Iridium-Catalyzed Asymmetric Hydrogenation of Benzo[b]thiophene 1,1-Dioxides

Article abstract of DOI:10.1002/anie.201701409

An efficient iridium-catalyzed asymmetric hydrogenation of substituted benzothiophene 1,1-dioxides is described. The use of iridium complexes with chiral pyridyl phosphinite ligands provides access to highly enantiomerically enriched sulfones with substituents at the 2- and 3-position. Sulfones of this type are of interest as core structures of agrochemicals and pharmaceuticals. Moreover, they can be further reduced to chiral 2,3-dihydrobenzothiophenes.

Full text of DOI:10.1002/anie.201701409

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201701409
German Edition: DOI: 10.1002/ange.201701409
Asymmetric Catalysis
Iridium-Catalyzed Asymmetric Hydrogenation of Benzo[b]thiophene
1,1-Dioxides
Paolo Tosatti and Andreas Pfaltz*
Abstract: An efficient iridium-catalyzed asymmetric hydro-
genation of substituted benzothiophene 1,1-dioxides is de-
scribed. The use of iridium complexes with chiral pyridyl
phosphinite ligands provides access to highly enantiomerically
enriched sulfones with substituents at the 2- and 3-position.
Sulfones of this type are of interest as core structures of
agrochemicals and pharmaceuticals. Moreover, they can be
further reduced to chiral 2,3-dihydrobenzothiophenes.
Following our studies of iridium N,P complexes as
catalysts for the asymmetric hydrogenation of furans and
benzofurans,[3b] we investigated benzothiophenes as sub-
strates, but without success. Consequently, we decided to
study benzothiophene 1,1-dioxides as surrogates that could be
converted into chiral 2,3-dihydrobenzothiophenes by reduc-
tion of the sulfone group. We reasoned that the reduced
aromatic character and the absence of sulfur lone pairs, which
could inhibit the catalyst by coordination, would facilitate
hydrogenation. Moreover, Andersson and co-workers had
demonstrated that unsaturated sulfones are suitable sub-
strates for iridium-catalyzed asymmetric hydrogenation.[6]
Furthermore, chiral 2,3-dihydrobenzothiophene 1,1-dioxides
have found interest in agrochemistry and medicinal chemistry
as herbicides, insecticides,[7] and inhibitors of the hypoxia-
inducible factor HIF2a.[8]
T
he asymmetric hydrogenation of heteroaromatic com-
pounds has recently received much attention as an attractive,
straightforward method for the synthesis of chiral hetero-
cyclic compounds from readily available precursors.[1] Despite
substantial progress in this area, efficient enantioselective
catalysts for heteroaromatic substrates are still scarce.
During the last decade, several highly enantioselective
hydrogenation methods for indoles[1,2] and benzofurans[1,3]
have been reported. However, related benzothiophenes
have rarely been investigated as substrates. Only recently,
Glorius and co-workers reported an efficient chiral Ru
catalyst[4] for the enantioselective reduction of thiophenes
and benzothiophenes,[5] among other heteroaromatic com-
pounds[1f] (Scheme 1). Although this work marks a break-
through, the scope of the transformation with respect to
possible substrates is rather limited, especially in the case of
benzothiophenes, as only primary alkyl substituents at either
the 2- or the 3-position are tolerated.
For initial studies, we chose 2-phenylbenzothiophene 1,1-
dioxide (1a) as a test substrate for the screening of a series of
Ir catalysts developed by our research group (Table 1).[9]
Under a H2 atmosphere of 50 bar, the catalysts gave only
Table 1: Catalyst screening for the asymmetric hydrogenation of benzo-
thiophene 1,1-dioxide 1a.
Entry
L
Conv. [%][a] ee [%][b]
Entry
L
Conv. [%][a] ee [%][b]
1
2
3
4
5
6
7
L1 45
L2 70
L3 29
L4 68
L5 97
L6 31
L7 69
32
24
74
24
97
83
74
8
9
L8
L9
60
23
32
66
6
38
32
35
54
42
91
10
11
12
13
14
L10
L11
L12 >99
L13
L14
29
90
[a] Conversion was determined by GC analysis (see the Supporting
Information for details). [b] The ee value was determined by HPLC
analysis. BArF =tetrakis(3,5-bis(trifluoromethyl)phenyl)borate,
cod=1,5-cyclooctadiene, Cy=cyclohexyl.
Scheme 1. Enantioselective reduction of benzothiophenes and pro-
posed asymmetric hydrogenation of benzothiophene 1,1-dioxides.
[*] Dr. P. Tosatti, Prof. Dr. A. Pfaltz
Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: andreas.pfaltz@unibas.ch
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201701409.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
moderate to low conversion with the exception of Ir
complexes based on ligands L5, L12, and L14 (entries 5, 12,
and 14). N,P ligands with alkyl-substituted phosphine or
phosphinite units showed higher activity than their aryl-
substituted analogues (entries 1, 3, 5, and 13 vs. entries 2, 4, 6,
and 14, respectively). Pleasingly, the most active catalyst,
[Ir(cod)L5]BArF, also induced the highest enantioselectivity,
affording 2a with 97% ee (Table 1, entry 5).
With a promising catalyst in hand, we briefly tested six
analogues of ligand L5 with different substituents on the
phosphorus atom (Cy, tBu) and the pyridine ring (H, Me, Ph).
The presence of both a di-tert-butyl phosphinite unit and
a phenyl group on the pyridine ring proved to be essential for
high conversion and enantioselectivity (see the Supporting
Information). Lowering of the hydrogen pressure from 50 to
10 bar reduced the conversion from 97 to 90% with no
apparent effect on the enantioselectivity. Therefore, the
original conditions specified in Table 1 were chosen for
further studies with a variety of 2- and 3-aryl benzothiophene
1,1-dioxides as substrates (Table 2).
a higher catalyst loading (2 mol%), full conversion and
97% ee were achieved. The o-Me derivative 1d, on the other
hand, gave only low conversion even with 2 mol% of the
catalyst, although the enantioselectivity remained high.
Apparently, the reaction is rather sensitive to steric hindrance
in the 2-position. The para-fluoro and para-methoxy deriva-
tives 1e and 1 f both reacted with high enantioselectivity. As
compared to 1a, the electron-withdrawing fluorophenyl
group in 1e lowered the reactivity, whereas the opposite
effect was observed for the para-methoxyphenyl derivative
1 f.
The same catalyst [Ir(cod)L5]BArF also performed well in
the asymmetric hydrogenation of analogous 3-aryl-substi-
tuted substrates. Benzothiophene 1,1-dioxides 1g and 1h
reacted with high levels of conversion and enantioselectivity
comparable to those observed for the 2-substituted isomers
1a and 1b. However, the increased steric hindrance of meta-
and ortho-tolyl substituents had a less dramatic effect for
3-aryl benzothiophene 1,1-dioxides. In fact, compound 1i
reacted smoothly in the presence of 1 mol% of the catalyst to
afford 2i with 92% conversion and 98% ee. Even compound
First, substrate 1a was compared with para-, meta-, and
ortho-tolyl analogues. A p-Me group (substrate 1b) had only
marginal effects on conversion (97 vs. 95%) and enantiose-
lectivity (97 vs. 98% ee), whereas a m-Me group (substrate
1c) slowed down the reaction significantly. However, at
1j,
bearing
an
ortho-tolyl
substituent
at
the
3-position, was reduced with 84% conversion and 94% ee,
although in this case an increased catalyst loading (2 mol%)
was necessary. Again, lower conversion was observed for the
electron-poor substrate 1k than for the electron-rich ana-
logue 1l, as well as somewhat lower enantioselectivity.
To examine the reactivity of alkyl-substituted substrates,
we subjected 2-methylbenzothiophene 1,1-dioxide (3a) to
hydrogenation under the standard conditions used for sub-
strates 1a–l (Table 3). Although high conversion into 4a
(97%) was observed, the level of enantioselectivity induced
by the catalyst based on ligand L5 was disappointing (entry 5).
Consequently, we screened several other iridium complexes
to identify a more selective catalyst for alkyl-substituted
substrates (Table 3). Whereas most catalysts reduced 3a with
poor conversion and enantioselectivity, [Ir(cod)L14]BArF
displayed high reactivity, affording product 4a with 99%
Table 2: Investigation of the scope of the reaction.[a]
Table 3: Catalyst screening for the asymmetric hydrogenation of benzo-
thiophene 1,1-dioxide 3a.
Entry
L
Conv. [%][a] ee [%][b]
Entry
L
Conv. [%][a] ee [%][b]
1
2
3
4
5
6
7
L1
L2
L3
9
20
25
13
28
8
9
L8 14
L9 10
L10 16
L11 25
L12 58
4
20
46
2
3
37
42
17
10
11
12
13
14
L4 >99[c]
92 (S)[d]
L5
L6
L7
97
9
3
5
36
11
L13
9
L14 99
[a] Reactions were carried out on a 33 mmol scale. Conversion was
determined by GC analysis and ee values were determined by HPLC
analysis. [b] The S absolute configuration was determined by single-
crystal X-ray analysis.[10] [c] The reaction was carried out with 2 mol% of
[Ir(cod)L5]BArF.
[a] Conversion was determined by GC analysis. [b] The ee value was
determined by HPLC analysis. [c] The reaction was also scaled up to
a 0.55 mmol scale (yield of the isolated product: 99%). [d] The S
absolute configuration was assigned on the basis of the optical rotation
of 5a (see Scheme 2).
2
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
conversion but poor enantioselectivity (entry 14). Surpris-
sterically hindered 2-isopropyl derivative 3e showed even
ingly, the Ir complex based on ligand L4, which differs from
L5 only in the size of the carbocycle fused to the pyridine ring,
turned out to be the most active and selective catalyst, giving
full conversion with 92% ee (entry 4). Further optimization of
the reaction conditions (see the Supporting Information)
revealed that for substrate 3a full conversion with slightly
higher stereoselectivity (93% ee) was possible in only 1 h at
a H2 pressure of 2 bar. Furthermore, variation of the
substituents on ligand L4 showed that both tert-butyl groups
on the phosphorus atom and the phenyl group flanking the
pyridine nitrogen atom are essential for good results, thus
paralleling the observations made earlier with L5 (see the
Supporting Information).
lower reactivity and was reduced with only 50% ee. Higher
enantioselectivity was observed with the catalyst derived from
ligand L5. When substrate 3e was hydrogenated with 2 mol%
of [Ir(cod)L5]BArF under 50 bar of hydrogen, 75% conver-
sion and an ee value of 84% were observed after 24 h.
Notably, substrate 3 f containing a protected alcohol func-
tionality displayed exceptionally high reactivity, being fully
reduced within 1 h under 2 bar of H2, however, with only
moderate enantioselectivity. Finally, we examined the
3-methyl-substituted benzothiophene 1,1-dioxide 3g.
Although this substrate proved far less reactive than the 2-
methyl isomer 3a, it was fully converted into product 4g
within 4 h under 50 bar of H2 with high enantioselectivity
(93% ee).
The results of further studies with a series of 2- and
3-alkyl-substituted benzothiophene 1,1-dioxides and the cat-
alyst [Ir(cod)L4]BArF are shown in Table 4. Replacement of
the methyl substituent in substrate 3a with an ethyl group led
to a decrease in reactivity and enantioselectivity. Longer
To demonstrate the synthetic value of the hydrogenation
products, we studied the reduction of selected chiral 2,3-
dihydrobenzothiophene 1,1-dioxides to the corresponding
2,3-dihydrobenzothiophenes (Scheme 2). With an excess of
Table 4: Asymmetric hydrogenation of substrates with alkyl substitu-
ents.
Scheme 2. Conversion of 2,3-dihydrobenzothiophene 1,1-dioxides into
2,3-dihydrobenzothiophenes, diastereoselective methylation of com-
pound 4g, and ORTEP view of (2R,3S)-6.[10] [a] The diastereomeric
ratio was determined by GC analysis of the crude reaction mixture.
LiAlH4 in THF, reactions proceeded smoothly in high yield
with negligible or no loss of enantiomeric purity, thus
providing access to highly enantiomerically enriched 2- and
3-substituted 2,3-dihydrobenzothiophenes 5a and 5g. More-
over, the acidity of hydrogen atoms next to the SO2 group
allows the introduction of an additional substituent at the
2-position. For example, we converted 3-methyl-2,3-dihydro-
benzothiophene dioxide (5g) into the trans-2,3-dimethyl
derivative 6 in high yield with a diastereomeric ratio of
81:19 by deprotonation with nBuLi and subsequent methyl-
ation with dimethyl sulfate. In this way, 2,3-disubstituted
dihydrobenzothiophenes are accessible. Such compounds
cannot be prepared by asymmetric hydrogenation because
[a] Reactions were carried out on a 33 mmol scale. Conversion was
determined by GC analysis and ee values were determined by HPLC
analysis on a chiral stationary phase (see the Supporting Information for
details). [b] The reaction was carried out with 2 mol% of [Ir(cod)L5]BArF.
[c] The reaction was also carried out on a 1.63 mmol scale (99% yield of
the isolated product, 93% ee). [d] The S absolute configuration was
determined by single-crystal X-ray analysis.[10] TBDPS=tert-butyldiphe-
nylsilyl.
reaction times were necessary for the reduction of 3b with
95% conversion to afford product 4b with 84% ee. Lower
temperatures resulted in drastically lower reactivity without
affecting the enantioselectivity (see the Supporting Informa-
tion). An n-propyl or benzyl group at the 2-position further
reduced the enantioselectivity. For the benzyl-substituted
substrate 3d, more forcing conditions had to be used (10 bar
H2 for 8 h) to obtain 4d with > 90% conversion. The more
=
of the lack of reactivity of tetrasubstituted C C bonds.
In summary, we have identified two chiral iridium N,P-
ligand complexes that enable the enantioselective hydro-
genation of benzothiophene 1,1-dioxides. Excellent enantio-
selectivity and high yields were observed for substrates
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
[2] For selected examples, see: a) A. Baeza, A. Pfaltz, Chem. Eur. J.
2010, 16, 2036 – 2039; b) D.-S. Wang, Q.-A. Chen, W. Li, C.-B.
Yu, Y.-G. Zhou, X. Zhang, J. Am. Chem. Soc. 2010, 132, 8909 –
8911; c) D.-S. Wang, J. Tang, Y.-G. Zhou, M.-W. Chen, C.-B. Yu,
Y. Duan, G.-F. Jiang, Chem. Sci. 2011, 2, 803 – 806; d) C. Li, J.
Chen, G. Fu, D. Liu, Y. Liu, W. Zhang, Tetrahedron 2013, 69,
6839 – 6844; e) Y. Duan, L. Li, M.-W. Chen, C.-B. Yu, H.-J. Fan,
Y.-G. Zhou, J. Am. Chem. Soc. 2014, 136, 7688 – 7700; f) T.
Touge, T. Arai, J. Am. Chem. Soc. 2016, 138, 11299 – 11305; g) Z.
Yang, F. Chen, Y. He, N. Yang, Q.-H. Fan, Angew. Chem. Int. Ed.
2016, 55, 13863 – 13866; Angew. Chem. 2016, 128, 14067 – 14070.
[3] For selected recent examples, see: a) N. Ortega, S. Urban, B.
Beiring, F. Glorius, Angew. Chem. Int. Ed. 2012, 51, 1710 – 1713;
Angew. Chem. 2012, 124, 1742 – 1745; b) L. Pauli, R. Tannert, R.
Scheil, A. Pfaltz, Chem. Eur. J. 2015, 21, 1482 – 1487.
bearing an aromatic substituent at either the 2- or the
3-position of the heterocyclic scaffold. Analogous alkyl-
substituted derivatives proved to be more demanding sub-
strates and gave less consistent results (69–93% ee; 75–100%
conversion). Subsequent reduction of the sulfone group gives
access to highly enantiomerically enriched dihydrothio-
phenes. This sequence enables the preparation of 2- and
3-aryl dihydrobenzothiophenes, which are not available by
the direct asymmetric hydrogenation of benzothiophenes as
described by Glorius and co-workers,[5] because their method
is not applicable to aryl-substituted derivatives.
[4] For an overview, see: D. Paul, B. Beiring, M. Plois, N. Ortega, S.
Kock, D. Schlꢀns, J. Neugebauer, R. Wolf, F. Glorius, Organo-
metallics 2016, 35, 3641 – 3646, and references therein.
[5] S. Urban, B. Beiring, N. Ortega, D. Paul, F. Glorius, J. Am. Chem.
Soc. 2012, 134, 15241 – 15244.
[6] a) T. Zhou, B. Peters, M. F. Maldonado, T. Govender, P. G.
Andersson, J. Am. Chem. Soc. 2012, 134, 13592 – 13595; b) B. K.
Peters, T. Zhou, J. Rujirawanich, A. Cadu, T. Singh, W. Rabten,
S. Kerdphon, P. G. Andersson, J. Am. Chem. Soc. 2014, 136,
16557 – 16562.
Acknowledgements
Financial support from the Swiss National Science Founda-
tion is gratefully acknowledged. We thank Dr. Marcus
Neuburger (University of Basel) for crystal-structure analy-
ses.
Conflict of interest
[7] a) H. Rempfler, A. Edmunds, A. De Mesmaeker, K. Seckinger
(Novartis AG), WO 9909023, 1999; b) M. Saitou, H. Sekiguchi,
S. Ogawa (Idemitsu Kosan Co., Ltd.), WO 2000069853, 2000;
c) M. Saitou, H. Sekiguchi, S. Ogawa (Idemitsu Kosan Co., Ltd.),
WO 2000020408, 2000; d) R. G. Hall, O. Loiseleur, J. Pabba, S.
Pal, A. Jeanguenat, A. Edmunds, A. Stoller (Syngenta AG), WO
2009010260, 2009; e) A. Edmunds, M. Mꢀhlebach, A. Stoller, O.
Loiseleur, A. Buchholz, O. F. Hueter, A. Bigot, R. G. Hall, D.
Emery, P. J. M. Jung, L. Lu, Y. Wu, R. Chen (Syngenta AG), WO
2015000715, 2015.
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · heterocyclic compounds ·
hydrogenation · iridium · N,P ligands
[8] a) D. D. Dixon, J. Grina, J. A. Josey, J. P. Rizzi, S. T. Schlachter,
E. M. Wallace, B. Wang, P. When, R. Xu, H. Yang (Peloton
Therapeutics, Inc.), WO 2015095048, 2015; b) P. Wehn, H. Yang
(Peloton Therapeutics, Inc.), US 20160362390, 2016.
[9] a) S. J. Roseblade, A. Pfaltz, Acc. Chem. Res. 2007, 40, 1402 –
1411; b) D. H. Woodmansee, A. Pfaltz, Chem. Commun. 2011,
47, 7912 – 7916.
[10] CCDC 928151 (2a), 928152 (2l), 928153 (4g), and 928154 (6)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
[1] For selected recent reviews, see: a) Z. Yu, W. Jin, Q. Jiang,
Angew. Chem. Int. Ed. 2012, 51, 6060 – 6072; Angew. Chem.
2012, 124, 6164 – 6177; b) D.-S. Wang, Q.-A. Chen, S.-M. Lu, Y.-
G. Zhou, Chem. Rev. 2012, 112, 2557 – 2590; c) Y.-M. He, F.-T.
Song, Q.-H. Fan, Top. Curr. Chem. 2014, 343, 145 – 190; d) V.
Ratovelomanana-Vidal, P. Phansavath, T. Ayad, M. R. Vitale in
Comprehensive Organic Synthesis, Vol. 8, 2nd ed. (Eds. P.
Knochel, G. A. Molander), Elsevier, Amsterdam, 2014,
pp. 741 – 793; e) T. J. Donohoe, C. R. Jones, C. Winter in
Comprehensive Organic Synthesis, Vol. 8, 2nd ed. (Eds. P.
Knochel, G. A. Molander), Elsevier, Amsterdam, 2014,
pp. 794 – 837; f) D. Zhao, L. Candish, D. Paul, F. Glorius, ACS
Catal. 2016, 6, 5978 – 5988; g) Z.-P. Chen, Y.-G. Zhou, Synthesis
2016, 1769 – 1781.
Manuscript received: February 8, 2017
Final Article published: && &&, &&&&
4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
P. Tosatti, A. Pfaltz*
&&&& — &&&&
Iridium-Catalyzed Asymmetric
Hydrogenation of Benzo[b]thiophene 1,1-
Dioxides
(Sul)fone a friend: The iridium-catalyzed
asymmetric hydrogenation of benzothio-
phene 1,1-dioxides provided access to
highly enantiomerically enriched sulfones
with substituents at the 2- and 3-position
(see scheme). Sulfones of this type are of
interest as core structures of agrochem-
icals and pharmaceuticals. They can also
be further reduced to chiral 2,3-dihydro-
benzothiophenes, which are not always
directly accessible by asymmetric hydro-
genation.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!