Br?nsted Acid-Catalyzed Three-Component Reaction of Anilines, α-Oxoaldehydes, and α-Angelicalactone for the Synthesis of Complex Pyrrolidones

Article abstract of DOI:10.1021/acs.joc.5b02354

A green and efficient three-component reaction of easily available anilines, α-oxoaldehydes, and α-angelicalactone was developed for the synthesis of highly functionalized pyrrolidones using dilute sulfuric acid as the catalyst. Products were obtained in good to high yields at room temperature and under solvent-free conditions. The reaction could also be performed on a multigram scale with the same efficiency.

Full text of DOI:10.1021/acs.joc.5b02354

Subscriber access provided by CARLETON UNIVERSITY
Note
Brønsted Acid Catalyzed Three-component Reaction
of Anilines, alpha-Oxoaldehydes and alpha-
Angelicalactone for the Synthesis of Complex Pyrrolidones
Congde Huo, and Yong Yuan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02354 • Publication Date (Web): 30 Nov 2015
Downloaded from http://pubs.acs.org on December 1, 2015
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 20
The Journal of Organic Chemistry
1
2
3
4
5
6
Brønsted Acid Catalyzed Three-component Reaction of Anilines, α-Oxoaldehydes and
α-Angelicalactone for the Synthesis of Complex Pyrrolidones
7
8
9
Congde Huo,* Yong Yuan
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
Key Laboratory of EcoꢀEnvironmentꢀRelated Polymer Materials Ministry of Education; College of
Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China.
Eꢀmail: huocongde1978@hotmail.com
Table of Contents Graphic
Abstract: A green and efficient threeꢀcomponent reaction of easily available anilines, αꢀoxoaldehydes
and αꢀangelicalactone was developed for the synthesis of highly functionalized pyrrolidones using
dilute sulfuric acid as the catalyst. Products were obtained in good to high yields at room temperature
and under solventꢀfree conditions. The reaction could also be performed on a multiꢀgram scale with
the same efficiency.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 20
1
2
3
4
5
6
7
8
9
Substituted pyrrolidones are valuable Nitrogenꢀcontaining heterocycles and ubiquitously
present in natural products and pharmaceutical drugs, which are associated with a broad
spectrum of biological activities.1 Therefore, exploring of new synthesis methods of this
fiveꢀmembered heterocycle skeletons from easily accessible starting materials with a simple
operation is of great significance. To our surprise, despite the widely recognized importance
and utility of these compounds, there is still relative rare general procedure that exists for their
synthesis.2
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
Multiꢀcomponent reactions (MCRs) have already become a useful synthetic tool in modern
organic chemistry, and they allow the construction of complex molecular structures from
simple and easily available precursors with high efficiency and stepꢀeconomic feature.3
In 2007, Lavilla's group reported a novel threeꢀcomponent reaction of anilines, glyoxylate and
α
ꢀangelicalactone to construct Nꢀarylated pyrrolidones in 3 steps (1, Sc(OTf)3; 2, SOCl2/Py; 3,
TFA) (Scheme 1).2a Very recently, our group reported a new efficient copperꢀcatalyzed aerobic
oxidative dehydrogenative formal [2 + 3] cyclization of glycine derivatives with
αꢀangelicalactone to construct N
ꢀarylated pyrrolidones (Scheme 1).2b
Scheme 1. Methods for the synthesis of 1,4,5ꢀtrisubstituted pyrrolidone
However, there are still some drawbacks in both processes. For the first one, only 5 successful
pyrrolidone examples were demonstrated with multiple steps and low yields (11ꢀ31%). In the
second one,
N
ꢀaryl glycine derivatives need to be prepared before the reactions. And
ACS Paragon Plus Environment

Page 3 of 20
The Journal of Organic Chemistry
1
2
3
4
moreover, in the both preparation methods of the
N
ꢀaryl pyrrolidones, metal catalysts were
5
6
7
8
used. As one of the main interests in heterocycles is their biological activity, which is always
sensitive to the residual amount of metal reagent in the final products.4 Therefore, develop of
general, convenient and environmentally benign strategies for the synthesis of these
compounds is still of great importance and interest.
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
Under above backgrounds and our own research interests on heterocycle synthesis,2b,5 we report here a
practical oneꢀpot threeꢀcomponent procedure for the synthesis of complex pyrrolidones under metalꢀ
and solventꢀ free conditions. Only diluted H2SO4 was required as the catalyst here and the reaction
could be easily performed on a large scale (Scheme 1).
During our studies of copperꢀcatalyzed aerobic oxidative dehydrogenative formal [2+3]
cyclization of glycine derivatives with αꢀangelicalactone, careful control experiments were
carried out to investigate the details of the mechanism.2b The results indicate that copper salt is
the catalyst for the oxidation of glycine derivatives to generate imine intermediates under
aerobic conditions.2b,6 Brønsted acid was utilized as a proton donor to improve the
electrophilicity of the imines and facilitate the following nucleophilic procedures between
imines and αꢀangelicalactone. This inspired us to develop a Brønsted acid catalyzed
threeꢀcomponent reaction of anilines,
highly functionalized pyrrolidones.
αꢀoxoaldehydes and αꢀangelicalactone to construct
Initially, we examined the reaction of
pꢀtoluidine 1a, ethyl 2ꢀoxoacetate 2a and
5ꢀmethylfuranꢀ2(3H)ꢀone 3a, conducted under room temperature in neat condition using
stoichiometric amounts of concentrated sulfuric acid as the catalyst. Solventꢀfree protocol
leads to a clean and economical technology not only with the increment of safety and the
reduction of cost, but also increased amounts of reactants can be achieved in the same
equipment without huge modifications.7 We were delighted to find that the designed
threeꢀcomponent condensation product 4a could be isolated from the reaction mixture in 46%
yield within 5 minutes (Table 1, entry 1). The concentration of the sulfuric acid was then
investigated (Table 1, entries 1ꢀ4). The best yield was obtained when 5 M sulfuric acid was
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 20
1
2
3
4
5
6
7
8
9
used. Further evaluation using a higher or lower catalyst loading indicated that the optimum
yield of 4a was obtained in the presence of 30 mol % 5 M sulfuric acid (Table 1, entry 7). In
the absence of a catalyst, the reaction did not occur. Following these results, other Brønsted
acids (HCl, HBr, pꢀTSA, TFA, AcOH, TfOH) were then screened for the threeꢀcomponent
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
N
ꢀaryl pyrrolidones synthesis. However, no further increase of the yields was observed (Table
1, entries 10ꢀ15). Furthermore, the reaction completes within 1 hour. The prolonged reaction
time did not affect the product yield much. it needs to mention that 4a was always obtained as
a pair of unseparable diastereoisomers (5:1). The diastereomeric ratio was determined by 1H
NMR spectroscopic analysis of the crude reaction mixtures, and the transꢀisomer was
identified as the major stereoisomer in accordance with the literature.2a, 2b
Table 1. Screening of Reaction Conditions[a]
O
O
NH2
O
N
O
OEt
+
+
O
O
O
neat, rt
OEt
1a
3a
2a
4a
t (h)
0.1
0.2
1
4a (yield %)[b]
Entry
Catalyst
46
54
1
2
H2SO4 (18 M, 50 mol %)
H2SO4 (10 M, 50 mol %)
H2SO4 (5 M, 50 mo l%)
H2SO4 (1 M, 50 mol %)
H2SO4 (5 M, 60 mol %)
H2SO4 (5 M, 40 mol %)
H2SO4 (5 M, 30 mol %)
H2SO4 (5 M, 25 mol %)
H2SO4 (5 M, 20 mol %)
HCl (conc, 60 mol %)
HBr (conc, 60 mol %)
TsOH (60 mol %)
61
3
2
29
4
1
51
5
1
61
6
1
63
7
1
59
8
1
56
9
1
49
10
11
12
13
14
15
1
47
[c]
[c]
[c]
[c]
1
52
1
57
TFA (60 mol %)
1
trace
55
AcOH (60 mol %)
1
TfOH (60 mol %)
[a] Reaction Conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3a (2.0 mmol). [b] Isolated Yields of the
isolated products. [c] The organic acids were used as pure compound.
ACS Paragon Plus Environment

Page 5 of 20
The Journal of Organic Chemistry
1
2
3
4
Table 2. Brønsted acid catalyzed threeꢀcomponent reaction of anilines, αꢀoxoaldehydes and
5
6
αꢀangelicalactone
7
8
O
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
O
NH2
O
R3
R2
N
conditions[a]
R
O
+
R3
R2
+
O
O
O
R
R1
R1
1
3
2
4
O
O
O
O
O
O
N
N
O
O
R2
R1
4a (63%, 4.9:1)
R2 = Me 4q (29%, 5.0:1)
R1 = Me
Et
iPr
4r (48%, 5.0:1)
4s (47%, 5.1:1)
4b (66%, 5.0:1)
4c (64%, 4.8:1)
4d (62%, 4.9:1)
4e (60%, 4.5:1)
4f (28%, 5.0:1)
4g (56%, 4.5:1)
4h (62%, 5.0:1)
4i (62%, 4.9:1)
4j (43%, 4.8:1)
4k (75%, 5.1:1)
4l (71%, 5.0:1)
4m (52%, 4.8:1)
4n (50%, 5.1:1)
4o (44%, 5.1:1)
4p (57%, 4.7:1)
iPr
nBu
tBu
Cl
NO2 4t (57%, 4.9:1)
Ph
O
MeO
EtO
PhO
F
O
O
N
O
R3
Cl
Br
I
NO2
CN
R3 = Me 4u (0 %)
C(O)OEt
O
O
O
O
O
O
N
N
O
R2
R1
R1 = Me; R2 = Me 4v (55%, 4.7:1)
R1 = Me; R2 = F
R1 = Me; R2 = Cl
R = Ph
4y (47 %, 9.3:1)
4w (58%, 4.8:1)
4x (55%, 4.7:1)
[a] Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (2.0 mmol), H2SO4 (5 M, 30 mol %), neat, rt,
1ꢀ2 h. [b] Yield of the isolated product. [c] Diastereomeric ratio.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 20
1
2
3
4
5
6
7
8
9
With the optimized reaction conditions in hand, we next examined the reaction scope of this
transformation. The typical results on the synthesis of substituted pyrrolidones via this
threeꢀcomponent process are shown in Table 2. A variety of substituted anilines were first
examined. The optimal conditions were compatible with a variety of substituents, including
methoxy, nitro, cyano and ester groups. No remarkable differences in reactivity were observed
when electronꢀwithdrawing or electronꢀdonating groups were present in the aromatic ring. It's
worth noting that this is complementary to our early developed copper catalyzed approach in
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
which Nꢀaryl glycine derivative bearing strong electronꢀwithdrawing group such as nitro group
cannot be oxidized to generate corresponding product. In particular, all kinds of halo
substituents could survive in the reaction, which provide useful handles for further
transformations. Moreover, molecules bearing a fluorine atom could have a significant effect
on their pharmacological properties.8 Anilines bearing groups at the paraꢀposition all furnished
the corresponding threeꢀcomponent products in good yields. Similarly, metaꢀSubstituted
anilines and polyꢀsubstituted anilines also delivered the corresponding products in moderate to
good yields. In contrast, no product was observed with orthoꢀmethylꢀsubstituted anilines as the
substrates. We were delighted to find that 2ꢀoxoꢀ2ꢀphenylacetaldehyde was also consistent
with the optimal conditions, leading to compound 4y in 47% yield.
Scheme 2. Scalability of the reaction to the multiꢀgram scale
Scalability is an important aspect of chemical industries.9 To examine the scalability of the
present methodology, a reaction of pꢀtoluidine 1a, ethyl 2ꢀoxoacetate 2a and αꢀangelicalactone
3a was performed at the 10 grams scale. The corresponding 4a was obtained in 69% isolated
yield as shown in Scheme 2. That is to say, here we present a practical and scalable synthetic
entry to the highly functionalized pyrrolidone derivatives.
ACS Paragon Plus Environment

Page 7 of 20
The Journal of Organic Chemistry
1
2
3
4
Scheme 3. 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
To gain some insight into the pathway of this catalytic threeꢀcomponent reaction, several
control experiments were conducted. This reaction possibly undergoes one of the two
pathways either with imine
intermediate [( )+ ] as shown in Scheme 3. The following reactions were carried out. (1)
Treatment of 1a with 2a gave imine intermediate , isolated with 75% yield after 1 hour
reaction time. Subsequently, was treated with 3a in the presence of sulfuric acid (5 M, 30
mol %), which led smoothly to the expected pyrrolidone 4a in 65% isolated yield. (2)
Treatment of 1a with 3a gave amide intermediate , isolated with 68% yield after 1 hour
reaction time. However, under identical conditions, the reaction between and 2a gave 4a in
0% yield. These results clearly indicated that this threeꢀcomponent reaction proceeded through
a stepwise ( )+ pathway.
Therefore, a tentative mechanism for the H2SO4ꢀcatalyzed threeꢀcomponent cyclization
reaction is proposed in Scheme 4. The iminium ion intermediate was generated under a
Brønsted acid catalyzed nucleophilic reaction. Subsequently, nucleophilic addition of activated
intermediate with ꢀangelicalactone occurred to give intermediate . Finally, an
A as the intermediate [(1+2)+3] or with amide B as the
1+3 2
A
A
B
B
1+2 3
C
C
α
D
intramolecular nucleophilic substitution and the following deprotonation lead to product 4.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 20
1
2
3
4
Scheme 4. Proposed mechanism
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
In conclusion, we have developed a simple, highly efficient and environmentally benign
threeꢀcomponent reaction of anilines, ꢀoxoaldehydes and ꢀangelicalactone, leading to
α
α
1,4,5ꢀtrisubstituted pyrrolidone derivatives by using Bronsted acid as the proton source under
solventꢀfree conditions. This protocol is also applicable on a gramꢀscale synthesis.
Experimental Section
General Information.
The starting materials, reagents and solvents, purchased from commercial suppliers, were used
without further purification. Analytical TLC was performed with silica gel GF254 plates, and the
products were visualized by UV detection. Flash chromatography was carried out using silica gel
200−300. 1HNMR (600 MHz) and 13CNMR (150 MHz) spectra were measured with CDCl3 as solvent.
Highꢀresolution mass spectra (HRMS) were measured on an electrospray ionization (ESI) apparatus
using time of flight (TOF) mass spectrometry.
General procedure for the preparation of highly functionalized pyrrolidones 4.
To a stirred mixture of αꢀangelicalactone (3, 2.0 mmol) αꢀoxoaldehydes (2, 1.0 mmol) and anilines (1,
1.0 mmol), H2SO4 (5 M, 30 mol%) were added. The reactions were performed at room temperature
and completed within 1ꢀ2 hours as monitored by TLC. The products 4 were isolated by silica gel
column chromatography using petroleum ether/acetone (v/v 4:1 to 3:1).
ACS Paragon Plus Environment

Page 9 of 20
The Journal of Organic Chemistry
1
2
3
4
Characterization of the products
5
6
7
8
Ethyl 3-acetyl-5-oxo-1-(p-tolyl)pyrrolidine-2-carboxylate (4a).2a, 2b light Yellow oil, 63% yield (182
mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 7.30 (d, J = 7.8, 2H), 7.16 (d, J = 7.9, 2H), 5.01
(d, J = 2.0, 1H), 4.16 (q, J = 7.1, 2H), 3.37 – 3.31 (m, 1H), 3.01 (dd, J = 17.2, 10.4, 1H), 2.73 (dd, J =
17.2, 3.9, 1H), 2.31 (s, 6H), 1.19 (t, J = 7.1, 3H). 13C NMR (151 MHz, CDCl3) δ 203.7, 171.3, 170.9,
136.2, 134.8, 129.6, 123.2, 62.5, 62.0, 47.5, 33.2, 28.0, 20.9, 14.0. Minor isomer: 1H NMR (600 MHz,
CDCl3) δ = 7.33 – 7.28 (m, 2H), 7.19 – 7.13 (m, 2H), 4.83 (d, J = 8.4, 1H), 4.14 – 4.09 (m, 2H), 3.76
– 3.69 (m, 1H), 3.19 (dd, J = 16.6, 11.9, 1H), 2.61 (dd, J = 16.6, 8.6, 1H), 2.31 (s, 6H), 1.21 – 1.16 (m,
3H). 13C NMR (151 MHz, CDCl3) δ 172.5, 169.5, 136.0, 134.9, 129.7, 122.4, 63.5, 48.4, 32.8, 27.6,
20.9, 13.9. HRMS (ESI) exact mass calcd for C16H20NO4 [M+H]+ m/z 290.1392, found 290.1385.
Ethyl 3-acetyl-1-(4-ethylphenyl)-5-oxopyrrolidine-2-carboxylate (4b).2b light Yellow oil, 66% yield
(200 mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 7.32 (d, J = 7.9, 2H), 7.19 (d, J = 8.0, 2H),
5.01 (d, J = 1.9, 1H), 4.17 (q, J = 7.1, 2H), 3.37 – 3.31 (m, 1H), 3.01 (dd, J = 17.2, 10.4, 1H), 2.73 (dd,
J = 17.2, 3.8, 1H), 2.62 (q, J = 7.6, 2H), 2.31 (s, 3H), 1.23 – 1.15 (m, 6H). 13C NMR (151 MHz,
CDCl3) δ 203.8, 171.2, 170.9, 142.4, 135.0, 128.4, 123.1, 62.5, 62.0, 47.5, 33.1, 28.3, 28.0, 15.4, 14.0.
Minor isomer: 1H NMR (600 MHz, CDCl3) δ = 7.35 – 7.30 (m, 2H), 7.21 – 7.15 (m, 2H), 4.83 (d, J =
8.4, 1H), 4.14 – 4.09 (m, 2H), 3.77 – 3.69 (m, 1H), 3.19 (dd, J = 16.5, 12.0, 1H), 2.65 – 2.58 (m, 3H),
2.31 (s, 3H), 1.24 – 1.15 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 172.4, 169.5, 142.2, 135.1, 128.5,
122.4, 63.4, 61.9, 48.4, 32.8, 29.9, 28.3, 13.9. HRMS (ESI) exact mass calcd for C17H22NO4 [M+H]+
m/z 304.1549, found 304.1545.
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
Ethyl 3-acetyl-1-(4-isopropylphenyl)-5-oxopyrrolidine-2-carboxylate (4c).2b light Yellow oil, 64%
yield (203 mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 7.33 (d, J = 8.0, 2H), 7.21 (d, J = 7.9,
2H), 5.01 (d, J = 3.1, 1H), 4.17 (q, J = 7.1, 2H), 3.37 – 3.30 (m, 1H), 3.01 (dd, J = 17.2, 10.4, 1H),
2.92 – 2.83 (m, 1H), 2.74 (dd, J = 17.2, 3.9, 1H), 2.31 (s, 3H), 1.22 (d, J = 6.9, 6H), 1.18 (t, J = 7.1,
3H). 13C NMR (151 MHz, CDCl3) δ 203.7, 171.2, 170.9, 147.0, 135.0, 127.0, 123.1, 62.5, 62.0, 47.5,
33.7, 33.2, 28.0, 23.9, 14.0. Minor isomer: 1H NMR (600 MHz, CDCl3) δ = 7.35 – 7.30 (m, 2H), 7.23
– 7.19 (m, 2H), 4.83 (d, J = 8.4, 1H), 4.15 – 4.08 (m, 2H), 3.76 – 3.69 (m, 1H), 3.19 (dd, J = 16.5,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 20
1
2
3
4
5
6
7
8
12.1, 1H), 2.91 – 2.84 (m, 1H), 2.62 (dd, J = 16.7, 8.5, 1H), 2.31 (s, 3H), 1.24 – 1.16 (m, 9H). 13C
NMR (151 MHz, CDCl3) δ 172.4, 169.6, 146.8, 135.2, 127.1, 122.4, 63.5, 48.5, 33.6, 32.8, 29.9, 13.9.
HRMS (ESI) exact mass calcd for C18H24NO4 [M+H]+ m/z 318.1705, found 318.1699.
9
Ethyl 3-acetyl-1-(4-butylphenyl)-5-oxopyrrolidine-2-carboxylate (4d).2b light brown oil, 62% yield
(205 mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 7.31 (d, J = 8.2, 2H), 7.16 (d, J = 8.1, 2H),
5.01 (d, J = 2.7, 1H), 4.17 (q, J = 7.1, 2H), 3.36 – 3.31 (m, 1H), 3.01 (dd, J = 17.2, 10.4, 1H), 2.74 (dd,
J = 17.2, 3.9, 1H), 2.57 (t, J = 7.7, 2H), 2.31 (s, 3H), 1.60 – 1.52 (m, 2H), 1.37 – 1.29 (m, 2H), 1.18 (t,
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
J = 7.1, 3H), 0.90 (t, J = 7.3, 3H). C NMR (151 MHz, CDCl3) δ 203.7, 171.2, 170.9, 141.1, 134.9,
1
129.0, 123.0, 62.5, 62.0, 47.5, 35.1, 33.4, 33.2, 28.0, 22.2, 14.0, 13.9. Minor isomer: H NMR (600
MHz, CDCl3) δ = 7.34 – 7.29 (m, 2H), 7.20 – 7.13 (m, 2H), 4.83 (d, J = 8.4, 1H), 4.15 – 4.09 (m, 2H),
3.75 – 3.69 (m, 1H), 3.19 (dd, J = 16.6, 12.0, 1H), 2.62 (dd, J = 16.7, 8.6, 1H), 2.59 – 2.55 (m, 2H),
13
2.31 (s, 3H), 1.59 – 1.52 (m, 2H), 1.37 – 1.29 (m, 2H), 1.20 – 1.15 (m, 3H), 0.93 – 0.88 (m, 3H). C
NMR (151 MHz, CDCl3) δ 172.4, 169.5, 140.9, 135.1, 129.0, 122.3, 63.5, 48.4, 35.0, 32.8, 29.9, 13.9.
HRMS (ESI) exact mass calcd for C19H26NO4 [M+H]+ m/z 332.1862, found 332.1864.
Ethyl 3-acetyl-1-(4-(tert-butyl)phenyl)-5-oxopyrrolidine-2-carboxylate (4e).2b light Yellow oil, 60%
yield (199 mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 7.37 (d, J = 8.6, 2H), 7.33 (d, J = 8.2,
2H), 5.01 (d, J = 1.6, 1H), 4.18 (q, J = 7.1, 2H), 3.36 – 3.30 (m, 1H), 3.01 (dd, J = 17.2, 10.4, 1H),
2.74 (dd, J = 17.2, 3.6, 1H), 2.31 (s, 3H), 1.29 (s, 9H), 1.19 (t, J = 7.0, 3H). 13C NMR (151 MHz,
CDCl3) δ 203.7, 171.2, 170.9, 149.2, 134.7, 125.9, 122.6, 62.4, 62.0, 47.5, 34.5, 33.2, 31.2, 28.0, 14.0.
Minor isomer: 1H NMR (600 MHz, CDCl3) δ = 7.39 – 7.36 (m, 2H), 7.35 – 7.32 (m, 2H), 4.83 (d, J =
8.3, 1H), 4.15 – 4.10 (m, 2H), 3.75 – 3.69 (m, 1H), 3.19 (dd, J = 16.6, 12.0, 1H), 2.62 (dd, J = 16.6,
8.5, 1H), 2.31 (s, 3H), 1.29 (s, 9H), 1.21 – 1.16 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 172.4, 169.6,
149.0, 134.9, 126.0, 121.9, 63.4, 48.5, 34.4, 32.8, 29.9, 13.9. HRMS (ESI) exact mass calcd for
C19H26NO4 [M+H]+ m/z 332.1862, found 332.1858.
Ethyl 1-([1,1'-biphenyl]-4-yl)-3-acetyl-5-oxopyrrolidine-2-carboxylate (4f). light Yellow oil and
white solid, 28% yield (98 mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 7.61 – 7.51 (m, 6H),
7.43 (t, J = 7.4, 2H), 7.34 (t, J = 7.3, 1H), 5.12 – 5.09 (m, 1H), 4.20 (q, J = 7.0, 2H), 3.41 – 3.34 (m,
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1H), 3.05 (dd, J = 17.2, 10.4, 1H), 2.78 (dd, J = 17.2, 1.9, 1H), 2.34 (s, 3H), 1.21 (t, J = 7.1, 3H). 13C
NMR (151 MHz, CDCl3) δ 203.7, 171.3, 170.8, 140.3, 139.0, 136.7, 128.8, 127.7, 127.4, 127.0, 122.9,
62.2, 62.2, 47.5, 33.3, 28.0, 14.0. Minor isomer: 1H NMR (600 MHz, CDCl3) δ = 7.62 – 7.50 (m, 6H),
7.45 – 7.40 (m, 2H), 7.36 – 7.31 (m, 1H), 4.92 (d, J = 8.3, 1H), 4.18 – 4.13 (m, 2H), 3.79 – 3.72 (m,
1H), 3.23 (dd, J = 16.5, 12.2, 1H), 2.65 (dd, J = 16.7, 8.5, 1H), 2.34 (s, 3H), 1.24 – 1.18 (m, 3H). 13C
NMR (151 MHz, CDCl3) δ 172.5, 169.5, 140.2, 136.8, 128.8, 127.7, 127.4, 126.9, 122.1, 63.2, 48.3,
32.9, 29.9, 14.0. HRMS (ESI) exact mass calcd for C21H22NO4 [M+H]+ m/z 352.1549, found
352.1541.
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
Ethyl 3-acetyl-1-(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxylate (4g).2a, 2b brown oil, 56% yield
(171 mg). Major isomer: 1H NMR (400 MHz, CDCl3) δ = 7.35 – 7.29 (m, 2H), 6.92 – 6.87 (m, 2H),
4.98 (d, J = 3.0, 1H), 4.17 (q, J = 7.1, 2H), 3.79 (s, 3H), 3.39 – 3.32 (m, 1H), 3.01 (dd, J = 17.2, 10.4,
13
1H), 2.73 (dd, J = 17.2, 4.1, 1H), 2.32 (s, 3H), 1.23 – 1.16 (m, 3H). C NMR (151 MHz, CDCl3) δ
203.8, 171.3, 170.9, 158.0, 130.2, 125.4, 114.3, 62.8, 62.0, 55.4, 47.5, 33.0, 28.0, 14.0. Minor isomer:
1H NMR (400 MHz, CDCl3) δ = 7.35 – 7.29 (m, 2H), 6.93 – 6.85 (m, 2H), 4.80 (d, J = 8.4, 1H), 4.15
– 4.10 (m, 2H), 3.79 (s, 3H), 3.77 – 3.70 (m, 1H), 3.18 (dd, J = 16.6, 11.8, 1H), 2.62 (dd, J = 16.6, 8.6,
1H), 2.32 (s, 3H), 1.20 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 203.8, 172.5, 169.6, 157.8, 130.3,
124.7, 114.4, 63.9, 61.9, 48.4, 32.6, 29.8, 13.9. HRMS (ESI) exact mass calcd for C16H20NO5 [M+H]+
m/z 306.1342, found 306.1344.
Ethyl 3-acetyl-1-(4-ethoxyphenyl)-5-oxopyrrolidine-2-carboxylate (4h).2b brown oil, 62% yield (198
mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 7.29 (d, J = 8.9, 2H), 6.88 – 6.84 (m, 2H), 4.96 (d,
J = 3.1, 1H), 4.18 – 4.13 (m, 2H), 4.00 (q, J = 7.0, 2H), 3.36 – 3.31 (m, 1H), 2.99 (dd, J = 17.2, 10.4,
1H), 2.71 (dd, J = 17.2, 4.1, 1H), 2.30 (s, 3H), 1.38 (t, J = 7.0, 3H), 1.20 – 1.16 (m, 3H). 13C NMR
(151 MHz, CDCl3) δ 203.8, 171.3, 170.9, 157.4, 130.0, 125.3, 114.9, 63.6, 62.8, 612.0, 47.5, 33.0,
28.0, 14.7, 14.0. Minor isomer: 1H NMR (600 MHz, CDCl3) δ = 7.32 – 7.27 (m, 2H), 6.90 – 6.83 (m,
2H), 4.78 (d, J = 8.4, 1H), 4.13 – 4.09 (m, 2H), 4.03 – 3.92 (m, 2H), 3.76 – 3.68 (m, 1H), 3.17 (dd, J =
16.6, 11.9, 1H), 2.60 (dd, J = 16.6, 8.6, 1H), 2.30 (s, 3H), 1.41 – 1.36 (m, 3H), 1.20 – 1.16 (m, 3H).
13C NMR (151 MHz, CDCl3) δ 203.8, 172.5, 169.6, 157.2, 130.1, 124.7, 114.9, 63.9, 61.9, 48.4, 32.6,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 20
1
2
3
4
5
6
7
8
9
29.8, 13.9. HRMS (ESI) exact mass calcd for C17H22NO5 [M+H]+ m/z 320.1498, found 320.1503.
Ethyl 3-acetyl-5-oxo-1-(4-phenoxyphenyl)pyrrolidine-2-carboxylate (4i).2b light Yellow oil, 62%
yield (228 mg). Major isomer: 1H NMR (400 MHz, CDCl3) δ = 7.42 – 7.30 (m, 4H), 7.15 – 7.08 (m,
1H), 7.04 – 6.95 (m, 4H), 5.01 (d, J = 3.0, 1H), 4.24 – 4.16 (m, 2H), 3.40 – 3.33 (m, 1H), 3.03 (dd, J =
17.3, 10.4, 1H), 2.74 (dd, J = 17.3, 4.0, 1H), 2.33 (s, 3H), 1.24 – 1.17 (m, 3H). 13C NMR (151 MHz,
CDCl3) δ 203.7, 171.3, 170.8, 156.8, 155.5, 132.5, 129.8, 125.0, 123.5, 119.1, 119.0, 62.6, 62.1, 47.5,
33.1, 28.0, 14.0. Minor isomer: 1H NMR (400 MHz, CDCl3) δ = 7.43 – 7.28 (m, 4H), 7.15 – 7.07 (m,
1H), 7.05 – 6.95 (m, 4H), 4.83 (d, J = 8.4, 1H), 4.16 – 4.12 (m, 2H), 3.80 – 3.69 (m, 1H), 3.20 (dd, J =
16.7, 11.9, 1H), 2.64 (dd, J = 16.7, 8.6, 1H), 2.32 (s, 3H), 1.25 – 1.17 (m, 3H). 13C NMR (151 MHz,
CDCl3) δ 203.6, 172.5, 169.5, 156.8, 155.3, 132.6, 129.8, 124.3, 123.6, 119.1, 63.6, 62.1, 48.4, 32.7,
29.9, 14.0. HRMS (ESI) exact mass calcd for C21H22NO5 [M+H]+ m/z 368.1498, found 368.1497.
Ethyl 3-acetyl-1-(4-fluorophenyl)-5-oxopyrrolidine-2-carboxylate (4j).2b light Yellow oil, 43% yield
(126 mg). Major isomer: 1H NMR (400 MHz, CDCl3) δ = 7.45 – 7.37 (m, 2H), 7.10 – 7.03 (m, 2H),
5.02 (d, J = 3.0, 1H), 4.18 (q, J = 7.1, 2H), 3.42 – 3.33 (m, 1H), 3.03 (dd, J = 17.3, 10.4, 1H), 2.73 (dd,
J = 17.3, 4.0, 1H), 2.33 (s, 3H), 1.23 – 1.16 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.7, 171.3,
170.6, 161.5, 159.8, 133.4, 133.4, 125.3, 125.3, 115.9, 115.8, 62.4, 62.1, 47.4, 33.0, 28.0, 14.0. Minor
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
isomer: H NMR (400 MHz, CDCl3) δ = 7.45 – 7.36 (m, 2H), 7.12 – 7.00 (m, 2H), 4.83 (d, J = 8.4,
1H), 4.15 – 4.10 (m, 2H), 3.80 – 3.70 (m, 1H), 3.19 (dd, J = 16.7, 11.9, 1H), 2.64 (dd, J = 16.7, 8.6,
1H), 2.33 (s, 3H), 1.24 – 1.14 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.6, 172.5, 169.3, 161.2,
159.6, 133.5, 133.5, 124.5, 124.5, 116.0, 115.8, 63.5, 62.1, 48.2, 32.6, 29.9, 13.9. HRMS (ESI) exact
mass calcd for C15H17FNO4 [M+H]+ m/z 294.1142, found 294.1147.
Ethyl 3-acetyl-1-(4-chlorophenyl)-5-oxopyrrolidine-2-carboxylate (4k).2a, 2b light Yellow oil, 75%
yield (232 mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 7.40 (d, J = 8.4, 2H), 7.32 (d, J = 8.5,
2H), 5.03 (d, J = 2.5, 1H), 4.17 (q, J = 7.1, 2H), 3.37 – 3.32 (m, 1H), 3.02 (dd, J = 17.3, 10.4, 1H),
2.73 (dd, J = 17.3, 3.8, 1H), 2.31 (s, 3H), 1.20 (t, J = 7.0, 3H). 13C NMR (151 MHz, CDCl3) δ 203.5,
1
171.2, 170.6, 136.1, 131.5, 129.1, 123.9, 62.2, 62.0, 47.3, 33.2, 28.0, 14.0. Minor isomer: H NMR
(600 MHz, CDCl3) δ = 7.43 (d, J = 8.6, 2H), 7.35 – 7.30 (m, 2H), 4.84 (d, J = 8.4, 1H), 4.15 – 4.10 (m,
ACS Paragon Plus Environment

Page 13 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2H), 3.76 – 3.68 (m, 1H), 3.18 (dd, J = 16.7, 12.0, 1H), 2.62 (dd, J = 16.8, 8.5, 1H), 2.31 (s, 3H), 1.23
– 1.16 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.4, 172.4, 169.2, 136.2, 131.1, 129.2, 123.0, 63.0,
48.1, 32.8, 29.9, 13.9. HRMS (ESI) exact mass calcd for C15H17ClNO4 [M+H]+ m/z 310.0846, found
310.0850.
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
Ethyl 3-acetyl-1-(4-bromophenyl)-5-oxopyrrolidine-2-carboxylate (4l).2a, 2b light Yellow oil, 71%
yield (251 mg). Major isomer: 1H NMR (400 MHz, CDCl3) δ = 7.52 – 7.45 (m, 2H), 7.39 – 7.32 (m,
2H), 5.05 (d, J = 3.0, 1H), 4.23 – 4.14 (m, 2H), 3.41 – 3.31 (m, 1H), 3.02 (dd, J = 17.4, 10.4, 1H),
2.73 (dd, J = 17.4, 4.0, 1H), 2.32 (s, 3H), 1.23 – 1.18 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.5,
1
171.1, 170.5, 136.6, 132.1, 124.1, 119.3, 62.2, 61.9, 47.3, 33.2, 28.0, 14.0. Minor isomer: H NMR
(400 MHz, CDCl3) δ = 7.52 – 7.45 (m, 2H), 7.41 – 7.32 (m, 2H), 4.85 (d, J = 8.4, 1H), 4.15 – 4.11 (m,
2H), 3.78 – 3.69 (m, 1H), 3.19 (dd, J = 16.8, 11.9, 1H), 2.63 (dd, J = 16.8, 8.5, 1H), 2.32 (s, 3H), 1.24
– 1.17 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 172.5, 169.5, 136.0, 134.9, 129.7, 122.4, 63.5, 48.4,
37.8, 32.8, 27.6, 20.9, 13.9. HRMS (ESI) exact mass calcd for C15H17BrNO4 [M+H]+ m/z 354.0341,
found 354.0337.
Ethyl 3-acetyl-1-(4-iodophenyl)-5-oxopyrrolidine-2-carboxylate (4m).2b light Yellow oil, 52% yield
(209 mg). Major isomer: 1H NMR (400 MHz, CDCl3) δ = 7.68 (d, J = 8.4, 2H), 7.26 (d, J = 6.1, 2H),
5.05 (d, J = 2.8, 1H), 4.19 (q, J = 7.2, 2H), 3.39 – 3.32 (m, 1H), 3.02 (dd, J = 17.3, 10.4, 1H), 2.73 (dd,
J = 17.4, 3.9, 1H), 2.33 (s, 3H), 1.25 – 1.18 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.5, 171.1,
170.5, 138.0, 137.4, 124.2, 90.3, 62.2, 61.7, 47.2, 33.2, 28.0, 14.0. Minor isomer: 1H NMR (400 MHz,
CDCl3) δ = 7.72 – 7.64 (m, 2H), 7.28 – 7.22 (m, 2H), 4.85 (d, J = 8.4, 1H), 4.16 – 4.10 (m, 2H), 3.77
– 3.68 (m, 1H), 3.19 (dd, J = 16.6, 12.3, 1H), 2.63 (dd, J = 16.8, 8.6, 1H), 2.33 (s, 3H), 1.24 – 1.18 (m,
3H). 13C NMR (151 MHz, CDCl3) δ 203.4, 172.4, 169.2, 138.1, 137.5, 123.3, 89.8, 62.7, 62.2, 48.1,
32.9, 29.9, 13.9. HRMS (ESI) exact mass calcd for C15H17INO4 [M+H]+ m/z 402.0202, found
402.0200.
Ethyl 3-acetyl-1-(4-nitrophenyl)-5-oxopyrrolidine-2-carboxylate (4n). Yellow oil, 50% yield (160
mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 8.22 (d, J = 9.1, 2H), 7.71 (d, J = 8.9, 2H), 5.18 –
5.16 (m, 1H), 4.22 (q, J = 7.0, 2H), 3.42 – 3.37 (m, 1H), 3.08 (dd, J = 17.5, 10.5, 1H), 2.79 (dd, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 20
1
2
3
4
17.6, 2.6, 1H), 2.34 (s, 3H), 1.22 (t, J = 7.0, 3H). 13C NMR (151 MHz, CDCl3) δ 203.4, 171.6, 170.1,
5
6
1
144.2, 143.4, 124.6, 120.6, 62.6, 61.2, 46.9, 33.4, 27.9, 14.0. Minor isomer: H NMR (600 MHz,
7
8
9
CDCl3) δ = 8.05 (d, J = 8.9, 1H), 7.76 (d, J = 9.1, 2H), 6.61 (d, J = 8.8, 1H), 4.98 (d, J = 8.3, 1H), 4.19
– 4.12 (m, 2H), 3.79 – 3.72 (m, 1H), 3.24 (dd, J = 16.8, 12.3, 1H), 2.69 (dd, J = 16.9, 8.4, 1H), 2.34 (s,
3H), 1.25 – 1.19 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.2, 172.8, 168.7, 143.9, 143.5, 124.8,
119.7, 62.5, 62.2, 47.7, 33.1, 30.0, 13.9. HRMS (ESI) exact mass calcd for C15H17N2O6 [M+H]+ m/z
321.1087, found 321.1091.
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
Ethyl 3-acetyl-1-(4-cyanophenyl)-5-oxopyrrolidine-2-carboxylate (4o). light Yellow oil, 44% yield
(132 mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 7.67 – 7.61 (m, 4H), 5.14 – 5.11 (m, 1H),
4.20 (q, J = 7.1, 2H), 3.40 – 3.34 (m, 1H), 3.06 (dd, J = 17.5, 10.5, 1H), 2.80 – 2.73 (m, 1H), 2.33 (s,
3H), 1.23 – 1.19 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.4, 171.4, 170.2, 141.7, 133.0, 121.1,
118.5, 108.5, 62.5, 61.2, 47.0, 33.4, 28.0, 14.0. Minor isomer: 1H NMR (600 MHz, CDCl3) δ = 7.72 –
7.62 (m, 4H), 4.92 (d, J = 8.3, 1H), 4.18 – 4.12 (m, 2H), 3.76 – 3.70 (m, 1H), 3.26 – 3.19 (m, 1H),
2.67 (dd, J = 16.9, 8.5, 1H), 2.33 (s, 3H), 1.23 – 1.19 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.2,
172.7, 168.8, 141.8, 133.1, 120.2, 118.4, 108.2, 62.1, 47.8, 33.1, 30.0, 13.9. HRMS (ESI) exact mass
calcd for C16H17N2O4 [M+H]+ m/z 301.1188, found 301.1190.
Ethyl 3-acetyl-1-(4-(ethoxycarbonyl)phenyl)-5-oxopyrrolidine-2-carboxylate (4p). light Yellow oil,
57% yield (198 mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 8.04 (d, J = 8.1, 2H), 7.58 (d, J =
8.0, 2H), 5.16 – 5.10 (m, 1H), 4.35 (q, J = 7.0, 2H), 4.18 (q, J = 7.1, 2H), 3.39 – 3.33 (m, 1H), 3.05
(dd, J = 17.4, 10.5, 1H), 2.77 (dd, J = 17.4, 2.5, 1H), 2.33 (s, 3H), 1.37 (t, J = 7.0, 3H), 1.19 (t, J = 7.1,
3H). 13C NMR (151 MHz, CDCl3) δ 203.4, 171.3, 170.5, 165.8, 141.6, 130.5, 127.3, 120.7, 62.3, 61.6,
60.9, 47.1, 33.4, 28.0, 14.3, 14.0. Minor isomer: 1H NMR (600 MHz, CDCl3) δ = 8.07 – 8.00 (m, 2H),
7.62 (d, J = 8.2, 2H), 4.94 (d, J = 8.4, 1H), 4.33 – 4.28 (m, 2H), 4.16 – 4.10 (m, 2H), 3.77 – 3.69 (m,
1H), 3.23 (dd, J = 16.5, 12.3, 1H), 2.65 (dd, J = 16.8, 8.4, 1H), 2.33 (s, 3H), 1.40 – 1.35 (m, 3H), 1.22
– 1.16 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.3, 172.6, 169.1, 165.8, 141.7, 130.6, 127.0, 119.8,
62.5, 48.0, 33.1, 29.9, 13.9. HRMS (ESI) exact mass calcd for C18H22NO6 [M+H]+ m/z 348.1447,
found 348.1452.
ACS Paragon Plus Environment

Page 15 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ethyl 3-acetyl-5-oxo-1-(m-tolyl)pyrrolidine-2-carboxylate (4q). light brown oil, 29% yield (84 mg).
Major isomer: 1H NMR (400 MHz, CDCl3) δ = 7.29 – 7.18 (m, 3H), 7.03 (d, J = 7.3, 1H), 5.04 (d, J =
3.1, 1H), 4.18 (q, J = 7.1, 2H), 3.39 – 3.30 (m, 1H), 3.02 (dd, J = 17.2, 10.4, 1H), 2.75 (dd, J = 17.2,
4.1, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 1.20 (t, J = 7.1, 3H). 13C NMR (151 MHz, CDCl3) δ 203.7, 171.2,
170.9, 139.0, 137.3, 128.8, 127.2, 123.7, 120.0, 62.4, 62.0, 47.5, 33.3, 28.0, 21.4, 14.0. Minor isomer:
1H NMR (400 MHz, CDCl3) δ = 7.33 – 7.18 (m, 3H), 7.06 – 6.99 (m, 1H), 4.86 (d, J = 8.4, 1H), 4.15
– 4.10 (m, 2H), 3.77 – 3.69 (m, 1H), 3.21 (dd, J = 16.7, 11.9, 1H), 2.62 (dd, J = 16.7, 8.5, 1H), 2.36 –
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
2.30 (m, 6H), 1.23 – 1.16 (m, 3H). C NMR (151 MHz, CDCl3) δ 203.7, 172.5, 169.5, 139.0, 137.5,
128.9, 126.9, 123.0, 119.2, 63.4, 48.4, 32.9, 29.9, 21.5, 13.9. HRMS (ESI) exact mass calcd for
C16H20NO4 [M+H]+ m/z 290.1392, found 290.1391.
Ethyl 3-acetyl-1-(3-isopropylphenyl)-5-oxopyrrolidine-2-carboxylate (4r).2b light Yellow oil, 48%
yield (152 mg). Major isomer: 1H NMR (400 MHz, CDCl3) δ = 7.30 – 7.25 (m, 3H), 7.11 – 7.06 (m,
1H), 5.04 (d, J = 3.3, 1H), 4.21 – 4.14 (m, 2H), 3.39 – 3.33 (m, 1H), 3.03 (dd, J = 17.2, 10.3, 1H),
2.94 – 2.86 (m, 1H), 2.76 (dd, J = 17.2, 4.3, 1H), 2.32 (s, 3H), 1.24 (d, J = 6.9, 6H), 1.18 (t, J = 6.1,
3H). 13C NMR (151 MHz, CDCl3) δ 203.8, 171.2, 170.9, 149.9, 137.4, 128.9, 124.3, 121.0, 120.4,
1
62.5, 62.0, 47.5, 34.1, 33.3, 28.0, 23.8, 23.8, 14.0. Minor isomer: H NMR (400 MHz, CDCl3) δ =
7.34 – 7.21 (m, 3H), 7.13 – 7.04 (m, 1H), 4.87 (d, J = 8.4, 1H), 4.15 – 4.11 (m, 2H), 3.77 – 3.69 (m,
1H), 3.22 (dd, J = 16.6, 11.9, 1H), 2.96 – 2.84 (m, 1H), 2.64 (dd, J = 16.6, 8.5, 1H), 2.32 (s, 3H), 1.27
– 1.22 (m, 6H), 1.21 – 1.16 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.7, 172.4, 169.6, 150.0, 137.6,
129.0, 124.1, 120.3, 119.6, 63.4, 48.5, 34.1, 32.9, 29.8, 13.9. HRMS (ESI) exact mass calcd for
C18H24NO4 [M+H]+ m/z 318.1705, found 318.1711.
Ethyl 3-acetyl-1-(3-chlorophenyl)-5-oxopyrrolidine-2-carboxylate (4s).2b light Yellow oil, 47% yield
(145 mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 7.53 (t, J = 1.9, 1H), 7.35 – 7.32 (m, 1H),
7.30 – 7.26 (m, 1H), 7.19 – 7.16 (m, 1H), 5.04 (d, J = 3.0, 1H), 4.22 – 4.16 (m, 2H), 3.37 – 3.33 (m,
1H), 3.02 (dd, J = 17.4, 10.4, 1H), 2.74 (dd, J = 17.4, 3.6, 1H), 2.32 (s, 3H), 1.22 – 1.19 (m, 3H). 13C
NMR (151 MHz, CDCl3) δ 203.5, 171.1, 170.5, 138.7, 134.6, 130.0, 126.1, 122.6, 120.3, 62.3, 61.9,
1
47.3, 33.2, 28.0, 14.0. Minor isomer: H NMR (600 MHz, CDCl3) δ = 7.60 – 7.57 (m, 1H), 7.36 –
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 20
1
2
3
4
5
6
7.32 (m, 1H), 7.30 – 7.26 (m, 1H), 7.19 – 7.14 (m, 1H), 4.86 (d, J = 8.4, 1H), 4.17 – 4.12 (m, 2H),
3.75 – 3.68 (m, 1H), 3.19 (dd, J = 16.8, 12.0, 1H), 2.63 (dd, J = 16.8, 8.5, 1H), 2.32 (s, 3H), 1.23 –
7
8
13
1.18 (m, 3H). C NMR (151 MHz, CDCl3) δ 203.4, 172.4, 169.1, 138.8, 134.7, 130.1, 125.8, 121.7,
9
119.4, 62.8, 48.2, 32.9, 29.9, 13.9. HRMS (ESI) exact mass calcd for C15H17ClNO4 [M+H]+ m/z
310.0846, found 310.0843.
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
Ethyl 3-acetyl-1-(3-nitrophenyl)-5-oxopyrrolidine-2-carboxylate (4t). light Yellow oil, 57% yield
(182 mg). Major isomer: 1H NMR (600 MHz, CDCl3) δ = 8.31 (s, 1H), 8.05 (d, J = 8.3, 1H), 7.95 (d, J
= 8.1, 1H), 7.55 (t, J = 8.2, 1H), 5.16 – 5.14 (m, 1H), 4.25 – 4.18 (m, 2H), 3.44 – 3.40 (m, 1H), 3.07
(dd, J = 17.4, 10.5, 1H), 2.82 – 2.74 (m, 1H), 2.35 (s, 3H), 1.26 – 1.20 (m, 3H). 13C NMR (151 MHz,
CDCl3) δ 203.4, 171.4, 170.2, 148.5, 138.8, 129.9, 127.6, 120.3, 116.5, 62.5, 61.5, 47.1, 33.2, 28.0,
14.0. Minor isomer: 1H NMR (600 MHz, CDCl3) δ = 8.34 (s, 1H), 8.08 – 7.99 (m, 1H), 7.96 – 7.92 (m,
1H), 7.58 – 7.52 (m, 1H), 4.97 (d, J = 8.3, 1H), 4.19 – 4.13 (m, 2H), 3.81 – 3.73 (m, 1H), 3.24 (dd, J =
16.6, 12.0, 1H), 2.69 (dd, J = 16.7, 8.4, 1H), 2.35 (s, 3H), 1.27 – 1.19 (m, 3H). 13C NMR (151 MHz,
CDCl3) δ 203.3, 172.7, 168.9, 148.5, 138.9, 130.0, 126.9, 120.0, 115.7, 62.4, 48.0, 32.9, 30.0, 13.9.
HRMS (ESI) exact mass calcd for C15H17N2O6 [M+H]+ m/z 321.1087, found 321.1085.
Ethyl 3-acetyl-1-(3,4-dimethylphenyl)-5-oxopyrrolidine-2-carboxylate (4v).2b light Yellow oil, 55%
yield (167 mg). Major isomer: 1H NMR (400 MHz, CDCl3) δ = 7.21 (s, 1H), 7.13 – 7.08 (m, 2H), 5.00
(d, J = 3.1, 1H), 4.18 (q, J = 7.1, 2H), 3.38 – 3.29 (m, 1H), 3.01 (dd, J = 17.2, 10.4, 1H), 2.73 (dd, J =
17.2, 4.1, 1H), 2.32 (s, 3H), 2.23 (d, J = 8.8, 6H), 1.24 – 1.18 (m, 3H). 13C NMR (151 MHz, CDCl3) δ
203.8, 171.2, 170.9, 137.4, 135.1, 135.0, 130.1, 124.6, 120.7, 62.6, 62.0, 47.6, 33.2, 28.0, 19.9, 19.3,
1
14.0. Minor isomer: H NMR (400 MHz, CDCl3) δ = 7.25 – 7.22 (m, 1H), 7.13 – 7.07 (m, 2H), 4.82
(d, J = 8.4, 1H), 4.15 – 4.10 (m, 2H), 3.77 – 3.68 (m, 1H), 3.19 (dd, J = 16.6, 11.9, 1H), 2.61 (dd, J =
16.6, 8.5, 1H), 2.32 (s, 3H), 2.26 – 2.21 (m, 6H), 1.23 – 1.17 (m, 3H). 13C NMR (151 MHz, CDCl3) δ
203.8, 172.5, 169.6, 137.5, 135.1, 134.8, 130.1, 124.0, 120.0, 63.6, 48.5, 32.8, 29.9, 19.9, 19.3, 13.9.
HRMS (ESI) exact mass calcd for C17H22NO4 [M+H]+ m/z 304.1549, found 304.1551.
Ethyl 3-acetyl-1-(3-fluoro-4-methylphenyl)-5-oxopyrrolidine-2-carboxylate (4w).2b light brown oil,
58% yield (178 mg). Major isomer: 1H NMR (400 MHz, CDCl3) δ = 7.31 – 7.26 (m, 1H), 7.16 (t, J =
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
8.3, 1H), 7.07 (dd, J = 8.2, 2.1, 1H), 5.02 (d, J = 3.0, 1H), 4.20 (q, J = 7.1, 2H), 3.38 – 3.31 (m, 1H),
3.02 (dd, J = 17.3, 10.4, 1H), 2.74 (dd, J = 17.3, 4.0, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 1.25 – 1.19 (m,
3H). 13C NMR (151 MHz, CDCl3) δ 203.5, 171.1, 170.6, 161.8, 160.1, 136.5, 136.4, 131.4, 131.4,
117.4, 117.4, 109.9, 109.7, 62.2, 62.0, 47.3, 33.2, 28.0, 14.1, 14.1, 14.0. Minor isomer: 1H NMR (400
MHz, CDCl3) δ = 7.36 – 7.31 (m, 1H), 7.19 – 7.12 (m, 1H), 7.10 – 7.03 (m, 1H), 4.84 (d, J = 8.4, 1H),
4.17 – 4.12 (m, 2H), 3.77 – 3.68 (m, 1H), 3.20 (dd, J = 16.7, 12.0, 1H), 2.63 (dd, J = 16.7, 8.5, 1H),
2.32 (s, 3H), 2.24 (s, 3H), 1.25 – 1.18 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.5, 172.3, 169.3,
131.5, 131.5, 116.5, 116.5, 109.1, 108.9, 63.0, 48.2, 32.9, 29.9, 13.9. HRMS (ESI) exact mass calcd
for C16H19FNO4 [M+H]+ m/z 308.1298, found 308.1299.
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
Ethyl 3-acetyl-1-(3-chloro-4-methylphenyl)-5-oxopyrrolidine-2-carboxylate (4x).2b light brown oil,
55% yield (178 mg). Major isomer: 1H NMR (400 MHz, CDCl3) δ = 7.50 (d, J = 1.8, 1H), 7.27 – 7.19
(m, 2H), 5.02 (d, J = 2.6, 1H), 4.23 – 4.16 (m, 2H), 3.39 – 3.31 (m, 1H), 3.02 (dd, J = 17.3, 10.4, 1H),
2.73 (dd, J = 17.3, 4.0, 1H), 2.34 (s, 3H), 2.33 (s, 3H), 1.22 (t, J = 7.1, 3H). 13C NMR (151 MHz,
CDCl3) δ 203.6, 171.2, 170.6, 136.2, 134.5, 134.0, 131.0, 123.3, 120.9, 62.2, 62.0, 47.3, 33.1, 28.0,
19.5, 14.0. Minor isomer: 1H NMR (400 MHz, CDCl3) δ = 7.56 – 7.52 (m, 1H), 7.25 – 7.19 (m, 2H),
4.84 (d, J = 8.4, 1H), 4.17 – 4.12 (m, 2H), 3.77 – 3.68 (m, 1H), 3.19 (dd, J = 16.7, 12.0, 1H), 2.63 (dd,
J = 16.7, 8.5, 1H), 2.36 – 2.30 (m, 6H), 1.28 – 1.18 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 203.5,
172.4, 169.2, 136.4, 134.6, 133.7, 131.1, 122.5, 120.0, 63.0, 62.1, 48.2, 32.8, 29.9, 19.5, 13.9. HRMS
(ESI) exact mass calcd for C16H19ClNO4 [M+H]+ m/z 324.1003, found 324.0998.
4-Acetyl-5-benzoyl-1-(p-tolyl)pyrrolidin-2-one (4y). light brown oil, 47% yield (151 mg). Major
isomer: 1H NMR (400 MHz, CDCl3) δ = 7.94 (dd, J = 8.3, 1.2, 2H), 7.63 (dd, J = 10.6, 4.3, 1H), 7.50
(t, J = 7.7, 2H), 7.35 (d, J = 8.4, 2H), 7.13 (d, J = 8.3, 2H), 6.25 (d, J = 2.2, 1H), 3.21 – 3.15 (m, 1H),
3.10 (dd, J = 16.8, 10.9, 1H), 2.74 (dd, J = 16.8, 2.5, 1H), 2.29 (d, J = 6.8, 6H). 13C NMR (101 MHz,
CDCl3) δ 204.2, 195.8, 171.6, 136.0, 135.1, 134.4, 133.6, 129.6, 129.2, 128.5, 123.2, 63.7, 47.6, 33.5,
27.8, 20.9. HRMS (ESI) exact mass calcd for C15H17N2O6 [M+H]+ m/z 321.1087, found 321.1088.
Acknowledgements
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
1
2
3
4
5
6
We thank the National Natural Science Foundation of China (21262029, 21562037) and the Fok Ying
Tong Education Foundation (141116) for financially supporting this work.
7
8
9
Supporting Information Available: Copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
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
References and Footnotes
(1) (a) Guntern, A.; Ioset, J. R.; Queiroz, E. F.; Sandor, P.; Foggin, C. M.; Hostettmann, K. J. Nat.
Prod. 2003, 66, 1550. (b) Vergnon, A. L.; Pottorf, R. S.; Winters, M. P.; Player, M. R. J. Comb. Chem.
2004, 6, 903. (c) Fenical, W.; Jensen, P. R.; Palladino, M. A.; Lam, K. S.; Lloyd, G. K.; Potts, B. C.
Bioorg. Med. Chem. 2009, 17, 2175. (d) Bell, I. M.; Gallicchio, S. N.; Abrams, M.; Beshore, D. C.;
Buser, C. A.; Culberson, J. C.; Davide, J.; EllisꢀHutchings, M.; Fernandes, C.; Gibbs, J. B.; Graham, S.
L.; Hartman, G. D.; Heimbrook, D. C.; Homnick, C. F.; Huff, J. R.; Kassahun, K.; Koblan, K. S.; Kohl,
N. E.; Lobell, R. B.; Lynch, J. J.; Jr.; Miller, P. A.; Omer, C. A.; Rodrigues, A. D.; Wash, E. S.;
Williams, T. M. J. Med. Chem. 2001, 44, 2933. (e) Masse, C. E.; Morgan, A. J.; Adams, J.; Panek, J. S.
Eur. J. Org. Chem. 2000, 2513. (f) Ng, P. Y.; Tang, Y.; Knosp, W. M.; Stadler, H. S.; Shaw, J. T. Angew.
Chem. Int. Ed. 2007, 46, 5352. (g) Kenda, B. M.; Matagne, A. C.; Talaga, P. E.; Pasau, P. M.;
Differding, E.; Lallemand, B. I.; Frycia, A. M.; Moureau, F. G.; Klitgaard, H. V.; Gillard, M. R.; Fuks,
B.; Michel, P. J. Med. Chem. 2004, 47, 530.
(2) (a) Isambert, N.; Cruz, M.; Arévalo, M. J.; Gómez, E.; Lavilla, R. Org. Lett. 2007, 9, 4199. (b)
Huo, C.; Yuan, Y.; Chen, F.; Tang, J.; Wang, Y. Org. Lett. 2015, 17, 4208. (c) Brokaite, K.;
Mickevicius, V.; Mikulskiene, G. Chemistry of Heterocyclic Compounds 2006, 42, 1158. (d) Yeh,
C.ꢀH.; Korivi, R. P.; Cheng, C.ꢀH. Angew. Chem. Int. Ed. 2008, 47, 4892. (e) Wong, Y.ꢀC.;
Parthasarathy, K.; Cheng, C.ꢀH. J. Am. Chem. Soc. 2009, 131, 18252. (f) Pelletier, S. M.ꢀC.; Ray, P. C.;
Dixon, D. J. Org. Lett. 2009, 11, 4512. (g) Umemura, S.; McLaughlin, M.; Micalizio, G. C. Org. Lett.
2009, 11, 5402.
(3) (a) Zhu, J.; Wang, Q.; Wang, M. Multicomponent Reactions in Organic Synthesis, WileyꢀVCH:
Weinheim, 2014. (b) Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Soc. Rev. 2014, 43, 4633. (c)
Brauch, S.; van Berkel, S. S.; Westermann, B. Chem. Soc. Rev. 2013, 42, 4948. (d) Isambert, N.;
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Duque, M. del M. S.; Plaquevent, J.ꢀC.; Génisson, Y.; Rodriguez, J.; Constantieux, T. Chem. Soc. Rev.
2011, 40, 1347. (e) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969. (f)
Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Soc. Rev. 2010, 39, 4402.
9
(4) Feng, J.ꢀB.; Wu, X.ꢀF. Green Chem. 2015, 17, 4522.
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
(5) (a) Huo, C.; Yuan, Y.; Wu, M.; Jia, X.; Wang, X.; Chen, F.; Tang, J. Angew. Chem. Int. Ed. 2014,
53, 13544. (b) Huo, C.; Chen, F.; Yuan, Y.; Xie, H.; Wang, Y. Org. Lett. 2015, 17, 5028. (c) Huo, C.;
Yuan, Y.; Chen, F.; Wang, Y. Adv. Synth. Catal. 2015, 357, DOI: 10.1002/adsc.201500513. (d) Huo, C.;
Xie, H.; Wu, M.; Jia, X.; Wang, X.; Chen, F.; Tang, J. Chem. Eur. J. 2015, 21, 5723. (e) Huo, C.; Wu,
M.; Jia, X.; Xie, H.; Yuan, Y.; Tang, J. J. Org. Chem. 2014, 79, 9860. (f) Huo, C.; Xu, X.; An, J.; Jia,
X.; Wang, X.; Wang, C. J. Org. Chem. 2012, 77, 8310. (g) Huo, C.; An, J.; Chang, W.; Jia, X.; Kang,
L.; Wu, M. Tetrahedron 2013, 69, 6375. (h) Huo, C.; Sun , C.; Hu, D.; Jia, X.; Xu X.; Liu, Z.
Tetrahedron Lett. 2011, 52, 7008.
(6) (a) Zhao, L.; Li, C.ꢀJ. Angew. Chem. Int. Ed. 2008, 47, 7075. (b) Zhao, L.; Baslé, O.; Li, C.ꢀJ.
PNAS. 2009, 106, 4106. (c) Xie, J.; Huang, Z.ꢀZ. Angew. Chem. Int. Ed. 2010, 49, 10181. (d) Zhang,
G.; Zhang, Y.; Wang, R. Angew. Chem. Int. Ed. 2011, 50, 10429. (e) Gao, X.ꢀW.; Meng, Q.ꢀY.; Xiang,
M.; Chen, B.; Feng, K.; Tung, C.ꢀH.; Wu, LꢀZ. Adv. Synth. Catal. 2013, 355, 2158. (f) Wei, W.ꢀT.;
Song, R.ꢀJ.; Li, J.ꢀH. Adv. Synth. Catal. 2014, 356, 1703. (g) Zhu, Z.ꢀQ.; Bai, P.; Huang, Z.ꢀZ. Org.
Lett. 2014, 16, 4881. (h) Huo, C.; Wang, C.; Wu, M.; Jia, X.; Xie, H.; Yuan, Y. Adv. Synth. Catal. 2014,
356, 411. (i) Li, Y.ꢀJ.; Li, X.; Zhang, S.ꢀX.; Zhao, Y.ꢀL.; Liu, Q. Chem. Commun. 2015, 51, 11564.
(7) (a) Singh, M. S.; Chowdhury, S. RSC Adv. 2012, 2, 4547. (b) Tanaka, K.; Toda, F. Chem. Rev.
2000, 100, 1025. (c) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P. Chem.
Rev. 2009, 109, 4140. (d) Garay, A. L.; Pichon, A.; James, S. L. Chem. Soc. Rev. 2007, 36, 846. (e)
Cléophax, J.; Liagre, M.; Loupy, A.; Petit, A. Organic Process Research & Development 2000, 4,
498.
(8) (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3. (b) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Zhang, L.; Li, Z.; Liu, Z.ꢀQ. Org. Lett. 2014, 16,
3688. (d) Li, Z.; Cui, Z.; Liu, Z.ꢀQ. Org. Lett. 2013, 15, 406.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
1
2
3
4
5
6
7
8
9
(9) (a) Sharma, H.; Kaur, N.; Singh, N.; Jang, D. O. Green Chem. 2015, 17, 4263. (b) Hummel, J. R.;
Ellman, J. A. Org. Lett. 2015, 17, 2400. (c) Fiset, D.; Charette, A. B. RSC Adv. 2012, 2, 5502. (d)
Hanhan, N. V.; Tang, Y. C.; Tran, N. T.; Franz, A. K. Org. Lett. 2012, 14, 2218. (e) Weix, D. J.; Ellman,
J. A. Org. Lett. 2003. 5, 1317.
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