Z-Selective Hydrothiolation of Racemic 1,3-Disubstituted Allenes: An Atom-Economic Rhodium-Catalyzed Dynamic Kinetic Resolution

Article abstract of DOI:10.1002/anie.201507623

A Z-selective rhodium-catalyzed hydrothiolation of 1,3-disubstituted allenes and subsequent oxidation towards the corresponding allylic sulfones is described. Using the bidentate 1,4-bis(diphenylphosphino)butane (dppb) ligand, Z/E-selectivities up to >99:1 were obtained. The highly atom-economic desymmetrization reaction tolerates functionalized aromatic and aliphatic thiols. Additionally, a variety of symmetric internal allenes, as well as unsymmetrically disubstituted substrates were well tolerated, thus resulting in high regioselectivities. Starting from chiral but racemic 1,3-disubstituted allenes a dynamic kinetic resolution (DKR) could be achieved by applying (S,S)-Me-DuPhos as the chiral ligand. The desired Z-allylic sulfones were obtained in high yields and enantioselectivities up to 96 % ee.

Full text of DOI:10.1002/anie.201507623

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International Edition: DOI: 10.1002/anie.201507623
German Edition: DOI: 10.1002/ange.201507623
Asymmetric Catalysis
Z-Selective Hydrothiolation of Racemic 1,3-Disubstituted Allenes: An
Atom-Economic Rhodium-Catalyzed Dynamic Kinetic Resolution
Adrian B. Pritzius and Bernhard Breit*
Abstract: A Z-selective rhodium-catalyzed hydrothiolation of
1,3-disubstituted allenes and subsequent oxidation towards the
corresponding allylic sulfones is described. Using the bidentate
1,4-bis(diphenylphosphino)butane (dppb) ligand, Z/E-selec-
tivities up to > 99:1 were obtained. The highly atom-economic
desymmetrization reaction tolerates functionalized aromatic
and aliphatic thiols. Additionally, a variety of symmetric
internal allenes, as well as unsymmetrically disubstituted
substrates were well tolerated, thus resulting in high regiose-
lectivities. Starting from chiral but racemic 1,3-disubstituted
allenes a dynamic kinetic resolution (DKR) could be achieved
by applying (S,S)-Me-DuPhos as the chiral ligand. The desired
Z-allylic sulfones were obtained in high yields and enantiose-
lectivities up to 96% ee.
R
ecently we described several highly selective methods for
Scheme 1. Rhodium-catalyzed hydrothiolation of allenes and bioactive
the addition of pronucleophiles to terminal allenes[1,2] and
alkynes,[3] which can be regarded as atom-economic[4] alter-
natives to known allylic substitutions[5] and allylic oxida-
tions.[6] In this respect we developed the first asymmetric
hydrothiolation[7] of free aromatic and aliphatic thiols to
terminal allenes to obtain branched allylic thioethers, and
after oxidation, the corresponding allylic sulfones with
excellent regio- and enantioselectivities (Scheme 1).[8]
À
compounds including a-stereogenic C S bonds. m-CPBA=m-chloro-
perbenzoic acid.
selectivity compared with naphthalene-2-thiol (1) suggested
that steric reasons are important for a high Z selectivity.
Accordingly, Z selectivities increased when going from
p-methylthiophenol (3; 74:26) to o-methylthiophenol (5;
91:9). When using the sterically demanding naphthalene-1-
Since many bioactive compounds such as Montelukast,[9a]
Hepatitis C virus NS3/4A inhibitors,[9b] and others[9c–e] include
thiol, the allylic sulfone
6 was obtained in excellent
À
a-stereogenic C S bonds, the synthesis of higher-substituted
Z/E selectivity of 93:7.
allylic thioethers[10,11] and sulfones[12,13] could be seen as an
important synthetic tool in organic chemistry[14,15] and drug
synthesis. Furthermore, a-stereogenic allylic Z-configured
thioethers showed activity against allergic asthma and other
immediate hypersensitivity diseases.[16] Thus we were curious
to see whether we could transfer our initial methodology to
1,3-disubstituted allenes. Herein we describe the first rho-
dium-catalyzed, highly Z-selective and, if desired, asymmet-
ric, hydrothiolation of 1,3-disubstituted allenes. After opti-
mization of the reaction conditions using naphthalene-2-thiol
and nona-4,5-diene with addition of p-toluenesulfonic acid
(PTSA), the sulfone 1 was obtained in 80% yield and 91:9
Z selectivity (Table 1).[17–19] Furthermore, we investigated the
scope of different aromatic thiols for this hydrothiolation.
Applying thiophenol as a suitable nucleophile the sulfone 2
was obtained in moderate Z/E selectivity of 78:22. The lower
A number of functionalized thiophenol derivatives were
tolerated (7–12; Table 1). Especially, sulfones with electron-
withdrawing substituents gave excellent Z selectivities with
up to > 98:2 (77%), for example, when using p-fluorothio-
phenol (8). Also other electron-deficient thiols such as
p-chloro- and p-bromothiophenol resulted in good selectiv-
ities and high yields of up to 86% (9 and 10). In addition to
this, a free phenol function is well tolerated (11). We next
focused on the use of aliphatic thiols. To our surprise, the use
of (4-methoxyphenyl)methanethiol gave the product 13 with
an E selectivity of 70:30. Conversely when 2,2,2-trifluoro-
ethanethiol was used the sulfone 14 was obtained exclusively
in the Z configuration. Also a homobenzyl- and furfurylmer-
captane were compatible with this methodology where high
Z selectivities of up to 91:9 could be achieved (15 and 16).
Next we focused on the scope of the allene coupling
partners (Table 2). Symmetrically alkylated allenes were
found to be suitable for this reaction and Z/E selectivities of
up to 93:7 were obtained (17 and 18). Even cyclic internal
allenes were tolerated. The coupling worked particularly well
with cyclotrideca-1,2-diene, where the desired product 20 was
obtained in a high yield with a good Z selectivity of 92:8. By
applying cyclonona-1,2-diene, this methodology gave access
[*] A. B. Pritzius, Prof. Dr. B. Breit
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507623.
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Table 1: Scope with respect to aromatic and aliphatic thiols with
Table 2: Scope with respect to different 1,3-disubstituted allenes using
nona-4,5-diene.
p-fluorothiophenol.
[a] Yield of the isolated isomeric mixtures. [b] Z/E selectivity of the
sulfone determined by 1H NMR analysis of the crude reaction mixture.
[c] Regioselectivity of the sulfone determined by 1H NMR analysis of the
crude reaction mixture; only allylic products detected. [d] Z/E selectivity
of major regioisomer.
Table 3: Asymmetric hydrothiolation of 1,3-disubstituted allenes.
[a] Yield of the isolated isomeric mixtures. [b] Z/E selectivity of the
sulfone determined by 1H NMR analysis of the crude reaction mixture.
cod=1,5-cyclooctadiene, dppb=1,4-bis(diphenylphosphino)butane.
to the unique functionalized medium-ring-sized product 19,
exclusively with the Z configuration. Furthermore, unsym-
metrical 1,3-disubstituted allenes were applied (21–23). As
the reaction was performed with nona-1,2-dien-1-ylbenzene,
21 was obtained as a single regioisomer, showing exclusively
E configuration.[20] In addition to this, we also performed the
reaction using nona-1,2-dien-1-ylcyclohexane. The a-cyclo-
hexylsulfone 22 was obtained with a high Z selectivity of
89:11 and a regioselectivity of 76:24. Even a free alcohol
function is well tolerated (23).
To explore whether this methodology allows the prepa-
ration of enantiomerically enriched thioethers and sulfones
starting from racemic 1,3-disubstituted allenes, a screening of
chiral ligands was undertaken. As a result, (S,S)-Me-DuPhos
led to the desired product 1a albeit a higher catalyst loading
was needed (Table 3). Control experiments revealed that this
process occurs as a dynamic kinetic resolution.[17] Thus, yields
up to 83% and enantioselectivities up to 96% ee were
achieved. When utilizing cyclonona-1,2-diene, the fully
Z-configured product 19a was obtained in good yield, albeit
with only a moderate ee value. However when the 13-
[a] Yield of the isolated isomeric mixtures. [b] Z/E selectivity of the
sulfone determined by 1H NMR analysis of the crude reaction mixture.
[c] The ee value was determined by HPLC analysis using chiral stationary
phase. [d] Using 1.0 mol% [{Rh(cod)Cl}2] and 2.0 mol% (S,S)-Me-
DuPhos, sulfone 1a was obtained in 57% yield, 95:5 Z/E selectivity, and
91% ee. [e] Absolute configuration was determined by single-crystal
X-ray analysis of 1a.[17]
membered cyclic allene was applied the desired sulfone 20a
could be achieved with a Z/E selectivity of 91:9 in 80% ee.
To gain first insights into the mechanism for this dynamic
kinetic resolution we synthesized an enantioenriched 1,7-
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diphenylhepta-3,4-diene (62% ee). By applying the presented
reaction conditions (in absence of thiol) we observed
a complete racemization of the allene within less than
1 hour (Scheme 2).[21,22] Additionally, kinetic experiments
for the catalysis were pursued, and gave a yield of only
27% within the first hour, thus showing that the hydro-
thiolation is by far slower than the racemization of the allene.
Furthermore, the hydrothiolation with the enantioenriched
1,7-diphenylhepta-3,4-diene and p-fluorothiophenol led to
the product 18a with apparently the same results as when
racemic allene was applied. Based on these experiments we
propose the following mechanism (Scheme 3).[23] An oxida-
Scheme 4. 1,3-syn-Chirality transfer by a [2,3] Evans–Mislow rearrange-
ment. [a] Z/E Selectivity determined by 1H NMR spectroscopy of the
crude reaction mixture of the corresponding sulfone. [b] The ee value
was determined by HPLC analysis using chiral stationary phase. [c] The
ee value of 24 was determined after oxidation to sulfone. [d] Yield of
isolated product. [e] Absolute configuration was determined by com-
parison of the specific rotation of the literature known reduced
alcohol.[26]
accordance with previous reports, this transformation pro-
ceeded by a 1,3-syn-chirality transfer to generate 25 with an
enantioselectivity of 86% ee in 74% yield.[25b]
To conclude, we have found the first rhodium-catalyzed
atom-economic addition of free thiols to 1,3-disubstituted
allenes. By using dppb as bidentate ligand and
30 mol% PTSA as an additive, the reaction led
to the desired higher substituted allylic sulfones
with excellent Z selectivities and high yields. The
reaction tolerates a broad variety of aromatic
and aliphatic thiols. Furthermore, a wide scope
of different symmetrical and unsymmetrical
acyclic and cyclic 1,3-disubstituted allenes were
efficient reaction partners. Starting from racemic
internal allenes with a rhodium(I)/(S,S)-Me-
DuPhos catalyst a dynamic kinetic resolution
occurred, thus furnishing the corresponding
Z-allylic thioethers and sulfones in high enan-
tioselectivities. Extension of this powerful meth-
odology to more complex systems is ongoing in
our group.
Scheme 2. Racemization experiment of enantioenriched 1,7-diphenyl-
hepta-3,4-diene.[17,21,22]
Acknowledgements
This work was supported by the DFG, the
Scheme 3. Mechanistic proposal for the highly Z-selective dynamic kinetic resolu-
International Research Training Group “Cata-
lysts and Catalytic Reactions for Organic Syn-
thesis” (IRTG 1038), the Fonds der Chemischen
Industrie, and the Krupp Foundation. We thank
tion.[17]
tive addition of the thiol forms the rhodium(III) species A.[7h]
The following hydrometalation of the racemized allene,
forming the Z double bond (B),[23a] will deliver the
s-allylcomplex C1 which might be in equilibrium with the
p-allyl isomer C2. The product is likely to be formed either by
reductive elimination or by an intermolecular attack of
a second thiolate (D).
To demonstrate the synthetic utility of this methodology,
we subjected the thioether 24 to the reaction conditions of an
Evans–Mislow rearrangement (Scheme 4).[24] To our delight,
when using 2.0 equivalents of m-CPBA, the in situ generated
sulfoxide directly underwent a [2,3] sigmatropic rearrange-
ment to form the pure E-configurated allylic alcohol 25.[25a] In
Umicore, BASF, and Wacker for generous gifts of chemicals.
Ina Rohleff and Dr. Daniel Kratzert are acknowledged for
skillful technical assistance and X-ray analysis.
Keywords: allenes · asymmetric catalysis ·
dynamic kinetic resolution · rhodium · sulfones
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[17] See the Supporting Information for further details.
[18] Trisubstituted allenes, subjected to the given conditions, did not
furnish any product.
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À
[19] Sulfonic acids are known for their ability to generate [Rh] H
species. Thus, we assume the formal oxidative addition of the
thiol is facilitated by the PTSA. For recent literature in this field
see: Y. Yang, E. G. Moschetta, R. M. Rioux, ChemCatChem
2013, 5, 3005 – 3013.
[20] We assumed that under the given reaction conditions an acid-
catalyzed isomerization via the benzylic cation led to the
thermodynamically favored E isomer. See the Supporting Infor-
mation for a plausible mechanism.
[21] We propose the racemization of 1,3-disubstituted allenes as
À
follows: After a hydrometalation by a given [Rh] H species
(generated either by PTSA or via oxidation of ethanol) a s-p-
s allyl-rhodium-isomerization might take place. For recent
[25] a) To prevent an oxidation towards the sulfone the reaction must
be performed at very low temperature. b) A plausible explan-
ation for the slightly erosion of the ee value might be the fact that
the minor E isomer of 24 forms the (S)-allyl alcohol 25.
[26] S. Ohta, Bull. Chem. Soc. Jpn. 1986, 59, 1181 – 1188.
publication of
a similar mechanism, see: D. N. Tran, N.
Cramer, Angew. Chem. Int. Ed. 2013, 52, 10630 – 10634;
Angew. Chem. 2013, 125, 10824 – 10828. For the first example
of a dynamic kinetic resolution of allenes, see: J. Deska, C.
del Pozo Ochoa, J. E. Bäckvall, Chem. Eur. J. 2010, 16, 4447 –
4451.
[22] Since a racemization of the allene took place even in the absence
Received: August 17, 2015
À
of PTSA we assume that a formation of a [Rh] H species,
Published online: September 29, 2015
15822 www.angewandte.org
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Angew. Chem. Int. Ed. 2015, 54, 15818 –15822