On the synthesis of arylpropiolic acids and investigations towards the formation of vinyl chlorides by HCl addition during esterification reactions

Article abstract of DOI:10.1055/s-0030-1258399

The synthesis protocol for the preparation of different arylpropiolic acids using the Negishi reaction and the addition of HCl to the alkyne moiety of these acids in subsequent esterification reactions using SOCl² was examined. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258399

6
42
PAPER
On the Synthesis of Arylpropiolic Acids and Investigations towards the For-
mation of Vinyl Chlorides by HCl Addition During Esterification Reactions
S
M
ynthesis of
A
rylpropi
a
olic
A
cids
a
r
nd HCl
k
A
ddition
D
u
o
ring Esterification Hapke,* Karolin Kral, Anke Spannenberg
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Fax +49(831)128151213; E-mail: marko.hapke@catalysis.de
Received 16 November 2010; revised 25 November 2010
ditions using a nucleophilic catalyst (Scheme 2). Howev-
Abstract: The synthesis protocol for the preparation of different
arylpropiolic acids using the Negishi reaction and the addition of
HCl to the alkyne moiety of these acids in subsequent esterification
er, this simple synthetic scheme turned out to be not as
simple as we thought. In the first step, the arylpropiolic
acid ester 2 was prepared from 1-iodo-2-methoxynaph-
thalene and the organozinc reagent 1 by a modified proce-
dure using the Negishi reaction in excellent yields, after
the Sonogashira reaction had yielded only minor amounts
reactions using SOCl was examined.
2
Key words: alkynes, esterification, addition reactions, vinyl chlo-
rides, Negishi reaction
6
of 2. Following the hydrolysis of ester 2, the obtained
acid 3 was treated with thionyl chloride under moderate
conditions to yield the acid chloride 4. The final esterifi-
cation with propargylic alcohol was done in the presence
of 4-dimethylaminopyridine (DMAP) in dichloro-
methane.
Functionalized acetylenes today are a basic building block
for the preparation of complex organic molecules. Prom-
1
inent uses include substance classes like ynamides, alky-
nylphosphines, enynes, halogenated alkynes, and many
2
more. For the elaboration of complex structures contain-
ing alkyne moieties cross-coupling reactions like the To our surprise 6 was exclusively isolated in up to 57%
Sonogashira reaction gained unprecedented importance yield after repeated attempts. The formation of 6 is evi-
1
due to their high versatility and most often mild condi- dent from the H NMR spectrum by the presence of the
3
tions and chemoselectivity. The Sonogashira reaction is
also regularly used for the assembly of starting materials
O
O
I
BrZnC≡CCOOEt (1)
Pd(PPh3)4, THF
65 °C, 35 h
for studies on asymmetric cobalt-catalyzed cycloaddition
4
OMe
reactions, utilizing functionalized diynes. These investi-
gations often require also the introduction of different
functional groups like ester, amide, ketone, or amine con-
nected to the alkyne, frequently employing standard cou-
pling procedures for connecting two single functionalized
OMe
2
(91%)
5
alkynes, for example, esterification reactions.
NaOH
H2O
EtOH
During our synthetic studies we needed to synthesize
diyne 5, in which the triple bonds are connected by an es-
ter group (for the strategic bond connections, see
Scheme 1).
O
Cl
O
OH
Our approach was aimed at the synthesis of arylpropiolic
acid 3 via ester 2, conversion to the acid chloride 4, and
esterification with propargyl alcohol under standard con-
SOCl2 (neat)
OMe
OMe
4
3 (81%)
esterification
of acid chloride
DMAP, propargyl alcohol
CH2Cl2, 25 °C
O
O
O
O
cross-coupling
OMe
OMe
O
O
H
O
Cl
5
O
OMe
OMe
Scheme 1 Key steps for the synthesis of diyne 5 connected by an
ester group
5
6 (57%)
SYNTHESIS 2011, No. 4, pp 0642–0652
x
x
.
x
x
.2
0
1
1
Advanced online publication: 10.01.2011
DOI: 10.1055/s-0030-1258399; Art ID: Z27710SS
Georg Thieme Verlag Stuttgart · New York
Scheme 2 Attempted preparation of compound 5 and the formation
of the unexpected vinyl chloride 6
©

PAPER
Synthesis of Arylpropiolic Acids and HCl Addition During Esterification
643
significant resonance of the vinyl proton at d = 6.72 ppm. protocols for Sonogashira coupling reactions with elec-
6b
After evaluation of all obtained analytical data, it was con- tron-deficient alkynes are also much less developed, the
cluded that an addition/esterification sequence had oc- Negishi cross-coupling reaction as the general method of
curred, in which one molecule of HCl had selectively choice was generally applied for the alkynylation with
added in a syn fashion to the alkyne C≡C bond, yielding ethyl propiolate. However, in several experiments utiliz-
the vinyl chloride 6. Final confirmation came in the form ing the aryl bromides, we found either little conversion or
of an X-ray structure analysis of a suitable single crystal, low yields of the expected alkynylated products under
unambiguously confirming the molecular structure of the standard cross-coupling conditions. To obviate the
E-configured vinyl chloride 6 with the chlorine atom in screening for a more suitable catalyst system, it was de-
7
the 3-position (Figure 1).
cided to enhance the reactivity of the substrates by simply
using an aromatic Finkelstein reaction for the transforma-
tion of the bromides into the corresponding iodides, some
of which are commercially available but exceedingly ex-
1
2
pensive. Following this procedure, the iodides 8, 10, 12,
and 14 were obtained, some contaminated with small
amounts of the unreacted bromides (Table 1). The ob-
tained yield for the 9-iodoanthracene (8, Table 1, entry 1)
was quite low. In the final example (entry 4) the exchange
reaction led to the nearly quantitative formation of pure
iodide, very conveniently yielding the formerly unknown
2
-iodoindene (14) from 2-bromoindene (13).
Table 1 Preparation of Aryl Iodides by Halide Exchange Reactions
Figure 1 Molecular structure of vinyl chloride 6
NaI, CuI, 1,4-dioxane
1
10 °C, 12–24 h
Ar Br
Ar
8, 10,
12, 14
I
ligand:
A quick literature survey showed that the above reaction
has been studied in some detail before, especially for the
addition of hydrogen halides to substituted propiolic acids
7, 9,
1
1, 13
NH2
NH2
8
in aqueous solution. Obviously due to the higher proton
concentrations involved in these reactions, slightly differ- Entry Aryl group
ent reaction pathways can be expected for reactions in or-
X = Br X = I
Yield (I/Br ratio)
22% (1:3)
X
ganic solvents or without any solvent. In some more
recent work, the reactions of 2,3-acetylenic acids with two
1
7
9
8a
well-known chlorination agents, thionyl chloride and ox-
alyl chloride, in DMF as the organic solvent have been re-
9
,10
X
X
ported. The selective addition of HCl to the triple bond
of propargylic acids with thionyl chloride yielding exclu-
sively the 3-chloroalk-2-enoic acids or esters is therefore
2
3
10a
92% (12:1)
N
9
a relatively new discovery. The necessary HCl was con-
sidered to come from the precedent chlorination reaction
of the carboxylic acid group, which actually is the only
source of HCl, when moisture is excluded. Conditions re-
lated even closer to our observation came from the reac-
tion of neat 3-trimethylsilylprop-2-ynoic acid with neat
11
13
12a
14
78% (4:1)
4
98% (100:0)
X
1
1
thionyl chloride. The reaction produced the expected
acid chloride as well as the HCl-addition product at the
C≡C bond in different ratios. No selectivity for either one
was accounted for, but at least the regioselective addition
of the chlorine in 3-position of the propiolic acid moiety
was observed. Some mechanistic experiments already in-
dicated the necessity of the carboxylic acid proton for the
HCl addition in aprotic media.
a
Mixture with unreacted bromide.
Because of foreseeable separation issues these mixtures
containing mostly the higher reactive iodide were directly
applied to the subsequent palladium-catalyzed cross-cou-
pling reaction with the alkynylzinc reagent 1. The results
of these Negishi cross-coupling reactions with the differ-
ent bromides and iodides as well as the subsequent sapon-
ifications are reported in Table 2. The coupling reactions
in general provided very good yields of the arylpropi-
olates 18, 20, 22, 24, 26, 28, 30 with two exceptions. The
reaction of 8 (Table 2, entry 1) gave the product 18 only
Due to the intriguing results it was decided to look at the
synthesis of different arylpropiolic acids and the broader
scope of the esterification reaction for other arylpropiolic
acids. The chosen aryl groups are based on the naphtha-
lene, anthracene, isoquinoline, or phenyl backbone, pro-
viding differentially sized aryl moieties. While the
Synthesis 2011, No. 4, 642–652 © Thieme Stuttgart · New York

6
44
M. Hapke et al.
PAPER
with 23% yield from the iodide, the unreacted bromide 7 the corresponding vinyl chlorides structurally related to 6.
obviously been completely unreacted. For 14 (entry 4) the The results of these investigations are shown in Table 3.
cross-coupling reaction yielded only 18% of the expected
ester 24 from pure 14. The successful coupling reactions
It is interesting to note that in the case of acid 2 the exclu-
sive and stereoselective formation of the vinyl ester 32
are then followed by the hydrolysis of the carboxylic ester
was observed (Table 3, entry 1) as in our initial observa-
under basic conditions to furnish the free carboxylic acids.
tion (Scheme 1), however, ethanol was used here instead
As it turned out, the use of potassium hydroxide was sig-
of propargylic alcohol as the alcohol component. It can
nificantly superior to the use of sodium hydroxide in
therefore be deduced that the structure of the alcohol plays
terms of improving the yields to higher amounts of the
no role for the addition process, as would have been ex-
pected, because the alcoholysis of the acid chloride is the
free acids. The characterization of the free acids 19, 21,
2
3, 25, 27, 29, 31 turned out to be quite difficult due to sol-
final step of the esterification process. Only in entry 2 us-
ing anthracene as aryl group, the nearly exclusive forma-
tion of the syn-addition product 34 was also observed with
comparable yields. A very small amount (10%) of the ex-
pected ester 18 was also formed.
ubility reasons; however, sufficient proof for identifica-
tion was obtained from NMR and MS analysis.
Table 2 Synthesis of Arylpropiolic Acids via the Corresponding
Esters Using a Cross-Coupling/Saponification Sequence
In all other cases except entry 5, the predominant products
were the regular esters with yields ranging from 31–78%.
In entries 4, 6, and 7, the addition products 38/39, 42/43
and 44/45 were obtained in rather trace amounts, which is
interesting to compare with the entry 1, because the start-
ing materials 3, 23, and 27 are based on the naphthalene
group and are structurally very similar, differing only at
the 2-position. Obviously the size and substitution of the
aryl fragment plays an important role for the outcome of
the reaction, and even small structural variations seem to
play a noticeable role.
1
2
. BrZnC≡CCOOEt (1)
Pd2dba3⋅CHCl3, dppf
THF, 65 °C
. KOH, H2O, 25 °C
Ar
I
Ar
COOH
8
, 10, 12,
19, 21, 23, 25, 27, 29, 31
1
4–17
X = Ia
b
b
Entry Aryl (Ar) group
X = CO Et X = CO H
2 2
X
1
8a
18 (23)
20 (98)
19 (48)
21 (23)
It is noteworthy that when the 2-indenylcarboxylic acid is
used, the formation of the addition product 40/41 is slight-
ly preferred over the pure esterification product 24. The
overall combined yield is lower than in all other cases ex-
cept entry 7.
X
2
10a
N
X
12a
Finally, the use of the phenyl group was examined in two
cases (entries 7 and 8). Again a pronounced effect was ob-
served for the acid 31, possessing an ortho-methoxy sub-
stituent. Here, the isolated yield of the ester 30 was found
to be doubled compared to the unsubstituted ester 28.
However, in the first case also a much larger amount of
the addition product 46/47 has been found.
3
22 (83)
24 (18)
26 (77)
23 (49)
25 (66)
27 (74)
4
14
15
X
X
5
For the only heteroaromatic propiolic acid 21 the ratio be-
tween simple esterification to the addition-esterification
sequence product (20 vs. 36/37) is close to 1:1, which is
the only case observed without larger selectivity for either
one.
X
6
16
17
28 (70)
30 (72)
29 (53)
31 (35)
The observed selectivity for the formation of the E/Z
products from the addition reaction was found to be in
general rather small except for the cases mentioned above
X
OMe
7
(
entries 1 and 2). The ratios in Table 3 give a sense for the
overall selectivity of the HCl addition in the addition–
esterification sequence.
a
Containing residual aryl bromide from the synthesis.
Isolated yields (in %).
b
It is an important message from these experiments that the
simple esterification procedure of arylpropiolic acids us-
ing SOCl as the chlorinating and dehydrating agent with-
2
After having successfully prepared a variety of different
arylpropiolic acids, we investigated the reactivity in the
esterification sequence that we had already attempted for
the preparation of ester 5, in order to elucidate the influ-
ence of the aryl substituent for the possible formation of
out organic solvents and subsequent reaction with an
alcohol can lead to unexpected and unpredictable results.
This is surprising in view of the fact that some investigat-
ed substrates only show very small structural differences.
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Synthesis of Arylpropiolic Acids and HCl Addition During Esterification
645
Table 3 Attempted Esterification Reactions of the Arylpropiolic Acids and the Obtained Addition and Esterification Products
esterification
product
product of HCl addition and
subsequent esterification
1
2
. SOCl2, 25 °C, 8 h
. DMAP, CH2Cl2
EtOH, 0 °C, then 25 °C
COOEt
H
COOEt
H
Cl
Cl
Ar
COOH
, 19, 21, 23,
5, 27, 29, 31
+
COOEt
+
3
2
Ar
Ar
Ar
2
, 18, 20, 22,
32–47
2
4, 26, 28, 30
Entry
Arylpropiolic acid
Arylpropiolic ethyl ester
Addition products (E/Z)
Yield of ester (%)/
yield of addition product (%)a
ratio addition product (E/Z)
R1
COOH
COOEt
Cl
R2
0
E/Z
/66
OMe
1
b
OMe
OMe
1
2
3
3
2 (E: R = H, R = CO Et)
2
3
2
1
2
3 (Z: R = CO Et, R = H)
2
R1
COOH
COOEt
Cl
R2
1
E/Z
0/61
2
3
b
1
2
3
3
4 (E: R = H, R = CO Et)
2
1
2
9
1
18
1
2
5 (Z: R = CO Et, R = H)
2
R1
COOH
COOEt
Cl
R2
3
8/29
E/Z = ~2:1
N
N
N
1
2
3
3
6 (E: R = H, R = CO Et)
2
20
1
2
7 (Z: R = CO Et, R = H)
2
R1
COOH
COOEt
Cl
R2
6
5/4
4
5
6
Me
Me
E/Z = ~2:1
1
2
3
3
8 (E: R = H, R = CO Et)
2
2
2
3
5
22
1
2
9 (Z: R = CO Et, R = H)
2
Cl
R1
14/55
E/Z = ~1:2
COOH
COOEt
R2
1
2
24
40 (E: R = H, R = CO Et)
2
1
2
4
1 (Z: R = CO Et, R = H)
2
R1
COOH
COOEt
Cl
R2
7
7/2
E/Z = ~1:1
1
2
4
4
2 (E: R = H, R = CO Et)
2
27
26
1
2
3 (Z: R = CO Et, R = H)
2
Synthesis 2011, No. 4, 642–652 © Thieme Stuttgart · New York

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46
M. Hapke et al.
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Table 3 Attempted Esterification Reactions of the Arylpropiolic Acids and the Obtained Addition and Esterification Products (continued)
esterification
product
product of HCl addition and
subsequent esterification
1
2
. SOCl2, 25 °C, 8 h
. DMAP, CH2Cl2
EtOH, 0 °C, then 25 °C
COOEt
H
COOEt
H
Cl
Cl
Ar
COOH
, 19, 21, 23,
5, 27, 29, 31
+
COOEt
+
3
2
Ar
Ar
Ar
2
, 18, 20, 22,
32–47
2
4, 26, 28, 30
Entry
Arylpropiolic acid
Arylpropiolic ethyl ester
Addition products (E/Z)
Yield of ester (%)/
yield of addition product (%)a
ratio addition product (E/Z)
R1
COOH
COOEt
Cl
R2
3
E/Z
1/4
7
c
1
2
4
4
4 (E: R = H, R = CO Et)
2
2
3
9
1
28
1
2
5 (Z: R = CO Et, R = H)
2
R1
COOH
COOEt
Cl
R2
7
8/13
OMe
8
OMe
OMe
E/Z = ~3:1
1
2
4
4
6 (E: R = H, R = CO Et)
2
7 (Z: R = CO Et, R = H)
30
1
2
2
a
Ester and addition product were isolated together and the ratio determined by GC-MS analysis, due to the small amounts of addition product
in some cases.
b
c
1
Only a very small amount of Z-configured addition product was found in the H NMR spectra.
Only the E-configured addition product was found.
Several additional reactions were performed to evaluate
the usefulness of products and obtain more information on
the addition process. First, the Suzuki reaction for the
functionalization of the isolated vinyl chloride 6
H
H
O
Cl
Ph
COOR
OMe
O
OMe
a) or b)
(Scheme 3) was attempted. As coupling partners, either
phenylboronic acid or the corresponding potassium phe-
nyltrifluoroborate was employed under standard coupling
conditions with Pd(OAc) or Pd(PPh ) Cl as the catalyst.
The products 48 and 49 were isolated in largely different
yields and concluded the use of the phenylboronic acid as
superior. Interestingly, the obtained coupling products 48
as well as 49 were isolated as the esters of the alcohols,
which were part of the coupling reaction solvent. There-
fore, the coupling reaction proceeded under transesterifi-
cation of the propargyl ester moiety of 6.
6
48 (R = Me, 15%)
9 (R = Et, 49%)
4
a) K CO , MeOH, Pd(OAc) , PhBF K, 100 °C
b) K2CO3, EtOH, toluene, H2O, Pd(PPh3)2Cl2, PhB(OH)2, 80 °C
2
3
2
3
2
3 2
2
Scheme 3 Suzuki cross-coupling reaction with vinyl chloride 6
COOH
R1
Br
R2
a) SOBr2 (1 equiv),
CH2Cl2, –78 °C–25 °C
b) EtOH
OMe
OMe
A much less often used halogenating reagent for the prep-
1
3
aration of acid halides is thionyl bromide. The reaction
3
5
5
0 (E: R1 = H, R2 = COOEt)
1 (Z: R1 = COOEt, R2 = H)
of SOBr with 3 was investigated in analogy to the reac-
2
tion with SOCl (Scheme 4). However, some experimen-
2
50/51 overall yield: 20%
tal changes needed to be made compared to the reaction
(ratio E/Z 5:1)
with SOCl to prevent the excessive bromination of the
2
Scheme 4 Reaction of acid 3 with thionyl bromide
substrate by SOBr . Therefore, only one equivalent of
2
SOBr was applied and the reaction was started at low
2
temperature (–78 °C). The isolation of the brominated vi- lower yield compared to 6 (Scheme 2) and 32 (Table 3)
nyl ester as a mixture of the isomers 50/51 and in much showed that the use of different halides in the halogenat-
Synthesis 2011, No. 4, 642–652 © Thieme Stuttgart · New York

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Synthesis of Arylpropiolic Acids and HCl Addition During Esterification
647
ing agent, certainly can account for a different outcome of come towards chlorinated aryl vinyl esters versus aryl
this reaction. No formation of the ester 2 was observed.
propiolic acid esters is hard to predict.
Finally, we were interested to prove in simple experi-
ments that the hydrogen atom in the newly formed vinyl The NMR spectra were recorded on Bruker ARX 300 ( H, 300
esters can be traced back to the carboxylic acid proton MHz; C, 75 MHz) and Bruker ARX 400 ( H, 400 MHz; C, 100
1
1
3
1
13
MHz) spectrometers at 298 K; and the individual measurement con-
ditions are given with the data. Chemical shifts are reported in ppm
relative to the H and C residue signals of the deuterated solvent
(Scheme 5). For this reason, deuterium was first intro-
duced into the carboxylic acid moiety by treating the acid
several times with D O at 80 °C. After each treatment,
1
13
3
1
13
2
(
CDCl : d = 7.26 for H and d = 77.16 for C). Signals were as-
3
1 13
the D O was removed under vacuum, additional D O add-
2
2
signed on the basis of H, C, HMQC, and HMBC NMR experi-
ments. Mass spectra were obtained with a mass spectrometer MAT
ed, and the procedure repeated. Finally, the CO D-deuter-
2
ated acid 3 was dried thoroughly under vacuum and was 95XP from ThermoElectron at an ionizing voltage of 70 eV or for
then reacted with SOCl . The reaction product, after re- ESI mass spectrometry an ESI-TOF-MS 6210 (Agilent) was used.
2
Only characteristic fragments containing the isotopes of highest
abundance are listed. Relative intensities in percentages are given in
parentheses. Melting points are not corrected. Elemental analyses
were done with a Mikroanalysator TrueSpec CHNS Micro from
moval of excessive SOCl , was investigated immediately
by NMR spectroscopy, showing a much smaller proton
signal for the expected vinyl proton of d -52 compared to
undeuterated 4, giving positive evidence of the incorpora-
2
1
Leco. Reactions with sensitive substances or intermediates were
tion of deuterium. In a second experiment, 3 was reacted carried out in an argon atmosphere, using standard Schlenk tech-
with SOCl first, followed by quenching the acid chloride niques with dry, oxygen-free solvents. All liquid reagents were dis-
2
tilled and/or dried under argon prior to use. Pd dba ·CHCl was
with CD OD. The analysis of the deuterated reaction
2
3
3
3
1
4
prepared according to known procedures. All other compounds
not referenced were commercially available. The eluents for col-
umn chromatography used for purification of reaction products
were mixtures of EtOAc and n-hexane in various ratios [a mixture
with a 1:10 (v/v) ratio proved to be effective in many cases].
product d -53, obtained in 54% yield, corroborated that no
3
deuterium was detected at the vinylic double bond, ex-
cluding any addition from the deuterated methanol.
D
Cl
Cl
Organozinc Reagent Solution 1
1
2
) D2O, 80 °C
) SOCl2
In a 250 mL Schlenk flask, i-Pr NH (5.7 mL, 40.5 mmol) was dis-
O
OMe
2
solved in THF (30 mL). At 0 °C, n-BuLi (25.3 mL, 40.5 mmol) was
added and stirred for 30 min at this temperature. Afterwards, the so-
lution was cooled down to –78 °C, combined with a solution of eth-
yl propiolate (4.1 mL, 40.5 mmol) in THF (10 mL) and stirred for 1
COOH
d1-52
h. At the same time ZnBr (9.5 g, 42.2 mmol) was dissolved in THF
2
OMe
H
(30 mL) and added to the solution at –78 °C and stirred for an addi-
1
2
) SOCl2
) DMAP
CD3OD
OCD3
Cl
tional 1 h, allowing the solution to warm up to r.t. over 8 h. During
this time the color of the solution changed from yellow to dark
brown. The solution was estimated to contain 0.25 mmol/mL orga-
nozinc reagent, which was used with this concentration. The solu-
tion was stored in the fridge, but the use of the reagent after some
days caused significant drop in the yields of the cross-coupling re-
action.
O
3
OMe
d3-53 (54%)
Scheme 5 Deuterium incorporation in the addition product d -52
1
and d -53 to prove the heritage of the hydrogen added to the triple
bond of arylpropiolic acid 3
3
Halogen Exchange; General Procedure 112
A Schlenk tube was charged with the bromide (1.0 mmol; if solid at
r.t.), CuI (5.0 mol%), ligand (10 mol%) and NaI (2.0 mmol), evac-
In summary we have investigated the HCl addition to dif- uated, and back-filled with argon at least three times. The corre-
ferent arylpropiolic acids during the esterification using sponding bromide (if liquid at 25 °C) was dried over molecular
sieves, the required amount diluted with 1,4-dioxane (5 mL) and
added to the reaction mixture after the above procedure. 1,4-Diox-
SOCl as the halogenation agent and subsequent reaction
with an alcohol. The different arylpropiolic acids were
2
ane (20 mL) was added to the Schlenk tube and the reaction mixture
prepared by Negishi cross-coupling reaction of the aryl io-
was stirred at 110 °C for 12–24 h. The resulting suspension was
dides – some of which were prepared by copper-catalyzed
halogen exchange – with the appropriate alkynylzinc re-
then allowed to cool to 25 °C. The reaction was quenched with sat.
NH Cl (20 mL) and extracted with CH Cl (3 × 20 mL). The com-
4
2
2
agent and subsequent saponification. The addition reac- bined organic phases were washed with brine (20 mL) and dried
tion was found to proceed stereoselectively in only a few (Na SO ). After removal of all volatiles, the residue was purified by
2
4
column chromatography (Table 1).
cases, giving the mixed E/Z vinyl isomers in most other
cases with largely varying yields besides the expected
arylpropiolic acid esters. The molecular structure of one
addition product was unambiguously solved by X-ray dif-
fraction, establishing the E-configuration of the newly
Negishi Cross-Coupling Reaction; General Procedure 2
Halide (10 mmol), Pd dba ·CHCl (263 mg, 0.25 mmol, 2.5 mol%),
2
3
3
dppf (282 mg, 0.5 mmol, 5 mol%), THF (75 mL), and the orga-
nozinc reagent solution 1 (14 mmol, 1.4 equiv) were stirred for 24–
formed double bond. The investigation showed that even 48 h at 50 °C under argon atmosphere. The reaction mixture was al-
when strongly related arylpropiolic acids are reacted with lowed to cool to 25 °C, quenched with sat. NH Cl (20 mL), and ex-
4
tracted several times with EtOAc. The combined organic phases
SOCl followed by esterification with an alcohol, the out-
2
were washed with H O (10 mL) and brine (10 mL), and dried
2
Synthesis 2011, No. 4, 642–652 © Thieme Stuttgart · New York

6
48
M. Hapke et al.
PAPER
(
Na SO ). After removal of all volatiles, the residue was purified by
Anal. Calcd for C H ClO (300.06): C, 67.89; H, 4.36. Found: C,
2
4
17 13
3
column chromatography (Table 2).
68.14; H, 4.57.
Hydrolysis; General Procedure 315
The prepared esters (5 mmol) were hydrolyzed in MeOH (5 mL)
with aq KOH (5 mL containing 320 mg, 8 mmol) and stirred at
9-Iodoanthracene (8)
Prepared from 9-bromoanthracene (7; 3.0 g, 11.7 mmol), following
General Procedure 1, to give 2.74 g of the product mixture 7 and 8,
and 8 in 22% (775 mg) yield. The product formation was confirmed
2
5 °C for 12 h. The reaction was quenched with H O (10 mL), acid-
2
1
19
ified with 0.5 M aq HCl, and extracted several times with CH Cl .
by the known H NMR data.
2
2
The combined organic phases were washed with brine (10 mL) and
dried (Na SO ). Finally all volatiles were removed and the product
4-Iodoisoquinoline (10)20
2
4
was isolated, and dried under vacuum (Table 2).
Prepared from 4-bromoisoquinoline (9; 1.5 g, 7.2 mmol), following
General Procedure 1 to afford 1.81 g of the product mixture of 9 and
10, and the iodo congener 10 in 92% yield (1.69 g).
Esterification; General Procedure 4
The carboxylic acids (1.33 mmol) were treated with an excess of
SOCl (2 mmol) and stirred for 8 h at 25 °C. The excess SOCl was
1-Iodo-2-methylnaphthalene (12)
2
2
evaporated under vacuum until a solid residue was obtained. The
obtained residue was then dissolved in CH Cl (10 mL). DMAP
Prepared from the corresponding bromide 11 (4.06 g, 13.6 mmol),
following General Procedure 1, to give 3.35 g of a product mixture
of 11 and 12, and 12 in 78% (2.84 g) yield. Positive identification
2
2
(
191 mg, 1.56 mmol) was weighed out in a Schlenk flask and evac-
2
1
uated three times and back-filled with argon. CH Cl (20 mL) and
was obtained by comparison with the data from literature.
2
2
EtOH (0.08 mL, 1.4 mmol) or propargyl alcohol (0.08 mL, 1.4
mmol) were added to the DMAP. At 0 °C both solutions were com-
bined and stirred for 1 h. Afterwards the reaction mixture was al-
lowed to reach 25 °C and stirred for additional 8 h. The reaction was
2-Iodo-1H-indene (14)
Prepared by reacting 2-bromo-1H-indene (13; 4.05 g, 33.8 mmol)
according to General Procedure 1; yield: 3.65 g (98%); mp 33–
quenched with H O (10 mL), acidified with HCl (0.5 M), and ex-
34 °C.
2
tracted with CH Cl (3 × 30 mL). The combined organic phases are
1
2
2
H NMR (300 MHz, CDCl ): d = 7.50 (dd, J = 7.3, 0.7 Hz, 1 H),
3
washed with brine (10 mL) and dried (Na SO ). After removal of all
2
4
7
.46–7.37 (m, 2 H), 7.33 (dd, J = 1.6, 7.3 Hz, 1 H), 7.29–7.28 (m, 1
volatiles, the residue was purified by column chromatography
Table 3).
H), 3.65 (br s, 2 H).
1
(
3
C NMR (75 MHz, CDCl ): d = 144.9, 144.8, 141.2, 126.4, 124.6,
3
1
22.8, 119.6, 94.6, 49.0.
Ethyl 3-(2-Methoxynaphthalen-1-yl)propiolate (2)
Prepared from 1-iodo-2-methoxynaphthalene (5.67 g, 19.6 mmol)
and 1 (94 mL, 23.5 mmol), following General Procedure 2; yield:
+
MS (EI, 70 eV): m/z (%) = 242 (28, [M ]), 115 (100).
+
HRMS (EI): m/z calcd for C H I (M ): 241.9587; found: 241.9590.
9
7
4
.54 g (91%). The spectroscopic data are in accordance with the
16
published data.
Anal. Calcd for C
H I (242.06): C, 44.66; H, 2.91. Found: C, 44.72;
9 7
H, 2.95.
3
-(2-Methoxynaphthalen-1-yl)propiolic Acid (3)
Prepared in 81% yield (4.92 g) by the hydrolysis of ester 2 (6.87 g,
Ethyl 3-(Anthracen-9-yl)propiolate (18)
2
7 mmol), following General Procedure 3. The spectroscopic data
Prepared by reacting a mixture of 7 and 8 containing 1.4 g (5.5
mmol) of 8 and organozinc reagent 1 (30.8 mL, 7.7 mmol), follow-
ing General Procedure 2; yield: 340 mg (23%); mp 81–83 °C.
1
1
7
are in accordance with the published data.
3
-(2-Methoxynaphthalen-1-yl)propiolic Acid Chloride (4)18
Prepared from acid 3, following the first part of General Procedure
H NMR (300 MHz, CDCl ): d = 8.54 (dd, J = 8.7, 1.0 Hz, 1 H),
3
8
1
.50 (s, 1 H), 7.85 (ddd, J = 7.3, 4.8, 1.2 Hz, 1 H), 7.64 (dd, J = 6.7,
.3 Hz, 1 H),7.61 (dd, J = 6.6, 1.3 Hz, 1 H), 7.52 (ddd, J = 8.4, 6.6,
4
.
1
H NMR (300 MHz, CDCl ): d = 7.93 (d, J = 9.2 Hz, 1 H), 7.81 (d,
1.1 Hz, 1 H), 4.43 (q, J = 7.1 Hz, 2 H), 1.45 (t, J = 7.1 Hz, 3 H).
3
J = 8.4 Hz, 1 H), 7.71 (dd, J = 7.7, 0.8 Hz, 1 H), 7.50 (ddd, J = 8.5,
13
C NMR (75 MHz, CDCl ): d = 154.6, 134.3, 131.0, 130.9, 129.0,
3
6
.8, 1.3 Hz, 1 H), 7.39 (ddd, J = 8.3, 6.8, 1.2 Hz, 1 H), 7.28 (d,
1
27.9, 126.3, 126.1, 113.0, 91.7, 83.5, 62.3, 14.5.
J = 9.2 Hz, 1 H), 6.97 (s, 1 H), 3.97 (s, 3 H).
+
MS (EI, 70 eV): m/z (%) = 274 (52, [M ]), 229 (17), 202 (100), 100
(
10).
(
E)-Prop-2-ynyl 3-Chloro-3-(2-methoxynaphthalen-1-yl)acry-
late (6)
HRMS (+ESI): m/z calcd for C H O (M + H): 275.1067; found:
275.1063.
1
9
15
2
Prepared from 4 (1.1 g, 4.9 mmol), following General Procedure 4;
yield: 826 mg (57%); mp 76–77 °C.
1
3-(Anthracen-9-yl)propiolic Acid (19)
Prepared by the hydrolysis of 18, following General Procedure 3 in
H NMR (400 MHz, CDCl ): d = 7.92 (d, J = 9.0 Hz, 1 H), 7.81 (d,
3
J = 8.2 Hz, 1 H), 7.76 (dd, J = 8.6, 1.2 Hz, 1 H), 7.50 (ddd, J = 8.6,
6
J = 9.0 Hz, 1 H), 6.72 (s, 1 H), 4.47 (dd, J = 2.5, 1.5 Hz, 2 H), 3.98
(
4
8% yield (120 mg); mp 240 °C (dec.).
.8, 1.3 Hz, 1 H), 7.37 (ddd, J = 8.3, 6.8, 1.2 Hz, 1 H), 7.30 (d,
1
H NMR (300 MHz, CDCl ): d = 8.54 (d, J = 7.0 Hz, 2 H), 8.49 (s,
3
s, 3 H), 2.34 (t, J = 2.5 Hz, 1 H).
1 H), 8.00 (d, J = 8.5 Hz, 2 H), 7.66–7.59 (m, 2 H), 7.54–7.48 (m, 2
1
3
H).
C NMR (100 MHz, CDCl ): d = 162.3, 153.3, 147.8, 131.7, 130.9,
3
1
3
1
5
28.8, 128.4, 127.6, 124.1, 123.6, 123.0, 119.9, 113.1, 77.4, 74.9,
6.8, 51.9.
C NMR (75 MHz, CDCl ): d = 154.9, 134.3, 134.2, 131.4, 130.9,
3
129.0, 128.7, 128.0, 127.9, 127.6, 127.3, 126.2, 125.7, 114.1, 91.5,
84.1.
+
MS (EI, 70 eV): m/z (%) = 300 (72, [M ]), 265 (24), 245 (14), 221
(
10), 217 (44), 209 (15), 202 (42), 182 (82), 152 (23), 139 (100).
Ethyl 3-(Isoquinolin-4-yl)propiolate (20)
Prepared by reacting the product mixture of 9 and 10 containing 306
mg of 10 (1.2 mmol) and organozinc reagent 1 (6.7 mL, 1.68
+
HRMS (EI): m/z calcd for C H ClO (M ): 300.0548; found:
3
1
7
13
3
00.0548.
Synthesis 2011, No. 4, 642–652 © Thieme Stuttgart · New York

PAPER
Synthesis of Arylpropiolic Acids and HCl Addition During Esterification
3-(2,3-Dihydro-1H-inden-2-yl)propiolic Acid (25)
649
mmol), following General Procedure 2; yield: 264 mg (98%); mp
5
1–52 °C.
Prepared by hydrolysis of ester 24 (50 mg, 0.24 mmol), following
1
General Procedure 3; yield: 31 mg (66%).
H NMR (300 MHz, CDCl ): d = 9.27 (s, 1 H), 8.81 (s, 1 H), 8.23
3
1
(
7
d, J = 8.3 Hz, 1 H), 8.01 (d, J = 8.1 Hz, 1 H), 7.83 (ddd, J = 8.5,
H NMR (300 MHz, CDCl ): d = 8.29 (d, J = 8.0 Hz, 1 H), 8.17 (d,
3
.0, 1.3 Hz, 1 H), 7.68 (ddd, J = 8.4, 6.7, 1.1 Hz, 1 H), 4.35 (q,
J = 8.1 Hz, 1 H), 8.03 (ddd, J = 8.5, 6.9, 1.3 Hz, 1 H), 8.02 (s, 1 H),
J = 7.1 Hz, 2 H), 1.39 (t, J = 7.2 Hz, 3 H).
3.68 (s, 2 H).
1
3
13
C NMR (75.5 MHz, CDCl ): d = 154.2, 153.8, 148.7, 132.0,
C NMR (75 MHz, CDCl ): d = 155.3, 144.8, 141.7, 129.6, 127.5,
3
3
1
28.5, 128.2, 124.8, 112.6, 81.3, 87.4, 62.4, 14.2.
127.2, 123.9, 123.5, 122.6, 94.1, 84.4, 42.3.
+
MS (EI, 70 eV): m/z (%) = 225 (36, [M ]), 180 (60), 153 (100), 125
Ethyl 3-Naphthalen-1-ylpropiolate (26)
This compound was obtained in 77% yield (1.16 g) after the reac-
tion between 1-iodonaphthalene (15; 1.7 g, 6.7 mmol) and 1 (30.2
mL, 9.4 mmol), following General Procedure 2.
1
(
18).
+
HRMS (EI): m/z calcd for C H NO (M ): 225.0784; found:
1
4
11
2
2
25.0784.
H NMR (300 MHz, CDCl ): d = 8.34 (d, J = 8.4 Hz, 1 H), 7.93 (d,
3
3
-(Isoquinolin-4-yl)propiolic Acid (21)
J = 8.3 Hz, 1 H), 7.85 (ddd, J = 7.3, 4.8, 1.2 Hz, 1 H), 7.62 (ddd,
J = 8.4, 6.8, 1.5 Hz, 1 H), 7.54 (ddd, J = 8.3, 6.8, 1.4 Hz, 1 H), 7.45
This compound was isolated after hydrolysis of 20 (100 mg, 0.44
mmol) under basic conditions, following General Procedure 3;
yield: 21 mg (23%); mp 155–156 °C.
(
dd, J = 7.3, 1.1 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 1.40 (t, J = 7.1
Hz, 3 H).
1
H NMR (300 MHz, CDCl ): d = 9.16 (s, 1 H), 8.72 (s, 1 H), 8.14
3
13
C NMR (75 MHz, CDCl ): d = 154.3, 133.8, 133.2, 133.0, 131.4,
3
(
(
1
dd, J = 8.3, 0.9 Hz, 1 H), 7.96 (ddd, J = 8.5, 6.9, 1.3 Hz, 1 H), 7.81
1
28.5, 127.7, 127.0, 125.8, 125.2, 117.3, 85.5, 85.4, 62.3, 14.3.
ddd, J = 8.5, 6.9, 1.3 Hz, 1 H), 7.67 (ddd, J = 8.2, 6.9, 1.1 Hz, 1 H).
+
3
MS (GC-MS): m/z (%) = 224 (57, [M ]), 179 (65), 152 (100), 139
C NMR (75.5 MHz, CDCl ): d = 151.8, 144.7, 134.8, 131.7,
3
(
10).
1
29.8, 128.3, 128.0, 125.9, 119.7, 91.5, 84.1.
+
HRMS (EI): m/z calcd for C H O (M ): 224.0832; found:
1
5
12
2
Ethyl 3-(2-Methylnaphthalen-1-yl)propiolate (22)
Prepared by the Pd-catalyzed cross-coupling reaction of the product
mixture of 11 and 12 containing 790 mg of 12 (2.95 mmol) and or-
ganozinc reagent 1 (16.5 mL, 4.13 mmol), following General Pro-
cedure 2; yield: 580 mg (83%).
224.0828.
3-Naphthalen-1-ylpropiolic Acid (27)22
This compound was isolated from the hydrolysis reaction of 26 (1.0
g, 4.46 mmol) in 74% (650 mg) yield, following General Procedure
1
3; mp 114–115 °C.
H NMR (300 MHz, CDCl ): d = 8.30 (dd, J = 8.7, 7.3 Hz, 1 H),
3
1
7
7
.82 (d, J = 8.4 Hz, 2 H), 7.62–7.57 (m, 1 H), 7.51–7.46 (m, 1 H),
.35 (dd, J = 8.4, 3.0 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 2.71 (s, 3
H NMR (400 MHz, CDCl ): d = 8.35 (d, J = 8.2 Hz, 1 H), 7.99 (d,
3
J = 8.4 Hz, 1 H), 7.90 (dd, J = 7.1, 1.2 Hz, 1 H), 7.66 (ddd, J = 8.3,
6.8, 1.4 Hz, 1 H), 7.58 (ddd, J = 8.3, 6.8, 1.4 Hz, 1 H), 7.49 (dd,
J = 7.3, 1.0 Hz, 1 H).
H),1.41 (t, J = 7.0 Hz, 3 H).
1
3
C NMR (75 MHz, CDCl ): d = 154.5, 142.8, 130.7, 128.8, 128.3,
3
1
3
1
1
28.0, 127.7, 127.4, 126.1, 125.6, 115.9, 89.8, 83.5, 62.3, 21.5,
C NMR (100 MHz, CDCl ): d = 158.1, 133.9, 133.8, 133.2, 132.1,
3
4.3.
128.7, 128.0, 127.2, 125.8, 125.3, 116.9, 87.4, 84.8.
+
+
MS (EI, 70 eV): m/z (%) = 238 (43, [M ]), 193 (37), 166 (100), 139
MS (EI, 70 eV): m/z (%) = 196 (75, [M ]), 179 (26), 152 (100), 126
(
10).
(19), 76 (54), 63 (26), 44 (37).
+
+
HRMS (ESI): m/z calcd for C H O (M ): 238.0989; found:
HRMS (EI): m/z calcd for C H O (M ): 196.0519; found:
1
6
14
2
13
8
2
2
38.0989.
196.0519.
3
-(2-Methylnaphthalen-1-yl)propiolic Acid (23)
Ethyl 3-Phenylpropiolate (28)23
Prepared from iodobenzene (16; 0.96 mL, 8.6 mmol) and 1 (48.2
Prepared from 22 (70 mg, 0.29 mmol), following General Proce-
dure 3; yield: 30 mg (49%).
mL, 12.04 mmol) in accordance to General Procedure 2; yield: 1.05
1
g (70%).
H NMR (300 MHz, CDCl ): d = 8.54 (d, J = 7.0 Hz, 2 H), 8.49 (s,
3
1
1
H), 8.00 (d, J = 8.5 Hz, 2 H), 7.66–7.59 (m, 2 H), 7.54–7.48 (m, 2
H NMR (300 MHz, CDCl ): d = 7.59–7.56 (m, 2 H), 7.44–7.33 (m,
3
H), 2.61 (s, 3 H).
3 H), 4.29 (q, J = 7.1 Hz, 2 H), 1.35 (t, J = 7.1 Hz, 3 H).
1
3
13
C NMR (75 MHz, CDCl ): d = 154.9, 134.3, 134.2, 131.4, 130.9,
C NMR (75 MHz, CDCl ): d = 154.2, 137.6, 133.1, 130.8, 130.3,
3
3
1
8
29.0, 128.7, 128.0, 127.9, 127.6, 127.3, 126.2, 125.7, 114.1, 91.5,
4.1.
128.8, 119.8, 86.2, 80.9, 62.1, 14.3.
+
MS (EI, 70 eV): m/z (%) = 174 (12, [M ]), 129 (100), 102 (84), 75
(
23).
Ethyl 3-(2,3-Dihydro-1H-inden-2-yl)propiolate (24)
Prepared from 14 (2.6 g, 10.7 mmol) and 1 (60 mL, 15 mmol), fol-
lowing General Procedure 2; yield: 420 mg (18%); mp 51–52 °C.
1
+
HRMS (EI): m/z calcd for C H O (M ): 174.0675; found:
1
11 10
2
74.0675.
H NMR (300 MHz, CDCl ): d = 7.46–7.743 (m, 2 H), 7.40 (dd,
-Phenylpropiolic Acid (29)24
3
3
J = 1.9, 0.5 Hz, 1 H), 7.33–7.29 (m, 2 H), 4.30 (q, J = 7.1 Hz, 2 H),
Prepared from 28 (1.0 g, 5.74 mmol), following General Procedure
3
.60 (d, J = 1.9 Hz, 2 H), 1.36 (t, J = 7.1 Hz, 3 H).
3
; yield: 445 mg (53%); mp 115–116 °C.
1
3
C NMR (75 MHz, CDCl ): d = 154.2, 143.8, 143.6, 143.0, 127.3,
1
3
H NMR (300 MHz, CDCl ): d = 9.51 (s, 1 H, OH), 7.63–7.60 (m,
3
1
27.2, 123.9, 123.5, 122.5, 85.1, 83.6, 62.2, 42.3, 14.2.
2
H), 7.49–7.39 (m, 3 H).
+
MS (EI, 70 eV): m/z (%) = 212 (20, [M ]), 167 (17), 140 (100).
13
C NMR (75 MHz, CDCl ): d = 158.6, 133.4, 131.3, 128.9, 119.2,
3
+
HR (EI): m/z calcd for C H O (M ): 212.0832; found: 212.0827.
89.2, 80.3.
1
4
12
2
Synthesis 2011, No. 4, 642–652 © Thieme Stuttgart · New York

6
50
M. Hapke et al.
PAPER
+
MS (EI, 70 eV): m/z (%) = 146 (61, [M ]), 129 (53), 118 (33), 102
100), 89 (11), 76 (29), 63 (12), 51 (14), 44 (13).
HRMS (+ESI): m/z calcd for C H O (M + H): 275.1067; found:
275.1063.
1
9
15
2
(
HRMS (ESI): m/z calcd for C H O (M + H): 147.0441; found:
9
7
2
3
4/35
1
47.0438.
+
MS (EI, 70 eV): m/z (%) = 310 (30, [M ]), 275 (18), 236 (14), 202
Ethyl 3-(2-Methoxyphenyl)propiolate (30)25
Prepared by Pd-catalyzed cross-coupling reaction of 1-iodo-2-
methoxybenzene (17; 6.2 mL, 45 mmol) with 1 (252 mL, 63 mmol),
following General Procedure 2. The expected ester 30 was obtained
in 72% yield (6.59 g) after chromatography.
(100).
+
HRMS (EI): m/z calcd for C H ClO (M ): 310.0755; found:
310.0751.
1
9
15
2
Ethyl 3-(Isoquinolin-4-yl)propiolate (20)/Ethyl 3-Chloro-3-(iso-
quinolin-4-yl)acrylate (36/37)
Prepared from 21 (20 mg, 0.1 mmol), following General Procedure
1
H NMR (300 MHz, CDCl ): d = 7.44 (dd, J = 7.5, 1.7 Hz, 1 H),
3
7
6
1
.33 (ddd, J = 8.7, 7.0, 1.8 Hz, 1 H), 6.86 (dd, J = 7.5, 1.0 Hz, 1 H),
.83 (d, J = 8.5 Hz, 1 H), 4.22 (q, J = 7.1 Hz, 2 H), 3.81 (s, 3 H),
.27 (t, J = 7.1 Hz, 3 H).
1
4
; yield: 16 mg (20/36/37). In the H NMR spectrum two significant
signals at 6.91 and 6.76 ppm were detected in a ratio of ~2:1 (E/Z),
which belong to the vinyl hydrogens. The yields were determined
1
3
C NMR (75 MHz, CDCl ): d = 170.2, 161.5, 134.8, 132.3, 120.5,
1
3
by H NMR spectroscopy.
1
10.7, 108.7, 84.6, 83.1, 61.9, 55.7, 14.0.
+
20
MS (EI, 70 eV): m/z (%) = 204 (30, [M ]), 159 (25), 132 (100), 115
+
MS (EI, 70 eV): m/z (%) = 225 (28, [M ]), 180 (51), 153 (100), 125
16).
(
17), 103 (12), 88 (14), 77 (23).
(
+
HRMS (EI): m/z calcd for C H O (M ): 204.0781; found:
2
1
2
12
3
+
HRMS (EI): m/z calcd for C H NO (M ): 225.0784; found:
04.0782.
14 11
2
2
25.0784.
3
-(2-Methoxyphenyl)propiolic Acid (31)23
3
6/37
Prepared by the hydrolysis of 30 (6.59 g, 32.3 mmol) in 35% yield
+
MS (EI, 70 eV): m/z (%) = 261 (53, [M ]), 226 (15), 198 (22), 188
100), 180 (22), 161 (19), 153 (57), 126 (51), 76 (11).
(3.2 g) according to General Procedure 3.
(
1
H NMR (300 MHz, CDCl ): d = 7.54 (dd, J = 7.7, 1.7 Hz, 1 H),
3
7
6
.44 (ddd, J = 8.8, 6.9, 1.8 Hz, 1 H), 6.95 (dd, J = 7.6, 0.9 Hz, 1 H),
.91 (d, J = 8.4 Hz, 1 H), 3.91 (s, 3 H).
Ethyl 3-(2-Methylnaphthalen-1-yl)propiolate (22)/
Ethyl 3-Chloro-3-(2-methylnaphthalen-1-yl)acrylate (38/39)
Prepared from 23 (10 mg, 0.05 mmol), following General Proce-
1
3
C NMR (75 MHz, CDCl ): d = 162.0, 158.0, 135.4, 133.1, 120.7,
3
1
1
11.0, 108.5, 86.4, 84.1, 56.0.
dure 4; yield: 9 mg (22/38/39). In the H NMR spectrum two signif-
+
+
icant signals at 6.80 and 6.41 ppm were detected in a ratio of ~2:1
MS (ESI, 70 eV): m/z (%) = 199 (6, [M + Na]), 177 (3, [M + H]),
02 (8).
(
E/Z), which belong to the vinyl hydrogens. The yields were deter-
1
1
mined by H NMR spectroscopy.
+
HRMS (ESI): m/z calcd for C H O (M ): 177.0546; found:
1
0
9
3
1
77.0545.
2
2
+
MS (EI, 70 eV): m/z (%) = 238 (42, [M ]), 193 (20), 166 (100).
Ethyl 3-Chloro-3-(2-methoxynaphthalen-1-yl)acrylate (32/33)
Prepared from 3 (200 mg, 0.88 mmol), following General Proce-
dure 4; yield: 170 mg (66%).
+
HRMS (ESI): m/z calcd for C H O (M ): 238.0989; found:
2
1
6
14
2
38.0989.
1
H NMR (300 MHz, CDCl ): d = 7.91 (d, J = 9.1 Hz, 1 H), 7.82–
3
38/39
MS (EI, 70 eV): m/z (%) = 274 (30, [M ]), 239 (16), 229 (14), 201
31); 165 (100).
7
.78 (m, 2 H), 7.51 (ddd, J = 8.6, 6.8, 1.3 Hz, 2 H), 7.37 (ddd,
+
J = 8.3, 6.8, 1.1 Hz, 1 H), 7.30 (d, J = 9.0 Hz, 1 H), 6.69 (s, 1 H),
6
(
.26 (s, 0.04 H), 3.98 (s, 3 H), 3.88 (q, J = 7.1 Hz, 2 H), 0.86 (t,
J = 7.1 Hz, 3 H).
Ethyl 3-(2,3-Dihydro-1H-inden-2-yl)propiolate (24)/
1
3
C NMR (75.5 MHz, CDCl ): d = 163.4, 153.2, 146.0, 131.4,
Ethyl 3-Chloro-3-(2,3-dihydro-1H-inden-2-yl)acrylate (40/41)
Prepared from 25 (10 mg, 0.05 mmol), following General Proce-
3
1
28.3, 127.5, 124.3, 124.0, 123.5, 113.1, 60.4, 56.9, 13.8.
1
dure 4; yield: 9 mg (24/40/41). In the H NMR spectrum two signif-
+
MS (EI, 70 eV): m/z (%) = 290 (71, [M ]), 255 (37), 245 (18), 231
icant signals at 6.90 and 6.33 ppm were detected in a ratio of 2:1
(
(
12), 227 (11), 217 (37), 209 (28), 202 (27), 183 (65), 168 (12), 152
26), 139 (100).
(
E/Z), which belong to the vinyl hydrogens. The yields were deter-
1
mined by H NMR spectroscopy.
HRMS (ESI): m/z calcd for C H ClO + Na (M + Na): 313.0602;
1
6
15
3
found: 313.0606.
24
+
MS (EI, 70 eV): m/z (%) = 212 (20, [M ]), 167 (17), 140 (100).
Ethyl 3-(Anthracen-9-yl)propiolate (18)/
Ethyl 3-(Anthracen-9-yl)-3-chloroacrylate (34/35)
Prepared from 19 (20 mg, 0.08 mmol), following General Proce-
dure 4; yield: 10 mg (18/34/35). In the H NMR spectrum, two sig-
nificant signals at 6.93 and 6.44 ppm were observed in a ratio of
+
HRMS (EI): m/z calcd for C H O (M ): 212.0832; found:
1
4
12
2
2
12.0827.
1
4
0/41
+
MS (EI, 70 eV): m/z (%) = 248 (36, [M ]), 202 (100), 184 (13), 168
14), 139 (87), 115 (12), 69 (10).
3
3:1 (E/Z), which can be traced back to the vinyl hydrogen atoms.
(
1
The yields were determined by H NMR spectroscopy.
HRMS (EI): m/z calcd for C H ClO : 248.0599; found: 248.0604.
1
4
13
2
1
8
+
MS (EI, 70 eV): m/z (%) = 274 (43, [M ]), 229 (14), 202 (100), 100
(
11).
Synthesis 2011, No. 4, 642–652 © Thieme Stuttgart · New York

PAPER
Synthesis of Arylpropiolic Acids and HCl Addition During Esterification
651
Ethyl 3-(Naphthalen-1-yl)propiolate (26)/
Ethyl 3-Chloro-3-(naphthalen-1-yl)acrylate (42/43)
were washed with aq 0.5 M HCl (10 mL) and brine (20 mL), and
dried (Na SO ). The solvent was removed under reduced pressure.
2
4
Prepared from 27 (100 mg, 0.51 mmol), following General Proce-
dure 4; yield: 90 mg (26/42/43). In the H NMR spectrum two sig-
Purification by chromatography on silica gel (elution with n-hex-
ane) yielded 15% (8 mg) of 48.
1
nificant signals at 6.63 and 6.39 ppm were found in a ratio of 1:1
1
H NMR (300 MHz, CDCl ): d = 8.27 (d, J = 8.3 Hz, 1 H), 7.86 (d,
3
(
E/Z), which belong to the vinyl hydrogens. The yields were deter-
J = 9.0 Hz, 1 H), 7.79 (d, J = 7.6 Hz, 1 H), 7.74–7.71 (m, 2 H),
7
1
mined by H NMR spectroscopy.
.55–7.52 (m, 4 H), 7.39 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 7.29 (s, 1
H), 6.91 (s, 1 H), 4.06 (s, 3 H), 3.76 (s, 3 H).
2
6
+
+
MS (EI, 70 eV): m/z (%) = 318 (49, [M ]), 287 (10), 259 (100), 243
HRMS (EI): m/z calcd for C H O (M ): 224.0832; found:
2
1
5
12
2
(25), 226 (15), 215 (29), 107 (10).
24.0828.
+
HRMS (EI): m/z calcd for C H O (M ): 318.1251; found:
HRMS (ESI): m/z calcd C H O (M + H): 225.0910; found:
2
21 18
3
1
5
13
2
3
18.1257.
25.0915.
Ethyl 3-(2-Methoxynaphthalen-1-yl)-3-phenylacrylate (49)27
A mixture of vinyl chloride 6 (40 mg, 0.13 mmol), phenylboronic
4
2/43
+
MS (EI, 70 eV): m/z (%) = 260 (30, [M ]), 224 (13), 215 (23), 187
42), 179 (18), 152 (100), 75 (12), 44 (12), 32 (15).
acid (21 mg, 0.17 mmol), and PdCl (PPh ) (0.5 mg, 0.007 mmol)
(
2
3 2
in toluene (4 mL), aq Na CO (18 mg, 0.13 mmol, in 2 mL H O),
2
3
2
and EtOH (1 mL) was heated for 4 h to 80 °C. Afterwards, the reac-
tion mixture was cooled to 25 °C, water (5 mL) was added and the
toluene layer was separated. The aqueous layer was extracted with
EtOAc (2 × 10 mL) and the combined organic extracts were dried
Ethyl 3-Phenylpropiolate (28)/
Ethyl 3-Chloro-3-phenylacrylate (44/45)
Prepared from 29 (100 mg, 0.68 mmol), following General Proce-
dure 4; yield: 40 mg (28/44/45). In the H NMR spectrum only one
significant signal at 6.54 ppm was found, which was assigned to one
vinyl isomer. The yields were determined by H NMR spectrosco-
py.
1
(
Na SO ), filtered, and the filtrate evaporated to dryness under re-
2 4
1
duced pressure. The crude product thus obtained was purified by
column chromatography on silica gel using n-hexane–EtOAc (10:1,
v/v) as eluent; yield: 21 mg (49%).
2
8
1
H NMR (300 MHz, CDCl ): d = 8.27 (d, J = 8.3 Hz, 1 H), 7.86 (d,
3
+
MS (EI, 70 eV): m/z (%) = 174 (13, [M ]), 129 (100), 102 (77), 75
20).
J = 9.1 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 2 H), 7.55 (ddd, J = 8.7, 6.9,
(
1
.4 Hz, 2 H), 7.39 (ddd, J = 8.4, 7.0, 1.2 Hz, 3 H), 7.32 (d, J = 4.4
Hz, 1 H), 7.28 (s, 1 H), 6.91 (s, 1 H), 4.22 (q, J = 7.1 Hz, 2 H), 4.06
s, 3 H), 2.36 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z calcd for C H O (M + H): 175.0754; found:
1
1
1
11
2
(
75.0755.
+
MS (EI, 70 eV): m/z (%) = 332 (36, [M ]), 277 (50), 259 (100), 244
28), 215 (30).199 (17), 183 (16), 32 (12).
4
4/45
(
+
MS (EI, 70 eV): m/z (%) = 210 (30, [M ]), 181 (18), 165 (100), 138
24), 102 (50).
+
HRMS (EI): m/z calcd for C H O (M ): 332.1407; found:
3
2
2
20
3
(
32.1411.
+
HRMS (EI): m/z calcd for C H ClO (M ): 210.0442; found:
1
1
11
2
2
10.0441.
Ethyl 3-Bromo-3-(2-methoxynaphthalen-1-yl)acrylate (50/51)
Acid 3 (0.2 mg, 0.88 mmol) was dissolved in CH Cl (5 mL), cooled
2
2
Ethyl 3-(2-Methoxyphenyl)propiolate (30)/
Ethyl 3-Chloro-3-(2-methoxyphenyl)acrylate (46/47)
to –78 °C and SOBr (0.068 mL, 0.88 mmol) was added via a sy-
2
ringe. Afterwards, the solution was allowed to reach 25 °C. The ex-
cess SOBr2 was evaporated under vacuum until the residue
appeared as a solid. Subsequently the second part of General Proce-
dure 4 was followed; yield: 60 mg (20%).
Prepared from 31 (140 mg, 0.74 mmol), following General Proce-
1
dure 4; yield: 140 mg (30/46/47). In the H NMR two significant
signals at 6.49 and 6.42 ppm were found in a ratio of ~3:1 (E/Z),
which can be assigned to the vinyl hydrogens. The yields were de-
1H NMR (300 MHz, CDCl
(
(
): d = 7.89 (d, J = 9.2 Hz, 1.4 H), 7.79
d, J = 9.3 Hz, 2.4 H), 7.82 (ddd, J = 8.4, 6.7, 1.2 Hz, 1.4 H), 7.36
ddd, J = 8.5, 6.7, 1.2 Hz, 1.4 H), 7.29 (s, 1.4 H), 7.26 (s, 1.4 H),
1
3
termined by H NMR spectroscopy.
3
0
+
6.90 (s, 1 H), 6.51 (s, 0.2 H) 3.984 (s, 3 H), 3.974 (s, 0.6 H), 3.85 (q,
MS (EI, 70 eV): m/z (%) = 204 (34, [M ]), 159 (28), 132 (100), 115
17), 103 (10), 88 (11), 77 (20).
J = 7.2 Hz, 2.4 H), 0.83 (t, J = 7.1 Hz, 3 H) 0.54 (t, J = 7.1 Hz, 0.6
(
1
H). The ratio of the isomers 50/51 was determined by H NMR
HRMS (ESI): m/z calcd for C H O (M + H): 205.0859; found:
1
2
13
3
spectroscopy: E/Z = 5:1.
2
05.0862.
1
3
C NMR (75 MHz, CDCl ): d = 163.4, 152.7, 136.9, 131.3, 130.7,
3
1
28.8, 128.3, 127.6, 127.4, 125.4, 124.2, 124.1, 123.6, 60.5, 56.9,
4
6/47
+
13.7.
MS (EI, 70 eV): m/z (%) = 240 (29, [M ]), 209 (92), 195 (59), 181
100), 152 (24), 131 (63), 103 (16), 89 (32), 77 (11), 63 (16).
+
(
MS (EI, 70 eV): m/z (%) = 336 (40, [M ]), 334 (40), 255 (64), 227
(
64), 211 (34), 182 (45), 168 (11), 152 (23); 139 (100).
HRMS (ESI): m/z calcd for C H ClO (M + H): 241.0626; found:
1
2
14
3
+
2
41.0628.
HRMS (+ESI): m/z calcd for C16
H16BrO
3
(M ): 335.0277; found:
3
35.0275.
Methyl 3-(2-Methoxynaphthalen-1-yl)-3-phenylacrylate (48)26
To solid potassium phenyltrifluoroborate (32 mg, 0.17 mmol), vinyl
chloride 6 (50 mg, 0.17 mmol), K CO (71 mg, 0.52 mmol), and
d
(52)
-3-Chloro-3-(2-methoxynaphthalen-1yl)acryloyl Chloride
1
2
3
Pd(OAc) (0.2 mg, 0.09 mmol) was added MeOH (20 mL) as sol-
For the deuterium exchange experiment, the acid 3 (90 mg, 0.4
2
vent. The solution was stirred at 100 °C for 4 h, then cooled to
mmol) was treated with D O (1 mL) and stirred at 80 °C in a
2
2
5 °C, and diluted with H O (10 mL). The aqueous phase was ex-
Schlenk tube for 24 h. Afterwards, the solution was evaporated un-
der vacuum and the procedure was repeated two times. The deuter-
2
tracted with CH Cl (3 × 30 mL) and the combined organic phases
2
2
Synthesis 2011, No. 4, 642–652 © Thieme Stuttgart · New York

6
52
M. Hapke et al.
PAPER
ated acid was then reacted with an excess of SOCl . After stirring
application of direct zincation of ethyl propiolate following
a reported literature protocol. However, the procedure did
not work out well in our hands for this case: (a) Anastasia,
L.; Negishi, E. Org. Lett. 2001, 3, 3111. (b) The superiority
of the Negishi vs. the Sonogashira protocol for the coupling
of electron-deficient alkynes with alkenyl halides has been
investigated earlier: Negishi, E.; Mingxing, Q.; Fanxing, Z.;
Anastasia, L.; Babinski, D. Org. Lett. 2003, 5, 1597.
2
for 8 h at 25 °C, the excess of SOCl was evaporated under vacuum.
2
1
The H NMR analysis of the residue dissolved in anhyd CDCl
3
showed that deuterium had been incorporated in the double bond of
the acrylic acid derivative.
1
H NMR (300 MHz, CDCl ): d = 7.93 (d, J = 9.2 Hz, 1 H), 7.81 (d,
3
J = 8.4 Hz, 1 H), 7.71 (dd, J = 7.7, 0.8 Hz, 1 H), 7.50 (ddd, J = 8.5,
6
.8, 1.3 Hz, 1 H), 7.39 (ddd, J = 8.3, 6.8, 1.2 Hz, 1 H), 7.28 (d,
(
7) The crystallographic data for compound 6 have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication CCDC 797405. Copies of the
data can be obtained free of charge on application to CCDC,
J = 9.2 Hz, 1 H), 6.97 (s, 0.3 H), 3.97 (s, 3 H).
d3-3-Methyl 3-Chloro-3-(2-methoxynaphthalen-1-yl)acrylate
(
53)
12 Union Road, Cambridge CB2 1EZ, UK [fax:
Prepared following General Procedure 4, but CD OD (0.37 mL, 9.3
3
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
mmol) was used in the esterification reaction; mp 93–94 °C; yield:
(
(
8) Earlier detailed studies: (a) Adams, R.; Ludington, R. S.
J. Am. Chem. Soc. 1945, 67, 794. (b) Bowden, K.; Price, M.
J. J. Chem. Soc. B 1970, 1466. (c) Bowden, K.; Price, M. J.
J. Chem. Soc. B 1970, 1472.
9) Urdaneta, N. A.; Herrera, J. C.; Salazar, J.; López, S. E.
Synth. Commun. 2002, 32, 3003.
(10) Urdaneta, N. A.; Salazar, J.; Herrera, J. C.; López, S. E.
Synth. Commun. 2004, 34, 657.
11) Medvedeva, A. S.; Andreev, M. V.; Safronova, L. P.;
1
35 mg (54%).
1
H NMR (300 MHz, CDCl ): d = 7.91 (d, J = 9.0 Hz, 1 H), 7.81 (d,
3
J = 7.8 Hz, 1 H), 7.78 (d, J = 8.5 Hz, 1 H), 7.50 (ddd, J = 8.5, 6.7,
1
.4 Hz, 1 H), 7.38 (ddd, J = 8.4, 6.7, 1.1 Hz, 1 H), 7.31 (d, J = 9.2
Hz, 1 H), 6.70 (s, 1 H), 3.98 (s, 3 H).
1
3
C NMR (75 MHz, CDCl ): d = 163.7, 153.2, 146.5, 131.5, 130.9,
3
1
3
1
28.8, 128.4, 127.5, 124.1, 123.7, 123.5, 120.1, 113.1, 56.8. The C
(
NMR signal for the CD group was not detectable.
3
Afonin, A. V. Russ. J. Org. Chem. 2005, 41, 1493.
12) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
+
MS (EI, 70 eV): m/z (%) = 279 (79, [M ]), 244 (74), 216 (42), 209
(
(
96), 202 (23), 182 (43), 168 (12), 152 (21), 139 (100).
14844.
HRMS (+ESI): m/z calcd for C H D ClO (M + H): 280.0814;
found: 280.0819.
(13) Saraf, S. D.; Zaki, M. Synthesis 1973, 612.
(14) Hegedus, L. S. In Organometallics in Synthesis; Schlosser,
M., Ed.; Wiley: Chichester, 1997, 448.
1
5
11
3
3
(
15) Khurana, J. M.; Chauhan, S.; Bansal, G. Monatsh. Chem.
004, 135, 83.
16) Shibata, Y.; Hirano, M.; Tanaka, K. Org. Lett. 2008, 10,
829.
Acknowledgment
2
(
This work was supported by the Leibniz-Institut für Katalyse e.V.
LIKAT). We thank Prof. Uwe Rosenthal for his enduring support
2
(
(
(
17) Müller, G.; Wessig, P. Chem. Commun. 2006, 4524.
18) The acid chloride 4 was mentioned in the literature,
however, no spectral data were given: Imase, H.; Suda, T.;
Shibata, Y.; Noguchi, K.; Hirano, M.; Tanaka, K. Org. Lett.
and helpful discussions.
References
2
009, 11, 1805.
19) Suzuki, H.; Kondo, A.; Inouye, M.; Ogawa, T. Synthesis
986, 121.
20) (a) van Veldhuizen, A.; van Dijk, M.; Sanders, G. M. Org.
Magn. Reson. 1980, 13, 105. (b) Zoltewicz, J. A.; Maier, N.
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(
1) (a) Brandsma, L. Synthesis of Acetylenes, Allenes and
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Diederich, F.; Stang, P. J.; Tykwinski, R. R., Eds.; Wiley-
VCH: Weinheim, 2005.
(
(
1
(2) Recent reviews on functionalized alkynes: Ynolates:
(
a) Shindo, M. Tetrahedron 2007, 63, 10.
(
21) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. S. R.; Basak, A. K.;
Narsaiah, A. V. Adv. Synth. Catal. 2004, 346, 77.
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Chem. Soc. 1981, 103, 6133.
Alkynylphosphines: (b) Kondoh, A.; Yorimitsu, H.;
Oshima, K. Chem. Asian J. 2010, 5, 398. Ynamides:
(
(
(
2
c) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem. Int. Ed.
010, 49, 2840. (d) DeKorver, K. A.; Li, H.; Lohse, A. G.;
Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
010, 110, 5064.
2
(
(
(
(
24) Noro, M.; Masuda, T.; Ichimura, A. S.; Koga, N.; Iwamura,
(
(
3) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.
4) Recent example from our group: Hapke, M.; Kral, K.;
Fischer, C.; Spannenberg, A.; Gutnov, A.; Redkin, D.;
Heller, B. J. Org. Chem. 2010, 75, 3993.
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25) Aitken, R. A.; Horsburgh, E. R.; McCreadie, J. G.; Seth, S.
J. Chem. Soc., Perkin Trans. 1 1994, 1727.
26) General synthetic procedure: Molander, G. A.; Biolatto, B.
J. Org Chem. 2003, 68, 4302.
27) General synthetic procedure: Ali, N. M.; McKillop, A.;
Mitchell, M. B.; Rebelo, R. A.; Wallbank, P. J. Tetrahedron
(
5) Otera, J.; Nishikido, J. Esterification, 2nd ed.; Wiley-VCH:
Weinheim, 2010.
(
6) The organozinc reagent was prepared by lithiation of ethyl
propiolate with LDA, followed by subsequent
transmetallation with anhyd ZnCl . We also investigated the
1992, 48, 8117.
2
Synthesis 2011, No. 4, 642–652 © Thieme Stuttgart · New York