Direct synthesis of 4,4-disubstituted N-silyl-1,4-dihydropyridines

Article abstract of DOI:10.1016/j.tet.2005.11.069

An unprecedented method for the preparation of 4,4-disubstituted 1,4-dihydropyridines is presented. It is based on the trapping reaction of 4-substitued N-silylpyridinium ions. When performed with dialkylmagnesium reagents, such as iPr₂Mg, silyl protected 4,4-disubstituted 1,4-dihydropyridines were obtained in up to quantitative yields. High 1,4-selectivity was found for sterically demanding nucleophiles, whereas small nucleophiles (Me₂Mg) tend to yield 1,2-addition-products. Grignard, dialkylzinc and organocopper reagents were found to give either no addition products or less favorable results. Reduction of the obtained 1,4-dihydropyridine with NaCNBH₃ in the presence of HCl, followed by treatment with tert-butyl dicarbonate provided the corresponding N-Boc protected piperidines with high yields.

Full text of DOI:10.1016/j.tet.2005.11.069

Tetrahedron 62 (2006) 2395–2404
Direct synthesis of 4,4-disubstituted N-silyl-1,4-dihydropyridines
*
¨
Jan Brackow and Klaus T. Wanner
¨ ¨ ¨
Department Pharmazie-Zentrum fur Pharmaforschung, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 7,
¨
Haus C, D-81377 Munchen, Germany
Received 13 September 2005; revised 25 November 2005; accepted 28 November 2005
Available online 20 December 2005
Abstract—An unprecedented method for the preparation of 4,4-disubstituted 1,4-dihydropyridines is presented. It is based on the trapping
reaction of 4-substitued N-silylpyridinium ions. When performed with dialkylmagnesium reagents, such as iPr2Mg, silyl protected 4,4-
disubstituted 1,4-dihydropyridines were obtained in up to quantitative yields. High 1,4-selectivity was found for sterically demanding
nucleophiles, whereas small nucleophiles (Me2Mg) tend to yield 1,2-addition-products. Grignard, dialkylzinc and organocopper reagents
were found to give either no addition products or less favorable results. Reduction of the obtained 1,4-dihydropyridine with NaCNBH3 in the
presence of HCl, followed by treatment with tert-butyl dicarbonate provided the corresponding N-Boc protected piperidines with high yields.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the 1,4-regioselectivity of related reactions of N-silyl-
quinolinium10 ions is poor, though it may be improved by
increasing the bulk of the N-silyl moiety. It is well
documented that the regioselectivity of addition reactions
to N-acylpyridinium ions is strongly influenced by the
substituents present on the pyridine ring: for example, when
a substituent is present in the 4-position, nucleophiles
almost exclusively add to the 2- and 6-position of the ring
system.11 However, corresponding data for N-silyl-
pyridinium ions are still missing. So far, even the question
whether 4-substituted N-silylpyridinium ions are susceptible
to nucleophilic addition reactions at all has not been
examined, although such trapping reactions might be
synthetically quite useful. Actually, one would expect that
the presence of a sterically demanding N-silyl group would
shield the 2- and 6-position and thus force a nucleophile to
add to the 4-position of the N-silylpyridinium ion even if a
substituent is already present in this position. As a result 4,4-
disubstituted N-silyl-1,4-dihydopyridines and finally, after
desilylation, the parent compounds should be formed. So
far, only a few scattered examples for the direct preparation
of 4,4-disubstituted 1,4-dihydropyridines from activated
pyridine derivatives are known. These are limited to
N-alkyl- and N-acylpyridinium salts possessing an ester
function in the 4-position, which when treated with alkyl or
acyl halides and zinc give the 4,4-disubstituted products
presumably by a radical process.12 In addition to these
examples 4-addition to 4-substituted pyridine derivatives
has only been observed for intramolecular processes leading
to spirocyclic compounds.13 But usually multistep syntheses
are required for the construction of 4,4-disubstituted
1,4-dihydropyridines.14 We therefore thought it would be
1,4-Dihydropyridines (DHP) constitute important classes of
compounds, with many derivatives being found especially
among natural products and bioactive agents.1 Regioselec-
tive addition of nucleophilic reagents to N-acylpyridinium
ions is a common method in the preparation of 1,2- and
1,4-dihydropyridines. When Grignard2 or organotin3
reagents are used mainly 2-substituted 1,2-dihydropyridines
are formed. In contrast, the use of organotitanium4 reagents
and lithium–dialkylcuprates5 leads almost exclusively to the
formation of 4-substituted 1,4-dihydropyridines, which is
also the case when Grignard and organozinc reagents
admixed with copper(I) salts are employed.6 The regio-
selectivity of the nucleophilic attack on the pyridinium
cation is believed to follow the HSAB principle. According
to this principle relatively hard nucleophiles are predicted to
display a preference for the addition to the 2-position of the
pyridine ring and relatively soft nucleophiles for the
4-position.7 Whereas N-ayclpyridinium ions are widely
used for nucleophilic addition reactions, related examples
with N-silylpyridinium ions are scarce. According to the
work of Akiba et al.8 with N-silylpyridinium ions derived
from pyridine, these intermediates are susceptible to
nucleophilic addition reactions of Grignard reagents leading
to 1,4-addition products with high regioselectivity. Similar
results were found, for N-silylpyridinium ions derived
methyl nicotinate.9 Compared to N-silylpyridinium ions
Keywords: Dihydropyridines (DHP); Piperidines; Pyridinium salts;
Dialkylmagnesium reagents.
Corresponding author. Tel.: C49 89 218077249; fax: C49 89
218077247; e-mail: klaus.wanner@cup.uni-muenchen.de
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.069

¨
J. Brackow, K. T. Wanner / Tetrahedron 62 (2006) 2395–2404
2396
a highly rewarding endeavor to establish a method for the
direct synthesis of 4,4-disubstituted 1,4-dihydropyridines
from N-silylpyridinium ions. In the present paper, we report
the successful implementation of this plan.
When nBuMgCl (2.9 M in Et2O) was used as a nucleophile,
the corresponding 4-addition product 4b was isolated in
34% (Table 1, entry 4). Interestingly, the reaction failed
when Et2O as solvent for the Grignard reagent (nBuMgCl)
was replaced by THF. With BnMgCl, using again Et2O as
solvent (1.0 M) the reaction even came to completion and
gave the 1,4-addition product 4c in high yield (90%) and
with good regioselectivity (Table 1, entry 7). Various other
organometallic compounds as well as the pyridine deriva-
tive 1b were checked for their suitability in this reaction.
However, all of these reactions failed except for the ones
employing higher order cuprates for which at least small
amounts of the 1,4-addition products could be isolated or
observed by 1H NMR (Table 1, entries 10 and 11).
2. Results and discussion
Initial experiments were performed with pyridine 1a
(Table 1) and triisopropylsilyl triflate (TIPS triflate 2a) as
activating agent. The 4-phenyl group present in 1a was
chosen because of its inertness towards basic conditions and
the TIPS group as it should efficiently shield the 2- and
6-position of the pyridine ring (Scheme 1). We were very
pleased to find that upon treatment of 1a with one equivalent
of TIPS triflate at room temperature followed by 2 equiv of
EtMgCl (2.0 M in Et2O) at K78 8C the 4,4-disubstituted
dihydropyridine 4a was formed. Under optimized con-
ditions the yield of 4a amounted to 28%. Interestingly, 4a
was sufficiently stable for isolation, in contrast to the 1,2-
addition product, which probably had already been oxidized
during the quench reaction to give the aromatic species 5a.
But according to the 1H NMR of the crude product only 1%
of the latter was formed. Thus, the addition reaction had
proceeded with a high regioselectivity in favor of the
1,4-addition. But unfortunately, even under optimized
conditions 64% of the starting material 1a were still present
We speculated that the failure and the low yields observed
for some of the trapping reactions of 3 using Grignard
reagents were caused by the halide ions that had been
introduced with the organometallic species. Due to their
higher nucleophilicity compared to the triflate ion, the
halide ion should shift the equilibrium between the
N-silylpyridinium ion 3 and the free pyridine 1 towards
the latter. This might hamper or even prevent trapping
reactions of 3 especially when they are slow. To shed some
light on this question we performed additional trapping
reactions of 3 with ethyl and n-butyl Grignard reagents
exhibiting bromide and iodide instead of chloride as counter
ion. With EtMgBr the yield of 4a improved to 44% (Table 1,
entry 2) as compared to the addition reaction of EtMgCl
1
in the crude product (according to H NMR).
Table 1. Addition of various organometallic compounds to N-triisopropylsilylpyridinium ions
1) TIPS-OTf (2a)
CH2Cl2 , rt.
N
R1
2) R2M, -78 ˚C to -50 ˚C.
3) phosphate buffer
pH 7.0, 1.0 M
1a R1 = Ph
1b R1 = Bn
R1
N
R1
+
iPr3Si
N
R2
R2
4
5
Entry
Start. mat.
R2Ma
Product
Yield
4 (%)b
Product ratio
4/5/1 (%)c
1
2
3
4
5
6
7
8
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1b R1ZBn
1b R1ZBn
EtMgCl
EtMgBr
EtMgI
4a 5a
4a 5a
4a 5a
4b 5b
4b 5b
4b 5b
4c 5c
4d 5d
4e 5e
4b 5b
4e 5e
4a 5a
4b 5b
4i 5i
28
44
30
34
20
12
90
0
35/1/64
46/7/47
35/1/64
36/11/53
27/4/69
13/0/87
90/10/0
0/0/100
0/0/100
nde
nBuMgCld
nBuMgBr
nBuMgI
BnMgCl
PhMgBr
MeMgBr
9
0
11
10
11
12
13
14
15
nBu2CuCNLi2
Me2CuCNLi2
Et2Zn
nBuLi
EtMgBr
nBuMgCl
f
—
3/0/97
0
0
0
0
0/0/100
0/0/100
0/0/100
0/0/100
4k 5k
a In Et2O.
b Isolated yield.
1
c According to H NMR of the crude reaction product.
d With nBuMgCl in THF no reaction occurred.
e Not determined.
f
Not isolated.

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J. Brackow, K. T. Wanner / Tetrahedron 62 (2006) 2395–2404
2397
R2M
R1
When Et2Mg (Table 2, entry 1) instead of ethyl Grignard
reagents (Table 1, entry 1–3) was used the yield of the
4-addition product 4a rose to 78%. Moreover, the
regioselectivity was quite satisfactory (90/4; Table 2,
entry 1). When using Bn2Mg the yield, which had already
been very high (Table 1, entry 7, 90%), remained more or
less unaffected, while the regioselectivity (Table 2, entry 3;
4c/5c 95/2) was significantly improved. Finally, employing
iPr2Mg the reaction proceeded with complete control of the
regioselectivity providing the 4-addition product in 91%
yield (Table 2, entry 6).
R
R3SiOTf (2)
R Si N+
R
N
R1
TfO–
1
3
R2
R1
R2M
R3Si
N
4
Scheme 1. Directing nucleophilic attack towards the 4-position of a
pyridine nucleus.
To uncover the impact of the N-silyl moiety on the outcome
of the addition reactions experiments employing trimethyl-
silyl triflate 2b and triphenylsilyl triflate 2c as activating
agents were performed. In case of trimethylsilyl triflate
mediated trapping reactions employing Et2Mg and Bn2Mg
as nucleophiles the results were far less satisfying both in
respect to yield and regioselectivity (see Table 3, entries
1–2). But for the addition of iPr2Mg regioselectivity and
yield were only slightly diminished (see Table 3, entry 3).
The most negative results had been yielded by the reaction
of Et2Mg. The addition products 4p and 5a were formed
only in minute amounts and, interestingly, the regio-
selectivity had been inverted. In addition, all N-trimethyl-
silyl derivatives 4p–4r were highly susceptible to hydrolysis
and thus barley isolable. The use of the bulkier triphenylsilyl
group gave some increased stability but for Et2Mg and
Bn2Mg the yields of the desired product were distinctly
(4a: 28%; Table 1, entry 1). However, using EtMgI a yield
similar to the one of the addition reaction of EtMgCl was
observed (30 vs 28%, compare Table 1, entries 3 and 1). In
case of the addition of a n-butyl residue, the yield became
distinctly lower when nBuMgBr instead of nBuMgCl was
used, and showed a further drop when nBuMgI was
employed (Table 1, entries 4–6). Although there was,
obviously, no clear correlation between the yield of 4a and
the nucleophilicity of the counter ion of the Grignard
reagent that could have supported our assumption, we
thought it worth employing dialkylmagnesium derivatives
as nucleophilic trapping reagents. The required magnesium
compounds were prepared from Grignard reagents by
precipitation of MgX2.
Table 2. Addition of various dialkylmagnesium reagents to N-triisopropylsilylpyridinium ions
1) TIPS-OTf (2a)
CH2Cl2, rt.
N
R1
2) (R2)2Mg, -78 ˚C to -50 ˚C.
3) phosphate buffer
pH 7.0, 1.0 M
1a R1 = Ph
1b R1 = Bn
R1
R1
iPr3Si
N
N
+
R2
R2
5a-o
4a-o
Entry
Start. mat.
(R2)2Mga
Product
Yield
4 (%)b
Product ratio
4/5/1 (%)c
1
2
3
4
5
6
7
8
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1a R1ZPh
1b R1ZBn
1b R1ZBn
1b R1ZBn
1b R1ZBn
1b R1ZBn
1b R1ZBn
Et2Mg
4a 5a
4b 5b
4c 5c
4d 5d
4e 5e
4f 5f
4g 5g
4h 5h
4i 5i
4k 5k
4l 5l
4m 5m
4n 5n
4o 5o
78
82
92
0
90/4/6
100/0/0
95/2/3
nBu2Mg
Bn2Mg
Ph2Mg
Me2Mg
iPr2Mg
tBu2Mg
Allyl2Mg
Et2Mg
nBu2Mg
Bn2Mg
iPr2Mg
tBu2Mg
Allyl2Mg
5/95d/0
0/59/41
99/0/1
0
91
56
20
73
54
85
78
5
80/3/17e
20/78d/2
86/2/12
54/6/40
95/0/5
100/0/0
6/0/94f
21/70/9
9
10
11
12
13
14
12
a After addition of the organomagnesium compound to the N-silylpyridinium ion at K78 8C the mixture was slowly warmed to K50 8C.
b Isolated yield.
1
c According to H NMR of the crude reaction product.
d Sum of 5 and non oxidized 1,2-addition product, which were both present.
e Yield 63%, ratio 86/2/12 when addition performed by warming the mixture from K78 8C to room temperature.
Yield 29%, ratio 32/0/68 when addition performed by warming the mixture from K78 8C to room temperature.
f

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2398
Table 3. Variation of the N-trialkylsilyl group in the trapping reactions of N-silylpyiridinium ions
1) R3SiOTf (2b,c)
CH2Cl2, rt.
N
Ph
2) (R2)2Mg, -78 ˚C to -50 ˚C.
3) phosphate buffer
pH 7.0, 1.0 M
1a
R2
+
R3Si
N
N
Ph
Ph
4p-u
2b: R = Me
2c: R = Ph
R2
5a,c,d
Entry
R3SiOTf
(R2)2Mga
Product
Yield
4 (%)b
Product ratio
4/5/1 (%)c
1
2
3
4
5
6
Me3SiOTf
Me3SiOTf
Me3SiOTf
Ph3SiOTf
Ph3SiOTf
Ph3SiOTf
Et2Mg
Bn2Mg
iPr2Mg
Et2Mg
Bn2Mg
iPr2Mg
4p 5a
4q 5c
4r 5f
4s 5a
4t 5c
4u 5f
0
45
90
0
48
86
1/4/95
66/9/25
91/2/7
11/30/59
49/7/44
98/1/1
a After addition of the organomagnesium compound to the N-silylpyridinium ion at K78 8C the mixture was slowly warmed to K50 8C.
b Isolated yield.
1
c According to H NMR of the crude reaction product.
lower than those obtained with TIPS triflate as activating
agent (Table 3, entries 4–6). Additionally, with Et2Mg a
reversed selectivity in favor of 5a was observed again
(compare Table 2, entry 1 with Table 3, entry 4).
the N-silyl derivative of 1b. Therefore, in case of the
addition of tBu2Mg to 1b it also seems likely that a
deprotonation reaction of the benzylic position occurs,
which finally diminishes the yield of the addition
product. Actually, it is quite intriguing that the reactivity
of the benzylic position (in 1b) had no or only a
secondary effect on the other addition reactions
performed with 1b. The sharp drop in yield observed
for the addition of tBu2Mg is possibly due to its higher
steric demand in addition to his higher basicity as
compared to the other Grignard reagents.
Consequently, for additional trapping reactions varying the
diorganomagnesium compounds again, TIPS triflate was
used for the activation of the pyridine moiety. In case of
nBu2Mg the 1,4-addition product 4b was formed exclu-
sively and in high yield (Table 2, entry 2). Even with
tBu2Mg the addition reaction proceeded smoothly providing
4g in good yield and with high regioselectivity (Table 2,
entry 7).
At first sight one might be tempted to assume that the
regioselectivity observed in the trapping reactions of 1a and
1b is a function of the softness, according to the HSAB
principle, of the alkyl moiety of the organomagnesium
compound used. Particularly, since relatively soft nucleo-
philes (such as Et2Mg, nBu2Mg, iPr2Mg, tBu2Mg) add
preferentially to the 4-position of the pyridine ring, whereas
harder nucleophiles (allyl2Mg, Ph2Mg) give mainly the
respective 2-addition products. However, with Me2Mg the
2-addition is more favored than with Ph2Mg or allyl2Mg
(see Table 2, entries 6–8), whereas according to the HSAB
principle the opposite should be true. Therefore, it is more
likely that the regioselectivity is dominated by the size and
the steric demand of the nucleophile and depends only
partly on the softness of the reagent. This is also indicated
by the results of the trapping reaction with varying N-silyl
groups according to which the size of the nucleophile as
well as the steric demand of the N-silyl moiety play
important roles for the regioselectivity.
In contrast, Ph2Mg, Me2Mg and allyl2Mg with sterically
less demanding residues reacted predominantly in the
2-position to yield the pyridine derivatives 5d, 5e and 5h
after aqueous workup as the major product (Table 2, entries
4, 5 and 8).
Additionally, a further set of experiments was performed
with the pyridine derivative 1b. The results of these
trapping reactions closely paralleled those obtained for
1a. The yield for the 4-addition product 4 obtained from
1b was significantly lower only with tBu2Mg (Table 2,
entry 13, 4n, 5%). But when the reaction was performed
by increasing the temperature (from K78 8C) not only to
K50 8C but to room temperature, the yield rose to 29%
(ratio 4/5/1Z32/0/68). For the addition of tBu2Mg to 1a
both the yield that had already been quite satisfying
(from 56 to 63%) and the product ratio [from 80/3/17 to
86/2/12 (5/4/1)] improved slightly when the reaction
temperature was allowed to reach room temperature. The
insufficient outcome of the addition of tBu2Mg to 1b
(yield 5%, see Table 2, entry 13) under standard
conditions could be the result of a competing deprotona-
tion reaction. It is obvious that the benzylic position of
1b is highly acidic, which should be even more true for
The N-triisopropylsilyl-1,4-dihydropyridines prepared in
this study were found to be sufficiently stable for isolation.
Although, chromatography on standard silica gel columns
caused considerable decomposition, the recovery of the
materials was almost quantitative when aluminum oxide
was used for purification (neutral, Brockmann activity III15).

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2399
Table 4.
R1
R2
O
O
R1
R2
1) NaBH3CN, MeOH
2M HCl in Et2O
Si N
N
2) Boc2O, NaHCO3
dioxane/H2O
4d,e,m
6a-c
Entry
Start. mat.
Product
R1
R2
Yield
6 (%)a
1
2
3
4f
4g
4m
6a
6b
6c
Ph
Ph
Bn
iPr
tBu
iPr
90
95
92
a Isolated yield.
Stored under nitrogen atmosphere at K20 8C the isolated
N-triisopropylsilyl-1,4-dihydropyridines were stable for
weeks.
recorded in CDCl3 or CD2Cl2 at 500 and 125 MHz,
respectively. Infrared spectra were obtained on a Perkin-
Elmer Model 1600 FTIR spectrometer. Microanalytical data
for carbon, hydrogen and nitrogen were determined on a
Heraeus Rapid Analyser and on a Elementar Vario EL
Analyser. Flash chromatography was performed with
50–150 mesh aluminium oxide (neutral Brockmann
activity III).
Having established a highly efficient access to N-triisopro-
pylsilyl-1,4-dihydropridines we set out to explore the utility
of these compounds for the preparation of related 4,4-
disubstituted piperidines. Interestingly, synthetic methods
giving access to this class of compounds are still rare.16
4.2. General procedure for the preparation of dialkyl-
magnesium reagents18 (GP1)
It turned out that the desired transformation can be
efficiently accomplished by treating the respective N-triiso-
propylsilyl-silyl-1,4-dihydropyridine in Et2O with
NaCNBH3 and etheral HCl. Under these conditions not
only a reduction of the double bonds but also, though not
unexpected, a removal of the N-silyl group occurs. To allow
for a more convenient isolation the formed amines were
finally trapped with di-tert-butyl dicarbonate (Boc2O)
providing the corresponding Boc protected piperidine
derivatives. Thus, from the N-silyl derivatives 4f, 4g and
4m the corresponding piperidine derivatives 6a–c were
obtained in yields of R90%, which clearly demonstrates the
efficiency of this approach (Table 4).
Commercially available alkylmagnesium halide solutions in
Et2O or THF were 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 suspensions were
centrifuged to yield clear colorless R2Mg solutions.
Complete precipitation of magnesium halide was verified
by addition of a few drops of 1,4-dioxane. The clear R2Mg
solutions were kept under nitrogen at 4 8C.
4.3. General procedure for the preparation of 4,4-
disubstituted N-silyl-1,4-dihydropyridines (GP2)
3. Conclusion
The corresponding 4-substituted pyridine was dissolved in
CH2Cl2 and treated with 1.0 equiv TIPS triflate at room
temperature. After stirring at ambient temperature for 15 min
the colorless solution was cooled to K78 8C, followed by
dropwise addition of a twofold excess of R2Mg solution. The
resulting yellow to deep red colored mixture was slowly
warmed to K50 8C and quenched after the time given by
addition of 2 ml phosphate buffer (pH 7, c 1.0 M). The
aqueous layer was extracted with CH2Cl2 (4!7 ml). The
combined organic layers were dried (MgSO4), and concen-
trated in vacuo. Column chromatography at aluminum oxide
(neutral, Brockmann activity III, pentane; addition of CH2Cl2
to dissolve side products was necessary in some cases) yielded
the final product. The final compound was stored under N2
atmosphere at K20 8C to avoid oxidation.
In summary, we have presented an easy and straightforward
method for the preparation of 4,4-disubstituted 1,4-
dihydropyridines with a wide variety of substituents. It is
based on unprecedented trapping reactions of 4-substituted
N-silylpyridinium ions with organomagnesium compounds.
The obtained 4,4-disubstituted 1,4-dihydropyridines have
been demonstrated to give rapid access to fully saturated
4,4-disubstituted piperidine derivatives, which adds a new
method to the few existing for the preparation of piperidine
derivatives with a quaternary carbon in 4-position. Further
studies exploring the scope of the trapping reaction of
N-silylpyridinum ions mentioned above for the synthesis of
highly functionalized 1,4-dihydropyridines are in progress.
4. Experimental
4.4. General procedure for the preparation of 4,4-
disubstituted N-Boc protected piperidines (GP3)
4.1. General experimental
The corresponding 4,4-disubstituted N-silyl-1,4-dihydro-
pyridine was dissolved in CH2Cl2 and treated with 2.5 equiv
of NaBH3CN in MeOH at room temperature. After addition
of 5.0 equiv 2 M HCl in Et2O the mixture was stirred for 1 h
All reactions were performed using flame-dried glassware
under N2 atmosphere. All solvents were freshly dried using
standard17 procedures. 1H and 13C NMR spectra were

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J. Brackow, K. T. Wanner / Tetrahedron 62 (2006) 2395–2404
2400
at room temperature and subsequently quenched with
aqueous 5 M KOH. The water phase was extracted with
CH2Cl2. The raw material resulting from the combined
organic layers was dissolved in a 1:1 mixture of dioxane and
water containing NaHCO3 and treated with 1.1 equiv of
Boc2O. After stirring over night the mixture was extracted
with CH2Cl2. The organic extracts were concentrated and
the resulting residue purified by CC on silica gel.
4.4.3. 4-Benzyl-4-phenyl-1-triisopropylsilyl-1,4-dihydro-
pyridine (4c). According to GP2 from 4-phenylpyridine
(1a, 38.8 mg, 0.25 mmol), TIPS triflate (76.6 mg, 67.4 ml,
0.25 mmol) in CH2Cl2 (2 ml) and Bn2Mg (1.0 ml, 0.5 M in
Et2O), reaction time 10 h.
Yield 92.8 mg (92%), colorless crystals, mp 81 8C. TLC
RfZ0.37 (aluminum oxide 60 neutral, n-pentane). 1H NMR
(CDCl3) dZ0.95 (d, JZ7.5 Hz, 18H, CH3), 1.15 (sept,
JZ7.5 Hz, 3H, CH(CH3)2), 3.03 (s, 2H, CH2), 4.51 (d,
JZ8.0 Hz, 2H, NCH]CH), 5.96 (d, JZ8.0 Hz, 2H,
NCH]CH), 7.09–7.15 (m, 3H, Haromat), 7.16–7.20 (m,
3H, Haromat), 7.38 (t, JZ7.5 Hz, 2H, Haromat), 7.49 (d,
JZ7.5 Hz, 2H, Haromat). 13C NMR (CDCl3, DEPT) dZ11.2
(d), 17.7 (q), 43.2 (s), 50.0 (t), 105.9 (d, NC]C), 125.3
(d, Caromat), 125.5 (d, Caromat), 126.7 (d, NC]C), 127.3 (d,
Caromat), 128.0 (d, Caromat), 128.1 (d, Caromat), 131.3 (d,
Caromat), 139.3 (s, Caromat), 152.2 (s, Caromat). MS (CI,
CHC5 ); m/z (%): 404 (100) [MC1]C, 312 (84), 287 (12),
195 (22), 187 (11), 183 (6), 157 (6), 141 (7). IR (film): n~Z
3053 cmK1, 2985, 2305, 1422, 1264, 895, 746, 706. Anal.
Calcd for C27H37NSi (403.69): C 80.33, H 9.24, N 3.47.
Found C 80.34, H 9.26, N 3.41.
4.4.1. 4-Ethyl-4-phenyl-1-triisopropylsilyl-1,4-dihydro-
pyridine (4a). According to GP2 from 4-phenylpyridine
(1a, 38.8 mg, 0.25 mmol), TIPS triflate (76.6 mg, 67.4 ml,
0.25 mmol) in CH2Cl2 (2 ml) and Et2Mg (1.0 ml, 0.5 M in
Et2O), reaction time 10 h.
Yield 66.6 mg (78%), colorless crystals, mp 59 8C. TLC
RfZ0.69 (aluminum oxide 60 neutral, n-pentane). 1H NMR
(CDCl3) dZ0.95 (t, JZ7.5 Hz, 3H, CH2CH3), 1.11 (d, JZ
7.5 Hz, 18H, CHCH3), 1.30 (sept, JZ7.5 Hz, 3H, CHCH3),
1.68 (q, JZ7.5 Hz, 2H, CH2CH3), 4.36 (d, JZ8.0 Hz, 2H,
NCH]CH), 6.15 (d, JZ8.0 Hz, 2H, NCH]CH), 7.12–
7.16 (m, 1H, Haromat), 7.30–7.34 (m, 2H, Haromat), 7.40–7.43
(m, 2H, Haromat). 13C NMR (CDCl3, DEPT) dZ10.0 (q),
11.4 (d), 17.9 (q), 35.0 (t), 42.2 (s), 106.1 (d, NC]C), 125.1
(d, Caromat), 126.7 (d, NC]C), 128.0 (d, Caromat), 128.2 (d,
Caromat), 152.6 (s, Caromat). MS (CI, CHC5 ); m/z (%): 324
(100) [MC1]C, 312 (33), 157 (4), 147 (4). IR (film): n~Z
3054 cmK1, 2984, 2304, 1423, 1265, 895, 746. Anal. Calcd
for C22H35NSi (341.62): C 77.35, H 10.33, N 4.10. Found C
77.33, H 10.39, N 4.05.
4.4.4. 4-Isopropyl-4-phenyl-1-triisopropylsilyl-1,4-
dihydropyridine (4f). According to GP2 from 4-phenyl-
pyridine (1a, 38.8 mg, 0.25 mmol), TIPS triflate (76.6 mg,
67.4 ml, 0.25 mmol) in CH2Cl2 (2 ml) and iPr2Mg (1.0 ml,
0.5 M in Et2O), reaction time 4 h.
Yield 81.0 mg (91%), colorless oil. TLC RfZ0.58
(aluminum oxide 60 neutral, n-pentane). 1H NMR
(CDCl3) dZ0.82 (d, JZ6.7 Hz, 6H, CH3), 1.09 (d,
JZ7.4 Hz, 18H, SiCH(CH3)2), 1.26 (sept, JZ7.4 Hz, 3H,
SiCH(CH3)2), 2.07 (sept, JZ6.7 Hz, 1H, CH(CH3)2), 4.97
(d, JZ8.5 Hz, 2H, NCH]CH), 6.14 (d, JZ8.5 Hz, 2H,
NCH]CH), 7.13 (tt, JZ7.2/1.4 Hz, 1H, Haromat), 7.30–7.38
(m, 4H, Haromat). 13C NMR (125 MHz, CDCl3, DEPT) dZ
11.4 (d), 17.8 (q), 17.9 (q), 37.4 (d), 45.5 (s), 104.2 (d,
NC]C), 124.7 (d, Caromat), 126.7 (d, Caromat), 128.1 (d,
Caromat), 128.5 (d, NCH]CH)., 151.5 (s). MS (CI, CHC5 );
m/z (%): 356 (100) [MC1]C, 312 (48), 235 (9), 189 (5), 184
(5), 157 (7), 147 (9). IR (film): n~Z3054 cmK1, 2985, 2868,
2305, 1666, 1423, 1265, 895, 739, 706. Anal. Calcd for
C23H37NSi (355.64): C 77.68, H 10.49, N 3.94. Found C
74.64, H 10.65, N 3.93.
4.4.2. 4-n-Butyl-4-phenyl-1-triisopropylsilyl-1,4-dihydro-
pyridine (4b). (A) According to GP2 from 4-phenylpyridine
(1a, 77.6 mg, 0.5 mmol), TIPS triflate (153.2 mg, 134.8 ml,
0.5 mmol) in CH2Cl2 (4 ml) and Bu2Mg (2.0 ml, 0.5 M in
Et2O), reaction time 10 h.
Yield 151.6 mg (82%), colorless crystals, mp 85–86 8C.
1
TLC RfZ0.76 (aluminum oxide 60 neutral, n-pentane). H
NMR (CDCl3) dZ0.92 (t, JZ7.2 Hz, 3H, CH3), 1.11 (d,
JZ7.4 Hz, 18H, CH3), 1.28 (sept, JZ7.4 Hz, 3H,
CH(CH3)2), 1.31–1.39 (m, 4H, CH2), 1.65 (m, 2H, CH2),
4.40 (d, JZ8.3 Hz, 2H, NCH]CH), 6.12 (d, JZ8.3 Hz,
2H, NCH]CH), 7.14 (tt, JZ7.2/1.1 Hz, 1H, Haromat), 7.33
(m, 2H, Haromat), 7.42 (m, 2H, Haromat). 13C NMR (CDCl3,
DEPT) dZ11.4 (d), 12.3 (q), 17.9 (q), 23.3 (t), 28.3 (t), 41.6
(s), 42.9 (t), 106.7 (d, NC]C), 125.1 (d, Caromat), 126.6 (d,
NC]C), 127.8 (d, Caromat), 128.0 (d, Caromat), 152.7 (s,
Caromat). MS (CI, CHC5 ); m/z (%): 370 (100) [MC1]C, 312
4.4.5. 4-tert-Butyl-4-phenyl-1-triisopropylsilyl-1,4-
dihydropyridine (4g). According to GP2 from 4-phenyl-
pyridine (1a, 38.8 mg, 0.25 mmol), TIPS triflate (76.6 mg,
67.4 ml, 0.25 mmol) in CH2Cl2 (2 ml) and tBu2Mg (1.0 ml,
0.5 M in Et2O). After addition of the organometallic reagent
the mixture was slowly warmed to room temperature,
reaction time 10 h.
(53), 178 (7), 156 (6), 147 (5). IR (Film): n~Z3054 cmK1
,
2986, 2868, 2305, 1665, 1422, 1265, 895, 740, 705. Anal.
Calcd for: C27H37NSi (369.67): C 77.98, H 10.63, N 3.79.
Found. C 77.98, H 10.73, N 3.79.
(B) A solution of 4-phenylpyridine (1a, 38.8 mg,
0.25 mmol) in CH2Cl2 (2 ml) was treated with TIPS triflate
(76.6 mg, 67.4 ml, 0.25 mmol), and stirred for 15 min at
room temperature. After cooling to K78 8C the mixture was
transferred via cannula to a prior prepared solution of
Yield 58.6 mg (63%), colorless crystals, mp 74 8C. TLC
RfZ0.64 (aluminum oxide 60 neutral, n-pentane). 1H NMR
(CDCl3) dZ0.86 (s, 9H, CH3), 1.04 (d, JZ7.4 Hz, 18H,
HCH(CH3)2), 1.24 (sept, JZ7.4 Hz, 3H, CH(CH3)2), 5.12
(d, JZ8.5 Hz, 2H, NCH]CH), 6.11 (d, JZ8.5 Hz, 2H,
NCH]CH), 7.10 (t, JZ7.4 Hz, 1H, Haromat), 7.23–7.26 (m,
2H, Haromat), 7.29–7.31 (m, 2H, Haromat). 13C NMR (CDCl3,
DEPT) dZ11.3 (d), 17.8 (q), 25.9 (q), 38.6 (s), 45.9 (s),
19
Bu2CuCNLi2 (2.0 equiv) in Et2O kept at K78 8C. Then
the resulting red colored mixture was allowed to warm up to
0 8C. After 4 h it was quenched and worked up as described
above. Yield of 4b: 11%.

¨
J. Brackow, K. T. Wanner / Tetrahedron 62 (2006) 2395–2404
2401
103.0 (d, NC]C), 124.7 (d, Caromat), 127.0 (d, NC]C),
127.4 (d, Caromat), 128.4 (d, Caromat), 149.1 (s, Caromat). MS
(CI, CHC5 ); m/z (%): 370 (100) [MC1]C, 312 (67), 292 (5),
(d, JZ7.3 Hz, 18H, CH(CH3)2), 1.16 (sept, JZ7.6 Hz,
3H, CH(CH3)2), 1.19–1.23 (m, 2H, CH2), 1.27–1.34 (m, 4H,
CH2), 1.55 (s, 2H, CH2Ph), 4.11 (d, JZ8.3 Hz, 2H,
NCH]CH), 5.92 (d, JZ8.3 Hz, 2H, NCH]CH),
7.11–7.14 (m, 3H, Haromat), 7.19–7.22 (m, 2H, Haromat).
13C NMR (CDCl3, DEPT) dZ11.3 (q), 14.2 (d), 17.7 (q),
23.3 (t), 28.6 (t), 39.5 (s), 43.9 (t), 52.0 (t), 106.3 (d,
NC]C), 125.3 (d, Caromat), 127.2 (d, NC]C), 128.7 (d,
Caromat), 131.0 (d, Caromat), 139.3 (s, Caromat). MS (CI,
CHC5 ); m/z (%): 384 (70) [MC1]C, 292 (100), 147 (5). IR
(film): n~Z3053 cmK1, 2960, 2867, 1668, 1288, 1265, 895,
737, 705. Anal. Calcd for C28H39NSi (383.70): C 78.26, H
10.77, N 3.65. Found C 77.96, H 10.77, N 3.61.
184 (8), 156(12), 147 (9), 119 (6). IR (film): n~Z3054 cmK1
,
2984, 2868, 2305, 1666, 1422, 1265, 895, 740, 706. Anal.
Calcd for C27H37NSi (369.67): C 77.98, H 10.63, N 3.79.
Found C 77.80, H 10.65, N 3.72.
4.4.6. 4-Allyl-4-phenyl-1-triisopropylsilyl-1,4-dihydro-
pyridine (4h). According to GP2 from 4-phenylpyridine
(1a, 38.8 mg, 0.25 mmol), TIPS triflate (76.6 mg, 67.4 ml,
0.25 mmol) in CH2Cl2 (2 ml) and allyl2Mg (1.0 ml, 0.5 M in
Et2O), reaction time 2 h.
Yield 17.9 mg (20%), colorless oil. TLC RfZ0.61 (alumi-
num oxide 60 neutral, n-pentane). H NMR (CDCl3) dZ
4.4.9. 4-Dibenzyl-1-triisopropylsilyl-1,4-dihydropyridine
(4l). According to GP2 from 4-benzylpyridine (1b, 40.6 mg,
38.2 ml, 0.25 mmol), TIPS triflate (76.6 mg, 67.4 ml,
0.25 mmol) in CH2Cl2 (2 ml) and Bn2Mg (1.0 ml, 0.5 M
in Et2O), reaction time 10 h.
1
1.10 (d, JZ7.5 Hz, 18H, SiCH(CH3)2), 1.26 (sept, JZ
7.5 Hz, 3H, SiCH(CH3)2), 2.53 (d, JZ7.0 Hz, 2H, CH2),
4.46 (d, JZ8.0 Hz, 2H, NCH]CH), 5.01–5.05 (m, 2H,
CH]CH2), 5.79–5.88 (m, 1H, CH]CH2), 5.96 (d, JZ
8.0 Hz, 2H, NCH]CH), 7.16 (t, JZ7.5 Hz, 1H, Haromat),
7.34 (t, JZ7.5 Hz, 2H, Haromat), 7.42 (d, JZ7.5 Hz, 2H,
Haromat). 13C NMR (CDCl3, DEPT) dZ11.4 (d), 17.9 (q),
41.5 (s), 48.1 (t), 106.4 (d, NC]C), 116.2 (t, CH]CH2),
125.2 (d, Caromat), 126.7 (d, NC]C), 127.9 (d, Caromat),
128.1 (d, Caromat), 136.4 (CH]CH2), 152.7 (s, Caromat). MS
(CI, CHC5 ); m/z (%): 354 (98) [MC1]C, 312 (100), 236
Yield 88.8 mg (85%), colorless crystals, mp 101–102 8C.
1
TLC RfZ0.48 (aluminum oxide 60 neutral, n-pentane). H
NMR (CDCl3) dZ0.84 (d, JZ7.4 Hz, 18H, CH(CH3)2),
1.02 (sept, JZ7.4 Hz, 3H, CH(CH3)2), 2.66 (s, 4H, CH2),
4.18 (d, JZ8.3 Hz, 2H, NCH]CH), 5.75 (d, JZ8.3 Hz,
2H, NCH]CH), 7.11–7.16 (m, 6H, Haromat), 7.19–7.22 (m,
4H, Haromat). 13C NMR (CDCl3, DEPT) dZ11.3 (d), 17.5
(q), 41.5 (s), 51.5 (t), 105.7 (d, NC]C), 125.4 (d, Caromat),
127.3 (d, NC]C), 128.8 (d, Caromat), 131.0 (d, Caromat),
139.6 (s, Caromat). MS (CI, CHC5 ); m/z (%): 418 (48) [MC
1]C, 326 (100), 170 (7), 147 (8), 119 (7), 105 (11). IR (film):
n~Z3055 cmK1, 2986, 1422, 1265, 896, 741, 706. Anal.
Calcd for C28H39NSi (417.72): C 80.51, H 9.41, N 3.35.
Found C 80.34, H 9.26, N 3.31.
(20), 184 (6), 156 (16), 147 (11). IR (film): n~Z3053 cmK1
,
2985, 2304, 1665, 1421, 1265, 895, 739, 705. Anal. Calcd
for C23H35NSi (353.63): C 78.12, H 9.98, N 3.96. Found C
78.02, H 10.07, N 3.89.
4.4.7. 4-Benzyl-4-ethyl-1-triisopropylsilyl-1,4-dihydro-
pyridine (4i). According to GP2 from 4-benzylpyridine
(1b, 81.2 mg, 76.4 ml, 0.5 mmol), TIPS triflate (153.2 mg,
134.8 ml, 0.5 mmol) in CH2Cl2 (4 ml) and Et2Mg (2.0 ml,
0.5 M in Et2O), reaction time 10 h.
4.4.10. 4-Benzyl-4-isopropyl-1-triisopropylsilyl-1,4-
dihydropyridine (4m). According to GP2 from 4-benzyl-
pyridine (1b, 40.6 mg, 38.2 ml, 0.25 mmol), TIPS triflate
(76.6 mg, 67.4 ml, 0.25 mmol) in CH2Cl2 (2 ml) and iPr2Mg
(1.0 ml, 0.5 M in Et2O), reaction time 2 h.
Yield 129.8 mg (73%), colorless oil. TLC RfZ0.67
(aluminum oxide 60 neutral, n-pentane). 1H NMR
(CDCl3) dZ0.87 (t, JZ7.4 Hz, 3H, CH2CH3), 0.98 (d,
JZ7.4 Hz, 18H; CH(CH3)2), 1.16 (sept, JZ7.4 Hz, 3H,
CH(CH3)2), 1.23 (q, JZ7.4 Hz, 2H, CH2CH3), 2.52 (s, 2H,
CH2Ph), 4.06 (d, JZ8.3 Hz, 2H, NCH]CH), 5.96 (d, JZ
8.3 Hz, 2H, NCH]CH), 7.11–7.14 (m, 3H, Haromat),
7.19–7.22 (m, 2H, Haromat). 13C NMR (CDCl3, DEPT) dZ
11.3 (d), 11.3 (q), 17.7 (q), 36.1 (t), 40.0 (s), 41.8 (t), 42.9
(t), 105.6 (d, NC]C), 125.3 (d, Caromat), 127.2 (d, NC]C),
129.1 (d, Caromat), 131.0 (d, Caromat), 139.3 (s, Caromat). MS
(CI, CHC5 ); m/z (%): 356 (56) [MC1]C, 264 (100), 147 (4).
IR (film): n~Z2958 cmK1, 2867, 1671. Anal. Calcd for
C28H39NSi (355.64): C 77.68, H 10.49, N 3.94. Found C
77.58, H 10.63, N 3.89.
Yield 71.8 mg (78%), colorless oil. TLC RfZ0.70 (alumi-
1
num oxide 60 neutral, n-pentane). H NMR (CDCl3) dZ
0.94 (d, JZ7.4 Hz, 18H, SiCH(CH3)2), 0.95 (d, JZ6.9 Hz,
6H, CH(CH3)2), 1.12 (sept, JZ7.4 Hz, 3H, SiCH(CH3)2),
1.40 (sept, JZ6.9 Hz, 1H, CH(CH3)2), 2.56 (s, 2H, CH2Ph),
4.11 (d, JZ8.5 Hz, 2H, NCH]CH), 5.89 (d, JZ8.3 Hz,
2H, NCH]CH), 7.08–7.14 (m, 3H, Haromat), 7.17–7.20 (m,
2H, Haromat). 13C NMR (CDCl3, DEPT) dZ11.3 (d), 17.7
(q), 18.0 (q), 38.5 (d), 43.0 (s), 48.3 (t), 104.1 (d, NC]C),
125.2 (d, Caromat), 127.1 (d, Caromat), 129.0 (d, Caromat),
131.0 (d, NC]C), 140.4 (s, Caromat). MS (CI, CHC5 ); m/z
(%): 370 (65) [MC1]C, 326 (10), 278 (100), 147 (7), 122
(7). IR (film): n~Z3054 cmK1, 2985, 2867, 2305, 1668,
1422, 1265, 895, 740, 706. Anal. Calcd for C24H39NSi
(369.67): C 77.98, H 10.63, N 3.79. Found C 78.02, H 10.70,
N 3.76.
4.4.8. 4-Benzyl-4-n-butyl-1-triisopropylsilyl-1,4-dihydro-
pyridine (4k). According to GP2 from 4-benzylpyridine
(1a, 81.1 mg, 76.4 ml, 0.5 mmol), TIPS triflate (153.2 mg,
134.8 ml, 0.5 mmol) in CH2Cl2 (4 ml) and nBu2Mg (2.0 ml,
0.5 M in Et2O), reaction time 5 h.
4.4.11. 4-Benzyl-4-tert-butyl-1-triisopropylsilyl-1,4-
dihydropyridine (4n). According to GP2 from 4-benzyl-
pyridine (1b, 40.6 mg, 38.2 ml, 0.25 mmol), TIPS triflate
(76.6 mg, 67.4 ml, 0.25 mmol) in CH2Cl2 (2 ml) and
tBu2Mg (1.0 ml, 0.5 M in Et2O). After addition of the
Yield 103.0 mg (54%), colorless crystals, mp 47 8C. TLC
RfZ0.68 (aluminum oxide 60 neutral, n-pentane). 1H NMR
(CDCl3) dZ0.89 (t, JZ7.1 Hz, 3H, CH2CH3), 0.98

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J. Brackow, K. T. Wanner / Tetrahedron 62 (2006) 2395–2404
2402
organometallic reagents the mixture was slowly warmed to
room temperature, reaction time 10 h.
4.4.14. 4-Isopropyl-4-phenyl-1-trimethylsilyl-1,4-
dihydropyridine (4r). According to GP2 from 4-phenyl-
pyridine (1a, 77.6 mg, 0.5 mmol), TMS triflate (111.2 mg,
90.4 ml, 0.5 mmol) in CH2Cl2 (2 ml) and iPr2Mg (2.0 ml,
0.5 M in Et2O), reaction time 3 h.
Yield 28.1 mg (29%), colorless crystals, mp 74–75 8C. TLC
RfZ0.69 (aluminum oxide 60 neutral, n-pentane). 1H NMR
(CDCl3) dZ0.90 (d, JZ7.3 Hz, 18H, SiCH(CH3)2), 0.97 (s,
9H, C(CH3)3), 1.08 (sept, JZ7.6 Hz, 3H, SiCH(CH3)2),
2.54 (s, 2H, CH2Ph), 4.26 (d, JZ8.5 Hz, 2H, NCH]CH),
5.81 (d, JZ8.5 Hz, 2H, NCH]CH), 7.05–7.10 (m, 3H,
Yield 122.1 mg (90%), colorless oil. TLC RfZ0.9
(aluminum oxide 60 neutral, n-pentane/CH2Cl2 9:1). 1H
NMR (CDCl3) dZ0.19 (s, 9H, Si(CH3)3), 0.78 (d, JZ
6.6 Hz, 6H, CH(CH3)2), 2.01 (sept, JZ6.6 Hz, 3H,
CH(CH3)2), 4.55 (d, JZ8.3 Hz, 2H, NCH]CH), 6.16 (d,
JZ8.5 Hz, 2H, NCH]CH), 7.08–7.12 (m, 1H, Haromat),
7.28–7.33 (m, 4H, Haromat). 13C NMR (CDCl3, DEPT)
dZK1.4 (q), 17.7 (q), 37.7 (d), 45.6 (s), 104.5 (d, NC]C),
124.8 (d, Caromat), 126.6 (d, Caromat), 127.3 (d, NC]C),
128.2 (d, Caromat), 151.7 (s, Caromat). MS (CI, CHC5 ); m/z
(%): 272 (100) [MC1]C, 228 (85), 204 (6), 200 (11), 194
H
aromat), 7.14–7.18 (m, 2H, Haromat). 13C NMR (CDCl3,
DEPT) dZ11.2 (d), 17.6 (q), 25.3 (q), 38.4 (s), 43.4 (t), 45.4
(s), 103.3 (d, NC]C), 125.0 (d, Caromat), 127.0 (d, Caromat),
128.8 (d, Caromat), 131.2 (d, NC]C), 141.6 (s, Caromat). MS
(CI, CHC5 ); m/z (%): 384 (92) [MC1]C, 326 (51), 292
(100), 170 (9), 157 (8), 147 (15). IR (film): n~Z3054 cmK1
,
2985, 1422, 895, 740, 706. Anal. Calcd for C24H39NSi
(383.70): C 78.22, H 10.77, N 3.65. Found C 78.22, H 10.55,
N 3.57.
(5), 181 (8), 156 (7), 105 (9). IR (film): n~Z3053 cmK1
,
2956, 1667, 1598, 1295, 1253, 1092, 997, 843, 759. Anal.
Calcd for C17H25NSi (271.48): C 75.21, H 9.28, N 5.16.
Found C 74.97, H 9.43, N 5.38.
4.4.12. 4-Allyl-4-benzyl-1-triisopropylsilyl-1,4-dihydro-
pyridine (4o). According to GP2 from 4-benzylpyridine
(1b, 40.6 mg, 38.2 ml, 0.25 mmol), TIPS triflate (76.6 mg,
67.4 ml, 0.25 mmol) in CH2Cl2 (2 ml) and allyl2Mg (1.0 ml,
0.5 M in Et2O), reaction time 10 h.
4.4.15. 4-Benzyl-4-phenyl-1-triphenylsilyl-1,4-dihydro-
pyridine (4t). According to GP2 from 4-phenylpyridine
(1a, 38.8 mg, 0.25 mmol), triphenylsilyl triflate (1.0 ml,
0.25 M in CH2Cl2) in CH2Cl2 (2 ml) and Bn2Mg (1.0 ml,
0.5 M in Et2O), reaction time 3 h.
Yield 10.8 mg (12%), colorless oil. TLC RfZ0.62 (alumi-
num oxide 60 neutral, n-pentane) 1H NMR (CDCl3) dZ0.98
(d, JZ7.3 Hz, 18H, CH(CH3)2), 1.36 (sept, JZ7.3 Hz, 3H,
CH(CH3)2), 2.09 (dt, JZ7.1/1.4 Hz, 2H, CH2CH]CH2),
2.57 (s, 2H, CH2Ph), 4.17 (d, JZ8.3 Hz, 2H, NCH]CH),
4.97–5.05 (m, 2H, CH]CH2), 5.88–5.97 (m, 3H,
CH]CH2, NCH]CH), 7.12–7.15 (m, 3H, Haromat),
7.20–7.23 (m, 2H, Haromat). 13C NMR (CDCl3, DEPT) dZ
11.3 (d), 17.7 (q), 36.4 (s), 49.1 (t), 50.9 (t), 105.9 (d,
NC]C), 115.8 (t, CH]CH2), 125.5 (d), 127.3 (d), 128.8
(d), 130.9 (d), 136.7 (d), 139.0 (s). MS (CI, CHC5 ); m/z (%):
368 (92) [MC1]C, 326 (49), 276 (100), 236 (5), 147 (6). IR
(film): n~Z3027 cmK1, 2944, 2866, 2350, 1670, 1464, 1287,
1057. HRMS (70 eV) calcd for C24H37NSi [MC]: 367.2701.
Found 367.2695.
Yield 61.3 mg (48%), colorless crystals, mp 133–134 8C.
TLC RfZ0.64 (aluminum oxide 60 neutral, n-pentane/
1
CH2Cl2 9:1). H NMR (CD2Cl2) dZ3.04 (s, 2H, CH2Ph),
4.62 (d, JZ8.5 Hz, 2H, NCH]CH), 5.95 (d, JZ8.5 Hz,
2H, NCH]CH), 7.13–7.15 (m, 2H, Haromat), 7.18–7.21 (m,
1H, Haromat), 7.29–7.30 (m, 3H, Haromat), 7.35–7.38 (m, 8H,
Haromat), 7.41–7.50 (m, 11H, Haromat). 13C NMR (CD2Cl2,
DEPT) dZ43.5 (s), 50.1 (t), 107.2 (d, NC]C), 125.5
(d, Caromat), 125.8 (d, Caromat), 126.6 (d, NC]C), 127.4
(d, Caromat), 128.0 (d, Caromat), 128.1 (d, Caromat), 128.2
(d, Caromat), 130.3 (d, Caromat), 131.4 (d, Caromat), 132.0
(s, Caromat), 135.9 (d, Caromat), 139.4 (s, Caromat), 151.9
(s, Caromat). MS (EI); m/z (%): 505 (1) [MC], 414 (100), 259
(86), 181 (14), 105 (6), 91 (5). IR (Film): n~Z3428 cmK1
,
3022, 2343, 1667, 1428, 1288, 1114, 697. HRMS (70 eV)
calcd for C36H31NSi [MC]: 505.2226. Found 505.2227.
4.4.13. 4-Benzyl-4-phenyl-1-trimethylsilyl-1,4-dihydro-
pyridine (4q). According to GP2 from 4-phenylpyridine
(1a, 38.8 mg, 0.25 mmol), TMS triflate (55.6 mg, 45.2 ml,
0.25 mmol) in CH2Cl2 (2 ml) and Bn2Mg (1.0 ml, 0.5 M in
Et2O), reaction time 3 h.
4.4.16.
4-Isopropyl-4-phenyl-1-triphenylsilyl-1,4-
dihydropyridine (4u). According to GP2 from 4-phenyl-
pyridine (1a, 38.8 mg, 0.25 mmol), triphenylsilyl triflate
(1.0 ml, 0.25 M in CH2Cl2) in CH2Cl2 (2 ml) and iPr2Mg
(1.0 ml, 0.5 M in Et2O), reaction time 3 h.
Yield 36.1 mg (45%), colorless crystals, mp 51–52 8C. TLC
RfZ0.9 (aluminum oxide 60 neutral, n-pentane/CH2Cl2
1
9:1). H NMR (CDCl3) dZ0.06 (s, 9H, Si(CH3)3), 3.04 (s,
Yield 98.9 mg (86%), colorless oil. TLC RfZ0.66
(aluminum oxide 60 neutral, n-pentane/CH2Cl2 9:1). 1H
NMR (CD2Cl2) dZ0.86 (d, JZ6.9 Hz, 6H, CH(CH3)2),
2.09 (sept, JZ6.9 Hz, 1H, CH(CH3)2), 4.62 (d, JZ8.3 Hz,
2H, NCH]CH), 6.16 (d, JZ8.3 Hz, 2H, NCH]CH), 7.13–
7.16 (m, 1H, Haromat), 7.33–7.37 (m, 4H, Haromat), 7.40–7.43
(m, 6H, Haromat), 7.46–7.50 (m, 3H, Haromat), 7.62–7.64 (m,
6H, Haromat). 13C NMR (CD2Cl2, DEPT) dZ18.2 (q), 37.8
(d), 45.9 (s), 105.9 (d, NC]C), 125.3 (d, Caromat), 126.9
(d, Caromat), 128.4 (d, Caromat), 128.5 (d, NC]C), 128.8
(d, Caromat), 130.7 (d, Caromat), 132.5 (s, Caromat), 136.3
(d, Caromat), 151.6 (s, Caromat). MS (CI, CHC5 ); m/z (%): 458
2H, CH2), 4.59 (d, JZ8.2 Hz, 2H, NCH]CH), 5.98 (d, JZ
8.2 Hz, 2H, NCH]CH), 7.01–7.03 (m, 2H, Haromat), 7.14–
7.20 (m, 4H, Haromat), 7.34–7.37 (m, 2H, Haromat) 7.42–7.45
(m, 2H, Haromat). 13C NMR (CDCl3, DEPT) dZK1.2 (q),
43.1 (s), 50.7 (t), 106.5 (d, NC]C), 125.3 (d), 125.5 (d),
126.5 (d), 126.7 (d), 127.1 (d), 128.2 (d), 131.1 (d), 138.7 (s,
C
aromat), 151.6 (s, Caromat). MS (CI, CHC5 ); m/z (%): 320
(88) [MC1]C, 248 (19), 228 (100), 156 (28). IR (film): n~Z
3024 cmK1, 2952, 2359, 1666, 1598, 1293, 1253, 1098,
1036, 840, 735, 698. Anal. Calcd for C17H25NSi (271.48): C
78.94, H 7.89, N 4.38. Found C 78.80, H 7.82, N 4.30.

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J. Brackow, K. T. Wanner / Tetrahedron 62 (2006) 2395–2404
2403
(100) [MC1]C, 414 (39), 380 (6), 259 (13). IR (film): n~Z
[MC1]C, 262 (100), 218 (13). IR (KBr): n~Z2968 cmK1
,
2872, 1689. Anal. Calcd for C20H31NO2 (317.48): C 75.67,
H 9.84, N 4.41. Found C 75.53, H 9.91, N 4.40.
3049 cmK1, 2958, 1669, 1428, 1292, 1114, 699. HRMS
(70 eV) calcd for C32H31NSi [MC] 457.2226. Found
457.2231.
4.4.20. 4-Benzyl-4-isopropyl-piperidine-1-carboxylic
acid tert-butyl ester (6c). According to GP3 from 4m
(151.1 mg, 0.409 mmol), NaBH3CN (64.1 mg, 1.02 mmol)
in MeOH (3 ml), HCl 2 M in Et2O (1.28 ml) and Boc2O
(98.2 mg, 0.450 mmol).
4.4.17. 2,4-Diphenyl-pyridine (5d). According to GP2
from 4-phenylpyridine (1a, 77.6 mg, 0.5 mmol), TIPS
triflate (153.2 mg, 134.8 ml, 0.5 mmol) in CH2Cl2 (4 ml)
and Ph2Mg (4.0 ml, 0.25 M in Et2O), the reaction mixture
was warmed to room temperature during 12 h. The
reaction was quenched by addition of 2 ml 2 M HCl. The
mixture was stirred for 15 min, before adding 3 ml, 2 M
NaOH solution and extraction with CH2Cl2. The crude
product was purified by CC on silica gel.
Yield 120 mg (92%), colorless crystals, mp 84–85 8C. TLC
RfZ0.34 (SiO2, n-pentane/EtOAc 95:5). 1H NMR
(400 MHz, C2D2Cl4, 100 8C) dZ0.96 (d, JZ6.8 Hz, 6H,
CH(CH3)2), 1.34–1.39 (m, 2H, NCH2CH2), 1.46 (s, 9H,
C(CH3)3), 1.57–1.62 (m, 2H, NCH2CH2), 1.97 (sept, JZ
6.8 Hz, 1H, CH(CH3)2), 2.69 (s, 2H, CH2Ph), 3.38–3.50 (m,
4H, NCH2), 7.15–7.32 (m, 5H, Haromat). 13C NMR
(100 MHz, C2D2Cl4, DEPT, 100 8C) dZ16.7 (q, CH3),
28.6 (q, CH3), 30.1 (d, CH), 31.0 (t, CH2), 37.3 (s), 38.8 (t,
CH2Ph), 39.8 (t, NCH2), 79.0 (s), 126.0 (d, Caromat), 127.9
(d, Caromat), 130.9 (d, Caromat), 138.8 (s, Caromat), 155.2 (s,
CO). MS (CI, CHC5 ); m/z (%): 318 (2) [MC1]C, 262 (100),
218 (11). IR (KBr): n~Z2973 cmK1, 1679, 1418, 1155. Anal.
Calcd for C20H31NO2 (317.48): C 75.50, H 9.89, N 4.42.
Found C 75.23, H 9.96, N 4.42.
Yield 47.9 mg (41%), colorless oil. TLC RfZ0.24 (SiO2,
1
n-pentane/EtOAc 95:5). H NMR (CDCl3) dZ7.43–7.55
(m, 7H, Haromat), 7.71 (d, JZ7.0 Hz, 2H, Haromat), 7.95 (s,
1H, Haromat), 8.06 (d, JZ7.0 Hz, 2H, Haromat), 8.76 (d, JZ
5.3 Hz, 1H, NCHZCH). HRMS (70 eV) calcd for C17H13N
[MC] 231.1048. Found 231.1036. Spectroscopic data for
1H, 13C NMR and IR are in accordance with those
previously published.20
4.4.18. 4-Isopropyl-4-phenyl-piperidine-1-carboxylic
acid tert-butyl ester (6a). According to GP3 from 4d
(150.8 mg, 0.424 mmol), NaBH3CN (66.6 mg, 1.06 mmol)
in MeOH (3 ml), HCl 2 M in Et2O (2.12 ml) and Boc2O
(101.9 mg, 0.467 mmol).
Acknowledgements
We thank Monika Simon for her assistance with editing and
proofreading.
Yield 115.3 mg (90%), colorless crystals, mp 83–84 8C.
TLC RfZ0.28 (SiO2, n-pentane/EtOAc 95:5). 1H NMR
(500 MHz, C2D2Cl4, 80 8C) dZ0.75 (d, JZ6.6 Hz, 6H,
CH(CH3)2), 1.46 (s, 9H, C(CH3)3), 1.66–1.72 (m, 3H,
CH(CH3)2 and NCH2CH2), 2.28–231 (m, 2H, NCH2CH2),
2.79–2.84 (m, 2H, NCH2), 3.85–3.88 (m, 2H, NCH2), 7.23–
7.28 (m, 3H, Haromat), 7.35–7.38 (m, 2H, Haromat). 13C NMR
(125 MHz, C2D2Cl4, DEPT, 80 8C) dZ17.3 (q, CH3), 28.6
(q, CH3), 32.7 (t, CH2), 38.5 (d, CH), 40.7 (t, CH2), 43.5 (s),
79.0 (s), 125.8 (d, Caromat), 128.0 (d, Caromat), 128.4
(d, Caromat), 141.5 (s, Caromat), 155.0 (s, CO). MS (CI,
CHC5 ); m/z (%): 304 (6) [MC1]C, 248 (100), 204 (13). IR
(KBr): n~Z2972 cmK1, 2867, 1685. Anal. Calcd for
C19H29NO2 (303.45): C 75.21, H 9.63, N 4.62. Found C
75.15, H 9.77, N 4.61.
References and notes
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acid tert-butyl ester (6b). According to GP3 from 4e
(91.9 mg, 0.249 mmol), NaBH3CN (39.1 mg, 0.622 mmol)
in MeOH (2 ml), HCl 2 M in Et2O (1.24 ml) and Boc2O
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Yield 75.9 mg (95%), colorless crystals, mp 107 8C. TLC
RfZ0.28 (SiO2, n-pentane/EtOAc 95:5). 1H NMR
(500 MHz, C2D2Cl4, 80 8C) dZ0.85 (s, 9H, C(CH3)3),
1.45 (s, 9H, OC(CH3)3), 1.77–1.83 (m, 2H, NCH2CH2),
2.30–2.33 (m, 2H, NCH2CH2), 2.61–2.66 (m, 2H, NCH2),
3.92–3.95 (m, 2H, NCH2), 7.23–7.28 (m, 3H, Haromat),
7.34–7.37 (m, 2H, Haromat). 13C NMR (125 MHz, C2D2Cl4,
DEPT, 80 8C) dZ26.1 (q, CH3), 28.6 (q, CH3), 29.3 (t,
CH2), 36.1 (s), 40.9 (t, CH2), 43.4 (s), 78.9 (s), 125.8
(d, Caromat), 127.6 (d, Caromat), 129.9 (d, Caromat), 139.8
(s, Caromat), 155.0 (s, CO). MS (CI, CHC5 ); m/z (%): 318 (12)
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