Studies in N-amino-3-aza Cope rearrangements

Article abstract of DOI:10.1016/j.tetlet.2008.10.047

The first examples of a N-amino-3-aza Cope rearrangement as well as the first N-amino-anion 3-aza Cope rearrangement are reported. These occur in good to excellent yields and in short reaction times.

Full text of DOI:10.1016/j.tetlet.2008.10.047

Tetrahedron Letters 49 (2008) 7355–7357
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Studies in N-amino-3-aza Cope rearrangements
*
*
Paulo M. C. Glória, Sundaresan Prabhakar , Ana M. Lobo
Secção de Química Orgânica Aplicada, Departamento de Química, CQFB-REQUIMTE and SINTOR-UNINOVA, Campus FCT-UNL, Quinta da Torre, 2829-516 Monte de Caparica, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The first examples of a N-amino-3-aza Cope rearrangement as well as the first N-amino-anion 3-aza Cope
rearrangement are reported. These occur in good to excellent yields and in short reaction times.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 16 September 2008
Revised 2 October 2008
Accepted 10 October 2008
Available online 17 October 2008
Keywords:
3-aza Cope
Rearrangement
Thermolysis
Anionic
Hydrazine
Pyrazolone
The increasing concern about green processes in organic syn-
thesis makes rearrangements the tool of choice to give access to
new functionalities in a molecule with maximum atom economy.1
One of these rearrangements is the 3-aza Cope rearrangement,
which permits an easy way to access imines and aldehydes by
hydrolysis of the former. Because these rearrangements normally
require drastic conditions2 (i.e., high temperatures and prolonged
reaction times), a large body of work has focused on finding condi-
tions and catalysts for such transformations.3 For example, the
presence of an oxygen attached to the 3-position of these systems
enables the rearrangement to be conducted at lower temperatures
and in good yields.4 In this Letter, the first examples of a N-amino-
3-aza Cope rearrangement as well as its N-anion counterpart are
reported.
The N-allyl-N-(N0,N0-dimethyl) enamines (4a–d) required for
our study were prepared by treating the bromine salts 2a,b (ob-
tained by reaction of N,N-dimethylhydrazine (1) and the corre-
sponding allyl bromide) with NaH. These underwent a2,3 (or1,2
)
rearrangement affording the N-allyl-N0,N0-dimethyl-hydrazines
(3a,b), and were added to the required Michael acceptors without
further purification due to their propensity to be oxidized by air5
(Scheme 1).
Table 1
Rearrangement of N-allyl-N-(N0 ,N0 -dimethyl) enamines
No.
4
Reaction time (min)
Yield of 5 (%)
1
2
3
4
a: R1 = H; R2 = H; R3 = CO2Me
b: R1 = H; R2 = CO2Et; R3 = CO2Et
c: R1 = Me; R2 = H; R3 = CO2Me
d: R1 = Me; R2 = CO2Et; R3 = CO2Et
10
5
30
15
73
82
79
80
Scheme 1.
* Corresponding authors. Tel.: +351 21 2948300; fax: +351 21 2948550.
E-mail address: aml@fct.unl.pt (A. M. Lobo).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.047

7356
P. M. C. Glória et al. / Tetrahedron Letters 49 (2008) 7355–7357
In order to compare the effect of the additional nitrogen in the
3-position with the case when a silyloxy group is present in the
same position,4 enamines 4a–d were subjected to thermolysis in
o-dichlorobenzene under reflux at 180 °C, but no reaction was ob-
served after 7 days. It was then decided to raise the temperature to
259 °C by carrying the thermolysis in diphenylether under reflux,
and under this condition the rearrangement occurs smoothly with
very short reaction times and good yields affording the hydrazones
5a–d (Table 1).6
Despite the fact that the [3,3] sigmatropic rearrangement of the
hydrazine derivatives 4a–d required a higher temperature (259 °C)
than the rearrangement of the corresponding hydroxylamine
derivatives (180 °C),4 it was shown that the presence of the addi-
tional nitrogen atom in the 3-position still favours the 3-aza Cope
rearrangement as evidenced by the short reaction time (Scheme
2a), when compared to a system with an alkyl group connected
in the same 3-position (Scheme 2b).7
Scheme 3.
Following the theoretical study of Gilbert and Cousins,8 which
suggests that a negative charge in the nitrogen connected to posi-
tion 3 of a 3-aza Cope system should favour the rearrangement, it
was decided to study the 3-aza Cope rearrangement of pyrazolone
derivatives 8a–c. These should rearrange as described in Scheme 3,
and pyrazolone 8a when treated with base can generate the N-ami-
no-anion 3-aza Cope system 8a0.
The substrates were prepared by condensation of phenylaceto-
nitrile with ethyl benzoate followed by hydrolysis of the nitrile
with HCl in EtOH. Reaction of the ester 11 with the adequate
hydrazine afforded the corresponding pyrazolones 12a–c, which
were alkylated to give the required allyl pyrazolones 8a–c (Scheme
4). During the alkylation of pyrazolone 12a hydrolysis of the BOC
group was observed, but no formation of the corresponding alkyl-
ation product in this position could be detected.
after characterization was shown not to be the rearrangement
product 9a, but instead the O-alkylated product as a mixture of iso-
mers with a ratio Z/E of 4.5:1, respectively (Scheme 5).
A possible mechanism for this transformation could involve an
initial [3,3] (or [1,3]) rearrangement followed by a retro Claisen
rearrangement with subsequent isomerization of the double bond.
In conclusion, the first examples of a N-amino 3-aza Cope rear-
rangement as well as the first N-amino-anion 3-aza Cope rear-
rangement are reported. These occur in good to excellent yields
and in short reaction times.
The pyrazolones 8a–c were subjected to thermolysis in o-
dichlorobenzene (180 °C). Pyrazolones 8b and 8c afforded the
corresponding rearrangement product, while for pyrazolone 8a
no reaction was observed after 7 days. However, when the temper-
ature was raised to 259 °C by refluxing in diphenylether pyrazo-
lone 8a, the rearranged product 9a was isolated albeit in only
20% yield after 30 min and accompanied by extensive decomposi-
tion (Table 2).
When treated with NaH at room temperature, the pyrazolone
8a did not show any reactivity. The mixture was then refluxed in
o-dichlorobenzene (180 °C) affording a product in 60% yield that
Scheme 4.
Scheme 2.
Table 2
Rearrangement of pyrazolones derivatives
No.
8
Reaction time (min)
Yield of 9 (%)
1
2
3
a: R = H
b: R = Me
c: R = Ph
30
15
10
20a
92
95
a
Reaction in Ph2O (259 °C).
Scheme 5.

P. M. C. Glória et al. / Tetrahedron Letters 49 (2008) 7355–7357
7357
2.42 (2H, m), 2.76 (6H, s), 3.34 (1H, q, J = 7.2 Hz), 3.68 (3H, s), 5.03 (1H, d,
J = 10.4 Hz), 5.07 (1H, d, J = 17.1 Hz), 5.75 (1H, m), 6.48 (1H, d, J = 6.8 Hz). ESIMS
m/z: 184,12146 (C9H16N2O4 require 184,12118).
Acknowledgements
We thank Fundação para a Ciência e a Tecnologia (FC&T, Lisbon,
Portugal) for partial financial support (Project POCTI/QUI/36456).
One of us (P.M.C.G.) is grateful for the award of a fellowship from
FC&T.
7. The rearrangement of enamine 6 (Scheme 2b) was accomplished with the
formation of allyl diethylmalonate (16, 52% yield). The formation of this can be
explained by
a competitive reaction initiated by a Hofmann elimination
affording cyclohexene and the enamine 140 . This can rearrange to form the
imine 15, which can then liberate HCN affording the allyl diethylmalonate (16)
References and notes
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Green Chem. 2007, 9, 976–979.
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J. Am. Chem. Soc. 1944, 66, 1684–1688.
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6. Typical experimental procedure: A solution 0.14 M of the (E)-methyl 3-(1-allyl-
2,2-dimethylhydrazinyl) acrylate (4a, Table 1, entry 1) in diphenylether (1 ml)
was heated under reflux until all the starting materials had been consumed
(10 min) (tlc control, silica, n-hexane/AcOEt 2:1 as eluent). Evaporation of the
solvent under reduced pressure, followed by purification of the residue by ptlc,
gave the stable hydrazone (5a, Table 1, entry 1), as a light yellow oil (73% yield).
Selected spectroscopic data: Compound 4a: IR (neat) 1694 (C@O) cmꢀ1
;
1H NMR
(400 MHz, CDCl3 d): 2.45 (6H, s), 3.57 (3H, s), 3.70 (2H, d, J = 5.6 Hz), 4.71 (1H, d,
J = 8.7 Hz), 5.18–5.12 (2H, m), 5.73 (1H, m), 7.47 (1H, d, J = 11.8 Hz); EIMS m/z
185 [(M+H)+, 100], 184 (M+, 73), 153 (C8H13N2O+, 61), 143 (C6H11N2O2þ, 51).
8. Gilbert, J. C.; Cousins, K. R. Tetrahedron 1994, 50, 10671–10684.
Compound 5a: IR (neat) 1737 (C@O) cmꢀ1 1H NMR (400 MHz, CDCl3) d: 2.57–
;