Reactivity of bis-vinylphosphates obtained from imide derivatives. Synthesis of 2,6-disubstituted 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.tetlet.2005.03.136

The Pd-catalyzed functionalization of lactam-derived vinyl phosphates has become an important tool in the last decade for the synthesis of nitrogen-containing heterocycles. By using this method, we were able to introduce alkenyl, aryl and heteroaryl groups on bis-vinylphosphate derivatives to provide efficient access to 2,6-disubstituted 1,4-dihydropyridines.

Full text of DOI:10.1016/j.tetlet.2005.03.136

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3703–3705
Reactivity of bis-vinylphosphates obtained from imide
derivatives. Synthesis of 2,6-disubstituted 1,4-dihydropyridines
Deborah Mousset, Isabelle Gillaizeau,* Jwanro Hassan, Franck Lepifre,
*
´
Pascal Bouyssou and Gerard Coudert
´ ´ ´
Institut de Chimie Organique et Analytique, UMR 6005, Universite d’Orleans, BP 6759, 45067 Orleans cedex 2, France
Received 9 March 2005; accepted 21 March 2005
Available online 11 April 2005
Abstract—The Pd-catalyzed functionalization of lactam-derived vinyl phosphates has become an important tool in the last decade
for the synthesis of nitrogen-containing heterocycles. By using this method, we were able to introduce alkenyl, aryl and heteroaryl
groups on bis-vinylphosphate derivatives to provide efficient access to 2,6-disubstituted 1,4-dihydropyridines.
Ó 2005 Elsevier Ltd. All rights reserved.
Due to the rich chemistry of nitrogen-containing com-
pounds and their evident biological interest, synthesiz-
ing N-heterocycles has been a central and important
theme within organic chemistry. The functionalization
of lactams by Pd-catalyzed coupling reactions of the
corresponding vinyl phosphates has gained increasing
importance in the synthesis of heterocyclic compounds.
In fact, phosphate-activated intermediates were found to
be more robust than the corresponding triflates. Nico-
laou et al. especially reported on the phosphate activa-
tion of both N-acyllactam1 and lactone2 derivatives.
The usefulness of lactam-derived vinyl phosphates was
also described by Occhiato and co-workers.3 Recently,
N-alkyl ketene aminal phosphates derived from N-alkyl
lactam precursors were applied to asymmetric synthe-
ses4 and also to an intramolecular Heck cyclization.5
aged. In fact dihydropyridines (DHPs) show interesting
features that make them very attractive for use in org-
anic synthesis. Furthermore few examples of 2,6-disub-
stituted dihydropyridines have been described and
most of them have been synthesized from the corres-
ponding pyridine or pyridinium salt.7 We wish to report
herein an efficient preparation of 2,6-disubstituted di-
hydropyridines using the Pd-catalyzed coupling reac-
tions of the bis-vinylphosphates 3 and 4 according to a
methodology previously developed in our group.8
As shown in Scheme 1, both N-Boc glutarimide deriv-
atives 1 and 2 were prepared in high yield (respectively,
in 84% and 95% yield) by reaction of the corresponding
glutarimide with di-tert-butyldicarbonate in acetonitrile
for 15 h. Treatment of both imides 1 and 2 with LDA at
ꢀ78 °C in THF provided a hardly soluble bis-enolate,
which was trapped by reaction with diphenylchloro-
phosphate (2.4 equiv, THF, ꢀ78 to 20 °C) to give, as
expected after complete conversion, bis-vinylphosphates
3 and 4. These compounds were then isolated by silica
gel column chromatography, respectively, in 64% and
70% yields as stable compounds.
In a previous work, we reported the preparation of cyc-
lic six-, seven- and thirteen-membered ene-carbamates
substituted on C2 by aryl or heteroaryl groups using
an extension of the Suzuki reaction involving the palla-
dium coupling of boronic acids and lactam-derived vinyl
phosphates.6 Encouraged by the success of this model
reaction, extension of this approach for the preparation
of bis-substituted dihydropyridine derivatives was envis-
These new bis-vinylphosphates 3 and 4 were then sub-
jected to typical organometallic coupling reactions.
Firstly, according to a Stille-type coupling, the reaction
of bis-vinylphosphate 3 in the presence of catalytic
Pd(PPh3)4 and anhydrous LiCl in refluxing THF for
2 h remarkably afforded the desired compounds 5, 6
and 7 in fair to good yields (cf. Scheme 2). The results
of these coupling reactions are presented in Table 1.
Keywords: 2,6-Disubstituted 1,4-dihydropyridines; Ene-carbamate;
Vinylphosphate; Palladium coupling reaction.
*
Corresponding authors. Tel.: +33 238 494 583; fax: +33 238 417
281; e-mail addresses: isabelle.gillaizeau@univ-orleans.fr; gerard.
coudert@univ-orleans.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.136

3704
D. Mousset et al. / Tetrahedron Letters 46 (2005) 3703–3705
O
O
P
b
a
P
N
(PhO)2
O
O
(OPh)2
O
N
H
O
O
N
O
84%
64%
Boc
3
Boc
1
a
b
O
O
P
P
95%
70%
(PhO)2
O
N
O
(OPh)2
O
N
O
O
N
H
O
Boc
4
Boc
2
Scheme 1. Reagents and conditions: (a) Boc2O, DMAP cat., CH3CN, RT, 15 h; (b) (i) 2.6 equiv LDA, THF, ꢀ78 °C, 2 h; (ii) 2.4 equiv
ClP(O)(OPh)2, ꢀ78 °C to RT, 15 h.
Table 2. Suzuki coupling reactions on bis-vinylphosphates 3 and 4a
O
P
O
P
Bis-vinylphosphate
R or Ar
Products
Yield (%)
c
N
(PhO)2
O
O
(OPh)2
R, Ar
N
Ar, R
3
8b
88
Boc
Boc
3
5-7
S
3
9
83
Scheme 2. Reagents and conditions: (c) 10 mol% Pd(PPh3)4, 4 equiv
RSnBu3 or ArSnBu3, 3 equiv LiCl, THF, 3 h, reflux (cf. Table 1).
O
3
3
10
11
25
60
Table 1. Stille coupling reactions on bis-vinylphosphate 3a
S
Bis-vinylphosphate R or Ar
Products Yield (%)
O
3
5
88
3
3
12
5
61
54
O
3
6
7
66
54
O
3
4
4
13
14
85
70
a All the compounds were fully characterized by analytical and spec-
troscopic methods.
S
One of the attractive features of our approach lies in
its inherent versatility since a wide range of reactants
could be used. A Pd-catalyzed Suzuki–Miyaura coup-
ling reaction9 of the bis-vinylphosphates 3 and 4 was
subsequently applied. Using different boronic acid
derivatives the corresponding 2,6-disubstituted dihydro-
pyridines 5, 8–14 were easily isolated in good yields (cf.
Table 2 and Scheme 3). In the case of bis-phenyl deriv-
ative 8, the coupling reaction was complete in only
30 min. For the introduction of the unsubstituted vinyl
moiety (compound 5, Tables 1 and 2), a better yield
was observed with the Stille coupling compared to the
Suzuki–Miyaura reaction (88% yield instead of 54%
yield). The Heck reaction had already been reported as
a serious competitor in the case of vinylboronic esters.10
a All the compounds were fully characterized by analytical and spec-
troscopic methods.
b Reaction time 30 min.
O
P
O
P
d
N
(PhO)2
O
O
(OPh)2
R, Ar
N
Ar, R
Boc
Boc
3
5, 8-12
O
O
d
P
P
In conclusion, we have described the syntheses of
2,6-dialkenyl-, 2,6-diaryl- and 2,6-diheteroaryl-1,4-dihy-
dropyridines through a series of palladium-catalyzed
reactions via the corresponding bis-vinylphosphates.
All these compounds are of great interest as intermedi-
ates in the elaboration of more complex molecules
exhibiting biological activity. Further studies on the
Ar
N
Ar
(PhO)2
O
N
O
(OPh)2
Boc
Boc
13-14
4
Scheme 3. Reagents and conditions: (d) (i) 10 mol% PdCl2(PPh3)2
THF, RT, 10 min; (ii) 3 equiv ArB(OH)2 or RB(OH)2, 2 equiv Na2CO3
2 M, EtOH, reflux, 3 h (cf. Table 2).

D. Mousset et al. / Tetrahedron Letters 46 (2005) 3703–3705
3705
General procedure for the Stille coupling reaction. Prep-
aration of 1-(tert-butoxycarbonyl)-2,6-divinyl-1,4-dihy-
reactivity of these 1,4-dihydropyridine derivatives are
currently in progress in our laboratory.
dropyridine (5). To
a stirred solution of bis-vinyl
phosphate 3 (0.74 mmol, 500 mg) in THF (2.5 mL), tri-
butyl(vinyl)tin (2.95 mmol, 863 lL), anhydrous lithium
chloride (4.43 mmol, 188 mg) and Pd(PPh3)4 (0.074 mmol,
51 mg), were added under argon. The mixture was refluxed
for 3 h. After cooling to room temperature, the reaction
mixture was diluted with water, ethyl acetate was then
added. The organic layer was separated, dried (MgSO4)
and the solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography
(silica gel, petroleum ether/EtOAc 8:2). Compound 5 was
isolated as an orange solid. Yield: 151 mg (88%). Mp 134–
135 °C. 1H NMR (250 MHz, CDCl3) d (ppm) 1.44 (s, 9H,
References and notes
1. Nicolaou, K. C.; Shi, G.-Q.; Namoto, K.; Bernal, F.
Chem. Commun. 1998, 1757–1758.
2. Nicolaou, K. C.; Shi, G.-Q.; Ga¨rtner, G. P.; Yang, Z.
J. Am. Chem. Soc. 1997, 119, 5467–5468.
3. (a) Occhiato, E. G. Mini-Reviews in Organic Chemistry
2004, 1(2), 149–162; (b) Lo Galbo, F.; Occhiato, E. G.;
Guarna, A.; Faggi, C. J. Org. Chem. 2003, 68, 6360–6368,
and references cited herein.
4. Jiang, J.; De Vita, R. J.; Doss, G. A.; Goulete, M. T.;
Wyvratt, M. J. J. Am. Chem. Soc. 1999, 121, 593–594.
5. Coe, J. W. Org. Lett. 2000, 2, 4205–4208.
0
0 0
,
t-Bu); 2.74 (t, 2H, H4, J = 5 Hz); 5.08 (d, 2H, H2 and H2
0
Jcis = 10 Hz); 5.35 (d, 2H, H2 and H2 , Jtrans = 17 Hz); 5.70
0 0
0
0 0
,
(t, 2H, H3 and H5, J = 5 Hz); 6.35(dd, 2H, H1 and H1
6. (a) Lepifre, F.; Clavier, S.; Bouyssou, P.; Coudert, G.
Tetrahedron 2001, 57, 6969–6975; (b) Lepifre, F.; Buon,
C.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron
Lett. 1999, 40, 6373–6376.
7. (a) Lounasmaa, M.; Tolvanen, A. In Comprehensive
Heterocyclic Chemistry II; Katrisky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5,
p 135; (b) Lavilla, R. J. Chem. Soc., Perkin Trans. 1 2002,
1141–1156; (c) Charrette, A. B.; Grenon, M.; Lemire, A.;
Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123,
11829–11830; (d) Lavilla, R.; Bernabeu, M. C.; Carranco,
I.; Diaz, J. L. Org. Lett. 2003, 5, 717–720.
Jcis = 10 Hz and Jtrans = 17 Hz). 13C NMR (62.8 MHz,
CDCl3) d (ppm) 24.6 (C4); 28.2 (C(CH3)3); 81.4 (C(CH3)3);
112.8 (CH2@); 119.3 (C3, C5); 133.1 (CH@); 141.8 (C2, C6);
152.8 (C@O). IR mmax (KBr) 2979, 2930 (C–H); 1715
(C@O); 1596. SM (IS) m/z 234 [M + H]+.
General procedure for the Suzuki coupling reaction.
Preparation of 1-(tert-butoxycarbonyl)-2,6-diphenyl-1,4-
dihydropyridine (8). To a solution of bis-vinyl phosphate
3 (0.74 mmol, 500 mg) in THF (2.5 mL) under argon
PdCl2(PPh3)2 (0.074 mmol, 51 mg) was added. The mixture
was stirred during 15 min then phenylboronic acid
(3.69 mmol, 449 mg), 2 M Na2CO3 (aq) (1.25 mL) and a
few drops of EtOH were added. The mixture was refluxed
for 30 min. After cooling, ethyl acetate was added, the
organic layer was separated and dried (MgSO4). After
evaporation of the solvent, the residue was purified by flash
column chromatography (silica gel, petroleum ether/EtOAc
8:2). Compound 8 was isolated as a white solid. Yield:
305 mg (88%). Mp 126–127 °C. 1H NMR (250 MHz,
CDCl3) d (ppm) 1.03 (s, 9H, t-Bu); 2.94 (t, 2H, H4,
J = 5 Hz); 5.78 (t, 2H, H3 and H5, J = 5 Hz); 7.24–7.40 (m,
6H, Har); 7.52–7.57 (m, 4H, Har). 13C NMR (62.8 MHz,
CDCl3) d (ppm) 24.9 (C4); 27.6 (C(CH3)3); 81.3 (C(CH3)3);
116.9 (C3, C5); 125.4, 127.3, 128.3, 138.9 (Car); 142.6 (C2,
C6); 152.3 (C@O). IR mmax (KBr) 2971, 2930, 2812 (C–H);
1716 (C@O); 1670, 1629, 1598. HRMS (IE) m/z calcd for
[C22H23NO2ꢀÅCO2-t-Bu]+ 232.1126; found 232.1112.
9. (a) Miyaura, N.; Suzuki, A. J. Chem. Soc. Chem. Commun.
1979, 866–867; (b) In an issue dedicated to 30 years of
cross-coupling chemistry: Miyaura, N. J. Organomet.
Chem. 2002, 653, 54–57.
8. Typical procedure: Preparation of the bis-vinylphosphate
(3): To a solution of 1-(tert-butoxycarbonyl)-2,6-dioxopi-
peridine 1 (4.69 mmol, 1.0 g) in THF (9 mL) at ꢀ78 °C
under argon, LDA (12.19 mmol, 2 M in hexane, 6.1 mL)
was added dropwise. After stirring for 2 h at ꢀ78 °C,
diphenyl chlorophosphate (11.25 mmol, 2.4 mL) was
added and the mixture was allowed to warm up to room
temperature over 15 h. The reaction was quenched by slow
addition of H2O. Ethyl acetate was then added, the
organic layer was separated and dried (MgSO4) and the
solvent was evaporated. The residue was purified by flash
column chromatography (silica gel, petroleum ether/
EtOAc 6:4) to afford compound 3 (2.03 g, 64%) as a
1
brown oil. H NMR (250 MHz, CDCl3) d (ppm) 1.41 (s,
9H, t-Bu); 2.75–2.78 (m, 2H, H4); 5.36–5.40 (m, 2H, H3 et
H5); 7.14–7.33 (m, 20H, Har). 13C NMR (62.8 MHz;
CDCl3) d (ppm) 21.5 (C4); 27.9 (C(CH3)3); 83.9 (C(CH3)3);
101.7 (C3, C5); 120.2, 120.3, 125.6, 129.9 (Car); 141.4, 141.5
(C6, C2); 150.4, 150.6 (Car); 151.3 (C@O). IR mmax (NaCl
film) 3071, 2980 and 2934 (C–H); 1743 (C@O); 1590, 1493
and 1457 (C@C); 1345 (P@O). SM (IS) m/z 678,50
[M + H]+.
10. (a) Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron
Lett. 1993, 34, 3599–3602; (b) Stewart, S. K.; Whiting, A.
J. Organomet. Chem. 1994, 482, 293–300.