Highly chemoselective, sterically sensitive NHC-catalysed amine acylation with pyridil

Article abstract of DOI:10.1039/c9cc06937b

A new strategy for the protection of amines has been developed involving reaction with pyridil under the influence of N-heterocyclic carbene catalysis. The methodology is capable of distinguishing between two amines characterised by small differences in steric bulk and the resulting pyridoyl amides can be cleaved without requiring either strongly acidic or basic hydrolysis.

Full text of DOI:10.1039/c9cc06937b

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Highly chemoselective, sterically sensitive
NHC-catalysed amine acylation with pyridil†
Cite this: Chem. Commun., 2019,
5, 13526
5
Amy C. Maguire, Vikas Kumar and Stephen J. Connon
*
Received 5th September 2019,
Accepted 15th October 2019
DOI: 10.1039/c9cc06937b
rsc.li/chemcomm
A new strategy for the protection of amines has been developed when the steric discrepancy between amino groups is exceedingly
13
involving reaction with pyridil under the influence of N-heterocyclic small has been considerably less successful.
carbene catalysis. The methodology is capable of distinguishing The state-of-the-art in this domain is the recent comprehensive
between two amines characterised by small differences in steric bulk study of the use of 9 as an acylating agent by Doyle et al. (Fig. 1B).
and the resulting pyridoyl amides can be cleaved without requiring The heterocycle could transfer a single benzoyl group with con-
14
either strongly acidic or basic hydrolysis.
sistently (and uniformly) outstanding selectivity to a range of
polyamines: for instance – diamine 8 could be transformed into
The wide utility of amide bonds continues to inspire chemists to the monobenzoyl-protected 10 in excellent yield; driven by the
formation of an aromatic conjugate base of the leaving group 11.
We recently developed an N-heterocyclic carbene (NHC)-catalysed While the selectivity possible is akin to that which one would
1
2
develop new and unconventional methods for their synthesis.
3
4,5
oxidative amidation of aldehydes which allows the coupling of expect from biocatalysis – the harsh acidic/basic conditions
15
benzaldehydes 1 with a range of primary and secondary amines 2 required to cleave N-benzoyl amides (no aroyl variants of 9 were
in the presence of precatalyst 3, 1,2,4-triazole, stoichiometric DBU reported) and the non-trivial synthesis of 9 from simple starting
16
and phenazine (4) to produce amides 5 in good to excellent materials are two obstacles to the adoption of this technology as
yields at ambient temperature. We could show that the reaction a protection group strategy in complex molecule synthesis.
proceeded through symmetrical 1,2-diketones of general type 6
Herein we report the development of an NHC-catalysed highly
(Fig. 1A). In addition, in the absence of the 1,2,4-triazole nucleo- chemoselective acylation of amines and challenging diamines
philic co-catalyst, it was postulated that amidation occurred via
the sterically hindered pre-transition state assembly 7.
6
,7
The steric congestion associated with 7 (see the ESI† for a
mechanistic rationale) led us to speculate that the system could
potentially be adapted to bring about highly chemoselective amine
acylation with a view to developing a new, sterically sensitive
strategy for the protection of the least hindered amino function-
ality in a molecule. Despite impressive advances in protection–free
8
synthesis, the temporary masking of amine (Lewis)-basicity and
9
nucleophilicity via a variety of methods usually remains a sine
qua non in the synthesis of complex molecules.
While the selective acylation of primary over secondary
10
amines in polyamines is often possible, and the exploitation
11,12
of biomolecules to achieve high selectivity has been reported,
the use of a small molecule to discriminate between two amines
School of Chemistry Trinity Biomedical Sciences Institute, Trinity College Dublin,
1
52-160 Pearse Street, Dublin 2, Ireland. E-mail: connons@tcd.ie;
Tel: +35318961306
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9cc06937b
†
Fig. 1 NHC catalysed oxidative amination of aldehydes, chemoselective
amine acylation using a pyrazol-4-one and amine acylation using pyridil.
1
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(
e.g. 13) using pyridil (12) as a commercially available unconven- Table 2 Chemoselective acylation of diamines
tional acylating agent to give products such as 14 in excellent yield
Fig. 1C). Significantly, we show that the pyridoyl-unit is demon-
(
strably cleavable without resorting to either strongly acidic or basic
aqueous conditions.
We began by examining the ability of pyridil (12) to acylate a
range of amines of general type 2 under the influence of
carbene catalysis (in the absence of catalyst, no reaction occurs)
a
Entry
Diamine
Product
Yield (%)
b
1
7
1
94
98
98
77
94
98
in the presence of phenazine (4) to generate product amides
1
8
15–26 (Table 1). Simple primary benzyl-, allyl- and propargyl
amines could be acylated in good-excellent yields to yield
pyridine derivatives 15–18 respectively. Substitution at the b-carbon
of a primary amine is well tolerated (i.e. amide 19), however,
while acylation of primary amines substituted at the a-carbon
atom is possible in good yield (i.e. products 20 and 21), these
are clearly more difficult substrates for the system – pointing to
the possibility of being able to discriminate between these
groups in acylation events.
The cyclic secondary amines pyrrolidine and piperidine could
be smoothly transformed to 22 and 23, however, the installation
of an electron-withdrawing group on the piperidine-ring led to
significantly decreased efficacy (i.e. amide 24). More sterically
encumbered secondary amines such as dipropylamine and
N-methylbenzylamine gave rise to 25 and 26 respectively in
moderate yield.
2
3
b
4
5
6
a
b
Isolated yield. 0.5 eq. of 12 utilised.
amine differing only by one N-methyl substituent. Gratifyingly,
Next, a small library of diamines was selected to further acylation occurred exclusively at the less hindered site to
probe the acylation proclivities of the system and its ability to furnish 32 in near quantitative yield (entry 2). In a similar vein,
discriminate between amino groups in different steric environ- the system is capable of selecting between two primary amines
ments (Table 2).
distinguished only by an a-methyl group at carbon (i.e. 8) to
The acylation of diamine 29 – which incorporates both a product 33 in 98% yield (entry 3).
primary amine and a cyclic secondary amino unit – with 12
None of the reactions outlined above produced bis-acylated
proceeded chemoselectively to afford 30 in excellent yield (entry 1). products. To provide a significant challenge in this context; we
Since the piperidine amine is sterically encumbered by the examined the monoacylation of diamine 34 (an important mole-
chain at the 2-position, the acylation of 31 was next examined. cule in asymmetric catalysis); which is notoriously difficult to
19–21
Here the competition is between a primary and a secondary monoacylate chemoselectively without using excess amine.
Under NHC catalysis the reaction formed the monoacyl product
5 in reduced yet appreciable yield; with the remainder bis-acylated
3
Table
1
Influence of amine structure on NHC-catalysed acylation
material (entry 4).
by pyridil
The methodology can also act upon steric variations between two
different secondary amines. For instance, the preference for efficient
reaction at the N-Me group associated with diamine 36 over its N-iPr
counterpart is clear (entry 5). More strikingly, complete N-Me vs. N-Et
selectivity is possible under these conditions – affording amide 38
from amine 13 in 98% yield (entry 6). We are not aware of another
small molecule-based system capable of such discriminatory ability
in the acylation of secondary amines in the literature.
To put these results in context: in our hands the acylation of
either 29, 31 or 33 by either one equivalent of benzoyl chloride
(1.0 eq.) or (Boc)
2 2 2
O (1.0 eq.) in either THF or CH Cl (0.1 M) in
the presence of NEt
provided only bis-acylated products and starting materials. No
monoacyl compounds were formed.
3
at temperatures from ambient to À78 1C
We considered that intramolecular hydrogen bonding
may be an actor in the experiments summarised in Table 2.
Accordingly, we carried out the competition experiments out-
lined in Scheme 1.
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requiring heating under strongly acidic or basic aqueous con-
ditions (Scheme 2).
Tertiary amides can be deprotected in an ad hoc-designed
one-pot procedure involving alkylation with iodoethanol
followed by ring closure in the presence of dry camphorsulfonic
acid (CSA) to generate the corresponding heterocyclic lactone 42 –
which precipitates from solution and facilitates purification – and
the deprotected salt 43 (Scheme 2A). Amides which are the
product of chemoselective acylation and incorporate free amino
groups on the pendant chain such as 38 can be first Boc-
protected and then subjected to similar conditions to generate
the double ammonium salt 45 via 44 (Scheme 2B).
Simple secondary amides (e.g. 15) can be deprotected via initial
carbamate formation to give 46, followed by treatment with sodium
borohydride to afford the Boc-protected 47 (Scheme 2C), whereas
Scheme 1 Influence of N- and C-substitution on competition experiments.
22
When pyridil was offered a choice between benzylamine (39) a similar strategy involving installation of two Boc-groups allows
and equimolar loadings of its N-methyl analogue 40, 15 was the the cleavage of secondary amides incorporating a secondary amine
sole amide detected and isolated (Scheme 1A). Similarly, competi- such (e.g. formation of 49 from 32 via 48, (Scheme 2D)).
tion for acylation between 39 and its a-methyl variant 41 resulted
In summary, the use of pyridil as an unconventional acylating
in the smooth and exclusive formation of 15 and the complete agent for reaction with a range of primary and secondary
absence of the more hindered product 21 (Scheme 1B). Thus it amines in the presence of an N-heterocyclic carbene catalyst
would appear that the ability of the system to acylate the least is reported. The system is able to easily discriminate between
hindered N-atom in a diamine is related to steric sensitivity and amines in a diamine – always reacting at the least hindered
not the formation of intramolecular hydrogen bonds between the N-atom. Thus, in general, primary amines can be acylated
termini of either the substrates or products.
in preference to secondary analogues (even when the steric
While dramatic levels of chemoselectivity are possible, difference derives from a methyl group), while two primary
for the system to be considered of potential utility relative to amines can be distinguished based on substituents at the
(for example) benzoylation, the amide must be cleavable under adjacent C-atom (again, discrepancies as small as a methyl
milder conditions. After considerable experimentation, a suite group are sufficient for total control). In the case of secondary
of conditions were developed under which any amide generated amines, the reaction is unprecedentedly sterically discerning
by the study could be deprotected in high yield without for a small molecule-based system: an N-Me group can be
exclusively acylated in the presence of an N-Et unit.
Competition experiments demonstrated that the origin of
this selectivity is not ascribable to intramolecular hydrogen
bonding between the amines. Novel methods were developed
which allow the resulting monoacylated pyridoyl amides to be
cleaved without requiring the harsh acidic and basic hydrolytic
conditions associated with benzoyl protection of aliphatic
amines; thereby allowing the methodology to potentially serve
as a highly chemoselective protection group strategy for amino
groups.
We are grateful to Science Foundation Ireland and the Solid
State Pharmaceutical Centre (12/RC/2275) for financial support.
Conflicts of interest
There are no conflicts to declare.
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Scheme 2 Pyridoyl-amide cleavage.
1
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