Copper-catalyzed carbochlorination or carbobromination via radical cyclization of aryl amines

Article abstract of DOI:10.1016/j.tetlet.2016.02.054

A copper-catalyzed radical carbochlorination or carbobromination is reported. Intramolecular cyclization occurred through aryl radicals generated in situ from bench-stable aryl amines with aqueous hydrogen halides as the halogen sources. A variety of (3-h

Full text of DOI:10.1016/j.tetlet.2016.02.054

Tetrahedron Letters 57 (2016) 1438–1441
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Copper-catalyzed carbochlorination or carbobromination via radical
cyclization of aryl amines
a,
Jianing Ouyang a, Xiaolong Su a, Yu Chen b, Yaofeng Yuan a, , Yi Li
⇑
⇑
a Department of Chemistry, Fuzhou University, Fuzhou 350116, China
b Department of Chemistry and Biochemistry, Queens College & The Graduate Center, City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed radical carbochlorination or carbobromination is reported. Intramolecular cyclization
occurred through aryl radicals generated in situ from bench-stable aryl amines with aqueous hydrogen
halides as the halogen sources. A variety of (3-halomethyl)-1,2-dihydrobenzofuran derivatives were pre-
pared in up to 92% yield through this one-pot protocol utilizing widely available starting materials.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 3 December 2015
Revised 2 February 2016
Accepted 15 February 2016
Available online 15 February 2016
Keywords:
Copper catalysis
Radical cyclization
Aryl amines
Hydrogen halides
(3-Halomethyl)-1,2-dihydrobenzofuran
Radical cyclizations followed by trapping with radical scav-
engers have been proven to be a powerful and versatile way for
construction of mono- or polycyclic compounds bearing additional
functional groups.1 Featured with mild reaction conditions and
high regioselectivities, intramolecular radical addition of aryl rad-
icals2 to the O-tethered C–C double bonds and subsequent trapping
by halogen sources would probably be one of the most direct
strategies to (3-halomethyl)-1,2-dihydrobenzofuran derivates.
Early in 1987, Pattenden and coworkers documented a radical
trapping methodology to the synthesis of (3-chloromethyl)-1,2-
dihydrobenzofuran or (3-bromomethyl)-1,2-dihydrobenzofuran.3
This protocol was based on the irradiation of an organocobalt com-
plex with excess amount of methanesulfonyl chloride (7 equiv) or
bromotrichloromethane (10 equiv) as halogen sources (Fig. 1a).
Separately in 2006 and 2014, Fagnoni group and Yoshimi group
reported atom-economical approaches to the synthesis of (3-halo-
methyl)-1,2-dihydrobenzofuran derivates via photolysis of aryl
chlorides, aryl bromides or aryl iodides, albeit with limited sub-
strate scopes and moderate regioselectivities (Fig. 1b).4 Mejis and
Beckwith group developed alternative methods for the formation
of these compounds through radical cyclization starting from aryl
diazonium salts, with stoichiometric amount of corresponding
cupric halides acting both as the radical initiators and halogen
sources (Fig. 1c).5a–d With cupric halides as the SET (single
electron-transfer) reagents, aryl radicals were generated from the
aryl diazonium salts and underwent further intramolecular
cyclization and halogenation. Given the fact that most diazonium
salts are explosive and relatively difficult to store and handle,
Wang group explored the use of aryl amines for the generation of
the corresponding aryl diazonium salts in situ.6a,b,f Recently,
Studer and coworkers disclosed an efficient carboiodination reac-
tion via intramolecular radical cyclization of aryl diazonium salts
which were generated in situ from aryl amines.7 In an effort to
develop a facile access to 3-(halomethyl)-2,3-dihydrobenzofuran
analogues, we enclosed herein a search for a useful copper-catalyzed
Previous strategies:
O
initiation
(a)
Cl
MeSO2
[Co]
Br
or C Cl3
O
O
hv
(b)
(c)
Cl(Br)
Cl Br
(
)
O
CuCl2
Br
or Cu
2
N2BF4
This work:
O
O
Cat. Cu (I)
(d)
aq HCl(Br)
t-BuONO
Cl Br
( )
NH2
⇑
Corresponding authors.
Figure 1. Radical carbochlorination/carbobromination.
http://dx.doi.org/10.1016/j.tetlet.2016.02.054
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

J. Ouyang et al. / Tetrahedron Letters 57 (2016) 1438–1441
1439
Table 1
At the outset, we carried out the reaction without any metal
catalyst, and no desired product was formed (entry 1, Table 1).
We then tried the reaction in the standard Meerwein arylation
condition with CuCl2 as the catalyst. Disappointingly, no expected
cyclization product was formed (entry 2, Table 1). However, we
were delighted to find that CuCl was capable of catalyzing the reac-
tion to give the desired product, albeit in a low yield of 24% (entry
3, Table 1). Several other copper(I) salts or iron salts were further
tested, but showed negative catalytic reactivity in this reaction
(entries 4–7, Table 1). It is worth noting that n-Bu4NI which per-
formed well as a SET reagent7,8 was not a suitable initiator for car-
bochlorination, affording the carboiodination product only (entry
8, Table 1). The reaction did not proceed in CH2Cl2 or CH3OH (entry
9 and 10, Table 1), probably due to the poor solubility of diazonium
salt intermediates in these solvents. Moderate yield was obtained
in DMSO (entry 11, Table 1). To our delight, the yield of 2a was
improved dramatically when switching to acetone as the solvent
(entry 12, Table 1). Increasing the amount of aq HCl to 2.5 equiv
resulted in an obviously higher yield (86%, entry 13, Table 1), while
a further increase (3.0 equiv) gave a slightly lower yield of 74%
(entry 14, Table 1). Delightedly, Cu(CH3CN)4BF4 was proved to be
the superior catalyst with 92% yield (entry 15, Table 1).
Optimization of the reaction conditionsa
t-BuONO (1.1 eq)
Cl
aq H (2.0 eq)
O
O
CuCl (10 mol%)
CH3CN
NH2
1a
0
oC to rt, 3h
2a
Cl
Entry Variations from the standard conditions
Yieldb,c
(%)
1
2
3
4
5
6
7
8
Without CuCl
CuCl2 instead of CuCl
None
Fe(II) or Fe(III) salts instead of CuCl
CuTc instead of CuCl
CuI instead of CuCl
N.P.
N.P.
24
N.P.
N.P.
N.P.
N.P.
N.P.
Trace
N.P.
53
77
86
74
92
CuBr instead of CuCl
n-Bu4NI instead of CuCl
CH2Cl2 instead of CH3CN
CH3OH instead of CH3CN
DMSO instead of CH3CN
Acetone instead of CH3CN
2.5 equiv HCl, with acetone as the solvent
3.0 equiv HCl, with acetone as the solvent
9
10
11
12
13
14
15
Cu(CH3CN)4BF4 instead of CuCl, with 2.5 equiv HCl and
acetone as the solvent
Having established the optimal condition (entry 15, Table 1), we
evaluated the scope and limitations of this carbochlorination. A
variety of aryl amines have been explored as the starting materials
for this transformation, and the results are listed in Scheme 1.
The reaction scope with the substituted 2-allyloxyaniline (1)
was first investigated. A variety of substituents/functional groups
on the aromatic moiety, ranging from the electron-donating groups
(2b–2d, Scheme 1) to electron-withdrawing groups (2e–2g,
Scheme 1), remained intact during the reaction and generally the
expected cyclic carbochlorination products were obtained in good
to excellent yields. Notably, the substrate with the methoxyl group,
which was not synthetically efficient in the reported radical
a
Reaction conditions: t-BuONO (0.55 mmol) was added to a mixture of 1a
(0.50 mmol), the catalyst (0.05 mmol), and aq HCl in solvent (5.0 mL) at 0 °C, and
then the reaction system was warmed to room temperature and stirred for 3 h.
b
Yield of isolated 2a.
N.P.: no product, while 1a was all consumed to the corresponding diazonium
c
salt.
radical cyclization protocol employing widely available aqueous HCl
or HBr as the halogen sources and bench-stable aryl amines as start-
ing materials (Fig. 1d). This methodology featured with easy-handle
protocol and cheap halogen sources. Key results for the reaction
optimization are summarized in Table 1.
2
R
t-BuONO (1.1 eq), aq HCl (2.5 eq)
Cu(CH CN) BF (10 mol%)
3
Y
3
Y
R
3
4
4
1
R
n
1
n
R
o
acetone, 0 C to rt, 3 h
2
NH
R
2
Cl
1
2
R
O
O
O
O
O
O
Me
F
MeO
MeOCO
2b
2f
2a (92%)
2e (91%)
(84%)
(87%)
2c (87%)
Cl
Cl
Cl
Cl
Cl
Cl
2d
Cl
(88%)
O
F
O
Cl
2h (89%)
Cl
2g (87%)
anti:syn 10:1
O
O
O
O
2l
Cl
2j
2k
Cl
(68%)
(88%)
Cl
(91%)
2i
(85%)
Cl
Ph
d.r. 1.3:1
d.r. 4.5:1
d.r. 5.5:1
O
O
Ts
N
O
S
2m (70%)
2n
2p (61%)
(7%)
Me
2o
2s
(90%)
(72%)
Cl
Cl
Cl
Cl
anti:syn 9:1
O
O
3
Cl
2t (64%)
2q (50%)
Cl
Cl
Cl
2r (54%)
Scheme 1. Radical carbochlorination.

1440
J. Ouyang et al. / Tetrahedron Letters 57 (2016) 1438–1441
2
R
Br
t-BuONO (1.1 eq), aq H (2.5 eq)
3
Y
3
Y
R
Cu(CH CN) BF (10 mol%)
3
4
4
1
R
n
1
n
R
o
acetone, 0 C to rt, 3 h
2
NH
2
R
Br
3
1
R
O
O
O
O
O
Br
Br
3h
3i
(90%)
3a (92%)
(91%)
Br
Br
3j
Br
(91%)
Br
Br
Ph
trans:cis 10:1
d.r. 3.5:1
Ts
N
S
O
3o (92%)
3m (71%)
3n
3p
(35%)
(21%)
O
Br
trans:cis 9:1
O
Br
3t
(78%)
3s
(80%)
Br
Scheme 2. Radical carbobromination.
carboiodination,7 was well-tolerated in this optimized condition to
give the desired product in 87% yield (2c, Scheme 1). Substituents
on the allyl moiety were also investigated. Substrates with
10-methyl group underwent efficient radical cyclization, providing
the desired compound 2h in 89% yield with good dr of 10:1. A pro-
duct with quaternary carbon centers was formed smoothly from
20-methyl substituted 2-allyloxyaniline (85%, 2i, Scheme 1).
was obtained solely in 64% yield, presumably formed through
Meerwein arylation pathway.
As portrayed in Scheme 2, this methodology proved to be
equally successful for the intramolecular carbobromination with
a wide range of 2-allyloxylanilines (up to 92% yield). When aq
HBr was employed instead of aq HCl, copper-catalyzed intramolec-
ular radical carbobromination occurred smoothly to give the cyclic
bromides (3a–3t, Scheme 2). Likely due to the more readily
electrophilic nature of bromide than chloride, the yields of carbo-
bromination products were generally higher than the correspond-
ing carbochlorination analogues.
With 30-methyl group, the reaction also occurred efficiently in
88% yield though the dr was poor (2j, Scheme 1). When switching
to more sterically hindered 30-phenyl group, the corresponding
product 2k was synthesized in excellent yield with a satisfactory
dr value of 4.5:1. Attempt to cascade radical dicyclization was
unsuccessful with diallyl aryl amine, and only carbochlorination
product 2l was isolated in moderate yield with dominantly one
single isomer. 10,30-Bisubstituted allyl substrate showed similar
reactivity to give the desired product 2m in a moderate yield.
Comparably, 30,30-dimethyl 2-allyloxyaniline is much less reactive
with a disappointing yield of 7% (2n, Scheme 1). To our delight,
besides O-tethered substrates, 2-allyl anilines with CH2-, N-, or
S-connectors readily underwent carbochlorination, leading to the
synthesis of the corresponding indoline 2o, benzothiophene 2p,
2q, or 2r, in gratifying yields. We then studied the 6-exo radical
cyclization and the desired 2s was isolated in 72% yield.
Unfortunately, further investigation of the 7-exo cyclization could
not proceed under the applied conditions, and aryl chloride 2t
To shed light on the mechanism of the above reactions, we con-
ducted the following experiments (Scheme 3).
Under the identical carbochlorination conditions, additional
5.0 equiv TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was added
as radical scavenger. As anticipated, the adduct 4a formed domi-
nantly in 85% yield, with no detection of carbochlorination product
2a by crude NMR (Scheme 3a). This result strongly supports an
involvement of a radical mechanism in the copper-catalyzed car-
bochlorination. 2-Allyloxylphenyl diazonium tetrafluoroborate
was employed under modified conditions with different chloride
sources. With 1.1 equiv cuprous chloride acting both as the catalyst
and chloride source, carbochlorination product 2a formed merely in
30% yield. Contradistinctively, with Cu(CH3CN)4BF4 (10 mol %) as
the catalyst and 1.1 equiv (aq HCl) or 1.1 equiv Bu4NCl as the
t-BuONO (1.1 eq)
aq HCl (2.5 eq)
O
O
+
(a)
(b)
N
O
O
N
NH2
1a
Cu(CH3CN)4BF4 (10 mol%)
4a
(5.0 eq.)
85%
O
O
conditions
Cl
O
N2BF4
2a
CuCl (1.1 eq): 30%
aq HCl (1.1 eq), Cu(CH3CN)4BF4 (10 mol%): 89%
Bu4NCl (1.1 eq), Cu(CH3CN)4BF4 (10 mol%): 93%
Cu(CH3CN)4BF4
O
O
(10 mol%)
(c)
Cl
Br
Bu4NCl (1.1 eq)
Bu4NBr (1.1 eq)
N2BF4
2a
3a
17 : 83
Scheme 3. Mechanistic study.

J. Ouyang et al. / Tetrahedron Letters 57 (2016) 1438–1441
1441
O
O
References and notes
O
-N2
t-BuONO
HX
N2X
NH2
SET
I
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Cu(I)
Cu(II)X
O
O
ISET
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Figure 2. Proposed mechanism for copper-catalyzed carbochlorination.
chloride source, 89% or 93% yield of 2a was achieved, respectively,
(Scheme 3b). As shown in Scheme 3c, 2a and 3a were formed in a
ratio of 17:83 in the presence of n-Bu4NCl (1.1 equiv) and n-Bu4NBr
(1.1 equiv).
Based on these studies, a postulated reaction pathway is illus-
trated in Figure 2. Firstly, reaction of aryl amine with t-BuONO
and a hydrogen halide generated the corresponding diazonium
salt, which was subsequently reduced to aryl radical I by Cu(I)
through a SET procedure. Next, intramolecular radical cyclization
of I led to the alkyl radical II. The latter was oxidized by Cu(II)X
and the final product was formed through a halogen transfer (ISET)
process.9
In summary, we have disclosed efficient copper-catalyzed
intramolecular radical carbochlorination or carbobromination
reaction, using aryl amines as starting materials with aqueous
hydrogen halides as the readily available halogen source, providing
a facile synthetic approach to relevant 3-halomethyl-2,3-dihy-
drobenzofuran derivatives. The ready availability of starting mate-
rials, easy-handle protocol, and cheap halogen sources make the
current methodology particularly interesting for synthesis.
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Acknowledgments
Financial support from National Natural Science Foundation of
China (21402028) and Fuzhou University (022537) is gratefully
acknowledged.
Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.02.
054.