Pd-Catalyzed Coupling of Thioamides with N-Tosylhydrazones/Trapping by Esters Cascade Reaction

Article abstract of DOI:10.1021/acs.orglett.0c03796

N,N-Disubstituted thioamides coupled with N-tosylhydrazones under Pd(TFA)2/tBuXPhos catalyst and NaOtBu, and the intermediates from palladium carbene migratory insertion containing β-hydrogen were trapped by intramolecular esters activated by BF3·Et2O ins

Full text of DOI:10.1021/acs.orglett.0c03796

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Letter
Pd-Catalyzed Coupling of Thioamides with N‑Tosylhydrazones/
Trapping by Esters Cascade Reaction
Zhongliang Cai,† Zhi Yao,† and Liqin Jiang*
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ABSTRACT: N,N-Disubstituted thioamides coupled with N-tosylhydrazones under Pd(TFA)2/tBuXPhos catalyst and NaOtBu, and
the intermediates from palladium carbene migratory insertion containing β-hydrogen were trapped by intramolecular esters activated
by BF3·Et2O instead of undergoing β-H elimination, providing polyfunctional thiophen-3(2H)-ones with sulfur-containing
tetrasubstituted carbon centers in moderate to good yields. The reaction features the formation of three bonds in a single operation,
odorless, safe, and easily available substrates, wide substrate scope, and excellent functional group tolerance.
been documented to realize the trapping of active inter-
ulfur-containing heterocycles exist widely in natural
1
Sproducts, drugs, biological compounds, and materials. mediates as above. Due to their low electrophilicity,
competitive 1,2-proton transfer might be faster. Dual-metal-
catalyzed carbene sp2 C−H functionalization/Conia−ene
cascade reactions have also been reported.8 Diazo compounds
bearing alkyls have never been used in the above reactions due
to their instability and difficulty in separation and purification.
N-Tosylhydrazones are safe and easily available precursors of
diazo compounds and have attracted considerable attention.9
Palladium-catalyzed cross-couplings involving N-tosylhydra-
zones bearing alkyl groups normally give alkenyl products via
β-H elimination of the metal alkyl intermediates generated
from palladium carbene migratory insertion.9a,b For example,
Yamaguchi reported that thioesters reacted with N-tosylhyr-
azones under Pd-catalysis to furnish Z-alkenyl thioethers
(Scheme 1, previous work, 1).10 Reactions of heteroatom
nucleophiles (X-H) with N-tosylhydrazones under transition-
metal free conditions could lead to X-H insertion products. For
example, thiophenols/mercaptans coupled with N-tosylhydra-
zones under basic conditions to give S-H insertion products
(Scheme 1, previous work, 2).11 Under photoredox conditions,
thiophenols/mercaptans and N-tosylhydrazones have been
Odorless, nontoxic, and easily available starting materials for
preparing sulfur-containing heterocycles are highly desirable.
Recently, we reported the ready synthesis of N,N-disubstituted
thioamides bearing α,α-diesters from malonate esters and
thiocarbamoyl fluorides2 in which the sulfur atom was derived
from sulfur (S8).3 Thioamides, which are odorless and
nontoxic/low toxic, have been widely used to synthesize
sulfur-containing heterocycles via intramolecular coupling
reactions including C−H functionalizations.2,4 Metal-catalyzed
intramolecular or intermolecular reactions of thioamides with
hydrazones or α-diazocarbonyl compounds to transform CS
to CC bonds have also been reported.5 However,
intermolecular reactions involving thioamides in a single
operation for the construction of complex and diversified
heterocycles with sulfur-containing tetrasubstituted carbon
centers are underdeveloped. Sulfur heterocycles in this class
exist in natural products such as thiolactomycin and
thiotetroamide as well as in biological compounds demonstrat-
ing anticancer,1d weight loss,1d antibacterial,6a−c antimalar-
ial,6d,e antituberculosis,6f,g and pesticidal activities.6h
The Hu group pioneered the development of a series of
multicomponent reactions of trapping of ylides or zwitterionic
intermediates derived from nucleophiles and diazocarbonyl
compounds by electrophiles such as aldehydes, ketones,
imines, or α,β-unsaturated compounds to form tetrasubstituted
carbon centers.7 The challenge of these methods lies in the 1,2-
proton transfer in the active intermediates. Esters have never
Received: November 15, 2020
Published: January 6, 2021
https://dx.doi.org/10.1021/acs.orglett.0c03796
© 2021 American Chemical Society
Org. Lett. 2021, 23, 311−316
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whether the palladium intermediates containing β-hydrogens,
formed via palladium carbine migratory insertion, could be
trapped by more challenging esters instead of undergoing β-
hydride elimination. To the best of our knowledge, the
formation of a second bond at the same carbon of the
palladium carbene, which also contains β-hydrogens, via 1,2
addition or 1,2 addition/elimination with electrophiles such as
esters has never been explored and accomplished.
Scheme 1. Reactions of Sulfur Reagents with N-
Tosylhydrazones
We envision expanding the use of N,N-disubstituted
thioamides bearing α,α-diesters 1 to intermolecular reactions
with N-tosylhydrazones 2 (Scheme 1, this work). Under
suitable catalytic systems, a base abstracts the α-H of
thiocarbonyl of 1 to form thioenolate anion I, which
coordinates with the metal of the carbene III derived from
N-tosylhydrazone 2 to give the intermediate V, followed by
carbene migratory insertion to give VI. The resulting
intermediate VI or the anion derived from VI losing metal
might then undergo cascade intramolecular 1,2-addition/
elimination with an ester functionality activated by a co-
catalyst, selectively delivering polyfunctional thiophen-3(2H)-
one 3 (Scheme 1, this work). Various undesired pathways exist
that could minimize or halt the formation of the desired
products. For instance, β-H elimination or protonation of VI
yields 4 or 5. N-Tosylhydrazones 2 might also self-condense to
form N−H insertion products 6. Thioamides 1 might also
react with 2 to transform the CS bond into a CC bond,
furnishing enamines 7 (Scheme 1, this work, other possible
products). Herein, we disclose that N,N-disubstituted thio-
amides 1 couple with N-tosylhydrazones 2 bearing alkyl
reported to form carbanion intermediates, which can then be
trapped by CO2 or aldehydes but cannot be trapped by
ketones (Scheme 1, previous work, 3).12 Our question was
t
substituents under Pd(II) catalysis, BuXPhos as the ligand,
a
Table 1. Optimization of the Reaction Conditions for 3
b
entry
catalyst
ligand
base
additive
T (°C)
solvent
yield (%)
c
d
1
2
3
4
5
6
7
8
Pd(TFA)2
Rh2(OAc)4
AgTFAtfa)
CuI
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
90
90
90
90
90
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
MeCN/toluene (1:1)
23
<5%
9
c
d
d
d
d
d
d
c
c
12
14
39
45
29
28
48
50
62
54
65
70
0
c
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
BINAP
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
tBuXPhos
tBuXPhos
tBuXPhos
tBuXPhos
c
90
c
100
100
100
100
100
100
100
100
100
100
100
100
100
100
c
d
LiOtBu
c
d
9
NaH
c
d
10
NaOSiMe3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOSiMe3
NaOtBu
11
12
13
14
15
16
17
18
19
20
FeCl3
AlCl3
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
6
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
0
NaOtBu
NaOtBu
41
55
tBuXPhos
a
Reaction conditions: 1a (0.15 mmol), 2a (0.375 mmol), 10 mol % of catalyst, 20 mol % of ligand, 50 mol % of additive, NaOtBu (0.6 mmol)
b
c
d
reacted in 3 mL of anhydrous solvent for 12 h. Isolated yield. 2a (0.3 mmol, 2.0 equiv). NaOtBu (0.3 mmol, 2.0 equiv). X-Phos: 2-
(dicyclohexylphosphino)-2′,4′,6′-tri(isopropyl)biphenyl; BuXPhos: 2-di-tert-butylphosphino-2′,4′,6′-tri(isopropyl)biphenyl.
t
312
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a
and with BF3·Et2O as the co-catalyst to selectively access
polyfunctional thiophen-3(2H)-ones with sulfur-containing
tetrasubstituted carbon centers in moderate to good yields.
We started our studies with 1a and 2a as model substrates.
Selected results are shown in Table 1 (details are provided in
the Supporting Information (SI)). Initially, palladium catalysts
including Pd(TFA)2, Pd(OAc)2, Pd2(dba)3, and Pd(PPh3)4
were investigated in the reaction of 0.15 mmol of 1a, 2.0 equiv
of 2a, and 2.0 equiv of NaOtBu in the presence of 10 mol % of
palladium catalyst in MeCN at 90 °C under N2 (Table 1, entry
1, and SI). Pd(TFA)2 was optimal and afforded the desired
product 3a in 23% yield (Table 1, entry 1, and SI). Catalysts
based on other metals such as Rh, Ag, and Cu were tried but
led to inferior results compared to Pd(TFA)2 (Table 1, entries
2−4, and SI). Then we attempted to investigate the effect of
the ligands under Pd(TFA)2 during this transformation. 20
mol % of ligand including BINAP, dppp, dppb, Xantphos,
PCy3, PPh3, or X-Phos was added to the entry 1 conditions
(Table 1, entries 5, 6, and SI). It was found that X-Phos was
optimal (Table 1, entry 6). Next, different solvents and
temperatures were screened. It was found that mixed solvents
of MeCN and toluene (1:1) at 100 °C (oil bath temperature)
improved the yield of 3a to 45% (Table 1, entry 7) and N−H
insertion product 6a (21% yield) was the main byproduct.
Evaluation of other bases revealed that only NaOSiMe3 gave a
slightly higher yield of 3a than NaOtBu (Table 1, entries 8−10,
and SI), but further study demonstrated that NaOSiMe3 was
not compatible with Lewis acid additives (SI). We improved
NaOtBu to 4.0 equiv and 2a to 2.5 equiv, leading to 3a in 50%
yield with 8a (main byproduct) in 25% yield (Table 1, entry
11). We found that introducing an additive such as FeCl3,
AlCl3, or BF3·Et2O to activate the ester functionality (Table 1,
entries 12−14) under NaOtBu to facilitate the desired pathway
and BF3·Et2O was superior (Table 1, entries 12−14). Finally,
Scheme 2. Substrate Scope of the Cascade Reactions
t
ligands including Xantphos, DPEphos, DavePhos, BuXPhos,
S-Phos, and RuPhos were screened (Table 1, entry 15, and SI).
tBuXPhos furnished the desired 3a in 70% yield (Table 1, entry
15), which was identified as the optimized conditions for 3a.
The use of sealing tube under the otherwise same conditions
afforded 3a in 71% yield (SI). Decreasing the amounts of
catalyst or ligand both led to a decrease in the yield of 3a (SI).
Deletion experiments demonstrated that Pd(TFA)2 and
NaOtBu were crucial for this cascade reaction (entries 17
t
and 18), and BuXPhos and BF3·Et2O improved the reactivity
and selectivity for 3a (Table 1, entries 19 and 20).
With the optimized conditions in hand, we investigated the
substrate scope of the novel cascade reactions of N,N-
disubstituted thioamides 1 and N-tosylhydrazones 2 (Scheme
2). N-Tosylhydrazones 2 were first investigated. N-Tosylhy-
drazones 2 bearing para (2b−2g)-, meta (2h−2j)-, or ortho
(2k)-electron-withdrawing substituted aryls proceeded
smoothly to afford the corresponding products 3b−3k in
moderate to good yields. It is important to note that fluoro
(2b, 2k), chloro (2c, 2h), bromo (2d, 2i), trifluoromethyl (2e,
2j), ester (2f), and even cyano (2g) were all well tolerated.
Fluoro, chloro, and bromo could serve as handles for further
elaboration, and trifluoromethyl is a privileged group in
medicinal chemistry. The reactivity of 2l bearing electron-
donating p-methoxy-substituted aryl with 1a was sluggish, but
still moderate yields of the desired product 3l could be
obtained via slightly improved amounts of the catalyst and the
ligand. N-Tosylhydrazone 2m bearing heterocycle 2-thienyl
was also tolerated. N-Tosylhydrazone 2n bearing a longer alkyl
a
Reaction conditions: 1 (0.15 mmol), 2 (0.375 mmol), 10 mol % of
Pd(TFA)2, 20 mol % of BuXPhos, 50 mol % of BF3·Et2O, NaOtBu
t
(0.6 mmol) reacted in 3 mL of MeCN and toluene (1:1) for 12 h.
b
c
d
Isolated yield. 1 mmol. 15 mol % of Pd(TFA)2, 30 mol % of
e
tBuXPhos. 15 mol % of Pd(OAc)2, 30 mol % of P(2-furyl)3, 2 (4.0
equiv), NaOtBu (5.5 equiv).
was relatively inert, furnishing the desired product in low yield
(10%). However, a moderate yield of 37% of 3n could be
obtained by the use of Pd(OAc)2/P(2-furyl)3 catalytic system
with improving amounts of 2n and the base. It is worth noting
that N-tosylhydrazones (2o and 2p) bearing two aryls were
also compatible in the cascade reaction (3o and 3p). In
addition, N-tosylhydrazone 2q bearing a phenyl and an ester as
313
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the safe precursor of methyl phenyldiazoacetate afforded the
desired product 3q in 54% yield.
of the enantioselective product 3a was obtained (see the details
in the SI). Thus, the anions VII (Scheme 4) are more likely to
be the trapped intermediates in this cascade process.
Then we turned our attention to the scope of the substrate
1. As illustrated in Scheme 2, an array of N,N-disubstituted
thioamides bearing α,α-diesters 1 could bifunctionalize a single
carbon of N-tosylhydrazones 2 smoothly. Thioamides 1
bearing other esters, including ethyl esters (1r), isopropyl
esters (1s), and benzyl esters (1t), were compatible (3r−3t).
Thioamides 1 with para- or meta-electron-donating and
electron-withdrawing substituted aryls on nitrogen both
afforded the desired product 3u−3aa in moderate to good
yields. Methoxy (1u, 1z), fluoro (1v), chloro (1w, 1aa),
trifluoromethyl (1x), and keto (1y) in aryls on nitrogen of 1
were all tolerated. In addition, Thioamides 1 containing other
alkyl substitutions on nitrogen, including ethyl (3ab),
isopropyl (3ac), n-hexyl (3ad), and 3-methoxypropyl (3ae),
were all well tolerated, smoothly delivering the corresponding
products 3ab−3ae in moderate to good yields.
Scheme 4. Proposed Mechanism
A one-pot reaction from 2.5 equiv of acetophenone, 2,5
equiv of 4-methylbenzenesulfonohydrazide (which form 2a
followed by the removal of solvent), and 1.0 equiv of 1a
worked to afford 3a in 61% yield (Scheme 3, a). Derivatization
A plausible mechanism for this novel reaction is proposed in
Scheme 4. NaOtBu abstracts the α-H of thiocarbonyl of 1 to
form the thioenolate anion I, which might coordinate with the
palladium catalyst to give the palladium complex IV. The
complex IV and the diazo compound II derived from N-
tosylhydrazone 2 under NaOtBu might form the palladium
carbene V, which undergoes carbene migratory insertion to
give the intermediate VI. The organopalladium moiety in VI
attacks the intramolecular ester activated by BF3·Et2O to afford
product 3. Also, intermediate VI might produce the anion VII
along with recovery of Pd(TFA)2/tBuXPhos, and then the
anion VII attacks the intramolecular ester activated by BF3·
Et2O to afford the product 3 via addition/elimination.
Alternatively, Pd(TFA)2/tBuXPhos reacts with the diazo
compound II derived from N-tosylhydrazone 2 to give the
metal carbene intermediate III. Then the thioenolate anion I
derived from 1 might undergo ligand exchange with III to give
the intermediate V, which forms VI via carbene migratory
insertion followed by the similar intramolecular cyclization as
above to afford 3. In addition, the thioenolate anion I directly
attacks the carbene carbon of III also might form the
intermediate VI, and then the intermediate VI directly or the
anion VII derived from VI undergoes cyclization to furnish 3.
In conclusion, N,N-disubstituted thioamides bearing α,α-
diesters coupled with N-tosylhydrazones bearing alkyls with
Pd(TFA)2 as the catalyst, tBuXPhos as the ligand, and NaOtBu
as the base at 100 °C and the formed intermediates were
unprecedentedly trapped by intramolecular ester function-
alities activated by co-catalyst BF3·Et2O, affording polyfunc-
tional thiophen-3(2H)-ones with sulfur-containing tetrasub-
stituted carbon centers in moderate to good yields. This
represents the first time that the formed organopalladium
intermediates containing β-hydrogen from palladium carbene
migratory insertion selectively form the second bond at the
same carbon via 1,2-addition/elimination with esters instead of
undergoing β-hydrogen eliminations. The novel cascade
reaction utilizes odorless, nontoxic, safe, and easily available
starting materials. Wide substrate scope and a broad range of
functional groups are tolerated. Products possess rich and
valuable structures in medicinal chemistry and materials.
Developing other novel reactions to selectively construct
Scheme 3. One-Pot Protocol and Product Derivatization
of the products was investigated. Product 3a was reduced by
NaBH4 to furnish 9a and 9a′ in 53% total yield with 4:1
diastereoselectivity, and the stereochemistry was assigned using
1D NOESY spectra of 9a and 9a′ (Scheme 3 (b, 1) and SI).
Product 3a reacted with 1.2 equiv of EtMgBr and 2.0 equiv of
MeLi under −78 °C, and only the ester group in 3a was
transformed into ketone to furnish 10a in moderate yield
(Scheme 3 (b, 2)). As mentioned above, the reaction is
compatible with halogen atoms which can be used as handles
for functionalization. Product 3d reacted with phenylboronic
acid under the reaction conditions reported by Buchwald13 to
afford 11a in 87% yield (Scheme 3 (b, 3)). In addition, some
chiral ligands instead of tBuXPhos were investigated, but none
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03796.
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Experimental procedures and spectroscopic character-
1
ization data, H and 13C NMR spectra of the new
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AUTHOR INFORMATION
Corresponding Author
■
Liqin Jiang − School of Chemistry and Molecular Engineering,
East China Normal University, Shanghai 200241, China;
orcid.org/0000-0002-9751-7510; Email: lqjiang@
sat.ecnu.edu.cn, jiangliqin_777@163.com
Authors
Zhongliang Cai − School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200241, China
Zhi Yao − School of Chemistry and Molecular Engineering,
East China Normal University, Shanghai 200241, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03796
Author Contributions
†Z.C. and Z.Y. contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Science and
Technology Commission of Shanghai Municipality (No.
15ZR1410500).
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