Multicomponent synthesis of pyroglutamic acid derivatives: Via Knoevenagel-Michael-hydrolysis-lactamization-decarboxylation (KMHL-D) sequence

Article abstract of DOI:10.1039/c8ob02473a

A novel and practical method for the synthesis of 3-substituted pyroglutamic acid derivatives is described. One pot multicomponent reaction of Meldrum's acid, aldehyde and Schiff's base followed an unprecedented chemoselective Knoevenagel-Michael-hydrolysis-lactamization domino sequence to afford 4-carboxy 3-substituted pyroglutamic acid derivatives under mild conditions. A carboxy intermediate formed appears to accelerate its own formation. The generality of the synthesis is exemplified by the use of a wide variety of aldehydes including enolizable aliphatic aldehydes, while substrates are stable under reaction conditions.

Full text of DOI:10.1039/c8ob02473a

Organic &
Biomolecular Chemistry
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Multicomponent synthesis of pyroglutamic acid
derivatives via Knoevenagel–Michael-hydrolysis-
lactamization-decarboxylation (KMHL-D)
sequence†
Cite this: Org. Biomol. Chem., 2019,
17, 561
Tushar M. Khopade,
Ramakrishna G. Bhat
Prakash K. Warghude,
*
Amol D. Sonawane
and
A novel and practical method for the synthesis of 3-substituted pyroglutamic acid derivatives is described.
One pot multicomponent reaction of Meldrum’s acid, aldehyde and Schiff’s base followed an unpre-
cedented chemoselective Knoevenagel–Michael-hydrolysis-lactamization domino sequence to afford
4-carboxy 3-substituted pyroglutamic acid derivatives under mild conditions. A carboxy intermediate
formed appears to accelerate its own formation. The generality of the synthesis is exemplified by the use
of a wide variety of aldehydes including enolizable aliphatic aldehydes, while substrates are stable under
reaction conditions.
Received 4th October 2018,
Accepted 18th December 2018
DOI: 10.1039/c8ob02473a
rsc.li/obc
oglutamic esters providing a new entry to the synthesis of sub-
stituted pyroglutamic acid derivatives. Alkylidene Meldrum’s
Introduction
Pyroglutamic acid and its derivatives are a valuable class of acid 5, as an excellent Michael acceptor, is utilized in various
compounds, being found ubiquitously in various natural pro- C–C and C–N bond-forming Michael addition reactions
ducts and pharmaceuticals.1 Their core structure can be trans- leading to a range of chiral Meldrum’s acid derivatives and
formed easily into functionalized piperidines and pyrrolidi- biologically active compounds.5,6 It also acts as an excellent C3
nones which find extensive applications in peptidomimetics2 synthon for several synthetic applications. Taking this into
and neuroexcitatory chemistry.3 Because of these important account, we planned a novel multicomponent route to access
applications, synthesis of the pyroglutamic acid scaffold is a pyroglutamic esters (Scheme 1).
highly desirable target. Pyroglutamic acid and its derivatives
have been synthesized by multicomponent as well as by multi-
step approaches, with the multicomponent strategy having
proven to be a fruitful synthetic tool.4 An Ugi reaction of keto-
acid, ammonium acetate and isocyanide provides a quick
access to the pyroglutamyl amide framework.4a–e In addition,
Lavilla4e and Huo4g have reported multicomponent construc-
tion of N-aryl pyroglutamic acid derivatives from anilines,
α-oxoaldehydes and α-angelica lactones. The principal short-
comings of these procedures are limited substrate scope and
limited toleration of substituents on the lactam ring.
Therefore, the development of a facile and general protocol to
address these shortcomings is of considerable importance.
Herein, we report a practical multicomponent synthesis of pyr-
Department of Chemistry, Indian Institute of Science Education and Research
(IISER)-Pune, Dr Homi Bhabha Road, Pashan, 411008 Pune, Maharashtra, India.
E-mail: rgb@iiserpune.ac.in
†Electronic supplementary information (ESI) available: Synthetic procedures,
characterization data. CCDC 1814265. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c8ob02473a
Scheme 1 Proposed synthesis of pyroglutamic ester via KMHL-D
sequence.
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Our proposed synthetic route (Scheme 1) uses a novel ate 4a′ in situ by heating the reaction mixture afforded the
chemoselective
Knoevenagel–Michael-hydrolysis-lactamiza- desired product 4a (tert-butyl 2-phenyl pyroglutamate) along
tion-decarboxylation (KMHL-D) sequence. Kobayashi7a and with traces of inseparable impurities. Alternatively, upon base/
several other groups have reported stepwise formal [3 + 2] acid work-up of the undecarboxylated product 4a′ followed by
cycloaddition reaction of
a
Schiff’s base and an reflux in toluene for 6 h, the desired product 4a was obtained
α,β-unsaturated ester for the synthesis of highly substituted in 65% yield with good diastereoselectivity (3.6 : 1, Table 1,
pyrrolidine derivatives.7 In this regard, the possibility of a com- entry 1) free of any side products. The structure of 4a was con-
petitive formal [3 + 2] cycloaddition reaction between Schiff’s firmed by NMR and its relative stereochemistry was assigned
base 3a and alkylidene Meldrum’s acid 5 is an alternative by single crystal XRD analysis (see ESI, section 3†).12
outcome for the proposed reaction (Scheme 1, path b). We Gratifyingly, the proposed reaction took place in one pot albeit
naively assumed that Schiff’s base may undergo Michael with only a trace amount of Michael addition by-product 7a
addition with α,β-unsaturated alkylidene Meldrum’s acid 5 fol- (see Scheme 1). In order to achieve the decarboxylation in situ
lowed by lactamization to give the corresponding pyroglutamic and to fully suppress the formation of by-product 7a, we
ester 4 (Scheme 1, path a).8 The second challenge is to sup- screened a series of Lewis base organocatalysts such as DBU,
press the formation of compound 7 by an undesired Michael Hünig’s base, DMAP and DABCO.11 Even though all these cata-
addition of acetone (a by-product of the desired reaction) to lysts afforded the corresponding 4a′ smoothly, they proved
alkylidene Meldrum’s acid 5 (Scheme 1, path c).9
ineffective for the decarboxylation of intermediate 4a′ at rt
To test the feasibility of the desired sequence, we carried under various solvent conditions and prolonged reaction times
out a model reaction of Meldrum’s acid 1, benzaldehyde 2a (Table 1, entries 2–10). The desired reaction did not work in
and Schiff’s base 3a [N-(diphenylmethylene)glycine tert-butyl polar solvents such as DMSO, DMF and water (Table 1, entries
ester] in the presence of 20 mol%10 of Lewis base11 such as 11–13).
Et3N as a catalyst in chloroform at rt (Table 1, entry 1). We
These results prompted us to explore the use of phase trans-
observed that alkylidene Meldrum’s acid 5a underwent further fer catalysis under alkaline conditions for the decarboxylation
reaction with Schiff’s base 3a to afford the undecarboxylated of intermediate acid 4a′. Surprisingly, the reaction of 1, 2a and
acid intermediate 4a′ in 72% yield after 24 h. It is interesting 3a in the presence of nBu4NBr (5 mol%) as a phase transfer
to note that the formal [3 + 2] cycloaddition product did not catalyst with a stoichiometric amount of base (NaOH, 1 equiv.)
form even after prolonged reaction time. Attempt to decarboxyl- in a water-rich biphasic solvent system was unsuccessful even
Table 1 Screening of catalysts and solventsa,b,c,d
Entry
Catalyst (mol%)
Solvent
4a Yieldb (%)
drc (trans/cis)
1
2
3
4
5
6
7
8
Et3N (20 mol%)
DBU (20 mol%)
DMAP (20 mol%)
DABCO (20 mol%)
iPrNEt2 (20 mol%)
iPrNEt2 (20 mol%)
iPrNEt2 (20 mol%)
iPrNEt2 (20 mol%)
iPrNEt2 (20 mol%)
iPrNEt2 (20 mol%)
iPrNEt2 (20 mol%)
iPrNEt2 (20 mol%)
iPrNEt2 (20 mol%)
nBu4NBr (5 mol%)
nBu4NBr (5 mol%)
—
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
ACN
THF
MTBE
Toluene
EtOAc
DMSO
DMF
Water
65
62
59
61
68
52
50
51
66
62
NR
NR
NR
NR
55
61
58
53
65
56
54
3.6 : 1
3.0 : 1
3.5 : 1
3.5 : 1
3.6 : 1
3.7 : 1
3.6 : 1
3.1 : 1
3.3 : 1
3.6 : 1
—
—
—
—
3.6 : 1
3.6 : 1
3.6 : 1
3.6 : 1
3.6 : 1
3.5 : 1
3.5 : 1
9
10
11
12
13
14d
15
16
17
18
19
20
21
H2O : toluene(5 : 1)d
H2O : toluene(5 : 1)
H2O : toluene(5 : 1)
Toluene
CHCl3
EtOAc
MeCN
MTBE
—
—
—
—
—
a Reaction conditions: Meldrum’s acid 1 (1.4 mmol, 1 equiv.), benzaldehyde 2a (1.47 mmol, 1.05 equiv.), Schiff’s base 3a (2.1 mmol, 1.5 equiv.)
catalyst (5–20 mol%), various solvents at rt for 24 h, then base/acid workup followed by reflux in toluene for 6 h for decarboxylation. b Isolated
yield after purification by column chromatography. c dr was calculated by 1H NMR. d 1 equiv. of NaOH used. NR-No reaction.
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after prolonged reaction time (Table 1, entry 14). We conclude result established the catalytic role of Meldrum’s acid 1 in the
that the desired Knoevenagel condensation did not proceed to reaction pathway or its necessity in the hydrolysis of Schiff’s
afford 5a because of the requirement for the acid catalysis base 3a.
from Meldrum’s acid 1 (pKa 4.9),6b voided by the addition of
To understand the role of in situ generated water during the
NaOH. However, it is interesting to note that acid intermediate reaction, we performed the reaction in the presence of mole-
4a′ was isolated in 66% yield when a neutral phase transfer cular sieves (4 Å). We observed that Meldrum’s acid 1 was com-
condition was employed without addition of a strong base.13 pletely consumed to afford the intermediate 6a (confirmed by
Subsequently, isolated acid 4a′ was refluxed in toluene to HRMS, see ESI, section 1†) in 6 h. We believe that a trace
obtain the desired product 4a in 55% yield with good amount of primary amine 3a′ present along with starting
diastereoselectivity (Table 1, entry 15). These results suggest material 3a may have catalyzed the reaction to form intermedi-
that the desired reaction may proceed under neutral con- ate 6a in the absence of water. Attempts to isolate 6a using
ditions without additional catalysis to furnish intermediate chromatography (silica gel) only resulted in compound 4a′.
4a′. This conclusion was further supported by the fact that
Based on the experimental evidence, we propose that slow
reaction proceeded smoothly in the absence of any external hydrolysis of Schiff’s base 3a generates primary amine catalyst
catalyst or base to afford the intermediate 4a′ and eventually tert-butyl glycinate 3a′ that catalyzes the Knoevenagel conden-
affording desired product 4a with good yield (Table 1, sation of Meldrum’s acid 1 and benzaldehyde 2a to generate
entry 16).
Knoevenagel product 5a. The Michael addition of Schiff’s base
These results led us to believe that the reaction is catalyzed 3a to 5a affords intermediate 6a. Further, the acidic nature of
by the trace amount of primary amine catalyst 3a′ which may the reaction medium initiates hydrolysis followed by lactami-
be present along with the starting material 3a or due to zation of intermediate 6a to afford undecarboxylated pyroglu-
primary amine catalyst 3a′ generating in situ via hydrolysis of tamate ester 4a′ (Scheme 2). We surmise that further acid cata-
Schiff’s base 3a (Scheme 2). We surmise that relatively acidic lyzed conversion of intermediate 6a into carboxylic acid 4a′ is
Meldrum’s acid 1 may catalyze the hydrolysis of Schiff’s base probably autocatalytic14 involving acid 4a′ catalyzed hydrolysis
3a to afford the primary amine 3a′. of imine 6a [4a′ (pKa 3.93) is stronger acid than intermediate
In order to optimize the reaction conditions, we screened 6a (pKa 7.75) and Meldrum’s acid 1 (pKa 4.9)].
the reaction in different solvents (Table 1, entries 17–21) and
In order to understand further, we proposed to conduct
ethyl acetate proved to be the optimum solvent for the reaction kinetic analysis by monitoring on the yield of 4a′ during the
(using base/acid workup followed by refluxing in toluene for reaction by time dependent 1H-NMR.15 This analysis showed
6 h) to afford desired product 4a. While in situ formation of 4a′ that Meldrum’s acid 1 and benzaldehyde 2a were almost comple-
1
was confirmed by H NMR (see ESI, section 1†), the base/acid tely consumed within 15 min (see Appendix I, ESI, section 1†).
work up proved to be necessary for obtaining the intermediate We further observed that the formation of 4a′ proceeded
4a′ in good yield.
slowly at first leading to a rapid and significant increase in the
In order to investigate and validate the role of Meldrum’s yield of 4a′, whose, yield remained almost constant after 6 h
acid 1 for the hydrolysis of Schiff’s base 3a, we carried out a (see Appendix I, ESI, section 1†). We believe that the initial
reaction of Schiff’s base 3a, Meldrum’s acid 1 (1 equiv., pKa 4.9 slow hydrolysis of 6a is due to the low concentration of 4a′
in water) and a stoichiometric amount of water in ethyl (induction period, up to 1 h, see Fig. 1). However, the rate of
acetate. The reaction was monitored by time dependent proton hydrolysis of 6a and the subsequent formation of 4a′ increases
NMR spectroscopy. The formation of benzophenone over a rapidly with the increase in concentration of 4a′.
period of time clearly indicates that the hydrolysis of Schiff’s
The rate of formation of product 4a′ increased rapidly (after
base 3a in the reaction mixture (Scheme 2, see ESI, section 1† 1 h) and then levelled off, complimentary to the rise and fall
for NMR study). On the other hand, we did not observe the in the yield of intermediate 6a (Fig. 1, red and black curves).
hydrolysis of Schiff’s base 3a when stirred with water for a pro- These data show the yield of 4a′ follows a sigmoidal curve after
longed reaction time in the absence of Meldrum’s acid 1. This an induction period of 1 h, probably signature of the autocata-
lytic process. The addition of 4a′ (10 mol%) to the reaction did
not discernibly reduce the initial lag period,14b though this
might have been a consequence of experimental time limit-
ation. It seems likely that the required acidic environment
must be present from the outset to initiate hydrolysis of inter-
mediate 6a and this may be provided by Meldrum’s acid 1 and
later during the course of the reaction by 4a′. The result of
kinetic analysis is in accordance with the experimental results
on yields.
Having optimized reaction conditions in hand, the scope of
the KMHL-D three component reaction was investigated by the
use of a range of aldehydes (2a–2t) and two Schiff’s bases
Scheme 2 Plausible reaction mechanism.
(3a, 3b) (Table 2 ).
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Scheme 3 Deprotection of ester.
hydes such as 1/2-naphthaldehyde (2o and 2p) and heteroaro-
matic aldehydes such as 2-furfural (2q) and 2-thiophenecar-
boxaldehyde (2r) reacted smoothly to afford 4o–4r in good
yields (up to 65%) with diastereoselectivity up to >20 : 1. In
order to explore a wider scope for this method, the reaction
was performed with aliphatic aldehydes. This was successful,
even for enolizable aldehydes such as propanal and isovaler-
aldehyde leading to the corresponding pyroglutamic esters
(4s–4t) albeit in more modest yields (up to 41%) and with
limited diastereoselectivity (up to 2 : 1 dr). Use of the benzyl
ester of Schiff’s base 3b also proved to be viable, providing
product 4u with moderate yield (56%) with good diastereo-
selectivity (10 : 1). The practicality of the method was demon-
strated by gram scale syntheses of compounds 4a (55% yield)
and 4h (59% yield). The trans stereochemistry of the major
isomers of the compounds 4b–4u was assigned based by
analogy to that of compound 4a.
Fig. 1 1H NMR analysis of the formation of 4a’. 1H-NMR kinetic experi-
ments for the reaction of Meldrum’s acid 1 (300 mg, 2.08 mmol), benz-
aldehyde 2a (225 µL, 2.2 mmol), Schiff’s base 3a (800 mg, 2.7 mmol) and
1,3,5-trimethoxy benzene (350.1 mg, 2.08 mmol, as an internal standard)
in 8 mL ethyl acetate at room temperature (25 °C). To quantify the time
course of this reaction, we followed the production of 4a’ by 1H NMR
spectroscopy. Aliquots were sampled at various time intervals, solvent
(EtOAc) evaporated, and the residue dissolved in CDCl3 for NMR
analysis.
Table 2 Substrate scopea,b,c
In order to demonstrate the practical utility of the protocol,
pyroglutamic acid derivative 8 was prepared starting from pyro-
glutamic benzyl ester 4u under hydrogenolytic conditions
(Scheme 3).16
Conclusions
We have developed a simple, practical and mild protocol to
access 3-substituted pyroglutamic acid derivatives using an un-
precedented
Knoevenagel–Michael-hydrolysis-lactamization-
decarboxylation (KMHL-D) sequence. The reaction works well
in the absence of external catalyst or facilitating reagent. This
novel one pot protocol tolerates a wide variety of aldehydes
including enolizable aliphatic aldehydes under mild reaction
conditions. The enantioselective development of this reaction
is in progress.
a Reaction conditions: Meldrum’s acid 1 (1.4 mmol, 1 equiv.), aldehyde
2 (1.47 mmol, 1.05 equiv.), Schiff’s base 3 (2.1 mmol, 1.5 equiv.) in
EtOAc at rt, 24 h then then base/acid workup followed by reflux in
toluene for 6 h for decarboxylation. b Isolated yield after purification
by column chromatography. c dr calculated by 1H NMR.
Experimental section
General methods
Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without purification.
Different aromatic aldehydes containing electron-donating Meldrum’s acid was purchased from Spectrochem. Aldehydes
and -withdrawing functional groups led to the corresponding and ketones were purchased from Aldrich, Spectrochem and
desired pyroglutamic esters (4b–4n) in moderate to good yields Alfa-aeser. Compounds 3a and 3b were prepared according to
(up to 72% yield) with moderate to excellent diastereo- reported procedure.17 All reactions were carried out in oven
selectivity (up to >20 : 1 dr). Similarly, bicyclic aromatic alde- dried glassware. Thin-layer chromatography (TLC) was per-
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formed using silica gel 60 GF254 pre-coated aluminum backed
plates (2.5 mm). Visualization was accomplished by examin-
Conflicts of interest
ation under UV light at 254 nm and/or ninhydrin stain. There are no conflicts to declare.
Column chromatography was performed using silica gel
(200–300 mesh) eluting with petroleum ether and ethyl
acetate. NMR spectra were recorded with tetramethylsilane as
1
Acknowledgements
internal standard. H NMR spectra were recorded at 400 MHz,
and 13C NMR spectra were recorded at 100 MHz (Bruker and
R. G. B. thanks DST-SERB (EMR/2015/000909), Govt. of India
for a generous research grant. T. M. K. and A. D. S. thank
CSIR, New Delhi for fellowship. P. K. W. thanks UGC, New
Delhi for a fellowship. The authors thank IISER Pune for finan-
cial assistance.
Jeol). Chemical shifts (δ) are reported in ppm downfield from
CDCl3 (δ = 7.26 ppm) and CD3OD (δ = 4.87 and 3.31 ppm) for
1H NMR and relative to the central CDCl3 resonance (δ =
77.16 ppm) and CD3OD (δ = 49.00) for 13C NMR spectroscopy.
Coupling constants (J) are given in Hz. IR spectra were
obtained using a FT-IR spectrophotometer as neat and are
reported in cm−1. Samples were analyzed by high-resolution
mass spectrometry using ESI TOF.
Notes and references
General procedure for the synthesis of 3-substituted
pyroglutamic acid derivative 4
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In an oven-dried 10 mL round bottom flask with a Teflon-
coated stir bar, Meldrum’s acid 1 (200 mg, 1.39 mmol,
1 equiv.) was dissolved in 6 mL of EtOAc. Then benzaldehyde
2a (150 µL, 1.47 mmol, 1.06 equiv.) and Schiff’s base 3a
(532.9 mg, 1.8 mmol, 1.3 equiv.) were added and the reaction
mixture was stirred for 24 h at rt. On completion of the reac-
tion (monitored by TLC), the reaction mixture was directly
transferred in to a separating funnel and portioned between
saturated aq. NaHCO3 solution (25 mL) and EtOAc (20 mL).
The aqueous layer containing pyroglutamic acid derivative 4a′
was separated and the bicarbonate extraction repeated twice.
The combined aqueous layers were acidified with 1 N aq. HCl
solution till solution became turbid (pH ∼2). After which, the
pyroglutamic acid derivative 4a′ was then back-extracted with
EtOAc (3 × 20 mL) and the combined organic layers were
washed with brine and dried over anhydrous Na2SO4. The
organic extract was evaporated under vacuum to afford 4a′.
The crude pyroglutamic acid derivative 4a′ was dissolved in
2 mL toluene and refluxed for 6 h in order to effect complete
decarboxylation (monitored by TLC). Toluene was then
evaporated and the crude product 4a purified by column
chromatography on silica gel using petroleum ether/ethyl
acetate as eluent. Product 4a was obtained as a white solid in
65% yield.
trans-tert-Butyl 5-oxo-3-phenylpyrrolidine-2-carboxylate (4a).
Compound 4a was synthesized following the general procedure
and was obtained as white solid (235 mg, 65% trans/cis; 3.6 : 1,
after recrystallization from DCM/n-hexane solvent system trans/
cis 20 : 1).
M.p. 110–112 °C. 1H NMR (400 MHz, CDCl3) δ 7.38–7.34
(m, 2H), 7.30–7.26 (m, 3H), 6.31 (s, 1H), 4.15 (d, J = 6.0 Hz,
1H), 3.68–3.63 (m, 1H), 2.85 (dd, J = 17.3, 9.5 Hz, 1H), 2.54 (dd,
J = 17.3, 7.4 Hz, 1H), 1.43 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ 176.5, 170.3, 141.9, 129.1, 127.6, 127.2, 82.8, 63.6, 44.4, 38.4,
28.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H20NO3
262.1443, found 262.1450. FTIR cm−1 (neat) 3233, 2978, 2927,
1702, 1453, 1370, 1236, 1154, 845.
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