Substrate-Dependent Mechanistic Divergence in Decarboxylative Heck Reaction at Room Temperature

Article abstract of DOI:10.1021/acs.joc.6b00100

We report herein a Pd(II)-catalyzed Heck-type coupling between arene carboxylic acids and alkenes at room temperature. Mechanistically, the reaction proceeds in two distinct pathways where electron-rich substrates undergo a palladium(II)-catalyzed decarboxylation and electron-deficient substrates proceed through silver(I)-assisted decarboxylation. Dimethyl sulfoxide (DMSO) or sulfide ligands have positive and negative roles in the reaction outcome, respectively. The present protocol is combined for the peptide modification under mild reaction conditions.

Full text of DOI:10.1021/acs.joc.6b00100

Subscriber access provided by ORTA DOGU TEKNIK UNIVERSITESI KUTUPHANESI
Article
Substrate-Dependent Mechanistic Divergence in
Decarboxylative Heck Reaction at Room Temperature
Asik Hossian, Samir Kumar Bhunia, and Ranjan Jana
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00100 • Publication Date (Web): 19 Feb 2016
Downloaded from http://pubs.acs.org on February 20, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
Substrate-Dependent Mechanistic Divergence in Decarboxylative Heck
7
8
9
Reaction at Room Temperature
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Asik Hossian, Samir Kumar Bhunia, and Ranjan Jana*
Organic and Medicinal Chemistry Division, CSIRꢀIndian Institute of Chemical Biology,
4 Raja S. C. Mullick Road, Jadavpur, Kolkataꢀ700032, West Bengal, India
Academy of Scientific and Innovative Research, Kolkata
Fax: (+91) 33 2473 5197; Eꢀmail: rjana@iicb.res.in
Abstract: We report herein, a Pd(II)ꢀcatalyzed Heckꢀtype coupling between arene carboxylic acids and
alkenes at room temperature. Mechanistically, the reaction proceeds in two distinct pathways where
electronꢀrich substrates undergo a palladium(II)ꢀcatalyzed decarboxylation and electronꢀdeficient
substrates proceed through silver(I)ꢀassisted decarboxylation. Dimethylsulfoxide (DMSO) or sulfide
ligands have positive and negative roles in the reaction outcome respectively. The present protocol is
combined for the peptide modification under mild reaction conditions.
INTRODUCTION
The decarboxylative crossꢀcoupling of arene carboxylic acids with olefins and aryl electrophiles
provides an attractive approach for the alkene functionalization and biaryl synthesis.1 Inexpensive and
readily available carboxylic acid as nucleophilic coupling partner is a userꢀfriendly alternative to the air
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 47
1
2
3
4
5
6
7
8
9
and moisture sensitive organometallic reagents. In a seminal report in 2002, Myers and coworkers
reported a decarboxylative Heckꢀtype olefination of arene carboxylic acids.2 However, one of the major
pitfalls in decarboxylative crossꢀcoupling is the requirement of high reaction temperature (120ꢀ190 oC)
which restricts its application in the synthesis of complex molecular frameworks. Owing to the
prevalence of stilbenes in numerous natural product, bioactive molecules and high tech materials
(Figure 1),3 we were particularly interested to the development of decarboxylative Heckꢀtype coupling
at room temperature.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Representative example of some important stilbenes
Although, palladiumꢀcatalyzed decarboxylative coupling of nitroalkanes4 and αꢀketocarboxylic acids5
at room temperature is known, there is no report of decarboxylative crossꢀcoupling of arene
carboxylates at room temperature. We report here for the first time a palladiumꢀcatalyzed
decarboxylative Heckꢀtype coupling at room temperature (Scheme 1). We also report the substrateꢀ
dependent mechanistic variation and distinct role of dimethylsulfoxide/sulfide ligands in the present
transformation.
Scheme 1. Decarboxylative Heck-arylation with olefins
2
ACS Paragon Plus Environment

Page 3 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RESULTS AND DISCUSSION
From literature it was evident that o,o’ꢀdisubstitution facilitates carbon dioxide extrusion.6 In addition,
from our previous experience with the decarboxylative allylation of orthoꢀ nitrobenzoic acids, we
realized that the incipient anion which is generated after decarboxylation needs to be stabilized for
further crossꢀcouplings.7 Thus we rationalized that either 2,6ꢀ dimethoxy benzoic acid or
pentafluorobenzoic acid could be model substrates to study room temperature decarboxylative crossꢀ
coupling which will be a major advancement in this field.
Initially, we started screening for decarboxylative Heck reaction between 2,6ꢀdimethoxybenzoic acid
and styrene under the Myers’s original conditions. But a trace amount of corresponding Heck product
was isolated at room temperature. However, a good yield of the coupling product was isolated after 36 h
stirring. In search for alternative oxidants to stoichiometric silver carbonate, 1,4ꢀbenzoquinone (BQ)
was found to be suitable.8 Finally, an excellent yield of the stilbene product was obtained after stirring
the reaction mixture for 36 hours at room temperature with 10 mol % palladium catalyst loading and 2.0
equiv of 1,4ꢀbenzoquinone.
Being encouraged, several alkene partners were examined. A wide variety of styrenes having electronꢀ
withdrawing and electronꢀdonating substituents underwent decarboxylative coupling providing high to
excellent yields (Scheme 2). Fluoroꢀ, chloroꢀ, bromoꢀ, (3cꢀ3e, 3ae, Scheme 2) and remarkably acetoxyꢀ
(3g, 3af, Scheme 2) groups were intact under the reaction conditions demonstrating the mild nature of
this present protocol. Besides styrenes, activated alkenes such as acrylonitrile, (3n, Scheme 2) acrylates
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 47
1
2
3
4
5
6
7
8
9
(3oꢀ3r, 3ag, Scheme 2) also provided the corresponding crossꢀcoupling products. Interestingly,
unactivated allylbenzenes (3sꢀ3u, Scheme 2), allyl acetate (3v, Scheme 2), allyl malonate (3x, 3ah,
Scheme 2), and unactivated terminal alkene (3y, Scheme2) also afforded the corresponding coupling
products in good to moderate yields and good styrenyl selective products under slightly higher catalyst
loading. The Heck coupling with an allyl alcohol (3w, Scheme 2) provided the corresponding ketone
product via selective βꢀhydride elimination in moderate yield.6b Remarkably, 1,4ꢀdivinylbenzene
provided the double crossꢀcoupling product in one stroke (3m, Scheme 2). 2,6ꢀDiethoxyꢀ (3z, Scheme
2) and 2,6ꢀdibenzyloxy (3aa, Scheme 2) benzoic acid also provided the corresponding coupling
products in excellent yields. However, benzoic acid, mesitylenecarboxylic acid, 2ꢀmethoxy benzoic
acid, and heteroaryl carboxylic acids such as pyridineꢀ2ꢀcarboxylic acid, and benzofuranꢀ2ꢀcarboxylic
acid did not furnish any desired product. It was found that o,oꢀdialkoxy substitution is essential for
decarboxylative coupling at room temperature presumably due to coordination between oxygen and
arylpalladium species.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Substrate scope with electron-rich carboxylic acidsa,b,c
4
ACS Paragon Plus Environment

Page 5 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
OR
O
OR
Pd(TFA)2 (10 mol %)
R3
R3
OH
BQ (2.0 equiv)
5% DMSO-DMF
25 oC, 36 h
+
R2
OR
R2
R1
OR
R1
1
2
3
1 equiv
1.5 equiv
9
Ar = 2,6-dimethoxybenzene
R
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ar
Ar
NO2
Ar
Ar
O
3a
3b
3c
3d
3e
: R = H, 94%
3h
3i
: 93%
: 84%
t
: R = Bu, 94%
F
F
: R = F, 87%
: R = Cl, 82%
: R = Br, 74%
: R = OMe, 60%
F
F
Ar
F
3f
3g
: R = OAc, 95%
3j
: 86%
3k
: 85%
Ar
CN
Ar
Ar
Ar
Ar
OMe
3n
: 64%
3l
: 76%
3m
: 72%
O
(E/Z = 4:3)
R
O
OMe
Ar
Ar
OR
d
3o
3p
3q
3r
3s
3t
: R = Me, 81%
: R = nBu, 74%
: R = Ph, 73%
: 40%
O
: R = H, 55% , (l/b = 50:1)
d
: R = F, 57% , (l/b = 49:1)
: R = OMe, 42%d (l/b = 49:1)
3u
O
Ar
OAc
Ar
OEt
Ar
O
OEt
d
e
3v
3w
3x
OR
: 67 % , (l/b = 30:1)
: 38%
OMe
: 65%d (l/b = 25:1)
O
O
Ar
OR
3z
: R = Et, 90%
d
3aa
: R = Bn, 75%
3y
: 40% , (l/b = 20:1)
Ar' = 2,4,6-trimethoxybenzene
R
Ar'
3ad
Ar'
Cl
Ar'
CH3
3ab
3ac
3ae: 91%
: R = H, 93%
: R = Ph, 82%
: 90%
O
OAc
O
Ar'
OEt
Ar'
OnBu
Ar'
OMe
O
d
OEt
3af
3ag
: 70%
: 85%
3ah
: 62% , (l/b = 12:1)
aConditions: The reaction was carried out in 0.2 mmol scale, 0.06 M. bYield refer to here is the average
of at least two experiments. cUnless otherwise stated E/Z ratio of the Heck products are >20:1 as
determined by 1H NMR. d20 mol % Pd(TFA)2 and 3.0 equiv BQ were used. ereaction time 48 h.
Next we turned our attention to the pentafluoroarenes as they exhibit distinct chemical and physical
properties to their hydrocarbon counterpart.9 Also an increasing use of perfluorinated compounds in
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 47
1
2
3
4
5
6
7
8
9
material science, biomedical and bioanalytical research, defense, refrigeration, and domestic appliances
has been observed.10 Therefore, introduction of perfluorinated moiety into the organic backbone has
become a fascinating field of research in the last years.11 However, the metalꢀcatalyzed crossꢀcoupling
reaction with this highly electronꢀdeficient arenes poses a great challenge, due to poor coordination with
the metal center and reluctance to undergo crossꢀcoupling. A seminal work of palladiumꢀcatalyzed Heck
coupling between pentafluorohalobenzene (X = I, Br) and styrenes was reported by the Espinet and
Milstein groups.12 Recently, an oxidative Heck coupling between pentafluorobenzene and styrenes were
reported by the Zhang group,13a and a decarboxylative allylation of pentafluorobenzoates was reported
by the Gooβen group at 120 oC and 110 oC respectively.13b Direct oxidative crossꢀcoupling with
perfluoroarenes also an emerging field of research.14
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To examine decarboxylative Heck coupling with electronꢀdeficient substrates, pentafluorobenzoic acid
was employed under the optimized reaction conditions but no product was formed. Since PdII/AgI
combination is essential for the decarboxylative coupling of electronꢀdeficient substrates,15
benzoquinone was replaced by silver carbonate. Still no Heck product was isolated. Surprisingly, the
reaction in pure DMF only provided the Heck product at room temperature. This is in sharp contrast to
the earlier reports where addition of 5% dimethylsulphoxide (DMSO) in dimethylformamide (DMF)
was found to improve the yield at elevated temperature. Finally, the desired Heckꢀproducts were
obtained with 10 mol % Pd(tfa)2 and 2.0 equiv of Ag2CO3 in good yields after 16 h stirring at room
temperature.
With this optimized reaction conditions we explored the substrate scope. A wide variety of substituted
styrenes provided the Heck product in high yields. Besides alkyl substituents, halogens (6bꢀ6d, 6kꢀ6m,
Scheme 3), labile acetoxy (6i, 6t, Scheme 3) and tertꢀbutyldimethylsilyoxy (6j, Scheme 3) groups were
compatible under these mild reaction conditions. The reaction was also reproduced in gram scale in
comparable yield. However, 2,3,4,5ꢀtetrafluoro and 2,6ꢀdifluoro benzoic acids provided the coupling
product at 120 oC (6u, 6v, Scheme 3). Interestingly, the reaction with allylbenzene at 120 oC provided
6
ACS Paragon Plus Environment

Page 7 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the corresponding allylation product in high yield and selectivity (6w, Scheme 3). Activated alkenes
such as methyl acrylate afforded only a trace amount of Heck product under the same reaction
conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Substrate scope with perfluorobenzoic acidsa,b,c
aConditions: The reaction was carried out in 0.2 mmol scale, 0.06 M. bYield refer to here is the average
of at least two experiments. cE/Z ratio of the Heck products are >20:1 as determined by 1H NMR. d120
oC was used. e20 mol % Pd(TFA)2, 3.0 equiv Ag2CO3 and 5% DMSOꢀDMF were used, reaction time 4
h.
REACTION MECHANISM
In their report, the Myers group applied a general reaction conditions for electronꢀrich and electronꢀ
deficient carboxylic acids. In addition, experimental and theoretical mechanistic investigation was
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 47
1
2
3
4
5
6
7
8
9
performed exclusively based on the electronꢀrich substrates.16 In their study with catalytic and
stoichiometric palladium(II)trifluoroacetate, it was observed that decarboxylation occurs by palladium
salt where silver salt acts as an oxidant for catalytic turnover.16b However, the mechanism for electronꢀ
deficient substrate was illusive. In this present study, we have also observed that electronꢀrich 2,6ꢀ
dimethoxybenzoic acid undergoes decarboxylative Heck reaction by a catalytic amount of palladium(II)
bistrifluoroacetate where silver(I) carbonate was replaced by benzoquinone for practical applications. A
stoichiometric palladium salt also reproduced the same result in the absence of benzoquinone (Scheme
4a). Additionally, a control experiment suggests that even a superstoichiometric amount of silver(I)
carbonate (2 equiv) did not furnish decarboxylation of the 2,6ꢀdimethoxybenzoic acid in the absence of
palladium at room temperature (Scheme 4b). However, exclusive decarboxylative protonation product
was observed by the Larrosa group with 10 mol % Silver(I) carbonate at 120 oC.17 In sharp contrast, in
the absence of silver salt the reaction with electronꢀdeficient pentafluorobenzoic acid did not proceed
even with stoichiometric amount of palladium(II) bistrifluoroacetate (Scheme 4c). However, either
stoichiometric (2 equiv) or a catalytic amount (20 mol %) of silver(I) carbonate resulted in
decarboxylative protonation product exclusively (Scheme 4d). Additionally, a catalytic amount of
silver(I) carbonate (20 mol %), palladium(II) bistrifluoroacetate (10 mol%), and benzoquinone (2.0
equiv) afforded the corresponding Heck product from the pentafluorobenzoic acid and styrene albeit in
low yield (35%) (Scheme 4e). Therefore, electronꢀdeficient substrates may follow a distinct pathway for
the decarboxylative Heck reaction from electronꢀrich substrates at room temperature. A similar
observation was also observed by the Su group where 2,4ꢀdimethoxybenzoic acid underwent
decarboxylative protonation with stoichiometric palladium(II)trifluoroacetate at 80 oC but 2ꢀ
nitrobenzoic acid was unreactive. On the other hand, electronꢀdeficient 2ꢀnitrobenzoic acid afforded
decarboxylative protonation exclusively with superstoichiometric amount of silver(I) carbonate (3.0
equiv) only. Ultimately, a Pd/Ag bimetallic system was applied for the Cꢀ3 selective arylation of indoles
with electronꢀdeficient nitrobenzoic acids.15,18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
ACS Paragon Plus Environment

Page 9 of 47
The Journal of Organic Chemistry
1
2
3
4
Scheme 4. Control Experiments
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Interestingly, in the earlier reports dimethylsulfoxide (DMSO) or other sulfide ligands exhibited a
prominent role in decarboxylative, direct alkenylation or allylic CꢀH activations where addition of 5%
DMSO as a cosolvent was found to improve yields and catalytic efficiency.2,16,19 From NMR and crystal
structure studies, the Myers group has also shown that DMSO acts as a ligand on the arylpalladium
species in decarboxylative Heckꢀtype coupling.16b In sharp contrast, for the first time we have observed
that DMSO or sulfide ligand exhibit a negative role in the decarboxylative alkenylation reaction
between pentafluorobenzoic acid and styrene at room temperature. A careful study revealed that the
yield of the alkenylation product was decreased successively with the increase of DMSO (Figure 2)
with respect to the pentafluorobenzoic acid. In lieu of pure DMF (Scheme 4d), 5% DMSOꢀDMF also
furnished the decarboxylative protonation product exclusively suggesting that DMSO has no role in
siverꢀmediated decarboxylation. Therefore, DMSO may act as a ligand on the palladium and influence
negatively for the subsequent crossꢀcoupling processes with electronꢀdeficient carboxylic acids. The
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 47
1
2
3
4
5
6
7
8
9
same trend was also observed with phenyl methyl sulfide. Although, the exact reason for this negative
effect of DMSO is not clear at this moment but this room temperature decarboxylation will leads to the
development of new crossꢀcoupling reactions under mild conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Negative role of sulfoxide or sulfide ligand in the heck reaction between pentafluorobenzoic
acid and styrene at room temperature
Based on earlier reports and the present study it is speculated that depending of the electronic nature
of the carboxylic acids a mechanistic divergence is observed in the decarboxylative Heck coupling
reaction. The electronꢀrich substrates may follow a palladiumꢀcatalyzed decarboxylation where
dimethylsulfoxide acts as a ligand and benzoquinone plays as an oxidant for catalytic turnover as shown
in path a, Scheme 5.1h Whereas, pentafluorobenzoic acid may undergo a silverꢀassisted decarboxylation
which forms a arylpalladium species after transmetalation as depicted in path b, Scheme 5.
Subsequently, the arylpalladium species undergoes migratory alkene insertion and βꢀhydride elimination
to provide the Heck product and palladium(0). Finally, the palladium(0) is oxidized either by silver(I)
salt or benzoquinone in path a and path b respectively to complete the catalytic cycle.
Scheme 5. Plausible Mechanism
10
ACS Paragon Plus Environment

Page 11 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Ar CO2H
PdII
AgI
AgI
R
Ar
path a Pd(0)
path b
BQ
-hydride
elimination
Ar CO2Ag
PdII
R
9
CO2
Ar
PdII
Ar CO2Pd
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ar Ag
alkene
insertion
CO2
PdII
transmetalation
R
Ar Pd
Next we turned our attention to utilize the decarboxylative Heck product for further useful
transformations. Under basic conditions, the pentafluoroarene moiety, 6a undergoes an activated
aromatic nucleophilic substitution (SNAr) with indole selectively at the paraꢀposition to afford (7,
Scheme 6). The remaining fluorenes are further substituted by excess pyrazoles to provide (8, Scheme
6).20 Development of novel synthetic methods for the postsynthetic modification of peptide is an
attractive research field.21 In this vein, we have applied the decarboxylative Heck product for the
arylation with cysteine. To demonstrate with the sulfur nucleophiles, the Heck product 6a was reacted
with benzyl mercaptan to afford (9, Scheme 6) in excellent yield. Similarly, it also underwent activated
aromatic nucleophilic substitution (SNAr) with the protected cysteine selectively at the paraꢀposition to
provide (10, Scheme 6).
Scheme 6. Product derivatization
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 47
1
2
3
4
5
6
7
8
F
F
Ph
tBuONa (1.1 equiv)
DMA, 0 oC-rt, 1 h
6a
+
N
F
N
H
F
1 equiv
7
: 85%
9
N
N
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
tBuONa (1.1 equiv)
DMA, 0 oC-rt, 1 h
7
+
N
N
N
N
N
H
N
5 equiv
8
: 98%
F
F
S
Ph
Tris (12 equiv)
DMF, rt, 12 h
6a
+
HS
Ph
Ph
F
1.2 equiv
F
9
: 90 %
F
MeO2C
HS
NHBoc
F
Ph
Tris 2.0 equiv
DMF, RT
4.5 h
6a
+
MeO2C
S
F
1 equiv
NHBoc
F
10
: 84 %
CONCLUSION
In conclusion, we have developed a decarboxylative Heckꢀtype coupling between arene carboxylic
acids and alkenes at room temperature. A substrateꢀdependent mechanistic divergence was observed
where electronꢀrich arene carboxylic acids undergo palladiumꢀcatalyzed decarboxylation and electronꢀ
deficient arene carboxylic acids undergo silverꢀassisted decarboxylation. Similarly, dimethylsulfoxide
or other sulfide ligands exhibit positive and negative roles respectively in the present transformation.
The pentafluoroarene moiety obtained from the crossꢀcoupling was further derivatized via activated
aromatic nucleophilic substitution (SNAr) with nitrogen and sulfur nucleophiles. Therefore, this room
temperature reaction sequence is useful for peptide modification under mild reaction conditions.
EXPERIMENTAL SECTION
General Information
Melting points were determined in open endꢀcapillary tubes and are uncorrected. TLC was performed
on silica gel plates (Merck silica gel 60, f254), and the spots were visualized with UV light (254 and
365 nm) and KMnO4 stain. H and 13C{1H} NMR spectra were recorded in CDCl3 using TMS as the
1
12
ACS Paragon Plus Environment

Page 13 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
internal standard. The 19F NMR spectra were recorded in CDCl3 solvent using hexafluorobenzene as the
internal standard. HRMS (m/z) were measured using EI (magnetic sector, positive ion) and ESI (Qꢀ
TOF, positive ion) techniques. Infrared (IR) spectra were recorded on Fourier transform infrared
spectroscopy; only intense peaks were reported.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Experimental Procedure for the Decarboxylative Heck Reaction between Electron-rich
Carboxylic Acids and Alkenes.
To an ovenꢀdried 15 mL sealed tube, a mixture of carboxylic acids (0.20 mmol, 1.0 equiv), palladium
(II)trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv) and 1,4ꢀbenzoquinone (43 mg, 0.4 mmol, 2.0 equiv)
was taken. Then dry DMF (3.0 mL) and DMSO (0.15 mL) were added to it. After purging the reaction
vessel with nitrogen, the corresponding alkene (0.30 mmol, 1.5 equiv) was added to the reaction
mixture via microliter syringe and the vessel was sealed with a screw cap. The reaction mixture was
allowed to stir for 36 h at room temperature. After completion (as detected by TLC), the reaction
mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was
washed with aqueous NaOH solution (2N, 10 mL), water (10 mL), and brine solution (10 mL), dried
over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was
purified by column chromatography using ethyl acetate/hexane as eluent to afford the desired product.
1-(2,6-Dimethoxystyryl)benzene, 3a, Scheme 2.22 The same general procedure was followed
by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), styrene (35 µL, 0.3 mmol, 1.5
equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀbenzoquinone (43 mg,
0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 96:4 hexane/ethyl acetate) afforded
1
the desired product as a colourless oil, (45 mg, 94%). H NMR (300 MHz, CDCl3): δ 7.61 (d, J = 6.8
Hz, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 16.5 Hz, 1H), 7.37 (t, J = 7.2 Hz, 2H), 7.24 (t, J = 7.5 Hz,
1H), 7.19 (t, J = 8.4 Hz, 1H), 6.62 (d, J = 8.4 Hz, 2H), 3.92 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3): δ
158.5, 139.2, 132.2, 128.4, 128.0, 126.8, 126.3, 119.8, 114.6, 103.9, 55.7; IR (neat): υmax 2934, 1584,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 47
1
2
3
4
5
6
1470, 1248, 1106, 976, 749 cmꢀ1; HRMS (EI, m/z) calcd. for C16H16O2 [M]+: 240.1150; found:
240.1157.
7
8
9
1-(2,6-Dimethoxystyryl)-4-tert-butylbenzene, 3b, Scheme 2. The same general procedure
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀtertꢀbutylstyrene
(55 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 96:4
1
hexane/ethyl acetate) afforded the desired product as a white solid, (56 mg, 94%), mp 98ꢀ100 ºC. H
NMR (300 MHz, CDCl3): δ 7.54 (d, J = 16.8 Hz, 1H), 7.42ꢀ7.48 (m, 3H), 7.35 (d, J = 8.4 Hz, 2H), 7.14
(t, J = 8.4 Hz, 1H), 6.58 (d, J = 8.1 Hz, 2H), 3.87 (s, 6H), 1.33 (s, 9H); 13C{1H} NMR (75 MHz,
CDCl3): δ 158.6, 149.9, 136.6, 132.2, 127.8, 126.1, 125.4, 119.2, 115.1, 104.0, 55.8, 34.5, 31.3; IR
(neat): υmax 2958, 1581, 1470, 1252, 1108, 770 cmꢀ1; HRMS (ESI, m/z) calcd. for C20H24O2Na [M +
Na]+: 319.1674; found: 319.1694.
1-(2,6-Dimethoxystyryl)-4-fluorobenzene, 3c, Scheme 2. The same general procedure was
followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀfluorostyrene (36 µL,
0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 96:4
1
hexane/ethyl acetate) afforded the desired product as a colourless oil, (45 mg, 87%). H NMR (600
MHz, CDCl3): δ 7.57 (d, J = 16.8 Hz, 1H), 7.51ꢀ7.54 (m, 2H), 7.40 (d, J = 16.8 Hz, 1H), 7.20 (t, J = 8.4
Hz, 1H), 7.05 (t, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 3.92 (s, 6H); 13C{1H} NMR (150 MHz,
CDCl3): δ 162.0 (d, J = 244.5 Hz), 158.6, 135.4 (d, J = 3.0 Hz), 131.1, 128.1, 127.8 (d, J = 7.5 Hz),
119.6 (d, J = 1.5 Hz), 115.3 (d, J = 2.1 Hz), 114.6, 104.0, 55.8; 19F NMR (470 MHz, CDCl3): δ ꢀ119.0
(s, 1F); IR (neat): υmax 2935, 1590, 1506, 1470, 1246, 1106, 775 cmꢀ1; HRMS (ESI, m/z) calcd. for
C16H15FO2Na [M + Na]+: 281.0954; found: 281.0929.
14
ACS Paragon Plus Environment

Page 15 of 47
The Journal of Organic Chemistry
1
2
3
4
5
1-(2,6-Dimethoxystyryl)-4-chlorobenzene, 3d, Scheme 2. The same general procedure was
6
7
8
9
followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀchlorostyrene (38 µL,
0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 96:4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
hexane/ethyl acetate) afforded the desired product as a colourless oil, (45 mg, 82%). H NMR (300
MHz, CDCl3): δ 7.54 (d, J = 16.8 Hz, 1H), 7.41ꢀ7.48 (m, 3H), 7.30 (d, J = 8.4 Hz, 2H), 7.18 (t, J = 8.1
Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 3.90 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3): δ 158.6, 137.8, 132.4,
130.9, 128.6, 128.4, 127.6, 120.5, 114.4, 103.9, 55.8; IR (neat): υmax 2935, 1585, 1484, 1249, 1109, 975,
774 cmꢀ1; HRMS (ESI, m/z) calcd. for C16H15ClO2Na [M + Na]+: 297.0658; found: 297.0681.
1-(2,6-Dimethoxystyryl)-4-bromobenzene, 3e, Scheme 2. The same general procedure was
followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀbromostyrene (40 µL,
0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 96:4
1
hexane/ethyl acetate) afforded the desired product as a colourless oil, (47 mg, 74%). H NMR (600
MHz, CDCl3): δ 7.53 (d, J = 16.8 Hz, 1H), 7.46ꢀ7.48 (m, 3H), 7.42 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 8.4
Hz, 1H), 6.61 (d, J = 8.4 Hz, 2H), 3.91 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3): δ 158.6, 138.3,
131.5, 130.9, 128.4, 127.9, 120.6, 120.5, 114.4, 103.9, 55.8; IR (neat): υmax 2935, 1584, 1475, 1249,
1106, 772 cmꢀ1; HRMS (ESI, m/z) calcd. for C16H15BrO2Na [M + Na]+: 341.0153; found: 341.0155.
2-(4-Methoxystyryl)-1,3-dimethoxybenzene, 3f, Scheme 2.23 The same general procedure
was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀvinylanisole (40
µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 95:5
1
hexane/ethyl acetate) afforded the desired product as a white solid, (32 mg, 60%), mp 71ꢀ73 ºC. H
NMR (300 MHz, CDCl3): δ 7.54 (d, J = 16.5 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 16.5 Hz,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 47
1
2
3
4
5
6
7
8
9
1H), 7.16 (t, J = 8.4 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 3.90 (s, 6H), 3.84 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3): δ 158.8, 158.4, 132.0, 131.8, 127.6, 127.5, 117.8, 114.9, 113.8,
103.9, 55.7, 55.2; IR (neat): υmax 2937, 1601, 1581, 1469, 1249, 1106, 1033, 773 cmꢀ1; HRMS (EI, m/z)
calcd. for C17H18O3 [M]+: 270.1256; found: 270.1257.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(2,6-Dimethoxystyryl)phenyl acetate, 3g, Scheme 2. The same general procedure was
followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀacetoxystyrene (46 µL,
0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 95:5
1
hexane/ethyl acetate) afforded the desired product as a colourless oil, (57 mg, 95%). H NMR (300
MHz, CDCl3): δ 7.54ꢀ7.60 (m, 3H), 7.42 (d, J = 16.5 Hz, 1H), 7.19 (t, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4
Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 3.91 (s, 6H), 2.32 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 171.3,
160.1, 151.3, 138.9, 133.0, 129.9, 129.0, 123.3, 122.0, 116.3, 105.7, 57.5, 22.9; IR (neat): υmax 2937,
1760, 1584, 1504, 1195, 1105, 772 cmꢀ1; HRMS (ESI, m/z) calcd. for C18H18O4Na [M + Na]+:
321.1103; found: 321.1115.
1-(2,6-Dimethoxystyryl)-3-nitrobenzene, 3h, Scheme 2. The same general procedure was
followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 3ꢀnitrostyrene (42 µL,
0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv.). Column chromatography (SiO2, eluting with 95:5
1
hexane/ethyl acetate) afforded the desired product as a yellow solid, (53 mg, 93%), mp 116ꢀ118 ºC. H
NMR (600 MHz, CDCl3): δ 8.37 (s, 1H), 8.04ꢀ8.06 (m, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.59ꢀ7.66 (m,
2H), 7.49 (t, J = 8.4 Hz, 1H), 7.23 (t, J = 8.4 Hz, 1H), 6.62 (d, J = 8.4 Hz, 2H), 3.93 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3): δ 158.8, 148.6, 141.2, 132.0, 129.6, 129.2, 129.1, 122.9, 121.3, 120.9, 113.7,
103.9, 55.8; IR (neat): υmax 1527, 1473, 1343, 1107, 737 cmꢀ1; HRMS (EI, m/z) calcd. for C16H15NO4
[M]+: 285.1001; found: 285.1013.
16
ACS Paragon Plus Environment

Page 17 of 47
The Journal of Organic Chemistry
1
2
3
4
5
(E)-1-(2,6-Dimethoxyphenyl)-2-(3,5-dimethoxyphenyl)ethene, 3i, Scheme 2. The same
6
7
8
9
general procedure was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv),
3,5ꢀdimethoxystyrene (49 mg, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol,
0.1 equiv), and 1,4ꢀbenzoquinone (50 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
with 9:1 hexane/ethyl acetate) afforded the desired product as a colourless oil, (45 mg, 84%). H NMR
(600 MHz, CDCl3): δ 7.53 (d, J = 16.8 Hz, 1H), 7.46 (d, J = 16.8 Hz, 1H), 7.19 (t, J = 8.4 Hz, 1H), 6.73
(d, J = 1.8 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 6.40 (t, J = 2.4 Hz, 1H), 3.91 (s, 6H), 3.86 (s, 6H);
13C{1H} NMR (150 MHz, CDCl3): δ 160.8, 158.6, 141.4, 132.3, 128.2, 120.4, 114.6, 104.5, 104.0, 99.4,
55.8, 55.3; IR (neat): υmax 2937, 2838, 1587, 1472, 1153, 773 cmꢀ1; HRMS (ESI, m/z) calcd. for
C18H20O4Na [M + Na]+: 323.1259; found: 323.1278.
2-(2,6-Dimethoxystyryl)naphthalene, 3j, Scheme 2. The same general procedure was
followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 2ꢀvinylnaphthalene (46
mg, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 96:4
1
hexane/ethyl acetate) afforded the desired product as a white solid, (50 mg, 86%), mp 136ꢀ138 ºC. H
NMR (300 MHz, CDCl3): δ 7.75ꢀ7.87 (m, 6H), 7.62 (d, J = 16.8 Hz, 1H), 7.40ꢀ7.49 (m, 2H), 7.20 (t, J
= 8.4 Hz, 1H), 6.63 (d, J = 8.4 Hz, 2H), 3.94 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3): δ 158.7, 136.9,
133.9, 132.9, 132.4, 128.2, 128.0, 127.96, 127.7, 126.2, 126.1, 125.4, 123.8, 120.4, 114.9, 104.1, 55.8;
IR (neat): υmax 1583, 1470, 1242, 1105, 772 cmꢀ1; HRMS (EI, m/z) calcd. for C20H18O2 [M]+: 290.1307;
found: 290.1310.
1-(2,6-Dimethoxystyryl)-2,3,4,5,6-pentafluorobenzene, 3k, Scheme 2. The same general
procedure was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv),
pentafluorostyrene (42 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1
equiv), and 1,4ꢀbenzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 47
1
2
3
4
5
6
7
8
9
with 96:4 hexane/ethyl acetate) afforded the desired product as a white solid, (56 mg, 85%), mp 146ꢀ
148 ºC. 1H NMR (600 MHz, CDCl3): δ 7.75 (d, J = 17.4 Hz, 1H), 7.47 (d, J = 16.8 Hz, 1H), 7.24 (t, J =
8.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 2H), 3.92 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3): δ 158.9, 144.6
(dm, J = 249.0 Hz), 139.1, (dm, J = 250.5 Hz), 137.7 (dm, J = 247.5 Hz), 129.6, 128.6 (t, J = 9.0 Hz),
116.2, 114.2 (td, J = 13.5 Hz, 4.5 Hz), 113.8, 103.8, 55.8 (d, J = 3.0 Hz); 19F NMR (470 MHz, CDCl3):
δ ꢀ144.6 (dd, J = 26.8 Hz, 8.9 Hz, 2F), ꢀ159.5 (t, J = 26.3 Hz, 1F), ꢀ165.0 (td, J = 26.3 Hz, 8.9 Hz, 2F);
IR (neat): υmax 1585, 1496, 1245, 1108, 1000, 774 cmꢀ1; HRMS (EI, m/z) calcd. for C16H11F5O2 [M]+:
330.0679; found: 330.0665.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(2-Methoxystyryl)-1,3-dimethoxybenzene, 3l, Scheme 2. The same general procedure
was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 2ꢀvinylanisole (40
µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 96:4
1
hexane/ethyl acetate) afforded the desired product as a white solid, (41 mg, 76%), mp 66ꢀ68 ºC. H
NMR (300 MHz, CDCl3): δ 7.87 (d, J = 16.8 Hz, 1H), 7.64 (dd, J = 7.5 Hz, 0.9 Hz, 1H), 7.39 (d, J =
16.8 Hz, 1H), 7.11ꢀ7.25 (m, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.4 Hz,
2H), 3.88 (s, 6H), 3.86 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 158.6, 156.7, 128.6, 128.0, 127.8,
127.2, 126.2, 120.7, 120.4, 115.4, 110.8, 104.0, 55.8, 55.6; IR (neat): υmax 2935, 2837, 1586, 1468,
1243, 1106, 746 cmꢀ1; HRMS (ESI, m/z) calcd. for C17H18O3Na [M + Na]+: 293.1154; found: 293.1147.
1,4-Bis(2,6-dimethoxystyryl)benzene, 3m, Scheme 2. The same general procedure was
followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 1,4ꢀdivinylbenzene (22
µL, 0.15 mmol, 0.75 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 9:1
hexane/ethyl acetate) afforded the desired product as a yellow solid, (29 mg, 72%), mp 180ꢀ182 ºC. 1H
NMR (600 MHz, CDCl3): δ 7.61 (d, J = 16.2 Hz, 2H), 7.54 (s, 4H), 7.50 (d, J = 16.8 Hz, 2H), 7.18 (t, J
18
ACS Paragon Plus Environment

Page 19 of 47
The Journal of Organic Chemistry
1
2
3
4
13
= 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 4H), 3.93 (s, 12H); C{1H} NMR (150 MHz, CDCl3): δ 158.6,
5
6
7
8
138.0, 132.2, 127.9, 126.5, 119.3, 115.0, 104.0, 55.8; IR (neat): υmax 1582, 1472, 1251, 1105, 770 cmꢀ1;
HRMS (EI, m/z) calcd. for C26H26O4 [M]+: 402.1831; found: 402.1833.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-3-(2,6-Dimethoxyphenyl)acrylonitrile, 3n, Scheme 2. The same general procedure was
followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), acrylonitrile (20 µL, 0.3
mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀbenzoquinone
(43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate)
1
afforded the desired product as a colourless oil, (24 mg, 64%). H NMR (600 MHz, CDCl3): δ 7.82 (d,
J = 16.8 Hz, 1H), 7.28ꢀ7.34 (m, 2H), 7.22 (d, J = 12.0 Hz, 1H), 6.59 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.4
Hz, 2H), 6.42 (d, J = 16.8 Hz, 1H), 5.58 (d, J = 12.0 Hz, 1H), 3.89 (s, 12H); 13C{1H} NMR (150 MHz,
CDCl3): δ 158.8, 158.2, 141.4, 141.0, 132.0, 131.6, 120.2, 117.3, 111.9, 111.6, 103.7, 103.6, 99.9, 98.4,
55.8, 55.4; IR (neat): υmax 2936, 2210, 1696, 1601, 1475, 1249, 1112, 777 cmꢀ1; HRMS (ESI, m/z)
calcd. for C11H11NO2Na [M + Na]+: 212.0687; found: 212.0691.
(E)-Methyl 3-(2,6-dimethoxyphenyl)acrylate, 3o, Scheme 2.1h The same general procedure
was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), methyl acrylate (27
µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 9:1
1
hexane/ethyl acetate) afforded the desired product as a white solid, (36 mg, 81%), mp 70ꢀ72 ºC. H
NMR (300 MHz, CDCl3): δ 8.14 (d, J = 16.2 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 6.88 (d, J = 16.2 Hz,
1H), 6.55 (d, J = 8.4 Hz, 2H), 3.87 (s, 6H), 3.79 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 169.0,
160.0, 135.6, 131.2, 120.2, 112.1, 103.6, 55.7, 51.4; IR (neat): υmax 2942, 1703, 1618, 1255, 1161, 1104,
748 cmꢀ1; HRMS (EI, m/z) calcd. for C12H14O4 [M]+: 222.0892; found: 222.0902.
(E)-Butyl 3-(2,6-dimethoxyphenyl)acrylate, 3p, Scheme 2. The same general procedure
was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), butyl acrylate (43
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 47
1
2
3
4
5
6
µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 9:1
7
1
8
9
hexane/ethyl acetate) afforded the desired product as a colourless oil, (39 mg, 74%). H NMR (300
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl3): δ 8.14 (d, J = 16.2 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 6.88 (d, J = 16.5 Hz, 1H), 6.55 (d, J
= 8.4 Hz, 2H), 4.20 (t, J = 6.6 Hz, 2H), 3.88 (s, 6H), 1.64ꢀ1.74 (m, 2H), 1.38ꢀ1.50 (m, 2H), 0.96 (t, J =
7.5 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 168.6, 159.8, 135.2, 131.0, 120.5, 112.1, 103.5, 63.9,
55.6, 30.8, 19.1, 13.7; IR (neat): υmax 2959, 1706, 1623, 1587, 1474, 1255, 1109, 744 cmꢀ1; HRMS (EI,
m/z) calcd. for C15H20O4 [M]+: 264.1362; found: 264.1346.
(E)-Phenyl 3-(2,6-dimethoxyphenyl)acrylate, 3q, Scheme 2. The same general procedure
was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), phenyl acrylate (45
mg, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 9:1
1
hexane/ethyl acetate) afforded the desired product as a white solid, (41.5 mg, 73%), mp 106ꢀ108 ºC. H
NMR (300 MHz, CDCl3): δ 8.36 (d, J = 16.2 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.33 (t, J = 8.4 Hz, 1H),
7.26 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 7.11 (d, J = 16.2 Hz, 1H), 6.61 (d, J = 8.4 Hz, 2H),
3.93 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3): δ 167.0, 160.2, 151.2, 137.4, 131.8, 129.4, 125.5, 121.9,
119.6, 112.1, 103.7, 55.8; IR (neat): υmax 1735, 1619, 1478, 1254, 1131, 738 cmꢀ1; HRMS (ESI, m/z)
calcd. for C17H16O4Na [M + Na]+: 307.0946; found: 307.0957.
(E)-Methyl 3-(2,6-dimethoxyphenyl)-2-methylacrylate, 3r, Scheme 2.24 The same
general procedure was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv),
methyl methacrylate (32 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol,
0.1 equiv), and 1,4ꢀbenzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting
1
with 9:1 hexane/ethyl acetate) afforded the desired product as a colourless oil, (19 mg, 40%). H NMR
(600 MHz, CDCl3): δ 7.54 (s, 1H), 7.28 (t, J = 8.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 2H), 3.83 (s, 6H), 3.81
20
ACS Paragon Plus Environment

Page 21 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(s, 3H), 1.79 (d, J = 1.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 168.7, 157.7, 131.9, 130.9, 129.7,
113.4, 103.5, 55.6, 51.8, 15.2; IR (neat): υmax 2950, 2840, 1710, 1587, 1470, 1253, 1105, 745 cmꢀ1;
HRMS (ESI, m/z) calcd. for C13H16O4Na [M + Na]+: 259.0946; found: 259.0934.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-((E)-3-(2,6-Dimethoxyphenyl)prop-1-enyl)benzene, 3s, Scheme 2. The same general
procedure was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv),
allylbenzene (40 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (13.4 mg, 0.04 mmol, 0.1
equiv), and 1,4ꢀbenzoquinone (65 mg, 0.4 mmol, 3.0 equiv). Column chromatography (SiO2, eluting
1
with 95:5 hexane/ethyl acetate) afforded the desired product as a colourless oil, (28 mg, 55%). H NMR
(600 MHz, CDCl3): δ 7.33 (d, J = 7.2 Hz, 2H), 7.25ꢀ7.28 (m, 2H), 7.13ꢀ7.20 (m, 2H), 7.09 (d, J = 8.4
Hz, 2H), 6.32ꢀ6.41 (m, 2H), 3.85 (s, 6H), 3.58 (d, J = 6.0 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ
158.2, 138.1, 129.4, 129.0, 128.3, 127.1, 126.5, 126.0, 116.5, 103.8, 55.8, 26.4; IR (neat): υmax 2927,
1728, 1593, 1469, 1254, 1110, 729 cmꢀ1; HRMS (ESI, m/z) calcd. for C17H18O2Na [M + Na]+:
277.1204; found: 277.1179.
1-Fluoro-4-((E)-3-(2,6-dimethoxyphenyl)prop-1-enyl)benzene, 3t, Scheme 2. The same
general procedure was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀ
fluoroallylbenzene (41 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (13.4 mg, 0.04 mmol,
0.1 equiv), and 1,4ꢀbenzoquinone (65 mg, 0.4 mmol, 3.0 equiv). Column chromatography (SiO2, eluting
with 95:5 hexane/ethyl acetate) afforded the desired product as a white solid, (31 mg, 57%), mp 68ꢀ70
ºC. 1H NMR (600 MHz, CDCl3): δ 7.28ꢀ7.31 (m, 2H), 7.19 (t, J = 8.4 Hz, 1H), 6.96 (t, J = 8.4 Hz, 2H),
6.60 (d, J = 8.4 Hz, 2H), 6.36 (d, J = 15.6 Hz, 1H), 6.25ꢀ6.30 (m, 1H), 3.86 (s, 6H), 3.58 (d, J = 6.0 Hz,
2H); 13C{1H} NMR (150 MHz, CDCl3): δ 161.7 (d, J = 243.0 Hz), 158.2, 134.2 (d, J = 3.0 Hz), 128.7
(d, J = 3.0 Hz), 128.3, 127.3 (d, J = 7.5 Hz), 127.2, 116.4, 115.1 (d, J = 21.0 Hz), 103.8, 55.8, 26.4; 19F
NMR (470 MHz, CDCl3): δ ꢀ119.6 (s, 1F); IR (neat): υmax 2929, 1592, 1470, 1255, 1107, 839 cmꢀ1;
HRMS (EI, m/z) calcd. for C17H17FO2 [M]+: 272.1213; found: 272.1208.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 47
1
2
3
4
5
2-(4-Methoxycinnamyl)-1,3-dimethoxybenzene, 3u, Scheme 2.8 The same general
6
7
8
9
procedure was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀ
methoxyallylbenzene (46 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (13.4 mg, 0.04
mmol, 0.1 equiv), and 1,4ꢀbenzoquinone (65 mg, 0.4 mmol, 3.0 equiv). Column chromatography (SiO2,
eluting with 95:5 hexane/ethyl acetate) afforded the desired product as a white solid, (24 mg, 42%), mp
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
70ꢀ72 ºC. H NMR (600 MHz, CDCl3): δ 7.26 (d, J = 9.0 Hz, 2H), 7.17 (t, J = 8.4 Hz, 1H), 6.81 (d, J =
8.4 Hz, 2H), 6.58 (d, J = 8.4 Hz, 2H), 6.34 (d, J = 15.6 Hz, 1H), 6.18ꢀ6.23 (m, 1H), 3.85 (s, 6H), 3.79
(s, 3H), 3.55 (d, J = 6.6 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ 158.4, 158.2, 131.1, 128.8,
127.05, 127.02, 126.8, 116.8, 113.7, 103.8, 55.8, 55.2, 26.4; IR (neat): υmax 2930, 1597, 1510, 1469,
1250, 1111, 833 cmꢀ1; HRMS (EI, m/z) calcd. for C18H20O3 [M]+: 284.1412; found: 284.1408.
2,6-Dimethoxycinnamyl acetate, 3v, Scheme 2.8 The same general procedure was followed
by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), allylacetate (33 µL, 0.3 mmol, 1.5
equiv), palladium (II) trifluoroacetate (13.4 mg, 0.04 mmol, 0.1 equiv), and 1,4ꢀbenzoquinone (65 mg,
0.6 mmol, 3.0 equiv). Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded
the desired product as a colourless oil, (32 mg, 67%). 1H NMR (600 MHz, CDCl3): δ 7.18 (t, J = 8.4
Hz, 1H), 6.99 (d, J = 16.2 Hz, 1H), 6.71ꢀ6.76 (m, 1H), 6.56 (d, J = 8.4 Hz, 2H), 4.75 (dd, J = 6.6 Hz,
0.6 Hz, 2H), 3.86 (s, 6H), 2.11 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 171.0, 158.6, 128.6, 126.8,
125.0, 113.3, 103.8, 67.1, 55.7, 21.1; IR (neat): υmax 2938, 1737, 1587, 1472, 1247, 772 cmꢀ1; HRMS
(ESI, m/z) calcd. for C13H16O4Na [M + Na]+: 259.0946; found: 259.0923.
3-(2,6-Dimethoxyphenyl)-1-phenylpropan-1-one, 3w, Scheme 2.6b The same general
procedure was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 1ꢀ
phenylpropꢀ2ꢀenꢀ1ꢀol (40 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol,
0.1 equiv), and 1,4ꢀbenzoquinone (43 mg, 0.4 mmol, 2.0 equiv) except the reaction was run for 48 h.
Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
22
ACS Paragon Plus Environment

Page 23 of 47
The Journal of Organic Chemistry
1
2
3
4
1
white solid, (20.5 mg, 38%), mp 88ꢀ90 ºC. H NMR (600 MHz, CDCl3): δ 8.02 (dd, J = 8.4 Hz, 1.2 Hz,
5
6
7
8
9
2H), 7.54ꢀ7.57 (m, 1H), 7.45ꢀ7.47 (m, 2H), 7.18 (t, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 2H), 3.81 (s,
6H), 3.14ꢀ3.17 (m, 2H), 3.08ꢀ3.11 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ 200.6, 158.2, 137.0,
132.7, 128.4, 128.2, 127.1, 117.4, 103.5, 55.6, 38.3, 18.5; IR (neat): υmax 2937, 1682, 1593, 1471, 1254,
1107, 778, 693 cmꢀ1; HRMS (ESI, m/z) calcd. for C17H18O3Na [M + Na]+: 293.1154; found: 293.1130.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Diethyl 2-(2,6-dimethoxycinnamyl)malonate, 3x, Scheme 2.8 The same general procedure
was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), diethyl 2ꢀ
allylmalonate (60 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (13.4 mg, 0.04 mmol, 0.1
equiv), and 1,4ꢀbenzoquinone (65 mg, 0.6 mmol, 3.0 equiv). Column chromatography (SiO2, eluting
1
with 9:1 hexane/ethyl acetate) afforded the desired product as a colourless oil, (44 mg, 65%). H NMR
(600 MHz, CDCl3): δ 7.12 (t, J = 8.4 Hz, 1H), 6.74 (t, J = 16.2 Hz, 1H), 6.51ꢀ6.58 (m, 3H), 4.19ꢀ4.26
(m, 4H), 3.82 (s, 6H), 3.51 (t, J = 7.8 Hz, 1H), 2.83 (td, J = 7.8 Hz, 1.2 Hz, 2H), 1.28 (t, J = 6.6 Hz,
6H); 13C{1H} NMR (150 MHz, CDCl3): δ 169.1, 158.2, 129.7, 127.7, 123.0, 114.4, 103.9, 61.3, 55.6,
52.5, 34.0, 14.0; IR (neat): υmax 2981, 1732, 1585, 1472, 1251, 1113, 772 cmꢀ1; HRMS (ESI, m/z) calcd.
for C18H24O6Na [M + Na]+: 359.1471; found: 359.1468.
(E)-4-Methoxybenzyl 5-(2,6-dimethoxyphenyl)pent-4-enoate, 3y, Scheme 2. The same
general procedure was followed by using 2,6ꢀdimethoxybenzoic acid (36.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀ
methoxybenzyl pentꢀ4ꢀenoate (66 mg, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (13.4 mg,
0.04 mmol, 0.1 equiv), and 1,4ꢀbenzoquinone (65 mg, 0.6 mmol, 3.0 equiv). Column chromatography
(SiO2, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as colourless oil, (28.5 mg,
1
40%). H NMR (600 MHz, CDCl3): δ 7.31 (d, J = 8.4 Hz, 2H), 7.13 (t, J = 8.4 Hz, 1H), 6.88 (d, J =
8.4 Hz, 2H), 6.70 (d, J = 16.2 Hz, 1H), 6.57ꢀ6.62 (m, 1H), 6.56 (d, J = 8.4 Hz, 2H), 5.08 (s, 2H), 3.83
(s, 6H), 3.82 (s, 3H), 2.58ꢀ2.61 (m, 2H), 2.53ꢀ2.56 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ 173.2,
159.5, 158.2, 132.7, 130.0, 128.2, 127.5, 121.2, 114.6, 113.9, 103.9, 65.9, 55.7, 55.2, 34.5, 30.0; IR
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 47
1
2
3
4
5
6
(neat): υmax 2928, 1732, 1586, 1514, 1469, 1248, 1111, 823 cmꢀ1; HRMS (ESI, m/z) calcd. for
C21H24O5Na [M + Na]+: 379.1521; found: 379.1530.
7
8
9
1-(2,6-Diethoxystyryl)benzene, 3z, Scheme 2. The same general procedure was followed by
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
using 2,6ꢀdiethoxybenzoic acid (42 mg, 0.2 mmol, 1.0 equiv), styrene (35 µL, 0.3 mmol, 1.5 equiv),
palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀbenzoquinone (43 mg, 0.4 mmol,
2.0 equiv). Column chromatography (SiO2, eluting with 95:5 hexane/ethyl acetate) afforded the desired
1
product as a white solid, (48 mg, 90%), mp 55ꢀ57 ºC. H NMR (300 MHz, CDCl3): δ 7.72 (d, J = 16.5
Hz, 1H), 7.50ꢀ7.56 (m, 3H), 7.36 (t, J = 7.5 Hz, 2H), 7.21ꢀ7.26 (m, 1H), 7.13 (t, J = 8.4 Hz, 1H), 6.57
(d, J = 8.4 Hz, 2H), 4.12 (q, J = 6.9 Hz, 4H), 1.51 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (75 MHz, CDCl3):
δ 158.1, 139.5, 132.1, 128.4, 128.0, 126.8, 126.3, 120.2, 114.8, 104.9, 64.2, 14.9; IR (neat): υmax 2978,
1582, 1458, 1247, 1116, 1083, 748 cmꢀ1; HRMS (ESI, m/z) calcd. for C18H20O2Na [M + Na]+:
291.1361; found: 291.1352.
1-((3-(Benzyloxy)-2-styrylphenoxy)methyl)benzene, 3aa, Scheme 2. The same general
procedure was followed by using 2,6ꢀdibenzyloxybenzoic acid (67 mg, 0.2 mmol, 1.0 equiv), styrene
(35 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 95:5
1
hexane/ethyl acetate) afforded the desired product as a white solid, (59 mg, 75%), mp 88ꢀ90 ºC. H
NMR (600 MHz, CDCl3): δ 7.70 (d, J = 16.8 Hz, 1H), 7.62 (d, J = 16.8 Hz, 1H), 7.51 (d, J = 7.8 Hz,
4H), 7.41ꢀ7.43 (m, 6H), 7.36 (t, J = 7.8 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.14
(t, J = 7.8 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 5.19 (s, 4H); 13C{1H} NMR (150 MHz, CDCl3): δ 157.8,
139.2, 137.1, 132.7, 128.5, 128.4, 127.9, 127.8, 127.2, 126.9, 126.3, 119.7, 115.8, 105.9, 70.8; IR
(neat): υmax 2926, 1728, 1582, 1452, 1254, 1104, 741 cmꢀ1; HRMS (ESI, m/z) calcd. for C28H24O2Na [M
+ Na]+: 415.1674; found: 415.1674.
24
ACS Paragon Plus Environment

Page 25 of 47
The Journal of Organic Chemistry
1
2
3
4
5
1,3,5-Trimethoxy-2-styrylbenzene, 3ab, Scheme 2.25 The same general procedure was
6
7
8
9
followed by using 2,4,6ꢀtrimethoxybenzoic acid (42.5 mg, 0.2 mmol, 1.0 equiv), styrene (35 µL, 0.3
mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀbenzoquinone
(43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 9:1 hexane/ethyl acetate)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
afforded the desired product as a colourless oil, (50 mg, 93%). H NMR (600 MHz, CDCl3): δ 7.55 (d,
J = 7.8 Hz, 2H), 7.50 (d, J = 16.2 Hz, 1H), 7.44 (d, J = 16.2 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.22 (t, J
= 7.2 Hz, 1H), 6.20 (s, 2H), 3.91 (s, 6H), 3.86 (s, 3H); C{1H} NMR (150 MHz, CDCl3): δ 160.2,
13
159.5, 139.7, 129.9, 128.4, 126.5, 126.1, 119.8, 108.1, 90.8, 55.8, 55.3; IR (neat): υmax 2938, 1597,
1461, 1328, 1210, 1119, 813 cmꢀ1; HRMS (ESI, m/z) calcd. for C17H18O3Na [M + Na]+: 293.1154;
found: 293.1140.
2-(4-Phenylstyryl)-1,3,5-trimethoxybenzene, 3ac, Scheme 2. The same general procedure
was followed by using 2,4,6ꢀtrimethoxybenzoic acid (42.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀvinylbiphenyl
(54 mg, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and 1,4ꢀ
benzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 9:1
1
hexane/ethyl acetate) afforded the desired product as a white solid, (57 mg, 82%), mp 150ꢀ152 ºC. H
NMR (600 MHz, CDCl3): δ 7.64ꢀ7.66 (m, 2H), 7.59ꢀ7.62 (m, 4H), 7.53 (d, J = 16.8 Hz, 1H), 7.45ꢀ7.49
(m, 3H), 7.35 (t, J = 7.2 Hz, 1H), 6.21 (s, 2H), 3.92 (s, 6H), 3.87 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3): δ 160.3, 159.6, 141.0, 139.1, 138.8, 129.3, 128.7, 127.1, 127.0, 126.8, 126.6, 120.0, 108.2,
90.8, 55.8, 55.3; IR (neat): υmax 1592, 1458, 1326, 1218, 1153, 1119, 766 cmꢀ1; HRMS (ESI, m/z) calcd.
for C23H22O3Na [M + Na]+: 369.1467; found: 369.1467.
2-(2-Methylstyryl)-1,3,5-trimethoxybenzene, 3ad, Scheme 2.26 The same general
procedure was followed by using 2,4,6ꢀtrimethoxybenzoic acid (42.5 mg, 0.2 mmol, 1.0 equiv), 2ꢀ
methylstyrene (39 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1
equiv), and 1,4ꢀbenzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 47
1
2
3
4
with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (51 mg, 90%), mp 86ꢀ88
5
6
1
ºC. H NMR (300 MHz, CDCl3): δ 7.62ꢀ7.69 (m, 2H), 7.24 (d, J = 16.5 Hz, 1H), 7.08ꢀ7.19 (m, 3H),
7
6.17 (s, 2H), 3.87 (s, 6H), 3.84 (s, 3H), 2.39 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 160.2, 159.4,
138.7, 135.3, 130.1, 128.0, 126.5, 126.0, 124.9, 120.8, 108.6, 90.8, 55.8, 55.3, 20.0; IR (neat): υmax
2936, 1586, 1460, 1198, 1118, 809 cmꢀ1; HRMS (ESI, m/z) calcd. for C18H20O3Na [M + Na]+:
307.1310; found: 307.1308.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(3-Chlorostyryl)-1,3,5-trimethoxybenzene, 3ae, Scheme 2.26 The same general
procedure was followed by using 2,4,6ꢀtrimethoxybenzoic acid (42.5 mg, 0.2 mmol, 1.0 equiv), 3ꢀ
chlorostyrene (38 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1
equiv), and 1,4ꢀbenzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting
with 9:1 hexane/ethyl acetate) afforded the desired product as a white solid, (55 mg, 91%), mp 80ꢀ82
1
ºC. H NMR (600 MHz, CDCl3): δ 7.51 (t, J = 1.8 Hz, 1H), 7.42 (d, J = 1.8 Hz, 2H), 7.38 (d, J = 7.8
Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.15ꢀ7.17 (m, 1H), 6.19 (s, 2H), 3.90 (s, 6H), 3.86 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3): δ 160.5, 159.6, 141.7, 134.3, 129.5, 128.2, 126.2, 125.9, 124.3, 121.2, 107.6,
90.7, 55.7, 55.3; IR (neat): υmax 2961, 1586, 1462, 1326, 1220, 1117, 962, 796 cmꢀ1; HRMS (ESI, m/z)
calcd. for C17H17ClO3Na [M + Na]+: 327.0764; found: 327.0783.
4-(2,4,6-Trimethoxystyryl)-2-methoxyphenyl acetate, 3af, Scheme 2. The same general
procedure was followed by using 2,4,6ꢀtrimethoxybenzoic acid (42.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀ
acetoxyꢀ3ꢀmethoxystyrene (57 mg, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02
mmol, 0.1 equiv), and 1,4ꢀbenzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2,
eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a white solid, (61 mg, 85%), mp
1
105ꢀ107 ºC. H NMR (600 MHz, CDCl3): δ 7.43 (d, J = 16.8 Hz, 1H), 7.33 (d, J = 16.2 Hz, 1H), 7.10ꢀ
7.11 (m, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.19 (s, 2H), 3.898 (s, 3H), 3.896 (s, 6H), 3.86 (s, 3H), 2.33 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3): δ 169.2, 160.3, 159.5, 150.9, 138.9, 138.4, 129.3, 122.6, 120.2,
26
ACS Paragon Plus Environment

Page 27 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
118.6, 110.0, 107.9, 90.8, 55.9, 55.8, 55.3, 20.7; IR (neat): υmax 2933, 1761, 1598, 1460, 1118, 817 cmꢀ
1; HRMS (ESI, m/z) calcd. for C20H22O6Na [M + Na]+: 381.1314; found: 381.1336.
7
8
9
(E)-Butyl 3-(2,4,6-trimethoxyphenyl)acrylate, 3ag, Scheme 2.27 The same general
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
procedure was followed by using 2,4,6ꢀtrimethoxybenzoic acid (42.5 mg, 0.2 mmol, 1.0 equiv), butyl
acrylate (43 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv),
and 1,4ꢀbenzoquinone (43 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 8:2
1
hexane/ethyl acetate) afforded the desired product as a white solid, (41 mg, 70%), mp 79ꢀ81 ºC. H
NMR (300 MHz, CDCl3): δ 8.09 (d, J = 16.2 Hz, 1H), 6.75 (d, J = 16.2 Hz, 1H), 6.11 (s, 2H), 4.19 (t, J
= 6.6 Hz, 2H), 3.87 (s, 6H), 3.84 (s, 3H), 1.64ꢀ1.73 (m, 2H), 1.37ꢀ1.50 (m, 2H), 0.96 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3): δ 169.1, 162.6, 161.1, 135.4, 117.4, 105.7, 90.3, 63.8, 55.6, 55.3,
30.9, 19.2, 13.8; IR (neat): υmax 2939, 1699, 1602, 1461, 1156, 1119, 815 cmꢀ1; HRMS (ESI, m/z) calcd.
for C16H22O5Na [M + Na]+: 317.1365; found: 317.1360.
Diethyl 2-(2,4,6-trimethoxycinnamyl)malonate, 3ah, Scheme 2. The same general
procedure was followed by using 2,4,6ꢀtrimethoxybenzoic acid (42.5 mg, 0.2 mmol), diethyl 2ꢀ
allylmalonate (60 µL, 0.3 mmol, 1.5 equiv.), palladium (II) trifluoroacetate (13.4 mg, 0.04 mmol, 0.1
equiv.), and 1,4ꢀbenzoquinone (65 mg, 0.6 mmol, 3.0 equiv.). Column chromatography (SiO2, eluting
1
with 8:2 hexane/ethyl acetate) afforded the desired product as a colourless oil, (45 mg, 62%). H NMR
(600 MHz, CDCl3): δ 6.66 (d, J = 16.2 Hz, 1H), 6.38ꢀ6.43 (m, 1H), 6.12 (s, 2H), 4.18ꢀ4.23 (m, 4H),
3.81 (s, 3H), 3.80 (s, 6H), 3.48 (t, J = 7.8 Hz, 1H), 2.80 (t, J = 7.8 Hz, 2H), 1.27 (t, J = 7.2 Hz, 6H);
13C{1H} NMR (150 MHz, CDCl3): δ 169.2, 159.8, 159.0, 127.2, 122.8, 107.7, 90.6, 61.2, 55.6, 55.2,
52.6, 34.0, 14.0; IR (neat): υmax 2939, 1729, 1604, 1462, 1124, 1036, 814 cmꢀ1; HRMS (ESI, m/z) calcd.
for C19H26O7Na [M + Na]+: 389.1576; found: 389.1563.
General Experimental Procedure for the Decarboxylative Heck Reaction between Electron-
Deficient Carboxylic Acids and Vinyl Arenes.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 47
1
2
3
4
5
6
7
8
9
To an ovenꢀdried 15 mL sealed tube, a mixture of pentafluorobenzoic acid (0.20ꢀ0.24 mmol, 1.0ꢀ1.2
equiv), palladium(II)trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and silver carbonate (110 mg, 0.4
mmol, 2.0 equiv) was taken then dry DMF (3.0 mL) was added to it. After purging with nitrogen, the
corresponding styrenes (0.20ꢀ0.30 mmol, 1.0ꢀ1.5 equiv) were added via microliter syringe and the
vessel was sealed with a screw cap. The reaction mixture was allowed to stir for 16 h at room
temperature. After completion (as detected by TLC), the reaction mixture was poured into water (20
mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water (10 mL x 2)
and brine (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced
pressure. The crude product was purified by column chromatography using ethyl acetate/hexane as
eluent to afford the desired product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1,2,3,4,5-Pentafluoro-6-styrylbenzene, 6a, Scheme 3.19 The same general procedure was
followed by using pentafluorobenzoic acid (42.5 mg, 0.2 mmol, 1.0 equiv), styrene (35 µL, 0.3 mmol,
1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1 equiv), and silver carbonate (110 mg,
0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting with 98:2 hexane/ethyl acetate) afforded
1
the desired product as a white solid, (36 mg, 66%), mp 132ꢀ134 ºC. H NMR (300 MHz, CDCl3): δ 7.53
(d, J = 7.5 Hz, 2H), 7.31ꢀ7.47 (m, 4H), 6.98 (d, J = 16.8 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3): δ
144.8 (dm, J = 248.8 Hz), 139.7 (dm, J = 252.8 Hz), 137.7 (dm, J = 248.2 Hz), 137.1 (td, J = 8.2 Hz,
2.6 Hz), 136.4, 128.9, 128.8, 126.8 112.6 (d, J = 2.4 Hz), 112.4 (td, J = 13.6 Hz, 4.2 Hz); 19F NMR (470
MHz, CDCl3): δ ꢀ146.0 (dd, J = 21.6 Hz, 7.0 Hz, 2F), ꢀ159.8 (t, J = 20.7 Hz, 1F), ꢀ166.2 (td, J = 20.7
Hz, 7.0 Hz, 2F); IR (neat): υmax 1523, 1493, 1000, 959, 754 cmꢀ1; HRMS (EI, m/z) calcd. for C14H7F5
[M]+: 270.0468; found: 270.0448.
1-(4-Fluorostyryl)-2,3,4,5,6-pentafluorobenzene, 6b, Scheme 3.19 The same general
procedure was followed by using pentafluorobenzoic acid (42.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀ
fluorostyrene (36 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1
28
ACS Paragon Plus Environment

Page 29 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
equiv), and silver carbonate (110 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting
with 98:2 hexane/ethyl acetate) afforded the desired product as a white solid, (36 mg, 62%), mp 110ꢀ
7
1
8
112 ºC. H NMR (600 MHz, CDCl3): δ 7.51 (dd, J = 8.4 Hz, 5.4 Hz, 2H), 7.39 (d, J = 16.8 Hz, 1H),
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
7.09 (t, J = 8.4 Hz, 2H), 6.89 (d, J = 16.8 Hz, 1H); C{1H} NMR (150 MHz, CDCl3): δ 163.1 (d, J =
248.0 Hz), 144.8 (dm, J = 249.0 Hz), 139.7 (dm, J = 253.5 Hz), 137.7 (dm, J = 249.0 Hz), 135.9 (td, J =
9.0 Hz, 1.5 Hz), 132.6 (d, J = 3.0 Hz), 128.5 (d, J = 7.5 Hz), 115.9 (d, J = 22.5 Hz), 112.4, 112.2 (td, J =
13.5 Hz, 4.5 Hz); 19F NMR (470 MHz, CDCl3): δ ꢀ115.2 (s, 1F), ꢀ146.1 (dd, J = 21.2 Hz, 7.5 Hz, 2F), ꢀ
159.6 (t, J = 20.7 Hz, 1F), ꢀ166.1 (td, J = 21.2 Hz, 7.5 Hz, 2F); IR (neat): υmax 1519, 1492, 1240, 1003,
958 cmꢀ1; HRMS (EI, m/z) calcd. for C14H6F6 [M]+: 288.0374; found: 288.0365.
1-(4-Chlorostyryl)-2,3,4,5,6-pentafluorobenzene, 6c, Scheme 3. The same general
procedure was followed by using pentafluorobenzoic acid (42.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀ
chlorostyrene (38 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1
equiv), and silver carbonate (110 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting
with 98:2 hexane/ethyl acetate) afforded the desired product as a white solid, (44 mg, 73%), mp 98ꢀ100
1
ºC. H NMR (600 MHz, CDCl3): δ 7.47 (d, J = 8.4 Hz, 2H), 7.37ꢀ7.41 (m, 3H), 6.96 (d, J = 16.8 Hz,
1H); 13C{1H} NMR (150 MHz, CDCl3): δ 144.8 (dm, J = 249.2 Hz), 139.8 (dm, J = 253.5 Hz), 137.8
(dm, J = 249.2 Hz), 135.7 (td, J = 9.0 Hz, 3.0 Hz), 134.9, 134.7, 129.0, 128.0, 113.2 (d, J = 1.5 Hz),
112.0 (td, J = 13.5 Hz, 4.5 Hz); 19F NMR (470 MHz, CDCl3): δ ꢀ142.6 (dd, J = 22.1 Hz, 7.0 Hz, 2F), ꢀ
156.0 (t, J = 20.7 Hz, 1F), ꢀ162.8 (td, J = 20.7 Hz, 6.6 Hz, 2F) ; IR (neat): υmax 1520, 1490, 1004, 958,
811 cmꢀ1; HRMS (EI, m/z) calcd. for C14H6ClF5 [M]+: 304.0078; found: 304.0061.
1-(4-Bromostyryl)-2,3,4,5,6-pentafluorobenzene, 6d, Scheme 3. The same general
procedure was followed by using pentafluorobenzoic acid (42.5 mg, 0.2 mmol, 1.0 equiv), 4ꢀ
bromostyrene (39 µL, 0.3 mmol, 1.5 equiv), palladium (II) trifluoroacetate (6.7 mg, 0.02 mmol, 0.1
equiv), and silver carbonate (110 mg, 0.4 mmol, 2.0 equiv). Column chromatography (SiO2, eluting
29
ACS Paragon Plus Environment