Platinum-Catalyzed α,β-Desaturation of Cyclic Ketones through Direct Metal–Enolate Formation

Article abstract of DOI:10.1002/anie.202013628

The development of a platinum-catalyzed desaturation of cyclic ketones to their conjugated α,β-unsaturated counterparts is reported in this full article. A unique diene-platinum complex was identified to be an efficient catalyst, which enables direct metal-enolate formation. The reaction operates under mild conditions without using strong bases or acids. Good to excellent yields can be achieved for diverse and complex scaffolds. A wide range of functional groups, including those sensitive to acids, bases/nucleophiles, or palladium species, are tolerated, which represents a distinct feature from other known desaturation methods. Mechanistically, this platinum catalysis exhibits a fast and reversible α-deprotonation followed by a rate-determining β-hydrogen elimination process, which is different from the prior Pd-catalyzed desaturation method. Promising preliminary enantioselective desaturation using a chiral-diene-platinum complex has also been obtained.

Full text of DOI:10.1002/anie.202013628

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7956–7961
International Edition:
German Edition:
doi.org/10.1002/anie.202013628
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Catalysis
Platinum-Catalyzed a,b-Desaturation of Cyclic Ketones through Direct
Metal–Enolate Formation
Ming Chen and Guangbin Dong*
Dedicated to Professor Barry M. Trost on the occasion of his 80th birthday
À
À
Abstract: The development of a platinum-catalyzed desatura-
tion of cyclic ketones to their conjugated a,b-unsaturated
counterparts is reported in this full article. A unique diene-
platinum complex was identified to be an efficient catalyst,
which enables direct metal-enolate formation. The reaction
operates under mild conditions without using strong bases or
acids. Good to excellent yields can be achieved for diverse and
complex scaffolds. A wide range of functional groups, includ-
ing those sensitive to acids, bases/nucleophiles, or palladium
species, are tolerated, which represents a distinct feature from
other known desaturation methods. Mechanistically, this
platinum catalysis exhibits a fast and reversible a-deprotona-
tion followed by a rate-determining b-hydrogen elimination
process, which is different from the prior Pd-catalyzed
desaturation method. Promising preliminary enantioselective
desaturation using a chiral-diene-platinum complex has also
been obtained.
polarizable C X or C O (X: halogen) bonds, is much less
common.[8] Thus, a broader functional group tolerance could
be anticipated with the Pt0/PtII catalysis. However, compared
to palladium, platinum-catalyzed carbonyl desaturation has
been extremely rare. In 2018, we reported our preliminary
study of a PtII-catalyzed carbonyl desaturation through an in
situ soft-enolization approach.[9]
A strong Lewis acid,
Bu2BOTf, was needed to generate the corresponding boron
enolate prior to the catalytic desaturation. As such, acid-
sensitive functional groups, for example, ketals and silyl
ethers, were not compatible under these conditions. To the
best of our knowledge, the Pt-catalyzed desaturation of
carbonyl compounds through direct enolization remained an
unknown transformation. Herein, we describe a full story of
Introduction
As a fundamental organic transformation, a,b-desatura-
tion of carbonyl compounds has found increasing importance
in synthetic strategy planning and is frequently used in
complex molecule synthesis.[1,2] Compared to conventional
approaches, the transition metal-catalyzed desaturation gen-
erally operates under mild conditions and avoids strong
oxidants, highly toxic reagents or multi-step operations.
Among various transition metal-catalyzed carbonyl desatu-
ration methods reported to date,[3] those catalyzed by
palladium are most widely used. The reaction mechanism
involves rate-determining PdII-enolate formation followed by
rapid b-hydrogen elimination and regeneration of PdII via
oxidation.[4,1d] According to how the PdII enolate is formed,
three types of Pd-catalyzed desaturation have been developed
(Scheme 1a), including (i) stepwise enolization, for example,
Saegusa–Ito oxidation,[5] (ii) in situ enolization, for example,
forming zinc or boron enolates in one pot via hard or soft
enolization,[6] and (iii) direct enolization by PdII, which does
not require forming enolates prior to the catalysis.[7]
On the other hand, unlike palladium or nickel, oxidative
addition of low valent platinum with electrophiles, such as
[*] M. Chen, G. Dong
Department of Chemistry, University of Chicago
Chicago, IL 60637 (USA)
E-mail: gbdong@uchicago.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202013628.
Scheme 1. Pd and Pt-catalyzed desaturation of carbonyl compounds.
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the development of a Pt-catalyzed direct desaturation of
To gain insights into the roles of each reactant, control
cyclic ketones without using strong bases or acids, which
provides an efficient method to access a,b-unsaturated
enones commonly found in bioactive compounds (Sche-
me 1b).[10] Complementary to other desaturation methods,
a wide range of sensitive functional groups are tolerated. A
well-defined diene-PtII complex has been identified as the
optimal catalyst, and detailed mechanistic studies reveal
a different mechanistic feature from the analogous Pd-
catalyzed desaturation.
experiments were carried out (for more details, see Support-
ing Information). Clearly, the platinum catalyst is critical to
this transformation, as no product was observed in the
absence of (COD)Pt(TFA)2 (entry 1). A survey of different
oxidants revealed that simple BQ is most effective. Interest-
ingly, in the absence of oxidant, quantitative yield of the
product based on Pt was obtained, suggesting that BQ may
not play as a ligand in this reaction (entry 2). While base was
not essential, the reaction was promoted by insoluble
inorganic bases, such as BaO (entry 3). For comparison,
soluble organic bases, such as Et3N, DIPEA, DBU and
KOtBu, shut down the reaction by poisoning the Pt catalyst. A
range of other Pt complexes have been examined as catalysts
(entry 4). First, (COD)Pt(OAc)2 gave very poor yield (8%),
suggesting the importance of the electron-deficient trifluor-
oacetate ligand. The Pt0 catalyst, that is, Pt(PPh3)4, gave no
conversion. The combination of Pt(COD)Cl2 and AgTFA,
which was intended to form (COD)Pt(TFA)2 in situ, was less
effective. The reactivity was even lower when using Pt-
(MeCN)2Cl2 instead, indicating the positive contribution of
the COD ligand. For comparison, the use of other metals,
such as Pd, Ir and Rh, gave much inferior results using COD
as ligand. The addition of strongly coordinative ligands has
also been examined (entry 5). While most ligands significantly
inhibited the reaction, the use of bisphosphines (L2 and L3)
and P/N ligand (L7) yielded a small amount of product 2a. It
is worth to point out that the reaction can be carried out under
air, albeit forming 12% yield of the phenol side-product (2a’),
which indicates that the participation of oxygen may cause
over oxidation (entry 6). When 5 mol% of the catalyst was
used, 58% yield was still obtained (entry 7). While slower, the
reaction can still take place at lower temperatures, such as
508C and even room temperature (entries 8 and 9). Finally,
among different solvents tested, aromatic solvents are more
effective (entries 10 and 11); by contrast, more polar solvents,
such as 1,4-dioxane and THF, gave no desired product.
With the optimized conditions in hand, the substrate
scope was next explored (Table 2). First, substitution at
cyclohexanone a,b,g-positions can all be tolerated (2a–
2ar).[12] For a-substituted ketones, high site-selectivity was
obtained with reaction taking place almost exclusively at the
less substituted site (2d and 2e). While lower selectivity was
observed with b-substituted substrates, the major product was
still formed via desaturation at the less bulky side (2 f).
Gratifyingly, steric bulkiness at either the a,b,g-positions does
not appear to significantly affect the reaction yields (2g–2k).
As expected, this platinum catalysis condition can tolerate
a wide range of functional groups, including acid-sensitive
moieties, such as TBS ether (2p), acetal (2q), ketal (2u and
2v) and aryl boronate (2ar), and nucleophile/base sensitive
moieties, such as OTs (2m), ester (2n, 2y, 2z, 2bg, 2bk and
2bl), alkyl halide (2r and 2w) and aldehyde (2an). In
particular, functional groups that can easily react with
palladium, such as aryl iodide (1s, 1t and 1ac), aryl bromide
(2ad), alkyl iodide (1r), alkyl bromide (1w) and pinacol
boronate (2ar), were compatible. In addition, an acidic
secondary sulfonamide (NHTs, 2x) was tolerated. Moreover,
common functional groups, such as trifluoromethyl (2ak),
Results and Discussion
Our study began with employing cyclohexanone 1a as the
model substrate. After extensive optimization, a well-defined
(COD)Pt(TFA)2 complex was found to be the optimal
catalyst, whose structure was unambiguously confirmed by
X-ray crystallography (Table 1).[11] With BQ (1,4-benzoqui-
none) and insoluble BaO as the oxidant/base combination,
the desired a,b-unsaturated ketone 2a was obtained in 86%
yield. The corresponding over-oxidation product, phenol 2a’,
was only generated in a trace amount.
Table 1: Selected optimization studies.
Entry Variations from the “standard” condi-
tions
Yield [%] of 2a/2a’/
1a[a]
1
2
Without (COD)Pt(TFA)2 (C1)
Without BQ (Ox1)
0/0/100
10/0/85
3
Without BaO (B1)
32/2/54
4
5
6
C2–5 instead of (COD)Pt(TFA)2
L1–7 as the additional ligand
carried out in air
Listed below
Listed below
78/12/4
7
8
5 mol% (COD)Pt(TFA)2, 48 h
508C, 48 h
58/10/26
65/0/32
9
10
11
room temperature, 48 h
solvent=PhH
solvent=toluene
16/0/80
80/6/10
74/6/16
[a] Each reaction was run on a 0.1 mmol scale in a sealed 4 mL vial under
N2 for 12 h; yields were determined by 1H NMR using CH2Br2 as the
internal standard. [b] 25 mol% of AgTFA was added. TFA=trifluoroa-
cetate, COD=1,5-cyclooctadiene, BQ=1,4-benzoquinone.
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Table 2: Substrate scope.[a,b]
[a] Each reaction was run on a 0.1 mmol scale in a sealed 4 mL vial for 12 h. [b] Isolated yields. [c] The reaction was carried out without adding BaO as
the base at 1208C. [d] Product 2at exists as a single diastereomer. The relative stereochemistry is tentatively assigned. [e] Reaction time was 48 h.
brsm=based on recovered starting materials. Ts =p-toluenesulfonyl, TBS=tert-Butyldimethylsilyl, Bz=benzoyl, Piv=pivaloyl, Ad=1-Adamantanyl.
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nitro (2al), nitrile (2am), cyclopropane (2y), alkene (2z) and
To examine the practicality of this method, a large-scale
alkyne (2aa), remained intact. It is interesting to note that
terminal olefin 1ao underwent complete migration to form
the conjugated product, implying the involvement of metal-
hydride species. It is of note that cyclohexanones containing
sulfides, terminal alkynes, free alcohols, or carboxylic acids
proved to be challenging substrates under the current
conditions (see Supporting Information).
reaction of 1a was carried out [Eq. (1)]. On a 3.0 mmol scale,
the desired cyclohexenone 2a was still isolated in 78% yield.
The reaction was highly selective for desaturation of six-
membered ketones. Linear ketones (2ai) and cyclopenta-
nones (2aq and 2bd) were much less reactive under the
standard conditions. This is likely not related to the pKa of
Efforts were then carried out to gain some mechanistic
insights. To better understand the catalytic system, the kinetic
profiles of the reaction with substrate 1a were obtained
(Figure S1). First, no induction period was observed. The
À
their a C H bonds as cyclopentanone is known to be more
acidic than cyclohexanone.[13] While the exact reason remains
unclear at this stage and will be investigated thoroughly in the
future, it is surprising that five-membered ketones 1as and
1at afforded the desired product in good yields in the absence
of base at an elevated temperature. In addition, N and O-
containing six-membered heterocyclic ketones generally gave
satisfactory yields (2au–2ay), and 2,2-dimethyl b-tetralone
reacted smoothly to deliever the unsaturated product (2az) in
high yield. Moreover, moderate reactivity was observed with
seven-membered cyclic ketones (1ba–1bc).
reaction proceeded with a high initial reaction rate
(0.5 mMminÀ1) and became slower after 2 hours (at around
60% conversion). The product formation was plateaued after
6 hours. Notably, the mass balance was nearly perfect in this
period, indicating that there was minimal decomposition of
the substrate or product. Formation of phenol side-product
(2a’) did not take place until the late stage of the reaction
after the main reaction was nearly finished.
To understand the selectivity for the mono-desaturation
and to investigate if product inhibition exists, the kinetic
profiles of the reaction with cyclohexanone 1b and the
competition reaction between 1b and cyclohexenone 2k were
measured (Figure S2). Substrate 1b was used for easier
Notably, cyclohexanones derived from or tethered with
bioactive natural products, such as dehydroandrosterone
(2bd), cholesterol (2be, 2bk and 2bn), a-tocopherol (2bf),
oleanolic acid (2bg), 4H-Santonin (2bh), nootkatone (2bi),
and androsterone (2bj), all afforded the desired desaturation
products in good to excellent yields. High site-selectivity was
observed with a-substituted substrates (2bh, 2bk and 2bl). It
is interesting that desaturation did not take place at the sides
t
analysis due to the distinguished Bu peaks. The g,g-disub-
stituted 2k was used as it would unlikely undergo aerobic
oxidation to give a phenol. Based on the initial reaction rates
and final product yields of these two reactions, it became clear
À
that conjugated enones, despite with more acidic a-C H
À
with more acidic C H bonds (those with a-CO2Et substitu-
bonds, are much less reactive towards further dehydrogen-
ation under this platinum-catalyzed conditions (vide supra,
2bm), which explains the high mono-desaturation selectivity.
On the other hand, the results also suggest that enone
products do not inhibit the reaction with saturated substrates.
To understand the reversibility of the platinum-enolate-
forming step, two control experiments were conducted
(Scheme 3). Treatment of substrate 1c with 10 mol%
(COD)Pt(TFA)2 in D2O for 8 h gave 99% D at the a position
[Eq. (2)]. In contrast, no deuterium incorporation was found
in the absence of the platinum catalyst [Eq. (3)]. These results
suggest that the H/D exchange at ketone a position can be
efficiently catalyzed by the Pt complex without aid of base,
implying a fast and reversible formation of the platinum
enolate intermediate in this reaction.
ents, 2bk and 2bl); instead, the less bulky sides reacted
exclusively, implying that a-deprotonation is unlikely to be
the rate-determining step for the Pt-catalyzed desaturation
(vide infra). Note that epimerization with 2bk and 2bl did not
occur. Moderate selectivity was observed for the b-substituted
substrates (1bi and 1bj). When enone 1bn was used as the
substrate, the reaction proceeded at a much lower rate, giving
the corresponding dienone in moderate yield.
Interestingly, b,g-unsaturated ketones (1bo and 1bp)
selectively dehydrogenated at the alkene side to afford the
conjugated 1,3-diene products (Scheme 2), which are in sharp
contrast to the outcomes of the corresponding saturated
substrates (1bj and 1bk). We postulate that formation of a p-
allyl-Pt intermediate is likely the driving force for such
products.
To gain insights into the turnover-limiting step (TLS), the
kinetic isotope effect (KIE) of the reactions was studied
(Scheme 4). The competitive experiment showed that no
Scheme 3. Studies of the deprotonation step with the platinum cata-
Scheme 2. Desaturation of b,g-unsaturated cyclic ketones.
lyst.
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Figure 1. Proposed catalytic cycle.
not been reported.[16] As a promising preliminary result, when
an optically pure bicyclo[2.2.2]octane-2,5-diene, namely
(R,R)-Ph-bod, was employed as the ligand (instead of
COD), 30% ee of the cyclohexenone product (2c) was
obtained [Eq. (4)]. This indicates the feasibiltiy of developing
enantioselective ketone desaturation using chiral diene
ligands. Efforts on improving both the enantioselectivity
and conversion are ongoing.
Scheme 4. Kinetic isotope effect studies.
primary KIE was observed at the ketone a-position; both
competitive and parallel reactions showed large primary KIE
values (4.0 and 4.4, respectively) when using the b-deuterated
substrate, which correlates well with the prior Hartwigꢀs
mechanistic study of b-hydrogen elimination from
organoplatinum(II) enolate complexes.[14] In addition, the
kinetic orders of the substrate (1c), the Pt catalyst [(COD)Pt-
(TFA)2] and the oxidant (BQ) have been determined using
the initial-rate method (Figure S18). The reaction exhibited
first-order dependence on both the catalyst and the substrate,
and zero-order on the oxidant. These results are consistent Conclusion
with elimination of the ketone b-hydrogen to be the TLS, as
À
the TLS should not be deprotonation of the a-C H bond due
to the lack of primary KIE at that position and must involve
the substrate based on the kinetic orders. This mechanistic
feature is in sharp contrast to Stahlꢀs Pd/O2 system,[15] in which
In summary, the platinum-catalyzed a,b-desaturation of
cyclic ketones through direct metal enolate formation has
been developed. The reaction operates under mild conditions
without need of strong bases or acids. The tolerance of a large
variety of sensitive functional groups and substitution pat-
terns makes this method attractive for use in the synthesis of
complex bioactive molecules. The key for the success of this
transformation is the employment of a diene ligand. Addi-
tionally, the promising preliminary result obtained in this
study will motivate the development of enantioselective
dehydrogenation of cyclic ketones. Finally, mechanistic stud-
ies reveal a fast and reversible Pt-enolate formation, which is
followed by a rate-determining b-hydrogen elimination
process. This distinct mechanistic feature departs from the
known palladium-catalyzed carbonyl dehydrogenation reac-
tions, and thus could inspire the discovery of new platinum-
catalyzed carbonyl functionalization methods.
À
the a-C H cleavage is the TLS. It is also different from
Newhouseꢀs base-mediated in situ enolization/dehydrogen-
ation methods, which involve a rate-determining reductive
elimination of the PdIIHX species.[6a]
While some mechanistic details remain unclear and are
topics of ongoing investigations, the data based on the above
studies allow us to propose a hypothesis for the catalytic cycle
(Figure 1). The catalytic cycle starts with fast and reversible
deprotonation of ketone a-C H bonds by the Pt catalyst.
II
À
The resulting PtII-enolate then undergoes a turnover-limiting
b-hydrogen elimination to give the enone and a PtII-hydride
species. The enone product subsequently dissociates from the
Pt center via ligand exchange, and the PtII catalyst is
regenerated through oxidation of the PtII-hydride species by
BQ. A plausible role of the insoluble base is to neutralize the
hydroquinone (HBQ) byproduct, though in the case of five-
membered cyclic ketones the reaction worked much better
without base.
Acknowledgements
We thank University of Chicago and NSF (CHE-1855556) for
financial support. Professors Chuan He and Jack Halpern are
thanked for the generous gift of platinum salts. Dr. Cheng-
To the best of our best knowledge, transition metal-
catalyzed enantioselective direct desaturation of ketones has
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T. R. Newhouse, J. Am. Chem. Soc. 2016, 138, 1166 –1169; c) Y.
peng Wang and Mr. Jiaxin Xie are acknowledged for sharing
chemicals and helpful discussions. Dr. Xiu Liu and Mr.
Shusuke Ochi are acknowledged for X-ray crystallography.
Mr. Alexander Rago is thanked for proofreading the manu-
script.
Zhao, Y. Chen, T. R. Newhouse, Angew. Chem. Int. Ed. 2017, 56,
13122 –13125; Angew. Chem. 2017, 129, 13302 –13305; d) D.
Huang, Y. Zhao, T. R. Newhouse, Org. Lett. 2018, 20, 684 –687;
e) S. M. Szewczyk, Y. Zhao, H. A. Sakai, P. Dube, T. R. New-
house, Tetrahedron 2018, 74, 3293 –3300; f) Y. Sakamoto, T.
Amaya, T. Suzuki, T. Hirao, Chem. Eur. J. 2016, 22, 18686 –
18689; g) M. Chen, G. Dong, J. Am. Chem. Soc. 2017, 139,
7757 –7760.
Conflict of interest
[7] For the desaturation involving direct formation of Pd-enolates,
see: a) R. J. Theissen, J. Org. Chem. 1971, 36, 752 –757; b) Y.
Shvo, A. H. I. Arisha, J. Org. Chem. 1998, 63, 5640 –5642; c) T.
Diao, S. S. Stahl, J. Am. Chem. Soc. 2011, 133, 14566 –14569;
d) W. Gao, Z. He, Y. Qian, J. Zhao, Y. Huang, Chem. Sci. 2012, 3,
883 –886; e) T. Diao, T. J. Wadzinski, S. S. Stahl, Chem. Sci. 2012,
3, 887 –891; f) M.-M. Wang, X.-S. Ning, J.-P. Qu, Y.-B. Kang,
ACS Catal. 2017, 7, 4000 –4003; For examples involving enamine
catalysis, see: g) J. Zhu, J. Liu, R. Ma, H. Xie, J. Li, H. Jiang, W.
Wang, Adv. Synth. Catal. 2009, 351, 1229 –1232; h) J. Liu, J. Zhu,
H. Jiang, W. Wang, J. Li, Chem. Asian J. 2009, 4, 1712 –1716.
[8] C. Mateo, C. Fernµndez-Rivas, D. J. Cµrdenas, A. M. Echavar-
ren, Organometallics 1998, 17, 3661 –3669.
[9] M. Chen, A. J. Rago, G. Dong, Angew. Chem. Int. Ed. 2018, 57,
16205 –16209; Angew. Chem. 2018, 130, 16437 –16441.
[10] a) Y. Yang, H. Sun, Y. Zhou, S. Ji, M. Li, Nat. Prod. Res. 2009, 23,
1007 –1012; b) S. M. Fang, C.-B. Cui, C. W. Li, C. J. Wu, Z. J.
Zhang, L. Li, X. J. Huang, W. C. Ye, Mar. Drugs 2012, 10, 1266 –
1287; c) M. Frçhlich, N. Albermann, A. Sauer, I. Walter-Sack,
W. E. Haefeli, J. Weiss, Biochem. Pharmacol. 2004, 68, 2409 –
2416; d) T. Honda, B. V. Rounds, L. Bore, H. J. Finlay, F. G.
Favaloro, Jr., N. Suh, Y. Wang, M. B. Sporn, G. W. Gribble, J.
Med. Chem. 2000, 43, 4233 –4246; e) M. D. MØndez-Robles,
H. H. Permady, M. E. Jaramillo-Flores, E. C. Lugo-Cervantes,
A. Cardador-Martinez, A. A. Canales-Aguirre, F. Lopez-Della-
mary, C. M. Cerda-Garcia-Martinez, A. A. Canales-Aguirre, F.
Lopez-Dellamary, C. M. Cerda-Garcia-Rojas, J. Tamariz, J. Nat.
Prod. 2006, 69, 1140.
The authors declare no conflict of interest.
Keywords: dehydrogenation ·desaturation ·enantioselectivity ·
ketones ·platinum catalysis
[1] a) D. R. Buckle, I. L. Pinto in Comprehensive Organic Synthesis,
Vol. 7 (Eds.: B. M. Trost, I. Fleming, Pergamon, Oxford, 1991,
pp. 119 –149; b) R. C. Larock, Comprehensive Organic Trans-
formations, Wiley, New York, 1999, pp. 251 –256; For recent
reviews, see: c) J. Muzart, Eur. J. Org. Chem. 2010, 3779 –3790;
d) A. V. Iosub, S. S. Stahl, ACS Catal. 2016, 6, 8201 –8213; e) T.
Hirao, J. Org. Chem. 2019, 84, 1687 –1692; f) C. Wang, G. Dong,
ACS Catal. 2020, 10, 6058 –6070.
[2] a) A. Turlik, Y. Chen, T. R. Newhouse, Synlett 2016, 27, 331 –
336; b) A. W. Schuppe, T. R. Newhouse, J. Am. Chem. Soc. 2017,
139, 631 –634; c) A. W. Schuppe, D. Huang, Y. Chen, T. R.
Newhouse, J. Am. Chem. Soc. 2018, 140, 2062 –2066; d) M.
Elkin, A. C. Scruse, A. Turlik, T. R. Newhouse, Angew. Chem.
Int. Ed. 2019, 58, 1025 –1029; Angew. Chem. 2019, 131, 1037 –
1041; e) A. Turlik, Y. Chen, A. C. Scruse, T. R. Newhouse, J. Am.
Chem. Soc. 2019, 141, 8088 –8092; f) A. W. Schuppe, Y. Zhao, Y.
Liu, T. R. Newhouse, J. Am. Chem. Soc. 2019, 141, 9191 –9196;
g) X. Zhang, X. Cai, B. Huang, L. Guo, Z. Guo, Y. Jia, Angew.
Chem. Int. Ed. 2019, 58, 13380 –13384; Angew. Chem. 2019, 131,
13514 –13518.
[3] For Ni catalysis, see: a) D. Huang, S. M. Szewczyk, P. Zhang,
T. R. Newhouse, J. Am. Chem. Soc. 2019, 141, 5669 –5674; For
Cu catalysis, see: b) L. Liang, G. Yang, F. Xu, Y. Niu, Q. Sun, P.
Xu, Eur. J. Org. Chem. 2013, 6130 –6136; c) X. Jie, Y. Shang, X.
Zhang, W. Su, J. Am. Chem. Soc. 2016, 138, 5623 –5633; d) Y.
Shang, X. Jie, K. Jonnada, S. N. Zafar, W. Su, Nat. Commun.
2017, 8, 2273 –2280; e) M. Chen, G. Dong, J. Am. Chem. Soc.
2019, 141, 14889 –14897; f) For Ir catalysis, see: Z. Wang, Z. He,
L. Zhang, Y. Huang, J. Am. Chem. Soc. 2018, 140, 735 –740;
g) M. G. Manas, L. S. Sharninghausen, E. Lin, R. H. Crabtree, J.
Organomet. Chem. 2015, 792, 184 –189; h) For Ru catalysis, see:
C. S. Yi, D. W. Lee, Organometallics 2009, 28, 947 –949.
[4] D. Wang, A. B. Weinstein, P. B. White, S. S. Stahl, Chem. Rev.
2018, 118, 2636 –2679.
[5] For the desaturation involving stepwise enolization, see: a) Y.
Ito, T. Saegusa, J. Org. Chem. 1978, 43, 1011 –1013; b) Y. Ito, M.
Suginome, Handbook of Organopalladium Chemistry for Or-
ganic Synthesis, Vol. 2, Wiley, New York, 2002, pp. 2873 –2904;
c) I. Shimizu, J. Tsuji, J. Am. Chem. Soc. 1982, 104, 5844 –5847;
d) I. Shimizu, I. Minami, J. Tsuji, Tetrahedron Lett. 1983, 24,
1797 –1800; e) I. Minami, K. Takahashi, I. Shimizu, T. Kimura, J.
Tsuji, Tetrahedron 1986, 42, 2971 –2977.
[11] Deposition Number 2014058 (for [(COD)Pt(TFA)2]) contains
the supplementary crystallographic data for this paper. These
data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum
Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
[12] Unsubstituted cyclohexanone also worked well and gave 82%
yield.
[13] F. G. Bordwell, H. E. Fried, J. Org. Chem. 1991, 56, 4218.
[14] E. J. Alexanian, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130,
15627 –15635.
[15] T. Diao, D. Pun, S. S. Stahl, J. Am. Chem. Soc. 2013, 135, 8205 –
8212.
[16] For the enamine oxidation-based enantioselective dehydrogen-
ation of ketones, which is also the only report of asymmetric
carbonyl dehydrogenation, see: L. Zhu, L. Zhang, S. Luo,
Angew. Chem. Int. Ed. 2018, 57, 2253 –2258; Angew. Chem.
2018, 130, 2275 –2280.
Manuscript received: October 12, 2020
[6] For the desaturation involving in situ enolization followed by
transmetallation, see: a) Y. Chen, J. P. Romaire, T. R. Newhouse,
J. Am. Chem. Soc. 2015, 137, 5875 –5878; b) Y. Chen, A. Turlik,
Revised manuscript received: December 11, 2020
Accepted manuscript online: January 18, 2021
Version of record online: February 24, 2021
Angew. Chem. Int. Ed. 2021, 60, 7956 –7961
ꢀ 2021 Wiley-VCH GmbH
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