A Nucleophilic Activation of Carboxylic Acids by Proline: Oxa-Michael Addition to Methyl Vinyl Ketone under Solvent-Free Conditions

Article abstract of DOI:10.1055/s-0036-1588172

A serendipitous nucleophilic activation of carboxylic acids by proline helped to achieve a direct hydrocarboxylation of methyl vinyl ketone at 60 °C under solvent-free conditions. A variety of carboxylic acids were used successfully in this oxa-Michael addition, affording useful 4-acyloxy-2-butanones in moderate yields. The reactions are carried out under solvent-free conditions, and the products are isolated in high purity by a simple work-up procedure without any need for column chromatographic purification, imparting a green quotient to the protocol. A heterodimeric non-covalent interaction between the amino acid and the carboxylic acid appears to be the most plausible mechanistic interpretation for the nucleophilic activation; additionally, the possible activation of the Michael acceptor by iminium ion formation presents an interesting case of proline acting as a bifunctional catalyst.

Full text of DOI:10.1055/s-0036-1588172

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
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A. K. Jha et al.
Letter
Synlett
A Nucleophilic Activation of Carboxylic Acids by Proline: Oxa-
Michael Addition to Methyl Vinyl Ketone under Solvent-Free
Conditions
Ajit Kumar Jha
CO2H
Heena Inani
O
O
N
H
O
O
Srinivasan Easwar*
R
OH
R
O
60 °C
Department of Chemistry, Central University of Rajasthan,
NH-8, Bandarsindri, Distt. Ajmer, Rajasthan 305817, India
easwar.srinivasan@curaj.ac.in
R = aryl, alkyl, styryl, etc.
nucleophilic activation of a carboxylic acid by proline
solvent-free conditions; 20 examples; up to 68% yield
no column chromatographic purification required
Received: 07.02.2017
Accepted after revision: 17.03.2017
Published online: 10.04.2017
another case where a carboxylic acid nucleophile could be
envisioned. The use of alcohol donors in the reaction is well
known and affords structural motifs such as β-hydroxyke-
tones which are ubiquitous in natural products.5 However,
the use of a carboxylic acid as the donor in the reaction has
understandably been difficult due to the challenges in acti-
vating the nucleophile and also a more pronounced revers-
ibility factor. The few literature reports in this regard deal
mostly with the intramolecular version, entwined either
with a supporting reaction or involving a masked acid,
leading to the formation of lactones.6 On the other hand,
the intermolecular version employing a direct nucleophilic
activation of a carboxylic acid has seldom been achieved
barring a couple of reports.7,8 Focusing specifically on
methyl vinyl ketone as the Michael acceptor, addition of a
carboxylic acid would grant access to 4-acyloxy-2-buta-
nones and eventually 1,3-butanediols, structural motifs
that find numerous applications as potential building
blocks in natural product synthesis.9 In the literature, acyl-
oxy butanones have generally been accessed by esterifica-
tion of 4-hydroxy-2-butanone using the corresponding acid
chloride,10 among other singular examples.7,11–13 On a paral-
lel note, considerable research attention of late is being de-
voted to the development of more sustainable organocata-
lytic protocols.14 Solvent-free and aqueous reactions pro-
vide the most straightforward approach to address the
problem of using toxic organic solvents, the single biggest
contributing factor to the sheer magnitude of waste in
chemical manufacture. Further in this direction, protocols
which deliver pure products by a simple work-up procedure
without the need for column chromatography reduce the
use of solvents to a bare minimum. The research efforts of
our group focus on developing environment-friendly meth-
odologies for effecting important C–C bond forming reac-
tions and other novel transformations. In light of this and
the preceding discussion, we wish to report a unique nucle-
DOI: 10.1055/s-0036-1588172; Art ID: st-2017-b0090-l
Abstract A serendipitous nucleophilic activation of carboxylic acids by
proline helped to achieve a direct hydrocarboxylation of methyl vinyl
ketone at 60 °C under solvent-free conditions. A variety of carboxylic
acids were used successfully in this oxa-Michael addition, affording use-
ful 4-acyloxy-2-butanones in moderate yields. The reactions are carried
out under solvent-free conditions, and the products are isolated in high
purity by a simple work-up procedure without any need for column
chromatographic purification, imparting a green quotient to the proto-
col. A heterodimeric non-covalent interaction between the amino acid
and the carboxylic acid appears to be the most plausible mechanistic
interpretation for the nucleophilic activation; additionally, the possible
activation of the Michael acceptor by iminium ion formation presents
an interesting case of proline acting as a bifunctional catalyst.
Key words carboxylic acids, proline, heterodimeric association, bi-
functional catalysis, enones, oxa-Michael addition, solvent-free, hydro-
carboxylation
Nucleophilic activation of carboxylic acids has always
been a challenging task in organic synthesis. One of the best
examples has been the Mitsunobu reaction,1 where a com-
bination of reagents and steps leads to a nucleophilic car-
boxylate that delivers the famous ‘inverted’ ester. More re-
cently, Benjamin List and co-workers demonstrated a re-
markable nucleophilic activation of carboxylic acids by a
BINOL-derived phosphoric acid.2,3 The authors carried out
extensive studies to illustrate a heterodimeric association
of the two acidic components that led to the activation of
carboxylic acid as a nucleophile. The concept was applied to
a highly enantioselective ring-opening of aziridines by car-
boxylic acids2a and later to epoxide systems as well.2b,c This
was perhaps the first instance of a general mode of carbox-
ylic acid activation in the realm of organocatalysis. Oxa-
Michael addition, a reaction that constitutes an important
class in carbon–heteroatom bond formation,4 represents
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
A. K. Jha et al.
Letter
Synlett
ophilic activation of carboxylic acids by proline in an oxa-
Michael addition to methyl vinyl ketone under solvent-free
conditions. To our knowledge, the protocol represents the
first instance of such activation of carboxylic acids by pro-
line and presumably corroborates earlier observations by
List with regard to heterodimeric interaction.2,3 The prod-
ucts – esters resulting from a direct hydrocarboxylation of
the double bond of the α,β-unsaturated ketone – are isolat-
ed in high purity by a simple aqueous work-up, circum-
venting the need for a column chromatographic purifica-
tion.
tion run without proline showed just traces of product for-
mation, while the use of pyrrolidine also resulted in paltry
conversion, clearly indicating the participation of the amino
acid moiety (entries 1 and 2). Upon increasing the amount
of proline from 10 to 50 mol%, a reasonable improvement in
the efficiency was observed, although the yield of the ad-
duct remained moderate (entries 3–5); prolonging the reac-
tion to 15 hours using 0.5 equivalents of proline helped to
increase the yield to 62%, which eventually proved to be op-
timum (entry 6). Interestingly, the use of a stoichiometric
amount of proline proved detrimental, resulting in a sharp
drop in the yield (entry 7). The reaction was quite sluggish
at room temperature and did not help to improve the yield
even over 24 hours (entries 8 and 9). In the quest for better
yields, the reaction was reinforced with an additional two
equivalents of the acceptor, but resulted in only a marginal
improvement (entry 10), whereas introduction of the acid
after complete dissolution of proline in 1 had a negative im-
pact (entry 11). The use of solvents proved damaging to the
reaction (entries 12–15). The reaction in water was particu-
larly poor, exhibiting only trace amounts of the product.
Recently, we reported
a proline-mediated Baylis–
Hillman reaction of methyl vinyl ketone with aldehydes;
the reaction proceeded smoothly at 60 °C under solvent-
free conditions to deliver the desired adduct in very good
yields.15 In the course of this study, we repeatedly observed
prominent formation of a side product in the reaction with
p-chlorobenzaldehyde. Upon isolation and characterisation
by 1H NMR, this product turned out to be a 4-acyloxy-2-bu-
tanone,12 formed as a result of an oxa-Michael addition of
the corresponding carboxylic acid – present as an impurity
in the aldehyde – to methyl vinyl ketone. Intrigued by this
result, we carried out a reaction under the same conditions
using a stoichiometric amount of the carboxylic acid and
were delighted to obtain the 4-acyloxy-2-butanone as the
exclusive product; further, the product was isolated in high
purity, albeit in a moderate yield, by a simple work-up pro-
cedure negating the need for a column chromatographic
purification. Despite the modest yield, we felt attracted by
the nucleophilic activation of a carboxylic acid by proline
and the green quotient of the protocol. Of further note,
while methyl vinyl ketone (1) is the electrophile in the
present reaction, the Baylis–Hillman reaction under nearly
identical conditions reported from our group earlier had 1
as the nucleophilic component.15 Such a reversal of roles of
1 when reacting with an aldehyde or a carboxylic acid is in-
teresting (Scheme 1). Prompted by these features, we em-
barked upon a full-fledged study of the efficacy of the reac-
tion.
Table 1 Optimisation of the Reaction Conditionsa
O
O
O
HO2C
proline
O
(conditions)
Cl
3a
Cl
1
2a
Entry
Proline
(equiv) (equiv)
1
Solvent/additive
Temp
(°C)
Time Yield (%)
(h)
(μL)
of 3ab
1
–
3
3
3
3
3
3
3
3
3
5
3
2
2
2
2
3
3
–
60
6
trace
12
39
46
54
62
24
15
53
57
24
7
2
0.5c
0.1
0.3
0.5
0.5
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
–
60
60
60
60
60
60
r.t.
r.t.
60
60
60
60
60
60
60
60
6
6
6
6
3
–
4
–
5
–
6
–
15
6
7
–
The nucleophile in the preceding discussion – p-chloro-
benzoic acid (2a) – was chosen for the optimisation studies,
the results of which are collated in Table 1. A control reac-
8
–
6
9
–
24
6
10
11d
12
13
14
15
16
17
–
–
6
O
EtOH (500)
toluene (500)
THF (500)
H2O (500)
H2O (25)
H2O (100)
6
proline
ArCO2H, 60 °C
proline
ArCHO, 60 °C
(ref. 15)
6
25
22
trace
27
11
1
6
(this work)
6
OH
O
O
O
6
Ar
Ar
O
6
a All reactions were carried out using 1 mmol of 2a.
b Refers to isolated yields.
Baylis–Hillman adduct
1 as nucleophilic component
oxa-Michael adduct
1 as electrophilic component
c Pyrrolidine was used instead of proline.
Scheme 1 Difference in reactivity of methyl vinyl ketone towards alde-
hydes and carboxylic acids under nearly identical conditions
d Acid 2a was added after complete dissolution of proline in methyl vinyl ke-
tone.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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A. K. Jha et al.
Letter
Synlett
The role of water in organocatalysis has always been in-
triguing16 and several mechanistic studies have been un-
dertaken to rationalise its beneficial presence.17 Remark-
able enhancement in efficiency and stereoselectivity has
been achieved, particularly in the domain of asymmetric al-
dol reactions, with the addition of small quantities of water.
In this context, two more reactions were attempted to
check whether using water just as an additive had a favour-
able impact, but the results turned out to be disappointing
(entries 16 and 17). Nevertheless, the detrimental effect of
water served to strengthen the plausibility of a non-cova-
lent interaction of the carboxylic acid with proline, in a
manner similar to the activation using phosphoric acid de-
scribed by List.
It was evident that the reaction was not progressing be-
yond a certain conversion threshold, alluding to a compet-
ing retro-Michael process in play. Although the optimal
yield was unspectacular, we were yet keen to explore the
scope of the reaction. The optimised conditions were thus
employed to access a wide array of acyloxy butanones from
acids of various types, aromatic as well as aliphatic, bearing
different functional groups. The reaction proved to be gen-
eral in applicability and quite a few interesting structural
motifs were formed, as illustrated in Figure 1. At the outset,
a variety of aromatic acids were tested, comprising ortho-,
meta-, para- as well as disubstituted benzoic acids, and af-
forded adducts 3b–j in yields in the range of 35–68%. Fol-
lowing this, reactions with two acid functionalities bearing
a second reactive functional group, namely salicylic acid
and 2-formylbenzoic acid, were attempted; the former
turned out to be a reluctant nucleophile, presumably due to
the presence of an intramolecular H-bond donor that pre-
vents the proposed interaction of the carboxylic acid with
the catalyst. Nonetheless, it is worth noting that the reac-
tion yielded the ester adduct 3k exclusively; the product
corresponding to addition of the perceivably more nucleo-
philic phenol moiety was not observed. The use of 2-form-
ylbenzoic acid was quite interesting, yielding two products
– the minor product 3l (8% yield) corresponded to the stan-
dard addition of the carboxylate, whereas the major prod-
uct, which was confirmed by 1H NMR to be 3m (57% yield),
derived from an oxa-Michael addition of the lactol form of
the carboxy aldehyde to 1. Ketals of this type have recently
been shown to have antibacterial, antifungal and even mild
genotoxic activity.19 The presence of an electrophilic alde-
hyde in the above reaction adds the possibility of a cascade
cyclisation to eventually form a seven-membered lactone,
but such a product was not observed. The use of the dicar-
boxylic acids – phthalic and succinic – was taken up next;
both reactions led to the formation of interesting bis-ad-
ducts 3n and 3o, with the aromatic acid proving much
more efficient than the aliphatic analogue. Aliphatic acids
turned out to be disappointing donors – only phenylacetic
acid delivered the corresponding adduct 3s in a yield com-
parable to that of the aromatic counterparts. Lastly, cin-
namic acid, foremost among aromatic α,β-unsaturated ac-
ids, was also tested and gave a reasonable yield of the
Michael adduct 3t. A cascade cyclisation involving the dou-
ble bond of the parent acid would have been interesting but
did not transpire. Protocols involving minimal use of sol-
vents could be attractive from an industrial perspective. In
this regard, we were pleased that a reaction on a 10 mmol
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Br
O2N
Cl
MeO
3e (6 h; 35%)
3d (6 h; 45%)
3c (15 h; 42%)
3b (15 h; 68%)
3f (6 h; 45%)
O
O
O
O
O
O
O
O
O2N
O
O
O
O
O
O
O
OH
F
Cl
NO2
3j (6 h; 44%)
3h (6 h; 45%)
3i (15 h; 38%)
3g (6 h; 50%)
3k (15 h; 36%)
O
O
O
O
O
O
O
O
O
O
O
O
O
Cl
O
O
O
O
O
3p (15 h; 23%)
O
O
O
O
O
3l (15 h; 8%)
3m (15 h; 57%)
3o (6 h; 22%)a
3n (6 h; 48%)a
O
O
O
O
O
O
O
O
O
O
O
O
O
F3C
O
O
3s (15 h; 50%)
Cl
3a (15 h; 33%)c
3q (15 h; 20%)
3r (15 h; 30%)b
3t (15 h; 48%)
Figure 1 Nucleophilic activation of various carboxylic acids by proline: oxa-Michael adducts obtained by the reaction with methyl vinyl ketone.18 a
equiv of 1 were used. b Reaction was carried out at 40 °C. c Reaction was carried out using 10 mmol of 2a.
5
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A. K. Jha et al.
Letter
Synlett
Path 'a'
Path 'b'
O
O H
O
RCO2H
O
R
RCO2H
H
O
O
O
O
O
O
O
H
N
CO2H
H
R
O
R
N
N
H
N
O
H
heterodimeric association
(non-covalent activation)
H
H
H
proline
O
Path 'c'
O
O
path 'a'/'b'
O
O
O
CO2H
O
O
N
H
O
R
R
O
CO2H
N
N
H
R
O
O
O
O
H
H
iminium formation
(covalent activation)
oxa-Michael addition
Scheme 2 Proposed heterodimeric activation of carboxylic acid by proline
scale of p-chlorobenzoic acid (2a) using the optimised con-
ditions proceeded to yield one gram of the pure adduct 3a
(33% yield). An important aspect of the reaction is that it
fails to proceed in the presence of a solvent, as seen earlier
in Table 1, which poses a challenge regarding the use of oth-
er common enones. Disappointingly, our attempts to carry
out this reaction on a chalcone using acetonitrile or toluene
as a solvent ended in vain. We also checked the reaction
with two other liquid enones, namely cyclohexenone and
3-methylbut-3-ene-2-one, but unfortunately these reac-
tions too were not successful.20
The mechanism of the reaction would evidently require
a separate deeper study; nonetheless, guided by List’s in-
sightful work in this regard and our own observations, we
have attempted to construct credible pathways to ra-
tionalise the nucleophilic activation of the carboxylic acid.
The most plausible mechanism, much along the lines out-
lined by List,2a,3 would involve a heterodimeric association
between the amino acid and the carboxylic acid resulting in
activation of the latter (Scheme 2, path ‘a’). Alternatively,
the zwitterionic form of the amino acid may be considered,
leading to an ‘opposite’ non-covalent interaction between
the two acids as depicted by path ‘b’. Such an association
could also activate the carboxylic acid to add to the double
bond. Alternatively, it would be reasonable to propose that
the actual electrophile in the entire process is a LUMO-low-
ered iminum ion formed by the interaction of proline with
the α,β-unsaturated carbonyl species, as depicted by path
‘c’; the rest of the mechanism could then follow one of the
pathways ‘a’ or ‘b’. This would imply a unique dual activa-
tion of both electrophile and nucleophile by proline via co-
valent and non-covalent modes of interaction, respectively.
In our opinion, this would indeed be a remarkable reflec-
tion of proline’s ability for bifunctional catalysis. It is worth
reiterating at this juncture that, as reported by our group
earlier,15 in the presence of an electrophilic aldehyde under
identical conditions, an opposite nucleophilic activation of
methyl vinyl ketone by proline has been achieved.
In summary, we feel that the nucleophilic activation of
carboxylic acids by proline is both unique and interesting.
The oxa-Michael addition to methyl vinyl ketone delivered
4-acyloxy-2-butanones – valuable synthons that could
serve as important intermediates – albeit in modest yields.
Structural motifs generated in this work, such as the ketal
adduct and the dicarboxylic acid adducts, add to the appeal
of the reaction. Further, the reaction is performed under
solvent-free conditions and the products are isolated in
high purity by a simple work-up procedure without the
need for a column chromatographic purification, imparting
green features to the protocol. The proposed mechanistic
pathways understandably require a more detailed study.
This is especially so since proline itself has not been popu-
lar in exclusive non-covalent catalysis, although proline-
mediated enamine catalysis does involve H-bonding as an
important factor. Thus, although the application of the con-
cept is currently singular, and succeeds in modest yields,
the knowledge that proline is armed with a potential to
participate in such heterodimeric activation – apart from
its obvious ability to activate carbonyl species – is quite ex-
citing for future work in this direction.
Acknowledgment
Research funding by the Department of Science and Technology
(DST), the Government of India and the University Grants Commis-
sion (UGC), India, is gratefully acknowledged. A.K.J. thanks the Central
University of Rajasthan (CURAJ) for a fellowship. H.I. thanks UGC for a
Senior Research Fellowship. The authors thank the CURAJ for support.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588172.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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A. K. Jha et al.
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Synlett
References and Notes
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(18) Proline (0.5 mmol) was added to methyl vinyl ketone (1; 3.0
mmol) in a 5 mL vial and stirred for 5 min at room temperature.
p-Chlorobenzoic acid (2a; 1.0 mmol) was then added, and the
reaction mixture was stirred at 60 °C for 15 h. The reaction
mixture was then allowed to cool to room temperature, diluted
with EtOAc (4 mL) and washed with 10% aqueous NaHCO3
(6 mL × 3). The organic layer was dried over Na2SO4 and con-
centrated in vacuo to isolate the pure product 3a12 (140 mg,
62%) as a cream-coloured solid. 1H NMR (CDCl3, 500 MHz):
δ = 7.93 (d, J = 8.8 Hz, 2 H), 7.40 (d, J = 8.8 Hz, 2 H), 4.58 (t,
J = 6.3 Hz, 2 H), 2.90 (t, J = 6.3 Hz, 2 H), 2.23 (s, 3 H). 13C NMR
(CDCl3, 125 MHz): δ = 205.57, 165.55, 139.50, 131.00, 128.73,
128.37, 60.01, 42.27, 30.32.
(19) Maslat, A. O.; Al-Hamdany, R.; Faftah, Z.; Mahrath, A. J.;
Abussaud, M. J. Toxicol. Environ. Chem. 2003, 85, 149.
(20) Reactions attempted with the other enones have not been tabu-
lated.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E