Mustard Carbonate Analogues as Sustainable Reagents for the Aminoalkylation of Phenols

Article abstract of DOI:10.1002/ejoc.202100328

N,N-dialkyl ethylamine moiety can be found in numerous scaffolds of macromolecules, catalysts, and especially pharmaceuticals. Common synthetic procedures for its incorporation in a substrate relies on the use of a nitrogen mustard gas or on multistep syntheses featuring chlorine hazardous/toxic chemistry. Reported herein is a one-pot synthetic approach for the easy introduction of aminoalkyl chain into different phenolic substrates through dialkyl carbonate (β-aminocarbonate) chemistry. This new direct alcohol substitution avoids the use of chlorine chemistry, and it is efficient on numerous pharmacophore scaffolds with good to quantitative yield. The cytotoxicity via MTT of the β-aminocarbonate, key intermediate of this synthetic approach, was also evaluated and compared with its alcohol precursor.

Full text of DOI:10.1002/ejoc.202100328

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Mustard carbonate analogues as sustainable reagents for the
aminoalkylation of phenols
Authors: Mattia Annatelli, Giacomo Trapasso, Claudio Salaris,
Cristiano Salata, Sabrina Castellano, and Fabio Arico'
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100328
Link to VoR: https://doi.org/10.1002/ejoc.202100328
01/2020

10.1002/ejoc.202100328
European Journal of Organic Chemistry
COMMUNICATION
Mustard carbonate analogues as sustainable reagents for the
aminoalkylation of phenols
Mattia Annatelli,[a] Giacomo Trapasso,[a] Claudio Salaris,[b] Cristiano Salata,[b] Sabrina Castellano[c] and
Fabio Aricò*[a]
[a]
Dr. M. Annatelli, Dr. G. Trapasso, Prof. F. Aricò
Department of Environmental Sciences Informatics and Statistics
Ca’ Foscari University
Campus Scientifico, Via Torino 155, 30172 Venezia Mestre (IT)
E-mail: fabio.arico@unive.it
[b]
[c]
Dr. Claudio Salaris, Prof. Cristiano Salata
Department of Molecular Medicine
Padua University
via Gabelli 63, 35121 Padova (IT)
Prof. Sabrina Castellano
Department of Pharmacy
University of Salerno
Via Giovanni Paolo II, 132 - 84084 Fisciano, Salerno (IT)
Supporting information for this article is given via a link at the end of the document.
Mustard Gases
S
-Aminocarbonates
S
Abstract: N,N-dialkyl ethylamine moiety can be found in numerous
scaffolds of macromolecules, catalysts and especially
pharmaceuticals. Common synthetic procedures for its incorporation
in a substrate relies on the use of a nitrogen mustard gas or on
multistep syntheses featuring chlorine hazardous/toxic chemistry.
Herein is reported a one-pot synthetic approach for the easy
introduction of aminoalkyl chain via dialkyl carbonate (-
aminocarbonate) chemistry into different phenolic substrates. This
new direct alcohol substitution avoids the use of chlorine chemistry,
and it is efficient on numerous pharmacophore scaffolds with good to
quantitative yield. The cytotoxicity via MTT of the -aminocarbonate,
key intermediate of this synthetic approach, was also evaluated and
compared with its alcohol precursor.
Cl
Cl
H3CO2CO
OCO2CH3
1
5
CH3
N
CH3
N
H3CO2CO
OCO2CH3
OCO2CH3
Cl
Cl
Cl
2
6
S
S
H3C
H3C
H3C
3
7
CH3
N
CH3
N
Cl
H3C
OCO2CH3
4
8
Mustard Gas and -Aminocarbonates Anchimeric effect
Nitrogen and sulfur mustards (Figure 1; 1-4), also called yperites,
occupy a peculiar place in chemistry history; from battlefields to
the first cancer treatment, their story covers almost 200 years.
Bis(2-chloroethyl)sulfide 1, discovered in 1822,[1] was described
as a malodorous, high boiling compound able to aggressively
attack the hydrated parts of the body, like eyes and lungs,
leading, in case of prolonged exposure, to death.[2-3]
CH3
NuH
Cl
N
H3C
CH3
Nu
Cl
N
N
+ HCl
CH3
N
NuH
CH3
H3C
Nu
CH3OCO2
OCO2CH3
N
N
+ CO2 + MeOH
In 1942 Goodman and Gilman, demonstrated that nitrogen
mustards, ß-chloroethylamines 2, were effective as cytotoxic
agents. Their studies led to clinical investigations of nitrogen
mustards to treat a non-Hodgkin’s lymphoma, paving the way for
anticancer chemotherapy.[4] Despite their well-known toxicity and
undesired adverse effects, some nitrogen mustard drugs are still
considered first-line therapy for certain types of cancer.
Nitrogen yperites have been also investigated as versatile
electrophiles in the preparation of catalysts,[5] macromolecules,[6]
and numerous pharmaceuticals. Such great interest in these
molecules is grounded on their exceptional electrophile behavior
enhanced by the nitrogen anchimeric assistance (Neighboring
Group Participation, NGP) (Figure 1).[7] In fact, mustard gases
can undergo fast intramolecular nucleophilic substitution to form
an aziridinium ring that acts as electrophilic trap leading to
effective alkylation of chemical building blocks or biological
macromolecules (Figure 1).
Figure 1. Structure and reactivity of mustard gas versus ß-aminocarbonates.
The chemistry that underlies mustard gases has been
extensively used to insert basic amine-containing side chains
into pharmacophore scaffolds. This moiety, incorporated in
several class of compounds such as Tamoxifen, Raloxifene,
Amiodarone, Phenyltoloxamine, Trifenagrel, Trimethobenzamide,
etc. (Figure 2), engage in crucial interactions with target
macromolecules and, as expected, subtle variations in the
aminoalkyl chain structural features greatly influence the
pharmacodynamic and/or pharmacokinetic profile of the
compound. Therefore, in
a
hit-to-lead and lead-to-drug
candidate optimization process,[8] several compounds should be
synthesized to optimize this fragment.
1
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10.1002/ejoc.202100328
European Journal of Organic Chemistry
COMMUNICATION
OH
O
OEt
O
K2CO3
N
+
+
a)
b)
N
+
+
OH
EtO
OEt
CH3CN
10
9
OEt
O
O
K2CO3
PhOH
CH3CN
N
N
N
OH
+ EtO
OEt
OCO2Et
11
2
BAc
10
9
2
(NGP alkylation)
(BAl
)
Scheme 1. a) One-pot alkylation approach via ß-aminocarbonates formed in-
situ versus b) two steps alkylation approach.
The one-pot alkylation reaction was initially investigated by
reaction
of
phenol,
2-dimethylaminoethanol
and
diethylcarbonate (DEC) in 1.0:1.5:1.5 mol ratio in the presence
of potassium carbonate as a base (Table 1). DEC was preferred
to dimethyl carbonate (DMC) due to its higher boiling point that
renders it more suitable for this synthetic approach.
Figure 2. Pharmaceuticals incorporating N,N-dialkyl ethylamine moiety in their
backbone structures.
If we consider phenolic moieties, which are preferred precursors
of numerous pharmacophore scaffolds (Figure 1),[9] there are
three main synthetic approaches for the introduction of the
aminoalkyl chain in the molecular backbone, besides the
anchimerically driven nucleophilic substitution via N-(2-
chloroethyl)dialkylamine:
Table 1. One-pot alkylation: optimization of the reaction conditions[a]
#
K2CO3
CH3CN
mL
Temp.
°C
Time
h
Selectivity %[b]
Yield
[c]
Eq. mol.
9
10
%
1
2
1.00
1.00
1.00
1.00
1.00
1.00
1.00
-
50
50
50
50
50
30
100
50
50
50
140 to 180
140 to 200
180
24
8
8
8
6
8
8
8
8
8
92
96
90
98
92
90
92
12
93
93
8
4
92
75
74
98
85
92
80
-
 Nucleophilic
aromatic
substitution
between
a
(2-
hydroxyethyl)dialkylamine and an aryl halide; [10]
 Mitsunobu reaction of (2-hydroxyethyl)dialkylamine with a
(substituted) phenol; this synthesis mainly employs diethyl
azodicarboxylate (DEAD) a well-known toxic and potentially
explosive reagent;[11]
 Nucleophilic aliphatic substitution, i.e., reaction of dialkylamine
and a (2-halide)ethoxyaryl substrate.[12]
These synthetic procedures are in general multistep and have
as common features the use of hazardous/toxic chlorine
chemistry and the necessity for time-consuming purification of
the products.
3[d]
4
10
2
200
5
200
8
6
200
10
8
7
200
8
200
88
7
Over the years, it has been demonstrated that the replacement
of a halogen atom by a carbonate moiety via dialkyl carbonate
(DAC) chemistry has led to safer and greener syntheses.[13] In
this context, we have recently reported a new class of organic
carbonates, i.e. ß-aminocarbonates 5-8 (Figure 1), as green
homologues of mustard gas.[14] Their syntheses and related
reactivity have been investigated employing different reaction
conditions (Scheme 1b);[15] data collected confirmed that ß-
aminocarbonates retain the anchimeric effect of their mustard
gas analogues, without showing evidence for toxic properties.
Herein, we described for the first time a one-pot procedure
(Scheme 1a) for the high yielding introduction of the N,N-dialkyl
ethylamine moiety by reaction of its alcohol precursor with a
nucleophile (phenol) in the presence of a dialkyl carbonate
9
0.25
0.50
200
86
81
10
200
7
[a]
Reaction conditions: Phenol: 2-dimethylaminoethanol: DEC
:
K2CO3
1.0:1.5:1.5:1.0 mol ratio; Reactions were conducted in autoclave, Conversion
[b]
was always quantitative unless differently specified;
Calculated via GC-MS
and 1H NMR; [c] Isolated yield; [d] Conversion of phenol was 90%.
Preliminary tests were conducted by controlling the reaction
temperature; the autoclave was at first heated at 140 °C (4
hours) to maximize the formation of 2-(dimethylamino)ethyl
ethylcarbonate 11. The temperature was then increased to
180 °C (20 hours) to promote the anchimerically driven
alkylation (#1; Table 1). In these conditions phenol was
quantitatively converted with 92% selectivity toward the alkylated
product N,N-dimethyl-2-phenoxyethanamine 9. The pure
compound was recovered by rapid extraction in a separating
funnel to remove potassium carbonate, the excess of DEC and
alcohol. Ethoxybenzene 10, formed in small amounts as a by-
product, was distilled off whilst evaporating the excess solvent.
The reaction was repeated, now increasing the temperature of
the alkylation to 200 °C and reducing the reaction time to a total
of 8 hours (#2; Table 1). Despite observing a similar phenol
conversion and product selectivity, the isolated yield of
compound 9 was markedly lower.
2
(DAC). The latter is used for the in-situ formation, via the BAc
mechanism, of ß-aminocarbonate 11 that acts as an alkylating
agent via nitrogen NGP (Scheme 1a). Different substrates have
been investigated including precursors of commercially available
drugs. This one-pot alkylation approach is a striking example of
chlorine-free direct substitution of an alcohol, indicated as one of
the key Green Chemistry research areas for pharmaceuticals
manufacturers.[16] Furthermore, an in vitro toxicity study has
been conducted on ß-aminocarbonate 11 and its alcohol
precursor, giving an insight into the cytotoxicity values of the
reagents for the synthetic procedure proposed.
2
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10.1002/ejoc.202100328
European Journal of Organic Chemistry
COMMUNICATION
On the other hand, the anchimerically driven alkylation was very
efficient when carried out without varying the temperature (#3-4;
Table 1) reaching 98% isolated yield of 9.
Further experiments included: i) reducing the reaction time (#5;
Table 1); ii) investigating the effect of the regent concentration
(#6-7; Table 1); iii) decreasing the amount of potassium
carbonate (#8-10; Table 1).
The aromatic diols hydroquinone and bisphenol-A were also
investigated as substrates for the one-pot double alkylation
reaction, resulting in the formation of bis(N,N-dimethyl
ethylamine) derivatives 26 and 27 in almost quantitative yield.
The high yielding alkylation observed on bifunctional substrates
raises the possibility of applying this procedure in the synthesis
of macromolecules such as macrocycles or polymers.
In all these trials N,N-dimethyl-2-phenoxyethanamine 9 was the
main reaction product with isolated yields ranging from 80 to
92%. Interestingly if the reaction is conducted without base,
ethoxybenzene 10 formed in high yield, while the alkylated
product 9 was present only in trace amounts (#8; Table 1); this
result confirms the importance of a base in promoting the
formation of ß-aminocarbonate 11, that is the key reaction
intermediate.
O
O
O
N
N
N
MeO
Cl
NC
12 87%
O
13 80%
O
14 58%
t-Bu
O
N
N
N
It is noteworthy that in this one-pot alkylation approach, DAC
chemistry is exploited at its full potential; in fact, DEC acts as in-
situ ethoxycarbonylating agent via the BAc2 mechanism, leading
to an unsymmetrical carbonate able to selectively alkylate the
phenol via nitrogen NGP; formation of the ethoxy derivatives 10
via concurrent BAl2 mechanism is negligible (see Scheme 1b).
With the optimized reaction conditions in hand (#4; Table 1), the
scope and limitations of this procedure were next investigated
employing differently substituted phenols or amino alcohols
(Figure 3, see also supporting information).
p-Methoxy- and p-chlorophenol were converted to the
corresponding alkylated compounds 12-13 in excellent yield.
Phenols p-substituted with electron-withdrawing groups (-NO2
and -CN) have also been tested. As expected, the enhanced
phenolic acidity of these substrates affects the selectivity
towards the NGP driven alkylation leading to moderate yields of
the wanted products 14 and 17.
O2N
15
16
17
o-NO2 24%
m-NO2 60%
p-NO2 64%
18 58%
19 85%
t-Bu
O
O
N
N
O
N
t-Bu
67%
90%
75%[b]
22
20
21
24
O
O
O
N
N
N
O
25 78%
23
79%
90%
N
O
N
N
N
N
O
O
O
Similar results were observed when the nitro group was
positioned in ortho or meta to the phenolic hydroxy moiety.
Sterically hindered o-nitrophenol showed modest conversion
(40%) and selectivity toward the alkylated product 15 (60%).
N,N-dimethyl-2-(2-naphthoxy)ethanamine 18 was obtained from
β-naphthol in only moderate yield; a quite unexpected result in
consideration of its similar nucleophilic behavior with phenol.
2-tert-Butylphenol and 2,6-di-tert-butylphenol were selected as
sterically hindered substrates. The alkylated product 19 formed
readily in good yield. On the other hand, di-tert-butylphenol,
resulted in only partially conversion (67%) although the
selectivity toward the wanted alkylated product was quantitative.
A range of different N,N-dialkyl aminoalcohols were next
investigated. Reaction of 2-(diethylamino)ethanol with phenol
and DEC led to the related N,N-diethyl-2-phenoxyethanamine 21
in high yield. 1-(2-Hydroxyethyl)pyrrolidine, 1-piperidinylethanol
and 4-(2-hydroxyethyl)morpholine, incorporating 5- and 6-
membered cyclic structures, gave the alkylated products 22-24
in excellent yields despite the more sterically hindered nature of
their related aziridinium ring.
26
90%
27
99%
N
O
O
O
N
N
O
[a]
28 75% (99%)[a]
29 60% (99%)
30 50% (99%)[a]
N
O
O
N
O
N
O
O
[a]
[a]
31 88% (98%)
32 nd (69%)
33 nd (94%)[a]
Figure 3. One-pot alkylation conditions (Scheme 1a): ArOH:aminoalcohol:
DEC:K2CO3 1.0:1.5:1.5:1.0 mol ratio at 200 °C for 8 hour. For compounds 26-
27 the molar ratio used were HOArOH:2-dimethylaminoethanol:DEC:K2CO3
1.0:3.0:3.0:2.0 mol ratio. Yields were calculated via 1H NMR and GC-MS
[a]
analysis.
Alkylations employing ß-aminocarbonate 11 (Scheme 1b); ArOH:
It is noteworthy that morpholine-containing side chains are
incorporated in numerous pharmacophore scaffolds exhibiting
optimum anti-malarial[17] and antitumor[18] activity, as well as
having great potential in the treatment of Alzheimer’s disease.[19]
N,N-dimethyl-2-phenoxypropanamine 25 was obtained in 78%
yield from 3-(diethylamino)propanol; in this case a strained four-
member 1,1-dimethylazetidinium[20] is the key intermediate
leading to the alkylated product.
ß-aminocarbonate 11 1.00: 1.50 mol ratio at 200 °C for 8 hours.
To further explore the value of this approach in drug discovery,
we also tested different nucleophiles commonly used in the
development of bioactive small molecules. For these
compounds (28-33), in consideration of their more complex
structure, we compared the one-pot alkylation procedure
(Scheme 1a) with the previously reported methodology where 2-
3
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10.1002/ejoc.202100328
European Journal of Organic Chemistry
COMMUNICATION
(dimethylamino)ethyl ethylcarbonate 11 was used as reagent
(Scheme 1b). In the latter synthetic approach, experiments were
conducted in the absence of a base.
colorimetric test commonly used for the nonradioactive
quantification of cellular viability and cytotoxicity.[25] As shown in
Figure 4, compounds reduced the cell viability in a dose
dependent manner only at high concentrations. The trend of the
reduction of cell viability was comparable for both compounds at
24 and 48 hours post treatment. In particular, the alcohol and ß-
aminocarbonate 11 cytotoxic concentration capable of reducing
the cell viability by 50% (CC50) were 16.85 vs 14.67 mM and
9.15 vs 10.92 mM, respectively. These values indicate that the
tested compounds are safer than many commercially available
pharmaceuticals.[26]
Phenyltoloxamine 28, used as an enhancing agent for
analgesics and antitussives, was obtained in high yield from its
precursor 2-benzylphenol via the one-pot synthetic approach.
Introduction of the N,N-dimethyl ethylamine moiety employing
previously synthetized ß-aminocarbonate 11 was even more
effective, as the alkylated product was achieved in quantitative
yield. The higher yield of the second methodology was to some
extent expected as it was previously demonstrated that the use
of a base, indispensable for the one pot procedure (see #8;
Table 1), decreases the selectivity towards the anchimerically
driven alkylation due to the formation of more nucleophilic
phenoxide anions.[14]
Similar results were achieved in the preparation of 3-[(N,N-
dimethyl)2-amminoethoxy]pyridine 29, a building block used for
Structure-Activity Relationship (SAR) studies for nicotinic
acetylcholine
(nACh)
receptor
ligands,[21]
and
4-
(dimethylaminoethoxy)benzophenone 30, the building block for
the synthesis of several estrogen receptor modulators related to
Tamoxifene and Toremifene.[22] The one-pot alkylation reaction
afforded 60% and 50% yields respectively, and quantitative
yields were obtained when the reactions were performed
employing directly with the ß-aminocarbonate 11.
Moxisylite precursor 31 was achieved in excellent yield in both
the investigated procedures.
More challenging substrates, i.e. hydroxybenzaldehydes that
incorporate two reactive moieties were then investigated. The
related O-aminoalkylated derivatives 32-33 are important
building blocks used extensively in pharmaceutical preparation
(trimethoxy benzamide and Trifenagrel), and in drug
development for the synthesis of different heterocyclic
compounds such as imidazole containing heterocycles[23], as
well as for decoration of pharmacophore scaffolds (e.g.
generation of appendage diversity on the rhodanine core, a
privileged scaffold in medicinal chemistry).[24]
Anchimerically driven alkylation of 4-hydroxybenzaldehyde and
2-hydroxybenzaldehyde was not efficient as - due to the
presence of the aldehyde moiety - concurrent reactions took
place leading to numerous by-products. It was thus decided to
protect the aldehyde moiety of the two precursors via acetylation
with ethylene glycol under acidic condition (see supporting
information). However, one-pot alkylation (according to Scheme
1a) of the resulting 4- and 2-(1,3-dioxolan-2-yl)phenol was not
successful: most probably the basic conditions led to the
deprotection of the substrates that then underwent concurrent
Figure 4. Effect of compounds on cell viability analyzed by MTT assay. Data
(mean ± SD, N = 3 experiments in quadruplicate) are percentages of cell
vitality, no treated set as 100%.
In conclusion, in this work we have reported the first one-pot
approach to facile incorporation of basic amine-containing side
chains in phenolic scaffolds. This synthetic procedure is not
dependent on chlorine chemistry, and the so-formed alkylated
products are obtained in good to excellent yields. All compounds
were isolated as pure and fully characterized.
In this synthetic approach, DAC chemistry is at its full potential;
DEC leads to in-situ formation of ß-aminocarbonate 11 (BAc2
mechanism) that sequentially alkylates the substrate via the
nitrogen NGP.
The DAC-mediated NGP alkylation has been applied to
numerous substrates and proven in the preparation of several
pharmaceutical compounds or related intermediates. In only two
cases – compounds 32-33 – was the one-pot alkylation reaction
not effective, although the target products could still be obtained
in high yield by employing directly the ß-aminocarbonate 11.
Cytotoxicity evaluation via the MTT assay demonstrated that 2-
(dimethylamino)ethyl ethylcarbonate, 11 and its alcohol
precursor have very limited toxicity.
It should be mentioned that the mutagenicity of compound 11
might still be an issue since the aziridinium ion is the key
intermediate for the alkylation reaction promoted by β-
aminocarbonates, as well as mustard gases. However, the main
difference is the higher temperature required for the herein
proposed procedure, which is typical of DAC-promoted
reactions.
Conversely,
when
the
protected
4-
hydroxybenzaldehyde and 2-hydroxybenzaldehyde were reacted
with 2-(dimethylamino)ethyl ethylcarbonate 11 in the absence of
a base, the N,N-dimethyl ethylamine derivatives 33-34 were
recovered in good to almost quantitative yield. It is noteworthy
that deprotection of the aldehyde group in both products was
conducted directly on the reaction mixture by addition of
trifluoroacetic acid, evaporation of the exceeding solvent and
rapid extraction (see supporting information).
Finally, in order to obtain an insight into the toxicity of the ß-
aminocarbonate 11 employed in the experiments reported here,
either added as a reagent or formed in situ, its cytotoxicity was
evaluated using the MTT assay and compared to its alcohol
precursor 2-dimethylaminoethanol. The MTT assay is
a
4
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10.1002/ejoc.202100328
European Journal of Organic Chemistry
COMMUNICATION
alkylation[13] and it is an additional indication of the lower toxicity
of ß-aminocarbonates compared to their chlorine homologues.
Future work on this novel, one-pot, anchimerically driven
alkylation reaction include investigations on other carbonate
homologues of mustard gases, as well as potential applications
for the synthesis and functionalization of macromolecules.
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Acknowledgements
Prof. C. Salata wants to acknowledge for funding DOR 2020,
Padova University. Prof. S. Castellano wants to acknowledge for
funding Regione Campania (Italy) grant “Combattere la
resistenza tumorale: piattaforma integrata multidisciplinare per
un approccio tecnologico innovativo alle oncoterapie
CAMPANIA ONCOTERAPIE” (Project B61G18000470007).
–
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Richardson, F. Roschangar, A. Steven, F. J. Weiberth, Green Chem.,
2018, 20, 5082–5103.
Keywords: Green Chemistry • chlorine-free • direct alcohol
substitution • dialkyl carbonate • Neighbouring group
participation
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10.1002/ejoc.202100328
European Journal of Organic Chemistry
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The nitrogen mustard gas moiety is present as a basic, amine-containing side chain in numerous pharmacophore scaffolds engaging
in crucial interactions with targeted biological macromolecules. Herein is reported a one-pot synthetic approach for the easy
introduction of nitrogen mustard-like moieties via dialkyl carbonate chemistry into different phenolic substrates. The scope and
limitations of this reaction as a chlorine-free direct substitution of the phenolic -OH group have been investigated.
Institute and/or researcher Twitter usernames: Unive Ca' Foscari
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This article is protected by copyright. All rights reserved.