1,4,5,6-tetrahydropyrimidinium halides ligands for Suzuki-Miyaura cross-coupling of unactivated aryl chlorides

Article abstract of DOI:10.3987/COM-05-10363

Four functionalized bis(1,4,5,6-tetrahyropyrimidinium) salts (2a-d) have been prepared and characterized by conventional spectroscopic methods and elemental analyses. A highly effective, easy to handle and environmentally benign process for palladium mediated Suzuki cross-coupling was developed. The in situ prepared three component system Pd(OAc)₂ / bis(1,4,5,6-tetrahyropyrimidinium) bromides (2a-d) and Cs₂CO ₃ catalyses quantitatively the Suzuki cross-coupling of deactivated aryl chloride.

Full text of DOI:10.3987/COM-05-10363

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HETEROCYCLES, Vol. 65, No. 6, 2005, pp. 1439 - 1445
Received, 2nd February, 2005, Accepted, 23rd March, 2005, Published online, 24th March, 2005
1,4,5,6-TETRAHYDROPYRIMIDINIUM HALIDES LIGANDS FOR SUZUKI-
MIYAURA CROSS-COUPLING OF UNACTIVATED ARYL CHLORIDES
Bülent Alıcı,a İsmail Özdemir,a* Nevin Gürbüz,a Engin Çetinkaya,b and Bekir Çetinkayab
a İnönü University, Faculty of Science and Arts, Department of Chemistry, 44280
Malatya, Turkey
b
Department of Chemistry, Ege University, 35100, Bornova-İzmir, Turkey
* Corresponding author; Fax: +90 422 341 0037, e-mail: iozdemir@inonu.edu.tr
Abstract- Four functionalized bis(1,4,5,6-tetrahyropyrimidinium) salts (2a-d)
have been prepared and characterized by conventional spectroscopic methods
and elemental analyses. A highly effective, easy to handle and environmentally
benign process for palladium mediated Suzuki cross-coupling was developed.
The in situ prepared three component system Pd(OAc)2 / bis(1,4,5,6-
tetrahyropyrimidinium) bromides (2a-d) and Cs2CO3 catalyses quantitatively
the Suzuki cross-coupling of deactivated aryl chloride.
INTRODUCTION
Suzuki coupling reaction1 has, over the past decade or so, established itself as a powerful method for the formation of
carbon-carbon bonds. The coupling of two sp2-centered carbons remains an important goal as well as a challenge for
synthetic organic chemists. Chloroarenes are generally readily available and inexpensive and, therefore the productive
activation of C-Cl bonds in chloroarenes is of significant industrial interest. Traditionally, however, the C-Cl bond in
chloroarenes has been found to be comparatively inert.2 For along time, the use of unactivated aryl chlorides as
substrates in Suzuki-Miyaura cross-coupling was not feasible. Instead, more costly and less readily available aryl
iodides and aryl bromides had to be used. Buchwald3 and Fu4 were the first to independtly developed catalyst systems
based on electron-rich, sterically demanding phosphine ligands, which allow the Suzuki-Miyaura cross-coupling of
many unactivated aryl chlorides. However, the major drawback of these is that the phosphine ligands are
comparatively difficult to make or rather expensive. Furthermore, tertiary phosphines require air-free handling
to prevent their oxidation and are susceptible to P-C bond cleavage at elevated temperatures.5 The application
of N-heterocyclic carbene (NHC)6 ligands in the reaction was first reported by Herrmann in 1998.7
The NHC complexes are cost efficient to prepare, insensitive to air and moisture and are thermally stable in
both the solid state and in solution; the carbenes are non-dissociative ligands. However, the development of
new ligands or the application of existing ligands in these reactions, particularly those involving aryl chlorides

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as substrates, is still of considerable importance. Recently, we have developed improved procedures Heck and
Suzuki reactions of aryl chlorides making use of novel ligands 1,3-bis(dialkyl)imidazolium and
benzimidazolinium salts.8
Although the nature of the NHC ligand on complexes has a tremendous influence on the rate of catalyzed
reactions, the use of 1,4,5,6-tetrahyropyrimidinium ligands in coupling reactions is a neglected area. In order
to find more efficient palladium catalysts we have prepared a series of new bis(1,4,5,6-
tetrahyropyrimidinium) bromides LHX (2) (Scheme 1). We now report the use of the in situ generated
catalytic system composed of commercially available and stable reagents, the Pd(OAc)2 as palladium source,
bis(1,4,5,6-tetrahyropyrimidinium) (2a-d) as a carbene precursor and Cs2CO3 as a base for cross coupling of
aryl chlorides with phenylboronic acid.
RESULTS AND DISCUSSION
Bis(1,4,5,6-tetrahyropyrimidinium) bromides (2a-d) are conventional NHC precursors. According to Scheme
1, the salts (2a-d) were obtained in almost quantitative yield by quarternazition of 1-alkyl(1,4,5,6-
tetrahyropyrimidine)9 in DMF with alkyl bromides.8
(CH2)n
CH3
N
N
+
N
+
DMF
2Br-
+
Br(CH2)nBr
N
N
N
CH3
CH3
1
2
n = 1
n = 2
n = 3
n = 4
a
b
c
d
Scheme 1
The structures of 2 were determined by their characteristic spectroscopic data and elemental analyses
(EXPERIMENTAL). 13C NMR chemical shifts were consistent with the proposed structure; the imino carbon
appeared as a typical singlet in the 1H-decoupled mode in the 154.8, 154.4, 150.5 and 153.5 ppm respectively
1
for pyrimidinium salts 2a-d. The H NMR spectra of the pyrimidinium salts furher supported the assigned
structures; the resonances for C(2)-H were observed as sharp singlets in the 8.7, 8.5, 8.4 and 8.3 ppm
respectively for 2a-d. The IR spectral data for pyrimidinium salts (2a-d) clearly indicate the presence of the –
C=N- group with a ν(C=N) vibration at 1697, 1694, 1690 and 1699 cm-1 respectively for 2a-d.
The palladium-catalyzed cross-coupling of arylboronic acids with aryl halides has been shown to proceed
under a variety of conditions: A wide range of bases and solvents, as well as catalysts, have been employed
with varying degrees of success according to the substrates. To find optimum conditions a series of

HETEROCYCLES, Vol. 65, No. 6, 2005
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experiments has been performed with 4-chloroanisole and phenylboronic acid as model compounds. As a base,
Cs2CO3 was the best choice and as a solvent dioxane was found to be better than other solvents. After having
established the optimised coupling reaction conditions, the scope of the reaction and efficiencies of the salts
were evaluated by investigating the coupling of C6H5B(OH)2 with various p-substituted aryl chlorides. The
results were summarized in Table 1.
Table 1. The Suzuki coupling reaction of aryl chlorides with phenylboronic acid
Pd(OAc)2 (1.0 mol %)
2a-d (2.0 mol %)
R
Cl
+
B(OH)2
R
Cs2CO3
Entry
1
R
COCH3
COCH3
COCH3
COCH3
CH3
CH3
CH3
CH3
CHO
CHO
CHO
CHO
OCH3
OCH3
OCH3
OCH3
H
LHX
Yielda-d (%)
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
93
95
89
87
80
84
76
73
94
96
91
89
80
86
84
81
90
93
86
82
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
H
H
H
a
Reaction conditions: 1.0 mmol of R-C6H4Cl-p, 1.5 mmol of phenylboronic acid, 2 mmol Cs2CO3, 1 mmol %
b
Pd(OAc)2, 2 mmol % 2, dioxane (3 mL), Purity of compounds is checked by NMR spectrum and yields are based on
aryl chloride. c All reactions were monitered by TLC, d temperature 80 °C, 2 h.
Under those conditions, p-chloroacetophenone, p-chlorotoluene, p-chlorobenzaldehyde, p-chloroanisole and
chlorobenzene react very cleanly with phenylboronic acid in goods yields (Table 1, Entries 2, 6, 10, 14 and
18).
Table 1 summarizes our results from the screening of four pyrimidinium salts, for Suzuki cross-coupling
reaction. Several trends are readily apparent. First, the procedure is simple and does not require induction
periods. Second, the scope of this reaction is broad and includes aryl chlorides that are activated or

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HETEROCYCLES, Vol. 65, No. 6, 2005
deactivated. Third, all complexes led to good conversions at low catalyst concentration (1 mmol %). It is
evident that the NHC precursors that contain pyrimidinium (2a-d) are the most effective of the salts examined.
In conclusion, we have developed a new type of easily prepared bis(1,4,5,6-tetrahyropyrimidinium) salts LHX
(2a-d) ligands in the Suzuki-Miyaura coupling reaction. Through the use of LHX and Pd(OAc)2 as a pre-
catalyst mixture, aryl halides undergo efficient coupling reactions with C6H5B(OH) in the presence of
2
Cs2CO3. The procedure is simple and efficient towards various aryl halides and does not require induction
periods.
EXPERIMENTAL
All reactions were performed using Schlenk-type flask under argon and standard high vacuum-line techniques.
1
Solvents were analytical grade and distilled under Ar from sodium benzophenone (Et2O, dioxane). H NMR
and 13C NMR spectra were recorded using a Bruker AC300P FT spectrometer operating at 300.13 MHz (1H),
75.47 MHz (13C). FT-IR spectra were recorded on a Mattson 1000 spectrophotometer. Elemental analyses
were performed by TUBITAK Microlab.
Preparation of 3,3’-dimethyl-1,1’-methylenedi(1,4,5,6-tetrahyropyrimidinium) diibromide (2a)
To a solution of 1-methyl-1,4,5,6-tetrahydropyrimidine ( 0.98 g, 10 mmol) in DMF (10 mL) was added
slowly dibromomethane (0.87 g, 5 mmol) at 25 °C and the resulting mixture was stirred at rt for 6 h. Ether
(15 mL) was added to obtain a white crystalline solid which was filtered off. The solid was washed with
ether (3x15 mL), dried under vacuum and the crude product was recrystallized from ethanole / ethere. Yield:
1
1.65 g, 89 %. mp 197-198 °C, IR (KBr) υ= 1697 cm-1 (-CH=N-). H NMR (DMSO-d6, ) δ : 2.2 (4H, quintet,
J = 5.9 Hz, H-5), 3.3 (6H, s, NCH3); 3.5 (4H, t, J = 6.0 Hz, H-6)], 3.6 (4H, t, J = 5.8 Hz, H-4); 5.2 (2H, s, H-
bridge); 8.7 (2H, s, 2-H). 13C NMR (DMSO-d6) δ : 18.5 (NCH3); 42.3 (C-5), 45.6 (C-6), 46.8 (C-4), 71.2 (C-
bridge), 154.8 (C-2). Anal. Calcd for C11H22N4Br2: C, 35.70; H, 5.99; N, 15.14. Found: C, 35.66; H, 5.89; N
15.11.
Preparation of 3,3’-dimethyl-1,1’-ethylenedi(1,4,5,6-tetrahyropyrimidinium) dibromide (2b)
Compound (2b) was prepared in the same way as 2a from 1-methyl-1,4,5,6-tetrahydropyrimidine (0.98 g, 10
mmol) and 1,2-dibromoethane ( 0.94 g, 5 mmol) to give white crystals of 2b. The crude product was
1
recrystallized from ethanole / ethere. Yield: 1.75 g, 91 %. mp 242-243 °C, IR υ = 1696 cm-1 (-CH=N-). H
NMR (DMSO-d6) δ : 2.2 (4H, quintet, J= 5.8 Hz, H-5), 3.3 (6H, s, NCH3), 3.5 (4H, t, J = 6.0 Hz, H-6), 3.6
13
(4H, t, J= 5.9 Hz, H-4), 3.9 (4H, s, NCH2CH2 N), 8.5 (2H, s, H-2). C NMR (DMSO-d6) δ : 18.9 (NCH3),

HETEROCYCLES, Vol. 65, No. 6, 2005
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41.8 (C-5), 43.2 (C-6), 45.1 (C-4), 52.2 (C-bridge) 154.4 (C-2). Anal. Calcd for C12H24N4Br2: C, 37.52; H,
6.30; N, 14.58. Found: C, 37.39; H, 6.21; N, 14.21.
Preparation of 3,3’-dimethyl-1,1’-propylenedi(1,4,5,6-tetrahyropyrimidinium) dibromide (2c)
Compound (2c) was prepared in the same way as 2a from 1-methyl-1,4,5,6-tetrahydropyrimidine ( 0.98 g, 10
mmol) and 1,3-dibromopropane (1.01 g, 5 mmol) to give white crystals of 2c. The crude product was
recrystallized from ethanole / ethere. Yield: 1.80 g, 91 %. mp 120-121°C, IR υ= 1690 cm-1 (-CH=N-). 1H
NMR (DMSO-d6) δ : 2.2 (4H, quintet, J = 6.1 Hz, H-5); 3.3 (6H, s, NCH3); 3.5 (12H, m, H-6 and bridge
13
NCH2CH2CH2N ), 3.6 (4H, t, J= 7.3 Hz, H-4), 8.4 (2H, s, H-2). C NMR (DMSO-d6) δ: 8.9 (NCH3), 25.8
(bridge, -NCH2CH2CH2N=), 41.4 (C-5), 42.68 (C-6), 44.9 (C-4), 52.03 (bridge - NCH2CH2CH2N-), 150.5
(C-2). Anal. Calcd for C13H26N4Br2: C, 39.21; H, 6.58; N, 14.07. Found: C, 39.15; H, 6.51; N, 13.98.
Preparation of 3,3’-dimethyl-1,1’-buthylenedi(1,4,5,6-tetrahyropyrimidinium) dibromide (2d)
Compound (2d) was prepared in the same way as 2a from 1-methyl-1,4,5,6-tetrahydropyrimidine ( 0.98 g, 10
mmol) and 1,4-dibromobutane ( 1.08 g, 5 mmol) to give white crystals of 2d. The crude product was
1
recrystallized from ethanole / ethere. Yield: 1.92 g, 93 %. mp 138-139°C, IR υ= 1699 cm-1 (-CH=N-). H
NMR (DMSO-d6) δ: 1.7-1.8 (4H, m, bridge -NCH2CH2CH2CH2N), 2.2 (4H, quintet, J = 5.8 Hz, H-5), 3.3 (6H,
s, NCH3), 3.3-3.4 (12H, m, ring H-4,-6 and bridge-NCH2CH2CH2CH2N), 8.3 (2H, s, H-2). 13C NMR (DMSO-
d6) δ : 18.9 (NCH3), 24.5 (bridge -NCH2CH2CH2CH2N-), 41.4 (C-5), 42.6 (C-6), 44.9 (C-4), 54.6 (bridge -
NCH2CH2CH2CH2N-), 153.5 (C-2). Anal. Calcd for C14H28N4Br2: C, 40.79; H, 6.85; N, 13.59. Found: C,
40.64; H, 6.49; N, 13.89.
General Procedure for the Suzuki Type Coupling reactions. Pd(OAc)2 (1 mmol %),
bis(tetrahydropyrimidinium) bromides (2a-d) (2 mmol %), aryl chloride (1.0 mmol), phenylboronic acid (122
mg; 1.5 mmol), Cs2CO3 (652 mg; 2 mmol) dioxane (3 mL) were added in a small Schlenk tube under argon
and the mixture was heated at 80 oC for 2 h. At the conclusion of the reaction mixture was cooled, extracted
with ther, filtered through a pad of silicagel with copious washings, concentrated and purified by flash
chromatography on silicagel. Purity of compounds is checked by NMR spectrum and yields are based on aryl
chloride.
ACKNOWLEDGEMENTS
The Technological and Scientific Research Council of Türkiye TÜBİTAK TBAG-2474 (104T085),
(TÜBİTAK COST D17) and İnönü University Research Fund are gratefully acknowledged for support of this
work.

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