A Chemoselective α-Oxytriflation Enables the Direct Asymmetric Arylation of Amides

Article abstract of DOI:10.1016/j.chempr.2019.05.006

Until recently, the direct oxidative oxysulfonylation of carbonyl compounds was limited to ketones. Here, we report the first direct oxytriflation of simple, non-activated amides. Amide umpolung with triflic anhydride and pyridine-N-oxide in the absence of external nucleophiles directly leads to the formation of reactive α-triflates in a single step, which provides a platform for the deployment of valuable downstream α-functionalization reactions. The utility of this method was demonstrated by in situ clean conversion to their corresponding bromides, as desirable starting materials for nickel-catalyzed deracemizing enantioselective arylation. This approach not only enables a telescoped asymmetric arylation of unsubstituted amides but also extends its scope because of the broad chemoselectivity and functional group tolerance of the method. Amides bearing a functional group in α-position are found in many natural products and drugs. The direct α-functionalization of amides is one of the most popular approaches to access these moieties. Classically, the α-functionalization of amides has been dominated by enolate chemistry; however, carboxamides are among the least C-H acidic carbonyl derivatives, and the presence of further carbonyl or carboxyl groups (such as esters and ketones) is therefore not usually tolerated. Here, we report the first direct α-oxytriflation of simple, non-activated amides using triflic anhydride and pyridine-N-oxide in the absence of external nucleophiles, which provides a platform for the deployment of valuable downstream α-functionalization reactions. The utility of this method was demonstrated by in situ clean conversion to the corresponding bromides, which are valuable starting materials for nickel-catalyzed deracemizing enantioselective arylation. A direct and chemoselective α-oxytriflation of simple and non-activated amides has been developed. This approach provides a platform for the development of valuable downstream α-functionalization reactions of amides. Furthermore, the combination of α-oxytriflation of amides and nickel-catalyzed Suzuki reaction provides an efficient approach for direct asymmetric α-arylation of simple amides.

Full text of DOI:10.1016/j.chempr.2019.05.006

Article
A Chemoselective a-Oxytriflation Enables the
Direct Asymmetric Arylation of Amides
Jing Li, Martin Berger, Wojciech
Zawodny, Marwan Simaan,
Nuno Maulide
nuno.maulide@univie.ac.at
HIGHLIGHTS
Umpolung reactivity in the
a-functionalization of amides
First direct and selected
a-oxytriflation of simple, non-
activated amides
Asymmetric arylation of
unsubstituted amides and non-
activated amides
A direct and chemoselective a-oxytriflation of simple and non-activated amides
has been developed. This approach provides a platform for the development of
valuable downstream a-functionalization reactions of amides. Furthermore, the
combination of a-oxytriflation of amides and nickel-catalyzed Suzuki reaction
provides an efficient approach for direct asymmetric a-arylation of simple amides.
Li et al., Chem 5, 1–9
July 11, 2019 ª 2019 Published by Elsevier Inc.
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Article
A Chemoselective a-Oxytriflation Enables
the Direct Asymmetric Arylation of Amides
Jing Li,1 Martin Berger,1 Wojciech Zawodny,1 Marwan Simaan,1 and Nuno Maulide1,2,
*
SUMMARY
The Bigger Picture
Amides bearing a functional
group in a-position are found in
many natural products and drugs.
The direct a-functionalization of
amides is one of the most popular
approaches to access these
moieties. Classically, the
Until recently, the direct oxidative oxysulfonylation of carbonyl compounds was
limited to ketones. Here, we report the first direct oxytriflation of simple, non-
activated amides. Amide umpolung with triflic anhydride and pyridine-N-oxide
in the absence of external nucleophiles directly leads to the formation of reac-
tive a-triflates in a single step, which provides a platform for the deployment
of valuable downstream a-functionalization reactions. The utility of this method
was demonstrated by in situ clean conversion to their corresponding bromides,
as desirable starting materials for nickel-catalyzed deracemizing enantioselec-
tive arylation. This approach not only enables a telescoped asymmetric arylation
of unsubstituted amides but also extends its scope because of the broad chemo-
selectivity and functional group tolerance of the method.
a-functionalization of amides has
been dominated by enolate
chemistry; however,
carboxamides are among the least
C-H acidic carbonyl derivatives,
and the presence of further
carbonyl or carboxyl groups (such
as esters and ketones) is therefore
not usually tolerated. Here, we
report the first direct
INTRODUCTION
A popular approach for the direct nucleophilic substitution of alcohols entails their
temporary conversion into pseudohalides by sulfonylation agents. While the direct
introduction of this reactive functionality by a-oxysulfonylation of carbonyls is a
desirable transformation, it remains a rather challenging process, which is so far
limited to CH-acidic active methylene compounds and ketones.1–7 (Figure 1A)
The direct a-oxysulfonylation of esters or amides, on the other hand, remains
an elusive transformation, which can only be realized by sulfonylation of a-hydrox-
yamide precursors. (Figure 1B) This approach not only requires multistep
synthesis but also mandates prior a-hydroxylation, a challenge in its own right. In
particular, in comparison to carbonyl functionalities such as esters or ketones,
the a-hydroxylation of carboxamides is all the more problematic since the latter
are among the least C-H acidic of the members of the carbonyl family. Methods
for oxidative functionalization based on enolate formation by the use of strong
bases are problematic because of poor functional group compatibility.8–10 Further-
more, such approaches will eventually fail when a-hydroxylation of amides is
attempted in the presence of more CH-acidic functionalities such as ketones or
esters.
a-oxytriflation of simple, non-
activated amides using triflic
anhydride and pyridine-N-oxide
in the absence of external
nucleophiles, which provides a
platform for the deployment of
valuable downstream
a-functionalization reactions. The
utility of this method was
demonstrated by in situ clean
conversion to the corresponding
bromides, which are valuable
starting materials for nickel-
catalyzed deracemizing
enantioselective arylation.
Our group has a long-standing interest in the chemoselective activation of amides
inspired by pioneering early work of Ghosez11,12 and, more recently, Charette,13–16
Movassaghi,17–19 Huang,20–25 and others.26–28 We recently developed a robust
approach for the a-oxyamination29,30 of amides by use of triflic anhydride (Tf2O)
and TEMPO29 (Figure 1B). Reductive cleavage of the resulting aminoxylation prod-
ucts (e.g., using zinc in acetic acid) afforded the desired a-hydroxyamides. Although
this approach displays high efficiency when the alcohol is the desired product, addi-
tional operations (raising the overall step count) would be necessary if oxysulfonyla-
tion is the ultimate aim. Direct oxysulfonylation of amides would be unprecedented
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Figure 1. Methods for a-Oxysulfonylation of Carbonyl Compounds
(A) Previous approaches for the direct oxysulfonylation of carbonyl groups, limited to ketones and
malonates.
(B) Synthesis of a-oxytriflated amides requiring multistep synthesis.
(C) Direct a-triflation of simple amides via the umpolung of amides in absence of nucleophiles, as
presented herein.
and highly desirable, especially as the products would be reactive synthetic assets for
downstream applications. Here (Figure 1C), we present (to the best of our knowl-
edge) the first direct a-oxytriflation of amides as a platform enabling the deployment
of other, valuable a-functionalization reactions.
RESULTS AND DISCUSSION
1University of Vienna, Institute of Organic
Reaction Discovery
Chemistry, Wahringer Strasse 38, 1090 Vienna,
¨
Austria
Intrigued by our previous a-arylation of amides utilizing Tf2O-mediated activa-
tion,31–33 we initially set out to develop an asymmetric variant. (Scheme 1A) Among
investigated approaches, we hypothesized that addition of a chiral nitrone (Ox1)34 to
an in situ generated keteniminium salt A from amide 1a would lead to addition
2Lead Contact
*Correspondence: nuno.maulide@univie.ac.at
https://doi.org/10.1016/j.chempr.2019.05.006
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Scheme 1. Unexpected a-OTf Amide Formation
In (A) is the initially designed asymmetric arylation of amides and unexpected isolation of
triflate 2a and in (B) and (C) is the screening of oxidants and amides, revealing pyridine-N-oxide
(PNO, Ox 3) as an ideal oxidant and indolylamide 2c as an optimal substrate. Abbreviations are as
follows: Tf2O, trifluoromethanesulfonic anhydride; DCM, dichloromethane.
product B, which should ideally be poised to undergo [3,3]-sigmatropic rearrange-
ment potentially with chirality transfer to the desired enantiomerically enriched
a-arylated amide C. Unexpectedly, a different compound was formed cleanly in
very good nuclear magnetic resonance (NMR) yield and identified to be triflate 2a.
This surprising observation can be explained by release of an imine from intermedi-
ate B and unusual attack of the weakly nucleophilic triflate counterion, generating
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the a-triflated amide (see Figures S1 and S2 for further information). To further un-
derstand this process, we screened a number of N- or S-oxides (Ox1-Ox6), revealing
that pyridine N-oxide (PNO) or lutidine N-oxide (LNO) performed best, yielding the
labile triflate in essentially quantitative yield. (Scheme 1B) In contrast, sulfoxides
(such as DMSO or diphenylsulfoxide) did not produce any triflate.
It is important to point out that a-OTf carbonyl compounds are usually labile inter-
mediates prone to decomposition during the purification by column chromatog-
raphy and compound 2a is no exception.35,36 Upon attempted purification by
column chromatography, only trace amounts of triflate were retrieved. Fast flash
chromatography at ꢀ30ꢁC was required to obtain pure triflate in 80% isolated
yield. Since this amide a-oxytriflation proceeds in a very clean fashion, purification
of the products is best avoided, and they can be directly subjected to further
functionalization in situ (see Figure S3 for further information). We then turned
our attention toward amide substrates carrying different substitution at nitrogen,
which also quickly outlined the boundaries of the method. (Scheme 1C) It
was found that amides structurally predestined for Friedel-Crafts-type cyclization
by presence of N-benzyl groups will prefer to undergo a-arylation instead of
a-oxytriflation (see Table S1 for further information).31 However, amides bearing
N-alkyl groups such as 1a or aromatic amides for which cyclization is impeded
because of nascent ring strain readily undergo triflate formation. While the
triflate of N-phenylamide 2b was formed in good yield, indolyl-amide 1c proved
superior in delivering the triflate in a very clean manner and nearly quantitative
NMR yield.
Cognizant of the high chemical reactivity of these triflates, we decided to leverage
this efficient approach for a-OTf amide formation toward the originally planned
asymmetric a-arylation transformation. Inspired by previous reports of arylation of
a-halogenated carbonyl compounds with aryl nucleophiles (e.g., 9-BBN, ArZnX,
and ArMgX)37–44 we initially hoped that this in situ, easily generated a-trifloxy func-
tionality might open a path to the direct asymmetric a-arylation of amides via tran-
sition-metal catalysis.45 Indeed, Fu has pioneered an efficient enantioconvergent
a-arylation of a-halogenated amides with Ar-(9-BBN) reagents using nickel-cata-
lyzed Suzuki cross-coupling.37 Since indolyl amides are also the reagents of choice
for that cross-coupling, we carried out initial experiments to that end, quickly finding
that a-OTf amides are not responsive to nickel catalysis.
Substrate Scope Studies of Cross-coupling
Fortunately, the high reactivity of the triflates allowed conversion to the required
halides by simple addition of tetraethylammonium bromide (NEt4Br) to the reaction
mixture directly after the triflation step. In the event, nucleophilic substitution pro-
ceeded very rapidly (<10 min) at room temperature, generating the corresponding
a-brominated amides in very high yield. As a simple filtration gave analytically pure
bromides, we directly subjected them to Fu cross-coupling37 conditions with small
modifications (Figure 2). The choice of solvent proved to be crucial for the sensitive
reaction, and solvent exchange to a heptane-diethyl ether mixture proved to be
crucial in order to afford the desired a-arylated amides in good yields and enantio-
meric ratios. Bromination of the amides is operationally simple and can be easily
performed within 1 h, essentially obviating the use of pre-halogenated amides.
(see Table S2 for further information) As demonstrated with simple alkylated
amides (3a-3f) or heteroatom substituents (3g and 3h), the overall yields and enan-
tiomeric excesses are typically very good, reflecting the overall efficiency of our
a-oxysulfonylation procedure (Scheme 2). Rather than a simple juxtaposition of
4
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Figure 2. Demonstrating Synthetic Utility of a-OTf Amide
Shown in (A) is the rapid conversion into corresponding bromide and in (B) is the direct
subjection of crude bromides to enantioconvergent cross-coupling using a modified procedure
by Fu.37
protocols, our procedure further provides an expansion of the scope of asymmetric
arylation chemistry. This is showcased by the tolerance of carbonyl groups such as
ketone 3l or ester 3k, otherwise inaccessible if base-promoted halogenation reac-
tions were considered for the preparation of the corresponding substrates. We also
screened various borane nucleophiles, consistently leading to products (3m-3t) in
good yields.
The indolylamide motif offers synthetic versatility for further modifications.
(Scheme 3) Cleavage of such amides can easily be achieved after their conversion
to the corresponding indole analogs via 2,3-dichloro-5,6-dicyano-p-benzoqui-
none (DDQ) oxidation without erosion of enantiomeric purity as previously
shown by Fu37 (Scheme 3A). Besides this cleavage to carboxylic acids, we
expanded further the synthetic utility by ozonolysis at C2-C3, yielding 2-amino-
benzaldehyde 6 as an ideal precursor for the synthesis of heterocycles.46–49
Pinnick oxidation of 6 and subsequent treatment with Ac2O yielded a-chiral ben-
zoxazinone 7 in excellent yield.50 In addition, simply stirring of 6 in aqueous
ammonia gave access to a biologically active core represented by quinazoline
8 in quantitative yield.51,52 Alternatively, amide (G)-5 could be easily converted
to the N-(2-phenylpropyl)indole 9 in high yield by simple catalytic reduction,53
while C-2 arylation by Pd-catalyzed C-H activation proceeded smoothly to
afford 10.54
Conclusions
In conclusion, the first direct a-oxytriflation of amides was developed. The reaction
proceeds with chemoselectivity for amides in presence of more electrophilic
carbonyl functionalities and high functional group tolerance. The sensitive triflates
were formed in high purity and can be directly subjected to in situ functionalization.
As a demonstration, we deployed these reactive intermediates in the direct asym-
metric a-arylation of amides, with extended scope enabled by the newly developed
transformation. This direct oxysulfonylation of amides is a promising avenue for the
development of useful transformations.
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Scheme 2. Scope of a-Arylation of Simple Amides, Enabled by Pre-unctionalization Using Our Operationally Simple a-Oxysulfonylation Approach
All reactions were conducted on 0.25 mmol scale under optimized conditions. All yields refer to pure, isolated materials. See the Supplemental
Information for details of conditions.
6
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Scheme 3. Interconversions of the Privileged Indolylamide Moiety
Reaction conditions:
(a) 3u (1 equiv) and DDQ (2 equiv) in toluene at 80ꢁC for 2 h.
(b) LiOH (3.76 equiv), H2O2 in THF overnight.
(c) 3b (1 equiv) and DDQ (2 equiv) in toluene at 80ꢁC for 2 h.
(d) O3, then Me2S, and then K2CO3/MeOH.
(e) Pinnick oxidation, then Ac2O for 1 h at 130ꢁC.
(f) 6 (0.2 mmol) in EtOH (0.5 mL) + 25% NH3 solution (0.5 mL) for 9 h were used.
(g) (G)-5 (0.2 mmol), PhSiH3 (3 equiv), NiCl2.glyme (10%) in toluene at 130ꢁC for 24 h.
(h) (G)-5 (0.2 mmol), Pd(TFA)2 (10%), AgOAc (3 equiv), t-BuCOOH (2 equiv) at 90ꢁC for 12 h.
Abbreviations are as follows: DDQ, 2,3-dichloro-5,6-dicyano-p-benzoquinone; LiOH, lithium
hydroxide; H2O2, hydrogen peroxide; Ac2O, acetic anhydride; O3, ozone; PhSiH3, phenylsilane;
NH3, ammonia.
EXPERIMENTAL PROCEDURES
Representative Umpolung and Cross-coupling Procedure
Amide 1 (0.25 mmol) and 2-iodopyridine (2.2 equiv, 58.5 mL, 0.55 mmol) was dis-
solved in dry DCM (2.5 mL). At 0 ꢁC, trifluoromethanesulfonic anhydride (1.1 equiv,
46.3 mL, 0.275 mmol) was added and the reaction was stirred for 5 min. Then, pyri-
dine N-oxide (1.1 equiv, 26.2 mg, 0.275 mmol) was added, the ice bath was
removed, and the mixture was stirred for 10 min at room temperature until decolor-
ization was complete. Tetraethylammonium bromide (2 equiv, 105 mg, 0.5 mmol)
was added, and the mixture was stirred for 10 min. HCl (4 equiv, 2.0 M solution in
Et2O, 0.5 mL) was added, the mixture was stirred for 1 min, and the mixture was
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filtered with a small pad of silica gel and then washed with Et2O (20 mL). After
removal of solvent in vacuo, the residue was suspended in Et2O (dry, 1.25 mL) and
added to a separate flask containing nickel(II) bromide 2-methoxyethyl ether com-
plex (10 mol %, 8.8 mg, 0.025 mmol), (1R,2R)-(+)-N,N0-Dimethyl-1,2-bis[3-(trifluoro-
methyl)phenyl] ethanediamine (13 mol %, 12.2 mg, 0.032 mmol), Ph-(9-BBN) (1.5
equiv, 74.3 mg, 0.37 mmol), KOt-Bu (1.3 equiv, 36.5 mg, 0.325 mmol) (all reagents
were charged in a glove box) and n-butanol (1.5 equiv, 34 mL, 0.37 mmol) in heptane
(dry, 1.25 mL) at 0ꢁC. The mixtures were stirred vigorously overnight at this temper-
ature. After addition of aqueous Na2CO3 solution (sat., 10 mL), the product was ex-
tracted with EtOAc (3 3 10 mL). The combined organic layers were dried with
MgSO4, concentrated and purified by column chromatography silica gel to afford
the desired products.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2019.05.006.
ACKNOWLEDGMENTS
Generous support of our research programs by the University of Vienna is acknowl-
edged. We are grateful for financial support of this research by the European Research
Council (ERC) (CoG VINCAT) and the Austrian Science Fund (FWF) (Project P30226).
N.M. is the recipient of the Lieben Preis of the Austrian Academy of Sciences.
AUTHOR CONTRIBUTIONS
N.M. conceived and supervised the project. J.L., M.B., W.Z., and M.S. conducted the
experimental work. J.L., M.B., W.Z., and N.M. co-wrote the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: February 21, 2019
Revised: April 6, 2019
Accepted: May 3, 2019
Published: May 27, 2019
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