A modular synthesis of functionalized pyridines through lewis-acid-mediated and microwave-assisted cycloadditions between azapyrylium intermediates and alkynes

Article abstract of DOI:10.1002/ejoc.201100765

In this report we describe the synthesis of differentially functionalized pyridine derivatives 3 and the related 3-bromo-substituted pyridines 11. Dissociation of 6H-1,2-oxazine precursors (1a, 1b, 5, 6, or 12) in situ, mediated by boron trifluoride-diethyl ether, generates the azapyrylium intermediates A, which undergo hetero-Diels-Alder reactions with various mono- and disubstituted alkynes 2. In general, these pyridine syntheses proceeded with high efficiencies and were very flexible with respect to all positions in the pyridine cores. For the 3-phenyl-substituted pyridine derivatives 3a-3j and 11a-11f the best results were obtained by a new microwave-assisted protocol, which is clearly superior to the previously used conventional procedure at low temperature in dichloromethane. Furthermore, 3-(trifluoromethyl)- and 3-acryloyl-substituted 6H-1,2-oxazines reacted cleanly under microwave irradiation conditions to furnish the expected pyridine derivatives 3k and 3l in respectable yields. The 3-bromo-substituted pyridines 11 were further functionalized through palladium-catalyzed couplings such as Suzuki or Sonogashira reactions, which led smoothly to tri- or tetrasubstituted pyridine derivatives such as 19-21 and 23. Reductive debromination of 11e afforded the pyridine 17 in excellent yield, whereas oxidation of the pyridinyl thioether 3g with oxone led to the corresponding sulfoxide 24. Our method thus establishes a new and versatile approach to highly substituted pyridine derivatives. A simple method for the modular synthesis of substituted pyridines is disclosed. Microwave-assisted reactions between azapyrylium intermediates (generated in situ) and alkynes afforded the corresponding pyridine derivatives in good to excellent yields. The functional group tolerance in this process is very good and allows a variety of subsequent reactions.

Full text of DOI:10.1002/ejoc.201100765

FULL PAPER
DOI: 10.1002/ejoc.201100765
A Modular Synthesis of Functionalized Pyridines through Lewis-Acid-
Mediated and Microwave-Assisted Cycloadditions between Azapyrylium
Intermediates and Alkynes
Igor Linder,[a] Markus Gerhard,[a] Luise Schefzig,[a] Michal Andrä,[a] Christoph Bentz,[a]
Hans-Ulrich Reissig,*[a] and Reinhold Zimmer*[a]
Keywords: Pyridines / Azapyrylium ions / 1,2-Oxazines / Microwave chemistry / Cross-coupling / Hetero-Diels–Alder
reaction / Cycloaddition / Nitrogen heterocycles
In this report we describe the synthesis of differentially func-
tionalized pyridine derivatives 3 and the related 3-bromo-
substituted pyridines 11. Dissociation of 6H-1,2-oxazine pre-
cursors (1a, 1b, 5, 6, or 12) in situ, mediated by boron trifluor-
ide–diethyl ether, generates the azapyrylium intermediates
A, which undergo hetero-Diels–Alder reactions with various
mono- and disubstituted alkynes 2. In general, these pyridine
syntheses proceeded with high efficiencies and were very
flexible with respect to all positions in the pyridine cores. For
the 3-phenyl-substituted pyridine derivatives 3a–3j and 11a–
11f the best results were obtained by a new microwave-as-
methane. Furthermore, 3-(trifluoromethyl)- and 3-acryloyl-
substituted 6H-1,2-oxazines reacted cleanly under micro-
wave irradiation conditions to furnish the expected pyridine
derivatives 3k and 3l in respectable yields. The 3-bromo-sub-
stituted pyridines 11 were further functionalized through pal-
ladium-catalyzed couplings such as Suzuki or Sonogashira
reactions, which led smoothly to tri- or tetrasubstituted pyr-
idine derivatives such as 19–21 and 23. Reductive debromin-
ation of 11e afforded the pyridine 17 in excellent yield,
whereas oxidation of the pyridinyl thioether 3g with oxone
led to the corresponding sulfoxide 24. Our method thus es-
sisted protocol, which is clearly superior to the previously tablishes a new and versatile approach to highly substituted
used conventional procedure at low temperature in dichloro-
pyridine derivatives.
Introduction
est in organic chemistry. New methods allowing the prepa-
ration of diversely functionalized pyridine derivatives are
still highly desirable.
Pyridines constitute a very important class of monocyclic
nitrogen-containing heterocycles, and thanks to their wide
spectrum of applications they unquestionably represent one
of the most studied heterocyclic systems.[1] As a conse-
quence of this importance, a large number of strategies for
the synthesis of polyfunctionalized specifically substituted
pyridine derivatives have been developed. The spectrum of
efficient and flexible pyridine syntheses includes simple con-
densation reactions, such as the classical Hantzsch reaction,
various cycloadditions, and numerous transition-metal-pro-
moted processes, as well as novel and powerful multicom-
ponent reactions, as illustrated in Scheme 1.[2] Because of
the important role of this heterocyclic skeleton as a compo-
nent in biologically active compounds,[3] natural products,[4]
or functional materials (e.g., as building blocks in supra-
molecular chemistry[5] or as ligands in transition-metal ca-
talysis[6]) the design of new strategies for the efficient syn-
thesis of pyridine derivatives continues to be of great inter-
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustrasse 3, 14195 Berlin, Germany
Fax: +49-30-8385-5367
E-mail: hans.reissig@chemie.fu-berlin.de
rzimmer@chemie.fu-berlin.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100765.
Scheme 1. Selected strategies for the synthesis of highly substituted
pyridine derivatives.
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Functionalized Pyridines through Cycloadditions of Azapyrylium Intermediates
In this account we describe in full detail our efforts relat- Table 1. Synthesis of the 2-phenyl-substituted pyridine derivatives
3.[a]
ing to the synthesis of pyridine derivatives through cycload-
ditions between 1,2-azapyrylium intermediates (generated
in situ) and mono- or disubstituted alkynes. We have pre-
viously reported some preliminary examples[7] and now
wish to disclose more results to demonstrate the scope and
limitations of this approach to pyridine synthesis.
Entry
1
R1
2
R2
R3
Method 3
Yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
H
H
H
2a
2a
2a
H
H
H
H
H
Ph
Ph
Ph
H
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
A
B
C
A
B
A
B
B
B
B
B
B
B
B
3a 67%[b]
3a
3a
96%
64%
1b Me 2a
1b Me 2a
1a
1a
1b Me 2b
1b Me 2c
1a
3b 39%[b]
3b
68%
H
H
2b
2b
3c 48%[b]
3c
3d
3e
3f
62%
53%
51%
48%
84%
Results and Discussion
cyclopropyl
PhS
PhS
H
2d
In a previous communication we reported on the forma-
tion of pyridine derivatives from easily available 6H-1,2-ox-
azines[8] of type 1 (Scheme 2). Treatment of compounds 1
with boron trifluoride–diethyl ether at –78 °C in the pres-
1b Me 2d
3g
[c]
1a
1a
1a
H
H
H
2e PMBOCH2
2f
2g
Ph
3h 63%[d]
H
imidazolyl[e]
3i
3j
54%
49%
(CH2)11
ence of the alkynes 2 in excess furnished the products 3 in [a] Reaction and conditions are shown in Scheme 2. [b] Taken from
ref.[7] [c] PMB = p-methoxybenzyl. [d] R2 = CH2OH. [e] 2-Methyl-
low to moderate yields.[7] We therefore became interested in
finding improved reaction conditions that would enhance
the applicability of this flexible and new approach to pyr-
idine synthesis. In particular, we wanted to test alternative
synthetic techniques such as microwave-assisted reactions.
When the reaction between the 6H-1,2-oxazine 1a and
phenylacetylene (2a) was performed in the presence of
boron trifluoride–diethyl ether in 1,2-dichloroethane at
70 °C under microwave irradiation conditions (Method B)
the expected 2-phenyl-substituted pyridine derivative 3a[9]
was formed in excellent yield (Table 1, Entry 2), a result that
compares very well with the previously employed condi-
tions (Method A), which provided 3a in only 67% yield
(Entry 1). In order to examine the scope of the new micro-
wave-assisted conditions[10] we then studied a range of
mono- and disubstituted alkynes 2 together with the 6H-
1,2-oxazines 1a and 1b. As shown in Table 1, the reactions
proceeded smoothly to give the corresponding 2-phenyl-
substituted pyridine derivatives 3b and 3c in yields better
than those obtained by Method A as applied earlier (En-
tries 4–7). Substituents and functional groups such as cy-
clopropyl, imidazolyl, or phenylthio groups are tolerated
well under the conditions of Method B (Entries 8–11, 13).
Not surprisingly, the use of 1-(p-methoxybenzyl)-3-phen-
ylprop-2-yne (2e) led to the deprotected 3-hydroxymethyl-
substituted pyridine 3h in 63% yield as product (Entry 12).
Most remarkably, a cyclic alkyne was also successfully con-
verted into the corresponding bicyclic pyridine derivative 3j
(Entry 14).
1,5-diphenylimidazol-4-yl.[12]
We were surprised that the 1,2-azapyrylium intermedi-
ates A[11] are sufficiently stable to survive the fairly high
temperatures and to act as heterodiene components under
the harsh microwave conditions employed (see mechanistic
interpretation in Scheme 4). We even have to assume that
the formation and reaction of A essentially start at room
temperature and were possibly not complete under our pre-
viously applied conventional conditions (Method A). The
microwave conditions apparently help to enhance the con-
version of the 1,2-oxazines 1 and strongly improve the over-
all efficacy of the pyridine synthesis. A control experiment
carried out with 1a and 2a gave a significantly lower yield
(64%) of the expected pyridine derivative 3a, indicating that
conventional heating in 1,2-dichloroethane at 70 °C over-
night (Method C) is less efficient (cf. Entries 2 and 3).
In general, 6H-1,2-oxazines such as 1b are accessible by
base- or acid-promoted isomerization of the precursor 5-
methylene-4H-1,2-oxazine 4 (Scheme 3),[8] which is ob-
tained as the primary cycloadduct from the hetero-Diels–
Alder reaction between methoxyallene and α-nitrosostyrene
(produced in situ).[13] We also investigated the preparation
of a pyridine derivative directly with compound 4 as precur-
sor. This transformation was examined with 4 and 1-(phen-
ylthio)prop-1-yne (2d) under the microwave-assisted reac-
tion conditions (Method B). Gratifyingly, the expected pyr-
idine derivative 3g was formed in a yield comparable with
that of the procedure mentioned above in Table 1
(Scheme 3), making the overall route to 3g more straight-
forward.
Scheme 2. Synthesis of the 2-phenyl-substituted pyridine deriva-
tives 3. (a) Method A: BF3·OEt2, CH2Cl2, –78 °C to room temp.,
18 h; b) Method B: BF3·OEt2, DCE, 70 °C, microwave irradiation,
1 h; c) Method C: BF3·OEt2, DCE, 70 °C, overnight. DCE = 1,2-
dichloroethane.
Scheme 3. Preparation of the pyridine derivative 3g from the 5-
methylene-substituted 4H-1,2-oxazine 4. (a) Method B: BF3·OEt2,
DCE, 70 °C, microwave irradiation, 1 h.
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FULL PAPER
A plausible mechanism for the formation of the pyridine
For the preparation of 3-alkynyl-substituted pyridine de-
derivatives 3 from 1 is illustrated in Scheme 4. Firstly, the rivatives we applied Methods A and B to reactions between
6-alkoxy-6H-1,2-oxazines 1 could undergo dissociation with the 4-alkynyl-substituted 6H-1,2-oxazines 7a or 7b[17] and
assistance from Lewis acids such as BF3·OEt2 or TiCl4,[14] phenylacetylene (2a) or hex-1-yne (2h). The desired 3-alk-
leading to the corresponding 1,2-azapyrylium ions A. These ynyl-substituted pyridine derivatives 8a and 8b were isolated
intermediates would be able to act as heterodiene compo- in moderate yields (Scheme 6). These results should be com-
nents in ionic [4+2] cycloadditions, and subsequent reac- pared with the reaction between 1a and 1,4-diphenylbuta-
tions with the alkynes 2 could provide the bridged bicyclic 1,3-diyne (9) as dienophile component, which afforded a
intermediates B. These could furnish the pyridines 3 complex mixture of products from which the pyridine 8a
through retro-Diels–Alder reactions, together with the form- could be isolated only in disappointingly poor yield.
yl cation, which would dissociate into carbon monoxide and
a proton. The gain in aromaticity is certainly the major
driving force for this process. Despite the multistep charac-
ters of the transformations and the assumed sensitivities of
the intermediates A and B the overall efficacies of pyridine
formation are remarkable, with yields in the 48–96% range
(Table 1).
Scheme 6. Preparation of the 3-alkynyl-substituted pyridine deriva-
tives 8a,b. (a) Method B: BF3·OEt2, DCE, 70 °C, microwave irradi-
ation, 1 h; (b) Method A: BF3·OEt2, CH2Cl2, –78 °C to room
temp., 18 h.
The results described above show that alkyne units either
Scheme 4. Proposed mechanism for the formation of pyridine de-
in the 1,2-oxazine or in the dienophile are not well tolerated
under standard conditions. We hence became interested in
developing an alternative approach with incorporation of
the Lewis-acid-sensitive functionalities at a later stage. The
easily accessible 4-bromo-substituted 6H-1,2-oxazine 10[17]
(Scheme 7) was subjected to both methods described above.
As shown in Table 2, the resulting 3-bromo-substituted pyr-
idines 11 were obtained in good yields. Again it was ob-
served that Method B is superior to Method A (cf. En-
tries 1/2 and 3/4). Nevertheless, the yields of the 3-bromo-
pyridine derivatives 11 are generally lower than those for
the corresponding products 3 without bromo substituents
(cf. 3a in Table 1, Entry 2 and 11a in Table 2, Entry 2). With
the 4,5-dibromo-6H-1,2-oxazine 12[17] (Scheme 8) and
phenylacetylene (2a) the expected 3,4-dibromopyridine de-
rivative 13 was isolated only in very poor yield (12%), with
recovery of 63% of the starting material 12. These results
indicate that the electron-withdrawing bromo substituents
rivatives.
We next examined various 6H-1,2-oxazines bearing 3-
substituents other than phenyl (e.g., electron-withdrawing
groups such as trifluoromethyl[15] or MeO2CCH=CH[16]). It
had previously been observed that the synthesis of pyridines
from the 3-(trifluoromethyl)-substituted 6H-1,2-oxazine 5
failed with Method A.[7] Gratifyingly, reactions between 5
and 2a or between 6 and 2b under microwave conditions
(Method B) afforded the corresponding pyridine derivatives
3k and 3l in at least moderate yields (Scheme 5).
Scheme 5. Preparation of the 2-substituted pyridine derivatives
3k,l. (a) Method A: BF3·OEt2, CH2Cl2, –78 °C to room temp., Scheme 7. Preparation of the 3-bromo-2-phenylpyridine derivatives
18 h; (b) Method B: BF3·OEt2, DCE, 70 °C, microwave irradiation,
1 h.
11. (a) Method A: BF3·OEt2, CH2Cl2, –78 °C to room temp., 18 h;
(b) Method B: BF3·OEt2, DCE, 70 °C, microwave irradiation, 1 h.
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Functionalized Pyridines through Cycloadditions of Azapyrylium Intermediates
strongly hamper the formation of the azapyrylium species
A, hence making the Diels–Alder step less likely and lead-
ing to low levels of conversion.
Table 2. Synthesis of the 3-bromo-2-phenylpyridine derivatives
11.[a]
Entry
2
R1
R2
Method
11
Yield
1
2
3
4
5
6
7
8
2a
2a
2h
2h
2d
2i
H
H
H
Ph
Ph
nBu
nBu
PhS
A
B
A
B
B
B
B
B
11a
11a
11b
11b
11c
11d
11e
11f
22%
76%
19%
51%
68%
50%
37%
63%
H
Me
Ph
Ph
MeOCH2
BnOCH2
2j
2k
4-MeOC6H4 MeOCH2
[a] Reaction and conditions are shown in Scheme 7.
Scheme 9. Synthesis of compounds 15 and 16. (a) Method B:
BF3·OEt2, DCE, 70 °C, microwave irradiation, 1 h.
Scheme 8. Preparation of the 3,4-dibromo-2-phenylpyridine deriva-
tive 13. (a) Method B: BF3·OEt2, DCE, 70 °C, microwave irradia-
tion, 1 h.
The successful preparation of pyridines as shown in
Schemes 2, 3, 5, 6, 7, and 8 caused us to extend the series of
functionalized heterocycles by employment of compounds
bearing more than one alkyne unit. We therefore chose
1,3,5-triethynylbenzene (14, Scheme 9) as a suitable alkyne
component. Application of Method B to treatment of 14
with the 1,2-oxazine 1a (excess, 5 equiv.) afforded a very low
yield of the expected symmetrical star-shaped product 15
together with the disubstituted product 16 as the major
component. No attempts to optimize this reaction have
been undertaken so far. Nevertheless, the obtained alkynyl-
substituted compound 16 could be an interesting building
block in an ongoing research project directed towards the
formation of self-assembled monolayers.[18] The alkyne 16
was used as component in a Sonogashira coupling with 4Ј-
nonaflyl-substituted terpyridine and provided the expected
unsymmetrical molecule, for study by scanning tunneling
microscopy (STM).[19]
The synthetic usefulness of the obtained 3-bromo-substi-
tuted pyridine derivatives 11 depends on their ability to un-
dergo subsequent reactions. These compounds did indeed
serve as suitable components for palladium-catalyzed reac-
tions (Scheme 10).
Firstly, the pyridine derivative 11e was treated with hy-
drogen in the presence of catalytic amounts of palladium
on charcoal in methanol to provide an excellent yield of the
debrominated product 17 in a chemoselective fashion, still
bearing the untouched benzyl ether moiety. More interest-
ing are palladium-catalyzed cross-couplings of these
bromo-substituted pyridines. The Sonogashira reaction be-
Scheme 10. Palladium-catalyzed reactions of the 3-bromopyridines
11a, 11b and 11e. (a) H2, Pd/C, MeOH, room temp., 90 min. (b)
PdCl2(PPh3)2, CuI, Et3N, 70 °C, 2 h. (c) Pd(OAc)2, PPh3, K2CO3,
DMF, 80 °C, 48 h. (d) Pd(OAc)2, PPh3, K2CO3, DMF, 80 °C, 4 d.
(e) PdCl2(PPh3)2, CuI, iPr2NH, 70 °C, 48 h.
tween the 3-bromopyridine 11e and methyl propargyl ether of the heterocycle 11a with (3-methoxyphenyl)boronic acid
(18) by a standard protocol afforded the alkynyl-substituted and with styrylboronic acid furnished the expected trisub-
pyridine derivative 19 in good yield. The Suzuki couplings stituted pyridine derivatives 20 and 21, respectively, in ca.
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H.-U. Reissig, R. Zimmer, et al.
FULL PAPER
(triplet), q (quartet), m (multiplet), mc (centered multiplet), dd
(doublet of doublet), br. s (broad singlet). Due to overlapping sig-
nals not all signals of carbon atoms in the aromatic region could be
assigned. For detailed peak assignments 2D spectra were measured
(COSY, HMBC, and HMQC). IR spectra were measured with a
Nicolet 5 SXC FT-IRD spectrometer or with a Nexus FT-IR spec-
trometer fitted with a Nicolet Smart DuraSample IR ATR. MS
and HRMS analyses were performed with Finnigan MAT 711 (EI,
80 eV, 8 kV), MAT CH7A (EI, 80 eV, 3 kV), or CH5DF (FAB,
3 kV), Varian Ionspec QFT-7 (ESI-FT ICRMS), and Agilent 6210
60% yield. In contrast, when the 3-bromo-6-butylpyridine
11b was treated with (trimethylsilyl)acetylene (22) by the
standard Sonogashira protocol the product 23 was obtained
in 28% yield. It appears that the initially formed coupling
product underwent desilylation and oxidative Glaser-type
coupling under the employed reaction conditions to form
the dialkyne 23.
An alternative option for functional group transforma-
tion is offered by the phenylthio groups in pyridine deriva-
tives such as 3g. This compound was smoothly oxidized (ESI-TOF) instruments. Elemental analyses were carried out with
a Perkin–Elmer CHN Analyzer 2400 and a Vario EL Elemental
Analyzer. Melting points were measured with a Reichert apparatus
(Thermovar) and are uncorrected. The 1,2-oxazines 1a,[8c] 1b,[8b]
4,[8b] 5,[8c] 7a and 7b,[17] and 12[17] and the alkynes 2i, 2j,[21] 2k,[22]
2f,[12] 2g,[23] and 18[24] were prepared according to literature pro-
cedures.
under standard conditions in the presence of oxone as rea-
gent to afford the corresponding sulfoxide 24 in excellent
yield (Scheme 11).
Typical Procedure for Pyridine Synthesis at Low Temperature
(Method A): The 6H-1,2-oxazine 1 (1 equiv.) was dissolved in dry
CH2Cl2 (20 mLmmol–1) under argon, and the alkyne 2 (2–
10 equiv.) was added at –78 °C. The mixture was then treated with
BF3·OEt2 (2 equiv.) and allowed to warm to room temperature
overnight. After addition of H2O (20 mLmmol–1), the organic layer
was extracted with CH2Cl2 (3ϫ20 mLmmol–1), and the combined
extracts were dried (Na2SO4). After evaporation of the solvent, the
residue was purified by column chromatography.
Scheme 11. Oxidation of the pyridine derivative 3g into the sulfox-
ide 24. (a) Oxone (2 equiv.), acetone, H2O, room temp., 2 h.
Conclusions
Typical Procedure for Pyridine Synthesis under Microwave Condi-
tions (Method B): The 6H-1,2-oxazine 1 (1 equiv.) was placed in a
microwave tube under argon and dissolved in 1,2-dichloroethane.
The alkyne 2 (1.5–8 equiv.) and BF3·OEt2 (2 equiv.) were then
added. The reaction mixture was irradiated in the microwave oven
at 350 W and 70 °C for 1 h. After cooling to room temperature, the
mixture was quenched with H2O (7–10 mLmmol–1) and extracted
with CH2Cl2 (3ϫ8–20 mLmmol–1). The combined organic layers
were dried with Na2SO4, filtered, and concentrated. The crude
product was purified by column chromatography.
We have been able to demonstrate that Lewis-acid-medi-
ated and microwave-assisted reactions between 6H-1,2-ox-
azines and appropriate mono- or disubstituted alkynes via
azapyrylium intermediates allow synthetically useful and
practical access to pyridine derivatives in a highly flexible
manner. Of particular value is the fact that the easily access-
ible 3-bromo-substituted pyridines 11 can be further func-
tionalized through palladium-catalyzed reactions. Even
acid-sensitive groups such as alkynyl substituents can be
successfully installed on the pyridine core, as demonstrated
by the synthesis of product 19. With the access to the (tri-
fluoromethyl)- and acryloyl-substituted pyridines 3k and 3l
we have successfully extended the collection of highly func-
tionalized pyridines. It is known that pyridine derivatives of
this type are potentially useful compounds as pharmaceuti-
cals.[2s,3i,20]
2,6-Diphenylpyridine (3a): The 6H-1,2-oxazine 1a (113 mg,
0.556 mmol), phenylacetylene (2a, 454 mg, 4.45 mmol), and
BF3·OEt2 (140 μL, 1.11 mmol) in 1,2-dichloroethane (5 mL) were
used in the typical procedure (Method B). The crude product was
purified by column chromatography (silica gel; toluene/hexane, 4:1)
to give 3a (121 mg, 96%) as colorless crystals, m.p. 80–81 °C (ref.[9]
m.p. 81.5–82 °C). The NMR spectroscopic data are consistent with
those reported.
Preparation of the Pyridine 3a by Heating without Microwave Con-
ditions (Method C): The 6H-1,2-oxazine 1a (203 mg, 1.00 mmol)
was dissolved in 1,2-dichloroethane (8 mL) under argon. After ad-
dition of phenylacetylene (2a, 408 mg, 4.00 mmol) and BF3·OEt2
(280 μL, 2.00 mmol), the reaction mixture was stirred at 70 °C
overnight. After cooling to room temperature, the mixture was
quenched with H2O (8 mL) and extracted with CH2Cl2
(3ϫ10 mL). The combined organic layers were dried with Na2SO4,
filtered, and concentrated. The crude product was purified by col-
umn chromatography on silica gel (toluene/hexane, 4:1) to give 3a
(148 mg, 64%).
Experimental Section
General Methods: Reactions were generally performed under argon
in flame-dried flasks. Solvents and reagents were added by syringe.
Solvents were dried by standard procedures. Reagents were pur-
chased and used as received without further purification unless
otherwise stated. Microwave-assisted reactions were carried out in
a microwave oven (“micro Chemist”, MLS GmbH). Unless stated
otherwise, products were purified by flash chromatography on silica
gel (230–400 mesh, Merck or Fluka) or by HPLC (Nucleosil 50–
5). Yields refer to analytically pure samples. NMR spectra were
recorded with Bruker (AC 250, AC 500) and JOEL (Eclipse 500
and ECX 400) instruments. Chemical shifts are reported relative to
TMS (1H: δ = 0.00 ppm) or CDCl3 (1H: δ = 7.26 ppm; 13C: δ =
77.0 ppm). Integrals are in accordance with assignments; coupling
constants are given in Hz. All 13C NMR spectra are proton-decou-
pled. Multiplicity is indicated as follows: s (singlet), d (doublet), t
3,4-Dimethyl-6-phenyl-2-(phenylthio)pyridine (3g): The 5-methyl-
ene-4H-1,2-oxazine 4 (113 mg, 0.556 mmol), 1-(phenythio)prop-1-
yne (2d, 659 mg, 4.45 mmol), and BF3·OEt2 (140 μL, 1.11 mmol)
in 1,2-dichloroethane (5 mL) were used in the typical procedure
(Method B). The crude product was purified by column
chromatography (silica gel; toluene/hexane, 4:1) to give 3g (121 mg,
75%) as a colorless solid, m.p. 104–106 °C. 1H NMR (CDCl3,
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Functionalized Pyridines through Cycloadditions of Azapyrylium Intermediates
400 MHz): δ = 2.28, 2.31 (2 s, 3 H each, Me), 7.22–7.31, 7.33–7.42, 3-Bromo-5-(methoxymethyl)-6-(4-methoxyphenyl)-2-phenylpyridine
7.55–7.60, 7.67–7.73 (4 m, 4 H, 3 H, 2 H, 2 H, Py, Ph) ppm. 13C
(11f): A mixture of the 6H-1,2-oxazine 10 (150 mg, 0.532 mmol),
NMR (CDCl3, 100.6 MHz): δ = 14.6, 20.1 (2 q, Me), 118.3, 126.2, BF3·OEt2 (130 μL, 1.06 mmol), and 3-(4-methoxyphenyl)propargyl
127.9, 128.3, 128.4, 128.6, 131.9, 134.5, 138.6, 146.1, 153.1, 157.0
methyl ether (2k, 375 mg, 2.13 mmol) in DCE (4 mL) was treated
as described in the typical procedure (Method B). The mixture was
allowed to cool to room temperature, diluted with water (5 mL),
and extracted with CH2Cl2 (3ϫ10 mL). The combined organic
phases were dried with Na2SO4 and concentrated to dryness. The
residue was purified by chromatography on silica gel (hexane/
EtOAc, 6:1) to give 11f (129 mg, 63%) as a yellow solid, m.p. 95–
(6 d, s, d, 4 s, Py, Ph) ppm. IR (ATR): ν = 3080–3030 (=C–H),
˜
2950–2870 (C–H) cm–1. C19H17NS (291.4): calcd. C 78.31, H 5.88,
N 4.81, S 11.00; found C 78.47, H 6.00, N 4.80, S 11.28.
2-(2-Methyl-1,5-diphenyl-1H-imidazol-4-yl)-6-phenylpyridine (3i):
The 6H-1,2-oxazine 1a (104 mg, 0.500 mmol), BF3·OEt2 (0.13 mL,
1.00 mmol), and the alkyne 2f (129 mg, 0.515 mmol) in 1,2-dichloro-
ethane (3 mL) were used in the typical procedure (Method B). The
crude product was purified by chromatography on silica gel (hex-
ane/EtOAc, 4:1 to 1:1) to give 3i (104 mg, 54%) as a yellow oil. 1H
NMR (CDCl3, 250 MHz): δ = 2.38 (s, 3 H, Me), 7.09–7.40, 7.46–
7.50 (2 m, 13 H, 2 H, Py, Ph), 7.54 (d, J = 8.1 Hz, 1 H, Py), 7.70
(dd, J = 7.4, 8.1 Hz, 1 H, Py), 7.84 (d, J = 7.4 Hz, 1 H, Py) ppm.
13C NMR (CDCl3, 100.6 MHz): δ = 14.1 (q, Me), 117.1, 119.3,
126.7, 127.2, 128.0, 128.1, 128.4, 129.2, 131.0, 131.6, 132.3, 136.5,
136.8, 136.9, 139.1 (9 d, 4 s, d, s, Py, Im, Ph), 145. 1 (s, Im), 153.4,
1
97 °C. H NMR (CDCl3, 500 MHz): δ = 3.44, 3.85 (2 s, 3 H each,
OMe), 4.45 (s, 2 H, CH2), 6.95–6.98, 7.39–7.45, 7.54–7.61, 7.72–
7.76 (4 m, 2 H, 3 H, 2 H, 2 H, Ph), 8.14 (s, 1 H, 4-H) ppm. 13C
NMR (CDCl3, 125.8 MHz): δ = 55.3, 58.5 (2 q, OMe), 71.0 (t,
CH2), 117.5 (s, C-3), 127.8, 128.6, 129.5, 130.4, 131.0, 131.1, 131.2
(5 d, 2 s, Ph), 139.5 (s, C-5), 142.0 (d, C-4), 156.2 (s, C-6), 156.3 (s,
C-2) ppm. HRMS (ESI-TOF): calcd. for C20H18BrNO2 [M – H]+
384.0599, found 384.0591. C20H18BrNO2 (384.3): calcd. C 62.51,
H 4.72, N 3.65; found C 62.05, H 4.67, N 3.64.
155.5 (2 s, C-2, C-6) ppm. IR (ATR): ν = 3060–2840 (=C–H,
˜
Reaction between 1a and 1,3,5-Triethynylbenzene (14): A mixture
of the 6H-1,2-oxazine 1a (1.02 g, 5.00 mmol), BF3·OEt2 (1.00 mL,
8.00 mmol), and 1,3,5-triethynylbenzene (14, 150 mg, 1.00 mmol)
in DCE (5 mL) was treated as described in the typical procedure
(Method B). The mixture was allowed to cool to room temperature,
diluted with water (7 mL), and extracted with CH2Cl2 (3ϫ15 mL).
The combined organic phases were dried with Na2SO4 and concen-
trated to dryness. The residue was purified by chromatography on
silica gel (hexane/EtOAc, 6:1, 4:1 to 1:1) to give a mixture (16 mg)
of 15 and 16 (3:1, calcd. 3% 15, 0.5% 16) as a pale yellow oil, as
well as 16 (39 mg, 9.5%) as a pale yellow solid, m.p. 120–122 °C.
C–H), 1600 (C=C) cm–1. HRMS (ESI-TOF): calcd. for C27H21N3
[M + H]+ 388.1808, found 388.1849; calcd. for [M + Na]+ 410.1628,
found 410.1667.
3-Bromo-2,6-diphenylpyridine (11a): The 4-bromo-6H-1,2-oxazine
10 (614 mg, 2.18 mmol), phenylacetylene (2a, 2.23 g, 21.8 mmol),
and BF3·OEt2 (622 mg, 4.38 mmol) in CH2Cl2 (20 mL) were used
in the typical procedure (Method A). The crude product was puri-
fied by column chromatography (alumina; hexane/EtOAc, 10:1
then 8:1) to give 11a (151 mg, 22%) as a yellow oil.
The 4-bromo-6H-1,2-oxazine 10 (113 mg, 0.556 mmol), phenyl-
acetylene (2a, 454 mg, 4.45 mmol), and BF3·OEt2 (140 μL,
1.11 mmol) in 1,2-dichloroethane (5 mL) were also used in the typi-
cal procedure (Method B). The crude product was purified by col-
umn chromatography (silica gel; toluene/hexane, 4:1) to give 11a as
a yellow oil (131 mg, 76%). 1H NMR (CDCl3, 250 MHz): δ = 7.39–
7.49 (m, 6 H, Ph), 7.52 (d, J = 8.3 Hz, 1 H, 5-H), 7.76–7.81 (m, 2
H, Ph), 7.97 (d, J = 8.3 Hz, 1 H, 4-H), 8.00–8.05 (m, 2 H, Ph)
ppm. 13C NMR (CDCl3, 125.8 MHz): δ = 119.2 (s, Ar), 119.8 (d,
C-5), 126.9, 127.9, 128.7, 129.6 (4 d, Ar, Ph), 138.2, 139.8 (2 s, Ph),
1
Compound 15: H NMR (CDCl3, 400 MHz): δ = 7.32–7.45, 7.50–
7.59, 7.64–7.67, 7.78–7.95, 8.20–8.25 (5 m, 4 H, 6 H, 3 H, 5 H, 3
H, Ph, Py, Ar), 8.26 (d, J = 1.5 Hz, 3 H, Py), 9.03 (s, 3 H, Py)
ppm. HRMS (ESI-TOF): calcd. for C39H27N3 [M + H]+ 538.2283,
1
found 538.2286. Compound 16: H NMR (CDCl3, 400 MHz): δ =
3.21 (s, 1 H, ϵCH), 7.43–7.48, 7.50–7.55 (2 m, 2 H, 4 H, Ph), 7.75
(d, J = 6.0 Hz, 2 H, Py), 7.79 (d, J = 6.3 Hz, 2 H, Py), 7.86 (dd, J
= 6.0, 6.3 Hz, 2 H, Py), 8.18–8.23 (m, 4 H, Ph), 8.35 (d, J = 1.4 Hz,
2 H, Py), 8.95 (t, J = 1.4 Hz, 2 H, Py) ppm. 13C NMR (CDCl3,
125.8 MHz): δ = 77.4 (d, ϵCH), 83.8 (s, ϵC), 118.8, 119.1, 122.9,
126.1, 127.0, 128.7, 129.1, 131.0, 137.6, 139.3, 140.1 (2 d, s, 6 d, 2
141.9 (d, C-4), 155.7, 157.4 (2 s, Ar) ppm. IR (neat): ν = 3105–
˜
2980 (=CH, C–H) cm–1. MS (EI, 80 eV, 80 °C): m/z (%) = 311 (31)
[M]+, 230 (100) [M – Br]+, 288 (17), 77 (35) [C6H5]+. HRMS (EI,
80 eV): calcd. for C17H12BrN 309.01532, found 309.01475.
s, Ph, Ar, Py), 155.7, 156.9 (2 s, Py) ppm. IR (ATR): ν = 3065–
˜
2850 (=C–H, C–H) cm–1. HRMS (ESI-TOF): calcd. for C30H20N2
[M + H]+ 409.1705, found 409.1709.
3-Bromo-5-(methoxymethyl)-2,6-diphenylpyridine (11d): A mixture
of the 6H-1,2-oxazine 10 (150 mg, 0.532 mmol), BF3·OEt2 (156 mg, 5-[(Benzyloxy)methyl]-3-(3-methoxyprop-1-yn-1-yl)-2,6-diphenylpyr-
1.06 mmol), and methyl 3-phenylpropargyl ether (2i, 117 mg,
0.800 mmol) in DCE (4 mL) was treated as described in the typical
procedure (Method B). The mixture was allowed to cool to room
temperature, diluted with water (5 mL), and extracted with CH2Cl2
idine (19): The pyridine derivative 11e (67 mg, 0.155 mmol), methyl
propargyl ether (18, 109 mg, 1.55 mmol), PdCl2(PPh3)2 (11.2 mg,
0.016 mmol), and CuI (1.5 mg, 0.008 mmol) were dissolved in Et3N
(5 mL) in a heat-gun-dried and argon-flushed flask, and the reac-
(3ϫ10 mL). The combined organic phases were dried with Na2SO4 tion mixture was stirred at 70 °C for 2 h. The solvent was then
and concentrated to dryness. The residue was purified by
chromatography on silica gel (hexane/EtOAc, 4:1) to give 11d
(93 mg, 50%) as a pale yellow solid, m.p. 83–86 °C. 1H NMR
removed under reduced pressure, and the residue was dissolved in
EtOAc (5 mL), washed with water (5 mL), and dried with Na2SO4.
Purification of the crude product by column chromatography
(CDCl3, 250 MHz): δ = 3.41 (s, 3 H, OMe), 4.51 (s, 2 H, CH2), (SiO2; hexane/EtOAc, 4:1) afforded the 3-alkynyl-substituted pyr-
7.36–7.47, 7.56–7.61, 7.71–7.76 (3 m, 6 H, 2 H, 2 H, Ph), 8.16 (s,
1 H, 4-H) ppm. 13C NMR (CDCl3, 125.8 MHz): δ = 58.6 (q, OMe),
70.8 (t, CH2), 118.2 (s, C-3), 127.8, 128.2, 128.6, 129.0, 129.5 (5 d,
Ph), 131.4 (s, C-5), 139.3, 139.7 (2 s, Ph), 141.9 (d, C-4), 156.4,
156.5 (2 s, C-2, C-6) ppm. HRMS (ESI-TOF): calcd. for
C19H16BrNO [M – H]+ 354.0488, found 354.0506. C19H16BrNO
(354.2): calcd. C 64.42, H 4.55, N 3.95; found C 64.00, H 4.38, N
4.03.
idine 19 (48 mg, 74%) as a pale yellow oil. 1H NMR (CDCl3,
250 MHz): δ = 3.39 (s, 3 H, OMe), 4.28 (s, 2 H, CH2), 4.53, 4.60
(AB system, JAB = 15.7 Hz, 4 H, CH2), 7.20–7.55, 7.60–7.65, 7.95–
8.05 (3 m, 11 H, 2 H, 2 H, Ph), 8.10 (s, 1 H, 4-H) ppm. 13C NMR
(CDCl3, 125.8 MHz): δ = 57.7 (q, OMe), 60.4, 69.0, 72.9 (3 t,
OCH2), 84.4, 90.5 (2 s, CϵC), 115.6, 127.9, 128.2, 128.4, 128.5,
128.7, 129.1, 129.3, 137.7, 139.15, 139.2 (s, 7 d, 2 s, Ph, Py), 142.9
(d, C-4), 157.2, 158.3 (2 s, C-2, C-6) ppm. IR (neat): ν = 3105–
˜
Eur. J. Org. Chem. 2011, 6070–6077
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6075

H.-U. Reissig, R. Zimmer, et al.
FULL PAPER
2980 (=CH, C–H), 2200 (CϵC) cm–1. C29H25NO2 (419.5): calcd.
C 83.03, H 6.01, N 3.34; found C 83.60, H 6.39, N 3.03.
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3,4-Dimethyl-6-phenyl-2-(phenylsulfinyl)pyridine (24): A solution of
oxone (1.24 g, 2.02 mmol) dissolved in water (6 mL) was added to
a solution of the pyridine 3g (280 mg, 0.962 mmol) in acetone
(25 mL). The mixture was stirred at room temperature for 2 h and
was then diluted with water (40 mL). The aqueous phase was ex-
tracted with CH2Cl2 (3ϫ25 mL). The combined organic phases
were washed with water (2ϫ20 mL) and brine (1ϫ20 mL), dried
with MgSO4, and concentrated to dryness. The residue was purified
by chromatography on silica gel (hexane/EtOAc, 4:1) to give 24
(261 mg, 88%) as colorless crystals, m.p. 170–171 °C. 1H NMR
(CDCl3, 400 MHz): δ = 2.32, 2.47 (2 s, 3 H each, Me), 7.36–7.50
(m, 6 H, Ph), 7.56 (s, 1 H, 5-H), 7.73–7.79, 7.95–8.01 (2 m, 2 H
each, Ph) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 12.3, 19.8 (2
q, Me), 122.9, 125.1, 126.6, 128.5, 128.8, 129.2, 130.5, 130.9, 137.7,
[3]
143.6, 149.6, 154.4, 160.2 (7 d, 6 s, Py, Ph) ppm. IR (ATR): ν =
˜
3055–3030 (=C–H), 2910–2855 (C–H), 1085 (S=O) cm–1.
C19H17NOS (307.4): calcd. C 74.24, H 5.57, N 4.56, S 10.44; found
C 73.94, H 5.60, N 4.55, S 10.66.
Supporting Information (see footnote on the first page of this arti-
cle): Procedures for the synthesis of 2e, 3b–d, 3f–h, 3j–l, 8a, 8b, 11b,
11c, 11e, 13, 17, 20, 21, 23, and 24a.
Acknowledgments
We are most grateful for generous support of this work by the
Deutsche Forschungsgemeinschaft and the Bayer Schering Pharma
AG. We also thank Giaime Rancan, Stefan Krug, and Sascha
Schaller for their experimental assistance.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6070–6077

Functionalized Pyridines through Cycloadditions of Azapyrylium Intermediates
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[14] For the generation of 1,2-azapyrylium ions, BF3·OEt2 is often
the Lewis acid of choice. Only in few cases is it recommendable
to use a stronger Lewis acid such as TiCl4: a) R. Zimmer, H.-
U. Reissig, Synthesis 1989, 908–911; b) R. Zimmer, H.-U. Reis-
sig, H. J. Lindner, Liebigs Ann. Chem. 1992, 621–624. Alterna-
tively, 1,2-azapyrylium intermediates can also be generated by
treatment of 6H-1,2-oxazines with Brønsted acids instead of
Lewis acids; see: c) R. Zimmer, M. Buchholz, M. Collas, J.
Angermann, K. Homann, H.-U. Reissig, Eur. J. Org. Chem.
2010, 4111–4121.
[15] R. Zimmer, H.-U. Reissig, J. Org. Chem. 1992, 57, 339–347.
[16] R. Zimmer, M. Collas, R. Czerwonka, U. Hain, H.-U. Reissig,
Synthesis 2008, 237–244.
[17] R. Zimmer, E. Schmidt, M. Andrä, M.-A. Duhs, I. Linder, H.-
U. Reissig, Beilstein J. Org. Chem. 2009, 5, No. 44.
[24] W. Reppe, Justus Liebigs Ann. Chem. 1955, 596, 1–224.
Received: May 30, 2011
Published Online: August 25, 2011
Eur. J. Org. Chem. 2011, 6070–6077
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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