Asymmetric rhodium-catalyzed addition of thiols to allenes: Synthesis of branched allylic thioethers and sulfones

Article abstract of DOI:10.1002/anie.201411402

A highly regio- and enantioselective hydrothiolation of terminal allenes, a reaction which fulfills the criteria of atom economy, is reported. Applying two chiral rhodium catalyst systems, a wide variety of thiols and allenes could be coupled. Oxidation g

Full text of DOI:10.1002/anie.201411402

Angewandte
Chemie
DOI: 10.1002/anie.201411402
Asymmetric Catalysis
Asymmetric Rhodium-Catalyzed Addition of Thiols to Allenes:
Synthesis of Branched Allylic Thioethers and Sulfones**
Adrian B. Pritzius and Bernhard Breit*
Abstract: A highly regio- and enantioselective hydrothiolation
of terminal allenes, a reaction which fulfills the criteria of atom
economy, is reported. Applying two chiral rhodium catalyst
systems, a wide variety of thiols and allenes could be coupled.
Oxidation gave access to the corresponding allylic sulfones in
essentially enantiomerically pure form. The reaction tolerates
a variety of functional groups and labeling experiments gave
first insights into the reaction mechanism of this new method-
ology.
Furthermore, a-chiral thioethers and sulfones are impor-
tant structural motifs in natural products and drugs such as
Dorzolamide,[12a] Montelukast,[12b] Hepatitis C virus NS3
inhibitors,[12c] and others[13] (Figure 1). The thioether spongia-
cysteine showed antimicrobial activity against rice blast
fungus Pyricularia oryzae.[14] Allylic thioethers, and especially
the diallylsulfide, are known for their chemopreventive
properties in several tumor models.[15]
T
he development of new asymmetric carbon–heteroatom
bond-forming reactions which fulfill the criteria of atom
economy are of immanent importance to the evolution of
chemical synthesis.[1] In this respect we recently developed
atom-economic rhodium-catalyzed addition reactions of
pronucleophiles to allenes[2] and alkynes,[3] which could be
regarded as an atom-economic alternative to the metal-
catalyzed allylic substitution[4] and allylic oxidation.[5] These
reactions allow highly branched regio- and enantioselective
À
À
À
formation of C O, C N, and C C bonds and hence, give
direct access to a number of synthetically and medicinally
interesting building blocks.[6,7] With the goal to further extend
the synthetic utility of this methodology, we became inter-
ested in developing a hitherto unknown asymmetric addition
of thiols to allenes, which would enable a direct atom-
economic entry to a-chiral thioethers[8] and after oxidation, to
a-chiral sulfones,[9] both of which are well-known as valuable
building blocks in organic synthesis (Scheme 1).[10,11]
Figure 1. a-Chiral thioethers and sulfones in drugs and natural prod-
ucts.
Although there are several examples for the hydrothio-
[16]
À
lation of unsaturated C C bonds towards vinylic thioethers,
the direct hydrothiolation of terminal allenes to the branched
allylic products is rare.[17] Herein we report the first highly
enantioselective rhodium-catalyzed atom-economic hydro-
thiolation of terminal allenes with free thiols towards
branched allylic thioethers and their corresponding sulfones.
In initial experiments with cyclohexylallene and thiophenol,
we discovered that when employing the nonchiral DPEphos
ligand (L1) the title reaction did indeed proceed, thus yielding
the branched allylic thioether 1a in good regioselectivity but
with moderate yield (Table 1, entry 1). After further optimi-
zation (entry 2–5), we were delighted to identify (R)-Difluor-
phos (L5) as the best ligand, which performed with increased
yield (92%), regioselectivity (> 99%), and a satisfying
ee value of 92% (entry 6). To avoid an isomerization towards
the linear isomer, we decided to generate the allylic sulfone
2a by performing an oxidative work-up with m-CPBA.[18,19]
With these optimal catalysts and reaction conditions in
hand, we next focused on the scope of thiols (Table 2). We
were pleased to find that a number of thiophenol derivatives
were excellent reaction partners and gave the corresponding
allylic sulfones in good to excellent yields, along with high
Scheme 1. Rhodium-catalyzed hydrothiolation of terminal allenes.
m-CPBA=m-chloroperbenzoic acid.
[*] A. B. Pritzius, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie, Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
[**] This work was supported by the DFG, the International Research,
Training Group “Catalysts and Catalytic Reactions for Organic,
Synthesis” (IRTG 1038), the Fonds der Chemischen Industrie, and
the Krupp Foundation. We thank Umicore, BASF, and Wacker for
generous gifts of chemicals. Ina Rohleff is acknowledged for skillful
technical assistance.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411402.
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Table 1: Ligand screening and optimization.
Table 2: Scope of aromatic thiols with cyclohexylallene.
Entry
Ligand
1a/1bE,Z/1c/1d[a]
Yield [%][b]
ee [%][c]
1
2
3
4
1
2
3
4
4
5
82:18:0:0
>99:1:0:0
70:30:0:0
59:39:2:0
80:20:0:0
>99:1:0:0
52
77
59
62
74
92
rac.
4
62
93
90
92
5[d]
6[e]
[a] Regioselectivity determined by 1H NMR analysis of the crude reaction
mixture. [b] Combined yield of all product isomers. [c] Determined by
HPLC analysis using a chiral stationary phase. [d] Reaction performed in
pure EtOH, 0.2m, 1.2 equiv allene, 108C, 16 h, 1.0 mol% [{Rh(cod)Cl}2],
2.0 mol% ligand L4 and 10 mol% PTSA·H2O followed by an oxidative
work-up with m-CPBA. [e] Reaction performed in pure EtOH, 0.2m,
1.2 equiv allene, À158C, 16 h, 1.0 mol% [{Rh(cod)Cl}2], 2.0 mol%
ligand L5 followed by an oxidative work-up with m-CPBA. cod=1,5-
cyclooctadiene, DCE=1,2-dichloroethane.
[a] Combined yield of all product isomers. [b] Regioselectivity deter-
mined by 1H NMR analysis of crude reaction mixture. [c] The ee value
was determined by HPLC analysis using a chiral stationary phase.
[d] Absolute configuration was determined by comparison of the specific
rotation with literature data.[9a] [e] After trituration with n-pentane.
Moreover, aliphatic thiols were explored. Since the
aliphatic thioethers are more stable, oxidative work-up was
considered unnecessary in these cases. However, under the
standard reaction conditions with L5, the reaction completely
failed. Fortunately, by applying more forcing conditions and
employing ligand L4 good yields and enantioselectivities
could be obtained (Table 4). The highest ee value of 96% was
observed with 2-mercaptoethanol.
A preliminary investigation of the mechanism was done
by deuterium-labeling experiments using [D1]naphthalene-2-
thiol. Based on earlier results with carboxylic acids and
anilines we expected deuterium incorporation at all positions
of the double bond (Scheme 2).[6a,b]
regio- and enantioselectivities (2a–k). For the o-methylthio-
phenol, the ee value fell slightly to 87% (2b), while excellent
enantioselectivities of 94% ee each were obtained for m- and
p-methylthiophenol (2c–d). While the reaction with fluorine,
chlorine, and bromine substituents proved compatible, a sig-
nificant drop in enantioselectivity occurred when applying p-
nitro-substituted thiophenol (2e). Conversely, an electron-
donating substituent such as the p-methoxythiophenol gave
excellent results in both yield and selectivities (2j). Upon
trituration with n-pentane, the sulfone 2j could be obtained in
essentially enantiomerically pure form (99% ee) in good yield
(78%), thus demonstrating the practicality of this new
method for the preparation of enantiopure allylic sulfones.
Additionally, naphthalene-2-thiol was an excellent substrate
(2k). The naphthalene-2-thiol was chosen as the model thiol
for the allene screening, since we hoped to increase the
chances to obtain crystalline products.
As expected, a-alicyclic allenes were suitable coupling
partners in the title reaction, and led to the corresponding
allylic sulfones in high yields and enantioselectivities (4–5;
Table 3). Linear-alkyl-substituted allenes also behaved well in
terms of yield and enantioselectivties (6–8). In addition,
a benzoate, a silylether and even a free hydroxy group were
well-tolerated (9–12).
Scheme 2. Deuterium-labeling experiments with [D1]naphthalene-2-
thiol. a) [{Rh(cod)Cl}2] (1.0 mol%), (R)-Difluorphos (2.0 mol%), sol-
vent 0.2m, À158C, 16 h, then work-up with m-CPBA. Incorporation of
1
deuterium was determined by H NMR spectroscopy and mass spec-
trometry (see the Supporting Information for further details).
2
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Table 3: Scope of terminal allenes using naphthalene-2-thiol.
Scheme 3. Plausible mechanism for the rhodium-catalyzed hydrothiola-
tion.
Scheme 4. Functionalization of branched allylic sulfones and thioeth-
ers. a) [Rh(CO)2acac] (0.5 mol%), 6-DPPon (10 mol%), H2/CO (1:1),
20 bar, toluene, 808C, 20 h, linear/branched >98%, yield: 94%.
b) DCE, m-CPBA, 808C, 16 h, yield: 89%, d.r.=2.3:1.0. c) Et2O, SOCl2,
yield: 86% d) Et2O, LiAlH4, HCl 1m, yield: 78%. acac=acetylaceto-
nate.
[a] Combined yield of all product isomers. [b] Regioselectivity deter-
mined by 1H NMR analysis of crude reaction mixture. [c] The ee value
was determined by HPLC analysis using a chiral stationary phase.
Bz=benzoyl, TBS=tert-butyldimethylsilyl.
Table 4: Asymmetric hydrothiolation with aliphatic thiols.
To explore the possible functionalization of the allylic
sulfones, we performed a variety of different transformations
(Scheme 4). The hydroformylation of the terminal double
bond using our self-assembling 6-diphenylphosphinopyridone
(6-DPPon) hydroformylation catalyst led to the aldehyde 16
in an excellent linear/branched selectivity of greater than
98% with a 94% yield.[21] Reaction with m-CPBA furnished
the corresponding epoxide 17 in good yield of 89% (d.r. =
2.3:1.0). Additionally, the functionalization of the thioether
part was explored. Hence, the primary alcohol 13 was
successfully transformed into the corresponding chloride 18
in 86% yield by using thionyl chloride. Reduction of the ethyl
ester 15 with LiAlH4 resulted in thioether 19 with 78% yield.
In conclusion, we have developed a highly regio- and
enantioselective hydrothiolation of terminal allenes which
fulfills the criteria of atom economy. Applying two chiral
rhodium catalyst systems, a wide variety of thiols and allenes
could be coupled. Oxidation gave access to the corresponding
allylic sulfones in enantiomerically pure form. The reaction
tolerates a variety of functional groups and labeling experi-
ments gave first insights into the reaction mechanism of this
new methodology. Further mechanistic investigations and
extension of the methodology to more complex thiols and
allenes are ongoing.
[a] Yield of isolated product. [b] Regioselectivity determined by 1H NMR
analysis of crude reaction mixture. [c] The ee value was determined by
HPLC analysis using a chiral stationary phase. [d] Starting from the
corresponding 3-mercaptopropionic acid an in situ esterification oc-
curred, where ee values of 86% were obtained. PTSA=p-toluenesulfonic
acid.
Interestingly, we found deuterium incorporation exclu-
sively at the 2-position of the allylic sulfone, and it suggests
the mechanism depicted in Scheme 3. An oxidative addition
of the thiol forms the RhIII species A.[16j] Here, in contrast to
previous observations, an exclusive hydrometalation of the
more substituted double bond of the allene will deliver the p-
allyl complex B which might be in equilibrium with the s-allyl
isomer C.[20] The product is likely to be formed from B either
by reductive elimination, or by an intermolecular attack of
a second thiolate.
Received: November 25, 2014
Published online: && &&, &&&&
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Keywords: asymmetric catalysis · enantioselectivity · ethers ·
rhodium · sulfur
.
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Chem. 2005, 117, 6976 – 6986; b) B. Breit, W. Seiche, J. Am.
Chem. Soc. 2003, 125, 6608 – 6609; c) W. Seiche, A. Schusch-
kowski, B. Breit, Adv. Synth. Catal. 2005, 347, 1488 – 1494; d) U.
Gellrich, W. Seiche, M. Keller, B. Breit, Angew. Chem. Int. Ed.
2012, 51, 11033 – 11038; Angew. Chem. 2012, 124, 11195 – 11200;
e) V. Agabekov, W. Seiche, B. Breit, Chem. Sci. 2013, 4, 2418 –
2422; f) U. Gellrich, D. Himmel, M. Meuwly, B. Breit, Chem.
Eur. J. 2013, 19, 16272 – 16281.
[17] For hydrothiolation of special heteroatom-substituted terminal
allenes and carbonylative hydrothiolations, see: a) W.-J. Xiao, H.
Alper, J. Org. Chem. 1999, 64, 9646 – 9652; b) W.-J. Xiao, G.
Vasapollo, H. Alper, J. Org. Chem. 1998, 63, 2609 – 2612; c) W.
Klop, P. A. A. Klusener, L. Brandsma, Recl. Trav. Chim. Pays-
Bas 1984, 103, 27 – 29; d) D. Goeppel, I. Mꢅnster, R. Brꢅckner,
Tetrahedron 1994, 50, 3687 – 3708.
[18] a) P. Brownbridge, S. Warren, J. Chem. Soc. Perkin Trans. 1 1976,
2125 – 2132; b) E. Schaumann, A. Kirschning, F. Narjes, J. Org.
Chem. 1991, 56, 717 – 723.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
A. B. Pritzius, B. Breit*
&&& — &&&
Asymmetric Rhodium-Catalyzed Addition
of Thiols to Allenes: Synthesis of
Branched Allylic Thioethers and Sulfones
All about S: The rhodium-catalyzed
valuable branched allylic thioethers and
sulfones in high regio- and enantioselec-
tivity. By varying the ligand and reaction
conditions both aromatic and aliphatic
thiols were tolerated.
enantioselective hydrothiolation of ter-
minal monosubstituted allenes with aro-
matic and functionalized aliphatic thiols
permits the atom-economic synthesis of
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!