Efficient Synthesis of Highly Enantioenriched Δ1-Pyrrolines

Article abstract of DOI:10.1055/s-0034-1380144

A general and efficient asymmetric synthesis of Δ¹-pyrrolines by a one-pot nitro-reduction, cyclization, and dehydration of (R,E)-1,5-diphenyl-3-(nitromethyl)-5-pent-4-en-1-ones with iron and aqueous hydrochloric acid has been developed. The Δ¹-pyrrolines were obtained with excellent enantioselectivities (up to 99%) and high yields (up to 83%).

Full text of DOI:10.1055/s-0034-1380144

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 846–850
letter
846
D. I. S. P. Resende et al.
Letter
Synlett
Efficient Synthesis of Highly Enantioenriched Δ1-Pyrrolines
R1
O
Diana I. S. P. Resendea
Samuel Guieua,b
R1
N
NO2
R1
O
Cristina G. Oliva*a,1
Artur M. S. Silva*a
R2
THF–MeOH
(2:1, anhyd)
R3
+
Fe (activated)
AcOH
R2
38–83% yield
96–99% ee
O
R2
R3
a Department of Chemistry, QOPNA, University of Aveiro,
3810-193 Aveiro, Portugal
b Department of Chemistry, CICECO, University of Aveiro,
3810-193 Aveiro, Portugal
H
8 examples
R3
artur.silva@ua.pt
Received: 27.11.2014
Accepted after revision: 14.01.2015
Published online: 17.02.2015
logically active compounds such as hemes, chlorophylls and
alkaloids, and these rings have been used as building blocks
for the development of new drugs.4 Recently, our group re-
ported the synthesis of new boranil derivatives based on a
Δ1-pyrroline core leading to new fluorophores.5 The syn-
thesis of Δ1-pyrrolines is well documented2,4,6,7 and usually
involves reductive cyclization of γ-nitro carbonyl com-
pounds.8,9 However, asymmetric versions of these reactions
are scarce.10,11 Shibata et al.10 have recently reported the en-
antioselective synthesis of β-trifluoromethylated pyrrolines
through organocatalyzed-conjugate addition of nitrometh-
ane to β-trifluoromethylated enones, followed by a nitro-
reduction, cyclization and dehydration sequence in a one-
pot procedure. Despite the very straightforward methodol-
ogy, the need for a trifluoromethyl group restricts its scope
and limits its application to particular cases.
DOI: 10.1055/s-0034-1380144; Art ID: st-2014-d0977-l
Abstract A general and efficient asymmetric synthesis of Δ1-pyrrolines
by a one-pot nitro-reduction, cyclization, and dehydration of (R,E)-1,5-
diphenyl-3-(nitromethyl)-5-pent-4-en-1-ones with iron and aqueous
hydrochloric acid has been developed. The Δ1-pyrrolines were obtained
with excellent enantioselectivities (up to 99%) and high yields (up to
83%).
Key words pyrrolines, reductive cyclization, Michael addition, stereo-
selectivity
Nitrogen-containing heterocycles are important core
structures in natural and synthetic biologically active com-
pounds.2,3 In particular, 3,4-dihydro-2H-pyrroles,4 also
called Δ1-pyrrolines, can be found in a wide variety of bio-
R1
O
NO2
R1
O
MeNO2
R2
R3
R2
R3
2
1
(R)-3
R1 = H, OH, NH2
R2 = H, Me, OMe, Cl, Br, F, CN
3 = H, OMe, NO2
yield 19–97%; ee 87–99%
after recrystallization ee > 99%
Et
R
OMe
N
H
NH
N
CF3
N
S
CF3
organocatalyst 2
Scheme 1 Enantioselective addition of nitromethane to (E,E)-1,5-diarylpenta-2,4-dien-1-ones 1 organocatalyzed by 2
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 846–850

847
D. I. S. P. Resende et al.
Letter
Synlett
Table 1 Screening of Reduction Methods on the One-Pot Nitro-Reduction, Cyclization and Dehydration of (R)-3a
Entry
Conditions
Temp. (°C)
Time (h)
Yield (%)
(R)-4a
(R)-5a
1a
2b
3c
4c
5c
6c
DMF–H2O (1:1), Zn, conc. HCl
80
r.t.
65
65
65
80
30
15
15
15
15
15
5
31
58
63
72
36
15
35
10
17
8
CHCl3, Sn, concd HCl
THF–MeOH (2:1), Fe, AcOH
THF–MeOH (2:1), Fe (activated), AcOH
THF–MeOH (2:1, anhyd), Fe (activated), AcOH
THF–MeOH (2:1), Fe (activated), AcOH
14
a Reaction conditions: 3a (0.169 mmol), concd HCl (0.34 mL), Zn powder (0.846 mmol), DMF–H2O (1:1, 0.34 mL), 80 °C, 30 h.
b Reaction conditions: 3a (0.169 mmol), concd HCl (5.6 mL), Sn powder (14.0 mmol), CHCl3 (15 mL), r.t., 15 h.
c Reaction conditions: 3a (0.31 mmol), AcOH (4.98 mmol), Fe (14.0 mmol), THF–MeOH (2:1, 6 mL), 65 °C, 15 h, nitrogen atmosphere.
N
Recent studies in our laboratory have led to the develop-
ment of a new methodology for the asymmetric 1,4-Mi-
NO2
O
chael addition of nitromethane to 1,5-diarylpenta-2,4-
(R)-4a
dien-1-ones 1 (Scheme 1).12,13 In the presence of organocat-
Reductant
+
alyst 2, (R,E)-1,5-diaryl-3-(nitromethyl)-5-pent-4-en-1-
ones (R)-3 have been obtained with excellent enantioselec-
tivity (up to 99%) and isolated yields (up to 97%). We then
wished to go one step further, and use these enantiomeri-
cally pure compounds for the synthesis of enantiopure Δ1-
pyrroline derivatives. In this communication, we present a
general methodology for the synthesis of several highly en-
antioenriched Δ1-pyrroline derivatives through a one-pot,
nitro-reduction, cyclization, dehydration of the (R,E)-1,5-
diaryl-3-(nitromethyl)-5-pent-4-en-1-ones 3.
–O
N
(R)-3a
Reductant: Zn, Sn, Fe, Pd/C-HCO2NH4
(R)-5a
Scheme 2 Reduction methods tested on the one-pot nitro-reduction,
cyclization, dehydration of (R,E)-1,5-diaryl-3-(nitromethyl)-5-pent-4-
en-1-ones 3
To investigate the reactivity of the (R,E)-1,5-diaryl-3-
(nitromethyl)-5-pent-4-en-1-ones 3 towards the reductive
cyclization of the nitro group, our investigation began with
a screening of metal-mediated reduction methods that have
already been described (Scheme 2,Table 1).9,10,14 The first
two reductive systems examined involved Zn/HCl (entry 1)
and Sn/HCl (entry 2) and the Δ1-pyrroline 4a was obtained
in low yields (5–31%). Nevertheless, through HPLC analysis,
it was possible to note the absence of racemization of the
asymmetric carbon, which allowed us to obtain Δ1-pyrro-
line 4a in excellent enantiomeric excess (>99%). However,
formation of the corresponding Δ1-pyrroline-N-oxide 5a
was also observed, in amounts higher than the desired
product. Finally, reduction with Fe/AcOH provided better
results, and Δ1-pyrroline 4a was obtained in good yield (en-
try 3). Further studies on the influence of the temperature,
absence of water and oxygen, as well as the use of preacti-
vated iron15 were performed (entries 4–6). The best results
were obtained by using a mixture of anhydrous tetrahydro-
furan and methanol (2:1) under nitrogen, activated iron (14
mmol) as reducing agent, and acetic acid (4.98 mmol) as a
proton source.
It is worth mentioning that, under these conditions, not
only was the Δ1-pyrroline 4a obtained in a very good yield
(72%), but the formation of Δ1-pyrroline-N-oxide 5a was re-
duced to only 8% yield.
Table 2 Scope of the One-Pot Nitro-Reduction, Cyclization and Dehy-
dration of 3a
Entry
3
R1
R2
Yield (R)-4 ee (R)-4
(%) (%)
Yield (R)-5
(%)
1
2
3
4
5
6
7
3b
3c
3d
3e
3f
Me
H
83
>99
6
11
5
OMe
Cl
H
73
49
67
44
40b
38
>99
>99
>99
>99
>99
>99
H
F
H
6
Br
H
9
3g
3h
NO2
H
H
0c
4
OMe
a Reaction conditions: 3b–h (0.31 mmol), AcOH (4.98 mmol), Fe (14.0
mmol), THF–MeOH (2:1, 6 mL), 65 °C, 15 h, nitrogen atmosphere.
b (R,E)-2-(4-Aminophenyl)-4-styryl-Δ1-pyrroline (4g) was obtained.
c (R,E)-1-(4-Aminophenyl)-3-(nitromethyl)-5-phenyl-5-pent-4-en-1-one (3i)
was obtained in 57% yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 846–850

848
D. I. S. P. Resende et al.
Letter
Synlett
After establishing these optimal reaction conditions, the
scope of the reaction was investigated by using a range of
derivatives 3b–h (Scheme 3,Table 2). The Δ1-pyrrolines (R)-
4b–h16 were obtained in moderate to good yields (38–83%)
and excellent enantiomeric excesses (99%) for all the syn-
thesized derivatives (entries 1–7).
In the case of nitro derivative 3g (Table 2, entry 6), it
was observed that reduction of the aromatic nitro group re-
sulted in the formation of (R,E)-2-(4-aminophenyl)-4-sty-
ryl-Δ1-pyrroline (4g). Furthermore, for this derivative,
the corresponding N-oxide (R)-5 was not formed; instead,
(R,E)-1-(4-aminophenyl)-3-(nitromethyl)-5-phenyl-5-pent-
4-en-1-one (3i) was obtained.
The mechanism for the formation of Δ1-pyrrolines 4 in-
volves reduction of the nitro group to the corresponding
amine intermediate II, which, after a cyclization and dehy-
dration sequence, affords the desired products. On the oth-
er hand, formation of Δ1-pyrroline-N-oxides 5 as by-prod-
ucts results from cyclization of the partially reduced hy-
droxylamine intermediate I (Scheme 4).
The synthesis of the novel Δ1-pyrroline derivatives (R)-
4b–h occurred without racemization. All enantiomeric ex-
cesses were determined by HPLC analysis (see the Support-
ing Information). The absolute configuration of 4d and 4e
were confirmed by X-ray diffraction studies (Figure 1).17
In conclusion, we have described a very efficient syn-
thesis of Δ1-pyrroline derivatives through a one-pot nitro-
reduction, cyclization and dehydration sequence of (R,E)-
N
R2
NO2
R1
O
THF–MeOH
(2:1, anhyd)
(R)-4
+
–O
Fe (activated)
AcOH
+
R1
R2
N
(R)-3
R2
R1
(R)-5
Scheme 3 Synthesis of highly enantioenriched Δ1-pyrroline derivatives
NO2
O
R1
R2
(R)-3
OH
H
N
NH2
O
O
R1
R2
R1
R2
I
II
H
HO
HO
N
N
HO
R2
R2
R1
R1
IV
III
– H2O
– H2O
–O
+
N
N
R2
R2
R1
R1
(R)-4
(R)-5
Scheme 4 Proposed mechanism for the formation of the Δ1-pyrrolines (R)-4 and Δ1-pyrroline-N-oxides 5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 846–850

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D. I. S. P. Resende et al.
Letter
Synlett
(8) Black, D. S.; Edwards, G. L.; Evans, R. H.; Keller, P. A.; Laaman, S.
M. Tetrahedron 2000, 56, 1889.
(9) Liang, Y.; Dong, D.; Lu, Y.; Wang, Y.; Pan, W.; Chai, Y.; Liu, Q.
Synthesis 2006, 3301.
(10) Kawai, H.; Kitayama, T.; Tokunaga, E.; Matsumoto, T.; Sato, H.;
Shiro, M.; Shibata, N. Chem. Commun. 2012, 48, 4067.
(11) Lee, M.; Lee, Y.-J.; Park, E.; Park, Y.; Ha, M. W.; Hong, S.; Lee, Y.-
J.; Kim, T.-S.; Kim, M.-h.; Park, H.-g. Org. Biomol. Chem. 2013, 11,
2039.
(12) Oliva, C. G.; Silva, A. M. S.; Paz, F. A. A.; Cavaleiro, J. A. S. Synlett
2010, 1123.
(13) Oliva, C. G.; Silva, A. M. S.; Resende, D. I. S. P.; Paz, F. A. A.;
Cavaleiro, J. A. S. Eur. J. Org. Chem. 2010, 3449.
(14) Silva, E. M. P.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett 2011, 2740.
(15) A mixture of iron powder (30 g) and 10% HCl (25 mL) was
stirred vigorously for 1 min. The solution was then filtered off
and the iron powder was washed successively with distilled
water (5 × 25 mL) and absolute EtOH (5 × 25 mL).
Figure 1 Molecular structure of 4d (a) and 4e (b). Thermal ellipsoids
are shown at the 50% probability level, hydrogen atoms are shown with
an arbitrary radius (0.30 Å). C, grey; N, blue; Cl, green; F, yellow; H,
white
(16) Synthesis of 4a–h; General Procedure: To a solution of (R,E)-
1,5-diaryl-3-(nitromethyl)-5-pent-4-en-1-ones 3a–h (0.31
mmol) in a mixture of THF–MeOH (2:1, 6 mL) was successively
added at r.t., AcOH (4.98 mmol) and activated iron powder (14.0
mmol). The resulting mixture was heated at 65 °C for 15 h
under a nitrogen atmosphere. After cooling to r.t., the reaction
mixture was filtered through Celite and rinsed with EtOAc. The
resultant solution was washed with sat. aq NaHCO3, brine, dried
over Na2SO4, filtered and concentrated under reduced pressure.
The resulting residue was purified by column chromatography
(hexane–EtOAc, 80:20). Finally the residues were crystallized
from hexane–EtOAc to furnish the desired compounds 4a–h.
Compound 4a: Yield: 72%; brown oil. 1H NMR (300 MHz,
CDCl3): δ = 7.85 (dd, J = 7.0, 2.3 Hz, 2 H, H-2′,6′), 7.45–7.19 (m,
8 H, H-3′,5′, H-4′, H-2′′,6′′, H-3′′,5′′, H-4′′), 6.47 (d, J = 15.8 Hz,
1 H, H-β), 6.24 (dd, J = 15.8, 7.9 Hz, 1 H, H-α), 4.33 (dd, J = 15.6,
7.2 Hz, 2 H, H-5), 3.90 (dd, J = 15.6, 5.1 Hz, 1 H, H-5), 3.36–3.19
(m, 2 H, H-3, H-4), 2.97–2.81 (m, 1 H, H-3). 13C NMR (75 MHz,
CDCl3): δ = 172.7 (C-2), 137.1 (C-1′′), 134.2 (C-1′), 132.2 (C-α),
130.5 (C-4′), 129.9 (C-β), 128.5 (C-3′,5′,C-3′′,5′′), 127.5 (C-2′,6′),
127.2 (C-4′′), 126.0 (C-2′′,6′′), 67.2 (C-5), 41.8 (C-3), 41.3 (C-4).
HRMS (ESI+): m/z [C18H17N + H]+ calcd for C19H17N: 248.1434;
found: 248.1433. HPLC (i-PrOH–hexane, 10:90; flow rate 0.7
mL/min; λ = 254 nm): tr = 10.90 [(R)-4a] min (ee = 99%).
Compound 4e: Yield: 44%; salmon solid; mp 110.6–111.3 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.71 (d, J = 8.6 Hz, 2 H, H-2′,6′), 7.55
(d, J = 8.6 Hz, 2 H, H-3′,5′), 7.37–7.18 (m, 5 H, H-2′′,6′′, H-3′′,5′′,
H-4′′), 6.46 (d, J = 15.8 Hz, 1 H, H-β), 6.23 (dd, J = 15.8, 8.2 Hz,
1 H, H-α), 4.38–4.24 (m, 1 H, H-5), 3.94–3.82 (m, 1 H, H-5),
3.38–3.16 (m, 2 H, H-3, H-4), 2.92–2.79 (m, 1 H, H-3). 13C NMR
(75 MHz, CDCl3): δ = 171.8 (C-2), 137.0 (C-1′′), 133.2 (C-4′),
132.0 (C-α), 131.7 (C-3′,5′), 130.2 (C-β), 129.1 (C-2′,6′), 128.6 (C-
3′′,5′′), 127.4 (C-4′′), 126.1 (C-2′′,6′′), 125.1 (C-1′), 67.4 (C-5),
41.8 (C-3), 41.4 (C-4). HRMS (ESI+): m/z [C18H16BrN + H]+ calcd
1,5-diaryl-3-(nitromethyl)-5-pent-4-en-1-ones 3. There
was no racemization of the asymmetric carbon, and the
trans-geometry of the double bond was retained. This
methodology is being applied in our laboratory to the syn-
thesis of Δ1-pyrroline boranyl complexes.
Acknowledgment
Thanks are due to the University of Aveiro and the Portuguese
Fundação para a Ciência e a Tecnologia (FCT) for funding the Organic
Chemistry Research Unit (project PEst- C/QUI/UI0062/2013), the
CICECO Associate Laboratory (PEst-C/CTM/LA0011/2013) and the
Portuguese National NMR Network (RNRMN). D.I.S.P.R. and S.G. also
thank the FCT for a doctoral grant (SFRH/BD/62696/2009) and a post-
doctoral grant (SFRH/BPD/70702/2010), respectively.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380144.
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References and Notes
(1) Current address: Medicinal Chemistry Section, Experimental
Therapeutics Programme, CNIO (Spanish National Cancer
Research Centre), Madrid, Spain.
(2) Huang, P.-Q. Asymmetric Synthesis of Five Membered Ring Het-
erocycles, In Asymmetric Synthesis of Nitrogen Heterocycles;
Royer, J., Ed.; Wiley-VCH: Weinheim, 2009.
for
C18H17BrN: 326.0539; found: 326.0537. HPLC (i-PrOH–
hexane, 10:90; flow rate 0.7 mL/min; λ = 254 nm): tr = 13.07
[(R)-4e] min (ee = 99%).
(3) Pinder, A. R. Nat. Prod. Rep. 1992, 9, 491.
(17) Crystal data for 4d: C18H16ClN; M = 281.77; orthorhombic; space
group P212121; Z = 4; a = 5.6675(7) Å, b = 7.8846(12) Å, c =
32.643(3) Å, α = β = γ = 90.00°; V = 1458.7(3) Å3; colorless
crystal with crystal size of 0.10 × 0.08 × 0.04 mm was used. Of a
total of 2942 reflections collected, 2022 were independent (Rint
= 0.0968). Final R1 = 0.0614 [I > 2σ(I)] and wR2 = 0.1591 (all
data). Crystal data for 4e: C18H16FN; M = 265.32; orthorhombic;
space group P212121; Z = 4; a = 5.6544(6) Å, b = 7.9709(8) Å, c =
(4) Asghari, S.; Qandalee, M. Synth. Commun. 2010, 40, 2172.
(5) Cardona, F.; Rocha, J.; Silva, A. M. S.; Guieu, S. Dyes Pigm. 2014,
111, 16.
(6) Marrec, O.; Christophe, C.; Billard, T.; Langlois, B.; Vors, J.-P.;
Pazenok, S. Adv. Synth. Catal. 2010, 352, 2825.
(7) Shvekhgeimer, M. G. A. Chem. Heterocycl. Compd. 2003, 39, 405.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 846–850

850
D. I. S. P. Resende et al.
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31.048(3) Å, α = β = γ = 90.00°; V = 1399.4(2) Å3; colourless flake
with crystal size of 0.50 × 0.20 × 0.04 mm. Of a total of 3068
reflections collected, 2834 were independent (Rint = 0.0380).
Final R1 = 0.0336 [I > 2σ(I)] and wR2 = 0.0796 (all data). CCDC-
1033064 and 1033065 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/datarequest/cif.
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