Regioselective and Transition-Metal-Free Addition of tert -Butyl Magnesium Reagents to Pyridine Derivatives: A Convenient Method for the Synthesis of 3-Substituted 4- tert -Butylpyridine Derivatives

Article abstract of DOI:10.1055/s-0036-1589025

A variety of 3,4-disubstituted pyridine derivatives with a tert -butyl group in the 4-position were synthesized in a transition-metal-free, two-step reaction sequence from 3-substituted pyridine precursors. Highly regioselective addition of t -Bu ₂ Mg to TIPS-activated pyridines and an efficient microwave-assisted aromatization with sulfur as oxidant afforded the desired 3,4-disubstituted pyridine derivatives in moderate to excellent yields. The method is compatible with many functional groups such as ester, amide, halide, nitrile or alkyne groups present in the 3-position.

Full text of DOI:10.1055/s-0036-1589025

SYNTHESIS
0
0
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-
7
8
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1
1
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–J
paper
A
en
S. Rappenglück et al.
Paper
Synthesis
Regioselective and Transition-Metal-Free Addition of tert-Butyl
Magnesium Reagents to Pyridine Derivatives: A Convenient
Method for the Synthesis of 3-Substituted 4-tert-Butylpyridine
Derivatives
Sebastian Rappenglücka
microwave-assisted oxidation
regioselective addition
Karin V. Niessenb
Thomas Seegerb
Franz Worekb
Horst Thiermannb
Klaus T. Wanner*a
t-Bu
t-Bu
1) TIPSOTf
2) t-Bu2Mg
R
R
R
S8, naphthalene
microwave
N
N
N
0
0
0
0
0-
0
0
3
4-
3
9
9
1-
4
2
5
Si(i-Pr)3
a Ludwig-Maximilians-Universität München, Department
für Pharmazie – Zentrum für Pharmaforschung,
Butenandtstr. 5-13, Haus C, 81377 Munich, Germany
klaus.wanner@cup.uni-muenchen.de
b Bundeswehr Institute of Pharmacology and Toxicology,
Neuherbergstraße 11, 80937 Munich, Germany
12 examples
43–95% yield
10 examples
55–83% yield
Received: 27.03.2017
Accepted: 07.04.2017
Published online: 18.05.2017
DOI: 10.1055/s-0036-1589025; Art ID: ss-2017-z0199-op
step reactions comprising the addition of nucleophiles to N-
acylpyridinium ions and subsequent oxidation are often the
methods of choice.11 Although the latter strategy is of high
value in synthetic organic chemistry, it is less suited for the
synthesis of 4-tert-butyl substituted pyridine derivatives,7
because the addition of tert-butyl nucleophiles to N-
acylpyridinium ions as well as the subsequent rearomatiza-
tion often proceed with low yields.12 Recently, Knochel et al.
reported a regioselective synthesis of 4-substituted pyri-
dine derivatives including 4-(tert-butyl)nicotinonitrile, em-
ploying pyridine derivatives activated by BF3·OEt2 and
Grignard reagents in combination with LiCl or organozinc
reagents as nucleophiles.13 This method, however, requires
pyridine derivatives with an electron-withdrawing group in
the C-3 position. In addition, this approach suffers from the
low stability of the formed dihydropyridine intermediates,
precluding purification by chromatography, which can thus
only be accomplished at the stage of the oxidized end prod-
uct. This may be tedious if a starting material with similar
physicochemical properties is still present. Alternatively, as
described by Ready et al., lithium reagents may be added to
4-pyridineboronic esters to afford 4-substituted pyridines,
such as 4-tert-butylpyridine.14 Although highly attractive,
this route suffers from the limited availability of boronic es-
ters.
Abstract A variety of 3,4-disubstituted pyridine derivatives with a tert-
butyl group in the 4-position were synthesized in a transition-metal-
free, two-step reaction sequence from 3-substituted pyridine precur-
sors. Highly regioselective addition of t-Bu2Mg to TIPS-activated pyri-
dines and an efficient microwave-assisted aromatization with sulfur as
oxidant afforded the desired 3,4-disubstituted pyridine derivatives in
moderate to excellent yields. The method is compatible with many
functional groups such as ester, amide, halide, nitrile or alkyne groups
present in the 3-position.
Key words 3,4-disubstituted pyridines, N-activation, heterocycles, di-
organomagnesium, nucleophilic addition, microwave
Pyridines represent important building blocks in organ-
ic synthesis and are widely used in medicinal chemistry.1,2
As a substructure of a more complex molecule, they are
very common in many natural products, biologically active
compounds including drugs, and as key substrates for mul-
ticomponent reactions.3 Pyridine derivatives exhibiting a
tert-butyl group are not as widely distributed, but they are
still found in pharmaceutical compounds such as anti-in-
flammatory agents,4 cancer therapeutics,5 and nervous sys-
tem agents.6 Notably, 3,4-disubstituted pyridine derivatives
with a tert-butyl group in the 4-position can be found in
many C17,20-lyase inhibitors developed for prostate cancer
therapy.7
The regioselective trapping reactions of N-silylpyridini-
um ions with diorganomagnesium reagents represent an
efficient approach to 4,4-disubstituted N-silyl-1,4-dihydro-
pyridines15 and dihydronicotinates,16 as previously report-
ed by us.
Based on these results, we envisaged that a related ap-
proach might allow a highly efficient and versatile access to
4-tert-butyl substituted pyridine derivatives with both
Well-known methods for the functionalization of pyri-
dine derivatives such as cross-coupling reactions8 or C–H
activations9 suffer from β-H elimination and homocoupling
side reactions if tertiary alkyllithium or alkylmagnesium
reagents are employed.10 Thus, de novo synthesis or two-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

B
S. Rappenglück et al.
Paper
Synthesis
electron-withdrawing and electron-donating groups in the
3-position. Herein, we wish to report on the successful im-
plementation of this plan.
the product 4 were constantly present. Accordingly, the
yield of the purified product did not appropriately reflect
the outcome of the reaction. Therefore, to determine regio-
selectivities and yields in every case, the amount of the
products 1,2-dihydropyridine (5), 1,4-dihydropyridine (3)
and 4-tert-butylpyridine (4) was quantified directly from
the crude material obtained after aqueous workup by
1H NMR spectroscopy employing 2,4,6-collidine as internal
standard and by using the 13C-1H satellite peak integration
technique developed by Claridge for the assessment of
product ratios.17 The high regioselectivity of the trapping
reactions meant that the amount of 1,2-dihydropyridine 5
present in the crude reaction product did not suffice for a
reliable NMR spectroscopic characterization of 5. Therefore,
the trapping reaction of TIPSOTf activated pyridine with
t-BuMgCl was performed in THF at 0 °C, resulting in lower
regioselectivity and thus giving isomer 5 in sufficient
amounts (Table 1, entry 9).
To avoid the separate preparation of the diorganomag-
nesium reagent that had given far superior results com-
pared with the readily available Grignard reagent, next the
use of diorganomagnesium generated in situ was investi-
gated. Thus, to a solution of the pyridinium ion 2 at –85 °C,
first 4.4 equivalents 1,4-dioxane and subsequently 4.0
equivalents of precooled t-BuMgCl were added (Table 1, en-
try 4). In this case, the combined yield for 3 and 4 rose to
88%, thus being almost identical to the result obtained for
To study the first step, the addition reaction for the in-
troduction of a substituent in the 4-position, unsubstituted
pyridine (1) was used as a model system because it is de-
void of electron-donating or electron-withdrawing effects.
For initial experiments, the reaction conditions published
for the preparation of 4,4-dihydropyridines were used.15,16
Thus, pyridine was first treated with 1.0 equivalents of
TIPSOTf (15 min at r.t. in CH2Cl2) and subsequently with 2.0
equivalents of t-BuMgCl (Table 1, entry 2) or t-Bu2Mg (Table
1, entry 1) at –78 °C. This afforded 1,4-dihydropyridine 3
and traces of its oxidation product 4-tert-butylpyridine (4)
in a combined yield of 31% and 82%, respectively. As expect-
ed from previous results, the dialkylmagnesium reagent
proved to provide far better yields than the Grignard re-
agent.15,16 Interestingly, for the addition of t-BuMgCl, the
yield increased from 31% to 41% when the reaction tem-
perature was lowered from –78 to –85 °C and the Grignard
reagent was cooled to –85 °C prior to the addition (Table 1,
entry 3).
The high susceptibility of 1,4-dihydropyridine 3 to oxi-
dation meant that the product obtained after aqueous
workup was contaminated with 4-tert-butylpyridine (4),
the amount of which varied with each reaction. Moreover,
even in dihydropyridine 3 purified by LC, small amounts of
Table 1 Trapping Reaction of 2 with tert-Butyl Magnesium Reagents under Different Reaction Conditions
t-Bu
t-Bu
TfO
TIPSOTf (1.05 equiv)
CH2Cl2, r.t., 15 min
1) 1,4-dioxane, Trxn
+
+
N
2) t-BuM (2.0 equiv, Tt-BuM),
16 h
N
N
N
t-Bu
N
Si(i-Pr)3
Si(i-Pr)3
Si(i-Pr)3
1
2
3
4
5
1,4-Dioxane (equiv) 3/4/5a
Yield 3/4 (%)a
Tt-BuM (°C)
Entry
T
rxn (°C)
t-BuM (2.0 equiv)
c
1
2
3
4
5
6
7
8
–78
–78
–85
–85
–85
–85
–85
–85
r.t.
t-Bu2Mg in THF/Et2O (1:1)
t-BuMgCl in Et2O
–
–
–
–
–
(82)b
(31)
(41)
(88)
(90)
(97)
(90)
c
c
c
r.t.
–
–85
–85
–85
–85
–85
–85
t-BuMgCl in Et2O
–
t-BuMgCl in Et2Od
4.4
–
t-Bu2Mg in THF/Et2O (1:1)
t-Bu2Mg in THF/Et2O (1:1)
t-Bu2Mg in THF
96.4:2.9:0.7
96.5:3.1:0.4
95.3:3.5:1.2
2.2
2.2
2.2
t-Bu2Mg in Et2O
98:2:0
9:1:0
(98)
9 4
9
0
r.t.
t-BuMgCl in Et2Of
–
78:9:13
(20)e
a Yield and product ratio of 3, 4, and 5 in the crude material were determined by 1H NMR spectroscopy with 2,4,6-collidine as internal standard. Yield after
aqueous workup is given in parentheses.
b Combined yield from two experiments because yields were strongly varying.
c Could not be determined.
d 4.0 equivalents were used.
e CH2Cl2 was replaced by THF after N-activation.
f 1.2 equivalents t-BuMgCl were used.
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S. Rappenglück et al.
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Synthesis
the conventional trapping reaction of 2 with t-Bu2Mg at
–85 °C, which had afforded the desired products 3 and 4, in
90% yield (entry 5). A higher amount of dioxane, in turn, did
not appear useful because it negatively influenced the ho-
mogeneity of the reaction mixture. Furthermore, 1,4-diox-
ane was also found to improve the combined yield for 3 and
4 for the trapping reaction of 2 with previously prepared di-
alkylmagnesium from 90% to 97% (compare entries 5 and
6). In this case, 2.2 equivalents dioxane proved to be suffi-
cient.
Once additional 1,4-dioxane is present in the reaction
mixture, it is likely that the Schlenk equilibrium between
the Grignard and the diorganomagnesium species is contin-
uously driven towards the latter, thus leading to an im-
proved yield. Finally, the influence of the composition of the
solvent containing t-Bu2Mg was studied. Interestingly,
when Et2O/THF (1:1; Table 1, entries 1, 5 and 6) was re-
placed with pure THF, the yield decreased from 97% to 90%
and the regioselectivity reduced from 99.6:0.4 to 98.8:1.2
(entry 7). In contrast, Et2O turned out to be far more favor-
able for the dialkylmagnesium addition reaction, affording
the desired 1,4-dihydropyridine 3 in almost quantitative
yield of 98% according to NMR analysis with no 2-isomer 5
being detected (entry 8). After purification by flash chro-
matography, 1,4-dihydropyridine 3 and its oxidation prod-
uct 4 could finally be isolated in an excellent combined
yield of 94%. Clearly, the generation of the dialkylmagne-
sium reagent in situ with 1,4-dioxane is a very efficient and
labor-saving approach, allowing the use of commercially
available Grignard reagents. However, given that the com-
bined application of previously formed dialkylmagnesium
reagent and dioxane had led to better results with regard to
yield and regioselectivity, it was used in all further addition
reactions with the pyridinium salts.
In the next step, a mild and efficient method for the oxi-
dation of 4-tert-butyl-N-silyl-1,4-dihydropyridines had to
be established. For this purpose, both air-labile dihydropyr-
idine 3 and air-stable dihydronicotinate 716 were selected
as model compounds and were subjected to oxidation reac-
tions with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ),18 MnO2,19 Pd/C, Pd/C with tetrabutylammonium flu-
oride (TBAF), o-chloranil,20 SeO2,21 and S8/naphthalene (Ta-
ble 2).21 Reaction of dihydropyridine 3 and dihydronicoti-
nate 7 with DDQ afforded the corresponding 4-tert-butyl
substituted oxidation products, pyridine derivative 4 and
nicotinate 8, in very low to moderate yields of only 13% (en-
try 1) and 41% (entry 7), respectively. With Pd/C and ambi-
ent air, 1,4-dihydropyridine 3 was easily oxidized under
mild conditions, to give the aromatic compound 6 (81%; en-
try 2), whereas dihydronicotinate 7 turned out to be inert
under these conditions (entry 4), which was also true when
SeO2 was applied to the latter (entry 10). In addition, only
traces of pyridine derivative 8 were found if the oxidation of
1,4-dihydronicotinate 7 was attempted with MnO2 at room
Table 2 Oxidation of 4-tert-Butyl-N-silyl-1,4-dihydropyridines 3 and 7
t-Bu
t-Bu
R
R
oxidant, solvent
T, t
N
N
Si(i-Pr)3
R = H, 3
R = COOEt, 7
R = H, 4 (6 hydrochloride)
R = COOEt, 8
Entry
Dihydropyridine Oxidant (equiv)
Solvent
T (°C)
t (min)
Prod.
Yield (%)
1
2
3
3
3
7
7
7
7
7
7
7
7
DDQ (1.1)
CH2Cl2
r.t.
30
16 h
10
4
6
6
8
8
8
8
8
8
8
8
13
Pd/C (0.05)
S8 (1.1)
1,4-dioxane
naphthalene
1,4-dioxane
no solvent
CH2Cl2
r.t.
81
3
200a
r.t.
90
4
Pd/C (0.05)
MnO2 (5.0)
MnO2 (10)
16 h
16 h
180
60
eductb
trace
5
r.t.
e
6
60c
r.t.
–
7
DDQ (1.5)
CH2Cl2
41
8
o-chloranil (2.0)
Pd/C (0.05), TBAF (2.0)
SeO2 (1.4)
CH2Cl2
50
60
29d
e
9
1,4-dioxane
THF
r.t.
16 h
16 h
10
–
10
11
r.t.
eductb
96
S8 (1.1)
naphthalene
200a
a Microwave-assisted reaction, MW: 300 W.
b Starting material was completely recovered.
c Microwave assisted reaction, MW: 100 W.
d Contaminated with 16% ethyl nicotinate, because the tert-butyl group was lost during the oxidation.
e Full conversion into ethyl nicotinate.
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S. Rappenglück et al.
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Synthesis
temperature (entry 5). Astonishingly, for the reaction of 7
with MnO2 in CH2Cl2, if the temperature was raised to 60 °C
by microwave irradiation19 (entry 6) the tert-butyl group
was lost, leading to ethyl nicotinate as the final product. To
a lesser extent (16%), loss of the tert-butyl group was also
observed if 7 was reacted with o-chloranil in CH2Cl2 at 60 °C
(entry 8). Reaction with Pd/C and TBAF for desilylation (en-
try 9) gave again only ethyl nicotinate. Given the lability of
the tert-butyl group observed for the oxidation reactions,
we tested a sulfur-mediated aromatization as a promising
alternative, although known procedures using sulfur in
boiling xylene22 or toluene23 suffer from very long reaction
times of up to 3 days.
To our delight, oxidation of 7 with sulfur in naphthalene
under microwave heating to 200 °C led to complete conver-
sion within 10 minutes, affording the desired 4-tert-butyl
substituted nicotinate 8 in an excellent yield of 96% (Table 2,
entry 11). In the same way, 3 could also be smoothly trans-
formed into 4 and was isolated as hydrochloride 6 in 90%
yield (entry 3).
In neither case was side product formation observed.
Compared with the conventional sulfur mediated oxida-
tions, the method reported herein using microwave for
heating, represents a valuable alternative.
The optimized method described above for the addition
of diorganomagnesium reagents to TIPSOTf activated pyri-
dines and oxidation of the resulting N-silyl-1,4-dihydropyr-
idines to the respective aromatic compounds was finally
applied to the synthesis of a series of 3-substituted 4-tert-
butylpyridine derivatives (Table 3). Thus, for the addition of
a tert-butyl residue, pyridine derivatives 9a–j and rac-9k24
(entries 1–11) were activated by treatment with 1.05
equivalents TIPSOTf (2.0 equivalents in the case of 9i)25 and
subsequently treated with 2.0 equivalents of t-Bu2Mg in
CH2Cl2 at –85 °C after prior addition of 2.2 equivalents 1,4-
dioxane. The resulting 1,4-dihydropyridines 7, 10b–j, and
rac-10k were finally oxidized to the corresponding 3-sub-
stituted 4-tert-butylpyridine derivatives 8, 11b–I, and rac-
11k with sulfur in naphthalene under microwave heating
or, in the case of ethynyl substituted pyridine 11j, with Pd/C
in ambient air.
Table 3 Substrate Scope of the Activation, Trapping, and Oxidation Method for the Synthesis of 4-tert-Butylpyridine Derivatives
t-Bu
t-Bu
1) TIPSOTf (1.05 equiv), CH2Cl2
15 min, r.t. –85 °C
2) 1,4-dioxane (2.2 equiv)
S8 (1.1 equiv)
naphthalene (15 equiv)
R
R
R
3) t-Bu2Mg (2.0 equiv, cooled
to –85 °C), 16 h
MW (300 W)
200 °C, 10 min
N
N
N
Si(i-Pr)3
9a–j
rac-9k
7, 10a–j
rac-10k
8, 11a–j
rac-11k
Entry
Educt
DHP
Product
(Yield (%)a)
Yield (%)b
83
O
t-Bu
O
OEt
OEt
1
2
3
4
5
9a
9b
9c
9d
9e
7 (86)c
10b (89)
10c (93)
10d (78)
10e (95)
8
N
N
N
t-Bu
Me
OMe
Cl
Me
11b
11c
11d
11e
78
64
69
72
N
t-Bu
OMe
N
N
N
N
t-Bu
Cl
N
t-Bu
Br
Br
N
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

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Synthesis
Table 3 (continued)
Entry
Educt
9f
DHP
Product
11f
(Yield (%)a)
Yield (%)b
30
t-Bu
CN
CN
6
10f (43)
N
N
t-Bu
F
F
7
9g
10g (86)
10h (88)
10i (74)
11g
47d
75
N
N
t-Bu
Ph
Ph
O
8
9h
11h
N
N
O
NMe2
N
t-Bu
9
9i
11i
50e
31f
NMe2
N
t-Bu
10
11
9j
10j (89)
11j
N
N
t-Bu
62g,h
N
Me
N
rac-9k
rac-10k (81)
rac-11k
Me
N
N
a Yield of 1,4-dihydropyridine (DHP) was determined by 1H NMR spectroscopic analysis of the crude material after aqueous workup with 2,4,6-collidine as inter-
nal standard.
b Overall yield for both steps.
c Yield according to a reported procedure: 52%.16
d Isolated as the hydrochloride.
e N-activation with TIPSOTf (2.0 equiv).25
f Oxidation with Pd/C at room temperature.
g Trapping reaction with t-Bu2Mg (1.1 equiv).
h Oxidation reaction at 120 °C.
The synthesis of the intermediate 1,4-dihydropyridines
(7, 10b–j, and rac-10k) was found to be highly regioselec-
tive and independent of the electron-withdrawing or elec-
tron-donating nature of the C-3 substituent. As a conse-
quence, 1,4-addition products were strongly favored. Fur-
thermore, t-Bu2Mg clearly did not react with any of the
functional groups present in the pyridine starting material,
resulting mostly in good to excellent yields of the trapping
product (74–95%). An exception was 3-cyanopyridine (9f;
Table 3, entry 6) because the yield for the addition product
10f amounted only to 43%. In addition, variation of the
amount of TIPSOTf or t-Bu2Mg from 1.0 to 2.0 equivalents
applied in the reaction for both reagents did not lead to any
improvement. Synthesis of known dihydropyridine 7 (entry
1) was achieved in 86% yield (lit.: 52%),16 constituting a sig-
nificant improvement on our previously reported trapping
reaction.
High chemoselectivity was also observed for the trans-
formation of rac-nicotine (rac-9k, Table 3, entry 11) into
1,4-dihydronicotinate rac-10k in 81% yield. Moreover, no
silylation of the N-methylpyrrolidine ring followed by a ring
opening was observed.26 The next step, the sulfur mediated
oxidation, proceeded smoothly within 10 minutes at 200 °C
in a microwave reactor for the 3-substituted 1,4-dihydropy-
ridines bearing an ester (7; entry 1), a methyl (10b; entry
2), a methoxy (10c; entry 3), a chloride (10d; entry 4), a
bromide (10e; entry 5), a nitrile (10f; entry 6), a phenyl
(10h; entry 8) or an amide group in the 3-position (10i; en-
try 9), providing the respective aromatic pyridine deriva-
tives in 68–96% yield. In contrast, in the case of the oxida-
tion of 3-fluoro substituted dihydropyridine 10g (entry 7)
the yield of the oxidation product 11g amounted to only
55% because partial decomposition occurred. Notably, dihy-
dronicotine rac-10k (entry 11) decomposed at 200 °C, but
underwent complete oxidation within 10 minutes at a dis-
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S. Rappenglück et al.
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Synthesis
tinctly reduced temperature (i.e., 120 °C) with sulfur and
naphthalene, yielding racemic 4-tert-butylnicotine rac-11k
in good yield (77%).
Preparation of Di-tert-butylmagnesium Solution29
Commercially available t-BuMgCl (2 M in Et2O) was diluted with THF
or Et2O at r.t. to afford a 1 M solution, which was carefully treated with
1,4-dioxane (1.2 equiv). The resulting suspension was stirred over-
night at r.t., centrifuged, and the clear and colorless supernatant was
transferred by using a cannula into a Schlenk flask. The concentration
was determined by titration according to Chong’s procedure.30
Given that dihydropyridine 10j (Table 3, entry 10) ap-
peared to be labile in the presence of sulfur and naphtha-
lene at 120 °C or 200 °C, clearly due to the ethynyl group in
the 3-position, the oxidation was carried out under very
mild conditions. Treatment of dihydropyridine 10j with
Pd/C at room temperature and ambient air (for method de-
velopment see Table 2, entry 2) finally gave 4-(tert-butyl)-
3-ethynylpyridine (11j) in 35% yield.
Synthesis of 4-tert-Butylpyridines; General Procedure
Trapping Reaction (GP-A)
TIPSOTf (1.05 equiv) was added to a solution of the corresponding
pyridine derivative (1.0 equiv) in CH2Cl2 (6 mL/mmol) and the result-
ing mixture was stirred at r.t. for 15 min. The solution was cooled to
–85 °C, treated with 1,4-dioxane (2.2 equiv) and, after 5 min, a –85 °C
cold solution of t-Bu2Mg (2.0 equiv) was added by using a transfer
cannula. The reaction mixture was quenched after 16 h by the addi-
tion of water (6 mL/mmol) and saturated aqueous NaCl (10
mL/mmol). The aqueous phase was extracted with CH2Cl2 (3 × 15
mL/mmol), the combined organic layers were washed with saturated
aqueous NaCl (15 mL/mmol), dried over Na2SO4, and the solvents
were removed under reduced pressure. Quantitative analysis of the
crude product by 1H NMR spectroscopy using 2,4,6-collidine as inter-
nal standard revealed the amounts of the corresponding dihydropyri-
dine and of its oxidation product. The crude material was then puri-
fied by flash chromatography (FC) to give the corresponding 4-tert-
butyl-1,4-dihydropyridine as intermediate product.
In conclusion, we developed a new transition-metal-
free method for the synthesis of 3,4-disubstituted pyridine
derivatives with a tert-butyl group in the 4-position and a
series of substituents in the 3-position. To our knowledge,
this is the first study focused on the introduction of a tert-
butyl group into the 4-position of pyridine derivatives. Dis-
tinct advantages of our method are the high chemoselectiv-
ity and the excellent C-4 regioselectivity of the addition re-
action. The method also benefits from the possibility to pu-
rify the N-silyl-1,4-dihydropyridine intermediates if
necessary prior to oxidation to the aromatic compounds,
which also proceeds very smoothly. Furthermore, many
synthetically important functional groups such as an alkyl-
aryl ether, ester, amide, halide, nitrile, alkyne, and tertiary
amine are well tolerated by this methodology, which may
be useful for further functionalization reactions. To explore
the full potential of this method, further studies with re-
gard to the applicability of a more diverse set of diorgano-
magnesium reagents such as diaryl-, secondary, and prima-
ry dialkylmagnesium compounds are under way.
Oxidation Reaction (GP-B)
Sulfur (1.1 equiv) and naphthalene (15 equiv) were added to the cor-
responding 4-tert-butyl-1,4-dihydropyridine and the resulting mix-
ture was stirred at 200 °C under microwave conditions (300 W) for
10 min. The resulting residue was dissolved in Et2O (15 mL/mmol)
and the organic phase was washed with NaOH (2 × 15 mL/mmol). The
combined aqueous layers were re-extracted with Et2O (15 mL/mmol)
and the combined organic layers were extracted with 2 M HCl
(3 × 10 mL/mmol). The acidic aqueous layers were washed with Et2O
(15 mL/mmol) and the pH was adjusted to 9–10 by addition of K2CO3.
The aqueous layer was extracted with CH2Cl2 (3 × 15 mL/mmol) and
the combined organic layers were dried over MgSO4. The solvent was
removed under reduced pressure and the crude product was purified
by FC.
Anhydrous reactions were carried out in vacuum-dried glassware un-
der argon atmosphere. Microwave reactions were performed in
sealed glass vials with a CEM Discover SP microwave synthesizer. THF,
Et2O, 1,4-dioxane, and CH2Cl2 were distilled prior to use under nitro-
gen atmosphere and dried according to standard procedures;27 all
other chemicals were used as purchased from commercial sources.
TLC was carried out with plates purchased from Merck (silica gel 60
4-(tert-Butyl)-1-(triisopropylsilyl)-1,4-dihydropyridine (3) and
4-(tert-Butyl)pyridine (4)
F
254 on aluminum sheet). Flash chromatography (FC) was carried out
with Merck silica gel 60 (40–63 μm mesh size) as stationary phase or
activated basic alumina Brockmann I (150 μm mesh size) from
Sigma–Aldrich, which was adjusted to the given activity grade.28
Melting points were determined with a BÜCHI 510 melting point ap-
paratus and are uncorrected. IR spectroscopy was performed with an
FTIR Spectrometer 1600 and Paragon 1000 (PerkinElmer); oils were
measured as film and solid samples as KBr pellets, all IR data are given
in cm–1. High-resolution (HR) mass spectrometry was performed with
a Finnigan MAT 95 (EI) and Finnigan LTQ FT (ESI). 1H and 13C NMR
spectra were recorded with a Bruker BioSpin Avance III HD (400 or
500 MHz) using TMS as internal standard and integrated with
MestReNova (Version 10.0.2–15465), Mestrelab Research S.L. 2015.
Prepared according to GP-A from 1 (79 mg, 1.0 mmol, 81 μL) in CH2Cl2
(6 mL) with TIPSOTf (0.32 g, 1.0 mmol, 0.28 mL), 1.4-dioxane (0.19 g,
2.2 mmol, 0.19 mL, 2.2 equiv) and t-Bu2Mg (0.35 M in Et2O, 2.0 mmol,
5.7 mL). Reaction time: 2 h. Quantitative analysis revealed 279 mg
(95%) of 3 and 4 mg (3%) of 4. Purification of the crude material by FC
(Al2O3-basic, activity III, n-pentane) afforded 3 together with traces of
its oxidation product 4.
Yield: 263 mg (94%)*; colorless oil; Rf = 0.95 (SiO2; n-pentane/Et2O,
1:1).
IR (film): 3055, 2948, 2867, 1669, 1606, 1463, 1388, 1360, 1290,
1130, 1090, 1017, 988, 883, 854, 788, 713, 687 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

G
S. Rappenglück et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 0.83 (s, 9 H, C(CH3)3, 3), 1.08 (d, J =
7.3 Hz, 18 H, CH(CH3)2, 3), 1.19–1.27 (m, 3 H, CH(CH3)2, 3), 1.32 (s,
0.1 × 9 H, CH3, 4), 2.66 (t, J = 4.2 Hz, 1 H, CHC(CH3)3, 3), 4.50–4.53 (m,
2 H, NCHCH, 3), 6.04–6.08 (m, 2 H, NCH, 3), 7.27–7.28 (m, 0.1 × 2 H,
NCHCH, 4), 8.50–8.51 (m, 0.1 × 2 H, NCH, 4).
13C NMR (125 MHz, CDCl3): δ = 11.39 (CH(CH3)2, 3), 17.84 (CH(CH3)2,
3), 26.05 (C(CH3)3, 3), 30.51 (C(CH3)3, 4), 34.65 (C(CH3)3, 4), 36.12
(C(CH3)3, 3), 43.40 (CC(CH3)3, 3), 101.18 (NCHCH, 3), 120.71 (NCHCH,
4), 130.07 (NCH, 3), 149.67 (NCH, 4), 159.91 (NCHCHCH, 4).
4-(tert-Butyl)-3-methoxypyridine (11c)
According to GP-A, a solution of 9c (108 mg, 963 μmol, 100 μL) in
CH2Cl2 (6 mL) was treated with TIPSOTf (319 mg, 1.01 mmol, 280 μL),
1,4-dioxane (187 mg, 2.12 mmol, 180 μL) and t-Bu2Mg (0.45 M in Et2O,
1.93 mmol, 4.28 mL). Quantitative analysis revealed 227 mg (73%) of
dihydropyridine 10c and 32 mg (20%) of the oxidation product 11c.
Purification by FC (Al2O3-basic, activity III, n-pentane). Oxidation of
dihydropyridine 10c was performed according to GP-B with sulfur
(34.0 mg, 1.06 mmol) and naphthalene (1.85 g, 14.4 mmol). Purifica-
tion by FC (SiO2; n-pentane/Et2O, 1:1) afforded 11c.
* According to 1H NMR spectroscopic analysis, isolated product after
Yield: 102 mg (64%); colorless liquid; Rf = 0.22 (SiO2; n-pentane/Et2O,
1:1).
flash chromatography contained 250 mg (85%) of 3 and 13 mg (9%) of
4.
IR (film): 3105, 3056, 2999, 2959, 2914, 2869, 2840, 1590, 1546,
1488, 1463, 1416, 1393, 1362, 1305, 1262, 1239, 1214, 1190, 1171,
4-(tert-Butyl)pyridin-1-ium Chloride (6)
1103, 1087, 1025, 933, 892, 850, 828, 800, 695 cm–1
.
Prepared according to GP-B from a mixture of 3 and 4 (282.6 mg; 0.28
g, 0.96 mmol of 3 and 2.6 mg, 19 μmol of 4)* with sulfur (35 mg, 1.1
mmol) and naphthalene (1.9 g, 15 mmol). Purification by FC (SiO2; n-
pentane/Et2O, 1:1) afforded 4 as a colorless liquid, which was treated
with 2 M HCl in Et2O (2.0 mL, 4.0 mmol) to give the corresponding hy-
drochloride 6.
1H NMR (500 MHz, CDCl3): δ = 1.36 (s, 9 H, (CH3)3), 3.94 (s, 3 H, OCH3),
7.15 (d, J = 5.0 Hz, 1 H, NCHCH), 8.17 (d, J = 4.9 Hz, 1 H, NCHCH), 8.21
(s, 1 H, NCHCOCH3).
13C NMR (125 MHz, CDCl3): δ = 28.90 (C(CH3)3), 34.79 (C(CH3)3), 55.68
(OCH3), 121.04 (NCHCH), 133.96 (NCHCOCH3), 142.73 (NCHCH),
146.64 (CC(CH3)3), 154.73 (NCHCOCH3).
Yield: 0.15 g (90%); colorless hygroscopic solid.
HRMS (EI): m/z [M]+ calcd for C10H15NO: 165.1148; found: 165.1155.
IR (KBr): 2970, 1637, 1606, 1504, 1464, 1378, 1273, 1211, 1122, 1066,
1005, 929, 823, 741, 714 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.44–1.45 (m, 9 H, (CH3)3), 7.91 (d, J =
6.4 Hz, 2 H, NCHCH), 8.72–8.76 (m, 2 H, NCH).
13C NMR (125 MHz, CDCl3): δ = 30.16 ((CH3)3), 36.73 (C(CH3)3), 123.97
(NCHCH), 140.32 (NCH), 171.89 (NCHCHC).
HRMS (ESI): m/z [M – Cl–]+ calcd for C9H14N: 136.1121; found:
136.1121.
4-(tert-Butyl)-3-chloropyridine (11d)
According to GP-A, a solution of 9d (0.29 g, 2.5 mmol, 0.25 mL) in CH2-
Cl2 (15 mL) was treated with TIPSOTf (0.83 g, 2.6 mmol, 0.73 mL), 1,4-
dioxane (0.49 g, 5.5 mmol, 0.47 mL) and t-Bu2Mg (0.43 M in Et2O, 5.0
mmol, 12 mL). Quantitative analysis revealed 641 mg (78%) of dihy-
dropyridine 10d. Purification by FC (Al2O3-basic, activity III, n-pen-
tane). Oxidation of dihydropyridine 10d was performed according to
GP-B with sulfur (88 mg, 2.8 mmol) and naphthalene (4.8 g, 38
mmol). Purification by FC (SiO2; n-pentane/Et2O, 3:1) afforded 11d.
* Determined by 1H NMR spectroscopic analysis with 2,4,6-collidine
as internal standard prior to the synthesis.
Yield: 291 mg (69%); clear brownish liquid; Rf = 0.50 (SiO2; n-pen-
tane/Et2O, 3:1).
4-(tert-Butyl)-3-methylpyridine (11b)
According to GP-A, a solution of 9b (93 mg, 1.0 mmol, 97 μL) in CH2Cl2
(6 mL) was treated with TIPSOTf (0.32 g, 1.0 mmol, 0.28 mL), 1,4-diox-
ane (0.19 g, 2.2 mmol, 0.19 mL) and t-Bu2Mg (0.43 M in Et2O, 2.0
mmol, 4.7 mL). Quantitative analysis revealed 260 mg (85%) of dihy-
dropyridine 10b and 6 mg (4%) of the oxidation product 11b. Purifica-
tion by FC (Al2O3-basic, activity III, n-pentane). Oxidation of dihydro-
pyridine 10b was performed according to GP-B with sulfur (35 mg,
1.1 mmol) and naphthalene (1.9 g, 15 mmol). Purification by FC (SiO2;
n-pentane/Et2O, 1:1) afforded 11b.
IR (film): 3038, 3000, 2963, 2874, 1580, 1482, 1471, 1398, 1366,
1289, 1259, 1199, 1135, 1090, 1042, 932, 831, 748, 685 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.47 (s, 9 H, (CH3)3), 7.30 (d, J = 5.3 Hz,
1 H, NCHCH), 8.38 (d, J = 5.2 Hz, 1 H, NCHCH), 8.49 (s, 1 H, NCHCCl).
13C NMR (125 MHz, CDCl3): δ = 28.68 (C(CH3)3), 36.09 (C(CH3)3),
122.19 (NCHCH), 131.52 (NCHCCl), 147.89 (NCHCH), 151.28 (NCHC-
Cl), 155.20 (CC(CH3)3).
HRMS (EI): m/z [M]+ calcd for C9H12ClN: 169.0653; found: 169.0651.
Yield: 116 mg (78%); colorless oil; Rf = 0.46 (SiO2; n-pentane/Et2O,
1:1).
3-Bromo-4-(tert-butyl)pyridine (11e)
IR (film): 3102, 2966, 2874, 1590, 1539, 1485, 1461, 1403, 1380,
1365, 1308, 1260, 1240, 1201, 1174, 1102, 1084, 1037, 1022, 995,
According to GP-A, a solution of 9e (0.32 g, 2.0 mmol, 0.19 mL) in
CH2Cl2 (12 mL) was treated with TIPSOTf (0.66 g, 2.1 mmol, 0.58 mL),
1,4-dioxane (0.39 g, 4.4 mmol, 0.38 mL) and t-Bu2Mg (0.45 M in Et2O,
4.0 mmol, 8.9 mL). Quantitative analysis revealed 708 mg (95%) of di-
hydropyridine 10e. Purification by FC (Al2O3-basic, activity III, n-pen-
tane). Oxidation of dihydropyridine 10e was performed according to
GP-B with sulfur (71 mg, 2.2 mmol) and naphthalene (3.8 g, 30
mmol). Purification by FC (SiO2; n-pentane/Et2O, 4:1) afforded 11e.
929, 852, 829, 798, 755, 694 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.40 (s, 9 H, (CH3)3), 2.49–2.51 (m, 3 H,
CH3), 7.21 (d, J = 5.3 Hz, 1 H, NCHCH), 8.28–8.30 (m, 1 H, NCHC(CH3)),
8.32–8.34 (m, 1 H, NCHCH).
13C NMR (100 MHz, CDCl3): δ = 20.01 (CCH3), 29.89 (C(CH3)3), 35.78
(C(CH3)3), 120.55 (NCHCH), 131.34 (NCHCCH3), 147.75 (NCHCH),
152.94 (NCHC(CH3)), 156.55 (CC(CH3)3).
Yield: 308 mg (72%); clear colorless liquid; Rf = 0.38 (SiO2; n-pen-
tane/Et2O, 4:1).
HRMS (EI): m/z [M]+ calcd for C10H15N: 149.1199; found: 149.1198.
IR (film): 3082, 3038, 2998, 2967, 2873, 1579, 1481, 1467, 1397,
1365, 1288, 1257, 1229, 1197, 1130, 1088, 1025, 1016, 931, 918, 831,
747, 732, 680 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

H
S. Rappenglück et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 1.50 (s, 9 H, (CH3)3), 7.32 (d, J = 5.2 Hz,
1 H, NCHCH), 8.41 (d, J = 5.3 Hz, 1 H, NCHCH), 8.67 (s, 1 H, NCHCBr).
13C NMR (125 MHz, CDCl3): δ = 28.74 (C(CH3)3), 36.65 (C(CH3)3),
121.10 (NCHCBr), 122.76 (NCHCH), 148.37 (NCHCH), 154.21 (NCHC-
Br), 156.57 (CC(CH3)3).
tane). Oxidation of dihydropyridine 10g was performed according to
GP-B with sulfur (0.11 g, 3.3 mmol) and naphthalene (5.8 g, 45
mmol). Purification by FC (SiO2; n-pentane/Et2O, 2:1) afforded 4-
(tert-butyl)-3-fluoropyridine as a colorless liquid, which was treated
with 2 M HCl in Et2O (4.5 mL, 9.0 mmol) to yield the corresponding
hydrochloride 11g.
HRMS (EI): m/z [M]+ calcd for C9H12BrN: 213.0148; found: 213.0140.
Yield: 267 mg (47%); colorless solid; mp 125 °C; Rf (4-(tert-butyl)-3-
fluoropyridine) = 0.39 (SiO2; n-pentane/Et2O, 2:1).
4-(tert-Butyl)pyridine-3-carbonitrile (11f)
IR (film): 3040, 3070, 2994, 2963, 2875, 2699, 2517, 2076, 2052,
2025, 1900, 1643, 1595, 1526, 1513, 1485, 1460, 1400, 1368, 1349,
According to GP-A, a solution of 9f (0.21 g, 2.0 mmol) in CH2Cl2 (12
mL) was treated with TIPSOTf (0.66 g, 2.1 mmol, 0.58 mL), 1,4-diox-
ane (0.39 g, 4.4 mmol, 0.38 mL) and t-Bu2Mg (0.46 M in Et2O, 4.0
mmol, 8.7 mL). Quantitative analysis revealed 276 mg (43%) of dihy-
dropyridine 10f. Purification by FC (Al2O3-basic, activity III; n-pen-
tane/Et2O, 9:1). Oxidation of dihydropyridine 10f was performed ac-
cording to GP-B with sulfur (71 mg, 2.2 mmol) and naphthalene (3.8
g, 30 mmol). Purification by FC (SiO2; n-pentane/EtOAc, 1:1) afforded
11f.
1256, 1236, 1226, 1205, 1150, 1106, 1078, 1028, 858, 827, 813 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.51 (d, J = 1.1 Hz, 9 H, (CH3)3), 7.88–
7.93 (m, 1 H, NCHCH), 8.61 (d, J = 4.6 Hz, 1 H, NCHCF), 8.68 (d, J =
6.0 Hz, 1 H, NCHCH).
13C NMR (125 MHz, CDCl3): δ = 28.73 (d, J = 3.1 Hz, C(CH3)3), 36.39 (d,
J = 3.1 Hz, C(CH3)3), 125.60 (d, J = 5.4 Hz, NCHCH), 130.11 (d, J =
38.3 Hz, NCHCF), 137.51 (d, J = 4.4 Hz, NCHCH), 158.07 (d, J = 9.2 Hz,
CC(CH3)3), 159.58 (d, J = 259.8 Hz, CF).
Yield: 96 mg (30%); yellow solid; mp 38–39 °C; Rf = 0.31 (SiO2; n-pen-
HRMS (EI): m/z [M]+ calcd for C9H13FN: 154.1027; found: 154.1026.
tane/EtOAc, 1:1).
IR (KBr): 3043, 2986, 2972, 2878, 2224, 1584, 1541, 1485, 1468, 1403,
1373, 1266, 1236, 1207, 1189, 1107, 1071, 981, 942, 930, 842, 788,
4-(tert-Butyl)-3-phenylpyridine (11h)
764, 695 cm–1
.
According to GP-A, a solution of 9h (0.47 g, 3.0 mmol, 0.44 mL) in
CH2Cl2 (18 mL) was treated with TIPSOTf (1.0 g, 3.2 mmol, 0.87 mL),
1,4-dioxane (0.58 g, 6.6 mmol, 0.57 mL) and t-Bu2Mg (0.44 M in Et2O,
6.0 mmol, 14 mL). Quantitative analysis revealed 976 mg (88%) of di-
hydropyridine 10h. Purification by FC (Al2O3-basic, activity III, n-pen-
tane). Oxidation of dihydropyridine 10h was performed according to
GP-B with sulfur (0.11 g, 3.3 mmol) and naphthalene (5.8 g, 45
mmol). Purification by FC (SiO2; n-pentane/Et2O, 1:2) afforded 11h.
1H NMR (500 MHz, CDCl3): δ = 1.52 (s, 9 H, (CH3)3), 7.40 (d, J = 5.4 Hz,
1 H, NCHCH), 8.68 (d, J = 5.4 Hz, 1 H, NCHCH), 8.82 (s, 1 H, NCHCCN).
13C NMR (125 MHz, CDCl3): δ = 29.36 (C(CH3)3), 35.85 (C(CH3)3),
108.56 (NCHCCN), 118.10 (CN), 120.85 (NCHCH), 153.03 (NCHCH),
155.06 (NCHCCN), 162.37 (CC(CH3)3).
HRMS (EI): m/z [M]+ calcd for C10H12N2: 160.0995; found: 160.0997.
The analytical data were consistent with those previously reported.13
Yield: 477 mg (75%); colorless solid; mp 106–107 °C; Rf = 0.36 (SiO2;
n-pentane/Et2O, 1:2).
Ethyl 4-(tert-Butyl)pyridine-3-carboxylate (8)
IR (film): 3025, 3000, 2964, 2953, 1959, 1894, 1850, 1820, 1770,
1598, 1584, 1538, 1478, 1457, 1439, 1400, 1364, 1302, 1256, 1232,
According to GP-A, a solution of 9a (305 mg, 2.00 mmol, 276 μL) in
CH2Cl2 (12 mL) was treated with TIPSOTf (663 mg, 2.10 mmol, 582
μL), 1,4-dioxane (388 mg, 4.40 mmol, 376 μL) and t-Bu2Mg (0.43 M in
Et2O, 4.00 mmol, 9.30 mL). Quantitative analysis revealed 628 mg
(86%) of dihydropyridine 7. Purification by FC (SiO2; n-pentane/EtOAc,
9:1). Oxidation of dihydropyridine 7 was performed according to GP-
B with sulfur (70.5 mg, 2.20 mmol) and naphthalene (3.85 g, 30.0
mmol). Purification by FC (SiO2; hexanes/EtOAc, 4:1) afforded 8.
1201, 1092, 1070, 1036, 1006, 992, 842, 774, 710, 696 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.18 (s, 9 H, (CH3)3), 7.25–7.29 (m, 2 H,
CCHCHCH), 7.36–7.40 (m, 4 H, NCHCH, CCHCHCH, CCHCHCH), 8.16 (s,
1 H, NCHCCCHCHCH), 8.45 (d, J = 5.5 Hz, 1 H, NCHCH).
13C NMR (125 MHz, CDCl3): δ = 31.83 (C(CH3)3), 36.85 (C(CH3)3),
121.54 (NCHCH), 127.63 (CCHCHCH), 127.87 (CCHCHCH), 130.75
(CCHCHCH), 137.83 (CCHCHCH), 141.76 (NCHCCCHCHCH), 149.07
(NCHCH), 152.63 (NCHCCCHCHCH), 156.57 (CC(CH3)3).
Yield: 343 mg (83%); slightly yellowish oil; Rf = 0.42 (SiO2; hex-
anes/EtOAc, 4:1).
HRMS (EI): m/z [M]+ calcd for C15H17N: 211.1361; found: 211.1355.
IR (film): 2969, 2910, 2873, 1728, 1586, 1544, 1487, 1468, 1448,
1403, 1367, 1302, 1275, 1258, 1231, 1202, 1173, 1135, 1094, 1065,
1016, 959, 932, 873, 858, 837, 787, 754, 724, 687 cm–1
.
4-(tert-Butyl)-N,N-dimethylpyridine-3-carboxamide (11i)
According to GP-A, a solution of 9i (0.45 g, 3.0 mmol) in CH2Cl2 (18
mL) was treated with TIPSOTf (1.9 g, 6.0 mmol, 1.7 mL), 1,4-dioxane
(0.58 g, 6.6 mmol, 0.57 mL) and t-Bu2Mg (0.39 M in Et2O, 6.0 mmol, 15
mL). Quantitative analysis revealed 810 mg (74%) of dihydropyridine
10i. Purification by FC (Al2O3-basic, activity III; n-pentane/EtOAc/CH2Cl2,
3:1:1). Oxidation of dihydropyridine 10i was performed according to
GP-B with sulfur (0.11 g, 3.3 mmol) and naphthalene (5.8 g, 45
mmol). Purification by FC (Al2O3-basic, activity III; EtOAc/CH2Cl2, 2:3)
afforded 11i.
1H NMR (500 MHz, CDCl3): δ = 1.39–1.42 (m, 12 H, (CH3)3, CH2CH3),
4.40 (q, J = 7.2 Hz, 2 H, CH2), 7.35 (d, J = 5.5 Hz, 1 H, NCHCH), 8.51 (s,
1 H, NCHCCO), 8.55 (d, J = 5.5 Hz, 1 H, NCHCH).
13C NMR (125 MHz, CDCl3): δ = 14.07 (CH3CH2), 30.49 ((CH3)3), 36.01
(C(CH3)3), 61.85 (CH2CH3), 121.45 (NCHCH), 129.22 (NCHCCO), 149.36
(NCHCCO), 150.94 (NCHCH), 156.71 (NCHCHC), 169.87 (CCOOCH2).
HRMS (EI): m/z [M]+ calcd for C12H17NO2: 207.1254; found: 207.1257.
4-(tert-Butyl)-3-fluoropyridin-1-ium Chloride (11g)
Yield: 312 mg (50%); clear yellowish oil; Rf = 0.26 (Al2O3; EtOAc/CH2Cl2,
According to GP-A, a solution of 9g (0.29 g, 3.0 mmol, 0.26 mL) in
CH2Cl2 (18 mL) was treated with TIPSOTf (1.0 g, 3.2 mmol, 0.87 mL),
1,4-dioxane (0.58 g, 6.6 mmol, 0.57 mL) and t-Bu2Mg (0.44 M in Et2O,
6.0 mmol, 14 mL). Quantitative analysis revealed 805 mg (86%) of di-
hydropyridine 10g. Purification by FC (Al2O3-basic, activity III, n-pen-
2:3).
IR (film): 2961, 2871, 1638, 1585, 1543, 1484, 1394, 1365, 1262,
1216, 1199, 1117, 1092, 1055, 933, 916, 843, 759, 696, 660 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

I
S. Rappenglück et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.38 (s, 9 H, (CH3)3), 2.85 (s, 3 H, NCH3),
3.13 (s, 3 H, NCH3), 7.36 (dd, J = 5.5/0.6 Hz, 1 H, NCHCH), 8.26–8.29
(m, 1 H, NCHCCO), 8.50 (d, J = 5.5 Hz, 1 H, NCHCH).
13C NMR (100 MHz, CDCl3): δ = 30.41 (C(CH3)3), 34.85 (NCH3), 36.23
(C(CH3)3), 39.36 (NCH3), 122.14 (NCHCH), 131.24 (NCHCCO), 148.05
(NCHCCO), 149.84 (NCHCH), 155.95 (CC(CH3)3), 170.79 (CO).
13C NMR (100 MHz, CDCl3): δ = 22.90 (NCH2CH2), 31.39 (C(CH3)3),
35.53 (C(CH3)3), 36.41 (NCHCH2), 40.29 (NCH3), 56.82 (NCH2CH2),
65.61 (NCHCH2), 119.71 (NCHCH), 138.32 (CH3NCHC), 147.71
(NCHCH), 151.76 (NCHCCHNCH3), 156.24 (CC(CH3)3) ppm.
HRMS (EI): m/z [M]+ calcd for C14H22N2: 218.1783; found: 218.1774.
HRMS (EI): m/z [M + H]+ calcd for C12H19N2O: 207.1492; found:
207.1532.
Funding Information
This study was funded by the German Ministry of Defense
4-(tert-Butyl)-3-ethynylpyridine (11j)
(E/U2AD/CF514/DF561).
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6
1)
According to GP-A, a solution of 9j (0.32 g, 3.0 mmol) in CH2Cl2 (18
mL) was treated with TIPSOTf (1.0 g, 3.2 mmol, 0.87 mL), 1,4-dioxane
(0.58 g, 6.6 mmol, 0.57 mL) and t-Bu2Mg (0.42 M in Et2O, 6.0 mmol, 14
mL). Quantitative analysis revealed 848 mg (89%) of dihydropyridine
10j. Purification by FC (Al2O3-basic, activity III; n-pentane). The color-
less oil was dissolved in 1,4-dioxane (0.6 mL), treated with Pd/C (10%
Pd, 0.16 g, 0.15 mmol) and the resulting suspension was stirred for 9
days at r.t. The mixture was filtered over Celite, washed with Et2O (80
mL) and the organic layer was extracted with 2 M HCl (3 × 30 mL). The
combined aqueous layers were washed with Et2O (40 mL), neutralized
with K2CO3, and extracted with CH2Cl2 (3 × 30 mL). The combined or-
ganic layers were dried over MgSO4 and the solvent was removed un-
der reduced pressure. The residue was purified by FC (SiO2; n-pen-
tane/Et2O, 1:1) to yield 11j.
Supporting Information
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-15890025.
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References
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Yield: 146 mg (31%); colorless liquid; Rf = 0.47 (SiO2; n-pentane/Et2O,
1:1).
IR (film): 3298, 3205, 3035, 2992, 2963, 2909, 2871, 2098, 1583,
1537, 1483, 1463, 1448, 1398, 1365, 1291, 1263, 1203, 1193, 1102,
1075, 933, 850, 835, 789, 697 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.49–1.50 (m, 9 H, (CH3)3), 3.52 (s, 1 H,
CCH), 7.24–7.25 (m, 1 H, NCHCH), 8.44 (d, J = 5.4 Hz, 1 H, NCHCH),
8.65 (s, 1 H, NCHCCCH).
13C NMR (100 MHz, CDCl3): δ = 29.07 (C(CH3)3), 35.87 (C(CH3)3), 81.96
(CCH), 85.75 (CCH), 117.74 (NCHCCCH), 120.13 (NCHCH), 149.30
(NCHCH), 155.79 (NCHCCCH), 160.55 (CC(CH3)3).
HRMS (EI): m/z [M]+ calcd for C11H13N: 159.1048; found: 159.1049.
rac-4-(tert-Butyl)-3-(1-methylpyrrolidin-2-yl)pyridine (rac-11k)
According to GP-A, a solution of rac-9k (810 mg, 5.00 mmol, 798 μL)
in CH2Cl2 (30 mL) was treated with TIPSOTf (1.66 g, 5.25 mmol, 1.45
mL), 1,4-dioxane (969 mg, 11.0 mmol, 941 μL) and t-Bu2Mg (0.41 M in
Et2O, 5.50 mmol, 13.4 mL). Quantitative analysis revealed 1.53 g (81%)
of dihydropyridine rac-10k. Purification by FC (Al2O3-basic, activity
III; hexanes/EtOAc, 4:1). Oxidation of dihydropyridine rac-10k was
performed according to GP-B with sulfur (176 mg, 5.50 mmol) and
naphthalene (9.61 g, 75.0 mmol) at 120 °C. Purification by FC (SiO2;
Et2O/Et3N, 97:3) afforded rac-11k.
Yield: 671 mg (62%); colorless solid; mp 63 °C; Rf = 0.48 (SiO2;
Et2O/Et3N, 97:3).
IR (film): 3101, 3070, 3042, 2995, 2963, 2935, 2906, 2873, 2831,
2772, 2662, 1589, 1535, 1482, 1459, 1414, 1403, 1366, 1350, 1319,
1296, 1255, 1234, 1219, 1192, 1173, 1154, 1113, 1083, 1043, 974,
963, 922, 900, 841, 827, 709, 592, 573, 520 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.42 (s, 9 H, (CH3)3), 1.63–1.74 (m, 1 H,
NCHCHH), 1.76–1.87 (m, 1 H, NCH2CHH), 1.96–2.09 (m, 1 H,
NCH2CHH), 2.19 (s, 3 H, NCH3), 2.22–2.37 (m, 2 H, NCHCHH, NCH-
HCH2), 3.24–3.31 (m, 1 H, NCHHCH2), 3.82 (t, J = 8.2 Hz, 1 H, NCHCH2),
7.16 (d, J = 5.4 Hz, 1 H, NCHCH), 8.35 (d, J = 5.4 Hz, 1 H, NCHCH), 8.96
(s, 1 H, NCHCCHNCH3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

J
S. Rappenglück et al.
Paper
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