Metal-free S-arylation of cysteine using arenediazonium salts

Article abstract of DOI:10.1021/acs.joc.7b03160

A mild chemoselective method for S-arylation of cysteine has been developed in an open-flask procedure under metal-free conditions using arenediazonium salts in methanol.

Full text of DOI:10.1021/acs.joc.7b03160

Subscriber access provided by the Henry Madden Library | California State University, Fresno
Article
Metal-free S-arylation of cysteine using arenediazonium salts
Naganaboina Naveen, Saumitra Sengupta, and Srinivasan Chandrasekaran
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03160 • Publication Date (Web): 26 Feb 2018
Downloaded from http://pubs.acs.org on February 26, 2018
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.
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 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Metal-free S-arylation of cysteine using arenediazonium salts
Naganaboina Naveen, Saumitra Sengupta* and Srinivasan Chandrasekaran*
Department of Organic Chemistry, Indian Institute of Science, Bangalore, Karnataka, India 560012.
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
scn@iisc.ac.in
Graphical Abstract:
ABSTRACT
A mild chemoselective method for Sꢀarylation of cysteine has been developed in an openꢀ
flask procedure under metalꢀfree conditions using arenediazonium salts in methanol.
Introduction
Siteꢀselective modification of amino acids in proteins is an active area of research in chemical
biology.1 Cysteine, by virtue of its low natural abundance (< 2%)2 and armed with a highly
nucleophilic thiol group, is an attractive target for siteꢀselective modification of proteins. A
number of methods have been developed for cysteine conjugation,3 among which, Michael
addition of cysteine is the most widely used strategy. However, the fate of these Michael
adducts can widely vary depending on reaction conditions, leading to a number of side
products arising out of retroꢀMichael reaction, thiol exchange, ring opening in case of
maleimides, etc,4 which necessitates exploration of new methodologies that can provide
chemically robust cysteine conjugates. SꢀArylation of cysteine appeared to be an attractive
strategy towards this end, not only due to the irreversible nature of the reaction and the
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 23
1
2
3
4
5
6
7
8
9
chemical stability of Sꢀaryl bonds but also, for opportunities that it could provide for
photolabelling of cysteine peptides and proteins using photoactive aryl payloads. Moreover,
NꢀAcetyl Sꢀarylcysteines (arylmercapturic acids) constitute an important class of urine
biomarkers for aromatic carcinogenesis arising out of the glutathione transferase pathway,5
whereas peptidomimetic S-arylcysteines are common pharmacophores that are present in a
number of antiꢀHIV drug candidates, including the approved drug nelfinavir.6 Taken together,
these prospects provided a strong impetus to develop an efficient synthetic procedure for Sꢀ
arylation of cysteine under mild reaction conditions. The current repertoire of Sꢀarylation of
cysteine is limited to SNAr displacement reactions of activated aromatics (limited substrate
scope)7 and Pdꢀcatalyzed Sꢀarylation reactions,8 the latter being recently used by the groups
of Buchwald and Davies for bioꢀorthogonal Sꢀarylation of cysteine peptides and proteins.9
However, Buchwald’s method requires an excess of the independently prepared oxidative
addition complex of aryl triflates with lowꢀvalent palladium,9a whereas Pdꢀbased methods
require special ligands, such as xantphos PdꢀG3 precatalyst, to obtain good yields.8c Chanꢀ
Lam type10 or photoredoxꢀNi catalyzed11 Sꢀarylation of cysteine requires harsh reaction
conditions and/or are substrate specific. In view of these limitations and in continuation of
our interests in the utilization of arenediazonium salts in organic synthesis12,13 and in the
synthesis of modified chalcogenide amino acids,14 we explored the Sꢀarylation of cysteine
using arenediazonium salts, taking advantage of their superior reactivity over aryl halides in
Pdꢀcatalyzed13 and radical reactions.15 Our preliminary results that have resulted in a mild
new metal-free synthesis of Sꢀarylcysteines is reported herein. Cu2O mediated Sꢀarylation of
cysteine with arenediazonium salts, known since the early 50’s, have found little application
due to their operational complexity and impure product formation.16 Recently, Auꢀcatalyzed
reactions of cysteine with arenediazonium salts was reported.17 We, while looking for metalꢀ
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
free conditions, were attracted to a recent report on radical aromatic substitution with
2
ACS Paragon Plus Environment

Page 3 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
arenediazonium salts using ascorbic acid as a green radical initiator18 and wished to apply the
same for Sꢀarylation of cysteine via a SRN pathway. It may be noted that although SRN1
reaction of aromatic thiols with arenediazonium salts (StadlerꢀZiegler reaction) has been
widely described for the synthesis of unsymmetrical diaryl sulfides,19 similar reports with
aliphatic thiols (of which cysteine is a prototype) are scarce.20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RESULTS AND DISCUSSION
SꢀArylation of NHꢀBoc cysteine methyl ester (1) with 4ꢀchlorobenzenediazonium
tetrafluoroborate (2a) was studied as a model for optimization of the reaction conditions.
Ascorbic acid (10%) catalyzed reactions of 1 with 2a (1.2ꢀ1.5 equiv.) in laboratory grade
o
MeOH at 0ꢀ15 C gave the desired S-arylcysteine 3a in 37ꢀ40% yield but was accompanied
with substantial amounts of the cysteine dimer 4 (20ꢀ23%) (entries 1 & 2, Table 1). The yield
of 3a could be increased to 55% using 2 equivalents of the diazonium salt (entry 3, Table 1)
but increasing the amount of ascorbic acid had no effect on the yield of 3a (entry 4, Table 1).
Reactions carried out for longer periods did not improve the yield whereas at elevated
temperatures, coloured resinous impurities were formed at the expense of the desired product.
While looking for conditions to improve the yield of 3a, we came across reports that solvent
MeOH itself can induce homolytic dediazoniation of diazonium salts to form aryl radicals via
diazoꢀether intermediates21 and questioned the seemingly redundant role of ascorbic acid as
the radical initiator. Indeed, in absence of ascorbic acid, reaction of 1 with 2a in MeOH in
presence of NaHCO3 (1 equiv), gave a higher yield (73%, entry 5, Table 1) which could be
further optimized using 3 equivalents of NaHCO3 to give 89% yield of 3a after
chromatographic purification (entry 6, Table 1). The presence of a base was essential, since
without the base, the diazoꢀsulfide 5 was observed as the major product (entry 7, Table1).
NaOAc was ineffective as a base for this reaction. EtOH could also be used as a solvent
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 23
1
2
3
Table 1. Optimization of S-arylation of 1 with the diazonium salt 2a
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
Entry
1
2
Additive
Solvent
Yield %a
3a
(equiv.) (equiv.) (mol %)
4
5
1
1
1
1
1
1
1
1
1
1
1
1
1
1.2
1.5
2
Asc. Ac (10%)
Asc. Ac (10%)
Asc. Ac (10%)
Asc. Ac (20%)
NaHCO3 (1)
NaHCO3 (3)
ꢀꢀꢀꢀꢀ
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
37 23 <5
40 20 <5
55 <10 <5
56 <10 <5
73 <5 <5
89 <5 <5
10 <5 <55b
73 <5 <5
53 ND ND
60 ND ND
36 ND ND
54 23 <5
2
3
4
2
5
2
6
2
7
2
8
2
NaHCO3 (3)
NaHCO3 (3)
NaHCO3 (3)
NaHCO3 (3)
NaHCO3 (3)
9
2
THF
10
11
12
2
dioxane
DMF
2
2
CH3CN
aisolated yields, b from 1HꢀNMR product mixture
for this reaction but nonꢀalcoholic solvents like THF, dioxane, DMF or CH3CN all turned out
to be inferior choices (entries 8ꢀ12). The reaction was completely inhibited by TEMPO,
indicative of a radical pathway.22 A number of arenediazonium salts 2a-t were then used for
the Sꢀarylation reaction of 1 under the optimized conditions (cf. entry 6, Table 1) and the
results are shown in Table 2.
4
ACS Paragon Plus Environment

Page 5 of 23
The Journal of Organic Chemistry
1
2
3
Table 2. S-Arylation of cysteine ester 1 with aryl diazonium salts 2a-2t
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
a 1 (1 equiv.), 2 (2 equiv.), NaHCO3 (3 equiv.), MeOH, 0ꢀ15 oC. b isolated yields.
As expected for a radical pathway, the product yields were uniformly high irrespective of the
substitution pattern on the diazonium salt used (ortho, meta or para). Even with sterically
hindered ortho, ortho’ꢀdisubstituted diazonium salts, moderate to good yields of the Sꢀ
arylation products 3o, 3p could be obtained, demonstrating the superiority of this method
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 23
1
2
3
4
5
6
7
8
9
over the Pdꢀcatalyzed Sꢀarylation regimen. Of particular interest are the Sꢀarylation products
3c, 3d, 3f arising out of the bromoꢀ and iodoꢀsubstituted diazonium salts, the latter (3f), in
particular, being impossible to obtain via the Pdꢀcatalyzed methods. These results, while
attesting to the superior reactivity of the diazonium group over the halides in the radical
pathway, offer further options for product diversification via various Pdꢀcatalyzed coupling
reactions. Heterocyclic (3m) as well as photoactive naphthyl groups (3n) could also be
introduced on cysteine by this procedure in good yields. As expected, diazonium salts bearing
electron withdrawing groups gave higher yields of the products 3a-q visꢀaꢀvis those with
electronꢀdonating substituents (3r-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
The chemoselectivity of this S-arylation reaction was briefly examined in presence of other
amino acids through intermolecular competition experiments (robustness screen).23
Table 3. Chemo-selective S-arylation of 1 with 2a in presence of other amino-acids
a1 (1 equiv), 2a (2 equiv.), amino acid (1 equiv.), NaHCO3 (5 equiv), MeOH, 0ꢀ15 o C,
3h;bisolated yields; cZꢀLꢀtyrosine used; d LꢀGlutamine sodium salt used.
6
ACS Paragon Plus Environment

Page 7 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Most gratifyingly, reactions of 2a were found to be highly selective for cysteine (1) in
presence of several amino acids (Table 3). The observed selectivities against tryptophan and
tyrosine are highly significant since these amino acids are known to undergo azoꢀcoupling
reaction with diazonium salts under basic conditions. It has also been demonstrated that even
in the presence of acidic hydroxyl groups of tyrosine the reaction is selective at the thiol end
of cysteine.
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
A plausible mechanism of this reaction, drawn in analogy to the radical chain mechanism
proposed for StadlerꢀZiegler reactions,24 is shown in Scheme 1.
Scheme 1. Plausible radical chain mechanism for S-arylation of cysteine with
arenediazonium salts
Thus, initially in the presence of base, thiolate I is formed which then reacts with diazosalt II
forms azoꢀsulfide III, upon rate limiting one electron reduction, would give rise to the aryl
radical IV and the cysteine anion V. Subsequent innerꢀcage combination between IV and V
followed by electron loss would then lead to the Sꢀarylcysteine 3. Azoꢀsulfides derived from
electron deficient diazonium salts (III, X = EWG) are easily reduced due to their favorable
redox potentials15a and hence, gave higher yields of the products visaꢀvis their electron rich
counterparts (III, X = EDG). MeOH could also provide an independent pool of aryl radical
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 23
1
2
3
4
5
6
7
8
9
IV via formation of the diazoꢀether VII,21b which might compensate for unwanted side
reactions of IV, such as Hꢀradical capture, dimerization, etc., thereby improving the yields.
MeOH might also stabilize the anion V through solvation, thereby facilitating the rate
limiting one electron reduction of III.
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 improve the yields with electron rich diazonium salts, we decided to conduct the
reaction under a strongly basic medium. This, we thought, would provide a higher initial
concentration of V through complete deprotonation of the aliphatic SHꢀgroup of cysteine
which could then react with the azosulfide III as an electron donor24 and/or cause a switch
towards SRN2 mechanism,20a rendering III more prone to homolytic fission.
Table 4. S-Arylation of NH-Ac cysteine (6) with arenediazonium salts (2)a
8
ACS Paragon Plus Environment

Page 9 of 23
The Journal of Organic Chemistry
1
2
3
4
a 6 (1 equiv.), 2 (2 equiv.), NaOMe (4 equiv.) in MeOH at 0ꢀ15 oC. b isolated yields,
c purified by HPLC.
5
6
In the event, switching to NaOMe as the base and using NHꢀAc cysteine (6) as the substrate,
7
8
o
electron rich diazonium salts underwent facile Sꢀarylation reactions in MeOH at 0ꢀ15 C to
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
give the corresponding Sꢀarycysteines 7a-d in 68ꢀ85% yields (Table 4). It is likely that under
these conditions, a portion of the diazonium salt would independently give rise to aryl
radicals via in-situ formation of aryl diazotates.25 Since the products 7a-d are examples of
arylmercapturic acids which are important urinary biomarkers for aromatic carcinogenesis,5
we decided to extend this reaction to other diazonium salts in order to develop a facile new
synthetic route to this class of compounds. Towards this end, a number of substituted
diazonium salts were then used for S-arylation of 6 under the above conditions to provide the
corresponding arylmercapturic acids 7e-7l in good yields (Table 4). When we applied this
method for the biologically important tripeptide glutathione, we were delighted to isolate the
Sꢀaryl glutathione derivatives 7m and 7n in good yields. The operational simplicity and ready
availability of anilines, makes this procedure a superior alternative to the previous syntheses
reported for arylmercapturic acids,5b,7c,10b including the recently reported xantphos PdꢀG3 preꢀ
catalyst mediated coupling of 6 with aryl iodides.8c
CONCLUSION
In summary, a mild chemoselective method for Sꢀarylation of cysteine has
been developed in an openꢀflask procedure using arenediazonium salts under metalꢀfree
conditions.28 The reaction which probably takes place under a radical chain mechanism is
crucially dependent on the use of methanol as solvent.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 23
1
2
3
4
5
6
7
8
EXPERIMENTAL SECTION
General Experimental Methods
All the reagents used in this work were obtained commercially and used without
9
further purification unless otherwise mentioned.
methyl ester (97%), ꢀAcetylꢀ ꢀcysteine (98%),
N
ꢀ(tertꢀButoxycarbonyl)ꢀ
Lꢀcysteine
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
L
L
ꢀGlutathione reduced (98%) and
NaHCO3 (LR grade) were purchased and used without any further purification. LR
grade MeOH was used as solvent. Thinꢀlayer chromatography (TLC) was performed
using silica gel GF254 coated aluminum plates and the visualization of spots were done
using UV illumination and charring the TLC plates sprayed with PMA solution.
Column chromatography was performed on silica gel 100−200 mesh, using ethyl
acetate/ petꢀether or methanol/ dichloromethane mixture as eluent. H, 13C NMR
1
spectra of the synthesized compounds was recorded on 400 MHz NMR spectrometer
using solutions in CDCl3 / MeOD. Chemical shifts (1H, 13C ) refer to using TMS as an
internal standard or the central line of CDCl3 (7.26 ppm, 77.16 ppm), and MeOD (3.3
ppm, 49.0 ppm) peaks. IR spectra were recorded using FTꢀIR spectrometer. High
resolution mass spectra (HRMS) were recorded using QꢀTOF Mass Spectrometer
(ESIꢀHRMS). Melting points were determined using SMP10 melting range apparatus
and are uncorrected.
The aryldiazonium salts were synthesized from their corresponding anilines
using previously reported literature procedures.26, 27 The data of new compounds are
presented here and some of the compounds synthesized in this work are reported in the
literature.8c, 11a, 11b, 17
General procedure for
methyl ester:
S
-arylation of N-(tert-Butoxycarbonyl)-L-cysteine
10
ACS Paragon Plus Environment

Page 11 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Nꢀ(tertꢀButoxycarbonyl)ꢀLꢀcysteine methyl ester, 1 (75 mg, 0.319 mmol, 1 equiv.) was
weighed in a clean round bottom flask, MeOH (3 mL) was added and reaction mixture was
cooled using iceꢀbath. After stirring for 5 min., NaHCO3 (80 mg, 0.957 mmol, 3 equiv.), and
substituted aryldiazonium salt (2a-2t, 2 equiv.) were added. The reaction mixture was stirred
(0ꢀ15 °C) for 3 h and the crude residue was directly loaded on a silica gel column and eluted
with ethyl acetate/petꢀether (1/10) to get the pure products (3a-3t).
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
Methyl N-(tert-butoxycarbonyl)-S-(4-chlorophenyl)-L-cysteinate (3a):
Yield: 89% (98 mg), light brown solid, mp: 54ꢀ56 °C; IR (neat, cmꢀ1): 2975, 1747, 1712,
1
1504, 1359, 1213, 1165. H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.35 (m, 2H), 7.23ꢀ7.26 (m,
2H), 5.32 (d, J = 6.8 Hz, 1H), 4.54ꢀ4.56 (m, 1H), 3.58 (s, 3H), 3.37 (dd, J = 14, 4.4 Hz, 1H),
3.31 (dd, J = 14, 4.8 Hz, 1H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.9, 155, 133.5,
133.3, 132.5, 129.3, 80.3, 53.5, 52.5, 37.5, 28.4. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C15H20ClNO4SNa 368.0699; Found 368.0698.
Methyl N-(tert-butoxycarbonyl)-S-(3-chlorophenyl)-L-cysteinate (3b):
Yield: 82% (90 mg), Dark red oily liquid; IR (neat, cmꢀ1): 3020, 1745, 1709, 1498, 1356,
1214, 1164, 1015, 743. 1H NMR (400 MHz, CDCl3): δ 7.30ꢀ7.31 (m, 1H), 7.18ꢀ7.21 (m, 1H),
7.11ꢀ7.16 (m, 2H), 5.28 (d, J = 7.2 Hz, 1H), 4.51ꢀ 4.53 (m, 1H), 3.53 (s, 3H), 3.31ꢀ3.35 (m,
2H), 1.35 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.9, 155.1, 137.2, 134.8, 130.3, 130.2,
128.7, 127.2, 80.4, 53.4, 52.6, 37.1, 28.4. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C15H20ClNO4SNa 368.0699; Found 368.0677.
Methyl S-(4-bromophenyl)-N-(tert-butoxycarbonyl)-L-cysteinate (3c): 17
1
Yield: 75% (93 mg); H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.34 (m, 2H), 7.19ꢀ7.22 (m, 2H),
5.24 (d, J = 7.2 Hz, 1H), 4.48ꢀ4.50 (m, 1H), 3.52 (s, 3H), 3.32ꢀ3.33 (m, 2H), 1.34 (s, 9H). 13C
NMR (100 MHz, CDCl3): δ 170.9, 154.9, 134.3, 132.6, 132.2, 121.2, 80.3, 53.5, 52.6, 37.4,
28.4.
Methyl S-(2-bromophenyl)-N-(tert-butoxycarbonyl)-L-cysteinate (3d):
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 23
1
2
3
Yield: 73% (91 mg), Dark orange liquid; IR (neat, cmꢀ1): 2976, 1747, 1713, 1504, 1360,
4
5
1
1250, 1166. H NMR (400 MHz, CDCl3): δ 7.56 (dd, J = 8, 1.2 Hz, 1H), 7.41ꢀ7.43 (m, 1H),
6
7
8
9
7.26 (td, J = 8 Hz, 1.2 Hz, 1H), 7.05ꢀ7.23 (m, 1H), 5.37 (d, J = 6.4 Hz, 1H), 4.59ꢀ 4.61 (m,
1H), 3.62 (s, 3H), 3.39ꢀ3.41 (m, 2H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171,
136.1, 133.4, 131.3, 128.2, 127.9, 125.8, 80.3, 53.2, 52.6, 36.4, 28.4. HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C15H20BrNO4SNa 412.0194; Found 412.0195.
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
Methyl N-(tert-butoxycarbonyl)-S-(4-fluorophenyl)-L-cysteinate (3e): 17
1
Yield: 76% (80 mg); H NMR (400 MHz, CDCl3): δ 7.38ꢀ7.42 (m, 2H), 6.95ꢀ7.0 (m, 2H),
5.33 (d, J = 7.2 Hz, 1H), 4.51ꢀ4.53 (m, 1H), 3.55 (s, 3H), 3.24ꢀ3.34 (m, 2H), 1.40 (s, 9H). 13C
NMR (100 MHz, CDCl3): δ 171.1, 165.3 (d, J = 245 Hz), 155 (d, J = 8.3 Hz), 134.1 (d, J =
8.3 Hz), 129.8, 116.2 (d, J = 21.7 Hz), 80.2, 53.4, 52.5, 38.4, 28.3.
Methyl N-(tert-butoxycarbonyl)-S-(4-iodophenyl)-L-cysteinate (3f): 17
1
Yield: 60% (84 mg); H NMR (400 MHz, CDCl3): δ 7.58ꢀ7.60 (m, 2H), 7.12ꢀ7.14 (m, 2H),
5.30 (d, J = 7.2 Hz, 1H), 4.55ꢀ 4.57 (m, 1H), 3.59 (s, 3H), 3.29ꢀ3.39 (m, 2H), 1.41 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 170.9, 154.9, 138, 132.5, 92.2, 80.3, 53.4, 52.6, 37, 28.3.
Methyl N-(tert-butoxycarbonyl)-S-(4-cyanophenyl)-L-cysteinate (3g): 11a
Yield: 71% (76 mg); 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 8 Hz, 2H), 7.36 (d, J = 8 Hz,
2H), 5.37 (d, J = 6.4 Hz, 1H), 4.57ꢀ4.59 (m, 1H), 3.63 (s, 3H), 3.48 (dd, J = 14, 4.4 Hz, 1H),
3.37 (dd, J = 13.6, 4.4 Hz, 1H), 1.37 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.6, 154.9,
143, 132.3, 128.3, 118.6, 109.2, 80.4, 53.2, 52.7, 35.1, 28.2.
Methyl N-(tert-butoxycarbonyl)-S-phenyl-L-cysteinate (3h): 17
1
Yield: 55% (54 mg); H NMR (400 MHz, CDCl3): δ 7.40ꢀ7.42 (m, 2H), 7.26ꢀ7.30 (m, 2H),
7.19ꢀ7.23 (m, 1H), 5.35 (d, J = 6.0 Hz, 1H), 4.56ꢀ4.57 (m, 1H), 3.54 (s, 3H), 3.37ꢀ3.38 (m,
2H), 1.42 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.2, 154.1, 133.9, 130.2, 128.2, 126.2,
76.3, 52.4, 51.4, 36.4, 27.4.
Methyl N-(tert-butoxycarbonyl)-S-(4-(trifluoromethyl)phenyl)-L-cysteinate (3i): 17
Yield: 66% (80 mg); 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4
Hz, 2H), 5.32 (d, J = 6.4 Hz, 1H), 4.61ꢀ4.62 (m, 1H), 3.62 (s, 3H), 3.49 (dd, J = 14, 4.4 Hz,
12
ACS Paragon Plus Environment

Page 13 of 23
The Journal of Organic Chemistry
1
2
3
4
5
1H), 3.40 (dd, J = 14, 4.4 Hz, 1H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 169.9, 154,
139.8, 129.3, 128.5, 124.9 (q, J = 37.4 Hz), 124.5, 79.5, 52.5, 51.7, 35.1, 27.4.
6
7
Methyl N-(tert-butoxycarbonyl)-S-(3-(trifluoromethyl)phenyl)-L-cysteinate (3j):
8
9
Yield: 61% (74 mg); Light orange solid, mp: 50ꢀ52 °C; IR (neat, cmꢀ1): 2973, 2926, 1746,
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
1711, 1592, 1505, 1322, 1218, 1166, 1129, 1016. H NMR (400 MHz, CDCl3): δ 7.65 (s,
1H), 7.57ꢀ7.59 (m, 1H), 7.46ꢀ7.47 (m, 1H), 7.39ꢀ7.41 (m, 1H), 5.34 (m, 1H), 4.60ꢀ 4.63 (m,
1H), 3.58 (s, 3H), 3.42ꢀ3.49 (m, 2H), 1.42 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.7,
154.9, 143.8, 136.6, 133.6, 129.4, 127, 123.6, 80.4, 53.2, 52.4, 36.9, 28.2. HRMS (ESIꢀTOF)
m/z: [M + Na]+ Calcd for C16H20F3NO4SNa 402.0963; Found 402.0958.
Methyl N-(tert-butoxycarbonyl)-S-(4-nitrophenyl)-L-cysteinate (3k):
Yield: 70% (80 mg); Dark red solid, mp: 84ꢀ86 °C; IR (neat, cmꢀ1): 3021, 1745, 1709, 1513,
1436, 1341, 1214, 1164, 1089, 849, 742.1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.8 Hz,
2H), 7.42 (d, J = 8.4 Hz, 2H), 5.37 (d, J = 6.4 Hz, 1H), 4.63ꢀ4.64 (m, 1H), 3.69 (s, 3H), 3.56
13
(dd, J = 13.6, 4.4 Hz, 1H), 3.43 (dd, J = 14, 4.8 Hz, 1H), 1.41(s, 9H). C NMR (100 MHz,
CDCl3): δ 170.6, 155.2, 145.7, 127.7, 126.3, 124.1, 80.8, 53.3, 52.9, 35.2, 28.4. HRMS (ESIꢀ
TOF) m/z: [M + Na]+ Calcd for C15H20N2O6SNa 379.0940; Found 379.0941.
Methyl N-(tert-butoxycarbonyl)-S-(3-nitrophenyl)-L-cysteinate (3l):
Yield: 62% (70 mg); Dark red solid, mp: 99ꢀ101 °C; IR (neat, cmꢀ1): 2977, 2923, 1744, 1710,
1
1589, 1526, 1350, 1219, 1165, 1120, 1022. H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 8.03
(dd, J = 8.4, 1.2 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 8 Hz, 1H), 5.35 (d, J = 6.8 Hz,
1H), 4.60ꢀ 4.62 (m, 1H), 3.65 (s, 3H), 3.51 (dd, J = 14, 4 Hz, 1H), 3.4 (dd, J = 14, 4.8 Hz,
1H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.8, 155.1, 148.6, 138.3, 135.6, 129.8,
124.4, 121.5, 80.6, 53.4, 52.8, 36.7, 28.3. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C15H20N2O6SNa 379.0940; Found 379.0936.
Methyl N-(tert-butoxycarbonyl)-S-(2-chloropyridin-3-yl)-L-cysteinate (3m):
Yield: 78% (86 mg); Dark red semisolid; IR (neat, cmꢀ1): 2970, 2924, 1745, 1709, 1511,
1
1437, 1382, 1218, 1164, 1032, 861. H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 4.8 Hz, 1H),
7.74 (d, J = 7.6 Hz, 1H), 7.18ꢀ7.21 (m, 1H), 5.35 (d, J = 6.8 Hz, 1H), 4.60ꢀ4.62 (m, 1H), 3.68
(s, 3H), 3.36ꢀ3.47 (m, 2H), 1.42 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.7, 155.1, 146.6,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 23
1
2
3
4
5
138.4, 132.7, 122.8, 80.5, 53.1, 52.8, 35, 28.3. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
Calcd for C14H19ClN2O4SNa 369.0652; Found 369.0656.
6
7
Methyl N-(tert-butoxycarbonyl)-S-(naphthalen-1-yl)-L-cysteinate (3n): 8c
8
9
Yield: 74% (85 mg); 1H NMR (400 MHz, CDCl3): δ 8.43 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.6
Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H),7.69ꢀ7.72 (m, 1H), 7.59 (dt, J = 6.8 Hz, 1.2 Hz, 1H), 7.51ꢀ
7.54 (m, 1H), 7.4 (t, J = 7.6 Hz, 1H), 5.35 (d, J = 6.8 Hz, 1H), 4.56ꢀ4.57 (m, 1H), 3.47 (s,
3H), 3.41ꢀ3.44 (m, 2H), 1.38 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.1, 155, 134.2,
133.5, 131.8, 131.3, 128.8, 128.7, 126.9, 126.4, 125.6, 125.4, 80.1, 53.5, 52.3, 37.6, 28.3.
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
Methyl N-(tert-butoxycarbonyl)-S-(2,6-dichlorophenyl)-L-cysteinate (3o):
Yield: 51% (62 mg); Orange oil; IR (neat, cmꢀ1): 2974, 1747, 1713, 1636, 1501, 1429, 1359,
1
1164, 1016. H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 8 Hz, 2H), 7.17 (t, J = 8 Hz, 1H),
5.52 (d, J = 6.8 Hz, 1H), 4.52ꢀ4.54 (m, 1H), 3.56 (s, 3H), 3.51 (dd, J = 14, 3.6 Hz, 1H), 3.38
(dd, J = 14, 4.4 Hz, 1H), 1.38 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.7, 155.1, 141.2,
132.2, 130.2, 128.8, 80.2, 53.5, 52.6, 37.3, 28.4. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C15H19Cl2NO4SNa 402.0310; Found 402.0311.
Methyl N-(tert-butoxycarbonyl)-S-(2-chloro-6-methylphenyl)-L-cysteinate (3p):
Yield: 71% (81 mg); Light orange gummy oil; IR (neat, cmꢀ1): 2976, 1749, 1709, 1636, 1503,
1
1442, 1358, 1218, 1165, 1056, 855. H NMR (400 MHz, CDCl3): δ 7.28ꢀ7.30 (m, 1H), 7.12ꢀ
7.14 (m, 2H), 5.40 (d, J = 6.8 Hz, 1H), 4.49ꢀ4.51 (m, 1H), 3.53 (s, 3H), 3.39 (dd, J = 14, 4.4
Hz, 1H), 3.31 (dd, J = 14, 4.4 Hz, 1H), 2.54 (s, 3H), 1.41 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 171.1, 152.3, 145, 140.1, 129.5, 129, 128, 80.2, 53.6, 52.5, 37.2, 28.4, 22.6. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H22ClNO4SNa 382.0856; Found 382.0852.
Methyl N-(tert-butoxycarbonyl)-S-(2-methyl-3-nitrophenyl)-L-cysteinate (3q):
Yield: 72% (85mg); Orange solid, mp: 71ꢀ73 °C; IR (neat, cmꢀ1): 1709, 1636, 1524, 1357,
1
1164, 1016. H NMR (400 MHz, CDCl3): δ 7.60ꢀ7.64 (m, 2H), 7.25ꢀ7.29 (m, 1H), 5.32 (d, J
= 6.4 Hz, 1H), 4.58ꢀ4.59 (m, 1H), 3.63 (s, 3H), 3.44 (dd, J = 14, 4.8 Hz, 1H), 3.34 (dd, J =
13.6, 4.8 Hz, 1H), 2.54 (s, 3H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.8, 155,
151.5, 138.5, 134.2, 132.8, 126.7, 122.5, 80.5, 53.3, 53.7, 36.8, 28.4, 16.7. HRMS (ESIꢀTOF)
m/z: [M + Na]+ Calcd for C16H22 N2O6SNa 393.1096; Found 393.1098.
14
ACS Paragon Plus Environment

Page 15 of 23
The Journal of Organic Chemistry
1
2
3
Methyl N-(tert-butoxycarbonyl)-S-(4-methoxyphenyl)-L-cysteinate (3r): 17
4
5
6
7
8
9
Yield: 45% (49 mg); 1H NMR (400 MHz, CDCl3): δ 7.32 (dd, J = 6.8, 2 Hz, 2H), 6.76 (dd, J
= 6.8, 2 Hz, 2H), 5.26 (d, J = 7.2 Hz, 1H), 4.42ꢀ4.44 (m, 1H), 3.72 (s, 3H), 3.47 (s, 3H), 3.18
(d, J = 4.4 Hz, 2H), 1.35 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.3, 159.6, 155.2, 134.6,
124.9, 114.8, 80.2, 55.5, 53.4, 52.4, 38.9, 28.4.
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
Methyl N-(tert-butoxycarbonyl)-S-(p-tolyl)-L-cysteinate (3s): 11b
1
Yield: 39% (40 mg); H NMR (400 MHz, CDCl3): δ 7.3 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8
Hz, 2H), 5.34 (d, J = 6.8 Hz, 1H), 4.52ꢀ 4.53 (m, 1H), 3.53 (m, 3H), 3.3ꢀ3.31 (m, 2H), 2.3 (s,
3H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.2, 155.1, 137.4, 131.8, 129.9, 80.1,
53.4, 52.4, 37.9, 28.4, 21.1.
Methyl N-(tert-butoxycarbonyl)-S-(3,5-dimethylphenyl)-L-cysteinate (3t):
Yield: 36% (39 mg); Light red gummy oil; IR (neat, cmꢀ1): 2973, 1751, 1710, 1644, 1507,
1589, 1361, 1166, 1025. 1H NMR (400 MHz, CDCl3): δ 7.01 (s, 2H), 6.83 (s, 1H), 5.36 (d, J
= 7.6 Hz, 1H), 4.54ꢀ 4.55 (m, 1H), 3.55 (s, 3H), 3.33ꢀ3.34 (m, 2H), 2.26 (s, 6H), 1.41 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 171.2, 155.1, 138.7, 134.2, 128.9, 128.7, 80.1, 53.3, 52.3,
37.2, 28.3, 21.2. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H25NO4SNa 362.1402;
Found 362.1395
General procedure for S-arylation of N-acetyl-L-cysteine:
NꢀacetylꢀLꢀcysteine 6 (75 mg, 0.459 mmol, 1 equiv.) was taken in a clean round bottom flask,
MeOH (3 mL) was added and reaction mixture was cooled in iceꢀbath. After stirring for 5
min., NaOMe (4 equiv. 102 ꢁL, 1 molar stock solution prepared by dissolving freshly cut
sodium in dry methanol), substituted aryldiazonium salt (2a-2l, 2 equiv.) was added. The
reaction mixture was stirred for 3 hours below 15 °C. The crude reaction mixture was
acidified with 1N HCl at 0ꢀ5 C followed by addition of 2 mL iceꢀcold water. The reaction
mixture was extracted with CH2Cl2, organic layer washed with brine and concentrated at
room temperature in vacuo. The crude residue was loaded on a silica gel column and eluted
with CH2Cl2/MeOH (1/10) to get the pure products (7a-7l).
N-Acetyl-S-(4-methoxyphenyl)-L-cysteine (7a): 8c
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 23
1
2
3
4
5
6
7
8
Yield: 76% (94 mg); 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8
Hz, 2H), 4.43 (dd, J = 8.4, 4.0 Hz, 1H), 3.76 (s, 3H), 3.35 (dd, J = 14, 4.0 Hz, 1H), 3.07 (dd,
J = 14, 8.4 Hz, 1H), 1.92 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 173.1, 160.8, 135.2, 126.7,
115.6, 55.8, 54.6, 38.9, 22.5.
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
N-Acetyl-S-(2-methoxyphenyl)-L-cysteine (7b):
Yield: 79% (97 mg); Light pink semi solid. IR (neat, cmꢀ1): 3425, 2976, 1749, 1709, 1636,
1218, 855. 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H),
6.97 (d, J = 8 Hz, 1H), 6.9 (t, J = 7.6 Hz, 1H), 4.48 (dd, J = 8.4, 4 Hz, 1H), 3.86 (s, 3H), 3.43
13
(dd, J = 14, 4.4 Hz, 1H), 3.12 (dd, J = 13.6, 8.4 Hz, 1H), 1.91 (s, 3H). C NMR (100 MHz,
CDCl3): δ 173.7, 159.6, 132.9, 129.7, 123.5, 121.9, 112.2, 56.2, 53.6, 34.7, 22.3. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C12H15NO4SNa 292.0619; Found 292.0620.
N-Acetyl-S-(p-tolyl)-L-cysteine (7c): 8c
Yield: 85% (99 mg); 1H NMR (400 MHz, CDCl3): δ 7.28 (d, J = 8 Hz, 2H), 7.1 (d, J = 8 Hz,
2H), 4.48 (dd, J = 7.2, 4 Hz, 1H), 3.43 (dd, J = 13.6, 4 Hz, 1H), 3.15 (dd, J = 13.6, 4 Hz, 1H),
2.27 (s, 3H),1.94 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 173.2, 137.9, 133, 132, 130.7, 54.5,
37.5, 22.4, 21.
N-Acetyl-S-(3,5-dimethylphenyl)-L-cysteine (7d):
Yield: 84% (103 mg); Pink solid, mp: 118ꢀ120 °C. IR (neat, cmꢀ1): 3448, 1643, 1219, 1040,
1
821. H NMR (400 MHz, CDCl3): δ 6.99 (s, 2H), 6.82 (s, 1H), 4.46 (dd, J = 8, 4 Hz, 1H),
3.48 (dd, J = 14, 4 Hz, 1H), 3.17 (dd, J = 13.6, 8 Hz, 1H), 2.24 (s, 6H), 1.88 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 176.2, 172.8, 165.6, 139.6, 136.9, 128, 128.4, 55.5, 37.1, 22.7,
21.3. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C13H17NO3SNa 290.0827, Found
290.0829.
N-Acetyl-S-phenyl-L-cysteine (7e): 8c
Yield: 75% (82 mg); 1H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8 Hz, 2H), 7.28 (t, J = 8 Hz,
2H), 7.22ꢀ7.18 (m, 1H), 4.52 (dd, J = 8, 4 Hz, 1H), 3.5 (dd, J = 14, 4 Hz, 1H), 3.20 (dd, J =
13.6, 8 Hz, 1H), 1.89 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 173.2, 136.9, 131.2, 130.1,
127.6, 54.5, 36.8, 22.4.
N-Acetyl-S-(4-fluorophenyl)-L-cysteine (7f): 8c
16
ACS Paragon Plus Environment

Page 17 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Yield: 72% (85 mg); 1H NMR (400 MHz, CDCl3): δ 7.47ꢀ7.5 (m, 2H), 7.06ꢀ7.1 (m, 2H), 4.45
(dd, J = 8, 4 Hz, 1H), 3.50 (dd, J = 13.6, 4 Hz, 1H), 3.20 (dd, J = 13.6, 4 Hz, 1H), 1.95 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 173.3 (d, J = 15 Hz), 172.3, 163.2 (dd, J = 244, 24 Hz),
134.7ꢀ134.9 (m), 131.2, 117.1, 53.6, 37.5, 22.3.
9
N-Acetyl-S-(4-chlorophenyl)-L-cysteine (7g): 8c
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
Yield: 70% (88 mg); 1H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4
Hz, 2H), 4.52 (dd, J = 8, 4.8 Hz, 1H), 3.46 (dd, J = 14, 4.4 Hz, 1H), 3.19 (dd, J = 14, 8 Hz,
1H), 1.89 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 173.3, 135.7, 133.7, 132.8, 130.1, 53.8,
36.8, 22.3.
N-Acetyl-S-(4-bromophenyl)-L-cysteine (7h): 8c
1
Yield: 69% (101 mg); H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.4 Hz, 2H), 7.33 (d, J =
8.4 Hz, 2H), 4.53 (m, 1H), 3.54 (dd, J = 13.6, 2.8 Hz, 1H), 3.26 (dd, J = 13.6, 7.6 Hz, 1H),
1.94 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 173.2, 136, 133.1, 132.9, 121.4, 53.5, 36.3,
22.3.
N-Acetyl-S-(4-(trifluoromethyl)phenyl)-L-cysteine (7i): 8c
Yield: 74% (104 mg); 1H NMR (400 MHz, CDCl3): δ 7.56ꢀ7.5 (m, 4H), 4.52 (dd, J = 7.6, 4.4
Hz, 1H), 3.64 (dd, J = 14, 4.4 Hz, 1H), 3.27ꢀ3.34 (m, 1H), 1.89 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 173.4, 173.1, 142.8, 129.7 (d, J = 35 Hz), 126.9, 126.7ꢀ126.8 (m), 124.3, 53.4,
35.2, 22.3.
N-Acetyl-S-(3-(trifluoromethyl)phenyl)-L-cysteine (7j):
Yield: 79% (111 mg); Yellow solid, mp: 122ꢀ124 °C. IR (neat, cmꢀ1): 3196, 1714, 1649,
1422, 1188, 880. 1H NMR (400 MHz, CDCl3): δ 7.68 (m, 2H), 7.52ꢀ7.55 (m, 2H), 4.62 (dd, J
= 7.6, 3.6 Hz, 1H), 3.58 (dd, J = 14,.4.4 Hz, 1H), 3.30ꢀ3.37 (m, 1H), 1.94 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 173.3, 173.2, 138.7, 134.2, 132.3 (d, J = 32 Hz), 130.8, 126.9 (d, J =
3.6 Hz), 124.1 (d, J = 3.6 Hz), 53.5, 36, 22.2. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C12H12F3NO3SNa 330.0388; Found 330.0384
N-Acetyl-S-(2-bromophenyl)-L-cysteine (7k): 8c
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 23
1
2
3
4
5
6
7
8
Yield: 68% (99 mg); 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8 Hz, 1H), 7.44 (d, J = 8 Hz,
1H), 7.3 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 4.55 (dd, J = 8, 4.4 Hz, 1H), 3.55 (dd, J
= 13.6, 4 Hz, 1H), 3.26 (dd, J = 13.6, 4 Hz, 1H), 1.94 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 173.3, 138.5, 134.1, 130.1, 129.1, 128.2, 124.7, 54.4, 35.8, 22.5.
9
N-Acetyl-S-(naphthalen-1-yl)-L-cysteine (7l): 8c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Yield: 81% (107 mg); H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 8 Hz, 1H), 7.85 (d, J = 8
Hz, 1H), 7.76 (d, J = 8 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.47ꢀ7.55 (m, 2H), 7.4 (t, J = 7.6
Hz, 1H), 4.44 (dd, J = 8, 4 Hz, 1H), 3.54 (dd, J = 13.6, 4 Hz, 1H), 3.26 (dd, J = 13.2, 8.4 Hz,
1H), 1.83 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 173.2, 135.5, 134.4, 133.9, 130.8, 129.6,
128.9, 127.5, 127.3, 126.7, 125.9, 55.3, 37.7, 22.5.
General procedure for S-arylation of glutathione:
Glutathione (100 mg, 0.325 mmol, 1 equiv.) was taken in a clean round bottom flask, MeOH
(6 mL) was added and reaction mixture was cooled in iceꢀbath. After stirring for 5 min.,
NaOMe (5 equiv. 84 ꢁL, 1 molar stock solution prepared by dissolving freshly cut sodium in
dry methanol) and aryldiazonium salt (2a, 5 equiv.) were added. The reaction mixture was
stirred for 3 hours below 15 °C. The crude reaction mixture was dissolved in 6 mL of
acetonitrile ꢀH2O( 2:1) and was filtered through 2 micron filter paper. The clear solution was
lyophilized to get a powder. It was then purified by HPLC ( Phenomenex, Jupiter 4µ proteo
90 Å, 250 X 10.00 mm, 4 micron Cꢀ 18 column, flow rate 2 mL/min, concentration H2Oꢀ
CH3CN: 95ꢀ5 to 5ꢀ95, gradient 36 minutes. Injection volume: 0.25 µL.) to get the pure
products.
2-amino-5-((1-((carboxymethyl)amino)-1-oxo-3-(phenylthio)propan-2-yl)amino)-5-
oxopentanoic acid (7m) 8c
Yield: 68% (14.1 mg for 1 mL out of 6 mL reaction mixture). 1H NMR (400 MHz, CDCl3): δ
7.40 (d, J = 7.6 Hz, 2H), 7.29 (t, J = 7.2 Hz, 2H), 7.19ꢀ7.23 (m, 1H), 4.53 (dd, J = 8.8, 4.8
Hz, 1H), 3.89 (m, 1H), 3.84 (s, 2H), 3.44 (dd, J = 14, 4.8 Hz, 1H), 3.14 (dd, J = 14, 9.2 Hz,
1H), 2.48ꢀ2.49 (m, 2H), 2.12ꢀ2.14 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 173.2, 171.4,
135.1, 130.1, 128.8, 126.5, 52.9, 40.5, 35.3, 31.1, 25.8.
2-amino-5-((1-((carboxymethyl)amino)-3-((4-chlorophenyl)thio)-1-oxopropan-2-
yl)amino)-5-oxopentanoic acid (7n) 8c
18
ACS Paragon Plus Environment

Page 19 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Yield: 62% (15 mg for 1 mL out of 6 mL reaction mixture).1H NMR (400 MHz, CDCl3): δ
7.39 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.52 (dd, J = 8.8, 4.8 Hz, 1H), 3.94 (t, J =
6.4 Hz, 1H), 3.85(s, 2H), 3.43 (dd, J = 14, 5.2 Hz, 1H), 3.13 (dd, J = 14, 8.8 Hz, 1H), 2.51ꢀ
2.54 (m, 2H), 2.11ꢀ2.18 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 174.4, 172.6, 172.5, 171.5,
135.3, 133.9, 132.9, 130.2, 54.1, 53.7, 41.8, 36.8, 32.4, 27.
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
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra of synthesized compounds
Corresponding Author
* Email: scn@orgchem.iisc.ernet.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
NN thanks UGC (DSKPDF), India for a postꢀdoctoral fellowship. SS thanks Professor
V.Krishnan, Coordinator, TWAS Regional Office for Central and South Asia, Bangalore for
support as a Visiting Professor at the Organic Chemistry Department, Indian Institute of
Science. The work was supported by DST (SERB Fellowship to SC). Prof. P. Balaram and
Prof. G. Mugesh are thanked for help in HPLC analysis.
REFERENCES
1. (a) Sletten, E. M.; Bertozzi, C. R.; Angew. Chem. Int. Ed. 2009, 48, 6974. (b) Basle, E.;
Joubert, N.; Pucheault, M. Chem. Biol. 2010, 17, 213. (c) Spicer, C. D.; Davies, B. G. Nature
Commun. 2014, 5, 4740. (d) Boutureira, O.; Bernardes, G. J. L. Chem Rev. 2015, 115, 2174.
(e) Koniev, O.; Wagner, A. Chem. Soc. Rev. 2015, 44, 5495.
2. Fodje, M. N.; AlꢀKaradaghi, S. Protein Eng. 2002, 15, 353.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 23
1
2
3
4
5
3. (a) Chalker, J. M.; Bernardes, G. J. L.; Lin, Y. A.; Davies, B. G. Chem. Asian J. 2009, 4,
630. (b) Gunnoo, S. B.; Madder, A. ChemBioChem. 2016, 17, 529.
6
7
8
9
4. (a) Baldwin, A. D.; Kiick, K. L. Bioconjugate Chem. 2011, 22, 1946. (b) Toda, N.; Asano,
S.; Barbas, C. F. Angew Chem. Int. Ed. 2013, 52, 12592. (c) Lyon, R. P.; Setter, J. R.; Bovee,
T. D.; Doronina, S. O.; Hunter, J. H.; Anderson, M. E.; Balasubramanian, C. L.; Duniho, S.
M.; Leiske, C. I.; Li, F.; Senter, P. D. Nature Biotechnol. 2014, 32, 1059. (d) Fontaine, S. D.;
Reid, R.; Robinson, L.; Ashley, G. W.; Santi, D. V. Bioconjugate Chem. 2015, 26, 145.
5. (a) Mannervik, B. Adv. Enzymol. Relat. Areas Mol. Biol. 1985, 57, 357. (b) Hanzlik, R. P.;
Weller, P. E.; Desai, J.; Zheng, J.; Hall, L. R.; Slaughter, D. E. J. Org. Chem.1990, 55, 2736.
(c) Medeiros, A. M.; Bird, M. G.; Witz, G. J. Toxicol. Environ. Health. 1997, 51, 519. (d)
Angerer, J.; Ewers, U.; Wilhelm, M. Int. J. Hyg. Environ. Health. 2007, 210, 201.
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
6. (a) Kaldor, S. W.; Kalish, V. J.; Davies II, J. F.; Shetty, B. V.; Fritz, J. E.; Appelt, K.;
Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.;
Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.;
Reich, S. H.; Su, K. S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979. (b) Nakatani, S.;
Hidaka, K.; Ami, E.; Nakahara, K.; Sato, A.; Nguyen, J. –T.; Hamada, Y.; Hori, Y.; Ohnishi,
N.; Nagai, A.; Kimura, T.; Hayashi, Y.; Kiso, Y. J. Med. Chem. 2008, 51, 2992.
7. (a) Kondoh, A.; Yorimitsu, H.; Oshima, K. Tetrahedron, 2006, 62, 2357. (b) Ayral, E.;
Gloanec, P.; Berge, G.; de Nanteuil, G.; Mennecier, P.; Rupin, A.; Verbeuren, T. J.; Fulcrand,
P.; Martinez, J.; Hernandez, J. –F. Bioorg. Med. Chem. Lett. 2009, 19, 1386. (c) Spokoyny,
A. M.; Zou, Y.; Ling, J. J.; Yu, H.; Lin, Y. –S.; Pentelute, B. L. J. Am. Chem. Soc. 2013, 135,
5946. (d) Lee, J. –J.; Ha, S.; Kim, H. –J.; Ha, H. J.; Lee, H. –Y. Lee, K. –J. ACS Chem. Biol.
2014, 9, 2883. (e) Harris, P. A.; King, B. W.; Bandyopadhyay, D.; Berger, S. B.;
Campobasso, N.; Capriotti, C. A.; Cox, J. A.; Dare, L.; Dong, X.; Finger, J. N.; Grady, L. C.;
Hoffman, S. J.; Jeong, J. U.; Kang, J.; Kasparcova, V.; Lakdawala, A. S.; Lehr, R.; McNulty,
20
ACS Paragon Plus Environment

Page 21 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
D. E.; Nagilla, R.; Ouellette, M. T.; Pao, C. S.; Rendina, A. R.; Schaeffer, M. C.;
Summerfield, J. D.; Swift, B. A.; Totoritis, R. D.; Ward, P.; Zhang, A.; Zhang, D.; Marquis,
R. W.; Bertin, J.; Gough, P. J. J. Med. Chem. 2016, 59, 2163. (f) Gimenez, D.; Dose, A.;
Robson, N. L.; Sanford, G.; Cobb, S. L.; Coxon, C. R. Org. Biomol. Chem. 2017, 15, 4081.
8. (a) Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1995, 36, 4133. (b) Moreau, X.;
Campagne, J. –M.; Meyer, G.; Jutand, A. Eur. J. Org. Chem. 2005, 3749. (c) AlꢀShuaeeb, R.
A. A.; Kolodych, S.; Koniev, O.; Delacroix, S.; Erb, S.; Nicolay, S.; Cintrat, J. –C.; Brion, J.
–D.; Cianferani, S.; Alami, M.; Wagner, A.; Messaoudi, S. Chem. Eur. J. 2016, 22, 11365.
9. (a) Vinogradova, E. V.; Zhang, C.; Spokoyny, A. L.; Pentelute, B. L.; Buchwald, S. L.
Nature 2015, 526, 687. (b) Willwacher, J.; Raj, R.; Mohammed, S.; Davies, B. G.; J. Am.
Chem. Soc. 2016, 138, 8678.
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
10. (a) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019. (b) Krouzelka,
J.; Linhart, I. Eur. J. Org. Chem. 2009, 6336.
11. (a) Jouffroy, M.; Kelly, C. B.; Molander, G. A. Org. Lett. 2016, 18, 876. (b) Oderinde, M.
S.; Frenette, M.; Robbins, D. W.; Aquila, B.; Johannes, J. W. J. Am. Chem. Soc. 2016, 138,
1760.
12. Reviews on arenediazonium salts in organic synthesis: (a) Roglans, A.; PlaꢀQuintana, A.;
MorenoꢀManas, M. Chem. Rev. 2006, 106, 4622. (b) Taylor, J. G.; Moro, A. V.; Correia, C.
R. D. Eur. J. Org. Chem. 2011, 1403. (c) Felpin, F. –X.; NassarꢀHardy, L.; Le Callonnec, F.;
Fouquet, E. Tetrahedron 2011, 67, 2815. (d) Mo, F.; Dong, G.; Zhang, Y.; Wang, J. Org.
Biomol. Chem. 2013, 11, 1582. (e) Oger, N.; Le Grognec, E.; Felpin, F. –X. Org. Chem.
Front. 2015, 2, 590.
13. (a) Sengupta, S.; Bhattacharyya, S. J. Chem. Soc. Perkin Trans. 1, 1993, 1943. (b) Bhar,
D.; Chandrasekaran, S. Synthesis 1994, 785. (c) Sengupta, S.; Bhattacharya, S. Tetrahedron
Lett., 1995, 36, 4475. (d) Sengupta, S.; Bhattacharyya, S. J. Org. Chem. 1997, 62, 3405. (e)
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 23
1
2
3
4
5
Sengupta, S.; Sadhukhan, S. K. Tetrahedron Lett., 1998, 39, 715. (f) Sengupta, S.;
Sadhukhan, S. K. Org. Synth., 2002, 79, 52.
6
7
8
9
14. (a) Baig, N. B. R.; Sudhir, V. S.; Chandrasekaran, S. Tetrahedron: Asymmetry 2008,19,
1424. (b) Baig, N. B. R.; Kanimozi, C.; Sudhir, V. S.; Chandrasekaran, S. Synlett, 2009,
1227. (c) Baig, N. B. R.; Chandrakala, R. N.; Sudhir, V. S.; Chandrasekaran, S. J. Org.
Chem., 2010, 75, 2910.
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
15. (a) Galli, C. Chem. Rev. 1988, 88, 765. (b) Bonin, H.; Sauthier, M.; Felpin, F. –X. Adv.
Synth. Catal. 2014, 356, 645. (c) Kindt, S.; Heinrich, M. R. Synthesis 2016, 1597. (d)
Hofmann, J.; Heinrich, M. R. Tetrahedron Lett. 2016, 57, 4334.
16. (a) West, H. D.; Mathura, G. R.; Black, L. A. J. Biol. Chem. 1951, 193, 133. (b) Parke, D.
V.; Williams, R. T. Biochem. J. 1951, 48, 624. (c) Boyland, E.; Manson, D.; Nery, R. J.
Chem. Soc. 1962, 606.
17. Peng, H.; Cai, R.; Xu, C.; Chen, H.; Shi, X. Chem. Sci. 2016, 7, 6190.
18. Crisostomo, F. P.; Martin, T.; Carrillo, R. Angew. Chem. Int. Ed. 2014, 53, 2181.
19. Wang, X.; Cuny, G. D.; Noel, T. Angew. Chem. Int. Ed. 2013, 52, 7860 and references
cited therein.
20. (a) Barbero, M.; Degani, I.; Diulgheroff, N.; Dughera, S.; Fochi, R.; Migliaccio, M. J.
Org. Chem. 2000, 65, 5600.(b) Li, Y.; Pu, J.; Jiang, X. Org. Lett., 2014, 16, 2692. (c) Li, Y.;
Xie, W.; Jiang, X. Chem. Eur. J. 2015, 21, 16059.
21. (a) Canning, P. S. J.; Maskill, H.; McCrudden, K.; Sexton, B. Bull. Chem. Soc. Jpn. 2002,
75, 789. (b) FernandezꢀAlonso, A.; BravoꢀDiaz, C. Org. Biomol. Chem. 2008, 6, 4004 and
references cited therein.
22. The HRMS data of the crude reaction did not show any peak for the product or the 4ꢀ
chlorophenylꢀTEMPO adduct; cysteineꢀTEMPO adduct peak was observed (ESI).
22
ACS Paragon Plus Environment

Page 23 of 23
The Journal of Organic Chemistry
1
2
3
4
5
23. (a) Collins, K. D.; Glorius, F. Acc. Chem. Res. 2015, 48, 619. (b) Zhu, Y.; Bauer, M.;
Ackermann, L. Chem. Eur. J., 2015, 21, 9980.
6
7
8
9
24. Dell’Erba, C.; Houmam, A.; Novi, M.; Petrillo, G.; Pinson, J. J. Org. Chem. 1993, 58,
2670 and references cited therein.
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
25. (a) Pratsch, G.; Wallaschkowski, T.; Heinrich, M. R. Chem. Eur. J., 2012, 18, 11555. (b)
Kindt, S.; Wicht, K.; Heinrich, M. R. Org. Lett., 2015, 17, 6122. (c) Kindt, S.; Wicht, K.; M.
Heinrich, R. Angew. Chem. Int. Ed., 2016, 55, 8744.
26. Dai, J.ꢀJ.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.ꢀJ.; Lu, X.; Liu, L.; Fu, Y. J. Am.
Chem. Soc. 2013, 135, 8436.
27. (a) Zhang, N.; Quan, Z.ꢀJ.; Zhang, Z.; Da, Y.ꢀX.; Wang , X.ꢀC. Chem. Commun. 2016,
52, 14234. (b) Cornilleau, T.; Hermange, P.; Fouquet, E. Chem. Commun. 2016, 52,
10040. (c) Perretti, M. D.; Monzón, D. M.; Crisóstomo, F. P.; Martín, V. S.; Carrillo, R.
Chem. Commun. 2016, 52, 9036. (d) Nelson, H. M.; Reisberg, S. H.; Shunatona, H. P.;
Patel, J. S.; Toste. F. D. Angew. Chem. Int. Ed. 2014, 53, 2181.
28. During preparation of this manuscript, a Sꢀarylation reaction of cysteine with
arenediazonium salts under photoredox conditions appeared in the literature: Bottecchia,
C.; Rubens, M.; Gunnoo, S. M.; Hessel, V.; Madder, A.; Noel, T. Angew. Chem. Int. Ed.
2017, 56, 12702.
23
ACS Paragon Plus Environment