1,3-dipolar cycloaddition reactions of 4-silacyclohex(hept)-2-en-1-one derivatives: Synthesis of novel azasilabicyclic compounds

Article abstract of DOI:10.1055/s-1998-1588

[3+2] Cycloaddition reactions of N-benzyl-azomethine ylide with 4-silacyclohex(hept)-2-en-1-ones provides novel 3-aza-1-silabicyclo[3.4.0]hexanes and 3-aza-1-silabicyclo[3.5.0] heptanes.

Full text of DOI:10.1055/s-1998-1588

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1,3-Dipolar Cycloaddition Reactions of 4-Silacyclohex(hept)-2-en-1-one Derivatives:
Synthesis of Novel Azasilabicyclic Compounds
D. Damour, M. Barreau, V. Fardin, F. Dhaleine, M. Vuilhorgne and S. Mignani*
Rhône-Poulenc Rorer S.A. Centre de Recherche de Vitry-Alfortville, 13 Quai Jules Guesde-BP 14, 94403, Vitry-sur-Seine Cedex,
France, Fax 33 1 55 71 81 29
Received 14 October 1997
Abstract :
3b via
[3+2] cycloaddition reaction of the azomethine ylide
[3+2] Cycloaddition reactions of N-benzyl-azomethine ylide
derivative
with 4-silacyclohex(hept)-2-en-1-ones provides novel 3-aza-1-
silabicyclo[3.4.0]hexanes and 3-aza-1-silabicyclo[3.5.0] heptanes.
1,3-dipole 2 with 4-silacyclohex- and 4-silacyclohept-2-enones 1a and
1b. The cycloadducts 3a,b were then N-debenzylated to give the
corresponding NH derivatives 4a,b as outlined in Scheme 1.
5
1a
1b
The silacycloalkenones and were prepared via three- and five-step
syntheses, respectively, in ~12% yield, both starting from commercially
available divinyldiphenylsilane as shown in Scheme 2.
The [3+2] cycloaddition reaction of azomethine ylides with ethylenic
compounds represents an outstanding tool in organic synthesis to
1
provide various five-membered nitrogen heterocycles , generally with
2
6
high regio- and stereoselectivities.
Thus, 4,4-diphenyl-4-silacyclohexan-1-one 6a was prepared in a one-
step synthesis via hydroboration reaction in 60% yield from 5 as
described previously , whereas 4,4-diphenyl-4-silacycloheptane-1-one
To the best of our knowledge, only two [3+2] cycloaddition reactions of
azomethine ylide with a carbon-carbon multiple bond bearing a silicon
substituent have been described. In both cases, the azomethine ylide
used was C-unsubstituted and was generated from trimethylamine-N-
oxide in presence of a large excess of LDA. Thus, Roussi et al.
described the preparation of 3-trimethylsilyl-4-phenyl-2,5-dihydro-
7
6b was prepared from 6a in a two-step synthesis through a one-carbon
7
homologation reaction in 83% overall yield. Silacyclohexanone 6a was
directly transformed to the silacyclohexenone 1a by the condensation of
methyl benzenesulfinate in the presence of NaH affording 7a which was
8
3
transformed to 1a by an elimination of sulfenic acid at room
pyrrole starting from 1-phenyl-2-(trimethylsilyl)acetylene , and recently
temperature in 20% yield.
we described the preparation of 5-aza-1,1-diphenyl-1-silabicyclo[3.3.0]-
octane derivatives from the corresponding 4-substituted-1-
silacyclopent-2-enes. These findings prompted us to study the
additions of various azomethine ylides with cyclic β-silyl-substituted
α,β-unsaturated ketones. Herein, we wish to report the construction of
the novel fused sililano-pyrrole derivative 3a and the silepano-pyrrole
Silacycloheptenone 1b was synthesized in a two-step synthesis from 6b
which was first converted to the corresponding 2-bromo derivative 7b in
45% yield under standard radical conditions. β-Elimination in refluxing
2,4,6-collidine generated then the required silacycloheptenone 1b in
51% yield.
4
Scheme 1

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Scheme 3
Once the olefinic dipolarophiles 1a and 1b had been prepared, they were
subjected to [3+2] cycloaddition reaction with the azomethine ylide 2
generated in situ from N-n-butoxymethyl-N-trimethylsilylmethyl
benzylamine 8 in the presence of a catalytic amounts of trifluoroacetic
acid through an alkoxy elimination and subsequent desilylation
10
process (Scheme 3).
Thus, starting from 1a, condensation of 8 afforded the desired
tetrahydropyrrole derivative 3a in very low yield (2.5%), besides the
oxazolidine-dicycloadduct 9 (2% yield) derived from cycloaddition
reactions of two equivalents of ylide 2 with both the carbonyl group and
the double bond moieties of 1a. Surprisingly, cycloaddition of 8 with
the seven-membered silacycloheptenone 1b afforded exclusively
11
cycloadduct 3b in 47% yield. These studies demonstrate the crucial
influence of the size of the β-silyl-substituted α,β-unsaturated ketone
dipolarophile on the regioselectivity of the [3+2] cycloaddition. This
different behaviour of 1a and 1b is probably due to either varied
polarization of the conjugated β-silyl α,β-unsaturated ketone system or
to steric effects (during the dipole approach) or both.
Investigating alternative routes to 3a, we found that the [3+2]
cycloaddition of 2 with silacyclohexenone 11 afforded cycloadduct 12
11,12
13
in an epimeric ratio of ~4/1
transformed to 3a
in 70% yield , which was then
11
by a tandem hydrogenolysis-decarboxylation
reaction in 69% yield (Scheme 4). Introduction of an electron-
withdrawing group such as benzyloxycarbonyl in position 2 of 1a
enhanced the reactivity of the carbon-carbon double bond and produced
exclusively the mono-adduct 12.
The synthesis of 11 started from 6a, which was converted to the
corresponding 2-benzyloxycarbonyl-4-silacyclohexanone derivative 10
using dibenzylcarbonate as electrophile in the presence of KH in 56%
yield. Then, regioselective oxidation of 10 with 2,3-dichloro-5,6-
dicyanoquinone (DDQ) in acetic acid/dioxane mixture afforded 11 in
56%. Note that introduction of an electron-withdrawing substituent such
as a benzyloxycarbonyl group in position 2 of the carbonyl moiety
regioselectively produced the mono-oxidation product 11, while the
same reaction conditions applied to 6a generated 4,4-diphenyl-4-
With 3a and 3b in hand, we turned our attention to the synthesis of N-
11
11
debenzylated derivatives 4a and 4b which were crucial starting
materials for the preparation of tetrahydropyrrole derivatives 14a,b and
15a,b as shown in Scheme 5. The synthesis of these sila-derivatives was
6
silacyclohexadien-1-one in 40% yield.

February 1998
SYNLETT
155
initiated pursuing our goals to prepare either biologically active silicon
compounds which do not possess any known carbon counterpart or to
References and Notes
(1) For reviews, see : Tsuge, O ; Kanemasa, S. Advances in
Heterocyclic Chemistry, 45, 231
Carruthers, W.
14
study silyl analogues of known bioactive carbon compounds in order to
1989
,
;
15
determine the sila-substitution effects.
‘Cycloaddition Reactions in Organic Synthesis’, Vol. 8, ed. by
Baldwin, J. E. ; Magnus, F. R. S. ; Magnus, P. D. Pergamon Press,
Contemporary Organic Synthesis,
1990, pp. 269-331 ; Dell, C. P.
4, 87 and references cited therein.
1997,
(2) McDouall, J. J. W. ; Robb, M. A. ; Niazi, U. ; Bernardi, F. ;
Schlegel, H. B. J. Am. Chem. Soc. 1987, 109, 4642 and references
cited therein.
(3) Beugelmans, R. ; Chastanet, J. ; Roussi, G. Heterocycles 1987, 26,
3197.
(4) Damour, D. ; Doerflinger, G. ; Mignani, S. Heterocycles 1997,
accepted for publication.
(5) All new compounds gave satisfactory analytical and spectroscopic
1
data ( H-NMR, IR, MS); in addition correct elemental analyses
has been determined for 14a, b and 15a, b.
(6) To the best of our knowledge only 4,4-dimethyl-4-silacyclohex-2-
enone has been described: Felix, R. A. ; Weber, W. P. J. Org.
Chem. 1972, 37, 2323.
(7) Damour, D. ; Renaudon, A. ; Mignani, S. Synlett 1995, 111.
(8) Silacyclohexenone 1a was also prepared in low yield (1-15%)
either via dehalogenation reaction through the syntheses of
compound 16 or via decarboxylation-dehydrogenation reaction of
17 using Pd(OAc) (see, Minani, I.; Takahashi, K.; Shimizu, I.;
2
Tsuji, J. Tetrahedron 1986, 42, 2971) as depicted in Scheme 6.
Facile N-debenzylation of 3a and 3b was achieved using vinyl
16
11
11
chloroformate affording 13a and 13b in good yields which were
11
then hydrolyzed with a conc. HCl/dioxane mixture to give 4a and
4b in 73% and 85% yield, respectively. Pure amide derivatives 14a
11
and 15a were obtained by condensation of (2-methoxyphenyl)acetyl
chloride under standard conditions giving cis-adduct 14a and trans-
adduct 15a in 52% and 19% yield, respectively, after purification by
17
chromatography on silica gel.
The condensation of (2-
methoxyphenyl)acetic acid in presence of 1-hydroxy-benzotriazole
(HOBT) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydro-
chloride (EDCI) with 4b under standard conditions afforded pure 14b
(9) Field, L.; Locke, J. M. Org. Syntheses 1966, 46, 62.
(10) Terao, Y. ; Kotaki, H. ; Imai, N. ; Achiwa, K. Chem. Lett. 1984,
18
and 15b in 54% and 21% yield, respectively.
1117.
In summary, we have developed a methodology for the preparation of
novel perhydrosilolano[2,3-c]pyrrole derivatives 3a,b ; 4a,b ; 14a,b and
15a,b based on a 1,3-cycloaddition reaction with 4-silacyclo- hex(hept)-
2-enones.
(11) The epimeric ratios for compounds 3a, 12 and 13a were ~3/2, ~4/
1
1 and ~3/1 respectively, and were determined by H-NMR,
whereas for the compound 4b, the ratio (~1/1) was determined by
13
C-NMR. The cis-isomers 14a and 14b and the trans-isomers
15a and 15b were isolated in pure form by flash chromatography
on silica gel (see Scheme 5). The formation of cis- and trans-
cycloadduct mixture could result from either a non-stereospecific
1,3-cycloaddition reaction (vs the cycloaddition of 2 with 4,4-
diphenyl-cyclohex-2-en-1-one, see ref. 12) or a subsequent stereo-
isomerisation reaction (see for example, Huisgen, R.; Weinberger,
R. Tetrahedron Lett. 1985, 26, 5119 and references cited therein).
Acknowledgements : We wish to thank A. Renaudon, the analytical
team for technical and analytical assistance respectively, J. F. Peyronel
and coll. and Prof. G. Manuel (Université Paul Sabatier, Toulouse,
France) for interesting and valuable discussions.
(12) a) Under the same reaction conditions, condensation of N-
methoxymethyl-N-trimethylsilylmethylbenzylamine with 4,4-

156
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SYNLETT
diphenyl-cyclohex-2-en-1-one gave only the corresponding cis-2-
benzyl-7,7-diphenyl-2-perhydroisoindol-4-one in 80% yield
(Peyronel, J. F. ; Truchon, A. ; Moutonnier, C. ; Garret, C.,
Bioorg. & Med. Chem. Lett. 1992, 2, 37) b) Other examples of
stereoselective condensations of azomethine ylides (generated
14a: white solid, m.p. 155°C, R =0.4 (cyclohexane/AcOEt
mixture, 25/75). IR (KBr pellets) ν cm : 3425, 3070, 3040, 3005,
f
-1
2930, 2840, 1705, 1630, 1600, 1585, 1565, 1495, 1460, 1440,
1
1425, 1250, 1110, 1030, 750 , 700. H NMR (DMSO(d6), 600
MHz) (the amide function gives way to an equilibrated mixture of
two rotamers A and B in a 6/4 ratio, coalescence occurred at 433
K) δ : 1.55-1.80 (m, 2x2H, H7, A and B), 2.55-2.65 (m, 2x2H, H6,
A and B), 2.68 (m, 1H, H1aβ, A), 2.77 (m, 1H, H1aβ, B), 2.85 (d,
J=16Hz, 1H, H2α, A), 3.45 (m, 1H, H2β, A), 3.10 (d, J=16Hz,
1H, H2α, B), 3.58 (m, 1H, H2β, B), 3.30 (m, 1H, H4β, A), 4.16
(d, J=9Hz, 1H, H4α, A), 3.08 (m, 1H, H4β, B), 4.08 (d, J=9Hz,
1H, H4α, B), 3.56 (m, 1H, H4aβ, A), 3.40 (m, 1H, H4aβ, B), 3.40
from
oxazolidinone
or
N-substituted-N-alkoxymethyl-N-
trimethylsilylmethylamine derivatives) giving only cis
cycloadducts from the corresponding cyclic enones: see, Hosomi,
A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1984, 1117; Ogata, M. ;
Matsumoto, H.; Shimizu, S. ; Nakai, H. ; Motokawa, K. ; Miwa,
H. ; Matsuura, S. ; Yoshida, T. Eur. J. Med. Chem. 1991, 26, 889;
Ogata, M. ; Matsumoto, H., Shimizu, S. ; Kida, S. EP 0359172
(C.A. 114: 6288); Carmosin, R. J.; Carson, J. R.; Pitis, M. US
5523412 (C.A. 125: 142548).
( AB, J=12Hz, 2H, N-COCH -, B), 3.55 ( AB, J=12Hz, 2H, N-
2
COCH -, A), 3.60 and 3.88 (two s, 2X3H, -OCH , A and B), 6.85
2
3
(t, J=7Hz, H5’, 2x1H, A and B), 6.92 (d, J=7Hz, 1H, H3’) and
6.97 (d, J=7Hz, 1H, H3’) A and B, 7.82 (m, 2x1H, H6’, A and B),
7.1-7.6 (m, 2x11H, other phenyl groups, A and B).
(13) The [3+2] cycloaddition reaction of 11 affording 12 is given
hereafter as a representative experimental procedure :
To a stirred solution of 11 (9.4g, 23.6 mmol), N-n-butoxymethyl-
13
C NMR (DMSO(d6), 100.6 MHz) δ : 7.8 (C7), 25.9 (C6), 27.6
N-trimethylsilylmethylbenzylamine (13.1g, 47.2 mmol), CH Cl
2
2
(C1a), 45.8 and 46.6 (C4), 46.6 or 46.9 (C2), 47.0 (N-CO-CH -),
(190 ml) under nitrogen, was added dropwise CF CO H (2.3 ml,
30 mmol). An exothermic reaction was observed, and the resulting
mixture was stirred for 1 h at room temperature. This solution was
2
3
2
49.8 and 51.5 (C4a), 55.2 (-CH ), 110.0 (C3’), 120 (C5’), 124.0
3
(C1’), 136.0 (C4’), 136.0 (C6’), 157.0 (C2’), 168.2 and 168.3 (N-
CO-CH -), 210.0 (C5), 133.0 (ipsoC), 128.0-134.0 (Phenyl
groups). NOESY connectivities (400 MHz):
then neutralized with Na CO and the reaction mixture was stirred
2
2
3
for an additional 15 min at room temperature. The insoluble
precipitate was filtered, and CH Cl (20 ml) was then added. The
2
2
organic phase was concentrated in vacuo, and the resulting orange
oil was purified by flash chromatography on silica gel (eluant :
CH Cl ) to give 8.7g of 12 (70%) as a yellow oil.
2
2
(14) For previous work in this field, see : Damour, D., Barreau, M.,
Dutruc-Rosset, G., Doble, A., Piot, O. Mignani, S. Bioorg. &
Med. Chem. Lett. 1994, 4, 415 ; Mignani, S., Damour, D. Synth.
Commun. 1994, 2017 ; Boukkerroud, R., Manuel, G., Mignani, S.,
Damour, D. J. Organomet. Chem. 1994, 484, 119 ; Mignani, S.,
Damour, D. French Patent Applications, FR 2689892 (C.A. 120:
323854) ; FR 2689893 (C.A. 121: 9696) ; FR 2689894 (C.A. 120:
323853).
+.
MS (EI, 70eV) : m/z 455 (M ), 334, 199, 181, 121, 105, 91
(100%). Anal. Calc. for C
H NO Si : C, 73.82 ; H, 6.42 ; N,
28 29 3
3.07 ; Si, 6.16. Found : C, 74.2 ; H, 6.7 ; N, 3.0 ; Si, 6.2.
(15) The 7,7-diphenylperhydroisoindol-4-one 18 which is a close C-
analogue of 14a, revealed interesting activity in [3H]-Substance P
15a: white solid, m.p. 60°C, R =0.6 (cyclohexane/AcOEt mixture,
f
-1
25/75). IR (KBr pellets) ν cm : 3425, 3070, 3040, 3000, 2925,
(SP) binding assay in rat membranes with IC of 60 nM. (for
50
2850, 1710, 1640, 1600, 1585, 565, 1495, 1465, 1440, 1425,
1245, 1110, 1030, 755, 740, 700, 710.
The relative stereochemistry of 15a was conferred from 14a.
previous work, see: Fardin, V.; Garret, C. Eur. J. Pharmacol.
201, 231; Peyronel, J-F.; Truchon, A.; Moutonnier, C.;
1991,
Garret, C. Bioorg. & Med. Chem. Lett. 1992, 2, 37; Peyronel, J-F.
; Tabart, M.; Achard, D.; Malleron, J-L.; Grisoni, S.; Carruette,
A.; Montier, F.; Moussaoui, S.; Fardin, V.; Garret, C. Eur. J. Med.
1
H NMR (DMSO(d6), 250 MHz, the amide function gives way to
an equilibrated mixture of two conformers in a 1/1 ratio) δ : 1.40
and 1.80 (m, 2x2H, H7), 2.5-2.9 (m, 2x2H, H6), 2.0-2.1 (m, 2x1H,
H1a), 3.0-3.4 (m, 2x2H, H4), 2.95 (t,1H, J=11Hz, H2), 3.3 (m,
1H, H2), 3.90 (dd, 1H, J=7.5 and 11.0Hz, H2), 4.15 (dd, 1H, J=7.5
Chem.
, 30, 576s).
1995
and 9 Hz, H2), 3.75 (s, 3H, -OCH ), 3.80 (s, 3H, -OCH ), 3.5 (m,
3
3
2x1H, H4a), 3.5 (m, 2x2H, N-COCH -), 6.8-7.2 (m, 2x1H, H6’),
2
7.3-7.6 (m, 2x11H, other phenyl groups). MS (EI, 70eV) : m/z
+.
455 (M ), 334, 199, 181, 121, 105 (100%). Anal. Calc. for
C
H NO Si : C, 73.82 ; H, 6.42 ; N, 3.07 ; Si, 6.16. Found : C,
28 29 3
73.7 ; H, 6.9 ; N, 3.0 ; Si, 5.4.
(16) Olofson, R. A.; Schnur, R. C.; Bunes, L.; Pepe, J. P. Tetrahedron
Lett. 1977, 18, 1567.
3
(18) Only the cis-adducts 14a and 14b inhibited the binding of [ H]-SP
to membrane preparations of rat brain with IC of 136 and 356
nM, respectively, vs 60 nM for the carbon analogue 18 (see ref.
15), whereas the trans-adducts 15a and 15b exhibited very weak
50
(17)
binding activities (IC ( 3µM).
50