Acylamino-Directed Specific Sequential Difunctionalizations of Anilides via Metal-Free Relay Reactions for p-Oxygen and o-Nitrogen Incorporation

Article abstract of DOI:10.1021/acs.joc.8b02636

Novel acylamino-directed relay disubstitutions realize the sequential difunctionalizations of anilides (1) under mild and metal-free conditions for the first time. This [bis(trifluoroacetoxy)iodo]benzene (PIFA) and BF₃·Et₂O promoted straightforward reaction produces a series of p-acetoxyl- or p-alkoxyl-o-nitro-N-arylamides (2), which are key scaffolds of various drugs, functional materials, and bioactive molecules. The flexibility with respect to the functional groups in these products affords this novel protocol excellent versatility for synthetic applications.

Full text of DOI:10.1021/acs.joc.8b02636

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Article
Acylamino-Directed Specific Sequential Difunctionalizations of Anilides
via Metal-Free Relay Reactions for p-Oxygen and o-Nitrogen Incorporation
Yameng Wan, Zhiguo Zhang, Nana Ma, Jingjing Bi, and Guisheng Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02636 • Publication Date (Web): 18 Dec 2018
Downloaded from http://pubs.acs.org on December 26, 2018
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Acylamino-Directed Specific Sequential Difunctionalizations of Anilides via Metal-Free Relay Re-
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actions for p-Oxygen and o-Nitrogen Incorporation
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Yameng Wan, Zhiguo Zhang,* Nana Ma, Jingjing Bi, Guisheng Zhang*
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Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innova-
tion Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of
Organic Functional Molecules and Drug Innovation, School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang, Henan 453007, China.
*Fax: (+86)-373-332-5250; E-mail: zgs6668@yahoo.com or zhangzg@htu.edu.cn
ABSTRACT: Novel acylamino-directed relay disubstitutions realize the sequential difunctionalizations
of anilides (1) under mild and metal-free conditions for the first time. This [bis-
(trifluoroacetoxy)iodo]benzene (PIFA) and BF3·Et2O promoted straightforward reaction produces a se-
ries of p-acetoxyl- or p-alkoxyl-o-nitro-N-arylamides (2), which are key scaffolds of various drugs,
functional materials, and bioactive molecules. The flexibility with respect to the functional groups in
these products affords this novel protocol excellent versatility for synthetic applications.
■ INTRODUCTION
N-(4-Hydroxyl- or alkoxyl-2-nitrophenyls (2) are key precursors to the important scaffolds of many
therapeutic agents (e.g. esomeprazole and omeprazole, pantoprazole, and osimertinib), organic func-
tional materials,1 and numerous bioactive compounds 2 (Figure 1).
Figure 1. Representative Drugs, Materials, and Bioactive Compounds.
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To date, no straightforward methods have appeared for construction of these key precursors 2. For
example, N-(4-methoxy-2-nitrophenyl)acetamide (2l) is a key intermediate in the synthesis of omepra-
zole and esomeprazole, two drugs used in treatment of dyspepsia, peptic ulcer disease, gastro-
esophageal reflux disease, laryngopharyngeal reflux, and Zollinger–Ellison syndrome.3 In the most
straightforward previously reported methods,4 2l was prepared via four steps starting from anisole
(Scheme 1). Thus, developing a mild and step-economical method for synthesis of widely-used inter-
mediates 2 is a significant and urgently demanded task.
Scheme 1. The Routes to Omeprazole.
Direct difunctionalization is a useful strategy that has been extensively explored to access various
valuable, complex molecules via the simultaneous construction of two C–A (A = C, N, O, … etc.)
bonds starting from a low-cost and readily accessible feedstock.5 A large number of difunctionalizations
have been reported starting from alkenes,6 alkynes,7 dienes,8 allenes,9 C60 fullerenes,10 and biaryls,11 as
well as several special cases using arylketones,12 alicyclic amines,13 and ethylarenes.14 Additionally,
arenes have also been successfully used in this type of difunctionalization reaction, usually via a vicinal
difunctionalization in the manner of a tandem or a stepwise reaction.15 However, a literature review dis-
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closes that the sequential difunctionalization of arenes has rarely been explored thus far.16 To date, a
controllable and regioselective difunctionalization of arenes with different functional groups has not
been reported.
9
Based on the known ability of N-acyl anilines to undergo nucleophilic or electrophilic reactions at the
aryl ring via the oxidation of the acylamide group or by using acylamide as a directing group,1a,17 we
envisioned that acylamino-directed relay disubstitutions might realize the difunctionalization of arenes
with different functional groups, thereby achieving the one-step synthesis of compounds 2 from the
readily available anilides 1 (Scheme 2). Subsequently, a conceptual DFT18 analysis (a computational
method that treats the electron density as the fundamental property) was performed to obtain the reactiv-
ity order of the delocalized arenium ion with various ROH species. The calculated Fukui function (f0+)
values are presented in the Table S1 in the Supporting Information. The conceptual DFT results clearly
showed that the reactivity of the para-position was much greater than that of the ortho-position, which
further demonstrated the feasibility of our proposed protocol.
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Scheme 2. One-pot Strategy for the Construction of 2 from 1.
H
N
H
H
O
N
N
N
ROH
O
O
O
O
RO
NO2
ortho-directing
RO
NO2
+
+
0.13 (fo
)
0.20 (fo
)
Hypervalent organoiodine reagents, possessing the characteristics of ready availability, nontoxicity,
and environmental benignity, have been widely used in organic synthesis to construct carbon–carbon,
carbon–heteroatom, and hetero–heteroatom bonds leading to various new compounds.19-21 Based on the-
se literature studies of the hypervalent organoiodine-promoted functionalizations of arenes, we attempt-
ed to employ hypervalent organoiodine reagents as the oxidants in the direct sequential difunctionaliza-
tion of arylamides by successive para-oxygen and ortho-nitrogen incorporation in a one-pot reaction.
■ RESULTS AND DISCUSSION
Here, we report a route to controllable and regioselective sequential difunctionalizations of anilides
via dehydrogenative oxygen atom incorporation followed by nitrogen atom incorporation. The trans-
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formation includes a relay disubstitution reaction co-promoted by PIFA and BF3·OEt2. Notably, the
formation of C–N and C–O bonds occurs via the cleavage of two C(sp2)-H bonds with simple AcOH (or
ROH) and stoichiometric HNO3 as the oxygen source and nitrogen source, respectively, under mild
conditions. It is also worth noting that the novel reaction is conducted under non-sulfuric acid and met-
al-free conditions, whereas concentrated H2SO4 or a metal catalyst are often essential in conventional
nitration procedures,22 which tend to suffer from poor regioselectivity. In particular, the absence of a
metal is favorable for applications in pharmaceutical production. Its ease and simplicity promise to ren-
der the present new reaction useful in medicinal chemistry, materials science, and biochemistry. To the
best of our knowledge, it may be the first example of sequential difunctionalizations of arenes with dif-
ferent functional groups, and allows facile construction of the key precursors 2 in a single reaction step.
Firstly, the commercially available N-phenylacetamide (1a) was selected as a model substrate to ex-
plore the optimal conditions for this tandem sequential difunctionalization reaction. The key experi-
ments are summarized in Table 1. In the beginning, in the presence of PIFA and BF3·OEt2 in AcOH,21d
five nitrate species serving as nitro group sources, including AgNO2,23 NaNO2,24 AgNO3,25 Cu(NO3)2,26
and Fe(NO3)3·9H2O,16a were screened, having been chosen on the basis of a literature search. It was
found that all of them afforded the target compound 4-acetamido-3-nitrophenyl acetate (2a) in not more
than 52% yield (Table 1, entries 1–5). Pleasingly, the yield of 2a improved to 73% when compound 1a
(0.3 mmol) was treated with PIFA (1.5 equiv), BF3·OEt2 (2.0 equiv), and HNO3 (65–68% aq., 1.0 equiv)
in AcOH (3 mL) at 40 °C after 1.5 h (Table 1, entry 6). However, increasing or decreasing the amount
of PIFA, BF3·OEt2, HNO3, and AcOH, as well as the reaction temperature, failed to improve the yield
of product 2a (Table 1, entries 7–15). Two other hypervalent iodine(III) reagents, namely (diacetoxy-
iodo)benzene (PIDA) and PhIO, showed a lower reactivity than PIFA in the reaction (Table 1, entries 16
and 17). Additionally, the iodine(V) reagents 2-iodoxybenzoic acid (IBX) and Dess-Martin periodinane
(DMP) were confirmed to be entirely inefficient for the transformation, and most of the starting material
was recovered (Table 1, entries 18 and 19).27
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Table 1. Survey of the Reaction Conditions.a
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Entry
Oxidant
(equiv)
NS (equiv)
additive
Yield of 2a/%
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(equiv)
1
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.0)
PIFA (2.0)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIDA (1.5)
PhIO (1.5)
DMP (1.5)
IBX (1.5)
AgNO2 (1.0)
NaNO2 (1.0)
AgNO3 (1.0)
Cu(NO3)2 (1.0)
Fe(NO3)3·9H2O (1.0)
HNO3 (1.0)
HNO3 (1.0)
HNO3 (1.0)
HNO3 (1.5)
HNO3 (1.0)
HNO3 (1.0)
HNO3 (1.0)
HNO3 (1.0)
HNO3 (1.0)
HNO3 (1.0)
HNO3 (1.0)
HNO3 (1.0)
HNO3 (1.0)
HNO3 (1.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (1.5)
BF3·OEt2 (2.5)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
20
23
48
45b
52
73
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58d
35e
42f
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0g
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0h
a Unless otherwise indicated, all reactions were carried out with 1a (0.3 mmol), hypervalent organ-
oiodine reagents, NS, BF3·OEt2 in 2 mL of AcOH at 40 °C in 1.5 h. NS = nitro group sources.
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b 40% of 1a was recovered.
c 3 mL of AcOH was used.
d 1 mL of AcOH was used.
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e Reaction was performed at 25 °C.
f Reaction was performed at 60 °C.
g 47% of 1a was recovered.
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h 85% of 1a was recovered.
As shown in Scheme 3, the variation of R1 was investigated first. It was found that a range of anilines,
with various substituted formyl substituents on the nitrogen atom, was viable in this transformation (1a–
k), and the desired difunctionalization products 2a–k were obtained in 41–76% yields. Notably, these
removable amino protecting groups provide opportunities for further functionalization or modification
of these molecules. Several kinds of alcohols as different RO− anion donors were also reacted with 1a
under the optimized conditions to extend the reaction scope. It was found that the reactions proceeded
well in methanol, 2,2,2-trifluoroethanol, benzyl alcohol, and even propargyl alcohol and gave the corre-
sponding difunctionalized products 2l–o in 42–65% yields. Delightfully, the α-naphthylamides 1p and
1q also afforded target compounds 2p and 2q in 35% and 42% yields, respectively. Reactions of methyl
phenylcarbamate (1r) performed in AcOH and MeOH provided the desired difunctionalized derivatives
2r and 2s in 44% and 47% yields, respectively, thus indicating the generality and flexibility of the reac-
tion. Furthermore, two related difunctionalizations were attempted with methyl-substituted anilines N-
(o-tolyl)acetamide (1t) and N-(m-tolyl)acetamide (1u) as precursors. It was found that 2t and 2u were
formed, respectively, as the only products. The reaction of the starting material N-phenylfuran-2-
carboxamide (1v) occurred regiospecifically on the benzene ring, and produced compound 2v in the
yield of 62%, without the formation of other substituted furan derivatives. The structures of 2 were fur-
ther confirmed by a single-crystal X-ray diffraction analysis of 2m and 2s (see the Supporting Infor-
mation for details: Figures S1-S2, Tables S2-S5).
Scheme 3. Extension of the Reaction Scope.a
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a Unless otherwise indicated, all of the reactions were carried out with 1 (0.3 mmol), PIFA (1.5 equiv),
BF3·OEt2 (2.0 equiv), HNO3 (1.0 equiv) in 2 mL of AcOH at 40 °C.
b The reaction was carried out in 0.75 mL of AcOH and 0.25 mL of MeOH.
c The reaction was carried out in 2 mL of 2,2,2-trifluoroethanol.
d The reaction was carried out in 0.75 mL of AcOH and 0.25 mL of PhCH2OH.
e The reaction was carried out in 0.75 mL of AcOH and 0.25 mL of propargyl alcohol.
f The reaction was carried out at 20 °C.
In the above reaction, a by-product was isolated and identified as the multi-substituted phenol 3, the
O-deacetyl product of 2, through characterization by 1H NMR, 13C NMR, and HMRS. This observation
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prompted us to explore a diverse synthesis of multi-substituted phenols 317a directly starting from the
same starting material 1. Accordingly, we randomly selected several N-aryl amides 1 for the three-step
tandem reactions. It was found that compounds 1a, 1d, 1e, 1i, 1j, 1k, and 1t reacted smoothly to pro-
duce the multi-substituted phenol derivatives 3a, 3d, 3e, 3i, 3j, 3k, and 3t in the yield of 56%, 49%,
65%, 44%, 52%, 52%, and 56%, respectively (Scheme 4). Although the yields of this tandem reaction
were relatively moderate, so far it is the most efficient method for synthesis of the useful p-hydroxyl-o-
nitro-anilides.
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Scheme 4. Extension of the Reaction Scope.a
a Unless otherwise indicated, all of the reactions were carried out with 1 (0.3 mmol), PIFA (1.5 equiv),
BF3·OEt2 (2.0 equiv), HNO3 (1.0 equiv) in 2 mL of AcOH at 80 °C.
b The reaction was performed at 60 °C.
A literature review showed that alkoxy-, amino-, and/or nitro-containing multisubstituted aryl deriva-
tives, including 3 and 4–9 (Scheme 5), are very important and versatile building blocks for the synthesis
of various bioactive compounds (Figure 1). To our delight, the products (2 or 3) of the new reaction
could be readily converted to these species (4–9) in high yields (88–98%) by further deprotection and/or
reduction reaction of 2 or 3.
Scheme 5. Preparation of Partial Protected Derivatives of 4-Hydroxy-benzene-1,2-diamine.
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Another important application of these products 2 and 3 is the ready access that they give to benzoim-
idazoles (10), which represent a class of potentially useful scaffolds for the development of new drugs
(Scheme 6). For example, the reduction of the acyl-protected product 2l resulted in the formation of the
fused product 1H-benzodimidazole 10l in 86% yield in the presence of iron powder at 60 °C for 0.5 h.
Similarly, to our delight, compound 2k also responded under the same conditions to give the intramo-
lecular cyclization product 1H-benzodimidazole 10k in 85% yield. We confidently expect that the mul-
tiple chemically modifiable functional groups on 10k will permit of further derivatization. The above
observations indicated the useful and flexible characteristics of this novel amphiphilic reaction, thereby
affording this straightforward protocol excellent versatility for synthetic applications.
Scheme 6. One-step Conversion of Products 2 to Imidazoles.
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A preliminary mechanistic study was then carried out (Scheme 7, Eqs 1–10). We obtained difunction-
alized compounds 2a and 11a in 55% and 29% yields, respectively, by quenching the reaction of 1a un-
der the optimized conditions after 30 min (Eq 1). A further control experiment indicated that the isolated
compound 11a could be smoothly transformed to the target product 2a under the optimized conditions
after 1 hour (Eq 2). However, the reaction performed with 12a did not afford product 2a, and most of
the starting material 1a was recovered (Eq 3). These results disclosed that the para-acetoxylation reac-
tion of 1 occurred first to generate the intermediate 11 in our process. In addition, tertiary amide 1w did
not afford the desired product 2w, and most of the starting material 1w was recovered, which suggested
the importance of the hydrogen atom on the nitrogen in this sequential difunctionalization reaction (Eq
4). Furthermore, the mechanistic role of each reagent, including PIFA and BF3·OEt2, in each step was
also investigated. By comparing the results of the reactions in the presence of PIFA and BF3·OEt2 (Eq 5)
with those in the absence of PIFA or BF3·OEt2 (Eqs 6 and 7), it was deduced that the first step from 1 to
11 probably proceeded through a Lewis acid-assisted oxidative para-acetoxylation pathway. Further
investigation of the second step from 11 to 2 showed that the intermediate 11a generated 2a in higher
yield when assisted by BF3·OEt2 than by PIFA (Eqs 8 and 9), but failed to afford the desired compound
2a in the absence of PIFA and BF3·OEt2 (Eq 10). These results imply that the second step of the reac-
tion most likely proceeds through an electrophilic substitution pathway.
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Scheme 7. Control Experiments.
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PIFA (1.5 equiv)
4
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7
BF3 OEt2 (2.0 equiv)
NHAc
2a
1a
(1)
+
HNO3 (65~68% aq., 1.0 equiv)
AcOH (2 mL), 40 oC, 30 min
AcO
55%
11a: 29%
8
9
PIFA (1.5 equiv)
BF3 OEt2 (2.0 equiv)
2a
11a
(2)
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HNO3 (65~68% aq., 1.0 equiv)
AcOH (2 mL), 40 oC, 1.5 h
43%
PIFA (1.5 equiv)
NHAc
BF3 OEt2 (2.0 equiv)
2a
(3)
(4)
NO2
HNO3 (65~68% aq., 1.0 equiv)
AcOH (2 mL), 40 oC, 15.5 h
0%
12a: 94% was recovered
PIFA (1.5 equiv)
BF3 OEt2 (2.0 equiv)
NAc
NO2
NAc
HNO3 (65~68% aq., 1.0 equiv)
AcOH (2 mL), 40 oC, 10 h
AcO
1w: 85% was recovered
2w: 0%
PIFA (1.5 equiv)
BF3 OEt2 (2.0 equiv)
(5)
(6)
1a
11a
AcOH (2 mL), 40 oC, 10 min
86%
BF3 OEt2 (2.0 equiv)
1a
11a
AcOH (2 mL), 40 oC, 18 h
93% was recovered
0%
PIFA (1.5 equiv)
11a
1a
(7)
AcOH (2 mL), 40 oC, 18 h
79%
18% was recovered
BF3 OEt2 (2.0 equiv)
2a
11a
(8)
HNO3 (65~68% aq., 1.0 equiv)
AcOH (2 mL), 40 oC, 1 h
83%
PIFA (1.5 equiv)
HNO3 (65~68% aq., 1.0 equiv)
11a
(9)
2a
AcOH (2 mL), 40 oC, 17 h
27% was recovered
30%
HNO3 (65~68% aq., 1.0 equiv)
AcOH (2 mL), 40 oC, 12 h
(10)
2a
11a
0%
94% was recovered
A plausible mechanism for this sequential difunctionalization reaction (Scheme 8) is proposed on the
basis of the control experiments and previous reports. Nucleophilic attack of PIFA on anilides 1 forms
the iodonium intermediate A. Then, a nitrenium ion B, which is stabilized by the charge delocalization
on the phenyl ring, is formed after cleavage of the N–I bond, simultaneously releasing one molecule of
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iodobenzene. The extensively charge-delocalized intermediate C is highly preferred and trapped by
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AcOH or alcohols to give the para-acetoxylated intermediate D. Then, aromatization occurs with D,
leading to the separable intermediate 15. Using BF3·OEt2 as a Lewis acid dramatically accelerated the
transformation of 1 to 15. Finally, ortho-nitration of 15 takes place to afford 2 via a possible amido
group-directed electrophilic substitution pathway. The amido moiety of 15 traps the nitro ion generated
in situ to give a charged intermediate 16, which rearranges through a six-membered ring transition state
to form the delocalized arenium ion 17 for ortho-substitution, and the consequent loss of a H+ produces
the corresponding o-nitrated product 2.
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Scheme 8. Proposed Mechanism.
■ CONCLUSION
In summary, we have developed a novel, straightforward method for the synthesis of valuable p-
acetoxyl or p-alkoxyl-o-nitro-N-arylamide derivatives that involves the sequential difunctionalizations
of C(sp2)-H bonds to incorporate an oxygen atom followed by a nitrogen atom. The new reaction pro-
ceeds under mild conditions in the presence of PIFA and employs simple and readily available anilides
as substrates, and simple AcOH (or ROH) and stoichiometric HNO3 as the oxygen and nitrogen source,
respectively. All of these features, as well as its sulfuric acid-free and metal-free conditions, make this
method highly efficient and suited to practical implementation. Importantly, the method provides multi-
substituted arylamide products that can be readily transformed to various useful small organic building
blocks, which would be of benefit for synthetic organic chemistry, medicinal chemistry, materials chem-
istry, and biochemistry.
■ EXPERIMENTAL SECTION
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General remarks. All reagents were purchased from commercial sources and used without further
treatment, unless otherwise indicated. All starting compounds 1a-v were purchased from commercial
sources unless 1b, 1j and 1q. The concentration of HNO3 was 65–68%. Petroleum ether (PE) used here
refers to the 60–90 °C boiling point fraction of petroleum. Ethyl acetate is abbreviated as EA. 1H NMR
and 13C{1H} NMR spectra were recorded on a Bruker Avance/600 (1H: 600 MHz, 13C: 150 MHz at
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25 °C) or Bruker Avance/400 (1H: 400 MHz, C: 100 MHz at 25 °C) with tetramethylsilane as the in-
ternal standard. Data are represented as follows: chemical shift, integration, multiplicity (br = broad, s =
singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, and m = multiplet), and coupling con-
stants in Hertz (Hz). All high-resolution mass spectra (HRMS) were measured on a mass spectrometer
by using electrospray ionization orthogonal acceleration time-of-flight (ESI-OA-TOF), and the purity of
all samples used for HRMS (>95%) was confirmed by 1H NMR and 13C{1H} NMR spectroscopic analy-
sis. Melting points were measured on a melting point apparatus equipped with a thermometer and were
uncorrected. All reactions were monitored by thin-layer chromatography (TLC) with GF254 silica gel-
coated plates, and in general, the reaction was assumed to have completed 1 h after the starting material
1 was completely consumed. Flash chromatography was carried out on SiO2 (silica gel 200–300 mesh).
Typical experimental procedure for 1 (1b as an example):19b,28 Lauroyl chloride (2.5 mL, 11 mmol)
was dissolved in 20 mL dichloromethane along with aniline (931 mg, 10 mmol) and triethylamine (1.67
mL, 12 mmol). After stirring for four hours the reaction mixture was washed with 10% HCl, sat Na-
HCO3, dried over Na2SO4. After filtration and concentration, the crude product was purified by a short
flash silica gel column chromatography (eluent: EA/PE = 1/10) to give N-phenyldodecanamide 1b as a
white solid (2.64 g, 95%).
Typical experimental procedure for 2 (2a as an example): To a round-bottom flask (25 mL) were
added N-phenylacetamide 1a (41 mg, 0.3 mmol), HNO3 (20 μL, 0.3 mmol), BF3·OEt2 (74 μL, 0.6
mmol), PIFA (194 mg, 0.45 mmol), the mixture was well stirred for 1.5 h in AcOH (2 mL) at 40 oC in
oil bath (the whole process was closely monitored by TLC). After the completion of the reaction, the
reaction was quenched by water (10 mL), the mixture was extracted with dichloromethane (3 × 5 mL).
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The combined organic layers were dried over Na2SO4. After filtration and concentration, the crude
product was purified by a short flash silica gel column chromatography (eluent: EA/PE = 1/10) to give
4-acetamido-3-nitrophenyl acetate 2a as a yellow solid (52 mg, 73%).
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Typical experimental procedure for 3 (3a as an example): To a round-bottom flask (25 mL) were
added N-phenylacetamide 1a (41 mg, 0.3 mmol), HNO3 (20 μL, 0.3 mmol), BF3·OEt2 (74 μL, 0.6
mmol), PIFA (194 mg, 0.45 mmol), the mixture was well stirred for 2.5 h in AcOH (2 mL) at 60 oC in
oil bath (the whole process was closely monitored by TLC). After the completion of the reaction, the
reaction was quenched by water (10 mL), the mixture was extracted with dichloromethane (3 × 5 mL).
The combined organic layers were dried over Na2SO4. After filtration and concentration, the crude
product was purified by a short flash silica gel column chromatography (eluent: EA/PE = 1/5) to give N-
(4-hydroxy-2-nitrophenyl) acetamide 3a as a yellow solid (33 mg, 56%).
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Typical experimental procedure for 4, 6, 7 and 8 (4 as an example):29 To a round-bottom flask (25
mL) were added 4-(((benzyloxy)carbonyl)amino)-3-nitrophenyl acetate 2i (99 mg, 0.3 mmol), Pd/C
catalyst (10%, 64 mg, 0.6 mmol) under argon at RT. The reaction mixture was placed under vacuum and
the atmosphere was replaced with hydrogen. (the whole process was closely monitored by TLC). After
thecompletion of the reaction, the solution was filtered through a pad of Celite with EtOAc and filtrate
was concentrated in vacuo to afford the 3,4-diaminophenyl acetate 4 as a white solid (49 mg, 98%).
Typical experimental procedure for 5 and 9 (6 as an example):30 To a round-bottom flask (25 mL)
were added N-(4-hydroxy-2-nitrophenyl)acetamide 3a (59 mg, 0.3 mmol), SOCl2 (27 μL, 0.24 mmol),
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the mixture was well stirred for 0.5 h in MeOH (2 mL) at 70 C in oil bath (the whole process was
closely monitored by TLC). After the completion of the reaction, the K2CO3 was were added the
mixture and then he mixture was well stirred for 0.5 h at RT. The reaction was quenched by water (10
mL), the mixture was extracted with dichloromethane (3 × 5 mL). The combined organic layers were
dried over Na2SO4. After filtration and concentration, the crude product was purified by a short flash
silica gel column chromatography (eluent: EA/PE = 2/1) to give 6-methoxy-2-methyl-1H-
benzo[d]imidazole 5 as a white solid (41 mg, 89%).
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Typical experimental procedure for 10 (10l as an example):31 To a round-bottom flask (25 mL) were
added N-(4-methoxy-2-nitrophenyl)acetamide 2l (63 mg, 0.3 mmol), Fe (101mg, 1.8 mmol), the mixture
was well stirred for 0.5 h in AcOH (2 mL) at 60 oC (the whole process was closely monitored by TLC).
After the completion of the reaction, the reaction was quenched by water (10 mL), the mixture was
extracted with dichloromethane (3 × 5 mL). The combined organic layers were dried over Na2SO4. After
filtration and concentration, the crude product was purified by a short flash silica gel column
chromatography (eluent: EA/PE = 2/1) to give 6-methoxy-2-methyl-1H-benzo[d]imidazole 10l as a
yellow solid (41 mg, 84%).
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N-phenyldodecanamide (1b).32 The product was isolated by flash chromatography (eluent: EA/PE =
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1/10) as a white solid (2.64 g, 95%). HNMR (600 MHz, CDCl3) δ 7.98 (s, 1H), 7.53 (d, J = 7.8 Hz,
2H), 7.26 (t, J = 7.2 Hz, 2H), 7.06 (t, J = 6.9 Hz, 2H), 2.33 (t, J = 7.2 Hz, 2H), 1.69 (t, J = 6.9 Hz, 2H),
1.35-1.25 (m, 16H), 0.88 (t, J = 6.6 Hz, 3H).
2,2,2-trichloroethyl phenylcarbamate (1j).33 The product was isolated by flash chromatography
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(eluent: EA/PE = 1/20) as a white solid (2.47 g, 93%). H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0
Hz, 2H), 7.37-7.31 (m, 2H), 7.12 (t, J = 7.4 Hz, 1H), 4.83 (s, 2H).
N-(naphthalen-1-yl)picolinamide (1q).34 The product was isolated by flash chromatography (eluent:
EA/PE = 1/10) as a yellow solid (2.29 g, 92%).1H NMR (600 MHz, CDCl3) δ 10.77 (s, 1H), 8.72 (s,
1H), 8.41 (d, J = 7.2 Hz, 1H), 8.37 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.96 (t, J = 7.5 Hz, 1H),
7.90 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.63-7.51 (m, 4H).
4-Acetamido-3-nitrophenyl acetate (2a). The product was isolated by flash chromatography (eluent:
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EA/PE = 1/10) as a yellow solid (52 mg, 73%); Mp: 137-140 C; H NMR (600 MHz, CDCl3) δ 10.26
(s, 1H), 8.81 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.40 (d, J = 9.6 Hz, 1H), 2.32 (s, 3H), 2.29 (s, 3H). 13C
NMR (150 MHz, CDCl3) δ 168.92, 168.85, 145.1, 136.2, 132.6, 129.6, 123.1, 118.7, 25.5, 20.9. HRMS
(ESI), m/z calcd. for C10H10N2NaO5 ([M+Na]+) 261.0482, found: 261.0487.
3-Nitro-4-propionamidophenyl acetate (2b). The product was isolated by flash chromatography
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(eluent: EA/PE = 1/2) as a light yellow solid (83 mg, 71%); Mp: 88-90 oC; 1H NMR (600 MHz, CDCl3)
δ 10.30 (s, 1H), 8.85 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.40 (d, J = 9.6 Hz, 1H), 2.48 (t, J = 7.5 Hz, 2H),
2.32 (s, 3H), 1.75 (t, J = 7.2 Hz, 2H), 1.25-1.38 (m, 16H), 0.87 (t, J = 6.3 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 172.3, 168.9, 145.0, 136.1, 132.9, 129.6, 123.1, 118.7, 38.7, 31.9, 29.6, 29.4, 29.3, 29.3, 29.1,
25.4, 22.7, 20.9, 14.1. HRMS (ESI), m/z calcd. for C20H30N2NaO5 ([M+Na]+) 401.2047, found:
401.2053.
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3-Nitro-4-pivalamidophenyl acetate (2c). The product was isolated by flash chromatography (eluent:
EA/PE = 1/20) as a yellow solid (62 mg, 74%); Mp: 86-87 oC; 1H NMR (600 MHz, CDCl3) δ 10.69 (s,
1H), 8.89 (d, J = 9.6 Hz, 1H), 8.01 (s, 1H), 7.41 (d, J = 9.6 Hz, 1H), 2.32 (s, 3H), 1.36 (s, 9H). 13C NMR
(150 MHz, CDCl3) δ 177.9, 168.9, 145.0, 136.2, 133.3, 129.7, 123.0, 118.8, 40.6, 27.5, 20.9. HRMS
(ESI), m/z calcd. for C13H16N2NaO5 ([M+Na]+) 303.0951, found: 303.0945.
3-Nitro-4-(2-phenylacetamido)phenyl acetate (2d). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/15) as a yellow solid (49 mg, 52%); Mp: 122-123 C; H NMR
(600 MHz, CDCl3) δ 10.20 (s, 1H), 8.84 (d, J = 9.0 Hz, 1H), 7.93 (s, 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.39
(s, 1H), 7.38-7.34 (m, 3H), 3.82 (s, 2H), 2.30 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 170.3, 168.9,
145.2, 136.2, 133.2, 132.5, 129.7, 129.5, 129.4, 128.1, 122.9, 118.7, 45.8, 20.9. HRMS (ESI), m/z calcd.
for C16H14N2NaO5 ([M+Na]+) 337.0795, found: 337.0803.
4-Benzamido-3-nitrophenyl acetate (2e). The product was isolated by flash chromatography (eluent:
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EA/PE = 1/20) as a light yellow solid (68 mg, 76%); Mp: 135-136 C; H NMR (600 MHz, CDCl3) δ
11.28 (s, 1H), 9.05 (d, J = 9.0 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H),
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7.54 (t, J = 7.5 Hz, 2H), 7.47 (d, J = 9.0 Hz, 1H), 2.34 (s, 3H). C NMR (150 MHz, CDCl3) δ 168.9,
165.7, 145.3, 136.4, 133.9, 133.2, 132.8, 129.9, 129.1, 127.4, 123.1, 118.9, 21.0. HRMS (ESI), m/z
calcd. for C15H12N2NaO5 ([M+Na]+) 323.0638, found: 323.0641.
4-(4-Methoxybenzamido)-3-nitrophenyl acetate (2f). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/15) as a yellow solid (64 mg, 65%); Mp: 152-153 C; H NMR
(400 MHz, CDCl3) δ 11.22 (s, 1H), 9.05 (d, J = 9.2 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 8.8
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Hz, 2H), 7.46 (dd, J = 9.2, 2.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 2.34 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 168.9, 165.2, 163.2, 145.0, 136.1, 133.5, 129.9, 129.4, 126.1, 123.0, 118.8, 114.3,
55.6, 20.9. HRMS (ESI), m/z calcd. for C16H14N2NaO6 ([M+Na]+) 353.0744, found: 353.0746.
3-Nitro-4-(4-nitrobenzamido)phenyl acetate (2g). The product was isolated by flash chromatography
(eluent: EA/PE = 1/10) as a yellow solid (42 mg, 41%); Mp: 178-180 oC; 1H NMR (600 MHz, CDCl3) δ
11.39 (s, 1H), 9.02 (d, J = 9.0 Hz, 1H), 8.40 (d, J = 7.8 Hz, 2H), 8.16 (d, J = 8.4 Hz, 2H), 8.09 (s, 1H),
7.52 (d, J = 9.1 Hz, 1H), 2.36 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 168.8, 163.6, 150.3, 145.9, 139.3,
136.6, 132.3, 130.0, 128.6, 124.3, 123.1, 119.2, 21.0. HRMS (ESI), m/z calcd. for C15H11N3NaO7
([M+Na]+) 368.0489, found: 368.0500.
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4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-nitrophenyl acetate (2h). The product was
isolated by flash chromatography (eluent: EA/PE = 1/10) as a yellow solid (68 mg, 54%); Mp: 156-157
oC; 1H NMR (600 MHz, CDCl3) δ 9.93 (s, 1H), 8.56 (d, J = 9.0 Hz, 1H), 8.01 (s, 1H), 7.79 (d, J = 7.2
Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 7.47-7.39 (m, 3H), 7.35 (t, J = 7.3 Hz, 2H), 4.52 (d, J = 7.2 Hz, 2H),
4.32 (t, J = 7.2 Hz, 1H), 2.33 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 168.9, 152.9, 144.6, 143.4, 141.3,
135.9, 133.0, 129.7, 127.9, 127.2, 125.0, 121.7, 120.1, 118.8, 68.0, 46.8, 20.9. HRMS (ESI), m/z calcd.
for C23H18N2NaO6 ([M+Na]+)441.1057, found:441.1051.
4-(((Benzyloxy)carbonyl)amino)-3-nitrophenyl acetate (2i). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/25) as a yellow solid (51 mg, 52%); Mp: 126-127 C; H NMR
(600 MHz, CDCl3) δ 9.85 (s, 1H), 8.62 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.43-7.36 (m, 6H), 5.24 (s, 2H),
2.32 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 169.0, 153.0, 144.6, 135.9, 135.4, 133.1, 129.7, 128.7,
128.6, 128.5, 128.5, 121.7, 118.8, 67.8, 20.9. HRMS (ESI), m/z calcd. for C16H14N2NaO6 ([M+Na]+)
353.0744, found:353.0735.
3-Nitro-4-(((2,2,2-trichloroethoxy)carbonyl)amino)phenyl acetate (2j). The product was isolated by
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flash chromatography (eluent: EA/PE = 1/50) as a yellow solid (60 mg, 54%); Mp: 105-107 C; H
NMR (600 MHz, CDCl3) δ 10.00 (s, 1H), 8.57 (d, J = 9.0 Hz, 1H), 8.02 (s, 1H), 7.44 (d, J = 9.0 Hz, 1H),
4.87 (s, 2H), 2.33 (s, 3H).13C NMR (150 MHz, CDCl3) δ 168.8, 151.3, 145.2, 136.3, 132.1, 129.7, 121.8,
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119.0, 94.7, 74.8, 20.9. HRMS (ESI), m/z calcd. for C11H9Cl3N2NaO6 ([M+Na]+) 392.9418,
found:392.9416.
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4-(2-Chloroacetamido)-3-nitrophenyl acetate (2k). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/20) as a yellow solid (47 mg, 57%); Mp: 174-176 C; 1H NMR
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(400 MHz, CDCl3) δ 11.31 (s, 1H), 8.81 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.45 (dd, J = 9.2,
2.8 Hz, 1H), 4.25 (s, 2H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.8, 165.3, 146.0, 136.8, 131.3,
129.5, 122.9, 119.0, 43.1, 20.9. HRMS (ESI), m/z calcd. for C10H9ClN2NaO5 ([M+Na]+) 395.0092,
found: 395.0084.
N-(4-Methoxy-2-nitrophenyl)acetamide (2l). The product was isolated by flash chromatography
(eluent: EA/PE = 1/5) as a yellow solid (33 mg, 53%); Mp: 114-115 oC; 1H NMR (400 MHz, CDCl3) δ
10.05 (s, 1H), 8.63 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 2.8 Hz, 1H), 7.23 (dd, J = 9.3, 3.2 Hz, 1H), 3.86 (s,
3H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.8, 155.0, 128.5, 123.9, 123.4, 108.5, 56.0, 25.4.
HRMS (ESI), m/z calcd. for C9H10N2NaO4 ([M+Na]+) 233.0533, found: 233.0533.
N-(2-Nitro-4-(2,2,2-trifluoroethoxy)phenyl)acetamide (2m). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/15) as a yellow solid (54 mg, 65%); Mp: 95-97 C; 1H NMR (400
MHz, CDCl3) δ 10.13 (s, 1H), 8.74 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.30 (dd, J = 9.4, 3.0
Hz, 1H), 4.40 (q, J = 8.0 Hz, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.0, 152.3, 136.6,
130.1, 124.3, 124.03 (d, J = 15.3 Hz), 121.5, 110.3, 66.25 (q, J = 36.9 Hz).
N-(4-(Benzyloxy)-2-nitrophenyl)acetamide (2n). The product was isolated by flash chromatography
(eluent: EA/PE = 1/20) as a yellow solid (36 mg, 42%); Mp: 104-107 oC; 1H NMR (400 MHz, CDCl3) δ
10.07 (s, 1H), 8.64 (d, J = 9.6 Hz, 1H), 7.75 (d, J = 3.2 Hz, 1H), 7.43-7.35 (m, 5H), 7.30 (dd, J = 9.4,
3.0 Hz, 1H), 5.10 (s, 2H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.0, 154.0, 137.0, 135.7, 128.8,
128.6, 128.4, 127.6, 124.0, 123.9, 109.9, 70.7, 25.4. HRMS (ESI), m/z calcd. for C15H14N2NaO4
([M+Na]+)309.0846., found: 309.0845
N-(2-Nitro-4-(prop-2-yn-1-yloxy)phenyl)acetamide (2o). The product was isolated by flash
chromatography (eluent: EA/PE = 1/10) as a yellow solid (34 mg, 48%); Mp: 90-93 oC; 1H NMR (400
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MHz, CDCl3) δ 10.10 (s, 1H), 8.67 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 3.2 Hz, 1H), 7.31 (dd, J = 9.4, 3.0
Hz, 1H), 4.7 (d, J = 2.4 Hz, 1H), 2.57 (t, J = 2.4 Hz, 1H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
168.9, 152.6, 129.2, 124.1, 123.8, 110.3, 56.5, 25.5. HRMS (ESI), m/z calcd. for C11H11N2O4 ([M+H]+)
235.0713, found:235.0720.
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2-Hydroxy-3,3-dimethoxy-N-(4-nitrophenyl)butanamide (2p). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/15) as a yellow solid (30 mg, 35%); Mp: 215-217 C; H NMR
(400 MHz, DMSO) δ 10.53 (s, 1H), 8.33-8.27 (m, 1H), 8.11-8.05 (m, 1H), 7.90 (s, 1H), 7.85-7.77 (m,
2H), 2.49 (s, 3H), 2.18 (s, 3H). 13C NMR (100 MHz, DMSO) δ 169.2, 144.6, 141.9, 129.9, 129.8, 128.7,
125.8, 125.4, 121.9, 113.7, 22.9, 20.7. HRMS (ESI), m/z calcd. for C14H12N2NaO5 ([M+Na]+) 311.0638,
found:311.0631.
3-Nitro-4-(picolinamido)naphthalen-1-yl acetate (2q). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/15) as a light yellow solid (44 mg, 42%); Mp: 170-172 C; H
NMR (600 MHz, CDCl3) δ 11.15 (s, 1H), 8.77 (d, J = 4.8 Hz, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.18 (d, J =
8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.98-7.92 (m, 2H), 7.74 (t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.5 Hz,
1H), 7.58 (t, J = 6.0 Hz, 1H), 2.52 (s, 3H).13C NMR (100 MHz, CDCl3) δ 168.8, 163.4, 148.7, 148.6,
145.1, 140.9, 137.7, 130.0, 130.0, 129.6, 128.3, 127.5, 127.2, 126.8, 123.0, 121.9, 113.5, 21.0. HRMS
(ESI), m/z calcd. for C18H13N3NaO5 ([M+Na]+) 374.0747, found:374.0741.
4-((Methoxycarbonyl)amino)-3-nitrophenyl acetate (2r). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/15) as a light yellow solid (34 mg, 44%); Mp: 130-132 C; H
NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 8.62 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.41 (dd, J =
9.2, 2.4 Hz, 1H), 3.84 (s, 3H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.0, 153.6, 144.5, 133.2,
129.7, 121.6, 118.8, 53.0, 21.0. HRMS (ESI), m/z calcd. for C10H10N2NaO6 ([M+Na]+) 277.0431, found:
277.0432.
Methyl (4-methoxy-2-nitrophenyl)carbamate (2s). The product was isolated by flash
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1
chromatography (eluent: EA/PE = 1/20) as a light yellow solid (32 mg, 47%); Mp: 135-137 C; H
NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.43 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 3.2 Hz, 1H), 7.23 (dd, J =
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9.4, 3.0 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 154.3, 153.8, 136.5, 129.1,
123.9, 122.3, 108.3, 55.9, 52.8. HRMS (ESI), m/z calcd. for C9H10N2NaO5 ([M+Na]+) 249.0482, found:
249.0483.
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4-Acetamido-3-methyl-5-nitrophenyl acetate (2t). The product was isolated by flash chromatography
(eluent: EA/PE = 1/15) as a yellow solid (48 mg, 63%); Mp: 165-167 oC; 1H NMR (600 MHz, CDCl3) δ
8.20 (s, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 2.32 (s, 6H), 2.23 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 168.8,
168.4, 147.9, 144.9, 139.9, 129.3, 127.5, 116.4, 23.8, 21.0, 19.3. HRMS (ESI), m/z calcd. for
C11H12N2NaO5 ([M+Na]+) 275.0638, found: 275.0633.
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4-Acetamido-2-methyl-5-nitrophenyl acetate (2u). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/10) as a yellow solid (42 mg, 56%); Mp: 130-132 C; H NMR
(600 MHz, CDCl3) δ 10.33 (s, 1H), 8.70 (s, 1H), 7.92 (s, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H).
13C NMR (150 MHz, CDCl3) δ 168.0, 167.8, 142.9, 139.6, 133.3, 131.7, 122.8, 118.1, 24.6, 19.6, 16.0.
HRMS (ESI), m/z calcd. for C11H12N2NaO5 ([M+Na]+) 275.0638, found: 275.0639.
4-(Furan-2-carboxamido)-3-nitrophenyl acetate (2v). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/10) as a yellow solid (54 mg, 62%); Mp: 139-141 C; H NMR
(600 MHz, CDCl3) δ 11.36 (s, 1H), 8.99 (d, J = 9.0 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.46
(dd, J = 9.3, 2.7 Hz, 1H), 7.32 (d, J = 3.6 Hz, 1H), 6.61-6.60 (m, 1H), 2.34 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ 168.9, 156.4, 147.2, 145.4, 145.3, 136.3, 132.6, 129.7, 123.0, 119.0, 116.6, 112.8, 21.0.
HRMS (ESI), m/z calcd. for C13H10N2NaO6 ([M+Na]+) 313.0431, found: 313.0435.
N-(4-Hydroxy-2-nitrophenyl)acetamide (3a). The product was isolated by flash chromatography
(eluent: EA/PE = 1/5) as a yellow solid (33 mg, 56%); Mp: 153-155 oC; 1H NMR (600 MHz, DMSO) δ
10.21 (s, 1H), 9.92 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.25 (s, 1H), 7.08 (d, J = 9.0 Hz, 1H), 1.99 (s, 3H).
13C NMR (100 MHz, DMSO) δ 168.3, 154.6, 143.8, 127.6, 122.5, 120.8, 110.4, 23.0. HRMS (ESI), m/z
calcd. for C8H9N2O4 ([M+H]+) 197.0557, found: 197.0558.
N-(4-Hydroxy-2-nitrophenyl)-2-phenylacetamide (3d). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/10) as a yellow solid (40 mg, 49%); Mp: 125-127 C; H NMR
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(600 MHz, DMSO) δ 10.23 (s, 1H), 10.11 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.34-7.20 (m, 6H), 7.09 (d,
J = 8.4 Hz, 1H), 3.64 (s, 2H). 13C NMR (150 MHz, DMSO) δ 169.6, 155.1, 143.7, 135.8, 129.7, 128.8,
127.9, 127.9, 123.2, 121.6, 110.9. HRMS (ESI), m/z calcd. for C14H12N2NaO4 ([M+Na]+) 295.0689,
found: 295.0698.
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N-(4-Hydroxy-2-nitrophenyl)benzamide (3e). The product was isolated by flash chromatography
(eluent: EA/PE = 1/10) as a yellow solid (50 mg, 65%); Mp: 224-226 oC; 1H NMR (600 MHz, DMSO)
δ 10.43 (s, 1H), 10.30 (s, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 7.2 Hz, 1H), 7.54 (t, J = 7.2 Hz, 3H),
7.35 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H). 13C NMR (150 MHz, DMSO) δ 165.7, 155.5, 144.5, 134.3, 132.5,
129.1, 128.8, 128.0, 123.3, 121.3, 111.1. HRMS (ESI), m/z calcd. for C13H10N2NaO4 ([M+Na]+)
281.0533, found: 281.0533.
Benzyl (4-hydroxy-2-nitophenyl)carbamate (3i). The product was isolated by flash chromatography
(eluent: EA/PE = 1/20) as a yellow solid (38 mg, 44%); Mp: 162-164 oC; 1H NMR (400 MHz, DMSO)
δ 10.22 (s, 1H), 9.55 (s, 1H), 7.39-7.33 (m, 6H),, 7.29 (d, J = 2.8 Hz, 1H), 7.09 (dd, J = 8.8, 2.8 Hz, 1H),
5.11 (s, 2H). 13C NMR (100 MHz, DMSO) δ 154.4, 153.9, 143.1, 136.4, 128.4, 128.0, 127.9, 127.3,
123.1, 121.2, 110.6, 66.1. HRMS (ESI), m/z calcd. for C14H13N2O5 ([M+H]+) 289.0819, found:
289.0823.
2,2,2-Trichloroethyl (4-hydroxy-2-nitrophenyl)carbamate (3j). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/20) as a yellow oil (51 mg, 52%); H NMR (600 MHz, DMSO) δ
10.34 (s, 1H), 9.94 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.31 (s 1H), 7.12 (d, J = 8.4, 1H), 4.89 (s, 2H). 13C
NMR (150 MHz, DMSO) δ 155.6, 153.2, 144.4, 128.7, 122.5, 121.5, 111.3, 96.2, 74.2. HRMS (ESI),
m/z calcd. for C9H7Cl3N2NaO5 ([M+Na]+) 350.9313, found: 350.9324.
2-Chloro-N-(4-hydroxy-2-nitrophenyl)acetamide (3k). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/20) as a yellow solid (36 mg, 52%); Mp: 219-221 C; H NMR
(600 MHz, DMSO) δ 10.34 (s, 2H), 7.50 (dd, J = 9.0, 3.0 Hz, 1H), 7.33 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H).
4.29 (s, 2H). 13C NMR (100 MHz, DMSO) δ 165.0, 155.0, 143.2, 127.5, 121.9, 121.2, 110.6, 42.8.
HRMS (ESI), m/z calcd. for C10H10ClN2O2 ([M+H]+) 225.0425, found: 225.0432.
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N-(4-Hydroxy-2-methyl-6-nitrophenyl)acetamide (3t). The product was isolated by flash
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chromatography (eluent: EA/PE = 1/10) as a yellow solid (35 mg, 56%); Mp: 187-189 C; H NMR
(400 MHz, DMSO) δ 10.18 (s, 1H), 9.51 (s, 1H), 7.06 (d, J = 2.8 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 2.17
(s, 3H), 1.97 (s, 3H). 13C NMR (100 MHz, DMSO) δ 168.6, 155.2, 147.3, 138.5, 121.3, 120.4, 108.3,
22.5, 17.9. HRMS (ESI), m/z calcd. for C9H11N2O4 ([M+H]+) 211.0713, found: 211.0720.
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3,4-Diaminophenyl acetate (4). The product was isolated by flash chromatography (eluent: EA/PE =
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1/1) as a purple solid (49 mg, 98%); Mp: 168-170 C; H NMR (600 MHz, DMSO) δ 6.44 (d, J = 8.4
Hz, 1H), 6.23 (d, J = 3.0 Hz, 1H), 6.08 (dd, J = 8.4, 2.4 Hz, 1H), 4.61 (s, 2H), 4.37 (s, 2H), 2.16 (s, 3H).
13C NMR (150 MHz, DMSO) δ 170.1, 142.6, 136.2, 133.0, 114.5, 109.6, 108.0, 21.3. HRMS (ESI), m/z
calcd. for C8H11N2O2 ([M+H]+) 167.0815, found: 167.0819.
4-Amino-3-nitrophenol (5). The product was isolated by flash chromatography (eluent: EA/PE = 1/2)
as a yellow solid (45 mg, 98%); Mp: > 300 oC; 1H NMR (400 MHz, DMSO) δ 7.32 (s, 1H), 7.03 (d, J =
8.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.11 (s, 3H). 13C NMR (100 MHz, DMSO) δ 147.5, 139.6, 130.0,
127.0, 120.7, 107.6. HRMS (ESI), m/z calcd. for C6H6N2NaO3 ([M+Na]+) 177.0271, found: 177.0254.
N-(2-Amino-4-hydroxyphenyl)acetamide (6). The product was isolated by flash chromatography
(eluent: EA/PE = 1/1) as a yellow solid (44 mg, 88%); Mp: 189-191 oC; 1H NMR (400 MHz, DMSO) δ
8.90 (s, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.12 (d, J = 2.0 Hz, 1H), 5.94 (dd, J = 8.4, 2.0 Hz, 1H), 4.73 (s,
2H), 1.96 (s, 3H). 13C NMR (100 MHz, DMSO) δ 168.2, 155.7, 143.7, 126.9, 115.4, 103.3, 100.1, 23.0.
HRMS (ESI), m/z calcd. for C8H11N2O2 ([M+H]+) 167.0815, found: 167.0817.
4-Acetamido-3-aminophenyl acetate (7). The product was isolated by flash chromatography (eluent:
EA/PE = 1/3) as a yellow solid (56 mg, 89%); Mp: 150-152 oC; 1H NMR (400 MHz, DMSO) δ 9.07 (s,
1H), 7.11 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.25 (dd, J = 8.4, 2.8 Hz, 1H), 5.05 (s, 2H), 2.21
(s, 3H), 2.02 (s, 3H). 13C NMR (100 MHz, DMSO) δ 169.2, 168.4, 148.4, 143.2, 126.1, 120.9, 108.8,
108.3, 23.2, 20.8. HRMS (ESI), m/z calcd. for C10H12N2NaO3 ([M+Na]+) 231.0740, found: 231.0750.
N-(2-Amino-4-(2,2,2-trifluoroethoxy)phenyl)acetamide (8). The product was isolated by flash
chromatography (eluent: EA/PE = 1/1) as a purple solid (56 mg, 89%); Mp: 201-203 oC; 1H NMR (600
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MHz, DMSO) δ 9.01 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.35 (s, 1H), 6.22 (d, J = 8.4 Hz, 1H), 4.96 (s,
2H), 4.60 (dd, J = 17.7 Hz, 8.7, 2H), 2.00 (s, 3H). 13C NMR (150 MHz, DMSO) δ 168.8, 155.8, 144.2,
127.2, 118.7, 102.4, 102.3, 79.3 (d, J = 33.6 Hz), 65.2 (q, J = 33.7 Hz), 23.6. HRMS (ESI), m/z calcd.
for C10H12F3N2O2 ([M+H]+) 249.0845, found: 249.0855.
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2-Nitro-4-(2,2,2-trifluoroethoxy)aniline (9). The product was isolated by flash chromatography
(eluent: EA/PE = 1/1) as a yellow solid (56 mg, 89%); Mp: 147-149 oC; 1H NMR (400 MHz, CDCl3) δ
7.61 (d, J = 3.2 Hz, 1H), 7.16 (dd, J = 9.0, 3.0 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 6.00 (s, 2H), 4.33 (q, J
= 8.0 Hz, 2H). 13C NMR (150 MHz, CDCl3) δ 148.3, 141.0, 127.0, 124.0, 122.2, 120.5, 108.8, 66.7 (q, J
= 35.6 Hz). HRMS (ESI), m/z calcd. for C8H8F3N2O3 ([M+H]+) 237.0482, found: 237.0486.
6-Methoxy-2-methyl-1H-benzo[d]imidazole (10l).35 The product was isolated by flash
chromatography (eluent: EA/PE = 1/1) as a white solid (41 mg, 86%); Mp: 134-136 oC; 1H NMR (600
MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.84 (d, J = 9.0, 1H), 3.82 (s, 3H), 2.58 (s, 3H).
HRMS (ESI), m/z calcd. for C9H11N2O ([M+H]+) 163.0866, found: 163.0872.
2-(Chloromethyl)-1H-benzo[d]imidazol-6-yl acetate (10k). The product was isolated by flash
chromatography (eluent: EA/PE = 2/5) as a white solid (57 mg, 85%); Mp: 156-158 oC; 1H NMR (600
MHz, DMSO) δ 7.57 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H), 2.28 (s,
3H). 13C NMR (150 MHz, DMSO) δ 170.1, 151.3, 146.6, 139.1, 136.9, 117.5, 116.0, 108.8, 38.7, 21.3.
HRMS (ESI), m/z calcd. for C10H10ClN2O2 ([M+H]+) 225.0425, found: 225.0430.
4-Acetamidophenyl acetate (11a). The product was isolated by flash chromatography (eluent: EA/PE
= 3/10) as a white solid (56 mg, 89%); Mp: 151-152 oC; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.8
Hz, 2H), 7.35 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 2.29 (s, 3H), 2.16 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ 169.8, 168.3, 146.8, 135.6, 122.0, 120.9, 24.5, 21.1. HRMS (ESI), m/z calcd. for C10H11NNaO3
([M+Na]+) 216.0631, found: 216.0632.
N-(2-Nitrophenyl)acetamide (12a). The product was isolated by flash chromatography (eluent:
EA/PE = 1/18) as a yellow solid; Mp: 90-92 oC; 1H NMR (600 MHz, CDCl3) δ 10.33 (s, 1H), 8.77 (d, J
= 9.0 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H),7.65 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 2.30 (s, 3H).
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13C NMR (150 MHz, CDCl3) δ 169.0, 136.3, 136.0, 134.9, 125.7, 123.2, 122.2, 25.6. HRMS (ESI), m/z
calcd. for C8H8N2NaO3 ([M+Na]+) 203.0427, found:203.0420.
■ ASSOCIATED CONTENT
9
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI:
Computational data, X-ray crystallographic data and NMR spectra copies for compounds (PDF)
■ AUTHOR INFORMATION
Corresponding Authors
*E-mail: zgs6668@yahoo.com
*E-mail: zhangzg@htu.edu.cn.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We thank the NSFC (U1604285, 21272057, 2121772032 and 21702051), PCSIRT (IRT1061), the 111
Project (D17007), Henan Provincial Natural Science Foundation (162300410180), Science &
Technology Innovation Talents in Universities of Henan Province (17HASTIT002), and Outstanding
Young Talent Cultivation Project Funding of Henan Normal University (14YR002). Leo Holroyd, PhD,
from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English text of a draft
of this manuscript.
■ REFERENCES
(1) (a) McCutcheon, D. C.; Paley, M. A.; Steinhardt, R. C.; Prescher, J. A. Expedient Synthesis of
Electronically Modified Luciferins for Bioluminescence Imaging. J. Am. Chem. Soc. 2012, 134, 7604-
7607; (b) Muth, M. A.; Carrasco-Orozco, M.; Thelakkat, M. Liquid-Crystalline Perylene Diester
Polymers with Tunable Charge-Carrier Mobility. Adv. Funct. Mater. 2011, 21, 4510-4518.
(2) (a) Muth, A.; Subramanian, V.; Beaumont, E.; Nagar, M.; Kerry, P. Development of a Selective
Inhibitor of Protein Arginine Deiminase 2. J. Med. Chem. 2017, 60, 3198-3211; (b) Reynolds, D.; Hao,
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