Addition of organocopper reagents to N-alkylpyridinium salts. A flexible access to polysubstituted dihydropyridines

Article abstract of DOI:10.1016/S0040-4039(00)02006-2

The addition of a series of organocopper (alkyl, vinyl, allyl, and ethynyl) reagents to 3-acyl-N-alkylpyridinium salts, followed by acylation of the intermediate 1,4- of 1,2-dihydropyridines with trichloroacetic anhydride has been studied.

Full text of DOI:10.1016/S0040-4039(00)02006-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 585–588
Addition of organocopper reagents to N-alkylpyridinium salts. A
flexible access to polysubstituted dihydropyridines
M.-Llu¨ısa Bennasar,* Cec´ılia Juan and Joan Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
Received 20 September 2000; accepted 7 November 2000
Abstract—The addition of a series of organocopper (alkyl, vinyl, allyl, and ethynyl) reagents to 3-acyl-N-alkylpyridinium salts,
followed by acylation of the intermediate 1,4- or 1,2-dihydropyridines with trichloroacetic anhydride has been studied. © 2001
Elsevier Science Ltd. All rights reserved.
Good C-4 regioselectivity upon reaction with N-
acylpyridinium salts has usually been achieved with
organocopper reagents.1 Thus, Gilman homocuprates
(R2CuLi),1a copper-catalyzed Grignard reagents,1b,c
mono-organocopper reagents (RCu),1d,f and mixed cop-
per–zinc organometallics1e have been shown to afford
4-substituted N-acyl-1,4-dihydropyridines. In contrast,
there is scarce information about the same process with
N-alkylpyridinium salts.1f,2 In this context, we have
recently developed a synthetic entry to 3,5-diacyl-4-
phenyl-1,4-dihydropyridines by the use of the chemo-
and regioselective addition of the higher order (HO)
heterocuprate Ph2Cu(CN)Li2 to the 4-position of sev-
eral 3-acyl-N-alkylpyridinium salts, with subsequent
acylation of the resulting 1,4-dihydropyridines with
trichloroacetic anhydride (TCAA).3
Me
Me
Me
N
Me
–
I
+
N
N
R
R
" RCu"
N
+
+
CO2Me
CO2Me
CO2Me
CO2Me
1
R
Me
N
Me
N
Me
N
TCAA
R
R
+
+
Cl3COC
CO2Me
Cl3COC
CO2Me
Cl3COC
CO2Me
R
c
a
b
2
3
4
R = Me
R = Bu
R = Ph
5
6
7
R = CH2=CH–CH2
R = CH2=CH
R = PhC(=CH2)
Scheme 1.
Keywords: acylation; copper and compounds; pyridines; pyridinium salts.
* Corresponding author. Tel.: 34 934024540; fax: 34 934021896; e-mail: bennasar@farmacia.far.ub.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02006-2

586
M.-L. Bennasar et al. / Tetrahedron Letters 42 (2001) 585–588
We present here a complete study of the above addi-
tion–acylation sequence using a series of alkyl, vinyl,
allyl and ethynyl organocopper reagents (‘RCu’,
Scheme 1) in order to prepare diversely substituted
3,5-diacylated 1,2- and 1,4-dihydropyridines. 1,2-Dihy-
dropyridines are useful building blocks for alkaloid
synthesis,4 whereas 1,4-dihydropyridines can be consid-
ered as privileged structures in Medicinal Chemistry
since they display binding at a variety of receptor sites.5
1.5 h. After extractive workup and concentration, the
resulting residue was dissolved in anhydrous THF (35
ml) and treated with TCAA (0.6 ml, 3.6 mmol) at 0°C
for 3 h. Workup followed by flash chromatography
(SiO2, 8:2 hexanes–AcOEt) gave pure 3b (0.44 g, 70%).
In contrast, (phenylethynyl)copper reagents (entries 5–
8) react preferentially at the a-position of the pyridine
ring to give mixtures of C-2 and C-6 adducts (4a and
4c). As can be observed in Table 1, the lower the
reactivity of the organometallic reagent [(HO
cyanocuprate>lower order (LO) cyanocuprate>HO zinc
cyanocuprate7>LO zinc cyanocuprate], the higher the
C-6 regioselectivity, although the yield progressively
decreases. Interestingly, the corresponding copper-cata-
lyzed Grignard reagent (entry 9) afforded exclusively
the C-2 adduct 4a. This result probably reflects a
coordination between magnesium and the carbonyl
oxygen atom of 1.
For our study we initially selected N-methylpyridinium
salt 1 and allowed it to react with the organocopper
reagents6 listed in Table 1.
In contrast with the results reported in the phenyl
series,3 the use of alkyl (methyl or butyl) HO
cyanocuprates R2Cu(CN)Li2 (entries 1 and 2) gave only
low yields of mixtures of C-4 and C-6 adducts (2b,c and
3b,c) after treatment of the crude reaction mixtures
with TCAA. In these series, the corresponding Gilman
homocuprates Me2CuLi and Bu2CuLi (entries 3 and 4)
proved to be the most efficient reagents for the regiose-
lective introduction of an alkyl group at the 4-position
of the pyridine ring as occurs in previous examples
found in the literature.1f,2a With these cuprates, the
addition–acylation sequence led to the 3,5-diacylated
C-4 adducts 2b and 3b as the major products in good
yields, especially in the butyl series.
The preferential attack at the a-positions of the pyri-
dine ring was also observed with allylcopper reagents
(entries 10 and 11), formation of the C-4 adduct 5b
only being detected from the Gilman homocuprate
(allyl)2CuLi. No reaction took place with allyl-
tributyltin.8
The a-regioselectivity obtained with the above
(phenylethynyl)- and allylcopper reagents was not sur-
prising since it is known that these reagents are prone
to undergoing 1,2-addition to enones.6 Similarly, com-
plete C-6 regioselectivity has been observed in the reac-
tion of a 3-substituted N-acylpyridinium salt with
(Me3SiCꢀC)2CuLi or (allyl)Cu.1f
The preparation of dihydropyridine 3b is representa-
tive. In a typical run, pyridinium salt 1 (0.5 g, 1.79
mmol) was added in portions to a cooled (−40°C)
solution of Bu2CuLi (4.5 mmol) in anhydrous THF (35
ml), and the mixture was stirred at this temperature for
With respect to the introduction of a vinyl residue upon
the pyridine ring we first investigated the behavior of a
‘simple’ vinyl group: the Gilman homocuprate (entry
12) only provided a-adducts, whereas the HO
cyanocuprate (entry 13) led to mixtures of a- and
g-adducts; the best ratio of the C-4 vinyl adduct 6b was
obtained using the mixed alkyl vinyl HO cyanocuprate9
(entry 14). In contrast, a complex mixture was obtained
when pyridinium salt 1 was allowed to react with
vinylmagnesium chloride in the presence of CeCl3,10
and no reaction was observed with (vinyl)2
Cu(CN)(MgCl)2. On the other hand, the mixed methyl
a-styryl HO cyanocuprate (entry 15) reacts preferen-
tially at the C-6 position of the pyridine ring to give
dihydropyridine 7c as the major product in high yield.
A similar result was obtained from the corresponding
copper-catalyzed vinyl Grignard reagent (entry 16).
Table 1. Reactions of pyridinium salt 1 with organo-
copper reagents with subsequent TCAA acylation
Entry RCua
Productb a/b/c
Yield
(%)c
ratio
1
2
3
4
5
6
7
8
Me2Cu(CN)Li2
Bu2Cu(CN)Li2
Me2CuLi
Bu2CuLi
2
3
2
3
4
4
4
4
4
5
5
6
6
6
7
7
0/10/90
20
20
40
77
68
30
18
<10
65
86
75
30
55
60
90
65
0/55/45
0/70/30
0/90/10
50/0/50
40/0/60
20/0/80
0/0/100
100/0/0
40/20/40
50/0/50
50/0/50
40/20/40
30/40/30
0/20/80
0/15/85
(PhCꢀC)2Cu(CN)Li2
(PhCꢀC)Cu(CN)Li
(PhCꢀC)2Cu(CN)(ZnCl)2
(PhCꢀC)Cu(CN)(ZnCl)
(PhCꢀC)MgBr/CuIcat
(CH2ꢁCH-CH2)2CuLi
(CH2ꢁCH-CH2)2Cu(CN)Li2
(CH2ꢁCH)2CuLi
(CH2ꢁCH)2Cu(CN)Li2
(CH2ꢁCH)MeCu(CN)Li2
d
9
10
11
12
13
14
15
16
It is worth mentioning that the extension of the addi-
tion-TCAA acylation sequence from 3-acetylpyridinium
salt 8 and the organocopper reagents depicted in
Scheme 2 (in each case we selected the reagent that had
provided the best g-regioselectivity from salt 1)
afforded only the corresponding C-4 adducts 9–11,
although the overall yields were considerably lower
than in the above methoxycarbonyl series. This result
might reflect the instability of the initially formed a-
adducts under the acylation conditions.
e
[PhC(ꢁCH2)]MeCu(CN)Li2
[PhC(ꢁCH2)]MgBr/CuIcat
a Prepared following general procedures reported in reference 6.
b All products were fully characterized by spectroscopic analysis
(NMR) and gave satisfactory HRMS and/or combustion data.
c Isolated yields of chromatographically pure material.
d Prepared according to reference 7.
e Prepared from a-(trimethylstannyl)styrene according to reference
9b.

M.-L. Bennasar et al. / Tetrahedron Letters 42 (2001) 585–588
587
Bn
Bn
"RCu"
Product
R = Me (20%)
10 R = CH2=CH (30%)
11 R = PhC(=CH2) (30%)
–
N
Cl
+
1. "RCu"
2. TCAA
Me2CuLi
(CH2=CH)Me Cu(CN)Li2
[PhC(=CH2)]MeCu(CN)Li2
N
9
Cl3COC
COMe
COMe
R
8
9-11
Scheme 2.
5a + 5c
or
6a + 6c
2b or 3b
11
MeONa
MeOH
MeONa
MeOH
MeONa
MeOH
Bn
Me
Me
N
N
R
N
MeO2C
COMe
MeO2C
CO2Me
MeO2C
CO2Me
R
15 R = CH2=CH–CH2 (90%)
16 R = CH2=CH (85%)
12 R = Me (85%)
13 R = Bu (90%)
14
(90%)
Scheme 3.
Finally, (trichloroacetyl)-1,4-dihydropyridines 2b, 3b
and 11 were subjected to a haloform-type reaction with
sodium methoxide in methanol11 to give the corre-
sponding diesters 12–14 in excellent yields (Scheme 3).
Interestingly, this transformation allows the conversion
of the mixtures of trichloroacetylated C-2 and C-6
adducts 5a,c and 6a,c into single 1,2-dihydropyridine-
3,5-dicarboxylic esters 15 and 16, respectively.
References
1. (a) Piers, E.; Soucy, M. Can. J. Chem. 1974, 52, 3563–
3564. (b) Comins, D. L.; Abdullah, A. H. J. Org. Chem.
1982, 47, 4315–4319. (c) Comins, D. L.; Stroud, E. D.;
Herrick, J. J. Heterocycles 1984, 22, 151–157. (d) Akiba,
K.; Iseki, Y. Wada, M.; Bull. Chem. Soc. Jpn. 1984, 57,
1994–1999. (e) Shiao, M. J.; Liu, K. H.; Lin, L. G.
Synlett 1992, 655–656. (f) Mangeney, P.; Gosmini, R.;
Raussou, S.; Commerc¸on, M.; Alexakis, A. J. Org. Chem.
1994, 59, 1877–1888.
2. (a) Wenkert, E.; Angell, E. C.; Drexler, J.; Moeller, P. D.
R.; Pyrek, J. S.; Shi, Y. J.; Sultana, M.; Vankar, Y. D. J.
Org. Chem. 1986, 51, 2995–3000. (b) Hilgeroth, A.;
Baumeister, U. Angew. Chem., Int. Ed. 2000, 39, 576–578.
3. Bennasar, M.-L.; Juan, C.; Bosch, J. Tetrahedron Lett.
1998, 39, 9275–9278.
4. (a) Comins, D. L.; Joseph, S. P. In Advances in Nitrogen
Heterocycles; Moody, C. J., Ed.; JAI Press: London,
1996; Vol. 2, pp. 251–294. (b) Comins, D. L.; LaMunyon,
D. H.; Chen, X. J. Org. Chem. 1997, 62, 8182–8187. (c)
Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J.
J. Org. Chem. 1999, 64, 2184–2185. (d) Kuethe, J. T.;
Comins, D. L. Org. Lett. 2000, 2, 855–857.
5. (a) 4-Aryl-3,5-diacyl-1,4-dihydropyridines are potent
blockers of calcium channels and widely used in treating
cardiovascular diseases. See, for instance: Goldmann, S.;
Stoltefuss, J. Angew. Chem., Int. Ed. 1991, 30, 1559–1578.
In conclusion, the above results provide a flexible route
to diversely substituted 1,2- and 1,4-dihydropyridines
bearing electron-withdrawing groups at the 3- and 5-
positions. Starting from easily accessible 3-acyl-N-
alkylpyridinium salts, our approach involves the
sequential introduction of substituents at the a- (or g)
and the free b-position of the pyridine ring by nucle-
ophilic addition of a suitable organocopper reagent
followed by acylation of the resultant 1,2- (or 1,4-)
dihydropyridine.
Acknowledgements
Financial support from the DGICYT, Spain (project
PB94-0214) is gratefully acknowledged. Thanks are also
due to the ‘Comissionat per a Universitats i Recerca’
(Generalitat de Catalunya) for Grant 1999SGR00079
and for a fellowship to C.J.

588
M.-L. Bennasar et al. / Tetrahedron Letters 42 (2001) 585–588
(b) For 4-alkyl-1,4-dihydropyridines as PAF (platelet
M.; Yoshioka, M.; Kawanisi, M. J. Org. Chem. 1988, 53,
3507–3512. (b) For the indium-mediated allylation, see:
Loh, T.-P.; Lye, P.-L.; Wang, R.-B.; Sim, K.-Y. Tetra-
hedron Lett. 2000, 41, 7779–7783.
activation factor) antagonists, see: Sunkel, C.-E.; Fau de
Casa-Juana, M.; Santos, L.; Go´mez, M.-M.; Villarroya,
M.; Gonza´lez-Morales, M.-A.; Priego, J.-G.; Ortega, M.-
P. J. Med. Chem. 1990, 33, 3205–3210. (c) For 4-
(phenylethynyl)-1,4-dihydropyridines as A3 adenosine
receptor antagonists, see: Jiang, J. L.; Li, A.-H.; Jang,
S.-Y.; Chang, L.; Melman, N.; Moro, S.; Ji, X.;
Lobkovsky, E.; Clardy, J.; Jacobson, K. A. J. Med.
Chem. 1999, 42, 3055–3065.
9. It is known that mixed alkyl vinyl HO cyanocuprates
selectively transfer vinyl versus methyl ligands in their
reaction with enones: (a) Lipshutz, B. H.; Wihelm, R. S.;
Kozlowski, J. A. J. Org. Chem. 1984, 49, 3938. (b)
Behling, J. R.; Babiak, K. A.; Ng, J. S.; Campbell, A. L.;
Moretti, R.; Koerner, M.; Lipshutz, B. H. J. Am. Chem.
Soc. 1988, 110, 2641–2643.
6. In Organocopper Reagents. A Practical Approach; Taylor,
R. J. K., Ed.; Oxford University Press: Oxford, 1994.
7. Yamamoto, Y.; Chounan, Y.; Tanaka, M.; Ibuka, T. J.
Org. Chem. 1992, 57, 1024–1026.
10. Imamoto, T.; Hatajima, T.; Ogata, K. Tetrahedron Lett.
1991, 32, 2787–2790.
11. (a) Bennasar, M.-L.; Vidal, B.; Bosch, J. J. Org. Chem.
1995, 60, 4280–4286. (b) For a typical experimental pro-
cedure, see reference 3.
8. (a) For the reaction of this organotin derivative with
N-acylpyridinium salts, see: Yamaguchi, R.; Moriyasu,
.