mechanis ic expe imen s
In o de o shed ligh in o he eac ion mechanism, se e al
expe imen s we e ca ied ou . Fi s o all, we s udied he
species o med om he mix u e o Pd(OAc)
2
and PCy
3
.We
obse ed he coo dina ion o wo phosphines o palladium
ace a e esul ing in he complex [Pd(OAc)
2
(PCy
3
)
2
] as well as
[Pd(PCy
3
)
2
] wi h he concomi an oxida ion o one phos-
phine (eqn (3) and Fig. S1, ESI†).
34
The e o e, Pd(0) species
can be easily o med om he p eca aly ic mix u e, consum-
ing some o he phosphine added, which ac s as a educing
agen . This is consis en wi h he p e o med complex
[Pd(PCy
3
)
2
]alsobeingefficien in he ca aly ic eac ion
(en y 17, Table 2).
PdðOAcÞ2þ2 PCy3!
Toluene‐d8
25°C½PdðOAcÞ2ðPCy3Þ2þOPCy3þ½PdðPCy3Þ2
ð3Þ
Kine ic expe imen s we e ca ied ou using he eac ion
be ween oluene and p-CF
3
-C
6
H
4
B as a model (eqn (4)).
Using he a iable ime no maliza ion analysis (VTNA)
epo ed by Bu és,
35
he esul s showed a i s -o de depen-
dence on palladium in a concen a ion ange o 2.8–5.6 mM
(Fig. 1). The use o much lowe ca alys concen a ions led o
a e y slow eac ion, so he hypo he ical change in ca alys
o de om one o wo, some imes obse ed in some bi-
me allic p ocesses a e y low ca alys concen a ions,
27,28
was
no ound. A ze o-o de dependence on he concen a ion o
he a yl b omide o a yl chlo ide was obse ed (see ESI,
sec ion 1.5.2†). The kine ic iso ope effec was de e mined,
and la ge alues we e ound o bo h p-CF
3
-C
6
H
4
B (KIE = 4.0
±0.5)andp-CF
3
-C
6
H
4
Cl(KIE=3.5±0.3)when wosepa a e
expe imen s we e ca ied ou using oluene and oluene-d
8
,
consis en wi h C–H ac i a ion being he u no e limi ing
s ep (eqn (4) and sec ion 1.5.1, ESI†).
ð4Þ
The mechanis ic scheme o his dual sys em has o explain
he ad an age o bo h ligands and accoun o he ac ha he
op imal me al- o-ligand mol a io is Pd/bipy-6-OH/PCy
3
=
1 : 0.5 : 1. Mo eo e , conside ing he educ ion o Pd(0) men-
ioned abo e, he ac ual phosphine amoun p esen unde
ca aly ic condi ions can be smalle . Also, he kine ic expe i-
men s show ha he C–H ac i a ion s ep is u no e limi ing
and ha he C–H clea age is assis ed by he coope a ing bipy-
6-O (c . en ies 1 and 3–5, Table 2). The dual sys em is ac i e
o a yl chlo ides, whe eas he monoligand (bipy-6-OH) sys em
is no , e en a he highe empe a u e used o he eac ion
(130 °C). This poin s o he in ol emen o PCy
3
in he oxi-
da i e addi ion s ep.
The plausible mechanis ic pa hway is ep esen ed in
Scheme 5. I shows a bime allic p ocess h ough wo diffe en
palladium complexes ac ing in a syne gis ic way: on one cycle,
PCy
3
is coo dina ed o hal o he palladium cen e s and on
Fig. 1 Plo s de i ed om he a iable ime no maliza ion analysis (VTNA). O e lay o plo s gi es he o de in he ca alys (powe alue in abscissa
axis). [Ca ] = Pd(OAc)
2
/0.5 bipy-6-OH/PCy
3
; he gi en concen a ion co esponds o he Pd p ecu so . See he ESI o de ails (sec ion 1.5.2).†
Scheme 5 Reac ion pa hway o he Pd/bipy-6-OH/PCy
3
dual ligand
sys em.
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he o he , a bipy-6-OH-con aining complex. The oxida i e
addi ion o a yl b omide occu s on he phosphine complex.
Meanwhile, he coo dina ion and C–H ac i a ion o oluene
akes place in he bipy-6-OH complex. A e dep o ona ion o
he ligand, which easily occu s in he p esence o Cs
2
CO
3
,a
ansme ala ion s ep be ween bo h me al cen e s places he
o ganic g oups coo dina ed o a phosphine complex ha
would unde go he educ i e elimina ion s ep, leading o he
inal p oduc and he Pd(0) complex ha een e s he ca aly ic
cycle.
We pe o med some independen s oichiome ic expe i-
men s in o de o p obe his p oposal. Ligand exchange expe i-
men s we e ca ied ou i s , as shown in Scheme 6. We used
isolable, well-de ined model de i a i es ha show analogies o
he complexes o med a e he C–H ac i a ion p ocess (com-
plexes 4and 6) o as a esul o he oxida i e addi ion o he
a yl halide (complex 1). Complex 4, as a model complex wi h a
coo dina ed neu al ligand bipy-6-OH, was eac ed wi h 2
equi alen s o PCy
3
in he sol en mix u e used in he ca aly ic
expe imen s ( oluene/DMA, 1 : 1 / ). A complex wi h wo co-
o dina ed PCy
3
(5) and ee bipy-6-OH was o med a e a ew
minu es a oom empe a u e (Scheme 6a and Fig. S3–S7,
ESI†).
The same expe imen was ca ied ou using he p e o med
complex 6, whe e he coo dina ing ligand is dep o ona ed and
monoanionic (bipy-6-O). I has been shown p e iously ha he
coo dina ion abili y o he ligand is be e when i is dep o o-
na ed.
11a
One hou a e he addi ion o phosphine a oom
empe a u e, he o ma ion o a new complex was obse ed,
which we en a i ely assigned o complex 7(Scheme 6b). The
eac ion e ol ed o he o ma ion o complex 5a e hea ing
he mix u e a 100 °C o 30 min (Fig. S8–S10, ESI†). This
shows ha he subs i u ion o he bipy-6-O by PCy
3
is mo e
difficul han in he case o bipy-6-OH; howe e , i is occu ing
unde he ca aly ic condi ions. The e e se eac ion, he subs i-
u ion o a coo dina ed PCy
3
by he bipy idone ligand, was
also es ed. Bipy-6-OH was added o complex 1in oluene/
DMA (1 : 1), and no changes in he eac ion mix u e we e
obse ed. The addi ion o cesium ca bona e o dep o ona e
he ligand led o he same esul s bo h a oom empe a u e
and a 100 °C (Scheme 6c and Fig. S11, ESI†). These expe i-
men s clea ly show ha he coo dina ion abili y o he ligands
p esen in he ca alysis ollows he end PCy
3
> bipy-6-O >
bipy-6-OH. Thus, an excess o phosphine will ha e a de imen-
al effec in he eac ion by coo dina ing o palladium p e e -
en ially and dec easing he concen a ion o he bipy-6-O com-
plexes, esponsible o he u no e limi ing s ep. This is
obse ed in he ca aly ic expe imen s (c . en ies 1, 15 and 13,
14 in Table 2). When an excess o bipy-6-OH is added, he ela-
i e concen a ion o bo h ypes o complexes is no al e ed sig-
ni ican ly, and he effec on he eac ion a e is no impo an
(c . en ies 1 and 13, Table 2).
Bo h syne gis ic ca aly ic cycles in Scheme 5 a e connec ed
by a ansme ala ion s ep, and he easibili y o he a yl
exchange be ween palladium cen e s was es ed by using wo
model complexes o bo h in e connec ing cycles. The bipy-6-
O complex 8was p epa ed in si u by b omide abs ac ion and
dep o ona ion o 4using sil e ca bona e. A e il a ion o
he insoluble sil e byp oduc s, complex 1was added o he
solu ion o 8and hea ed a 100 °C. The coupling p oduc C
6
F
5
-
C
6
H
4
-p-CF
3
was clea ly obse ed by
19
F NMR (14%, e e ing o
he o al amoun o pen a luo ophenyl species) along wi h
[PdB (C
6
F
5
)(PCy
3
)
2
](5) as a esul o he subs i u ion o he
bipy-6-O ligand by he ee phosphine gene a ed in he
decomposi ion eac ion (Scheme 7a and Fig. S12 in he ESI†).
A ac ion o he added phosphine in he ca alysis is con-
sumed in he educ ion o Pd(OAc)
2
o Pd(0), as shown in he
expe imen in eqn (3); because o his, he ac ual amoun o
PCy
3
unde ca aly ic condi ions would lead o a phosphine
complex wi h a a io o PCy
3
/Pd < 2. The e o e, he palladium
complex wi h only one coo dina ed PCy
3
(2) was es ed as he
ansme ala ion pa ne o 8. The expe imen was done in he
same way as men ioned abo e, and complex 2was added o
he in si u gene a ed 8, hen he mix u e was hea ed a 100 °C.
A e 3 h, 48% o he coupling p oduc was o med (Scheme 7b
and Fig. S13, ESI†). The addi ion o cesium ca bona e (also
Scheme 7 T ansme ala ion expe imen s.Scheme 6 Ligand exchange expe imen s.
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p esen in he ca aly ic eac ions) has no in luence in he
amoun o C
6
F
5
-C
6
H
4
-p-CF
3
ob ained (45%). These expe i-
men s show ha a ansme ala ion s ep be ween a bipy-6-O
palladium complex and a phosphine-con aining Pd-de i a i e
is possible, and i is a plausible elemen a y s ep in he ca aly ic
cycle. An excess o phosphine dis a o s his p ocess, which is
mo e efficien o monophosphine de i a i e 2, and his con-
ibu es o he slow a e obse ed o he ca aly ic eac ions
upon he addi ion o highe amoun s o phosphine (c . en ies
1, 15 and 13, 14 in Table 2). The in e se dependence o he
ansme ala ion a e on he concen a ion o he ligand has
been s udied o o he me al combina ions such as Au/Pd o
Sn/Pd in he con ex o S ille couplings.
36–38
The na u e o he in e media es in he C–H ac i a ion
When his dual bipy-6-OH/PCy
3
ca aly ic sys em is compa ed o
ha enabled by he coope a ing bipy-6-OH only, he e a e some
diffe ences ha a e wo h men ioning. The bipy-6-OH-only
sys em shows no signi ican diffe ences in eac i i y o a enes
wi h elec on-wi hd awing o elec on-dona ing g oups, and he
egioselec i i y obse ed a o s he me a isome in all cases.
29
In
con as , he dual sys em showed an effec o he elec onic p o-
pe ies o he a ene in he eac ion a e as de e mined by he
moni o ing o he ini ial a e o he di ec a yla ion o oluene,
e hyl benzoa e and anisole wi h p-CF
3
-C
6
H
4
B . The k
obs
o each
expe imen a e p esen ed in Table 3; hey show ha he eac ion
is as e o a enes wi h elec on-dona ing g oups (anisole) han
o a enes wi h elec on-wi hd awing g oups (e hyl benzoa e). In
he o me case, he o ho/pa a selec i i y is a o ed. These da a
poin o mo e elec ophilic palladium in e media es in ol ed in
he C–H ac i a ion s ep o he dual sys em.
When bipy-6-OH is used as he only ligand, he oxida i e
addi ion o he a yl halide leads o a yl palladium in e -
media es such as c4–c5 in Fig. 2, whe e he C–H ac i a ion
akes place as has been es ed expe imen ally in model
complexes.
11a,29
In he dual sys em, his elemen a y s ep
would happen in a palladium complex wi h he bipy-6-O co-
o dina ed, which is esponsible o he C–H bond ac i a ion,
and o example, an ace a e (c2, Fig. 2a) ins ead o he mo e
elec on- ich complex c5 wi h an a yl g oup ha is in ol ed in
he monoligand ca aly ic cycle (Fig. 2b). DFT calcula ions o
he C–H ac i a ion s ep on a simple model we e ca ied ou
using he M06 unc ional and including sol a ion in he
op imiza ions h ough he SMD implici sol en me hod
(DMA) a he expe imen al empe a u e (100 °C, see compu-
a ional de ails in he ESI†). A o al ΔΔG
‡
o 26.9 kcal mol
−1
was ound ia c2 (Fig. 2a). The calcula ed ΔΔG
‡
o he C–H
ac i a ion ia in e media e c5 was ound o be highe
(28.4 kcal mol
−1
, Fig. 2b). This accoun s o he diffe ence in
ac i i y o bo h sys ems.
39
The in e media e complex c2 wi h a
coo dina ed ace a e is he mos plausible in e media e s. a
b omide-liga ed de i a i e [Pd(bipy-6-O)B ( oluene)] since,
gi en he highe solubili y o cesium ace a e s. cesium
b omide in he sol en used, he equilib ium c1–c2 is expec ed
o be less dis a o ed when CsB is o med. A hypo he ical C–H
ac i a ion in a ca ionic complex wi h bo h bipy-6-O and PCy
3
coo dina ed o palladium was also calcula ed, bu he o al
ΔΔG
‡
ound ises o 37.2 kcal mol
−1
, which makes he in ol e-
men o such species unlikely (Fig. 2c).
Compa ing bo h ansi ion s a es in Fig. 2a and b, i can be
seen ha he C–H and C–Pd bond dis ances o TS c2–c3 a e
Table 3 Ra e cons an s o he a yla ion o a enes wi h diffe en elec-
onic p ope ies wi h p-CF
3
-C
6
H
4
B
a
A ene P oduc k
obs
(M min
−1
)
Anisole p-CF
3
-C
6
H
4
-C
6
H
4
(OMe) 3.6 ± 0.3 × 10
−4
Toluene p-CF
3
-C
6
H
4
-C
6
H
4
Me 2.7 ± 0.1 × 10
−4
E hyl benzoa e p-CF
3
-C
6
H
4
-C
6
H
4
CO
2
E 7.3 ± 0.7 × 10
−5
a
Reac ion condi ions shown in en y 1, Table 2.
Fig. 2 DFT p ofiles o he C–H ac i a ion in: (a) he dual bipy-6-OH/
PCy
3
ca aly ic sys em; (b) he ca aly ic sys em ha uses bipy-6-OH only;
(c) a complex wi h bo h bipy-6-O and phosphine ligands coo dina ed o
palladium. Ene gies in kcal mol
−1
.
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sligh ly sho e han hose in TS c4–c5, indica ing ha he
mechanism o C–H ac i a ion has an elec ophilic CMD cha -
ac e (eCMD, also known as BIES, base-assis ed in e nal elec-
ophilic subs i u ion),
40,41
whe e he ansi ion s a e is cha ac-
e ized by mo e ad anced me al–ca bon bonding and less C–H
bond clea age, as discussed by Wang and Ca ow.
41
This is in
ag eemen wi h he highe a e obse ed o elec on- ich
a enes.
Thus, because he oxida i e addi ion s ep is happening in a
phosphine complex and no in he bipy-6-O complex
(Scheme 5), he na u e o he in e media es in he u no e
limi ing C–H ac i a ion s ep is modi ied, lowe ing he o e all
ba ie o he eac ion and making he whole sys em mo e
ac i e.
Conclusions
The mix u e o a coope a ing bipy idone ligand, capable o
assis ing he C–H ac i a ion s ep (bipy-6-OH), and a phosphine
(PCy
3
) in combina ion wi h Pd(OAc)
2
in a sui able mol a io
o ms a e y ac i e ca alys o he challenging di ec a yla ion
o simple a enes. The dual ligand combina ion is mo e ac i e
han he monoligand Pd/bipy-6-OH ca alys , and he eac ions
can be ca ied ou unde milde condi ions (sho eac ion
imes and a dec ease in empe a u e by 30 °C). Besides he
common a yl iodides o b omides, he sys em is also capable
o a yla ing simple a enes using a yl chlo ides. This expands
he u ili y o his eac ion o a wide ange o eac an s.
The inc ease in ac i i y o he dual sys em occu s by a no el
combined me al–ligand coope a ion (MLC) o C–H ac i a ion
and a syne gis ic Pd–Pd mechanism. Two ca aly ic cycles
ope a e: (a) a Pd/PCy
3
sys em whe e he A X oxida i e addi ion
and he bia yl educ i e elimina ion ake place, and (b) a Pd/
bipy-6-OH sys em whe e he C–H ac i a ion occu s ia MLC
wi h no in ol emen o he phosphine ligand. Bo h cycles a e
connec ed by ansme ala ion o an a yl g oup om one Pd o
ano he Pd cen e (Scheme 5). The p esence o he phosphino
palladium species ac s in ac as a Pd-a yl ese oi and, as a
esul , a change in he na u e o he species esponsible o
he C–H ac i a ion o he a ene occu s. This species bea s a
mo e elec ophilic me al cen e and leads o a lowe ba ie o
C–H ac i a ion, he u no e limi ing s ep, p oducing an
o e all accele a ion effec . Thus, he bene icial effec o he
addi ional ligand is no a di ec in ol emen in he u no e
limi ing s ep o he eac ion ia coo dina ion o he key in e -
media e, bu he opening o a diffe en pa hway which
indi ec ly in luences he na u e o he in e media e whe e he
C–H clea age akes place.
Expe imen al
Gene al conside a ions
1
H,
13
C{
1
H},
31
P{
1
H} and
19
F NMR spec a we e eco ded on
Agilen MR-500, Agilen MR-400 o B uke AV-400 spec-
ome e s a he LTI/UVa. Chemical shi s (in δuni s, ppm)
we e e e enced o SiMe
4
(
1
H and
13
C), CFCl
3
(
19
F) and H
3
PO
4
(85%,
31
P). The spec al da a we e eco ded a 298 K unless
o he wise no ed. HRMS analyses we e ca ied ou on a B uke
Maxis Impac mass spec ome e a he LTI/UVa. Elemen al
analyses we e ca ied ou in a The mo Scien i ic FLASH
2000 mic oanalyze (a he Pa que Cien í ico Tecnológico/
UBU).
Sol en s we e dis illed om app op ia e d ying agen s
unde ni ogen and s o ed o e 3 Å o 4 Å molecula sie es
( oluene) o used di ec ly om s o age wi h he d ying agen
(anisole, e hyl benzoa e, α,α,α- i luo o oluene, luo obenzene
and N,N-dime hylaniline). DMA, pinacolone, oluene-d
8
and
py idine we e pu chased as anhyd ous and s o ed unde ni o-
gen o e 3 Å o 4 Å molecula sie es. In he case o DMA, used
as co-sol en in he ca aly ic eac ions, he d ying p ocedu e
was as ollows: i was s o ed o e molecula sie es o a week
and hen ans e ed o a lask wi h eshly ac i a ed molecula
sie es and kep o ano he week p io o use.
The haloa yl de i a i es, cesium ca bona e, palladium
ace a e, PR
3
(R = Cy, Ph,
Bu), (PCy
3
H)BF
4
, X-Phos, 2,2′-bipy i-
dine, N-ace ylglycine, and 2-py idone a e comme cially a ail-
able and we e pu chased and used as ecei ed unless o he -
wise no ed. [2,2′-Bipy idin]-6(1H)-one (bipy-6-OH),
11a
[2,2′-
bipy idin]-4(1H)-one (bipy-4-OH),
11a
[Pd(bipy-6-OH)B (C
6
F
5
)]
(4),
11a
(NBu
4
)[Pd(bipy-6-O)B (C
6
F
5
)] (6),
11a
[Pd(C
6
H
4
-p-CF
3
)I
(TMEDA)],
42
and [Pd
2
dba
3
].CHCl
3
,
43
we e p epa ed acco ding
o he p ocedu es in he li e a u e.
Ca aly ic eac ions
Gene al p ocedu e o he di ec a yla ion o a enes. Pd
(OAc)
2
(3.8 mg, 0.017 mmol), bipy-6-OH (1.5 mg,
0.0085 mmol) and cesium ca bona e (222 mg, 0.68 mmol)
we e in oduced in a Schlenk lask unde a ni ogen a mo-
sphe e. The co esponding a yl halide (0.34 mmol), PCy
3
(4.7 mg, 0.017 mmol) dissol ed in he co esponding a ene
(1.5 mL) and DMA (1.5 mL) we e added o he lask. The
mix u e was s i ed a 100 °C and checked by
19
F NMR a he
indica ed ime. When o al con e sion was obse ed, he
sol en was e apo a ed in acuo, and he o ganic p oduc was
ex ac ed wi h a mix u e o n-hexane (8 mL) and e hyl ace a e
(2 mL). The ex ac was il e ed h ough kieselgu and e apo -
a ed o d yness. The p oduc s we e checked by NMR and
GC-MS. C ude yields and isome a ios we e de e mined by
19
F
NMR o he c ude mix u e o
1
H NMR o samples wi hou
luo ine.
Syn hesis o palladium complexes
[PdB (C
6
H
4
-p-CF
3
)(PCy
3
)
2
] (1). [PdB (C
6
H
4
-p-CF
3
), TMEDA]
(76.1 mg, 0.17 mmol) and d y dichlo ome hane (2 mL) we e
in oduced in o a N
2
- lushed lask. PCy
3
(95.3 mg, 0.34 mmol)
was added, and he eac ion mix u e was s i ed a oom emp-
e a u e o 3 h. The sol en was emo ed, and cold E
2
Owas
added o he esidue. A yellow solid appea ed. The solid was
il e ed, washed wi h cold E
2
O and ai d ied. Yield: 115.7 mg
(76%).
1
H NMR (500.13 MHz, δ, CDCl
3
): 7.55 (d, J= 8.3 Hz, 2H,
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H
me a
), 7.16 (d, J= 8.3 Hz, 2H, H
o ho
), 2.10–0.96 (m, 66H,
H
PCy3
).
13
C{
1
H} NMR (125.78 MHz, δ, CDCl
3
): 161.9 (C
ipso
),
138.2 (C
me a
), 124.9 (C
CF3
)*, 124.5 (C
pa a
), 122.5 (C
o ho
), 34.2
(pseudo- ,
1
J
P–C
= 9.6 Hz, CH PCy
3
), 30.1 (s, CH
2
PCy
3
), 27.6
(pseudo- ,
2
J
P–C
= 5.2 Hz, CH
2
PCy
3
), 26.5 (s, CH
2
PCy
3
).
19
F
NMR (470.168 MHz, δ, CDCl
3
): −62.06 (s, CF
3
).
31
P{
1
H} NMR
(202.31 MHz, δ, CDCl
3
): 19.8. *The chemical shi was de e -
mined by
13
C–
19
F HSQC. HRMS (ESI-TOF): calcd o
C
43
H
70
F
3
P
2
Pd (M −B )
+
811.395, ound 811.3946.
[Pd(µ-B )(C
6
H
4
-p-CF
3
)(PCy
3
)]
2
(2). Following a simila syn-
hesis desc ibed in he li e a u e,
44
[Pd(C
6
H
4
-p-CF
3
)(µ-OAc)
(PCy
3
)]
2
(100 mg, 0.08 mmol) was dissol ed in CH
2
Cl
2
(1 mL),
and NBu
4
B (69 mg, 0.21 mmol) was added o he mix u e
while s i ing. Ace one (10 mL) and wa e (0.2 mL) we e added
o he solu ion. A whi e solid appea ed. The mix u e was
s i ed a oom empe a u e o 3 h. The suspension was il-
e ed, and he solid was washed wi h wa e and ace one and
ai -d ied. Yield: 70 mg (67%).
1
H NMR (500.13 MHz, δ, CDCl
3
):
7.55 (d, J= 7.6 Hz, 2H, H
o ho
), 7.18 (d, J= 7.6 Hz, 2H, H
me a
),
2.0–0.93 (m, 33H, H
PCy3
).
13
C{
1
H} NMR (125.78 MHz, δ,
CDCl
3
): 157.4 (C
ipso
), 136.3 (C
o ho
), 125.2 (C
pa a
)*, 124.8 (C
CF3
)
*, 122.9 (C
me a
), 35.1 (d, J
P–C
= 22 Hz, C
ipso
, PCy
3
), 30 (s, C
me a
,
PCy
3
), 27.4 (d, J
P–C
= 11 Hz, C
o ho
, PCy
3
), 26.3 (s, C
pa a
, PCy
3
).
19
F NMR (470.168 MHz, δ, CDCl
3
): −61.95 (s, CF
3
).
31
P{
1
H}
NMR (202.31 MHz, δ, CDCl
3
): 37.74. *The chemical shi was
de e mined by
13
C–
19
F HSQC and HMBC. Anal. calc. o
C
50
H
74
B
2
F
6
P
2
Pd
2
: C, 49.08%; H, 6.10%; ound: C, 49.07%; H,
6.11%.
Addi ional expe imen al in o ma ion, cha ac e iza ion and
kine ic da a, spec a o he compounds and compu a ional
de ails (pd ), as well as ca esian coo dina es o he calcu-
la ed species (xyz ile) can be ound in he ESI.†
Au ho con ibu ions
C. P. and M. G. Z. conduc ed he in es iga ion unde A. C. A.’s
supe ision. A. C. A. w o e he manusc ip , and C. P. p epa ed
he ESI.†All au ho s con ibu ed o he concep ualiza ion o
he p ojec and he e iew and edi ing o he manusc ip .
Da a a ailabili y
The da a suppo ing his a icle ha e been included as pa o
he ESI.†
Conflic s o in e es
The e a e no con lic s o decla e.
Acknowledgemen s
We acknowledge he inancial suppo o he Spanish MICIU
(AEI, PID2022-142100NB-I00) and he Jun a de Cas illa y
León- FEDER (VA087-18 ellowship o CP), as well as he
join suppo o he EU/MICINN/JCyL (C17.I01.P01.S21,
H
2
Me Amo).
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O ganic Chemis y F on ie s Resea ch A icle
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Open Access A icle. Published on 30 Oc obe 2024. Downloaded on 2/17/2025 8:40:44 AM.
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