One-pot synthesis of amides from aldehydes and amines via C-H bond activation

Article abstract of DOI:10.1021/ol302175v

A one-pot synthesis of amides from aldheydes with N-chloroamines, prepared in situ from amines, has been developed. Both aliphatic and aromatic aldehydes and many types of mono- and disubstituted amines are tolerant in this transformation. This cross-coupling reaction appears simple and convenient, has a wide substrate scope and makes use of cheap, abundant, and easily available reagents.

Full text of DOI:10.1021/ol302175v

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5014–5017
One-Pot Synthesis of Amides from
Aldehydes and Amines via CꢀH Bond
Activation
Roberta Cadoni, Andrea Porcheddu, Giampaolo Giacomelli, and Lidia De Luca*
ꢀ
Dipartimento di Chimica e Farmacia, Universita degli Studi di Sassari, Via Vienna 2,
I-07100 Sassari, Italy
ldeluca@uniss.it
Received August 5, 2012
ABSTRACT
A one-pot synthesis of amides from aldheydes with N-chloroamines, prepared in situ from amines, has been developed. Both aliphatic and
aromatic aldehydes and many types of mono- and disubstituted amines are tolerant in this transformation. This cross-coupling reaction appears
simple and convenient, has a wide substrate scope and makes use of cheap, abundant, and easily available reagents.
The amide bond is the key chemical connection present
in many natural important polymers such as peptides
and proteins, as well as in synthetic ones such as nylon.1
The amide functional group is contained in many small-
molecule drugs, marketed agrochemical products, and syn-
thetic intermediates for fine chemical industry. Amide bonds
are typically synthesized by acylation of amines with carb-
oxylic acid derivatives (acid chloride, anhydride, active
esters, etc.):itisthemostcommonmethodologyusedinthe
synthesis of current pharmaceuticals, accounting for 16%
of all reactions. However, this strategy has the innate draw-
back of producing a stoichiometric amount of waste product
and of using highly hazardous reagents.2 To circumvent these
problems, alternative methods for amide synthesis were
developed, such as the Staudinger reaction,3 the Schmidt
reaction,4 the Beckmann rearrangement,5 aminocarbon-
ylation of haloarenes,6 iodonium-promoted R-halo ni-
troalkane amine coupling,7 direct amide synthesis from
alcohols with amines or nitroarenes,8 hydroamination of
alkynes,9 amidation of thioacids with azides,10 and trans-
amidation of primary amides.11
(7) Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465, 1027–
1032.
(8) (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
790–792. (b) Nordstom, L. U.; Vogt, H.; MadsenR. J. Am. Chem. Soc.
2008, 130, 17672–17673. (c) Zweifel, T.; Naubron, J. V.; Grutzmacher,
H. Angew. Chem., Int. Ed. 2009, 48, 559–563. (d) Ghosh, S. C.
Muthaiah, S.; Zhang, Y.; Xu, X.; Homg, S. H. Adv. Synth. Catal.
2009, 351, 2643–2649. (e) Zhang, Y.; Chen, C.; Ghosh, S. C.; Li, Y.;
Hong, S. H. Organometallics 2010, 29, 1374–1378. (f) Cheng, C.; Hong,
S. H. Org. Biomol. Chem. 2011, 9, 20–26. (g) Wang, Y.; Zhu, D.; Tang,
L.; Wang, S.; Wang, Z. Angew. Chem., Int. Ed. 2011, 50, 8917–8921. (h)
Soule, J.-F.; Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc. 2011, 133,
18550–18553. (i) Kegnaes, S.; Mielby, J.; Mentzel, U. V.; Jensen, T.;
Fristrup, P.; Riisager, A. Chem. Commun. 2012, 48, 2427–2429. (j) Xiao,
F.; Liu, Y.; Tang, C.; Deng, G.-J. Org. Lett. 2012, 14, 984–987 and
references herein.
(9) (a) Cho, S.; Yoo, E.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005,
127, 16046–16047. (b) Chen, Z.-W.; Jiang, H.-F.; Pan, X.-Y.; He, Z.-J.
Tetrahedron 2011, 67, 5920–5927.
(10) (a) Kolakowski, R. V.; Shangguan, N.; Sauers, R. R.; Williams,
L. J. J. Am. Chem. Soc. 2006, 128, 5695–5702. (b) Zhang, X.; Li, F.; Lu,
X. W.; Liu, C. F. Bioconjugate Chem. 2009, 20, 197–200.
(1) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471–479.
(2) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606–631.
(3) (a) Saxo, E.; Bertozzi, C. Z. Science 2000, 287, 2007–2010. (b)
Damkaci, F.; De Shong, P. J. Am. Chem. Soc. 2003, 125, 4408–4409. (c)
Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353–1406.
(4) (a) Ribelin, T.; Katz, C. E.; English, D. G.; Smith, S.; Manukyan,
A. K.; Day, V. W.; Neuenswander, B.; Poutsma, J. L.; Aube, J. Angew.
Chem., Int. Ed. 2008, 47, 6233–6235. (b) Lang, S.; Murphy, J. A. Chem.
Soc. Rev. 2006, 35, 146–156.
(5) (a) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett.
2007, 9, 3599–3601. (b) Hashimoto, M.; Obora, Y.; Sakaguchi, S; Ishii,
Y. J. Org: Chem 2008, 73, 2894–2897.
(6) (a) Martinelli, J. R.; Clark, T. p.; Watson, D. A.; Munday, R. H.;
Buchwald, S. L. Angew. Chem. 2007, 119, 8612–8615. (b) Nanayakkara,
P.; Alper, H. Chem. Commun. 2003, 2384–2385.
(11) (a) Dineen, T. A.; Zajac, M. A.; Myers, A. G. J. Am. Chem. Soc.
2006, 128, 16046–16047. (b) Allen, C. L.; Atkinson, B. N.; Williams,
J. M. J. Angew. Chem., Int. Ed. 2012, 51, 1383–1386. (c) Tamura, M.;
Tonomura, T.; Shimizu, K.-I.; Satsuma, A. Green Chem. 2012, 14, 717–
724. (d) Zhang, M.; Imm, S.; Bahn, S.; Neubart, L.; Neumann, H.;
Beller, M. Angew. Chem., Int. Ed. 2012, 51, 3905–3909.
r
10.1021/ol302175v
Published on Web 09/14/2012
2012 American Chemical Society

An elegant alternative pathway, which is more atom
economic and makes use of cheap and abundant starting
materials, is the oxidative amidation of aldehyde with
amines.12 The best accepted mechanism of the oxidative
amidation of aldehydes with amines consists of the forma-
tion of a hemiaminal intermediate, which is subsequently
oxidized to the amide (Scheme 1).
with N-chloroamines, which were prepared in situ starting
from the corresponding amines and without any purifica-
tion, by use of tert-butyl hydroperoxide (TBHP) as an oxi-
dant, under base-free conditions and catalyzed by easily
accessible copper salts (Scheme 2).
Scheme 2. Synthesis of Amides via a Cross-Coupling between
Aldehydes and N-Chloroamines
Scheme 1. Accepted Mechanism of the Oxidative Amidation of
Aldehydes with Amines
Our investigation began by treating dibenzylamine 1a
(1 equiv) with N-chlorosuccinimide (NCS) (1.1 equiv)
in acetonitrile at room temperature for 3 h. The corre-
sponding N-benzyl-N-chloro-1-phenylmethanamine 2a was
quantitatively formed (monitored by TLC). This reaction
mixture, containing the N-chloroamine generated in situ,
was successively treated, without any purification, with
heptaldehyde 3a (5 equiv), Cu(OAc)2 (0.14 mol %), and
tert-butyl peroxybenzoate (TBPB 5 equiv) under reflux,
for 50 min (the reaction was monitored by TLC until the
disappereance of N-chloroamine) generating the amide 4a
in 38% yield (Table 1, entry 1). In order to find the opti-
mum reaction conditions various parameters, of the sec-
ond step, such as catalyst, oxidant, stoichiometric mole
ratio of reactants, and temperature, were tested. We per-
formed the same reaction by the use of tert-butyl hydro-
peroxide (TBHP) instead of TBPB obtaining the product
with a significant improvement in yield (Table 1, entry 2).
No product formation was detected employing H2O2 and
oxone (Table 1, entries 3 and 4). Then different CuII and
CuI saltsweretestedtoexaminetheir effect on the formation
product. Cu(Acac)2 showed less activity than Cu(OAc)2
giving the desired amide 4a in 65% yield (Table 1, entry 5).
CuCl2 and CuBr showed less activity than Cu(OAc)2 giving
the desired amide 4a in 36% and 47% yields respectively
(Table 1, entries 6 and 7). No reaction was observed in the
absence of a copper catalyst (Table 1, entry 8).
Generally these reactions are catalyzed by metals, such
as Cu,13 Rh,14 Ru,15 Pd,16 Ni,17 and Fe.18 Nevertheless,
mostof the methodsoutlinedabove sufferfrom drawbacks
derived from the steric attributes of the amine and the
aldheyde, the formation and stability of the hemiaminal
intermediate, the use of expensive transition metal cata-
lysts, the limited substrate scope, and the utilization of
coreagents. Therefore, the development of different amide
formation reactions remains a great goal. The generation
of new methods for direct conversion of CꢀH bonds into
CꢀN bonds appers to be a critical but appealing challenge
in organic chemistry, but compared with widely developed
and age long CꢀO and CꢀC bond formations via CꢀH
bond activation, the CꢀN bond formation from CꢀH’s
seems more problematic and was reported just in recent
years.19 Wan20a and Wang20b recently published two in-
teresting examples of CꢀN bond formation via CꢀH alde-
hyde bond activation. Their papers report on the synthesis
of amides through a cross-coupling reaction between alde-
hydes and N,N-disubstituted formamides. Even though
the methodologies suffer from some drawbacks,21 undu-
bitably the amidation of aldehydes via CꢀH bond activa-
tion is a fundamentally different method for amide bond
formation.22 Herein, we wish to report on a new and effi-
cient one-pot procedure for the direct amidation of aldehydes
With the respect to the amount of 1a in the reaction, it
was found that 5 equiv was optimal. However, at the end of
the reaction (Table 1, entry 2), 60% of unreacted aldehyde
was recovered. When less than 5 equiv of aldehyde and
TBHP were used the yield of amide 4a decreased (Table 1,
entries 9ꢀ11). No product formation was observed when
performing the reaction without the oxidant (TBHP)
(Table 1, entry 13) or using Bu4NI as an organocatalyst
(Table 1, entry 14).
After the optimized reaction conditions were found, we
tested the methodology with an array of commercially avail-
able amines and aldheydes. Aliphatic aldehydes provided the
resultant amides in good yields (Scheme 3, 4aꢀb), even when
(12) Ghosh, S. C.; Ngiam, J. S. Y.; Chai, C. L. L.; Seayad, A. M.;
Dang, T. T.; Chen, A. Adv. Synth. Catal. 2012, 354, 1407–1412 and
refereces herein.
(13) Yoo, W.; Li, C. J. Am. Chem. Soc. 2006, 128, 13064–13065.
(14) Tillack, A.; Rudloff, I.; Beller, M. Eur. J. Org. Chem. 2001, 66,
523–528.
(15) Naota, T.; Murahashi, S. Synlett 1991, 693–694.
(16) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Synthesis 1983, 474–476.
(17) Nakagawa, K.; Onoue, H.; Minami, K. Chem. Commun. 1966,
17–18.
(18) Ghosh, S. C.; Ngiam, J. S. Y.; Chai, C. L. L.; Seayad, A. M.;
Dang, T. T.; Chen, A. Adv. Synth. Catal. 2012, 354, 1407–1412.
(19) (a) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293–
1314. (b) Lyons, T. W.; Sanford, M. Chem. Rev. 2011, 110, 1147–1169.
(c) Correa, A.; M Mancheno, O. G.; Bolm, C. Chem. Soc. Rev. 2008, 37,
1108–1117.
(20) (a) Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew.
Chem., Int. Ed. 2012, 51, 3231–3235. (b) Xu, K.; Hu, Y.; Zhang, S.; Zha,
Z.; Wang, Z. Chem.;Eur. J. 2012, 18, 9793–9797.
(21) The procedures tolerate the use of only aromatic aldehydes or
substituted benzyl alcohols and only N,N-disubstituted formamides.
(22) Zhang, C.; Zong, X.; Zhang, L.; Jiao, N. Org. Lett. 2012, 14,
3280–3283.
Org. Lett., Vol. 14, No. 19, 2012
5015

Table 1. Synthesis of Amides: Optimization of the Reaction
Conditions
Scheme 3. Aldehydes and Amines Diversity
entrya
oxidant
catalyst
yield (%)b
1
TBPB
TBHP
H2O2
Cu(OAc)2 H2O
38
76
ꢀ
3
2
Cu(OAc)2 H2O
3
3
Cu(OAc)2 H2O
3
4
oxone
TBHP
TBHP
TBHP
TBHP
TBHPc
TBHP
TBHP
TBHP
ꢀ
Cu(OAc)2 H2O
ꢀ
3
5
Cu(Acac)2
CuCl2
CuBr
ꢀ
65
36
47
ꢀ
6
7
8
9
Cu(OAc)2 H2O
72
65d
25e
26f
3
10
11
12
13
14
Cu(OAc)2 H2O
3
Cu(OAc)2 H2O
3
Cu(OAc)2 H2O
3
g
Cu(OAc)2 H2O
ꢀ
3
h
TBHP
Bu4NI
ꢀ
a Reaction conditions: dibenzylamine 1a (1 equiv), N-chlorosuccini-
mide (NCS) (1.1 equiv), in acetonitrile at room temperature for 3 h. To
this reaction mixture were added heptaldehyde 3a (5 equiv), catalyst
(0.14 mol %), and oxidant (5 equiv) under reflux, until the disappearance
of N-chloroamine monitored by TLC. b Yield refers to isolated product
after column chromatography. c TBHP (3.7 equiv). d Heptaldehyde 3a
(3.7 equiv). e Reaction performed using 3a (2.5 equiv) and TBHP (2.5 equiv).
f Reaction performed at room temperature. g Reaction performed without
TBHP. h Reaction performed using Bu4NI as catalyst.
they were sterically hindered (Scheme 3, 4cꢀd). Aromatic
aldehydes with a widespread range of functional groups
both an electron-donating group, such as benzylic CꢀH
(Scheme 3, 4h) and OMe (Scheme 3, 4g and 4q), and
-withdrawing group, such as NO2 (Scheme 3, 4j), were
well tolerated providing the desired amides in moderate
to excellent yields. Aromatic aldehydes with carbonyl
substituents such as ester and ketone gave good results
too (Scheme 3, 4kꢀl).
Scheme 4. Proposed Mechanism of Amide Formation
The reaction carried out on an aldehyde with a halide
substituent on the aromatic ring gave the corresponding
amide, which could be further transformed by traditional
cross-coupling reactions (Scheme 3, 4i). To prove the
synthetic utility of the method, thiophene-2-carbaldehyde
was subjected to optimized conditions, giving the desired
heteroaryl amide (Scheme 3, 4m) in good yield. The
reaction was tested with a series of N,N-dialkyl-N-chloro-
amines showing excellent tolerance. Acyclic (Scheme 3,
4a, 4cꢀd, 4fꢀh, and 4m) as well as cyclic N-chloroamines
(Scheme 3, 4b, 4e, and 4iꢀl) showed to be effective in this
reaction. Furthermore monosubstituted N-chloramines gave
the corresponding N-monosubstituted amides (Scheme 3,
4nꢀq). With regards to the reaction mechanism, a plausible
catalytic cycle is presented in Scheme 4.
(23) (a) Rothenberg, G.; Feldberg, L.; Wiener, H.; Sasson, Y. J. Chem.
Soc., PerkinTrans. 21998, 2429–2434. (b) Minisci, F.; Fontana, F.; Araneo,
S.; Recupero, F.; Banfi, S.; Quici, S. J. Am. Chem. Soc. 1995, 117, 226–232.
5016
Org. Lett., Vol. 14, No. 19, 2012

following Wan20a and Li,25 obtaining the TEMPO adduct D
(Scheme 5).
Scheme 5. Trapping of the Acyl Radical
In conclusion we have reported a novel example of CꢀN
bond formation via copper catalyzed CꢀH aldehyde bond
activation. The methodology was employed to prepare
amides directly from aliphatic and aromatic aldehydes and
variously substituted amines. The procedure reported here-
in appears to be simple and convenient, has a wide scope,
and uses cheap and easily available reagents. Additional
studies on the mechanistic details, different catalysts, and
expansion of the scope of the reaction are currently under-
way in our laboratory.
In the first step (Scheme 4, eq 1) CuII reacts with TBHP
forming a tert-butylperoxy radical, CuI and Hþ following
the mechanism proposed in literature.23 The protonated
N-chloroamineA (Scheme4, eq2) isthenconvertedintoan
amino radical B by a redox reaction following Minisci
(Scheme 4, eq 3).24The aldehyde reacts with the tert-butyl-
peroxy radical generating an acyl radical C (Scheme 4,
eq 4), as reported in literature by Wan20 and Li.25 In the
end the acyl radical C and the amino radical B couple
to form the desired amide (Scheme 4, eq 5). To con-
firm this hypothesis, the acyl radical, generated in situ from
benzaldehyde under our reaction conditions, was trap-
ped with 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO),
Acknowledgment. This work was financially supported
by Regione Autonoma della Sardegna within the project:
“High-throughput screening (HTS) per l’identificazione di
nuove molecule per il trattamento della Sclerosi Laterale
Amiotrofica e della Malattia di Parkinson”.
Supporting Information Available. Experimental pro-
cedures, characterization of products, and copies of 1H and
13C NMR spectra are provided. The material is available
free of charge via the Internet at http://pubs.acs.org.
(24) Minisci, F. Synthesis 1973, 1–24 and references therein.
(25) Liu, W.; Li, Y.; Li, Z. J. Am. Chem. Soc. 2011, 133, 10756–10759.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5017