Reduction of Aryl Halides into Arenes with 2-Propanol Promoted by a Substoichiometric Amount of a tert-Butoxy Radical Source

Article abstract of DOI:10.1055/s-0035-1561342

Aryl halides are reduced into the corresponding arenes in high yields, using 2-propanol, cesium carbonate, and di-tert-butyl peroxide (or di-tert-butyl hyponitrite) as a reductant/solvent, a base, and a radical initiator, respectively. This simple system reduces a wide variety of aryl bromides, chlorides, and iodides through single-electron-transfer mechanism with high functional-group tolerance.

Full text of DOI:10.1055/s-0035-1561342

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© Georg Thieme Verlag Stuttgart · New York
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R. Ueno et al.
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Reduction of Aryl Halides into Arenes with 2-Propanol Promoted
by a Substoichiometric Amount of a tert-Butoxy Radical Source
Ryota Uenoa
Cs2CO3 (1.2 equiv)
Takashi Shimizua
Eiji Shirakawa*b
t-BuOOt-Bu or
t-BuON=NOt-Bu (0.2 equiv)
H
R
R
+
X
H
OH
a Department of Chemistry, Graduate School of Science,
Kyoto University, Kyoto, Kyoto 606-8502, Japan
b Department of Applied Chemistry for Environment,
School of Science and Technology, Kwansei Gakuin
University, Sanda, Hyogo 669-1337, Japan
eshirakawa@kwansei.ac.jp
(80 equiv)
X = Br, Cl, I
R = NMe2, CO2H,
Ac, CN, CF3,
alkynylalkyl, alkenylalkyl, etc.
Received: 01.12.2015
Accepted after revision: 11.01.2016
Published online: 27.01.2016
bromides and chlorides. Here we report a simple reduction
system consisting of 2-propanol, Cs2CO3, and a t-BuO•
source,5 where aryl halides including bromides and chlo-
rides are converted into the corresponding arenes with high
functional-group tolerance.
DOI: 10.1055/s-0035-1561342; Art ID: st-2015-r0932-c
Abstract Aryl halides are reduced into the corresponding arenes in
high yields, using 2-propanol, cesium carbonate, and di-tert-butyl per-
oxide (or di-tert-butyl hyponitrite) as a reductant/solvent, a base, and a
radical initiator, respectively. This simple system reduces a wide variety
of aryl bromides, chlorides, and iodides through single-electron-trans-
fer mechanism with high functional-group tolerance.
One of the most effective protocols thus far examined is
shown in entry 1 of Table 1. Treatment of 4-bromoanisole
(1a) with Cs2CO3 (1.2 equiv) and t-BuOOt-Bu (0.2 equiv) in
2-propanol (80 equiv) at 120 °C for three hours gave anisole
(2a) in 97% yield, where (p-methoxyphenyl)anisoles (3a)
were produced as a regioisomeric mixture (o/m/p =
60:40:<1) in 0.4% yield. Bianisoles 3a are most likely to be
produced through homolytic aromatic substitution on 1a
by p-methoxyphenyl radical with H• followed by reduction
of the bromoarene moieties.6 No reduction took place at
50 °C, at which temperature there is little homolysis of t-
BuOOt-Bu, or in the absence of t-BuOOt-Bu.7 In contrast,
even at 50 °C, the reduction took place by use of t-
BuON=NOt-Bu, which readily undergoes thermal homolysis
at this temperature to give t-BuO• and N2 (Table 1, entry 4).8
All these results show that t-BuO• plays a crucial role in the
reduction. The reaction in a decreased amount (30 equiv) of
2-propanol retarded the reduction and increased genera-
tion of 3a to 0.4% (Table 1, entry 5), whereas use of an in-
creased amount (2.4 equiv) of Cs2CO3 considerably suppress
formation of 3a to 0.2% (Table 1, entry 6). Use of other alkali
metal carbonates was much less effective (Table 1, entries 7
and 8). Although the conditions in entry 4 (Table 1) scored a
yield comparable to those in entry 1, we chose entry 1 as
standard conditions because t-BuOOt-Bu is more readily
available than t-BuON=NOt-Bu.
Key words reduction, radical chain mechanism, anion radical, ketyl,
tert-butoxy radical
Reduction of aryl halides (ArX) into arenes (ArH) is an
important transformation not only in organic synthesis but
also in environmental protection since several harmful hal-
ogen-containing compounds (e.g., dioxins, polychlorobi-
phenyls) can be detoxified.1,2 Reduction using a combina-
tion of a hydride source and a transition-metal catalyst
such as palladium is one of the most typical methods for
the reduction.3 Although the transition-metal-catalyzed re-
ductions achieve high tolerance towards various functional
groups, it suffers from high cost of transition-metal cata-
lysts and incompatibility with carbon–carbon unsaturated
bonds. On the other hand, single-electron reduction is also
effective for activation of ArX, in particular for those having
a relatively low-lying LUMO. The successive elimination of
X– from the resulting anion radical, [ArX]•–, gives Ar•, which
is readily reduced into ArH by a hydrogen donor. Bunnett
and co-workers reported such a method using NaOMe and
K2S2O8, where formaldehyde ketyl generated through hy-
•–
drogen abstraction from NaOMe by SO4 is considered to
The protocol shown in entry 1 of Table 1 is applicable to
reduction of various aryl bromides, chlorides, and iodides
into the corresponding arenes.9 Phenyl bromides having no
or alkyl substituents are reduced in high yields by treat-
ment of Cs2CO3 (1.2 equiv) and t-BuOOt-Bu (0.2 equiv) in 2-
act as a single-electron reductant toward ArX and to be re-
generated through hydrogen abstraction from NaOMe by
Ar•.4 However, the method employs a large excess amount
of NaOMe and is applied merely to aryl iodides but not to
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Table 1 Reduction of 4-Bromoanisolea
OMe
base (1.2 equiv)
t-BuO • source (0.2 equiv)
+
+
MeO
MeO
Br
MeO
H
3 h
OH
(80 equiv)
1a
2a
3a
Entry
Base (equiv)
t-BuO• source
Temp (°C)
Conv. of 1a (%)b
Yield of 2a (%)b
1
2
3
4
5c
6
7
8
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (2.4)
K2CO3 (1.2)
Na2CO3 (1.2)
t-BuOOt-Bu
t-BuOOt-Bu
none
120
50
>99.9
<0.1
<0.1
>99.9
90
97
<0.1
<0.1
96
120
50
t-BuON=NOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
120
120
120
120
82
>99.9
20
99
19
2
0.5
a The reaction was carried out under a nitrogen atmosphere for 3 h using 4-bromoanisole (1a, 82 mg, 0.25 mmol), 2-PrOH (1.5 mL, 0.020 mol), a base (0.30
mmol), and t-BuO• source (0.050 mmol).
b Determined by GC using decane as an internal standard.
c A reduced amount (7.5 mmol) of 2-PrOH was used.
propanol (80 equiv) at 120 °C for 3 or 24 hours (Scheme 1,
entries 1–3). Reduction of 2-bromonaphthalene (1e) under
the standard conditions suffered from a relatively large
amount (6%) of formation of 1,2′- and 2,2′-binaphthyls (3e),
giving reduction product 2e only in 85% yield (Scheme 1,
entry 4). This must be due to high reactivities of 1e and 2e
towards radicals, accepting addition of 2-naphthyl radical
more readily than monocyclic benzene derivatives. Use of
an increased amount (240 equiv) of 2-propanol suppressed
the side reaction to an acceptable level (1%) and raised the
yield of 2e to 93% (Scheme 1, entry 5). In the reaction of 4-
bromo-N,N-dimethylaniline (1f) under the standard condi-
tions (24 h), a large amount (8%) of a dimer of 1f, N,N′-di-
methyl-N,N′-diphenylethylenediamine, was produced,
probably through homocoupling of N-methyl-N-phenyl-
aminomethyl radical. The side reaction was suppressed
again by use of 240 equivalents of 2-propanol (Scheme 1,
entry 6). The reduction is tolerant towards carboxylic acids
and alkynes (Scheme 1, entries 7 and 8). Worthy of note is
the stability of alkynes in this reaction as they are frequent-
ly incompatible with transition-metal-catalyzed reduc-
tions. Heteroaryl bromides are also reduced, though a larger
amount (0.4 equiv) of t-BuOOt-Bu was required (Scheme 1,
entries 9 and 10). As for hexabromobenzene (1k), all the
bromine atoms are converted into hydrogen atoms, using
appropriate amounts of the reagents (Scheme 1, entry 11).
The reduction is applicable also to iodobenzene but is reluc-
tant for chlorobenzene (8% yield with 13% conversion)
(Scheme 1, entries 12 and 13), and thus selective reduction
of aryl bromides over chlorides is possible (Scheme 1, entry
14). However, aryl chlorides are reduced when they have a
low-lying LUMO as in the case with 3-chloropyridine (1′′m)
and 4-chlorobiphenyl (1′′n), the LUMOs of which are low-
ered, respectively, by the electron-deficient character of the
pyridine ring and a conjugating substituent (Scheme 1, en-
tries 15 and 16). The result that a chlorine atom on biphenyl
is removed shows that the reduction is a promising method
to detoxify polychlorobiphenyls (PCB).1
The reduction of the aryl bromides shown in Scheme 2
under the standard conditions induced side reactions other
than the biaryl formation. Thus, ketone (1o), trifluorometh-
yl (1p), cyano (1q), alkene (1r), and thiazole (1s) moieties
suffered, respectively, from reduction into alcohol (1o), hy-
drodefluorination (1p), conversion into amide (1q), hydro-
hydroxymethylation (1r), and nucleophilic aromatic substi-
tution at 2-position (1s). All these side reactions are sup-
pressed by lowering the reaction temperature from 120 °C
to 50 °C by use of t-BuON=NOt-Bu as a t-BuO• source (cf. Ta-
ble 1, entry 4), leading to high yields of the reduction prod-
ucts.
The reduction is considered to proceed through a mech-
anism similar to that proposed by Bunnett and co-workers.4
As shown in Scheme 3, thermal homolysis of t-BuOOt-Bu
gives t-BuO•, which abstracts H• from cesium isopropoxide
(steps a and b). Single-electron transfer (SET) from the re-
sulting acetone ketyl I to ArX 1 gives anion radical,
Cs+[ArX]•– II, which undergoes homolysis to give Ar• III and
CsX (step c and d). Ar• III abstracts H• from cesium iso-
propoxide to be converted into reduction product 2 and re-
generate ketyl I (step e). Otherwise, Ar• III reacts with ArX
1, and in some cases also with ArH 2, to give ArAr 3. Thus,
the selectivity for 2 over 3 should depend on reaction rates
of step e and addition of Ar• to the aromatic rings. Actually,
the selectivity is higher when concentration of cesium iso-
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Cs2CO3 (1.2 equiv)
t-BuOOt-Bu (0.2 equiv)
+
Ar–X
Ar–H
120 °C
OH
1
2
(80 equiv)
Substrate (Product), Entry Number, Yield, Time
Br
Br
1b
1) 95% (3 h)
Br
1c
2) 92% (3 h)
Br
1d
1e
3) 98% (24 h)
4) 85% (3 h)
5) 93% (24 h)a
Br
Me2N
Br
1f
HO2C
Br
1g
Br
1h
N
1i
Hex
6) 95% (24 h)a
7) 92% (24 h)
8) 90% (24 h)
9) 90% (24 h)b
Br
Br
Br
Br
H
H
N
Br
1j
Br
H
H
I
Cl
1"b
13) 8% (3 h)
HN
1k
1'b
12) 100% (3 h)
Br
H
H
10) 85% (24 h)b
11) 87% (24 h)c
product
Cl
Br Cl
H
Cl
1"m
15) 100% (3 h)
Cl
N
1l
1"n
product
14) 93% (3 h)
16) 90% (3 h)
Scheme 1 Reduction of aryl halides using t-BuOOt-Bu as a radical initiator. Reagents and conditions: The reaction was carried out under a nitrogen
atmosphere at 120 °C for 3 or 24 h using an aryl halide 1 (0.25 mmol), 2-PrOH (1.5 mL, 0.020 mol), Cs2CO3 (0.30 mmol), and t-BuOOt-Bu (0.050
mmol). The yields were determined by GC using decane as an internal standard. For products having a relatively high boiling point, the yields of the
isolated products are given (entries 7, 8, 10, and 16). a 2-PrOH (4.6 mL, 60 mmol) was used. b t-BuOOt-Bu (0.10 mmol) was used. c t-BuOOt-Bu (0.20
mmol) and Cs2CO3 (1.8 mmol) were used.
Cs2CO3 (1.2 equiv)
t-BuON=NOt-Bu (0.2 equiv)
Ar–Br
+
Ar–H
50 °C, 3 h
OH
1
2
(80 equiv)
Substrate, Entry Number, Yield
O
N
S
Br
1s
Br
1o
F3C
Br
1p
NC
Br
1q
Br
1r
1) 94%
2) 92%
3) 81%
4) 95%a
5) 89%
Scheme 2 Reduction of aryl halides using t-BuON=NOt-Bu as a radical initiator. Reagents and conditions: The reaction was carried out under a nitrogen
atmosphere at 50 °C for 3 h using an aryl bromide 1 (0.25 mmol), 2-PrOH (1.5 mL, 0.020 mmol), Cs2CO3 (0.30 mmol), and t-BuON=NOt-Bu (0.050
mmol). The yields were determined by GC using decane as an internal standard. a 2-PrOH (4.6 mL, 60 mmol) was used.
proxide is higher (cf. Table 1, entries 1 vs. 5 and 6 vs. 1). The
reactivity order of aryl halides is fairly consistent with SET
mechanism (step c): aryl iodides and bromides are more re-
active than aryl chlorides, which are reduced only when
their LUMO energy levels are lowered (cf. Scheme 1, entries
13, 15, and 16).
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References and Notes
1/2 t-BuOOt-Bu
O
(1) (a) Harrad, S.; Robson, M.; Hazrati, S.; Baxter-Plant, V. S.;
Deplanche, K.; Redwood, M. D.; Macaskie, L. E. J. Environ. Monit.
2007, 9, 314. (b) Safe, S. H. Crit. Rev. Toxicol. 1994, 85, 131.
(2) For overview on the methods to reduce aryl halides into arenes,
see: Smith, M. B. March's Advanced Organic Chemistry; Wiley:
Hoboken, 2013, 7th ed., 647–648.
(3) For a recent example, see: Bhattacharjya, A.; Klumphu, P.;
Lipshutz, B. H. Org. Lett. 2015, 17, 1122; and references cited
therein.
(4) (a) Bunnett, J. F.; Wamser, C. C. J. Am. Chem. Soc. 1967, 89, 6712.
(b) Tomaselli, G. A.; Cui, J.-J.; Chen, Q.-F.; Bunnett, J. F. J.
Chem. Soc., Perkin Trans. 2 1992, 9. (c) Tomaselli, G. A.;
Bunnett, J. F. J. Org. Chem. 1992, 57, 2710. (d) Bunnett, J. F. Acc.
Chem. Res. 1992, 25, 2.
(5) A combination of LiAlH4 as a reductant with t-BuOOt-Bu as a
radical initiator is used for reduction of aryl halides under pho-
toirradiation, see: (a) Beckwith, A. L. J.; Goh, S. H. J. Chem.
Soc., Chem. Commun. 1983, 905. (b) Beckwith, A. L. J.; Goh,
S. H. J. Chem. Soc., Chem. Commun. 1983, 907.
(6) p-Methoxyphenyl radical possibly reacts also with anisole (2a).
However, it would give p-(p-methoxyphenyl)anisole in addition
to ortho and meta isomers. No generation of the para isomer
shows that such a reaction hardly took place under the reaction
conditions.
(7) The half-life of t-BuOOt-Bu is reported to be more than 1000 h
even at 80 °C. See: Walling, C. Tetrahedron 1985, 41, 3887.
(8) t-BuON=NOt-Bu is reported to undergo decomposition into
t-BuO• and N2 with t1/2 = 29 min at 65 °C. See: Kiefer, H.; Traylor,
T. G. Tetrahedron Lett. 1966, 7, 6163.
Cs+ [Ar–X] • –
Ar–X
1
c
a
II
b
t-BuO•
d
OCs
I
t-BuOH
H
CsX
OCs
e
Ar •
Ar–H
2
III
CsHCO3
H
Cs2CO3
H
OCs
OH
Scheme 3 A plausible reaction mechanism
In conclusion, we have developed a simple method to
reduce aryl halides into arenes with high functional-group
tolerance, where a radical chain mechanism initiated by t-
BuO• is operative, employing 2-propanol and Cs2CO3 as a re-
ductant/solvent and a base, respectively. This method is ex-
pected to be utilized for detoxification of harmful halogen-
containing compounds such as PCB.
(9) General Procedure
To a 3 mL vial equipped with a stir bar in a glove box were
added successively an aryl halide 1 (0.25 mmol), 2-PrOH (1.5
mL, 0.020 mol), Cs2CO3 (97.7 mg, 0.30 mmol), and t-BuOOt-Bu
(8.8 mg, 0.050 mmol). The vial was taken out of the glove box
and stirred at 120 °C for 3 or 24 h. Decane was added to the
reaction mixture as an internal standard for GC analysis. After
dilution with EtOAc (1.0 mL), an aliquot was subjected to GC
analysis. For products having a boiling point that is high enough
not to be lost in evacuation process, addition of H2O (20 mL)
was followed by extraction with EtOAc (3 × 20 mL). The com-
bined organic layer was dried over MgSO4, filtered, and concen-
trated in vacuo. The residue was subjected to silica gel chroma-
tography (PTLC) to give the corresponding arene 2.
Acknowledgment
This work has been supported financially in part by Grant-in-Aid for
Challenging Exploratory Research (26620082 to E.S.). R.U. thanks the
JSPS for a Research Fellowship for Young Scientists.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561342.
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