Functionalization of 1,3,4-Oxadiazoles and 1,2,4-Triazoles via Selective Zincation or Magnesiation Using 2,2,6,6-Tetramethylpiperidyl Bases

Article abstract of DOI:10.1021/acs.orglett.0c00238

We report the metalation of the 1,3,4-oxadiazole and 1,2,4-triazole scaffolds via regioselective zincation or magnesiation using the TMP bases (TMP = 2,2,6,6-tetramethylpiperidyl) TMP₂Zn·2LiCl, TMP₂Zn·2MgCl₂·2LiCl, TMPMgCl

Full text of DOI:10.1021/acs.orglett.0c00238

This is an open access article published under an ACS AuthorChoice License, which permits
copying and redistribution of the article or any adaptations for non-commercial purposes.
pubs.acs.org/OrgLett
Letter
Functionalization of 1,3,4-Oxadiazoles and 1,2,4-Triazoles via
Selective Zincation or Magnesiation Using 2,2,6,6-
Tetramethylpiperidyl Bases
́
̈
̈
Kuno Schwarzer, Carl Phillip Tullmann, Simon Graßl, Bartosz Gorski, Cara E. Brocklehurst,
and Paul Knochel*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00238
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We report the metalation of the 1,3,4-oxadiazole and 1,2,4-triazole scaffolds via regioselective zincation or
magnesiation using the TMP bases (TMP = 2,2,6,6-tetramethylpiperidyl) TMP2Zn·2LiCl, TMP2Zn·2MgCl2·2LiCl, TMPMgCl·LiCl,
and TMPZnCl·LiCl under mild conditions in THF. Subsequent trapping with various electrophiles including hydroxylamino
benzoates gives access to functionalized heterocycles while tolerating many functional groups.
These heterocycles have also been utilized as functional
ubstituted five-membered heterocycles such as function-
Salized 1,3,4-oxadiazoles and 1,2,4-triazoles are common materials such as electron-transporting, hole-blocking materials
in the construction of organic light-emitting diodes (OLEDs).6
Most synthetic approaches toward functionalized 1,3,4-
oxadiazoles and 1,2,4-triazoles involve a late-stage formation
of the heterocycle starting from a properly substituted
precursor.7 In consequence, the installation of various
substituents may require multiple precursors, which compli-
cates medicinal screening experiments. Therefore, we envi-
sioned a more general approach involving the metalation of
these scaffolds followed by trapping reactions with electro-
philes. However, the metalation of 1,3,4-oxadiazole has not yet
been reported, and in the case of N-substituted 1,2,4-triazoles,
only the lithiation with BuLi is known from the literature.8
Previously, we have demonstrated that sterically hindered
TMP-magnesium bases (TMP = 2,2,6,6-tetramethylpiperidyl)
such as TMPMgCl·LiCl (5) or TMP2Mg·2LiCl (6) and TMP-
zinc bases like TMPZnCl·LiCl (7), TMP2Zn·2LiCl (8),
structural moieties in pharmaceutical compounds (Figure 1).1
Examples include raltegravir (1)2 and maraviroc (2),3 which
are used for the treatment of HIV, the iron chelator deferasirox
(3),4 as well as alprazolam (4),5 which is used in the
medication of anxiety disorders.
Received: January 16, 2020
Figure 1. Pharmaceuticals containing a 1,3,4-oxadiazole or 1,2,4-
triazole ring.
https://dx.doi.org/10.1021/acs.orglett.0c00238
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
TMP2Zn·2MgCl2·2LiCl (9), or TMPZnOPiv·LiCl (10) allow
the metalation of a range of different heterocycles under mild
conditions while tolerating a variety of functional groups.9
Therefore, we envisioned a selective double functionalization
of 1,3,4-oxadiazole (11) and N-substituted 1,2,4-triazoles (12)
using TMP bases (Scheme 1).
prepared base TMP2Zn·2MgCl2·2LiCl (9),10 resulting in a
complete zincation within 20 min at 25 °C (Scheme 3). The
Scheme 3. Zincation of Monosubstituted 1,3,4-Oxadiazoles
of Type 14 Using TMP2Zn·2MgCl2·2LiCl (9) Followed by
Electrophilic Amination Leading to Aminated 1,3,4-
Oxadiazoles of Type 16
Scheme 1. Stepwise Functionalization of 1,3,4-Oxadiazole
(11) and N-Substituted 1,2,4-Triazoles of Type 12 Using
a
the TMP Bases 8, 9, and 5
a
R = Pr, Bn.
Preliminary studies have shown that in the case of 1,3,4-
oxadiazole (11) the freshly prepared base TMP2Zn·2LiCl
(8)10 provided the best results, leading to a complete
conversion after 5 min at 25 °C.11 The resulting zincated
1,3,4-oxadiazole 13 was subsequently submitted to Negishi
cross-coupling (Scheme 2).12 A mixture of Pd(dba)2 (3 mol
Scheme 2. Zincation of 1,3,4-Oxadiazole (11) Using
TMP2Zn·2LiCl (6) Followed by Negishi Coupling Leading
to Monosubstituted 1,3,4-Oxadiazoles of Type 14
a
Isolated yields of analytically pure product.
zincated heterocycles 15 were then aminated at 25 °C using
hydroxylamino benzoates15a,b in the presence of 15% Cu-
(OTf)2, providing a variety of aminated 1,3,4-oxadiazoles of
type 16 in 54−98% yield.15 This sequence proceeded well with
both electron-rich (16b, 16f, 16i, 16j) as well as electron-
deficient (16c, 16d, 16h) 1,3,4-oxadiazoles. The scope of
hydroxylamino benzoates was also explored, including reagents
derived from morpholine, diallyl amine, azepane, and
piperazine, leading to the products 16a−16g in 70−98%
yield. In addition, a variety of amines bearing functional groups
such as an ester (16h), a protected ketone (16i−16j), or an
amide (16k) could be prepared in 79−94% yield.
a
b
Isolated yields of analytically pure product. Using 7.5% Pd(PPh3)4
In the case of N-propyl and N-benzyl 1,2,4-triazoles (12a,b),
complete magnesiation was achieved within 30 min at 0 °C
using TMPMgCl·LiCl (5) (Scheme 4). The resulting
magnesiated triazoles of type 17 were trapped with a variety
of electrophiles such as iodine, allylic bromides, benzaldehyde,
and benzoyl chloride, providing the 5-substituted 1,2,4-
triazoles 18a−18h in 79−95% yield. In addition, a metalation
with TMPZnCl·LiCl (7) under the same conditions enabled
Pd-catalyzed Negishi cross-couplings with both electron-rich
(18i−18j) as well as electron-poor aryl halides (18k) in 78−
94% yield. Finally, zincation followed by copper-catalyzed
electrophilic amination with hydroxylamino benzoates derived
from morpholine, nipecotic acid, and sertraline16 led to the 5-
aminated 1,2,4-triazoles 18l, 18m, and 18n in 70−95% yield.
To prepare fully functionalized 1,2,4-triazoles of type 19,
two approaches have been developed (Scheme 5). On one
hand, a double magnesiation of N-propyl 1,2,4-triazole (12a)
was achieved by using an excess of TMPMgCl·LiCl (7, 4.0
at 50 °C.
%) and XantPhos13 (3 mol %) provided excellent results with a
variety of electron-poor aryl iodides at 25 °C, producing the
desired cross-coupling products 14a−14e, 14h, and 14i in 73−
98% yield. When employing electron-rich aryl iodides,
14
Pd(PPh3)4 (7.5 mol %) was the best catalyst and afforded
the heterocycles 14f and 14g in 63−90% yield (50 °C, 2 h).
Due to the relatively low reactivity of the intermediate
organozinc species 13, various functional groups were
tolerated, including an ester (14b), a chloride (14c), a nitrile
(14d), an amine (14g), and a nitro group (14h). In addition,
heterocyclic iodides, such as 6-iodoquinoline and 2-iodothio-
phene, have been successfully coupled, providing the hetero-
cycles 14j and 14k in 92% yield.
With the monosubstituted 1,3,4-oxadiazoles of type 14 in
hand, we performed a second metalation using the freshly
B
https://dx.doi.org/10.1021/acs.orglett.0c00238
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Using the N-2-iodobenzyl-protected 1,2,4-triazole 12c, a
copper-catalyzed cyclization was performed after a zincation
with TMPZnCl·LiCl (7, 1.5 equiv, 0 °C, 30 min, Scheme 6).
The cyclization was completed after 18 h at 40 °C and afforded
5H-[1,2,4]triazolo[5,1-a]isoindole17 (20) in 94% yield.
Scheme 4. Metalation of N-Substituted 1,2,4-Triazoles of
Type 12 Using TMPMgCl2·LiCl (5) Followed by
Electrophile Trapping Leading to Functionalized 1,2,4-
Triazoles of Type 18
Scheme 6. Copper-Catalyzed Cyclization of a Zincated
1,2,4-Triazole
In summary, we achieved the full functionalization of both
1,3,4-oxadiazole (11) as well as 1,2,4-triazoles (12) utilizing
the sterically hindered TMP-magnesium and TMP-zinc bases
TMP2Zn·2LiCl (8), TMP2Zn·2MgCl2·2LiCl (9), TMPMgCl·
LiCl (5), and TMPZnCl·LiCl (7). The metalations were
achieved under mild conditions (0 or 25 °C) in THF, and the
subsequent trappings with various electrophiles, including
electrophilic amination reagents, gave access to substituted
heterocycles while tolerating many functional groups. Further
extensions are currently explored in our laboratories.
a
b
Isolated yields of analytically pure product. Zincation using
TMPZnCl·LiCl (7) and subsequent cross-coupling catalyzed with
c
ASSOCIATED CONTENT
* Supporting Information
5% Pd(OAc)2 and 10% SPhos. Zincation using TMPZnCl·LiCl (7)
■
sı
and subsequent amination catalyzed with 15% Cu(OTf)2.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00238.
Scheme 5. Double Functionalization of N-Propyl 1,2,4-
Triazole (12a) Leading to Fully Functionalized 1,2,4-
Triazoles of Type 19
Additional screening data, experimental procedures, and
1
compound characterization data, including copies of H
and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Paul Knochel − Department Chemie, Ludwig-Maximilians-
̈
̈
̈
Universitat Munchen, 81377 Munchen, Germany;
orcid.org/0000-0001-7913-4332; Email: paul.knochel@
cup.uni-muenchen.de
Authors
Kuno Schwarzer − Department Chemie, Ludwig-Maximilians-
̈
̈
̈
̈
Universitat Munchen, 81377 Munchen, Germany
Carl Phillip Tu
̈
llmann − Department Chemie, Ludwig-
̈
̈
̈
Maximilians-Universitat Munchen, 81377 Munchen, Germany
Simon Graßl − Department Chemie, Ludwig-Maximilians-
Universitat Munchen, 81377 Munchen, Germany
Bartosz Gorski − Faculty of Chemistry, University of Warsaw,
02-093 Warsaw, Poland
a
Isolated yields of analytically pure product.
̈
̈
̈
́
Cara E. Brocklehurst − Global Discovery Chemistry, Novartis
Institutes for BioMedical Research, 4057 Basel, Switzerland;
orcid.org/0000-0002-0484-5540
equiv, 0 °C, 30 min). Subsequent trapping with cyclohexyl
bromide provided the double allylated triazole 19a in 73%
yield. Also, transmetalation to zinc followed by a Negishi cross-
coupling with 4-iodoanisole led to the formation of the double
arylated triazole 19b in 52% yield. On the other hand, a second
metalation of monosubstituted 1,2,4-triazoles of type 18 could
be achieved using TMPMgCl·LiCl (5, 2.0 equiv, 0 °C, 30 min)
or TMPZnCl·LiCl (7, 1.2 equiv, 0 °C, 30 min). This
procedure was used to allylate the 3-amino triazole 18l as
well as to aminate the 3-anisyl triazole 18i, giving access to the
fully functionalized triazoles 19c and 19d in 80% and 87%
yield.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00238
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the LMU Munich and the DFG for financial support.
We thank Albemarle (Hoechst, Germany) for the generous gift
■
C
https://dx.doi.org/10.1021/acs.orglett.0c00238
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
́
of chemicals. Bartosz Gorski thanks the Erasmus+ program of
the European Union for financial support.
REFERENCES
■
(1) (a) Khalilullah, H.; Ahsan, M. J.; Hedaitullah, M.; Khan, S.;
Ahmed, B. Mini-Rev. Med. Chem. 2012, 12, 789. (b) Kharb, R.;
Sharma, P. C.; Yar, M. S. J. Enzyme Inhib. Med. Chem. 2011, 26, 1.
(2) Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.;
Ferrara, M.; Fiore, F.; Gardelli, C.; Paz, O. G.; Hazuda, D. J.; Jones,
P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.;
Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.;
Witmer, M. V.; Rowley, M. J. Med. Chem. 2008, 51, 5843.
(3) Dorr, P.; Westby, M.; Dobbs, S.; Griffin, P.; Irvine, B.;
Macartney, M.; Mori, J.; Rickett, G.; Smith-Burchnell, C.; Napier, C.;
Webster, R.; Armour, D.; Price, D.; Stammen, B.; Wood, A.; Perros,
M. Antimicrob. Agents Chemother. 2005, 49, 4721.
(4) Heinz, U.; Hegetschweiler, K.; Acklin, P.; Faller, B.; Lattmann,
R.; Schnebli, H. P. Angew. Chem., Int. Ed. 1999, 38, 2568.
(5) Hester, J. B.; Rudzik, A. D.; Kamdar, B. V. J. Med. Chem. 1971,
14, 1078.
(6) (a) Hughes, G.; Bryce, M. R. J. Mater. Chem. 2005, 15, 94.
(b) Han, J. J. Mater. Chem. C 2013, 1, 7779. (c) Sasabe, H.; Kido, J.
Chem. Mater. 2011, 23, 621.
̌
(7) (a) Jakopin, Z.; Dolenc, M. S. Curr. Org. Chem. 2008, 12, 850.
(b) Moulin, A.; Bibian, M.; Blayo, A.-L.; El Habnouni, S.; Martinez, J.;
Fehrentz, J.-A. Chem. Rev. 2010, 110, 1809.
(8) (a) Micetich, R. G.; Spevak, P.; Hall, T. W.; Bains, B. K.
Heterocycles 1985, 23, 1645. (b) Ohta, S.; Kawasaki, I.; Fukuno, A.;
Yamashita, M.; Tada, T.; Kawabata, T. Chem. Pharm. Bull. 1993, 41,
1226.
(9) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 2958. (b) Clososki, G. C.; Rohbogner, C. J.;
Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7681. (c) Wunderlich, S.
H.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7685. (d) Mosrin,
M.; Knochel, P. Org. Lett. 2009, 11, 1837. (e) Stathakis, C. I.;
Bernhardt, S.; Quint, V.; Knochel, P. Angew. Chem., Int. Ed. 2012, 51,
9428. (f) Stathakis, C. I.; Manolikakes, S. M.; Knochel, P. Org. Lett.
2013, 15, 1302.
(10) The base was prepared according to the procedure detailed in
the Supporting Information and used within 3 h. A longer storage of
the base reduces the yields significantly.
(11) For a detailed description of the preliminary studies, see the
Supporting Information.
(12) King, A. O.; Okukado, N.; Negishi, E.-I. J. Chem. Soc., Chem.
Commun. 1977, 19, 683.
(13) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995,
14, 3081.
(14) Friesen, R. W.; Allouche, E. M. D. e-EROS Encyclopedia of
Reagents in Organic Synthesis; Wiley: Hoboken, NJ, 2017; p 1.
(15) (a) Graßl, S.; Chen, Y.-H.; Hamze, C.; Tullmann, C. P.;
̈
Knochel, P. Org. Lett. 2019, 21, 494. (b) Chen, Y.-H.; Graßl, S.;
Knochel, P. Angew. Chem., Int. Ed. 2018, 57, 1108. Chen, Y.-H. Angew.
Chem. 2018, 130, 1120. (c) McDonald, S. L.; Hendrick, C. E.; Wang,
Q. Angew. Chem., Int. Ed. 2014, 53, 4667. (d) Bouarfa, S.; Graßl, S.;
Ivanova, M.; Langlais, T.; Bentabed-Ababsa, G.; Lassagne, F.; Erb, W.;
Roisnel, T.; Dorcet, V.; Knochel, P.; Mongin, F. Eur. J. Org. Chem.
2019, 2019, 3244.
(16) Koe, B. K.; Weissmann, A.; Welch, W. M.; Browne, R. G.
Psychopharmacol. Bull. 1983, 19, 687.
(17) Barbero, N.; SanMartin, R.; Domínguez, E. Org. Biomol. Chem.
2010, 8, 841.
D
https://dx.doi.org/10.1021/acs.orglett.0c00238
Org. Lett. XXXX, XXX, XXX−XXX