Visible-Light-Induced Deaminative Thioesterification of Amino Acid Derived Katritzky Salts via Electron Donor-Acceptor Complex Formation

Article abstract of DOI:10.1021/acs.orglett.9b03284

A visible-light-mediated deaminative thioesterification of amino acid derived Katritzky salts with thiobenzoic acid has been developed, which provides a novel synthetic method for the synthesis of α-mercapto acid derivatives under mild conditions. This ph

Full text of DOI:10.1021/acs.orglett.9b03284

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Induced Deaminative Thioesterification of Amino Acid
Derived Katritzky Salts via Electron Donor−Acceptor Complex
Formation
Mingcheng Yang,† Tianpeng Cao,† Tianxiao Xu,† and Saihu Liao*,†,‡
†Key Laboratory of Molecule Synthesis and Function Discovery, College of Chemistry, Fuzhou University, 2 Xueyuan Road, Fuzhou
350116, P.R. China
‡Beijing National Laboratory for Molecular Sciences (BNLMS), Fuzhou University, Fuzhou 350116, P.R. China
S
* Supporting Information
ABSTRACT: A visible-light-mediated deaminative thioester-
ification of amino acid derived Katritzky salts with thiobenzoic
acid has been developed, which provides a novel synthetic
method for the synthesis of α-mercapto acid derivatives under
mild conditions. This photoredox catalyst-free generation of
alkyl radicals via C−N bond cleavage is enabled by the
formation of an electron-donor−acceptor (EDA) complex
between the Katritzky salt and thiobenzoic acid anion, which
represents a new entry for EDA complex chemistry.
photoinduced C−N bond cleavage, which to the best of our
known remains elusive.
isible-light-mediated transformation has drawn consid-
Verable and increasing research interest in the past decade
due to its advantages such as mild conditions, versatile
reactivity, and no need for a special apparatus as required by
ultraviolet induced reactions, etc., and significant progress has
been achieved.1 Abundant and widely available α-amino acids
are among the most studied targets in photoredox catalysis,
and extension to the modification of peptides and proteins has
also gained success recently.2 However, in contrast to the
extensively studied and well-established decarboxylative
approaches,3 the corresponding photoinduced deaminative
transformations based on the alkyl radicals generated from the
cleavage of a C−N bond of α-amino acids or their derivatives
are far less investigated. The challenge lies on the high stability
and high bond dissociation energy of the unactivated C−N
bonds.4 In 2017, the Watson group reported an elegant
generation of alkyl radicals in a nickel-catalyzed cross-coupling
reaction via the C−N bond scission of Katritzky salts,5 which
can be readily prepared from amines by a simple condensation
with the bench-stable 2,4,6-triphenylpyrylium tetrafluorobo-
rate.6 Subsequently, Glorius et al. demonstrated that visible-
light-induced photoredox conditions can also be adopted to
cleave the C−N bond of the Katritzky salts to generate alkyl
radicals.7 These seminal and inspiring studies have drawn
much attention of chemists to utilize amines as radical
precursors in the past two years, and brought in the
development of a series of deaminative C−C and C−B bond
formation reactions based on Katritzky salts.8,9 In light of the
significance and recent increasing demand for sulfur-containing
compounds in a broad array of fields, including organic
synthesis, biological study, and materials science,10,11 we aim to
develop novel C−S bond formation methods based on this
In photocatalytic transformations, as most common organic
compounds have no absorption in the band of visible light,
typically a photocatalyst is required to harness the visible light
and initiate the reaction via single-electron transfer or energy
transfer. Recently, photoinduced transformation involving an
electron donor−acceptor (EDA) complex formation that
eliminates the need of external photocatalysts is emerging as
an appealing approach for the design of new photoinduced
radical transformations.12 Recently, we found that upon
activation in the Katritzky salt form, α-amino acid ester can
readily undergo deaminative thioesterification through a
visible-light-induced single-electron transfer process of EDA
complexes between the Katritzky salt and thiobenzoic acid
anion, delivering the thioesters in high yields, which can be
readily converted to the free thiols by hydrolysis (Figure 1, A).
This approach represents a novel and facile method for the
synthesis of α-mercapto acids and derivatives, and the mild
conditions endow the reaction a good tolerance to functional
groups or moieties such as phenol, sulfide, and indole, avoiding
the use of oxidizing reagents or potentially explosive diazonium
salts.13 In addition, this method can be further extended to the
deaminative thiolation with aryl and alkyl thiols. α-Mercapto
acids, as an analogue of α-amino acid and lactic acid, are a key
structure of many biologically active molecules and drugs, such
as tiopronin, modafinil, armodafinil, retapamulin, lesinurad, etc.
(Figure 1, B).14
Received: September 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03284
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Next, the reaction scope was examined by treating a variety
of amino acid derived Katritzky salts under the optimized
reaction conditions. As shown in Scheme 1, the phenylalanine-
derived methyl, ethyl, and benzyl esters, all gave the desired
products in high isolated yields (3a−c, 86−96%). Different
substituents at the phenyl group were also tested. To our
delight, a hydroxyl group without protection could be directly
used, delivering the corresponding products 3d in 89% yield,
while the product 3e from DOPA was obtained in 99% yield.
Fluoro substitution gave the product 3f in 76% yield, while an
electron-withdrawing nitro group gave 3g in 47% yield. The
reaction with homophenylalanine-derived salt delivered the
product in 75% yield (3h), while 3i was obtained in 80% yield
from the glutamic acid derived salt. Asparagine can also be
converted in good yield (3j). Interestingly, serine-derived
Katritzky salt underwent dehydration and only the correspond-
ing acrylate salt was isolated,15 which reacted with 2 equiv of
thiobenzoic acid in a conjugate addition/deaminative thio-
esterification sequence to give the dithioester product 3k in
58% yield. With homoserine, the cyclized product 3l was
isolated in 54% yield. Alanine, leucine, methionine, and lysine
can also be readily transformed into the desired product in
good yields (3m−p). It is worth mentioning that methionine-
derived product 3o possesses a strong, sweet smell. The indole
group was also compatible with the current conditions (3q).
Moreover, a lactam substrate from S-ATBA was also examined
under the standard conditions and gave the corresponding
thioester product 3r in 49% yield.
To our delight, the current conditions can be extended to
the thiolation reaction with aryl and alkyl thiols. As shown in
Scheme 2, a range of thiols could be applied to this
transformation. Under standard conditions, we could easily
obtain thioethers (4a, 4b, and 4c) in good yields from alkyl or
long-chain alkyl thiols. Secondary thiols such as cyclohexyl
mercaptan provided 4d in 81% yield, while 3-mercapto-2-
butanone (racemic) delivered the desired product 4e in 58%
yield (1:1 dr). Moreover, various thiophenols could also react
smoothly to deliver the corresponding products 4f−l in 58−
91% yields. Both electron-donating (−Me, −t-Bu, −OMe) and
electron-withdrawing substituents (−F, −CF3) could be well
accommodated and gave the corresponding thioethers in good
to high yields.
As an extension of the methodology, a gram-scale reaction
with 1e was also demonstrated under the standard conditions,
which gave the desired deaminative thioesterification product
3e in nearly quantitative yield. Subsequent treatment of
thioester 3e with aq NaOH could readily release the free thiol,
α-mercapto ester 5, in 93% yield (Figure 2A). To examine the
possible asymmetric induction with the electron donor−
acceptor (EDA) complex, we measured the enantiomeric
excess of the product 3a that obtained under standard
conditions with enantiomerically pure (R)-phenylalanine-
derived Katritzky salt, but almost no chirality transfer to the
product 3a was observed (1.3% ee, Figure 2B). In addition, the
vinyl Katritzky salt 1k obtained from serine enables us to
design a Michael addition/intramolecular deaminative thio-
lation sequence with 1,2-benzenedithiol. To our delight, this
tandem reaction proceeded well and could deliver the desired
benzo-1,4-dithiane product 6 in 54% yield (Figure 2C).
To gain some insight about the electron donor−acceptor
(EDA) complex formation and the visible-light-induced single
electron transfer radical cross-coupling mechanism, we
measured the UV−vis absorption of different combinations
Figure 1. (A) Photoinduced deaminative thioesterification; (B) α-
mercapto acid related bioactive molecules and drugs.
We commenced our study with phenylalanine-derived
Katritzky salt 1a as the model substrate, which can be readily
prepared in one step by treating the corresponding amino acid
ester with commercially available 2,4,6-triphenylpyrylium
tetrafluoroborate. Commercially available thiobenzoic acid 2a
was chosen as the sulfur source and DIPEA as the base. Upon
extensive reaction optimization, a clean reaction was achieved
by performing the reaction in dichloromethane (DCM) at
room temperature under the irradiation of blue LEDs (6 W),
delivering the desired product 3a in 99% NMR yield (Table 1,
a
Table 1. Optimization of the Reaction Conditions
a
b
entry
variation from the standard conditions
yield (%)
1
2
3
4
5
6
7
8
9
none
99
98
92
70
93
98
89
97
NP
NP
TEA instead of DIPEA
DABCO instead of DIPEA
Na2CO3 instead of DIPEA
MeCN instead of DCM
toluene instead of DCM
DMA instead of DCM
1,4-dioxane instead of DCM
without light
10
without base
a
Standard conditions: 1a (0.05 mmol), 2a (0.10 mmol), DIPEA (0.10
mmol), DCM (0.5 mL), 6 W blue LEDs, room temperature, under
b
argon, 24 h. Yield was determined by 1H NMR with benzyl ether as
an internal standard. NP = no product was observed.
entry 1). Other organic bases like TEA and DABCO are
effective as well (entry 2 and 3), while inorganic base Na2CO3
was also usable, albeit with a lower yield (entry 4). Reactions
can also be performed in other solvents such as acetonitrile,
toluene, N,N-dimethylacetamide (DMA), and 1,4-dioxane with
high yields in general (89−98% yield, entries 5−8). Control
experiments indicated that both light and base are crucial for
the present transformation (entry 9 and 10). No product
formed when the reactions were conducted in the dark (entry
9).
B
DOI: 10.1021/acs.orglett.9b03284
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Substrate Scope of Amino Acid Derivatives
Scheme 2. Substrate Scope of Thiols for Synthesis of
Thioether
Figure 2. Reaction extension.
suggesting the formation of EDA complex between the
Katritzky salt and thiobenzoic acid anion. In particular, the
absorption of the reaction mixture (1a + 2a + DIPEA) at the
band of blue light irradiation (Blue LEDs, λmax 458 nm) was
much stronger than other combinations of reaction compo-
nents. It is worth mentioning that the brown color of the
reaction mixture faded and turned almost colorless (Figure 3A,
from V to VI) upon completion of the reaction. Moreover,
under the standard conditions, the addition of TEMPO can
inhibit the reaction, and no product was observed by 1H NMR
and HRMS analysis of the crude reaction mixture. Instead, the
radical resulted from the C−N bond cleavage could be trapped
of the reactants and conducted several trapping and control
experiments. As shown in Figure 3A, both the solution of 1a
and 2a are colorless (I and II). Mixing 1a and 2a showed
almost no color change (III). However, upon the addition of
base, the resulting 1a/2a/DIPEA solution immediately turned
brown (V). This dramatic color change is consistent with the
enhanced absorption in the visible-light region (Figure 3B),
C
DOI: 10.1021/acs.orglett.9b03284
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
complex A with Katritzky salts 1 through an anion-exchange
process. The EDA complex, which exhibits strong absorption
at the visible light region, can be excited by blue light
irradiation, thus inducing a single-electron transfer from the
anion part to the cation part in B. The resulting radical C from
Katritzky salt undergoes an irreversibe fragmentation by the
loss of the pyridine byproduct to give radical intermediate D.
Radical D can undergo an in-cage radical cross-coupling with
the thioacid radical to afford the desired deaminative thioester
product 3 (path a). An alternative pathway may be also
involved: D could add to the thioacid anion to form the
anionic radical intermediate E, which can subsequently transfer
one electron to 1 to generate the product 3 and intermediate C
concurrently to reinitiate the reaction (path b).
In conclusion, a novel and efficient visible-light-mediated
deaminative thioesterfication reaction of amino acid derived
Katritzky salts with thiobenzoic acid has been developed. This
reaction provides a novel and facile method for synthesis of α-
mercapto acid derivatives under mild reaction conditions and
shows a good functional group compatibility. Further
extension to visible-light-induced thiolation reactions has also
been demonstrated with various alkyl and aryl thiols. This
light-mediated transformation proceeds without the need of
external photocatalyst, and a mechanism involving the
formation of an EDA complex between the Katritzky salt
and thioacid anion was proposed, which also represents a new
entry for EDA complex chemistry.
Figure 3. Mechanistic studies. (A) The colors of DCM solutions of
(I) 1a; (II) 2a; (III) 1a and 2a; (IV) 1a and DIPEA; (V) mixture of
1a, 2a and DIPEA prior to irradiation and after 24 h irradiation (VI).
(B) UV−vis absorption spectra. (C) Radical-trapping experiment.
(D) Control reaction in dark. (E) HRMS spectrum of the TEMPO
trapping experiment.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03284.
by TEMPO, and the adduct 7 was identified by HRMS (Figure
3C,E). In contrast, when the reaction was carried out in the
dark, neither 3a nor 7 was detected (Figure 3D).
On the basis of our observations and previously reported
mechanisms on EDA complex,12 a possible mechanism was
proposed for the thioesterification of Katritzky salts as outlined
in Figure 4. Upon addition of a base such as DIPEA, the
thiobenzoic acid is deprotonated and generates the EDA
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: shliao@fzu.edu.cn.
ORCID
Saihu Liao: 0000-0002-0251-8757
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Natural Science Foundation of
China (No. 21602028), the Recruitment Program of Global
Experts, and Fuzhou University for the financial support.
REFERENCES
■
(1) For selected reviews and perspectives, see: (a) Narayanam, J. M.
R.; Stephenson, C. R. J. Visible Light Photoredox Catalysis:
Applications in Organic Synthesis. Chem. Soc. Rev. 2011, 40, 102−
113. (b) Xuan, J.; Xiao, W.-J. Visible-Light Photoredox Catalysis.
Angew. Chem., Int. Ed. 2012, 51, 6828−6838. (c) Prier, C. K.; Rankic,
D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with
Transition Metal Complexes: Applications in Organic Synthesis.
Chem. Rev. 2013, 113, 5322−5363. (d) Schultz, D. M.; Yoon, T. P.
Solar Synthesis: Prospects in Visible Light Photocatalysis. Science
Figure 4. Proposed mechanism for the photoinduced thioesterfica-
tion.
̈
2014, 343, 985−994. (e) Marzo, L.; Pagire, S. K.; Reiser, O.; Konig,
D
DOI: 10.1021/acs.orglett.9b03284
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
B. Visible-Light Photocatalysis: Does It Make a Difference in Organic
Synthesis? Angew. Chem., Int. Ed. 2018, 57, 10034−10072.
Radical coupling from alkyl amines. Nat. Catal. 2019, 2, 473−476.
(j) Yi, J.; Badir, S.-O.; Kammer, L. M.; Ribagorda, M.; Molander, G.
A. Deaminative Reductive Arylation Enabled by Nickel/Photoredox
Dual Catalysis. Org. Lett. 2019, 21, 3346−3351.
(2) For selected reviews and perspectives, see: (a) Bottecchia, C.;
̈
Noel, T. Photocatalytic Modification of Amino Acids, Peptides, and
Proteins. Chem. - Eur. J. 2019, 25, 26−42. (b) Mondal, S.;
Chowdhury, S. Adv. Synth. Catal. 2018, 360, 1884−1910. (c) Malins,
L. R. Decarboxylative Couplings as Versatile Tools for Late-stage
Peptide Modifications. Pept. Sci. 2018, 110, No. e24049. (d) de-
Gruyter, J. N.; Malins, L. R.; Baran, P. S. Residue-Specific Peptide
Modification: A Chemist’s Guide. Biochemistry 2017, 56, 3863−3873.
(e) Isenegger, P. G.; Davis, B. G. Concepts of Catalysis in Site-
Selective Protein Modifications. J. Am. Chem. Soc. 2019, 141, 8005−
8013.
(3) For selected reviews and perspectives, see: (a) Xuan, J.; Zhang,
Z. G.; Xiao, W.-J. Visible-light-induced decarboxylative functionaliza-
tion of carboxylic acids and their derivatives. Angew. Chem., Int. Ed.
2015, 54, 15632−15641. (b) Wei, Y.; Hu, P.; Zhang, M.; Su, W.
Metal-catalyzed Decarboxylative C-H Functionalization. Chem. Rev.
(9) For recent examples on light-mediated reactions, see: (a) Hu, J.;
Wang, G.; Li, S.; Shi, Z. Selective C−N Borylation of Alkyl Amines
Promoted by Lewis Base. Angew. Chem., Int. Ed. 2018, 57, 15227−
15231. (b) Ociepa, M.; Turkowska, J.; Gryko, D. Redox-Activated
Amines in C(sp3)−C(sp) and C(sp3)−C(sp2) Bond Formation
Enabled by Metal-Free Photoredox Catalysis. ACS Catal. 2018, 8,
11362−11367. (c) Zhang, M.-M.; Liu, F. Visible-light-mediated
Allylation of Alkyl radicals with Allylic Sulfones via a Deaminative
Strategy. Org. Chem. Front. 2018, 5, 3443−3446. (d) Sandfort, F.;
Strieth-Kalthoff, F.; Klauck, F. J. R.; James, M. J.; Glorius, F.
Deaminative Borylation of Aliphatic Amines Enabled by Visible Light
Excitation of an Electron Donor−Acceptor Complex. Chem. - Eur. J.
2018, 24, 17210−17214. (e) Wu, J.; He, L.; Noble, A.; Aggarwal, V.
K. Photoinduced Deaminative Borylation of Alkylamines. J. Am.
Chem. Soc. 2018, 140, 10700−10704. (f) Jiang, X.; Zhang, M.-M.;
Xiong, W.; Lu, L.-Q.; Xiao, W.-J. Deaminative (Carbonylative) Alkyl-
Heck-type Reactions Enabled by Photocatalytic C−N Bond
Activation. Angew. Chem., Int. Ed. 2019, 58, 2402−2406. (g) Klauck,
F. J. R.; Yoon, H.; James, M. J.; Lautens, M.; Glorius, F. Visible-Light-
Mediated Deaminative Three-Component Dicarbofunctionalization
of Styrenes with Benzylic Radicals. ACS Catal. 2019, 9, 236−241.
(h) Fu, M.-C.; Shang, R.; Zhao, B.; Wang, B.; Fu, Y. Photocatalytic
Decarboxylative Alkylations Mediated by Triphenylphosphine and
Sodium Iodide. Science 2019, 363, 1429−1434. (i) Kim, Y.; Lee, K.;
Mathi, G. R.; Kim, I.; Hong, S. Visible-Light-Induced Cascade Radical
Ring-Closure and Pyridylation for the Synthesis of Tetrahydrofurans.
Green Chem. 2019, 21, 2082−2087. (j) Zhu, Z.-F.; Zhang, M.-M.; Liu,
F. Radical Alkylation of Isocyanides with Amino Acid-/Peptide-
derived Katritzky Salts via Photoredox Catalysis. Org. Biomol. Chem.
2019, 17, 1531−1534.
̈
2017, 117, 8864−8907. (c) Schwarz, J.; Konig, B. Decarboxylative
Reactions with and without Light − a Comparison. Green Chem.
2018, 20, 323−361.
(4) Ouyang, K.; Hao, W.; Zhang, W.-X.; Xi, Z. Transition-Metal-
Catalyzed Cleavage of C-N Single Bonds. Chem. Rev. 2015, 115,
12045−12090.
(5) Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P.
Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross
Couplings via C−N Bond Activation. J. Am. Chem. Soc. 2017, 139,
5313−5316.
(6) (a) Bapat, J. B.; Blade, R. J.; Boulton, A. J.; Epsztajn, J.; Katrizky,
A. R.; Lewis, J.; Molina-Buendia, P.; Nie, P.-L.; Ramsden, C. A.
Pyridines as Leaving Groups in Synthetic Transformations:
Nucleophilic Displacements of Amino Groups, and Novel Prepara-
tions of Nitriles and Isocyanates. Tetrahedron Lett. 1976, 17, 2691−
2694. (b) Katritzky, A. R.; Marson, C. M. Pyrylium Mediated
Transformations of Primary Amino Groups into Other Functional
Groups. Angew. Chem., Int. Ed. Engl. 1984, 23, 420−429. (c) Sowmiah,
(10) For most recent reviews, see: (a) Shen, C.; Zhang, P.; Sun, Q.;
Bai, S.; Andy Hor, T. S.; Liu, X. Recent Advances in C-S Bond
Formation via C-H Bond Functionalization and Decarboxylation.
Chem. Soc. Rev. 2015, 44, 291−314. (b) Dunbar, K. L.; Scharf, D. H.;
Litomska, A.; Hertweck, C. Enzymatic Carbon−Sulfur Bond
Formation in Natural Product Biosynthesis. Chem. Rev. 2017, 117,
5521−5577. (c) Boyd, D. A. Sulfur and its Role in Modern Materials
Science. Angew. Chem., Int. Ed. 2016, 55, 15486−15502. (d) Qiao, Z.;
Jiang, X. Recent Developments in Sulfur−Carbon Bond Formation
Reaction Involving Thiosulfates. Org. Biomol. Chem. 2017, 15, 1942−
1946. (e) Naowarojna, N.; Cheng, R.; Chen, L.; Quill, M.; Xu, M.;
Zhao, C.; Liu, P. Mini-Review: Ergothioneine and Ovothiol
Biosyntheses, an Unprecedented Trans-Sulfur Strategy in Natural
Product Biosynthesis. Biochemistry 2018, 57, 3309−3325.
S.; Esperanca̧ , J. M. S. S.; Rebelo, L. P. N.; Afonso, C. A. M.
Pyridinium Salts: from Synthesis to Reactivity and Applications. Org.
Chem. Front. 2018, 5, 453−493.
(7) Klauck, F. J. R.; James, M. J.; Glorius, F. Deaminative Strategy
for the Visible-Light-Mediated Generation of Alkyl Radicals. Angew.
Chem., Int. Ed. 2017, 56, 12336−12339.
(8) For recent examples on Ni- and other metal-catalyzed reactions,
see: (a) Liao, J.; Guan, W.; Boscoe, B. P.; Tucker, J. W.; Tomlin, J.
W.; Garnsey, M. R.; Watson, M. P. Transforming Benzylic Amines
into Diarylmethanes: Cross-Couplings of Benzylic Pyridinium Salts
via C−N Bond Activation. Org. Lett. 2018, 20, 3030−3033. (b) Guan,
W.; Liao, J.; Watson, M. P. Vinylation of Benzylic Amines via C−N
Bond Functionalization of Benzylic Pyridinium Salts. Synthesis 2018,
50, 3231−3237. (c) Liao, J.; Basch, C. H.; Hoerrner, M. E.; Talley, M.
R.; Boscoe, B. P.; Tucker, J. W.; Garnsey, M. R.; Watson, M. P.
Deaminative Reductive Cross-Electrophile Couplings of Alkylpyr-
idinium Salts and Aryl Bromides. Org. Lett. 2019, 21, 2941−2946.
(d) Plunkett, S.; Basch, C. H.; Santana, S. O.; Watson, M. P.
Harnessing Alkylpyridinium Salts as Electrophiles in Deaminative
Alkyl−Alkyl Cross-Couplings. J. Am. Chem. Soc. 2019, 141, 2257−
2262. (e) Martin-Montero, R.; Yatham, V. R.; Yin, H.; Davies, J.;
Martin, R. Ni-catalyzed Reductive Deaminative Arylation at sp3
Carbon Centers. Org. Lett. 2019, 21, 2947−2951. (f) Ni, S.; Li, C.-
X.; Yu, M.; Han, J.; Wang, Y.; Yan, H.; Pan, Y. Ni-Catalyzed
Deaminative Cross-Electrophile Coupling of Katritzky Salts with
Halides via C−N Bond Activation. Sci. Adv. 2019, 5, No. eaaw9516.
(g) Yue, H.; Zhu, C.; Shen, L.; Geng, Q.; Hock, K. J.; Yuan, T.;
Cavallo, L.; Rueping, M. Nickel-Catalyzed C−N Bond Activation:
Activated Primary Amines as Alkylating Reagents in Reductive Cross-
Coupling. Chem. Sci. 2019, 10, 4430−4435. (h) Li, C.-L.; Jiang, X.;
Lu, L.-Q.; Xiao, W.-J.; Wu, X.-F. Cobalt(II)-Catalyzed Alkoxycarbo-
nylation of Aliphatic Amines via C−N Bond Activation. Org. Lett.
2019, 21, 6919−6923. (i) Kong, D.; Moon, P.-J.; Lundgren, R.- J.
(11) For selected reports in 2019, see: (a) Laudadio, G.;
Barmpoutsis, E.; Schotten, C.; Struik, L.; Govaerts, S.; Browne, D.
̈
L.; Noel, T. Sulfonamide Synthesis through Electrochemical Oxidative
Coupling of Amines and Thiols. J. Am. Chem. Soc. 2019, 141, 5664−
5668. (b) Laudadio, G.; Bartolomeu, A. d. A.; Verwijlen, L. M. H. M.;
̈
Cao, Y.; de Oliveira, K. T.; Noel, T. Sulfonyl Fluoride Synthesis
through Electrochemical Oxidative Coupling of Thiols and Potassium
Fluoride. J. Am. Chem. Soc. 2019, 141, 11832−11836. (c) Liu, D.; Ma,
H.-X.; Fang, P.; Mei, T.-S. Nickel-Catalyzed Thiolation of Aryl
Halides and Heteroaryl Halides through Electrochemistry. Angew.
Chem., Int. Ed. 2019, 58, 5033−5037. (d) Kang, Y. S.; Zhang, P.; Li,
M. Y.; Chen, Y. K.; Xu, H. J.; Zhao, J.; Sun, W. Y.; Yu, J. Q.; Lu, Y.
Ligand-Promoted RhIII-Catalyzed Thiolation of Benzamides with a
Broad Disulfide Scope. Angew. Chem., Int. Ed. 2019, 58, 9099−9103.
(e) Ouhib, F.; Grignard, B.; Van Den Broeck, E.; Luxen, A.; Robeyns,
K.; Van Speybroeck, V.; Jerome, C.; Detrembleur, C. A Switchable
Domino Process for the Construction of Novel CO2-Sourced Sulfur-
Containing Building Blocks and Polymers. Angew. Chem. 2019, 131,
11894−11899. (f) Wang, X.; Wang, B.; Yin, X.; Yu, W.; Liao, Y.; Ye,
J.; Wang, M.; Hu, L.; Liao, J. Palladium-Catalyzed Enantioselective
Thiocarbonylation of Styrenes. Angew. Chem., Int. Ed. 2019, 58,
E
DOI: 10.1021/acs.orglett.9b03284
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
12264−12270. (g) Zhang, Y.; Xu, X.; Zhu, S. Nickel-Catalysed
selective migratory hydrothiolation of alkenes and alkynes with thiols.
Nat. Commun. 2019, 10, 1752. (h) Xu, J.; Zhang, F.; Zhang, S.;
Zhang, L.; Yu, X.; Yan, J.; Song, Q. Radical Promoted C(sp2)-S
Formation and C(sp3)-S Bond Cleavage: Access to 2-Substituted
Thiochromones. Org. Lett. 2019, 21, 1112−1115. (i) Bogonda, G.;
Patil, D. V.; Kim, H. Y.; Oh, K. Visible-Light-Promoted Thiyl Radical
Generation from Sodium Sulfinates: A Radical−Radical Coupling to
Thioesters. Org. Lett. 2019, 21, 3774−3779. (j) Wei, L.; Wu, C.;
Tung, C.-H.; Wang, W.; Xu, Z. Decarboxylative Sulfenylation of
Amino acids via Metallaphotoredox Catalysis. Org. Chem. Front. 2019,
6, 3224−3227.
(14) (a) Scott, K. A.; Njardarson, J. T. Analysis of US FDA-
Approved Drugs Containing Sulfur Atoms. Top. Curr. Chem. 2019,
376 (5), 1−34. (b) McKinnell, R. M.; Fatheree, P.; Choi, S.-K.;
Gendron, R.; Jendza, K.; Blair, B. O.; Budman, J.; Hill, C. M.; Hegde,
L. G.; Yu, C.; McConn, D.; Hegde, S. S.; Marquess, D. G.; Klein, U.
Discovery of TD-0212, an Orally Active Dual Pharmacology AT1
Antagonist and Neprilysin Inhibitor (ARNI). ACS Med. Chem. Lett.
2019, 10, 86−91. (c) Jain, A. K.; Vaidya, A.; Ravichandran, V.;
Kashaw, S. K.; Agrawal, R. K. Recent Developments and Biological
Activities of Thiazolidinone Derivatives: A Review. Bioorg. Med. Chem.
2012, 20, 3378−3395. (d) Spengler, J.; Boettcher, C.; Albericio, F.;
Burger, K. Hexafluoroacetone as Protecting and Activating Reagent:
New Routes to Amino, Hydroxy, and Mercapto Acids and Their
Application for Peptide and Glyco- and Depsipeptide Modification.
Chem. Rev. 2006, 106, 4728−4746.
(12) For selected recent examples on EDA complex chemistry, see:
́
́
(a) Arceo, E.; Jurberg, I. D.; Alvarez-Fernandez, A.; Melchiorre, P.
Photochemical Activity of a Key Donor−Acceptor Complex can Drive
Stereoselective Catalytic α-Alkylation of Aldehydes. Nat. Chem. 2013,
5, 750−756. (b) Nappi, M.; Bergonzini, G.; Melchiorre, P. Metal-Free
Photochemical Aromatic Perfluoroalkylation of α-Cyano Arylacetates.
Angew. Chem., Int. Ed. 2014, 53, 4921−4925. (c) da Silva, G. P.; Ali,
(15) For details, see the Supporting Information.
A.; da Silva, R. C.; Jiang, H.; Paixao, M. W. Tris(trimethylsilyl)silane
̃
and Visible-light Irradiation: a New Metal- and Additive-free
Photochemical Process for the Synthesis of Indoles and Oxindoles.
Chem. Commun. 2015, 51, 15110−15113. (d) Kandukuri, S. R.;
́
Bahamonde, A.; Chatterjee, I.; Jurberg, I. D.; Escudero-Adan, E. C.;
Melchiorre, P. X-Ray Characterization of an Electron Donor−
Acceptor Complex that Drives the Photochemical Alkylation of
Indoles. Angew. Chem., Int. Ed. 2015, 54, 1485−1489. (e) Quint, V.;
́
Morlet-Savary, F.; Lohier, J.-F.; Lalevee, J.; Gaumont, A.-C.; Lakhdar,
S. Metal-Free, Visible Light-Photocatalyzed Synthesis of Benzo[b]-
phosphole Oxides: Synthetic and Mechanistic Investigations. J. Am.
Chem. Soc. 2016, 138, 7436−7441. (f) Spell, M. L.; Deveaux, K.;
Bresnahan, C. G.; Bernard, B. L.; Sheffield, W.; Kumar, R.; Ragains, J.
R. A Visible-Light-Promoted O-Glycosylation with a Thioglycoside
Donor. Angew. Chem., Int. Ed. 2016, 55, 6515−6519. (g) Liu, B.; Lim,
C.-H.; Miyake, G. M. Visible-Light-Promoted C−S Cross-Coupling
via Intermolecular Charge Transfer. J. Am. Chem. Soc. 2017, 139,
13616−13619. (h) Miao, Y.; Li, T.; Li, P.; Wang, L. Three-
Component Reactions of Isocyanides, Alkynes, and Sulfinic Acids by
Electron Donor−Acceptor Complex. Org. Lett. 2018, 20, 1735−1739.
(i) Sandfort, F.; Strieth-Kalthoff, F.; Klauck, F. J. R.; James, M. J.;
Glorius, F. Deaminative Borylation of Aliphatic Amines Enabled by
Visible Light Excitation of an Electron Donor−Acceptor Complex.
Chem. - Eur. J. 2018, 24, 17210−17214. (j) James, M. J.; Strieth-
Kalthoff, F.; Sandfort, F.; Klauck, F. J. R.; Wagener, F.; Glorius, F.
Visible-Light-Mediated Charge Transfer Enables C−C Bond For-
mation with Traceless Acceptor Groups. Chem. - Eur. J. 2019, 25,
8240−8244. (k) Wu, J.; Grant, P. S.; Li, X.; Noble, A.; Aggarwal, V. K.
Catalyst-Free Deaminative Functionalizations of Primary Amines by
Photoinduced Single-Electron Transfer. Angew. Chem., Int. Ed. 2019,
58, 5697−5701. (l) Li, Y.; Ma, F.; Miao, T.; Wang, L. Hydrogen and
Sulfonyl Radical Generation for the Hydrogenation and Arylsulfony-
lation of Alkenes Driven by Photochemical Activity of Hydrogen
Bond Donor−Acceptor Complexes. Adv. Synth. Catal. 2019, 361,
1606−1616. (m) Liu, J.-L.; Zhu, Z.-F.; Liu, F. Cyanofluorination of
Vinyl Ethers Enabled by Electron Donor−Acceptor Complexes. Org.
Chem. Front. 2019, 6, 241−244.
(13) (a) Blommaert, A.; Turcaud, S.; Anne, C.; Roques, B. P. Small
Tripeptide Surrogates with Low Nanomolar Affinity as Potent
Inhibitors of the Botulinum Neurotoxin B Metallo-proteolytic
Activity. Bioorg. Med. Chem. 2004, 12, 3055−3062. (b) Nam, J.;
Lee, S.-K.; Kim, K. Y.; Park, Y. S. Asymmetric Syntheses of α-
Mercapto Carboxylic Acid Derivatives by Dynamic Resolution of N-
Methyl Pseudoephedrine α-Bromo Esters. Tetrahedron Lett. 2002, 43,
8253−8255. (c) Kortylewicz, Z. P.; Galardy, R. E. Phosphoramidate
Peptide Inhibitors of Human Skin Fibroblast Collagenase. J. Med.
Chem. 1990, 33, 263−273. (d) For a reported explosion, see:
Laquidara, J. 3-[Ethoxy(thiocarbonyl)thio]quinoline explosion. Chem.
Eng. News 2001, 79, 6.
F
DOI: 10.1021/acs.orglett.9b03284
Org. Lett. XXXX, XXX, XXX−XXX