Chemoselective Intermolecular Cross-Enolate-Type Coupling of Amides

Article abstract of DOI:10.1021/jacs.7b08813

A new approach for the synthesis of 1,4-dicarbonyl compounds is reported. Chemoselective activation of amide carbonyl functionality and subsequent umpolung via N-oxide addition generates an electrophilic enolonium species that can be coupled with a wide range of nucleophilic enolates. The method conveys broad functional group tolerance on both components, does not suffer from formation of homocoupling byproducts and avoids the use of transition metal catalysts.

Full text of DOI:10.1021/jacs.7b08813

Communication
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX-XXX
Chemoselective Intermolecular Cross-Enolate-Type Coupling of
Amides
Daniel Kaiser,‡ Christopher J. Teskey,‡ Pauline Adler, and Nuno Maulide*
Institute of Organic Chemistry, University of Vienna, Wahringer Strasse 1090, Vienna, Austria
̈
S
* Supporting Information
harnessing of this discrete electrophilic entity for attack of an
ABSTRACT: A new approach for the synthesis of 1,4-
dicarbonyl compounds is reported. Chemoselective
activation of amide carbonyl functionality and subsequent
umpolung via N-oxide addition generates an electrophilic
enolonium species that can be coupled with a wide range
of nucleophilic enolates. The method conveys broad
functional group tolerance on both components, does not
suffer from formation of homocoupling byproducts and
avoids the use of transition metal catalysts.
external carbon nucleophile as a new approach for the
preparation of 1,4-dicarbonyl compounds (Figure 1d).
Significantly, this amounts to a cross-coupling of different
carbonyl compounds with the α-position of an amide, a
transformation that has previously not been reported.13
mpolung is the German term coined for reversal of innate
Upolarity and, as a pivotal concept in organic chemistry,
can lead to streamlining of syntheses by realizing nonclassical
disconnections.1 It is conventionally taught in undergraduate
organic chemistry courses in conjunction with the retro-
synthetic disconnection of 1,4-dicarbonyl compounds (Figure
1a). Indeed, the most convergent approach implies the
combination of a “naturally polarized” enolate with an
“umpoled” enolate, or enolonium, species (Figure 1a, red
disconnection).
There have been a number of reports using iodine oxidants
to generate such enolonium species in situ to enable their
coupling with incoming nucleophiles.2,3 Recently, Szpilman and
co-workers conclusively characterized an enolonium species
when using Koser’s reagent and a Lewis acid with a silyl enol
ether (derived from an aryl ketone) (Figure 1b).4 Under certain
conditions where no external nucleophile is present, the silyl
enol ether undergoes dimerization to generate a 1,4-dicarbonyl
compound. This result is of particular interest because although
several different approaches have been previously described for
the synthesis of this compound class,5 notably the oxidative
heterocoupling of lithium enolates by Baran and co-workers
(Figure 1c),6 flexible methods still remain scarce. In particular,
homocoupling is a typical problem of oxidative strategies, while
quaternary center formation is often not possible. We envisaged
that we might be able to develop a more controlled union of
enolonium and enolate species such that good yields of the
cross-coupling products could be obtained to generate versatile
1,4-dicarbonyl compounds.
Figure 1. Previous approaches and our proposal.
We were well aware of a number of potential problems in
executing the selective union of the electrophilic, umpoled
amide species and the incoming nucleophilic enolate with the
desired regioselectivity (cf. center marked with green ● in
Figure 1d). First, several other competitive nucleophilic species
such as 2-iodopyridine or lutidine are bound to populate the
reaction mixture. Second, alternative reaction pathways such as
elimination or attack at other electrophilic sites on the
Our group has a long-standing interest in the chemoselective
activation of amides inspired by the early work from the groups
of Ghosez,7 and more recently Charette,8 Movassaghi,9 and
others.10 We were interested in developing a methodology that
exploited our recently reported chemistry on triflic anhydride
(Tf2O) mediated activation of amides with N-oxides to
generate an enolonium equivalent.11,12 Herein, we report the
Received: August 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b08813
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
keteniminium ion itself or the intermediate A (see centers
marked with red ● in Figure 1d) are available.
the desired product (2l), albeit in diminished yield. Under the
same conditions, sulfone product 2m and ethyl N-diphenyl-
methylene glycine adduct 2n could be prepared in synthetically
useful yields with practical handles for further elaboration.
Upon scaling up the reaction to 2 mmol scale, we were also
pleased to see no decline in yield (2c).
Our attention next turned to investigating the functional
group tolerance and substrate scope on the amide component
of the reaction (Scheme 2a). We were pleased to see that, in
Aware of these possible pitfalls, we began our initial
investigations using the sodium salt of malonate derivatives as
nucleophiles, added to the in situ generated electrophilic
enolonium species A. Careful optimization of the reaction
conditions highlighted several key parameters (see the SI for a
detailed description). 2-Iodopyridine (3 equiv used initially)
was identified as the ideal base, assuring the formation and
stabilization of the intermediate keteniminium ion.8a Further-
more, the use of 2,6-lutidine N-oxide (LNO) as the oxidant was
found to give consistently high yields; additionally, it is the
reagent of choice from an economical point of view. Though
variation of the reaction time and temperature did not lead to
an improved yield, we were pleased to find that a decrease of
the amount of 2-iodopyridine (2.2 equiv) led to the formation
of the desired product 2a in a very pleasing yield of 83% (see
Scheme 1). Using our optimized conditions, we found that, in
Scheme 2. Scope of Amides
Scheme 1. Scope of Sodium Enolates
addition to alkenes (2o), alkynes (2p) and simple alkanes
(2q),14 it was possible to include nitrile (2r) and halide (2s)
moieties. Different substitution on the nitrogen atom did not
overtly affect the yield (2t and 2u) and notably, a substrate with
a removable PMB group also underwent the transformation
(2v). Additionally, 2v serves as, to the best of our knowledge,
the first example of chemoselective addition of an enolate to the
α-position of an amide in the presence of another carbonyl
derivative. To further showcase the unique chemoselectivity of
our reaction, we expanded the scope of amides containing
additional carbonyls (ester 2w and ketone 2x; here the α-
proton is normally considered more reactive due to its lower
pKa). In both cases, we saw no byproducts where the new C−C
bond had been formed adjacent to the additional carbonyl: only
next to the amide group. This unusual chemoselectivity is a
hallmark of the present method. Though alkenes of varying
chain-lengths were tolerated in the majority of cases (2o, 2y,
2z), the failure to form 2aa constituted a minor limitation
(Scheme 2b).15
With this initial success, we were intrigued to see how far the
range of enolates could be extended beyond malonates
(Scheme 3). In this regard, we began by taking the lithium
enolate of acetophenone (generated by deprotonation with
lithium diisopropylamide at −78 °C) and adding this as before
to activated amide 1a. The product was formed in a good yield
(2ab, and, as before, this could be scaled up without any ill-
effect). Simple acetone could also be used, albeit giving the
a
b
c
Reaction run on 2 mmol scale. Ratio of isolated products. Relative
configuration not determined.
addition to unsubstituted malonates (2b and 2c), the reaction
conditions also tolerated a range of functional groups on the
malonate component: notably alkenes (2a), alkynes (2f),
nitriles (2g), halides (2h and 2i) and acetals (2j) which allow
significant opportunity for further functionalization. Further-
more, this approach allowed us to form quaternary centers
adjacent to tertiary centers in good to excellent yields (2a and
2d−j). Moving beyond malonates, malonamide was a
competent nucleophile (2k) and malononitrile also afforded
B
DOI: 10.1021/jacs.7b08813
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 3. Scope of Lithium Enolates
Scheme 4. Derivatization of Products
a
Relative configuration not determined.
We envisaged a novel heterocycle synthesis whereby
activation of 2ab with triflic anhydride would lead to
intramolecular trapping by the ketone to transiently afford
furan 3′. To our delight, upon treatment with a suitable
dienophile and acid, this underwent clean [4+2]-cycloaddition
and aromatization to form phthalimide 3 in excellent yield
(Scheme 4a). Next, we applied our recently developed
conditions for α-oxidation of amides.17 In the event, butene-
1,4-dione 4 was produced after elimination of the newly
introduced OTMP moiety (Scheme 4b).
In line with the reactivity portrayed in Scheme 4a, the
treatment of 2d with triflic anhydride led to the formation of
putative intermediate 5′, the product of cyclization of one ester
moiety onto the activated amide. Treatment of this activated
ester with allyl mercaptan afforded 5. Importantly, this is the
product of selective monoactivation and effective desymmetr-
isation of the diester moiety.18
In conclusion, we have developed a chemoselective
intermolecular cross-coupling of amides. This novel approach
to the construction of 1,4-dicarbonyl compounds allows the
coupling of enolates derived from malonates, ketones, esters,
amides, lactams and lactones to the α-position of amides via an
enolonium intermediate. This unprecedented reaction allows
quaternary center formation and shows broad tolerance of
functionality on both the amide and the incoming nucleophile,
including functional groups carrying acidic protons such as
ketones, esters and nitriles. Importantly, it virtually negates the
production of homocoupled products. The traceless nature of
the reaction allows iterative selective amide activation, which
we have taken advantage of for subsequent derivatization. We
anticipate that this novel disconnection will stimulate a number
of new synthetic strategies.
a
b
Reaction run on 1 mmol scale. Ratio of separately isolated products.
c
d
Relative configuration not determined. Major diastereomer depicted.
product in moderate yield (2ac) and β-ionone was also a
successful ketone substrate (2ad). Different ester enolates (2ae
and 2af) could be used with 2af being noteworthy in that it
showed that a quaternary center could be formed (a crystal
structure was obtained of this product to unambiguously verify
the structure, CCDC 1569559; see the SI for details).
Interestingly, this method also allowed access to amide−
amide heterocoupled products: the lithium enolate of
dimethylacetamide gave the product in good yield (2ag) and
2ah was formed in excellent yield. Furthermore, the cyclic
enolate derived from N-methyl-2-piperidone yielded product
2ai with high diastereomeric ratio (a crystal structure was again
obtained, CCDC 1577972; see the SI for details). Lactones also
reacted smoothly (2aj) and we were delighted to isolate the
product 2ak from the reaction with the enolate derived from
the natural product Sclareolide. Finally, it was important to
demonstrate that the use of lithium enolates was also
compatible with other amides containing reactive functional
groups. In light of this, we were able to show the compatibility
of ester and ketone enolates with substrates containing
functional groups of similar pKa (2al−2ao). This showcases
how enolate−enolonium coupling is competitive with proton
transfer between the incoming nucleophile and pre-existing
carbonyl functionality in the enolonium partner.
One distinct feature of our method that we were keen to take
advantage of is the “traceless” nature of amide activation:16 this
functional handle still remains in the products so we could
again selectively activate this group over the newly installed,
second carbonyl functionality. In order to demonstrate this
unique reactivity, we opted to treat several 1,4-dicarbonyls with
triflic anhydride (Scheme 4).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b08813.
■
S
Data for C21H29NO4 (CIF)
Data for C20H28O2N2 (CIF)
C
DOI: 10.1021/jacs.7b08813
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Xiao, K.-J.; Wang, Y.; Xia, X.-E. J. Org. Chem. 2015, 80, 2861.
Experimental procedures and characterization data for all
new compounds (PDF)
(d) Lumbroso, A.; Catak, S.; Sulzer-Mosse,
Tetrahedron Lett. 2015, 56, 2397. (e) Lumbroso, A.; Behra, J.; Kolleth,
A.; Dakas, P.-Y.; Karadeniz, U.; Catak, S.; Sulzer-Mosse, S.; De
Mesmaeker, A. Tetrahedron Lett. 2015, 56, 6541. (f) Kolleth, A.;
Lumbroso, A.; Tanriver, G.; Catak, S.; Sulzer-Mosse, S.; De
́
S.; De Mesmaeker, A.
́
AUTHOR INFORMATION
Corresponding Author
*nuno.maulide@univie.ac.at
ORCID
Christopher J. Teskey: 0000-0003-0776-5674
Nuno Maulide: 0000-0003-3643-0718
■
́
Mesmaeker, A. Tetrahedron Lett. 2016, 57, 2697. (g) Huang, P.-Q.;
Huang, Y.-H.; Xiao, K.-J. J. Org. Chem. 2016, 81, 9020. (h) Tona, V.;
de la Torre, A.; Padmanaban, M.; Ruider, S.; Gonzal
J. Am. Chem. Soc. 2016, 138, 8348. (i) Di Mauro, G.; Maryasin, B.;
Kaiser, D.; Shaaban, S.; Gonzalez, L.; Maulide, N. Org. Lett. 2017, 19,
́
ez, L.; Maulide, N.
́
3815. (j) Shaaban, S.; Tona, V.; Peng, B.; Maulide, N. Angew. Chem.,
Int. Ed. 2017, 56, 10938. (k) Tona, V.; Maryasin, B.; de la Torre, A.;
Author Contributions
‡These authors contributed equally.
́
Sprachmann, J.; Gonzalez, L.; Maulide, N. Org. Lett. 2017, 19, 2662.
(11) Kaiser, D.; de la Torre, A.; Shaaban, S.; Maulide, N. Angew.
Chem., Int. Ed. 2017, 56, 5921.
(12) Da Costa, R.; Gillard, M.; Falmagne, J. B.; Ghosez, L. J. Am.
Chem. Soc. 1979, 101, 4381.
(13) For examples of selective amide activation, see: (a) Chen, Y.;
Turlik, A.; Newhouse, T. R. J. Am. Chem. Soc. 2016, 138, 1166.
(b) Chen, M.; Dong, G. J. Am. Chem. Soc. 2017, 139, 7757. (c) Kaiser,
D.; Maulide, N. J. Org. Chem. 2016, 81, 4421. (d) Ruider, S. A.;
Maulide, N. Angew. Chem., Int. Ed. 2015, 54, 13856.
(14) Branching in the α- or β-position of the amide was less well
tolerated. α-Branched amides tend to undergo desaturation (also cf. ref
12). β-Branched amides lead to lower yields, presumably due to a
sterically congested enolonium intermediate A. In this context,
isovaleramide 1n could be transformed to product 6 in 20% yield.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support of this research by the FWF (Fellowship M
2274 to C.J.T.; P 30226 to N.M.), the ERC (CoG VINCAT
682002 to N.M.) and the Austrian Academy of Sciences (DOC
Fellowship to D.K.) is acknowledged. We are grateful to the
University of Vienna for continued support of our research
programs.
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DOI: 10.1021/jacs.7b08813
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX