Oxidative amidation of benzyl alcohols with amino acid esters mediated by N-hydroxysuccinimide/phenyliodine diacetate

Article abstract of DOI:10.1080/00397911.2017.1281960

A simple protocol involving metal-free oxidative amidation of benzyl alcohols with amino acid esters has been presented. The amidation proceeds in a radical pathway unlike in conventional metal-mediated extrusion of dihydrogen. The method is advantageous in terms of metal-free conditions, nonexpensive commercial starting substrates. Also various substituents in the starting materials are tolerated and sterically hindered amino acid side chains could provide good yields of amide products.

Full text of DOI:10.1080/00397911.2017.1281960

Oxidative Amidation of Benzyl alcohols with Amino acid Esters mediated by N-
hydroxysuccinimide/phenyliodine diacetate
Mandipogula Mahesh2, Veladi Panduranga1, Girish Prabhu1, Roopesh Kumar L1, P.
Venkata Ramana2, Vommina V. Sureshbabu1
1Peptide Research Laboratory, Department of Studies in Chemistry, Central College
Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore , India
2Department of Chemistry, Sri Krishnadevaraya University, Ananthapuramu, Andhra
Pradesh, India.
Corresponding to author: Vommina V. Sureshbabu Email: hariccb@gmail.com;
sureshbabuvommina@rediffmail.com; hariccb@hotmail.com.
Abstract
A simple protocol involving metal free oxidative amidation of benzyl alcohols with
amino acid esters has been presented. The amidation proceeds in a radical pathway unlike
in conventional metal mediated extrusion of dihydrogen. The method is advantageous in
terms of metal free conditions, non expensive commercial starting substrates. Also
various substituents in the starting materials are tolerated and sterically hindered amino
acid side chains could provide good yields of amide products.
Graphical Abstact
KEYWORDS: N-hydroxysuccinimide; phenyliodine diacetate; amide; oxidation; benzyl
alcohol & amino acid.
1

INTRODUCTION
The amide bond is ubiquitous in organic and biological chemistry.[1] It is a key functional
group in peptides, polymers, and many natural products.[2] Amides are present in a broad
spectrum of compounds of pharmaceutical, agricultural, and material interests.[3] The
most common prevalent method for the synthesis of the amides is treatment of activated
carboxylic acid derivatives with amine precursors.[4] Emerging methods for oxidative
amide formation have been reviewed in several recent reviews.[5] Various alternative
strategies such as the Staudinger reaction,[6] Schmidt reaction[7] and the Beckmann
rearrangement[8] have been developed. However, in most of these methods, use of excess
of coupling partners, stoichiometric amounts of various reagents are required and
equimolar amounts of by-products are produced as waste. Other methodologies to access
amides include hydrative amide synthesis with alkynes,[9] thioacid/ester ligation
methods,[10] aminocarbonylation of aryl halides.[11]
One of the most attractive methods include oxidative amidation of alcohols and
aldehydes that can circumvent carboxylic acid isolation. Catalytic amidation of aldehydes
employ metal catalysts such as ruthenium, rhodium, copper and stoichiometric amounts
of bases.[12] In addition, coupling of primary amines and alcohols make use of expensive
metal catalysts such as ruthenium, rhodium, gold and silver complexes.[13] Presumably,
the reaction proceeds through the intermediate aldehyde which reacts with the amine to
give a hemiaminal that is subsequently dehydrogenated to the amide. However the
2

drawbacks include limited activity with sterically hindered alcohols or amines and less
basic aromatic amines.
Despite elegant protocols in metal catalysed oxidative amide bond formation, there are
limited reports for metal free variations.[14-16] Metal free processes involving tandem
oxidative amidation of aldehydes which are particularly attractive from environmental
and economical stand point. Yao et al. reported oxidative amide formation from
aldehydes using N-hydroxysuccinimide and PhI(OAc)2 under mild conditions in
moderate to good yields.[14] Also few examples of oxidative amide formation from
alcohols and amines using o-iodoxybenzoic acid were reported. In another report novel
glycosyl carboxamides were prepared from aldehydes and amines using PhI(OAc)2 in the
presence of ionic liquid at ambient temperature.[15] Other metal free oxidative amidation
of alcohols using peroxide as oxidant have also been reported albeit at high temperature
conditions.[16] We envisaged preparing metal free amide formation from benzyl alcohols
with chiral systems viz. amino acid esters. The amino acid esters were chosen as amine
components for our study so as to determine the viability of the protocol with steric
effects of amino acid side chains as well as to find the possibility of epimerization under
the present conditions.
RESULTS AND DISCUSSION
Initially, several amino acids were converted to the corresponding esters ii employing
reported protocol. In a typical experiment, benzyl alcohol i in MeCN was treated with
PhI(OAc)2 at room temperature (Scheme 1). After 10 min, N-hydroxysuccinimide was
3

added followed by amino acid ester ii and then the reaction mixture was stirred for 1-2 h
until the TLC showed complete disappearance of the NHSI ester. Gratifyingly, the
reaction completed within 30 min. The desired amide product iii was isolated in 90%
yield after simple aqueous work up followed by purification over silica gel column
chromatography. The optimization of reaction with respect to the solvent, temperature
and molar equivalents of NHSI and PhI(OAc)2 was then investigated. Importantly no
product was observed in the absence PhI(OAc)2 or with PhI(OAc)2 alone. Screening of
various solvents such as dichloromethane (CH2Cl2), tetrahydrofuran (THF), ethyl acetate
(EtOAc) and N,N-dimethylformamide (DMF) revealed MeCN to be the optimum solvent
(Table 1 Scheme 1). Higher equivalents of NHSI and PhI(OAc)2 did not improve the
output of the reaction (Table 1 Scheme1), whereas lesser equivalent of PhI(OAc)2 led to a
decrease in the yield of the product.
The optimized protocol was then generalized to benzyl alcohols with differently
substituted aryl moieties with both electron donating as well as withdrawing nature. Also
various sterically hindered amino acid esters were employed to obtain the desired amide
products in moderate to good yields (Table 2).
All the reactions had clean profile and the products were obtained in good yields after
purification by column chromatography on silica gel. The structures of the product
amides were confirmed by 1H NMR, 13C NMR and mass spectrometric analyses. Though
the present reaction conditions were mild, the possibility of racemization was studied in
4

the case of two enantiomeric amides Bn-L-Ala-OMe 4 and Bn-D-Ala-OMe 4*. The
chiral-HPLC profiles of 4 and its enantiomer 4* showed retention times of Rt 12.740 and
18.078 min respectively. The equimolar mixture of 4 & 4* showed distinct retention
times Rt 12.267 and 18.248 min, thus confirming the absence of racemisation.
A possible reaction mechanism is presented in scheme 2, in which alcohol a is oxidized
(after a ligand exchange around the iodine atom)[17] to corresponding aldehyde b with
NHSI as a catalyst. Then aldehyde b reacts with NHSI giving the corresponding
hemiaminal c. NHSI is oxidized to the corresponding succinimide N-oxy radical (SINO)
which abstracts a proton from the hemiaminal c generating the corresponding hemiaminal
radical d,[14] which on rapid oxidation provide ester e. Finally ester e undergoes a
nucleophilic substitution by the amino acid ester to amides.
In summary, a simple metal free protocol for oxidative amidation of benzyl alcohols with
amino acid esters has been developed. The PhI(OAc)2 acts as stoichiometric oxidant for
the formation of N-hydroxysuccinimide ester which then undergoes amidation by
reaction with amino acid esters. The method has several advantageous such as metal free
conditions, non expensive commercial starting substrates, broad substrate scope in both
alcohols with various substituents and sterically hindered amino acid esters in providing
good yields of amide products.
ACKNOWLEDGEMENTS
We gratefully acknowledge University Grants Commission, Govt. of India for the
financial assistance. One of the authors, VP thanks CSIR for SRF.
5

SUPPLEMENTARY DATA
Spectroscopic data (1H, 13C NMR and mass spectra) of compounds can be found in the
online version at ………
EXPERIMENTALSECTION
General procedure for the synthesis of amides derived from benzyl alcohols and amino
acid esters:
To a solution of benzyl alcohol (1 mmol) in MeCN (10 mL) was added PhI(OAc)2 (1
mmol) and the reaction was stirred for 10 min. Then NHSI (1.5 mmol) was added and
stirring was continued for 15 min. To this mixture, amino acid ester (1 mmol) was added
under nitrogen atmosphere. The reaction was stirred for 1-2 h at room temperature till the
completion of reaction (consumption of NHSI ester by TLC analysis). The reaction
mixture was quenched with water and extracted with EtOAc. (10 mL X 3). The combined
organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was
purified by column chromatography on silica gel (n-hexane-EtOAc).
REFERENCES
[1] Arthur, G. The Amide Linkage: Selected Structural Aspects in Chemistry,
Biochemistry, and Materials Science (Wiley-Interscience, 2000).
[2] a) Sewald, N.; Jakubke, H.-D. In: Peptides, Chemistry and Biology; Wiley-VCH,
Weinheim, Germany, 2002; b) I. Johansson in Kirk-Othmer Encyclopedia of Chemical
6

Technology: Amides, Fatty Acids (Ed.: J. I. Kroschwitz), 5th Ed.; Wiley, Hoboken, NJ,
2004, Vol. 2, pp. 442–463.
[3] (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev., 1997, 97, 2243; (b) Katritzky, A.
R.; He, H.-Y.; Suzuki, K. J. Org. Chem., 2000, 65, 8210; (c) Pandey, J.; Sharma, A.;
Tiwari, V. K.; Dube, D.; Ramachandran, R.; Chaturvedi, V.; Sinha, S.; Mishra, N. M.;
Shulka, P. K.; Tripathi, R. P. J. Comb. Chem., 2009, 11, 422; (d) Fraxedas, J. Molecular
Organic Materials: From Molecules to Crystalline Solids; Cambridge University Press:
Cambridge, 2006.
[4] Larock, R. C. Comprehensive Organic Transformation; VCH: New York, 1999.
[5] (a) Pattabiraman, V. R.; Bode, J. W. Nature., 2011, 480, 471; (b) Valeur, E.; Bradley,
M. Chem. Soc. Rev., 2009, 38, 606; (c) Allen, C. L.; Williams, J. M. Chem. Soc. Rev.,
2011, 40, 3405; (d) Ekoue-Kovi, K.; Wolf, C. Chem. Eur. J., 2008, 14, 6302;
[6] (a) Saxon, E.; Bertozzi, C. R. Science., 2000, 287, 2007; (b) Nilsson, B. L.; Kiessling,
L. L.; Raines, R. T. Org. Lett., 2000, 2, 1939; (c) Damkaci, F.; DeShong, P. J. Am. Chem.
Soc., 2003, 125, 4408.
[7] (a) Ribelin, T.; Katz, C. E.; English, D. G.; Smith, S.; Manukyan, A. K.; Day, V. W.;
, J. Angew. Chem., Int. Ed., 2008, 47, 6233; (b)
Tani, K.; Stoltz, B. M. Nature., 2006, 441, 731.
[8] (a) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett., 2007, 9, 3599; (b)
Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem., 2008, 73, 2894.
[9] (a) Cho, S.; Yoo, E.; Bae, I.; Chang, S. J. Am. Chem. Soc., 2005, 127, 16046; (b)
Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int. Ed., 2006, 45, 3154.
[10] (a) Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. Science., 1994, 266, 776;
(b) Merkx, R.; Brouwer, A. J.; Rijkers, D. T. S.; Liskamp, R. M. J. Org. Lett., 2005, 7,
7

1125; (c) Shangguan, N.; Katukojvala, S.; Greenerg, R.; Williams, L. J. J. Am. Chem.
Soc., 2003, 125, 7754.
[11] Nanayakkara, P.; Alper, H. Chem. Commun., 2003, 18, 2384.
[12] a) Noata, T.; Murahashi, S. I.; Synlett., 1991, 693; b) Tillack, A.; Rudloff, I.; Beller,
M. Eur. J. Org. Chem., 2001, 523; c) Yoo, W. J.; Li, C. J.; J. Am. Chem. Soc., 2006, 128,
13064; d) Suto, Y.; Yamagiwa, N.; Torisawa, Y. Tetrahedron Lett., 2008, 49, 5732; (e)
Chang, J. W. W.; Chan, P. W. H. Angew. Chem., Int. Ed., 2008, 47, 1138; (f) Muthaiah,
S.; Ghosh, S. C.; Jee, J.-E.; Chen, C.; Zhang, J.; Hong, S. H. J. Org. Chem., 2010, 75,
3002.
[13] a) Chen, C.; Hong, S. H. Org. Biomol. Chem., 2011, 9, 20; b) Wang, Y.; Zhu, D.;
Tang, L.; Wang, S.; Wang, Z. Angew. Chem., Int. Ed., 2011, 50, 8917; c) Kegnaes, S.;
Mielby, J.; mentzel, U. V.; Jensen, T.; Fistrup, P.; Riisager A.; Chem. Commun., 2012, 48,
2427.
[14] Yao, H.; Tang, Y.; Yamamoto K.; Tetrahedron Lett., 2012, 53, 5094.
[15] Prasad, V.; Kale, R. R.; Mishra, B. B.; Kumar, D.; Tiwari, V. K. Org. Lett., 2012, 14,
2936.
[16] a) Reddy, K. R.; Maheswari, C. U.; Venkateshwar, M.; Kantam; M. L. Eur. J. Org.
Chem., 2008, 3619; b) Xiao, F.; Liu, Y.; Tang, C.; Deng, G.-J. Org. Lett., 2012, 14, 984;
c) Achar, T. K.; Mal, P. J. Org. Chem., 2015, 80, 666; d) Karimi, M.; Saberi, D.; Azizi,
K.; Arefi, M.; Heydari, A. Tetrahedron Lett., 2014, 55, 5351.
[17] a) Seveno, A.; Morel, G.; Marchand, A. F. et E.; Tetrahedron Lett., 1977, 38, 3349.
b) Schardt, B. C.; Hill, C. L.; Inorg. Chem., 1983, 22, 1563.
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Table 1 Optimization of reaction conditions for oxidative amidation of benzyl alcoholsa
Entry
Solvent
Equivalents of
Time
Yield
(%)b
90
NHSI/PhI(OAc)2 (min)
1
2
3
4
5
6
7
8
MeCN
THF
1.5/1
2/1.5
2/1.5
2/1.5
2/1.5
1.5/1.5
2/2
30
45
84
CH2Cl2
EtOAc
DMF
60
76
110
120
30
65
60
MeCN
MeCN
MeCN
88
60
55
1.5/0.5
60
40
a Reactions were monitored by TLC. b Isolated yield after column chromatography
9

Table 2 NHSI/PIDA mediated oxidative amidation of benzyl alcohols with amino acid
esters
Entry Benzyl alcohol
1
Amino acid ester Amide
Yield
95
2
3
88
90
4
5
92
89
6
7
91
94
10

8
9
92
85
11

Scheme 1. Oxidative amidation of benzyl alcohols with amino acid esters
12

Scheme 2. Possible mechanism for amidation
13