Synthesis and reactivity of imide-derived bisvinyl phosphates. Reactivity of 2,6-disubstituted 1,4-dihydropyridines

Article abstract of DOI:10.1021/jo0607360

Symmetrical and unsymmetrical 2,6-disubstituted dihydropyridines were prepared in high yields under mild conditions using the Suzuki and Stille Pd-catalyzed coupling reactions of imide-derived bisvinyl phosphates with a range of aryl, heteroaryl, and alkenyl moieties. The alkylation reaction at C-4 easily afforded original tri- and tetrasubstituted dihydropyridines. Hydrolysis of the latter under acidic condition provided efficiently either open-chain 1,5-diketones or di- or trisubstituted pyridines.

Full text of DOI:10.1021/jo0607360

Synthesis and Reactivity of Imide-Derived Bisvinyl Phosphates.
Reactivity of 2,6-Disubstituted 1,4-Dihydropyridines
Deborah Mousset, Isabelle Gillaizeau,* Andre´a Sabatie´, Pascal Bouyssou, and
Ge´rard Coudert*
ICOA, UMR 6005, UniVersite´ d’Orle´ans, BP 6759, 45067 Orle´ans Cedex 2, France
isabelle.gillaizeau@uniV-orleans.fr; gerard.coudert@uniV-orleans.fr.
ReceiVed April 6, 2006
Symmetrical and unsymmetrical 2,6-disubstituted dihydropyridines were prepared in high yields under
mild conditions using the Suzuki and Stille Pd-catalyzed coupling reactions of imide-derived bisvinyl
phosphates with a range of aryl, heteroaryl, and alkenyl moieties. The alkylation reaction at C-4 easily
afforded original tri- and tetrasubstituted dihydropyridines. Hydrolysis of the latter under acidic condition
provided efficiently either open-chain 1,5-diketones or di- or trisubstituted pyridines.
Introduction
gashira,4 Negishi,5 and Kumada-Tamao6 reactions and were also
applied in total synthesis.7
Enol phosphates represent versatile intermediates in the
construction of complex organic molecules.1 The ability to easily
convert enol phosphates into a myriad of functional motifs of
synthetic relevance is well-known. In particular, this moiety has
proved to be a robust and versatile partner for cross-coupling
reactions mediated by Pd(0) and Ni(0). Enol phosphates have
in fact, in a few cases, proved to work better in such reactions
than their triflate counterparts owing to higher stability, higher
reaction yield, and easier work up. The ability of enol phosphates
to undergo these cross-coupling reactions in the presence of
various heteroatoms makes them attractive functional groups
for the construction of various substituted heterocyclic systems.
Enol phosphates were used in Suzuki,1i,1e,2 Stille,1h,2d,3 Sono-
In a recent paper,8 using a methodology developed in our
group, we described an efficient synthesis of 2,6-disubstituted
dihydropyridines under mild conditions using the Suzuki and
Stille Pd-catalyzed coupling reactions of imide-derived bisvinyl
phosphates with a range of aryl, heteroaryl, and alkenyl moieties.
As part of our interest in using readily available enol phosphates
in the synthesis of new heterocyclic compounds, we wish to
report herein a general methodology for the synthesis of
(2) (a) Lo Galbo, F.; Occhiato, E. G.; Guarna, A.; Faggi, C. J. Org.
Chem. 2003, 68, 6360-6368. (b) Huffman, M. A.; Yasuda, N. Synlett 1999,
471-473. (c) Campbell, I. B.; Guo, J.; Jones, E.; Steel, P. G. Org. Biomol.
Chem. 2004, 2, 2725-2727. (d) Larsen, U. S.; Martiny, L.; Begtrup, M.
Tetrahedron Lett. 2005, 46, 4261-4263.
(3) (a) Nicolaou, K. C.; Shi, G. Q.; Namoto, K.; Bernal, F. Chem.
Commun. 1998, 1757-1758.
(4) cf. References 2a and 3a.
(1) (a) Nicolaou, K. C.; Shi, G. Q.; Gunzner, J. L.; Ga¨rtner, P.; Yang, Z.
J. Am. Chem. Soc. 1997, 119, 5467-5468. (b) Buon, C.; Chacun-Lefevre,
L.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron 2000, 56, 605-614.
(c) Sasaki, M.; Ishikawa, M.; Fuwa, H.; Tachibana, K. Tetrahedron 2002,
58, 1889-1911. (d) Coe, J. W. Org. Lett. 2000, 2, 4205-4208. (e) Lepifre,
F.; Clavier, S.; Bouyssou, P.; Coudert, G. Tetrahedron 2001, 57, 6969-
6975. (f) Wu, J.; Yang, Z. J. Org. Chem. 2001, 66, 7875-7878. (g) Moraes,
D. N.; Barrientos-Astigarraga, R. E.; Castelani, P.; Comasseto, J. V.
Tetrahedron 2000, 56, 3327-3337. (h) Bouyssou, C. B.; Coudert, G.
Tetrahedron Lett. 1999, 40, 701-702. (i) Nan, Y.; Yang, Z. Tetrahedron
Lett. 1999, 40, 3321-3324. (j) Fugami, K.; Oshima, K.; Utimoto, K. Chem.
Lett. 1987, 2203-2206. (k) Takai, K.; Sato, M.; Oshima, K.; Nozaki, H.
Bull. Chem. Soc. Jpn. 1984, 57, 108-115. (l) Sato, M.; Takai, K.; Oshima,
K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 1609-1612. (m) Takai, K.;
Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21, 2531-2534.
(5) Jiang, J. L.; Devita, R. J.; Doss, G. A.; Goulet, M. T.; Wyvratt, M.
J. J. Am. Chem. Soc. 1999, 121, 593-594.
(6) (a) Liao, Y.; Hu, Y. H.; Wu, H.; Zhu, Q.; Donovan, M.; Fathi, R.;
Yang, Z. Curr. Med. Chem. 2003, 10, 2285-2316. (b) Wu, J.; Yang, Z. J.
Org. Chem. 2001, 66, 7875-7878. (c) Miller, J. A. Tetrahedron Lett. 2002,
43, 7111-7114. (d) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199-
1205. (e) Hayashi, T.; Fujiwa, T.; Okamoto, Y.; Katsuro, Y.; Kumada, M.
Synthesis 1981, 1001-1002.
(7) (a) Takakura, H.; Sasaki, M.; Honda, S.; Tachibana, K. Org. Lett.
2002, 2771-2774.
(8) Mousset, D.; Gillaizeau, I.; Hassan, J.; Lepifre, F.; Bouyssou, P.;
Coudert, G. Tetrahedron Lett. 2005, 46, 3703-3705 and references cited
herein.
10.1021/jo0607360 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/08/2006
J. Org. Chem. 2006, 71, 5993-5999
5993

Mousset et al.
TABLE 1. Suzuki and Stille Coupling Reactions on Bisvinyl
polysubstituted dihydropyridines and/or pyridines which are of
great interest as intermediates in medicinal chemistry.9 Dihy-
dropyridines (DHPs) exhibit interesting features that make them
attractive for use in organic synthesis. Furthermore, only a few
examples of 2,6-disubstituted dihydropyridines have been
described so far, and most of them have been synthesized from
the corresponding pyridine or pyridinium salt.10
Phosphates 1 and 2d
In this paper, we give a full account of our investigations
which focus primarily on the preparation of 2,6-disubstituted
dihydropyridines derivatives symmetrical or not by using Pd-
catalyzed coupling reactions. Second, we also investigated the
reactivity of the dihydropyridine by performing functionalization
reactions at C-4 and by applying hydrolysis conditions.
Results and Discussion
As previously described,8 the cross-coupling reactions of
bisenolphosphates 1 and 2, obtained from the corresponding
glutarimides via the bislithium enolate, afforded the 2,6-
disubstituted dihydropyridines 3-12 in high yields. Table 1
summarizes the most significant experiments of this study. The
boronic acids or tin reagents are commercially available except
for 2-methylstannylbenzodioxine (entry 2, Table 1).3b The N-Boc
group was initially used as an electron withdrawing protecting
group since it is easily removable under acidic conditions.
After the successful preparation of symmetrical 2,6-disub-
stituted dihydropyridines, we turned our attention to more
interesting unsymmetrical dihydropyridine derivatives. To achieve
this goal, we first investigated the two-step Suzuki-Miyaura
reactions. The key step was the selective monocoupling reaction.
Unfortunately, by reducing first the quantity of boronic acid
under the same conditions as above (1.1 equiv PhB(OH)2, 5
mol % PdCl2(PPh3)2, 2 equiv Na2CO3 (2M), EtOH, reflux 30
min) or by applying Hirao and Sakurai conditions12 on bisvinyl
phosphate 2 (110 mol % PhB(OH)2, 1.5 mol % Pd2(dba)3, 3.6
mol % Cy3P, 200 mol % Cs2CO3 in dioxane at 85 °C during
24 h) we were not able to isolate the desired monosubstituted
dihydropyridine derivative. After only 1 h, we recovered
bissubstituted product 11 (in 40% yield) accompanied by
unreacted starting material 2 (in 50% yield). The monosubsti-
tuted dihydropyridine derivative appeared indeed to be more
reactive than the starting bisvinyl phosphate 2. Thus, we decided
to introduce both substituents successively (Scheme 1. To this
aim, we first prepared monovinyl phosphate 14 by treatment
of the N-Boc glutarimide 138 with LiHMDS (1.2 equiv) at -78
°C followed by the addition of diphenyl chlorophosphate. After
workup and purification by chromatography, compound 14 was
isolated in 74% yield. It should be noted that we selected the
spiro derivative 13 for its greater stability than its nonspiro
a Conditions: 10 mol % Pd(PPh3)4, 4 equiv RSnBu3, 3 equiv LiCl, THF,
3 h, reflux.11 b Conditions: (i) 10 mol % PdCl2(PPh3)2 THF, RT, 10 min;
(ii) 3 equiv RB(OH)2, 2 equiv Na2CO3 2 M, EtOH, reflux, 3 h. c Reaction
time: 30 min. d All the compounds were fully characterized by analytical
and spectroscopic methods.
counterpart. We then attempted the first Suzuki coupling reaction
under similar conditions. The monosubstituted derivative 15 was
then isolated in 77% yield. Starting from the latter, and by using
the same protocol, enol phosphate 16 was synthesized in 78%
yield. A second Suzuki coupling reaction enabled us to obtain
the desired unsymmetrical 2,6-dihydropyridines 17a-f in
remarkably high yields (cf. Table 2). In the case of compounds
17a,b, we also had the opportunity to test a new palladium
catalyst prepared by Nolan’s group.13 Under these conditions
(1.1 equiv PhB(OH)2, 10 mol % (IMes)Pd(η3-2-methylallyl)-
(9) Chhillar, A. K.; Arya, P.; Mukherjee, C.; Kumar, P.; Yadav, Y.;
Sharma, A. K.; Yadav, V.; Gupta, J.; Dabur, R.; Jha, H. N.; Watterson, A.
C.; Parmarn V. S.; Prasad, A. K.; Shrama, G. Bioorg. Med. Chem. 2006,
14, 973-981.
(10) (a) For dihydropyridines chemistry reviews see Lavilla, R. J. Chem.
Soc., Perkin Trans. 1 2002, 1141-1156. (b) Lounasmaa, M.; Tolvanen, A.
In ComprehensiVe Heterocyclic Chemistry II; Katrisky, A. R., Rees, C. W.,
Scriven, E. F. V.; Eds.; Pergamon: Oxford, U.K., 1996; Vol. 5, p 135. (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. (e) Ishar, M. P.
S.; Kumar, K.; Kaur, S.; Kumar, S.; Girdhar, N. K.; Sachar, S.; Marwaha,
A.; Kapoor, A. Org. Lett. 2001, 3, 2133-2136. (f) Jakubowicz, K; Wong,
Y.-S.; Chiaroni, A.; Be´ne´chie, M.; Marazano, C. J. Org. Chem. 2005, 70,
7780-7783.
(13) Navarro, O.; Oonishi, Y.; Kelly, R. A.; Stevens, E. D.; Briel, O.;
Nolan, S. P. J. Organomet. Chem. 2004, 689, 3722-3727 and references
cited therein.
(11) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033-3040.
(12) Mao, L.; Sakurai, H.; Hirao, T. Synthesis 2004, 2535-2539.
5994 J. Org. Chem., Vol. 71, No. 16, 2006

BisVinyl Phosphate and 1,4-Dihydropyridine
SCHEME 1a
TABLE 3. FunctionalizAtion Reactions at C-4 of Dihydropyridine
6a
a (a) (i) 1.2 equiv LiHMDS, THF, -78 °C, 1.5 h; (ii) 1.2 equiv
ClP(O)(OPh)2, -78 °C, 2 h (74%). (b) (i) 5 mol % PdCl2(PPh3)2, THF,
TA, 10 min; (ii) 2.5 equiv PhB(OH)2, 2 equiv Na2CO3 (2 M), EtOH, reflux
2 h (77%). (c) (i) 1.2 equiv LiHMDS, THF, -78 °C, 1.5 h; (ii) 1.2 equiv
ClP(O)(OPh)2, -78 °C, 1 h (78%). (d) (i) 5 mol % PdCl2(PPh3)2, THF,
TA, 10 min; (ii) 2.5 equiv RB(OH)2, 2 equiv Na2CO3 (2 M), EtOH, reflux
2 h. (e) 5 mol % Pd(PPh3)4, 2 equiv RSnBu3 or RSnMe3, 1.5 equiv LiCl,
THF, 2 h, reflux. (cf. Table 2).
TABLE 2. Synthesis of Unsymmetrical 2,6-Dihydropyridine
Derivatives 17a-f from the Monovinyl Phosphate 16
a Reagents and conditions: (i) 1.1 equiv n-BuLi, THF, -78 °C, 5 min;
(ii) 3 equiv electrophile, -78 °C, 2 h; (iii) NH4Cl sat.
tetrahydropyridines by an acid-catalyzed rearrangement under
mild conditions.16
Hence, we decided to introduce various substituents at C-4
by preparing the 4-lithio derivative of 2,6-diphenyl-1,4-dihy-
dropyridine 6, chosen as a model compound. The best results
were obtained using 1.1 equiv of n-BuLi at -78 °C for only 5
min. The 4-lithio derivative was trapped with a range of
electrophiles (3 equiv) leading to the required 4-substituted
derivatives 18a-g in high yields (cf. Table 3). The use of
another base such as LDA resulted in a dramatic decrease of
the yield because of unreacted starting material. Compound 6
was found to be quite sensitive to basic conditions. Thus, if
reaction times were superior to 5 min, it also resulted in lower
overall yields.
Encouraged by these promising results, we then explored the
bisfunctionalization reaction at the C-4 position. A first attempt
was made starting from the 4-methyl derivative 18a. Optimal
conditions were determined to be 1.1 equiv of t-BuLi at -78
°C for only 5 min, followed by the addition of the second
electrophile (3 equiv). In this case, using iodomethane as the
electrophile, 4,4-dimethyl-2,6-diphenyl-dihydropyridine 19a was
isolated in quantitative yield (cf. Table 4). However, variations
in the nature of the electrophile had a dramatic influence on
Cl,12 2 equiv Na2CO3 (2M), EtOH, reflux 30 min) we success-
fully obtained the desired substituted dihydropyridines 17a and
17b, respectively, in 75% and 70% yield. To the best of our
knowledge, it is the first application of this catalyst in the
palladium coupling reaction onto a vinyl phosphate moiety.
Our next aim was then to functionalize the C-4 position.
Creating variations of these 1,4-dihydropyridines is an important
task. To the best of our knowledge, there is no literature
precedent for the direct alkylation of 1,4-dihydropyridines at
the C-4 position. Some alkylations are described on the
piperidine skeleton but in each case via the 2-methoxy-1,2,5,6-
tetrahydropyridine moiety. Matsumura et al. reported the
regioselective introduction of substituents at C-4 of a piperidine
ring by using the addition of a Grignard reagent in the presence
of CuBr14 or by the stereoselective addition of dimethyl
alkylmalonate in the presence of TiCl4 in Et3N/CH2Cl2.15 Torii
et al. also described an easy access to 4-hydroxy-1,2,3,4-
(14) Shono, T.; Terauchi, J.; Ohki, Y.; Matsumura, Y. Tetrahedron Lett.
1990, 31, 6385-6386.
(15) Matsumura, Y.; Yoshimoto, Y.; Horikawa, C.; Maki, T.; Watanabe,
M. Tetrahedron Lett. 1996, 37, 5715-5718.
(16) Torii, S.; Inokuchi, T.; Akahosi, F.; Kubota, M. Synthesis 1987,
242-245.
J. Org. Chem, Vol. 71, No. 16, 2006 5995

Mousset et al.
TABLE 5. Hydrolysis of Dihydropyridine Derivativesa
TABLE 4. Second Functionalization at C-4 of Dihydropyridines
18A and 18ba
a Reagents and conditions: (i) 1.1 equiv t-BuLi, THF, -78 °C, 5 min;
b
(ii) 3 equiv electrophile, 2 h, -78 °C; (iii) NH4Cl sat. The bisallylic
compound 19d could also be obtained by using a “one pot” procedure
without isolation of the monocoupling derivative 18b (cf. experimental part).
SCHEME 2. Metathesis Cyclization Reaction on the
Bisallylic Compound 19da
a Reagents and conditions: 3 N HCl/EtOAc, RT, 4 h.
Treatment of various dihydropyridines with 3 N HCl in ethyl
acetate promoted ring opening and gave the corresponding open-
chain diketones in very good yields (Table 5). This methodology
provides easy access to original 1,5-diketones not described yet
or not otherwise easily accessible. In addition, treatment of
dihydropyridines derivatives with anhydrous TFA afforded the
corresponding di- or trisubstituted pyridines 22a-f in high yields
(See Table 6).
a Conditions and reagents: Ruthenium catalyst16 (10 mol %), toluene,
60 °C, 15 h.
In conclusion, we demonstrated the usefulness of synthesizing
enol phosphates derived from imides. These compounds are
versatile starting materials for palladium catalyzed cross-
coupling reactions giving efficient access to a range of 2,6-
disubstituted 1,4-dihydropyridines. On the latter’s C-4 position,
selective mono- or bissubstitution was achieved in good yield.
This work demonstrates the potential of our methodology.
Moreover, hydrolysis under acidic conditions of the dihydro-
pyridine derivatives provides a direct and efficient route either
to original 1,5-diketones or to various di- or trisubstituted
pyridines. Because different patterns of substitution on the
heterocycle are compatible with the reaction conditions, the
proposed methodology could be very useful for the synthesis
of natural products and biologically active compounds contain-
ing piperidine moieties. Indeed, the application of this meth-
odology to the synthesis of more complex heterocyclic structures
is currently under investigation in our laboratory via the study
of the reactivity of the enamide double bond.
the reactivity of these dihydropyridine derivatives (cf. Table 4,
entries 2-3). For more hindered groups, the best strategy was
to carry out the first step with the allyl group for example. (Table
4, entries 4-6).
As we had it in hand, we decided to perform a ring-closing
metathesis reaction on bisallylic compound 19d. Treatment of
the latter using a second generation ruthenium catalyst17 afforded
the desired cyclized derivative 20 in quantitative yield (cf.
Scheme 2). Finally starting from commercially available glu-
tarimide, the original unsaturated spiro derivative 20, an
unsaturated analogue of compound 11, was obtained in only
five steps and in 48% global yield.
With the goal of valorising these substituted dihydropyridines,
we then examined their behavior under acidic conditions.
(17) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem.
Soc. 1999, 121, 2674-2678.
5996 J. Org. Chem., Vol. 71, No. 16, 2006

BisVinyl Phosphate and 1,4-Dihydropyridine
TABLE 6. Di- or Trisubstituted Pyridines 22a-fa
(2.5 mL) under argon, PdCl2(PPh3)2 (0.074 mmol, 51 mg) was
added. The flask was evacuated and backfilled with argon three
times, and the mixture was stirred during 15 min. Then, phenyl-
boronic acid (3.69 mmol, 449 mg), 2M Na2CO3 (aqueous solution)
(1.25 mL), and 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 chroma-
tography (silica gel, PE then PE/EtOAc 8:2) to afford 6 (88% yield)
1
as a white solid: mp 126-127 °C. H NMR (250 MHz, CDCl3):
δ (ppm) 1.03 (s, 9H); 2.94 (t, 2H, J ) 5 Hz); 5.78 (t, 2H, J ) 5
Hz); 7.24-7.40 (m, 6H); 7.52-7.57 (m, 4H). 13C NMR (250 MHz;
CDCl3): δ (ppm) 24.9, 27.6, 81.3, 116.4, 125.4, 127.3, 128.3, 138.9,
142.6, 152.3. IR νmax (KBr): 2971, 2930, 2812, 1716, 1670, 1629,
1598. MS (IE): m/z 354.50 [M + H]+. HRMS (IE): m/z calcd for
[C22H23-CO2-t-Bu]+, 232.1126; found, 232.1112.
1-(tert-Butoxycarbonyl)-2,6-dithianaphten-2-yl-1,4-dihydro-
pyridine (7). The Suzuki coupling reaction was carried out as
described in the general procedure (B) by using thianaphtene-2-
boronic acid. The reaction was completed in 3 h. After purification
by flash column chromatography (silica gel, PE then PE/EtOAc
9:1), the desired compound 7 was isolated as a yellow solid (83%
1
yield): mp 149-150 °C. H NMR (250 MHz, CDCl3): δ (ppm)
0.82 (s, 9H); 3.08 (t, 2H, J ) 5 Hz); 5.83 (t, 2H, J ) 5 Hz); 7.32-
7.44 (m, 4H); 7.49 (s, 2H); 7.85-7.88 (m, 2H); 8.08-8.11 (m,
2H). 13C NMR (250 MHz; CDCl3): δ (ppm) 24.7, 27.5, 81.2, 116.9,
120.7, 122.2, 122.8, 122.9, 123.1, 123.3, 124.3, 124.4, 124.7, 124.8,
135.1, 136.4, 137.9, 140.2, 141.0, 152.1. IR νmax (KBr): 3018, 2976,
2938, 1700, 1640, 1571, 1545. MS (IE): m/z 344.05 [M-•CO2t-
Bu]+. HRMS (IE): m/z [M-•CO2t-Bu]+ calcd for C21H14NS2,
344.0567; found, 344.0562.
8-(tert-Butoxycarbonyl)-7,9-diphenyl-8-aza-spiro[4.5]deca-6,9-
diene (11). The Suzuki coupling reaction was carried out as
described in the general procedure (B) by using phenylboronic acid.
The reaction was completed in 3 h. After purification by flash
column chromatography (silica gel, PE then PE/EtOAc 9:1), the
desired compound 11 was isolated as a white solid (85% yield):
1
a Reagents and conditions: 6.4 equiv TFA, CH2Cl2, RT, 4 h.
mp 137-138 °C. H NMR (250 MHz, CDCl3): δ (ppm) 1.03 (s,
9H); 1.74-1.82 (m, 8H); 5.67 (s, 2H); 7.25-7.40 (m, 6H); 7.54-
7.57 (m, 4H). 13C NMR (250 MHz; CDCl3): δ (ppm) 24.0; 27.6;
40.8; 45.6; 81.1; 125.5; 126.4; 127.2; 128.2; 139.0; 140.5; 152.3.
IR νmax (KBr): 3017, 2956, 2874, 1707, 1520, 1494, 1450. MS
(IE): m/z 286.50 [M-•CO2t-Bu]+. HRMS (IE): m/z [M-•CO2t-Bu]+
calcd for C21H20N, 286.1595; found, 286.1576.
Experimental Section
Only representative procedures and characterizations of the
products are described here. Full details can be found in the
Supporting Information.
8-(tert-Butoxycarbonyl)-7,9-dithianaphten-2-yl-8-aza-spiro-
[4.5]deca-6,9-diene (12). The Suzuki coupling reaction was carried
out as described in the general procedure (B) by using thianaphtene-
2-boronic acid. The reaction was completed in 3 h. After purification
by flash column chromatography (silica gel, PE then PE/EtOAc
8:2), the desired compound 11 was isolated as an orange solid (70%
Author: The chemical abbreviation P.E. was used in the
paragraphs below. If this is not polyethylene (PE), please define
General Procedure (A) for the Stille Coupling Reaction.
1-(tert-Butoxycarbonyl)-2,6-di-(1,4-benzodioxin-2-yl)-1,4-dihy-
dropyridine (4). To a stirred solution of bisvinyl phosphate 1 (0.74
mmol, 500 mg) in THF (2.5 mL), trimethyl(benzodioxin)tin (3.69
mmol, 1.09 g) and anhydrous lithium (4.43 mmol, 188 mg) were
added under argon, then the flask was evacuated and backfilled
with argon three times. Under argon, Pd(PPh3)4 (0.074 mmol, 51
mg) was added, and 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 and
dried (MgSO4), and the solvent evaporated under reduced pressure.
The residue was purified by flash column chromatography (silica
gel, PE/EtOAc 8:2) to afford 4 (66% yield) as a yellow solid: mp
1
yield): mp 142-143 °C. H NMR (250 MHz, CDCl3): δ (ppm)
1.17 (s, 9H); 1.82 (s, 8H); 5.98 (s, 2H); 7.28-7.37 (m, 4H); 7.42
(s, 2H); 7.74-7.82 (m, 4H). 13C NMR (250 MHz; CDCl3): δ (ppm)
24.3, 27.8, 40.4, 46.4, 82.1, 119.7, 123.3, 123.6, 124.3, 124.4, 124.9,
128.8, 135.8, 139.2, 140.1, 152.0. IR νmax (KBr): 3077, 2963, 2874,
1718, 1593, 1489, 1457. MS (IE): m/z 401.50 [M-•CO2t-Bu]+.
HRMS (IE): m/z [M-•CO2t-Bu]+ calcd for C25H20NS2, 398.1037;
found, 398.1008.
9-{(Phenyloxy)-[bisphosphoryl]oxy}-8-(tert-butoxycarbonyl)-
8-aza-spiro[4.5]deca-9-en-7-one (14). To a solution of 8-(tert-
butoxycarbonyl)-7,9-dioxo-8-aza-spiro[4.5]decane 138 (0,75 mmol,
200 mg) in THF (7 mL) at -78 °C under argon, LiHMDS (0.9
mmol, 1 M in THF, 0.9 mL) was added dropwise. After being
stirred for 1.5 h at -78 °C, a solution of diphenyl chlorophosphate
(0.9 mmol, 0.186 mL) in THF (3 mL) was added. After 1 h at -78
°C, the reaction was quenched by the slow addition of H2O. Ethyl
acetate was then added, the organic layer was separated and dried
(MgSO4), and the solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography (silica
1
99-100 °C. H NMR (250 MHz, CDCl3): δ (ppm) 1.44 (s, 9H);
2.75 (t, 2H, J ) 5 Hz); 5.93 (t, 2H, J ) 5 Hz); 6.17 (s, 2H); 6.67-
7.00 (m, 8H). 13C NMR (250 MHz; CDCl3): δ (ppm) 24.1, 28.1,
82.5, 116.2, 116.3, 117.3, 124.1, 124.2, 124.4, 134.2, 134.6, 142.2,
142.7, 152.3. IR νmax (KBr): 2926, 2854, 1751, 1600, 1494, 1463.
MS (IE): m/z 446 [M + H]+.
General Procedure (B) for the Suzuki Coupling Reaction.
1-(tert-Butoxycarbonyl)-2,6-diphenyl-1,4-dihydropyridine (6). To
a solution of bisvinyl phosphate 1 (0.74 mmol, 500 mg) in THF
J. Org. Chem, Vol. 71, No. 16, 2006 5997

Mousset et al.
gel, toluene/EtOAc 9:1 with 0.5% Et3N) to afford the monovinyl
phosphate 13 (74%) as a colorless oil. 1H NMR (250 MHz,
CDCl3): δ (ppm) 1.49 (s, 9H); 1.50-1.65 (m, 8H); 2.41 (s, 2H);
5.27 (d, 1H, J ) 2.2 Hz); 7,22-7,26 (m, 6H); 7,33-7,39 (m, 4H).
13C NMR (250 MHz; CDCl3): δ (ppm) 23.7, 27.7, 38.5, 41.1, 44.0,
85.3, 103.6, 103.7, 120.1, 120.2, 126.0, 130.1, 138.5, 150.4, 168.8.
IR νmax (NaCl film): 3017, 2962, 2875, 1780, 1741, 1698, 1489,
1456, 1343. MS (IS): m/z 500.51 [M + H]+.
8-(tert-Butoxycarbonyl)-9-phenyl-8-aza-spiro[4.5]deca-9-en-
7-one (15). To a solution of monovinyl phosphate 14 (1.8 mmol,
900 mg) in THF (10 mL) under argon, PdCl2(PPh3)2 (0.18 mmol,
75 mg) was added. The flask was evacuated and backfilled with
argon three times, and the mixture was stirred during 15 min. Then,
phenylboronic acid (4.51 mmol, 550 mg), 2 M Na2CO3 (aqueous)
(2.9 mL), and a few drops of EtOH were added. The mixture was
refluxed for 2 h. After the mixture cooled, ethyl acetate was added,
and the organic layer was separated and dried (MgSO4). After
evaporation of the solvent, the residue was purified by flash column
chromatography (silica gel, PE then PE/EtOAc/DCM 8:1:1) to
afford 14 (77% yield) as a colorless oil. 1H NMR (250 MHz,
CDCl3): δ (ppm) 1.14 (s, 9H); 1.67-1.78 (m, 8H); 2.54 (s, 2H);
5.48 (s, 1H); 7,30-7,36 (m, 5H). 13C NMR (250 MHz; CDCl3): δ
(ppm) 24.1, 27.3, 38.2, 42.4, 44.7, 84.0, 122.7, 125.9, 126.0, 128.3,
128.6, 132.4, 137.5, 138.4, 150.3, 170.7. IR νmax (NaCl film): 3060,
2980, 2847, 1771, 1698, 1493, 1447. MS (IS): m/z 328.50 [M +
H]+.
bonyl)-4-methyl-2,6-diphenyl-1,4-dihydropyridine (18a). To a
solution of the 1-(tert-butoxycarbonyl)-2,6-diphenyl-1,4-dihydro-
pyridine (6) (0.45 mmol, 150 mg) in THF (3 mL) at -78 °C under
argon, n-BuLi (0.49 mmol, 1.6 M in hexane, 310 µL) was added
dropwise. After the mixture was stirred for 5 min at -78 °C, methyl
iodide (1.35 mmol, 0.84 mL) was added dropwise, and the mixture
was stirred for 2 h at -78 °C. The reaction was quenched by the
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 chromatog-
raphy (silica gel, PE/EtOAc 9:1) to afford 18a (97% yield) as a
1
yellow oil. H NMR (250 MHz, CDCl3): δ (ppm) 1.02 (s, 9H);
1.28 (d, 3H, J ) 7 Hz); 3.10-3.22 (m, 1H); 5.62 (d, 2H, J ) 3.5
Hz); 7.24-7.41 (m, 6H); 7.54-7.57 (m, 4H). 13C NMR (250 MHz;
CDCl3): δ (ppm) 20.7, 27.6, 30.2, 81.2, 123.1, 125.5, 125.9, 127.4,
128.3, 138.9, 141.4, 152.2. IR νmax (NaCl film): 2977, 2930, 2872,
1717, 1600, 1578, 1557. MS (IS): m/z 348.30 [M + H]+. HRMS
(IE): m/z [M-HCO2t-Bu]+• calcd for C18H15N, 245.1204; found,
245.1178.
4-Allyl-1-(tert-butoxycarbonyl)-2,6-diphenyl-1,4-dihydropy-
ridine (18b). The functionalization reaction was carried out as
described in the general procedure (D) by using allyl bromide. After
purification by flash column chromatography (silica gel, PE/EtOAc
9:1), the desired compound 18b was isolated as a yellow solid (74%
1
yield): mp 128-129 °C. H NMR (250 MHz, CDCl3): δ (ppm)
1.02 (s, 9H); 2.35 (t, 2H, J ) 7 Hz); 3.13-3.20 (m, 1H); 5.08-
5.16 (m, 2H); 5.67 (d, 2H, J ) 3.5 Hz); 5.78-5.95 (m, 1H); 7.24-
7.41 (m, 6H); 7.54-7.57 (m, 4H). 13C NMR (250 MHz; CDCl3):
δ (ppm) 27.6, 35.1, 39.3, 81.3, 117.2, 120.7, 125.6, 127.4, 128.3,
135.7, 138.9, 142.1, 152.1. IR νmax (KBr): 2976, 2925, 2889, 1711,
1675, 1634, 1593. MS (IS): m/z 374.30 [M + H]+. HRMS (IE):
m/z [M-•C3H5]+ calcd for C22H22NO2, 332.1650; found, 332.1640.
General Procedure (E) for the second Functionalization
Reaction on the C-4 Position of Dihydropyridine (18). 1-(tert-
Butoxycarbonyl)-4,4-dimethyl-2,6-diphenyl-1,4-dihydropyri-
dine (19a). To a solution of the 1-(tert-butoxycarbonyl)-4-methyl-
2,6-diphenyl-1,4-dihydropyridine (18a) (0.30 mmol, 104 mg) in
THF (2 mL) at -78 °C under argon, t-BuLi (0.33 mmol, 1.7 M in
hexane, 200 µL) was added dropwise. After the solution was stirred
for 5 min at -78 °C, methyl iodide (0.90 mmol, 600 µL) was added,
and the mixture was stirred for 2 h at -78 °C. The reaction was
quenched by the 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, PE/EtOAc 8:2) to afford 19a
7-{(Phenyloxy)-[bisphosphoryl]oxy}-8-(tert-butoxycarbonyl)-
9-phenyl-8-aza-spiro[4.5]deca-6,9-diene (16). To a solution of
compound 15 (0,31 mmol, 100 mg) in THF (8 mL) at -78 °C
under argon, LiHMDS (0.52 mmol, 1 M in THF, 0.52 mL) was
added dropwise. After stirring for 1.5 h at -78 °C, a solution of
diphenyl chlorophosphate (0.46 mmol, 0.95 mL) in THF (3 mL)
was added. After 2 h at -78 °C, the reaction was quenched by the
slow addition of H2O. Ethyl acetate was then added, the organic
layer was separated and dried (MgSO4), and the solvent was
evaporated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, toluene/EtOAc 9:1) to
1
afford the vinyl phosphate 16 (78% yield) as a colorless oil. H
NMR (250 MHz, CDCl3): δ (ppm) 1.18 (s, 9H); 1.66-1.71 (m,
8H); 5.26 (d, 1H, J ) 2 Hz); 5.60 (s, 1H); 7,16-7,45 (m, 15H).
13C NMR (250 MHz; CDCl3): δ (ppm) 21.5, 23.9, 27.8, 40.5, 45.2,
45.3, 111.5, 111.6, 82.3, 120.2, 120.3, 125.3, 125.5, 125.6, 126.2,
127.3, 128.1, 128.2, 129.1, 129.8, 137.8, 137.9, 140.4, 141.4, 141.6,
150.6, 150.7, 151.8, 151.9. IR νmax (NaCl film): 2956, 2872, 1731,
1691, 1489, 1456, 1345. MS (IS): m/z 560.60 [M + H]+.
General Procedure (C) for the Suzuki Coupling Reaction.
7-(Thianaphten-2-yl)-8-(tert-butoxycarbonyl)-9-phenyl-8-aza-
spiro[4.5]deca-6,9-diene (17a). To a solution of monovinyl
phosphate 16 (0.18 mmol, 100 mg) in THF (1.5 mL) under argon,
PdCl2(PPh3)2 (0.02 mmol, 7.5 mg) was added. The flask was
evacuated and backfilled with argon three times, and the mixture
was stirred during 15 min. Then, thianaphtene-2-boronic acid (0.36
mmol, 64 mg), 2 M Na2CO3 (aqueous) (0.5 mL), and a few drops
of EtOH were added. The mixture was refluxed for 3 h. After the
mixture cooled, ethyl acetate was added, and the organic layer was
separated and dried (MgSO4). After evaporation of the solvent, the
residue was purified by flash column chromatography (silica gel,
PE then PE/EtOAc 8:2) to afford 17a (80% yield) as an orange
solid: mp 64-65 °C. 1H NMR (250 MHz, CDCl3): δ (ppm) 1.02
(s, 9H); 1.70-1.74 (m, 8H); 5.64 (s, 2H); 5.88 (s, 1H); 7,14-7,34
(m, 6H); 7,48-7,52 (m, 2H); 7,64-7,73 (m, 2H). 13C NMR (250
MHz; CDCl3): δ (ppm) 24.2, 27.7, 40.6, 46.1, 81.6, 119.4, 122.3,
123.6, 124.2, 124.4, 125.6, 126.6, 127.5, 128.3, 128.7, 135.5, 138.7,
139.2, 140.1, 140.9, 142.7, 152.5. IR νmax (KBr): 3022, 2968, 2864,
1715, 1616, 1502, 1456. MS (IS): m/z 444.50 [M + H]+. HRMS
(IE): m/z [M-•CO2t-Bu]+ calcd for C23H20NS, 342.1316; found,
342.1332.
1
(100% yield) as a white solid: mp 106-107 °C. H NMR (250
MHz, CDCl3): δ (ppm) 1.02 (s, 9H); 1.24 (s, 6H); 5.60 (s, 2H);
7.24-7.40 (m, 6H); 7.56 (d, 4H, J ) 7 Hz). 13C NMR (250 MHz;
CDCl3): δ (ppm) 27.6, 29.1, 34.1, 81.1, 123.1, 125.6, 127.4, 128.2,
138.9, 139.0, 140.4, 141.4, 152.3. IR νmax (KBr): 2969, 2918, 2874,
1707, 1507, 1469, 1450. MS (IS): m/z 362.00 [M + H]+. HRMS
(IE): m/z [M-CH3-CO2t-Bu]+• calcd for C18H15N, 245.1204; found,
245.1219.
1-(tert-Butoxycarbonyl)-4-allyl-4-methyl-2,6-diphenyl-1,4-di-
hydropyridine (19b). Starting from the compound 18a, the second
functionalization reaction was carried out as described in the general
procedure (E) by using allyl bromide. After purification by flash
column chromatography (silica gel, PE/EtOAc 9.5:0.5), the desired
compound 19b was isolated (34% yield).
Starting from the compound 18b, the reaction was carried out
as described in the general procedure (E) by using methyl iodide.
After purification by flash column chromatography, the desired
compound 19b was isolated (100% yield) as a beige oil. 1H NMR
(250 MHz, CDCl3): δ (ppm) 1.01 (s, 9H); 1.23 (s, 3H); 2.27 (d,
2H, J ) 7 Hz); 5.07 (m, 2H); 5.51 (s, 2H); 5.75-5.92 (m, 1H);
7.25-7.40 (m, 6Hr); 7.54-7.56 (m, 4H). 13C NMR (250 MHz;
CDCl3): δ (ppm) 27.6, 29.6, 37.6, 46.5, 81.1, 118.0, 125.3, 125.6,
127.1, 127.4, 128.2, 128.8, 134.3, 139.0, 141.1, 152.1. IR νmax
(KBr): 2960, 2924, 2846, 1721, 1598, 1574, 1550. MS (IS): m/z
General Procedure (D) for the Functionalization Reaction
on the C-4 Position of Dihydropyridine (6). 1-(tert-Butoxycar-
5998 J. Org. Chem., Vol. 71, No. 16, 2006

BisVinyl Phosphate and 1,4-Dihydropyridine
388.50 [M + H]+. HRMS (IE): m/z [M-•C3H5]+ calcd for C23H24-
NO2, 346.1807; found, 346.1826.
General Procedure (G) for the Aromatization Reaction. 2,6-
Diphenyl-pyridine (22a).20 To a solution of the 1-(tert-butoxy-
carbonyl)-2,6-diphenyl-1,4-dihydropyridine 6 (0.15 mmol, 50 mg)
in dry DCM (0.5 mL) at room temperature under argon, trifluo-
roacetic acid (1.28 mmol, 100 µL) was added dropwise. The mixture
was stirred for 4 h at room temperature. The reaction was quenched
with an aqueous solution of saturated Na2CO3; dichloromethane
was then added. The organic layer was separated and dried
(MgSO4), and the solvent was evaporated. The crude solid was
washed with petroleum ether, then filtrated to afford the desired
disubstituted pyridine 22a (95% yield) as a yellow solid: mp 80-
81 °C. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.39-7.57 (m, 6H);
7.66-7.69 (m, 2H); 7.77-7.83 (m, 1H); 8.12-8.17 (m, 4H). 13C
NMR (250 MHz; CDCl3): δ (ppm) 118.8, 127.1, 128.8, 129.1,
137.6, 139.6, 157.0. IR νmax (KBr): 2964, 2924, 2872, 1589, 1598,
1567. MS (IS): m/z 232.5 [M + H]+.
8-(tert-Butoxycarbonyl)-7,9-diphenyl-8-aza-spiro[4.5]deca-
2,6,9-triene (20). A solution of bisallylic compound 19d (213 mg,
0.51 mmol) and Nolan’s ruthenium catalyst16 (43 mg, 0.05 mmol)
in degassed toluene was refluxed for 15 h (until TLC shows
complete conversion of the substrate). Evaporation of the solvent
followed by flash chromatography (silica gel, PE/EtOAc 9.5/0.5)
provides compounds 20 (100% yield) as a yellow solid: mp 120-
121 °C. 1H NMR (250 MHz, CDCl3): δ (ppm) 1.03 (s, 9H); 2.55-
(s, 4H); 5.76 (s, 2H); 5.80 (s, 2H); 7.25-7.40 (m, 6H); 7.54-7.58
(m, 4H). 13C NMR (250 MHz; CDCl3): δ (ppm) 27.7, 48.0, 44.5,
81.3, 125.0, 125.6, 125.8, 127.6, 127.7, 128.3, 128.4, 129.4, 139.0,
140.6, 152.4. MS (IS): m/z 386.5 [M + H]+. HRMS (IE): m/z
[M]+• calcd for C26H27NO2, 385.2041; found, 385.2049.
Acknowledgment. The authors thank gratefully Professor
Steve Nolan (New Orleans, USA) for his gift of ruthenium
metathesis catalyst and palladium catalyst.
General Procedure (F) for the Hydrolysis Reaction. 1,5-
Diphenyl-pentane-1,5-dione (21a).18 To a solution of the 1-(tert-
butoxycarbonyl)-2,6-diphenyl-1,4-dihydropyridine (6) (0.30 mmol,
100 mg) in EtOAc (2 mL) at room temperature under argon, a 3 N
solution of hydrochloric acid (1 mL) was added, and the mixture
was stirred for 2 h. The mixture was diluted with H2O (5 mL),
EtOAc (4 mL) was added, and the organic layer was washed with
a solution of saturated aqueous Na2CO3. The organic layer was
separated and dried (MgSO4), and the solvent was evaporated. The
residue was purified by flash column chromatography (silica gel,
PE/EtOAc 9:1) to afford 21a (100% yield) as a white solid: mp
65-66 °C. 1H NMR (250 MHz, CDCl3): δ (ppm) 2.15-2.26 (m,
2H); 3.13 (t, 4H, J ) 7 Hz); 7.43-7.59 (m, 6H); 7.97-8.00 (m,
4Hr). 13C NMR (250 MHz; CDCl3): δ (ppm) 18.8, 37.7, 128.2,
128.7, 133.2, 136.9, 197.4. IR νmax (KBr): 2970, 2938, 2900, 1692,
1576, 1449. MS (IS): m/z 253.00 [M + H]+.
Supporting Information Available: Detailed experimental
procedures, full characterization of new compounds,1H and 13C
NMR spectra for compounds 1-12 and 14-22. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0607360
(18) Imagawa, H.; Kurisaki, T.; Nishizawa, M. Org. Lett. 2004, 6, 3679-
3681.
(19) Owsley, D. C.; Nelke, J. M.; Bloomfield, J. J. J. Org. Chem. 1973,
38, 901-903.
(20) Pena, M. A.; Sestelo, J. P.; Sarandeses, L. A. Synthesis 2005, 485-
492.
(21) Meth-Cohn, O.; Jiang, H. J. Chem. Soc., Perkin Trans. 1 1998, 22,
3737-3745.
(22) Oda, K.; Nakagami, R.; Niszonohi, N.; Machida, M. Chem.
Commun. 1999, 2371-2372.
J. Org. Chem, Vol. 71, No. 16, 2006 5999