Nickel-Catalyzed Reductive Cycloisomerization of Enynes with CO2

Article abstract of DOI:10.1021/acs.joc.7b01034

Carboxylate groups are ubiquitous in bioactive molecules. The syntheses of carboxylates from petroleum feedstock require a series of oxidation reactions. CO₂ represents a cheap and sustainable, preoxidized C1 source. Herein, we describe a simple, selective, and mild procedure for the construction of (hetero)cyclic α,β-unsaturated carboxylic acids from 1,6- and 1,7-enyes and CO₂. Terminal 1,7-enynes and sterically hindered alkenes experience a change in regioselectivity and form unconjugated carboxylic acids. Mechanistic studies of the reductive cyclization suggest a hydride insertion pathway, explaining the change in regioselectivity caused by steric effects and distinguishing this work from previous reactions involving CO₂.

Full text of DOI:10.1021/acs.joc.7b01034

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Nickel-Catalyzed Reductive Cycloisomerization of Enynes with CO2
Justin Blaise Diccianni, Tyler Heitmann, and Tianning Diao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01034 • Publication Date (Web): 14 Jun 2017
Downloaded from http://pubs.acs.org on June 16, 2017
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 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Nickel-Catalyzed Reductive Cycloisomerization of
Enynes with CO2
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
Justin B. Diccianni, Tyler Heitmann, and Tianning Diao*
Department of Chemistry, New York University, 100 Washington Square East
New York, NY 10003
E-Mail: diao@nyu.edu
ABSTRACT
Carboxylate groups are ubiquitous in bioactive molecules. The syntheses of carboxylates
from petroleum feedstock require a series of oxidation reactions. CO2 represents a cheap and
sustainable, pre-oxidized C1 source. Here, we describe a simple, selective, and mild procedure
for the construction of (hetero)cyclic α,β-unsaturated carboxylic acids from 1,6- and 1,7-enyes
and CO2. Terminal 1,7-enynes and sterically hindered alkenes experience a unique change in
regioselectivity and form unconjugated carboxylic acids. Mechanistic studies of the reductive
cyclization suggest a hydride insertion pathway, explaining the change in regioselectivity caused
by steric effects and distinguishing this work from previous reactions involving CO2.
I. Introduction
The vast majority of chemicals are derived from petroleum products via a series of oxidation
reactions to increase the oxidation state of carbon and install functional groups. Carbon dioxide
represents a sustainable, inexpensive, and clean C1 source, in which the carbon center is already
highly oxidized.1 The advantages of CO2 as a chemical feedstock underlie recent efforts to
develop catalytic methods of incorporating CO2 into organic molecules. 2 In particular,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 36
1
2
3
4
5
6
functionalization reactions of alkenes and alkynes have provided new synthetic tools for the
sustainable construction of molecules.3
7
8
9
Cyclic molecules with α,β-unsaturated carbonyl functional groups are ubiquitous in bioactive
molecules and synthetic intermediates.4 In light of the recent advances in the field of Ni
catalyzed reductive functionalization of alkenes and alkynes,5 including work by Martin, Ma, and
others, we sought to extend the scope of these reactions to the preparation of α,β-unsaturated
cyclic compounds from CO2. Here, we report a Ni-catalyzed reductive cycloisomerization of
enynes6 that couples CO2 to form α,β-unsaturated carboxylic acids. The simple and mild
conditions provide high yields of a broad scope of cyclic and heterocyclic carboxylic acids. In
addition, we have conducted mechanistic studies and evaluated possible pathways, including
ones invoked in previous CO2 coupling reactions. Our studies suggest that the reaction proceeds
via a classic hydride insertion pathway, which is distinct from previous cyclization reactions to
incorporate CO2.3
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
II. Results
We initiated our investigation using malonate derived enyne 1a as a model substrate and
evaluated various conditions for the reductive cycloisomerization with CO2 (Table 1). Mori and
coworkers utilized Ni(cod)2 and PPh3 to catalyze the cyclization of bis-dienes with CO2.3b This
catalyst system exhibits no reactivity in the cyclization of 1a in the presence of Et2Zn as the
reductant (Table 1, entry 1). Replacing PPh3 with 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-
ylidene (IPr) resulted in the formation of the desired cyclic α,β-unsaturated acid 2a in 81% yield
(entry 2). The incorporation of CO2 into the alkyne is highly selectively, exclusively forming the
Z-isomer. The use of NiCl2(DME) (DME = dimethoxyethane) as the Ni precursor generated 2a
in a lower yield (entry 3). Louie and coworkers discovered that the pre-generated Ni(IPr)2
ACS Paragon Plus Environment

Page 3 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
catalyst outperforms the mixture of Ni(cod)2 and IPr in their [2+2+2] cycloaddition reactions.3a
We prepared Ni(IPr)2 via an optimized literature procedure,7 and indeed Ni(IPr)2 was superior to
the mixture of Ni(cod)2 and IPr, giving 2a in 99% yield (entry 4). We then continued to
investigate the stereo and electronic effects of the NHC ligands. Increasing the electron-donating
ability of the carbene and decreasing its steric protection led to reduced yields (entries 5-7). We
evaluated a variety of reductants as a replacement for Et2Zn, including EtZnCl, AlEt3, and
Et3SiH, but they failed to produce the product. Ultimately, the optimal conditions for the
cyclization were comprised of Ni(IPr)2 as the catalysts and Et2Zn as the reductant.
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
Table 1. Development of the Conditions for the Cycloisomerization of Enyne 1a with CO2a
[Ni] (2 mol%)
MeO2C
MeO2C
MeO2C
MeO2C
Me
CO2H
Et2Zn
(2.5 equiv)
+ CO2
(1 atm)
THF
22 ºC, 12 h
2a Me
1a
Catalyst
Yield (%)b
IPr:
Entry
iPr
iPr
c
N
N
1
2
3
4
5
6
7
0
Ni(cod)2/PPh3
Ni(cod)2/IPrc
iPr
iPr
81
40
99
42
11
10
SIPr:
iPr
NiCl2(DME)/IPrc
Ni(IPr)2
iPr
N
N
iPr
iPr
Ni(SIPr)2
IMes/SIMes:
N
Ni(IMes)2
N
Ni(SIMes)2
a Conditions:1a (0.05 mmol), Ni(IPr)2 (2 mol%), ZnEt2 (0.15 mmol), THF (1 mL), CO2 (1 atm),
12 h at 23 °C. b NMR yields using TMS as the internal standard. c 4 mol % ligand.
We explored the scope of the reductive cycloisomerization with 1 atm of CO2 (Table 2).
Methyl and benzyl malonate derived substrates underwent straightforward cyclization to afford
the cyclic α,β-unsaturated acids 2a and 2b in high yields. Terminal alkyne 1c proceeded to
generate the 5-membered product 2c in 64% yield. Aromatic alkyne 1d gave acid 2d in 60%
yield. Cyclization of 1,7-enyne 1e gave rise to the six-membered product 2e in 58% yield.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 36
1
2
3
4
5
6
7
8
9
Unsubstituted 1,6-enyne 1f lacked reactivity, suggesting the Thorpe-Ingold effect plays a crucial
role in facilitating the cyclization. In addition, sterically hindered olefins, such as geminal
disubstituted substrate 1g, exhibited no reactivity.
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
The reaction conditions tolerate heteroatoms, giving rise to a variety of piperidine,
pyrrolidine, and furan derivatives (2h-2q). We used single crystal X-ray diffraction to confirm
the structure and the stereochemistry of 2j. α-Phenyl substituted tosylamide 2l was formed as a
mixture of cis and trans-diastereomers in a 1:3 ratio, while α-methyl substituted tosylamide 2m
was formed as a 1:1 mixture of diastereomers. We assigned the diastereomers via NOESY
experiments. The tosyl- protecting group of the amine substrates could be substituted by
benzoyl- and Boc groups, giving rise to 2n and 2o in 74% and 57% yields, respectively. The use
of free amines, however, did not result in any product formation. Allyl- propargyl ethers
underwent cyclization to generate carboxylic acids 2p and 2q in good yields.
Table 2. Scope of the Reductive Cycloisomerization with CO2 Incorporated to Alkynesa
Ni(IPr)2 (2 mol%)
Et2Zn (2.5 equiv)
Me
X
X
+
CO2
CO2H
THF, 22 ºC, 12 h
(1 atm)
R
R
1
2
ACS Paragon Plus Environment

Page 5 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
RO2C
RO2C
MeO2C
MeO2C
Me
CO2H
Me
CO2H
MeO2C
Me
MeO2C
CO2H
Me
2e: 58% c
Me
2a: R = Me, 96%
2b: R = Bn, 90%
R
2c: R = H, 64%
2d: R = Ph, 60%
7
8
9
Me
CO2H
MeO2C
MeO2C
Me
TsN
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
Me
Ph
TMS
1f: 0%
1g: 0%
2h: 62%
Ts
Me
CO2H
2i: R = Me, 87%
2j: R = Et, 91% b
2k: R = TMS, 76% b
N
N
2i
2j
R
R
Me
O
Ts
Me
RN
Me
CO2H
CO2H
R
CO2H
Me
Me
2n: R = Bz, 74% c
2o: R = Boc, 57% b
2p: R = Me, 72%
2q: R = Ph, 60% b,c
2l: R = Ph, 82%
(cis: trans = 1:3 )
2m: R = Me, 90%
(cis: trans = 1:1)
a Conditions: Enyne = 0.5 mmol. Isolated yields. b 4% Ni(IPr)2. c Crude product treated with
TMSCHN2 and isolated as methyl ester.
When we evaluated terminal 1,7-enynes, we observed a change in the regioselectivity of the
CO2 incorporation from the alkynes to the alkenes (Scheme 1). Allyl-homopropargyl and
homoallyl-propargyl substrates, 3a-3c and 3d-3f, respectively, underwent cyclization to form
carboxylic acids 4a-4f. In contrast with the regioselectivity observed for 1,6-enynes 2a-2q, 1,7-
enynes 3a-3f, bearing terminal alkynes, incorporated CO2 onto the olefin. This reaction tolerated
N- and O-heteroatoms and afforded piperidine and tetrahydropyran derivatives. In addition,
introducing a phenyl substituent on the olefin led to the same change in regioselectivity of the
CO2 incorporation to afford saturated carboxylate 4g as a 10:1 mixture of diastereomers. The
addition of the hydride to the alkyne was exclusively cis to the newly formed C–C bond in 4g.
Scheme 1. Scope of Reductive Cyclization with CO2 Incorporated to Alkenes
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 36
1
2
3
4
Ni(IPr)2 (2 mol%)
Et2Zn (2.5 equiv)
X
H
X
CO2H
+
CO2
THF, 22 ºC, 12 h
5
6
7
8
3a-3c
(1 atm)
4a: X = O, 25%
4b: X = TsN, 81% (at 60 ºC)
4c: X = (MeO2C)2C, 44%
9
Ni(IPr)2 (2 mol%)
Et2Zn (2.5 equiv)
X
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
X
CO2H
+
CO2
THF, 22 ºC, 12 h
(1 atm)
H
4d: X = O, 15%
4e: X = TsN, 52%
4f: X = (MeO2C)2C, 57%
3d-3f
Ni(IPr)2 (2 mol%)
(1 atm)
Et2Zn (2.5 equiv)
Ph
MeO2C
H
MeO2C
MeO2C
CO2
Ph
MeO2C
CO2Me
THF, 60 ºC, 12 h
TMSCHN2
H
Me
3g
Me
4g
(60%, d.r. = 10:1)
We next turned our focus to probing the mechanism. In the presence of 0.5 equivalents of
CO2, relative to the enyne substrate, the cyclization reaction of 1d proceeded under standard
conditions to form the carboxylation product 2d accompanied by a reductive cycloisomerization
product 5d (eq 1).8 Cyclization of 1a with ZnEt2-d10 formed carboxylic acid 2a-D in 85% isolated
yield (Scheme 2). 1H and 13C NMR spectra established that a single deuterium atom was
incorporated into the methyl group in 97% efficiency. The use of ZnEt2-d10 in the cyclization of
3b led to >99% deuterium incorporation into the terminal olefin of 4b. The diastereoselectivity
of the deuterium incorporation is high with the deuterium cis- to the newly formed C–C bond,
and no H/D scrambling observed. We conducted kinetic studies for the carboxylation of 1a
using NMR analysis. The reaction time course fits to a first order kinetic model (Figure 1A).9
Comparing the reaction rates with ZnEt2 and ZnEt2-d10 revealed a kinetic isotope effect of 0.911
± 0.1 (Figure 1B).
ACS Paragon Plus Environment

Page 7 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
MeO2C
MeO2C
Me
MeO2C
MeO2C
ZnEt2 (2.5 equiv)
Ni(IPr)2 (2 mol %)
CO2H
30%
2d
Ph
(1)
+
~0.5 equiv CO2
MeO2C
MeO2C
1d
THF, rt
Ph
Me
then H3O+
H
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
5d
Ph
64%
Scheme 2. Cyclization of 1a and 3d with ZnEt2-d10
MeO2C
MeO2C
MeO2C
97%
D
ZnEt2-d10 (2.5 equiv)
Ni(IPr)2 (2 mol %)
MeO2C
CO2 (1atm)
THF, 22 ºC, 12 h
(85%)
CO2H
1a
2a-D
ZnEt2-d10 (2.5 equiv)
Ni(IPr)2 (4 mol%)
TsN
CO2H
TsN
CO2 (1atm)
THF, 60 ºC, 12 h(
61%)
D
>99%
3b
4b-D
(A)
(B)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 36
1
2
3
4
5
6
7
8
9
Figure 1. Kinetic profiles of reductive cyclization of 1a with Et2Zn (A) and Et2Zn-d10 (B).
Conditions: [1a]0 = 0.021 M, [Et2Zn]0 = 0.050 mM, CO2 = 1 atm, solvent = THF, temperature =
22 ºC, internal standard = tetramethylsilane.
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
We conducted spectroscopic studies of the catalytic reaction and a series of stoichiometric
experiments to elucidate the nature of the Ni catalyst. The EPR spectrum of a reaction mixture of
2a under standard conditions frozen to 10 K showed no signal. When we monitored the
stoichiometric reaction of Ni(IPr)2 with 1a in the presence of ZnEt2 and CO2 by in-situ 1H NMR
spectroscopy, we observed a diamagnetic Ni species. When CO2 and/or Et2Zn were excluded
from the reaction, no conversion of 1a was detected. Mixing stoichiometric Ni(IPr)2 and enyne
1a resulted in no reaction. When CO2 was introduced to the dark purple solution of Ni(IPr)2, the
1
color immediately changed to yellow. Upon addition of enyne 1a, the H NMR spectrum of the
mixture exhibits a new Ni species but no conversion of 1a (Figure S1). Introducing Et2Zn to the
reaction mixture resulted in formation of 2a.
III. Discussion
The experiments presented above allow us to evaluate possible pathways for the reductive
cyclization. The formation of reductive cycloisomerization product 5d in the presence of
insufficient CO2 (eq 1) suggests that cyclization occurs prior to the incorporation of CO2.
Deuterium labeling studies with Et2Zn-d10 (Scheme 2) reveal that the hydrogen atom
incorporated into the product originates from Et2Zn. The lack of H/D scrambling suggests that
hydride insertion is irreversible. The negligible KIE with Et2Zn-d10 implies that steps involving
the cleavage of the C–H bonds of Et2Zn and Ni–hydride are fast. Analysis of the reaction mixture
1
by EPR spectroscopy excludes Ni(I) or Ni(III) species as the catalyst resting state. H NMR
ACS Paragon Plus Environment

Page 9 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
studies of the catalyst activation provide circumstantial evidence for diamagnetic intermediates
involved in catalysis.
7
8
9
Our stoichiometric experiments establish that Ni(IPr)2 alone does not react with the enyne
substrate. Both CO2 and Et2Zn are crucial to activate the Ni catalyst. The reaction of CO2 with
Ni(0) results in an immediate color change, possibly forming side-on adduct 6, as is known for
Ni(0)-phosphine complexes.10 The enyne substrate 1a, however, does not react with 6, evident
from stoichiometric studies (Figure S1). Based on previous studies by Dong and coworkers,11
(IPr)2Ni(0)-CO2 adduct 6 can transmetallate with Et2Zn to form intermediate 7 (Scheme 3). Upon
release of ethylene, β-H elimination gives rise to Ni–H 8, which enters the catalytic cycle.
Alternatively, nucleophilic addition of Et2Zn to the carbonyl of 6 could form intermediate 9,
followed by β-H elimination to generate Ni(II)–H 10. Consistent with this proposal, Ni(II)
precursors, such as NiCl2(DME), are active in catalyzing the reductive cyclization reaction
(Table 1, entry 3). We attribute the lower yield of NiCl2(DME) compared with Ni(IPr)2 to
catalyst decomposition when the coordination of IPr to NiCl2(DME) is incomplete.
Scheme 3. Proposed Activation of the Ni Catalyst by CO2 and Et2Zn
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
O
O
H
O
-
(IPr)2Ni
OZnEt
(IPr)2Ni
OZnEt
(IPr)2Ni
Et
O
7
8
H
6
H
OZnEt
OZnEt
H3C
H
(IPr)2Ni O
10
+ Et2Zn
(IPr)2Ni
O
9
Oxidative cycloaddition of alkenes and alkynes with Ni(0) has been invoked in Ni-catalyzed
reductive coupling reactions5f and early reports in Ni-mediated CO2 functionalization.12 If the
reductive cyclization proceeded through this pathway, CO2 could undergo nucleophilic attack by
the metallocycle intermediate followed by reductive cleavage with Et2Zn (Scheme 4, Path 1).
This pathway is consistent with our observation that cyclization precedes the incorporation of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 36
1
2
3
4
5
6
CO2, but is inconsistent with the lack of reactivity between enyne 1a and Ni(IPr)2 in
stoichiometric studies.13
7
8
9
Scheme 4. Possible Pathways of Ni-Catalyzed Reductive Cycloisomerization
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
CO2, Et2Zn
Path 1
[NiII]
X
[Ni0]
R
X
[NiII]
O
Et2Zn
Path 2
X
[NiII]
O
[Ni0]
O
R
O
X
[NiII]
ZnEt
X
X
CO2
Path 3
CO2H
X
NiIIH
[Ni0], Et2Zn
n
R
2
R
R
R
ZnEt
H
1 or 3
X
CO2
Path 4
[NiII–H]
X
[NiII]
[NiII]
(Et2Zn)
R
R
CO2
[NiII]
[NiII]
Path 5
[NiII–H]
X
X
CO2H
X
H
R = H
4
Louie and coworkers proposed a cycloaddition between CO2, Ni(0), and an alkyne.3a It is
conceivable that a similar reaction could form a metallolactone, which inserts into the alkene and
generate the final product (Scheme 4, Path 2). This pathway is inconsistent with cyclization
preceding the incorporation of CO2, evident from the formation of reductive cyclization product
5d. In addition, the lack of reactivity between Ni(IPr)2, enyne 1a, and CO2 in the absence of
Et2Zn contrasts with Path 2.
In a Ni-catalyzed reductive cyclization of diynes with CO2, Ma and coworkers invoked
transmetallation between a Ni(0)-alkyne adduct and Et2Zn to afford a vinyl-zinc intermediate
(Scheme 4, Path 3). Further olefin insertion generates the cyclized product.3g The vinyl-Zn
intermediate is responsible for the nucleophilic attack on CO2 to form the carboxylic acid. In the
report by Ma, reductive cyclization of the diynes occurs in high yield in the absence of CO2.3g In
ACS Paragon Plus Environment

Page 11 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
contrast, our reductive cyclization did not produce any cyclized product in the absence of CO2.
This observation provides circumstantial evidence to rule out Ma’s mechanism.
7
8
9
Our mechanistic data are consistent with Path 4. The reaction initiates by the insertion of a
Ni(II)–H species into the alkene, followed by subsequent insertion of the alkyne and activation
of CO2. When terminal 1,7-enyne 3a-f and 1,6-enyne 3g, with steric hindrance on alkene, were
used as the substrate, the initial insertion of Ni(II)–H favors the more reactive and sterically more
accessible alkyne (Path 5).14 This change of insertion sequence results in the incorporation of
CO2 into the alkene and forms saturated acids 4a-g. It is noteworthy that the unique change in
selectivity with substrates 3a-g provides further evidence to exclude Paths 2 and 3, which cannot
account for the observed steric effect on the change of insertion sequence.
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
Collectively, we propose the catalytic cycle shown in Scheme 5 to account for our
experimental observations. Irreversible, insertion of Ni–H into the alkene, followed by insertion
of the alkyne, gives rise to a vinyl–Ni intermediate 11, which may directly react with CO2
(Pathway A).15 Subsequent transmetallation with Et2Zn forms a Ni–Et intermediate, which
undergoes β-H elimination to regenerate the Ni–H species. Alternatively, the activation of CO2
could be preceded by transmetallation to Zn, forming a vinylzinc species which ultimately reacts
with CO2 (Pathway B).3c Our current data do not distinguish these two pathways, and ongoing
research focuses on elucidating the role of Zn salts in activating CO2.
Scheme 5. Proposed Catalytic Cycle
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 36
1
2
3
4
X
5
6
7
8
[Ni]–H
Me
Me
CO2[Zn]
X
[Ni]–Et
Me
X
X
H
Me
[Ni]
9
ZnEt
Et2Zn
Pathway B
CO2
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
Me
Me
Et2Zn
Me
X
Me
[Ni]
11
X
CO2[Ni]
Me
Me
CO2
Pathway A
IV. Conclusion
In conclusion, we have developed a simple, selective, and mild procedure for constructing
(hetero)cyclic α,β-unsaturated carboxylic acids from 1,6- and 1,7-enyes and CO2. Increasing the
steric hindrance on alkene or decreasing the steric hindrance on alkyne results in a unique change
in the regioselectivity of the carboxylation to afford unconjugated carboxylic acids. Our
mechanistic studies suggest a hydride insertion mechanism is operative, which distinguishes this
work from previous reactions in incorporating CO2.
Experimental
General Considerations. All air- and moisture- sensitive manipulations were carried out in a
nitrogen-filled glove box. Solvents were dried and deoxygenated by passing through alumina in a
solvent purification system. Ni(cod)2 was purchased from Strem and used without further
purification. Chloroform-d, benzene-d6, and bromoethane-d5 were purchased from Cambridge
Isotope Laboratories. Substrates 1a-g, 1i-k, 1o-q, 3a, and 3d-f were synthesized according to
literature procedures.16a-n
1H and 13C NMR spectra were recorded on Bruker 600, 500, and 400 MHz Avance
spectrometers. The chemical shifts (δ) are given in parts per million and referenced to residual
solvent peaks or TMS internal standard. The following abbreviations were used to describe
ACS Paragon Plus Environment

Page 13 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, m = multiplet, br =
broad. IR spectra were recorded on a Nicolet 6700 FT-IR spectrometer. X-ray crystallographic
data were collected on Bruker AXS SMART APEXII single crystal diffractometer. High-
resolution mass spectra (HRMS) were collected on an Agilent 6224 TOF LC/MS. Reactions
were monitored by thin layer chromatography (TLC) on Merck TLC Silica gel 60 F254 plates and
compounds were visualized by UV light (254 nm) or KMnO4 staining. Column chromatography
was performed on Merck Silica gel 60 (0.015-0.040 mm). Carbon dioxide was purchased from
Airgas and was passed through 2 Drierite columns before use. Melting points were measured
using a Mel-Temp apparatus with open glass capillaries.
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
Ni(IPr)2. A 20 mL scintillation vial was charged with Ni(cod)2 (100 mg, 0.36 mmol, 1 equiv)
and 6 mL THF. With stirring, IPr17 (282 mg, 0.73 mmol, 2 equiv) was added in 6 mL THF. The
solution quickly turned dark brown, then black. After stirring overnight, solvent was removed
under vacuum, the residue was dissolved in 10 mL toluene, and stirring was continued for a
further 12 hours. After repeating the cycle two more times, volatiles were removed under
vacuum and black residue was suspended in pentane (5 mL) and filtered. The solid was washed
with pentane twice and dried under vacuum to give 166 mg (0.20 mmol, 56%) of Ni(IPr)2 as a
black, microcrystalline solid. The filtrate was stored at –35 °C. After 24 hours, the supernatant
was removed and the solids were dried under vacuum to afford 35 mg (0.04 mmol, 11%) of
Ni(IPr)2 (67% overall). The solid was stored at –35 °C. Solutions of Ni(IPr)2 were found to
decompose over several days at room temperature. The spectroscopic data is in agreement with
the previous reports.18 1H NMR (600 MHz, C6D6) δ 7.28 (t, J = 7.7 Hz, 4H), 7.08 (d, J = 7.7 Hz,
8H), 6.11 (s, 4H), 3.06 (sept, J = 6.9 Hz, 8H), 1.25 (d, J = 6.9 Hz, 24H), 1.10 (d, J = 6.9 Hz,
24H). 13C {1H} NMR (151 MHz, C6D6) δ 193.5, 145.4, 139.3, 123.3, 120.8, 28.3, 24.5, 23.9.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 36
1
2
3
4
5
6
7
8
9
Procedure for Screening Reaction Conditions: An oven-dried 25 mL bomb flask was
charged with the nickel catalyst, ligand, and THF (0.8 mL) in a nitrogen-filled glovebox. The
flask was sealed and removed from the glovebox. Under a stream of CO2, enyne 1a (0.05 mmol,
1 equiv) was added as a solution in 0.1 mL THF. After addition of the reductant (2.5 equiv), the
flask was degassed three times by the freeze-pump-thaw method. The specified amount of CO2
was then introduced to the flask and the mixture stirred vigorously for 12 hours at the specified
temperature. The mixture was cooled in an ice bath, diluted with 2 mL EtOAc, and quenched
with 3 mL 1 M HCl. The aqueous phase was extracted with 2 mL EtOAc three times. The
combined organic phase was dried over Na2SO4. Solvent was removed under vacuum. The
crude material was dissolved in CDCl3 (0.6 mL) followed by the addition of TMS internal
standard (0.02 mmol from a stock solution in CDCl3) and analysis by NMR spectroscopy. All
yields were determined by NMR spectroscopy (Table S1).
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 Procedure for Cyclization Reactions in Bomb Flasks (General Procedure A):
An oven-dried 25 mL bomb flask was charged with Ni(IPr)2 (2-4%) and THF (0.8 mL) in a
glovebox. The flask was sealed and removed from the glovebox. Under a stream of CO2, enyne
1a-q or 3a-g (0.05 mmol, 1 equiv) was added as a solution in 0.1 mL THF. After the addition of
ZnEt2 (2.5 equiv) in 0.1 mL THF the solution became turbid. The flask was degassed three times
by the freeze-pump-thaw method. The flask was filled with one atmosphere of CO2. After
stirring vigorously for 12 hours the mixture was cooled in an ice bath, diluted with 2 mL EtOAc,
and quenched with ~3 mL 1 M HCl (or sat. NH4Cl for substrate 1o). The aqueous phase was
extracted 3 x 2 mL EtOAc. The combined organic phase was washed with brine and dried over
Na2SO4. The crude material was dissolved in CDCl3 (0.6 mL) with TMS (0.02 mmol from a
ACS Paragon Plus Environment

Page 15 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
stock solution in CDCl3) added and analyzed by NMR spectroscopy. The crude material was
then purified by chromatography on silica with elution by mixtures of CHCl3 and MeOH.
General Procedure for Cyclization Reactions in Round-Bottom Flasks (RBF) (General
Procedure B): An oven-dried 50 mL RBF was charged with Ni(IPr)2 (2-4%) and THF (8 mL) in
a glovebox. The flask was sealed with a septum and brought out of the glovebox. The flask was
purged with a balloon of CO2 until the solution turned yellow. The balloon was refilled and
enyne 1a-q or 3a-g (0.5 mmol, 1 equiv) was added in 1 mL THF. ZnEt2 (2.5 equiv) was added
dropwise in 1 mL THF and the solution became turbid. The mixture was stirred vigorously for
12 hours. The CO2 balloon was replaced every 4-8 hours due to corrosion of the balloon by
ZnEt2. The mixture was cooled in an ice bath, diluted with 10 mL EtOAc, and quenched with ~5
mL 1 M HCl (or sat. NH4Cl for substrate 1o). The aqueous phase was extracted with EtOAc
three times. The combined organic phase was washed twice with brine and dried over Na2SO4.
Solvent was removed under vacuum to give the crude products, which were purified by
recrystallization (carboxylic acids 2i and 2j), conversion to the corresponding methyl ester with
TMSCHN2 followed by chromatography on silica with hexane/EtOAc (esters 2e, 2n, 2q, and
4g), or chromatography of the free acids on silica with CHCl3/MeOH (all other carboxylic acids).
General Procedure for Methylation of Carboxylic Acids (General Procedure C): The
crude material was dissolved in 3 mL toluene and 2 mL MeOH were added. The solution was
cooled in an ice bath and TMSCHN2 (3 equiv, 2 M in hexane) was added dropwise. The ice bath
was removed and the solution stirred at room temperature for 1 hour. Acetic acid was added
dropwise until the yellow color of TMSCHN2 faded, then solvent was removed under vacuum.
The methyl esters were then purified by column chromatography on silica with elution by hexane
and EtOAc.
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
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 36
1
2
3
4
5
6
7
8
9
Procedure for Kinetic Experiments: In parallel, several oven-dried 25 mL bomb flasks
were charged with Ni(IPr)2 (0.001 mmol, 0.02 equiv, 0.8 mL THF) from a stock solution in THF,
in a glovebox. The flasks were sealed and removed from the glovebox. Under a stream of CO2,
enyne 1a (0.05 mmol, 1 equiv) was added from a stock solution in THF (0.1 mL). After the
addition of ZnEt2 or ZnEt2-d10 (2.5 equiv) in 0.1 mL THF from a stock solution, the flask was
degassed three times by the freeze-pump-thaw method. The flask was filled with one
atmosphere of CO2. After stirring vigorously for the specified time the mixture was cooled in an
ice bath, diluted with 2 mL EtOAc, and quenched with ~3 mL 1 M HCl. The aqueous phase was
extracted 3 x 2 mL EtOAc. The combined organic phase was washed with brine and dried over
Na2SO4. The crude material was dissolved in CDCl3 (0.6 mL) with TMS (0.02 mmol from a
stock solution in CDCl3) added and analyzed by NMR spectroscopy. Kinetic experiments were
repeated twice in order to assure reproducibility.
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
Stoichiometric Reaction Between Ni(IPr)2, CO2, and 1a. A J-Young NMR tube was
charged with a solution of Ni(IPr)2 (8 mg, 0.009 mmol, 1 equiv) and enyne 1a (2 mg, 0.009
mmol, 1 equiv) in 0.6 mL C6D6. The NMR spectrum of this solution showed no reaction even
after 2 days at room temperature. The tube was degassed and refilled with CO2, causing the
solution to turn yellow/orange. The NMR spectrum of this mixture showed Ni(IPr)2 had been
consumed and a new Ni species formed. Enyne 1a was unreactive with this new Ni species
(Figure S1).
Reaction with Substoichiometric CO2:An oven-dried 25 mL bomb flask was charged with
Ni(IPr)2 (0.005 mmol, 0.02 equiv) and 4 mL THF in a glovebox. The flask was sealed and
removed from the glovebox. Under a stream of CO2, enyne 1d (0.25 mmol, 1 equiv) was added
in 0.5 mL THF followed by ZnEt2 (2.5 equiv) in 0.5 mL THF. The flask was degassed three
ACS Paragon Plus Environment

Page 17 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
times by the freeze-pump-thaw method. Using a gas addition bulb and standard Schlenk
technique, 0.5 equivalents of CO2 were condensed into the flask. The mixture was stirred
overnight, cooled in an ice bath, and quenched with 1 M HCl. The aqueous phase was extracted
with EtOAc three times. The combined organic phase was washed twice with brine and dried
over Na2SO4. Solvent was removed under vacuum to give the crude products (Figure S2), which
were purified by chromatography on silica with 100% CHCl3 à 100:1 CHCl3:MeOH to give 2d
(25 mg, 0.075 mmol, 30%) and 5d (46 mg, 0.16 mmol, 64%) as colorless oils. The
spectroscopic data for compound 5d matches with that reported in the literature.19
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)-dimethyl 3-benzylidene-4-methylcyclopentane-1,1-dicarboxylate (5d). H NMR (400
MHz, CDCl3) δ 7.33 (m, 4H), 7.21 (m, 1H), 6.22 (q, J = 2.4 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H),
3.39 (d, J = 17.6 Hz, 1H), 3.21 (dd, J = 17.2, 2.8 Hz, 1H), 2.77 (m, 1H), 2.60 (ddd, J = 12.8, 7.2,
13
1.6 Hz, 1H), 1.77 (dd, J = 12.4, 11.6 Hz, 1H), 1.22 (d, J = 6.4 Hz, 1H). C NMR (101 MHz,
CDCl3) δ 172.3, 172.2, 146.0, 137.9, 128.3, 126.2, 121.5, 109.7, 59.0, 52.8, 41.5, 39.1, 39.0,
18.3.
(Z)-2-(4,4-bis(methoxycarbonyl)-2-methylcyclopentylidene)propanoic acid (2a). Following
General Procedure B with enyne 1a and purification of the crude material via column
chromatography (100% CHCl3 → 10:1 CHCl3:MeOH) afforded 2a as a colorless solid in 96%
yield (130 mg, 0.48 mmol). Mp 66−68 °C. 1H NMR (600 MHz, CDCl3) δ 3.75 (s, 3H), 3.71 (s,
3H), 3.59 (m, 1H), 3.28 (d, J = 18.3 Hz, 1H), 2.96 (d, J = 18.3 Hz, 1H), 2.59 (dd, J = 13.5, 8.2
Hz, 1H), 2.17 (dd, J = 13.5, 3.5 Hz, 1H), 1.86 (s, 3H), 1.04 (d, J = 7.1 Hz, 3H). C {1H} NMR
13
(151 MHz, CDCl3) δ 173.2, 172.5, 172.2, 162.7, 119.4, 58.1, 53.01, 52.96, 41.8, 40.8, 37.7,
20.5, 16.3. HRMS (ESI-TOF) m/z: [(M+H) – H2O]+ Calcd for C13H17O5 253.1071; Found
253.1070. TLC: Rf = 0.20 (40:1 CHCl3:MeOH).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 36
1
2
3
4
5
6
7
8
9
(Z)-2-(4,4-bis((benzyloxy)carbonyl)-2-methylcyclopentylidene)propanoic acid (2b).
Following General Procedure B with enyne 1b and purification of the crude material via column
chromatography (100% CHCl3 → 10:1 CHCl3:MeOH) afforded 2b as a colorless oil in 90%
yield (0.45 mmol, 190 mg). 1H NMR (600 MHz, CDCl3) δ 7.32 (m, 6H), 7.28 – 7.26 (m, 2H),
7.23 (m, 2H), 5.18-5.10 (m, 4H), 3.60 (br, 1H), 3.30 (d, J = 18.2 Hz, 1H), 2.99 (d, J = 18.1 Hz,
1H), 2.65 (dd, J = 13.5, 8.3 Hz, 1H), 2.17 (dd, J = 13.5, 3.8 Hz, 1H), 1.83 (s, 3H), 1.03 (d, J =
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
7.1 Hz, 3H). C {1H} NMR (151 MHz, CDCl3) δ 172.6, 171.6 , 171.3 , 162.8, 135.3 , 135.2 ,
13
128.6 , 128.6, 128.4, 128.4, 128.2, 128.0, 119.4, 67.6, 67.4, 58.4, 41.8, 40.7, 37.7, 20.7, 16.4.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H27O6 423.1808; Found 423.1802. TLC: Rf =
0.64 (10:1 CHCl3:MeOH).
(Z)-2-(4,4-bis(methoxycarbonyl)-2-methylcyclopentylidene)acetic acid (2c).
Following General Procedure B with enyne 1c and purification of the crude material via
column chromatography (100% CHCl3 → 10:1 CHCl3:MeOH) afforded 2c as a tan oil in 64%
1
yield (0.32 mmol, 82 mg). This compound slowly isomerizes to the E isomer. H NMR (500
MHz, CDCl3) δ 5.78 (s, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.54 (q, J = 7.0 Hz, 1H), 3.31 (dt, J =
17.2, 2.0 Hz, 1H), 2.95 (d, J = 17.2 Hz, 1H), 2.73 (ddd, J = 13.6, 8.4, 2.0 Hz, 1H), 2.03 (dd, J =
13.6, 8.4 Hz, 1H), 1.16 (d, J = 7.0 Hz, 3H). C {1H} NMR (151 MHz, CDCl3) δ 171.9, 171.6,
13
170.8, 147.4, 123.8, 58.2, 53.02, 52.99, 42.8, 41.6, 36.3, 20.5. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C12H16O6Na 279.0840; Found 279.0858. TLC: Rf = 0.38 (20:1
CHCl3:MeOH).
(Z)-2-(4,4-bis(methoxycarbonyl)-2-methylcyclopentylidene)-2-phenylacetic acid (2d).
Following General Procedure B with enyne 1d and purification of the crude material via
column chromatography (100% CHCl3 → 100:1 CHCl3:MeOH) afforded 2d as a colorless oil in
ACS Paragon Plus Environment

Page 19 of 36
The Journal of Organic Chemistry
1
2
3
4
1
60% yield (0.30 mmol, 100 mg). H NMR (500 MHz, CDCl3) δ 7.39 – 7.34 (m, 2H), 7.32 –
5
6
7
8
7.28 (m, 1H), 7.16 (dd, J = 8.1, 1.3 Hz, 2H), 3.70 (br s, 4H), 3.66 (s, 3H), 3.05 (dd, J = 17.8, 1.9
Hz, 1H), 2.74 – 2.65 (m, 2H), 2.09 (dd, J = 13.6, 5.2 Hz, 1H), 1.20 (d, J = 7.0 Hz, 3H). 13C {1H}
NMR (151 MHz, CDCl3) δ 172.0, 171.7, 171.3, 165.6, 138.0, 129.2, 128.4, 127.5, 126.5, 58.2,
52.9, 52.9, 41.61, 41.59, 37.1, 20.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H21O6
333.1338; Found 333.1307. TLC: Rf = 0.48 (10:1 CHCl3:MeOH).
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
Dimethyl (Z)-3-(1-methoxy-1-oxopropan-2-ylidene)-4-methylcyclohexane-1,1-dicarboxylate
(2e). Following General Procedure B followed by General Procedure C with enyne 1e and
purification of the crude material via column chromatography (10:1 hexane:EtOAc) afforded 2e
1
as a slightly yellow oil in 58% yield (0.29 mmol, 87 mg) (82% b.r.s.m.). H NMR (500 MHz,
CDCl3) δ 3.74 (s, 3H), 3.712 (s, 3H), 3.710 (s, 3H) 3.15 (ddd, J = 14.3, 2.1, 1.1 Hz, 1H), 3.13 –
3.07 (m, 1H), 2.44 (dd, J = 14.4, 1.4 Hz, 1H), 2.20 (dq, J = 13.7, 3.6 Hz, 1H), 2.03 (td, J = 13.7,
4.2 Hz, 1H), 1.91 (d, J = 1.4 Hz, 3H), 1.68 (tt, J = 13.7, 4.2 Hz, 1H), 1.54 (dq, J = 14.0, 3.6 Hz,
1H), 1.14 (d, J = 7.1 Hz, 3H). C {1H} NMR (151 MHz, CDCl3) δ 172.4, 170.8, 170.7, 144.9,
13
123.7, 77.4, 56.8, 53.0, 52.6, 51.6, 32.6, 30.0, 26.0, 18.6, 15.5. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C15H23O6 299.1490; Found 299.1496. TLC: Rf = 0.20 (10:1 hexane:EtOAc).
(E)-2-(3-methyl-1-tosylpiperidin-4-ylidene)-2-(trimethylsilyl)acetic acid (2h). Following
General Procedure B with enyne 1h and purification of the crude material via column
chromatography (100% CHCl3 → 100:1 CHCl3:MeOH) afforded 2h as a colorless oil in 62%
yield (0.31 mmol, 123 mg). 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 8.2 Hz, 2H), 7.31 (d, J =
8.2 Hz, 2H), 3.91 (dq, J = 8.2, 2.6 Hz, 1H), 3.59 (d, J = 11.3 Hz, 1H), 2.76 (d, J = 6.9 Hz, 1H),
2.64 (dd, J = 13.3, 5.3 Hz, 1H), 2.43 (s, 3H), 2.38 – 2.29 (m, 1H), 2.22 – 2.13 (m, 1H), 1.30 (d, J
= 6.9 Hz, 3H), 1.16 (t, J = 7.6 Hz, 1H), 0.17 (s, 9H). 13C {1H} NMR (151 MHz, CDCl3) δ 176.1,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 36
1
2
3
4
5
6
7
8
9
153.8, 143.7, 133.1, 130.8, 129.7, 127.6, 52.3, 47.2, 36.7, 28.8, 21.5, 18.2, –0.2. HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C18H28NO4SSi 382.1508; Found 382.1503. TLC: Rf = 0.33 (10:1
CHCl3:MeOH).
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)-2-(4-methyl-1-tosylpyrrolidin-3-ylidene)propanoic acid (2i). Following General
Procedure B with enyne 1i and purification of the crude material via recrystallization from
CH2Cl2/hexane afforded 2i as an off-white solid in 87% yield (0.44 mmol, 136 mg). Mp 99–101
°C. 1H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.16 (d, J
= 16.6 Hz, 1H), 3.68 – 3.51 (m, 2H), 3.35 (d, J = 9.1 Hz, 1H), 2.98 (dd, J = 9.1, 6.1 Hz, 1H),
2.43 (s, 3H), 1.75 (s, 3H), 1.18 (d, J = 6.9 Hz, 3H). 13C {1H} NMR (151 MHz, CDCl3) δ 171.0,
157.8, 143.9, 132.1, 129.8, 127.9, 119.2, 55.4, 52.1, 37.8, 21.6, 19.6, 15.8. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C15H20NO4S 310.1108; Found 310.1115. TLC: Rf = 0.15 (20:1
CHCl3:MeOH).
(E)-2-(4-methyl-1-tosylpyrrolidin-3-ylidene)butanoic acid (2j). Following General Procedure
B with enyne 1j and purification of the crude material via recrystallization from CH2Cl2/hexane
afforded 2j as a colorless solid in 91% yield (0.46 mmol, 147 mg). Mp 83–84 °C. 1H NMR (600
MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 4.20 (d, J = 16.4 Hz, 1H),
3.64 (d, J = 16.4 Hz, 1H), 3.60 – 3.52 (m, 1H), 3.33 (d, J = 9.1 Hz, 1H), 2.98 (dd, J = 9.1, 6.1
Hz, 1H), 2.43 (s, 3H), 2.17 (dq, J = 14.7, 7.4 Hz, 1H), 2.09 (dq, J = 14.4, 7.4 Hz, 1H), 1.18 (d, J
= 7.0 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). C {1H} NMR (151 MHz, CDCl3) δ 171.5, 157.2,
13
144.0, 132.0, 129.8, 127.9, 125.7, 55.2, 51.2, 37.7, 23.8, 21.6, 19.7, 12.8. HRMS (ESI, m/z):
calcd for C16H21NO4S[M+H+]: 324.1265, found 324.1264. TLC: Rf = 0.15 (20:1 CHCl3:MeOH).
(Z)-2-(4-methyl-1-tosylpyrrolidin-3-ylidene)-2-(trimethylsilyl)acetic acid (2k).
ACS Paragon Plus Environment

Page 21 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Following General Procedure B with enyne 1k and purification of the crude material via
column chromatography (100% CHCl3 → 10:1 CHCl3:MeOH) afforded 2k as a tan oil in 76%
yield (0.38 mmol, 140 mg). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H), 7.34 (d, J =
8.2 Hz, 2H), 4.08 (d, J = 15.4 Hz, 1H), 3.61 (d, J = 15.4 Hz, 1H), 3.27 – 3.19 (m, 1H), 3.19 –
3.11 (m, 1H), 2.98 (dd, J = 9.1, 6.1 Hz, 1H), 2.43 (s, 3H), 1.13 (d, J = 7.0 Hz, 3H), 0.15 (s, 9H).
13C {1H} NMR (101 MHz, CDCl3) δ 176.0, 160.2, 144.0, 131.9, 129.8, 128.3, 127.8, 54.3, 51.3,
39.0, 21.5, 19.9, –0.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H26NO4SSi 368.1347;
Found 368.1325. TLC: Rf = 0.19 (30:1 CHCl3:MeOH).
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)-2-(4-methyl-5-phenyl-1-tosylpyrrolidin-3-ylidene)propanoic acid (2l). Following General
Procedure B with enyne 1l and purification of the crude material via column chromatography
(100% CHCl3 → 100:1 CHCl3:MeOH) afforded 2l as a colorless oil in 82% yield (0.41 mmol,
158 mg, d.r. = 3:1 anti:syn). Separation of the diastereomers was not possible and they were
1
characterized as a mixture. Anti isomer: H NMR (600 MHz, CDCl3) δ 7.54 (d, J = 8.2 Hz,
2H), 7.29 (m, J = 8.6 Hz, 2H), 7.23 – 7.16 (m, 4H), 7.06 (m, 1H), 4.77 (s, 1H), 4.31 (dt, J = 16.9,
1.6 Hz, 1H), 4.21 (dd, J = 16.9, 1.1 Hz, 1H), 3.64 (m, 1H), 2.38 (s, 3H), 1.82 (s, 3H), 1.05 (d, J =
7.0 Hz, 3H). C {1H} NMR (151 MHz, CDCl3) δ 171.7, 157.7, 143.4, 144.7, 129.5, 128.6,
13
128.4, 127.6, 127.5, 127.2, 126.0, 71.1, 51.7, 47.1, 21.5, 20.4, 16.0. Syn isomer:1H NMR (500
MHz, CDCl3) δ 7.54 (d, J = 8.2 Hz, 2H), 7.29 (m, 7H), 4.39 (d, J = 17.5 Hz, 1H), 4.25 (d, J =
6.3 Hz, 1H), 4.04 (d, J = 16.4 Hz, 1H), 3.71 – 3.57 (m, 1H), 2.43 (s, 3H), 1.79 (s, 3H), 0.81 (d, J
= 7.1 Hz, 1H). C {1H} NMR (151 MHz, CDCl3) δ 172.4, 155.9, 153.9, 144.1, 135.7, 129.6,
13
128.7, 128.2, 127.8, 120.0, 118.8, 69.0, 53.7, 44.3, 21.6, 20.2, 15.4. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C21H24NO4S 386.1421; Found 386.1417. TLC: Rf = 0.43 (10:1
CHCl3:MeOH).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 36
1
2
3
4
5
6
7
8
9
(E)-2-(4,5-dimethyl-1-tosylpyrrolidin-3-ylidene)propanoic acid (2m). Following General
Procedure B with enyne 1m and purification of the crude material via column chromatography
(100% CHCl3 → 100:1 CHCl3:MeOH) afforded 2m as a colorless oil in 90% yield (0.45 mmol,
146 mg, d.r. = 1:1 anti:syn). Separation of the diastereomers was not possible and they were
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
characterized as a mixture. Anti isomer: H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.1 Hz,
2H), 7.31 (d, J = 8.1 Hz, 2H), 4.26 (d, J = 17.2 Hz, 1H), 3.78 (q, J = 6.5 Hz, 1H), 3.66 (dd, J =
17.3, 1.4 Hz, 1H), 3.29 (q, J = 7.0 Hz, 1H), 2.42 (s, 3H), 1.80 (s, 3H), 1.09 (d, J = 7.0 Hz, 3H),
0.78 (d, J = 7.0 Hz, 3H). 13C {1H} NMR (151 MHz, CDCl3) δ 172.1, 158.1, 143.7, 136.4, 129.9,
127.4, 120.4, 63.9, 50.4, 45.7, 21.8, 19.5, 16.0, 15.5. Syn isomer:1H NMR (500 MHz, CDCl3)
δ 7.69 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 4.15 – 4.07 (m, 1H), 4.03 (dt, J = 16.9, 1.5
Hz, 1H), 3.43 (sept, J = 6.6 Hz, 1H), 3.06 (sept, J = 6.3 Hz, 1H), 2.43 (s, 3H), 1.74 (s, 3H), 1.40
(d, J = 6.4 Hz, 3H), 1.13 (d, J = 6.5 Hz, 3H). 13C {1H} NMR (151 MHz, CDCl3) δ 172.1, 156.7,
144.1, 132.3, 130.0, 128.1, 118.7, 59.8, 54.4, 43.3, 21.8, 19.5, 16.2, 13.9. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C16H22NO4S 324.1270; Found 324.1259. TLC: Rf = 0.23 (30:1
CHCl3:MeOH).
Methyl (E)-2-(1-benzoyl-4-methylpyrrolidin-3-ylidene)propanoate (2n). Following General
Procedure B followed by General Procedure C with enyne 1n and purification of the crude
material via column chromatography (3:1 hexane:EtOAc) afforded 2n as a colorless oil in 74%
yield (0.37 mmol, 96 mg). 1H NMR (500 MHz, CDCl3) δ 7.49 (m, 2H), 7.42 (m, 3H), 4.70 (d, J
= 19.0 Hz, 1H), 4.17 (d, J = 19.0 Hz, 1H), 3.74 (s, 3H), 3.64 (m, 2H), 3.39 (d, J = 9.9 Hz, 1H),
1.89 (s, 3H), 1.11 (d, J = 6.7 Hz, 3H). 13C {1H} NMR (151 MHz, CDCl3) δ 170.0, 167.4, 154.8,
136.1, 130.1, 128.4, 127.2, 119.8, 56.7, 51.5, 49.8, 38.0, 19.7, 15.9. HRMS (ESI-TOF) m/z:
ACS Paragon Plus Environment

Page 23 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
[M+Na]+ Calcd for C16H19NO3Na 296.1263; Found 296.1247. TLC: Rf = 0.17 (3:1
hexane:EtOAc).
7
8
9
(E)-2-(1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-ylidene)propanoic acid (2o). Following
General Procedure B with enyne 1o and purification of the crude material via column
chromatography (100% CHCl3 → 100:1 CHCl3:MeOH) afforded 2o as a colorless oil in 57%
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
yield (0.29 mmol, 73 mg). Some peaks in the H and 13C NMR spectra appear as broad
1
multiplets due to the Boc group. H NMR (500 MHz, CDCl3) δ 4.25 – 4.03 (br m, 1H), 4.03 –
3.84 (br m, 1H), 3.61 (br s, 1H), 3.35 (br m, 2H), 1.76 (br s, 2H), 1.40 (s, 9H), 1.09 (d, J = 7.0
Hz, 3H). 13C {1H} NMR (151 MHz, CDCl3) δ 171.2, 155.0, 118.5, 79.8, 53.7 (br m), 50.3, 38.0
(br m), 28.5, 20.5, 15.8, 8.9. HRMS (ESI-TOF) m/z: [(M+NH4)– H2O]+ Calcd for C13H23N2O3
255.1701; Found 255.1703. TLC: Rf = 0.43 (10:1 CHCl3:MeOH).
(E)-2-(4-methyldihydrofuran-3(2H)-ylidene)propanoic acid (2p). Following General
Procedure B with enyne 1p and purification of the crude material via column chromatography
(100% CHCl3 → 100:1 CHCl3:MeOH) afforded 2p as a colorless oil in 72% yield (0.36 mmol,
1
56 mg). H NMR (600 MHz, CDCl3) δ 4.58 (d, J = 16.0 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H),
3.85-3.79 (m, 2H), 3.57 (m, 1H), 1.80 (s, 3H), 1.21 (d, J = 7.0 Hz, 3H). C {1H} NMR (151
13
MHz, CDCl3) δ 171.9, 162.3, 116.7, 76.2, 71.4, 38.9, 18.9, 15.5. HRMS (ESI-TOF) m/z:
[(M+H) – H2O]+ Calcd for C8H11O2 139.0754; Found 139.0754. TLC: Rf = 0.44 (10:1
CHCl3:MeOH).
Methyl (E)-2-(4-methyldihydrofuran-3(2H)-ylidene)-2-phenylacetate (2q). Following
General Procedure B followed by General Procedure C with enyne 1q and purification of the
crude material via column chromatography (10:1 hexane:EtOAc) afforded 2q as a colorless oil in
60% yield (0.3 mmol, 70 mg). 1H NMR (500 MHz, CDCl3) δ 7.36 (t, J = 7.3 Hz, 2H), 7.30 (t, J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 36
1
2
3
4
5
6
= 7.2 Hz, 1H), 7.14 (d, J = 7.3 Hz, 2H), 4.31 (d, J = 16.1 Hz, 1H), 4.00 (d, J = 16.1 Hz, 1H), 3.92
(dd, J = 8.5, 5.6 Hz, 1H), 3.78 (d, J = 8.5 Hz, 1H), 3.71 (s, 3H), 3.68 (m, 1H), 1.30 (d, J = 7.0
7
8
9
Hz, 3H). C {1H} NMR (151 MHz, CDCl3) δ 166.8, 162.1, 137.4, 128.8, 128.6, 127.7, 124.6,
13
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
76.1, 71.5, 51.9, 38.7, 18.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H17O3 233.2824;
Found 233.2831. TLC: Rf = 0.23 (10:1 hexane:EtOAc).
2-(4-Methylenetetrahydro-2H-pyran-3-yl)acetic acid (4a). Following General Procedure B
with enyne 3a and purification of the crude material via column chromatography (100% CHCl3
→ 10:1 CHCl3:MeOH) afforded 4a as a colorless oil in 25% yield (0.13 mmol, 20 mg). 1H NMR
(600 MHz, CDCl3) δ 4.81 (s, 1H), 4.76 (s, 1H), 3.78 (dd, J = 11.0, 3.8 Hz, 1H), 3.70 (dqd, J =
15.1, 6.7, 3.0 Hz, 2H), 3.49 (dd, J = 10.9, 5.3 Hz, 1H), 2.76 (dt, J = 11.0, 6.7 Hz, 1H), 2.62 (dd, J
= 15.9, 6.7 Hz, 1H), 2.52 (dd, J = 15.9, 7.7 Hz, 1H), 2.38 (dt, J = 12.0, 5.3 Hz, 1H), 2.24 (dt, J =
13.8, 5.3 Hz, 1H). C {1H} NMR (151 MHz, CDCl3) δ 174.7, 146.0, 108.6, 72.8, 69.8, 40.2,
13
34.2, 34.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C8H13O3 157.0859; Found 157.0847.
TLC: Rf = 0.43 (10:1 CHCl3:MeOH).
2-(4-Methylene-1-tosylpiperidin-3-yl)acetic acid (4b). Following General Procedure B with
enyne 3b at 60 °C and purification of the crude material via column chromatography (100%
CHCl3 → 10:1 CHCl3:MeOH) afforded 4b as a colorless solid in 81% yield (0.41 mmol, 125
mg). Mp 160–161 °C. 1H NMR (600 MHz, CDCl3) δ 7.63 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3
Hz, 2H), 4.76 (d, J = 13.5 Hz, 2H), 3.25 – 3.19 (m, 1H), 3.04 (d, J = 4.8 Hz, 2H), 2.91 (ddd, J =
11.4, 8.5, 4.0 Hz, 1H), 2.84 (m, 1H), 2.61 (d, J = 1.4 Hz, 2H), 2.42 (m, 4H), 2.26 (ddd, J = 13.5,
6.2, 4.0 Hz, 1H). 13C {1H} NMR (151 MHz, CDCl3) δ 176.5, 145.0, 143.8, 133.5, 129.8, 127.7,
110.4, 51.6, 47.9, 38.8, 35.3, 32.5, 21.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H20NO4S
310.1113; Found 310.1104. TLC: Rf = 0.33 (10:1 CHCl3:MeOH).
ACS Paragon Plus Environment

Page 25 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2-(5,5-bis(methoxycarbonyl)-2-methylenecyclohexyl)acetic acid (4c). Following General
Procedure B with enyne 3c and purification of the crude material via column chromatography
(100% CHCl3 → 10:1 CHCl3:MeOH) afforded 4c as a colorless solid in 44% yield (0.22 mmol,
59 mg). Mp 102–104 °C. 1H NMR (500 MHz, CDCl3) δ 4.78 (s, 1H), 4.60 (s, 1H), 3.79 (s, 3H),
3.70 (s, 3H), 2.66 (m, 2H), 2.51 (dt, J = 13.0, 2.8 Hz, 1H), 2.45 (dq, J = 13.0, 3.1, 2.8 Hz, 1H),
2.39 – 2.30 (m, 2H), 2.22 (td, J = 13.6, 4.3 Hz, 1H), 1.76 (td, J = 13.2, 4.5 Hz, 1H), 1.58 (t, J =
12.5 Hz, 1H). 13C {1H} NMR (151 MHz, CDCl3) δ 176.4, 172.4, 171.3, 148.6, 106.5, 55.3, 53.0,
52.9, 38.5, 37.2, 35.7, 33.0, 32.8. HRMS (ESI-TOF) m/z: [(M+H) – H2O]+ Calcd for C13H17O5
253.1071; Found 253.1073. TLC: Rf = 0.31 (10:1 CHCl3:MeOH).
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-methylenetetrahydro-2H-pyran-4-yl)acetic acid (4d). Following General Procedure B
with enyne 3d and purification of the crude material via column chromatography (100% CHCl3
→ 10:1 CHCl3:MeOH) afforded 4d as a colorless oil in 15% yield (0.08 mmol, 12 mg). 1H NMR
(600 MHz, CDCl3) δ 4.92 (s, 1H), 4.77 (s, 1H), 4.17 (d, J = 12.2 Hz, 1H), 4.00 – 3.91 (m, 2H),
3.63 (td, J = 11.3, 2.6 Hz, 1H), 2.82 – 2.69 (m, 2H), 2.40 (dd, J = 15.3, 7.2 Hz, 1H), 1.92 – 1.85
(m, 1H), 1.51 (dtd, J = 13.1, 10.7, 4.2 Hz, 1H). C {1H} NMR (151 MHz, CDCl3) δ 175.9,
13
145.9, 108.4, 72.9, 67.2, 36.7, 36.6, 34.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C8H13O3
157.0859; Found 157.0866. TLC: Rf = 0.33 (10:1 CHCl3:MeOH).
2-(3-methylene-1-tosylpiperidin-4-yl)acetic acid (4e). Following General Procedure B with
enyne 3e and purification of the crude material via column chromatography (100% CHCl3 →
1
10:1 CHCl3:MeOH) afforded 4e as a tan oil in 52% yield (0.26 mmol, 80 mg). H NMR (600
MHz, CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 5.02 (s, 1H), 4.79 (s, 1H),
4.01 (d, J= 12 Hz, 1H), 3.66 – 3.59 (m, 1H), 3.06 (d, J = 12 Hz, 1H), 2.71 – 2.58 (m, 2H), 2.44
(m, 4H), 2.31 (dd, J = 15.9, 7.7 Hz, 1H), 1.89 (dq, J = 12.6, 4.2 Hz, 1H), 1.43 (dtd, J = 13.1,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 36
1
2
3
4
5
6
7
8
9
10.9, 4.2 Hz, 1H). 13C {1H} NMR (151 MHz, CDCl3) δ 176.5, 143.7, 142.4, 132.9, 129.7, 127.8,
110.7, 52.7, 45.6, 36.9, 36.3, 31.4, 21.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H20NO4S
310.1113; Found 310.1108. TLC: Rf = 0.42 (10:1 CHCl3:MeOH).
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-(4,4-bis(methoxycarbonyl)-2-methylenecyclohexyl)acetic acid (4f). Following General
Procedure B with enyne 3f and purification of the crude material via column chromatography
(100% CHCl3 → 10:1 CHCl3:MeOH) afforded 4f as a colorless oil in 57% yield (0.29 mmol, 77
mg). 1H NMR (500 MHz, CDCl3) δ 4.84 (s, 1H), 4.70 (s, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 2.91
(dd, J = 13.5, 1.6 Hz, 1H), 2.68 – 2.53 (m, 3H), 2.35 (dd, J = 15.1, 7.3 Hz, 2H), 1.95-1.86 (m,
2H), 1.48 – 1.37 (m, 1H). C {1H} NMR (151 MHz, CDCl3) δ 176.6, 171.9, 171.0, 145.5,
13
109.8, 57.0, 52.9, 52.7, 40.0, 38.5, 37.0, 30.4, 30.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C13H19O6 271.1176; Found 271.1173. TLC: Rf = 0.36 (10:1 CHCl3:MeOH).
Dimethyl(E)-3-ethylidene-4-(2-methoxy-2-oxo-1-phenylethyl)cyclopentane-1,1-dicarboxylate
(4g). Following General Procedure B with enyne 3g at 60 °C followed by General Procedure C
and purification of the crude material via column chromatography (4:1 hexane:EtOAc) afforded
1
4g as a colorless oil in 60% yield (0.30 mmol, 108 mg). H NMR (500 MHz, CDCl3) δ 7.34-
7.24 (m, 5H), 5.30 (m, 1H), 3.70 (s, 3H), 3.67 (s, 3H), 3.64 (s, 3H), 3.49 (d, J = 10.7 Hz, 1H),
3.01 (d, J = 16.6 Hz, 1H), 2.90 (d, J = 19.9 Hz, 1H), 2.24 – 2.15 (m, 1H), 1.64 – 1.59 (m, 3H),
1.58 (s, 2H). C {1H} NMR (151 MHz, CDCl3) δ 173.9, 172.4, 172.1, 140.7, 137.5, 128.7,
13
128.6, 127.5, 117.9, 57.9, 56.2, 52.83, 52.77, 52.0, 45.3, 37.8, 36.9, 14.8. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C20H25O6 361.1651; Found 361.1651. TLC: Rf = 0.43 (3:1
hexane:EtOAc).
EtLi-d5.20 An oven-dried 25 mL bomb flask was evacuated and refilled with Ar. Pentane (15
mL) was added to the flask, followed by Li0 (~400 mg, 57 mmol, 10 equiv) in small chunks.
ACS Paragon Plus Environment

Page 27 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
EtBr-d5 was added (0.43 mL, 5.7 mmol, 1 equiv) and the flask was sealed. The mixture was
stirred vigorously at 40 °C for 16 hours. In a N2-filled glovebox, the mixture was filtered
through Celite. The filtrate was concentrated under vacuum to give EtLi-d5 as a colorless,
crystalline solid (202 mg, 4.9 mmol, 85%). 13C {1H} NMR (151 MHz, C6D6) δ 10.1 (sept), –1.3
(m).
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
ZnEt2-d10. The deuterated zinc reagent was generated in situ by a modified literature
procedure21 and used without isolation. ZnCl2 (16 mg, 0.12 mmol, 1 equiv) was dissolved in 1
mL Et2O in a 4 mL vial. EtLi-d5 (10 mg, 0.24 mmol, 2 equiv) was added in 0.5 mL Et2O and the
solution became turbid. After stirring for 1 hour at 23 °C, 0.5 mL pentane was added to
precipitate LiCl and the mixture was filtered. The filtrate was concentrated under vacuum and
titrated with I2 before use.22
(Z)-2-(4,4-bis(methoxycarbonyl)-2-(methyl-d)cyclopentylidene)propanoic
acid
(2a-D).
Following General Procedure A with enyne 1a and ZnEt2-d10 (2.5 equiv) followed by purification
of the crude material via column chromatography (100% CHCl3 → 10:1 CHCl3:MeOH) afforded
2a-D as a colorless solid in 85% yield (0.043 mmol, 12 mg) with 97% deuterium incorporation.
1
Mp 65–68 °C. H NMR (600 MHz, CDCl3) δ 3.77 (s, 3H), 3.73 (s, 3H), 3.60 (m, 1H), 3.30 (d,
J = 18.3 Hz, 1H), 2.98 (d, J = 18.3 Hz, 1H), 2.61 (dd, J = 13.5, 8.2 Hz, 1H), 2.19 (dd, J = 13.5,
3.5 Hz, 1H), 1.88 (s, 3H), 1.04 (d, J = 7.1 Hz, 2H). 13C {1H} NMR (151 MHz, CDCl3) δ 172.5,
172.3, 172.2, 162.7, 119.2, 58.1, 53.0, 52.9, 41.8, 40.8, 37.7, 20.2 (t), 16.4. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C13H18DO6 272.1244; Found 272.1238. TLC: Rf = 0.20 (40:1
CHCl3:MeOH).
(Z)-2-(4-(methylene-d)-1-tosylpiperidin-3-yl)acetic acid (4b-D). Following General
Procedure A with enyne 3b and ZnEt2-d10 (2.5 equiv) at 60 °C and purification of the crude
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 36
1
2
3
4
5
6
7
8
9
material via column chromatography (100% CHCl3 → 100:1 CHCl3:MeOH) afforded 4b-D as a
colorless solid in 61% yield (0.031 mmol, 10 mg) with >99% deuterium incorporation. Mp 158–
160 °C. 1H NMR (600 MHz, CDCl3) δ 7.63 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 4.75
(s, 1H), 3.28 – 3.17 (m, 1H), 3.04 (d, J = 4.5 Hz, 2H), 2.91 (ddd, J = 11.4, 8.4, 4.0 Hz, 1H), 2.88
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
– 2.80 (m, 1H), 2.61 (d, J = 7.2 Hz, 2H), 2.45 (m, 1H), 2.42 (s, 3H), 2.30 – 2.22 (m, 1H). C
{1H} NMR (151 MHz, CDCl3) δ 175.2, 144.8, 143.6, 133.4, 129.7, 127.6, 110.0 (t), 51.4, 47.8,
38.7, 36.0, 32.3, 21.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H19DNO4S 311.1170;
Found 311.1167. TLC: Rf = 0.33 (10:1 CHCl3:MeOH).
N-(but-2-yn-1-yl)-4-methyl-N-(1-phenylallyl)benzenesulfonamide (1l). 1-Phenylprop-2-en-1-
ol (154 mg, 1.15 mmol, 1 equiv) was dissolved in 10 mL dry THF under N2. PPh3 (477 mg, 1.81
mmol, 1.6 equiv) and TsNHBoc (325 mg, 1.2 mmol, 1.05 equiv) were added and the solution
was cooled to 0 °C. DEAD (0.8 mL of 40% solution in toluene, 1.9 mmol, 1.7 equiv) was added
dropwise and the reaction was stirred for 1 hour at 0 °C then 8 hours at room temperature. The
solution was diluted with EtOAc and quenched with sat. NH4Cl (aq). The aqueous phase was
extracted 2 x 5 mL EtOAc. The combined organic phase was washed with 2 x 10 mL brine and
dried over Na2SO4. Solvent was removed and the yellow residue was dissolved in 5 mL DCM
and treated with 3 mL TFA. The solution was stirred for 2 hours and solvent was removed to
give a yellow oil. Purification was accomplished via column chromatography on silica using 4:1
hexane:EtOAc to give 4-methyl-N-(1-phenylallyl)-p-toluenesulfonamide as a slightly yellow oil
(233 mg, 0.81 mmol, 70%). The spectroscopic data for this compound are in agreement with the
published spectra.23 4-Methyl-N-(1-phenylallyl)-p-toluenesulfonamide (66 mg, 0.23 mmol, 1
equiv) was dissolved in 6 mL dry THF and treated with NaH (60% in mineral oil, 12 mg, 0.28
mmol, 1.2 equiv). The mixture was stirred until the evolution of H2 ceased (30 minutes). 1-
ACS Paragon Plus Environment

Page 29 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
bromobut-2-yne (0.03 mL, 0.3 mmol, 1.3 equiv) was added and the mixture was stirred for 12
hours. The reaction was diluted with EtOAc and quenched with sat. NH4Cl (aq). The aqueous
phase was extracted 2 x 5 mL EtOAc and the combined organic phase was washed with brine
and dried over MgSO4. The product was purified via column chromatography on silica using
10:1 hexane:EtOAc giving a colorless oil (41 mg, 0.12 mmol, 65%). The spectroscopic data for
this compound are in agreement with the published spectra.24 1H NMR (600 MHz, CDCl3) δ
7.74 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 3.3 Hz, 2H), 7.23 – 7.16 (m, 5H), 6.14 (ddd, J = 17.1, 10.3,
7.6 Hz, 1H), 5.56 (d, J = 7.6 Hz, 1H), 5.19 (dt, J = 10.3, 1.2 Hz, 1H), 5.10 (dt, J = 17.1, 1.3 Hz,
1H), 4.01 (dq, J = 18.2, 2.4 Hz, 1H), 3.70 (dq, J = 18.2, 2.4 Hz, 1H), 2.37 (s, 3H), 1.51 (t, J = 2.4
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
Hz, 3H). C {1H} NMR (151 MHz, CDCl3) δ 143.0, 138.2, 137.9, 134.2, 129.0, 128.4, 128.1,
13
127.9, 127.8, 119.0, 80.7, 74.5, 63.7, 34.5, 21.6, 3.4.
N-allyl-N-(but-2-yn-1-yl)benzamide (1n). A 50 mL RBF was charged with 15 mL DMF and
60 mg of a 60% dispersion of NaH in mineral oil (1.3 mmol, 1.3 equiv) under N2. The mixture
was cooled in an ice bath and N-allylbenzamide (162 mg, 1 mmol, 1 equiv) was added as a
solution in 5 mL DMF. The mixture was stirred at 0 °C for 20 minutes, then 1-bromobut-2-yne
(0.11 mL, 1.26 mmol, 1.26 equiv) was added dropwise. The mixture was stirred at room
temperature for 12 hours, then the reaction mixture was diluted with EtOAc and quenched with
sat. NH4Cl (aq). The aqueous phase was extracted 4 x 5 mL EtOAc and the combined organic
phase was washed with 2 x 10 mL H2O, 2 x 10 mL brine, and dried over MgSO4. Column
chromatography on silica with 10:1 hexane:EtOAc gave the product as a slightly yellow oil (203
1 13
mg, 0.95 mmol, 95%). The H and C NMR spectra are broad due to restricted rotation around
the benzamide. 1H NMR (500 MHz, CDCl3) δ 7.60-7.38 (br m, 5H), 5.95-5.69 (br m, 1H), 5.26
(dq, J = 10.2, 1.4 Hz, 2H), 4.38-4.19 (br m, 2H), 4.06-3.83 (br m, 2H), 1.86 (s, 3H) C {1H}
13
ACS Paragon Plus Environment