Metal-Free Formal Oxidative C?C Coupling by In Situ Generation of an Enolonium Species

Article abstract of DOI:10.1002/anie.201701538

Much contemporary organic synthesis relies on transformations that are driven by the intrinsic, so-called “natural”, polarity of chemical bonds and reactive centers. The design of unconventionally polarized synthons is a highly desirable strategy, as it generally enables unprecedented retrosynthetic disconnections for the synthesis of complex substances. Whereas the umpolung of carbonyl centers is a well-known strategy, polarity reversal at the α-position of a carbonyl group is much rarer. Herein, we report the design of a novel electrophilic enolonium species and its application in efficient and chemoselective, metal-free oxidative C?C coupling.

Full text of DOI:10.1002/anie.201701538

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201701538
German Edition: DOI: 10.1002/ange.201701538
Umpolung
À
Metal-Free Formal Oxidative C C Coupling by In Situ Generation of
an Enolonium Species
Daniel Kaiser+, Aurꢀlien de la Torre+, Saad Shaaban, and Nuno Maulide*
Abstract: Much contemporary organic synthesis relies on
transformations that are driven by the intrinsic, so-called
“natural”, polarity of chemical bonds and reactive centers. The
design of unconventionally polarized synthons is a highly
desirable strategy, as it generally enables unprecedented
retrosynthetic disconnections for the synthesis of complex
substances. Whereas the umpolung of carbonyl centers is
a well-known strategy, polarity reversal at the a-position of
a carbonyl group is much rarer. Herein, we report the design of
a novel electrophilic enolonium species and its application in
À
efficient and chemoselective, metal-free oxidative C C cou-
pling.
Figure 1. Umpolung of carbonyl compounds.
P
olarity reversal at a reactive center, termed umpolung, is
a powerful tool in organic synthesis. Given how much of
contemporary organic synthesis hinges on transformations
that are driven by the intrinsic, so-called “natural”, polarity of
chemical bonds and reactive centers, this unconventional
approach opens up entirely new opportunities in synthesis.
The most commonly used “umpoled” synthon is the acyl
anion equivalent, which allows inversion of the polarity at
a (usually electrophilic) carbonyl center, thereby rendering it
nucleophilic (Figure 1A). Acyl anion equivalents can be
generated by various methods, from thioacetals in the
classical Corey–Seebach reaction[1] to NHC-catalyzed trans-
formations.[2] On the other hand, polarity reversal at the a-
position to a carbonyl group (usually a nucleophilic center by
virtue of enolization) is much less common (Figure 1B).
Besides methods necessitating a leaving group in the a-
position to the carbonyl group, this problem was only recently
addressed by the group of MacMillan, who merged organo-
catalysis and SOMO activation.[3,4] Despite the significant
advance it provided, this approach requires a careful match-
ing of redox potentials. Of special interest is the method
developed by the group of Miyata which is based on the
formation of an N-alkoxyenamine intermediate that can be
reacted with organoaluminum nucleophiles and, thus, entails
a formally electrophilic a-carbon atom.[5] Other methods
were reported by the research groups of Zard[6] and Szpil-
man.[7] Despite these latest developments, achieving umpo-
lung reactivity at the a-position to carbonyl centers remains
a largely unmet challenge. In particular, umpolung at the a-
position of amides has only rarely been reported.
The electrophilic activation of amides by using triflic
anhydride has emerged over the years as a powerful tool in
organic chemistry. Since the seminal work by Ghosez and co-
workers[8] as well as by the group of Charette,[9] advances in
this field allowed a range of chemoselective transforma-
tions.[10] Our group recently reported a chemo- and stereose-
lective modular a-amination of amides based on amide
activation.[11] One unexpected result caught our attention
during this study (Scheme 1). In the case of a substrate
containing an ester appendage at a suitable distance from the
amide a-position, a tricyclic product II was formed instead of
the expected amination product. Our mechanistic interpreta-
tion of this result suggested that the putative intermediate I
was trapped by nucleophilic attack of the ester. In this case,
the intermediate I behaved as a partially electrophilic (and
thus “umpoled”) enamine. We envisaged generating an
electrophilic enolonium species in a similar fashion by using
the combination of an activated amide and a suitable O-
nucleophile bearing a leaving group. Pyridine N-oxides were
recently used in this sense by the research groups of Hashmi,
Ye, and Zhang to generate related intermediates.[12] Herein,
we report the use of pyridine N-oxides in a novel approach to
trigger chemoselective umpolung reactivity at the a-position
of amides. The transformations described herein constitute
À
formal metal-free oxidative C C coupling, thus addressing
a contemporary challenge in organic synthesis.[13]
The envisioned reaction was studied on the model
substrate dibenzylamide 1a, which can undergo intramolec-
ular cyclization to afford the isoquinolinone 2a. Extensive
studies showed the optimized conditions involved the use of
2,6-lutidine-N-oxide (LNO) and 2-iodopyridine in aceto-
nitrile (see the Supporting Information for details of the
optimization). The use of molecular sieves was crucial to
avoid reproducibility issues. The generality and functional-
[*] D. Kaiser,[+] Dr. A. de la Torre,[+] S. Shaaban, Prof. Dr. N. Maulide
Institute of Organic Chemistry, University of Vienna
Wꢀhringer Strasse 38, 1090 Wien (Austria)
E-mail: nuno.maulide@univie.ac.at
Homepage: http://maulide.univie.ac.at
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
https://doi.org/10.1002/anie.201701538.
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À
Scheme 1. Proposed approach for polarity reversal and formal C C
coupling.
group tolerance of the reaction was then evaluated under
those conditions by using various substrates (Scheme 2).
Various linear and branched amides provided the desired
À
products of C C coupling in moderate to good yields (2a–c).
Similar to most transformations involving the activation of
amides by triflic anhydride, our reaction proved to be tolerant
of several sensitive functional groups, including ketones (2d),
esters (2e), nitriles (2 f), alkenes (2g), sulfonamides (2h), and
halides (2i). Aryl acetamides 1j–s with a wide array of
functionalization and substitution patterns were also suitable
substrates in the reaction and afforded the corresponding
products in high yields. The higher yields observed for these
substrates are consistent with the hypothesis of an electro-
philic enolonium intermediate, whose LUMO would be
stabilized by overlap of the p-system of the aromatic ring.
a-Trisubstituted products could be obtained from a-branched
substrates, with 2t and spirocyclic 2u obtained in moderate
yields. Interestingly, the transformations depicted in
Scheme 2. Substrate scope of various dibenzylamides for the umpo-
lung arylation. [a] 2-Fluoropyridine and pyridine N-oxide were used.
See the Supporting Information for further details. LNO=lutidine
N-oxide, brsm=based on recovered starting material.
(more substrates can be found in the Supporting Informa-
tion). X-ray analysis of dihydrobenzo[f]isoquinolinone 2ad
confirmed the assigned structures unambiguously. Thiophene
also proved to be a suitable partner for this reaction, although
the formation of 2ae was slightly more sluggish. In addition,
N-phenylamides 1af and 1ag could be converted into
oxindoles 2af and 2ag, respectively, through a 5-endo-trig
cyclization disfavored according to Baldwin rules.
Olefinic moieties also proved to be competent nucleo-
philic agents (Scheme 3), as exemplified by the formation of
dihydropyridinone 2ah, and tetrahydropyridinone 2ai. Of
special interest is the possibility of forming the endocyclic
(2ah) or exocyclic (2ai) olefin product selectively, depending
on the choice of starting material. Interestingly, these
Scheme 2 correspond to an array of chemo- and regioselective
[14]
À
enolate C H arylation reactions (formal coupling of two
À
C H bonds) which do not require any transition metal or
strong base promoter and, thus, are tolerant of a broad range
of functional groups.
We then turned our attention to the use of unsymmetrical
tertiary amides (Scheme 3). In the event, increasing the steric
bulk on the nitrogen atom led to more efficient reactions,
likely by populating conformers ideally disposed for cycliza-
tion (2v–2y). Moreover, macrolactams 1z and 1aa were
transformed smoothly into the bridged dihydroisoquinoli-
nones 2z and 2aa, respectively. Amides with various elec-
tronically and regiochemically substituted benzyl groups
afforded the desired compounds 2ab–ad in good yields
À
À
reactions are formal C H ene and C H Sakurai processes.
We then explored the possibility of performing our
reaction in a diastereoselective fashion (Scheme 4). The use
of chiral amides 1aj–1al led to diastereoselective cyclization,
with 2aj–2al obtained in good to excellent yields and
moderate to good diastereoselectivities (up to 7.1:1).[15]
Notably, no epimerization was observed after submitting
2
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mechanism, the 18O-labeled amide 1o (93% 18O) led to
product 2o with complete loss of the 18O label (Scheme 5).[17]
Gram-scale reaction of N,N-dibenzylphenylacetamide
(1j) afforded lactam 2j in 99% yield, compared to a 85%
yield on a 0.2 mmol scale (Scheme 6a). With this material in
hand, diverse functionalizations were carried out: the biolog-
Scheme 5. 18O-Labeling experiment.
Scheme 3. Substrate scope of amides and nucleophiles in the umpo-
lung functionalization. LNO=lutidine N-oxide.
Scheme 6. Product derivatizations and applications. a) BH3·DMS
(6 equiv), THF, 0 to 258C, 2 h, 99%; b) Lawesson’s reagent
(1.5 equiv), pyridine (0.1 equiv), PhMe, 1158C, 1.5 h, 97%; c) phenol
(3 equiv), H3PO4, 1508C, 22 h, 49%; d) DDQ (1.05 equiv), DCE, 808C,
16 h, 77%. DMS=dimethylsulfide, DDQ=2,3-dichloro-5,6-dicyano-
1,4-benzoquinone, DCE=1,2-dichloroethane.
ically relevant tetrahydroisoquinoline scaffold (3) could be
obtained in quantitative yield by reduction,[17] thionation led
to 4 in similar yield,[18] while selective exocyclic debenzylation
delivered secondary amide 5.[19] 2-Benzyl-4-phenylisoquino-
lin-3(2H)-one (6) was formed by selective oxidation of 2j with
DDQ. The synthetic utility of this method was further
exemplified by an expeditious synthesis of McN-5652,
a highly potent blocker of serotonin 5-HT transporter
uptake, in two steps from (2-phenyl)pyrrolidine amide 1am
(Scheme 6b).[20,21]
À
Scheme 4. Diastereoselective C C coupling.
diastereopure 2ak to the reaction conditions, thereby proving
the kinetic nature of the selectivities.
We further aimed to better understand the mechanism of
our reaction. Various experiments were performed, including
a comparision of the relative abilities of LNO and diphenyl
sulfoxide to effect the oxidative coupling (see Scheme S1 in
the Supporting Information for detailed mechanistic experi-
ments).[16] Notably, and in agreement with our proposed
In summary, we herein present a conceptually new
approach for achieving polarity reversal at the a-center of
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À
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Acknowledgements
Generous support of this research by the ERC (FLATOUT,
StG 278872), the FWF (P27194), the DFG, and the University
of Vienna is acknowledged. D.K. is a recipient of a DOC
Fellowship of the Austrian Academy of Sciences.
Conflict of interest
The authors declare no conflict of interest.
Keywords: amide activation · chemoselectivity ·
keteniminium ions · oxidative C C coupling · umpolung
À
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Manuscript received: February 12, 2017
Revised: March 11, 2017
Final Article published: && &&, &&&&
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Communications
Umpolung
D. Kaiser, A. de la Torre, S. Shaaban,
N. Maulide*
&&&& — &&&&
À
Metal-Free Formal Oxidative C C
Coupling by In Situ Generation of an
Enolonium Species
Umpole me: The design of unconven-
tionally polarized synthons is a highly
desirable strategy in synthesis. While the
umpolung of carbonyl centers is a well-
known strategy, polarity reversal at the a-
position to a carbonyl group is much
rarer. The design of a novel electrophilic
enolonium species for chemoselective,
À
metal-free oxidative C C coupling is now
reported.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!