Interrupting the [Au]-Catalyzed Nitroalkyne Cycloisomerization: Trapping the Putative α-Oxo Gold Carbene with Benzo[ c]isoxazole

Article abstract of DOI:10.1021/acs.orglett.1c00539

The [Au]-catalyzed nitroalkyne cycloisomerization of 2-alkynylnitrobenzenes leading to anthranils has been interrupted by possible trapping of the postulated intermediate α-oxo gold carbene with an external nucleophile such as benzo[c]isoxazole (anthranil). At the outset, this provides a simple synthesis of highly functionalized 3-acyl-(2-formylphenyl)-2H-indazoles with the sequential C-O, C-N, and N-N bond formations. This provides indirect support for the existence of α-oxo gold carbenes in the [Au]-catalyzed internal redox processes of nitroalkynes.

Full text of DOI:10.1021/acs.orglett.1c00539

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Letter
Interrupting the [Au]-Catalyzed Nitroalkyne Cycloisomerization:
Trapping the Putative α‑Oxo Gold Carbene with Benzo[c]isoxazole
Pawan S. Dhote and Chepuri V. Ramana*
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ABSTRACT: The [Au]-catalyzed nitroalkyne cycloisomerization of 2-
alkynylnitrobenzenes leading to anthranils has been interrupted by
possible trapping of the postulated intermediate α-oxo gold carbene with
an external nucleophile such as benzo[c]isoxazole (anthranil). At the
outset, this provides a simple synthesis of highly functionalized 3-acyl-(2-
formylphenyl)-2H-indazoles with the sequential C−O, C−N, and N−N
bond formations. This provides indirect support for the existence of α-
oxo gold carbenes in the [Au]-catalyzed internal redox processes of
nitroalkynes.
he 2H-indazole scaffold is one of the prominent
Tpharmacophores well explored in medicinal chemistry
with a good number of approved medicines spanning across a
broad range of therapeutic applications.1,2 The “Cadogan and
Davis−Beirut reactions” that forge a 2H-indazole heterocyclic
core via an intramolecular N−N bond formation are the two
important reactions applied in the synthesis of this heterocyclic
core.3,4 In both the reactions, initially a nitro group undergoes
either a reduction or an internal redox process leading to a
reactive nitroso intermediate. In the case of the Davis−Beirut
reaction, the intramolecular nucleophilic attack and/or a 5-
centered 6π-electrocyclization of the nitroso intermediate
results in an indazole N-oxide that undergoes either an
internal redox reaction or deoxygenation. On the other hand,
in the classical mechanism proposed for the Cadogan indazole
synthesis, the nitroso intermediate further reduces to a nitrene
that adds to the imine, though the possibility of the former
process has also been established.5 Despite their widespread
utility, the harsh conditions/reagents employed for generating
the reactive nitroso intermediates warrants the availability of
milder reagents/conditions that are amicable for sensitive
functional/protecting groups.
In this context, we speculated on the possibility of trapping
the nitroso stabilized α-oxo gold carbene intermediates that are
proposed in the catalytic cyclization of o-alkynylnitrobenzenes
with N-centered nucleophiles.6−9 The cycloisomerization of o-
alkynylnitrobenzenes (trivially known as nitrotolans) leading to
isatogens is one of the earliest redox neutral reactions,
documented as early as in 1881 by Bayer during the course
of his classic research on indigo.6 In 2003, a seminal
contribution by Yamamoto’s group revealed the possibility of
affecting this nitroalkyne cycloisomerization under gold
catalysis.7 Importantly, it has been revealed by Yamamoto’s
group that, depending upon the pendant substituent on the
alkyne, the nitroalkyne cycloisomerization proceeds in
complementary paths leading to either isatogen (when the
substituent is aryl) and/or isomeric anthranil (exclusively with
alky substituent). By isolating a nitroso-stabilized α-oxo alkyl
iridium intermediate, Crabtree’s group revealed that the overall
process is a metal-mediated internal redox process leading to
an α-oxo iridium carbene intermediate.8 A similar mechanism
even in gold(I\III)-catalyzed nitroalkyne internal redox
processes with complementary regioselectivity during the
initial oxygen transfer has been extended by Liu and our
groups.9
These nitroso stabilized α-oxo gold carbene intermediates
provide a handle for the carbene for exchange with N-centered
nucleophiles10 and also the reactive nitroso group in the
proximity, for the subsequent N−N bond formation.11
However, in this event, the carbene exchange process has to
compete with the original intramolecular cyclization of the α-
oxo gold carbene intermediate that leads to anthranil. As
shown in Scheme 1, in the presence of anthranil 4 that is
known to exchange with the goldcarbenes,12 the reaction is
expected to provide an imine that should undergo Davis-Beirut
cyclization leading to the indazole 5 (or its N-oxide if it is
sufficiently stable13) with simultaneous C−N and N−N bond
formations.
Received: February 15, 2021
Published: March 19, 2021
https://doi.org/10.1021/acs.orglett.1c00539
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2632−2637
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ethane solvent, we got a poor conversion, resulting mainly with
the formation of the anthranil 3a in small amounts.
Gratifyingly, when we switched the solvent to toluene, the
uncharacterized product 5aa that was encountered with AuBr3
was obtained in 54% yield along with the anthranil 3a (12%).
Gratifyingly, the spectral data and single crystal X-ray crystal
structure analysis of compound 5aa revealed that it was the
desired indazole and, importantly, it proved the point that the
intermolecular trapping of gold carbene that results during the
nitroalkyne cycloisomerization was possible. With these results,
we next proceeded further to improve the yield of the reaction.
As shown in Table 1, our initial attempts with changing the
solvent were not encouraging (entries 5−8). This prompted us
to explore the other gold(III) and cationic gold(I)-complexes
in this pursuit. As shown, in Table 1 (entry 9), with
dichloro(2-pyridinecarboxylato)gold(III) (PicAuCl2, entry 9)
the requisite indazole was obtained as a major product in
moderate yields. Similarly, with AuCl and with other cationic
gold(I)-complexes, the results are not encouraging (entries
10−13). In the majority of the cases, the cycloisomerization
leading to anthranil 3a was the major event, along with the
formation of the requisite 5aa. Gratifyingly, with AuCl3, in
toluene, when the reaction was heated to 80 °C, the yield of
5aa was improved to 57% and the anthranil 3a was also
obtained in 10% yield (entry 14). Finally, when the reaction
was carried out by slow addition of 1a to a solution of 2a and
AuCl3 catalyst at rt, the yield of 5aa was improved to 69%, and
the formation of the cycloisomerization product 3a was also
minimized (entry 15).
Scheme 1. Nitroalkyne Cycloisomerization and Associated
Nitroso Stabilized α-Oxo Metal Carbene Intermediate and
Possible Interruption with an External N-Based Nucleophile
Leading to Indazoles
To examine these hypothetical possibilities, initially, employ-
ing 1-(but-1-yn-1-yl)-2-nitrobenzene (1a) as a substrate, we
examined its cycloisomerization in the presence of anthranil 4a
following reported conditions using AuBr3 (in toluene) and
Pd(CH3CN)2Cl2 (in acetonitrile) complexes. As shown in
Table 1 (entries 1 and 2), with the palladium complex,
a
Table 1. Optimization of the Reaction Conditions
As illustrated in Scheme 2, a wide range of substituted
nitroalkynes have been employed to examine the scope of the
reaction and to understand how the substituents influence the
outcome. Initially, we employed the substrates having different
pendant substituents on the alkyne unit. As shown, changing
the length of the side chain did not alter the reaction outcome,
and it was also found that the protecting groups such as O-
acetyl and O-TBS placed on this alkyl chain were intact.
Interestingly, with the cyclopropyl substituted alkyne, the
intramolecular cyclization was successfully completed and
resulted in the requisite indazole 5ha as a minor product and
the corresponding anthranil 4h as the major product. For the
substrates 5ia−5la having different substituents placed para to
the alkyne unit, the outcome of the reaction was influenced.
For example, when a carboxylate as well as cyano was present,
the yield was 72% (5ka) and 77% (5la) revealing that the
presence of an electron-withdrawing group (EWG) at this
position had a stabilizing effect on the intermediate gold
carbene. In contrast, when the substituent was fluorine, the
yield was reduced to 47% (5ia), which indicates that σ-
acceptors at this position are not compatible. When a methyl
group 5ja was present at this position, the yield was only 56%.
It is noteworthy that the good yield was retained even when
the reaction was carried out on 500 mg scale (5aa, 65% yield).
Next, we varied the substituents on the anthranil ring. When
halogen-substituted anthranils were employed as the sub-
strates, the reactions in general resulted in the corresponding
indazoles 5ab−5ad in low to moderate yields depending upon
the position of the halogen atom. The yields are poor when the
halogen is placed para to the nitrogen. On the other hand, with
5-methyl and 5-carboxymethyl anthranils 4e and 4f respec-
tively, the corresponding indazoles were obtained in good to
moderate yields. Interestingly, when a methoxy group is placed
on the anthranil ring, there was no interception of the original
Yield (%)
b
b
Entry
Catalyst
Solvent
PhMe
MeCN
ClCH2CH2Cl
PhMe
MeCN
1,4-Dioxane
PhCF3
PhCl
PhMe
PhMe
PhMe
PhMe
5aa
2a or 3a
1
2
3
4
5
6
7
8
AuBr3
trace
−
64 (3a)
69 (2a)
trace (3a)
12 (3a)
−
Pd(CH3CN)2Cl2
AuCl3
−
54
−
−
44
49
42
35
26
20
27
57
69
AuCl3
AuCl3
AuCl3
AuCl3
−
13 (3a)
10 (3a)
10 (3a)
24 (3a)
38 (3a)
46 (3a)
42 (3a)
10 (3a)
trace (3a)
AuCl3
9
PicAuCl2
AuCl
PPh3AuCl/AgSbF6
IPrAuCl/AgOTf
(ArO)3PAuCl/AgNTf2
AuCl3
10
11
12
13
14
15
PhMe
PhMe
PhMe
c
d
AuCl3
a
In general, the reactions were carried out with 0.2 mmol of 1a and
0.22 mmol of 4a in 2 mL of solvent and 5 mol % of catalyst at rt with
a reaction time of 3−4 h. Isolated yield. Reaction was carried at 80
°C. Slow addition of 1a through syringe pump at rt for 4 h.
b
c
d
isatogen 2a was obtained exclusively.14 On the other hand,
with the AuBr3,7 the corresponding anthranil 3a was mainly
obtained with trace amounts of a new product, with the
expected mass corresponding to the desired indazole 5aa.
Next, we examined the reactions with AuCl3, which had
shown superior reactivity over AuBr3 in nitroalkyne cyclo-
isomerizations.15 However, in the prescribed 1,2-dichloro-
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incompatible and the reactions employing either of these
substrates gave mainly the corresponding anthranil derivatives.
In addition, when the alkyne end carries a bulky group or an
alkyl chain having EWGs, the intramolecular cyclization is
facile over the intermolecular carbene exchange, indicating that
both steric and electronic factors play important roles. To
show the utility, the selective homologation of the aldehyde
group present in these products has been carried out
employing the stable Wittig ylides (see Scheme S1, Supporting
Information). The reactions are highly selective and proceed
smoothly at rt to provide the corresponding E-olefins in
excellent yields.
Scheme 2. Reaction Scope and Limitations
To probe whether this overall process involves the anthranil
3a as an intermediate, control experiments have been carried
out by employing 3a as a substrate under the optimized
conditions in the presence of 4a. Even after prolonged reaction
times, both 4a and 3a were intact, thus revealing that the
internal redox cascade process was interrupted prior to the
formation of 3a and presumably by the carbene transfer from
the intermediate α-oxo gold carbene to the nitrogen of
anthranil 4a. Next, the concern is about the possible
intermolecular functionalization of alkyne with the anthranil
4 leading to an α-imino gold carbene16 followed by oxygen
transfer from the nitro group17 (Scheme 3, eq 4) and finally
Scheme 3. Control Experiments to Support the Involvement
of the α-Oxo Gold Carbene Intermediate (Eqs 1−3) and
Alternative Possibility for the Formation of Indazole (Eq 4)
internal nitroalkyne redox process and the corresponding
anthranil was obtained exclusively.9a Next, we examined the
compatibility of a C3-methyl substituted anthranil 4g employ-
ing different nitroalkynes. The results are encouraging, and the
corresponding 2H-indazole containing an o-acyl group on the
pendant aryl ring were obtained in moderate to good yields
(5bg, 5cg, 5dg, 5jg, and 5 kg). In this case also, the nitroalkyne
1k having the carboxylate group gave the best results. On the
contrary, the nitroalkyne or the anthranil having methoxy or
hydroxyl substitutes on the aryl ring were found to be
the N−N bond formation. As a control, the phenyl substituted
nitroalkyne 1r, when treated with 4a under the optimized
conditions (Scheme 3, eq 2), gave exclusively isatogen 2r via 5-
exo-dig cyclization. This indicated that the isomeric α-oxo gold
carbene involved in this process prefers the intramolecular
cyclization over the intermolecular carbene interception and
importantly that the possibility of anthranil addition to the
alkyne and subsequent α-imino gold carbene formation is not
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operational. An additional control experiment was conducted
by carrying the reaction in the presence of excess styrene
(known/used to trap the gold carbenes).18 Although the
expected cyclopropane product could not be isolated in
reasonable amounts to characterize, the LCMS analysis
showed its presence in the crude reaction mixture (Scheme
3, eq 3).
Further, competition experiments were done employing the
alkynes 8a−8c, which are known to be functionalized with the
anthranil 4a (leading to an α-imino gold carbene intermediate)
under current conditions and also under the conditions\gold-
complex reported for the same transformation.19−21 As shown
in Scheme 4, the reaction of 1a and 4a in the presence of
Davis−Beirut cyclization with, importantly, one of the
nitrogens having been incorporated externally.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00539.
1
Characterization data H, 13C NMR/DEPT and HRMS
spectra of all new compounds (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1a, 1d−1f, 1i−1m, 2a, 3a, 3d−3g, 3i−3m,
5aa−5la; 5ab, 5cb, 5jb, 5kc, 5lc, 5ad, 5cd−5ed, 5be,
5je, 5le, 5bf, 5ef, 5jf, 5bg, 5dg, 5eg, 5jg, 5kg, 7a−7c,
8a−8c (ZIP)
Scheme 4. Competition Experiments to Support the
Involvement of the α-Oxo Gold Carbene Intermediate
Accession Codes
CCDC 2050267 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Chepuri V. Ramana − Division of Organic Chemistry, CSIR-
National Chemical Laboratory, Pune 411 008, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India; orcid.org/0000-0001-5801-
311X; Email: vr.chepuri@ncl.res.in
Author
Pawan S. Dhote − Division of Organic Chemistry, CSIR-
National Chemical Laboratory, Pune 411 008, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00539
ethynyl cyclopropane (8a) under the prescribed conditions
and Au[I]-catalyst/Ag-additive catalysts resulted in a mixture
of the reported product 9aa (42%) and indazole 5aa (12%).19
When the same reaction was carried out under the current
conditions, it provided mainly the indazole 5aa along with the
anthranil 3a. Similar results were obtained in the competition
experiments employing alkyne 8b or 8c.20,21 In general, with
the reported complexes, the reaction between the anthranil 4a
and the alkyne 8 is facile, and with AuCl3, the nitroalkyne
redox process seems to be operating exclusively. Thus, these
competition experiments clearly indicate that, unlike with the
other complexes, it appears that AuCl3 selectively activates the
nitroalkyne 1a over the competing terminal alkyne, and this
provides indirect evidence for an internal oxygen transfer
leading to an α-oxo gold carbene intermediate, and subsequent
carbene transfer to the nitrogen present in the anthranil 4.
In summary, a novel synthesis of functionalized 2H-
indazoles is described, employing easily accessible o-nitro-
alkynes and anthranils under gold catalysis. At the outset, the
current results provide indirect support for the proposed
nitroso-stabilized α-oxo gold carbene intermediate in the
nitroalkyne cycloisomerization leading to anthranil. In
addition, this also provides a mild and catalytic approach for
the availability of the key nitroso intermediates required in the
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge CSIR (India) for funding this
project, DST-INSPIRE for a research fellowship to P.S.D., and
Dr. Srinu Tothadi (CSIR-National Chemical Laboratory) for
carrying the single crystal X-ray diffraction studies. The crystal
structure for 5aa has been deposited with the Cambridge
Structural Database (CCDC 2050267).
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1-ethynyl Benzenes with N-Hydoxyanilines to Yield 2-Amino-
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