Aminofluorene-Mediated Biomimetic Domino Amination-Oxygenation of Aldehydes to Amides

Article abstract of DOI:10.1021/acs.orglett.6b02465

A conceptually novel biomimetic strategy based on a domino amination-oxygenation reaction was developed for direct amidation of aldehydes under metal-free conditions employing molecular oxygen as the oxidant. 9-Aminofluorene derivatives acted as pyridoxamine-5′-phosphate equivalents for efficient, chemoselective, and operationally simple amine-transfer oxygenation reaction. Unprecedented RNH transfer involving secondary amine to produce secondary amides was achieved. In the presence of ¹⁸O₂, ¹⁸O-amide was formed with excellent (95%) isotopic purity.

Full text of DOI:10.1021/acs.orglett.6b02465

Letter
pubs.acs.org/OrgLett
Aminofluorene-Mediated Biomimetic Domino Amination−
Oxygenation of Aldehydes to Amides
Santanu Ghosh and Chandan K. Jana*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
S
* Supporting Information
ABSTRACT: A conceptually novel biomimetic strategy based on a
domino amination−oxygenation reaction was developed for direct
amidation of aldehydes under metal-free conditions employing
molecular oxygen as the oxidant. 9-Aminofluorene derivatives acted
as pyridoxamine-5′-phosphate equivalents for efficient, chemo-
selective, and operationally simple amine-transfer oxygenation reaction. Unprecedented RNH transfer involving secondary
amine to produce secondary amides was achieved. In the presence of 18O2, 18O-amide was formed with excellent (95%) isotopic
purity.
mide is a ubiquitous functionality of organic molecules and
forms an essential part of many natural products, medicinal
Scheme 1. (a) Alanine Aminotransferase (ALT) Catalyzed
Transamination. (b) Our Hypothesis for Biomimetic
Amination−Umpolung Functionalization of Carbonyls. (c)
This Work: Metal-Free Biomimetic Amination−Oxygenation
of Aldehydes to Amides
A
drugs, and functional materials.1 The primary way to form an
amide bond is the classical condensation of a carboxylic acid with
an amine. The reactions are promoted by coupling reagents,
which produce superstoichiometric amounts of waste.2 To
circumvent this, different methods using catalytic amounts of
coupling reagents, which are primarily based on boron and other
metal-based complexes, have been developed.3 Alternatively,
oxidative coupling of an aldehyde/alcohol with an amine is one of
the elegant approaches that have been developed as a direct
method for amide synthesis.4,5 Other direct alternatives include
amidation involving α-keto acids,6 α-bromo nitroalkanes,7 and
Staudinger ligation.8,9 However, the practicability of these
methods was reduced due to the involvement of metallic
reagents and hazardous oxidants (e.g., hypervalent iodine,
KMnO4, etc.). In addition, most often these methods require
sensitive reaction conditions. Molecular oxygen has been used as
a viable alternative to hazardous oxidants; however, this worked
only in the presence of metallic reagents/catalyst.4h,i On the
other hand, carbene-catalyzed direct amidation of aldehydes was
achieved under metal-free conditions.10 However, prefunction-
alized aldehydes, stoichiometric organic oxidants (e.g., nitroxides
and quinones), or electrochemical oxidation were essential for
the reactions. Herein, we present a mechanistically different
metal-free approach for direct amidation of aldehydes via
biomimetic domino amination−oxygenation reactions, which
uses molecular oxygen as the oxidant (Scheme 1c).
In an aminotransferase-catalyzed transamination, coenzyme
pyridoxyl-5′-phosphate (PLP) is aminated, producing pyridox-
amine-5′-phosphate (PMP) which subsequently transfers the
amine group to keto acid A to provide amino acid E (Scheme
1a).11 Ketamine B, which is formed in a reaction of PMP with the
keto acid, undergoes deprotonative isomerization to anion C.
Protonation of C produces the corresponding aldimine D, which
after hydrolysis provides alanine (E) and PLP.
chiral or achiral amines and amino acids.12 Currently, our group
is working on the development of metal- and hazardous oxidant-
Various suitable amines, which mimic the activity of PMP,
were developed for the transamination reactions to produce
Received: August 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02465
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
free organic transformations.13 Along that line, we thought that
the reaction of the anion in C with any other electrophile except
proton would lead to the amination−umpolung functionaliza-
tion of carbonyl carbon of A (Scheme 1b).14 Therefore, we
anticipated that molecular oxygen would be a suitable electro-
phile to test our hypothesis because oxygen was found to oxidize
the related azomethine anion in lucifarase-catalyzed biological
reactions (Scheme S1).15 We decided to employ commercially
available 9-aminofluorene (1) as the PMP analogue to ease the
deprotonative isomerization through a stabilized aromatic anion
(13, see Scheme 5).13 Surprisingly, 9-aminofluorene was not
known as a transaminating agent despite of its potential.
Our investigation started with a reaction of 4-methoxybenzal-
dehyde and 9-aminofluorene in the presence of triethylamine
under oxygen atmosphere (Table S1). The desired 4-
methoxybenzamide (2) was produced with 50% isolated yield.
Different reaction conditions, such as varying solvents, temper-
atures, reactant stoichiometry, etc., were evaluated to optimize
the reaction (Table S1). The best result (83% of 2 in 1.5 h) was
obtained in a triethylamine-catalyzed reaction of 1 and aldehyde
in refluxing toluene under oxygen atmosphere. The use of
benzylamine and 4-fluorobenzylamine, replacing 9-aminofluor-
ene, did not yield the desired amide under the same conditions.
However, a trace amount of 2 was identified using diphenyl-
methylamine (entry 10).
reaction conditions. The functional groups (e.g., OR, NR2, OH,
Ar−Br, alkene), which are sensitive to oxidizing agent and
transition-metal-mediated reaction, were found to be well
accepted in this reaction. Substrates having both electron-
donating (e.g., OH, OMe, NMe2) and electron-withdrawing
(e.g., NO2, F, Cl) groups were efficiently reacted to produce the
desired amides. The oxidizable heteroaromatic thiophene ring
also remained intact during the reaction to yield 4r.
The amination−oxygenation reaction was also applied for the
synthesis of natural amide 4p (Scheme S2). Additionally, the
reaction was found to be effective in gram-scale synthesis, which
indicated its potential for practical application (Scheme S3).
Moreover, the byproduct 9-fluorenone can be recycled after
conversion to the corresponding 9-aminofluorene derivative.
Although there have been several reports on the trans-
amination (NH2 transfer) using primary amine,12 to our surprise,
there was no example where RNH was transferred involving
secondary amine. Therefore, we were interested in investigating
the possibility of RNH transfer involving secondary amines to
obtain the corresponding secondary amides. Accordingly,
different secondary amines 5a−e were reacted with various
aldehydes under the standard reaction conditions to afford the
corresponding secondary amides 6a−h with good yields
(Scheme 3).16 Under these conditions, 9-(N-benzylamino)-
Scheme 3. Scope in RNH-Transfer Oxygenation
The scope of the metal-free and biomimetic amination−oxy-
genation of aldehydes using oxygen as the ecologically viable
oxidant was tested next. Different aryl, heteroaryl, and alkenyl
aldehydes 3a−v reacted smoothly to produce the corresponding
primary carboxamides 4a−v with good to excellent yields
(Scheme 2). Various functional groups were tolerated under the
Scheme 2. Scope in NH2-Transfer Oxygenation Forming
Primary Carboxamides
a
Obtained from one-pot amidation−transamidation reaction.
fluorene was unable to provide corresponding amide 6i with
isolable yields. However, the desired benzyl amides 6i−k along
with tertiary amides 6l were also obtained directly from the
corresponding aldehydes via a one-pot current amidation to
primary amide and its subsequent transamidation17 reaction with
suitable primary and secondary amines (Scheme S4).
Several additional experiments were carried out to better
understand the mechanism and chemoselectivity of the amine-
transfer−oxygenation reaction (Scheme 4).16 Reaction of
benzoic acid and 9-aminofuorene under the standard reaction
conditions did not yield the desired benzamide (eq 1). This ruled
out the possibility of amide formation via thermal condensation
of amine with carboxylic acid that can be formed in situ by
oxidation of aldehyde. On the other hand, the desired benzamide
2 (60%) was isolated from the reaction of preformed aldimine 7
(eq 2). This observation suggested azomethine 7 or its derivative
B
DOI: 10.1021/acs.orglett.6b02465
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
deprotonation of 12 and furnished stabilized azomethine anion
13. Anion 13 or its mesomer 14 reacted with molecular oxygen to
provide hydroperoxide 15 or its regioisomer. Hydroperoxide 15
could react further to furnish the corresponding dioxazolidine 16,
which on subsequent thermal decomposition would provide the
desired amide 17 and 9-fluorenone (path a). However, the base-
mediated O−O bond cleavage of hydroperoxide 15 followed by
hydrolysis of resulting imine 18 could also provide the desired
products (path b).
Scheme 4. Investigations on Chemoselectivity and
Mechanism of the Reaction
Mass spectrometric analysis of the reaction mixture identified
peroxide derivatives 15a (R = H) or 16a (R = H) (Scheme 6a I).
Scheme 6. (a) Observed and Calculated Mass with Isotopic
Pattern for Compound 15a or 16a (I), 15b or 16b (II), 2-18O
with 95% 18O (III), and 9-Fluoreneo-18O with 62% 18O (IV).
(b) Amination−oxygenation Reaction in the Presence of 18O2
(Preparation of 18O-Amide) and H218O
12 (Scheme 5) as a possible intermediate of the reaction. The
reduced yield of benzamide obtained from the reaction, which
was carried out without an oxygen balloon, indicated the
necessity of molecular oxygen for the reaction (Table S1, entry
7). A competition experiment was performed to investigate the
relative reactivity of primary and secondary amines (eq 3).
Expectedly, a lower yield (20%) of secondary amide 6c (vs 40%
of primary amide 2) was obtained due to the reduced reactivity of
the corresponding bulky secondary amine 5c as compared to
primary amine 1. Other experiments were carried out to test the
chemoselectivity of the reaction (eqs 4−6). The amides 6a and 2
were isolated from the reactions shown in eqs 4 and 5,
respectively. Amide 6c and methyl (ArCO2Me) ester were not
formed. Thus, the results demonstrated the excellent chemo-
selectivity of this coupling reaction in the presence of other
potential coupling partners like alcohol (eq 5) and amine (eq 4).
Similarly, the aldehyde functionality in 8 reacted selectively in the
presence of ester moiety to obtain corresponding amide 9 with
very good yield (72%, eq 6). Further, the results from the
reactions shown in eq 4 and 5 suggested that amines, which are
attached with a fluorenyl moiety, were specifically transferred to
form corresponding amides.
The mass of a similar species 15b (R = H) or 16b (R = H) was
also found in the reaction with 4-chlorobenzaldehyde (Scheme
6a, II). This observation suggested that the reaction occurs
through the peroxide intermediate 15 or 16. However, the mass
corresponding to compound 18 was not observed.
The reaction was also performed in the presence of 18O2 to
gain further insights into the mechanism (Scheme 6b). Amide
2-18O was formed having 95% of 18O incorporation, which was
observed from mass spectrometric analysis (Scheme 6a, III). At
the same time, incorporation of 62% of 18O was observed in 9-
fluorenone (Scheme 6a, IV).18 However, incorporation of 18O
did not occur in amide 2 when the reaction was carried out in the
presence of H218O (Scheme S5). In contrast, 9-fluorenone
formed in the reaction was found to have 16% of 18O.18
Therefore, in the presence 18O2, formation of amide 2 and 9-
fluorenone, both with high levels of 18O, indicated that the
reactions proceed via dioxazolidine 16 (path a). Importantly, the
observations also revealed that the 18O-labeled amides with
excellent isotopic purity can be prepared by this method just by
performing the reaction in the presence of 18O2.
On the basis of the experimental evidence, a plausible
mechanism for the base-catalyzed metal-free biomimetic amine
transfer and subsequent molecular oxygen mediated oxidation of
aldehydes to amides is proposed in Scheme 5. Condensation of
aldehyde 11 and 9-aminofluorenyl derivative 10 occurred to
provide corresponding aldimine 12. Triethylamine promoted
Scheme 5. Proposed Reaction Mechanism
We have disclosed an unprecedented approach for chemo-
selective direct amidation of aldehydes based on a biomimetic
amination−oxygenation. This environmentally benign method
used triplet molecular oxygen as the oxidant without the aid of
metallic reagents and other hazardous oxidants. In addition to the
facile synthesis of primary amides via NH2 transfer, RNH transfer
involving secondary amine was also achieved for the first time,
C
DOI: 10.1021/acs.orglett.6b02465
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Mizuno, N. Catal. Sci. Technol. 2013, 3, 318. (f) Vanjari, R.; Guntreddi,
T.; Singh, K. N. Green Chem. 2014, 16, 351.
(6) (a) Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem., Int. Ed.
2006, 45, 1248. (b) Carrillo, N.; Davalos, E. A.; Russak, J. A.; Bode, J. W.
J. Am. Chem. Soc. 2006, 128, 1452. (c) Sanki, A. K.; Talan, R. S.; Sucheck,
S. J. J. Org. Chem. 2009, 74, 1886.
(7) (a) Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465,
1027. (b) Leighty, M. W.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc.
2012, 134, 15233. (c) Schwieter, K. E.; Johnston, J. N. Chem. Commun.
2016, 52, 152.
providing corresponding secondary amides. Mass spectrometric
and isotope-labeling studies revealed that the oxygenation of
azomethine ylide occurred through the dioxazolidine inter-
mediate. 18O-Amides can be prepared easily by performing this
reaction in the presence of 18O2. The proposed amination−
umpolung functionalization strategy can also be applied for
direct derivatization of carbonyl compounds employing other
(e.g., carbon-based) electrophiles. The results of the ongoing
related investigations will be reported in due course.
(8) (a) Staudinger, H.; Meyer, J. U. Helv. Chim. Acta 1919, 2, 635.
(b) Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. A. Org. Lett. 2000, 2, 2141.
(9) Other methods: (a) Hirano, T.; Uehara, K.; Kamata, K.; Mizuno,
N. J. Am. Chem. Soc. 2012, 134, 6425. (b) Ueda, T.; Konishi, H.; Manabe,
K. Org. Lett. 2012, 14, 5370. (c) Battilocchio, C.; Hawkins, J. M.; Ley, S.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02465.
■
S
V. Org. Lett. 2014, 16, 1060. (d) Tomas
̀
-Mendivil, E.; Cadierno, V.;
Menendez, M. I.; Lopez, R. Chem. - Eur. J. 2015, 21, 16874. (e) Zhao, Z.;
́
́
Additional schemes and table and experimental procedure
(PDF)
NMR spectra (PDF)
Wang, T.; Yuan, L.; Hu, X.; Xiong, F.; Zhao, J. Adv. Synth. Catal. 2015,
357, 2566. (f) Kaur, S.; Kumar, M.; Bhalla, V. Chem. Commun. 2015, 51,
4085. (g) Seo, H.; Cho, Y.; Lee, Y.; Cheon, C. J. Org. Chem. 2015, 80,
11993. (h) Shimokawa, S.; Kawagoe, Y.; Moriyama, K.; Togo, H. Org.
Lett. 2016, 18, 784.
AUTHOR INFORMATION
■
(10) (a) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798.
(b) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796. (c) De
Sarkar, S.; Studer, A. Org. Lett. 2010, 12, 1992. (d) De Sarkar, S.;
Grimme, S.; Studer, A. J. Am. Chem. Soc. 2010, 132, 1190. (e) Green, R.
A.; Pletcher, D.; Leach, S. G.; Brown, R. C. D. Org. Lett. 2016, 18, 1198.
(11) (a) Martell, A. E. Acc. Chem. Res. 1989, 22, 115. (b) Zhu, D.; Hua,
L. Biotechnol. J. 2009, 4, 1420.
Corresponding Author
*E-mail: ckjana@iitg.ernet.in.
ORCID
Chandan K. Jana: 0000-0002-6296-1240
Notes
(12) (a) Xie, Y.; Pan, H.; Liu, M.; Xiao, X.; Shi, Y. Chem. Soc. Rev. 2015,
44, 1740. (b) Han, J.; Sorochinsky, A. E.; Ono, T.; Soloshonok, V. A.
Curr. Org. Synth. 2011, 8, 281.
(13) For reviews, see: (a) Mahato, S.; Jana, C. K. Chem. Rec. 2016, 16,
1477. (b) Haldar, S.; Mahato, S.; Jana, C. K. Asian J. Org. Chem. 2014, 3,
44. (c) Haldar, S.; Roy, S. K.; Maity, B.; Koley, D.; Jana, C. K. Chem. -
Eur. J. 2015, 21, 15290.
(14) Wu, Y.; Hu, L.; Li, Z.; Deng, L. Nature 2015, 523, 445.
(15) White, E. H.; Miano, J. D.; Umbreit, M. J. Am. Chem. Soc. 1975, 97,
198.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.G. thanks IITG for fellowships. We acknowledge financial
support from SERB (EMR/2014/001176) and CSIR
(02(0211)/13/EMR-II). We thank Mr. S. Banerjee (Prof. T.
K. Paine’s group, IACS, Kolkata) for assisting us in performing
labeling experiments.
(16) Oxidation of amine and incomplete conversion led to the
relatively lower yields.
REFERENCES
■
(1) For a review, see (a) Breneman, C. M., Greenberg, A., Liebman, J.
F., Eds. The Amide Linkage: Structural Significance in Chemistry,
Biochemistry, and Materials Science; John Wiley & Sons: New York,
2002. (b) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb.
Chem. 1999, 1, 55.
(2) (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61,
10827. (b) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
(c) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
(3) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem. Soc.
Rev. 2014, 43, 2714.
(17) For a review, see: (a) Lanigan, R. M.; Sheppard, T. D. Eur. J. Org.
Chem. 2013, 2013, 7453. For selected reports, see: (b) Allen, C. L.;
Atkinson, B. N.; Williams, J. M. J. Angew. Chem., Int. Ed. 2012, 51, 1383.
(c) Nguyen, T. B.; Sorres, J.; Tran, M. Q.; Ermolenko, L.; Al-Mourabit,
A. Org. Lett. 2012, 14, 3202. (d) Wu, J.-W.; Wu, Y.-D.; Dai, J.-J.; Xu, H.-J.
Adv. Synth. Catal. 2014, 356, 2429.
(18) Reduced 18O levels in 9-fluorenone in the presence of 18O2 and
incorporation of 18O in the presence of H218O were observed due to the
formation of 9-fluorenone from the other side reactions (see the
Supporting Information, Scheme S5).
(4) For reviews on metal-mediated reactions, see: (a) Ekoue-Kovi, K.;
Wolf, C. Chem. - Eur. J. 2008, 14, 6302. (b) Allen, C. L.; Williams, J. M. J.
Chem. Soc. Rev. 2011, 40, 3405. For selected reports, see:
(c) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
790. (d) Fujiwara, H.; Ogasawara, Y.; Yamaguchi, K.; Mizuno, N. Angew.
Chem., Int. Ed. 2007, 46, 5202. (e) Owston, N. A.; Parker, A. J.; Williams,
J. M. J. Org. Lett. 2007, 9, 73. (f) Yamaguchi, K.; Kobayashi, H.; Oishi, T.;
Mizuno, N. Angew. Chem., Int. Ed. 2012, 51, 544. (g) Ghosh, S. C.;
Ngiam, J. S. Y.; Seayad, A. M.; Tuan, D. T.; Chai, C. L. L.; Chen, A. J. Org.
Chem. 2012, 77, 8007. (h) Srimani, D.; Balaraman, E.; Hu, P.; Ben-
David, Y.; Milstein, D. Adv. Synth. Catal. 2013, 355, 2525. (i) Miyamura,
́
H.; Min, H.; Soule, J.-F.; Kobayashi, S. Angew. Chem., Int. Ed. 2015, 54,
7564. (j) Kumar Achar, T.; Mal, P. Adv. Synth. Catal. 2015, 357, 3977.
(5) Oxidant-based reactions: (a) Shie, J.; Fang, J. J. Org. Chem. 2003,
68, 1158. (b) Ekoue-Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429. (c) Nie,
R.; Shi, J.; Xia, S.; Shen, L.; Chen, P.; Hou, Z.; Xiao, F. J. Mater. Chem.
2012, 22, 18115. (d) Gualtierotti, J.; Schumacher, X.; Fontaine, P.;
Masson, G.; Wang, Q.; Zhu, J. Chem. - Eur. J. 2012, 18, 14812.
(e) Yamaguchi, K.; Kobayashi, H.; Wang, Y.; Oishi, T.; Ogasawara, Y.;
D
DOI: 10.1021/acs.orglett.6b02465
Org. Lett. XXXX, XXX, XXX−XXX