Metal-halogen exchange using tri-n-butyl lithium magnesate in the diazine series: Diazine 49

Article abstract of DOI:10.1055/s-2006-941580

We report herein the 'metal-halogen exchange' reaction in the diazine series with lithium tri-n-tributylmagnesate. The reaction was performed with 2-iodopyrazine, 2-methylsulfanyl-4-iodopyrimidine and 3-iodo-6-phenylpyridazine. Benzophenone, aldehydes and

Full text of DOI:10.1055/s-2006-941580

1
586
LETTER
Metal–Halogen Exchange Using tri-n-Butyl Lithium Magnesate in the Diazine
Series: Diazine 49
M
F
etal–Haloge
r
n Exchan
é
ge Using T
d
ri-
n
-Butyl
L
é
ithium Ma
r
IRCOF, Laboratoire de Chimie Organique Fine et Hétérocyclique, UPRES-A 6014, INSA, B.P. 08, 76131 Mont St Aignan Cedex, France
Fax +33(2)35522962; E-mail: alain.turck@insa-rouen.fr
Received 14 February 2006
and 2-iodopyrazine, 2-methylsulfanyl-4-iodopyrimidine
Abstract: We report herein the ‘metal–halogen exchange’ reaction
and 3-iodo-6-phenylpyridazine. These iodo and bromo
in the diazine series with lithium tri-n-tributylmagnesate. The
derivatives were readily obtained from the commercial
reaction was performed with 2-iodopyrazine, 2-methylsulfanyl-4-
iodopyrimidine and 3-iodo-6-phenylpyridazine. Benzophenone, chloro precursors.7
aldehydes and diphenylsulfur were used as electrophiles affording
alcohols and phenylsulfanyl derivatives with satisfactory to good
lithium tri-n-butyl magnesate using benzaldehyde as elec-
yields.
First tests with 2-chloropyrazine or 2-bromopyrazine and
trophile were unsuccessful and the starting material was
recovered. However, the use of 2-iodopyrazine (1) led to
Key words: ate complex, magnesium, diazines, lithium, iodine
good yields with various electrophiles (Scheme 1,
Table 1).
The interest in diazines for pharmaceutical products or as
building blocks for various applications within materials
science and supramolecular chemistry has led to extensive
efforts to develop preparative methods in these series.
N
N
1
) 0.35 equiv nBu3MgLi, THF, –10 °C, 2.5 h
2) E+, –10 °C to r.t., 18 h
N
I
N
E
In our laboratory, the directed ortho-metalation has been
1
2–5
developed and used to synthesize a range of diazine
derivatives. Halogen atoms were identified as good
Scheme 1
1
ortho-directing groups. Another way to use halogenated
compounds is to replace the halogen by a metal leading to
Table 1 Functionalization of 2-Iodopyrazine by Metal–Halogen
Exchange
8
‘
metal–halogen exchange’ reactions with alkyllithium
E+
E
Product
Yield (%)
such as butyllithium.
This reaction was widely used in the aromatic and hetero-
aromatic series, however, in the diazine series, the com-
petitive reaction (nucleophilic addition of butyllithium on
the diazine ring) may interfere. Nevertheless, some exam-
MeOPhCHO
PhSSPh
PhCOPh
MeCHO
MeOPhCH(OH)
PhS
2
3
4
5
84
86
70
81
PhC(OH)Ph
MeCH(OH)
2
ples with 5-bromo- or iodopyrimidines and with diazines
3
bearing electron-donating groups have been reported. A
‘
metal–halogen exchange’ has also been performed with
4
LTMP and fully substituted diazines.
In all cases, neither the starting material nor any butylated
Another way to perform ‘metal–halogen exchange’ is by compound coming from nucleophilic addition to the
use of Grignard reagents. In the diazine series there are pyrazine ring were recovered.
2
c,5
few examples of Grignard reagents. In our laboratory
some diazinic Grignard reagents have been prepared, the
best results being obtained when electron-donating
groups were present on the ring, but in all cases the yields
were moderate. For all these reasons an efficient method
to perform ‘metal–halogen exchange’ would be very use-
ful. The recent development of the use of lithium tri-alkyl-6
magnesate to functionalize pyridines or quinolines
prompted us to test this methodology in the diazine series.
We planned to test the halogen–metal exchange with lith-
Experiments in the pyrimidine series were carried out
with 2-methylsulfanyl-4-iodopyrimidine (6) (Scheme 2,
Table 2).
N
SMe
) 0.35 equiv nBu3MgLi, THF, –10 °C, 2.5 h
N
SMe
1
N
N
+
2
) E , –10 °C to r.t., 18 h
I
E
6
7–10
ium tri-n-butylmagnesate and readily available represen- Scheme 2
tatives of each diazine series such as 2-chloro-, 2-bromo-
Using 6, neither starting material nor butylated com-
pounds were found as seen previously with 1.
SYNLETT 2006, No. 10, pp 1586–1588
Advanced online publication: 12.06.2006
2
1
.0
6
.2
0
0
6
DOI: 10.1055/s-2006-941580; Art ID: D04806ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Metal–Halogen Exchange Using tri-n-Butyl Lithium Magnesate
1587
Table 2 Functionalization of 2-Methylsulfanyl-4-iodopyrimidine
by Metal–Halogen Exchange
E
H
Bu
I
8
1) 0.35 equiv n-Bu3MgLi, THF,
–10 °C, 2.5 h
N
N
N
N
N
N
N
N
+
+
E+
E
Product
Yield (%)
+
2) E , –10 °C to 35 °C, 18 h
MeO(C H )CHO
MeO(C H )CH(OH)
7
8
86
85
78
79
Ph
Ph
Ph
Ph
6
4
6
4
11
12, 14–17
13
19
PhSSPh
PhS
Scheme 4
PhCOPh
MeCHO
PhC(OH)Ph
MeCH(OH)
9
10
was not beneficial (entries 2 and 3). Reaction at 35 °C
ever 18 hours precluded the use of acetaldehyde as elec-
trophile but isobutyraldehyde and cyclohexanecarbox-
aldehyde led to the expected products (entries 6 and 7).
For studies in the pyridazine series, 3-iodo-6-phenyl-
pyridazine (11) was used. A preliminary test with p-meth-
oxybenzaldehyde as electrophile afforded two products:
the expected product 12 and a dehalogenated pyridazine
In summary, in contrast to BuLi halogen exchange, which
needs low temperatures, lithium tri-n-butylmagnesate
leads to ‘metal–halogen’ exchange at room temperature or
5 °C. The yields are moderate to good and the method is
not restricted to electron rich compounds as is the case for
Grignard derivatives in these diazine series.
1
3 as major product (Scheme 3). This result urged us to
3
change the experimental conditions.
(
C6H4)OMe
I
CHOH
H
1) 0.35 equiv nBu3MgLi, THF, –10 °C, 2.5 h
) MeO(C6H4)CHO, –10 °C to r.t., 18 h
References and Notes
N
N
N
N
N
N
+
(1) (a) Turck, A.; Plé, N.; Mongin, F.; Queguiner, G.
Tetrahedron 2001, 57, 4489. (b) Turck, A.; Plé, N.;
Queguiner, G. Heterocycles 1994, 37, 2149.
2
Ph
Ph
Ph
11
(2) (a) Parkanyi, C.; Cho, N. S.; Yoo, G. S. J. Organometal.
Chem. 1988, 342, 1. (b) Friseen, A. E.; Marcelis, A. T. M.;
Buurman, C. A.; Pollmann, C. A. M.; Van der Plas, H. C.
Tetrahedron 1989, 45, 5611. (c) Langley, B. W. J. Am.
Chem. Soc. 1956, 78, 2136. (d) Ulbricht, B. W. J. Am.
Chem. Soc. 1959, 6, 225. (e) Arai, I.; Daves, G. D. J. Chem.
Soc., Chem. Commun. 1976, 69. (f) Strekowski, L. Roczniki
Chemii 1975, 49, 1643. (g) Brown, D.; Ogden, R. C. J.
Chem. Soc., Perkin Trans. 1 1981, 723. (h) Strekowski, L.;
Watson, R. J. Org. Chem. 1986, 51, 3226. (i) Yokoyama,
M.; Ikene, T.; Ochiai, Y.; Momotake, A.; Yamaguchi, K.;
Togo, H. J. Chem. Soc., Perkin Trans. 1 1998, 2185.
12
13
22%
60%
Scheme 3
A ‘reverse addition’ reaction was tested as in all the
previous experiments the iodo compounds were slowly
added to a solution of lithium tri-n-butylmagnesate. Tri-n-
butyllithium magnesate was slowly added to a solution of
1
1, and improved yields were obtained but 13 and the
butylated compound 19 were also isolated in small
amounts. The experimental problems might be due to the
poor solubility of 11 in THF (Scheme 4, Table 3).
(
j) Yokoyama, M.; Ikenogami, T.; Togo, H. J. Chem. Soc.,
Perkin Trans. 1 2000, 2067. (k) Hanessian, S.; Machaalani,
R. Tetrahedron Lett. 2003, 44, 8321. (l) von Angerer, S. In
Science of Synthesis, Vol. 16; Black, D. St. C., Ed.; Thieme:
Stuttgart, 2004, 379. (m) Rajkumar, T. V.; Binkley, S. B. J.
Med. Chem. 1963, 6, 550.
The results were improved when the temperature was
raised to 35 °C but the use of diethyl ether instead of THF
Table 3 Reverse Addition with 3-Iodo-6-phenylpyridazine9
Entry
Electrophile
Solvent
Product
12
Yield (%)
13
30
3
19
–
1a
2
3
4
5
6
MeO(C H )CHO THF
41
59
55
62
50
57
56
6
4
MeO(C H )CHO THF
12
7
6
4
MeO(C H )CHO Et O
12
5
9
6
4
2
PhSSPh
PhCOPh
THF
14
2
4
THF
THF
THF
15
0
5
(Me) CHCHO
16
2
7
2
7
Cy-CHO
17
1
8
a
For entry 1, temperature was r.t. and for all the other cases it was raised to 35 °C.
Synlett 2006, No. 10, 1586–1588 © Thieme Stuttgart · New York

1
588
F. Buron et al.
LETTER
(
3) (a) Hirschberg, A.; Peterkofsky, A.; Spoerri, P. E. J.
Heterocycl. Chem. 1965, 2, 209. (b) Hertz, H. S.;
8.50 (s, 1 H, H ), 8.36 (d, 1 H, J = 2.5 Hz, H ), 8.31 (d, 1 H,
3
6
J = 2.5 Hz, H ), 7.18 (d, 2 H, J = 8.7 Hz, HPh2,6), 6.76 (d, 2
5
Kabacinski, F. F.; Spoerri, P. E. J. Heterocycl. Chem. 1969,
H, J = 8.7 Hz, HPh3,5), 5.71 (s, 1 H, CH), 4.74 (m, 1 H, OH),
1
3
6, 239. (c) Baker, R.; Street, L. J.; Reeve, A. J.; Saunders, J.
3.68 (s, 3 H, OCH3). C NMR (CDCl ): d = 159.4 (CPh4),
3
J. Chem. Soc., Chem. Commun. 1991, 760. (d) Sato, N. In
Science of Synthesis, Vol. 16; Black, D. St. C., Ed.; Thieme:
Stuttgart, 2004, 751. (e) Stevenson, T. M.; Crouse, B. A.;
Thieu, T. V.; Gebreysus, C.; Piotrowski, D. L. Abstracts of
157.5 (C ), 143.2–143.0 (C , C and C ), 134.2 (CPh1), 128.2
2
3
5
6
(CPh2,6), 114.2 (CPh3,5), 73.9 (CH), 55.3 (OCH ). IR (KBr):
3
3352, 2930, 2840, 1613, 1513, 1469, 1403, 1304, 1249,
–
1
1149, 1064, 832, 582 cm . Anal. Calcd for C H N O
1
2
12
2
2
th
Papers, 228 National Meeting of the American Chemical
(216.24): C, 66.65; H, 5.59; N, 12.96. Found: C, 66.90; H,
5.47; N, 12.91.
2-Methylsulfanyl-4-(1-hydroxy-4-methoxyphenyl-
Society, Philadelphia, 2004; American Chemical Society:
Washington DC, 2004. (f) Street, L. J.; Baker, R.; Book, T.;
Reeve, A. J.; Saunders, J.; Willson, T.; Marwood, R. S.;
Patel, S.; Freedman, S. J. Med. Chem. 1992, 35, 295.
4) (a) Plé, N.; Turck, A.; Couture, K. Tetrahedron 1994, 50,
methyl) Pyrimidine (7)
Prepared according to procedure 1. H NMR (CDCl ): d =
8.33 (d, 1 H, J = 5.3 Hz, H ), 7.21 (d, 2 H, J = 8.7 Hz, HPh2,6),
1
3
(
6
1
0299. (b) Toudic, F.; Plé, N.; Turck, A.; Queguiner, G.
6.81 (d, 2 H, J = 8.7 Hz, HPh3,5), 6.72 (d, 1 H, J = 5.1 Hz, H5),
5.53 (d, 1 H, J = 3.8 Hz, CH), 4.51 (m, 1 H, OH), 3.73 (s, 3
Tetrahedron 2002, 58, 283.
1
3
(
5) (a) Abarbri, M.; Knochel, P. Synlett 1999, 1577.
H, OCH ), 2.53 (s, 3 H, SCH ). C NMR (CDCl ): d = 172.2
3 3 3
(b) Leprêtre, A.; Turck, A.; Plé, N.; Knochel, P.; Queguiner,
(C and C ), 159.8 (C ), 157.3 (C ), 133.6 (CPh1), 129.6
2 4 Ph4 6
G. Tetrahedron 1999, 56, 265. (c) Momotake, A.; Mito, J.;
Yamaguchi, K.; Togo, H.; Yokoyama, M. J. Org. Chem.
(CPh2,6), 114.5 (CPh3,5), 113.5 (C ), 74.3 (CH), 55.4 (OCH ),
5
3
14.3 (SCH ). IR (KBr): 3369, 2929, 2836, 1565, 1513, 1349,
3
–
1
1998, 63, 7207. (d) Shimura, A.; Momotake, A.; Togo, H.;
1249, 1174, 1032, 832 cm . Anal. Calcd for C H N O S
13 14 2 2
Yokoyama, M. Synthesis 1999, 495. (e) Momotake, A.;
Togo, H.; Yokoyama, M. J. Chem. Soc., Perkin Trans. 1
(262.33): C, 59.52; H, 5.38; N, 10.68. Found: C, 59.34; H,
5.42; N, 10.75.
1
999, 1193.
(9) Procedure 2 for 2-Iodo-6-phenylpyridazine.
A solution of n-BuLi (1.6 M in hexane, 0.66 mmol) was
added to a cold (–10 °C) stirred solution of n-butyl-
magnesium chloride (0.33 mmol) in THF (5 mL). After 1 h
at –10 °C, The solution was added in a solution of 2-iodo-6-
phenylpyridazine (1 mmol) in THF (2 mL) at –30 °C and the
mixture was stirred at –10 °C for 2.5 h. The electrophile (1.5
mmol) was then added at –10 °C; the mixture was stirred at
this temperature for 1 h, then brought to, and kept at, 35 °C
(
(
6) (a) Dumouchel, S.; Mongin, F.; Trécourt, F.; Queguiner, G.
Tetrahedron 2003, 59, 8629. (b) Dumouchel, S.; Mongin,
F.; Trécourt, F.; Queguiner, G. Tetrahedron Lett. 2003, 44,
2
033.
7) (a) Hirschberg, A.; Spoerri, P. E. J. Org. Chem. 1961, 26,
907. (b) Street, L. J.; Baker, R.; Book, T.; Reeve, A.;
1
Saunders, J. J. Med. Chem. 1992, 35, 295. (c) Majeed, A. J.;
Antonsen, O.; Benneche, T.; Undheim, K. Tetrahedron
1989, 45, 993.
for 18 h before addition of H O (1 mL). The reaction mixture
2
(
8) Procedure 1 for 2-Iodopyrazine and 4-Iodo-2-methyl-
sulfanylpyrimide.
was diluted with EtOAc (50 mL). The organic layer was
dried over MgSO and evaporated. The crude product was
4
A solution of n-BuLi (1.6 M in hexane, 0.66 mmol) was
added to a cold (–10 °C) stirred solution of n-butyl-
magnesium chloride (0.33 mmol) in THF (5 mL). After 1 h
at –10 °C a solution of iododiazine (1 mmol) in THF (2 mL)
was added at –30 °C and the mixture was stirred at –10 °C
for 2.5 h. The electrophile (1.5 mmol) was then added at
purified by column chromatography on silica gel.
Representative Spectroscopic Data
3-(1-Hydroxy-4¢-methoxyphenylmethyl)-6-phenyl
Pyridazine (12)
1
Prepared according to procedure 2. Mp 140 °C. H NMR
(CDCl ): d = 8.05 (m, 2 H, HPh2,6), 7.77 (d, 1 H, J = 8.9 Hz,
3
–10 °C; the mixture was stirred at this temperature for 1 h
H ), 7.40 (m, 6 H, H , HPh¢2,6, HPh3,4,5), 6.88 (d, 2 H, J = 8.7
5
4
and kept at r.t. for 18 h before addition of H O (1 mL). The
reaction mixture was diluted with EtOAc (50 mL). The
Hz, HPh¢3,5), 6.02 (s, 1 H, CH), 5.02 (m, 1 H, OH), 3.78 (s, 3
2
1
3
H, OCH3). C NMR (CDCl ): d = 161.7 (CPh¢4), 159.6 (C3
3
organic layer was dried over MgSO and evaporated. The
and C ), 135.9 (C ), 134.1 (C ), 130.3–124.9 (C , C ,
4
6
Ph1
Ph¢1
4
5
crude product was purified by column chromatography on
silica gel.
Representative Spectroscopic Data
CPh2,6, CPh¢2,6, CPh4, CPh3,5), 114.3 (CPh¢3,5), 74.4 (CH), 55.4
(OCH ). IR (KBr): 3135, 2999, 2933, 2838, 1611, 1514,
3
–
1
1433, 1251, 1171, 1064, 813, 692 cm . Anal. Calcd for
C H N O (292.34): C, 73.96; H, 5.52; N, 9.58. Found: C,
2
-(1-Hydroxy-4-methoxyphenylmethyl) Pyrazine (2)
1
8
16
2
2
1
Prepared according to procedure 1. H NMR (CDCl ): d =
73.68; H, 5.48; N, 9.32.
3
Synlett 2006, No. 10, 1586–1588 © Thieme Stuttgart · New York