Platinum-Catalyzed Desaturation of Lactams, Ketones, and Lactones

Article abstract of DOI:10.1002/anie.201811197

The development of a general platinum-catalyzed desaturation of N-protected lactams, ketones, and lactones to their conjugated α,β-unsaturated counterparts is reported. The reaction operates under mildly acidic conditions at room temperature or 50 °C. It is scalable and tolerates a wide range of functional groups. The complementary reactivity to the palladium-catalyzed desaturation is demonstrated in the efficient conversion of iodide, bromide, and sulfur-containing substrates.

Full text of DOI:10.1002/anie.201811197

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Accepted Article
Title: Platinum-catalyzed Desaturation of Lactams, Ketones and
Lactones
Authors: Ming Chen, Alexander J Rago, and Guangbin Dong
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Platinum-catalyzed Desaturation of Lactams, Ketones and
Lactones
Ming Chen†, Alexander J. Rago† and Guangbin Dong*,†
In memory of Professor Jack Halpern.
Abstract: The development of
a
general platinum-catalyzed
redox-active C−X bonds (Scheme 1b).
desaturation of N-protected lactams, ketones, and lactones to their
conjugated α,β-unsaturated counterparts is reported. The reaction is
operated under mildly acidic conditions at room temperature or 50
oC. It is scalable and tolerates a wide range of functional groups.
The complementary reactivity to the palladium-catalyzed
desaturation is demonstrated in the efficient conversion of iodide,
bromide and sulfur-containing substrates.
Desaturation of carbonyl compounds is a strategically important
transformation.[1] This is not only because the resulting electron-
deficient conjugated alkenes are frequently found in bioactive
natural products and drugs (Figure 1),[2] but also because these
α,β-unsaturated moieties are often utilized as versatile
intermediates for subsequent β-functionalization or α,β-
difunctionalization of carbonyl compounds.[3] Among various α,β-
desaturation methods, the catalytic approaches are primarily
dominated by using palladium, which involves formation of a
Pd(II)-enolate, followed by β-hydrogen elimination and further
oxidation of the Pd(0) intermediate back to the Pd(II) catalyst.[4]
While it has been demonstrated to be a highly powerful reaction
Figure 1. Representative bioactive natural products and drugs containing α,β-
unsaturated carbonyl moieties.
Scheme 1. Platinum-catalyzed desaturation of carbonyl compounds
for desaturating
including ketones, esters, cyanides, carboxylic acids and amides
efficiently,[5]
some limitation still exists for the palladium
a diverse range of carbonyl compounds,
catalysis. For example, Pd(0) is known to undergo facile
oxidative addition with aryl iodides and halogen-abstraction with
alkyl halides,[6] thus compatibility of these structural motifs in the
Pd-catalyzed desaturation could be a major concern (vide infra,
Table 3). Scattered examples of using other transition metals,
such as Cu,[7] Ir[8] and Ru[9], for catalytic desaturation of carbonyl
compounds have also been reported, but the generality of these
methods has not been fully established. Stimulated by such a
chemoselectivity challenge, we herein describe the development
of a platinum-catalyzed desaturation method suitable for various
lactams, ketones, and lactones with complementary reactivity to
the palladium catalysis.
Despite in the same group, homogeneous platinum catalysis
has found much fewer applications compared with palladium
catalysis to date.[10] We were inspired by the facts that oxidative
addition of Pt(0) with C−X (X: halogen) bonds is less common
than the one of Pd(0)[11] and β-hydrogen elimination with a Pt(II)
enolate has been observed by Hartwig and co-workers[12]
(Scheme 1a). Thus, we hypothesized that Pt(II) salts could be
capable of catalyzing ketone desaturation without affecting these
To test the hypothesis, valeroalactam 1a was employed as a
model substrate. Indeed, when using Pt(COD)Cl2 as the pre-
catalyst, a catalytic amount of AgTFA as a chloride scavenger,
and diallyl carbonate (DAC) as the oxidant, the desired α,β-
unsaturated lactam 2a was obtained in 98% yield at room
temperature through in situ forming a boron-enolate intermediate
(Table 1).[5m,13] To gain more insights of this reaction, the role of
each reactant was explored through control experiments. First,
no product was observed without Pt(COD)Cl2 or AgTFA (entries
1 and 2). A range of other metal complexes has also been
examined (entry 3). First, PtCl2 cannot catalyze this reaction and
Pt(MeCN)2Cl2 only gave
a 15% yield. In contrast, using
Pt(COD)(TFA)2 in the absence of the silver salt still afforded
80% yield of 2a, which indicated that the TFA anion is important
and the silver metal is not critical for the reactivity. Other metal
complexes except Pd gave no or low reactivity. While Pd(TFA)2
could still give 41% yield of the desired product 2a, its efficiency
is lower than the Pt(COD)Cl2/AgTFA system; interestingly, the
corresponding Pd(COD)Cl2/AgTFA combination gave no desired
product. A number of oxidants have been examined (entry 4).
The quinone-type oxidants previously used in the Pd-catalyzed
[†]Department of Chemistry, University of Chicago, Chicago, Illinois, 60637,
United States
* Correspondence: gbdong@uchicago.edu (G. D.)
Supporting information for this article is given via a link at the end of the
document.
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desaturation[5m] showed low to moderate reactivity, whereas the
allyl oxidants employed by Newhouse and co-workers[5g,5h] were
found to be more effective in this case. Ultimately, allyl
carbonates proved to be superior. Unsurprisingly, soft
enolization using Bu2BOTf and DIPEA remained critical for the
lactam activation (entries 5 and 6). The platinum loading could
be further reduced to 5-6 mol% without significantly
compromising the yield (entries 7 and 8). A survey of solvent
effect suggested that aromatic solvents, such as toluene and
fluorobenzene, are optimal, although 1,4-dioxane also delivered
the product in 92% yield (entries 9 and 10).
With the optimized conditions in hand, the substrate scope
was explored (Table 2). First, various substitutions on
valeroalactams at the β, γ, and δ-positions can all be tolerated
(2a-2s). Note that, compared with the prior Pd system,[5m] higher
yields and full conversion for these lactams were obtained with
the Pt catalyst. This is advantageous because it is typically very
difficult to separate the unsaturated products from the remaining
starting materials; for example, pure products 2m, 2n, and 2p
were not obtained previously under the Pd-catalyzed
conditions.[5m] Gratifyingly, a wide range of functional groups
were compatible, which included aryl chloride (2d), bromide (2e),
ester (2f), trifluoromethyl (2g), nitro (2h), nitrile (2i), sulfone (2j),
ketone (2p), electron-rich aromatic rings (2k and 2l) and alkyne
(2n). In the presence of an additional enolizable tertiary amide,
desaturation of lactam 1o still occurred selectively at the lactam
moiety. In addition, lactams with different ring sizes (2t-2v) were
effective substrates. Moreover, Ts was not a suitable protecting
group in the prior Pd-catalyzed desaturation; but here good to
excellent yields of the Ts-protected lactams were achieved,[14]
suggesting that the platinum condition is more general.
Table 1. Selected optimization studies.
Next, benzofused lactams with different ring sizes were
examined. In the case of benzofused six-member ring
substrates, high yields and excellent chemoselectivity were
observed and the products underwent simultaneous
deprotection to give 2-quinolones 4a-4f. Benzofused seven- and
eight-membered substrates also worked; fluorobenzene was
found to be a better solvent for the benzofused eight-membered
compounds (4l-4n). Finally, the feasibility of desaturating
ketones and lactones was also tested with the Pt catalysis (6a-
8g). Cyclohexanones and benzofused six- and seven-
membered ketones were competent substrates. Note that
desaturation of 2-substituted cyclohexanones preferred to occur
at the less sterically hindered side. δ-Lactones with or without
benzofused scaffolds could give the corresponding unsaturated
products. A linear ester (8c) also reacted albeit in a lower
efficiency.
To show the complementarity of this method to the Pd-
catalyzed desaturation, substrates containing aryl iodides, alkyl
bromides and thioethers were investigated under both the Pt
and Pd catalysis conditions (Table 3). It is clear that aryl iodides
(9a, 9c, 9e, 9f, 9g and 9j) that were not tolerated under the Pd
conditions did not interfere with the reactions catalyzed by
platinum. On the other hand, substrates that contain alkyl
bromides (9b, 9d and 9h)[15] gave low yields with the Pd
catalysis; but they worked well under the Pt conditions. Recently,
we found that thioethers could direct sp3 C−H activation reaction
using Pd catalysis;[16] while such a substrate (9i) gave no
desired product with Pd, it became a competent substrate for the
Pt-catalyzed desaturation. Thus, the platinum-catalyzed
desaturation can be more chemoselective.
[a] Each reaction was run on a 0.1 mmol scale in a sealed 4 mL vial for 24 h;
yields were determined by 1H NMR using CH2Br2 as the internal standard. [b]
1.3 equiv. [c] No AgTFA was added. [d] 50 oC was used. TFA = trifluoroacetate,
DAC = diallyl carbonate, COD = 1,5-cyclooctadiene.
Table 2. Substrate scope with lactams, ketones and lactones.[a,b]
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R
N
O
R
N
O
O
O
O
O
Pt cat.
O
O
R'
R'
'standard' condition
R''
R''
R
R
1 or 3
5
7
2 or 4
6
8
Benzofused Lactams[f]
Lactams
O
MeO
O
PGF
Ar =
N
O
N
O
N
N
H
O
H
H
Me
Br
EtOOC
Ar
4a, 94%
4b, 91%
4c, 96%
Cl
2d,
2e, 93%
2b, 95%
2c, 93%
94%
H
O
N
4e, 84%
O
O
O
N
O
N
H
O
N
H
O
Me
NC
MeOOC
F3C
NO2
2h, 96%
4f, 80%
4d, 76%
2f, 98%
2g, 96%
2i, 91%
MeO
EtOOC
O
O
O
O
S
O
N
N
PGF
MeO
N
PGF
N
PGF
O
O
Me
R
PGF
O
2j, 95%
2k, 97%
2l, 97%
2m, 94%
R = OMe, 4i, 62%[c]
R = Br, 4j, 78%[c]
4g, 72%[c]
4h, 85%[c]
4k, 71%[c]
O
H
H
N
O
H
tBu
O
O
N
PGF
N
PGF
N
O
O
O
O
PGF
2n, 90%
2o, 88%
2p, 85%
4l, 45%[c,d]
4m, 48%[c,d]
4n, 41%[c,d]
O
N
O
O
O
O
PGF
PGF
ketones and lactones
PGF
PGF
PGF
OH
N
N
O
N
N
O
O
O
O
Ph
Ph
2q, 72%[c]
2r, 90%
2s, 88%[c]
2t, 65%[c]
2u, 85%[c]
Ph
3,4-di-Cl-C6H3
Ph
6a, 60%[d]
6b, 54%[d]
6c, 62%[d]
6d, 55%[d]
6e, 40%[d]
PGF
O
O
O
O
Ts
N
Ts
N
O
O
N
Ts
O
O
O
O
N
O
Me
Ph
OEt
+
2v, 51%[c]
2w, 93%
2x, 66%[c]
2y, 95%
6f, 39%[d]
8a, 70%[d]
8b, 67%[d]
8c, 40%[d,e]
6f', 9%[d]
O
Ph
Ph
O
O
Ts
N
Ar =
O
O
Bz
Br
O
O
Ar
Ph
8g, 78%[d]
O
O
2z, 83%
2za, 86%
2zb, 83%
8d, 82%[d]
8e, 85%[d]
8f, 88%[d]
[a] Each reaction was run on a 0.2 mmol scale in a sealed 4 mL vial for 24 h. [b] Isolated yields. [c] 50 oC was used. [d] PhF was used as the solvent. [e]
Separation of the pure product from the starting material was difficult and 24% of the starting material remained. [f] These products underwent simultaneous
deprotection during the desaturation reaction. PGF = COC6F5. Ts= p-toluenesulfonyl.
To test the practicality of this method, gram-scale reactions
were carried out with 5 mol% of the platinum pre-catalyst.
protecting group could be easily removed to reveal the free
lactam (10) under mild conditions. The α,β-unsaturated lactams
could undergo diverse efficient conjugate addition reactions to
form β-tertiary or quaternary stereocenters through C−C, C−N,
C−S and C-Si bond formation.[18]
Satisfactory
yields
were
obtained
with
either
the
perfluorobenzoyl- or Ts-protected substrates (Scheme 2). A
variety of transformations has been employed to extend the
utilities of this desaturation method (Scheme 3). First, the acyl
Scheme 2. Gram-scale reactions.
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10.1002/anie.201811197
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COMMUNICATION
Table 3. Complementary to the Pd-catalyzed desaturation.[a,b]
In summary, the first platinum-catalyzed desaturation of
carbonyl compounds has been developed. The reaction
operates at room temperature or 50 oC, with tolerating a wide
range of functional groups. Complementary features to the prior
palladium-catalyzed methods have been disclosed. Such a
unique chemoselectivity could be useful for complex molecule
synthesis. It is also anticipated that the unique mode of reactivity
discovered here should inspire the future exploration of other
platinum-catalyzed reactions.
O
O
Pt vs Pd cat.
'standard' condition
X
X
OH
OH
O
O
O
O
I
Br
O
9c, Pt: 90%[d]
Pd[e]: 0%[c,d]
9a, Pt: 68%[d]
Pd[e]: 0%[c,d]
9b, Pt: 65%[d]
Pd[e]: 18%[c,d]
I
O
PG
I
O
O
O
N
Acknowledgements
N
O
Br
PGF
9g, Pt: 75%[c]
Pd[e]: 0%[c]
I
9d, Pt: 72%[d]
Pd[e]: 24%[c,d]
We thank University of Chicago for a startup fund. M.C. thanks
Shanghai Institute of Organic Chemistry for a postdoc fellowship.
Professors Chuan He and Jack Halpern are thanked for the gifts
of platinum salts. Mr. Chengpeng Wang is acknowledged for
checking the experiments.
9e, PG = COC6F5, Pt: 92%; Pd[e]: 0%[c,d]
9f, PG = Ts,
Pt: 90%; Pd[e]: 0%[c,d]
OEt
O
9h, Pt: 88%[c]
Pd: 6%[c]
O
N
PGF
O
Br
O
S
PGF
N
O
O
O
Keywords: desaturation • lactam • ketone • lactone • platinum
I
catalysis
O
O
9i, Pt: 75%[d]
Pd[e]: 0%[c,d]
9j, Pt: 86%
Pd[e]: 0%[c]
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Entry for the Table of Contents
COMMUNICATION
Ming Chen, Alexander J. Rago and
Guangbin Dong*
Page No. – Page No.
Platinum-catalyzed Desaturation of
Lactams, Ketones and Lactones
The first platinum-catalyzed desaturation of N-protected lactams, ketones and lactones
is reported. The reaction is operated under mild conditions, scalable and
chemoselective. In particular, functional groups incompatible under the palladium-
catalyzed desaturation conditions were tolerated by the platinum catalyst.
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