Phthalimide-Carried Disulfur Transfer to Synthesize Unsymmetrical Disulfanes via Copper Catalysis

Article abstract of DOI:10.1021/acscatal.9b04326

A versatile Cu-catalyzed cross-coupling reaction to various unsymmetrical disulfanes has been presented, from phthalimide-carried disulfur transfer reagents and commercially available boronic acids under mild and practical conditions. The method features the unprecedented use of phthalimide-carried disulfurating reagents (Harpp reagent) in cross-coupling chemistry and is highlighted by the broad substrate scopes, even applicable for the transfer of aryl-disulfur moieties (ArSS-). Notably, the robustness of this methodology is shown by the late-stage modification of bioactive scaffolds of coumarin, estrone, and captopril.

Full text of DOI:10.1021/acscatal.9b04326

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Letter
Phthalimide-Carried Disulfur Transfer to Synthesize
Unsymmetrical Disulfanes via Copper Catalysis
Jiao-xia Zou, Jin-hong Chen, Tao Shi, Yong-sheng Hou, Fei Cao, Yong-
qiang Wang, Xiao-dong Wang, Zhong Jia, Quanyi Zhao, and Zhen Wang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04326 • Publication Date (Web): 08 Nov 2019
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ACS Catalysis
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Phthalimide-Carried Disulfur Transfer to Synthesize Unsymmetrical
Disulfanes via Copper Catalysis
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Jiaoxia Zou,‡, [a] Jinhong Chen,‡, [a] Tao Shi,‡, [a], * Yongsheng Hou,[a] Fei Cao,[b] Yongqiang Wang,[a]
Xiaodong Wang,[a] Zhong Jia,[c] Quanyi Zhao,[a] Zhen Wang[a], [b],
*
a School of Pharmacy, Lanzhou University, West Donggang Road. No. 199, Lanzhou 730000, China.
b State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, China.
c The Second People’s hospital of Lanzhou City, Lanzhou 730000, Gansu, China.
ABSTRACT: A versatile Cu-catalyzed cross-coupling reaction to various unsymmetrical disulfanes has been presented, from
phthalimide-carried disulfur transfer reagents and commercially available boronic acids under mild and practical conditions.
The method features the unprecedented use of phthalimide-carried disulfurating reagents (Harpp reagent) in cross-coupling
chemistry, and is highlighted by the broad substrate scopes, even applicable for the transfer of aryl-disulfur moieties (ArSS-
). Notably, the robustness of this methodology is shown by the late-stage modification of bioactive scaffolds of coumarin,
estrone and captopril.
KEYWORDS: phthalimide-carried disulfur transfer, unsymmetrical disulfanes, cross-coupling, Harpp reagent analogs,
modification
a) Traditional approach to synthesize disulfanes through S-S bond construction:
Disulfide bond (S-S) as a critically important structural
bridge, plays vital and multiple roles in oxidative folding,
Oxidation, SN2
S
R2
R1S-X
+
R2S-Y
R1
S
stability, and biological functions of peptides and proteins
in living entities,1 as well as maintaining the cellular redox
balance in cell survival.2 In pharmaceuticals, disulfide bond
is an ubiquitous subunit and has profound effect on its
pharmacological activities.3 Meanwhile, disulfide bond is
also utilized as a self-immolative linker unit in monoclonal
antibodies (mAbs) – drug conjugates for tumor-targeting
drug delivery.4 Additionally, some specific chemicals
containing disulfide bonds are able to release a biologically
important cellular signaling molecule - hydrogen sulfide
(H2S) to mediate a series of physiological and pathological
processes.5 In addition to the aforementioned significance
in life science, disulfide bond is abundant and important in
food chemistry,6 functional materials,7 natural products,8
and bioactive molecules9 (Figure 1). All of these attributes
of disulfide bond make the incorporation of it into organic
frameworks receive significant attention in chemistry and
related domains. According to the literatures, there are two
Exchange etc.
b) Pioneering works of C-S bond construction to synthesize disulfanes:
Cross-coupling or
NuH or
L
S
R2
S
S
R1
S
R1
Electrophile
nucleophilic substitution
R1=alkyl
L
=Fm, Ac, OMe, Ts
Challenges:
fragile S-S bond, competitive desulfuration, inapplicable to aryl disulfur moieties
c) Conventional usage of Harpp reagent:
O
SN2
Harpp
reagent
N
SSMe
R-SH or R-SAc
R-SSSMe
O
Harpp reagent
Our work
d)
[Cu], Bipy, K3PO4
L
S
S
R2
R2B(OH)2
R1
L
S
S
R1
H2O, THF, 40 o
C
=Phthalimide
R1=alkyl or aryl
60 examples
Simple and practical conditions
Broad substrate scopes
Applicable to aryl disulfur moieties
Novel sulfur transfer application of Harpp reagent analogs
O
H
Scheme 1. Preparation of disulfanes.
N
S
N
Me
Me
N
S
O
N
H
S
S
S
strategies to access unsymmetrical disulfanes: initiated
from S-S bond construction10 and C-S bond construction11-13
respectively (Scheme 1). Conventional methodologies in the
former strategy, including oxidation, SN2 replacement, and
exchange pathways etc.,10 suffer from some longstanding
restraints like undesirable homocoupling byproducts. C-S
Bond formation as an emerged strategy to deliver
unsymmetrical disulfanes has brought the disulfane
chemistry into a new sight, and several pioneering works
like cross-coupling or nucleophilic substitution of
S
N
N
Me
Me
N
S
OH
S
Me
NH2
O
N
H
Prosultiamine
anti-Vitamin B1 deficiency drug
Disulfiram
anti-alcoholic drug
O
Peptide or protein
HO
O
H
O
S
O
Cytotoxic
molecule
N
S
S
S
S
S
N
O
Missile
Linker
Antibody
H
Garlicin
O
Aranotin
antiviral
OH
Antibody-Drug Conjugates (ADC)
Figure 1. Representative and widespread S-S bond.
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ACS Catalysis
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[f]TEMPO (0.30 mmol, 1.5 equiv) was added. [g]BHT (0.30 mmol,
nucleophilic or electrophilic disulfur reagents (RSS-L) have
been disclosed by Xian11, Jiang12 and Xu13 (Scheme 1b).
Despite significant progress, these reports share identical
challenges like competitive desulfuration and unable to
transfer ArSS- moieties onto aryls to deliver diaryl
disulfanes, and this may be due to the hyperconjugation of
ArSS- weakens the S-S bond. In this context, a versatile and
robust disulfur reagent or new catalytic process has to be
explored for resolving these key problems.
1.5 equiv) was added. [h] Air instead of Ar.
1
2
3
4
5
6
7
8
type coupling to furnish categories of structurally
diversified disulfanes (Scheme 1d).
We commenced our studies by choosing 2-
(benzylsulfinothioyl)isoindoline-1,3-dione (1d) as the
model disulfur reagent to react with phenylboronic acid
(2a) in the presence of 20 mol % Cu(OAc)2, 20 mol % 2, 2’-
bipyridine (Bipy), and 2 equivalents of NaOAc under argon
(Ar) atmosphere at 40 oC for 10 h, and the desired product
3a was obtained in 49% yield (Table 1, entry 1). Next, a
series of copper catalysts were examined but no
enhancement on the yield was observed (entries 2 - 3; Table
S1). Given the significance of base in transmetalation
process,15 a range of strong and weak bases were screened
and K3PO4 was found
Since firstly synthesized by David N. Harpp, Harpp rea-
gent was mainly employed as electrophile to react with
thiols or RSAc in natural product synthesis to afford
trisulfides14 (Scheme 1c). Although several decades have
passed by, new application of this kind of reagent has been
rarely explored. Inspired by the aforementioned pioneering
works and challenges, we envisioned Harpp reagent may
serve as a desired disulfur transfer reagent for the weak
coordination between oxygen in the phthalimide and
copper could induce the selective oxidation insertion of
copper into N-S bond. After extensive studies, we herein
disclose a new usage of Harpp reagent analogs in Cu-
catalyzed Chan-Lam
9
10
11
12
13
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Table 2. Substrate scopes of boronic acids[a], [b]
O
Cu(OAc)2 (20 mol%), Bipy (20 mol%)
S
Bn
R1B(OH)2
N
SSBn
R1
S
K3PO4, H2O (x equiv), THF, 40 o
C
1d
2
3
O
SSBn
SSBn
SSBn
SSBn
Table 1. Optimization of reaction[a]
[d]
[e]
69%
63%[c]
Me
t-Bu
MeO
3a
89%
3d
3b
3c
81%
O
SSBn
[Cu], Ligand, base
SSBn
SSBn
SSBn
S
Ph
N
SSBn
1d
PhB(OH)2
Bn
S
sol., Temp., Ar, Time
H2O (x mmol)
OHC
3a
i-PrO
MeS
MeOC
2a
O
3f
62%
3e
3g
3h
74%
50%
77%
Ph
t-Bu
Ph
t-Bu
O
SSBn
SSBn
Me
Me
SSBn
SSBn
Ph
B
H
N
PhBF3K
trace
Ph Bpin
trace
Me2N
O
2' 73%
Me
EtO2C
N
N
N
N
L6
L13
3j
57%
3i
3k
3l
58%
49%
48%
O
O
Entry [Cu]
Ligand
Cu(OAc)2 Bipy
Base
Sol.
yield/%b
49
SSBn
SSBn
SSBn
SSBn
54%[f]
63%
F
Cl
Br
I
1
NaOAc CH3CN
NaOAc CH3CN
NaOAc CH3CN
3n
55%
3m
3o
3p
65%
SSBn
SSBn
SSBn
SSBn
2
CuBr2
CuI
Bipy
Bipy
27
3
33
F3CO
F3C
Me
MeO2S
NC
3q
3r
3s
3t
70%
55%
69%
61%
4
Cu(OAc)2 Bipy
Cu(OAc)2 Bipy
Cu(OAc)2 Bipy
Cu(OAc)2 L6
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
-
CH3CN
CH3CN
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
37
SSBn
SSBn
SSBn
SSBn
5
54
3u
80%
3x
53%
61%
3w
67%
3v
64%
OMe
Cl
Me
Ph
F
6
67
SSBn
SSBn
Me
Cl
7
69
SSBn
3aa
SSBn
8
9[c]
Cu(OAc)2 L13
61
3y
3z
3ab
64%
68%
72%
SSBn
NO2
Cu(OAc)2 Bipy
89
F3C
SSBn
F
SSBn
F
F
SSBn
OMe
10[d] Cu(OAc)2 Bipy
11[e] Cu(OAc)2 Bipy
81
MeO
3ae
41%
3ad
CF3
37%
3ac
58
53%
F
F
[d]
61%
3af
SSBn
12
13
14
15
-
Bipy
-
N.R.
N.R.
N.R.
81[f]/76[g]
21
SSBn
SSBn
O
O
Cu(OAc)2
MeO
69%
N
SSBn
3ag
3ah
3ai
3aj
%
51
75%
78%
Cu(OAc)2 Bipy
SSBn
SSBn
Cu(OAc)2 Bipy
K3PO4
K3PO4
Ph
SSBn
N
16[h] Cu(OAc)2 Bipy
N
N
Ph
3ak
3al
3am
69%
52%
65%
[a]Reaction conditions: 1d (0.20 mmol, 1.0 equiv), 2a (0.40
mmol, 2.0 equiv), [Cu] (0.04 mmol, 0.2 equiv), ligand (0.04
mmol, 0.2 equiv), base (0.40 mmol, 2.0 equiv) and THF (2 mL)
at 40 oC for 10 h under argon atmosphere. [b]Isolated yields.
[c]H2O: 1.5 equiv. [d]0.28 mmol (1.4 equiv) of 2a and K3PO4 was
added. [e]0.20 mmol (1.0 equiv) of 2a and K3PO4 was added.
SSBn
S
SSBn
61%
SSBn
57%
SSBn
54%
3an
3ao
3ap
3aq
48%
aStandard conditions: 1d (0.20 mmol, 1.0 equiv), 2 (0.40 mmol,
2.0 equiv), Cu(OAc)2 (0.04 mmol, 0.2 equiv), Bipy (0.04 mmol,
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ACS Catalysis
0.2 equiv), H2O (0.30 mmol, 1.5 equiv), K3PO4 (0.40 mmol, 2.0
alkyl disulfur groups (R2 = alkyl), this reaction also
performed smoothly giving the corresponding
unsymmetrical disulfanes in moderate to good yields (4e -
4m, 46% - 71%).
o
b
c
1
2
3
4
5
6
7
8
equiv) and THF (2 mL) , 40 C, 10 h, Ar. Isolated yields. H2O:
3.0 equiv. dH2O: 2.0 equiv. eH2O: 1.0 equiv. fH2O: 2.5 equiv.
to be the optimal base providing 3a in 54% yield (entries 4-
5; Table S2). As for solvents, THF afforded the target
product 3a in 67% yield (entry 6; Table S3). When several
kinds of mono-, di- and tridentate ligands were tested
(entries 7 - 8; Table S4), the yield was slightly increased as
di-tert-butyl bipyridine employed (entry 7). However, we
still chose Bipy as the ligand to continue optimization for
economic considerations. Neither elevated nor reduced
temperature was beneficial for the transformation (Table
S5). Since water would probably increase the solubility of
bases, we screened different equivalents of water in the
reaction, and the yield dramatically jumped to 89% when
1.5 equiv H2O was added (entry 9; Table S6). Decreasing the
amount of base and boronic acid decreased the yield
Finally, the robustness of this method was shown by the
late-stage modification of the scaffolds of natural products
and pharmaceuticals (Table 4). Disulfur motif BnSS- was
smoothly installed at C7-position of coumarin, which is a
universally bioactive scaffold in many natural products
(3ar, 51%). Modification of estrone, a natural hormone as
well as a medication, was also achieved to deliver 3as and
3at in moderate yields (3as, 50%; 3at, 40%). Besides,
captopril, a potent and competitive angiotensin-converting
enzyme (ACE) inhibitor used in the treatment of
hypertension, was successfully modified (4n, 49%) through
preparation of phthalimide-carried disulfur reagent (1n),
and the structure of 4n was characterized by X-ray
diffraction (CCDC Number:1948200).
9
10
11
12
13
14
15
16
17
18
19
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21
22
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53
54
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58
59
60
(entries 10
-
11; Table S7). Additionally, other
organoboronic reagents such as PhBpin, PhBF3K, and
boronic acid ester 2’ were also explored, but merely 2’
yielded the product 3a in 73% (Table 1). Control
experiments showed copper catalyst, ligand, and base were
indispensable for the reaction (entries 12 - 14). Inert
atmosphere was also crucial for this transformation as the
yield of 3a fell to 21% when the reaction was performed
under Air instead of Ar (entry 16).
Table 3. Substrate scopes of disulfur transfer rea-
gents[a,b]
Cu(OAc)2 (20 mol%)
Bipy (20 mol%), K3PO4
H2O (1.5 equiv), THF, 40 o
O
S
R2
R1B(OH)2
N
SSR2
R1
S
C
1
2
4
O
t-Bu
S
Ph
S
Ph
S
S
S
S
With the optimized reaction conditions in hand, we
investigated the substrate scopes with respect to varieties
of boronic acids. As shown in Table 2, both electron-
donating and electron-withdrawing substituents at para-,
meta- and ortho-positions of arylboronic acids provided the
corresponding products in moderate to good yields (3a -
3ag, 37% - 89%). Notably, various sensitive functional
groups such as -CHO, -CO-, -CO2-, -CONMe2, -CON(H)-, -vinyl,
-OCF3, -CF3, -CN, -SO2Me, -NO2 etc. were all tolerant in this
reaction. Di-fluoro, di-trifluoromethyl and tri-fluoro
substituted highly electron-deficient aryl boronic acids also
proceeded smoothly under the standard conditions (3ac -
3ae, 37% - 53%). On the whole, no apparent electrical effect
was observed in this reaction. Sterically hindered
arylboronic acids afforded the target products 3aa and 3af
in good yields as well (3aa, 72%; 3af: 61%), as well as fused
aromatic rings and hetero-aromatic rings (3ah - 3ak, 51% -
78%). Remarkably, BnSS- motif was successfully inserted
into several important organic optoelectronic material
frameworks, such as triphenylamine, fluorine, carbazole,
and diben-zo[b,d]thiophene (3al - 3ao, 48% - 65%).16
Vinylboronic acids were applicable to afford unsymmetrical
disulfanes under the standard conditions (3ap, 61%; 3aq,
54%). Unfortunately, when cyclopropylboronic acid and
cyclo-pentylboronic acid were used, no corresponding
target products were obtained. This is presumably because
their transmetalation with transition metals is more
difficult than that of aryl and alkenyl boronic acids, as well
as the inferior stability of alkylboronic acids.17
Ph
S
Ph
S
S
Me
Cl
4a
4a'
4b
4c
63%
54%
47%
61%
S
S
Ph
S
Ph
Ph
S
S
Ph
S
OMe
4f
54%
Ph
4g
53%
4e
71%
Ph
S
S
S
S
n-C12H25
S
4i
57%
4h
51%
S
4j
48%
Ph
Ph
S
S
Ph
Ph
S
S
S
CO2Me
55%
S
S
4l
4k
53%
4m
46%
aStandard conditions: 1 (0.20 mmol, 1.0 equiv), 2 (0.40 mmol,
2.0 equiv), Cu(OAc)2 (0.04 mmol, 0.2 equiv), Bipy (0.04 mmol,
0.2 equiv), H2O (0.30 mmol, 1.5 equiv), K3PO4 (0.40 mmol, 2.0
equiv) and THF (2 mL) , 40 oC, 10 h, Ar. bIsolated yields.
Table 4. Late-stage modification of natural product and
pharmaceuticals[b]
O
Cu(OAc)2 (20 mol%)
Bipy (20 mol%), K3PO4
H2O (1.5 equiv), THF, 40 o
S
R2
O
R1B(OH)2
N
SSR2
R1
S
C
1
2
3
O
Coumarin
Estrone
O
Me
Me
BnSS
O
O
H
H
H
R=4-MePh 3at
H
H
H
RSS
BnSS
3as
50%
3ar
51%
CH3
40%
Subsequently, we further examined the compatibility of
diverse disulfur transfer reagents under the standard
conditions (Table 3). Gratifyingly, aryl disulfur transfer
groups (R2 = Aryl) were unprecedentedly feasible under our
system even in moderate yields (4a’, 4a - 4c, 47% - 63%).
With respect to benzyl and primary, secondary or tertiary
Ph
S
S
O
OMe
N
O
4n
49%
Captopril methyl ester
ORTEP of 1n[a]
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b
aNon-hydrogen atoms are shown as 30% ellipsoids. Isolated
yields.
Corresponding Author
* shit18@lzu.edu.cn
* zhenw@lzu.edu.cn
1
2
3
4
5
6
7
8
9
Author Contributions
Based on the control experiments in Table 1 (entries 12 -
15) and literatures,18 a possible mechanism was described
in Scheme 2. Initially, transmetalation (I) of boronic acid
derivatives took place. In this step, water may play a crucial
role in facilitating the transmetalation in some aspects,
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
ASSOCIATED CONTENT
Supporting Information
Synthetic procedures, and characterization data and spectra of
compounds, CIF data for compound 1n and other additional
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
similar to previous works.15, 17, 19 In addition to increasing
15, 19c
10
11
12
13
14
15
16
17
18
19
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the solubility of K3PO4 and Cu(OAc)2,
it was likely to
favor the generation of more-reactive boronate anion 2’’ in
19
the presence of K3PO4,17,
and also contribute to
suppressing the formation of less-reactive boroxine 2’’’
which was easily produced by trimerization of boronic
acids.17, 19c Despite these hypotheses, the exact role of water
remains unclear to date. Following the transmetalation,
ACKNOWLEDGMENT
disproportionation (II) of CuII species B proceeds to give CuI
18c
intermediate C and CuIII.18b,
Subsequently, oxidation
We acknowledge the financial support from the Recruitment
Program of Global Experts (1000 Talents Plan), the
Fundamental Research Funds for the Central Universities
(lzujbky-2019-ct08) and the Natural Science Foundation of
Gansu Province (18JR3RA417).
insertion of C into N-S bond takes place to form D (III).18a, 18d
Lastly, reductive elimination of D releases the target
product and CuI (IV), which go through transmetalation (V)
to reenter the next catalytic cycle.18
In summary, we have disclosed an unprecedented
phthalimide-carried disulfur transfer strategy to deliver
categories of unsymmetrical disulfanes. The reaction was
highlighted by the use of low-cost metal catalyst and
excellent compatibility with diversely sensitive functional
groups, especially applicable for the transfer of aryldisulfur
moieties (ArSS-) onto aryls to deliver diaryl disulfanes.
Meanwhile, the robust nature of the reaction was
demonstrated by the late-stage modification of natural
product and pharmaceuticals. The practical reaction
conditions and extensive applicability of this reaction
suggest it may have further applications in sulfur-
containing lead compounds discovery, and related works
are under progress in our lab.
REFERENCES
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(b) Hogg, P. J. Disulfide Bonds as Switches for Protein Function.
Trends Biochem. Sci. 2003, 28, 210-214; (c) Góngora-Benítez, M.;
Tulla-Puche, J.; Albericio, F. Multifaceted Roles of Disulfide Bonds.
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L
Possible transformations of boronic acids
II
CuII
2 or 2''
I
CuIILn
R1 Cu
in the presence of water:
B
CuIII
A
L
2''
:
a) Formation of boronate anion
II
K3PO4, H2O
R1B(OH)2
R1B(OH)3
L
2
2''
2 or 2''
V
I
CuI
More reactive
R1 Cu
C
E
L
2'''
:
b) Hydrolyzation of boroxine
R1
III
IV
1
S
R1
O
Trimerization
R1B(OH)2
B
S
R1
R2
O
B
O
B
III
Hydrolyzation
2
Cu N
R2SS
R1
O
R1
2'''
D
O
Less reactive
Scheme 2. A possible mechanism.
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Insert Table of Contents artwork here
4
Simple and practical conditions
5
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8
[Cu], Bipy, K3PO4
H2O, THF, 40 o
Broad substrate scopes
L
S
R2
S
R2B(OH)2
S
R1
L
S
R1
Applicable to aryl disulfur moieties
C
Novel disulfur transfer application
of Harpp reagent analogs
=Phthalimide
R1=alkyl or aryl
60 examples
O
O
Me
H
Me
CH3
N
Ph
S
BnSS
O
O
O
S
H
H
9
OMe
O
H
H
H
10
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18
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BnSS
p-TolylSS
Estrone
Coumarin
Captopril methyl ester
6
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