Palladium-Catalyzed C–S Bond Formation of Stable Enamines with Arene/Alkanethiols: Highly Regioselective Synthesis of β-Amino Sulfides

Article abstract of DOI:10.1002/ejoc.201600588

A direct and regiocontrolled thiolation method to access β-amino sulfides through the palladium-catalyzed C(sp²)–H functionalization of stable enamines was described. The reaction was realized under mild conditions by adding an external phosphi

Full text of DOI:10.1002/ejoc.201600588

DOI: 10.1002/ejoc.201600588
Communication
C–H Functionalization
Palladium-Catalyzed C–S Bond Formation of Stable Enamines
with Arene/Alkanethiols: Highly Regioselective Synthesis of ꢀ-
Amino Sulfides
Yaojia Jiang,*[a,b] Gaohui Liang,[b] Cong Zhang,[b] and Teck-Peng Loh*[a,b,c]
Abstract: A direct and regiocontrolled thiolation method to ac- posed according to the obtained results. The DFT calculation
cess ꢀ-amino sulfides through the palladium-catalyzed C(sp2)–
H functionalization of stable enamines was described. The reac-
tion was realized under mild conditions by adding an external
phosphine ligand to prevent poisoning of the palladium cata-
lyst by the sulfuric reagents. A possible mechanism was pro-
results were consistent with the experiment data, which gave
the E isomers of the ꢀ-amino sulfides. The reaction was also
performed on a gram scale and shows potential application in
organic synthesis.
Introduction
The synthesis of organosulfur compounds through simple C–
S bond-forming reactions is of crucial importance in organic
synthesis and chemical biology.[1] In particular, the ꢀ-amino
sulfide scaffold, containing a cysteine-type skeleton, is featured
widely in natural products and drugs and also plays a pivotal
role in biological chemistry [Figure 1 (a), precursor of native
chemical ligation (NCL)].[2] Therefore, many researchers have di-
rected their efforts towards the development of new methods
for the construction of ꢀ-amino sulfide compounds.[3]
Figure 1. Representative useful ꢀ-amino sulfide derivatives; Trt = triphenyl-
methyl (trityl).
During the course of the total synthesis of ECT-743, synthetic
chemists have found that it is essential to introduce a C–S bond
to construct the ꢀ-amino sulfide moiety.[4] Following the pio-
neering work of Yu and co-workers, who employed Cu to medi-
ate the direct thioetherification of arene C–H bonds with arene-
thiols,[5] significant achievements have been uncovered by em-
ploying different sulfur sources and catalytic systems.[6] A nickel
catalytic system was developed for the thiolation of C(sp2)–H[7]
and C(sp3)–H[8] bonds by several groups independently. Deng
demonstrated the possibilities of constructing this moiety
through a silver-mediated reaction of enamides by using aryl
disulfides.[3c] However, the use of arene/alkanethiols as sulfur
sources resulted in low yields or no desired product. Recently,
Wang's group disclosed a facile and atom-economical method
to construct ꢀ-acetamido sulfides through the metal-free direct
difunctionalization of alkenes with thiols and nitriles.[9] During
the course of the preparation and submission of the present
manuscript, Wan's group reported a catalytic method for the
thiolation of enaminones and related enamines by using a KIO3/
air system.[10] We envisage that palladium-catalyzed C–S bond
formation of enamines may yield the desirable ꢀ-amino sulfide
fragment. To prevent poisoning of the catalyst by the sulfur
reagent, we thought that a suitable ligand that could bind to
the transition metal might circumvent this problem.[11] With our
continued interest in the functionalization of C(sp2)–H
bonds,[12] we herein report a direct “catalytic dehydrogenative
cross-coupling” reaction between simple thiols and enamines
to construct ꢀ-amino sulfides by using a catalytic amount of Pd
(Scheme 1). This reaction works with a wide variety of enamines
and arene/alkanethiols.
[a] School of Chemistry and Molecular Engineering (SCME), Jiangsu National
Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing
Tech University (Nanjing Tech),
30 South Puzhu Road, Nanjing 211816, P. R. China
[b] Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced
Materials (IAM), Jiangsu National Synergetic Innovation Center for
Advanced Materials (SICAM), Nanjing Tech University (Nanjing Tech),
5 Xinmofan Road, Nanjing 210009, P. R. China
[c] Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University,
637616 Singapore
E-mail: iamyjjiang@njtech.edu.cn
Results and Discussion
teckpeng@ntu.edu.sg
http://www1.spms.ntu.edu.sg/~cbc/cv/teckpeng/index.htm
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600588.
Our initial exploration began by treating (E)-3-(dimethylamino)-
1-phenylprop-2-en-1-one (1a) with benzenethiol (2a) by using
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oxidants (Table 1, entries 13 and 14). Other transition metals,
such as rhodium and ruthenium, were also examined for the
direct thiolation of the C(sp2)–H bond, but a significant de-
crease in yield was observed (Table 1, entries 15 and 16).
Using the optimized reaction conditions, benzenethiol was
examined in coupling reactions with a variety of enamines to
Table 1. Optimization of the reaction conditions for C–S bond construction.[a]
Scheme 1. Synthesis of ꢀ-amino sulfide derivatives; DCE = 1,2-dichloroethane.
a catalytic amount of Pd(OAc)2 in CH3CN at 75 °C under a nitro-
gen atmosphere. We were delighted to find that desired C–S
coupling product 3aa was obtained, albeit in low yield, by us-
ing metal oxidants (Table 1, entries 2 and 3), whereas the reac-
tion was completely suppressed without the use of an oxidant
(Table 1, entry 1). The geometrical configuration of coupling
product 3 was supported by NOESY analysis (3aa) and was fur-
ther confirmed by single-crystal X-ray diffraction analysis
(Table 2/Figure 2, 3ba).[13] The low yield was probably due to
poisoning of the palladium catalyst by the thiol. With the pre-
liminary positive result in hand, different ligands were tested
by using this catalytic system to improve the reaction efficiency.
It was found that phosphine ligands (Table 1, entries 5–7) en-
hanced the reactivity more than nitrogen ligands (Table 1, en-
try 4), especially if dppe was used, which gave the desired prod-
uct in 42 % yield. Gratifyingly, the yield was improved to 91 %
upon performing the reaction under an oxygen atmosphere
(Table 1, entry 8). It is noteworthy that the oxidant combination
of Cu(OAc)2/air as well as PhI(OAc)2/O2 also gave the desired
product in yields of 73 and 74 %, respectively (Table 1, entries 9
and 10), whereas silver acetate exerted a negative effect on the
reaction (Table 1, entry 11). Non-metallic oxidants such as tert-
butyl hydroperoxide (TBHP) and benzoquinone were investi-
gated and gave lower yields than those obtained with metal
Entry Catalyst
Ligand
Oxidant
Yield [%][b,c]
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[RhIIICp*Cl2]2
Rubpy[d]
–
–
–
–
–
Mn(OAc)3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2/O2
Cu(OAc)2/air
PIDA/O2
AgOAc/O2
TBHP
12
26
2
2,2′-bipyridine
dppb
P(Cy)3
dppe
dppe
dppe
dppe
dppe
dppe
dppe
–
33
34
42
91
73
74
26
18
9
10
11
13
14
15
16
benzoquinone 32
Cu(OAc)2/O2
hγ
[d]
12
5
–
[a] Unless otherwise noted, reactions were performed with 1a (0.10 mmol),
2a (0.12 mmol), Pd catalyst (7.5 mol-%), ligand (15.0 mol-%), and oxidant
(0.10 mmol) in CH3CN (0.1
atmosphere; dppb = 1,4-bis(diphenylphosphanyl)butane, P(Cy)3 = tricyclo-
hexylphosphine, dppe = ethylenebis(diphenylphosphine), PIDA = PhI(OAc)2,
Cp* = η5-pentamethylcyclopentadienyl, bpy = 2,2′-bipyridyl. [b] Yield was
determined by GC analysis against an internal standard. [c] The remaining
materials were 1a and PhSSPh. [d] By using a catalyst loading of 2 mol-%.
M, 1 mL) at 75 °C for 24–36 h under a nitrogen
Figure 2. X-ray structure of 3ba.
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produce ꢀ-amino sulfide derivatives 3 (Table 2). In general, the alized enamines were also studied to extend the potential ap-
reaction tolerated a broad range of substituents to afford the plication of this methodology. In view of the reactivity of the
trans-ꢀ-sulfuryl-enamine regioisomers in good to excellent nitro group as a synthetic precursor of amine and other aza
yields. Initially, enaminones with various substituents were groups,[15] the thiolation reaction of (E)-N,N-dimethyl-2-nitro-
tested under the standard reaction conditions. To examine the ethenamine was performed. Delightfully, 3ma was obtained in
electronic effects of the substituents at the keto site of the en- a promising yield with a higher catalyst loading (20 mol-%).
aminones, substrates with aryl groups bearing electron-donat- Next, we turned our attention to examine the influence of the
ing and electron-withdrawing groups were subjected to the op- N-substituents on the 3-aminoalkenolates in our reaction. Gen-
timized reaction conditions. Whereas a substrate with an elec- erally, both acyclic and cyclic amino groups were well tolerated
tron-deficient aryl group provided the desired product in good under the established reaction conditions. By changing the N-
yield (see product 3ba), a decreased yield was observed with a substituent to an alkyl or aryl group, the desired thiolation
substrate bearing an electron-rich aryl group (see product 3ca). product was obtained in excellent yield (85 and 80 % for 3na
Substituents such as heterocycles and vinyl groups remained and 3oa, respectively). On the other hand, an electron-donating
intact during the reaction (see products 3da, 3ea, and 3fa). substituent such as a methoxy group had a slightly negative
Excellent regioselectivity occurred at the ꢀ site of the enamines influence on the transformation and gave 3pa in 67 % yield. It
rather than the other reactive C(sp2)–H bonds in the hetero- should be noted that if the substrate was substituted with allyl/
cycles and chalcones. Halogen substituents (i.e., F, Cl, Br, and I) benzyl groups including other active C(sp2)–H/C(sp3)–H bonds,
at the para position of the phenyl group were also well toler- these reactions proceeded smoothly under the palladium cata-
ated (see products 3ga–3ja). Notably, the bromo and iodo func- lyst system to afford the ꢀ-thiolation products with absolute
tionalities could be further employed in many useful coupling regioselectivity (see products 3ta and 3ua). These active func-
reactions.[14] Alkyl-substituted substrates with a simple iso- tional groups allow the construction of complex molecules con-
propyl group (see product 3ka) or multiple functionalities (see taining a sulfur moiety after subsequent derivatization.
product 3la) provided single regioisomers in excellent yields of
84 and 90 %, respectively. Besides enaminones, other function-
The generality of the reaction was also examined with a vari-
ety of thiols bearing aromatic and aliphatic substituents
(Table 3). The reaction worked well for ortho- and para-halogen-
substituted benzenethiols (see products 3ab–3ae) under the
standard conditions, and the desired products were delivered
Table 2. Substrate scope of the enamines.[a,b]
Table 3. Substrate scope of thiols.[a,b]
[a] Unless otherwise noted, the reactions were performed with 1 (0.20 mmol),
2a (0.24 mmol), Pd(OAc)2 (7.5 mol-%), dppe (15.0 mol-%), and Cu(OAc)2
[a] Unless otherwise noted, the reactions were performed with 1 (0.20 mmol),
2 (0.24 mmol), Pd(OAc)2 (7.5 mol-%), dppe (15.0 mol-%), and Cu(OAc)2
(0.20 mmol) in CH3CN (0.1
M, 2 mL) at 75 °C for 24–36 h under an oxygen
(0.20 mmol) in CH3CN (0.1 M, 2 mL) at 75 °C for 36 h under an oxygen
atmosphere. [b] Yield of isolated product. [c] Using 20 mol-% Pd(OAc)2 and
40 mol-% dppe.
atmosphere. [b] Yield of isolated product. [c] By using PhI(OAc)2 (0.20 mmol)
instead of Cu(OAc)2.
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in good to excellent yields (76–83 %). Notably, halogen substit-
uents (i.e., F, Cl, and Br) on the aryl group are important func-
tionalities that allow these substrates to be further functional-
ized or derivatized. Examination of the electronic influence of
the aryl group revealed that electron-donating groups gave ex-
cellent results (see products 3ag–sg), whereas an electron-with-
drawing substituent had a deleterious electronic effect on the
reaction and resulted in a decreased yield of 65 % (see product
3af). Naphthalene-1-thiol was well suited to this reaction proto-
col, and it delivered the corresponding product, (Z)-3-(dimethyl-
amino)-2-(naphthalen-1-ylthio)-1-phenylprop-2-en-1-one (3ah),
in 77 % yield. Finally, an alkanethiol was also examined, and the
desired ꢀ-thiolation product was obtained in 68 % yield (see
product 3ai) by using PhI(OAc)2 instead of Cu(OAc)2 as the
oxidant.
To check the feasibility of the thiolation of enamine deriva-
tives in a preparative demand, the reaction was performed on
a gram scale (Scheme 2). To our delight, the reaction proceeded
smoothly and generated the corresponding product in 75 %
yield under the standard catalytic conditions. ꢀ-Amino sulfide
derivatives are versatile synthetic intermediates that are widely
utilized for the synthesis of pharmaceuticals and natural prod-
ucts. For example, 3aa could be easily transformed into pyraz-
ole 5aa, which is a key intermediate for the synthesis of FAAH
(fatty acid amide hydrolase) inhibitors.[16] Besides, the amine
moiety of ꢀ-amino sulfides is capable of undergoing facile
hydrolysis, which leads to enolates, and this further allows other
useful functionalization to generate organosulfur molecules.[3c]
On the basis of the results in hand, a plausible Heck-type
mechanism is proposed, as depicted in Scheme 3.[14c] Initially,
Pd(OAc)2 reacts with 1,1′-disulfanediyldibenzene (2a′, probably
generated from the oxidation of PhSH) to give palladium–sulfur
complex A.[17] This hypothesis is supported by a control experi-
ment in which 2a′ was used instead of benzenethiol (2a). Palla-
dium complex A then coordinates with the C=C bond of ena-
mine 1, which leads to intermediate B, and this species is subse-
quently deprotonated to afford C. Reduction and elimination
processes then take place to give ꢀ-amino sulfide 3 and Pd0.
The catalytic cycle can be realized through a Wacker oxidation
process in the presence of Cu(OAc)2 under an oxygen atmos-
phere.
Scheme 3. A proposed mechanism.
31G(d)/LanL2DZ level of theory],[18] the palladium prefers to at-
tach the ꢀ site of the enamine from the same side of the C–H
bond, which leads to retention of configuration in the E isomer
of product 3. The calculation is consistent with the experimen-
tal result (see the Supporting Information for details of the cal-
culation).
Conclusion
In summary, we developed a method for the regioselective syn-
thesis of ꢀ-amino sulfides through palladium-catalyzed C(sp2)–
To better understand the reaction pathway that gives only
the E thiolation isomer, a theory calculation experiment was
performed (Figure 3). According to DFT calculations [B3LYP/6-
Figure 3. Geometry of transition state from B to C.
Scheme 2. Gram-scale synthesis of ꢀ-amino sulfides and its applications.
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[5] X. Chen, X.-S. Hao, C. E. Goodhue, J.-Q. Yu, J. Am. Chem. Soc. 2006, 128,
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H functionalization of enamines by using simple thiols. The re-
action was realized by adding an external phosphine ligand
to prevent poisoning of the palladium catalyst by the sulfuric
reagents. The results reveal the possible coexistence of transi-
tion metals and reactive thiols in the area of C–H functionaliza-
tion. Furthermore, the formed cysteine-type products possess
the potential to be used in the area of native chemical ligation
in biological chemistry. Research in this direction and the appli-
cation of this method for the synthesis of ECT-743 are in
progress in our group, and the results will be reported in due
course.
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Experimental Section
Synthesis of 3aa: An oven-dried Schlenk tube was charged with
1a (35.1 mg, 0.20 mmol), 2a (24.6 μL, 0.24 mmol), Pd(OAc)2 (3.4 mg,
7.5 mol-%), dppe (12.0 mg, 15.0 mol-%), and Cu(OAc)2 (0.20 mmol,
36.3 mg) in CH3CN (2 mL) under an oxygen atmosphere. The mix-
ture was heated at 75 °C for 36 h. After cooling, the mixture was
directly concentrated and purified by flash chromatography (10 to
20 % ethyl acetate in hexane) to afford 3aa (48.7 mg, 86 %).
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Supporting Information (see footnote on the first page of this
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[13] CCDC 1452382 (for 3ba) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
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Acknowledgments
The authors gratefully acknowledge funding from the National
Natural Science Foundation, P. R. China (grant number
21502089), and the Starting Funding of Research, Nanjing Tech
University. The Nanyang Technological University (NTU), the
Singapore Ministry of Education Academic Research Fund
[Tier 1: MOE2015-T1-001-070 (RG5/15) and MOE2014-T1-001-
102 (RG9/14)], and the Singapore National Research Foundation
(NRF2015NRF-POC001-024) are gratefully thanked for generous
financial support. Dr. Li Yongxing (NTU) is thanked for single-
crystal X-ray diffraction analysis and Prof. Liu Chuan-Fa (NTU)
for his careful proofreading and useful discussions.
Keywords: Oxygen · Phosphane ligands · Thiolation ·
Dehydrogenation · C–H functionalization
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Received: March 13, 2016
[4] E. J. Corey, D. Y. Gin, R. S. Kania, J. Am. Chem. Soc. 1996, 118, 9202–9203.
Published Online: ■
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Communication
C–H Functionalization
Y. Jiang,* G. Liang, C. Zhang,
T.-P. Loh* ............................................... 1–6
Palladium-Catalyzed C–S Bond For-
mation of Stable Enamines with
Arene/Alkanethiols: Highly Regiose-
lective Synthesis of ꢀ-Amino Sulf-
ides
From poisoning to activation: Thiols of enamine derivatives with simple thi-
are normally considered to poison the ols through a “catalytic dehydrogen-
transition-metal catalysts that are used ative cross-coupling” process under
in coupling chemistry. We herein de- mild oxidative conditions; dppe = eth-
velop a new palladium-catalyzed sys- ylenebis(diphenylphosphine).
tem that allows the direct thiolation
DOI: 10.1002/ejoc.201600588
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