Synthesis of novel 1,2,4-trizaole- and isoxazol(in)e-containing heterocycles

Article abstract of DOI:10.1016/j.tetlet.2016.06.034

A route for the regiospecific synthesis of 3-(triazol-3-yl)-1,2-isoxazol(in)e-5-yl-aryl derivatives has been developed by intermolecular 1,3-dipolar cycloaddition chemistry, and novel annulated compounds having triazole/isoxazole have been prepared by emp

Full text of DOI:10.1016/j.tetlet.2016.06.034

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel 1,2,4-trizaole- and isoxazol(in)e-containing
heterocycles
⇑
Alicia K. Franzen, William J. Marshall, Kyung-Ho Park
DuPont Central Research and Development, E. I. duPont de Nemours and Company, Experimental Station, PO Box 8352, Wilmington, DE 19880, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A route for the regiospecific synthesis of 3-(triazol-3-yl)-1,2-isoxazol(in)e-5-yl-aryl derivatives has been
developed by intermolecular 1,3-dipolar cycloaddition chemistry, and novel annulated compounds hav-
ing triazole/isoxazole have been prepared by employing intramolecular nitrile oxide 1,3-dipolar
cycloaddition.
Received 12 May 2016
Revised 7 June 2016
Accepted 8 June 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Triazole
Isoxazole
Isoxazoline
Aldoxime, nitrile oxide
1
,3-Dipolar cycloaddition
Annulated ring system
The triazole heterocycle has played an important role in agro-
chemical and medicinal2 applications. Similarly, the isoxazol(in)
e moiety has been employed extensively to modulate the biolog-
A retrosynthetic analysis of the targeted structure 2 is shown in
1
Scheme 2. The desired isoxazole can be obtained via the nitrile
3
7
oxide 1,3-dipolar cycloaddition reaction of key intermediate
ical activity of various other motifs, including triazoles. Thus, isox-
azole-containing triazoles have been prepared previously by
several groups for biological evaluation.4 For example, as shown
aldoxime 3 with alkyne derivatives. 1,2,4-Triazoles functionalized
with aldoxime at the 5-position are typically prepared from the
corresponding aldehydes 4, which are synthesized by oxidation
5
8
in Scheme 1, 4-(triazol-5-yl)-1,2-isoxazol-5-yl-aryl derivatives 1
of the alcohol derived from the starting triazole 5.
have been prepared using triazole and methyl benzoate derivatives
as starting materials. The heterocycle isoxazole was introduced in
the last step via replacement of dimethyl amine with hydroxy-
lamine, followed by ring closure. The resulting class of isoxazole-
containing triazoles exhibited insecticidal and acaricidal activities.
As part of our efforts in the preparation and biological evalua-
tion of novel heterocycles containing both triazoles and isoxazol
As depicted in Scheme 3, our initial attempts to prepare alde-
hyde 10 included the oxidation of primary alcohol 9, which can
be obtained from the reduction of the corresponding acid 8. To pre-
9
pare this acid, triazole 6 was treated with n-BuLi followed by car-
bon dioxide at À78 °C to afford lithium carboxylate 7. However,
upon neutralization of this lithium salt using hydrochloric acid,
the resultant acid 8 proved unstable, losing carbon dioxide and
reverting back to the starting material 6 in almost quantitative
yield. Even in the absence of HCl, it was observed that the isolated
solid lithium salt 7 slowly converted back to the starting material 6
due to moisture sensitivity.
To avoid undesirable decarboxylation, the lithium salt 7 was
neither acidified nor isolated. Instead, in situ methylation was
employed to afford the stable methyl ester 11. The desired for-
myl-substituted triazole 10 was then obtained via reduction of
(
1
in)es, we were interested in the triazole/isoxazole regioisomer of
, and disclose herein a useful route for the synthesis of 3-(tria-
zol-3-yl)-1,2-isoxazol-5-yl-aryl derivatives 2. Furthermore, 2 can
introduce additional molecular diversity at the 4-position of the
6
isoxazole via bromination followed by Suzuki cross-coupling.
The 3-position of the isoxazole in 1 is inert to halogenation and
therefore is unable to undergo a similar type of transformation
(Fig. 1).
1
1 with LAH to afford alcohol 9, followed by Swern oxidation
(Scheme 4).
⇑
Corresponding author. Tel.: +1 302 529 5887.
E-mail address: kyunghopark19@hotmail.com (K.-H. Park).
http://dx.doi.org/10.1016/j.tetlet.2016.06.034
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0
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2
A. K. Franzen et al. / Tetrahedron Letters xxx (2016) xxx–xxx
R1
N
R2
R2
N
N
N
Me N
R2
R1
2
O
R1
R1
Ph
n-BuLi
THF
N
R2
N
N
+
N
N
O
N
N
MeO
MeO
N
O
N
NH OH.HCl
NMe2
2
MeO
Ph
Ph
Ph
1
O
Scheme 1. Route to 4-(triazol-5-yl)-1,2-isoxazol-5-yl-aryl derivatives.
2
N
O1
3
R2
2
R1
N
N
1
N
4
R2
O
N
N
4
5
3
5
N
N
Ph
R1
Ph
-(Triazol-5-yl)-1,2-isoxazol-5-yl-aryl
1
2
4
3-(Triazol-3-yl)-1,2-isoxazol(in)-5-yl-aryl
Figure 1. Regioisomer 2 (triazol-3-yl & 3,5-disubstituted isoxazole), compared with 1 (triazol-5-yl & 4,5-disubstituted isoxazole).
N
OH
N
N
N
R2
N
N
N
N
O
N
N
N
N
N
CHO
N
H
Ph
Ph
Ph
R1
R1
R1
Ph
R1
2
3
4
5
+
R2
Scheme 2. Retrosynthetic analysis of targeted structure 2.
OH
O
LiO C
N
2
N
N
N
N
1
.
N
N
moisture
LiOH
N
N
n-BuLi
N
N
N
-
CO2
o
-
78 C
THF
2
.
8
6
CO2
7
6
HCl
H
OH
N
N
O
HO C
2
N
-
CO2
Swern
oxidation
N
N
N
LAH
N
N
N
1
0
9
8
Scheme 3. Attempt to introduce an aldehyde functional group at the 5-position of 1,2,4-triazole.
Subsequently, a much more straightforward protocol10 employ-
line derivative 16 (Scheme 5, Table 1). To reduce the amount of
dimerized adduct 14, an excess of dipolarophile (10 equiv) was
used at room temperature.
ing n-BuLi/DMF was applied to introduce the formyl group at the
triazole 5-position. Thus, triazole 6-a11 was converted to 10-a in
a single step in 75% yield. Reaction of the aldehyde-containing tri-
azoles 10 and 10-a with hydroxylamine and triethylamine afforded
the corresponding precursor aldoximes 12 and 12-a in good yield.
Utilizing the Husigen method,7 nitrile oxide 13 was generated
in situ in the presence of bleach; this allowed for 1,3-dipolar
cycloadditions to be carried out with several dipolarophiles, pro-
viding 15 (e.g., the targeted regioisomer 2), along with its isoxazo-
Due to the dominance of steric over electronic effects, nitrile
oxides generally undergo 1,3-dipolar cycloaddition reactions with
terminal alkynes or alkenes to afford 3,5-disubsituted
isoxazoles or isoxazolines, respectively, as the major regioisomers.
It has been previously reported that exclusive formation of 3,5-dis-
ubstituted isoxazoles can be achieved via copper(I)-catalyzed
1
2
1,3-dipolar cycloaddition to terminal alkynes. On the other hand,
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A. K. Franzen et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
MeO C
LiO C
2
2
N
N
1
.
N
1
2
. removing THF
N
N
n-BuLi
N
N
N
N
MeI
CO2
THF
.
DMF
1
1 70%
6
7
LAH
THF
one pot reaction
H
O
OH
N
N
N
Swern
oxidation
N
N
N
1
0
86%
9 60%
Scheme 4. Preparation of triazole 10 functionalized with a formyl group at the 5-position.
R1
HO
N
-O
H
H
O
N+
Ph
N
N
N
NaOCl
N
N
NH OH.HCl
N
N
N
O
N
2
N
N
N
N
N
Et N
3
O
R1
R1
R1
N
N
N
12 (R1 = isopropyl), 82%
12-a (R = phenyl), 88%
1
1
0 (R1 = isopropyl)
0-a (R = phenyl)
1
3
R1 Ph
1
1
7
5%
14
R2
R2
N
1
2
. n-BuLi
. DMF
R2
O
N
O
N
R2
N
N
N
N
N
N
N
N
R1
-a (R1 = phenyl)
Scheme 5. Route to 3-(triazol-3-yl)-1,2-isoxazol(in)-5-yl-aryl derivatives 15 and 16.
R1
R1
6
1
5
16
Table 1
3
-(Triazol-3-yl)-1,2-isoxazol(in)-5-yl-aryl derivatives 15 and 16
Compound
R1
R2
Yielda (%)
1
1
1
1
1
1
1
1
1
5-a
5-b
5-c
5-d
5-e
5-f
5-g
5-h
6
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Ph
Ph
Ph
Ph
Isopropyl
Ph
3-Pyridyl
2-F-Ph
2-Pyridyl
4-NC-Ph
4-N,N-Dimethyl-Ph
3-MeO-Ph
Biphenyl
Ph
67
68
64
70
66
69
80
72
89
a
Isolated yield.
Figure 2. X-ray structure of 3,5-disubstitued isoxazoline (compound 16).
3
,4-disubstituted isoxazoles are formed as the major regioisomers
13
in ruthenium(II)-catalyzed 1,3-dipolar cycloadditions. In our syn-
thesis, even without the aforementioned Cu(I) catalyst, 3,5-disub-
stituted regioisomers were observed exclusively. The connectivity
With this 1,3-dipolar cycloaddition methodology in hand, we
undertook the construction of novel annulated ring systems con-
taining both isoxazol(in)e and triazole moieties tethered together
about a central pyridine-derived core. As illustrated in Scheme 6,
1
7
of compound 16 was confirmed via X-ray crystallography (Fig. 2).
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4
A. K. Franzen et al. / Tetrahedron Letters xxx (2016) xxx–xxx
OHC
N
N
N
1.
n-BuLi, THF
N
N
NH .TFA
N
O
2
N
N
2
.
DMF
1
,2-dichlorobenzene
17
1
1
8 (N-homoallyl) 31%
8-a (N-homopropargyl) 14%
19 (N-homoallyl) 76%
19-a (N-homopropargyl)18%
NH OH.HCl
2
NaOAc
THF/MeOH/H O
2
-O
HO
O
N
O
N
N+
C
N
N
C
N
N
H
N
NaOCl
THF
N
N
N
N
N
N
N
N
22 47%
22-a 68%
2
1 (N-homoallyl)
20 (N-homoallyl) 57%
20-a (N-homopropargyl)71%
2
1-a (N-homopropargyl)
Scheme 6. Route to novel annulated ring systems 22 and 22-a containing both isoxazol(in)e and triazole tethered together about a central pyridine-derived core.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.06.
0
34. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
Figure 3. X-ray structure of annulated heterocycle (compound 22) containing both
isoxazoline and triazole about a central pyridine-derived core.
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3.
we designed the synthetic route to the fused heterocyclic com-
pounds to include an intramolecular nitrile oxide cycloaddition
4. (a) Khanage, S.; Mohite, P.; Pandhare, R.; Appala, R. Marmara Pharm. J. 2012, 16,
134; (b) Granberg, K.; Holm, B. WO 2009054791 A1 20090430.; (c) Isaac, M.;
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Dallas, J. L.; Kurth, M. J. ACS Comb. Sci. 2012, 14, 280.
1
4
(
INOC) as the key step. We began our efforts by preparing
9
N-homoallyl substituted triazole 18 from oxadiazole 17.
Compound 19, containing a formyl group at the 5-position of the
triazole, was synthesized in good yield (76%) via lithiation of 18
followed by treatment with DMF. However, attempts at formylat-
ing 18-a, which contains an N–homopropargyl group, under the
same conditions resulted primarily in decomposition to an
5
.
(a) Braun, R.; Willms, L.; Heinemann, I.; Hauserhaha, I.; Dietrich, H.; Gatzweiler,
E.; Rosinger, C.; WO 2013104705 A1 20130718.; (b) Shibata, Y; Aoyagi, K.;
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(a) Sakakibara, T.; Kume, T.; Hase, T. Chem. Express 1989, 4, 85; (b) Organ, M. G.;
Alimsiz, S. C.; Sayah, M.; Hoi, K. H.; Lough, A. J. Angew. Chem., Int. Ed. 2009, 48,
2383.
6.
7.
8.
9.
Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984; Vol. 2, p 1.
Ahmad, N. M. In Name reactions for Functional Group Transformations; Li, J. J.,
Corey, E. J., Eds.; John Wiley & Sons, Inc.: New Jersey, 2007; p 291.
Chen, X.; Liu, R.; Xu, Y.; Zou, G. Tetrahedron 2012, 68, 4813.
1
N-unsubstituted triazole 5 (R = H) and a low yield of 19-a.
Subsequent formation of aldoximes 20 and 20-a from correspond-
ing 19 and 19-a, followed by intramolecular nitrile oxide cycload-
dition of in situ formed 21 and 21-a, afforded the annulated
heterocycles 22 and 22-a, respectively. The structure of the annu-
lated compound 22 was confirmed via X-ray crystallography
10. Jacques, B.; Eloi, A.; Chavarot-Kerlidou, M.; Rose-Munch, F.; Rose, E.; Gerard,
H.; Herson, P. Organometallics 2008, 27, 2505.
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241; Padwa, A., Pearson, W. H., Eds.; Synthetic Applications of 1,3-Dipolar
2
1
7
(Fig. 3).
1
In conclusion, routes for the regiospecific synthesis of 3-(tria-
1
5
3
zol-3-yl)-1,2-isoxazol(in)e-5-yl-aryl derivatives (15, 16)
and
novel annulated compounds (22, 22-a)16 have been developed,
Cycloaddition Chemistry toward Heterocyles and Natural Products 2002, 407.
5. General procedure for the Synthesis of 3-(traizol-3-yl)-1,2-isoxazol-5-yl-aryl
derivatives 15 or 16: To the solution of aldoxime (12, 0.648 mmol) and
dipolarophile (10 equiv) in THF (8 mL) was added bleach (NaOCl; 6.15%,
1
employing intermolecular and intramolecular nitrile oxide 1,3-
dipolar cycloadditions, respectively. Exploiting this methodology,
the construction of compound libraries as well as the evaluation
of biological activities are underway.
2
.5 equiv) slowly for 20 min at rt. The reaction mixture was stirred at rt for 2 h,
then the resultant mixture was treated with ethyl acetate and water. The
organic layer was separated, dried (MgSO ), and purified by column
4
chromatography using hexane and ethyl acetate as an eluent to provide pure
product 15 or 16.
6. Procedure for the Synthesis of 3-phenyl-5,6,6a,7-tetrahydro[1,2]oxazolo[3,4-c]
Acknowledgements
1
[
1,2,4]triazolo[4,3-a][yridine (22): To the solution of aldoxime (20, 0.3 g,
We thank Dr. J Feldman for copy-editing this manuscript.
1.24 mmol) in THF (10 mL) was added bleach (NaOCl; 6.15%, 2.5 equiv)
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A. K. Franzen et al. / Tetrahedron Letters xxx (2016) xxx–xxx
dropwise via a syringe at room temperature. The reaction mixture was stirred
2.08–1.99 (m, 1H). 13C NMR (125 MHz, CD
5
2
Cl
2
): d 156.02, 149.59, 145.81,
at rt for 2 h, then the resultant mixture was treated with ethyl acetate and
131.93, 130.23, 129.80, 127.29, 75.48, 46.41, 45.72, 27.87.
17. Crystallographic data for the structures in this paper have been deposited at
the Cambridge Crystallographic Data Centre as supplementary publication nos.
CCDC #1430300 and 1430301. Copies of these data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk or via www.ccdc.cam.ac.
uk/conts/retrieving.html.
water. The organic layer was extracted with ethyl acetate (3 Â 30 mL), dried
(
4
MgSO ), and concentrated under reduced pressure. The resultant solid was
stirred with small amount of ethyl acetate (10 mL), then filtered to provide
pure product 22 as a solid (0.14 g, 47% yield). mp: 253–254 °C (decom), LC/MS:
+
1
m/z 241.1 (M +1), H NMR (500 MHz, CD
2 2
Cl ): d 7.78–7.76 (m, 2H), 7.60–7.58
(
m, 3H), 4.90 (m, 1H), 4.38–4.30 (m, 2H), 3.90–3.84 (m, 2H), 2.57–2.52 (m, 1H),
Please cite this article in press as: Franzen, A. K.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.034