(2-Fluoroallyl)palladium complexes as intermediates in Pd-catalyzed Tsuji-Trost 2-fluoroallylations: Synthesis and reactivity

Article abstract of DOI:10.1016/j.jfluchem.2020.109553

The first examples of π-(2-fluoroallyl)palladium complexes were synthesized, isolated and characterized including chloride dimers, neutral chloride or cationic triflate complexes bearing PPh₃ or SPhos as the ligands. Preliminary reactivity patterns indicating strong dependence of the chemoselectivity on “hardness” of the nucleophile and the ligand type were studied.

Full text of DOI:10.1016/j.jfluchem.2020.109553

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(2-Fluoroallyl)palladium complexes as intermediates in Pd-catalyzed
Tsuji-Trost 2-fluoroallylations: Synthesis and reactivity
Angelina Y.U. Bobrova, Maxim A. Novikov, Igor A. Mezentsev, Yury
V. Tomilov
PII:
S0022-1139(20)30104-4
DOI:
https://doi.org/10.1016/j.jfluchem.2020.109553
FLUOR 109553
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(2-Fluoroallyl)palladium complexes as intermediates in Pd-catalyzed
Tsuji-Trost 2-fluoroallylations: synthesis and reactivity
Angelina Yu. Bobrova1,2, Maxim A. Novikov1*, Igor A. Mezentsev1,2, and Yury V. Tomilov1
1 N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
2 Higher Chemical College of the Russian Academy of Sciences, D. I. Mendeleev University of
Chemical Technology of Russia, 125047 Moscow, Russian Federation
Graphical Abstract
(For the Web only)
(For the Print)
Highlights
 Synthesis of the first examples of -(2-fluoroallyl)palladium complexes.
 Neutral chloride and cationic triflate complexes bearing PPh3 or SPhos as the
ligands.
 Reactivity studying with most common C-, O-, N-, S-nucleophiles.
 Dependence of the chemoselectivity on “hardness” of the nucleophile and the ligand
type.
1

Abstract
The first examples of -(2-fluoroallyl)palladium complexes were synthesized, isolated and
characterized including chloride dimers, neutral chloride or cationic triflate complexes bearing
PPh3 or SPhos as the ligands. Preliminary reactivity patterns indicating strong dependence of the
chemoselectivity on “hardness” of the nucleophile and the ligand type were studied.
Keywords
2-fluoroallylation, palladium complexes, Tsuji-Trost allylation, fluoroalkenes
1. Introduction
Tsuji-Trost allylic substitution has found a very broad application in modern organic
synthesis in both achiral and enantioselective versions [1–5]. High synthetic potential of allylic
alkylation causes a great attention of chemists for synthesis of biologically active organofluorine
molecules. In the case of fluorinated allylic electrophiles, it can give easy and highly diastereo-
and enantioselective access to functionalized fluoroalkenes — a very important class of
bioisosters of amide bond in oligopeptides [6–8].
However, previously studied for this purpose fluorinated allylic esters were found to be
challenging substrates [9]. Higher temperatures and longer reaction times compared to non-
fluorinated analogues are required. Additionally, side substitution of fluorine at central carbon is
a dominant process in many cases (with malonates [10], amides [11], phenolates [12]) that leads
to the formation of disubstitution product (Scheme 1, top).
2

Scheme 1. Application of 2-fluoroallyl acetates and gem-difluorocyclopropanes in Pd-catalyzed Tsuji-
Trost allylation
Quite recently, ring-opening of gem-difluorocyclopropanes catalyzed by Pd(0) in the
presence of Buchwald’s biarylphosphine ligands was developed as a promising alternative to 2-
fluoroallyl acetates for allylic alkylation of various nucleophiles (Scheme 1, bottom). These
reports demonstrated that C-nucleophiles [13], as well as O,N- [13] and S-nucleophiles [14] led
to target products of mono-substitution with no evidence of di-substitution reported. More
recently, the use of gem-difluorocyclopropanes as sources of 2-fluoroallylic electrophiles in
Suzuki cross-coupling with boronic esters was noted [15].
All these reactions were assumed to proceed via formation of -(2-fluoroallyl)palladium
complexes that, however, have never been prepared yet or at least detected in reaction mixtures.
In the current work, we report isolation of the first examples of (2-fluoroallyl)palladium
complexes and studying of their reactivity toward common nucleophiles.
2. Results and Discussion
After screening of various pathways to (2-fluoroallyl)palladium complexes, we have found
that the easiest one is the reaction of 2-fluoroallyl chlorides 1a–d with Li2PdCl4 in MeOH using
3

CO as a reducing agent (Scheme 2). Four examples of (2-fluoroallyl)palladium chloride dimers
2a–d were prepared in moderate to high yields; and three of them were characterized by X-Ray
crystallography (Fig. 1).
Scheme 2. Synthesis of (2-fluoroallyl)palladium chloride
dimeres 2a-d (a contaminated with 15 mol.% of unknown
impurity contained presumably 1-[Me2C=CF–CH2–Pd]
moiety)
2a
2b
2c
CCDC 1995196
CCDC 1995198
CCDC 1995197
Figure 1. Single crystal X-ray structures of complexes 2a–c. Atoms are represented as thermal ellipsoids
(р=50%)
Encouraged with these results, we tried to prepare several neutral and ionic 2-fluoroallyl
complexes with phosphine ligands. Addition of 1 equiv. of PPh3 or SPhos to dimer 2a afforded
complexes 3a,b in high yields, respectively (Scheme 3). Removing of chloride-anion with
AgOTf preceding to addition of ligands, allowed to obtain ionic complexes 4a,b with two PPh3
ligands or with one SPhos ligand (Scheme 3). On the contrary, attempts to prepare ionic
4

t
complexes with Bipy and BuXPhos ligands failed, likely due to their instability. Thus, Bipy
complex decomposed during crystallization forming free Bipy and unknown products, whereas
tBuXPhos complex decomposed even in THF solution after 1 h forming Pd-black and a
complicated by-product mixture.
Scheme 3. Synthesis of neutral and ionic -(2-fluoroallyl)palladium complexes
(Abbreviation: SPhos = 2-dicyclohexylphosphino-2´,6´-dimethoxybiphenyl)
Preliminary screening of reactivity patterns depending on the ligand was made using
sodium dimethyl methylmalonate as a model nucleophile. (2-Fluorocinnamyl)palladium
complexes were generated using the same strategy as for complexes 4a,b — elimination of
chloride in 2a with AgOTf followed by addition of a ligand (See Table 1). Reactions with the
malonate proceeded smoothly at room temperature in most cases affording products of mono- or
disubstitution 5 or 6 depending on the ligand according to the mechanism presented in Scheme 1
(see path A for mono-adduct 5 and path B for bis-adduct 6). The highest yields of
t
monosubtitution product 5 were obtained using PPh3, SPhos, BuXPhos and XantPhos as the
ligands (Table 1, Entries 1–4). Other monodentate phosphine ligands PCy3 and PtBu3 gave low
yield of 5 (Entries 5, 6). Notably, in the case of PtBu3, formation of fluorinated side product was
observed that was preliminary assigned as the isomer of 5 with terminal double bond (Entry 6,
product 7). Other bidentate ligands dppp, dppb and (R)-BINAP (Table 1, Entries 8–10) except
dppe (Entry 7) gave 5 as the major product along with impurity of side product of disubstitution
6. Weakly bonded pyridine and tmeda gave low yields (Entries 11, 12); whereas bidentate Bipy
and Phen gave disubstitution product 6 selectively, however, in moderate yields (Entries 13, 14).
All these results are in a good agreement with previously studied reactivity of (2-
chloroallyl)palladium complexes [16], as well as with ligand screening in catalytic version of
this reaction in ref. [10]. However, analyzing these results, one should not forget that complexes
suggested as intermediate in these reactions could be instable (as shown above for tBuXPhos and
5

Bipy complexes, Entries 3 and 13 in Table 1) and so other structures are probably involved in
reaction mechanism in these cases.
Table 1. Reaction of ionic complexes 4a,b with sodium dimethyl methylmalonate
Yield, (%)
Ligand
(L)
Entry
Mono-adduct 5 Bis-adduct 6
1
2
2 PPh3
SPhos
89
79
79
87
6
0
0
3
tBuXPhos
XantPhos
2 PCy3
0
4
0
5
0
2 PtBu3
29
6
0
a
6
7
dppe
dppp
22
21
8
8
71
85
87
7
9
dppb
10
11
12
13
14
(R)-BINAP
2 Py
7
1
tmeda
Bipy
0
25
66
55
0
Phen
0
a
A fluorinated side product is formed in 15% yield (NMR data) which may be
preliminary assigned to compound 7
(7)
Abbreviations: tBuXPhos
XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; dppe
=
2-di-tert-butylphosphino-2´,4´,6´-triisopropylbiphenyl;
1,2-
=
=
bis(diphenylphosphino)ethane; dppp = 1,3-bis(diphenylphosphino)propane; dppb = 1,4-
bis(diphenylphosphino)butane; (R)-BINAP = (R)-(+)-2,2´-bis(diphenylphosphino)-1,1´-
binaphthalene; tmeda = 1,2-bis(dimethylamino)ethane; Bipy = 2,2´-bipyridine; Phen =
1,10-phenanthroline.
Isolated complexes 4a,b were further studied in reactions with model O-, N- and S-
nucleophiles. On the contrary to malonates, almost all these nucleophiles require elevated
reaction temperatures. A ratio between central and terminal additions strongly depends on
nucleophile hardness (see Table 2). Phenoxide gave only products of central addition; but
6

depending on the ligand the major product was either diaryl ether 8a (with PPh3, entry 1), or
benzofuran derivative 9. The selectivity of sodium benzyl(tosyl)amide addition depends on the
ligand — SPhos gave only 2-fluoroallyl sulfamide 10a via terminal addition (Entry 4); whereas
PPh3 resulted in major central addition affording disulfamido substituted product 8b (Entry 3).
On the opposite, both diethylamine and sodium 4-methylbenzenesulfinate reacted via pure
terminal addition with the formation of 2-fluoroallyl amine 10b or sulfone 10c (Entries 5–8).
Notably, reaction with HNEt2 proceeded smoothly even at room temperature affording more than
90% yields of allylamine 10b.
Table 2. Reaction of ionic complexes 4a,b with O-, N- and S-nucleophiles.a
Entry Nucleophile
Complex 4
4a (2 PPh3)
4b (SPhos)
Yield (%)
Mono-adduct
Bis-adduct
4-FC6H4OK
Bn(Ts)NNa
1
–
8a (24%,
Z/E 76:24)b
c
2
3
–
–
4a (2 PPh3) 10a (7)
8b (23%,
E/Z 71:29)
4
5
6
7
4b (SPhos)
4a (2 PPh3) 10b (97)
4b (SPhos) 10b (91)
10a (69)
–
–
–
–
d
HNEt2
4-MeC6H4SO2Na
4a (2 PPh3) 10c (86%, Z/E
98:2)
8
4b (SPhos)
10c (64%, Z/E
–
96:4)
a
Reaction conditions: Pd-complex 4 (0.025 mmol), Nucleophile (0.075 mmol),
b
THF (2.5 mL), 80°C, 4 h. Additionally 2-benzyl-5-fluorobenzofuran (9) was
c
d
obtained in yield 28%. Benzofuran 9 was obtained in yield 43%. Room
temperature, 24 h.
(9)
Another known mode of reactivity of allyl palladium complexes is transmetalation
followed by reductive elimination that is operated under cross-coupling conditions. To test the
reactivity of (2-fluoroallyl)palladium complexes in the processes of this type, we used neutral
complexes 3a,b with PPh3 or SPhos as the ligands, respectively. These complexes successfully
7

reacted with phenyltriolborate 11 and diboron reagent B2pin2 as model cross-coupling partners
leading to 2-fluoro-1,3-diphenylpropene 12 or 2-fluorocinnamyl boronate 13, respectively (Table
3). In both cases elevated temperatures were required again. Replacement of halide counterion
with acetate is well-known way to accelerate transmetalation step in Suzuki and Suzuki-Miyaura
reactions. However, in the cases of complexes 3a,b, the influence of acetate counterion was not
large. For Suzuki coupling with triolborate 11, addition of AgOAc lowered the yields (Entries
3,4 vs. 1,2). Moreover, for PPh3-complex 3a it induced side dimerization of 2-fluorocinnamyl
fragment giving 14 as a single isomer (Entry 3). For Suzuki-Miayura coupling with B2pin2,
AgOAc did not affect on PPh3-complex reaction, whereas accelerate slightly the reaction of
SPhos-complex 3b (Entry 8 vs. 6). Also notable is formation of side fluoroalkene 15 in the case
PPh3-complex — a product of formal “hydrolysis” of 3a (Entries 5, 7).
Table 3. Neutral complexes 3a,b in cross-coupling conditions a
Entry
Nucleophile
Complexes 3
Yields (%)
X
L
1
2
3
4
Cl
Cl
PPh3
SPhos
PPh3
40
48
30
33
–
–
OAc
OAc
33
–
SPhos
5
6
7
8
B2pin2
Cl
Cl
PPh3
SPhos
PPh3
70
50b
72
21
–
OAc
OAc
23
–
SPhos
64c
a Reaction conditions: Pd-complex 3a or 3b (0.025 mmol), AgOAc (0–0.025 mmol),
–
Nucleophile (0.075 mmol), THF (2.5 mL), 80°C (for PhB(OR)3 ) or 60° (for B2pin2),
4 h; b 48% of 3b were recovered; c 24% of 3b were recovered;
3. Conclusions
In summary, we have synthesized and fully characterized the first examples of -(2-
fluoroallyl)palladium complexes. The key point is preparation of -(2-fluoroallyl)palladium
chloride dimers from 2-fluoroallyl chlorides with Li2PdCl4 in MeOH using CO as a reducing
agent. Using 2-fluorocinnamyl dimer so obtained, we have demonstrated the possibility of
isolation of neutral chloride and ionic triflate complexes bearing PPh3 or SPhos as the ligands,
8

t
whereas similar complexes with BuXPhos and Bipy were found to be unstable. Synthesized
complexes with PPh3 and SPhos ligands, as well as generated one pot with various P- and N-
mono- and bidentate ligands were studied in reactions with C-, N-, O- and S-nucleophiles
showing strong dependence of the chemoselectivity on “hardness” of the nucleophile and the
ligand type.
4. Experimental part
4.1. General Information
2-Fluoroallyl chlorides 1a–c were prepared by CuCl-catalyzed ring-opening isomerization
of corresponding gem-chlorofluorocyclopropanes according to [17]. Pure sample of 1d was
prepared by chlorination of 3,3-dimethyl-2-fluoroallyl alcohol (ref. [18]) with SOCl2 in pyridine.
Carbon monoxide was generated by portionwise addition of HCO2H to conc. H2SO4 and passed
through a washing bottle with conc. H2SO4 for drying. Nucleophiles for the reaction with Pd-
complexes were obtained in following ways: a 0.05 M batch solution of sodium dimethyl
methylmalonate was prepared prior to use from NaH (dispersion in mineral oil) and 1.2 excess of
dimethyl methylmalonate in THF for 1 h at 0°C. 4-FC6H4OK was prepared from 4-fluorophenol
and KOH in anhydrous EtOH. A suspension of Bn(Ts)NNa in THF (“concentration” ca. 0.03 M)
was prepared for each reaction separately prior to use from NaH and 1.2 excess of BnNHTs in
THF for 1 h at 0°C. Diethylamine was distilled over KOH prior to use. 4-MeC6H4SO2Na was
prepared by reduction of TsCl with Zn in water followed by quenching with NaOH.
Tetrabutylammonium phenyltriolborate 11 was prepared as previously published [19]. B2pin2
was purchased from ABCR and used as received. THF was distilled over LiAlH4, stored over 4A
Linde type molecular sieves. Dichloromethane was distilled over KOH prior to use.
All reactions were carried out under argon atmosphere using standard Schlenk technique
unless otherwise stated. Silica gel 60 (40–63 m, Merck) was used for column chromatography.
TLC analysis was made on standard Merck plates with F254-inducator using UV or KMnO4
solution for visualization. GC analysis was performed on Chromatec Crystal 2000M gas
chromatograph (capillary column Macherey-Nagel OPTIMA-1, 300  0.025 cm, 100%
1
19
31
13
dimethylpolysiloxane (0.25 m), carrier gas – He, detector – FID). H, F, P and C NMR
spectra were recorded on Varian Inova 400 (400.1, 376.4, 161.9 and 100.6 MHz, respectively) or
Bruker AVANCE II 300 (300.1, 282.3, 121.5 and 75.4 MHz, respectively) in CDCl3 or C6D6
containing TMS ( = 0 ppm) and C6F6 ( = –162.2 ppm) as internal standards. GC/MS analysis
was performed on gas chromatographer Chromatec Crystal 5000.2 with Thermo DSQ II (EI, 70
eV, 200°C) mass-detector. HRMS were recorded on Bruker micrOTOF equipment using electro
9

spray ionization (ESI). Elemental analyses were made in Laboratory of microanalysis IOC RAS
on Perkin-Elmer Series II 2400 CHN Analyzer.
4.2. Synthesis of (2-fluoroallyl)palladium chloride dimers 2a–d. General Procedure.
Modified procedure from ref. [16] was used. A mixture of PdCl2 (1–5 mmol) and LiCl (4
equiv., 4–20 mmol) was dissolved in water (0.3–1.5 mL) under gentle heating on a plate of
magnetic stirrer. After cooling to room temperature, this solution was transferred to a three-neck
round bottom flask and diluted with MeOH (6–30 mL). Then, 2-fluoroallyl chloride 1a–d (4
equiv., 1–20 mmol) was added; and CO was bubbled through the solution with stirring on a
magnetic stirrer for 30 min to 2 h. During this period color changed from deep brown to yellow
and a yellow precipitate formed; then bubbling was continued for 1 h more. Next, the reaction
mixture was diluted with CH2Cl2 and water. Organic layer was separated, dried over Na2SO4 and
concentrated on a rotary evaporator. The residue was washed with hexane and recrystallized by
slow diffusion of hexane into CH2Cl2 solution in a fridge overnight (except 2d, see below). The
crystals were collected, washed with hexane and dried under high vacuum.
4.2.1. -(2-Fluoro-3-phenylallyl)palladium chloride dimer 2a
This compound was obtained by the general procedure on a 5 mmol scale as yellow
microcrystals (1.308 g, 92% yield, Z/E = 92:8).
Z-isomer: 1H NMR (300.1 MHz, CDCl3) : 7.65–7.55 (m, 2H, arom.), 7.45–7.33 (m, 1H), 7.36–
7.17 (m, 2H), 4.47 (d, J = 22.1 Hz, 1H, PhCH=), 3.86 (dd, J = 8.9, 4.5 Hz, 1H, =CH2 (cis to F)),
2.88 (dd, J = 28.4, 4.5 Hz, 1H, =CH2 (trans to F)). 19F NMR (282.4 MHz, CDCl3) : –107.1 (m).
13C{1H} NMR (75.5 MHz, CDCl3) : 144.3 (d, J = 299.6 Hz, -CF=), 132.9 (d, J = 3.0 Hz, C-
arom.), 129.9 (d, J = 4.4 Hz, CH-arom.), 129.0 (d, J = 0.8 Hz, CH-arom.), 129.0 (s, CH-arom.),
69.8 (d, J = 6.6 Hz, PhCH=), 47.4 (d, J = 14.4 Hz, =CH2). HRMS (ESI) m/z: [(2-F-
cinnamyl)Pd(CH3CN)]+, Calcd. for C11H11FNPd+ 281.9905; Found 281.9917. Anal.: calcd. for
C9H8FClPd: C, 39.02; H, 2.91. Found: C, 38.91, H, 3.01.
E-isomer: 1H NMR (400.0 MHz, CDCl3) : (aromatic signal overlapped with Z-isomer), 5.95 (d,
J = 10.8 Hz, 1H, PhCH=), 4.14–4.07 (m, 1H, =CH2 (cis to F)), 3.47 (dd, J = 32.0, 4.5 Hz, 1H,
=CH2 (trans to F)). 19F NMR (376.4 MHz, CDCl3) : –102.7 (m).
4.2.2. -(2-Fluorocyclohept-2-enyl)palladium chloride dimer 2b
This compound was obtained by the general procedure on a 1 mmol scale as yellow
octahedrons (123.2 mg, 48% yield).
10

1H NMR (400.0 MHz, CDCl3) : 5.01–4.90 (m, 2H, 2 -CH=), 2.06–1.88 (m, 4H, CH2), 1.62–
19
1.50 (m, 2H, CH2), 1.50 – 1.38 (m, 2H, CH2). F NMR (376.4 MHz, CDCl3) : –103.2 (br. s).
13C{1H} NMR (100.6 MHz, CDCl3) : 140.8 (d, J = 287.8 Hz, CF), 72.9 (d, J = 14.5 Hz, 2 -
CH=), 29.53 (d, J = 4.1 Hz, 2 CH2), 26.31 (s, 2 CH2). HRMS (ESI) m/z: [(2-F-
cycloheptenyl)Pd]+, Calcd. for C7H10FPd+ 218.9799; Found 218.9798. [(2-F-
cycloheptenyl)Pd(CH3CN)]+, Calcd. for C9H13FNPd+ 260.0065; Found 260.0072. Anal.: calcd.
for C7H10FClPd: C, 32.97; H, 3.95. Found: C, 32.89, H, 3.80.
4.2.3. -(3-Fluoropent-3-en-2-yl)palladium chloride dimer 2c
This compound was obtained by the general procedure on a 1 mmol scale as yellow
microcrystals (83.8 mg, 38% yield, Z/E = 98/2).
1H NMR (400.0 MHz, CDCl3) : 3.54 (dq, J = 20.9, 6.6 Hz, 2H, 2 -CH=), 1.28 (d, J = 6.5 Hz,
19
13
6H, 2 CH3). F NMR (376.4 MHz, CDCl3) : –118.8 (t, J = 21.0 Hz). C{1H} NMR (100.6
MHz, CDCl3) : 145.8 (d, J = 294.9 Hz, CF), 63.2 (d, J = 12.3 Hz, 2 -CH=), 11.4 (d, J = 2.6 Hz,
2 CH3). HRMS (ESI) m/z: [(2-F-3,3-Me2All)Pd]+, Calcd. for C5H8FNPd+ 281.9905; Found
281.9917. [(2-F-3,3-Me2All)Pd(CH3CN)]+, Calcd. for C11H11FNPd+ 281.9905; Found 281.9917.
HRMS (ESI) m/z: [(2-F-1,3-Me2All)Pd]+, Calcd. for C5H8FPd+ 192.9641; Found 192.9642. [(2-
F-1,3-Me2All)Pd(CH3CN)]+, Calcd. for C7H11FNPd+ 233.9908; Found 233.9909. Anal.: calcd.
for C5H8FClPd: C, 26.23; H, 3.52. Found: C, 26.25; H, 3.47.
4.2.4. -(2-Fluoro-3-methylbut-2-enyl)palladium chloride dimer 2d
Obtained by the general procedure on a 1 mmol scale as yellow solids. Complex 2d was
found to be soluble in hexane and precipitated as yellow oil during attempts to recrystallize.
(68.1 g, 25% yield, contaminated with 15 mol.% of unknown impurity contained presumably 1-
[Me2C=CFCH2Pd] moiety).
1H NMR (400.0 MHz, CDCl3) : 3.86 (dd, J = 9.7, 4.7 Hz, 1H, =CH2 (cis to F)), 3.15 (dd, J = 30.9, 4.7
Hz, 1H, =CH2 (trans to F)), 1.42 (d, J = 1.8 Hz, 3H, CH3), 1.25 (d, J = 1.8 Hz, 3H, CH3). 19F NMR
(376.4 MHz, CDCl3) : –108.5 (br. d, J = 30.8 Hz). 13C{1H} NMR (100.6 MHz, CDCl3) : 143.3
(d, J = 291.2 Hz, CF), 81.3 (d, J = 11.2 Hz, Me2C=), 45.6 (d, J = 15.7 Hz, =CH2), 22.8 (s, CH3),
20.0 (d, J = 5.0 Hz, CH3). HRMS (ESI) m/z: [(2-F-3,3-Me2All)Pd]+, Calcd. for C5H8FPd+
192.9641; Found 192.9644. [(2-F-3,3-Me2All)Pd(CH3CN)]+, Calcd. for C7H11FNPd+ 233.9908;
Found 233.9913. Anal.: calcd. for C5H8FClPd: C, 26.23; H, 3.52. Found: C, 25.49; H, 3.25.
1
(Impurity): H NMR (400.0 MHz, CDCl3) : 3.80 (dd, J = 4.1, 1.6 Hz, 1H, in CH2), 2.98 (t, J = 1.4
Hz, 1H, in CH2), 2.17 (d, J = 2.5 Hz, 3H, CH3), 1.66 (d, J = 19.0 Hz, 3H, CH3). 19F NMR (376.4 MHz,
13
CDCl3) : –113.3 (m). C{1H} NMR (100.6 MHz, CDCl3) : 124.2 (d, J = 272 Hz, CF, from
11

{1H,13C}-HMBC), 111.7 (d, J = 17.4 Hz, Me2С=), 57.7 (d, J = 6.2 Hz, CH2), 20.6 (d, J = 25.4
Hz, CH3), 17.4 (d, J = 3.9 Hz, CH3).
4.3. Synthesis of (triphenylphosphine)(3-2-fluoro-3-phenylallyl)palladium chloride 3a
A Schlenk flask was charged with 2a (0.10 mmol, 64.0 mg) and PPh3 (0.20 mmol, 63.8
mg) and filled with argon on a Schlenk line. Benzene (4.2 mL) was added and the yellow
solution was stirred at room temperature for 3 h; then, evaporated to dryness on a rotary
evaporator and redissolved in CH2Cl2 (1.0 mL). The product was precipitated by addition of
hexane (5.0 mL) and crystallization in a fridge overnight. The precipitate was filtered off,
washed with hexane and dried under high vacuum, affording 3a as yellow solids (125.7 mg, 94%
yield).
1H NMR (400.0 MHz, C6D6) : 7.83 (d, J = 7.7 Hz, 2H in Ph), 7.76–7.68 (m, 6H in PPh3), 7.20
(t, J = 7.7 Hz, 2H in Ph), 7.09 (d, J = 7.4, 1H in Ph), 7.04–6.87 (m, 9H in PPh3), 4.72 (dd, J =
29.2, 10.0 Hz, 1H, PhCH=), 2.26 (br. s, 2H, =CH2). 19F NMR (376.4 MHz, C6D6) : –101.1 (br.
s). 31P{1H} NMR (161.9 MHz, C6D6) : 27.0 (br. s). 13C{1H} NMR (100.6 MHz, CDCl3) :
147.5 (dd, J = 290.6, 7.5 Hz, CF), 134.2 (d, J = 12.6 Hz, CH-arom.), 130.7 (d, J = 2.5 Hz, CH-
arom.), 130.0 (t, J = 4.9, 3.8 Hz, CH-arom.), 128.8 (d, J = 8.2 Hz, CH-arom.), 128.7 (s, CH-
arom.), 128.4 (s, CH-arom.), 85.0 (dd, J = 30.6, 6.7 Hz, PhCH=), 46.3 (d, J = 16.1 Hz, =CH2).
HRMS (ESI) m/z: [(2-F-cinnamyl)Pd(PPh3)]+, Calcd. for C27H23FPPd+ 503.0561; Found
503.0565. [(2-F-cinnamyl)Pd(PPh3)(CH3CN)]+, Calcd. for C29H26FNPPd+ 544.0827; Found
544.0831. Anal.: calcd. for C27H23FClPPd: C, 60.13; H, 4.30. Found: C, 59.81, H, 3.32.
4.4. Synthesis of (3-2-fluoro-3-phenylallyl)palladium(2-cyclohexylphosphino-2’,6’-
dimethoxybiphenyl) chloride 3b
A Schlenk flask was charged with 2a (0.68 mmol, 377.4 mg) and SPhos (1.36 mmol, 560.0
mg) and filled with argon on a Schlenk line. Toluene (2.4 mL) was added and the reaction
mixture was stirred at room temperature for 2 h. During the first 15 min, precipitation of a
yellow solid was observed. Next, the mixture was diluted with pentane (5.7 mL) and left in a
freezer overnight for complete crystallization. The precipitate was filtered off, washed with
pentane and dried under high vacuum, affording 3b as yellow solids (788.1 mg, 84% yield).
1H NMR (400.0 MHz, C6D6) : 7.85 (d, J = 7.7 Hz, 2H, arom.), 7.58 (t, J = 8.5 Hz, 1H, arom.),
7.24 (t, J = 7.6 Hz, 2H, arom.), 7.14–6.95 (m, 5H, arom.), 6.31 (br. s, 2H, 2CH orto to OMe in
SPhos), 4.13 (dd, J = 29.9, 9.6 Hz, 1H, PhCH=), 3.51–3.02 (m, 8H, 2OMe + =CH2), 2.54–2.15
19
(m, 2H, Cy), 2.10–1.96, 1.91–1.38, 1.34–0.98 (m, Cy, 20H total). F NMR (376.4 MHz, C6D6)
: –103.6 (dt, J = 29.8, 21.2 Hz). 31P{1H} NMR (161.9 MHz, C6D6) : 38.8 (br. s). 13C{1H}
12

NMR (75.5 MHz, CDCl3) : 158.1 (s), 146.1 (dd, J = 288.2, 6.8 Hz), 139.9 (d, J = 7.6 Hz), 135.8
(d, J = 11.2 Hz), 133.4–133.0 (m), 131.1 (d, J = 31.5 Hz), 129.6 (dd, J = 6.0, 3.0 Hz), 129.2 (s),
128.5 (d, J = 1.7 Hz), 127.7 (s), 125.8 (d, J = 9.1 Hz), 120.0–119.4 (m), 103.8 (s), 86.1 (dd, J =
29.3, 5.7 Hz), 55.5 (s), 40.7 (d, J = 15.4 Hz), 35.6 (d, J = 21.0 Hz), 29.8 (s), 27.4 (d, J = 11.9
Hz), 27.2 (d, J = 13.5 Hz), 26.2 (d, J = 1.6 Hz). HRMS (ESI) m/z: [(2-F-cinnamyl)Pd(SPhos)]+,
Calcd. for C35H43FO2PPd+ 651.2027; Found 651.2018. Anal.: calcd. for C35H43ClFO2PPd: C,
61.14; H, 6.30. Found: C, 60.28, H, 6.39.
4.5. Synthesis of bis(triphenylphosphine)(3-2-fluoro-3-phenylallyl)palladium triflate 4a
A Schlenk flask was charged with 2a (0.25 mmol, 138.5 mg) and AgOTf (0.50 mmol,
129.5 mg) and filled with argon on a Schlenk line. THF (10 mL) was added and the reaction
mixture was stirred for 1 hour. The resulted suspension was filtered under argon through a pad of
Celite (Sigma-Aldrich, cat. no. 06858). Addition 5 mL of THF were used to wash the Celite® S.
To the filtrate, PPh3 (1.0 mmol, 262.3 mg) was added; and the resulted solution was stirred for 2
h. Then it was concentrated on a rotary evaporator to ca. 5 mL and diluted with 100 mL of n-
hexane. Immediately formation of light beige precipitate was observed. The mixture was left for
2 hours at room temperature; the solids were filtered off, washed with hexane and dried under
high vacuum, affording 4a as light beige solids (409.8 mg, 90% yield).
1H NMR (400.0 MHz, CDCl3) : 7.42–7.22 (m, 18H, PPh3), 7.16–7.05 (m, 12H, PPh3), 6.96 (t, J
= 7.5 Hz, 1H, Ph), 6.91 (d, J = 7.8 Hz, 2H, Ph), 6.74 (t, J = 7.7 Hz, 2H, Ph), 5.62 (dd, J = 31.6,
10.4 Hz, 1H, PhCH=), 3.92 (ddd, J = 34.9, 9.8, 5.0 Hz, 1H, =CH2 (trans to F)), 3.35 (dt, J =
19
11.9, 5.7 Hz, 1H, cis to F)). F NMR (376.4 MHz, CDCl3) : –78.6 (s, 3F, OTf), –94.7 (td, J =
31
33.2, 12.5 Hz, 1F, CF). P{1H} NMR (161.9 MHz, CDCl3) : 27.1 (dd, J = 45.8, 2.2 Hz), 25.9
(d, J = 45.8 Hz). 13C{1H} NMR (100.6 MHz, CDCl3) : 147.9 (dt, J = 288.6, 7.2 Hz, CF), 133.8
(d, J = 8.5 Hz, CH in PPh3), 133.7 (d, J = 8.7 Hz, CH in PPh3), 131.0 (d, J = 2.5 Hz, CH in
PPh3), 130.9 (dd, J = 44.2, 1.7 Hz, C in PPh3), 130.6 (d, J = 2.4 Hz, CH in PPh3), 130.2–130.0
(m, CH in Ph), 129.3 (dd, J = 42.6, 1.4 Hz, C in PPh3), 129.0 (d, J = 10.7 Hz, CH in PPh3), 128.7
(d, J = 10.5 Hz, CH in PPh3), 128.1 (br. s, CH in Ph), 127.7 (br. s, CH in Ph), 85.4 (d, J = 28.7
Hz, PhCH=), 61.9 (dd, J = 29.9, 14.1 Hz, =CH2). HRMS (ESI) m/z: [(2-F-cinnamyl)Pd(PPh3)2]+,
Calcd. for C45H38FP2Pd+ 765.1478; Found 765.1476. Anal.: calcd. for C46H38F4O3P2PdS: C,
60.37; H, 4.19. Found: C, 61.08, H, 3.99.
13

4.6. Synthesis of (3-2-fluoro-3-phenylallyl)palladium(2-cyclohexylphosphino-2´,6´-
dimethoxybiphenyl) triflate 4b
This complex was prepared using the procedure described for 4a, using 2a (0.25 mmol,
139.3 mg), AgOTf (0.50 mmol, 129.2 mg) and SPhos (206.3 mg). After the reaction completed,
the formation of light-yellow precipitate was observed. The reaction mixture was diluted with 45
mL of anhydrous Et2O and left in a freezer for 3 h. The solids were filtered off, washed with
anhydrous Et2O and dried under high vacuum, affording 4b as light-yellow solids (273.4 mg,
68% yield).
1H NMR (400.0 MHz, CDCl3) : 7.72–7.65 (m, 1H, arom.), 7.54–7.42 (m, 5H, arom), 7.35–7.27
(m, 2H, arom.), 6.83–6.76 (m, 1H, arom.), 6.48 (br. s, 1H, SPhos, CH orto to MeO), 6.19 (t, J =
8.3 Hz, 1H, SPhos, CH meta to MeO), 5.63 (br. s, 1H, SPhos, CH orto to MeO), 5.12 (dd, J =
33.0, 9.5 Hz, 1H, PhCH=), 3.95–3.28 (m, 8H, 2MeO + =CH2), 2.53–2.15 (m, 2H, CH in Cy),
2.09–1.61 (m, 10H, CH2 in Cy), 1.61–1.04 (m, 10H, CH2 in Cy). 19F NMR (282.4 MHz, CDCl3)
31
: –78.6 (s, 3F, OTf), –100.3 (dtd, J = 32.8, 21.7, 4.1 Hz, 1F, CF). P{1H} NMR (121.5 MHz,
CDCl3) : –60.7 (br. s). 13C{1H} NMR (75.5 MHz, CDCl3) : 159.2 (s), 145.1 (s), 144.8 (s),
144.3 (dd, J = 285.6, 8.4 Hz), 135.7 (s), 135.1 (s), 132.8 (br. s), 132.5 (d, J = 2.3 Hz), 132.4 (s),
131.8 (s), 131.4 (d, J = 12.9 Hz), 129.4 (t, J = 2.5, 1.4 Hz), 129.0 (dd, J = 6.2, 3.1 Hz), 128.7 (d,
J = 2.4 Hz), 128.2 (d, J = 5.5 Hz), 103.6 (br. s), 100.2 (d, J = 4.4 Hz), 96.4 (dd, J = 24.8, 3.9 Hz),
56.3 (br. s), 40.6 (d, J = 15.9 Hz), 37.0 (d, J = 24.3 Hz), 29.3 (br. s), 28.7 (s), 27.1 (d, J = 13.7
Hz), 27.0 (d, J = 11.6 Hz), 25.7 (s). HRMS (ESI) m/z: [(2-F-cinnamyl)Pd(SPhos)]+, Calcd. for
C35H43FO2PPd+ 651.2027; Found 651.2017. Anal.: calcd. for C36H43F4O5PPdS: C, 53.90; H,
5.41. Found: C, 54.12, H, 5.31.
4.7. Reactions of (2-fluoroallyl)palladium complexes with sodium dimethyl methylmalonate
(Table 1)
A modified procedure from ref. [16] was used. A 20-mL screw neck vial was charged with
a Ligand (0.025 mmol for bidentate ligands, 0.050 mmol for monodentate ligands), sealed with a
septum and filled with argon on a Schlenk line through a needle. An aliquot of 0.10 M solution
of (2-fluorocinnamyl)palladium triflate in THF was added (0.025 mmol, 2.5 mL, freshly
prepared from dimer 2a and AgOTf), and the mixture was stirred for 30 min. Then, a 0.50M
solution of sodium dimethyl methylmalonate in THF was added (0.125 mmol, 2.5 mL, 5 equiv.).
The reaction mixture was stirred at room temperature for 24 h, then quenched with 5.7 M
solution of HCl in dioxane (30–40 L, 7–9 equiv.) and evaporated on a rotary evaporator to
dryness. Then mesitylene and 4-fluorobenzotrifluoride were added (internal standards for 1H and
19F NMR, respectively), and the mixture was dissolved in ca. 0.8 mL of CDCl3, filtered through
14

a short pad of Celite® S and analyzed by 1H and 19F NMR and GC/MS. Results are presented in
the Table 1.
Products 5 and 6 were identified by characteristic signals that were the same to previously
published [10]. Side product 7 could only be preliminary identified (see characteristic NMR
signals and MS data below) as dimethyl 2-(2-fluoro-1-phenylallyl)-2-methylmalonate.
1H NMR (400.0 MHz, CDCl3) (selected peaks) : 4.71 (dd, J = 18.6, 3.1 Hz, 1H, PhCH<), 4.58
19
(d, J = 18.8 Hz, 1H, =CH2 (cis to F)), 4.41 (dd, J = 50.1, 3.1 Hz, 1H, =CH2 (trans to F)). F
NMR (376.4 MHz, CDCl3) : –96.7 (dt, J = 50.3, 18.7 Hz). MS (EI) m/z: 280 ([M+], 5), 221
(43), 201 (9), 188 (10), 146 (14), 135 (100), 115 (53), 109 (9).
4.8. Reactions of (2-fluoroallyl)palladium complexes 3 and 4 with nucleophiles (Tables 2, 3)
A 20 mL screw neck vial was charged with a complex 3 or 4 (0.025 mmol). In a stream of
argon, THF (2.5 mL) and Nucleophile (4-FC6H4OK, Bn(Ts)NNa, HNEt2, 4-MeC6H4SO2Na,
triolborate 11 or B2pin2) (0.075 mmol, 3 equiv.) were added. The vial was sealed and stirred at
80°C (or 60°C for B2pin2) on an oil bath for 4 h. The reaction mixture was concentrated on a
rotary evaporator to ca. 1 mL; 4-fluorobenzotrifluoride as an internal standard was added; the
mixture was filtered through a short pad of Celite® S and analyzed by 19F NMR and GC/MS.
To detect the formation of products of disubstitution that do not contain any fluorine atom,
the reaction mixture was quenched with 5.7 M solution of HCl in dioxane (30–40 L, 7–9
equiv.) and evaporated on a rotary evaporator to dryness (except reactions with diethylamine,
that were diluted with Et2O, washed with 10% K2CO3 solution, dried over K2CO3, concentrated
on a rotary evaporator). Then, mesitylene and 4-fluorobenzotrifluoride as internal standards were
added; the mixture was dissolved in ca. 0.8 mL of CDCl3, filtered through a short pad of Celite®
S and analyzed by 1H and 19F NMR and GC/MS.
The products were identified by characteristic NMR signals using previously published
data or compared to authentic samples: 8b — [11], 10a — [13], 10b — [20], 12 — [15], 13 —
[17], 14 — [18], 15 — [21]. Compounds 8a and 9 are unpublished, authentic samples were
prepared by previously published procedures for similar compounds [12] (see below).
Compound 10c was previously published only in a PhD. thesis of one the author of the current
paper [22], therefore, the procedure is listed below.
4.8.1. 2,3-Bis(4-fluorophenyloxy)-1-phenylpropene 8a
According to published procedure [12], starting from 2-fluorocinnamyl acetate (195.1 mg,
1.0 mmol), 4-fluorophenol (341.1 mg, 3.0 mmol), Pd(PPh3)4 (116.8 mg, 0.10 mmol) and Cs2CO3
(925.3 mg, 2.8 mmol) in toluene (5.0 mL) at 100°C for 10 h, 8a was obtained as a clear viscous
oil that slowly crystallized at 20°C (169.9 mg, 53% yield, Z/E = 84/16, Rf = 0.28, eluent — n-
15

hexane/benzene/EtOAc 300:100:1). Z-Configuration of the major isomer was confirmed by nOe
cross-peak between =CH– and –CH2OAr protons in {1H,1H}-NOESY.
1
Z-8a: H NMR (400.0 MHz, CDCl3) : 7.60–7.53 (m, 2H, arom.), 7.42–7.17 (m, 4H, arom.),
7.10–6.90 (m, 5H, arom.), 6.89 – 6.78 (m, 2H, arom.), 6.29 (s, 1H, =CH), 4.52 (s, 2H, -
19
CH2OAr). F NMR (376.4 MHz, CDCl3) : –121.2 (tt, J = 8.3, 4.6 Hz, 1F), –123.4 (tt, J = 8.4,
4.3 Hz, 1F). 13C{1H} NMR (100.6 MHz, CDCl3) : 158.6 (d, J = 241.1 Hz, CF-arom.), 157.7 (d,
J = 239.1 Hz, CF-arom.), 154.4 (d, J = 2.1 Hz, C-arom.), 151.2 (d, J = 2.2 Hz, C-arom.), 147.1
(s, C-arom.), 128.9 (s, CH-arom.), 128.6 (s, CH-arom.), 127.8 (s, CH-arom.), 118.5 (d, J = 8.3
Hz, CH-arom.), 117.9 (s, =CH), 116.3 (d, J = 23.9 Hz, CH-arom.), 116.2 (d, J = 7.5 Hz, CH-
arom.), 115.9 (d, J = 23.1 Hz, CH-arom.), 67.9 (s, CH2O).
E-8a: 1H NMR (400.0 MHz, CDCl3) : (aromatic signals are overlapped with Z-isomer), 6.04 (s,
1H, =CH), 4.71 (s, 2H, CH2OAr). 19F NMR (376.4 MHz, CDCl3) : –119.4 (tt, J = 7.9, 4.8 Hz,
1F), –123.7 (tt, J = 8.4, 4.4 Hz, 1F).
4.8.2. 2-Benzyl-5-fluorobenzofuran 9
According to published procedure [12], starting from 2-fluorocinnamyl acetate (201.5 mg,
1.0 mmol), 4-fluorophenol (579.9 mg, 5.2 mmol), [(2-Methallyl)PdCl]2 (19.5 mg, 0.05 mmol),
dppp (41.3 mg, 0.10 mmol) and Cs2CO3 (933.0 mg, 2.9 mmol) in dioxane(5.0 mL) at 100°C for
10 h, 9 was obtained as a clear oil (112.7 mg, 55% yield, Rf = 0.31, eluent — n-
hexane/benzene/EtOAc 100:10:0.1).
1H NMR (400.0 MHz, CDCl3) : 7.36–7.22 (m, 6H, arom.), 7.10 (dd, J = 8.6, 2.6 Hz, 1H, CH-
arom.), 6.90 (td, J = 9.1, 2.7 Hz, 1H, CH-arom.), 6.32 (d, J = 1.1 Hz, 1H, CH-furan), 4.07 (s, 2H,
CH2). 19F NMR (376.4 MHz, CDCl3) : –122.1 (td, J = 9.0, 4.1 Hz). 13C{1H} NMR (100.6 MHz,
CDCl3) : 159.8 (s, C-arom.), 159.2 (d, J = 237.3 Hz, CF-arom.), 151.2 (s, C-arom.), 136.9 (s, C-
arom.), 129.6 (d, J = 10.7 Hz, C-arom.), 129.0 (s, CH-arom.), 128.7 (s, CH-arom.), 127.0 (s, CH-
arom.), 111.5 (d, J = 9.7 Hz, CH-arom.), 111.0 (d, J = 26.3 Hz, CH-arom.), 106.1 (d, J = 25.0
Hz, CH-arom.), 103.7 (d, J = 3.8 Hz, CH-arom.), 35.1 (s, CH2). MS (EI) m/z: 226 ([M+], 53),
225 (100), 207 (5), 196 (23), 149 (47).
4.8.3. 1-[(2-fluoro-3-phenylallyl)sulfonyl]-4-methylbenzene 10c
A vial was charged with 2-bromo-2-fluoro-1-phenylcyclopropane (108.2 mg, 0.50 mmol),
p-TolSO2Na (107.1 mg, 0.60 mmol) and CuBr (14.3 mg, 0.10 mmol). In a steam of argon,
anhydrous DMSO was added (0.50 mL); the vial was sealed and heated on an oil bath at 100°C
for 24 h. The reaction mixture was diluted with CH2Cl2, washed with satd. NH3, water and brine,
and dried over K2CO3. After evaporation of the solvent on a rotary evaporator, the residue was
16

purified by column chromatography on silica eluting with n-hexane/EtOAc (gradient from 50:1
to 5:1) to give 10c as colorless solvent solids (137.3 mg, 95% yield, Z/E 80:20).
1
Z-10c: H NMR (200.1 MHz, CDCl3)  7.75–7.85 (m., 2H, arom.), 7.19–7.44 (m., 7H, arom.),
5.62 (d, J = 37.2 Hz, 1H, =CH), 4.05 (d, J = 18.7 Hz, 2H, CH2SO2), 2.43 (s, 3H, CH3). 19F NMR
13
(188.3 MHz, CDCl3)  –101.6 (dt, J = 37.2, 18.7 Hz). C{1H} NMR (50.3 MHz, CDCl3) 
148.4 (d, J = 265 Hz, =CF), 145.3 (s, C-arom.), 135.3 (s, C-arom.), 132.1 (d, J = 3.3 Hz, C-
arom.), 129.9 (s, CH-arom.), 128.9 (d, J = 7.5 Hz, CH-arom.), 128.6 (s, CH-arom.), 128.6 (s,
CH-arom.), 128.2 (d, J = 2.3 Hz, CH-arom.), 114.2 (d, J = 6.7 Hz, =CH), 61.0 (d, J = 29.4 Hz,
CH2SO2), 21.7 (s, CH3). HRMS (ESI) m/z: [M+Na]+, Calcd. for C16H15FO2SNa+ 313.0669;
Found 313.0658.
E-10c: 1H NMR (200.1 MHz, CDCl3)  (aromatic signals are overlapped with Z-10c) 6.53 (d, J
19
= 19.6 Hz, 1H, –CH=), 4.18 (d, J = 20.5 Hz, 2H, CH2SO2). F NMR (188.3 MHz, CDCl3)  –
99.0 (td, J = 20.5, 19.6 Hz).
Declaration of interests
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was funded by Russian Science Foundation (RSF) according to the research project №
19-73-00320. Crystal structure determination was performed in the Department of Structural
Studies of Zelinsky Institute of Organic Chemistry, Moscow. Authors greatly thank Dr. Roman
A. Novikov from ZIOC RAS for 1D and 2D NMR assistance.
Supplementary Data
Copies of 1H, 19F, 31P and 13C NMR spectra.
X-Ray crystallography data for compounds 2a-c.
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