Cross-coupling of dissimilar ketone enolates via enolonium species to afford non-symmetrical 1,4-diketones

Article abstract of DOI:10.3762/bjoc.14.84

Due to their closely matched reactivity, the coupling of two dissimilar ketone enolates to form a 1,4-diketone remains a challenge in organic synthesis. We herein report that umpolung of a ketone trimethylsilyl enol ether (1 equiv) to form a discrete enol

Full text of DOI:10.3762/bjoc.14.84

Cross-coupling of dissimilar ketone enolates via enolonium
species to afford non-symmetrical 1,4-diketones
Keshaba N. Parida, Gulab K. Pathe, Shimon Maksymenko and Alex M. Szpilman*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 992–997.
Department of Chemical Sciences, Ariel University, 4070000 Ariel,
Israel
doi:10.3762/bjoc.14.84
Received: 10 February 2018
Accepted: 03 April 2018
Published: 03 May 2018
Email:
Alex M. Szpilman* - amszpilman@gmail.com
* Corresponding author
This article is part of the Thematic Series "Hypervalent iodine chemistry in
organic synthesis".
Keywords:
1,4-diketones; enolates; enolonium species; hypervalent iodine;
ketones; umpolung
Guest Editor: T. Wirth
© 2018 Parida et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Due to their closely matched reactivity, the coupling of two dissimilar ketone enolates to form a 1,4-diketone remains a challenge in
organic synthesis. We herein report that umpolung of a ketone trimethylsilyl enol ether (1 equiv) to form a discrete enolonium
species, followed by addition of as little as 1.2–1.4 equivalents of a second trimethylsilyl enol ether, provides an attractive solution
to this problem. A wide array of enolates may be used to form the 1,4-diketone products in 38 to 74% yield. Due to the use of two
TMS enol ethers as precursors, an optimization of the cross-coupling should include investigating the order of addition.
Introduction
Substituted 1,4-dicarbonyl compounds are key intermediates for lyzed coupling of an acid chloride with premade isolable
the preparation of numerous natural products and active phar- indium homoenolates (In(CH2CHRC=OR')2), 1.2 equiv rela-
maceutical ingredients (APIs) with important biological activi- tive to the acid chloride) to give the corresponding 1,4-di-
ties. This is due to the facile conversion of 1,4-dicarbonyl com- ketones [5]. Yet the direct coupling of two enolates is inar-
pounds into five-membered heterocycles such as thiophenes, guably the shortest and most direct path to 1,4-dicarbonyl com-
furans, and pyrroles. Consequently, numerous multistep ap- pounds. However, while oxidative dimerization of enolates is
proaches to unsymmetrical 1,4-dicarbonyl compounds involv- fairly straightforward [6,7], the coupling of two dissimilar
ing, e.g., SN2-type displacements [1] or highly functionalized enolates is contrastingly highly challenging. The more similar
substrates such as β-ketoesters [2,3] or β-ketosulfones [4] have in steric and electronic properties the two dissimilar enolates
been developed. Recently, Loh reported the palladium-cata- become, the more difficult it becomes to achieve a selective
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Beilstein J. Org. Chem. 2018, 14, 992–997.
cross-coupling rather than a statistical mixture of the two The final example is the intermolecular cross-coupling of two
dimers and the desired unsymmetrical adduct. This may be dissimilar trimethylsilyl enol ethers described herein
overcome by using a large excess of one of the coupling part- (Scheme 1e).
ners [8-10], but this approach reduces the overall efficiency of
the process. Thomson [11] and Wirth [6,7,12] both circum- Results and Discussion
vented the selectivity and reactivity problem by making use of a Previously we have established that as little as 1.25 equiv of
temporary silicon connection strategy to render the reaction Koser’s reagent and 1.25 equiv of boron trifluoride in dichloro-
intramolecular. In both cases, the two ketone enolates were methane constituted an optimal recipe for preparing a variety of
coupled successively to dimethyldichlorosilane. Thomson enolonium species. We have also shown that the enolonium
achieved the cross-coupling by using cerium(IV) as a one-elec- species 4 (R1 = Ph, R2 = H) can be produced from the corre-
tron oxidant [11]. Importantly for the discussion of the present sponding TMS enol ether 1 (R1 = Ph, R2 = H) and subse-
work, Wirth’s strategy relied on a hypervalent iodine [13-15] quently coupled with a second molecule of enol ether 1/5
mediated oxidative cross-coupling. Although these processes (R1/3 = Ph, R2/4 = H) to afford the 1,4-diketone 7 in 71% yield
add a further step to the process, carrying out the cross- (Scheme 2) [31]. We therefore focused on identifying the
coupling in an intramolecular fashion has the double advantage minimum amount of the second enolate that would lead to
of avoiding homocoupling as well as helping to overcome low optimal yields and found that as little as 1.2–1.4 equiv provided
reactivity in hindered systems such as cyclohexanone [12].
the desired 1,4-diketones in acceptable yields without the need
for a large excess of the second coupling partner (Scheme 2).
To the best of our knowledge there are only five examples of Since the two coupling partners are both trimethylsilyl enol
successful intermolecular couplings of dissimilar enolates. Two ethers, an advantage of this method is that the optimization of
of these examples involve the coupling of amide enolates with the coupling of a given enolate pair may be investigated by
ketone enolates. Baran reported that stoichiometric Cu(2-ethyl- simply reversing the order of addition. In general, the major
hexanoate)2 or Fe(acac)3 (2 equiv) are able to selectively competing side reaction was the nucleophilic attack by the
oxidize imides, including Evan’s-type chiral imides, to the cor- tosylate on the enolonium species 4. Only in the rare cases
responding radicals. The formed radical then reacts selectively mentioned below homocoupling did take place.
with a ketone lithium enolate followed by a second SET step to
complete the transformation (Scheme 1a) [16,17]. A different The enolonium species 4 (R1 = Ph, R2 = H) reacts readily with
approach, developed by Maulide, relies on the highly efficient both electron-rich and electron-poor TMS enol ethers 5
umpolung of amides into enolonium species using triflic an- (Scheme 2). Thus, the cross-coupling of 4 (R1 = Ph, R2 = H)
hydride, a pyridine base and pyridine N-oxides (Scheme 1b). with the TMS enol ether 5 (R3 = p-MeOC6H4, R4 = H) afforded
These enolonium species have been shown to react intramolecu- compound 8 in 72% yield with no oxidation of the electron-rich
larly with N-benzyl groups [18-24]. The same principle has also aromatic ring observed. The only side product being tosyloxy-
been applied to the α-oxidation of amides [25]. Recently, acetophenone. The same enolonium species 4 (R1 = Ph, R2 = H)
Maulide showed that this powerful concept provides as solu- reacts with the TMS enol ether 5 (R3 = p-O2NC6H4, R4 = H) to
tion to the coupling of amides with a large variety of ketone form 9 in 65% yield.
enolates to give 1,4-dicarbonyl compounds [26]. However, the
radical-based method of Baran and the umpolung method of The method is by no means restricted to enolonium species of
Maulide both take advantage of the selective activation of an acetophenone as may be observed from the formation of the
amide and are therefore not amenable to ketone enolates. whole series of para-halogenated 1,4-diketones. Thus, the
MacMillan reported the organocatalytic oxidative enantioselec- p-fluoro-, p-chloro-, and p-bromo-substituted enolonium
tive coupling of in situ formed aldehyde enamines with excess species 4 (R3 = p-X-C6H4, R4 = H, X = F, Cl, or Br) were
(2 equiv) trialkylsilyl enol ethers (Scheme 1c) [27]. This reac- generated and used in the cross-coupling with TMS enol ether 5
tion was proposed to proceed through a mechanism involving (R3 = Ph, R4 = H) to give the products in 69% (10), 67% (11),
the attack of an enamine radical on the trialkylsilyl enol ether. and 62% (12) yield, respectively. In case of the reverse addi-
tion, namely reacting enolonium species 4 (R1 = Ph, R2 = H)
The last two examples concern the even more challenging with TMS enol ether 5 (R3 = p-Cl-C6H5, R4 = H), product 11
cross-coupling of two dissimilar ketone enolates. In this context was isolated in 53% yield. Therefore, for non-commercially
Hirao achieved the intermolecular cross-coupling by taking available enolates it could be advantageous to try both orders of
advantage of the different oxidation potentials of boron enolates addition to achieve an optimal result. Indeed, when the iodo-
and trimethylsilyl enol ethers to achieve selectivity with substituted enolonium species 4 (R1 = p-I-C6H4, R2 = H) was
vanadium (V, 0.625 equiv) as the oxidant (Scheme 1d) [28-30]. prepared and reacted with TMS enol ether 5 (R3 = Ph, R4 = H)
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Beilstein J. Org. Chem. 2018, 14, 992–997.
Scheme 1: Oxidative intermolecular cross-coupling of dissimilar enolates.
the desired product 13 is obtained in less than 10% yield yield achieved here therefore reflects issues unique to the reac-
accompanied with the homo-dimers and tosyloxylated ketones tion with the second enolate and not the stability of the enolo-
as byproducts. In contrast, reversing the order of addition of the nium species itself. Based on the formation of dimers of both
TMS-enol ethers afforded 13 in 68% yield. It should be noted ketones used, we speculate that this is due to partial oxidation of
that we have previously used the enolonium species 4 the second enolate by 4 (R1 = p-I-C6H4, R2 = H), perhaps due
(R1 = p-I-C6H4, R2 = H) successfully in the coupling with to relatively slower cross-coupling. Irrespective, these issues are
2-methylindole and N-methyl-2-methylindole and obtained the easily avoided simply by using the reverse addition to give the
products in 77% and 74% yield, respectively [32]. The low desired product 13 in good yield.
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Beilstein J. Org. Chem. 2018, 14, 992–997.
Scheme 2: Scope of the homo- and heterocoupling of enolates. The purple bond indicates the bond formed. The blue-colored fragments indicate the
first TMS enol ether used to produce the electrophilic enolonium species 4 and the red fragments indicate the second TMS enol ether used as nucleo-
phile 5. All yields are isolated yields.
The choice of the order of addition is also of importance for Thus, when the strategy of converting the least hindered enolate
substrates with more sterical hindrance. Here the trend is clear: into the enolonium species 4 is used even highly hindered TMS
it is advantageous to use the less sterically hindered TMS enol enol ethers 5 may be used with formation of tertiary carbon
ether to generate the enolonium species 4 followed by the addi- centers. Thus, the enolonium species 4 (R1 = Ph, R2 = H)
tion of the more sterically hindered TMS enol ether 5. For ex- reacted with TMS enol ether 5 (R1 = Ph, R2 =Ph) to afford the
ample, the addition of enolonium species 4 (R1 = Ph, R2 = Me) cross-coupling product 15 in 55% yield. The same enolonium
to the TMS enol ether 5 (R3 = Ph, R4 = H) led to formation of species could be cross-coupled with the TMS enol ether of
the product 14 in 30% yield with significant formation of cyclohexanone to afford the product 16 in 38% yield. Reversing
1-tosyloxypropiophenone as the major byproduct. However, the order of addition in this case led to only trace amounts of
when the order of addition was reversed, i.e., the enolonium the desired cross-coupling product. On the other hand, using
species 4 (R1 = Ph, R2 = H) was cross-coupled with TMS enol 3 equiv of cyclohexanone TMS enol ether, similarly to the
ether 5 (R3 = Ph, R4 = Me) the same product 14 was obtained in conditions used by Maulide (Scheme 1b) [26] and MacMillan
74% yield. Apparently, in these cases the sterically hindered (Scheme 1c) [27], led to the product 16 in 78% yield. The cross-
nature of the enolonium species leads it to react faster with the coupling of 4 (R1 = Ph, R2 = H) with the hindered TMS enol
less-hindered tosylate despite its poor electronic nucleophilicity. ether of tetralone (1.2 equiv) afforded 17 in 50% yield.
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Beilstein J. Org. Chem. 2018, 14, 992–997.
Importantly, also double-bond containing ketones may be used
in the reaction. For example, 4 (R1 = Ph, R2 = H) reacted with
the TMS enol ether of cyclohexenone to give 19 in 51% yield
and the reaction with the TMS enol ether of (E)-4-phenylbut-3-
en-2-one led to formation and isolation of 18 in 65% yield
(Scheme 2). Given the ubiquity of heterocycles in natural prod-
ucts and modern APIs it is also of importance that cross-cou-
pling of the easily oxidized TMS enol ether 5 (R3 = 2-thio-
phenyl, R4 = H) with 4 (R1 = Ph, R2 =H) afforded 20 in
51% yield.
Supporting Information
Supporting Information File 1
Experimental, characterization data and copies of NMR
spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-84-S1.pdf]
Acknowledgements
This research was supported by Ariel University. AMS
acknowledges support by the Israel Science Foundation (grant
no. 1914/15).
Since both meso-23 and rac-23 are well-described in the litera-
ture [33], we chose to study the diastereoselectivity of the reac-
tion using the dimerization of enol ether 21. The geometry of
the TMS enol ether 21 was established as being exclusively Z
based on 2D-NOE NMR (Scheme 3). The enolate 21 was then
converted into enolonium species 22 and cross-coupled with a
second equivalent of 21 to give the two separable diastereoiso-
mers of 23 one meso and one rac in 6:1 diastereoselectivity.
This in conjunction with earlier work from our group [34] indi-
cates that enolonium species of type 4 (Scheme 1 and
Scheme 2) are mostly configurationally stable under the condi-
tions used.
ORCID® iDs
Alex M. Szpilman - https://orcid.org/0000-0001-7790-4129
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