Regioselective β-Csp3-Arylation of β-Alanine: An Approach for the Exclusive Synthesis of Diverse β-Aryl-β-amino Acids

Article abstract of DOI:10.1021/acs.joc.8b02887

An approach for the synthesis of a variety of new β-aryl-β-amino acids has been developed via a palladium-catalyzed auxiliary-directed regioselective Csp³-H arylation of the unactivated β-methylene bond of β-alanine. The use of 8-aminoquinoline amide as an auxiliary efficiently directs the desired regioselective β-Csp³-H functionalization. The developed protocol enables the easy and straightforward access to several high-value β-aryl-β-amino acids useful for peptide engineering, starting from inexpensive and readily available β-alanine precursors in moderate to excellent yields.

Full text of DOI:10.1021/acs.joc.8b02887

Subscriber access provided by UNIV OF BARCELONA
Article
Regioselective #-Csp3-Arylation of #-Alanine: An Approach
for the Exclusive Synthesis of Diverse #-Aryl-#-Amino Acids
Sushobhan Chowdhury, Roopal Vaishnav, Namita Panwar, and Wahajul Haq
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02887 • Publication Date (Web): 04 Feb 2019
Downloaded from http://pubs.acs.org on February 4, 2019
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 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 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.
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 28
The Journal of Organic Chemistry
1
2
3
4
5
Regioselective β-Csp3-Arylation of β-Alanine: An Approach for the
Exclusive Synthesis of Diverse β-Aryl-β-Amino Acids
6
7
8
Sushobhan Chowdhury*,a Roopal Vaishnava, Namita Panwara and Wahajul Haqa,b
a
b
9
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031, India
Academy of Scientific and Innovative Research, New Delhi 11000, India
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
Abstract. An approach for the synthesis of a variety of new β-aryl-β-amino acids has been developed
via a palladium catalyzed auxiliary directed regioselective Csp3-H arylation of unactivated β-
methylene bond of β-alanine. The use of 8-aminoquinoline amide as an auxiliary efficiently directs the
desired regioselective β-Csp3-H functionalization. The developed protocol enables the easy and
straight-forward access to the several high value β-aryl-β-amino acids useful for peptide engineering
starting from inexpensive and readily available β-alanine precursors in moderate to excellent yields.
Introduction:
The importance of natural as well as the nonproteinogenic β-amino acids and non-natural linkages
consisting of those units are widely acknowledged.1 Several important drugs and drug like molecules,
structural motifs presented in biological systems consist of β-amino acids e.g. β-alanine and its
derivatives (Figure 1).2,3 It has been observed that incorporation of β-amino acids into peptide chains
induces new secondary and tertiary structures leading to their unique biological activity in different
cases. The change in the helical pitch of the peptide arising due to the incorporation of β-amino acids
can lead to their different interaction with DNA and makes them biologically active.4,5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 28
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1: Examples of bioactive molecules with β-amino acid.
Owing to their importance several synthetic methods have been derived to access natural as well as
non-natural β-amino acids e.g. Mannich reactions, Kowalsky rearrangements, radical reactions,
isoxazoline intermediates, organocatalysis, enzymatic hydrolysis of β-lactams, and metal catalysis
etc.6-9 The other routes include the step up modification of α-amino acids using Arndt-Eistert protocol,
oxazoline carbonylation/hydrolysis approach but unfortunately they came up with the limitations of
using hazardous components like diazomethane or carbon monoxide, multiple steps and the lack of
substrate versatility.1,10-11 Thus a precise method like straightforward functionalization of the simple,
inexpensive and readily available β-alanine can be a highly desirable alternative choice to access
diverse β-amino acids.
Apart from the initial works of Daugulis and Corey et al. a lot of advancement has been observed
over the last few years in the field of auxiliary directed regioselective Csp3-/Csp2-H functionalization
of amino acids. But interestingly the major attention was centred on the synthetic modifications of α-
amino acids and related derivatives.10,11 The probable reasons are the high natural abundancy of a
variety of enantiopure α-amino acids affording a range of excellent substrates to study and the relative
ease in their desired Csp3-H functionalization. More advantageously in most of the cases the desired
functionalization ends up with predefined stereochemistry induced by the neighbouring chiral
environment of the α-amino acid substrates (Figure 2). In this regard the β-amino acids with their flat
structures and remote positioning of the respective amino and carboxyl groups are comparatively tough
targets for the regioselctive Csp3-H functionalization (Figure 2) and thus are considerably less studied
although there exists immense synthetic and application scope of the β-amino acids and related
structures.
ACS Paragon Plus Environment

Page 3 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Structure-reactivity comparison of α- and β-amino acids.
Taking into account the importance and challenges of the issue we focused on the development of a
straightforward protocol for the synthesis of β-amino acids and related structures. To our delight we
report here our recently developed method for the auxiliary directed, palladium catalyzed
regioselective β-functionalization of inexpensive and readily available β-alanine via the activation of
comparatively unactivated β-Csp3-H-bond to directly generate a wide range of important natural as
well as nonproteinogenic β-aryl-β-amino acids with diverse architectural scope (Scheme 1, eq. 3).
Scheme 1. Directing group assisted Pd-catalyzed arylation of unactivated β-C(sp3)−H bonds.
In earlier reports Daugulis et al. demonstrated the auxiliary directed Pd(II)/Pd(IV)-catalyzed
arylation of comparatively unactivated β-Csp3-H-bonds of carboxylic acid amides (Scheme 1, eq. 1).12
Gradually, the concept has been utilized for β-Csp3-H functionalization of different α-amino acids
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 28
1
2
3
4
5
6
7
(Scheme 1, eq. 2).10-11,13 Later the similar concept was also used for β-Csp3-H arylation of alkanoic
amides with very limited and specific aryl scope.14 We anticipated that this might be a potential route
to achieve our desired β-Csp3-H functionalization of β-alanine.
8
9
Results and Discussion:
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 order to achieve the regioselective β-Csp3-H functionalization, an auxiliary directed Pd(II)/Pd(IV)
catalytic pathway was attempted on N-protected β-alanine (I) using its suitable amide as the directing
group. The chelating ability of the amide auxiliary is important to direct the regioselective
functionalization of β-Csp3-H as it actively involves in the cyclometalation and promotes oxidative
addition by stabilizing the high energy Pd(IV) intermediate (III). Additionally it can also decrease the
possibility of β-hydride elimination by saturating the coordination sites on palladium through the
formation of a preferred five-membered fused palladacycle (II/III) (Figure 3).10,12 Unlike α-amino
acids the sp3-carbon to be activated in this case will be α-to the amine with a possibility to impart its
effect on the proceeding catalytic sequence.
Figure 3: Proposed Pd(II)/Pd(IV)-catalytic pathway for the β-Csp3-H-functionalization.
A close review of the recent literature reveals that generally nitrogenous specifically amine based
auxiliaries are used for the Palladium catalysed functionalization of unactivated Csp3-H bonds of amino
acids and related derivatives (Figure 4).10a Out of the mentioned directing groups we opted N-
phthalimido protected β-alanine using 8-amino quinoline and thiomethyl aniline amide as the
auxiliaries for the initial screening.
ACS Paragon Plus Environment

Page 5 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4: Directing groups used for Csp3-H-functionalization of amino acid derivatives.
The initial trial prompted us to opt the former one (8-amino quinoline amide of β-alanine) 1a as the
preferred substrate to screen for the standardization of the protocol. A mixture of β-alanine substrate
o
1a (0.25 mmol) and phenyl iodide 2a (4.0 equiv., 1.0 mmol) was heated at 110 C in presence of
Pd(OAc)2 (10 mol%) and AgOAc (1.5 equiv.) which led to the formation of the desired product in 30%
yield (Table 1, Entry 1). Consequently we screened the reaction in different solvents (0.5 M) under
heating condition and an increased yield of the desired β-arylated product 3a (65%) was observed in
t-
3:1 mixture of TCE and BuOH which was set to be the optimized solvent system for the protocol
(Table 1, Entries 2-12). Different silver additives were also tested but 1.5 equiv. of AgOAc was found
to be optimum (Table 1, Entries 13-17). The use of other additives could not lead to any more increment
in the yield (Table 1, Entries 18-21). Since 10 mol% Pd(OAc)2 led to the 65% of the product (Table 1,
Entry 11), it can be realized that grossly 5 mol% of the catalyst might be needed for ~30% product
formation (Table 1, Entry 22) and thus another 5 mol% increment in the catalyst loading may increase
the product yield to the desired extent. To our delight the assumption worked well and a descent yield
(86%) of the desired β-arylated product was achieved with 15 mol% Pd(OAc)2 (Table 1, Entry 22).
A drastic decrease in the yield of the reaction was observed when the reaction was performed in
absence of AgOAc or using NaOAc instead of silver (Table 1, Entry 23, 24). It indicates the importance
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 28
1
2
3
4
5
6
7
8
9
of silver in the reaction. It is also evident from the literature review that silver plays a crucial role to
initiate/promote/complete the catalytic cycle.15a Since the yield of the product in absence of silver
shows the catalyst turn over number>2 it is clear that silver does not necessarily take part in the
regeneration of catalyst.
Two critical roles of silver can be understood in case of our reaction. In the initial step silver salt
helps in the deprotonation to form the initial cylometallated complex which is also facilitated to some
extent by the use of external base. It is also evident from our trial reaction with base like NaOAc in
absence of silver salt which slightly improved the yield (Table 1, Entry 24). Silver plays another crucial
role in the final step of reductive elimination by scavenging the iodide generated after each catalytic
cycle.
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
Moreover, it is apparent from our screening reactions that the common counter acetate anion of silver
is particularly helpful in our case than other silver additives probably because it shares common acetate
counterpart with palladium catalyst. In this context the contribution of silver in the regeneration of
catalyst cannot be completely ruled out.
The amount of aryl iodide was fixed solely on the basis of the best yield of the product with the full
consumption of starting amino acid precursor which is the limiting component here. When 1.5 equiv.
Phenyliodide was used, only 55% yield of the desired product was observed with the remaining of the
unreacted starting amino acid precursor. It is evident from the well-established Pd(II)/Pd(IV) catalytic
cycle that the key step here is the formation of Pd(IV)-intermediate through the oxidative addition of
aryl iodide. So excess aryl iodide is needed to push the key step forward and the amount of excess aryl
iodide varies from one reaction to another depending on the substrate and conditions.15b,c It is worth
to mention during work up a satisfactory portion of the excess aryl iodide can be recovered.
Table 1. Optimization of the 8-aminoquinoline amide directed β-Csp3-H arylation of β-alanine.a
Catalyst
(mol%)
Additives
(equiv.)
Temp Time Yieldb
Entry
Solvent
(°C)
110
110
110
140
(h)
15
15
15
15
(%)
30
Trace
-
1
2
3
4
Pd(OAc)2 (10) AgOAc (1.5)
Pd(OAc)2 (10) AgOAc (1.5)
Pd(OAc)2 (10) AgOAc (1.5)
Pd(OAc)2 (10) AgOAc (1.5)
-
Toluene
Dioxane
Xylene
Trace
ACS Paragon Plus Environment

Page 7 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
5
6
7
8
Pd(OAc)2 (10) AgOAc (1.5)
ACN
DMF
DMSO
DCE
TCE
80
140
140
reflux
140
110
140
140
140
140
140
140
140
15
15
15
15
15
15
10
10
15
15
15
15
15
-
-
-
Pd(OAc)2 (10) AgOAc (1.5)
Pd(OAc)2 (10) AgOAc (1.5)
Pd(OAc)2 (10) AgOAc (1.5)
Pd(OAc)2 (10) AgOAc (1.5)
Pd(OAc)2 (10) AgOAc (1.5)
Pd(OAc)2 (10) AgOAc (1.5)
Pd(OAc)2 (10) AgOAc (1.5)
Pd(OAc)2 (10) AgOAc (2.0)
Pd(OAc)2 (10) Ag2CO3 (1.5)
Pd(OAc)2 (10) Ag3PO4 (1.5)
Pd(OAc)2 (10) AgOTf (1.5)
Pd(OAc)2 (10) AgTFA (1.5)
30
50
-
65
52
63
48
52
38
42
9
10
11
12
13
14
15
16
17
t-BuOH
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
TCE+ t-BuOH (3:1)
TCE+ H2O (3:1)
TCE+ t-BuOH (3:1)
TCE+ t-BuOH (3:1)
TCE+ t-BuOH (3:1)
TCE+ t-BuOH (3:1)
TCE+ t-BuOH (3:1)
AgOAc (1.5),
PivOH (0.2)
18
19
20
21
Pd(OAc)2 (10)
TCE+ t-BuOH (3:1)
TCE+ t-BuOH (3:1)
TCE+ t-BuOH (3:1)
TCE+ t-BuOH (3:1)
140
140
140
140
15
15
15
15
51
57
58
64
AgOAc (1.5),
TFA (1.0)
Pd(OAc)2 (10)
AgOAc (1.5),
Oxone (1.0)
Pd(OAc)2 (10)
AgOAc (1.5),
NaOAc (1.5)
Pd(OAc)2 (10)
22
23
24
Pd(OAc)2 (15) AgOAc (1.5) TCE+ t-BuOH (3:1)
140
140
140
7
15
15
86
36
45
Pd(OAc)2 (15)
-
TCE+ t-BuOH (3:1)
TCE+ t-BuOH (3:1)
Pd(OAc)2 (15) NaOAc (1.5)
a All the reactions were performed in 0.25 mmol scale with 1:4 substrate 1 to aryl iodide 2 ratio under
stipulated temperature and time. b Isolated yields are given.
With the optimization condition in hand we attempted to explore the substrate tolerance of the
developed protocol. As evident from Table 2, aryl iodides bearing electron donating or electron neutral
substituents react faster than those bearing electron withdrawing substituents. Para-substituted aryl
iodides are the best tolerated under the developed condition with the formation of the desired products
in excellent yields. The reaction is sluggish in case of meta-substituted aryl iodides affording the
corresponding β-arylated products in moderate yields while the ortho-substituted aryl iodides failed to
generate the desired β-arylated products (Table 2). Heteroaryl iodides e.g. 2- and 3-iodothiophene
worked well under the optimized condition giving moderate to good yields of the corresponding
products whereas 3-iodopyridine ended up with trace amount of product (Table 2).
Table 2. Substrate scope for the auxilary directed β-Csp3-H-Arylation of β-amino acids.a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 28
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In case of meta- and ortho-substituted aryl iodides β-hydride elimination of the substrate appeared
to be the major competitive side reaction decreasing the yield of the desired product (Scheme 2).
Scheme 2: Predominant β-hydride elimination in case of ortho/meta-substituted aryl iodides.
The β-elimination is often a common problem for the developed protocols using this DG-mediated
palladium catalyzed functionalization strategy. Except in discrete cases16 often the problem remained
ACS Paragon Plus Environment

Page 9 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
unresolved and ended up with decreased yields of the desired products limiting the scope of the
developed protocols. Since in case of β-alanine the problem is quite severe, so in our next attempt we
tried to resolve the problem of β-elimination in case of reactions with the sterically hindered meta- and
ortho-substituted aryl iodides.
Table 3: Steric modification of the precursor to minimize β-elimination for
ortho-and meta-substituted aryl iodides.
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 anticipated that the hindrance will be more from the phthalimide protected amine side since it is
vicinal to the site of activation. Therefore we tried to reduce the bulkiness of the palladium intermediate
by replacing the phthalimide protecting group with the succinimide of the corresponding substrate. To
our delight the strategy solved the problem to a good extent yielding the desired β-arylated products in
good yields for meta-substituted aryl iodides with full consumption of starting material and low to
moderate yield for ortho-substituted aryl iodides keeping rest of the starting material unreacted (Table
3). Interestingly the β-elimination side product was observed only in few cases in negligible amount.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 28
1
2
3
4
5
6
7
8
9
We extended the scope of the protocol by screening its compatibility with aryl iodides bearing
chemically susceptible groups. Notably, the protocol was found to be highly compatible with aryl
iodides bearing hydroxyl (-OH), carboxyl (-COOH) and nitro (-NO2) substituents yielding the
corresponding β-arylated products in good to excellent yields. Since reaction is sluggish for aryl iodides
bearing electron withdrawing groups, it did not proceed at all for aryl iodides bearing nitro (-NO2)
group at para- and ortho-position where it is highly electron withdrawing by both of its –I and strongest
–R effects. In case of meta-NO2 only weak –I effect operates and thus makes the corresponding reaction
feasible. However none of the iodoanilines worked well under this condition giving the corresponding
product in trace amount (Table 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
Table 4. Scopes of the protocol for aryl iodides bearing chemically susceptible substituents.a
We further explored the compatibility of the protocol in gram scale synthesis. To our delight the
protocol worked well in gram scale with the substrate 1a giving 3a in good yield (79%). Finally, the
AQ-auxiliary was successfully removed from the β-arylated product 3a in sequential steps following
initially reported Chen’s protocol to get back the corresponding native β-aryl-β-amino acids 8 in
satisfactory yield (76%) (Scheme 3).17
Scheme 3: Gram scale compatibility of the protocol and removal of directing group (DG).
ACS Paragon Plus Environment

Page 11 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conclusion:
In conclusion we have developed an efficient, generalized straightforward approach for the
regioselctive β-functionalization of β-alanine. Notably, the directing group mediated palladium
catalyzed protocol is compatible to a wide variety of aryl iodides leading to the corresponding β-aryl-
β-amino acids in satisfactory yields. The predominant problem of β-elimination is also solved
reasonably by reducing the steric effect in the palladium intermediate by choosing less bulky N-
protecting group. Thus the protocol offers straightforward access to a variety of protected non-
proteinogenic β-aryl-β-amino acids starting from simple, inexpensive β-alanine precursors enabling
their further transformation to the native β-amino acids suitable for peptide and drug research.
Experimental Section:
General information:
All reactions were carried out in oven or flame dried glassware with magnetic stirring. The
chemicals were purchased from Sigma-Aldrich, Alfa-Aesar, TCI-chemicals and Spectrochem Pvt. Ltd.
Solvents were procured from Merck, CDH, Finar Ltd. and QUALIGENS. Unless noted all the
chemicals and the solvents were used as received. Reactions were monitored by thin layer
chromatography (TLC) on readymade TLC silica gel 60F254 plates (Merck, Dermstadt, Germany). The
TLC plates were either seen directly under UV light or developed under iodine vapors, Dragendorff's
stain or by charring with HBr/Ninhydrin solution. Silica gel of 100-200 mesh was used for column
chromatography. High resolution mass spectrometry (HRMS) data for all new products were obtained
under ESI model apparatus equipped with TOF analyzer (Available models are Waters Agilent 6520-
Q-TofMS/MS system and JEOL-AccuTOF JMST100LC). 1H NMR spectra were recorded on 300,400
and 500MHz spectrometers at room temperature in appropriate solvents using TMS as internal standard
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 28
1
2
3
4
5
6
7
or the solvent signals as secondary standards and the chemical shifts (δ) are shown in ppm scales. 13C
spectra were recorded at 75, 100 and 125MHz with complete proton decoupling. 19F spectra were
recorded at 376 MHz.
8
9
Synthesis of β-alanine precursors:
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
Synthesis of 3-(1,3-Dioxoisoindolin-2-yl)-N-(quinolin-8-yl)propanamide 1a:14a
Step 1: Synthesis of 3-(1,3-dioxoisoindolin-2-yl)propanoic acid: A mixture of β-alanine (C3H7NO2)
(40.0 mmol, 3.563 g) and phthalic anhydride (C8H4O3) (40.0 mmol, 5.924 g) were taken in a 250 mL
round bottom flask fitted with a guard tube. The mixture was stirred at 160 ̊C for 5 h. After the
stipulated time period the mixture was cooled down to room temperature, dissolved in minimum
amount of boiling methanol. Upon diluting the solution with ice-water the phthalimide protected β-
alanine was crushed out as white solid. The precipitate was filtered through sintered funnel, dried and
used for the next step.
Step 2a: Synthesis of acid chloride: 10.0 mmol (2.19 g) of phthalimide protected β-alanine was
suspended in 20.0 mL of dry DCM in a round bottom flask. To it 1.8 mL (2.5 equiv.) of oxalyl chloride
(COCl)2 was added at 0 ̊C followed by few drops of N,N-dimethylformamide (DMF). The mixture was
allowed to come to r.t. and stirred for 6 h. After the stipulated time corresponding acid chloride thus
formed was dried in rotary evaporator to get a muddy residue.
Step 2b: Synthesis of 8-aminoquinoline amide precursor: 8-aminoquinoline (11.0 mmol, 1.6 g) was
taken in a 250 mL 2-neck round bottom flask. To it 20.0 mL of dry DCM was added and the solution
was stirred for 10 min. in a ice bath. The acid chloride obtained in the previous step was dissolved in
20.0 mL dry DCM and added to it dropwise followed by the dropwise addition of 1.5 equiv. (2.0 mL)
of triethylamine (Et3N) at 0 ̊C under nitrogen atmosphere and the whole mixture was stirred for
overnight. After the completion of reaction as monitored by TLC, the mixture was diluted with 20.0
mL DCM and washed with saturated solution of ammonium chloride (NH4Cl) followed by 2 times
washing with the saturated solution of sodiumbicarbonate (NaHCO3). The organic layer was collected,
dried over anhydrous sodium sulfate (Na2SO4) and concentrated on rotary evaporator. The crude
product was purified by column chromatography on silica gel with increasing amount of ethyl acetate
in hexane to afford the desired compound as off white solid.
Synthesis of 3-(1,3-dioxoisoindolin-2-yl)-N-(2-(methylthio)phenyl)propanamide 1b:
ACS Paragon Plus Environment

Page 13 of 28
The Journal of Organic Chemistry
1
2
3
4
5
Step 1: Synthesis of 3-(1,3-dioxoisoindolin-2-yl)propanoic acid: A mixture of β-alanine (C3H7NO2)
(40.0 mmol, 3.563 g) and phthalic anhydride (C8H4O3) (40.0 mmol, 5.924 g) were taken in a 250 mL
6
7
round bottom flask fitted with a guard tube. The mixture was stirred at 160 ̊C for 5 h. After the
8
9
stipulated time period the mixture was cooled down to room temperature, dissolved in minimum
amount of boiling methanol. Upon diluting the solution with ice-water the phthalimide protected β-
alanine was crushed out as white solid. The precipitate was filtered through sintered funnel, dried and
used for the next step.
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
Step 2a: Synthesis of acid chloride: 10.0 mmol (2.19 g) of phthalimide protected β- alanine was
suspended in 20.0 mL of dry DCM in a round bottom flask. To it 1.8 mL (2.5 equiv.) of oxalyl chloride
(COCl)2 was added at 0 ̊C followed by few drops of N,N-dimethylformamide (DMF). The mixture was
allowed to come to r.t. and stirred for 6 h. After the stipulated time corresponding acid chloride thus
formed was dried in rotary evaporator to get a muddy residue.
Step 2b: Synthesis of 2-thiomethyl anilineamide precursor:13b 11.0 mmol (1.38 mL) of 2-
(methylthio)aniline in 20.0 mL of DCM was taken in a 250 mL round bottom flask and the solution
was stirred for 10 min. in a ice bath. The acid chloride obtained in the previous step was dissolved in
20.0 mL dry DCM and added to it dropwise followed by the dropwise addition of 1.5 equiv. (2.0 mL)
of triethylamine (Et3N) at 0 ̊C under nitrogen atmosphere and the whole mixture was stirred for
overnight. After the completion of reaction as monitored by TLC, the mixture was diluted with 20.0
mL DCM and washed with saturated solution of ammonium chloride (NH4Cl) followed by washing
with the saturated solution of sodiumbicarbonate (NaHCO3). The organic layer was collected, dried
over anhydrous sodium sulfate (Na2SO4) and concentrated on rotary evaporator. The crude product
was purified by column chromatography on silica gel with increasing amount of ethyl acetate in hexane
to afford the desired compound as yellowish white solid.
Synthesis of 3-(2,5-dioxopyrrolidin-1-yl)-N-(quinolin-8-yl)propanamide 5:
Step 1: Synthesis of 3-(2,5-dioxopyrrolidin-1-yl)propanoic acid:15a A mixture of 20.0 mmol (1.80
g) of β-alanine(C3H7NO2) and 20.0 mmol (2.00 g) of succinic anhydride (C4H2O3) were taken in a 100
mL round bottom flask fitted with a guard tube. The above mixture was stirred at 160 ̊C for 8h. After
the stipulated time period the reaction mixture was cooled down to room temperature. The pasty
material was suspended in 20.0 mL of boiling chlroform and the turbid solution was filtered. The flask
and filter cake were rinsed with the additional of 5.0 mL chloroform. The combined filterates were
cooled down to room temperature and then placed in referigerator for overnight. The resulting beige
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 28
1
2
3
4
5
coloured prcipitate thus formed was collected by vaccum filtration and further dried in rotary
evaporator.
6
7
8
9
Step 2a: Synthesis of acid chloride: 10.0 mmol (1.71 g) of succinamide protected β- alanine in 20.0
mL of dry DCM was taken in a round bottom flask. To it 1.8 mL (2.5 equiv.) of oxalyl chloride (COCl)2
was added at 0 ̊C followed by few drops of N,N-dimethylformamide (DMF). The mixture was allowed
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 come at r.t. and stirred for 6 h. After the stipulated time corresponding acid chloride thus formed
was dried in rotary evaporator to get a muddy residue.
Step 2b: Synthesis of final 8-aminoquinoline amide precursor: 8-aminoquinoline (11.0 mmol, 1.6
g) was taken in a 250 mL 2-neck round bottom flask. To it 20.0 mL of dry DCM was added and the
solution was stirred for 10 min. in a ice bath. The acid chloride obtained in the previous step was
dissolved in 20.0 mL dry DCM and added to it dropwise followed by the dropwise addition of 1.5
equiv. (2.0 mL) of triethylamine (Et3N) at 0 ̊C under nitrogen atmosphere and the whole mixture was
stirred for overnight. After the completion of reaction as monitored by TLC, the mixture was diluted
with 20.0 mL DCM and washed with water. The organic layer was collected, dried over anhydrous
sodium sulfate (Na2SO4) and concentrated on rotary evaporator. The crude product was purified by
column chromatography on silica gel with increasing amount of ethyl acetate in hexane to afford the
desired compound as off white solid.
General Procedure for the Synthesis of β-aryl-β-amino acids:
A screw-capped reaction tube with a magnetic bead was charged with 0.5 mmol of the β-alanine
precursor. To it 1.0 mL solvent (TCE+t-BuOH in 3:1 ratio) was added followed by the addition of aryl
iodide (1.5-4.0 equiv.), Pd(OAc)2 (15 mol%) and AgOAc (1.5 equiv.). The resultant mixture was
heated at requisite temperature for the required period of time with checking TLC at a regular time
interval to monitor the maximum consumption of the starting material. After the stipulated period of
time the crude reaction mixture was diluted with 10 mL DCM and filtered through G3 sintered glass
funnel. The residue was further washed with DCM (2x5 mL). For carboxylic acid and phenolic
compounds ethyl acetate was used for dilution of the reaction mixture. All the portions of the filtrate
was collected together, reduced to minimum volume under vacuo and directly charged into column.
The product was purified by column chromatography over silica gel with increasing amount of ethyl
acetate in hexane or toluene. In case of acidic and phenolic compounds acetic was used with the eluting
solvent.
ACS Paragon Plus Environment

Page 15 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Deprotection of 8-amino quinoline amide directing group:16
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
Step 1: A reaction tube was charged with a solution of compound 3a (0.3 mmol, 1 equiv) in dry
acetonitrile (4.0 mL). To it 4-(dimethylamino)pyridine (0.4 mmol, 1.3 equiv) and Boc anhydride (0.4
mmol, 1.3 equiv) was added subsequently. The whole reaction mixture was stirred at room temperature
for 24 hours and then concentrated under reduced pressure. The crude mixture was purified by column
chromatography over silica gel in 40% ethylacetate in hexane to give the N-Boc intermediate as white
foam in 92% yield.
Step 2: The N-Boc intermediate obtained in previous step was dissolved totally (0.27 mmol, 1 equiv)
in THF and water (3.0 mL+1.0 mL) and taken in a 25 mL round bottom flask. The solution was cooled
to 0 oC followed by the addition of 30% hydrogen peroxide (2.4 mmol, 9 equiv) and lithium hydroxide
o
monohydrate (0.3 mmol, 1.1 equiv). The reaction mixture was stirred at 0 C for 3 hours. After the
time period the reaction was quenched at 0 oC with 1.5 M aqueous sodium thiosulfate and the solvent
was concentrated under reduced pressure. The residue solution was was acidified to pH 2 with 10%
HCl solution and extracted with ethyl acetate (10 mL) twice. The organic extracts were dried over
anhydrous sodium sulfate, concentrated under reduced pressure and purified by column
chromatography over silica gel using increasing amount of methanol in DCM to afford the pure
compound as sticky white solid in 83% yield.
Characterization data of the isolated compounds:
1
3-(1,3-Dioxoisoindolin-2-yl)propanoic acid:14a Yield: 82% (7.2 g), Texture: white solid, H NMR
(501 MHz, DMSO-d6) δ 12.34 (s, 1H), 7.87 – 7.82 (m, 4H), 3.80 (t, J = 7.4 Hz, 2H), 2.61 (t, J = 7.4
Hz, 2H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 172.5, 168.1, 134.8, 132.1, 123.5, 34.1, 32.8.
3-(1,3-Dioxoisoindolin-2-yl)-N-(quinolin-8-yl)propanamide 1a: Yield: 75% (2.8 g), Texture: off
1
white solid, Rf = 0.4 (30% EtOAc/hexane). H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 8.74 – 8.69
(m, 2H), 8.13 (dd, J = 8.3, 1.6 Hz, 1H), 7.85 – 7.81 (m, 2H), 7.72 – 7.67 (m, 2H), 7.53 – 7.46 (m, 2H),
7.41 (dd, J = 8.3, 4.2 Hz, 1H), 4.19 (t, J = 7.3 Hz, 2H), 3.02 (t, J = 7.3 Hz, 2H); 13C{1H} NMR (101
MHz, CDCl3) δ 168.3, 168.1, 148.1, 138.2, 136.3, 134.2, 133.9, 132.1, 127.9, 127.3, 123.3, 121.6,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 28
1
2
3
4
5
+
121.6, 116.7, 36.0, 34.3; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C20H16N3O3 =346.1186;
Found=346.1181.
6
7
8
9
3-(1,3-Dioxoisoindolin-2-yl)-N-(2-(methylthio)phenyl)propanamide 1b: Yield: 81% (2.7 g),
Texture: Yellowish white solid, Rf = 0.5 (30% EtOAc/hexane). 1H NMR (400 MHz, CDCl3) δ 8.28 –
8.24 (m, 2H), 7.86 – 7.82 (m, 2H), 7.73 – 7.69 (m, 2H), 7.44 (d, J = 7.5 Hz, 1H), 7.26 (dd, J = 8.9, 5.8
Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 4.13 (t, J = 7.3 Hz, 2H), 2.89 (t, J = 7.1 Hz, 2H), 2.33 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 168.1, 137.9, 134.0, 132.7, 132.1, 129.0, 128.8, 125.5, 124.6, 123.3, 120.9,
35.8, 34.2, 18.9; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C18H17N2O3S+= 341.0954;
Found=341.0957.
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
3-(2,5-Dioxopyrrolidin-1-yl)propanoic acid:15a Yield: 87% (3.0 g), Texture: beige coloured solid, 1H
NMR (400 MHz, DMSO-d6) δ 3.57 (t, J = 7.6 Hz, 2H), 2.60 (s, 4H), 2.4 (t, J = 7.6 Hz, 2H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 177.6, 172.4, 34.3, 32.0, 28.4.
3-(2,5-Dioxopyrrolidin-1-yl)-N-(quinolin-8-yl)propanamide 5: Yield: 72% (2.1 g), Texture: off
white solid, Rf = 0.1 (50% EtOAc/hexane). 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 8.74 (ddd, J =
8.7, 5.5, 1.8 Hz, 2H), 8.14 (dd, J = 8.3, 1.6 Hz, 1H), 7.58 – 7.40 (m, 3H), 4.00 (t, J = 7.3 Hz, 2H), 2.90
(t, J = 7.3 Hz, 2H), 2.71 (s, 4H).; 13C{1H} NMR (101 MHz, CDCl3) δ 177.0, 168.2, 148.1, 138.2, 136.4,
134.1, 127.9, 127.4, 121.7, 121.6, 116.6, 35.1, 28.2; HRMS (ESI-TOF) m/z: [M+H]+ calculated for
+
C16H16N3O3 = 298.1186; Found=298.1181.
3-(1,3-Dioxoisoindolin-2-yl)-3-phenyl-N-(quinolin-8-yl)propanamide 3a: Yield: 85% (178 mg),
1
Texture: White solid; Rf = 0.45 (30% EtOAc/hexane). H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H),
8.74 (dd, J = 4.2, 1.6 Hz, 1H), 8.70 – 8.65 (m, 1H), 8.09 (dd, J = 8.3, 1.6 Hz, 1H), 7.79 – 7.75 (m, 2H),
7.64 – 7.60 (m, 4H), 7.44 – 7.26 (m, 6H), 6.09 (dd, J = 10.0, 5.6 Hz, 1H), 4.12 (dd, J = 15.8, 10.0 Hz,
1H), 3.49 (dd, J = 15.7, 5.7 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 168.1, 148.2, 139.1,
138.2, 136.2, 134.2, 133.9, 131.9, 128.8, 128.1, 127.9, 127.8, 127.3, 123.3, 121.6, 116.6, 51.4, 39.4;
+
HRMS (ESI-TOF) m/z: [M+H]+ calculated for C26H20N3O3 =422.1499; Found=422.1502.
3-(1,3-Dioxoisoindolin-2-yl)-N-(quinolin-8-yl)-3-(p-tolyl)propanamide 3b: Yield: 83% (180 mg),
Texture: White solid; Rf = 0.5 (30% EtOAc/hexane). 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 8.74
(dd, J = 4.2, 1.7 Hz, 1H), 8.69 – 8.65 (m, 1H), 8.09 (dd, J = 8.3, 1.7 Hz, 1H), 7.78 – 7.74 (m, 2H), 7.63
– 7.59 (m, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.42 (dq, J = 12.5, 4.0 Hz, 3H), 7.14 (d, J = 7.9 Hz, 2H), 6.05
(dd, J = 10.0, 5.7 Hz, 1H), 4.08 (dd, J = 15.7, 10.0 Hz, 1H), 3.47 (dd, J = 15.7, 5.7 Hz, 1H), 2.29 (s,
ACS Paragon Plus Environment

Page 17 of 28
The Journal of Organic Chemistry
1
2
3
4
5
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 168.7, 148.1, 138.2, 137.9, 136.2, 136.1, 134.2, 133.8,
131.9, 129.4, 127.8, 127.3, 123.3, 121.6, 116.6, 51.1, 39.4, 21.1; HRMS (ESI-TOF) m/z: [M+H]+
6
7
+
calculated for C27H22N3O3 =436.1656; Found-436.1656.
8
9
3-(1,3-Dioxoisoindolin-2-yl)-N-(quinolin-8-yl)-3-(m-tolyl)propanamide 3c: Yield: 56% (122 mg),
Texture: white solid; Rf = 0.5 (30% EtOAc/hexane). 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 8.75
(dd, J = 4.2, 1.6 Hz, 1H), 8.72 – 8.64 (m, 1H), 8.10 (dd, J = 8.3, 1.6 Hz, 1H), 7.83 – 7.73 (m, 2H), 7.68
– 7.59 (m, 2H), 7.49 – 7.36 (m, 5H), 7.23 (dd, J = 11.6, 5.0 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.05 (dd,
J = 10.1, 5.6 Hz, 1H), 4.12 (dd, J = 15.7, 10.1 Hz, 1H), 3.47 (dd, J = 15.7, 5.6 Hz, 1H), 2.34 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 168.1, 148.1, 139.0, 138.5, 138.2, 136.2, 134.2, 133.8,
131.9, 128.9, 128.7, 128.6, 127.8, 127.3, 124.9, 123.3, 121.6, 116.6, 51.4, 39.4, 21.5; HRMS (ESI-
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
+
TOF) m/z: [M+H]+ calculated for C27H22N3O3 =436.1656; Found=436.1642.
3-(1,3-Dioxoisoindolin-2-yl)-3-(4-methoxyphenyl)-N-(quinolin-8-yl)propanamide 3d: Yield: 81%
(182 mg), Texture: Off white solid; Rf = 0.5 (30% EtOAc/hexane). 1H NMR (400 MHz, CDCl3) δ 9.91
(s, 1H), 8.72 (d, J = 32.2 Hz, 2H), 8.13 (d, J = 8.2 Hz, 1H), 7.78 (dd, J = 5.0, 2.7 Hz, 2H), 7.64 – 7.57
(m, 4H), 7.46-7.43 (m, 3H), 6.87 (d, J = 8.4 Hz, 2H), 6.06 – 6.02 (m, 1H), 4.07 (dd, J = 15.5, 9.9 Hz,
1H), 3.77 (s, 3H), 3.49 (dd, J = 15.4, 5.3 Hz, 1H).; 13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 168.2,
159.3, 148.0, 138.1, 136.4, 134.2, 133.8, 132.0, 131.3, 129.3, 127.9, 127.3, 123.3, 121.6, 121.5, 116.8,
+
114.1, 55.2, 50.9, 39.5; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C27H22N3O4 =452.1605;
Found=452.1613.
3-(4-Chlorophenyl)-3-(1,3-dioxoisoindolin-2-yl)-N-(quinolin-8-yl)propanamide 3e: Yield: 77%
(175 mg), Texture: White solid; Rf = 0.4 (30% EtOAc/hexane). 1H NMR (400 MHz, CDCl3) δ 9.89 (s,
1H), 8.74 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 – 8.64 (m, 1H), 8.10 (dd, J = 8.3, 1.6 Hz, 1H), 7.81 – 7.76 (m,
2H), 7.66 – 7.63 (m, 2H), 7.58 (dd, J = 8.9, 2.1 Hz, 2H), 7.46 – 7.39 (m, 3H), 7.32 – 7.29 (m, 2H), 6.07
(dd, J = 9.5, 6.1 Hz, 1H), 4.03 (dd, J = 15.7, 9.5 Hz, 1H), 3.52 (dd, J = 15.7, 6.1 Hz, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 168.2, 167.7, 148.2, 138.2, 137.5, 136.3, 134.1, 134.0, 131.8, 129.4, 128.9,
127.8, 127.2, 123.4, 121.7, 121.6, 116.7, 50.7, 39.3; HRMS (ESI-TOF) m/z: [M+H]+ calculated for
+
C26H19ClN3O3 =456.1109; Found=456.1108.
3-(1,3-Dioxoisoindolin-2-yl)-3-(4-fluorophenyl)-N-(quinolin-8-yl)propanamide 3f: Yield: 79%
(173 mg), Texture: White solid; Rf = 0.5 (30% EtOAc/hexane). 1H NMR (501 MHz, CDCl3) δ 9.89 (s,
1H), 8.71 (d, J = 44.6 Hz, 2H), 8.11 (d, J = 8.1 Hz, 1H), 7.79 (s, 2H), 7.64-7.62 (m, 4H), 7.45 – 7.41
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 28
1
2
3
4
5
6
7
8
9
(m, 3H), 7.02 (t, J = 8.4 Hz, 2H), 6.07 (dd, J = 8.7, 6.6 Hz, 1H), 4.04 (dd, J = 15.5, 9.7 Hz, 1H), 3.51
(dd, J = 15.6, 5.8 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.2, 167.8, 162.4 (d, J = 247.0 Hz),
148.2, 138.2, 136.3, 134.9 (d, J = 3.2 Hz), 134.1, 133.9, 131.8, 129.8 (d, J = 8.2 Hz), 127.8, 127.2,
123.4, 121.7, 121.6, 116.7, 115.6 (d, J = 21.5 Hz), 50.7, 39.5; 19F NMR (376 MHz, CDCl3) δ -113.80;
+
HRMS (ESI-TOF) m/z: [M+H]+ calculated for C26H19FN3O3 =440.1405; Found=440.1397.
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
3-(1,3-Dioxoisoindolin-2-yl)-3-(3-fluorophenyl)-N-(quinolin-8-yl)propanamide 3g: Yield: 61%
(133 mg), Texture: White solid; Rf = 0.5 (30% EtOAc/hexane). 1H NMR (400 MHz, CDCl3) δ 9.90 (s,
1H), 8.76 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 – 8.64 (m, 1H), 8.11 (dd, J = 8.3, 1.6 Hz, 1H), 7.81-7.78 (m,
2H), 7.67 – 7.64 (m, 2H), 7.47-7.28 (m, 6H), 6.97 (td, J = 8.4, 1.7 Hz, 1H), 6.08 (dd, J = 9.7, 5.9 Hz,
1H), 4.06 (dd, J = 15.8, 9.7 Hz, 1H), 3.50 (dd, J = 15.8, 5.9 Hz, 1H);13C{1H} NMR (101 MHz, CDCl3)
δ 168.2, 167.7, 162.9 (d, J = 246.8 Hz) 148.2, 141.4 (d, J = 6.9 Hz), 138.2, 136.3, 134.1, 134.0, 131.8,
130.3 (d, J = 8.2 Hz), 127.8, 127.2, 123.6 (d, J = 2.2 Hz), 123.4, 121.7 (d, J = 6.3 Hz), 116.7, 115.3,
115.05, 115.00 (d, J = 22.2 Hz), 50.8, 39.3; 19F NMR (376 MHz, CDCl3) δ -112.02; HRMS (ESI-TOF)
+
m/z: [M+H]+ calculated for C26H19FN3O3 =440.1405; Found=440.1396.
3-(3-Chloro-4-fluorophenyl)-3-(1,3-dioxoisoindolin-2-yl)-N-(quinolin-8-yl)propanamide
3h:
1
Yield: 52% (123 mg), Texture: White solid; Rf = 0.45 (30% EtOAc/hexane). H NMR (400 MHz,
CDCl3) δ 9.99 (s, 1H), 8.78 (dd, J = 4.1, 1.3 Hz, 1H), 8.70 – 8.65 (m, 1H), 8.17 – 8.15 (m, 1H), 7.83 –
7.79 (m, 2H), 7.74 (dd, J = 6.9, 2.2 Hz, 1H), 7.69 – 7.64 (m, 2H), 7.55 (ddd, J = 8.5, 4.4, 2.3 Hz, 1H),
7.49 – 7.44 (m, 3H), 7.11 (t, J = 8.7 Hz, 1H), 6.06 (dd, J = 9.4, 6.2 Hz, 1H), 4.03 (dd, J = 15.8, 9.4 Hz,
1H), 3.57 (dd, J = 15.8, 6.2 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.1, 167.6, 157.8 (d, J =
247.0 Hz), 147.9, 137.8, 136.7, 136.2 (d, J = 3.7 Hz), 134.1, 133.9, 131.7, 130.4, 128.0 (d, J = 7.3 Hz),
127.9, 127.4, 123.5, 121.7 (d, J = 23.2 Hz), 121.2 (d, J = 17.8 Hz), 117.1, 116.8 (d, J = 21.2 Hz), 50.3,
39.2; 19F NMR (376 MHz, CDCl3) δ -115.88; HRMS (ESI-TOF) m/z: [M+H]+ calculated for
+
C26H18ClFN3O3 =474.1015; Found=474.1018.
3-(1,3-Dioxoisoindolin-2-yl)-N-(quinolin-8-yl)-3-(3-(trifluoromethyl)phenyl)propanamide
3i:
1
Yield: 54% (132 mg), Texture: White solid; Rf = 0.5 (30% EtOAc/hexane). H NMR (400 MHz,
CDCl3) δ 9.91 (s, 1H), 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 – 8.63 (m, 1H), 8.10 (dd, J = 8.3, 1.6 Hz,
1H), 7.92 – 7.77 (m, 4H), 7.67 – 7.62 (m, 2H), 7.56 – 7.39 (m, 5H), 6.15 (dd, J = 9.8, 5.8 Hz, 1H), 4.11
(dd, J = 15.8, 9.8 Hz, 1H), 3.52 (dd, J = 15.8, 5.8 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 168.2,
167.5, 148.2, 140.0, 138.2, 136.3, 134.1, 131.8, 131.5, 131.2 (q, J = 32.4 Hz), 129.4, 127.8, 127.2,
ACS Paragon Plus Environment

Page 19 of 28
The Journal of Organic Chemistry
1
2
3
4
5
125.1 (q, J = 3.6 Hz), 124.8 (d, J = 3.7 Hz), 123.9 (q, J = 272.6 Hz), 123.5, 121.7, 121.6, 116.7, 50.9,
39.2; 19F NMR (376 MHz, CDCl3) δ -62.48; HRMS (ESI-TOF) m/z: [M+H]+ calculated for
6
7
+
C27H19F3N3O3 = 490.1373; Found=490.1379.
8
9
Ethyl-4-(1-(1,3-dioxoisoindolin-2-yl)-3-oxo-3-(quinolin-8-ylamino)propyl)benzoate 3j: Yield:
78% (192 mg), Texture: White solid; Rf = 0.4 (10% EtOAc/Toluene). 1H NMR (501 MHz, CDCl3) δ
9.90 (s, 1H), 8.74 – 8.66 (m, 2H), 8.10 (d, J = 7.6 Hz, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 1.9
Hz, 2H), 7.67 (dd, J = 24.8, 5.0 Hz, 4H), 7.45 – 7.40 (m, 3H), 6.15 (dd, J = 8.6, 6.6 Hz, 1H), 4.35 (q,
J = 7.0 Hz, 2H), 4.07 (dd, J = 15.6, 9.7 Hz, 1H), 3.54 (dd, J = 15.7, 5.8 Hz, 1H), 1.36 (t, J = 7.0 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.2, 167.7, 166.1, 148.2, 143.7, 138.2, 136.2, 134.1, 134.0,
131.8, 130.3, 130.1, 127.8, 127.8, 127.2, 123.4, 121.7, 121.6, 116.6, 60.9, 51.0, 39.1, 14.3; HRMS
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
+
(ESI-TOF) m/z: [M+H]+ calculated for C29H24N3O5 = 494.1710; Found=494.1712.
3-([1,1'-Biphenyl]-4-yl)-3-(1,3-dioxoisoindolin-2-yl)-N-(quinolin-8-yl)propanamide 3l: Yield:
53% (131 mg), Texture: White solid; Rf = 0.5 (30% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3) δ
9.92 (s, 1H), 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.72 – 8.64 (m, 1H), 8.10 (dd, J = 8.3, 1.7 Hz, 1H), 7.84 –
7.75 (m, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.67 – 7.60 (m, 2H), 7.59 – 7.50 (m, 4H), 7.47 – 7.36 (m, 5H),
7.33 (dd, J = 4.9, 3.7 Hz, 1H), 6.14 (dd, J = 9.8, 5.8 Hz, 1H), 4.13 (dd, J = 15.7, 9.8 Hz, 1H), 3.55 (dd,
J = 15.7, 5.8 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 168.3, 168.0, 148.2, 141.1, 140.6, 138.3,
138.1, 136.2, 134.2, 133.9, 131.9, 128.8, 128.4, 127.9, 127.5, 127.4, 127.3, 127.1, 123.4, 121.6, 121.6,
+
116.7, 51.1, 39.4; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C32H24N3O3 =498.1812;
Found=498.1809.
3-(1,3-Dioxoisoindolin-2-yl)-N-(quinolin-8-yl)-3-(thiophen-2-yl)propanamide 3m: Yield: 55%
(117 mg), Texture: Pale yellow solid; Rf = 0.55 (10% EtOAc/Toluene). 1H NMR (501 MHz, CDCl3)
δ 9.89 (s, 2H), 8.77 – 8.68 (m, 4H), 8.11 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 3.0 Hz, 4H), 7.65 (d, J = 1.8
Hz, 4H), 7.46 – 7.22 (m, 6H), 6.95 (s, 2H), 6.36 (dd, J = 9.2, 6.1 Hz, 2H), 4.06 (dd, J = 15.6, 9.7 Hz,
2H), 3.56 (dd, J = 15.6, 5.7 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.7, 167.4, 148.2, 141.5,
138.2, 136.2, 134.1, 133.9, 131.9, 127.8, 127.2, 126.7, 126.6, 125.5, 123.4, 121.7, 121.6, 116.7, 46.5,
40.8; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C24H18N3O3S+=428.1063; Found=428.1051.
3-(1,3-Dioxoisoindolin-2-yl)-N-(quinolin-8-yl)-3-(thiophen-3-yl)propanamide 3n: Yield: 72%
(153 mg), Texture: Pale yellow solid; Rf = 0.6 (10% EtOAc/Toluene). 1H NMR (501 MHz, CDCl3) δ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 28
1
2
3
4
5
6
7
8
9
9.88 (s, 1H), 8.77 – 8.68 (m, 2H), 8.12 (d, J = 8.2 Hz, 1H), 7.80 – 7.79 (m, 2H), 7.66 – 7.65 (m, 2H),
7.47 – 7.26 (m, 6H), 6.18 (dd, J = 9.3, 6.0 Hz, 1H), 4.02 (dd, J = 15.5, 9.8 Hz, 1H), 3.49 (dd, J = 15.5,
5.6 Hz, 1H);13C{1H} NMR (101 MHz, CDCl3) δ 168.1, 167.9, 148.1, 139.6, 138.2, 136.3, 134.2, 133.9,
131.9, 127.8, 127.3, 127.2, 126.2, 123.5, 123.3, 121.6, 121.6, 116.7, 46.7, 39.9; HRMS (ESI-TOF)
m/z: [M+H]+ calculated for C24H18N3O3S+=428.1063; Found=428.1061.
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
3-(1,3-Dioxoisoindolin-2-yl)-N-(quinolin-8-yl)acrylamide 4: Texture: Off white sticky solid; Rf =
0.45 (10% EtOAc/Toluene). 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.90 (dd, J = 7.4, 1.4 Hz, 1H),
8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.18 (dd, J = 8.3, 1.6 Hz, 1H), 8.13 (d, J = 14.2 Hz, 1H), 8.00 – 7.96
(m, 2H), 7.88 – 7.75 (m, 3H), 7.60 – 7.52 (m, 2H), 7.48 (dd, J = 8.3, 4.2 Hz, 1H), 7.42 (d, J = 14.2 Hz,
1H); 13C{1H} NMR (126 MHz, CDCl3) δ 165.7, 164.1, 148.2, 138.4, 136.4, 135.1, 134.7, 131.5, 129.3,
+
127.9, 127.5, 124.2, 121.7, 116.9, 111.8; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C20H14N3O3
= 344.1030; Found=344.1024.
3-(2,5-Dioxopyrrolidin-1-yl)-3-(3-fluorophenyl)-N-(quinolin-8-yl)propanamide 6a: Yield: 81%
1
(158 mg), Texture: Pale yellow sticky solid; Rf = 0.3 (50% EtOAc/Hexane). H NMR (400 MHz,
CDCl3) δ 9.85 (s, 1H), 8.74 (ddd, J = 13.3, 6.6, 3.1 Hz, 2H), 8.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.52 – 7.46
(m, 2H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.35 – 7.25 (m, 3H), 7.01 – 6.96 (m, 1H), 5.89 (dd, J = 10.1,
5.6 Hz, 1H), 4.00 (dd, J = 15.7, 10.2 Hz, 1H), 3.34 (dd, J = 15.7, 5.6 Hz, 1H), 2.65 (s, 4H); 13C{1H}
NMR (101 MHz, CDCl3) δ 177.2, 167.8, 162.8 (d, J = 246.4 Hz), 148.3, 140.8 (d, J = 7.1 Hz), 138.2,
136.3, 134.1, 130.3 (d, J = 8.2 Hz), 127.9, 127.3, 123.7 (d, J = 2.3 Hz), 121.7 (d, J = 10.1 Hz), 116.7,
19
115.4, 115.2, 115.1 (d, J = 22.2), 51.5, 38.2, 28.1; F NMR (376 MHz, CDCl3) δ -112.04; HRMS
+
(ESI-TOF) m/z: [M+H]+calculated for C22H19FN3O3 = 392.1405; Found=392.1406.
3-(3-Bromophenyl)-3-(2,5-dioxopyrrolidin-1-yl)-N-(quinolin-8-yl)propanamide 6b: Yield: 76%
1
(170 mg), Texture: Pale yellow sticky solid; Rf = 0.25 (50% EtOAc/Hexane). H NMR (400 MHz,
CDCl3) δ 9.84 (s, 1H), 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 8.66 (p, J = 4.4 Hz, 1H), 8.10 (dd, J = 8.3, 1.7
Hz, 1H), 7.73 (t, J = 1.7 Hz, 1H), 7.51 – 7.39 (m, 5H), 7.18 (t, J = 7.9 Hz, 1H), 5.85 (dd, J = 10.1, 5.6
Hz, 1H), 3.98 (dd, J = 15.7, 10.1 Hz, 1H), 3.32 (dd, J = 15.7, 5.6 Hz, 1H), 2.63 (s, 4H); 13C{1H} NMR
(101 MHz, CDCl3) δ 177.2, 167.7, 148.2, 140.6, 138.2, 136.3, 134.0, 131.4, 131.1, 130.3, 127.8, 127.2,
126.8, 122.7, 121.8, 121.7, 116.6, 51.4, 38.1, 28.1; HRMS (ESI-TOF) m/z: [M+H]+ calculated for
+
C22H19BrN3O3 = 452.0604; Found=452.0603.
ACS Paragon Plus Environment

Page 21 of 28
The Journal of Organic Chemistry
1
2
3
4
5
3-(3-Chlorophenyl)-3-(2,5-dioxopyrrolidin-1-yl)-N-(quinolin-8-yl)propanamide 6c: Yield: 79%
1
(161 mg), Texture: Pale yellow sticky solid; Rf = 0.2 (50% EtOAc/Hexane). H NMR (400 MHz,
6
7
8
9
CDCl3) δ 9.85 (s, 1H), 8.80 (dd, J = 4.2, 1.7 Hz, 1H), 8.71 – 8.66 (m, 1H), 8.15 (dd, J = 8.3, 1.7 Hz,
1H), 7.59 (s, 1H), 7.52 – 7.43 (m, 4H), 7.30-7.26 (m, 2H), 5.87 (dd, J = 10.2, 5.6 Hz, 1H), 4.01 (dd, J
= 15.7, 10.2 Hz, 1H), 3.33 (dd, J = 15.7, 5.6 Hz, 1H), 2.66 (s, 4H); 13C{1H} NMR (101 MHz, CDCl3)
δ 177.1, 167.7, 148.3, 140.3, 138.2, 136.3, 134.6, 134.1, 130.0, 128.5, 128.2, 127.9, 127.3, 126.3,
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
+
121.8, 121.7, 116.7, 51.5, 38.2, 28.1; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C22H19ClN3O3 =
408.1109; Found=408.1100.
Methyl-3-(1-(2,5-dioxopyrrolidin-1-yl)-3-oxo-3-(quinolin-8-ylamino)propyl)benzoate 6d: Yield:
72% (155 mg), Texture: Pale yellow sticky solid; Rf = 0.2 (50% EtOAc/Hexane). 1H NMR (400 MHz,
CDCl3) δ 9.86 (s, 1H), 8.79 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (t, J = 4.5 Hz, 1H), 8.23 (s, 1H), 8.14 (dd, J
= 8.3, 1.6 Hz, 1H), 8.02 – 7.94 (m, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 4.5 Hz, 2H), 7.46 – 7.40
(m, 2H), 5.96 (dd, J = 10.3, 5.5 Hz, 1H), 4.06 (dd, J = 15.6, 10.3 Hz, 1H), 3.91 (s, 3H), 3.37 (dd, J =
15.6, 5.5 Hz, 1H), 2.66 (s, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.2, 167.8, 166.7, 148.3, 138.8,
138.2, 136.3, 134.1, 132.6, 130.7, 129.6, 129.0, 128.9, 127.9, 127.3, 121.8, 121.7, 116.7, 52.2, 51.6,
+
38.2, 28.1; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C24H22N3O5 = 432.1554; Found=432.1555.
3-(2,5-Dioxopyrrolidin-1-yl)-3-(2-methoxyphenyl)-N-(quinolin-8-yl)propanamide 6g: Yield: 42%
1
(85 mg)%, Texture: Pale yellow sticky solid; Rf = 0.3 (50% EtOAc/Hexane). H NMR (400 MHz,
CDCl3) δ 9.84 (s, 1H), 8.79 (dd, J = 4.2, 1.7 Hz, 1H), 8.71 (dd, J = 6.2, 2.8 Hz, 1H), 8.15 (dd, J = 8.3,
1.7 Hz, 1H), 7.53 – 7.43 (m, 4H), 7.30 – 7.25 (m, 1H), 6.95 (td, J = 7.6, 0.9 Hz, 1H), 6.89 (d, J = 8.2
Hz, 1H), 6.24 (dd, J = 11.0, 4.6 Hz, 1H), 3.96 – 3.87 (m, 4H), 3.24 (dd, J = 15.4, 4.6 Hz, 1H), 2.67 (s,
4H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.4, 168.7, 156.6, 148.2, 138.3, 136.3, 134.3, 129.2, 128.1,
127.9, 127.4, 126.4, 121.6, 121.5, 120.4, 116.6, 110.7, 55.6, 46.8, 38.0, 28.1; HRMS (ESI-TOF) m/z:
+
[M+H]+ calculated for C23H22N3O4 =404.1605; Found=404.1606.
3-(3,5-Bis(trifluoromethyl)phenyl)-3-(2,5-dioxopyrrolidin-1-yl)-N-(quinolin-8-yl)propan amide
6h: Yield: 75% (190 mg), Texture: White solid; Rf = 0.3 (50% EtOAc/Hexane). 1H NMR (400 MHz,
CDCl3) δ 9.88 (s, 1H), 8.79 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 – 8.64 (m, 1H), 8.14 (dd, J = 8.3, 1.7 Hz,
1H), 8.07 (s, 2H), 7.83 (s, 1H), 7.51 – 7.43 (m, 3H), 6.02 (dd, J = 10.0, 5.7 Hz, 1H), 4.04 (dd, J = 15.7,
10.0 Hz, 1H), 3.39 (dd, J = 15.7, 5.7 Hz, 1H), 2.70 (s, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.0,
167.0, 148.3, 140.8, 138.2, 136.3, 133.9, 132.1 (q, J = 33.5 Hz), 128.6 (d, J = 2.8 Hz), 127.9, 127.2,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 28
1
2
3
4
5
123.1 (q, J = 272.9 Hz), 122.4 (p, J = 3.8 Hz), 121.9, 121.7, 116.7, 51.1, 37.8, 28.0; 19F NMR (376
+
MHz, CDCl3) δ -62.77; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C24H18F6N3O3 = 510.1247;
6
7
Found=510.1245.
8
9
3-(3,4-Dimethylphenyl)-3-(2,5-dioxopyrrolidin-1-yl)-N-(quinolin-8-yl)propanamide 6i: Yield:
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
77% (155 mg), Texture: Pale yellow gelly; Rf = 0.2 (50% EtOAc/Hexane). H NMR (400 MHz,
CDCl3) δ 9.85 (s, 1H), 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.73 – 8.68 (m, 1H), 8.14 (dd, J = 8.3, 1.6 Hz,
1H), 7.52 – 7.42 (m, 3H), 7.33 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 7.5 Hz, 1H), 5.84 (dd, J = 10.4, 5.4 Hz,
1H), 4.05 (dd, J = 15.6, 10.5 Hz, 1H), 3.30 (dd, J = 15.5, 5.4 Hz, 1H), 2.61 (s, 4H), 2.25 (s, 3H), 2.23
(s, 3H); C{1H} NMR (101 MHz, CDCl3) δ 177.3, 168.3, 148.2, 138.3, 136.9, 136.8, 136.3, 135.9,
13
134.2, 129.9, 129.3, 127.9, 127.3, 125.4, 121.6, 116.6, 51.9, 38.5, 28.1, 19.8, 19.4; HRMS (ESI-TOF)
+
m/z: [M+H]+ calculated for C24H24N3O3 =402.1812; Found=402.1812.
3-(2,4-Dimethoxyphenyl)-3-(2,5-dioxopyrrolidin-1-yl)-N-(quinolin-8-yl)propanamide 6k: Yield:
37% (80 mg), Texture: White solid; Rf = 0.25 (50% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3) δ
9.82 (s, 1H), 8.78 (dd, J = 4.2, 1.7 Hz, 1H), 8.73 – 8.68 (m, 1H), 8.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.52 –
7.42 (m, 4H), 6.48 – 6.43 (m, 2H), 6.17 (dd, J = 10.8, 4.9 Hz, 1H), 3.90 – 3.79 (m, 7H), 3.22 (dd, J =
15.3, 4.9 Hz, 1H), 2.64 (s, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.3, 168.6, 160.6, 157.8, 148.1,
138.3, 136.3, 134.3, 129.0, 127.9, 127.3, 121.6, 121.5, 118.8, 116.6, 104.1, 98.5, 55.6, 55.3, 46.3, 38.3,
28.1; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C24H24N3O5 =434.1710; Found=434.1708.
+
4-(1-(1,3-Dioxoisoindolin-2-yl)-3-oxo-3-(quinolin-8-ylamino)propyl)benzoic acid 7a: Yield: 80%
(186 mg), Texture: White solid; Rf = 0.45 (EtOAc/Toluene/Acetic acid in 10:88:2 ratio). 1H NMR (400
MHz, DMSO-d6) δ 10.39 (s, 1H), 8.90 (d, J = 3.8 Hz, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.36 (d, J = 8.2
Hz, 1H), 8.05 – 7.54 (m, 10H), 7.49 (t, J = 7.9 Hz, 1H), 5.96 (t, J = 7.7 Hz, 1H), 3.80 (d, J = 8.2 Hz,
2H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.1, 168.1, 167.4, 149.2, 144.3, 138.7, 136.9, 135.1,
134.8, 131.7, 130.6, 130.0, 128.3, 127.8, 127.5, 123.7, 122.5, 122.4, 117.6, 50.6, 38.4; HRMS (ESI-
+
TOF) m/z: [M+H]+ calculated for C27H20N3O5 = 466.1397; Found=466.1398.
3-(1-(1,3-Dioxoisoindolin-2-yl)-3-oxo-3-(quinolin-8-ylamino)propyl)benzoic acid 7b: Yield: 74%
(172 mg), Texture: White solid; Rf = 0.45 (EtOAc/Toluene/Acetic acid in 10:88:2 ratio). 1H NMR (501
MHz, DMSO-d6) δ 10.43 (s, 1H), 8.90 (dd, J = 4.2, 1.6 Hz, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.35 (dd, J
= 8.3, 1.5 Hz, 1H), 8.13 (s, 1H), 7.94 – 7.73 (m, 6H), 7.67 – 7.56 (m, 2H), 7.50 (dt, J = 14.4, 7.9 Hz,
2H), 5.96 (t, J = 7.8 Hz, 1H), 3.83 (d, J = 7.8 Hz, 2H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.3,
ACS Paragon Plus Environment

Page 23 of 28
The Journal of Organic Chemistry
1
2
3
4
5
168.2, 167.5, 149.3, 140.1, 138.7, 136.9, 135.1, 134.8, 132.3, 131.6, 129.4, 129.1, 128.6, 128.3, 127.3,
+
123.7, 122.6, 122.5, 117.6, 50.7, 38.4; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C27H20N3O5 =
6
7
466.1397; Found=466.1395.
8
9
3-(1,3-Dioxoisoindolin-2-yl)-3-(4-hydroxyphenyl)-N-(quinolin-8-yl)propanamide 7c: Yield: 77%
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
(170 mg), Texture: Off white solid; Rf = 0.5 (EtOAc/Toluene/Acetic acid in 10:88:2 ratio). H NMR
(501 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.56 (s, 1H), 8.88 (s, 1H), 8.42 (d, J = 7.5 Hz, 1H), 8.35 (d, J
= 8.2 Hz, 1H), 7.82 (d, J = 5.5 Hz, 4H), 7.60 (dd, J = 15.4, 6.4 Hz, 2H), 7.49 (t, J = 7.9 Hz, 1H), 7.32
(d, J = 8.2 Hz, 2H), 6.73 (d, J = 8.2 Hz, 2H), 5.77 (t, J = 7.7 Hz, 1H), 3.76 (dd, J = 15.3, 9.6 Hz, 2H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 169.4, 168.3, 157.2, 149.3, 138.6, 136.9, 135.1, 134.7, 131.6,
129.9, 128.9, 128.2, 127.3, 123.6, 122.6, 122.5, 117.5, 115.7, 50.6, 38.8; HRMS (ESI-TOF) m/z:
+
[M+H]+ calculated for C26H20N3O4 = 438.1448; Found=438.1449.
3-(2,5-Dioxopyrrolidin-1-yl)-3-(3-hydroxyphenyl)-N-(quinolin-8-yl)propanamide 7d: Yield: 58%
1
(110 mg), Texture: Off white solid; Rf = 0.3 (EtOAc/Hexane/Acetic acid in 50:48:2 ratio). H NMR
(400 MHz, CDCl3) δ 9.85 (s, 1H), 8.76 (dd, J = 4.2, 1.6 Hz, 1H), 8.66 (p, J = 4.4 Hz, 1H), 8.12 (dd, J
= 8.3, 1.6 Hz, 1H), 7.50 – 7.40 (m, 3H), 7.20-7.08 (m, 3H), 6.79 (dd, J = 8.0, 1.7 Hz, 1H), 5.83 (dd, J
= 10.4, 5.3 Hz, 1H), 4.03 (dd, J = 15.6, 10.5 Hz, 1H), 3.32 (dd, J = 15.6, 5.4 Hz, 1H), 2.62 (s, 4H);
13C{1H} NMR (101 MHz, CDCl3) δ 177.7, 168.4, 156.6, 148.3, 139.8, 138.2, 136.4, 134.0, 130.0,
127.9, 127.3, 121.9, 121.7, 119.7, 116.9, 115.6, 115.1, 52.1, 38.3, 28.1; HRMS (ESI-TOF) m/z:
+
[M+H]+ calculated for C22H20N3O4 = 390.1448; Found=390.1440.
3-(2,5-Dioxopyrrolidin-1-yl)-3-(3-nitrophenyl)-N-(quinolin-8-yl)propanamide 7f: Yield: 76%
1
(160 mg), Texture: Off white solid; Rf = 0.35 (60% EtOAc/Hexane). H NMR (400 MHz, CDCl3) δ
9.88 (s, 1H), 8.79 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 – 8.63 (m, 1H), 8.45 (t, J = 1.9 Hz, 1H), 8.14 (dd, J =
8.3, 1.7 Hz, 2H), 7.91 (d, J = 7.8 Hz, 1H), 7.54 – 7.43 (m, 4H), 6.01 (dd, J = 9.6, 6.1 Hz, 1H), 3.98 (dd,
J = 15.7, 9.6 Hz, 1H), 3.47 (dd, J = 15.7, 6.1 Hz, 1H), 2.70 (s, 4H); 13C{1H} NMR (101 MHz, CDCl3)
δ 177.1, 167.3, 148.4, 148.3, 140.3, 138.2, 136.3, 134.4, 133.9, 129.8, 127.9, 127.2, 123.3, 123.1,
121.9, 121.7, 116.7, 51.1, 37.9, 28.1; HRMS (ESI-TOF) m/z: [M+H]+ calculated for C22H19N4O5 =
+
419.1350; Found=419.1352.
3-(1,3-Dioxoisoindolin-2-yl)-3-phenylpropanoic acid 8: Yield: Yield: 76% (70 mg), Texture: White
solid; Rf = 0.6 (10% MeOH in DCM). 1H NMR (501 MHz, CDCl3) δ 7.81 – 7.78 (m, 2H), 7.69 – 7.67
(m, 2H), 7.51 (d, J = 7.4 Hz, 2H), 7.33 – 7.25 (m, 3H), 5.80 (dd, J = 9.9, 5.8 Hz, 1H), 3.84 (dd, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 28
1
2
3
4
5
17.0, 9.9 Hz, 1H), 3.28 (dd, J = 17.0, 5.8 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.5, 168.1,
138.4, 134.1, 131.8, 128.8, 128.3, 127.8, 123.4, 50.6, 29.7; HRMS (ESI-TOF) m/z: [M+H]+ calculated
6
7
+
for C17H14NO4 = 296.0917; Found=296.0912.
8
9
Supporting Information:
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 Supporting Information is available free of charge on the ACS Publications website.
Copies of 1H NMR, 13C{1H} NMR, 19F NMR of the synthesized compounds.
AUTHOR INFORMATION:
Corresponding Author
* Email: sushobhanchem10@gmail.com
Notes
The authors declare no competing financial interest.
Acknowledgements:
Authors sincerely acknowledge CSIR-CDRI for providing laboratory space and research facilities.
S.C. thanks DST (SERB wing and INSPIRE division) for providing fellowship and research grants
(NPDF-file no. PDF/2016/003851 and INSPIRE Faculty programme-Registration No.: IFA17-
CH274). We are thankful to the SAIF division, CSIR-CDRI, for the analytical facilities.
References:
1) a) Boge, T. C.; Georg, G. I. Enantioselective Synthesis of β-Amino Acids (Ed.: E. Juaristi), Wiley-
VCH, New York, 1997; pp. 1–43; b) Tamariz, J. Enantioselective Synthesis of b-Amino Acids (Ed.: E.
Juaristi), Wiley-VCH, New York, 1997; pp. 45–66; c) Spiteller, P.; von Nussbaumin, F.
Enantioselective Synthesis of β-Amino Acids, 2nd ed. (Eds.: E. Juaristi, V. Soloshonok), Wiley,
Hoboken, 2005; pp. 19–91; d) Ashfaq, M.; Tabassum, R.; Ahmad, M. M.; Hassan, N. A.; Oku H.
Enantioselective Synthesis of β-amino acids: A Review. Med. Chem. 2015, 5, 295-309.
2) C. N. C. Drey in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, Vol. 4 (Ed.:
B. Weinstein), Marcel Dekker, New York, 1977, pp. 242-299.
3) a) Casettari, L.; Vllasaliu, D.; Lam, J. K. W.; Soliman, M.; Illum, L. Biomedical applications of
amino acid-modified chitosans: A review. Biomaterials 2012, 33, 7565-7583; b) Fujiya, N. M.;
Tavares, M. F. M. Analysis of underivatized amino acids in protein hydrolysates for cosmetic
ACS Paragon Plus Environment

Page 25 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
application by capillary electrophoresis. J. Sep. Sci. 2003, 26, 562-568; c) Sadovnikova, M. S.; Belikov,
V. M. Industrial Applications of Amino-acids. Russ. Chem. Rev. 1978, 47, 199-212; d) Grauer, A.;
Konig, B. Peptidomimetics – A Versatile Route to Biologically Active Compounds. Eur. J. Org. Chem.
2009, 30, 5099-5111; e) Albericio, F.; Kruger, H. G. Therapeutic peptides. Future Med. Chem. 2012,
4, 1527-1531; f) Craik, D. J.; Fairlie, D. P.; Liras, S.; Price, D. The future of peptide-based drugs.
Chem. Biol. Drug Des. 2013, 81, 136-147; g) Kaspar, A. A.; Reichert, J. M. Future directions for
peptide therapeutics development. Drug Discovery Today 2013, 18, 807-817.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4) a) Geueke, B.; Namoto, K.; Seebach, D.; Kohler, H.-P. E. A Novel β-Peptidyl Aminopeptidase
(BapA) from Strain 3-2W4 Cleaves Peptide Bonds of Synthetic β-Tri- and β-Dipeptides. J. Bacteriol.
2005, 187, 5910-5917; b) Geueke, B.; Namoto, K.; Agarkova, I.; Perriard, J.-C.; Kohler, H.-P. E.;
Seebach, D. Bacterial Cell Penetration by β3‐Oligohomoarginines: Indications for Passive Transfer
through the Lipid Bilayer. Chem-BioChem 2005, 6, 982-985; c) Seebach, D.; Schaeffer, L.; Gessier,
F.; BindschFdler, P.; JFger, C.; Josien, D.; Kopp, S.; Lelais, G.; Mahajan, Y. R.; Micuch, P.; Sebesta,
R.; Schweizer, B. W. Enantioselective Preparation of 2‐Aminomethyl Carboxylic Acid Derivatives:
Solving the β2‐Amino Acid Problem with the Chiral Auxiliary 4‐Isopropyl‐5,5‐diphenyloxazolidin‐2‐
one (DIOZ). Preliminary Communication. Helv. Chim. Acta. 2003, 86, 1852-1861; d) Abele, S.;
Guichard, G.; Seebach, D. (S)‐β3‐Homolysine‐ and (S)‐β3‐Homoserine‐Containing β‐Peptides: CD
Spectra in Aqueous Solution. Helv. Chim. Acta 1998, 81, 2141-2156; e) Guichard, G.; Abele, S.;
Seebach, D. Preparation of N‐Fmoc‐Protected β2‐ and β3‐Amino Acids and their use as building blocks
for the solid‐phase synthesis of β‐peptides. Helv. Chim. Acta 1998, 81, 187-206.
5) a) Horne, W. S.; Price, J. L.; Keck, J. L.; Gellman, S. H. Helix Bundle Quaternary Structure from
α/β-Peptide Foldamers. J. Am. Chem. Soc. 2007, 129, 4178- 4180; b) Sadowsky, J. D.; Fairlie, W. D.;
Hadley, E. B.; Lee, H.-S.; Umezawa, N.; Nikolovska-Coleska, Z.; Wang, S.; Huang, D. C. S.; Tomita,
Y.; Gellman, S. H. Crystallographic Characterization of Helical Secondary Structures in α/β-Peptides
with 1:1 Residue Alternation. J. Am. Chem. Soc. 2007, 129, 139-154; c) Chi, Y.; Gellman, S. H.
Enantioselective Organocatalytic Aminomethylation of Aldehydes:ꢀ A Role for Ionic Interactions and
Efficient Access to β2-Amino Acids. J. Am. Chem. Soc. 2006, 128, 6804-6805; d) Lee, H. S.; Park, J.
S.; Kim, B. M.; Gellman, S. H. Efficient synthesis of enantiomerically pure beta2-amino acids via
chiral isoxazolidinones. J. Org. Chem. 2003, 68, 1575-1578; e) Raguse, T. L.; Lai, J. R.; Gellman, S.
H. Evidence that the β‐Peptide 14‐Helix is Stabilized by β3‐Residues with Side‐Chain Branching
Adjacent to the β‐Carbon Atom. Helv. Chim. Acta 2002, 85, 4154-4164.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 28
1
2
3
4
5
6
7
8
9
6) a) Song, J.; Wang, Y.; Deng, L. The Mannich Reaction of Malonates with Simple Imines Catalyzed
by Bifunctional Cinchona Alkaloids: Enantioselective Synthesis of β-Amino Acids. J. Am. Chem. Soc.
2006, 128, 6048-6049; b) Gray, D.; Concellon, C.; Gallagher, T. Kowalski Ester Homologation.
Application to the Synthesis of β-Amino Esters. J. Org. Chem. 2004, 69, 4849-4851; c) Sibi, M. P.;
Patil, K. Enantioselective radical reactions. Evaluation of nitrogen protecting groups in the synthesis
of β2-amino acids. Tetrahedron: Asymmetry 2006, 17, 516-519; d) Fuller, A. A.; Chen, B.; Minter, A.
R.; Mapp, A. K. Succinct Synthesis of β-Amino Acids via Chiral Isoxazolines. J. Am. Chem. Soc. 2005,
127, 5376-5383.
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) a) Chi, Y.; Gellman, S. H. Enantioselective Organocatalytic Aminomethylation of Aldehydes:ꢀ A
Role for Ionic Interactions and Efficient Access to β2-Amino Acids. J. Am. Chem. Soc. 2006, 128,
6804-6805; b) Guerin, D. J.; Miller, S. J. Asymmetric Azidation−Cycloaddition with Open-Chain
Peptide-Based Catalysts. A Sequential Enantioselective Route to Triazoles. J. Am. Chem. Soc. 2002,
124, 2134-2136.
8) a) Li, X.-G.; Kanerva, T. Lipases in β-Dipeptide Synthesis in Organic Solvents, Org. Lett. 2006, 8,
5593-5596; b) Liljeblad, A.; Kanerva, L. T. Biocatalysis as a profound tool in the preparation of highly
enantiopure β-amino acids. Tetrahedron 2006, 62, 5831-5854; c) Forro, E.; Paal, T.; Tasnadi, G.;
Fulop, F. A New Route to Enantiopure β‐Aryl‐Substituted β‐Amino Acids and 4‐Aryl‐Substituted β‐
Lactams through Lipase‐Catalyzed Enantioselective Ring Cleavage of β‐Lactams, Adv. Synth. Catal.
2006, 348, 917-923; d) Ma, J. A. Recent Developments in the Catalytic Asymmetric Synthesis of α‐
and β‐Amino Acids. Angew. Chem. Int. Ed. 2003, 42, 4290-4299.
9) Byrne, C. M.; Church, T. L.; Kramer, J. W.; Coates, G. W. Catalytic Synthesis of β3-Amino Acid
Derivatives from α-Amino Acids. Angew. Chem. Int. Ed. 2008, 47, 3979 –3983 and references therein.
10) a) Mondal, S.; Chowdhury, S. Recent Advances on Amino Acid Modifications via C–H
Functionalization and Decarboxylative Functionalization Strategies. Adv. Synth. Catal. 2018, 360,
1884-1912 and references therein; b) He, G.; Wang, B.; Nack, W. A.; Chen, G. Syntheses and
Transformations of α-Amino Acids via Palladium-Catalyzed Auxiliary-Directed sp3 C–H
Functionalization. Acc. Chem. Res. 2016, 49, 635−645; c) A. F. M. Noisier; Brimble, M. A. C–H
Functionalization in the Synthesis of Amino Acids and Peptides. Chem. Rev. 2014, 114, 8775−8806
and references therein; d) Najera, C.; Sansano, J. M. Catalytic asymmetric synthesis of alpha-amino
acids. Chem. Rev. 2007, 107, 4584−4671; e) Sengupta, S.; Mehta, G. Late stage modification of
ACS Paragon Plus Environment

Page 27 of 28
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
peptides via CH activation reactions. Tetrahedron Lett. 2017, 58, 1357-1372; f) Easton, C. J. Free-
Radical Reactions in the Synthesis of alpha-Amino Acids and Derivatives. Chem. Rev. 1997, 97, 53–
82; g) Brandhofer, T.; Mancheño, O. G. Site‐Selective C–H Bond Activation/Functionalization of
Alpha‐Amino Acids and Peptide‐Like Derivatives. Eur. J. Org. Chem. 2018, 6050-6067.
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
11) a) Wasa, M.; Engle, K. M.; Yu, J.-Q. Pd(0)/PR3-Catalyzed Intermolecular Arylation of sp3 C−H
Bonds. J. Am. Chem. Soc., 2009, 131, 9886–9887; b) Wasa, M.; Chan, K. S. L.; Zhang, X.-G.; He, J.;
Miura, M.; Yu, J.-Q. Ligand-Enabled Methylene C(sp3)–H Bond Activation with a Pd(II) Catalyst. J.
Am. Chem. Soc., 2012, 134, 18570–18572; c) Wasa, M.; Yu, J.-Q. Amide-Directed Arylation of sp C-
H Bonds using Pd(II) and Pd(0) Catalysts. Tetrahedron 2010, 66, 4811-4815; d) Guan, M.; Pang, Y.;
Zhang, J.; Zhao, Y. Pd-Catalyzed sequential β-C(sp3)–H arylation and intramolecular amination of δ-
C(sp2)–H bonds for synthesis of quinolinones via an N,O-bidentate directing group. Chem. Commun.,
2016, 52, 7043-7046; e) Zhu, Y., Chen, X.; Yuan, C.; Li, G.; Zhang, J.; Zhao, Y. Pd-catalysed ligand-
enabled carboxylate-directed highly regioselective arylation of aliphatic acids. Nat. Commun. 2017, 8,
14904 doi: 10.1038/ncomms14904 (2017); f) Castro, L. C. M.; Chatani, N. Palladium(II)‐Catalyzed
ortho‐C-H Arylation/Alkylation of N‐Benzoyl α‐Amino Ester Derivatives. Chem.- Eur. J. 2014, 20,
4548-4553; g) Kim, J.; Sim, M.; Kim, N.; Hong, S. Asymmetric C–H functionalization of
cyclopropanes using an isoleucine-NH2 bidentate directing group. Chem. Sci. 2015, 6, 3611-3616.
12) a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. Highly Regioselective Arylation of sp3 C−H Bonds
Catalyzed by Palladium Acetate. J. Am. Chem. Soc. 2005, 127, 13154-13155; b) Shabashov, D.;
Daugulis, O. Auxiliary-Assisted Palladium-Catalyzed Arylation and Alkylation of sp2 and sp3
Carbon−Hydrogen Bonds. J. Am. Chem. Soc. 2010, 132, 3965–3972.
13) a) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Novel Acetoxylation and C−C Coupling Reactions
at Unactivated Positions in α-Amino Acid Derivatives. Org. Lett. 2006, 8, 3391-3394; b) Tran, L. D.;
Daugulis, O. Nonnatural Amino Acid Synthesis by Using Carbon–Hydrogen Bond Functionalization
Methodology. Angew. Chem. Int. Ed. 2012, 51, 5188 –5191.
14) a) Hu, P.; Bach, T. Synthesis of Alkyl-Substituted Pyridines by Directed Pd(II)-Catalyzed C–H
Activation of Alkanoic Amides. Synlett 2015, 26, 2853–2857; b) Gou, Q.; Liu, G.; Zhou, L.; Chen, S.;
Qin, J. Palladium‐Catalyzed Base‐Promoted Arylation of Unactivated C(sp3)–H Bonds by Aryl
Iodides: A Practical Approach To Synthesize β‐Aryl Carboxylic Acid Derivatives. Eur. J. Org. Chem.
2017, 6314–6318.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 28
1
2
3
4
5
6
7
8
9
15) a) Lotz, M. D.; Camasso, N. M.; Canty, A. J.; Sanford, M. S. Role of Silver Salts in Palladium
Catalyzed Arene and Heteroarene C−H Functionalization Reactions. Organometallics 2017, 36,
165−171; b) Li, Q.; Nie, J.; Yang, F.; Zheng, R.; Zou, G.; Tang, Jie. Homocoupling of Aryl Iodides
Catalyzed by Cyclopalladated Complexes of Tertiary Arylamines. Chin. J. Chem. 2004, 22, 419-421;
c) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed Ligand-Directed C-H Functionalization
Reactions. Chem. Rev. 2010, 110, 1147–1169.
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
16) a) Zhang, X.; He, G.; Chen, G. Palladium-catalyzed β-C(sp3)–H arylation of phthaloyl alanine with
hindered aryl iodides: synthesis of complex β-aryl α-amino acids. Org. Biomol. Chem. 2016, 14, 5511–
5515; b) Chen, K.; Zhang, S.-Q.; Xu, J.-W.; Hu, F.; Shi, B.-F. A general and practical palladium-
catalyzed monoarylation of β-methyl C(sp3)–H of alanine. Chem. Commun., 2014, 50, 13924-13927;
c) Liu, J.; Xie, Y.; W.; Zeng, Lin, D.; Deng, Y.; Lu, X. Pd(II)-Catalyzed Pyridine N-Oxides Directed
Arylation of Unactivated Csp3–H Bonds. J. Org. Chem. 2015, 80, 4618–4626; d) D. Mu, F. Gao, G.
Chen, G. He, Palladium-Catalyzed β-C–H Arylation of Alkyl Carboxamides with Sterically Hindered
Aryl Iodides Using ortho-Sulfinyl Aniline Auxiliaries. ACS Catal., 2017, 7, 1880–1885.
17) a) Feng, Y.; Chen, G. Total Synthesis of Celogentin C by Stereoselective C-H Activation. Angew.
Chem. Int. Ed. 2010, 49, 958 –961; b) Wang, B.; Lu, C.; Zhang, S.-Y.; He, G.; Nack, W. A.; Chen, G.
Palladium-Catalyzed Stereoretentive Olefination of Unactivated C(sp3)–H Bonds with Vinyl Iodides
at Room Temperature: Synthesis of β-Vinyl α-Amino Acids. Org. Lett. 2014, 16, 6260–6263.
ACS Paragon Plus Environment