Photochemical Preparation of 1,2-Dihydro-3 H-indazol-3-ones in Aqueous Solvent at Room Temperature

Article abstract of DOI:10.1021/acs.joc.8b02356

o-Nitrosobenzaldehyde is a reactive intermediate useful in the synthesis of nitrogen heterocycles. Previous strategies for using o-nitrosobenzaldehyde involve its isolation via chromatography and/or formation under harsh conditions. Herein, this intermedi

Full text of DOI:10.1021/acs.joc.8b02356

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Note
Photochemical Preparation of 1,2-Dihydro-3H-indazol-3-
ones in Aqueous Solvent at Room Temperature
Jie S. Zhu, Niklas Kraemer, Clarabella J. Li, Makhluf J. Haddadin, and Mark J. Kurth
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02356 • Publication Date (Web): 23 Nov 2018
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The Journal of Organic Chemistry
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Photochemical Preparation of 1,2-Dihydro-3H-indazol-3-ones in
Aqueous Solvent at Room Temperature
Jie S. Zhu,§† Niklas Kraemer,§† Clarabella J. Li,† Makhluf J. Haddadin,‡ Mark J. Kurth†*
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† 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
Scheme 1. Generation of 7 in situ for indazolone synthesis.
ABSTRACT: o-Nitrosobenzaldehyde is a reactive intermediate
useful in the synthesis of nitrogen heterocycles. Previous strategies
for using o-nitrosobenzaldehyde involve its isolation via chroma-
tography and/or formation under harsh conditions. Herein, this in-
termediate was photochemically generated in situ from o-nitroben-
zyl alcohols in a mild, efficient manner for the construction of 1,2-
dihydro-3H-indazol-3-ones using an aqueous solvent at room tem-
perature. This convenient reaction offers several advantages over
reported methods. The commercially available photoreactor em-
ployed 3x18W bulbs outputting broad emission above 365 nm.
Despite this, the deprotection of 6 is generally accomplished un-
der mild conditions suitable for studying various biological sys-
tems.10 Therefore, we envisioned that an indazolone forming reac-
tion (6 ® 7 ® indazolone) could potentially also be realized under
gentle photochemical conditions – this UV-mediated strategy
would be one of the most mild and convenient indazolone synthetic
methods reported.11 Herein, we detail the development and imple-
mentation of a photochemical route to indazolones from o-nitro-
benzyl alcohols and primary amines.
Expanding the toolkit for 1,2-dihydro-3H-indazol-3-one (inda-
zolone) construction is highly desirable because these heterocycles
afford a plethora of interesting biological activities with valuable
pharmaceutical applications (Figure 1).1 For example, 1 and 2 have
anti-viral and anti-bacterial activites,2 3 has shown anti-hypergly-
cemic properties,3 4 is an anti-tumor agent,4 5 is an angiotensin II
receptor antagonist,5 and other cases in the literature.6
We first attempted to synthesize indazolone 1 by simply treating
a mixture of o-nitrobenzyl alcohol and n-butylamine with UV light.
This reaction was initially carried out in deionized water but re-
sulted in a complex mixture. We reasoned that employing condi-
tions more favorable for the formation of 7 would give better re-
sults, since the mechanism of 6 ® 7 is pH dependent.10,12 There-
fore, the experiment was repeated using aqueous phosphate-buff-
ered saline (PBS) solution, which is known to stabilize the pH and
has been shown to be suitable for the generation of 7.10 To our de-
light, indazolone 1 was the major product observed by LCMS un-
der these reaction conditions.
Table 1. Light source optimization.a
Figure 1. Biologically relevant indazolones.
Our group recently modified the Davis–Beirut reaction1,7 to exploit
the fact that suitably strong bases facilitate the formation of aci-
nitronate intermediates8 and developed this chemistry for the direct
synthesis of indazolones from o-nitrobenzyl alcohol and proposed
that the reaction proceeded via o-nitrosobenzaldehyde 7 as the key
intermediate (Scheme 1; R1 = H).9 However, that reported protocol
required quite forcing conditions – 20 equiv KOH at 100 °C.9 The
o-nitrobenzyl moiety (cf., 6) is a photolabile protecting group for
heteroatoms10 where the key role of light in the deprotection is gen-
eration of an aci-nitro species. The most commonly cited disad-
vantage of this group’s photodeprotection is that cargo release is
accompanied by the generation of highly reactive 7.10
aReaction conditions: o-nitrobenzyl alcohol (0.5 mmol, 1 equiv),
primary amine (2.5 mmol, 5 equiv), PBS solution (6.5 mL), 24 h.
Isolated yields are reported.
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Next, the effectiveness of multiple light sources was investi-
o-nitrobenzyl alcohol to reactive intermediate 7 is not as fast. In-
deed, when the reaction was stopped after 2 hours, indazolone was
formed in only 21% yield with 64% recovered starting alcohol (en-
try 12). The effect of concentration was studied (entries 13-16) and
it was found that the reaction performed best with increased vol-
umes of solvent. That said, it is interesting that the reaction delivers
indazolone with only a modest decrease in yield when carried out
under neat conditions (entry 13 vs 17). Lowering the temperature
to 0 °C (8 hours) resulted in a 48% yield with 24% starting alcohol
(entry 18). In contrast, the reaction gave indazolone in 55% yield
with 29% starting alcohol at 30 °C (entry 19). Using quartz reaction
vessels was effective but not required for product formation (entries
20 and 21).
1
2
3
4
5
6
7
8
gated, including a Rayonet RMR-600 equipped with either eight
lamps outputting single wavelength (254 nm, 300 nm, or 350 nm)
light, a ThermalSpa 49135 equipped with three 18W UVA bulbs
outputting light above 365 nm,13 and a 500W halogen lamp output-
ting broad spectrum light. Regardless of wavelength, the Rayonet
reactor resulted in lower indazolone yield compared to the Ther-
malSpa (Table 1; entries 1-3 vs 4) and the 500W halogen lamp gave
indazolone 1 in only 11% yield (entry 5). In addition, the tempera-
ture of the reaction mixture with the halogen lamp was difficult to
control and the bulb had a much higher operating wattage require-
ment. Using sunlight as the light source was not considered due to
standard operating procedure constraints. Therefore, the Thermal-
Spa was selected for further optimization for its relative low cost,
moderate operating temperature, and ease of use.13
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With optimized conditions in hand (Table 2, entry 13), the sub-
strate scope of this photochemical indazolone-forming reaction was
explored (Table 3). As hoped, various alkyl amines gave the corre-
sponding alkyl indazolones (1, 2, 8, 9, 10, 11, 12, 18, and 19) in
good yield. The synthesis of 9 was accomplished in 53% yield even
though n-heptylamine is not soluble in PBS solution. Photocleav-
age of aryl halide bonds is known to be radical-mediated.15 As a
After selecting the photoreactor, optimization of the reaction be-
gan. Since the reaction mixture was not homogeneous after irradi-
ation, the PBS solution was diluted with 5 or 10% DMSO to im-
prove solubility; however, this did not result in more indazolone
formation (Table 2, entries 2 and 3). At this point, the air-cooling
system was adjusted (see Supporting Information) so that the solu-
tion’s final temperature did not exceed 30 °C, which resulted in a
modest increase in yield (entry 4). iPrOH and THF were used as
solvents and gave comparable yields to PBS (entries 5 and 6).
Next, the amount of amine was investigated (entries 7-10); the re-
action is most successful when the amine equivalence was between
two and five. Although some o-nitrobenzyl systems can be trans-
formed to o-nitrosobenzaldehyde quite rapidly,14 the conversion of
Table 3. Indazolone substrate scope.a
PBS solution
hn2630 °C, 24 h
H
N
NO2
R1
R1
N
R2
R2
OH
H2N
O
H
H
N
H
N
N
N
N
N
O
O
O
b
1
9
2
8
: 67% (55%)
: 65%
: 74%
H
N
H
N
H
N
Table 2. Reaction optimization.a
N
N
N
6
conditions
H
NO2
N
O
O
O
hn
N
10
11
: 53%
: 74%
: 71%
OH
H2
N
O
1
H
N
H
N
H
N
O
Ph
N
N
N
amine
(equiv)
temp
(°C)
time
(h)
yield
(%)
Cl
entry
1
solvent
O
O
O
6.5 mL PBS
5
5
45
45
24
59
57
12
15
13
14
: 59%
: 69%
: 10%
1
(dechlorination product : 9%)
2
6.5 mL PBSb
24
3
4
6.5 mL PBSc
6.5 mL PBS
5
5
45
30
24
24
57
66
H
N
H
N
H
N
N
N
N
5
6
7
8
6.5 mL iPrOH
6.5 mL THF
6.5 mL PBS
6.5 mL PBS
5
5
2
1
30
30
30
30
24
24
24
24
63
55
62
17
O
O
O
16
17
: 69%
: 55%
: 56%
H
N
H
N
H
N
N
N
N
9
6.5 mL PBS
6.5 mL PBS
6.5 mL PBS
10 mL PBS
10 mL PBS
4 mL PBS
2 mL PBS
0.5 mL PBS
neat
0.5
10
2
30
30
30
30
30
30
30
30
30
0
24
24
18
2
n.d.d
35
10
11
12
13
14
15
16
17
18
19
20f
21g
O
O
O
18: 74%
19: 63%
20: 0%
56
2
21e
H
N
H
N
H
N
2
24
24
24
24
24
8
67
N
N
N
2
62
2
33
O
O
O
21: 69%
22: 56%
23: 51%
2
19
2
60
O
H
N
H
N
H
N
48e
55e
54e
50e
N
10 mL PBS
10 mL PBS
10 mL PBS
10 mL PBS
2
N
N
N
2
30
30
30
8
O
O
O
2
24
24
24a
24b
25
26
(N-allyl): 63%
(N-propargyl): 60%
: 83%
: 62%
2
aReaction carried out in a ThermalSpa photoreactor on 0.5 mmol
scale in solvent unless otherwise noted. Isolated yields are reported.
aReaction conditions: ThermalSpa photolysis of o-nitrobenzyl al-
cohol (0.5 mmol, 1 equiv), primary amine (1.0 mmol, 2 equiv),
PBS solution (10 mL), 30 °C, 24 h. Isolated yields are reported. b5
mmol scale reaction.
c
d
e
b5% DMSO. 10% DMSO. Complex mixture. Starting material
f
g
recoverable. In a 20 mL Biotage microwave vial. In a 25 mL
Chemglass recovery flask.
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The Journal of Organic Chemistry
result, reaction of (5-chloro-2-nitrophenyl)methanol with n-butyla-
reported here significantly reduces the overall harshness of the re-
action conditions and this UV-mediated route overcomes several
established substrate scope limitations.
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mine gave indazolone 14 in only 10% yield with indazolone 1 as a
side product in 9% yield (note: three side-products having m/z
<100 were found by LCMS with each accounting for <10% of the
recovered mass). Under strongly alkaline conditions,9 (3-methyl-2-
nitrophenyl)methanol provided the corresponding indazolone 15 in
marginal yields after 48 h reaction time – presumably due to issues
related to benzylic proton acidity affecting aci-nitronate anion for-
mation. In contrast, this problem was eliminated under the reaction
conditions reported here and 15 was obtained in 69% yield. Simi-
larly, the reaction of (3-methyl-2-nitrophenyl)-methanol with cy-
clopentylamine gave indazolone 16 in 55% yield and cyclohexyla-
mine gave indazolone 17 in 56% yield. Unfortunately, aniline
failed to provide 20 (LCMS suggests that N,2-diphenyl-2H-inda-
zol-3-amine was formed in low yield, but this preliminary observa-
tion could not be verified due to isolation issues).
Experimental Section
All chemicals were purchased from standard commercial suppli-
ers and used without further purification. Anhydrous solvents were
dispensed from a solvent purification system utilizing dry neutral
alumina or prepared using dry molecular sieves. Analytical TLC
was performed using precoated plates (silica gel 60 F254) and vis-
ualized with UV light or an I2 chamber. Flash chromatography in
glass columns was performed using 60 Å 230−400 mesh silica gel
(Fisher). 1H NMR spectra and proton decoupled 13C NMR spectra
were obtained on 400 MHz Bruker, 600 MHz Varian, or 800 MHz
Bruker NMR spectrometers. 1H and 13C chemical shifts (δ) are re-
ported in parts per million (ppm) relative to residual solvent peaks
or TMS. Multiplicities are given as s (singlet), d (doublet), t (tri-
plet), q (quartet), p (pentet), hex (hextet), h (heptet), and m (multi-
plet). Coupling constants (J) are given in Hz. For HRMS analysis,
samples were analyzed by flow-injection analysis with a Thermo
Fisher Scientific LTQ Orbitrap (San Jose, CA) operated in the cen-
troided mode. Samples were injected into a mixture of 50%
MeOH/H2O and 0.1% formic acid at a flow of 0.2 mL/min. Source
parameters were 5.5 kV spray voltage, capillary temperature of
275 °C, and sheath gas setting of 20. Spectral data were acquired at
a resolution setting of 100,000 fwhm with the lockmass feature,
which typically results in sufficient mass accuracy. Uncorrected
melting point values were gathered using a Stanford Research Sys-
tems OptiMelt MPA100. LCMS analysis was carried out using a
Waters 2695 equipped with an Ascentis Express C18, 2.7 micron
HPLC column using a gradient of MeCN/H2O with 0.1% formic
acid. The HLPC was also equipped with an inline Water 996 pho-
todiode array detector operating between 250-800 nm and Waters
micromass ZQ mass spectrometer in ESI+ mode. Photochemical
reactions were carried out in Rayonet RQV-5 quartz reaction ves-
sels. Light sources used were a Globe Electric 500W portable yel-
low work light equipped with 1x500W halogen T3 double-ended
clear RSC base light bulbs (The Home Depot), a Rayonet RMR-
600 with fan and merry-go-round unit using 8xRMR-2537A,
8xRMR-3000A, or 8xRMR-3500A lamps (The Southern New
England Ultraviolet Co.), or a ThermalSpa 49135 UV Auto Gel
Light Nail Dryer equipped with 3xPL-18W/UVA bulbs operating
in continuous mode (Amazon).13 Pictures and description of the
photoreactor setups are shown in the SI.
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Another challenging class of substrates for base-mediated inda-
zolone formation9 is reactions of benzylic amines, due to side-reac-
tions associated with the benzylic hydrogen’s acidity. Here, in the
absence of base, benzylamine gave 21 in 69% yield. α-Substituted
benzylic amines gave 22 in 56% yield and 23 in 51% yield. Finally,
although the light source selected is known to promote [2+2] cy-
cloaddition,13 we were delighted to find that allylamine gave 24a in
63% yield and did not have dimerization issues. Likewise, propar-
gylamine gave indazolone 24b in 60% yield and using amines con-
taining heterocycles resulted in indazolones 25 and 26 in 83% and
62% yield, respectively.
The proposed mechanistic model for this reaction is as follows
(Scheme 2). The reaction begins by generation of aci-nitro inter-
mediate A from o-nitrobenzyl alcohol.10 The aci-nitro intermediate
then undergoes a 6π electrocyclization to generate N-hydroxy an-
thranil species B. Ring fragmentation occurs to form C and subse-
quent loss of water gives o-nitrosobenzaldehyde 7. The primary
amine then undergoes condensation with 7 at the nitroso and/or the
aldehyde to give D and/or E, respectively.9 Intermediates D and E
can both lead to indazolone ring formation through events involv-
ing cyclization/dehydration/tautomerization.
Scheme 2. Proposed reaction mechanism.
O-
N+
OH
N+
O
N
OH
N
hn
O
OH
O
OH
OH
OH
OH
OH
A
B
C
General Procedure for Indazolone Synthesis. A stir bar, o-
nitrobenzyl alcohol (0.5 mmol), amine (1.0 mmol), and PBS solu-
tion (10 mL) were added to a 16x125 mm quartz test tube. The top
of the test tube was covered and sealed using Parafilm. This reac-
tion mixture was then suspended inside the ThermalSpa UV source,
with approximately 2.5 cm distance between the light source and
irradiation vessel (no filters were employed). House air cooling de-
livered via Tygon tubing was used for the duration of the 24 h re-
action to maintain the reaction temperature at 30 °C (the reaction
mixture temperature was measured by thermometer at the end of
the reaction). The reaction mixture was transferred using dichloro-
methane to a solution of HCl (30 mL, 1 M), and then extracted us-
ing dichloromethane (3 x 50 mL). The organic layers were com-
bined, dried using magnesium sulfate, and filtered. Dichloro-
methane was removed using rotatory evaporation and the crude
mixture was purified by flash column chromatography on silica gel
with a gradient of dichloromethane and methanol – generally, the
gradient was with 50 mL of 1% methanol in dichloromethane fol-
lowed by 200 mL 2.5% methanol in dichloromethane followed by
50 mL 5% methanol in dichloromethane. Compounds 14 and 25
were purified using a CombiFlash Rf+ (Teledyne Isco). Note: 25
O
N
H2O
H
R
N
O
N
H
OH
N
D
N
R
O
OH
N
O
R
H
7
N
O
E
In summary, we report a green photochemical route to inda-
zolones from o-nitrobenzyl alcohols and primary amines in an
aqueous solvent at room temperature using an affordable, low-
power, and easy to operate photoreactor. These reactions proceed
through o-nitrosobenzaldehyde as the key reactive intermediate.
Although exploiting this intermediate in base-mediated indazolone
synthesis was previously demonstrated by our group, the protocol
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remained in the acidic aqueous layer, which was dried and sub-
jected to purification directly.
2-Cyclohexyl-1,2-dihydro-3H-indazol-3-one (11). Yield: 77
mg (71%) as yellow foam. 1H NMR (400 MHz, CDCl3) δ 9.06 (s,
1H), 7.73 (d, J=7.9, 1H), 7.43 (t, J=7.6, 1H), 7.23 (d, J=8.2, 1H),
7.09 (t, J=7.6, 1H), 4.44 – 4.27 (m, 1H), 1.88 – 1.60 (m, 7H), 1.38
– 1.22 (m, 2H), 1.16 – 1.02 (m, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 161.6, 146.5, 131.4, 123.4, 121.7, 118.6, 112.3, 53.5,
31.0, 25.5, 25.2; HRMS (Orbitrap): Calcd for [C13H17N2O+,
M+H]+: 217.1335, found: 217.1334. Data matches literature va-
lues.9
1
2
3
4
5
6
7
8
Procedure for Large Scale Synthesis of 1. A stir bar, o-ni-
trobenzyl alcohol (0.77 g, 5 mmol), amine (0.99 mL, 10 mmol),
and PBS solution (100 mL) were added to a 125 mL Chemglass
recovery flask. This reaction mixture was then suspended inside the
ThermalSpa UV source, with approximately 0.5 cm distance be-
tween the light source and irradiation vessel (no filters were em-
ployed). House air cooling delivered via Tygon tubing was used for
the duration of the 24 h reaction to maintain the reaction tempera-
ture at 30 °C (the reaction mixture temperature was measured by
thermometer at the end of the reaction). The reaction mixture was
transferred using dichloromethane to a solution of aq. HCl (300
mL, 1 M), and then extracted using dichloromethane (3 x 100 mL).
The organic layers were combined, dried using magnesium sulfate,
and filtered. The dichloromethane was removed using rotatory
evaporation and the crude mixture was purified by flash column
chromatography on silica gel with a 2.5% methanol in dichloro-
methane solution. Yield: 524 mg (55%) as brown oil.
2-Phenethyl-1,2-dihydro-3H-indazol-3-one (12). Yield: 70 mg
(59%) as yellow solid; mp: 156-158 °C. 1H NMR (400 MHz,
CDCl3) δ 8.64 (s, 1H), 7.79 (d, J=7.9, 1H), 7.49 (t, J=7.7, 1H), 7.28
– 7.11 (m, 7H), 4.17 (t, J=7.5, 2H), 3.10 (t, J=7.5, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 162.2, 146.5, 138.1, 131.7, 128.71,
128.69, 126.7, 123.5, 122.1, 118.5, 112.3, 45.8, 34.7. HRMS (Or-
bitrap): Calcd for [C15H15N2O+, M+H]+: 239.1179, found:
239.1185. Data matches literature values.9
9
10
11
12
13
14
15
16
17
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20
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44
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48
49
50
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58
59
60
2-Butyl-6-methoxy-1,2-dihydro-3H-indazol-3-one
(13).
1
Yield: 76 mg (69%) as beige powder; mp: 101-103 °C. H NMR
(400 MHz, CDCl3) δ 8.09 (s, 1H), 7.65 (d, J=8.7, 1H), 6.74 (d,
J=8.8, 1H), 6.62 (d, J=2.1, 1H), 3.81 (s, 3H), 3.80 (t, J=7.4, 2H),
1.69 (p, J=7.4, 2H), 1.38 – 1.23 (m, 2H), 0.89 (t, J=7.4, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 163.2, 162.5, 148.5, 124.6,
112.2, 112.0, 95.0, 55.6, 44.1, 30.3, 19.9, 13.6; HRMS (Orbitrap):
2-Butyl-1,2-dihydro-3H-indazol-3-one (1). Yield: 64 mg
(67%), brown oil; 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 7.73
(d, J=8.2, 1H), 7.45 (t, J=7.6, 1H), 7.22 (d, J=8.2, 1H), 7.11 (t,
J=7.6, 1H), 3.89 (t, J=7.2, 2H), 1.73 (q, J=7.4, 2H), 1.29 (h, J=7.4,
2H), 0.86 (t, J=7.2, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.8,
146.1, 131.5, 123.3, 121.7, 118.1, 112.1, 43.9, 30.4, 19.9, 13.6;
HRMS (Orbitrap): Calcd for [C11H15N2O+, M+H]+: 191.1179,
found: 191.1176. Data matches literature values2
+
Calcd for [C12H17N2O2 , M+H]+: 221.1285, found: 221.1281.
2-Butyl-5-chloro-1,2-dihydro-3H-indazol-3-one (14). Yield:
1
12 mg (10%) as tan solid; mp: 172-174 °C. H NMR (400 MHz,
CDCl3) δ 7.84 (s, 1H), 7.76 (s, 1H), 7.53 – 7.40 (m, 1H), 7.15 (d,
J=8.6, 1H), 3.87 (t, J=7.3, 2H), 1.73 (q, J=7.4, 2H), 1.34 (p, J=7.4,
2H), 0.92 (t, J=7.3, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
161.2, 144.8, 132.0, 128.1, 123.3, 120.4, 113.6, 44.2, 30.3, 19.9,
13.6; HRMS (Orbitrap): Calcd for [C11H14ClN2O+, M+H]+:
225.0789, found: 225.0784. Data matches literature values.9
2-Isopropyl-1,2-dihydro-3H-indazol-3-one (2). Yield: 57 mg
(65%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H),
7.75 (d, J=7.9, 1H), 7.50 – 7.41 (m, 1H), 7.23 (d, J=8.2, 1H), 7.13
(t, J=7.5, 1H), 4.79 (hept, J=6.8, 1H), 1.36 (d, J=6.8, 6H);
13C{1H} NMR (101 MHz, CDCl3) δ 162.0, 146.9, 131.5, 123.5,
122.1, 119.1, 112.5, 46.0, 20.4; HRMS (Orbitrap): Calcd for
[C10H13N2O+, M+H]+: 177.1022, found: 177.1019. Data matches
literature values.2
2-Butyl-7-methyl-1,2-dihydro-3H-indazol-3-one (15). Yield:
72 mg (69%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.73 (s,
1H), 7.56 (d, J=7.8, 1H), 7.26 (d, J=7.3, 1H), 7.04 (t, J=7.5, 1H),
3.85 (t, J=7.4, 2H), 2.38 (s, 3H), 1.71 (p, J=7.4, 2H), 1.27 (h, J=7.4,
2H), 0.85 (t, J=7.4, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.4,
145. 8, 131.8, 122.2, 120.8, 118.2, 118.1, 44.0, 30.4, 19.9, 15.9,
13.6; HRMS (Orbitrap): Calcd for [C12H17N2O+, M+H]+: 205.1335,
found: 205.1333. Data matches literature values.9
2-(Tert-butyl)-1,2-dihydro-3H-indazol-3-one (8). Yield: 70
mg (74%) as tan solid; mp: decomposes at 190 °C. 1H NMR (400
MHz, CDCl3) δ 7.74 (d, J=7.8, 1H), 7.45 (t, J=7.7, 1H), 7.30 (s,
1H), 7.22 – 7.09 (m, 2H), 1.63 (s, 9H); 13C{1H} NMR (101 MHz,
CDCl3) δ 163.9, 146.7, 131.5, 123.5, 122.3, 121.0, 112.3, 58.4,
27.5; HRMS (Orbitrap): Calcd for [C11H15N2O+, M+H]+: 191.1179,
found: 191.1178. Data matches literature values.9
2-Cyclopentyl-7-methyl-1,2-dihydro-3H-indazol-3-one (16).
Yield: 60 mg (55%) as red amorphous solid. 1H NMR (400 MHz,
CDCl3) δ 7.60 (d, J=7.8, 1H), 7.27 (d, J=7.5, 1H), 7.26 (s, 1H), 7.09
(t, J=7.5, 1H), 4.88 (q, J=9.2, 6.3, 1H), 2.38 (s, 3H), 2.06 – 1.92
(m, 2H), 1.89 – 1.76 (m, 4H), 1.71 – 1.56 (m, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 163.2, 146.3, 132.0, 122.8, 122.5, 121.0,
119.5, 55. 0, 29.9, 24.4, 15.8; HRMS (Orbitrap): Calcd for
[C13H17N2O+, M+H]+: 217.1335, found: 217.1334.
2-Heptyl-1,2-dihydro-3H-indazol-3-one (9). Yield: 62 mg
1
(53%) as brown oil. H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H),
7.80 (d, J=7.9, 1H), 7.49 (t, J=7.7, 1H), 7.24 (d, J=8.3, 1H), 7.21 –
7.12 (m, 1H), 3.88 (t, J=7.3, 2H), 1.76 (p, J=7.3, 2H), 1.34 – 1.21
(m, 10H), 0.86 (t, J=6.7, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
161.8, 146.2, 131.5, 123.4, 121.8, 118.2, 112.1, 44.3, 31.7, 28.9,
28.4, 26.7, 22.5, 14.0; HRMS (Orbitrap): Calcd for [C14H21N2O+,
M+H]+: 233.1648, found: 233.1644.
2-Cyclohexyl-7-methyl-1,2-dihydro-3H-indazol-3-one (17).
1
Yield: 65 mg (56%) as brown oil. H NMR (400 MHz, CDCl3) δ
7.65 (s, 1H), 7.60 (d, J=7.8, 1H), 7.28 (d, J=7.2, 1H), 7.08 (t, J=7.5,
1H), 4.37 – 4.26 (m, 1H), 2.41 (s, 3H), 1.87 – 1.76 (m, 5H), 1.72 –
1.66 (m, 2H), 1.37 – 1.30 (m, 2H), 1.19 – 1.13 (m, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 162.5, 146.3, 132.0, 122.54, 122.46,
121.0, 119.2, 53.5, 30.8, 25.5, 25.2, 15.9; HRMS (Orbitrap): Calcd
for [C14H19N2O+, M+H]+: 231.1492, found: 231.1490.
2-Cyclopentyl-1,2-dihydro-3H-indazol-3-one (10). Yield: 75
mg (74%) as dark orange solid; mp: 102-104 °C. H NMR (400
1
MHz, CDCl3) δ 9.12 (s, 1H), 7.70 (d, J=7.9, 1H), 7.42 (t, J=7.7,
1H), 7.22 (d, J=8.2, 1H), 7.09 (t, J=7.5, 1H), 4.88 (p, J=7.9, 1H),
2.00 – 1.72 (m, 6H), 1.65 – 1.51 (m, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 162.08, 146.55, 131.43, 123.26, 121.80, 118.49, 112.38,
54.86, 30.16, 24.44; HRMS (Orbitrap): Calcd for [C12H15N2O+,
M+H]+: 203.1179, found: 203.1176. Data matches literature va-
lues.9
2-Butyl-5-methyl-1,2-dihydro-3H-indazol-3-one (18). Yield:
76 mg (74%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.07 (s,
1H), 7.52 (s, 1H), 7.29 (d, J=8.4, 1H), 7.11 (d, J=8.4, 1H), 3.84 (t,
J=7.3, 2H), 2.37 (s, 3H), 1.77 – 1.66 (m, 2H), 1.39 – 1.23 (m, 2H),
0.89 (t, J=7.4, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 162.4,
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145.0, 133.0, 132.0, 123.0, 119.3, 112.1, 44.0, 30.3, 21.0, 19.9,
2-((Tetrahydrofuran-2-yl)methyl)-1,2-dihydro-3H-indazol-
3-one (26). Yield: 68 mg (62%) as dark orange solid; mp: 121-
123 °C. 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.84 (d, J=7.9,
1H), 7.48 (t, J=7.7, 1H), 7.24 – 7.12 (m, 2H), 4.35 – 4.25 (m, 1H),
4.22 – 4.11 (m, 1H), 3.99 – 3.87 (m, 1H), 3.84 – 3.66 (m, 2H), 2.13
– 1.99 (m, 1H), 1.97 – 1.84 (m, 2H), 1.73 – 1.60 (m, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 161.7, 146.5, 131.6, 123.8, 122.1,
118.7, 112.1, 78.9, 68.4, 46.7, 28.6, 25.7; HRMS (Orbitrap): Calcd
13.6; HRMS (Orbitrap): Calcd for [C12H17N2O+, M+H]+: 205.1335,
found: 205.1334.
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2-(Cyclopropylmethyl)-1,2-dihydro-3H-indazol-3-one (19).
Yield: 59 mg (63%) as red crystals; mp: 139-141 °C. 1H NMR (400
MHz, CDCl3) δ 7.82 (d, J=7.8, 1H), 7.78 (s, 1H), 7.50 (t, J=7.8,
1H), 7.24 (d, J=8.2, 1H), 7.18 (t, J=7.5, 1H), 3.74 (d, J=7.1, 2H),
1.19 – 1.13 (m, 1H), 0.64 – 0.56 (m, 2H), 0.44 – 0.37 (m, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ 162.2, 146.8, 131.7, 123.8,
122.5, 119.4, 112.4, 48.7, 9.6, 3.6; HRMS (Orbitrap): Calcd for
[C11H13N2O+, M+H]+: 189.1022, found: 189.1022.
+
for [C12H15N2O2 , M+H]+: 219.1128, found: 219.1124.
ASSOCIATED CONTENT
Supporting Information
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2-Benzyl-1,2-dihydro-3H-indazol-3-one (21). Yield: 77 mg
(69%) as black crystals; mp: 170-172 °C. H NMR (400 MHz,
The Supporting Information is available free of charge on the ACS
Publications website.
1
CDCl3) δ 7.82 (d, J=7.5, 1H), 7.46 (t, J=7.7, 1H), 7.35 – 7.23 (m,
6H), 7.22 – 7.09 (m, 2H), 5.00 (s, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 162.6, 162.5, 146.94, 146.88, 135.5, 131.91, 131.89,
128.96, 128.93, 128.84, 128.38, 128.30, 128.27, 128.19, 128.17,
124.00, 123.95, 122.71, 122.59, 119.1, 112.51, 112.49, 47.99,
47.97; HRMS (Orbitrap): Calcd for [C14H13N2O+, M+H]+:
225.1022, found: 225.1016. Data matches literature values.7
Characterization data: 1H and 13C NMR spectra (PDF).
AUTHOR INFORMATION
Corresponding Author
*mjkurth@ucdavis.edu
Author Contributions
§These authors contributed equally.
2-(1-Phenylethyl)-1,2-dihydro-3H-indazol-3-one (22). Yield:
66 mg (56%) as black oil. 1H NMR (400 MHz, CDCl3) δ 7.80 (d,
J=7.6, 1H), 7.48 – 7.23 (m, 7H), 7.19 – 7.13 (m, 2H), 5.85 (q, J=7.0,
1H), 1.74 (d, J=7.1, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
162.2, 147.97, 146.95, 139.4, 139.34, 139.31, 131.7, 128.8, 128.1,
128.0, 127.33, 127.26, 123.9, 123.83, 123.81, 122.41, 122.37,
122.34, 119.22, 119.17, 112.6, 52.2, 17.6, 17.52, 17.49; HRMS
(Orbitrap): Calcd for [C15H15N2O+, M+H]+: 239.1179, found:
239.1174.
ORCID
Jie S. Zhu: 0000-0003-3009-4135
Mark J. Kurth: 0000-0001-8496-6125
ACKNOWLEDGMENT
The authors gratefully acknowledge financial support from the Na-
tional Institutes of Health (DK072517 and DK067003). Funding
for NMR spectrometers was provided by National Science Foun-
dation (DBI722538 and CHE9808183) and National Institute of
Environmental Health (ES005707-13) grants. The authors thank
Dr. Ping Yu (UC Davis) for assistance with NMR spectroscopy and
Prof. Jared T. Shaw (UC Davis) for helpful discussions. J.S.Z. is
supported by the UC Davis Tara K. Telford CF Fund, UC Davis
Dissertation Year Fellowship, and R. Bryan Miller Graduate Fel-
lowship. N.K. is supported by the UC Davis Provost’s Undergrad-
uate Fellowship.
2-(1,2,3,4-Tetrahydronaphthalen-1-yl)-1,2-dihydro-3H-in-
1
dazol-3-one (23). Yield: 68 mg (51%) as brown foam. H NMR
(400 MHz, CDCl3) δ 7.93 (d, J=7.9, 1H), 7.55 – 7.49 (m, 1H), 7.27
– 7.11 (m, 6H), 6.51 (s, 1H), 5.89 (t, J=7.4, 1H), 2.98 – 2.81 (m,
2H), 2.29 – 2.21 (m, 1H), 2.15 – 2.04 (m, 2H), 1.96 – 1.86 (m, 1H);
13C{1H} NMR (201 MHz, CDCl3) δ 162.7, 146.8, 139.0, 133.3,
131.7, 129.7, 127.8, 127.4, 126.7, 124.0, 122.7, 119.6, 112.6, 52.4,
29.3, 28.6, 21.2; HRMS (Orbitrap): Calcd for [C17H17N2O+,
M+H]+: 265.1335, found: 265.1334.
2-Allyl-1,2-dihydro-3H-indazol-3-one (24a). Yield: 55 mg
(63%) as red solid; mp: 116-118 °C. 1H NMR (400 MHz, CDCl3)
δ = 7.94 (s, 1H), 7.82 (d, J=7.8, 1H), 7.55 – 7.46 (m, 1H), 7.27 –
7.14 (m, 2H), 5.99 – 5.83 (m, 1H), 5.37 – 5.24 (m, 2H), 4.51 (dd,
J=5.9, 1.6, 2H); 13C{1H} NMR (201 MHz, CDCl3) δ = 162.2,
146.7, 131.8, 131.7, 123.7, 122.4, 119.3, 118.9, 112.3, 46.6; HRMS
(Orbitrap): Calcd for [C10H11N2O+, M+H]+: 175.0866, found:
175.0865.
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1
Yield: (60%) as pale pink amorphous solid. H NMR (400 MHz,
CD2Cl2) δ = 7.78 (d, J=7.8, 1H), 7.57 (t, J=7.8, 1H), 7.29 (d, J=8.2,
1H), 7.24 (t, J=7.5, 1H), 7.17 (s, 1H), 4.63 (d, J=2.3, 2H), 2.43 (t,
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1
(25). Yield: 96 mg (83%) as yellow fibers. H NMR (400 MHz,
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1H), 7.15 (t, J=7.3, 1H), 4.33 (broad, 2H), 3.11 (broad, 2H), 2.10
(broad, 4H), 1.95 (broad, 4H); 13C{1H} NMR (201 MHz, CD3) δ =
162.3, 146.7, 132.5, 122.6, 122.1, 116.2, 112.2, 54.4, 52.5, 40.8,
22.6; HRMS (Orbitrap): Calcd for [C13H18N3O+, M+H]+: 232.1444,
found: 232.1446.
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ACS Paragon Plus Environment

Page 7 of 7
The Journal of Organic Chemistry
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H
N
NO2
R2
R1
R1
N
R2
H2N
OH
365 nm
H2O, 30 °C, 24 h
O
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mild conditions
aqueous solvent
inexpensive photoreactor
commercially available
building blocks
21 examples
ACS Paragon Plus Environment