N-N Bond Formation between Primary Amines and Nitrosos: Direct Synthesis of 2-Substituted Indazolones with Mechanistic Insights

Article abstract of DOI:10.1021/acs.orglett.8b01655

A concise, one-step route to indazolones from primary alkyl amines and o-nitrobenzyl alcohols is reported. The key step in this readily scalable indazolone forming process involves base-mediated in situ o-nitrobenzyl alcohol → o-nitrosobenzaldehyde conversion. Although this functional group interconversion is known to be useful for 2H-indazole synthesis, its reactivity was modulated for indazolone formation.

Full text of DOI:10.1021/acs.orglett.8b01655

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
N−N Bond Formation between Primary Amines and Nitrosos: Direct
Synthesis of 2‑Substituted Indazolones with Mechanistic Insights
Jie S. Zhu,† Niklas Kraemer,† Marina E. Shatskikh,† Clarabella J. Li,† Jung-Ho Son,†
Makhluf J. Haddadin,‡ Dean J. Tantillo,† and Mark J. Kurth*,†
†Department of Chemistry, University of California Davis, 1 Shields Avenue, Davis, California 95616, United States
‡Department of Chemistry, American University of Beirut, Beirut, Lebanon
S
* Supporting Information
ABSTRACT: A concise, one-step route to indazolones from
primary alkyl amines and o-nitrobenzyl alcohols is reported. The
key step in this readily scalable indazolone forming process
involves base-mediated in situ o-nitrobenzyl alcohol → o-
nitrosobenzaldehyde conversion. Although this functional group
interconversion is known to be useful for 2H-indazole synthesis,
its reactivity was modulated for indazolone formation.
Scheme 1. Representative Indazolone Synthetic Methods
itrogen heterocycles are highly privileged structures, and
Ndue to their exceptional properties, the development of
safe, efficient, and operationally convenient methods for
nitrogen heterocycle synthesis is of paramount importance.
Our group pioneered the development of the Davis−Beirut
reaction1 for 2H-indazole synthesis, and we have also
employed the acid or electrophile mediated hydrolysis of
2H-indazoles to 1,2-dihydro-3H-indazolones (herein referred
to as indazolones).2 These N−N bond containing heterocycles
have demonstrated considerable potential as therapeutic
agents.1 The construction of N−N bonds commonly involves
electrochemical methods,3 oxidative protocols,4 or reductive
conditions.5 Consequently, the syntheses of 2H-indazoles and
indazolones are generally accomplished with the N−N bond
already in place (Scheme 1); for example, through the use
hydrazine and its derivatives.6 Hydrazines are known to
present considerable hazards, and there have been attempts to
improve safety at scale through flow chemistry.6d There is
currently no literature precedent for direct access to
substituted indazolones from safe, diverse, and commercially
available building blocks. Herein, we report a one-step,
transition-metal-free, redox-neutral, and scalable synthesis of
indazolones from relatively benign starting materialsprimary
alkyl amines and o-nitrobenzyl alcohols.
The o-nitrobenzyl moiety is known for its utility as a
photolabile protecting group.7 However, its deprotection
generates highly reactive o-nitrosobenzaldehyde (2; Scheme
2) and this is often cited as a significant disadvantage.7
Reactive 2 is a reagent for 2H-indazole synthesis, and its
generation involves a straightforward photochemical trans-
formation from o-nitrobenzyl alcohol 1.8 That said, practical
applications of 2 are limited because of poor bench stability;
i.e., it is prone to air oxidation to o-nitrobenzoic acid.9
Recently, we discovered that base treatment can deprotect o-
nitrobenzyl compounds, generating o-nitrosobenzaldehyde
(2).9
This discovery affords a method to generate 2 in situ where
its reactivity can then be exploited. We envisioned that the
reaction of 2 with a primary amine could potentially yield both
2H-indazoles (4) and indazolones (5; Scheme 2) by formation
of nitrosoimine 3 via pathways A and B, respectively. When 1
was heated at 100 °C with KOH and butylamine in EtOH/
H2O (5 mL/0.5 mL), both 2H-indazole (4) and indazolone
(5) were obtained in a 76:24 ratio. Although this 4/5 mixture
was generated under these reaction conditions, pathway A was
easy to shut down since secondary alcohols fail to participate in
the Davis−Beirut reaction to effectively form 2H-indazoles;10
thus, switching the solvent to isopropanol was expected to
Received: May 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01655
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Reactivity of 2 with Butylamine
Scheme 3. Scope of This Indazolone Forming Reaction
greatly skew product distribution in favor of 5. Indeed, when
the reaction was carried out with isopropanol instead of
ethanol as the solvent, 5 was formed with complete selectivity
(Table 1, entry 1).
Table 1. Optimizing Indazolone Formation
KOH
(equiv)
iPrOH
(mL)
H2O
(mL)
amine
(equiv)
temp
(°C)
yield
a
entry
(%)
1
2
3
4
5
6
7
8
10
10
5
5
5
5
5
6.5
5
5
5
5
5
5
5
4.5
3.5
5
1.5
1.5
1.5
1.5
0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
5
10
5
100
100
100
100
100
60
54
40
56
n.d.
n.d.
42
54
73
73
72
25
28
71
58
b
10
10
10
10
20
20
30
20
8
0
b
10
10
10
10
5
5
2
2
5
90
100
100
100
100
100
100
100
150
9
10
11
12
13
14
20
20
20
2.5
1.5
5
5
c
b
15
n.d.
a
b
c
Isolated yield. Complex mixture. 2 h reaction time.
This indazolone forming process was then optimized by
systemically varying the reaction conditions (Table 1).
Optimal conditions employ 5 equiv of amine and 20 equiv
of KOH (entry 9) at 100 °C. Further increases in amine (entry
8) or KOH (entry 10) do not increase yields. The yield of the
reaction decreased sharply when suboptimal amounts of either
KOH (entry 1) or amine (entry 11) were employed. Excluding
either amine or water from the reaction resulted in a complex
mixture (entries 4 and 5), and attempts to accelerate the
reaction by elevating the temperature to 150 °C also resulted
in a complex mixture (entry 15).
With these optimized reaction conditions in hand, the
substrate scope of this indazolone-forming process was
explored (Scheme 3). The reaction tolerates a wide range of
o-nitrobenzyl alcohols and alkylamines. The scaled up (15 g of
o-nitrobenzyl alcohol) synthesis of 5 presented no problems,
and in fact, the reaction proceeded better than expected with
an 89% yield. The reaction to form 6 was not complete after 24
h, and starting materials could be isolated. Prolonging the
heating time to 48 h did not improve the yield significantly.
a
Reaction conditions: o-nitrobenzyl alcohol (0.5 mmol, 1 equiv),
primary amine (2.5 mmol, 5 equiv), KOH (10 mmol, 20 equiv),
iPrOH/H2O (5 mL/1.5 mL, 0.077 M), 100 °C, 24 h. Isolated yields
b
are reported. Scaled up reaction from 15 g of starting alcohol.
c
Recovered starting material (57%).
However, this was not a problem for 7. Yield comparisons for 6
vs 7 and 17 vs 18 further highlight the steric demands of the
nitrosoimine intermediate, which was perhaps already obvious
due to the failure of isopropoxide to add to 3. Bulky tert-
butylamine can be utilized for indazolone formation (see 8,
Scheme 3), which is a significant advantage because 8 cannot
be accessed through N-alkylation of unsubstituted indazo-
lones.6 Indazolone 12 spontaneously crystallized to large cubic
crystals upon routine purification, and the X-ray structure was
obtained (see Scheme 3). Interestingly, the starting material
for indazolones 19, 20, and 21 features a chlorine para to the
B
DOI: 10.1021/acs.orglett.8b01655
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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nitro group and, importantly, SNAr was not a competing side
reactiona clear advantage compared to many hydrazine-
based indazolone synthetic methods.6 Some exceptions to the
generality of this indazolone-forming protocol were found
during substrate scope studies, and the rationale for these cases
are given, as follows. The yield of 13 is lower than average
because the electron-donating methoxy impacts the rates of
base-mediated aci-nitronate anion formation and imine
formation. It was disappointing to find that anilines were not
effective for indazolone formation and p-anisidine only
provided indazolone 15 in 17% yield. This is perhaps due to
the reduced nucleophilicity of aniline vs alkylamine nitrogens.
Finally, benzylic, allylic, and propargylic amines result in
complex reaction mixtures that do not contain the targeted
indazolones (22−24) due to side reaction or stability issues
(vide infra).
Scheme 5. Reaction Mechanism and Rationale
Indeed, it was surprising that 22 was not isolated from the
reaction of 1 + benzylamine because the reaction of 2 +
benzylamine is a known route to 22 (Scheme 4). Due to the
Scheme 4. Reaction of 22 in KOH
In the present work (red structures in Scheme 5B), o-
nitrobenzyl alcohol (1) is converted to o-nitrosobenzaldehyde
(2) by heating with KOH in isopropanol. Addition of an amine
to give 2-nitrosoimine (2 → 33 → 30) is a nonproductive
pathway because it is well established that the Davis−Beirut
reaction fails to deliver 2H-indazoles when isopropanol is
employed as the solvent.10 Indeed, when heating under KOH/
isopropanol conditions, 30 and 2 are known to be in
equilibrium.14 With conversion of o-nitrosobenzaldehyde (2)
to 2H-indazole blocked by the steric demands of isopropanol,
the productive reaction pathway becomes hemiaminal
heterocyclization (33 → 34) with subsequent dehydration
and tautomerization to give the observed indazolone product.
The fact that the Davis−Beirut reaction delivers the 2H-
indazole product in quite high yield in methanol or ethanol
(with 10% added water-optimized Davis−Beirut conditions)
suggests 33 → 34 is less effective than 31 → 32. In the
indazolone protocol reported here, the isopropoxy analog of 31
does not form, which causes the reaction to proceed via
heterocyclization of 33 (→ 34) to deliver the indazolone
product. While this mechanistic model explains the formation
of 26 (Scheme 4) from reaction of 1 + benzylamine (i.e., the
acidic benzylic hydrogens cause benzylic anion to intercept the
nitroso moiety of 30), it does not explain the isolation of 25
(Scheme 4). This side product offers evidence for the
formation of intermediate 35 (Scheme 5B), which arises
from amine condensation with the nitroso moiety of 2. While 2
is expected to react kinetically with the amine via the aldehyde
to form an imine, DFT calculations show that amine
suspicion that perhaps the product was decomposing,
authentic 22 was synthesized using a literature route11 and
subjected to the optimized indazolone-forming reaction
conditions. After 12 h, 22 did not decompose; therefore,
22−24 are presumably not formed in the reaction. Indeed,
careful evaluation of the reaction mixture from 1 + benzyl-
amine led to the isolation of side products 3-phenylcinnoline
(25) and 2-phenylquinazoline (26) in 15% and 13% yield,
respectively.
A mechanistic model for indazolone formation from 1 is
formulated on the basis of the following considerations
(Scheme 5). The possibility of amine attacking the nitro
group (i.e., 27a → 27b; Scheme 5A) as the initiating step is
challenging because, although intramolecular heteroatom
additions to a nitro group are known,12 intermolecular
additions are less likely; for example, base-mediated H2O18
oxygen exchange at the nitro groups does not occur.13 Also, as
a backdrop, the typical Davis−Beirut reaction (blue structures
in Scheme 5B; o-nitrobenzylamine 28 → 2H-indazole)
proceeds by aci-nitronate anion 29 formation followed by
internal oxidation of the benzylic carbon with concomitant
reduction of the nitro to deliver nitrosoimine intermediate 30.
Subsequent addition of primary alkoxide to the imine of 30
gives hemiaminal ether 31, and heterocyclization (i.e., N−N
bond formation) gives heterocycle 32. Loss of water from 32
completes the Davis−Beirut reaction, giving the 2H-indazole
product.11
C
DOI: 10.1021/acs.orglett.8b01655
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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acidic methylene hydrogens, cinnoline products like 25 are not
expected to form and this might allow 35 to provide an
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nitrosobenzaldehyde. Subsequent condensation with primary
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Accession Codes
CCDC 1838472 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.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mjkurth@ucdavis.edu.
ORCID
Jie S. Zhu: 0000-0003-3009-4135
Dean J. Tantillo: 0000-0002-2992-8844
Mark J. Kurth: 0000-0001-8496-6125
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors dedicate this work in memory of Milo G.
Schoening, a wonderful and gracious mentor. The authors
gratefully acknowledge financial support from the National
Institutes of Health (DK072517 and DK067003) and the NSF
XSEDE program (CHE030089 to D.J.T.). J.S.Z. is supported
by a fellowship from the UC Davis Tara K. Telford CF Fund.
M.E.S. and N.K. are supported by the UC Davis Provost’s
Undergraduate Fellowship.
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DOI: 10.1021/acs.orglett.8b01655
Org. Lett. XXXX, XXX, XXX−XXX