Regioselective addition of organomagnesium reagents to N-silyl activated nicotinic acid esters-a convenient method for the synthesis of 4,4-disubstituted 1,4-dihydronicotinates

Article abstract of DOI:10.1016/j.tet.2009.05.008

The addition of RMgX or R₂Mg to nicotinic acid esters, activated with triisopropylsilyl triflate, was investigated. The regioselectivity of this reaction, where 4-unsubstituted and 4-substituted pyridine derivatives were employed as starting ma

Full text of DOI:10.1016/j.tet.2009.05.008

Tetrahedron 65 (2009) 5824–5833
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective addition of organomagnesium reagents to N-silyl activated
nicotinic acid estersda convenient method for the synthesis of 4,4-
disubstituted 1,4-dihydronicotinates
*
Christian A. Sperger, Klaus T. Wanner
Department of PharmacydCenter for Drug Research, Ludwig-Maximilians-University Munich, Butenandtstr. 7, Haus C, D-81377 Mu¨nchen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The addition of RMgX or R2Mg to nicotinic acid esters, activated with triisopropylsilyl triflate, was
investigated. The regioselectivity of this reaction, where 4-unsubstituted and 4-substituted pyridine
derivatives were employed as starting materials, was examined. Depending on the structure of the
organomagnesium reagent varying ratios of 1,2-, 1,4-, and 1,6-regioisomers were obtained but in any case
the 1,4-addition products were clearly predominating. Desilylation of the isomeric pure addition prod-
ucts with LiOH provided stable 4,4-disubstituted dihydropyridines, which could be easily N-alkylated
with alkylhalides in high yield. Furthermore, it was shown that the silyl protecting group of the obtained
dihydropyridines can be easily replaced by an acyl group.
Received 11 February 2009
Received in revised form 23 April 2009
Accepted 5 May 2009
Available online 9 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
described by Goldmann,6 who synthesized a spirocyclic dihy-
dropyridine derivative with a sulfoxy moiety, which he subjected to
In the last few decades a large number of different synthetic
concepts for the formation of 1,4-dihydropyridines have been de-
veloped. Besides the Hantzsch1 type synthesis, the different
methods are mostly based on addition reactions to activated pyri-
dine derivatives, i.e., pyridinium salts.2 Depending on the nature of
the nucleophile, these intermediates are attacked at the 2-, 4- or 6-
position. Based on the HSAB-principle relatively hard nucleophiles
like Grignard reagents are shown to form predominantly 1,2-dihy-
dropyridines whereas lithium-dialkylcuprates3 or organozinc re-
agents5 preferentially add to the 4-position of the pyridine ring. In
addition, the formation of 1,4-dihydropyridines is strongly influ-
a reductive desulfination reaction to give upon a ring opening re-
action a 4,4-disubstituted 1,4-dihydropyridine. Clayden et al.
reported the formation of spirocyclic dihydropyridines with the
spirocyclic center in 4-position by intramolecular cyclization in-
volving anionic nucleophiles.7 He further published the spirocycli-
zation reaction of N-arylisonicotinamides induced by the
generation of electrophilic pyridinium cation intermediates.8
Another concrete example is the addition of benzyltin reagents to g-
substituted N-acylpyridinium salts. According to Yamaguchi and co-
workers,9 the alkylation of activated pyridines, which are
substituted with an electron withdrawing group in 4-position, leads
selectively to 4,4-disubstituted 1,4-dihydropyridines. In a recent
study, we reported the regioselective formation of 4,4-disubstituted
1,4-dihydropyridines, by trapping reactions of N-silylpyridinium
ions with nucleophiles.10 It had been found that quarternisation of
enced by substituents in the g-position of the pyridine derivative.
In this context Almqvist et al.4 reported that the addition of orga-
nozinc derivatives in the presence of catalytic amounts of
CuCN$2LiBr to 2- or 3-substituted N-acylpyridinium salts led
selectively to 4-substituted 1,4-dihydropyridines. However, when
4-picoline was used as a substrate only the corresponding 1,2-
dihydropyridine was formed. Merelya few methods are reported for
the preparation of 4,4-disubstitued dihydropyridines. For example,
acid catalyzed condensation of 3,3-disubstituted glutaraldehydes
with either secondary amines or primary amides leads to 1,4-
dihydropyridines exhibiting two substituents in 4-position.5 A se-
rious drawback of this method is the laborious and often complex
synthesis of the required glutaraldehydes. Another method was
g-substituted pyridine derivatives with triisopropylsilyl triflate fol-
lowed by the addition of an organomagnesium reagent at ambient
temperature led to the formation of 4,4-disubstituted dihydropyr-
idines with high regiocontrol. Herein we report on an extension of
the application of N-silylpyridinium ion chemistry, the direct syn-
thesis of 4,4-disubstituted 1,4-dihydronicotinic acid derivatives.
2. Results and discussion
The first series of experiments was performed with ethyl nico-
tinate (1). Though our study primarily aimed at the synthesis of
* Corresponding author. Tel.: þ49 89 2180 77249; fax: þ49 89 2180 77247.
E-mail address: klaus.wanner@cup.uni-muenchen.de (K.T. Wanner).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.008

C.A. Sperger, K.T. Wanner / Tetrahedron 65 (2009) 5824–5833
5825
4,4-disubstituted 1,4-dihydropyridines, compound 1 seemed in-
teresting as a starting point, as trapping reactions of this pyridine
derivative 1, activated with triisopropylsilyl triflate (2), would
provide insight in the reactivity and regioselectivity of the parent
system. Grignard reagents like dialkyl- and diarylmagnesium de-
rivatives had been successfully employed in our earlier study,10
mentioned above. Accordingly, these reagents were employed here
as well. All trapping reactions were carried out in the same way. In
brief, 1 equiv of 1 was treated with an equimolar amount of silyl
triflate 2 at room temperature (for 15 min in CH2Cl2) followed by
2 equiv of the respective organomagnesium reagent at ꢀ75 ꢁC. The
reaction mixture was allowed to react for 3 h before it was
quenched by addition of phosphate buffer and extracted with
CH2Cl2 to give a crude product, which was characterized by 1H NMR
spectroscopy prior to its purification by column chromatography.
According to 1H NMR analysis in all cases the 1,4-dihydropyridine
derivatives 4a–e resulting from a 1,4-addition reaction had formed
alone or in combination with the 1,6-addition products 5a–e, but
with the amount of the latter, when present, always being distinctly
lower than those of the former compound. But in no case the
regioisomeric 1,2-addition products were found in the crude
product (Table 1).
In case of the trapping reaction of 3 with MeMgBr according to
1H NMR analysis only 21% of the regioisomeric addition products 4a
and 5a was present in the crude product but 79% of the starting
material 1 (Table 1, entry 1). Also the regioselectivity of the reaction
reflected by the ratio of the regioisomers 4a and 5a amounting to
80/20 was not fully pleasing. Column chromatography yielded fi-
nally only 7% of the major isomer, the 1,4-addition product 4a. In
contrast, when Me2Mg was employed, both the product/educt ratio
((4aþ5a)/1¼52/48) and the regioselectivity were significantly im-
proved (4a/5a¼92/8; Table 1, entry 2). After column chromato-
graphy 4a was isolated in a 41% yield. Trapping the intermediate 3
with iso-propylmagnesium chloride resulted in the exclusive for-
mation of 4b (4b/5b¼100/0), which was isolated in 45% yield (Table
1, entry 3). When i-Pr2Mg was used instead, the product/educt ratio
((4bþ5b)/1) rose from 71/29 to 96/4 (Table 1, compare entry
3 to entry 4). But this time also 5% of the corresponding
1,6-dihydropyridine 5b was present in the crude product. As ob-
served for related compounds the 1,6-dihydropyridine derivative
5b was completely oxidized during workup and the subsequent
column chromatography. Accordingly, it did not interfere with the
isolation of the major isomer 4b, which was finally obtained in
a yield of 60% (Table 1, entry 4).
Further trapping reactions with t-BuMgCl and t-Bu2Mg as nu-
cleophiles proceeded both with high regioselectivity (4c/5c¼98/2;
Table 1, entries 5 and 6). Again the product/educt ratio and the yield
of the 1,4-addition product 4c were higher when the di-
organomagnesium derivative, i.e., t-Bu2Mg ((4cþ5c)/1¼95/5) in-
stead of t-BuMgCl ((4cþ5c)/1¼68/32) was used. When benzyl- or
phenylmagnesium reagents were employed the nucleophilic attack
occurred exclusively at the 4-position of the N-silylpyridinium salt
3 (4d/5d¼100/0, 4e/5e¼100/0; Table 1, entries 7–10). Bn2Mg and
Ph2Mg both affected a higher product/educt ratio ((4dþ5d)/1¼92/
8, (4eþ5e)/1¼85/15; Table 1, entries 8 and 10) as compared to the
reaction with BnMgCl ((4dþ5d)/1¼60/40; Table 1, entry 7) and
PhMgBr ((4eþ5e)/1¼65/35; Table 1, entry 9), respectively. Also the
yields significantly increased when the respective diorgano-
magnesium derivatives instead of the Grignard reagents were used.
Thus, whereas the addition of BnMgCl provided 52% of the desired
1,4-dihydropyridine derivative 4d, 79% of this product was isolated
when Bn2Mg was employed (Table 1, entries 7 and 8). Using Ph2Mg
instead of PhMgCl as a trapping reagent increased the yield of 4e
from 55% to 70% (Table 1, entries 9 and 10).
Further experiments were conducted with 4-phenylsubstituted
nicotinic acid derivative 6. Compound 6 was picked for two reasons.
First of all, we wanted to gain insight how addition reactions to
nicotinic acid ester 1 are altered in the presence of a 4-substituent.
In addition, the 4-phenylsubstituted nicotinic acid 6 differs from
a starting compound used in an earlier study for analogous reactions
only by the additional ester function.10 Accordingly, results from
experiments with 6, when compared with those from the afore-
mentioned study, should also allow to uncover the influence of an
ester group in 3-position on the outcome of the addition reactions.
Finally, we were interested to establish a synthetic access to 4,4-
disubstituted dihydropyridines provided with an ester function.
Table 1
Additiona of organomagnesium reagents to N-silylpyridinium ion 3
O
R
O
O
O
OEt
TfO-
RM
OEt
+
OEt
OEt
TIPSOTf (2)
N+
Si
R
CH2Cl2, rt
N
Si
N
Si
N
1
3
4a-e
5a-e
Entry
Nucleophile (RM)
Product/educt ratiob
1,4-Dihydropyridine
Product no.
4/5
(4þ5)/1
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
MeMgBr
Me2Mg
i-PrMgCl
i-Pr2Mg
t-BuMgCl
t-Bu2Mg
BnMgCl
Bn2Mg
80/20
92/8
100/0
95/5
98/2
98/2
100/0
100/0
100/0
100/0
21/79
52/48
71/29
96/4
68/32
95/5
60/40
92/8
65/35
85/15
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
7
41
45
60
30
52
52
79
55
70
PhMgBr
Ph2Mg
a
Compound 1 was dissolved in CH2Cl2 and treated with 1 equiv of silyl triflate 2 at room temperature. After 15 min the solution was cooled to ꢀ75 ꢁC and 2.0 equiv of the
corresponding organomagnesium reagent was added. After 3 h work up was performed by addition of phosphate buffer (pH 7, c¼1.0 M) and extraction of the aqueous layer
with CH2Cl2.
b
According to 1H NMR of the crude product.
Isolated yield.
c

5826
C.A. Sperger, K.T. Wanner / Tetrahedron 65 (2009) 5824–5833
Treatment of N-silylpyridinium salt 7 with methylmagnesium
respectively (Table 2, entries 3 and 4). In contrast the 1,2- and 1,6-
adducts 9b and 10b, that had formed only in minor amounts, could
not be isolated. According to 1H NMR analysis, the regioselectivity of
the alkylation of activated 6 with i-PrMgCl or i-Pr2Mg was highly
satisfying amounting to 99/1/0 and 100/0/0, respectively (8c/9c/10c;
Table 2, entries 8 and 9). In line with the product/educt ratio that
was most pleasing for the diorganomagnesium compound
((8cþ9cþ10c)/6¼97/3) the 4,4-disubstituted dihydropyridine 8c was
isolated in 63% and 91% yields, respectively (Table 2, entries 8 and 9).
When sterical demanding t-BuMgCl was employed the regiose-
lectivity was also quite satisfactory (8d/9d/10d¼94/6/0; Table 2, en-
try 10). According to 1H NMR analysis a 1,6-addition occurred only in
6%. Column chromatography provided the 1,4-addition 8d in a 47%
yield. Changing the nucleophile from t-BuMgCl to t-Bu2Mg led to
a somewhat lower C-4-selectivity of 86% (8d/9d/10d¼86/14/0; Table
compounds led to complex reaction mixtures so that neither
a product could be identified nor isolated (Table 2, entries 1 and 2).
Satisfying results were achieved when ethylmagnesium reagents
were employed (Table 2, entries 3 and 4). As observed for 3, the use of
the diethylmagnesium compound led to an almost complete con-
sumption of the starting material ((8bþ9bþ10b)/6¼98/2; Table 1,
entry 4), whereas in case of the reaction with the Grignard reagent
significant amounts of the starting material
6 remained left
((8bþ9bþ10b)/6¼58/42; Table 1, entry 3). Thereby the reagents had
added preferentially to the C-4-position of 7, but to a significant ex-
tent also the 1,2- and 1,6-addition products 9b and 10b had been
formed the ratio of the regioisomers amounting to 61/35/4 (8b/9b/
10b) for EtMgCl and to 64/22/14 (8b/9b/10b) for Et2Mg. For the 4,4-
disubstituted regioisomer 8b the yields amounted to 20% and 55%,
Table 2
Additiona of various organomagnesium reagents to N-triisopropylsilylpyridinium ions 7
Ph
O
OEt
RM
2)
TIPSOTf (
N+
Ph
O
Si
N
TfO- EtO
6
7
Ph
O
R
O
Ph
O
R
Ph
OEt
OEt
OEt
+
R
+
N
Si
N
Si
N
Si
8a-g
9a-g
10a-g
Entry
Nucleophile (RM)
Cu(I)-salt (15 mol %)
Product/educt ratiob
1,4-Dihydropyridine
Product no.
8/9/10
dd
dd
(8þ9þ10)/6
d
Yieldc (%)
e
1
2
3
4
5
6
7
8
MeMgBr
Me2Mg
EtMgCl
Et2Mg
EtMgCl
EtMgCl
Et2Mg
d
8a
8a
e
d
d
d
61/35/4
64/22/14
97/3/0
99/1/0
76/14/1
99/1/0
100/0/0
94/6/0
86/14/0
dd
58/42
98/2
33/67
70/30
45/55
70/30
97/3
40/60
89/11
d
8b
8b
8b
8b
8b
8c
20
55
15
25
23
63
91
47
d
CuBr$Me2S
CuCN
CuBr$Me2S
d
iPrMgCl
iPr2Mg
tBuMgCl
tBu2Mg
AllMgCl
All2Mg
BnMgCl
Bn2Mg
BnMgCl
BnMgCl
Bn2Mg
BnMgCl
BnMgCl
BnMgCl
BnMgCl
BnMgCl
PhMgCl
Ph2Mg
9
d
8c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
d
8d
8d/9d
8e
d
56/5f
e
d
e
d
dd
d
8e
d
72/28/0
50/49/1
95/5/0
85/15/0
62/38/0
99/1/0
59/41/0
90/10/0
92/8/0
85/15/0
90/10/0
98/2/0
69/31
98/2
95/5
46/54
66/34
95/5
95/5
60/40
46/54
43/57
13/87
63/37
8f/9f
8f/9f
8f
8f
8f
8f
8f/9f
8f
8f
8f
38/7
45/24
41
40
28
38
31/25
38
39
44
d
CuBr$Me2S
Me2Sg
CuBr$Me2S
CuCN
CuCNh
Bu4NþIꢀ
Bu4NþBrꢀ
Bu4NþClꢀ
d
8g
8g
7
46
d
a
Compound 6 was dissolved in CH2Cl2 and treated with 1 equiv of silyl triflate 2 at room temperature. After 15 min the solution was cooled to ꢀ75 ꢁC and 2.0 equiv of the
corresponding organomagnesium reagent was added. Work up was performed by addition of phosphate buffer (pH 7, c¼1.0 M) and extraction of the aqueous layer with CH2Cl2.
b
According to 1H NMR of the crude product.
Isolated yield.
Not determinable.
Not isolated.
Contaminated with 9% 8d.
Addition of 20 mol %.
1.0 equiv.
c
d
e
f
g
h

C.A. Sperger, K.T. Wanner / Tetrahedron 65 (2009) 5824–5833
5827
2, entry 11) but again to a higher product/educt ratio ((8dþ9dþ10d)/
6¼89/11 and a higher yield of 8d (56%). The corresponding 1,6-ad-
dition product 9d was isolated in 5% yield, but according to 1H NMR
analysis, it was still contaminated with 9% of regioisomer 8d. Treat-
ment of N-silylpyridinium salt 7 with allylmagnesium nucleophiles
led similar to the reactions with methylmagnesium reagents to
complex product mixtures (Table 2, entries 12 and 13). According to
1H NMR analysis, the addition of BnMgCl to 7 yielded a product with
a product ratio of 8f/9f/10f¼72/28/0 in favor of the 1,4-addition
product 8f. From this mixture 8f could be isolated in a 38% yield and,
in addition, the corresponding 1,6-dihydropyridine 9f, in 7% yield
(Table 2, entry 14). Based on the results obtained with ethyl- and
isopropylmagnesium reagents (Table 2, entries 3, 4 and 8, 9), it was
expected that the application of Bn2Mg as a nucleophile (Table 2,
entry 15) would improve both, the regioselectivity and the yield for
this reaction. However, the ratio of the 1,4- and 1,6-addition products
was extremely low and amounted approximately to 1:1 (8f/9f/
10f¼50/49/1; Table 2, entry 15). According to 1H NMR analysis, this
time also the corresponding 1,2-addition product 10f was present in
the reaction mixture, though in very low amount (1%). Column
chromatography provided the addition products 8f and 9f in 45% and
24% yields, respectively. When PhMgCl was used as a nucleophile the
1,4-adduct 8g prevailed in a 90:10 ratio over the 1,6-dihydropyridine
9g (8g/9g/10g¼90/10/0; Table 2, entry 24). As obvious from the
product/educt ratio ((8gþ9gþ10g)/6¼13/87), only low amounts of
the addition products had formed. Accordingly, only 7% of the major
regioisomer 8g could be isolated. More satisfying results were
obtained when the corresponding diphenylmagnesium organyl was
employed. In line with the distinctly improved product/educt ratio
((8gþ9gþ10g)/6¼63/37), the yield of 8g rose to 46%. Besides also the
regioselectivity had improved slightly (8g/9g/10g¼98/2/0, Table 2,
entry 25).
For the trapping reactions of triisopropylsilyl activated 4-phe-
nylpyridine Braeckow and Wanner10 had found that the yields for
the 1,4-addition products are significantly higher when diorgano-
magnesium derivatives instead of the Grignard reagents are used.
This phenomenon was observed here as well. But the regiose-
lectivities reported by Braeckow et al. for alkylation reactions of
triisopropylsilyl activated 4-phenylpyridine were in some cases
significantly different from those obtained for the corresponding
reactions with triisopropylsilyl activated nicotinate 7 in this study.
Whereas i-Pr2Mg and t-Bu2Mg (Table 2, entries 9 and 11) as trap-
ping reagents showed, independent of the pyridine derivative,
a very high C-4-selectivity, the reactions carried out with the other
diorganomagnesium compounds led to a different outcome. Et2Mg
and Bn2Mg added predominantly at the C-4 position when acti-
vated 4-phenyl pyridine served as a substrate.
In contrast, trapping of activated 6 with Et2Mg or Bn2Mg (Table 2,
entries 4 and 15) resulted in a mixture of regioisomers in which the
proportion of the C-4 adducts 8b and 8f amounted only to 64% (8b/
9b/10b¼64/22/14) and 50% (8f/9f/10f¼50/49/1), respectively. Fur-
thermore, for reactions of the parent system, the triisopropylsilyl
activated 4-phenylpyridine with Me2Mg, Allyl2Mg and Ph2Mg as
nucleophiles a predominant attack at the C-2 position has been
reported. In contrast, when 7 was reacted with Me2Mg and Allyl2Mg
(Table 2, entries 2 and 13), respectively, only complex mixtures of
products were obtained and Ph2Mg added almost exclusively to the
4-position of 7 providing the 4,4-disubstituted dihydropyridine 8g
(Table 2, entry 25).
Prompted by the disappointing results obtained with benzyl- and
ethylmagnesium reagents as nucleophiles (Table 2, entries 3, 4 and
14, 15), we performed some additional experiments with the aim to
optimize the 1,4-regioselectivity of these reactions. In case of 4-
unsubstituted pyridine derivatives it is well documented that when
catalytic amounts of Cu(I)-salts are present the addition of organo-
magnesium compounds to N-acylpyridinium salts proceeds almost
exclusively to the 4-position.11 Thus, it seemed worthwhile to study
the influence of different Cu(I)-salts on the reaction of organo-
magnesium reagents with 4-substituted N-silylpyridinium salts. The
respective alkylation reactions were thereby conducted under the
same conditions as those described above, but with the corre-
sponding Cu(I)-salt being present (Table 2, entries 5–7 and 16–20).
The first experiment performed with ethylmagnesium chloride in
the presence of 15 mol % CuBr$Me2S proceeded with a significantly
improved regioselectivity. As compared to the uncatalyzed version,
the proportion of the C-4 adduct 8b rose from 61% (8b/9b/10b¼61/
35/4) to 97% (8b/9b/10b¼97/3/0). Unfortunately, the product/educt
ratio was distinctly lower ((8b/9b/10b)/6¼33/67, instead of 58/42;
Table 2, compare entry 5 with entry 3) and 4,4-disubstituted addi-
tion product 8b was only isolated in a 15% yield. When EtMgCl was
replaced by Et2Mg, keeping everything else the same, the regiose-
lectivity became lower (8b/9b/10b¼76/14/1; Table 2, entry 7). But
when EtMgCl was combined with 15 mol % CuCN instead of 15 mol %
CuBr$Me2S the nucleophile added almost exclusively to the 4-posi-
tion of 7 the ratio of the regioisomers amounting to 8b/9b/10b¼99/
1/0 (Table 2, entry 6). Unfortunately, in this case neither the product/
educt ratio nor the isolated yield of 8b was satisfying ((8bþ9bþ10b)/
6¼70/30, yield 25%, Table 2, entry 6).
Further experiments were performed with organomagnesium
derivatives with a benzyl residue (Table 2, entries 16–20). The al-
kylation reaction with benzylmagnesium chloride in the presence
of 15 mol % CuBr$Me2S showed, according to 1H NMR analysis,
a significant improvement of the C-4-selectivity compared to the
reaction without any additive (Table 2, compare entries 14 and 16).
While the reaction without any additive had given rise to a medi-
ocre 72% proportion of the desired 1,4-dihydropyridine 8f (8f/9f/
10f¼72/28/0, Table 2, entry 14), the presence of catalytic amounts
of CuBr$Me2S led to a satisfying 95% yield (8f/9f/10f¼95/5/0, Table
2, entry 16). Thereby, the yield of 8f remained quite unaffected
(41%, Table 2, compare entries 14 and 16). When Bn2Mg instead of
the benzyl Grignard reagent was used, the regioselectivity only
slightly rose (8f/9f/10f¼62/38/0, Table 2, entry 18), and the yield
sank (28%, Table 2, entry 18) as compared to the uncatalyzed re-
action, similar to what had been observed for the corresponding
reactions with ethyl magnesium derivatives (Table 2, compare en-
tries 15 and 18 and entries 4 and 7).
To determine whether Me2S introduced with the copper catalyst
might have affected the regiochemistry, an additional experiment
was performed with 20 mol % Me2S (Table 2, entry 17). It is con-
ceivable that Me2S coordinates to the organometallic compound
and thus modifies its electronic properties or that it affects the
position of the equilibrium between the free pyridine 6 and the N-
silylpyridinium salt 7. In fact, the proportion of the 4-addition
product 8f rose significantly when 20 mol % Me2S was employed
(8f/9f/10f¼85/15/0; Table 2, entry 17, compare with entry 14). After
column chromatography 1,4-dihydropyridine 8f was isolated in 40%
yield. Thus, already the addition of Me2S itself improves the regio-
selectivity of the Grignard addition reaction (Table 2, entry 17) but
obviously less than it is the case with CuBr$Me2S (Table 2, entry 16).
When another Cu(I)-salt, i.e.,15 mol % CuCN was employed (Table 2,
entry 19) the C-4-selectivity, which had already been very high with
CuBr$Me2S (Table 2, entry 16), was further improved. According to
1H NMR analysis the ratio between the 1,4- and the 1,6-adduct now
amounted to 99:1 (8f/9f) with no 1,2-isomer 10f being present (8f/
9f/10f¼99/1/0; Table 2, entry 19). Also the product/educt ratio was
quite pleasing ((8fþ9fþ10f)/6¼95/5; Table 2, entry 19), and com-
pound 8f was isolated in a 38% yield (Table 2, entry 19).
As a consequent extension of the experiment employing cata-
lytic amounts of CuCN an addition reaction with 2 equiv of a pre-
formed ‘higher order cyanocuprate’ was performed. Though the
product/educt ratio remained unchanged ((8fþ9fþ10f)/6¼95/5;
Table 2, entry 20), the regioselectivity declined dramatically, to 59/

5828
C.A. Sperger, K.T. Wanner / Tetrahedron 65 (2009) 5824–5833
41/0 (8f/9f/10f; Table 2, entry 20). After column chromatography
31% of the 1,4-dihydropyridine 8f, and 25% of the corresponding
1,6-regioisomer 9f was obtained.
It is well known that the reactivity of RMgX or R2Mg is modified
by addition of different salts like ROꢀMþ or Alk4NþXꢀ.12 According
to Pajerski et al. Grignard reagents 11 when combined with tet-
raalkylammonium salts 12 may form organomagnesiate salts 13.12c
Ph
Ph
1) NaH, DMF, rt
2) RX, rt
COOEt
COOEt
N
H
N
R
15
17 R = Me (90%)
18 R = Bn (85%)
19 R = Allyl (83%)
Scheme 2. N-Alkylation of 19.
Bu4N+ X-
RMgX2- Bu4N+
RMgX
+
ð1Þ
11
12
13
COOEt
AcCl, CH2Cl2
micro wave, 9 h, 65 °C
COOEt
N
Therefore, further addition reactions of benzylmagnesium
chloride to N-silylpyridinium 7 were undertaken, but this time in
the presence of various tetrabutylammonium halides. However,
only catalytic amounts of these salts were employed, as additional
halide ions, due to their higher nucleophilicity compared to triflate
ions, run the risk of shifting the equilibrium between the N-silyl-
pyridinium salt 7 and the free pyridine 6 toward the latter.10
When 10 mol % tetrabutylammonium iodide or bromide was
added, the regioselectivity rose significantly in favor of the C-4
addition product 8f. Whereas in the absence of any additive the
ratio of regioisomers had been 72/28/0 (8f/9f/10f, Table 2, entry 14),
it amounted to 90/10/0 and 92/8/0 (8f/9f/10f) when tetrabutyl-
ammonium iodide and bromide, respectively, were present (Table
2, entries 21 and 22). But the yields for the 1,4-dihydropyridine 8f
did not change significantly (38–39%, Table 2, compare entries 14,
21 and 22). In case of tetrabutylammonium chloride as additive the
increase in regioselectivity was far less pronounced (8f/9f/10f¼85/
15/0; Table 2, entry 23). According to the above data the addition of
tetrabutylammonium halides leads to an improved regioselectivity
in the addition of Grignard reagents to N-silylpyridinium salt 7,
which points toward the formation of organomagnesium salts 13 as
reactive intermediates.
N
Si
O
14
20 (74%)
Scheme 3. Reaction of 14 with acetyl chloride.
also the 4,4-disubstituted dihydropyridine 14 could be deprotected
with LiOH in MeOH providing 16 in 86% yield (Scheme 1).
The deprotected dihydropyridine derivatives provide easy ac-
cess to their N-alkyl substituted counterparts as exemplified by the
conversion of 15 (Scheme 2). Deprotonation with NaH in DMF to
generate the anion of 15 and subsequent treatment with alkyl ha-
lides, methyl iodide, allyl and benzyl bromide, provided the cor-
responding alkylated products 17–19 in good yields (83–90%).
Further experiments revealed that the N-silyl-1,4-dihydropyr-
idine derivatives can be easily transformed to the corresponding N-
acyl substituted compounds by reacting them with acid chlorides.
When 14, selected as an example, was heated together with acetyl
chloride under microwave conditions the N-acyldihydropyridine
20 was formed, which was isolated in 74% yield (Scheme 3).
Addition reactions of organomagnesium derivatives to N-silyl-
pyridinium ions not only provide an efficient access to N-sily-4,4-
dihydropyridines but also to the corresponding saturated piperidine
derivatives, easily accessible by reduction with NaBH4 as demon-
strated earlier.10 To further explore the versatility of the N-silyl-1,4-
dihydropyridines as synthetic building blocks the removal of the
N-silyl group to provide the parent compounds was studied. As
a representative example dihydropyridine 8c was used. At first
fluoride based reagents were tested as they are most common to
effect desilylation reactions. But despite extensive experimentation
employing tetrabutylammonium fluoride on silica gel as a fluoride
source in THF at various temperatures (up to 50 ꢁC and for 20 h) no
more than 27% of the desilylated product 15 was obtained.
Finally, LiOH in MeOH was found to efficiently effect the desired
desilylation reaction of 8c. Applying 1.6 equiv of LiOH in MeOH at
room temperature for 20 h, conditions found optimal for this re-
action, afforded 15 in 91% yield. To expand the desilylation reaction
on another substrate a 4,4-diethylsubstituted dihydropyridine 14
was synthesized from ethyl 4-ethylpyridine-3-carboxylate follow-
ing the general procedure for the trapping reactions of 7. Like 8c
3. Conclusion
To sum up, it has been shown, that the addition of various
organomagnesium reagents to
g-unsubstituted N-silyl activated
ethyl nicotinates leads almost selectively to 4,4-disubstituted 1,4-
dihydropyridines. When 4-substituted nicotinic acid derivatives
were employed as starting materials, the regiochemistry is strongly
influenced by the organomagnesium reagent. While sterically
demanding magnesium nucleophiles preferentially add at the
4-position of the 4-substituted pyridine moiety, benzyl- and
ethylmagnesium compounds showed a comparatively high C-6-
selectivity. Employing catalytic amounts of different additives, e.g.,
Cu(I)-salts or tetrabutylammonium halides led to an improved 1,4-
regioselectivity. The 4,4-disubstituted dihydropyridines obtained
were easily deprotected in high yields when treated with lithium
hydroxide at ambient temperature. N-Alkylation of these products
led to N-alkyl-1,4-dihydropyridines. Finally, the silyl group of the
dihydropyridines can be easily replaced by an acyl group upon
treatment with an acid chloride.
4. Experimental
R1
R2
a) TBAF, THF, reflux
or
COOEt
R1
R2
COOEt
4.1. General experimental
b) LiOH, MeOH, rt
N
Si
N
H
All reactions were performed using flame-dried glassware un-
der argon atmosphere. All solvents were freshly dried using stan-
dard procedures.1 1H and 13C NMR spectra were recorded on
a JNMR-GX 400 (Joel, 400 MHz) or a JNMR-GX 500 (Joel, 500 MHz)
spectrometer, respectively. Infrared spectra were obtained on
a Perkin Elmer Model 1600 FT-IR spectrometer. Microanalytical
8c R1 = Ph, R2 = iPr
14 R1 = R2 = Et
15 (a: 27%, b: 91%)
16 (b: 86% )
Scheme 1. Deprotection of the nitrogen moiety.

C.A. Sperger, K.T. Wanner / Tetrahedron 65 (2009) 5824–5833
5829
data for carbon, hydrogen, and nitrogen were determined on
a Heraeus Rapid Analyser and on an Elementar Vario EL Analyser.
Flash chromatography was performed with 40–63 mesh silica gel
or 50–150 mesh aluminum oxide (neutral Brockmann activity III).
Preparative HPLC was performed with a HibarÒ LiChrosorbÒ Si 60
1H, NCH]CH), 5.89 (dd, J¼8.0/1.3 Hz, 1H, NCH]CH), 7.25 (d,
J¼1.3 Hz, 1H, NCH]C) ppm. 13C NMR (CDCl3)
d¼11.3 (q, 3C,
CH(CH3)2), 14.4 (q, 1C, CH2CH3), 17.7 (q, 3C, CH(CH3)2), 17.9 (d, 3C,
CH(CH3)2), 25.1 (q, 1C, CH3), 26.5 (d, 1C, CH]CHCH), 106.1 (s, 1C,
NCH]C), 110.7 (d, 1C, NCH]CH), 126.2 (d, 1C, NCH]CH), 140.8 (d,
1C, NCH]C), 168.7 (s,1C, CO) ppm. MS (CI, CHþ5 ): m/z (%)¼324 (100)
[MþH]þ, 308 (29), 278 (17). IR (film): 3057 cmꢀ1, 2949, 2894, 2868,
1696, 1660,1590, 1463, 1306,1257, 1240,1183. HRMS (EI, 70 eV): Mþ
calcd for C18H33NO2Si (323.2281): found 323.2297.
Procedure B: According to procedure Awith Me2Mg (0.45 M in Et2O,
35.9 mg, 0.662 mmol,1.47 mL) instead of MeMgCl. Purification by flash
chromatography on Al2O3 yielded 44 mg (41%) of 4a as a yellow oil.
column (5
m
m, 25ꢂ250 nm). Ethyl-4-phenylpyridin-3-carboxylat 6
was synthesized according a literature procedure.1
4.2. General procedure for the preparation of
dialkylmagnesium reagents1 (GP1)
Commercial available alkylmagnesium halide solution in Et2O
was diluted with Et2O to yield 1.0 M stock solutions. 1,4-Dioxane
(1.1 equiv) was added slowly to the mechanically stirred Grignard
solution at room temperature. The heterogeneous solution was
stirred over night to complete precipitation. The resulting sus-
pension was centrifuged to yield clear R2Mg solutions, which were
stored under nitrogen at 4 ꢁC.
4.7. Ethyl 4-isopropyl-1-triisopropylsilyl-1,4-
dihydropyridine-3-carboxylate 4b
Procedure A: According to GP2 from 1 (100 mg, 0.662 mmol), 2
(203 mg, 0.662 mmol, 182
mL) in CH2Cl2 (8 mL) and i-PrMgCl (2 M
in Et2O, 136 mg, 1.32 mmol, 662
mL). Work up was performed with
4.3. General procedure for the addition of organomagnesium
reagents to N-silylpyridinium salts (GP2)
phosphate buffer (8 mL) and triple extraction with CH2Cl2 (25 mL
each). Purification by flash chromatograpy on SiO2 (n-pentane/
EtOAc¼80/20).
The corresponding nicotinic acid derivate was dissolved in
CH2Cl2 and treated with 1.0 equiv of triisopropylsilyl triflate 2 at
room temperature. After 15 min the clear solution was cooled to
ꢀ75 ꢁC, followed by dropwise addition of the magnesium reagent.
The resulting yellow to red colored mixtures were stirred at ꢀ75 ꢁC
for 3 h. Work up was performed by addition of phosphate buffer
(pH 7, c¼1.0 M) and extraction of the aqueous layer with CH2Cl2.
The combined organic layers were dried (MgSO4) and concentrated
in vacuo. Flash chromatography on silica gel yielded the final
products, which were stored under argon atmosphere at ꢀ20 ꢁC.
Yield 105 mg (45%), colorless oil. TLC Rf¼0.36 (n-heptane/Et2O¼50/
50, SiO2). 1H NMR (CDCl3)
d
¼0.81 (d, J¼7.0 Hz, 3H, CH(CH3)2), 0.86 (d,
J¼7.0 Hz, 3H, CH(CH3)2), 1.08 (d, J¼7.5 Hz, 9H, CH(CH3)2), 1.09 (d,
J¼7.5 Hz, 9H, CH(CH3)2), 1.26 (t, J¼7.1 Hz, 3H, CH2CH3), 1.23–1.37 (m,
3H, CH(CH3)2), 1.75–1.88 (m, 1H, CH(CH3)2), 3.32 (dd, J¼5.1/3.5 Hz, 1H,
CH]CHCH), 4.06–4.23 (m, 2H, CH2CH3), 4.77 (dd, 7.9/5.1 Hz, 1H,
NCH]CH), 6.05 (dd, J¼7.9/1.2 Hz, 1H, NCH]CH), 7.36 (d, J¼1.2 Hz, 1H,
NCH]C) ppm. 13C NMR (CDCl3)
d¼11.3 (d, 3C, CH(CH3)2), 14.4 (q, 1C,
CH2CH3), 17.2 (q, 1C, CH(CH3)2), 17.7 (q, 6C, CH(CH3)2), 18.7 (q, 1C,
CH(CH3)2), 33.0 (d, 1C, CH(CH3)2), 37.7 (d, 1C, CH]CHCH), 59.2 (t, 1C,
CH2CH3), 104.0 (s, 1C, NCH]C), 104.8 (d, 1C, NCH]CH), 128.4 (d, 1C,
NCH]CH), 141.8 (d, 1C, NCH]C), 168.9 (s, 1C, CO) ppm. MS (CI, CHþ5 ):
4.4. General procedure for desilylation (GP3)
m/z (%)¼352 (100) [MþH]þ, 308 (85). IR (film):
n
¼3053 cmꢀ1, 2958,
The corresponding N-silylprotected dihydropyridine in metha-
nol was stirred together with LiOH for the time given. Subsequent
removal of the solvent in vacuo and purification of the raw material
by flash chromatography on silica gel yielded the desired
dihydropyridine.
2867, 2305, 1718, 1684. Anal. Calcd for C20H37NO2Si (351.61): C 68.32, H
10.61, N 3.98. Found: C 68.35, H 11.03, N 4.01.
Procedure B: According to procedure A with i-Pr2Mg (0.4 M in
Et2O, 151 mg, 1.32 mmol, 3.30 mL) instead of i-PrMgCl. Purification
by flash chromatography on SiO2 yielded 139 mg (60%) of 4b as
a colorless solid.
4.5. General procedure for N-alkylation of 15 (GP4)
4.8. Ethyl 4-tert-butyl-1-triisopropylsilyl-1,4-
To a suspension of NaH (2.0 equiv) in DMF was added a solution
of 15 at room temperature followed by stirring for 15 min. To this
obtained turbid solution a 1.5 fold excess of the corresponding alkyl
halide was added. After the time given, the reaction was quenched
with water. The aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried (MgSO4) and concentrated in
vacuo. The raw material was purified by flash chromatography on
silica gel to yield the desired product.
dihydropyridine-3-carboxylate 4c
Procedure A: According to GP2 from 1 (50 mg, 0.33 mmol), 2
(101 mg, 0.331 mmol, 91.0
mL) in CH2Cl2 (4 mL) and t-BuMgCl
(1.7 M in Et2O, 77.1 mg, 0.660 mmol, 389
m
L). Work up was per-
formed with phosphate buffer (4 mL) and triple extraction with
CH2Cl2 (20 mL each). Purification by flash chromatography on SiO2
(n-heptane/EtOAc¼97/3).
Yield 37 mg (30%), colorless oil. TLC Rf¼0.57 (SiO2, n-heptane/
4.6. Ethyl 4-methyl-1-triisopropylsilyl-1,4-dihydro-
pyridine-3-carboxylate 4a
Et2O¼50/50). 1H NMR (CDCl3):
¼0.80 (s, 9H, C(CH3)3), 1.06 (d,
d
J¼7.6 Hz, 9H, CH(CH3)2), 1.07 (d, J¼7.6 Hz, 9H, CH(CH3)2), 1.24
(t, J¼7.1 Hz, 3H, CH2CH3), 1.30 (sept., J¼7.6 Hz, 3H, CH(CH3)2), 3.15
(d, J¼6.0 Hz, 1H, CH]CHCH), 4.04–4.20 (m, 2H, CH2CH3), 4.88 (dd,
J¼7.6/6.0 Hz, 1H, NCH]CH), 6.10 (dd, J¼7.6/1.1 Hz, 1H, NCH]CH),
Procedure A: According to GP2 from 1 (50 mg, 0.33 mmol), 2
(101 mg, 0.331 mmol, 91.0
mL) in CH2Cl2 (4 mL) and MeMgCl (2.0 M
in Et2O, 49.6 mg, 0.662 mmol, 331
mL). Work up was performed
7.42 (d, J¼1.1 Hz, 1H, NCH]C) ppm. 13C NMR (CDCl3):
¼11.4 (q, 3C,
d
with phosphate buffer (4 mL) and triple extraction with CH2Cl2
(20 mL each). Purification by flash chromatograpy on Al2O3 (n-
pentane/EtOAc¼90/10).
CH(CH3)2), 14.4 (q, 1C, CH2CH3), 17.8 (q, 6C, CH(CH3)2), 26.1 (q, 3C,
C(CH3)3), 38.4 (s, 1C, C(CH3)3), 41.1 (d, 1C, CH]CHCH), 59.3 (t, 1C,
CH2CH3), 103.1 (s, 1C, NCH]C), 106.1 (d, 1C, NCH]CH), 128.2 (d, 1C,
NCH]CH), 142.0 (d, 1C, NCH]C), 170.3 (s, 1C, CO) ppm. MS (CI,
CHþ5 ): m/z (%)¼366 (97, [MþH]þ), 320 (28), 308 (100). IR (film):
Yield 7.5 mg (7%), yellow oil. TLC Rf¼0.55 (n-heptane/Et2O¼50/
50, SiO2). 1H NMR (CDCl3)
d
¼1.08–1.10 (m, 3H, CH3), 1.10 (d,
J¼7.2 Hz, 9H, CH(CH3)2), 1.11 (d, J¼7.2 Hz, 9H, CH(CH3)2), 1.26 (t,
J¼7.2 Hz, 3H, CH2CH3), 1.22–1.36 (m, 3H, CH(CH3)2), 3.30–3.36 (m,
1H, CH]CHCH), 4.09–4.23 (m, 2H, CH2CH3), 4.83 (dd, J¼8.0/4.7 Hz,
n
¼3059 cmꢀ1, 2949, 2896, 2869, 1697, 1653, 1585, 1463, 1251. Anal.
Calcd for C21H39NO2Si (365.64): C 68.98, H 10.75, N 3.83. Found: C
68.91, H 10.75, N 3.86.

5830
C.A. Sperger, K.T. Wanner / Tetrahedron 65 (2009) 5824–5833
Procedure B: According to procedure A with t-Bu2Mg (0.4 M in
with phosphate puffer (5 mL) and triple extraction with CH2Cl2
(20 mL each). Purification by flash chromatography on SiO2 (n-
pentane/CH2Cl2¼94/6) provided 8b as colorless crystals.
Et2O, 91.4 mg, 0.660 mmol, 1.66 mL) instead of t-BuMgCl. Purifica-
tion by flash chromatography on SiO2 yielded 62 mg (52%) of 4c as
a colorless oil.
Yield 18.2 mg (20%), colorless crystals, mp 63–65 ꢁC. TLC Rf¼0.60
(n-heptane/Et2O¼50/50, SiO2). 1H NMR (CDCl3)
¼0.98 (t, J¼7.2 Hz,
d
4.9. Ethyl 4-benzyl-1-triisopropylsilyl-1,4-dihydro-
pyridine-3-carboxylate 4d
6H, COOCH2CH3, CH2CH3), 1.14 (d, J¼7.5 Hz, 9H, CH(CH3)2), 1.15 (d,
J¼7.5 Hz, 9H, CH(CH3)2), 1.36 (sept., J¼7.5 Hz, 3H, CH(CH3)2), 1.50–
1.61 (m, 1H, CH2CH3), 2.54–2.64 (m, 1H, CH2CH3), 3.82–3.97 (m, 2H,
COOCH2CH3), 4.34 (d, J¼7.9 Hz, 1H, NCH]CH), 6.03 (dd, J¼7.9/
1.2 Hz, 1H, NCH]CH), 7.12 (tt, J¼7.3/1.3 Hz, 1H, Hpara), 7.26–7.31 (m,
2H, Hmeta), 7.42–7.46 (m, 2H, Hortho), 7.56 (d, J¼1.2 Hz, 1H,
Procedure A: According to GP2 from 1 (50 mg, 0.33 mmol), 2
(101 mg, 0.331 mmol, 91.0
mL) in CH2Cl2 (4 mL) and BnMgCl (1.0 M
in Et2O, 59.8 mg, 0.397 mmol, 397
mL). Work up was performed
with phosphate buffer (5 mL) and triple extraction with CH2Cl2
(20 mL each). Purification by flash chromatography on Al2O3 (n-
pentane/Et2O¼70/30).
NCH]C) ppm. 13C NMR (CDCl3)
d¼10.7 (q, 1C, CH2CH3), 11.2 (d, 3C,
CH(CH3)2), 14.0 (q, 1C, COOCH2CH3), 17.7 (q, 3C, CH(CH3)2), 17.8 (q,
3C, CH(CH3)2), 30.3 (t,1C, CH2CH3), 43.9 (s,1C, CH]CHC), 58.9 (t,1C,
COOCH2CH3), 105.2 (s, 1C, NCH]C), 113.7 (d, 1C, NCH]CH), 134.8
(d, 1C, NCH]CH), 125.1 (d, 1C, Cpara), 127.3 (d, 2C, Carom.), 127.5 (d,
2C, Carom.), 141.7 (d, 1C, NCH]C), 152.4 (s, 1C, Carom.), 168.3 (s, 1C,
CO) ppm. MS (EI, 70 eV): m/z (%)¼384 (100) [MþꢀC2H5]. IR (film):
Yield 68.0 mg (52%), colorless oil. TLC Rf¼0.66 (n-pentane/
Et2O¼50/50, SiO2). 1H NMR (CDCl3)
d
¼1.00 (d, J¼7.4 Hz, 9H,
CH(CH3)2), 1.02 (d, J¼7.4 Hz, 9H, CH(CH3)2), 1.17–1.27 (m, 3H,
CH(CH3)2), 1.28 (t, J¼7.1 Hz, 3H, CH2CH3), 2.69 (dd, J¼12.9/7.8 Hz,
1H, CH2Ph), 2.78 (dd, J¼12.9/3.7 Hz, 1H, CH2Ph), 3.62–3.67 (m, 1H,
CHCHC), 4.11–4.23 (m, 2H, CH2CH3), 4.70 (dd, J¼7.8/4.8 Hz, 1H,
NCH]CH), 5.86 (dd, J¼7.8/1.1 Hz, 1H, NCH]CH), 7.09–7.15 (m, 3H,
Harom.), 7.18–7.24 (m, 3H, 2Harom., NCH]C) ppm. 13C NMR (CDCl3)
n
¼3085 cmꢀ1, 3056, 3023, 2949, 2894, 2869, 1698, 1660, 1576, 1463,
1307. Anal. Calcd for C25H39NO2Si (413.68): C 72.59, H 9.50, N 3.39.
Found: C 72.43, H 9.45, N 3.36.
Procedure B: According to procedure A with Et2Mg (0.45 M in
d
¼11.2 (q, 6C, CH(CH3)3), 17.6 (q, 3C, CH(CH3)3), 14.5 (q, 1C, CH2CH3),
Et2O, 36.3 mg, 0.440 mmol, 975 mL) instead of EtMgCl. Flash chro-
matography on SiO2 provided 50 mg (55%) of 8b as colorless crystals.
Procedure C: According to GP2 from 6 (25.0 mg, 0.110 mmol), 2
34.0 (d, 1C, CHCHC), 44.4 (t, 1C, CH2CH3), 59.4 (t, 1C, CH2Ph), 103.9
(s, 1C, NCH]C), 108.0 (d, 1C, NCH]CH), 125.6 (d, 1C, Cpara), 127.3 (d,
1C, NCH]CH), 127.8 (d, 2C, Carom.), 129.9 (d, 2C, Carom.), 139.5 (s, 1C,
Carom.),141.9 (d,1C, NCH]C),168.7 (s,1C, CO) ppm. MS (CI, CHþ5 ): m/z
(33.7 mg, 30.3
mL, 0.11 mmol) in CH2Cl2 (3 mL) and EtMgCl (2.8 M in
Et2O, 19.5 mg, 0.220 mmol, 79.0
mL), but with the addition of
(%)¼400 (58) [MþH]þ, 354 (12), 308 (100). IR (film):
n
¼3062 cmꢀ1
,
CuBr$Me2S (3.40 mg, 0.017 mmol) before 2 was introduced. Work
up was performed with phosphate buffer (3 mL) and triple ex-
traction with CH2Cl2 (15 mL each). Purification by flash chroma-
tography on SiO2 yielded 7 mg (15%) of 8b.
3028, 2944, 2867, 1722, 1683, 1589, 1277. HRMS (ESIþ): [MþH]þ
calcd for C24H38NO2Si (400.2672), found 400.2670.
Procedure B: According to procedure A with Bn2Mg (0.4 M in
Et2O, 138 mg, 0.397 mmol, 933
mL) instead of BnMgCl. Purification
Procedure D: According to C with Et2Mg (0.4 M in Et2O, 18.1 mg,
by flash chromatography on Al2O3 yielded 103 mg (79%) of 4d as
0.220 mmol, 550 mL) instead of EtMgCl. Flash chromatography on
a colorless oil.
SiO2 provided 10.6 mg (23%) of 8b as colorless crystals.
Procedure E: According to C with CuCN (1.60 mg, 0.017 mmol)
instead of CuBr$Me2S. Flash chromatography on SiO2 provided
11.4 mg (25%) of 8b as colorless crystals.
4.10. Ethyl 4-phenyl-1-triisopropylsilyl-1,4-dihydro-
pyridine-3-carboxylate 4e
Procedure A: According to GP2 from 1 (50 mg, 0.33 mmol), 2
4.12. Ethyl 4-isopropyl-4-phenyl-1-triisopropylsilyl-
1,4-dihydropyridine-3-carboxylate 8c
(101 mg, 0.331 mmol, 91.0
mL) in CH2Cl2 (4 mL) and PhMgBr
(2.97 M in Et2O, 54.2 mg, 0.397 mmol, 223
m
L). Work up was per-
formed with phosphate buffer (5 mL) and triple extraction with
CH2Cl2 (15 mL each). Purification by flash chromatography on Al2O3
(n-pentane/Et2O¼70/30).
Procedure A: According to GP2 from 6 (200 mg, 0.880 mmol), 2
(270 mg, 242
mL, 0.880 mmol) in CH2Cl2 (10 mL) and i-PrMgCl
(2.0 M in Et2O,181 mg,1.76 mmol, 880
m
L). Work up was performed
Yield 70 mg (55%), colorless crystals, mp 63–65 ꢁC. TLC Rf¼0.74
with phosphate buffer (10 mL) and triple extraction with CH2Cl2
(30 mL each). Purification by flash chromatography on SiO2 (n-
pentane/EtOAc¼94/6).
(n-pentane/Et2O¼50/50, SiO2). 1H NMR (CDCl3)
¼1.12 (t, J¼7.1 Hz,
d
3H, CH2CH3), 1.14 (d, J¼7.5 Hz, 9H, CH(CH3)2), 1.15 (d, J¼7.5 Hz, 9H,
CH(CH3)2), 1.36 (sept., J¼7.5 Hz, 3H, CH(CH3)2), 3.93–4.09 (m, 2H,
CH2CH3), 4.49 (d, J¼4.7 Hz, 1H, CHCHC), 4.93 (dd, J¼7.8/4.7 Hz, 1H,
NCH]CH), 6.02 (dt, J¼7.8/1.2 Hz, 1H, NCH]CH), 7.13–7.18 (m, 1H,
Hpara), 7.25–7.31 (m, 4H, Harom.), 7.42 (d, J¼1.2 Hz, 1H,
NCH]C) ppm. MS (CI, CHþ5 ): m/z (%)¼386 (100) [MþH]þ, 340 (24),
Yield 239 mg (63%), colorless oil. TLC Rf¼0.34 (n-heptane/
Et2O¼50/50, SiO2). 1H NMR (CDCl3)
d¼0.84 (d, J¼6.8 Hz, 3H,
CH(CH3)2), 1.00 (d, J¼6.8 Hz, 3H, CH(CH3)2), 1.04–1.11 (m, 3H,
CH2CH3), 1.14 (d, J¼7.5 Hz, 9H, CH(CH3)2), 1.15 (d, J¼7.5 Hz, 9H,
CH(CH3)2), 1.15 (sept., J¼7.5 Hz, 3H, CH(CH3)2), 3.30 (sept., J¼6.8 Hz,
1H, CH(CH3)2), 3.84–4.00 (m, 2H, CH2CH3), 4.59 (d, J¼8.1 Hz, 1H,
NCH]CH), 6.24 (dd, J¼8.1/1.4 Hz, 1H, NCH]CH), 7.10 (tt, J¼7.5/
1.1 Hz, 1Hpara), 7.27 (t, J¼7.5 Hz, 2H, Hmeta), 7.34 (d, J¼1.4 Hz, 1H,
NCH]C), 7.53 (dd, J¼7.5/1.1 Hz, 2H, Hortho) ppm. 13C NMR (CDCl3)
308 (82). IR (film):
1658, 1590, 1463, 1298, 1252. Anal. Calcd for C23H35NO2Si (385.61):
C 71.64, H 9.15, N 3.63. Found: C 71.41, H 9.35, N 3.57.
n
¼3060 cmꢀ1, 3026, 2947, 2893, 2868, 1698,
Procedure B: According to procedure A with Ph2Mg (0.4 M in
Et2O,179.7 mg, 0.397 mmol, 993
mL) instead of PhMgBr. Purification
d
¼11.3 (d, 3C, CH(CH3)3), 14.1 (q, 1C, CH2CH3), 16.0 (q, 1C, CH(CH3)3),
by flash chromatography on Al2O3 yielded 89 mg (70%) of 4e as
a colorless solid.
17.8 (q, 6C, CH(CH3)3), 20.4 (q, 1C, CH(CH3)3), 30.2 (d, 1C, CH(CH3)3),
47.1 (s, 1C, CH]CHCH), 58.9 (t, 1C, CH2CH3), 107.6 (d, 1C, NCH]CH),
107.8 (s, 1C, NCH]C), 125.0 (d, 1C, Cpara), 126.6 (d, 1C, NCH]CH),
126.9 (d, 2C, Cmeta), 129.8 (d, 2C, Cortho), 139.8 (d, 1C, NCH]C), 149.1
(s, 1C, Carom.), 168.0 (s, 1C, CO) ppm. MS (CI, CHþ5 ): m/z (%)¼428
4.11. Ethyl 4-ethyl-4-phenyl-1-triisopropylsilyl-1,4-
dihydropyridine-3-carboxylate 8b
(100) [MþH]þ, 384 (94), 350 (12). IR (film):
n
¼3086 cmꢀ1, 3057,
Procedure A: According to GP2 from 6 (50.0 mg, 0.220 mmol), 2
3019, 2948, 2868, 1698, 1622, 1575, 1463, 1269, 1251. Anal. Calcd for
C26H41NO2Si (427.71): C 73.01, H 9.66, N 3.27. Found: C 72.81, H
10.06, N 3.25.
(64.7 mg, 60.5
mL, 0.220 mmol) in CH2Cl2 (4 mL) and EtMgCl (2.8 M
in Et2O, 39.1 mg, 0.440 mmol, 156
mL). Work up was performed

C.A. Sperger, K.T. Wanner / Tetrahedron 65 (2009) 5824–5833
5831
Procedure B: According to procedure A with i-Pr2Mg (0.4 M in
Et2O, 195 mg, 1.76 mmol, 880 L) instead of i-PrMgCl. Purification
by flash chromatography on SiO2 yielded 345 mg (91%) of 8c as
1H, NCH]CH), 7.08–7.21 (m, 6H, Harom.), 7.23 (d, J¼1.3 Hz, 1H,
NCH]C), 7.34 (t, J¼7.7 Hz, 2H, Harom.), 7.51–7.56 (m, 2H, Har-
m
om.) ppm. 13C NMR (CDCl3):
d¼11.0 (d, 3C, CH(CH3)2), 14.2 (q, 1C,
a colorless oil.
CH2CH3), 17.4 (q, 3C, CH(CH3)2), 17.5 (q, 3C, CH(CH3)2), 44.1 (t, 1C,
CH2), 45.3 (s, 1C, CH]CHC), 59.0 (t, 1C, CH2CH3), 105.9 (s, 1C,
NCH]C), 113.4 (d, 1C, NCH]CH), 124.5 (d, 1C, NCH]CH), 125.3 (d,
1C, Carom.), 125.6 (d, 1C, Carom.), 127.4 (d, 2C, Carom.), 127.5 (d, 2C,
Carom.), 127.6 (d, 2C, Carom.), 131.0 (d, 2C, Carom.), 140.1 (s, 1C, Carom.),
141.9 (d, 1C, NCH]C), 152.3 (s, 1C, Carom.), 168.3 (s, 1C, CO) ppm. MS
(CI, CHþ5 ): m/z (%)¼476 (85) [Mþ2H]þ, 430 (16), 384 (100). IR (film):
4.13. Ethyl 4-tert-butyl-4-phenyl-1-triisopropylsilyl-
1,4-dihydropyridine-3-carboxylate 8d and ethyl 2-tert-
butyl-4-phenyl-1-triisopropylsilyl-1,6-dihydropyridine-
3-carboxylate 9d
Procedure A: According to GP2 from 6 (50.0 mg, 0.220 mmol), 2
n
¼3085 cmꢀ1, 3059, 3027, 2947, 2893, 2867, 1696, 1661, 1575, 1463,
(74.2 mg, 66.6
mL, 0.240 mmol) in CH2Cl2 (5 mL) and t-Bu2Mg (0.4 M
1279, 1235. Anal. Calcd for C30H41NO2Si (474.75): C 75.74, H 8.69, N
2.94. Found: C 75.47, H 8.74, N 2.84.
in Et2O, 61.0 mg, 0.440 mmol,1.1 mL). Work up was performed with
phosphate buffer (10 mL) and triple extraction with CH2Cl2 (25 mL
each). Purification by flash chromatography on SiO2 (n-pentane/
Yield (9f): 7 mg (7%), colorless oil. TLC Rf¼0.19 (n-heptane/
Et2O¼50/50, SiO2). 1H NMR (CDCl3)
d
¼0.96 (t, J¼7.1 Hz, 3H,
EtOAc¼95/5) followed by preparative HPLC (Si 60, 5
m
m, heptane/
CH2CH3), 1.16 (d, J¼7.5 Hz, 9H, CH(CH3)2), 1.17 (d, J¼7.5 Hz, 9H,
CH(CH3)2), 1.39 (sept., J¼7.5 Hz, 3H, CH(CH3)2), 2.55 (dd, J¼12.2/
3.9 Hz, 1H, CH2), 3.16 (dd, J¼12.2/11.0 Hz, 1H, CH2), 3.88–4.11 (m,
3H, CH2CH3, NCH), 4.86 (d, J¼6.5 Hz, 1H, NCHCH), 7.13–7.18 (m, 2H,
Harom.), 7.20–7.28 (m, 6H, Harom.), 7.31–7.37 (m, 2H, Harom.), 7.75 (d,
EtOAc¼98/2, 20 mL/min, 8d: tR¼26.59 min, 9d: tR¼32.83 min).
Yield (8d) 54.6 mg (56%), colorless crystals, mp 95–96 ꢁC. TLC
Rf¼0.67 (n-heptane/EtOAc¼50/50, SiO2). HPLC (Si 60, heptane/
EtOAc¼95/5, 0.75 mL/min, tR¼6.42 min). 1H NMR (CDCl3)
¼0.88 (t,
d
J¼7.2 Hz, 3H, CH2CH3), 1.13 (d, J¼7.5 Hz, 18H, CH(CH3)2), 1.19 (s, 9H,
C(CH3)3), 1.36 (sept., J¼7.5 Hz, 3H, CH(CH3)2), 3.74–3.87 (m, 2H,
CH2CH3), 4.68 (d, J¼7.8 Hz, 1H, NCH]CH), 6.02 (dd, J¼7.8/1.2 Hz,
1H, NCH]CH), 7.05 (t, J¼7.4 Hz, 1H, Hpara), 7.21 (t, J¼7.4 Hz, 2H,
Hmeta), 7.55 (d, J¼1.2 Hz, 1H, NCH]C), 7.60 (d, J¼8.5 Hz, 2H, Hor-
J¼1.2 Hz, 1H, NCH]C) ppm. 13C NMR (CDCl3)
d¼11.6 (d, 3C,
CH(CH3)2), 14.0 (q, 1C, CH2CH3), 18.1 (q, 3C, CH(CH3)2), 18.2 (q, 3C,
CH(CH3)2), 39.8 (t, 1C, CH2), 54.8 (d, 1C, NCH), 59.0 (t, 1C, CH2CH3),
107.3 (s, 1C, NCH]C), 112.4 (d, 1C, NCHCH), 126.4 (d, 1C, Carom.),
126.5 (d, 1C, Carom.), 127.4 (d, 2C, Carom.), 127.7 (d, 2C, Carom.), 128.2
(d, 2C, Carom.), 130.0 (d, 2C, Carom.), 136.4 (s, 1C, Carom.), 137.7 (s, 1C,
Carom.), 141.7 (s, 1C, Carom.), 148.0 (d, 1C, NCH]C), 166.8 (s, 1C,
CO) ppm. MS (CI, CHþ5 ): m/z (%)¼476 (84) [Mþ2H]þ, 430 (20), 384
tho) ppm. 13C NMR (CDCl3)
d
¼11.3 (d, 3C, CH(CH3)2), 13.8 (q, 1C,
CH2CH3), 17.8 (q, 6C, CH(CH3)2), 27.4 (q, 3C, C(CH3)3), 40.6 (s, 1C,
C(CH3)3), 50.0 (s, 1C, CH]CHC), 58.8 (t, 1C, CH2CH3), 106.6 (s, 1C,
NCH]C), 112.9 (d, 1C, NCH]CH), 123.6 (d, 1C, NCH]CH), 124.2 (d,
1C, Cpara), 126.6 (d, 2C, Cmeta), 130.1 (d, 2C, Cortho), 141.4 (d, 1C,
NCH]C), 150.7 (s, 1C, Carom.), 169.5 (s, 1C, CO) ppm. MS (CI, CHþ5 ):
m/z (%)¼442 (100) [MþH]þ, 396 (11), 384 (81), 364 (12). IR (KBr):
(100). IR (film):
n
¼3081 cmꢀ1, 3059, 3027, 2948, 2894, 2868, 1693,
1614, 1600, 1539. HRMS (EI, 70 eV): Mþ calcd for C23H34NO2Si
(384.2359), found 384.2369.
Procedure B: According to procedure A with Bn2Mg (0.4 M in
Et2O, 90.9 mg, 0.440 mmol, 1.10 mL) instead of BnMgCl. Flash
chromatography on SiO2 provided 47 mg (45%) of 8f as colorless
crystals and 35 mg (24%) of 9f as a colorless oil.
n
¼3056 cmꢀ1, 3006, 2967, 2950, 2865, 1689, 1654, 1568. Anal. Calcd
for C27H43NO2Si (441.74): C 73.42, H 9.81, N 3.17. Found: C 73.44, H
9.67, N 3.15.
Yield (9d) 5 mg (5%, contaminated with 9% 8d), colorless oil. TLC
Rf¼0.67 (n-heptan/EtOAc¼50/50, SiO2). HPLC tR¼6.98 min (Si 60,
Procedure C: According to GP2 from 6 (25.0 mg, 0.110 mmol), 2
(33.7 mg, 30.3
mL, 0.110 mmol) in CH2Cl2 (3 mL) and BnMgCl (1.0 M
heptane/EtOAc¼95/5, 0.75 mL/min). 1H NMR (CDCl3)
d
¼0.89 (t,
in Et2O, 33.2 mg, 0.220 mmol, 220 mL), but in the presence of
J¼7.0 Hz, 3H, CH2CH3), 0.92 (s, 9H, C(CH3)3), 1.13 (d, J¼7.6 Hz, 9H,
CH(CH3)2), 1.15 (d, J¼7.6 Hz, 9H, CH(CH3)2), 1.34 (sept., J¼7.6 Hz, 3H,
CH(CH3)2), 3.66 (dd, J¼6.9/1.0 Hz, 1H, NCHCH), 3.82–4.00 (m, 2H,
CH2CH3), 5.07 (d, J¼6.9 Hz, 1H, NCHCH), 7.15–7.27 (m, 5H, Harom.),
7.73 (d, J¼1.0 Hz, 1H, NCH]C) ppm. MS (CI, CHþ5 ): m/z (%)¼442
(100) [MþH]þ, 396 (27), 384 (96). HRMS (ESIþ): MþþH calcd for
C27H44NO2Si (442.3141), found 442.3128.
CuBr$Me2S (3.40 mg, 0.017 mmol) before 2 was introduced. Work
up was provided with phosphate buffer (3 mL) and triple extraction
with CH2Cl2 (15 mL each). Flash chromatography on SiO2 provided
21 mg (41%) of 8f as colorless crystals.
Procedure D: According to procedure C with Bn2Mg (0.4 M in
Et2O, 45.4 mg, 0.220 mmol, 550 mL) instead of BnMgCl. Flash
chromatography on SiO2 provided 14.5 mg (28%) of 8f as colorless
Procedure B: According to procedure A with t-BuMgCl (1.7 M in
crystals.
Et2O, 51.4 mg, 0.440 mmol, 259
mL) instead of t-Bu2Mg. Flash chro-
Procedure E: According to procedure C with Me2S (1.6 mL,
matographyonSiO2 provided45.4 mg(47%)of8dascolorlesscrystals.
0.022 mmol) instead of CuBr$Me2S. Flash chromatography on SiO2
provided 20.7 mg (40%) of 8f as colorless crystals.
4.14. Ethyl 4-benzyl-4-phenyl-1-triisopropylsilyl-
1,4-dihydropyridine-3-carboxylate 8f and ethyl
6-benzyl-4-phenyl-1-triisopropylsilyl-1,6-dihydropyridine-
3-carboxylate 9f
Procedure F: According to procedure C with CuCN (1.6 mg,
0.022 mmol) instead of CuBr$Me2S. Flash chromatography on SiO2
provided 38 mg (38%) of 8f as colorless crystals.
Procedure G: According to procedure C with TBAI (8.1 mg,
0.022 mmol) instead of CuBr$Me2S. Flash chromatography on SiO2
provided 40.2 mg (38%) of 8f as colorless crystals.
Procedure A: According to GP2 from 6 (50.0 mg, 0.220 mmol), 2
(67.4 mg, 60.5
in Et2O, 66.4 mg, 0.440 mmol, 440
m
L, 0.220 mmol) in CH2Cl2 (4 mL) and BnMgCl (1.0 M
Procedure H: According to procedure C with TBABr (7.1 mg,
0.022 mmol) instead of CuBr$Me2S. Flash chromatography on SiO2
provided 41 mg (39%) of 8f as colorless crystals.
Procedure I: According to procedure C with TBACl (0.5 M in
CH2Cl2, 6.1 mg, 0.022 mmol, 44.0 mL) instead of CuBr$Me2S. Flash
mL). Work up was performed
with phosphate buffer (5 mL) and triple extraction with CH2Cl2
(20 mL each). Purification by flash chromatography on SiO2 (n-
pentane/EtOAc¼94/6) whereas regioisomer 8f eluated first.
Yield (8f) 40 mg (38%), colorless crystals, mp 129–130 ꢁC. TLC
chromatography on SiO2 provided 45.9 mg (44%) of 8f as colorless
crystals.
Rf¼0.25 (n-heptane/Et2O¼50/50, SiO2). 1H NMR (CDCl3)
¼0.91 (d,
d
J¼7.4 Hz, 9H, CH(CH3)2), 0.94 (d, J¼7.4 Hz, 9H, CH(CH3)2), 1.05
(t, J¼7.1 Hz, 3H, CH2CH3), 1.08–1.20 (m, 3H, CH(CH3)2), 2.90 (d,
J¼13.0 Hz, 1H, CH2), 3.97 (d, J¼13.0 Hz, 1H, CH2), 3.90–4.08 (m, 2H,
CH2CH3), 4.50 (d, J¼7.9 Hz, 1H, NCH]CH), 5.79 (dd, J¼7.9/1.3 Hz,
Procedure I: BnMgCl (1.0 M in Et2O, 66.4 mg, 0.440 mmol,
440 mL) was added dropwise to a suspension of CuCN (19.7 mg,
0.220 mmol) in THF (1.5 mL) at ꢀ78 ꢁC. After stirring for 30 min
at ꢀ78 ꢁC and 10 min at rt the cyanocuprate solution was used

5832
C.A. Sperger, K.T. Wanner / Tetrahedron 65 (2009) 5824–5833
according to GP2 with 6 (40.0 mg, 0.176 mmol) and 2 (53.9 mg,
48.4 L, 0.176 mmol) in CH2Cl2 (2.5 mL). Flash chromatography on
SiO2 provided 26.0 mg (31%) of 8f as colorless crystals and 21.1 mg
(25%) of 9f as a colorless oil.
Yield 405 mg (91%), colorless crystals, mp 96–101 ꢁC. TLC
m
Rf¼0.18 (n-heptane/Et2O¼50/50, Al2O3). 1H NMR (CDCl3)
¼0.84 (d,
d
J¼6.7 Hz, 3H, CH(CH3)2), 1.03 (d, J¼6.7 Hz, 3H, CH(CH3)2), 1.10 (t,
J¼7.1 Hz, 3H, CH2CH3), 3.35 (sept., J¼6.7 Hz, 1H, CH(CH3)2), 3.84–
4.02 (m, 2H, CH2CH3), 4.53 (dd, J¼8.1/1.3 Hz, 1H, NCH]CH), 5.64 (s,
1H, NH), 6.26 (ddd, J¼8.1/4.4/1.3 Hz, 1H, NCH]CH), 7.09–7.14 (m,
1H, Hpara), 7.25–7.31 (m, 3H, 2Hmeta, NCH]C), 7.54–7.59 (m, 2H,
4.15. Ethyl 4,4-diphenyl-1-triisopropylsilyl-1,4-
dihydropyridine-3-carboxylate 8g
Hortho) ppm. 13C NMR (CDCl3)
d
¼14.2 (q, 1C, CH(CH3)2), 16.0 (q, 1C,
Procedure A: According to GP2 from 6 (30.0 mg, 0.132 mmol), 2
CH(CH3)2), 20.5 (q, 1C, CH2CH3), 30.2 (d, 1C, CH(CH3)2), 47.9 (s, 1C,
CH]CHC), 59.1 (t, 1C, CH2CH3), 105.8 (s, 1C, NCH]C), 105.9 (d, 1C,
NCH]CH), 122.9 (d, 1C, NCH]CH), 125.1 (d, 1C, Cpara), 127.0 (d, 2C,
Cmeta), 129.7 (d, 2C, Cortho), 135.5 (d, 1C, NCH]C), 149.1 (s, 1C, Carom.),
167.7 (s, 1C, CO) ppm. MS (ESIþ): m/z (%)¼270 (26) (Mþ), 228 (83),
(40.1 mg, 35.9
mL, 0.132 mmol) in CH2Cl2 (4 mL) and PhMgBr
(2.97 M in Et2O, 54.2 mg, 0.397 mmol, 223
m
L). Work up was per-
formed with phosphate buffer (5 mL) and triple extraction with
CH2Cl2 (20 mL each). Purification by flash chromatography on SiO2
(n-pentane/EtOAc¼95/5).
200 (100). IR (film):
1662, 1597, 1477, 1366, 1280, 1223, 1147. Anal. Calcd for C17H21NO2
(271.36): C 75.25, H 7.80, N 5.16. Found: C 75.31, H 7.86, N 5.23.
n
¼3415 cmꢀ1, 3388, 3058, 2969, 2872, 1672,
Yield 4.3 mg (7%), colorless crystals, mp 124–126 ꢁC. TLC Rf¼0.38
(n-heptane/Et2O¼50/50, SiO2). 1H NMR (CDCl3)
¼0.91 (t, J¼7.2 Hz,
d
3H, CH2CH3), 1.03 (d, J¼7.7 Hz, 9H, CH(CH3)2), 1.15 (d, J¼7.7 Hz, 9H,
CH(CH3)2), 1.33–1.44 (m, 3H, CH(CH3)2), 3.90–4.04 (m, 2H, CH2CH3),
5.26 (d, J¼6.6 Hz, 1H, NCH]CH), 5.83 (d, J¼1.1 Hz, 1H, NCH]C),
6.84 (dd, J¼6.6/1.1 Hz,1H, NCH]CH), 7.10–7.14 (m, 2H, Harom.), 7.18–
7.30 (m, 6H, Harom.), 7.48–7.52 (m, 2H, Harom.) ppm. 13C NMR (CDCl3)
4.18. Ethyl 4,4-diethyl-1,4-dihydropyridine-3-carboxylate 16
According to GP 3 from 14 (150 mg, 0.410 mmol) and LiOH
(19.6 mg, 0.820 mmol) in MeOH (3 mL) for 36 h. After removal of
the solvent the raw product was purified by flash chromatography
on SiO2 (isohexane/EtOAc¼85/15).
d
¼11.7 (d, 3C, CH(CH3)2), 13.8 (q, 1C, CH2CH3), 17.9 (q, 3C, CH(CH3)2),
18.0 (q, 3C, CH(CH3)2), 54.8 (d, 1C, NCH]CHC), 59.6 (t, 1C, CH2CH3),
106.1 (s, 1C, NCH]C), 107.5 (d, 1C, NCH]CH), 126.2 (d, Carom.), 126.7
(d, Carom.), 127.0 (d, Carom.), 127.4 (d, Carom.), 127.7 (d, Carom.), 127.8 (d,
Carom.), 141.7 (d, 1C, NCH]C), 143.9 (s, 1C, Carom.), 147.4 (s, 1C, Carom.),
167.3 (s, 1C, CO) ppm. MS (CI, CHþ5 ): m/z (%)¼462 (100) [MþH]þ. IR
Yield 74 mg (86%), colorless crystals, mp 125–127 ꢁC. TLC
Rf¼0.48 (EtOAc, SiO2). 1H NMR (CDCl3)
d
¼0.81–0.96 (m, 6H,
CH2CH3), 1.22 (t, J¼7.2 Hz, 3H, OCH2CH3), 2.04–2.13 (m, 4H,
CH2CH3), 4.00 (dd, J¼8.1/1.5 Hz, 1H, NCH]CH), 4.08 (q, J¼7.2 Hz,
2H, OCH2CH3), 5.31 (s, 1H, NH), 6.05 (ddd; J¼8.1/4.2/1.3 Hz, 1H,
NCH]CH), 7.36 (dd, J¼5.7/1.3 Hz, 1H, NCH]C) ppm. 13C NMR
(film):
n
¼3053 cmꢀ1, 3025, 2947, 2890, 2868, 1706, 16.73, 1510,
1257, 1226. Anal. Calcd for C29H39NO2Si (461.73): C 75.44, H 8.51, N
3.03. Found: C 75.11, H 8.50, N 3.00.
(CDCl3)
d
¼10.6 (q, 2C, CH2CH3), 14.4 (q, 1C, COOCH2CH3), 34.4 (t, 2C,
Procedure B: According to procedure A with Ph2Mg (0.31 M in
Et2O, 47.1 mg, 0.264 mmol, 850 mL) instead of PhMgBr. Flash chro-
matography provided 28 mg (46%) of 8g as colorless crystals.
CH2CH3), 42.4 (s,1C, CH]CHC), 59.0 (t,1C, COOCH2CH3),101.1 (s,1C,
NCH]C), 111.7 (d, 1C, NCH]CH), 123.6 (d, 1C, NCH]CH), 138.9 (d,
1C, NCH]C), 168.3 (s, 1C, CO) ppm. MS (CI, CHþ5 ): m/z (%)¼272 (51),
242 (50), 226 (48), 210 (100) [MþH]þ,196 (45), 180 (48), 108 (57). IR
4.16. Ethyl 4,4-diethyl-1-triisopropylsilyl-1,4-
dihydropyridine-3-carboxylate 14
(KBr):
n
¼3340 cmꢀ1, 3103, 2994, 2962, 2930, 2870,1676,1649,1597,
1506, 1291. Anal. Calcd for C12H19NO2 (209.28): C 68.87, H 9.15, N
6.69. Found: C 68.87, H 9.05, N 6.58.
According to GP2 from ethyl 4-ethylpyridin-3-carboxylate12
(100 mg, 0.558 mmol), 2 (172.7 mg, 154 mL, 0.558 mmol) in CH2Cl2
(8 mL) and Et2Mg (0.4 M in Et2O, 92.3 mg, 1.12 mmol, 2.79 mL).
Work up was performed with phosphate buffer (15 mL) and triple
extraction with CH2Cl2 (40 mL each). Purification by flash chro-
matography on SiO2 (isohexane/EtOAc¼95/5) provided 14, which
was contaminated with 3% of the C-6 substituted regioisomer.
Yield 149 mg (73%), yellow oil. TLC Rf¼0.53 (n-heptane/
4.19. Ethyl 4-isopropyl-1-methyl-4-phenyl-1,4-
dihydropyridine-3-carboxylate 17
According to GP4 from 15 (100 mg, 0.369 mmol) in DMF (3 mL),
NaH (17.7 mg, 0.737 mmol) in DMF (3 mL) and MeI (78.5 mg,
0.553 mmol, 34.6 mL). Work up was performed after 2.5 h by ad-
EtOAc¼50/50, SiO2). 1H NMR (CDCl3)
d¼0.79–0.85 (m, 6H, CH2CH3),
dition of water (15 mL) and extraction with CH2Cl2 (3ꢂ30 mL). The
combined organic layers were washed with a saturated NaCl so-
lution (20 mL) and dried over MgSO4. The raw product was purified
by flash chromatography on SiO2 (isohexane/EtOAc¼80/20).
Yield 95 mg (90%), colorless crystals, mp 103–106 ꢁC. TLC
1.07 (d, J¼7.5 Hz, 18H, CH(CH3)2), 1.20–1.33 (m, 6H, CH(CH3)2,
COOCH2CH3), 2.01–2.12 (m, 4H, CH2CH3), 4.06 (d, J¼8.0 Hz, 1H,
NCH]CH), 4.08 (q, J¼7.1 Hz, 2H, COOCH2CH3), 6.02 (dd, J¼8.0/
1.3 Hz, 1H, NCH]CH), 7.43 (d, J¼1.3 Hz, 1H, NCH]C) ppm. 13C NMR
(CDCl3)
d
¼10.6 (q, 2C, CH2CH3), 11.3 (d, 3C, CH(CH3)2), 14.3 (q, 1C,
Rf¼0.52 (n-heptane/Et2O¼50/50, Al2O3). 1H NMR (CDCl3)
¼0.82 (d,
d
COOCH2CH3), 17.7 (q, 6C, CH(CH3)2), 34.2 (t, 2C, CH2CH3), 41.6 (s, 1C,
CH]CHC), 58.9 (t, 1C, COOCH2CH3), 102.9 (s, 1C, NCH]C), 113.3 (d,
1C, NCH]CH), 127.3 (d, 1C, NCH]CH), 143.5 (d, 1C, NCH]C), 168.7
(s, 1C, CO) ppm. MS (CI, CHþ5 ): m/z (%)¼366 (100) [MþH]þ, 336 (30),
J¼6.8 Hz, 3H, CH(CH3)2), 1.00 (d, J¼6.8 Hz, 3H, CH(CH3)2), 1.10 (t,
J¼7.1 Hz, 3H, CH2CH3), 3.07 (s, 3H, NCH3), 3.34 (sept., J¼6.8 Hz, 1H,
CH(CH3)2), 3.86–4.00 (m, 2H, CH2CH3), 4.55 (d, J¼8.1 Hz, 1H,
NCH]CH), 6.05 (dd, J¼8.1/1.8 Hz, 1H, NCH]CH), 7.08–7.13 (m, 1H,
Hpara), 7.12 (d, J¼1.8 Hz, 1H, NCH]C), 7.25–7.30 (m, 2H, Hmeta), 7.55
320 (20). IR (KBr):
n
¼2959 cmꢀ1, 2869,1696,1664,1586,1462,1264.
HRMS (EI, 70 eV): Mþ calcd for C19H34NO2Si (348.2723), found
348.2734.
(dd, J¼8.5/1.1 Hz, 2H, Hortho) ppm. 13C NMR (CDCl3)
¼14.2 (q, 1C,
d
CH2CH3), 16.0 (q, 1C, CH(CH3)2), 20.6 (q, 1C, CH(CH3)2), 29.9 (d, 1C,
CH(CH3)2), 40.8 (q, 1C, NCH3), 47.4 (s, 1C, CH]CHC), 59.0 (t, 1C,
CH2CH3), 104.7 (s, 1C, NCH]C), 107.0 (d, 1C, NCH]CH), 125.0 (d, 1C,
Cpara), 126.9 (d, 2C, Cmeta), 127.9 (d, 1C, NCH]CH), 129.6 (d, 2C,
Cortho), 140.1 (d, 1C, NCH]C), 149.0 (s, 1C, Carom.), 167.7 (s, 1C,
CO) ppm. MS (CI, CHþ5 ): m/z (%)¼286 (92) [MþH]þ, 242 (100), 240
4.17. Ethyl 4-isopropyl-4-phenyl-1,4-dihydropyridine-
3-carboxylate 15
According to GP 3 from 8c (700 mg, 1.64 mmol) and LiOH
(71.0 mg, 2.96 mmol) in MeOH (18 mL) for 28 h. After removal of
the solvent the raw product was purified by flash chromatography
on SiO2 (isohexane/EtOAc¼80/20).
(28), 208 (40). IR (film):
1686, 1584, 1397, 1291, 1193. Anal. Calcd for C18H23NO2 (285.39): C
75.76, H 8.12, N 4.91. Found: C 75.80, H 8.29, N 4.78.
n
¼3078 cmꢀ1, 3054, 2964, 2930, 2865,

C.A. Sperger, K.T. Wanner / Tetrahedron 65 (2009) 5824–5833
5833
4.20. Ethyl 1-benzyl-4-isopropyl-4-phenyl-1,4-
dihydropyridine-3-carboxylate 18
n
¼3081 cmꢀ1, 3060, 2967, 2936, 2900, 2865, 1685, 1585, 1574, 1418,
1297, 1283. Anal. Calcd for C20H25NO2 (311.43): C 77.14, H 8.09, N
4.50. Found: C 77.05, H 8.07, N 4.44.
According to GP4 from 15 (100 mg, 0.369 mmol) in DMF (2 mL),
NaH (17.7 mg, 0.737 mmol) in DMF (3 mL) and benzyl bromide
(65.8 mL, 94.6 mg, 0.553 mmol). Work up was performed after 3.5 h
4.22. Ethyl 1-acetyl-4,4-diethyl-1,4-dihydropyridine-
3-carboxylate 20
by addition of water (10 mL) and extraction with CH2Cl2 (3ꢂ30 mL).
The combined organic layers were washed with a saturated NaCl
solution (20 mL) and dried over MgSO4. The raw product was pu-
rified by flash chromatography on SiO2 (isohexane/EtOAc¼90/10).
Yield 113 mg (85%), yellow crystals, mp 64–67 ꢁC. TLC Rf¼0.34
A solution of 14 (100 mg, 0.273 mmol) and AcCl (58.3 mL, 64.4 mg,
0.820 mmol) in CH2Cl2 (4 mL) was heated to 65 ꢁC under microwave
conditions. After 9 h, the colorless solution was quenched by addi-
tion of phosphate puffer (15 mL). The aqueous layer was extracted
three times with EtOAc (25 mL each). The combined organic layers
were washed with a saturated NaCl solution (25 mL), dried (MgSO4),
and concentrated in vacuo. Compound 20 was purified by flash
chromatography on SiO2 (isohexane/EtOAc¼90/10).
(n-heptan/Et2O¼50/50, SiO2). 1H NMR (CDCl3)
¼0.82 (d, J¼6.6 Hz,
d
3H, CH(CH3)2), 1.03 (d, J¼6.6 Hz, 3H, CH(CH3)2), 1.09 (t, J¼7.2 Hz, 3H,
CH2CH3), 3.36 (sept., J¼6.6 Hz, 1H, CH(CH3)2), 3.86–4.00 (m, 2H,
CH2CH3), 4.44 (s, 2H, CH2), 4.58 (d, J¼8.2 Hz, 1H, NCH]CH), 6.09
(dd, J¼8.2/1.6 Hz, 1H, NCH]CH), 7.11 (t, J¼7.4 Hz, 1H, Hpara), 7.24–
7.41 (m, 8H, NCH]C, Harom.), 7.53–7.57 (m, 2H, Harom.) ppm. 13C
Yield 51.0 mg (74%), colorless oil. TLC Rf¼0.31 (n-heptan/
1
EtOAc¼50/50, SiO2). H NMR (tetrachlorethane, 100 ꢁC)
d¼0.82 (t,
NMR (CDCl3)
d
¼14.2 (q, 1C, CH2CH3), 16.0 (q, 1C, CH(CH3)2), 20.6 (q,
J¼7.4 Hz, 6H, CH2CH3), 1.16–1.28 (m, 2H, CH2CH3), 1.32 (t, J¼6.9 Hz,
3H, COOCH2CH3), 2.07–2.17 (m, 2H, CH2CH3), 2.29 (s, 3H, COCH3),
4.23 (q, J¼6.9 Hz, 3H, COOCH2CH3), 4.58 (d, J¼8.3 Hz,1H, NCH]CH),
6.99 (br s, 1H, NCH]CH), 8.06 (br s, 1H, NCH]C) ppm. 13C NMR
1C, CH(CH3)2), 30.0 (d, 1C, CH(CH3)2), 47.7 (s, 1C, CH]CHC), 57.5 (t,
1C, CH2), 59.1 (t, 1C, CH2CH3), 105.3 (s, 1C, NCH]C), 107.5 (d, 1C,
NCH]CH), 125.1 (d, 1C, Carom.), 126.9 (d, 2C, Carom.), 127.0 (d, 2C,
Carom.), 127.1 (d, 1C, NCH]CH), 127.8 (d, 1C, Carom.), 128.8 (d, 2C,
Carom.),129.7 (d, 2C, Carom.),137.3 (s,1C, Carom.),139.8 (d,1C, NCH]C),
148.8 (s, 1C, Carom.), 167.6 (s, 1C, CO) ppm. MS (CI, CHþ5 ): m/z (%)¼362
(tetrachlorethane, 100 ꢁC)
d¼9.6 (q, 2C, CH2CH3), 14.1 (q, 1C,
COOCH2CH3), 20.9 (q, 1C, COCH3), 33.1 (t, 2C, CH2CH3), 42.8 (s, 1C,
CHC), 59.9 (t, 1C, COOCH2CH3), 112.7 (s, 1C, NCH]C), 117.5 (d, 1C,
NCH]CH),121.3 (d,1C, NCH]CH),133.4 (d,1C, NCH]C),166.2 (s,1C,
CO),166.3 (s,1C, CO) ppm. MS (CI, CHþ5 ): m/z (%)¼252 (100) [MþH]þ,
(100) [MþH]þ, 318 (39), 284 (8). IR (film):
n
¼3086 cmꢀ1, 3062,
3029, 2968, 2935, 2871, 1693, 1582, 1574, 1454, 1445, 1415, 1365,
1287. Anal. Calcd for C24H27NO2 (361.49): C 79.74, H 7.53, N 3.87.
Found: C 79.62, H 7.55, N 3.81.
222 (36), 180 (33). IR (KBr):
n
¼3115 cmꢀ1, 2964, 2932, 2874, 1698,
1673, 1609, 1459, 1374, 1320, 1228. Anal. Calcd for C14H21NO3
(251.33.28): C 66.91, H 8.42, N 5.57. Found: C 66.72, H 8.66, N 5.62.
4.21. Ethyl 1-allyl-4-isopropyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylate 19
References and notes
1. Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1–82.
According to GP4 from 15 (50.0 mg, 0.184 mmol) in DMF (1 mL),
2. (a) Lemire, A.; Grenon, M.; Pourashraf, M.; Charrette, A. Org. Lett. 2004, 6, 3517–
3520; (b) Hoesl, C. E.; Maurus, M.; Pabel, J.; Polborn, K.; Wanner, K. T. Tetra-
hedron 2002, 58, 6757–6770; (c) Comins, D. L.; Killpack, M. O.; Despagnet, E.;
Zeller, E. Heterocycles 2002, 58, 505–519; (d) Rudler, H.; Denise, B.; Xu, Y.;
Parlier, A.; Vaissermann, J. J. Org. Chem. 2005, 17, 3724–3744; (e) Shing, T. L.;
Chia, W. L.; Shiao, M. J.; Chau, T. Y. Synthesis 1991, 10, 849–850; (f) Shiao, M. J.;
Chia, W. L.; Shing, T. L.; Chow, T. J. J. Chem. Res., Synop. 1992, 247; (g) Yamaguchi,
R.; Nakazano, Y.; Matsuki, T.; Hata, E. I.; Kawanishi, M. Bull. Chem. Soc. Jpn. 1987,
60, 215–222; (h) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1984, 25, 3297–
3300; (i) Piers, E.; Soucy, M. Can. J. Chem. 1974, 52, 3563–3564; (j) Shiao, M. J.;
Chia, W. L.; Peng, C. J.; Shen, C. C. J. Org. Chem. 1993, 58, 3162–3164; (k) Ya-
maguchi, R.; Nakazano, Y.; Kawanishi, M. Tetrahedron Lett. 1983, 24, 1801–1804.
3. Wallace, D. J.; Gibb, A. D.; Cottrell, I. F.; Kennedy, D. J.; Brands, K. M. J.; Dolling,
U. H. Synthesis 2001, 12, 1784–1789.
4. Wang, X.; Kauppi, A. M.; Olsson, R.; Almqvist, F. Eur. J. Org. Chem. 2003, 23,
4586–4592.
5. Kukla, M. J.; Breslin, H. J.; Gill, A. J. Med. Chem. 1990, 33, 223–228.
6. Goldmann, S. Angew. Chem. 1981, 93, 798–799.
7. (a) Clayden, J.; Hamilton, S. D.; Rukhsana, T. M. Org. Lett. 2005, 7, 3673–3676; (b)
Arnott, G.; Clayden, J.; Hamilton, S. D. Org. Lett. 2006, 8, 5325–5328.
8. Arnott, G.; Brice, H.; Clayden, J.; Blaney, E. Org. Lett. 2008, 10, 3089–3092.
9. Yamaguchi, R.; Moriyasu, M.; Kawanisi, M. Tetrahedron Lett. 1986, 27, 211–214.
10. Bra¨ckow, J.; Wanner, K. T. Tetrahedron 2006, 62, 2395–2404.
NaH (8.80 mg, 0.369 mmol) in DMF (1 mL) and allyl bromide
(24.0 mL, 33.4 mg, 0.276 mmol). Work up was performed after 2.5 h
by addition of water (15 mL) and extraction with CH2Cl2 (3ꢂ30 mL).
The combined organic layers were washed with a saturated NaCl
solution (20 mL) and dried over MgSO4. The raw product was pu-
rified by flash chromatography on SiO2 (isohexane/EtOAc¼90/10).
Yield 48 mg (83%), colorless crystals, mp 76–77 ꢁC. TLC Rf¼0.43
(n-heptane/Et2O¼50/50, SiO2). 1H NMR (CDCl3)
¼0.83 (d, J¼6.6 Hz,
d
3H, CH(CH3)2), 1.01 (d, J¼6.6 Hz, 3H, CH(CH3)2), 1.09 (t, J¼7.1 Hz, 3H,
COOCH2CH3), 3.35 (sept., J¼6.6 Hz, 1H, CH(CH3)2), 3.85 (dt, J¼5.1/
1.6 Hz, 2H, NCH2), 3.87–4.01 (m, 2H, CH2CH3), 4.58 (d, J¼8.2 Hz, 1H,
NCH]CH), 5.23–5.32 (m, 2H, NCH2CH]CH2), 5.80–5.91 (m, 1H,
NCH2CH]CH2), 6.08 (dd, J¼8.2/1.8 Hz, 1H, NCH]CH), 7.11 (tt,
J¼7.4/1.2 Hz,1H, Hpara), 7.15 (d, J¼1.8 Hz,1H, NCH]C), 7.25–7.31 (m,
2H, Hmeta), 7.53–7.57 (m, 2H, Hortho) ppm. 13C NMR (CDCl3)
d
¼14.2
(q, 1C, CH2CH3), 16.0 (q, 1C, CH(CH3)2), 20.6 (q, 1C, CH(CH3)2), 30.1
(d, 1C, CH(CH3)2), 47.7 (s, 1C, CH]CHC), 56.2 (t, 1C, NCH2), 59.0 (t,
1C, CH2CH3), 105.1 (s, 1C, NCH]C), 107.1 (d, 1C, NCH]CH), 117.7 (t,
1C, NCH2CH]CH2), 125.1 (d, 1C, Cpara), 127.0 (d, 2C, Cmeta), 127.1 (d,
1C, NCH]CH), 129.7 (d, 2C, Cortho), 133.6 (d, 1C, NCH2CH]CH2),
139.5 (d, 1C, NCH]C), 149.0 (s, 1C, Carom.), 167.7 (s, 1C, CO) ppm. MS
(CI, CHþ5 ): m/z (%)¼312 (62) [MþH]þ, 268 (100), 234 (21). IR (film):
´
11. Masdeu, C.; Diaz, J. L.; Miguel, M.; Jimenez, O.; Lavilla, R. Tetrahedron Lett. 2004,
45, 7907–7909.
12. (a) Chastrette, M.; Amououx, R.; Subit, M. J. Organomet. Chem. 1974, 78, 303–
311; (b) Richey, H. G.; DeStephano, J. P. J. Org. Chem. 1990, 55, 3281–3286; (c)
Pajerski, A. D.; Chubb, J. E.; Fabicon, R. M.; Richey, H. G. J. Org. Chem. 2000, 65,
2231–2235.