Lipophilic NHC assisted one-pot synthesis of syncarpamide analogues in aqueous medium

Article abstract of DOI:10.1039/c9nj00134d

Lipophilic NHC catalysis in aqueous medium was reported for the synthesis of biologically relevant (a)symmetrically substituted and unsymmetrically substituted syncarpamide analogues. All the reported reactions were performed in the absence of any expensive metal salts or additives. A diverse array of syncarpamide analogues was obtained in good yields. Lipophilic NHC catalysis was also extended to chemoselective transesterification reactions.

Full text of DOI:10.1039/c9nj00134d

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Lipophilic NHC assisted one-pot synthesis of
syncarpamide analogues in aqueous medium†
Cite this:DOI: 10.1039/c9nj00134d
Pavithira Suresh and Subramaniapillai Selva Ganesan
*
Lipophilic NHC catalysis in aqueous medium was reported for the synthesis of biologically relevant
a)symmetrically substituted and unsymmetrically substituted syncarpamide analogues. All the reported
(
Received 9th January 2019,
Accepted 20th March 2019
reactions were performed in the absence of any expensive metal salts or additives. A diverse array of
syncarpamide analogues was obtained in good yields. Lipophilic NHC catalysis was also extended to
chemoselective transesterification reactions.
DOI: 10.1039/c9nj00134d
rsc.li/njc
Introduction
Amongst the diverse array of green solvents, water has been well
1
,2
acclaimed as the green solvent par excellence. In addition to
its environmentally benign nature, water greatly accelerates the
reaction between lipophilic reactants through the ‘‘hydrophobic
3
–5
hydration effect’’.
In spite of such elegance, it would be
difficult to perform the reaction in aqueous medium if the reactants
have distinctly different solubility in water. One such example is
the reaction between hydrophilic aminoethanol and lipophilic
cinnamate ester derivatives which results in the formation of
biologically relevant syncarpamide analogues. Naturally derived
syncarpamide shows good antiplasmodial activity (IC50 = 2.04 mM)
and hence the synthesis of novel syncarpamide analogue skeletons
Chart 1 NHC catalyzed syncarpamide analogue synthesis in water.
is essential to combat multidrug-resistant Plasmodium falciparum reactions in an aqueous medium under one-pot operation is
6
,7
strains (Chart 1).
syncarpamide analogues are also distributed in natural products.
Tenaglin is a representative example of a symmetrically acylated tion and amidation reactions have been previously reported in
Apart from their biological significance, highly desirable.
Though N-heterocyclic carbene (NHC) mediated transesterifica-
9
10
8
amino alcohol derivative obtained from plant resources (Chart 1).
organic solvents, one-pot, concomitant transesterification and
The conventional synthesis of syncarpamide analogues was amidation reactions in aqueous medium are challenging. Unlike
carried out in chlorinated organic solvents in the presence of metal–NHC complexes, the major disadvantage of performing
excess DCC/DMAP reagents under a strictly moisture-free environ- NHC organocatalysis in the aqueous medium is the facile
6
ment. Additionally, unsymmetrically substituted derivatives were protonation of metal-free naked NHC since the pK
a
1
of the
1
synthesized by a multi-step reaction which involves (i) O-acylation imidazolium cations (23.8) is higher than that of water. Lemc-
of azido alcohols, (ii) transformation of azide to amine function- off and co-workers gave a detailed account on NHC catalysis
ality, followed by (iii) N-acylation, in which each step is devoid of performed in the aqueous medium and highlighted the difficulty
6
12
aqueous medium. Hence, identification of a catalytic system in performing NHC organocatalysis in the aqueous medium.
which performs consecutive amidation and transesterification Our proposed scheme is given in Chart 1.
1
3,14
In recent years, ‘‘surfactant-like catalysts’’
are increas-
1
5
ingly being investigated instead of simple surfactants or
Department of Chemistry, School of Chemical and Biotechnology,
SASTRA Deemed University, Thanjavur-613401, Tamil Nadu, India.
E-mail: selva@biotech.sastra.edu; Fax: +91 4362 264120
16,17
emulsion droplets
to perform organic transformations in
the aqueous medium. These surfactant-like catalysts not only
catalyze the reaction but also provide a larger interface for the
immiscible phases of the reactants and the aqueous medium.
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9nj00134d
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Polarz and co-workers recently reported the synthesis of surfactant- Table 1 Screening of reaction conditions for NHC catalysis in aqueous
a
medium
like NHC by anchoring a lipophilic alkyl chain far away from the
reactive NHC–metal head to perform interfacial catalysis in aqueous
14
medium. We have decided to tether a lipophilic alkyl chain directly
on to the NHC nitrogen atom which could facilitate a reaction
between hydrophilic aminoethanol and lipophilic cinnamate ester
18,19
derivatives. Unlike amphiphilic metal catalyzed reactions,
investigations on NHC organocatalysis in the aqueous medium
20
are largely confined to benzoin condensation reactions.
Results and discussion
The choice of NHC is essential for the success of one-pot
amidation/transesterification reactions. The use of (benz)imi-
dazolium based NHCs is preferred over triazolium derived NHC
since the latter could lead to the LUMO activation of a,b-unsaturated
b
S. no NHC Substrate Base Solvent Temp (1C) Time (h) Yield (%)
2
1,22
1
2
3
4
5
6
7
8
9
1
1
A
1b
1b
1b
1b
1b
1b
1b
1b
1a
K
K
K
K
K
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
H
H
H
H
H
H
2
2
2
2
2
2
O
O
O
O
O
O
RT
RT
RT
RT
50 1C
RT
RT
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
10
37
55
73
esters.
and transesterification reactions performed with aminoethanol
and 4-nitrophenylcinnamate ester 1b with N-aryl imidazolium
The preliminary investigation on one-pot amidation
B
C
D
D
D
D
D
D
D
E
2
Impure
30
NHC precatalysts A and B gave the corresponding product 3a in
poor yields (Table 1, entries 1 and 2). Since N-alkyl substituted
DBU
c
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
THF
Brine 50 1C
—
9
d
NHCs have higher nucleophilicity and better electron donating
50
82
e
f
23
H
2
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
O
RT
RT
RT
RT
RT
RT
RT
ability than the corresponding N-aryl counterparts, the N-alkylated
imidazolium/benzimidazolium NHC precatalysts C–H were pre-
0
1
1c/1d
1a
1a
Impure
—
pared. Among N-alkyl substituents, sterically more demanding 12
F
o5
13
14
15
G
H
I
1a
1a
1b
76
—
—
lipophilic dodecyl substituted NHCs are unique since they shift the
20
Wanzlick equilibrium towards the free carbene side (Scheme 1).
Moreover, the presence of the lipophilic chain greatly assists the
performance of the desired organic transformation in aqueous
a
To a mixture of amino alcohol 2 (0.2 mmol), substituted ester 1
(0.2 mmol) in water (2 mL), potassium carbonate (0.3 mmol) and NHC
b
c
medium. As predicted, the reactions performed with NHC pre- (0.02 mmol) were added. Yields are for the isolated products. Formation
d
of products not observed. At room temperature, formation of products
catalysts C and D gave the corresponding product in moderate to
e
not observed. Presence of unreacted 1 was observed in the reaction
medium, if the reaction was performed for less than 12 h; the use of
good yields (entries 3 and 4).
Increasing the reaction temperature from RT to 50 1C or excess amino alcohol 2 (0.2 mmol) is required for the completion of the
f
reaction. The reaction performed in D
2
O solvent took 20 h for completion
changing the inorganic base to DBU drastically affected the
yield of the product (entries 5 and 6). To identify the role of the
solvent, the reaction was performed in THF under optimized
conditions. However, it gave only the amidation product
instead of the desired product 3a (entry 7). Similarly, the
reaction performed with brine solution instead of water also
did not yield the desired outcome (entry 8). These results show that
the synergetic combination of sterically demanding lipophilic
benzimidazolium NHC and water is essential for the success of
this reaction. Under optimized reaction conditions, changing the
leaving group from 4-nitrophenyl (1b) to the phenyl group (1a)
and 3a was obtained in 80% yield.
Scheme 1 Wanzlick equilibrium.
It was presumed that the presence of electron withdrawing
marginally improved the product yield to 82% (entry 9 vs. 4) whilst substituents at the aromatic ring would enhance the electro-
the use of benzyl cinnamate (1c) or methyl cinnamate (1d) instead philicity of the carbonyl carbon and pave the way for facile
of 1a did not yield the desired outcome (entry 10). Hence, it was amidation and transesterification reactions. Hence, after optimizing
decided to carry out further reactions with phenyl cinnamate ester the reaction conditions, the substrate scope of the reaction was
itself.
screened with diverse phenyl cinnamate derivatives with electron
To further understand the role of NHC, the reaction was withdrawing substituents (Fig. 1). Interestingly, irrespective of
carried out under optimized conditions with NHC precatalysts the nature of the substituents, the syncarpamide analogues 3b–f
E–H. Among these, the sterically demanding lipophilic imidazolium were obtained in good yields. The reaction conditions were mild
NHC precatalyst gave superior yield (entry 13 vs. 11 and 12). enough to keep the cyano substituent intact in 3e. The use of the
This shows that the nature of the alkyl group tethered on to the unsubstituted phenyl ester instead of cinnamate ester gave only
NHC dictates the course of the reaction.
the amidation product 3g. Movassaghi et al. reported a similar
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Fig. 1 Substrate scope.
amidation reaction of aromatic ester with amino alcohol
1
0
derivatives. The scope of the reaction was further extended to
chiral amino alcohols such as R-(À)-2-phenylglycinol, S(À)-2-
amino-3-phenyl-1-propanol and R(À)-2-amino-1-phenylethanol.
For chiral derivatives, the reaction mixture needs to be heated
to 60 1C for 5 hours and the reaction gave the products 3h–o in
good yields. Apart from cinnamate esters and b-amino alcohol
substrates, the reaction was found to be general for b-heterocyclic
esters, g-amino alcohols, and also dialcohol/diamine derivatives.
The products 3p–3s and 3v–y were obtained in good yields.
However, the reaction carried out with b-alkyl ester did not yield
the desired products 3t–u.
Unlike symmetrical derivatives, one-pot synthesis of unsym-
metrically substituted derivatives requires a multi-step reaction,
vide supra. Caulitenin is a representative example of an unsym-
metrically acylated amino alcohol derivative obtained from
8
natural sources. Preliminary investigations on the one-pot
synthesis of unsymmetrical derivatives by the reaction of two
different esters gave a complex mixture of products. All attempts
to enhance the reaction yield failed to yield the desired outcome.
Hence, it was decided to perform sequential amidation followed
by a transesterification reaction. After careful screening and
optimization, we have identified that K CO can efficiently carry
Chart 2 NHC catalyzed unsymmetrically substituted analogue synthesis.
Scope and limitations of NHC organocatalysis in aqueous
medium
2
3
out the amidation of unactivated methyl benzoate derivatives,
which on further NHC mediated transesterification gave the The NHC organocatalysis was screened with lipophilic/primary/
corresponding unsymmetrically substituted derivatives 4a–4d secondary and sterically hindered tertiary alcohol derivatives
(Chart 2).
(Chart 3). The reaction carried out with lipophilic stearyl
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Chart 3 Scope and limitations of NHC organocatalysis in aqueous
medium.
alcohol and aromatic naphthol in aqueous medium gave the
desired products 5d and 5e in good yields (Chart 3(i)). The
reaction also proceeded smoothly with the secondary alcohol
but not with the tertiary alcohol. Increasing the reaction
temperature also did not change the course of the reaction
with respect to the tertiary alcohol. The benzoin derivative 5g
obtained by the transesterification of the secondary alcohol is a
valuable intermediate for the synthesis of substituted indole
Fig. 2 NMR investigations of one-pot amidation/transesterification.
10
ethanolamine has higher reactivity than benzyl amine, the highly
soluble nature of the former in water could have suppressed the
formation of 5j. In addition, due to the presence of the lipophilic
aromatic moiety, facile amidation of benzyl amine takes place with
lipophilic NHC. To confirm the stability of the lipophilic NHC in the
aqueous medium, we performed the representative 3a synthesis, by
2
4
derivatives.
Preferential acylation of a primary alcohol in the presence of
secondary alcohols or phenols in an aqueous medium is an
arduous task. Hence, such transformations are invariably per-
formed in an organic solvent medium under a strictly moisture-
2
generating NHC in H O, followed by the addition of substrates after
9
,25,26
free environment.
In our method, the selective acylation
a 30 minute interval (Chart 3(v)). As expected, the desired amidation/
transesterification product was formed, albeit in marginally lesser
yields. This shows that the lipophilic dodecyl NHC is not much
affected by the presence of water.
of a primary alcohol in the presence of a secondary alcohol
derivative was achieved in good yields (Chart 3(ii)). Movassaghi
et al. reported that NHC mediated amidation of esters with
amino alcohols proceeds via initial transesterification followed
1
0
by rapid O to N acyl-transfer. To check this hypothesis, we
Mechanistic investigations
performed the transesterification/amidation reaction of 1b in
the presence of benzyl alcohol and benzyl amine (Chart 3(iii)). To further confirm the activation of exchangeable NH
2
/OH
Interestingly, we obtained the corresponding amidation product protons by the NHC, we carried out the following NMR experi-
5
5
i in 78% yield with trace amounts of transesterification product ment. The addition of K
2 3
CO to the ethanolamine solution in
h. The preferential formation of the amidation product over the CDCl shows the presence of an exchangeable protons peak at
3
transesterification product could be due to the activation of the 3.1 ppm (Fig. 2(iii)). The combined addition of both NHC D and
amine moiety by the NHC for the nucleophilic addition the K CO base resulted in the disappearance of the exchange-
2
3
2
7
reaction and/or an uncatalyzed selective amidation reaction able protons peak (Fig. 2(iv)). This confirms that NHC D
over transesterification. A competitive amidation reaction per- activates both NH /OH groups for the nucleophilic substitution
2
2
8
formed with both ethanolamine and benzyl amine resulted in reaction. Based on the results obtained a detailed mechanism
the formation of product 5i instead of 5j (Chart 3(iv)). Though is given in the ESI.†
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Conclusions
8 H. Greger, M. Hofer, K. Teichmann, J. Schinnerl, C. M.
Pannell, S. Vajrodaya and O. Hofer, Phytochemistry, 2008, 69,
A versatile and convenient method was developed for the one-
pot synthesis of syncarpamide analogues. All the reactions were
carried out in the aqueous medium and the products were
obtained in good yields. In addition, the lipophilic NHC was
utilized to perform chemoselective amidation reactions in the
presence of alcohols and esterification of a primary alcohol in
the presence of a secondary alcohol.
9
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There are no conflicts to declare.
Acknowledgements
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