Ligand-Controlled Regiodivergent Thiocarbonylation of Alkynes toward Linear and Branched α,β-Unsaturated Thioesters

Article abstract of DOI:10.1002/anie.202106079

Thiocarbonylation of alkynes offers an ideal procedure for the synthesis of unsaturated thioesters. A robust ligand-controlled regioselective thiocarbonylation of alkynes is developed. Utilizing boronic acid and 5-chlorosalicylic acid as the acid additive to in situ form 5-chloroborosalicylic acid (5-Cl-BSA), and bis(2-diphenylphosphinophenyl)ether (DPEphos) as the ligand, linear α,β-unsaturated thioesters were produced in a straightforward manner. Switching the ligand to tri(2-furyl)phosphine can turn the reaction selectivity to give branched products. Remarkably, this approach also represents the first example on thiocarbonylation of internal alkynes.

Full text of DOI:10.1002/anie.202106079

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Accepted Article
Title: Ligand-Controlled Regiodivergent Thiocarbonylation of Alkynes
toward Linear and Branched α,β-Unsaturated Thioesters
Authors: Xiao-Feng Wu, Han-Jun Ai, and Wangyang Lu
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10.1002/anie.202106079
Angewandte Chemie International Edition
RESEARCH ARTICLE
Ligand-Controlled Regiodivergent Thiocarbonylation of Alkynes
toward Linear and Branched α,β-Unsaturated Thioesters
Han-Jun Ai,[a] Wangyang Lu,[b] and Xiao-Feng Wu*[a]
[a]
H.-J. Ai, Prof. Dr. X.-F. Wu, Leibniz-Institutfür Katalyse e.V. an der UniversitätRostock, Albert-Einstein-Straße 29a, 18059 Rostock(Germany); Prof. Dr.
X.-F. Wu, Dalian National Laboratoryfor Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023 Dalian, Liaoning,
China, E-mail: xiao-feng.wu@catalysis.de
[b]
Prof. Dr. W. Lu, National Engineering Lab for Textile Fiber Materials& Processing Technology (Zhejiang), Zhejiang Sci-Tech University, Hangzhou
310018, China
Supporting information for this articleis given via a link at theend of the document.
Abstract: Thiocarbonylation of alkynes offers an ideal procedure for
the synthesis of unsaturatedthioesters. In this report, a robust ligand-
controlled regioselective thiocarbonylation of alkynes is developed.
Utilizing boronic acid and 5-chlorosalicylic acid as the acid additive to
in-situ form 5-chloroborosalicylic acid (5-Cl-BSA), and bis(2-
diphenylphosphinophenyl)ether (DPEphos) as the ligand, linear α,β-
unsaturated thioesters were produced in a straightforward manner.
Switching the ligand to tri(2-furyl)phosphine can turn the reaction
selectivity to give branched products. Remarkably, this approach also
represents the first example on thiocarbonylation of internal alkynes.
Introduction
Transition-metal-catalyzed
carbonylation
reaction
is
fundamentally important organic transformation by its modularity
and the use of carbon monoxide as a cheap and abundant C1
source.[1] Meanwhile, the development of catalytic processes for
selective transformations is one of the key goals in organic
synthesis. By controlling the regioselectivity, branched and linear
products can be obtained selectively from the same substrates.
Although recent years have witnessed the successes of
regioselective hydroformylation,[2] alkoxycarbonylation,[3] and
aminocarbonylation,[4] the development of regioselective
thiocarbonylation hasbeen much limited.[5-10] Thismight be partly
due to the strong binding affinitiesof sulfur-containingcompounds
to late-transition metals affecting the coordination of ligand with
catalyst.[11] And the selectivity of the catalyst system is mainly
influenced by the properties of the ligands.[12] Therefore, the
pursuit of an alternative catalytic system might constitute,
conceptuality aside, a worthwhile endeavor for regiodivergent
thiocarbonylation.
Unsaturated thioesters are potent compounds in
biosyntheticand organicsyntheticchemistry,[13] which usually act
as important intermediates to provide the essential
chemoselectivity in the synthesis of complexed bioactive
moleculesand naturalproducts.[14] Besides classiccondensation
reactions,[13] the thiocarbonylative transformation of alkynes
provides an ideal option for producing α,β-unsaturated
thioesters.[6-9] The first example on transition-metal-catalyzed
thioformylation of acetyleneswasreported by Ogawa and Sonoda’
group in 1990s (Scheme 1A, top), and a small amount of the
thiocarbonylation products could be observed when palladium
catalyst was used.[6b] Their subsequent work showed that
platinum catalysts could improve the selectivity toward the
branched product (Scheme 1A, bottom).[6c,d,f]
Scheme 1. Transition-metal-catalyzed thiocarbonylation of alkynes.
The
main
contributions
of
palladium-catalyzed
thiocarbonylation were accomplished by Xiao, Alper et al.[7] who
mainly focused on the transformation of allenes[7b],
vinylcyclopropanes[7g]
,
1,3-dienes[7b,d,e,f]
.
However,
thiocarbonylation reactions of alkynes have been very rarely
reported,[8,9] and it is likewise limited by the poor selectivity, more
unfortunately, to date, almost no functionalgroupsare compatible
within this class of reactions (Scheme 1B). Under this premise,
we wondered whether a new catalyticblueprint could be designed
to afford high regioselectivity and excellent functional group
compatibilityforthe thiocarbonylationof alkynes. We been able to
realize this goal finally after extensive systematic studies. Our
protocol is characterized by its ligand-controlled regioselectivity
pattern, wide substrate scope and unprecedented functional
group compatibility (Scheme 1C).
1
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RESEARCH ARTICLE
Results and Discussion
knowledge,[18] we believed that the regioselectivity of the
branched product can be improved by the choice of proper
monodentate ligand. As expected, as shown in Table 2, the yield
of 4 significantly increased (form trace to 25%) when replacing
DPEphoswith triphenylphosphine (L22). After experimenting, we
found that the yield of 4 increased with decreasing electron cloud
Our investigations started with palladium-catalyzed
thiocarbonylation of phenylacetylene 1 and thiophenol2 at 110 ℃
under CO atmosphere (10 bar) in CH3CN (Table 1). We utilized
boric acid (B(OH)3, 10 mol%) and 5-chlorosalicylic acid (5-Cl-SA,
20 mol%) to in-situ form 5-chloroborosalicylic acid (5-Cl- density of the ligand (Table 2, entries 1-5). When tri(2-
BSA).[4f,15] It acted as a mild proton additive to facilitate the
reaction and, more importantly, to prevent the deactivation of the
ligand underacidicconditions, thusfurther avoiding the formation
of metal plating.[16] Subsequently, a variety of bisphosphine
ligands were screened at the first stage. Although conventional
ligands (L1-L7, L11) barelyallowed the reaction to proceed, these
observations contributed to our perception that the bite angle of
the ligand[17] may have a significant effect on the transformation.
The improved yieldsof the desired product 3 were obtained when
ferrocenylphosphines (L8-L10) were used as the ligand.
Meanwhile, the Xantphos-type ligands such as BenzoXantphos
(L12), Xantphos (L13), SiXantphos (L14), and NiXantphos(L15)
were applied in the reaction, however, still only moderate yields
(53%-61%) were available. The direct hydrothiolation productsof
1 and 2 were the main byproducts observed in these cases.
Encouragingly, an important improvement in the yield of 3 was
achieved when employing ligands with more appropriate bite
angles (DPEphos-type ligands, L16-L20). Finally, 87% yield of
the desired product 3 was produced with DPEphos as the ligand
(L16). Notably, under our best reaction conditions, a control
experiment with 30 mol% of 5-chlorosalicylicacid was performed,
the desired product 3 was formed in 61% yield with diphenyl
disulfide as the majorby-product.
furyl)phosphine (L25) was selected as the ligand, the yield up to
50% can be achieved. In the testing of catalyst precursors,
Pd(dba)2 and Pd(CH3CN)2Cl2resulted in the best results(Table 2,
entries 6-9). Finally, after a judicious choice of the reaction
concentration and the ratio of the substrates, an optimal reaction
condition was constituted, delivering 4 in 80%yield (Table 2,
entries 10-11). Notably, traces of linear product could still be
detected. Additionally, the use of equal amount of thiolhere is to
avoid the further reaction between product 4 and the rest thiol
which reduced the yield of 4 in consequence.
Table 2. Optimization ofthe thiocarbonylation toward the branched product.[a]
Entry
1
Pd catalyst
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
PdCl2
Ligand
L22
L21
L23
L24
L25
L25
L25
L25
L25
L25
L25
Yield [%][b]
25
2
20
3
33
4
49
Table 1. Optimization ofthe thiocarbonylation toward the linear product.[a]
5
50
6
40
7
Pd(OAc)2
Pd(dba)2
Pd(CH3CN)2Cl2
Pd(dba)2
Pd(dba)2
46
8
62
9
62
10
11
74[c]
80[c,d]
[a] Conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd catalyst (5 mol%), ligand (10
mol%), B(OH)3 (10 mol%), 5-Cl-SA (20 mol%), CO (20 bar), CH3CN (1 mL),
stirred at 120 ℃ for 14 h. [b]Yields were determinedby GC with hexadecane as
the internal standard. [c]CH3CN (1.5 mL). [d]0.2 mmol of 2 was used. 5-Cl-SA =
[a] Conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd(TFA)2 (5 mol%), ligand (5
mol%), B(OH)3 (10 mol%), 5-Cl-SA (20 mol%), CO (10 bar), CH3CN (1.0 mL),
stirred at 110 ℃ for 14 h. Yields were determined by GC with hexadecane as
5-chlorosalicylic acid.
the internal standard. 5-Cl-SA = 5-chlorosalicylic acid.
When we optimized the linear thioester, trace amount of the
branched thioester 4 was detected. According to our
2
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RESEARCH ARTICLE
Figure 1. Scope of thiocarbonylation toward linear α,β-unsaturated thioesters. Reaction conditions: alkynes (0.2 mmol), thiols (0.24mmol), Pd(TFA)2 (5 mol%),
DPEphos (5 mol%), B(OH)3 (10 mol%), 5-Cl-SA (20 mol%), in CH3CN (1.0 mL), stirredunder CO (10 bar) at 110 ℃ for 14 h. Unlessotherwise noted, theratio of
the product: E/Z > 20/1. Isolated yields. (A) Scope of thiophenols. (B) Scope of alkyl mercaptan. (C) Scope ofaryl alkynes. (D) Scope ofalkyl alkynes. [a]Determined
by NMR. [b]1,3-dietnynylbenzene (0.1mmol) and 1-mercaptooctane (0.2 mmol) were used. [c]1,6-heptadiyne (0.1 mmol) and 1-mercaptooctane (0.24 mmol) were
used. [d] 90% purity. [e] 95% purity. Oct= octyl; TMS = trimethylsilyl; TES = Triethylsilyl.
3
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Figure 2. Scope of thiocarbonylation toward branched α,β-unsaturated thioesters. Reaction conditions: alkynes (0.2 mmol), thiols (0.2 mmol), Pd(dba)2 (5
mol%), L25 (10 mol%), B(OH)3 (10 mol%), 5-Cl-SA (20 mol%), in CH3CN (1.5 mL), stirredunder CO (20 bar) at 120 ℃ for 14 h. Isolatedyields. (A) Scope of thiols.
(B) Scope of aryl alkynes. (C) Scope of alkyl alkynes. [a] 95% purity.
4
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Figure 3. Scope of thiocarbonylation of internal alkynesand bioactive molecules. [a]Method A: alkynes (0.2 mmol), thiols (0.24 mmol), Pd(TFA)2 (5 mol%),
DPEphos (5 mol%), B(OH)3 (10 mol%), 5-Cl-SA (20 mol%), in CH3CN (1.0 mL), stirred under CO (10bar) at 110 ℃ for 14 h. [b]Method B:alkynes (0.2mmol), thiols
(0.2 mmol), Pd(dba)2 (5 mol%), L25 (10 mol%), B(OH)3 (10 mol%), 5-Cl-SA (20 mol%), in CH3CN (1.5 mL), stirred under CO (20 bar) at 120 ℃ for 14 h. [c]The
reaction proceeded for 24 h. Isolated yields. (A) Scope of internal alkynes. (B) Modification of bioactive molecules. [d] 95% purity.
With the optimal conditions in hand, the scope of the
transformation was carried out immediately. First, the
thiocarbonylation of alkynes toward linear α,β-unsaturated
thioesterswas conducted (Figure 1). As evident from the results
compiled in Figure 1A, both ortho-, meta-, and para-substituted
thiophenols can be successfully applied to the reaction and
provided the corresponding thioesters in moderate to excellent
yields (Figure 1A, 3-23). Notably, the steric hindrance (10-11) or
electronic nature (12-13) of thiophenols hardly effected the
transformation. The broad synthetic applicability of the reaction
was also reflected in the successful thiocarbonylation of benzyl
mercaptan (24), primary mercaptans (25-26, 29-30), secondary
mercaptan (27), and tert-butyl mercaptan (28). Subsequently, a
variety of aryl acetylenes were tested under our standard
conditions(Figure 1C). Besidesalkyland halogen groups(31-40),
structures containing methoxy (37), trifluoromethyl (41), acetyl
(42), ester (43), cyano (44, 45), hydroxymethyl (46), phenol (47),
carboxyl (48), nitro (49), thiophene (50), pyridine (51), or
sulfonamide (52) can also perfectly be tolerated. The excellent
functional groups compatibility demonstrated the robustness of
this protocol. Aliphatic alkynes, as an interesting class of
unsaturated hydrocarbons, were afterwardstested in thissystem
and transformed into the corresponding linear thioestersin good
yields(Figure 1D). Even alkyl chloride (58) or organosilanes (60-
62) could be accommodated, thus constituting an orthogonal
gateway for subsequent manipulation via cross-coupling
reactions. Interestingly, diacetylenes could be directly converted
to dithioesters, albeit in lower yields (53, 66). Notably, in some
cases, the productcontainssmallamount of the other regioisomer
and vinylthioether(noncarbonylation product) asimpuritieswhich
is very difficult to separate from ourtargetproduct.
We next turned ourattention to studythe preparative scope of
the branched products (Figure 2). Similarly, both thiophenolsand
alkyl mercaptansperformed wellunder the conditions (Figure 2A).
The high regioselectivityof the method is nicelyillustrated by the
fact that even sterically hindered thiols were successfully
converted to branched thioestersin moderateto good yields(67,
68, 83, 84). In addition, various aryl acetylenes passed the test
5
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10.1002/anie.202106079
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RESEARCH ARTICLE
and delivered the corresponding products in satisfactory yields
(Figure 2B). Likewise, a number of functional groups such as
acetyl (85), trifluoromethyl (86), ester (87), carboxyl (88), phenol
(89), hydroxymethyl(90), cyano (91), nitro (92), sulfonamide (93),
and halides (94-98) could be accommodated. Furthermore, the
alkyl alkynesposed no problems(Figure 2C). Notably, the tertiary
acetylenes afforded the linear products under the conditions, no
corresponding branched thioesters could be detected (106-108).
We speculate that thisresult is mainlydue to the sterichindrance
effect from the substrates. It is important to mention that the
regioisomers(10-20mol%) can be formed in some casesas well
which can not be removed from our target product.
To the best of our knowledge, a catalytic thiocarbonylation
reaction of internalalkynes hasnot been reported yet. Gratifyingly,
as shown in Figure 3A, acetylenesend-capped with either arenes
or aliphatic motifs were successfully converted to the desired
unsaturated thioesters in moderate to excellent yields (109-124).
Importantly, no need to reoptimize the reaction conditions
(Method A and B), which is a rather valuable finding that
demonstrates the generality of our protocol. The primary (109,
112), secondary (110), benzylic (114), phenyl (115), and even
tert-butyl mercaptans(111, 113) well carbonylative cross-coupled
with alkyl internal alkynes and delivered the corresponding
products in good yields. Furthermore, our robust Pd-catalyzed
thiocarbonylation event could be extended to the use of π-
extended system, diarylacetylenes, albeit with prolonged reaction
time (116-121). Asymmetric internal alkyneswere tested as well,
however, in which the ligands lost their regulatory role. Neither
bidentate (Method A) normonodentate ligands(Method B) could
achieve the regioselectivity for them. The reaction site here was
based on the nature of the substrates. With increasing steric
hinderance (Me- to Et- to Ph-), the selectivitywasgraduallylosted
(122-124). 1-Phenyl-2-(tert-butyl)-acetylene could be involved in
the reaction, which was proved by GC-MS, however, only trace
amount of the thiocarbonylation product was detected, and the
structure could be not determined. Interestingly, the TMS group
of trimethyl(phenylethynyl)silane was shed in the reaction (125).
Finally, some examplesof bioactive molecule, such as Lbuprofen,
Azaspirodecanedione, and Uracilderivatives substituted alkynes
were tested and applicable to the reaction (Figure 3B). The
stereoselectivity in all these tested cases were outstanding,
except 123 which might be due to the non-influenceable steric
effect of the methyl group.
Scheme 2. Mechanistic proposal.
A possible reaction mechanism is proposed to illustrate the
regioselectivity (Scheme 2). We favor an initial generation of Pd-
H complex I or I’ in the presence of acid additives and bidentate
or monodentate ligand. Then, the anti-Markovnikov or
Markovnikov addition of Pd-H complex with alkynes delivers the
corresponding linear or branched intermediate II or II’, which will
be transformed into acylpalladium complex III or III’ through the
coordination and insertion of CO. Finally, thiol attacks the
acylpalladium complex to provide the desired α,β-unsaturated
thioesters and regenerate the LPdII−H complex for the next
catalyticcycle.
Conclusion
In summary, we have discovered a general ligand-controlled
regiodivergent thiocarbonylation of alkynes. By employing 5-Cl-
BSA as the mild acid additive, variousdesired linear orbranched
α,β-unsaturated thioesters can be regioselective produced in a
straightforward manner. Remarkably, our approach also
represents the first example on thiocarbonylation of internal
alkynes. The wide substrate scope, high regio- and
stereoselectivity, excellent functional group compatibility,
robustness, and generalityof the protocol suggest that it can be a
powerful alternative to known methodologies for preparing α,β-
unsaturated thioesters.
Acknowledgements
We thank the Chinese Scholarship Council (CSC) for financial
support. We also thank the analytical team of LIKAT for their
excellent analyticsupport.
Keywords: Ligand-controlled • palladium catalyst •
Regioselective • Thiocarbonylation • Thioester
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RESEARCH ARTICLE
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This article is protected by copyright. All rights reserved.

10.1002/anie.202106079
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table of Contents
A ligand-controlled regioselective thiocarbonylation of alkynesis reported. Variouslinear and branched α,β-unsaturated thioesters are
produced in a straightforward manner. This protocolis characterized by itsligand-controlled regioselectivitypattern, wide substrate
scope and unprecedented functionalgroup compatibility. Remarkably, thisapproach also represents thefirst example on
thiocarbonylation of internalalkynes.
8
This article is protected by copyright. All rights reserved.