Synthesis of a new C-15 phosphorus ylide used for the preparation of someβend-group retinoid derivatives

Article abstract of DOI:10.1080/00397910903531938

A synthesis of a new C-15 phosphorus ylide from a C-14 enaminone is reported. This reagent, which undergoes selective 1,2- or 1,4-additions with saturated and unsaturated aldehydes, may find some synthetic use for the preparation ofβend-group retinoid der

Full text of DOI:10.1080/00397910903531938

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Synthesis of a New C-15 Phosphorus
Ylide Used for the Preparation of Some
β-End-Group Retinoid Derivatives
Alain Valla a , Nathalie Méheux a , Dominique Cartier a , Benoist Valla
a , Laurent Dufossé b & Roger Labia a
a Chimie et Biologie des Substances Naturelles, CNRS , Quimper,
France
b Laboratoire de Chimie des Substances Naturelles et des Sciences
des Aliments , Université de La Réunion , Saint-Denis, France
Published online: 15 Dec 2010.
To cite this article: Alain Valla , Nathalie Méheux , Dominique Cartier , Benoist Valla , Laurent
Dufossé & Roger Labia (2010) Synthesis of a New C-15 Phosphorus Ylide Used for the Preparation of
Some β-End-Group Retinoid Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:2, 184-190, DOI: 10.1080/00397910903531938
To link to this article: http://dx.doi.org/10.1080/00397910903531938
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Synthetic Communications1, 41: 184–190, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531938
SYNTHESIS OF A NEW C-15 PHOSPHORUS YLIDE
USED FOR THE PREPARATION OF SOME b-END-
GROUP RETINOID DERIVATIVES
1
Alain Valla, Nathalie Meheux, Dominique Cartier,
1
1
´
Benoist Valla, Laurent Dufosse, and Roger Labia
1
2
1
´
1Chimie et Biologie des Substances Naturelles, CNRS, Quimper, France
2Laboratoire de Chimie des Substances Naturelles et des Sciences des
´
Aliments, Universite de La Reunion, Saint-Denis, France
´
A synthesis of a new C-15 phosphorus ylide from a C-14 enaminone is reported. This reagent,
which undergoes selective 1,2- or 1,4-additions with saturated and unsaturated aldehydes,
may find some synthetic use for the preparation of b-end-group retinoid derivatives.
Keywords: Enaminones; phosphorus ylide; retinoids
Phosphorus ylides react with aldehydes or ketones to give alkenes, wherein Z olefins
predominate in aliphatic systems and E olefins predominate in conjugated systems[1–3]
(Scheme 1).
This reaction, discovered by Wittig, was used in the BASF processes for
vitamin A, b-carotene, and other carotenoid productions.[4–6] (Scheme 2 illustrates
the last steps of vitamin A synthesis.)
We have recently published some research in the retinoid field, using a new
enaminone 1, derived from b-ionone.[7] This compound could be obtained directly,
in nearly quantitative yield (Scheme 3), by condensation with N,N-dimethyl forma-
mide dimethylacetal (DMF-DMA).
Benary’s synthesis[8] (reaction of organometallic derivatives on enamino-
ketones) yielded b-substituted a,b-unsaturated ketones (Scheme 4). These enamino-
ketones were further named enaminones by Greenhill.[9]
Enaminones have been used previously for the synthesis of natural products[10]
and heterocyclic derivatives.[11]
Reaction of the Wittig reagent, methylene triphenylphosphorane (generated in
situ by reaction of tBuOK on methyl triphenylphosphonium chloride or bromide)
with 1 led to a new C-15 phosphorus ylide 2, which, taking into consideration of
1
its complex H NMR spectrum, could be represented by several mesomeric forms
(Scheme 5). This ylide could be stored for several months at ꢀ20 ꢁC, which makes
it an interesting intermediate in the retinoid field.
Received September 30, 2009.
Address correspondence to Alain Valla or Roger Labia, Chimie et Biologie des Substances
´
Naturelles, FRE 2125, CNRS 6, rue de l’Universite 29000, Quimper, France. E-mail: alain.valla@
neuf.fr; roger.labia@univ.brest.fr
184

C-15 PHOSPHORUS RETINOID YLIDE
185
Scheme 1. Usual Wittig reaction.
Scheme 2. Last steps of BASF synthesis of vitamin A.
Scheme 3. b-Ionone, DMF-DMA (1.5 eq), Dean–Stark, 80 ꢁC, 6 h, and reflux, 12 h.
Scheme 4. Benary’s synthesis of b-substituted a,b-unsaturated ketones.
The condensation of 2 with saturated aliphatic aldehydes, such as acetalde-
hyde, propionaldehyde, or butyraldehyde, led to alkenes 3–5, and their formation
could be explained by the mechanism show in Scheme 6.
Scheme 5. Methylenetriphenylphosphonium bromide (2 eq.) and tBuOK (2 eq.), ether, reflux, 30 min, then
enaminone 1, ether, reflux, 45 min.

186
A. VALLA ET AL.
A single isomer was obtained for compounds 3 to 5 (double bond C10¼C13)
that suggested the mechanism reported in Scheme 6.
It was previously shown that ketones (in particular cases) reacted with phos-
phorus ylides, according to a Michael reaction,[12] and this nonclassical Wittig
reaction has been previously reported by Corey et al.[13] (Scheme 7).
Surprisingly, the condensation with a,b-unsaturated aldehydes, such as
acrolein, 2-butenal, and 2-methylacrolein, led to cyclohexadiene derivatives 6–8.
This formation could be explained by the mechanism pathway described in
Scheme 8.
When the b-carbon of conjugated aldehyde was dialkyl-substituted, such as
3-methyl-2-butenal, citral, or was inaccessible, such as benzaldehyde, the reaction
proceeded according to the first way (Scheme 6, products 3–5) and led to 9–11
=
Scheme 6. (3) R Me; (4) R Et; (5) R Pr. Ylure 2, aldehyde (4 eq. for volatile or 2 eq. for others), ether,
=
=
reflux, 1 h.
Scheme 7.
Scheme 8. (6) R1 ¼ R2 ¼ H; (7) R1 ¼ H, R2 ¼ Me; (8) R1 ¼ Me, R2 ¼ H.

C-15 PHOSPHORUS RETINOID YLIDE
187
Scheme 9.
(Scheme 9). This fact could strength the idea that the two suggested mechanisms
could be concurrent.
In conclusion, this new phosphorane, which possesses good reactivity, was
easily obtained in two steps from b-ionone. New ethylenic or cyclohexadienic
retinoids could be easily synthesized using this useful synthon.
EXPERIMENTAL
1
All reactions were carried out under an argon atmosphere. H NMR spectra
were recorded at 400 MHz, and 13C NMR spectra were recordeded at 100 MHz
on a Bruker Avance DPX-400 instrument with CDCl3 as solvent. Chemical shifts
are reported in parts per million (ppm) at room temperature (23 ꢁC). Infrared (IR)
spectra (KBr) were run on a Bruker IF 55 spectrometer and absorbances are
reported in centimetersꢀ1
.
Compound 2: A mixture of 14.2 g (40 mmol) of methylenetriphenylphospho-
nium bromide in 50 mL of dry ether and 4.5 g (40 mmol) of tBuOK was refluxed
for 30 min, and 4.95 g (20 mmol) of enaminone 1 in 30 mL of ether was added.
The reflux was prolonged for 45 min. The crude mixture was cooled, and the KBr
was filtered off. The ether was removed under reduced pressure, and the phosphorus
ylide 2 was washed with ethyl acetate, filtered off quickly, and stored at ꢀ25 ꢁC
(7.60 g, 81%). 1H and 13C NMR spectra showed complex data, because of the
presence of mesomeric forms.
General Procedure for Synthesis of Compounds 3 to 11
Ylure 2 (500 mg, 1.05 mmol) in 15 mL of ether was added to 4 eq. of aldehyde
for volatile aldehydes (i.e., those with 4 carbons or less) or 2 eq. for the others. After
1 h at reflux, the solvent and residual volatile aldehydes were removed under reduced
pressure, and the crude products were purified by chromatography (SiO2, CH2Cl2);
yellow to orange oils.
Selected Data
=
Compound 3. R Me, reaction with acetaldehyde, yield 40%. IR (film): nC¼O
1655. H NMR: 1.10 (sl, 6H, 1a-CH3, 1b-CH3); 1.50 (m, 2H, 2-CH2); 1.60 (m, 2H,
:
1

188
A. VALLA ET AL.
3-CH2); 1.80 (s, 3H, 5a-CH3); 1.90 (d, 3H, J ¼ 7.2, 14-CH3); 2.09 (m, 2H, 4-CH2);
5.42 (m, 2H, 12-CH2); 6.33 (m, 1H, 13-CH); 6.35 (q, 1H, J ¼ 7.2, 11-CH); 6.50 (d,
1H, J ¼ 16.0, 8-CH); 6.65 (dd, 1H, J ¼ 11.5, J ¼ 17.7, 11-CH); 7.40, (d, 1H,
J ¼ 16.0, 7-CH). 13C NMR: Cq: 34.0 (1); 136.0; 136.4; 140.9; 194.1 (CO). CH:
128.6; 129.4; 134.1; 143.9. CH2: 18.8; 33.5; 39.7; 119.1. CH3: 14.1; 21.6; 28.65 (1a,
1b). Anal. calc. for C17H24O: C, 83.55; H, 9.90; O, 6.55. Found: C, 83.32; H, 9.99;
O, 6.69.
=
Compound 4. R Et, reaction with propionaldehyde, 85%. IR (film): nC¼O
1
1660. H NMR: 1.08 (s, 6H, 1a-CH3, 1b-CH3); 1.10 (t, 3H, J ¼ 7.5, 15-CH3); 1.49
(m, 2H, 2-CH2); 1.63 (m, 2H, 3-CH2); 1.80 (s, 3H, 5a-CH3); 2.09 (m, 2H; 4-CH2);
2.35 (m, 2H, 14-CH2); 5.40 (m, 2H, 12-CH2); 6.20 (t, 1H, J ¼ 8.0, 13-CH); 6.40 (d,
1H; J ¼ 15.3, 8-CH); 6.60 (dd; 1H, J ¼ 11.2, J ¼ 17.7, 11-CH); 7.40 (d, 1H;
J ¼ 15.3, 7-CH). 13C NMR: Cq: 34.1 (1); 136.2; 136.4; 139.3; 194.6 (CO). CH:
129.0; 129.7; 140.9; 144.2. CH2: 18.8; 21.6; 33.6; 39.7; 119.1. CH3: 13.7; 21.7;
28.65; 28.6 (1a, 1b). Anal. calc. for C18H26O: C, 83.67; H, 10.14; O, 6.19. Found:
C, 83.51; H, 10.23; O, 6.26.
=
Compound 5. R C3H7, reaction with butyraldehyde, 70%. IR (film): nC¼O
1
1660. H NMR: 0.91 (t, J ¼ 7.4, 16-CH3); 1.08 (s, 6H, 1a-CH3, 1b-CH3); 1.34 (m,
2H, 15-CH2); 1.50 (m, 2H, 2-CH2); 1.64 (m, 2H, 3-CH2); 1.79 (s, 3H, 5-CH3); 2.08
(m, 2H, 4-CH2); 2.32 (q, 2H, J ¼ 7.4, 14-CH2); 5.39 (dd, 2H, J ¼ 16.0, J ¼ 11.3,
12-CH2); 6.20 (t, 1H, J ¼ 7.4, 13-CH); 6.43 (d, 1H, J ¼ 16.0, 8-CH); 6.61 (dd, 1H,
J ¼ 16.0, J ¼ 11.3, 11-CH); 7.37 (d, 1H, J ¼ 16.0, 7-CH). 13C NMR: Cq: 33.8 (1);
134.6; 136.5; 137.0; 194.5 (CO). CH: 129.1; 127.7; 138.7; 144.0. CH2: 18.8; 21.7;
31.3; 33.6; 39.7; 119.1. CH3: 13.9; 22.3; 28.7 (1a, 1b). Anal. calc. for C19H28O: C,
83.77; H, 10.36; O, 5.87. Found: C, 83.55; H, 10.44; O, 6.01.
1
Compound 6. Reaction with acrolein, 85%. IR (film) nC¼O 1646. H NMR:
1.08 (s, 6H, 1a-CH3, 1b-CH3); 1.50 (m, 2H, 2-CH2); 1.63 (m, 2H, 3-CH2); 1.80 (s,
3H, 5a-CH3); 2.08 (m, 2H, 4-CH2); 2.30 (m, 2H, 14-CH2); 2.53 (m, 1H, J ¼ 10,
15-CH2); 6.10 (m, 1H, 13-CH); 6.25 (m, 1H, 12-CH); 6.70 (d, 1H, J ¼ 15.7, 8-CH);
6.90 (d, 1H, J ¼ 5.2, 11-CH); 7.38 (d, 1H, J ¼ 15.7, 7-CH). 13C NMR: Cq: 33.8
(1); 134.6; 136.5; 137.0; 189.9 (CO). CH: 124.0; 125.0; 132.5; 134.6; 141.8. CH2:
18.7; 20.0; 22.7; 33.8; 39.5. CH3: 21.6; 28.6 (1a, 1b). Anal. calc. for C18H24O: C,
84.32; H, 9.44; O, 6.24. Found: C, 84.03; H, 9.60; O, 6.37.
Compound 7. Reaction with 3-methyl-acrolein, 80%. IR (film) nC¼O 1647. 1H
NMR: 0.98 (d, 3H, J ¼ 7.1, 15-CH3); 1.07 (s, 6H, 1a-CH3, 1b-CH3); 1.47 (m, 2H,
2-CH2); 1.61 (m, 2H, 3-CH2); 1.79 (s, 3H, 5a-CH3); 2.06 (m, 2H, 4-CH2); 2.76 (m,
2H, 14-CH2); 3.02 (m, 1H, 15-CH); 6.10 (m 1H, 12-CH); 6.73 (d, 1H, J ¼ 15.75,
8-CH); 6.88 (m, 1H, 11-CH); 7.38 (d, 1H, J ¼ 15.75, 7-CH). 13C NMR: Cq: 33.9
(1); 134.7; 165.5; 137.1; 189.8 (CO). CH: 34.0; 123.2; 125.2; 131.5; 132.8. CH2:
18.9; 30.8; 33.4; 39.7. CH3: 19.0; 21.6; 28.6 (1a, 1b). Anal. calc. for C19H26O: C,
84.39; H, 9.69; O, 5.92. Found: C, 84.26; H, 9.89; O, 5.85.
Compound 8. Reaction with 2-methyl-acrolein, 45%. IR (film) nC¼O 1648. 1H
NMR: 1.0 (s, 6H, 1a-CH3, 1b-CH3); 1.0 (t, 3H, J ¼ 7.1, 14-CH3); 1.46 (m, 2H,
3-CH2); 1.60 (m, 2H, 2-CH2); 1.77 (s, 3H, 5a-CH3); 2.04 (m, 2H, 4-CH2); 2.20 and

C-15 PHOSPHORUS RETINOID YLIDE
189
2.68 (2 m, 2H, 14-CH2); 2.47 (m, 1H, 15-CH); 5.44 (m, 1H, 12-CH); 6.69 (d, 1H,
J ¼ 15.75, 8-CH); 6.90 (m, 1H, 11-CH); 7.39 (d, 1H, J ¼ 15.75, 7-CH). 13C NMR:
CO: 190.2. CH: 123.0; 125.4; 132.1; 141.1; 141.9. CH2: 18.9; 28.7; 34.0; 39.6. CH3:
18.9; 21.7; 28.7 (1a, 1b). Anal. calc. for C19H26O: C, 84.39; H, 9.69; O, 5.92. Found:
C, 84.27; H, 9.90; O, 5.83.
Compound 9. Reaction with 3-methyl-2-butenal, 41%. IR (film) nC¼O 1659.
1H NMR: 1.10 (s, 6H, 1a-CH3, 1b-CH3); 1.50 (m, 2H, 2-CH2); 1.64 (m, 2H;
3-CH2); 1.72 (s, 3H, 5a-CH3); 1.91 and 1.94 (2s, 6H, 15a-CH3, 15b-CH3); 2.09 (m,
2H, 4-CH2); 5.46 (m, 2H, 12-CH2); 6.39 (d, 1H, J ¼ 11.8, 14-CH); 6.55 (d, 1H,
J ¼ 15.75, 8-CH); 6.76 (m, 1H, 11-CH); 7.39 (d, 1H, J ¼ 15.75, 7-CH). 13C NMR:
CO: 193.4. CH: 121.0; 128.7; 130.1; 132.8; 143.0. CH2: 18.8; 33.5; 39.7; 119.8.
CH3: 18.8; 21.7; 28.7 (1a, 1b). Anal. calc. for C20H28O: C, 84.45; H, 9.92; O, 5.62.
Found: C, 84.39; H, 10.00; O, 5.61.
1
Compound 10. Reaction with citral, 50%. IR (film) nC¼O 1659. H NMR:
1.10 (s, 6H, 1a-CH3, 1b-CH3); 1.50 (m, 2H, 2-CH2); 1.61 and 1.67 (6H, 19-CH3);
1.63 (m, 2H, 3-CH2); 1.65 (m, 2H; 17-CH2); 1.67 (s, 3H, 5a-CH3); 1.81 (s, 3H,
15a-CH3); 2.09 (m, 2H, 4-CH2); 2.20 (m, 2H, 16-CH2); 5.10 (m, 1H, 18-CH); 5.47
(m, 2H, 12-CH2); 6.38 (d, 1H, J ¼ 11.8, 14-CH); 6.55 (d, 1H; J ¼ 15.8, 8-CH); 6.73
(m, 1H, 11-CH); 7.10 (d, 1H, J ¼ 11.8, 13-CH); 7.41 (d, 1H, J ¼ 15.8, 7-CH). 13C
NMR: CO: 193.4. CH: 120.8; 123.4; 128.7; 130.2; 132.1; 132.9. CH2: 18.9; 25.7;
33.6; 39.8; 40.8; 119.9. CH3: 17.4; 17.7; 21.8; 25.0; 28.8 (1a, 1b). Anal. calc. for
C25H36O: C, 85.17; H, 10.29; O, 4.54. Found: C, 85.01; H, 10.34; O, 4.65.
1
Compound 11. Reaction with benzaldehyde, 60%. IR (film) nC¼O 1660. H
NMR: 1.11 (s, 6H, 1a-CH3, 1b-CH3); 1.51 (m, 2H, 2-CH2); 1.64 (m, 2H, 3-CH2);
1.82 (s, 3H, 5a-CH3); 2.11 (m, 2H, 4-CH2); 5.52 (m, 2H, 12-CH2); 6.52 (d, 1H,
J ¼ 16.1, 8-CH); 6.76 (m, 1H, 11-CH); 7.04 (S, 1H, 13-CH); 7.35–7.45 (m, 5H,
C6H5); 7.48 (d, 1H, J ¼ 16.1, 7-CH). 13C NMR: CO: 195.1. CH: 128.3; 128.6;
129.1; 129.9; 130.9; 144.7. CH2: 18.8; 34.1; 39.8; 120.7. CH3: 21.8; 29.6 (1a, 1b). Anal.
calc. for C22H26O: C, 86.23; H, 8.55; O, 5.22. Found: C, 86.03; H, 8.85; O, 5.12.
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