New nitrogenated siloxy butadienes from 1,3-dichloroacetone

Article abstract of DOI:10.1016/j.tetlet.2006.12.039

New 1-formamido-2-siloxy-1,3-butadienes have been generated from 1,3-dichloroacetone by means of phosphorane formation, formamido substitution, Wittig olefination and silylation. The procedure demonstrates the utility and versatility of this methodology for the formation of polysubstituted dienes, designed as useful building blocks for the synthesis of polycyclic alkaloids and related analogues.

Full text of DOI:10.1016/j.tetlet.2006.12.039

Tetrahedron Letters 48 (2007) 907–910
New nitrogenated siloxy butadienes from 1,3-dichloroacetone
*
´
Dulce Alonso, Esther Caballero, Manuel Medarde and Fernando Tome
Laboratorio de Quı´mica Orga´nica y Farmace´utica, Facultad de Farmacia, 37007 Salamanca, Spain
Received 29 September 2006; revised 8 November 2006; accepted 11 December 2006
Abstract—New 1-formamido-2-siloxy-1,3-butadienes have been generated from 1,3-dichloroacetone by means of phosphorane for-
mation, formamido substitution, Wittig olefination and silylation. The procedure demonstrates the utility and versatility of this
methodology for the formation of polysubstituted dienes, designed as useful building blocks for the synthesis of polycyclic alkaloids
and related analogues.
Ó 2006 Elsevier Ltd. All rights reserved.
In previous papers we described the preparation and
synthetic potential of new 1-phthalimido-2-siloxy-4-
aryl-1,3-butadienes1 in the research directed to the syn-
thesis, using the Diels–Alder cycloaddition reaction,
and evaluation of new cytotoxic agents based on natural
products.2 In view of the synthetic possibilities of 2-sil-
oxy-4-aryl-1,3-butadienes carrying a nitrogen substitu-
ent at position-1 and certain difficulties encountered
during the recovery of the free amino group from the
phthalimido moiety, we decided to prepare other dienes
in this series.
Although there are several possibilities for introducing
this type of nitrogen substituent, we chose the formamido
group, because the presence of the formyl substituent not
only opens the possibility of its removal, but also sug-
gests its use for further cyclisation reactions regarding
the synthesis of fused polyheterocyclic systems (Fig. 1).
Figure 1. 1-Formamido-2-siloxy-4-aryl-1,3-butadienes and examples of their potential applications in synthesis.
Keywords: 1-Formamido-1,3-butadienes; 1,3-Dichloroacetone; Diels–Alder.
*
Corresponding author. Tel.: +34 923 294528; fax: +34 923 294515; e-mail: frena@usal.es
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.039

908
D. Alonso et al. / Tetrahedron Letters 48 (2007) 907–910
We planned our synthesis of the depicted 1-formamido-
2-siloxy-4-(2-nitrophenyl)-1,3-butadienes 1–3 from 1,3-
dichloroacetone, a useful starting material previously
used in the preparation of related dienes,3 according to
the sequence in Scheme 1. As a nitrogen nucleophile
we used sodium diformylamide, generated by the treat-
ment of formamide with sodium methoxide followed
by evaporation to dryness, which has been described
to produce N-formylaminomethyl ketones and N,N-
diformylaminomethyl ketones by reaction with a-halo-
ketones.4 The formation of these reaction products
depends on the solvent used, the former being obtained
in ethanol and the latter produced in acetonitrile,
although both are of interest because they yield free
amino groups upon treatment with HCl.5
Figure 2. Diels–Alder reaction of dienes 2 and 3 with maleimide.
the hydrogens at positions 3a,4,7,7a demonstrated that
the cycloadducts produced were those derived from
the endo-approaches between both reagents. Especially
significant were the NOE effects observed on H-3a and
H-7 upon irradiation of the proton geminal to the
formamido group (H-4) (Fig. 2).
In our case, the substitution reaction failed in ethanol or
acetonitrile but afforded the monoformyl derivative N-
[2-oxo-3-(triphenylphosphoranylidene)propyl]formamide
(4) in suitable yields when dimethylformamide was used
as a solvent.6,7 The Wittig reaction of 4 with 2-nitro-
benzaldehyde yielded enone 5, which was readily con-
verted into dienes 1, 2 and 3 by silylenolisation with
the corresponding triflates.
When we compared these products with endo stereo-
chemistry with 4-phthalimido analogue 8, which was
previously identified as the exo isomer, we found that
the spectroscopic data were very similar in all the cases.
For this reason, we have now rekindled our interest in
the study of the stereochemistry of this compound 8
and of the other previously published cycloadducts 9
and 10 (Fig. 3).
Once the synthesis of dienes 1, 2 and 3 had been success-
fully achieved, we assayed these compounds for the
Diels–Alder reaction with maleimide, a representative
dienophile that is also suitable for the synthesis of poly-
cyclic heteroaromatic compounds carrying a [c]-fused
pyrrole ring. In the reaction of dienes 2 and 3 with
maleimide, the cycloaddition products were produced
under standard conditions (only ketone 5 was obtained
from reactions with diene 1 because of its lower stabil-
ity). After isolation and spectroscopic analysis of
The exo stereochemistry of cycloadducts 9 and 10 was
unequivocally assigned through X-ray diffraction stud-
ies.1,9 This exo-cycloaddition result can be explained in
terms of high crowding in the (less favourable) endo
transition state, produced by the presence of the 1-
phthalimido and 4-aryl (2-nitrophenyl, N-benzenesul-
8
cycloadducts 6 and 7, the NOE effects between all
Scheme 1. Synthesis of dienes 1 (R = TMS), 2 (R = TIPS) and 3 (R = TBDMS). Reagents and conditions: (i) (a) PPh3, THF, reflux, 3 h; (b) Na2CO3
(0.8 mol/mol), H2O/MeOH, rt, 30 min (65%); (ii) NaN(CHO)2, DMF, 100 °C, 30 min (60%); (iii) 2-nitrobenzaldehyde, toluene, reflux, 90 min (55%);
(iv) TfOSiR3 (2.5–4.0 mol/mol), CH2Cl2, rt, 1–2 h, then Et3N (2 mol/mol) (>90%).
Figure 3. Cycloadducts from 1-phthalimido-2-siloxy-1,3-butadienes.

D. Alonso et al. / Tetrahedron Letters 48 (2007) 907–910
909
phonylindol-3-yl) substituents of the diene together with
the quinone or the maleimide substituents.
Based on these results, we had also previously proposed
an exo stereochemistry for 8, although in this case it
could not be confirmed by X-ray methods. However,
comparison of NOE experiments carried out for 8 and
for the new compounds 6 or 7 established that all three
compounds had the same endo stereochemistry, such
that we have now corrected the exo stereochemistry pre-
viously described for 8.
Figure 5. Reaction of cycloadduct 7 with osmium tetraoxide–barium
chlorate.
In light of these results, the stereochemical course of the
Diels–Alder reaction observed in previous papers1–3
and in this work for 1-unsubstituted, 1-formamido and
1-phthalimido substituted 4-aryl-2-siloxy-1,3-butadienes
is depicted in Figure 4, where the required transition
states for each case are represented. The exo stereochem-
istry was produced when the 1-phthalimido and 4-aryl
substituents were present, except in the case of 2-nitro-
phenyl at position C4 reacting with maleimide, which
yielded the endo stereoisomer. The absence of substitu-
ents at position C1 afforded endo products, as was
observed in the new cycloadducts described here, with
the formamido group at C1. The combination of substit-
uents around the reacting core, depending on the degree
of crowding produced in each case, must be responsible
for the stereochemistry of the final products.
moiety, whereas the secondary hydroxyl group was
characterised by the signal of the hydrogen as a doublet
at 4.17 ppm and the chemical shift of this carbon at
75.5 ppm. The proposed stereochemistry was deduced
from the NOE effects and the couplings observed
between protons H-6 and H-7 in NMR (J = 11.0 Hz)
corresponding to a trans-diaxial disposition (Fig. 5).
In order to synthesise an oxazole-fused system, several
reactions were carried out. For instance, attempts to
hydrolise the siloxy group under fluoride (TBAF) or
acid conditions led to unaltered 6 or 7, whereas the
use of FeCl3 as a Lewis acid produced the oxazole deriv-
ative 12, attainable from a ketoformamido intermediate,
cyclisation and retro-Diels–Alder as shown in Scheme 2.
In conclusion, we describe a straightforward prepara-
tion of new 1-formamido-2-siloxy-4-aryl-1,3-butadienes
of interest for the synthesis of polycyclic systems. The
stereochemical outcome of their Diels –Alder reaction
with maleimides is compared with that observed for re-
lated dienes; in the present case the endo-cycloaddition
products are in agreement with the lower degree of
crowding of the 1-formamido substituent upon compar-
ison with the 1-phthalimido analogues.
The obtained cycloadducts can be transformed into
more elaborated diverse compounds. In this respect,
polysubstituted hexahydroisoindoles were obtained.
Osmium tetraoxide–barium chlorate oxidation10 of 7
11
produced the silylated derivative 11
instead of the
usually produced hydroxy-ketone.12 The structure of
this compound was established by NMR H and 13C
1
data: the signals corresponding to the TBDMS group
and to a quaternary carbon at 97.2 ppm allowed us to
establish the presence of the geminal hydroxy/siloxy
Acknowledgements
Financial support came from the Junta de Castilla y
´
Leon (SA048/03), the Spanish MEC (CTQ2004-00369)
and European FEDER funds.
References and notes
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1. (a) Caballero, E.; Alonso, D.; Pelaez, R.; Alvarez, N.;
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´
Puebla, P.; Sanz, F.; Medarde, M.; Tome, F. Tetrahedron
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´
2005, 61, 6871–6878; (b) Caballero, E.; Alonso, D.; Pelaez,
Scheme 2.

910
D. Alonso et al. / Tetrahedron Letters 48 (2007) 907–910
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1.5 Hz, H-7a); 3.48 (1H, dd, J = 8.3, 5.3 Hz, H-3a); 0.85
(9H, s, TBDMS); 0.15 (3H, s, TBDMS); 0.14 (3H, s,
TBDMS). 13C NMR (d ppm) 178.6 (C); 175.6 (C); 161.1
(CH); 150.8 (C); 149.6 (C); 134.4 (C); 132.7 (CH); 131.8
(CH); 128.4 (CH); 124.8 (CH); 101.4 (CH); 46.1 (CH);
45.5 (CH); 45.1 (CH); 36.4 (CH); 19.0 (C); 17.7 (3CH3);
ꢀ4.7 (CH3); ꢀ5.2 (CH3).
´
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11. Compound 11: Mp 190 °C (diethyl ether). HRMS m/z
calcd for C21H30N3O8Si 479.1618, found 479.1621. 1H
NMR (d ppm): 8.32 (1H, s, NHCHO); 8.22 (1H, s, NH);
7.96 (1H, d, J = 7.4 Hz, H-30); 7.87 (1H, d, J = 7.0 Hz,
NHCHO0); 7.73 (1H, m, H-60); 7.71 (1H, m, H-50); 7.46
(1H, dd, J = 7.8, 1.2 Hz, H-40); 4.65 (1H, dd, J = 7.4,
7.0 Hz, H-4); 4.17 (1H, d, J = 11.0 Hz, H-6); 3.82 (1H, m,
H-7a); 3.80 (1H, m, H-7); 3.35 (1H, dd, J = 9.6, 7.4 Hz, H-
3a); 0.85 (9H, s, TBDMS); 0.15 (3H, s, TBDMS); 0.14
(3H, s, TBDMS). 13C NMR (d ppm) 177.4 (C); 175.8 (C);
164.2 (CHO); 150.3 (C); 132.4 (CH); 132.1 (C); 131.7
(CH); 128.2 (CH); 124.8 (CH); 97.2 (C); 75.5 (CH); 53.3
(CH); 42.3 (CH); 40.0 (2CH); 25.8 (3CH3); 17.8 (C); ꢀ2.9
(CH3); ꢀ3.2 (CH3).
´
´
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sodium diformylamide in DMF (Ref. 5) 30 min at 100 °C
produced a 60% yield of 4. With longer periods of time or
higher temperature, 3-hydroxypyrrol and triphenylphos-
phine oxide were obtained, from an internal Wittig
reaction, as the major products.
8. Compound 7 (R = TBDMS): HRMS m/z calcd for
C21H28N3O6Si 446.1747, found 446.1783. 1H NMR (d
ppm) 8.32 (1H, s, CHO); 7.96 (1H, d, J = 8.1 Hz, H-30);
7.76 (1H, t, J = 8.1 Hz, H-50); 7.46 (1H, t, J = 8.1 Hz, H-
40); 7.28 (1H, d, J = 8.1 Hz, H-60); 5.01 (1H, m, H-4); 4.96
(1H, m, H-6); 4.26 (1H, m, H-7); 3.82 (1H, dt, J = 8.3,
12. A similar arrangement of functional groups has been
reported to occur from dihydroxylation of silyl enol
ethers. See, among others, the following references for
further details: (a) Jauch, J. Tetrahedron 1994, 50, 12903–
12912; (b) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron
Lett. 1998, 39, 7819–7822; (c) McCormick, J. P.; Tomasik,
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