First synthesis of 7-amido-[1,2,4]triazolo[1,5-a]pyrimidines using halogen-metal exchange

Article abstract of DOI:10.1016/j.tet.2008.04.084

A new and efficient methodology for the preparation of novel 7-carboxyl-triazolopyrimidine derivatives via the halogen-metal exchange is described. In addition, we showed that this new method can be useful for the synthesis of amides, esters, and ketones by using different carbamoyl chlorides, isocyanides or acyl chlorides as electrophile.

Full text of DOI:10.1016/j.tet.2008.04.084

Tetrahedron 64 (2008) 6372–6376
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
First synthesis of 7-amido-[1,2,4]triazolo[1,5-a]pyrimidines
using halogen–metal exchange
*
Florian Montel, Clemens Lamberth, Pierre M.J. Jung
Syngenta Crop Protection Muenchwilen AG, Research Chemistry, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and efficient methodology for the preparation of novel 7-carboxyl-triazolopyrimidine derivatives
via the halogen–metal exchange is described. In addition, we showed that this new method can be useful
for the synthesis of amides, esters, and ketones by using different carbamoyl chlorides, isocyanides or
acyl chlorides as electrophile.
Received 19 March 2008
Received in revised form 18 April 2008
Accepted 22 April 2008
Available online 25 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
The [1,2,4]triazolo[1,5-a]pyrimidine heterobicycle constitutes
a well-established scaffold in crop protection chemistry.1 For in-
stance, the herbicide family of [1,2,4]triazolo[1,5-a]pyrimidine
sulfonanilides are potent inhibitors of acetohydroxyacid synthase
(AHAS).2 This class of compounds, which was discovered in the mid
1980s by Dow, is very effective for controlling various broadleaf and
grass weed species at low doses while maintaining high levels of
selectivity to agronomically important crop species. As an example,
the triazolopyrimidine herbicide flumetsulam 1 has been de-
veloped for the use in corns and soybeans, whereas metosulam 2 is
applied in corns and cereals (Fig. 1).
On the other hand, 7-amino-[1,2,4]triazolo[1,5-a]pyrimidines
such as BAS600 33 are a new class of fungicides active against
a broad range of different plant diseases.4 Such compounds, which
were discovered by Shell in the early 1990s,5 have now been
identified as promoters of tubulin polymerization with a paclitaxel-
like mode of action. In addition, very similar molecules, such as TTI-
237 4, were claimed as potent anti-cancer agents by Wyeth.6 In the
context of a program directed toward the synthesis of analogues of
this class of fungicides with improved biological properties, we
became interested in developing a synthesis of [1,2,4]triazolo[1,5-
a]pyrimidines having an amido group in position 7. In this article,
we describe the first synthesis of such compounds.
Initial theoretical studies demonstrated that the route involving
construction of the bicycle were long and were not considered.7
Radical reactions starting with the derivative 78 or 6 were tested
and not successful. We tried also to apply the Minisci reaction9 on 6
to introduce CH2OH in position 7.10 These experiments failed to
Figure 1. [1,2,4]Triazolo[1,5-a]pyrimidine herbicides, fungicides, and anti-cancer
agents.
provide any of the desired compound. We then turned our atten-
tion to the paths shown in Scheme 1.
2. Results and discussion
2.1. Synthesis via the 5-chloro-6-(2,4,6-trifluorophenyl)-
[1,2,4]triazolo[1,5-a]pyrimidine-7-carbonitrile
First, we tried the path A, in which the amide could be obtained
via a cyanide derivative (Scheme 2).
11
The preparation of 9 from 7 was briefly described.
In our
hands, the introduction of a cyanide in position 7 was not easily
obtained via simple addition of MCN. In order to solve this problem,
* Corresponding author.
E-mail address: pierre.jung@syngenta.com (P.M.J. Jung).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.084

F. Montel et al. / Tetrahedron 64 (2008) 6372–6376
6373
due to the replacement of the chlorine, which is a worse electron
withdrawing group than the tosylsulfinate.
Several conditions tested to transform the cyanide group into an
acid or directly into esters or amides failed.15 It seems that the
corresponding carboxylate is unstable and is converted in low yield
into the reduced compound 6. Only the reaction of 9 in pure H2SO4
gave the desired compound 10 in 63% yield. The reaction of 10 with
a mixture of MeI (2 equiv)/NaH (2 equiv) in DMSO16 gave the cor-
responding amide 11 in 28% yield. All attempts to prepare mono-
alkylated amine from 10 were unsuccessful.17 Cross-coupling
reactions were also tried on 7, but we only isolated the reduced
compound 6 in low yields or in complex mixtures.18 An alternative
approach to prepare these amides is the direct functionalization of
7 in amide or ester via halogen–metal exchange reaction.
Scheme 1. Different approaches used to prepare the amide in position 7.
2.2. Synthesis via halogen–metal exchange reaction
Our first attempt to generate an organometallic species in po-
sition 7, from 7 via a halogen–metal exchange reaction failed. In
order to solve this problem, we turned our attention onto the
synthesis of 8. The reaction of 7 with HI in acetone gave 8 in 58%
yield (Scheme 3).19 However, cross-coupling reactions with 8 were
not successful.
Scheme 2. Preparation of amide in position 7 via cyanide derivative.
we investigated the experimental conditions for this trans-
formation, the result is shown in the Table 1.
We were surprised not to observe the formation of 9 with
standard conditions (entries 1–4),12 only degradation products
were obtained. The same result was observed at 80 ꢀC with or
without catalyst (entries 5 and 6). At 0 ꢀC, the reaction was very
slow and we didn’t observe the formation of the product. Traces of
9 were detected after 2 weeks of reaction at 25 ꢀC by LC–MS (entry
7). Finally, the best conditions found without catalyst were at 40 ꢀC
after 7 days (entry 9). Based on this result, we tried to increase the
yield of the reaction by using a catalyst. The presence of DMAP has
positive effect on the yield (entry 10). The use of a crown ether (18-
C-6-O), which is known to accelerate this type of reaction13 affords
9 with only 31% of yield (entry 11). Finally, the best result was
obtained with the use of sodium tolylsulfinate as catalyst (entry
12).14 It is well known that in this kind of reaction, the rate-
determining step is not the leaving group departure but the nu-
cleophilic attack. The positive effect of the catalyst, in this case, is
Scheme 3. Iodination of 7.
For the metal–halogen exchange, we used either t-BuLi or
i-PrMgCl in THF. The influence of the experimental conditions of
this halogen metal exchange20 was analysed by quenching the re-
action with ClCO2Me. Detailed investigations of these reactions
showed that the reaction is strongly dependent on the tempera-
ture, the reaction time, and the solubility of the starting material.
The results obtained by using the t-BuLi in THF to realize
the halogen–metal exchange reaction is disclosed in Table 2
(Scheme 4).
At ꢁ78 ꢀC, the halogen–metal exchange reaction failed, proba-
bly due to the poor solubility of the starting material at this tem-
perature (entry 1). The first assays at higher temperatures were done,
but after 1 h at ꢁ60 ꢀC or ꢁ50 ꢀC only complex mixtures were
obtained and only few percents of the dimeric compound 14 were
isolated. The first improvement for this halogen–metal exchange
reaction came from the decreasing the reaction time from 1 h to
30 min before quenching. In this case, we isolated for the first time
4% of the desired 12 (entry 4). On decreasing the reaction time to
5 min, 12 was obtained in 12% yield (entry 5). Attempts to decrease
the concentration afforded only side product 13 or 15 in less than
Table 1
Optimization of the cyanation reaction
Entrya
T (ꢀC)
MCN
Solvent
Yield of 9 (%)
1
2
3
4
5
6
7
8
120
110
100
80
80
80
rt
KCN
CuCN
KCN
KCN
DMF
NMP
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
d
d
d
db
Table 2
KCN
d
Optimization of the halogen–metal exchange reaction with t-BuLi
KCNþMePhSO2Na
KCNþMePhSO2Na
KCN
d
dc
Entrya
T (ꢀC)
Reaction time
[c]
Solvent
t-BuLi (equiv)
Yield (%)
rt
d
1
2
3
4
5
6
7
8
ꢁ78
ꢁ60
ꢁ50
ꢁ50
ꢁ50
ꢁ50
ꢁ60
ꢁ78
1 h
1 h
1 h
30 min
<5 min
<1 min
<1 min
<1 min
0.2
0.2
0.2
0.2
0.2
0.4
0.2
0.2
THF
THF
THF
THF
THF
THF
THF/DME
THF/HMPT
2
2
2
2
2
2
2
2
da
d
d
4
12
db
18
28
9
40
40
40
40
KCN
23d
25d
31d
53d
10
11
12
KCNþDMAP
KCNþ18-C-6-O
KCNþMePhSO2Na
a
Reaction: c¼0.5 M, 1 equiv of MCN, 1 mmol scale.
b
Eight percent of the compound corresponding to the replacement of the Cl in 7
by Me2N was isolated.
c
a
Traces in LC–MS after 2 weeks.
7 days.
Starting material.
d
b
Seven percent of 15 and traces of 13.

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F. Montel et al. / Tetrahedron 64 (2008) 6372–6376
Table 4
Preparation of amides, ester, and ketone by using halogen–metal exchange reaction
Compound
R¼
Yield (%)
11
16
17
18
19
20
Me2N–
Allyl2N–
–N–(CH2)4–
–N–(CH2)2–O–(CH2)2–
MeNH
33
35
26
32
23
16
Me
Scheme 4. Halogen–metal exchange reaction on 8 with t-BuLi.
10% of yield. We were surprised to isolate these compounds be-
cause the addition of t-BuLi to pyrimidines is not described and
only one example was found in the literature with t-BuMgBr.21 The
product 13 is more surprising and is probably coming from the over
reaction of the anionic 14 with ClCO2Me. Finally, the use of a mix-
ture of solvents to solubilize our starting material (THF/DME 1:1 or
HMPT/THF 1:10) gave the desired compound in a moderate 28%
yield (entries 7 and 8).22
Scheme 6. Preparation of derivatives from 8.
3. Conclusion
In summary, we have developed the first method for the prep-
aration of new 7-carboxyl-triazolopryimidines derivatives via the
halogen–metal exchange reaction on a electron deficient hetero-
cyclic structure. The prepared compounds are currently been tested
to evaluate their biological activity.
The same type of study was done by using Knochel’s method
(Scheme 5, Table 3).23
Scheme 5. Halogen exchange reaction on 8 with i-PrMgCl.
The halogen–metal exchange reaction using i-PrMgCl is highly
temperature and time dependent. The optimal temperature that
we found is around ꢁ25 ꢀC. At higher temperature, we observed
only degradation of the starting material and at lower temperature
the desired product was not obtained or only in traces (entries 1–5).
As previously, the quench must be done as soon as possible after
the addition of the Grignard reagent (entries 6 and 7). Finally, we
noted that a higher dilution affords only the product corresponding
to the addition of the i-Pr in position 4 (entry 8). The best result was
obtained by treating 8 with 1.1 equiv of i-PrMgCl in THF at ꢁ25 ꢀC
and quenching with an excess of ClCO2Et (entry 7, 33%).
4. Experimental
4.1. General experimental information
All experiments sensitive to air and/or to moisture were carried
out under an argon atmosphere in dried glassware assembled un-
der a stream of argon. Nuclear magnetic resonance spectra were
recorded on Brucker Ultrashield Avance (1H, 400 MHz; 13C,
100 MHz) spectrometers. Solvents and reagents were purchased
from commercial source and used without further purification. THF
is purchased anhydrous from Aldrich Chemical Co. and used
without further purification.
Finally, we applied the best experimental conditions found with
i-PrMgCl to prepare amides, ester, and ketone using as electrophile
different carbamoyl chlorides, isocyanides or acyl chlorides (Table
4, Scheme 6 and see Section 4).
The compound 7 was prepared according to the procedure de-
scribed in the BASF patents US 6,297,251, US 6,117,876, and WO
9846607.
Table 3
4.2. Synthesis of 7-iodo-5-chloro-6-(2,4,6-trifluorophenyl)-
1,2,4-triazolo[1,5-a]pyrimidine (8)
Optimization of the halogen–metal exchange reaction with i-PrMgCl
Entrya
T (ꢀC)
Reaction time
[c]
i-PrMgCl (equiv)
Yield (%)
Compound7(4.1 g)wassolubilizedin100 mLofacetone,andthen
50 mL of an aqueous solution of HI (55%) was added slowly at rt. After
2 h, 7 had disappeared completely and the solvents were removed
under vacuum and the residue was purified on silica (cyclohexane/
AcOEt 6:1) to give 7-iodo-5-chloro-6-(2,4,6-trifluorophenyl)-1,2,4-
triazolo[1,5-a]pyrimidine 8 as a white powder (2.38 g, 58% yield). 1H
1
2
3
4
5
6
7
8
rt
1 h
30 min
1 h
30 min
<5 min
<5 min
1 min
1 min
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.4
1
1
1
1
1
1
1
1
d
0
d
ꢁ20
ꢁ40
ꢁ50
ꢁ25
ꢁ25
ꢁ25
d
db
db
12
33
d
NMR (400 MHz; CDCl3):
(100 MHz; CDCl3):
d
6.82 (t, J¼6 Hz, 2H), 8.51 (s, 1H). 13C NMR
a
d
101.3, 111.5, 121.4, 151.9 154.6, 156.0, 159.1, 161.6,
All reactions were done in THF.
The starting material was recovered.
b
163.2, 166.5. ESP MS (positive ion spectrum) m/z: 410.

F. Montel et al. / Tetrahedron 64 (2008) 6372–6376
6375
4.3. Synthesis of 7-cyano-5-chloro-6-(2,4,6-trifluorophenyl)-
a thermometer. Then, 275
mL (1.1 equiv, 0.55 mmol) of i-PrMgCl
1,2,4-triazolo[1,5-a]pyrimidine (9)
(2 M in THF) was added as fast as possible on the mixture in order to
keep the temperature below ꢁ20 ꢀC. After the end of the addition of
i-PrMgCl, 4 equiv of the electrophile was added rapidly to the
mixture and the bath was removed rapidly and the ball was heated
with a hair drier till the intern temperature was equal to 25 ꢀC. After
30 min at rt, 10 mL of a saturated solution was added to the mix-
ture. The aqueous phase was extracted three times with AcOEt. The
combined organic layers were dried on anhydrous Na2SO4 and
evaporated in vacuum. The residue was purified on silica to give as
a white powder the amides or the esters.
Compound 7 (1.55 g, 5 mmol) was solubilized in 30 mL of DMF,
and then 232 mg (0.15 mmol, 0.3 equiv) of sodium tosylsulfinate
and 357.5 mg (5.5 mmol, 1.1 equiv) of potassium cyanide were
added to the mixture. After 7 days at 40 ꢀC, 7 had disappeared, then
DMF was removed under vacuum and the residue was purified on
silica (cyclohexane/AcOEt 4:1) to give 821 mg of 7-cyano-5-chloro-
6-(2,4,6-trifluorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine 9 (53%) as
a white powder. 1H NMR (400 MHz; CDCl3):
8.52 (s, 1H). 13C NMR (100 MHz; CDCl3):
101.8, 107.7, 118.8, 122.2,
d
6.90 (t, J¼6 Hz, 2H),
d
153.5, 156.3, 158.1, 159.4, 162.0, 163.9, 166.5. ESP MS (positive ion
spectrum) m/z: 310.
4.6.1. 5-Chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo-
[1,5-a]pyrimidine-7-carboxylic acid ethyl ester (12)
See typical procedure for the halogen exchange reaction on 8
4.4. Synthesis of 5-chloro-6-(2,4,6-trifluoro-phenyl)-
and quench with ethyl chloroformate. 1H NMR (400 MHz; CDCl3):
[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid amide (10)
d
1.19 (t, J¼6.5 Hz, 3H), 4.03 (q, J¼7.0 Hz, 2H), 6.79 (q, J¼6 Hz, 2H),
8.51 (s, 1H). 13C NMR (100 MHz; CDCl3):
d
19.2, 64.1, 100.9, 110.2,
Compound 9 (620 mg, 2 mmol) was solubilized in 10 mL of pure
H2SO4. After 9 days this solution was added slowly on 1 L of ice and
neutralized by NaHCO3. The aqueous phase was extracted three
times with AcOEt. The combined organic layers were dried on an-
hydrous Na2SO4 and evaporated in vacuum. The residue was puri-
fied on silica (AcOEt/cyclohexane 2:1) to give as a white powder
412 mg of 5-chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo[1,5-
a]pyrimidine-7-carboxylic acid amide 10 (63%). 1H NMR (400 MHz;
139.8, 154.1, 157.2, 157.6, 158.0, 159.7, 162.1, 163.1. ESP MS (positive
ion spectrum) m/z: 357.
4.6.2. 1-[5,50-Dichloro-6,60-bis-(2,4,6-trifluoro-phenyl)-7H-
[7,70]bi[[1,2,4]triazolo[1,5-a]pyrimidinyl]-4-yl]-2,2-dimethyl-
propan-1-one (13)
1H NMR (400 MHz; CDCl3):
d 1.35 (s, 9H), 6.39 (s, 1H), 6.45 (t,
J¼6 Hz, 1H), 6.58 (t, J¼6 Hz, 1H), 6.62 (t, J¼6 Hz, 1H), 6.89
DMSO-d6):
d
6.95 (t, J¼6 Hz, 2H), 8.22 (br s, 1H), 8.44 (br s, 1H), 8.58
(t, J¼6 Hz, 1H), 7.58 (s, 1H), 8.42 (s, 1H). 13C NMR (100 MHz; CDCl3):
(s, 1H). 13C NMR (100 MHz; DMSO-d6):
d
100.6, 108.9, 144.8, 153.5,
d 26.9, 41.6, 59.0, 87.6, 101.9, 111.4, 132.2, 144.0, 149.6, 150.2, 154.3,
156.3, 156.5, 158.5, 159.0, 161.3, 162.3. ESP MS (positive ion spec-
156.7, 157.2, 160.2, 163.4, 173.4. ESP MS (positive ion spectrum)
trum) m/z: 327.
m/z: 653.
4.5. Synthesis of the 5-chloro-6-(2,4,6-trifluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid
dimethylamide (11)
4.6.3. 5,50-Dichloro-6,60-bis-(2,4,6-trifluoro-phenyl)-4,7-dihydro-
[7,70]bi[[1,2,4]triazolo[1,5-a]pyrimidinyl] (14)
1H NMR (400 MHz; DMSO-d6):
6.57 (t, J¼6 Hz, 1H), 6.61 (t, J¼6 Hz, 1H), 6.99 (t, J¼6 Hz, 1H), 7.59 (s,
d
6.41 (s,1H), 6.45 (t, J¼6 Hz,1H),
4.5.1. Method A, dialkylation of 10
1H), 8.43 (s, 1H), 12.4 (br s, 1H). 13C NMR (100 MHz; DMSO-d6):
Compound 10 (108 mg, 0.33 mmol) and 40
mL (0.66 mmol,
d 59.0, 87.7, 100.8, 101.2, 111.4, 132.1, 144.0, 149.7, 150.2, 154.3, 156.7,
2 equiv) of MeI were solubilized in 1.0 mL of anhydrous DMF. Then,
at 0 ꢀC, 28 mg of NaH (0.66 mmol, 2 equiv, 55% in mineral oil) was
added to the mixture. After 20 min, 10 has disappeared completely
in LC–MS. The mixture is quenched with 10 mL on water. The
aqueous phase was extracted three times with AcOEt. The com-
bined organic layers were dried on anhydrous Na2SO4 and evapo-
rated in vacuum. The residue was purified on reversed phase
chromatography (Apparatus: Varian Prostar; injector: Gilson 215.
157.1. ESP MS (positive ion spectrum) m/z: 568.
4.6.4. 5-tert-Butyl-7-iodo-6-(2,4,6-trifluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyrimidine (15)
1H NMR (400 MHz; DMSO-d6):
d
1.41 (s, 9H), 6.74 (t, J¼6.5 Hz,
2H), 8.40 (s, 1H). 13C NMR (100 MHz; DMSO-d6):
d
28.4, 39.6, 100.9,
115.2, 135.5, 154.5, 155.1, 156.3, 159.7, 162.1, 163.0, 165.5. ESP MS
(positive ion spectrum) m/z: 433.
Column Sunfire Prep C OBD, 10
m
m, 19ꢂ150 mm; flow: 30 mL/min;
grad: 80% MeCN/H2O to 100% MeCN; wavelength: 254 nm) to give
as a white powder 32.1 mg of 5-chloro-6-(2,4,6-trifluoro-phenyl)-
[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid dimethylamide
11 (28%).
4.6.5. 5-Chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo-
[1,5-a]pyrimidine-7-carboxylic acid diallylamide (16)
See typical procedure for the halogen exchange reaction on 8
and quench with N,N-diallylcarbamyl chloride. 1H NMR (400 MHz;
CDCl3):
d
3.52 (dd, J¼6 and 12 Hz, 1H), 3.57 (dd, J¼5 and 13 Hz, 1H),
4.5.2. Method B
3.75 (dd, J¼6 and 12 Hz, 1H), 4.24 (dd, J¼5 and 13 Hz, 1H), 4.95–5.16
(m, 4H), 5.93 (m, 1H), 5.62 (m, 1H), 6.79 (q, J¼6 Hz, 1H), 8.51 (s, 1H).
See typical procedure for the halogen exchange reaction on 8
and quench with N,N-dimethylcarbamyl chloride. 1H NMR
13C NMR (100 MHz; CDCl3):
d 47.9, 50.7, 100.3, 101.6, 110.0, 118.8,
(400 MHz; CDCl3):
d
2.81 (s, 3H), 3.01 (s, 3H), 6.78 (m, 2H), 8.50 (s,
34.8, 37.0, 100.7, 101.8, 110.2,
120.8, 130.4, 131.5, 143.6, 154.0, 157.3, 157.6, 157.7. ESP MS (positive
ion spectrum) m/z: 408.
1H). 13C NMR (100 MHz; CDCl3):
d
143.8, 153.9, 157.4, 157.7, 158.0, 162.6, 163.0, 165.5. ESP MS (positive
on spectrum) m/z: 356.
4.6.6. [5-Chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo-
[1,5-a]pyrimidin-7-yl]-pyrrolidin-1-yl-methanone (17)
4.6. Typical procedure for the halogen exchange reaction on 8
and quench with an electrophile
Method B: see typical procedure for the halogen exchange re-
action on 8 and quench with 1-pyrrolidinylcarbonyl chloride. 1H
NMR (400 MHz; CDCl3):
3.60–3.70 (m, 1H), 6.70–6.85 (m, 3H), 8.50 (s, 1H). 13C NMR
(100 MHz; CDCl3): 24.0, 25.6, 45.5, 46.4, 100.6, 101.6, 110.0, 144.1,
154.0, 156.1, 157.6, 161.0, 161.8, 163.0, 165.5. ESP MS (positive ion
spectrum) m/z: 382.
d 1.72–1.95 (m, 4H), 3.10–3.40 (m, 3H),
Compound 8 (205 mg, 0.5 mmol) was dried three times at
100 ꢀC under vacuum for 30 min. Anhydrous THF (2.5 mL) was
added to the powder. The solution was cooled at ꢁ23 ꢀC with a solid
CO2/CCl4 bath. The temperature was controlled in situ with
d

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(e) Kleschick, W. A.; Costales, M. J.; Gerwick, B. C.; Holtwick, J. B.; Meikle, R. W.;
Monte, W. T.; Pearson, N. R.; Snider, S. W.; Subramanian, M. V.; VanHeertum, J. C.;
Vinogradoff, A. P. Synthesis and Chemistry of Agrochemicals III; Baker, D. R.,
Fenyes, J. G., Steffens, J. J., Eds.; ACS Symposium Series 504; American Chemical
Society: Washington, DC, 1992; pp 10–16; (f) Kleschick, W. A.; Costales, M. J.;
Dunbar, J. E.; Meikle, R. W.; Monte, W. T.; Pearson, N. R.; Snider, S. W.;
Vinogradoff, A. P. Pestic. Sci. 1990, 29, 341.
3. Serey, R. A.; Torres, R.; Latorre, B. A. Cienc. Inv. Agr. 2007, 34, 215.
4. 191 Patent applications on triazolopyrimidine fungicides have been published
by six different companies between 1993 and 2007.
4.6.7. [5-Chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo-
[1,5-a]pyrimidin-7-yl]-morpholin-4-yl-methanone (18)
Method B: see typical procedure for the halogen exchange re-
action on 8 and quench with 4-morpholinocarbonyl chloride. 1H
NMR (400 MHz; CDCl3):
1H), 3.45–3.60 (m, 3H), 3.70–3.81 (m, 2H), 6.81 (q, J¼7.0 Hz, 2H),
8.50 (s,1H). 13C NMR (100 MHz; CDCl3):
42.4, 44.5, 46.6, 64.7, 66.3,
d
3.09 (m, 1H), 3.20 (m, 1H), 3.39 (t, J¼3 Hz,
d
100.4, 101.8, 110.4, 143.0, 153.9, 156.6, 157.4, 157.8, 163.1. ESP MS
(positive ion spectrum) m/z: 398.
5. Pees, K.J.; Albert, G. (Shell) European Patent Application 550113, 1993 (Chem.
Abstr. 1993, 119, 271190).
6. (a) Zhang, N.; Ayral-Kaloustian, S.; Nguyen, T.; Afragola, J.; Hernandez, R.; Lucas,
J.; Gibbons, J.; Beyer, C. J. Med. Chem. 2007, 50, 319; (b) Zhang, N.; Ayral-
Kaloustian, S.; Nguyen, T.; Hernandez, R.; Beyer, C. Bioorg. Med. Chem. Lett. 2007,
17, 3003.
7. Jelich, K.; Kraemer, W.; Santel, H. J.; Schmidt, R. R.; Strang, H; Bayer A.-G. DE
3640155, 1988; Jelich, K.; Santel, H. J.; Schmidt, R. R; Bayer A.-G. DE3534651,
1987.
8. Compound 7 is prepared according to the following patent of BASF: Pees, K.-J.;
Albert, G. U.S. Patent 6,297,251, 2001 or Pees, K.-J.; Albert, G. U.S. Patent
6,117,876, 2000; Pees, K.-J; Albert, G. WO9846607, 1998.
9. Minisci, F. Synthesis 1973, 1, 1 and references cited therein.
10. We used standard Minisci conditions: (NH4)2(SO4)2 (2.0 equiv), H2SO4, MeOH,
reflux, 5 h.
4.6.8. 5-Chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo-
[1,5-a]pyrimidine-7-carboxylic acid methylamide (19)
Method B: see typical procedure for the halogen exchange re-
action on 8 and quench with methyl isocyanate. 1H NMR (400 MHz;
CDCl3):
d
2.96 (d, J¼3 Hz, 3H), 6.76 (t, J¼6.5 Hz, 2H), 8.54 (s, 1H),
27.0,
9.21 (br s, 1H), 9.24 (br s, 1H). 13C NMR (100 MHz; CDCl3):
d
100.7, 107.5, 114.4, 138.8, 154.3, 156.3, 157.0, 158.9, 159.3, 161.3,
162.4, 165.0. ESP MS (positive ion spectrum) m/z: 342.
11. Blettner, C.; Tormo, J.; Mueller, B.; Gewehr, M.; Grammenos, W.; Grote, T.;
Huenger, U.; Rheinheimer, J.; Schaefer, P.; Schieweck, F.; Schwoegler, A.;
Wagner, O.; Speakman, J.-B.; Jabs, T.; Strathmann, S.; Schoefl, U.; Scherer, M.;
Stierl, R. WO2006034848, 2006.
12. Dias, R. S.; Freitas, A. C. C.; Barreiro, E. J.; Goins, D. K.; Nanayakkara, D.;
McChesney, J. D. Boll. Chim. Farma. 2000, 139, 14; Usui, T.; Tsubone, Y.; Tanaka,
A. J. Heteroat. Chem. 1985, 22, 849.
4.6.9. 1-[5-Chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo
[1,5-a]pyrimidin-7-yl]-ethanone (20)
Method B: see typical procedure for the halogen exchange re-
action on 8 and quench with acetyl chloride. 1H NMR (400 MHz;
CDCl3):
d
2.70 (s, 3H), 6.78 (t, J¼6.5 Hz, 3H), 8.52 (s, 1H). 13C NMR
(100 MHz; CDCl3): d 29.9, 101.2, 109.4, 144.7, 154.2, 157.4, 157.8, 159.4,
13. Crowley, P.; Syngenta A. G. Unpublished results.
161.9, 163.0, 165.5, 191.3. ESP MS (positive ion spectrum) m/z: 327.
14. Miyashita, A.; Suzuki, Y.; Ohta, K.; Higashino, T. Heterocycles 1994, 39, 345.
15. Most of the methods tested are described in Larock, R. C. Comprehensive Organic
Transformations, 2nd ed.; Wiley-VCH: New York, NY, 1999.
16. The standard procedure was modified and the electrophile introduced before
NaH to trap immediately the formed anion.
Acknowledgements
17. The monoanion of the amide 10 is not stable: a mixture of 10 in THF with
1 equiv of NaH at 0 ꢀC for 10 min gave as only product, the reduced compound 6
(8% yield).
We would like to thank Tammo Winkler for NMR analysis.
18. The Sonogashira coupling (Susvilo, I.; Palskyte, R.; Tumkevicius, S.; Bruk-
stus, A. Chem. Heterocycl. Compd. 2005, 41, 268); the Stille coupling
(Wang, J.-F.; Zhang, L.-R.; Yang, Z.-J.; Zhang, L.-H. Bioorg. Med. Chem. 2004,
12, 1425); the Suzuki coupling (Wang, Y. D.; Johnson, S.; Powell, D.;
McGinnis, J. P.; Miranda, M.; Rabindran, S. K. Bioorg. Med. Chem. Lett. 2005,
15, 3763) were tested by using standard methods described in the litera-
ture on pyrimidines.
19. Anderson, R. J.; Hill, J. B.; Morris, J. C. J. Org. Chem. 2005, 70, 6204; Johns, B. A.;
Gudmundsson, K. S.; Turner, E. M.; Allen, S. H.; Samano, V. A.; Ray, J. A.; Free-
man, G. A.; Boyd, F. L.; Sexton, C. J.; Selleseth, D. W.; Creech, K. L.; Moniri, K. R.
Bioorg. Med. Chem. 2005, 13, 2397.
20. For an overview of this reaction, see: Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed.
2003, 42, 4302 and references cited therein.
21. Evans, R. F.; Savage, G. P.; Gough, D. A. Aust. J. Chem. 1990, 43, 733.
22. The low yield could be explained by the reactivity of the t-BuLi toward DME,
which is known in the literature: Stanetty, P.; Milhovilovic, M. D. J. Org. Chem.
1997, 62, 1541.
References and notes
1. For some recent reviews on crop protection chemistry see: (a) Lamberth, C.
Heterocycles 2007, 71, 1467; (b) Lamberth, C. Heterocycles 2006, 68, 561; (c)
Lamberth, C. Heterocycles 2005, 65, 667; (d) Jeschke, P. ChemBioChem 2004, 5,
570; (e) Stetter, J.; Lieb, F. Angew. Chem. 2000, 112, 1792; Angew. Chem., Int. Ed.
2000, 39, 1725.
2. (a) Johnson, T. C.; Mann, R. K.; Schmitzer, P. R.; Gast, R. E.; deBoer, G. J. Modern
Crop Protection Compounds; Kra¨mer, W., Schirmer, U., Eds.; Wiley-VCH: Wein-
heim, 2007; pp 93–114; (b) Kleschick, W. A. In Herbicides Inhibiting Branched-
chain Amino Acid Biosynthesis: Recent Developments; Stetter, J., Ed.; Chemistry of
Plant Protection; Springer: Berlin, 1994; Vol. 10, pp 119–143; (c) Costales, M. J.;
Kleschick, W. A.; Gerwick, B. C. Synthesis and Chemistry of Agrochemicals III;
Baker, D. R., Fenyes, J. G., Steffens, J. J., Eds.; ACS Symposium Series 504;
American Chemical Society: Washington, DC, 1992; pp 26–33; (d) Kleschick, W.
A.; Carson, C. M.; Costales, M. J.; Doney, J. J.; Gerwick, B. C.; Holtwick, J. B.;
Meikle, R. W.; Monte, W. T.; Little, J. C.; Pearson, N. R.; Snider, S. W.; Sub-
ramanian, M. V.; VanHeertum, J. C.; Vinogradoff, A. P. Synthesis and Chemistry of
Agrochemicals III; Baker, D. R., Fenyes, J. G., Steffens, J. J., Eds.; ACS Symposium
Series 504; American Chemical Society: Washington, DC, 1992; pp 17–25;
23. It has to be noted that the use of i-Pr2MgCl$LiCl complex was tried for this
exchange, we isolated only 14: Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 159.