Efficient Route to 1,3-Di-N-imidazolylbenzene. A Comparison of Monodentate vs Bidentate Carbenes in Pd-Catalyzed Cross Coupling

Article abstract of DOI:10.1021/ol035906z

(Equation Presented) A new bis(carbene) ligand architecture has been developed and was evaluated in the Suzuki-Miyaura cross-coupling reaction of various aryl halides with phenylboronic acid. Several new bis(carbene) ligands were tested in different carbe

Full text of DOI:10.1021/ol035906z

ORGANIC
LETTERS
2
003
Vol. 5, No. 25
847-4849
Efficient Route to
,3-Di-N-imidazolylbenzene. A
4
1
Comparison of Monodentate vs
Bidentate Carbenes in Pd-Catalyzed
Cross Coupling
Victor C. Vargas, Ramel J. Rubio, T. Keith Hollis,* and Martha E. Salcido
Department of Chemistry, UniVersity of California-RiVerside,
RiVerside, California 92521-0403
keith.hollis@ucr.edu
Received September 29, 2003
ABSTRACT
A new bis(carbene) ligand architecture has been developed and was evaluated in the Suzuki−Miyaura cross-coupling reaction of various aryl
halides with phenylboronic acid. Several new bis(carbene) ligands were tested in different carbene:Pd ratios. Pd(OAc) and Pd (dba) were
2
2
3
2
compared for efficiency as a Pd source. It was found that the Pd(OAc) /bis(carbene) system formed a catalyst for the activation of chlorobenzene.
Due to our interest in preparing stable ligands for selected
catalytic processes, we prepared 1,3-bis(imidazolium)-
benzene, a precursor to bidentate carbenes. Initial evaluations
as ligands for palladium-catalyzed cross coupling reactions
are reported. Palladium-catalyzed cross-coupling reactions
are one of the most widely used modern methodologies in
benes as ligands has been the activation of aryl chlorides
under mild conditions with high yields.
4
a,7
(3) (a) Weskamp, T.; Schattenmann, W. C.; Spiegler, M.; Herrmann,
W. A. Angew. Chem., Int. Ed. 1998, 37, 2490. (b) Weskamp, T.;
Schattenmann, W. C.; Spiegler, M.; Herrmann, W. A. Angew. Chem., Int.
Ed. 1999, 38, 262. (c) F u¨ rstner, A.; Ackermann, L.; Gabor, B.; Goddard,
R.; Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel, O. R. Chem. Eur. J.
2001, 7, 3236. (d) Cho, Y. S.; Han, J. S.; Yoo, B. R.; Kang, S. O.; Jung,
I. N. Organometallics 1998, 17, 570.
1
organic synthesis. N-Heterocyclic carbenes (NHC) have
been exploited as ligands for transition metal catalysis.
Carbenes have been shown to be effective ligands for ROMP
(
4) (a) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
1
999, 64, 3804. (b) Grasa, G. A.; Viciu, M. S.; Huang, J.; Zhang, C.; Trudell,
2
3
catalysis, RCM catalysis, Pd-catalyzed cross-coupling reac-
M. L.; Nolan, S. P. Organometallics 2002, 21, 2866. (c) Gstottmayr, C.
W. K.; Bohm, V. P. W.; Herdtweck, E.; Grosche, M.; Herrmann, W. A.
Angew. Chem., Int. Ed. 2002, 41, 1363. (d) Bohm, V. P. W.; Gstottmayr,
C. W. K.; Weskamp, T.; Herrmann, W. A. J. Organomet. Chem. 2000,
4
5
6
tions, and hydrogenation among many. One of the most
notable accomplishments achieved with N-heterocyclic car-
595, 186.
(
5) (a) Vazquez-Serrano, L. D.; Owens, B. T.; Buriak, J. M. Chem.
(
1) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Metal-
Commun. 2002, 2518. (b) Poyatos, M.; Sanau, M.; Peris, E. Inorg. Chem.
2003, 42, 2572. (c) Poyatos, M.; Mata, J. A.; Falomir, E.; Crabtree, R. H.;
Peris, E. Organomet. 2003, 22, 1110. (d) Fogg, D. E.; Amoroso, D.; Drouin,
S. D.; Snelgrove, J.; Conrad, J.; Zamanian, F. J. Mol. Catal. Chem. 2002,
190, 177.
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds. Wiley-
VCH: Weinheim, Germany, 1998. (c) Palladium Reagents in Organic
Syntheses; Heck, R., F.; Academic Press: London, 1985. (d) Organic
Synthesis with Palladium Compounds; Tsuji, J.; Springer-Verlag: Berlin,
1
980. (e) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
2) (a) Bielawski, C. W.; Grubbs, R. H. Angew. Chem., Int. Ed. 2000,
9, 2903. (b) Frenzel, U.; Weskamp, T.; Kohl, F. J.; Schattenman, W. C.;
(6) (a) For reviews see: Herrmann, W. A. Angew. Chem., Int. Ed. 2002,
41, 1290. (b) Herrmann, W. A.; Weskamp, T.; Bohm, V. P. W. AdV.
Organomet. Chem. 2001, 48, 1. (c) Jafarpour, L.; Nolan, S. P. AdV.
Organomet. Chem. 2001, 46, 181.
(
3
Nuyken, O.; Herrmann, W. A. J. Organomet. Chem. 1999, 586, 263.
1
0.1021/ol035906z CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/13/2003

1,3-Di-N-imidazolyl benzene was required to prepare the
bis(imidazolium) salts, precursors to the desired NHCs. To
our knowledge, the best previously reported synthesis of 1,3-
di-N-imidazolyl benzene involved four steps from 1,3-
8
diaminobenzene for which no yield was reported. We report
here a high yielding one-step synthesis from 1,3-dibromo-
9
benzene and imidazole (Scheme 1). The reaction is based
Scheme 1. Synthesis of 1,3-Bis(imidazolyl) Benzene
10
on precedent from the preparation of the 1,2 analogue. This
reaction has been performed on a multigram scale with a
Figure 1. Imidazolium salts evaluated.
7
7% unoptimized yield.
The imidazolium salts were prepared by combining the
evaluated, 5,11b along with three imidazolium salts featuring
the 1,3 phenylene architecture 3, 4, and 6.
bis(imidazole) 1 with various alkyl halides and heating as
outlined in Scheme 2.1
1,12
These facile syntheses provided
Our initial catalytic evaluation of the salts as ligand
precursors for Pd followed the protocol developed by Nolan
4
a
for aryl chlorides. The carbenes have been implicated as
the efficacious ligand derived from combining imidazolium
Scheme 2. Synthesis of Bis(imidazolium) Salts
2 3
salts with Cs CO
under the reaction conditions,15 which
would produce a bis(carbene)Pd complex with ligands 3-6.
Presented in Table 1 are the results of evaluating the catalysis
(
12) Compounds 3 and 6 were prepared by combining bis(imidazolyl)-
benzene (1 equiv) and an alkyl iodide (1.25 equiv) and then heating to 150
C. The resulting two-phase mixture was cooled to room temperature
°
whereupon the lower layer solidified. The top layer was decanted and the
solid washed with CH2Cl2. CH2Cl2 (5 mL) was added and heated on a steam
bath until the solid melted, yielding a solution. When the solution was
cooled, a white precipitate was formed, which was collected, washed with
CH2Cl2/hexane (1:1), and dried under vacuum. Compound 3 (0.32 g,
efficient access to the requisite imidazolium salt13,14 and is
amenable to combinatorial synthesis of carbene ligands.
For purposes of comparison, we have evaluated several
ligand precursors, illustrated in Figure 1. The N-heterocyclic
carbene precursor 2, N,N-bis(mesityl)imidazolium chloride,
which has been demonstrated to be highly effective in Pd-
catalyzed cross-couplings by Nolan4 was chosen for com-
parison. An analogue of the recently prepared methylene-
bridged bis(imidazolium) reported by Crabtree was also
1
44%): H NMR (300 MHz, DMSO) δ 9.76 (s, 2 H), 8.44 (d, 2 H J )
1
3
1
0.2), 7.98 (d, 2 H J ) 6.2) 4.02 (s, 4 H) 0.15 (s 18H); C (75 MHz,
CDCl3) δ 138.7, 136.5, 131.0, 124.9, 122.1, 114.5, 110.0, 42.2, -2.3;
MS(EI) m/z 383.2075 (M+; calcd for C H N Si , 383.2087). Compound
20
31
4
2
1
6
(
(0.15 g, 0.71 mmol): H NMR (300 MHz, DMSO) δ 9.87 (s, 2 H), 8.15
s, 2 H) 8.00 (s, 2 H), 7.81 (m, 4 H), 3.98 (s 6 H); 13C (75 MHz, CDCl3)
a
δ 138.8, 136.5, 131.0, 125.2, 121.6, 120.3, 114.4, 37.2; MS(EI) m/z 225.1127
+
(M ; calcd for C13H13N4, 225.1140).
(
13) Compound 4 was prepared by combining 1,3-bis(imidazolyl)
benzene (0.2 g, 0.94 mmol), benzyl bromide (0.4 g, 1.2 mmol), and toluene
10 mL) and heating to 120 °C. The precipitate was collected and washed
(
1
(
7) For a reference to activation of aryl chlorides employing phosphine
ligands, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37,
387.
8) (a) Akabane, R.; Tanaka, M.; Matsuo, K.; Koga, N.; Matsuda, K.;
with benzene and then dried under vacuum: yield ) 0.2 g, 33%; H NMR
(300 MHz, DMSO) δ 10.25 (s, 2 H), 8.48 (s, 2 H), 8.41 (s, 1 H), 8.13 (s,
1
3
3
2 H), 8.07-7.94 (m, 3 H), 7.57-7.42 (m, 10 H), 5.56 (s, 4 H); C (75
MHz, CDCl3) δ 136.7, 136.4, 135.0, 132.6, 129.7, 129.3, 124.3, 123.5,
(
+
Iwamura, H. J. Org. Chem. 1997, 62, 8854. (b) Smith, L. R.; Wilkinson,
C. F. Biochem. Pharmacol. 1978, 27, 1383.
122.4, 53.3; MS(EI) m/z 391.1909 (M ; calcd for C26H23N4, 391.1923).
(14) Compound 5 was prepared by combining diiodomethane (0.21 g,
0.8 mmol), 1-phenylimidazol (0.22 g, 1.58 mmol), and toluene (10 mL)
and heating to 120 °C. The precipitate was collected and washed with
benzene and then dried under vacuum, yielding a white solid (0.13 g,
30%): 1H NMR (300 MHz, DMSO) δ 10.0 (s, 2 H), 8.44 (s, 2 H), 8.25 (s
(
9) Compound 1 was prepared by combining 1,3-dibromobenzene (2.5
mL, 21 mmol), imidazole (3.5 g, 52 mmol), K2CO3 (7.2 g, 52 mmol), CuO
0.4 g, 5.2 mmol), and DMSO (20 mL). The solution was heated at 150 °C
(
for 48 h. The reaction was cooled, and the DMSO was distilled at low-
13
pressure, yielding an off-white solid. Chromatography on silica gel (25:1)
2 H), 7.81-7.65 (m, 10 H), 6.80 (s, 2 H); C (75 MHz, CDCl3) δ 138.0,
1
+
eluting with CH2Cl2/MeOH (10:1) gave a white solid (3.3 g, 77%):
H
136.6, 135.2, 130.8, 124.3, 123.8, 122.8, 59.6; MS(EI) m/z 301.1454 (M ;
NMR (300 MHz, CDCl3) δ 7.92 (pseudo-t, J ) 1.0 2 H), 7.67-7.62 (m,
calcd for C19H17N4, 301.1453).
1
H), 7.47 (m, 2 H), 7.44 (m, 1 H), 7.36 (t, J ) 1.5, 2 H), 7.30 (m, 2 H);
(15) General catalytic procedure using Pd2(dba)3. Under an atmosphere
of Ar, a solution of 1,4-dioxane (3 mL), aryl halide (1 mmol), and PhB(OH)2
(1.5 mmol) was added to a vial charged with a magnetic stir bar, Pd2(dba)3
(1.5 mol %) and Cs2CO3 (2.0 mmol). Imidazolium salt with a 2:1 carbene:
palladium ratio: 2, 6.0 mol %; 3, 3.0 mol %; 4, 3.0 mol %; 5, 3.0 mol %;
6, 3.0 mol %. Imidazolium salt with a 1:1 carbene:Pd ratio: 2, 3.0 mol %;
3, 1.5 mol %; 4, 1.5 mol %; 5, 1.5 mol %; 6, 1.5 mol %. The vial was
placed in an 80 °C heating block and stirred for 2 h. An aliquot was analyzed
by GC.
1
3
C (75 MHz, CDCl3) δ 138.6, 135.5, 131.5, 131.0, 120.1, 118.1, 114.5;
+
MS(EI) m/z 210.0903 (M ; calcd for C12H10N4, 210.0905). Anal. Calcd
for C12H10N4: C, 68.56; H, 4.79; N, 26.65. Found: C, 68.23; H, 4.60; N,
2
6.65.
(10) So, Y. Macromolecules 1992, 25, 516.
11) (a) Dzyuba, S. V.; Bartsch, R. A. J. Heterocycl. Chem. 2001, 38,
(
2
2
65. (b) Albrecht, M.; Crabtree, R. H.; Mata, J.; Peris, E. Chem. Commun.
002, 32.
4848
Org. Lett., Vol. 5, No. 25, 2003

Table 1. Carbene:Pd Ratio of 2:1, Comparison of Both
Monodentate and Bidentate Ligands with Various Substratesa
2 3
Table 2. Carbene:Pd Ratio of 1:1, Comparison of Pd (dba) vs
Pd(OAc)
2
with Chlorobenzene and Bromobenzenea
X ) Clb
X ) Brb
X ) Ib
entry
ligandb
X
Pd2(dba)3c,d
Pd(OAc)2d,e
entry
ligand
1
2
3
4
5
6
7
8
9
2
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
92%
56%
2%
42%
1%
24%
0%
15%
0%
80%
84%
24%f
80%
38%f
92%
5%f
95%
17%f
15%
1
2
3
4
5
2
3
4
5
6
46%
0%
0%
0%
0%
47%
54%
69%
19%
70%
87%
82%
90%
95%
100%
3
4
5
6
a
Reaction conditions: aryl halide (1.0 mmol), PhB(OH)2 (1.5 mmol),
Cs2CO3 (2.0 mmol), Pd2(dba)3 (1.5 mol %), ligand (3.0 or 6.0 mol %),
,4-dioxane (3 mL), 80 °C, 2 h. b GC yields.
1
1
0
11%
a
Reaction conditions: arly halide (1.0 mmol), PhB(OH)2 (1.5 mmol),
with a carbene:Pd ratio of 2:1 for chlorobenzene, bromo-
benzene, and iodobenzene.
b
Cs2CO3 (2 mmol), 1,4-dioxane (3 mL). Ligand 2: 3.0 mol %. Ligands 3,
, 5 and, 6: 1.5 mol %, 80 °C, 2 h. Pd2(dba)3 (1.5 mol %). GC yields.
Pd(OAc)2 (3.0 mol %) was used. 18 h.
c
d
4
e
f
At a 2:1 carbene:Pd ratio, only the bis(mesitylene) NHC
ligand 2 yielded a system that activated chlorobenzene. This
system, previously reported by Nolan, was taken as the
bis(carbene) precursor 5 and Pd(OAc)
activity (5%) with chlorobenzene. All of the catalyst systems
showed high reactivity with bromobenzene with Pd(OAc)
as Pd source except Me-imidazolium 6. This difference
appears to be a result of steric hindrance. With Pd (dba)
the activities of bromobenzene also appear to be influenced
by steric factors since the activity increased with increasing
steric bulk (2 > 3 > 4 > 5 > 6) at the carbene coordination
site. The bis(carbene) ligands are comparable to or better
than the bis(mesitylene) NHC for activating bromobenzene
at a 1:1 carbene:Pd ratio. The 1:1 carbene:Pd system is faster
than the 2:1 carbene:Pd systems, which is consistent with a
monocarbene Pd complex as the active catalyst.
In conclusion, we report an efficient synthesis of a new
carbene ligand architecture and demonstrated its efficiency
in Pd-catalyzed cross-coupling reactions. Further study is
underway to optimize the reactivity of the bis(NHC) precur-
2
sors for chlorobenzene activation with Pd(OAc) , and work
is also under way to compare transition metal complexes of
Ir, Rh, Ru, and Pd to explore their catalytic activity.
2
showed only trace
4a
benchmark catalyst system. Ligand precursors 3, 4, and 6
yielded catalytic systems that were equal to or better than 2
for activating bromobenzene. Methylene-bridged bis(carbene)
precursor 5 yielded a system with only poor reactivity toward
bromobenzene. All five ligand precursors (2-6) yielded
2
2
3
2
active catalysts for the reaction of PhB(OH) with iodo-
benzene.
Presented in Table 2 are the catalytic results obtained when
evaluating reactivity at a 1:1 carbene:Pd ratio for chloro-
benzene and bromobenzene. The Pd source was also varied
for comparison.16 With the
2 3 2
(dba) and Pd(OAc)
using Pd
:1 carbene:Pd ratio, bis(mesitylene) NHC precursor 2
produced a highly active catalyst system as Nolan has
reported (entry 1, Pd (dba) ). Surprisingly, this system was
less reactive with bromobenzene than with chlorobenzene
entries 1 and 2). At a 1:1 carbene:Pd ratio, bis(carbene)
precursors 3, 4, and 6 yielded no reactivity with Pd (dba)
In contrast, when Pd(OAc) was the Pd source, ligand
1
2
3
(
2
3
.
2
precursors 3, 4, and 6 showed significantly improved catalytic
activity (entries 3, 5, 7, and 9). The catalyst derived from
Acknowledgment. The authors wish to thank the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, and the University of California,
Cancer Research Coordinating Committee, for partial support
of this work. We gratefully acknowledge the assistance of
Dr. Richard Kondrat and Mr. Ron New with mass spectral
analyses.
(16) General catalytic procedure using Pd(OAc)2. Under an atmosphere
of Ar, a solution of 1,4-dioxane (1 mL) was added to a vial charged with
a magnetic stir bar and Pd(OAc)2 (3.0 mol %), Cs2CO3 (2.0 mmol), and
imidazolium salt (2, 3.0 mol %; 3, 1.5 mol %; 4, 1.5 mol % 5, 1.5 mol %;
6
, 1.5 mol %) with a 1:1 carbene:Pd ratio. The vial was then placed in a 80
°C heating block and stirred for 30 min. The vial was cooled, and a solution
of 1,4-dioxane (3 mL), aryl halide (1 mmol), and PhB(OH)2 (1.5 mmol)
was then added. The vial was then heated to 80 °C and stirred for 2 h. An
aliquot was analyzed by GC.
OL035906Z
Org. Lett., Vol. 5, No. 25, 2003
4849