Formation of substituted 1-naphthols and related products via dimerization of alkyl 3-(o-halo(het)aryl)-oxopropanoates based on a CuI-catalyzed domino C-arylation/condensation/aromatization process

Article abstract of DOI:10.1016/j.tet.2016.04.067

Substrates bearing both a β-ketoester moiety and a (het)aryl halide structure element were dimerized to 1-naphthols and related products in the presence of catalytic amounts of CuI in isopropanol. The reaction starts with an intermolecular C-arylation, which is followed by an intramolecular condensation. The final aromatization delivers the highly substituted products with yields up to 81%.

Full text of DOI:10.1016/j.tet.2016.04.067

Tetrahedron 72 (2016) 3454e3467
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formation of substituted 1-naphthols and related products via
dimerization of alkyl 3-(o-halo(het)aryl)-oxopropanoates based
on a CuI-catalyzed domino C-arylation/condensation/aromatization
process
a
a
a
a
€
Heike Weischedel , Kavitha Sudheendran , Alevtina Mikhael , Jurgen Conrad ,
Wolfgang Frey b, Uwe Beifuss a
Bioorganische Chemie, Institut fur Chemie, Universitat Hohenheim, Garbenstraße 30, D-70599 Stuttgart, Germany
,
*
a
€
€
b
€
€
Institut fur Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Substrates bearing both a b-ketoester moiety and a (het)aryl halide structure element were dimerized to
Received 15 March 2016
Received in revised form 21 April 2016
Accepted 22 April 2016
1-naphthols and related products in the presence of catalytic amounts of CuI in isopropanol. The reaction
starts with an intermolecular C-arylation, which is followed by an intramolecular condensation. The final
aromatization delivers the highly substituted products with yields up to 81%.
Ó 2016 Elsevier Ltd. All rights reserved.
Available online 25 April 2016
Keywords:
C-Arylation
Copper
Cross-coupling
Dimerization
Domino reaction
1. Introduction
and aryl bromides are routinely employed as C-arylation reagents
in Hurtley type reactions. Acyclic and cyclic
b-diketones, acyclic
The C-arylation of active methylene compounds ranks among
the most important copper-catalyzed cross-coupling reactions.1
This transformation has been introduced by Hurtley in 1929 who
b-ketoesters, malonic esters, cyanoacetic esters and malononitriles
are particular suitable as CH acidic compounds. In addition to
intermolecular reactions the intramolecular version of the Hurtley
reaction has also been addressed and exploited for the construc-
tion of different carbo- and heterocycles, such as
3,4-dihydronaphthalen-2(1H)-ones6a and oxindoles.6b The syn-
thetic value of the Hurtley reaction for the preparation of carbo-
and heterocycles can be broadened significantly by its combination
with other transformations to new domino reactions.7,8 Typical
examples include the copper-catalyzed reactions between
reacted 2-bromobenzoic acid with several b-dicarbonyls, such as
acetyl acetone, ethyl acetoacetate and diethyl malonate, using
copper bronze or copper acetate as the catalyst and sodium eth-
oxide as the base in boiling anhydrous ethanol.2 The scope of the
classical Hurtley reaction is narrow since it is limited to 2-
halobenzoic acids and similar activated substrates. For many de-
cades, reactions with non activated substrates such as aryl halides
could only be carried out with success by employing strong bases,
high loads of the copper-source and harsh reaction conditions.3
Only over the last decade, we have witnessed remarkable prog-
ress in the development of mild reaction conditions for the copper-
catalyzed C-arylation of CH acidic compounds with non activated
aryl halides.4 The achievements made can be primarily attributed
to the use of additives with complex forming abilities, such as di-
amines, amino acids and carboxylic acids.5 Nowadays, aryl iodides
1,2-dihaloarenes and
ans9a and dibenzofurans,9b the transformations of o-halophenols
with
-dicarbonyls to benzofuran-2(3H)ones10 and the reactions of
both unprotected and protected o-haloanilines with -dicarbonyls
b-dicarbonyls for the synthesis of benzofur-
b
b
for the preparation of indoles.11 Other substrates for domino re-
actions including copper-catalyzed C-arylations are o-halobenzyl-
amines for the synthesis of isoquinolines,12 o-halobenzamides for
the preparation of isoquinolin-1(2H)-ones13a and benzimidazo
[1,2-b]iso-quinolin-ones,13b and o-halobenzyl halides for the con-
struction of either naphthalenes14a,b or 4H-chromenes.14b
This work focuses on an aspect of copper-catalyzed arylations
that has not yet been addressed: the dimerization of substrates
* Corresponding author. Tel.: þ49 711 459 22171; fax: þ49 711 459 22951;
e-mail address: ubeifuss@uni-hohenheim.de (U. Beifuss).
http://dx.doi.org/10.1016/j.tet.2016.04.067
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
3455
Table 1
containing both a b-ketoester moiety and a (het)aryl halide struc-
Impact of different bases and additives on the Cu(I)-catalyzed dimerization of 1aa
tural element. Here, we report on the conversion of two alkyl 3-(o-
halo(het)aryl)-3-oxopropanoates into substituted 3-aryl-1-
naphthols and related products. The copper-catalyzed process is
based on a domino C-arylation/condensation/aromatization.
2. Results and discussion
We wondered whether it is possible to achieve the dimerization
of alkyl 3-(o-haloaryl)-3-oxopropanoates 1 under the conditions of
a Cu(I)-catalyzed cross-coupling to deliver 3-aryl-1-naphthols 2 as
outlined in Scheme 1.
Entry
Base (equiv)
Additive (mol %)
Yield 2a (%)
1
2
3
4
5
6
7
8
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
K2CO3 (1.5)
K3PO4 (1.5)
DABCO (1.5)
NaHCO3 (1.5)
K2CO3 (1.0)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
d
26
12b
34
17b
40
32
d
d
d
d
d
d
d
d
18
37
2
9
d
10
11
12
13
14
15
16
17
18
19
20
21
1.10-Phenanthroline (30)
DMEDA (30)
16
30
44
49
50
48
38
52
44
43
54c
L-Proline (30)
Acetic acid (30)
Propionic acid (30)
Pivalic acid (30)
Isovaleric acid (30)
Picolinic acid (30)
Propionic acid (50)
Propionic acid (80)
Propionic acid (120)
Propionic acid (30)
Scheme 1. Proposed dimerization of two 3-(o-haloaryl)-3-oxopropanoates 1.
A report on the formation of traces of such dimerization prod-
ucts upon reaction between an alkyl 3-(o-haloaryl)-3-
oxopropanoate and a
concerning the feasibility of the transformation envisaged. The
conversion of two molecules of methyl 3-(20-bromophenyl)-3-
oxopropanoate (1a) into the 3-aryl-1-naphthol 2a was chosen as
the model reaction.
a
All reactions were performed using 1 mmol of 1a in 2 mL DMF in a sealed vial.
b
-dicarbonyl15 confirmed our assumption
b
c
The reactions were run under air.
The reaction was run in the presence of molecular sieves 4 A.
ꢀ
slightly improved when the transformation was run in the pres-
ence of 50 mol % propionic acid (Table 1, entry 18). A further in-
crease of the amount of the acidic additive to 80 and 120 mol %,
resp., had no positive effect on the yield (Table 1, entries 19 and
20). Interestingly, the yield of 2a could be improved slightly when
To achieve the dimerization, 1 mmol of 1a was reacted with
2 mmol of Cs2CO3 as the base and 20 mol % of CuI as the catalyst in
DMF under argon at 100 ꢀC for 24 h (Table 1, entry 1). Fortunately,
the exclusive formation of the 3-aryl-1-naphthol 2a was observed,
albeit in low yield (26%). For optimizing the model reaction, the
effect of different bases, additives, catalysts and solvents on the
outcome of the transformation was studied. To start with, the role
of the base and the additive was addressed (Table 1). When the
amount of Cs2CO3 was decreased from 2.0 to 1.5 equiv, the yield of
2a increased to 34% (Table 1, entry 3). Control experiments that
were run under air demonstrated that it is advantageous to per-
form the transformations under argon (Table 1, entries 2 and 4).
Then, it was studied whether Cs2CO3 can be replaced with other
bases, such as K2CO3, K3PO4, DABCO and NaHCO3 (Table 1, entries
5e8). K2CO3 turned out to give the best yields. With 1.5 equiv
K2CO3, 40% of the product could be isolated (Table 1, entry 5).
Interestingly, the 3-aryl-1-naphthol 2a could be isolated in 37%
yield when the amount of K2CO3 was further decreased to
1.0 equiv (Table 1, entry 9).
ꢀ
molecular sieves 4 A were added to the reaction mixture (Table 1,
entry 21). Since propionic acid is cheaper than pivalic acid, all
further optimizations were run in the presence of this carboxylic
acid.
The influence of different Cu-sources and solvents was studied
next (Table 2). Exploratory experiments were performed under
the conditions of Table 1, entry 21. They clearly demonstrated that
the formation of 2a can not only be catalyzed by CuI, but also by
a range of other Cu(I) compounds, such as CuBr, CuCl, Cu2O and
Cu(I)acetate (Table 2, entries 2e5), by elemental copper (Table 2,
entry 8) and Cu(II) compounds such as Cu(II)acetate and Cu(OTf)2
(Table 2, entries 6 and 7). Even in the absence of any copper-source
the product 2a was formed in 30% yield (Table 2, entry 11).
However, it should be noted a) that with none of the other Cu-
sources the yield obtained with 20 mol % CuI (Table 2, entry 1)
could be improved and b) that with Cu-powder and Cu(II)acetate
the yield was not higher than in the absence of any Cu-source
(Table 2, entries 8, 6 and 11). It is also remarkable that the yield
of 2a was only slightly lower when the amount of CuI was de-
creased from 20 to 5 mol % (Table 2, entry 10) As a result, all fur-
ther experiments were run with only 5 mol % CuI as the catalyst.
Next, we focused on the effect of different solvents on the outcome
of the model reaction. For this purpose, the transformation was
run in a number of solvents which have been used successfully in
Cu(I)-catalyzed cross couplings. The yield could not be improved
by running the reaction in other polar aprotic solvents, such as
acetonitrile, DMSO and DMA (Table 2, entries 12e14). It came as
a surprise that the yield of 2a could be increased considerably
Next, the effect of different additives on the yield of the model
reaction was evaluated. For this purpose,
b-ketoester 1a was
reacted under the conditions of Table 1, entry 5 in the presence of
30 mol % of a number of additives, which have proven their value
in numerous Cu(I)-catalyzed reactions. However, 1,10-
phenanthroline, DMEDA as well as L-proline were found not
suitable to improve the yield of 2a (Table 1, entries 10e12). For-
tunately, it turned out that acidic additives, such as acetic acid,
propionic acid, pivalic acid, isovaleric acid and picolinic acid are
particularly useful to increase the yield of the model reaction
(Table 1, entries 13e17). Best results were achieved with propionic
acid and pivalic acid which allowed the isolation of 2a in 49 and
50%, resp. (Table 1, entries 14 and 15). The yield of 2a could be

3456
H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
Table 2
Table 3
Influence of the Cu-source and the solvent on the Cu(I)-catalyzed dimerization of 1aa
Influence of bases, additives and Cu-sources on the dimerization of 1a with iso-
propanol as the solventa
Entry Catalyst (mol %) Solvent
T (ꢀC) Time (h) Yield 2a (%)
Entry
Additive
Base
Catalyst
Yield 2a (%)
1
2
3
4
5
6
7
8
CuI (20)
DMF
DMF
DMF
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
16
24
16
16
16
54
46
47
36
34
30
35
25
37
45
30
42
30
30
82
42
60
64
79b
75
67c
70
61
2
b
b
b
b
b
CuBr (20)
CuCl (20)
Cu2O (20)
Cu(I)acetate (20) DMF
Cu(II)acetate (20) DMF
Cu(OTf)2 (20)
Cu-powder (20)
CuI (10)
Cu(I) (5)
d
1
2
3
4
5
6
7
8
Pivalic acid
Acetic acid
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
(NH4)2CO3
K3PO4
d
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu2O
CuI
d
72
70
69
62c
64c
71
59
76
d
Isovaleric acid
Propionic acid
Propionic acid
Propionic acid
Propionic acid
Propionic acid
Propionic acid
d
DMF
DMF
DMF
DMF
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
9
b
DMF
10
11
12
13
14
15
16
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
55
73
56
58
70d
34
4
b
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Acetonitrile
DMSO
DMA
Isopropanol
Water
Propionic acid
Propionic acid
Propionic acid
Propionic acid
Propionic acid
Propionic acid
b
b
b
b
e
1,2-Dichlorobenzene 100
THF
d
100
100
80
85
80
a
The reactions were performed in a sealed tube with 1 mmol of 1a, 5 mol %
Isopropanol
Isopropanol
Isopropanol
Ethanol
Methanol
Ethylene glycol
ꢀ
catalyst, 30 mol % additive, 1.0 equiv base and molecular sieve 4 A in 2 mL iso-
propanol under argon.
b
The purity of the potassium carbonate was 99.0%.
The reactions were performed with 15 mol % additive (entry 4) and 7.5 mol %
c
80
80
additive (entry 5).
d
The reaction was performed with 1 mol % catalyst.
The purity of the potassium carbonate was 99.995%.
a
e
The reactions were performed in a sealed vial with 1 mmol of 1a, molecular
ꢀ
sieves 4 A in 2 mL solvent under argon.
b
The reaction was performed with 1 equiv base.
The reaction was performed in a flask equipped with reflux condenser and
experiment confirmed the assumption that product formation
takes place only under basic conditions (Table 3, entry 9). Experi-
ments with CuBr, CuCl and Cu2O demonstrated that with none of
these Cu-sources the yield observed with CuI could be improved
(Table 3, entries 11e13). Lowering the amount of CuI from 5 to
1 mol % caused a decrease of the yield of 2a from 79 to 70% (Table 3,
entry 14). The fact that even in the absence of any Cu-source the
yield of 2a amounted to 34% (Table 3, entry 15) suggested the as-
sumption that a SNAr reaction mechanism may be operative in this
transformation. On the other hand, the purity of the K2CO3
employed did not exceed 99%. So, it could not be excluded that the
transformation is catalyzed by trace amounts of Cu present in the
base. This is why the reaction was repeated under copper-free
conditions using 99.995% pure K2CO3. Using this protocol, 2a was
isolated in only 4% (Table 3, entry 16). The result of this control
experiment emphasizes the role of the Cu-catalyst for this trans-
formation. The finding also corroborates the assumption of a cop-
per-catalyzed transformation. In our opinion a SNAr reaction
mechanism can be ruled out. It was also found that a reduction of
the amount of propionic acid is not advisable, since the yield of 2a
in the presence of 15 and 7.5 mol % propionic acid, respectively,
amounted only to 62 and 64%, respectively (Table 3, entries 4 and
5). Interestingly, even in the absence of any acidic additive 2a could
be isolated in 55% yield (Table 3, entry 10).
c
a balloon filled with argon.
when the reaction was performed in either protic solvents such as
water and isopropanol (Table 2, entries 15 and 16) or in less polar
solvents such as 1,2-dichlorbenzene and THF (Table 2, entries 17
and 18). With isopropanol as the solvent, the yield of 2a amounted
to 82% (Table 2, entry 15). Further experiments with isopropanol
as the solvent revealed that a reduction of the amount of K2CO3
from 1.5 to 1.0 equiv (Table 2, entry 19) as well as a decrease of the
reaction temperature from 100 to 80 ꢀC (Table 2, entry 20) had
only minor effects on the yield. It should also be mentioned that
the reaction can also be performed under standard reflux condi-
tions (Table 2, entry 21). The successful use of isopropanol
prompted us to evaluate other alcohols as the reaction medium. It
was found that ethanol as well as methanol can be used as solvents
at 80 ꢀC; however, the yields did not exceed the yield obtained
with isopropanol (Table 2, entries 22 and 23). With ethylene glycol
as the solvent only traces of 2a were formed (Table 2, entry 24).
This might be due to the chelating properties of this diol.
As the optimal solvent was identified only during the final stage
of the optimization process it was decided to reoptimize the
transformation in isopropanol with regard to additives, bases and
Cu-sources. For this purpose, 1a was reacted with 30 mol % of an
acidic additive, 1.0 equiv of a base and 5 mol % of a catalyst in iso-
propanol at 100 ꢀC for 24 h (Table 3). Reactions with different acidic
additives using K2CO3 as base and CuI as Cu-source were performed
with pivalic acid, acetic acid and isovaleric acid; however, the yields
of 2a did not exceed 72% (Table 3, entries 1e3). Reactions with
different bases established that the formation of 2a could also be
achieved using Na2CO3, (NH4)2CO3 and K3PO4 as the base, albeit in
lower yields than with K2CO3 (Table 3, entries 6e8). A control
To summarize the results of the optimization, the highest yield
of 2a was obtained when the dimerization of 1a was carried out
with 5 mol % CuI as catalyst, 0.3 equiv of propionic acid as additive
and 1 equiv of K2CO3 as base in isopropanol at 100 ꢀC for 24 h in
ꢀ
a sealed tube in the presence of molecular sieves 4 A.
With the optimized reaction conditions in hand, the substrate
scope of the new CuI-catalyzed dimerization was studied. The re-
quired bisfunctionalized substrates 1 were easily accessible via
standard methods from readily available starting materials. The

H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
Table 4 (continued )
3457
alkyl 3-(o-haloaryl)-3-oxopropanoates 1aek were synthesized by
Claisen condensation between an alkyl 2-halobenzoate and an alkyl
acetate with yields up to 81% (for details, see Experimental Sec-
tion).16,17 Substrates 1l and 1m were prepared in two steps:
Reformatsky reaction between 2-bromobenzaldehyde and bro-
moacetic esters delivered the corresponding 3-(o-haloaryl)-3-
hydroxypropanoates, which were oxidized to give the 3-(o-halo-
aryl)-3-oxopropanoates 1l and 1m (for details, see Experimental
Section).18
Entry
1
2 Yield (%)
6
Table 4
CuI-catalyzed dimerizations of alkyl 3-(o-haloaryl)-3-oxopropanoates 1aem to the
correspondingdialkyl 2-(o-haloaryl)-4-hydroxynaphthalene-1,3-dicarboxylates2aema
7
Entry
1
2 Yield (%)
8
1
9
2
3
4
5
10
11
12
(continued on next page)

3458
H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
Table 4 (continued )
standard conditions delivered the corresponding benzo[b]thio-
phene 2n in 53% yield (Scheme 2).
Entry
1
2 Yield (%)
In summary, it was demonstrated that in addition to the model
compound 1a several alkyl 3-(o-halo(het)aryl)-3-oxopropanoates
1ben can serve as substrates for the new dimerization. The
transformations afforded the substituted 1-naphthols and related
compounds 2aen exclusively with yields up to 81%.
13
a
The reactions were performed in a sealed tube with 1 mmol of alkyl 3-(o-halo-
aryl)-3-oxopropanoate 1 in 2 mL isopropanol.
After the successful preparation of the substrates 1aem, they
were subjected to the dimerization using the optimized conditions
of Table 2, entry 19. In order to study the influence of the o-halogen
substituent on the outcome of the transformation, the 3-(20-iodo-
phenyl)-3-oxopropanoate 1b and the 3-(20-chlorophenyl)-3-
oxopropanoate 1c were reacted. It was found that in addition to
the bromo derivative 1a the iodo as well as the chloro compound
could serve as substrates for the dimerization (Table 4, entries 2 and
3). The observation that the highest yield was obtained with the 3-
(20-bromophenyl)-3-oxopropanoate 1b is in accordance with re-
sults obtained earlier.14,19e21
Next, we turned our attention to different ester functionalities. It
was demonstrated that the dimerization was also successful with
the ethyl ester 1d and the allyl ester 1e (Table 4, entries 4 and 5).
Notably, the best result was observed with the allyl ester 1e as
substrate. Further experiments revealed that the transformation
could also be achieved with substituted 3-(o-bromoaryl)-3-
oxopropanoates carrying one or more additional substituents on
the aryl ring. It turned out that the reaction tolerates a number of
substituents, including halogens at C-50 and C-40 (fluorine), a CF3
group at C-50, and a methoxy group at C-50. It seems that the po-
sition of the additional substituent has an influence on the yield.
With electron withdrawing substituents in 50-position the yields of
the 1-naphthols are in the range between 63 and 69% (Table 4,
entries 6, 7, 8, 10 and 11). An electron withdrawing group in para
position to the ketoester moiety seems to lower the yield as ex-
emplified by the reaction of 1i (Table 4, entry 9). Finally, it was
demonstrated that the transformation can also be achieved with
substituted 3-(o-bromoaryl)-3-oxopropanoates carrying two addi-
tional substituents on the aryl ring. With the tetrasubstituted
substrates 1l and 1m, the products 2l and 2m were isolated with 61
and 67% yield, respectively (Table 4, entries 12 and 13).
Scheme 3. Plausible reaction mechanism for the dimerization of 1a to 2a.
It is plausible to suppose that the first step of the domino pro-
cess is an intermolecular Cu(I)-catalyzed C-arylation of two mole-
cules of
b-ketoester 1a which is followed by an intramolecular
condensation of 3a to 4a and aromatization to deliver the 3-aryl-1-
naphthol 2a (Scheme 3). However, it cannot be excluded that the
sequence of reactions starts with an intermolecular condensation
to give 5a as an intermediate. Intramolecular C-arylation leads to
the central intermediate 4a which in turn aromatizes to the cor-
responding 1-naphthol 2a. In the presence of a Cu-catalyst, none of
the intermediates could be isolated, regardless of the reaction
conditions. This is why we turned our attention to the reaction of 1a
under copper-free conditions. As already mentioned, the reaction
of 1a under basic conditions at 100 ꢀC using K2CO3 of 99% purity
delivered 2a exclusively in 34% yield (Table 3, entry 15). We hoped
that decreasing the reaction temperature would result in the for-
mation of any of the intermediates as side products. This is why the
transformation was performed at 80 ꢀC, 50 ꢀC and at room tem-
perature. Unfortunately, this hope was not fulfilled: At 80 ꢀC and
50 ꢀC only the product 2a was isolated with 28% and 12% yield,
respectively. At room temperature no reaction took place at all and
the substrate 1a was recovered.
Scheme 2. CuI-catalyzed dimerization of methyl 3-(30-bromothien-2-yl)-3-
oxopropanoate (1n) to dimethyl 2-hydroxy-4-(300-bromothien-2-ylbenzo[b]thiophene-
3,5-dicarboxylate (2n).
To demonstrate that the new transformation is not restricted to
3-(o-haloaryl)-3-oxopropanoates, but can also be performed with
3-(o-halohetaryl)-3-oxopropanoates, methyl 3-(30-bromothien-2-
yl)-3-oxopropanoate (1n) was chosen as substrate. The thiophene
derivative was obtained by reaction of 2-acetyl-3-bromothiophene
with dimethylcarbonate in 69% yield. Reaction of 1n under

H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
3459
attached to C-2 is nearly coplanar to the naphthalene core, while
the ester moiety at C-4 is not in plane. The interplanar angle for the
C-2 ester moiety and the naphthalene core is 4.1(3)ꢀ. The short
distance of 2.542(2) Ǻ between O-3 and O-4 is a hint for an intra-
molecular hydrogen bond between O-3eH-3 as donor and O-4 as
acceptor. The H-3eO-4 distance is 1.71(3) Ǻ and the relevant angle
is 153(3)ꢀ. In contrast to the planar arrangement of the ester
function at C-2 the haloaryl moiety attached to C-3 is nearly per-
pendicular to the planar naphthalene core. The interplanar angles
are 86.0(1)ꢀ and 84.07(4)ꢀ. It is also interesting to see that the
distance between Br-1 and O-1 is really short, 2.981(2)ꢀ,
respectively.
Fig. 1. 1H spin systems and important gHMBC correlations (black arrows) and super
long-range D-HSQHMBC correlations (gray arrows) for compound 2a.
All compounds presented were characterized by UV, IR and NMR
spectroscopy as well as by mass spectrometry. The full assignment of
the 1H and 13C chemical shifts and the unambiguous structure elu-
cidation are demonstrated for compound 2a. 1-Naphthol 2a contains
five 1H spin systems I-V (Fig. 1): spin system I consists of the OH-
group attached to carbon C-4, spin system II is made up of the four
protons attached to C-5, C-6, C-7 and C-8 of ring B. Spin system III
contains the four protons attached to C-300, C-400, C-500 and C-600 of
ring C, whereas the fourth and fifth spin system are made up of 3
protons each of the two ester functionalities at C-1 and C-3. The
sequences of the protons and their directly attached carbons in spin
systems II and III (rings B and C) were evaluated by analysis of the
DQFCOSY and gHSQC spectrum. By 3JCH correlations in the standard
1He13C gHMBC spectrum (optimized for JCH¼8 Hz) between the
protons O-H, 5-H, 8-H, 400-H and 600-H and the corresponding carbon
atoms the assignment of the quaternary carbons C-2, C-3, C-4, C-4a,
C-8a and C-200 (black arrows) could be achieved. To fix the positions
of the two ester functionalities of the fourth and fifth spin systems
the standard gHMBC providing mainly 2JCH and 3JCH correlations was
3. Conclusions
In summary, it has been demonstrated that the dimerization of
alkyl 3-(o-halo(het)aryl)-3-oxopropanoates, i.e., compounds
bearing both a b-ketoester and a (het)aryl halide moiety, can be
achieved by means of a copper-catalyzed domino process. The CuI-
catalyzed reactions of the easily available alkyl 3-(o-halo(het)
aryl)-3-oxopropanoates deliver the substituted 3-aryl-1-
naphthols and related products as the result of a domino in-
termolecular C-arylation/intramolecular Knoevenagel type con-
densation/aromatization process with yields up to 81%. The
method provides an efficient and selective access to interesting
organic building blocks in one-pot. Due to their high functional
density, including a 3-haloaryl moiety, they are predestinated for
further modification.
4. Experimental section
4.1. General
not sufficient, so super long-range D
-bsgHMBC22 was used. Thus, the
4
observed JCH correlations (grey arrows) allow unequivocally the
assignment of the positions C-1, C-2 and C-100.
All commercially available reagents were used without further
purification. Glassware was dried for 24 h at 120 ꢀC in an oven.
Solvents used in reactions were distilled over appropriate drying
agents prior to use. Solvents used for extraction and purification
were distilled prior to use. Reaction temperatures are reported as
bath temperatures. Thin-layer chromatography (TLC) was per-
formed on precoated aluminum plates (silica gel Merck 60 F254) and
visualized by UV light (254 nm) and/or by immersion in an etha-
nolic vanillin solution or by immersion in a KMnO4 solution fol-
lowed by heating. Products were purified by flash chromatography
on silica gel (MN 60, 0.04e0.063 mm; Marcherey & Nagel).
€
Melting points were determined on a Buchi Melting Point ap-
paratus B-545 and are uncorrected. IR spectra were measured on
a Bruker Alpha FT-IR spectrometer. UV/Vis spectra were recorded
on a Cary 4E spectrophotometer. 1H and 13C NMR spectra were
recorded at 300 (75) MHz and 500 (100) MHz on Varian Unity Inova
spectrometers using CDCl3 as solvent. The 1H and 13C chemical
shifts were referenced to residual solvent signals at
(CDCl3) relative to TMS as internal standard. DQFCOSY, HSQC-,
gHMBC-, and -bsgHMBC-spectra were recorded on an NMR
d H/C 7.26/77.00
Fig. 2. Structure of dimethyl 2-(200-bromo-500-chlorophenyl)-6-chloro-4-hydroxynaph-
thalene-1,3-dicarboxylate (2h), derived from X-ray crystal structure analysis.
D
spectrometer at 300 MHz or 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), quin (quintet), m (multiplet), and ov (overlapped).1D and
2D homonuclear NMR spectra were measured with standard pulse
sequences. Low-resolution electron 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 spec-
trometer Finnigan MAT 95, for the measurement of exact mass
electrospray ionization mass spectra [ESI (HRMS)] a Bruker Dalto-
nik spectrometer micrOTOF-Q was used. Intensities are reported as
percentages relative to the base peak (I¼100%).
Unequivocal evidence for the structure of 1-naphthol 2h was
provided by single crystal X-ray diffraction. Fig. 2 illustrates the
planar structure of the naphthalene moiety carrying a hydroxyl
group at C-1, ester functions at C-2 and C-4, an aryl group at C-3 and
a chlorine atom at C-8.y It is interesting to see that the ester function
y
CCDC 1406374 (2g) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

3460
H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
3
3
4
4.2. Synthesis and characterization of starting materials 1aen
(ddd, J(30-H, 40-H)¼7.6 Hz, J(50-H, 40-H)¼7.7 Hz, J(60-H, 40-H)¼
3
1.8 Hz, 2H, 40-H, ketone and enol), 7.33 (ddd, J(40-H, enol, 50-H,
3
4
4.2.1. General procedures I for the synthesis of starting materials
1aen. Compounds 1aeg, ien were synthesized according to gen-
eral procedures I. Compound 1h was commercially available.
Method A:16,17 A two-necked round-bottomed flask equipped
with a reflux condenser and a magnetic stir bar was charged with
the 2-bromobenzoic acid (20 mmol) and freshly distilled methanol
(25 mL). The solution was heated in a hot water bath, conc. H2SO4
(8 mmol) was added slowly and the reaction mixture was refluxed
for 24 h. After cooling to room temperature around half of the
amount of the solvent was removed in vacuo and the residue was
partitioned between water (50 mL) and diethyl ether (70 mL). The
organic layer was separated and washed with saturated NaHCO3
(2ꢁ50 mL), water (50 mL) and brine (50 mL), dried over anhydrous
MgSO4 and the volatiles were removed under reduced pressure.
The crude product thus obtained was purified by flash chroma-
tography on silica gel to afford the alkyl-2-halobenzoate.
In a two-necked round-bottomed flask equipped with a reflux
condenser and a magnetic stir bar the alkyl 2-halobenzoate
(22.5 mmol) was dissolved in freshly distilled dry THF (30 mL)
under argon. The solution was cooled to 0 ꢀC using an ice bath and
NaH (60% in mineral oil, 15 mmol) was added portionwise. After
stirring for 15 min a solution of the alkyl acetate (15 mmol) in dry
THF (30 mL) was added dropwise to the reaction mixture at 0 ꢀC.
The mixture was warmed up, stirred at room temperature for 2 h
and heated under reflux for 24 h. After cooling to room temperature
around half of the amount of the solvent was removed in vacuo and
the reaction mixture was diluted with toluene (50 mL). The
resulting mixture was washed with 2N HCl (50 mL), saturated
NH4Cl (50 mL), dried over anhydrous MgSO4 and the volatiles were
removed under reduced pressure. The crude product was purified
by flash column chromatography on silica gel to afford the alkyl 3-
(20-halophenyl)-3-oxo-propanoate 1.
enol)¼7.3 Hz, J(60-H, enol, 50-H, enol)¼7.8 Hz, J(30-H, enol, 50-H,
3
enol)¼1.7 Hz, 1H, 50-H, enol), 7.39 (ddd, J(40-H, ketone, 50-H,
3
4
ketone)¼7.4 Hz, J(60-H, ketone, 50-H, ketone)¼7.6 Hz, J(30-H, ke-
3
tone, 50-H, ketone)¼1.2 Hz, 1H, 50-H, ketone), 7.50 (ddd, J(50-H,
3
ketone, 60-H, ketone)¼7.8 Hz, J(50-H, enol, 60-H, enol)¼8.4 Hz,
4J(40-H, 60-H)¼1.8 Hz, 2H, 60-H, ketone and enol), 7.62 (dd, J(40-H,
3
30-H)¼7.8 Hz, 4J(50-H, 30-H)¼1 Hz, 2H, 30-H, ketone and enol), 12.33
(s, 1H, OH, enol); 13C NMR (75 MHz, CDCl3)
d 48.49 (C-2, ketone),
51.51 (C-100, enol), 52.38 (C-100, ketone), 92.85 (C-2, enol), 119.15 (C-
20, ketone), 120.93 (C-20, enol), 127.30 (C-50, enol), 127.53 (C-50,
ketone), 129.49 (C-60, ketone), 130.19 (C-60, enol), 131.19 (C-40, enol),
132.37 (C-40, ketone), 133.74 (C-30, enol), 133.93 (C-30, ketone),
135.66 (C-10, enol), 139.89 (C-10, ketone),167.20 (C-1, ketone), 171.94
(C-3, enol), 172.82 (C-1, enol) and 195.43 (C-3, ketone); MS (EI,
70 eV) m/z (%) 256 (6) [M]þ, 185 (92), 177 (100), 89 (18), 76 (34), 69
(22), 50 (18); HRMS (EI, Mþ) calculated for C10H9BrO3 255.9735
found 255.9758.
4.2.3. Methyl 3-(20-iodophenyl)-3-oxopropanoate (1b). According
to general procedure I, method A, methyl 2-iodobenzoate (8.0 g,
30 mmol), methyl acetate (1.5 g, 20 mmol) and NaH (60% in mineral
oil, 0.8 g, 20 mmol) were reacted in THF at 70 ꢀC for 24 h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1) gave
methyl 3-(20-iodophenyl)-3-oxopropanoate (1b) as a yellow oil in
51% yield (3.2 g, 11 mmol); Rf 0.42 (petroleum ether:EtOAc¼9:1); IR
(ATR)
n 1739 (CO ester), 1696 (CO ketone), 1630 (OCC enol), 1579,
1560, 1434, 1386, 1320, 1243, 1200, 1149, 1055, 1010, 756 cmꢂ1; UV
(MeCN) lmax (log ε) 222 (4.16) nm; 1H NMR (300 MHz, CDCl3)
d 3.74
(s, 3H,100-H, ketone), 3.8 (s, 3H,100-H, enol), 3.99 (s, 2H, 2-H, ketone),
5.35 (s, 1H, 2-H, enol), 7.06e7.12 (m, 1H, 40-H, enol), 7.16 (ddd, 3J(30-
3
H, ketone, 40-H, ketone)¼7.8 Hz, J(50-H, ketone, 40-H, ketone)¼
7.7 Hz, 4J(60-H, ketone, 40-H, ketone)¼1.8 Hz, 1H, 40-H, ketone), 7.40
3
3
Method B:18 A two-necked round-bottomed flask equipped
with a reflux condenser and a magnetic stir bar was charged with
the 2-bromobenzaldehyde (10 mmol) and freshly distilled toluene
(50 mL). Zn powder (15 mmol) and methyl bromoacetate
(15 mmol) were added slowly under argon and the reaction mix-
ture was heated at 100 ꢀC for 2 h. After completion, the reaction
mixture was poured into saturated NH4Cl (50 mL) and extracted
with dichloromethane (3ꢁ30 mL). The combined organic layers
were washed with brine (50 mL), dried over anhydrous MgSO4 and
concentrated in vacuo.
(ddd, J(50-H, ketone, 60-H, ketone)¼8.5 Hz, J(50-H, enol, 60-H,
enol)¼8.6 Hz, 4J(40-H, 60-H)¼1.1 Hz, 2H, 60-H, ketone and enol), 7.48
3
3
4
(ddd, J(60-H, 50-H)¼8.6 Hz, J(40-H, 50-H)¼7.8 Hz, J(30-H, 50-H)¼
1.9 Hz, 2H, 50-H, ketone and enol), 7.91 (d, 3J(40-H, enol, 30-H, enol)¼
3
7.9 Hz, 1H, 30-H, enol), 7.95 (dd, J(40-H, ketone, 30-H, ketone)¼
7.9 Hz, 4J(50-H, ketone, 30-H, ketone)¼1 Hz, 1H, 30-H, ketone), 12.27
(s, 1H, OH, enol); 13C NMR (75 MHz, CDCl3)
d 47.84 (C-2, ketone),
51.56 (C-100, enol), 52.50 (C-100, ketone), 91.40 (C-20, ketone), 92.58
(C-2, enol), 94.33(C-20, enol), 128.02 (C-50, enol), 128.11 (C-50, ke-
tone), 128.78 (C-60, ketone), 129.53 (C-60, enol), 131.16 (C-40, enol),
132.35 (C-40, ketone), 139.70 (C-10, enol), 140.25 (C-30, enol), 141.08
(C-30, ketone), 142.41 (C-10, ketone), 167.13 (C-1, ketone), 172.73 (C-
1, enol), 174.11 (C-3, enol), 195.69 (C-3, ketone); MS (EI, 70 eV) m/z
(%) 304 (22) [M]þ, 272 (25), 231 (98), 177 (100), 146 (19), 135 (38),
121 (25), 105 (38), 89 (46), 77 (56), 69 (43), 50 (74); HRMS (EI, Mþ)
calculated for C10H9IO3 303.9596 found 303.9591.
The crude methyl 3-(20-bromophenyl)-3-hydroxypropanoate
thus obtained (ca. 7 mmol) was dissolved in dichloromethane
(100 mL) and pyridinium chlorochromate (PCC) (14 mmol) was
added portionwise. After stirring for 8 h at room temperature Celite
was added and the reaction mixture was stirred for another 10 min
at room temperature. The reaction mixture was filtered and con-
centrated in vacuo. The crude product was purified by flash column
chromatography on silica gel to afford the corresponding alkyl 3-
(20-halophenyl)-3-oxopropanoate 1.
4.2.4. Methyl 3-(20-chlorophenyl)-3-oxopropanoate (1c). According
to general procedure I, method A, methyl 2-chlorobenzoate (5.2 g,
30 mmol), methyl acetate (1.5 g, 20 mmol) and NaH (60% in mineral
oil, 0.8 g, 20 mmol) were reacted in THF at 70 ꢀC for 24 h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1) gave
methyl 3-(20-chlorophenyl)-3-oxopropanoate (1c) as a yellow oil in
41% yield (1.8 g, 8 mmol); Rf 0.57 (petroleum ether:EtOAc¼9:1); IR
4.2.2. Methyl 3-(20-bromophenyl)-3-oxopropanoate (1a). According
to general procedure I, method A, methyl 2-bromobenzoate (21.8 g,
101 mmol), methyl acetate (5 g, 68 mmol) and NaH (60% in mineral
oil, 2.7 g, 67.5 mmol) were reacted in THF at 70 ꢀC for 24 h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1) gave
methyl 3-(20-bromophenyl)-3-oxopropanoate (1a) as a yellow oil in
64% yield (11.01 g, 43.02 mmol); Rf 0.48 (petroleum ether:
(ATR)
n 1743 (CO ester), 1698 (CO ketone), 1625 (OCC enol), 1589,
1566, 1470, 1434, 1387, 1323, 1272, 1245, 1200, 1150, 1069, 1008,
760 cmꢂ1; UV (MeCN) lmax (log ε) 209 (4.30), 243 (3.82) nm; 1H
EtOAc¼9:1); IR (ATR)
n
1742 (CO ester),1700 (CO ketone),1626 (OCC
NMR (300 MHz, CDCl3) d
3.74 (s, 3H, 100-H, ketone), 3.81 (s, 3H,100-H,
enol), 1586, 1562, 1510, 1432, 1387, 1322, 1269, 1245, 1201, 1175,
enol), 4.06 (s, 2H, 2-H, ketone), 5.57 (s, 1H, 2-H, enol), 7.32 (ov, 2H,
1059, 1020, 757 cmꢂ1; UV (MeCN) lmax (log ε) 207 (4.39), 244 (3.93)
50-H, ketone and enol), 7.35 (ov, 2H, 30-H, ketone and enol), 7.43
nm; 1H NMR (300 MHz, CDCl3)
d
3.73 (s, 3H, 100-H, ketone), 3.80 (s,
(dd-like, 2H, 40-H, ketone and enol), 7.56 (dd, J(50-H, enol, 60-H,
3
3H, 100-H, enol), 4.03 (s, 2H, 2-H, ketone), 5.46 (s, 1H, 2-H, enol), 7.26
enol)¼6.8 Hz, 4J(40-H, enol, 60-H, enol)¼2.7 Hz, 1H, 60-H, enol), 7.61

H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
3461
3
4
(dd, J(50-H, ketone, 60-H, ketone)¼7.3 Hz, J(40-H, ketone, 60-H,
ketone), 7.33 (ddd, 3J(40-H, enol, 50-H, enol)¼7.6 Hz, 3J(60-H, enol, 50-
ketone)¼1 Hz, 1H, 60-H, ketone), 12.38 (s, 1H, OH, enol); 13C NMR
H, enol)¼7.7 Hz, J(30-H, enol, 50-H, enol)¼1.8 Hz, 1H, 50-H, enol),
4
(75 MHz, CDCl3)
d
48.92 (C-2, ketone), 51.56 (C-100, enol), 52.45 (C-
7.39 (ddd, 3J(40-H, ketone, 50-H, ketone)¼7.3 Hz, 3J(60-H, ketone, 50-
4
100, ketone), 93.02 (C-2, enol), 126.81 (C-50, enol), 127.10 (C-50, ke-
tone), 130.06 (C-60, ketone), 130.13 (C-60, enol), 130.61 (C-30, enol),
130.76 (C-40, enol), 131.12 (C-30, ketone), 131.56 (C-20, enol), 132.16
(C-20, ketone), 132.68 (C-40, ketone), 133.49 (C-10, enol), 167.42 (C-1,
ketone), 170.50 (C-3, enol), 173.00 (C-1, enol), 194.56 (C-3, ketone);
MS (EI, 70 eV) m/z (%) 212 (8) [M]þ, 181 (12), 177 (89), 139 (100), 111
(55), 89 (27), 75 (51), 69 (29), 50 (21); HRMS (EI, Mþ) calculated for
H, ketone)¼7.4 Hz, J(30-H, ketone, 50-H, ketone)¼1.3 Hz, 1H, 50-H,
3
3
ketone), 7.44 (ddd, J(30-H, 40-H)¼7.6 Hz, J(50-H, 40-H)¼7.7 Hz,
4J(60-H, 40-H)¼1.8 Hz, 2H, 40-H, ketone and enol), 7.51 (ddd, 3J(50-H,
enol, 60-H, enol)¼7.5 Hz, 3J(50-H, ketone, 60-H, ketone)¼7.4 Hz, 4J(40-
H, 60-H)¼1.8 Hz, 2H, 60-H, ketone and enol), 7.65 (ddd, 3J(40-H, ke-
tone, 30-H, ketone)¼7.3 Hz, 3J(40-H, enol, 30-H, enol)¼7.8 Hz, 4J(50-H,
30-H)¼2.3 Hz, 2H, 30-H, ketone and enol), 12.32 (s, 1H, OH, enol); 13C
C
10H9ClO3 212.0240 found 212.0246.
NMR (75 MHz, CDCl3) d
48.66 (C-2, ketone), 65.12 (C-100, enol), 65.43
(C-100, ketone), 92.99 (C-2, enol), 118.06 (C-300, ketone), 118.80 (C-300,
enol), 119.19 (C-20, ketone), 120.37 (C-20, enol), 127.31 (C-50, enol),
127.53 (C-50, ketone), 129.54 (C-60, ketone), 130.21 (C-60, enol),
132.37 (C-200, enol), 132.53 (C-200, ketone), 133.36 (C-40, ketone),
133.77 (C-40, enol), 133.92 (C-30, ketone), 134.32 (C-30, enol), 135.68
(C-10, enol), 139.94 (C-10, ketone), 166.62 (C-1, ketone), 172.15 (C-3,
enol), 172.24 (C-1, enol), 195.36 (C-3, ketone); MS (EI, 70 eV) m/z (%)
284 (3) [M]þ, 203 (100), 183 (97), 161 (38), 155 (27), 120 (31), 89
(11), 76 (17), 69 (12); HRMS (EI, Mþ) calculated for C12H11BrO3
281.9892 found 281.9886.
4.2.5. Ethyl 3-(20-bromophenyl)-3-oxopropanoate (1d). According
to general procedure I, method A, methyl 2-bromobenzoate (3.7 g,
17 mmol), ethyl acetate (1.0 g, 11 mmol) and NaH (60% in mineral
oil, 0.45 g, 11 mmol) were reacted in THF at 70 ꢀC for 24 h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1) gave
ethyl 3-(20-bromophenyl)-3-oxopropanoate (1d) as a yellow oil in
71% yield (2.2 g, 8 mmol); Rf 0.57 (petroleum ether:EtOAc¼9:1); IR
(ATR)
n 1738 (CO ester), 1701 (CO ketone), 1627 (OCC enol), 1586,
1563, 1467, 1406, 1382, 1318, 1268, 1243, 1192, 1149, 1087, 1024,
757 cmꢂ1; UV (MeCN) lmax (log ε) 208 (4.22) nm; 1H NMR
3
(300 MHz, CDCl3)
d
1.24 (t, J(100-H, ketone, 200-H, ketone)¼7.2 Hz,
4.2.7. Methyl 3-(20,50-dibromophenyl)-3-oxopropanoate
(1f). According to general procedure I, method A, methyl 2,5-
dibromobenzoate (4.0 g, 14 mmol), methyl acetate (0.7 g,
9 mmol) and NaH (60% in mineral oil, 0.4 g, 10 mmol) were reacted
in THF at 70 ꢀC for 24 h. Column chromatography on silica gel
(petroleum ether:EtOAc¼9:1) gave methyl 3-(20,50-dibromo-
phenyl)-3-oxopropanoate (1f) as a white solid in 55% yield (1.7 g,
5 mmol): mp 62e63 ꢀC; Rf 0.60 (petroleum ether:EtOAc¼9:1); IR
3H, 200-H, ketone), 1.33 (t, 3J(100-H, enol, 200-H, enol)¼7.2 Hz, 3H, 200-
3
H, enol), 4.01 (s, 2H, 2-H, ketone), 4.18 (q, J(200-H, ketone, 100-H,
3
ketone)¼7.2 Hz, 2H, 100-H, ketone), 4.27 (q, J(200-H, enol, 100-H,
enol)¼7.2 Hz, 2H,100-H, enol), 5.45 (s,1H, 2-H, enol), 7.26 (ddd, 3J(30-
H, 40-H)¼7.8 Hz, 3J(50-H, 40-H)¼7.6 Hz, 4J(60-H, 40-H)¼1.8 Hz, 2H, 40-
3
H, ketone and enol), 7.33 (ddd, J(40-H, enol, 50-H, enol)¼7.6 Hz,
3J(60-H, enol, 50-H, enol)¼7.4 Hz, J(30-H, enol, 50-H, enol)¼2.1 Hz,
4
3
1H, 50-H, enol), 7.38 (ddd, J(40-H, ketone, 50-H, ketone)¼7.6 Hz,
(ATR)
1550, 1441, 1382, 1274, 1223, 1199, 1081, 1026, 1007, 801, 732 cmꢂ1
UV (MeCN) lmax (log ε) 240 (3.60), 218 (3.87) nm; 1H NMR
(300 MHz, CDCl3)
3.75 (s, 3H, 100-H, ketone), 3.82 (s, 3H, 100-H,
n 3069 (w; OH), 1735 (CO ketone), 1623 (OCC enol), 1574,
3J(60-H, ketone, 50-H, ketone)¼7.4 Hz, J(30-H, ketone, 50-H,
;
4
3
ketone)¼1.2 Hz, 1H, 50-H, ketone), 7.50 (ddd, J(50-H, enol, 60-H,
enol)¼7.8 Hz, 3J(50-H, ketone, 60-H, ketone)¼7.9 Hz, 4J(40-H, 60-H)¼
d
3
1.8 Hz, 2H, 60-H, ketone and enol), 7.63 (dd, J(40-H, 30-H)¼7.8 Hz,
enol), 4.02 (s, 2H, 2-H, ketone), 5.48 (s, 1H, 2-H, enol), 7.39 (dd,
4
4J(50-H, 30-H)¼1 Hz, 2H, 30-H, ketone and enol), 12.43 (s, 1H, OH,
3J(30-H, enol, 40-H, enol)¼8.4 Hz, J(60-H, enol 40-H, enol)¼2.2 Hz,
3
enol); 13C NMR (75 MHz, CDCl3)
d
14.16 (C-20, ketone), 14.38 (C-20,
1H, 40-H, enol), 7.44 (dd, J(30-H, ketone, 40-H, ketone)¼8.4 Hz,
enol), 48.89 (C-2, ketone), 60.69 (C-100, enol), 61.62 (C-100, ketone),
93.35 (C-2, enol), 119.34 (C-20, ketone), 121.08 (C-20, enol), 127.45
(C-50, enol), 127.64 (C-50, ketone), 129.66 (C-60, ketone), 130.36 (C-
60, enol), 131.29 (C-40, enol), 132.46 (C-40, ketone), 133.89 (C-30,
ketone), 134.04 (C-30, enol), 135.94 (C-10, enol), 140.14 (C-10, ketone),
166.90 (C-1, ketone), 172.05 (C-3, enol), 172.69 (C-1, enol), 195.73
(C-3, ketone); MS (EI, 70 eV) m/z (%) 270 (7) [M]þ, 191 (100), 183
(21), 163 (66), 89 (17), 76 (22), 69 (18), 50 (12); HRMS (EI, Mþ)
calculated for C11H11BrO3 269.9892 found 269.9885.
4J(60-H, ketone 40-H, ketone)¼2.1 Hz, 1H, 40-H, ketone), 7.50 (d,
3
3J(40-H, 30-H)¼8.3 Hz, 2H, 30-H, ketone and enol), 7.62 (d, J(40-H,
3
ketone, 60-H, ketone)¼2.3 Hz, 1H, 60-H, ketone), 7.64 (d, J(40-H,
enol, 60-H, enol)¼2.4 Hz, 1H, 60-H, enol), 12.31 (s, 1H, OH, enol); 13C
NMR (75 MHz, CDCl3)
d
48.32 (C-2, ketone), 51.69 (C-100, enol),
52.57 (C-100, ketone), 93.39 (C-2, enol), 117.67 (C-50, ketone), 119.66
(C-50, enol), 121.21 (C-20, enol), 121.60 (C-20, ketone), 132.28 (C-60,
ketone), 133.10 (C-60, enol), 134.10 (C-40, enol), 135.14 (C-40, ke-
tone), 135.23 (C-30, enol), 135.26 (C-30, ketone), 137.25 (C-10, enol),
141.49 (C-10, ketone), 166.86 (C-1, ketone), 170.25 (C-3, enol),
172.65 (C-1, enol), 194.20 (C-3, ketone) ppm; MS (EI, 70 eV) m/z (%)
336 (2) [M]þ, 263 (69), 255 (100), 235 (15), 213 (2), 156 (6), 89 (4),
75 (11); HRMS (ESI, [MþH]þ) calculated for C10H8Br2O3 338.8874
found 338.8850.
4.2.6. Allyl 3-(20-bromophenyl)-3-oxopropanoate (1e). According to
general procedure I, method A, methyl 2-bromobenzoate (4.8 g,
22 mmol), allyl acetate (1.5 g,15 mmol) and NaH (60% in mineral oil,
0.6 g, 15 mmol) were reacted in THF at 70 ꢀC for 24 h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1) gave
allyl 3-(20-bromophenyl)-3-oxopropanoate (1e) as a yellow oil in
35% yield (1.5 g, 5 mmol); Rf 0.43 (petroleum ether:EtOAc¼9:1); IR
4.2.8. Methyl 3-(20-bromo-50-chlorophenyl)-3-oxopropanoate
(1g). According to general procedure I, method A, methyl 2-
bromo-5-chlorobenzoate (7.6 g, 30 mmol), methyl acetate (1.5 g,
20 mmol) and NaH (60% in mineral oil, 0.8 g, 20 mmol) were
reacted in THF at 70 ꢀC for 24 h. Column chromatography on silica
gel (petroleum ether:EtOAc¼9:1) gave methyl 3-(20-bromo-50-
chlorophenyl)-3-oxopropanoate (1g) as a white solid in 49% yield
(2.9 g, 10 mmol): mp 58e59 ꢀC; Rf 0.61 (petroleum ether:
(ATR) n 3689 (w; OH), 1738 (CO ester), 1701 (CO ketone), 1627 (OCC
enol), 1586, 1562, 1467, 1429, 1399, 1269, 1241, 1186, 108, 982, 930,
757 cmꢂ1; UV (MeCN) lmax (log ε) 209 (4.17), 245 (3.64) nm; 1H
NMR (300 MHz, CDCl3)
d
4.06 (s, 2H, 2-H, ketone), 4.62 (ov, 1H, 100-
Ha, enol), 4.64 (ov, 1H,100-Ha, ketone), 4.72 (dt-like, 3J(200-H, enol,100-
Hb, enol)¼5.7 Hz, 1H, 100-Hb, enol), 4.81 (dt-like, 3J(200-H, ketone, 100-
Hb, ketone)¼5.7 Hz, 1H, 100-Hb, ketone), 5.22 (dd-like, 3J(200-H, enol,
EtOAc¼9:1); IR (ATR)
n 3088 (w; OH), 1707 (CO ketone), 1621 (OCC
enol), 1579, 1438, 1383, 1338, 1276, 1226, 1198, 1099, 1086, 1012,
3
300-H(Z), enol)¼10.0 Hz, 1H, 300-H(Z), enol), 5.33 (dd-like, J(200-H,
ketone, 300-H(Z), ketone)¼10.9 Hz,1H, 300-H(Z), ketone), 5.42 (dd-like,
3J(200-H, enol, 300-H(E), enol)¼17.1 Hz, 1H, 300-H(E), enol), 5.49 (dd-
like, 3J(200-H, ketone, 300-H(E), ketone)¼17.2 Hz, 1H, 300-H(E), ketone),
5.50 (s, 1H, 2-H, enol), 5.88 (m, 1H, 200-H, enol), 6.02 (m, 1H, 200-H,
878, 785 cmꢂ1; UV (MeCN) lmax (log ε) 216 (4.29) nm; 1H NMR
(300 MHz, CDCl3)
d
3.76 (s, 3H, 100-H, ketone), 3.82 (s, 3H, 100-H,
enol), 4.03 (s, 2H, 2-H, ketone), 5.49 (s,1H, 2-H, enol), 7.24 (dd, 3J(30-
4
H, 40-H)¼8.5 Hz, J(60-H, 40-H)¼2.6 Hz, 2H, 40-H, ketone and enol),

3462
H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
4
7.50 (d, J(40-H, 60-H)¼2.6 Hz, 2H, 60-H, ketone and enol), 7.55 (d,
93.55 (C-2, enol), 122.97 (C-20, ketone), 123.19 (d, 1J(F, ketone, C-1000
3J(40-H, 30-H)¼8.6 Hz, 2H, 30-H, ketone and enol), 12.32 (s, 1H, OH,
ketone)¼250 Hz, C-1000, ketone), 123.36 (d, J(F, enol, C-1000 enol)¼
1
enol); 13C NMR (75 MHz, CDCl3)
d
48.31 (C-2, ketone), 51.67 (C-100,
250 Hz, C-1000, enol),125.17 (C-20, enol),126.38 (q-like, 3J(F, ketone, C-
60, ketone)¼7 Hz, C-60, ketone),127.12 (q-like, 3J(F, enol, C-60, enol)¼
enol), 52.55 (C-100, ketone), 93.35 (C-2, enol), 116.90 (C-20, ketone),
118.85 (C-20, enol), 129.43 (C-60, ketone), 130.15 (C-60, enol), 131.14
(C-40, enol), 132.30 (C-40, ketone), 133.54 (C-50, enol), 133.95 (C-50,
ketone), 134.88 (C-30, enol), 134.99 (C-30, ketone), 136.92 (C-10,
enol), 141.19 (C-10, ketone), 166.85 (C-1, ketone), 170.31 (C-3, enol),
172.64 (C-1, enol), 194.22 (C-3, ketone); MS (EI, 70 eV) m/z (%) 292
(6) [M]þ, 211 (100), 189 (17), 169 (12), 89 (8), 75 (17), 69 (24); HRMS
(EI, Mþ) calculated for C10H8BrClO3 289.9345 found 289.9336.
3
7 Hz, C-60, enol), 127.60 (q-like, J(F, enol, C-40, enol)¼7 Hz, C-40,
enol), 128.68 (q-like, 3J(F, ketone, C-40, ketone)¼7 Hz, C-40, ketone),
2
130.02 (q-like, J(F, enol, C-50, enol)¼33 Hz, C-50, enol), 130.29 (q-
2
like, J(F, ketone, C-50, ketone)¼33 Hz, C-50, ketone), 134.47 (C-30,
enol),134.55 (C-30, ketone),136.40 (C-10, enol),140.69 (C-10, ketone),
166.73 (C-1, ketone), 170.18 (C-3, enol), 172.56 (C-1, enol), 194.40 (C-
3, ketone); MS (EI, 70 eV) m/z (%) 324 (3) [M]þ, 293 (7), 251 (33), 246
(44), 223 (49), 203 (10), 144 (100), 125 (25), 69 (24); HRMS (EI, Mþ)
calculated for C11H8BrF3O3 323.9609 found 323.9605.
4.2.9. Methyl 3-(20-bromo-40-fluorophenyl)-3-oxopropanoate
(1i). According to general procedure I, method A, methyl 2-
bromo-4-fluorobenzoate (3.7 g, 16 mmol), methyl acetate (0.8 g,
11 mmol) and NaH (60% in mineral oil, 0.4 g, 11 mmol) were reacted
in THF at 70 ꢀC for 24 h. Column chromatography on silica gel
(petroleum ether:EtOAc¼9:1) gave methyl 3-(20-bromo-40-fluo-
rophenyl)-3-oxopropanoate (1i) as a yellow solid in 47% yield (1.4 g,
5 mmol): mp 49e50 ꢀC; Rf 0.54 (petroleum ether:EtOAc¼9:1); IR
4.2.11. Methyl
3-(20-bromo-50-methoxyphenyl)-3-oxopro-panoate
(1k). According to general procedure I, method A, methyl 2-bromo-
5-methoxybenzoate (7.5 g, 30 mmol), methyl acetate (1.5 g,
20 mmol) and NaH (60% in mineral oil, 0.8 g, 20 mmol) were
reacted in THF at 70 ꢀC for 24 h. Column chromatography on silica
gel (petroleum ether:EtOAc¼9:1) gave methyl 3-(20-bromo-50-
methoxyphenyl)-3-oxopropanoate (1k) as a yellow oil in 60% yield
(ATR)
1027, 861, 767 cmꢂ1; UV (MeCN) lmax (log ε) 212 (4.41), 254 (4.07)
nm; 1H NMR (300 MHz, CDCl3) 3.81 (s, 3H, 100-H, ketone), 3.86 (s,
n 1722 (CO ketone), 1596, 1492, 1431, 1256, 1230, 1184, 1112,
(3.4 g, 12 mmol); Rf 0.46 (petroleum ether:EtOAc¼9:1); IR (ATR):
n
d
1742 (CO ester), 1702 (CO ketone), 1630 (OCC enol), 1590, 1567,
1465, 1440, 1392, 1287, 1224, 1195, 1150, 1089, 1015, 810 cmꢂ1; UV
3H, 100-H, enol), 4.01 (s, 2H, 2-H, ketone), 5.44 (s, 1H, 2-H, enol), 7.04
3
3
(ddd-like, J(60-H, enol, 50-H, enol)¼8.5 Hz, J(40-F, enol, 50-H,
(MeCN) lmax (log ε) 222 (4.24) nm; 1H NMR (300 MHz, CDCl3)
d 3.73
enol)¼11.0 Hz, 4J(30-H, enol, 50-H, enol)¼2.5 Hz, 1H, 50-H, enol), 7.10
(s, 3H, 100-H, ketone), 3.786 (s, 6H, 1000-H, ketone and 1000-H, enol),
3.794 (s, 3H, 100-H, enol), 4.03 (s, 2H, 2-H, ketone), 5.48 (s, 1H, 2-H,
3
3
(ddd-like, J(60-H, ketone, 50-H, ketone)¼8.1 Hz, J(40-F, ketone, 50-
H, ketone)¼10.4 Hz, 4J(30-H, ketone, 50-H, ketone)¼2.4 Hz, 1H, 50-H,
enol), 6.81 (dd, J(30-H, ketone, 40-H, ketone)¼8.8 Hz, J(60-H, ke-
3
4
3
4
ketone), 7.35 (dd-like, J(40-F, 30-H)¼8.9 Hz, J(50-H, 30-H)¼2.5 Hz,
tone, 40-H, ketone)¼3 Hz, 1H, 40-H, ketone), 6.86 (dd, 3J(30-H, enol,
2H, 30-H, ketone and 30-H, enol), 7.48 (dd, 3J(50-H, enol, 60-H, enol)¼
40-H, enol)¼8.8 Hz, J(60-H, enol, 40-H, enol)¼3 Hz, 1H, 40-H, enol),
4
4
4
8.6 Hz, J(40-F, enol, 60-H, enol)¼5.9 Hz, 1H, 60-H, enol), 7.58 (dd,
7.02 (d, J(40-H, 60-H)¼3 Hz, 2H, 60-H, ketone and enol), 7.47 (d,
3J(50-H, ketone, 60-H, ketone)¼8.8 Hz, J(40-F, ketone, 60-H,
3J(40-H, ketone, 30-H, ketone)¼8.9 Hz, 1H, 30-H, ketone), 7.48 (d,
3J(40-H, enol, 30-H, enol)¼8.9 Hz, 1H, 30-H, enol), 12.32 (s, 1H, OH,
4
ketone)¼5.9 Hz, 1H, 60-H, ketone), 12.32 (s, 1H, OH, enol); 13C NMR
(75 MHz, CDCl3)
d
48.28 (C-2, ketone), 52.03 (C-100, enol), 55.59 (C-
enol); 13C NMR (75 MHz, CDCl3) 48.33 (C-2, ketone), 51.50 (C-100,
d
2
100, ketone), 92.94 (C-2, enol), 112.92 (C-20, enol), 114.62 (d, J(F-40,
enol), 52.37 (C-100, ketone), 55.52 (C-1000, enol), 55.61 (C-1000, ketone),
92.83 (C-2, enol),109.21 (C-20, ketone),111.07 (C-20, enol),114.66 (C-
60, ketone), 115.35 (C-60, enol), 117.36 (C-40, enol), 118.55 (C-40, ke-
tone), 134.46 (C-30, enol), 134.60 (C-30, ketone), 136.17 (C-10, enol),
140.57 (C-10, ketone), 158.67 (C-50, enol), 158.82 (C-50, ketone),
167.17 (C-1, ketone), 171.62 (C-3, enol), 172.78 (C-1, enol), 195.36 (C-
3, ketone); MS (EI, 70 eV) m/z (%) 286 (8) [M]þ, 213 (18), 207 (100),
185 (45), 170 (25), 150 (37), 91 (10), 78 (40), 63 (80); HRMS (EI, Mþ)
calculated for C11H11BrO4 285.9841 found 285.9840.
2
enol, C-50, enol)¼21 Hz, C-50, enol), 114.86 (d, J(F-40, ketone, C-50,
ketone)¼21 Hz, C-50, ketone), 119.74 (C-20, ketone), 121.05 (d, 2J(F-
40, enol, C-30, enol)¼25 Hz, C-30, enol), 121.46 (d, 2J(F-40, ketone, C-
30, ketone)¼25 Hz, C-30, ketone), 131.52 (d, 3J(F-40, enol, C-60, enol)¼
9 Hz, C-60, enol), 131.69 (d, 3J(F-40, ketone, C-60, ketone)¼9 Hz, C-60,
ketone), 131.89 (d, 4J(F-40, enol, C-10, enol)¼4 Hz, C-10, enol), 135.70
(d, 4J(F-40, ketone, C-10, ketone)¼4 Hz, C-10, ketone), 163.60 (d, 1J(F-
40, enol, C-40, enol)¼250 Hz, C-40, enol), 164.00 (d, 1J(F-40, ketone, C-
40, ketone)¼250 Hz, C-40, ketone), 167.10 (C-1, ketone), 170.82 (C-3,
enol), 172.68 (C-1, enol), 193.76 (C-3, ketone); MS (EI, 70 eV) m/z (%)
276 (1) [M]þ, 244 (36), 215 (100), 195 (49), 170 (8), 78 (9), 63 (20);
HRMS (EI, Mþ) calculated for C10H8BrFO3 273.9641 found 273.9643.
4.2.12. Methyl 3-(20-bromo-40,50-dimethoxyphenyl)-3-oxopro-pan-
oate (1l). According to general procedure I, method B, 6-
bromoveratraldehyde (2.5 g, 10 mmol), Zn powder (1 g, 15 mmol)
and methyl bromoacetate (2.3 g, 15 mmol) were reacted in toluene
at 100 ꢀC for 2 h. The crude methyl 3-(20-bromo-40,50-dimethoxy-
phenyl)-3-hydroxypropanoate and PCC (2 equiv) were reacted in
dichloromethane at room temperature for 8 h. Column chroma-
tography on silica gel (petroleum ether:EtOAc¼9:1) gave methyl 3-
(20-bromo-40,50-dimethoxyphenyl)-3-oxopro-panoate (1l) as a yel-
low oil in 43% yield (over 2 steps) (1.4 g, 4 mmol); Rf 0.15 (petro-
4.2.10. Methyl 3-(20-bromo-50-trifluoromethylphenyl)-3-oxo-
propanoate (1j). According to general procedure I, method A,
methyl 2-bromo-5-trifluoromethylbenzoate (4 g, 14 mmol), methyl
acetate (0.7 g, 9 mmol) and NaH (60% in mineral oil, 0.4 g, 9 mmol)
were reacted in THF at 70 ꢀC for 24 h. Column chromatography on
silica gel (petroleum ether:EtOAc¼9:1) gave methyl 3-(20-bromo-
50-trifluoromethylphenyl)-3-oxopropanoate (1j) as a yellow solid in
61% yield (1.9 g, 6 mmol): mp 51e52 ꢀC; Rf 0.63 (petroleum
leum ether:EtOAc¼9:1); IR (ATR)
n 1738 (CO ester), 1687 (CO
ketone), 1590, 1563, 1505, 1437, 1372, 1333, 1255, 1198, 1166, 1058,
ether:EtOAc¼9:1); IR (ATR)
n
1729 (CO ketone), 1695, 1606 (OCC
1019, 787 cmꢂ1; UV(MeCN) lmax (log ε) 234 (4.29), 277 (3.88) nm;
enol), 1440, 1322, 1290, 1245, 1201, 1110, 1083, 1015, 986, 827 cmꢂ1
;
1H NMR (300 MHz, CDCl3) 3.75 (s, 3H, 100-H, ketone), 3.81 (s, 3H,
d
UV (MeCN) lmax (log ε) 208 (4.04) nm; 1H NMR (300 MHz, CDCl3)
100-H, enol), 3.88 (s, 3H,10000-H, enol), 3.90 (s, 3H,10000-H, ketone), 3.92
(2, 6H, 1000-H, ketone and enol), 4.11 (s, 2H, 2-H, ketone), 5.57 (s, 1H,
2-H, enol), 7.05 (s, 1H, 30-H, ketone), 7.06 (s, 1H, 30-H, enol), 7.22 (s,
2H, 60-H, ketone and enol), 12.41 (s, 1H, OH, enol); 13C NMR
d
3.75 (s, 3H, 100-H, ketone), 3.83 (s, 3H, 100-H, enol), 4.06 (s, 2H, 2-H,
3
ketone), 5.51 (s, 1H, 2-H, enol), 7.51 (dd, J(30-H, enol, 40-H, enol)¼
8.3 Hz, 4J(60-H, enol, 40-H, enol)¼2 Hz,1H, 40-H, enol), 7.58 (dd, 3J(30-
H, ketone, 40-H, ketone)¼8.4 Hz, 4J(60-H, ketone, 40-H, ketone)¼2 Hz,
1H, 40-H, ketone), 7.75 (d-like, 2H, 60-H, ketone and enol), 7.79 (s, 2H,
30-H, ketone and enol), 12.36 (s, 1H, OH, enol); 13C NMR (75 MHz,
(75 MHz, CDCl3)
d
48.45 (C-2, ketone), 51.44 (C-100, ketone), 52.32
(C-100, enol), 56.09 (C-10000, ketone and enol), 56.29 (C-1000, ketone and
enol), 92.32 (C-2, enol), 111.64 (C-20, enol), 112.13 (C-20, ketone),
112.39 (C-30, enol), 113.04 (C-60, ketone and enol), 116.43 (C-30,
CDCl3) d
48.26 (C-2, ketone), 51.72 (C-100, enol), 52.52 (C-100, ketone),

H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
3463
ketone), 127.31 (C-10, enol), 130.94 (C-10, ketone), 148.11 (C-50, enol),
148.17 (C-50, ketone), 150.51 (C-40, enol), 152.12 (C-40, ketone),
167.63 (C-1, ketone), 171.32 (C-3, enol), 172.93 (C-1, enol), 193.37 (C-
3, ketone); MS (EI, 70 eV) m/z (%) 316 (14) [M]þ, 284 (7), 244 (12),
138 (29), 222 (9), 180 (12), 157 (6), 108 (8), 93 (8); HRMS (EI, Mþ)
calculated for C12H13BrO5 315.9946 found 315.9973.
(two times). Then, the methyl 3-(20-bromophenyl)-3-oxopropanoate
1 (1 mmol), propionic acid (22 mg, 0.3 mmol) and freshly distilled
isopropanol (2 mL) were added and the reaction mixture was stirred
at 100 ꢀC for 24 h. After cooling to room temperature, the reaction
mixture was diluted with water (15 mL) and extracted with EtOAc
(3ꢁ20 mL). The combined organic layers were dried over anhydrous
MgSO4, filtered and the solvents were evaporated in vacuo. The
crude product was purified by flash column chromatography on
silica gel to afford the 1-naphthol 2 in analytically pure form.
4.2.13. Methyl 3-(60-bromobenzo[d][10,30]dioxol-50-yl)-3-oxo-prop-
anoate (1m). According to general procedure I, method B, 6-
bromopiperonal (2.3 g, 10 mmol), Zn powder (1 g, 15 mmol) and
methyl bromoacetate (2.3 g, 15 mmol) were reacted in toluene at
100 ꢀC for 2 h. The crude methyl 3-(60-bromobenzo[d][10,30]dioxol-
50-yl)-3-hydroxypropanoate and PCC (2 equiv) were reacted in
4.3.2. Dimethyl 2-(200-bromophenyl)-4-hydroxynaphthalene-1,3-
dicarboxylate (2a). According to general procedure II, methyl 3-
(20-bromophenyl)-3-oxopropanoate (1a) (257 mg, 1.0 mmol), CuI
(10 mg, 5 mol %), K2CO3 (138 mg, 1.0 mmol), and propionic acid
(22 mg, 0.3 mmol) were reacted in isopropanol (2 mL) at 100 ꢀC for
24 h. Column chromatography on silica gel (petroleum ether:
EtOAc¼9:1) afforded dimethyl 2-(200-bromophenyl)-4-hydroxy-
naphthalene-1,3-dicarboxylate (2a) as a yellow solid in 79% yield
(150 mg, 0.36 mmol): mp 108e109 ꢀC; Rf 0.49 (petroleum ether:
EtOAc¼9:1); IR (ATR) nmax 2948 (OH), 1722 (s; CO ester), 1648, 1621,
1575, 1444, 1403, 1342, 1239, 1212, 1162, 1101, 981, 771, 754,
731 cmꢂ1; UV (MeCN) lmax (log ε) 224 (4.64), 258 (4.62), 344 (3.95)
dichloromethane at room temperature for
8
h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1) gave
methyl 3-(60-bromobenzo[d][10,30]dioxol-50-yl)-3-oxo-propanoate
(1m) as a yellow solid in 37% yield (over 2 steps) (1.2 g, 4 mmol): mp
62e63 ꢀC; Rf 0.23 (petroleum ether:EtOAc¼9:1); IR (ATR)
n 3056 (w;
OH),1724 (CO ketone),1689,1612 (OCC enol),1500,1480,1439,1385,
1316, 1273, 1236, 1192, 1111, 1024, 998, 924, 885 cmꢂ1; UV (MeCN)
lmax (log ε) 232 (4.15), 281 (3.58) nm; 1H NMR (300 MHz, CDCl3)
d
3.74 (s, 3H, 100-H, ketone), 3.80 (s, 3H, 100-H, enol), 4.02 (s, 2H, 2-H,
ketone), 5.46 (s,1H, 2-H, enol), 6.02 (s, 2H, 20-H, enol), 6.05 (s, 2H, 20-
H, ketone), 6.98 (s,1H, 40-H, enol), 7.05 (s,1H, 70-H, enol), 7.06 (s,1H,
70-H, ketone), 7.08 (s, 1H, 40-H, ketone), 12.34 (s, 1H, OH, enol); 13C
nm; 1H NMR (500 MHz, CDCl3) 3.49 (s, 3H, 20-H), 3.52 (s, 3H, 2000-
d
H), 7.20 (ddd, 3J(500-H, 400-H)¼7.2 Hz, 3J(300-H, 400-H)¼7.9 Hz, 4J(600-H,
400-H)¼2.0 Hz, 1H, 400-H), 7.24 (d-like, 1H, 6-H00), 7.33 (ddd, 3J(400-H,
500-H)¼7.1 Hz, 3J(600-H, 500-H)¼7.5 Hz, 4J(300-H, 500-H)¼1.2 Hz, 1H, 500-
H), 7.600 (ddd, 3J(400-H, 300-H)¼7.8 Hz, 4J(500-H, 300-H)¼1.2 Hz, 5J(600-
H, 300-H)¼0.4 Hz, 1H, 300-H), 7.602 (ddd, 3J(5-H, 6-H)¼8.5 Hz, 3J(7-H,
6-H)¼6.8 Hz, 4J(8-H, 6-H)¼1.3 Hz,1H, 6-H), 7.69 (ddd, 3J(6-H, 7-H)¼
6.8 Hz, 3J(8-H, 7-H)¼6.8 Hz, 4J(5-H, 7-H)¼1.4 Hz, 1H, 7-H), 7.81
(ddd, 3J(7-H, 8-H)¼8.3 Hz, 4J(6-H, 8-H)¼1.3 Hz, 5J(5-H, 8-H)¼0.7 Hz,
1H, 8-H), 8.52 (ddd, 3J(6-H, 5-H)¼8.4 Hz, 4J(7-H, 5-H)¼1.4 Hz, 5J(8-
H, 5-H)¼0.7 Hz, 1H, 5-H), 12.87 (s, 1H, OH); 13C NMR (75 MHz,
NMR (75 MHz, CDCl3) d
48.37 (C-2, ketone), 51.48 (C-100, enol), 52.38
(C-100, ketone), 92.66 (C-2, enol), 102.24 (C-20, enol), 102.57 (C-20,
ketone),109.72 (C-40, ketone and enol),112.47 (C-60, enol),113.67 (C-
60, ketone),113.91 (C-70, ketone and enol), 128.79 (C-50, enol),132.71
(C-50, ketone), 147.29 (C-3a0, enol), 147.48 (C-3a0, ketone), 149.57 (C-
7a0, enol), 150.88 (C-7a0, ketone), 167.41 (C-1, ketone), 171.46 (C-3,
enol), 172.85 (C-1, enol), 193.57 (C-3, ketone); MS (EI, 70 eV) m/z (%)
300 (9) [M]þ, 227 (100), 221 (95),199 (15),111 (11), 62 (7); HRMS (EI,
Mþ) calculated for C11H9BrO5 299.9633 found 299.9643.
CDCl3)
d
51.88 (C-20), 52.30 (C-2000), 104.97 (C-3), 123.95 (C-200),
124.38 (C-5), 124.44 (C-4a), 124.45 (C-1), 125.00 (C-8), 126.50 (C-
500), 126.67 (C-6), 128.62 (C-400), 130.10 (C-600), 130.82 (C-7), 131.51
(C-300), 132.40 (C-8a), 135.97 (C-2), 141.34 (C-100), 162.59 (C-4),
168.62 (C-10), 171.55 (C-1000); MS (EI, 70 eV) m/z (%) 416 (20) [M]þ,
384 (23), 335 (22), 303 (100), 272 (17), 187 (10), 57 (3); HRMS (EI,
Mþ) calculated for C20H15BrO5 414.0103 found 414.0094.
4.2.14. Methyl 3-(30-bromothien-2-yl)-3-oxopropanoate
(1n). According to general procedure I, method A, 2-acetyl-3-
bromothiophene (2.0 g, 10 mmol), dimethylcarbonate (4.7 g,
53 mmol) and NaH (60% in mineral oil, 0.8 g, 20 mmol) were reacted
in THF at 70 ꢀC for 8 h. Column chromatography on silica gel (pe-
troleum ether:EtOAc¼9:1) gave methyl 3-(30-bromothien-2-yl)-3-
oxopropanoate (1n) as a yellow oil in 69% yield (1.8 g, 7 mmol); Rf
4.3.3. Dimethyl 2-(200-iodophenyl)-4-hydroxynaphthalene-1,3-
dicarboxylate (2b). According to general procedure II, methyl 3-(20-
iodophenyl)-3-oxopropanoate (1b) (304 mg, 1.0 mmol), CuI (10 mg,
5 mol %), K2CO3 (138 mg, 1.0 mmol), and propionic acid (22 mg,
0.3 mmol) were reacted in isopropanol (2 mL) at 100 ꢀC for 24 h.
Column chromatography on silica gel (petroleum ether:EtOAc¼9:1)
afforded dimethyl 2-(200-iodophenyl)-4-hydroxynaphthalene-1,3-
dicarboxylate (2b) as a yellow solid in 60% yield (140 mg,
0.31 mmol): mp 146e147 ꢀC; Rf 0.62 (petroleum ether:EtOAc¼9:1);
IR (ATR) nmax 2947 (OH), 1734 (s; CO ester), 1655, 1620, 1577, 1446,
1401, 1344, 1241, 1213, 1162, 1099, 989, 756 cmꢂ1; UV (MeCN) lmax
(log ε) 226 (4.59), 259 (4.58), 343 (3.82) nm; 1H NMR (500 MHz,
0.36 (petroleum ether:EtOAc¼9:1); IR (ATR)
n 1737 (CO ester), 1653
(CO ketone),1614 (OCC enol),1490,1436,1400,1325,1268,1236,1198,
1144, 1017, 1015, 873, 730 cmꢂ1; UV (MeCN) lmax (log ε) 278 (4.10)
nm; 1H NMR (300 MHz, CDCl3) 3.77 (s, 3H,100-H, ketone), 3.81 (s, 3H,
d
100-H, enol), 4.12 (s, 2H, 2-H, ketone), 6.20 (s, 1H, 2-H, enol), 7.07 (d-
3
like, J(50-H, enol, 40-H, enol)¼5.3 Hz, 1H, 40-H, enol), 7.16 (d-like,
3J(50-H, ketone, 40-H, ketone)¼5.2 Hz, 1H, 40-H, ketone), 7.43 (d-like,
3J(40-H, enol, 50-H, enol)¼5.2 Hz, 1H, 50-H, enol), 7.59 (d-like, 3J(40-H,
ketone, 50-H, ketone)¼5.2 Hz, 1H, 50-H, ketone), 12.56 (s, 1H, OH,
enol); 13C NMR (75 MHz, CDCl3)
d
47.59 (C-2, ketone), 51.64 (C-100,
enol), 52.49 (C-100, ketone), 89.04 (C-2, enol), 111.02 (C-30, enol),
115.08 (C-30, ketone), 128.69 (C-40, enol), 132.93 (C-50, enol), 133.51
(C-40, ketone), 133.70 (C-50, ketone), 138.09 (C-20, enol), 138.14 (C-20,
ketone), 164.26 (C-3, enol), 167.29 (C-1, ketone), 173.36 (C-1, enol)
184.75 (C-3, ketone); MS (EI, 70 eV) m/z (%) 264 (4) [M]þ,191 (72),183
(100),163 (2),117 (2), 83 (10), 69 (5); HRMS (ESI, [MþNa]þ) calculated
for C8H7BrO3S MþNa 286.9171 found 286.9172.
CDCl3)
d
3.49 (s, 3H, 20-H), 3.51 (s, 3H, 2000-H), 7.02 (ddd, 3J(500-H, 400-
H)¼7.7 Hz, 3J(300-H, 400-H)¼7.8 Hz, 4J(600-H, 400-H)¼1.7 Hz, 1H, 400-H),
7.24 (dd, 3J(500-H, 600-H)¼7.5 Hz, 4J(400-H, 600-H)¼1.5 Hz,1H, 6-H00), 7.34
(ddd, 3J(400-H, 500-H)¼7.4 Hz, 3J(600-H, 500-H)¼7.5 Hz, 4J(300-H, 500-H)¼
1.0 Hz, 1H, 500-H), 7.60 (ddd, 3J(5-H, 6-H)¼7.0 Hz, 3J(7-H, 6-H)¼7.1 Hz,
4J(8-H, 6-H)¼1.0 Hz, 1H, 6-H), 7.69 (ddd, 3J(6-H, 7-H)¼6.8 Hz, 3J(8-H,
7-H)¼7.1 Hz, 4J(5-H, 7-H)¼1.2 Hz, 1H, 7-H), 7.80 (d, 3J(7-H, 8-H)¼
3
4
4.3. Synthesis and characterization of 2aen
8.4 Hz, 1H, 8-H), 7.87 (dd, J(400-H, 300-H)¼7.9 Hz, J(500-H, 300-H)¼
1.2 Hz, 1H, 300-H), 8.53 (d, 3J(6-H, 5-H)¼8.4 Hz, 1H, 5-H), 12.94 (s, 1H,
4.3.1. General procedure II for the CuI-catalyzed synthesis of
2aen. An oven-dried 10 mL vial equipped with a magnetic stir bar
was charged with CuI (0.05 mmol, 10 mg) and K2CO3 (1 mmol,
138 mg). The sealed tube was evacuated and backfilled with argon
OH); 13C NMR (75 MHz, CDCl3) 51.80 (C-20), 52.31 (C-2000), 99.78 (C-
d
200), 104.81 (C-3), 124.31 (C-4a), 124.35 (C-5), 124.42 (C-1), 125.72 (C-
8),126.66 (C-6),127.22 (C-500),128.42 (C-400),129.25 (C-600),130.82 (C-
7),132.37 (C-8a),137.85 (C-300),138.69 (C-2),145.26 (C-100),162.63 (C-

3464
H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
4), 168.50 (C-10), 171.40 (C-1000); MS (EI, 70 eV) m/z (%) 462 (22) [M]þ,
430 (5), 335 (46), 303 (100), 275 (30), 247 (25), 232 (17), 204 (13),187
(22),176 (17),151 (10), 94 (6); HRMS (EI, Mþ) calculated for C20H15IO5
461.9964 found 461.9971.
for 24 h. Column chromatography on silica gel (petroleum
2-(200-bromophenyl)-4-
hydroxynaphthalene-1,3-dicarboxylate (2e) as a yellow oil in
81% yield (189 mg, 0.41 mmol); Rf 0.34 (petroleum ether:
ether:EtOAc¼9:1) afforded diallyl
EtOAc¼9:1); IR (ATR)
n 2950 (OH), 1724 (s; CO ester), 1649, 1620,
4.3.4. Dimethyl 2-(200-chlorophenyl)-4-hydroxynaphthalene-1,3-
dicarboxylate (2c). According to general procedure II, methyl 3-(20-
chlorophenyl)-3-oxopropanoate (1c) (213 mg,1.0 mmol), CuI (10 mg,
5 mol %), K2CO3 (138 mg, 1.0 mmol), and propionic acid (22 mg,
0.3 mmol) were reacted in isopropanol (2 mL) at 100 ꢀC for 24 h.
Column chromatography on silica gel (petroleum ether:EtOAc¼9:1)
afforded dimethyl 2-(200-chlorophenyl)-4-hydroxynaphthalene-1,3-
dicarboxylate (2c) as a yellow oil in 48% yield (95 mg, 0.26 mmol);
1577, 1444, 1402, 1340, 1238, 1163, 1100, 1016, 930, 751 cmꢂ1; UV
(MeCN) lmax (log ε) 259 (4.42), 343 (3.60) nm; 1H NMR (500 MHz,
CDCl3)
d
4.34 (m, 1H, 20-Ha), 4.46 (m, 1H, 2000-Ha), 4.63 (dt-like,
3J(30-H, 20-Hb)¼4.9 Hz, 1H, 20-Hb), 4.81 (dt-like, J(3000-H, 2000-Hb)¼
3
3
5.5 Hz, 1H, 2000-Hb), 5.27 (dd-like, J(3000-H, 4000-H(Z))¼7.0 Hz, 1H,
3
4000-H(Z)), 5.29 (dd-like, J(30-H, 40-H(Z))¼7.1 Hz, 1H, 40-H(Z)), 5.42
3
(dd-like, J(3000-H, 4000-H(E))¼17.3 Hz, 1H, 4000-H(E)), 5.50 (dd-like,
3J(30-H, 40-H(E))¼17.3 Hz, 1H, 40-H(E)), 6.04 (m, 1H, 3000-H), 6.07 (m,
1H, 30-H), 7.19 (ddd, 3J(300-H, 400-H)¼7.3 Hz, 3J(500-H, 400-H)¼7.4 Hz,
4J(600-H, 400-H)¼2.2 Hz, 1H, 400-H), 7.26 (ov, 1H, 600-H), 7.30 (ov, 1H,
Rf 0.51 (petroleum ether:EtOAc¼9:1); IR (ATR)
n 2950 (OH), 1724 (s;
CO ester), 1651, 1620, 1575, 1443, 1401, 1340, 1215, 1160, 1101, 813,
3
753 cmꢂ1; UV (MeCN) lmax (log ε) 214 (4.54), 258 (4.55), 343 (3.75)
500-H), 7.55 (dd-like, J(400-H, 300-H)¼8.2 Hz, 1H, 300-H), 7.60 (ddd,
nm; 1H NMR (500 MHz, CDCl3)
d
3.48 (s, 3H, 20-H), 3.51 (s, 3H, 2000-H),
3J(5-H, 6-H)¼7.1 Hz, 3J(7-H, 6-H)¼7.0 Hz, 4J(8-H, 6-H)¼0.8 Hz, 1H,
6-H), 7.69 (ddd, 3J(6-H, 7-H)¼6.9 Hz, 3J(8-H, 7-H)¼7.3 Hz, 4J(5-H,
7-H)¼1.3 Hz, 1H, 7-H), 7.83 (dd, 3J(7-H, 8-H)¼7.7 Hz, 4J(6-H, 8-
H)¼1.6 Hz, 1H, 8-H), 8.52 (d, 3J(6-H, 5-H)¼8.4 Hz, 1H, 5-H),
7.25 (m, 1H, 300-H), 7.27 (m, 1H, 600-H), 7.28 (m, 1H, 400-H), 7.40 (m, 1H,
500-H), 7.59 (ddd, 3J7-H, 6-H 7.0 Hz, 3J(5-H, 6-H)¼7.0 Hz, 4J(8-H, 6-H)¼
1.1 Hz, 1H, 6-H), 7.68 (ddd, 3J(8-H, 7-H)¼6.9 Hz, 3J(6-H, 7-H)¼7.0 Hz,
4J(5-H, 7-H)¼1.3 Hz, 1H, 7-H), 7.80 (d, 3J(7-H, 8-H)¼8.4 Hz, 1H, 8-H),
8.51 (d, 3J(6-H, 5-H)¼8.4 Hz, 1H, 5-H), 12.87 (s, 1H, OH); 13C NMR
12.90 (s, 1H, OH); 13C NMR (75 MHz, CDCl3)
d
65.43 (C-2000), 69.48
(C-20), 105.08 (C-3), 113.57 (C-200), 117.45 (C-40), 118.06 (C-4000),
120.38 (C-1), 124.37 (C-5), 124.46 (C-4a), 124.97 (C-8), 126.51 (C-
500), 126.66 (C-6), 128.65 (C-400), 130.36 (C-600), 130.84 (C-7), 131.74
(C-300), 132.32 (C-3000), 132.72 (C-30), 133.36 (C-8a), 135.83 (C-2),
141.49 (C-100), 162.74 (C-4), 167.84 (C-10), 170.86 (C-1000); MS (EI,
70 eV) m/z (%) 467 (1) [M]þ, 442 (4), 382 (7), 335 (7), 329 (15),
303 (46), 288 (11), 272 (8) 204 (4), 187 (8), 111 (4), 88 (3); HRMS
(EI, Mþ) calculated for C24H19BrO5 466.0416 found 466.0431.
(75 MHz, CDCl3) d
51.94 (C-20), 52.32 (C-2000), 104.98 (C-3), 124.42 (C-
5), 124.47 (C-4a), 124.65 (C-1), 124.99 (C-8), 125.66 (C-300), 126.70 (C-
6), 128.37 (C-500),128.61 (C-400),130.11 (C-600),130.86 (C-7),132.44 (C-
8a),133.75 (C-200),134.49 (C-2),139.51 (C-100),162.64 (C-4),168.72 (C-
10), 171.62 (C-1000); MS (EI, 70 eV) m/z (%) 370 (10) [M]þ, 340 (6), 335
(11), 303 (84), 288 (15), 272 (9), 260 (6), 223 (8), 187 (13), 113 (5), 97
(7), 85 (15), 71 (21), 57 (29); HRMS (EI, Mþ) calculated for C20H15ClO5
370.0608 found 370.0585.
4.3.7. Dimethyl 2-(200,500-dibromophenyl)-6-bromo-4-hydroxy-
naphthalene-1,3-dicarboxylate (2f). According to general pro-
cedure II, methyl 3-(20,50-dibromophenyl)-3-oxopropanoate (1f)
(335 mg,1.0 mmol), CuI (10 mg, 5 mol %), K2CO3 (138 mg,1.0 mmol),
and propionic acid (22 mg, 0.3 mmol) were reacted in isopropanol
(2 mL) at 100 ꢀC for 24 h. Column chromatography on silica gel
(petroleum ether:EtOAc¼9:1) afforded dimethyl 2-(200,500-dibromo-
phenyl)-6-bromo-4-hydroxynaphthalene-1,3-dicarboxylate (2f) as
a white solid in 67% yield (190 mg, 0.33 mmol): mp 182e183 ꢀC; Rf
4.3.5. Diethyl 2-(200-bromophenyl)-4-hydroxynaphthalene-1,3-
dicarboxylate (2d). According to general procedure II, ethyl 3-(20-
bromophenyl)-3-oxopropanoate (1d) (271 mg,1.0mmol), CuI (10 mg,
5 mol %), K2CO3 (138 mg, 1.0 mmol), and propionic acid (22 mg,
0.3 mmol) were reacted in isopropanol (2 mL) at 100 ꢀC for 24 h.
Column chromatography on silica gel (petroleum ether:EtOAc¼9:1)
afforded diethyl 2-(200-bromophenyl)-4-hydroxynaphthalene-1,3-
dicarboxylate (2d) as a yellow oil in 71% yield (158 mg, 0.36 mmol);
Rf 0.53 (petroleum ether:EtOAc¼9:1); IR (ATR)
n
2981 (OH), 1722 (s;
0.52 (petroleum ether:EtOAc¼9:1); IR (ATR)
n 2948 (OH), 1715 (s;
CO ester), 1656, 1618, 1570, 1485, 1331, 1220, 1166, 1114, 993, 804,
CO ester), 1649, 1620, 1576, 1443, 1402, 1238, 1216, 1100, 1017, 815,
751 cmꢂ1; UV (MeCN) lmax (log ε) 258 (4.46), 343 (3.77) nm; 1H NMR
778 cmꢂ1; UV (MeCN) lmax (log ε) 233 (4.55), 267 (4.47), 361 (3.59)
(500 MHz, CDCl3)
d
0.78 (t, 3H, 30-H), 0.95 (t, 3H, 3000-H), 3.98 (m, 2H,
nm; 1H NMR (500 MHz, CDCl3)
d
3.56 (s, 3H, 20-H), 3.58 (s, 3H, 2000-
20-H), 4.16 (m, 2H, 2000-H), 7.21 (ddd, 3J(300-H, 400-H)¼8.0 Hz, 3J(500-H,
400-H)¼7.7 Hz, 4J(600-H, 400-H)¼2.0 Hz, 1H, 400-H), 7.27 (dd, 3J(500-H, 600-
H)¼7.7 Hz, 4J(400-H, 600-H)¼2.3 Hz, 1H, 600-H), 7.30 (ddd, 3J(400-H, 500-
H)¼7.7 Hz, 3J(600-H, 500-H)¼7.3 Hz, 4J(300-H, 500-H)¼1.5 Hz, 1H, 500-H),
7.58 (dd, 3J(400-H, 300-H)¼7.8 Hz, 4J(500-H, 300-H)¼1.0 Hz, 1H, 300-H), 7.60
(ddd, 3J(5-H, 6-H)¼7.3 Hz, 3J(7-H, 6-H)¼7.0 Hz, 4J(8-H, 6-H)¼1.2 Hz,
1H, 7-H), 7.68 (ddd, 3J(6-H, 7-H)¼7.0 Hz, 3J(8-H, 7-H)¼6.9 Hz, 4J(5-H,
7-H)¼1.2 Hz,1H, 7-H), 7.83 (d, 3J(7-H, 8-H)¼8.3 Hz,1H, 8-H), 8.52 (d,
3J(6-H, 5-H)¼8.3 Hz, 1H, 5-H), 13.03 (s, 1H, OH); 13C NMR (75 MHz,
H), 7.35 (dd, J(300-H, 400-H)¼8.5 Hz, J(600-H, 400-H)¼2.4 Hz, 1H, 400-
H), 7.40 (d, 4J(400-H, 600-H)¼2.4 Hz, 1H, 600-H), 7.46 (d, 3J(400-H, 300H)¼
8.4 Hz, 1H, 300-H), 7.69 (d, 3J(7-H, 8-H)¼8.9 Hz, 1H, 8-H), 7.76 (dd,
3J(8-H, 7-H)¼8.8 Hz, 4J(5-H, 7-H)¼2.1 Hz, 1H, 7-H), 8.67 (d, 4J(7-H,
5-H)¼2.2 Hz, 1H, 5-H), 12.86 (s, 1H, OH); 13C NMR (75 MHz, CDCl3)
3
4
d
52.15 (C-20), 52.66 (C-2000), 105.51 (C-3), 120.17 (C-500), 121.34 (C-6),
122.71 (C-200),124.31 (C-1),125.76 (C-4a),126.87 (C-8),126.88 (C-5),
130.86 (C-8a), 131.75 (C-400), 132.64 (C-600), 132.88 (C-300), 134.20 (C-
7), 135.02 (C-2), 142.97 (C-100), 161.65 (C-4), 167.77 (C-10), 170.98 (C-
1000); MS (EI, 70 eV) m/z (%) 572 (20) [M]þ, 540 (25), 493 (50), 461
(100), 446 (12), 402 (6), 365 (6), 295 (4), 267 (9), 230 (12), 187 (10),
84 (34); HRMS (ESI, [MþNa]þ) calculated for C20H13Br3O5 [MþNa]
592.8205 found 592.8176.
CDCl3)
d
12.91 (C-30), 13.61 (C-3000), 61.12 (C-20), 61.39 (C-2000), 104.97
(C-3), 113.27 (C-200), 120.04 (C-1), 124.33 (C-5), 124.51 (C-4a), 124.98
(C-8),126.48 (C-500),126.59 (C-6),128.61 (C-400),130.50 (C-600),130.73
(C-7), 131.53 (C-300), 133.12 (C-8a), 135.69 (C-2), 141.63 (C-100), 162.66
(C-4),168.15 (C-10),171.22 (C-1000); MS (EI, 70 eV) m/z (%) 442 (3) [M]þ,
382 (9), 349 (18), 317 (31), 303 (70), 288 (22), 272 (18), 233 (14), 187
(27), 176 (21), 151 (5), 88 (5), 69 (5); HRMS (EI, Mþ) calculated for
4.3.8. Dimethyl 2-(200-bromo-500-chlorophenyl)-6-chloro-4-
hydroxynaphthalene-1,3-dicarboxylate (2g). According to general
C22H19BrO5 442.0416 found 442.0415.
procedure
II,
methyl
3-(20-bromo-50-chlorophenyl)-3-
oxopropanoate (1g) (292 mg, 1.0 mmol), CuI (10 mg, 5 mol %),
K2CO3 (138 mg, 1.0 mmol), and propionic acid (22 mg, 0.3 mmol)
were reacted in isopropanol (2 mL) at 100 ꢀC for 24 h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1) affor-
ded dimethyl 2-(200-bromo-500-chlorophenyl)-6-chloro-4-hydroxy-
naphthalene-1,3-dicarboxylate (2g) as a white solid in 65% yield
4.3.6. Diallyl 2-(200-bromophenyl)-4-hydroxynaphthalene-1,3-
dicarboxylate (2e). According to general procedure II, allyl 3-(20-
bromophenyl)-3-oxopropanoate (1e) (283 mg, 1.0 mmol), CuI
(10 mg, 5 mol %), K2CO3 (138 mg, 1.0 mmol), and propionic acid
(22 mg, 0.3 mmol) were reacted in isopropanol (2 mL) at 100 ꢀC

H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
3465
(155 mg, 0.32 mmol): mp 198e199 ꢀC; Rf 0.51 (petroleum ether:
3J(600-H, 500-H)¼8.1 Hz, 3J(400-F, 500-H)¼8.0 Hz, 4J(300-H, 500-H)¼2.4 Hz,
1H, 500-H), 7.20 (m, 1H, 600-H), 7.35 (ddd, 3J(5-H, 6-H)¼8.2 Hz, 3J(7-F,
6-H)¼8.1 Hz, 4J(8-H, 6-H)¼2.4 Hz,1H, 6-H), 7.37 (dd, 3J(400-F, 300-H)¼
EtOAc¼9:1); IR (ATR)
n 2950 (OH), 1715 (s; CO ester), 1656, 1621,
1574, 1463, 1334, 1220, 1166, 1116, 996, 805, 741 cmꢂ1; UV (MeCN)
lmax (log ε) 230 (4.62), 265 (4.50), 361 (3.63) nm; 1H NMR
8.3 Hz, J(500-H, 300-H)¼2.5 Hz, 1H, 300-H), 7.45 (dd, 3J(7-F, 8-H)¼
4
(500 MHz, CDCl3)
d
3.56 (s, 3H, 20-H), 3.57 (s, 3H, 2000-H), 7.21 (dd,
10.3 Hz, 4J(6-H, 8-H)¼2.2 Hz, 1H, 8-H), 8.53 (dd, 3J(6-H, 5-H)¼
9.1 Hz, 4J(7-F, 5-H)¼5.7 Hz, 1H, 5-H), 13.02 (s, 1H, OH); 13C NMR
3J(300-H, 400-H)¼8.5 Hz, J(600-H, 400-H)¼2.5 Hz, 1H, 400-H), 7.25 (d,
4J(400-H, 600-H)¼2.5 Hz, 1H, 600-H), 7.53 (d, 3J(400-H, 300H)¼8.5 Hz, 1H,
300-H), 7.63 (dd, 3J(8-H, 7-H)¼8.9 Hz, 4J(5-H, 7-H)¼2.2 Hz, 1H, 7-H),
7.77 (d, 3J(7-H, 8-H)¼8.9 Hz, 1H, 8-H), 8.49 (d, 4J(7-H, 5-H)¼2.2 Hz,
4
(75 MHz, CDCl3)
d
52.1 (C-20), 52.52 (C-2000), 104.61 (C-3), 109.45 (d,
2J(F, C-8)¼23 Hz, C-8), 113.67 (d, 2J(F, C-500)¼21 Hz C-500), 116.79 (d,
2J(F, C-6)¼25 Hz, C-6), 119.01 (d, 2J(F, C-300)¼25 Hz, C-300), 119.62 (C-
200), 121.41 (d, 4J(F, C-4a)¼2 Hz, C-4a), 124.05 (d, 4J(F, C-1)¼4 Hz, C-
1H, 5-H), 12.86 (s, 1H, OH); 13C NMR (75 MHz, CDCl3) 52.13 (C-20),
d
3
52.65 (C-2000), 105.52 (C-3), 121.99 (C-200), 123.59 (C-5), 124.21 (C-1),
125.46 (C-4a), 126.87 (C-8), 128.79 (C-400), 129.87 (C-600), 130.62 (C-
8a), 131.65 (C-7), 132.57 (C-500), 132.58 (C-300), 133.25 (C-6), 134.98
(C-2), 142.68 (c-100), 161.74 (C-4), 167.83 (C-10), 171.02 (C-1000); MS
(EI, 70 eV) m/z (%) 482 (20) [M]þ, 450 (17), 402 (46), 371 (100), 353
(25), 252 (51), 166 (46), 111 (25), 69 (18); HRMS (EI, Mþ) calculated
for C20H15Br OCl2O5 481.9323 found 481.9351.
1), 127.59 (d, 3J(F, C-5)¼10 Hz, C-5), 130.76 (d, J(F, C-600)¼8 Hz, C-
600),134.12 (d, 3J(F, C-8a)¼10 Hz, C-8a),137.26 (d, 4J(F, C-100)¼4 Hz, C-
100), 161.52 (d, 1J(F, C-400)¼250 Hz, C-400), 162.71 (C-4), 164.04 (d, 1J(F,
C-7)¼250 Hz, C-7), 168.08 (C-10), 171.32 (C-1000); MS (EI, 70 eV) m/z
(%) 449 (8) [M]þ, 371 (33), 339 (100), 324 (17), 308 (12), 224 (8);
HRMS (EI, Mþ) calculated for C20H13Br F2O5 449.9914 found
449.9903.
4.3.9. Diethyl 2-(200-bromo-500-fluorophenyl)-6-fluoro-4-hydroxy-
naphthalene-1,3-dicarboxylate (2h). According to general pro-
cedure II, methyl 3-(20-bromo-50-fluorophenyl)-3-oxopropanoate
(1h) (289 mg, 1.0 mmol), CuI (10 mg, 5 mol %), K2CO3 (138 mg,
1.0 mmol), and propionic acid (22 mg, 0.3 mmol) were reacted in
isopropanol (2 mL) at 100 ꢀC for 24 h. Column chromatography on
silica gel (petroleum ether:EtOAc¼9:1) afforded diethyl 2-(200-
bromo-500-fluorophenyl)-6-fluoro-4-hydroxy-naphthalene-1,3-
dicarboxylate (2h) as a white solid in 66% yield (159 mg,
0.33 mmol): mp 97e98 ꢀC; Rf 0.69 (petroleum ether:EtOAc¼9:1);
4.3.11. Dimethyl 2-(200-bromo-500-trifluoromethylphenyl)-6-trifluoro-
methyl-4-hydroxynaphthalene-1,3-dicarboxylate (2j). According to
general procedure II, methyl 3-(20-bromo-50-trifluoromethylphenyl)-
3-oxopropanoate (1j) (325 mg,1.0 mmol), CuI (10 mg, 5 mol %), K2CO3
(138 mg, 1.0 mmol), and propionic acid (22 mg, 0.3 mmol) were
reacted in isopropanol (2 mL) at 100 ꢀC for 24 h. Column chroma-
tography on silica gel (petroleum ether:EtOAc¼9:1) afforded di-
methyl 2-(200-bromo-500-trifluoromethyl-phenyl)-6-trifluoromethyl-
4-hydroxynaphthalene-1,3-dicarboxylate (2j) as a white solid in
69% yield (190 mg, 0.35 mmol): mp 169e170 ꢀC; Rf 0.51 (petroleum
IR (ATR)
1326, 1183, 1102, 979, 772 cmꢂ1; UV (MeCN) lmax (log ε) 224
(4.55), 261 (4.49), 346 (3.63) nm; 1H NMR (500 MHz, CDCl3)
0.86
n
2982 (OH), 1719 (s; CO ester), 1649, 1592, 1404, 1342,
ether:EtOAc¼9:1); IR (ATR)
n 2947 (OH), 1719 (s; CO ester), 1654,
1422, 1390, 1317, 1240, 1114, 1080, 1025, 838, 826 cmꢂ1; UV (MeCN)
d
lmax (log ε) 226 (4.63), 259 (4.50) 339 (3.79) nm; 1H NMR (500 MHz,
(t, 3H, 30-H), 1.01 (t, 3H, 3000-H), 4.05 (m, 2H, 20-H), 4.13 (m, 2H, 2000-
H), 6.98 (ddd, 3J(300-H, 400-H)¼8.3 Hz, 3J(500-F, 400-H)¼8.4 Hz, 4J(600-
H, 400-H)¼2.9 Hz, 1H, 400-H), 7.03 (dd, 3J(500-F, 600-H)¼8.6 Hz, 4J(400-
H, 600-H)¼2.8 Hz, 1H, 600-H), 7.45 (ddd, 3J(8-H, 7-H)¼8.6 Hz, 3J(6-F,
CDCl3)
d
3.54 (s, 3H, 20-H), 3.55 (s, 3H, 2000-H), 7.51 (dd, 3J(300-H, 400-H)¼
8.2 Hz, 4J(600-H, 400-H)¼2.1 Hz, 1H, 400-H), 7.54 (d-like, 1H, 6-H00), 7.76
3
(d, J(400-H, 300-H)¼8.2 Hz, 1H, 300-H), 7.87 (dd, 3J(8-H, 7-H)¼8.9 Hz,
4J(5-H, 7-H)¼1.8 Hz, 1H, 7-H), 7.95 (d, 3J(7-H, 8-H)¼8.7 Hz, 1H, 8-H),
3
7-H)¼8.8 Hz, 4J(5-H, 7-H)¼2.7 Hz, 1H, 7-H), 7.53 (dd, J(400-H,
8.84 (s, 1H, 5-H), 13.03 (s, 1H, OH); 13C NMR (75 MHz, CDCl3)
d 52.14
300H)¼8.7 Hz, 4J(500-F, 300-H)¼5.3 Hz, 1H, 300-H), 7.86 (dd, 3J(7-H, 8-
H)¼9.2 Hz, 4J(6-F, 8-H)¼5.3 Hz, 1H, 8-H), 8.12 (dd, 3J(6-F, 5-H)¼
9.6 Hz, 4J(7-H, 5-H)¼2.5 Hz, 1H, 5-H), 12.97 (s, 1H, OH); 13C NMR
(C-20), 52.72 (C-2000), 105.76 (C-3), 121.63 (d, 1J(F, C-10000)¼250 Hz, C-
10000), 122.43 (q-like, 3J(F, C-5)¼9 Hz, C-5), 123.97 (C-1), 124.44 (C-4a),
125.55 (q-like, 3J(F, C-400)¼8 Hz, C-400),125.93 (d, 1J(F, C-100000)¼250 Hz,
C-100000), 126.38 (C-8), 126.65 (q-like, 3J(F, C-7)¼7 Hz, C-7), 126.73 (q-
(75 MHz, CDCl3) d
12.99 (C-30), 13.64 (C-3000), 61.40 (C-20), 61.73 (C-
2000), 105.37 (C-3), 108.58 (d, 2J(F, C-5)¼23 Hz, C-5), 115.68 (d, 2J(F,
like, J(F, C-600)¼7 Hz, C-600), 127.8 (C-200), 128.94 (q-like, 2J(F, C-6)¼
3
2
2
C-400)¼22 Hz, C-400), 117.89 (d, J(F, C-600)¼23 Hz, C-600), 119.0 (d,
33 Hz, C-6), 129.35 (q-like, J(F, C-500)¼33 Hz, C-500), 132.26 (C-300),
4J(F, C-200)¼3 Hz, C-200), 120.74 (d, 2J(F, C-7)¼25 Hz, C-7), 124.32 (C-
1), 125.96 (d, 3J(F, C-4a)¼9 Hz, C-4a), 127.86 (d, 3J(F, C-8)¼9 Hz, C-
8), 129.18 (d, 4J(F, C-8a)¼1 Hz, C-8a), 132.68 (d, 3J(F, C-300)¼8 Hz, C-
300), 133.84 (C-2), 143.17 (d, 3J(F, C-100)¼8 Hz, C-100), 161.03 (d, 1J(F,
C-6)¼50 Hz, C-6), 161.16 (d, 1J(F, C-500)¼250 Hz, C-500), 161.93 (C-4),
167.58 (C-10), 170.77 (C-1000); MS (EI, 70 eV) m/z (%) 478 (14) [M]þ,
431 (15), 398 (56), 353 (96), 325 (100), 235 (43), 203 (41), 167
(43), 149 (82), 111 (56), 77 (59), 57 (50); HRMS (EI, Mþ) calculated
for C22H17BrF2O5 478.0227 found 478.0229.
133.87 (C-8a), 136.88 (C-2), 141.9 (C-100), 163.08 (C-4), 167.51 (C-10),
170.83 (C-1000); MS (EI, 70 eV) m/z (%) 548 (9) [Mꢂ1]þ, 515 (10), 469
(24), 438 (100), 423 (14), 324 (8); HRMS (EI, Mþ) calculated for
C22H13BrF6O5 549.9851 found 549.9872.
4.3.12. Dimethyl 2-(200-bromo-500-methoxyphenyl)-4-hydroxy-6-
methoxy-naphthalene-1,3-dicarboxylate (2k). According to general
procedure
II,
methyl
3-(20-bromo-50-methoxyphenyl)-3-
oxopropanoate (1k) (287 mg, 1.0 mmol), CuI (10 mg, 5 mol %),
K2CO3 (138 mg, 1.0 mmol), and propionic acid (22 mg, 0.3 mmol)
were reacted in isopropanol (2 mL) at 100 ꢀC for 24 h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1) affor-
ded dimethyl 2-(200-bromo-500-methoxyphenyl)-4-hydroxy-6-
methoxynaphthalene-1,3-dicarboxylate (2k) as a white solid in
63% yield (189 mg, 0.41 mmol): mp 122e123 ꢀC; Rf 0.12 (petroleum
4.3.10. Dimethyl 2-(200-bromo-400-fluorophenyl)-7-fluoro-4-
hydroxynaphthalene-1,3-dicarboxylate (2i). According to general
procedure
II,
methyl
3-(20-bromo-40-fluorophenyl)-3-
oxopropanoate (1i) (275 mg, 1.0 mmol), CuI (10 mg, 5 mol %),
K2CO3 (138 mg, 1.0 mmol), and propionic acid (22 mg, 0.3 mmol)
were reacted in isopropanol (2 mL) at 100 ꢀC for 24 h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1) affor-
ded dimethyl 2-(200-bromo-400-fluorophenyl)-7-fluoro-4-hydroxy-
naphthalene-1,3-dicarboxylate (2i) as a white solid in 23% yield
(53 mg, 0.12 mmol): mp 94e95 ꢀC; Rf 0.56 (petroleum ether:
ether:EtOAc¼9:1); IR (ATR)
n 2944 (OH), 1720 (s; CO ester), 1650,
1623, 1573, 1434, 1408, 1330, 1239, 1180, 1002, 960, 781, 737 cmꢂ1
;
UV (MeCN) lmax (log ε) 236 (4.56), 270 (4.51), 358 (3.46) nm; 1H
NMR (500 MHz, CDCl3)
d
3.52 (s, 3H, 20-H), 3.56 (s, 3H, 2000-H), 3.78
3
(s, 3H, 100000-H), 3.98 (s, 3H, 10000-H), 6.75 (dd, J(300-H, 400-H)¼8.7 Hz,
4J(600-H, 400-H)¼3 Hz, 1H, 400-H), 6.82 (d, 4J(400-H, 600-H)¼3 Hz, 1H, 6-
H00), 7.32 (dd, 3J(8-H, 7-H)¼9.1 Hz, 4J(5-H, 7-H)¼2.6 Hz, 1H, 7-H),
EtOAc¼9:1); IR (ATR)
1580, 1438, 1402, 1329, 1229, 1178, 1142, 1100, 876, 795, 743 cmꢂ1
UV (MeCN) lmax (log ε) 214 (4.55), 259 (4.56) nm; 1H NMR
(500 MHz, CDCl3)
3.54 (s, 3H, 20-H), 3.56 (s, 3H, 2000-H), 7.06 (ddd,
n 2947 (OH), 1713 (s; CO ester), 1653, 1628,
;
3
7.45 (d, J(400-H, 300-H)¼8.8 Hz, 1H, 300-H), 7.72 (d, 3J(7-H, 8-H)¼
d
9.1 Hz, 1H, 8-H), 7.78 (d, 4J(7-H, 5-H)¼2.8 Hz, 1H, 5-H), 12.78 (s, 1H,

3466
H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
OH); 13C NMR (75 MHz, CDCl3)
d
51.96 (C-20), 52.37 (C-2000), 55.56 (C-
(2 mL) at 100 ꢀC for 24 h. Column chromatography on silica gel
(petroleum ether:EtOAc¼9:1) afforded dimethyl 2-hydroxy-4-
(300-bromothien-200-yl)benzo[b]thiophene-3,5-dicarboxylate (2n)
as a white solid in 53% yield (108 mg, 0.25 mmol): mp 35e36 ꢀC;
10000 and C-100000), 102.57 (C-5), 105.35 (C-3), 114.65 (C-400), 114.9 (C-
200), 115.67 (C-600), 123.14 (C-7), 124.23 (C-1), 125.69 (C-4a), 126.68
(C-8), 127.53 (C-8a), 131.99 (C-300), 133.49 (C-2), 142.24 (C-100),
158.23 (C-500),158.36 (C-6),161.21 (C-4),168.76 (C-10) and 171.68 (C-
1000); MS (EI, 70 eV) m/z (%) 474 (8) [M]þ, 395 (31), 363 (98), 335 (24),
292 (8), 182 (7); HRMS (EI, Mþ) calculated for C22H19BrO7 474.0314
found 474.0319.
Rf 0.46 (petroleum ether:EtOAc¼9:1); IR (ATR)
n 2945 (OH), 1721
(s; CO ester), 1661, 1573, 1543, 1475, 1418, 1388, 1339, 1315, 1218,
1192, 1139, 1077, 881, 863, 704 cmꢂ1; UV (MeCN) lmax (log ε) 248
(4.47), 336 (3.85) nm; 1H NMR (500 MHz, CDCl3)
d
3.64 (s, 3H, 20-
3
H), 3.67 (s, 3H, 2000-H), 7.01 (d, J(500-H, 400-H)¼5.3 Hz, 1H, 400-H),
3
4.3.13. Dimethyl 2-(200-bromo-400,500-dimethoxyphenyl)-4-hydroxy-
6,7-dimethoxy-naphthalene-1,3-dicarboxylate (2l). According to
general procedure II, methyl 3-(20-bromo-40,50-dimethoxyphenyl)-
3-oxopropanoate (1l) (317 mg, 1.0 mmol), CuI (10 mg, 5 mol %),
K2CO3 (138 mg, 1.0 mmol), and propionic acid (22 mg, 0.3 mmol)
were reacted in isopropanol (2 mL) at 100 ꢀC for 24 h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1)
7.34 (d, J(500-H, 400-H)¼5.3 Hz, 1H, 500-H), 7.55 (d, 3J(6-H, 7-H)¼
5.5 Hz, 1H, 6-H), 7.77 (d, 3J(7-H, 6-H)¼5.5 Hz, 1H, 7-H), 12.23 (s,
1H, OH); 13C NMR (75 MHz, CDCl3)
d
52.29 (C-2000), 52.94 (C-20),
106.84 (C-3), 111.16 (C-300), 123.02 (C-5), 124.40 (C-6), 125.56 (C-
500), 129.40 (C-400), 129.52 (C-1a), 131.09 (C-5a), 132.83 (C-7),
136.37 (C-4), 141.87 (C-200), 159.28 (C-2), 167.49 (C-1000), 171.12 (C-
10); MS (EI, 70 eV) m/z (%) 428 (5) [M]þ, 347 (85), 315 (100), 300
(29), 284 (10), 256 (4), 200 (5), 168 (9), 111 (14); HRMS (ESI,
[MþNa]þ) calculated for C16H11BrO5S2 [MþNa] 448.9123 found
448.9152.
afforded
dimethyl
2-(200-bromo-400,500-dimethoxyphenyl)-4-
hydroxy-6,7-dimethoxy-naphthalene-1,3-dicarboxylate (2l) as
a yellow solid in 61% yield (158 mg, 0.30 mmol): mp 176e177 ꢀC; Rf
0.20 (petroleum ether:EtOAc¼8:2); IR (ATR)
CO ester), 1651, 1503, 1438, 1241, 1206, 1168, 1015, 975, 836 cmꢂ1
UV (MeCN) lmax (log ε) 204 (4.62), 242 (3.50), 267 (4.75), 358 (3.50)
n 2949 (OH), 1720 (s;
;
Acknowledgements
nm; 1H NMR (500 MHz, CDCl3)
d
3.54 (s, 3H, 20-H), 3.57 (s, 3H, 2000-
We thank Mr. Mario Wolf (Institut fur Chemie, Universitat
Hohenheim) for recording NMR spectra and Dipl.-Ing. (FH) Joachim
€
€
H), 3.82 (s, 3H,10000000-H), 3.93 (s, 3H,1000000-H), 3.98 (s, 3H,100000-H), 4.06
(s, 3H, 10000-H), 6.78 (s, 1H, 600-H), 7.07 (s, 1H, 4-H00), 7.09 (s, 1H, 8-H),
€
€
Trinkner (Institut fur Organische Chemie, Universitat Stuttgart) for
recording ESI spectra.
7.76 (s, 1H, 5-H), 12.75 (s, 1H, OH); 13C NMR (75 MHz, CDCl3)
d 52.03
(C-20), 52.42 (C-2000), 55.96 (C-100000), 56.09 (C-10000), 56.15 (C-1000000),
56.16 (C-10000000), 103.04 (C-5), 103.94 (C-8), 104.27 (C-3), 113.37 (C-
600), 114.34 (C-300), 114.45 (C-200), 119.46 (C-4a), 123.32 (C-1), 128.77
(C-8a), 133.52 (C-100), 134.70 (C-2), 147.51 (C-400), 148.32 (C-500),
149.75 (C-6), 153.12 (C-7), 160.94 (C-4), 169.25 (C-10), 171.83 (C-1000);
MS (EI, 70 eV) m/z (%) 532 (11) [Mꢂ2]þ, 454 (84), 422 (81), 395 (84),
227 (13), 204 (10); HRMS (EI, Mþ) calculated for C24H23BrO9
534.0525 found 534.0549.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.04.067.
References and notes
1. For reviews on copper-catalyzed C-arylations, see (a) Beletskaya, I. P.; Fed-
erov, A. Y. In Copper-mediated Cross-coupling Reactions; Evano, G., Blanchard,
N., Eds.; Wiley & Sons: Hoboken, New Jersey, 2014; pp 283e311; (b) Lindley,
J. Tetrahedron 1984, 40, 1433e1456; (c) Beletskaya, I. P.; Cheprakov, A. V.
Coord. Chem. Rev. 2004, 248, 2337e2364; (d) Ma, D.; Cai, Q. Acc. Chem. Res.
2008, 41, 1450e1460; (e) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev.
2008, 108, 3054e3131; (f) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed.
2009, 48, 6954e6971; (g) Johannson, C. C. C.; Colacot, T. J. Angew. Chem., Int.
Ed. 2010, 49, 676e707; (h) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110,
1082e1146; (i) Liu, Y.; Wan, J.-P. Chem.dAsian. J. 2012, 7, 1488e1501; (j)
Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowen, P. C. Chem. Soc. Rev.
2014, 43, 3525e3550.
4.3.14. Dimethyl 6-(60-bromobenzo[d][10,30]dioxol-50-yl)-8-hydroxy-
naphtho[2,3-d][1,3]dioxole-5,7-dicarboxylate (2m). According to
general procedure II, methyl 3-(60-bromobenzo[d][10,30]dioxol-50-
yl)-3-oxo-propanoate (1m) (301 mg, 1.0 mmol), CuI (10 mg, 5 mol
%), K2CO3 (138 mg, 1.0 mmol), and propionic acid (22 mg, 0.3 mmol)
were reacted in isopropanol (2 mL) at 100 ꢀC for 24 h. Column
chromatography on silica gel (petroleum ether:EtOAc¼9:1)
afforded
dimethyl
6-(60-bromobenzo[d][10,30]dioxol-50-yl)-8-
2. Hurtley, W. R. H. J. Chem. Soc. 1929, 1870e1873.
hydroxynaphtho[2,3-d][1,3]dioxole-5,7-dicarboxylate (2m) as
3. For selected publications, see (a) Bruggink, A.; McKillop, A. Tetrahedron 1975,
31, 2607e2619; (b) Setsune, J.; Matsukawa, K.; Wakemoto, H.; Kitao, T. Chem.
Lett. 1981, 367e370; (c) Setsune, J.; Matsukawa, K.; Kitao, T. Tetrahedron Lett.
1982, 23, 663e666; (d) Suzuki, H.; Yi, Q.; Inoue, J.; Kusume, K.; Ogawa, T. Chem.
Lett. 1987, 887e890; (e) Pivsa-Art, S.; Fukui, Y.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1996, 69, 2039e2042; (f) Bryson, T. A.; Stewart, J. J.; Gibson, J. M.;
Thomas, P. S.; Berch, J. K. Green Chem. 2003, 5, 174e176.
4. For selected publications, see (a) Okuro, K.; Furuune, M.; Miura, M.; Nomura,
M. J. Org. Chem. 1993, 58, 7606e7607; (b) Hennessy, E. J.; Buchwald, S. L. Org.
Lett. 2002, 4, 269e272; (c) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer,
M. Chem.dEur. J. 2004, 10, 5607e5622; (d) Jiang, Y.; Wu, N.; Wu, H.; He, M.
Synlett 2005, 2731e2734; (e) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y.
Org. Lett. 2007, 9, 3469e3472; (f) Zeevart, Z. G.; Parkinson, C. J.; de Koning,
C. B. Tetrahedron Lett. 2007, 48, 3289e3293; (g) Mino, T.; Yagishita, F.; Shi-
buya, M.; Kajiwara, K.; Shindo, H.; Sakamoto, M.; Fujita, T. Synlett 2009,
2457e2460; (h) Kidwai, M.; Bhardwaj, S.; Poddar, R. Beilstein J. Org. Chem.
2010, 6 (35); (i) Liu, J.; Zeng, R.; Zhou, C.; Zou, J. Chin. J. Chem. 2011, 29,
309e313.
5. For a review on ligands in copper-catalyzed reactions, see (a) Surry, D. S.;
Buchwald, S. L. Chem. Sci. 2010, 1, 13e31 for selected publications, see; (b)
Wang, Y. F.; Deng, W.; Liu, L.; Gao, Q. X. Chin. Chem. Lett. 2005, 16, 1197e1200;
(c) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693e4695; (d) Pei, L.; Qian, W.
Synlett 2006, 1719e1723.
6. (a) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427e6431; (b) Lu, B.; Ma, D. Org. Lett.
2006, 8, 6115e6118.
7. For a book on domino reactions, see:Domino Reactions in Organic Synthesis;
Tietze, L. F., Brasche, G., Gericke, K. M., Eds.; Wiley-VCH: Weinheim, 2006.
8. For reviews on copper-catalyzed domino reactions for the synthesis of het-
erocycles, see (a) Liu, Y.; Wan, J.-P. Org. Biomol. Chem. 2011, 9, 6873e6894; (b)
a yellow solid in 67% yield (169 mg, 0.34 mmol): mp 151e152 ꢀC; Rf
0.35 (petroleum ether:EtOAc¼8:2); IR (ATR)
n 2950 (OH), 1709 (s;
CO ester), 1655, 1617, 1477, 1458, 1429, 1210, 1176, 1032, 932, 862,
643 cmꢂ1; UV (MeCN) lmax (log ε) 203 (4.53), 238 (4.32), 268 (4.63)
nm; 1H NMR (500 MHz, CDCl3) 3.59 (s, 3H, 2000-H), 3.60 (s, 1H, 200-
d
H), 6.02 (m, 2H, 20-H) 6.10 (m 2H, 2-H), 6.73 (s, 1H, 40-H), 7.05 (s, 1H,
70-H), 7.07 (s, 1H, 4-H), 7.75 (s, 1H, 9-H), 12.65 (s, 1H, OH); 13C NMR
(75 MHz, CDCl3)
d
52.03 (C-200), 52.48 (C-2000), 101.02 (C-9), 101.73
(C-20), 101.85 (C-2), 101.97 (C-70), 104.57 (C-7), 110.38 (C-40), 111.84
(C-4), 114.81 (C-60), 120.88 (C-8a), 124.06 (C-5), 130.3 (C-4a), 134.17
(C-50), 134.64 (C-6), 146.43 (C-7a0), 147.29 (C-3a0), 148.11 (C-9a),
151.46 (C-3a), 161.14 (C-8), 168.77 (C-100), 171.58 (C-1000); MS (EI,
70 eV) m/z (%) 502 (9) [M]þ, 462 (9), 423 (100), 391 (95), 363 (78),
332 (11), 303 (36), 275 (13), 247 (10), 188 (14), 174 (9), 149 (7), 111
(5); HRMS (EI, Mþ) calculated for C22H15BrO9 501.9899 found
501.9875.
4.3.15. Dimethyl 2-hydroxy-4-(300-bromothien-200-yl)benzo[b]thio-
phene-3,5-dicarboxylate (2n). According to general procedure II,
methyl 3-(30-bromothien-2-yl)-3-oxopropanoate (1n) (263 mg,
1.0 mmol), CuI (10 mg, 5 mol %), K2CO3 (138 mg, 1.0 mmol), and
propionic acid (22 mg, 0.3 mmol) were reacted in isopropanol

H. Weischedel et al. / Tetrahedron 72 (2016) 3454e3467
3467
Liu, T.; Fu, H. Synthesis 2012, 44, 2805e2824; (c) Gulevich, A. V.; Dudnik, A. S.;
Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084e3213; (d) Ball, C. J.;
Willis, M. C. Eur. J. Org. Chem. 2013, 425e441; (e) Liao, Q.; Yang, X.; Xi, C. J. Org.
Chem. 2014, 79, 8507e8515.
9. (a) Lu, B.; Wang, B.; Zhang, Y.; Ma, D. J. Org. Chem. 2007, 72, 5337e5341; (b)
Aljaar, N.; Malakar, C. C.; Conrad, J.; Strobel, S.; Schleid, T.; Beifuss, U. J. Org.
Chem. 2012, 77, 7793e7803.
10. For selected publications, see (a) Setsune, J.-I.; Ueda, T.; Shikata, K.; Matsukawa,
K.; Iida, T.; Kitao, T. Tetrahedron 1986, 42, 2647e2656; (b) Konopelski, J. P.;
Hottenroth, J. M.; Oltra, H. M.; Veliz, E. A.; Yang, Z.-C. Synlett 1996, 609e611; (c)
Hang, H. C.; Drotleff, E.; Elliott, G. I.; Ritsema, T. A.; Konopelski, J. P. Synthesis
1999, 3, 398e400.
11. For selected publications, see (a) Tanimori, S.; Ura, H.; Kirihata, M. Eur. J. Org.
Chem. 2007, 3977e3980; (b) Chen, Y.; Xie, X.; Ma, D. J. Org. Chem. 2007, 72,
9329e9334; (c) Chen, Y.; Wang, Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625e628;
(d) Yang, X.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2010, 352,
1033e1038; (e) Kobayashi, K.; Komatsu, T.; Yokoi, Y.; Konishi, H. Synthesis 2011,
764e768; (f) Ali, M. A.; Punniyamurthy, T. Synlett 2011, 623e626.
12. Wang, B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma, D. Org. Lett. 2008, 10, 2761e2763.
13. For selected publications, see (a) Wang, F.; Liu, H.; Fu, H.; Jiang, Y.; Zhao, Y. Org.
Lett. 2009, 11, 2469e2472; (b) Lu, J.; Gong, X.; Yang, H.; Fu, H. Chem. Commun.
2010, 4172e4174.
14. (a) Sudheendran, K.; Malakar, C. C.; Conrad, J.; Beifuss, U. Adv. Synth. Catal. 2013,
355, 2400e2416; (b) Malakar, C. C.; Schmidt, D.; Conrad, J.; Beifuss, U. Org. Lett.
2011, 13, 1972e1975.
15. Xu, H.; Li, S.; Liu, H.; Fu, H.; Jiang, Y. Chem. Commun. 2010, 7617e7619.
16. Hatano, B.; Miyoshi, K.; Sato, H.; Ito, T.; Ogata, T.; Kijimi, T. Tetrahedron Lett.
2010, 51, 5399e5401.
17. Tietze, L. F.; Redert, T.; Bell, H. P.; Hellkamp, S.; Levy, L. M. Chem.dEur. J. 2008,
14, 2527e2535.
18. Jagdale, A. R.; Youn, S. W. Eur. J. Org. Chem. 2011, 3904e3910.
19. Malakar, C. C.; Baskakova, A.; Conrad, J.; Beifuss, U. Chem.dEur. J. 2012, 18,
8882e8885.
20. Sudheendran, K.; Malakar, C. C.; Conrad, J.; Beifuss, U. J. Org. Chem. 2012, 77,
10194e10210.
21. Aljaar, N.; Malakar, C. C.; Conrad, J.; Frey, W.; Beifuss, U. J. Org. Chem. 2013, 78,
154e166.
22. Abdel-Mohsen, H. T.; Conrad, J.; Beifuss, U. J. Org. Chem. 2013, 78, 7986e8003.