Arylation of aryl chlorides, a convenient method for the synthesis of new potential triazolic fungicides

Article abstract of DOI:10.1016/j.tet.2013.11.067

We evaluated two alternative routes for the arylation of known chlorinated fungicides. The first pathway involved a S_RN1 substitution, followed by Stille reaction, while the second consisted in a one step reaction by the Suzuki coupling. Both methodologies were useful to obtain new products that could be potential fungicides.

Full text of DOI:10.1016/j.tet.2013.11.067

Tetrahedron xxx (2013) 1e6
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Arylation of aryl chlorides, a convenient method for the synthesis
of new potential triazolic fungicides
*
Natividad Herrera Cano, Ana N. Santiago
ꢀ
ꢀ
INFIQC, Departamento de Química Organica, Facultad de Ciencias Químicas, Universidad Nacional de Cordoba, Ciudad Universitaria,
ꢀ
Cordoba 5000, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
We evaluated two alternative routes for the arylation of known chlorinated fungicides. The first pathway
involved a SRN1 substitution, followed by Stille reaction, while the second consisted in a one step reaction
by the Suzuki coupling. Both methodologies were useful to obtain new products that could be potential
fungicides.
Received 3 September 2013
Received in revised form 17 November 2013
Accepted 19 November 2013
Available online xxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Electron transfer
Herbicide
Thiolate group
DFT
1. Introduction
importance in organic chemistry.3 The initiation step of these cross-
coupling reactions involves the assembling of two molecules to the
Triazoles have been widely used as fungicides in different coun-
tries, controlling fungi, such as Septoria tritici or Gibberella zeae.1 The
triazolic plant protection fungicides include 1-(4-clorofenoxi)-3,3-
dimetil-1-(1H-1,2,4-triazol-1-il) butan-2-one (triadimefonÒ) (1) and
1-(4-chlorophenyl)-3-cyclopropyl-2-(1H-1,2,4-triazol-1-yl)butan-1-
ol (cyproconazoleÒ) (2). TriadimefonÒ and cyproconazoleÒ are chlo-
rinated triazolic analogs, relatively stable under natural conditions,
which have become prominent pollutants for soils and aquatic sys-
tems. These azoles are systemic, having a broad antifungal spectrum.
Systemic azoles inhibit cytochrome P-450 enzymatic system as well
metal, via the formation of metalecarbon bonds. In the next step,
these carbon atoms couple between them, leading to the formation
of a new carbonecarbon single bond. These reactions are catalyzed
by zerovalent palladium and can utilize an arylhalide (ArX) as the
electrophilic coupling partner. The nucleophilic coupling partner can
be an organometallic compound, namely Ar0M, where M is typically
zinc, boron or tin (Eq. 1).
as fungal 1,4-a-demethylase, avoiding the synthesis of ergosterol and,
thus, decreasing the viability of the fungal cell.2 The inhibition of
demethylase involves the bind of the heme iron atom, belonging to
ferric cytochrome P450, to the nitrogen-4 of triazolic compounds,
which constitutes the active site of the molecule. In order to produce
new fungicides, less toxic to the environment, we decided to in-
vestigate two alternative routes for the arylation of triadimefon or
cyproconazole, substituting the chloride atom but retaining the tri-
azole ring and, thus, keeping potential bioactivity of new synthetic
products.
ð1Þ
These reactions begin generating an organopalladium complex
ArPdX, arising from the reaction between the arylhalide and Pd(0).
The insertion of palladium in a CeCl bond requires high energy,
which leads to slow initiation steps when aryl chlorides are used,4
requiring special conditions to get good synthetic results.5 Several
advances have been reported to this respect. Buchwald studied
inactive aryl chlorides (neutral or electron rich)6 by Suzuki
reactions for the first time. A study of Littke and Fu proposes
a general method by the cross-coupling of aryl chlorides using Pd/
P(tBu)3. However, some aryl chlorides require the use of special
Many cross-coupling reactions are palladium-catalyzed reactions,
involving the formation of a new CeC bond, which are of great
* Corresponding author. Tel./fax: þ54 351 4334170; e-mail address: santiago@fcq.
unc.edu.ar (A.N. Santiago).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.067
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2
N. Herrera Cano, A.N. Santiago / Tetrahedron xxx (2013) 1e6
ligands for these reactions.7 Moreover, electron deficient aryl
chlorides react with arylboronic acids.8 Also, non-active aryl chlo-
rides require using sterically hindered phosphine ligands for these
reactions.3b,9
inhibited by inhibitors of SRN1 reactions,11 such as p-dinitrobenzene
(p-DNB) (Table 1 entries 4 and 5).
One alternative way for substrates having non-reactive chlo-
rides for the Stille reaction may be using stannyl derivatives, since
stannyl compounds are good substrates in these reactions.10 The
reaction of ꢀSnMe3 ions with aryl chlorides, by unimolecular
Radical Nucleophilic Substitution (SRN1),11 is important to syn-
thesize these stannyl intermediates. A sequence of SRN1, followed
by a cross-coupling reaction (Stille type) has been developed to
obtain polyphenylated compounds as shown in Eq. 2.12 It is also
known that some organostannane compounds have also anti-
fungal activities.13
ð3Þ
In the same way, the photostimulated reaction of 2 with ꢀSnMe3
ions afforded 98% yields of the substitution product (4), using liquid
NH3 as the solvent (Eq. 4) (Table 1 entry 6). This reaction was also
light catalyzed and inhibited with p-DNB (Table 1 entries 7 and 8).
ð4Þ
ð2Þ
Our main goal was to synthesize novel environmentally friendly
fungicides. Therefore, we decided to investigate the dechlorination
of chloro-fungicides in two different ways. In the first approach, we
studied a sequence of SRN1 followed by a Stille cross-coupling re-
action, catalyzed by Pd(0). This methodology involves two steps,
with the first providing a simple method for the preparation of
compounds bearing trimethylstannyl groups. The second approach
consists of a simple and efficient one step procedure for the Suzuki
coupling of chloro-fungicides with organoboron compounds.
The stannanes synthesized in Eqs. 3 and 4 are stable organo-
metallic compounds in addition to good nucleophilic coupling
partners through Stille reactions, using mild reaction conditions.
The Stille reaction has been used as an alternative to the Negishi
and Suzuki reactions for substrates with sensitive functional
groups. However, the toxicity of organotin compounds has limited
their industrial use.
The reaction of 3 with iodobenzene (5) and PdCl2(PPh3)2 as
catalyst in DMF did not occur, showing decomposition of 3 in this
solvent (Table 2, entry 1). Nevertheless, using toluene, the coupling
reaction was observed. Moreover, the reaction was increased using
PPh3 as ligand, providing 77% yield of 6 (Eq. 5) (Table 2, entries 2e4).
2. Results and discussion
2.1. Tandem reactions: SRN1 followed by Stille
Reactions of triadimefon (1) and cyproconazole (2) with Me3Snꢀ
gave organostannanes as substitution products through the SRN
1
mechanism. These stannanes were used as intermediates in Stille
reactions, providing arylated products. For instance, the photo-
stimulated reaction of 1 with ꢀSnMe3 ions afforded 36e77% yields
of the substitution product (3), using liquid NH3 as the solvent (Eq.
3) (Table 1 entries 1e3). This reaction was catalyzed by light and
ð5Þ
Table 1
Reactions of triadimefon (1) and cyproconazole (2) with ꢀSnMe3 ions in liquid
ammonia
Entry
Substrate
(10ꢀ3 M)
Nucleophile
(10ꢀ3 M)
Conditions
(min)
Clꢀa
%
Yield of isolated
product
Table 2
1
2
3
4
5
6
7
8
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
2 (2.0)
2 (2.0)
2 (2.0)
ꢀSnMe3 (2.6)
ꢀSnMe3 (6.0)
ꢀSnMe3 (6.0)
ꢀSnMe3 (6.0)
ꢀSnMe3 (6.0)
ꢀSnMe3 (6.0)
ꢀSnMe3 (6.0)
ꢀSnMe3 (6.0)
h
h
h
y
y
y
(60)
(90)
(180)
55
3, 36b
3, 77b
3, 77
dc
Stille cross-couplings of 3 with iodobenzene catalyzed by PdCl2(PPh3)2 during 48 ha
100
100
d
Catalyst
Ligand
Additive Solvent
CsF, CuI DMFb
Yield of 6 (%)
dc
CsF, CuI Toluened 5%e
Dark (180)
h
h
Dark (90)
h
1
2
3
4
5 mol % PdCl2(PPh3)2
10 mol % PdCl2(PPh3)2
30 mol % PdCl2(PPh3)2
d
d
d
y
d (90)
(90)
10
100
10
dc
y
4, 98
dc
dc
CsF, CuI Toluened 7%e
10 mol % PdCl2(PPh3)2 40 mol % PPh3 CsF, CuI Toluened 77%f
ye (90)
d
Concentrations of substrate and nucleophile were 6.0 10ꢀ2 M.
The reaction was carried out at 80 ꢁC.
Only substrate decomposed.
Reactions were carried out at 100e110 ꢁC.
Only product observed by GC trace with respect to substrate.
Isolated yield.
a
b
c
d
e
f
a
Chloride ions were determined by potentiometry.
5e10% chlorophenol was observed.
Substrate was recovered.
With 30% p-DNB added.
With 20% p-DNB added.
b
c
d
e
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N. Herrera Cano, A.N. Santiago / Tetrahedron xxx (2013) 1e6
3
After determining the best reaction conditions for triadimefon (3),
using 5 as electrophile, we evaluated other electrophiles. Thus, the
reaction of 3 with 1-fluoro-4-iodobenzene (7), 1-iodonaphthalene
(8), and 1-iodo-4-methoxybenzene (9), rendered 84%, 5%, and 10%
yields, respectively (Eq. 4) (Table 3, entries 3, 5, and 7). The reaction
using 8 as electrophile gave 11 (5%) together homocoupling product,
recovering only 8 (20%) probably due to steric problems. The reaction
using 9 as electrophile afforded 12 (10%) together with 6 (25%) as
product. In order to understand the formation of 6, we carried out the
reaction changing the catalyst and the ligand for Pd2(dba)3/P(C6H12).
Inthese conditionsthe formation ofhomocoupling product withPh is
not possible. However, in the reaction 6 was also formed. We can
presume that 12 is probably an intermediate for the formation of 6
where theOMe groupwaslost. Finally, itisworthytomentionthat6 is
a compound known with fungicide activity.14
The reaction of 1 with phenylboronic acid and Pd(OAc)2 at either
roomtemperature or 85ꢁC did notoccur, even using a biggerligandas
[Pd2(dba)3]. Homocoupling product and triphenylboroxine15 were
present in all reactions. However, 2 reacts with phenylboronic acid
and Pd(OAc)2 at 85 ꢁC affording 40% of coupling product (6) (Table 4,
entry 1).
Table 4
Suzuki cross-couplings of triadimefon (1) and cyproconazole (2) with phenylboronic
acid
Entry Halide Catalyst
Ligand
Conditions
Yield of
product %
a
1
1
Pd(OAc)2
3 equiv KF, THF
80 ꢁC, 24 h
6, 40
Table 3
Stille cross-couplings of triadimefon (3) and cyproconazole (4) catalyzed by 10 mol %
PdCl2(PPh3)2, in toluene using 40 mol % PPh3 and CsF
2
3
1
1
Pd/C
Pd/C
DELPhosd
Ligandless
TBAB, NaOH, H2O
140 ꢁC, 6 h
d
d
Entry
Electrophile
Me3SneR
Yield of coupling product (%)a
R¼Trb
6, 77c
13, 97
10, 84
14, 78
11, 5e
15, 5
2 equiv K2CO3, DMA/H2Oe
80 ꢁC, 48 h
1
2
3
4
5
6
7
8
5, PhI
5, PhI
R¼Cypd
R¼Trb
7, 1-F,4-IPh
7, 1-F,4-IPh
8, 1-INaph
8, 1-INaph
9, 4-IAnf
9, 4-IAn
R¼Cypd
R¼Trb
4
5
1
2
Pd/C
Pd/C
2 equiv K2CO3, DMA/H2Oe 6, 85b
80 ꢁC, 48 h
R¼Cypd
R¼Trb
12, 10g
16, dh
R¼Cypd
2 equiv K2CO3, DMA/H2Oe 13, 100c
a
Isolated yield.
Tr as triadimefonyl.
Together with reduced substrate (TrH).
Cyp as cyproconazoyl.
Together homocoupling product, substrate (20%) and substrate decomposed.
An as anisyl.
80 ꢁC, 24 h
b
c
d
e
f
a
Ac as acetate.
b
g
Phenylboronic acid (2 equiv) was added each 12 h (6 equiv of phenylboronic
Together with TrH (5%), substrate (10%) and phenol (5%). The last product in-
acid were used).
dicates substrate decomposition.
c
h
Phenylboronic acid (2 equiv) was added each 12 h (4 equiv of phenylboronic
Substrate (80%).
acid were used).
d
DELPhos: bis(2-diphenylphosphinophenyl)ether.
DMA/H2O (20/1).
e
In the same way, 4 reacts with iodobenzene and PdCl2(PPh3)2 as
catalyst in toluene, using PPh3 as ligand, affording 97% yield of the
coupling product (13) (Eq. 6) (Table 3, entry 2). In order to syn-
thesize more derivatives; we carried out reactions starting from 4
with 7, 8, and 9, which gave 78%, 5%, and 0% yield, respectively (Eq.
6) (Table 3, entries 4, 6, and 8).
Various aryl chlorides reacted by SuzukieMiyaura cross-coupling
using aqueous conditions.16 These environmentally friendly condi-
tions utilize ligandless Pd/C (Pd concentrations 0.2e2 mol %), which
allows easy separation of the catalyst at the end of the reaction. We
carried out reactions of 1 with phenylboronic acid using H2O and
bis(2-diphenylphosphino phenyl)ether (DELPhos) as ligands without
observing cross-coupling reaction (Table 4, entry 2).
Considering reports from Sowa,17 we tested reactions of 1 with
phenylboronic acid using DMA/H2O (20/1) with and without li-
gands. So, the reaction of 1 with phenylboronic acid, ligandless, and
Pd/C did not gave a cross-coupling product. However, when
biphenylPCy2 was used, 85% 6 was obtained (Table 4, entries 3 and
4). In the same way, 2 rendered 100% cross-coupling product (13)
using these condition (Table 4, entry 5).
ð6Þ
After determining the best condition for the reaction of these
compounds with phenylboronic acid as electrophile, we further
tested different electrophiles. Thus, the reaction of 1 with p-F
C6H4B(OH)2, naphthalene B(OH)2, and o-MeOC6H4B(OH)2 rendered
98%, 5%, and 24% yield, respectively (Table 5, entries 1e3).
In order to decrease the reaction time we used a microwave
oven. Optimal reaction conditions were found using 1 with phe-
nylboronic acid and Pd/C. We started using the dynamic mode, but
the yield of the coupling product was very low (20%). So, we con-
tinued using the pulsed mode at 85 ꢁC, which rendered 40% of the
product.
2.2. One step Suzuki coupling
The Suzuki reaction with triadimefon (1) and cyproconazole (2)
can be applied to afford products similar to those found using tan-
dem reactions. In these reactions, chlorinated fungicides react with
organoboron compounds, catalyzed by Pd, which could afford cross-
coupling products in one step. The stability and weak nucleophilic
nature of organoboron compounds has made this reaction very
practical. Furthermore, boron compounds are generally non-toxic
and the reactions can be done under mild conditions. These facts
have made the reaction popular in the pharmaceutical industry.
Finally, we increased the temperature to 105 ꢁC, affording the
best yield for the cross-coupling product 6 (97%, Table 6, entries
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4
N. Herrera Cano, A.N. Santiago / Tetrahedron xxx (2013) 1e6
Table 5
Suzuki coupling of triadimefon (3) and cyproconazole (4) with different boronics acids and (2-biphenyl)dicyclohexylphosphine as ligand
Entry
RC6H4B(OH)2
Yield (%) of product from 1
Yield (%) of product from 2
Conventionala
(48 h)
MWb
(4 h)
Conventionala
(48 h)
MWb
(4 h)
1
2
10, 98c
11, 5e
10, 95d
11, 5%e
14, 92%c
15, 36%c
14, 83%d
15, 56%d
3
17, 24%e
17, 26%e
18, 24%e
18, 23%e
a
Arylboronic acid (2 equiv) was added each 12 h (4 equiv of arylboronic acid were used, except with 4-fluorophenylboronic acid that 2 equiv was used).
Arylboronic acid (2 equiv) was added each 2 h (4 equiv of arylboronic acid were used, except with 4-fluorophenylboronic acid that 3 equiv and 3 h of reaction were used).
Isolated yields.
Products rendered with GC using internal standard.
Organic products were determined by GC using relative areas.
b
c
d
e
Table 6
reactiontime considerably. Despite the poor reactivity of aryl
chloride in Suzuki reaction, this research shows that aryl chlorides
highly functionalized can react effectively under the conditions
described.
Microwave-mediated Suzuki coupling of triadimefon (3) and phenylboronic acida
4. Experimental section
4.1. Reagents
Entry
Conditions
Yield (%)
1
2
3
Tꢁ¼80 ꢁC. Dynamic mode
6, 20
6, 40
6, 97
Tꢁ¼80 ꢁC. Microwave irradiation¼50 W
Tꢁ¼105 ꢁC. Microwave irradiation¼50 W
a
Sn(CH3)3Cl, halobenzenes, boronic acids, catalysts, ligands, CsF,
CuI, and K2CO3 were commercially available and used as received.
Liquid ammonia was distilled under nitrogen and metallic Na.
Toluene was also distilled under nitrogen. Both were used imme-
diately after the distillation.
Arylhalide (0.5 mmol), 1 mmol of PhB(OH)2, 2 mmol of K2CO3, 2.35 mL of DMA
with 0.15 mL of water.
1e3). So, we continued subsequent reactions using this last con-
dition. Thus, the reaction of 1 with p-FPhB(OH)2, naphthalene
B(OH)2, and o-MeOC6H4B(OH)2 rendered 95%, 5%, and 26% yield,
respectively (Table 5, entries 1e3). It is worthy to mention that the
yield of synthetized products was similar using either conventional
heating or microwave irradiation. However, the use of microwave
decreased the reaction time considerably.
In the same way, 2 reacted with different arylboronic acid
affording cyproconazole derivates (14, 15, and 18) in variable yields.
With 2 as substrate, the reaction using MW irradiation gave also
similar yields but lesser reaction time (Table 5, entries 1e3).
4.2. General methods
Irradiation was performed in a reactor equipped with two 400-
W UV lamps, with maximal emission at 350 nm (Philips Model
HPT, water-refrigerated). 1H and 13C NMR spectra were recorded
on a High Resolution Spectrometer Advance 400 (working fre-
quency 400 MHz and 100 MHz, respectively), at ambient tem-
perature in CDCl3 (Aldrich). Radial chromatography separations
were achieved on a chromatotron 7924. Mass spectra were
recorded on a Bruker, MicroTOF Q II equipment, operated with an
ESI source operated in (positive/negative) mode, using nitrogen as
nebulizing and drying gas and sodium formiate 10 mM as internal
calibrant. MW-induced reactions were performed in a single mode
instrument (CEM Focused MicrowaveÔ Synthesis System, Model
Discover) equipped with noncontact infrared sensor to measure
the temperature, direct pressure control system by measurement
of pressure of the reaction vessel contents, and cooling system by
compressed air.
3. Conclusions
We have studied two alternative pathways for the arylation of
commercial fungicides, allowing the synthesis of new compounds
with potential fungicide activity, substituting the chloride atom for
less toxic groups, but retaining the triazolic moiety, which could
result in new fungicides, with similar activity but less toxic to the
environment. The two proposed paths allow the easy arylation of
aryl chlorides and can be used alternatively. Moreover, we have
shown that using Pd/C and water as solvent, it was possible to
afford Suzuki cross-couplings, allowing the efficient synthesis of
several substituted fungicides in one step. This catalytic system was
also studied under microwave irradiation, lowering the
€
The melting points were determined on a Buchi 510 fusiometro
without correction. The potentiometric titration of halides in the
aqueous phases was carried out using a pH meter Model 420A
Digital Seybold, equipped with Ag/Agþ electrode.
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N. Herrera Cano, A.N. Santiago / Tetrahedron xxx (2013) 1e6
5
4.2.1. Photostimulated reactions of 1 or 2 with ꢀSn(CH3)3 anions in
liquid ammonia. The following procedure is representative of these
reactions. Sn(CH3)3Cl (1.5 mmol) and metallic Na (3.6 mmol, 20%
excess) were added to 150 mL of distilled ammonia. Na was added
slowly in small pieces until total fade occurred. Then, 20 min after
the last addition, when no more solid was present, the Me3Snꢀ ions
were ready for use (characterized by a lemon yellow solution).
Substrate 1 or 2 (0.5 mmol) was added to the solution and the
reaction mixture irradiated for 90 min. The reaction was then
quenched with an excess of ammonium nitrate and the ammonia
allowed to evaporate under a hood. The solid was dissolved in
water and extracted with dichloromethane. The organic extract
was analyzed by GC and the products were isolated by vacuum
130.4; 137.7; 144.2; 151.8; 156.2; 203.2. HRMS [MNa]þ exact mass
calcd for C17H25N3O2Sn 446.0866, found: 446.0898.
4.3.2. 3-Cyclopropyl-1-(1H-1,2,4-triazol-1-yl)-2-(4-(trimethyl
stannyl)phenyl)butan-2-ol (4). The product was isolated as yellow
þ
ꢁ
€
oil after Kugelrohr distillation (120e125 C/1 mmHg). MS (EI ) m/z
(%): 421 (1), 420 (2), 419 (1), 418 (2), 406 (40), 405 (18), 404 (34),
403 (18), 402 (18), 356 (15), 353 (13), 352 (69), 351 (28), 350 (54),
349 (21), 348 (30), 269 (36), 268 (14), 267 (32), 266 (15), 265 (20),
208 (25), 207 (100), 186 (40), 165 (37), 163 (30), 161 (19), 135 (19),
133 (23), 119 (17). 1H NMR (400 MHz, CDCl3):
d
(ppm) ꢀ0.023e0.15
(m, 2H); 0.15e0.24 (d, J¼2.65 Hz, 9H); 0.36e0.64 (m, 3H);
0.67e0.91 (m, 2H); 0.99 (d, J¼6.83 Hz, 2H); 1.05e1.20 (m, 1H);
1.21e1.32 (m, 1H); 4.11e4.41 (d, 1H); 4.44e4.58 (dd, J¼14.01,
2.54 Hz, 1H); 4.93e5.05 (dd, J¼14.01, 6.13 Hz, 1H); 5.28 (br s, OH);
7.16 (d, J¼7.71 Hz, 1H); 7.29e7.39 (m, 3H); 7.68 (d, 1H); 7.79 (d, 1H).
€
distillation using a Kugelrohr equipment.
4.2.2. Dark reactions of 1 or 2 with ꢀSn(CH3)3 anions in liquid am-
monia. This procedure was similar to that for the previous reaction,
except that the reaction flask was wrapped with aluminum foil.
13C NMR (100 MHz, CDCl3):
d
(ppm) ꢀ9.2; 3.1; 3.2; 6.4; 7.8; 13.1;
13.7; 14.7; 15.4; 47.5; 47.9; 57.4; 58.46; 79.7; 80.1; 125.0; 126.1;
135.6; 135.9; 141.20; 141.27; 141.3; 142.9; 144.3; 144.6; 151.8. HRMS
[MH]þ exact mass calcd for C18H27N3OSn 422.1252, found:
422.1231.
4.2.3. Inhibited reactions with ꢀSn(CH3)3 anions in liquid ammo-
nia. The procedure was similar to the above reactions, except that
20 mol % of p-DNB was added to the solution of the nucleophile
before adding the substrate.
4.3.3. 1-(Biphenyl-4-yloxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)
butan-2-one (6). The product was isolated as white solid after
column chromatography using ethyl acetate. 1H NMR (400 MHz,
4.2.4. Stille cross-coupling reactions catalyzed by Pd. The following
procedure is representative for all Stille-type reactions. In a Schlenk
tube, equipped with nitrogen and magnetic stirrer, CsF
(0.474 mmol) was added and heated for 3 h in vacuum. After that
PdCl2(PPh3)2 (0.024 mmol), PPh3 (0.096 mmol), CuI (0.024 mmol)
were added, respectively. The tube was deoxygenated and refilled
with nitrogen three times before adding toluene (3 mL). Next, the
corresponding organotin compound (0.237 mmol in 2 mL of tolu-
ene) and PhI (0.237 mmol) were added to the reaction mixture. The
solution was heated at 100 ꢁC for 48 h. After the reaction was
cooled, water was added followed by extraction with dichloro-
methane. Reaction products were isolated by column chromatog-
raphy or by radial thin layer chromatography.
CDCl3),
d (ppm): 1.32 (s, 9H); 6.99 (s, 1H); 7.04e7.10 (d, 2H,
J¼8.49 Hz); 7.29e7.36 (t, 1H, J¼7.15 Hz); 7.38e7.45 (t, 2H,
J¼7.15 Hz); 7.47e7.55 (d, 2H, overlapping, J¼8.49 Hz); 7.47e7.55 (m,
2H); 8.00 (s, 1H); 8.49 (s, 1H). 13C NMR (100 MHz, CDCl3),
d (ppm):
26.1; 44.1; 83.8; 116.4; 127.2; 127.6; 129.0; 129.2; 137.5; 140.4;
144.3; 151.9; 155.4; 203.1. MS (EIþ) m/z (%): 335 (12), 281 (5), 265
(3), 250 (100), 223 (3), 208 (10), 169 (33), 85 (15), 69 (2), 57 (85).
HRMS [MH]þ exact mass calcd for C20H21N3O2 336.1707, found:
336.1714. Mp: 125.5e126.5 ꢁC.
4.3.4. 1-(40-Fluorobiphenyl-4-yloxy)-3,3-dimethyl-1-(1H-1,2,4-
triazol-1-yl)butan-2-one (10). The product was isolated as white
solid after column chromatography using ethyl acetate. 1H NMR
4.2.5. Suzuki cross-coupling reactions catalyzed by Pd. The follow-
ing procedure is representative for all Suzuki-type reactions. In
(400 MHz, CDCl3), d (ppm): 1.32 (s, 9H); 6.98 (s, 1H); 7.03e7.13 (dd,
4H, J¼8.59 Hz); 7.41e7.48 (m, 4H); 8.00 (s, 1H); 8.49 (s, 1H). 13C
a
Schlenk tube with magnetic stirring and nitrogen, Pd/C
NMR (100 MHz, CDCl3), d (ppm): 26.5; 44.1; 83.7; 115.9; 116.1;
(0.025 mmol), phenylboronic acid (1 mmol), K2CO3 (1 mmol), and
ligand (0.011 mmol) were added, respectively. Next, a mixture of
dimethylacetamide (2.35 mL) and water (0.15 mL) was added to the
reaction mixture. The tube was deoxygenated and refilled with
nitrogen three times before adding 1 or 2 (0.5 mmol). The reaction
was heated to 80 ꢁC for 48 h. After, the reaction was cooled, water
was added followed by extraction with dichloromethane. The or-
ganic extract was analyzed by GC and GCeMS. Products were iso-
lated by column chromatography, radial thin layer chromatography
or preparative chromatography plate.
116.5; 128.7; 128.8; 128.9; 136.5; 144.3; 151.9; 155.3; 203.0. MS
(EIþ) m/z (%)¼284 (2), 283 (18), 282 (100), 263 (3), 207 (3), 200 (8),
199 (54), 186 (7), 171 (12), 170 (23), 83 (46), 69 (17), 55 (13). HRMS
[MH]þ exact mass calcd for C20H20FN3O2: 354.1612, found:
354.1608. Mp: 107.3e108.7 ꢁC.
4.3.5. 3,3-Dimethyl-1-(4-(naphthalen-1-yl)phenoxy)-1-(1H-1,2,4-
triazol-1-yl)butan-2-one (11). The product was isolated as colorless
oil after preparative thin layer chromatography using ethyl acetate.
1H NMR (400 MHz, CDCl3),
d (ppm): 1.25 (s, 9H); 7.34e7.61 (m, 7H);
7.82 (d, 1H, J¼6.91 Hz); 7.84e7.96 (dd, 4H, J¼8.11 Hz); 8.41 (s, 1H);
8.43 (s, 1H). MS (EIþ) m/z (%)¼387 (3), 386 (13), 385 (42), 301 (19),
300 (84), 273 (7), 272 (22), 246 (6), 245 (4), 233 (6), 232 (229), 231
(28), 222 (2), 220 (50), 219 (99), 204 (10), 203 (50), 202 (56), 201
(15), 192 (39), 191 (23), 190 (31), 189 (44), 57 (100). HRMS [MH]þ
exact mass calcd for C24H23N3O2: 386.1869, found: 386.1871.
4.2.6. Suzuki cross-coupling reactions catalyzed by Pd in microwave
oven. This procedure was similar to that for the previous reaction,
except that the reaction was irradiated with microwave.
4.3. Isolation and characterization
4.3.1. 3,3-Dimethyl-1-(1H-1,2,4-triazol-1-yl)-1-(4-(trimethylstannyl)
4.3.6. 1-(40-Methoxybiphenyl-4-yloxy)-3,3-dimethyl-1-(1H-1,2,4-
triazol-1-yl)butan-2-one (12). The product wasisolatedaswhite solid
after preparative thin layer chromatography using dichloromethane.
phenoxy)butan-2-one (3). The product was isolated as dark brown
þ
ꢁ
ꢁ
€
oil after Kugelrohr distillation (120e125 C/1 mmHg). MS (EI ) m/z
(%): 423 (1), 408 (86), 340 (3), 338 (1), 323 (6), 241 (14), 243 (19),
255 (4), 189 (66), 165 (30), 57 (100). 1H NMR (400 MHz, CDCl3),
1HNMR(400MHz,CDCl3),
d(ppm):1.30(s,9H);3.82(s,3H);6.84e7.14
(m, 5H); 7.35e7.57 (dd, 4H, J¼8.67 Hz); 7.98 (s, 1H); 8.47 (s, 1H). 13
C
d
(ppm): 0.26 (s, 9H); 1.30 (s, 9H); 6.96 (s, 1H); 6.98e7.00 (d, 2H,
J¼8.54 Hz); 7.40e7.42 (d, 2H, J¼8.54 Hz); 7.97 (s, 1H); 8.44 (s, 1H).
13C NMR (100 MHz, CDCl3),
(ppm): ꢀ9.18; 26.5; 44.1; 83.5; 115.8;
NMR (100 MHz, CDCl3), d (ppm): 26.4; 31,2; 55,6; 83.8; 114.6; 116.1;
116.3; 128.2; 128.5; 130.4; 133.0; 144.2; 151.8; 155.5; 207.3. MS (EIþ)
d
m/z (%)¼366 (3), 365 (13), 280 (9), 252 (5), 211 (5), 200 (15),199 (100),
Please cite this article in press as: Herrera Cano, N.; Santiago, A. N., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.11.067

6
N. Herrera Cano, A.N. Santiago / Tetrahedron xxx (2013) 1e6
183(6),171 (13),168 (5),156(6),140(5),139(7),128(8), 57 (21). HRMS
[MH]þ exact mass calcd for C21H23N3O3: 366.1818, found: 366.1820.
57.5; 79.9; 125.6; 126.1; 126.4; 126.9; 127.3; 127.9; 128.0; 128.6;
129.8; 131.9; 134.1; 139.8; 140.4; 140.7; 141.8. MS (EIþ) m/z (%): 383
(1), 365 (1), 315 (26), 314 (100), 297 (6), 296 (12), 232 (10), 231 (46),
203 (26), 202 (46), 82 (18), 69 (15). HRMS [MH]þ exact mass
calcd for C25H25N3O: 384.2070, found: 384.2084.
4.3.7. 1-(20-Methoxybiphenyl-4-yloxy)-3,3-dimethyl-1-(1H-1,2,4-
triazol-1-yl)butan-2-one (17). The product was isolated as white
solid after preparative thin layer chromatography using dichloro-
methane. 1H NMR (400 MHz, CDCl3),
d
(ppm): 1.27 (s, 9H); 3.87 (s,
3H); 6.99 (s, 1H); 7.08e7.15 (dd, 4H, J¼8.55 Hz); 7.45e7.51 (m, 4H);
8.11 (s, 1H); 8.57 (s, 1H). 13C NMR (100 MHz, CDCl3),
(ppm): 25.4;
4.3.11. 3-Cyclopropyl-2-(20-methoxybiphenyl-4-yl)-1-(1H-1,2,4-
triazol-1-yl)butan-2-ol (18). The product was isolated as colorless
oil after preparative thin layer chromatography using ethyl acetate.
d
43.3; 54.1; 83.8; 115.2; 128.3; 128.6; 129.7; 129.9; 138.5; 141.6;
144.8; 154.9; 157.4; 203.7. MS (EIþ) m/z (%)¼367 (1), 366 (8), 365
(32), 281 (18), 280 (100), 253 (6), 252 (29), 212 (19), 211 (23), 200
(22), 199 (39), 185 (8), 183 (15), 168 (33), 139 (14), 128 (21), 57 (78).
HRMS [MH]þ exact mass calcd for C21H23N3O3: 366.1818, found:
366.1820.
1H NMR (400 MHz, CDCl3),
d (ppm): 0.03e1.39 (m, 5H); 1.65 (s, 3H);
2.04 (s, 1H); 3.84 (s, 3H); 5.12 (br s OH overlapping); 4.82e5.25 (m,
2H, overlapping); 6.90e7.03 (m, 2H); 7.38e7.75 (m, 8H). 13C NMR
(100 MHz, CDCl3),
d (ppm): 1.4; 55.7; 114.3; 114.4; 114.5; 114.6;
128.7; 128.8; 128.9; 129.0; 132.1; 132.2; 132.3; 132.4; 132.5; 132.6;
132.7; 134.2; 134.3; 134.4; 134.5; 162.8. MS (EIþ) m/z (%): 296 (2),
295 (23), 294 (100), 253 (5), 252 (10), 251 (8), 190 (7), 189 (37), 188
(18), 176 (9), 174 (10), 161 (8), 159 (9), 147 (10), 146 (10), 135 (7), 134
(14), 133 (19), 105 (58), 104 (13), 91 (22), 77 (19). HRMS [MH]þ exact
mass calcd for C22H25N3O2: 364.2025, found: 364.2030.
4.3.8. 2-(Biphenyl-4-yl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)bu-
tan-2-ol (13). The product was isolated as colorless oil after column
chromatography using dichloromethane/ethyl acetate (80/20). 1H
NMR (400 MHz, CDCl3),
d (ppm): 0.28e0.72 (m, 7H); 1.06 (d, 3H,
J¼7.07 Hz); 1.29e1.41 (m, 1H); 4.44 (br s, OH); 4.56 (d, 1H,
J¼13.5 Hz, overlapping); 5.00 (d, 1H, J¼13.5 Hz, overlapping)
7.36e7.61 (m, 4H, overlapping); 7.78 (s, 1H); 7.88 (s, 1H). 13C NMR
Acknowledgements
This work was supported in part by ACC, CONICET, SECYT, and
ANPCyT. N.H.C. gratefully acknowledges receipt of a fellowship
from CONICET.
(100 MHz, CDCl3),
d (ppm): 3.2; 6.5; 13.7; 14.8; 47.6; 57.5; 79.8;
125.9; 26.8; 127.0; 127.3; 127.7; 129.1; 140.1; 140.6; 140.7; 144.6;
151.9.
Minor isomer 1H NMR (400 MHz, CDCl3),
d (ppm): 0.028e0.72
References and notes
(m, 7H), 0.91 (d, 3H, J¼7.07 Hz); 1.16e1.29 (m, 1H); 4.25 (br s, OH);
4.56 (d, 1H, J¼13.5 Hz, overlapping); 5.00 (d, 1H, J¼13.5 Hz, over-
lapping) 7.36e7.61 (m, 4H, overlapping); 7.78 (s, 1H); 7.88 (s, 1H).
MS (EIþ) m/z (%): 267 (2), 266 (18), 265 (100), 197 (3), 196 (1),
182 (53), 180 (1), 168 (29), 154 (13), 82 (14), 69 (11). HRMS [MH]þ
exact mass calcd for C21H23N3O: 334.1914, found: 334.1914.
1. Klix, M. B.; Verreet, J.-A.; Beyer, M. Crop Prot. 2007, 26, 683.
2. (a) Taton, M.; Ullmann, P.; Benveniste, P.; Rahier, A. Pestic. Biochem. Physiol.
1988, 30, 178; (b) Neha Singhal, N.; Sharma, P. K.; Dudhe, R.; Kumar, N. J. Chem.
Pharm. Res. 2011, 3, 126; (c) Sadaba, B.; García-Quetglas, E.; Azanza, J. R. Rev. Esp.
ꢀ
Quimoterap. 2004, 17, 71.
3. (a) Seechurn, C. J.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int.
Ed. 2012, 51, 5062; (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
4. Fitton, P.; Rick, E. A. J. Organomet. Chem. 1971, 28, 287.
4.3.9. 3-Cyclopropyl-2-(40-fluorobiphenyl-4-yl)-1-(1H-1,2,4-triazol-
1-yl)butan-2-ol (14). The product was isolated as colorless oil after
radial chromatography using ethyl acetate. 1H NMR (400 MHz,
ꢀ
5. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359 and references cited therein.
6. Old, D. W.; Wolf, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722.
7. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387.
8. (a) Shen, W. Tetrahedron Lett. 1997, 38, 5575; (b) Cooke, G.; De Cremiers, H. A.;
Rotello, V. M.; Tarbit, B.; Vanderstraeten, P. E. Tetrahedron 2001, 57, 2787.
9. Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 722.
CDCl3),
d
(ppm): 0.015e0.80 (m, 6H), 1.05 (d, 3H, J¼6.62 Hz);
1.21e1.29 (m, 1H); 4.24 (br s, OH); 4.53 (d, 1H, J¼14.03 Hz, over-
lapping); 4.99 (d, 1H, J¼14.03 Hz, overlapping) 7.05e7.56 (m, 8H,
overlapping); 7.78 (s, 1H); 7.88 (s, 1H). 13C NMR (100 MHz, CDCl3),
ꢀ
10. Corsico, E. F.; Rossi, R. A. Synlett 2000, 230.
~ꢀ~
11. (a) Rossi, R. A.; Pierini, A. B.; Penenory, A. B. Chem. Rev. 2003, 103, 71; (b) Rossi,
~ꢀ~
d
(ppm): 3.2; 6.5; 13.7; 14.8; 47.6; 57.5; 79.8; 125.9; 26.8; 127.0;
R. A.; Penenory, A. B. In The Photostimulated SRN1 Process: Reaction of Haloarenes
127.3; 127.7; 129.1; 140.1; 140.6; 140.7; 144.6; 151.9. MS (EIþ) m/z
(%): 284 (1), 283 (16), 282 (100), 264 (3), 249 (1), 214 (2), 200 (7),
199 (54), 186 (6), 185 (43), 82 (38), 69 (11). HRMS [MH]þ exact mass
calcd for C21H22FN3O: 352.1820, found: 352.1823.
with Carbanions, 2nd ed.; Horspool, W. M., Lenel, F., Eds.; CRC Handbook of
Organic Photochemistry and Photobiology; CRC: Boca Raton, USA, 2004; Vol. 47,
p 1; (c) Rossi, R. A. Photoinduced Aromatic Nucleophilic Substitution Reactions
In Synthetic Organic Photochemistry; Griesbeck, A. G., Mattay, J., Eds.; Marcel
Dekker: New York, NY, 2005; p 495; (d) Rossi, R. A.; Pierini, A. B.; Santiago, A. N.
In Organic Reactions; Paquette, L. A., Bittman, R., Eds.; Wiley & Sons: New york,
NY, 1999; 54, p 1.
4.3.10. 3-Cyclopropyl-2-(4-(naphthalen-1-yl)phenyl)-1-(1H-1,2,4-
triazol-1-yl)butan-2-ol (15). The product was isolated as white
solid after preparative thin layer chromatography using dichloro-
~
12. Basso, S. M.; Montanez, J. P.; Santiago, A. N. Lett. Org. Chem. 2008, 5, 633.
13. (a) Pellerito, L.; Nagy, L. Coord. Chem. Rev. 2002, 224, 111; (b) Crowe, A. J. Appl.
Organomet. Chem. 1987, 1, 331.
14. http://www.alanwood.net/pesticides/bitertanol.html.
yloxy)- -(1,1-dimethylethyl)-1H-1,2,4-triazole-1-ethanol known as Bitertanol
is the active metabolite of 6.
b
-([1,10-Biphenyl]-4-
methane/ethyl acetate (75/25). 1H NMR (400 MHz, CDCl3),
d (ppm):
a
0.016e0.77 (m, 7H); 1.12 (d, 3H, J¼6.62 Hz); 1.26 (m, 1H); 4.96 (br s,
OH); 4.53 (d, 1H, J¼14.03 Hz, overlapping); 4.99 (d, 1H, J¼14.03 Hz,
overlapping) 7.11e7.53 (m, 8H, overlapping); 7.78 (s, 1H); 7.88 (s,
15. Hennion, G. F.; McCusker, P. A.; Ashby, E. C.; Rutkowski, A. J. J. Am. Chem. Soc.
1957, 79, 5194.
ꢀ
€
16. Lysen, M.; Kohler, K. Synlett 2005, 1671.
1H). 13C NMR (100 MHz, CDCl3),
d
(ppm): 3.2; 6.6; 13.8; 14.9; 47.7;
17. LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R., Jr. Org. Lett. 2001, 3, 1555.
Please cite this article in press as: Herrera Cano, N.; Santiago, A. N., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.11.067