Synthesis of substituted monohalobenzenes via ortho-selective cross-coupling of dihalobenzenes with electron-donating ortho-directing groups

Article abstract of DOI:10.1055/s-2008-1067270

Dihalobenzenes that possess directing groups such as OH, CH₂OH, NH₂, NHAc, or NHBoc were subjected to ortho-selective cross-coupling with Grignard reagents in the presence of palladium-based catalysts to give the corresponding substituted monohalobenzenes. For the dibromo- and dichlorophenols and anilines, hydroxylated terphenylphosphines 1 and 2 were found to be effective ligands for palladium, whereas tricyclohexylphosphine was preferable for the dichlorobenzyl alcohols, dichloroanilides, and difluorobenzenes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067270

3180
PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Substituted Monohalobenzenes via Ortho-Selective Cross-
Coupling of Dihalobenzenes with Electron-Donating Ortho-Directing Groups
O
rtho-Selectiv
h
e
Cross-Cou
u
pling of Dih
n
Manabe Initiative Research Unit, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan
Fax +81(48)4624662; E-mail: keimanabe@riken.jp
PSP
Received 16 July 2008
No132
Abstract: Dihalobenzenes that possess directing groups such as OH, CH2OH, NH2, NHAc, or NHBoc were subjected to ortho-selective
cross-coupling with Grignard reagents in the presence of palladium-based catalysts to give the corresponding substituted monohaloben-
zenes. For the dibromo- and dichlorophenols and anilines, hydroxylated terphenylphosphines 1 and 2 were found to be effective ligands for
palladium, whereas tricyclohexylphosphine was preferable for the dichlorobenzyl alcohols, dichloroanilides, and difluorobenzenes.
Key words: cross-coupling, palladium, site-selective, Grignard reagents, dihalobenzenes
PR'2
DG
DG
ligand (cat.)
Pd (cat.)
X
R
OH
ligand = PCy3,
+ RMgBr
THF
X'
X'
1: R' = Cy
2: R' = Ph
X, X' = Br, Cl, F
DG = OH, CH2OH, NH2, NHAc, NHBoc
R = aryl, heteroaryl, alkenyl, benzyl
Scheme 1 Palladium-catalyzed ortho-selective cross-coupling of dihalobenzenes with electron-donating directing groups
Multisubstituted halobenzenes constitute an important features: (1) For the dibromophenols and anilines (entries
class of compounds, and are widely employed as impor- 1–8), a palladium complex bearing terphenylphosphine
tant drug components.1 These halobenzenes are also syn- 16–8 or 24a significantly accelerated the ortho-selective
thetically useful because the halo substituent can be cross-coupling – other phosphines did not exhibit any
readily converted to other groups. To date, therefore, nu- ortho-selectivity. Although the reactions resulted in small
merous methods have been developed for the preparation amounts of the doubly cross-coupled products, the forma-
of various multisubstituted halobenzenes.2 Site-selective tion of the corresponding isomeric products were not ob-
cross-coupling of dihalobenzenes offers an attractive served. (2) For the dichlorophenols and anilines, the
method for the preparation of substituted monohaloben- terphenylphosphines, especially 1, were the most active
zenes,3 because various substituted dihalobenzenes, espe- ligands to give the ortho-coupled products in good yields
cially the dichloro ones, are commercially available. (entries 9–13). Neither the isomeric products nor the
However, such reactions have yet to be investigated in de- doubly-cross-coupled products were obtained. (3) For the
tail. Recently, we have developed the ortho-selective dichlorophenols and anilines, PCy3 also induced ortho-
cross-coupling of dihalobenzenes that possess electron- selective cross-coupling, while the reactions were slower
donating ortho-directing groups, using Grignard reagents than those induced by 1 and 2 (entries 15–17). It should be
in the presence of palladium-based catalysts noted that PCy3 did not exhibit ortho-selectivity for dibro-
(Scheme 1).4,5 Although electron-donating groups typi- mophenols and anilines. (4) For the dichlorobenzenes that
cally retard the oxidative addition step in cross-coupling possess CH2OH, NHAc, or NHBoc groups, ortho-selec-
reactions, the presence of these groups is essential in our tivity was also observed (entries 18–20). Contrary to the
reactions for the acceleration at the ortho-position. Here- reactions of phenols and anilines, PCy3 accelerated the
in, we describe the features of this method.
cross-coupling more than 1 and 2. (5) For the difluoroben-
zenes, ortho-selectivity was also observed (entries 21–
24). PCy3 accelerated the reactions more effectively than
1 and 2, and the air-stable PdCl2(PCy3)2, which is com-
mercially available, was found to be a highly effective cat-
alyst. It is noteworthy that, despite the presence of
electron-donating group at the ortho-position, the strong
C–F bond was found to be reactive under these conditions.
(6) In the case of entry 14, the ortho-chloro group reacted
preferentially over the para-bromo group when 1 or 2 was
As summarized in Table 1, the reactions of dihaloben-
zenes with Grignard reagents readily afforded products
with an R group at the position ortho (relative to the di-
recting group). This reaction system has the following
SYNTHESIS 2008, No. 19, pp 3180–3182
x
x.
x
x
.
2
0
0
8
Advanced online publication: 05.09.2008
DOI: 10.1055/s-2008-1067270; Art ID: Z16608SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Ortho-Selective Cross-Coupling of Dihalobenzenes
3181
used. This unusual selectivity was not observed with of simple alkyl Grignard reagent such as BuMgCl did not
PCy3. (7) Similarly, the ortho-fluoro group was more re- afford the desired product, but simply resulted in the re-
active than the para-chloro group, even when PCy3 was duction of the halo group.
used as a ligand (entries 25–28). (8) With regard to the
Because the reactions required 3–4 equivalents of the
Grignard reagents, not only aryl but also heteroaryl, alke-
Grignard reagents (Table 1), our method was reinvestigat-
nyl, and benzyl were effective. In contrast, however, use
Table 1 Ortho-Selective Cross-Coupling
DG
DG
X
catalyst
THF
R
+ RMgBr
(3–4 equiv)
X'
X'
Entry
1
X
X¢
DG
OH
OH
OH
OH
OH
OH
NH2
NH2
OH
OH
OH
OH
NH2
OH
OH
OH
NH2
R
Catalysta
A
Conditions
25 °C, 2 h
25 °C, 2 h
25 °C, 2 h
25 °C, 72 h
50 °C, 5 h
25 °C, 2 h
25 °C, 10 h
25 °C, 10 h
50 °C, 4 h
50 °C, 20 h
50 °C, 13 h
50 °C, 24 h
50 °C, 4 h
50 °C, 2 h
50 °C, 18 h
50 °C, 18 h
50 °C, 18 h
50 °C, 18 h
50 °C, 4 h
50 °C, 8 h
50 °C, 24 h
70 °C, 24 h
50 °C, 24 h
50 °C, 24 h
50 °C, 24 h
50 °C, 24 h
50 °C, 24 h
70 °C, 66 h
Yield (%)
71
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
4-Br
4-Br
4-Br
4-Br
4-Br
5-Br
4-Br
5-Br
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Br
4-Cl
5-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-F
4-MeOC6H4 (4 equiv)
4-MeOC6H4 (4 equiv)
3-MeOC6H4 (4 equiv)
2-thienyl (4 equiv)
PhCH2 (4 equiv)
2
B
89
3
B
84
4
A
66
5
A
55
6
4-MeOC6H4 (4 equiv)
4-MeOC6H4 (4 equiv)
4-MeOC6H4 (4 equiv)
4-MeOC6H4 (3 equiv)
2-thienyl (4 equiv)
4-ClC6H4 (3 equiv)
Me2C=CH (3 equiv)
4-MeOC6H4 (3 equiv)
4-MeOC6H4 (4 equiv)
4-MeOC6H4 (3 equiv)
4-MeOC6H4 (3 equiv)
4-MeOC6H4 (3 equiv)
4-MeOC6H4 (3 equiv)
4-MeOC6H4 (3 equiv)
4-MeOC6H4 (3 equiv)
Ph (3 equiv)
B
65
7
B
76
8
B
63
9
A
99
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
A
73
A
63
A¢
A
66
93
B
58
C
91
C¢
C¢
C
95
87
CH2OH
NHAc
NHBoc
OH
99
C
71
C¢
D
55
85
F
4-F
OH
4-FC6H4 (3 equiv)
D
85
F
5-F
OH
4-MeC6H4 (3 equiv)
4-MeOC6H4 (3 equiv)
4-MeOC6H4 (3 equiv)
Ph (3 equiv)
D
79
F
5-F
CH2OH
OH
D
81
F
4-Cl
4-Cl
4-Cl
4-Cl
D
76
F
OH
D
81
F
OH
Me2C=CH (3 equiv)
4-MeOC6H4 (3 equiv)
D
75
F
NH2
D¢
49
a A: Pd2(dba)3 (1 mol%), 1·HBF4 (2.4 mol%). A¢: Pd2(dba)3 (2 mol%), 1·HBF4 (4.8 mol%). B: Pd2(dba)3 (1 mol%), 2 (2.4 mol%). C: Pd2(dba)3
(1 mol%), PCy3 (2.4 mol%). C¢: Pd2(dba)3 (2 mol%), PCy3 (4.8 mol%). D: PdCl2(PCy3)2 (2 mol%). D¢: PdCl2(PCy3)2 (4 mol%).
Synthesis 2008, No. 19, 3180–3182 © Thieme Stuttgart · New York

3182
S. Ishikawa, K. Manabe
PRACTICAL SYNTHETIC PROCEDURES
Pd2(dba)3 (6.6 mg, 0.0072 mmol), and 1·HBF4 (9.1 mg, 0.0172
mmol) was added a solution of MeMgBr in THF (0.97 M, 0.81 mL,
0.790 mmol) under argon at 0 °C. After stirring for 5 min, the mix-
ture was allowed to warm to 50 °C, stirred for 5 min, and then 4-
MeOC6H4MgBr in THF (0.5 M, 1.58 mL, 0.790 mmol) was added.
After stirring for 10 h, the reaction was quenched with 10% aq HCl
(5 mL). The mixture was extracted with EtOAc (3 × 5 mL), and the
combined EtOAc extracts were washed with brine (5 mL) and dried
(Na2SO4). The residue obtained by removal of the solvent was pu-
rified by chromatography over silica gel (hexane–CH2Cl2, 1:2) to
give the desired product as a yellow oil; yield: 155 mg (92%).
1) Pd2(dba)3 (1mol%)
1⋅HBF4 (2.4 mol%)
MeMgBr (1.1 equiv)
THF
OMe
OH
OH
Cl
2) 4-MeOC6H4MgBr
(1.1 equiv)
50 °C, 10 h
92%
Cl
Cl
Scheme 2
ed to improve the efficiency. As shown in Scheme 2, the
optimized method involves the use of MeMgBr instead of
the precious Grignard reagents for the deprotonation of
the OH group of the substrate, and the OH and HBF4
groups of the ligand. In addition, the amount of 4-
MeOC6H4MgBr could be further reduced to 1.1 equiva-
lents, although a longer reaction time was required to af-
ford the product in high yield.
IR (neat): 3531, 3426, 1607, 1517, 1481, 1249, 1179, 1039, 834
cm–1.
1H NMR (400 MHz, CDCl3): d = 3.85 (3 H, s), 5.19 (1 H, br s), 6.89
(1 H, d, J = 8.8 Hz), 7.01 (2 H, d, J = 8.8 Hz), 7.18 (1 H, dd, J = 2.8,
8.8 Hz), 7.19 (1 H, d, J = 2.8 Hz), 7.36 (2 H, d, J = 8.8 Hz).
13C NMR (100 MHz, CDCl3): d = 55.35, 114.81, 116.95, 125.38,
127.84, 128.44, 129.21, 129.72, 130.10, 151.13, 159.62.
HRMS (ESI): m/z calcd for C13H10ClO2 [M – H]–: 233.0364; found:
In conclusion, we have developed a novel method for the
synthesis of substituted monohalobenzenes based on
ortho-selective cross-coupling of dihalobenzenes bearing
electron-donating ortho-directing groups. High yields and
high reaction rates can be realized by the proper choice of
catalysts. The reactions described here provide efficient
routes toward the synthesis of multisubstituted benzenes.
233.0369.
Anal. Calcd for C13H11ClO2: C, 66.53; H, 4.72. Found: C, 66.52; H,
4.84.
Acknowledgment
This work was partly supported by a Grant-in-Aid for Scientific
Research on Priority Areas ‘Advanced Molecular Transformation
of Carbon Resources’ from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
1H and 13C NMR spectra were recorded on a JEOL JNM-A400
1
spectrometer. CDCl3 was used as the solvent. For H NMR mea-
surements, TMS (d = 0) in CDCl3 served as the internal standard.
For 13C NMR measurements, CDCl3 (d = 77.00) served as the inter-
nal standard. Melting points (uncorrected) were measured using a
Stanford Research Systems OptiMelt. IR spectra were recorded on
a JASCO FT/IR-4100 spectrometer. ESI-MS spectra were obtained
using a Bruker Daltonics micrOTOF spectrometer.
References
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Ortho-Selective Cross-Coupling; 5-Bromo-4¢-methoxybiphen-
yl-2-ol; Typical Procedure (Table 1, Entry 2)
To a solution of 2,4-dibromophenol (109 mg, 0.432 mmol),
Pd2(dba)3 (4.0 mg, 0.0043 mmol), and 1·HBF4 (4.5 mg, 0.010
mmol) in THF (0.43 mL) under argon at –78 °C was added a solu-
tion of 4-MeOC6H4MgBr in THF (0.5 M, 3.46 mL, 1.73 mmol). Af-
ter 10 min, the mixture was allowed to warm to 25 °C. After stirring
for 2 h, the reaction was quenched with 10% aq HCl (5 mL). The
mixture was extracted with EtOAc (3 × 5 mL), and the combined
EtOAc extracts were washed with brine (5 mL) and dried (Na2SO4).
The residue obtained by removal of the solvent was purified by
chromatography over silica gel (hexane–CH2Cl2, 1:2) to give the
desired product as a white solid; yield: 108 mg (89%); mp 72.8–
76.7 °C.
(d) Ackermann, L.; Althammer, A. Angew. Chem. Int. Ed.
2007, 46, 1627. (e) Houpis, I. N.; Hoeck, J.-P. V.; Tilstam,
U. Synlett 2007, 2179. (f) Ishii, Y.; Chatani, N.; Yorimitsu,
S.; Murai, S. Chem. Lett. 1998, 27, 157. (g) Wang, T.;
Alfonso, B. J.; Love, J. A. Org. Lett. 2007, 9, 5629. For
site-selective cross-coupling of polyhalogenated
heteroarenes, see: (h) Schröter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245. (i) Fairlamb, I. J. S. Chem.
Soc. Rev. 2007, 36, 1036.
IR (ATR): 3421, 1487, 1232, 1182, 1030, 1011, 833, 800 cm–1.
(4) (a) Ishikawa, S.; Manabe, K. Chem. Lett. 2007, 36, 1304.
(b) Ishikawa, S.; Manabe, K. Org. Lett. 2007, 9, 5593.
(c) Manabe, K.; Ishikawa, S. Synthesis 2008, 2645.
(5) For reviews on cross-coupling with Grignard reagents, see:
(a) Tsuji, J. Palladium Reagents and Catalysts; Wiley: West
Sussex, 2004, 335. (b) Cepanec, I. Synthesis of Biaryls;
Elsevier: Oxford, 2004, 83.
(6) Ishikawa, S.; Manabe, K. Chem. Lett. 2007, 36, 1302.
(7) The design of these terphenylphosphines is based on
biphenylphosphines developed by Buchwald et al., see:
Wolfe, J. P.; Buchwald, S. L. Angew. Chem. Int. Ed. 1999,
38, 2413.
1H NMR (400 MHz, CDCl3): d = 3.86 (3 H, s), 5.16 (1 H, s), 6.85
(1 H, d, J = 8.4 Hz), 7.02 (2 H, d, J = 8.8 Hz), 7.32 (1 H, dd, J = 2.4,
8.4 Hz), 7.33 (1 H, d, J = 2.4 Hz), 7.35 (2 H, d, J = 8.8 Hz).
13C NMR (100 MHz, CDCl3): d = 55.38, 112.67, 114.86, 117.43,
127.71, 129.79, 130.13, 131.43, 132.63, 151.70, 159.70.
HRMS (ESI): m/z calcd for C13H10BrO2 [M – H]–: 276.9859,
278.9839; found: 276.9852, 278.9837.
Anal. Calcd for C13H11BrO2: C, 55.94; H, 3.97. Found: C, 56.00; H,
3.92.
5-Chloro-4¢-methoxybiphenyl-2-ol (Scheme 2)
To a mixture of 2,4-dichlorophenol (117 mg, 0.718 mmol),
(8) Phosphine 1 was purified and stored as the HBF4 salt.
Synthesis 2008, No. 19, 3180–3182 © Thieme Stuttgart · New York