Alkyne hydrothiolation catalyzed by a dichlorobis(aminophosphine) complex of palladium: Selective formation of cis-configured vinyl thioethers

Article abstract of DOI:10.1002/chem.201200388

Cis all round: Dichlorobis[1-(dicyclohexylphosphanyl)piperidine]palladium, [(P{(NC₅H₁₀)(C₆H₁₁) ₂})₂Pd(Cl)₂], is a highly efficient alkyne hydrothiolation catalyst and the first generally applicable system that selectively generates cis-configured anti-Markovnikov adducts in excellent yields within only a few minutes at 120 °C in the presence of only 0.05 mol % of the catalyst (see scheme).

Full text of DOI:10.1002/chem.201200388

COMMUNICATION
DOI: 10.1002/chem.201200388
Alkyne Hydrothiolation Catalyzed by a Dichlorobis(aminophosphine)
Complex of Palladium: Selective Formation of cis-Configured Vinyl
Thioethers
Roman Gerber and Christian M. Frech*[a]
Vinyl sulfides are very important synthetic intermediates
in total syntheses and as precursors to a wide range of func-
tionalized molecules. Furthermore, sulfur-containing organic
compounds commonly exhibit biological activity, and hence
are frequently found in naturally occuring compounds.
Moreover, these compounds have found applications in ma-
terials science,[1–5] and thus are valuable synthetic targets.
The increasing demand for vinyl thioethers expedited the
development of new synthetic methods for these target com-
pounds. The most attractive process for their preparation is
the (100% atom efficient) alkyne hydrothiolation reaction
(Scheme 1).
form [{Ni
tris(3,5-dimethylpyrazolyl)borate),[7i–l] selective formation of
the anti-Markovnikov adducts with a trans-configuration
(type B) has been obtained when [Rh(Cl)
(PPh3)3][7g,m] or N-
(SAr)2}n],[7r] or [Tp*Rh
ACHUTGTNRNENUG CAHTUNGTREN(NUGN PPh3)2] (Tp*=hydro-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
heterocyclic carbene based AuI complexes were applied.[7]
However, although desirable, a generally applicable alkyne
hydrothiolation catalyst for the high-yielding synthesis of
cis-configured anti-Markovnikov adducts of type C has not
yet been reported, and hence is the subject of intense inves-
tigation within this field of research.[8]
We report herein the catalytic activity of dichloroACHTUNGTRENNUNG{bisACHTUNGTRENNUNG[1-
(dicyclohexylphosphanyl)piperidine]}palladium (1),[9] a gen-
À
erally applicable C C bond-
forming catalyst, in the hydro-
thiolation of alkynes with thiols.
[(PACHTUNRTGENNUG{(NC5H10)ACHUTTGNERN(NUGN C6H11)2})2Pd(Cl)2]
(1) is the first generally applica-
ble alkyne hydrothiolation cata-
lyst that selectively generates
cis-configured anti-Markovni-
Scheme 1. General scheme for the transition-metal-catalyzed hydrothiolation of a terminal alkyne with a thiol.
Although few specific cases of selective transformations
have been reported for this process under transition-metal-
free reaction conditions,[6] the addition of thiols to alkynes
(under photochemical or basic conditions) usually lacks ste-
reocontrol of the double-bond geometry, resulting in mix-
tures of cis and trans anti-Markovnikov adducts of type B
and C and/or, with specific substrates, proceeding very
slowely (even at high reaction temperatures). This means
that these reactions are only of very limited practicability. In
contrast, transition-metal-catalyzed versions of alkyne hy-
drothiolation processes often exhibit excellent selectivity,
and thus have been successfully applied for selective product
formation.[7] For example, whereas the Markovnikov-type
vinyl sulfides A were selectively formed when alkyne hydro-
kov adducts of type C. The addition products were obtained
in excellent yields within a few minutes at 1208C with N,N-
dimethylpyrrolidone (NMP) and NaOH as the solvent and
base in the presence of only 0.05 mol% of the catalyst, that
is, at far lower catalyst loadings than typically applied for
this type of reaction. The catalyst was quantitatively pre-
pared within a few minutes by treatment of suspensions of
[Pd(Cl)2ACTHNUTRGENUG(N cod)] (cod=cycloocta-1,5-diene) in toluene with
two equivalents of 1-(dicyclohexylphosphanyl)piperidine
under N2 at 258C (Scheme 2).[9a]
thiolations were catalyzed by [PdACHTUNGTRNEUNG
(OAc)2],[7c,e] [CpNi-
Scheme 2. Synthesis of dichlorobis[1-(dicyclohexylphosphanyl)piperidi-
ne]palladium (1; Cy=cyclohexyl).
ACHTUNGTRENNUNG(NHC)(Cl)] (Cp=cyclopentadienyl; NHC=N-heterocyclic
carbene),[7q] oligomeric nickel dithiolate complexes of the
The aminophosphine-based complex 1 was assumed to be
an ideal alkyne hydrothiolation catalyst because, in contrast
to its phosphine-based analogue, it proved to efficiently pro-
mote the formation of palladium nanoparticles. These nano-
particles have been shown to be the catalytically active spe-
cies in Suzuki, Heck, and cyanation reactions.[9a,c–e] Further-
more, this catalyst can also operate through homogeneous
[a] R. Gerber, Dr. C. M. Frech
Department of Inorganic Chemistry, University of Zꢀrich
8057 Zꢀrich (Switzerland)
Fax : (+41)44-635-46-92
E-mail: chfrech@aci.uzh.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200388.
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mechanisms, as was recently
demonstrated to be the case in
the Negishi cross-coupling reac-
tion.[9b] Experimental observa-
tions clearly indicate that the
alkyne hydrothiolation was cat-
alyzed through
a
molecular
mechanism. Consequently, 1 is
not only a generally applicable
À
C C cross-coupling catalyst,
but also an efficient catalyst in
the hydrothiolation of, for ex-
ample, acetylenes, providing an
initial indication of the general
À
applicability of 1 in C C and
À
C X bond-forming reactions.
Figure 1. Possible catalytic cycles for alkyne hydrothiolation with aromatic and aliphatic thiols.[12] Aminophos-
phine dissociation (and re-coordination) may be involved at any of the reactions steps.
Catalysis: Complex 1 is a highly
active and reliable hydrothiola-
tion catalyst, which efficiently
promotes the nucleophilic attack (Figure 1, right) of a wide
range of aromatic, benzylic, and aliphatic thiolates on aro-
matic alkynes (see Tables 1 and 2) to give the anti-Markov-
nikov-type products C cleanly (Scheme 1) with excellent
regio- and stereoselectivities, conversion rates, and yields.
For example, thermal treatment (1208C) of thiophenol with
ethynylbenzene selectively yielded the anti-Markovnikov-
type addition product phenyl (Z)-2-phenylethenyl sulfide
almost quantitatively within only a few minutes.[10] The for-
mation of the cis-configured vinyl sulfide was confirmed by
1H NMR spectroscopy, and the spectrum showed two dou-
blet signals due to the olefinic protons at d=6.90 and
3
6.52 ppm with coupling constants of JHH =11.1 Hz. Similar
selectivities, conversion rates, and product yields were ob-
tained for other aromatic thiols, such as 2-methylbenzene-
thiol, 4-methoxybenzenethiol, 4-aminobenzenethiol, pyri-
dine-2-thiol, 4-bromobenzenethiol, 3-bromobenzenethiol,
and 2-bromobenzenethiol, as well as aliphatic thiols, such as
octane-1-thiol, cyclohexanethiol, furan-2-ylmethanethiol,
phenylmethanethiol, and 2-phenylethanethiol. To expand
Table 1. Hydrothiolation of aromatic alkynes with aliphatic and aromatic thiols, catalyzed by 1.[a]
[a] Reaction conditions: alkyne (1.3 mmol), thiol (1.0 mmol), NaOH (1.0 mmol), NMP (2 mL), catalyst (0.05 mol%) in solution (THF), at 1208C. The
conversions and product ratios (cis/trans/gem) were determined by GC/MS and are based on the amount of thiol, as well as by NMR spectroscopy. Isolat-
ed yields are given in brackets and were obtained after 15 min of reaction time.
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Alkyne Hydrothiolation
COMMUNICATION
À
the scope of this process even further, reactions were per-
formed with different aryl-substituted alkynes, including 1-
ethynyl-4-fluorobenzene, 1-ethynyl-4-bromobenzene, and 2-
ethynylpyridine, for which the anti-Markovnikov adducts of
type C were selectively formed within only 15 min (Table 1)
for all of the reactions examined.
Pd S bond (Figure 1, left) over nucleophilic attack
(Figure 1, right).
The reaction mechanisms described herein are assumed to
operate in these reactions. Both, the alkyne insertion mecha-
nism and the nucleophilic attack are initiated by the oxida-
tive addition of a thiol to the metal center of bis[1-(dicyclo-
hexylphosphanyl)piperidine]palladium(0) (2), which is gen-
erated by the reaction of 1 with OHÀ.[11] This results in the
formation of the respective thiolate hydride complexes, and
is followed by alkyne coordination. Whereas a subsequent
nucleophilic attack affords the palladium hydride vinyl sul-
fide intermediate when aromatic alkynes were used, migra-
Internal alkynes also react with thiols to yield the respec-
tive addition products, but require slightly prolonged reac-
tion times (2 h) for high conversions. For example, thermal
treatment of 1,1’-ethyne-1,2-diyldibenzene with thiophenol
exclusively gave phenyl (Z)-2-phenylethenyl sulfide, that is,
the addition product with cis-configuration, in a yield of
93%. The same stereoselectivity was observed if other thiols
were applied in the reaction (Table 2). However, although
smooth product formation was noticed, the use of unsym-
metrical internal alkynes proceeded with rather modest re-
gioselectivity. For example, thermal treatment of prop-1-yn-
1-ylbenzene with thiophenol (or 1-hexanethiol) gave mix-
tures of phenyl (1E)-1-phenylprop-1-en-2-yl sulfide and
phenyl (1Z)-1-phenylprop-1-en-2-yl sulfide (or hexyl (1E)-1-
phenylprop-1-en-2-yl sulfide and hexyl (1Z)-1-phenylprop-1-
en-2-yl sulfide) in a ratio between 1:1 and 2:1, in favor of
the less-hindered isomer, most probably due to a change in
the mechanism (for details of the formation of different ad-
dition products through the alkyne insertion mechanism and
the nucleophilic attack, see Figure 1).
À
tion into the Pd S bond is favored for aliphatic alkynes. Re-
action steps involving cis/trans isomerization of vinyl sul-
fides, however, have been excluded because the transforma-
tion of phenyl (Z)-2-phenylethenyl sulfide into its E isomer
by thermal treatment (under the reaction conditions applied
for the catalysis) was not observed. Reductive elimination
(or an eventual protonolysis) yields the addition products
and regenerates the catalyst for both mechanisms. Although
not explicitly mentioned, aminophosphine dissociation and
re-coordination may be involved at any of the reaction
steps. However, initial formation of complex 2 by reaction
of 1 with OHÀ gained strong experimental support: whereas
the conversion rates and product selectivities remain the
same for all types of substrate when alkyne hydrothiolation
reactions are catalyzed by 1 in the presence of only
10 mol% of the base, mixtures of all possible addition prod-
ucts and their isomers are formed with aliphatic alkynes in
the absence of base. This is most probably due to product
formation by both the alkyne insertion mechanism and the
nucleophilic attack mechanism.[12] Even more importantly,
complex 2 is an excellent alkyne hydrothiolation catalyst,
showing the same catalytic ac-
On the other hand, if aliphatic alkynes (e.g., 1-octyne)
were thermally treated with thiols, the branched Markovni-
kov-type addition products A, which are susceptible to iso-
merization, were favorably formed (ꢀ80%). The striking
difference in product selectivity obtained with aliphatic al-
kynes is most probably due to their lower ligating tendency,
favoring, in contrast to aromatic alkynes, insertion into the
tivity and product selectivity
Table 2. Hydrothiolation of aliphatic (terminal), as well as internal alkynes with thiols, catalyzed by 1.[a]
with both aliphatic and aromat-
ic substrates as complex 1, even
in the absence of base. Further-
more, treatment of 2 with phe-
nylmethanethiol, for example,
instantly yielded the respective
hydride thiolate pal
complex [(P{(NC5H10)-
(C6H11)2})2Pd(H)(SCH2C6H5)]
ACHTUNGTRENUNlNG adium(II)
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(3) at 258C as proposed in the
catalytic cycle. Significantly,
complex 3 also shows the same
catalytic performance and prod-
uct selectivity, in the presence
and absence of base, as 1 and
2.[13] Finally, molecular mecha-
nisms do indeed operate, as the
involvement of palladium nano-
particles has been excluded
(see below).
[a] Reaction conditions: alkyne (1.3 mmol), thiol (1.0 mmol), NaOH (1.0 mmol), NMP (2 mL), catalyst
(0.05 mol%) in solution (THF), at 1208C. The conversions and product ratios (cis/trans/gem) were determined
by GC/MS and are based on the amount of thiol, as well as by NMR spectroscopy. Isolated yields are given in
brackets and were obtained after 15 min when the reactions were performed with terminal alkynes and after
2 h with internal alkynes.
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C. M. Frech et al.
Mechanistic investigations: The following experimental ob-
servations clearly indicate that a molecular mechanism oper-
ates in this reaction:[14] 1) Neither sigmoidal-shaped kinetics
with induction periods, which are characteristic of metallic
particle formation, nor autocatalytic surface growth that can
lead to soluble monodisperse nanoclusters (or insoluble
bulk-metal formation) have been observed.[15] In contrast,
approximately 70% of the product formation was typically
observed within one minute. 2) The presence of a large
excess of metallic mercury in reaction mixtures of the thiol,
alkyne, and catalyst had no effect either on the rate of con-
version or on the product yields. The same observations
were made if poly(4-vinylpyridine) (PVPy; 2% cross-linked
with divinylbenzene) was added instead.[16] 3) No effect on
the conversion rates or on the product yields was observed
if 0.1 or 0.5 equivalents (relative to the catalyst) of thio-
phene, CS2 or PPh3 were present in the reaction mixtures.
4) No evidence of the presence of palladium nanoparticles
was obtained from UV/Vis spectra of the reaction mix-
tures.[17] Lastly, 5) The catalytic activities of the aminophos-
Acknowledgements
This work was supported by the University of Zurich and the Swiss Na-
tional Science Foundation (SNSF).
À
Keywords: alkynes · aminophosphines · cis selectivity · C S
bond formation · hydrothiolation · reaction mechanisms
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phine-based complexes [(PACHTUNRGTNENUG{(NC5H10)3ÀnHCAUTNTGREN(NUNG C6H11)n})2Pd(Cl)2]
(with n=0–2) are comparable, whereas a slightly lower level
of activity was found for their phosphine-based analogue,
providing a very strong indication that a molecular mecha-
nism operates.[18]
In conclusion, dichlorobis[1-(dicyclohexylphosphanyl)pi-
peridine]palladium, [(PACHTNURTGENNU{G (NC5H10)ACHUTTGNRNE(NNGU C6H11)2})2Pd(Cl)2] (1),
À
a generally applicable C C bond-forming catalyst is one of
the most effective and versatile alkyne hydrothiolation cata-
lysts. Moreover, complex 1 is the first generally applicable
system that converts aromatic alkynes and aliphatic or aro-
matic thiols into cis-configured anti-Markovnikov-type vinyl
thioethers in excellent yields within a few minutes at 1208C,
in the presence of only 0.05 mol% of catalyst. In addition,
the alkyne hydrothiolation reaction is tolerant of a broad
range of functional groups, including ethers, amines, halides,
and nitrogen-containing heterocycles. Thus it demonstrates
the outstanding catalytic activity, selectivity, and hence, gen-
eral applicability of complex 1 in this process, making the
aminophosphine-based system the catalyst of choice for the
high-yielding synthesis of cis-configured anti-Markovnikov
adducts of type C through hydrothiolation of aromatic al-
kynes. On the other hand, branched Markovnikov-type ad-
dition products A were selectively formed if aliphatic al-
kynes were applied in the reaction. Mechanistic investiga-
tions indicate that a molecular mechanism operatates in the
alkyne hydrothiolation with initial formation of bis[1-(dicy-
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major product, although with a slightly reduced stereoselectivity.
This observation confirms the highly ligating properties of aromatic
alkynes and supports a nucleophilic attack mechanism, but also indi-
cates that complex 1 may be involved in the catalytic cycle (at least
in the first few cycles) in the absence of base. However, the forma-
tion of thiolate complexes of the type [(P
ACHTUNGTRENNUNG{(NC5H10)-
A
R
ACHTUNGTRENNUNG
panied by HCl liberation), or oligomeric palladium dithiolate com-
plexes cannot be excluded during catalysis.[7g] In contrast, their for-
mation seems possible because it was confirmed that complexes of
the type [(PACHTUNGRTENN{GU (NC5H10)ACHTUGNTERN(NUGN C6H11)2})2Pd(SR)2] gave the same catalytic ac-
tivity, as well as product selectivity, as complex 1.[13]
[13] It should be noted that the formation of dithiolate–bis(aminophos-
phine) complexes during catalysis, possibly by reaction of the hy-
dride thiolate complexes with another thiol molecule (accompanied
by formation of H2), is highly probable, given that
bis(phenylmethanethiolate)ACHTNUTRGNEUNG{bis[1-(dicyclohexylphosphinyl)piperidi-
ne]}palladium(II) (4), for example, was found to be an efficient
alkyne hydrothiolation catalyst, showing exactly the same activity
and product selectivity with aromatic and aliphatic substrates (even
in the absence of base) as 1, (2), and 3. Moreover, whereas H2 gen-
eration was indeed detected by gas chromatography in all reactions
tested (with both aliphatic and aromatic alkynes) with 1 in the pres-
ence of base, 2, and 3, no H2 formation was detected for reactions
with 1 in the absence of base (similar to the mechanism proposed by
Ogawa and co-workers).[7g]
[8] To be more precise, some rhodium- and iridium-based complexes
have been screened in the hydrothiolation of phenylacetylene with
thiophenol, of which some complexes were found to give the cis-
configured anti-Markovnikov adducts (C) as the major product (see:
S. Burling, L. D. Field, B. A. Messerle, K. Q. Vuong, P. Turner,
Dalton Trans. 2003, 4181). In addition, individual reports of related
reactions have been published, which selectively yield the cis-config-
ured vinyl sulfides C: Wang and co-workers, for example, reported
the synthesis of (Z)-1-alkenyl sufides through copper-catalyzed
alkyne hydrothiolation with diaryl disulfides in the presence of large
amounts of sodium hydroxymethylsulfinate as a radical initiator
(see: Z.-L. Wang, R.-Y. Tang, P.-S. Luo, C.-L. Deng, P. Zhong, J.-H.
Li, Tetrahedron 2008, 64, 10670). Another recently introduced reac-
tion is the copper-catalyzed decarboxylative thiolation of arylpro-
piolic acids, which selectively gives (Z)-vinyl sulfides in high yields
after 24 h at 908C in NMP and CsCO3 as the solvent and base (see:
S. Ranjit, Z. Duan, P. Zhang, X. Liu, Org. Lett. 2010, 12, 4134).
[9] a) J. L. Bolliger, C. M. Frech, Chem. Eur. J. 2010, 16, 4075; b) J. L.
Bolliger, C. M. Frech, Chem. Eur. J. 2010, 16, 11072; c) R. Gerber,
M. Oberholzer, C. M. Frech, Chem. Eur. J. 2012, 18, 2978; d) J. L.
Bolliger, M. Oberholzer, C. M. Frech, Adv. Synth. Catal. 2011, 353,
945; e) M. Oberholzer, R. Gerber, C. M. Frech, Adv. Synth. Catal.
2012, 354, 627.
[10] It is important to note that although very slow (ꢀ90% conversion
after 24 h at 1208C), the anti-Markovnikov addition products of
type C were selectively formed when phenylacetylene was allowed
to react with thiophenol or n-octanethiol in the presence of a base
under catalyst-free reaction conditions. Moreover, alkyne hydrothio-
lation reactions (catalyzed by 1) also proceed at ambient reaction
temperatures. For example, the addition of thiophenol to ethynyl-
benzene was complete after one hour; the product selectivity, how-
ever, was significantly lower, with 65% formation of the anti-Mar-
kovnikov addition product of type C, and hence is of very limited
practicability.
[14] For a comprehensive review article about the problem of distin-
guishing true homogeneous catalysis from soluble or other metallic
particle heterogeneous catalysis under reducing conditions, see: J. A.
Widegren, R. G. Finke, J. Mol. Catal. A: Chem. 2003, 198, 317.
[15] For details, see: a) M. A. Watzky, R. G. Finke, J. Am. Chem. Soc.
1997, 119, 10382; b) J. A. Widegren, M. A. Bennett, R. G. Finke, J.
Am. Chem. Soc. 2003, 125, 10301.
[16] PVPy is a palladium trap that can effectively inhibit catalysis when
nanoparticles are the catalytically active form of a catalyst. Never-
theless, it should be mentioned that Pd nanoparticles immobilized
on PVPy spheres have also been applied as the catalyst in Heck re-
actions. Therefore, this test is not definitive and neither conclusively
proves nor rules out either catalysis by the surface of Pd nanoparti-
cles or molecular Pd0 species, but can strongly support the conclu-
sions drawn from other tests. For details, see: K. Yu, W. Sommer,
M. Weck, C. W. Jones, J. Catal. 2004, 226, 101, and references there-
in.
[17] J. A. Creighton, D. G. Eadon, J. Chem. Soc. Faraday Trans. 1991, 87,
3881.
[18] The steric bulk of the aminophosphine-based ligands 1,1’,1’’-(phos-
phanetriyl)tripiperidine, 1,1’-(cyclohexylphosphanediyl)dipiperidine,
1-(dicyclohexylphosphanyl)piperidine, and tricyclohexylphosphine is
almost identical, as are their s-donor strengths (as indicated by the
CO stretching frequency of complexes of the type cis-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG[(PR3)-
(NC5H10)Mo(CO)4],[19] which is indicative of the electron density at
the metal centers).[9e] Thus, similar catalytic activities are expected
to be obtained when molecular mechanisms are the mode of action,
whereas a dramatic difference in their performance should be ob-
tained when palladium nanoparticles are involved in the catalytic
cycle (compare with results obtained for these catalysts in the Heck,
Suzuki, and Negishi reactions).[9a,b,e]
[19] A. L. Morris, J. T. York, J. Chem. Educ. 2009, 86, 1408.
[11] V. V. Grushin, C. Bensimon, H. Alper, Inorg. Chem. 1994, 33, 4804.
[12] This is in contrast to hydrothiolation reactions performed with aro-
matic alkynes, which are also highly regioselective in the absence of
a base and therefore still give the addition products of type C as the
Received: February 6, 2012
Revised: April 24, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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C. M. Frech et al.
Cis all round: Dichlorobis[1-(dicyclo-
hexylphosphanyl)piperidine]palladium,
Homogeneous Catalysis
[(PACTHNURTGENNUG{(NC5H10)ACHTUGNTNER(NUGN C6H11)2})2Pd(Cl)2], is
R. Gerber, C. M. Frech* . . . . &&&& — &&&&
a highly efficient alkyne hydrothiola-
tion catalyst and the first generally
applicable system that selectively gen-
erates cis-configured anti-Markovnikov
adducts in excellent yields within only
a few minutes at 1208C in the presence
of only 0.05 mol% of the catalyst (see
scheme).
Alkyne Hydrothiolation Catalyzed by
a Dichlorobis(aminophosphine)
Complex of Palladium: Selective
Formation of cis-Configured Vinyl
Thioethers
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www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!