Diastereoselective Rhodium-Catalyzed Hydrogenation of 2-Oxindoles and 3,4-Dihydroquinolones

Article abstract of DOI:10.1021/acs.orglett.0c03427

The benzene ring of indolin-2-ones (2-oxindoles) and 3,4-dihydroquinol-2-ones was converted to a saturated cyclohexane ring by hydrogenation in the presence of the rhodium complex Cy(CAAC)Rh(cod)Cl. The stereoselectivity of the process was found to be high with respect to both external substituent R1 within the saturated part of the heterocyclic ring and substituent X on the benzene ring. Twenty-one hexahydroindolin-2(3H)-ones (70-99% yield, dr = 83/17 to >99/1) and twelve octahydro-2(1H)-quinolinones (87-96% yield, dr = 64/36 to >99/1) were obtained with the major diastereoisomer exhibiting the hydrogen atoms in an all-cis arrangement. The high tolerance toward functional groups and the compatibility with existing stereogenic centers are key features of the hydrogenation protocol presented here.

Full text of DOI:10.1021/acs.orglett.0c03427

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Letter
Diastereoselective Rhodium-Catalyzed Hydrogenation of
2‑Oxindoles and 3,4-Dihydroquinolones
Christian H. Schiwek, Christian Jandl, and Thorsten Bach*
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ABSTRACT: The benzene ring of indolin-2-ones (2-oxindoles)
and 3,4-dihydroquinol-2-ones was converted to a saturated
cyclohexane ring by hydrogenation in the presence of the rhodium
complex Cy(CAAC)Rh(cod)Cl. The stereoselectivity of the process
was found to be high with respect to both external substituent R1
within the saturated part of the heterocyclic ring and substituent X
on the benzene ring. Twenty-one hexahydroindolin-2(3H)-ones
(70−99% yield, dr = 83/17 to >99/1) and twelve octahydro-
2(1H)-quinolinones (87−96% yield, dr = 64/36 to >99/1) were
obtained with the major diastereoisomer exhibiting the hydrogen atoms in an all-cis arrangement. The high tolerance toward
functional groups and the compatibility with existing stereogenic centers are key features of the hydrogenation protocol presented
here.
n recent years, extensive efforts have been made to expand
the chemical structure space that can be accessed by organic
I
synthesis. In particular, the desire to escape the restrictions of
heteroaromatic compounds has been a major incentive for
devising new synthetic methods.1 The hydrogenation of arenes
or heteroarenes represents one of the easiest and most
straightforward transformations that leads from aromatic
unsaturation to alicyclic or heterocyclic products.2,3 The
development of new hydrogenation protocols has flourished
over the past ten years, and notable contributions to the field
of new defined molecular (pre)catalysts for selective arene
hydrogenations have been made by the groups of Zeng,4
Glorius,5 and others.6
Figure 1. Topics of the current hydrogenation study (left) and
structure of hydrogenation catalyst 1 (right; dipp = 2,6-diisopropyl-
phenyl; cod = 1,5-cyclooctadiene).
the benzene ring and with a minor focus on the facial
diastereoselectivity of substrates with a stereogenic center at
position C3 and/or C4.
Contributions from our group to the exploration of the
chemical structure space have so far focused on photochemical
transformations that are suited to achieving a large increase in
complexity in a single operation.7 However, it was also noted
that several enantiomerically enriched compounds, which can
be readily accessed using photochemistry,8 contain an arene
ring, which in turn invites a hydrogenation to increase
structural diversity. In this context, the hydrogenation of 2-
oxindoles and 3,4-dihydroquinolones attracted our intention,
in particular because studies of these compounds are limited.
Previous work on oxindole hydrogenation focused on the use
of platinum,9 palladium,10 or rhodium11 as a heterogeneous
hydrogenation catalyst with only a few studies addressing the
diastereoselectivity of this process.12 Even less work has been
done with 3,4-dihydroquinolones, and the diastereoselectivity
of their hydrogenation remains unexplored. In the study
presented here, we investigated the hydrogenation of the title
compounds (Figure 1) with a major focus on the
diastereoselectivity of substrates that are substituted (X) on
The choice of catalyst 1 with a cyclic (alkyl)(amino)carbene
(CAAC) ligand13 as the preferred hydrogenation catalyst was
based on the work by Zeng and co-workers, who have shown it
to be competent for the hydrogenation of parent oxindole and
of quinol-2(1H)-one.4a Although complex 1 is employed as a
defined compound, it has been shown that nanoparticles are
the catalytically active species.5e,6f Optimization experiments
(GLC analysis) were performed with oxindole 2a (Scheme 1,
where X, R, and R1 = H). It was found that toluene, methanol,
Received: October 14, 2020
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The other oxindoles subjected to the hydrogenation
conditions carried substituents at position C6 (substrates 2h
and 2i) or C5 (substrates 2k−2u) of the benzene ring. The
major issue here was the stereospecificity of the reactions,
which translates into a question of induced diastereoselectivity.
It is known that the complete arene ring is not reduced by a
simultaneous delivery of six hydrogen atoms but that the
reaction occurs stepwise via consecutive syn stereospecific
double bond reductions.3−6 The observed selectivity is thus
induced by the first stereogenic center(s) created in the
hydrogenation process. In previous work, the all-cis selectivity
for the hydrogenation was more pronounced in a nonpolar
solvent.4c,5a−d However, we found for the oxindoles that even
in TFE the all-cis products clearly prevailed. All diastereo-
selectivities were found to exceed a dr of 83:17, and the
functional group tolerance was high, including COOMe, F,
CF3, OH, NHBoc, and BPin groups (Pin = pinacolato).
Notable features of the hydrogenation protocol relate to the
chemoselectivity of the process when compared to previous
observations. The hydroxyl group was not converted to a
ketone;4a the fluoro substituent was not removed (competing
hydro-defluorination15), and free NH groups5c,d were
tolerated. The all-cis configuration of major products was
confirmed by single-crystal X-ray crystallography of represen-
tative examples [products 3n, 3q, and 3s (see the Supporting
Information for further details)].
Scheme 1. Scope and Diastereoselectivity of the Rh-
Catalyzed Hydrogenation of Oxindoles
Encouraged by the wide scope of the oxindole hydro-
genations, we turned our attention to the hydrogenation of 3,4-
dihydro-2(1H)-quinolones (dihydroquinolones). With parent
compound 4a (X = H), we verified that the reaction occurred
at positions C4a and C8a exclusively as a cis hydrogenation
(Scheme 2). Product 5a was expectedly obtained as a single
product with no indication for the trans isomer. A substituent
variation within the quinolone core was studied at position C6
(substrates 4b−4d) and position C7 (substrates 4e−4k). The
higher flexibility of a six-membered piperidinone ring (as
opposed to a five-membered pyrrolidinone ring) might be
and trifluoroethanol (TFE) represent suitable solvents for the
reaction (for details, see the Supporting Information). The
more polar solvent TFE required the lowest hydrogen pressure
(5.0 MPa), and a catalyst loading of 2.5 mol % was sufficient to
reach full conversion at 50 °C after 24 h. Before the application
of hydrogen pressure, the reaction mixture was a yellow
solution, but it turned colorless during the reaction with
concomitant formation of a dark precipitate.
Scheme 2. Induced Diastereoselectivity (5b−5k) of the Rh-
Catalyzed Hydrogenation of Dihydroquinolones
Under optimized conditions (Scheme 1, reactions run on a
0.5 mmol scale), product 3a was obtained in 95% yield as a
single diastereoisomer, indicating that the two stereogenic
centers at C3a and C7a of the octahydroindol-2-one core are
established selectively. Their cis relationship was confirmed on
the basis of a comparison with authentic material. In all other
products, the two annulated rings were exclusively linked in a
cis fashion. Diastereomeric ratios (dr) refer to the position at a
third stereogenic center relative to C3a and C7a.
Hydrogenation of N-substituted substrates 2b and 2c (Boc
= tert-butoxycarbonyl) delivered products 3b and 3c,
respectively. A methyl substituent at position C3 induced a
high facial diastereoselectivity in the hydrogenation product
with a clear preference for the all-cis substituted products 3d,
3e, and 3f (dr = 85:15 to 87:13) with only little influence
exerted by the nitrogen substituent. An ethyl group instead of a
methyl group in position C3 did not alter the extent of the
facial diastereoselectivity (product 3g; dr = 86:14). The
relative configuration of the major diastereoisomer obtained by
hydrogenation of 3d was established by comparison of its
spectroscopic data with those of authentic material.14
B
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responsible for the reduced stereoselectivity observed with
some substrates. A high diastereoselectivity (dr ≥ 89:11) was
achieved with 6-COOMe (product 5d) and with O-protected
hydroxyl groups at C7 (products 5f−5i; TBDMS = tert-
butyldimethylsilyl; TIPS = triisopropylsilyl; TES = triethylsil-
yl). While other heterogeneous catalysts are known to lead to
the cleavage of ether and silyl ether bonds,16 no deoxygenation
was observed under the used conditions. A scale-up of the
hydrogenation reaction was unproblematic, and the yields
obtained in the hydrogenation reactions leading to products 3t
and 5f remained unchanged when performed on a 5 mmol
scale (see the Supporting Information for further details).
Yields of all dihydroquinolone hydrogenations were high (87−
94%), and the relative configuration of the major products was,
like in the oxindole case, established by single-crystal X-ray
crystallography (products 5d and 5f).
pronounced selectivity as compared to more flexible substrates
(cf. products 5c, 5j, and 5k).
The high diastereoselectivity obtained in the hydrogenation
of boronates 3t and 3u invited further studies regarding their
conversion into consecutive products. In a first set of
experiments, we attempted a direct substitution of the
boronate by a carbon nucleophile (Scheme 4). In recent
Scheme 4. Stereoretentive Substitution of Boronate 3t by
Vinyl Magnesium Bromide to Give Product 3v and by 2-
Furyl Lithium to Give Product 3w
With a method for the hydrogenation of oxindoles and
dihydroquinolones in hand, we studied two more elaborated
compounds 6 and 8 (Scheme 3) that were obtained by
Scheme 3. High Diastereoselectivity and Retention of
Configuration of the Rh-Catalyzed Hydrogenation of
Enantiomerically Enriched Oxindole 6 and
Dihydroquinolone 8
years, reactions of this type have been successfully developed
by the Aggarwal group and have become a reliable tool for the
construction of stereogenic centers that bear exclusively carbon
substituents.17 It could be shown for boronate 3t (Scheme 4)
that Grignard reagents such as vinyl magnesium bromide as
well as aryl lithium reagents such as 2-furyl lithium induced a
clean substitution and gave products 3v and 3w, respectively.
For the formation of product 3v, iodine was used as the
oxidant to induce the stereoretentive migration of the vinyl
group in the Zweifel olefination.18,19 In the reaction with furyl
lithium, N-bromosuccinimide (NBS) served the same
purpose.17b Both processes occurred stereospecifically, and
the diastereomeric ratio (dr = 95/5) remained unaltered.
In a second set of experiments, N-Boc-protected product 3u
was employed, which can be obtained directly by hydro-
genation (Scheme 1) or by N-Boc protection of compound 3t
(Boc2O, DMAP in THF; 96%). It was shown that the
conversions of the boronate into versatile trifluoroborate20 10
and into free boronic acid 11 proceed in good yields (Scheme
5) without compromising the integrity of the stereogenic
centers.
previously reported methods.8 Spirocyclopropyl oxindole 6,
which can be enantiomerically enriched by a photocatalytic
deracemization reaction,8b was further purified to 99%
enantiomeric excess (ee) and subjected to the hydrogenation
conditions. The chloro substituents and the cyclopropyl ring
were compatible with the optimized reaction conditions, and
saturated tricyclic product 7 was obtained as a single
diastereoisomer. The enantiopurity of the compound remained
unchanged. In analogy to the facial diastereoselectivity
observed for 3d−3g, it is assumed that the hydrogenation
occurred from the more accessible face of the substrate. The
fact that the hydrogenation conditions do not compromise the
integrity of stereogenic centers, even at acidic positions, was
confirmed for the 2f → 3f reaction (Scheme 1). The substrate
was employed in 95% ee, and the product showed the same
optical purity as the starting material (see the Supporting
Information for further details). Tricyclic dihydroquinolone 8
was prepared by an enantioselective [2+2] photocycloadditio-
n,8a and it was used in the hydrogenation reaction without
further enrichment of the ee. Under standard conditions, a
comprehensive arene reduction was achieved and a single
product 9 was isolated. The three newly formed stereogenic
centers were generated with perfect facial diastereoselectivity.
It is likely that the cyclobutane ring lends more rigidity to the
piperidinone core, which in turn is responsible for the
Scheme 5. Conversion of Boronic Acid Pincacol Ester 3u
into Trifluoroborate 10 and Boronic Acid 11
In summary, the substrate scope of the Rh-catalyzed arene
hydrogenation has been expanded to two important classes of
heterocyclic compounds. Two or, in most cases, three
stereogenic centers are formed in a single operation with a
predictable outcome. The high facial diastereoselectivity and
the functional group tolerance of the hydrogenation protocol
show potential for its application in the total synthesis of
biologically relevant compounds.
C
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(3) For reviews with a focus on the hydrogenation of arenes, see:
(a) Wiesenfeldt, M. P.; Nairoukh, Z.; Dalton, T.; Glorius, F. Selective
Arene Hydrogenation for Direct Access to Saturated Carbo- and
Heterocycles. Angew. Chem., Int. Ed. 2019, 58, 10460−10476.
(b) Giustra, Z. X.; Ishibashi, J. S. A.; Liu, S.-Y. Homogeneous metal
catalysis for conversion between aromatic and saturated compounds.
Coord. Chem. Rev. 2016, 314, 134−181. (c) Foppa, L.; Dupont, J.
Benzene partial hydrogenation: advances and perspectives. Chem. Soc.
Rev. 2015, 44, 1886−1897. (d) Qi, S.-C.; Wei, X.-Y.; Zong, Z.-M.;
Wang, Y.-K. Application of supported metallic catalysts in catalytic
hydrogenation of arenes. RSC Adv. 2013, 3, 14219−14232. (e) Wang,
D.; Chen, Q.; Lu, X.; Zhou, Y. Asymmetric Hydrogenation of
Heteroarenes and Arenes. Chem. Rev. 2012, 112, 2557−2290.
(f) Dyson, P. J. Arene hydrogenation by homogeneous catalysts:
fact or fiction? Dalton Trans. 2003, 15, 2964−2974.
(4) For examples, see: (a) Wei, Y.; Rao, B.; Cong, X.; Zeng, X.
Highly Selective Hydrogenation of Aromatic Ketones and Phenols
Enabled by Cyclic (Amino)(alkyl)carbene Rhodium Complexes. J.
Am. Chem. Soc. 2015, 137, 9250−9253. (b) Ling, L.; He, Y.; Zhang,
X.; Luo, M.; Zeng, X. Hydrogenation of (Hetero)aryl Boronate Esters
with a Cyclic (Alkyl)(amino)carbene−Rhodium Complex: Direct
Access to cis-Substituted Borylated Cycloalkanes and Saturated
Heterocycles. Angew. Chem., Int. Ed. 2019, 58, 6554−6558.
(c) Zhang, X.; Ling, L.; Luo, M.; Zeng, X. Accessing Difluoromethy-
lated and Trifluoromethylated cis-Cycloalkanes and Saturated
Heterocycles: Preferential Hydrogen Addition to the Substitution
Sites for Dearomatization. Angew. Chem., Int. Ed. 2019, 58, 16785−
16789.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03427.
■
sı
Materials and methods, optimization of reaction
conditions, synthetic procedures and full character-
ization of new compounds (3e−3w, 5b−5k, and 7−
11), spectroscopic data, NMR spectra, etc. (PDF)
Accession Codes
CCDC 2036220−2036224 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Thorsten Bach − Department Chemie and Catalysis Research
Center (CRC), Technische Universität München, 85747
Garching, Germany; orcid.org/0000-0002-1342-0202;
Email: thorsten.bach@ch.tum.de
Authors
(5) For examples, see: (a) Wiesenfeldt, M. P.; Nairoukh, Z.; Li, W.;
Glorius, F. Hydrogenation of fluoroarenes: Direct access to all-cis-
(multi)fluorinated cycloalkanes. Science 2017, 357, 908−912.
(b) Wiesenfeldt, M. P.; Knecht, T.; Schlepphorst, C.; Glorius, F.
Silylarene Hydrogenation: A Strategic Approach that Enables Direct
Access to Versatile Silylated Saturated Carbo- and Heterocycles.
Angew. Chem., Int. Ed. 2018, 57, 8297−8300. (c) Wollenburg, M.;
Moock, D.; Glorius, F. Hydrogenation of Borylated Arenes. Angew.
Chem., Int. Ed. 2019, 58, 6549−6553. (d) Nairoukh, Z.; Wollenburg,
M.; Schlepphorst, C.; Bergander, K.; Glorius, F. The formation of all-
cis-(multi)fluorinated piperidines by a dearomatization−hydrogena-
tion process. Nat. Chem. 2019, 11, 264−270. (e) Moock, D.;
Wiesenfeldt, M. P.; Freitag, M.; Muratsugu, S.; Ikemoto, S.; Knitsch,
Christian H. Schiwek − Department Chemie and Catalysis
Research Center (CRC), Technische Universität München,
85747 Garching, Germany
Christian Jandl − Department Chemie and Catalysis Research
Center (CRC), Technische Universität München, 85747
Garching, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03427
Notes
The authors declare no competing financial interest.
̈
R.; Schneidewind, J.; Baumann, W.; Schafer, A. H.; Timmer, A.; Tada,
M.; Hansen, M. R.; Glorius, F. Mechanistic Understanding of the
Heterogeneous, Rhodium-Cyclic (Alkyl)(Amino)Carbene-Catalyzed
(Fluoro-)Arene Hydrogenation. ACS Catal. 2020, 10 (11), 6309−
6317. (f) Wollenburg, M.; Heusler, A.; Bergander, K.; Glorius, F.
trans-Selective and Switchable Arene Hydrogenation of Phenol
Derivatives. ACS Catal. 2020, 10, 11365−11370.
ACKNOWLEDGMENTS
Financial support by the Deutsche Forschungsgemeinschaft
(Grant Ba 1372/17-2) is gratefully acknowledged. O.
Ackermann, F. Pecho, and J. Kudermann (all TU Mu
are acknowledged for their help with HPLC and GLC analyses.
The authors thank Thilo Kratz (TU Munchen) for his support
■
̈
nchen)
(6) Examples: (a) Wang, Y.; Yao, J.; Li, H.; Su, D.; Antonietti, M.
Highly Selective Hydrogenation of Phenol and Derivatives over a
Pd@Carbon Nitride Catalyst in Aqueous Media. J. Am. Chem. Soc.
2011, 133, 2362−2365. (b) Liu, H.; Jiang, T.; Han, B.; Liang, S.;
Zhou, Y. Selective Phenol Hydrogenation to Cyclohexanone Over a
Dual Supported Pd−Lewis Acid Catalyst. Science 2009, 326, 1250−
1252. (c) Snelders, D. J. M.; Yan, N.; Gan, W.; Laurenczy, G.; Dyson,
P. J. Tuning the Chemoselectivity of Rh Nanoparticle Catalysts by
Site-Selective Poisoning with Phosphine Ligands: The Hydrogenation
of Functionalized Aromatic Compounds. ACS Catal. 2012, 2, 201−
207. (d) Nelson, N. C.; Manzano, J. S.; Sadow, A. D.; Overbury, S.
H.; Slowing, I. I. Selective Hydrogenation of Phenol Catalyzed by
Palladium on High-Surface-Area Ceria at Room Temperature and
Ambient Pressure. ACS Catal. 2015, 5, 2051−2061. (e) Stalzer, M.
M.; Nicholas, C. P.; Bhattacharyya, A.; Motta, A.; Delferro, M.;
Marks, T. J. Single-Face/All-cis Arene Hydrogenation by a Supported
Single-Site d0 Organozirconium Catalyst. Angew. Chem., Int. Ed. 2016,
55, 5263−5267. (f) Tran, B. L.; Fulton, J. L.; Linehan, J. C.; Lercher,
J. A.; Bullock, R. M. Rh(CAAC)-Catalyzed Arene Hydrogenation:
Evidence for Nanocatalysis and Sterically Controlled Site-Selective
̈
and advice about the photochemical reactions.
REFERENCES
■
(1) (a) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland:
Increasing Saturation as an Approach to Improving Clinical Success. J.
Med. Chem. 2009, 52, 6752−6756. (b) Pitt, W. R.; Parry, D. M.;
Perry, B. G.; Groom, C. R. Heteroaromatic Rings of the Future. J.
Med. Chem. 2009, 52, 2952−2963. (c) Taylor, R. D.; MacCoss, M.;
Lawson, A. D. G. Rings in Drugs. J. Med. Chem. 2014, 57, 5845−5859.
(d) Passador, K.; Thorimbert, S.; Botuha, C. ‘Heteroaromatic Rings of
the Future’: Exploration of Unconquered Chemical Space. Synthesis
2019, 51, 384−398.
(2) For reviews of dearomatization reactions, see: (a) Okumura, M.;
Sarlah, D. Visible-Light-Induced Dearomatizations. Eur. J. Org. Chem.
2020, 1259−1273. (b) Wertjes, W. C.; Southgate, E. H.; Sarlah, D.
Recent advances in chemical dearomatization of nonactivated arenes.
Chem. Soc. Rev. 2018, 47, 7996−8017. (c) Roche, S. P.; Porco, J. A.,
Jr. Dearomatization Strategies in the Synthesis of Complex Natural
Products. Angew. Chem., Int. Ed. 2011, 50, 4068−4093.
Hydrogenation. ACS Catal. 2018, 8, 8441−8449. (g) Yu, C.; Kutt, A.;
̈
D
https://dx.doi.org/10.1021/acs.orglett.0c03427
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
̈
̈
Roschenthaler, G.-V.; Lebl, T.; Cordes, D. B.; Slawin, A. M. Z.; Buhl,
M.; O’Hagan, D. Janus Face All-cis 1,2,4,5-tetrakis(trifluoromethyl)-
and All-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)- Cyclohexanes. Angew.
Chem., Int. Ed. 2020, 59, 19905.
of acidic ruthenium dihydrogen complexes. J. Organomet. Chem. 2003,
679, 32−42. (b) Ikawa, T.; Hattori, K.; Sajiki, H.; Hirota, K. Solvent-
modulated Pd/C-catalyzed deprotection of silyl ethers and chemo-
selective hydrogenation. Tetrahedron 2004, 60, 6901−6911.
(17) (a) Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.;
Aggarwal, V. K. Enantiospecific sp2−sp3 coupling of secondary and
tertiary boronic esters. Nat. Chem. 2014, 6, 584−589. (b) Odachowski,
M.; Bonet, A.; Essafi, S.; Conti-Ramsden, P.; Harvey, J. N.; Leonori,
D.; Aggarwal, V. K. Development of Enantiospecific Coupling of
Secondary and Tertiary Boronic Esters with Aromatic Compounds. J.
Am. Chem. Soc. 2016, 138, 9521−9532. (c) Armstrong, R. J.;
Niwetmarin, W.; Aggarwal, V. K. Synthesis of Functionalized Alkenes
by a Transition-Metal-Free Zweifel Coupling. Org. Lett. 2017, 19,
2762−2765.
(18) (a) Zweifel, G.; Arzoumanian, H.; Whitney, C. C. A convenient
stereoselective synthesis of substituted alkenes via hydroboration-
iodination of alkynes. J. Am. Chem. Soc. 1967, 89, 3652−3653.
(b) Zweifel, G.; Fisher, R. P.; Snow, J. T.; Whitney, C. C. Convenient
synthesis of trans olefins from alkynes via hydroboration-cyanohalo-
genation. J. Am. Chem. Soc. 1972, 94, 6560−6561.
(19) For a recent review, see: Armstrong, R. J.; Aggarwal, V. K. 50
Years of Zweifel Olefination: A Transition-Metal-Free Coupling.
Synthesis 2017, 49, 3323−3336.
(20) For some key references, see: (a) Dreher, S. D.; Dormer, P. G.;
Sandrock, D. L.; Molander, G. A. Efficient Cross-Coupling of
Secondary Alkyltrifluoroborates with Aryl ChloridesReaction
Discovery Using Parallel Microscale Experimentation. J. Am. Chem.
Soc. 2008, 130, 9257−9259. (b) Butters, M.; Harvey, J. N.; Jover, J.;
Lennox, A. J. J.; Lloyd-Jones, G. C.; Murray, P. M. Aryl
Trifluoroborates in Suzuki−Miyaura Coupling: The Roles of
Endogenous Aryl Boronic Acid and Fluoride. Angew. Chem., Int. Ed.
2010, 49, 5156−5160. (c) Lee, J. C. H.; McDonald, R.; Hall, D. G.
Enantioselective preparation and chemoselective cross-coupling of
1,1-diboron compounds. Nat. Chem. 2011, 3, 894−899. (d) Li, L.;
Zhao, S.; Joshi-Pangu, A.; Diane, M.; Biscoe, M. R. Stereospecific Pd-
Catalyzed Cross-Coupling Reactions of Secondary Alkylboron
Nucleophiles and Aryl Chlorides. J. Am. Chem. Soc. 2014, 136,
14027−14030. (e) Primer, D. N.; Karakaya, I.; Tellis, J. C.; Molander,
G. A. Single-Electron Transmetalation: An Enabling Technology for
Secondary Alkylboron Cross-Coupling. J. Am. Chem. Soc. 2015, 137,
2195−2198. (f) Lou, Y.; Cao, P.; Jia, T.; Zhang, Y.; Wang, M.; Liao, J.
Copper-Catalyzed Enantioselective 1,6-Boration of para-Quinone
Methides and Efficient Transformation of gem-Diarylmethine
Boronates to Triarylmethanes. Angew. Chem., Int. Ed. 2015, 54,
12134−12138.
(7) (a) Næsborg, L.; Jandl, C.; Zech, A.; Bach, T. Complex
Carbocyclic Skeletons from Aryl Ketones through a Three-Photon
Cascade Reaction. Angew. Chem., Int. Ed. 2020, 59, 5656−5659.
(b) Zech, A.; Jandl, C.; Bach, T. Concise Access to the Skeleton of
Protoilludane Sesquiterpenes through a Photochemical Reaction
Cascade: Total Synthesis of Atlanticone C. Angew. Chem., Int. Ed.
2019, 58, 14629−14632 and references cited therein.
̈
(8) (a) Troster, A.; Alonso, R.; Bauer, A.; Bach, T. Enantioselective
Intermolecular [2 + 2] Photocycloaddition Reactions of 2(1H)-
Quinolones Induced by Visible Light Irradiation. J. Am. Chem. Soc.
2016, 138, 7808−7811. (b) Li, X.; Kutta, R. J.; Jandl, C.; Bauer, A.;
Nuernberger, P.; Bach, T. Angew. Chem., Int. Ed. 2020, DOI: 10.1002/
anie.202008384.
(9) (a) Jones, G.; Stevens, T. S. The alkaloids of Gelsemium
sempervirens. Part II. J. Chem. Soc. 1953, 2344−2350. (b) Mokotoff,
M.; Hill, S. T. Ultra-High Field (600 MHz) NMR Spectroscopy in
Solving Conformational Problems: cis-Octahydroindoles. J. Heterocycl.
Chem. 1988, 25, 65−71.
(10) Pascard, C.; Guilhem, J.; Vincent, M.; Remond, G.; Portevin,
B.; Laubie, M. Configuration and preferential solid-state conforma-
tions of perindoprilat (S-9780). Comparison with the crystal
structures of other ACE inhibitors and conclusions related to
structure-activity relationships. J. Med. Chem. 1991, 34, 663−669.
(11) Schann, S.; Bruban, V.; Pompermayer, K.; Feldman, J.; Pfeiffer,
B.; Renard, P.; Scalbert, E.; Bousquet, P.; Ehrhardt, J. Synthesis and
Biological Evaluation of Pyrrolinic Isosteres of Rilmenidine. Discovery
of cis-/trans-Dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyr-
rol-2-yl)-amine (LNP 509), an I1 Imidazoline Receptor Selective
Ligand with Hypotensive Activity. J. Med. Chem. 2001, 44, 1588−
1593.
(12) (a) Valls, N.; Bonjoch, J.; Bosch, J. Diastereoselective synthesis
of all-cis-perhydropyrrolo[3,2,1-hi]indol-7-one. A building block for
the synthesis of D-norpandolane-type alkaloids. J. Org. Chem. 1992,
́
́
̃
ez,
57, 2508−2511. (b) Arizpe, A.; Sayago, F. J.; Jimenez, A. I.; Ordon
M.; Cativiela, C. Stereodivergent Synthesis of Two Novel α-
Aminophosphonic Acids Characterised by a cis-Fused Octahydroin-
dole System. Eur. J. Org. Chem. 2011, 3074−3081. (c) Katayev, D.;
Kajita, H.; Togni, A. Magnesium-Catalyzed Electrophilic Trifluor-
omethylation: Facile Access to All-Carbon Quaternary Centers in
Oxindoles. Chem. - Eur. J. 2017, 23, 8353−8357. (d) Rocaboy, R.;
Dailler, D.; Baudoin, O. A Four-Step Synthesis of ( )-γ-Lycorane via
Pd0-Catalyzed Double C(sp2)−H/C(sp3)−H Arylation. Org. Lett.
2018, 20, 772−775.
(13) For reviews of the seminal work of Bertrand and co-workers on
CAAC ligands, see: (a) Soleilhavoup, M.; Bertrand, G. Cyclic
(Alkyl)(Amino)Carbenes (CAACs): Stable Carbenes on the Rise.
Acc. Chem. Res. 2015, 48, 256−266. (b) Melaimi, M.; Jazzar, R.;
Soleilhavoup, M.; Bertrand, G. Cyclic (Alkyl)(amino)carbenes
(CAACs): Recent Developments. Angew. Chem., Int. Ed. 2017, 56,
10046−10068. (c) Jazzar, R.; Soleilhavoup, M.; Bertrand, G. Cyclic
(Alkyl)- and (Aryl)-(amino)carbene Coinage Metal Complexes and
Their Applications. Chem. Rev. 2020, 120, 4141−4168.
(14) Sato, T.; Nakamura, N.; Ikeda, K.; Okada, M.; Ishibashi, M.;
Ikeda, M. Formation of five-membered lactams by 5-endo-trigonal
radical cyclisations of 2-chloro-N-(cycloalk-1-enyl)acetamides: new
synthesis of erythrinane skeleton. J. Chem. Soc., Perkin Trans. 1 1992,
18, 2399−2407.
(15) (a) Kuehnel, M. F.; Lentz, D.; Braun, T. Synthesis of
Fluorinated Building Blocks by Transition-Metal-Mediated Hydro-
defluorination Reactions. Angew. Chem., Int. Ed. 2013, 52, 3328−
3348. (b) Whittlesey, M. K.; Peris, E. Catalytic Hydrodefluorination
with Late Transition Metal Complexes. ACS Catal. 2014, 4, 3152−
3159.
(16) (a) Takei, I.; Nishibayashi, Y.; Ishii, Y.; Mizobe, Y.; Uemura, S.;
Hidai, M. Novel catalytic hydrogenolysis of silyl enol ethers by the use
E
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