Chemoselective formal β-functionalization of substituted aliphatic amides enabled by a facile stereoselective oxidation event

Article abstract of DOI:10.1039/c9sc03715b

Aliphatic C-H functionalization is a topic of current intense interest in organic synthesis. Herein, we report that a facile and stereoselective dehydrogenation event enables the functionalization of aliphatic amides at different positions in a one-pot fa

Full text of DOI:10.1039/c9sc03715b

Chemical
Science
View Article Online
View Journal
EDGE ARTICLE
Chemoselective formal b-functionalization of
substituted aliphatic amides enabled by a facile
stereoselective oxidation event†
Cite this: DOI: 10.1039/c9sc03715b
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Adriano Bauer and Nuno Maulide
*
Aliphatic C–H functionalization is a topic of current intense interest in organic synthesis. Herein, we report
Received 28th July 2019
Accepted 29th August 2019
that a facile and stereoselective dehydrogenation event enables the functionalization of aliphatic amides at
different positions in
a one-pot fashion. Derivatives of relevant pharmaceuticals were formally
DOI: 10.1039/c9sc03715b
functionalized in the b-position in late-stage manner. A single-step synthesis of incrustoporine from
rsc.li/chemical-science
a simple precursor further showcases the potential utility of this approach.
7
the a-position via rearrangement and Umpolung chemistry.
Introduction
However, the method depicted in Scheme 1b is limited to a-
8a
The carbonyl functional group remains one of the most important unsubstituted amides. In this manuscript, we report a stereo-
synthetic handles in organic chemistry. While the a-carbon selective and mild a,b-dehydrogenation and how it enables not
atom and the ipso-position of this ubiquitous structural motif can only the direct formal b-C(sp )–H functionalization of simple
be modied in many ways, the direct modication of the b- amides under a metal-free regime, but also the functionaliza-
1,2
3
2
position is more elusive. With the advent of C–H functionaliza- tion of multiple carbon atoms in a,b and g-positions.
tion, transformation of molecular moieties which are traditionally
1–3
perceived as unreactive became feasible. The past decades have
witnessed an explosive wealth of accomplishments regarding this
3
family of transformations. Relying on the transient generation of
internally chelated, cyclopalladated intermediates such as 2
(
Scheme 1a), this mode of C–H functionalization has been effec-
4
tively exploited particularly for b-methyl carbonyl derivatives. The
emerging eld of photoredox catalysis has also proven to be
5
a powerful tool for the b-functionalization of cyclic ketones.
More conventional approaches make use of classical Michael
addition strategies. However, the requisite a,b-unsaturated
carbonyl compound is not always readily available. While the
oxidative dehydrogenation of a-branched chloroenamines has
8b
been previously realized by Ghosez et al. (though no E/Z
selectivity was described), we have recently disclosed a sele-
nium-mediated, one-pot a,b-dehydrogenation of amides (cf. –
4
/ 5, Scheme 1b) in moderate to good yields. More recently
a stepwise dehydrogenation using a-TEMPO (tetramethylpi-
peridinyloxyl) amides as intermediates for the dehydrogenation
8
c
of linear amides has been reported.
This approach is predicated on the electrophilic activation of
carboxamides, a reactivity mode that enables transformations
6
a–d
ranging from the venerable [2 + 2] cycloaddition
substitution
and ipso
6
e–g
reactions all the way to the functionalization of
Scheme 1 (a) Previous work on b-C–H functionalization of aliphatic,
quaternary carboxamides. (b) Earlier report on dehydrogenation of
carboxamides by electrophilic activation. (c) Chemoselective, formal
remote functionalization of carboxamides enabled by stereoselective
dehydrogenation.
Institute of Organic Chemistry, University of Vienna, W a¨ hringer Straße 38, 1090
Vienna, Austria. E-mail: nuno.maulide@univie.ac.at
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c9sc03715b
1
This journal is © The Royal Society of Chemistry 2019
Chem. Sci.

View Article Online
Chemical Science
Edge Article
Results and discussion
Preliminary results
During our studies on the Umpolung functionalization of
7
amides, we observed that a-branched amides deviate from
Umpolung reactivity at the a-carbon. Instead, treatment of a-
branched amides with triuoromethanesulfonic anhydride
(
Tf O), 2-iodo pyridine and pyridine N-oxide (PNO) resulted in
2
clean and high-yielding a,b-dehydrogenation rather than the
9
Umpolung reactivity we had previously observed. Moreover, a-
aryl-substituted amides gave quantitative yield with the exclu-
sive formation of one alkene-isomer. Importantly, careful
analysis revealed that the dehydrogenation of a-aryl substituted
amides gave exclusively the Z-olen (by NMR), whose structure
was conrmed by NOESY-NMR spectroscopy (cf. Scheme 2a, 6a
/
7a). On the other hand, a-branched dialkyl amides typied
by 12 afforded an inseparable mixture of regio- and stereoiso-
mers (Scheme 2b) with moderate selectivity. In particular, when
the isopropyl-substituted, a-branched amide 14 was submitted
to the reaction conditions we observed (Scheme 2c) equal
amounts of the expected tetrasubstituted alkene 15a and the
unexpected b,g-dehydrogenated amide 15b by NMR. The latter
product is presumably formed by a Wagner–Meerwein rear-
rangement of the putative unstable carbocation 16 as shown
Scheme 3 Proposed mechanism and stereochemical model for the
observed high stereoselectivity of the dehydrogenation event.
14
14
to an a-carbocationic amide 20 (Scheme 3). A rationale for the
high Z/E selectivity is provided by the model shown in Scheme 3.
Efficient mesomeric stabilization of the putative carbocationic
intermediate mandates perpendicular arrangement of the
adjacent aromatic moiety, resulting in restricted rotation of the
(Scheme 2c). It is noteworthy that 14 reacted sluggishly.
The dehydrogenation reaction leads to very similar results
14
arene substituent. This exacerbates steric hindrance consid-
erations, disfavoring a scenario where even a methyl group in
the b-position is on the same side as the arene ring. As steric
congestion increases during formation of the double bond, it is
likely that elimination is greatly favoured from the thermody-
namically favored conformer 20a.
regardless of whether 2-chloro- or 2-bromo pyridine is used
instead of 2-iodo pyridine (a relevant piece of information for
future developments, vide infra. See the ESI for further details†).
No reaction intermediates en route to dehydrogenation could
be detected by NMR spectroscopy. We believe that the reaction
proceeds by swi fragmentation of the enolonium species 19a
One pot a,b-epoxidation
This surprisingly stereoselective and efficient result (quantitative
conversion within minutes at room temperature) encouraged us
to leverage in situ oxidation in order to achieve formal remote
functionalization reactions. In particular, we were looking to
draw on the high diastereoselectivity of the dehydrogenation
event. In our hands, Prilezhaev oxidation using meta-chlor-
operbenzoic acid (commercial grade mCPBA) proceeded
10
smoothly in quantitative yield at room temperature (Scheme 4).
When we investigated the possibility of a one pot proce-
dure an unexpected hurdle was encountered, in that the
Scheme 2 (a) Preliminary results. (b) Dehydrogenation of purely
aliphatic a-branched amides. (c) Unexpected formation of a b,g-
a
b 1
dehydrogenated amide. Yield refers to the pure isolated product.
H
Scheme 4 a,b-Epoxidation of a simple amide. See ESI† for detailed
reaction conditions. Yield refers to the pure isolated product.
a
NMR yield with mesitylene as the internal standard.
Chem. Sci.
This journal is © The Royal Society of Chemistry 2019

View Article Online
Edge Article
Chemical Science
original procedure using 2-iodo pyridine for the dehydroge-
nation step was not compatible with the Prilezhaev oxidation,
most likely due to the easily oxidized iodine atom. This issue
was readily circumvented by using 2-chloro pyridine instead.
Pivotal to the one-pot procedure with 2-chloro pyridine was
the addition of an acid quencher (water or an aqueous
NaHCO
3
solution) before adding mCPBA, owing to the high
acidity of protonated 2-chloropyridine present in the solution
1
2
(
pK
a
¼ 0.49 in H
2
O).
By use of this procedure, formal a,b-oxygenation of simple
amide 6a was achieved in 93% isolated yield in one pot. The
reaction proceeds with a very similar yield on a gram scale. As
shown in Scheme 5a, this transformation has some generality
and tolerates a range of functional groups, such as esters
(
10d, 10f), nitriles (10e) and silyl ethers (10c). Electron-
withdrawing (such as pCF , 10n) and -donating groups
such as OMe, cf. 10j) are well tolerated at diverse positions of
3
(
ꢀ
the aryl substituent (Scheme 5a). Heating to 40 C was found
to be generally benecial during the epoxidation event to
enhance conversion in cases were the aromatic ring is elec-
1
1
tronically impoverished. The use of aqueous NaHCO
3
instead of water enables successful reaction for acid-sensitive
substrates (e.g. TBS protected alcohol, cf. 10c) or sensitive
products (electron rich aromatics in proximity to the formed
epoxide, cf. 10j). Diastereoselectivity was found to be excellent
in all cases: the only case in which the other diastereoisomer
1
was detected in the crude reaction mixture (in traces by H
NMR, d.r. > 25 : 1) is the sterically congested product 10b.
These epoxides can serve as precursors to more elaborated
architectures as depicted in Scheme 5b. NaHMDS-mediated
deprotonation of 10e, which was obtained in good yield
using the present protocol, led to diastereoselective intra-
1
3
molecular epoxide opening. The resulting tertiary alcohol
2, which contains three contiguous stereogenic centers, was
2
obtained as a single diastereoisomer.
One pot b-oxidation and oxidative C–C bond cleavage
Interestingly (Scheme 6a), when the acid scavenger was omitted
in the domino a,b-oxidation of amide 6a, a-ketoamide 23a was
obtained as the major product, accompanied by trace amounts
of a-acetoxyamide 24a and b-ketoamide 9a. Selectivity can be
steered exclusively towards b-ketoamide 9a by adding rst
a non-aqueous proton-scavenger (Na

2
HPO
uoroacetic acid, TFA). When the puried b-ketoamide 9a
isolated in 88% yield) was treated with mCPBA in DCM, we
4
) and then acid (tri-
15
(
observed a-ketoamide 23a as the main product with the a-ace-
toxy derivative 24a as a side product. We thus propose a mech-
anistic scenario (Scheme 6b) whereby acid-induced Meinwald
15
Scheme 5 (a) Product scope of the one pot desaturation–epoxidation
reaction. Reactions were carried out on a 0.2 mmol scale in DCM (0.2
rearrangement of epoxide 10a delivers ketone 9a. Baeyer–Vil-
liger oxidation of the latter with mCPBA (preferential migration
ꢀ
M) with Tf
2
O (1.1 eq.), 2-Cl Py (2.2 eq.), PNO (1.3 eq.) at 0 C then r.t.,
16
of the benzylic substituent) combined with nucleophilic attack
a
2
H O and mCPBA (3.0 eq.) at r.t. Yield refers to the pure isolated
17
of mCPBA anion/Kornblum–DeLaMare rearrangement
b
c
product.
Saturated aqueous NaHCO
3
used instead of water.
ꢀ
d
accounts for the formation of products 23a and 24a. In partic- Reaction was heated to 40 C during epoxidation Reaction was
ular, the b-oxidation of an amide to a b-ketoamide (6a / 9a) is,
to the best of our knowledge, an unknown transformation with
ꢀ
carried out in 1,2-DCE instead of DCM and heated to 60 C during
epoxidation. (b) Application of one of the products.
potential synthetic utility.
This journal is © The Royal Society of Chemistry 2019
Chem. Sci.

View Article Online
Chemical Science
Edge Article
Scheme 8 Product scope of the desaturation – 1,4 addition reaction
on biologically relevant substrates. Reactions were carried out on
2
a 0.2 mmol scale in 1,2-DCE (0.2 M) with Tf O (1.1 eq.), 2-I Py (2.2 eq.),
ꢀ
ꢀ
b
a
PNO (1.3 eq.) at 0 C then 60 C, AcSH (4.0 eq.), Et
3
N (2.0 eq.). Yield
ꢀ
refers to the isolated product. Reaction was heated to 60 C during
desaturation.
Scheme 6 (a) Alternative pathway towards different ketoamides. See
ESI† for detailed reaction conditions. (b) Proposed mechanism.
22
formal direct b-thiolation. As shown in Scheme 8, several
derivatives of relevant drugs and biologically active compounds
could be thus converted into their b-thiolated analogues.
Namely, the dimethylamides of Ibruprofen, Naproxen, Flu-
briprofen and Ketoprofen all underwent b-thiolation in good to
quantitative yields (cf. Scheme 6, 8r,s,t,v). Moreover, this
chemistry allows interconversion of proteogenic aminoacid
derivatives: an amide derivative of alanine 6u was converted
into the corresponding cysteine derivative 8u in 76% yield. The
metal-free character of these transformations and the substrate
complementarity to metal-catalysed processes are worthy of
note.
Synthesis of 2-furanones
18
When combined with allylic oxidation, the mild dehydrogena-
tion chemistry described herein results in a one-step synthesis of
butenolides from simple carboxamides (Scheme 7). The oxidation
is most likely followed by nucleophilic displacement of the R–O–
Se–OH functionality via the amide carbonyl. The stereoretention
of the double bond geometry during oxidation is noteworthy, and
the absence of products with inversion of the double bond
conguration can be rationalised by the transition state of the
19
[2,3] rearrangement of intermediate 26 (ref. 20). The reaction
enables, for instance, the single-step preparation of the antifungal
natural product incrustoporine 11q (or analogues such as 11g).
21
Conclusion
One pot b-thiolation
In conclusion, we have shown herein that a facile and chemo-
Finally, when combined with the addition of thioacetic acid selective dehydrogenation event can be leveraged to achieve
under basic conditions, the chemistry reported herein results in a plethora of one-pot oxidations/functionalisations of carbox-
amides. This results in formal direct a,b-epoxidation, direct
conversion to a- or b-ketoamides at will and the one-step
interconversion of a simple linear amide into butenolides by
formal a,b,g-oxidation. The ability to deploy this chemistry in
a formal b-thiolation hints at its potential utility for late-stage
derivatization.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Scheme 7 One-pot synthesis of butenolides. Reactions were carried
Funding of this work by the Austrian Science Fund (FWF,
P30226) and the European Research Council (ERC, CoG 682002
VINCAT) is acknowledged. We thank the University of Vienna
out on a 0.2 mmol scale in 1,2-DCE (0.1 M) with Tf
2
O (1.1 eq.), 2-I Py
(2.0 eq.)
ꢀ
(
2.2 eq.), PNO (1.3 eq.) at 0 C then r.t., 1,4-dioxane and SeO
2
ꢀ
a
at 80 C. Yield refers to the pure, isolated product.
Chem. Sci.
This journal is © The Royal Society of Chemistry 2019

View Article Online
Edge Article
Chemical Science
for its continued and generous support of our research
programs. Dr J. Li (Univ. Vienna) is acknowledged for the
discovery of the dehydrogenation reaction. Dr W. Zawodny and
Dr M. Vayer (both Univ. Vienna) are gratefully acknowledged for
proofreading and editing.
M. Gillard, J. B. Falmagne and L. Ghosez, J. Am. Chem.
Soc., 1979, 101, 4381–4383; (c) M.-M. Wang, G.-H. Sui,
X.-C. Cui, H. Wang, J.-P. Qu and Y.-B. Kang, J. Org. Chem.,
2019, 84, 8267–8274.
9 The reaction proceeds well with 2-halo pyridines (except for
2-uoro pyridine) and 2-OMe pyridine, allowing quantitative
dehydrogenation within 60 minutes. For optimization
details, see the ESI.†
References
1
D. W. Knight, in Reference Module in Chemistry, Molecular 10 N. Prilezhaev, Ber. Dtsch. Chem. Ges., 1909, 42, 4811–4815.
Sciences and Chemical Engineering: Organic Methodology and 11 The ortho-Cl analogue was observed in reasonable NMR
Organic Synthesis, Elsevier Inc., 2013.
S. Caron, in Practical synthetic organic chemistry, Wiley & Sons
Inc., 2011.
For recent reviews on C–H functionalization see: (a)
P. Gandeepan, T. M u¨ ller, D. Zell, G. Cera, S. Warratz and
L. Ackermann, Chem. Rev., 2019, 119, 2192–2452; (b) C. Ma,
yields, but the product could not be isolated in satisfactory
yields due to difficult purication.
12 (a) D. D. Perrin, in Dissociation constants of organic bases in
aqueous solution, Butterworths, London, 1965; (b) Aer
addition of water to the reaction mixture, the pH of the
aqueous layer was qualitatively measured to be #1.
2
3
P. Fang and T.-S. Mei, ACS Catal., 2018, 8, 7179–7189; (c) 13 (a) G. Stork, L. D. Cama and D. R. Coulson, J. Am. Chem. Soc.,
H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A. K. Singh
and A. Lei, Chem. Rev., 2017, 117, 9016–9085; (d)
D. J. Abrams, P. A. Provencher and E. J. Sorensen, Chem.
Soc. Rev., 2018, 47, 8925–8967.
1974, 96, 5268–5270; (b) G. Stork and J. F. Cohen, J. Am.
Chem. Soc., 1974, 96, 5270–5272; (c) S. G. Levine and
M. P. Bonner, Tetrahedron Lett., 1989, 30, 4767–4770; (d)
K. Takahashi, K. Komine, Y. Yokoi, J. Ishihara and
S. Hatakeyama, J. Org. Chem., 2012, 77, 7364–7370.
4
(a) P.-X. Shen, L. Hu, Q. Shao, K. Hong and J.-Q. Yu, J. Am.
Chem. Soc., 2018, 140, 6545–6549; (b) M. Wasa, K. M. Engle 14 Anchimeric stabilization, as previously reported for similar
and J.-Q. Yu, J. Am. Chem. Soc., 2009, 131, 9886–9887; (c)
Z. Huang and G. Dong, Tetrahedron Lett., 2014, 55, 5869–
species, probably results in an equilibrium with the
corresponding 3-membered iminium ether. For related
references, see: (a) D. J. Pasto and M. P. Serve, J. Am. Chem.
Soc., 1965, 87, 1515–1521; (b) J. P. B ´e gu ´e and
M. Charpentier-Morize, Acc. Chem. Res., 1980, 13, 207–212.
5889; (d) H. Park, N. Chekshin, P.-X. Shen and J.-Q. Yu,
ACS Catal., 2018, 8, 9292–9297; (e) M. Wasa and J.-Q. Yu,
Tetrahedron, 2010, 66, 4811–4815; (f) T. G. Saint-Denis,
R. Y. Zhu, G. Chen, Q.-F. Wu and J.-Q. Yu, Science, 2018, 15 (a) Z. Wang, Meinwald Rearrangement, in Comprehensive
3
59, eaao4798; (g) Q.-F. Wu, P.-X. Shen, J. He, X.-B. Wang,
Organic Name Reactions and Reagents, Wiley, Hoboken, NJ,
2010, pp. 1880–1882; (b) J. Meinwald, S. S. Labana and
M. S. Chadha, J. Am. Chem. Soc., 1963, 85, 582–585.
F. Zhang, Q. Shao, R.-Y. Zhu, C. Mapelli, J. X. Qiao,
M. A. Poss and J.-Q. Yu, Science, 2017, 355, 499–503.
5
6
(a) F. R. Petronijevi ´c , M. Nappi and D. W. C. MacMillan, J. 16 (a) A. Baeyer and V. Villiger, Ber. Dtsch. Chem. Ges., 1899, 32,
Am. Chem. Soc., 2013, 135, 18323–18326; (b) J. Ma,
A. R. Rosales, X. Huang, K. Harms, R. Riedel, O. Wiest and
E. Meggers, J. Am. Chem. Soc., 2017, 139, 17245–17248.
For reviews on the activation of amides with chapters
3625–3633; (b) G.-J. ten Brink, I. W. C. E. Arends and
R. A. Sheldon, Chem. Rev., 2004, 104, 4105–4124.
17 N. Kornblum and H. E. DeLaMare, J. Am. Chem. Soc., 1951,
73, 880–881.
including their functionalization see: (a) D. Kaiser, 18 (a) H. L. Riley, J. F. Morley and N. A. C. Friend, J. Chem. Soc.,
A. Bauer, M. Lemmerer and N. Maulide, Chem. Soc. Rev.,
1932, 1875–1883; (b) A. Guillemonat, Ann. Chim. Appl., 1939,
2018, 47, 7899–7925; (b) L. Ghosez, Angew. Chem., Int. Ed.
11, 143–211.
Engl., 1972, 11, 852–853; (c) A. Sidani, J. Marchand-Brynaert 19 For examples of domino allylic oxidation/lactonization see:
and L. Ghosez, Angew. Chem., Int. Ed. Engl., 1974, 13, 267–
68; (d) R. Bisceglia and C. J. Cheer, J. Chem. Soc., Chem.
Commun., 1973, 165–166; (e) O. Wallach, Liebigs Ann.
(a) N. Danieli, Y. Mazur and F. Sondheimer, Tetrahedron
Lett., 1961, 2, 310–312; (b) R. M. Patel, V. G. Puranik and
N. P. Argade, Org. Biomol. Chem., 2011, 9, 6312–6322.
2
Chem., 1877, 184, 1–127; (f) J. v. Braun and A. Heymons, 20 (a) H. Rapoport and U. T. Bhalerao, J. Am. Chem. Soc., 1971,
Chem. Ber., 1929, 62, 409–413; (g) L. Ghosez, B. Haveaux
and H. G. Viehe, Angew. Chem., Int. Ed. Engl., 1969, 8, 454–
93, 4835–4840; (b) C. S. Ra and G. Park, Tetrahedron Lett.,
2003, 44, 1099–1102; (c) D. A. Singleton and C. Hang, J.
Org. Chem., 2000, 65, 7554–7560.
455.
7
8
(a) P. Adler, C. J. Teskey, D. Kaiser, M. Holy, H. H. Sitte and 21 A. Lu, J. Wang, T. Liu, J. Han, Y. Li, M. Sin, J. Chen, H. Zhang,
N. Maulide, Nat. Chem., 2019, 11, 329–334; (b) D. Kaiser,
L. Wang and Q. Wang, J. Agric. Food Chem., 2014, 62, 8799–
C. J. Teskey, P. Adler and N. Maulide, J. Am. Chem. Soc.,
8807.
2017, 139, 16040–16043; (c) D. Kaiser, A. de la Torre, 22 (a) A. U. Rajshekhar, N. K. Rana and V. K. Singh, Tetrahedron
S. Shaaban and N. Maulide, Angew. Chem., Int. Ed., 2017,
Lett., 2013, 54, 1911–1915; (b) L. Hintermann and
A. Turo ˇc kin, J. Org. Chem., 2012, 77, 11345–11348.
56, 5921–5925.
(a) C. J. Teskey, P. Adler, C. R. Gonçalves and N. Maulide,
Angew. Chem., Int. Ed., 2019, 58, 447–451; (b) R. Da Costa,
This journal is © The Royal Society of Chemistry 2019
Chem. Sci.