An Approach to Nonsymmetric Bis(tertiary phosphine oxides) Comprising Heterocyclic Fragments via the Pd-Catalyzed Phosphorylation

Article abstract of DOI:10.1055/s-0040-1706419

Nonsymmetric tertiary phosphine oxides with different five- and six-membered heterocyclic fragments such as pyridine, 2,2′-bipyridine, 1,10-phenantroline, quinoline, imidazole, and thiazole were synthesized in good yields via the successive introduction of phosphine oxide groups into the initial dihalogenated heterocycles by means of Pd-catalyzed phosphorylation reaction. The synthesis of pyridine-type compounds is hindered by competing double coupling, while for five-membered heterocycles the principal difficulty is the dehalogenation. Both side processes were successfully suppressed by the use of an excess of a dihalide (which can be easily recovered during the product purification step), proper phosphine ligand for palladium, and nonpolar solvent such as toluene.

Full text of DOI:10.1055/s-0040-1706419

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
en
G. G. Zakirova et al.
Letter
Synlett
An Approach to Nonsymmetric Bis(tertiary phosphine oxides)
Comprising Heterocyclic Fragments via the Pd-Catalyzed
Phosphorylation
Gladis G. Zakirova*
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0-0
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3-3
7
2
5-
5
1
6
5
Pd-catalyzed cross-coupling
Dmitrii Yu. Mladentsev
0
0
0
0-0
0
0
1-
9
9
4
5-4
8
2
7
R12POH
R22POH
HetAr
R1
P
R2
R1
HetAr
HetAr
Nataliya N. Borisova
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0
0
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9
1
R1
R2
R1
P
P
X
X
X
Department of Chemistry, Lomonosov Moscow State
University, 1/3 Leninskie Gory, GSP-1, 119991 Moscow,
Russian Federation
O
O
O
R1,R2 = alkyl, aryl
X = Br, Cl
6 examples
52−85% yield
10 examples
47−89% yield
gladisz@yandex.ru
S
N
N
N
N
N
N
N
N
N
∗ successive functionalization of two electrophilic centers
∗ use of readily available starting materials
∗ access to nonsymmetric phosphine oxides
Received: 01.05.2020
Accepted after revision: 20.07.2020
Published online: 26.08.2020
(SPOs) and halogenated heterocycles.19,20 In our previous
studies, (hetero)aromatic (di)halides were subjected to the
double coupling with two equivalents of the same SPO.
However, selective monophosphorylation of a molecule
bearing two identical sites (for example, substitution of one
chlorine atom in 2,6-dichloropyridine) remains essentially
unexplored. Thus, the purposes of the present study are (1)
to investigate possible approaches to the monophosphory-
lation of heterocyclic dihalides with the formation of
monohalophosphine oxides, which can be used for further
functionalization by means of cross-coupling or related
chemistry and (2) to synthesize a series of heterocyclic
bis(phosphine oxides) by the successive introduction of two
different SPOs into Pd-catalyzed phosphorylation.
DOI: 10.1055/s-0040-1706419; Art ID: st-2020-v0262-l
Abstract Nonsymmetric tertiary phosphine oxides with different five-
and six-membered heterocyclic fragments such as pyridine, 2,2′-bipyri-
dine, 1,10-phenantroline, quinoline, imidazole, and thiazole were syn-
thesized in good yields via the successive introduction of phosphine ox-
ide groups into the initial dihalogenated heterocycles by means of Pd-
catalyzed phosphorylation reaction. The synthesis of pyridine-type
compounds is hindered by competing double coupling, while for five-
membered heterocycles the principal difficulty is the dehalogenation.
Both side processes were successfully suppressed by the use of an ex-
cess of a dihalide (which can be easily recovered during the product pu-
rification step), proper phosphine ligand for palladium, and nonpolar
solvent such as toluene.
A number of nitrogen heterocycles such as 2,6-dichloro-
pyridine (PyCl2), 6,6′-dichloro-2,2′-bipyridine (BipyCl2),
2,9-dichloro-1,10-phenanthroline (PhenCl2), 8-bromo-2-
chloroquinoline (QuinBrCl), 2,4-dibromothiazole (ThzBr2),
and 2,4-dibromo-1-methyl-1H-imidazole (ImBr2) were se-
lected as electrophilic reaction partners. The work was
started from the cross-coupling between equimolar
amounts of Ph2POH and QuinBrCl (Scheme 1) because of
the presence in dihalide’s structure of two different halo-
gen atoms which may have different reactivity in cross-
coupling process. During the first stage compound 1 was
successfully synthesized (resonance shift in 31P NMR spec-
trum is about 20 ppm, in the characteristic range for tertia-
ry phosphine oxide group near the nitrogen atom in hetero-
cycle). Thus, the chlorine atom which is located in ortho po-
sition of pyridine ring reacts faster than the bromine. The
possibility of the SNAr mechanism operation as the plausi-
ble explanation was ruled out by the uncatalyzed reaction
results. The subsequent cross-coupling of 1 with n-Oct2POH
resulted in the formation of the quinoline-based nonsym-
metric tertiary phosphine oxide 2 in good yield.
Key words cross-coupling, phosphorylation, nonsymmetric phos-
phine oxide, palladium, heterocycles, dehalogenation
Tertiary phosphine oxides (TPOs) have a number of ap-
plications;1–5 one of the most interesting and promising is
their use as ligands for different metals, especially from f-
block.6,7 Such complexes possess potentially valuable pho-
tophysical properties8–12 and upon the complexation the
extractive separation of actinide and lanthanide ions mix-
tures can be achieved as a part of the spent nuclear fuel re-
processing cycle.13–15 Due to the high complexity of bipha-
sic multicomponent extraction systems, it is often difficult
to establish the structure–property relationships, therefore
the search for a compound with valuable properties usually
proceeds in a form of screening through a library of similar
substances. In the framework of our ongoing research in the
field of the f-elements chemistry,16–18 the access to a num-
ber of structurally diverse heterocycle-based phosphine ox-
ides is needed, and it was found that palladium-catalyzed
phosphorylation is the method of choice for the synthesis
of such compounds from secondary phosphine oxides
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
G. G. Zakirova et al.
Letter
Synlett
Ph2POH (1.05 equiv)
Pd(OAc)2 (2 mol%)
dppf (4 mol%)
Oct2POH (1.2 equiv)
Pd(OAc)2 (2.5 mol%)
dppf (5 mol%)
Ph
P
Ph
P
Ph
Ph
N
N
Cl
N
Oct
Oct
Cs2CO3, PhMe
110 °C, 5 h
Cs2CO3, PhMe
110 °C, 20 h
P
O
Br
QuinBrCl
Br
O
O
1, 80%
2, 78%
Scheme 1 Synthesis of mono- and bis(phosphorylated) quinoline derivatives
The attempts to introduce one Ph2PO group into other
pyridine heterocycles (PyCl2, BipyCl2, PhenCl2) using equi-
molar ratio of the coupling partners led to the mixtures
consisting mainly of mono and bis(phosphorylated) deriva-
tives of these heterocycles (Supporting Information (SI): Ta-
ble S1, No. 1, 2, 4, 7). These results are the evidence that
some acceleration of the second phosphorylation occurs af-
ter the installation of the first phosphine oxide group. The
decrease of the reaction temperature (SI: Table S1, No. 1, 2)
as well as the increase of a catalyst loading (SI: Table S1, No.
5, 6) had only insignificant influence on the outcome in all
cases. To solve the problem of the bis(phosphine oxides)
formation the amount of Ph2POH was reduced twice rela-
tive to dichloroheterocycles keeping all other conditions
unchanged. The approach worked well in the cases of PyCl2
and BipyCl2 (double phosphorylation byproducts were not
observed in 31P NMR of reaction mixtures) in contrast to
PhenCl2 (product/byproduct ratio was about 1:1). Addi-
tional optimization of phosphine ligand (SI: Table S1, No. 9–
12) revealed that DPEPhos was more effective ligand for the
synthesis of 5. Thus, the compounds 3–5 were successfully
synthesized in good yields (Table 1); it should be noted that
the excess of a dichloroheterocycle can be readily recovered
during the chromatographic purification of a target phos-
phine oxide that makes their further utilization possible.
For obtaining the nonsymmetric tertiary phosphine oxides
6–10 the compounds 3–5 were introduced in the cross-
coupling reaction with several SPOs. n-Oct2POH reacted
slower than (3,5-Me2Ph)2POH therefore the reaction with
the former was conducted for 20 h (instead of 7 h for the
latter) and with increased amount of the catalyst. It is inter-
esting to note that the reaction with (4-CF3Ph)2POH (with
the formation of 10) was carried out in toluene since only
decomposition of the SPO was found in DMF, which is con-
sistent with our previous observations.20 Moreover, using
toluene as a solvent, Py[(4-CF3Ph)2P(O)]2 (10А) was suc-
cessfully obtained (see the SI) in high yield (which was
shown to be impossible in DMF).20 The reasons for such a
behavior are currently under investigation.
Table 1 Synthesis of Mono- and Bis(phosphorylated) Derivatives of
Pyridine, Bipyridine, and Phenanthroline
Ph2POH
(0.55 equiv)
R2POH
(1.2 equiv)
Ph
Ph
HetAr
HetAr
HetAr
Ph
Ph
R
R
P
O
P
P
Cl
Cl
Cl
(i) or (ii)
(iii), (iv), (v)
O
O
6–9
3–5
Compound
HetAr
R
Yield (%)a
Conditionsb
3
4
Py
–
–
–
81c
85c
71c
89
(i)
Bipy
Phen
Py
(i)
5
(ii)
(iii)
(iv)
(iv)
(iv)
(v)
6
m-xylyl
n-Oct
7
Py
78
8
Bipy
Phen
Py
n-Oct
85
9
n-Oct
47
10
4-CF3Ph
75
a Reactions were carried out at 110 °C at 0.3–3 mmol scale, all yields are
isolated.
b Conditions (i): Pd(OAc)2 (1 mol%), dppf (2 mol%), K2CO3, DMF, 7 h. Condi-
tions: (ii) Pd(OAc)2 (2 mol%), DPEPhos (4 mol%), K2CO3, DMF, 7 h; (iii)
Pd(OAc)2 (1 mol%), dppf (2 mol%), Cs2CO3, DMF, 7 h; (iv) Pd(OAc)2 (2.5
mol%), dppf (5 mol%), Cs2CO3, DMF, 20 h; (v) Pd(OAc)2 (5 mol%), DPEPhos
(10 mol%), Cs2CO3, PhMe, 20 h.
c At Ph2POH (1.05 equiv), Pd(OAc)2 (1 mol%), dppf (2 mol%), K2CO3, DMF, 7
h, the contents of 3, 4 and 5 were less than 75%, 72% and 50%, respectively.
use of substoichiometric amount of Ph2POH: with 0.6 equiv
(relative to ThzBr2) the reaction produced only unreacted
ThzBr2 and 11 without monobromothiazole. In the case of
imidazole, any amount of SPO led to monobromoimidazole
formation, so to maximize the yield of 12 0.8 equiv (relative
to ImBr2) was used. For both heterocycles the phosphoryla-
tion reaction showed strong dependence upon the phos-
phine ligand employed and the best outcome was obtained
with dppf. It should be noted that unreacted dihalides can
be recovered easily during the purification of products. It is
also noteworthy that not only the SPO concentration and
the phosphine ligand, but the solvent plays a role (SI: S4,
No. 6, 7) in the debromination process as well. When com-
paring the outcomes of reactions in DMF and PhMe one can
see that the debromination predominates over cross-cou-
pling in the former solvent. There are two mechanistic pos-
sibilities: DMF can act as debrominating agent by itself21–23
or it can accelerate the SPO-mediated debromination owing
to its high polarity, since the charged intermediates were
proposed for related transformations.24
Unlike to pyridine-type heterocycles reactions of Thz-
Br2 and ImBr2 with Ph2POH led not only to desired prod-
ucts and bis(phosphorylated) compounds but also to by-
products resulted from debromination (SI: Tables S2, S4). In
the absence of a catalyst the debromination was the main
reaction pathway (SI: S2, No. 9; S4, No. 12–14). The best re-
sults for the synthesis of 11 were achieved (Table 2) by the
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
G. G. Zakirova et al.
Letter
Synlett
Table 2 Synthesis of Mono- and Bis(phosphorylated) Derivatives of
Thiazole and Imidazole
To our surprise, the reaction between 12 and equimolar
amount of Ph2POH led almost exclusively to 16 (85% isolat-
ed yield) without significant debromination, but the reac-
tion was rather slow, so the increased catalyst loading was
used in this case (Table 2). It is somewhat unexpected that
in the first coupling imidazole framework was more sus-
ceptible to debromination than thiazole, while for the sec-
ond one the reverse situation occurred.
SPO
Pd(OAc)2
dppf
SPO
Pd(OAc)2
DPEPhos
X
X
R
P
Ph
P
Ph
P
X
R
Ph
Ph
Br
N
N
Br
Br
Cs2CO3
PhMe
Cs2CO3
PhMe
N
O
O
O
100 °C
100 °C
X = S, NMe
11, 12
13−16
Compd
X
R
–
SPO
(equiv)
[Pd]/L
(mol%)
Time
(h)
Yield
(%)a
Additional cross-coupling reactions between the two
five-membered heterocyclic dibromides and Ph2POH
(2.4 equiv relative to halides) were conducted (SI: Table S2,
No. 1–5; Table S4, No. 1–3). No conditions tested previously
for single couplings worked in these runs, the desired com-
pounds 11, 12, 15, and 16 presented only in trace amounts
while the main products resulted from debromination of
either starting dibromides or intermediate bromophos-
phine oxides. These experiments showed that the debromi-
nation is highly and unpredictably dependent on the con-
centration of the SPO in solution (as well as on its struc-
ture) and one-pot double phosphorylation is essentially
unattainable for these two azoles.
11
12
13
14
15
16
S
Ph2POH
(0.6)
2/4
4/8
5.5
5.5
20
20
5
61
NMe
S
–
Ph2POH
(0.8)
52b
71
Oct
Oct
Ph
Oct2POH
(1.2)
2.5/5
5/10
2.5/5
10/20
NMe
S
Oct2POH
(1.2)
75
Ph2POH
(0.6)
88c
85
NMe
Ph
Ph2POH
(1.2)
5
In conclusion, herein we report on the synthetic route
for the preparation of a new type of nonsymmetric tertiary
phosphine oxides based on different heterocyclic fragments
by successive introduction of phosphine oxide groups by
the Pd-catalyzed cross-coupling reaction.25,26 This approach
allows one to obtain the target compounds from readily (ei-
ther synthetically or commercially) available reagents in
two stages with good-to-high yields. In the case of pyri-
dine-type heterocyclic halides the main difficulty was the
double coupling at equimolar reagents ratio, while for
azoles the key issue was dehalogenation reaction. Both is-
sues were successfully solved by the proper choice of sup-
porting ligand for palladium and reagents stoichiometry.
a Isolated yield.
b At Ph2POH (1.1 equiv), Pd(OAc)2 (4 mol%), dppf (8 mol%), Cs2CO3, PhMe,
5.5 h, the content of 12 was less than 50%.
c At Ph2POH (1.2 equiv), Pd(OAc)2 (2.5 mol%), DPEPhos (5 mol%), Cs2CO3,
PhMe, 7 h, the content of 15 was less than 27%.
Having obtained the compounds 11 and 12, we used
them further to synthesize the nonsymmetric TPOs based
on the thiazole and imidazole frameworks (13 and 14, re-
spectively, Table 2). Yields of target products were higher
when using DPEPhos instead of dppf; in addition, to suc-
cessfully attain the compound 14 it was necessary to use an
increased amount of the catalyst.
To study the influence of the substituents at a phospho-
rus atom in an SPO on the second cross-coupling it was de-
cided to synthesize bis(diphenylphosphine oxides) 15 and
16 from 11 and 12, respectively. The use of less nucleophilic
aromatic SPO (in comparison with n-Oct2POH) is important
for the understanding of the reactivity of 11 and 12 in pal-
ladium-catalyzed phosphorylation and in particular the re-
lationship between the electron density at a phosphorus
atom in an SPO and the rate of debromination.
Funding Information
Results have been obtained under support of the Russian Science
Foundation (RSF, Grant No. 16-13-10451).
R
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si
a
n
S
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n
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4
5
1)
Acknowledgment
Analogously to the reaction with Oct2POH, the cross-
coupling of 11 with Ph2POH was also suffered from the de-
bromination side process (SI: Table S3). In addition, the use
of dppf as a ligand led to higher content of debrominated
product, than in experiments conducted with DPEPhos (SI:
Table S3, No. 4, 5). For the synthesis of the thiazole-based
compound the best results were achieved by the use of sub-
stoichiometric amount of Ph2POH (Table 2): under these
conditions only 11 and 15 were detected in reaction mix-
ture. The yield of 15 was as high as 88% (based on SPO) and
unreacted 11 was recovered successfully.
The authors are grateful to the Moscow State University (Russian Fed-
eration) for the opportunity to use the NMR facilities of the Center for
Magnetic Tomography and Spectroscopy.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706419.
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References and Notes
(1) Etter, M. C.; Baures, P. W. J. Am. Chem. Soc. 1988, 110, 639.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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G. G. Zakirova et al.
Letter
Synlett
(2) Hazra, S.; Hoshimoto, Y.; Ogoshi, S. Chem. Eur. J. 2017, 23,
15238.
and then evaporated to dryness.
For reactions Conducted in Toluene
(3) Kotani, S.; Nakajima, M. Tetrahedron Lett. 2020, 61, 151421.
(4) Sugiura, M.; Nakajima, M. In Encyclopedia of Reagents for
Organic Synthesis; EROS 2010.
(5) Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47,
1560.
(6) Giesbrecht, E. Pure Appl. Chem. 1979, 51, 925.
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(8) Kido, J.; Okamoto, Y. Chem. Rev. 2002, 102, 2357.
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7229.
After cooling, the reaction mixture was evaporated to dryness.
Then, the mixture was diluted with CH2Cl2 (40 mL/mmol) and
washed with water and brine (40 mL/mmol). The organic layer
was dried over Na2SO4 and the CH2Cl2 was removed under
reduced pressure. Notice that all compounds with two phos-
phine oxide groups are beige-to-brown solids or slowly solidi-
fying viscous brown oils.
(26) Analytical Data for Compound 2
1H NMR (400 MHz, CDCl3):  = 8.52–8.57 (m, 1 H, HQuin), 8.42–
8.45 (m, 1 H, HQuin), 8.37–8.40 (m, 1 H, HQuin), 8.06 (d, 1 H,
J = 8.2 Hz, HQuin), 7.77 (t, 1 H, J = 7.6 Hz, HQuin), 7.66–7.71 (m, 4
H, 2-HPh), 7.56–7.60 (m, 2 H, 4-HPh), 7.45–7.49 (m, 4 H, 3-HPh),
1.61–1.77 (m, 4 H, HOct), 1.32–1.45 (m, 2 H, HOct), 0.97–1.27 (m,
22 H, HOct), 0.83 (t, 6 H, J = 7.2 Hz, HOct). 13C NMR (101 MHz,
CDCl3):  = 157.39 (d, J = 129.3 Hz, 1 C), 146.79 (dd, J = 20.5,
7.6 Hz, 1 C), 138.68 (d, J = 4.2 Hz, 1 C), 137.55 (d, J = 9.0 Hz, 1 C),
132.44 (1 C), 132.37 (d, J = 2.4 Hz, 2 C), 132.10 (d, J = 9.8 Hz, 4
C), 131.47 (d, J = 104.8 Hz, 2 C), 131.61 (1 C), 128.65 (d,
J = 12.6 Hz, 4 C), 128.30 (d, J = 4.2 Hz, 1 C), 128.01 (d, J = 10.7 Hz,
(15) Bhattacharyya, A.; Mohapatra Prasanta, K. Radiochim. Acta
2019, 107, 931.
(16) Zakirova, G. G.; Matveev, P. I.; Mladentsev, D. Y.; Evsiunina, M.
V.; Tafeenko, V. A.; Borisova, N. E. Mendeleev Commun. 2019, 29,
463.
(17) Matveev, P. I.; Borisova, N. E.; Andreadi, N. G.; Zakirova, G. G.;
Petrov, V. G.; Belova, E. V.; Kalmykov, S. N.; Myasoedov, B. F.
Dalton Trans. 2019, 48, 2554.
(18) Bhattacharyya, A.; Ansari, S. A.; Matveev, P. I.; Zakirova, G. G.;
Borisova, N. E.; Petrov, V. G.; Sumyanova, T.; Verma, P. K.;
Kalmykov, S. N.; Mohapatra, P. K. Dalton Trans. 2019, 48, 16279.
(19) Zakirova, G. G.; Mladentsev, D. Y.; Borisova, N. E. Tetrahedron
Lett. 2017, 58, 3415.
(20) Zakirova, G. G.; Mladentsev, D. Y.; Borisova, N. E. Synthesis 2019,
51, 2379.
(21) Zawisza, A. M.; Muzart, J. Tetrahedron Lett. 2007, 48, 6738.
(22) Zawisza, A. M.; Ganchegui, B.; González, I.; Bouquillon, S.;
Roglans, A.; Hénin, F.; Muzart, J. J. Mol. Catal. A: Chem. 2008,
283, 140.
1 C), 124.08 (d, J = 21.6 Hz, 1 C), 31.70 (2 С), 30.91 (d,
J = 14.6 Hz, 2 C), 29.80 (d, J = 68.9 Hz, 2 C), 29.12 (2 C), 29.01 (2
C), 22.56 (2 C), 21.34 (d, J = 4.4 Hz, 2 C), 14.05 (2 C). 31P NMR
(162 MHz, CDCl3):  = 41.64, 27.76. HRMS (ESI+): m/z [M + H]+
calcd for C37H49NO2P2 + H+: 601.3239; found: 601.3233.
Analytical Data for Compound 7
1H NMR (400 MHz, CDCl3):  = 8.38 (t, 1 H, J = 6.5 Hz, 3-HPy),
8.18 (t, 1 H, J = 5.7 Hz, 5-HPy), 8.00–8.05 (m, 1 H, 4-HPy), 7.76–
7.81 (m, 4 H, 2-HPh), 7.52–7.56 (m, 2 H, 4-HPh), 7.42–7.46 (m, 4
H, 3-HPh), 1.78–1.92 (m, 4 H, HOct), 1.46–1.58 (m, 2 H, HOct),
1.08–1.33 (m, 22 H, HOct), 0.86 (t, 6 H, J = 7.1 Hz, HOct). 13C NMR
(101 MHz, CDCl3):  = 157.34 (dd, J = 114.6, 17.3 Hz, 1 C), 156.98
(dd, J = 128.2, 16.0 Hz, 1 C), 136.47 (t, J = 8.0 Hz, 1 С), 131.70 (d,
J = 104.8 Hz, 2 С), 132.00 (2 C), 131.90 (d, J = 8.6 Hz, 4 C),
128.94–129.33 (m, 2 С), 128.21 (d, J = 12.3 Hz, 4 C), 31.63 (2 C),
30.88 (d, J = 13.6 Hz, 2 С), 28.87–28.92 (m, 4 C), 28.54 (d,
J = 69.1 Hz, 2 C), 22.49 (2 C), 21.21 (d, J = 3.7 Hz, 2 C), 13.98 (2
C). 31P NMR (162 MHz, CDCl3):  = 42.65, 21.79. HRMS (ESI+):
m/z [M + Na]+ calcd for C33H47NO2P2 + Na+: 574.2974; found:
574.2973.
(23) Molina de la Torre, J. A.; Espinet, P.; Albéniz, A. C. Organometal-
lics 2013, 32, 5428.
Analytical Data for Compound 8
(24) Abbas, S.; Hayes, C. J.; Worden, S. Tetrahedron Lett. 2000, 41,
3215.
(25) Scale, halide/SPO ratio, catalytic system loading, and yield are
shown in Scheme 1, Table 1, and Table 2 for each tertiary phos-
phine oxide product.
1H NMR (600 MHz, CDCl3):  = 8.48 (d, 1 H, J = 8.1 Hz, HBipy),
8.32–8.35 (m, 1 Н, HBipy), 8.30 (d, 1 H, J = 8.0 Hz, HBipy), 8.10–
8.12 (m, 1 Н, HBipy), 7.99 (td, 1 Н, J = 7.8, 3.8 Hz, HBipy), 7.90–7.93
(m, 5 Н, 2-HPh, HBipy), 7.51 (t, 2 H, J = 7.4 Hz, 4-HPh), 7.41–7.46
(m, 4 Н, 3-HPh), 1.99–2.11 (m, 4 H, HOct), 1.62–1.71 (m, 2 H, HOct),
1.36–1.45 (m, 2 H, HOct), 1.27–1.35 (m, 2 Н, HOct), 1.10–1.22 (m,
16 Н, HOct), 0.78 (t, 6 H, J = 6.9 Hz, HOct). 13C NMR (151 MHz,
CDCl3):  = 156.15 (d, J = 117.5 Hz, 1 С), 155.75 (d, J = 131.0 Hz,
1 С), 155.34 (d, J = 18.9 Hz, 1 С), 155.25 (d, J = 17.4 Hz, 1 С),
137.19 (d, J = 19.2 Hz, 1 С), 137.13 (d, J = 18.1 Hz, 1 С), 132.81
(d, J = 104.3 Hz, 2 С), 132.02 (d, J = 9.5 Hz, 4 С), 131.88 (d,
J = 2.0 Hz, 2 С), 128.56 (d, J = 20.0 Hz, 1 С), 128.24 (d, J = 12.1 Hz,
4 С), 128.13 (d, J = 19.0 Hz, 1 С), 122.33 (d, J = 9.7 Hz, 1 С),
122.32 (d, J = 8.8 Hz, 1 С), 31.63 (2 С), 30.84 (d, J = 13.9 Hz, 2 С),
28.89 (2 С), 28.86 (2 С), 28.46 (d, J = 68.1 Hz, 2 С), 22.46 (2 С),
21.28 (d, J = 4.0 Hz, 2 С), 13.94 (2 С). 31P NMR (162 MHz, CDCl3):
An oven-dried Schlenk flask was evacuated and back-filled with
argon three times. Heteroaryl (di)halide, base (1.3 equiv relative
to SPO), and a solution of an SPO in an anhydrous solvent
(7 mL/mmol per halogen) were added to the flask. The solution
was bubbled with argon for 10 min and Pd(OAc)2 and a phos-
phine ligand were added to the flask simultaneously. The
resulting mixture was stirred and heated at the indicated tem-
perature for the given time. Workup procedures are described
below for two different solvents. Final purification of crude
products was achieved by column chromatography on silica gel
(40–60 um) using CH2Cl2–MeOH as eluent.
For Reactions Conducted in DMF
 = 42.64, 21.45. HRMS (ESI+): m/z [M
+
Na]+ calcd for
After cooling, the reaction mixture was poured into a fourfold
excess of brine. The mixture was extracted three times with
CH2Cl2 (40 mL/mmol each). The combined organic layers were
washed with brine to remove traces of DMF, dried over Na2SO4,
C
38H50N2O2P2 + Na+: 651.3240; found: 651.3243.
Analytical Data for Compound 9
1H NMR (400 MHz, CDCl3):  = 8.66 (dd, 1 H, J = 8.1, 4.3 Hz,
3-HPhen), 8.46–8.59 (m, 1 H, 8-HPhen), 8.40–8.45 (m, 2 H, 4-HPhen),
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

E
G. G. Zakirova et al.
Letter
Synlett
7-HPhen), 8.28–8.34 (m, 4 H, 2-HPh), 7.89–7.94 (m, 2 H, 5-HPhen, 6-
Phen), 7.47–7.51 (m, 2 H, 4-HPh), 7.41–7.45 (m, 4 H, 3-HPh),
154.96 (dd, J = 96.2, 19.9 Hz, 1 C), 134.34 (d, J = 20.3 Hz, 1 C),
132.65 (d, J = 2.4 Hz, 2 C), 131.62 (d, J = 10.1 Hz, 4 C), 130.94 (d,
J = 109.8 Hz, 2 C), 128.55 (d, J = 12.9 Hz, 4 C), 31.67 (2 C), 30.83
(d, J = 14.4 Hz, 2 C), 29.55 (d, J = 69.7 Hz, 2 C), 28.95 (4 C), 22.51
(2 C), 21.35 (d, J = 3.7 Hz, 2 C), 14.02 (2 C). 31P NMR (162 MHz,
CDCl3):  = 39.43, 18.92. HRMS (ESI+): m/z [M + H]+ calcd for
H
2.19–2.36 (m, 4 H, HOct), 1.68–1.81 (m, 2 H, HOct), 1.40–1.53 (m,
2 H, HOct), 1.04–1.33 (m, 20 H, HOct), 0.77 (t, 6 H, J = 7.0 Hz, HOct).
13C NMR (101 MHz, CDCl3):  = 157.69 (d, J = 118.6 Hz, 1 C),
157.21 (d, J = 132.2 Hz, 1 C), 146.12 (d, J = 19.0 Hz, 1 C),145.85
(d, J = 20.1 Hz, 1 C), 136.05 (d, J = 25.6 Hz, 1 C), 135.96 (d,
J = 24.9 Hz, 1 C), 132.79 (d, J = 103.3 Hz, 2 C), 132.03 (d,
J = 9.0 Hz, 4 C), 131.62 (d, J = 2.6 Hz, 2 C), 129.29 (d, J = 2.6 Hz, 1
C), 129.22 (d, J = 2.6 Hz, 1 C), 128.18 (d, J = 12.0 Hz, 4 C), 128.17
(1 C), 127.82 (1 C), 125.99 (d, J = 18.8 Hz, 1 C), 125.88 (d,
J = 21.0 Hz, 1 C), 31.59 (2 C), 30.95 (d, J = 13.6 Hz, 2 C), 28.94 (2
C), 28.92 (2 C), 28.71 (d, J = 67.8 Hz, 2 C), 22.45 (2 C), 21.40 (d,
C
31H45NO2P2S + H+: 558.2719; found: 558.2711.
Analytical Data for Compound 14
1H NMR (600 MHz, CDCl3):  = 7.80–7.83 (m, 4 H, 2-HPh), 7.63 (s,
1 H, 5-HIm), 7.55–7.57 (m, 2 H, 4-HPh), 7.45–7.48 (m, 4 H, 3-HPh),
4.02 (s, 1 H, HMe), 1.83–1.94 (m, 4 H, HOct), 1.56–1.65 (m, 2 H,
H
Oct), 1.23–1.46 (m, 22 H, HOct), 0.88 (t, 6 H, J = 7.1 Hz, HOct).
13C NMR (151 MHz, CDCl3):  = 142.66 (dd, J = 143.8, 15.2 Hz, 1 C),
136.22 (dd, J = 128.5, 14.4 Hz, 1 C), 132.98 (dd, J = 24.2, 3.4 Hz, 1
C), 131.19 (d, J = 2.8 Hz, 2 C), 131.8 (d, J = 111.7 Hz, 2 C), 131.61
(d, J = 10.2 Hz, 4 C), 128.33 (d, J = 12.9 Hz, 4 C), 35.19 (1 C),
31.72 (2 C), 30.94 (d, J = 14.5 Hz, 2 C), 29.50 (d, J = 71.1 Hz, 2 C),
29.04 (2 C), 28.99 (2 C), 22.53 (2 C), 21.42 (d, J = 4.0 Hz, 2 C),
14.02 (2 C). 31P NMR (243 MHz, CDCl3):  = 41.48, 21.10. HRMS
(ESI+): m/z [M + H]+ calcd for C32H48N2O2P + H+: 554.3191;
found: 554.3186.
J = 4.2 Hz,
2
C), 13.93 (2 C). 31P NMR (162 MHz, CDCl3):
+
 = 43.64, 16.55. HRMS (ESI+): m/z [M + 1/2Ca2+
]
calcd for
C
40H50N2O2P2 + 1/2Ca2+: 672.3155; found: 672.3159.
Analytical Data for Compound 13
1H NMR (400 MHz, CDCl3):  = 8.47 (dd, 1 H, J = 2.9, 2.1 Hz, 5-
Thz), 7.83–7.88 (m, 4 H, 2-HPh), 7.57–7.61 (m, 2 H, 4-HPh), 7.46–
7.51 (m, 4 H, 3-HPh), 1.95–2.02 (m, 4 H, HOct), 1.53–1.66 (m, 2 H,
Oct), 1.20–1.41 (m, 22 H, HOct), 0.87 (t, 6 H, J = 7.0 Hz, HOct). 13
NMR (101 MHz, CDCl3):  = 167.64 (dd, J = 124.5, 17.9 Hz, 1 C),
H
H
C
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E