Copper-catalyzed double intramolecular ullmann coupling for the synthesis of diastereomerically and enantiomerically pure 4b,9b-dihydrobenzofuro[3,2-b]benzofurans

Article abstract of DOI:10.1002/ejoc.201501132

The copper-catalyzed double intramolecular Ullmann coupling of syn-1,2-bis(2-bromoaryl)ethane-1,2-diols with catalytic amounts of Cu^II oxinate as the copper source, K₃PO₄ as a base, and KI as a reductant in aqueous acetoni

Full text of DOI:10.1002/ejoc.201501132

FULL PAPER
DOI: 10.1002/ejoc.201501132
Copper-Catalyzed Double Intramolecular Ullmann Coupling for the Synthesis
of Diastereomerically and Enantiomerically Pure 4b,9b-Dihydrobenzofuro-
[3,2-b]benzofurans
[a]
[a]
[a]
Hans-Georg Imrich, Jürgen Conrad, and Uwe Beifuss*
Keywords: Homogeneous catalysis / Cyclization / Copper / Fused-ring systems / Polycycles / Oxygen heterocycles
The copper-catalyzed double intramolecular Ullmann cou-
diastereomerically and enantiomerically pure form and
yields of up to 90%. The substrates can be obtained in both
diastereomerically and enantiomerically pure form by cata-
lytic dihydroxylation of the corresponding (E)-stilbenes.
pling of syn-1,2-bis(2-bromoaryl)ethane-1,2-diols with cata-
II
lytic amounts of Cu oxinate as the copper source, K
3
PO
4
as
a base, and KI as a reductant in aqueous acetonitrile selec-
tively delivers 4b,9b-dihydrobenzofuro[3,2-b]benzofurans in
Introduction
O-nucleophiles or two N-nucleophiles, and the reaction of
dinucleophiles with two aryl halides. Only isolated cases of
transition-metal-catalyzed intramolecular diarylations of
diols, diamines, and related compounds have been reported
The copper-catalyzed Ullmann coupling[1] has been de-
veloped into an important synthetic tool for efficient O-
arylation with aryl halides. The method allows the forma-
tion of diaryl ethers as well as the synthesis of alkyl aryl
ethers in high yields.[ As well as intermolecular couplings,
copper-catalyzed intramolecular O-arylations are also
[8]
to date.
Some natural products containing a 4b,9b-dihydrobenzo-
furo[3,2-b]benzofuran moiety are known, including the
2]
anti-inflammatory baeckeins F–I from the roots of Baeckea
[
3]
known. They allow the synthesis of a number of O-het-
[9a]
frutescens,
la.
and cyclorocaglamide from Aglaia oligophyl-
[
3a]
erocycles, including benzo[b]furans,
2,3-dihydrobenzo-
[9b]
Synthetic 4b,9b-dihydrobenzofuro[3,2-b]benzofurans
[
3b]
[3c]
[3d–3f]
furans, 1,2-benzisoxazoles, benzo[d]oxazoles,
4H-
have been shown to have remarkable photochromic proper-
[
3g]
[3b]
1
-benzopyrans,
chromans,
2,3-dihydro-1,4-benzoxa-
[10a,10b]
ties.
Other 4b,9b-dihydrobenzofuro[3,2-b]benzofuran
[
3h]
[3i]
zines,
9H-xanthene-9-ones,
2,3,4,9-tetrahydro-1H-
derivatives are useful ligands for the Pd-catalyzed telomeriz-
[
3j]
[3k]
xanthen-1-ones,
2,3,4,9-tetrahydro-benzoxazocines,
[10c]
ation of 1,3-butadiene and methanol,
catalyzed carbonylation of methanol.
as well as the Rh-
Only a few syn-
and 12H-chromeno[2,3-b]quinolin-12-ones.[ Furthermore,
it has been established that copper-catalyzed O-arylations
can be combined with other transformations in domino re-
3l]
[10d]
thetic methods are available for the preparation of the
[10]
4
b,9b-dihydrobenzofuro[3,2-b]benzofuran skeleton. They
[
4]
actions. This approach has proved valuable for the prepa-
include the Claisen rearrangement of 1,4-diaryloxy-2-
[
5]
ration of numerous heterocyclic systems. Some typical ex-
amples include benzofurans,
[10a,10b,11a–11c]
butynes,
the oxidative cyclization of 2,2Ј-di-
[5a]
benzoxazoles,[5b,5c] spiro-
3,4-dihydrodibenzo[b,d]furan-1(2H)-
[11d–11f]
hydroxystilbenes
and 8,8Ј-hydroxylated binaphth-
[
5d–5f]
cyclic oxindoles,
[11g]
ols,
the reductive coupling/cyclization of 2-hydroxy-
[
5g]
[5h,1]
[5j]
ones, 4H-chromenes,
1,4-benzodioxanes, 1,4-benz-
[11h]
[11i]
acetophenones
and 2-hydroxybenzaldehydes,
and the
[
5j]
1,4-benzoxathiines,[5k] and dibenzoxazepin-
oxazines,
[11j]
condensation between glyoxal and p-cresol.
[
5l]
ones. In contrast, the use of chiral substrates in inter-
as well as intramolecular copper-catalyzed O-arylations has
been investigated less.[ Another research area that has not
been fully developed is that of double Ullmann couplings.
A few examples of intermolecular double couplings are
In this paper, we present a new approach to the synthesis
of bisannulated bisheterocyclic systems. Our approach in-
volves a double intramolecular cyclization of 1,2-bis(2-
haloaryl)-substituted 1,2-bisnucleophiles A, such as 1,2-di-
ols, 1,2-disulfides, 1,2-diamines, 1,2-amino alcohols, 1,2
aminothiols, and similar substrates, to give B (Scheme 1).
Obviously, the double intramolecular cyclizations are not
restricted to 1,2-bis(2-haloaryl)-substituted 1,2-bisnucleo-
philes A, but can also be applied to a multitude of other
bis(2-haloaryl)-substituted bisnucleophiles C (Scheme 1).
In this study, we demonstrate that this concept can be
realized, using the copper-catalyzed double intramolecular
6]
[
7]
known, such as the reaction of aryl dihalides with two
[
a] Bioorganische Chemie, Institut für Chemie, Universität
Hohenheim,
Garbenstraße 30, 70599 Stuttgart, Germany
E-mail: ubeifuss@uni-hohenheim.de
https://bioorganische-chemie.uni-hohenheim.de/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501132.
7718
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7718–7734

Copper-Catalyzed Double Intramolecular Ullmann Coupling
Results and Discussion
The reaction of syn-1,2-bis(2-bromophenyl)ethane-1,2-
diol (syn-4a) to give 4b,9b-dihydrobenzofuro[3,2-b]benzo-
furan (5a) was chosen as the model reaction. This substrate
is particularly suitable since it can easily be obtained in ra-
cemic as well as enantiomerically pure form by dihydrox-
ylation of the corresponding (E)-stilbene [i.e., (E)-2a]. For
the synthesis of symmetrical as well as unsymmetrical sub-
stituted (E)-stilbenes, a number of procedures, such as the
[
12]
McMurry coupling,
the homocoupling of benzyl hal-
[
13]
ides, and the Wittig–Horner olefination have been estab-
Scheme 1. The double intramolecular heteroarylation of syn-1,2-
bis(2-haloaryl)substituted 1,2-bisnucleophiles and related sub- lished.
strates – a new approach to the synthesis of bisannulated bishetero-
[
14]
The required (E)-stilbene [i.e., (E)-2a] was ob-
tained either by McMurry coupling of 2-bromobenz-
aldehyde (1a) in 84% yield, or by homocoupling of 2-
bromobenzyl bromide (3a) in 76% yield (Scheme 3).
Upjohn dihydroxylation
0.26 mol-%) and N-methylmorpholine N-oxide (NMO;
equiv.) delivered racemic 1,2-diol rac-syn-4a in 90% yield.
Enantiomerically pure 1,2-diol (+)-syn-4a was prepared in
cyclic systems.
[
15]
of E-2a with K OsO (OH)
Ullmann coupling of syn-1,2-bis(2-haloaryl)ethane-1,2-di-
ols D to give 4b,9b-dihydrobenzo[3,2-b]furobenzofurans E
as an example. It was envisaged that only syn-1,2-bis(2-
haloaryl)ethane-1,2-diols D would undergo intramolecular
bis-O-arylation to give E; anti-1,2-bis(2-haloaryl)ethane-
2 2 4
(
2
8
6% yield using the enantioselective Sharpless dihydrox-
[
16]
ylation.
1,2-diols F were expected to deliver the products of intra-
With the model substrates in hand, the copper-catalyzed
double intramolecular Ullmann coupling was studied. For
this purpose, rac-syn-4a was subjected to conditions that
have proved successful for intramolecular O-arylations,[
i.e., with CuI (10 mol-%), an additive (20 mol-%), such as
molecular mono-O-arylation G (Scheme 2).
3]
8-hydroxyquinoline, DMEDA (N,NЈ-dimethylethylenedi-
amine), or 1,10-phenanthroline, and a base (4 equiv.), like
Cs CO , K PO , or K CO , in toluene as a solvent at
2
3
3
4
2
3
110 °C for 3 d (Table 1, entries 1–6). The outcome of these
initial experiments was disappointing, since the yield of the
double Ullmann product did not exceed 5%. It turned out
that the polarity of the solvent plays a crucial role. When
the reactions were run in the polar aprotic solvent DMF,
the yields improved considerably. The reaction of rac-syn-
4
a with CuI (10 mol-%), Cs CO (4 equiv.), and 8-hydroxy-
2 3
quinoline (20 mol-%) in DMF delivered rac-cis-5a in 34%
yield after 3 d at 120 °C (Table 1, entry 7). The reaction
time could be shortened from 72 h to 2 h without a signifi-
cant decrease of the yield (Table 1, entry 8). In the absence
of any ligand, rac-cis-5a was formed in 21% yield (Table 1,
Scheme 2. Bis-O-arylation of syn-1,2-bis(2-haloaryl)ethane-1,2-di-
ols and mono-O-arylation of anti-1,2-bis(2-haloaryl)ethane-1,2-di-
ols.
Scheme 3. Synthesis of syn-1,2-bis(2-bromophenyl)ethane-1,2-diol (4a) in racemic as well as enantiomerically pure form. LiHMDS =
lithium hexamethyldisilazide.
Eur. J. Org. Chem. 2015, 7718–7734
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7719

H.-G. Imrich, J. Conrad, U. Beifuss
FULL PAPER
Table 1. Optimization of the reaction of rac-syn-4a using CuI as the catalyst.[a]
Entry Base
Ligand (mol-%)
Solvent
T [°C]
Time [h]
Yield of rac-cis-5a [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
Cs
2
CO
PO
3
8-hydroxyquinoline (20)
8-hydroxyquinoline (20)
DMEDA (20)
1,10-phenanthroline (20)
8-hydroxyquinoline (20)
8-hydroxyquinoline (20)
8-hydroxyquinoline (20)
8-hydroxyquinoline (20)
–
toluene
toluene
toluene
toluene
toluene
toluene
DMF
DMF
DMF
DMF
DMF
110
110
110
110
110
110
120
120
120
25
72
72
72
72
72
72
72
2
5
1
1
2
–
K
3
4
Cs
2
Cs
2
CO
CO
3
3
K
2
CO
3
Na CO
2
3
–
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
CO
CO
CO
CO
CO
CO
CO
3
34
31
21
–
2
2
2
2
2
2
3
3
3
3
3
3
2
0
1
2
3
4
5
6
–
72
72
72
72
72
72
72
8-hydroxyquinoline (20)
8-hydroxyquinoline (20)
8-hydroxyquinoline (20)
8-hydroxyquinoline (20)
8-hydroxyquinoline (20)
8-hydroxyquinoline (20),
molecular sieves (4 Å)
8-hydroxyquinoline (20)
25
–
NMP
120
120
120
120
120
20
51
48
47
56
H
H
CH
CH
2
O
O
K
K
K
3
PO
PO
PO
4
4
4
2
3
3
3
CN
CN
3
17
K
3
PO
4
CH
3
CN/H
2
O, 1:1
120
72
68
[a] In all cases, 0.5 mmol of rac-syn-4a was used.
entry 9). Decreasing the reaction temperature to room tem- ligand under the conditions of Table 1, entry 17. To our de-
perature was counterproductive (Table 1, entries 10 and 11). light, the yield of rac-cis-5a improved to 81% (Table 2, en-
Subsequently, the influence of solvent and base was studied try 1). It seems reasonable to suppose that KI acts to reduce
2
+
+ [18]
in more detail.
Cu to Cu .
However, rac-cis-5a was also formed in
With Cs CO as the base, the yield increased to 51% 61% yield in the absence of KI (Table 2, entry 2).
2
3
when the reaction was run in H O (Table 1, entry 13). A
A further increase in the yield of rac-cis-5a was achieved
2
similar yield was achieved when Cs CO was replaced with when CuSO was replaced with copper bis(8-hydroxyquin-
2
3
4
II
[19]
2+
K PO as the base (Table 1, entry 14). Since K PO is a olate), also known as Cu oxinate. Cu can form a vari-
3
4
3
4
much cheaper base than Cs CO , all further reactions were ety of complexes with 8-hydroxyquinoline as
a
li-
Depending on the reaction conditions, com-
could also be run in CH CN without an appreciable drop plexes with one or two molecules of 8-hydroxyquinoline are
2
3
[
19a,19b]
run with K PO . The reaction with K PO as the base gand.
3
4
3
4
3
[
19b]
in the yield (Table 1, entry 15). Interestingly, the yield im- obtained.
In the presence of strongly coordinating
–
–
–
proved slightly to 56% when the transformation was carried anions like F , Cl , or Br , the formation of complexes of
–
–
–
out in the presence of molecular sieves (4 Å) (Table 1, en- the type Cu(C H NO)X (X = F , Cl , or Br ) is observed,
9
6
try 16). More remarkably, the yield increased to 68% when while in the absence of such anions Cu(C H NO) and
9
6
2
the transformation was run in a mixture of CH CN and Cu(C H NO) ·2H O
are
formed.
The
hydrate
3
9
6
2
2
H O (1:1 v/v), which forms a two-phase system under these Cu(C H NO) ·2H O loses water when it is heated to 28 °C
2
9
6
2
2
[19b]
conditions (Table 1, entry 17). All further experiments were to give the anhydrous compound Cu(C H NO) .
9
6
2
therefore carried out in a 1:1 mixture of water and an or- Cu(C H NO) is a planar complex that can exist in both
9
6
2
ganic solvent.
α and β forms. The α form consists of a chain of planar
The results presented in Table 1 show that the combina- Cu(C H NO) molecules, while the β form exists as a di-
9
6
2
[
19a]
tion of CuI (10 mol-%) as the copper source and 8-hydroxy- mer-like unit.
The pure α form undergoes a transforma-
[
19b]
quinoline as the ligand is suitable for the intramolecular tion into the β form when it is heated to 210 °C.
Since
the 8-hydroxyquinoline ligand can easily be exchanged for
I
bis-O-arylation of the model compound. So far, the Cu
[
19b]
salt/8-hydroxyquinoline system has been used for the aryl- other ligands,
these complexes, which are usually pre-
[
17a]
[17b]
ation of KOH
and nBu NOH,
of aliphatic pared in situ, are potential catalysts. In addition to the al-
4
[
3b]
[17c]
alcohols,
and also of phenols.
We wondered whether ready mentioned O-arylations, a variety of other reactions,
I
[19c]
the Cu catalyst could be replaced by a combination of a including C-vinylations of arylboronic acids,
Cu compound and a reductant (Table 2). For this purpose, ations of pyridine-2(1H)-ones,
rac-syn-4a was treated with a combination of CuSO4 imidazoles,
10 mol-%) and KI (4 equiv.) in the absence of any further benzyl alcohol and tert-butyl hydroperoxide,
N-aryl-
II
[19d]
[19e]
pyridazones
and
[
19f]
and the synthesis of methyl benzoates from
[
19g]
(
can be cat-
7720
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Eur. J. Org. Chem. 2015, 7718–7734

Copper-Catalyzed Double Intramolecular Ullmann Coupling
II
[a]
Table 2. Optimization of the reaction of rac-syn-4a using Cu /KI systems.
Entry
Cu source
mol-%)
KI
[equiv.]
Base
(equiv.)
Solvent
Yield of cis-5a
(
[%]
1
2
3
4
5
6
7
8
9
CuSO
4
4
(10)
(10)
4
–
4
–
4
4
4
4
4
4
4
2
1
0.2
4
4
K
K
K
K
3
3
3
3
PO
PO
PO
PO
4
4
4
4
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(3)
(2)
(1)
CH
CH
CH
CH
CH
3
3
3
3
3
CN/H
CN/H
CN/H
CN/H
CN/H
2
2
2
2
2
O
O
O
O
O
81
61
93
76
51
38
53
69
53
16
CuSO
II
Cu oxinate (10)
II
Cu oxinate (10)
II
Cu oxinate (10)
2 3
K CO
II
Cu oxinate (10)
K
K
K
K
K
3
3
3
3
3
PO
PO
PO
PO
PO
–
4
4
4
4
4
C
2
H
5
CN/H
2
O
II
Cu oxinate (10)
tBuOH/H O
2
II
Cu oxinate (10)
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
CN/H
2
O
O
O
O
O
O
O
O
O
II
Cu oxinate (10)
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
2
2
2
2
2
2
2
2
II
10
11
12
13
14
15
16
Cu oxinate (10)
II
[b]
Cu oxinate (10)
–
II
Cu oxinate (10)
K
K
K
K
K
3
3
3
3
3
PO
PO
PO
PO
PO
4
4
4
4
4
(4)
(4)
(4)
(4)
(4)
89
90
83
66
II
Cu oxinate (10)
II
Cu oxinate (10)
II
Cu oxinate (5)
[c]
–
–
[a] In all cases, 0.5 mmol of rac-syn-4a was used. [b] rac-syn-4a was recovered in 82% yield. [c] rac-syn-4a was recovered in 87% yield.
alyzed by CuII oxinate or by using a copper source in the
II
presence of 8-hydroxyquinoline as a ligand. With Cu oxin-
ate (10 mol-%) and K PO (4 equiv.) in a mixture of
3
4
CH CN and H O (1:1 v/v), the cyclization product was iso-
3
2
lated in 93% yield (Table 2, entry 3). Just as when CuSO4
was used as the catalyst, the product was also formed in the
absence of KI (Table 2, entry 4). It seems that the combina-
tion of CH CN and H O as a solvent system and K PO
3
2
3
4
as a base gives the best results (Table 2, entries 3 and 5–7).
Finally, we studied whether the amounts of K PO , KI, and
3
4
II
Cu oxinate could be decreased. Lowering the amount of
K PO from 4 to 3, 2, and 1 equiv. resulted in a marked
3
4
decrease in the yields (Table 2, entries 8–10). Not surpris-
ingly, the formation of rac-cis-5a was not observed at all in
the absence of base (Table 2, entry 11). Under these condi-
tions, rac-syn-4a was recovered in 82% yield. Our attempts
to lower the amount of KI were met with more success. It
turned out that the KI load could be decreased from 4 to 2
and 1 equiv., respectively, without any significant effect on
the yields (Table 2, entries 12 and 13). Even when the reac-
tion was run with as little as 20 mol-% KI, the yield of rac-
Scheme 4. Monitoring the progress of the transformation of rac-
syn-4a into rac-cis-5a using H NMR spectroscopy.
1
We assumed that the reaction proceeds in two discrete
cis-5a was 83% (Table 2, entry 14). Decreasing the amount steps. The first step is the intramolecular cyclization of rac-
of the copper catalyst was also tested. However, when the syn-4a to 2-aryl-3-hydroxy-substituted rac-cis-6a.[
20]
This
II
amount of Cu oxinate was decreased from 10 to 5 mol-%, substance can then undergo intramolecular cyclization to
the yield decreased by 27% (Table 2, entries 3 and 15). A deliver 4b,9b-dihydrobenzofuro[3,2-b]benzofuran (rac-cis-
control experiment confirmed that the reaction could not 5a). As an indicator signal for the substrate, the singlet at δ
be run in the absence of a copper catalyst. In this case, only = 5.3 ppm (which corresponds to the protons 1-H and 2-
87% of the starting material was isolated (Table 2, en- H of rac-syn-4a) was chosen (Scheme 4). The formation of
try 16). To optimize the reaction time, the progress of the intermediate rac-cis-6a was followed using the doublet at δ
model reaction was followed by 1H NMR spectroscopy = 5.85 ppm, which was assigned to 2-H of 6a. A character-
(Scheme 4).
istic signal for the product (i.e., rac-cis-5a) is the singlet res-
Eur. J. Org. Chem. 2015, 7718–7734
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7721

H.-G. Imrich, J. Conrad, U. Beifuss
FULL PAPER
onating at δ = 6.3 ppm. It corresponds to the protons 4b- cis-5a), obtained in 90% yield, was analyzed by chiral
[
21b]
H and 9b-H.
HPLC.
The two enantiomers could be separated, and
1
Analysis of the H NMR spectra taken at the outset of were found to be formed in a 1:1 ratio. HPLC analysis of
the reaction (0 min), and after reaction times of 30 min, 2 h, the product resulting from the reaction of pure (+)-syn-4a
2
d, and 3 d clearly shows that after just 30 min a consider- revealed that (–)-cis-5a was formed exclusively. The enantio-
able amount of rac-syn-4a (ca. 80%) had been transformed meric product [i.e., (+)-cis-5a] was not detected at all. These
into a ca. 1:2 mixture of rac-cis-5a and rac-cis-6a. It seems results clearly demonstrate that the new method can be used
that after 2 h, most of the substrate (ca. 95%) had been for the synthesis of enantiomerically pure 4b,9b-dihydro-
consumed. At this time, the ratio of rac-cis-5a and rac-cis- benzofuro[3,2-b]benzofurans. Next, the cyclization of the
6a was 1.2:1. The transformation of the remaining ca. 5% corresponding anti diol (i.e., meso-4a) was studied. Due to
of substrate rac-syn-4a into rac-cis-6a and the further cycli- steric restraints, we expected this compound to only un-
zation to rac-cis-5a proceeds remarkably slowly. Even after dergo intramolecular monoarylation. The required anti diol
a reaction time of 2 d, traces of rac-syn-4a and rac-cis-6a (i.e., meso-4a) was prepared by Wittig reaction between 2-
could be detected. At this time, the ratio of rac-cis-6a:rac- bromobenzaldehyde (1a) and (2-bromobenzyl)triphenyl-
cis-5a was ca. 1:20. Only after a reaction time of 3 d was phosphonium bromide (7) to give the diastereomerically
the transformation of rac-syn-4a into rac-cis-5a complete. pure (Z)-stilbene [i.e., (Z)-2a], and subsequent Upjohn di-
As a result, it turned out that the reaction time could not hydroxylation (Scheme 5). As expected, the reaction of anti
II
be decreased substantially.
1,2-diol meso-4a with Cu oxinate (10 mol-%) in the pres-
Having established optimized reaction conditions ence of K PO (4 equiv.) and KI (4 equiv.) at 120 °C for 3 d
3
4
(
Table 2, entry 13), we studied whether the new reaction (conditions of Table 2 entry 3) exclusively delivered trans-
could also be used for the synthesis of enantiomerically 2,3-disubstituted 2,3-dihydrobenzofuran rac-trans-6a as the
pure 4b,9b-dihydrobenzofuro[3,2-b]benzofurans, i.e., product of an intramolecular monoarylation in 46% yield.
whether the reaction of enantiomerically pure diol (+)-syn-
We wondered whether the reactivity of rac-syn-4b, i.e.,
exclusively delivers enantiomerically pure product the cyclization precursor with two chlorine atoms instead
[21a]
4a
(–)-cis-5a, or whether the transformation is accompanied by of two bromine atoms would be high enough to undergo
racemization. For this purpose, rac-syn-4a was subjected to intramolecular arylation(s). For this purpose, rac-syn-4b
the optimized reaction conditions, and the product (i.e., rac- was prepared in 80% yield by dihydroxylation of (E)-2b,
Scheme 5. Synthesis of anti 1,2-diol meso-4a and its copper-catalyzed monoarylation t0 giveo rac-trans-6a.
Scheme 6. Synthesis of rac-syn-4b and its reaction under copper-catalyzed conditions.
722
7
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Copper-Catalyzed Double Intramolecular Ullmann Coupling
Scheme 7. Synthesis of rac-syn-4c and its reaction under copper-catalyzed conditions.
which in turn was obtained in 65% yield by McMurry cou-
pling of 1b (Scheme 6). It turned out that rac-syn-4b did
not cyclize under the reaction conditions given in Table 2,
entry 3.
Next, the “mixed” cyclization precursor rac-syn-1-(2-
chlorophenyl)-2-(2-bromophenyl)ethane-1,2-diol (rac-cis-
4
2
c) was synthesized in 93% yield by dihydroxylation of (E)-
c, which was obtained by a Wittig–Horner reaction be-
tween 2-chlorobenzaldehyde (1b) and diethyl (2-bromo-
phenyl)methylphosphonate (8a) in 93% yield (Scheme 7).
II
Reaction of rac-syn-4c with Cu oxinate (10 mol-%) under
the conditions of Table 2, entry 13 delivered the monoaryl-
ation product (i.e., rac-cis-6b) in 68% yield, and even 5%
of the diarylation product (i.e., rac-cis-5a). This result not
only confirms the higher reactivity of aryl bromides in com-
parison to aryl chlorides, but also demonstrates that our
method can be used for the synthesis of trans-2,3-disubsti- Scheme 8. Preparation of 1,2-diols rac-syn-4(a,e,h).
tuted 3-hydroxy-2,3-dihydrobenzofurans.
Finally, the scope of the new method for the synthesis of
b,9b-dihydrobenzofuro[3,2-b]benzofurans was studied. For unambiguously established by mass spectrometry and
this purpose, a number of symmetrical and unsymmetrical NMR spectroscopy, including 2D NMR spectroscopy for
The structures of all of the substrates and products were
4
1
13
(
E)-stilbenes 2d–2i were dihydroxylated to deliver the corre- the full assignment of the H and C chemical shifts. As
sponding 1,2-diols [i.e., rac-syn-4(d–i)]. Symmetrically sub- an example, the structure of (4bRS, 9bRS)-4b,9b-dihy-
stituted (E)-stilbenes 2e and 2h were obtained by homocou- drobenzofuro[3,2-b]benzofuran (rac-cis-5a) was unambigu-
pling of the corresponding ortho-bromobenzyl bromides ously established by mass spectrometry and NMR spec-
troscopy. The signals were assigned by 1H, C, COSY,
13
(Scheme 8).
Unsymmetrically substituted (E)-stilbenes 2d, 2f, 2g, and HSQC, and HMBC NMR spectroscopy (Figure 1). Since
1
2
i were prepared by Wittig–Horner olefination between or- rac-cis-5a is a C -symmetric compound, its H NMR spec-
2
tho-bromobenzaldehydes 1a or 1c and diethylphosphonates trum shows only five signals: a singlet at δ = 6.29 ppm (4b-
a–8d (Table 3). H and 9b-H), and a spin system consisting of two doublet-
All of the 1,2-diols [i.e., rac-syn-4(d–i)] were subjected to like multiplets at δ = 6.87 ppm (1-H and 6-H) and δ =
8
the optimized reaction conditions established for the trans- 7.54 ppm (4-H and 9-H) and two triplet-like multiplets at δ
formation of rac-syn-4a into rac-cis-5a (Table 2, entry 13). = 6.97 ppm (3-H and 8-H) and δ = 7.28 ppm (2-H and 7-
1
1
Irrespective of the substitution pattern of the substrates, the H). Analysis of the H, H-COSY correlations reveal a typi-
double intramolecular Ullmann reaction took place. In all cal ABCD spin system, consistent with a 1,2-disubstituted
cases, the cis-4b,9b-dihydrobenzofuro[3,2-b]benzofurans benzene derivative. The remarkably strong downfield shift
were formed exclusively with yields ranging between 55 and of the signal representing the two chemically equivalent
90% (Table 4). The comparatively low yield for the trans- protons 4b-H and 9b-H can be rationalized as a combina-
formation of rac-syn-4f into rac-cis-5d might be due to par- tion of the diamagnetic aromatic ring current and the in-
tial hydrolysis of the nitrile group under the reaction condi- ductive effect of the oxygen atoms at positions 5 and 10.
tions. Thus, we have shown that the transformation toler- Due to the C symmetry of rac-cis-5a, 4b-H and 9b-H are
2
ates a number of substituents, including fluoro, chloro, chemically equivalent and are represented by a singlet. For
methoxy, and nitrile groups.
this reason it was impossible to directly determine the rela-
Eur. J. Org. Chem. 2015, 7718–7734
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7723

H.-G. Imrich, J. Conrad, U. Beifuss
FULL PAPER
Table 3. Preparation of 1,2-diols rac-syn-4(d,f,g,i).
tive configuration based on the size of the vicinal coupling furans and related heterocycles.[22] A comparison of the size
3
constant J
. However, substitution of one of the of the vicinal coupling constants in cis- and trans-2,3-disub-
4
b-H,9b-H
1
2
C carbon atoms at C-4b or C-9b by its 13C isotop pro- stituted 2,3-dihydrobenzofurans is of particular interest.
duces an ABX spin system (or an AAЈX system if one ig- For (2RS,3RS)-2-(2-bromophenyl)-2,3-dihydrobenzofuran-
1
nores the very small H chemical shift difference of A and 3-ol (rac-cis-6a), i.e., the intermediate of the copper-cata-
1
3
3
AЈ induced by the C isotope shift). From the two doublets lyzed double intramolecular O-arylation,
J2-H,3-H
of doublets centered at δ = 6.29 ppm the outer one split by has a value of 6.5 Hz, whereas for (2RS,3SR)-2-(2-bromo-
1
3
3
JCH = 162.9 Hz reveals the vicinal coupling constant phenyl)-2,3-dihydrobenzofuran-3-ol (rac-trans-6a) J2-H,3-H
J(4b-H,9b-H) = 7.6 Hz. The inner doublet of doublets split amounts to only 1.7 Hz. The observation that in the two
3
2
1
by J(4b-H, 9b-H) and J is overlapped by the strong H 2-(2-bromophenyl)-2,3-dihydrobenzofuran-3-ols rac-cis-6a
CH
1
2
3
(bonded to C) resonance at δ = 6.29 ppm. The size of the and rac-trans-6a Jcis-2,3 is significantly larger than
3
[22]
vicinal coupling is typical for cis-3a,8b-furo[3,2-b]benzo-
Jtrans-2,3 is corroborated by earlier reports.
In addition,
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Copper-Catalyzed Double Intramolecular Ullmann Coupling
Table 4. Copper-catalyzed reactions of 1,2-diols rac-syn-4(d–i).[a]
Pro.[24] In the second step, the optimized structure was sub-
sequently reoptimized at the AM1 level, followed by the
RHF/3-21G level, and finally by the B3LYP/6-31G(d) level
of theory within the Gaussian 03 package. In the final step,
1
the gas-phase H coupling constant was calculated at the
mPW1PW91/6-311+G(2d,p)//mPW1PW91/6-31G(d) level
1
1
of theory. These calculations gave a H, H coupling con-
3
stant of J4
= 7.9 Hz. The calculated value is in good
b-H,9b-H
agreement with the observed coupling constant of
3
J4b-H,9b-H = 7.5 Hz.
Figure 1. Important HMBC correlations of rac-cis-5a.
Conclusions
In summary, we present a copper-catalyzed double intra-
molecular O-arylation of substituted syn-1,2-bis(2-bromo-
aryl)ethane-1,2-diols to give the corresponding 4b,9b-di-
hydrobenzofuro[3,2-b]benzofurans in diastereomerically
II
and enantiomerically pure form. Using Cu oxinate as the
catalyst, K PO as the base, KI as a reductant, and aceto-
3
4
nitrile/water as the reaction medium, the method gives
yields of up to 90%. The substrates are readily available in
racemic and enantiomerically pure form using established
synthetic methods. The use of an enantiomerically pure syn-
1,2-bis(2-bromoaryl)ethane-1,2-diol as substrate resulted in
the formation of a single enantiomer of the product, as veri-
fied by chiral HPLC. The transformation tolerates several
substituents, including fluoro, chloro, methoxy, and nitrile
1
groups. Monitoring the reaction by H NMR spectroscopy
confirmed that it can be considered as a double intramolec-
ular O-arylation with a 2-(2-bromoaryl)-2,3-dihydrobenzo-
furan-3-ol as an intermediate. With an anti-1,2-bis(2-
bromoaryl)ethane-1,2-diol as substrate, the double intramo-
lecular O-arylation does not occur. Instead, the monoaryl-
ation product is formed exclusively in diastereomerically
pure form.
[a] In all cases, 2 mmol of rac-syn-4 was used.
Experimental Section
the cis configuration of (2RS,3RS)-2-(2-chlorophenyl)-2,3-
dihydrobenzofuran-3-ol (rac-cis-6b), which has a vicinal J2-
3
General Remarks: Acetonitrile and solvents used for extraction and
purification were distilled prior to use. Tetrahydrofuran was dried
using sodium/benzophenone. All reagents were used without fur-
ther purification. Reaction temperatures are reported as bath tem-
peratures. Thin-layer chromatography (TLC) was carried out on
aluminum-backed plates coated with silica gel with F254 indicator
coupling constant of 6.5 Hz, was confirmed by the
H,3-H
observation of a ROESY correlation between 2-H and 3-H.
The cis configuration of rac-cis-5e was confirmed by com-
putational studies. The calculations reported here were per-
formed within density functional theory, using the
(
Merck). Compounds were visualized with UV light (λ = 254 nm),
Gaussian 03 package.[
23] 1
H coupling constants were calcu-
and by immersion in a KMnO solution or in an ethanolic vanillin
4
lated for rac-cis-5e as follows: the rigid structures were opti- solution, followed by heating. Products were purified by flash
mized with the MM2 force field implemented in Chem3D chromatography on silica gel, 0.04–0.063 mm mesh (Macherey–Na-
Eur. J. Org. Chem. 2015, 7718–7734
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7725

H.-G. Imrich, J. Conrad, U. Beifuss
FULL PAPER
gel & Co), or by crystallization. Melting points were recorded with
a Büchi B-545 melting-point apparatus with open capillary tubes.
IR spectra were measured with a Bruker Alfa FTIR spectrometer.
UV/Vis spectra were recorded with a Varian Cary 50 instrument.
(Z)-1,2-Bis(2-bromophenyl)ethene [(Z)-2a]:[26] A solution of KOtBu
(1.34 g, 14 mmol) in tetrahydrofuran (40 mL) was added portion-
wise to a stirred solution of 2-bromobenzyltriphenylphosphonium
bromide (7; 5.17 g, 10.1 mmol) in tetrahydrofuran (160 mL) under
argon at 25 °C. The mixture was stirred for 5 min, then 2-bromo-
benzaldehyde (1a; 2.44 g, 13.2 mmol) was added dropwise at 25 °C.
The reaction mixture was stirred overnight at 25 °C, then it was
filtered through silica gel, and the solvent was removed under re-
duced pressure. Flash chromatography of the crude product over
silica gel (petroleum ether) gave (Z)-1,2-bis(2-bromophenyl)ethene
1
13
H and C NMR spectra were recorded at 500/125 or 300/75 MHz
using Varian Unity Inova spectrometers, with CDCl as the solvent.
The H and C chemical shifts were referenced to residual solvent
signals at δH/C = 7.26/77.00 ppm (CDCl ). HSQC, HMBC, and
3
1
13
3
COSY spectra were recorded with Varian Unity Inova spectrome-
ters at 300 and 500 MHz. Coupling constants J [Hz] were directly
taken from the spectra, and are not averaged. Splitting patterns
are designated as s (singlet), d (doublet), t (triplet), q (quartet), m
1
[(Z)-2a] (3.04 g, 8.99 mmol, 89%) as a colorless oil. H NMR
3
(300 MHz, CDCl ): δ = 6.79 (s, 2 H, 1-H and 2-H), 6.91–7.09 (m,
3
4
13
(multiplet), and br (broad). 1D and 2D homonuclear NMR spectra
6 H), 7.57 (dd, J = 7.0, J = 2.1 Hz, 2 H) ppm. C NMR
(75 MHz, CDCl ): δ = 124.0, 126.9, 128.8, 130.9, 132.6, 137.0 ppm.
were measured with standard pulse sequences. Copies of the NMR
spectra were prepared using SpinWorks.[ Low-resolution elec-
tron-impact mass spectra [MS (EI)] and exact-mass electron-impact
mass spectra [HRMS (EI)] were obtained at 70 eV using a double-
focusing sector-field mass spectrometer (Finnigan MAT 95). Low-
resolution electrospray-ionization mass spectra [MS (ESI)] and ex-
act-mass electrospray-ionization mass spectra [HRMS (ESI)] were
obtained using a Bruker Daltonics (micro TOFQ) instrument. In-
tensities are reported as percentages relative to the base peak (I =
3
25]
MS (EI): m/z (%) = 336 (12), 178 (100).
Synthesis of (E)-1,2-Bis(2-chlorophenyl)ethene [(E)-2b] by McMurry
Coupling of 2-Chlorobenzaldehyde (1b)
(E)-1,2-Bis(2-chlorophenyl)ethene [(E)-2b]:[27]
TiCl
(24.7 g,
4
130 mmol) was added dropwise to an ice-cooled mixture of Zn
(16.4 g, 250 mmol) and dry THF (150 mL). Then, 2-chlorobenzal-
dehyde (1b; 140.7 g, 100 mmol) was added dropwise. The mixture
was heated at reflux for 24 h. The mixture was then cooled to room
temperature, and filtered, and the solvent was evaporated under
100%).
General Procedure I for the Preparation of Symmetrical Stilbenes 2
reduced pressure. The resulting residue was dissolved in CH
2 2
Cl
from Benzyl Bromides 3:[
13b]
The benzyl bromide 3 (20 mmol) was
(
30 mL), the solution was filtered through silica gel, and the solvent
placed in a Schlenk flask under argon. LiHMDS solution (1 m in
tetrahydrofuran; 44 mL) was added dropwise with stirring at 0 °C.
After the addition was complete, the reaction mixture was stirred
was evaporated under reduced pressure. Crystallization of the crude
product from petroleum ether gave (E)-1,2-bis(2-chlorophenyl)eth-
[27]
ene [(E)-2b] (8.12 g, 32.6 mmol, 65%), m.p. 95–96 °C (ref.
m.p.
for 20 min at 0 °C. Saturated aqueous NH
4
Cl solution (20 mL) was
1
9
f
6–97 °C). R = 0.28 (petroleum ether). H NMR (300 MHz,
): δ = 7.23 (ddd, 2ϫ J ≈ 7.5, J = 1.8 Hz, 2 H), 7.30 (ddd,
ϫ J ≈ 7.5, J = 1.5 Hz, 2 H), 7.40 (dd, J = 7.8, J = 1.6 Hz, 2
H), 7.50 (s, 2 H), 7.75 (dd, J = 7.7, J = 1.8 Hz, 2 H) ppm.
NMR (75 MHz, CDCl ): δ = 126.9, 127.0, 127.3, 128.9, 129.8,
33.6, 135.2 ppm. MS (EI): m/z (%) = 248 (33) [M] , 213 (21), 178
then added, and the mixture was extracted with tert-butylmethyl
ether (3ϫ 30 mL). The combined organic layers were washed with
3
4
CDCl
2
3
3
4
3
4
saturated aqueous NH
and dried with Na SO
pressure. The resulting residue was dissolved in dichloromethane
50 mL), the solution was filtered through silica gel, and the prod-
4
Cl solution (30 mL), and water (30 mL),
3
4
13
C
2
4
. The solvent was removed under reduced
3
+
1
(
(
100), 151 (10), 88 (11).
uct was crystallized from methanol to give the stilbene 2.
(
E)-1-(2-Bromostyryl)-2-chlorobenzene [(E)-2c]: 2-Chlorobenzalde-
General Procedure II for the Preparation of Unsymmetrical Stilbenes
hyde (1b; 1.41 g, 10 mmol) and diethyl (2-bromophenyl)methyl-
phosphonate (8a; 3.07 g, 10 mmol) were used according to general
procedure II. Crystallization from methanol gave (E)-1-(2-bromo-
styryl)-2-chlorobenzene [(E)-2c] (2.73 g, 9.3 mmol, 93%) as a color-
14]
2
from 2-Bromobenzaldehydes 1 and Benzylphosphonates 8:[
Aliquat 336 (1.5 mL) was added to a stirred mixture of toluene
20 mL) and aqueous NaOH (50%; 20 mL). A solution of the 2-
bromobenzaldehyde 1 (25 mmol) and the benzylphosphonate 8
25 mmol) in toluene (10 mL) was added dropwise at 25 °C. The
(
less solid. R
f
= 0.62 (petroleum ether), m.p. 89–90 °C. IR: ν˜ = 3051,
(
1
1
586, 1561, 1472, 1436, 1324, 1276, 1252, 1216, 1156, 1123, 1139,
mixture was heated at reflux for 30 min. The mixture was then
cooled to room temperature, and the aqueous layer was separated
and extracted with toluene (2ϫ 30 mL). The combined organic lay-
–1
3
017, 956, 855, 750, 719, 663, 557, 543 cm . UV (CH CN): λmax
1
(
logε) = 293 (4.32), 230 (4.17), 209 (4.38) nm. H NMR (500 MHz,
3
4
CDCl ): δ = 7.15 (ddd, 2ϫ J ≈ 7.7, J4Ј-H,6Ј-H = 1.7 Hz, 1 H, 4Ј-
3 4
3
ers were washed with saturated aqueous NH
4
Cl (30 mL), and brine
H), 7.23 (ddd, 2ϫ J ≈ 7.8, J4ЈЈ-H,6ЈЈ-H = 1.7 Hz, 1 H, 4Ј-H), 7.30
(2ϫ 30 mL). The solvent was removed under reduced pressure. The
3
4
(ddd, 2ϫ J ≈ 7.5,
J
5ЈЈ-H,3ЈЈ-H = 1.4 Hz, 1 H, 5ЈЈ-H), 7.34 (ddd,
1.3 Hz, H, 5Ј-H), 7.40 (dd,
3ЈЈ-H,4ЈЈ-H = 7.9, J3ЈЈ-H,5ЈЈ-H = 1.4 Hz, 1 H, 3ЈЈ-H), 7.45 (s, 2 H, 1-
resulting residue was dissolved in dichloromethane (100 mL), and
the solution was filtered through silica gel. Evaporation of the sol-
vent, followed by crystallization of the crude product from meth-
anol delivered the stilbene 2.
3
4
2
ϫ J
≈
7.5,
J
5Ј-H,3Ј-H
=
1
3
4
J
3
4
H and 2-H), 7.60 (dd, J3Ј-H,4Ј-H = 8.0, J3Ј-H,5Ј-H = 1.3 Hz, 1 H, 3Ј-
H), 7.71–7.77 (m, 2 H, 6Ј-H and 6ЈЈ-H) ppm. C NMR (125 MHz,
13
CDCl
27.5 (C-1 or C-2), 127.6 (C-5Ј), 129.0 (C-4ЈЈ), 129.2 (C-4Ј), 129.8
C-3ЈЈ), 129.9 (C-1 or C-2), 133.1 (C-3Ј), 133.6 (C-2ЈЈ), 135.1 (C-
3
): δ = 124.3 (C-2Ј), 126.9 (C-6ЈЈ), 127.0 (C-5ЈЈ), 127.1 (C-6Ј),
(
E)-1,2-Bis(2-bromophenyl)ethene
[(E)-2a]:[26]
2-Bromobenzyl
1
(
bromide (3a; 5.02 g, 20 mmol) was used according to general pro-
cedure I. Crystallization from methanol gave (E)-1,2-bis(2-bromo-
phenyl)ethene [(E)-2a] (2.56 g, 7.57 mmol, 76%) as a colorless so-
+
1
1
ЈЈ), 136.9 (C-1Ј) ppm. MS (EI): m/z (%) = 292 (33) [M] , 213 (7),
78 (100), 151 (6), 88 (7). HRMS (EI): calcd. for C14 10BrCl
H
[26]
lid. R
f
= 0.30 (petroleum ether), m.p. 110–111 °C (ref. m.p. 108–
+
[M] 291.9654; found 291.9653.
1
3
1
08.5 °C). H NMR (300 MHz, CDCl ): δ = 7.15 (ddd, J = 8.0,
3
3
4
3
4
J = 7.3 Hz, J = 1.7 Hz, 2 H), 7.34 (ddd, 2ϫ J ≈ 7.5, J = 1.3 Hz,
(E)-2-(2-Bromostyryl)-1-bromo-4-methoxybenzene
[(E)-2d]:
2-
3
4
2
H), 7.41 (s, 2 H), 7.60 (dd, J = 7.6, J = 1.3 Hz, 2 H) 7.73 (dd,
Bromobenzaldehyde (1a; 4.63 g, 25 mmol) and diethyl (2-bromo-5-
methoxyphenyl)methylphosphonate (8b; 9.30 g, 25 mmol) were
used according to general procedure II. Crystallization from meth-
anol gave (E)-2-(2-bromostyryl)-1-bromo-4-methoxybenzene [(E)-
3
4
13
J = 7.9, J = 1.7 Hz, 2 H) ppm. C NMR (75 MHz, CDCl
3
): δ =
1
(
24.2, 127.2, 127.7, 129.2, 130.1, 133.1, 136.8 ppm. MS (EI): m/z
+
%) = 336 (11) [M] , 178 (100).
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Copper-Catalyzed Double Intramolecular Ullmann Coupling
+
2
d] (5.19 g, 14.1 mmol, 56%) as a colorless solid. R
f
= 0.24 (petro-
361 (35) [M] , 283 (4), 203 (100), 175 (30), 150 (10), 101.5 (67), 88
+
leum ether), m.p. 90–91 °C. IR: ν˜ = 2969, 1585, 1460, 1432, 1404,
1
(76), 75 (21). HRMS (EI): calcd. for [C15
360.9099.
H
9
Br
2
N] 360.9096; found
331, 1289, 1248, 1229, 1210, 1172, 1113, 1041, 1013, 953, 938,
8
59, 830, 815, 801, 757, 736, 714, 671, 631, 608, 559, 522, 497, 483,
–1
4
2
52, 402 cm . UV (CH
CN): λmax (logε) = 291 (4.30), 231 (4.27), (E)-2-(2-Bromostyryl)-1-bromo-4-chlorobenzene [(E)-2g]: 2-Bromo-
3
22 (4.28) nm. 1H NMR (500 MHz, CDCl
): δ = 3.86 (s, 3 H,
benzaldehyde (1a; 4.65 g, 25 mmol) and diethyl (2-bromo-5-chloro-
phenyl)methylphosphonate (8d; 8.55 g, 25 mmol) were used accord-
ing to general procedure II. Crystallization from methanol gave
3
3
4
OCH
3
), 6.70 (dd,
J
4Ј-H,3Ј-H = 8.8,
J
4Ј-H,6Ј-H = 3.1 Hz, 1 H, 4Ј-
3
3
4
H), 7.15 (ddd, J4ЈЈ-H,3ЈЈ-H = 8.0, J4ЈЈ-H,5ЈЈ-H = 7.3 Hz, J4ЈЈ-H,6ЈЈ-H
1
=
4
.7 Hz, 1 H, 4ЈЈ-H), 7.24 (d, J6Ј-H,4Ј-H = 3.0 Hz, 1 H, 6Ј-H), 7.34 (E)-2-(2-bromostyryl)-1-bromo-4-chlorobenzene [(E)-2g] (5.44 g,
3
3
4
(
ddd, J5ЈЈ-H,4ЈЈ-H ≈ 7.5, J5ЈЈ-H,6ЈЈ-H ≈ 7.5 Hz, J5ЈЈ-H,3ЈЈ-H = 1.4 Hz, 14.6 mmol, 58%) as a colorless solid. R
f
= 0.55 (petroleum ether),
H, 5ЈЈ-H), 7.34 (d, J1-H,2-H or 3J2-H,1-H = 16.1 Hz, 1 H, 1-H or
3
1
2
m.p. 89–91 °C. IR: ν˜ = 3055, 1792, 1575, 1467, 1436, 1394, 1322,
-H), 7.39 (d, J1-H,2-H or 3J2-H,1-H = 16.1 Hz, 1 H, 1-H or 2-H),
3
1240, 1215, 1190, 1096, 1046, 1022, 956, 913, 872, 838, 805, 748,
3
3
–1
7
.48 (d, J3Ј-H,4Ј-H = 8.8 Hz, 1 H, 3Ј-H), 7.59 (dd, J3ЈЈ-H,4ЈЈ-H = 8.0, 713, 667, 558, 541, 509, 466, 449 cm . UV (CH
3
CN): λmax (logε)
4
3
1
J
3ЈЈ-H,5ЈЈ-H = 1.3 Hz, 1 H, 3ЈЈ-H), 7.72 (dd, J
6ЈЈ-H,5ЈЈ-H = 7.8, = 291 (4.32), 214 (4.39) nm. H NMR (500 MHz, CDCl ): δ = 7.13
3
4J6ЈЈ-H,4ЈЈ-H = 1.7 Hz, 1 H, 6ЈЈ-H) ppm. C NMR (125 MHz, (dd, J4Ј-H,3Ј-H = 8.6, J4Ј-H,6Ј-H = 2.5 Hz, 1 H, 4Ј-H), 7.17 (ddd,
13
3
4
3
3
4
CDCl
1
1
3
): δ = 55.6 (OCH
3
), 112.4 (C-6Ј), 115.0 (C-2Ј), 115.3 (C-4Ј),
J
4ЈЈ-H,3ЈЈ-H = 7.9, J4ЈЈ-H,5ЈЈ-H = 7.5 Hz, J4ЈЈ-H,6ЈЈ-H = 1.7 Hz, 1 H,
3
24.3 (C-2ЈЈ), 127.2 (C-6ЈЈ), 127.7 (C-5ЈЈ), 129.3 (C-4ЈЈ), 130.19 (C- 4ЈЈ-H), 7.30 (d,
or C-2), 130.20 (C-1 or C-2), 133.1 (C-3ЈЈ), 133.6 (C-3Ј), 136.7
J1-H,2-H = 16.1 Hz, 1 H, 1-H), 7.34 (ddd,
3
5ЈЈ-H,4ЈЈ-H ≈ 7.8, 3J5ЈЈ-H,6ЈЈ-H≈ 7.8 Hz,
4
J
J
5ЈЈ-H,3ЈЈ-H = 1.4 Hz, 1 H,
3
3
(
(
(
C-1ЈЈ), 137.5 (C-1Ј), 159.1 (C-5Ј) ppm. MS (EI): m/z (%) = 366 5ЈЈ-H), 7.39 (d, J2-H,1-H = 16.1 Hz, 1 H, 2-H), 7.51 (d, J3Ј-H,4Ј-H
34) [M] , 208 (100), 193 (45), 163 (46), 139 (14), 104 (31). HRMS = 8.5 Hz, 1 H, 3Ј-H), 7.60 (dd,
+
3
4
3ЈЈ-H,5ЈЈ-H
J3ЈЈ-H,4ЈЈ-H = 7.8, J =
+
4
EI): calcd. for C15
E)-1,2-Bis(2-bromo-5-methoxyphenyl)ethene [(E)-2e]:[28] 1-Bromo-
-(bromomethyl)-4-methoxybenzene (3b; 5.64 g, 20.2 mmol) was
H12Br
2
O [M] 365.9249; found 365.9246.
1.7 Hz, 1 H, 3ЈЈ-H), 7.67 (d, J6Ј-H,4Ј-H = 2.5 Hz, 1 H, 6Ј-H), 7.70
3
4
13
(
dd, J6ЈЈ-H,5ЈЈ-H = 7.8, J6ЈЈ-H,4ЈЈ-H = 1.7 Hz, 1 H, 6ЈЈ-H) ppm.
C
(
3
NMR (125 MHz, CDCl ): δ = 121.9 (C-2Ј), 124.4 (C-2ЈЈ), 126.6
2
(
(
(
(
(
6Ј), 127.2 (C-6ЈЈ), 127.7 (C-5ЈЈ), 129.0 (C-1), 129.1 (C-4Ј), 129.6
used according to general procedure I. Crystallization of the crude
product from methanol gave (E)-1,2-bis(2-bromo-5-meth-
oxyphenyl)ethene [(E)-2e] (3.12 g, 7.84 mmol, 78%) as a colorless
C-4ЈЈ), 131.1 (C-2), 133.2 (C-3ЈЈ), 133.8 (C-5Ј), 134.1 (C-3Ј), 136.4
+
C-1ЈЈ), 138.3 (C-1Ј) ppm. MS (EI): m/z (%) = 370 (29) [M] , 292
7), 256 (11), 212 (100), 177 (66), 150 (25), 106 (71), 75 (29). HRMS
solid. R
f
= 0.15 (petroleum ether), m.p. 152–154 °C (ref.[28] m.p.
+
EI): calcd. for [C14
H
9
Br
2
Cl] 369.8754; found 369.8760.
1
1
8
54–155 °C). IR: ν˜ = 2926, 2837, 1872, 1588, 1572, 1458, 1407,
340, 1285, 1247, 1229, 1203, 1168, 1116, 1042, 1012, 952, 865,
41, 798, 729, 707, 617, 565, 499, 467, 454, 395 cm . H NMR
(
(
E)-1,2-Bis(2-bromo-5-chlorophenyl)ethene [(E)-2h]: 1-Bromo-2-
bromomethyl)-4-chlorobenzene (3c; 5.70 g, 20 mmol) was used ac-
–1 1
3
(
3 3
300 MHz, CDCl ): δ = 3.85 (s, 6 H, OCH ), 6.75 (dd, J4Ј-H,3Ј-H =
cording to general procedure I. Crystallization of the crude product
from methanol gave (E)-1,2-bis(2-bromo-5-chlorophenyl)ethene
3
4
4
J
4ЈЈ-H,3ЈЈ-H = 8.8, J4Ј-H,6Ј-H = J4ЈЈ-H,6ЈЈ-H = 3.0 Hz, 2 H, 4Ј-H and
ЈЈ-H), 7.23 (d, 4J6Ј-H,4Ј-H = J6ЈЈ-H,4ЈЈ-H = 3.0 Hz, 2 H, 6Ј-H and
4
4
[(E)-2h] (3.47 g, 8.53 mmol, 85%) as a colorless solid. R
f
= 0.50
3
6
J
ЈЈ-H), 7.33 (s, 2 H, 1-H and 2-H), 7.47 (d,
J
3Ј-H,4Ј-H
13
=
(
petroleum ether), m.p. 184–185 °C. IR: ν˜ = 3054, 1736, 1574, 1548,
3
3ЈЈ-H,4ЈЈ-H = 8.8 Hz, 2 H, 3Ј-H and 3ЈЈ-H) ppm. C NMR
1
6
454, 1394, 1317, 1264, 1237, 1209, 1092, 1023, 957, 897, 868, 815,
(
(
(
75 MHz, CDCl
3
): δ = 55.6 (OCH ), 112.4 (C-6Ј and C-6ЈЈ), 115.0
3
–
1
95, 584, 553, 448 cm . UV (CH
3
CN): λmax (logε) = 288 (3.91),
C-2Ј and C-2ЈЈ), 115.4 (C-4Ј and C-4ЈЈ), 130.3 (C-1 and C-2), 133.6
C-3Ј and C-3ЈЈ), 137.4 (C-1Ј and C-1ЈЈ), 159.1 (C-5Ј and C-5ЈЈ)
1
2
18 (4.07) nm. H NMR (300 MHz, CDCl ): δ = 7.14 (dd,
3
3
3
4
4
J
4Ј-H,3Ј-H = J4ЈЈ-H,3ЈЈ-H = 8.6, J4Ј-H,6Ј-H = J4ЈЈ-H,6ЈЈ-H = 2.5 Hz, 2
+
ppm. MS (EI): m/z (%) = 396 (5) [M] , 317 (5), 238 (100), 223 (36),
3
H, 4Ј-H and 4ЈЈ-H), 7.29 (s, 2 H, 1-H and 2-H), 7.52 (d, J3Ј-H,4Ј-H
208 (2), 195 (18), 180 (5), 152 (11).
3
4
=
J
3ЈЈ-H,4ЈЈ-H = 8.5 Hz, 2 H, 3Ј-H and 3ЈЈ-H), 7.65 (d, J6Ј-H,4Ј-H
=
4
13
(E)-4-(2-Bromostyryl)-3-bromobenzonitrile [(E)-2f]: 2-Bromobenz-
J6ЈЈ-H,4ЈЈ-H = 2.4 Hz, 2 H, 6Ј-H and 6ЈЈ-H) ppm. C NMR
aldehyde (1a; 1.85 g, 10 mmol) and diethyl (2-bromo-4-cya-
nophenyl)methylphosphonate (8c; 3.33 g, 10 mmol) were used ac-
cording to general procedure II. Crystallization from methanol
gave (E)-4-(2-bromostyryl)-3-bromobenzonitrile [(E)-2f] (3.05 g,
(75 MHz, CDCl ): δ = 122.1 (C-2Ј and C-2ЈЈ), 127.0 (C-6Ј and C-
6ЈЈ), 129.4 (C-4Ј and C-4ЈЈ), 130.1 (C-1 and C-2), 133.8 (C-5Ј and
3
C-5ЈЈ), 134.2 (C-3Ј and C-3ЈЈ), 137.9 (C-1Ј and C-1ЈЈ) ppm. MS
+
(EI): m/z (%) = 404 (5) [M] , 278 (25), 246 (100), 210 (16), 176
+
8.4 mmol, 84%) as a colorless solid. R
f
= 0.56 (petroleum ether/
(32), 138 (7). HRMS (EI): calcd. for C H Br Cl [M] 403.8364;
1
4
8
2
2
dichloromethane, 7:3), m.p. 156–158 °C. IR: ν˜ = 3062, 2225, 1736,
found 403.8369.
1
9
593, 1478, 1433, 1387, 1326, 1271, 1225, 1191, 1041, 1022, 954,
–
1
04, 888, 845, 821, 785, 754, 738, 666, 591, 564, 460, 443 cm . UV (E)-2-(2-Bromostyryl)-1-bromo-4-fluorobenzene [(E)-2i]: 2-Bromo-
1
(CH
3
CN): λmax (logε) = 312 (4.27), 239 (4.12), 210 (4.41) nm. H 5-fluorobenzaldehyde (1c; 5.09 g, 25 mmol) and diethyl (2-bromo-
3
NMR (500 MHz, CDCl
3
): δ = 7.20 (ddd,
J4ЈЈ-H,3ЈЈ-H ≈ 7.9, phenyl)methylphosphonate (8a; 7.68 g, 25 mmol) were used accord-
3
4
J
4ЈЈ-H,5ЈЈ-H ≈ 7.9 Hz, J4ЈЈ-H,6ЈЈ-H = 1.7 Hz, 1 H, 4ЈЈ-H), 7.36 (ddd,
ing to general procedure II. Crystallization from methanol gave
(E)-2-(2-bromostyryl)-1-bromo-4-fluorobenzene [(E)-2i] (4.49 g,
12.6 mmol, 50%) as a colorless solid. R = 0.55 (petroleum ether),
f
m.p. 87–89 °C. IR: ν˜ = 3053, 1793, 1573, 1464, 1409, 1326, 1268,
3J5ЈЈ-H,4ЈЈ-H ≈ 7.3, J5ЈЈ-H,6ЈЈ-H ≈ 7.3 Hz, J5ЈЈ-H,3ЈЈ-H = 1.2 Hz, 1 H,
3
4
3
3
5ЈЈ-H), 7.46 (d, J1-H,2-H = 16.2 Hz, 1 H, 1-H), 7.52 (d, J2-H,1-H
=
3
4
16.1 Hz, 1 H, 2-H), 7.61 (ddd, J5Ј-H,6Ј-H = 8.2, J5Ј-H,3Ј-H = 1.7 Hz,
3
4
J = 0.6 Hz, 1 H, 5Ј-H), 7.62 (dd, J3ЈЈ-H,4ЈЈ-H = 8.0, J3ЈЈ-H,5ЈЈ-H
=
=
1249, 1202, 1158, 1100, 1049, 1022, 975, 953, 875, 798, 741, 712,
3
6ЈЈ-H,5ЈЈ-H = 7.9, 4
–1
1.3 Hz, 1 H, 3ЈЈ-H), 7.72 (dd,
J
J
6ЈЈ-H,4ЈЈ-H
672, 630, 592, 557, 511, 451, 397 cm . UV (CH
3
CN): λmax (logε)
): δ = 6.90
3
1
1
.7 Hz, 1 H, 6ЈЈ-H), 7.80 (d, J6Ј-H,5Ј-H = 8.2 Hz, 1 H, 6Ј-H), 7.88 = 291 (4.28), 232 (4.16) nm. H NMR (500 MHz, CDCl
3
3
3Ј-H,5Ј-H = 1.7 Hz, 1 H, 3Ј-H) ppm. 13C NMR (125 MHz,
3
3
4
(d,
J
(ddd, J4Ј-H,5Ј-F = 8.8, J4Ј-H,3Ј-H = 7.8 Hz, J4Ј-H,6Ј-H = 3.0 Hz, 1 H,
3
7.9, 3J4ЈЈ-H,5ЈЈ-H
CDCl
3
): δ = 112.4 (C-4Ј), 117.4 (CN), 124.1 (C-2Ј), 124.6 (C-2ЈЈ), 4Ј-H), 7.17 (ddd,
J
4ЈЈ-H,3ЈЈ-H
=
=
7.5 Hz,
4
3
1
1
1
27.3 (overlapped, C-6Ј), 127.3 (overlapped, C-6ЈЈ), 127.8 (C-5ЈЈ),
28.4 (C-1), 130.1 (C-5Ј), 131.0 (C-4ЈЈ), 133.3 (C-3ЈЈ), 133.4 (C-2),
35.9 (C-1ЈЈ), 136.4 (C-3Ј), 141.5 (C-1Ј) ppm. MS (EI): m/z (%) = = 1.3 Hz, 1 H, 5ЈЈ-H), 7.40 (d, J2-H,1-H = 16.1 Hz, 1 H, 2-H), 7.43
J
4ЈЈ-H,6ЈЈ-H = 1.7 Hz, 1 H, 4ЈЈ-H), 7.33 (d, J1-H,2-H = 16.2 Hz, 1 H,
1-H), 7.34 (ddd, J5ЈЈ-H,4ЈЈ-H ≈ 7.6, J5ЈЈ-H,6ЈЈ-H ≈ 7.6 Hz, 4J5ЈЈ-H,3ЈЈ-H
3
3
3
Eur. J. Org. Chem. 2015, 7718–7734
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7727

H.-G. Imrich, J. Conrad, U. Beifuss
FULL PAPER
(
dd, 3
J
6Ј-H,5Ј-F = 9.7, 4
J
6Ј-H,4Ј-H = 3.0 Hz, 1 H, 6Ј-H), 7.54 (dd, (m, 2 H), 7.14 (ddd, J = 7.9, J = 7.7, J = 1.8 Hz, 2 H), 7.34
3
3
4
3
4
3
4
3
4
J3Ј-H,4Ј-H = 8.8,
3ЈЈ-H,4ЈЈ-H = 8.0,
J3Ј-H,5Ј-F = 5.3 Hz, 1 H, 3Ј-H), 7.60 (dd,
(ddd, 2ϫ J ≈ 7.5, J = 1.2 Hz, 2 H), 7.46 (dd, J = 8.0, J = 1.2 Hz,
3 4 13
3
4
J
J
3ЈЈ-H,5ЈЈ-H = 1.3 Hz, 1 H, 3ЈЈ-H), 7.71 (dd, 2 H), 7.69 (dd, J = 7.9, J = 1.7 Hz, 2 H) ppm. C NMR
3J6ЈЈ-H,5ЈЈ-H = 7.8, J6ЈЈ-H,4ЈЈ-H = 1.7 Hz, 1 H, 6ЈЈ-H) ppm. C NMR (75 MHz, CDCl
4
13
): δ = 75.2, 122.9, 127.5, 129.5, 129.7, 132.8, 138.8
3
+
(
125 MHz, CDCl
3
): δ = 113.7 (d, JC,F = 23.5 Hz, C-6Ј), 116.4 (d,
C,F = 22.9 Hz, C-4Ј), 118.3 (d, JC,F = 3.0 Hz, C-2Ј), 124.4 (C-2ЈЈ), 77 (52).
27.2 (C-6ЈЈ), 127.7 (C-5ЈЈ), 129.2 (d, JC,F = 2.3 Hz, C-2), 129.6 (C-
ЈЈ), 131.2 (d, JC,F = 0.8 Hz, C-1), 133.2 (C-3ЈЈ), 134.2 (d, JC,F
.1 Hz, C-3Ј), 136.4 (C-1ЈЈ), 138.5 (d, JC,F = 7.8 Hz, C-1Ј), 162.1
ppm. MS (EI): m/z (%) = 370 (1) [M] , 185 (100), 157 (5), 107 (9),
J
1
4
8
(
1
1RS,2SR)-1,2-Bis(2-bromophenyl)ethane-1,2-diol (meso-4a):[30] (Z)-
,2-Bis(2-bromophenyl)ethene [(Z)-2a] (1.69 g, 5 mmol) was used
according to general procedure III with a reaction time of 3 d.
=
(
d, JC,F = 247.1 Hz, C-5Ј) ppm. MS (EI): m/z (%) = 354 (31)
Crystallization from petroleum ether gave (1RS,2SR)-1,2-bis(2-
+
[M] , 276 (4), 196 (100), 175 (19), 98 (52), 85 (17), 75 (7). HRMS
bromophenyl)ethane-1,2-diol (meso-4a; 968 mg, 2.6 mmol; 52%) as
+
9 2
(EI): calcd. for C14H Br F [M] 353.9050; found 353.9057.
1
a colorless solid, m.p. 113–114 °C. H NMR (300 MHz, CDCl
3
): δ
3
General Procedure III for the Preparation of syn Diols 4 by Di-
hydroxylation of Stilbenes 2:[ A mixture of N-methylmorpholine
N-oxide [50% (w/w) aqueous solution; 937 mg, 8.0 mmol], acetone
= 2.65 (br. s, 2 H, OH), 5.56 (s, 2 H, 1-H and 2-H), 7.10 (ddd, J
= 7.9, J = 7.2 Hz, J = 2.1 Hz, 2 H), 7.21 (ddd, 2ϫ J ≈ 7.1, J =
1.3 Hz, 2 H), 7.27 (dd, J = 7.8, J = 2.0 Hz, 2 H), 7.40 (dd, J =
15]
3
4
3
4
3
4
3
4
13
(
(
8.0 mL), water (2.5 mL), and potassium osmate(VI) dihydrate
5 mg, 13.5 μmol, 0.26 mol-%) was stirred for 30 min at 25 °C.
3
7.9, J = 1.3 Hz, 2 H) ppm. C NMR (75 MHz, CDCl ): δ = 74.4,
124.0, 127.1, 129.2, 129.3, 132.1, 137.9 ppm. MS (EI): m/z (%) =
Then, stilbene 2 (5.0 mmol) was added, and the reaction mixture
370 (1), 185 (100), 157 (5), 107 (8), 77 (41).
was stirred for the given time at 25 °C. After the reaction was com-
plete, aqueous FeSO (30 mL) was added, and the mixture was
4
stirred for 30 min. The mixture was then extracted with ethyl acet-
ate (4ϫ 10 mL), and the combined organic layers were washed with
(
(
1RS,2RS)-1,2-Bis(2-chlorophenyl)ethane-1,2-diol (rac-syn-4b):[31]
E)-1,2-bis(2-chlorophenyl)ethene [(E)-2b] (1.25 g, 5 mmol) was
used according to general procedure III with a reaction time of
4 h. Crystallization from petroleum ether gave (1RS,2RS)-1,2-
bis(2-chlorophenyl)ethane-1,2-diol (rac-syn-4b; 1.13 g, 4.0 mmol,
2
4
brine (2ϫ 10 mL), and dried with MgSO . The solvents were re-
moved under reduced pressure, and the residue was filtered through
silica gel (dichloromethane). Analytically pure syn diol 4 was ob-
tained by crystallization of the crude product.
8
1
=
f
0%) as a colorless solid. R = 0.12 (dichloromethane), m.p. 146–
47 °C (ref.[ m.p. 145–146 °C). H NMR (300 MHz, CDCl
31]
1
): δ
3
2.78–2.84 (m, 2 H), 5.32–5.38 (m, 2 H), 7.18–7.34 (m, 6 H), 7.66
1RS,2RS)-1,2-Bis(2-bromophenyl)ethane-1,2-diol (rac-syn-4a):[29] (dd, J = 7.7, J = 1.6 Hz, 2 H) ppm. C NMR (75 MHz, CDCl
3
4
13
):
(
3
(
E)-1,2-Bis(2-bromophenyl)ethene [(E)-2a] (1.69 g, 5 mmol) was
δ = 73.0, 126.8, 129.09, 129.13, 129.4, 132.6, 137.2 ppm. MS (EI):
m/z (%) = 282 (1), 165 (1), 141 (100), 107 (6), 77 (25).
used according to general procedure III, with a reaction time of
d. Crystallization from petroleum ether gave (1RS,2RS)-1,2-bis(2-
bromophenyl)ethane-1,2-diol (rac-syn-4a) (1.67 g, 4.5 mmol, 90%)
as a colorless solid. R = 0.12 (dichloromethane), m.p. 119–121 °C
m.p. 121–122 °C). IR: ν˜ = 3283, 2935, 1591, 1568, 1490,
3
(1RS,2RS)-1-(2-Bromophenyl)-2-(2-chlorophenyl)ethane-1,2-diol
(rac-syn-4c): (E)-1-(2-Bromostyryl)-2-chlorobenzene [(E)-2c]
(1.47 g, 5 mmol) was used according to general procedure III with
f
[
29]
(ref.
a reaction time of 24h. Crystallization from petroleum ether gave
1
1
4
2
2
440, 1429, 1384, 1336, 1296, 1276, 1224, 1196, 1115, 1046, 1020,
(
(
(
1RS,2RS)-1-(2-bromophenyl)-2-(2-chlorophenyl)ethane-1,2-diol
rac-syn-4c; 1.52 g, 4.65 mmol, 93%) as a colorless solid. R = 0.10
dichloromethane), m.p. 141–142 °C. IR: ν˜ = 3277, 1593, 1568,
005, 945, 844, 832, 752, 725, 690, 674, 630, 614, 570, 529, 488,
–1 1
f
3
54 cm . H NMR (300 MHz, CDCl ): δ = 2.85 (s, 2 H), 5.32 (s,
3
3
4
H), 7.14 (ddd, J = 7.9, J = 7.4, J = 1.8 Hz, 2 H), 7.34 (ddd,
1
7
λ
471, 1436, 1385, 1337, 1276, 1193, 1118, 1024, 1006, 844, 752,
3
4
3
4
ϫ J ≈ 7.5, J = 1.3 Hz, 2 H), 7.45 (dd, J = 8.0, J = 1.3 Hz, 2
–
1
28, 709, 679, 630, 614, 570, 532, 464, 455 cm . UV (CH
3
CN):
): δ = 2.79
s, 2 H, OH), 5.31–5.38 (m, 2 H, 1-H and 2-H) 7.14 (ddd,
3
4
13
H), 7.69 (dd, J = 7.8, J = 1.8 Hz, 2 H) ppm. C NMR (75 MHz,
CDCl ): δ = 75.2, 122.9, 127.5, 129.6, 129.7, 132.8, 138.7 ppm. MS
(
1
max (logε) = 263 (2.35) nm. H NMR (500 MHz, CDCl
3
3
(
+
EI): m/z (%) = 370 (1) [M] , 185 (100), 165 (34), 157 (79), 105
60), 77 (75), 51 (92).
3
3
4
J
4Ј-H,3Ј-H = 7.8, J4Ј-H,5Ј-H = 7.6 Hz, J4Ј-H,6Ј-H = 1.1 Hz, 1 H, 4Ј-
(
3
4
H), 7.22 (ddd, 2ϫ J ≈ 7.6, J4ЈЈ-H,6ЈЈ-H = 1.1 Hz, 1 H, 4ЈЈ-H), 7.27
3
4
Asymmetric Dihydroxylation of (E)-1,2-bis(2-Bromophenyl)ethene (dd, J3ЈЈ-H,4ЈЈ-H = 7.9, J3ЈЈ-H,5ЈЈ-H = 1.3 Hz, 1 H, 3ЈЈ-H), 7.30 (ddd,
(E)-2a] Using the Sharpless Olefin Dihydroxylation Method[
16]
3
3
J = 7.4, J = 7.3 Hz, J5ЈЈ-H,3ЈЈ-H = 1.3 Hz, 1 H, 5ЈЈ-H), 7.34 (ddd,
3
4
[
3
4
J = 7.6, J = 7.5 Hz, J5Ј-H,3Ј-H = 0.9 Hz, 1 H, 5Ј-H), 7.46 (dd,
(
1S,2S)-1,2-Bis(2-bromophenyl)ethane-1,2-diol [(+)-4a]:[8b] Meth-
3J3Ј-H,4Ј-H = 8.0, J3Ј-H,5Ј-H = 1.0 Hz, 1 H, 3Ј-H), 7.66–7.70 (m, 2
4
anesulfonamide (740 mg), water (36 mL), and tert-butyl alcohol
36 mL) were placed into a round-bottomed flask equipped with a
1
3
H, 6Ј-H and 6ЈЈ-H) ppm. C NMR (125 MHz, CDCl
3
): δ = 73.1
C-1 or C-2), 75.1 (C-1 or C-2), 122.9 (C-2Ј), 127.0 (C-5ЈЈ), 127.6
C-5Ј), 129.3 (C-4ЈЈ), 129.4 (C-4Ј, C-6Ј, C-3ЈЈ or C-6ЈЈ), 129.61 (C-
Ј, C-6Ј, C-3ЈЈ or C-6ЈЈ), 129.64 (C-4Ј, C-6Ј, C-3ЈЈ or C-6ЈЈ), 129.66
C-4Ј, C-6Ј, C-3ЈЈ or C-6ЈЈ), 132.88 (C-2ЈЈ), 132.9 (C-3Ј), 137.3 (C-
(
(
(
4
magnetic stirring bar. AD-mix α (10.55 g) was added, and the mix-
ture was cooled to 0 °C. Then, (E)-1,2-bis(2-bromophenyl)ethene
[(E)-2a] (2.45 g, 7.25 mmol) was added, and the mixture was stirred
(
for 3 d at 0 °C. Na SO was added, and the aqueous phase was
2
3
+
1
ЈЈ), 139.0 (C-1Ј) ppm. MS (EI): m/z (%) = 326 (6) [M] , 309 (2),
separated. The aqueous phase was extracted with tert-butylmethyl
ether (4ϫ 30 mL). The combined organic layers were washed with
aqueous KOH (2 m; 2ϫ 50 mL), and brine (50 mL). The solvents
were removed under reduced pressure. The residue was dissolved
in dichloromethane, and the solution was filtered through silica
gel. Most of the dichloromethane was then removed under reduced
pressure, and crystallization from petroleum ether gave (1S,2S)-1,2-
bis(2-bromophenyl)ethane-1,2-diol [(+)-4a] (2.32 g, 6.2 mmol,
2
47 (3), 229 (3), 185 (79), 157 (8), 141 (100), 105 (11), 77 (64).
+
HRMS (EI): calcd. for C14
25.9708.
H
12BrClO
2
[M] : 325.9709; found
3
(1RS,2RS)-1-(2-Bromo-5-methoxyphenyl)-2-(2-bromophenyl)ethane-
1,2-diol (rac-syn-4d): (E)-2-(2-Bromostyryl)-1-bromo-4-methoxy-
benzene [(E)-3d] (1.84 g, 5 mmol) was used according to general
procedure III with a reaction time of 3 d. Crystallization from pe-
troleum ether gave (1RS,2RS)-1-(2-bromo-5-methoxyphenyl)-2-(2-
bromophenyl)ethane-1,2-diol (rac-syn-4d; 1.49 g, 3.7 mmol, 74%)
8
6%) as a colorless solid, m.p. 106–107 °C. [α]
D
= +33.0 (c = 1.0,
[
8b]
ethanol) [ref. –33.0 (c = 1.28, ethanol) for the R,R enantiomer].
1
H NMR (300 MHz, CDCl
728
3
): δ = 2.79–2.84 (m, 2 H), 5.30–5.35 as a colorless solid. R
f
= 0.08 (dichloromethane), m.p. 99–100 °C.
7
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7718–7734

Copper-Catalyzed Double Intramolecular Ullmann Coupling
IR: ν˜ = 3392, 1599, 1571, 1472, 1412, 1252, 1192, 1160, 1135, 1119, (C-4ЈЈ), 130.70 (C5Ј or C-6Ј), 130.73 (C5Ј or C-6Ј), 132.9 (C-3ЈЈ),
1
5
046, 1013, 926, 895, 874, 840, 806, 755, 726, 680, 641, 618, 596,
135.8 (C-3Ј), 138.1 (C-1ЈЈ), 144.4 (C-1Ј) ppm. MS (EI): m/z (%) =
–1
+
49, 470, 452 cm . UV (CH
3
CN): λmax (logε) = 281 (3.64), 207
): δ = 2.63 (s, 2 H, OH),
3
.81 (s, 3 H, OCH ), 5.27 (d, J1-H,2-H = 5.6 Hz, 1 H, 1-H), 5.31
395 (Ͻ1) [M] , 211 (100), 185 (50), 157 (8), 131 (4), 102 (7), 77
1
+
(4.52) nm. H NMR (500 MHz, CDCl
3
(41), 51 (8). HRMS (EI): calcd. for C15
found 394.9152.
H11Br
2
NO
2
[M] 394.9151;
3
3
3
3
(
d, J2-H,1-H = 5.7 Hz, 1 H, 2-H), 6.71 (dd, J4Ј-H,3Ј-H = 8.8,
J
J
4
3
(1RS,2RS)-1-(2-Bromo-5-chlorophenyl)-2-(2-bromophenyl)ethane-
1,2-diol (rac-syn-4g): (E)-2-(2-Bromostyryl)-1-bromo-4-chlorobenz-
ene [(E)-2g] (1.86 g, 5 mmol) was used according to general pro-
cedure III with a reaction time of 3 d. Crystallization from petro-
leum ether gave (1RS,2RS)-1-(2-bromo-5-chlorophenyl)-2-(2-
bromophenyl)ethane-1,2-diol (rac-syn-4g; 1.87 g, 4.6 mmol, 92%)
4Ј-H,6Ј-H = 3.1 Hz, 1 H, 4Ј-H), 7.14 (ddd, J4ЈЈ-H,3ЈЈ-H ≈ 7.7,
3
4ЈЈ-H,5ЈЈ-H ≈ 7.7 Hz, 4
J4ЈЈ-H,6ЈЈ-H = 1.2 Hz, 1 H, 4ЈЈ-H), 7.24 (d,
4J6Ј-H,4Ј-H = 3.1 Hz, 1 H, 6Ј-H), 7.32 (d, J3Ј-H,4Ј-H = 8.8 Hz, 1 H,
3
3
Ј-H), 7.34 (ddd, 3J5ЈЈ-H,4ЈЈ-H ≈ 7.5, J5ЈЈ-H,6ЈЈ-H ≈ 7.5 Hz, J5ЈЈ-H,3ЈЈ-H
3
4
3
3
=
1
1
1.2 Hz, 1 H, 5ЈЈ-H), 7.46 (dd,
J
3ЈЈ-H,4ЈЈ-H = 7.8,
J
3ЈЈ-H,5ЈЈ-H
=
=
3
4
.7 Hz, 1 H, 3ЈЈ-H), 7.69 (dd, J6ЈЈ-H,5ЈЈ-H = 7.8, J6ЈЈ-H,5ЈЈ-H
.7 Hz, 1 H, 6ЈЈ-H) ppm. 1 C NMR (125 MHz, CDCl
3
f
as a colorless solid. R = 0.12 (dichloromethane), m.p. 124–125 °C.
3
): δ = 55.6
IR: ν˜ = 3321, 2943, 1759, 1589, 1458, 1431, 1385, 1322, 1297, 1267,
(OCH
3
), 75.18 (C-1 or C-2), 75.20 (C-1 or C-2), 113.2 (C-2Ј), 114.8
1
7
λ
188, 1118, 1097, 1062, 1022, 1003, 945, 900, 882, 846, 833, 815,
(
C-6Ј), 115.9 (C-4Ј), 123.0 (C-2ЈЈ), 127.5 (C-5ЈЈ), 129.6 (C-4ЈЈ),
–
1
55, 726, 678, 637, 617, 593, 543, 479, 465 cm . UV (CH
3
CN):
1
1
29.7 (C-6ЈЈ), 132.8 (C-3ЈЈ), 133.4 (C-3Ј), 138.7 (C-1ЈЈ), 139.6 (C-
1
+
max (logε) = 212 (2.67) nm. H NMR (500 MHz, CDCl ): δ = 2.79
3
3
Ј), 159.0 (C-5Ј) ppm. MS (EI): m/z (%) = 400 (Ͻ1) [M] , 216
3
(
s, 1 H, OH), 2.91 (s, 1 H, OH), 5.25 (d, J1-H,2-H or J2-H,1-H =
(100), 185 (22), 137 (10), 108 (54), 77 (24), 51 (5). HRMS (EI):
3
3
+
6.3 Hz, 1 H, 1-H or 2-H), 5.27 (d, J1-H,2-H or J2-H,1-H = 6.3 Hz,
1
calcd. for C15
1RS,2RS)-1,2-Bis(2-bromo-5-methoxyphenyl)ethane-1,2-diol (rac-
syn-4e): (E)-1,2-Bis(2-bromo-5-methoxyphenyl)ethene [(E)-2e]
1.99 g, 5 mmol) was used according to general procedure III with
a reaction time of 3 d. Crystallization from petroleum ether gave
1RS,2RS)-1,2-bis(2-bromo-5-methoxyphenyl)ethane-1,2-diol (rac-
syn-4e; 1.21 g, 2.8 mmol, 56 %) as a colorless solid. R = 0.09
dichloromethane), m.p. 151 °C. IR: ν˜ = 3497, 2932, 1654, 1601,
2 3
H14Br O [M] 399.9304; found 399.9307.
3
4
H, 1-H or 2-H), 7.12 (dd, J4Ј-H,3Ј-H = 8.5, J4Ј-H,6Ј-H = 2.7 Hz, 1
(
3
3
H, 4Ј-H), 7.15 (ddd,
J
4ЈЈ-H,3ЈЈ-H ≈ 7.6,
4ЈЈ-H,6ЈЈ-H = 1.7 Hz, 1 H, 4ЈЈ-H), 7.35 (ddd, J5ЈЈ-H,4ЈЈ-H ≈ 7.7,
J
4ЈЈ-H,5ЈЈ-H ≈ 7.6 Hz,
4
3
J
J
(
3
4
5ЈЈ-H,6ЈЈ-H ≈ 7.7 Hz,
J5ЈЈ-H,3ЈЈ-H = 1.2 Hz, 1 H, 5ЈЈ-H), 7.36 (d,
3J3Ј-H,4Ј-H = 8.5 Hz, 1 H, 3Ј-H), 7.46 (dd, J3ЈЈ-H,4ЈЈ-H = 8.0 Hz, 1
3
(
3
4
H, 3ЈЈ-H), 7.69 (dd, J6ЈЈ-H,5ЈЈ-H = 7.8, J6ЈЈ-H,4ЈЈ-H = 1.7 Hz, 1 H,
4
13
f
6
(
(
ЈЈ-H), 7.72 (d,
125 MHz, CDCl
C-2Ј), 122.8 (C-2ЈЈ), 127.6 (C-5ЈЈ), 129.6 (C-4Ј), 129.69 (C-6ЈЈ),
J
6Ј-H,4Ј-H = 2.6 Hz, 1 H, 6Ј-H) ppm. C NMR
(
3
): δ = 74.9 (C-1 or C-2), 75.1 (C-1 or C-2), 120.5
1
1
5
2
571, 1470, 1422, 1300, 1260, 1213, 1161, 1127, 1089, 1051, 1032,
011, 927, 898, 870, 833, 800, 767, 755, 728, 646, 627, 595, 538,
1
3
29.73 (C-4ЈЈ), 130.0 (C-6Ј), 132.9 (C-3ЈЈ), 133.67 (C-5Ј), 133.69 (C-
–1
09, 479, 463, 436 cm . UV (CH
3
CN): λmax (logε) = 284 (3.39),
03 (4.66) nm. H NMR (300 MHz, CDCl ): δ = 2.49 (s, 2 H, OH),
.82 (s, 6 H, OCH ), 5.28 (s, 2 H, 1-H and 2-H), 6.71 (dd,
Ј), 138.4 (C-1ЈЈ), 140.6 (C-1Ј) ppm. MS (EI): m/z (%) = 404 (Ͻ1)
1
+
3
[M] , 222 (21), 187 (100), 157 (10), 112 (14), 77 (44), 51 (8). HRMS
3
3
+
(
2 2
EI): calcd. for C14H11Br ClO [M] 403.8809; found 403.8793.
3
3
4
4
J
4Ј-H,3Ј-H = J4ЈЈ-H,3ЈЈ-H = 8.8, J4Ј-H,6Ј-H = J4ЈЈ-H,6ЈЈ-H = 3.1 Hz, 2
H, 4Ј-H and 4ЈЈ-H), 7.24 (d, J6Ј-H,4Ј-H = 4J6ЈЈ-H,4ЈЈ-H = 3.3 Hz, 2 H,
4
(1RS,2RS)-1,2-Bis(2-bromo-5-chlorophenyl)ethane-1,2-diol (rac-syn-
4h): (E)-1,2-Bis(2-bromo-5-chlorophenyl)ethene [(E)-2h] (2.04 g,
5 mmol) was used according to general procedure III with a reac-
tion time of 3 d. Crystallization from petroleum ether gave
Ј-H and 6ЈЈ-H), 7.33 (d, J3Ј-H,4Ј-H = 3J3ЈЈ-H,4ЈЈ-H = 8.8 Hz, 2 H, 3Ј-
3
6
13
H and 3ЈЈ-H) ppm. C NMR (75 MHz, CDCl
3
): δ = 55.6 (OCH
3
),
7
1
1
5.2 (C-1 and C-2), 113.4 (C-2Ј and C-2ЈЈ), 114.8 (C-6Ј and C-6ЈЈ),
16.0 (C-4Ј and C-4ЈЈ), 133.4 (C-3Ј and C-3ЈЈ), 139.6 (C-1Ј and C-
(
1RS,2RS)-1,2-bis(2-bromo-5-chlorophenyl)ethane-1,2-diol (rac-
syn-4h; (2.07 g, 4.7 mmol, 93 %) as a colorless solid. R = 0.13
f
ЈЈ), 159.0 (C-5Ј and C-5ЈЈ) ppm. MS (EI): m/z (%) = 430 (1)
+
(dichloromethane), m.p. 144–146 °C. IR: ν˜ = 3331, 1738, 1458,
1387, 1305, 1188, 1126, 1100, 1054, 1022, 935, 893, 805, 783, 716,
[M] , 216 (96), 187 (12), 172 (7), 137 (19), 108 (100), 78 (17), 63
+
(13). HRMS (ESI): calcd. for C16
2 4
H16Br O Na [M + Na] 452.9308;
–
1
6
(
41, 566, 541, 510, 488, 461, 429, 395 cm . UV (CH
3
CN): λmax
found 452.9325.
1
logε) = 274 (2.67) nm. H NMR (300 MHz, CDCl ): δ = 2.85 (s,
H, OH), 5.21 (s, 2 H, 1-H and 2-H), 7.13 (dd,
4Ј-H,3Ј-H
4ЈЈ-H,3ЈЈ-H = 8.5, J4Ј-H,6Ј-H = J4ЈЈ-H,6ЈЈ-H = 2.6 Hz, 2 H, 4Ј-H and
ЈЈ-H), 7.36 (d, J3Ј-H,4Ј-H = J3ЈЈ-H,4ЈЈ-H = 8.6 Hz, 2 H, 3Ј-H and
ЈЈ-H), 7.72 (d, J6Ј-H,4Ј-H = J6ЈЈ-H,4ЈЈ-H = 2.6 Hz, 2 H, 6Ј-H and
3
ЈЈ-H) ppm. C NMR (75 MHz, CDCl ): δ = 74.9 (C-1 and C-2),
20.4 (C-2Ј and C-2ЈЈ), 140.2 (C-1Ј and C-1ЈЈ), 129.8 (C-4Ј and C-
ЈЈ), 130.0 (C-6Ј and C-6ЈЈ), 133.8 (overlapped, C-5Ј and C-5ЈЈ),
3
3
-Bromo-4-[(1RS,2RS)-2-(2-bromophenyl)-1,2-dihydroxyethyl]-
3
2
J
=
benzonitrile (rac-syn-4f): (E)-4-(2-Bromostyryl)-3-bromobenzo-
nitrile [(E)-2f] (1.81 g, 5 mmol) was used according to general pro-
cedure III with a reaction time of 3 d. Crystallization from petro-
leum ether gave 3-bromo-4-[(1RS,2RS)-2-(2-bromophenyl)-1,2-di-
hydroxyethyl]benzonitrile (rac-syn-4f; 1.87 g, 4.7 mmol, 94%) as a
3
4
4
J
3
3
4
3
6
1
4
1
(
(
C
4
4
13
colorless solid. R
ν˜ = 3529, 3446, 3075, 2233, 1547, 1479, 1464, 1435, 1385, 1334,
f
= 0.10 (dichloromethane), m.p. 110–111 °C. IR:
33.8 (overlapped, C-3Ј and C-3ЈЈ) ppm. MS (ESI): m/z (%) = 439
100) [M + H] , 381 (24), 357 (6), 339 (13), 325 (11), 309 (21), 293
9), 265 (11), 253 (7), 220 (33), 171 (5). HRMS (EI): calcd. for
1
7
306, 1266, 1188, 1118, 1081, 1037, 1022, 904, 839, 821, 785, 773,
45, 701, 664, 615, 539, 509, 471, 443 cm . UV (CH CN): λmax
3
+
–1
1
(logε) = 289 (3.00), 281 (3.07), 241 (4.11) nm. H NMR (500 MHz,
+
14
H10Br
2
Cl
2
O
2
[M] 437.8419; found 437.8397.
CDCl ): δ = 2.80 (s, 1 H, OH), 3.05 (s, 1 H, OH), 5.25 (d,
3
3
3
J
2-H,1-H = 5.8 Hz, 1 H, 2-H), 5.30 (d, J1-H,2-H = 5.8 Hz, 1 H, 1-
(1RS,2RS)-1-(2-Bromo-5-fluorophenyl)-2-(2-bromophenyl)ethane-
1,2-diol (rac-syn-4i): (E)-2-(2-Bromostyryl)-1-bromo-4-fluorobenz-
ene [(E)-2i] (1.78 g, 5 mmol) was used according to general pro-
cedure III with a reaction time of 3 d. Crystallization from petro-
3
3
4
H), 7.17 (ddd, J4ЈЈ-H,3ЈЈ-H ≈ 7.7, J4ЈЈ-H,5ЈЈ-H ≈ 7.7 Hz, J4ЈЈ-H,6ЈЈ-H
=
≈
=
3
3
1
7
.7 Hz, 1 H, 4ЈЈ-H), 7.36 (ddd, J5ЈЈ-H,4ЈЈ-H ≈ 7.6, J5ЈЈ-H,6ЈЈ-H
4 3
.6 Hz, J5ЈЈ-H,3ЈЈ-H = 1.2 Hz, 1 H, 5ЈЈ-H), 7.46 (dd, J3ЈЈ-H,4ЈЈ-H
4
3
8
J
.0, J3ЈЈ-H,5ЈЈ-H = 1.2 Hz, 1 H, 3ЈЈ-H), 7.62 (dd, J5Ј-H,6Ј-H = 7.9, leum ether gave (1RS,2RS)-1-(2-bromo-5-fluorophenyl)-2-(2-
4
3
5Ј-H,3Ј-H = 1.7 Hz, 1 H, 5Ј-H), 7.69 (dd,
J
6ЈЈ-H,5ЈЈ-H = 7.9, bromophenyl)ethane-1,2-diol (rac-syn-4i) (1.64 g, 4.2 mmol, 84%)
= 0.11 (dichloromethane), m.p. 114–115 °C.
4J6ЈЈ-H,4ЈЈ-H = 1.7 Hz, 1 H, 6ЈЈ-H), 7.72 (d, J3Ј-H,5Ј-H = 1.6 Hz, 1 H, as a colorless solid. R
4
f
3
Ј-H), 7.86 (d, 3
125 MHz, CDCl
J
6Ј-H,5Ј-H = 8.1 Hz, 1 H, 6Ј-H) ppm. 13C NMR
): δ = 74.9 (C-1), 75.0 (C-2), 113.2 (C-4Ј), 117.2
IR: ν˜ = 3297, 1737, 1580, 1467, 1434, 1406, 1265, 1231, 1193, 1155,
(
(
3
1107, 1047, 1024, 1006, 945, 870, 844, 833, 813, 773, 754, 724, 680,
–
1
CN), 122.7 (C-2ЈЈ), 123.0 (C-2Ј), 127.7 (C-5ЈЈ), 129.7 (C-6ЈЈ), 130.0 640, 617, 594, 533, 471, 458, 402 cm . UV (CH
3
CN): λmax (logε)
Eur. J. Org. Chem. 2015, 7718–7734
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org 7729

H.-G. Imrich, J. Conrad, U. Beifuss
FULL PAPER
1
1
=
(
270 (3.07), 214 (4.35) nm. H NMR (500 MHz, CDCl
3
): δ = 2.78 chloroform) for the R,R enantiomer]. H NMR (300 MHz,
s, 1 H, OH), 2.90 (s, 1 H, OH), 5.26 (d, J1-H,2-H or 3J2-H,1-H
3
=
3
3
3
CDCl ): δ = 6.29 (s, 2 H), 6.87 (d, J = 8.0 Hz, 2 H), 6.98 (dd, J
3
3
3
3
4
5
.8 Hz, 1 H, 1-H or 2-H), 5.27 (d, J1-H,2-H or J2-H,1-H = 5.8 Hz, = 7.5, J = 7.4 Hz, 2 H), 7.28 (ddd, 2ϫ J ≈ 7.7, J = 1.4 Hz, 2 H),
3 3 3 13
1
H, 1-H or 2-H), 6.88 (ddd, J4Ј-H,5Ј-F = 8.8, J4Ј-H,3Ј-H = 7.6 Hz,
3
7.54 (d, J = 7.5 Hz, 2 H) ppm. C NMR (75 MHz, CDCl ): δ =
4
3
J
J
4Ј-H,6Ј-H = 3.2 Hz, 1 H, 4Ј-H), 7.16 (ddd, J4ЈЈ-H,3ЈЈ-H = 8.0, 86.4, 110.8, 121.1, 124.4, 126.5, 131.3, 160.0 ppm. MS (EI): m/z
4ЈЈ-H,5ЈЈ-H = 7.4 Hz, J4ЈЈ-H,6ЈЈ-H = 1.7 Hz, 1 H, 4ЈЈ-H), 7.35 (ddd, (%) = 210 (100) [M] , 181 (25), 152 (8), 105 (6), 76 (5).
3
4
+
3J5ЈЈ-H,4ЈЈ-H ≈ 7.5, J5ЈЈ-H,6ЈЈ-H ≈ 7.5 Hz, J5ЈЈ-H,3ЈЈ-H = 1.3 Hz, 1 H,
3
4
3
4
(4bRS,9bRS)-3-Methoxy-4b,9b-dihydrobenzofuro[3,2-b]benzofuran
rac-cis-5b): (1RS,2RS)-1-(2-Bromo-5-methoxyphenyl)-2-(2-
5ЈЈ-H), 7.40 (dd, J3Ј-H,4Ј-H = 8.8, J3Ј-H,5Ј-F = 5.3 Hz, 1 H, 3Ј-H),
(
7
.45–7.48 (m, overlapped, 2 H, 6Ј-H and 3ЈЈ-H), 7.69 (dd,
II
3
4
13
bromophenyl)ethane-1,2-diol (rac-syn-4d; 806 mg, 2.0 mmol), Cu
oxinate (70 mg, 0.2 mmol), KI (331 mg, 2.0 mmol), and K PO
1.70 g, 8.0 mmol) were used according to general procedure IV.
J
6ЈЈ-H,5ЈЈ-H = 7.8, J6ЈЈ-H,4ЈЈ-H = 1.8 Hz, 1 H, 6ЈЈ-H) ppm. C NMR
): δ = 74.9 (d, JC,F = 1.1 Hz, C-1), 75.1 (C-2),
16.7 (d, JC,F = 2.0 Hz, C-2Ј), 116.8 (d, JC,F = 22.9 Hz, C-4Ј), 117.0
d, JC,F = 23.8 Hz, C-6Ј), 122.8 (C-2ЈЈ), 127.6 (C-5ЈЈ), 129.70 (C-
ЈЈ or C-6ЈЈ), 129.72 (C-4ЈЈ or C-6ЈЈ), 132.9 (C-3ЈЈ), 133.9 (d, JC,F
7.9 Hz, C-3Ј), 138.5 (C-1ЈЈ), 141.1 (d, JC,F = 7.1 Hz, C-1Ј), 162.0
d, JC,F = 246.7 Hz, C-5Ј) ppm. MS (ESI): m/z (%) = 389 (29) [M
3
4
(
1
(
4
=
(
125 MHz, CDCl
3
(
Flash chromatography over silica gel (petroleum ether/dichloro-
methane, 1:1) gave (4bRS,9bRS)-3-methoxy-4b,9b-dihydrobenzo-
furo[3,2-b]benzofuran (rac-cis-5b; (308 mg, 1.28 mmol, 64%) as a
colorless solid. R = 0.29 (petroleum ether/dichloromethane, 1:1),
f
m.p. 167–168 °C. IR: ν˜ = 2833, 1596, 1484, 1464, 1430, 1279, 1141,
+
+
H] , 309 (100), 287 (76), 281 (20), 255 (13), 203 (17). HRMS
+
1105, 1030, 979, 951, 876, 846, 807, 778, 746, 716, 635, 591, 549,
2 2
(EI): calcd. for C14H11Br FO [M] 387.9104; found 387.9108.
–
1
5
15, 445, 419 cm . UV (CH
3
CN): λmax (logε) = 306 (3.53), 290
(3.61), 207 (4.27) nm. H NMR (500 MHz, CDCl ): δ = 3.79 (s, 3
), 6.26 (d, J4b-H,9b-H = 7.5 Hz, 1 H, 4b-H), 6.28 (d,
1
General Procedure IV for the Intramolecular Bis-O-arylation of 1,2-
Bis(2-haloaryl)ethane-1,2-diols 4: A 10 mL vial was equipped with
3
3
H, OCH
3
3
3
a magnetic stirring bar, and loaded with K
3
PO
4
(1.70 g, 8 mmol),
J9b-H,4b-H = 7.4 Hz, 1 H, 9b-H), 6.78 (d, J1-H,2-H = 8.8 Hz, 1 H,
II
3
4
Cu oxinate (70 mg, 0.2 mmol), KI (332 mg, 2.0 mmol), and 1,2- 1-H), 6.85 (dd overlapped, J2-H,1-H = 8.9, J2-H,4-H = 2.8 Hz, 1 H,
3
bis(2-haloaryl)ethane-1,2-diol 4 (2.0 mmol) under air. The vial was
sealed, evacuated, and refilled with argon three (3ϫ), then water
2-H), 6.87 (d, overlapped, J6-H,7-H = 8.1 Hz, 1 H, 6-H), 6.97 (dd,
3
3
4
J
8-H,7-H ≈ 7.5, J8-H,9-H ≈ 7.5 Hz, 1 H, 8-H), 7.08 (d, J4-H,2-H
=
3
3
(2 mL) and acetonitrile (2 mL) were added. The reaction mixture
2.8 Hz, 1 H, 4-H), 7.28 (ddd,
J
7-H,6-H ≈ 7.7,
J
7-H,8-H ≈ 7.7 Hz,
4
7-H,9-H = 1.4 Hz, 1 H, 7-H), 7.53 (ddd, J9-H,8-H = 7.6, 4J9-H,7-H
3
was stirred at 120 °C for 3 d. Brine (50 mL) was then added, and
the mixture was extracted with ethyl acetate (3ϫ 50 mL). The com-
bined organic layers were dried with Na
J
1
3
= 1.4 Hz, J = 0.7 Hz, 1 H, 9-H) ppm. C NMR (125 MHz,
CDCl ): δ = 56.1 (OCH ), 86.7 (C-9b), 86.9 (C-4b), 110.8 (C-6),
2
SO
4
, and concentrated
3
3
under reduced pressure. The residue was dissolved in dichlorometh-
ane, and the solution was filtered through silica gel and concen-
trated under reduced pressure. Analytically pure product was ob-
tained by column chromatography or crystallization.
110.9 (C-4), 111.1 (C-1), 118.0 (C-2), 121.2 (C-8), 124.6 (C-9a),
124.8 (C-4a), 126.5 (C-9), 131.3 (C-7), 154.0 (C-10a), 154.5 (C-3),
159.9 (C-5a) ppm. MS (EI, 70 eV): m/z (%) = 240 (100) [M] , 225
+
(56), 211 (27), 197 (49), 181 (10), 169 (20), 152 (5), 141 (19), 120
+
(
11), 115 (16). HRMS (EI): calcd. for C15
H
12
O
3
[M] 240.0781;
(
4bRS,9bRS)-4b,9b-Dihydrobenzofuro[3,2-b]benzofuran (rac-cis-
found 240.0759.
[
11i]
5a):
4a; 746 mg, 2.0 mmol), Cu oxinate (69 mg, 0.2 mmol), KI
PO (1.70 g, 8.0 mmol) were used ac-
cording to general procedure IV. After work up, (4bRS,9bRS)-
(1RS,2RS)-1,2-Bis(2-bromophenyl)ethane-1,2-diol (rac-syn-
II
(4bRS,9bRS)-3,8-Dimethoxy-4b,9b-dihydrobenzofuro[3,2-b]benzofu-
ran (rac-cis-5c): (1RS,2RS)-1,2-Bis(2-bromo-5-methoxyphenyl)eth-
(334 mg, 2.0 mmol), and K
3
4
II
ane-1,2-diol (rac-syn-4e; 865 mg, 2.0 mmol), Cu oxinate (70 mg,
4
1
b,9b-dihydrobenzofuro[3,2-b]benzofuran (rac-cis-5a; 379 mg,
.8 mmol, 90%) was isolated. Crystallization from methanol gave
3 4
0.2 mmol), KI (331 mg, 2.0 mmol), and K PO (1.70 g, 8.0 mmol)
were used according to general procedure IV. Flash chromatog-
raphy over silica gel (dichloromethane) gave (4bRS,9bRS)-3,8-di-
methoxy-4b,9b-dihydrobenzofuro[3,2-b]benzofuran (rac-cis-5c;
443 mg, 1.64 mmol, 82%) as a pale yellow solid. R = 0.24 (dichlo-
f
romethane), m.p. 181–183 °C. IR: ν˜ = 2836, 1611, 1485, 1468, 1449,
analytically pure (4bRS,9bRS)-4b,9b-dihydrobenzofuro[3,2-b]-
benzofuran (rac-cis-5a) as colorless needles. R = 0.32 (petroleum
ether/dichloromethane, 7:3), m.p. 117–120 °C (ref.[
f
11i]
m.p. 118–
19 °C). IR: ν˜ = 2964, 1598, 1478, 1461, 1312, 1221, 1166, 1100,
015, 915, 933, 842, 805, 744, 610, 561, 504, 440, 411 cm .
1
1
–
1 1
H
1430, 1308, 1287, 1235, 1145, 1142, 1025, 954, 857, 799, 747, 599,
–
1
NMR (300 MHz, CDCl
3
): δ = 6.29 (s, 2 H, 4b-H and 9b-H), 6.87
510, 465, 448 cm . UV (CH
3
CN): λmax (logε) = 304 (3.88), 226
(4.06), 205 (4.65) nm. H NMR (300 MHz, CDCl ): δ = 3.79 (s, 6
H, OCH ) 6.25 (s, 2 H, 4b-H and 9b-H), 6.77 (d,
6-H,7-H = 8.8 Hz, 2 H, 1-H and 6-H), 6.85 (dd, 3J2-H,1-H
3
3
1
(
d, J1-H,2-H = J6-H,7-H = 8.1 Hz, 2 H, 1-H and 6-H), 6.97 (ddd,
J
J
3
3
3-H,2-H = 3J8-H,7-H ≈ 7.4, 3J3-H,4-H = J8-H,9-H ≈ 7.4 Hz, J3-H,1-H
3
4
3
=
=
3
J
1-H,2-H
=
=
3
3
3
8-H,6-H = 0.9 Hz, 2 H, 3-H and 8-H), 7.28 (ddd, J2-H,1-H
J
3J7-H,6-H = 8.2, J2-H,3-H = J7-H,8-H = 7.4 Hz, J2-H,4-H = 4J7-H,9-H
3
3
4
3J7-H,6-H = 8.8, J2-H,4-H = J7-H,9-H = 2.8 Hz, 2 H, 2-H and 7-H),
4
4
1.2 Hz, 2 H, 2-H and 7-H), 7.54 (dd, J4-H,3-H = 3J9-H,8-H = 7.6,
3
7.06 (d, J4-H,2-H = 4J9-H,7-H = 2.5 Hz, 2 H, 4-H and 9-H) ppm.
4
13
C
=
4
4
13
J
4-H,2-H = J9-H,7-H = 1.3 Hz, 2 H, 4-H and 9-H) ppm. C NMR NMR (75 MHz, CDCl
3
): δ = 56.0 (OCH ), 87.1 (C-4b and C-9b),
3
(75 MHz, CDCl
3
): δ = 86.5 (C-4b and C-9b) 110.8 (C-1 and C-6),
110.8 (C-4 and C-9), 111.1 (C-1 and C-6), 117.9 (C-2 and C-7)
1
1
21.1 (C-3 and C-8), 124.4 (C-4a and C-9a), 126.5 (C-9 and C-4),
125.0 (C-4a and C-9a), 153.9 (C-10a and C-5a), 154.5 (C-3 and C-
+
31.3 (C-2 and C-7), 160.0 (C-10a and C-5a) ppm. MS (EI): m/z 8) ppm. MS (EI, 70 eV): m/z (%) = 270 (100) [M] , 255 (57), 241
+
(%) = 210 (100) [M] , 181 (39), 152 (18), 105 (11), 76 (11).
(9), 227 (27), 211 (7), 184 (8), 135 (7) ppm. HRMS (EI): calcd. for
+
16 14 4
C H O [M] 270.0887; found 270.0887.
(
4bS,9bS)-4b,9b-Dihydrobenzofuro[3,2-b]benzofuran [(–)-5a]:[8a]
(
2
8
1S,2S)-1,2-Bis(2-bromophenyl)ethane-1,2-diol [(+)-4a] (746 mg,
.0 mmol), Cu oxinate (69 mg, 0.2 mmol), KI (1310 mg,
(4bRS,9bRS)-4b,9b-Dihydrobenzofuro[3,2-b]benzofuran-2-carbo-
nitrile (rac-cis-5d): 3-Bromo-4-[(1RS,2RS)-2-(2-bromophenyl)-1,2-
dihydroxyethyl]benzonitrile (rac-syn-4f; 798 mg, 2.0 mmol), Cu
II
II
.0 mmol), and K
3
PO
4
(1.70 g, 8.0 mmol) were used according to
general procedure IV. After work up, (4bS,9bS)-4b,9b-dihydro-
benzofuro[3,2-b]benzofuran [(–)-5a] (355 mg, 1.7 mmol, 85%) was
3 4
oxinate (70 mg, 0.2 mmol), KI (331 mg, 2.0 mmol), and K PO
(1.70 g, 8.0 mmol) were used according to general procedure IV.
Flash chromatography over silica gel (petroleum ether/dichloro-
[8a]
D
isolated. [α] = –413.7 (c = 0.53, chloroform) [ref. +371 (c = 0.5,
7730
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7718–7734

Copper-Catalyzed Double Intramolecular Ullmann Coupling
methane, 1:1) gave (4bRS,9bRS)-4b,9b-dihydrobenzofuro[3,2-b]-
benzofuran-2-carbonitrile (rac-cis-5d; 369 mg, 1.1 mmol, 55%) as
(C-4a and C-9a), 126.5 (C-4 and C-9), 131.5 (C-2 and C-7), 158.5
(C-5a and C-10a) ppm. MS (EI): m/z (%) = 278 (100) [M] , 249
+
a pale yellow oil. R
f
= 0.31 (dichloromethane). IR: ν˜ = 2927, 2219,
(25), 243 (61), 215 (89), 208 (9), 186 (8), 152 (53), 139 (20), 126 (7),
108 (14), 93 (11), 75 (15), 63 (11).
1
8
λ
721, 1607, 1464, 1429, 1274, 1236, 1172, 1121, 1073, 1016, 960,
84, 846, 810, 746, 707, 689, 632, 549, 500, 462 cm . UV (CH
max (log ε) = 316 (3.63), 272 (3.99), 218 (4.09) nm. H NMR
–1
3
CN):
1
(4bRS,9bRS)-3-Fluoro-4b,9b-dihydrobenzofuro[3,2-b]benzofuran
3
(
6
1
500 MHz, CDCl
3
): δ = 6.28 (d, J4b-H,9b-H = 7.5 Hz, 1 H, 4b-H), (rac-cis-5g): (1RS,2RS)-1-(2-Bromo-5-fluorophenyl)-2-(2-bromo-
3
3
II
.39 (d, J9b-H,4b-H = 7.4 Hz, 1 H, 9b-H), 6.88 (d, J6-H,7-H = 8.0 Hz,
phenyl)ethane-1,2-diol (rac-syn-4i; 780 mg, 2.0 mmol), Cu oxinate
H, 6-H), 7.01 (dd, 3J8-H,7-H ≈ 7.7, J8-H,9-H ≈ 7.7 Hz, 1 H, 8-H), (70 mg, 0.2 mmol), KI (331 mg, 2.0 mmol), and K
PO (1.70 g,
.11 (s, 1 H, 1-H), 7.30 (d, J3-H,4-H = 7.5 Hz, 1 H, 3-H), 7.31 (dd, 8.0 mmol) were used according to general procedure IV. Flash
3
3
4
3
7
3
3
3
J
7-H,6-H ≈ 7.7, J7-H,8-H ≈ 7.7 Hz, 1 H, 7-H), 7.54 (d, J9-H,8-H
=
C
chromatography over silica gel (petroleum ether/dichloromethane,
7:3) gave (4bRS,9bRS)-3-fluoro-4b,9b-dihydrobenzofuro[3,2-b]-
3
13
7.3 Hz, 1 H, 9-H), 7.62 (d, J4-H,3-H = 7.7 Hz, 1 H, 4-H) ppm.
NMR (125 MHz, CDCl
3
): δ = 85.2 (C-4b), 87.6 (C-9b), 111.0 (C- benzofuran (rac-cis-5g; 370 mg, 1.62 mmol, 81%) as a colorless so-
), 114.4 (C-1), 114.7 (C-2), 118.4 (CN), 121.7 (C-8), 123.4 (C-9a),
lid. R = 0.25 (petroleum ether/dichloromethane, 7:3), m.p. 147–
149 °C. IR: ν˜ = 1597, 1482, 1326, 1237, 1214, 1175, 1128, 963, 934,
6
1
1
f
25.3 (C-3), 126.6 (C-9), 127.5 (C-4), 129.8 (C-4a), 131.8 (C-7),
–
1
59.8 (C-5a), 160.0 (C-10a) ppm. MS (EI): m/z (%) = 235 (100)
876, 812, 781, 744, 582, 513, 472, 427, 401 cm . UV (CH
3
CN):
+
1
[
[
M] , 206 (55), 178 (9), 151 (10). HRMS (EI): calcd. for C15
M] 235.0628; found 235.0629.
H
9
NO
2
λ
max (log ε) = 289 (3.75), 204 (4.51) nm. H NMR (500 MHz,
+
3
CDCl
3
): δ = 6.25 (d,
J
4b-H,9b-H = 7.5 Hz, 1 H, 4b-H), 6.33 (d,
3
3
4
J
9b-H,4b-H = 7.4 Hz, 1 H, 9b-H), 6.78 (dd, J1-H,2-H = 8.8, J1-H,3-F
(
(
4bRS,9bRS)-3-Chloro-4b,9b-dihydrobenzofuro[3,2-b]benzofuran
3
=
(
4.0 Hz, 1 H, 1-H), 6.88 (d, J6-H,7-H = 8.2 Hz, 1 H, 6-H), 6.97
rac-cis-5e): (1RS,2RS)-1-(2-Bromo-5-chlorophenyl)-2-(2-bromo-
ddd, overlapped, J2-H,1-H ≈ 8.8, 3J2-H,3-F ≈ 8.8 Hz, J2-H,4-H
3
4
=
II
phenyl)ethane-1,2-diol (rac-syn-4g; 816 mg, 2.0 mmol), Cu oxin-
3
3
2.8 Hz, 1 H, 2-H), 6.99 (ddd, overlapped, J8-H,7-H ≈ 7.5, J8-H,9-H
ate (70 mg, 0.2 mmol), KI (331 mg, 2.0 mmol), and K
.0 mmol) were used according to general procedure IV. Flash
chromatography over silica gel (petroleum ether/dichloromethane,
:3) gave (4bRS,9bRS)-3-chloro-4b,9b-dihydrobenzofuro[3,2-b]-
benzofuran (rac-cis-5e; 396 mg, 1.62 mmol, 81%) as a colorless so-
lid. R = 0.40 (petroleum ether/dichloromethane, 7:3), m.p. 137–
39 °C. IR: ν˜ = 3046, 1599, 1477, 1426, 1320, 1275, 1238, 1223,
167, 1117, 1099, 1073, 1014, 975, 952, 935, 900, 880, 864, 846,
3 4
PO (1.70 g,
4
3
≈
7.5 Hz, J8-H,6-H = 1.0 Hz, 1 H, 8-H), 7.22 (dd, J4-H,3-F = 7.7,
8
4
4-H,2-H = 2.9 Hz, 1 H, 4-H), 7.29 (ddd, J7-H,6-H ≈ 7.8, 3J7-H,8-H
3
J
≈
7
.8 Hz, 4J7-H,9-H = 1.4 Hz, 1 H, 7-H), 7.52 (d, J9-H,8-H = 7.5 Hz, 1
3
7
1
3
3
H, 9-H) ppm. C NMR (125 MHz, CDCl ): δ = 86.2 (C-4b), 87.2
3
2
(
C-9b), 110.9 (C-6), 111.3 (d, JC,F = 8.4 Hz, C-1), 113.0 (d, JC,F
f
2
=
24.6 Hz, C-4), 118.1 (d, JC,F = 24.5 Hz, C-2), 121.4 (C-8), 124.2
1
1
8
2
(
C-9a), 125.4 (d, JC,F = 8.6 Hz, C-4a), 126.5 (C-9), 131.5 (C-7),
4
1
1
1
56.0 (d, JC,F = 1.4 Hz, C-10a), 157.4 (d, JC,F = 238.6 Hz, C-3),
59.9 (C-5a) ppm. MS (EI): m/z (%) = 228 (100) [M] , 199 (74),
–
1
14, 793, 774, 744, 726, 680, 617, 596, 572, 511, 449, 417 cm .
+
1
3
UV (CH CN): λmax (logε) = 290 (3.67), 221 (4.11) nm. H NMR
500 MHz, CDCl ): δ = 6.24 (d, J4b-H,9b-H = 7.5 Hz, 1 H, 4b-H),
3
6
+
81 (4), 170 (12). HRMS (EI): calcd. for C14
H
9
FO
2
[M] 228.0581;
3
(
found 228.0584.
3
3
.33 (d, J9b-H,4b-H = 7.4 Hz, 1 H, 9b-H), 6.88 (br. d, J6-H,7-H
=
3
8
.2 Hz, 1 H, 6-H), 6.97 (d, J1-H,2-H = 8.6 Hz, 1 H, 1-H), 6.99 (ddd,
(
2RS,3RS)-2-(2-Bromophenyl)-2,3-dihydrobenzofuran-3-ol (rac-cis-
3
8-H,7-H ≈ 7.5, 3 8-H,9-H ≈ 7.5 Hz, 4J8-H,6-H = 1.0 Hz, 1 H, 8-H),
J
J
6
7
2
a): (1RS,2RS)-1,2-Bis(2-bromophenyl)ethane-1,2-diol (rac-syn-4a;
46 mg, 2.0 mmol), Cu oxinate (69 mg, 0.2 mmol), KI (334 mg,
.0 mmol), and K PO (427 mg, 2.0 mmol) were used according to
3 4
7
.22 (dd, 3J2-H,1-H = 8.6, 4J2-H,4-H = 2.3 Hz, 1 H, 2-H), 7.29 (ddd,
II
3
7-H,6-H = 8.7, 3J7-H,8-H = 7.7 Hz, 4J7-H,9-H = 1.5 Hz, 1 H, 7-H),
.49 (d, 4J4-H,2-H = 2.4 Hz, 1 H, 4-H), 7.52 (ddd, J9-H,8-H = 7.6,
J
3
7
2
8
1
4
1
general procedure IV. After work up, (4bRS,9bRS)-4b,9b-di-
hydrobenzofuro[3,2-b]benzofuran (rac-cis-5a; 67 mg, 0.32 mmol,
ϫJ ≈ 0.7 Hz, 1 H, 9-H) ppm. 13C NMR (125 MHz, CDCl
): δ =
3
5.8 (C-4b), 87.3 (C-9b), 110.9 (C-6), 111.9 (C-1), 121.4 (C-8),
24.0 (C-9a), 125.8 (C-3 or C-4a), 126.2 (C-3 or C-4a), 126.52 (C-
or C-9), 126.53 (C-4 or C-9), 131.3 (C-2), 131.6 (C-7), 158.7 (C-
1
6%) was isolated along with (2RS,3RS)-2-(2-bromophenyl)-2,3-
dihydrobenzofuran-3-ol (rac-cis-6a; 152 mg, 0.52 mmol, 26%).
Data for rac-cis-6a: R = 0.14 (petroleum ether/dichloromethane,
:3), m.p. 122–123 °C. IR: ν˜ = 3480, 2962, 1599, 1567, 1476, 1463,
f
0a), 159.9 (C-5a) ppm. MS (EI, 70 eV): m/z (%) = 244 (100)
7
1
9
+
[
M] , 215 (50), 209 (9), 181 (58), 152 (47), 126 (9), 76 (22), 63 (16).
HRMS (EI): calcd. for C14
436, 1410, 1306, 1264, 1227, 1176, 1150, 1109, 1049, 1027, 1014,
69, 920, 866, 832, 773, 746, 700, 675, 627, 614, 573, 498, 464,
+
H
9
ClO
2
[M] 244.0286; found 244.0286.
–
1
(
(
1
0
4bRS,9bRS)-3,8-Dichloro-4b,9b-dihydrobenzofuro[3,2-b]benzofuran
3
433 cm . UV (CH CN): λmax (logε) = 279 (3.47), 211 (3.94) nm.
[
11i]
1
3
rac-cis-5f):
(1RS,2RS)-1,2-Bis(2-bromo-5-chlorophenyl)ethane-
H NMR (500 MHz, CDCl
3
): δ = 1.41 (d, JOH,3-H = 6.9 Hz, 1 H,
,2-diol (rac-syn-4h; 882 mg, 2.0 mmol), Cu oxinate (70 mg, OH), 5.65 (dd, J3-H,OH ≈ 6.5, 3J3-H,2-H ≈ 6.5 Hz, 1 H, 3-H), 5.86
II
3
3
3
.2 mmol), KI (331 mg, 2.0 mmol), and K
3
PO
4
(1.70 g, 8.0 mmol)
(d, J2-H,3-H = 6.2 Hz, 1 H, 2-H), 7.02 (ddd, overlapped, J5-H,4-H ≈
3
4
were used according to general procedure IV. Flash chromatog-
raphy over silica gel (petroleum ether/dichloromethane, 1:1) gave
7.4, J5-H,6-H ≈ 7.4 Hz, J5-H,7-H = 0.7 Hz, 1 H, 5-H), 7.02 (d, over-
3 3
lapped, J7-H,6-H = 8.1 Hz, 1 H, 7-H), 7.24 (ddd, J4Ј-H,3Ј-H ≈ 7.8,
3
4
(
4bRS,9bRS)-3,8-dichloro-4b,9b-dihydrobenzofuro[3,2-b]benzo-
furan (rac-cis-5f; 430 mg, 1.54 mmol, 77%) as a colorless solid. R
0.4 (petroleum ether/dichloromethane, 1:1), m.p. 256–259 °C
J
4Ј-H,5Ј-H ≈ 7.8 Hz, J4Ј-H,6Ј-H = 1.6 Hz, 1 H, 4Ј-H), 7.34 (ddd,
3J6-H,5-H ≈ 7.9,
3
J
6-H,7-H ≈ 7.9 Hz, J6-H,4-H = 1.3 Hz, 1 H, 6-H),
4
f
3
3
=
7.38 (ddd, J5Ј-H,6Ј-H ≈ 7.4, J5Ј-H,4Ј-H ≈ 7.4 Hz, 3J5Ј-H,3Ј-H = 1.0 Hz,
1 H, 5Ј-H), 7.48 (dd, J4-H,5-H = 7.5, 4J4-H,6-H = 1.3 Hz, 1 H, 4-H),
7.63 (dd, J3Ј-H,4Ј-H = 7.9, 4J3Ј-H,5Ј-H = 1.1 Hz, 1 H, 3Ј-H), 7.65 (dd,
ref.[
11i]
m.p. 248–250 °C). IR: ν˜ = 1601, 1478, 1426, 1320, 1167,
117, 1072, 1031, 950, 814, 785, 745, 726, 693, 597, 576, 535, 516,
3
(
3
1
4
–1
3
J
6Ј-H,5Ј-H = 7.4, 4J6Ј-H,4Ј-H = 1.4 Hz, 1 H, 6Ј-H) ppm. C NMR
13
54, 427, 399 cm . UV (CH
3
CN): λmax (logε) = 292 (3.59), 227
): δ = 6.28 (s, 2 H, 4b-H
1
(
4.21) nm. H NMR (300 MHz, CDCl
3
3
(125 MHz, CDCl ): δ = 71.8 (C-3), 87.5 (C-2), 110.6 (C-7), 121.56
(C-2Ј), 121.58 (C-5), 126.3 (C-4), 127.5 (C-5Ј), 127.9 (C-3a), 128.7
3
3
and 9b-H), 6.80 (d, J1-H,2-H = J6-H,7-H = 8.7 Hz, 2 H, 1-H and 6-
H), 7.24 (dd, J2-H,1-H = 3J7-H,6-H = 8.5, J2-H,4-H = J7-H,9-H
3
4
4
=
(C-6Ј), 129.7 (C-4Ј), 130.9 (C-6), 132.5 (C-3Ј), 135.1 (C-1Ј), 159.5
.3 Hz, 2 H, 2-H and 7-H), 7.48 (d, J4-H,2-H = 4J9-H,7-H = 2.3 Hz, (C-7a) ppm. MS (EI): m/z (%) = 290 (39) [M] , 272 (100), 261 (33),
4
+
2
2
H, 4-H and 9-H) ppm. 13C NMR (75 MHz, CDCl
): δ = 86.6 169 (46), 165 (70), 121 (81), 97 (33), 71 (41), 57 (65). HRMS (EI):
3
+
(
C-4b and C-9b), 112.0 (C-1 and C-4), 125.8 (C-3 and C-8), 126.1
calcd. for C14
H11BrO
2
[M] 289.9937; found 289.9950.
www.eurjoc.org
Eur. J. Org. Chem. 2015, 7718–7734
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7731

H.-G. Imrich, J. Conrad, U. Beifuss
2RS,3SR)-2-(2-Bromophenyl)-2,3-dihydrobenzofuran-3-ol (rac- NMR spectra, and Dr. Alevtina Mikhael (Institut für Chemie, Uni-
FULL PAPER
(
trans-6a): (1RS,2SR)-1,2-Bis(2-bromophenyl)ethane-1,2-diol
versität Hohenheim) and Dipl.-Ing. (FH) Joachim Trinkner (Insti-
tut für Organische Chemie, Universität Stuttgart, Germany) for re-
cording mass spectra.
(
(
meso-4a; 742 mg, 2.0 mmol), CuII oxinate (69 mg, 0.2 mmol), KI
334 mg, 2.0 mmol), and K PO (1.70 g, 8.0 mmol) were used ac-
3
4
cording to general procedure IV. Crystallization from dichloro-
methane/petroleum ether gave (2RS,3SR)-2-(2-bromophenyl)-2,3-
dihydrobenzofuran-3-ol (rac-trans-6a; 266 mg, 0.92 mmol, 46%) as
[
1] For reviews on Ullmann couplings, see: a) C. Sambiagio, S. P.
Marsden, A. J. Blacker, P. C. McGowan, Chem. Soc. Rev. 2014,
43, 3525; b) G. Evano, N. Blanchard, Copper-Mediated Cross-
Coupling Reactions, Wiley, New Jersey, 2014; c) H. Lin, D. Sun,
Org. Prep. Proced. Int. 2013, 45, 341; d) Y. Liu, J.-P. Wan,
Chem. Asian J. 2012, 7, 1488; e) E. Sperotto, G. P. M.
Van Klink, G. Van Koten, J. G. De Vries, Dalton Trans. 2010,
f
a colorless solid. R = 0.13 (petroleum ether/dichloromethane, 7:3),
m.p. 106–107 °C. IR: ν˜ = 3238, 1599, 1568, 1474, 1464, 1439, 1313,
1
8
λ
291, 1256, 1234, 1164, 1120, 1099, 1036, 1013, 1000, 967, 878,
–1
44, 811, 746, 682, 638, 605, 573, 534, 485, 448 cm . UV (CH
3
CN):
1
max (logε) = 287 (3.65), 280 (3.66), 218 (4.17), 213 (4.196) nm. H
39, 10338; f) F. Monnier, M. Taillefer, Angew. Chem. Int. Ed.
3
3
NMR (500 MHz, CDCl ): δ = 2.47 (s, 1 H, OH), 5.22 (d, J3-H,2-H
2
009, 48, 6954; Angew. Chem. 2009, 121, 7088; g) D. Ma, Q.
3
=
1.7 Hz, 1 H, 3-H), 5.87 (d, J2-H,3-H = 2.1 Hz, 1 H, 2-H), 6.99
Cai, Acc. Chem. Res. 2008, 41, 1450; h) G. Evano, N. Blanch-
ard, M. Toumi, Chem. Rev. 2008, 108, 3054; i) I. P. Beletskaya,
A. V. Cheprakov, Coord. Chem. Rev. 2004, 248, 2337.
3
3
(
ddd, J5-H,4-H ≈ 7.5, J5-H,6-H ≈ 7.5 Hz, 4J5-H,7-H = 1.0 Hz, 1 H, 5-
H), 7.05 (dd, J7-H,6-H = 7.0, 4J7-H,5-H = 0.7 Hz, 1 H, 7-H), 7.16–
3
7
.19 (m, 1 H, 4Ј-H), 7.21–7.24 (m, overlapped, 2 H, 5Ј-H and 6Ј- [2] For copper-catalyzed intermolecular O-arylations, see: a) M. P.
3
3
4
H), 7.35 (ddd, J6-H,5-H ≈ 7.6, J6-H,7-H ≈ 7.6 Hz, J6-H,4-H = 1.5 Hz,
Drapeau, T. Ollevier, M. Taillefer, Chem. Eur. J. 2014, 20, 5231;
b) Y. Liu, S. K. Park, Y. Xiao, J. Chae, Org. Biomol. Chem.
2014, 12, 4747; c) A. V. Anzalone, T. Y. Wang, Z. Chen, V. W.
Cornish, Angew. Chem. Int. Ed. 2013, 52, 650; d) S. Yang, W.
Xie, H. Zhou, C. Wu, Y. Yang, J. Niu, W. Yang, J. Xu, Tetrahe-
dron 2013, 69, 3415; e) M. Wang, B. Yuan, T. Ma, H. Jiang, Y.
Li, RSC Adv. 2012, 2, 5528; f) D. Maiti, Chem. Commun. 2011,
3
1
7
H, 6-H), 7.38 (ddd, J4-H,5-H = 7.5, 2ϫJ ≈ 0.7 Hz, 1 H, 4-H),
3
13
.61 (ddd, J3Ј-H,4Ј-H = 7.8, 2ϫJ ≈ 0.8 Hz, 1 H, 3Ј-H) ppm.
C
NMR (125 MHz, CDCl
3
): δ = 79.3 (C-3), 90.9 (C-2), 110.4 (C-7),
1
1
1
21.67 (C-2Ј), 121.70 (C-5), 126.2 (C-4), 126.3 (C-3a), 126.5 (C-6Ј),
27.6 (C-5Ј), 129.3 (C-4Ј), 131.2 (C-6), 133.02 (C-3Ј) 138.0 (C-1Ј),
+
60.4 (C-7a) ppm. MS (EI): m/z (%) = 290 (50) [M] , 272 (31), 261
4
7, 8340; g) J.-P. Wan, C. Wang, Y. Liu, Org. Biomol. Chem.
(
25), 169 (63), 165 (58), 121 (100), 105 (17), 77 (24). HRMS (EI):
2011, 9, 6481; h) D. Maiti, S. L. Buchwald, J. Org. Chem. 2010,
+
calcd. for C14
H11BrO
2
[M] 289.9937; found 289.9942.
75, 1791; i) D. Maiti, S. L. Buchwald, J. Am. Chem. Soc. 2009,
131, 17423; j) D. Vuluga, J. Legros, B. Crousse, D. Bonnet-
(
2RS,3RS)-2-(2-Chlorophenyl)-2,3-dihydrobenzofuran-3-ol (rac-cis-
Delpon, Eur. J. Org. Chem. 2009, 3513; k) Q. Zhang, D. Wang,
X. Wang, K. Ding, J. Org. Chem. 2009, 74, 7187; l) Y.-H. Liu,
G. Li, L.-M. Yang, Tetrahedron Lett. 2009, 50, 343; m) R. A.
Altman, A. Shafir, A. Choi, P. A. Lichtor, S. L. Buchwald, J.
Org. Chem. 2008, 73, 284; n) J. Niu, H. Zhou, Z. Li, J. Xu, S.
Hu, J. Org. Chem. 2008, 73, 7814; o) N. Xia, M. Taillefer,
Chem. Eur. J. 2008, 14, 6037; p) J. W. W. Chang, S. Chee, S.
Maka, P. Buranaprasertsuk, W. Chavasiri, P. W. H. Chan, Tet-
rahedron Lett. 2008, 49, 2018; q) A. Shafir, P. A. Lichtor, S. L.
Buchwald, J. Am. Chem. Soc. 2007, 129, 3490; r) H. Zhang, D.
Ma, W. Cao, Synlett 2007, 2, 243; s) H. Rao, Y. Jin, H. Fu, Y.
Jiang, Y. Zhao, Chem. Eur. J. 2006, 12, 3636; t) H.-J. Cristau,
P. P. Cellier, S. Hamada, J.-F. Spindler, M. Taillefer, Org. Lett.
6
b): (1RS,2RS)-1-(2-Bromophenyl)-2-(2-chlorophenyl)ethane-1,2-
II
diol (rac-syn-4c; 495 mg, 2.0 mmol), Cu oxinate (70 mg,
.2 mmol), KI (331 mg, 2.0 mmol), and K PO (1.70 g, 8.0 mmol)
0
3
4
were used according to general procedure IV. Flash chromatog-
raphy over silica gel (petroleum ether/dichloromethane, 1:1) gave
(
2RS,3RS)-2-(2-chlorophenyl)-2,3-dihydrobenzofuran-3-ol (rac-cis-
b; (336 mg, 1.36 mmol, 68 %) as a colorless solid, and
4bRS,9bRS)-4b,9b-dihydrobenzofuro[3,2-b]benzofuran (rac-cis-
a; 19 mg, 0.09 mmol, 5%). Data for rac-cis-6b: R = 0.18 (petro-
leum ether/dichloromethane, 1:1), m.p. 118–119 °C. IR: ν˜ = 3414,
6
(
5
f
3
1
5
052, 1599, 1574, 1475, 1466, 1442, 1273, 1229, 1179, 1149, 1128,
107, 1052, 1035, 1015, 985, 935, 873, 832, 775, 745, 700, 634, 615,
2
004, 6, 913; u) D. Ma, Q. Cai, Org. Lett. 2003, 5, 3799; v) J.-
–
1
75, 561, 474, 438, 417 cm . UV (CH
3
CN): λmax (log ε) = 293
): δ = 1.39 (d,
F. Marcoux, S. Doye, S. L. Buchwald, J. Am. Chem. Soc. 1997,
1
(
3.44), 222 (4.47) nm. H NMR (500 MHz, CDCl
J
3
119, 10539.
3
3
3
OH,3-H = 6.6 Hz, 1 H, OH), 5.61 (dd, JOH,3-H ≈ 6.5, J3-H,2-H
.5 Hz, 1 H, 3-H), 5.89 (d, J2-H,3-H = 6.2 Hz, 1 H, 2-H), 7.01 (ddd,
≈
[3] For copper-catalyzed intramolecular O-arylations, see: a) C.
Chen, P. G. Dormer, J. Org. Chem. 2005, 70, 6964; b) J. Niu,
P. Guo, J. Kang, Z. Li, J. Xu, S. Hu, J. Org. Chem. 2009, 74,
5075; c) S. Udd, J. Jokela, R. Franzén, J. Tois, Tetrahedron Lett.
2010, 51, 1030; d) F. Wu, J. Zhang, Q. Wei, P. Liu, J. Xie, H.
Jiang, B. Dai, Org. Biomol. Chem. 2014, 12, 9696; e) P. Saha,
T. Ramana, N. Purkait, M. A. Ali, R. Paul, T. Punniyamurthy,
J. Org. Chem. 2009, 74, 8719; f) N. Barbero, M. Carril, R. San-
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10194; k) J. J. Sahn, S. F. Martin, Tetrahedron Lett. 2011, 52,
3
6
3
3
4
overlapped, J5-H,4-H ≈ 7.5, J5-H,6-H ≈ 7.5 Hz, J5-H,7-H = 1.0 Hz, 1
H, 5-H), 7.02 (d, overlapped, J7-H,6-H = 7.8 Hz, 1 H, 7-H), 7.29–
3
3
7
.36 (m, 3 H, 6-H, 5Ј-H and 4Ј-H), 7.45 (dd, J3Ј-H,4Ј-H = 7.4,
4
3Ј-H,5Ј-H = 1.8 Hz, 1 H, 3Ј-H), 7.48 (dm, J4-H,4-H = 7.7, 3J4-H,5-H
3
J
7.7 Hz, 1 H, 4-H), 7.67 (dd, J6Ј-H,5Ј-H = 7.3, 4J6Ј-H,4Ј-H = 2.1 Hz,
3
=
1
H, 6Ј-H) ppm. 13C NMR (125 MHz, CDCl
): δ = 72.0 (C-3), 85.8
3
(C-2), 110.6 (C-7) 121.6 (C-5), 126.3 (C-4), 127.0 (C-5), 128.0 (C-
3
a), 128.3 (C-6Ј), 129.29 (C-3Ј or C-4Ј), 129.34 (C-3Ј or C-4Ј), 130.9
(
(
(
C-6), 131.7 (C-2Ј), 133.5 (C-1Ј), 159.5 (C-7a) ppm. MS (EI): m/z
%) = 246 (92), 217 (52), 183 (20), 165 (16), 152 (6), 139 (11), 121
100), 105 (17), 89 (8). HRMS (EI): calcd. for C14
46.0448; found 246.0451.
Supporting Information (see footnote on the first page of this arti-
+
2
H11ClO [M]
6
855; l) X. Zhang, X. Guo, L. Fang, Y. Song, X. Fan, Eur. J.
2
Org. Chem. 2013, 8087.
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1
13
cle): H and C NMR spectra for compounds 2a–2i, 4a–4i, 5a–5g,
a, and 6b; computational studies on compound rac-cis-5e.
6
Acknowledgments
The authors thank Mario Wolf and Dipl.-Biol. Christina Braun-
berger (Institut für Chemie, Universität Hohenheim) for recording
7732
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7718–7734

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