The palladium catalysed biaryl cross-coupling of pyridazine triflates

Article abstract of DOI:10.1055/s-2001-9716

The scope of trifluoromethanesulfonic acid 6-methyl-pyridazine-3-yl ester as a coupling partner for biaryl synthesis via palladium catalysed Suzuki and Stille coupling conditions is reported.

Full text of DOI:10.1055/s-2001-9716

150
LETTER
The Palladium Catalysed Biaryl Cross-Coupling of Pyridazine Triflates
David J. Aldousa*, Shelley Bowera, Neil Moorcroft,a Michael Toddb
aDiscovery Chemistry, Aventis, Rainham Road South, Dagenham, Essex, RM10 7XS, UK
bSchool of Chemical and Life Sciences, The University of Greenwich, Wellington Street, Woolwich, London, SE18 6PF, UK
E-mail: david.aldous@aventis.com
Received 16 November 2000
palladium catalysed carbonylations,5 Songashira type6
Abstract: The scope of trifluoromethanesulfonic acid 6-methyl-py-
and vinyl stannane6b coupling reactions of trifluo-
romethanesulfonic acid pyridazine-3-yl esters are known.
However, to our knowledge no examples of palladium ca-
ridazine-3-yl ester as a coupling partner for biaryl synthesis via pal-
ladium catalysed Suzuki and Stille coupling conditions is reported.
Key words: biaryl, palladium, Suzuki reaction, Stille reaction,
talysed cross-coupling reactions of trifluoromethane-
pyridazine triflate
sulfonic acid pyridazine-3-yl esters to form biaryl
compounds have been reported. It was for these reasons
that we decided to investigate the utility of 3-trifluo-
Pyridazine, an electron deficient aromatic ring, with a
romethanesulfonyl-pyridazines in Stille and Suzuki biaryl
high dipole moment (m = 3.95 D) and being a hydrogen
cross couplings (Scheme).
bond acceptor has the attractive physicochemical property
of high water solubility.1 Water solubility is an important
feature in drug design; high concentrations of soluble drug
in the gastro-intestinal tract imply high maximum absorb-
able doses.2 Thus it is not surprising that advantages have
been taken of these properties in order to derive pharma-
cologically active agents as represented in Figure.
Scheme
Due to the nature of the pyridazine nucleus, introduction
of aryl and alkyl substituents by direct carbon-carbon
bond formation becomes an important issue. Historically,
functionalisation of the ring system is obviated by ring
synthesis and careful synthetic design. This has led to an
extensive range of pyridazine syntheses, many for specific
homologues and substitution patterns. Nevertheless, di-
rect introduction of carbon functionality is generally the
most convenient, as this allows variety to be introduced
into a synthetic scheme at a late stage.
Trifluoromethanesulfonic acid 6-methyl-pyridazine-3-yl
ester7 was reacted with a selection of aryl-stannanes and
aryl-boronates chosen to probe the impact of electronics
on the coupling and the results are described in Table.
Using a procedure based on Stille’s original conditions for
aryl triflates8 (1,4-dioxane, LiCl, 5 mol% Pd(PPh3)4)
3-methyl-6-thiophen-2-yl pyridazine was obtained from
tributyl-thiophen-2-yl-stannane in 77% yield (Table, en-
try 1). Under these conditions, the phenyl stannanes (Ta-
ble, entries 2 and 3) reacted slowly compared to the
electron rich thiophene analogue and the coupled products
were obtained in 22% and 6% yield respectively. Electron
deficient aryl stannanes proved to be much more sluggish,
indeed 3-tributylstannyl-pyridine proved so unreactive
that no reaction could be detected after heating at 85∞C for
23 hours (Table, entry 4). These results suggest a possible
electronic component to the reaction. Indeed, Wermuth et
al also found that no cross-coupling of pyridazine triflates
occurred with electron-deficient alkynestannanes.6a
The original publication on aryl triflate Suzuki cross-cou-
plings by Fu and Snieckus, reported the use of aqueous
Na2CO3 in 1,2-dimethoxyethane (DME) and Pd(PPh3)4
catalyst9 while Suzuki concurrently reported that aqueous
basic conditions were unsuitable for aryl triflates.10 In the
light of these reports and also the results of preliminary
stability studies of trifluoromethanesulfonic acid 6-meth-
yl-pyridazine-3-yl ester under aqueous base conditions,11
both aqueous and anhydrous Suzuki cross-couplings of
pyridazine triflates were investigated. The Table (entries
Figure
There are several examples of 3-halopyridazines reacting
in palladium catalysed cross coupling reactions with aryl
boronates3 and aryl stannanes.4 In addition, examples of
Synlett 2001, No. 1, 150–152 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Palladium Catalysed Biaryl Cross-Coupling of Pyridazine Triflates
151
purity by HPLC after a simple aqueous work-up and
chromatography. However, the reaction with 3-diethyl-
boranyl-pyridine (Table, entry 8) afforded a much lower
yield of product (15%) and a significant amount of 6-me-
thyl-2H-pyridazin-3-one (28%) was isolated. We rationa-
lise the low recovery of product in two ways: triflate
degradation due to hydrolysis under the aqueous base con-
ditions and the aqueous solubility of the product.
Table Cross-couplings with Trifluoromethanesulfonic Acid 6-
Methyl-pyridazine-3-yl Ester
It is interesting that the aqueous conditions used in the Su-
zuki reaction were found to be better than those used for
the corresponding Stille coupling. In each case, a higher
yield was obtained in a significantly shorter reaction time.
Of particular note is the reaction of 3-diethylboranyl-pyri-
dine, which successfully coupled under Suzuki conditions
(Table, entry 8) albeit in lower yield, whereas the corre-
sponding 3-tributylstannyl-pyridine failed to couple (Ta-
ble, entry 4). Similarly, the sluggish behaviour of the
phenyl stannanes (Table, entries 2 and 3) contrasts with
the higher yield under Suzuki conditions (Table, entries 6
and 7).
A range of heterogeneous anhydrous coupling methods
using inorganic bases were investigated with the aim of
finding reaction conditions where the rate of triflate hy-
drolysis was slow and the biaryl cross-coupling rate re-
mained high. Using thiophene-2-boronic acid, it was
found that the anhydrous conditions led to lower reactivity
compared with aqueous conditions. Using K3PO4 in either
1,4-dioxane or toluene at 85∞C, little of the desired prod-
uct was observed by TLC after 14 hours. The most effec-
tive conditions proved to be potassium carbonate in
toluene and after 14 hours, 33% of the desired product
could be obtained with thiophene-2-boronic acid (Table,
entry 9) although some trifluoromethanesulfonic acid
6-methyl-pyridazine-3-yl ester was still present. There-
fore, even with competitive hydrolysis, aqueous base con-
ditions proved more effective. Nevertheless, the presence
of starting material after 14 hours under non-aqueous con-
ditions is significant. This is seven times the time taken to
hydrolyse approximately two thirds of the starting triflate
under aqueous conditions.11 This indicates that anhydrous
conditions successfully inhibit the pyridazine triflate hy-
drolysis, but with concomitant reduction in cross-cou-
pling rate.
a yields refer to compounds isolated by chromatography on silica gel
unless specified. All compounds were >85% purity by HPLC. Com-
pounds were fully characterised and were in full agreement with
structures.
b not isolated.
c isolated as a mixture with 6-methyl-2H-pyridazine-3-one.
d product appeared water soluble & isolated yields may not fully
reflect reaction yields.
Conditions: (A) LiCl, Pd(PPh3)4 5mol%, 1,4-dioxane, 80-85∞C; (B)
Na2CO3 (aq), Pd(PPh3)4 5 mol%, DME; 65-85∞C; (C) K2CO3,
Pd(PPh3)4, toluene, 80 ∞C.
In summary, it has been demonstrated that trifluo-
romethanesulfonic acid 6-methyl-pyridazine-3-yl ester
undergoes Stille coupling with electron rich partners in
good yield and Suzuki cross-coupling with a variety of or-
ganoboron reagents under the conditions investigated in
generally excellent yield. 3-Diethylboranyl-pyridine
proved to be an exception which probably illustrates the
competition between the rate of coupling and the rate of
triflate hydrolysis. Though anhydrous conditions led to
the increased stability of trifluoromethanesulfonic acid
6-methyl-pyridazine-3-yl ester, the use of aqueous
Na2CO3 in DME generally gave a high yield, and rapid
coupling compared to competing triflate hydrolysis.
5-7) demonstrates that coupling trifluoromethanesulfonic
acid 6-methyl-pyridazine-3-yl ester with aryl-boronic ac-
ids and esters under the aqueous conditions described by
Fu9 (Pd(PPh3)4, aqueous Na2CO3, DME) furnish the de-
sired biaryl compounds in good to excellent yields (54-
84%). In spite of concerns of triflate lability under the ba-
sic hydrolysis conditions, coupling occurred at tempera-
tures up to 85 °C. These reactions occurred cleanly and
rapidly, with minimal starting triflate remaining after two
hours in all cases. The products were obtained in >98%
Synlett 2001, No. 1, 150–152 ISSN 0936-5214 © Thieme Stuttgart · New York

152
D. J. Aldous et al.
LETTER
was poured into water (10 mL) and extracted with dichloro-
methane (2 ¥ 15 mL). The organic extracts were dried over
Na2SO4 and concentrated in vacuo. Purification by flash
chromatography (Et2O/CH2Cl2/ cyclohexane 4:3:3) afforded
trifluoromethanesulfonic acid 6-methyl-pyridazine-3-yl ester
as a white solid (330 mg, 76% yield). HPLC analysis showed
98% purity of the desired product. Mp: 51 - 53 °C (lit., mp
59 °C); 1H NMR (CDCl3) d 7.56 (d, J = 9.0 Hz, 1H), 7.34 (d,
J = 8.9 Hz, 1H), 2.80 (s, 3H); IR: n (KBr, cm-1) 3071 (m), 1584
(w), 1566 (w), 1417 (s); LC-MS m/z 284 ([MH+CH3CN]+,
100%), 243 (MH+, 40%), 93 ([M - CF3O3S]+, 16%).
(8) Echavarren, A. M.; Stille, J. K.; J. Am. Chem. Soc. 1987, 109,
5478.
(9) Fu, J. M.; Snieckus, V. Tetrahedron Lett. 1990, 31, 1665.
(10) Oh-e, T.; Miyawa, N.; Suzuki, A. Synlett 1990, 221.
(11) Trifluoromethanesulfonic acid 6-methyl-pyridazine-3-yl ester
was heated at 80 ∞C in DME and aqueous Na2CO3 for 2 hours
as a mimic of the Suzuki coupling conditions. Following an
aqueous work-up, 6-methyl-2H-pyridazin-3-one accounted
for almost two thirds of the product. Only 25% of the starting
material remained. This suggests that hydrolysis may be a
competing decomposition product in certain Suzuki
couplings.
Acknowledgement
We thank Aventis for financial support of this work and for assi-
stance with spectroscopy.
References and Notes
(1) Pyridazine is completely miscible with water unlike benzene
which is almost completely immiscible (0.07% at 22 °C).
(2) Curatolo, W. Pharm. Sci. Technol. Today 1998, 1, 387.
(3) (a) Goodman, A. J.; Stanforth, S. P.; Tarbit, B. Tetrahedron
1999, 55, 15067. (b) Parrot, I.; Rival, Y.; Wermuth, C. -G.
Synthesis 1999, 7, 1163. (c) Turck, A.; Plé, N.; Mojovic, L.;
Quéguiner, G. Bull. Soc. Chim. Fr. 1993, 130, 488.
(4) Sosabowski, M.; Powell, P. J. Chem. Res. Synop. 1995, 10,
402.
(5) Rohr, M.; Toussaint, D.; Chayer, S.; Mann, A.; Suffert, J.;
Wermuth, C. -G. Heterocycles 1996, 43, 1459.
(6) (a) Toussaint, D.; Suffert, J.; Wermuth, C.-G. Heterocycles
1994, 38, 1273. (b) Toussaint, D.; Suffert, J.; Wermuth, C. -G.
Acta Chimica Slovenica 1994, 41, 253.
(7) Trifluoromethanesulfonic acid 6-methyl-pyridazine-3-yl ester
was prepared according to a modified version of the procedure
described in ref (6)(a) above: Trifluoromethanesulfonic
anhydride (2.7 mmol., 1.5 equiv) was added slowly drop-wise
to a stirred ice cooled suspension of 6-methyl-2H-pyridazin-
3-one (1.8 mmol., 1.0 equiv) and triethylamine (1.7 mmol.,
1.5 eq.) in dichloromethane (3 mL). After 6 hours, the mixture
Article Identifier:
1437-2096,E;2001,0,01,0150,0152,ftx,en;L14400ST.pdf
Synlett 2001, No. 1, 150–152 ISSN 0936-5214 © Thieme Stuttgart · New York