Cross-Coupling of Secondary Amides with Tertiary Amides: The Use of Tertiary Amides as Surrogates of Alkyl Carbanions for Ketone Synthesis

Article abstract of DOI:10.1002/cjoc.201900215

In recent years, exciting progress has been made in the field of direct transformation of amides, nevertheless, the condensation between two amides remains rare and restricted to homo-coupling reactions. Herein, we report the cross-coupling of secondary amides with tertiary amides, which provides a synthesis of ketones under mild conditions, and features the use of tertiary amides as surrogates of alkyl carbanions. The method relies on the coupling of enamines, generated from tertiary amides by catalytic partial reduction of tertiary amides with Vaska's catalyst, with nitrilium ions, formed in situ from secondary amides via activation with trifluoromethanesulfonic anhydride, and on the subsequent deformylation.

Full text of DOI:10.1002/cjoc.201900215

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Title: Cross-coupling of Secondary Amides with Tertiary Amides: The Use of Tertiary
Amides as Surrogates of Alkyl Carbanions for Ketone Synthesis
Authors: Shu-Ren Wang and Pei-Qiang Huang*
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Cross-coupling of Secondary Amides with Tertiary Amides: The Use of
Tertiary Amides as Surrogates of Alkyl Carbanions for Ketone Synthesis
Shu-Ren Wang and Pei-Qiang Huang *
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, P. R. China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Abstract In recent years, exciting progress has been made in the field of direct transformation of amides, nevertheless, the condensation between two
amides remains rare and restricted to homo-coupling reactions. Herein, we report the cross-coupling of secondary amides with tertiary amides, which
provides a synthesis of ketones under mild conditions, and features the use of tertiary amides as surrogates of alkyl carbanions. The method relies on the
coupling of enamines, generated from tertiary amides by catalytic partial reduction of tertiary amides with Vaska’s catalyst, with nitrilium ions, formed in
situ from secondary amides via activation with trifluoromethanesulfonic anhydride, and on the subsequent deformylation.
Scheme 1 Reported methods and our plan for the cross-coupling of
Amides
Introduction
Amides are found widespread ranging from proteins to
peptides and other natural products, and from pharmaceuticals to
materials. A number of methods have been developed for amide
synthesis. Thus, amides are widely used in organic synthesis and
medicinal chemistry either as starting materials or as synthetic
intermediates. As a result, the transformation of amides into
other classes of compounds at lower oxidation stages is in high
demand. However, due to the low electrophilicity of amide
carbonyl group as compare with other carbonyl compounds such
as aldehydes, ketones and esters, the direct transformation of
amide is underdeveloped. Actually, until very recently, multistep
methods have been widely used for amide transformation. [1]
In the past decade, thanks to the contribution[2,3] of research
groups of Charette,[4] Movassaghi,[5] Maulide,[2d,e,6] Huang,[2a,7]
Chida/ Sato,[8] Pace,[2f,h,9] Dixon,[10] et al,[11] exciting progress has
been made in the field of direct transformation of amides,[2]
nevertheless, the condensation between two amides remains rare
and restricted to homo-coupling reactions.[12] In 1992, Ogawa and
Sonoda reported the first deoxygenative homo-coupling of
tertiary amides to provide vicinal diaminoalkenes by an
unprecedented Sm/SmI2 system[12a] (Scheme 1, 1a). This was
followed by Fleming’s reductive homo-coupling of tertiary amides
to give enediamines using PhMe2SiLi[12b] (Scheme 1, 1b), Shono’s
electroreductive homo-coupling of aliphatic amides for the
synthesis of α-amino ketones[12c] (Scheme 1, 1c), Harrod’s
titanocene-catalyzed homo-coupling of tertiary amides in the
presence of organosilanes to form vicinal diamines[12d] (Scheme 1,
1d), and Kumagai/ Kawase’s Li/ 4,4’-di-tert-butylbiphenyl
(DBB)-mediated acyloin condensation of N,N-dimethylbenzamides
to yield 1,2-diaryl-1,2-diketones (benzils)[12e] (Scheme 1, 1e). In
Whilst the organometallic reagents addition to
N-methoxyl-N-methyl amides (Weinreb’s amides) is a reliable and
widely used method for the synthesis of ketones,[13] actually, it is
an indirect method for the transformation of carboxylic acids or
esters into ketones. The direct conversion of common amides to
ketones is rare. The first approach for the direct transformation of
secondary amides to ketones was developed independently by
Charette[4b] and our group[7d] in 2012. In 2015, our group reported
the first versatile direct transformation of tertiary amides to
ketones.[7e] Very recently, our group have developed two
organometallic reagent-free syntheses of ketones from secondary
2015, our group reported the first reductive homo-coupling of
secondary amides to yield vicinal diamines[12f] (Scheme 1, 1f). We
disclose herein a method for the cross-coupling of secondary
amides with tertiary amides that provides a synthesis of ketones
under mild conditions, and features the use of tertiary amides as
surrogates of alkyl carbanions.
*E-mail: pqhuang@xmu.edu.cn
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amides.[14] The methods relies on the nucleophilic addition of
enamine[14a] or alkenes[14b] with nitrilium ion intermediates,
generated in situ from secondary amides, and on the subsequent
in situ deformylation. In view of the possibility of catalytic partial
reduction of tertiary amides to enamines,[15] the use of the former
as precursor of the latter for C-C bond formation was envisaged.
Although Vaska's catalyst [IrCl(CO)(PPh3)2]-catalyzed reductive
functionalization of amide carbonyl has been reported by several
group,[7f,8c-e,10] to the best of our knowledge, the employment of
the possible enamine products as synthetic equivalents of enols
or enolates for C-C bond formation is unprecedented.
including acetoxy/1f, ester/1g, cyano/1h, tertiary amido/1i,
ketone/1j, aldehyde/1k, and nitro/1l groups can survive from the
reaction (Table 2, entries 6-12), and the reaction took place
chemoselectively at the secondary amide group. It is worth
mentioning that although such kind of chemoselectivity has been
observed by Charette in their elegant synthesis of ketones from
secondary amides,[4c] and by our group in the synthesis of
enimines/ enones and aromatic ketones[7f,g,I,j], those methods
required either the use of high dilution conditions (0.044 M),[4c] or
restricted to nucleophilic alkenes/ arenes[7f,g,I,j]
.
At the outset, the cross-coupling of secondary amide 1a and
tertiary amide 2a (2.0 equiv) was examined. In the event, in the
presence of 3 mol% of Vaska's catalyst,[16] amide 2a (2.0 equiv)
was reduced with PMHS (6.0 equiv toluene, 30 min) to give, the
presumed enamine B. The crude enamine was directly used for
the addition with nitrilium ion A, generated in situ by exposing a
CH2Cl2 solution of secondary amide 1a and 2-fluoropyridine to
Table 2 Scope of secondary amides
o
Tf2O at 0 C for 20 min.[7b] After being stirred at rt for 3 h, and
treated with a 3 M HCl, the desired ketone 3a was obtained in 19%
yield. Increasing equivalent of tertiary amide 2a from 2.0 to 3.0,
and 3.5 resulted in an increase of yield from 19% to 27% and 35%,
respectively. No further improvement was observed when 4.0
equiv of 2a was used. The failure to further increase the yield was
attributed to the volatility of the enamine that partially lost during
concentration. To check this possibility, amide 2b was used in
place of 2a. Indeed, when 2.0 equiv of 2b was use, ketone 3a was
obtained in 27% yield. Encouraged by this result, the equivalent of
tertiary amide 2b was further screened. As can be seen from Table
1, use of 3.5 equiv of 2b afforded an optimal yield of 82%.
Table 1 Optimization of reaction conditions
With the optimized reaction conditions in hand, scope of
secondary amides was first surveyed. As can be seen from Table 2,
for secondary benzamide derivatives, the reaction tolerated both
electron-donating (Me/1b, MeO/1c) and electron-withdrawing
groups (Cl/1d, CF3/1e) at para-position of benzamide (Table 2,
entries 2-5). Significantly, the reaction displayed excellent
functional group tolerance and chemoselectivity. Functional
groups that are reactive towards organometallic reagents
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Running title
Chin. J. Chem.
Table 3 Scope of tertiary amides in the one-pot coupling with secondary
amides
The condensation of meta-substituted benzamides such as
m-bromobenzamide 1m proceeded smoothly to give the desired
ketone 3n in 79% yield (entry 13), whereas ortho-substituted
benzamides such as o-methylbenzamide 1n failed to yield the
desired product (entry 14), which was attributed to steric
hindrance. Other aromatic amides such as 2-naphthamide 1o and
thiophene-2-carboxamide 1p as well as aliphatic amide 1q turned
out to be viable substrates (entries 15-17). As regarding the
N-substituent in secondary amide 1, that bearing other secondary
alkyl groups such as cyclohexyl (1r) worked well (entry 18); a
modest yield of 62% was obtained from amide bearing a primary
alkyl group such as ethyl group (1s) (entry 19), and N-allyl amide
1t afforded the corresponding ketone 3b in a low yield (43%)
(entry 20).
Next, scope of tertiary amide was examined. Although the
aforementioned reaction of amide 1a with 2a afforded ketone 3a
in a low isolated yield (35%), this ketone could be obtained in 71%
yield from the corresponding N,N-dibutylamide 2d (Table 3, entry
1). Moreover, the reaction of its one-carbon higher homologue 2c
produced the corresponding ketone 3s in 72% yield (entry 2).
These results are in support of our assumption about the
relationship between volatility of enamine B generated from
tertiary amide 2 and yield of ketone 3.
α-Arylacetamides 2e-2h are also viable substrates for the
coupling with secondary amide 1a, which afforded the
corresponding ketones 3t-3v in 77-82% yields (Table 3, entries
4-7). It is worth noting that N,N-dimethylamide bearing a phenyl
group (2e), the corresponding enamine being less volatile, served
as an effective surrogate of the corresponding alkyl carbanion to
yield ketone 3t in good yield (77%, entry 4). Notably, tertiary
amide bearing an acetoxy group (2i) also reacted smoothly to
produce the functionalized ketone 3w in 77% yield (entry 8).
para-Chlorophenylacetamide 2j reacted to give 3x in a modest
yield (45%, entry 9), whereas from ester-bearing amide 2k, only
trace of ketone 3y was observed (entry 10).
Conclusions
We have achieved the first cross-coupling of secondary
amides with tertiary amides. This novel transformation of amides
established a novel synthesis of ketones from common amides.
Remarkably, through this protocol, we demonstrated the
feasibility of employing neutral and highly stable tertiary amides
as surrogates of highly basic secondary alkyl carbanions. This
ensured the reaction be run under mild conditions. As a result,
the reaction showed excellent chemoselectivity and functional
group tolerance on the secondary amide partner at normal
concentration. Moreover, the tertiary amide partner was shown
to tolerate sensitive functional groups such as acetoxy group.
Work is in progress in our group to further extend this
chemoselective reaction, and the results will be reported in due
course.
Experimental
General procedure for cross-coupling of secondary amides
with tertiary amides:
To a 0.2 M solution of IrCl(CO)(PPh3)2 in toluene (9 mL; 0.0175
mmol of [Ir]) was added a tertiary amide (1.75 mmol) and PMHS
(777 mg, 3.5 mmol) at 25 ºC. After being stirred for 15 min, the
resultant residue was washed ten times with ether (50 mL in
total), and the combined organic phases were filtered through a
pad of Celite and the filtrate was concentrated under reduced
pressure to afford an essentially pure enamine, which was used as
it was. Then into a dry 25-mL round-bottom flask equipped with a
Chin. J. Chem. 2019, 37, XXX－XXX
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Wang et al.
Report
magnetic stirring bar were added successively a secondary amide
Chem. Soc. 2008, 130, 18-19. (b) Bechara, W. S.; Pelletier, G.;
Charette, A. B. Chemoselective synthesis of ketones and ketimines
by addition of organometallic reagents to secondary amides. Nat.
Chem. 2012, 4, 228-234. (c) Cyr, P.; Regnier, S.; Bechara, W. S.
Charette, A. B. Rapid Access to 3-Aminoindazoles from Tertiary
Amides. Org. Lett. 2015, 17, 3386-3389.
(0.5 mmol, 1.0 equiv),
2 mL of anhydrous CH2Cl2 and
2-fluoropyridine (0.6 mmol, 1.2 equiv) under an argon
atmosphere. After being cooled to 0 °C, trifluoromethanesulfonic
anhydride (Tf2O) (155 mg, 93 μL, 0.55 mmol, 1.1 equiv) was added
dropwise via a syringe and the reaction mixture was stirred for 10
min. To the resulting mixture, the crude enamine was added
dropwise at 0 °C. The mixture was allowed warming-up to room
temperature and stirred for 3 h. The reaction was quenched with
an aqueous HCl solution (3.0 M, 5.0 mL) and stirred for 5-6 h at
room temperature. The organic layer was separated and the
aqueous phase was extracted with ethyl ether (310.0 mL). The
combined organic layers were washed with brine (33.0 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel (hexane/EtOAc) to afford the
desired ketone.
[5] For selected examples, see: (a) Movassaghi, M.; Hill, M.; Ahmad, O. K.
Direct Synthesis of Pyridine Derivatives. J. Am. Chem. Soc. 2007, 129,
10096-10097. (b) Medley, J. W.; Movassaghi, M. Direct Dehydrative
N-Pyridinylation of Amides. J. Org. Chem. 2009, 74, 1341-1344. (c)
Mewald, M.; Medley, J. W.; Movassaghi, M. Concise and
Enantioselective
Total
Synthesis
of
(-)-Mehranine,
(-)-Methylenebismehranine, and Related Aspidosperma Alkaloids.
Angew. Chem., Int. Ed. 2014, 53, 11634-11639. (d) White, K. L.;
Mewald, M.; Movassaghi, M. Direct Observation of Intermediates
Involved in the Interruption of the Bischler−Napieralski Reaction. J.
Org. Chem. 2015, 80, 7403-7411.
[6] For selected examples, see: (a) Madelaine, C.; Valerio, V.; Maulide, N.
Supporting Information
Unexpected Electrophilic Rearrangements of Amides:
A
Stereoselective Entry to Challenging Substituted Lactones. Angew.
Chem., Int. Ed. 2010, 49, 1583-1586. (b) Tona, V.; Maryasin, B.; de la
Torre, A.; Sprachmann, J.; Gonzalez, L.; Maulide, N. Direct
Regioselective Synthesis of Tetrazolium Salts by Activation of
Secondary Amides under Mild Conditions. Org. Lett. 2017, 19,
2662-2665. (c) Kaiser, D.; de la Torre, A.; Shaaban, S.; Maulide, N.
Metal-Free Formal Oxidative C-C Coupling by In Situ Generation of an
Enolonium Species. Angew. Chem., Int. Ed. 2017, 56, 5921-5925. (d)
Kaiser, D.; Teskey, C. J.; Adler, P.; Maulide, N. Chemoselective
Intermolecular Cross-Enolate-Type Coupling of Amides. J. Am. Chem.
Soc. 2017, 139, 16040-16043.
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
The authors are grateful for the financial support provided
by the National Natural Science Foundation of China (21672176
and 21332007), and the National Key R&D Program of China
(2017YFA0207302).
References
[7] For selected examples, see: (a) Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang,
Y.; Huang, P.-Q. Direct, One-pot Sequential Reductive Alkylation of
Lactams/Amides with Grignard and Organolithium Reagents through
Lactam/Amide Activation. Angew. Chem., Int. Ed. 2010, 49,
3037-3040. (b) Xiao, K.-J.; Wang, Y.; Ye, K.-Y.; Huang, P.-Q. Versatile
One-Pot Reductive Alkylation of Lactams/Amides via Amide
Activation: Application to the Concise Syntheses of Bioactive
Alkaloids ()-Bgugaine, ()-Coniine, (+)-Preussin, and ()-Cassine.
Chem. -Eur. J. 2010, 16, 12792-12796. (c) Xiao, K.-J.; Wang, A.-E;
Huang, P.-Q. Direct Transformation of Secondary Amides into
Secondary Amines: Triflic Anhydride Activated Reductive Alkylation.
Angew. Chem., Int. Ed. 2012, 51, 8314-8317. (d) Xiao, K.-J.; Wang,
A.-E; Huang, Y.-H.; Huang, P.-Q. Versatile and Direct Transformation
of Secondary Amides into Ketones by Deaminative Alkylation with
Organocerium Reagents. Asian J. Org. Chem. 2012, 1, 130-132. (e)
Huang, P.-Q.; Wang, Y.; Xiao, K.-J.; Huang, Y.-H. A General Method
for the Direct Transformation of Common Tertiary Amides into
Ketones and Amines by Addition of Grignard Reagents. Tetrahedron
2015, 71, 4248–425. (f) Huang, P.-Q.; Ou, W.; Han, F. Chemoselective
Reductive Alkynylation of Tertiary Amides by Ir and Cu(I) Bis-Metal
Sequential Catalysis. Chem. Commun. 2016, 52, 11967-11970. (g)
Huang, P.-Q.; Huang, Y.-H.; Geng, H.; Ye, J.-L. Metal-Free C–H
Alkyliminylation and Acylation of Alkenes with Secondary Amides. Sci.
Rep. 2016, 6, 28801. (h) Huang, P.-Q.; Huang, Y.-H.; Wang, S.-R.
One-pot Synthesis of N-Heterocycles and Enimino Carbocycles by
[1] For two typical examples, see: (a) Heathcock, C. H. The Enchanting
Alkaloids of Yuzuriha. Angew. Chem., Int. Ed. 1992, 31, 665–681. (b)
Lee, A. S.; Liau, B. B.; Shair, M. D. A Unified Strategy for the Synthesis
of 7‑Membered-Ring-Containing Lycopodium Alkaloids. J. Am. Chem.
Soc. 2014, 136, 13442–13452.
[2] For reviews, see: (a) Huang, P.-Q. Direct Transformations of Amides:
Tactics and Recent Progress. Acta Chim. Sinica 2018, 76, 357-365. (b)
Kaiser, D.; Bauer, A.; Lemmerer, M.; Maulide, N. Amide Activation:
An Emerging Tool for Chemoselective Synthesis. Chem. Soc. Rev.
2018, 47, 7899-7925. (c) Sato, T.; Yoritate, M.; Tajima, H.; Chida, N.
Total Synthesis of Complex Alkaloids by Nucleophilic Addition to
Amides. Org. Biomol. Chem. 2018, 16, 3864-3875. (d) Kaiser, D.;
Maulide, N. Making the Least Reactive Electrophile the First in Class:
Domino Electrophilic Activation of Amides. J. Org. Chem. 2016, 81,
4421-4428. (e) Sato, T.; Chida, N. Nucleophilic Addition to
N-Alkoxyamides: Development and Application to the Total Synthesis
of Gephyrotoxin. J. Synth. Org. Chem., Jpn. 2016, 74, 599–610. (f)
Pace, V.; Holzer, W.; Olofsson, B. Increasing the Reactivity of Amides
towards Organometallic Reagents: An Overview. Adv. Synth. Catal.
2014, 356, 3697-3736. (g) Sato, T.; Chida, N. Nucleophilic addition to
N-alkoxyamides. Org. Biomol. Chem. 2014, 12, 3147-3150. (h) Pace,
V.; Holzer, W. Chemoselective Activation Strategies of Amidic
Carbonyls towards Nucleophilic Reagents. Aust. J. Chem. 2013, 66,
507-510. (i) Seebach, D. Generation of Secondary, Tertiary, and
Quaternary Centers by Geminal Disubstitution of Carbonyl Oxygens.
Angew. Chem., Int. Ed. 2011, 50, 96-101.
Tandem
Dehydrative
Coupling–Reductive
Cyclization
of
Halo-sec-Amides and Dehydrative Cyclization of Olefinic sec-Amides.
Org. Chem. Front. 2017, 4, 431-444. (i) Huang, P.-Q. Huang, Y.-H.
Further Studies on The Direct Synthesis of ,-Unsaturated
Ketimines and ,-Enones by Chemoselective Dehydrative Addition
of Functionalized Alkenes to Secondary Amides. Chin. J. Chem. 2017,
35, 613-620. (j) Ye, J.-L.; Zhu, Y.-N.; Geng, H.; Huang, P.-Q.
Metal-Free Synthesis of Quinolines by Direct Condensation of
Amides with Alkynes: Revelation of N-Arylnitrilium Intermediates by
2D NMR Techniques. Sci. China: Chem. 2018, 61, 687-694. (k) Fan, T.;
[3] For pioneering work, see: (a) Falmagne, J. B.; Escudero, J.;
Taleb-Saharaoui, S.; Ghosez, L. Cyclobutanone and Cyclobutenone
Derivatives by Reaction of Tertiary Amides with Alkenes or Alkynes.
Angew. Chem., Int. Ed. 1981, 20, 879-880. (b) Sisti, N. J.; Fowler, F.
W.; Grierson, D. S. N-Phenyl-2-cyano-1-azadienes: New Versatile
Heterodienes in the Diels-Alder Reaction. Synlett 1991, 816-818.
[4] For selected examples, see: (a) Barbe, G.; Charette, A. B. Highly
Chemoselective Metal-Free Reduction of Tertiary Amides. J. Am.
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.
Chin. J. Chem. 2019, 37, XXX－XXX

Running title
Chin. J. Chem.
Wang, A.; Li, J.-Q.; Ye, J.-L.; Zheng, X.; Huang, P.-Q. Versatile One-Pot
Synthesis of Polysubstituted Cyclopent-2-enimines from
524, 79-83. (f) Romanens, A.; Bꢀlanger, G. Preparation of
Conformationally Restricted 2,2
-
and 2,2,3-Amino Esters and
,-Unsaturated Amides: Imino-Nazarov Reaction. Angew. Chem.,
Int. Ed. 2018, 57, 10352-10356. (l) Ou, W.; Han, F.; Hu, X.-N.; Chen, H.;
Huang, P.-Q. Iridium-Catalyzed Reductive Alkylations of Secondary
Amides. Angew. Chem., Int. Ed. 2018, 57, 11354-11358. (l) Wu, D.-P.;
He, Q.; Chen, D.-H.; Ye, J.-L.; Huang, P.-Q. A Stepwise Annulation for
the Transformation of Cyclic Ketones to Fused 6 and 7-Membered
Cyclic Enimines and Enones. Chin. J. Chem. 2019, 37, 315-322.
[8] For selected examples, see: (a) Shirokane, K.; Kurosaki, Y.; Sato, T.;
Chida, N. A Direct Entry to Substituted N-Methoxyamines from
N-Methoxyamides via N-Oxyiminium Ions. Angew. Chem., Int. Ed.
2010, 49, 6369-6372. (b) Shirokane, K.; Wada, T.; Yoritate, M.;
Minamikawa, R.; Takayama, N.; Sato, T.; Chida, N. Total Synthesis of
()-Gephyrotoxin by Amide-Selective Reductive Nucleophilic
Addition. Angew. Chem., Int. Ed. 2014, 53, 512-516. (c) Nakajima, M.;
Sato, T.; Chida, N. Iridium-Catalyzed Chemoselective Reductive
Nucleophilic Addition to N‑Methoxyamides. Org. Lett. 2015, 17,
1696-1699. (d) Katahara, S.; Kobayashi, S.; Fujita, K.; Matsumoto, T.;
Sato, T.; Chida, N. An Iridium-Catalyzed Reductive Approach to
Nitrones from N-Hydroxyamides. J. Am. Chem. Soc. 2016, 138,
5246-5249. (e) Katahara, S.; Kobayashi, S.; Fujita, K.; Matsumoto, T.;
Sato, T.; Chida, N. Reductive Approach to Nitrones from
N-Siloxyamides and N-Hydroxyamides. Bull. Chem. Soc. Jpn. 2017, 90,
893–904; (f) Takahashi, Y.; Yoshii, R.; Sato, T.; Chida, N.
Iridium-Catalyzed Reductive Nucleophilic Addition to Secondary
Amides. Org. Lett. 2018, 20, 5705-5708. (g) Hiraoka, S.; Matsumoto,
T.; Matsuzaka, K.; Sato, T.; Chida, N. Approach to Fully Substituted
Cyclic Nitrones from N-Hydroxylactam Derivatives: Development and
Application to the Total Synthesis of Cylindricine C. Angew. Chem.,
Int. Ed. 2019, 58, 4381-4385.
[9] For selected examples, see: (a) Pace, V.; de la Vega-Hernandez, K.;
Urban, E.; Langer, T. Chemoselective Schwartz Reagent Mediated
Reduction of Isocyanates to Formamides. Org. Lett. 2016, 18,
2750-2753. (b) Ielo, L.; Touqeer, S.; Roller, A.; Langer, T.; Holzer, W.;
Pace, V. Telescoped, Divergent, Chemoselective C1 and C1-C1
Homologation of Imine Surrogates: Access to Quaternary Chloro- and
Halomethyl-trifluoromethyl Aziridines. Angew. Chem., Int. Ed. 2019,
58, 2479-2484.
[10] (a) Gregory, A. W.; Chambers, A.; Hawkins, A.; Jakubec, P.; Dixon, D. J.
Iridium-Catalyzed Reductive Nitro-Mannich Cyclization. Chem. - Eur. J.
2015, 21, 111-114. (b) Tan, P. W.; Seayad, J.; Dixon, D. J. Expeditious
and Divergent Total Syntheses of Aspidosperma Alkaloids Exploiting
Iridium(I)-Catalyzed Generation of Reactive Enamine Intermediates.
Angew. Chem., Int. Ed. 2016, 55, 13436–13440. (c) Xie, L.-G.; Dixon,
D. J. Iridium-Catalyzed Reductive Ugi-Type Reactions of Tertiary
Amides. Nat. Commun. 2018, 9, 2841.
Derivatives Containing an All-Carbon Quaternary Center. Org. Lett.
2015, 17, 322-325. (g) Li, L.-H.; Niu, Z.-J.; Liang, Y.-M. Synthesis of
Functionalized Quinolines through a Reaction of Amides and Alkynes
Promoted by Triflic Anhydride/Pyridine. Chem. Eur. J. 2017, 23,
15300–15304. (h) Li, X. W. ; Lin, F. G.; Huang, K. M.; Wei, J. L.; Li, X. Y.;
Wang, X. Y.; Geng, X. Y.; Jiao, N. Selective -Oxyamination and
Hydroxylation of Aliphatic Amides. Angew. Chem., Int. Ed. 2017, 56,
12307–12311. (i) Li, L.-H.; Niu, Z.-J.; Liang, Y.-M. Synthesis of
Functionalized Quinolines through a Reaction of Amides and Alkynes
Promoted by Triflic Anhydride/Pyridine. Chem. Eur. J. 2017, 23,
15300–15304. (j) Xie, C.-M.; Luo, J.-S.; Zhang, Y.; Zhu, L.-L.; Hong, R. A
Chiral
Pentenolide-Based
Unified
Strategy
toward
Dihydrocorynantheal,
Dihydrocorynantheol,
Protoemetine,
Protoemetinol, and Yohimbane. Org. Lett., 2017, 19, 3592–3595. (k)
Chen, J.-J.; Long, W.-H.; Yang, Y.-G.; Wan, X.-B. Interception of
Secondary Amide Ylide with Sulfonamides: Catalyst-Controlled
Synthesis of N-Sulfonylamidine Derivatives. Org. Lett. 2018, 20,
2663–2666. (l) Li, L.-H.; Niu, Z.-J.; Liang, Y.-M. Transition-metal-free
Multinitrogenation of Amides by C–C Bond Cleavage:
A New
Approach to Tetrazoles. Chem. Commun. 2018, 54, 11148-11151. (m)
Trillo, P.; Slagbrand, T.; Adolfsson, H. Straightforward -Amino Nitrile
Synthesis Through Mo(CO)6-Catalyzed Reductive Functionalization of
Carboxamides. Angew. Chem., Int. Ed. 2018, 57, 12347-12351.
[12] (a) Ogawa, A.; Takami, N.; Sekiguchi, M.; Ryu, I.; Kambe, N.; Sonoda,
N. The First Deoxygenative Coupling of Amides by an Unprecedented
Samarium/Samarium Diiodide System. J. Am. Chem. Soc. 1992, 114,
8729–8730. (b) Fleming, I.; Ghosh, U.; Mack, S. R.; Clark, B. P. The
Reductive Coupling of Tertiary Amides to Give Enediamines Using
PhMe2SiLi. Chem. Commun. 1998, 711–712. (c) Kashimura, S.;
Ishifune, M.; Murai, Y.; Murase, H.; Shimomura, M.; Shono, T.
Electroreductive Coupling of Aliphatic Amides. A Useful Method for
the Synthesis of -Amino Ketones. Tetrahedron Lett. 1998, 39,
6199-6202. (d) Selvakumar, K.; Harrod, J. F. Titanocene-Catalyzed
Coupling of Amides in the Presence of Organosilanes to Form Vicinal
Diamines. Angew. Chem., Int. Ed. 2001, 40, 2129–2131. (e) Kumagai,
T.; Anki, T.; Ebi, T.; Konishi, A.; Matsumoto, K.; Kurata, H.; Kubo, T.;
Katsumoto, K.; Kitamura, C.; Kawase, T. An Effective Synthesis of
N,N-Dimethylamides from Carboxylic Acids and A New Route From
N,N-Dimethylamides to 1,2-Diaryl-1,2-diketones. Tetrahedron 2010,
66, 8968-8973. (f) Huang, P.-Q.; Lang, Q.-W.; Wang, A.-E; Zheng, J.-F.
Direct Reductive Coupling of Secondary Amides: Chemoselective
Formation of Vicinal Diamines and Vicinal Amino Alcohols. Chem.
Commun. 2015, 51, 1096-1099.
[13] Nahm, S.; Weinreb, S. M. N-Methoxy-N-Methylamides as Effective
Acylating Agents. Tetrahedron Lett. 1981, 22, 3815–3818.
[11] For selected important contribution from other groups, see: (a)
Bꢀlanger, G.; Larouche-Gauthier, R.; Mꢀnard, F.; Nantel, M.; Barabꢀ,
F. Intramolecular Additions of Various π-Nucleophiles to
Chemoselectively Activated Amides and Application to the Synthesis
of ()-Tashiromine. J. Org. Chem. 2006, 71, 704-712. (b) Zhou, H.-B.;
Liu, G.-S.; Yao, Z.-J. Highly Efficient and Mild Cascade Reactions
[14] (a) Liu, Y.-P.; Wang, S.-R.; Chen, T.-T.; Yu, C.-C.; Wang, A.-E; Huang,
P.-Q. Enamines as Surrogates of Alkyl Carbanions for the Direct
Conversion of Secondary Amides to -Branched Ketones. Adv. Synth.
Catal. 2019, 361, 971-975. (b) Geng, H.; Huang, P.-Q. Ketone
Synthesis by Direct, Orthogonal Chemoselective Hydroacylation of
Alkenes with Amides: Use of Alkenes as Surrogates of Alkyl
Carbanions. Chin. J. Chem. 2019, 37, DOI: 10.1002/cjoc.201900252.
[15] Motoyama, Y.; Aoki, M.; Takaoka, N.; Aoto, R.; Nagashima, H. Highly
Efficient Synthesis of Aldenamines from Carboxamides by
Iridium-Catalyzed Silane-Reduction/Dehydration Under Mild
Conditions. Chem. Commun. 2009, 1574-1576.
Triggered
Trifluoromethane-sulfonate and
by
Bis(triphenyl)oxodiphosphonium
Concise Total Synthesis of
a
Camptothecin. Org. Lett. 2007, 9, 2003-2006. (c) Cui, S. L.; Wang, J.;
Wang, Y. G. Synthesis of Indoles via Domino Reaction of N-Aryl
Amides and Ethyl Diazoacetate. J. Am. Chem. Soc. 2008, 130,
13526-13527. (d) Vincent, G.; Guillot, R.; Kouklovsky, C.
Stereodivergent Synthesis of Substituted N,O-Containing Bicyclic
Compounds by Sequential Addition of Nucleophiles to
N-Alkoxybicyclolactams . Angew. Chem., Int. Ed. 2011, 50, 1350-1353.
(e) Hie, L.; Nathel, N. F. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang,
Y.-F.; Liu, P.; Houk, K. N.; Garg, N. K. Conversion of Amides to Esters
by the Nickel-Catalysed Activation of Amide C–N Bonds. Nature 2015,
[16] Vaska, L.; DiLuzio, J. W. Carbonyl and Hydrido-Carbonyl Complexes of
Iridium by Reaction With Alcohols. Hydrido Complexes by Reaction
with Acid. J. Am. Chem. Soc. 1961, 83, 2784–2785.
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Chin. J. Chem. 2019, 37, XXX－XXX
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Entry for the Table of Contents
Page No. 7
Cross-coupling of Secondary Amides with
Tertiary Amides: The Use of Tertiary Amides as
Surrogates of Alkyl Carbanions for Ketone
Synthesis
We report the cross-coupling of secondary amides with tertiary amides, which provides a synthesis
of ketones under mild conditions, and features the use of tertiary amides as surrogates of alkyl
carbanions.
Shu-Ren Wang and Pei-Qiang Huang*
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template
© 2018 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.