Rhodium-catalyzed mono- and divinylation of 1-phenylpyrazoles and related compounds via regioselective C-H bond cleavage

Article abstract of DOI:10.1021/jo901485v

(Chemical Equation Presented) The selective 2-mono- and 2,6-divinylations of (N-containing heteroaryl)benzenes can be achieved effectively through rhodium-catalyzed oxidative coupling reactions with alkenes. The installation of two different vinyl groups

Full text of DOI:10.1021/jo901485v

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Rhodium-Catalyzed Mono- and Divinylation of 1-Phenylpyrazoles and
Related Compounds via Regioselective C-H Bond Cleavage
Nobuyoshi Umeda, Koji Hirano, Tetsuya Satoh,* and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
satoh@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Received July 11, 2009
The selective 2-mono- and 2,6-divinylations of (N-containing heteroaryl)benzenes can be achieved
effectively through rhodium-catalyzed oxidative coupling reactions with alkenes. The installation
of two different vinyl groups is also possible by a simple one-pot manner. Thus, a series of
1,3-divinylbenzene derivatives, some of which exhibit solid-state fluorescence, is readily prepared.
Introduction
vinylation with alkenes has not been extensively explored. As
some rare examples, we demonstrated that 2-phenylphenols,3
N-(arylsulfonyl)-2-phenylanilines,4 and benzoic acids4,5 un-
dergo the direct oxidative vinylation under palladium or
Transition metal-catalyzed C-C bond formation reac-
tions via C-H bond cleavage have attracted much attention
from the atom- and step-economic point of view, and various
catalytic processes involving different modes to activate the
ubiquitously available bond have been developed.1 Among
the most promising strategies is the chelation-assisted
version with the aid of directing groups including carbonyl,
imino, and pyridyl functions. Particularly, the vinylation
at the ortho positions of arenes having such a functional
group via oxidative coupling with readily available alkenes
seems to be a useful method to selectively construct
π-conjugated vinylarene frameworks, which can be widely
seen in organic materials.2 However, the straightforward
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Satoh, T.; Miura, M. J. Org. Chem. 2008, 73, 298.
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Lett. 2009, 11, 1317. (b) Katagiri, T.; Mukai, T.; Satoh, T.; Hirano, K.;
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7094 J. Org. Chem. 2009, 74, 7094–7099
Published on Web 08/20/2009
DOI: 10.1021/jo901485v
r
2009 American Chemical Society

Umeda et al.
JOCArticle
TABLE 1. Reaction of 1-Phenylpyrazole (1a) with Styrene (2a)a
% yieldb
entry
1 (mmol)
2 (mmol)
Cu(OAc)2 H2O (mmol)
3
temp (°C)
time (h)
3a
4a
1
2
3
4
0.5
1
0.5
0.5
0.5
0.5
1.2
1.2
1
1
2
2
60
60
60
100
10
3
10
2
72
81 (81)
27
7
67
90 (82)
3
0
aReaction conditions: [(Cp*RhCl2)2] (0.005 mmol) and DMF (3 mL) under N2. bGC yield. The value in parentheses indicates the yield after
purification.
SCHEME 1. Mono- and Divinylation of 1-Phenylpyrazole with
Alkenes
TABLE 2. Reaction of 1-Phenylpyrazole (1a) with Alkynes 2a
product, % yieldb
entry
2
R
conditions time (h)
3
4
1
2
3
4
5
6
7
8
2b 4-MeC6H4
2b 4-MeC6H4
2c 4-(t-Bu)C6H4
2c 4-(t-Bu)C6H4
2d 4-MeOC6H4
2d 4-MeOC6H4
2e 4-ClC6H4
A
B
A
B
A
B
A
B
A
B
A
B
6
2
7
6
3
2
3
2
7
2
2
2
2
2
1
2
2
3b, 79 (69) 4b, 5
4b, 89 (86)
3c, 80 (72)
3d, 81 (74)
3e, - (74)
3f, - (77)
3g , - (76)
3h, 62 (57)
3i, 85 (79)
3j, - (76)f
rhodium catalysis. Since them, some reports concerning
monovinylation of limited substrates under palladium cata-
lysis have been disclosed.6 During our further studies
of oxidative couplings using rhodium catalysts,7 we have
succeeded in conducting the ortho-vinylation of 1-phenylpyr-
azoles and related compounds with various alkenes in the
presence of a rhodium catalyst and a copper oxidant
(Scheme 1). Interestingly, not only monovinylated products
but also divinylated ones can be obtained selectively, depend-
ing on the reaction conditions.8 Furthermore, a stepwise,
one-pot divinylation with two different alkenes can also be
performed to afford the corresponding unsymmetrically
substituted 1,3-divinylbenzene derivatives selectively.9 These
m-phenylene vinylene structures are common units in fine
chemicals such as luminescent materials, liquid crystals, and
nonlinear optical materials as well as herbicides.10 The results
obtained for the vinylation reactions are described herein.
4c, - (74)
4d, - (64)
4e, 68 (58)
4f, 80 (77)
4g, - (81)
4h, - (78)
4i, - (77)
2e 4-ClC6H4
9c 2f 2-naphthyl
10c 2f 2-naphthyl
11 2g CO2(n-Bu)
12 2g CO2(n-Bu)
13 2h CO2(t-Bu)
14 2h CO2(t-Bu)
15 2i CO2Cye
16 2i CO2Cye
17 2j CN
Ad
Bd
Ad
Bd
Ad
aReaction conditions A: 1a (1 mmol), 2 (0.5 mmol), [(Cp*RhCl2)2]
(0.005 mmol), Cu(OAc)2 H2O (1 mmol), DMF (3 mL) at 60 °C under N2.
Conditions B: 1a (0.5 mmol), 2 (1.2 mmol), [(Cp*RhCl2)2] (0.005 mmol),
3
Cu(OAc)2 H2O (2 mmol), DMF (3 mL) at 100 °C under N2. bGC yield.
3
The value in parentheses indicates the yield after purification.
c[(Cp*RhCl2)2] (0.01 mmol) was used. dAfter the vinylation reaction, the
resulting mixture was treated with PdCl2(PhCN)2 (0.05 mmol) in mesity-
lene (3 mL) under N2 at 150 °C for 15 h. eCy = cyclohexyl. fE/Z = 3/1.
Results and Discussion
In an initial attempt, 1-phenylpyrazole (1a) (0.5 mmol) was
treated with styrene (2a) (0.5 mmol) in the presence of [Cp*Rh-
Cl2]2 (0.005 mmol, 1 mol %) and Cu(OAc)2 H2O (1 mmol) in
3
DMF (3 mL) at 60 °C under N2 for 10 h. As a result, mono- and
divinylated products, 3a and 4a, were formed in 72% and 27%
yields, respectively (entry 1 in Table 1, Cp* = pentamethyl-
cyclopentadienyl).11 Expectedly, the yield of 3a was improved
by using an excess amount of 1a up to 81% (entry 2, conditions
A). Meanwhile, the use of 1a and 2a in a ratio of 0.5:1.2 gave 4a
predominantly in 67% yield, along with a small amount of 3a
(entry 3). At 100 °C, 3a completely disappeared, and 4a was
obtained exclusively in 90% yield (entry 4, conditions B).
(9) (a) Zhang, X.; Liu, A.; Chen, W. Org. Lett. 2008, 10, 3849. (b) Wang,
C.; Tan, L.-S.; He, J.-P.; Hu, H.-W.; Xu, J.-H. Synth. Commun. 2003, 33, 773.
(c) Sengupta, S.; Sadhukhan, K. Tetrahedron Lett. 1998, 39, 715. (d) Tao, W.;
Nesbitt, S.; Heck, R. F. J. Org. Chem. 1990, 55, 63. (e) Spencer, A. J.
Organomet. Chem. 1984, 265, 323.
(10) For example, see: (a) Tang, Y.; Wang, Y.; Wang, X.; Xun, S.; Mei,
C.; Wang, L.; Yan, D. J. Phys. Chem. B 2005, 109, 8813. (b) Tang, Y.; Wang,
Y.; Wang, G.; Wang, H.; Wang, L.; Yan, D. J. Phys. Chem. B 2004, 108,
12921. (c) Konstandakopoulou, F. D.; Iconomopoulou, S. M.; Gravalos, K.
G.; Kallitsis, J. K. Chem. Mater. 2000, 12, 2957. (d) Hidaka, T.; Nakatani, H.;
Yamanaka, K. Jpn. Kokai Tokkyo Koho, JP 03056449, 1991. (e) Pavia, M. R.;
Moos, W. H.; Hershenson, F. M. J. Org. Chem. 1990, 55, 560. (f) Noller, K.;
Kosteyn, F.; Meier, H. Chem. Ber. 1988, 121, 1609. (g) Colle, R.; Gozzo, F.;
Camaggi, G.; Siddi, G. Jpn. Kokai Tokkyo Koho, JP 53127425, 1978.
(11) It was confirmed by blank experiments that both the Rh-complex
and the Cu-salt were needed in conducting the reaction effectively.
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TABLE 3. Synthesis of Unsymmetrically Substituted Divinylbenzenesa
aReaction conditions: (i) 1a (0.6 mmol), 2 (0.5 mmol), [(Cp*RhCl2)2] (0.012 mmol), Cu(OAc)2 H2O (2.4 mmol), DMF (3 mL) at 60 °C under N2 for
3
2-7 h. (ii) 20 (2 mmol) at 100 °C for 2 h. bIsolated yield. c4a (0.043 mmol) and 4g (0.17 mmol) were also formed. dGC yield. e4a (0.17 mmol) and 4g (0.055
mmol) were also formed. f4g (0.16 mmol) was also formed. The amount of 4f was not determined. gAfter the vinylation reactions, the resulting mixture
was treated with PdCl2(PhCN)2 (0.06 mmol) in mesitylene (3 mL) under N2 at 150 °C for 15 h. h4b (0.012 mmol) was also formed. i4d (0.12 mmol) and 4e
(0.030 mmol) were also formed.
SCHEME 2. Plausible Mechanism for the Vinylation of
1-Phenylpyrazole (1a) with Alkenes 2
methoxy- (2d), and chloro- (2e) substituted styrenes with 1a
proceeded smoothly to give 3b-e and 4b-e selectively
(entries 1-8 in Table 2). 2-Vinylnaphthalene (2f) and n-butyl
acrylate (2g) also underwent the coupling reactions without
any difficulties (entries 9-12). The reactions of 1a with
tert-butyl- (2h) and cyclohexyl- (2i) acrylates gave the corre-
sponding vinylated products as mixtures of geometrical
isomers. Fortunately, treatment of the E-Z mixtures with
PdCl2(PhCN)2 (0.05 mmol) in mesitylene (3 mL) under N2 at
150 °C for 15 h induced isomerization around their CdC
double bonds to form thermodynamically stable E- and E,E-
isomers (entries 13-16).12 The reaction of acrylonitrile (2j)
under conditions A also gave monovinylation product 3j as
an E-Z mixture (ca. 1:1). In contrast to the cases of 3h and
Under monovinylation conditions A and divinylation
conditions B, the reactions of methyl- (2b), tert-butyl- (2c),
(12) Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67, 4627.
7096 J. Org. Chem. Vol. 74, No. 18, 2009

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3i, however, the isomerization of 3j could not be completed
by treatment with the Pd-catalyst to result in an E-rich
mixture (E/Z = 3/1, entry 17). The divinylation with 2j
was found to be sluggish and 3j was obtained as a major
product in 51% yield even under conditions B.
The reaction of 1a with 2 seems to proceed via similar steps
to those proposed for the oxidative coupling of 1a with
internal alkynes by using the [Cp*RhCl2]2/Cu(OAc)2 H2O
3
system.8b Thus, as depicted in Scheme 2, coordination of the
2-N atom of 1a to Rh(III)X3 and the subsequent directed
cyclorhodation at the 20-position afford a rhodacycle
A. Then, alkene insertion occurs to produce an intermediate
B, which undergoes β-hydrogen elimination13 to form 3
together with HRh(III)X2. The latter releases HX to form
the Rh(I)X species, which is reoxidized to Rh(III)X3 by
Cu(OAc)2. The second vinylation may proceed by the same
mechanism to produce 4.
Next, the stepwise, one-pot synthesis of unsymmetrically
substituted 1,3-divinylbenzene derivatives was examined.
Thus, in the initial step, 1a (0.6 mmol) was treated with 2a
(0.5 mmol) in the presence of [Cp*RhCl2]2 (0.012 mmol)
FIGURE 1. Fluorescence spectra of 4h (A), 4l (B), 4b (C), and
anthracene (D) in the solid state upon excitation at 350 nm.
and Cu(OAc)2 H2O (2.4 mmol) in DMF (3 mL) at 60 °C
3
as well as phenylpyrazoles (entries 4-6). In the case with the
latter substrate, only monovinylated product 5e was obtained
even under conditions B (entry 6). This may be due to similar
steric reasons to those in the case with 1c.
In summary, we have demonstrated that the rhodium-
catalyzed ortho-vinylation of phenylpyrazoles with alkenes
proceeds efficiently via C-H bond cleavage. 2-Phenylpyr-
idine and -imidazole also undergo the reaction. Some pro-
ducts possessing tert-butyl group(s) at the appropriate
position(s) show relatively strong solid-state fluorescence.
under N2 for 2 h. Then, 2g (2 mmol) was added as the second
alkene, and the resulting mixture was kept at 100 °C for 2 h
to give the corresponding divinylated product 4j in 70%
overall yield (entry 1 in Table 3). Reversing the addition
order of alkenes 2a and 2g did not affect the final yield of 4j
(entry 2). A naphthyl-substituted derivative 4k was also
synthesized by the sequential coupling by using alkenes 2f
and 2g (entry 3). Reactions using 2h as the second alkene
required the treatment with PdCl2(PhCN)2 to obtain E,E-4l
and 4m (entries 4 and 5), as in the symmetrical divinylation
(entry 14 in Table 2). It should be noted that these tert-
butoxycarbonyl-substituted products 4l and 4m were formed
as luminescent solids (vide infra), while n-butoxycarbonyl
derivatives 4j and 4k were obtained as oils. An unsymme-
trically substituted 1,3-distyrylbenzene 4n could also be
constructed via successive divinylation with two styrenes 2e
and 2d (entry 6).
Experimental Section
General Procedure for Monovinylation of Phenylpyrazoles
1 with Alkynes 2 under Conditions A. To a 20 mL two-necked
flask were added pyrazole 1 (1 mmol), alkene 2 (0.5 mmol),
[(Cp*RhCl2)2] (0.005 mmol, 1 mol %, 3 mg), Cu(OAc)2 H2O
3
(1 mmol, 200 mg), 1,2-diphenylethane (ca. 50 mg) as internal
standard, and DMF (3 mL). The resulting mixture was stirred
under N2 at 60 °C. GC and GC-MS analyses of the mixtures
confirmed formation of 3. Then the reaction mixture was cooled
to room temperature and extracted with Et2O (100 mL) and
ethylenediamine (2 mL). The organic layer was washed with
water (100 mL, three times) and dried over Na2SO4. Product
3 was isolated by column chromatography on silica gel, using
hexane-ethyl acetate as eluant.
Some divinylated products showed solid-state fluores-
cence in a range of 390-520 nm (see the Supporting
Information). Notably, 4h and 4l exhibited relatively strong
emissions compared to a typical emitter, anthracene, by
factors of 3.0 and 2.3, respectively (λemis 394 and 405 nm,
A and B versus D in Figure 1). It is apparent that the
introduction of bulky tert-butyl groups at the appropriate
positions of 1,3-divinylbenzene molecules significantly en-
hances the intensity of solid-state fluorescence.
We also examined the mono- and divinylations of other
phenylazoles and a phenylpyridine with styrene (2a). 3-Methyl-
1-phenylpyrazole (1b) underwent the reactions under condi-
tions A and B to afford the corresponding mono- and diviny-
lated products 5b and 6b in 84% and 88% yields, respectively
(entries 1 and 2 in Table 4). In contrast, the divinylation of a
sterically more hindered substrate, 3,5-dimethyl-1-phenylpyr-
azole (1c), was sluggish, and monovinylated product 5c was
produced predominantly under both conditions A and B (entry
3). As substrates in the present reactions, 2-phenylpyridine (1d)
and 1-methyl-2-phenylimidazole (1e) could also be employed
1-[2-((E)-2-Phenylethenyl)phenyl]-1H-pyrazole (3a) (entry 2 in
Table 1):7f oil; isolated yield 81%; 1H NMR (400 MHz, CDCl3)
δ 6.47 (dd, J = 1.8, 2.2 Hz, 1H), 6.94 (d, J = 16.2 Hz, 1H), 7.04
(d, J = 16.2 Hz, 1H), 7.20-7.27 (m, 1H), 7.28-7.34 (m, 2H),
7.35-7.46 (m, 5H), 7.65 (d, J = 2.2 Hz, 1H), 7.74-7.80 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 106.6, 123.9, 126.3, 126.6, 126.7,
127.9, 128.1, 128.4, 128.6, 131.2, 131.5, 133.0 137.0, 138.8, 140.7;
HRMS m/z calcd for C17H14N2 (Mþ) 246.1157, found 246.1148.
General Procedure for Divinylation of Phenylpyrazoles 1 with
Alkynes 2 under Conditions B. To a 20 mL two-necked flask were
added pyrazole 1 (0.5 mmol), alkene 2 (1.2 mmol), [(Cp*RhCl2)2]
(0.005 mmol, 1 mol %, 3 mg), Cu(OAc)2 H2O (2 mmol, 399 mg),
3
1,2-diphenylethane (ca. 50 mg) as internal standard, and DMF
(3 mL). The resulting mixture was stirred under N2 at 100 °C. GC
and GC-MS analyses of the mixtures confirmed formation of
4. Then the reaction mixture was cooled to room temperature
and extracted with Et2O (100 mL) and ethylenediamine (4 mL).
The organic layer was washed with water (100 mL, three times)
(13) The precedent dissociation of the 2-N atom in B may be involved, as
in the reaction of 1a with alkynes (see ref 8b).
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TABLE 4. Reaction of Phenylazoles or Phenylpyridine 1 with Styrene (2a)a
aReaction conditions A: 1 (1 mmol), 2a (0.5 mmol), [(Cp*RhCl2)2] (0.01 mmol), Cu(OAc)2 H2O (1 mmol), DMF (3 mL) at 60 °C under N2.
3
Conditions B: 1 (0.5 mmol), 2a (1.2 mmol), [(Cp*RhCl2)2] (0.01 mmol), Cu(OAc)2 H2O (2 mmol), DMF (3 mL) at 100 °C under N2. bIsolated yield. c6b
3
was also formed in 12% yield. d5b was also formed in 7% yield. e6d was also formed in 10% yield.
and dried over Na2SO4. Product 4 was isolated by column
chromatography on silica gel, using hexane-ethyl acetate as
eluant.
standard, and DMF (3 mL). The resulting mixture was stirred
under N2 at 60 °C for 2-7 h. Then alkene 20 (2 mmol) was added
and the reaction temperature was increased to 100 °C. After 2 h,
the reaction mixture was cooled to room temperature and
extracted with Et2O (100 mL) and ethylene diamine (4 mL).
The organic layer was washed with water (100 mL, three times)
and dried over Na2SO4. Product 4 was isolated by column
chromatography on silica gel, using hexane-ethyl acetate as
eluant.
1-[2,6-Bis((E)-2-phenylethenyl)phenyl]-1H-pyrazole (4a) (entry 4
in Table 1):7f mp 170-171 °C; isolated yield 82%; 1H NMR
(400 MHz, CDCl3) δ 6.50 (d, J = 16.1 Hz, 2H), 6.52 (dd, J =
1.8, 2.2 Hz, 1H), 7.01 (d, J = 16.2 Hz, 2H), 7.19-7.24 (m, 2H),
7.25-7.33 (m, 8H), 7.46 (t, J= 7.7 Hz, 1H), 7.54 (d, J=2.2 Hz,
1H), 7.69 (d, J=7.7 Hz, 2H), 7.86 (d, J=1.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 106.3, 123.2, 124.8, 126.7, 127.9, 128.6, 129.3,
131.6, 132.9, 136.2, 136.7, 137.0, 140.6; HRMS m/z calcd for
C25H20N2 (Mþ) 348.1626, found 348.1623. Anal. Calcd for
C25H20N2: C, 86.17; H, 5.79; N, 8.04. Found: C, 85.91; H, 5.93;
N, 7.89.
1-{2-[(E)-2-(n-Butoxycarbonyl)ethenyl]-6-[(E)-2-phenylethenyl]-
phenyl}-1H-pyrazole (4j) (entry 1 in Table 3): oil; isolated yield
1
70%; H NMR (400 MHz, CDCl3) δ 0.93 (t, J = 7.4 Hz, 3H),
1.32-1.42 (m, 2H), 1.57-1.65 (m, 2H), 4.12 (t, J = 6.6 Hz, 2H),
6.29 (d, J= 16.1 Hz, 1H), 6.48 (d, J= 16.2 Hz, 1H), 6.53 (t, J=
2.2 Hz, 1H), 7.02 (d, J = 16.2 Hz, 1H), 7.11 (d, J = 16.1 Hz,
1H), 7.21-7.33 (m, 5H), 7.49 (dd, J = 7.7, 8.0 Hz, 1H), 7.53
(d, J=2.2 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.80 (d, J=8.1 Hz,
1H), 7.84 (d, J=2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7,
19.1, 30.6, 64.4, 106.8, 121.3, 122.6, 125.9, 126.7, 127.2, 128.2,
General Procedure for One-Pot Synthesis of Unsymmetrically
Substituted 1,3-Divinylbenzenes 4j-n. To a 20 mL two-necked
flask were added 1a (0.6 mmol, 86 mg), alkyne 2 (0.5 mmol),
[(Cp*RhCl2)2] (0.012 mmol, 2.4 mol %, 7 mg), Cu(OAc)2 H2O
3
(2.4 mmol, 479 mg), 1,2-diphenylethane (ca. 50 mg) as internal
7098 J. Org. Chem. Vol. 74, No. 18, 2009

Umeda et al.
JOCArticle
128.6, 129.4, 132.2, 132.8, 133.4, 136.5, 136.7, 137.7, 139.2, 141.0,
166.3; HRMS m/z calcd for C24H24N2O2 (Mþ) 372.1838, found
372.1840.
Sports, Science and Technology, Japan and the Kurata
Memorial Hitachi Science and Technology Foundation.
Supporting Information Available: Characterization data of
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This work was partly supported by
Grants-in-Aid from the Ministry of Education, Culture,
J. Org. Chem. Vol. 74, No. 18, 2009 7099