Baylis-Hillman-derived N,N′-disubstituted piperazines: Structural and preliminary computational studies

Article abstract of DOI:10.1016/j.tetlet.2011.03.133

Exploratory studies towards the preparation of potential HIV-1 protease and integrase inhibitors have led to the synthesis of Baylis-Hillman-derived N,N′-disubstituted piperazines. X-ray crystallographic, computer modelling and NMR techniques have been us

Full text of DOI:10.1016/j.tetlet.2011.03.133

Tetrahedron Letters 52 (2011) 2972–2976
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Baylis–Hillman-derived N,N0-disubstituted piperazines: structural
and preliminary computational studies
Kenudi C. Idahosa a, Yi-Chen Lee a, Dubekile Nyoni a, Perry T. Kaye a, , Mino R. Caira b
⇑
a Department of Chemistry and Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown, 6140, South Africa
b Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Exploratory studies towards the preparation of potential HIV-1 protease and integrase inhibitors have led
to the synthesis of Baylis–Hillman-derived N,N0-disubstituted piperazines. X-ray crystallographic, com-
puter modelling and NMR techniques have been used to elucidate questions concerning configurational
preferences, reaction pathways and the apparent difference in susceptibility towards aza-Michael reac-
tions exhibited by methyl acrylate and methyl vinyl ketone (MVK) derived Baylis–Hillman substrates.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 16 February 2011
Revised 15 March 2011
Accepted 25 March 2011
Available online 1 April 2011
Keywords:
Baylis–Hillman
aza-Michael
Piperazines
X-ray crystallography
Diffusion-ordered spectroscopy (DOSY)
2D NOE (NOESY)
Computational studies
1. Introduction
symmetrically substituted products 6 and 8 has alerted us to the
potential of this approach in accessing suitably elaborated C2-sym-
The Baylis–Hillman reaction affords multifunctional adducts
with considerable potential for synthetic elaboration.1 More specif-
ically, the a,b-unsaturated carbonyl moiety is susceptible to conju-
metric products as potential HIV-1 PR and dual-action PR/IN inhib-
itors. Of more immediate interest is the fact that these compounds
have provided an opportunity to address three issues relevant to
future applications of the methodology. These concern: (i) the ste-
reochemistry of the double bond in the series of compounds 7 and
8; (ii) the apparent diastereoselectivity of their formation; and (iii)
the observed difference in reactivity towards aza-Michael addition
exhibited by the methyl acrylate derived Baylis–Hillman adducts 4
and their MVK-derived analogues 5.
gate addition while, under suitable conditions, the allylic alcohol
moiety may be expected to permit nucleophilic allylic (SN0) dis-
placement. Our ongoing research on applications of Baylis–Hillman
methodology in synthesis has led to the preparation of various
benzannulated heterocyclic systems, including quinolines2 and
coumarins.3 We have become increasingly aware of the fact that
acrylate ester derived Baylis–Hillman adducts generally react read-
ily with primary or secondary amines in aza-Michael reactions,
whereas their methyl vinyl ketone (MVK) derived analogues do
not.4 Thus, in exploratory studies towards the development of po-
tential HIV-1 protease (PR) and integrase (IN) inhibitors, the
methyl acrylate derived adducts 4a–d (Scheme 1) were found to
undergo direct conjugate addition of piperazine permitting isola-
tion of the corresponding bis-substituted piperazines 6a–d, albeit
in variable yields following chromatographic purification. Forma-
tion of the analogous MVK-derived bis-substituted piperazines
8a,b,e,f, on the other hand, required the intermediacy of the acti-
vated chloromethyl derivatives 7a,b,e,f. While the reaction condi-
tions have not been optimised, the isolation of these
2. Discussion
DABCO-catalysed reaction of the 2-nitrobenzaldehydes 1 with
methyl acrylate (2) or MVK (3) afforded the corresponding
Baylis–Hillman adducts 4a-d and 5a,b,e,f.5 The chloromethyl
derivatives 7a,b,e,f were obtained in essentially quantitative yield
by hydrochlorinationꢀdehydration of the corresponding Baylis–
Hillman adducts 5a,b,e,f, using HCl generated by the prior,
cautious addition of acetyl chloride to cold, dry ethanol.6 Conver-
sion of allyl acetates into allyl chlorides occurs under similar
conditions,7 while treatment of Baylis–Hillman adducts under
Vilsmeier–Haack conditions,8 has been shown to afford the rear-
ranged allyl chlorides; these reactions have been presumed to
0
follow SN or SN mechanisms. While formation of the chloromethyl
⇑
Corresponding author. Tel.: +27 (0)46 6028268; fax: +27 (0)46 6225109.
E-mail address: P.Kaye@ru.ac.za (P.T. Kaye).
derivatives 7a,b,e,f could also proceed via acid-catalysed allylic
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.133

K. C. Idahosa et al. / Tetrahedron Letters 52 (2011) 2972–2976
2973
R4 OH
O
R3
R2
O
R1 R2 R3 R4
NO2
R1
R1
N
O2N
R2
R3
H
H
H
H
H
H
H
N
a
b
c
d
6a-d
For R5 = OMe
OMe H
O
H
H
H
Cl
-OCH2O- H
ii
O
OH R4
R4
R1
R3
CHO
NO2
R4 OH
O
R4
O
R2
R3
R2
R3
R2
R5
i
iii
1
For R5 = Me
NO2 Cl
O
NO2
R1
R1
R5
5
4a-d:
R = OMe
7a,b,e,f
5a,b,e,f: R5 = Me
5
2
: R = OMe
ii
3: R5 = Me
R4
O
R3
R1 R2 R3 R4
R2
NO2
R1
N
a
H
H
H
H
H
H
H
H
R1
b
e
f
OMe H
N
O2N
R2
R3
H
H
Cl
H
H
Cl
O
R4
8a,b,e,f
Scheme 1. Reagents: (i) DABCO, CHCl3; (ii) piperazine, THF; (iii) CH3COCl, EtOH, 0 °C then 5.
substitution (SN0), the possibility of a conjugate addition-elimina-
tion pathway cannot be excluded a priori. Computational analysis,
using Gaussian03,9 of the two pathways was undertaken and the
results appear to support the conjugate additionꢀelimination
pathway. Thus, a scan at the HF/3-21G level involving initial pro-
tonation of the carbonyl oxygen in the parent system 5a (to give
I; Fig. 1), followed by step-wise approach of Clꢀ (from an initial dis-
tance of 2.5 Å) led, spontaneously, to the 1,4-addition product III,
dehydration and tautomerism of which would afford compound
7a. On the other hand, initial protonation of the hydroxylic oxygen
(to give II––necessary for allylic displacement), followed by
step-wise approach of Clꢀ, led via proton transfer to the carbonyl
oxygen to give structure I and, thence, to the same 1,4-addition
product III. Thus, protonation of the hydroxy oxygen appears to
permit intramolecular catalysis of the conjugate addition pathway
rather than promoting the allylic substitution (SN0) pathway!
Moreover, the LUMO for the parent system 5a corresponds largely
to the
a,b-unsaturated carbonyl system (see Fig. 4)––an observa-
tion consistent with the 1,4-addition route. The most stable
conformations of both the acrylate ester and the MVK-derived
Baylis–Hillman adducts (4a and 5a, respectively) appear to be
characterised by hydrogen-bonding between the hydroxy and
carbonyl groups––a chelate effect which is also evident in the
hydrochlorination sequence illustrated in Figure 1 and which
accounts for the diastereocontrol in the dehydration step.
Reaction of each of the Baylis-Hillman adducts 4a–d with piper-
azine10 was, initially, expected to afford the corresponding mono-
substituted esters.11 1H NMR analysis of the crude product from
the reaction with substrate 4a, while indicating the presence of a
contaminant, appeared to support this expectation. However,
HRMS analysis of the chromatographed material obtained from
the reaction with substrate 4a revealed a base peak at m/z 560,
which corresponds to the disubstituted piperazine 6a, as well as
a peak at m/z 324 which would correspond to [M+1] for the
H
H
H
H
O
O
O
O
proton
transfer
NO2
NO2
II
I
X
H
H
O
O
O
dehydration
and
mono-substituted analogue.
A Diffusion-Ordered Spectroscopy
tautomerism
(DOSY) NMR experiment was therefore run to establish whether
both of the products were present or only the disubstituted deriv-
ative 6a (with the peak at m/z 324 arising from fragmentation). In
the pseudo-chromatographic 2D DOSY NMR experiment, the
pulsed field gradient (PFG) and the deuterated solvent serve as
the ‘mobile phase’, permitting ‘separation’ of two or more com-
pounds, whose differences in size and shape affect their mobility
Cl
NO2
NO2 Cl
7a
III
Figure 1. Results of calculations at the HF/3-21G level of step-wise approach of Clꢀ
to the protonated structures I and II.

2974
K. C. Idahosa et al. / Tetrahedron Letters 52 (2011) 2972–2976
-0.653
O
-0.586
O
NO2
OH
OH
NO2
0.972
0.550
MeO
-0.018
-0.166
-0.400
-0.346
4a
5a
Figure 4. Molecular orbitals and Mulliken atomic charges for compounds 4a (LUMO+1) and 5a (LUMO), calculated at the MP2/6-31G(d) level on structures previously
optimised at the B3LYP/6-31G+(d) level.
and diffusion coefficients.12 The DOSY experiment clearly indicated
the presence of a ‘single’ component, comprising a mixture of dia-
stereomeric disubstituted piperazines 6a; a similar result was ob-
tained for compound 6d, and HRMS analysis supported the
formation of all four of the disubstituted piperazines 6a–d as dia-
stereomeric mixtures.
chair form and the bulky 2-acetyl-3-(2-nitrophenyl)-2-propenyl
groups are linked to it via the equatorial bonds C15–N16
(1.468(2) Å). In particular, the analysis provided unequivocal char-
acterisation of the geometry around the double bond C10–C11
[1.334(2) Å]. Relevant torsion angles are C1-C10-C11-C15
[-4.8(2)°] and C1–C10–C11–C12 [178.0(1)°]. The plane of the aro-
matic ring is nearly orthogonal to the plane defined by C10, C11
and their bonded atoms (torsion angle C2–C1–C10–C11
[ꢀ81.9(2)°], and the nitro groups are located above and below
the piperazine ring, slightly rotated out of their respective aromatic
ring planes {C1–C6–N7–O9 [18.3(2)°]}. Two intermolecular C-
Hꢁ ꢁ ꢁO hydrogen bonds (both involving carbonyl oxygen atom
O13 as acceptor with aromatic C–H donor groups) contribute to
crystal cohesion.
In order to elucidate the apparent lack of reactivity of the MVK-
derived Baylis–Hillman adducts (5) under aza-Michael conditions,
preliminary theoretical studies were undertaken to compare the
nature of the LUMOs and the relevant atomic charges associated
with the methyl acrylate derived Baylis–Hillman adduct 4a and
the MVK-derived analogue 5a. Conformational searches were con-
ducted, initially, at the AM1 level using PC-SPARTAN-pro.16 The
lowest energy conformer, in each case, exhibited hydrogen-bond-
ing between the carbonyl group and the hydroxy hydrogen––the
preferred arrangement retained in obtaining geometry-optimised
structures at the B3LYP/6-31G(d) level using Gaussian03.9 The
LUMO surfaces and relevant Mulliken atomic charges were calcu-
lated at the MP2/6-31G(d) level, and examination of the results,
which are illustrated in Figure 4 reveals that: (i) the LUMO for
the acrylate ester 4a is associated with the 2-nitrophenyl moiety,
whereas the molecular orbital of interest for nucleophilic attack
The MVK-derived bis-substituted piperazines 8a,b,e,f were ob-
tained by reacting the corresponding chloromethyl derivatives
7a,b,e,f with piperazine in THF,13 and various methods were ex-
plored to determine the configuration of the double bonds and,
by implication, in the activated chloromethyl precursors, viz., 1D
(3JYꢀC@O) and 2D (NOESY and HOESY14) NMR methods, and single
crystal X-ray analysis of the parent system 8a. The fully coupled
13C NMR data for the heteronuclear three-bond coupling between
the carbonyl carbon and the vinylic proton (3JYꢀC@O) was compli-
cated by coupling with the proximate methyl and methylene pro-
tons and, in any event, unambiguous assignment on the basis of
such data really requires the availability of both diastereomeric
forms.15 While the Heteronuclear NOE Spectrosopy (HOESY)
experiments, conducted on three of the N,N0-bis-substituted piper-
azines, also failed to provide convincing configurational evidence,
the NOESY spectra for all four compounds 8a,b,e,f consistently re-
vealed NOE interactions between the methyl and vinylic protons as
illustrated in Figure 2. The consequent NMR-based (E)-configura-
tional assignments are clearly in agreement with the X-ray struc-
ture of compound 8a (Fig. 3).
The X-ray intensity data were collected at ꢀ100 °C, and the di-
rect methods solution and full-matrix least-squares refinement
proceeded routinely. The structure of molecule 8a is required by
space group symmetry to lie on a crystallographic inversion centre
(Z = 2, space group P21/n). The piperazine ring adopts the normal
on the
for the vinyl ketone 5a is associated, essentially, with the
unsaturated carbonyl moiety; and (iii) polarisation of the
,b-unsaturated carbonyl moiety is clearly greater in the methyl
a,b-unsaturated carbonyl system is LUMO+1; (ii) the LUMO
a,b-
a
H
Me
acrylate derived adduct 4a with the result that the electron density
(Mulliken charge = ꢀ0.346) on the terminal vinylic carbon is signif-
icantly less than on the corresponding centre in the MVK-derived
analogue 5a (ꢀ0.400). Interestingly, similar results were obtained
for the unsubstituted phenyl analogues. The consequent attenua-
tion of electrophilicity would seem to account for the apparent
reluctance of the MVK-derived adducts (5) to undergo the uncatal-
ysed aza-Michael reaction with piperazine. It is perhaps significant
that, in both systems, approach of piperazine to the b-vinylic car-
bon is characterised by the development of bifurcated hydrogen-
bonding between the amino proton and the N and one of the O
atoms of the ortho-NO2 group. This development is expected to
O
NO2
N
N
O2N
O
8a
Me
H
Figure 2. NOE interactions indicated in the NOESY spectrum of compound 8a.

K. C. Idahosa et al. / Tetrahedron Letters 52 (2011) 2972–2976
2975
Figure 3. X-ray structure of N,N0-bis[(E)-2-acetyl-3-(2-nitrophenyl)-2-propenyl]piperazine (8a), showing the crystallographic numbering and thermal ellipsoids drawn at the
50% probability level.
5. For general procedures and known compounds, see: Familoni, O. B.; Klaas, P. J.;
increase the hardness of the nucleophilic 2° amine and, hence, the
Lobb, K. A.; Pakade, V. E.; Kaye, P. T., Org. Biomol. Chem., 2006, 4, 3960-3965.
importance of electrostatic interaction in the initial phase of the
Compound 4d is also known.18
reaction.17
Analytical data for new compounds are as follows.
In conclusion, the N,N0-disubstituted piperazines 6a–d and
8a,b,e,f reported in this study constitute interesting models for
the development of novel compounds as potential HIV-1 protease
and integrase inhibitors, while the structural and preliminary the-
oretical studies have provided useful insights into their formation.
Crystallographic data (excluding structure factors) for the struc-
ture in this Letter have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication no. CCDC
810815. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
Methyl 3-hydroxy-2-methylene-3-(3-methoxy-2-nitrophenyl)propanoate (4b), as
colourless crystals (0.48 g, 65%), mp 108–109 °C (found, M+ꢀNO2: 221.083260.
Calcd for C12H13O5, M: 221.081384); vmax/cmꢀ1 (Nujol) 3485 (OH) and 1706
(C@O); dH (400 MHz; CDCl3) 3.25 (1H, br s, OH), 3.70 (3H, s, COOCH3), 3.88 (3H,
s, ArOCH3), 5.62 (1H,s, CHOH), 5.86 and 6.41 (2H, 2ꢂ s, CH2), 6.99 (1H, d,
J = 7.9 Hz, 60-H), 7.09 (1H, d, J = 7.89 Hz, 40-H) and 7.41 (1H, t, J = 8.2 Hz, 50H); dC
(100 MHz; CDCl3) 52.1 (COCH3), 56.5 (ArOCH3), 68.3 (CHOH), 112.2, 119.3,
127.4, 131.3, 134.4, 139.6, 140.4 and 150.9 (C@CH2 and Ar-C) and 166.1 (C@O).
Methyl 3-(6-chloro-2-nitrophenyl)-3-hydroxy-2-methylenepropanoate (4c), as a
dark brown solid, (0.91 g, 86%), mp 99–101 °C (found, M+ꢀH2O: 252.989934.
Calcd for C11H8ClNO4, M: 252.990376); vmax/cmꢀ1 (Nujol) 3335 (OH) and 1704
(C@O); dH (400 MHz; CDCl3) 2.86 (1H, br s, OH), 3.73 (3H, s, CH3), 5.73 (1H, s,
CHOH), 6.17 and 6.44 (2H, 2ꢂ s, CH2), 7.38 (1H, t, J = 8.1 Hz, Ar-H), 7.51 (1H, dd,
J = 8.0 and 0.9 Hz, Ar-H) and 7.59 (1H, dd, J=8.0 and 1.1 Hz, Ar-H); dC (100 MHz;
CDCl3) 52.2 (CH3), 68.9 (CHOH), 122.8, 127.8, 129.3, 131.7, 133.3, 135.6, 138.0
and 151.4 (C@CH2 and Ar-C) and 166.3 (C@O).
4-Hydroxy-4-(4-chloro-2-nitrophenyl)-3-methylenebutan-2-one (5e), as
a
transparent, golden brown oil (0.31 g, 44%); tmax (ATR)/cmꢀ1 3412 (OH) and
1671 (C@O); dH (400 MHz, CDCl3) 2.26 (3H, s, CH3), 4.16 (1H, br s, CHOH), 5.77
(1H, s, CHOH), 6.09 and 6.11 (2H, 2ꢂ s, CH2), 7.51 (1H, d, J = 8.8 Hz, Ar-H), 7.64
(1H, d, J = 7.6 Hz, Ar-H) and 7.82 (1H, d, J = 2.0 Hz, Ar-H); dC (100 MHz; CDCl3),
25.7 (CH3), 66.0 (CHOH), 124.2, 126.4, 130.0, 133.1, 133.7, 135.4, 147.0 and
148.7 (C@CH2 and Ar-C) and 199.2 (C@O).
Acknowledgements
The authors thank the National Research Foundation (NRF;
Grant no. 62273), the Medical Research Council of South Africa
(MRC) and Rhodes University for generous financial support and
Mr A. Soper and Dr P. Kempgens for assistance with the DOESY
and HOESY experiments, respectively. M.R.C. thanks the University
of Cape Town and the NRF for research support. Any opinion, find-
ings and conclusions or recommendations expressed in this mate-
rial are those of the authors and therefore the NRF does not accept
any liability in regard thereto.
6. The general procedure for the preparation of the chloromethyl derivatives
(7a,b,e,f): which were used without further purification, is illustrated by the
following example. (The chloromethyl derivative 7a is known, having also been
prepared directly via a TiCl4-catalysed Baylis–Hillman reaction.19
)
Ethanolic HCl was generated in situ by cautiously adding AcCl (1.0 mL)
dropwise to cold, dry EtOH (2.0 mL) in a reaction flask, fitted with a reflux
condenser and cooled on an ice-bath; the mixture was then stirred for 5 min.
(CAUTION! The reaction between AcCl and EtOH is exothermic!) 4-Hydroxy-3-
methylene-4-(3-methoxy-2-nitrophenyl)butan-2-one (5b) (0.67 g, 2.7 mmol)
in EtOH (1.0 mL) was added to the ethanolic HCl, the flask was stoppered and
the mixture stirred overnight at room temperature. Excess solvent and
unreacted HCl were evaporated in vacuo to afford, as dark brown crystals, 3-
chloromethyl-4-(3-methoxy-2-nitrophenyl)but-3-en-2-one (7b) (0.73 g, 100%),
mp 66–68 °C (found, M: 269.0427. Calcd for C12H12NO4Cl, M: 269.0455); tmax
(ATR)/cmꢀ1 1671 (C@O); dH (400 MHz; CDCl3) 2.42 (3H, s, CH3), 3.93 (3H, s,
OCH3), 4.25 (2H, s, CH2), 7.14 (1H, d, J = 8.4 Hz, Ar-H), 7.27 (1H, d, J = 8.0 Hz, Ar-
H), 7.49 (1H, s, 4-H) and 7.55 (1H, m, Ar-H); dC (100 MHz; CDCl3) 25.9 (CH3),
References and notes
1. Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891.
2. Familoni, O. B.; Kaye, P. T.; Klaas, P. J. Chem. Commun. 1998, 2563–2564.
3. Olomola, T. O.; Klein, R.; Lobb, K. A.; Sayed, Y.; Kaye, P. T. Tetrahedron Lett. 2010,
51, 6325–6328.
4. Lee, Y-C. MSc thesis, Rhodes University, 2009. Idahosa, K. C., unpublished data.

2976
K. C. Idahosa et al. / Tetrahedron Letters 52 (2011) 2972–2976
36.9 (CH2), 56.6 (OCH3), 113.9 (C-4), 120.8, 121.8, 128.2, 131.8, 135.5, 140.9
and 151.4 (Ar-C and C@CH) and 196.3 (C@O).
N,N0-Bis[2-carbomethoxy-3-hydroxy-3-(4,5-methylenedioxy-2-nitrophenyl)propyl]-
piperazine (6d)20, as a yellow wax (40 mg, 7%) (found [M+]1: 649.1995. Calcd for
3-Chloromethyl-4-(4-chloro-2-nitrophenyl)but-3-en-2-one (7e), as a dark brown
C
28H33N4O14, MH+: 649.1988); mmax KBr/cmꢀ1 3349 (OH) and 1730 (C@O); dH
oil (4.0 g, 100%);
t
max (ATR)/cmꢀ1 1671 (C@O); dH (400 MHz; CDCl3) 2.49 (3H, s,
(400 MHz; CDCl3) 2.58 (8H, m, NCH2), 2.78 (2H, m, CHCH2), 2.99 (2H, m, CHCH2),
3.54 (6H, s, OCH3), 5.62 (2H, m, CHOH), 6.09 (4H, s, OCH2O), 7.15 (2H, s, Ar-H) and
7.33 (2H, s, Ar-H); dC (100 MHz; CDCl3) 30.1 (NCH2), 48.8 (CHCH2), 52.5 (OCH3),
59.1 (CHCH2), 72.3 (CHOH), 103.3 (OCH2O), 105.5, 108.3, 134.3, 142.9, 147.6 and
152.1 (Ar-C) and 172.1 (C@O).
CH3), 4.14 (2H, s, CH2), 7.66 (1H, m, Ar-H), 7.72 (1H, m, 60-H), 7.90 (1H, s, 4-H)
and 8. 19 (1H, s, Ar-H); dC (100 MHz; CDCl3) 25.9 (CH3), 36.8 (CH2), 125.4,
128.5, 131.6, 134.1, 136.1, 138.1, 138.9 and 147.3 (C@CH and Ar-C) and 196.3
(C@O).
3-Chloromethyl-4-(5-chloro-2-nitrophenyl)but-3-en-2-one (7f), as
a
black oil
11. Such compounds may well have been observed,4 but our interest and initial
studies have focused on the isolated N,N0-disubstituted piperazines 6a-d.
12. Huo, R.; Wehrens, R.; Buydens, L. M. C. J. Magn. Reson. 2004, 169, 257–269;
Bradley, A.; Krishnamurthy, K.; Hu, H. J. Magn. Reson. 2005, 172, 110–117;
Shrot, Y.; Frydman, L. J. Magn. Reson. 2008, 195, 226–231; Carrara, C.; Viel, S.;
Delaurent, C.; Ziarelli, F.; Excoffier, G.; Caldarelli, S. J. Magn. Reson. 2008, 194,
303–306.
(3.8 g, 94%); mmax KBr/cmꢀ1 1677 (C@O); dH (400 MHz; CDCl3) 2.51 (3H, s,
CH3), 4.17 (2H, s, CH2), 7.56 (1H, dd, J = 1.0 and 8.8 Hz, Ar-H), 7.67 (1H, d,
J = 1.2 Hz, Ar-H), 7.91 (1H, s, 4-H) and 8.18 (1H, d, J = 8.8 Hz, Ar-H); dC
(100 MHz; CDCl3) 26.0 (CH3), 36.7 (CH2), 126.7, 130.2, 130.4, 131.9, 138.3,
138.8, 140.8 and 145.2 (C@CH and Ar-C) and 196.3 (C@O).
7. Yadav, V. K.; Babu, K. G. Tetrahedron 2003, 59, 9111–9116.
8. Liu, Y.; Xu, D.; Xu, Z.; Zhang, Y. Oppi Briefs 2007, 39, 190–195.
13. The general procedure for the preparation of the MVK-derived bis-substituted
piperazines 8a,b,e-f is illustrated by the following example.
9. Gaussian 03, Revision E.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.;
Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda,
Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.;
Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford,
S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T., Al-Laham, M. A., Peng, C. Y., Nanayakkara, A.,
Challacombe, M., Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez,
C.; Pople, J. A., Gaussian, Inc., Wallingford CT, 2004.
A
solution of (Z)-3-chloromethyl-4-(2-nitrophenyl)but-3-en-2-one (7a)
(1.00 g; 4.2 mmol) and piperazine (0.36 g; 4.2 mmol) in dry THF (2.0 mL) was
stirred in a stoppered flask for 5 d. The solvent was removed in vacuo and the
crude product was flash chromatographed [on Silica gel; elution with EtOAc-
hexane (1:1)]. Evaporation of the solvent in vacuo, followed by trituration with
EtOAc-hexane [1:1] afforded, as bright yellow crystals, N,N0-bis[(E)-2-acetyl-3-
(2-nitrophenyl)-2-propenyl]-1,4-piperazine (8a) (0.19 g, 19%), mp 174–176 °C
(found [M+1]: 493.2103. Calcd for C26H29N4O6, MH+; 493.2087); mmax (ATR)/
cmꢀ1 1654 (C@O); dH (400 MHz, CDCl3) 2.01 (8H, s, NCH2), 2.44 (6H, s, CH3),
3.04 (4H, s, CCH2), 7.52 (4H, t, J = 8.6 Hz, Ar-H), 7.63 (2H, t, J = Ar-H), 7.81 (2H, s,
C@CH), and 8.13 (2H, d, J = 8.0 Hz, Ar-H); dC (100 MHz,CDCl3) 26.5 (CH3), 52.5
(NCH2), 52.6 (CHCH2), 124.6, 129.1, 131.0, 131.9, 133.2, 138.8, 139.3 and 147.5
(C@CH and Ar-C) and 199.7 (C@O).
N,N0-Bis[(E)-2-acetyl-3-(3-methoxy-2-nitrophenyl)-2-propenyl]piperazine (8b),
as an off-white, fluffy solid (0.17 g, 22%), mp 204-206 °C (found: C, 60.9; H,
6.2; N, 9.8. Calcd. for C28H32N4O8: C, 60.9; H, 5.8; N, 10.1%.); mmax (ATR)/cmꢀ1
1669 (C@O); dH (400 MHz, CDCl3); 2.24 (8H, br s, NCH2), 2.35 (6H, s, COCH3),
3.16 (4H, s, CCH2), 3.90 (6H, s ArOCH3) 7.04 (2H, d, J = 8.0 Hz, Ar-H), 7.20 (2H, d,
J = 7.6 Hz, Ar-H), 7.32 (2H, s, Ar-H), and 8.43 (2H, t, J = 8.0 Hz, Ar-H); dC
(100 MHz,CDCl3) 26.8 (COCH3), 52.7 (NCH2), 53.1 (CCH2), 56.5 (ArOCH3), 112.6,
122.0, 129.4, 131.0, 133.1, 140.5, 142.8 and 150.9 (C@CH and Ar-C) and 199.8
(C@O).
10. The general procedure for the preparation of compounds 6a–d is illustrated by the
following example.
A
solution of methyl 3-hydroxy-2-methylene-3-(2-nitrophenyl)propanoate
(4a) (1.30 g, 5.48 mmol) and piperazine (0.41 g, 4.8 mmol) in dry THF (5 mL)
was stirred in a stoppered flask at rt for 24 h. The solvent was removed in
vacuo and the crude product flash chromatographed [on silica gel; elution with
hexane-EtOAc (1:1)] to afford, as
carbomethoxy-3-hydroxy-3-(2-nitrophenyl)propyl]piperazine
55%), mp 78–82 °C (found [M+1]: 561.2214. Calcd for C26H33N4O10
a
yellowish-green solid, N,N0-bis[2-
(6a)20
(0.74 g,
MH+:
,
N,N0-Bis[(E)-2-acetyl-3-(4-chloro-2-nitrophenyl)-2-propenyl]piperazine (8e), as a
bright-yellow powder (0.06 g, 9%), mp 139–140 °C (found [M+1]: 561.1281.
Calcd. for C26H27N4O6Cl2, MH+: 561.1308); mmax (ATR)/cmꢀ1 1689 (C@O); dH
(400 MHz, CDCl3) 2.06 (8H, d, J = 16 Hz, NCH2), 2.45 (6H, s, CH3), 3.05 (4H, s,
CCH2), 7.61 (4H, 2ꢂ d, J = 8.0 Hz, Ar-H), 7.75 (2H, s, Ar-H), and 8.12 (2H, s, Ar-
H); dC (100 MHz,CDCl3) 26.4 (CH3), 52.4 (NCH2), 52.5 (CCH2), 124.8 (2C), 130.2,
132.3, 133.3, 135.0, 137.7 and 139.9 (C@CH and Ar-C) and 199.2 (C@O).
N,N0-Bis[(E)-2-acetyl-3-(5-chloro-2-nitrophenyl)-2-propenyl]piperazine (8f), as
bright yellow crystals (0.04 g, 13%), mp 197–199 °C (found: C, 55.5; H, 4.8;
N, 9.9. Calcd for C24H26N4O6Cl2: C, 55.6; H, 4.7; N, 10.0%.); mmax (ATR)/cmꢀ1
1686 (C@O); dH (400 MHz, CDCl3) 2.09 (8H, br s, NCH2), 2.46 (6H, s, CH3), 3.06
(4H, s, CCH2), 7.47 (2H, d, J = 8.8 Hz, Ar-H), 7.83 (4H, d, J = 12.4 Hz, Ar-H) and
8.10 (2H, dd, J = 2.0 and 8.8 Hz, Ar-H), dC (100 MHz,CDCl3) 26.3 (CH3), 52.2
(NCH2), 52.5 (CCH2), 126.0, 129.0, 131.5, 133.5, 137.9, 140.1 and 145.9 (C@CH
and ArC) and 199.1 (C@O).
561.2197); mmax KBr/cmꢀ1 3353 (OH) and 1732 (C@O); dH (400 MHz; CDCl3)
2.77 and 3.03 (4H, 2ꢂ m, CHCH2), 3.26 (2H, m, CHCH2), 3.50 (6H, s, OCH3), 3.78
(8H, m, NCH2), 5.54 (2H, d, J = 5.2 Hz, CHOH), 7.40 (2H, t, J = 4.8 Hz, Ar-H), 7.56
(2H, t, J = 5.0 Hz, Ar-H), 7.62 (2H, d, J = 4.4 Hz, Ar-H) and 7.75 (2H, d, J = 5.6 Hz,
Ar-H); dC (100 MHz; CDCl3) 47.9 (CHCH2), 52.0 (OCH3), 52.1 (NCH2), 59.2
(CHCH2), 73.3 (CHOH), 124.3, 128.6, 129.3, 132.4, 136.1 and 149.0 (Ar-C) and
171.7 (C@O).
N,N0-Bis[2-carbomethoxy-3-hydroxy-3-(3-methoxy-2-nitrophenyl)propyl]piperazine
(6b)20
C
,
as
a yellow oil (0.12 g, 8%) (found [M+1]: 621.2392. Calcd for
28H37N4O12, MH+: 621.2408); mmax KBr/cmꢀ1 3358 (OH) and 1730 (C@O); dH
(400 MHz; CDCl3) 2.14-2.74 (10H, m, CHCHA and NCH2), 3.04 (2H, m, CHCHB),
3.28 (2H, m, CHCH2), 3.61(6H, s, OCH3), 3.85 (6H, s, Ar-OCH3), 5.07 (2H, t,
J = 9.8 Hz CHOH), 6.87 (2H, d, J = 7.6 Hz Ar-H), 6.94 (2H, m, Ar-H) and 7.31 (2H,
m, Ar-H); dC (100 MHz; CDCl3) 47.3 (CHCH2), 51.9 (OCH3), 56.6 (NCH2), 56.4
(Ar-OCH3), 59.7 (NCH2), 75.3 (CHOH), 112.0, 119.9, 130.4, 134.5, 140.2 and
151.0 (Ar-C) and 171.2 (C@O).
14. Yu, C.; Levy, G. C. J. Am. Chem. Soc. 1984, 106, 6533–6537.
15. Goldberg, O.; Dreiding, A. S. Helv. Chim. Acta 1976, 59, 1904–1910.
16. PC SPARTAN-pro v.1.05, Wavefunction Inc., Irvine.
17. Clayden, J. P.; Greeves, N.; Warren, S.; Wothers, P. D. in: Organic Chemistry;
Oxford University Press: Oxford, 2001.
N,N0-Bis[2-carbomethoxy-3-hydroxy-3-(6-chloro-2-nitrophenyl)propyl]piperazine
(6c)20
C
,
as
a
yellow solid (30 mg, 5%) (found [M+1]: 629.1357. Calcd for
26H31N4O10Cl2, MH+: 629.1417); mmax KBr/cmꢀ1 3375 (OH) and 1728 (C@O);
dH (400 MHz; CDCl3) 2.15 and 2.40 (8H, 2ꢂ m, NCH2), 2.54 (4H, m, CHCH2), 3.50
(6H, s, OCH3), 3.59 (2H, m, CHCH2), 5.58 (2H, m, CHOH), 7.29-7.57 (6H, m, Ar-H);
dC (100 MHz; CDCl3) 44.3 (CHCH2), 48.8 (OCH3) 52.2 (NCH2), 56.6 (CHCH2), 73.7
(CHOH), 123.0, 128.9, 133.1, 134.9, 151.5 and 170.8 (Ar-C) and 173.4 (C@O).
18. Madapa, S.; Singh, V.; Batra, S. Tetrahedron 2006, 62, 8740–8747.
19. Shi, M.; Jian-Kang, J.; Shi-Cong, C. Molecules 2001, 6, 852–868.
20. As a mixture of diastereomers; NMR data cited for the major diastereomer.