Direct ortho-Selective Amination of 2-Naphthol and Its Analogues with Hydrazines

Article abstract of DOI:10.1021/acs.joc.8b00421

Described herein is a regioselective ortho-amination of 2-naphthol and its analogues with substituted hydrazines. It provides a direct methodology for the synthesis of N-arylaminated naphthol derivatives without the formation of related 1,1′-biaryl-2,2′-diamine or carbazole byproducts. Specifically, using N,N-disubstituted hydrazine precursors, N-unsubstituted ortho-aminated derivatives and related secondary amines can be formed in ethylene glycol in moderate to excellent yields. Variation of substrates to N,N′-diarylhydrazines and N-methyl-N,N′-diarylhydrazines led to N-aryl-1-amino-2-naphthol compounds. It is noted that biologically interesting indazole motifs can be facilely created by the reaction of N,N′-dialkylhydrazines with 2-naphthols. These ortho-amination reactions have the advantage of one-pot operation without the use of transition metal catalysts.

Full text of DOI:10.1021/acs.joc.8b00421

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Direct Ortho-Selective Amination of 2-
Naphthol and Its Analogues with Hydrazines
lei jia, Qiang Tang, Meiming Luo, and Xiaoming Zeng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00421 • Publication Date (Web): 12 Apr 2018
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Direct Ortho-Selective Amination of 2-Naphthol and Its
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Analogues with Hydrazines
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Lei Jia†, Qiang Tang†,‡, Meiming Luo*† and Xiaoming Zeng*†
†Key Laboratory of Green Chemistry and Technology of Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China
‡College of Pharmacy, Chongqing Medical University, Chongqing 400016, P. R.
China
Email: luomm@scu.edu.cn; zengxiaoming@scu.edu.cn
TOC Graphic
Abstract:
Described herein is a regioselective orthoꢀamination of 2ꢀnaphthol and its analogues
with substituted hydrazines. It provides a direct methodology for the synthesis of
Nꢀarylaminated naphthol derivatives without the formation of related
1,1'ꢀbiarylꢀ2,2'ꢀdiamine or carbazole byproducts. Specifically, using N,Nꢀdisubstituted
hydrazine precursors, Nꢀunsubstituted orthoꢀaminated derivatives and related
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secondary amines can be formed in ethylene glycol in moderate to excellent yields.
Variation of substrates to N,N'ꢀdiarylhydrazines and NꢀmethylꢀN,N'ꢀdiarylhydrazines
led to Nꢀarylꢀ1ꢀaminoꢀ2ꢀnaphthol compounds. It is noted that biologically interesting
indazole motifs can be facilely created by the reaction of N,N'ꢀdialkylhydrazines with
2ꢀnaphthols. These orthoꢀamination reactions have the advantage of oneꢀpot operation
without the use of transition metal catalysts.
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Introduction
Aromatic amines are found in a wide range of materials, natural products and
biologically active compounds, which usually serve as fundamental units for the
buildup of pharmaceuticals.1 Various methods for the creation of arylamine motifs
have been developed, typically mediated by traditional transition metalꢀcatalyzed
carbonꢀnitrogen crossꢀcoupling reactions with aromatic electrophiles such as aryl
halides and triflates.1c, 2 The direct amination of aromatic hydrocarbons provides a
valuable alternative to these traditional strategies and recently has attracted great
attention,3ꢀ5 which is typically effected by oxidative CꢀH/NꢀH coupling,3 by
electrophilic attack,4 or through nitrogen radical intermediates.5 These reactions
generally do not need to preꢀfunctionalize aromatics and enable the formation of C–N
bonds by a single operation step.
Aminophenols occur in many dyes,6 pharmaceuticals,7 and biological compounds.8
These compounds are commonly formed by multiꢀstep reactions such as
nitration/reduction, Nꢀalkylation and/or Nꢀarylation in low overall yields.9 When
compared with other aromatics, naturally abundant phenols have rarely been utilized
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as precursors for direct amination reactions, which often suffer from a prominent
selectivity issue because of the existence of multiple reactive sites of phenols and ease
of concomitant homocoupling.10 Recently, Li and coꢀworkers reported the amination
of phenols by ipsoꢀsubstitution to produce arylamine.11 The groups of Patureau and
Xia independently reported the crossꢀdehydrogenative coupling (CDC) amination of
phenols with phenothiazines, phenoxazines and acyclic diarylamines in the presence
of oxidants (Eq 1, Scheme 1).12 We recently showed that the use of
OꢀbenzoylꢀNꢀalkylhydroxylamines and benzoyl aldehyde oximes as aminating agents
allowed realizing the ironꢀcatalyzed synthesis of alkylaminophenols and benzoxazoles
(Eq 2, Scheme 1).13a,b Bella and Jørgenson disclosed an organocatalytic amination of
2ꢀnaphthols using diazodicarboxylate as aminating reagent in the formation of
substituted hydrazines (Eq 3, Scheme 1).13d Phenols were reported to react with
amines via cyclohexaꢀ3,5ꢀdieneꢀ1,2ꢀdione intermediates in the presence of copper
catalyst and oxidants to form various orthoꢀaminated products such as benzoxazole,
benzoxazinone, aminophenol and Nꢀarylpyrrolidine (Eq 4, Scheme 1).14aꢀf Moreover,
Lumb and coꢀworkers also found when the amines were replaced with hydrazine or
hydrazide, orthoꢀazophenols were produced (Eq 5, Scheme 1).14g With
N,Nꢀdisubstituted hydrazines, we found that the reaction of 2ꢀnaphthols formed
aminonaphthols under neat conditions (Eq 6, Scheme 1).15a,b However, only
Nꢀunsubstituted products containing NH2 moiety can be accessed by this protocol.
The use of other types of substituted hydrazines as precursors to react with naphthols
has not been explored yet. Herein, we demonstrate a detail study on the direct
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orthoꢀselective arylamination and cyclization of 2ꢀnaphthol and its analogues with
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respect to the reaction scope and limitation by the use of different types of substituted
hydrazines. It provides a new strategy for the synthesis of Nꢀarylꢀsubstituted
1ꢀaminoꢀ2ꢀnaphthols and indazole compounds (Eq 7, Scheme 1).
H
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Ar1
Ar2
N
OH
(1)
Ar1
Ar2
oxidant
solvent
+
OH
R
N
H
R
R3 R2
N
H
R3
OH
FeCl3 (10 mol%)
toulene, RT
OH
R1
(2)
(3)
+
BzO N
O
R1
X
R2
X
X = CH, N
OtBu
OtBu
O
H
H
N
OH
N
N
OtBu
OtBu
organocatalyst
O
N
+
R
OH
R
O
R2
R2
H
R2 R2
N
O
OH
[Cu], O2, amine
N
N
N
R1
O
(4)
O
O
O
O
OH
R1
R1
R1
R1
via
R1
H
R2
[Cu], O2, R2NHNH2
O
OH
N
N
R1
(5)
(6)
OH
R1
O
via
R1
H
NH2
X
OH
R2
X
OH
R2
R3
R1
N
NH2
+
R1
NH
R3
+
90-130 oC
R4
X = CH, N
R3
R3
R1
N
N
H
NH
R2
(R4 = H, Me)
X
OH
H
X
OH
R1
(7)
R5
N
N
R5
X = CH, N
H
R5
N
R1
N
R5
H
Scheme 1. Direct orthoꢀamination reactions of phenols
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Results and Discussion
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Ortho-amination of 2-naphthol and its analogues with N,N-disubstituted
hydrazines
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In our preliminary study, the reaction of 2ꢀnaphthol and its analogues with
N,Nꢀdisubstituted hydrazines was performed under solventꢀfree conditions.15a
However, the amination suffered from harsh conditions and must be conducted at
high temperature for some substrates, which facilitated the melt of reactants and
resulted in a homogeneous reaction. We questioned whether it’s possible to carry out
the orthoꢀamination at lower temperature in organic solvent. We then sought to study
the effect of solvents on the transformation. As shown in Table 1, the use of THF,
CHCl3, EtOAc, MeOH and EtOH as solvents did not largely promote the
orthoꢀamination reaction (entries 1–6). By contrast, the formation of the
1ꢀaminoꢀ2ꢀnaphthol (3a) in preparatively useful yield was observed when performing
o
the amination in ethylene glycol at 80 C. Ethylene glycol as a highly polar solvent
could be in favor of the dissociation of 2ꢀnaphthol to form naphthalenꢀ2ꢀolate anion
and protonated hydrazine, so that facilitated the reaction, which was in accordance
with the reaction mechanism proposed by using the density functional theory.15b
Table 1. Studying the effect of solvent on the orthoꢀamination of 2ꢀnaphthol with
NꢀmethylꢀNꢀphenylhydrazine[a]
NH2
CH3
H
OH
OH
N
N
solvent
reflux
CH3
NH2
+
+
1a
4a
2a
3a
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Entry
Solvent
THF
Time / h Yield of 3a[b]
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2
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19
15
10
10
4
41
36
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35
47
53
88
chloroform
EtOAc
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3
4[c]
5
methanol
methanol
ethanol
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7[d]
ethylene glycol
[a]Reaction conditions: 2ꢀnaphthol (1a, 2 mmol), NꢀmethylꢀNꢀphenylhydrazine (2a, 2 mmol),
argon atmosphere, solvent (1 mL), monitored by TLC. [b]Isolated yields. [c]25 oC. [d]80 oC.
The substrate scope of 2ꢀnaphthol derivatives (1) was next explored by the
treatment with NꢀmethylꢀNꢀphenylhydrazine (2a) (Table 2). 2ꢀNaphthols containing
electronꢀdonating groups such as methoxy, methyl, tertꢀbutyl and hydroxyl reacted
with NꢀmethylꢀNꢀphenylhydrazine smoothly in ethylene glycol to form the
orthoꢀaminated products in excellent yields (3b–3f). Functionalities of bromide, ester
and cyano were tolerated by the reaction system, and the related products 3g, 3h and
3i can be facilely prepared by this method. Whereas 1ꢀnaphthol and phenol did not
react with 2a. It was noteworthy that the amination with 6ꢀ, 7ꢀ, or 8ꢀhydroxyquinoline
in ethylene glycol proceeded fast to give the corresponding orthoꢀaminated
hydroxyquinolines (3l, 3m and 3n) in better yields than that under solventꢀfree
conditions at high temperature.15a
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Table 2. Regioselective orthoꢀamination of 2ꢀnaphthol and its analogues with
NꢀmethylꢀNꢀphenylhydrazine[a]
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NH2
OH
H3CO
3d, 85%
NH2
OH
3f, 88%
[a]Reaction conditions: naphthol (1, 5 mmol), NꢀmethylꢀNꢀphenylhydrazine (2a, 5 mmol), argon
atmosphere, ethylene glycol (2.5 mL). [b]2 equivalents of hydrazine were used.
The scope of N,Nꢀdisubstituted hydrazines (2) was then probed through the
reactions with 2ꢀnaphthol (1a) (Table 3). 1ꢀAminoꢀ2ꢀnaphthol (3a) and the
corresponding amines were obtained in moderate to excellent yields in ethylene
glycol. It was noted that in ethylene glycol at 80 °C, the reaction of
NꢀbenzylꢀNꢀphenylhydrazine (2c) and N,Nꢀdiphenylhydrazine (2d) with 2ꢀnaphthol
furnished 1ꢀaminoꢀ2ꢀnaphthol (3a) in 85% and 86% yield, respectively (entry 3 and 4).
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Under neat conditions, however, the amination reaction did not occur at a temperature
lower than 100 °C.15a
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Table 3. Regioselective orthoꢀamination of 2ꢀnaphthol and its analogues with
N,Nꢀdisubstituted hydrazines [a]
Entry
1
Hydrazine 2
Yield of 3a
Yield of 4
88%
2
3
4
5
6
7
8
87%
85%
86%
89%
86%
91%
73%
[a]Reaction conditions: 2ꢀnaphthol (1a, 5 mmol), N,Nꢀdisubstituted hydrazine (2, 5 mmol), argon
atmosphere, ethylene glycol (2.5 mL). [b]The yield was not measured.
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The reaction of N-monosubstituted hydrazines and hydrazine hydrate with
2-naphthol
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The reactions between Nꢀmonosubstituted hydrazines and hydrazine hydrate with
2ꢀnaphthol usually resulted in the substitution of the phenolic hydroxyl group of
2ꢀnaphthol by hydrazine residue, and then followed by benzidine rearrangement to
produce the corresponding 1,1'ꢀbiarylꢀ2,2'ꢀdiamines or carbazoles in the case of
Nꢀarylhydrazines.16 In contrast to those results, we found that in ethylene glycol, the
reaction of 2ꢀnaphthol with Nꢀphenylhydrazine and Nꢀ(2ꢀnapththyl)hydrazine led to
the orthoꢀaminated product of 1ꢀaminoꢀ2ꢀnaphthol (3a) in good yield without the
formation of related 1,1'ꢀbiarylꢀ2,2'ꢀdiamine or carbazole compounds (Table 4, entries
1 and 2). Interestingly, the reaction of hydrazine hydrate with 2ꢀnaphthol in ethylene
glycol also furnished 1ꢀaminoꢀ2ꢀnaphthol (3a) in 42% yield along with 45% of
2ꢀnapththylamine (Table 4, entry 3). 1,1'ꢀBinaphthylꢀ2,2'ꢀdiamine was not detected. In
the process, the reaction of hydrazine hydrate with 2ꢀnaphthol firstly produced
2ꢀnaphthylhydrazine16 which could be detected from TLC analysis and isolated, and
then the resulting 2ꢀnaphthylhydrazine reacted with the residual 2ꢀnaphthol as shown
in entry 2 to give 3a and 2ꢀnaphthylamine. Notably, the reaction of
tertꢀbutylhydrazine with 2ꢀnaphthol did not form the orthoꢀaminated compound 3a,
but 1ꢀ(tertꢀbutyl)ꢀ2ꢀ(naphthalenꢀ2ꢀyl)diazene was obtained in 41% yield. The azo
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compound
might
be
formed
by
air
oxidation
of
1ꢀ(tertꢀbutyl)ꢀ2ꢀ(naphthaleneꢀ2ꢀyl)hydrazine which was derived from the substitution
of the phenolic hydroxyl group of 2ꢀnaphthol with hydrazine residue.16
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Table 4. Orthoꢀamination of 2-naphthol with monoꢀsubstituted hydrazine and
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hydrazine in ethylene glycol[a]
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Entry
1
Hydrazine
Yield of 3a
RNH2
72%
2
66%
3
4
42%
0%[b]
0%
[a]Reaction conditions: 2ꢀnaphthol (1a, 5 mmol), hydrazine (5 mmol), argon atmosphere, ethylene
glycol, (2.5 mL). [b]1ꢀ(Tertꢀbutyl)ꢀ2ꢀ(naphthalenꢀ2ꢀyl)diazene was obtained in 41% yield.
The reaction of N,N'-disubstituted hydrazines with 2-naphthol and its analogues
N,N'ꢀDiarylhydrazines are appealing substrates for the orthoꢀamination with
2ꢀnaphthol, which may provide a new entry to the synthesis of arylaminoꢀcontaining
derivatives. However, because of the ease of benzidine rearrangement and
dismutation into anilines and azobenzenes under thermal conditions, especially in
hydroxylic solvents,17 the orthoꢀamination by the use of N,N'ꢀdiarylhydrazines
remains a great challenge. By the treatment of N,N'ꢀdiphenylhydrazine with 1a, we
found that the related anilines and azobenzenes were produced as major compounds
through dismutation reaction. Then, we turned our attention to explore the reaction of
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N,N'ꢀdiphenylhydrazine (5a) with 2ꢀnaphthol (1a) under neat conditions. When
performing the reaction at 120 °C, we were pleased to find that
1ꢀphenylaminoꢀ2ꢀnaphthol (6a) was formed in 61% yield (Table 5). This finding
provides an unprecedent and effective method for direct introduction of an arylamino
group to the αꢀposition of 2ꢀnaphthol. The substrate scope of 2ꢀnaphthol derivatives
was examined by treating with N,N'ꢀdiphenylhydrazine. 2ꢀNaphthols bearing
electronꢀdonating groups such as methoxy, hydroxyl and methyl were amenable to the
transformation, giving the 1ꢀphenylaminoꢀ2ꢀnaphthol products 6b–6e in moderate
yields. Importantly, sensitive functionality of bromide was well retained in the
reaction to give the product 6f in 62% yield. Whereas the arylamination of ethyl
6ꢀhydroxyꢀ2ꢀnaphthoate with 5a did not occur. The phenylaminated
hydroxyquinolines (6h and 6i) were prepared from the reaction of
N,N'ꢀdiphenylhydrazine with 6ꢀ and 7ꢀhydroxyquinoline in 37% and 32% yield,
respectively.
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The arylamination of 2ꢀnaphthol with diverse substituted N,N'ꢀdiarylhydrazines
was conducted. As expected, diarylhydrazines bearing both electronꢀdonating and
electronꢀwithdrawing groups reacted with 1a smoothly to form the desired products
6jꢀ6o. The retained substituents of chloride and fluoride in the products may open
upon an opportunity for lateꢀstage functionalization. Only moderate yields were
obtained, which was largely due to the incomplete conversion of phenols and some
dismutation of N,N'ꢀdiarylhydrazine. The structure of product 6m was further verified
by Xꢀray singleꢀcrystal diffraction analysis (see the Supporting Information).
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Table 5. Orthoꢀarylamination of N,N'ꢀdiarylhydrazines with 2ꢀnaphthol and its
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analogues[a]
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NH
H3CO
OH
6b, 53%
[a]Reaction conditions: naphthol (1, 5 mmol), N,N'ꢀdiarylhydrazines (5, 7.5 mmol), argon
atmosphere.
Inspired by the results of orthoꢀarylamination of 2ꢀnaphthols, we next probed the
possibility of incorporation of an alkylamino group onto the αꢀposition of 2ꢀnaphthols
by using N,N'ꢀdialkylhydrazine. Our initial efforts focused on studying the reaction of
2ꢀnaphthol (1a) with N,N'ꢀdibutylhydrazine (7a). Surprisingly, performing the
reaction at 120 °C under neat conditions, we found that 1a was completely consumed
and an unexpected cyclization product 3ꢀbutylꢀ1ꢀpropylꢀ3Hꢀbenzo[e]indazole (8a)
was formed in 75% yield instead of the anticipatory αꢀaminated product (Table 6). It
was worthy to note that this demonstrated the first example of the synthesis of
biologically interesting indazole compounds18 by the reaction of hydrazines with
2ꢀnaphthols.
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Subsequently, we examined the scope of 2ꢀnaphthols by the treatment with
N,N'ꢀdibutylhydrazine (7a) for the preparation of functionalized indazole motifs. The
incorporation of electronꢀdonating groups such as methoxy, hydroxyl and tertꢀbutyl
into the backbones of 2ꢀnaphthols had no effect on the transformation, forming the
desired 3ꢀbutylꢀ1ꢀpropylꢀ3Hꢀbenzo[e]indazoles (8bꢀ8e) in good yields. The
cyclization reaction tolerated bromide function (8f). In addition, octylꢀsubstituted
indazole 8h could also be prepared by this protocol. The reactivity of
NꢀalkylꢀN'ꢀarylhydrazine in the cyclization was examined, whereas the
orthoꢀaminated compound or indazole was not detected in this case.
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11
12
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Table 6. Cyclization for the synthesis of functionalized indazole motifs[a]
[a]Reaction conditions: 2ꢀnaphthol (1, 2 mmol), N,N'ꢀdialkylhydrazine (7, 6 mmol), argon
atmosphere, 120 oC.
Ortho-arylamination of 2-naphthol and its analogues by the reaction with
trisubstituted hydrazines
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After the realization of the orthoꢀarylamination of 2ꢀnaphthols with
N,N'ꢀdisubstituted hydrazines, the use of trisubstituted hydrazines as reactants for the
transformation was investigated. As shown in Table 7, the reaction between
NꢀmethylꢀN,N'ꢀdiphenylhydrazine with 2ꢀnaphthol (1a) occurred in high selectivity,
giving the Nꢀphenylꢀ1ꢀaminoꢀ2ꢀnaphthol 6a as the sole aminated product in good
yield both in ethylene glycol and neat system (entry 1). Notably, the
NꢀmethylꢀNꢀphenylꢀ1ꢀaminoꢀ2ꢀnaphthol was not formed in the reaction. We also
noticed that the arylamination proceeded faster in ethylene glycol than in solventꢀfree
system. 2ꢀNaphthols bearing methoxy, methyl and bromide function were suitable
substrates, providing related 1ꢀphenylaminoꢀ2ꢀnaphthol products (6b-e) in good
yields.
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Table 7. Orthoꢀarylamination by the use of NꢀmethylꢀN,N'ꢀdiphenylhydrazine[a]
Entry
Naphthol 1
Amination product 6
6a, 89% (85%)[b]
6b, 83%
1
2
3
4
5
6d, 82%
6e, 83%
6f, 81%
[a]Reaction conditions: 2ꢀnaphthol (1, 5 mmol), NꢀmethylꢀN,N'ꢀdiaryhydrazine (9a, 5 mmol),
argon atmosphere, ethylene glycol (2.5 mL). [b]No solvent.
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Variation of the aryl groups in trisubstituted hydrazines allowed the synthesis of
diverse substituted arylaminated products. The preparation of methyl, fluoro and
chloroꢀcontaining 1ꢀphenylaminoꢀ2ꢀnaphthols (6j-n) by this method was successful
(Table 8, entries 1ꢀ5). When 2ꢀnaphthol (1a) was treated with
NꢀmethylꢀNꢀphenylꢀN'ꢀarylhydrazines which have two different aryl groups, the
related aryl group rather than phenyl was incorporated into the scaffold of
aminonaphthols to form methylꢀ, fluoroꢀ and chloroꢀcontaining products in over 80%
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yield
(entries
6ꢀ10).
Unsurprisingly,
with
by
the
treatment
of
NꢀmethylꢀNꢀarylꢀN'ꢀphenylhydrazine
2ꢀnaphthol
(1a),
1ꢀphenylaminoꢀ2ꢀnaphthol (6a) was produced in good yield (entries 11ꢀ15). However,
the reactions of 2ꢀnaphthol (1a) with other types of triꢀ or tetraꢀsubstituted hydrazines
such
as
N,N'ꢀdibutylꢀNꢀmethylhydrazine,
N,N'ꢀdibutylꢀNꢀphenylhydrazine,
Nꢀanilinoꢀpiperidine and N,N'ꢀdimethylꢀN,N'ꢀdiphenylhydrazine did not give the
aminated products.
Table 8. Orthoꢀamination of 2ꢀnaphthol with NꢀmethylꢀN,N'ꢀdiarylhydrazine[a]
R7
R7
H
N
OH
N
NH
ethylene glycol
120 o
N
R6
R6
+
OH
+
H
C
4
1a
9
6
Entry
Hydrazine 9
Product 6
6j, 84%
6k, 83%
6l, 82%
1
2
3
9b, R6 = R7 = 4ꢀMe
9c, R6 = R7 = 3ꢀMe
9d, R6 = R7 = 4ꢀF
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9e, R6 = R7 = 4ꢀCl
9f, R6 = R7 = 3ꢀCl
6m, 79%
6n, 74%
6j, 84%
6k, 85%
6l, 85%
6m, 81%
6n, 89%
6a, 83%
6a, 85%
6a, 86%
6a, 82%
6a, 81%
6
9g, R6 = H, R7 = 4ꢀMe
9h, R6 = H, R7 = 3ꢀMe
9i, R6 = H, R7 = 4ꢀF
9j, R6 = H, R7 = 4ꢀCl
9k, R6 = H, R7 = 3ꢀCl
9l, R6 = 4ꢀMe, R7 = H
9m, R6 = 3ꢀMe, R7 = H
9n, R6 = 4ꢀF, R7 = H
9o, R6 = 4ꢀCl, R7 = H
9p, R6 = 3ꢀCl, R7 = H
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[a]Reaction conditions: 2ꢀnaphthol (1, 5 mmol), NꢀmethylꢀN,N'ꢀdiaryhydrazine (9, 5 mmol), argon
atmosphere, ethylene glycol (2.5 mL).
Conclusion
In summary, we have developed the direct orthoꢀarylamination and cyclization of
2ꢀnaphthol and its analogues by the use of arylꢀ or alkylꢀsubstituted hydrazines as
amino sources. This transition metalꢀfree protocol can be used to introduce arylamino
scaffolds onto the ortho position of 2ꢀnaphthols, thus providing a novel entry to the
synthesis of orthoꢀarylaminated products that usually can not be directly prepared by
previous methodology. In particular, biologically appealing indazole compounds can
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be facilely prepared by the reaction of 2ꢀnaphthols with N,N'ꢀdialkylhydrazines,
which do not form the related orthoꢀamination compounds. The advantages of simple
operation, transition metalꢀfree conditions of the present protocol make it attractive
for future applications in organic synthesis.
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Experimental Section
General methods
1
NMR spectra were obtained on a Bruker 400 (400 MHz for H NMR; 100 MHz for
13C NMR). 1H NMR chemical shifts are reported in parts per million (ppm) relative to
TMS, with the residual solvent peak used as an internal reference. Multiplicities are
reported as follows: singlet (s), doublet (d), doublet of doublets (dd), triplet (t), triplet
of doublets (td), quartet (q), multiplet (m), and broad resonance (br). HRMS analyses
were made on a Bruker Daltonics Bio TOFꢀQ Mass Spectrometer using ESI or
MALDIꢀTOF ionization. Column chromatography was performed with silica gel
(200ꢀ300 mesh). Thin layer chromatography was carried out using Merck silica gel
GF254 plates. Commercially available reagents were used without further
purification.
6ꢀTertꢀbutylꢀ2ꢀnaphthol, 7ꢀmethoxyꢀ2ꢀnaphthol, 6ꢀmethylꢀ2ꢀnaphthol and ethyl
6ꢀhydroxyꢀ2ꢀnaphthoate were prepared following the procedures previously
reported.19 NꢀAlkylꢀarylhydrazines were prepared from the corresponding
arylhydrazines, while N,Nꢀdiarylhydrazines and N,Nꢀdialkylhydrazines were prepared
from the appropriate secondary amines.20 N,N'ꢀdiarylhydrazines were prepared from
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reduction of the corresponding azo compounds.21 N,N'ꢀdialkylhydrazines and
5
6
7
monoalkylhydrazines
were
prepared
from
the
alkylation
of
8
9
diꢀtertꢀbutylhydrazineꢀ1,2ꢀdicarboxylate
followed
by
hydrolysis.22
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NꢀMethylꢀN,N'ꢀdiarylhydrazines were prepared from the methylation of
N,N'ꢀdiarylhydrazines or the reaction of NꢀhydroxylꢀNꢀarylacetamide with
Nꢀmethylꢀarylamine.23
General procedure for the reaction of N,N-disubstituted hydrazines with
2-naphthol and its analogues in ethylene glycol
Under argon atmosphere, NꢀmethylꢀNꢀarylhydrazine (2, 5 mmol) was added to a
mixture of 2ꢀnaphthols (1, 5 mmol) and ethylene glycol (2.5 mL). The mixture was
heated in an oil bath at 80 °C for 4ꢀ10 h (tracked by TLC). After cooled down, water
(20 mL) was introduced and the residue was extracted with ethyl acetate. The
combined extracts were washed with saturated brine and dried with anhydrous sodium
sulfate. The solvent was removed in vacuum and the residue was purified by flash
column chromatography on silica gel (gradient elution: hexane to hexane/ethyl acetate
(1:1)) to afford products 3 and 4.
1-Amino-2-naphthol (3a): Yield: 88% (0.70 g); gray solid; m.p.> 142 °C (decomp.);
1H NMR (400 MHz, DMSOꢀd6) δ 9.15 (br s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.65 (d, J
= 8.0 Hz, 1H), 7.29 (t, J = 7.0 Hz, 1H), 7.20 (t, J = 7.1 Hz, 1H), 7.07 (s, 2H), 4.96 (br
s, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ 139.4, 129.3, 129.0, 128.3, 124.22, 124.18,
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122.7, 121.9, 118.0, 116.5; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C10H10NO
160.0757; Found 160.0742.
7
8
9
7-Methoxy-1-amino-2-naphthol (3b): Yield: 86% (0.82 g); white solid; m.p.
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1
120~121 °C; H NMR (400 MHz, DMSOꢀd6) δ 9.13 (br s, 1H), 7.56 (d, J = 9.2 Hz,
1H), 7.28 (d, J = 1.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.86
(dd, J = 8.8 Hz, 2.0 Hz, 1H), 4.82 (br s, 2H), 3.86 (s, 3H); 13C NMR (100 MHz,
DMSOꢀd6) δ 156.7, 140.0, 129.8, 128.4, 125.2, 124.4, 116.6, 115.5, 115.2, 100.8,
55.4; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C11H12NO2 190.0863; Found
190.0859.
1-Amino-2,7-naphthalenediol (3c): Yield: 87% (0.76 g); gray solid; m.p.> 200 °C
(decomp.); 1H NMR (400 MHz, DMSOꢀd6) δ 9.36 (s, 1H), 9.07 (br s. 1H), 7.51 (d, J
= 8.8 Hz, 1H), 7.10 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.82 (d,
J = 8.8 Hz, 1H), 4.45 (br s, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ 154.6, 139.9,
129.8, 127.3, 126.2, 123.8, 117.2, 115.5, 115.0, 103.6; HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C10H10NO2 176.0706; Found 176.0711.
1-Amino-6-methoxy-2-naphthol (3d): Yield: 85% (0.80 g); gray solid; m.p.
1
123~125 °C; H NMR (400 MHz, DMSOꢀd6) δ 8.89 (br s, 1H), 7.86 (d, J = 9.2 Hz,
1H), 6.94ꢀ7.06 (m, 4H), 4.91 (br s, 2H), 3.80 (s, 3H); 13C NMR (100 MHz,
DMSOꢀd6) δ 155.2, 137.9, 130.0, 129.8, 123.6, 119.6, 118.5, 116.6, 115.1, 106.4,
55.3; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C11H12NO2 190.0863; Found
190.0868.
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1-Amino-6-methyl-2-naphthol (3e): Yield: 88% (0.76 g); gray solid; m.p.
5
6
7
1
144~146 °C; H NMR (400 MHz, DMSOꢀd6) δ 9.01 (br s, 1H), 7.84 (d, J = 8.6 Hz,
8
9
1H), 7.41 (s, 1H), 7.13 (dd, J = 8.6 Hz, 1.2 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.95 (d,
J = 8.6 Hz, 1H), 4.88 (br s, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ
138.8, 131.4, 129.3, 129.2, 127.1, 126.4, 122.5, 121.9, 118.1, 115.7, 21.4; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C11H12NO 174.0913; Found 174.0919.
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6-(Tert-butyl)-1-amino-2-naphthol (3f): Yield: 88% (0.95 g); white solid; m.p.
1
154~156 °C; H NMR (400 MHz, DMSOꢀd6) δ 8.87 (br s. 1H), 7.85 (d, J = 8.8 Hz,
1H), 7.56 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.04 (s, 2H), 4.85 (br s. 2H), 1.34 (s, 9H);
13C NMR (100 MHz, DMSOꢀd6) δ 144.6, 138.9, 129.1, 128.9, 123.0, 122.9, 122.5,
121.8, 118.0, 116.5, 34.7, 31.6; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C14H18NO
216.1383; Found 216.1381.
6-Bromo-1-amino-2-naphthol (3g): Yield: 89% (1.05 g); gray solid; m.p.> 162 °C
(decomp.); 1H NMR (400 MHz, DMSOꢀd6) δ 9.35 (br s, 1H), 7.93 (d, J = 9.2 Hz, 1H),
7.90 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H),
13
7.05 (d, J = 8.4 Hz, 1H), 5.08 (br s, 2H); C NMR (100 MHz, DMSOꢀd6) δ 139.9,
130.2, 130.0, 129.9, 126.8, 124.6, 122.4, 119.0, 115.8, 115.6; HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C10H9BrNO 237.9862; Found 237.9857.
Ethyl 5-amino-6-hydroxy-2-naphthoate (3h): Yield: 85% (0.98 g); gray solid; m.p.
1
131~133 °C; H NMR (400 MHz, DMSOꢀd6) δ 9.58 (br s. 1H), 8.40 (d, J = 1.6 Hz,
1H), 8.07 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.31 (d, J = 8.4 Hz,
1H), 7.20 (d, J = 8.4 Hz, 1H), 5.12 (br s. 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2
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Hz, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 166.7, 142.0, 131.4, 129.7, 127.7, 125.7,
123.9, 122.9, 122.5, 118.7, 118.5, 60.9, 14.8; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd
for C13H14NO3 232.0968; Found 232.0973.
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5-Amino-6-hydroxy-2-naphthonitrile (3i): Yield: 82% (0.75 g); gray solid; m.p.>
156 °C (decomp.); 1H NMR (400 MHz, DMSOꢀd6) δ 9.79 (br s, 1H), 8.29 (d, J = 1.4
Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.51 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.23 (s, 2H), 5.22
(br s, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ 142.4, 135.0, 130.1, 127.6, 124.6, 124.0,
123.6, 120.4, 119.2, 117.5, 104.7; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C11H9N2O 185.0709; Found 185.0705.
5-Amino-6-hydroxylquinoline (3l): Yield: 75% (0.60 g); gray solid; m.p.
1
165ꢀ168°C; H NMR (400 MHz, DMSOꢀd6) δ 9.41 (br s, 1H), 8.60 (dd, J = 4.0 Hz,
1.2 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.31ꢀ7.27 (m, 2H), 7.20 (d, J = 8.8 Hz, 1H),
13
5.15 (br s, 2H); C NMR (100 MHz, DMSOꢀd6) δ 147.2, 143.8, 139.4, 130.4, 129.6,
120.9, 119.1, 118.8, 117.1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C9H9N2O
161.0709; Found 161.0711.
8-Amino-7-hydroxylquinoline (3m): Yield: 73% (0.58 g); gray solid; m.p.
1
168ꢀ170 °C; H NMR (400 MHz, DMSOꢀd6) δ 9.42 (br s, 1H), 8.68 (dd, J = 4.0 Hz,
1.6 Hz, 1H), 8.11 (dd, J = 8.4 Hz, 1.6 Hz,1H), 7.26 (q, J = 4.0 Hz, 1H), 7.17 (d, J =
8.4 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 5.06 (br s, 2H); 13C NMR (100 MHz,
DMSOꢀd6) δ 147.9, 141.7, 138.5, 136.2, 130.3, 123.2, 118.8, 118.7, 114.8; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C9H9N2O 161.0709; Found 161.0707.
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7-Amino-8-hydroxyquinoline (3n): Yield: 77% (0.62 g); colourless oil; H NMR
(400 MHz, DMSOꢀd6) δ 9.08 (br s, 1H), 8.66 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.08 (dd, J
= 8.0 Hz, 1.6 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.16 (q, J = 4.0 Hz, 1H), 7.12 (d, J =
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8.8 Hz, 1H), 5.09 (br s, 2H); C NMR (100 MHz, DMSOꢀd6) δ 148.5, 138.9, 136.2,
135.8, 134.8, 121.4, 119.3, 118.4, 117.3; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C9H9N2O 161.0709; Found 161.0713.
General procedure for the reaction of hydrazine hydrate and mono-substituted
hydrazine with 2-naphthol in ethylene glycol
Under argon atmosphere, hydrazine hydrate or monoꢀsubstituted hydrazine (5 mmol)
was added to a mixture of 2ꢀnaphthol (1a, 5 mmol) and ethylene glycol (2.5 mL). The
mixture was heated in an oil bath at 90 °C for 15~21 h (tracked by TLC). After cooled
down, water (20 mL) was introduced and the residue was extracted with ethyl acetate.
The combined extracts were washed with saturated brine and dried with anhydrous
sodium sulfate. The solvent was removed in vacuum and the residue was purified by
flash column chromatography on silica gel (gradient elution: hexane to hexane/ethyl
acetate (1:1)) to provide 1ꢀaminoꢀ2ꢀnaphthol (3a) and monoꢀsubstituted amine.
General procedure for the reaction of N,N'-diarylhydrazines with 2-naphthol
and its analogues
Under argon atmosphere, a mixture of 2ꢀnaphthol (1, 5.0 mmol) and
N,N'ꢀdiarylhydrazine (5, 7.5 mmol) was heated in an oil bath at 120 °C for 5~10 h
(tracked by TLC). After cooled down, dichloromethane (50 mL) was introduced and
the residue was decolorized by activated carbon. After filtration, the solvent was
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removed in vacuum and the residue was purified by flash column chromatography on
silica gel (gradient elution: hexane to hexane/ethyl acetate (10:1)) to provide
arylamine and 1ꢀarylaminoꢀ2ꢀnaphthol (6).
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1-Phenylamino-2-naphthol (6a): Yield: 61% (0.72 g); gray solid; m.p. 155ꢀ156 °C;
1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.66
(d, J = 8.3 Hz, 1H), 7.38 (td, J = 6.8 Hz, 1.2 Hz, 1H), 7.30ꢀ7.34 (m, 2H), 7.18 (t, J =
7.5 Hz, 2H), 6.83 (t, J = 7.4 Hz, 1H), 6.65 (d, J = 7.9 Hz, 2H), 6.54 (br s, 1H), 5.27
13
(br s, 1H); C NMR (100 MHz, CDCl3) δ 152.1, 146.7, 132.1, 129.6, 129.1, 128.7,
127.0, 123.5, 121.5, 119.8, 118.6, 116.9, 114.2; HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C16H14NO 236.1070; Found 236.1075.
7-Methoxy-1-phenylamino-2-naphthol (6b): Yield: 53% (0.70 g); gray solid; m.p.
1
128ꢀ130 °C; H NMR (400 MHz, CDCl3) δ 7.68ꢀ7.72 (m, 2H), 7.14ꢀ7.20 (m, 3H),
6.92ꢀ6.98 (m, 2H), 6.83 (t, J = 7.3 Hz, 1H), 6.67 (d, J = 7.6 Hz, 2H), 6.56 (br s, 1H),
5.17 (br s, 1H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 152.7, 146.5,
133.4, 130.3, 129.6, 128.8, 124.9, 119.8, 118.0, 115.5, 114.3, 114.2, 100.7, 55.2;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H16NO2 266.1176; Found 266.1179.
1-Phenylamino-2,7-naphthalendiol (6c): Yield: 45% (0.57 g); gray solid; m.p.
1
167ꢀ169 °C; H NMR (400 MHz, CDCl3) δ 7.71 (t, J = 7.8 Hz, 2H), 7.14ꢀ7.20 (m,
3H), 6.90ꢀ6.93 (m, 2H), 6.84 (t, J = 7.4 Hz, 1H), 6.64 (d, J = 7.6 Hz, 2H), 6.55 (br s,
13
1H), 5.11 (br s, 2H); C NMR (100 MHz, DMSOꢀd6) δ 155.7, 151.4, 148.1, 134.2,
129.7, 128.6, 126.6, 123.2, 118.6, 116.4, 115.2, 115.1, 113.2, 104.2; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C16H14NO2 252.1019; Found 252.1021.
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6-Methoxy-1-phenylamino-2-naphthol (6d): Yield: 61% (0.81 g); gray solid; m.p.
5
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132ꢀ134 °C; H NMR (400 MHz, DMSOꢀd6) δ 9.17 (s, 1H), 7.58ꢀ7.63 (m, 2H), 7.34
8
9
(s, 1H), 7.20ꢀ7.24 (m, 2H), 7.01ꢀ7.05 (m, 3H), 6.58 (t, J = 7.1 Hz, 1H), 6.47 (d, J =
7.7 Hz, 2H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.0, 150.4, 146.7, 130.5,
129.6, 127.7, 127.3, 123.1, 119.7, 119.5, 118.9, 117.4, 114.2, 107.0, 55.4; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C17H16NO2 266.1176; Found 266.1178.
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6-Methyl-1-phenylamino-2-naphthol (6e): Yield: 63% (0.79 g); gray solid; m.p.
1
142ꢀ144 °C; H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.8 Hz, 1H), 7.56ꢀ7.59 (m,
2H), 7.16ꢀ7.29 (m, 4H), 6.83 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 8.0 Hz, 2H), 6.44 (br s,
13
1H), 5.23 (br s, 1H), 2.45 (s, 3H); C NMR (100 MHz, DMSOꢀd6) δ 150.0, 147.9,
131.5, 130.3, 128.8, 128.6, 128.0, 126.9, 125.7, 122.5, 120.1, 118.7, 116.6, 113.4,
20.8; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H16NO 250.1226; Found
250.1229.
6-Bromo-1-phenylamino-2-naphthol (6f): Yield: 62% (0.97 g); gray solid; m.p.
1
134ꢀ136 °C; H NMR (400 MHz, DMSOꢀd6) δ 9.69 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H),
7.69 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.45ꢀ7.49 (m, 2H), 7.31 (d, J = 8.8
Hz, 1H), 7.04 (t, J = 7.5Hz, 2H), 6.60 (t, J = 7.2 Hz, 1H), 6.46 (d, J = 7.7 Hz, 2H); 13C
NMR (100 MHz, DMSOꢀd6) δ 151.2, 147.6, 130.7, 129.7, 128.70, 128.66, 125.7,
125.0, 120.5, 120.1, 116.9, 115.6, 113.4; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C16H13BrNO 314.0175; Found 314.0172.
5-Phenylamino-6-hydroxyquinoline (6h): Yield: 37% (0.44 g); gray solid; m.p.
1
230ꢀ232 °C; H NMR (400 MHz, DMSOꢀd6) δ 9.78 (s, 1H), 8.67 (dd, J = 4.0 Hz,
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1.4Hz, 1H), 8.08 (d, J = 8.4Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.49ꢀ7.51 (m, 2H), 7.38
(dd, J = 8.5 Hz, 4.1 Hz, 1H), 7.07 (t, J = 8.2 Hz, 2H), 6.61 (t, J = 7.3 Hz, 1H), 6.48 (d,
J = 7.7 Hz, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ 150.8, 147.6, 147.0, 143.6, 130.7,
128.7, 127.4, 127.0, 122.0, 120.9, 119.8, 117.0, 113.4; HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C15H13N2O 237.1022; Found 237.1025.
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8-Phenylamino-7-hydroxyquinoline (6i): Yield: 32% (0.38 g); gray solid; m.p.
1
227ꢀ229 °C; H NMR (400 MHz, DMSOꢀd6) δ 9.84 (s, 1H), 8.72 (dd, J = 4.2 Hz, 1.6
Hz, 1H), 8.22 (dd, J = 8.2 Hz, 1.5 Hz, 1H), 7.59ꢀ7.61 (m, 2H), 7.29ꢀ7.32 (m, 2H),
7.06 (t, J = 8.2 Hz, 2H), 6.61ꢀ6.68 (m, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 150.9,
149.6, 146.4, 144.6, 136.5, 128.6, 123.9, 123.3, 122.7, 120.0, 119.1, 118.1, 115.7;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H13N2O 237.1022; found 237.1024.
1-(p-Tolylamino)-2-naphthol (6j): Yield: 52% (0.65 g); gray solid; m.p. 134ꢀ136 °C;
1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.66
(d, J = 8.3 Hz, 1H), 7.37 (t, J = 7.2 Hz, 1H), 7.29ꢀ7.32 (m, 2H), 6.98 (d, J = 8.2 Hz,
2H), 6.55ꢀ6.58 (m, 3H), 5.15 (br s, 1H), 2.24 (s, 3H); 13C NMR (100 MHz,
DMSOꢀd6) δ 150.5, 145.5, 132.0, 129.0, 128.6, 128.0, 126.2, 125.7, 125.2, 122.6,
120.6, 118.7, 113.6, 20.1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H16NO
250.1226; Found 250.1229.
1-(m-Tolylamino)-2-naphthol (6k): Yield: 51% (0.63 g); gray solid, m.p.
1
100ꢀ101 °C; H NMR (400 MHz, CDCl3) δ 7.75ꢀ7.81 (m, 2H), 7.65 (d, J = 8.3 Hz,
1H), 7.35ꢀ7.39 (m, 1H), 7.29ꢀ7.33 (m, 2H), 7.05 (t, J = 8.1 Hz, 1H), 6.64 (d, J = 7.5
Hz, 1H), 6.54 (s, 1H), 6.42ꢀ6.44 (m, 2H), 5.12 (br s, 1H), 2.21 (s, 3H); 13C NMR (100
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MHz, DMSOꢀd6) δ 150.8, 147.9, 137.6, 132.2, 128.54, 128.49, 128.0, 126.5, 125.8,
122.7, 122.5, 120.2, 118.7, 117.6, 114.0, 110.7, 21.3; HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C17H16NO 250.1226; Found 250.1228.
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1-(4-Fluorophenylamino)-2-naphthol (6l): Yield: 53% (0.67 g); gray solid, m.p.
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132ꢀ134 °C; H NMR (400 MHz, CDCl3) δ 7.76ꢀ7.82 (m, 2H), 7.61 (d, J = 8.4 Hz,
1H), 7.38 (t, J = 7.1 Hz, 1H), 7.31 (t, J = 8.1 Hz, 2H), 6.84ꢀ6.88 (m, 2H), 6.54ꢀ6.57
(m, 3H), 5.13 (br s, 1H); 13C NMR (100 MHz, DMSOꢀd6) δ 150.6, 144.4, 132.0,
128.6, 128.0, 126.5, 125.9, 122.7, 122.3, 120.4, 118.7, 115.1, 114.9, 114.2, 114.1;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H13FNO 254.0976; Found: 254.0978.
1-(4-Chlorophenylamino)-2-naphthol (6m): Yield: 47% (0.63 g); gray solid, m.p.
1
100ꢀ102 °C; H NMR (400 MHz, CDCl3) δ 7.77ꢀ7.83 (m, 2H), 7.61 (d, J = 8.3 Hz,
1H), 7.40 (t, J = 7.1 Hz, 1H), 7.29ꢀ7.35 (m, 2H), 7.12 (d, J = 8.7 Hz, 2H), 6.57 (d, J =
13
8.7 Hz, 2H), 6.44 (br s, 1H), 5.23 (br s, 1H); C NMR (100 MHz, CDCl3) δ 152.0,
145.3, 131.8,129.9, 129.6, 129.5, 129.4, 128.7, 127.2, 123.6, 121.3, 118.2, 117.8,
116.9, 115.4; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H13ClNO 270.0680;
Found 270.0683.
1-(3-Chlorophenylamino)-2-naphthol (6n): Yield: 43% (0.58 g); gray solid, m.p.
99ꢀ101 °C; 1H NMR (400 MHz, CDCl3) δ 7.77ꢀ7.82 (m, 2H), 7.60 (d, J = 8.3 Hz, 1H),
7.39 (t, J = 7.2 Hz, 1H), 7.29ꢀ7.35 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.78 (dd, J = 7.9
Hz, 1.0 Hz, 1H), 6.59 (t, J = 1.8 Hz, 1H), 6.48 (dd, J = 8.1 Hz, 1.8 Hz, 1H), 6.41 (s,
1H), 5.22 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 152.0, 148.0, 135.4, 131.8, 130.6,
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129.6, 129.5, 128.7, 127.2, 123.7, 121.2, 119.9, 117.8, 117.0, 114.2, 112.4; HRMS
(ESI) m/z: [M+H]+ Calcd for C16H13ClNO 270.0680; Found 270.0682.
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1-(4-(Trifluoromethyl)phenylamino)-2-naphthol (6o): Yield: 34% (0.52 g); gray
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solid, m.p. 110ꢀ112 °C; H NMR (400 MHz, CDCl3) δ 7.83 (t, J = 8.1 Hz, 2H), 7.61
(d, J = 8.3 Hz, 1H), 7.40ꢀ7.43 (m, 3H), 7.31ꢀ7.37 (m, 2H), 6.68 (d, J = 8.4 Hz, 2H),
6.27 (s, 1H), 5.49 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 159.9, 149.5, 131.8, 129.72,
129.66, 128.8, 127.3, 127.0 (q, J = 3.8 Hz), 123.8, 121.2, 117.4, 117.1, 113.7; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C17H13F3NO 304.0944; Found 304.0947.
General procedure for the reaction of N,N'-dialkylhydrazines with 2-naphthol
and its analogues
Under an argon atmosphere, a mixture of 2ꢀnaphthol (1, 2 mmol) and
N,N'ꢀdialkylhydrazine (7, 6 mmol) was heated in an oil bath at 120 °C for 20~24 h
(tracked by TLC). After cooled down, dichloromethane (50 mL) was introduced and
the residue was decolorized by activated carbon. After filtration, the solvent was
removed in vacuum and the residue was purified by flash column chromatography on
silica gel (gradient elution: hexane to hexane/ethyl acetate (10:1)) to afford product 8.
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3-Butyl-1-propyl-3H-benzo[e]indazole (8a): Yield: 75% (0.40 g); colorless oil; H
NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.69 (d,
J = 9.0 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.46 (m, 2H), 4.39 (t, J = 7.1 Hz, 2H), 3.24
(t, J = 7.6 Hz, 2H), 1.97 (m, 4H), 1.38 (m, 2H), 1.10 (t, J = 7.3 Hz, 3H), 0.93 (t, J =
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 146.3, 138.9, 129.4, 129.0, 128.5, 128.0,
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127.3, 123.7, 122.9, 115.9, 110.4, 48.6, 32.4, 31.6, 22.1, 20.1, 14.2, 13.8; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C18H23N2 267.1856; Found 267.1861.
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3-Butyl-8-methoxy-1-propyl-3H-benzo[e]indazole (8b): Yield: 65% (0.39 g);
colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 2.4
Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.28 (d, J = 9,0 Hz, 1H), 7.09 (dd, J = 8.8 Hz, 2.5
Hz, 1H), 4.37 (t, J = 7.1 Hz, 2H), 3.98 (s, 3H), 3.23 (t, J = 7.6 Hz, 2H), 1.87ꢀ1.98 (m,
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4H), 1.30ꢀ1.39 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 159.0, 146.2, 139.3, 130.4, 129.8, 127.8, 124.1, 115.7, 114.0,
107.8, 104.0, 55.3, 48.6, 32.3, 31.6, 22.3, 20.1, 14.2, 13.7; HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C19H25N2O 297.1961; Found 297.1965.
3-Butyl-1-propyl-3H-benzo[e]indazol-8-ol (8c): Yield: 71% (0.40 g); gray solid;
m.p. 144ꢀ146 °C; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.7 Hz, 1H), 7.65 (d, J =
8.8 Hz, 2H), 7.26ꢀ7.28 (m, 1H), 7.04 (d, J = 8.8 Hz, 1H), 5.68 (br s, 1H), 4.41 (t, J =
7.0 Hz, 2H), 3.21 (t, J = 7.4 Hz, 2H), 1.89ꢀ1.94 (m, 4H), 1.29ꢀ1.39 (m, 2H), 1.07 (t, J
= 7.4 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 156.8,
145.1, 139.0, 130.5, 129.3, 127.5, 122.8, 114.44, 114.38, 107.4, 105.9, 47.5, 31.8,
30.7, 21.5, 19.3, 13.9, 13.5; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C18H23N2O
283.1805; Found 283.1808.
3-Butyl-7-methoxy-1-propyl-3H-benzo[e]indazole (8d): Yield: 68% (0.40 g); gray
solid; m.p. 67ꢀ69 °C. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.6 Hz, 1H), 7.63 (d,
J = 9.0 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.28ꢀ7.31 (m, 2H), 4.39 (t, J = 7.1 Hz, 2H),
3.94 (s, 3H), 3.22 (t, J = 7.6 Hz, 2H), 1.87ꢀ1.94 (m, 4H), 1.30ꢀ1.39 (m, 2H), 1.09 (t, J
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= 7.3 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 156.0, 145.6,
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138.1, 130.6, 127.2, 124.2, 123.0, 118.0, 116.1, 110.8, 109.1, 55.4, 48.6, 32.4, 31.5,
22.1, 20.1, 14.2, 13.8; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C19H25N2O
297.1961; Found 297.1964.
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7-(tert-Butyl)-3-butyl-1-propyl-3H-benzo[e]indazole (8e): Yield: 61% (0.39 g);
colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.7 Hz, 1H), 7.87 (d, J = 2.0
Hz, 1H), 7.72 (dd, J = 8.6 Hz, 2.1 Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 9.0
Hz, 1H), 4.39 (t, J = 7.1 Hz, 2H), 3.23 (t, J = 7.6 Hz, 2H), 1.87ꢀ1.97 (m, 4H),
1.30ꢀ1.47 (m, 11H), 1.09 (t, J = 7.3 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 146.5, 146.1, 138.8, 129.3, 128.4, 126.3, 125.7, 124.6, 122.6, 115.8,
110.2, 48.6, 34.6, 32.4, 31.5, 22.2, 20.1, 14.1, 13.7; HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C22H31N2 323.2482; Found: 323.2486.
7-Bromo-3-butyl-1-propyl-3H-benzo[e]indazole (8f): Yield: 61% (0.42 g); white
solid; m.p. 45ꢀ46 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.8 Hz, 1H), 8.05 (d,
J = 1.7 Hz, 1H), 7.70 (dd, J = 8.8 Hz, 1.9 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.47 (d, J
= 9.0 Hz, 1H), 4.39 (t, J = 7.2 Hz, 2H), 3.20 (t, J = 7.6 Hz, 2H), 1.85ꢀ1.95 (m, 4H),
13
1.30ꢀ1.39 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); C NMR (100
MHz, CDCl3) δ 146.2, 138.8, 131.0, 130.8, 130.3, 127.0, 126.9, 124.5, 117.0, 115.7,
111.5, 48.7, 32.4, 31.5, 22.0, 20.1, 14.1, 13.7; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd
for C18H22BrN2 345.0961; Found 345.0965.
1
1-Heptyl-3-octyl-3H-benzo[e]indazole (8h): Yield: 71% (0.54 g); colorless oil; H
NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.70 (d,
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