Tetrahedron Letters 59 (2018) 2615–2621

Contents lists available at ScienceDirect

Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Digest paper

Recent advances in chemoselective acylation of amines

Francesca Piazzolla ⇑, Andrea Temperini
Dipartimento di Scienze Farmaceutiche, Università degli studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy

a r t i c l e i n f o a b s t r a c t

Article history: N-chemoselective acylation of amines in the presence of competing nucleophiles, like alcohols and thiols,
Received 26 March 2018 is by no means a simple achievement in organic synthesis and even more difficulties arise when distinc-
Revised 15 May 2018 tions between primary, secondary, and aromatic amines need to be made. The present digest will review
Accepted 22 May 2018
some recent achievements in this field, ranging from transamidation reactions to carboxylic acid deriva-
Available online 26 May 2018
tives transacylations. In addition, more creative strategies, involving chemoenzymatic reactions and
metal-catalyzed acylations and carbonylations, will be discussed in order to furnish a concise view of
Keywords:
the state-of-the-art approaches to this synthetic challenge.
Amines
Amides
Ó 2018 Elsevier Ltd. All rights reserved.
N-chemoselectivity
Acylation

Contents

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2621

Acylation has always been used as straightforward and power- applications. However, the chemoselectivity of amides synthesis
ful tool for the protection of amino groups in multistep syntheses by amines acylation is not always satisfying in the presence of
or for their convenient activation towards further chemical trans- competing nucleophiles, which can be rather disappointing when
formations.1 This important reaction also allowed chiral resolution targeting total synthesis of complex structures.16,17 Actually, N-
of racemic amines2 and lactams3; not to mention the wide portfo- chemoselective acylation in the presence of unprotected alcohols
lio of natural products, drugs, and functional materials in which and thiols is still a challenging issue for organic chemists, and most
the amide building block can be found,4 thanks to its peculiar of the known protocols do not make appreciable distinction
chemical properties.5 From a biological point of view, it is undeni- between primary, secondary, and aromatic amines acylation.
able that the amide bond is possibly among the most important Herein, we wish to give an overview of the most recent reports
tassels of life mosaic, being the base of peptide structure and func- approaching this synthetic challenge, focusing on the reactions
tionality. Actually, selective acylation of peptide terminal6 or side that take place in a N-chemoselective fashion on polyamine sub-
chain7 amino groups is a challenging therapeutic and diagnostic strates and tolerate other unprotected nucleophiles. The synthetic
target in order to modify or identify specific proteins activities. strategies discussed in each paragraph will be accompanied by
As naturally acylated proteins may show peculiar biological (in)ac- selected examples of the products obtained, highlighting the selec-
tivity, it comes as a result that the identification of these molecules tivity achieved on substrates bearing multiple nucleophilic sites.
using selective biological probes has great importance for inves- When targeting N-acylation, long-known transamidation proce-
tigative purposes.8,9 dures between a chosen amine and an acyl donor amide18 cannot
Given the significance of amides in several fields, a considerable stay unmentioned, although they usually require harsh reaction
amount of present10,11 and less recent12,13 research effort has been conditions due to the poor electrophilic character of the amide car-
directed towards the development of straightforward, cheap, and bonyl group. Thanks to their inexpensiveness and ready availabil-
efficient syntheses of this moiety, also targeting the improvement ity, formamide and dimethylformamide (DMF) are by no doubt
of small14 and large scale15 protocols for research and industrial the most common acyl sources for this approach, as they can be
used in large excess as reaction medium. An improvement in reac-
tion condition mildness and yields has been recently reported by
⇑ Corresponding author. Blanchet and coworkers,19 as a result of the combined use of a
E-mail address: [email protected] (F. Piazzolla). Brønsted acid and a boron-containing Lewis acid in DMF

https://doi.org/10.1016/j.tetlet.2018.05.065
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
2616 F. Piazzolla, A. Temperini / Tetrahedron Letters 59 (2018) 2615–2621

Scheme 1. Chemoselective Lewis and Brønsted acid catalyzed transamidation.

Scheme 4. Chemoselective iodine mediated N-formylation.

with primary amines (Scheme 3),22 with no substantial change in

yields and chemoselectivity profile. This protocol was also
extended to demonstrate N vs O chemoselectivity but, in both
cases, no information about aromatic amines performance was
given.
Scheme 2. Chemoselective Fe (III) promoted transamidation. A part from amides, also carboxylic acids have been reported to
perform chemoselective N-acylation.23 In 2010, Kim and Jang24
described a convenient solvent-free amine formylation with formic
(Scheme 1). Although long reaction time was required to achieve acid and catalytic molecular iodine (Scheme 4). Thanks to the
the complete substrate conversion, a clear N vs O chemoselectivity in situ generation of HI and consequent activation of the carbonyl
could be observed in excellent yield. moiety toward nucleophilic attacks, the reaction takes place in
A sharper selectivity was demonstrated by the ferric nitrate cat- the presence of unprotected alcohols and phenols in reasonably
alyzed transamidation,20 which preferentially acylates primary short time but no experiments were carried out on substrates bear-
amines in the presence of secondary amines and primary alcohols ing competitive amino groups.
(Scheme 2). Indeed, it might be argued that this selectivity con- A comparable activation mechanism has been reported by Hu
trasts with the higher nucleophilic character of secondary amines, et al.25 in the same year. In their protocol, the carbonyl activation
compared to primary amines. The experimental data might be suc- was promoted by a catalytic amount of a thiamine hydrochloride
cessfully explained simply considering the steric impediment pre- (Scheme 5). Like in the previously mentioned case, an excess of for-
venting secondary amines from taking part to the reaction. The mic acid was employed, phenolic groups were well tolerated, and
appealing possibility of using unsubstituted, N-substituted, and no extended application to polyamino substrates has been
N,N-disubstituted amides as acyl donors gave this procedure a envisaged.
good reaction scope, allowing the introduction of a wide range of As far as the use of acids as acyl donors is concerned, a more
N-protecting acyl groups with very good yields and chemoselectiv- extensive N-chemoselective acylation study has been performed
ity, if long reactions time can be overlooked. However, the use of a by Brahmachari et al.,26 who used catalytic zinc acetate as Lewis
transition metal catalyst, the excess of acylating agent, and the acid in neat acetic acid under microwave irradiation (MW) to
refluxing toluene conditions do not make this procedure very achieve this goal (Scheme 6, path a). Admittedly, the easy and fast
attractive from an environmental point of view, inevitably exclud- procedure afforded a wide range of substituted aromatic and ali-
ing thermolabile substances from the substrates panel. phatic N-acetamides, with admirable yields and total N-selectivity
As an alternative, it is possible to use a slight excess of N-acyl- in the presence of other unprotected nucleophiles, like alcohols
sulfonamides as metal-free acylating reagents under mild condi- and thiols.
tions to react selectively with primary rather than secondary Acetyl groups can also be introduced performing the reaction
amines in relatively shorter time (Scheme 3).21 This acylating agent with a ceria-yttria based Lewis acid in neat acylating agent (i.e.
can be prepared from the corresponding sulfonamide and it is air- acetic anhydride) under conventional heating (Scheme 6, path
stable and easy to handle, thus opening a new lead toward polya- b).27 This innovative reactant still has all the advantages of filter-
mine selective acylation with outstanding yields. Later, a more able and reusable catalysts and has demonstrated the selective
drastic procedure described condensation of N-acylsulfonamides acylation of amines in the presence of alcohols but a wider section
of competition experiments would have been beneficial to better
understand the chemoselectivity profile.
Among Lewis acid catalyzed amidations, novel boronic acids
have recently been explored as reusable catalysts in solvent-free
direct condensations of amines and carboxylic acids (Scheme 6,
path c).28 In contrast with older boronic acid catalyzed amidations,
this reaction takes place at room temperature, thanks to the use of
molecular sieves as water scavengers. Although the procedure

Scheme 5. Heterocycle mediated activation of formic acid as chemoselective

Scheme 3. N-acylsulfonamide chemoselective N-acyl transfer. N-acylating agent.
 F. Piazzolla, A. Temperini / Tetrahedron Letters 59 (2018) 2615–2621 2617

Scheme 6. Lewis acid and base catalyzed chemoselective N-acylations.

shows a pleasant N-chemoselectivity in the presence of a phenolic It has also been suggested that N-acylations could be performed
moiety, when using a commercially unavailable catalyst (like in in aqueous media activating a slight excess of acylating agent (i.e.
Scheme 6, path b) time and resources required by its synthesis Ac2O) at room temperature by H-bonding with water molecules
should be carefully evaluated. (Scheme 7, path a).30 This can be added to the numerous general
A part from Lewis acids, also N-heterocyclic carbenes (NHC) advantages of in-water reactions, as, to some extent, the use of
have been used to activate carboxylic acid derivatives in N- water as environmentally benign solvent for the development of
chemoselective acylations of alkanolamines with esters (Scheme 6, a sustainable chemistry is considered one of the highest targets
path d).29 The authors suggested that N-chemoselectivity was of initiatives in green chemistry.
induced by Lewis base activity of the NHC, which in the first step Among in-water N-acylating reagents, di-tert-butyl dicarbonate
activated the hydroxy group of the alkanolamine toward transes- (Boc2O) showed total chemoselectivity for primary amines acyla-
terification. Final N-acyl transfer delivered the expected N-acylated tion in the presence of hindered secondary amines in competition
product with an unprotected alcoholic moiety. It is worthy to note experiments mixtures (e.g. cyclohexylamine vs dicyclohexylamine)
that this approach allowed the synthesis of heteroaryl-containing (Scheme 7, path b, competition experiments mixtures results not
amides, thanks to the use of heteroaryl substituted esters as acyl shown).31 When the steric hindrance is not very different (e.g. ben-
donors. zylamine vs dibenzylamine), preferential acylation of secondary

Scheme 7. Chemoselective N-acylations in water.

2618 F. Piazzolla, A. Temperini / Tetrahedron Letters 59 (2018) 2615–2621

amines occurs, due to their more accentuated nucleophilicity. Like- Reactions converting carboxylic acids into intermediate acylat-
wise, in this approach there is no complete chemoselectivity for ing chemical species have already been reviewed.36 A N-chemose-
aniline amidation in the presence of benzylamine, thus discourag- lective version of this approach has been developed by Rho and
ing the application of this method on polyamino substrates. coworkers,37 who used ethyl chloroformate (EtOCOCl) to generate
In-water activation of the acylating agent (e.g. acyl chloride) can mixed anhydrides from carboxylic acids (Scheme 9, path a). These
be increased by addition of magnesium oxide (MgO) as cheap and intermediates were then reacted with alkanolamines to give the
readily available complexing agent (Scheme 7, path c).32 Like in exclusive acylation of the amino group with surprising ease and
other in-water acylations, good reaction yields and compatibility appreciable yields. The two-step approach took place in a relatively
with unprotected alcohols are observed at room temperature but, short time under mild conditions but selectivity between different
in contrast with those approaches, no thiol substituent tolerance amino groups has not been explored.
has been explored, as it can be seen in the examples reported in More drastic conditions (refluxing toluene) were employed to
Scheme 7. form the corresponding silyl ester from a chosen carboxylic acid
To the best of our knowledge, only one in-water N-acylation has using tetramethyl othosilicate (TMOS) (Scheme 9, path b).38 The
shown appreciable selectivity between primary and secondary silyl ester intermediate selectively acylated alkanolamines on the
amines, a part from unprotected alcohols tolerance (Scheme 7, amino group. Conveniently, simple aqueous workup destroyed
path d).33 A suitable chlorinating agent, like N-chlorosucinimide TMOS excess and removed residual amidation components to
(NCS) or 1,3-dichloro-5,5-dimethylhydantoin (DCH) is used to gen- afford the expected products with no further purification.
erate in-situ a N-chloro-intermediate, which is then acylated by an In the context of our interest for protecting groups chemistry,39–43
appropriate acyltrifluoroborate. This peculiar amidating reagent our research group has developed a mild chemoselective protocol for
has recently become commercially available with different sub- the acylation of amines in the presence of alcohols, phenols, and thi-
stituents but it can also be readily prepared in laboratory to show ols by simply stirring the substrate in ethyl acetate (EtOAc) at room
customized features. temperature with a slight excess of Ac2O as acylating agent
As an alternative to MgO, heterogeneous phase chemoselective (Scheme 10).44 In most cases, this procedure delivered pure products
N-acylations have also been explored using alumina (Al2O3) in neat in appreciable yields with no need of chromatographic purification.
acylating agents (Scheme 8, path a)34 or calcium oxide (CaO) and Moreover, its chemoselectivity allowed the exclusive amidation of
acyl halides in a biomass-derived solvent, namely 2-methylte-
trahydrofuran (2-MeTHF) (Scheme 8, path b).35 In both examples,
the advantages of using a cheap, solid, and recyclable catalyst in
a procedure compatible with unprotected alcohols cannot be over-
looked, although no selectivity was assessed on polyamino sub-
strates. In addition, the mild reaction conditions, the very short
reaction time, the compatibility with aromatic and aliphatic alco-
hols, and the superb yields make the first procedure very attrac-
tive. The same can be said about the use of CaO, instead of Al2O3,
as both could act as efficient acid scavengers to trap the halo-
genidric acids generated by the use of acyl chlorides/bromides as
acylating agents, with similar outcomes. Scheme 10. Additive-free chemoselective N-acylation in EtOAc.

Scheme 8. Heterogeneous phase chemoselective N-acylations.

Scheme 9. Chemoselective N-acylation with carboxylic acids via acylating intermediates formation.
 F. Piazzolla, A. Temperini / Tetrahedron Letters 59 (2018) 2615–2621 2619

primary amines in the presence of secondary amines to give a highly afforded the expected product with almost quantitative yield and
customizable set of products. total selectivity.
Quite similarly, some years later Williams et al. reported an Another elegant example of selectivity was reported by
example of acid catalyzed amide formation using EtOAc as both Zacharie and coworkers,48 who achieved aromatic primary amine
solvent and acyl donor (Scheme 11).45 Although heating and long acylation in the presence of alkyl primary and secondary amines
reaction time were required, total N vs O, primary vs secondary thanks to their different pKa values (Scheme 14). The acetic acid
amines, and aliphatic vs aromatic amines selectivity could be buffer in dioxane warranted the alkylamine protonation and the
appreciated in good yields. consequential exclusive aromatic amine amidation with both
As far as the use of esters as acylating agents is concerned, men- anhydrides (Boc2O) and acyl chlorides, such as benzyl chlorofor-
tion should be made of the possibility to use isopropenyl acetate as mate (CbzCl) and 9-fluorenylmethyl chloroformate (FmocCl).
both reaction medium and N-chemoselective acylating agent Interestingly, this procedure is also compatible with unprotected
(Scheme 12).46 Conveniently, acetone is the only byproduct of alcohols with good yields.
the reaction and it can be easily distilled off with the excess of iso- Chemoselective N-acylating properties of selenium reagents
propenyl acetate, usually affording the pure amide in quantitative have also been documented. Selenoesters generated from terminal
yield. Moreover, this reaction takes place selectively on aliphatic alkynes49 or carboxylic acids50 are expected to be more reactive than
amines in the presence of aromatic amines and tolerates unpro- the corresponding thio- or oxo- esters, thanks to the weakness of the
tected alcohols. carbon-selenium bond. This property makes them the ideal agents
So far, we have mainly discussed N- vs O/S-acylation selectivity to perform N-acyl transfers (Scheme 15). Actually, selenoesters
and, when possible, favored primary amines vs secondary amines exclusively acylate alkyl amines rather than aromatic amines, and
selectivity. There is, however, an example in which it is possible to primary amines rather than secondary amines or unprotected alco-
promote secondary amines acylation in the presence of primary hols, with excellent yields and total chemoselectivity. Conveniently,
amines. Laduron and coworkers47 envisaged this possibility reflux-
ing a suitable diamine with Boc2O in 4-methyl-2-pentanone (MIBK)
under basic catalysis (Scheme 13). The base promoted the tempo-
rary primary amino group protection with MIBK via imine forma-
tion. This left the secondary amine available to react with the
stoichiometric acylating reagent and final aqueous deprotection

Scheme 14. pKa-based chemoselective N-acylation.

Scheme 11. Acid catalyzed chemoselective N-acylation in EtOAc.

Scheme 15. Selenoesters as N-chemoselective acylating reagents.

Scheme 12. Isopropenyl acetate as N-chemoselective acylating reagent and reac-

tion medium.

Scheme 13. Protection of primary amines via imine formation and subsequent Scheme 16. Chemoselective N-trifluoroacetylation via trifluoroacetylbenzotriazole
chemoselective acylation of secondary amines. transamidation.
2620 F. Piazzolla, A. Temperini / Tetrahedron Letters 59 (2018) 2615–2621

diphenyl diselenide is formed as sole byproduct and it can be recov- took place. This disadvantage should not be seen as an obstacle to
ered and reused in a new preparation of acylating reagents. the application of this procedure, as the authors envisaged inter-
Among the conceivable chemoselective N-acylating reagents, esting perspectives in biological chemistry for the chemoselective
heterocyclic acyl donors must be mentioned, too. Usually, the reac- partial protection of nucleosides with reasonable yields and short
tions involving this kind of reagents take place via transamidation reaction time.
from N-acyl heterocycles or heterocycle-substituted N-acyl More exotic acyl donors, namely N-acyl heterocycle53 and hete-
amines. Over 20 years ago, Katritzky and coworkers described a rocycle-substituted N-acyl amine,54 demonstrated the preferential
convenient amines acetylation strategy using commercially avail- N-acylation pattern (Scheme 18). In both cases, N-chemoselectivity
able trifluoroacetylbenzotriazole in slightly over stoichiometric was assessed in intermolecular, other than the usual intramolecu-
quantity, with satisfying yield and selectivity for amino groups vs lar, competition experiments, mixing primary and secondary ami-
alcohols, and primary vs secondary amines (Scheme 16).51 nes and measuring the final acetylation ratio. A part from the usual
To some extent, it would be correct to say that catalytic erbium preference for primary amines acylation, Kim’s report54 also
triflate activation of an excess of 1-acetylimidazole promoted in- demonstrated the preferential acylation of less hindered secondary
water chemoselective amine acylation under MW (Scheme 17).52 amino groups in the presence of more hindered a-substituted sec-
Indeed, no acetylation of secondary alcohols was detected but ondary amines. Yet, the lack of details in Kim’s report, the use of
simultaneous acetylation of primary amines and primary alcohols such a toxic solvent (carbon tetrachloride), and the absence of data
concerning the compatibility with other unprotected nucleophiles
certainly do not support a wide application of this approach. More-
over, like in Yoon’s approach,53 extra time and resources to synthe-
size and purify the acyl donor must be considered.
Among the kaleidoscopic panorama of approaches to N-acyla-
tion, also biochemical methodologies deserve to be mentioned.
As far as the hydroxy vs amino group acylation competition is con-
cerned, it is interesting to note that the use of Candida Antarctica B
lipase can be beneficial,55,56 even for the synthesis of pharmacolog-
ically active compounds like phenylacetylrinvanil (Scheme 19).57
Candida Antarctica B lipase (commercially known as NovozymÒ
435) can chemoselectively acylate amino groups in the presence
Scheme 17. Partially chemoselective N- and O- acylation mediated by 1-acetylim- of unprotected alcohols and phenols using a suitable carboxylic
idazole and Er(OTf)3. acid or ester as acyl donor with no trace of the competitive alcohol
(trans)esterification. Depending on the substrate, conventional
heating strategies can be used to promote the reaction, but MW
considerably contributes to shorten reaction time and increase
enzyme stability and recyclability. Nevertheless, considering the
similarities among the examples reported in literature, a wider
substrate scope would be highly desirable.
Another possibility to accomplish chemoselective N-acylation
involves CO2 fixation onto amines using transition-metal com-
plexes. For instance, Ding and coworkers58 developed an efficient
strategy to achieve this goal using a suitable ruthenium-pincer-
type catalyst whose activity is not affected by the presence of
hydroxy substituents on the amino-bearing substrate (Scheme 20).
Regrettably, the reaction has not been performed on aromatic ami-
nes and, like in some previously mentioned cases, no competition
experiments with primary and secondary amines were performed,
but N vs O chemoselectivity can be clearly appreciated with
astounding yield.
Given the ever-growing development that chemical ligation
chemistry has experienced in recent years,59 it is not possible to

Scheme 20. Chemoselective amine acylation via ruthenium catalyzed

Scheme 18. N-acylation chemoselectivity of various heterocyclic acyl-donors. carbonylation.

Scheme 19. Enzyme-catalyzed chemoselective N-acylation.

 F. Piazzolla, A. Temperini / Tetrahedron Letters 59 (2018) 2615–2621 2621

Scheme 21. General chemical ligation mechanism.

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