A general palladium-catalyzed cross-coupling of aryl fluorides and organotitanium (IV) reagents

Article abstract of DOI:10.1007/s00706-021-02796-6

Pd(OAc)₂/1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxy-piperidine was demonstrated to effectively catalyze cross-coupling of aryl fluoride and aryl(alkyl) titanium reagent. Both electron-deficient and electron-rich aryl fluoride can react effectively with nucleophile and provide extensive functional groups tolerance. 2-Arylated product was realized by selective activation of the C–F bond. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-021-02796-6

Monatshefte für Chemie - Chemical Monthly (2021) 152:823–832
https://doi.org/10.1007/s00706-021-02796-6
ORIGINAL PAPER
A general palladium‑catalyzed cross‑coupling of aryl fuorides
and organotitanium (IV) reagents
Xiao‑Yun He1
Received: 24 March 2021 / Accepted: 31 May 2021 / Published online: 15 July 2021
© Springer-Verlag GmbH Austria, part of Springer Nature 2021
Abstract
Pd(OAc)2/1-[2-(di-tert-butylphosphanyl)phenyl]-4-methoxy-piperidine was demonstrated to efectively catalyze cross-
coupling of aryl fuoride and aryl(alkyl) titanium reagent. Both electron-defcient and electron-rich aryl fuoride can react
efectively with nucleophile and provide extensive functional groups tolerance. 2-Arylated product was realized by selective
activation of the C–F bond.
Graphic abstract
OTf
OTs
Br
Cl
F
2-5%
Pd(OAc)2
2-5%
N
Ti(OiPr)3 L5
R = aryl, alkyl
R
Ar1
R
Ar1
+
P
O
Toluene/THF (2:1),
L5
up to 92%
-20 - 110 o
C, 12-24h
40 examples
Keywords Transition metal catalyzed · Aryl sulfonates · C–C bond · Aryl titanium reagents
Introduction
organotitanium was mainly used for their unique selectiv-
ity in the nucleophilic addition to carbonyl groups [17] as
well as their use as carbotitanation of olefns, dienes, and
alkynes [18]. In the past two decades, extensive eforts have
been devoted to the development of organotitaniums in TM-
catalyzed cross-coupling reactions. Several cross-coupling
reactions with organotitaniums [19–27] have been reported,
and most of them focused on reactions with organic bro-
mides and chlorides. The frst use of organotitaniums as the
nucleophilic partners in TM-catalyzed cross-coupling reac-
tions dated back to Hayashi’s [19] (Fig. 1a) report in 2002.
However, the substrates are limited to naphthyl trifates and
those with electron-defcient aryl trifates, bromides, and
chlorides. Nickel-catalyzed (as shown in Fig. 1b) [20] cross-
coupling between aryl bromides and chlorides with aryl tita-
nium reagents was reported by Paul Knochel, which extends
the range of substrates that tolerated ketone carbonyl and
ester group functional groups. Palladium-catalyzed (Fig. 1c)
[21] reactions between aryl bromides and aryl titanium rea-
gents ware reported for the preparation of biaryls. The car-
bon–carbon cross-couplings reaction of benzyl bromides
Transition metal (TM) catalyzed cross-coupling reactions
are widely used in pharmaceutical industry [1–3]. Aryl
iodides, bromides, and chlorides have played a central role
as electrophilic partners for carbon–carbon bond formations.
Aryl sulfonates are promising candidates for coupling part-
ners, since they can be obtained from inexpensive phenol
derivatives and TsCl or MsCl. The recent dramatic advances
in transition–metal catalysts have expanded the scope of
electrophiles. With electron-rich transition–metal complexes
that undergo smooth oxidative addition, the use of reactive
aryl fuorides can be reduced [4–16]. Electrophiles, such as
traditional halides (Cl, Br, and I) for TM-catalyzed cross-
couplings have attracted much interest. In the early days,
* Xiao-Yun He
61027391@qq.com
1
Department of Chemistry and Environmental Engineering,
Hebei Chemical and Pharmaceutical College, Shijiazhuang,
People’s Republic of China
Vol.:(0123456789)
1 3

824
X.-Y. He
Previous work
(a)
Pd(Ni) / ligand A
+
Ti(OiPr)3
R
X
R
THF
(Hayashi, 2002)
X = Br, Cl, OTf;
R = Me, Ar
1F
G
Ni / ligand B
+
X
Ar Ti(OiPr)3
(b)
(c)
R
THF
(Knochel, 2007)
X = Br, Cl;
ArCH
2-/Ar-/HetAr-Ti(OiPr)3
Ar2
Ar1
or
Ar2
Ar1
+
ArCH
2-/Ar-/HetAr-Br
Pd/(PCy
3)P(p-tolyl)3
Toluene
(Gau, 2009, 2010, 2012)
Ar
Br
Ni/glyme/ligand C / t-BuONa
+
R
CF3
Ar Ti(OiPr)3
R
CF3
(d)
(e)
THF
R = s-alkyl, Ar
(Gandelman, 2019, 2020)
R1
R2
R1
R2
+
X
Ti(OiPr)3 Pd(OAc)2/ligand D(ligand E/ligand F)
Toluene
X = Cl, Br,OMs,OTs
( Kwong, 2009,2020)
O
Me
Me
N
NMe2
PPh2
NMe2
O
PPh2
N
O
N
O
Fe
N
N
3
Ph
O
Ph
(R*)-(S*)-PPFA
PCy2
ligand E
P
Cy2
ligand D
ligand B
ligand C
ligand A
ligand F
This work
2-5%
2-5%
Pd(OAc)2
L5
FG2 Ar' Ti(OiPr)3
Ar
Ar' FG2
FG1
N
FG1
+
Ar X
1
Toluene/THF (2:1),
P
3
2
O
-20 - 110 o
C, 12-24 h
F
X =
, Cl, Br, OTf, OTs
L5
Fig. 1 Direct synthesis of organotitanium(IV) reagents
and chlorides and aryl titanium reagent were reported in
2010 [22]. The carbon–carbon coupling reaction of aryl
halide and benzyl titanium reagent was realized in 2012
[23]. Although the substrate has been expanded from aro-
matic groups to benzyl groups, and titanium reagents have
also expanded from aryl compounds to benzyl compounds,
the functional group tolerance is still very poor and limit
to cyano groups. Aryl titanium reagent was employed in
non-asymmetric cross-coupling transformations (Fig. 1d)
[24, 25] and achieved a better yield under low temperature.
Recently, palladium-catalyzed cross-coupling between aryl
tosylates, mesylates, and aryl titanium reagents was reported
by Kwong (Fig. 1e) [27]. When compared with the previous
reports [26], the reaction substrate has been expanded from
aryl halides to aryl(alkenyl) tosylates, mesylates.
For the C–F bond cleavage cross-coupling, especially
with organoboron (Suzuki) [11–13] and organozinc
(Negishi) [14–16], reactions are limited to aryl fluorides
with extremely electron-deficient nature or with ortho
group assistance, and electron-rich aryl compounds are
invariably less reactive. Therefore, efficient and versatile
methods with broad substrate scope and high selectivity
1 3

A general palladium‑catalyzed cross‑coupling of aryl fuorides and organotitanium (IV)…
825
are needed. Here we report an efficient protocol for
organotitanium-mediated cross-coupling reactions with a
variety of organic fluorides providing a new methodology
for carbon–carbon bond formation via C–F bond cleav-
age. In our exploration of C–F bond activation, we found
that Pd(OAc)2/L5 is an effective catalyst. To the best of
our knowledge, this is the first demonstration of cross-
coupling of activated and deactivated aryl fluorides with
organotitaniums and selective activation of C–F bonds in
2,5-dibromopyridine.
Results and discussion
At the outset of our research, the efects of twelve ligands
on the catalytic activity were examined in the Pd(OAc)2-
catalyzed cross-coupling of p-Ch3OPhTi(OiPr)3 (2a) with
p-fuorotoluene (1a) (Fig. 2), and the yields of the product
after 1, 3, 6, and 12 h are summarized in Fig. 2. 1-[2-[Di-
tert-butylphosphanyl)phenyl]-4-methoxypiperidine (L5) was
highly active with yield over 80%. In comparison, L2, L3,
L6, and L7 were less active. L1, L4, and L8 show poor
coupling activity (Fig. 2) under the same condition. Sim-
ple monophosphane and bisphosphanes (L9–L12), such as
Fig. 2 Efect of ligands (yields after 1 h, 3 h, 6 h, and 12 h)
1 3

826
X.-Y. He
DPEphos, Xantphos, PCy3, and P(tBu)3, gave<10% yield
of the coupling product after 12 h.
Pd(OAc)2 as the catalyst, a variety of solvents was tested
and it was found that the solvents used signifcantly afected
the reaction. For example, almost no product was obtained
when the reactions were performed in ether and CH2Cl2
(Table 1, entries 10, 12). We also tested other solvents
(dioxane and glyme) for the reaction, which shown moder-
ate yields (Table 1, entries 9, 11). The solvent THF gave
good yields (Table 1, entry 8), while toluene resulted poor
yields (Table 1, entry 5). Finally, we tested mixed solvent
for this reaction, 2:1 mixture of toluene and THF is a suit-
able solvent for cross-coupling. Further improvement of the
yield was carried out by changing the reaction temperature
from 80 to 110 °C (Table 1, entry 16). It was noted that
We also studied the efect of catalyst source, the solvent,
and other reaction conditions. The representative results
are shown in Table 1. In the frst round, toluene was cho-
sen as the solvent to evaluate the catalysts (Table 1, entries
1–7). It is shown that nickel catalyst sources, such as NiCl2,
Ni(OAc)2, Ni(acac)2, and NiCl2 • glyme gave the desired
product 3aa in low yield (Table 1, entries 1–4). Pd(acac)2
and Pd(dba)2 gave better results compared with those men-
tioned above (Table 1, entries 6 and 7). Pd(OAc)2 was the
best catalyst to give the corresponding coupling product in
81% yield (Table 1, entry 5). In the second round, using
Table 1 Screening of the reaction conditionsa
Entry
Catalysts
Solvent
Temp./°C
Time/h
Conv.
Yield/%b
1
2
3
4
5
6
7
8
NiCl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
Dioxane
Ether
Glyme
CH2Cl2
Toluene:THF (1:1)
Toluene:THF (1:2)
Toluene:THF (2:1)
Toluene:THF (2:1)
Toluene:THF (2:1)
Toluene:THF (2:1)
Toluene:THF (2:1)
Toluene:THF (2:1)
Toluene:THF (2:1)
Toluene:THF (2:1)
Toluene:THF (2:1)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
110
50
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
24
5
20
15
45
100
80
35
100
70
30
0
13
9
41
81
68
28
78
45
7
Ni(OAc)2
Ni(acac)2
NiCl2 • glyme
Pd(OAc)2
Pd(acac)2
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
10
11
12
13
14
15
16
17
18d
19d
20d
21d
22de
23
65
53
2
<5
100
100
100
100
35
100
100
89
80
71
85
89 (85)c
27
83
79
72
51
75
90
50
25
0
− 10
− 10
110
76
100
100
aReaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (2 mol%), L5 (2 mol%), solvent (1.0 cm3), under Ar
bGC yield using tridecane as an internal standard
cIsolated yields are given in parentheses
dLiCl 2.5 equiv
ePd(OAc)2 (5 mol%), L5 (5 mol%)
1 3

A general palladium‑catalyzed cross‑coupling of aryl fuorides and organotitanium (IV)…
827
a,b
Table 2 Palladium-catalyzed cross-coupling of aryl or heteroaryl fuorides with p-CH3OPhTi(OiPr)3
Entry Ar(Het)-X
Product
Entry Ar(Het)-X
Product
1
7
1a
3aa, 85%
1g
3ga, 82%
3ha, 89%
O
2
8
1h
1b
3ba, 54% (72%)e
F
3
9
S
3ia,78%
1i
1c
3ca, 83%c
4
10
1j
3ja, 91%
3ka, 86%
1d
3da, 85%
5
11
1k
1e
3ea, 78%
X
N
6
3fa, 78% (X = F)
89% (X = Cl)
91% (X = Br)
12
3la, 75% (X = F)
86% (X = OTf)d
81% (X = OTs)d
1l
1f
aReaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Pd(OAc)2 (2 mol%), L5 (2 mol%), toluene: THF=(2:1) (1.0 cm3) were stirred at 110 °C for
12 h under Ar atmosphere
bIsolated yields
c0.4 mmol of 2a
dL3 (2 mol%)
ePd(OAc)2 (5 mol%), L5 (5 mol%)
1 3

828
X.-Y. He
decreasing the temperature led to yield decrease (Table 1,
entry 17). However, the presence of lithium ion was impor-
tant (Table 1, entries 18–22). 2.5 equiv. of LiCl additive
improved the reaction result (Table 1, entry 18) signifcantly.
A similar phenomenon was observed by other groups [28,
29], the role of LiCl additive might enhance the elimina-
tion ability of fuorine as Lewis acid and strong Li–F bond
formation [16, 28–30]. The product yield cannot be further
improved by extending the reaction time (Table 1, entry 23).
With the optimal reaction conditions, we set out to exam-
ine the scope of aryl fuorides using p-MeOPhTi(OiPr)3 as
the nucleophilic reagent. Most reactions proceeded well
to give the desired products 3 with moderate/high yields
under identical conditions. Ortho-position substituted aryl
fuorides have major efect on the reaction. For example,
the reaction involving 2,6-dimethylphenyl fuoride (1b)
gave the corresponding product 3ba with 54% yield due
to the steric hindrance (Table 2, entry 2). Increasing the
amount of catalyst to 5%, the yield reached to 75%. On
the other hand, sterically hindered substituents on the
single substitution aryl fuorides have minor efect on the
reactions (Table 2, entry 5). Functional groups, including
COOH, COOEt, CONMe2, and SO2NMe2, SO2NO(CH2)2
can be tolerated. Reaction involving heteroaryl fuorides
also gave moderate/high product yield (Table 2, entries
9–12). Under the same conditions, it can be seen that both
aryl chloride and bromide gave higher yields (Table 2,
entry 6). Aryl tosylates, mesylates also achieved good cou-
pling yield (Table 2, entry 12).
and 3pk), it can be explained that the sterically hindered
substituents on the aryl titanium reagents have less efect
on the reactions (Table 3, entries 3sk, 3gk, and 3tk). On
the other hand, ortho-position substituted hindered substitu-
ents on the aryl fuorides have ruling efect on the reactions
(Table 3, entries 3qj and 3rj). Heteroaryl titanium reagents
were well compatible with this biaryl coupling reaction and
provided the heteroaryl-containing biaryls in good yields
(Table 3, entries 3qe, 3we, 3xe, 3oj, 3qj, and 3rj). To our
surprise, the alkyl titanium reagent have also achieved 61%,
53%, 39%, and 65% aryl–alkyl cross-coupling products,
respectively (Table 3, entries 3wn, 3 mn, 3mo, and 3vp).
Finally, we have compared the reactivity of (hetero)aryl
titanium compounds with the corresponding arylzinc halides
(Negishi cross-coupling). The reaction of 2,5-difuoropyridine
(1y) with arylTi(OEt)3 (2) aforded the 2-position arylated
products 3ya (88%) and 3yq (85%), respectively (Scheme 1a).
The same reaction with the arylzinc halide 2 gave only 3ya
(23%) and 3yq (19%), respectively, after 24 h. 5-Position
arylated product or biarylated product were not found in the
reaction system. Based on these fndings, we then investi-
gated the C–F bond activation in the presence of C–Cl bonds.
The reaction of (4-chlorophenyl)(2-fuorophenyl)methanone
with p-MeOPhTi(OiPr)3 selectively cleave a highly strong
bond (C–F) over a relatively weak bond (C–Cl) aforded an
ortho-arylated product (4-chlorophenyl)(4′-methoxy-[1,1′-
biphenyl]-2-yl)methanone in 91% yield (Scheme 1b).
Various titanium reagents were also tested for the cou-
plings. Functionalized heteroaryl titanium reagents reacting
with simple aryl fuorides or functionalized aryl fuorides
resulted no product under the optimized conditions. Lower-
ing the reaction temperature or increasing the amount of
catalyst did not improve product results. In comparison,
both aryl chloride and bromide can get higher yields under
the same conditions (Table 3, entries 3mb, 3mc, 3md,
3ul, 3vm). The reaction of the o-benzonitrile titanium rea-
gent with p-fuorotoluene gives a more satisfactory yield
(Table 3, entry 3al). The o-benzonitrile titanium reagent is
a stable compound at room temperature. The heterocyclic
thienyl titanium reagent and p-methoxyphenyl fuoride, chlo-
ride, and bromide have all achieved good results. p-Meth-
oxyphenyl tosylates and mesylates also achieved excellent
results under the action of L3 ligand (Table 3, entry 3me).
The easily enolizable ketone could be well tolerated and no
notable by-products resulting from the addition of (hetero)
aryl titanium reagents to this group (Table 3, entries 3ne,
3nf, and 3 ng). Fluorinated benzoic acid and (hetero)aryl
titanium reagents have achieved moderate results (Table 3,
entries 3cf, 3oh, 3oi, 3oj, 3ck, and 3pk). The sterically hin-
dered aryl titanium reagent at the ortho position has also
achieved good results (81% and 73%) (Table 3, entries 3ck
Conclusion
In conclusion, we have developed the frst active and general
system for the cross-coupling of aryl fuorides based on the
Pd(OAc)2/L5. Both activated and deactivated aryl fuorides
can be efciently coupled. Electron-rich and electron-def-
cient aryl(alkyl) titanium reagents were proven to be suitable
nucleophiles. Notably, heteroaryl ring and various sensitive
functional groups, including easily enolizable ketone, car-
boxylic acid, ester, nitrile, amide, sulfamide groups can be
well tolerated. We also confrmed that the 2-position selec-
tive activation of C–F bonds in 2,5-difuoropyridine, with
2-arylated products being obtained.
Experimental
Lithium chloride anhydrous, Ni(acac)2, NiCl2, Ni(OAc)2,
NiCl2·glyme, Pd(OAc)2, Pd(acac)2, and Pd(dba)2 were pur-
chased from Sigma-Aldrich. THF, dioxane were purchased
from Alfa Aesar. Other reagents are available commercially
and were used without further purifcation, unless other-
wise indicated. All reactions were carried out under an argon
1 3

A general palladium‑catalyzed cross‑coupling of aryl fuorides and organotitanium (IV)…
829
a,b
Table 3 Palladium-catalyzed cross-coupling of aryl or heteroaryl halides with various ArTi(OiPr)3
3me, 83%
89% (X = Cl)
92% (X = Br)
91% (X = OTf)f
86% (X = OTs)f
e
e
d
3mb , 11%
3mc , 25%
3md , 26%
65% (X = Cl)
81% (X = Br)
69% (X = Cl)
84% (X = Br)
71% (X = Cl)
87% (X = Br)
e
e
3nf , 32%
3ne , 29%
e
3ng , 34%
69% (X = Cl)
88% (X = Br)
72% (X = Cl)
87% (X = Br)
66% (X = Cl)
83% (X = Br)
3cf, 92%c
3oh, 89%c
3oj, 85%c
3oi, 88%c
3qj, 86%
3ck, 81%c
3sk, 82%
3rj, 57% (79%)
3pk, 73%c
3gk, 88%
d
3vm , 15%
d
3ul , 23%
3tk, 89%
3we, 81%
79% (X = Cl)
80% (X = Br)
85% (X = Cl)
89% (X = Br)
3al, 85%
3wh, 76%
3xe, 83%
g
g
g
3mn , 53%
3mo , 39%
3wn , 61%
g
3vp , 65%
1 3

830
X.-Y. He
Table 3 (continued)
aReaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (2 mol%, with respect to ArF), L5 (2 mol%), toluene:THF=(2:1) (1.0 cm3) were
stirred at 110 °C for 12 h under Ar atmosphere
bIsolated yields
c0.4 mmol of 2
dPd(OAc)2 (5 mol%), L5 (5 mol%),reaction performed at − 10 °C for 24 h
ePd(OAc)2 (5 mol%), L5 (5 mol%), reaction performed at − 20 °C for 24 h
fL3 (2 mol%)
gPd(dba)2 (2 mol%), L5 (2 mol%)
Scheme 1
(a)
(b)
atmosphere with dry solvents under anhydrous conditions,
unless otherwise noted. THF was dried over alumina under
N2 using a Grubbs-type solvent purifcation system. All aryl
titanium reagents were prepared from the corresponding
arylmagnesium halides. 1f, 1i, 1j, 1v were prepared accord-
ing to the literature procedures [31–34], and other aryl fuo-
rides were purchased from Alfa Aesar. L1, L2, L3, L4, L8
were prepared according to literature procedures [35–38],
DPEphos, Xantphos, PCy3, and P(tBu)3 were purchased from
Sigma-Aldrich, and L5 (1-[2-(di-tert-butylphosphanyl)-
phenyl]-4-methoxypiperidine), L6, L7 were the new ligand
reported by our research group [39]. Spectroscopy data of
the known compounds matches with the data reported in
the corresponding references. Reactions were monitored
by Agilent GC Series 6890 N and GCMS 7890A. All new
compounds were further characterized by HRMS (EI), and
1H and 13C NMR spectra were measured on a Bruker 400 M
spectrometer. 1H NMR and 13C NMR were recorded using
tetramethylsilane (TMS) in the solvent of deuterated chloro-
form (CDCl3) and deuterium oxide as the internal standard.
Chemical shifts were reported in parts per million. The peak
patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; dd, doublet of doublets; dt, doublet of triplets; and m,
multiplet. The coupling constant J is reported in hertz (Hz).
The products were purifed by column chromatography on
silica gel 300–400 mesh under an argon atmosphere.
General procedure A: the formation
of organo‑titanium reagents
The corresponding glassware was oven-dried (100 °C)
and cooled under a stream of argon gas. Aryl grignard
reagents, such as phenylmagnesium or 4-methylphenyl
magnesium were prepared according to the standard pro-
cedure. 2-Methoxypyridinyl grignard reagents were pre-
pared via bromine–magnesium exchange using i-PrMgCl,
other structure containing active hydrogen protons, such as
o-amidophenyl reagents neutralized by 2 equiv i-PrMgCl
frstly, while functionalized aryl Grignard reagents, such as
2-carboethoxyphenyl magnesium chloride were prepared via
iodine–magnesium exchange using i-PrMgCl·LiCl according
to Knochel’s method [40]. All of the Grignard reagents were
titrated before use [41].
The above Grignard reagents (20 mmol) were cooled
to 0 °C (functionalized Grignard reagents were cooled to
− 20 °C). In another two-necked 500 cm3 round-bottomed
fask under a nitrogen atmosphere, to a solution of 4.08 cm3
Ti(OiPr)4 (15.0 mmol) in 50 cm3 of THF at 0 °C was added
0.56 cm3 TiCl4 (5.0 mmol). The resulting solution was
warmed to room temperature and stirred for 30 min, giving
a ClTi(OiPr)3 solution (100 mmol). The ClTi(OiPr)3 solu-
tion was cooled to 0 °C or − 20 °C, and to this solution was
transferred the cold Grignard solution via a cannula. The
reaction mixture was warmed to room temperature and was
1 3

A general palladium‑catalyzed cross‑coupling of aryl fuorides and organotitanium (IV)…
831
allowed to react for 3 h (functionalized Grignard reagents
direct reaction for 8 h without heating). The volatile mate-
rial was removed completely under reduced pressure, and
under a nitrogen atmosphere, the residue was extracted with
n-hexane (3×40 cm3). The combined hexane solution was
concentrated and was cooled to − 20 °C, furnishing a solid
product of the aryltris(2-propoxo)titanium species.
dichloromethane (3×30 cm3). The combined organic phase
was dried over MgSO4 and concentrated to dryness under
reduced pressure. The residue was purifed by column chro-
matography to give the coupling product.
General procedure E: Palladium‑catalyzed biaryl
cross‑coupling reaction of functionalized aryl
fuorides with (hetero)aryl titanium reagents
General procedure B: Palladium‑catalyzed biaryl
cross‑coupling reaction of (hetero)aryl fuorides
with (hetero)aryl titanium reagents
In a glovebox, functionalized aryl fuorides (0.20 mmol),
Pd(OAc)2 (5 mol%), LiCl (0.20 mmol), and L5 (5 mol%)
were charged to a dried two-necked round-bottom reac-
tion fask quipped with an addition funnel, and ArTi(OiPr)3
(0.30 mmol) in 1 cm3 mixed solvents of toluene:THF (2:1)
was added. The mixture was stirred at − 20 °C for 24 h and
quenched with 10 cm3 of water. The solution was extracted
with dichloromethane (3×30 cm3). The combined organic
phase was dried over MgSO4 and concentrated to dryness
under reduced pressure. The residue was purifed by column
chromatography to give the coupling product.
In a glovebox, solid aryl fuorides (0.20 mmol), Pd(OAc)2
(2 mol%), and L5 (2 mol%) were charged to a dried two-
necked round-bottom reaction fask quipped with an addi-
tion funnel, and ArTi(OiPr)3 (0.30 mmol) in 1 cm3 mixed
solvents of toluene: THF (2:1) was added. The mixture
was stirred at room temperature for 15 min and warmed
to 110 °C and was allowed to react for 12 h and quenched
with 10 cm3 of water. The solution was extracted with
dichloromethane (3×30 cm3). The combined organic phase
was dried over MgSO4 and concentrated to dryness under
reduced pressure. The residue was purifed by column chro-
matography to give the coupling product.
5‑(2,6‑Dimethylphenyl)‑2‑methoxypyridine (3rj,
C14H15NO) was obtained following the general procedure
B. Purifcation via silica gel column chromatography (petro-
leum ether/ethyl acetate = 10/1, v/v) aforded the desired
1
General procedure C: Palladium‑catalyzed biaryl
cross‑coupling reaction of fuorinated benzoic acid
with (hetero)aryl titanium reagents
product. Yellow solid; m.p.: 44–47 °C; H NMR (CDCl3,
400 MHz): δ = 7.99 (dd, J = 2.4 Hz, J = 0.8 Hz, 1H), 7.39
(dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.21–7.12 (m, 3H), 6.84
(dd, J=8.4 Hz, J=0.7 Hz, 1H), 4.01 (s, 3H), 2.07 (s, 6H)
ppm; 13C NMR (CDCl3, 100 MHz): δ=163.1, 146.6, 139.7,
137.9, 136.9, 129.4, 127.5, 110.7, 53.4, 21.0 ppm; HRMS
(ESI): m/z calc. for C14H16NO ([M+H]+) 214.1154, found
214.1229.
In a glovebox, fluorinated benzoic acid (0.20 mmol),
Pd(OAc)2 (2 mol%), and L5 (2 mol%) were charged to a
dried two-necked round-bottom reaction flask quipped
with an addition funnel, and ArTi(OiPr)3 (0.40 mmol) in
1 cm3 mixed solvents of toluene:THF (2:1) was added. The
mixture was stirred at room temperature for 15 min and
warmed to 110 °C and was allowed to react for 12 h and
quenched with 10 cm3 of water. The solution was extracted
with dichloromethane (3×30 cm3). The combined organic
phase was dried over MgSO4 and concentrated to dryness
under reduced pressure. The residue was purifed by column
chromatography to give the coupling product.
2′‑Methoxy‑N,N‑dimethyl‑[1,1’‑biphenyl]‑4‑sulfona‑
mide (3gk, C15H17NO3S) was obtained following the gen-
eral procedure B. Purifcation via silica gel column chroma-
tography (petroleum ether/ethyl acetate=10/1, v/v) aforded
1
the desired product. Yellow solid; m.p.: 183–185 °C; H
NMR (CDCl3, 400 MHz): δ = 7.80 (d, J = 8.2 Hz, 2H),
7.70 (d, J=8.2 Hz, 2H), 7.40–7.32 (m, 2H), 7.08–7.01 (m,
2H), 3.84 (s, 3H), 2.77 (s, 6H) ppm; 13C NMR (CDCl3,
100 MHz): δ = 156.4, 143.2, 133.7, 130.8, 130.1, 129.7,
128.7, 127.4, 121.0, 111.4, 55.5, 38.0 ppm; HRMS (ESI):
m/z calc. for C15H18NO3S ([M + H]+) 292.0929, found
292.1004.
General procedure D: Palladium‑catalyzed biaryl
cross‑coupling reaction of (hetero)aryl fuorides
with functionalized heteroaryl titanium reagents
In a glovebox, (hetero)aryl fuorides (0.20 mmol), Pd(OAc)2
(5 mol%), LiCl (0.20 mmol), and L5 (5 mol%) were charged
to a dried two-necked round-bottom reaction fask quipped
with an addition funnel, and ArTi(OiPr)3 (0.40 mmol) in
1 cm3 mixed solvents of toluene:THF (2:1) was added.
The mixture was stirred at − 10 °C for 24 h and quenched
with 10 cm3 of water. The solution was extracted with
4′‑Benzoyl‑[1,1’‑biphenyl]‑2‑carbonitrile (3ul,
C
20H13NO) was obtained following the general proce-
dure E. Purifcation via silica gel column chromatography
(petroleum ether/ethyl acetate = 10/1, v/v) afforded the
desired product. Yellow solid; m.p.: 104–106 °C; 1H NMR
(CDCl3, 400 MHz): δ = 7.93 (dt, J = 8.2 Hz, J = 1.7 Hz,
1 3

832
X.-Y. He
16. Ohashi M, Kambara T, Hatanaka T, Saijo H, Doi R, Ogoshi S
(2011) J. Am. Chem. Soc. 133:3256
2H), 7.87–7.85 (m, 2H), 7.82–7.81 (m, 1H), 7.70–7.67 (m,
3H), 7.62–7.56 (m, 2H), 7.54–7.49 (m, 3H) ppm; 13C NMR
(CDCl3, 100 MHz): δ=196.2, 144.4, 142.1, 137.7, 137.4,
134.0, 133.1, 132.8, 130.6, 130.2, 128.9, 128.5, 128.4,
118.5, 111.4 ppm; HRMS (ESI): m/z calc. for C20H14NO
([M+H]+) 284.0997, found 284.1075.
17. Duthaler RO, Hafner A (1998). In: Beller M, Bolm C (eds) Transi-
tion Metals for Organic Synthesis, vol 1. Wiley-VCH, Weinheim,
p 447
18. Sato F, Urabe H, Okamoto S (2000) Chem. Rev. 100:2835
19. Han JW, Tokunaga N, Hayashi T (2002) Synlett 6:871
20. Dastbaravardeh N, Knochel P (2007) Synlett 13:2077
21. Yang T, Zhou SL, Chang FS, Chen CR, Gau HM (2009) Organo-
metallics 28:5715
Supplementary Information The online version contains supplemen-
22. Chen CR, Zhou SL, Biradar DB, Gau HM (2010) Adv. Syn. Catal.
352:1718
tary material available at https://doi.org/10.1007/s00706-021-02796-6.
23. Chang ST, Li QH, Chiang RT, Gau HM (2012) Tetrahedron
68:3956
Acknowledgements The author gratefully acknowledge the fnan-
cial support from Hebei Chemical & Pharmaceutical College and the
Higher Education Scientifc Research Project of Hebei Province (2020)
(SQ201044). The author is thankful to Hebei University of Science
& Technology for 13C NMR, 1H NMR, HRMS (ESI) measurement.
24. Varenikov A, Gandelman M (2019) J. Am. Chem. Soc. 141:10994
25. Varenikov A, Shapiro E, Gandelman M (2020) Org. Lett. 22:9386
26. Lee HW, Lam FL, So CM, Lau CP, Chan ASC, Kwong FY (2009)
Angew. Chem. Int. Ed. 48:7436
27. Lee HW, So CM, Yuen OY, Wong WT, Kwong FY (2020) Org.
Chem. Front. 7:926
28. Ohashi M, Doi R, Ogoshi S (2014) Chem. Eur. J. 20:2040
29. Shirakawa E, Tamakuni F, Kusano E, Uchiyama N, Konagaya W,
Watabe R, Hayashi T (2014) Angew. Chem. Int. Ed. 53:521
30. Duan H, Meng L, Bao D, Zhang H, Li Y, Lei A (2010) Angew.
Chem. Int. Ed. 49:6387
References
1. Hassan J, Sevignon M, Gozzi C, Schulz E, Lemaire M (2002)
Chem. Rev. 102:1359
31. Kumar S, Kumar GS, Kumar RA, Reddy NV, Reddy KR (2013)
Eur. J. Org. Chem. 7:1218
2. Corbet J, Mignani G (2006) Chem. Rev. 106:2651
3. Negishi E (2007) Bull. Chem. Soc. Jpn. 80:233
4. Ahrens T, Kohlmann J, Ahrens M, Braun T (2015) Chem. Rev.
115:931
32. O’Brien JP, Schuetz RD, Taft DD, Shea JL, Mork HM (1963) J.
Org. Chem. 28:1420
33. Greulich SW, Daniliuc CG, Studer A (2015) Org. Lett. 17:254
34. Konstantinovic J, Miklos T, Burojevic J, Djakovic OD, Srbljanovic
J, Stajner T, Verbic T, Zlatovic M, Machado M, Albuquerque IS,
5. Böhm VPW, Gstöttmayr CWK, Weskamp T, Herrmann WA
(2001) Angew. Chem. Int. Ed. 40:3387
6. Terao J, Ikumi A, Kuniyasu H, Kambe N (2003) J. Am. Chem.
Soc. 125:5646
Prudencio M, Sciotti RJ, Pecic S, D’Alessandro S, Taramelli D,
̂
Solaja BA (2016) J. Med. Chem. 59:264
7. Ackermann L, Born R, Spatz JH, Meyer D (2005) Angew. Chem.
Int. Ed. 44:7216
35. Bedford RB, Brenner PB, Carter E, Clifton J, Cogswell PM,
Gower NJ, Haddow MF, Harvey JN, Kehl JA, Murphy DM, Neeve
EC, Neidig ML, Nunn J, Snyder BER, Taylor J (2014) Organome-
tallics 33:5767
8. Yoshikai N, Mashima H, Nakamura E (2005) J. Am. Chem. Soc.
127:17978
9. Kim YM, Yu S (2003) J. Am. Chem. Soc. 125:1696
10. Widdowson DA, Wilhelm R (2003) Chem. Commun. 5:578
11. Schaub T, Backes M, Radius U (2006) J. Am. Chem. Soc.
128:15964
36. Li CJ (2020) Russ. J. Gen. Chem. 90:725
37. Ueda Y, Iwai T, Sawamura M (2018) Chem. Commun. 54:1718
38. Li PB, Lü B, Fu CL, Ma SM (2013) Adv. Syn. Cata. 355:1255
39. He X-Y (2021) J. Chem. Res. https://doi.org/10.1177/1747519821
994533
12. Gallon BJ, Kojima RW, Kaner RB, Diaconescu PL (2007) Angew.
Chem. Int. Ed. 46:7251
40. Krasovskiy A, Knochel P (2004) Angew. Chem. Int. Ed. 43:3333
41. Krasovskiy A, Knochel P (2006) Synthesis 5:890
13. Tobisu M, Xu T, Shimasaki T, Chatani N (2011) J. Am. Chem.
Soc. 133:19505
14. Terao J, Todo H, Watanabe H, Ikumi A, Kambe N (2004) Angew.
Chem. Int. Ed. 43:6180
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
15. Takachi M, Kita Y, Tobisu M, Fukumoto Y, Chatani N (2010)
Angew. Chem. Int. Ed. 49:8717
1 3