Synthesis of 2- and 3-pyridinyl(aryl)methanones

Article abstract of DOI:10.1023/A:1015585008246

A procedure was developed for the preparation of 2- and 3-pyridinyl(aryl)methanones by the reactions of aryllithium with methyl pyridinecarboxylate and methyl esters of substituted phenylcarboxylic acids.

Full text of DOI:10.1023/A:1015585008246

540
Russian Chemical Bulletin, International Edition, Vol. 51, No. 3, pp. 540—543, March, 2002
Brief Communications
Synthesis of 2ꢀ and 3ꢀpyridinyl(aryl)methanones
ꢀ
I. S. Popova, A. A. Formanovsky, and I. V. Mikhura
M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences,
16/10 ul. MiklukhoꢀMaklaya, 117997 Moscow, Russian Federation.
Fax: +7 (095) 330 55 92. Eꢀmail: synorg@ibch.ru
A procedure was developed for the preparation of 2ꢀ and 3ꢀpyridinyl(aryl)methanones by
the reactions of aryllithium with methyl pyridinecarboxylate and methyl esters of substituted
phenylcarboxylic acids.
Key words: aryl(pyridinyl)methanones, 2ꢀpyridinyllithium, 3ꢀpyridinyllithium, 4ꢀmethoxyꢀ
phenyllithium, acylation.
Pyridinyl(aryl)methanones are promising synthons in
sized in 71% yield by the reaction of BzOMe with a soluꢀ
tion of 2ꢀpyridinyllithium in THF at –100 °C.9
the synthesis of physiologically active compounds.
The aim of the present study was to develop a genꢀ
eral procedure for the synthesis of 2ꢀ and 3ꢀpyridiꢀ
nyl(aryl)methanones containing different, including acidꢀ
labile, substituents.
Among procedures for the synthesis of phenyl(pyriꢀ
dinyl)methanones, methods based on the use of organoꢀ
magnesium1—6 or organolithium compounds1,2,7—9 show
the most promise.
Attempts to prepare ketones containing acidꢀlabile
substituents in the aromatic nucleus by treating aromatic
nitriles with a solution of pyridinyllithium2,7—8 failed beꢀ
cause rather harsh conditions of subsequent acid hydrolyꢀ
sis of intermediate ketimines led to elimination of these
groups.
Our concern was to find conditions of condensation
precluding acid hydrolysis of the final products. We used
methyl esters of aromatic acids as acylating agents. Previꢀ
ously, phenyl(2ꢀpyridinyl)methanone has been syntheꢀ
Preliminary experiments based on an analogous apꢀ
proach demonstrated that lowering of the reaction temꢀ
perature as well as the reverse order of addition of the
reagents led to an increase in the yield of the target ketone
and a decrease in the yields of byꢀproducts. We found
solvents and reaction temperatures, which ensure solubilꢀ
ity of the components, the desired direction of condensaꢀ
tion, and the maximum yields of the target compounds.
For this purpose, we prepared 2(3)ꢀpyridinyllithium by
adding a solution of BunLi in hexane, which was cooled
to –90 °C, to a solution of 2ꢀ (1) or 3ꢀbromopyridine (2)
in a mixture of THF and Et2O cooled to the same temꢀ
perature. Then the reaction mixture was cooled to –110 °C
and treated with a solution of methyl ester of substituted
benzoic acid in toluene. Subsequent mild decomposition
of the resulting complex with an aqueous solution of
NH4Cl was not accompanied by elimination of the
methoxymethyl group. These modifications allowed us to
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 501—504, March, 2002.
1066ꢀ5285/02/5103ꢀ540 $27.00 © 2002 Plenum Publishing Corporation

2ꢀ and 3ꢀPyridinyl(aryl)methanones
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
541
Scheme 1
3
a
b
c
Ar
3
d
e
f*
f**
Ar
2ꢀ(MeOCH2O)C6H4
3ꢀ(MeOCH2O)C6H4
4ꢀ(MeOCH2O)C6H4
3ꢀClC6H4
4ꢀClC6H4
3ꢀC5H4N
2ꢀC5H4N
4: Ar = 2ꢀClC6H4 (a), 2ꢀ(MeOCH2O)C6H4 (b)
simplify the preparation of compounds 3e and 4a, which
have been described earlier, and to synthesize previꢀ
ously unavailable compounds 3a—d,f and 4b (Scheme 1,
Table 1).
The structures of the resulting compounds were estabꢀ
lished by 1H NMR spectroscopy (Table 2) and confirmed
by the data from elemental analysis (Table 1) and mass
spectrometry. The assignments of the signals in the
1H NMR spectra are consistent with those made based on
When performing the synthesis of compound 3f, we
found that the use of 3ꢀbromopyridine for the preparation
of the corresponding organolithium compound and its
subsequent acylation with methyl pyridineꢀ2ꢀcarboxylate
afforded compound 3f in 89% yield, whereas the use of
2ꢀbromopyridine and methyl pyridineꢀ3ꢀcarboxylate alꢀ
lowed the preparation of compound 3f in only 60% yield.
We believe that this fact is associated both with the higher
reactivity of 3ꢀpyridinyllithium compared to the correꢀ
sponding 2ꢀsubstituted derivative and the higher electroꢀ
philicity of the carbonyl component, viz., methyl pyriꢀ
dineꢀ2ꢀcarboxylate.
The aboveꢀconsidered scheme, as applied to the synꢀ
thesis of compound 3c, proved to be a poor choice. Thus
the reaction afforded a mixture of compounds from which
the target compound was isolated in low yield. Because of
this, we devised an alternative procedure for the synthesis
of compound 3c involving the preparation of the orgaꢀ
nolithium compound from 1ꢀbromoꢀ4ꢀ(methoxymethꢀ
oxy)benzene (5) under the aboveꢀdescribed conditions
followed by its treatment with a solution of methyl pyriꢀ
dineꢀ2ꢀcarboxylate. In this case, compound 3c was obꢀ
tained in virtually quantitative yield. Apparently, 2ꢀpyriꢀ
dinyllithium not only attacks the carbonyl carbon atom
but also is sufficiently nucleophilic that it cleaves the
methoxymethyl group in the para position.
1
simulation of the H NMR spectra with the use of the
ACD Labs program.
Experimental
1
The H NMR spectra were recorded on a Bruker AMXꢀ400
spectrometer (1H, 400 MHz) in DMSOꢀd6 relative to the reꢀ
sidual protons of the solvents. The melting points were deꢀ
termined on a Boetius hot stage (the rate of heating was
4 deg min–1). The mass spectra were obtained on a Kratos MSꢀ30
spectrometer (EI, 70 eV). The reactions were carried out under
an atmosphere of dry nitrogen. The solvents were thoroughly
purified and dried before use. A 1.5 M solution of BunLi in
hexane (Merck), 2ꢀ and 3ꢀbromopyridines, methyl 2ꢀchloroꢀ
benzoate, methyl 3ꢀchlorobenzoate, and methyl 3ꢀpyridineꢀ
carboxylate (all reagents were from Aldrich) were used. Methyl
2ꢀpyridinecarboxylate was synthesized according to a known
procedure.11 1ꢀBromoꢀ4ꢀ(methoxymethoxy)benzene and meꢀ
thyl esters of 2ꢀ, 3ꢀ, and 4ꢀ(methoxymethoxy)benzoic acids were
prepared according to a procedure described previously.12
Synthesis of 2ꢀ and 3ꢀpyridinyl(aryl)methanones (3a—f and
4a—b) (general procedure). A 1.5 M solution of BunLi in hexane
(200 mL) was added to a solution of 2ꢀ or 3ꢀbromopyridine (1 or
2) (47.4 g, 0.3 mol) in a mixture of THF (100 mL) and Et2O
(150 mL) at –90 °C under an inert atmosphere. The reaction
mixture was stirred at –90 °C for 15 min and cooled to –110 °C.
Then a solution of methyl ester of substituted benzoic acid or

542
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
Popova et al.
Table 1. Yields, melting points, and data from elemental analysis of the resulting compounds
Comꢀ
pound
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
(%)
С
Н
N
Cl
3a
3b
3c
3d
3e
3f
73
71
Oil
69.12
69.13
69.12
69.13
68.95
69.13
66.51
66.22
—
5.49
5.39
5.49
5.39
5.30
5.39
4.01
3.71
—
5.72
5.76
5.72
5.76
5.55
5.76
6.45
6.44
—
—
С14Н13NO3
С14Н13NO3
С14Н13NO3
С12Н8ClNO
—
Oil
Oil
79
—
—
43 a
96 b
86
16.18
16.29
—
78
65
(65—66)10
68
60 c
89 d
60
71.81
71.73
66.16
66.22
69.12
69.13
4.38
4.38
3.70
3.71
5.28
5.39
15.21
15.21
6.23
6.44
5.77
5.76
—
С11Н8N2O
С12Н8ClNO
С14Н13NO3
4a
4b
Oil
(50)2
62
16.45
16.29
—
70
a The yield of 3c prepared according to the general procedure.
b The yield of 3c prepared according to the specially devised procedure.
c 2ꢀPyridinyllithium and methyl pyridineꢀ3ꢀcarboxylate were used.
d 3ꢀPyridinyllithium and methyl pyridineꢀ2ꢀcarboxylate were used.
Table 2. Data from 1H NMR spectroscopy for the resulting compounds
Compound
1H NMR (DMSOꢀd6, J/Hz)
8.63 (d, 1 H, H(1), J = 5.2); 8.03 (dd, 1 H, H(3), J = 7.0, J = 5.5); 7.98 (d, 1 H, H(4), J = 7.0);
3a
7.62 (dd, 1 H, H(2), J = 5.5, J = 5.2); 7.49 (dd, 1 H, H(7), J = 7.0, J = 7.0); 7.41 (d, 1 H, H(5), J = 7.0);
7.18 (d, 1 H, H(8), J = 7.0); 7.10 (dd, 1 H, H(6), J = 7.0, J = 7.0); 5.50 (s, 2 H, OCH2O);
3.10 (s, 3 H, OCH3)
3b
3c
3d
8.72 (d, 1 H, H(1), J = 4.8); 8.06 (dd, 1 H, H(3), J = 5.0, J = 7.2); 7.98 (d, 1 H, H(4), J = 7.2);
7.67 (dd, 1 H, H(2), J = 4.8, J = 5.0); 7.60 (d, 1 H, H(5), J = 8.2); 7.47 (dd, 1 H, H(6), J = 8,2, J = 8.2);
7.33 (d, 1 H, H(7), J = 8.2); 5.30 (s, 2 H, OCH2O); 3.40 (s, 3 H, OCH3)
8.72 (d, 1 H, H(1), J = 8.3); 8.06 (dd, 1 H, H(2), J = 8.3, J = 8.5); 8.00 (d, 2 H, H(5,9), J = 8.6);
7.94 (d, 1 H, H(4), J = 9.3); 7.64 (dd, 1 H, H(3), J = 8.5, J = 9.3); 7.15 (d, 2 H, H(6,8), J = 8.6);
5.30 (s, 2 H, OCH2O); 3.40 (s, 3 H, OCH3)
8.74 (d, 1 H, H(1), J = 3.7); 8.09 (dd, 1 H, H(3), J = 4.0, J = 6.7); 8.07 (d, 1 H, H(5), J = 6.7);
8.0 (s, 1 H, H(8)); 7.93 (d, 1 H, H(7), J = 8.3); 7.75 (d, 1 H, H(4), J = 6.7); 7.71 (dd, 1 H, H(2), J = 3.7,
J = 4.0); 7.58 (dd, 1 H, H(6), J = 6.7, J = 8.3)
3e
3f
8.72 (d, 1 H, H(1), J = 4.5); 8.06 (dd, 1 H, H(3), J = 6.2, J = 7.4); 8.01 (d, 1 H, H(4), J = 7.4);
8.00 (d, 2 H, H(5), H(9), J = 8.3); 7.70 (dd, 1 H, H(2), J = 5,7, J = 6.2); 7.62 (d, 2 H, H(6), H(8), J = 8.3)
9.14 (s, 1 H, H(8)); 8.82 (d, 1 H, H(7), J = 4.0); 8.75 (d, 1 H, H(1), J = 4.5); 8.35 (d, 1 H, H(3), J = 7.4);
8.12 (br.s, 1 H, H(4)); 8.15 (br.s, 1 H, H(5)); 7.73 (dd, 1 H, H(2), J = 4.5, J = 7.4);
7.57 (d, 1 H, H(6), J = 4.0)
4a
4b
8.85 (d, 1 H, H(2), J = 6.3); 8.84 (s, 1 H, H(1)); 8.10 (d, 1 H, H(4), J = 7.4);
7.50—7.65 (m, 5 H, H(3), H(5), H(6), H(7), H(8))
8.83 (br.s, 1 H, H(1)); 8.79 (d, 1 H, H(2), J = 4.2); 8.06 (d, 1 H, H(4), J = 7.0); 7.58 (dd, 1 H, H(7),
J = 8.0, J = 9.3); 7.43 (d, 1 H, H(5), J = 8.0); 7.26 (d, 1 H, H(8), J = 9.3); 7.19 (dd, 1 H, H(6), J = 8.0,
J = 8.0); 5.10 (s, 2 H, OCH2O); 3.15 (s, 3 H, OCH3)

2ꢀ and 3ꢀPyridinyl(aryl)methanones
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 3, March, 2002
543
the corresponding methyl pyridinecarboxylate (0.3 mol) in toluꢀ
ene (100 mL) was added and the cooling bath was removed.
After 4 h, a saturated solution of NH4Cl (200 mL), water
(400 mL), and AcOEt (400 mL) were successively added to the
reaction mixture. The organic layer was separated, washed with
water (2×400 mL) and a saturated solution of NaCl (400 mL),
and dried over Na2SO4. The solvent was evaporated. Compounds
3d—f and 4b were recrystallized from hexane. Compounds 3a—c
and 4a were isolated by chromatography on a column with silica
gel (a 95 : 5 benzene—acetone mixture as the eluent).
[4ꢀ(Methoxymethoxy)phenyl](2ꢀpyridinyl)methanone (3c).
A 1.5 M solution of BunLi in hexane (200 mL) was added to a
solution of 1ꢀbromoꢀ4ꢀ(methoxymethoxy)benzene11 (5) (65.1 g,
0.3 mol) in a mixture of THF (100 mL) and Et2O (150 mL) at
–90 °C. The reaction mixture was stirred at –90 °C for 15 min
and cooled to –110 °C. Then a solution of methyl pyridineꢀ2ꢀ
carboxylate (41.1 g, 0.3 mol) in toluene (100 mL) was added
and the cooling bath was removed. After 4 h, a saturated soluꢀ
tion of NH4Cl (200 mL), water (400 mL), and AcOEt (400 mL)
were successively added to the reaction mixture. The organic
layer was separated, washed with water (2×400 mL) and a satuꢀ
rated solution of NaCl (400 mL), and dried over Na2SO4. The
solvent was evaporated. Compound 3c was purified by chromaꢀ
tography on a column with silica gel (a 95 : 5 benzene—acetone
mixture as the eluent). Compound 3c was isolated as a colorless
oil in a yield of 70.0 g (96%).
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Received June 27, 2001;
in revised form November 30, 2001