Synthesis of tetrahydropyrimidinium salts and their in situ catalytic activities towards the Buchwald-Hartwig amination reaction under microwave irradiation

Article abstract of DOI:10.3906/kim-1404-67

A series of asymmetrical substituted tetrahydropyrimidinium salts and different kinds of bridged bistetrahydropyrimidinium salts were prepared through the quaterization of tetrahydropyrimidine or the dehydrogenation of hexahydropyrimidine. They were chara

Full text of DOI:10.3906/kim-1404-67

Turk J Chem
2015) 39: 121 – 129
Turkish Journal of Chemistry
(
http://journals.tubitak.gov.tr/chem/
¨
˙
⃝
c TUBITAK
Research Article
doi:10.3906/kim-1404-67
Synthesis of tetrahydropyrimidinium salts and their in situ catalytic activities
towards the Buchwald–Hartwig amination reaction under microwave irradiation
∗
∗
Liangru YANG , Huanyu BIAN, Wenpeng MAI, Pu MAO ,
Yongmei XIAO, Dong WEI, Lingbo QU
School of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou, P.R. China
Received: 24.04.2014
•
Accepted: 02.09.2014
•
Published Online: 23.01.2015
•
Printed: 20.02.2015
Abstract: A series of asymmetrical substituted tetrahydropyrimidinium salts and different kinds of bridged bis-
tetrahydropyrimidinium salts were prepared through the quaterization of tetrahydropyrimidine or the dehydrogenation
of hexahydropyrimidine. They were characterized and used as NHC precursors in the palladium catalyzed Buchwald–
t
Hartwig amination reaction. The in situ formed catalytic system Pd(OAc)
2
/tetrahydropyrimidinium and BuOK cat-
alyzed the amination of heteroaryl halides and heterocyclic amines effectively, producing the heterocyclic amine func-
tionalized heteroaryl derivatives in high yields.
Key words: Tetrahydropyrimidinium salt, Buchwald–Hartwig amination, microwave irradiation, palladium catalysis,
N-heterocyclic carbene
1
. Introduction
The synthesis of N-containing molecules keeps attracting wide attention, as these structures are prevalent
in compounds with biological, pharmaceutical, and materials interest.1 Among the variety of useful meth-
ods to obtain these kinds of compounds, palladium-catalyzed Buchwald–Hartwig amination has become the
most versatile strategy because of its high functional group tolerance, single-step procedure, commercially
available starting materials, and mild reaction conditions.2
−5
Consequently, the development of new catalysts
and ligands for the Buchwald–Hartwig amination reaction continues to be a research hotspot. N-heterocyclic
carbenes (NHCs) have emerged as a very powerful class of ligands in organometallic chemistry and homoge-
neous catalysis, due to their stronger σ-donor character and higher thermal stability than phosphine-based
ligands in most cases.6,7 Probably due to the easy accessibility of the precursors of 5-membered NHCs, imi-
dazolium or imidazolinium derivatives, the synthesis of 5-membered NHC metal complexes and their catalytic
application have been investigated quite extensively. Due to the enhanced σ-donor ability and easy tunabil-
ity of the electronic property and steric effect, 6-, 7-, etc. ring expanded NHCs began to attract extensive
attention.8,9 In recent years, tetrahydropyrimidinium salts have been reported to be highly efficient ligands
for palladium catalyzed carbon-carbon bond formation, such as Suzuki coupling and the Heck reaction.1
0−12
The catalytic activities of metal-NHC complexes are directly related to the unique properties of the supporting
NHCs and sometimes chelating ligands exhibit special catalytic efficiency. Here we report the synthesis and
characterization of pyridinyl functionalized tetrahydropyrimidinium salts, asymmetrical di-substituted tetrahy-
dropyrimidinium salts, and bridged bis-tetrahydropyrimidinium salts. Their in situ catalytic performance in
∗
Correspondence: lryang@haut.edu.cn; maopu@haut.edu.cn
1
21

YANG et al./Turk J Chem
the palladium catalyzed Buchwald–Hartwig amination reaction of heteroaryl halides and heterocyclic amines
was also investigated.
2
. Results and discussion
Asymmetrical-substituted tetrahydropyrimidinium salts and different kinds of bridged di-tetrahydropyrimidinium
salts LHXs 1a–1i and 2a–2i were synthesized by modification of literature reports.13 The synthetic procedures
are outlined in Figures 1–4. The pure products were obtained by crystallization and characterized by ESI-MS,
EA, 1 H NMR, and 13 C NMR spectra.
As shown in Figure 1, asymmetrical-substituted tetrahydropyrimidinium halides LHX 1a were obtained
by the quaterization of N-methyl-1,4,5,6-tetrahydropyrimidine by 2-bromopyridine. Comparison of the proton
spectra of N-methyl-1,4,5,6-tetrahydropyrimidine and LHX 1a showed the appearance of additional signals
attributed to pyridinyl and downfield shift of the proton signals of the tetrahydropyrimidine ring. The chemical
shift of H-2 was downfielded from 6.82 to 9.33 ppm. Anion exchange reaction with NH4 PF6 in ethanol produced
the corresponding phosphate 2a. Comparison of the proton spectra of 1a and 2a showed a slight shift of H-2
from 9.33 to 9.29 ppm. Anion exchange affected the mp significantly, and LHXs 1a and 2a had mps of 163–165
◦
and 123–125 C, respectively.
i) R'X
N
N
N
N
R' = 2-Py-, X = Br
(1a, 78%)
ii) NH PF
4
Me
R'
Me
6
X-
X = PF6 (2a, 88%)
Figure 1. Synthesis of the asymmetrical di-substituted tetrahydropyrimidinium salts.
The synthesis of methylene bridged aryl-substituted tetrahydropyrimidinium salts 1b, 1c, 2b, and 2c are
shown in Figure 2. Reaction of 1-aryl-propyl-1,3-diamines with aqueous formaldehyde in MeOH produced bis(3-
aryl-hexahydropyrimidinyl)methanes, and the following dehydrogenation with NBS produced the methylene
bridged tetrahydropyrimidinium salts 1b and 1c. Anion exchange reaction with NH4 PF6 in ethanol produced
the corresponding phosphates 2b and 2c. In the proton spectra of 1b and 1c, the signals of methylene linker
appeared at 5.27 and 6.37 ppm, while the protons of H-2 appeared at 8.89 and 9.38 ppm respectively, indicating
the formation of quaternary tetrahydropyrimidinium salts. ESI-MS peaks at 497.4 and 581.5 corresponding to
[
M-Br]+ confirmed the successful dehydrogenation by NBS. Anion exchange reaction with NH4 PF6 in ethanol
produced the corresponding phosphates 2b and 2c. The conversion was confirmed by the change in the proton
spectra and mps.
HCHO
MeOH
i) NBS
ii) NH PF
H N
2
NHAr
N
N
N
N
N
N
N
N
4
6
Ar
Ar
Ar
Ar
(
X-)2
Ar = 2,4,6-Me -C H -, X = Br (1b, 66%)
3
6 2
X = PF (2b, 84%)
6
Ar = 2,6-(i-Pr) -C H -, X = Br (1c, 73%)
2
6 3
X = PF (2c, 89%)
6
Figure 2. Synthesis of the methylene bridged aryl-substituted tetrahydropyrimidinium salts.
Figures 3 and 4 show 2 different strategies for the synthesis of alkylene bridged alkyl-substituted bis-
tetrahydropyrimidinium salts. In Figure 3, using tetra-amine as starting material, the reaction with DMF-DMA
afforded ethylene bridged 1,4,5,6-tetrahydropyrimidine first, and the following quaterization with different alkyl
halides produced bridged bis-tetrahydropyrimidinium salts 1d and 1e carrying different substituents. In Figure
122

YANG et al./Turk J Chem
4, reaction of N-methyl-1,4,5,6-tetrahydropyrimidine with different alkylene dihalides afforded a series of bridged
bis-tetrahydropyrimidinium salts carrying different linkages.
i) R''X
N
N
N
N
ii) NH PF6
4
N
N
N
N
(
)2
R''
( )2
X-)2
R''
(
DMF-DMA
H
R'' = i-Pr, X = Br (1d, 43%)
X = PF6 (2d, 54%)
H
N
H N
2
N
NH2
R'' = C H -CH , X = Br (1e, 65%)
6 5 2
X = PF (2e, 83%)
(
)2
6
Figure 3. Synthesis of the ethylene bridged alkyl-substituted tetrahydropyrimidinium salts from tetra-amine.
i) ClCH2
ii) NH PF
CH Cl
2
N
N
N
N
N
N
Me
Me
4
6
(
X-)2
N
N
X = Cl (1f, 76%)
X = PF6 (2f, 83%)
Me
i) X(CH ) X
2
n
N
N
Me
( )n
X-)2
Me
ii) NH PF
4
6
(
n = 1, X = I (1g, 52%), X = PF (2g, 59%)
6
n = 2, X = Br (1h, 47%), X = PF6 (2h, 67%)
n = 4, X = Br (1i, 51%), X = PF6 (2i, 54%)
Figure 4. Synthesis of the alkylene bridged methyl-substituted tetrahydropyrimidinium salts from tetrahydropyrimidine.
MW irradiation has been successfully utilized in the formation of a variety of carbon–heteroatom and
carbon–carbon bonds.14 Having series of different tetrahydropyrimidinium salts in hand, their in situ catalytic
t
activities towards MW assisted Buchwald–Hartwig amination was investigated. Initially, using BuOK as base,
DME as solvent, and the reaction of 2-bromopyridine with morpholine as a model, the potential of different
tetrahydropyrimidinium salts in the MW assisted Pd(OAc)2 catalyzed Buchwald–Hartwig amination was tested.
The results showed that all the tetrahydropyrimidinium salts could accelerate the amination reaction effectively
and pyridinyl functionalized hexaphosphate (2a) afforded the highest yield.
Using LHX 2a as ligand precursor, a brief screening of solvents and bases was performed by running the
reaction of 2-bromopyridine with morpholine as a model (Table 1). Among the bases tested, t BuOK proved
to be the best. K2 CO3 or Cs2 CO3 improved the yields slightly, while KOH did not work here at all (Table
1, entries 1–4). Besides DME, solvents dioxane, DMF, and toluene were tested and the results showed that
dioxane produced comparable yield, while DMF and toluene produced inferior yields (Table 1, entries 4–7).
Choosing DME as solvent and t BuOK as base, the effect of catalyst loading and reaction time on the model
reaction was then investigated. As listed in Table 1, the blank reaction produced the target product in 2% yield,
and addition of LHX 2a did not change the yield (Table 1, entries 8 and 9). Addition of Pd(OAc)2 increased
the yield to 27% (Table 1, entry 10), still obviously lower than the yield by addition of both Pd(OAc)2 and
LHX 2a (Table 1, entry 4), indicating that the LHX 2a could be effective ligand precursors for Pd catalyzed
Buchwald–Hartwig amination. Results obtained under different reaction times proved that 40 min should be
the appropriate MW irradiation time (Table 1, entries 4, 11, and 12). Compared to traditional oil bath heating,
MW irradiation accelerated the reaction markedly (Table 1, entries 4 and 13). These results are consistent with
the literature and the microwave irradiation gave the same results as conventional heating but in a very short
time.15
1
23

YANG et al./Turk J Chem
a
Table 1. Screening of reaction conditions.
Pd(OAc) , LHX 2a
2
Br
HN
O
N
O
Solvent, Base, MW
N
N
Entry
Solvent Base
Pd(OAc)2 LHX 2a Time Yield (%)
(
mol%)
(mol%)
10
10
10
10
10
10
20
0
10
0
10
10
10
(min)
20
20
20
20
20
20
20
20
20
20
40
1
2
3
4
5
6
7
8
9
1
1
1
1
DME
DME
DME
DME
dioxane
DMF
toluene
DME
DME
DME
DME
DME
DME
KOH
K2CO3
Cs2CO3
5
5
5
5
5
5
10
0
0
5
5
5
5
3
15
10
61
58
6
19
2
2
27
92
49
30
t
BuOK
BuOK
BuOK
BuOK
BuOK
BuOK
BuOK
BuOK
BuOK
t
t
t
t
t
t
0
1
2
3
t
t
60
24 h
t
b
BuOK
a
◦
Reaction condition: 1.0 mmol 2-bromopyridine, 3.0 mmol morpholine, 2.0 mmol base, 2.0 mL solvent, 100 C, MW
b
1
50 W. Oil bath heating.
The feasibility of the catalytic application of LHX 2a towards the Buchwald–Hartwig amination of
heteroaryl halides and heterocyclic amines was further explored by expanding the substrates, and the results
are listed in Table 2. Under the standard conditions, 2-bromopyridine coupled with morpholine, pyrrolidine, or
1H-benzo[d]imidazole smoothly, producing the target products in high yields (Table 2, entries 1–3). Exploration
of the reaction of heteroaryl chlolides (2-chloropyridine and 2-chloropyrimidine) with heterocyclic amines also
produced satisfactory results and the target coupling products were obtained in high yields (Table 2, entries
4–9). The experimental results indicated that LHX 2a could accelerate the Buchwald–Hartwig amination of
heteroaryl bromides or chlorides effectively.
Table 2. Buchwald–Hartwig amination of heteroaryl halides with heterocyclic amines.
Pd(OAc) , LHX 2a
2
R
R
Ar
X
+
HN
Ar N
R' tBuOK, DME, MW
R'
Entry Ar-X
RR’NH
Ar-NRR’ Yields (%)
1
2
3
4
5
6
7
8
9
2-bromopyridine
2-bromopyridine
2-bromopyridine
2-chloropyridine
2-chloropyridine
2-chloropyridine
2-chloropyrimidine morpholine
2-chloropyrimidine pyrrolidine
2-chloropyrimidine 1H-benzo[d]imidazole 3f
morpholine
pyrrolidine
1H-benzo[d]imidazole 3c
morpholine
pyrrolidine
1H-benzo[d]imidazole 3c
3a
3b
92
97
77
88
84
74
79
87
93
3a
3b
3d
3e
a
t
Reaction condition: 1.0 mmol Ar-X, 3.0 mmol RR’NH, 2.0 mmol BuOK, 0.05 mmol Pd(OAc)
2
, 0.10 mmol LHX 2a,
2
.0 mL DME, MW 150 W, 40 min.
124

YANG et al./Turk J Chem
3
. Conclusion
We have reported the efficient synthesis of asymmetrical substituted tetrahydropyrimidinium salts and different
kinds of bridged bis-tetrahydropyrimidinium salts through different strategies and their catalytic application
in MW assisted Buchwald–Hartwig amination. The results showed that under the standard conditions, using
t
BuOK as base, DME as solvent, Pd(OAc)2 as catalyst, tetrahydropyrimidinium salt as ligand precursor,
heteroaryl bromide or chloride coupled with heterocyclic amines under MW irradiation, producing the target
compounds in high yields. The application of these tetrahydropyrimidinium salts in MW assisted Buchwald–
Hartwig amination showed them to be efficient ligand precursors. Research on their metalation and catalytic
activities towards other carbon–heteratom and carbon–carbon bond formation reactions is in progress in our
lab.
4
. Experimental
All experiments were performed in air unless indicated otherwise. All reagents and solvents were analytical
grade materials purchased from commercial sources and used as received unless otherwise stated. Reactions
were monitored by TLC (Qingdao Haiyang Chemical Co. Ltd. Silica gel 60 F254) and detected using a UV/Vis
lamp (254 nm). Column chromatography was performed on Qingdao Haiyang Chemical Co. Ltd. Gel 60
(
200–300 mesh).
NMR spectra were recorded at 25 C on a 400 MHz Bruker spectrometer. Chemical shifts (δ in ppm,
◦
1
13
coupling constants J in Hz) were referenced to the internal solvent (CDCl3 , δ H = 7.24 ppm, C = 77.0
1
13
ppm; DMSO-d6 , δ H = 2.50 ppm, C = 40.0 ppm). EA were obtained from a Thermo Flash 2000. ESI-MS
spectra were recorded on a Bruker Esquire 3000.
4
.1. Synthesis of asymmetrical-substituted tetrahydropyrimidinium halides LHX 1a
A 25-mL flask containing N-methyl-1,4,5,6-tetrahydropyrimidine (1.47 g, 15 mmol) and 2-bromo-pyridine (2.84
◦
g, 18 mmol) was heated in an oil bath at 100 C for 48 h under Ar, after which time a red brown viscous
oil formed. The oil was cooled to r.t. and then washed with ether 3 times. Crystallization of the residue in
EtOH-Et2 O produced the pure product.
1-Methyl-3-(2-pyridinyl)-1,4,5,6-tetrahydropyrimidinium bromide (1a): Yield 78%, 3.00 g; brown solid;
mp 163–165 C; 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.50–8.49 (m, 1H), 8.06–8.01 (m, 1H), 7.59
◦
(
d, J = 8.4 Hz, 1H), 7.42–7.39 (m, 1H), 3.93 (t, J = 5.8 Hz, 2H), 3.55 (t, J = 5.8 Hz, 2H), 3.43 (s, 3H,),
2
4
.22–2.16 (m, 2H) ppm; 13 C NMR (100 MHz, DMSO-d6) δ 151.8, 151.6, 148.6, 140.2, 122.5, 113.0, 46.3, 43.1,
1.6, 18.8 ppm; ESI-MS m/z: 176.0 [M-Br]+ .
4
.2. Synthesis of the methylene bridged diaryl-substituted tetrahydropyrimidinium dibromides
LHXs 1b and 1c
Following a literature report,16 reaction of 1-aryl-propyl-1,3-diamine with aqueous formaldehyde in methanol
produced bis-(3-aryl-hexahydropyrimidinyl)methane. Bis(3-aryl-hexahydropyrimidinyl)methane (1.98 mmol)
was dissolved in absolute 1,2-dimethoxy-ethane (50 mL) and treated with NBS (0.705 g, 3.96 mmol). The
reaction mixture was stirred at room temperature for 2 h before the volatile compounds were removed in vacuo
and a brown, oily residue remained. Crystallization of the residue in EtOH afforded the pure products.
3,3’-DiMes-1,1’-methylenedi(1,4,5,6-tetrahydropyrimidinium) dibromides (1b): Yield 66%, 0.76 g; white
1
25

YANG et al./Turk J Chem
solid; mp 186–188 C; 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 7.08 (s, 4H), 5.27 (s, 2H), 3.75–3.68
◦
(
m, 8H), 2.57 (s, 6H), 2.29–2.28 (m, 16H) ppm; 13 C NMR (100 MHz, DMSO-d6) δ 156.3, 139.8, 137.2, 135.2,
1
29.8, 71.8, 46.0, 41.7, 29.9, 20.9, 17.6 ppm; ESI-MS m/z: 497.4 [M-Br]+ .
,3’-Di(2,6-diisopropyl-phenyl)-1,1’-methylenedi(1,4,5,6-tetrahydropyrimidinium) dibromides (1c): Yield
3
3%, 0.96 g; white solid; mp 312–314 C; 1 H NMR (400 MHz, CDCl3) δ 9.38 (s, 2H), 7.43 (t, J = 5.8 Hz,
H), 7.27–7.22 (m, 4H), 6.37 (s, 2H), 4.41 (s, 4H), 3.85 (s, 4H), 3.09–3.03 (m, 4H), 2.30 (m, 4H), 1.24 (t, J =
.5 Hz, 24 H) ppm; 13 C NMR (100 MHz, CDCl3) δ 154.7, 145.6, 135.9, 131.0, 125.0, 71.8, 48.2, 42.3, 28.5,
5.1, 24.1, 18.7 ppm; ESI-MS m/z: 581.5 [M-Br]+ .
◦
7
2
6
2
4
.3. Synthesis of the ethylene bridged dialkyl-substituted tetrahydropyrimidinium dibromides
LHXs 1d and 1e
1
,1’-Ethylenebis(l,4,5,6-tetrahydropyrimidine): Following a literature report,17 a 25-mL flask containing N,N’-
bis(3-aminopropyl)ethylenediamine (4.14 g, 23.95 mmol), DMF-DMA (6.3 g, 52.9 mmol), and toluene (10 mL)
◦
was heated in an oil bath at 100 C for 3 h under Ar before all the volatiles were removed under vacuum. The
residue was characterized as the crude product of 1,1’-ethylenebis(l,4,5,6-tetrahydropyrimidine) and used for
the next reaction directly.
3
,3’-Diisopropyl-1,1’-ethylenedi(1,4,5,6-tetrahydropyrimidinium) dibromides (1d): To a 25-mL flask con-
taining a DMF (3 mL) solution of 1,1’-ethylenebis(l,4,5,6-tetrahydropyrimidine) (0.97 g, 5 mmol), 2-bromopropane
1.4 g, 11 mmol) was added slowly and the mixture was then stirred at room temperature for 8 h under Ar.
The mixture was then washed with Et2 O 3 times. Crystallization of the residue in EtOH-Et2 O produced the
(
pure product. Yield 43%, 0.92 g; white solid; mp 258–260 C; 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 2H),
.95–3.87 (m, 2H), 3.77 (s, 4H), 3.48 (t, J = 5.5 Hz, 4H), 3.36 (s, 4H), 1.98 (t, J = 5.4 Hz, 4H), 1.25 (d, J
6.6 Hz, 12H) ppm; 13 C NMR (100 MHz, DMSO-d6) δ 152.6, 56.3, 51.6, 43.7, 39.2, 20.4, 19.1 ppm; ESI-MS
m/z: 359.2 [M-Br]+ .
◦
3
=
3,3’-Dibenzyl-1,1’-ethylenebis(1,4,5,6-tetrahydropyrimidinium) dibromides (1e): Compound 1e was pre-
pared by the same procedure as 1d from 1,1’-ethylenebis(l,4,5,6-tetrahydropyrimidine) (0.97 g, 5 mmol) and
benzyl bromide (1.88 g, 11 mmol). Yield 65%, 1.70 g; white solid; mp 234–236 C; 1 H NMR (400 MHz,
◦
DMSO-d6) δ 8.99 (s, 2H), 7.45–7.40 (m, 10H), 4.70 (s, 4H), 3.84 (s, 4H), 3.51 (t, J = 5.4 Hz, 4H), 3.27 (t, J
=
5.5 Hz, 4H), 1.97 (t, J = 5.2 Hz, 4H) ppm; 13 C NMR (400 MHz, DMSO-d6) δ 154.1, 134.6, 129.3, 129.0,
28.8, 57.5, 51.8, 43.1, 42.6, 18.7 ppm; ESI-MS m/z: 455.4 [M-Br]+ .
1
4
.4. Synthesis of the alkylene bridged dimethyl-substituted tetrahydropyrimidinium dihalides
f–1i
,3’-Dimethyl-1,1’-(1,2-phenylenebis(methylene))di(1,4,5,6-tetrahydropyrimidinium) dichlorides (1f): To a 25-
mL flask containing a DMF (3 ML) solution of N-methyl-1,4,5,6-tetrahydropyrimidine (0.98 g, 10 mmol),
,4-bis(chloromethyl)benzene (0.88 g, 5 mmol) was added slowly and the mixture was then stirred at room
temperature for 12 h under Ar. The mixture was then washed with Et2 O 3 times. Crystallization of the
1
3
1
residue in EtOH-Et2 O produced the pure product. Yield 76%, 1.41 g; white solid; mp 184–185 C; 1 H NMR
◦
(
(
400 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.42 (m, 4H), 4.89 (s, 4H), 3.37 (t, J = 5.5 Hz, 4H), 3.22 (s, 6H), 3.16
t, J = 5.4 Hz, 4H), 1.98 (t, J = 5.3 Hz, 4H) ppm; 13 C NMR (100 MHz, DMSO-d6) δ 154.2, 133.5, 129.6,
1
29.1, 54.4, 44.7, 42.1, 41.9, 18.7 ppm; ESI-MS m/z: 335.3 [M-Cl]+ .
126

YANG et al./Turk J Chem
3,3’-Dimethyl-1,1’-methylenedi(1,4,5,6-tetrahydropyrimidinium) diiodides (1g): Compound 1g was pre-
pared by the same procedure as 1f from N-methyl-1,4,5,6-tetrahydropyrimidine (0.98 g, 10 mmol) and di-
iodomethane (1.34 g, 5 mmol). Yield 52%, 1.21 g; white solid; mp 222–224 C; 1 H NMR (400 MHz, DMSO-
d6) δ 8.55 (s, 2H), 4.99 (s, 2H), 3.39–3.35 (m, 8H), 3.21 (s, 6H), 2.05–2.00 (m, 4H) ppm; 13 C NMR (100 MHz,
DMSO-d6) δ 154.5, 70.5, 45.1, 42.5, 41.0, 18.3 ppm; ESI-MS m/z: 337.2 [M-I]+ .
◦
3,3’-Dimethyl-1,1’-ethylenedi(1,4,5,6-tetrahydropyrimidinium) dibromides (1h): Compound 1h was pre-
pared by the same procedure as 1f from N-methyl-1,4,5,6-tetrahydropyrimidine (0.98 g, 10 mmol) and 1,2-
dibromoethane (0.94 g, 5 mmol). Yield 47%, 0.90 g; white solid; mp 196–198 C; 1 H NMR (400 MHz,
◦
DMSO-d6) δ 8.57 (s, 2H), 3.71 (s, 4H), 3.42 (d, J = 5.6 Hz, 4H), 3.34 (t, J = 5.7 Hz, 4H), 3.18 (s, 6H),
2
.02–1.97 (m, 4H) ppm; 13 C NMR (100 MHz, DMSO-d6) δ 153.9, 51.5, 44.7, 42.6, 41.8, 18.7 ppm; ESI-MS
m/z: 303.2 [M-Br]+ .
3,3’-Dimethyl-1,1’-butylenedi(1,4,5,6-tetrahydropyrimidinium) dibromides (1i): Compound 1i was pre-
pared by the same procedure as 1f from N-methyl-1,4,5,6-tetrahydropyrimidine (0.98 g, 10 mmol) and 1,4-
dibromobutane (1.08 g, 5 mmol). Yield 51%, 1.05 g; white solid; mp 162–164 C; 1 H NMR (400 MHz,
◦
DMSO-d6) δ 8.52 (s, 2H), 3.45 (s, 4H), 3.36–3.30 (m, 8H), 3.16 (s, 6H), 2.01–1.96 (m, 4H), 1.58 (s, 4H) ppm;
1
3
C NMR (100 MHz, DMSO-d6)vδ 153.2, 53.6, 44.6, 42.1, 41.6, 23.8, 18.7 ppm; ESI-MS m/z: 331.2 [M-Br]+ .
4
.5. Synthesis of tetrahydropyrimidinium hexafluorophosphates 2a–2i
To a 50-mL flask containing an EtOH (25 mL) solution of tetrahydropyrimidinium halides (15 mmol), 10
mL aqueous solution of NH4 PF6 (20 mmol for mono-tetrahydropyrimidinium halides and 40 mmol for di-
tetrahydropyrimidinium halides) was added and the mixture was then stirred at room temperature for 15 h
before all the volatiles were evaporated. The residue was dissolved in 20 mL of CH2 Cl2 , washed with H2 O,
dried, and evaporated. Crystallization of the residue in EtOH produced the pure product.
1-Methyl-3-(2-pyridinyl)-1,4,5,6-tetrahydropyrimidinium hexafluorophosphate (2a): Yield 88%, 4.24 g;
brown solid; mp 123–125 C; 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.51 (m, 1H), 8.06–8.02 (m, 1H),
◦
7.55 (d, J = 8.4 Hz, 1H), 7.43–7.40 (m, 1H), 3.92 (t, J = 5.8 Hz, 2H), 3.54 (t, J = 5.8 Hz, 2H), 3.42 (s, 3H),
2
1
1
.19 (m, 2H) ppm; 13 C NMR (100 MHz, DMSO-d6) δ 151.8, 151.6, 148.6, 140.2, 122.6, 112.7, 46.1, 43.0, 41.6,
8.7 ppm. Anal. Calcd for C10 H14 F6 N3 P (321.2): C, 37.39; H, 4.39; N, 13.08; Found: C, 37.41; H, 4.40; N,
3.07.
3,3’-DiMes-1,1’-methylenedi(1,4,5,6-tetrahydropyrimidinium) di-hexafluorophosphate (2b): Yield 84%,
◦
8
5
.93 g; white solid; mp 237–238 C; 1 H NMR (400 MHz, DMSO-d6) δ 8.78–8.68 (2s, 2H), 7.10–7.08 (2s, 4H),
.11 (d, J = 8.0 Hz, 2H), 3.65–3.63 (m, 4H), 3.56–3.53 (m, 4H), 2.71 (s, 3H), 2.30–2.27 (m, 19H) ppm; 13
C
NMR (100 MHz, DMSO-d6) δ 156.5, 139.9, 137.2, 135.2, 129.9, 56.1, 45.7, 41.6, 28.7, 21.0, 17.5 ppm; Anal.
Calcd for C27 H38 F12 N4 P2 (708.55): C, 45.77; H, 5.41; N, 7.91. Found: C, 45.75; H, 5.39; N, 7.89.
3,3’-Di(2,6-diisopropyl-phenyl)-1,1’-methylenedi(1,4,5,6-tetrahydropyrimidinium) di-hexafluorophosphate
2c): Yield 89%, 10.54 g; white solid; mp 302–304 C; 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 7.56 (t,
◦
(
J = 8.0 Hz, 2H), 7.45 (t, J = 7.6 Hz, 4H), 5.16 (s, 2H), 3.68 (t, J = 5.0 Hz, 4H), 3.58 (t, J = 5.6 Hz, 4H),
2
1
.95–2.90 (m, 4H), 2.34 (t, J = 4.8 Hz, 4H), 1.29–1.23 (m, 24 H) ppm; 13 C NMR (100 MHz, DMSO-d6) δ
56.0, 145.9, 136.5, 131.3, 125.5, 72.4, 48.0, 41.3, 28.2, 25.0, 24.4, 18.4 ppm; Anal. Calcd for C33 H50 F12 N4 P2
(
792.71): C, 50.00; H, 6.36; N, 7.07. Found: C, 49.98; H, 6.35; N, 7.09.
1
27

YANG et al./Turk J Chem
3,3’-Diisopropyl-1,1’-ethylenedi(1,4,5,6-tetrahydropyrimidinium) di-hexafluorophosphate (2d): Yield 54%,
◦
4
4
.51 g; white solid; mp 237–240 C; 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 2H), 3.84–3.81 (m, 2H), 3.68 (s,
H), 3.41 (t, J = 5.6 Hz, 4H), 3.35 (t, J = 5.6 Hz, 4H), 2.00–1.94 (m, 4H), 1.24 (d, J = 6.7 Hz, 12H) ppm; 13
C
NMR (100 MHz, DMSO-d6) δ 152.6, 56.6, 51.8, 43.5, 39.2, 20.3, 19.0gppm; Anal. Calcd for C16 H32 F12 N4 P2
(
570.38): C, 33.69; H, 5.65; N, 9.82. Found: C, 33.67; H, 5.63; N, 9.84.
,3’-Dibenzyl-1,1’-ethylenebis(1,4,5,6-tetrahydropyrimidinium) di-hexafluorophosphate (2e): Yield 83%,
3
8
.12 g; white solid; mp 238–240 C; 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 2H), 7.47–7.38 (m, 10H), 4.64
◦
(
(
s, 4H), 3.78 (s, 4H), 3.44 (t, J = 5.4 Hz, 4H), 3.25 (t, J = 5.7 Hz, 4H), 1.99–1.95 (m, 4H) ppm; 13 C NMR
100 MHz, DMSO-d6) δ 154.3, 134.5, 129.4, 129.1, 129.0, 58.0, 52.0, 42.9, 42.7, 18.7 ppm; Anal. Calcd for
C24 H32 F12 N4 P2 (666.47): C, 43.25; H, 4.84; N, 8.41. Found: C, 43.27; H, 4.86; N, 8.39.
3,3’-Dimethyl-1,1’-(1,2-phenylenebis(methylene))di(1,4,5,6-tetrahydropyrimidinium) di-hexafluorophosp-
hate (2f): Yield 83%, 7.35 g; white solid; mp 182–184 C; 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 2H),
◦
7
4
.47–7.40 (m, 4H), 4.77 (s, 4H), 3.36 (t, J = 5.7 Hz, 4H), 3.21 (s, 6H), 3.16 (t, J = 5.6 Hz, 4H), 2.00–1.98 (m,
H) ppm; 13 C NMR (100 MHz, DMSO-d6) δ 154.1, 133.2, 129.2, 129.2, 54.4, 44.7, 42.3, 42.0, 18.7 ppm; Anal.
Calcd for C18 H28 F12 N4 P2 (590.37): C, 36.62; H, 4.78; N, 9.49. Found: C, 36.64; H, 4.76; N, 9.51.
,3’-Dimethyl-1,1’-methylenedi(1,4,5,6-tetrahydropyrimidinium) di-hexafluorophosphate (2g): Yield 59%,
3
.43 g; white solid; mp 199–202 C; 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 2H), 4.93 (s, 2H), 3.36 (t, J =
◦
4
5
.8 Hz, 4H), 3.30 (t, J = 5.8 Hz, 4H), 3.20 (s, 6H), 2.02–2.00 (m, 4H) ppm; 13 C NMR (100 MHz, DMSO-d6)
δ 154.6, 70.7, 45.1, 42.4, 40.8, 18.3 ppm; Anal. Calcd for C11 H22 F12 N4 P2 (500.25): C, 26.41; H, 4.43; N,
11.20. Found: C, 26.44; H, 4.43; N, 11.19.
3,3’-Dimethyl-1,1’-ethylenedi(1,4,5,6-tetrahydropyrimidinium di-hexafluorophosphate (2h): Yield 67%,
.17 g; white solid; mp 189-191 C; 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 2H), 3.64 (s, 4H), 3.37–3.30 (m,
◦
5
8
H), 3.16 (s, 6H), 2.00–1.97 (m, 4H) ppm; 13 C NMR (100 MHz, DMSO-d6) δ 154.1, 51.7, 44.7, 42.4, 42.0, 18.6
ppm; Anal. Calcd for C12 H24 F12 N4 P2 (514.27): C, 28.03; H, 4.70; N, 10.89. Found: C, 28.04; H, 4.73; N,
10.90.
3,3’-Dimethyl-1,1’-butylenedi(1,4,5,6-tetrahydropyrimidinium) di-hexafluorophosphate (2i): Yield 54%,
.39 g; white solid; mp 153–155 C; 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 2H), 3.44 (s, 4H), 3.40–3.32 (m,
H), 3.16 (s, 6H), 2.01–1.97 (m, 4H), 1.58 (s, 4H) ppm; 13 C NMR (100 MHz, DMSO-d6) δ 153.3, 53.9, 44.6,
2.0, 41.7, 23.9, 18.7 ppm; Anal. Calcd for C14 H28 F12 N4 P2 (542.33): C, 31.01; H, 5.20; N, 10.33. Found: C,
1.00; H, 5.23; N, 10.35.
◦
4
8
4
3
4
.6. General procedure for the Buchwald–Hartwig amination reaction under microwave irradia-
tion
The Buchwald–Hartwig amination reaction under microwave irradiation was conducted in a CEM Discover
apparatus. A 10-mL Teflon vessel was charged with 1.0 mmol of hetero-aryl halide, 3.0 mmol of amine, 2.0 of
mmol base, 0.05 mmol of Pd(OAc)2 , 0.10 mmol of LHX, and 2.0 mL of solvent. The mixture was irradiated at
◦
1
50 W at 100 C for the specified time and then allowed to cool. The reaction mixture was extracted 3 times
with diethyl ether, and the combined organic extracts were washed with water, dried (MgSO4), and evaporated
to dryness. Purification of the residue by flash chromatography on silica gel afforded the pure products.
3
a: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.19–8.18 (m, 1H), 7.49–7.45 (m, 1H), 6.65–6.60 (m,
128

YANG et al./Turk J Chem
2
1
H), 3.79 (t, J = 4.8 Hz, 4H), 3.47 (t, J = 4.8 Hz, 4H) ppm; 13 C NMR (100 MHz, CDCl3) δ 159.6, 147.9,
37.5, 113.8, 106.9, 66.7, 45.6 ppm.
3
b: Yellow oil; 1 H NMR (400 MHz, CDCl3) δ 8.08–8.07 (m, 1H), 7.42–7.29 (m, 1H), 6.42–6.39 (m,
H), 6.24–6.22 (d, J = 8.5 Hz, 1H), 3.34 (t, J = 6.7 Hz, 4H), 1.91–1.87 (m, 4H) ppm; 13 C NMR (100 MHz,
1
CDCl3) δ 157.2, 148.0, 136.8, 110.9, 106.4, 46.5, 25.4 ppm.
c: Yellow oil; 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.35 (t, J = 2.4 Hz, 1H, HPy), 7.90–7.88
m, 1H), 7.75–7.72 (m, 1H), 7.60–7.56 (m, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.22–7.17 (m, 2H), 7.02–7.00 (m, 1H)
ppm; 13 C NMR (100 MHz, CDCl3) δ 167.7, 149.9, 149.5, 144.6, 141.3, 139.0, 132.3, 132.1, 131.0, 128.8, 124.2,
3
(
1
3
1
23.3 ppm.
3
d: Yellow oil; 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 4.7 Hz, 2H), 6.38 (t, J = 4.7 Hz, 1H),
.67–3.62 (m, 8H) ppm; 13 C NMR (100 MHz, CDCl3) δ 161.6, 157.6, 110.1, 66.6, 44.0 ppm.
3
e: Yellow oil; 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 4.7 Hz, 2H, H-5, H-7), 6.13 (t, J = 4.7 Hz,
H, H-6), 3.26 (t, J = 6.4 Hz, 4H, H-1, H-4), 1.67 (t, J = 6.4 Hz, 4H, H-2, H-3) ppm; 13 C NMR (100 MHz,
CDCl3) δ 159.9, 157.3, 108.5, 46.2, 25.2 ppm.
f: White solid; mp 138–139 C; 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.94 (d, J = 4.8 Hz,
H), 8.53 (d, J = 7.8 Hz, 1H), 7.80-7.78 (m, 1H), 7.49 (t, J = 4.8 Hz, 1H), 7.45–7.35 (m, 2H) ppm; 13 C NMR
100 MHz, DMSO-d6) δ 170.0, 159.8, 155.9, 145.0, 142.3, 131.9, 124.9, 124.1, 120.5, 119.5, 115.8 ppm.
◦
3
2
(
Acknowledgments
We thank the National Natural Science Foundation of China (No. 21172055), the Program for Innovative
Research Team from Zhengzhou (131PCXTD605), and the Plan for Scientific Innovation Talent of Henan
University of Technology (No. 11CXRC10) for their financial support of this work.
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