One-pot preparation of piperazines by regioselective ring-opening of non-activated arylaziridines

Article abstract of DOI:10.1039/c2ob07099e

Herein we report a new straightforward synthesis of cis and trans 2,5-disubstituted N,N-dialkylpiperazines, even in enantioenriched form, by reacting non-activated N-alkyl arylaziridines in the presence of a catalytic amount of a Lewis acid. A stereochemi

Full text of DOI:10.1039/c2ob07099e

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COMMUNICATION
One-pot preparation of piperazines by regioselective ring-opening of
non-activated arylaziridines†
Piera Trinchera,a Biagia Musio,a Leonardo Degennaro,a Anna Moliterni,b Aurelia Falcicchiob and
Renzo Luisi*a
Received 14th December 2011, Accepted 12th January 2012
DOI: 10.1039/c2ob07099e
C–N bond cleavage, to the best of our knowledge, has never
been reported (Scheme 1).9
Herein we report a new straightforward synthesis of cis and
trans 2,5-disubstituted N,N-dialkylpiperazines, even in enan-
tioenriched form, by reacting non-activated N-alkyl arylazir-
idines in the presence of a catalytic amount of a Lewis acid.
A stereochemical and NMR investigation revealed useful
mechanistic insights for this process.
During our investigations on the chemistry of N-alkyl-2-aryl-
aziridines, we found that the use of BH3 as the LA gave stable
complexes amenable to further elaboration.10 Nevertheless, it
was found that in the presence of metal halides, the same non-
activated aziridines of the kind 1 underwent either dimerization
to the corresponding piperazines 2 or polymerization depending
on the reaction conditions (Scheme 2).
Aziridines are widely used versatile building blocks for the syn-
thesis of a variety of biologically and pharmaceutically important
molecules.1 Several synthetic methods for aziridines have been
developed and their use as chiral building blocks has also
emerged recently.2 In the past decades, much interest has been
devoted to the development of new synthetic methodologies
based on aziridine reactivity. Well established synthetic routes
are based either on the nucleophilic ring-opening3 of this spring-
loaded heterocyclic system or on the regioselective metalation–
electrophile trapping sequence without ring-opening.4 However,
where the aziridine reactivity is concerned, the nature of the
nitrogen substituent can play a pivotal role. With reference to
ring-opening reactions, aziridines have been classified as “acti-
vated” (those bearing an electron-withdrawing group) and “non-
activated” (those bearing an electron-donating group) depending
on the nature of the N-substituent.5 Activated 2-phenylaziridines,
in the presence of a Lewis acid (LA) or heat, undergo formal
[3 + 2] cycloaddition reactions with non-activated alkenes,
nitriles and ketones6,7 through the corresponding masked 1,3-
dipole; instead, in the presence of a LA and a nucleophile, a
regioselective attack at the benzylic position (C2) is often
observed (Scheme 1).8
A look into the literature revealed an old report by Dick11 on
the formation of piperazinium halides from C-unsubstituted N-
alkylaziridines, while De Kimpe exploited the reactivity of
β-chloro- or β-tosyloxyethylamines in the preparation of C-
unsubstituted piperazines.12 Moreover, He et al.13 reported N,N′-
diethyl piperazines as side products (<15% yield) in reactions of
N-alkyl C2-substituted aziridines with CO2.
Since the piperazine ring is found in a large number of bio-
logically active compounds,14 and this heterocycle finds use as a
ligand in asymmetric catalysis,15 we decided to investigate this
Non-activated 2-phenylaziridines, upon N-complexation with
a LA, react with a nucleophile almost exclusively at the benzylic
position, while reactivity as a formal 1,3-dipole obtained by a
Scheme 1 Reactivity of “activated” and “non-activated” aziridines.
aDipartimento Farmaco – Chimico, Università degli Studi di Bari “Aldo
Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy.
E-mail: luisi@farmchim.uniba.it
bIstituto di Cristallografia ICC-CNR, Via Amendola 122/o, I-70125
Bari, Italy
†Electronic supplementary information (ESI) available: Experimental
procedures and analytical data of new compounds. CCDC reference
numbers 859214–859216. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2ob07099e
Scheme 2 Reactivity of N-alkylaziridines with LAs.
1962 | Org. Biomol. Chem., 2012, 10, 1962–1965
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reaction with the aim to improve the yields of piperazine while
reducing the amount of the polymeric by-products.
and (R,R)-2a,i together with meso-2a,h,i were obtained, respect-
ively (Scheme 3).20 The absolute configuration of chiral pipera-
zines (S,S)-2a and (R,R)-2a suggested that the reaction occurred
with net retention of configuration with respect to the starting
aziridines.21
The results obtained with chiral aziridines were a little surpris-
ing. With the exception of (R,R)-2i,22 erosion of the enantio-
meric ratio occurred to a small extent in chiral piperazines (S,S)-
2a,h and (R,R)-2a, and the presence of the meso form, requiring
an inversion of configuration at the benzylic carbon, should be
explained.
To shed light on the mechanism of this reaction and also on
the role of the LA, an NMR investigation was undertaken.
Racemic and enantioenriched aziridines were analyzed by 1H
NMR in CD3CN at 60 °C in the presence of catalytic (5%) and
stoichiometric amounts of MgBr2, respectively. From the 1H
NMR analysis of 1a it was found that in the presence of a
In order to find the optimal reaction conditions for this dimeri-
zation, aziridines 1a–e were first investigated. Several LAs were
tested (ZnCl2, MgBr2, CsF, CeCl3, CuBr, (NH4)2Ce(NO3)6,
InCl3) against different reaction conditions (solvent, temperature
and LA amount), and it was found that the use of MgBr2 in
acetonitrile at 60 °C furnished appreciable yields of the corre-
sponding piperazines 2a–d as a 1 : 1 mixtures of two easily
separable diastereoisomers (Table 1). The MgBr2 was tested
either in stoichiometric or catalytic (5%) amount. As can be seen
in Table 1, the use of a catalytic amount of the LA gave faster
reactions and higher conversions of the starting material.
However, with a sterically demanding N-substituent, such as the
tert-butyl group, the reaction did not take place with 1 equiv. of
LA and occurred to a small extent with 5% of LA (Table 1). The
structure and stereochemistry of diastereoisomeric piperazines
2a–d and meso-2a–d were ascertained by NMR and HPLC
analysis.16 The stereochemistry of meso-2a,n and 2f were
confirmed by X-ray analysis.17 It is worth pointing out that a
2,3-substitution was erroneously assigned to reported piperazine
2b,13a and that the stereochemistry of this kind of piperazines
has never been assessed before.
Table 2 Dimerization of aziridines 1f–r
Under the optimized conditions (5% MgBr2, CH3CN, 60 °C),
the scope of the reaction was investigated using N-methyl-2-aryl
aziridines 1f–r. As reported in Table 2, the reaction occurred
with good yields, furnishing mixtures of diastereoisomeric piper-
azines 2f–r and meso-2f–r.18 However, they were easily separ-
able and their stereochemistry was assigned by analogy to 2a–d
and meso-2a–d.19
Next, we turned our attention to the reactivity of enantio-
enriched aziridines (S)-1a,h and (R)-1a,i (er >98 : 2) with the
aim to prepare optically active piperazines, and disclose useful
mechanistic information.
Aziridine 1
R
Ar
Yielda,b (%)
1f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-ClC6H4
4-BrC6H4
2-BrC6H4
2-MeC6H4
2,4,6-(Me)3C6H2
2-Naphthyl
3-MeOC6H4
4-MeOC6H4
2-(CH2vCHCH2)C6H4
3-CF3C6H4
75
75
70
73
75
80
60
60
65
80
80
75
50c
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
When chiral aziridines (S)-1a,h and (R)-1a,i reacted with a
catalytic amount of MgBr2 (5%), chiral piperazines (S,S)-2a,h
4-CF3C6H4
2-n-PrC6H4
2-Me-5-FC6H3
Table 1 Dimerization of aziridines 1a–e
a Overall yields of the two diastereoisomers. b As a 1 : 1 diastereomeric
mixture of 2f–r/meso-2f–r. c After flash chromatography only the meso
form was isolated.
Aziridine 1
R
t (h) MgBr2 (equiv.) Yielda,b (%) SMc (%)
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
Me
Me
Et
15
5
65
20
1
0.05
1
0.05
1
0.05
1
0.05
1
0.05
85
90
54
90
45
70
76
80
Nr
<5d
15
<2
46
5
55
20
24
20
100e
90
Et
n-Pr 89
n-Pr
i-Pr
i-Pr
5
90
20
t-Bu 90c
t-Bu 53
a Overall isolated yields of the two diastereoisomers. b As a 1 : 1
diastereomeric mixture of 2a–d/meso-2a–d. c Recovered starting
material (SM). d The corresponding piperazines were detected only by
GC-MS analysis. e The starting material was recovered unchanged.
Scheme 3 Synthesis of enantioenriched piperazines.
Org. Biomol. Chem., 2012, 10, 1962–1965 | 1963
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Fig. 1 1H NMR investigation on aziridine 1a (partial spectra shown
for clarity). (a) Aziridine 1a + 5% MgBr2, CD3CN, 60 °C after 30 min,
signals of 1a, 2a and meso-2a are shown. (b) Aziridine 1a + 100%
MgBr2, CD3CN, 60 °C, CH–CH2 patterns are shown.
Scheme 4 Proposed mechanism for the conversion of aziridines into
piperazines.
substitution on 4,26 would give chiral piperazine (S,S)-2a via an
intramolecular nucleophilic attack at the terminal position of the
aziridinium ion.27 Instead, intermediate (S,S)-7, which should
derive from 5, undergoes intramolecular nucleophilic attack at
the benzylic position of the aziridinium ion to give meso-2a.28
In this mechanism, the excess of free aziridine is required for the
reaction to occur.29 In addition, the regioselectivity of the ring-
opening reaction, involving the terminal position, is quite
unusual for non-activated aziridines.
In conclusion a new straightforward synthesis of 2,5-disubsti-
tuted piperazines starting from readily available N-alkyl aziri-
dines has been developed. Further investigations are underway in
order to expand the applicability of this process and control the
stereoselectivity.
Fig. 2 1H NMR investigation on chiral aziridine (S)-1h + 5% MgBr2,
CD3CN, 60 °C (partial spectra shown for clarity).
stoichiometric amount of MgBr2 a fast and quantitative bromide-
promoted ring-opening reaction occurred leading to the corre-
sponding bromo amines or amides23 (Fig. 1b). The ring-opening
reaction occurred with a preference for the benzylic position and
the reaction mixture remained unchanged even after 24 h at
70 °C.24,25
Acknowledgements
This work was carried out under the framework of the National
Project “FIRB
–
Futuro in Ricerca” (code: CINECA
RBFR083M5N) and supported by the University of Bari.
In striking contrast, in the presence of a catalytic amount of
MgBr2 a mixture of piperazines and starting aziridine was
observed after 30 min and complete conversion was obtained in
2 h. Under these conditions, the ring-opening product was not
observed even in trace amounts (Fig. 1a).
The NMR investigation on chiral aziridine (S)-1h in the pres-
ence of a catalytic amount of MgBr2 gave results similar to those
observed for 1a (Fig. 2). After mixing of (S)-1h and MgBr2
(5%), the spectra recorded at 5 min showed the presence of (S)-
1h, meso-2h and traces of (S,S)-2h (Fig. 2). However, the con-
version of (S)-1h into the corresponding piperazines was com-
plete in 5 h, and still there was no evidence for ring-opening
derivatives (Fig. 2).
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18 Attempts to use N-alkylaziridines bearing a C2-alkyl group failed, and
only complex mixtures were recovered.
19 The relative stereochemistry was assigned by comparison of the 1H NMR
chemical shifts of the benzylic protons (see ref. 16).
20 The absolute configuration of chiral piperazine (R,R)-2a was confirmed
by comparison of the optical rotation of the corresponding mono hydro-
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c 0.3, H2O); (see K. Fuji, K. Tanaka and H. Miyamoto, Tetrahedron:
Asymmetry, 1993, 4, 247–259).
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21 Opposite optical rotation values were found for (S,S)-2a ([α]D +56.4,
c 0.5, CHCl3) and (R,R)-2a ([α]D −56.4, c 0.5, CHCl3).
22 It is likely that the ortho substituent could affect the reaction stereoselec-
tivity (see mechanism and ref. 25).
23 An ESI-MS analysis of the reaction mixture collected directly from the
NMR tube revealed the presence of the bromo amines.
24 It has been demonstrated that, with a stoichiometric amount of MgBr2,
the work-up procedure with water always gave a mixture of piperazines
and starting aziridine so justifying the results reported in Table 1 with 1
equiv. of MgBr2.
25 Examples of MgBr2-mediated ring opening of activated aziridines have
been reported, see: G. Righi, T. Franchini and C. Bonini, Tetrahedron
Lett., 1998, 39, 2385–2388.
26 Aziridine (S)-1a should attack mainly the terminal position of 3. Attack
at the benzylic position, occurring with inversion of configuration, would
give (S,R)-7 which would generate (S,R)-2,6-disubstituted piperazine (not
observed) and (R,R)-2a to a small extent.
14 For examples, see: (a) M. L. Lopez-Rodriguez, D. Ayala, B. Benhamu,
M. J. Morcillo and A. Viso, Curr. Med. Chem., 2002, 9, 443–469;
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A. E. Jacobson and K. C. Rice, J. Med. Chem., 2000, 43, 4840–4849;
(c) K. Samanta and G. Panda, Chem.–Asian J., 2011, 6, 189–197;
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K. Murano, H. Matsuda and H. Miyake (Fujisawa Pharmaceuticals)
WO9637489A1, 1996.
27 Nucleophilic attack at the benzylic position would lead to (S,R)-2,6-dis-
ubstituted piperazine which has not been observed.
28 Nucleophilic attack at the terminal position would lead to (S,S)-2,6-disub-
stituted piperazine which has not been observed.
29 However, we cannot rule out the regioselective ring opening of the aziri-
dinium ions of (S,S)-6,7 by the bromide, followed by an intramolecular
nucleophilic substitution. For a similar example see: M. Yu. Moskalik
and B. A. Shainyan, Russ. J. Org. Chem., 2011, 47, 568–571.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1962–1965 | 1965