Conjugated addition of bis(oxazolinyl)zinc to substituted 2-nitrovinyl benzenes: an alternative synthesis of (±)-Rolipram

Article abstract of DOI:10.1016/j.tetlet.2006.12.007

In this letter we present a new 2,4,4-trimethyl-2-oxazoline anion-zinc derivative that has a remarkable thermal stability when compared with the corresponding cyanocuprate counterpart. The yields from conjugated addition to several 2-nitrovinyl benzenes are moderate to good and the reaction itself is easier to execute and cleaner. As an application, this methodology was applied to an alternative synthesis of (±)-Rolipram, a drug with several interesting biological activities.

Full text of DOI:10.1016/j.tetlet.2006.12.007

Tetrahedron Letters 48 (2007) 1507–1509
Conjugated addition of bis(oxazolinyl)zinc to substituted
2-nitrovinyl benzenes: an alternative synthesis of ( )-Rolipram
*
´
´
Alfredo R. M. Oliveira, Jose A. F. P. Villar, Fabio Simonelli, Rogerio A. Gariani,
Celso L. Wosch and Paulo H. G. Zarbin
Departamento de Quı´mica, Universidade Federal do Parana´, PO Box 19081, 81531-990 Curitiba-PR, Brazil
Received 19 April 2006; revised 30 November 2006; accepted 4 December 2006
Available online 17 January 2007
Abstract—In this letter we present a new 2,4,4-trimethyl-2-oxazoline anion-zinc derivative that has a remarkable thermal stability
when compared with the corresponding cyanocuprate counterpart. The yields from conjugated addition to several 2-nitrovinyl benz-
enes are moderate to good and the reaction itself is easier to execute and cleaner. As an application, this methodology was applied to
an alternative synthesis of ( )-Rolipram, a drug with several interesting biological activities.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
N
N
N
Zn
2
Cu(CN)Li2
2
Conjugated addition is a recognized method for the con-
struction of new carbon–carbon bond employing an
organometallic compound.1 Conversely, nitroolefins
are powerful Michael acceptors and versatile intermedi-
ates, since the nitro group can be converted into a vari-
ety of functional groups, among them, an amino group.2
Organozinc compounds generally display a remarkable
functional group tolerance3 and polyfunctional mole-
cules can be obtained by the conjugate addition of this
type of reagent. However, the results are dependent
not only on the structure of the Michael acceptor but
also on the nature of the nucleophile to be transferred.4,5
O
(2)
O
O
(1)
(3)
Li
Figure 1. 2,4,4-Trimethyl-2-oxazoline anion derivatives.
investigate the thermal stability and chemical reactivity
of the zinc derivative9 (3), as shown in Figure 1.
2. Results and discussion
Compound (3) was available from the reaction of 2,4,4-
trimethyl-2-oxazoline anion (1) and a stock solution of
ZnCl2 (0.5 mol/L) in THF at À78 ꢁC (Scheme 1). The
resulting bis(oxazolinyl)zinc (3) shows remarkable ther-
mal stability and is easier to obtain than compound (2).
As pointed out previously,6 the 1,4-transfer of the 2,4,4-
trimethyl-2-oxazoline anion (1) would be very useful as
a carboxymethyl equivalent addition procedure. As
expected, the addition of lithiated anion (1) to a,b-unsatu-
rated systems yielded ꢀ20% of the 1,4-addition product
in a complex mixture of side products. In fact, the con-
jugated addition of bis(oxazolinyl)cyanocuprates (2) to
a,b-unsaturated systems has been recently reported
and was applied to the synthesis of lactams, and d or
c-amino acids.7,8 However, the thermal stability of
cyanocuprates (2) was a major drawback and compound
(2) readily decomposes above À30 ꢁC limiting its appli-
cations. To overcome this limitation, we decided to
In order to understand the scope and limitations of this
system, bis(oxazolinyl)zinc (3) was reacted with the
2-nitrovinyl benzene derivatives (4–8), which were
prepared by condensing nitromethane with an appropri-
ate aromatic aldehyde.10 The results are summarized in
Table 1.
N
N
ZnCl /THF
2
Zn
2
O
(1)
(0.5 mol/L)
O
Li
-78 ºC
0 ºC
(3)
*
Corresponding author. Tel.: +55 41 3361 3269; fax: +55 41 3361
3186; e-mail: armo@quimica.ufpr.br
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.007

1508
A. R. M. Oliveira et al. / Tetrahedron Letters 48 (2007) 1507–1509
Table 1.
Table 2.
Electrophileb
Product
(%)a
95
Electrophileb
Product
(%)a
O2N
NO2
N
O
O
N
O
95
(4)
Ph
Ph
HO
(9)
(14)
Ph
Ph
(18)
O2N
N
NO2
73
70
O
(5)
O
O
Cl
N
(10)
93
Cl
p
-O2NPh
Ph
HO
(15)
O2N
Ph
p
-O2NPh
NO2
N
(19)
O
(6)
(7)
O
MeO
OH
(11)
(12)
N
O
MeO
80
80
O2N
NO2
N
(20)
(16)
O
60
15
N
EtO
CN
EtO
O
NH2
OMe
(17)
OMe
O2N
(21)
N
NO2
a Isolated yield.
O
b All compounds were identified by 1H NMR and 13C NMR and gave
consistent data.
(8)
N
(13)
N
a Isolated yield.
sponding zinc cyanocuprate, which was immediately
reacted with 2-cyclohexen-1-one, yielding a mixture of
1,2 and 1,4 addition products as shown in Scheme 2.
Adding a third equivalent of oxazoline lithium anion
to the zinc cyanocuprate above gave better 1,4 addition
results and exhibits a similar thermal stability.
b All compounds were identified by 1H NMR and 13C NMR and gave
consistent data.
The addition of bis(oxazolinyl)zinc (3), to 2-nitrovinyl
benzene (4) at À78 ꢁC, followed by slow warming to
room temperature, yielded (9) in a 95% yield.11 This
reaction gave consistent results, even after maintaining
compound (3) for 5 h at 0 ꢁC before the addition of
(4). No ypso-type substitution product was detected.12
All the yields obtained are moderate to good and the
reactions were clean and easy to purify. An exception
was the amino compound (8), which gave a poor addi-
tion result, probably due to its low solubility in cold
THF.13
This methodology was successfully applied to the syn-
thesis of ( )-Rolipram17 (26) (a c-lactam), which is an
inhibitor of (PDE)-IV,18 a cyclic adenosine monophos-
phate (cAMP)-specific phosphodiesterase. Rolipram
also is employed in the treatment of depression.19 To
accomplish this synthesis, 2-nitrovinyl benzene substrate
(24)20 was prepared in two steps from isovanilin (23) in
an 82% overall yield. The addition of bis(oxazolinyl)zinc
(3) to (24) afforded, after work up, compound (25)21 in
an 80% yield. Compound (25) was then hydrolyzed
and esterified22 to the corresponding ethyl ester in a
72% crude yield. The resulting mixture was reduced23
Besides 2-nitrovinyl benzene derivatives, three enones
(14–16) and one 2-cyanovynil benzene derivative (17)
were also tested as electrophiles. As expected, only 1,2-
addition compounds were isolated in excellent yields
(Table 2). However, the addition of compound (3) to
the cyanoalkene derivative (17) gave a result similar to
the one reported by Fustero et al.14 using saturated nitr-
iles (Blaise reaction).15 In our example, compound (21)
was isolated as a mixture of isomers.
O
N
O
1) CuCN.2LiCl
O
HO
N
N
+
Zn
O
O
Another attempt to modify the chemical reactivity of (1)
was made by using copper cyanide salt16 as the additive
and changing the lithium anion/zinc ratio. The addition
of CuCNÆ2LiCl to compound (3), at À78 ꢁC followed by
a slow warming to 0 ꢁC, presumably generates the corre-
n
2)
(3)
n = 2 (20) - 43%
n = 3 (20) - 23%
(22) - 41%
(22) - 70%
n = 2, 3
Scheme 2.

A. R. M. Oliveira et al. / Tetrahedron Letters 48 (2007) 1507–1509
1509
argon, was cooled in a dry ice/acetone bath (À78 ꢁC) and
n-BuLi (4.2 mmol) was added dropwise. After stirring for
30 min at À78 ꢁC, a solution of ZnCl2 (4.2 mL of 0.5 mol/
L in THF) was added to the oxazoline anion and the
resulting solution was stirred at À78 ꢁC for 15 min and
transferred to an ice bath at 0 ꢁC for 30 min. After this
period, the solution was cooled at À78 ꢁC and a solution
of appropriate 2-nitrovinyl benzene (2 mmol) in dry THF
(4 mL) was added. The reaction was slowly warmed to
room temperature, then quenched with saturated aqueous
NH4Cl solution. The mixture was extracted with ethyl
acetate (3 · 20 mL) and dried over anhydrous Na2SO4.
The product was isolated by filtration, followed by solvent
removal under vacuum and then purified by flash chro-
matography (ethyl acetate/hexane 2:1). Spectral data of
O
HO
, K CO , 90%
Br
O
NO
2
2
3
1)
H
(24)
2) MeNO , NH OAc, 91%
MeO
2
4
MeO
(23)
O
THF
N
Zn
2
-78ºC
rt
80%
(3)
N
O
O
N
H
O
1) H SO , EtOH, 5% H O
O
NO
2
4
2
2
1
72% crude yield
(9): H NMR (200 MHz, CDCl3) d: 1.10 (s, 3H); 1.18 (s,
MeO
,
2) NiCl NaBH , EtOH
3H); 2.67 (d, J = 7.8 Hz, 2H); 3.79–3.97 (m, 3H); 4.79 (dd,
J1 = 12.72 Hz, J2 = 8.02 Hz, 1H); 4.73 (dd, J1 = 12.72 Hz,
J2 = 7.05 Hz, 1H); 7.20–7.33 (m, 5H). 13C NMR (50 MHz,
CDCl3) d: 28.18; 32.13; 41.10; 67.18; 79.11; 79.46; 127.40;
127.93; 129.00; 138.38; 162.40.
MeO
2
4
(26)
(25)
80%
Scheme 3.
12. Rimkus, A.; Sewald, N. Org. Lett. 2002, 4, 3289–
3291.
13. When the THF solution was cooled to À78 ꢁC most of
compound (8) precipitates and is recovered at the end of
the reaction.
to the corresponding amino ester to form lactam (26)24
in an 80% yield (Scheme 3).
´
14. Fustero, S.; Dıaz, D.; Barluenga, J.; Aguilar, E. Tetra-
Acknowledgements
hedron Lett. 1992, 33, 3801–3804.
´
15. (a) Fustero, S.; Dıaz, M. D.; Asensio, A.; Navarro, A.;
The authors gratefully acknowledge the financial sup-
Kong, J.-S.; Aguilar, E. Tetrahedron 1999, 55, 2695–2712;
(b) Lee, A. S. Y.; Cheng, R.-Y. Tetrahedron Lett. 1997, 38,
443–446.
´
port of CNPq, CAPES and Fundac¸ao Araucaria and
˜
the fellowship from CAPES to J.A.F.P.V. and R.A.G.
16. Knochel, P.; Rozema, M. J.; Tucker, C. E. In Organo-
copper Reagents: A Practical Approach; Taylor, R. J. K.,
Ed.; Oxford University Press: Oxford, UK, 1994.
17. Demnitz, J.; LaVecchia, L.; Bacher, E.; Keller, T. H.;
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21. Spectral data of (25): 1H NMR (200 MHz, CDCl3) d: 1.07
(s, 3H); 1.13 (s, 3H); 1.40–1.60 (m, 2H); 1.40–1.90 (m, 6H);
2.59 (d, J = 7.81 Hz, 2H); 3.70–3.90 (m, 6H); 4.53 (dd,
J1 = 12.45 Hz, J2 = 8.05 Hz, 1H); 4.66 (m, 3H); 6.60–6.80
(m, 3H). 13C NMR (50 MHz, CDCl3) d: 149.88; 147.98;
130.85; 125.63; 119.52; 114.70; 112.37; 80.73; 79.98; 56.22;
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1
2.00 ppm (m, 8H); 2.48 (dd, J2 = 8.8 Hz, J2 = 17.22 Hz,
1H); 2.73 (dd, J1 = 8.8 Hz, J2 = 16.82 Hz, 1H); 3.39 (dd,
J1 = 7.05 Hz, J1 = 8.8 Hz); 3.50–3.85 (m, 2H); 3.84 (s,
3H); 4.70–4.83 (m, 1H); 6.43 (s, 1H); 6.75–6.87 (m, 3H).
13C NMR (50 MHz, CDCl3): 24.22; 33.02; 38.31; 40.19;
49.98; 56.35; 80.81; 112.43; 114.06; 119.02; 134.74; 148.13;
177.97.
11. General procedure: A flask containing 2,4,4-trimethyl-2-
oxazoline (0.535 mL, 4.2 mmol) and 9 mL of THF under