Palladium-catalyzed monoarylation of arylhydrazines with aryl tosylates

Article abstract of DOI:10.1021/acs.joc.0c01599

A palladium-catalyzed C-N bond coupling reaction between arylhydrazines and aryl tosylates for facile synthesis of unsymmetrical N,N-diarylhydrazines has been developed. Employing the catalyst system of Pd(TFA)2 associated with newly developed phosphine ligand L1, the monoarylation of arylhydrazine proceeds smoothly to afford desired products in good-to-excellent yields (up to 95%) with good functional group compatibility. This method provides an alternative synthetic pathway for accessing structurally diversified N,N-diarylhydrazines from simple and easily accessible coupling components.

Full text of DOI:10.1021/acs.joc.0c01599

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Article
Palladium-catalyzed Monoarylation of Arylhydrazines with Aryl Tosylates
Yange Huang, Pui Ying Choy, Junya Wang, Man Kin Tse,
Raymond Wai-Yin Sun, Albert Sun Chi Chan, and Fuk Yee Kwong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01599 • Publication Date (Web): 14 Sep 2020
Downloaded from pubs.acs.org on September 15, 2020
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Palladium-catalyzed Monoarylation of Arylhydrazines with Aryl
Tosylates
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Yange Huang,†,‡ Pui Ying Choy,†,‡ Junya Wang,† Man-Kin Tse,§ Raymond Wai-Yin
Sun,§ Albert Sun-Chi Chan§ and Fuk Yee Kwong*,†,‡
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†Shenzhen Municipal Key Laboratory of Chemical Synthesis of Medicinal Organic Molecules,
Shenzhen Research Institute, The Chinese University of Hong Kong, No. 10, Second Yuexing
Road, Shenzhen 518507, China
‡State Key Laboratory of Synthetic Chemistry and Department of Chemistry, The Chinese
University of Hong Kong, New Territories, Shatin, Hong Kong, China.
§Guangzhou Lee & Man Technology Co. Ltd. Rm 401, Blk A, 8 Huanshi Avenue South, Nansha,
Guangzhou, China
Email: fykwong@cuhk.edu.hk
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
KEYWORDS: phosphine, palladium, phenylhydrazine, monoarylation, aryl tosylate
R
R
OTs
2.0 mol% Pd(TFA)2
L1
NH2
R'
N
6.0 mol%
Me
N
+
K3PO4, DMF
100 °C, 24 h
H
N
OMe
OMe
H2N
Cy2P
31 examples
up to 95% yield
R'
R = -Me, -OMe, -C(O)Me, -CN, -COOMe...
R' = -F, -Me, -OMe, -SO2NH2, -CF3...
L1
Abstract.
A palladium-catalyzed C–N bond coupling reaction between arylhydrazines and aryl
tosylates for facile synthesis of unsymmetrical N,N-diarylhydrazines has been developed.
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Employing the catalyst system of Pd(TFA)2 associated with newly developed phosphine
ligand L1, the monoarylation of arylhydrazine proceeds smoothly to afford desired
products in good-to-excellent yields (up to 95%) with good functional group compatibility.
This method provides an alternative synthetic pathway for accessing structurally
diversified N,N-diarylhydrazines from simple and easily accessible coupling components.
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Introduction
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Arylhydrazines are resourceful building blocks in synthetic organic chemistry. They are
widely used for assembling of a myriad of nitrogen-containing heterocycles, such as
indole,1 indazole,2 carbazole,3 and 1,2,4-benzotriazine derivatives4 (Figure 1A). In
particular, the unsymmetrical N,N-diarylhydrazines display distinctive physicochemical
and biological properties that are favorable to medicinal chemistry (Figure 1B & C).5 In
addition to fruitful applications in pharmaceutical chemistry, hydrazine functional group
also serves as an effective directing group in many aromatic CH bond functionalizations
(Figure 1D).6 Given the versatility of arylhydrazine, there is a demand of exploring new
synthetic method to allow easy manipulation of the substitution pattern of these important
motifs.
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(A) Hydrazine motif serves as precursors to synthesize heterocyclic compounds, e.g. indoles
R
R'
[Ti] or [Zr] or [Co]
[H+] or Zeolites
O
HZ
R
N
N
R'
N
R'
NH2
Ph
[Ru], Z = O
[Pd], Z = NH
R
(B) Hydrazine motif serves as
part of bioactive molecules
(C) Hydrazine motif serves as precursors to synthesize high-
value compounds in pharmaceuticals
S
Z
H
H
S
N
Me
NH
N
N
Me
N
N
RO
O
S
N
•
Na
N
H2N
Me
OH
Therapeutic agents for diabetes
Potent
-adrenergic
Inhibitors of human
papilloma virus (HPV)
antagonists
(D) Hydrazine motif serves as directing groups in catalysis
O
Me Cl
Cl
HN
R
R
N
•
HCl
N
EWG
Me
O
NH2
EWG
N
NH2
N
NH
N
R
N
R
[M]
HN
N
NH2
[M]
M = Rh, Co, Pd, etc.
Me
O
H
R'
Tachykinin receptors antagonists
R'
Figure 1. A brief glance of arylhydrazine scaffold in bioactive molecules and catalysis.
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Traditional method for preparing N,N-diarylhydrazines is the Hofmann reaction of
1,1-diarylureas7 and the oxidation of diaryl amines followed by reduction of the resulting
aryl diazonium salts (Figure 2A).8 Nevertheless, multistep synthetic pathway, harsh
reaction conditions, narrow functional group compatibility, expensive starting materials,
and low product yields may limit the attractiveness. In fact, modern catalysis has emerged
as a powerful tool for constructing aromatic C–N bond.9 This strategy demonstrates as a
possible alternative of preparing N,N-diarylhydrazines.
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(A) Reduction of aryl diazonium salts
 Formation of aniline side products
 Requires expensive starting materials
 Narrow function group compatibility
 Harsh reaction conditions
NO
N
NH2
N
[Zn]
R
R'
R
R'
AcOH
(B) Cu-catalyzed N-arylation of hydrazones with arylboronic acids
PG
HN
PG
NH
PG
N
Ar
OH
Ar
NH2
B
Ar
NH2
NH
N
N
N
deprotection
NBS
OH
[Cu]
R'
R'
R'
R'
R'
(C) Cu-catalyzed N-arylation of hydrazides/ hydrazones with aryl halides
PG
NH
PG
NH
NH2
N
R
X
[Cu]
H2NNH2
HN
N
+
R
R'
R
R'
PG = Boc, Phth...
R'
 Use of protecting groups
 Requires tedious multistep
X = Br or I
(D) Cu-catalyzed N-arylation of phenylhydrazine with aryl halides
NH2
X
 Only 4 examples were shown
 Formation of side products
(e.g. anilines, arenes)
NH2
N
HN
[Cu]
+
R
R
R'
R'
Challenges:
(E) Pd-catalyzed N-arylation of phenylhydrazine with ArOTs
NH2
NH2
NH2
HN
NH2
N
OTs
HN
[Pd]/ ligand
+
R
R'
R
N
N
R'
this work
Figure 2. Selected synthetic methods of N,N-diarylhydrazines
N-Arylation of amides/ hydrazides/ hydrazones under copper catalysis have been
precedents.10 Yet, tedious deprotection of Boc or Phth group was required to afford the
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desirable N,N-diarylhydrazines (Figure 2B & C).11 The reaction scheme of accessing
substituted arylhydrazine without reciprocal protecting/deprotecting step remains
sporadically studied. Perhaps this synthetic route suffers from the formation of
byproducts such as arene and aniline, along with the desired products (i.e. Ar-NH-NH2
serves as aryl and amine sources12 and even as initiator of direct arylation13). In 2006, a
streamlined copper-catalyzed N-arylation of phenylhydrazine with aryl iodides/bromides
was reported (Figure 2D).14 Four successful examples were shown and the reaction time
was found to be 36 hours. In fact, it would be attractive to explore new method for facile
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and modular synthesis of unsymmetrically substituted N,N-diarylhydrazines.
In
continuing our relevant research works of investigating ligand system for tackling
monoarylation of multi-arylation-possible substrates,15 and C–N bond coupling
reactions,16 we herein report the first general examples of Pd-catalyzed monoarylation of
arylhydrazine with aryl tosylates for affording N,N-diarylhydrazines.
Results and Discussion
In order to probe the feasibility of the monoarylation of arylhydrazine, non-activated
4-tert-butylphenyl tosylate and phenylhydrazine were initially employed as benchmarking
substrates. Poor conversions were observed with XPhos and SPhos whereas
CataCXium PCy and Xantphos were found to be ineffective.17 An array of our
indolylphosphine ligands were tested for their efficacy in promoting this reaction (Scheme
1). Ligands having N-PCy2 and C3(indole)-PCy2 moieties, for instance, NPCy-o-Andole-
phos, CPCy-Phendole-phos and CPCy-o-Andole-phos were found to be entirely
ineffective. It is interesting to show that only the dialkylphosphino component located at
the 2-arene position of ligands were able to catalyze this reaction. Among new ligands
L1-L3 surveyed, L1 gave the best product yield. No reaction was observed when less
electron-rich L2 was used as the ligand. This result was possibly due to the incapability
of facilitating oxidative cleavage of the C(Ar)−O bond of aryl tosylate. The ligand structure
L1 was unambiguously characterized by single crystal X-ray crystallographic analysis.
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Scheme 1. An evaluation of our proprietary indolylphosphines and new ligands L1-L3 in
Pd-catalyzed monoarylation of phenylhydrazinea
7
8
9
OTs
NH2 2.0 mol% Pd(OAc)2
NH2
N
HN
ligand
8.0 mol%
+
K3PO4, DMF
90 °C, 24 h
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t-Bu
t-Bu
1a
2a
3aa
PCy2
Ligands:
OMe
N
N
PCy2
Me
NPCy o-Andole-phos, 0%
CPCy Phendole-phos, 0%
PCy2
OMe
PCy2
PCy2
N
N
N
Me
Me
Me
OMe
CPCy o-Andole-phos, 0%
CM-phos, 73%
MeO-CM-phos, 80%
PR2
PCy2
N
N
Me
Me
OMe
OMe
OMe
OMe
L2
L3
: R = Ph, 0%
: R = i-Pr, 75%
L1
CCDC 2003751
, 85%
aReaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Pd(OAc)2 (2.0 mol%), ligand (8.0 mol%; Pd/L = 1:4),
K3PO4 (0.6 mmol) and DMF (1.5 mL) were stirred at 90 °C under nitrogen atmosphere for 24 h. GC yields
using tetradecane as the internal standard were reported.
Table 1. Initial reaction conditions screening of Pd-catalyzed monoarylation of
phenylhydrazine with 1aa
OTs
NH2
Pd source
NH2
N
HN
L1
+
base, solvent
temp, 24 h
t-Bu
t-Bu
1a
2a
3aa
solvent
entry
catalyst (mol%)
base
% yieldb
1
2
Pd(OAc)2 (2.0)
Pd(OAc)2 (2.0)
Pd(OAc)2 (2.0)
Pd(OAc)2 (2.0)
Pd(OAc)2 (2.0)
K3PO4
K2CO3
DMF
DMF
DMF
DMF
DMF
85
70
84
82
78
3
Cs2CO3
K3PO4H2O
K3PO4
4
5c
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6d
7e
Pd(OAc)2 (2.0)
Pd(OAc)2 (2.0)
Pd(OAc)2 (2.0)
Pd(OAc)2 (2.0)
Pd(OAc)2 (2.0)
Pd(OAc)2 (2.0)
PdCl2(ACN)2 (2.0)
PdCl2(COD) (2.0)
Pd(TFA)2 (2.0)
Pd2(dba)3 (1.0)
Pd(TFA)2 (1.0)
Pd(TFA)2 (2.0)
Pd(TFA)2 (2.0)
Pd(TFA)2 (2.0)
Pd(TFA)2 (2.0)
Pd(TFA)2 (2.0)
Pd(TFA)2 (2.0)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMF
DMF
89
73
8
t-BuOH
DMA
67
9
82
10
11
12
13
14
15
16
17f
18g
19h
20i
21j
22k
toluene
DMA:DMF = 1:1
DMF
68
83
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87
DMF
92
DMF
95
DMF
87
DMF
87
DMF
40
DMF
90
DMF
97 (95)
85
DMF
DMF
73
DMF
80
aReaction conditions: 1a (0.2 mmol), 2a (1.0 mmol), Pd source (as indicated), Pd/L1 = 1:4, base (0.6 mmol),
PhB(OH)2 (0.01 mmol) and solvent (1.0 mL) were stirred at 90 °C under nitrogen for 24 h. bYields were
determined by GC-FID with tetradecane as the internal standard. Isolated yield was shown in parentheses.
c1.5 equiv. of K3PO4 was used. 100 °C was used. 105 °C was used. Pd/L = 1:1 was used. Pd/L = 1:2
d
e
f
g
h
i
j
k
was used. Pd/L = 1:3 was used. 3.0 equiv. of 2a was used. No PhB(OH)2 was added. Phenylhydrazine
hydrochloride (2.0 equiv.) and K3PO4 (5.0 equiv.) were used instead of 2a.
Having identified the effective ligand, we next put effort to investigate the best
reaction parameters fit for the Pd/L1 catalyst system (Table 1). Commonly used K3PO4,
Cs2CO3 and K3PO4H2O bases gave comparable results (entry 1 vs entries 3-4).
Lowering the amount of K3PO4 gave a lower product yield (entry 1 vs entry 5). DMF
provided a better result than t-BuOH and other common organic solvents (entry 1 vs
entries 8-11). Pd(TFA)2 metal source showed the best performance among others
investigated (entry 1 vs entries 12-15).18 Reducing the Pd catalyst loading to 1.0 mol%
resulted a drop of product yield. (entry 14 vs entry 16). The best metal-to-ligand ratio was
found to be 1:3 (entry 14 vs entries 17-19). Phenylhydrazine hydrochloride salt, a more
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stable form of phenylhydrazine, was also tested as the coupling partner, yet a 75% yield
was given (entry 14 vs entry 22).
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9
Encouraged by the optimized Pd/L1 catalyst system, we then turned our attention
to examine the substrate scope (Scheme 2). In general, the reaction proceeded smoothly
with a broad spectrum of aryl tosylates. Electron-neutral (Scheme 2, products 3aa-3da),
-rich (Scheme 2, product 3fa), and -deficient (Scheme 2, products 3ea, 3ga) aryl tosylates
were well-tolerated. Particular functional groups, including methyl ester, nitrile, and
enolizable keto moieties (Scheme 2, products 3ja, 3la, and 3ma, respectively) remained
intact under these reaction conditions. When 3-acetamidophenyl tosylate (1o) was used
as coupling partner, the N-arylation reaction occurred selectively at the hydrazine NH
instead of the amido NH position (Scheme 2, product 3oa). Heterocycles such as
quinoline, pyrrole, and pyridine were all compatible under this catalyst system (Scheme
2, products 3pa, 3qa, and 3ra, respectively). Sterically congested naphthalen-1-yl
tosylate (1t) did not afford the targeted N,N-diarylhydrazine but 3ta was resulted (Scheme
3). A similar example was demonstrated by Stradiotto in 2010 for the N-arylation of
phenylhydrazine with aryl chloride using Pd/Mor-DalPhos catalyst system (in which N,N’-
diarylhydrazines was formed).19
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Scheme 2. Palladium-catalyzed monoarylation of phenylhydrazine with aryl tosylatesa
NH2 2.0 mol% Pd(TFA)2
OTs
NH2
N
HN
L1
6.0 mol%
+
R
R
K3PO4, DMF
100 °C, 24 h
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1
2a
3
NH2
N
NH2
N
NH2
N
Me
t-Bu
Me
3ca
95%, 87%b
94%
86%
3aa
3ba
NH2
N
NH2
N
NH2
N
Me
Me
NC
MeO
3da
3ea
3ha
3fa
77%
83%
87%
NH2
NH2
N
NH2
N
N
O
O
F
Ph
OR
3ia
R = Me, 80%c
R = Et, 71%c
c
3ga
75%
88%
3ja
NH2
N
NH2
N
NH2
N
CN
3ma
O
Me
90%c
3ka
84%
82%
3la
NH2
N
NH2
NH2
N
N
O
NH
Me
N
O
OEt
70%c
90%c,d
3pa
90%
3na
3oa
NH2
N
NH2
N
NH2
N
O
N
O
N
e
86%c
64%c
65%
3qa
3ra
3sa
aReaction conditions: 1 (0.5 mmol), 2a (2.5 mmol), Pd(TFA)2 (2.0 mol%), L1 (6.0 mol%; Pd/L = 1:3), K3PO4
(1.5 mmol), PhB(OH)2 (0.02 mmol) and DMF (1.5 mL) were stirred at 100 °C under nitrogen for 24 h.
Isolated yields were reported. Reaction times were not optimized for each substrate. bIsolated yields of
gram-scale synthesis (10.0 mmol, 2.09 g). 1.0 mmol of 2a was used. dNo PhB(OH)2 was added. e1.5
c
mmol% of 2a was used.
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Scheme 3. Palladium-catalyzed N-arylation of steric hindered 1t with 2aa
6
7
8
9
NH2
2.0 mol% Pd(TFA)2
OTs
HN
H
N
L1
6.0 mol%
+
N
H
K3PO4, DMF
100 °C, 24 h
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1t
2a
3ta
77%
see SI for X-ray structure
aReaction conditions: 1t (0.5 mmol), 2a (1.0 mmol), Pd(TFA)2 (2.0 mol%), L1 (6.0 mol%), K3PO4 (1.5 mmol),
PhB(OH)2 (0.02 mmol) and DMF (1.5 mL) were stirred at 100 °C under nitrogen for 24 h. Isolated yield.
When 4-oxo-2-phenylchroman-6-yl tosylate (1u) was used as the coupling partner,
an unexpected side product 3ua was generated in 89% yield (Scheme 4). It is believed
that 1u underwent condensation to give flavanone hydrazone, followed by alkali
hydrolysis and cyclization to afford the pyrazoline 3ua. This transformation was
confirmed to proceed in the absence of palladium complex. The structure of 3ua was
confirmed by X-ray crystallography (see Supporting Information for detail).
Scheme 4. Formation of pyrazoline by reaction of 1u with 2aa
NH2
2.0 mol% Pd(TFA)2
L1
O
O
OH
HN
N
N
6.0 mol%
TsO
+
K3PO4, DMF
100 °C, 24 h
Ph
HO
1u
2a
3ua
89%
see SI for X-ray structure
3ua
yield of
reaction conditions differ from the above
w/o Pd(TFA)2
88%
87%
L1
w/o Pd(TFA)2 and
aReaction conditions: 1u (0.5 mmol), 2a (1.0 mmol), Pd(TFA)2 (2.0 mol%), L1 (6.0 mol%), K3PO4 (1.5 mmol),
PhB(OH)2 (0.02 mmol) and DMF (1.5 mL) were stirred at 100 °C under nitrogen for 24 h. Isolated yield.
The scope of the monoarylation reaction with respect to other substituted
arylhydrazines was next investigated and the results are compiled in Scheme 5.
Arylhydrazines with different substitution patterns, in terms of electronic properties and
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substitution positions on the arene ring, were tested. In general, the corresponding N,N-
diarylhydrazines were furnished in good-to-excellent yields. It should be noted that 4-
hydrazineylbenzenesulfonamide hydrochloride (2m) having three different NH groups,
was found to be a feasible substrate to afford the desired product 3bm.
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Scheme 5. Palladium-catalyzed monoarylation of arylhydrazine hydrochloride 2 with aryl
tosylate 1ba
NH2
2.0 mol% Pd(TFA)2
L1
OTs
NH2
N
HN
6.0 mol%
• HCl
R'
+
R'
K3PO4, DMF
100 °C, 24 h
1b
2
3
NH2
N
NH2
NH2
N
Me
N
Me
Me
Me
Me
3bb
3bc
3bd
92%
80%
81%
NH2
N
NH2
N
NH2
N
Me
Me
OMe
F
F
3be
3bf
3bg
88%
83%
90%
81%
60%b
NH2
N
NH2
N
NH2
CF3
N
CF3
CF3
96%
3bh
3bi
3bj
86%
NH2
N
NH2
N
NH2
N
O
O
S
Me
NH2
S
O
O
3bk
3bl
3bm
71%
80%
aReaction conditions: 1b (0.5 mmol), 2 (1.0 mmol), Pd(TFA)2 (2.0 mol%), L1 (6.0 mol%; Pd/L = 1:3), K3PO4
(2.5 mmol), PhB(OH)2 (0.02 mmol) and DMF (1.5 mL) were stirred at 100 °C under nitrogen for 24 h.
b
Isolated yields were reported. Reaction times were not optimized for each substrate. 1.5 mmol of K3PO4
was used.
In conclusion, we have developed an efficient Pd/L1 catalyst system for the first
general monoarylation of arylhydrazine with aryl tosylates. The structure of L1 was
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unambiguously characterized and its efficacy was found more successful than the
corresponding CM-phos and MeO-CM-phos in dealing with this arylation process. The
newly reported Pd/L1 system exhibited good functional group compatibility (e.g. methyl
ester, NH amido, enolizable keto, and heterocycles etc.) and offered good-to-excellent
product yields (up to 95%). This method provides an alternative synthetic pathway for
preparing structurally diverse N,N-diarylhydrazines from simple and readily accessible
coupling partners. We believe this newly developed palladium catalyst system will be
useful in other CN coupling processes in relevance.
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Experimental Section
General Information. Unless otherwise noted, all reagents were purchased from
commercial suppliers and used without further purification. All Pd-catalyzed cross-
coupling reactions were performed in Rotaflo®(England) re-sealable screw-cap Schlenk
tube (approx. 20 mL volume) in the presence of Teflon coated magnetic stirrer bar (4 mm
× 10 mm). Toluene were freshly distilled over sodium under nitrogen.20 N,N-
Dimethylformamide (DMF) was distilled from calcium hydride under reduced pressure.
Dichloromethane was freshly distilled over calcium hydride under nitrogen atmosphere.
t-BuOH was first distilled over sodium and stored with calcium hydride under nitrogen. A
new bottle of n-butyllithium was used (note: since the concentration of n-BuLi from old
bottles may vary, a titration is highly recommended prior to use). Ligand NPCy o-Andole-
phos,21 CPCy Phendole-phos,22 CPCy o-Andole-phos,23 CM-phos24 and MeO-CM-
phos25 were developed by Kwong and prepared according to literatures.26 Thin layer
chromatography was performed on precoated silica gel 60 F254 plates. Silica gel (230-
1
400 mesh) was used for column chromatography. H NMR spectra were recorded on a
500 MHz spectrometer. Spectra were referenced internally to the residual proton
resonance in CDCl3 (δ 7.26 ppm), or with TMS (δ 0.00 ppm) as the internal standard.
Chemical shifts (δ) were reported as part per million (ppm) in δ scale downfield from TMS.
13C NMR spectra were recorded on a 126 MHz spectrometer and the spectra were
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referenced to CDCl3 (δ 77.0 ppm, the middle peak). Coupling constants (J) were reported
in Hertz (Hz). Mass spectra (EI-MS and ES-MS) were recorded on a Mass Spectrometer.
High-resolution mass spectra (HRMS) were obtained on a ESI- Q Exactive Focus
Orbitrap mass spectrometer which the ionization method is electrospray ionization (ESI).
GC-MS analysis was conducted on a GCD system. Products described in GC yield were
obtained on the basis of authentic samples/ n-tetradecane calibration standard from GC-
FID system.
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Preparation of 2-(2-(dicyclohexylphosphino)-4,5-dimethoxyphenyl)-1-methyl-1H-
indole (L1)
1-(2-Bromo-4,5-dimethoxyphenyl)ethan-1-one.27 An oven-dried 250-mL single-neck
round-bottom flask equipped with a Teflon-coated magnetic stir bar was charged with 4,5-
dimethoxyacetophenone (9.01 g, 50.0 mmol) and N-bromosuccinimide (9.79 g, 55.0
mmol) in [bmim]PF6 (100.0 mL). The solution was placed in preheated oil bath (27 °C)
overnight. After completion of the reaction, as indicated by TLC and GC-MS, the reaction
mixture was washed with diethyl ether several times. The organic layer was concentrated
under rotary evaporation. The crude product was purified by flash column
chromatography on silica gel to afford 1-(2-bromo-4,5-dimethoxyphenyl)ethan-1-one. Off
1
white powder, 64% yield (8.45 g). Hexane: Ethyl acetate = 4:1, Rf = 0.33. H NMR (500
MHz, CDCl3): δ 7.13 (s, 1H), 7.03 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 2.66 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3): δ 199.5, 151.6, 148.1, 132.7, 116.4, 112.6, 111.8, 56.3, 56.1,
30.4.
2-(2-Bromo-4,5-dimethoxyphenyl)-1H-indole.28
round-bottom flask equipped with a Teflon-coated magnetic stir bar was charged with 1-
(2-bromo-4,5-dimethoxyphenyl)ethan-1-one (7.77 g, 30.0 mmol) and
An oven-dried 250-mL single-neck
phenylhydrazine(3.6 mL, 36.0 mmol) via syringe. Phosphoric acid (15.0 mL) was added
slowly and the reaction mixture was stirred for 30 min. Polyphosphoric acid (50.0 g) was
added to the reaction mixture slowly with continuous stirring, and then placed in a
preheated oil bath (85 °C) for 15 min. The bath temperature was raised to 105 °C and
the reaction mixture was heated for 40 min. After completion of the reaction, the resulting
mixture was then poured into ice water and extracted with water and dichloromethane for
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several times. The organic layer was separated and the aqueous layer was washed with
4
5
dichloromethane.
The combined organic layer was concentrated under rotary
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evaporation. The crude product was purified by flash column chromatography on silica
gel to afford 2-(2-bromo-4,5-dimethoxyphenyl)-1H-indole ligand precursor. Pale yellow
powder, 75% yield (7.47 g). Hexane: Ethyl acetate = 4:1, Rf = 0.26. 1H NMR (500 MHz,
CDCl3): δ 8.61 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 H, 1H), 7.22 (t, J = 7.5
Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 6.74 (m, 1H), 3.92 (s, 3H),
3.90 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 149.3, 148.4, 136.5, 136.1, 128.2, 125.7,
122.4, 120.6, 120.1, 116.3, 113.8, 111.6, 110.9, 102.8, 56.2, 56.1.
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N-Methyl-2-(2′-bromo-4′,5′-dimethoxyphenyl)indole. An oven-dried 250-mL three-neck
round-bottom flask was equipped with a Teflon-coated magnetic stir bar, and charged
with sodium hydride (60 % dispersion in mineral oil, washed with anhydrous hexane
before use) (0.96 g of NaH in oil, 24.0 mmol). The necks were fitted with pressure-
equalizing dropping funnel and charged with 2-(2-bromo-4,5-dimethoxyphenyl)-1H-indole
(6.64 g, 20.0 mmol), rubber septum and nitrogen stopcock inlet. The flask was evacuated
and backfilled with nitrogen three times. Anhydrous tetrahydrofuran (5.0 mL) was added
to the reaction flask via syringe to form a suspension of sodium hydride. The suspension
was cooled to 0 °C in ice-water bath. The solution of 2-(2-bromo-4,5-dimethoxyphenyl)-
1H-indole was added dropwise via dropping funnel to the reaction mixture. Upon
completion of addition, the reaction mixture was allowed to reach room temperature and
stirred for 30 min. Dimethyl sulfate (1.9 mL, 20.6 mmol) was added and the mixture was
stirred for overnight. After completion of the reaction, methanol was added to quench the
reaction and the mixture was extracted with water and ethyl acetate. The combined
organic layer was concentrated and purified by column chromatography to afford N-
methyl-2-(2’-bromo-4’,5’-dimethoxyphenyl)indole ligand precursor. Pale yellow solid,
91% yield (6.30 g), m.p. = 50.3-53.5 °C. Hexane: Ethyl acetate = 4:1, Rf = 0.46. 1H NMR
(500 MHz, CDCl3): δ 7.74 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 8.0 H, 1H), 7.34 (t, J = 7.5 Hz,
1H), 7.25-7.22 (m, 2H), 6.99 (s, 1H), 6.59 (s, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.64 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3): δ 149.6, 147.7, 139.4, 136.8, 127.3, 125.8, 121.4, 120.3,
119.5, 115.2, 115.0, 114.9, 109.3, 101.6, 55.9, 55.8, 30.3; HRMS (ESI) m/z: [M + H]+
Calcd for C17H17BrNO2 346.0437; Found 346.0434.
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2-(2-(Dicyclohexylphosphino)-4,5-dimethoxyphenyl)-1-methyl-1H-indole (L1). N-Methyl-
2-(2’-bromo-4’,5’-methoxyphenyl)indole (3.46 g, 10.0 mmol) was dissolved in freshly
distilled THF (25.0 mL) at room temperature under nitrogen atmosphere. The solution
was cooled to -78 °C in dry ice/acetone bath. Titrated n-BuLi (11.0 mmol) was added
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dropwise with a syringe.
After the reaction mixture was stirred for 30 min,
chlorodicyclohexylphosphine (2.64 mL, 12 mmol) in THF was added. The reaction was
allowed to warm to room temperature and stirred overnight. The solvent was removed
under reduced pressure. The product was recrystallized by methanol to afford 2-(2-
(dicyclohexylphosphino)-4,5-dimethoxyphenyl)-1-methyl-1H-indole (L1). Off-white solid,
1
54% yield (2.50 g), m.p. = 164.0-164.8 °C. Hexane: Ethyl acetate = 4:1, Rf = 0.64. H
NMR (500 MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.20 (t, J =
7.5 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.07 (s, 1H), 6.85 (d, J = 3.0 Hz, 1H), 6.37 (s, 1H),
3.99 (s, 3H), 3.86 (s, 3H), 3.50 (s, 3H), 1.72–1.63 (m, 11H), 1.28–1.07 (m, 11H). 13C{1H}
NMR (126 MHz, CDCl3): δ 148.9, 148.4, 141.2 (overlapped), 136.6, 134.3, 134.1, 128.3,
128.1, 127.6, 121.1, 120.2, 119.4, 114.6, 114.5, 109.5, 103.2, 103.1, 56.1, 55.8, 35.4,
33.4, 30.8, 30.7, 30.0, 27.3, 26.4. 31P{1H} NMR (202 MHz, CDCl3): δ −10.43. HRMS
(ESI) m/z: [M + H]+ Calcd for C29H39NO2P 464.2712, Found 464.2707.
Preparation of 2-(2-(diphenylphosphino)-4,5-dimethoxyphenyl)-1-methyl-1H-indole
(L2)
N-Methyl-2-(2′-bromo-4′,5′-dimethoxyphenyl)indole (0.69 g, 2.0 mmol) was dissolved in
freshly distilled THF (10.0 mL) at room temperature under nitrogen atmosphere. The
solution was cooled to −78 °C in dry ice/acetone bath. Titrated n-BuLi (2.2 mmol) was
added dropwise with a syringe. After the reaction mixture was stirred for 30 min,
chlorodiphenylphosphine (0.43 mL, 2.4 mmol) in THF was added. The reaction was
allowed to warm to room temperature and stirred overnight. The solvent was removed
under reduced pressure. The product was recrystallized by methanol to afford 2-(2-
(diphenylphosphino)-4,5-dimethoxyphenyl)-1-methyl-1H-indole (L2). Off-white solid, 49%
1
yield (0.45 g), m.p. = 166.9-168.3 °C, Hexane: Ethyl acetate = 4:1, Rf = 0.54. H NMR
(500 MHz, CDCl3): δ 7.52 (d, J = 7.5 Hz, 1H), 7.31-7.29 (m, 7H), 7.23-7.21 (m, 5H), 7.09
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(t, J = 7.5 Hz, 1H), 6.89 (d, J = 3.5 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 6.21 (s, 1H), 3.88 (s,
4
5
13
3H), 3.62 (s, 3H), 3.48 (s, 3H); C{1H} NMR (126 MHz, CDCl3): δ 149.0, 148.9, 139.3,
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139.2, 137.9, 137.8, 136.8, 133.4, 133.3, 131.8, 131.5, 130.2, 130.1, 128.3, 128.2 , 128.1,
127.3, 121.2, 120.3, 119.3, 116.0, 114.1 (overlapped), 109.2, 103.6, 103.5, 55.8, 55.5,
30.4 (overlapped); 31P{1H} NMR (202 MHz, CDCl3): δ −13.22. HRMS(ESI) m/z: [M + H]+
Calcd for C29H27NO2P 452.1173; Found 452.1173.
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Preparation of 2-(2-(diisopropylphosphino)-4,5-dimethoxyphenyl)-1-methyl-1H-
indole (L3)
N-Methyl-2-(2′-bromo-4′,5′-dimethoxyphenyl)indole (0.69 g, 2.0 mmol) was dissolved in
freshly distilled THF (10 mL) at room temperature under nitrogen atmosphere. The
solution was cooled to −78 °C in dry ice/acetone bath. Titrated n-BuLi (2.2 mmol) was
added dropwise with a syringe. After the reaction mixture was stirred for 30 min,
chlorodiisopropylphosphine (0.38 mL, 2.4 mmol) in THF was added. The reaction was
allowed to warm to room temperature and stirred overnight. The solvent was removed
under reduced pressure. The product was recrystallized by methanol and n-hexane to
afford 2-(2-(diisopropylphosphino)-4,5-dimethoxyphenyl)-1-methyl-1H-indole (L3). Off-
white solid, 55% yield (0.42 g), m.p. = 112.3-114.8 °C, n-Hexane: Ethyl acetate = 4:1, Rf
= 0.74. 1H NMR (500 MHz, CDCl3): δ 7.64 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H),
7.24 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.11 (s, 1H), 6.90 (d, J = 3.0 Hz, 1H),
6.42 (s, 1H), 4.00 (s, 3H), 3.89 (s, 3H), 3.55 (s, 3H), 2.21 (bs, 1H), 1.90 (bs, 1H), 1.01 (s,
12H); 13C{1H} NMR (126 MHz, CDCl3): δ 148.9, 148.4, 141.0 (overlapped), 136.5, 134.0,
133.8, 128.5, 128.3, 127.5, 121.0, 120.1, 119.3, 114.5 (overlapped), 114.3, 114.2, 109.3,
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103.1 (overlapped), 55.9, 55.7, 30.6 (overlapped), 25.6, 23.2, 20.1, 18.3; P{1H} NMR
(202 MHz, CDCl3): δ −2.01. HRMS(ESI) m/z: [M + H]+ Calcd for C23H31NO2P 384.2086
found 384.2086.
General Procedures for Ligand and Reaction Condition Screenings
Pd source (indicated in Table 1) and ligand (indicated in Table 1) were loaded into
Schlenk tube with a Teflon-coated magnetic stirrer bar (4.5 mm x 12 mm). The tube was
evacuated and backfilled with nitrogen (3 cycles). Precomplexation was applied by
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adding freshly distilled DCM (1.0 mL) and Et3N (0.05 mL) into the tube. The solution was
stirred and warmed using oil bath (~50°C) for about 1 min until the solvent started boiling.
After cooling down, the solvent in tube was removed under high vacuum. 4-tert-
Butylphenyl tosylate (1a) (60.8 mg, 0.2 mmol), phenylboronic acid (1.2 mg, 0.01 mmol)
and base (indicated in Table 1) were loaded into the Schlenk tube which was again
evacuated and re-filled with nitrogen for three times. Phenylhydrazine (2a) (the
equivalence was indicated in Table 1 with respect to 1a) and the solvent (0.6 mL) were
added while the mixture was being stirred at room temperature for ∼10 min. The Schlenk
tube was then placed in a preheated oil bath (temperature indicated in Table 1) for 24
hours. The reaction tube was allowed to reach room temperature. Water, ethyl acetate
and n-tetradecane (52 μL, internal standard) were added to the mixture. The organic
layer was subjected to GC analysis. The GC yield was previously calibrated by authentic
sample/ n-tetradecane calibration curve.
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General Procedures for monoarylation of Substituted Phenylhydrazines with Aryl
Tosylates
Pd(TFA)2 (3.3 mg, 0.01 mmol), L1 (13.8 mg, 0.03 mmol) were loaded into a Schlenk tube
equipped with a Teflon-coated magnetic stir bar. The tube was evacuated and flushed
with nitrogen for three cycles. Precomplexation was applied by adding freshly distilled
DCM (1.0 mL) and Et3N (0.10 mL) into the tube. The solution was stirred and warmed
using oil bath (~50 °C) for about 1 min until the solvent started boiling. After cooling down,
the solvent in tube was removed under high vacuum. Aryl tosylates (0.5 mmol), PhB(OH)2
(1.4 mg, 0.02 mmol), and K3PO4 (0.318 g, 1.5 mmol) were loaded to the Schlenk tube
which was again evacuated and re-filled with nitrogen for three times. DMF (1.5 mL) was
then added while the mixture was being continuously stirred at room temperature for ∼5
min. Phenylhydrazine derivatives (1.0-2.5 mmol, indicated in Scheme’s footnote) was
added via syringe. The tube was then placed into a preheated oil bath (100 °C) and
stirred for 24 hours. After completion of reaction, the reaction tube was allowed to cool
to room temperature and quenched with water and diluted with ethyl acetate. The organic
layer was separated and the aqueous layer was washed with ethyl acetate. The filtrate
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was concentrated under reduced pressure. The crude product was purified by flash
column chromatography on silica gel (230-400 mesh) to afford the desired product.
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1-(4-(tert-Butyl)phenyl)-1-phenylhydrazine (Scheme 1 and 2, Product 3aa)
Yield: 95% (114 mg for 0.5 mmol scale) and 87% (2.09 g for 10 mmol scale). Off white
solid, m.p. = 69.3-65.4 °C. Rf = 0.63 (Ethyl acetate: Hexane = 1:4). 1H NMR (500 MHz,
CDCl3) δ 7.36 (d, J = 7.0 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 8.0 Hz, 4H), 6.96
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(t, J = 7.5 Hz, 1H), 4.14 (s, 2H), 1.36 (s, 9H); C{1H} NMR (126 MHz, CDCl3) δ 149.3,
146.6, 145.4, 128.8, 125.9, 120.9, 120.1, 118.1, 34.2, 31.3; HRMS (ESI) m/z: [M + H]+
Calcd for C16H21N2 241.1699; Found 241.1698.
N,N-Diphenylhydrazine (Scheme 2, Product 3ba)8d
1
Yield: 94% (86 mg). Light yellow oil. Rf = 0.57 (Ethyl acetate: Hexane = 1:4). H NMR
(500 MHz, CDCl3) δ 7.36 (t, J = 7.5 Hz, 4H), 7.29 (d, J = 8.0 Hz, 4H), 7.06 (t, J = 7.0 Hz,
2H), 4.18 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 149.0, 128.9, 121.8, 119.3.
1-(3,5-Dimethylphenyl)-1-phenylhydrazine (Scheme 2, Product 3ca; Scheme 4,
Product 3bc)
Yield: 86% (91 mg for product 3ca) and 80% (85 mg for product 3bc). Light yellow oil. Rf
1
= 0.63 (Ethyl acetate: Hexane = 1:4). H NMR (500 MHz, CDCl3) δ 7.31-7.28 (m, 2H),
7.21 (d, J = 8.0 Hz, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.86 (s, 2H), 6.68 (s, 1H), 4.13 (s, 2H),
2.29 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 149.3, 149.2, 138.7, 128.9, 124.1, 121.3,
119.0, 117.7, 21.4; HRMS (ESI) m/z: [M + H]+ Calcd for C14H17N2 213.1386; Found
213.1385.
1-(3,4-Dimethylphenyl)-1-phenylhydrazine (Scheme 2, Product 3da; Scheme 4,
Product 3bd)
Yield: 83% (88 mg for product 3da) and 81% (86 mg for product 3bd). Light yellow oil. Rf
1
= 0.60 (Ethyl acetate: Hexane = 1:4). H NMR (500 MHz, CDCl3) δ 7.29 (t, J = 7.5 Hz,
2H), 7.18 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 7.02-7.01 (m, 1H),
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6.94 (t, J = 7.0 Hz, 1H), 4.12 (s, 2H), 2.28 (s, 6H); C{1H} NMR (126 MHz, CDCl3) δ
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149.7, 147.1, 137.4, 131.3, 130.2, 128.7, 122.6, 120.5, 118.7, 117.6, 19.9, 19.0; HRMS
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(ESI) m/z: [M + H]+ Calcd for C14H17N2 213.1386; Found 213.1385.
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4-(1-Phenylhydrazinyl)benzonitrile (Scheme 2, Product 3ea)
Yield: 87% (91 mg). Off white solid. Rf = 0.26 (Ethyl acetate: Hexane = 1:4). 1H NMR (500
MHz, CDCl3) δ 7.42 (t, J = 8.0 Hz, 4H), 7.30 (d, J = 7.5 Hz, 2H), 7.25-7.22 (m, 1H), 7.12
(d, J = 8.5 Hz, 2H), 4.21 (s, 2H); 13C NMR{1H} (126 MHz, CDCl3) δ 152.4, 146.7, 133.0,
129.9, 126.0, 124.1, 120.1, 114.5, 100.5; HRMS(ESI) m/z: [M + H]+ Calcd for C13H12N3
210.1025; Found 210.1025.
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1-(4-Methoxyphenyl)-1-phenylhydrazine (Scheme 2, Product 3fa; Scheme 4,
Product 3be)29
Yield: 77% (82 mg for product 3fa); 88% (94 mg for product 3be). Off white solid. Rf =
0.49 (Ethyl acetate: Hexane = 1:4). 1H NMR (500 MHz, CDCl3) δ 7.25 - 7.19 (m, 4H), 7.05
(d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.85 (t, J = 7.5 Hz, 1H), 4.09 (s, 2H), 3.82 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 156.5, 150.4, 142.7, 128.8, 124.7, 119.7, 115.9,
114.7, 55.5.
1-(4-Fluorophenyl)-1-phenylhydrazine (Scheme 2, Product 3ga; Scheme 4, Product
3bg)1e
Yield: 75% (76 mg for product 3ga); 90% (91 mg for product 3bg). Light yellow oil. Rf =
0.53 (Ethyl acetate: Hexane = 1:4). 1H NMR (500 MHz, CDCl3) δ 7.28 (t, J = 7.5 Hz, 2H),
7.22-7.20 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.01 (t, J = 8.0 Hz, 2H), 6.96 (t, J = 7.5 Hz,
1H), 4.13 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 158.7 (d, JF = 0.24 Hz), 149.6, 145.3
(d, JF = 0.003 Hz), 129.0, 122.6 (d, JF = 0.008 Hz, 2C), 121.2, 117.8, 115.7 (d, JF = 0.02
Hz, 2C); 19F{1H} NMR (470 MHz, CDCl3) δ -120.3.
Phenyl (4-(1-phenylhydrazinyl)phenyl)methanone (Scheme 2, Product 3ha)
Yield: 88% (127 mg). Light yellow solid, m.p. = 89.3-90.8 °C. Rf = 0.74 (Ethyl acetate:
Hexane = 1:1). 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 4H), 7.54 (t, J = 7.5 Hz,
1H), 7.46 -7.38 (m, 2H), 7.34 (d, J = 7.5 Hz, 2H), 7.19 (t, J = 7.5 Hz, 2H), 7.15 (d, J = 8.0
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Hz, 3H), 4.27 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 195.2, 152.7, 147.0, 138.7, 132.0,
131.4, 129.6, 129.5, 127.9 (overlapped), 125.2, 123.6, 113.9; HRMS (ESI) m/z: [M + H]+
Calcd for C19H17N2O 289.1335; Found 289.1331.
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Methyl 4-(1-phenylhydrazinyl)benzoate (Scheme 2, Product 3ia)
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Yield: 80% (97 mg). Light yellow oil. Rf = 0.29 (Ethyl acetate: Hexane = 1:4). H NMR
(500 MHz, CDCl3) δ 7.88 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 (d, J = 7.5 Hz,
2H), 7.17 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 2H), 4.22 (s, 2H), 3.86 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 167.1, 152.8, 147.4, 130.8, 129.6, 125.1, 123.5, 120.5, 114.4,
51.7; HRMS (ESI) m/z: [M + H]+ Calcd for C14H15N2O2 243.1128; Found 243.1126.
Ethyl 4-(1-phenylhydrazineyl)benzoate (Scheme 2, Product 3ja)30
1
Yield: 71% (91 mg). Light yellow oil. Rf = 0.33 (Ethyl acetate: Hexane = 1:4). H NMR
(500 MHz, CDCl3) δ 7.89 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.31 (d, J = 7.5 Hz,
2H), 7.16 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 4.34-4.30 (q, J = 7.0 Hz, 2H), 4.22
(s, 2H), 1.36 (t, J =7.0 Hz, 3H); C{1H} NMR (126 MHz, CDCl3) δ 166.5, 152.6, 147.3,
13
130.7, 129.4, 124.8, 123.2, 120.8, 114.3, 60.3, 14.3.
1-(2-Naphthalenyl)-1-phenylhydrazine (Scheme 2, Product 3ka; Scheme 4, Product
3bk)7b
Yield: 84% (98 mg for product 3ra); 71% (83 mg for product 3bk). Light yellow oil. Rf =
0.51 (Ethyl acetate: Hexane = 1:4). 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 1H),
7.75 (t, J = 7.5 Hz, 2H), 7.60 (s, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.44 (dd, J = 9.0, 2.0 Hz,
1H), 7.41-7.36 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 4.25 (s, 2H);
13C{1H} NMR (126 MHz, CDCl3) δ 149.0, 146.5, 134.2, 129.4, 129.0, 128.4, 127.4, 126.8,
126.2, 123.9, 122.3, 120.6, 120.0, 113.8.
1-(3-(1-Phenylhydrazinyl)phenyl)ethan-1-one (Scheme 2, Product 3la)
Yield: 90% (102 mg). Light yellow oil. Rf = 0.23 (Ethyl acetate: Hexane = 1:4). 1H NMR
(500 MHz, CDCl3) δ 7.82 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.34-
7.30 (q, J = 8.0 Hz, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 7.5 Hz, 1H), 4.20 (s, 2H),
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2.57 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 198.3, 149.4, 148.6, 138.0, 129.4, 129.0,
123.3, 122.6, 121.0, 120.8, 117.2, 26.8; HRMS (ESI) m/z: [M + H]+ Calcd for C14H15N2O
227.1178; Found 227.1177.
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3-(1-Phenylhydrazinyl)benzonitrile (Scheme 2, Product 3ma)31
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Yield: 82% (86 mg). Light yellow oil. Rf = 0.34 (Ethyl acetate: Hexane = 1:4). H NMR
(500 MHz, CDCl3) δ 7.43 (s, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 1H), 7.24
(d, J = 7.0 Hz, 3H), 7.16 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 4.15 (s, 2H); 13C{1H}
NMR (126 MHz, CDCl3) δ 149.7, 147.7, 129.8, 129.5, 125.0, 123.0, 122.6, 120.4, 119.3,
119.2, 112.6.
Ethyl 3-(1-phenylhydrazineyl)benzoate (Scheme 2, Product 3na)
1
Yield: 70% (90 mg). Light yellow oil. Rf = 0.39 (Ethyl acetate: Hexane = 1:4). H NMR
(500 MHz, CDCl3) δ 7.91(s, 1H), 7.61(d, J = 7.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.34-
7.28 (m, 3H), 7.23 (d, J = 8.5 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 4.38-4.33 (q, J = 7.5 Hz,
2H), 4.20 (s, 2H), 1.37 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 166.6, 149.1,
148.6, 131.3, 129.2, 128.7, 122.8, 122.6, 122.1, 120.3, 119.0, 60.9, 14.2; HRMS (ESI)
m/z: [M + H]+ Calcd for C15H17N2O2 257.1284; Found 257.1282.
N-(3-(1-Phenylhydrazinyl)phenyl)acetamide (Scheme 2, Product 3oa)
Yield: 90% (108 mg). Off white solid, m.p. = 98.5-101.7 °C. Rf = 0.51 (Ethyl acetate:
1
Hexane = 1:1). H NMR (500 MHz, CDCl3) δ 7.47 (s, 1H), 7.37 (s, 1H), 7.29 (t, J = 7.5
Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.00
(t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.0 Hz, 1H), 4.12 (s, 2H), 2.11 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 168.7, 149.6, 148.6, 138.6, 129.1, 129.0, 122.5, 120.3, 114.3, 112.9, 110.0,
24.3; HRMS (ESI) m/z [M + Na]+ Calcd for C14H15N3ONa 264.1107; Found 264.1105.
1-(3-(1-Phenylhydrazinyl)phenyl)-1H-pyrrole (Scheme 2, Product 3pa)
Yield: 90% (112 mg). Off white solid, m.p. = 91.1-92.5 °C. Rf = 0.46 (Ethyl acetate: Hexane
= 1:4). 1H NMR (500 MHz, CDCl3) δ 7.37 (t, J = 7.5 Hz, 2H), 7.32-7.28 (m, 4H), 7.12-7.09
(m, 3H), 7.06 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.36 (s, 2H), 4.19 (s, 2H);
13C{1H} NMR (126 MHz, CDCl3) δ 150.2, 148.5, 141.3, 129.7, 129.3, 123.3, 121.1, 119.3,
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114.8, 112.8, 110.0, 109.9; HRMS (ESI) m/z: [M + H]+ Calcd for C16H16N3 250.1339;
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Found 250.1336.
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6-(1-Phenylhydrazinyl)quinoline (Scheme 2, Product 3qa)
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Yield: 86% (101 mg). Light yellow solid, m.p. = 96.7-98.5 °C. Rf = 0.37 (Ethyl acetate:
Hexane = 1:1). 1H NMR (500 MHz, CDCl3) δ 8.73 (dd, J = 4.0, 1.0 Hz, 1H), 7.98 (d, J =
8.5 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.61 (dd, J = 9.5, 2.5 Hz, 1H), 7.48 (d, J = 2.5 Hz,
1H), 7.37 (t, J = 7.5 Hz, 2H), 7.32-7.30 (m, 3H), 7.11 (t, J = 7.5 Hz, 1H), 4.29 (s, 2H);
13C{1H} NMR (126 MHz, CDCl3) δ 148.6, 147.9, 147.1, 144.5, 134.7, 129.7, 129.4, 129.3,
123.7, 123.3, 121.5, 121.4, 111.4; HRMS (ESI) m/z: [M + H]+ Calcd for C15H14N3 236.1182;
Found 236.1180.
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3-(1-Phenylhydrazinyl)pyridine (Scheme 2, Product 3ra)32
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Yield: 64% (59 mg). Light yellow oil. Rf = 0.25 (Ethyl acetate: Hexane = 1:1). H NMR
(500 MHz, CDCl3) δ 8.54 (s, 1H), 8.15 (d, J = 4.5 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.34
(t, J = 7.5 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.15 (m, 1H), 7.08 (t, J = 7.5 Hz, 1H), 4.19 (s,
2H); 13C{1H} NMR (126 MHz, CDCl3) δ 148.1, 145.2, 141.8, 140.3, 129.5, 124.4, 123.6,
123.2, 120.7.
1-(Benzo[d][1,3]dioxol-5-yl)-1-phenylhydrazine (Scheme 2, Product 3sa)
1
Yield: 61% (74 mg). Light yellow oil. Rf = 0.51 (Ethyl acetate: Hexane = 1:4). H NMR
(500 MHz, CDCl3) δ 7.24 (t, J = 7.5 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.89 (t, J = 7.5 Hz,
1H), 6.78 (d, J = 8.0 Hz, 2H), 6.72 (dd, J = 8.0, 2.0 Hz, 1H), 5.96 (s, 2H), 4.08 (s, 2H);
13C{1H} NMR (126 MHz, CDCl3) δ 150.1, 148.1, 144.1, 144.1, 128.8, 120.2, 116.6, 115.8,
108.3, 104.6, 101.2; HRMS (ESI) m/z: [M + H]+ Calcd for C13H13N2O2 229.0972; Found
229.0971.
1-(Naphthalen-1-yl)-2-phenylhydrazine (Scheme 3, Product 3ta)33
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Yield: 77% (90 mg). Off white solid. Rf = 0.61 (Ethyl acetate: Hexane = 1:3). H NMR
(500 MHz, CDCl3) δ 7.86 (d, J = 7.5 Hz, 2H), 7.53-7.48 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H),
7.33 (t, J = 7.5 Hz, 1H), 7.24 (t, J = 7.5 Hz, 2H), 7.03 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 7.5
13
Hz, 2H), 6.87 (t, J = 7.0 Hz, 1H), 6.31 (s, 1H), 5.68 (s, 1H); C{1H} NMR (126 MHz,
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119.6, 112.5, 106.2.
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2-(1,5-Diphenyl-4,5-dihydro-1H-pyrazol-3-yl)benzene-1,4-diol (Scheme 4, Product
3ua)
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Yield: 89% (147 mg). Off white solid, m.p. = 129.8-133.2 °C. Rf= 0.65 (1:1 Ethyl acetate:
n-Hexane). 1H NMR (500 MHz, CDCl3) δ 10.45 (s, 1H), 7.36-7.33 (m, 2H), 7.30-7.27 (m,
3H), 7.19 (t, J = 7.5 Hz, 2H), 6.93 (t, J = 8.5 Hz, 3H), 6.84 (t, J = 7.5 Hz, 1H), 6.75 (dd, J
= 8.5, 2.5 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 5.17 (dd, J = 7.5, 12.5 Hz, 1H), 4.92 (s, 1H),
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3.81 (m, 1H), 3.13 (dd, J = 7.5, 17.5 Hz, 1H); C{1H} NMR (126 MHz, CDCl3) δ 151.1,
149.0, 148.1, 143.8, 141.7, 129.3, 129.1, 127.9, 125.9, 120.0, 117.7, 117.1, 116.5, 113.3,
113.2, 63.3, 43.8; HRMS(ESI) m/z: [M + H]+ Calcd for C21H19N2O2 331.1441; Found
331.1438.
1-(4-Methylphenyl)-1-phenylhydrazine (Scheme 4, Product 3bb)29
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Yield: 92% (91 mg). Light orange oil. Rf = 0.57 (Ethyl acetate: Hexane = 1:4). H NMR
(500 MHz, CDCl3) δ 7.31-7.28 (m, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.18 (s, 3H), 6.96 (t, J =
7.5 Hz, 1H), 4.15 (s, 2H), 2.38 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 149.6, 146.8,
132.4, 129.7, 128.8, 121.0, 120.7, 117.8, 20.7.
1-(4-Isopropylphenyl)-1-phenylhydrazine (Scheme 4, Product 3bf)
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Yield: 83% (94 mg). Light yellow oil. Rf = 0.63 (Ethyl acetate: Hexane = 1:4). H NMR
(500 MHz, CDCl3) δ 7.29 (t, J = 7.5 Hz, 2H), 7.20 (s, 6H), 6.95 (t, J = 7.5 Hz, 1H), 4.14
13
(s, 2H), 2.95-2.90 (m, 1H), 1.29 (d, J = 7.0 Hz, 6H); C{1H} NMR (126 MHz, CDCl3) δ
149.4, 147.0, 143.3, 128.8, 127.0, 121.8, 121.7, 117.9, 33.4, 24.0; HRMS (ESI) m/z: [M
+ H]+: Calcd for C15H19N2 227.1543; Found 227.1542.
1-Phenyl-1-(4-(trifluoromethyl)phenyl)hydrazine (Scheme 4, Product 3bh)
Yield: 86% (108 mg). Light yellow oil. Rf = 0.51 (Ethyl acetate: Hexane = 1:4). 1H NMR
(500 MHz, CDCl3) δ 7.45 (d, J = 8.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 8.0 Hz,
13
2H), 7.20 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 7.0 Hz, 1H), 4.19 (s, 2H); C{1H} NMR (126
MHz, CDCl3) δ 151.8, 147.8, 129.6, 126.1 (q, JF = 0.004 Hz, 1C), 124.8, 123.6, 123.0,
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121.2 (q, JF = 0.03 Hz, 1C), 115.4; 19F{1H} NMR (470 MHz, CDCl3) δ -61.3; HRMS (ESI)
m/z: [M + H]+ Calcd for C13H12F3N2 253.0947; Found 253.0946.
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1-(3,5-Bis(trifluoromethyl)phenyl)-1-phenylhydrazine (Scheme 4, Product 3bi)
Yield: 96% (153 mg). Light yellow oil. Rf = 0.55 (Ethyl acetate: Hexane = 1:4). 1H NMR
(500 MHz, CDCl3) δ 7.55 (s, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.26
(d, J = 10.0 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 4.22 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3)
δ 150.3, 147.2, 132.0 (q, JF = 0.02 Hz, 2C), 130.1, 126.8, 125.9, 123.3 (q, JF = 0.27 Hz,
2C), 115.0 (q, JF = 0.003 Hz, 2C), 112.2 (q, JF = 0.04 Hz, 2C); 19F{1H} NMR (470 MHz,
CDCl3) δ -63.0; HRMS (ESI) m/z: [M + H]+ Calcd for C14H11F6N2 321.0821; Found
321.0822.
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1-(3-Fluorophenyl)-1-phenylhydrazine (Scheme 4, Product 3bj)34
1
Yield: 81% (82 mg). Light yellow oil. Rf = 0.57 (Ethyl acetate: Hexane = 1:4). H NMR
(500 MHz, CDCl3) δ 7.36 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 7.5 Hz, 2H), 7.17 (q, J = 7.5 Hz,
1H), 7.11 (t, J = 7.5 Hz, 1H), 6.94-6.89 (m, 2H), 6.59 (t, J = 8.0 Hz, 1H), 4.16 (s, 2H);
13C{1H} NMR (126 MHz, CDCl3) δ 163.4 (d, JF = 0.24 Hz, 1C), 151.1(d, JF = 0.01 Hz, 1C),
148.4, 129.9 (d, JF = 0.01 Hz, 1C), 129.4, 123.8, 121.8, 112.6 (d, JF = 0.003 Hz, 1C),
107.0 (d, JF = 0.009 Hz, 1C), 104.3 (d, JF = 0.03 Hz, 1C); 19F{1H} NMR (470 MHz, CDCl3)
δ -112.4.
1-(4-(Methylsulfonyl)phenyl)-1-phenylhydrazine (Scheme 4, Product 3bl)
Yield: 80% (105 mg). Off white solid, m.p. = 126.0-128.7 °C. R = 0.63 (Ethyl acetate:
f
Hexane = 1:1). 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.5 Hz, 2H), 7.40 (t, J = 7.5 Hz,
2H), 7.30 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 8.5 Hz, 2H), 4.26 (s,
13
2H), 2.98 (s, 3H); C{1H} NMR (126 MHz, CDCl3) δ 153.3, 146.8, 129.8, 128.9, 128.5,
126.0, 124.2, 114.1, 44.8; HRMS (ESI) m/z: [M + Na]+ Calcd for C13H14SN2O2Na
285.0668; Found 285.0665.
4-(1-Phenylhydrazineyl)benzenesulfonamide (Scheme 4, Product 3bm)
Yield: 60% (79 mg). White solid, m.p. = 144.1-146.0 °C. Rf = 0.30 (Ethyl acetate: Hexane
= 1:1). 1H NMR (500 MHz, DMSO-D6) δ 7.59-7.58 (m, 2H), 7.39-7.35 (m, 4H), 7.18-7.16
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(m, 2H), 7.13-7.09 (m, 1H), 7.07 (s, 2H), 5.21 (s, 2H); C{1H} NMR (126 MHz, DMSO-
4
5
D6) δ 152.2, 147.8, 133.5, 129.6, 127.2, 124.4, 123.2, 114.8; HRMS(ESI) m/z: [M + Na]+
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Calcd for C12H13N3SO2Na 286.0620; Found 286.0618.
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Supporting Information Available: Copies of H NMR, C NMR, P NMR and F
NMR spectra, as well as X-ray crystallographic data of L1, product 3aa, 3ta and 3ua. This
material is available free of charge via the Internet at http://pubs.acs.org.
Author Information
ORCID:
Fuk Yee Kwong: 0000-0001-9105-1740
Pui Ying Choy: 0000-0003-2765-0110
Notes
The authors declare no competing financial interest.
Acknowledgements
We thank the Science, Technology and Innovation Commission of Shenzhen Municipality
(JCYJ20180307150641423); Guangdong Basic and Applied Basic Research Foundation
(2019A1515011357), and General Research Fund (GRF: 14304519) for financial
support. We also thank Lee & Man Chemical Co. and Guangdong Province Zhu Jiang
Talents Plan (No.: 2016ZT06C090) and Guangzhou City Talents Plan (No. CYLJTD-
201609) for financial support. We are thankful for financial support from the Innovation
and Technology Commission (HKSAR, China) to the State Key Laboratory of Synthetic
Chemistry. We are grateful to Ms. Bella Chan (CUHK) for X-ray analysis and Ms. Sarah
Ng (CUHK) for HRMS analysis.
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