Metal-Free Synthesis of N-Aryl Amides using Organocatalytic Ring-Opening Aminolysis of Lactones

Article abstract of DOI:10.1002/cssc.201700415

Catalytic ring-opening of bio-sourced non-strained lactones with aromatic amines can offer a straightforward, 100 % atom-economical, and sustainable pathway towards relevant N-aryl amide scaffolds. Herein, the first general, metal-free, and highly efficient N-aryl amide formation is reported from poorly reactive aromatic amines and non-strained lactones under mild operating conditions using an organic bicyclic guanidine catalyst. This protocol has high application potential as exemplified by the formal syntheses of drug-relevant molecules.

Full text of DOI:10.1002/cssc.201700415

Accepted Article
Title: Metal-Free Synthesis of N-Aryl Amides using Organocatalytic
Ring-Opening Aminolysis of Lactones
Authors: Arjan Willem Kleij, Wusheng Guo, José Enrique Gómez, Luis
Martínez-Rodríguez, Nuno A. G. Bandeira, and Carles Bo
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Metal-Free Synthesis of N-Aryl Amides using Organocatalytic
Ring-Opening Aminolysis of Lactones
Wusheng Guo,[a] José Enrique Gómez,[a] Luis Martínez-Rodríguez,[a] Nuno A. G. Bandeira,[a][b][c] Carles
Bo[a][d] and Arjan W. Kleij*[a][e]
Abstract: Catalytic ring-opening of bio-sourced non-strained lactones
with aromatic amines can offer a straightforward, 100% atom-
economical and sustainable pathway towards relevant N-aryl amide
scaffolds. We herein report the first general, metal-free and highly
efficient N-aryl amide formation from poorly reactive aromatic amines
and non-strained lactones under mild operating conditions using an
organic bicyclic guanidine catalyst. This protocol has high application
potential as exemplified by the formal syntheses of drug relevant
molecules.
minimal waste generation under metal-free conditions is thus of
great importance.[4,5]
Catalyst-free ring-opening aminolysis (ROA) of non-strained
lactones using aryl amines has so far only been realized under
ultrahigh pressure (9000 atm) with poor conversion and quite
limited scope.[6] Alternatively, pre-activation of the aromatic amine
with butyl lithium or addition of over-stoichiometric amounts of
sensitive and flammable reagents such as AlMe3 prior to ring-
opening proved to be feasible approaches (Scheme 1) also in the
context of total synthesis.[7] These harsh reaction conditions,
however, may limit the functional group tolerance, scalability and
practical application of these processes, and moreover a
substantial amount of waste and metal residues are produced. As
far as we know, the only known catalytic approach for the ROA of
a non-strained lactone in the presence of an aromatic amine
requires a tungstate based catalyst under microwave conditions
at temperature beyond 100ºC with a fairly limited scope.[8]
Therefore, the development of a general catalytic ROA strategy
involving readily available lactones under metal-free and
attractive mild conditions enabling the preparation of N-aryl
amides has significant incentives. Such methodology with
minimal waste release and scalability potential can rejuvenate N-
aryl amide bond formation reactions addressing the ever
increasing requirements for sustainable methods in modern
organic synthesis.
Introduction
Amide bonds are ubiquitous in nature and constitute key
connecting linkages in peptides and proteins in living organisms.
Moreover, it has been estimated that as many as 25% of all the
current pharmaceuticals contain amide bonds, and three relevant
examples (Acetaminophen, Aubagio and Prilocaine) are
presented in Scheme 1.[1] Recently, amides also have found
important applications in materials science, such as
semiconductors and polymers as amide units combine properties
including high stability and conformational diversity.[2] Although
tremendous success in amide synthesis has been witnessed in
the past decades,[3] the general concerns surrounding
concomitant and significant waste production, cost-related
features and the avoidance of metal residues ending up in
commercial products have raised serious concerns regarding
amide synthesis in the pharmaceutical industry and biological
applications.[4] Consequently, the development of protocols with
[a]
Dr. W. Guo, J. E. Gómez, Dr. L. Martínez-Rodríguez, Dr. N. A. G.
Bandeira, Prof. C. Bo, Prof. A. W. Kleij
Institute of Chemical Research of Catalonia (ICIQ), the Barcelona
Institute of Science and Technology, Av. Països Catalans 16, 43007 –
Tarragona (Spain)
E-mail: akleij@iciq.es
[b]
[c]
Centro de Química e Bioquímica, Faculdade de Ciências,
Universidade de Lisboa, Campo Grande, 1749-016 Lisboa (Portugal)
Centro de Química Estrutural, Instituto Superior Técnico,
Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa
(Portugal)
Scheme 1. Organocatalytic approach (below) towards N-aryl amides using
[d]
[e]
Departament de Química Física i Inorgánica, Universitat Rovira i
Virgili, Marcel·lí Domingo s/n, 43007 Tarragona (Spain)
Catalan Institute for Research and Advanced Studies (ICREA), Pg.
Lluis Companys 23, 08010 – Barcelona (Spain)
lactones and aromatic amines as reaction partners.
TBD proved to be an efficient catalyst in various
transformations based on hydrogen bonding activation mode.[9]
In particular, TBD has been used as catalyst for the ring-opening
of lactones by alcohols and ring-opening polymerization of
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Screening of reaction conditions and organocatalysts for the synthesis of N-aryl amide 1 from aniline and -butyrolactone.[a]
Entry
Aniline [equiv]
Catalyst
Amount [mol%]
T [ºC]
Time [h]
Yield of 1 [%][b]
1
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.2
1.2
0.8
1.2
1.2
1.2
‒
TBD
‒
100
25
65
65
65
65
65
65
65
65
65
65
65
65
65
40
40
40
40
40
40
40
40
26
18
12
26
26
26
26
26
26
26
26
26
26
26
26
12
12
24
24
24
24
24
24
0
64
73
60
62
41
0
30
30
30
20
10
30
30
30
30
30
30
30
30
30
30
30
30
40
30
30
30
30
3
TBD
4
TBD
5
TBD
6
TBD
7
MTBD
DBU
8
8
9
DMAP
TMG
HMTA
PG
0
10
11
12
13
14
15
16
17
18
19
20
21[c]
22[d]
23[e]
0
0
5
Urea
0
Thiourea A
Thiourea B
TBD
0
<2
73
70
82
80
72
30
38
22
TBD
TBD
TBD
TBD
TBD
TBD
TBD
[a] 0.40 mmol of lactone, the indicated number of equivalents of aniline, and the catalyst were combined and reacted for the required time under neat conditions
and open to air. [b] NMR yield using mesitylene as internal standard. [c] Using toluene as solvent (0.4 mL). [d] Using CH3CN as solvent (0.4 mL). [e] Using DCM as
solvent (0.4 mL).
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Figure 1: Free energies (kcal/mol) of the reaction pathway toward the formation of an N-aryl amide from aniline and γ-BL using TBD as catalyst (dark bold line),
and from aniline and a seven-membered lactone (gray dashed line, smaller print) for comparison. The 3D molecular representations show the key interactions and
intermediates in this proton relay mechanism.
lactides[9d-e] and the formation of amides from -butyrolactone and
benzylamine.[9f] In a wider context, the catalytic amidation of
acyclic esters by amines using TBD catalyst also has been
reported.[9e,f] Inspired by the success of TBD-mediated hydrogen
bonding activation, we envisioned that the use of TBD as a
catalyst would trigger the reaction of lactones and unreactive aryl
amines based on a “proton-relay” strategy.
Herein we report N-aryl amide formation using non-strained
lactones and aromatic amines under mild, sustainable and metal-
free conditions (Scheme 1). The process is broadly applicable to
the conversion of a wide range of lactones with different ring sizes
(up to 16) and substituted aromatic amines leading to the
formation of N-aryl amides with synthetically useful hydroxy end-
groups. The newly developed strategy has been applied in the
preparation of pharmaceutically relevant amide compounds
demonstrative of the synthetic potential of these hydroxyl-
functionalized amide scaffolds.
our delight, the use of TBD as catalyst (30 mol%) gave an
appreciable NMR yield of the N-aryl amide product 1 (73%) after
reaction at 65oC for 12 h (entry 3); prolonging the reaction time
did not improve the yield of 1. Decreasing the TBD loading to 10%
still resulted in substantial product formation though more slowly
(entry 6). N-methyl protected TBD (MTBD) did not show any
reactivity (entry 7) highlighting the importance of the free N-H
fragment in TBD to initiate a hydrogen-bond activation of both
substrates. Other N-heterocyclic structures lacking proton-relay
capability including DMAP, 1,1,3,3-tetramethylguanidine and
hexamethylene-tetramine, and simple (thio)ureas did not show
any reactivity under these conditions (entries 8-13). Known
hydrogen-bond activators such as DBU (entry 8) and pyrogallol
(entry 12) proved to be reactive under these conditions but gave
a significantly poorer yield of <10% compared to the use of TBD.
Finally the catalytic reaction using TBD (30 mol%, solvent-free)
was optimized by lowering the temperature to 40oC and reducing
the amount of aniline to 1.2 equiv giving N-aryl amide 1 in 82%
yield (entry 18). The use of solvents (entries 21-23) gave slower
catalysis illustrated by the lower yields of 1 (22-38%).
Results and Discussion
Mechanistic considerations
Screening studies
The overall (low) activation Gibbs free energy (17.5 kcal/mol) for
the formation of N-aryl amide 1 derived from a five-membered
lactone was determined by DFT analysis (Figure 1) reinforcing the
experimental observation that the TBD-mediated conversion of -
BL is feasible under mild operating conditions. The mechanistic
steps mainly include proton storage and release processes, i.e.
We started our investigation by considering the reaction between
aniline and γ-butyrolactone (-BL) as a model reaction (Table 1).
As expected, the control reaction in the absence of any catalyst
at 100oC did not result in any detectable conversion after 26 h in
line with the challenging nature of this transformation (entry 1). To
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proton-relay. The TBD and reactant ensemble is taken as the
energy reference. The rate limiting step is the concerted,
nucleophilic addition of the aniline and proton transfer to the
catalyst, a process which requires 17.5 kcal/mol (ΔG‡) to reach
the transition state TS1. Equilibrium then occurs between species
Int. 1 and Int. 2 which consists of a proton transfer between the
oxygen atom in the newly formed adduct and TBD. This leads to
the ring opening step whereby the C—O bond is broken restoring
the sp2 character of the attacked carbon centre (Int. 3). The final
step is the proton transfer from TBD-H+ to the alkoxide moiety.
Another exploratory avenue that was pursued was how the
reaction kinetics changes upon expanding the lactone ring size.
A seven-membered lactone was chosen as an additional
substrate. Intuitively the aminolysis of a seven-membered lactone
may seem more feasible since larger-size rings are
thermodynamically less stable. However, the calculations
suggested that the rate determining step (TS1) has a larger
barrier height with respect to the amination of γ-BL (Figure 1). The
origin of this increase is for a larger part due to enthalpy: ΔH‡(TS1)
= +22.9 kcal/mol for the amination of the seven-membered
lactone whereas for the amination of γ-BL the enthalpy term
ΔH‡(TS1) is +18.4 kcal/mol. The TS1 structures show clear
differences as the seven-membered lactone exhibits longer bond
distances between the implicated atoms holding together the
trimolecular ensemble (see Supporting Information for more
details).
The presence of primary alkyl amines, being much more
nucleophilic than aromatic ones, gave rise to excellent yields of
the respective amides in quite short reaction times (88-97%, 15
and 16). The same reactions proved, however, to be far more
sluggish in the absence of TBD under similar conditions as
observed in various total syntheses in which air-sensitive and
stoichiometric AlMe3 was required to promote the reactions.[7d,e]
Importantly, comparing the protocol reported previously using
sensitive metal reagents,[7] the present ROA of -BL using aniline
can be easily performed at larger scale (40 mmol; upscale factor
100) open to air with an excellent isolated yield of amide 1 (R =
H; 82%), and thus illustrates the practical aspect of this
methodology.
In both cases the mechanistic steps that only involve proton
exchange are barrier-less. The comparative data suggest that
larger ring size lactones are probably more lethargic substrates
and require thus activation at higher temperature: this is indeed
what can be observed experimentally (vide infra).
Substrate scope studies
The substrate scope was then investigated under the optimized
conditions using various amines and -BL as reaction partners
(Figure 2, a). In general, good to excellent isolated yields of the
amides 116 of up to 97% were obtained. A variety of functional
groups are tolerated using this procedure including electron-
donating (2, 3, 7, 11 and 12) and remarkably also strongly
electron-withdrawing groups (810) present in the para or meta
position of the aniline scaffold. In these latter cases only modest
product formation was achieved, and an increase in the reaction
temperature or catalyst loading did not substantially improve the
yield of amides 810 (Table S1-S4). Notably, when p-
phenylenediamine was used as amine reagent, mono-amide 7
(85%) was produced selectively in excellent yield. The installation
of an indole unit (13) having importance in drug development
programs is also readily accomplished. The reactions of ortho-
substituted and more sterically demanding secondary
anilines/amines (such as N-methyl aniline) proved to be
unproductive (see Tables S5-S8). This result may be expected
since the formation of the required ternary transition state (Figure
1; TS1) depends on the steric requirements of both the lactone
and amine substrate, with sterically more demanding secondary
anilines/amines likely not being productive in this TBD-mediated
process.
Figure 2. Scope in amine reaction partners (a) and post-modification of the N-
aryl amide 1 derived from -BL (b). All reactions were performed with 0.40 mmol
lactone, 1.2 eq. of aromatic amine, 40ºC, 24 h, open to air, all yields are of the
isolated product. [i] 100 L solvent, 16 h. [ii] lactone/amine = 4:1, 80ºC, 24 h.
[iii] lactone/amine = 3:2, TBD (50 mol%), 80ºC, 100 h. [iv] 0.40 mmol of aromatic
amine, 0.48 mmol of lactone, 4 h.
These N-aryl amides are useful intermediates and provide an
easy entry to various other functional molecules (Figure 2, b). For
example, treatment of N-aryl amide 1 with acetic anhydride at rt
gave virtually quantitative yield of the ester 17. The alkyl bromide
derivative 18 (95%) could be easily prepared by an Appel-type
reaction using CBr4.[10] Reduction of amide 1 with LiAlH4 afforded
the primary N-aryl amino alcohol 19 (91%). Interestingly, oxidative
conversion of amide 1 using KMnO4 under basic conditions or
utilizing tosyl chloride yielded the corresponding N-aryl
succinimide 20 and N-phenyl γ-lactam 21, respectively, instead of
the corresponding acid and tosylated product. This illustrates the
thermodynamically stable character of 5-membered ring systems
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and the tendency towards fast cyclization through an
intramolecular nucleophilic attack of the amide group onto the -
carbon in compound 1. It is worth noting that -lactams are
important structural motifs of biologically active natural products
and drug molecules.[11]
commercially available, a direct entry towards enantioenriched
amides is facilitated.
Heteroatoms (such as N and O) in the 6-membered lactones
did not affect the efficiency of the ROA reaction (cf., 31 and 32).
The conversion of a 7-membered lactone to produce amide 35
was sluggish at lower temperatures, but fortunately the reaction
proceeded smoothly at 100ºC giving 35 in good yield (Figure 3, b:
89%) using an increased amount of aniline. Notably, at a higher
temperature of 100ºC, the ROA also proved to be suitable for the
preparation of the long hydroxy-alkyl N-aryl amide 33 (n = 13,
76%); compounds such as 33 having both hydrophilic and
hydrophobic ends can find use as templates in the area of self-
assembled materials.[12] The preparation of amides 33 and 35
typically requires higher reaction temperatures for efficient
conversion as a result of a steric effect which is governed by the
non-planar conformations of larger ring-size lactones, and
consequently are more energy demanding with respect to the
formation of the requisite key ternary transition state (TS1 in
Figure 1). The difference in reactivity between 5- and 7-
membered lactones was also supported by DFT analysis,
showing a larger energetic span for the 7-membered lactone
conversion (Figure 1 and SI).
Figure 3. ROA of various lactones with different ring sizes (a) and end-group
conversion of 6- and 7-membered lactones (b). All reactions performed with
0.40 mmol lactone, 1.2 eq. of amine, 40ºC, 24 h, open to air, all yields are of the
isolated product. [i] 2.5 eq. aniline, 100ºC, 24 h. [ii] 2.2 eq. aniline, 70ºC, 19 h.
[iii] 3 h, 40 L CH3CN used. [iv] 2.5 eq. aniline, 100ºC.
Figure 4. Preparation of pharmaceutically relevant compounds 43 and 46.
Conditions used: [i] ethyl chloroformate (1.3 eq.), anhydrous THF, NEt3 (1.3 eq.),
0ºC, 30 min; then filtration, hydroxylamine (3 eq.), MeOH, rt, 1 h. [ii] CBr4 (1.3
eq.), PPh3 (1.3 eq.), CH2Cl2, rt, 14h. [iii] diethyl methylphosphonite (1.6 eq.),
120ºC, 10 h. All yields are of the isolated products.
Further exploration of the product scope was carried out using
various and functionalized 5 to 7-membered lactones as
substrates (Figure 3). Gratifyingly, a variety of 5-membered
lactones with ,  or -position substituted reacted well and
afforded the corresponding N-phenyl amides 2228 in moderate
to good yields. The presence of both alkyl (27 and 28) and
(substituted) aryl groups (22 and 2426) in the -position of the 5-
membered lactone substrate is endorsed. The conversion of -
methyl-γ-butyrolactone (cf., synthesis of 23; 40%) was found to
be quite challenging even at elevated temperatures. Enantiopure
amides 27 and 28 (ee > 98%) could be prepared from their
enantio-enriched lactone precursors (ee > 95%, commercial
substrates) and epimerization during the ROA process was not
observed. Since the latter are reasonably cheap and
Unlike the behaviour observed for N-aryl amide 1 derived from
the 5-membered -BL, the tosylation and oxidation of N-aryl
amides 34 and 35, derived from 6- and 7-membered lactones
respectively, led to the formation of the tosylates 36 and 37, and
carboxylic acids 38 and 39 under ambient conditions (Figure 3, b)
and no cyclization was observed in these cases unlike in the case
of 5-membered ring products 20 and 21 (Figure 2).[13]
Hydroxyl amides have found to be important building blocks
and intermediates in synthetic chemistry and biology.[7d-e,14] The
present developed organocatalytic protocol can be valorised as a
key step for the preparation of pharmaceuticals (Figure 4).
Vorinostat (43) could be prepared in three steps using the
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amides 24 and 26 were prepared according to a previously reported
protocol.[18] The lactones used for the preparation of amides 31 and 32
were prepared as described previously.[19]
developed catalytic ROA process starting off with 9-membered
lactone 40. Vorinostat is known for the treatment of CTCL, a type
of cancer of the immune system and designated as a SAHA
(“suberoyl-anilide-hydroxamic acid”) type compound.[15] The
developed ROA process was applied to lactone 40 using aniline
and afforded N-aryl amide 41 in 71% yield. The N-aryl amide
intermediate was then oxidized to the carboxylic acid compound
42 (92%) finally nucleophilic substitution in the activated acid
species in the presence of hydroxyl amine furnished the targeted
product 43 in 62% yield. As a Vorinostat analogue, the
phosphorus-based N-aryl amide 46 was also found to be
biologically active[16] and it could be easily prepared from the ROA
of the 7-membered lactone 44 leading first to the N-aryl amide 35
(89%), which was converted to compound 45 (91%) by an Appel-
type bromination, followed by a nucleophilic substitution of the
bromide by phosphonite to furnish the phosphorus-based SAHA
analogue 46 (89%). The easy access to compounds 43 and 46
suggests that this organocatalytic ROA process is suitable for the
preparation of a wide array of SAHA analogues with different
chain lengths.
Typical procedure for the amide formation
A screw-capped vial was charged with the respective lactone (0.40 mmol,
1 eq.), amine (0.48 mmol, 1.2 eq.), TBD catalyst (30 mol%, 0.017 g). The
reaction mixture was stirred at 40ºC for 24 h. Then, the product was
purified by flash chromatography affording the corresponding product. All
purified products were fully characterized by 1H/13C NMR spectra (19
F
NMR spectra were acquired where necessary), IR and HRMS. Full details
are provided in the Supporting Information.
DFT details
The Gaussian09 program (rev. D.01)[20] was used to calculate the reaction
path. Truhlar’s[21] hybrid Minnesota 06 (M06) exchange and correlation
density functionals with def2-TZVPP basis sets,[22,23] were used for all the
models using default integration grid settings. Geometry optimizations
were computed in vacuo and additionally, potential energies and analytic
Hessians were re-evaluated with a single point calculation using an
ultrafine integration grid and the integral equation formalism of the
polarizable continuum solvation model (IEFPCM) scheme, using the
electronic density in accordance with Truhlar’s scheme (SMD),[24,25] with
the default settings for aniline. Molecular 3D renderings were made with
the Chemcraft program.[26] Optimised structures are deposited at the
iochem-BD repository (doi:10.19061/iochem-bd-1-21).[27]
Conclusions
In summary, the first general organocatalytic synthesis of
valuable N-aryl amide scaffolds with wide functional diversity is
presented through ROA of various ring-size lactones (featuring
57, 9, or 16 membered rings) by electron deficient aromatic
amines. This method is based on the use of a readily available
organocatalyst (TBD) enabling otherwise non-feasible catalytic
ring-opening of the lactone partner under mostly highly mild and
attractive reaction conditions (40ºC, neat, open to air). This new
ROA process can be easily scaled up and tolerates various
functional groups present either in the (aromatic) amine or lactone
substrate. The developed catalytic approach enables the use of
bio-based 5-, 6- and 7-membered lactones such as -
butyrolactone, -valerolactone and -caprolactone[17] as platform
molecules and their conversion into various valuable chemicals
as demonstrated in the synthesis of Vorinostat and its
phosphorus-based analogue. Hence, this metal-free and general
route towards N-aryl amides with minimal waste release should
provide a highly attractive alternative for amide synthesis in both
academic laboratories and commercial settings.
Acknowledgements
We thank ICREA, the CERCA Program/Generalitat de Catalunya,
and the Spanish Ministerio de Economía y Competitividad
(MINECO) through projects CTQ-2014–60419-R, CTQ-2014-
52824-R, Consolider CTQ-2014-52974-REDC and the Severo
Ochoa Excellence Accreditation 2014–2018 through project SEV-
2013–0319. Dr. Noemí Cabello is acknowledged for providing the
mass analyses. W.G. thanks the Cellex foundation for funding of
a postdoctoral fellowship; J.E.G. acknowledges MINECO and
ICIQ for a Severo Ochoa/FPI pre-doctoral fellowship.
Keywords: aromatic amines • lactones • N-aryl amides •
organocatalysis • ring-opening aminolysis
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catalyst (TBD) were purchased from Aldrich or TCI and directly used
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were recorded at room temperature on a Bruker AV-300, AV-400 or AV-
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spectrometer. Mass spectrometric analyses were performed by the
Research Support Group at ICIQ. The lactones used for the preparation of
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This article is protected by copyright. All rights reserved.

10.1002/cssc.201700415
ChemSusChem
FULL PAPER
Entry for the Table of Contents:
FULL PAPER
Green Amides: A general, metal-
free organocatalytic process for N-
aryl amide synthesis has been
developed using cheap and readily
available lactones and aromatic
amines. The formal ring-opening
aminolysis (ROA) of the lactone
partner takes place under mild
reaction conditions and highlights
the use of potentially bio-sourced
lactones. The formal synthesis of
pharma-relevant SAHA compounds
is demonstrated using this new
ROA methodology.
Wusheng Guo, José Enrique Gómez,
Luis Martínez-Rodríguez, Nuno A. G.
Bandeira, Carles Bo and Arjan W.
Kleij*
Page No. – Page No.
Metal-Free Synthesis of N-Aryl
Amides using Organocatalytic
Ring-Opening Aminolysis of
Lactones
This article is protected by copyright. All rights reserved.