Diastereoselective Synthesis of Functionalized 5-Amino-3,4-Dihydro-2H-Pyrrole-2-Carboxylic Acid Esters: One-Pot Approach Using Commercially Available Compounds and Benign Solvents

Article abstract of DOI:10.1002/chem.202005262

A novel three-step four-transformation approach to highly functionalized 5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid esters, starting from commercially available phenylsulfonylacetonitrile, aldehydes, and N-(diphenylmethylene)glycine tert-butyl ester

Full text of DOI:10.1002/chem.202005262

Communication
doi.org/10.1002/chem.202005262
Chemistry—A European Journal
&
Catalysis
Diastereoselective Synthesis of Functionalized 5-Amino-3,4-
Dihydro-2H-Pyrrole-2-Carboxylic Acid Esters: One-Pot Approach
Using Commercially Available Compounds and Benign Solvents
Sara Meninno,*[a] Mario Carratœ,[a] Jacob Overgaard,[b] and Alessandra Lattanzi*[a]
Abstract:
A novel three-step four-transformation ap-
proach to highly functionalized 5-amino-3,4-dihydro-2H-
pyrrole-2-carboxylic acid esters, starting from commercial-
ly available phenylsulfonylacetonitrile, aldehydes, and N-
(diphenylmethylene)glycine tert-butyl ester, was devel-
oped. The one-pot strategy delivered this class of ami-
dines bearing, for the first time, three contiguous stereo-
centers, in good to high yield and diastereoselectivity. The
entire sequence was carried out using diethyl carbonate
and 2-methyl tetrahydrofuran as benign solvents, operat-
ing under metal-free conditions. The process could be
conveniently scaled-up, and the synthetic utility of the
products was demonstrated.
Figure 1. Bioactive and natural products bearing the 5-amino-3,4-dihydro-
2H-pyrrole-2-carboxylic acid unit.
Compounds bearing the 2-amino-1-pyrroline core are of signif-
icant interest in the area of medicinal chemistry, being a class
of small cyclic amidines with rigid non-planar scaffold, suitable
for the inhibition of the b-secretase 1 (BACE1),[1] an enzyme in-
volved in Alzheimer’s disease (Figure 1).[2] Moreover, the 5-
amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid unit is found in-
tegrated in natural pyrroloamide metabolites such as Norfor-
mycin and Anthelvencins A and B, exhibiting antivirus, antibac-
terial, and anthelmintic activities (Figure 1).
Scheme 1. Established stepwise approach to 5-amino-3,4-dihydro-2H-pyr-
role-2-carboxylic acid ester 1 and recent modification.
Application of 2-amino-1-pyrroline as ligands in metal cataly-
sis has been also reported.[4] The synthesis of amidines has
been largely explored over the years,[5] due to their wide appli-
cation in organic synthesis as strong bases/catalysts[6] and in-
termediates for the synthesis of heterocyclic compounds.
Among the cyclic amidines, the five-membered unit 5-amino-
3,4-dihydro-2H-pyrrole-2-carboxylic acid ester 1 has been exclu-
sively synthesized using pyroglutamic acid as the starting re-
agent, according to the approach illustrated in Scheme 1a.[8]
Although the three-step sequence provides key building-
block 1 in satisfactory overall yield, it has some limitations,
being unsuitable for any functionalization at positions 3 and 4
of the five-membered ring. Moreover, the stepwise approach
requires isolation of the intermediates along the sequence,
thus showing poor sustainability. Recently, Fustero and co-
workers reported an interesting stereoselective modification of
route a) adding a preliminary one-pot aza-Michael/lactamiza-
tion sequence, by reacting a-amino acid esters and trifluoro-
methyl crotonates (Scheme 1b).[9a] The procedure enabled the
formation of fluorinated derivatives, bearing a quaternary
center at position 2 and a tertiary stereocenter at position 3,
which proved to be potent BACE1 inhibitors.[9]
[a] Dr. S. Meninno, M. Carratœ, Prof. Dr. A. Lattanzi
Dipartimento di Chimica e Biologia “A. Zambelli”
Università di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano (Italy)
E-mail: smeninno@unisa.it
lattanzi@unisa.it
[b] Prof. Dr. J. Overgaard
Department of Chemistry, Aarhus University
Langelandsgade 140, 8000, Aarhus (Denmark)
Considering the paucity of synthetic strategies, one-pot ap-
proaches to new functionalized amidines of type 1, which pay
attention to environmental issues, would be highly desirable in
view of the utility of this scaffold in medicinal chemistry and
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202005262.
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biosynthetic studies.[10] Given our interest in the development
of stereoselective organocatalytic methodologies to prepare
heterocyclic compounds,[11] we envisaged a one-pot process
suitable to access 5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic
acid ester 5, functionalized at positions 3 and 4 (Scheme 2).
Table 1. Optimization study for the Michael addition and hydrolysis
step.[a]
[b]
Entry
Base
[mol%]
Solvent
t
[h]
d.r. 4’
Yield 5[c]
[%] (d.r.)[b]
5
1
2
3
4
5
6
7
8
9[d]
10[d]
11[d]
12[d]
13[d]
DABCO (20)
piperidine (20)
DMAP (20)
Cs2CO3 (20)
LiOH (20)
DIPEA (100)
DIPEA (100)
Et3N (100)
DIPEA (100)
DIPEA (100)
DIPEA (100)
DIPEA (100)
DIPEA (100)
THF
THF
THF
THF
THF
THF
THF
THF
24
77:23
n.d.
90:10
56:44
52:48
92:8
95:5
90:10
95:5
95:5
95:5
90:10
95:5
82 (77:23)
70 (52:48)
52 (89:11)
89 (50:50)
70 (54:46)
77 (91:9)
20 (95:5)
55 (90:10)
55 (95:5)
54 (95:5)
38 (95:5)
72 (90:10)
72 (95:5)
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
5
120
15
3
72
72
72
31
31
31
23
24
Scheme 2. One-pot approach to functionalized 5-amino-3,4-dihydro-2H-pyr-
role-2-carboxylic acid esters 5.
THF
AcOEt
MeTHF
EtOH
DEC
A base-promoted Knoevenagel condensation employing
commercially available aldehydes and aryl sulfonyl acetonitrile
would stereoselectively afford electron-poor alkene 2.[12] The
same reaction conditions would be suitable for the Michael ad-
dition of commercially available glycinate ester of benzophe-
none Schiff base to alkene 2. In situ mild acid hydrolysis of the
imine would give adduct 4, which according to previous
work[13] would undergo cyclization to 5-amino-3,4-dihydro-2H-
pyrrole-2-carboxylic acid ester 5 by NH2 attack onto the CN
group.
[a] Reaction conditions: 2a (0.1 mmol), 3 (0.12 mmol) in 0.2 mL of solvent.
In the hydrolysis step the reaction mixture was diluted in THF (0.5 mL)
and 60 mL of HCl 2n were added. [b] Determined by 1H NMR analysis on
the crude reaction mixture. [c] Yield of isolated product. [d] The Michael
reaction was carried out at 508C and at C=0.9m.
reoselectivity, which pleasingly improved up to 89:11 ratio (en-
tries 2 and 3). Inorganic bases, although being effective,
proved to be poorly stereoselective (entries 4 and 5). These
preliminary results prompted us to check tertiary amines in
order to achieve good levels of diastereoselectivity at stoichio-
metric loading. Pleasingly, sterically hindered N,N-disopropyl
ethyl amine (DIPEA) afforded 5a in 77% yield and 91:9 diaste-
reomeric ratio (d.r.) (entry 6). The tert-butyl ester glycinate ben-
zophenone Schiff base 3b was then reacted under the same
reaction conditions leading to 5b in 20% yield and 95:5 d.r.
(entry 7).
In this work, we report a first approach which enables to
functionalize positions 3 and 4 of the 5-amino-3,4-dihydro-2H-
pyrrole-2-carboxylic acid ester scaffold. A one-pot sequential
protocol has been conveniently developed using commercially
available reagents and benign solvents, exploiting a Knoevena-
gel condensation/Michael reaction/hydrolysis/cyclization se-
quence. The final heterocycles, which are of interest in differ-
ent areas, were selectively obtained in good to high yield and
diastereocontrol. Moreover, the sequence is scalable, and elab-
oration of the products has been demonstrated.
When using less sterically hindered triethyl amine under the
same reaction conditions, the conversion to product 5b in-
creased although a slightly decreased stereocontrol was ob-
served (entry 8). Finally, the first step was carried out at 508C
under more concentrated conditions using DIPEA (entry 9). In-
terestingly, the conversion increased after a shorter reaction
time and more importantly the stereoselectivity ratio was
maintained to 95:5. Under these conditions, the first step was
screened using more environmentally friendly solvents, such as
ethyl acetate, ethanol, 2-methyl tetrahydrofuran (MeTHF), and
diethyl carbonate (DEC) (entries 10–13). The solvents were
then removed under reduced pressure and the crude mixture
was hydrolyzed in THF under usual conditions. DEC was found
to be the most useful medium, providing compound 5b in
72% yield and 95:5 d.r. (entry 13).
At the outset of the study, model alkene 2a and ester glyci-
nate benzophenone Schiff bases 3 were reacted in order to
optimize the conjugate addition reaction to adduct 4’ by using
different bases (Table 1). The Michael addition was firstly per-
formed using ethyl ester glycinate benzophenone Schiff base
3a at room temperature in THF, followed by hydrolysis of the
crude mixture (entries 1–6). We were pleased to observe that
when using 20 mol% of 1,4-diazabicyclo[2.2.2]octane (DABCO),
the Michael addition proceeded satisfactorily to give the
adduct 4’a, which after treatment with 2n HCl underwent se-
1
lective cyclization to amidine 5a (entry 1). H NMR analysis of
the crude reaction mixtures of 4’a and 5a showed the pres-
ence of only two of out of four diastereomers, in 77:23 ratio,
which was maintained over the hydrolysis and cyclization
steps. The presence of the 2-imino tautomer 5’a of compoun-
d 5a was not observed, in agreement with previous data
(Scheme 2).[14] Piperidine and N,N-dimethylamino pyridine
(DMAP) provided the product with different efficiency and ste-
The structure and the relative configuration of the three ste-
reocenters were confirmed by single-crystal X-ray analysis on
the major diastereoisomer, which enabled us to assign the
compound as (trans,trans)-5b isomer (Figure 2).
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Table 2. Optimization study for the one-pot approach starting from
model reagents.[a]
Entry
Solvent1, T1 [8C],
t1 [h]
Solvent2,
t2 [h]
Solvent3,
t3 [h]
Yield 5b[b]
[%]
d.r.
5b[c]
1
2
3
4
5
DEC, RT, 8
DMC, RT, 8
DMC, RT, 8
DEC, RT, 9
DEC, 50, 3.5
DEC, 22
DMC, 24
DMC, 29
DEC, 25
DEC, 21
THF, 1.5
THF, 1
MeTHF, 1
DEC, 31
MeTHF, 1
75
75
77
66
77
92:8
88:12
90:10
94:6
Figure 2. ORTEP-drawing of the molecular structure of the major diastereo-
isomer (Æ)-5b with ellipsoids shown at 50% probability level. Color code:
oxygen (red), nitrogen (blue), sulfur (yellow), carbon (grey), hydrogen
(white).
92:8
[a] Reaction conditions: benzaldehyde (0.15 mmol), (phenylsulfonyl)aceto-
nitrile (0.15 mmol) DIPEA (0.15 mmol) in 150 mL of solvent. In the second
step 3b (0.18 mmol). After ending of Michael addition, DEC or DMC was
removed under reduced pressure. In the hydrolysis step the reaction mix-
ture was dissolved in THF or MeTHF (0.75 mL) and 100 mL of HCl 2N were
added. [b] Yield of isolated product. [c] Determined by 1H NMR analysis
on the crude reaction mixture.
Further optimization was then carried out starting from
commercially available benzaldehyde and phenyl sulfonylace-
tonitrile to include the Knoevenagel condensation step into
the one-pot procedure (Table 2). DEC was
used as the solvent for the condensation to
form the alkene at room temperature in the
presence of 1 equivalent of DIPEA (entry 1).
After the reagents were converted into
alkene 2a, compound 3b was added accord-
ing to the conditions reported in entry 13 of
Table 1.
Product 5b was isolated in 75% yield and
92:8 d.r. The same sequence performed in di-
methyl carbonate (DMC) for the first and
second step furnished compound 5b in
good yield but slightly reduced diastereose-
lectivity (entry 2). When THF was replaced by
more convenient MeTHF in the hydrolysis
and cyclization steps, the product 5b was re-
covered in 77% yield and 90:10 d.r. (entry 3).
The sequence was then entirely carried out
in DEC, which demonstrated to be the most
effective solvent for the stereocontrol
(entry 4). However, hydrolysis and cyclization
proceeded rather slowly and after a pro-
longed reaction time, product 5b was isolat-
ed in 66% yield. Finally, the reaction condi-
tions reported in entry 1 were modified re-
placing THF with MeTHF and performing the
Knoevenagel condensation at 508C (entry 5).
In this case, shorter reaction times could be
applied for the overall process and amidine
5b was recovered in 77% overall yield and
92:8 d.r.
Under conditions illustrated in entry 5 of
Table 2, the scope of the one-pot process
was next investigated (Figure 3). The protocol
appeared to be of general application start-
ing from differently substituted aromatic and
heteroaromatic aldehydes. Cyclic amidines
5c–f, bearing electron-withdrawing groups
Figure 3. Substrate scope in the synthesis of heterocycles 5. Reaction conditions: phenyl sulfonyla-
cetonitrile (0.15 mmol), aldehyde (0.15 mmol), DIPEA (0.15 mmol) in 150 mL of DEC at 508C until
disappearance of reagents. Then 3b (0.18 mmol) was added. After ending of Michael addition,
DEC was removed under reduced pressure. In the hydrolysis step, the reaction mixture was dis-
solved in MeTHF (0.75 mL) and 100 mL of HCl 2n were added. Yields refer to isolated product. d.r.
1
was determined by H NMR analysis on the crude reaction mixture. [a] t1 =16 h. [b] t1 =21 h. [c] t1,
t2 =2 h, 216 h.
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at para, meta, and ortho positions of the aromatic ring, were
isolated in good overall yield and high diastereoselectivity.
Compounds 5g–k, bearing electron-donating substituents in
the aromatic ring, were obtained in excellent overall yields (up
to 89%) and high diastereoselectivity. Interestingly, doubly
substituted starting aromatic aldehydes were smoothly con-
verted into the corresponding products 5l–n with high to ex-
cellent level of diastereocontrol (d.r. up to 97:3). Finally, cyclic
amidines 5o--s, bearing 2-naphthyl or oxygen-, sulfur-, and ni-
trogen-containing heteroaromatic moieties at position 3 of the
five-membered ring, were prepared in satisfactory yields and
moderate to high diastereoselectivity. It is important to point
out that the protocol can be effectively applied to incorporate
cheap and renewable platform molecules derived from bio-
mass, such as furfural and hydroxymethylfurfural, into amidines
of high added value (5p,q). The heterocyclic compounds 5p,q
were isolated in satisfactory overall yield and d.r., considering
the susceptibility of furfural and hydroxymethylfurfural to de-
composition. The protocol has some limitations when applied
to aliphatic aldehydes, which are known to suffer of competi-
tive pathways in the Knoevenagel condensation, affording the
alkenes in very low yields.[12b,15]
tions, reagent 5 underwent a stereoablative process leading to
the formation of products 6 and 7, bearing a new endocyclic
C=C double bond.[16]
Formation of the trans,trans-5 diastereoisomer has been ra-
tionalized assuming the involvement of an open transition
state in the Michael addition step (Scheme 4). The diastereo-
chemical outcome of the process is established in the Michael
addition step, since according to results reported in Table 1,
the diastereoselectivity is maintained after hydrolysis and cycli-
zation. Given the sterically demanding base used, the diaste-
reoselectivity would be consistent with an open transition
state model, where the trisubstituted alkene is attacked by the
(E)-N-protected glycine enolate in a staggered conformation
about the forming CÀC bond. The unfavorable OR/PhSO2 inter-
action in TS-II, suggests that TS-I should be energetically pre-
ferred. Protonation of the adduct from the less sterically hin-
dered face would give major adduct-4’ (blue). Hydrolysis and
cyclization would then proceed to give the final trans,trans-
amidine 5 (blue), whose structure was confirmed by X-ray anal-
ysis. Post-functionalizations illustrated in Scheme 3 are in
agreement with this proposal. After acetylation of com-
pounds 5 as mixture of diastereomers, a single trans-isomer of
product 6 was obtained via stereoablative removal of the epi-
meric stereocenter, as confirmed by single-crystal X-ray analy-
sis.
To verify the applicability of the process, model reaction was
scaled up at 1 g of phenyl sulfonylacetonitrile (Scheme 3).
Pleasingly, at the end of the process after aqueous work-up,
the crude mixture was crystallized in EtOH affording pure
major trans,trans-5b in 60% yield. Finally, post-functionaliza-
tions on the amidine reactive group using diastereomeric
mixtures of selected compounds 5b,c,i were performed
(Scheme 3). Under acetylation conditions compounds 5b,c,i
were converted into product 6a,b,c in 69, 72 and 53% yield as
the sole diastereoisomer, respectively. The structure of com-
pounds trans-6 was confirmed by single-crystal X-ray analysis
on diastereoisomer 6b. More interestingly, after treating model
amidine 5b with methyl acrylate, a single diastereoisomer of
the bicyclic product 7 was obtained in 69% yield, via an aza-
Michael addition/lactamization sequence. In all the elabora-
In summary, a novel and straightforward approach to func-
tionalized 5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid
esters has been efficiently developed. The process exploits a
Knoevenagel condensation/Michael addition/hydrolysis/cycliza-
tion sequence in a single flask to access libraries of cyclic ami-
dines of potential utility in medicinal chemistry. Cyclic amidines
are isolated in good to high yield and generally high diastereo-
selectivity. The feasibility of a convenient scale up procedure,
enabling the isolation of pure major diastereomer, has been
demonstrated. Of note, this one-pot protocol employs all com-
mercially available materials, green and biodegradable solvents
derived from renewable sources. Further investigations to
extend the one-pot approach to other suitable cyano-contain-
ing reagents are underway in our laboratory.
Scheme 3. Scale-up procedure and post-functionalizations of 5-amino-3,4-di-
hydro-2H-pyrrole-2-carboxylic acid esters 5. Only the major isomer of the
epimeric mixture at C-4 of compounds 5 is shown (5b d.r. 92:8; 5c d.r.
90:10; 5i d.r. 94:6).
Scheme 4. Proposed stereochemical outcome of the one-pot sequence.
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Zhou, P. Tian, Angew. Chem. Int. Ed. 2020, 59, 8004–8014; Angew. Chem.
2020, 132, 8080–8090.
Acknowledgements
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This work was supported by MUR and University of Salerno.
We thank the referees for useful suggestions. S.M. thanks MUR
and European Union for AIM— International attraction and mo-
bility call for researchers funded by PON RI 2014-2020.
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Keywords: amidines · diastereoselectivity · green solvents ·
metal-free · one-pot reaction
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Manuscript received: December 9, 2020
Revised manuscript received: January 18, 2021
Accepted manuscript online: January 19, 2021
[6] For reviews, see: a) J. E. Taylor, S. D. Bull, J. M. J. Williams, Chem. Soc. Rev.
2012, 41, 2109–2121; b) Y.-H. Wang, Z.-Y. Cao, Q.-H. Li, G.-Q. Lin, J.
Version of record online: February 11, 2021
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