Synthesis of Indazolones via Friedel-Crafts Cyclization of Blocked (Masked) N-Isocyanates

Article abstract of DOI:10.1021/acs.joc.7b01607

Nitrogen-substituted isocyanates (N-isocyanates) are rare amphoteric reagents with high, but underdeveloped synthetic potential. Herein, we study the formation of indazolones by Friedel-Crafts cyclization of N-isocyanates using blocked (masked) N-isocyanate precursors: the effect of the masking group and the reaction scope have been delineated. Substrate synthesis has also been improved using a reported copper-catalyzed coupling of arylbismuth(V) reagents that is compatible with the hemilabile OPh blocking group.

Full text of DOI:10.1021/acs.joc.7b01607

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Note
Synthesis of Indazolones via Friedel-Crafts
Cyclization of Blocked (Masked) N-Isocyanates
Eslam Basiouny Elkaeed, Jing An, and Andre Martin Beauchemin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01607 • Publication Date (Web): 22 Aug 2017
Downloaded from http://pubs.acs.org on August 23, 2017
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Synthesis of Indazolones via Friedel-Crafts Cyclization of Blocked
(Masked) N-Isocyanates
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Eslam B. Elkaeed,ab Jing An,a André M. Beauchemina*
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a) Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular
Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON, K1N 6N5, Canada.
b) Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884,
Egypt.
ABSTRACT: Nitrogen-substituted isocyanates (N-isocyanates) are rare amphoteric reagents with
high, but underdeveloped synthetic potential. Herein, we study the formation of indazolones by
Friedel-Crafts cyclization of N-isocyanates using blocked (masked) N-isocyanate precursors: the
effect of the masking group and the reaction scope have been delineated. Substrate synthesis has
also been improved using a reported copper-catalyzed coupling of arylbismuth (V) reagents that
is compatible with the hemilabile OPh blocking group.
The development of new synthetic methods to form nitrogen heterocycles continues to attract
significant interest, and this is stimulated by their importance as core subunits of pharmaceuticals
and agrochemicals. In this context, C-substituted isocyanates are common building blocks
(>100,000 publications and patents in the literature) and are often used in heterocyclic synthesis.
In contrast, synthetic applications of nitrogen-substituted isocyanates (N-isocyanates) are rare,1
despite the presence of the NNCO motif in over 50 agrochemicals and pharmaceuticals.2 This
scarcity is likely due to the amphotericity of these reactive intermediates, which contain both a
nucleophile and a potent electrophile in their structure, resulting in a tendency to dimerize even at
–40 °C.1 To pursue new reactivity of N-isocyanates in cycloadditions3 and cascade reactions,4 we
have recently developed an approach relying on blocked5 (masked) N-isocyanate reagents, which
suppresses side reactions through controlled release of N-isocyanates either upon heating or using
a base as catalyst. Given the importance of indazole and indazolone-derived cores (Scheme 1A),6
and the use of indazolones in medicinal chemistry including in anticancer,6a anti-inflammatory,7
antitumor,8 analgesic,9 antiviral,10 antihyperglycemic,11 antipsychotic12 and antihyperlipidemic13
efforts, we were drawn to indazolones as synthetic targets. Herein, a systematic investigation of
their synthesis through Friedel-Crafts cyclizations is presented, featuring the use of hydrazine
derivatives as N-isocyanate precursors (Scheme 1B).
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Scheme 1. (A) Examples of indazole and indazolone derivatives used as pharmaceuticals. (B) This
work: synthesis of indazolones from blocked (masked) N-isocyanates
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8
N
A
NMe2
Me
9
O
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O
NH
Benzydamine
(Analgesic, anti-inflammatory)
Granisetron
(Antiemetic)
N
N
Bn
N
N
Me
B
R2
R2
O
R2
N
(−HLG)
N
N
N
C
O
N
LG
R1
R1
R1
NH
H
Δ
Δ
O
Blocked N-isocyanate
N-Isocyanate
Many synthetic approaches have been developed to form indazolones (Scheme 2), including (1)
CuI/proline-catalyzed intramolecular C–N bond formation of 2-chloro-benzoichydrazides,14 (2)
PIFA-mediated formation of N- acylnitrenium intermediates, followed by intramolecular trapping
by the amine,15 (3) CuO-catalyzed coupling of 2-haloarylcarboxylic acids with methylhydrazine,16
(4) intramolecular [2+2] cycloaddition of ketene and N-nitroso compounds,17 (5) cyclization of N-
aryl-o-nitrobenzamides through a low-valent titanium reagent18 and (6) Rh-catalyzed C-H
activation/C-N bond formation and Cu-catalyzed N-N bond formation between arylimidates and
azides.19 These methods are complementary given the need to access various substitution patterns;
however most methods rely on disubstituted aromatic starting materials.
Scheme 2. Selected approaches to form indazolones
R1
Cl
(4)
(1)
O
N
R2
t-BuOK, rt, 18h
N
H
CuI
R2
N
R1
L-proline
CO2Et
N
H
O
R1
N
OH
(2)
(5)
NHR1
NHR3
NO2
PIFA
N R3
R2
TiCl4/Fe
R2
R2
NHR3
Base
O
R1, R3 = H, alkyl, aryl
O
X
O
(6)
H
(3)
R2
R2
CuO, K2CO3
NH2NHR1
[Rh], [Cu], O2
OH
NH
OR
R2
R1
N3
O
X= Cl, Br
R2
(7)
R2
N
Stollé's work
O
150-250 °C
Δ
N
N
C
N3
N
R1
NH
R1
R1
−N2
O
O
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In addition, there is the pioneering work of Stollé and co-workers, who reported in 1927 the
thermolysis of N,N-disubstituted carbamoyl azides to form indazolones (4 examples).20 This key
precedent showed that N,N-diaryl and N-alkyl-N-aryl carbamoyl azides undergo a thermal aza-
Curtius rearrangement, yielding the desired indazolone products after cyclization of the N-aryl-N-
isocyanates [(7), Scheme 2]. However, for two difficult cyclizations, significant amounts of N-
isocyanate dimer by-products were also isolated.21 This prior work, and its reinvestigation by
others22 offered a rare opportunity to compare the reactivity of N-isocyanates with that of their
blocked (masked) N-isocyanate precursors. In addition, an alternative route would address the
safety and scalability issues inherently associated with the use of azide precursors.
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Given the versatility of phenol as a blocking (masking) group for other synthetic applications of
N-isocyanates,1c phenyl carbazate 1a was selected as the model substrate for optimization of the
reaction conditions (Table 1).
Table 1. Optimization of reaction conditionsa
Me
N
NH
Me
N
O
N
OPh
H
Conditions
O
2a
1a
yieldb
(%)
entry T (°C)
additive
conc (M) solvent
t (h)
1
150
165
165
165
180
180d
180d
180d
180d
180d
180
180
180
-
0.1
0.1
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
2
2
2
2
3
3
3
3
3
3
3
3
3
48
2
-
81
3
-
0.5
66
4
-
0.05
0.1
85
5
-
>99 (79)c
6
-
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
diglyme
PhCF3
o-xylene
o-C6H4Cl2
PhCl
50
7
-
80
8
-
80
9
-
81
10
11
12
13
-
83
Acetic acide
Et3Ne
PhCl
73
PhCl
66
Citric acide
PhCl
6
a
All
reactions were carried out in sealed microwave vials unless specified. b NMR yield based on 1,3,5-
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trimethoxybenzene as internal standard. c Isolated yield d Conventional heating (oil bath). e 1 equiv
of the additive was used.
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Based on the conditions reported in the original work by Stollé using carbamoyl azides (~140 °C,
refluxing xylene)20 and in its reinvestigation by Reichen (~207 °C, refluxing tetralin),22 initial
cyclization attempts with carbazate 1a involved heating at 150 °C (Table 1). Since only a modest
48% yield was obtained (entry 1), subsequent attempts involved heating at higher temperatures
(entries 2-5). As expected, the use of more dilute solutions led to improved yields at 165 °C (entries
3-4), likely by minimizing dimerization of the N-isocyanate intermediate, which is a known side-
reaction.1 Gratifyingly, quantitative conversion was observed at 180 °C (0.1 M, entry 5), allowing
isolation of the desired indazolone 2a in a 79% yield. While heating was typically performed using
a microwave reactor, this reactivity also proceeded well upon conventional heating. Using these
conditions, solvent effects could be probed in several high-boiling solvents (entries 6-10). Only
the reaction in diglyme proved less efficient (entry 6), and the other aromatic solvents led to better
results (80-83% yield, entries 7-10). The selection of PhCF3 over the other solvents was made on
the basis of its low cost and ease of solvent evaporation. Finally, the effect of several additives
was investigated (e.g., entries 11-13). It was found that the addition of either acids or bases did not
improve the reaction yield or efficiency; moreover citric acid almost suppressed the reactivity (6%
yield).4e The use of both Brønsted [TsOH, MsOH, (PhO)2PO2H] and Lewis acids (AlCl3, TiCl4,
BF3·OEt2) was also explored to facilitate the process; unfortunately these trials were unsuccessful.
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Reasoning that the nature of the blocking group would also have an impact on reaction efficiency,
several hydrazine derivatives were synthesized to allow a thorough comparison. Substrates with
various leaving groups (1a1-a7, 1a), including alcohols, phenol, thiols and amines could then be
heated at 150 °C, 180 °C and 210 °C to probe their ability to serve as N-isocyanate precursors and
form indazolones (Table 2).
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Table 2. Survey of leaving groups
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7
8
Me
N
O
Me
N
NH
(−HLG)
N
LG
H
PhCF3 (0.1 M)
150-210 °C, 3 h
1a1-a7, 1a
2a
O
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yielda (%)
entry LG
(% unreacted SM)b
180 °C
150 °C
210 °C
43
(28)
0
29
(63)
1
2
3
4
5
6
7
8
Ot-Bu (1a1)
OMe (1a2)
NHPh (1a3)
SEt (1a4)
(100)
0
0
0
(100)
(100)
(100)
0
8
(78)
60
(25)
(100)
20
(70)
70
(5)
70
(0)
35
(20)
73
(4)
56
(0)
SPh (1a5)
0
34
(66)
80
(16)
OCH2CF3 (1a6)
N(i-Pr)2 (1a7)
OPh (1a)
(100)
25
(40)
82
(16)
75
(25)
45
(40)
>97
(0)
95
(0)
b
a
NMR yield based on 1,3,5-trimethoxybenzene as internal standard. Amount of unreacted
starting material determined using the internal standard.
Several reactivity trends were observed from this survey of different leaving (blocking) groups on
the N-isocyanate precursor (Table 2). The results indicated that the reaction can proceed in yields
around 70% using different groups, with several of them providing high reactivity at 180 °C under
microwave heating (PhOH, EtSH, PhSH and i-Pr2NH). Interestingly, the use of PhOH not only
afforded higher yields, but the yield did not vary significantly at a higher temperature (210 °C) in
contrast to what was observed for other groups such as PhSH and i-Pr2NH (entries 5, 7). While
this observation warrants further studies, it can be explained by the ability of phenol to reversibly
add to the N-isocyanate under the reaction conditions, in contrast to some groups that would act as
"irreversible" leaving groups either due to reduced nucleophilicity (PhSH) or steric hindrance
(i-Pr2NH). From these studies, it appeared that the optimal procedure for the preparation of
indazolones involves the use of the corresponding phenyl carbazates in PhCF3 (0.1 M), and heating
at 180 °C. The reactivity trends above are consistent with the Friedel-Crafts cyclization being the
rate determining step, occurring efficiently only above 150 °C; related precursors (LG = OPh) are
known to form N-isocyanate at ca. 80-100 °C.4a,b
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In order to investigate the scope of this cyclization reaction, a series of carbazates (1a-o) were
synthesized according to a 5-step literature procedure (1a-k) or one step procedure (1l-o) (see
Supporting Information for details).4d These substrates could then be subjected to the optimized
conditions to determine the reaction scope, which had not been fully delineated by Stollé or
Reichen using carbamoyl azides.20,22 The results are presented in Table 3.
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Table 3. Substrate scope for indazolone formation using phenyl carbazates as N-isocyanate
precursorsa
R2
N
O
R2
(−PhOH)
N
N
OPh
R1
NH
R1
H
PhCF3 (0.1 M)
150-200 °C, 3-7 h
1a-o
O
2a-o
Me
Bn
Me
Ph
N
N
N
N
NH
NH
NH
NH
Cl
2a
O
2b
O
O
O
2d
2c
3 h, 180 °C
76%
7 h, 180 °C
71%
3 h, 180 °C
79%
5 h, 180 °C
76%
Me
Me
Me
Me
Me
N
N
N
N
NH
NH
NH
NH
Me
Me
2e
2g
2h
2f
O
O
O
O
3 h, 180 °C
74%
3 h, 180 °C
70%
3 h, 180 °C
91%
3 h, 200 °C
35%
O
O
F
NH
N
Me
Me
N
N
N
NH
NH
NH
2j
O
2k
2i
2l
O
O
3 h, 200 °C
15%
4 h, 150 °C
95%
3 h, 180 °C
93%
5 h, 180 °C
95%
O
O
O
N
N
N
NH
NH
NH
O
O
O
2o
2n
2m
3 h, 180 °C
90%
3 h, 180 °C
99%
3 h, 180 °C
97%
a All reactions were carried out in sealed microwave vials. Isolated yields are shown.
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Gratifyingly, the scope of this indazolone synthesis using blocked (masked) βN-aryl-N-isocyanate
precursors proved quite general (Table 3). This method accommodates both βN-alkyl and -aryl
substituted phenyl carbazates. The bulkier and inductively electron-withdrawing phenyl group
(entry 2b) needed a longer reaction time (7 h) while the methyl, benzyl and isopropyl derivatives
behaved similarly with average yield around 75% after a short reaction time (3 h, entries 2a, 2c
and 2g). As expected for a Friedel-Crafts reaction, aromatic carbazates with weakly activating
substituents showed better reactivity than those with weakly deactivating groups: 4-methyl and 2-
methyl-phenycarbazates afforded 2e and 2h in 91% and 74% yields (3 h), while 4-chloro and 2-
fluoro-phenylcarbazate needed 5 h to give 76% and 95% yields (entries 2d, 2j). Higher reaction
temperatures were needed to achieve cyclization to form the 2,4-dimethyl-substituted (2f) and N-
allyl (2i) indazolones, but the yields remained relatively low which indicates that subtle changes
can result in reduced yields. Conversely, the reaction was successful with a naphthalene derivative
(entry 2k), providing an excellent yield (95%) at a lower reaction temperature (150 °C). Moreover,
the reaction tolerated the presence of heterocyclic substituents, forming products including furan
(2l) and a cyclic ether (2n) ring systems. The reaction also proceeded uneventfully in the presence
of an ester functional group (entry 2o). Finally, it is also worth noting that Stollé reported that
heating N-methyl-o-tolyl carbamoyl azide to form 2h proceeded in 28% yield, and that 13% of a
N-isocyanate dimer was also isolated.20a In contrast, formation of 2h proceeded efficiently from
upon heating the phenyl carbazate precursor 1h (74% yield), suggesting that this new procedure
may be advantageous for difficult cyclizations.23
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With a broadly applicable indazolone synthesis developed using aromatic carbazates as N-
isocyanate precursors, we felt that one aspect of the process could benefit from more practicality:
substrate synthesis. As indicated previously, several substrates (carbazates 1a-k) were prepared in
5 steps according to the general procedure in the literature.4d Seeking to facilitate substrate
preparation from N-alkyl carbazates, we were drawn to the reports by Mäeorg and Ragnarsson that
pentavalent organobismuth (V) compounds can act as aryl donors in the presence of copper salts.24
This procedure allowed for a chemoselective arylation the β nitrogen atom using Ph3Bi(OAc)2 and
catalytic amount of Cu(OAc)2 at room temperature (Scheme 3), thus providing an efficient access
to β-N,N-disubstituted phenyl carbazates. While previous reports showed that this arylation
strategy worked well with robust derivatives (LG = Ot-Bu, OBn, etc.),24,25 we were pleased that
the hemilabile OPh substituent did not act as a leaving group under the reaction conditions. This
suggests that this strategy could be used for the synthesis of other N-isocyanate precursors.
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Scheme 3. Arylation of phenyl carbazates using a pentavalent bismuth reagenta
5
6
7
8
R
O
R
O
N
cat. Cu(OAc)2
N
Ph
O
N
OPh
Ph3Bi(OAc)2
H
N
OPh
+
H
H
9
1ll-oo
1l-o
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R
Yield
89%
R
Yield
O
1l
1n
1o
70%
70%
O
1m
81%
O
a Conditions: Carbazates 1ll-oo (1 equiv), anhydrous Cu(OAc)2 (0.05 equiv), Ph3Bi(OAc)2 (2
equiv), stirred at room temperature in CH2Cl2 (0.2 M) for 15 min-12 h. Isolated yields are shown.
In summary, we have developed a methodology that provides ready access to indazolones from
variety of carbazates acting as masked N-isocyanate precursors. This study avoids the use of
carbamoyl azides to form the N-isocyanate reactive intermediates, and studied the outcome of the
reaction for various blocking groups to identify phenol as the optimal N-isocyanate blocking
group. The development of other reactivity of N-isocyanates is ongoing and will be reported in
due course.
EXPERIMENTAL SECTION
General Information. All commercially available materials were used without further
purification unless otherwise noted. Solvents for reactions were obtained from solvent system or
or dried over 4Å molecular sieves. Microwave reactions were performed using a Biotage Initiator
Eight microwave reactor and microwave vials. Reactions were monitored by analytical thin layer
chromatography (TLC), using aluminum-backed plates, cut to size. TLC visualization was
achieved by UV light followed by staining with a potassium permanganate solution and heating.
Flash column chromatography was carried out using 40-63 µm silica gel. 1H NMR and 13C NMR
spectra were recorded on 300 MHz and 400 MHz spectrometers at ambient temperature, except
1
where noted. Spectral data is reported in ppm using solvent as the reference. H NMR: CDCl3
13
1
(7.26 ppm), DMSO-d6 (2.50 ppm). C NMR: CDCl3 (77.16 ppm), DMSO-d6 (39.52 ppm). H
NMR data was reported as: multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sept =
septet, m = multiplet), coupling constants (J) in Hz, and integration. 13C NMR was reported
indicating information from DEPT experiments. Infrared (IR) spectra were obtained as thin films
or as neat solids on FTIR instruments. High resolution mass spectroscopy (HRMS) was performed
by magnetic sector electron impact (EI) or Q-TOF electrospray ionization (ESI).
Carbazates 1a-e,4d 1ll-nn26 and Ph3Bi(OAc)2 are known compounds and were prepared
6,7
following literature procedures.
tert-Butyl 2-methyl-2-phenylhydrazine-1-carboxylate (1a1). To a round bottom flask charged
with stirrer and a solution of 1-methyl-1-phenylhydrazine (1, 0.366 g, 3.00 mmol, 1 equiv) in
CH2Cl2 (0.5 M) was added Boc2O (0.785 g, 3.60 mmol, 1.2 equiv) at 0 °C. Then the reaction was
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refluxed for 12 hours. The mixture was allowed to cool down to room temperature, concentrated
and the residue was purified by flash chromatography (hexanes/CH2Cl2 = 1:3 ~ 0:1) to afford tert-
butyl 2-methyl-2-phenylhydrazine-1-carboxylate (1a1, 0.450 g, 68% yield) as a yellowish white
solid; mp 98-100 °C. TLC Rf = 0.64 in CH2Cl2. 1H NMR (300 MHz, CDCl3) δ ppm 7.23 - 7.36
(m, 2 H) 6.81 - 6.94 (m, 3 H) 3.21 (s, 3 H) 1.54 (s, 9 H). 13C NMR (101 MHz, CDCl3) δ 154.8 (C),
149.8 (C), 129.0 (CH), 119.2 (CH), 112.6 (CH), 80.8 (C), 40.8 (CH3), 28.2 (CH3). IR (neat) 3249,
2982, 2813, 1700, 1598, 1496, 1275, 1157, 1122 cm-1. HRMS (EI): Exact mass calcd for
C12H18N2O2 [M]+: 222.1368. Found: 222.1357.
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Methyl 2-methyl-2-phenylhydrazine-1-carboxylate (1a2). To a round bottom flask charged
with stirrer and a solution of 1-methyl-1-phenylhydrazine (1, 0.366 g, 3.00 mmol, 1 equiv) in
CH2Cl2 (0.5 M) were added pyridine (0.237 g, 3.00 mmol, 1 equiv) and methyl chloroformate
(0.310 g, 3.30 mmol, 1.1 equiv) at 0 °C. Then the reaction was stirred at room temperature for 2
hours. The mixture was concentrated and the residue was dissolved in water and extracted three
times with diethyl ether. The organic layers were combined, washed with brine, dried over Na2SO4.
After filtration, the solvent was concentrated and the residue was purified by flash chromatography
(hexanes/CH2Cl2 = 3:7 ~ 0:1) to afford methyl 2-methyl-2-phenylhydrazine-1-carboxylate (1a2,
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0.340 g, 63% yield) as yellow oil. TLC Rf = 0.35 in 20% EtOAc/hexanes. H NMR (300 MHz,
CDCl3) d 7.59 - 7.68 (m, 2H), 7.16 - 7.26 (m, 3H), 4.12 (s, 3H), 3.53 (s, 3H). 13C NMR (101 MHz,
CDCl3) d 156.5 (C), 149.7 (C), 129.2 (CH), 119.7 (CH), 113.1 (CH), 52.6 (CH3), 40.9 (CH3). IR
(neat) 3267, 2954, 1710, 1599, 1496, 1447, 1218, 1116, 1064 cm-1. HRMS (EI): Exact mass calcd
for C9H12N2O2 [M]+: 180.0899. Found: 180.0899.
General procedure 1 (substrates 1a3-a7). The substrates were prepared from phenyl carbazate
1a and the appropriate nucleophile, in a modification of a literature procedure.4a A round bottom
flask was charged with a stir bar, phenyl 2-methyl-2-phenylhydrazine-1-carboxylate (1a, 1 equiv),
a nucleophile (1-2 equiv), DBU (20 mol%) and THF (0.3 M). The mixture was refluxed for the
specified time, concentrated, and purified by flash column chromatography to afford the desired
product.
2-Methyl-N,2-diphenylhydrazine-1-carboxamide (1a3). Synthesized according to general
procedure 1 using 1a (0.484 g, 2.00 mmol, 1 equiv), aniline (0.102 g, 2.20 mmol, 1.1 equiv), DBU
(0.060 g, 0.40 mmol), and THF (6.6 mL), reflux overnight. The title compound was purified by
column chromatography (hexanes/EtOAc = 5:1) to give a white solid (0.315 g, 65%); mp 155-157
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°C. TLC Rf = 0.4 in 33% EtOAc/hexanes. H NMR (300 MHz, CDCl3) d ppm 7.78 (br s, 1 H)
7.45 - 7.52 (m, 2 H) 7.26 - 7.39 (m, 4 H) 6.99 - 7.11 (m, 4 H) 6.27 (s, 1 H) 3.22 (s, 3 H); 13C NMR
(101 MHz, CDCl3) d 155.5 (C), 149.8 (C), 137.9 (C), 129.4 (CH), 128.9 (CH), 123.3 (CH), 121.8
(CH), 119.4 (CH), 114.7 (CH), 42.7 (CH3). IR (neat) 3321, 3234, 1670, 1590, 1413, 1402, 1323,
1229 cm-1. HRMS (EI): Exact mass calcd for C14H15N3O [M]+: 241.1215. Found: 241.12193.
S-Ethyl 2-methyl-2-phenylhydrazine-1-carbothioate (1a4). Synthesized according to general
procedure 1 using 1a (0.484 g, 2.00 mmol, 1.0 equiv), ethanethiol (0.186 g, 3.00 mmol, 1.5 equiv),
DBU (0.060 g, 0.40 mmol), and THF (6.6 mL), reflux for 2 hours. The title compound was purified
by column chromatography (hexanes/EtOAc = 8:1) to give a white solid (0.270 g, 64%); mp 109-
110 °C. TLC Rf = 0.71 in 33% EtOAc/hexanes. 1H NMR (300 MHz, CDCl3) d 7.27 - 7.35 (m,
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2H), 6.87 - 7.03 (m, 4H), 3.17 (s, 3H), 2.84 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H); 13C NMR
(101 MHz, CDCl3) d 174.6 (C), 148.5 (C), 128.9 (CH), 120.6 (CH), 113.4 (CH), 41.2 (CH3), 22.8
(CH2), 14.6 (CH3). IR (neat) 3159, 3047, 2968, 2893, 2801, 1640, 1597, 1493, 1450, 1200 cm-1.
HRMS (EI): Exact mass calcd for C10H14N2OS [M]+: 210.08268. Found: 210.08368.
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S-Phenyl 2-methyl-2-phenylhydrazine-1-carbothioate (1a5). Synthesized according to general
procedure 1 using 1a (0.363 g, 1.50 mmol, 1 equiv), thiophenol (0.330 g, 3.00 mmol, 2 equiv),
DBU (0.045 g, 0.30 mmol), and THF (5 mL), reflux for 5 hours. The title compound was purified
by column chromatography (hexanes/CH2Cl2 = 1:9 ~ 0:1) to give a white solid (0.320 g, 83%)%);
mp 169-170 °C. TLC Rf = 0.46 in CH2Cl2. 1H NMR (300 MHz, CDCl3) d 7.49 - 7.57 (m, 2H),
7.32 - 7.45 (m, 5H), 7.03 (d, J = 6.7 Hz, 4H), 3.25 (s, 3H); 13C NMR (101 MHz, CDCl3) d 172.8
(C), 148.4 (C), 135.1 (C), 129.0 (CH), 128.8 (CH), 128.6 (CH), 128.0 (CH), 121.1 (CH), 113.8
(CH), 41.6 (CH3). IR (neat) 3164, 3065, 2876, 1667, 1597, 1496, 1439, 1266, 1113, 704 cm-1.
HRMS (EI): Exact mass calcd for C14H14N2OS [M]+: 258.0827. Found: 258.08027.
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2,2,2-Trifluoroethyl 2-methyl-2-phenylhydrazine-1-carboxylate (1a6). Synthesized according
to general procedure 1 using 1a (0.242 g, 1.00 mmol, 1 equiv), 2,2,2-trifluoroethanol (0.150 g,
1.50 mmol, 1.5 equiv), DBU (0.030 g, 0.20 mmol), and THF (3.3 mL), reflux for 12 hours. The
title compound was purified by column chromatography (hexanes/CH2Cl2 = 1:1) to give a white
solid (0.186 g, 75%); mp 103-104 °C. TLC Rf = 0.57 in 20% EtOAc/hexanes. 1H NMR (300 MHz,
CDCl3) d 7.24 - 7.35 (m, 2H), 6.79 - 7.00 (m, 4H), 4.53 (q, JH-F = 8.4 Hz, 2H), 3.18 (s, 3H); 13C
NMR (101 MHz, CDCl3) d 153.8 (C), 149.1 (C), 129.2 (CH), 120.3 (CH), 113.1 (C), 112.6 (CH),
61.0 (q, JC,F = 37 Hz, CH2), 40.8 (CH3). IR (neat) 3272, 2963, 2885, 1730, 1598, 1505, 1453, 1281,
1213, 1119 cm-1. HRMS (EI): Exact mass calcd for C10H11F3N2O2 [M]+: 248.0773. Found:
248.0760.
N,N-Diisopropyl-2-methyl-2-phenylhydrazine-1-carboxamide (1a7). Synthesized according to
general procedure 1 using 1a (0.242 g, 1.00 mmol, 1 equiv), diisopropylamine (0.111 g, 1.10
mmol, 1.1 equiv), DBU (0.030 g, 0.20 mmol), and THF (3.3 mL), reflux for 12 hours. The title
compound was purified by column chromatography (CH2Cl2) to give a white solid (0.127 g, 55%);
mp 122-124 °C. TLC Rf = 0.25 in CH2Cl2. 1H NMR (300 MHz, CDCl3) d 7.31 (dd, J = 1.5, 7.3
Hz, 2H), 6.82 - 6.93 (m, 3H), 6.18 (br s, 1H), 3.96 (sept., J = 6.9 Hz, 2H), 3.26 (s, 3H), 1.36 (d, J
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= 6.7 Hz, 12H); C NMR (101 MHz, CDCl3) d 156.7 (C), 150.4 (C), 129.0 (CH), 118.8 (CH),
112.5 (CH), 45.7 (CH), 41.4 (CH3), 21.4 (CH3). IR (neat) 3371, 2970, 1635, 1599, 1376, 1289 cm-
1. HRMS (EI): Exact mass calcd for C14H23N3O [M]+: 249.1841. Found: 249.1842.
General Procedure 2. Carbazates 1f-k were prepared according to a 5-step sequence. 2A: To a
solution of o-tolylhydrazine hydrochloride (A, 2.00 g, 16.3 mmol, 1 equiv) in MeOH (0.2 M) were
added triethylamine (3.31 g, 32.7 mmol, 2 equiv) and (Boc)2O (3.93 g, 18.0 mmol, 1.1 equiv) at 0
°C. Then the reaction was stirred at room temperature for 3 hours. The mixture was concentrated
and the residue was dissolved in EtOAc. The mixture was washed with water and brine, dried over
Na2SO4. After filtration, the solvent was concentrated and the residue was purified by flash
chromatography (hexanes/CH2Cl2 = 1:1 ~ 0:1) to afford tert-butyl 2-(o-tolyl)hydrazine-1-
carboxylate (B, 1.60 g, 44% yield) as a white solid.
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General Procedure 2B: To a solution of tert-butyl 2-(o-tolyl)hydrazine-1-carboxylate (B, 1.57 g,
7.09 mmol, 1.0 equiv) in CH2Cl2 (0.2 M) were added pyridine (1.12 g, 14.1 mmol, 2.0 equiv) and
NBS (1.38 g, 7.80 mmol, 1.1 equiv) at 0 °C. Then the reaction was stirred at room temperature for
20 minutes. The mixture was concentrated and the residue was purified by flash chromatography
(hexanes/EtOAc = 17:1) to afford tert-butyl 2-(o-tolyl)diazene-1-carboxylate (C, 1.41 g, 90%
yield) as an orange oil.
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General Procedure 2C: To a mixture of tert-butyl 2-(o-tolyl)diazene-1-carboxylate (C, 1.41 g,
6.41 mmol, 1.0 equiv) in THF (0.1 M) at –100 °C was added MeMgBr (3 M in Et2O, 2.13 mL, 1.0
equiv) under argon. Then the reaction was stirred at –100 °C for 20 minutes. The reaction was
quenched with sat. aq. NH4Cl. Then the mixture was extracted with EtOAc (30 mL x 3). The
combined organic layers were washed with brine (30 mL), dried over Na2SO4. After filtration, the
solvent was concentrated to give tert-butyl 2-methyl-2-(o-tolyl)hydrazine-1-carboxylate (D) as a
yellow oil, which was used in the next step without further purification.
General Procedure 2D: To a mixture of tert-butyl 2-methyl-2-(o-tolyl)hydrazine-1-carboxylate
(D, 1.49 g, 6.34 mmol, 1.0 equiv) in CH2Cl2 (0.5 M) was added TFA (3.61 g, 31.7 mmol, 5.0
equiv). Then the reaction was stirred at room temperature for 2 hours. The mixture was
concentrated to give 1-methyl-1-(o-tolyl)hydrazine (E) as a TFA salt, which was used in the next
step without further purification.
General Procedure 2E: To a mixture of 1-methyl-1-(o-tolyl)hydrazine (E, TFA salt, 0.340 g,
1.36 mmol, 1.0 equiv) and pyridine (0.215 g, 2.72 mmol, 2.0 equiv) in CH2Cl2 (0.2 M) at 0 °C was
added phenyl chloroformate (0.212 g, 1.36 mmol, 1.0 equiv). Then the reaction was stirred at room
temperature for 2 hours. The mixture was concentrated and the residue was dissolved in EtOAc
(50 mL). After extraction, the organic phase was washed with water (25 mL), brine (25 mL), dried
over Na2SO4. After filtration, the solvent was concentrated and the residue was purified by flash
chromatography (hexanes/EtOAc = 15:1) to afford phenyl 2-methyl-2-(o-tolyl)hydrazine-1-
carboxylate (1h, 0.203 g, 58% yield over 3 steps) as a white solid.
Phenyl 2-(2,4-dimethylphenyl)-2-methylhydrazine-1-carboxylate (1f). Synthesized according
to general procedure 2A-E using (2,4-dimethylphenyl)hydrazine hydrochloride (2.00 g, 11.6
mmol). The title compound was purified by column chromatography (hexanes/EtOAc = 12:1) to
give 1f (0.469 g, 15% over 5 steps) as a white solid; mp 113-115 °C. TLC Rf = 0.61 in 20%
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EtOAc/hexanes. H NMR (300 MHz, CDCl3) δ 7.29 - 7.42 (m, 2H), 7.07 - 7.26 (m, 4H), 6.94 -
7.07 (m, 2H), 3.15 (s, 3H), 2.39 (s, 3H), 2.31 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.4 (C),
151.0 (C), 146.2 (C), 134.4 (C), 132.7 (CH), 132.4 (CH), 129.5 (CH), 127.0 (CH), 125.7 (C), 121.7
(CH), 118.6 (CH), 43.3 (CH3), 21.0 (CH3), 18.6 (CH3). IR (neat) 3194, 3026, 2803, 1720, 1551,
1489, 1253, 1202 cn-1. HRMS (EI): Exact mass calcd for C16H18N2O2 [M]+: 270.1368. Found:
270.1373.
Phenyl 2-isopropyl-2-phenylhydrazine-1-carboxylate (1g). Synthesized according to general
procedure 2B-E using tert-butyl 2-phenylhydrazine-1-carboxylate (0.500 g, 2.40 mmol) and
isopropylmagmesium bromide (2.40 mmol). The title compound was purified by column
chromatography (hexanes/EtOAc = 15:1~10:1) to give 1g (0.149 g, 23% over 4 steps) as a white
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solid. TLC Rf = 0.41 in 10% EtOAc/hexanes. 1H NMR (300 MHz, CDCl3) δ 7.24 - 7.44 (m, 4H),
7.20 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 7.6 Hz, 1H), 6.81 - 7.01 (m, 3H), 6.47 (br s, 1H), 4.16 - 4.32
(m, 1H), 1.24 (d, J = 6.4 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 154.6 (C), 150.4 (C), 147.7 (C),
129.0 (CH), 125.1 (CH), 121.2 (CH), 120.9 (CH), 119.7 (CH), 113.7 (CH), 113.5 (CH), 50.8
(CH3). HRMS (EI): Exact mass calcd for C16H18N2O2 [M]+: 270.1368. Found: 270.1364.
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Phenyl 2-methyl-2-(o-tolyl)hydrazine-1-carboxylate (1h). Synthesized according to general
procedure 2A-E. The title compound was purified by column chromatography (hexanes/EtOAc =
15:1) to give 1h (0.203 g, 19% yield over 5 steps) as a white solid; mp 101-102 °C. TLC Rf = 0.24
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in 7% EtOAc/hexanes. H NMR (400 MHz, CDCl3) δ 7.33 - 7.39 (m, 2H), 7.18 - 7.25 (m, 4H),
7.01 - 7.18 (m, 3H), 6.68 (br s, 1H), 3.18 (s, 3H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
153.1 (C), 150.7 (C), 148.3 (C), 131.5 (CH), 129.3 (CH), 126.2 (CH), 125.4 (C), 124.5 (CH), 121.4
(CH), 118.3 (CH), 42.8 (CH3), 18.6 (CH3). IR (neat) 3197, 2960, 2884, 1721, 1594, 1507, 1243,
1201 cm-1. HRMS (EI): Exact mass calcd for C15H16N2O2 [M]+: 256.1212. Found: 256.1227.
Phenyl 2-allyl-2-phenylhydrazine-1-carboxylate (1i). Synthesized according to general
procedure 2B-E using tert-butyl 2-phenylhydrazine-1-carboxylate (0.500 g, 2.40 mmol) and
allylmagnesium bromide (2.40 mmol). The title compound was purified by column
chromatography (hexanes/EtOAc = 15:1) to give 1i (0.137 g, 27% over 4 steps) as a white solid.
TLC Rf = 0.54 in 20% EtOAc/hexanes. 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.39 - 7.45
(m, 2H), 7.15 - 7.28 (m, 5H), 6.89 (d, J = 8.0 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 5.88 - 6.06 (m,
1H), 5.37 (dd, J = 1.6, 17.2 Hz, 1H), 5.21 - 5.28 (m, 1H), 4.13 (d, J = 5.6 Hz, 2H). 13C NMR (75
MHz, DMSO-d6) δ 155.0 (C), 151.5 (C), 149.6 (C), 134.6 (CH), 130.3 (CH), 129.8 (CH), 126.1
(CH), 122.5 (CH), 119.6 (CH), 118.6 (CH2), 113.6 (CH), 55.8 (CH2). IR (neat) 3250, 1716, 1595,
1494, 1385, 1248, 1198, 1069, 1024 cm-1. HRMS (ESI): Exact mass calcd for C16H16N2O2 [M]+:
268.1212. Found: 268.1235.
Phenyl 2-(2-fluorophenyl)-2-methylhydrazine-1-carboxylate (1j). Synthesized according to
general procedure 2A-E using (2-fluorophenyl)hydrazine hydrochloride (2.00 g, 12.3 mmol). The
title compound was crystallized from (hexanes/EtOAc = 10:1) to give 1j (1.71 g, 53% over 5 steps)
as a white solid; mp 134-135 °C. TLC Rf = 0.35 in 20% EtOAc/hexanes. 1H NMR (400 MHz,
DMSO-d6) δ 10.04 (s, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.04 - 7.20 (m, 5H),
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6.97 (t, J = 8.0 Hz, 1H), 3.13 (s, 3H). C NMR (101 MHz, DMSO-d6) δ 153.7 (C), 153.2 (C),
150.4 (C), 137.9 (C), 129.1 (CH), 125.0 (CH), 124.2 (CH), 122.2 (CH), 121.3 (CH), 117.8 (CH),
116.2 (CH), 42.3 (CH3). IR (neat) 3214, 3026, 2997, 1722, 1596, 1489, 1249, 1212 cm-1. HRMS
(EI): Exact mass calcd for C14H13FN2O2 [M]+: 260.0961. Found: 260.0979.
Phenyl 2-methyl-2-(naphthalen-2-yl)hydrazine-1-carboxylate (1k). Synthesized according to
general procedure 2A-E using naphthalen-2-ylhydrazine hydrochloride (2.00 g, 10.3 mmol). The
title compound was purified by column chromatography (hexanes/EtOAc = 13:1~6:1) to give 1k
(0.480 g, 16% over 5 steps) as a white solid; mp 190-192 °C. TLC Rf = 0.43 in 20%
EtOAc/hexanes. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.77
(dd, J = 2.8, 8.1 Hz, 2H), 7.41 (t, J = 7.2 Hz, 3H), 7.18 - 7.33 (m, 5H), 7.17 (s, 1H), 3.27 (s, 3H).
13C NMR (101 MHz, DMSO-d6) δ 154.1 (C), 150.7 (C), 147.7 (C), 134.2 (C), 129.4 (C), 128.7
(CH), 127.6 (CH), 127.4 (CH), 126.5 (CH), 126.4 (CH), 125.4 (CH), 122.8 (CH), 121.7 (CH),
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115.8 (CH), 106.6 (CH), 40.5 (CH3). IR (neat) 3223, 2980, 2878, 1736, 1629, 1599, 1478, 1299
cm-1. HRMS (EI): Exact mass calcd for C18H16N2O2 [M]+: 292.1212. Found: 292.1242.
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Phenyl 2-(2-ethoxy-2-oxoethyl)hydrazine-1-carboxylate (1oo). Synthesized according to a
reported general procedure,25 by stirring O-phenyl carbazate (2.46 g, 16.1 mmol) and ethyl 2-
oxoacetate (1.65 g, 16.1 mmol). The crude reaction was diluted in 2:1 MeOH:AcOH (0.2 M) and
NaBH3CN (3.05 g, 48.6 mmol) was added and allowed to stir for 16 h. The title compound was
purified by column chromatography (10% EtOAc/CH2Cl2) to yield an amorphous white solid (1.52
g, 40%); mp 110-113 °C. TLC Rf = 0.21 in 10% EtOAc/CH2Cl2. 1H NMR (400 MHz, DMSO-d6)
d 9.13 (br s, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 5.10
(br s, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.59 (d, J = 4.7 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H). 13C NMR
(101 MHz, DMSO-d6) d 170.4 (C), 155.0 (C), 150.8 (C), 129.3 (CH), 125.0 (CH), 121.6 (CH),
60.1 (CH2), 51.9 (CH2), 14.1 (CH3). IR (film) 3283, 3217, 3094, 2988, 1742, 1717, 1550, 1491,
1427, 1379, 1197 cm-1. HRMS (EI): Exact mass calcd for C11H14N2O4 [M]+: 238.0954. Found:
238.0947.
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General Procedure 3 for the synthesis of carbazates 1l-o:24 To a solution of carbazates 1ll-oo
in CH2Cl2 (0.2 M), 0.05 equiv of anhydrous Cu(OAc)2 was added, followed by 2 equiv of
Ph3Bi(OAc)2. The reaction was stirred at room temperature for 15 min-12 h. After completion the
solids were removed by filtration, the filtrate was concentrated under reduced pressure and purified
by column chromatography to afford the desired product.
Phenyl 2-(furan-2-ylmethyl)-2-phenylhydrazine-1-carboxylate (1l). Synthesized according to
general procedure 3 using phenyl 2-(furan-2-ylmethyl)hydrazine-1-carboxylate (1ll, 0.139 g,
0.600 mmol), stirring for 1 h. The title compound was purified by column chromatography
(hexanes/EtOAc =5:1) to give 1l (0.165 g, 89%) as a white solid; mp 177-179 °C. TLC Rf = 0.32
in 20% EtOAc/hexanes. 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.66 (t, J = 1.2 Hz, 1H),
7.37 - 7.44 (m, 2H), 7.26 (t, J = 8.0 Hz, 3H), 7.13 (d, J = 7.7 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H),
6.79 - 6.85 (m, 1H), 6.45 (d, J = 1.4 Hz, 2H), 4.67 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 153.7
(C), 150.6 (C), 150.1 (C), 148.0 (C), 142.7 (CH), 129.3 (CH), 129.2 (CH), 125.6 (CH), 121.3 (CH),
120.5 (CH), 113.7 (CH), 110.4 (CH), 109.4 (CH), 49.0 (CH2). IR (neat) 3264, 2980, 1720, 1593,
1491, 1266, 1211 cm-1. HRMS (EI): Exact mass calcd for C18H16N2O3 [M]+: 308.1161. Found:
308.1153.
Phenyl 2-(2,3-dihydro-1H-inden-2-yl)-2-phenylhydrazine-1-carboxylate (1m). Synthesized
according to general procedure 3 using phenyl 2-(2,3-dihydro-1H-inden-2-yl)hydrazine-1-
carboxylate (1mm, 0.160 g, 0.600 mmol), stirring for 7 h. The title compound was purified by
column chromatography (hexanes/EtOAc = 7:1) to give 1m (0.166 g, 81%) as a white solid; mp
214-216 °C. TLC Rf = 0.43 in 13% EtOAc/hexanes. 1H NMR (300 MHz, DMSO-d6) δ 9.77 (s,
1H), 7.35 - 7.43 (m, 2H), 7.20 - 7.34 (m, 5H), 7.13 - 7.19 (m, 2H), 7.08 (d, J = 7.5 Hz, 2H), 7.02
(d, J = 8.0 Hz, 2H), 6.80 - 6.89 (m, 1H), 4.99 (quin, J = 7.5 Hz, 1H), 3.18 (d, J = 8.0 Hz, 4H). 13C
NMR (75 MHz, DMSO-d6) δ 155.1 (C), 150.7 (C), 148.6 (C), 141.2 (C), 129.4 (CH), 129.1 (CH),
126.3 (CH), 125.3 (CH), 124.4 (CH), 121.6 (CH), 119.2 (CH), 113.8 (CH), 59.9 (CH), 35.7 (CH2).
IR (neat) 3276, 2950, 1723, 1592, 1490, 1242, 1198 cm-1. HRMS (EI): Exact mass calcd for
C22H20N2O2 [M]+: 344.1525. Found: 344.1493.
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Phenyl 2-phenyl-2-(tetrahydro-2H-pyran-4-yl)hydrazine-1-carboxylate (1n). Synthesized
according to general procedure 3 using phenyl 2-(tetrahydro-2H-pyran-4-yl)hydrazine-1-
carboxylate (1nn, 0.141 g, 0.600 mmol), stirring for 5 h. The title compound was purified by
column chromatography (hexanes/EtOAc = 5:2) to give 1n (0.131 g, 70%) as a white solid; mp
192-193 °C. TLC Rf = 0.31 in 15% EtOAc/hexanes. 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s,
1H), 7.40 - 7.44 (m, 2H), 7.24 - 7.28 (m, 3H), 7.20 (dd, J = 0.9, 8.5 Hz, 2H), 6.94 (d, J = 7.8 Hz,
2H), 6.77 - 6.81 (m, 1H), 4.09 (t, J = 7.6 Hz, 1H), 3.93 (d, J = 11.2 Hz, 2H), 3.45 (dd, J = 7.5, 18.3
Hz, 2H), 1.70 (br s, 4H). 13C NMR (101 MHz, CDCl3) δ 154.6 (C), 150.3 (C), 147.0 (C), 129.1
(CH), 129.0 (CH), 125.3 (CH), 120.9 (CH), 120.1 (CH), 113.7 (CH), 67.0 (CH2), 56.4 (CH), 28.6
(CH2). IR (neat) 3273, 2955, 2828, 1730, 1593, 1490, 1287, 1214 cm-1. HRMS (EI): Exact mass
calcd for C18H20N2O3 [M]+: 312.1474. Found: 312.1471.
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Phenyl 2-(2-ethoxy-2-oxoethyl)-2-phenylhydrazine-1 carboxylate (1o). Synthesized according
to general procedure 3 using phenyl 2-(2-ethoxy-2-oxoethyl)hydrazine-1-carboxylate (1oo, 0.238
g, 1.00 mmol), stirring for 12 h. The title compound was purified by column chromatography
(hexanes/EtOAc = 4:1) to give 1o (0.220 g, 70%) as a yellow oil. TLC Rf = 0.22 in 20%
EtOAc/hexanes. 1H NMR (300 MHz, CDCl3) δ 7.66 (br s, 1H), 7.23 - 7.48 (m, 7H), 6.90 - 7.03
(m, 3H), 4.42 (br s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 169.9 (C), 153.4 (C), 150.2 (C), 147.3 (C), 128.9 (2xCH), 125.2 (CH), 120.8 (CH), 120.4
(CH), 112.8 (CH), 61.0 (CH2), 53.3 (CH2), 13.7 (CH3). IR (neat) 3293, 2981, 2937, 1727, 1598,
1493, 1373, 1179 cm-1. HRMS (EI): Exact mass calcd for C17H18N2O4 [M]+: 314.12666. Found:
314.12646.
General Procedure 4: A microwave vial was charged with a stir bar. The carbazate 1a-o and
α,α,α-trifluorotoluene (0.1 M) were added. The vial was capped and heated in a microwave reactor
for 3−7 hours at 150−200 °C. The reaction was cooled and the mixture was concentrated under
reduced pressure. The residue was purified either by crystallization or flash chromatography on
silica gel.
General Procedure for Conventional Heating: A sealed pressure tube was charged with a stir
bar. The carbazate 1a (0.1 mmol) and the solvent (0.05 M) were added. The vial was capped and
heated in wax bath for 3 hours at 180 °C. The reaction was cooled, the solvent was removed under
reduced pressure and the NMR yield was determined using 1,3,5-trimethoxybenzene as internal
standard.
1-Methyl-1,2-dihydro-3H-indazol-3-one (2a). Synthesized according to general procedure 4
using phenyl 2-methyl-2-phenylhydrazine-1-carboxylate (1a, 0.048 g) for 3 hours at 180 °C. The
residue was purified by column chromatography (hexanes/EtOAc = 2:1) to give 2a (0.020 g, 79%)
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as a white solid; mp 154-156 °C. TLC Rf = 0.37 in 33% EtOAc/hexanes. H NMR (300 MHz,
CDCl3) δ 7.79 (d, J = 8.0 Hz, 1H), 7.46 (ddd, J = 1.1, 7.0, 8.4 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H),
7.07 - 7.14 (m, 1H), 3.86 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.4 (C), 142.1 (C), 128.6 (CH),
121.1 (CH), 119.3 (C), 112.6 (CH), 108.7 (CH), 34.8 (CH3). IR (neat) 2942, 2543, 1616, 1580,
1537, 1445, 1307, 1288, 1178, 1009 cm-1. HRMS (EI): Exact mass calcd for C8H8N2O [M]+:
148.0637. Found: 148. 0652.
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1-Phenyl-1,2-dihydro-3H-indazol-3-one (2b). Synthesized according to general procedure 4
using phenyl 2,2-diphenylhydrazine-1-carboxylate (1b, 0.091 g) for 7 hours at 180 °C. The residue
was purified by column chromatography (hexanes/EtOAc = 2:1) to give 2b (0.045 g, 71%) as a
white solid; mp 222-224 °C. TLC Rf = 0.37 in 33% EtOAc/hexanes. 1H NMR (400 MHz, DMSO-
d6) δ 7.77 (dd, J = 3.7, 8.4 Hz, 2H), 7.69 (d, J = 7.5 Hz, 2H), 7.49 - 7.55 (m, 2H), 7.43 - 7.48 (m,
1H), 7.23 - 7.29 (m, 1H), 7.16 (t, J = 7.8 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 156.3 (C),
140.2 (C), 139.2 (C), 129.5 (CH), 128.3 (CH), 124.7 (CH), 120.6 (CH), 120.5 (CH), 120.3 (C),
114.8 (CH), 110.3 (CH). IR (neat) 2960, 2578, 1619, 1592, 1444, 1309, 1233 cm-1. HRMS (EI):
Exact mass calcd for C13H10N2O [M]+: 210.0793. Found: 210.0796.
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1-Benzyl-1,2-dihydro-3H-indazol-3-one (2c). Synthesized according to general procedure 4
using phenyl 2-benzyl-2-phenylhydrazine-1-carboxylate (1c, 0.063 g) for 3 hours at 180 °C. The
residue was crystallized from toluene to give 2c (0.034 g, 76%) as a white solid; mp 181-182 °C.
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 1H), 7.40 (ddd, J = 1.1, 7.0, 8.4 Hz, 1H), 7.26
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- 7.34 (m, 5H), 7.22 (d, J = 8.6 Hz, 1H), 7.09 (ddd, J = 0.7, 7.1, 7.9 Hz, 1H), 5.34 (s, 2H). C
NMR (101 MHz, CDCl3) δ 156.8 (C), 141.8 (C), 136.5 (C), 128.8 (CH), 128.7 (CH), 127.8 (CH),
127.4 (CH), 121.4 (CH), 119.6 (C), 113.3 (CH), 109.2 (CH), 52.4 (CH2). IR (neat) 2965, 2543,
1617, 1585, 1443, 1321, 1140 cm-1. HRMS (EI): Exact mass calcd for C14H12N2O [M]+: 224.0950.
Found: 224.0951.
5-Chloro-1-methyl-1,2-dihydro-3H-indazol-3-one (2d). Synthesized according to general
procedure 4 using phenyl 2-(4-chlorophenyl)-2 methylhydrazine-1-carboxylate (1d, 0.110 g) for 5
hours at 180 °C. The residue was crystallized from CH2Cl2 to give 2d (0.055 g, 76%) as a white
solid; mp 245-246 °C. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 1.4,
9.0 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H), 3.86 (s, 3H).13C NMR (101 MHz, CDCl3) δ 155.2 (C), 140.3
(C), 129.3 (CH), 124.9 (C), 120.3 (C), 113.0 (CH), 109.9 (CH), 34.9 (CH3). IR (neat) 2981, 2547,
1617, 1583, 1555, 1472, 1294, 1257, 1040 cm-1. HRMS (EI): Exact mass calcd for C8H7ClN2O
[M]+: 182.0247. Found: 182.0227.
1,5-Dimethyl-1,2-dihydro-3H-indazol-3-one (2e). Synthesized according to general procedure 4
using phenyl 2-methyl-2-(p-tolyl)hydrazine-1-carboxylate (1e, 0.102 g) for 3 hours at 180 °C. The
residue was purified by column chromatography (CH2Cl2/MeOH = 99:1) to give 2e (0.059 g, 91%)
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as a white solid; mp 202-203 °C. TLC Rf = 0.42 in 95% CH2Cl2/MeOH. H NMR (400 MHz,
CDCl3) δ 7.56 (s, 1H), 7.29 (d, J = 4.1 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H), 2.46 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 156.3 (C), 141.3 (C), 130.7 (CH), 128.8 (C), 120.2 (C), 113.0
(CH), 108.6 (CH), 35.0 (CH3), 21.1 (CH3). IR (neat) 2914, 2569, 1626, 1524, 1393, 1279, 1239,
1047 cm-1. HRMS (EI): Exact mass calcd for C9H10N2O [M]+: 162.07931. Found: 162.07655.
1,5,7-Trimethyl-1,2-dihydro-3H-indazol-3-one (2f). Synthesized according to general
procedure 4 using phenyl 2-(2,4-dimethylphenyl)-2-methylhydrazine-1-carboxylate (1f, 0.135 g)
for 3 hours at 200 °C. The residue was purified by column chromatography (hexanes/EtOAc = 2:1
~ 1:1) to give 2f (0.031 g, 35%) as a white solid; mp 177-179 °C. TLC Rf = 0.25 in 33%
EtOAc/hexanes. 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.02 (s, 1H), 3.88 (s, 3H), 2.60 (s,
3H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.5 (C), 142.3 (C), 132.8 (CH), 129.7 (CH),
120.3 (C), 118.2 (C), 115.0 (C), 38.1 (CH3), 20.5 (CH3), 18.6 (CH3). IR (neat) 2968, 2586, 1662,
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1531, 1451, 1272, 1223, 1019 cm-1. HRMS (EI): Exact mass calcd for C10H12N2O [M]+: 176.0950.
Found: 176.0959.
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1-Isopropyl-1,2-dihydro-3H-indazol-3-one (2g). Synthesized according to general procedure 4
using phenyl 2-isopropyl-2-phenylhydrazine-1-carboxylate 1g, 0.050 g) for 3 hours at 180 °C. The
residue was purified by column chromatography (CH2Cl2/MeOH = 98:2) to give 2g (0.022 g, 70%)
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as a white solid; mp 151-152 °C. TLC Rf = 0.17 in 97% CH2Cl2/MeOH. H NMR (400 MHz,
CDCl3) δ 7.81 (d, J = 8.2 Hz, 1H), 7.38 - 7.45 (m, 1H), 7.29 (s, 1H), 7.08 (t, J = 7.5 Hz, 1H), 4.66
(td, J = 6.7, 13.5 Hz, 1H), 1.55 (d, J = 6.7 Hz, 6H). C NMR (101 MHz, CDCl3) δ 156.8 (C),
141.0 (C), 128.1 (CH), 121.1 (CH), 118.9 (C), 112.7 (CH), 108.7 (CH), 49.7 (CH), 21.1 (CH3). IR
(neat) 2969, 2568, 1651, 1585, 1537, 1304, 1145 cm-1. HRMS (EI): Exact mass calcd for
C10H12N2O [M]+: 176.09496. Found: 176.09423.
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Table 3, indazolone 2h: 1,7-Dimethyl-1,2-dihydro-3H-indazol-3-one (2h). Synthesized
according to general procedure 4 using phenyl 2-methyl-2-(o-tolyl)hydrazine-1-carboxylate (1h,
0.128 g) for 3 hours at 180 °C. The residue was purified by column chromatography
(hexanes/EtOAc = 2:1) to give 2h (0.060 g, 74%) as a white solid; mp 217-219 °C. TLC Rf = 0.23
in 20% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.8 Hz, 1H), 7.16 (td, J = 1.0,
7.1 Hz, 1H), 6.96 - 7.03 (m, 1H), 4.00 (s, 3H), 2.67 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.7
(C), 142.4 (C), 130.4 (CH), 120.2 (C), 119.8 (CH), 118.9 (C), 113.9 (CH), 37.7 (CH3), 18.8 (CH3).
IR (neat) 2922, 2556, 1612, 1527, 1430, 1311, 1194 cm-1. HRMS (EI): Exact mass calcd for
C9H10N2O [M]+: 162.0793. Found: 162.0792.
Table 3, indazolone 2i: 1-Allyl-1,2-dihydro-3H-indazol-3-one (2i). Synthesized according to
general procedure 4 using phenyl 2-allyl-2-phenylhydrazine-1-carboxylate (1i, 0.085 g) for 3 hours
at 200 °C. The residue was purified by column chromatography (hexanes/EtOAc = 5:1 ~ 4:1) to
give 2i (0.008 g, 15%) as a white solid; mp 128-129 °C. TLC Rf = 0.23 in 20% EtOAc/hexanes.
1H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 1H), 7.41 - 7.48 (m, 1H), 7.24 (s, 1H), 7.11 (t,
J = 7.6 Hz, 1H), 5.91 - 6.08 (m, 1H), 5.20 - 5.30 (m, 2H), 4.77 (d, J = 5.5 Hz, 2H). 13C NMR (101
MHz, CDCL3) δ 157.2 (C), 142.4 (C), 132.6 (CH), 129.2 (CH), 121.8 (CH), 120.0 (CH2), 118.6
(C), 113.6 (CH), 109.5 (CH), 51.4 (CH2). IR (neat) 2987, 2557, 1615, 1544, 1445, 1304, 1252,
1201 cm-1. HRMS (EI): Exact mass calcd for C10H10N2O [M]+: 174.0793. Found: 174.0814.
7-Fluoro-1-methyl-1,2-dihydro-3H-indazol-3-one (2j). Synthesized according to general
procedure 4 using phenyl 2-(2-fluorophenyl)-2-methylhydrazine-1-carboxylate (1j, 0.130 g) for 5
hours at 180 °C. After cooling the precipitated solid was filtered, washed with petroleum ether and
allowed for air drying to give 2j (0.079 g, 95%) as a white solid; mp 218-219 °C. TLC Rf = 0.22
in 20% EtOAc/Hexane. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 7.6,
12.2 Hz, 1H), 6.98 (dt, J = 4.1, 7.8 Hz, 1H), 4.04 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.1
(C), 149.3 (C), 146.8 (C), 131.2 (CH), 119.4 (C), 116.5 (CH), 112.7 (CH), 37.0 (CH3). IR (neat)
2947, 2573, 1549, 1445, 1309, 1222, 1151 cm-1. HRMS (EI): Exact mass calcd for C8H7FN2O
[M]+: 166.05424. Found: 166.05462.
3-Methyl-2,3-dihydro-1H-benzo[e]indazol-1-one (2k). Synthesized according to general
procedure 4 using phenyl 2-methyl-2-(naphthalen-2-yl)hydrazine-1-carboxylate (1k, 0.088 g) for
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4 hours at 150 °C. After cooling the precipitated solid was filtered, washed with petroleum ether
and allowed for air drying to give 2k (0.057 g, 95%) as a white solid; mp 298-299 °C. TLC Rf =
0.21 in 33% EtOAc/hexanes. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 8.2 Hz, 1H), 7.93 (d,
J = 8.0 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.56 - 7.62 (m, 2H), 7.37 - 7.42 (m, 1H), 3.89 (s, 3H).
13C NMR (101 MHz, DMSO-d6) δ 155.4 (C), 138.9 (C), 128.1 (CH), 127.9 (CH), 127.5 (CH),
127.0 (C), 123.0 (CH), 122.2 (CH), 110.8 (C), 103.7 (CH), 34.7 (CH3). IR (neat) 2970, 2521, 1530,
1472, 1393, 1301, 1251, 1203 cm-1. HRMS (EI): Exact mass calcd for C12H10N2O [M]+: 198.0793.
Found: 198.0809.
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1-(Furan-2-ylmethyl)-1,2-dihydro-3H-indazol-3-one (2l). Synthesized according to general
procedure 4 using phenyl 2-(furan-2-ylmethyl)-2-phenylhydrazine-1-carboxylate (1l, 0.048 g) for
3 hours at 180 °C. The residue was purified by column chromatography (hexanes/EtOAc = 5:2) to
give 2l (0.031 g, 93%) as a white solid; mp 225-227 °C. TLC Rf = 0.23 in 30% EtOAc/hexanes.
1H NMR (400 MHz, CDCl3) δ 7.79 (td, J = 1.0, 8.1 Hz, 1H), 7.42 - 7.47 (m, 1H), 7.30 - 7.38 (m,
2H), 7.12 (ddd, J = 0.8, 7.0, 8.1 Hz, 1H), 6.35 - 6.39 (m, 1H), 6.30 (dd, J = 1.9, 3.2 Hz, 1H), 5.27
(s, 2H). 13C NMR (101 MHz, CDCl3) δ 157.6 (C), 150.0 (C), 142.9 (C), 142.6 (CH), 129.2 (CH),
121.7 (CH), 120.2 (C), 114.0 (CH), 110.8 (CH), 109.6 (CH), 109.1 (CH), 45.7 (CH2). IR (neat)
3090, 2969, 2576, 1621, 1586, 1421, 1321, 1225 cm-1. HRMS (EI): Exact mass calcd for
C12H10N2O2 [M]+: 214.0742. Found: 214.0738.
1-(2,3-Dihydro-1H-inden-2-yl)-1,2-dihydro-3H-indazol-3-one (2m). Synthesized according to
general procedure 4 using phenyl 2-(2,3 dihydro-1H-inden-2-yl)-2-phenylhydrazine-1-
carboxylate (1m, 0.040 g) for 3 hours at 180 °C. The residue was purified by column
chromatography (hexanes/EtOAc = 7:2) to give 2m (0.027 g, 90%) as a white solid; mp 220-222
°C. TLC Rf = 0.23 in 23% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3) δ 7.75 (td, J = 0.9, 8.0
Hz, 1H), 7.40 (ddd, J = 1.2, 7.1, 8.4 Hz, 1H), 7.27 - 7.30 (m, 2H), 7.24 (td, J = 3.3, 8.9 Hz, 3H),
7.06 - 7.11 (m, 1H), 5.28 (quin, J = 8.28 Hz, 1H), 3.48 (dd, J = 8.2, 15.9 Hz, 2H), 3.38 (dd, J =
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8.2, 15.9 Hz, 2H). C NMR (101 MHz, CDCl3) δ 157.0 (C), 142.2 (C), 140.1 (C), 128.6 (CH),
126.6 (CH), 124.3 (CH), 121.4 (CH), 119.5 (C), 113.6 (CH), 109.2 (CH), 59.2 (CH), 37.3 (CH2).
IR (neat) 2918, 2531, 1617, 1585, 1535, 1443, 1308, 1252 cm-1. HRMS (EI): Exact mass calcd for
C16H14N2O [M]+: 250.1106. Found: 250.1113.
1-(Tetrahydro-2H-pyran-4-yl)-1,2-dihydro-3H-indazol-3-one (2n). Synthesized according to
general procedure 4 using phenyl 2-phenyl-2-(tetrahydro-2H-pyran-4-yl)hydrazine-1-carboxylate
(1n, 0.110 g) for 3 hours at 180 °C. The residue was purified by column chromatography
(hexanes/EtOAc = 3:2 ~ 1:1) to give 2n (0.075 g, 99%) as a white solid; mp 242-244 °C. TLC Rf
= 0.22 in 40% EtOAc/hexanes. 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.1 Hz, 1H), 7.31 - 7.44
(m, 1H), 7.22 (d, J = 10.3 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.38 (tt, J = 4.1, 11.9 Hz, 1H), 4.14
(dd, J = 4.4, 11.6 Hz, 2H), 3.49 - 3.61 (m, 2H), 2.30 (dq, J = 4.7, 12.4 Hz, 2H), 1.86 (dd, J = 2.0,
12.8 Hz, 2H). 13C NMR (101 MHz, CDCL3) δ 156.6 (C), 141.0 (C), 128.2 (CH), 121.4 (CH), 119.3
(C), 112.8 (CH), 108.5 (CH), 67.2 (CH2), 54.9 (CH), 31.6 (CH2). IR (neat) 2955, 2926, 2833, 2523,
1614, 1583, 1538, 1442, 1381, 1311, 1236, 1144, 1125 cm-1. HRMS (EI): Exact mass calcd for
C12H14N2O2 [M]+: 218.10553. Found: 218.10507.
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Ethyl 2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)acetate (2o). Synthesized according to general
procedure 4 using phenyl 2-(2-ethoxy-2-oxoethyl)-2-phenylhydrazine-1-carboxylate (1o, 0.060 g)
for 3 hours at 180 °C. After cooling the precipitated solid was filtered, washed with petroleum
ether and allowed for air drying to give 2o (0.038 g, 97%) as a white solid; mp 196-197 °C. 1H
NMR (300 MHz, CDCl3) δ 7.79 (td, J = 1.0, 8.0 Hz, 1H), 7.46 (ddd, J = 1.1, 7.1, 8.4 Hz, 1H), 7.20
(d, J = 8.6 Hz, 1H), 7.14 (ddd, J = 0.7, 7.1, 8.0 Hz, 1H), 4.87 (s, 2H), 4.23 (q, J = 7.2 Hz, 2H),
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1.26 (t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3) δ 168.3 (C), 158.1 (C), 143.4 (C), 129.5
(CH), 121.8 (CH), 120.5 (C), 114.2 (CH), 109.1 (CH), 62.1 (CH2), 50.2 (CH2), 14.4 (CH3). IR
(neat) 2982, 2932, 2550, 1740, 1621, 1590, 1553, 1447, 1309, 1201 cm-1. HRMS (EI): Exact mass
calcd for C11H12N2O3 [M]+: 220.08479. Found: 220.08351.
ASSOCIATED CONTENT
NMR spectra for all new compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: andre.beauchemin@uottawa.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We thank the University of Ottawa and NSERC for support of this work and the Egyptian Ministry
of High Education for a scholarship E. B. E. We are grateful to Mr. Ryan Ivanovich (University
of Ottawa) for useful suggestions and for sharing reagents for this project. We also thank Dr. Adel
Ghiaty (Al-Azhar University) for encouragements, stimulating discussions and comments on the
manuscript and supporting information.
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R2
R2
N
O
R2
(−PhOH)
N
N
N
C
O
N
OPh
R1
R1
R1
NH
H
PhCF3, 150-200 °C
3-7 h
9
O
Blocked N-isocyanate
15 examples
up to 99 % yield
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N-Isocyanate
• Use of masked N-Isocyanate precursors allow a general route to indazolones
• Effect of blocking (leaving) group investigated / substrate synthesis improved
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