Synthesis of Pyridinyl-Pyrimidines via Pd-Catalyzed Cross-Coupling Reactions: A Comparison of Classical Thermal and Microwave Assisted Reaction Conditions

Article abstract of DOI:10.1055/s-2003-41414

The Negishi cross-coupling reaction was used for the synthesis of pyridinyl-pyrimidines utilizing classical thermal or microwave assisted conditions. The organozinc substrates were prepared from 2-fluoro-4-iodopyridine by conventional lithiation chemistry and subsequent transmetalation with ZnCl₂ or ZnI₂. Two different catalysts - Pd(PPh₃)₄ and Pd/C - were investigated for their ability to facilitate the cross coupling process with 2,4-dichloropyrimidine. We found that distribution and yield of desired compounds and possible by-products highly depend on the type of energy input. In contrast to thermal conditions, the microwave assisted method allowed efficient access to di-coupled compounds.

Full text of DOI:10.1055/s-2003-41414

1862
LETTER
Synthesis of Pyridinyl-Pyrimidines via Pd-Catalyzed Cross-Coupling Reac-
tions: A Comparison of Classical Thermal and Microwave Assisted Reaction
Conditions
Synthesis of
P
e
yridinyl-Py
t
rimidin
e
es via
P
d-C
r
atalyzed Cross
S
-Coupling Re
t
actionsanetty,* Michael Schnürch, Marko D. Mihovilovic
Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax +43(1)5880115494; E-mail: pstanett@pop.tuwien.ac.at
Received 29 July 2003
action and not utilizing a more convenient and flexible
Abstract: The Negishi cross-coupling reaction was used for the
lithiation strategy.7,8 These aspects prompted us to closer
synthesis of pyridinyl-pyrimidines utilizing classical thermal or mi-
investigate the Negishi-type cross-coupling variant. This
strategy offers the advantage of a one-pot reaction, hence,
crowave assisted conditions. The organozinc substrates were pre-
pared from 2-fluoro-4-iodopyridine by conventional lithiation
chemistry and subsequent transmetalation with ZnCl2 or ZnI2. Two avoiding the isolation of the intermediate metal species.
different catalysts – Pd(PPh3)4 and Pd/C – were investigated for
Microwave chemistry is well established in organic syn-
their ability to facilitate the cross coupling process with 2,4-dichlo-
thesis nowadays,9–11 with an increasing number of very
ropyrimidine. We found that distribution and yield of desired
recent contributions in the cross coupling field.12–22 In this
compounds and possible by-products highly depend on the type of
paper we report our preliminary results for the preparation
of different pyridinyl-pyrimidines via the Negishi reac-
tion using classical thermal and microwave assisted reac-
tion conditions. This special variant of coupling chemistry
has previously received hardly any attention in connection
with microwave irradiation.23 Using microwave irradia-
tion as energy source for a chemical transformation usual-
ly leads to a substantial acceleration of the reaction caused
by the higher temperature and pressure in the reaction
vessel. Since palladium catalyzed cross-coupling reac-
tions require elevated temperatures for a longer period of
time in many cases, microwave assisted methods offer the
potential advantage of decreased reaction times and fewer
by-products.
energy input. In contrast to thermal conditions, the microwave as-
sisted method allowed efficient access to di-coupled compounds.
Keywords: palladium catalyzed cross-coupling reactions, Negishi-
reaction, microwave assisted reactions, homogeneous catalysis,
heterogeneous catalysis
Palladium catalyzed cross-coupling reactions are an im-
portant and well established tool in modern organic syn-
thesis.1,2 Of the various methods, the Suzuki–Miyaura3
and the Stille4 reaction are the most commonly used.
These strategies offer the advantage of stable starting ma-
terials, which are simple to prepare in many cases. More-
over, Suzuki-type coupling reactions can be carried out in
aqueous media. Nevertheless, there are also a number of
limitations: tinorganyls are highly toxic and safety pre-
cautions have to be considered; a number of heterocyclic
boronic-acids5 could not be successfully prepared, so far.
Especially the corresponding boronic-acids of heterocy-
cles with two or more heteroatoms are barely reported in
the literature.6 Only few representatives have been pre-
pared via introduction of the metal within a cyclization re-
In first test-reactions the Negishi-coupling of 2,4-
dichloropyrimidine (3) with organozinc reagents prepared
from 2-fluoro-4-iodopyridine (1) was investigated.
Both iodo- and chloro-organozincs 2a,b can be prepared
via lithiation and subsequent transmetalation with ZnX2
(Scheme 1) using the same protocol and show similar re-
activity in the reaction. However, the reagent prepared
Scheme 1 Preparation of metal-organyl and coupling reaction of 2a,b with 2,4-dichloropyrimidine. Product formation dependent on amount
of organyl 2a,b (0.75–2.67 equiv) and reaction conditions (microwave irradiation or classic thermal). Catalyst is either Pd(PPh3)4 or Pd/C.
SYNLETT 2003, No. 12, pp 1862–1864
2
9
.0
9
.2
0
0
3
Advanced online publication: 28.08.2003
DOI: 10.1055/s-2003-41414; Art ID: D19403st.pdf
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Pyridinyl-Pyrimidines via Pd-Catalyzed Cross-Coupling Reactions
1863
from ZnI2 (2b) has some considerable advantages: ZnI2 is decreased reaction temperatures (entries 4–6). A reaction
by far less hygroscopic than ZnCl2, which makes it easier temperature of 100 °C in microwave mode was sufficient
to handle. We found the Negishi reaction to be highly to give complete conversion after 5 minutes. Under
susceptible to traces of moisture, especially when working optimized conditions (entry 6) the formation of homo
in small scale (100–200 mg), and good conversions were coupling product 5 could be essentially suppressed with
found to be highly dependent upon the quality of the the bis-coupling compound 6 as the only isolable side-
ZnCl2 used. A second advantage of the ZnI2-derived product. Substance 6 becomes the major reaction product,
organyl 2b is the greater solubility in ethereal solvents. when an excess of organozinc 2b is added to the reaction
Upon optimizing the parameters for the microwave mixture, as expected (entry 7). Formation of 6 was not
assisted coupling reaction we found that the organozinc observed under thermal conditions, even when applying
chloride forms heterogenous solutions in dry THF, which an excess of 2.
made it impossible to prepare a stock solution of this re-
Changing to the corresponding organozinc chloride 2a led
agent. This hampers the setup of parallel reaction series
to a substantial increase of homo coupling product (entry
involving different halides and utilizing the same organo-
8). This is attributed to the inhomogeneous mixture of 2a
upon transmetalation, leading to difficulties in reagent ad-
zinc for this specific heterocycle.
First the test-reaction was carried out under classical dition.
thermal conditions in dry THF under reflux and Pd(PPh3)4
as catalyst using 1.33 equivalents of organyl 2a or 2b. The
Based on recent results in microwave mediated coupling
reactions, we also investigated the feasibility of Pd/C as
desired product was formed after approximately 4 hours
cheaper and more convenient catalyst.24 However, under
with both organozinc reagents in excellent yields
forced reaction conditions using microwave, only moder-
(Table 1, entries 1 and 2). As a by-product compound 5
ate conversion to the desired product 4 was observed, with
was isolated in minor quantities, resulting from a homo-
considerable amounts of starting material remaining
coupling process.
(entries 9 and 10). The major product isolated for both
Switching to microwave as energy source, we started with metal organyls is the homo-coupling compound 5.
the optimization of the reaction temperature, utilizing re-
The major advantage of microwave assisted cross
agent 2b based on the above advantages in handling. At
coupling reaction towards pyridinyl-pyrimidine 4 is the
130 °C (entry 3) 4 was obtained as major product, as
substantially decreased reaction time as compared to
classical thermal conditions. The microwave mediated
methodology allows further development towards parallel
synthesis, while delivering comparable results to the ther-
expected, again accompanied by minor quantities of homo
coupling product 5. The microwave mediated reaction
gave also bis-coupled product 6, which was not observed
under thermal conditions. The amount of 6 was reduced at
mal mode in the synthesis of compound 4. To our under-
Table 1 Comparison of Thermal and Microwave Assisted Negishi Cross-Coupling Reaction.
Reaction parameters
Products isolated
Entry
X
Equiv
Temp Mw/
Time Catalyst
3
4
5
6
2a,b
(°C)
thermal (min)
1
2
Cl
I
1.33a
1.33
1.0
66
Therm. 240
Therm. 240
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd/C
–
90%b
90%b
85%c
81%c
87%c
90%b
tracesd
54%b
18%b
17%b
5%b
–
66
–
5%b
–
3
I
130
120
110
100
130
100
130
130
Mw
Mw
Mw
Mw
Mw
Mw
Mw
Mw
5
5
–
3%c
12%c
15%c
9%c
4%b
84%b
7%b
–
4
I
1.0
–
3%c
5
I
1.0
5
–
4%c
6
I
1.0
5
–
tracesd
23%b,e
36%b
70%b
30%b
7
I
2.67
1.0a
1.0
5
–
8
Cl
I
5
–
9
10
10
10%b
29%b
10
Cl
1.0a
Pd/C
–
a Equivalents can not exactly be determined because of the heterogenity of the stock solution.
b Isolated yield.
c Quantified by HPLC.
d Identified by HPLC.
e Based on 1 as precursor for 2a,b.
Synlett 2003, No. 12, 1862–1864 © Thieme Stuttgart · New York

1864
P. Stanetty et al.
LETTER
2,4-bis-(2-Fluoro-pyridin-4-yl)-pyrimidine (6): Colorless crys-
tals, mp = 238–240 °C. H NMR (200 MHz, d6-DMSO): d = 8.16
(d, 2 H, J = 4.6 Hz), 8.32 (d, 1 H, J = 4.8 Hz), 8.38 (d, 2 H, J = 5.1
Hz), 8.48 (t, 2 H, J = 4.8), 9.23 (d, 1 H, J = 4.7). 13C NMR (50 MHz,
d6-DMSO): d = 105.0 (d), 105.8 (d), 116.1 (s), 117.6 (d), 118.1 (d),
146.4–147.0 (m, 3 C), 148.0 (d), 157.9–158.1 (m, 2 C), 158.6 (d),
159.7 (d), 164.4 (d).
standing this is of importance for subsequent scale-up
purposes under classical conditions, which are still a
challenge utilizing microwave methodology. In this con-
text we could also demonstrate that ZnI2 is a very
convenient and facile substitute for the highly
hygroscopic ZnCl2 for the transmetalation process under
Negishi conditions.
1
In addition, the microwave mediated protocol also en-
abled a bis-coupling reaction, leading to compound 6.
This one-pot process represents a valuable expansion of
the methodology to less reactive halides, which cannot be
converted under standard thermal conditions.
Acknowledgment
This project was supported by Syngenta Crop Protection, Basel,
Switzerland. We would like to thank CEM for granting access to an
Explorer PLSTM microwave unit.
References
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Synlett 2003, No. 12, 1862–1864 © Thieme Stuttgart · New York