Selective Generation of (1H-1,2,4-Triazol-1-yl)methyl Carbanion and Condensation with Carbonyl Compounds

Article abstract of DOI:10.1002/ejoc.201701278

2-(1H-1,2,4-Triazol-1-yl)ethanols have received significant interest in agricultural and medicinal chemistry owing to their herbicidal and antifungal activities. To develop a versatile method to access these substituted triazoles, we explored the generation of the (1H-1,2,4-triazol-1-yl)methyl carbanion and its condensation with carbonyl compounds. By judicious choice of a suitable anion precursor (tributylstannyl group) or a stabilizing anion group (phenylsulfanyl or phenylsulfinyl group), a wide range of aldehydes and ketones reacted with the carbanions to give a large diversity of 2-(1H-1,2,4-triazol-1-yl)ethanols in good yields.

Full text of DOI:10.1002/ejoc.201701278

DOI: 10.1002/ejoc.201701278
Communication
Functionalized 1,2,4-Triazoles
Selective Generation of (1H-1,2,4-Triazol-1-yl)methyl Carbanion
and Condensation with Carbonyl Compounds
Pierrik Lassalas,[a] Aurélie Claraz,[a] Gaël Tran,[a] Jean-Pierre Vors,[b] Tomoki Tsuchiya,[b]
Pierre-Yves Coqueron,[b] and Janine Cossy*[a]
Abstract: 2-(1H-1,2,4-Triazol-1-yl)ethanols have received signifi- a suitable anion precursor (tributylstannyl group) or a stabiliz-
cant interest in agricultural and medicinal chemistry owing to ing anion group (phenylsulfanyl or phenylsulfinyl group), a wide
their herbicidal and antifungal activities. To develop a versatile range of aldehydes and ketones reacted with the carbanions to
method to access these substituted triazoles, we explored the give a large diversity of 2-(1H-1,2,4-triazol-1-yl)ethanols in good
generation of the (1H-1,2,4-triazol-1-yl)methyl carbanion and its yields.
condensation with carbonyl compounds. By judicious choice of
Introduction
1,2,4-triazol-1-yl)ethanols A (Scheme 1). The previously reported
syntheses of A relied on the addition of 1,2,4-triazole to epox-
ides[3] or to 2-chloro-1-aryl ethanols[4] as well as the addition of
organometallic reagents to aromatic ꢀ-keto triazoles[5]
[Scheme 1, Equation (1)]. Nevertheless, these processes in-
volved the preparation of a highly sensitive epoxide or were
limited to aromatic substituents, which hamper the discovery
of new potent biologically active 2-(1H-1,2,4-triazol-1-yl)ethanol
derivatives. To implement a more general and versatile method
for the preparation of A, we envisaged the specific generation
of anion B from C [Scheme 1, Equation (2)]. However, as anion
1,2,4-Triazoles and their derivatives were described for the first
time by Bladin et al. in 1885.[1] Owing to their antifungal and
herbicidal activities, the interest in 1,2,4-triazoles has grown ex-
ponentially during these last decades.[2] For example, commer-
cially available 3-amino-1,2,4-triazole exhibits potent herbicidal
activity, cyproconazole and tebuconazole are agricultural fungi-
cides, whereas fluconazole is an antifungal drug (Figure 1).
Figure 1. Biologically active 1,2,4-triazoles.
Considering the biological activities of these compounds, we
were interested in developing an easy method to access 2-(1H-
[a] Laboratory of Organic Chemistry, Institute of Chemistry, Biology and
Innovation (CBI), ESPCI Paris, CNRS (UMR8231), PSL Research University,
10 rue Vauquelin, 75231 Paris Cedex 05, France
E-mail: janine.cossy@espci.fr
https://www.lco.espci.fr/Home
[b] Bayer SAS, Small Molecule Research - Disease Control Chemistry,
14 Impasse Pierre Baizet, 69263 Lyon Cedex 09, France
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701278.
Scheme 1. Preparation of compounds A.
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B′ can be generated under basic conditions, undesired com-
pounds of type A′ can be obtained. Herein, we report the se-
lective reactivity of 1-methylene-1H-1,2,4-triazoles to access
compounds A.
Results and Discussion
Scheme 3. Formation of 6 from 5.
At first, the reactivity of 1-[(trimethylsilyl)methyl]-1H-1,2,4-tri-
azole (1) was investigated. The fluoride-catalyzed reaction of
1 with carbonyl compounds was previously reported by using
tetrabutylammonium fluoride (TBAF) or CsF.[6] However, only
aromatic aldehydes gave satisfactory yields. A mixture of A and
A′ was obtained with aromatic ketones, and competitive forma-
tion of the silyl enol ether was observed with enolizable carb-
onyl compounds. Replacement of the fluoride by a stoichiomet-
ric amount of an alkoxide (e.g., tBuOK or Me3SiOK) did not in-
crease the scope of the reaction.[7] Recently, it was shown that
the combination of Me3SiOK/nBu4NCl allowed the activation of
organotrimethylsilanes through the generation of a carbanion
equivalent that could react with carbonyl derivatives, and this
system was shown to be autocatalytic.[8] Thus, compound 1[9]
was treated with 0.1 equivalents of Me3SiOK/nBu4NBr (in situ
generation of Me3SiO–,nBu4N+) at room temperature in the
presence of benzaldehyde (4a) (Scheme 2). Under these condi-
tions, we were pleased to isolate the desired alcohol 2a in good
yield (71 %). Unfortunately, upon using nonaromatic aldehyde
4b, aromatic ketones 4c–e, and aliphatic ketone 4f, only desilyl-
ated product 3 was formed and compounds A were not iso-
lated.
in the transmetalation process, the addition of benzaldehyde
(4a) at –78 °C did not lead to alcohol 8a but to 9 in 62 % yield.
This unexpected product presumably arose from rapid 1,3-
Brook rearrangement of transient lithiated species
D
(Scheme 4).[12]
Scheme 4. Formation of 9 from 7 through a 1,3-Brook rearrangement.
The Brook rearrangement was efficiently slowed down by
decreasing the temperature to –98 °C, but an inseparable mix-
ture of compounds 8a/9 in a 1.3:1 ratio was still obtained. De-
lightfully, this ratio was improved to 9.5:1 by the addition of
benzaldehyde (4a) immediately after treatment of 7 with nBuLi.
These conditions enabled the isolation of desired product 8a in
76 % yield (Scheme 5).
Scheme 2. Me3SiOK/nBu4NBr-catalyzed condensation of 1 with carbonyl de-
rivatives 4.
Owing to the limited reactivity of 1 towards carbonyl deriva-
tives, the generation of carbanion B from 1-[(tributylstannyl)-
methyl]-1H-1,2,4-triazole (5) by metal–metal exchange was ex-
amined. Triazole 5[10] was treated with a stoichiometric amount
of nBuLi at –78 °C in THF, and after 5 min, benzaldehyde (4a)
was added. After 30 min at –78 °C, 2a was not obtained, but
alcohol 6 was isolated in 47 % yield (Scheme 3).
Scheme 5. Improvement of the reaction conditions to synthesize 8a from 7.
To circumvent this competitive deprotonation at C5, the C5
position of 5 was protected by a tert-butyldimethylsilyl (TBS)
Notably, the C5–Si bond of isolated alcohol 8a could be
group. Surprisingly, if TBS-protected triazole 7[11] was involved cleaved by a 1,5-Brook rearrangement (intermediate E) by treat-
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ment with potassium hexamethyldisilazane (KHMDS) (1 equiv.),
and TBS-protected alcohol 10a was obtained in 65 % yield
(Scheme 6).[13] Alternatively, 2a could be isolated in 59 % yield
if 8a was treated with TBAF.
Table 1. Reactivity of 7 with different carbonyl derivatives 4.
Scheme 6. Desilylation of C5 in 8a.
Other aldehydes and ketones were involved in the condensa-
tion process. The results are summarized in Table 1. Aliphatic
aldehyde 4b was unreactive (Table 1, entry 2), but aromatic and
heteroaromatic ketones led to 8 in moderate to good yields (45
to 62 %) (Table 1, entries 3–6). Noteworthy, enolizable ketones
4d and 4f were well tolerated. Nevertheless, if sterically hin-
dered ketones 4g and 4h were used, corresponding triazoles 8
were not formed (Table 1, entries 7 and 8).
As carbanions can be stabilized by a phenylsulfanyl group,[14]
we turned our attention to the generation of a phenylthio-sta-
bilized carbanion by deprotonation of 1-phenylthio-1H-1,2,4-tri-
azole[15] derivatives with nBuLi at –78 °C, and to avoid deproto-
nation at the C5 position,[16] the reactivity of 11[17] was consid-
ered. A representative set of aldehydes and ketones were tested
as electrophiles. The reaction proved to be quite general, and
the results are depicted in Table 2. Notably, sterically hindered
aromatic and aliphatic ketones 4g and 4h afforded the corre-
sponding alcohols 12 in good yields (Table 2, entries 7 and 8).
However, a limitation was observed with enolizable aliphatic
aldehyde 4b (Table 2, entry 2).
To transform 12 into compounds A, 12d was used as a
model substrate to realize the desulfurization. Treatment of 12d
with a large excess amount of Raney nickel in EtOH resulted in
sulfide 13d as the only isolable product (40 %). Triazole 2d was
eventually obtained in 67 % yield from 13d after treatment
with in situ generated Ni2B (from NiCl2·6H2O/NaBH4)[18]
(Scheme 7).[19]
mixture was too complex for structural determination, the re-
duction of crude sulfoxide 15 to sulfide 13 was directly realized
Scheme 7. Desulfurization of 12d.
To increase the stability of the anion and to avoid protection by using Zn/TiCl4.[21] The results are reported in Table 3. The
of the triazole at C5, sulfoxide 14[20] was evaluated as a carb- condensation of 14 with a wide range of aromatic and aliphatic
anion precursor. After treatment of 14 with LiHMDS at –78 °C aldehydes (Table 3, entries 1 and 2) and aromatic and
for 20 min, carbonyl derivatives 4 were added to the reaction enolizable ketones (Table 3, entries 4–7 and 9) was possible.
media. Owing to the presence of three stereogenic centers in Nevertheless, no reaction occurred with highly sterically
15, a complex mixture of diastereomers was obtained. If this hindered aromatic ketones 4c and 4g (Table 3, entries 3 and 8).
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Table 2. Reactivity of 11 with different carbonyl derivatives 4.
Table 3. Reactivity of 14 with different carbonyl derivatives 4.
[a] The diastereomeric ratios were determined by analysis of the crude mate-
rial by 1H NMR spectroscopy.
[a] The diastereomeric ratios were determined by analysis of the crude mate-
rial by 1H NMR spectroscopy.
Noteworthy, 15d could be isolated in 95 % yield, and direct
treatment of nonpurified 15d with Zn/TiCl4 afforded 13d in
92 % yield over two steps from 14, which proved that the re-
duction was nearly quantitative (Table 3, entries 4 and 5).
ment with NiCl2·6H2O/NaBH4 as described previously. The re-
Compounds 13b, 13d, and 13e were transformed in good sults of this reductive cleavage of the C–S bond are summarized
yields into compounds 2b, 2d, and 2e, respectively, by treat- in Scheme 8.
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with Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel) to afford 15.
Synthesis of 13 from Crude Residue 15: To a stirred suspension
of Zn in THF at 5 °C was added dropwise TiCl4, and the resulting
mixture was stirred for 30 min at 5–10 °C. Crude residue 15 was
added, and the resulting solution was stirred at 10–15 °C for 3 h.
After complete consumption of the starting material (monitored by
TLC), H2O was added, and the aqueous phase was extracted with
Et2O (3 ×). The combined organic layer was washed with a saturated
aqueous solution of NaHCO3 and brine, dried with Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (silica gel) to afford 13.
Scheme 8. Desulfurization of 13.
Acknowledgments
Conclusions
Bayer-CropScience is acknowledged for financial support.
In conclusion, we showed that 2-(1H-1,2,4-triazol-1-yl)ethanol
derivatives A could be obtained selectively by generation of the
(1H-1,2,4-triazol-1-yl)methyl carbanion. Among the precursors,
1-[(trimethylsilyl)methyl]-, 1-[(tributylstannyl)methyl]-, 1-[(phe-
nylsulfanyl)methyl], 1-[(phenylsulfinyl)methyl]-1H-1,2,4-triazoles,
and 1-[(phenylsulfinyl)methyl]-1H-1,2,4-triazoles were the best
to access a large diversity of 2-(1H-1,2,4-triazol-1-yl)ethanols 2
in good yields. We believe that, in the future, such a method
will find useful applications in the synthesis of new biologically
active compounds.
Keywords: Heterocycles · Carbanions · Deprotonation ·
Ketones · Aldehydes
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[10] See the Supporting Information for the synthesis of 5.
[11] See the Supporting Information for the synthesis of 7.
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Experimental Section
General Procedure for Table 1: To a stirred solution of 5-(tert-
butyldimethylsilyl)-1-[(tributylstannyl)methyl]-1H-1,2,4-triazole (7)
(1.17 equiv.) in THF at –98 °C was added dropwise nBuLi
(1.18 equiv.). Instantly, the solution turned yellow. Immediately at
the end of the addition, a solution of electrophile 4 (1 equiv.) in
THF was added dropwise at –98 °C, and the resulting solution was
stirred for 30 min at the same temperature. A saturated aqueous
solution of NH4Cl was added at –98 °C, and the mixture was
warmed up to room temperature. The aqueous phase was extracted
with EtOAc (3 ×). The combined organic layer was dried with
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (silica gel) to afford 8.
General Procedure for Table 2: To a stirred solution of 5-(methyl-
sulfanyl)-1-[(phenylsulfanyl)methyl]-1H-1,2,4-triazole (11) (1 equiv.)
in THF at –78 °C was added dropwise nBuLi (1.1 equiv.), and the
resulting bright yellow solution was stirred for 5 min. Electrophile
4 (1.2 equiv.) was added dropwise at –78 °C, and the resulting solu-
tion was stirred for 1 h. A saturated aqueous solution of NH4Cl
was added at –78 °C, and the mixture was warmed up to room
temperature. The aqueous phase was extracted with EtOAc (3 ×).
The combined organic layer was washed with brine, dried with
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (silica gel) to afford 12.
General Procedure for Table 3: To a stirred solution of 1-[(phenyl-
sulfinyl)methyl]-1H-1,2,4-triazole (14) (1 equiv.) in THF at –78 °C was
added dropwise LiHMDS (1.25 equiv.). After stirring for 20 min, elec-
trophile 4 (1.3 equiv.) was added dropwise at –78 °C, and the result-
ing solution was stirred for 2.5 h. A saturated aqueous solution of
NH4Cl was added at –78 °C, and the mixture was warmed up to
room temperature. The aqueous phase was extracted with EtOAc
(3 ×). The combined organic layer was washed with brine, dried
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[16] S. Shimizu, M. Ogata, Tetrahedron 1989, 45, 637–642.
[17] See the Supporting Information for the synthesis of 11.
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[19] Notably, the direct desulfurization of 12d with in situ generated Ni2B
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of NaH, the resulting sulfide derivative was oxidized to sulfoxide 14 with
NaIO4 (see the Supporting Information for more details).
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ment of 1,2,4-triazole with chloromethyl phenyl sulfide in the presence
Received: September 12, 2017
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