Accessing Multiple Classes of 2 H-Indazoles: Mechanistic Implications for the Cadogan and Davis-Beirut Reactions

Article abstract of DOI:10.1021/jacs.8b13481

The Cadogan cyclization is a robust but harsh method for the synthesis of 2H-indazoles, a valuable class of nitrogen heterocycles. Although nitrene generation by exhaustive deoxygenation is widely accepted as the operating mechanism in the reductive cyclization of nitroaromatics, non-nitrene pathways have only been theorized previously. Here, 2H-indazole N-oxides were synthesized through an interrupted Cadogan/Davis-Beirut reaction and are presented as direct evidence of competent oxygenated intermediates; mechanistic implications for both reactions are discussed. Isolation and characterization of these N-oxides enabled a formal Cadogan cyclization at room temperature for 2H-indazole synthesis.

Full text of DOI:10.1021/jacs.8b13481

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Article
Accessing Multiple Classes of 2H-Indazoles: Mechanistic
Implications for the Cadogan and Davis–Beirut Reactions
Jie S. Zhu, Clarabella J. Li, Ka Yi Tsui, Niklas Kraemer, Jung-
ho Son, Makhluf J. Haddadin, Dean J Tantillo, and Mark J. Kurth
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Mar 2019
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Journal of the American Chemical Society
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Accessing Multiple Classes of 2H-Indazoles: Mechanistic Implications
for the Cadogan and Davis–Beirut Reactions
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†§
†§
†
†
†
‡
Jie S. Zhu, Clarabella J. Li, Ka Yi Tsui, Niklas Kraemer, Jung-Ho Son, Makhluf J. Haddadin,
*
†
*†
Dean J. Tantillo, 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
‡
Supporting Information Placeholder
ABSTRACT: The Cadogan cyclization is a robust but harsh method for the synthesis of 2H-indazoles – a valuable class of
nitrogen heterocycles. Although nitrene generation by exhaustive deoxygenation is widely accepted as the operating
mechanism in the reductive cyclization of nitroaromatics, non-nitrene pathways have only been theorized previously.
Here, 2H-indazole N-oxides were synthesized through an interrupted Cadogan/Davis–Beirut reaction and are presented
as direct evidence of competent oxygenated intermediates; mechanistic implications for both reactions are discussed.
Isolation and characterization of these N-oxides enabled a formal Cadogan cyclization at room temperature for 2H-
indazole synthesis.
nitroaromatics. Analogous N–O bond-containing by-
products have not been observed in the Cadogan cycliza-
INTRODUCTION
The synthesis of nitrogen heterocycles is of paramount
importance due to their high value in pharmaceutical
applications. In particular, 2H-indazoles and their deriva-
tion, and a non-nitrene pathway has yet to be estab-
1
1
lished. This is perhaps due to the challenges associated
with stopping the Cadogan reaction at the 2H-indazole N-
oxide stage, because N–oxide containing heterocycles are
known to undergo rapid deoxygenation by phosphorous
1
tives have highly desirable therapeutic properties; for
2
3
4
5
example, modulation of PARP, VEGF, GK, and CRAF.
1
2
The Cadogan reaction is a classical reductive cyclization
reagents at just 60-70 °C. In contrast, hydroxy indoles are
resistant to deoxygenation by triethyl phosphite even at
method for synthesizing 2H-indazoles from nitroaromatic
6
6b
compounds. The reaction is generally carried out at high
>160 °C. Therefore, we have explored the chemistry of o-
temperatures, i.e. refluxing in excess trialkyl phosphites
or trialkyl phosphines (typically at >150 °C). Recent ad-
vances made by Aspnes and co-workers allow the Ca-
dogan reaction to proceed under milder, although not
nitrosoimine 2 (Scheme 1) under non-deoxygenating con-
ditions, with the complementary goals of developing syn-
thetically useful reactions and increasing understanding
of the Cadogan and related reactions.
7
mild, conditions (80 °C). The Cadogan cyclization using a
III
V
catalytic amount of phosphorous based on a P /P redox
cycling strategy has also been recently reported by Ra-
N
N
N
R
R
N
8
9
R
dosevich and Nazaré. This reductive heterocyclization is
widely accepted to proceed via a nitrene intermediate
derived by exhaustive deoxygenation of the nitro group
3
5
4
6
Cadogan
NO
X = CH=NR
O
N
O-
O-
N+
1a
2
N
this work
N+
R
N
N
X
R
(
Scheme 1; 1a → 2 → 3 → 4). This mechanistic model is
1b
2
X = CH
2
NHR Davis-
Beirut
O
N
supported by the fact that aromatic azides can also be
1
0
N
used to generate the targeted 2H-indazoles.
H
N
N
R
R
On the other hand, studies of the related Sundberg re-
ductive cyclization for indole synthesis have shown that
N–O bond-containing indole by-products can be isolated
OR’
7
OR’
8
Scheme 1. Previously proposed mechanism of the Ca-
dogan and Davis–Beirut reactions; concept of this work.
–
an observation that seems incompatible with a nitrene
6b
Our group previously reported the synthesis and appli-
cations of in situ generated o-nitrosobenzaldehyde in
connection with the Davis–Beirut synthesis of 3-alkoxy
H-indazoles and indazolones. Throughout these stud-
ies, nitrogen nucleophiles were found to react with the
mechanism. The Sundberg system has since been theo-
retically studied and a 5-center 6π electrocyclization was
1
1
found to be a viable alternative pathway. Taken together,
these results imply that more than one mechanistic path-
way may be operational in the reductive cyclization of
1
13
2
1
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Journal of the American Chemical Society
Page 2 of 8
nitroso group, leading us to suggest that the imine of 2
targeted mass for 2H-indazole N-oxide 10 and the mass
spectrum of this compound featured a fragment con-
sistent with N–O bond cleavage (see Table 1, mass spec-
trum at top right). This compound was isolated and the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
can be recruited to react intramolecularly with its nitroso
moiety to generate 2H-indazole N-oxide (Scheme 1; 2 → 5
« 6). Indeed, many well-known reactions are thought to
rely on an imine being nucleophilic at nitrogen, such as
1
3
C NMR data was in good agreement with N-oxide prod-
1
4
the Staudinger reaction for β-lactam synthesis, the Paal–
uct 10; these initial conditions gave 10 in only 15% yield
(Table 1; entry 1). Next, a variety of non-alcohol solvents
were screened (entries 2-7), and N-alkylation dominated
in all solvents explored except DMSO (entry 7), which
instead gave the N-oxide in 22% yield. The amount of
water present was critical for the success of the reaction:
water exclusion gave a complex mixture (entry 8) while
increasing the amount of water to 1 mL resulted in a yield
increase to 54% (entry 9). Further increasing the amount
of water to 1.5 mL lowered the yield of 10 to 47% (entry
1
5
Knorr pyrrole synthesis, the Shaw four-component reac-
1
6
tion for γ-lactam synthesis,
and the Castag-
1
7
noli−Cushman reaction for δ-lactam synthesis (note:
nucleophilic attack by imine intermediates has not been
fully demonstrated in all cases).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Biological activities of N-oxygenated derivatives of priv-
1
8
ileged heterocycles have been repeatedly demonstrated,
1
9
20
21
as shown by librium, minoxidil, tirapazamine, and the
2
2
widespread application of carbadox/olaquindox/cyadox.
1
0). The reaction was also sensitive to the equivalents of
The relative scarcity of 2H-indazole N-oxides perhaps
accounts for their lack of representation amongst clinical
candidates, although the anti-protozoal activity of 2H-
base used. For example, using 40 equivalents of KOH re-
duced the yield of 10 to 42% (entry 12), while using 10
equivalents of KOH resulted in a 78% yield (entry 13).
Further decreasing the amount of base to 5 or 2 equiva-
lents gave N-oxide in 58% yield (entries 14 and 15). As ex-
pected, increasing the reaction temperature above 40 °C
led to a complex mixture of products, which did not con-
tain the desired N-oxide (entries 16-19). Finally, n-
butylamine equivalents were varied, and the reaction was
found to be sensitive to this parameter. Decreasing the
amine to 1 equivalent resulted in a lower yield (entry 20),
but 2 equivalents gave similar results to 5 equivalents (en-
tries 13 and 21). Increasing to 10 equivalents of amine gave
the N-oxide in 91% yield (entry 22).
2
3
indazole N-oxides has been reported. Known methods
2
3
for their construction involve the use of cyanide salts,
2
4
25
isocyanides, 1,7-electrocyclizations, 1,3-dipolar cycload-
2
6
27
ditions, and rearrangements of sulfonyl amides. Here,
the development of a new and convenient method for 2H-
indazole N-oxide synthesis is disclosed, with an eye to-
ward empowering future studies on their medicinal po-
tential.
RESULTS AND DISCUSSION
For the proposed intramolecular cyclization between
the nitroso and the imine groups of 2 to occur, several
reaction manifolds must be shut down. First, the for-
mation of 2 must not involve external reduction of the
a
Table 1. Reaction Optimization
[M + H]+
[
M - O]
2
8
nitro group due to the possibility of over reduction. Se-
cond, the solvent for the reaction must not be a primary
alcohol due to the possibility of hemiaminal ether for-
mation, which ultimately would lead to the corre-
O-
N+
conditions
24 h
NO2
N
Br
H N
2
9
10
m/z
1
sponding 3-alkoxy-2H-indazole. To address these is-
Entry
Base
Amine
Solvent
Water
Heat
Yield
sues, the following strategies were applied. First, a
29
5 eq
5 eq
5 eq
5 eq
5 eq
6 mL PrOH
i
0.5 mL
0.5 mL
0.5 mL
0.5 mL
0.5 mL
0.5 mL
0.5 mL
0 mL
rt
rt
15%
N.D.b
N.D.b
N.D.b
straightforward base-mediated conversion of 9 → 2 (Ta-
1
2
20 eq KOH
20 eq KOH
20 eq KOH
20 eq KOH
20 eq KOH
20 eq KOH
20 eq KOH
20 eq KOH
20 eq KOH
20 eq KOH
6 mL 1,4-dioxane
6 mL THF
ble 1) was used rather than external reduction. Second,
i
3
rt
the reaction solvent employed was PrOH because it is not
4
6 mL MeCN
6 mL DCM
rt
13
effective at converting 2 to the corresponding hemiami-
rt
N.D.
N.D.b
b
5
29
6
5
eq
6 mL CHCl3
rt
nal ether or subsequent 3-isopropoxy 2H-indazole. In
30
5 eq
5 eq
5 eq
5 eq
5 eq
5 eq
5 eq
5 eq
5 eq
5 eq
5 eq
5 eq
5 eq
1 eq
2 eq
10 eq
rt
22%
N.D.c
54%
47%
35%
42%
78%
58%
58%
55%
7
6 mL DMSO
addition, base-mediated N-oxide deoxygenation or
8
6.5 mL DMSO
5.5 mL DMSO
5 mL DMSO
rt
indazolone formation could compete with the desired
9
1 mL
rt
13
cyclization. While base-mediated deoxygenation of the
10
11
1.5 mL
1 mL
rt
20 eq NaOt-bu
40 eq KOH
10 eq KOH
5 eq KOH
5.5 mL DMSO
5.5 mL DMSO
5.5 mL DMSO
5.5 mL DMSO
5.5 mL DMSO
5.5 mL DMSO
5.5 mL DMSO
5.5 mL DMSO
5.5 mL DMSO
5.5 mL DMSO
5.5 mL DMSO
5.5 mL DMSO
rt
target N-oxides was circumvented by lowering the reac-
12
1 mL
rt
tion temperature, indazolone formation is known to oc-
13
1 mL
rt
31
cur under ambient photochemical conditions. Nonethe-
less, despite the relative uncertainty regarding whether
indazolone formation would outcompete N-oxide for-
mation, the outlined conditions were selected as a launch
point for this investigation.
1 mL
rt
14
15
16
2 eq KOH
1 mL
rt
10 eq KOH
10 eq KOH
10 eq KOH
10 eq KOH
10 eq KOH
1 mL
40 °C
60 °C N.D.c
17
1 mL
N.D.c
18
1 mL
80 °C
0%d
19
1 mL 100 °C
20
1 mL
1 mL
1 mL
rt
rt
rt
32%
74%
91%
The reaction between o-nitrobenzyl bromide 9 and n-
10 eq KOH
21
i
butyl amine was performed in PrOH, water, and KOH at
10 eq KOH
22
room temperature to generate 2 in situ. LCMS analysis of
the crude reaction mixture after 24 hours revealed a mix-
ture of products, including indazolone (Table 1). Howev-
er, also in this mixture was a compound containing the
a
Reaction conducted on 0.5 mmol scale. Isolated yields
b
are reported. Major product is simple N-alkylation.
c
d
Complex mixture. 16% Deoxygenation product 2H-
indazole was isolated.
2
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Page 3 of 8
Journal of the American Chemical Society
The scope of the reaction was explored using both 2
conditions; e.g., N-aryl 2H-indazole N-oxide 24 was not
produced under either basic or photochemical conditions.
1
2
3
4
5
6
7
8
9
and 10 equivalents of amine (Table 2). Consistent with the
optimization studies described above, yields generally
increased when 10, rather than 2, equivalents of amine
were used (16, 21, and 22 are the exceptions). Yields of
~90% could be achieved in some cases; for example, com-
pound 11 was synthesized in 92% yield at small scale and a
comparable 89% yield at gram-scale. Much of the trifluo-
romethyl-containing N-oxide 22 was deoxygenated even
at room temperature. Using benzylamine as the starting
material did not deliver 23 under basic conditions due to
side-reactions leading to with 3-phenylquinazoline for-
When the amine or o-nitrobenzyl bromide component
of the reaction is either precious or of limited availability,
2
H-indazole N-oxides may alternatively be synthesized
using secondary o-nitrobenzyl amines (Table 3) by reduc-
tive amination of o-nitrobenzaldehyde using just 1 equiva-
lent of amine. Indeed, 10 was synthesized from the pre-
formed benzylic amine in a yield (72%) comparable to
that for the reaction using o-nitrobenzyl bromide (74%,
Table 2, where two equivalents of amine were used).
Compound 25 could not be synthesized from the amine
and benzyl bromide due to N-alkylation regioselectivity
issues, but reductive amination of o-nitrobenzaldehyde
followed by treatment with base gives 25 in 66% yield.
Disappointingly, the starting material for 26 was difficult
to dissolve in the DMSO/water mixture and consequent-
ly, the yield of 26 was only 33%. This was not an issue
with 27, which was isolated in 62% yield. Attempts to syn-
thesize N-aryl products (e.g., 28 and 24) again were not
successful; e.g., in targeting 24, p-anisidine was recovered
instead in 14% yield.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
mation, but when KOH was excluded and the reaction
31
was carried out under photochemical conditions, 23 was
obtained in 29% yield. Unfortunately, use of an aryl rather
than alkyl amine is incompatible with these reaction
a
Table 2. Base-mediated 2H-indazole-N-oxide synthesis
O-
N+
KOH
NO2
DMSO, H O
R1
+
R2
2
R1
H N
R2
2
N
Br
rt, 24 h
O-
N+
O-
N+
O-
N+
a
N
N
N
Table 3. Base-mediated 2H-indazole-N-oxide synthesis
O-
KOH
DMSO, H
0: 74% (91%)b
11: 92%
12: 61% (95%)b
NO2
N+
1
R1
2
O
R1
2
Gram-Scale: 89%
H
N
N
R
R2
rt, 24 h
O-
N+
O-
N+
O-
N+
O-
N+
O-
N+
O-
N+
N
N
N
N
Br
14: 52% (56%)b
N
N
N
13: 76%
15: 87%
Boc
NH
O-
N+
O-
N+
O-
N+
10: 72%
25: 66%
26: 33%
O
O
O-
N+
O-
N+
O-
N+
N
N
N
O
N
N
N
O
1
6: 54% (35%)b
17: 51% (73%)b
18: 61% (93%)b
27: 62%
28: 0%
24: 0% (14% p-anisidine)
O-
N+
N
O-
N+
O-
N+
O
a
Reaction conditions: o-nitrobenzyl amine (0.5 mmol),
N
N
KOH (5 mmol), DMSO (5.5 mL), water (1 mL), room tem-
perature, 24 hours reaction time. Isolated yields are re-
ported.
Cl
20: 36% (45%)b
21: 58% (45%)b
9: 17% (54%)b
1
F
O-
N+
N
O-
N+
N
O-
N+
N
F
F
O
The isolation of p-anisidine from the attempted synthe-
sis of 24 suggests that water/hydroxide promoted cleav-
2: 17% (13%)b
c
b
29
2
23 : 29% (0%)
24: 0%
age (akin to deprotection) of the nitroso imine may be
2H-Indazole: 11% (11%)b
operational under the reaction conditions reported here,
consistent with N-oxide 5/6 being in equilibrium with 2,
its ring-opened form (Scheme 1). This type of ring-
opening/ring-closing process is well documented in the
a
Reaction conditions: o-nitrobenzyl bromide (0.5 mmol),
amine (1 mmol), KOH (5 mmol), DMSO (5.5 mL), water (1
mL), room temperature, 24 hours reaction time. Isolated
b
32
yields are reported. Yield when 5 mmol amine was used.
literature for N-oxide heterocycles. While x-ray crystal
c
Under photochemical conditions.
structures for compounds 11, 12, and 16 (Figure 1) were
3
ACS Paragon Plus Environment
Figure 1. Crystal structures of 11, 12, and 16, respectively.

Journal of the American Chemical Society
Page 4 of 8
consistent with the proposed 2H-indazole N-oxide, it was
kcal/mol downhill in energy overall (Figure 3), consistent
with expectations for a reaction making a new P–O bond.
Such a process (1b → 2 → 4 in Scheme 1) may well occur
during Cadogan reactions. Oxygen transfer from N to P is
well-established in the literature for N-oxides (generally
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
not possible to rule out that perhaps the ring-closed form
is favored only in the solid state. Therefore, we turned to
1
3
solution NMR and compared experimental C NMR val-
ues for our compounds to reported literature values of
2
5
12
related compounds and found them to be in good
agreement. In addition, we sought an additional layer of
reassurance using quantum chemically computed NMR
requiring temperatures in the 60-70 °C range), but we
propose here that 2H-indazole N-oxide deoxygenation
would occur via a ring-opening then deoxygenation/ring-
closure process.
3
3
1
13
chemical shifts. Thus, the H and C chemical shifts for
11 and its ring-opened form were calculated using the
34
gauge-including atomic orbital (GIAO) method. The
geometries of all conformers for each structure were op-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
35
timized at the B3LYP/6-31+G(d,p) level. NMR calcula-
tions were performed on the optimized structures at the
36
mPW1PW91/6-311+G(2d,p) level, using the SMD contin-
37
uum model for chloroform. A linear scaling approach
33b,38
was used.
The calculated chemical shifts of 11 (Table 1
and 2 in the Supporting Information) were consistent
with the experimentally observed shifts (mean absolute
1
13
deviations of only 0.14 and 1.29 ppm for H and C chemi-
cal shifts, respectively). In contrast, computed shifts for
the ring opened form, which is predicted to be ~5
kcal/mol higher in energy than 11, deviate greatly from
the experimental shifts. Note that there exists a C–H•••O
interaction between the O and secondary amine carbon in
39
the lowest energy conformer of 11; conformers without
this interaction have significantly different chemical
shifts.
The proposed ring-closing mechanism was also subject-
ed to computational scrutiny (Figure 2) using a variety of
35,40
methods:
PCM(DMSO)-B3LYP/6-31+G(d,p),
41
PCM(DMSO)-B3LYP-D3(BJ)/6-31+G(d,p), SMD(DMSO)-
B3LYP-D3(BJ)/6-31+G(d,p), and PCM(DMSO)-M06-2X/6-
42
3
1+G(d,p). These methods provide a consistent picture
(
standard corrections for changing from gas phase to so-
lution were computed, but found not change the results;
see SI for details).
Conversion of 29 to 11 (Figure 2, top) is predicted to be
kinetically feasible and exergonic, consistent with exper-
iment. Conversion of 30 to 28 (Figure 2, bottom) is also
predicted to be feasible, if slightly less exergonic, despite
our inability to isolate 28, perhaps a result of as-yet uni-
dentified competing reactions.
Figure 2. Computed energetics (PCM(DMSO)-B3LYP-
D3(BJ)/6-31+G(d,p), free energies, kcal/mol; see SI for
results from other methods) for ring-closure reactions to
form 11 and 28.
Deoxygenation also can be carried out under reductive
conditions (Table 4). Unsurprisingly, the reduction of
these N-oxide bearing heterocycles occurred rapidly, even
at room temperature. Overall, the reported 1b → 2 → 6 →
In that heterocyclization is predicted to be facile for
structures such as 29, it is possible that this type of pro-
cess also occurs in classic Cadogan reactions, rather than,
or in addition to, nitrene formation. We carried out com-
putations on nitrene formation as well, examining both
singlet and triplet pathways (see SI for details) and have
yet to find a nitrene formation pathway with a lower bar-
rier than cyclization, although we cannot definitively rule
out this process as contributing.
4
reaction sequence is formally a Cadogan cyclization
carried out under phosphorous-free conditions at ambi-
ent temperature, the mildest conditions yet reported for
this type of nitroaromatic reductive cyclization.
Finally, prior to the isolation and characterization of
the N-oxide heterocycles reported here, 2 was the only
common intermediate in the Cadogan and Davis–Beirut
reactions (Scheme 1). However, it is possible that both
reactions also share structure 5 « 6. Indeed, when N-
oxide 10 was treated with typical Davis–Beirut conditions,
Based on the results of our calculations, we propose an
alternative route to formal Cadogan products in which a
phosphine (here, PMe ) is used to promote deoxygena-
3
tion. For example, we predict that deoxygenation of 29,
which is in equilibration with 11, has an activation barrier
of only less than 20 kcal/mol (relative to 29), whether
nitrogen or oxygen is attacked first, and is greater than 70
3
4
-alkoxy-2H-indazoles were obtained in high yields (Table
).
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Figure 3. Computed reaction pathways for the 29 → 32 conversion. Relative free energies (kcal/mol; PCM(DMSO)-
B3LYP-D3(BJ)/6-31+G(d,p)) are shown; see SI for results from other levels of theory and data for other, higher energy,
pathways.
a
Table 4. Derivatization of 2H-indazole N-oxides
ent conditions has significant implications for mechanis-
tic models of both the Cadogan and Davis–Beirut reac-
tions. For both transformations, N-oxides appear to be
competent intermediates.
O-
N+
KOH
MeOH
Zn, MeOH
1 M HCl
N
N
R1
N
R2
R1
R2
R1
R2
N
N
6
2
0 °C
4 h
rt,1 h
O
ASSOCIATED CONTENT
Supporting Information
Br
N
N
N
N
N
N
N
The Supporting Information is available free of charge on the
ACS Publications website.
31: 94%
32: 93%
33: 98%
1
Br
Experimental procedures, characterization data, H and
N
N
1
3
N
N
C NMR spectra, crystallographic information, and de-
tails of quantum chemical calculations (PDF).
N
O
O
O
Accession Codes
34: 90%
35: 80%
36: 92%
CCDC 1883187, 1883188, and 1883189 contain the supplemen-
tary crystallographic data for this paper. These data can be
a
Isolated yields are reported.
obtained
free
of
charge
via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing da-
ta_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
CONCLUSIONS
In summary, we report the design and optimization of a
method for controlling highly reactive nitroso imines,
using them to produce 2H-indazole N-oxides. This reac-
tion provides access, under mild conditions, to a syntheti-
cally and biologically underutilized class of N-oxide het-
erocycles. The structures of these compounds were de-
termined using x-ray crystallography and computational
NMR. Moreover, isolation of these N-oxides under ambi-
1
EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
*
*
mjkurth@ucdavis.edu
djtantillo@ucdavis.edu
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Author Contributions
Chemical Society (Resumed) 1965, 4831-4837. (b) Sundberg, R. J.
Deoxygenation of Nitro Groups by Trivalent Phosphorus. Indoles
from o-Nitrostyrenes. J. Org. Chem. 1965, 30, 3604-3610.
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§
J.S.Z. and C.J.L. contributed equally.
(
7) Genung, N. E.; Wei, L.; Aspnes, G. E. Regioselective
ORCID
Synthesis of 2H-Indazoles Using a Mild, One-Pot Condensation–
Cadogan Reductive Cyclization. Org. Lett. 2014, 16, 3114-3117.
(8) Nykaza, T. V.; Harrison, T. S.; Ghosh, A.; Putnik, R. A.;
Radosevich, A. T. A Biphilic Phosphetane Catalyzes N–N Bond-
Forming Cadogan Heterocyclization via PIII/PV═O Redox
Cycling. J. Am. Chem. Soc. 2017, 139, 6839-6842.
Jie S. Zhu: 0000-0003-3009-4135
Makhluf J. Haddadin: 0000-0001-9986-149X
Dean J. Tantillo: 0000-0002-2992-8844
Mark J. Kurth: 0000-0001-8496-6125
(
9) Schoene, J.; Bel Abed, H.; Schmieder, P.; Christmann, M.;
ACKNOWLEDGMENT
Nazaré, M. A General One-Pot Synthesis of 2H-Indazoles Using
an Organophosphorus–Silane System. Chem. Eur. J. 2018, 24,
9
(10) Chung, C. K.; Bulger, P. G.; Kosjek, B.; Belyk, K. M.; Rivera,
N.; Scott, M. E.; Humphrey, G. R.; Limanto, J.; Bachert, D. C.;
Emerson, K. M. Process Development of C–N Cross-Coupling
and Enantioselective Biocatalytic Reactions for the Asymmetric
Synthesis of Niraparib. Org. Process Res. Dev. 2014, 18, 215-227.
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The authors gratefully acknowledge financial support from
the National Institutes of Health (DK072517 and DK067003)
and NSF XSEDE program (CHE030089 to D.J.T.). Funding for
NMR spectrometers were provided by National Science
Foundation (DBI722538 and CHE9808183) and NIH National
Institute of Environmental Health Sciences ES00570713. J.S.Z.
is supported by the UC Davis Tara K. Telford CF Fund, UC
Davis Dissertation Year Fellowship, and R. Bryan Miller
Graduate Fellowship. N.K. is supported by the UC Davis
Provost’s Undergraduate Fellowship. We dedicate this work
in memory of Tara K. Telford, a young wife and mother of
twins, who inspired everyone who knew her by living so gra-
ciously and resolutely with cystic fibrosis.
090-9100.
(
11) Davies, I. W.; Guner, V. A.; Houk, K. N. Theoretical Evidence
for Oxygenated Intermediates in the Reductive Cyclization of
Nitrobenzenes. Org. Lett. 2004, 6, 743-746.
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ACS Paragon Plus Environment