Cross Mannich Reaction of Aldehydes; Efficient Synthesis of Substituted Pyridines

Article abstract of DOI:10.1055/s-2003-42435

Symmetrically and unsymmetrically substituted pyridines were obtained in highly efficient one-pot procedures starting from α-unbranched aldehydes and iminium salts.

Full text of DOI:10.1055/s-2003-42435

PAPER
2667
Cross Mannich Reaction of Aldehydes; Efficient Synthesis of Substituted
Pyridines
C
A
ross Mannic
h
Re
n
a
ction of
A
ld
d
ehydes; Syn
r
thesis of
e
Substituted
a
Pyridines s Winter, Nikolaus Risch*
Universität Paderborn, Fakultät für Naturwissenschaften, Department Chemie, Warburger Str. 100, 33098 Paderborn, Germany
Fax +49(5251)603245; E-mail: nr@chemie.upb.de
Received 26 September 2003; revised 1 September 2003
aminoalkylation of diverse nucleophiles showed that
Mannich bases obtained from -unbranched aliphatic al-3
dehydes 6 spontaneously undergo amine elimination.
Here, we report that these aldehydes are suitable building
blocks for the selective synthesis of symmetrically 3,5-
disubstituted 12 or unsymmetrically substituted pyridine
derivatives 15.
Abstract: Symmetrically and unsymmetrically substituted py-
ridines were obtained in highly efficient one-pot procedures starting
from -unbranched aldehydes and iminium salts.
Key words: aldehydes, domino reactions, Mannich bases, py-
ridines, imines
Symmetrically 3,5-disubstituted pyridines 12 are interest-
Due to the diversity of applications and the broad distribu-
tion of pyridine derivatives in nature, numerous synthetic
methods for these heterocyclic systems have been investi-
ing components for the formation of pyridine carboxylic
4
5
acids or macrocycles containing pyridine units. Howev-
er, their synthesis has hardly been described in the litera-
1
gated. Our studies in the field of ternary iminium salts led
6
ture. These methods are unfavorable because of long
to the development of efficient one-pot reactions yielding
a wide range of functionalized pyridines, bipyridines and
reaction times, formation of by-products and poor yields.
2
terpyridines. All these reactions are based on the ability
The synthesis of symmetrically 3,5-disubstituted py-
ridines 12 (four examples) was carried out according to
our procedure developed for the selective synthesis of U-
shaped terpyridines.2 The imines 7 were generated in
of Mannich bases 1 to form , -unsaturated ketones 2 by
thermally induced amine elimination. Enamines as well as
ketones 3 are easily alkylated by these Michael acceptors
to form 1,5-diketones 4 which can be converted to the cor-
responding pyridine derivatives 5 by treatment with a
source of ammonia (Scheme 1).
e,7
situ by heating a solution of the -unbranched aldehydes
8
6
in DMSO. A suspension of the iminium salts 8 in
DMSO was added to form the Mannich bases 9. Under the
reaction conditions the amine is eliminated. Subsequent-
ly, these Michael acceptors 10 react with a further equiv-
alent of the aldehydes 6 yielding 1,5-dicarbonyl
compounds 11 which are converted spontaneously to the
corresponding pyridine derivatives 12 (Scheme 2,
Table 1).
R1
O
R1
R3
R5
R2
NHR'2 Cl
R3
R2
R4
1
5
N
In principle, our results show, that -unbranched alde-
hydes 6 are well suited as the CH-acidic component for
the domino synthesis of pyridine derivatives (Scheme 3).
The rather low yields in the case of R = Et may be as-
cribed to the high volatility of n-butyraldehyde. This new
i) NH4OAc
ii) ox.
∆
- NHR'2Cl
O
1
R4
R1
O
O
O
R5
3
R2
R1
R2
R4
method may provide a broad range of symmetrically 3,5-
R3
R3
R5
2
4
Scheme 1 Formation of highly substituted pyridine derivatives
Table 1 Preparation of Symmetrically 3,5-Disubstituted Pyridines
1
2
4
from Mannich bases and ketones (R = aryl, H; R , R = aryl, alkyl or
1
2
3
5
cycloalkyl; R , R = H, aryl, alkyl or cycloalkyl)
Entry
2a
12b
2c
R1
Et
R2
H
Yield (%)
A multitude of cyclic and acyclic ketones 3 can be used.
Either the ketone itself or the -amino ketone 1 gives sym-
metrically or unsymmetrically substituted pyridine deriv-
atives 5 in very good yields. To the best of our
knowledge, enolizable aldehydes have not yet been used
17a
1
Et
Ph
H
26a
53b
48b
2
1
Ph
Ph
in the context of pyridine syntheses. Our research on the 12d
Ph
a
Yield after Kugelrohr distillation.
Yield after flash column chromatography.
SYNTHESIS 2003, No. 17, pp 2667–2670
x
x.
x
x
.
2
0
0
3
b
Advanced online publication: 14.10.2003
DOI: 10.1055/s-2003-42435; Art ID: T05703SS
Georg Thieme Verlag Stuttgart · New York
©

2
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A. Winter, N. Risch
PAPER
R2
N
R1
N
O
R1
O
R1
R1
R3
R2
R4
R2
NHR'2 Cl
- NHR'2Cl
12
R1
1
R3
15
6
i) cyclization
ii) oxidation
i) NH OAc
NH4OAc
4
∆
ii) oxidation
O
NH R2
O
NH
R1
O
O
O
R4
6
R2
R1
R2
R1
11 R1
R1
O
7
R3
14 R3
R4
2
Scheme 4 Selective synthesis of unsymmetrically substituted pyri-
dines 15
NR'2 Cl
R2
R1
8
6
Synthetic methods for the synthesis of pyridine deriva-
tives 15 have hardly been described in the literature so
far.10 Our general approach (six examples) allows the ef-
ficient and selective synthesis of unsymmetrically substi-
tuted mono- or bicyclic monopyridines and as well as
NH NR'2H Cl
R2
NH
R2
-
NR'2HCl
R1
9
R1 10
Scheme 2 Preparation of symmetrically 3,5-disubsituted pyridines bipyridines. To the best of our knowledge, compounds
12
1
5c,d represent novel classes of bipyridines as their sub-
stitution patterns have not been published before.
2
In extension to prior work that only focused on ketones 3
disubsituted pyridine derivatives in a straightforward syn-
thesis by the variation of the enolizable aldehydes 6 and
the iminium salts 8 employed.
as building blocks for the synthesis of different types of
pyridine derivatives, -unbranched aldehydes 6 were em-
ployed as starting material for both symmetrically 3,5-dis-
ubstituted and unsymmetrically substituted pyridine
derivatives 12 and 15. We expect that our methodology
can be extended to broad range of aldehydes yielding py-
ridine derivatives with a diverse substitution pattern.
On the other hand, this strategy is less suited for the selec-
tive synthesis of unsymmetrically 3,5-disubstituted deriv-
atives 13. If two different aldehydes 6 were applied in this
domino reaction, a statistic mixture of products was
formed independently of the order that the aldehydes were
added to the reaction mixture (13:12a:12c, 1:1:1).
All reagents were purchased from commercial sources and used
without further purification unless specified. All solvents were
dried and distilled according to standard procedures and stored un-
der argon. Chromatographic separation was performed on silica gel
Et
Ph
O
1
3a
N
N
(Kieselgel 60, Fa. Merck AG, 0.040–0.063 mm) or aluminum oxide
O
NR'2 Cl
Et
Et
(neutral, Akt. III, Fa. Macherey & Nagel, 0.063–0.200 mm). Mps
were obtained on a Büchi SMP-20 mp apparatus and are uncorrect-
ed. IR spectra were measured on a Nicolet 510 P FT-IR spectrome-
ter. All NMR spectra were recorded on a Bruker ARX 200
instrument (200 or 50 MHz). Mass spectra were recorded using a
Finigan MAT 8230 apparatus, GC-MS spectra were recorded on a
Finigan MAT Magnum TM spectrometer. Elemental analyses were
obtained on a Perkin–Elmer M240 analyzer.
+
1
2a
2c
6a
6b
Ph
Ph
1
N
Scheme 3 Synthesis of unsymmetrically 3,5-disubstituted pyridine
derivatives 13
Iminium salts 8 and Mannich base hydrochlorides 1 were synthe-
sized using literature procedures.
7
–9
9
-
Amino ketone hydrochlorides 1 are excellent starting Symmetrically 3,5-Disubstituted Pyridine Derivatives 12; Gen-
eral Procedure
A suspension of the aldehyde 6 (5.05 mmol) and the iminium salt 8
5.1 mmol) in DMSO (10 mL) was heated under argon until a clear
materials in the synthesis of different types of pyridine de-
rivatives. If a mixture of the -amino ketone hydrochlo-
ride 1 and the enolizable carbonyl compound 3 were
refluxed in EtOH in the presence of NH OAc, pyridine
derivatives 5 are obtained as shown in Scheme 1. We dis-
(
solution was obtained. In a second flask, a mixture of the aldehyde
6 (5.05 mmol) and ammonium acetate (5.5 mmol) in DMSO (5 mL)
was heated at 60 °C for 5 min. The warm mixture of the first flask
4
close, that also -unbranched aldehydes 6 can be used in was then added to the second one and the reaction mixture was heat-
this reaction cascade to form unsymmetrically substituted ed at 120 °C under argon for 15 h. After cooling r.t. it was poured
into H O (25 mL) and extracted with CH Cl (3 × 25 mL). The com-
pyridine derivatives 15 in acceptable yields (Scheme 4).
2
2
2
bined organic extracts were washed with H O (5 × 20 mL) and dried
2
Synthesis 2003, No. 17, 2667–2670 © Thieme Stuttgart · New York

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Cross Mannich Reaction of Aldehydes; Synthesis of Substituted Pyridines
2669
Table 2 Preparation of Unsymmetrically Substituted Pyridines 15 Prepared from Mannich Bases 1 and Phenylacetaldehyde 6b
Entry
Mannich base 1
Pyridine 15
Yield (%)a
37
15a
O
NHR'2 Cl
N
1
5b
O
45
41b
39
49
41
NHR'2 Cl
N
1
1
1
1
5c
5d
5e
5f
O
O
O
O
N
N
NHR'2 Cl
N
N
N
N
NHR'2 Cl
NHR'2 Cl
NHR'2 Cl
N
N
a
Yield after column chromatography on SiO2.
Yield after column chromatograph on Al O .
b
2
3
(
MgSO ). The solvent was removed in vacuo and the crude product
Unsymmetrically Substituted Pyridine Derivatives 15; General
Procedure
4
thus obtained was purified either by flash column chromatography
silica gel; EtOAc–hexane, 1:2) or Kugelrohr distillation.
(
A suspension of the aldehyde 6 (5 mmol), the Mannich base hydro-
chloride 1 (6 mmol) and ammonium acetate (16 mmol) in EtOH (25
mL) was heated at reflux for 3 h. After cooling, the solvent was
evaporated and the oily residue was treated with aq HCl (2 M; 15
mL). Non-basic components were separated by extraction with
3
,5-Diethylpyridine (12a)
6
a
Yield: 48 mg (17%); colorless liquid; bp 53 °C/2.5 mbar (lit. 52–
5
6 °C/2.6 mbar).
Et O (2 × 25 mL). The aq phase was made basic by addition of aq
2
3
,5-Diethyl-4-phenylpyridine (12b)
ammonia (25 mL; 25% NH –H O, 1:4) and extracted with CH Cl
3
2
2
2
6
a
Yield: 155 mg (26%); yellow oil (lit. 150 °C/2.5 mbar).
(3 × 20 mL). The combined organic phases were dried (MgSO4)
and the solvent was evaporated. The crude product was purified by
flash column chromatography (silica gel or neutral aluminum oxide,
CH Cl ).
3
,5-Diphenylpyridine (12c)
6
a
Yield: 247 mg (53%); colorless plates; mp 136 °C (lit. 138–
2
2
1
39 °C).
2
-tert-Butyl-5-phenylpyridine (15a)
1
0c
3
,4,5-Triphenylpyridine (12d)
Yield: 391 mg (37%); colorless oil (lit. mp 60 °C).
Yield: 298 mg (48%); white powder; mp 153 °C.
3
-Phenyl-5,6,7,8-tetrahydroquinoline (15b)
IR (KBr): 2938, 2641, 1680, 1607, 1411, 1232, 1165, 1091, 963,
1
0a
–1
Yield: 471 mg (45%); yellow oil (lit. bp 211 °C/24 mbar).
7
68 cm .
1
H NMR (CDCl ): d = 8.84 (s, 2 H,), 7.61–7.68 (m, 6 H), 7.25–7.53
m, 9 H).
3
3-Phenyl-5,6-dihydro[1,10]phenanthroline (15c)
Yield: 529 mg (41%); yellow crystals; mp 138 °C.
(
13C NMR (CDCl3): = 127.6, 127.7, 128.7, 129.0, 129.6, 129.9,
30.9, 136.2, 138.4, 143.2, 147.4.
IR (KBr): 3062, 2942, 1587, 1456, 1379, 1255, 1107, 1088, 775
1
–1
cm .
+
+
GC-MS (80 eV): m/z (%) = 308 (100, [M + 1] ), 307 (36, M ), 276
16), 199 (5).
1H NMR (CDCl3): = 8.85–9.01 (m, 1 H), 8.56–8.76 (m, 1 H),
(
7
7
.67–7.72 (m, 1 H), 7.61–7.66 (m, 1 H), 7.56–7.61 (m, 1 H), 7.39–
.56 (m, 3 H), 7.13–7.25 (m, 2 H), 2.95–3.04 (m, 4 H).
Anal. Calcd for C H N (307.4): C, 89.87; H, 5.57; N, 4.56. Found:
23
17
C, 89.81; H, 5.52; N, 4.67.
Synthesis 2003, No. 17, 2667–2670 © Thieme Stuttgart · New York

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A. Winter, N. Risch
PAPER
1
3C NMR (CDCl3): = 27.7, 27.8, 123.9, 127.5, 128.6, 129.4, References
1
29.5, 134.0, 134.4, 136.2, 136.7, 137.9, 147.7, 149.3, 150.9, 151.9.
(1) Balasubramanian, M.; Keay, J. G. In Comprehensive
Anal. Calcd for C H N (258.2): C, 83.69; H, 5.47; N, 10.84.
Found: C, 83.73; H, 5.52; N, 10.75.
1
8
14
2
Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.;
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996.
2) (a) Keuper, R.; Risch, N.; Flörke, U.; Haupt, H.-J. Liebigs
Ann. Org. Bioorg. Chem. 1996, 5, 705. (b) Keuper, R.;
Risch, N. Liebigs Ann. Org. Bioorg. Chem. 1996, 5, 717.
(c) Keuper, R.; Risch, N. Eur. J. Org. Chem. 1998, 1, 2609.
(d) Sielemann, D.; Keuper, R.; Risch, N. J. Prakt. Chem.
1999, 341, 487. (e) Sielemann, D.; Keuper, R.; Risch, N.
Eur. J. Org. Chem. 2000, 3, 543.
(
5
-Phenyl[2,2 ]bipyridyl (15d)
Yield: 432 mg (39%); yellow oil.
IR (film): 2927, 2816, 1588, 1524, 1463, 1256, 1248, 1109, 1067,
7
–1
72, 695 cm .
1
H NMR (200 MHz, CDCl ): = 8.79 (s, 1 H), 8.53–8.57 (m, 3 H),
3
7
.68–7.75 (m, 2 H), 7.29–7.38 (m, 5 H), 7.06–7.09 (m, 1 H).
(
(
(
(
3) Piper, S. Dissertation; Universität Paderborn: Germany,
2003.
4) Dietrich, D.; Reiff, H.; Ziemann, H.; Braden, R. Liebigs Ann.
Chem. 1973, 111.
5) Deuchert, K.; Hünig, S. New Trends in Heterocyclic
Chemistry; Elsevier: Amsterdam, 1979.
6) (a) Komatsu, M.; Ohgishi, H.; Takamatsu, S.; Ohshiri, Y.;
Agawa, T. Angew. Chem., Int. Ed. Engl. 1982, 3, 213.
13C NMR (50 MHz, CDCl3): = 119.7, 122.8, 123.1, 127.4, 128.0,
1
29.2, 131.2, 134.2, 135.9, 137.1, 149.5, 149.9, 155.7, 156.9.
+
GC-MS (80 eV): m/z (%) = 232 (100, M ), 204 (25), 102 (16), 78
(
18).
Anal. Calcd for C H N (232.3): C, 82.73; H, 5.21; N, 12.06.
Found: C, 82.77; H, 5.29; N, 11.94.
1
6
12
2
(
b) Komatsu, M.; Takamatsu, S.; Uesaka, M.; Yamamoto,
S.; Ohshiro, Y.; Agawa, T. J. Org. Chem. 1984, 49, 2691.
c) Vijn, R. J.; Arts, H. J.; Green, R.; Caselijns, A. M.
2
,5-Diphenyl-3-methylpyridine (15e)
6
Yield: 600 mg (49%); white powder; mp 130 °C (lit. 132 °C).
(
Synthesis 1994, 573. (d) Soldatenkov, A.; Fedorov, V. O.;
Chandra, R.; Polosin, V. M.; Mikaya, A. I.; Prostakov, N. S.
J. Org. Chem. USSR Engl. Transl. 1980, 16, 473.
7) Sielemann, D. Dissertation; Universität Paderborn:
Germany, 2000.
2
,5-Diphenylpyridine (15f)
1
0
Yield: 474 mg (41%); colorless crystals; mp 175 °C (lit. 177 °C).
(
(
Acknowledgment
8) Böhme, H.; Auterhoff, G. Chem. Ber. 1971, 104, 2013.
This project was supported by the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie and the Grünenthal
GmbH.
(9) Kinast, G.; Tietze, L. F. Angew. Chem. 1976, 88, 261.
(10) (a) Jeyashri, B.; Balasubrahmanyam, S. N. Indian J. Chem.
Sect. B 1985, 25, 341. (b) Kim, B. H.; Jeon, I.; Han, T. H.;
Park, H. J.; Jun, Y. M. J. Chem. Soc., Perkin Trans. 1 2001,
17, 2035. (c) Kagabu, S.; Ando, C.; Ando, J. J. Chem. Soc.,
Perkin Trans. 1 1994, 6, 739. (d) Katritzky, A. R.;
Mazurkiewicz, R.; Stevens, C. V.; Godeev, M. F. J. Org.
Chem. 1994, 59, 2740.
Synthesis 2003, No. 17, 2667–2670 © Thieme Stuttgart · New York