Rhodium-HMPT-catalyzed direct ortho arylation of phenols with aryl bromides

Article abstract of DOI:10.1016/j.tetlet.2003.09.151

Direct ortho arylation of phenols with aryl bromides catalyzed by a rhodium complex and hexamethylphosphorous triamide (HMPT) have been developed. A plausible reaction mechanism involving in situ generation of arylphosphites from phenols and HMPT, phosphorus-directed ortho metalation, and transesterification of the arylated arylphosphites with the substrate phenols is proposed.

Full text of DOI:10.1016/j.tetlet.2003.09.151

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8665–8668
Rhodium-HMPT-catalyzed direct ortho arylation of phenols with
aryl bromides
Shuichi Oi,* Shun-ichiro Watanabe, Susumu Fukita and Yoshio Inoue*
Department of Materials Chemistry, Graduate School of Engineering, Tohoku University, Sendai 980-8579, Japan
Received 26 August 2003; revised 16 September 2003; accepted 18 September 2003
Abstract—Direct ortho arylation of phenols with aryl bromides catalyzed by a rhodium complex and hexamethylphosphorous
triamide (HMPT) have been developed. A plausible reaction mechanism involving in situ generation of arylphosphites from
phenols and HMPT, phosphorus-directed ortho metalation, and transesterification of the arylated arylphosphites with the
substrate phenols is proposed.
© 2003 Elsevier Ltd. All rights reserved.
Transition metal-catalyzed cross-coupling reactions of
aromatic compounds have recently been recognized to
be of greatly useful synthetic utility. Reactions of vari-
ous arylmetal compounds with aryl halides or their
synthetic equivalents catalyzed by nickel or palladium
complexes are widely employed for preparations of
unsymmetrical biaryls.1 Recently, transition metal-cata-
lyzed direct CꢀC bond formation on the aromatic com-
pounds, involving the activation of aromatic CꢀH
bond, has been attracting much attention in terms of
synthetic efficiency and minimization of atomic waste.2
For the direct arylation of aromatic compounds, Miura
and co-workers reported that phenolic compounds such
as 1-naphthols and 2-phenylphenols,3 benzyl phenyl
ketones,4 benzanilides,5 and arylcarbinols6 were aryl-
ated with aryl halides in the presence of palladium
catalysts. We reported the arylation of pyridylbenzenes
with tetraarylstannanes catalyzed by rhodium(I)–phos-
phine complexes7 and the arylation and alkenylation of
pyridylbenzenes8 or aromatic imines9 with organic
halides catalyzed by ruthenium(II)–phosphine com-
plexes. Kakiuchi and co-workers reported the arylation
of arylketones with arylboronates catalyzed by ruthe-
nium complexes.10 In these reactions, coordination of
the functional groups, such as hydroxyl, pyridyl,
imono, and carbonyl groups, to the transition metals
promotes the ortho metalation, forming stable five- or
six-membered metallacycles. When phenols are con-
verted to phosphites, coordination of the phosphorus
atom should also direct the ortho metalation forming
the stable five-membered metallacycles. Actually, such
complex of ruthenium 1 was isolated by the reaction of
RuHCl(PPh3)4 with triphenylphosphite11 and was
applied as a catalyst to the direct ortho ethylation of
phenol with ethylene.12 The reaction mechanism of the
ethylation of phenol probably involves the transesterifi-
cation of the reacted triarylphosphite with the substrate
phenol, which makes the phosphorus atom recyclable.
These studies prompted us to examine the direct aryla-
tion of phenols with aryl halides via the phosphorus-
directed ortho metalation of intermediary aryl-
phosphites. We report here the ortho arylation of
phenols with aryl bromides catalyzed by rhodium-
HMPT system, which would involve the in situ genera-
tion of the corresponding arylphosphites, the
phosphorus-directed ortho metalation, and the transes-
terification of the arylated arylphosphites with the sub-
strate phenols.13
The reaction of meta-cresol (2a) with bromobenzene
(3a) was initially examined in the presence of various
transition metal complexes (5 mol% on metal),
triphenylphosphite (20 mol%), and K2CO3 (2.0 equiv.)
in toluene at 100°C for 20 h. Among the transition
metal complexes examined, chloro-bridged dimer com-
plex of Rh, [RhCl(cod)]2, was found to exhibit catalytic
activity affording the desired ortho phenylated product
Keywords: arylation; phenol; rhodium catalyst; aryl halide.
* Corresponding authors. E-mail: oishu@aporg.che.tohoku.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.151

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S. Oi et al. / Tetrahedron Letters 44 (2003) 8665–8668
(3b) and para-trifluoromethylbromobenzene (3c)
afforded the ortho-diarylphenols 5bb and 5bc in 62 and
41% yield, respectively (Eq. (4)).
4aa in 12% yield (Eq. (1)). However, a substantial
amount of phenylated products of phenol (4ba and 5ba)
were formed as byproducts, which would be caused by
the transesterification of 2a with triphenylphosphite. To
avoid the formation of these byproducts, the use of
hexamethylphosphorous triamide (HMPT) instead of
triphenylphosphite was found to be effective. The reac-
tion of HMPT with 2a would give the corresponding
arylphosphite in situ.14 Indeed, the reaction using 20
mol% of HMPT gave only the desired product 4aa in
17% yield (Eq. (2)). After optimization of reaction
conditions, 63% yield of 4aa and 22% yield of diphenyl-
ated product 5aa were obtained in the reaction using
2.4 equiv. of bromobenzene in the presence of 2.5 mol%
of [RhCl(cod)]2, 20 mol% of HMPT, 2.0 equiv. of
K2CO3, and 2.0 equiv. of Cs2CO3 in toluene at 100°C
for 20 h (Eq. (3)).15,16
(4)
An outline of a plausible reaction mechanism is shown
in Scheme 1. Initially, the reaction of substrate phenol
with HMPT would give the phenylphosphite 6. A con-
trol experiment confirmed that the reaction of HMPT
with an excess amount of phenol in the presence of
K2CO3 in toluene at 100°C gave a mixture of mono-
and di-phenylphosphite. The phenylphosphite 6 would
then react with the aryl halide and RhX in the presence
of base to give the five-membered rhodacycle 7. The
reductive elimination of the arylated phenylphosphite 8
from 7 regenerates RhX and the transesterification of 8
with potassium or cesium phenoxide gave the product
and phenylphosphite 6 again.
(1)
Although details for the formation of rhodacycle 7
from 6 with the aryl halide and RhX are not yet clear,
(2)
Table 1. Rhodium-HMPT-catalyzed phenylation of phe-
nols with bromobenzene16
(3)
The results of the reactions of phenols with bromoben-
zene under the optimized conditions are shown in Table
1. The reactions of meta-substituted phenols, meta-
cresol (2a), meta-trifluoromethylphenol (2e), and 2-
naphthol (2f), gave the mono-phenylated products
predominantly even when 2.4 equiv. of bromobenzene
was used (entries 1, 5, and 6). This is probably due to
the steric hindrance of the functional groups on meta
position. The reactions of phenol (2b) and para-cresol
(2d) gave the diphenylated products in good yields
(entries 2 and 4). The reaction of ortho-cresol (2c) also
proceeded smoothly to give the phenylated product 4ca
in 76% yield (entry 3). The reaction of 1-naphthol (2g)
gave not only the monophenylated product at 2-posi-
tion (4ga) in 43% yield but also the diphenylated
product at 2- and 8-psitions (5ga) in 32% yield (entry
7).
The reactions of phenol (2b) with substituted bro-
mobenzenes were then examined. para-Bromotoluene

S. Oi et al. / Tetrahedron Letters 44 (2003) 8665–8668
8667
phites. Further investigations to extend the scope of the
reaction are currently in progress.
References
1. (a) Knight, D. W. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
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(b) Kakiuchi, F.; Murai, S. In Activation of Unreactive
Bonds and Organic Synthesis; Murai, S., Ed.; Springer:
Berlin, 1999; pp. 47–79; (c) Fujiwara, Y.; Jintoku, T.;
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Kawamura, Y.; Satoh, T.; Miura, M.; Nomura, M.
Chem. Lett. 1999, 961.
Scheme 1.
two possible pathways can be assumed (Scheme 2). In
the pass a, oxidative addition of the aryl halide to RhX
generates the trivalent arylrhodium species 9,17 which
then reacts electrophilically with phosphite 6 by the aid
of the coordination of the phosphorus atom to give the
rhodacycle 7 after the elimination of HX. In the pass b,
oxidative addition of the phosphite 6 to RhX generates
the rhodium hydride complex 10 and the elimination of
HX gives the monovalent rhodacycle 11. Then, the
oxidative addition of the aryl halide to 11 gives the
rhodacycle 7.
4. Satoh, T.; Kametani, Y.; Terao, Y.; Miura, M.; Nomura,
M. Tetrahedron Lett. 1999, 40, 5345.
5. Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetra-
hedron Lett. 2000, 41, 2655.
6. (a) Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura,
M. J. Am. Chem. Soc. 2001, 123, 10407; (b) Terao, Y.;
Wakui, H.; Nomoto, M.; Satoh, T.; Miura, M.; Nomura,
M. J. Org. Chem. 2003, 68, 5236.
7. Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun. 1998, 2439.
8. Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.;
Inoue, Y. Org. Lett. 2001, 3, 2579.
In conclusion, the reaction reported herein provides a
useful method of direct arylation of the ortho positions
of phenols with the aryl bromides. In this reaction, the
arylphosphite is the key compound, which actually
undergoes the arylation reaction. However, there is no
need to prepare the arylphosphites correspond to the
substrate phenols because the in situ reaction of phe-
nols with HMPT generates the corresponding arylphos-
9. Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org. Lett. 2002,
4, 1783.
10. Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J.
Am. Chem. Soc. 2003, 125, 1698.
11. Parshall, G. W.; Knoth, W. H.; Schunn, R. A. J. Am.
Chem. Soc. 1969, 91, 4990.
12. Lewis, L. N.; Smith, J. F. J. Am. Chem. Soc. 1986, 108,
2728.
13. Fukita, S.; Watanabe, S.; Oi, S.; Inoue, Y. Abstracts of
the 81st Annual Meeting of Japan Chemical Society, 2002,
1G5-40. In the course of our study, rhodium-catalyzed
ortho arylation of phenols with aryl halides in the pres-
ence of phosphinite co-catalyst was reported: Bedford, R.
B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E.
Angew. Chem., Int. Ed. Engl. 2003, 42, 112.
14. Bentrude, W. G.; Johnson, W. D.; Khan, W. A. J. Org.
Chem. 1972, 37, 642.
15. The effect of the base was examined in the reaction of
phenol with bromobenzene (Table 1, entry 2). When 4
equiv. of K2CO3, Cs2CO3, and K2CO3/Cs2CO3 (1:1) was
used, the yields of 5ba were 13, 57, and 69%, respectively.
In all cases, only a small amount of 4ba was obtained.
16. Typical reaction procedure: To a mixture of [RhCl(cod)]2
(12.5 mg, 0.025 mmol), K2CO3 (276.4 mg, 2.0 mmol), and
Scheme 2.

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S. Oi et al. / Tetrahedron Letters 44 (2003) 8665–8668
Cs2CO3 (651.6 mg, 2.0 mmol) in toluene were added
(CDCl3, 125 MHz): l 150.7, 136.8, 134.3, 130.4, 129.5,
129.31, 129.26, 128.9, 128.2, 127.8, 126.5, 126.2, 123.9,
110.2. IR (KBr): 3515, 3054, 1626, 1437, 1173, 757, 707
cm−1. Anal calcd for C16H12O: C, 87.25; H, 5.49. Found:
phenols (1.0 mmol), HMPA (32.6 mg, 0.2 mmol), and
bromobenzene (376.8 mg, 2.4 mmol) and the mixture was
stirred at 100°C for 20 h under N2. After the reaction
mixture was cooled to room temperature, 10 mL of
diethyl ether and 10 mL of conc. HCl were added to the
reaction mixture and the mixture was stirred vigorously
for 1 h. Organic layer was extracted by diethyl ether,
washed with sat. NaCl aq., and dried over MgSO4. After
the solvent was removed, the residue was purified by
silica gel flash chromatography using hexane/AcOEt
(10:1). Spectroscopic data for new compounds: 4aa: 1H
NMR (CDCl3, 500 MHz): l 7.48–7.43 (m, 4H), 7.38–7.35
(m, 1H), 7.13 (d, 1H, J=8.1 Hz), 6.82–6.80 (m, 2H), 5.14
(s, 1H), 2.35 (s, 3H). 13C NMR (CDCl3, 125 MHz): l
135.2, 139.4, 137.1, 130.0, 129.2, 129.1, 127.6, 125.2,
121.7, 116.4, 21.2. IR (Neat): 3520, 3028, 2919, 1889,
1625, 1486, 1486, 1288, 1153, 942, 767, 701, 582, 461
cm−1. Anal calcd for C13H12O: C, 84.75; H, 6.57. Found:
1
C, 87.22; H, 5.60. 4ga: H NMR (CDCl3, 400 MHz): l
8.32–8.26 (m, 1H), 7.85–7.79 (m, 1H), 7.58–7.40 (m, 8H),
7.36 (d, 1H, J=8.4 Hz), 5.83 (s, 1H). 13C NMR (CDCl3,
62.5 MHz): l 147.7, 137.4, 134.2, 129.6, 29.3, 127.9,
127.6, 127.5, 126.5, 125.5, 124.3, 122.4, 121.2, 120.2. IR
(KBr): 3276, 1561, 1321, 1050, 814, 758, 695 cm−1. Anal
calcd for C18H12O: C, 87.25; H, 5.49. Found: C, 87.20; H,
1
5.63. 5ga: H NMR (CDCl3, 400 MHz): l 7.85 (dd, 1H,
J=8.2, 1.3 Hz), 7.56 (d, 1H, J=8.6 Hz), 7.53–7.49 (m,
4H), 7.48–7.433 (m, 5H), 7.425–7.37 (m, 2H), 7.30 (tt,
1H, J=7.4, 1.3 Hz), 7.23 (dd, 1H, J=7.2, 1.2 Hz), 5.72
(s, 1H). 13C NMR (CDCl3, 100 MHz): l 149.3, 142.1,
138.6, 137.1, 135.2, 129.8, 129.5, 129.2, 128.9, 128.6,
128.5, 128.3, 128.1, 127.0, 125.0, 124.1, 121.5, 120.8. IR
(KBr): 3483, 1577, 1491, 1362, 1092, 833, 761, 697 cm−1
.
1
C, 84.55; H, 6.70. 5aa: H NMR (CDCl3, 500 MHz): l
Anal calcd for C22H16O: C, 89.16; H, 5.44. Found: C,
7.57–7.55 (m, 2H), 7.51–7.48 (m, 2H), 7.44–7.39 (m, 3H),
7.34–7.31 (m, 3H), 7.22 (d, 1H, J=7.8 Hz), 6.93 (d, 1H,
J=7.8 Hz), 4.98 (s, 1H), 2.10 (s, 3H). 13C NMR (CDCl3,
125 MHz): l 149.6, 138.0, 136.7, 135.7, 130.2, 129.4,
139.24, 129.22, 128.6, 128.4, 128.0, 127.1, 125.7, 122.0,
20.4. IR (Neat): 3535, 3027, 2921, 1612, 1477, 1406, 1242,
1111, 775, 700 cm−1. Anal calcd for C19H16O: C, 87.66;
H, 6.19. Found: C, 87.81; H, 6.36. 4ea: mp 56.5–57.5°C.
1H NMR (CDCl3, 400 MHz): l 7.57–7.50 (m, 2H),
7.48–7.43 (m, 3H), 7.36–7.32 (m, 1H), 7.27–7.23 (m, 2H),
5.36 (s, 1H). 13C NMR (CDCl3, 100 MHz): l 152.6,
135.6, 131.521, 131.505, 131.2, 130.6, 129.6, 128.9, 128.7,
125.2, 117.552, 117.519, 117.478, 117.438, 113.078,
113.040, 113.002, 112.963. IR (KBr): 3326, 1417, 1338,
1
88.86; H, 5.71. 5bb: mp 89.6–90.6°C. H NMR (CDCl3,
400 MHz): l 7.45 (d, 4H, J=8.1 Hz), 7.30–7.23 (m, 6H),
7.03 (d, 1H, J=7.8 Hz), 5.40 (s, 1H) 2.41 (s, 6H). 13C
NMR (CDCl3, 100 MHz): l 149.4, 137.4, 134.6, 129.7,
129.5, 129.2, 128.6, 120.6, 21.2. IR (KBr): 3553, 1514,
1444, 1396, 1321, 1222, 828, 784, 749 cm−1. Anal calcd
for C16H12O: C, 87.56; H, 6.61. Found: C, 87.28; H, 6.77.
1
5bc: mp 124.4–126.4°C. H NMR (CDCl3, 400 MHz): l
7.75 (d, 4H, J=8.4 Hz), 7.68 (d, 4H, J=8.4 Hz), 7.03 (d,
2H, J=7.3 Hz), 7.12 (t, 1H, J=7.6 Hz), 5.21 (s, 1H). 13C
NMR (CDCl3, 100 MHz): l 149.2, 141.0, 130.6, 130.1,
129.797, 129.731, 127.8, 125.893, 125.587, 125.820,
125.783, 125.460, 122.8, 121.3, 119.6. IR (KBr): 3565,
1617, 1450, 1323, 1152, 1111, 1064, 851, 794, 750 cm−1
.
1167, 1116, 1076, 909, 695 cm−1
. Anal calcd for
Anal calcd for C20H12F6O: C, 62.83; H, 3.16. Found: C,
62.87; H, 3.26.
C13H9F3O: C, 65.55; H, 3.81. Found: C, 65.82; H, 3.90.
1
4fa: mp 118.0–118.5°C. H NMR (CDCl3, 500 MHz): l
17. (a) Mori, K.; Mizoroki, T.; Ozaki, A. Bull. Chem. Soc.
Jpn. 1976, 49, 758; (b) Ishiyama, T.; Hartwig, J. J. Am.
Chem. Soc. 2000, 122, 12043.
7.78 (d, 4H, J=8.3 Hz), 7.734 (s, 1H), 7.726 (d, 1H,
J=7.9 Hz), 7.75–7.51 (m, 4H), 7.46–7.42 (m, 2H), 7.34 (t,
1H, J=7.3 Hz), 7.33 (s, 1H) 5.24 (s, 1H). 13C NMR