Poster_Rotterdam_1 [Modo de compatibilidad]

Hetero-Diels–Alder Reaction of Phosphorus Substituted
Nitroso Alkenes with Cyclopentadiene: an Experimental and
Computational Study
July 8−12, 2012
Conference center "De Doelen"
Rotterdam, The Netherlands
Jesús M. de los Santos*, Roberto Ignacio, Gloria Rubiales, Domitila Aparicio and Francisco Palacios
Departamento de Química Orgánica I, Facultad de Farmacia, Centro de Investigaciones y Estudios Avanzados “Lucio Lascaray”, Universidad
del País Vasco UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
e-mail: jesus.delossantos@ehu.es
Introduction
Nitroso alkenes [1] I are functionalized nitroso derivatives, and the presence of an
adjacent double bond in conjugation with the nitroso moiety introduces new reactivity
centers in these substrates and then increases their synthetic value, especially as
heterodienes for a [4+2] cycloaddition reaction [2]. These nitroso alkenes I may react
with dienes, in a Diels–Alder reaction, either as dienophile (2π-electron system) through
the nitroso group (mode i) or involving the carbon–carbon double bond (mode ii), or as
4π-electron (heterodiene component) (mode iii) (see Scheme 1). This drove us to explore
the reactivity of phosphorus substituted nitroso alkenes I (R1 = POPh2, P(OEt)2) toward
conjugated cyclic dienes.
Scheme 1. Diels– Alder reactivity pattern of nitroso alkenes I with dienes.
Results and discusion
The addition of cyclopentadiene to the highly reactive 4-phosphinyl (1a, R = Ph) or 4phosphonyl nitroso alkene (1b, R = OEt), generated in situ from α-bromooximes [3],
in CH2Cl2 at room temperature was performed. The highly coloured 1,2-oxazabuta1,3-dienes 1 disappeared very fast, showing the end of the reaction with the
formation, rather than the hetero-Diels–Alder 1,2-oxazine 2, the phosphorated 2oxa-3-azabicyclic derivatives 3 in good yields as sole adducts (Scheme 2).
nDA
HDAb
HDAa
Figure 1. Fully optimized endo transition structures with the lower activation energies for the reaction of
nitroso alkene 1a and cyclopentadiene. The numbers given in parentheses correspond to the relative energy
differences (in Kcal/mol) of TS3aa–endo and TS4aa–endo with respect to TS1aa–endo calculated at
B3LYP/6-31G* + DZPVE level of theory. Numbers in square brackets are the relative energies differences
calculated at B3LYP(PCM)/6-31G* using methylene chloride as solvent.
For the reaction of TMS-cyclopentadiene and nitroso alkenes 1, at all of levels of
theory examined, thermodynamics favour cycloadducts 6a,b over 7a,b–endo
(corresponding to the nitroso-Diels-Alder reaction) . Therefore, in these cases
cycloadducts 6a,b could be the only compounds obtained under both kinetic and
thermodynamic control. These results are in agreement with the regioselectivity
observed experimentally for the reaction of nitroso alkenes 1 and TMScyclopentadiene.
Scheme 2. Nitroso-Diels–Alder reaction of phosphorated nitroso alkenes 1with cyclic dienes.
1,2-Oxazines 5 generated by heating compounds 3 seems to be the result of an
initial [4+2] cycloaddition, in which the nitroso alkene acts as a dienophile, through
the nitroso group, while the cyclopentadiene acts as diene to afford 2-oxa-3azabicyclic compounds 3. These adducts 3 may undergo an aza-Cope rearrangement
to give 1,2-oxazines 4 (Scheme 2). Compounds 4, with the bulky phosphorus
substituent at C–4 in anti position with respect to H–4a and H–7a, may suffer an
imine-enamine tautomeric process to give 1,2-oxazines 5 with the bulky phosphorus
substituent in syn position with respect to H–4a and H–7a, as confirmed by the NOE
experiments.
The reaction of nitroso alkenes 1 with other cyclic conjugated dienes, such as 5(trimethylsilyl)cyclopentadiene showed a different reactivity pattern, affording 1,2oxazine derivatives 6 in good yields and in a regio- and steroselective fashion
(Scheme 2). The formation of silylated oxazines 6 can be explained by a
regioselective [4+2] cycloaddition reaction with the nitroso alkene as the 4π-electron
system (Scheme 1, route iii). The initial formed oxazine with the bulky phosphorus
substituent at C–4 in anti position with respect to H–4a and H–7a epimerized to
oxazine 6. Computational studies showed that oxazine 6 is thermodynamically
favored because the latter is about 4 Kcal/mol-1 more stable than the former oxazine.
For the reaction of nitroso alkenes 1 with cyclopentadiene, upon the optimization at
the B3LYP/6-31G* + ZPVE level, the computational results indicate that the formation
of cycloadducts 3a,b–endo through transition state structures TS1a,b–endo, for the
nitroso-Diels–Alder reaction have lower activation barriers than those observed when
nitroso alkenes 1 act as heterodienes reacting through TS3–endo or TS4–endo for
the Hetero-Diels–Alder reaction (HDA) (Figure 1).
References
[1] For an excellent review see: Gilchrist, T. L. Chem. Soc. Rev. 1983, 12, 53–73.
[2] Selected reviews: (a) Gilchrist, T. L.; Wood, J. E. Comprehensive Heterocyclic
Chemistry II; Boulton, A. J., Ed.; Pergamon: Oxford, 1996; Vol. 6, pp 279–299. (b)
Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1–120.
[3] (a) de los Santos, J. M.; Ignacio, R.; Aparicio, D.; Palacios, F. J. Org. Chem. 2007,
72, 5202–5206. (b) de los Santos, J. M.; Ignacio, R.; Aparicio, D.; Palacios, F.;
Ezpeleta, J. M. J. Org. Chem. 2009, 74, 3444–3448. (c) de los Santos, J. M. Ignacio,
R.; Rubiales, G.; Aparicio, D.; Palacios, F. J. Org. Chem. 2011, 76, 6715–6725.
HDAb
nDA
Figure 2. endo Transition structures with the lower activation energies and adducts for the cycloaddition of
nitroso alkene 1b and TMS-cyclopentadiene. Bold numbers over the arrows correspond to the relative
energies calculated at B3LYP/6-31G* + ZPVE level. Numbers within parentheses correspond to relative
energies calculated at M06-2X/6-31G*//B3LYP/6-31G* + ZPVE level.
Conclusions
As far as we know, this process represents the first example of a tandem reaction of
an initial [4+2] cycloaddition reaction of the nitroso alkene, and subsequently a new
[3,3]-sigmatropic (aza-Cope) rearrangement to give 1,2-oxazine derivatives 5.
Computational and experimental studies indicate that conjugated nitroso alkenes 1
participate as 2π-electron components, through the nitroso group, toward
cyclopentadiene. However, nitroso alkenes 1 react as 4π-electron system toward
TMS-cyclopentadiene.
Acknowledgements
This work was financially supported by the Universidad del País Vasco–Departamento de
Educación, Universidades e Investigación del Gobierno Vasco (GIU-09/57; IT-422-10) and
Dirección General de Investigación del Ministerio de Ciencia e Innovación (DGI, CTQ200912156 BQU). We also thank SGIker technical support for computational resources, and
NMR spectra (MCINN, GV/EJ, European Social Found).