Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

Article abstract of DOI:10.3762/bjoc.15.237

An efficient sequence based on the Ugi-azide reaction and rhodium(III)-catalyzed intermolecular annulation has been established for the preparation of tetrazole-isoquinolone/pyridone hybrids. Several N-acylaminomethyltetrazoles were reacted with arylacety

Full text of DOI:10.3762/bjoc.15.237

Combining the Ugi-azide multicomponent reaction and
rhodium(III)-catalyzed annulation for the synthesis of
tetrazole-isoquinolone/pyridone hybrids
Gerardo M. Ojeda1,2, Prabhat Ranjan1, Pavel Fedoseev1, Lisandra Amable2,
Upendra K. Sharma1, Daniel G. Rivera*2 and Erik V. Van der Eycken*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2447–2457.
1Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Department of Chemistry, University of Leuven (KU Leuven),
Celestijnenlaan 200F, B-3001 Leuven, Belgium, 2Center for Natural
Product Research, Faculty of Chemistry, University of Havana,
Zapata y G, 10400, La Habana, Cuba and 3Peoples´ Friendship
University of Russia (RUDN University) Miklukho-Maklaya Street 6,
117198 Moscow, Russia
doi:10.3762/bjoc.15.237
Received: 28 May 2019
Accepted: 19 August 2019
Published: 16 October 2019
Associate Editor: T. J. J. Müller
Email:
© 2019 Ojeda et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Daniel G. Rivera* - dgr@fq.uh.cu; Erik V. Van der Eycken* -
erik.vandereycken@kuleuven.be
* Corresponding author
Keywords:
C–H activation; cyclization; isoquinolone; multicomponent reaction;
tetrazole
Abstract
An efficient sequence based on the Ugi-azide reaction and rhodium(III)-catalyzed intermolecular annulation has been established
for the preparation of tetrazole-isoquinolone/pyridone hybrids. Several N-acylaminomethyltetrazoles were reacted with arylacet-
ylenes to form the hybrid products in moderate to very good yields. The method relies on the capacity of the rhodium catalyst to
promote C(sp2)–H activation in the presence of a suitable directing group. The Ugi-azide reaction provides broad molecular diver-
sity and enables the introduction of the tetrazole moiety, which may further assist the catalytic reaction by coordinating the metal
center. The scope of the isoquinolones is very wide and may be extended to the preparation of complex compounds having hetero-
cyclic moieties such as pyridone, furan, thiophene and pyrrole, as well as the corresponding benzo-fused derivatives. The de-
veloped procedure is simple, reproducible and does not require inert conditions.
Introduction
Pyridones and isoquinolones are relevant heterocyclic scaffolds [5,6], including analgesic, antihypertensive, anti-inflammatory,
present in numerous bioactive compounds and natural products anticancer, antifungal and antimalarial activity (Figure 1). A
[1-4]. Similarly, molecules containing a tetrazole ring exhibit a key feature of the tetrazole ring is its bioisosteric character with
wide variety of pharmacological and antimicrobial properties the carboxylic acid and amide functional groups, which has
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Beilstein J. Org. Chem. 2019, 15, 2447–2457.
been considered of interest for medicinal chemistry applica-
tions [7,8]. In recent years, the preparation of hybrid hetero-
cyclic scaffolds including the tetrazole ring (either fused or
linked to other heterocycles) has rendered potent bioactive com-
pounds [9-13], which confirms the prospect of the tetrazole
hybridization strategy in drug discovery.
Among the most versatile methods for obtaining tetrazoles are
the Ugi-azide four-component reaction (Ugi-azide-4CR) [14-
16] and the 1,3-dipolar cycloaddition of azides with
(acyl)cyanides [17,18]. The Ugi-azide-4CR enables the incor-
poration of three different diversity-generating sites
(Scheme 1A), a feature that has been exploited for the construc-
tion of libraries of tetrazole-based compounds with potential
bioactivity [9-12,19]. A powerful approach for obtaining hybrid
heterocyclic compounds including the tetrazole ring comprises
an initial Ugi-azide-4CR followed by a cyclization step, involv-
ing some of the reactive functionalities previously installed in
the multicomponent process [20-26]. However, the interplay be-
tween the multicomponent synthesis of tetrazoles and metal-cat-
Figure 1: Bioactive molecules containing a tetrazole, pyridone or
isoquinolone ring.
Scheme 1: Approaches for the synthesis of tetrazoles and isoquinolones and their interplay as designed in this work.
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alyzed cyclization processes has remained underexploited [27]. methyltetrazoles 1a–s and 2a–l. The functionalized tetrazoles
Thus, we envisioned that the combination of an Ugi-azide-4CR were obtained in moderate to excellent yields over three steps
with modern metal-catalyzed C–C bond-forming methods without purification of the intermediates. In this strategy, three
would enable access to structurally novel compounds featuring different diversity sites could be generated, i.e., those derived
hybrid heterocycle platforms.
from the isocyano and aldehyde components and a third one
from the carboxylic acid used in the last acylation step. We
We focused on metal-catalyzed annulation approaches that sought to incorporate aryl or vinyl carboxylic acids to allow the
could form isoquinolones and pyridones linked to a tetrazole subsequent reaction with alkynes based on the C(sp2)–H activa-
ring, since such class of hybrid compounds is not described in tion of these aryl or vinyl moieties.
the literature. Several protocols based on C–H activation or
metal-catalyzed cyclizations are known to generate the As depicted in Table 1, we chose the tetrazolic substrate 1a for
isoquinolone and pyridone moieties and further assist their post- the optimization of the catalytic addition of diphenylacetylene
modifications, encompassing the use of catalysts based on com- (3a), a process involving the metal-catalyzed ortho-C–H activa-
plexes of Fe(III), Co(III), Ni(II), Cu(II), Ru(II), Rh(III), Ir(III), tion of the N-benzamidomethyltetrazole core followed by
Pd(II), Ag(I) and Au(I) [28-45]. Limitations of the latter isoquinolone-ring formation to furnish 4a.
strategy, such as the poor reactivity and regioselectivity, can be
overcome when a suitable directing group assists the reaction We endeavored two catalytic systems based on ruthenium and
[46,47]. Traditional directing groups for C–H activation include rhodium, which in our laboratory have proven success in this
amide, hydroxamide, carboxylate, pyridyl, quinolyl, carbonyl, type of cyclization [32,48]. First, the alkynylation protocol was
ether, hydroxy, oxazolinyl and cyano [47]. For example, Acker- attempted using the relatively cheap complex (p-cymene)ruthe-
mann et al. reported a Ru(II)-catalyzed synthesis of nium(II) chloride dimer, in the presence of copper(II) acetate as
isoquinolones using an N-methoxyamide as directing group for oxidant under conventional heating. Despite all effort put in this
the ortho-position and alkynyl bromide to achieve the regiose- attempt, the isolated yields were in the range of 14–62%, with
lective cyclization (Scheme 1B) [31]. In parallel, our group the highest yield achieved after 24 h of reaction using 10 mol %
has developed Ru(II) and Rh(III)-catalyzed inter- and intramo- of catalyst (results not shown, see Supporting Information
lecular annulations of aromatic rings with alkynes using a File 1). We next turned to rhodium catalysis, since despite the
secondary amide as directing group (Scheme 1C) [32,48]. In fact that rhodium-based catalysts are more expensive, they have
these protocols, the amide group plays a dual behavior of proven to be very efficient using lower catalyst loadings com-
directing group and reaction center, as it participates in the pared to ruthenium [30,32,39,55]. Fortunately, the use of
final ring-closing reductive elimination. Herein, we report the pentamethylcyclopentadienylrhodium(III) chloride dimer,
synthesis of a new class of tetrazolo-isoquinolone/pyridone [Cp*RhCl2]2, allowed reducing both the loading to 5 mol %
hybrids by means of a reaction sequence comprising an Ugi- and the reaction time to 12 h (Table 1). The addition of cesium
azide-4CR and a Rh(III)-catalyzed annulation as key steps acetate appeared to be required, probably to convert the pre-
(Scheme 1D).
catalyst into the active catalyst. After some additional optimiza-
tion varying the solvent (Table 1, entries 1–4), the isolated yield
of 4a was increased to 90% (Table 1, entry 4) with the use of
Results and Discussion
In previous works, our group has described a variety of synthe- tert-amyl alcohol (t-AmOH). Other experiments (Table 1,
tic approaches that combine the diversity-generating character entries 5–7) proved the importance of both cesium acetate and
of multicomponent reactions (MCRs) with the large synthetic copper(II) acetate for the reaction to proceed efficiently. The
scope of metal-catalyzed cyclization protocols [49-54]. In this use of the nonhygroscopic and cheaper sodium acetate de-
sense, we envisioned that the application of modern Ru(II) or creased the yield (Table 1, entry 5), whereas the absence of the
Rh(III)-catalyzed annulations on Ugi-azide-4CR-derived scaf- acetate salt additive led to a very low reaction yield (Table 1,
folds could be a promising strategy to generate novel hybrid entry 6). Neither removal of the oxidant (Table 1, entry 7) nor
compounds. As shown in Scheme 2, the design of the tetrazolic further modification of the reaction conditions, i.e., time, tem-
substrate included the incorporation of an N-acylaminomethyl perature, equivalents, concentration, was beneficial for increas-
moiety enabling the further metal-catalyzed transformations ing the yield. Interestingly, the catalyst loading could be
mediated by a C–H activation process. The method comprises reduced to 1 mol % without affecting the reaction efficiency
the initial Ugi-azide-4CR – in which several isocyanides and (Table 1, entry 13), although this result could not be repro-
aldehydes were reacted in parallel with trimethylsilyl azide and duced for all the substrates employed in this work. Conven-
tritylamine under microwave irradiation – followed by removal tional heating at 120 °C was used, while no inert atmosphere
of the trityl group and acylation to afford the N-acylamino- was required.
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Scheme 2: Scope of the Ugi-azide-4CR/deprotection/acylation sequence. Ugi-azide-4CR conducted at the 2.0 mmol scale with tritylamine (1.0 equiv),
aldehyde (1.5 equiv), isocyanide (1.1 equiv) and TMSN3 (1.1 equiv) in EtOH at 100 °C (MW radiation, two cycles of 15 min each).
Initially, we sought to assess the scope of the N-benz- substituents Me, Br and Cl leading to moderate yields of com-
amidomethyltetrazole bearing different substituents at the R and pounds 4b, 4c, and 4d, while a OMe substituent in this position
R2 position (see Scheme 1) in the Rh(III)-catalyzed reaction no product 4e was obtained. On the other hand, no significant
(Scheme 3). Thus, compounds 1a–o were reacted with effect was observed when the substituents were placed in the
diphenylacetylene under the optimized catalytic conditions to meta- or para-position (4f–m) of the amide group. It must be
furnish – eventually – the corresponding tetrazole/isoquinolone noted that for substrates bearing a halogen (1k–m) in the meta-
hybrids 4a–o. We first fixed the R2 substituent as H (derived position of the amide, a mixture of the two possible regio-
from paraformaldehyde as aldehyde component in the Ugi- isomers of compounds 4k, 4l and 4m was obtained. Fortu-
azide-4CR, Scheme 1) to better evaluate the effect of the sub- nately, the major isomers (shown in Scheme 3) could be isolat-
stituent in the phenyl ring. Interestingly, the presence of substit- ed as pure products corresponding to the less hindered isomer,
uents in the ortho-position of the amide group (acting as a in which the annulation took place in the para-position of the
directing group) decreased the yields, with substrates bearing halogen. When a Me substituent was present in the meta-posi-
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Table 1: Optimization of the reaction conditions with model compound 1a.a
Entry
Solvent
Additive
T (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7d
8
9
10
11
12e
13f
MeOH
THF
DMF
CsOAc
CsOAc
CsOAc
CsOAc
NaOAc
–
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
120
120
120
120
120
120
120
90
130
120
120
120
120
12
12
12
12
12
12
12
12
12
6
59
78
80
90c
73
14
48
87
70
87
80
84
90
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
24
12
12
aUnless otherwise stated, all reactions were carried out with 1a (0.25 mmol, 1.0 equiv), 3a (1.5 equiv), catalyst (5 mol %), oxidant (2.0 equiv), addi-
tive (0.5 equiv), in 1.5 mL of solvent (0.17 M) at the indicated temperature and reaction time. bYields were determined by quantitative 1H NMR using
3,4,6-trimethoxybenzaldehyde as internal standard. cIsolated yield of 88% after column chromatography. dNo oxidant was added. eThree equiv of
alkyne were used. f One mol % of catalyst was used. Cy: cyclohexyl; Cp*: 1,2,3,4,5-pentamethylcyclopentadienyl.
tion, only a single regiosomer of compound 4j was obtained. It Finally, aiming at producing tetrazole hybrids including other
is important to note that when R2 is different than H (i.e., iPr or heterocyclic moieties, the reaction was explored with substrates
Bn), no products (4n and 4o) were formed, presumably due to bearing acyl groups other than benzoyl (Scheme 5). Com-
the steric hindrance at the neighboring position of the amide pounds incorporating acrylamidomethyltetrazole fragments
and the tetrazole moiety.
reacted with diphenylacetylene to form the tetrazole/pyridone
hybrids 5a–c in good yields. In addition, very complex hybrid
The effect of the R1 substituent at the tetrazole ring and the aryl compounds based on heterocyclic, fused aromatic rings, such as
substituents of the alkyne (Ar, Scheme 1) on the efficiency of furan, benzofuran, pyrrole, benzopyrrole, thiophene, benzothio-
the annulation reaction were also evaluated. As shown in phene and naphthalene were also successfully synthesized
Scheme 4, the system is tolerant to a variety of substituents R1 (5d–l) in moderate to very good yields. The exceptions were the
(originating from the isocyanide component in the Ugi-azide- cases of indolopyridone 5i and thiazolopyridone 5k, the latter
4CR, see Scheme 1), with tetrazole/isoquinoline hybrids bear- one could not be obtained even after many attempts.
ing a benzyl (4p), a p-methoxyphenyl (4q) or a tert-butyl (4r)
group, respectively, being obtained in good yields. However, To explain the experimental observations of this work and
the presence of an ester functionality at the tetrazole ring (R1 = based on literature reports [28,30,32,39,41,42], we propose a
CH2CO2Me) led to a significant decrease in the yield of com- mechanism as depicted in Scheme 6. First, [Cp*RhCl2]2 under-
pound 4s (see Scheme 4). A plausible explanation might be that goes ligand exchange with CsOAc to form in situ the active
the presence of an additional coordinating ester group may trap catalyst. This is followed by addition of the substrate 1a via de-
the catalyst in a stable complex. Substituted diphenylacetylenes protonation of the amide to form complex A, in which it is very
led to good yields of compounds 4t and 4u, while 1,2-di(thio- likely that a tetrazole nitrogen atom forms a dative bond with
phen-2-yl)ethyne also rendered isoquinolone hybrid 4v in a the metal center. The next step is the crucial C–H activation of
very good yield. However, the reaction with 1,2-di(pyridin-3- the amide ortho-position leading to intermediate B with elimi-
yl)ethyne was not successful, nor was the employment of ali- nation of AcOH. There are examples in the literature support-
phatic alkynes or the terminal phenylacetylene.
ing the chelation of metal centers by a tetrazole ring during the
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Beilstein J. Org. Chem. 2019, 15, 2447–2457.
Scheme 3: Influence of substituents R and R2 on the reaction outcome. For compounds 4k–m the overall yield in parentheses refers to the mixture of
regioisomers.
C–H activation processes, in which the tetrazole may also act as migratory insertion furnishes the seven-membered metallacycle
directing group [55-61]. The closely related triazole ring has D. Finally, reductive elimination leads to compounds 4a and the
also been used for the C–H modification of amino acids and concomitant reoxidation of Rh(I) to Rh(III) by the Cu(II) salt
peptides and the formation of isoquinolones; so it is expected completes the catalytic cycle.
that in intermediate B the substrate behaves as a tridentate
ligand for the Rh(III) center [37,62-65]. However, such a com- Conclusion
plexation must be reversible to allow a further ligand exchange In conclusion, we have developed a versatile method for the
with the acetylene to form intermediate C. The subsequent preparation of a new family of tetrazole-isoquinolone/pyridone
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Beilstein J. Org. Chem. 2019, 15, 2447–2457.
Scheme 4: Influence of the alkyne and R1 substituent on the reaction outcome.
Scheme 5: Scope of acrylic, heterocyclic and ring-fused N-acylaminomethyl tetrazole substrates.
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Beilstein J. Org. Chem. 2019, 15, 2447–2457.
Scheme 6: Proposed reaction mechanism using substrates 1a and 3a.
hybrids. The protocol relies on a Rh(III)-catalyzed addition of signal (13C NMR). 13C NMR peak assignment was accom-
arylacetylenes to N-acylaminomethyltetrazoles derived from the plished from the DEPT-135 spectra. For thin-layer chromatog-
Ugi-azide-4CR. The C–H activation mediated annulation raphy, analytical TLC plates (Alugram G/UV254 and 70–230
proved to be successful with a variety of benzoyl, acryl and mesh silica gel (E. M. Merck) were used). Column chromatog-
heterocyclic carboxamide moieties, while the N-alkyl substitu- raphy was performed using silica gel (Merck, 60–120 mesh
ent of the tetrazole ring also proved to show a wide substrate size). Solvents for chromatography were used as commercial
scope. Overall, the reaction sequence is easy to implement and without previous distillation. The proportion of chromatograph-
does not require inert conditions. Based on the experimental ic solvents is presented as volume:volume ratios. Isolated com-
results, we believe that not only the amido group but also the pounds were submitted to HRMS using an Agilent 6220A Time
tetrazole ring takes part in the catalytic reaction mechanism by of Flight MSD spectrometer equipped with an ESI ionization
chelating Rh(III) upon activation of the amide ortho-position. source. IR spectra were recorded on a Bruker Alpha FTIR spec-
This work illustrates the synthetic potential of combining trometer. Only frequencies (ν, in cm−1) of the most relevant
isocyanide-based multicomponent reactions with metal-cata- peaks are reported. Melting points ranges were recorded on a
lyzed transformations to generate structural diversity and com- Reichert Thermovar apparatus and are uncorrected.
plexity. In addition, the hybrid nature of the final compounds
General procedure A for the synthesis of
makes them attractive for possible medicinal applications.
N-acylaminomethyltetrazoles
Experimental
General information
First step: synthesis of N-tritylaminomethyltetrazoles [66].
Tritylamine (2.0 mmol, 1.0 equiv) and aldehyde (3.0 mmol,
All starting materials were purchased from commercial sources 1.5 equiv) components were mixed in EtOH (2.0 mL) in a
and used without additional purification. Noncommercial aryl- sealed vial provided with a magnetic stirring bar. The reaction
acetylenes 3c and 3d were synthesized according to a reported was heated at 100 °C under MW irradiation for 15 minutes.
procedure [38]. 1H NMR and 13C NMR spectra were recorded Then, the isocyanide (2.2 mmol, 1.1 equiv) component and
on a 400 MHz or 600 MHz apparatus. Chemical shifts (δ) are azidotrimethylsilane (2.2 mmol, 1.1 equiv, 292 μL) were added
reported in ppm relative to TMS (1H NMR) and to the solvent into the reaction mixture and further heating followed at 100 °C
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Beilstein J. Org. Chem. 2019, 15, 2447–2457.
under MW irradiation for 15 minutes. The solvent was re-
moved under reduced pressure and the residue was used for the
next step without any purification.
Supporting Information
Supporting Information File 1
Experimental procedures and compound characterization
data.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-237-S1.pdf]
Second step: removal of the trityl group [66]. The N-trityl-
protected α-aminotetrazole obtained in the previous step was
dissolved in DCM (10 mL, 0.2 M) in a flask provided with a
magnetic stirring bar. TFA (4.0 mmol, 2.0 equiv, 154 μL) was
added dropwise at rt and the reaction was allowed to proceed
for 1 min. The reaction mixture was concentrated under reduced
pressure. The residue was dissolved with a mixture of heptane
and EtOAc 1:1 and poured over a silica bed wetted with the
same solvent mixture. The side product was washed out with
heptane and EtOAc 1:1. The N-deprotected aminomethyltetra-
zole was collected with a mixture of MeOH and DCM 1:1.
The solvent was removed under reduced pressure and the
residue was used for the next step without any further purifica-
tion.
Acknowledgements
G. M. O. is grateful to VLIR-UOS for financial support of a
Flemish-Cuba cooperation project (CU2018TEA458A101). We
acknowledge the FWO [Fund for Scientific Research – Flan-
ders (Belgium)] for financial support. We acknowledge the
support of RUDN University Program 5-100. DGR thanks KU
Leuven for a Senior Fellowship. We thank Liangliang Song for
his valuable suggestions. We are grateful to Jan Goeman for
HRMS measurements and Karel Duerinckx for the assistance
with NMR measurements.
Third step: acylation of deprotected aminomethyltetrazoles.
The N-deprotected aminomethyltetrazole obtained in the
previous step was dissolved in dried DMF (4.0 mL, 0.5 M) in a
flask provided with a magnetic stirring bar. The carboxylic acid
(2.0 mmol, 1.0 equiv) and TEA (10 mmol, 5.0 equiv, 1.39 mL)
were added and the mixture was cooled to 0 °C. Then, HBTU
(2.0 mmol, 1.0 equiv) was added portion-wise and the mixture
allowed to slowly reach rt. Then DMAP (0.2 mmol, 10 mol %)
was added and the reaction developed for 72 hours. The reac-
tion mixture was poured over 5% aqueous HCl (20 mL) under
vigorous stirring. Extractions with AcOEt (3 × 20 mL) fol-
lowed. The organic layers were combined, washed with satu-
rated aqueous NaHCO3 (3 × 20 mL), brine (20 mL) and dried
over anhydrous Na2SO4. The solvent was removed under
reduced pressure and the reaction crude was purified by LCC to
afford the desired N-acylaminomethyltetrazole.
ORCID® iDs
Gerardo M. Ojeda - https://orcid.org/0000-0002-9639-7852
Daniel G. Rivera - https://orcid.org/0000-0002-5538-1555
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