Studies in 3-oxy-assisted 3-aza Cope rearrangements

Article abstract of DOI:10.1039/b200469k

On thermolysis appropriately substituted N-silyloxy-N-allyl enamines undergo smooth 3,3-sigmatropic rearrangments to the corresponding N-silyloxy imino ethers.

Full text of DOI:10.1039/b200469k

Studies in 3-oxy-assisted 3-aza Cope rearrangements†
Mário J. S. Gomes, Lalit Sharma, Sundaresan Prabhakar,* Ana M. Lobo* and Paulo M. C. Glória (in
part)
Secção de Química Orgânica Aplicada, Departamento de Química, CQFB-REQUIMTE, and,
SINTOR-UNINOVA, campus FCT-UNL, Quinta da Torre, 2829 Monte de Caparica, Portugal.
E-mail: sp@dq.fct.unl.pt
Received (in Cambridge, UK) 15th January 2002, Accepted 21st February 2002
First published as an Advance Article on the web 11th March 2002
On thermolysis appropriately substituted N-silyloxy-N-allyl
enamines undergo smooth 3,3-sigmatropic rearrangments to
the corresponding N-silyloxy imino ethers.
substances provided the corresponding hydroxylamines. O-
Silylation6 of the latter furnished the title compounds 6. They
underwent nucleophilic addition smoothly7 to ethynyl-p-to-
lylsulfone and methyl propiolate to provide the N-silyloxy-N-
allyl enamines 1d required for our study (Scheme 1, Table
1).‡
Cope rearrangement is an important reaction in organic
synthesis. This pericyclic process involving 1,5-hexadienes
generally proceeds under drastic conditions (i.e. high tem-
peratures and prolonged reaction times) and in poor to modest
yield1 [eqn. (1); 1a to 2a]. The 3-aza analogue of the above
reaction involving uncharged molecules, first reported by Hill,2
also requires high temperatures for the rearrangements to occur
[eqn. (1); 1b to 2b]. Although the presence of an ether
functionality
Table 1 Michael addition products 1d from O-silyl hydroxylamines 6
O-Silyl
hydroxyl-
amine 6
1,4-Addition
product 1db
Yielda
(%)
#
Allyl alcohol 3
yielda(%)
1
2
3
4
5
6
7
R1 = R2 = R3 = H
63
R5 = SO2Tol
R5 = SO2Tol
R5 = SO2Tol
R5 = SO2Tol
R5 = SO2Tol
R5 = SO2Tol
R5 = CO2Me
70
72
76
78
77
75
70
R1 = R3 = H; R2 = Me 60
R2 = R3 = H; R1 = Me 58
R1 = R2 = H; R3 = Me 24
R1 = R3 = H; R2 = Ph 62
R2 = R3 = H; R1 = Ph 87
(1)
R1 = R2 = R3 = H
63
a Isolated yields. b R4 = H , Tol = p-MeSO2C6H4
The thermal rearrangements of the above substances were
conducted in o-dichlorobenzene under reflux (188 °C) (ca. 0.03
M) and the results are collected in Table 2.§
at C-3 [eqn. (1); 1c to 2c] in the all carbon framework has been
found to improve the overall efficiency of the process,3 the
effect of such a substituent in the 3-aza version is so far not
reported. We disclose in this communication the first experi-
mental realisation with the latter type of functionality which
consists of thermolysis of a number of N-silyloxy-N-allyl
enamines [eqn. (1); 1d to 2d] and show that the corresponding
3,3-sigmatropic rearrangement products, the oxime-ethers 2d,
are obtained in good to excellent yields.
O-Silyl-N-allyl hydroxylamines were secured as follows: the
appropriate allyl alcohol 3 and N,O-bis-tert-butoxycarbonyl
hydroxylamine (4) were condensed by Mitsunobu’s method4 to
give the corresponding N-allyl-O-acyl hydroxamic acid 5
(Scheme 1). Removal5 of the protecting groups from these
Examination of the Table shows that the reactions occur in
consistently good yield to provide the oxime ethers 2d as a
mixture of the syn and anti isomers. Under virtually identical
experimental conditions the cyclohexyl enamines 1b (R =
cyclohexyl; R1 = R2 = R3 = R4 = H; R5 = SO2Tol or R1 =
R2 = R3 = R4 = H; R5 = CO2Me) showed no tendency to
undergo the aza-Cope reaction, underlining the importance of
the silyloxy group in promoting the rearrangement.
The occurrence of 1,3-shifts in these reactions is excluded
because of the presence of the characteristic 2H multiplet due to
1
H2CNCH group in the H NMR spectra of the products 2d
(Table 2; entries 3 and 6) centred at ca. d 5.0 ppm and the
absence of the same in that of 2d (entry 4). In those reactions,
wherein two stereogenic centres are created in the products
(Table 2; entries 3 and 6), high diastereoselection was observed.
The oxime pair, in each case, contained one predominant
diastereomer ( > 80% by 1H NMR analysis).
Table 2 Rearrangement of N-silyloxy enamines 1d to oxime ethers 2d
Oxime
Reaction ether 2d Ratio
Time
(min)
yielda
(%)
syn+
#
Enamine 1d
antib
1
2
3
4
5
6
7
R1 = R2 = R3 = H; R5 = SO2Tol
80
82
81
79
80
80
78
80
63+37
82+18
50+50
50+50
99+1
37+63
60+40
R1 = R3 = H; R2 = Me; R5 = SO2Tol 70
R2 = R3 = H; R1 = Me; R5 = SO2Tol 165
R1 = R2 = H; R3 = Me; R5 = SO2Tol 25
R1 = R3 = H; R2 = Ph; R5 = SO2Tol 15
R2 = R3 = H; R1 = Ph; R5 = SO2Tol 240
Scheme 1 Reagents and conditions: i, diisopropylazodicarboxylate, PPh3;
THF, rt; ii, CF3CO2H (4 eq.), CH2Cl2, rt; iii, TBDMSCl, imidazole, DMF,
rt; iv, HCM CR5 (1 eq.), CH3CN or CH2Cl2, rt.
R1 = R2 = R3 = H; R5 = CO2Me
60
a Isolated yields. b By 1H NMR (see, ref. 8).
† Dedicated with respect to the late Professor T. R. Govindachari.
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CHEM. COMMUN., 2002, 746–747
This journal is © The Royal Society of Chemistry 2002

1151 cm21 1H NMR (400 MHz, CDCl3): 2.42 and 2.43 (3H, two s),
;
4.90–5.15 (2H, m), 6.82 and 7.36 (1H, two d).
In conclusion, the first examples of 3-silyloxy-assisted 3-aza
Cope reactions are reported. They are shown to occur in good to
excellent yields.
We thank Fundação para a Ciência e a Tecnologia (FC&T,
Portugal) for financial support (Project POCTI/QUI/36456) and
Dr S. N. Swami (Pfizer, UK) for the interest shown. Two of us,
M. J. S. G. and L. S., are grateful for the award of a doctoral and
a postdoctoral fellowship respectively, from FC&T.
1 A. C. Cope and E. M. Hardy, J. Am. Chem. Soc., 1940, 62, 441; H. Levy
and A. C. Cope, J. Am. Chem. Soc., 1944, 66, 1684.
2 R. K. Hill and N. W. Gilman, J. Chem. Soc., Chem. Commun., 1967, 619;
R. K. Hill and N. W. Gilman, Tetradedron Lett., 1967, 15, 1421. For a
review, see: R. P. Lutz, Chem. Rev., 1984, 84, 205. For examples of
asymmetric 3-aza Cope rearrangements, see: D. Enders, M. Knopp and
R. Schiffers, Tetrahedron: Asymmetry, 1996, 7, 1847.
Notes and references
‡ All addition products 1d were deduced (1H NMR) to possess the trans
arrangement of the olefinic bond bearing the electron withdrawing group
R5.
§ Typical experimental procedure: trans-1-N-allyl-N-(tert-butyldimethylsi-
lyloxy)amino-2-(p-tolylsulfonyl)ethylene (1d, Table 2, entry 1) (25 mg), in
o-dichlorobenzene (2 mL), was heated under reflux until all the starting
material had been consumed (80 min) (tlc control, silica, Et2O+n-hexane
1+3, as eluent). Evaporation of the solvent under reduced pressure, followed
by purification of the residue by ptlc, gave the product, a viscous oil (20.5
mg, 82% yield), as a mixture of syn and anti oxime-ethers (2d, Table 2,
entry 1). Selected spectroscopic data: IR (neat) 1642, 1597, 1325, 1252,
3 J. A. Berson and E. J. Walsh, J. Am. Chem. Soc., 1968, 90, 4729; Y.
Fujita, T. Onishi and T. Nishida, Synthesis, 1978, 934.
4 A. O. Stewart and D. W. Brooks, J. Org. Chem., 1992, 57, 5020.
5 R. D. Connell, T. Rein, B. Akermark and P. Helquist, J. Org. Chem.,
1988, 53, 3845.
6 J. C. Gilbert and K. R. Cousins, Tetrahedron, 1994, 50, 10671; E. J.
Corey and A. Venkateswarlu, J. Am. Chem. Soc., 1972, 94, 6190.
7 W. E. Truce and D. G. Brady, J. Am. Chem. Soc., 1966, 31, 3543.
8 R. M. Silverstein, Spectrometric Identification of Organic Compounds,
6th Edition; John Wiley and Sons, Chichester, UK, 1998, p. 210 (values
of d 7.25 and 6.65 attributed respectively to the imino proton
RCH = NOH of the syn and anti aldoximes).
CHEM. COMMUN., 2002, 746–747
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