Tert -Butyl Peroxybenzoate Mediated Selective and Mild N-Benzoylation of Ammonia/Amines under Catalyst- and Solvent-Free Conditions

Article abstract of DOI:10.1055/s-0034-1380811

A new protocol for the synthesis of amides from tert-butyl peroxybenzoate (TBPB) and ammonia/amines has been developed under catalyst- and solvent-free conditions. The ammonia, primary and secondary amines reacted smoothly with TBPB to furnish the corresponding primary, secondary, and tertiary amides in excellent yields. TBPB proved to be an efficient and highly chemoselective benzoylating reagent for aliphatic amines in the presence of aromatic amines/hydroxyl groups.

Full text of DOI:10.1055/s-0034-1380811

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1862–1866
letter
1862
D. K. T. Yadav, B. M. Bhanage
Letter
Synlett
tert-Butyl Peroxybenzoate Mediated Selective and Mild N-Benzoy-
lation of Ammonia/Amines under Catalyst- and Solvent-Free Con-
ditions
Dilip Kumar T. Yadav
O
O
Bhalchandra M. Bhanage*
R
O
O
N
neat, r.t.
O
R
HO
H
+
+
H2N
Department of Chemistry, Institute of Chemical Technology, N.
Parekh Marg, Matunga, Mumbai – 400 019, India
bm.bhanage@gmail.com
1°/2°/3° amide
metal-free
R = H, aliphatic,
benzylic, cyclic,
heterocyclic
bm.bhanage@ictmumbai.edu.in
base-free
solvent-free
chemoselective
scalable
Received: 31.03.2015
Accepted after revision: 21.04.2015
Published online: 08.06.2015
amines is usually not satisfactory. Subsequently, other ben-
zoylating reagents such as vinyl benzoate,8 N-benzoyltetra-
zole,9 N-acylbenzotriazole,10 2-benzoylthio-1-methylpyri-
dinium chloride,11 thiobenzoic acid,12 and N-benzoyloxazo-
lidin-2-one13 have been reported. Recently, benzoylation of
amines has been carried out via transamidation of carbox-
amides with amines catalyzed by benzoic acid under metal-
free conditions.14
tert-Butyl peroxybenzoate (TBPB) is a stable, easy-to-
prepare, and easy-to-handle reagent.15 To our surprise,
TBPB has not been used with ammonia/amines for the syn-
thesis of primary, secondary, and tertiary amides to date.
Herein, we report a practical method for the synthesis of
primary, secondary, and tertiary amides using TBPB as a
highly chemoselective benzoylating reagent under metal-,
base-, and solvent-free reaction conditions (Scheme 1).
In the course of our studies on the synthesis of organic
compounds using peroxides,16 we have observed that the
reaction of TBPB (1) with benzylamine (2a) leads to the for-
mation of N-benzyl benzamide (3a) in excellent yield and
TBHP as a byproduct (Scheme 1).
Our initial question was whether TBPB undergoes nuc-
leophilic substitution with benzyl amine or 2a undergoes
oxidation to form the corresponding aldehyde which fur-
ther reacts with another molecule of 2a in the presence of
TBPB oxidant giving the corresponding product 3a. There-
fore, we performed the reaction of TBPB with aqueous NH3,
tert-butylamine, and piperidine to provide the correspond-
ing primary, secondary, and tertiary amides 3m, 3o, and 3w
in excellent yields (Scheme 1). This confirms that TBPB un-
dergoes nucleophilic substitution with ammonia/amines to
provide corresponding amides.
With this rationale we assessed the scope of the devel-
oped protocol with various benzylic, primary, secondary,
cyclic, and heterocylic amines, and the results are present-
ed in Table 1 and Table 2.18 Firstly, different benzylic amine
derivatives were examined for the synthesis of various
DOI: 10.1055/s-0034-1380811; Art ID: st-2015-d0232-l
Abstract A new protocol for the synthesis of amides from tert-butyl
peroxybenzoate (TBPB) and ammonia/amines has been developed un-
der catalyst- and solvent-free conditions. The ammonia, primary and
secondary amines reacted smoothly with TBPB to furnish the corre-
sponding primary, secondary, and tertiary amides in excellent yields.
TBPB proved to be an efficient and highly chemoselective benzoylating
reagent for aliphatic amines in the presence of aromatic amines/
hydroxyl groups.
Key words tert-butyl peroxybenzoate, N-benzoylation, catalyst-free,
solvent-free, amides
Amides are important structural constituents in both
naturally occurring as well as synthetic compounds.1 Fur-
thermore, a survey in 2008 revealed that over 50% of all
drug molecules contain at least one amide bond.2 Hence, a
great amount of research has been carried out in the chem-
istry of amide bond formation and this remains an active
area in organic synthesis.3 Amide bond formation by N-acy-
lation of amines is currently the most widely used ap-
proach.4a Various acylating reagents such as carboxylic
acids, acid halides, anhydrides, acyl azides, N-acylimid-
azoles, alkyl esters, succinimidyl esters, p-nitrophenyl es-
ters, and pentafluorophenyl esters have been developed for
the N-acylation of amines.4b
Benzoylation has found wide application in nucleoside
and nucleotide chemistry and for resolution of amino
acids.5 Furthermore, benzoylation of amines is commonly
for protection for amines in a multistep synthetic processes
such as the synthesis of peptides, glycopeptides, amino
acids, aminoglycosides, β-lactams, alkaloids, and sphin-
gosines.6 Typically, benzoylation of amines is carried out by
using benzoyl chloride or benzoic anhydride in the pres-
ence of solvent.7 However, these reagents are highly reac-
tive and hence selectivity between aliphatic and aromatic
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1862–1866

1863
D. K. T. Yadav, B. M. Bhanage
Letter
Synlett
O
O
O
O
neat
N
H2N
O
HO
+
+
H
r.t., 6 h
3a 95%
1 (1 mmol)
2a (1.1 mmol)
O
O
O
O
O
neat
NH2
HO
aq NH3
+
+
r.t., 6 h
2m (1.1 mmol)
3m 95%
1 (1 mmol)
O
O
O
O
neat
O
N
H
H2N
+
+
+
HO
HO
r.t., 6 h
1 (1 mmol)
2o (1.1 mmol)
3o 91%
O
O
O
O
neat
O
N
HN
+
r.t., 12 h
1 (1 mmol)
2w (1.1 mmol)
3w 94%
Scheme 1 Benzoylation reaction of ammonia/amines with TBPB
amides. It was observed that the reaction of benzylamine
bearing electron-donating groups such as t-Bu and OMe af-
forded the corresponding products 3b–d in excellent yields
(Table 1, entries 2–4). Furthermore, substrates bearing halo
substituents (F, Cl) also provided the corresponding prod-
ucts 3e and 3f in excellent yields (Table 1, entries 5 and 6).
Next, 2g bearing the electron-withdrawing cyano group
also furnished the corresponding N-(4-cyanobenzyl)benz-
amide (3g) in 94% yield (Table 1, entry 7). The reaction of 1-
phenylethanamine (2h) with TBPB provided N-(1-phenyl-
ethyl)benzamide (3h) in 92% yield (Table 1, entry 8). Subse-
quently, various hetero benzylamine derivatives were also
studied, and the corresponding products 3i–l were ob-
tained in excellent yields (Table 1, entries 9–12). Further-
more, it was observed that reaction of 1 with aqueous am-
monia (25% aqueous solution of NH3) provided the corre-
sponding primary amide 3m in 95% yield (Table 1, entry
13). Next, the reaction of TBPB with various aliphatic
amines also furnished the respective products 3n–t in ex-
cellent yields (Table 1, entries 14–20). Furthermore, the re-
action of TBPB with representative secondary amines pro-
vided the corresponding tertiary amides 3u–x in excellent
yields (Table 1, entries 21–24). However, it was observed
that aniline, phenol, and hexanol did not react with TBPB
under the present reaction conditions.
Table 1 Substrate Study for the Synthesis of Amidesa
O
O
neat
r.t.
R
O
O
N
O
R
HO
+
H
+
H2N
3
4
2
1
Entry Ammonia/amine
Product
Time Yield of
(h)
3 (%)b
O
O
H2N
N
H
1
6
95
2a
3a
H2N
N
H
2
12
97
2b
3b
3c
3d
3e
O
H2N
N
H
3
12
14
10
96
93
94
O
O
2c
O
O
O
N
H
H2N
4
5
2d
O
H2N
N
H
F
F
2e
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1862–1866

1864
D. K. T. Yadav, B. M. Bhanage
Letter
Synlett
Table 1 (continued)
Entry Ammonia/amine
Product
Time Yield of
(h)
Entry Ammonia/amine
Product
Time Yield of
(h)
3 (%)b
3 (%)b
O
O
O
O
Cl
H2N
H2N
Cl
N
H
N
H
18
3
95
6
10
93
2r
2f
3r
3s
3f
H2N
H2N
N
H
N
H
19
3
3
95
96
94
93
94
93
7
12
94
CN
2s
CN
2g
3g
3h
3i
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H2N
H2N
N
H
N
H
20
8
10
12
12
10
10
6
92
92
94
95
94
95
94
91
96
97
2t
2h
3t
N
N
N
H2N
H
N
N
N
N
N
H
21
10
9
2u
2i
3u
3v
3w
3x
HN
H2N
N
N
H
N
N
22
12
12
12
10
11
12
13
14
15
16
17
2v
2j
3j
HN
23
H2N
N
H
N
2w
2k
3k
3l
HN
O
O
N
H
H2N
24
O
O
2l
2x
a Reaction conditions: 1 (1.0 mmol), aq NH3/amine (1.1 mmol), r.t.
b Isolated yield.
aq NH3
2m
NH2
Subsequently, it was observed that the reaction of TBPB-
3m
3n
3o
3p
3q
with 2-amino-, 3-amino-, and 4-amino-benzylamine 5a–c
proceeded chemoselectively providing the corresponding
aminobenzyl benzamides 6a–c in excellent yields (Table 2,
entries 1–3). Thus, this protocol can differentiate between
aliphatic and aromatic amines. Similarly, the reaction of 5d
and 5e bearing both hydroxyl and amino groups only re-
sults in N-benzoylation to furnish the corresponding prod-
ucts 6d and 6e in excellent yields (Table 2, entries 4 and 5).
Finally, it was observed that the reaction of 1,2-aminophe-
nol (5f) and 1,2-aminothiophenol (5g) did not proceed (Ta-
ble 2, entries 6 and 7). Subsequently, a gram-scale reaction
was also carried out successfully for the reaction of 1 with
2q to furnish the corresponding product 3q in 93% isolated
yield.
H2N
N
H
6
2n
N
H
6
H2N
2o
H2N
N
H
6
2p
H2N
n-C11H23
N
H
n-C11H23
2
2q
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1862–1866

1865
D. K. T. Yadav, B. M. Bhanage
Letter
Synlett
Table 2 Chemoselective Benzoylation of Aliphatic Aminesa
Acknowledgment
O
D.K.T.Y. is grateful to the UGC (University Grant Commission, India)
for providing a fellowship (SRF).
O
neat
r.t.
R
O
O
N
O
R
HO
H
+
+
H2N
1
5
6
Supporting Information
Supporting information for this article is available online at
Entry Amine
Product
Time Yield
(h)
of 6
http://dx.doi.org/10.1055/s-0034-1380811.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
(%)b
NH2
O
O
NH2
References and Notes
H2N
N
H
1
14
91
93
(1) (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Fischbach, M. A.; Walsh, C. T. Chem. Rev. 2006, 106,
3468. (c) Simonovic, M.; Steitz, T. A. Biochim. Biophys. Acta
2009, 1789, 612. (d) Paul, H. S.; Robert, L. K.; Russell, F. N. EP
0936864 (A1), 1999. (e) Malawska, B. Curr. Top. Med. Chem.
2005, 5, 69. (f) Funabashi, M.; Yang, Z.; Nonaka, K.; Hosobuchi,
M.; Fujita, Y.; Shibata, T.; Chi, X.; Van Lanen, S. G. Nat. Chem.
Biol. 2010, 6, 581. (g) Pelagalli, R.; Chiarotto, I.; Feroci, M.;
Vecchio, S. Green Chem. 2012, 14, 2251. (h) Yadav, D. K. T.;
Bhanage, B. M. RSC Adv. 2015, 5, 12387.
(2) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(3) (a) Larock, R. C. Comprehensive Organic Transformations, A Guide
to Functional Group Preparations, 2nd ed.; Wiley-VCH: New
York, 1999. (b) Charville, H.; Jackson, D.; Hodges, G.; Whiting, A.
Chem. Commun. 2010, 46, 1813. (c) Han, S.-Y.; Kim, Y.-A. Tetra-
hedron 2004, 60, 2447. (d) Gunanathan, C.; Ben-David, Y.;
Milstein, D. Science 2007, 317, 790. (e) Nordstrøm, L. U.; Vogt,
H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672. (f) Yang, X.;
Birman, V. B. Org. Lett. 2009, 11, 1499. (g) Bröhmer, M. C.;
Mundinger, S.; Bräse, S.; Bannwarth, W. Angew. Chem. Int. Ed.
2011, 50, 6175. (h) Hardee, D. J.; Kovalchuke, L.; Lambert, T. H. J.
Am. Chem. Soc. 2010, 132, 5002. (i) Jiang, H.; Liu, B.; Li, Y.; Wang,
A.; Huang, H. Org. Lett. 2011, 13, 1028.
(4) (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337. (b) Taylor, J. E.; Bull, S. D. Compre-
hensive Organic Synthesis, 2nd ed., Vol. 6; Elsevier: Oxford, 2014,
427–478.
(5) (a) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.
Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Pearson
Education: London, 2006, 815. (b) Prasad, A. K.; Kumar, V.;
Malhotra, S.; Ravikumar, V. T.; Sanghvib, Y. S.; Parmara, V. S.
Bioorg. Med. Chem. 2005, 13, 4467. (c) Stawinski, J.; Hozumi, T.;
Narang, S. A. J. Chem. Soc., Chem. Commun. 1976, 243.
5a
6a
6b
NH2
H2N
NH2
N
H
2
14
14
10
5b
O
H2N
N
H
3
94
90
NH2
NH2
5c
6c
6d
6e
O
O
OH
OH
N
H
H2N
5d
4
H2N
N
H
5
14
14
14
93
–
OH
OH
5e
NH2
HO
6
no reaction
no reaction
5f
NH2
HS
7
–
5g
a Reaction conditions: 1 (1.0 mmol), amine (1.1 mmol), r.t.
(6) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthe-
sis, 3rd ed.; John Wiley and Sons: New York, 1999.
b Isolated yield.
(7) (a) Pearson, A. L.; Roush, W. J. Handbook of Reagents for Organic
Synthesis: Activating Agents and Protecting Groups; John Wiley
and Sons: London, 1999, 42–44. (b) Moghadam, M.;
Tangestaninejad, S.; Mirkhani, V.; Mohammadpoor-Baltork, I.;
Babaghanbari, M.; Zarea, M.; Shariati, L.; Taghavi, S. A. J. Iran.
Chem. Soc. 2009, 6, 523. (c) Wang, T.; Zhang, Z.; Meanwell, N. A.
J. Org. Chem. 2000, 65, 4740. (d) Chattopadyay, G.; Chakraborty,
S.; Saha, C. Synth. Commun. 2008, 38, 4068. (e) Naik, S.;
Bhattacharjya, G.; Talukdar, B.; Patel, B. K. Eur. J. Org. Chem.
2004, 1254.
In summary, we have developed a novel, mild, efficient,
scalable, and highly selective protocol for the N-benzoyla-
tion of ammonia/amines with TBPB at room temperature.
Here, we have firstly demonstrated that TBPB can be uti-
lized as a new type of benzoylating reagent for ammonia
and aliphatic amines under solvent-, base-, and metal-free
conditions. The primary, secondary, and tertiary amide
products were all synthesized in excellent yields; hence,
this protocol may serve as an attractive alternative for
amide synthesis to those of the existing methods.
(8) Alalla, A.; Merabet-Khelassi, M.; Aribi-Zouioueche, L.; Riant, O.
Synth. Commun. 2014, 44, 2364.
(9) Bhat, B.; Sanghvi, Y. S. Tetrahedron Lett. 1997, 38, 8811.
(10) Katritzky, A. R.; Suzuki, K. H. J. Org. Chem. 2000, 65, 8210.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1862–1866

1866
D. K. T. Yadav, B. M. Bhanage
Letter
Synlett
(11) Yamada, M.; Watabe, Y.; Sakakibara, T.; Sudoh, R. J. Chem. Soc.,
Chem. Commun. 1979, 179.
(12) Mali, S. M.; Bhaisare, R. D.; Gopi, H. N. J. Org. Chem. 2013, 78,
5550.
(13) Yokomatsu, T.; Arakawa, A.; Shibuya, S. J. Org. Chem. 1994, 59,
3506.
(14) Wu, J.-W.; Wu, Y.-D.; Dai, J.-J.; Xu, H.-J. Adv. Synth. Catal. 2014,
356, 2429.
(15) (a) Wei, Y.; Yoshikai, N. Org. Lett. 2011, 13, 5504. (b) Guo, S.;
Wang, Q.; Jiang, Y.; Yu, J.-T. J. Org. Chem. 2014, 79, 11285.
(c) Cao, J.-J.; Zhu, T.-H.; Wang, S.-Y.; Gu, Z.-Y.; Wang, X.; Ji, S.-J.
Chem. Commun. 2014, 50, 6439. (d) Wei, W.; Zhang, C.; Xu, Y.;
Wan, X. B. Chem. Commun. 2011, 47, 10827.
(16) (a) Khemnar, A. B.; Bhanage, B. M. Eur. J. Org. Chem. 2014, 6746.
(b) Khemnar, A. B.; Bhanage, B. M. Org. Biomol. Chem. 2014, 12,
9631.
(17) (a) Wang, N.; Zou, X.; Ma, J.; Li, F. Chem. Commun. 2014, 50,
8303. (b) Rao, S. N.; Mohan, D. C.; Adimurthy, S. Org. Lett. 2013,
15, 1496. (c) Molander, G. A.; Hiebel, M. A. Org. Lett. 2010, 12,
4876.
(18) General Experimental Procedure for the Synthesis of Amide
from Ammonia/Amine and TBPB
identity of the compound was confirmed by 1H NMR and 13C
NMR spectroscopic methods.
N-(4-Methoxybenzyl)benzamide (3c)17a
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 7.1 Hz, 2 H), 7.48 (t, J =
7.2 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 2 H), 7.27 (d, J = 8.5 Hz, 2 H), 6.87
(d, J = 8.6 Hz, 2 H), 6.45 (br s, 1 H), 4.56 (d, J = 5.56 Hz, 2 H), 3.79
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.29, 159.11,
134.43, 131.50, 130.25, 129.31, 128.57, 126.95, 114.15, 55.31,
43.63 ppm.
N-(4-Fluorobenzyl)benzamide (3e)17a
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.0 Hz, 2 H), 7.49 (t, J =
7.3 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 2 H), 7.31–7.25 (m, 2 H), 7.0 (t, J =
8.6 Hz, 2 H), 6.67 (br s, 1 H), 4.58 (d, J = 5.58 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 167.45, 162.2 (d, JC–F = 244 Hz),
134.21, 134.07, 131.64, 129.53 (d, JC–F = 8 Hz), 128.60, 126.98,
115.56 (d, JC–F = 21 Hz), 43.33 ppm.
N-(3-Chlorobenzyl)benzamide (3f)17b
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.16 Hz, 2 H), 7.49 (t,
J = 8.4 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 2 H), 7.30 (s, 1 H), 7.25–7.18
(m, 3 H), 6.77 (br s, 1 H), 4.58 (d, J = 5.72 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 167.54, 140.34, 134.52, 134.04, 131.71,
129.99, 128.62, 127.80, 127.68, 127.01, 125.89, 43.42 ppm.
N-(4-Cyanobenzyl)benzamide (3g)17c
A mixture of TBPB (1 mmol) and requisite aq NH3 or amine (1.1
mmol) were charged in a round-bottom flask. The reaction
mixture was stirred at r.t. for the indicated time, and progress of
the reaction was monitored by TLC/GC. The crude product was
directly purified by column chromatography (silica gel, 100–
200 mesh, PE–EtOAc) to provide the desired pure product. The
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 7.9 Hz, 2 H), 7.59 (d,
J = 6.6 Hz, 2 H), 7.52 (t, J = 7.3 Hz, 1 H), 7.45–7.41 (m, 4 H), 6.89
(br s, 1 H), 4.67 (d, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.67, 143.96, 133.76, 132.47, 131.93, 128.70,
128.19, 127.02, 118.73, 111.21, 43.48 ppm.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1862–1866