Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz syntheses of tri- and tetrasubstituted pyridines

Article abstract of DOI:10.1515/znb-2016-0046

The concatenation of the modified Sonogashira alkynone synthesis and the Bagley-Bohlmann-Rahtz pyridine synthesis gives novel consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz (cBBR) syntheses of tri- and tetrasubstituted pyridines in a one-pot fashion. With these processes 15 differently substituted 3-ethoxycarbonyl 2-methylpyridines can be readily obtained in modest to moderate yields.

Full text of DOI:10.1515/znb-2016-0046

Z. Naturforsch. 2016; aop
Janis Dohe and Thomas J.J. Müller*
Consecutive three- and four-component
coupling-Bagley-Bohlmann-Rahtz syntheses
of tri- and tetrasubstituted pyridines
DOI 10.1515/znb-2016-0046
Pyridines can be accessed either by ring functionaliza-
Received March 2, 2016; accepted March 11, 2016
tion and transformation or by de novo syntheses [43, 44].
Among de novo pyridine formations one-pot multicom-
ponent syntheses by Tschitschibabin [45] (name spelled
as in the original publication [45]; engl. Chichibabin) and
Hantzsch [46] have become most attractive (Scheme 2).
However, a major drawback of the Tschitschibabin pyri-
dine synthesis lies in the high pressure which leads to the
formation of many byproducts. Although the Hantzsch
Abstract: The concatenation of the modified Sonogashira
alkynone synthesis and the Bagley-Bohlmann-Rahtz pyri-
dine synthesis gives novel consecutive three- and four-
component coupling-Bagley-Bohlmann-Rahtz (cBBR)
syntheses of tri- and tetrasubstituted pyridines in a one-
pot fashion. With these processes 15 differently substi-
tuted 3-ethoxycarbonyl 2-methylpyridines can be readily
obtained in modest to moderate yields.
(
dihydro)pyridine synthesis has become a useful tool for
the synthesis of many pyridines, among them the dihydro-
Keywords: alkynylation; catalysis; coupling; cyclocon- pyridine Nifedipine, a powerful medication in the treat-
densation; multicomponent reactions; pyridines.
ment of coronary diseases [47, 48], the downside of this
one-pot process are the necessity of an oxidation step to
the pyridine target and the inherent low degree of diversity.
For overcoming these limitations, a couple of years
ago we have disclosed versatile three- and four-component
syntheses of unsymmetrically substituted [49, 50] and
anellated pyridines [51, 52] initiated by a Pd/Cu-catalyzed
coupling-isomerization domino reaction [53–56]. Inter-
estingly, already in 1957, Bohlmann and Rahtz reported a
two-step pyridine synthesis by cyclization of an alkynone
with an enamine (Scheme 3) [57].
1
Introduction
The synthesis of pyridines [1, 2] and their derivatization
is an ongoing important topic in synthetic chemistry. In
addition numerous compounds containing the pyridine
core exhibit highly interesting properties. Besides their
application as building blocks in synthesis [3–8], supra-
molecular and coordination chemistry [9–16], and as
functional constituents in materials science [17–22] many
derivatives have raised particular interest due to their high
biological activity [23–35].
The amino-butadienone intermediate had to be iso-
lated and the employed high temperatures for the cyclo-
condensation step made the original protocol less attractive
for application until Bagley and coworkers used the Bohl-
mann-Rahtz synthesis in 1998 as an elegant key step in the
synthesis of promothiocin A for quickly establishing the
Today pyridines are commonly found in drugs and
agrochemicals. In particular, they are important active
ingredients in herbicides, fungicides and insecticides [36–
2
,3,6-trisubstituted pyridine core (Scheme 4) [58–60].
3
9], and furthermore in several potent pharmaceuticals
against, e.g. asthma, inflammation and coronary diseases
Scheme 1) [40]. Therefore, the development of novel syn-
theses of substituted pyridines is particularly important
41, 42].
Later, Bagley’s group undertook major efforts to
develop general two-component processes that circum-
vent the isolation of the amino-butadienone intermediate
by adjusting the reaction conditions, using microwave
irradiation, Brønsted or Lewis acid catalysis as well as
ethanol as a favorable solvent in the cyclization step
(Scheme 5) [61–63].
(
[
*
Corresponding author: Thomas J.J. Müller, Institut für Organische
Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität
Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany,
Fax: +49 (0)211 81 14324, E-mail: thomasjj.mueller@uni-duesseldorf.de
Janis Dohe: Institut für Organische Chemie und Makromolekulare
Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse
Another major achievement was the in-situ genera-
tion of the enamine by reaction of a β-ketoester with an
ammonia source furnishing a three-component variation
of the Bohlmann-Rahtz pyridine synthesis (Scheme 6)
[64–66].
1, D-40225 Düsseldorf, Germany
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ꢀꢀꢀꢀꢁꢀJ. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz syntheses
NO2
O
O
O
Cl
N
Cl
Cl
OH
MeO
OMe
+
N+
Br
N
Br
−
−
N
N
H
NC
CN
Nicotinic Acid
vitamin B3)
Nifedipine
Dowco 263
(fungicide)
Diquat dibromide
(herbicide)
(
(calcium channel blocker)
Scheme 1:ꢀExamples of biological active compounds containing a pyridine core.
Tschitschibabin pyridine synthesis
R1
R1
high pressure
O
3
+
NH3
R1
R1
N
Hantzsch (dihydro)pyridine synthesis
O
R3
O
R3
O
O
O
O
O
EtOH/AcOH
reflux
oxidation
2
OR2
R O
2
OR2
2
+
+
NH3
R O
R1
OR2
R3
H
R1
N
R1
R1
R1
N
H
Scheme 2:ꢀClassical pseudo four-component syntheses of pyridines by Tschitschibabin (top) and Hantzsch (bottom).
O
R2
R2
N
O
R4
EtOH, 50 °C
R4
120−170 °C, vacuum
− H2O
R4
R1
+
R1
R3
R2
H2N
H2N
R3
R1
R3
9
(
examples
72−90%)
Scheme 3:ꢀBohlmann-Rahtz pyridine synthesis.
O
OBn
O
H
N
O
NH2
O
OBn
N
S
HN
N
O
H
+
a) EtOH, 50 °C
O
N
EtO
N
EtO
N
O
N
b) neat, 140 °C
O
O
N
O
HN
S
N
NH2
O
BocHN
N
NH
O
O
BocHN
promothiocin A
Scheme 4:ꢀBohlmann-Rahtz pyridine synthesis as a key step in the synthesis of promothiocin A.
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J. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz synthesesꢂꢁꢀꢀꢀꢂ3
toluene-AcOH (5:1), 50 °C, 5−6 h
or
ZnBr2/Yb(OTf)3 (15 mol%), toluene, ∆, 5−24 h
or
amberlyst 15, toluene, 50°C, 26 h
or
DMSO, 170 °C (MW), 20 min
R3
N
or
O
toluene-AcOH (5:1), 170 °C (MW), 10 min
R2
NH2
1
R2
R4
+
R1
R3
R1
1
R4
R
R
R
R
= Me, Ph, (hetero)aryl
= CO2Et, CO2tBu
= H, Et, Ph, TMS
7 examples
24−96%)
2
3
4
(
= Me, CO2Et, p-ClC6H4, p-MeOC6H4
Scheme 5:ꢀBagley’s one-pot Bohlmann-Rahtz pyridine synthesis.
AcOH/ZnBr2/amberlyst 15
toluene, ∆, 20 h
R3
or
O
R2
O
EtOH, ∆, 24 h
R2
+
R4
+
NH4OAc
R1
R3
R1
1
R4
N
4 examples
38−98%)
R1 = Me, Ph, (hetero)aryl
(
2
R
R
R
= CO2Et, CO2tBu, C(O)NH2
3
4
= H, Et, Ph, TMS
= Me, Ph, p-ClC6H4, p-MeOC6H4
Scheme 6:ꢀBagley’s three-component Bohlmann-Rahtz pyridine synthesis.
Having expanded the cross-coupling avenue to 2-thienoyl chloride (1a), 1-hexyne (2a), and ethyl 3-ami-
Michael systems to catalytic ynone formation as an entry nocrotonate (3) as a model system to give ethyl 2-methyl-
to consecutive multicomponent syntheses of heterocycles 4-n-butyl-6-(thiophen-2-yl)pyridine-3-carboxylate
(4a)
[
67–70], we became interested in developing a coupling- (Scheme 7, Table 1).
Bagley-Bohlmann-Rahtz (cBBR) pyridine synthesis ini-
With a reaction temperature of 100°C for the Bagley-
tiated by catalytic ynone generation. Here, we report Bohlmann-Rahtz (BBR) step, a reaction time of 3 h was not
studies on consecutive three- and four-component pyri- sufficient (Table 1, entry 1) and full conversion was achieved
dine syntheses via the Bagley-Bohlmann-Rahtz avenue.
after 24 h (Table 1, entry 2). Increasing ethyl-3-aminocroto-
nate (3) from 1 to 2 equivalents caused a significant loss in
yield of pyridine 4a (Table 1, entry 5). A further increase of
the reaction temperature, for instance by microwave irra-
diation, either gave substantially lower yield or increased
2
Results and discussion
Starting from the outset of modified Sonogashira cou- decomposition (Table 1, entries 6, 9, 11, and 14). Interest-
pling as an entry to ynone formation from acid chlorides ingly, the absence of acetic acid led to considerably longer
and terminal alkynes [71, 72], we first set out to probe the reaction times to achieve full conversion (Table 1, entry
reaction conditions of the three-component process with 8). Unfortunately, Bagley’s best original conditions only
2
4
1
mol% Pd(PPh3)2Cl2
mol% CuI
.0 equiv NEt3, solvent, r. t., 2 h
nBu
O
O
OEt
+
nBu
Cl
NH2
O
N
Me
S
then:
3
S
Me
OEt
1
a
2a
4a
cosolvent, acid, T, t
Scheme 7:ꢀOptimization of the three-component cBBR synthesis of pyridine 4a.
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4
ꢀꢀꢀꢀꢁꢀJ. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz syntheses
Table 1:ꢀOptimization of the three-component cBBR synthesis of ethyl 2-methyl-4-n-butyl-6-(thiophen-2-yl)pyridine-3-carboxylate (4a).
Entryꢁ
Solvent
ꢁ
Ethyl ꢂ-amino- ꢁ
crotonate (ꢂ)
Cosolvent
ꢁ
Acid
ꢁ
T (°C) ꢁ
t (h)ꢁ
Yield of pyridine
a
ꢃa (%)
ꢃ
ꢄ
ꢇ
ꢉ
ꢅ
ꢋ
7
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
THF (ꢅ.ꢆ mL)
ꢄ
ꢄ
ꢄ
ꢃ.ꢆ equiv
ꢆ.0 equiv
ꢃ.ꢆ equiv
ꢃ.ꢆ equiv
ꢈ.ꢆ equivs
ꢈ.ꢆ equivs
ꢃ.ꢆ equiv
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
–
–
–
–
–
–
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
AcOH
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢃꢆꢆ
ꢆ00
ꢅꢆ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢇꢄ
ꢄꢃꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢉꢄ
n.i.b
ꢃ9
ꢈꢉ
ꢃꢉ
ꢈꢊ
ꢃꢃ
ꢇꢋ
ꢇꢊ
(
ꢃ7.ꢅ equivs)
THF (ꢅ.0 mL)
AcOH
ꢆꢇ.ꢅ equivs)
AcOH
ꢃ7.ꢅ equivs)
AcOH
ꢃ7.ꢅ equivs)
AcOH
ꢃ7.ꢅ equivs)
AcOH
ꢃ7.ꢅ equivs)
AcOH
(
Toluene (ꢅ.ꢆ mL)
(
ꢃ,ꢉ-dioxane (ꢅ.ꢆ mL) ꢄ
ꢃꢈꢆ
ꢃꢆꢆ
ꢃꢈꢆc
ꢃꢆꢆ
(
THF (ꢅ.ꢆ mL)
THF (ꢅ.ꢆ mL)
THF (ꢅ.ꢆ mL)
ꢄ
ꢄ
ꢄ
(
(
EtOH (ꢈ.ꢆ mL)ꢄ
EtOH (ꢅ.ꢆ mL)ꢄ
ꢈꢉꢄ
(
ꢈ.ꢆ equivs)
ꢌ
ꢊ
ꢄ
ꢄ
THF (ꢅ.ꢆ mL)
Toluene (ꢈ.ꢆ mL)
ꢄ
ꢄ
ꢈ.ꢆ equivs
ꢈ.ꢆ equivs
ꢄ
ꢄ
–
ꢄ
ꢄ
ꢃꢆꢆ
ꢄ
ꢄ
7ꢉꢄ
ꢃꢉꢄ
ꢃ7ꢆc
n.i.
b
–
–
–
–
–
–
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
AcOH
(
7.ꢆ equivs)
ꢃꢆ
ꢃꢃd
ꢃꢈ
ꢃꢇ
ꢃꢉ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
Toluene (ꢅ.ꢆ mL)
Toluene (ꢅ.ꢆ mL)
ꢄ
ꢄ
ꢃ.ꢆ equiv
ꢃ.ꢆ equiv
ꢃ.ꢆ equiv
ꢃ.ꢆ equiv
ꢈ.ꢆ equivs
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ZnBrꢈ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢃꢉꢆ
ꢃ7ꢆc
ꢃꢈꢆ
ꢃꢈꢆ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢈꢉꢄ
ꢈꢄ
ꢋ
(
ꢆ.ꢃꢌ equivs)
.
BF OEt
ꢃꢈ
n.i.b
–
ꢇ
ꢈ
(
ꢃ.ꢈꢅ equivs)
ꢃ,ꢉ-dioxane (ꢅ.ꢆ mL) ꢄ
ꢃ,ꢉ-dioxane (ꢅ.ꢆ mL) ꢄ
Amberlyst
ꢃꢅ (ꢃꢆꢆ mg)
PTSA
ꢈꢉꢄ
ꢈꢉꢄ
ꢋꢄ
(
ꢅ.ꢆ equivs)
PTSA
ꢈ.ꢆ equivs)
MeCN (ꢅ.ꢆ mL)
ꢄ
ꢃꢉꢆc
MW
–
(
a
b
c
Isolated yield after flash chromatography; n.i. (not isolated due to incomplete conversion or decomposition according to TLC); hold
d
temperature in the microwave cavity; coupling at ꢍ0°C, 1ꢍ h. Bold face refers to the optimal conditions in this study.
furnished 24% of compound 4a (Table 1, entry 3). Neither the acid chloride 1 and the alkyne 2, while ethyl 3-ami-
1
,4-dioxane, toluene or acetonitrile as solvents (Table 1, nocrotonate (3) was kept constant as a substrate in this
entries 3, 4, 9–14) nor the employment of different Brøn- study. Upon coupling acid chloride 1 and alkyne 2 in
sted or Lewis acids, such as PTSA (Table 1, entries 13 and the presence of catalytic amounts of Pd(PPh ) Cl and
3
2
2
14), amberlyst 15 (Table 1, entry 12), zinc bromide or boron CuI and triethylamine as a base, the formed ynone was
trifluoride etherate (Table 1, entries 10, 11) gave satisfying subsequently reacted with ethyl 3-aminocrotonate (3a)
yields. In summary, the conditions of entry 2 employing and acetic acid in the same reaction vessel at 100°C for
THF as a solvent and addition of 17.5 equivalents of acetic 24 h to give after purification 3-ethoxycarbonyl 2-meth-
acid for the BBR step performed at 100°C for 24 h turned ylpyridines 4 in low to moderate yields in the sense of a
out to give the highest yields of model compound 4a.
consecutive three-component coupling-BBR sequence
With these conditions in hand, the stage was set to (Scheme 8, Table 2). The structures of all compounds were
1
13
probe the scope at two points of diversity, namely from unambiguously assigned by extensive H and C NMR and
2
4
1
mol% Pd(PPh3)2Cl2
mol% CuI
.0 equiv NEt3, THF, r. t., 2 h
R2
O
O
R2
OEt
R1
+
Cl
NH2
O
R1
N
Me
then:
3 (1.0 equiv)
Me
OEt
1
2
4
AcOH (17.5 equivs), 100 °C, 24 h
Scheme 8:ꢀThree-component cBBR synthesis of 3-ethoxycarbonyl 2-methylpyridines 4.
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J. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz synthesesꢂꢁꢀꢀꢀꢂ5
Table 2:ꢀConsecutive three-component cBBR synthesis of 3-ethoxycarbonyl-2-methylpyridines 4.
Entry ꢁ
Acid chloride ꢆ
ꢁ
Alkyne ꢄ
ꢁ
ꢂ-Ethoxycarbonyl-ꢄ-methylpyridine ꢃ (%)a
nBu
ꢃ
ꢄ
Rꢃ ꢄ=ꢄ ꢈ-thienyl (ꢆa)
ꢄ
Rꢈ ꢄ=ꢄ n-butyl (ꢄa)ꢄ
CO2Et
N
Me
S
4
a (49)
nBu
ꢃ
ꢈ
ꢄ
R ꢄ=ꢄ p-MeOC H (ꢆb)ꢄ
ꢄa
ꢄa
ꢄ
ꢄ
ꢋ
ꢉ
2
CO Et
N
Me
4b (24)
MeO
nBu
ꢃ
ꢇ
ꢉ
ꢄ
ꢄ
R ꢄ=ꢄ p-ClC H (ꢆc)
ꢄ
ꢋ
ꢉ
CO2Et
Me
N
4c (37)
Cl
nBu
ꢃ
R ꢄ=ꢄ p-O NC H (ꢆd) ꢄ
ꢄa
ꢄ
ꢈ
ꢋ
ꢉ
2
CO Et
N
Me
4
d (29)
2
O N
Ph
N
ꢅ
ꢋ
ꢄ
ꢄ
ꢆa
ꢄ
ꢄ
Rꢈ ꢄ=ꢄ Ph (ꢄb)
ꢄ
ꢄ
CO2Et
Me
S
4e (20)
Ph
ꢃ
R ꢄ=ꢄ p-MeC H (ꢆe)
ꢄb
ꢋ
ꢉ
CO2Et
N
Me
4f (24)
Me
Ph
7
ꢄ
ꢆc
ꢄ
ꢄb
ꢄ
CO2Et
Me
N
4g (38)
Cl
Ph
N
ꢃ
ꢌ
ꢊ
ꢄ
ꢄ
R ꢄ=ꢄ o-FC H (ꢆf)
ꢄ
ꢄ
ꢄb
ꢄ
ꢄ
ꢋ
ꢉ
CO2Et
Me
4h (33)
F
CO2Et
ꢆa
Rꢈ ꢄ=ꢄ H (ꢄc)b
N
Me
S
4i (36)
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ꢀꢀꢀꢀꢁꢀJ. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz syntheses
Table 2ꢀ(continued)
Entry ꢁ
Acid chloride ꢆ
ꢆb
ꢁ
Alkyne ꢄ
ꢄc
ꢁ
ꢂ-Ethoxycarbonyl-ꢄ-methylpyridine ꢃ (%)a
CO2Et
ꢃꢆ
ꢄ
ꢄ
ꢄ
N
Me
4j (19)
MeO
CO2Et
ꢃꢃ
ꢄ
ꢆc
ꢄ
ꢄc
ꢄ
N
Me
4k (47)
Cl
CO2Et
ꢃꢈ
ꢃꢇ
ꢃꢉ
ꢄ
ꢄ
ꢆd
ꢆe
ꢄ
ꢄ
ꢄc
ꢄc
ꢄ
ꢄ
N
Me
4
l (52)
O2N
CO2Et
N
Me
4m (30)
Me
CO2Et
Me
ꢄ
ꢄ
ꢆf
ꢄ
ꢄ
ꢄc
ꢄc
ꢄ
ꢄ
N
4
n (55)
F
CO2Et
Me
ꢃꢅ
Rꢃ ꢄ=ꢄ Ph (ꢆg)
Ph
N
4o (28)
a
b
Isolated yield after flash chromatography; the employed alkyne 2c is (trimethylsilyl)acetylene.
IR spectroscopy, mass spectrometry and combustion anal- and phenyl substituents as representatives of alkyl and
ysis or HRMS.
aryl substitution are introduced in the 4-position of the
The isolated yields of this novel one-pot sequence fall pyridines 4.
in a range between 19–55%. Taking into account that three
Furthermore, we became interested in probing
new bonds are being formed, the yield per bond forming Bagley’s three-component Bohlmann-Rahtz pyridine
step counts to 57–82%.
synthesis, i.e. the in-situ formation of ethyl 3-aminocro-
In general, the yields for the trisubstituted pyridines tonate (3) by condensation of ethyl acetoacetate and
4
(Table 2, entries 9–15) are higher than for the tetrasu- an ammonia source after the cross-coupling step, and
bstituted derivatives (Table 2, entries 1–8). The variation developing it into a four-component cBBR pyridine
of electron withdrawing and electron donating groups in synthesis. Therefore, we chose the previous model system
the acid chloride 1 is generally possible and these polar (Scheme 7), however, now employing ethyl acetoacetate
functional groups are tolerated. As previously reported for (5) and ammonium acetate as third and fourth compo-
other one-pot synthesis initiated by catalytic ynone forma- nents for finding the optimal conditions for the formation
tion [67–70], when (trimethylsilyl)acetylene is employed of model pyridine 4a (Scheme 9, Table 3).
as alkyne the silyl group is concomitantly cleaved upon
Without the addition of a cosolvent and an acid the
Michael addition/cyclocondensation and, therefore, BBR step took 74 h to full conversion of the intermedi-
trisubstituted pyridines are the obvious reaction products. ate alkynone at 100°C and only 24% of product 4a could
For the synthesis of tetrasubstituted pyridines n-butyl be isolated (Table 3, entry 1). Ethanol as a cosolvent and
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J. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz synthesesꢂꢁꢀꢀꢀꢂ7
2
4
1
mol% Pd(PPh3)2Cl2
mol% CuI
.0 equiv NEt3, solvent, r. t., 2 h
nBu
O
O
OEt
+
nBu
Cl
O
O
N
Me
S
then:
5
S
Me
OEt
1
a
2a
4a
NH4OAc, cosolvent, acid, T, t
Scheme ꢈ:ꢀOptimization of the four-component cBBR synthesis of pyridine 4a.
increasing the reaction time from 24 to 74 h (Table 3, acetate and acetic acid, respectively, at 100°C for 24 h
entries 2 and 3) led to an increase in the yield of pyridine (Table 3, entry 8). Excessive acetic acid (Table 3, entries
4
a. However, upon reducing the amount of ammonium 10 and 13), unbalanced amounts of ethyl acetoacetate as
acetate to one equivalent caused a significant drop in well as omitting ethanol as a cosolvent (Table 3, entries
yield (Table 3, entry 4). Surprisingly, the increase in ethyl 13–16) and lower reaction temperatures (Table 3, entry
acetoacetate to two equivalents had a detrimental effect 9) always causes a drop in yield. It is also noteworthy to
on the yield (Table 3, entry 5). Expectedly, the addition of mention that the stronger acid PTSA is not an effective
acetic acid as a cocatalyst (Table 3, entries 6–11) caused catalyst (Table 3, entry 12) and 2-methoxyethanol and
an increase in the yield of the desired product, indicat- tert-butanol turned out to be poor cosolvents in the BBR
ing the crucial importance of buffered conditions. In this step, even at elevated reaction temperatures (Table 3,
optimization series the highest yield could be obtained entries 17 and 18) and toluene did not reach yields com-
with equimolar amounts of two equivalents of ammonium parable to those in ethanol (Table 3, entry 19). Dielectric
Table 3:ꢀOptimization of the four-component cBBR synthesis of ethyl 2-methyl-4-n-butyl-6-(thiophen-2-yl)pyridine-3-carboxylate (4a).
Entry ꢁ
NH OAcꢁ
Ethyl acetoacetateꢁ
(ꢅ) (equivs)
Cosolvent
ꢁ
Acid (equivs) ꢁ
T (°C)
ꢁ
t (h)ꢁ
Yield of pyridine
ꢃ
a
(
equivs)
ꢃa (%)
ꢃ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢈ.ꢆꢄ
ꢃꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢈ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢆ.0ꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢅꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢅꢄ
ꢃ.7ꢄ
ꢃ.7ꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
ꢃ.ꢆꢄ
–
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
–
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢆ00
7ꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢉꢆ
ꢃꢉꢆ
ꢃꢉꢆ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
7ꢉꢄ
7ꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢄꢃꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢆ.ꢅꢄ
ꢉꢄ
ꢈꢉ
ꢉꢉ
ꢈꢊ
ꢃꢈ
ꢃꢌ
ꢈꢇ
ꢉꢇ
ꢃꢉ
ꢃꢈ
ꢇꢋ
ꢇꢋ
ꢃꢆ
ꢈꢆ
ꢃꢉ
ꢇ
ꢈ
EtOH (ꢇ.ꢆ mL)
EtOH (ꢇ.ꢆ mL)
EtOH (ꢇ.ꢆ mL)
EtOH (ꢇ.ꢆ mL)
EtOH (ꢇ.ꢆ mL)
EtOH (ꢅ.ꢆ mL)
EtOH (ꢄ.0 mL)
EtOH (ꢈ.ꢆ mL)
EtOH (ꢈ.ꢆ mL)
EtOH (ꢈ.ꢆ mL)
EtOH (ꢈ.ꢆ mL)
–
–
ꢇ
ꢃꢆꢄ
–
ꢉ
ꢃ.ꢆꢄ
ꢃꢆꢄ
ꢃ.ꢆꢄ
ꢃꢆꢄ
–
ꢅ
–
ꢋ
AcOH (ꢆ.ꢅ)
AcOH (ꢃ.ꢆ)
AcOH (ꢄ.0)
AcOH (ꢈ.ꢆ)
7
ꢉ
ꢄ.0ꢄ
ꢈ.ꢆꢄ
ꢈ.ꢆꢄ
ꢇ.ꢆꢄ
ꢈ.ꢆꢄ
ꢈ.ꢆꢄ
ꢈ.ꢆꢄ
ꢃ7ꢄ
ꢊ
ꢃꢆ
ꢃꢃ
ꢃꢈ
ꢃꢇ
ꢃꢉ
ꢃꢅ
ꢃꢋ
ꢃ7
ꢃꢌ
ꢃꢊ
ꢈꢆ
ꢈꢃ
ꢈꢈ
ꢈꢇ
ꢈꢉ
AcOH (ꢇꢅ.ꢆ) ꢄ
AcOH (ꢈ.ꢆ)
PTSA (ꢈ.ꢆ)
ꢄ
ꢄ
AcOH (7ꢆ.ꢆ) ꢄ
AcOH (ꢃ7.ꢅ) ꢄ
–
EtOH (ꢃꢆ.ꢆ mL)
EtOH (ꢃꢆ.ꢆ mL)
–
ꢄ
ꢃ7ꢄ
AcOH (ꢅꢈ.ꢅ) ꢄ
ꢈꢉ
7
ꢈ.ꢆꢄ
ꢈ.ꢆꢄ
ꢃꢆꢄ
MeOCH CH OH (ꢈ.ꢆ mL) ꢄ
AcOH (ꢈ.ꢆ)
AcOH (ꢈ.ꢆ)
ꢄ
ꢄ
ꢈ
ꢈ
tBuOH (ꢈ.ꢆ mL)
Toluene (ꢅ.ꢆ mL)
EtOH (ꢈ.ꢆ mL)
–
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢃꢆ
ꢈꢉ
7
b
AcOH (ꢇꢅ.ꢆ) ꢄ
AcOH (ꢈ.ꢆ)
AcOH (ꢃ7.ꢅ) ꢄ
AcOH (ꢈ.ꢆ)
AcOH (ꢈ.ꢆ)
AcOH (ꢌ.7ꢅ) ꢄ
ꢈ.ꢆꢄ
ꢈ.ꢆꢄ
ꢄ
ꢃ7ꢆ (MW) ꢄ
ꢃꢈꢆ (MW) ꢄ
ꢃꢆꢆ
ꢃꢆꢆ
ꢃꢆꢆ
ꢌ
c
ꢈ.ꢆ ꢄ
EtOH (ꢈ.ꢆ mL)
EtOH (ꢈ.ꢆ mL)
–
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈꢉꢄ
ꢈ7
d
e
ꢈ.ꢆ ꢄ
n.i.
d
e
ꢈ.ꢆ ꢄ
n.i.
a
b
c
Isolated yield after flash chromatography; toluene was also employed for the coupling step instead of THF; (NH ) CO was employed as an
4
2
3
d
e
ammonia source; (NH )Cl was employed as an ammonia source; n.i. (not isolated due to incomplete conversion or decomposition accord-
ing to TLC). Bold face refers to the optimal conditions in this study.
4
Unauthenticated
Download Date | 5/16/16 7:47 PM

8
ꢀꢀꢀꢀꢁꢀJ. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz syntheses
heating with or without ethanol as a cosolvent in the BBR
step only gave poor yields of the desired product (Table
3
Experimental details
3
, entries 20 and 21). The more basic ammonium carbon-
ate as an ammonia source did not prove to be as suitable 3.1 General considerations
as ammonium acetate (Table 3, entry 22) and the more
acidic ammonium chloride turned out to be detrimental All cross coupling reactions were carried out in oven-dried
(
Table 3, entries 23 and 24). In summary, the conditions Schlenk or microwave tubes using septa and syringes
of entry 8 employing equimolar amounts of ammonium under a nitrogen atmosphere. Dry tetrahydrofuran and
acetate and acetic acid and ethanol as a cosolvent for the 1,4-dioxane were supplied by MBraun system MB-SPS-
BBR step performed at 100°C for 24 h turned out to give the 800. Chemicals were either commercially obtained from
highest yields of model compound 4a. These conditions ABCR GmbH & Co KG, Acros Organics, Alfa Aesar GmbH &
were employed to the one-pot four-component synthesis Co KG, Fluka, Merck KGaA, Riedel-de Haën, Sigma-Aldrich
of three selected examples furnishing the desired 3-ethox- Co and used as supplied or were already available in the
ycarbonyl-2-methylpyridines 4a, 4i, and 4j in low to mod- research group. All products were purified via column
erate yields (Scheme 10). Interestingly, the comparison of chromatography on silica gel 60 M (0.04–0.063 mm) from
the yields of the four-component process reveals that they Macherey-Nagel using flash technique under a pressure
®
are equal (compound 4a), lower (compound 4i), or higher of 2 bar. The crude mixtures were absorbed on Celite
(
compound 4j) than the corresponding three-component 545 (0.02–0.10 mm) from Carl Roth Gmbh (Karslruhe,
reaction (Table 2, entries 1, 9, and 10). However, taking Germany) before chromatographic purification. The reac-
into account that four new bonds are being formed in this tion progress was observed qualitatively using TLC Silica
novel consecutive four-component process the yield per gel 60 F254 aluminum sheets obtained by Merck KGaA.
bond forming step counts to 68–83%, the sequence can be The spots were detected with UV light at 254 nm and
1
13
considered to be quite efficient.
with aqueous potassium permanganate solution. H, C,
In conclusion we could expand the two- and three- and 135 DEPT spectra were recorded on Bruker AVIII-300
component Bagley variation of the Bohlmann-Rahtz and Bruker AVIII-600 spectrometers. CDCl was used as
3
pyridine synthesis into three- and four-component cBBR solvent. The resonance of CDCl was locked as internal
3
1
13
sequences in a one-pot fashion furnishing the targeted standard (CDCl : H δ ꢀ=ꢀ 7.26 ppm, C δ ꢀ=ꢀ 77.0 ppm). The
3
3
-ethoxycarbonyl-2-methylpyridines in modest to mod- multiplicities of signals were abbreviated as follows: s,
erate yields, however, with high average bond forming singlet; d, doublet; dd, doublet of doublets; ddd, doublet
yields. This novel process not only tolerates various elec- of doublets of doublets; t, triplet; dt, doublet of triplets;
tronic modulations in the 4- and 6-positions of the pyridyl td, triplet of doublets; tt, triplet of triplets; q, quartet; m,
core as introduced in the initial coupling step. In particu- multiplet. The type of carbon atom was determined on the
lar, the extension from the three- to the four-component basis of 135-DEPT NMR spectra. For the description of the
1
3
process indicated that the in-situ formation of the relevant
C NMR spectra primary carbon atoms are abbreviated
3
-aminocrotonate is delicate and only narrow variations as CH , secondary carbon atoms as CH , tertiary carbon
3
2
in the solvents, catalysts, ammonia sources, and stoichio- atoms as CH and quaternary carbon atoms as Cquat. EI mass
metries are permitted. Further studies directed to expand spectra were measured on a Finnigan MAT TSQ 7000 spec-
the coupling-cyclization concept to the formation of other trometer. HRMS ((+)-ESI) was measured on a Bruker maXis
six-membered hetero- and carbocycles are currently 4G instrument. IR spectra were obtained on a Shimadzu
underway.
IRAffinity spectrometer. The intensity of the signals was
2
4
1
mol% Pd(PPh3)2Cl2
mol% CuI
.0 equiv NEt3, THF, r. t., 2 h
R2
O
O
R2
OEt
R1
+
Cl
O
O
R1
N
Me
then:
5 (1.0 equiv)
Me
OEt
4a (R1 = 2-thienyl, R2 = nBu, 48%)
1
2
NH4OAc (2.0 equivs)
AcOH (2.0 equivs)
EtOH, 100 °C, 24 h
1
2
a
4
4
i (R = 2-thienyl, R = H, 21%)
j (R = p-MeOC6H4, R2 = H,a 31%)
1
a
Scheme 1ꢊ:ꢀFour-component cBBR synthesis of selected 3-ethoxycarbonyl-2-methylpyridines 4 ( (trimethylsilyl)acetylene (2c) was
employed as an alkyne).
Unauthenticated
Download Date | 5/16/16 7:47 PM

J. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz synthesesꢂꢁꢀꢀꢀꢂꢈ
abbreviated as follows: s (strong), m (medium), w (weak). aqueous NaHCO solution (20 mL) and brine (20 mL)
3
The melting points were measured on a Büchi Melting and dried with anhydrous magnesium sulfate. The crude
®
Point B-540 apparatus. Combustion analyses were carried product was adsorbed on Celite and purified by column
out on a Perkin Elmer Series II Analyser 2400 and an Ele- chromatography on silica gel.
mentar vario MICRO CUBE in the microanalytical labora-
tory of the Institut für Pharmazeutische und Medizinische
Chemie of Heinrich-Heine-Universität Düsseldorf.
3.3 General procedure (GP2) for the
consecutive four-component cBBR
synthesis of 3-ethoxycarbonyl-2-
methylpyridines 4
3
.2 General procedure (GP1) for the
consecutive three-component cBBR
synthesis of 3-ethoxycarbonyl-2-
methylpyridines 4
In a screw-cap Schlenk vessel Pd(PPh ) Cl (14 mg, 0.02
3
2
2
mmol, 2 mol%) and CuI (7 mg, 0.04 mmol, 4 mol%) were
placed and dry THF (5 mL) was added under a nitrogen
In a screw-cap Schlenk vessel Pd(PPh ) Cl (14 mg, 0.02 atmosphere. The yellow suspension was degassed with a
3
2
2
mmol, 2 mol%) and CuI (7 mg, 0.04 mmol, 4 mol%) were stream of nitrogen through a syringe for 2 min (for experi-
placed and dry THF (5 mL) was added under a nitrogen mental details see Table 5). Successively, triethylamine
atmosphere. The yellow suspension was degassed with a (0.14 mL, 1.0 mmol), the acid chloride 1 (1.0 mmol), and
stream of nitrogen through a syringe for 2 min (for experi- the terminal alkyne 2 (1.0 mmol) were added and the
mental details see Table 4). Successively, triethylamine reaction mixture was stirred at room temperature for 2 h
(
0.14 mL, 1.0 mmol), the acid chloride 1 (1.0 mmol), and to complete the conversion (monitored by TLC). Then
the terminal alkyne 2 (1.0 mmol) were added and the reac- ammonium acetate (154 mg, 2.0 mmol), ethyl acetoacetate
tion mixture was stirred at room temperature for 2 h to (5) (0.13 mL, 1.0 mmol), acetic acid (0.11 mL, 2.0 mmol),
complete the conversion (monitored by TLC). Then ethyl and ethanol (2 mL) were added under nitrogen and the
3
-aminocrotonate (3) (0.13 mL, 1.0 mmol) and acetic acid solution was heated to 100°C for 24 h. After cooling to
1 mL) were added under nitrogen and the solution was room temperature the solvents were removed in vacuo
(
heated at 100°C for 24 h. After cooling to room tempera- and the residue was dissolved in ethyl acetate (30 mL)
ture the solvents were removed in vacuo and the residue and extracted with a saturated aqueous NaHCO solu-
3
was dissolved in ethyl acetate (30 mL) and extracted with a tion (30 mL). The aqueous layer was extracted with ethyl
saturated aqueous NaHCO solution (30 mL). The aqueous acetate (20 mL) and the combined organic layers were
3
layer was extracted with ethyl acetate (20 mL) and the washed with saturated aqueous NaHCO solution (20 mL)
3
combined organic layers were washed with saturated and brine (20 mL) and dried with anhydrous magnesium
Table 4:ꢀExperimental details of the consecutive three-component cBBR synthesis of 3-ethoxycarbonyl-2-methylpyridines 4.
Entry ꢁ
Acid chloride ꢆ
ꢁ
Alkyne ꢄ
ꢁ
ꢂ-Ethoxycarbonyl-ꢄ-methylpyridine ꢃa
ꢃ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢃꢃꢆ μL (ꢃ.ꢆ mmol) of ꢆa ꢄ
ꢃꢇꢌ μL (ꢃ.ꢆ mmol) of ꢆb ꢄ
ꢃꢇꢈ μL (ꢃ.ꢆ mmol) of ꢆc ꢄ
ꢃꢌꢋ mg (ꢃ.ꢆ mmol) of ꢆd ꢄ
ꢃꢃꢆ μL (ꢃ.ꢆ mmol) of ꢆa ꢄ
ꢃꢇꢉ μL (ꢃ.ꢆ mmol) of ꢆe ꢄ
ꢃꢇꢈ μL (ꢃ.ꢆ mmol) of ꢆc ꢄ
ꢃꢈꢈ μL (ꢃ.ꢆ mmol) of ꢆf ꢄ
ꢃꢃꢆ μL (ꢃ.ꢆ mmol) of ꢆa ꢄ
ꢃꢇꢌ μL (ꢃ.ꢆ mmol) of ꢆb ꢄ
ꢃꢇꢈ μL (ꢃ.ꢆ mmol) of ꢆc ꢄ
ꢃꢌꢋ mg (ꢃ.ꢆ mmol) of ꢆd ꢄ
ꢃꢇꢉ μL (ꢃ.ꢆ mmol) of ꢆe ꢄ
ꢃꢈꢈ μL (ꢃ.ꢆ mmol) of ꢆf ꢄ
ꢃꢃꢋ μL (ꢃ.ꢆ mmol) of ꢆg ꢄ
ꢃꢃꢌ μL (ꢃ.ꢆ mmol) of ꢄa ꢄ
ꢃꢃꢌ μL (ꢃ.ꢆ mmol) of ꢄa ꢄ
ꢃꢃꢌ μL (ꢃ.ꢆ mmol) of ꢄa ꢄ
ꢃꢃꢌ μL (ꢃ.ꢆ mmol) of ꢄa ꢄ
ꢃꢃꢇ μL (ꢃ.ꢆ mmol) of ꢄb ꢄ
ꢃꢃꢇ μL (ꢃ.ꢆ mmol) of ꢄb ꢄ
ꢃꢃꢇ μL (ꢃ.ꢆ mmol) of ꢄb ꢄ
ꢃꢃꢇ μL (ꢃ.ꢆ mmol) of ꢄb ꢄ
ꢃꢉꢊ mg (ꢉꢊ%) of ꢃa
7ꢊ mg (ꢈꢉ%) of ꢃb
ꢃꢈꢇ mg (ꢇ7%) of ꢃc
ꢊꢊ mg (ꢈꢊ%) of ꢃd
ꢋꢉ mg (ꢈꢆ%) of ꢃe
ꢌꢃ mg (ꢈꢉ%) of ꢃf
ꢃꢇꢇ mg (ꢇꢌ%) of ꢃg
ꢃꢃꢈ mg (ꢇꢇ%) of ꢃh
ꢌꢌ mg (ꢇꢋ%) of ꢃi
ꢅꢈ mg (ꢃꢊ%) of ꢃj
ꢃꢇꢆ mg (ꢉ7%) of ꢃk
ꢃꢅꢆ mg (ꢅꢈ%) of ꢃl
77 mg (ꢇꢆ%) of ꢃm
ꢃꢉꢈ mg (ꢅꢅ%) of ꢃn
ꢋ7 mg (ꢈꢌ%) of ꢃo
ꢈ
ꢇ
ꢉ
ꢅ
ꢋ
7
ꢌ
b
ꢊ
ꢃꢉꢉ μL (ꢃ.ꢆ mmol) of ꢄc ꢄ
b
ꢃꢆ
ꢃꢃ
ꢃꢈ
ꢃꢇ
ꢃꢉ
ꢃꢅ
ꢃꢉꢉ μL (ꢃ.ꢆ mmol) of ꢄc ꢄ
b
ꢃꢉꢉ μL (ꢃ.ꢆ mmol) of ꢄc ꢄ
b
ꢃꢉꢉ μL (ꢃ.ꢆ mmol) of ꢄc ꢄ
b
ꢃꢉꢉ μL (ꢃ.ꢆ mmol) of ꢄc ꢄ
b
ꢃꢉꢉ μL (ꢃ.ꢆ mmol) of ꢄc ꢄ
b
ꢃꢉꢉ μL (ꢃ.ꢆ mmol) of ꢄc ꢄ
a
b
Isolated yield after flash chromatography; compound 2c is (trimethylsilyl)acetylene.
Unauthenticated
Download Date | 5/16/16 7:47 PM

1
ꢊꢀꢀꢀꢀꢁꢀJ. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz syntheses
Table 5:ꢀExperimental details of the consecutive four-component cBBR synthesis of 3-ethoxycarbonyl-2-methylpyridines 4.
Entry ꢁ
Acid chloride ꢆ
ꢁ
Alkyne ꢄ
ꢁ
ꢂ-Ethoxycarbonyl-ꢄ-
methylpyridine ꢃa
ꢃ
ꢈ
ꢇ
ꢄ
ꢄ
ꢄ
ꢃꢃꢆ μL (ꢃ.ꢆ mmol) of ꢆa ꢄ
ꢃꢃꢆ μL (ꢃ.ꢆ mmol) of ꢆa ꢄ
ꢃꢇꢌ μL (ꢃ.ꢆ mmol) of ꢆb ꢄ
ꢃꢃꢌ μL (ꢃ.ꢆ mmol) of ꢄa ꢄ
ꢃꢉꢋ mg (ꢉꢌ%) of ꢃa
ꢅꢈ mg (ꢈꢃ%) of ꢃi
ꢌꢉ mg (ꢇꢃ%) of ꢃj
b
ꢃꢉꢉ μL (ꢃ.ꢆ mmol) of ꢄc ꢄ
b
ꢃꢉꢉ μL (ꢃ.ꢆ mmol) of ꢄc ꢄ
a
b
Isolated yield after flash chromatography; compound 2c is (trimethylsilyl)acetylene.
®
+
sulfate. The crude product was adsorbed on Celite and (calcd. 328.190 for [C H NO –H] ). – MS ((+)-EI): m/z (%) ꢀ=ꢀ
2
0
25
3
+
+
+
purified by column chromatography on silica gel to give 327 (100) [M] , 298 (7) [M–C H ] , 282 (35) [M–C H O] , 270
2
5
2
5
+
+
the pure pyridines 4.
(8) [M–C H ] , 254 (9) [M–C H O ] , 213 (32), 135 (14). – IR:
4 9 3 5 2
−1
ν
̃ (cm ) ꢀ=ꢀ 2957 (m), 2932 (m), 2870 (w), 2837 (w), 1721 (s),
1
607 (m), 1580 (s), 1553 (m), 1512 (s), 1456 (m), 1443 (m),
3
.4 Ethyl 2-methyl-4-butyl-6-(thiophen-2-yl) 1422 (m), 1381 (m), 1366 (m), 1267 (s), 1250 (s), 1211 (s), 1173
(
(
s), 1144 (m), 1121 (m), 1109 (m), 1094 (m), 1072 (s), 1032
m), 932 (m), 833 (s), 810 (m), 787 (m), 770 (m), 745 (m), 729
pyridine-3-carboxylate (4a)
After chromatography on silica gel (n-hexane-ethyl acetate (m), 700 (m), 665 (m), 637 (m), 623 (m).
0:1) and according to GP1 149 mg (49%) and according
5
to GP2 146 mg (48%) of compound 4a was obtained as a
1
3
yellow oil. – H NMR (CDCl , 600 MHz): δ ꢀ=ꢀ 0.94 (t, J ꢀ=ꢀ 7.4 3.6 Ethyl 2-methyl-4-butyl-6-(4-chlorophe-
3
3
Hz, 3 H), 1.35–1.42 (m, 5 H), 1.61 (tt, J ꢀ=ꢀ 7.8, 6.5 Hz, 2 H),
nyl)pyridine-3-carboxylate (4c)
3
2
.57 (s, 3 H), 2.71–2.58 (m, 2 H), 4.41 (q, J ꢀ=ꢀ 7.1 Hz, 2 H), 7.10
3
3
(
dd, J ꢀ=ꢀ 4.9, 3.8 Hz, 1 H), 7.32 (s, 1 H), 7.39 (dd, J ꢀ=ꢀ 5.2, 0.8 According to GP1 and after flash chromatography on silica
13
Hz, 1 H), 7.57–7.65 (m, 1 H). – C NMR (CDCl , 150 MHz): δ ꢀ=ꢀ gel (n-hexane-ethyl acetate 50:1) 123 mg (37%) of com-
3
1
1
3.8 (CH ), 14.19 (CH ), 22.6 (CH ), 23.0 (CH ), 32.6 (CH ), 33.2 pound 4c was obtained as an orange oil. – H NMR (CDCl ,
3
3
2
3
2
3
3
3
(
CH ), 61.3 (CH ), 116.6 (CH), 125.0 (CH), 127.4 (Cquat), 127.9 600 MHz): δ ꢀ=ꢀ 0.94 (t, J ꢀ=ꢀ 7.4 Hz, 3 H), 1.40 (dt, J ꢀ=ꢀ 7.3,
2
2
(
CH), 128.0 (CH) 144.4 (Cquat), 150.1 (Cquat), 152.1 (Cquat), 155.3 10.5 Hz, 5 H), 1.57–1.67 (m, 2 H), 2.61 (s, 3 H), 2.63–2.70 (m, 2
+
3
3
(
Cquat), 168.8 (C ). – MS ((+)-EI): m/z (%) ꢀ=ꢀ 303 (100) [M] , H), 4.43 (q, J ꢀ=ꢀ 7.1 Hz, 2 H), 7.37 (s, 1 H), 7.42 (d, J ꢀ=ꢀ 8.5 Hz,
quat
+
+
+
3
13
2
2
74 (3) [M–C H ] , 258 (72) [M–C H O] , 246 (13) [M–C H ] , 2 H), 7.93 (d, J ꢀ=ꢀ 8.5 Hz, 2 H). – C NMR (CDCl , 151 MHz):
30 (19) [M–C H O ] , 189 (83), 173 (11), 159 (12), 98 (24). – δ ꢀ=ꢀ 13.8 (CH ), 14.2 (CH ), 22.6 (CH ), 23.2 (CH ), 32.7 (CH ),
2
5
2
5
4
9
3
+
3 5 2 3 3 2 3 2
(cm ) ꢀ=ꢀ 2957 (w), 2930 (w), 1719 (s), 1584 (s), 1553 (m), 33.3 (CH ), 61.4 (CH ), 118.2 (CH), 127.9 (Cquat), 128.4 (CH),
−1
IR: ν
̃
2
2
1
454 (m), 1267 (s), 1231 (m), 1198 (s), 1105 (s), 1080 (s), 1069 128.8 (CH), 135.2 (Cquat), 137.5 (Cquat), 150.1 (Cquat), 155.3 (Cquat),
(
m), 851 (s), 702 (s). – Anal. for C H NO S (303.4): calcd. C 155.9 (C ), 169.0 (C ). – MS ((+)-EI): m/z (%) ꢀ=ꢀ 331 (100)
17
21
2
quat
quat
3
5
+
35
+
35
+
6
7.29, H 6.98, N 4.62; found C 67.37, H 6.86, N 4.36.
[ Cl-M] , 303 (4) [ Cl-M–C H ] , 286 (74) [ Cl-M–C H O] ,
2
4
2
5
3
5
+
35
+
2
2
74 (21) [ Cl-M–C H ] , 258 (38) [ Cl-M–C H O ] , 245 (22),
4 9 3 5 2
−1
17 (47), 139 (34). – IR: ν̃ (cm ) ꢀ=ꢀ 3061 (w), 2957 (w), 2932
3
.5 Ethyl 2-methyl-4-butyl-6-(4-methoxy-
phenyl)pyridine-3-carboxylate (4b)
(w), 2872 (w), 2862 (w), 1721 (s), 1585 (s), 1576 (m), 1553 (m),
493 (m), 1454 (m), 1381 (m), 1366 (m), 1265 (s), 1211 (s),
177 (m), 1119 (s), 1103 (s), 1091 (s), 1070 (s), 1013 (s), 862
1
1
According to GP1 and after flash chromatography on silica (m), 833 (s), 777 (m), 745 (m), 719 (m), 662 (m), 633 (m), 611
gel (n-hexane-ethyl acetate 30:1) 79 mg (24%) of com- (m). – Anal. for C H ClNO (331.8): calcd. C 68.77, H 6.68,
1
9
22
2
1
pound 4b was obtained as a yellow oil. – H NMR (CDCl , N 4.22; found C 68.73, H 6.77, N 4.13.
3
3
3
00 MHz): δ ꢀ=ꢀ 0.94 (t, J ꢀ=ꢀ 7.3 Hz, 3 H), 1.33–1.47 (m, 5 H),
1
.55–1.69 (m, 2 H), 2.61 (s, 3 H), 2.63–2.73 (m, 2 H), 3.86 (s, 3
3
H), 4.42 (q, J ꢀ=ꢀ 7.2 Hz, 2 H), 6.85–7.10 (m, 2 H), 7.35 (s, 1 H), 3.7 Ethyl 2-methyl-4-butyl-6-(4-nitrophenyl)
13
7
.91–7.98 (m, 2 H). – C NMR (CDCl , 75 MHz): δ ꢀ=ꢀ 13.8 (CH ),
3
3
pyridine-3-carboxylate (4d)
1
4.2 (CH ), 22.6 (CH ), 23.2 (CH ), 32.7 (CH ), 33.3 (CH ), 55.4
3 2 3 2 2
(
CH ), 61.1 (CH ), 114.1 (CH), 117.8 (CH), 127.0 (Cquat), 128.4 According to GP1 and after flash chromatography on silica
3
2
(
1
CH), 150.1 (Cquat), 155.0 (Cquat), 156.8 (Cquat), 160.6 (Cquat), gel (n-hexane-ethyl acetate 30:1) 99 mg (29%) of com-
1
64.2 (Cquat), 169.1 (Cquat). – HRMS ((+)-ESI): m/z ꢀ=ꢀ 328.190 pound 4d was obtained as an orange oil. – H NMR (CDCl ,
3
Unauthenticated
Download Date | 5/16/16 7:47 PM

J. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz synthesesꢂꢁꢀꢀꢀꢂ11
3
6
00 MHz): δ ꢀ=ꢀ 0.94 (t, J ꢀ=ꢀ 7.4 Hz, 3 H), 1.37–1.43 (m, 5 H), 75 MHz): δ ꢀ=ꢀ 13.6 (CH ), 21.3 (CH ), 23.0 (CH ), 61.3 (CH ),
3
3
3
2
3
1
.63 (tt, J ꢀ=ꢀ 7.8, 6.6 Hz, 2 H), 2.63 (s, 3 H), 2.66–2.71 (m, 2 118.3 (CH), 126.5 (Cquat), 127.1 (CH), 127.9 (CH), 128.5 (CH),
3
H), 4.45 (q, J ꢀ=ꢀ 7.2 Hz, 2 H), 7.48 (s, 1 H), 8.14–8.19 (m, 2 128.5 (CH), 129.5 (CH), 135.7 (Cquat), 139.0 (Cquat), 139.5 (Cquat),
13
H), 8.28–8.31 (m, 2 H). – C NMR (CDCl , 150 MHz): δ ꢀ=ꢀ 149.1 (Cquat), 155.6 (Cquat), 157.3 (Cquat), 168.9 (Cquat). – MS ((+)-
3
+
+
1
3.8 (CH ), 14.2 (CH ), 22.6 (CH ), 23.1 (CH ), 32.7 (CH ), 33.2 EI): m/z (%) ꢀ=ꢀ 331 (87) [M] , 303 (15) [M–C H ] , 302 (62)
3 3 2 3 2 2 4
+ + +
(
CH ), 61.6 (CH ), 119.2 (CH), 123.9 (CH), 127.9 (CH), 129.0 [M–C H ] , 286 (100) [M–C H O] , 258 (8) [M–C H O ] , 237
2 2 2 5 2 5 3 5 2
+
(
Cquat), 144.80 (Cquat), 148.20 (Cquat), 150.50 (Cquat), 154.30 (19), 216 (31), 213 (18), 202 (25), 119 (21), 77 (10) [C H ] . –
6 5
−1
(
Cquat), 155.70 (Cquat), 168.60 (C ). – MS ((+)-EI): m/z (%) ꢀ=ꢀ IR: ν
̃
(cm ) ꢀ=ꢀ 3057 (w), 3030 (w), 2978 (w), 2963 (w), 2903
quat
+
+
+
3
42 (53) [M] , 313 (29) [M–C H ] , 297 (100) [M–C H O] , 285 (w), 2860 (w), 2359 (w), 2324 (w), 1719 (s), 1684 (m), 1584
2
5
2
5
+
+
(
29) [M–C H ] , 269 (37) [M–C H O ] , 228 (46), 221 (11), 181 (s), 1543 (s), 1516 (m), 1497 (m), 1445 (m), 1364 (m), 1343
4
9
3
5
2
−1
(
12). – IR: ν̃ (cm ) ꢀ=ꢀ 2959 (m), 2932 (m), 2872 (w), 1722 (s), (w), 1264 (s), 1238 (m), 1184 (m), 1140 (m), 1096 (s), 1072
1
1
584 (m), 1558 (m), 1518 (s), 1456 (m), 1418 (m), 1383 (m), (s), 1018 (m), 881 (m), 856 (m), 822 (s), 768 (s), 750 (m), 719
339 (s), 1317 (m), 1267 (s), 1213 (m), 1173 (m), 1121 (m), 1107 (m), 700 (s), 664 (m), 642 (m). – Anal. for C H NO (331.4):
2
2
21
2
(
m), 1096 (m), 1070 (m), 1013 (m), 851 (s), 789 (m), 762 (m), calcd. C 79.73, H 6.39, N 4.23; found C 79.55, H 6.45, N 3.99.
6
96 (m), 658 (m). – Anal. for C H N O (342.4): calcd. C
6.65, H 6.48, N 8.18; found C 66.84, H 6.47, N 8.17.
19 22 2 4
6
3
.1ꢊ Ethyl 2-methyl-4-phenyl-6-(4-chloro-
phenyl)pyridine-3-carboxylate (4g)
3
.8 Ethyl 2-methyl-4-phenyl-6-(thiophen-
-yl)pyridine-3-carboxylate (4e)
According to GP1 and after flash chromatography on silica
2
gel (n-hexane-ethyl acetate 50:1) 133 mg (38%) of com-
1
According to GP1 and after flash chromatography on silica pound 4g was obtained as an orange oil. – H NMR (CDCl ,
3
3
gel (n-hexane-dichloromethane 2:1) 64 mg (20%) of com- 300 MHz): δ ꢀ=ꢀ 1.01 (t, J ꢀ=ꢀ 7.1 Hz, 3 H), 2.72 (s, 3 H), 4.13 (q,
1
3
pound 4e was obtained as a yellow oil. – H NMR (CDCl , J ꢀ=ꢀ 7.1 Hz, 2 H), 7.38–7.48 (m, 7 H), 7.54 (s, 1 H), 7.96–8.02
3
3
13
3
00 MHz): δ ꢀ=ꢀ 0.99 (t, J ꢀ=ꢀ 7.2 Hz, 3 H), 2.67 (s, 3 H), 4.10 (q, (m, 2 H). – C NMR (CDCl , 75 MHz): δ ꢀ=ꢀ 13.6 (CH ), 23.1
3 3
3
3
J ꢀ=ꢀ 7.1 Hz, 2 H), 7.11 (dd, J ꢀ=ꢀ 5.0, 3.7 Hz, 1 H), 7.38–7.46 (m, (CH ), 61.3 (CH ), 118.2 (CH), 126.9 (Cquat), 127.1 (CH), 127.8
3
2
3
6
H), 7.48 (d, J ꢀ=ꢀ 0.6 Hz, 1 H), 7.64 (dd, J ꢀ=ꢀ 3.7, 1.2 Hz, 1 H). (CH), 128.4 (CH), 128.5 (CH), 128.9 (CH), 135.4 (Cquat), 137.1
13
–
C NMR (CDCl , 75 MHz): δ ꢀ=ꢀ 13.6 (CH ), 23.0 (CH ), 61.3 (Cquat), 138.7 (Cquat), 149.0 (Cquat), 155.8 (Cquat), 155.9 (Cquat),
3 3 3
+
35
(
CH ), 116.7 (CH), 125.4 (CH), 126.5 (Cquat), 127.8 (CH), 128.1 168.7 (C ). – MS ((+)-EI): m/z (%) ꢀ=ꢀ 351 (73) [ Cl-M] , 323
2 quat
+ +
35
35
35
(
CH), 128.3 (CH), 128.5 (CH), 128.5 (CH), 138.8 (Cquat), 144.1 (12) [ Cl-M–C H ] , 322 (35) [ Cl-M–C H ] , 306 (100) [ Cl-
2 4 2 5
+ +
35
(
Cquat), 149.1 (Cquat), 152.3 (Cquat), 156.0 (Cquat), 168.7 (Cquat). – M–C H O] , 278 (7) [ Cl-M–C H O ] , 257 (34), 237 (31), 202
2 5 3 5 2
+ +
−1
MS ((+)-EI): m/z (%) ꢀ=ꢀ 323 (100) [M] , 295 (8) [M–C H ] , (37), 141 (14). – IR: ν
̃
(cm ) ꢀ=ꢀ 3802 (w), 3690 (w), 3649 (w),
2
4
+
+
2
5
78 (99) [M–C H O] , 250 (3) [M–C H O ] , 209 (33), 84 (37), 3059 (w), 2978 (m), 2922 (m), 2901 (m), 2747 (w), 2374 (w),
2
5
3
5
2
−1
6 (71). – IR: ν̃ (cm ) ꢀ=ꢀ 3103 (w), 3059 (w), 2980 (w), 2930 2311 (w), 1721 (s), 1584 (s), 1572 (m), 1543 (m), 1491 (m),
(
w), 2853 (w), 1717 (s), 1580 (s), 1541 (s), 1495 (m), 1445 (m), 1445 (m), 1406 (m), 1381 (m), 1364 (m), 1263 (s), 1240 (m),
412 (m), 1387 (m), 1364 (m), 1265 (s), 1240 (s), 1221 (m), 1227 (m), 1179 (m), 1140 (m), 1098 (s), 1072 (s), 1013 (s), 833
1
1
171 (m), 1138 (m), 1078 (s), 1038 (m), 1013 (m), 874 (m), (s), 768 (s), 750 (m), 698 (s). – Anal. for C H ClNO (351.8):
47 (m), 802 (m), 780 (m), 750 (m), 698 (s), 671 (m), 638 calcd. C 71.69, H 5.16, N 3.98; found C 71.71, H 5.26, N 3.69.
m), 621 (m). – Anal. calcd. for C H NO S (323.4): C 70.56,
H 5.30, N 4.33, S 9.91; found C 70.31, H 5.46, N 4.04, S 9.68.
21 18 2
8
(
19 17 2
3
.11 Ethyl 2-methyl-4-phenyl-6-(2-fluoro-
phenyl)pyridine-3-carboxylate (4h)
3
.ꢈ Ethyl 2-methyl-4-phenyl-6-(4-tolyl)
pyridine-3-carboxylate (4f)
According to GP1 and after flash chromatography on silica
gel (n-hexane-ethyl acetate 30:1) and 112 mg (33%) of com-
1
According to GP1 and after flash chromatography on silica pound 4h was obtained as a red oil. – H NMR (CDCl , 300
3
3
gel (n-hexane-ethyl acetate 30:1) 81 mg (24%) of com- MHz): δ ꢀ=ꢀ 0.93 (t, J ꢀ=ꢀ 7.1 Hz, 3 H), 2.64 (s, 3 H), 4.05 (q,
1
3
3
3
pound 4f was obtained as a yellow oil. – H NMR (CDCl , J ꢀ=ꢀ 7.1 Hz, 2 H), 7.06 (ddd, J ꢀ=ꢀ 11.3 Hz, J ꢀ=ꢀ 8.2, 1.3 Hz, 1
3
H-F
3
5
3
00 MHz): δ ꢀ=ꢀ 1.01 (t, J ꢀ=ꢀ 7.1 Hz, 3 H), 2.41 (s, 3 H), 2.73 (s, H), 7.15–7.22 (m, 1 H), 7.25–7.38 (m, 6 H), 7.58 (d, J ꢀ=ꢀ 1.8
H-F
3
3
13
3
H), 4.12 (q, J ꢀ=ꢀ 7.1 Hz, 2 H), 7.27–7.31 (m, 2 H), 7.41–7.45 Hz, 1 H), 7.94 (td, J ꢀ=ꢀ 7.8, 1.9 Hz, 1 H). – C NMR (CDCl , 75
3
13
2
(
m, 5 H), 7.55 (s, 1 H), 7.91–7.98 (m, 2 H). – C NMR (CDCl , MHz): δ ꢀ=ꢀ 13.6 (CH ), 23.0 (CH ), 61.4 (CH ), 116.2 (d, J ꢀ=ꢀ
3
3
3
2
C-F
Unauthenticated
Download Date | 5/16/16 7:47 PM

1
2ꢀꢀꢀꢀꢁꢀJ. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz syntheses
3
2
3.0 Hz, CH), 122.4 (d, J ꢀ=ꢀ 9.1 Hz, CH), 124.5 (CH), 124.6 (CH), 122.9 (Cquat), 128.8 (CH), 130.9 (CH), 139.4 (Cquat), 158.6
C-F
2
(
CH), 126.8 (d, J ꢀ=ꢀ 11.6 Hz, Cquat), 127.1 (Cquat), 127.9 (CH), (Cquat), 159.8 (Cquat), 161.1 (Cquat), 166.6 (Cquat). – MS ((+)-EI):
C-F
3
4
+
+
1
28.5 (CH), 130.7 (d, J ꢀ=ꢀ 8.5 Hz, CH), 131.2 (d, J ꢀ=ꢀ 3.0 m/z (%) ꢀ=ꢀ 271 (100) [M] , 243 (21) [M–C H ] , 226 (46) [M–
C-F
C-F
2
4
+
+
−1
Hz, CH), 138.6 (Cquat), 148.5 (Cquat), 153.2 (Cquat), 155.6 (Cquat), C H O] , 198 (4) [M–C H O ] . – IR: ν
̃
(cm ) ꢀ=ꢀ 2980 (w), 2961
2
5
2
5
2
1
1
60.5 (d, J ꢀ=ꢀ 250.3 Hz, Cquat), 168.7 (Cquat). – MS ((+)-EI): (w), 2934 (w), 2835 (w), 1715 (s), 1580 (s), 1564 (m), 1512
C-F
+ +
m/z (%) ꢀ=ꢀ 335 (75) [M] , 320 (3) [M–CH ] , 306 (60) [M– (m), 1452 (m), 1288 (s), 1207 (w), 1182 (s), 1125 (m), 1107
3
+
+
+
C H ] , 290 (100) [M–C H O] , 262 (7) [M–C H O ] , 242 (16), (m), 1092 (s), 1074 (s), 1036 (s), 1022 (m), 982 (m), 826 (s),
2
4
2
5
3
5
2
−1
2
20 (33). – IR: ν
w), 2864 (w), 1721 (s), 1632 (m), 1614 (m), 1584 (s), 1545 (s),
491 (s), 1447 (m), 1383 (m), 1364 (m), 1265 (s), 1221 (m),
̃ (cm ) ꢀ=ꢀ 3304 (w), 3061 (w), 2980 (w), 2932 783 (s), 733 (m), 608 (s).
(
1
1
211 (m), 1173 (m), 1142 (m), 1111 (m), 1092 (s), 1072 (s), 1032 3.14 Ethyl 2-methyl-6-(4-chlorophenyl)
(
m), 1013 (m), 889 (m), 856 (m), 833 (m), 789 (m), 752 (s),
pyridine-3-carboxylate (4k)
7
31 (m), 689 (s), 669 (m), 652 (m), 683 (m), 621 (m). – Anal.
for C H FNO (335.4): calcd. C 75.21, H 5.41, N 4.18; found According to GP1 and after flash chromatography on silica
2
1
18
2
C 75.47, H 5.55, N 3.92.
gel (n-hexane-ethyl acetate 50:1) 130 mg (47%) of com-
pound 4k was obtained as an orange solid, m. p. 42–43°C
1
(
lit. [75]: 47–48°C). – H NMR (CDCl , 300 MHz): δ ꢀ=ꢀ 1.42 (t,
3
3
3
3
.12 Ethyl 2-methyl-6-(thiophen-2-yl)pyri-
J ꢀ=ꢀ 7.2 Hz, 3 H), 2.90 (s, 3 H), 4.40 (d, J ꢀ=ꢀ 7.1 Hz, 2 H), 7.44
3
3
3
(
8
d, J ꢀ=ꢀ 8.6 Hz, 2 H), 7.59 (d, J ꢀ=ꢀ 8.2 Hz, 1 H), 8.01 (d, J ꢀ=ꢀ
dine-3-carboxylate (4i)
3
13
.6 Hz, 2 H), 8.25 (d, J ꢀ=ꢀ 8.2 Hz, 1 H). – C NMR (CDCl ,
3
According to GP1 and after flash chromatography on 75 MHz): δ ꢀ=ꢀ 14.3 (CH ), 25.2 (CH ), 61.2 (CH ), 117.0 (CH),
3
3
2
silica gel (n-hexane-ethyl acetate 30:1) and 88 mg (36%) 123.9 (Cquat), 128.5 (CH), 129.0 (CH), 135.8 (Cquat), 136.9 (Cquat),
and according to GP2 52 mg (21%) of compound 4i was 139.4 (CH), 157.7 (Cquat), 160.0 (C ), 166.5 (C ). – MS ((+)-
quat
quat
3
5
+
35
+
obtained as a pale yellow solid, m. p. 58°C (lit. [73]: 58°C). EI): m/z (%) ꢀ=ꢀ 275 (100) [ Cl-M] , 260 (4) [ Cl-M–CH ] , 247
3
– 1
H NMR (CDCl , 300 MHz): δ ꢀ=ꢀ 1.41 (t, J ꢀ=ꢀ 7.1 Hz, 3 H), (24) [ Cl-M–C H ] , 230 (81) [ Cl-M–C H O] , 202 (13) [ Cl-
3
35
+
35
+
35
3
2
4
2
5
3
3
+
−1
2
.88 (s, 3 H), 4.38 (q, J ꢀ=ꢀ 7.1 Hz, 2 H), 7.13 (dd, J ꢀ=ꢀ 5.1, 3.7 M–C H O ] , 167 (27). – IR: ν̃ (cm ) ꢀ=ꢀ 3414 (w), 3098 (w),
3
5
2
3
3
Hz, 1 H), 7.45 (dd, J ꢀ=ꢀ 5.1, 1.1 Hz, 1 H), 7.52 (d, J ꢀ=ꢀ 8.2 Hz, 3071 (w), 2982 (w), 2899 (w), 2870 (w), 2849 (w), 1717 (s),
3
3
1
H), 7.71 (dd, J ꢀ=ꢀ 3.7, 1.1 Hz, 1 H), 8.21 (d, J ꢀ=ꢀ 8.3 Hz, 1 H). 1584 (s), 1557 (m), 1493 (m), 1454 (m), 1435 (m), 1410 (m),
13
–
C NMR (CDCl , 75 MHz): δ ꢀ=ꢀ 14.3 (CH ), 24.9 (CH ), 61.1 1389 (m), 1364 (m), 1263 (s), 1246 (s), 1194 (m), 1180 (m),
3
3
3
(
CH ), 115.7 (CH), 123.2 (Cquat), 126.3 (CH), 128.3 (CH), 129.1 1155 (m), 1092 (s), 1070 (s), 1011 (s), 982 (m), 972 (m), 907
2
(
CH), 139.4 (CH), 143.7 (Cquat), 154.0 (Cquat), 160.2 (Cquat), 166.2 (m), 866 (m), 833 (m), 822 (m), 783 (s), 739 (m), 679 (m),
+
(
Cquat). – MS ((+)-EI): m/z (%) ꢀ=ꢀ 247 (100) [M] , 219 (20) [M– 606 (m).
+
+
+
C H ] , 202 (79) [M–C H O] , 174 (11) [M–C H O ] , 147 (13),
2
4
2
5
3
5
2
−1
1
(
40 (11). – IR: ν̃ (cm ) ꢀ=ꢀ 2955 (w), 2922 (m), 2853 (w), 1709
s), 1582 (s), 1558 (m), 1460 (m), 1425 (m), 1261 (s), 1252 (s), 3.15 Ethyl 2-methyl-6-(4-nitrophenyl)pyri-
1
236 (s), 1169 (s), 1090 (s), 1078 (s), 1020 (m), 847 (s), 802
dine-3-carboxylate (4l)
(
m), 783 (s), 731 (m), 692 (s).
According to GP1 and after flash chromatography on silica
gel (n-hexane-ethyl acetate 20:1) and 150 mg (52%) of com-
1
3
.13 Ethyl 2-methyl-6-(4-methoxyphenyl)
pyridine-3-carboxylate (4j)
pound 4l was obtained as a yellow solid, m. p. 141°C. – H
3
NMR (CDCl , 300 MHz): δ ꢀ=ꢀ 1.43 (t, J ꢀ=ꢀ 7.1 Hz, 3 H), 2.93 (s,
3
3
3
3
H), 4.42 (q, J ꢀ=ꢀ 7.1 Hz, 2 H), 7.71 (d, J ꢀ=ꢀ 8.2 Hz, 1 H), 8.24
3
13
After flash chromatography on silica gel (n-hexane-ethyl (d, J ꢀ=ꢀ 9.0 Hz, 2 H), 8.28–8.37 (m, 3 H). – C NMR (CDCl , 75
3
acetate 20:1) and according to GP1 52 mg (19%) and accord- MHz): δ ꢀ=ꢀ 14.3 (CH ), 25.1 (CH ), 61.4 (CH ), 118.1 (CH), 124.0
3
3
2
ing to GP2 84 mg (31%) of compound 4j was obtained as (CH), 125.1 (Cquat), 128.1 (CH), 139.6 (CH), 144.1 (Cquat), 148.5
1
a colorless solid, m. p. 66°C (lit. [74]: 68°C). – H NMR (Cquat), 156.2 (Cquat), 160.3 (Cquat), 166.2 (Cquat). – MS ((+)-EI):
3
+
+
(
CDCl , 300 MHz): δ ꢀ=ꢀ 1.41 (t, J ꢀ=ꢀ 7.1 Hz, 3 H), 2.91 (s, 3 H), m/z (%) ꢀ=ꢀ 286 (100) [M] , 271 (8) [M–CH ] , 258 (40) [M–
3 3
+ + +
3
3
3
2
8
.87 (s, 3 H), 4.39 (q, J ꢀ=ꢀ 7.1 Hz, 2 H), 7.00 (d, J ꢀ=ꢀ 8.9 Hz, C H ] , 241 (96) [M–C H O] , 213 (19) [M–C H O ] , 166 (32),
2
4
2
5
3
5
2
3
3
−1
H), 7.56 (d, J ꢀ=ꢀ 8.3 Hz, 1 H), 8.04 (d, J ꢀ=ꢀ 8.9 Hz, 2 H), 140 (19). – IR: ν
̃
(cm ) ꢀ=ꢀ 2934 (w), 2980 (w), 2932 (w), 2897
3
13
.24 (d, J ꢀ=ꢀ 8.2 Hz, 1 H). – C NMR (CDCl , 75 MHz): δ ꢀ=ꢀ (w), 2847 (w), 1717 (s), 1580 (m), 1564 (m), 1516 (s), 1435
3
1
4.3 (CH ), 25.2 (CH ), 55.4 (CH ), 61.1 (CH ), 114.2 (CH), 116.6 (m), 1377 (m), 1366 (m), 1337 (s), 1323 (m), 1206 (m), 1187
3 3 3 2
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J. Dohe and T.J.J. Müller: Consecutive three- and four-component coupling-Bagley-Bohlmann-Rahtz synthesesꢂꢁꢀꢀꢀꢂ13
(
m), 1159 (m), 1107 (m), 1088 (s), 1070 (m), 1024 (m), 1009 (m), 806 (m), 791 (m), 756 (s), 743 (m), 721 (m), 698 (m),
m), 982 (m), 872 (m), 847 (s), 792 (m), 750 (s), 725 (m), 689 669 (m), 640 (m). – Anal. for C H FNO (259.3): calcd. C
(
1
5
14
2
(
4
m), 675 (m). Anal. for C H N O (286.3): calcd. C 62.93, H 69.49, H 5.44, N 5.40; found C 69.47, H 5.41, N 5.40.
15 14 2 4
.93, N 9.79; found C 62.95, H 4.94, N 9.54.
3
.18 Ethyl 2-methyl-6-phenylpyridine-3-
3
.16 Ethyl 2-methyl-6-(4-tolyl)pyridine-
-carboxylate (4m)
carboxylate (4o)
3
According to GP1 and after flash chromatography on silica
According to GP1 and after flash chromatography on silica gel (n-hexane-ethyl acetate 40:1) and 67 mg (28%) of com-
1
gel (n-hexane-ethyl acetate 40:1) 77 mg (30%) of com- pound 4o was obtained as an orange oil. – H NMR (CDCl ,
3
3
pound 4m was obtained as a yellow solid, m. p. 50°C (lit. 300 MHz): δ ꢀ=ꢀ 1.42 (t, J ꢀ=ꢀ 7.2 Hz, 3 H), 2.93 (s, 3 H), 4.40
1
3
3
3
[
60]: 54°C). – H NMR (CDCl , 300 MHz): δ ꢀ=ꢀ 1.42 (t, J ꢀ=ꢀ 7.1 (q, J ꢀ=ꢀ 7.1 Hz, 2 H), 7.38–7.57 (m, 3 H), 7.63 (d, J ꢀ=ꢀ 8.2 Hz, 1
3
3
13
Hz, 3 H), 2.41 (s, 3 H), 2.92 (s, 3 H), 4.39 (d, J ꢀ=ꢀ 7.1 Hz, 2 H), H), 8.01–8.14 (m, 2 H), 8.27 (d, J ꢀ=ꢀ 8.2 Hz, 1 H). – C NMR
3
7
.27–7.31 (m, 2 H), 7.60 (d, J ꢀ=ꢀ 8.2 Hz, 1 H), 7.93–8.00 (m, 2 (CDCl , 75 MHz): δ ꢀ=ꢀ 14.3 (CH ), 25.2 (CH ), 61.1 (CH ), 117.4
3
3
3
2
3
13
H), 8.25 (d, J ꢀ=ꢀ 8.2 Hz, 1 H). – C NMR (CDCl , 75 MHz): (CH), 123.7 (Cquat), 127.3 (CH), 128.8 (CH), 129.6 (CH), 138.4
3
δ ꢀ=ꢀ 14.3 (CH ), 21.3 (CH ), 25.2 (CH ), 61.1 (CH ), 117.0 (CH), (Cquat), 139.3 (CH), 159.0 (Cquat), 159.9 (Cquat), 166.6 (C ). –
3
3
3
2
quat
+
+
1
1
23.3 (Cquat), 127.2 (CH), 129.5 (CH), 135.6 (Cquat), 139.3 (CH), MS ((+)-EI): m/z (%) ꢀ=ꢀ 241 (91) [M] , 226 (7) [M–CH ] , 213
3
+
+
+
39.9 (Cquat), 159.0 (Cquat), 159.8 (Cquat), 166.6 (Cquat). – MS ((+)- (26) [M–C H ] , 196 (100) [M–C H O] , 168 (44) [M–C H O ] ,
2
4
2
5
3
5
2
+
+
−1
EI): m/z (%) ꢀ=ꢀ 255 (100) [M] , 240 (6) [M–CH ] , 227 (34) 141 (27), 115 (18), 84 (11). – IR: ν
̃
(cm ) ꢀ=ꢀ 3063 (w), 2980
3
+
+
+
[
(
(
(
(
(
M–C H ] , 210 (89) [M–C H O] , 182 (28) [M–C H O ] , 167 (w), 2932 (w), 2905 (w), 2872 (w), 1717 (s), 1582 (s), 1558
2
4
2
5
3
5
2
+
−1
30), 155 (15), 91 (11) [C H ] . – IR: ν̃ (cm ) ꢀ=ꢀ 3028 (w), 2980 (m), 1447 (m), 1435 (m), 1381 (m), 1371 (m), 1261 (s), 1246
7
7
w), 2930 (w), 2864 (w), 2733 (w), 1707 (s), 1672 (m), 1578 (s), 1206 (m), 1184 (m), 1152 (m), 1144 (m), 1090 (s), 1074
s), 1557 (m), 1510 (m), 1481 (m), 1454 (m), 1435 (m), 1412 (s), 1018 (m), 1001 (m), 847 (m), 754 (s), 731 (m), 708 (m),
m), 1391 (m), 1379 (m), 1362 (m), 1306 (m), 1265 (s), 1246 691 (s), 650 (m), 611 (m).
s), 1206 (m), 1184 (s), 1155 (m), 1117 (m), 1090 (s), 1072 (s),
1
018 (m), 984 (m), 966 (m), 943 (m), 907 (m), 860 (m), 820
(
m), 781 (s), 735 (m), 692 (m), 610 (m).
4
Supporting information
1
13
H, C, and 13-DEPT-135 NMR spectra of 3-ethoxycarbonyl-
3
.17 Ethyl 2-methyl-6-(2-fluorophenyl)
pyridine-3-carboxylate (4n)
2
-methylpyridines 4 are given as Supporting Information
available online (DOI: 10.1515/znb-2016-0046).
According to GP1 and after flash chromatography on silica
Acknowledgments: The authors cordially thank the Fonds
gel (n-hexane-ethyl acetate 50:1) and 142 mg (55%) of com-
der Chemischen Industrie for financial support.
1
pound 4n was obtained as a yellow oil. – H NMR (CDCl ,
3
3
3
00 MHz): δ ꢀ=ꢀ 1.42 (t, J ꢀ=ꢀ 7.2 Hz, 3 H), 2.92 (s, 3 H), 4.40 (q,
J ꢀ=ꢀ 7.1 Hz, 2 H), 7.16 (ddd, J ꢀ=ꢀ 11.4 Hz, J ꢀ=ꢀ 8.2, 1.2 Hz, 1
3
3
3
H-F
3
H), 7.28 (td, J ꢀ=ꢀ 7.5, 1.2 Hz, 1 H), 7.34–7.46 (m, 1 H), 7.71 (dd, References
3
5
3
J ꢀ=ꢀ 8.2 Hz, J ꢀ=ꢀ 2.3 Hz, 1 H), 8.08 (td, J ꢀ=ꢀ 7.8, 1.9 Hz, 1 H),
H-F
3
13
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8
.27 (d, J ꢀ=ꢀ 8.2 Hz, 1 H). – C NMR (CDCl , 75 MHz): δ ꢀ=ꢀ 14.3
3
2
(
CH ), 25.0 (CH ), 61.2 (CH ), 116.2 (d, J ꢀ=ꢀ 23.0 Hz, CH),
3
3
2
C F
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4
JC-F ꢀ=ꢀ 2.7 Hz, CH), 139.0 (CH), 155.0 (d, J ꢀ=ꢀ 2.2 Hz, Cquat),
C-F
1
1
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3
Synlett 2ꢊꢊꢈ, 241.
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Z. Naturforsch.ꢂ
ꢂ2016 | Volume x | Issue x(b)
Graphical synopsis
Janis Dohe and Thomas J.J. Müller
Consecutive three- and four-component
coupling-Bagley-Bohlmann-Rahtz
syntheses of tri- and tetrasubstituted
pyridines
DOI 10.1515/znb-2016-0046
Z. Naturforsch. 2016; x(x)b: xxx–xxx
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