Semireduction of alkynoic acids via a transition metal-free α borylation-protodeborylation sequence

Article abstract of DOI:10.1016/j.tet.2019.02.030

A method for the semi-reduction of alkynoic acids through an α-borylation and subsequent protodeborylation mechanism has been developed. The transition metal-free protocol is achieved through the activation of bis(pinacolato)diboron by an in situ generated carboxylate moiety yielding aryl acrylic acids. Our studies demonstrate an unprecedented dual role for the carboxylate anion that involves the activation of the diboron reagent and a directing effect in the α-borylation.

Full text of DOI:10.1016/j.tet.2019.02.030

Accepted Manuscript
Semireduction of alkynoic acids via a transition metal-free α borylation-
protodeborylation sequence
Astha Verma, R. Justin Grams, Brett P. Rastatter, Webster L. Santos
PII:
S0040-4020(19)30180-2
https://doi.org/10.1016/j.tet.2019.02.030
TET 30153
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 December 2018
Revised Date: 7 February 2019
Accepted Date: 14 February 2019
Please cite this article as: Verma A, Grams RJ, Rastatter BP, Santos WL, Semireduction of alkynoic
acids via a transition metal-free α borylation-protodeborylation sequence, Tetrahedron (2019), doi:
https://doi.org/10.1016/j.tet.2019.02.030.
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Semireduction of alkynoic acids via a
transition metal-free α borylation-
protodeborylation sequence
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Astha Verma, R. Justin Grams, Brett P. Rastatter and Webster L. Santos*
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061 USA

1
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Tetrahedron
journal homepage: www.elsevier.com
Semireduction of alkynoic acids via a transition metal-free α-borylation-
protodeborylation sequence
Astha Verma, R. Justin Grams, Brett P. Rastatter and Webster L. Santos*
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A method for the semi-reduction of alkynoic acids through an α-borylation and subsequent
protodeborylation mechanism has been developed. The transition metal-free protocol is achieved
through the activation of bis(pinacolato)diboron by an in situ generated carboxylate moiety
yielding aryl acrylic acids. Our studies demonstrate an unprecedented dual role for the
carboxylate anion that involves the activation of the diboron reagent and a directing effect in the
α-borylation.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Transition metal-free
Alkynoic acids
Boron
Reduction
Alpha borylation
1. Introduction
Vinyl boronic acids such as β-borylated α,β-unsaturated carbonyl
compounds serve as a versatile building blocks in organic
synthesis to facilitate various transformations such as carbon-
carbon and carbon-heteroatom bond formations.1-9 Advances in
transition metal-catalyzed conjugate addition reactions to
alkynoic acid derivatives provide easy access to borylated α,β-
unsaturated carbonyl compounds with high β-regioselectivity.10-15
However, methods to generate the regioisomeric α-borylated
product adjacent to a carbonyl motif are rare.16-18 Pioneering
work by Lipshutz demonstrated the α-borylation of acetylenic
esters using 3,4-addition of Cu-H followed by transmetalation
with pinacolborane affords the cis hydroboration product
(Scheme 1A).17 Tsuji also reported that Cu(I) catalysis can be
employed to selectively borylate the α- or β-position in acetylenic
substrates by selecting the appropriate borylating agent, e.g.,
pinacolborane or bis(pinacolato)diboron (B2pin2) (Scheme 1B).18
Recent reports have shown that diboron reagents such as B2pin2
form Lewis acid-base complexes in the presence of bases such as
alkoxides.19,20 The activation of the boron-boron bond facilitates
the transfer of the nucleophilic boryl moiety to electron deficient
systems, such as α,β-unsaturated carbonyl compounds, through
conjugate addition leading to β-borylation products.
Scheme 1. Approaches to alpha borylation of alkynoic
acid derivatives.
Due to the paucity of available methods for the formation of α-
borylation product, we became particularly interested in the
transition metal-free synthesis of α-borylated alkenoic acids from
alkynoic acids. We envisioned that the transition metal-free
process outlined in Scheme 1C would yield product 3 as the free
carboxylate, which is supported from prior investigations.21-23
Indeed, the α-borylation of acetylenic carbonyls (1) can be
affected by internal coordination of a carboxylate anion to B2pin2.
We hypothesize that the competition between α- versus β-
borylation is governed by the difference between the five- or six-
membered ring transition state energies affording 3 or 4,
respectively. The expected and kinetically favored 5-membered

2
Tetrahedron
Table 2. Substrate scope for α borylation protodeborylation
ring transition state would proceed through a pseudo 5-exo-dig
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of alkynoic acids.
process similar to mechanistic pathways observed in the
diboration22 and silaboration23 of alkynamides. Surprisingly, the
α-borylated or diborated product was not observed with alkynoic
acids. Instead, cinnamic acid was the major product. This is in
sharp contrast with previous work. For example, Uchiyama
developed a method involving the deprotonation of propargylic
alcohols by butyllithium followed by coordination of B2pin2 and
subsequent borylation to the α- and β-carbon, resulting in trans
diboration across the triple bond.21 A more related effort from the
our group involves the trans diboration of alkynamides by a
Brønsted base mediated complexation between pinBBdan22 or
pinBSiMe2Ph23 to an amide oxyanion resulting in a pseudo-
intramolecular reaction.
Isolated
Ratiob
Entry
1
R
temp, time
65 °C, 24 h
Yield of 6a
6:7
69 (97:3)
60 (63:37)
35 (81:19)
42 (83:17)
–
–
–
–
2
3
4
93 °C, 29 h
65 °C, 24 h
65 °C, 24 h
Herein, we report the first transition metal-free α-borylation-
protodeborylation of alkynoic acids utilizing the carboxylate
group as an internal Lewis base for activation and boryl transfer
to afford semi-reduced alkynoic acid derivatives. Mechanistic
studies suggest an efficient α-borylation process affords a
transient 1,1-boracarboxylate intermediate (3, Scheme 1) that
undergoes facile protodeboration upon acidic workup to generate
arylacrylic acids.
5
6
93 °C, 24 h
65 °C, 24 h
42 (95:5)
–
–
2. Results and Discussion
To develop the optimal reaction conditions, we performed the α-
borylation using 3-phenylpropiolic acid as the model substrate in
toluene using Cs2CO3 as the base and B2pin2 as the boron source.
During optimization, we discovered that crown ether is crucial
for the generation of the naked carboxylate anion for effective
activation of B2pin2. Conversely, in its absence the reaction was
6f
46 (88:12)
Cl
7
8
9
55 °C, 26 h
55 °C, 16 h
55 °C, 24 h
39 (99:1)
36 (98:2)
31 (93:7)
–
4:1
–
Table 1. Optimization of reaction conditions for α-borylation-
protodeborylation of alkynoic acidsa
Base
(equiv)
Cs2CO3
(1.2)
Crown ether
(equiv)
Temp,
time
Yieldb
6a
Entry
7
18-crown-6
(1.2)
10
11
12
65 °C, 18 h
93 °C, 24 h
65 °C, 22 h
30 (86:14)
6 (76:24)
30 (87:13)
–
–
–
1
2
100 °C, 1.5 h
100 °C, 7.5 h
100 °C, 24 h
100 °C, 24 h
100 °C, 3 h
100 °C, 24 h
100 °C, 6 h
65 °C, 24 h
65 °C, 24 h
65 °C, 24 h
65 °C, 24 h
41%
39%
43%
17%
30%
10%
38%
69%d
54%d
55%
38%
17%
K2CO3
(1.2)
18-crown-6
(1.2)
19%
Na2CO3
(1.2)
15-crown-5
(1.2)
3
25%
Li2CO3
(1.2)
12-crown-4
(1.2)
4c
5
–
–
NEt3
–
Reaction conditions: 5 (0.34 mmol), B2pin2 (0.51 mmol), toluene (1.5
mL). a E:Z ratio. bRatio determined from crude 1H NMR.
(1.2)
BuLi
12-crown-4
(1.2)
6
–
sluggish. As shown in Table 1, the reaction was complete in 1.5 h
at 100 °C (entry 1), yielding the α-borylated-protodeborylated 3-
phenylacrylic acid (6a) as the major product in 41% yield, and
decarboxylated α-borylation product (7) as the minor product in
17% yield. The formation of 7 at higher temperature could be
explained on the basis of a higher activation energy barrier for
the decarboxylation of α-borylated 3-phenyl acrylic acid.
Switching the base from Cs2CO3 to K2CO3 or Na2CO3 gave 6 and
7 in comparable yields but required longer reaction times (entries
2 and 3, respectively) possibly due to insolubility of the base in
toluene. Li2CO3 led to an incomplete reaction (entry 4).
Furthermore, the use of organic bases such as triethylamine and
butyl lithium resulted in low yield of 6, although no
decarboxylated borylated product 7 was observed (entries 5-6).
(1.2)
Cs2CO3
(1.2)
18-crown-6
(0.6)
7
22%
–
Cs2CO3
(1.2)
18-crown-6
(1.2)
8
CsOH
(1.2)
18.crown-6
(1.2)
9
–
Cs2CO3
(1.2)
18-crown-6
(1.2)
10e
–
Cs2CO3
18-crown-6
11e
(1.2)
(1.2)
aReaction conditions: 5 (0.34 mmol), B2pin2 (0.51 mmol), solvent 1.5
b
1
c
d
mL. Yield calculated using H NMR. Incomplete reaction. Isolated
yield. e THF was used as solvent. f DMF was used as solvent.

3
Reducing the equivalents of the crown ether did not improve the
yield of protodeborylated product 6 but resulted in longer
reaction time likely due to cesium-carboxylate ion pair formation
potentially hindering the reaction progress (entry 7). Finally,
reducing the temperature to 65 °C chemoselectively resulted in α-
borylation-protodeboration, producing cinnamic acid 6a in good
yield without forming product 7 (entry 8). Switching the base to
CsOH under the same reaction conditions resulted in reduced
yield (entry 9). Likewise, changing the solvent from toluene to
THF or DMF allowed inefficient conversion to the product
(entries 10-11).
conversion to 9. Importantly, the β-borylated 3-phenyl acrylic
1
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acid 9 was stable and was confirmed by H NMR of the crude
reaction mixture. No protodeborylation was observed. In
contrast, when α-borylated methyl 3-phenyl acrylate 10 was
treated with LiOH in THF:H2O, complete protodeborylation
occurred within 4.5
h giving a mixture of methyl 3-
phenylacrylate 11 and 3-phenylacrylic acid 12 in 47% yield. The
rapid formation of 12 suggests the instability of the α borylated-
3-phenylacrylic acid under basic conditions and that
protodeborylation is more facile than decarboxylation.
With the optimized reaction conditions in hand, we examined
the substrate scope for the sequential α-borylation-
protodeborylation of aryl alkynoic acids (Table 2). Temperature
control was crucial to avoid a completing loss of starting material
due to decarboxylation. Sterically encumbered mesityl group was
tolerated and afforded the product 6b in 60% as a mixture of
isomers (entry 2). tert-butyl and n-butyl groups in the para
position were efficient substrates although products 6c-d were
isolated in slightly reduced yields (entries 3-4). We observed that
substrates 5c-d underwent decarboxylation at temperatures
greater than 70 C. Similarly, the incorporation of electron
withdrawing substituents on the aryl ring led to pronounced
decarboxylation of starting material (5f-6i) at higher temperature.
Thus, at lower temperature substrates bearing chloro,
trifluoromethyl, 3,5-difluoro and trifluoromethoxy moieties
afforded the 6f-6i with excellent E:Z ratio. To further investigate
the substrate scope, we subjected enyne 5j under the reaction
conditions and isolated the α, β, δ, γ−conjugated diene 6j in 30%
yield. Unfortunately, the aliphatic substrate 5k resisted α-
borylation-protodeborylation even at higher temperatures, likely
due to steric clash with the pinacol. However, heterocycles such
as thiophene substrate 5l yielded 6l in modest yield. Nonetheless,
the corresponding aryl, heterocyclic, olefinic, and aliphatic
acrylic acids were obtained in good (6a-b) to moderate yields
(6c-l). As shown in Scheme 2, the reaction is amenable to scale-
up as 1 mmol of 3-phenylpropiolic acid afforded 40% cinnamic
acid 6a.
3. Conclusions
In summary, we have developed a transition metal-free
method for the α-borylation and subsequent protodeboration of
alkynoic acids to yield the corresponding semi-reduced products,
3-arylacrylic acids. The protocol affords a mechanistically
distinct process for the net reduction. Our studies demonstrate an
unprecedented dual role for the carboxylate anion that involves
the activation of the diboron reagent and a directing effect in the
α-borylation.
4. Experimental
4.1. General
The reactions were performed using a Schlenk line under an
inert atmosphere of nitrogen. NMR spectra were obtained on
JEOL Eclipse-plus 500 MHz spectrometer at 500 (1H) and 126
(13C) MHz, Unity-plus 400 at 400 (1H) and 101 (13C) MHz, or
Agilent 400-MR 400 MHz spectrometer at 400 (1H) or 100 (13C)
MHz. The chemical shifts are reported in δ (ppm), and coupling
constants are given in Hz. Other dry solvents were purchased
from EMD Millipore and were used as received. Column
chromatography was performed using Silica gel (ZEOprep 60
ECO 40–63 l) was purchased from AIC or SiliCycle. Dry THF
and toluene were obtained from Innovative Technology Pure
Solv-MD solvent purification system.
4.1.1. General Procedure for synthesis of alkynoic
acids
Procedure 4.1.1.1. This procedure was adapted from Linstadt
et al.25 To a solution of alkyne (13.5 mmol) in 40 mL of dry THF
at -78 °C was added n-BuLi (13.5 mmol). The resulting solution
Scheme 2. Scale up of compound 6a.
°
was stirred at -78 C for 30 min. The reaction mixture was
°
warmed to 0 C and the reaction was placed under a balloon of
To determine whether product 6a originated from the
protodeborylation of β- or α-borylated phenyl propiolic acid, we
prepared the starting materials β-boryl-824 and α-boryl-1017
(Scheme 3). As both compounds have the potential to undergo
protodeborylation, we subjected both to basic conditions.
Treatment of 8 with LiOH in THF:H2O for 24 h resulted in 25%
CO2 gas and vigorously stirred for 30 min. Then concentrated
HCl (10 mL), water (10 mL) and Et2O (30 mL) were added. The
aqueous layer was discarded, and the organic layer was extracted
with NaOH (1 M; 3 x 20 mL). The aqueous extracts were
acidified with concentrated HCl, extracted with Et2O (3 x 20
mL), washed with water and brine, dried with anhydrous MgSO4
and concentrated in vacuo. The resulting oil was purified by
column chromatography to afford the desired product.
Procedure 4.1.1.2. This procedure was adapted from Karad et
al.26 To a solution of propiolate (2.12 mmol) in ethanol (15 mL,
0.14 M) was added dropwise while stirring an aqueous sodium
hydroxide solution (9 mL, 1 M). After 2.5 h, the reaction mixture
was diluted with water (15 mL) and was washed with
dichloromethane (3 X 15 mL). The aqueous phase was acidified
with 20% HCl solution and extracted with dichloromethane (3 X
15 mL). The combined extracts were dried over Na2SO4 and
concentrated under reduced pressure to give the propiolic acid.
4.1.2. 3 3-mesitylpropiolic acid (5b)
Scheme 3. Saponification of β borylated 8 and α borylated
10.

4
Tetrahedron
70%, white solid; Synthesized by Procedure 4.1.1.1. 1H
4.1.12. 3-(5-methylthiophen-2-yl)propiolic acid (5l)
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1
NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 6.90 (s, 1H), 2.46 (s,
3H), 2.31 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 159.1, 143.1,
141.4, 128.2, 116.1, 87.81, 87.7, 77.5, 77.2, 76.8, 21.7, 20.9.
90%, off-white solid; Synthesized by Procedure 4.1.1.2. H
NMR (400 MHz, CDCl3) δ 10.25 – 9.71 (brs, 1H), 7.36 – 7.33
(dd, J = 3.72, 0.32 Hz, 1H), 6.73 – 6.69 (dq, J = 3.72, 1.04 Hz,
1H), 2.51 – 2.41 (d, J = 0.64 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 158.5, 147.8, 138.1, 126.3, 116.2, 84.2, 84.1, 15.7.
4.1.3. 3-(4-(tert-butyl)phenyl)propiolic acid (5c)
90%, light yellow solid; Synthesized by Procedure 4.1.1.1.
1H NMR (400 MHz, CDCl3) δ 7.55 – 7.52 (dt, J = 8.72, 1.96 Hz),
7.41 – 7.38 (dt, J =8.72, 1.92 Hz), 1.30 (s, 9H). 13C NMR (101
MHz, CDCl3) δ 158.4, 154.9, 133.2, 125.7, 115.9, 89.7, 79.6,
35.1, 31.0.
4.1.13. General Procedure for the synthesis of
acrylic acid derivatives
To a solution of alkynoic acid (1 equiv) in toluene at room
temperature was added Cs2CO3 (1.2 equiv) and 18-crown-6 (1.2
equiv), and the resulting reaction mixture was stirred for 30
minutes. Subsequently, B2pin2 (1.5 equiv) was added to the
solution and the reaction mixture was stirred for additional 16-29
h at the indicated temperature. The reaction was quenched with
0.33 M hydrochloric acid and extracted with ethyl acetate. The
combined organic extracts were washed with brine and dried over
sodium sulfate. The solution was filtered and concentrated in
vacuo. The residue was purified by silica gel chromatography
using a 2:98 ethyl acetate in hexane with 1% acetic acid isocratic
method to yield the desired product. Only the trans (major)
product are reported, which match the literature values.
4.1.4. 3-(4-butylphenyl)propiolic acid (5d)
40%, light yellow solid; Synthesized by Procedure 4.1.1.1.
1H NMR (400 MHz, CDCl3) δ. 7.53 – 7.48 (d, J = 8.16 Hz, 2H),
7.20 – 7.16 (d, J = 8.16 Hz, 2H), 2.65 – 2.58 (t, J = 7.68 Hz, 2H),
1.62 – 1.54 (p, J = 7.60 Hz, 2H), 1.38 – 1.27 (septet, J = 7.60 Hz,
2H), 0.93 – 0.87 (t, J = 7.36 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 157.9, 146.8, 133.3, 128.8, 116.1, 89.6, 79.6, 35.8,
33.2, 22.3, 13.9.
4.1.5. 3-(4-methoxyphenyl)propiolic acid (5e)
1
91%, off white solid; Synthesized by Procedure 4.1.1.1. H
4.1.14. Cinnamic acid(6a)
NMR (400 MHz, CDCl3) δ 7.60 – 7.54 (m, 1H), 6.94 – 6.87 (m,
1H), 3.85 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 162.1, 158.5,
135.5, 114.5, 111.0, 90.2, 79.8, 55.6.
69%, white solid. 1 H NMR (400 MHz, CDCl3) δ
7.81 (d, J = 16.0 Hz, 1H), 7.56 (dd, J = 6.7, 3.0 H z,
2H), 7.44 – 7.39 (m, 3H), 6.47 (d, J = 16.0 Hz, 1H).
1 3 C NMR (101 MHz, CDCl3) δ 172.4, 147.25, 134.2,
130.9, 129.1, 128.5, 117.4.
4.1.6. 3-(4-chlorophenyl)propiolic acid (5f)
1
89%, off-white solid; Synthesized by Procedure 4.1.1.1. H
NMR (400 MHz, DMSO-d6) δ 7.68 – 7.63 (m, 2H), 7.56 – 7.52
(m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 154.1, 135.82 134.4,
129.3, 117.9, 83.1, 82.6.
4.1.15. 3-mesitylacrylic acid (6b)
1
60% white solid. H NMR (400 MHz, CDCl3) δ 7.96 (d, J =
16.3 Hz, 1H), 7.15 (d, J = 12.0 Hz, 1H), 6.91 (s, 2H), 6.86 (s,
2H), 6.16 (d, J = 12.0 Hz, 1H), 6.08 (d, J = 16.3 Hz, 1H), 2.35 (s,
6H), 2.30 (s, 6H), 2.29 (s, 3H), 2.19 (s, 3H). 13C NMR (101 MHz,
Chloroform-d) δ 172.49, 170.75, 146.60, 145.83, 138.98, 137.22,
134.74, 132.23, 130.60, 129.44, 129.20, 128.13, 122.34, 122.29,
21.28, 21.22, 21.19, 20.30.
4.1.7. 3-(4-(trifluoromethyl)phenyl)propiolic acid
(5g)
1
83%, white solid; Synthesized by Procedure 4.1.1.1. H NMR
(500 MHz, DMSO-d6) δ 14.21 (bs, 1H), 7.87 – 7.77 (m, 4H). 13
C
NMR (126 MHz, DMSO-d6) δ 154.0, 133.3, 130.5 (q, J = 32.3
Hz), 125.9 (q, J = 3.7 Hz), 123.7 (q, J = 272.5 Hz) 123.4, 83.6,
82.2.
4.1.16. (E)-3-(4-(tert-butyl)phenyl)acrylic acid (6c)
1
35%, off-white solid. H NMR (400 MHz, CDCl3) δ 7.80 –
7.74 (d, J = 16.0 Hz, 1H), 7.50 – 7.46 (dt, J = 8.44, 1.68 Hz, 2H),
7.43 – 7.39 (dt, J = 8.48, 1.96 Hz, 2H), 6.43 – 6.38 (d, J = 15.96
Hz), 1.31 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 172.6, 154.4,
147.0, 128.2, 125.9, 125.1, 116.3, 34.9, 31.1.
4.1.8. 3-(3,5-difluorophenyl)propiolic acid(5h)
1
66%, off-white solid; Synthesized by Procedure 4.1.1.1. H
NMR (400 MHz, CD3CN) δ 9.92 (br s, 1H), 7.28 – 7.21 (m, 2H),
7.14 (tt, J = 9.3, 2.3 Hz, 1H). 13C NMR (101 MHz, CD3CN) δ
163.7 (dd, J = 248.4, 13.4 Hz), 153.9, 123.1 (t, J = 11.9 Hz),
117.3 – 116.6 (m), 108.1 (t, J = 25.8 Hz), 83.5 (t, J = 4.0 Hz),
82.3.
4.1.17. (E)-3-(4-butylphenyl)acrylic acid (6d)
42%, light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.79 –
7.73 (d, J = 16.0 Hz, 1H), 7.47 – 7.43 (d, J = 8.2 Hz, 2H), 7.21 –
7.17 (d, J = 8.2 Hz, 2H), 6.42 – 6.37 (d, J = 16.0 Hz, 1H), 2.64 –
2.59 (t, J = 7.8 Hz, 2H), 1.63 – 1.55 (m, 2H), 1.39 – 1.29 (m,
2H), 0.94 – 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 172.7, 147.1, 131.5, 130.3, 129.0, 128.4, 116.2, 35.6, 33.3,
22.3, 13.9.
4.1.9. 3-(4-(trifluoromethoxy)phenyl)propiolic
acid(5i)
95%, white solid; Synthesized by Procedure 4.1.1.2. 1H NMR
(400 MHz, CDCl3) δ 10.41 – 9.80 (brs, 1H), 7.69 – 7.64 (dt, J =
8.96, 2.52 Hz, 2H), 7.28 – 7.23 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 158.0, 151.0, 125.0, 120.9, 120.2 (d, J = 260.6 Hz),
117.6, 87.3, 80.5.
4.1.18. (E)-3-(4-methoxyphenyl)acrylic acid (6e)
42%, white solid. 1H NMR (400 MHz, CD3CN) δ 9.00 (s,
0H), 7.62 (d, J = 16.0 Hz, 1H), 7.60 – 7.55 (m, 2H), 7.01 – 6.92
(m, 1H), 6.33 (d, J = 16.0 Hz, 1H), 3.82 (s, 2H). 13C NMR (101
MHz, CD3CN) δ 168.3, 162.6, 145.7, 130.9, 128.0, 116.1, 115.3,
56.1.
4.1.10. 3-(cyclohex-1-en-1-yl)propiolic acid(5j)
99%, light brown solid; Synthesized by Procedure 4.1.1.2. 1H
NMR (400 MHz, CDCl3) δ 6.55 – 6.50 (m, 1H), 2.20 – 2.14 (m,
4H), 1.70 – 1.57 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 158.6,
143.7, 118.2, 91.3, 78.0, 27.9, 26.0, 21.8, 21.0.
4.1.19. (E)-3-(4-(trifluoromethyl)phenyl)acrylic
acid(6g)
4.1.11. 3-cyclohexylpropiolic acid(5k)
42%, white solid. 1H NMR (500 MHz, DMSO-d6) δ 12.62 (bs,
1H), 7.84 (dd, J = 77.9, 8.2 Hz, 4H), 7.66 (d, J = 16.1 Hz, 1H),
6.69 (d, J = 16.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ
167.2, 142.1, 138.3, 129.8 (q, J = 31.9 Hz), 128.9, 125.7 (q, J =
3.7 Hz), 124.0 (q, J = 272.2 Hz), 122.2.
1
90%, pale yellow oil; Synthesized by Procedure 4.1.1.1. H
NMR (400 MHz, CDCl3) δ 10.92 – 10.25 (brs, 1H), 2.56 – 2.48
(m, 1H), 1.86 – 1.78 (m, 2H), 1.74 – 1.65 (m, 2H), 1.56 – 1.45
(m, 3H), 1.38 – 1.26 (m, 3H). 13C NMR (101 MHz, CDCl3) δ
158.6, 91.2, 72.5, 31.2, 28.9, 25.5, 24.5.

5
16. J. Plamondon, Organometallics in chemical synthesis, 1971, 1,
4.1.20. (E)-3-(3,5-difluorophenyl)acrylic acid (6h)
ACCEPTED MANUSCRIPT
249-252.
36%, white solid. 1H NMR (400 MHz, Acetone-d6) δ 7.64 (d,
J = 16.0 Hz, 1H), 7.46 – 7.33 (m, 2H), 7.09 (tt, J = 9.1, 2.3 Hz,
1H), 6.66 (d, J = 16.0 Hz, 1H). 13C NMR (101 MHz, Acetone-d6)
δ 167.2 , 164.2 (dd, J = 247.0, 13.0 Hz), 142.8 (t, J = 3.0 Hz),
139.4 (t, J = 9.9 Hz), 122.4, 111.8 (dd, J = 26.1, 7.0 Hz), 105.8 (t,
J = 26.0 Hz).
17. B. H. Lipshutz, Ž. V. Bošković and D. H. Aue, Angew. Chem. Int.
Ed., 2008, 47, 10183-10186.
18. K. Semba, T. Fujihara, J. Terao and Y. Tsuji, Chem. Eur. J., 2012,
18, 4179-4184.
19. E. C. Neeve, S. J. Geier, I. A. I. Mkhalid, S. A. Westcott and T. B.
Marder, Chem. Rev., 2016, 116, 9091-9161.
20. R. D. Dewhurst, E. C. Neeve, H. Braunschweig and T. B. Marder,
Chem. Commun., 2015, 51, 9594-9607.
4.1.21. (E)-3-(4-(trifluoromethoxy)phenyl)acrylic
21. Y. Nagashima, K. Hirano, R. Takita and M. Uchiyama, J. Am.
Chem. Soc., 2014, 136, 8532-8535.
acid (6i)
31%, white solid. 1H NMR (400 MHz, CDCl3) δ 7.86 – 7.79
22. A. Verma, R. F. Snead, Y. Dai, C. Slebodnick, Y. Yang, H. Yu, F.
Yao and W. L. Santos, Angew. Chem. Int. Ed., 2017, 56, 5111-
5115.
(dt, J = 8.68, 1.92 Hz, 2H), 7.72 – 7.66 (d, J = 16.0 Hz, 1H), 7.42
– 7.35 (dd, J = 7.96, 0.8 Hz, 2H), 6.59 – 6.53 (d, J = 16.0 Hz). 13
C
23. R. Fritzemeier, W. L. Santos. Chem.- Eur. J. 2017, 23, 15534-
15537.
NMR (101 MHz, CDCl3) δ 166.6, 150.0, 142.7, 133.8, 130.0,
121.3, 120.4 (t, J = 254.7 Hz), 59.6.
24. C. L. Peck, J. A. Calderone and W. L. Santos, Synthesis, 2015, 47,
2242-2248.
4.1.22. (E)-3-(cyclohex-1-en-1-yl)acrylic acid (6j)
25. R. T. H. Linstadt, C. A. Peterson, D. J. Lippincott, C. I. Jette, B.
H. Lipshutz Angew. Chem. Int. Ed. 2014, 53, 4159-4163.
26. S. N. Karad, W.-K. Chung, R.-S. Liu, Chem. Comm. 2015, 51,
13004-13007.
30%, red solid. 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.31 (d, J
= 15.7 Hz, 1H), 6.23 – 6.16 (t, J = 4.6 Hz, 1H), 5.78 – 5.70 (d, J
= 15.7 Hz, 1H), 2.24 – 2.17 (m, 2H), 2.16 – 2.10 (m, 2H), 1.72 –
1.65 (m, 2H), 1.64 – 1.56 (m, 2H). 13C NMR (101 MHz, CDCl3)
δ 173.1, 150.5, 140.3, 134.9, 113.7, 26.5, 24.0, 21.9, 21.9.
4.1.23. (E)-3-cyclohexylacrylic acid (6k)
6%, pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.06 – 6.99
(dd, J = 15.8, 6.8 Hz, 1H), 5.80 – 5.74 (dd, J = 15.8, 1.4 Hz, 1H),
2.21 – 2.11 (m, 1H), 1.81 – 1.72 (m, 4H), 1.24 – 1.10 (m, 4H).
13C NMR (101 MHz, CDCl3) δ 157.2, 118.2, 40.5, 31.5, 25.6.
4.1.24. (E)-3-(5-methylthiophen-2-yl)acrylic acid
(6l)
30%, yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.77
(d, J = 15.5 Hz, 1H), 7.11 – 7.09 (d, J = 3.56 Hz, 1H), 6.75 – 6.72
(m, 1H), 6.13 – 6.07 (d, J = 15.6 Hz, 1H), 2.52 – 2.50 (d, J = 0.8
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.6, 145.1, 139.8,
137.2, 132.5, 126.7, 114.4, 15.9.
Acknowledgments
We acknowledge financial support by the National Science
Foundation (CHE-1414458).
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