Metal-Free Synthesis of 4-Chloroisocoumarins by TMSCl-Catalyzed NCS-Induced Chlorinative Annulation of 2-Alkynylaryloate Esters

Article abstract of DOI:10.1021/acs.joc.9b02793

4-Chloroisocoumarins can be conveniently prepared from 2-alkynylaryloate esters via the activation of alkynes by electrophilic chlorine, generated in situ from N-chlorosuccinimide (NCS) in the presence of 10 mol % trimethylsilyl chloride (TMSCl), which leads to 6-endo-dig-selective chlorinative annulation to give the desired products in moderate to quantitative yields. The procedure employs readily available reagents and can be conveniently carried out on a wide scope of substrates under mild conditions (0 °C to rt). Furthermore, the reaction is scalable for gram-scale preparation of 4-chloroisocoumarins. Additionally, 4-bromo- and 4-iodoisocoumarins can be prepared in moderate to good yields by replacing NCS with N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS), respectively.

Full text of DOI:10.1021/acs.joc.9b02793

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Article
Metal-Free Synthesis of 4-Chloroisocoumarins by TMSCl-Catalyzed
NCS-Induced Chlorinative Annulation of 2-Alkynylaryloate Esters
Krissada Norseeda, Nattawadee Chaisan, Charnsak
Thongsornkleeb, Jumreang Tummatorn, and Somsak Ruchirawat
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02793 • Publication Date (Web): 19 Nov 2019
Downloaded from pubs.acs.org on November 19, 2019
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Metal-Free Synthesis of 4-Chloroisocoumarins by TMSCl-
Catalyzed NCS-Induced Chlorinative Annulation of 2-
Alkynylaryloate Esters
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§
§
*,†,§
Krissada Norseeda, Nattawadee Chaisan, Charnsak Thongsornkleeb,
Jumreang
‡,§
‡,§
Tummatorn, and Somsak Ruchirawat
§
Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on
Environmental Health and Toxicology (EHT), Ministry of Education, 54 Kamphaeng Phet 6,
Laksi, Bangkok 10210, Thailand
†
Laboratory of Organic Synthesis, Chulabhorn Research Institute, 54 Kamphaeng Phet 6,
Laksi, Bangkok 10210, Thailand
‡
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6,
Laksi, Bangkok 10210, Thailand
Supporting Information Placeholder
ABSTRACT: 4-Chloroisocoumarins can be conveniently prepared from 2-alkynylaryloate
esters via the activation of alkyne by electrophilic chlorine, generated in situ from NCS in the
presence of 10 mol% of TMSCl, which led to 6-endo-dig-selective chlorinative annulation to
give the desired products in moderate to quantitative yields. The procedure employed readily
available reagents and can be conveniently carried out on a wide scope of substrates under
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mild conditions (0 °C to rt). Furthermore, the reaction was scalable for gram-scale
preparation of 4-chloroisocoumarins. Additionally, 4-bromo- and 4-iodoisocoumarins can be
prepared in moderate to good yields by replacing NCS with NBS and NIS, respectively.
INTRODUCTION
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1
Isocoumarins are generally an important and prevalent core structure in both natural and
2
-4
synthetic compounds of biological, pharmacological, and medicinal importance. Several
methods have been devised for their preparation. These methods are mostly relying on the
5
use of transition metal compounds as the promoters or catalysts in the halogenative
annulation strategy of 2-alkynylaryloate esters 1 (Scheme 1). For 4-Cl-isocoumarins (2Cl),
almost all methods are usually mediated by transition metal reagents, including
6
a
6b-e
6f
Hg(OAc)
2
/CuCl
2
combination, CuCl
2
,
ZnCl
2
,
both as promoters and sources of Cl
atom. More recently, InX
3
and GaX were utilized for the synthesis of 2X, however, only 2Br
3
6
g
and 2I could be prepared using this method. Metal-free methods for preparing 2Cl are far
less common. Earlier related examples of a cascade process starting from 2-alkynylaryl
7
d
carboxylic acid derivatives were elegantly illustrated by Du and co-workers, which utilized
BF Et O in conjunction with PhI(OAc) to affect divergent transformations of the
3
2
2
isocoumarin intermediate to provide fused and spiro polycyclic heterocycles. The same
research group also recently reported the first metal-free method for directly preparing 2Cl
7
e
from esters 1 by employing PhICl
2
3
as the chlorinating agent in CH CN at 70 °C. However,
8
the uncommon PhICl
2
was difficult to prepare and handle while the commercially available
material was rather expensive. Additionally, this reagent could only be used to prepare 2Cl,
but not 2Br and 2I, thus rendering this procedure rather inflexible and less versatile.
Scheme 1. Previously reported methods for the synthesis of 4-chloro- and other 4-
haloisocoumarins from 1.
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4-Cl-isocoumarins have long been recognized as an important class of potent irreversible
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inhibitors of serine proteases and esterases, a large and important family of enzymes with
1
0
crucial roles including blood coagulation, fertilization and protein turnover. Undesired
activities of these enzymes may lead to several disease states in human, including viral
1
1a
11b-c
11d
11e
11f
infections, stroke and inflammation,
arthritis, cancer, and Alzheimer’s disease.
Examples of some bioactive 4-Cl-isocoumarins are illustrated in Figure 1. 3,4-
1
2a
Dichloroisocoumarin (DCI, I) is a general inhibitor of several serine proteases. 3-Alkoxy-
7
4
-amino-4-Cl-isocoumarin (II), 3-alkoxy-4-Cl-7-guanidino-isocoumarin (III) and 7-amino-
-Cl-3-(3-isothioureidopropoxy)isocoumarin (NH
2
-CiTPrOIC, IV) have been found to be
1
2b
12c-d
suicide substrates for serine proteases, anti-coagulants
and inhibitors of A 40/42
1
2e-f
amyloid peptides production.
3-Cyclohexylbutoxy-4-Cl-isocoumarin (V) could effectively
9
g
bind and inhibit cholesterol esterase in the nM-range. More recently, 3-propyloxy-7-amino-
-Cl-isocoumarin (JCP174, VI) was identified as an enhancer of the host-cell invasion of
parasite Toxoplasma gondii via the covalent inhibition of human APT1 palmitoyl protein
4
1
2g
thioesterase-1 (TgPPT1).
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Figure 1. Examples of biologically active 4-Cl-isocoumarins.
We previously reported that the combination of N-halosuccinimide (NXS; X = Cl, Br, I) and
catalytic TMSCl could lead to the generation of halogen (X-Cl) species which could be
1
3a
utilized in electrophilic aromatic halogenation and in the synthesis of 4-haloisoxazoles
1
3b
from alkynyl-O-methyloximes. Due to the limitations encountered by other methods in
preparing 4-Cl-isocoumarins, herein we were compelled to report our development of a
metal-free chlorinative annulation method for direct conversion of 2-alkynylaryloate esters
(
1) to 4-Cl-isocoumarins (2Cl) under very mild conditions (0 °C to rt), employing readily
available, inexpensive and easy-to-handle NCS and TMSCl. The current protocol was
efficient and general in a wide range of substrates. It was also suitable for gram-scale
synthesis of 2Cl. In addition, 4-Br- and 4-I-isocoumarins (2Br and 2I) could be prepared by
this method in good yields, simply by switching NCS to NBS and NIS, respectively, thus
greatly widened the current repertoire of metal-free methods for the synthesis of 4-
haloisocoumarins in general.
RESULTS AND DISCUSSION
1
2
3
Substrate 1a (R = Me, R = H, R = Ph) was prepared and employed in the optimization
study as shown in Table 1.
a,b
Table 1. Optimization study of conversion of substrate 1a to isocoumarins 2aCl.
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c
Entry
Equiv of NCS
Equiv of TMSCl
Solvent
Temp.
Yield
69%
77%
44%
29%
68%
68%
73%
NR
1
1
1
1
1
1
1
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2
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5
5
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0
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0
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10
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.2
1.2
1.5
1.5
1.5
1.5
1.0
0.5
0.1
-
3
CH NO
2
rt
3
CH CN
rt
THF
rt
CH
CH
CH
CH
CH
CH
CH
2
3
3
3
3
3
3
3
Cl
2
rt
CN
CN
CN
CN
CN
CN
CN
rt
rt
rt
rt
0.1
0.1
0.1
rt
80%
93%
89%
0 °C
-30 °C
11
CH
a
b
Reactions were all conducted at 0.2–0.3 M of 1a. All reactions were complete within 1 h.
c
Isolated yields.
Using the combination of TMSCl and NCS, compound 1a was subjected to these reagents
under a variety of conditions. During the optimization, we also observed the formation of
side-product 3aCl in various amounts, resulted from dichlorination of the alkyne moiety
(
Scheme 2). Compound 1a was first subjected to 1.5 equiv each of NCS and TMSCl in
CH NO at rt. The reaction proceeded smoothly to give 69% of the desired product after 1 h
2aCl) (entry 1). We next attempted to study the effect of different solvents. As shown in
entries 2–4, when conducting the reactions with 1.5 equivalents of both NCS and TMSCl in
CH CN, THF and CH Cl at ambient temperature for 1 h, the reactions afforded the desired
product in 77%, 44% and 29% yields, respectively. The results in entries 1–4 showed that the
reaction proceeded most optimally in CH CN. We next investigated amounts of both NCS
3
2
(
3
2
2
3
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and TMSCl employed in the reaction using CH
3
CN as the solvent. As shown in entry 5, when
the reaction was conducted with 1.5 equiv of NCS and 1.0 equiv of TMSCl, product 2aCl
was obtained in lower yield (68%) compared to entry 2. When the amount of TMSCl was
reduced further to 0.5 equiv, identical yield of compound 2aCl was obtained (entry 6).
However, the yield became slightly better with 0.1 equiv (10 mol%) of TMSCl, providing
product 2aCl in 73% yield (entry 7). Using 1.5 equiv of NCS alone in the reaction without
TMSCl afforded no reaction, thus proving that TMSCl was crucial for the conversion (entry
8). We attempted to reduce the amount of NCS to 1.2 equiv while TMSCl was maintained at
0
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.1 equiv. As shown in entry 9 for the reaction conducted at rt, the conversion was complete
within 1 h to furnish the desired product in 80% yield. We continued to examine the effect of
temperature by conducting the reaction at 0 °C, while maintaining 1.2 equiv of NCS and 0.1
equiv of TMSCl, and found that the reaction went to completion within 1 h to afford the
desired product in 93% yield (entry 10). Decreasing the reaction temperature further to -30
°C resulted in slightly lower yield (entry 11). The optimal conditions were therefore
identified as requiring 10 mol% of TMSCl and 1.2 equiv of NCS to react with 1a in CH
3
CN
(0.2–0.3 M) at 0 °C which resulted in the complete conversion within 1 h to give 2aCl in
93% yield while minimizing the formation of 3aCl. Importantly, these conditions were much
milder and more convenient than those reported previously (Scheme 1). The proposed
mechanism of this transformation (Scheme 2) commenced with the generation of Cl in the
2
reaction mixture which then activated substrate 1 to probably give the alkyne–chlorine
complex A. The neighboring methyl ester group participation then ensued, leading to the
intramolecular annulation (pathway i) to give desired product 2Cl. However, it was also
possible for a vinyl cation C or C’ to form without the participation of the ester group. A
competing chloride ion addition to vinyl cation C or C’ (pathway ii) could take place non-
selectively to give side-product 3Cl as a mixture of (E)- and (Z)-isomers. However, addition
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of the ester group could also compete with addition of a chloride ion in the case of
intermediate C’ (i.e. pathway iii), which would eventually lead to product 2Cl.
Scheme 2. Proposed mechanism of the chlorinative annulation of compound 1.
1
1
1
1
1
1
1
1
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a
Scheme 3. Substrate scope of the chlorinative annulation.
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O
O
Z
Z
OMe 10 mol% TMSCl, 1.2 equiv NCS
R1 Ar
O
R1 Ar
CH CN, 0 ºC, 1 h
R2 (Aryl or Alkyl)
3
R2
Cl
1
2Cl (isolated yield)
O
O
O
O
O
O
O
Me
O
0
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Cl
Cl
Cl
Cl
Me
2aCl (93%)
2bCl (89%)
2cCl (78%)
2dCl (95%)
Me
O
O
O
O
O
OMe
O
O
O
Cl
Cl
Cl
Cl
OMe
F
2
eCl (74%)
2fCl (trace)b
2gCl (94%)
2hCl (89%)
OMe
O
O
O
O
O
O
O
Cl
O
Cl
Cl
Cl
Cl
Cl
Br
2iCl (73%)c
2kCl (89%)
2lCl (99%)
2jCl (99%)
Cl
O
O
O
O
O
O
O
O
NHAc
Cl
Cl
Cl
2oCl (-)e,g
O
Cl
CF3
CN
NO2
2pCl (71%)c
2
mCl (66%)d
2nCl (61%)g
O
O
O
O
O
O
O
N
Cl
qCl (-)
Cl
2rCl (-)
Cl
Cl
d,e
d,e
2sCl (12%)g
c,e
2
2tCl (-)
O
O
O
Me
MeO
O
O
O
Me
F
Cl
Cl
Cl
2wCl (-)
O
f,g
2uCl (86%)
2vCl (89%)
O
O
MeO
MeO
O
O
O
F
Cl
2xCl (-)f,g
O
Cl
2yCl (73%)
O
Cl
2zCl (74%)
O
Br
S
O
O
O
Cl
Cl
Cl
Cl
2ccCl (85%)g
2
aaCl (79%)
2bbCl (86%)
O
O
O
O
O
O
Me
F
H
Cl
2ffCl (-)g,h
Cl
Cl
Me
OMe
2
ddCl (92%)
2eeCl 99%)
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a
b
Reaction was conducted at 0.2–0.3 M of 1. Chlorination occurred para to OMe group to
c
d
afford side-product 1fCl. Reaction was warmed to rt. Reaction was heated at reflux.
e
f
g
Complex reaction mixture. Chlorination side-product 3Cl was obtained. Starting material
h
was recovered. Methyl 2-(2,2-dichloroacetyl)benzoate was obtained as a side-product (8%).
The generality of our method was next examined with other substrates as shown in Scheme 3.
Substrates 1b–d containing electronically neutral tolyl groups of different regioisomers on
the alkyne were tested. The reactions proceeded to give products 2bCl–2dCl in good to
excellent yields. The reactions of 2-tolyl- and 4-tolyl-substrates provided better yields of
products (89% and 95%, respectively) than 3-tolyl-substrate 1c. Next, substrates with
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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9
0
2
strongly electron-donating OMe group (1e–g) were investigated. The reaction of 1e (R = 2-
OMe-Ph) proceeded moderately well to give the desired product in 74% yield. However for
2
substrate 1f (R = 3-OMe-Ph), only trace amount of 2fCl was observed even after allowing a
prolonged reaction time (7 h); electrophilic chlorination on the 3-OMe-Ph ring para to the
OMe group became the major pathway to provide the corresponding aryl chloride (1fCl) in
8
6% yield. The strongly electron-donating 3-OMe group rendered the aryl ring more reactive
towards electrophilic chlorine than the alkyne, thus side-product 1fCl was obtained via
electrophilic aromatic chlorination (Scheme 4). Interestingly, this type of side-product was
not observed in the case of substrate 1e, perhaps due to the faster rate of intramolecular
2
annulation by the ester group than the electrophilic aromatic chlorination. Substrate 1g (R =
4-OMe-Ph) was smoothly converted to product 2gCl in excellent yield (94%). These results
corroborated well with the mechanism proposed in Scheme 2 that strong electron-donating
groups at the 2- and 4-positions of the alkynylaryl ring facilitated the desired annulation more
efficiently, possibly due to better stabilization of the cationic intermediate A.
Scheme 4. Reaction pathways of substrate 1f.
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2
Halogen-substituted R aryl rings were next investigated. The reaction of 1h (R = 4-F-Ph)
proceeded excellently to give the desired product in 89% yield. Reactions were also
attempted with substrates carrying Cl- and Br-substituted Ph rings (1i–l), all of which
afforded the desired products in good to excellent yields (73–99%). Among these, reaction of
2
1
i (R = 2-Cl-Ph) gave lower yield when compared to the others and the reaction also
required longer time (3 h) at rt, possibly due to steric effect imposed by the 2-Cl atom during
2
the annulation. The reactions were less efficient when R were electron-deficient aryl rings.
2
Compound 1m (R = 4-CF
3
-Ph) was converted to 2mCl in 66% yield while a similar
2
efficiency was also observed with 1n (R = 4-CN-Ph) which produced 2nCl in 61% yield
2
along with recovered 1n. With very strong electron-withdrawing NO group (1o), the desired
reaction was completely inhibited as only trace amount of 2oCl was detected. Among the
2
complex reaction mixture, unreacted 1o was also recovered. For compound 1p (R = 2-
NHAc-Ph), the reaction smoothly afforded 2pCl in 71% yield. The reaction was then
attempted with 3-pyridyl-containing 1q. Under standard conditions, no reaction was observed
even at rt. However, when the reaction was heated at reflux, a complex mixture resulted. The
basicity of the pyridine ring was suspected to interfere with the reaction conducted under
acidic conditions, thus adversely affecting the reaction outcome. In addition to substrates
containing aryl and heteroaryl alkynes, those with alkyl and cycloalkyl alkynes were also
investigated (1r–t). The reactions were sluggish at 0 °C; for 1r the reaction mixture was
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heated at reflux which resulted in decomposition while for substrate 1t the reaction went to a
complex reaction mixture even at rt. Only the reaction of 1s could furnish the desired 2sCl,
albeit in low yield (12%) while unreacted 1s was recovered.
2
The Ar rings were next varied in substrates 1u–cc while keeping R as Ph group. Most
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
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2
2
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0
substrates gave the desired products in good to excellent yields, including the thiophene
substrate (1cc) which was converted to 2ccCl in 85% yield with 15% of 1cc recovered. The
reactions were not successful with compounds 1w and 1x having strong electron-donating
OMe group para- to the alkyne moiety (C-5). These results were in a stark contrast to
substrate 1u having less electron-donating methyl group at C-5, which was successfully
converted to product 2uCl in excellent yield. It was suspected that in these two cases the
delocalization of electron density from the OMe group to the C-2 alkyne moiety effectively
competed with the annulation by the ortho-ester group and possibly led to the formation of
allenyl para-quinone methide-type intermediate D which further reacted with a chloride
anion to provide the corresponding (E/Z)-isomers of 3wCl and 3xCl along with the recovery
of the starting compounds (Scheme 5a). The results of substrates 1w and 1x were consistent
7e
with the result obtained by Du and co-workers who also proposed a similar mechanism in
the formation of an intermediate of type D. The reactions of 1dd and 1ee, with variations on
2
both Ar rings and R aryl groups, proceeded uneventfully to the corresponding products in
excellent yields in both cases. Furthermore, substrate 1ff containing terminal alkyne moiety
was also attempted. However, incomplete conversion was observed and dichloroacetyl
methyl ester side-product 1ff-diCl was obtained in 8% along with 66% of recovered 1ff. The
ketone product (1ff-diCl) was presumed to arise from the vinyl cation of type C which in this
case was intercepted faster with a molecule of water to give the corresponding chloroenol
(
E). This chloroenol intermediate then reacted further with another chlorine molecule to give
product 1ff-diCl (Scheme 5b).
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5
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5
5
6
Scheme 5. Formation of side-products 3wCl, 3xCl and 1ff-diCl.
0
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0
Moreover, substrates 4 bearing pendant alkylhydroxy group on the alkyne moiety, in the
presence of 2.0 equiv of NCS, could be converted to spirocyclic ethers 5Cl. The mechanism
was proposed in Scheme 6. Intermediate A (from Scheme 2) was believed to undergo
chlorinative cyclization with the pendant hydroxy group to give intermediate F which further
underwent chlorinative spirocyclic lactonization by the nearby methyl ester and upon
demethylation, 5Cl was obtained. The reaction failed in the case of substrate 4a while
1
4a
substrate 4b was successfully converted to the 4-membered spirocyclic ether 5bCl in
moderate yield (41%) after the reaction was warmed to stir at rt. The reaction provided the
1
4b
highest yield from substrate 4c (n = 3) to give the 5-membered spirocyclic ether 5cCl
(60%) while the reaction of 4d (n = 4) proceeded to give the corresponding 6-membered
1
4c
spirocycle 5dCl in low yield (23%) only after warming the reaction to rt and unreacted 4d
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was also recovered. However, the reactions of 4e, 4f, and 4g (n = 5, 6, and 8, respectively)
failed to give any 7-, 8- and 10-membered spirocyclic ether products.
a
Scheme 6. Substrate scope of the chlorinative spirocyclic lactonization and proposed
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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mechanism of formation of 5Cl.
a
b
c
Reaction was conducted at 0.2 M of 4. Reaction was warmed to rt. Complex reaction mixture.
d
Starting material was recovered.
The current protocol could be adapted to preparing 2aBr and 2aI from 1a by using NBS and
NIS in place of NCS which produced products 2aBr and 2aI in 50% and 79% yields,
respectively (Scheme 7a). Substrates with other alkyl ester groups were also suitable (Scheme
7b); ethyl (1aEt; R = Et), isopropyl (1ai-Pr; R = i-Pr), tert-butyl (1at-Bu; R = t-Bu) and
benzyl (1aBn; R = Bn) aryloate esters were all successfully converted to the desired product
2aCl in moderate to excellent yields. Furthermore, gram-scale preparation of product was
exemplified with conversion of 1.42 g (6.0 mmol) of 1a to 1.30 g (5.1 mmol, 84%) of 2aCl
(
Scheme 7c).
a,b
Scheme 7. Practical features of our method.
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a
b
c
Reactions were carried out at 0.2-0.3 M of 1a/1aR. Isolated yields. The reaction was carried out at
0
°C for 1 h followed by at rt for 3 h.
CONCLUSIONS
In conclusion, we disclosed a convenient procedure for the preparation of 4-Cl-isocoumarins
Cl from 2-alkynylaryloate esters 1 via chlorinative annulation. Several significant
2
advantages over the existing methods were revealed, including very mild and metal-free
conditions and 6-endo-dig-selective cyclization to give the desired products in moderate to
excellent yields with wide substrate scope. Additional advantages were the use of readily
available, inexpensive and convenient-to-handle TMSCl as the catalyst and NCS as the
chlorinating reagents, adaptability to preparing 4-Br- and 4-I-isocoumarins (2Br and 2I) and
amenability to preparing the desired isocoumarin products in gram-scale. With modification
of substrate structure and conditions, the reaction could be used to prepare spirocyclic ether
derivatives containing the isocoumarin scaffold. This method should be of great value to
synthetic and medicinal chemists for the preparation of 4-Cl-isocoumarins as well as other 4-
haloisocoumarin derivatives.
EXPERIMENTAL SECTION
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General Procedure. Commercial grade chemicals were used without further purification,
unless otherwise indicated. All solvents were used as received. Oven-dried glassware (110 °C
at least for 2 h) was used in all reactions. Crude reaction mixtures were concentrated under
reduced pressure on a rotary evaporator. Column chromatography was performed using silica
gel 60 (particle size 0.06–0.2 mm; 70–230 mesh ASTM). Analytical thin-layer
chromatography (TLC) was performed with silica gel 60 F254 aluminum sheets. Nuclear
1
1
1
1
1
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1
1
1
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3
magnetic resonance (NMR) spectra were recorded in deuteriochloroform (CDCl ) with 300
1
13
and 400 MHz spectrometers. Chemical shifts for H NMR and C NMR spectra are reported
in parts per million (ppm, δ), relative to tetramethylsilane (TMS) as the internal reference.
Coupling constants (J) are reported in Hertz (Hz). Infrared spectra were measured using an
–
1
FT-IR spectrometer and are reported in cm . High resolution mass spectra (HRMS) were
obtained using a time-of-flight (TOF) instrument.
General Procedure for the Synthesis of Methyl-, Ethyl- and Isopropyl 2-iodobenzoate. A
250-mL round-bottomed flask with a magnetic stir bar was charged with 2-iodobenzoic acid
2 4
(10 g, 40 mmol) and 0.10 L of 2.0 M aq. H SO solution in MeOH. The resulting mixture was
allowed to stir at reflux. Upon completion, the reaction mixture was diluted with 20 mL of
water and the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined
organic phases were washed with saturated aq NaCl solution (10 mL), dried over anh.
2 4
Na SO , filtered, and concentrated under reduced pressure to give 11 g (40 mmol) of crude
methyl 2-iodobenzoate which was used in the next step without further treatment.
Note: ethyl 2-iodobenzoate was obtained when EtOH was used and EtOH and i-PrOH were
used instead of MeOH to obtain ethyl 2-iodobenzoate and isopropyl 2-iodobenzoate,
respectively. tert-Butyl 2-iodobenzoate and benzyl 2-iodobenzoate were obtained from the
procedures below. These materials were then used in Sonogashira cross-coupling with
terminal alkynes.
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5
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5
5
5
5
5
6
General Procedure for the Synthesis of t-Butyl 2-iodobenzoate. A 50-mL round-bottomed
flask with a magnetic stir bar was charged with 2-iodobenzoic acid (443.5 mg, 1.79 mmol,
2 2
1.0 equiv) and 10.0 mL of CH Cl and cooled to 0 °C. The solution was added with N,N’-
dicyclohexylcarbodiimide (DCC) (410.0 mg, 1.99 mmol, 1.1 equiv), followed by 4-N,N-
dimethylaminopyridine (112.9 mg, 0.92 mmol, 0.52 equiv). After 10 min, the reaction was
added with tert-butanol (0.25 mL, 197.5 mg, 2.66 mmol, 1.5 equiv) by syringe. The reaction
mixture was allowed to warm and stir at rt overnight (18 h). After completion, the reaction
mixture was filtered through a pad of Celite® and the crude material was directly purified by
0
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SiO
2
column chromatography, eluting with 5% EtOAc-hexanes to give the desired product
(423.0 g, 1.39 mmol, 78%) as a colorless oil; IR (neat): υmax 2951, 1727, 1286, 1247, 1098,
–1 1
1
015, 740 cm ; H NMR (300 MHz, CDCl
3
) δ 7.98 (dd, 1H, J = 7.8, 1.2 Hz), 7.82 (dd, 1H, J
=
7.5, 1.5 Hz,), 7.48–7.45 (m, 2H), 7.42–7.31 (m, 4H), 7.14 (td, 1H, J = 7.5, 1.5 Hz), 5.37 (s,
1
3
1
2H); C{ H} NMR (75 MHz, CDCl
3
) δ 166.2, 141.3, 135.4, 134.9, 132.6, 131.0, 128.6,
+
128.5, 128.4, 127.8, 94.1, 67.4; HRMS (ESI-TOF) m/z: [M + Na] calcd for C14
H
11IO
2
Na
360.9696; found 360.9688.
General Procedure for the Synthesis of Benzyl 2-iodobenzoate. A 10-mL round-bottomed
flask with a magnetic stir bar was charged with 2-iodobenzoic acid (0.50 g, 2.0 mmol, 1.0
2 2
equiv) and 1.0 mL of CH Cl . The solution was added with N,N’-dicyclohexylcarbodiimide
(DCC) (0.46 g, 2.2 mmol, 1.1 equiv), followed by 4-N,N-dimethylaminopyridine (25 mg,
0.20 mmol, 0.10 equiv). After 5 min, the reaction was added with benzyl alcohol (0.22 mL,
0.23 g, 2.12 mmol, 1.06 equiv) by syringe. The reaction mixture was allowed to stir at rt
overnight (18 h) then quenched with aq HCl (6 M, 1 mL) and extracted with EtOAc (3 x 1
mL). The combined organic phases were washed with saturated aq NaCl solution (1 mL),
dried over anh. Na
2
SO
4
, filtered, and concentrated under reduced pressure to give the crude
column chromatography, eluting with 5–10% EtOAc-
extract which was purified by SiO
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hexanes to give the desired product (0.62 g, 1.8 mmol, 91%) as a colorless oil; IR (neat): υmax
–
1 1
2951, 1727, 1286, 1247, 1098, 1015, 740 cm ; H NMR (300 MHz, CDCl
3
) δ 7.98 (dd, 1H, J
=
7.8, 1.2 Hz), 7.82 (dd, 1H, J = 7.5, 1.5 Hz,), 7.48–7.45 (m, 2H), 7.42–7.31 (m, 4H), 7.14
13
1
(
td, 1H, J = 7.5, 1.5 Hz), 5.37 (s, 2H); C{ H} NMR (75 MHz, CDCl
3
) δ 166.2, 141.3,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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1
2
3
4
5
6
7
8
9
0
135.4, 134.9, 132.6, 131.0, 128.6, 128.5, 128.4, 127.8, 94.1, 67.4; HRMS (ESI-TOF) m/z: [M
+
+
2
Na] calcd for C14H11IO Na 360.9696; found 360.9688.
General Procedure for the Synthesis of Compounds 1a–o, 1q–ee, 1aEt, 1ai-Pr, 1at-Bu,
and 1aBn.
A 250-mL round-bottomed flask with a magnetic stir bar was charged with the crude methyl
3
2-iodobenzoate from the previous step, followed by 0.10 L of Et N. The resulting solution
was then added with Pd(PPh Cl (1.4 g, 2.1 mmol), followed by CuI (0.23 g, 2.1 mmol) to
3
)
2
2
give a yellow solution with solid suspension. The reaction mixture was degassed by a steady
stream of argon for 15 min, after which it was kept under argon atmosphere. Phenylacetylene
(5.5 mL, 5.1 g, 50 mmol) was then added into the reaction flask by a syringe. The reaction
mixture immediately turned black. The reaction mixture was then allowed to stir at rt under
argon atmosphere overnight (11 h). The reaction mixture was then diluted with saturated aq
NH
organic phases were washed with saturated aq NaCl solution (20 mL), dried over anh.
Na SO , filtered, and concentrated under reduced pressure. The crude material was purified
by SiO column chromatography, eluting 5% EtOAc-hexanes to give the desired product 1a
9.6 g, 41 mmol, 98%) as a yellow oil.
4
Cl solution (20 mL), followed by extraction with EtOAc (3 x 20 mL). The combined
2
4
2
(
Procedure for the Synthesis of Compound 1p. A 25-mL round-bottomed flask with a
magnetic stir bar was charged with 2-iodoaniline (0.65g, 3.0 mmol, 1.0 equiv), followed by
3 3 2 2
5.0 mL of Et N. The resulting solution was then added with Pd(PPh ) Cl (22 mg, 0.032
mmol, 0.010 equiv), followed by CuI (13 mg, 0.068 mmol, 0.023 equiv) to give a yellow
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6
solution with solid suspension. The reaction mixture was degassed by a steady stream of
argon for 15 min, after which it was kept under argon atmosphere. Ethynyltrimethylsilane
(0.50 mL, 0.35 g, 3.6 mmol, 1.2 equiv) was then added into the reaction flask by a syringe.
The reaction mixture immediately turned black. The reaction mixture was then allowed to stir
at rt under argon atmosphere overnight (16 h). The reaction mixture was diluted with
0
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saturated aq NH
phases were washed with saturated aq NaCl solution, dried over anh. Na
concentrated under reduced pressure to give 0.63 g of crude product. This crude material was
taken up in 20 mL of MeOH in a 150-mL round-bottomed flask and K CO (0.49 g, 3.6
4
Cl solution, followed by extraction with EtOAc. The combined organic
2
SO , filtered and
4
2
3
mmol, 1.2 equiv) was added to the reaction mixture. The resulting cloudy mixture was
allowed to stir at rt until the reaction was judged complete by TLC. Upon completion, the
reaction mixture was diluted with water followed by extraction with EtOAc. The combined
organic phases were washed with saturated aq NaCl solution, dried over anh. Na
2
SO
4
, filtered
column
and concentrated to crude orange oil. The crude material was purified by SiO
2
chromatography, eluting with 10–15% EtOAc-hexanes to give the desired 2-ethynylaniline
1
(
0.33 mg, 2.8 mmol, 93%) as pale orange oil; H NMR (300 MHz, CDCl
3
) δ 7.31 (dd, 1H, J
=
7.8, 1.8 Hz), 7.11 (ddd, 1H, J = 8.1, 7.5, 1.5 Hz), 6.73–6.25 (m, 2H), 4.22 (s, 2H), 3.37 (s,
1
5a
1H). Spectroscopic data for this compound were identical to those reported.
A 100-mL round-bottomed flask with a magnetic stir bar was charged with methyl 2-
iodobenzoate (0.64 g, 2.4 mmol, 1.1 equiv), 2-ethynylaniline (0.26 g, 2.2 mmol, 1.0 equiv)
3 3 2 2
and 10 mL of Et N. The resulting solution was then added with Pd(PPh ) Cl (30 mg, 0.042
mmol, 0.020 equiv) and the resulting yellow cloudy mixture was degassed by a steady stream
of argon for 15 min, after which it was kept under argon atmosphere. CuI (22 mg, 0.11 mmol,
0.052 equiv) was then quickly added to the cloudy reaction mixture which quickly turned
greenish yellow. This mixture was allowed to stir at rt under argon atmosphere overnight (16
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h) before it was diluted with saturated aq NH
4
Cl solution (5 mL) followed by extraction with
EtOAc (3 x 5 mL). The combined organic phases were washed with saturated aq NaCl
solution (5 mL), dried over anh. Na
oil. The crude material was purified by SiO
EtOAc-hexanes to give the desired
aminophenyl)ethynyl)benzoate) (0.51 g, 2.0 mmol, 91%) as bright yellow solid; mp. 62.5–
2
SO
4
, filtered, and concentrated to crude greenish yellow
column chromatography, eluting with 10–20%
aniline product (methyl 2-((2-
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–1 1
63.0 °C; IR (neat): υmax 3310 (br), 2925, 2854, 1738, 1525, 1294, 1079, 758 cm ; H NMR
(300 MHz, CDCl ) δ 7.96 (dd, 1H, J = 7.8, 1.2 Hz), 7.61 (dd, 1H, J = 7.8, 1.2 Hz), 7.43 (td,
H, J = 7.5, 1.5 Hz), 7.37 (dd, 1H, J = 7.5, 1.5 Hz), 7.33–7.18 (m, 1H), 7.10 (ddd, 1H J = 8.1,
3
1
7
13
1
.5, 1.5 Hz), 6.72–6.59 (m, 2H), 5.04 (br s, 2H), 3.85 (s, 3H); C{ H} NMR (75 MHz,
CDCl
3
) δ 166.0, 149.6, 133.4, 131.8, 130.3, 130.0, 129.9, 127.1, 124.4, 116.8, 113.9, 106.9,
+
93.5, 92.5, 52.0; HRMS (ESI-TOF) m/z: [M + Na] calcd for C16
H
13NO
2
Na 274.0838; found
274.0836.
A 10-mL round-bottomed flask with a magnetic stir bar was charged with the starting aniline
compound (96 mg, 0.38 mmol, 1.0 equiv) and 3.0 mL of CH Cl to give a clear yellow
solution. The solution was cooled to 0 °C and then added with Et N (60 µL, 44 mg, 43 mmol,
.1 equiv), followed by acetyl chloride (42 µL, 46 mg, 0.59 mmol, 1.5 equiv), by syringes.
After 15 min, the reaction was complete as judged by TLC. The reaction mixture was diluted
with CH Cl (1 mL) and water (1 mL). The combined organic phases were washed with
saturated aq NaCl solution (1 mL), dried over anh. Na SO , filtered, and concentrated under
reduced pressure to give crude pale yellow solid which was purified by SiO column
2
2
3
1
2
2
2
4
2
chromatography, eluting with 10–20 % EtOAc-hexanes to give the desired 1p (0.11 g, 0.37
mmol, 95%) as pale yellow solid.
Procedure for the Synthesis of Compound 1ff. A 50-mL round-bottomed flask with a
magnetic stir bar was charged with methyl 2-iodobenzoate (931.0 mg, 3.55 mmol, 1.0 equiv),
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followed by 10.0 mL of Et
3
3 2 2
N. The resulting solution was then added with Pd(PPh ) Cl (50.6
mg, 0.072 mmol, 0.020 equiv), followed by CuI (26.5 mg, 0.139 mmol, 0.040 equiv) to give
a yellow solution with solid suspension. The reaction mixture was degassed by a steady
stream of argon for 15 min, after which it was kept under argon atmosphere.
Ethynyltrimethylsilane (0.54 mL, 382.9 mg, 3.90 mmol, 1.10 equiv) was then added into the
reaction flask by a syringe. The reaction mixture immediately turned black. The reaction
mixture was then allowed to stir at rt under argon atmosphere overnight (18 h). Upon
0
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2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
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9
0
completion, the reaction mixture was diluted with saturated aq NH
extraction with EtOAc. The combined organic phases were washed with saturated aq NaCl
solution, dried over anh. Na SO , filtered and concentrated under reduced pressure to give
crude product which was purified by SiO column chromatography eluting with 5% EtOAc-
hexanes to yield 814.1 mg (99%) of methyl 2-((trimethylsilyl)ethynyl)benzoate as brown oil;
4
Cl solution, followed by
2
4
2
–1 1
IR (neat): υmax 2956, 2159, 1718, 1248, 839 cm ; H NMR (400 MHz, CDCl
3
) δ 7.89 (dd,
1H, J = 7.8, 0.8 Hz), 7.57 (d, 1H, J = 7.6 Hz), 7.42 (td, 1H, J = 7.6, 1.2 Hz), 7.34 (td, 1H, J =
1
3
1
7.8, 1.2 Hz), 3.91 (s, 3H), 0.28 (s, 9H); C{ H} NMR (100 MHz, CDCl
3
) δ 166.7, 134.3,
+
132.5, 131.3, 130.1, 128.0, 123.1, 103.2, 99.5, 51.8, -0.2; HRMS (ESI-TOF) m/z: [M + H]
16 2
calcd for C13H O Si 233.0992; found 233.0994.
A 50-mL round-bottomed flask containing a magnetic stir bar was charged with methyl 2-
((trimethylsilyl)ethynyl)benzoate (1.314 g, 5.65 mmol, 1.00 equiv) and 10.0 mL of MeOH.
2 3
The reaction solution was then added with K CO (790.0 mg, 5.72 mmol, 1.01 equiv) and the
resulting heterogeneous mixture was allowed to stir at rt for 1.5 h. The reaction was then
diluted with water and extracted with DCM. The combined organic phases were washed with
2 4
saturated aq NaCl solution, dried over anh. Na SO , filtered and concentrated under reduced
pressure to give 851.1 mg (94%) of the desired product 1ff as brown oil. This product was
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analytically pure as indicated by H NMR and was used in the reaction without further
treatment.
Methyl 2-(phenylethynyl)benzoate (1a): Yield 9.6 g (98%, yellow oil); IR (neat): υmax 2949,
–1
1
2
219, 1727, 1600, 1493, 1250, 1078, 754 cm ; H NMR (400 MHz, CDCl
3
) δ 7.97 (dd, 1H, J
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
8.0, 0.8 Hz), 7.64 (dd, 1H, J = 7.6, 1.3 Hz), 7.59–7.57 (m, 2H), 7.48 (t, 1H, J = 7.6 Hz),
13
1
7
3
.39–7.33 (m, 4H), 3.96 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 166.7, 134.0, 131.9,
131.8, 131.7, 130.5, 128.5, 128.4, 127.9, 123.7, 123.3, 94.4, 88.3, 52.2; HRMS (ESI-TOF)
+
m/z: [M + H] calcd for C16
H
13
O
2
237.0910; found 237.0911.
Methyl 2-(o-tolylethynyl)benzoate (1b): Yield 165.1 mg (72%, dark orange oil); IR (neat):
–1
1
υ
max 2950, 2213, 1729, 1492, 1249, 1077, 753 cm ; H NMR (300 MHz, CDCl
3
) δ 7.97 (dd,
1
7
H, J = 7.8, 1.2 Hz), 7.65 (dd, 1H, J = 7.8, 0.9 Hz), 7.54 (d, 1H, J = 7.5 Hz), 7.49 (dt, 1H, J =
.5, 1.5 Hz), 7.38 (td, 1H, J = 7.8, 1.2 Hz), 7.26–7.15 (m, 3H), 3.95 (s, 3H), 2.56 (s, 3H);
1
3
1
C{ H} NMR (75 MHz, CDCl
3
) δ 166.6, 140.3, 134.0, 132.1, 131.6, 131.5, 130.3, 129.4,
+
128.5, 127.7, 125.5, 123.8, 123.0, 93.3, 91.9, 52.1, 20.6.; HRMS (ESI-TOF) m/z: [M + H]
calcd for C17 251.1067; found 251.1070.
Methyl 2-(m-tolylethynyl)benzoate (1c): Yield 165.1 mg (72%, dark orange oil); IR (neat):
15 2
H O
–
1 1
υ
max 2950, 2210, 1729, 1599, 1490, 1250, 1078, 755 cm ; H NMR (300 MHz, CDCl
.97 (dd, 1H, J = 7.8, 1.2 Hz), 7.64 (dd, 1H, J = 7.8, 0.9 Hz), 7.49 (td, 1H, J = 7.5, 1.5 Hz),
7.40–7.35 (m, 3H), 7.25 (t, 1H, J = 7.5 Hz), 7.16 (d, 1H, J = 7.5 Hz), 3.97 (s, 3H), 2.36 (s,
3
) δ
7
1
3
1
3H); C{ H} NMR (75 MHz, CDCl
3
) δ 166.6, 137.9, 133.9, 132.2, 131.8, 131.6, 130.4,
1
29.4, 128.8, 128.2, 127.7, 123.8, 123.1, 94.5, 87.8, 52.1, 21.2.; HRMS (ESI-TOF) m/z: [M +
+
H] calcd for C17
15 2
H O 251.1067; found 251.1070.
Methyl 2-(p-tolylethynyl)benzoate (1d): Yield 367.0 mg (99%, yellow oil); IR (neat): υmax
–
1 1
2
3
950, 2217, 1716, 1510, 1249, 1077, 755 cm ; H NMR (400 MHz, CDCl ) δ 7.96 (dd, 1H, J
= 8.0, 0.8 Hz), 7.63 (dd, 1H, J = 8.0, 0.8 Hz), 7.50–7.46 (m, 3H), 7.36 (td, 1H, J = 7.6, 1.2
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
5
6
1
3
1
3
Hz), 7.16 (d, 2H, J = 7.6 Hz), 3.96 (s, 3H), 2.37 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ
166.8, 138.7, 133.9, 131.8, 131.6, 130.4, 129.1, 127.7, 123.9, 120.2, 94.6, 87.6, 52.1, 21.5;
+
HRMS (ESI-TOF) m/z: [M + H] calcd for C17
H
15
O
2
251.1067; found 251.1069.
Methyl 2-((2-methoxyphenyl)ethynyl)benzoate (1e): Yield 177.0 mg (86%, yellow oil); IR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–1 1
(
neat): υmax 2216, 1726, 1244, 1022, 749 cm ; H NMR (400 MHz, CDCl
7.8, 1.3 Hz), 7.67 (dd, 1H, J = 7.8, 1.3 Hz), 7.55 (dd, 1H, J = 7.6, 1.8 Hz), 7.46 (td, 1H, J =
7.6, 1.4 Hz), 7.37–7.27 (m, 2H), 6.94 (td, 1H, J = 7.5, 1.0 Hz), 6.89 (d, 1H, J = 8.4 Hz), 3.95
3
) δ 7.96 (dd, 1H, J
=
1
3
1
(s, 3H), 3.91 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 166.8, 159.9, 134.0, 133.7, 131.6,
1
31.5, 130.3, 129.9, 127.6, 123.9, 120.4, 112.4, 110.6, 92.1, 90.8, 55.7, 52.0; HRMS (ESI-
+
TOF) m/z: [M + Na] calcd for C17
14 3
H O Na 289.0835; found 289.0844.
Methyl 2-((3-methoxyphenyl)ethynyl)benzoate (1f): Yield 307.7 mg (99%, yellow oil); IR
–
1 1
(neat): υmax 2950, 2837, 2210, 1728, 1251, 1077, 755 cm ; H NMR (300 MHz, CDCl
3
) δ
7.95 (dd, 1H, J = 7.8, 1.2 Hz), 7.62 (dd, 1H, J = 7.8, 1.5 Hz), 7.44 (td, 1H, J = 7.8, 1.5 Hz),
7
.33 (td, 1H, J = 7.8, 1.5 Hz), 7.24 (t, 1H, J = 7.8 Hz), 7.17 (d, 1H, J = 7.8 Hz), 7.10 (s, 1H),
13
1
6
.88 (ddd, 1H, J = 8.1, 2.4, 1.2 Hz), 3.93 (s, 3H), 3.78 (s, 3H); C{ H} NMR (75 MHz,
CDCl
3
) δ 166.4, 159.2, 133.8, 131.7, 131.5, 130.3, 129.3, 127.8, 124.1, 123.4, 116.4, 114.9,
+
9
4.1, 87.9, 55.1, 52.0; HRMS (ESI-TOF) m/z: [M + Na] calcd for C17
H
14
O
3
Na 289.0835;
found 289.0834.
Methyl 2-((4-methoxyphenyl)ethynyl)benzoate (1g): Yield 216.3 mg (69%, yellow oil); IR
–
1 1
(
neat): υmax 2215, 1727, 1245, 1077, 830, 755 cm ; H NMR (300 MHz, CDCl
3
) δ 7.96 (dd,
1
1
H, J = 7.8, 1.4 Hz), 7.62 (dd, 1H, J = 7.7, 1.3 Hz), 7.57–7.41 (m, 3H), 7.35 (td, 1H, J = 7.6,
13
1
.4 Hz,), 6.89 (d, 2H, J = 8.8 Hz), 3.96 (s, 3H), 3.83 (s, 3H); C{ H} NMR (75 MHz,
CDCl
3
) δ 166.8, 159.8, 133.7, 133.2, 131.6, 130.4, 127.5, 124.1, 115.4, 114.0, 94.5, 87.1,
+
5
5.3, 52.1; HRMS (ESI-TOF) m/z: [M + H] calcd for C17
H
15
O
3
267.1016; found 267.1020.
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Methyl 2-((4-fluorophenyl)ethynyl)benzoate (1h): Yield 191.3 mg (94%, orange oil); IR
–
1 1
(neat): υmax 2951, 1728, 1717, 1507, 1251, 1224, 1077, 835, 755 cm ; H NMR (300 MHz,
CDCl ) δ 7.97 (ddd, 1H, J = 7.9, 1.5, 0.6 Hz), 7.66–7.60 (m, 1H), 7.60–7.52 (m, 2H), 7.48
td, 1H, J = 7.6, 1.5 Hz), 7.37 (td, 1H, J = 7.6, 1.4 Hz), 7.11–6.99 (m, 2H), 3.95 (s, 3H);
3
(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
3
C{ H} NMR (75 MHz, CDCl ) δ 166.9, 162.6 (d, J = 248 Hz), 161.0, 133.9, 133.6 (d, J = 8
Hz), 131.7, 131.7, 130.4, 127.9, 123.6, 119.4 (d, J = 4 Hz), 115.62 (d, J = 22 Hz), 93.2, 87.91
+
(d, J = 2 Hz), 52.1; HRMS (ESI-TOF) m/z: [M + Na] calcd for C16
H
11FO
2
Na 277.0635;
found 277.0637.
Methyl 2-((2-chlorophenyl)ethynyl)benzoate (1i): Yield 256.7 mg (97%, yellow oil); IR
–1
1
(
neat): υmax 2951, 1756, 1489, 1253, 1079, 753 cm ; H NMR (300 MHz, CDCl
3
) δ 7.96 (dd,
1
1
H, J = 7.9, 1.5 Hz), 7.68 (dd, 1H, J = 7.8, 1.4 Hz), 7.63–7.58 (m, 1H), 7.47 (td, 1H, J = 7.6,
1
3
1
.5 Hz), 7.42–7.33 (m, 2H), 7.27–7.19 (m, 2H), 3.94 (s, 3H); C{ H} NMR (75 MHz,
CDCl
123.1, 93.1, 90.8, 52.1; HRMS (ESI-TOF) m/z: [M + Na] calcd for C16
93.0340; found 293.0336.
Methyl 2-((3-chlorophenyl)ethynyl)benzoate (1j): Yield 220.3 mg (90%, yellow oil); IR
3
) δ 166.5, 135.7, 134.2, 133.4, 131.7, 131.5, 130.3, 129.4, 129.1, 128.1, 126.3, 123.1,
+
35
H
11 ClO
2
Na
2
–1 1
(
neat): υmax 2950, 1728, 1251, 1077, 754 cm ; H NMR (300 MHz, CDCl
3
) δ 7.97 (dd, 1H, J
=
7.8, 1.1 Hz), 7.61 (dd, 1H, J = 7.7, 1.0 Hz), 7.58–7.52 (m, 1H), 7.50–7.41 (m, 2H), 7.36 (td,
1
3
1
1H, J = 7.7, 1.4 Hz), 7.32–7.21 (m, 2H), 3.94 (s, 3H); C{ H} NMR (75 MHz, CDCl
3
) δ
166.3, 134.1, 133.9, 131.8, 131.6, 131.4, 130.4, 129.7, 129.5, 128.6, 128.1, 125.0, 123.1,
+
35
9
2.7, 89.3, 52.1; HRMS (ESI-TOF) m/z: [M + Na] calcd for C16
found 293.0348.
Methyl 2-((4-chlorophenyl)ethynyl)benzoate (1k): Yield 187.2 mg (86%, yellow oil); IR
H
11 ClO
2
Na 293.0340;
–
1 1
(
3
neat): υmax 1729, 1492, 1252, 1078, 821, 756 cm ; H NMR (300 MHz, CDCl ) δ 7.99 (dd,
1H, J = 7.8, 1.4 Hz), 7.64 (dd, 1H, J = 7.7, 1.4 Hz), 7.56–7.44 (m, 3H), 7.39 (td, 1H, J = 7.7,
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
5
5
5
5
6
1
3
1
1.4 Hz), 7.39–7.28 (m, 2H), 3.96 (s, 3H); C{ H} NMR (75 MHz, CDCl
3
) δ 166.5, 134.5,
134.0, 132.9, 131.8, 131.7, 130.5, 128.7, 128.1, 123.4, 121.8, 93.1, 89.1, 52.2; HRMS (ESI-
+
35
TOF) m/z: [M + H] calcd for C16
H
11 ClO
2
271.0520; found 271.0515.
Methyl 2-((4-bromophenyl)ethynyl)benzoate (1l): Yield 437.0 mg (93%, yellow oil); IR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–1 1
(
3
neat): υmax 2219, 1727, 1716, 1492, 1077, 822 cm ; H NMR (300 MHz, CDCl ) δ 7.96 (dd,
1
3
1
1
H, J = 7.8, 1.5 Hz), 7.61 (dd, 1H, J = 7.7, 1.4 Hz), 7.51–7.30 (m, 6H), 3.93 (s, 3H); C{ H}
3
NMR (75 MHz, CDCl ) δ 166.3, 133.8, 133.0, 132.9, 131.6, 131.5, 130.4, 128.0, 123.3,
+
79
122.7, 122.2, 93.1, 89.3, 52.1; HRMS (ESI-TOF) m/z: [M + Na] calcd for C16
36.9835; found 336.9830.
Methyl 2-((4-(trifluoromethyl)phenyl)ethynyl)benzoate (1m): Yield 515.6 mg (99%, orange
H
11 BrO
2
Na
3
–
1 1
solid); mp. 51.4–51.9 °C; IR (neat): υmax 1730, 1320, 1122, 841, 755 cm ; H NMR (300
MHz, CDCl ) δ 8.00 (dd, 1H, J = 7.8, 1.2 Hz), 7.69–7.60 (m, 5H), 7.52 (td, 1H, J = 7.5, 1.5
Hz), 7.42 (td, 1H, J = 7.8, 1.5 Hz), 3.96 (s, 3H); C{ H} NMR (75 MHz, CDCl
3
1
3
1
3
) δ 166.4,
134.1, 132.0, 131.9, 131.8, 130.6, 130.1, (q, J = 33 Hz), 128.5, 127.2, 125.3, (q, J = 4 Hz),
+
1
23.9 (q, J = 272 Hz), 123.1, 92.7, 90.5, 52.2; HRMS (ESI-TOF) m/z: [M + Na] calcd for
C
17
H
11
F
3
O
2
Na 327.0603; found 327.0600.
Methyl 2-((4-cyanophenyl)ethynyl)benzoate (1n): Yield 197.0 mg (95%, orange solid); mp.
–
1 1
9
5.9–96.1 °C; IR (neat): υmax 2223, 1705, 1292, 1125, 946, 756 cm ; H NMR (300 MHz,
CDCl ) δ 8.01 (d, 1H, J = 7.8 Hz), 7.71–7.58 (m, 5H), 7.53 (tt, 1H, J = 7.6, 1.6 Hz), 7.44 (tt,
1H, J = 7.7, 1.6 Hz), 3.96 (s, 3H); C{ H} NMR (75 MHz, CDCl
31.9, 131.8, 131.7, 130.5, 128.6, 128.1, 122.6, 118.4, 111.6, 92.4, 92.2, 52.1; HRMS (ESI-
3
1
3
1
3
) δ 166.0, 134.0, 132.1,
1
+
TOF) m/z: [M + Na] calcd for C17
2
H11NO Na 284.0682; found 284.0688.
Methyl 2-((4-nitrophenyl)ethynyl)benzoate (1o): Yield 220.3 mg (90%, yellow solid); mp.
–1 1
1
18.8–119.3 °C; IR (neat): υmax 2443, 2217, 1708, 1588, 1341, 1105, 752 cm ; H NMR (400
MHz, CDCl
3
) δ 8.11–8.06 (m, 2H), 7.91 (dd, 1H J = 7.8, 1.4 Hz), 7.61–7.57 (m, 2H), 7.55
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(dd, 1H, J = 7.7, 1.3 Hz), 7.42 (td, 1H, J = 7.6, 1.4 Hz), 7.34 (td, 1H, J = 7.7, 1.4 Hz,), 3.86
1
3
1
(s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 165.9, 146.9, 134.0, 132.2, 131.8, 130.5, 130.1,
+
1
28.7, 123.4, 122.4, 93.3, 92.0, 52.1; HRMS (ESI-TOF) m/z: [M + H] calcd for C16
H
12NO
4
282.0761; found 282.0758.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
6
0
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2
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4
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6
7
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0
1
2
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4
5
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7
8
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0
1
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4
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6
7
8
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Methyl 2-((2-acetamidophenyl)ethynyl)benzoate (1p): Yield 0.11 mg (95%, white solid); mp.
–
1
1
00.0–101.0 °C; IR (neat): υmax 3329, 2949, 2213, 1716, 1686, 1522, 1255, 1079, 748 cm ;
1
3
H NMR (300 MHz, CDCl ) δ 9.30 (br s, 1H), 8.61 (d, 1H, J = 8.4 Hz), 8.02 (dd, 1H, J = 7.8,
0.9 Hz), 7.61 (dd, 1H, J = 7.8, 0.9 Hz), 7.53–7.42 (m, 2H), 7.42–7.24 (m, 2H), 7.00 (td, 1H, J
1
3
1
=
3
7.6, 1.1 Hz), 3.85 (s, 3H), 2.40 (s, 3H); C{ H} NMR (75 MHz, CDCl ) δ 169.7, 165.8,
1
5
3
40.8, 133.6, 132.2, 131.7, 130.4, 129.8, 129.3, 127.8, 123.9, 122.5, 119.2, 111.2, 94.5, 90.7,
+
2.1, 24.4; HRMS (ESI-TOF) m/z: [M + Na] calcd for C18
H
15NO
3
Na 316.0944; found
16.0939.
Methyl 2-(pyridin-3-ylethynyl)benzoate (1q): Yield 234.2 mg (97%, yellow oil); IR (neat):
–
1 1
υ
max 2951, 2346, 1782, 1254, 1079, 758 cm ; H NMR (400 MHz, CDCl
.2 Hz), 8.56 (dd, 1H, J = 5.2, 1.6 Hz), 8.01 (dd, 1H, J = 8.0, 1.6 Hz), 7.67 (dd, 1H, J = 8.0,
.8 Hz), 7.52 (td, 1H, J = 7.6, 1.6 Hz), 7.42 (td, 1H, J = 7.6, 1.2 Hz), 7.31 (dd, 1H, J = 4.8,
3
) δ 8.81 (d, 1H, J =
1
0
0
1
1
3
1
3
.4 Hz), 7.29 (dd, 1H, J = 4.8, 0.8 Hz), 3.97 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ
66.3, 152.2, 152.2, 148.7, 138.5, 134.0, 131.8, 131.7, 130.5, 128.4, 123.0, 122.9, 120.4,
+
91.4, 90.7, 52.2; HRMS (ESI-TOF) m/z: [M + H] calcd for C15
H
12NO
2
238.0863; Found
238.0864.
Methyl 2-(hex-1-ynyl)benzoate (1r): Yield 100.2 mg (44%, yellow oil); IR (neat): υmax 2929,
–1
1
2
3
161, 1718, 1285, 1082, 708 cm ; H NMR (400 MHz, CDCl ) δ 7.88 (dd, 1H, J = 7.6, 0.8
Hz), 7.51 (dd, 1H, J = 7.6, 0.8 Hz), 7.42 (td, 1H, J = 7.6, 1.6 Hz), 7.30 (td, 1H, J = 7.6, 1.2
Hz), 3.91, (s, 3H), 2.48 (t, 2H, J = 6.8 Hz), 1.66–1.59 (m, 2H), 1.55–1.46 (m, 2H), 0.96 (t,
1
3
1
3
3H, J = 7.6 Hz); C{ H} NMR (100 MHz, CDCl ) δ 167.0, 134.2, 131.9, 131.4, 130.1,
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2
2
2
2
2
2
2
2
3
3
3
3
3
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5
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5
5
6
+
127.1, 124.4, 95.9, 79.1, 52.0, 30.7, 22.0, 19.4, 13.6; HRMS (ESI-TOF) m/z: [M + Na] calcd
Na 239.1043; found 239.1044.
Methyl 2-(cyclopropylethynyl)benzoate (1s): Yield 314.9 mg (99%, pale yellow oil); IR
16 2
for C14H O
–1
1
(neat): υmax 2951, 2230, 1728, 1248, 1077, 755 cm ; H NMR (300 MHz, CDCl
3
) δ 7.88 (dd,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
H, J = 7.8, 1.2 Hz), 7.48 (dd, 1H, J = 7.5, 1.2 Hz), 7.40 (td, 1H, J = 7.5, 1.2 Hz), 7.29 (td,
1
3
1
H, J = 7.5, 1.2 Hz), 3.91 (s, 3H), 1.56–1.47 (m, 1H), 0.95–0.81 (m, 4H); C{ H} NMR (75
MHz, CDCl
3
) δ 166.8, 134.0, 131.8, 131.4, 130.1, 126.9, 124.4, 99.1, 74.4, 51.9, 8.9, 0.5;
+
HRMS (ESI-TOF) m/z: [M + Na] calcd for C13
H
12
O
2
Na 223.0730; found 223.0736.
Methyl 2-(cyclohexylethynyl)benzoate (1t): Yield 110.3 mg (99%, yellow oil); IR (neat): υmax
–1
1
2
927, 1727, 1251, 1082, 721 cm ; H NMR (400 MHz, CDCl
Hz), 7.50 (dd, 1H, J = 7.7, 1.3 Hz), 7.41 (t, 1H, J = 7.5 Hz), 7.30 (t, 1H, J = 7.6 Hz), 3.91 (s,
H), 2.66 (tt, 1H, J = 8.8, 3.8 Hz), 1.95–1.85 (m, 2H), 1.83–1.72 (m, 2H), 1.66–1.47 (m, 3H),
3
) δ 7.87 (dd, 1H, J = 7.8, 1.4
3
1
3
1
1.42–1.31 (m, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 167.1, 134.1, 132.0, 131.4, 130.1,
+
127.0, 124.3, 99.8, 79.2, 52.0, 32.5, 29.9, 25.9, 24.8; HRMS (ESI-TOF) m/z: [M + Na] calcd
for C16H
18
O
2
Na 265.1199; found 265.1198.
Methyl 5-methyl-2-(phenylethynyl)benzoate (1u): Yield 184.0 mg (99%, yellow oil); IR
–
1 1
(neat): υmax 1730, 1500, 1205, 1078, 756 cm ; H NMR (400 MHz, CDCl
3
) δ 7.79–7.77 (m,
1
H), 7.59–7.54 (m, 2H), 7.52 (d, 1H, J = 7.9 Hz), 7.39–7.31 (m, 3H), 7.28 (ddd, 1H, J = 7.9,
1
3
1
3
1.9, 0.9 Hz), 3.95 (s, 3H), 2.38 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 166.8, 138.1,
133.8, 132.5, 131.6, 130.9, 128.2, 123.4, 120.6, 93.4, 88.3, 52.1, 21.2; HRMS (ESI-TOF)
+
m/z: [M + H] calcd for C17
H
15
O
2
251.1067; found 251.1067.
Methyl 4-methyl-2-(phenylethynyl)benzoate (1v): Yield 190.2 mg (99%, yellow oil); IR
–1
1
(neat): υmax 2950, 1727, 1291, 1254, 1080, 756 cm ; H NMR (400 MHz, CDCl
3
) δ 7.89 (d,
1
H, J = 8.0 Hz), 7.59–7.56 (m, 2H), 7.46 (d, 1H, J = 0.4 Hz), 7.37–7.32 (m, 3H), 7.17 (d, 1H,
1
3
1
3
J = 8.0 Hz), 3.94 (s, 3H), 2.37 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 166.6, 142.3,
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34.5, 131.7, 139.6, 128.9, 128.8, 128.4, 128.3, 123.6, 123.4, 93.8, 88.5, 52.0, 21.2; HRMS
+
(ESI-TOF) m/z: [M + Na] calcd for C17
H
14
O
2
Na 273.0886; found 273.0894.
Methyl 5-methoxy-2-(phenylethynyl)benzoate (1w): Yield 349.9 mg (79%, orange oil); IR
–1
1
(
neat): υmax 2924, 1740, 1232, 1089, 759 cm ; H NMR (400 MHz, CDCl
3
) δ 7.57–7.53 (m,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
H), 7.48 (d, 1H, J = 2.8 Hz), 7.36–7.31 (m, 3H), 7.02 (dd, 1H, J = 8.8, 2.8 Hz), 3.96 (s, 3H),
1
3
1
.84 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 166.5, 159.0, 135.3, 133.1, 131.5, 128.3,
+
128.1, 123.6, 118.2, 115.8, 115.0, 92.5, 88.1, 55.5, 52.2; HRMS (ESI-TOF) m/z: [M + Na]
calcd for C17 Na 289.0835; found 289.0830.
Methyl 4,5-dimethoxy-2-(phenylethynyl)benzoate (1x): Yield 278.3 mg (99%, orange solid);
14 3
H O
–1
1
mp. 89.6–89.8 °C; IR (neat): υmax 2949, 1722, 1518, 1209, 1002, 757 cm ; H NMR (400
MHz, CDCl ) δ 7.59–7.57 (m, 2H), 7.53 (s, 1H), 7.39–7.33 (m, 3H), 7.09 (s, 1H), 3.97 (s,
3
H), 3.96 (s, 6H); C{ H} NMR (100 MHz, CDCl ) δ 166.3, 151.6, 148.6, 131.6, 128.32,
3
13
1
3
128.30, 124.5, 123.5, 117.5, 115.7, 112.9, 93.0, 88.6, 56.12, 56.06, 52.1; HRMS (ESI-TOF)
+
m/z: [M + Na] calcd for C18
H
16
O
4
Na 319.0941; found 319.0941.
Methyl 5-fluoro-2-(phenylethynyl)benzoate (1y): Yield 140.7 mg (99%, orange oil); IR (neat):
–1
1
υ
max 2952, 2217, 1717, 1497, 1067, 755 cm ; H NMR (400 MHz, CDCl
3
) δ 7.67 (d, 1H d, J
=
9.2, 2.8 Hz), 7.62 (dd, 1H, J = 8.6, 5.5 Hz), 7.59–7.53 (m, 2H), 7.40–7.31 (m, 3H), 7.20 (td,
13
1
1
3
H, J = 8.2, 2.8 Hz), 3.96 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 165.5 (d, J = 3 Hz),
165.4, 161.5 (d, J = 249 Hz), 135.8 (d, J = 8 Hz), 133.7 (d, J= 8 Hz), 131.6, 128.5, 128.3,
123.1, 119.9 (d, J = 4 Hz), 119.2 (d, J = 22 Hz), 117.5 (d, J = 24 Hz), 94.0, 87.1, 52.4; HRMS
(
ESI-TOF) m/z: [M + Na]+ calcd for C16
2
H11FNaO 277.0635; Found 277.0635.
Methyl 4-fluoro-2-(phenylethynyl)benzoate (1z): Yield 386.4 mg (97%, orange oil); IR (neat):
–1
1
υ
max 2952, 2216, 1716, 1248, 1116, 757 cm ; H NMR (400 MHz, CDCl
3
) δ 8.00 (dd, 1H, J
=
8.8, 5.6 Hz), 7.59–7.57 (m, 2H), 7.39–7.36 (m, 3H), 7.33 (dd, 1H, J = 9.2, 2.8 Hz), 7.33 (td,
13
1
3
1H, J = 8.4, 2.4 Hz), 3.96 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 165.7, 164.3 (d, J =
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2
2
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2
2
2
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236 Hz), 133.1 (d, J = 10 Hz), 131.8, 128.9, 128.4, 128.0 (d, J = 3 Hz), 126.4 (d, J = 10 Hz),
122.8, 120.6 (d, J = 23 Hz), 115.3 (d, J = 22 Hz), 95.6, 87.1 (d, J = 3 Hz), 52.2; HRMS (ESI-
+
TOF) m/z: [M + Na] calcd for C16
H11FO
2
Na 277.0635; found 277.0630.
Methyl 4-chloro-2-(phenylethynyl)benzoate (1aa): Yield 304.3 mg (91%, yellow oil); IR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–1 1
(
neat): υmax 2221, 1732, 1716, 1285, 1101, 755 cm ; H NMR (300 MHz, CDCl
3
) δ 7.92 (d,
1H, J = 8.5 Hz), 7.63 (d, 1H, J = 2.2 Hz), 7.61–7.53 (m, 2H), 7.40–7.32 (m, 4H), 3.95 (s,
1
3
1
3H); C{ H} NMR (75 MHz, CDCl
3
) δ 165.8, 138.0, 133.6, 131.8, 131.8, 130.0, 128.8,
+
128.4, 128.1, 125.5, 122.8, 95.6, 87.0, 52.3; HRMS (ESI-TOF) m/z: [M + H] calcd for
3
5
C
16
H
11 ClO
2
Na 293.0340; found 293.0337.
Methyl 5-bromo-2-(phenylethynyl)benzoate (1bb): Yield 190.2 mg (99%, yellow oil); IR
–1 1
(
neat): υmax 2950, 1727, 1291, 1254, 1080, 756 cm ; H NMR (400 MHz, CDCl
3
) δ 8.11 (d,
1H, J = 2.0 Hz), 7.61–7.55 (m, 3H), 7.49 (d, 1H, J = 8.4 Hz), 7.37–7.34 (m, 3H), 3.96 (s,
1
3
1
3H); C{ H} NMR (100 MHz, CDCl
3
) δ 165.3, 135.1, 134.7, 133.4, 133.2, 131.7, 128.7,
+
128.4, 122.9, 122.7, 121.8, 95.5, 87.3, 52.4; HRMS (ESI-TOF) m/z: [M + H] calcd for
7
9
C
16
H
12 BrO
2
315.0015; found 315.0014.
Methyl 3-(phenylethynyl)thiophene-2-carboxylate (1cc): Yield 686.6 mg (99%, orange solid);
–
1
1
mp. 69.0–70.0 °C; IR (neat): υmax 2952, 1714, 1236, 1073, 880, 763 cm ; H NMR (400
MHz, CDCl ) δ 7.59–7.58 (m, 2H), 7.44 (d, 1H, J = 5.2 Hz), 7.35–7.34 (m, 3H), 7.19 (d, 1H,
J = 5.2 Hz), 3.92 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
1
3
1
3
) δ 161.7, 133.2, 132.0, 131.7,
+
130.4, 128.7, 128.3, 127.3, 122.8, 95.2, 83.9, 52.1; HRMS (ESI-TOF) m/z: [M + H] calcd
for C14H
11
O
2
S 243.0474; found 243.0472.
Methyl 5-methyl-2-(p-tolylethynyl)benzoate (1dd): Yield 146.0 mg (83%, yellow crystal); mp.
–1
1
6
1.3–61.8 °C; IR (neat): υmax 2921, 2216, 1729, 1513, 1203, 816 cm ; H NMR (400 MHz,
CDCl ) δ 7.76 (s, 1H), 7.50 (d, 1H, J = 8.0 Hz), 7.46 (d, 2H, J = 8.4 Hz), 7.25 (dd, 1H, J =
3
1
3
1
7.8, 1.2 Hz), 7.14 (d, 2H, J = 8.0 Hz), 3.94 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H); C{ H} NMR
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(100 MHz, CDCl
3
) δ 166.8, 138.3, 137.8, 133.7, 132.4, 131.4, 130.9, 129.0, 120.8, 120.3,
+
93.6, 87.6, 52.0, 21.4, 21.1; HRMS (ESI-TOF) m/z: [M + Na] calcd for C18
H
16NaO
2
287.1043; Found 287.1050.
Methyl 5-fluoro-2-((4-methoxyphenyl)ethynyl)benzoate (1ee): Yield 280.0 mg (90%, yellow
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
oil); H NMR (400 MHz, CDCl
3
) δ 7.66 (d, 1H, J = 9.2 Hz), 7.62–7.56 (m, 1H), 7.50 (d, 2H,
J = 8.2 Hz), 7.19 (t, 1H, J = 8.1 Hz), 6.88 (d, 2H, J = 8.2 Hz), 3.96 (s, 3H), 3.82 (s, 3H);
1
3
1
3
C{ H} NMR (100 MHz, CDCl ) δ 165.6, 161.4 (d, J = 249 Hz), 159.9, 135.6 (d, J = 8 Hz),
133.4 (d, J = 8 Hz), 133.2, 120.4 (d, J = 4 Hz), 119.2 (d, J = 22 Hz), 117.5 (d, J = 24 Hz),
+
115.2, 114.0, 94.2, 86.0, 55.3, 52.4; HRMS (ESI-TOF) m/z: [M + H] calcd for C17
H
14
O
3
F
285.0922; Found 285.0919.
Methyl 2-ethynylbenzoate (1ff): Yield 851.1 mg (94%, brown oil); IR (neat): υmax 3265, 2951,
–
1 1
1717, 1254, 758 cm ; H NMR (300 MHz, CDCl
3
) δ 7.95-7.92 (m, 1H), 7.62 (dd, 1H, J =
7.7, 1.2 Hz), 7.47 (td, 1H, J = 7.5, 1.5 Hz), 7.40 (td, 1H, J = 7.5, 1.5 Hz), 3.93 (s, 3H)), 3.41
1
3
1
(s, 1H); C{ H} NMR (75 MHz, CDCl
3
) δ 166.3, 134.9, 132.4, 131.6, 130.2, 128.4, 122.6,
+
82.2, 81.9, 52.1; HRMS (ESI-TOF) m/z: [M + H] calcd for C10
9
H O
2
161.0597; found
161.0597.
Ethyl 2-(phenylethynyl)benzoate (1aEt): Yield 465.5 mg (99%, dark orange oil); IR (neat):
–
1 1
υ
3
max 2982, 2218, 2164, 1725, 1721, 1247, 753, 690 cm ; H NMR (300 MHz, CDCl ) δ 7.97
(ddd, 1H, J = 7.8, 1.5, 0.3 Hz), 7.65 (ddd, 1H J = 7.8, 1.2, 0.3 Hz), 7.59–7.57 (m, 2H), 7.49
(td, 1H, J = 7.8, 1.5 Hz), 7.41–7.34 (m, 4H), 4.43 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2
1
3
1
Hz); C{ H} NMR (75 MHz, CDCl
3
) δ 166.4, 134.0, 132.2, 131.7, 131.5, 130.4, 128.4,
+
128.3, 127.9, 123.5, 123.3, 94.2, 88.2, 61.2, 14.3; HRMS (ESI-TOF) m/z: [M + H] calcd for
C
17
H
15
O
2
251.1067; found 251.1062.
Isopropyl 2-(phenylethynyl)benzoate (1ai-Pr): Yield 324.1 mg (99%, yellow oil); IR (neat):
–
1 1
υ
3
max 2980, 2218, 1708, 1493, 1289, 1250, 1105, 1072, 753 cm ; H NMR (300 MHz, CDCl )
ACS Paragon Plus Environment