The conversion of phenols to the corresponding aryl halides under mild conditions

Article abstract of DOI:10.1055/s-2005-861791

Mild, novel procedures have been developed for the syntheses of aryl halides from the corresponding phenols in modest to good yields via boronate ester intermediates.

Full text of DOI:10.1055/s-2005-861791

PAPER
547
The Conversion of Phenols to the Corresponding Aryl Halides
Under Mild Conditions
Conversion of
P
he
l
nols to
i
the
C
o
c
rresponding
i
Aryl
H
a
a
lides L. S. Thompson,a George W. Kabalka,b Murthy R. Akula,b John W. Huffman*a
a
Clemson University, Department of Chemistry, Clemson, South Carolina 29634-0973, USA
Fax +1(864)6566613; E-mail: huffman@clemson.edu
b
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, Tennessee 37996-1600, USA
Received 23 July 2004; revised 16 November 2004
version of phenols to aryl bromides under mild conditions
a synthetic route to the precursors to deoxy cannabinoids
1 would be available. Also, in connection with the synthe-
sis of a series of iodinated cyclooxygenase inhibitors there
was a need for a mild and efficient procedure for effecting
the conversion of a phenol to an aryl iodide. Although the
direct conversion of phenols to aryl halides has been re-
ported, the published procedures employ harsh conditions
and these protocols are not applicable to even somewhat
structurally sensitive molecules.5 We now describe a mild
three step procedure for carrying out these transforma-
tions in fair to good yields.
Abstract: Mild, novel procedures have been developed for the syn-
theses of aryl halides from the corresponding phenols in modest to
good yields via boronate ester intermediates.
Key words: aryl halides, phenols, boronates, halogenation, palladi-
um coupling
In connection with the proposed synthesis of a series of 1-
deoxy analogs (1, n = 0–5) of the Pfizer bicyclic non-tra-
ditional cannabinoids, such as CP-47497 (2, n = 5),1 a
method was needed for the preparation of 4-bromo-1,1-
dimethylalkylbenzenes (3, n = 0–5). Deoxy compounds 1
(Figure 1) were designed to be selective ligands for the
cannabinoid CB2 receptor,2 and although a number of es-
tablished synthetic methods can be envisioned for the
preparation of compounds 3 (Figure 1), none appeared at-
tractive. An obvious approach would involve synthesis of
the corresponding dimethyalkylbenzene followed by ha-
logenation (either directly or by nitration followed by ha-
lide replacement of the nitro group). However, previous
experience in our laboratory showed that Friedel–Crafts
alkylation of benzene with 2-methyl-2-butanol gave a
mixture containing only small amounts of 2-phenyl-2-
methylbutane with the majority of the product mixture
consisting of the isomeric 2-phenyl-3-methylbutane and
1-phenyl-2,2-dimethylpropane.3
The initially proposed route for this conversion
(Scheme 1) envisioned conversion of a phenol 4 to the
corresponding trifluoromethanesulfonate 5 which would
undergo palladium mediated conversion to the pinacolbo-
ronate ester 6.6 Alternatively, palladium catalyzed reac-
tion of triflates 5 with bis(neopentyl glycolato)diboron
would provide neopentylboronate esters (7, Scheme 2).7 It
was envisioned that direct conversion of boronate esters 6
to aryl bromides 8 would be carried out using chloramine-
T and NaBr in dilute acid, conditions reported by one of
us several years ago.8 However, reaction of pinacolbor-
onates 6 to give the corresponding aryl bromide did not af-
ford the desired product.9 The conversion of
pinacolboronates 6 to aryl bromides 8 was ultimately ef-
fected using copper (II) bromide.10 Interestingly, the di-
rect conversion of the neopentylboronates 7 to aryl
iodides 9 could be carried out efficiently using chloram-
ine-T and NaI (Scheme 2, Table 1).
OH
R
R
CH3
CH3
CH3
CH3
Tf2O, pyridine
CH2Cl2
pinacolborane, PdCl2
dppf, dioxane, NEt3
ArOH
ArOTf
(CH2)nCH3
(CH2)nCH3
4
5
1 R = H
3 R = Br
2 R = OH
10 R = OH
H3C
CH3
Figure 1
CuBr2, MeOH, H2O
O
B
CH3
CH3
ArBr
O
Alkylation of phenols with tertiary alcohols can be carried
out under relatively mild conditions,4 and Friedel–Crafts
alkylation of phenol with 2-methyl-2-butanol proceeded
smoothly to afford exclusively 2-(4-hydroxyphenyl)-2-
methylbutane. If a method could be developed for the con-
Ar
6
8
Scheme 1
Prior to the synthesis of halides 3 which required the prep-
aration of the corresponding phenol, the synthetic route
was applied to a series of commercially available phenols.
The preparation of aryl triflates 5 from the corresponding
SYNTHESIS 2005, No. 4, pp 0547–0550
x
x
.
x
x
.2
0
0
5
Advanced online publication: 18.01.2005
DOI: 10.1055/s-2005-861791; Art ID: M05304SS
© Georg Thieme Verlag Stuttgart · New York

548
A. L. S. Thompson et al.
PAPER
Table 1 Preparation of Aryl Iodides 9 from Phenols via Neopentyl-
boronate Esters 7a
Table 2 Preparation of Aryl Bromides from Phenol
Entry Phenol (4)
Yield (%)a
Entry
Phenol 4
Yield (%)b
Ar
5
6
8
Overall
yield
Ar
7
9 (Reaction time)
58 (10 min)
84 (5 min)
1
2
3
4
5
6
Ph
90
92
92
88
78
97
1
2
Ph
98
98
96
93
93
98
95
85
94
86
86
98
88
99
93
90b
57
33
67d
93
97
95
98
92
45
96
79
95
46
77
29
24
28
59
83
75
73
78
81
38
81
88
78
42
70
25c
12
9
p-CH3OC6H4
p-CH3COC6H4
m-CH3O2CC6H4
p-CH3C6H4
m-NO2C6H4
p-t-C4H9C6H4
2-Naphthyl
30 (6 h)
3
44 (4 h)
4
1-Naphthyl
78 (10 min)
No reaction (24 h)
5
2,5-(CH3)2C6H3
2,6-(CH3O)2C6H3
7-Hydroxycoumarin
m-ClC6H4
6
7
a For the general experimental methods see refs.7,8
b Isolated yield.
8
9
m-NO2C6H4
H3C
H3C
O
B
O
10
11
12
13
14
15
2-CH3O-5-CHOC6H4 91
35
76
72
62
74
67
CH3
CH3
10, n = 1
10, n = 2
10, n = 3
10, n = 4
10, n = 5
98
99
90
97
90
2
NaI
O
B
5
ArI
PdCl2/KOAc
dppf/dioxane
80 °C
chloramine-T
50% aq THF
Ar
O
7
9
Scheme 2
phenol 4 was carried out using a modification of the pub-
lished procedures11 and provided the trifluoromethane-
sulfonates as clear, colorless liquids in nearly quantitative
yields (Table 2). Conversion of aryl triflates 5 to boronate
esters 6 was carried out by coupling of the triflate with pi-
nacolborane using PdCl2(dppf) as catalyst.6 To optimize
the yields for this conversion, the conditions for the prep-
aration of the pinacolboronates were modified by carrying
out the reaction in dioxane at reflux rather than at 80 °C.
Also, the molar equivalents of pinacolborane were in-
creased from 1.5 to 3 in the case of aryl triflates, which
were ortho-substituted or contained strongly electron-
withdrawing groups (Table 2). If the substrate was both
ortho-substituted and contained a strongly electron-with-
drawing group, 4.5 equivalents of pinacolborane were
used. The final products are white or pale yellow solids,
which were obtained in yields of 57–99%, with the excep-
tion of the boronate ester derived from 3-nitrophenol,
which was formed in 33% yield. The boronate esters were
used in the subsequent step without further purification.
a Isolated yield.
b Partial reduction of the triflouromethanesulfonate occurs at this step
to give a mixture containing 60% coumarin and 40% of the boronate
ester.
c Plus 38% of coumarin. Yield determined by GC–MS.
d The carbonyl group was reduced in this step. The final product is 3-
bromo-4-methoxybenzyl alcohol.
as co-solvents and the reaction was carried out at reflux
(Table 2, entries 1–10). For phenols with electron-releas-
ing groups (entries 2, 5 and 6), plus 1- and 2-naphthol, the
yields are 70% or better, except for 2,5-dimethylphenol.
With electron-withdrawing groups the yields are de-
creased (entries 7–9), 3-hydroxy-4-methoxybenzalde-
hyde gave as a final product 3-bromo-4-methoxybenzyl
alcohol. With the exception of 1-bromo-2,6-dimethoxy-
benzene (entry 6)12 and 7-bromocoumarin (entry 7)13 all
of the bromides described in Table 2 are commercially
available. By application of this protocol to phenols 10,
the precursors to bromides 3 (Table 2, entries 11–15) pro-
vided bromides 3 in greater than 60% overall yields. Of
these compounds only 2-(4-bromophenyl)-2-methylbu-
tane (3, n = 1) has been reported previously.14 In the con-
version of phenols to iodides summarized in Table 1, the
yields for those compounds with electron-releasing
groups (entries 2 and 5) were again greater than 70%,
while with electron-withdrawing groups (entries 3, 4 and
6) the yields were considerably less and in the case of the
boronate ester of 3-nitrophenol (7, Ar = m-nitrophenyl,
entry 6), no iodide was obtained. With the exception of 3-
Conversion of boronate esters 6 to aryl bromides 8 was
carried out using a modification of a procedure described
a number of years ago by Nesmejanow et al. for the con-
version of arylboronic acids to the corresponding aryl bro-
mide using copper (II) bromide.10 Application of this
procedure to boronate esters 6 using the conditions de-
scribed by Nesmejanow, water at reflux, did not give sat-
isfactory yields. Since the boronate esters are insoluble in
water, various co-solvents were evaluated. Methanol, ac-
etone, and dioxane were explored and the best results
were obtained when methanol and water (1:1) were used
Synthesis 2005, No. 4, 547–550 © Thieme Stuttgart · New York

PAPER
Conversion of Phenols to the Corresponding Aryl Halides
549
carbomethoxyiodobenzene (Table 1, entry 4),15 all of the
aryl iodides are commercially available.
Preparation of Pinacol Boronates; General Procedure
The aryl triflate 5 (1 mmol) and Et3N (3 mmol) were added to
PdCl2(dppf) (3 mol%) dissolved in anhyd dioxane (5 mL). Pina-
colborane was added to the mixture. It was determined that 1.5
equiv were sufficient for starting materials that contained substitu-
tion in the para-position or electron-donating groups in the meta-
position. Electron-withdrawing meta-substituents required an addi-
tional 1.5 equiv of pinacolborane for each substituent. Similarly,
with ortho-substituents, an additional 1.5 equiv was required for
each substituent. The reaction was heated at reflux for 2–10 h until
TLC indicated that the starting material had been consumed. The re-
action was quenched with water (10 mL) and extracted with CH2Cl2
(3 × 25 mL). After drying (MgSO4), the solvent was removed to
give a brown solid, which contained the product mixed with the re-
covered palladium complex. This residue was taken up in petroleum
ether and filtered through MgSO4 to remove the catalyst. The sol-
vent was removed in vacuo to give the final products 6, which were
obtained as white to yellow solids in 57–99% yields (Table 2).
Although the use of this protocol for the synthesis of aryl
chlorides was not investigated in detail, in one experiment
the boronate ester derived from 4-tert-butylphenol was
converted to 4-chloro-tert-butylbenzene in 76% yield us-
ing copper (II) chloride in aqueous MeOH at reflux.
In conclusion, novel and mild procedures for the synthesis
of aryl halides from the corresponding phenol through bo-
ronic ester intermediates have been developed. These pro-
cedures have been carried out on a number of starting
materials and have advantages over published methods,
but the copper (II) bromide method is superior in most
cases. Different patterns of substitution and types of sub-
stituents require minor variations in the amounts of re-
agents used and the times required as noted previously.
The scale of the reaction does not appear to affect the
overall yields to an appreciable extent.
Preparation of Aryl Bromides; General Procedure
In a modification of the procedure reported by Nesmejanow et al.10
the boronate ester 6 (1 mmol) was dissolved in MeOH (10 mL).
Copper (II) bromide (3 mmol) in water (10 mL) was added and the
mixture was stirred at reflux for 2–6 h until the reaction was com-
plete as shown by TLC. The mixture was extracted with Et2O,
washed with brine, and dried (MgSO4). After the solvent was re-
moved in vacuo the crude product was purified by column chroma-
tography on silica gel with elution by petroleum ether to give the
desired aryl bromide 8 as a colorless liquid in 24–96% yield
(Table 2).
IR spectra were obtained using Nicolet 5DX or Magna spectrome-
ters. 1H NMR and 13C NMR spectra were recorded as CDCl3 solu-
tions using TMS as an internal standard on a Bruker 300AC or
JEOL 500 MHz spectrometer. Mass spectral analyses were per-
formed on a Hewlett-Packard 5890A capillary gas chromatograph
equipped with a mass sensitive detector. HRMS data were obtained
in the Mass Spectrometry Laboratory, School of Chemical Scienc-
es, University of Illinois. Et2O and THF were distilled from Na-ben-
zophenone ketyl immediately before use, and other solvents were
purified using standard procedures. Column chromatography was
carried out on Sorbent Technologies silica gel (32–63 mm) using pe-
troleum ether (bp 30–60 °C) and the indicated co-solvent as eluents.
GLC analyses were performed on the Hewlett-Packard 5890A GC–
MS using a 60 m carbowax column and He gas as a carrier. An ini-
tial column temperature of 60 °C was employed and the temperature
was increased at a rate of 15 °C/min to a maximum temperature of
300 °C with a total run time of 20 min. All new compounds were
homogeneous to GLC and/or TLC and 13C NMR.
4-Bromo-tert-amylbenzene14
Oil.
1H NMR (300 MHz, CDCl3): d = 0.65 (t, J = 7.4 Hz, 3 H), 1.23 (s,
6 H), 1.59 (q, J = 7.4 Hz, 2 H), 7.17 (d, J = 8.3 Hz, 2 H), 7.38 (d,
J = 8.2 Hz, 2 H).
13C NMR (75.5 MHz, CDCl3): d = 9.0, 28.3, 36.7, 37.7, 119.1,
127.8, 131.0, 148.4.
MS (EI): m/z (%) = 228 (12), 226 (12), 199 (98), 197 (100), 171
(34), 169 (35).
Preparation of Aryltrifluoromethanesulfonates; General Pro-
cedure
1-Bromo-4-(1,1-dimethylbutyl)benzene
Oil.
To the phenol (4, 1 mmol) in anhyd CH2Cl2 was added pyridine (2
mmol) and the solution was cooled to 0 °C. Trifluoromethane-
sulfonic anhydride (1.2 mmol) was added dropwise and the mixture
was warmed to r.t. The reaction was complete within 5 min as
shown by TLC. The mixture was diluted with Et2O, quenched with
10% aq HCl and washed successively with sat. NaHCO3, and brine.
After drying (MgSO4) the solvent was evaporated and the residue
was purified by column chromatography on silica gel using petro-
leum ether or mixtures of petroleum ether and Et2O as eluent to give
the triflates 5 as colorless to pale yellow clear liquids in 91–99%
yield (Table 2).
IR (CHCl3): 3085, 3044, 3008, 2959, 2930, 2870, 1490, 1396, 1370,
1114, 1084, 1072, 1008, 822, 732, 555 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.81 (t, J = 7.3 Hz, 3 H), 1.00–1.10
(m, 2 H), 1.26 (s, 6 H), 1.51–1.57 (m, 2 H), 7.19 (d, J = 8.7 Hz, 2
H), 7.40 (d, J = 8.7 Hz, 2 H).
13C NMR (125.8 MHz, CDCl3): d = 14.7, 17.9, 28.8, 37.6, 46.9,
119.1, 127.7, 131.0, 148.8.
MS (EI): m/z (%) = 242 (9), 240 (9), 199 (100), 197 (100), 171 (28),
169 (28).
HRMS: m/z calcd for C12H17Br: 240.0154; found: 240.0153.
Preparation of Neopentylboronates; General Procedure
A nitrogen flushed, two-necked, 25 mL round-bottomed flask was
charged with PdCl2(dppf) (0.03 mmol), KOAc (3.0 mmol) and
bis(neopentyl glycato)diboron (1.1 mmol). A solution of aryl tri-
flate (1.1 mmol) in DMSO (6 mL) was added and the solution
stirred for 3 h at 80 °C. The product was extracted into EtOAc,
washed with water, and dried over anhyd MgSO4. The organic sol-
vent was removed under reduced pressure and the product 7 was pu-
rified by column chromatography (silica gel, EtOAc–petroleum
ether, 1:9).
1-Bromo-4-(1,1-dimethylpentyl)benzene
Oil.
IR (CHCl3): 3090, 3062, 3045, 2959, 2929, 2866, 1487, 1400, 1376,
1110, 1092, 1086, 1008, 822, 752, 558 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.81 (t, J = 7.3 Hz, 3 H), 0.96–1.04
(m, 2 H), 1.19 (p, J = 7.3 Hz, 2 H), 1.25 (s, 6 H), 1.53–1.57 (m, 2
H), 7.18 (d, J = 8.7 Hz, 2 H), 7.39 (d, J = 8.7 Hz, 2 H).
13C NMR (125.8 MHz, CDCl3): d = 14.0, 23.3, 26.9, 28.8, 37.5,
44.2, 119.1, 127.7, 131.0, 148.7.
Synthesis 2005, No. 4, 547–550 © Thieme Stuttgart · New York

550
A. L. S. Thompson et al.
PAPER
MS (EI): m/z (%) = 256 (10), 254 (9), 199 (97), 197 (100), 171 (21),
(3) Thompson, A. L. S., unpublished work..
169 (21).
(4) (a) Dominianni, S. J.; Ryan, C. W.; De Armitt, C. W. J. Org.
Chem. 1977, 42, 344. (b) Huffman, J. W.; Joyner, H. H.;
Lee, M. D.; Jordan, R. D.; Pennington, W. T. J. Org. Chem.
1991, 56, 2081.
HRMS: m/z calcd for C13H19Br: 254.0670; found: 254.0664.
1-Bromo-4-(1,1-dimethylhexyl)benzene
(5) (a) Bay, E.; Bak, D. A.; Timony, P. E.; Leone-Bay, A. J.
Org. Chem. 1990, 55, 3415. (b) Bestman, H. J.; Schnabel,
K. H. Justus Liebigs Ann. Chem. 1966, 698, 106. (c) Wiley,
G. A.; Hershkowitz, R. L.; Rein, B. M.; Chung, B. C. J. Am.
Chem. Soc. 1964, 86, 964. (d) Albert, A.; Clarke, J. J. Chem.
Soc. 1964, 1666. (e) Park, J. D.; Rosser, R. W.; Lacher, J. R.
J. Org. Chem. 1962, 27, 1462. (f) Cramer, R.; Coffman, D.
D. J. Org. Chem. 1961, 26, 4164. (g) Price, C. C.; Roberts,
E. M. Org. Synth. Coll. Vol III; Wiley: New York, 1955,
272. (h) Bendich, A.; Russell, P. J.; Fox, J. J. J. Am. Chem.
Soc. 1954, 76, 6073. (i) Surrey, A. R.; Cutler, R. A. J. Am.
Chem. Soc. 1954, 76, 1109. (j) Baddiley, J.; Topham, A. J.
Chem. Soc. 1944, 678.
Oil.
IR (CHCl3): 3090, 3072, 3048, 2965, 2932, 2862, 1496, 1480, 1395,
1370, 1117, 1094, 1081, 1005, 823, 720, 561 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 (t, J = 6.9 Hz, 3 H), 0.95–1.10
(m, 2 H), 1.10–1.23 (m, 4 H), 1.25 (s, 6 H), 1.51–1.58 (m, 2 H), 7.17
(d, J = 8.6 Hz, 2 H), 7.39 (d, J = 8.6 Hz, 2 H).
13C NMR (75.5 MHz, CDCl3): d = 14.0, 22.5, 24.3, 28.8, 32.5, 37.5,
44.4, 119.1, 127.7, 131.0, 148.8.
MS (EI): m/z (%) = 270 (8), 268 (8), 199 (99), 197 (100), 171 (20),
169 (20).
HRMS: m/z calcd for C14H21Br: 268.0827; found: 268.0826.
(6) Murata, M.; Oyama, T.; Watanabe, W.; Masuda, Y. J. Org.
Chem. 2000, 65, 164.
(7) Kabalka, G. W.; Akula, M. R.; Zhang, J. Nucl. Med. Biol.
1-Bromo-4-(1,1-dimethylheptyl)benzene
Oil.
2002, 29, 841.
IR (CHCl3): 3093, 3077, 3060, 2969, 2928, 2860, 1489, 1468, 1396,
1104, 1093, 1085, 1008, 822, 732, 557 cm–1.
(8) Kabalka, G. W.; Sastry, K. A. R.; Sastry, U.; Somayaji, V.
Org. Prep. Proced. Int. 1982, 14, 359.
1H NMR (500 MHz, CDCl3): d = 0.84 (t, J = 6.9 Hz, 3 H), 0.97–1.08
(m, 2 H), 1.15–1.20 (m, 4 H), 1.20–1.24 (m, 2 H), 1.25 (s, 6 H),
1.53–1.58 (m, 2 H), 7.18 (d, J = 8.7 Hz, 2 H), 7.39 (d, J = 8.7 Hz, 2
H).
13C NMR (125.8 MHz, CDCl3): d = 14.1, 22.6, 24.6, 28.8, 30.0,
31.7, 37.5, 44.5, 119.1, 127.7, 131.0, 148.8.
(9) Pinacolboronates 6 could be converted to the corresponding
boronic acid using NaIO4 and NH4OAc. The boronic acids
were then converted to the aryl bromide under the conditions
described in ref.7 The overall yields for this procedure were
inferior to those developed subsequently.
(10) Nesmejanow, A. N.; Perewalowa, E. G.; Jurjewa, L. P.
Chem. Ber. 1960, 2729.
(11) For selected examples of experimental methods for the
preparation of trifluoromethanesulfonates, see: (a)Ritter,K.
Synthesis 1993, 735. (b) Stang, P. J.; Hanack, M.;
Subramanian, L. R. Synthesis 1982, 85. (c) Echavarren, A.
M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478.
(d) Tilley, J. W.; Danho, W.; Lovey, K.; Wagner, R.;
Swistok, J.; Makofske, R.; Michalewsky, J.; Triscari, J.;
Nelson, D.; Weatherford, S. J. Med. Chem. 1991, 34, 1125.
(e) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856.
(12) Kaliakoudas, D.; Eugster, C. H.; Ruedi, P. Helv. Chim. Acta
1990, 73, 48.
MS (EI): m/z = 284 (7), 282 (7), 199 (98), 197 (100), 171 (17), 169
(18).
HRMS: m/z calcd for C15H23Br: 282.0983; found: 282.0988.
Acknowledgment
The work at Clemson University was supported by grants R01
DA03590 and K05 DA15340, both from the National Institute on
Drug Abuse. The work at the University of Tennessee was suppor-
ted by the U.S. Department of Energy and the Robert H. Cole Foun-
dation.
(13) (a) Harayama, T.; Nakatsuka, K.; Nishioka, H.; Murakami,
K.; Hayashida, N.; Ishii, H. Chem. Pharm. Bull. 1994, 42,
2170. (b) Mitteilung, K.; Reisch, J.; Rosenthal, B. H. W.
Monatsh. Chem. 1987, 118, 871.
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Synthesis 2005, No. 4, 547–550 © Thieme Stuttgart · New York