One-pot highly diastereoselective annulation to N-unprotected tetrasubstituted 2-pyrrolines

Article abstract of DOI:10.1039/c4gc02191f

A one-pot DABCO-catalysed Michael addition of glycine imine-derived esters to trans-2-aroyl-3-arylacrylonitriles followed by a deprotection/cyclization/tautomerization sequence afforded tetrasubstituted N-unprotected trans-2-pyrrolines in up to 96% yield.

Full text of DOI:10.1039/c4gc02191f

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DOI: 10.1039/C4GC02191F
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One-pot highly diastereoselective annulation to N-
unprotected tetrasubstituted 2-pyrrolines
Cite this: DOI: 10.1039/x0xx00000x
Sara Meninno, Amedeo Capobianco, Andrea Peluso and Alessandra Lattanzi*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
reactions,7 metal-catalysed reactions,8 Michael addition/cyclization
A one-pot DABCO-catalysed Michael addition of glycine
imine-derived esters to trans-2-aroyl-3-arylacrylonitriles
sequence9 mainly giving access to di- and trisubstituted N-protected
2-pyrrolines.
followed by
a
deprotection/cyclization/tautomerization
The development of novel one-pot processes to obtain 2-pyrrolines
is highly desirable and attractive in terms of sustainability and
advantageous in terms of time, costs saving issues and minimal
manual operations. Being interested in the stereoselective synthesis
of a variety of heterocyclic compounds10 and inspired by reports on
stereoselective Michael addition reactions of glycine-derived imine
esters to ,-unsaturated ketones,11 we focused our efforts on the
sequence afforded tetrasubstituted
pyrrolines in up to 96% yield.
N-unprotected trans-2-
Among the nitrogen containing heterocycles, pyrrolines
(dihydropyrroles) are important structural moieties present in several
biologically active compounds and pharmaceuticals.1 Illustrative
examples are spirotryprostatin B 1, isolated from fermentation of
Aspergillus fumigatus BM939,2 showing growth inhibition toward
leukemia K562 and HL-60 cells, antramicin 2, isolated from
actinomycetes with significant sequence-selective DNA-alkylation
activity3 and synthetic tetrasubstitued 2-pyrrolidine 3-(±) showing
antiproliferative activity towards HeLa and MCF7/AZ cell lines
(Figure 1).4
development of
a convenient route to obtain challenging
tetrasubstituted N-unprotected 2-pyrrolines of type 6 (Scheme 1).
Herein we illustrate the feasibility of a sequential one-pot DABCO-
catalyzed Michael addition/deprotection/cyclization/tautomerization
approach starting from readily accessible glycine imine esters 4 and
trans-2-aroyl-3-arylacrylonitriles 5. trans-2-Pyrrolines 6 have been
isolated in good yield and high diastereoselectivity (Scheme 1).
Scheme 1 One‐pot sequential approach to trans‐2‐pyrrolines 6.
Herein, we also show that 2-pyrrolines 6 can be transformed by
oxidation or reduction into the corresponding fully substituted
pyrroles or pyrrolidines, respectively.
Alkene 5a and t-butyl ester glycinate benzophenone Schiff base 4a
were selected as model substrates to study the process, using
different amines as the catalyst (Table 1). First, the Michael addition
reaction was carried out for 20 h using 20 mol % loading of a base in
toluene as solvent (entries 1-6). Then the solvent was removed under
vacuum and the crude mixture was dissolved in THF at 0°C
followed by HCl 1N addition and stirring up to room temperature for
1 h. Secondary bases led to the formation of the expected product 6a
Fig. 1 Examples of naturally occurring and biologically active 2‐pyrrolines.
Pyrrolines have also been used as key-intermediates in total
synthesis of natural products and to access other classes of important
heterocycles such as pyrrolidines and pyrroles.5 A variety of studies
focused on approaches to obtain 3-pyrrolines,6 whereas
comparatively less attention has been devoted to the synthesis of 2-
pyrrolines. The most successful routes are centered on cycloaddition
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1‐3 | 1

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a All reactions were carried out using 5 (0.1 mmol), 4a (0.1 mmol), DABCO
(20 mol %), solvent (200 L) for the indicated time; then additional 200 L
in moderate yield and complete control of the diastereoselectivity for
the trans-isomer (entries 1 and 2).
b
of THF and 400 L of HCl (1N) were added at 0 °C. IsoVlaietwedArytiicelledOanflitneer
chromatography. c Determined by 1H-NMR analysDisO. I: 10.1039/C4GC02191F
Table 1. Optimization of the reaction conditionsa
Under the optimized conditions we studied the substrate scope of the
process by reacting a variety of alkenes 5 with compound 4a in the
presence of 20 mol% of DABCO in THF at room temperature (Table
2).
-Phenyl substituted alkenes with either electron-rich or electron-
poor groups at different positions were smoothly converted into the
corresponding trans-2-pyrrolines in good yields (entries 1-8).
Substitution is well-tolerated either at the aroyl portion and at the -
phenyl ring (entries 9-10).
Replacing the phenyl ketone with an aliphatic ketone as in alkene 4l
did not cause any detriment to the reaction sequence (entry 11),
whereas alkyl substitution at the -position of the alkene was found
to be detrimental for the reactivity (entry 12).
The feasibility of a one-pot telescoped synthesis of trans-2-
pyrrolines, starting directly from commercially available
benzaldehydes 7, aroylacetonitriles 8 and DABCO, via Knoevenagel
condensation/Michael
addition/deprotection/cyclization/tautomerization sequence has been
also demonstrated (Table 3).
Entry
Base
Solvent
Yield 6
trans/cis
4
(%)b
(%)b
1
2
pyrrolidine
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
THF
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
64
55
>20/<1
>20/<1
>20/<1
>20/<1
>20/<1
>20/1
2-piperidinemethanol
triethylamine
3
29
4
DABCO
DBU
90(83)
54
5
6
t-BuOK
DABCO
DABCO
DABCO
DABCO
DABCO
25
7c
8c
9c
10c
11c
46
>20/1
88(80)
88
>20/1
CH3CN
CH3OH
THF
>20/1
35
>20/1
Table 3. One-pot sequential synthesis of trans-2-pyrrolines
6
from
(74)
>20/1
commercially available aldehydes and aroylacetonitrilesa
a
All reactions were carried out using 5a (0.1 mmol), 4 (0.1 mmol), base (20
mol %), solvent (200 L) for 20 h; then additional 200 L of THF and 400
L of HCl (1N) were added at 0 °C. b Determined by 1H-NMR analysis of the
crude reaction mixture with an internal standard. Value in parenthesis
corresponds to isolated yield. c Reaction time for the first step was 16 h.
Among the tertiary bases tested (entries 3-5) DABCO afforded 2-
pyrroline 6a in good yield and high diastereoselectivity (entry 4). t-
BuOK proved to be a poor base for the process (entry 6). A solvent
screening for the first Michael addition step using DABCO as the
most effective base, showed THF to be as good as toluene (entry 8).
Being the most effective medium for all the steps, THF was chosen
as the reaction solvent to simplify the entire process. The reaction
performed with ethyl ester glycinate benzophenone Schiff base 4b
gave the trans-2-pyrroline 6b in slightly inferior yield (compare
entry 8 with entry 11).
Entry
R1
R2
Ph
t1,t2 (h)
Yield 6 (%)b
dr
(%)c
1
2
3
4
5
6
7
8
9
Ph
(4.5)(23)
(7)(24)
(6)(22)
(7)(22)
(7)(19)
(4)(21)
(6)(25)
(4)(24)
(5)(26)
6a
6c
6d
6f
77
70
60
82
73
62
55
70
66
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
Ph
4-t-BuC6H4
3-MeC6H4
Ph
Ph
Ph
4-BrC6H4
3-BrC6H4
4-NO2C6H4
2-naphthyl
Ph
6g
6h
6i
Ph
Ph
Table 2. One-pot diastereoselective annulation to trans-2-pyrrolines 6a
3-ClC6H4
4-MeOC6H4
6j
4-BrC6H4
6k
a
All reactions were carried out stirring 7 (0.25 mmol), 8 (0.25 mmol),
DABCO (20 mol %), solvent (500 L) and MS (20 mg) at 80 °C for the
indicated time (t1). The reaction mixture was cooled down at rt and 4a (0.25
mmol) was added, stirring maintained for the required time (t2). Toluene was
removed, the crude diluted with THF (1 mL) and then HCl (1N) (1 mL) was
added at 0 °C leaving the mixture to warm up to 30 °C. b Isolated yield after
chromatography. c Determined by 1H-NMR analysis.
Entry
R1
R2
Ph
time (h) Yield 6 (%)b dr (%)c
1
2
Ph
21
23
28
40
23
24
18
24
21
28
23
24
6a
6c
6d
6e
6f
96
68
78
77
75
68
80
50
58
75
87
-
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
-
Ph
4-t-BuC6H4
3-MeC6H4
The DABCO-catalysed Knoevenagel condensation was carried out
in toluene at 80 °C in the presence of molecular sieves. When the
conversion to alkenes 5 was almost complete, the mixture was
cooled down to room temperature and compound 4a was added. At
the end of the reaction, toluene was removed under vacuum, the
crude mixture diluted with THF before adding the HCl solution.
Pleasingly, trans-6 products were isolated in comparable yields than
those reported in Table 2, although the process could not be applied
to obtain product 6l.12 Notably, the one-pot process illustrated in
Table 3, is highly convenient as it embodies five steps and only three
3
Ph
4
Ph
Ph
2-MeC6H4
4-BrC6H4
3-BrC6H4
4-NO2C6H4
2-naphthyl
Ph
5
6
7
Ph
Ph
6g
6h
6i
8
Ph
9
3-ClC6H4
4-MeOC6H4
Ph(CH2)2
Ph
6j
10
11
12
4-BrC6H4
Ph
6k
6l
cyclohexyl
6m
2 | J. Name., 2012, 00, 1‐3
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operations: solvent evaporation, extraction and one column
purification.
Acknowledgements
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The synthetic utility of compounds 6 is exemplified by oxidation and
reduction to tetrasubstituted pyrroles and proline esters (Scheme
2).13
This work was supported financially by MIUR and Centro di Tecnologie
DOI: 10.1039/C4GC02191F
Integrate per la Salute (Project PONa3_00138), University of Salerno, for
600 MHz NMR instrumental time. We thank Dr. P. Iannece for assistance
with MS spectra analyses, Dr. P. Oliva with NMR spectroscopy and G.
Balistreri for experimental support.
Ph
CN
Ph
CN
DDQ
t-BuO2C
Ph
Ph
N
H
9
toluene/AcOEt 2:1
70 °C, 23 h
N
H
6a
t-BuO2C
Notes and references
78%
a Dipartimento di Chimica e Biologia, Università di Salerno, Via Giovanni
Paolo II, 84084, Fisciano, Italy. Fax:0039-089-969603; E-mail:
lattanzi@unisa.it
Ph
CN
Ph
CN
NaBH3CN
+
Electronic Supplementary Information (ESI) available: Experimental
procedures, characterization data and copies of NMR spectra for all new
compounds, computational details and predicted 1H-NMR chemical
shifts. See DOI: 10.1039/c000000x/
Ph
Ph
AcOH/CH2Cl2 1:1
0 °C, 2 h
N
N
H
t
-BuO C
t-BuO2C
2
H
11
10
74%, 10/11 70:30
Scheme 2 Derivatization of trans‐2‐pyrrolines to pyrroles and pyrrolidines.
1
For reviews, see: (a) E. Fattorusso and O. Taglialatela-Scafati,
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VCH: Weinheim, 2008; (b) F. Bellina and R. Rossi, Tetrahedron
2006, 62, 7213. For selected examples, see: (c) C. Marti and E. M.
Carreira, J. Am. Chem. Soc., 2005, 127, 11505.
The oxidation of compound 6a with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ), performed in toluene/AcOEt mixture at 70
°C, afforded pyrrole 9 in 78% yield. The reduction of 2-pyrroline 6a
was carried out using NaBH3CN in AcOH/CH2Cl2 medium at 0 °C.14
A mixture of proline esters 10 and 11 was isolated in 74% yield with
70:30 dr ratio.15 We have theoretically studied the reaction
mechanism and in agreement with indole reduction,13,16 the
protonation of the 4-position of compound 6a is the most plausible
event. The observed dr ratio can be traced back to the different free
energies of the two iminium ions I and II. According to DFT
computations, iminium ion I, giving rise to compound 10, is
predicted to be more stable by 1.5 kcal/mol than II, leading to
compound 11 (Fig. 2).
2
3
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Re-face.17
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Fig. 2 Protonated adducts of 6a and their predicted relative Gibbs free energies
(G, kcal/mol).
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diastereoselectivity. Notably, a one-pot sequence to trans-2-
pyrrolines can be conveniently applied starting directly from
4
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commercially available aldehydes and -cyanoketones. trans-2-
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12 DABCO did not catalyse the Knoevenagel reaction to compound 5l
.
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15 The relative configuration of the stereocentres for compounds 6a
,
10
1
and 11 were confirmed by NOESY experiments. Predicted H-NMR
chemical shifts of compounds 10 and 11 were also added (see the
ESI).
16 For hydrogenation of N-unprotected indoles and pyrroles under acidic
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805.
17 We anticipate that the most accessible TS for the reduction of iminium ion
leading to product 10 is predicted to be 4 kcal/mol more stable than TS
I
deriving from the attack of the reducing agent onto the Si-face, which
would lead to a product not observed experimentally.
4 | J. Name., 2012, 00, 1‐3
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DOI: 10.1039/C4GC02191F
An effective one-pot sequential Michael addition/deprotection/cyclization/tautomerization
approach to N-unprotected fully substituted trans-2-pyrrolines has been developed.