Preparation and reactions of pyridinyl tellurides

Article abstract of DOI:10.1002/jhet.5570380228

Tellurium-metal exchange reaction of n-butyl 2-pyridinyl telluride derivatives with n-butyllithium or dilithium dimethylcyanocuprate proceeded smoothly to give the corresponding 2-pyridinylmetal derivatives, which are important intermediates for functionalization of pyridines.

Full text of DOI:10.1002/jhet.5570380228

Mar-Apr 2001
Preparation and Reactions of Pyridinyl Tellurides
481
Manabu Shilai, Masanobu Uchiyama, Yoshinori Kondo* and Takao Sakamoto*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, 980-8578, Japan
Received October 2, 2000
Tellurium-metal exchange reaction of n-butyl 2-pyridinyl telluride derivatives with n-butyllithium or
dilithium dimethylcyanocuprate proceeded smoothly to give the corresponding 2-pyridinylmetal derivatives,
which are important intermediates for functionalization of pyridines.
J. Heterocyclic Chem., 38, 481 (2001).
Organometal compounds such as organolithiums or
Table 1
organocuprates play important roles in organic synthesis
[1] and therefore, the development of efficient methods for
the preparations of organometal compounds is of
importance. In recent years, organotellurium compounds
as precursors of organometal compounds have been
studied actively [2]. By treatment of diorganyl tellurides
with alkyllithiums or alkylcuprates, a tellurium-metal
exchange reaction occurs, generating organolithiums
(alkyl-, allyl-, aryl-, benzyl-, ethynyl- and vinyllithium) or
organocuprates, respectively. Acyl- and aroyllithiums are
also generated by the corresponding telluroesters.
The chemistry of pyridine derivatives has been studied
extensively because pyridine derivatives are important for
pharmaceuticals, chemicals and so on. Aryl and
heteroarylmetal compounds can be usually prepared by
halogen-metal exchange reaction or hydrogen-metal
exchange reaction. Especially, halogen-metal exchange
reaction of arylhalides has been developed as one of the
major tools of organic synthesis [3]. In 1987, Hiiro
reported a new method, which provides phenyllithium
compounds from corresponding tellurides via a tellurium-
lithium exchange reaction [4]. In connection with our
recent studies on pyridinylmetal derivatives [5], we have
investigated the preparations and reactions of n-butyl
2-pyridinyl telluride derivatives [6].
Preparation of n-Butyl 2-pyridinyl Telluride 2
Substituent X
Cl
Reaction time/h
20
Compound
Reaction temp.
Room temp.
Yield (%)
29
1a
Room temp.
60 °C
1a
1a
1a
1b
1b
1c
1c
Cl
Cl
Cl
Br
Br
I
72
24
92
20
92
20
92
33
41
61
55
70
56
62
Reflux
Room temp.
Reflux
Room temp.
Room temp.
I
Scheme 2 and Table 2. When compound 2 was treated with
dilithium dimethylcyanocuprate in tetrahydrofuran at
-20 °C and then 2-cyclohexen-1-one, the 1,4-addition as a
characteristic reaction of cuprates proceeded to give 3-(2-
pyridinyl)cyclohexanone 3d (41%). From these results, the
tellurium-metal exchange reaction is considered to
proceed to form the 2-pyridinylmetal intermediate.
Initially, n-butyl 2-pyridinyl telluride 2 was prepared by
the nucleophilic substitution of a 2-halopyridine and with
lithium n-butanetellurolate (Scheme 1, Table 1). Compound
2 was generated from each 2-halopyridine. However, n-butyl
3-pyridinyl telluride was scarcely generated from 3-bromo-
pyridine, and nucleophilic substitution at the 3-position of
the pyridine ring is known to be generally inactive.
Nucleophilic substitution of halopyridines with lithium
n-butanetellurolate was only found to proceed smoothly at
the 2-position of the pyridine ring.
We next examined this methodology using dihalo-
pyridines. First, preparation and reaction of n-butyl
6-chloro-2-pyridinyl telluride 5a was investigated
(Scheme 3). Though 2,6-dichloropyridine 4a possesses
two chlorine atoms, compound 5a was prepared as an
important precursor for monofunctionalization of
pyridines at the 2-position. Compound 5a was treated with
n-butyllithium in tetrahydrofuran at -78 °C and then
benzaldehyde, to give compound 6a. Similarly, n-butyl
3-chloro-2-pyridinyl telluride 5b was also investigated
(Scheme 3). The nucleophilic substitution reaction of
lithium n-butanetellurolate and then tellurium-lithium
exchange reaction proceeded at the 2-position, and
compound 6b was generated. For dihalopyridines, the
The tellurium-metal exchange reaction of compound 2
was then investigated using n-butyllithium and dilithium
dimethylcyanocuprate. The results are summarized in

482
Vol. 38
M. Shilai, M. Uchiyama, Y. Kondo and T. Sakamoto
Table 2
Reactions of n-Butyl 2-pyridinyl Telluride 2
Metalating reagent
BuLi
Reaction time
5 min
Electrophile
PhCHO
E
CH(OH)Ph
COPh
Product
3a
Yield (%)
Reaction temp./°C
-78
-78
-78
-20
-20
73
64
50
67
41
BuLi
5 min
PhCONMeOMe
ICH2CH2I
3b
5 min
I
3c
BuLi
1.5 h
PhCHO
CH(OH)Ph
3-oxocyclohexyl
3a
Me2Cu(CN)Li2
Me2Cu(CN)Li2
1.5 h
2-Cyclohexen-1-one
3d
regioselectivity of the halogen-metal exchange reaction is
of importance. For example, the halogen-metal exchange
reaction of 2,5-dibromopyridine 7 is known to proceed at
the 5-position and 2-bromo-5-lithiopyridine are generated
[7]. On the other hand, the 2-position selective halogen-
metal exchange reaction of compound 7 has been scarcely
known [8]. In order to develop a new method for regiose-
lective functionalization of 2,5-dibromopyridine, we
investigated the preparation of 5-bromo-2-lithiopyridine
and 2-bromo-5-lithiopyridine. For 5-bromo-2-lithiopyri-
dine, the preparation and reaction of n-butyl 5-bromo-2-
pyridinyl telluride 8 was carried out (Scheme 4).
Compound 8 was prepared by a similar manner to the
preparation of compound 2 and treated with n-butyllithium
in tetrahydrofuran at -78 °C and then benzaldehyde, to
give compound 9, which was functionalized selectively at
the 2-position. The tellurium-metal exchange reaction is
considered to proceed faster than the halogen-metal
exchange reaction because compound 10 was not detected.
And for 2-bromo-5-lithiopyridine, compound 7 was
treated with n-butyllithium in tetrahydrofuran at -100 °C
and then with benzaldehyde, to give compound 11, in
which the 5-position was selectively functionalized.
In summary, 2-pyridinyl tellurides were prepared easily
from 2-halopyridines and the tellurium-metal exchange
reaction is now available for the selective preparation of
2-metalopyridines. As for dihalopyridine, it has been
possible to prepare the desired monolithiopyridine by
using the tellurium-lithium exchange reaction of n-butyl
halopyridinyl tellurides, which can be easily prepared by
the substitution of lithium n-butanetellurolate.
EXPERIMENTAL
THF was distilled from sodium/benzophenone ketyl before
use. n-Butyllithium and methyllithium were titrated using
2,5-dimethoxybenzylalcohol before use. Melting points were
determined on a Yazawa micro melting point apparatus and are
uncorrected. The infrared spectra were taken on a JASCO IR-810
1
spectrophotometer. The H nmr spectra were recorded on a
Varian Gemini-2000 (300 MHz) spectrometer in deuterio-
chloroform solution and chemical shifts are reported in δ (ppm)
values relative to tetramethylsilane as an internal standard. Mass

Mar-Apr 2001
483
Preparation and Reactions of Pyridinyl Tellurides
spectra and high resolution mass spectra were recorded on a
JMX-DX303 and a JMX-AX500 mass spectrometer. Elemental
analyses were carried out on a yanaco CHN CORDER MT-5
apparatus.
Anal. Calcd. for C H IN: C, 29.30; H, 1.97; I, 61.91; N, 6.86.
5 4
Found: C, 29.26; H, 1.94; I, 61.82; N, 6.66.
Phenyl(2-pyridinyl)methanol (3a).
via Tellurium-Copper Exchange Reaction: Representative
Procedure B.
n-Butyl 2-Pyridinyl Telluride 2.
Typical Procedure.
Under an argon atmosphere, commercial methyllithium in
diethyl ether (1.07 M; 1.50 ml, 1.61 mmoles) was added to a
mixture of copper(I) cyanide (70.5 mg, 0.78 mmole) and dry
tetrahydrofuran (5 ml) at -78 °C and the mixture was stirred at
0 °C for 30 minutes. Telluride 2 (211 mg, 0.80 mmole) was added
to the mixture at -20 °C and stirred at -20 °C for 1.5 hours.
Benzaldehyde (84.9 mg, 0.80 mmole) was added to the mixture
at -20 °C and stirred at -20 °C for 10 minutes, and then the
mixture was allowed to warm gradually to room temperature and
stirred at room temperature for 20 hours. The mixture was diluted
with water (50 ml) and extracted with dichloromethane (50 ml
x 3). The organic layer was dried over dry magnesium sulfate.
The solvent was removed and the residue was purified by silica
gel column chromatography using n-hexane-ethyl acetate (4:1) as
a solvent. The solvent was removed to give 3a (99.1 mg, 67%) as
colorless prisms.
Under an argon atmosphere, commercial n-butyllithium in
n-hexane (1.39 M; 1.50 ml, 2.09 mmoles) was added to a mixture of
commercial tellurium (274 mg, 2.14 mmoles) and dry tetrahydro-
furan (8 ml) at room temperature and the mixture was stirred at
room temperature for 10 minutes. 2-Bromopyridine (317 mg,
2.01 mmoles) was added to the mixture at -78 °C and stirred at -78
°C for 10 minutes, and then the mixture was refluxed for 92 hours.
The mixture was diluted with water (50 ml) and extracted with
diethyl ether (50 ml x 3). The organic layer was dried over dry
magnesium sulfate. The solvent was removed and the residue was
purified by silica gel column chromatography using n-hexane:ethyl
acetate (4:1) as a solvent. The solvent was removed to give 2
1
(368 mg, 70%) as a viscous oil; H nmr: δ 0.93 (t, J = 7.3 Hz, 3H),
1.43 (sextet, J = 7.3 Hz, 2H), 1.89 (quintet, J = 7.3 Hz, 2H), 3.14
(t, J = 7.3 Hz, 2H), 7.01 (ddd, J = 1.1, 5.0 and 7.7 Hz, 1H), 7.32
(ddd, J = 1.8, 7.7 and 7.7 Hz, 1H), 7.46-7.49 (m, 1H), 8.46-8.48
3-(2-Pyridinyl)cyclohexanone 3d via Tellurium-Copper
Exchange Reaction.
+
130
(m, 1H); hrms: m/z 265.0111 (M ), calcd. C H N Te: 265.0109.
9
13
Phenyl(2-pyridinyl)methanol (3a).
According to the representative procedure B, 3d was given in
1
via Tellurium-Lithium Exchange Reaction: Representative
Procedure A.
41% yield as a colorless oil; ir (neat): ν 1708; H nmr: δ
1.72-3.24 (9H, m), 7.14-7.18 (2H, m), 7.64 (1H, ddd, J=1.9, 7.7,
+
7.7 Hz), 8.56-8.57 (1H, m); hrms: m/z 175.0987 (M ), calcd.
Under an argon atmosphere, commercial n-butyllithium in
n-hexane (1.35 M; 0.60 ml, 0.81 mmole) was added to a mixture of
telluride 2 (210 mg, 0.80 mmole) and dry tetrahydrofuran (10 ml)
at -78 °C and the mixture was stirred at -78 °C for 5 minutes.
Benzaldehyde (120 mg, 1.13 mmoles) was added to the mixture at
-78 °C and stirred at -78 °C for 10 minutes, and then the mixture
was allowed to warm gradually to room temperature and stirred at
room temperature for 20 hours. The mixture was diluted with
water (50 ml) and extracted with dichloromethane (50 ml x 3). The
organic layer was dried over dry magnesium sulfate. The solvent
was removed and the residue was purified by silica gel column
chromatography using n-hexane:ethyl acetate (4:1) as a solvent.
The solvent was removed to give 3a (109 mg, 73%) as colorless
C H NO: 175.0996.
11 13
Anal. Calcd. for C H NO: C, 75.40; H, 7.48; N, 7.99. Found:
11 13
C, 74.90; H, 7.64; N, 7.90.
n-Butyl 6-Chloro-2-pyridinyl Telluride (5a).
Representative Procedure C.
Under an argon atmosphere, commercial n-butyllithium in
n-hexane (1.35 M; 8.00 ml, 10.8 mmoles) was added to a
mixture of commercial tellurium (1.40 g, 11.0 mmoles) and dry
tetrahydrofuran (40 ml) at room temperature and the mixture
was stirred at room temperature for 10 minutes
2,6-Dichloropyridine (1.49 g, 10.0 mmoles) was added to the
mixture at -78 °C and stirred at -78 °C for 10 minutes, and then
the mixture was stirred at room temperature for 24 hours. The
mixture was diluted with water (100 ml) and extracted with
diethyl ether (100 ml x 3). The organic layer was dried over dry
magnesium sulfate. The solvent was removed and the residue
was purified by silica gel column chromatography using
n-hexane:ethyl acetate (4:1) as a solvent. The solvent was
1
prisms, mp 74 °C; H nmr: δ 5.27 (1H, brs), 5.75 (1H, s), 7.14-7.38
(7H, m), 7.60 (1H, ddd, J = 1.4, 7.7, 7.7 Hz), 8.54-8.55 (1H, m);
+
hrms: m/z 185.0842 (M ), calcd. C H NO: 185.0840.
12 11
Anal. Calcd. for C H NO: C, 77.81; H, 5.99; N, 7.56. Found:
12 11
C, 77.79; H, 6.16; N, 7.49.
Phenyl (2-Pyridinyl) Ketone 3b via Tellurium-Lithium
Exchange Reaction.
According to the representative procedure A, 3b was given in
1
removed to give 5a (1.28 g, 43%) as a viscous oil; H nmr: δ
1
64% yield as a colorless oil; H nmr: δ 7.44-7.64 (4H, m), 7.86-
0.94 (3H, t, J = 7.4 Hz), 1.43 (2H, sextet, J = 7.4 Hz), 1.90 (2H,
quintet, J = 7.4 Hz), 3.15 (2H, t, J = 7.4 Hz), 7.02-7.05 (1H, m),
7.24-7.29 (1H, m), 7.37-7.39 (1H, m); hrms: m/z 298.9753
+
8.12 (4H, m), 8.70-8.76 (1H, m); hrms: m/z 183.0691 (M ),
calcd. C H NO: 183.0684.
12
9
Anal. Calcd. for C H NO: C, 78.67; H, 4.95; N, 7.65. Found:
12
9
+
35
130
(M ), calcd. C H
ClN Te: 298.9720.
9
12
C, 78.70; H, 4.84; N, 7.64.
Phenyl(6-chloro-2-pyridinyl)methanol (6a).
2-Iodopyridine 3c via Tellurium-Lithium Exchange Reaction.
According to the representative procedure A, 3c was given in
Representative Procedure D.
1
50% yield as a colorless oil; H nmr: δ 7.26-7.34 (2H, m),
Under an argon atmosphere, commercial n-butyllithium in
n-hexane (1.35 M; 0.76 ml, 1.03 mmoles) was added to a mixture of
telluride 5a (313 mg, 1.05 mmoles) and dry tetrahydrofuran (10 ml)
+
7.72-7.75 (1H, m), 8.37-8.39 (1H, m); hrms: m/z 204.9398 (M ),
calcd. C H IN: 204.9387.
5
4

484
Vol. 38
M. Shilai, M. Uchiyama, Y. Kondo and T. Sakamoto
at -78 °C and the mixture was stirred at -78 °C for 5 minutes.
Benzaldehyde (130 mg, 1.22 mmoles) was added to the mixture at
-78 °C and stirred at -78 °C for 10 minutes, and then the mixture
was allowed to warm gradually to room temperature and stirred at
room temperature for 20 hours. The mixture was diluted with water
(50 ml) and extracted with dichloromethane (50 ml x 3). The
organic layer was dried over dry magnesium sulfate. The solvent
was removed and the residue was purified by silica gel column
chromatography using n-hexane:ethyl acetate (1:4) as a solvent.
The solvent was removed to give 6a (179 mg, 77%) as a viscous oil;
furan (5 ml) at -100 °C and the mixture was stirred at -78 °C for
3 hours. Benzaldehyde (42.9 mg, 0.40 mmole) was added to the
mixture at -78 °C and stirred at -78 °C for 1 hour, and then the
mixture was allowed to warm gradually to room temperature and
stirred at room temperature for 20 hours. The mixture was diluted
with saturated ammonium chloride (30 ml) and extracted with
dichloromethane (30 ml x 3). The organic layer was dried over
dry magnesium sulfate. The solvent was removed and the residue
was purified by silica gel column chromatography using
n-hexane:ethyl acetate (2:1) as a solvent. The solvent was
removed to give 11 (163 mg, 62%) as colorless prisms, mp
1
H nmr: δ 4.53 (1H, brs), 5.73 (1H, s), 7.09-7.12 (1H, m), 7.18-7.21
1
(1H, m), 7.25-7.39 (5H, m), 7.55 (1H, dd, J = 7.8, 7.8 Hz); hrms:
79-80 °C; H nmr: δ 2.20 (1H, brs), 5.84 (1H, s), 7.29-7.45
+
35
m/z 219.0442 (M ), calcd. C H
ClNO: 219.0450.
(6H, m), 7.55 (1H, dd, J = 2.6, 8.1 Hz), 8.39 (1H, d, J = 2.6 Hz);
12 10
+
79
hrms: m/z 262.9975 (M ), calcd. C
H
BrNO: 262.9946.
12 10
n-Butyl 3-Chloro-2-pyridinyl Telluride (5b).
Anal. Calcd. for C
H BrNO: C, 54.57; H, 3.82; Br, 30.25; N,
12 10
5.30. Found: C, 54.42; H, 3.96; Br, 30.30; N, 5.34.
According to the representative procedure C, 5b was given in
1
55% yield as a viscous oil; H nmr: δ 0.94 (3H, t, J = 7.4 Hz),
Acknowledgments.
1.44 (2H, sextet, J = 7.4 Hz), 1.89 (2H, quintet, J = 7.4 Hz), 3.16
(2H, t, J = 7.4 Hz), 6.96 (1H, dd, J = 4.6, 8.9 Hz), 7.41 (1H, dd, J
We are grateful to Ms Chizuru Yamazaki for carrying out a part
of the experiments of this work.
+
= 1.4, 8.0 Hz), 8.38-8.39 (1H, m); hrms: m/z 298.9728 (M ),
35
130
calcd. C H
ClN Te: 298.9720.
9
12
REFERENCES AND NOTES
Phenyl(3-chloro-2-pyridinyl)methanol (6b).
According to the representative procedure D, 6b was given in
[1a] V. Snieckus, M. Gray and M. Tinkl, In Comprehensive
Organometallic Chemistry II; E. W. Abel, F. G. A. Stone, G. Wilkinson
and A. McKillop, Eds.; Pergamon Press: Oxford, 1995; Vol. 11, 1; [b] B.
H. Lipshutz, In Comprehensive Organometallic Chemistry II; E. W. Abel,
F. G. A. Stone, G. Wilkinson and L. S. Hegedus, Eds.; Pergamon Press:
Oxford, 1995; Vol. 12, 59.
[2] N. Petragnani, Tellurium in Organic Synthesis, Academic
Press, London, 1994.
[3a] E. Negishi, Organometallics in Organic Synthesis, John
Wikey & Sons, New York, 1980; [b] C. Elschenbroich, A. Salzer,
Organometallics, VCH Verlagsgesellshaft mbH, 1989.
[4] T. Hiiro, N. Kambe, A. Ogawa, N. Miyoshi, S. Murai and N.
Sonoda, Angew. Chem., Int. Ed. Engl., 26, 1187 (1987).
[5a] T. Sakamoto, Y. Kondo, N. Murata and H. Yamanaka,
Tetrahedron Lett., 33, 5373 (1992); [b] T. Sakamoto, Y. Kondo, N.
Murata and H. Yamanaka, Tetrahedron, 49, 9713 (1993); [c] Y. Kondo,
N. Murata, T. Sakamoto and H. Yamanaka, Heterocycles, 37, 1467
(1994).
[6] A part of this work was communicated in: Y. Kondo, M.
Shilai, M. Uchiyama and T. Sakamoto, J. Chem. Soc., Perkin Trans. 1,
1781 (1996).
1
72% yield as colorless prisms, mp 70 °C; H nmr: δ 5.32 (1H, s),
6.00 (1H, s), 7.20-7.37 (5H, m), 7.65 (1H, dd, J = 1.4, 8.1 Hz),
+
8.54 (1H, dd, J = 1.4, 4.7 Hz); hrms: m/z 219.0432 (M ), calcd.
35
C
H
ClNO: 219.0450.
12 10
Anal. Calcd. for C
H ClNO: C, 65.61; H, 4.59; Cl, 16.14; N,
12 10
6.38. Found: C, 65.69; H, 4.80; Cl, 15.99; N, 6.62.
n-Butyl 5-Bromo-2-pyridinyl Telluride (8).
According to the representative procedure C, 8 was given in
1
55% yield as a viscous oil; H nmr: δ 0.93 (3H, t, J = 7.4 Hz),
1.43 (2H, sextet, J = 7.4 Hz), 1.88 (2H, quintet, J = 7.4 Hz), 3.13
(2H, t, J = 7.4 Hz), 7.35-7.38 (1H, m), 7.45 (1H, dd, J = 2.4, 8.3
+
Hz), 8.55-8.56 (1H, m); hrms: m/z 342.9225 (M ), calcd.
79
130
C H
BrN Te: 342.9415.
9
12
Phenyl(5-bromo-2-pyridinyl)methanol (9).
According to the representative procedure D, 9 was given in
1
70% yield as a viscous oil; H nmr: δ 4.75 (1H, brs), 5.73 (1H, s),
7.08-7.11 (1H, m), 7.26-7.37 (5H, m), 7.74 (1H, dd, J = 2.2, 8.5
+
Hz), 8.61-8.62 (1H, m); hrms: m/z 262.9970 (M ), calcd.
[7a] W. E. Parham and R. M. Piccirilli, J. Org. Chem, 42, 257
(1977); [b] J. Wicha and M. Masnyk, Heterocycles, 16, 521 (1981); [c] C.
Bolm, M. Ewald, M. Felder and G. Schlingloff, Chem. Ber., 125, 1169
(1992).
79
C
H
BrNO: 262.9946.
12 10
Phenyl(2-bromo-5-pyridinyl)methanol (11).
Under an argon atmosphere, commercial n-butyllithium in n-
hexane (1.39 M; 0.80 ml, 1.11 mmoles) was added to a mixture of
2,5-dibromopyridine (237 mg, 1.00 mmole) and dry tetrahydro-
[8] Recently, a selective lithiation of 2,5-dibromopyridine at the
2-position was reported: X. Wang, P. Rabbat, P. O'Shea, R. Tillyer, E. J. J.
Grabowski and P. J. Reider, Tetrahedron Lett., 41, 4335 (2000).