Synthesis of 2-aminobenzophenones through acylation of anilines with α-oxocarboxylic acids assisted by: Tert -butyl nitrite

Article abstract of DOI:10.1039/c8ob01846d

In this paper, a regioselective, efficient and convenient synthesis of 2-aminobenzophenones through acylation of anilines with α-oxocarboxylic acids assisted by tert-butyl nitrite is presented. Interestingly, tert-butyl nitrite acts as not only an efficient and mild nitrosation reagent, but also a sustainable oxidant required in the Pd(ii)-catalyzed decarboxylative acylation. Meanwhile, the NO unit turned out to be an easily introduced and readily removable directing group for the regioselective acylation.

Full text of DOI:10.1039/c8ob01846d

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Synthesis of 2-aminobenzophenones through
acylation of anilines with α-oxocarboxylic acids
assisted by tert-butyl nitrite†
Cite this: Org. Biomol. Chem., 2018,
16, 7737
a
Qianqian Wang,a,b Xinying Zhang *a and Xuesen Fan
*
In this paper, a regioselective, efficient and convenient synthesis of 2-aminobenzophenones through
acylation of anilines with α-oxocarboxylic acids assisted by tert-butyl nitrite is presented. Interestingly,
tert-butyl nitrite acts as not only an efficient and mild nitrosation reagent, but also a sustainable oxidant
required in the Pd(II)-catalyzed decarboxylative acylation. Meanwhile, the NO unit turned out to be an
easily introduced and readily removable directing group for the regioselective acylation.
Received 30th July 2018,
Accepted 2nd October 2018
DOI: 10.1039/c8ob01846d
rsc.li/obc
these literature methods are generally reliable, some of them
still suffer from limitations such as difficult-to-obtain
Introduction
The development of efficient and practical methods for the substrates, expensive catalysts, perishable intermediates, harsh
synthesis of 2-aminobenzophenone derivatives has remained a reaction conditions, and uncontrollable regioselectivity.
hot topic in organic and medicinal chemistry for a long time. Therefore, the search for new synthetic methods for the prepa-
This is mainly due to the fact that the 2-aminobenzophenone ration of 2-aminobenzophenones starting from easily obtain-
scaffold is present ubiquitously in natural products, drugs and able substrates and employing nontoxic, stable and easy-to-
functional materials.1 Moreover, 2-aminobenzophenones also handle acylating reagents is still of urgent demand.
serve as versatile building blocks in the synthesis of a plethora
In recent years, direct functionalizations of the inert aro-
of fine chemicals.1 Due to their importance, a number of matic C(sp2)–H bonds under the catalysis of transition-metal
elegant methods for the preparation of 2-aminobenzophe- (TM) catalysts have attracted much attention due to their excel-
nones have been developed so far, which mainly include: (i) lent step-economy and atom-efficiency.6 To realize the desired
Friedel–Crafts acylation of arenes with 2-nitrobenzoyl chloride C(sp2)–H bond derivations, a directing group (DG) is usually
generated in situ from the reaction of 2-nitrobenzoic acid with needed to enhance the reactivity of the substrates and to
oxalyl chloride followed by a separate reduction of the nitro control the regioselectivity via its interaction with the catalyst.
unit;2 (ii) reaction of 2-aminoaryl aldehydes with arylmagne- In this aspect, the easily obtainable nitroso compounds7 have
sium bromide followed by oxidation with CuCl2;2 (iii) Friedel– aroused intensive interest since the nitroso group has a high
Crafts acylation of arenes with 2-nitrobenzoic acid in the pres- affinity to interact with metals,8 and thus can be used as a
ence of Tf2O and BF3·Et2O followed by a separate reduction of powerful DG in TM-catalyzed inert C–H bond functionaliza-
the nitro group;2 (iv) Pd-catalyzed addition of arylboronic acids tions.9 Meanwhile, TM-catalyzed decarboxylative C–H
on 2-aminobenzonitriles;3 (v) insertion of benzyne into an functionalization is
a highly useful tool for C–C bond
amide bond;4 (vi) acylation of anilines with benzonitriles pro- formation with high efficiency and sustainability.10 Among
moted by a stoichiometric amount of BCl3/AlCl3;5 (vii) addition various acid substrates, α-oxocarboxylic acids are ideal acyl-
of 2-aminobenzonitriles with Grignard reagents;2 etc. While ation reagents through the TM-catalyzed decarboxylative C–C
bond formations owing to their easy availability and facile-to-
handle nature.11 In this aspect, Luo,12a Wang12b and Sun12c
have independently reported a Pd-catalyzed decarboxylative
acylation of N-nitrosoanilines with α-oxo-carboxylic acids.
While this novel acylation provides a highly valuable and
reliable synthesis of N-nitroso-2-aminobenzophenone deriva-
tives, it was also noticed, however, that the N-nitrosoaniline
substrates used therein were pre-prepared via nitrosation of
anilines by using a combination of sodium nitrite and strong
acid as the nitrosation reagent. These strong acidic conditions
aHenan Key Laboratory of Organic Functional Molecule and Drug Innovation,
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine
Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of
Education, School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, China. E-mail: xinyingzhang@htu.cn,
xuesen.fan@htu.cn
bSchool of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, China
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of compounds 4a–4hh, 5a–5r, A and 6. See DOI: 10.1039/c8ob01846d
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7737–7747 | 7737

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Optimization study on the formation of 4aa
may be incompatible with some perishable substrates. In
addition, a strong oxidant such as K2S2O8 or (NH4)2S2O8 has to
be employed in the acylation reactions to regenerate the Pd(II)
species, and arguably also to assist the decarboxylation of
α-oxocarboxylic acids.12 Moreover, the N-nitroso unit is usually
left behind in the 2-aminobenzophenone derivatives thus
obtained, and additional step(s) has to be taken for its removal.
To overcome these limitations, we designed a new synthetic
approach to N-nitroso-2-aminobenzophenones needing
neither the pre-nitrosation of the aniline substrates under
strong acidic conditions nor the use of a strong oxidant for the
decarboxylative acylation via an envisioned one-pot three-com-
ponent reaction of anilines with tert-butyl nitrite and
α-oxocarboxylic acids. The rationale behind this design is that
tert-butyl nitrite has been well proven as not only a convenient
and mild nitrosation reagent,13 but also as a sustainable
oxidant.14 It is thus expected that tert-butyl nitrite could firstly
react with aniline to give N-nitrosoaniline, and then act as an
oxidant to promote the Pd(II)-catalyzed acylation of
N-nitrosoaniline with α-oxocarboxylic acid to afford N-nitroso-
2-aminobenzophenone in one pot. If this could be successful,
we would then move forward to search for a suitable reducing
system to remove the NO unit of the in situ formed N-nitroso-2-
aminobenzophenones to realize an all-in-one-pot synthesis of
Entry Catalyst (mol%) Equiv. of 2 Solvent T (°C) Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (5)
Pd(TFA)2 (5)
PdCl2 (5)
Cu(OAc)2 (5)
Ag2CO3 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (3)
Pd(OAc)2 (10)
3
3
3
3
3
3
3
3
3
3
3
3
2
4
3
3
CH2Cl2 40
CH2Cl2 40
CH2Cl2 40
CH2Cl2 40
CH2Cl2 40
DCE
EA
75
60
0
0
0
88
32
40
15
30
76
86
75
89
79
88
40
40
40
THF
CH3CN 40
9
10
11
12
13
14
15
16
Et2O
DCE
DCE
DCE
DCE
DCE
DCE
40
30
50
40
40
40
40
a Reaction conditions: 1a (0.5 mmol), 3a (1 mmol), 2 mL of solvent,
air, 20 h. b Isolated yield.
2-aminobenzophenones from commercially available sub- more efficient than CH2Cl2, ethyl acetate (EA), THF, CH3CN
strates under mild conditions (Scheme 1). To achieve these and Et2O in mediating this reaction (entries 6–10). Next, it was
objectives, the following challenges should be addressed: (i) observed that reaction temperatures lower or higher than
the nitrosation might also occur with the active intermediates 40 °C gave diminished yields of 4a (entries 11 and 12).
t
generated in situ and (ii) the compatibility of different reaction Reducing the loading of BuONO from 3 equiv. to 2 equiv.
conditions of our newly designed cascade process is unknown. resulted in a remarkable decrease in the yield of 4a (entry 13),
Herein, we wish to report our results in this regard.
and increasing it to 4 equiv. did not improve the efficiency
obviously (entry 14). In addition, further screening showed
that the optimum loading of Pd(OAc)2 is 5 mol% (entry 6 vs.
entries 15 and 16).
Results and discussion
With the optimum conditions established, the suitability of
diversely substituted α-oxocarboxylic acids 3 was tested with 1a
and 2 as model substrates. As shown in Table 2, it turned out
that this reaction had a good tolerance of various functional
groups in that 3 with either a F, Br or Me unit attached on the
ortho-position, a Cl or Me group on the meta-position, or a F,
Cl, Br, Me, CF3 or MeO group on the para-position of the
2-phenyl unit reacted with 1a and 2 smoothly to give 4b–4l in
good to excellent yields. In addition, 3 bearing a bis- or tri-sub-
stituted 2-phenyl unit were also suitable for this reaction to
afford 4m–4o in moderate to good yields. Interestingly, the
reaction of 2-(naphthalen-1-yl)-2-oxoacetic acid or 2-(naphtha-
len-2-yl)-2-oxoacetic acid with 1a and 2 proceeded efficiently to
afford 4p and 4q in yields of 85% and 88%. Moreover, 2-
(furan-2-yl)-2-oxoacetic acid and 2-oxo-2-(thiophen-2-yl)acetic
acid participated in this reaction smoothly to give heteroaro-
matic ketones 4r and 4s in yields of 69% and 68%, respectively.
Finally, 2-oxopropanoic acid as an aliphatic unit substituted
substrate could also take part in this reaction, albeit the yield
of the corresponding product 4t is lower.
Our study was initiated by treating
a
mixture of
N-methylaniline (1a), tert-butyl nitrite (2) and 2-oxo-2-phenyl-
acetic acid (3a) with Pd(OAc)2 in CH2Cl2 at 40 °C under air for
20 h. To our delight, the expected cascade reaction took place
to give N-nitroso-2-aminobenzophenone 4a in a yield of 75%
(Table 1, entry 1). To improve the efficiency, several parameters
were screened. First, different catalysts including Pd(TFA)2,
PdCl2, Cu(OAc)2 and Ag2CO3 were tried, and they were found
to be less efficient than Pd(OAc)2 (entries 2–5 vs. entry 1). The
following study on the solvent effect revealed that DCE was
Next, the suitability of a number of diversely substituted
aniline derivatives 1 for this reaction was studied by using 2
Scheme 1 Our designed one-pot synthesis of 2-aminobenzophenones.
7738 | Org. Biomol. Chem., 2018, 16, 7737–7747
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Substrate scope for the preparation of 4 (I)a,b
Table 3 Substrate scope for the preparation of 4 (II)a,b
a Reaction conditions: 1 (0.5 mmol), 2 (1.5 mmol), 3a (1 mmol),
Pd(OAc)2 (0.025 mmol), DCE (2 mL), 40 °C, 20 h. b Isolated yield.
which underwent acylation at the less sterically encumbered
site to give 4v or 4w, and the formation of other possible regio-
isomers was not observed. It is also worth stressing that 1
bearing an electron-donating group (EDG) on the para-position
of the phenyl ring afforded the corresponding products in
a Reaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), 3 (1 mmol),
Pd(OAc)2 (0.025 mmol), DCE (2 mL), 40 °C, 20 h. b Isolated yield.
and 3a as model substrates, and the results are listed in higher yields than those with an electron-withdrawing group
Table 3. We were pleased to find that all the aniline derivatives (EWG) as representatively demonstrated in the formation of
tested herein took part in this cascade reaction smoothly to 4aa and 4cc vs. 4bb. Moreover, this reaction is compatible with
give the corresponding N-nitrosoaniline products 4u–4hh in a bis-substituted aniline substrate to give 4dd in a yield of
moderate to good yields. Interestingly, different substituents 76%. Interestingly, 1 with a N-ethyl unit could also react with 2
such as Me, MeO, F, Cl, Br and CF3 attached on different posi- and 3a to give 4ee and 4ff in excellent yields. On the other
tions of the phenyl ring of 1 were well compatible with the hand, 1 with a N-isopropyl group showed reduced efficiency
reaction conditions, making subsequent structural elaboration compared with its N-methyl/ethyl counterparts, presumably
of the phenyl skeleton possible. In comparison, substrates due to increased steric hindrance (4gg). Notably, an 8-acylated
bearing an ortho-substituent showed lower efficiency as tetrahydroquinoline derivative could also be easily obtained as
demonstrated in the formation of 4u, most likely due to steric shown in the formation of 4hh. This is an interesting appli-
hindrance. In addition, this reaction showed an excellent cation of this novel method as 8-acylquinoline derivatives are
regioselectivity for meta-Me or meta-F substituted anilines, valuable synthetic intermediates used in the preparation of
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7737–7747 | 7739

View Article Online
Paper
Organic & Biomolecular Chemistry
organic functional materials.15 Finally, N-methylpyridin-3- showed that the reaction could afford 5a in a yield of 67%
amine and N-methylnaphthalen-1-amine have also been tried when it was carried out at 80 °C (entry 6). Finally, we have also
as the amine substrates to react with 2 and 3a. From these varied the loadings of iron powder and NH4Cl. It turned out
reactions, the formation of the expected acylation products, N- that the optimum loadings are 4 equiv. for iron powder and 3
(4-benzoyl pyridin-3-yl)-N-methylnitrous amide (4ii) and N-(2- equiv. for NH4Cl (entries 8–11 vs. entry 6).
benzoyl naphthalen-1-yl)-N-methylnitrous amide (4jj), was not
With the optimum reaction conditions in hand, the gener-
observed.
ality of this convenient all-in-one-pot synthesis of 5 was
Thus far, we have established
a novel synthesis of studied. Thus, various anilines 1 and α-oxocarboxylic acids 3
N-nitroso-2-aminobenzophenones 4 via the cascade reactions were reacted with 2, respectively. It was concluded that
of anilines 1, tert-butyl nitrite 2 and α-oxocarboxylic acids 3 diversely substituted 1 and 3 could participate in this one-pot
with the elimination of the pre-nitrosation of aniline sub- multi-step cascade reaction smoothly to afford 2-aminobenzo-
strates under strong acidic conditions and the use of a strong phenones 5a–5r in reasonably good yields as shown in Table 5.
oxidant in the decarboxylative acylation process as encoun- It is also worth noting herein that a wide range of functional
tered in preceding procedures. As a further aspect, we contin- groups tolerated the reaction conditions very well, indicating
ued our study to explore the possibility of developing an all-in- that this is not only a convenient approach but also a general
one-pot synthesis of 2-aminobenzophenones 5 directly from 1, synthetic approach toward 2-aminobenzophenones from
2 and 3 by searching for a compatible reducing system to simple starting materials.
remove the NO unit left behind in the in situ generated 4
As a preliminary investigation into the reaction mechanism
without isolation and purification of the involved intermedi- for the formation of 4, we performed several control reactions.
ates. We believed that the successful establishment of this
envisioned synthesis would lead to a significant reduction of
the time and labor cost in the previously reported preparation
Table 5 Substrate scope for the preparation of 5a,b
of 2-aminobenzophenone derivatives. For this purpose, the
resulting mixture from the reaction of 1a with 2 and 3a was
treated with zinc powder at 60 °C for 10 h. Unfortunately, the
formation of the desired (2-(methylamino)phenyl)(phenyl)
methanone (5a) was not observed (Table 4, entry 1). With the
replacement of zinc with iron, a similar result was observed
(entry 2). Next, a combination of zinc powder with NH4Cl was
used as the reducing system. Under this circumstance, 5a was
obtained in a yield of 32% (entry 3). When a combination of
iron with NH4Cl was used, to our pleasure, the yield of 5a
increased to 62% (entry 4). Next, NH4Cl was replaced with
HOAc as the additive to give 5a in a lower yield of 51%
(entry 5). Further screening on the effect of temperature
Table 4 Optimization study for the synthesis of 5aa
Entry
Reductant (equiv.)
Additive (equiv.)
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
Zn (4)
Fe (4)
Zn (4)
Fe (4)
Fe (4)
Fe (4)
Fe (4)
Fe (3)
Fe (5)
Fe (4)
Fe (4)
60
60
60
60
60
80
100
80
80
80
80
0
0
NH4Cl (3)
NH4Cl (3)
HOAc (3)
NH4Cl (3)
NH4Cl (3)
NH4Cl (3)
NH4Cl (3)
NH4Cl (2)
NH4Cl (4)
32
62
51
67
66
60
65
62
66
9
10
11
a Reaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), 3a (1 mmol), a Reaction conditions: 1 (0.5 mmol), 2 (1.5 mmol), 3 (1 mmol),
Pd(OAc)2 (0.025 mmol), 2 mL of DCE, 40 °C, 20 h; then reductant, Pd(OAc)2 (0.025 mmol), 2 mL of DCE, 40 °C, 20 h; then iron powder
additive, 10 h. b Isolated yield.
(2 mmol), NH4Cl (1.5 mmol), 80 °C, 10 h. b Isolated yield.
7740 | Org. Biomol. Chem., 2018, 16, 7737–7747
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 5 Synthesis of an acridinone derivative 6 from 5c.
Scheme 2 Control experiment (I).
First, 1a was treated with 2 in DCE at 40 °C for 10 min. From
this reaction, N-methyl-N-phenylnitrous amide (A) was
obtained in a yield of 94% (Scheme 2, eqn (1)). Next, A was
treated with 3a in the presence of Pd(OAc)2 and tert-butyl
nitrite in DCE at 40 °C for 20 h to afford 4a in a yield of 92%
(Scheme 2, eqn (2)). These results tell that A should be a key
intermediate in the formation of 4a from the reaction of 1a
with 2 and 3a.
Scheme 6 Gram-scale synthesis of 4a and 5a.
reacts with 3a to afford intermediate C. The following oxidative
decarboxylation of complex C affords intermediate D. Next, a
reductive elimination occurs with D to provide 4a and release
the Pd(0) species, which is then oxidized by 2 to regenerate the
active Pd(II) catalyst for the next catalytic cycle.
Furthermore, it is well known that acridinone derivatives
are highly valuable in synthetic and medicinal chemistry.16 To
demonstrate the usability of the 2-aminobenzophenone
Second, a mixture of A and 3a was treated with Pd(OAc)2 in
DCE at 40 °C for 20 h in the absence of tert-butyl nitrite. From
this reaction, only
a trace amount of 4a was formed
(Scheme 3). This result demonstrates that the presence of tert-
butyl nitrite as an oxidant is crucial for the Pd(II)-catalyzed
C(sp2)–H acylation.
t
product obtained above, 5c was treated with BuOK in DMSO
at room temperature for 5 min. From this reaction, the corres-
ponding acridinone derivative 6 was obtained in a yield of
95%. In addition, the preparation of 6 has also been tried
through Cu(I)-catalyzed coupling. It turned out that treatment
of 5c with CuI and K2CO3 in DMF afforded 6 in a yield of 85%
(shown in Scheme 5).
Finally, to test whether these newly developed synthetic pro-
tocols are suitable for large-scale synthetic missions, the prep-
arations of 4a and 5a were carried out in an enlarged scale of
5 mmol. It turned out that under the optimum reaction con-
ditions described above, the corresponding cascade reactions
of 1a with 2 and 3a proceeded smoothly to afford 4a and 5a in
yields of 85% and 65%, respectively (Scheme 6).
Based on the above observations and literature reports,12
a
plausible mechanism to account for the formation of 4a is pro-
posed in Scheme 4. Firstly, the homolysis of tert-butyl nitrite
(2) under the reaction conditions gives a tert-butoxyl radical
and a NO radical, which then react with 1a to give intermedi-
ate A. Next, the in situ generated A undergoes an ortho-pallada-
tion with Pd(OAc)2 under the assistance of the NO moiety to
provide a five-membered palladacycle B. Subsequently, B
Conclusions
Scheme 3 Control experiment (II).
In summary, an efficient and regioselective synthesis of
N-nitroso-2-aminobenzophenones through the one-pot three-
component cascade reactions of anilines with tert-butyl nitrite
and α-oxocarboxylic acids under the catalysis of Pd(OAc)2 has
been established. To our knowledge, this is the first example
in which N-nitroso-2-aminobenzophenones were synthesized
directly from anilines and α-oxocarboxylic acids in a highly
regioselective manner by using tert-butyl nitrite as both a
nitrosation reagent and an oxidant. Moreover, direct treatment
of the resulting mixture from the acylation reactions with
Fe/NH4Cl led to a highly practical and all-in-one-pot prepa-
ration of 2-aminobenzophenones via the removal of the NO
unit that is left behind in the in situ generated N-nitroso-2-
aminobenzophenones without isolation and purification of
any involved intermediates. Compared with literature
Scheme 4 Plausible catalytic cycle accounting for the formation of 4a.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7737–7747 | 7741

View Article Online
Paper
Organic & Biomolecular Chemistry
methods, these novel protocols have notable features such as
simple starting materials, mild reaction conditions, high Yellowish oil (94 mg, 74%). H NMR (400 MHz, CDCl3) δ 2.40
N-Methyl-N-(2-(2-methylbenzoyl)phenyl)nitrous amide (4d).12c
1
efficiency and excellent regioselectivity.
(s, 3H), 3.04 (s, 3H), 6.99 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 7.6 Hz,
1H), 7.14 (d, J = 8.0 Hz, 1H), 7.22–7.28 (m, 2H), 7.43 (t, J =
7.2 Hz, 1H), 7.55–7.61 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ 20.6, 34.3, 123.3, 125.1, 128.3, 129.7, 130.9, 131.8, 131.9,
132.0, 135.7, 137.3, 139.6, 140.8, 196.8.
Experimental section
N-(2-(3-Chlorobenzoyl)phenyl)-N-methylnitrous amide (4e).12c
Yellowish oil (112 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 3.22
(s, 3H), 7.27 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H),
7.42–7.49 (m, 2H), 7.51–7.55 (m, 2H), 7.59–7.65 (m, 2H).
13C NMR (100 MHz, CDCl3) δ 34.2, 122.8, 127.7, 128.0, 129.4,
129.9, 130.2, 131.9, 133.3, 133.5, 134.8, 138.6, 140.6, 193.7.
N-Methyl-N-(2-(3-methylbenzoyl)phenyl)nitrous amide (4f).12c
Yellowish oil (113 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 2.36
(s, 3H), 3.25 (s, 3H), 7.28 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 7.6 Hz,
1H), 7.44–7.49 (m, 2H), 7.52–7.56 (m, 2H), 7.62 (dd, J1 = 8.0
Hz, J2 = 1.6 Hz, 1H), 7.68 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 21.2, 34.6, 123.3, 127.0, 128.0, 128.3,
130.0, 130.2, 131.5, 134.3, 134.4, 136.9, 138.4, 140.7, 195.3.
N-(2-(4-Fluorobenzoyl)phenyl)-N-methylnitrous amide (4g).12c
Yellowish oil (116 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 3.19
(s, 3H), 7.28 (dd, J1 = 6.8 Hz, J2 = 1.6 Hz, 2H), 7.35 (d, J =
All commercial reagents and solvents were used without
further purification. Melting points were recorded with a
micro-melting point apparatus and uncorrected. The H NMR
1
spectra were recorded at 400 MHz or 600 MHz, and the 13C
NMR spectra were recorded at 100 MHz or 150 MHz. Chemical
shifts were expressed in parts per million (δ), and were
reported as s (singlet), d (doublet), t (triplet), m (multiplet),
etc. The coupling constants J were given in Hz. High resolution
mass spectra (HRMS) were obtained via ESI mode by using a
MicrOTOF mass spectrometer. All the reactions were moni-
tored by thin-layer chromatography (TLC) using silica gel
plates (silica gel 60 F254 0.25 mm), and the components were
visualized by observation under UV light (254 and 365 nm).
A typical procedure for the synthesis of 4a and the
spectroscopic data of 4a–4hh
To a reaction tube equipped with a stir bar were sequentially 8.0 Hz, 1H), 7.43–7.46 (m, 1H), 7.51 (dd, J1 = 7.6 Hz, J2
=
added N-methylaniline (1a, 0.5 mmol), tert-butyl nitrite (2, 1.2 Hz, 1H), 7.55–7.62 (m, 3H). 13C NMR (150 MHz, CDCl3)
2
1.5 mmol), DCE (2 mL), Pd(OAc)2 (0.025 mmol) and 2-oxo-2- δ 34.4, 115.8 (d, JC–F = 21.9 Hz), 123.1, 128.0, 130.0, 131.7,
3
4
phenylacetic acid (3a, 1 mmol) with stirring. The solution was 132.3 (d, JC–F = 8.9 Hz), 133.3 (d, JC–F = 3.3 Hz), 134.0, 140.5,
stirred at 40 °C for 20 h. Upon completion of the reaction, the 165.9 (d, 1JC–F = 254.9 Hz), 193.6.
reaction mixture was diluted with brine (5 mL) and extracted
N-(2-(4-Chlorobenzoyl)phenyl)-N-methylnitrous amide (4h).12c
with EtOAc (8 mL × 3). The combined organic layers were Yellowish oil (112 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 3.19
dried over anhydrous Na2SO4 and concentrated under vacuum. (s, 3H), 7.27–7.29 (m, 2H), 7.34–7.36 (m, 1H), 7.43–7.46 (m,
The residue was purified by column chromatography on silica 1H), 7.51 (dd, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.55–7.62 (m, 3H).
gel and eluted with ethyl acetate/petroleum ether (10 : 1) to 13C NMR (100 MHz, CDCl3) δ 34.2, 122.9, 128.0, 128.9, 130.1,
give 4a in a yield of 88%. 4b–4hh were obtained in a similar 130.9, 131.8, 133.7, 135.3, 139.8, 140.5, 193.9.
manner.
N-(2-(4-Bromobenzoyl)phenyl)-N-methylnitrous amide (4i).12c
N-(2-Benzoylphenyl)-N-methylnitrous amide (4a).12c Yellowish Yellowish oil (124 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 3.29
1
oil (105 mg, 88%). H NMR (600 MHz, CDCl3) δ 3.24 (s, 3H), (s, 3H), 7.44 (d, J = 8.0 Hz, 1H), 7.53–7.62 (m, 6H), 7.70 (dd,
7.40 (t, J = 7.8 Hz, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.53 (t, J = J1 = 8.0 Hz, J2 = 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 34.3,
7.2 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.66–7.71 (m, 3H). 122.9, 128.0, 128.6, 130.1, 131.0, 131.8, 131.9, 133.7, 135.7,
13C NMR (150 MHz, CDCl3) δ 34.6, 123.2, 128.1, 128.5, 129.6, 140.5, 194.1.
130.3, 131.6, 133.5, 134.2, 136.9, 140.6, 195.2.
N-Methyl-N-(2-(4-methylbenzoyl)phenyl)nitrous amide (4j).12c
N-(2-(2-Fluorobenzoyl)phenyl)-N-methylnitrous amide (4b).12c Yellowish oil (100 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 2.31
Yellowish oil (110 mg, 85%). 1H NMR (600 MHz, CDCl3) δ 3.27 (s, 3H), 3.17 (s, 3H), 7.12 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz,
(s, 3H), 7.02–7.06 (m, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.40 (d, J = 1H), 7.43–7.47 (m, 1H), 7.52–7.60 (m, 4H). 13C NMR (100 MHz,
7.8 Hz, 1H), 7.49–7.52 (m, 1H), 7.55 (t, J = 7.2 Hz, 1H), CDCl3) δ 21.7, 34.6, 123.4, 128.1, 129.2, 129.8, 130.1, 131.4,
7.68–7.72 (m, 3H). 13C NMR (150 MHz, CDCl3) δ 34.3, 116.3 134.3, 134.5, 140.6, 144.4, 194.9.
2
4
(d, JC–F = 21.9 Hz), 122.9, 124.6 (d, JC–F = 3.3 Hz), 126.2 (d,
N-Methyl-N-(2-(4-(trifluoromethyl)benzoyl)phenyl)nitrous
amide (4k).12c Yellowish oil (117 mg, 76%). 1H NMR (400 MHz,
CDCl3) δ 3.20 (s, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.47 (t, J =
2JC–F = 11.0 Hz), 128.2, 130.1, 131.5, 132.1, 134.6 (d, JC–F
=
3
8.7 Hz), 135.4, 140.5, 160.8 (d, 1JC–F = 254.9 Hz), 191.5.
N-(2-(2-Bromobenzoyl)phenyl)-N-methylnitrous amide (4c).12c 7.6 Hz, 1H), 7.52–7.54 (m, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.63
Yellowish oil (118 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 3.23 (td, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H).
1
(s, 3H), 7.29–7.36 (m, 2H), 7.39–7.43 (m, 2H), 7.54 (td, J1
7.6 Hz, J2 = 1.2 Hz, 1H), 7.57–7.60 (m, 1H), 7.68–7.73 (m, 2H). 271.3 Hz), 125.5 (q, JC–F = 3.7 Hz), 128.0, 129.7, 130.2, 132.1,
13C NMR (100 MHz, CDCl3) δ 34.8, 120.4, 124.4, 127.4, 133.3, 134.4 (q, 2JC–F = 32.7 Hz), 139.9, 140.6, 193.9.
128.7, 131.3, 131.8, 132.5, 133.0, 133.87, 133.90, 139.3, 141.2,
194.3.
=
13C NMR (100 MHz, CDCl3) δ 34.0, 122.6, 123.5 (q, JC–F
=
3
N-(2-(4-Methoxybenzoyl)phenyl)-N-methylnitrous amide (4l).12c
Yellowish oil (121 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 3.18
7742 | Org. Biomol. Chem., 2018, 16, 7737–7747
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
(s, 3H), 3.77 (s, 3H), 6.79–6.82 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), J1 = 4.2 Hz, J2 = 1.2 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.46 (td,
7.45 (t, J = 7.2 Hz, 1H), 7.51 (dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.58–7.63 (m, 3H). 13C NMR
7.57 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.62–7.65 (m, 2H). 13C (100 MHz, CDCl3) δ 34.9, 124.0, 128.1, 128.2, 129.8, 131.6,
NMR (100 MHz, CDCl3) δ 34.8, 55.5, 113.8, 123.6, 128.1, 129.6, 134.3, 135.2, 135.3, 140.4, 143.7, 187.1.
130.0, 131.2, 132.2, 134.8, 140.5, 163.9, 193.9.
N-(2-Acetylphenyl)-N-methylnitrous amide (4t).12a Brown oil
1
N-(2-(3,4-Dimethoxybenzoyl)phenyl)-N-methylnitrous amide (29 mg, 33%). H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H), 3.44
(4m).12a Yellowish oil (124 mg, 83%). 1H NMR (400 MHz, (s, 3H), 7.37 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.52 (td, J1
=
CDCl3) δ 3.20 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 6.71 (d, J = 7.6 Hz, J2 = 0.8 Hz, 1H), 7.64 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.73
8.4 Hz, 1H), 7.13 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.37–7.39 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
(m, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.51 (dd, J1 = 7.2 Hz, J2
=
δ 27.9, 29.3, 111.2, 113.8, 117.6, 132.7, 135.1, 152.0, 200.8.
1.2 Hz, 1H), 7.56–7.60 (m, 1H). 13C NMR (100 MHz, CDCl3)
N-(2-Benzoyl-6-methylphenyl)-N-methylnitrous amide (4u).12c
1
δ 34.8, 56.0, 56.1, 109.9, 111.1, 123.7, 125.5, 128.0, 129.7, Yellowish oil (86 mg, 68%). H NMR (400 MHz, CDCl3) δ 2.29
130.0, 131.2, 134.7, 140.5, 149.2, 153.8, 193.9.
(s, 3H), 3.27 (s, 3H), 7.28–7.45 (m, 3H), 7.49 (t, J = 8.0 Hz, 1H),
N-(2-(Benzo[d][1,3]dioxole-5-carbonyl)phenyl)-N-methylnitrous 7.54–7.59 (m, 2H), 7.76 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz,
1
amide (4n). Yellowish oil (107 mg, 75%). H NMR (600 MHz, CDCl3) δ 17.9, 36.6, 127.4, 128.4, 128.9, 130.2, 133.60, 133.62,
CDCl3) δ 3.28 (s, 3H), 6.03 (s, 2H), 6.76 (d, J = 8.4 Hz, 1H), 7.23 136.0, 136.9, 137.9, 139.5, 195.8.
(dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.43
(dd, J1 = 7.8 Hz, J2 = 0.6 Hz, 1H), 7.51 (td, J1 = 7.8 Hz, J2
N-(2-Benzoyl-5-fluorophenyl)-N-methylnitrous amide (4v).12a
Yellow oil (110 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 3.23 (s,
=
0.6 Hz, 1H), 7.57 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.64 (td, J1 = 3H), 7.18 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.25 (td, J1 = 8.0 Hz,
7.8 Hz, J2 = 1.2 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 34.7, J2 = 2.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H),
102.0, 107.8, 109.0, 123.5, 126.9, 128.0, 129.9, 131.3, 131.5, 7.64–7.71 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 34.1, 110.4 (d,
2
134.6, 140.5, 148.3, 152.3, 193.4. HRMS calcd for 2JC–F = 24.0 Hz), 114.9 (d, JC–F = 21.1 Hz), 128.6, 129.5, 130.1
4
3
C15H12N2O4Na: 307.0689 [M + Na]+, found: 307.0701.
(d, JC–F = 3.7 Hz), 132.4 (d, JC–F = 9.4 Hz), 133.5, 136.9, 142.5
N-Methyl-N-(2-(2,4,6-trimethylbenzoyl)phenyl)nitrous amide (d, 3JC–F = 10.2 Hz), 163.9 (d, 1JC–F = 251.7 Hz), 194.1.
(4o).12c Yellowish oil (93 mg, 66%). 1H NMR (600 MHz, CDCl3) N-(2-Benzoyl-5-methylphenyl)-N-methylnitrous amide (4w).12c
δ 2.01 (s, 6H), 2.22 (s, 3H), 3.25 (s, 3H), 6.78 (s, 2H), 7.33 (dd, Yellowish oil (100 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 2.52
J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 7.42 (td, J1 = 7.8 Hz, J2 = 1.2 Hz, (s, 3H), 3.23 (s, 3H), 7.24 (s, 1H), 7.33–7.41 (m, 3H), 7.51–7.55
1H), 7.56 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.60 (td, J1 = 7.8 Hz, (m, 2H), 7.69–7.71 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 21.5,
J2 = 1.2 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 20.0, 21.2, 35.7, 34.7, 124.0, 128.5, 128.8, 129.6, 130.4, 131.5, 133.3, 137.2,
127.0, 129.0, 129.4, 132.1, 133.4, 135.0, 135.4, 136.3, 139.5, 140.8, 142.5, 195.3.
141.1, 198.6.
N-(2-Benzoyl-4-fluorophenyl)-N-methylnitrous amide (4x).12c
N-(2-(1-Naphthoyl)phenyl)-N-methylnitrous amide (4p).12a Yellowish oil (101 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 3.23
Yellowish oil (123 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 3.13 (s, 3H), 7.33–7.46 (m, 5H), 7.58 (t, J = 7.2 Hz, 1H), 7.72 (d, J =
(s, 3H), 7.34–7.38 (m, 1H), 7.41 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 34.8, 117.2 (d,
2
3
1H), 7.52–7.62 (m, 4H), 7.67–7.74 (m, 2H), 7.88 (dd, J1
7.6 Hz, J2 = 1.2 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.58 (d, J = 8.0 Hz), 128.7, 129.6, 133.8, 136.2, 136.3 (d, JC–F = 6.5 Hz),
8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 34.6, 123.8, 124.0, 136.9 (d, 4JC–F = 3.7 Hz), 161.5 (d, 1JC–F = 249.4 Hz), 193.7.
=
2JC–F = 24.0 Hz), 118.5 (d, JC–F = 22.6 Hz), 125.5 (d, JC–F
=
3
125.8, 126.7, 128.2, 128.3, 128.5, 130.3, 130.9, 131.1, 132.1,
133.5, 133.8, 134.9, 136.2, 141.1, 196.5.
N-(2-Benzoyl-4-chlorophenyl)-N-methylnitrous amide (4y).12c
Yellowish oil (112 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 3.15
N-(2-(2-Naphthoyl)phenyl)-N-methylnitrous amide (4q).12a (s, 3H), 7.30–7.36 (m, 3H), 7.47–7.53 (m, 2H), 7.57 (dd, J1
=
Yellowish oil (128 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 3.27 8.4 Hz, J2 = 2.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H). 13C NMR
(s, 3H), 7.48–7.62 (m, 4H), 7.69–7.74 (m, 2H), 7.84–7.88 (m, (150 MHz, CDCl3) δ 34.4, 124.3, 128.7, 129.6, 130.1, 131.5,
4H), 8.17 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 34.5, 123.3, 133.8, 134.0, 135.4, 136.3, 139.1, 193.7.
124.7, 126.9, 127.9, 128.1, 128.6, 128.8, 129.6, 130.3, 131.6,
132.0, 132.3, 134.2, 134.4, 135.7, 140.8, 195.1.
N-(2-Benzoyl-4-bromophenyl)-N-methylnitrous amide (4z).12c
Yellowish oil (119 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 3.21
N-(2-(Furan-2-carbonyl)phenyl)-N-methylnitrous amide (4r).12c (s, 3H), 7.31 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 8.0 Hz, 2H), 7.56 (t,
1
Yellowish oil (79 mg, 69%). H NMR (600 MHz, CDCl3) δ 3.30 J = 7.6 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.74 (d, J = 2.0 Hz, 1H),
(s, 3H), 6.45 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.02 (d, J = 7.78 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H). 13C NMR (100 MHz,
4.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.46 (dd, J1 = 7.2 Hz, J2 = CDCl3) δ 34.2, 121.7, 124.5, 128.7, 129.6, 133.0, 133.8, 134.5,
0.6 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.60 (td, J1 = 7.8 Hz, J2 = 135.6, 136.3, 139.6, 193.5.
1.2 Hz, 1H), 7.63 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H). 13C NMR
N-(2-Benzoyl-4-methylphenyl)-N-methylnitrous amide (4aa).12c
(100 MHz, CDCl3) δ 34.6, 112.6, 120.5, 123.6, 128.1, 130.1, Yellowish oil (108 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 2.48
131.9, 133.4, 140.6, 147.5, 152.1, 181.9. (s, 3H), 3.22 (s, 3H), 7.33 (d, J = 8.0 Hz, 1H), 7.39–7.44 (m, 3H),
N-Methyl-N-(2-(thiophene-2-carbonyl)phenyl)nitrous amide 7.48 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.72 (d, J = 7.6 Hz,
1
(4s).12c Yellowish oil (84 mg, 68%). H NMR (600 MHz, CDCl3) 2H). 13C NMR (150 MHz, CDCl3) δ 21.1, 34.7, 123.2, 128.5, 129.6,
δ 3.27 (s, 3H), 7.00 (dd, J1 = 4.8 Hz, J2 = 3.6 Hz, 1H), 7.35 (dd, 130.6, 132.2, 133.4, 134.2, 137.0, 138.3, 138.4, 195.5.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7737–7747 | 7743

View Article Online
Paper
Organic & Biomolecular Chemistry
N-(2-Benzoyl-4-(trifluoromethyl)phenyl)-N-methylnitrous amide
(1-Nitroso-1,2,3,4-tetrahydroquinolin-8-yl)(phenyl)methanone
(4bb).12c Yellowish oil (85 mg, 55%). 1H NMR (400 MHz, (4hh).12a Yellowish oil (113 mg, 85%). 1H NMR (400 MHz,
CDCl3) δ 3.26 (s, 3H), 7.40–7.44 (m, 2H), 7.55–7.59 (m, 2H), CDCl3) δ 2.06 (quint, J = 6.4 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H),
7.69–7.71 (m, 2H), 7.89 (s, 1H), 7.93 (dd, J1 = 8.4 Hz, J2
=
3.71 (t, J = 6.4 Hz, 2H), 7.34–7.44 (m, 5H), 7.49 (t, J = 7.6 Hz,
1.6 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 33.7, 122.7, 123.3 (q, 1H), 7.70–7.72 (m, 2H). 13C NMR (400 MHz, CDCl3) δ 21.3,
3
3
1JC–F = 270.2 Hz), 127.4 (q, JC–F = 3.2 Hz), 128.4 (q, JC–F
=
27.7, 43.3, 126.1, 128.37, 128.43, 129.1, 129.8, 130.5, 131.1,
2
3.3 Hz), 128.8, 129.5, 130.0 (q, JC–F = 32.9 Hz), 133.9, 134.1, 132.8, 135.0, 137.3, 194.9.
136.2, 143.2, 193.6.
N-(2-Benzoyl-4-methoxyphenyl)-N-methylnitrous amide (4cc).12c
A typical procedure for the synthesis of 5a and the
spectroscopic data of 5a–5r
Yellowish oil (111 mg, 82%). 1H NMR (600 MHz, CDCl3) δ 3.19
(s, 3H), 3.88 (s, 3H), 7.11 (d, J = 2.4 Hz, 1H), 7.17 (dd, J1
=
8.4 Hz, J2 = 2.4 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.40 (t, J = To a reaction tube equipped with a stir bar were sequentially
7.8 Hz, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 2H). added N-methylaniline (1a, 0.5 mmol), tert-butyl nitrite
13C NMR (150 MHz, CDCl3) δ 35.1, 55.9, 114.8, 117.3, 125.3, (2, 1.5 mmol), DCE (2 mL), Pd(OAc)2 (0.025 mmol) and 2-oxo-
128.5, 129.6, 133.5, 133.8, 135.8, 136.8, 159.2, 195.0.
2-phenylacetic acid (3a, 1 mmol) with stirring. The solution
N-(2-Benzoyl-3,5-dimethylphenyl)-N-methylnitrous amide (4dd). was stirred at 40 °C for 20 h. Then, iron powder (2 mmol) and
Yellow oil (102 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 2.25 (s, NH4Cl (1.5 mmol) were added to the resulting mixture. The
3H), 2.47 (s, 3H), 3.17 (s, 3H), 7.05 (s, 1H), 7.20 (s, 1H), 7.39 (t, tube was sealed and the reaction mixture was stirred at 80 °C
J = 7.6 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H). for 10 h. After being cooled to room temperature, it was
13C NMR (100 MHz, CDCl3) δ 19.8, 21.3, 34.9, 121.9, 128.7, diluted with brine (5 mL) and EtOAc (8 mL), and then filtered
129.2, 131.5, 132.0, 133.7, 137.40, 137.42, 140.0, 140.5, 196.6. and separated. The aqueous phase was extracted with EtOAc
HRMS calcd for C16H17N2O2: 269.1285 [M + H]+, found: (5 mL × 2). All the organic layers were combined, dried over
269.1283.
anhydrous Na2SO4, and concentrated under vacuum. The
N-(2-Benzoylphenyl)-N-ethylnitrous amide (4ee).12c Yellowish residue was purified by column chromatography on silica gel
oil (112 mg, 88%), a mixture of two isomers, the ratio of which and eluted with ethyl acetate/petroleum ether (30 : 1) to give 5a
being about 5 : 1. 1H NMR (400 MHz, CDCl3) δ 1.04 (t, J = in a yield of 67%. 5b–5r were obtained in a similar manner.
7.2 Hz, 3H), 1.42 (t, J = 7.2 Hz, 0.6H), 3.78 (q, J = 7.2 Hz, 2H),
(2-(Methylamino)phenyl)(phenyl)methanone (5a).9c Yellow
1
4.48 (q, J = 7.2 Hz, 0.4H), 7.06 (d, J = 8.0 Hz, 0.2H), 7.19–7.41 solid (71 mg, 67%), mp 71–72 °C. H NMR (600 MHz, CDCl3)
(m, 4H), 7.44–7.48 (m, 2.2H), 7.51–7.55 (m, 1H), 7.57–7.61 (m, δ 3.00 (d, J = 4.8 Hz, 3H), 6.57 (t, J = 7.2 Hz, 1H), 6.79 (d, J =
1H), 7.65 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 7.6 Hz, 0.4H). 8.4 Hz, 1H), 7.43–7.55 (m, 5H), 7.63 (d, J = 7.8 Hz, 2H), 8.58
13C NMR (150 MHz, CDCl3) δ 11.4, 14.2, 41.7, 49.7, 123.4, (brs, 1H). 13C NMR (100 MHz, CDCl3) δ 29.5, 111.1, 113.7,
126.9, 127.9, 128.4, 128.5, 128.6, 129.5, 129.8, 130.1, 130.3, 117.3, 128.1, 129.0, 130.7, 135.1, 135.5, 140.6, 152.8, 199.4.
131.4, 131.6, 133.4, 133.5, 134.8, 135.8, 136.1, 137.0, 137.3,
140.0, 194.5, 195.3.
(2-Fluorophenyl)(2-(methylamino)phenyl)methanone (5b).9c
1
Yellow oil (60 mg, 52%). H NMR (400 MHz, CDCl3) δ 2.92 (d,
N-(2-Benzoyl-4-methylphenyl)-N-ethylnitrous amide (4ff). J = 4.4 Hz, 3H), 6.43–6.47 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H),
Yellowish oil (120 mg, 90%), a mixture of two isomers, the 7.04–7.09 (m, 1H), 7.15 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H),
1
ratio of which being about 4.3 : 1. H NMR (400 MHz, CDCl3) 7.18–7.29 (m, 1H), 7.31–7.40 (m, 3H), 8.80 (brs, 1H). 13C NMR
2
δ 1.10 (t, J = 7.6 Hz, 3H), 1.47 (t, J = 7.2 Hz, 0.71H), 2.42 (s, (150 MHz, CDCl3) δ 29.4, 111.2, 114.0, 116.0 (d, JC–F
=
=
4
2
0.69H), 2.47 (s, 3H), 3.82 (q, J = 7.2 Hz, 2H), 4.52 (q, J = 7.2 Hz, 21.9 Hz), 117.4, 124.1 (d, JC–F = 3.3 Hz), 129.0 (d, JC–F
4
3
0.46H), 7.01 (d, J = 8.0 Hz, 0.22H), 7.32 (d, J = 8.0 Hz, 1H), 16.5 Hz), 129.6 (d, JC–F = 3.3 Hz), 131.4 (d, JC–F = 7.7 Hz),
7.38–7.47 (m, 4.68H), 7.52–7.59 (m, 1.36H), 7.72–7.74 (m, 2H), 135.4, 135.8, 152.8, 158.9 (d, 1JC–F = 247.2 Hz), 195.3.
7.79–7.81 (m, 0.47H). 13C NMR (150 MHz, CDCl3) δ 11.4, 14.2,
(2-Bromophenyl)(2-(methylamino)phenyl)methanone (5c).
1
21.0, 21.2, 41.8, 49.7, 123.6, 126.8, 128.3, 128.4, 129.8, 130.0, Yellow solid (72 mg, 50%), mp 82–83 °C. H NMR (400 MHz,
130.3, 130.5, 131.9, 132.1, 133.3, 133.4, 134.8, 137.0, 137.2, CDCl3) δ 2.91 (d, J = 4.8 Hz, 3H), 6.39 (t, J = 7.6 Hz, 1H), 6.67
138.3, 195.5. HRMS calcd for C16H16N2O2Na: 291.1104 [M + (d, J = 8.8 Hz, 1H), 7.08 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H),
Na]+, found: 291.1105.
N-(2-Benzoylphenyl)-N-isopropylnitrous
7.16–7.22 (m, 2H), 7.27–7.33 (m, 2H), 7.53 (d, J = 8.0 Hz, 1H),
amide
(4gg).12c 8.84 (brs, 1H). 13C NMR (100 MHz, CDCl3) δ 29.4, 111.3, 114.1,
Yellowish oil (96 mg, 72%), a mixture of two isomers, the ratio 116.4, 119.4, 127.1, 128.4, 130.3, 132.9, 135.6, 136.0, 142.1,
1
of which being about 5 : 4. H NMR (400 MHz, CDCl3) δ 1.17 153.1, 197.9. HRMS calcd for C14H13BrNO: 290.0175 [M + H]+,
(d, J = 6.8 Hz, 4.8H), 1.50 (t, J = 6.8 Hz, 6H), 4.56–4.63 (m, 1H), found: 290.0175.
4.75–4.82 (m, 0.8H), 7.03 (d, J = 7.6 Hz, 1H), 7.32–7.40 (m,
(3-Chlorophenyl)(2-(methylamino)phenyl)methanone (5d).
6.6H), 7.44–7.58 (m, 5.2H), 7.69–7.72 (m, 3.6H). 13C NMR Yellow oil (75 mg, 61%). H NMR (400 MHz, CDCl3) δ 3.00 (d,
(100 MHz, CDCl3) δ 19.7, 22.4, 48.9, 57.9, 126.5, 127.4, 128.1, J = 4.8 Hz, 3H), 6.57 (td, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H), 6.78–6.80
128.3, 128.4, 128.6, 129.7, 129.9, 130.28, 130.34, 130.8, 131.4, (m, 1H), 7.38–7.51 (m, 5H), 7.59 (t, J = 1.6 Hz, 1H), 8.58 (brs,
133.4, 133.5, 136.2, 136.6, 137.0, 137.1, 137.3, 138.5, 194.6, 1H). 13C NMR (150 MHz, CDCl3) δ 29.5, 111.3, 113.8, 116.7,
1
195.4.
127.0, 128.8, 129.4, 130.6, 134.2, 135.3, 135.5, 142.3, 152.9,
7744 | Org. Biomol. Chem., 2018, 16, 7737–7747
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
197.5. HRMS calcd for C14H12ClNONa: 268.0500 [M + Na]+, 128.8, 130.4, 135.7, 140.9, 146.2, 153.0, 198.8. HRMS calcd for
found: 268.0511.
C15H16NO: 226.1226 [M + H]+, found: 226.1225.
(2-(Methylamino)phenyl)(m-tolyl)methanone (5e).9c Yellow
(5-Bromo-2-(methylamino)phenyl)(phenyl)methanone (5l).9c
oil (77 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), Yellow solid (69 mg, 48%), mp 98–99 °C. H NMR (400 MHz,
1
2.86 (d, J = 5.2 Hz, 3H), 6.42–6.46 (m, 1H), 6.65 (d, J = 8.4 Hz, CDCl3) δ 2.88 (d, J = 5.2 Hz, 3H), 6.59 (d, J = 9.2 Hz, 1H),
1H), 7.21–7.24 (m, 2H), 7.26–7.32 (m, 3H), 7.39 (dd, J1
=
7.37–7.41 (m, 3H), 7.44–7.52 (m, 4H), 8.41 (brs, 1H). 13C NMR
8.0 Hz, J2 = 1.6 Hz, 1H), 8.44 (brs, 1H). 13C NMR (150 MHz, (150 MHz, CDCl3) δ 29.6, 104.9, 113.2, 118.6, 128.3, 129.0,
CDCl3) δ 21.4, 29.5, 111.1, 113.6, 117.4, 126.2, 127.9, 129.4, 131.2, 137.0, 137.6, 139.8, 151.5, 198.3.
131.4, 135.0, 135.6, 137.9, 140.7, 152.7, 199.6.
(2-(Methylamino)-5-(trifluoromethyl)phenyl)(phenyl)metha-
(4-Bromophenyl)(2-(methylamino)phenyl)methanone (5f).9c none (5m).9c Yellow oil (49 mg, 35%). 1H NMR (400 MHz,
Yellow solid (88 mg, 61%), mp 102–103 °C. 1H NMR (400 MHz, CDCl3) δ 3.01 (d, J = 5.2 Hz, 3H), 6.81 (d, J = 8.8 Hz, 1H),
CDCl3) δ 2.89 (d, J = 5.2 Hz, 3H), 6.44–6.48 (m, 1H), 6.67–6.69 7.46–7.50 (m, 2H), 7.53–7.61 (m, 4H), 7.75 (d, J = 1.6 Hz, 1H),
(m, 1H), 7.18–7.35 (m, 2H), 7.39 (dt, J1 = 8.8 Hz, J2 = 2.0 Hz, 8.83 (brs, 1H). 13C NMR (150 MHz, CDCl3) δ 29.5, 111.4, 115.5
2
1
2H), 7.51 (dt, J1 = 8.8 Hz, J2 = 2.0 Hz, 2H), 8.43 (brs, 1H). 13C (q, JC–F = 32.9 Hz), 116.2, 124.5 (q, JC–F = 269.1 Hz), 128.4,
3
3
NMR (150 MHz, CDCl3) δ 29.5, 111.3, 113.8, 116.8, 125.3, 129.0, 131.2 (q, JC–F = 3.3 Hz), 131.4, 132.7 (q, JC–F = 4.4 Hz),
130.6, 131.3, 135.2, 135.3, 139.4, 152.8, 198.0.
139.6, 154.3, 198.8.
(2-(Methylamino)phenyl)(4-(trifluoromethyl)phenyl)metha-
(5-Ethyl-2-(methylamino)phenyl)(phenyl)methanone (5n).
1
1
none (5g).9c Yellow solid (77 mg, 55%), mp 74–76 °C. H NMR Yellow oil (63 mg, 53%). H NMR (400 MHz, CDCl3) δ 1.05 (t,
(400 MHz, CDCl3) δ 2.90 (d, J = 5.2 Hz, 3H), 6.42–6.47 (m, 1H), J = 7.6 Hz, 3H), 2.40 (q, J = 7.6 Hz, 2H), 2.89 (d, J = 5.2 Hz, 3H),
6.69 (d, J = 8.4 Hz, 1H), 7.29 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 6.65 (dd, J1 = 7.2 Hz, J2 = 1.6 Hz, 1H), 7.19–7.22 (m, 2H),
7.32–7.36 (m, 1H), 7.57–7.64 (m, 4H), 8.57 (brs, 1H). 13C NMR 7.36–7.40 (m, 2H), 7.42–7.46 (m, 1H), 7.52–7.54 (m, 2H),
1
(100 MHz, CDCl3) δ 29.4, 111.4, 113.9, 116.5, 123.9 (q, JC–F
=
=
8.28–8.29 (m, 1H).13C NMR (150 MHz, CDCl3) δ 15.9, 27.7,
29.6, 111.3, 117.1, 128.0, 129.0, 129.2, 130.6, 134.0,
135.1, 140.7, 151.1, 199.2. HRMS calcd for C16H18NO: 240.1383
3
2
270.8 Hz), 125.1 (q, JC–F = 3.6 Hz), 129.0, 132.2 (q, JC–F
32.5 Hz), 135.3, 135.7, 143.9, 153.0, 197.8.
(4-Methoxyphenyl)(2-(methylamino)phenyl)methanone (5h).9c [M + H]+, found: 240.1383.
1
Yellow solid (73 mg, 61%), mp 97–98 °C. H NMR (400 MHz,
(2-(Ethylamino)phenyl)(phenyl)methanone (5o).9c Yellow oil
1
CDCl3) δ 2.85 (d, J = 5.2 Hz, 3H), 3.78 (s, 3H), 6.45–6.49 (m, (76 mg, 68%). H NMR (400 MHz, CDCl3) δ 1.27 (t, J = 7.2 Hz,
1H), 6.66 (d, J = 8.4 Hz, 1H), 6.85 (dt, J1 = 8.8 Hz, J2 = 2.8 Hz, 3H), 3.18–3.25 (m, 2H), 6.43 (td, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H),
2H), 7.28–7.32 (m, 1H), 7.41 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 7.27–7.31 (m, 1H), 7.33–7.43 (m, 4H),
7.55 (dt, J1 = 8.8 Hz, J2 = 2.8 Hz, 2H), 8.12–8.13 (m, 1H). 7.50–7.52 (m, 2H), 8.44 (brs, 1H). 13C NMR (100 MHz, CDCl3)
13C NMR (150 MHz, CDCl3) δ 29.5, 55.4, 111.0, 113.3, 113.6, δ 14.5, 37.4, 111.5, 113.5, 117.0, 128.1, 129.0, 130.7, 135.0,
117.9, 131.6, 132.9, 134.6, 135.0, 152.3, 162.1, 198.2.
135.6, 140.7, 151.9, 199.3.
(2-(Ethylamino)-4-methylphenyl)(phenyl)methanone (5p).
(2-(Methylamino)phenyl)(naphthalen-2-yl)methanone (5i).17
Yellow solid (81 mg, 62%), mp 103–104 °C. 1H NMR (400 MHz, Yellow oil (76 mg, 64%). H NMR (400 MHz, CDCl3) δ 1.19 (t,
1
CDCl3) δ 2.87 (d, J = 5.2 Hz, 3H), 6.42–6.46 (m, 1H), 6.67 (d, J = 5.2 Hz, 3H), 2.17 (s, 3H), 3.10–3.17 (m, 2H), 6.18 (dd, J1
=
J = 8.4 Hz, 1H), 7.31 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 7.40–7.47 8.4 Hz, J2 = 1.2 Hz, 1H), 6.41 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H),
(m, 3H), 7.63 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.77–7.81 7.24–7.28 (m, 2H), 7.30–7.34 (m, 1H), 7.40–7.43 (m, 2H), 8.45 (brs,
(m, 3H), 7.97 (s, 1H), 8.43–8.44 (m, 1H). 13C NMR (100 MHz, 1H). 13C NMR (150 MHz, CDCl3) δ 14.5, 22.3, 37.3, 111.6, 114.8,
CDCl3) δ 29.5, 111.2, 113.8, 117.6, 125.9, 126.7, 127.6, 127.8, 115.1, 128.0, 128.9, 130.4, 135.7, 140.9, 146.1, 152.1, 198.8. HRMS
128.0, 129.0, 129.7, 132.4, 134.4, 135.1, 135.6, 137.9, 152.8, calcd for C16H18NO: 240.1383 [M + H]+, found: 240.1382.
199.2.
(2-(Methylamino)phenyl)(thiophen-2-yl)methanone
(2-(Isopropylamino)phenyl)(phenyl)methanone (5q). Yellow
(5j). oil (66 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J =
1
Yellow oil (63 mg, 58%). H NMR (400 MHz, CDCl3) δ 2.82 (d, 6.4 Hz, 6H), 3.67–3.76 (m, 1H), 6.38–6.42 (m, 1H), 6.71 (d, J =
J = 5.2 Hz, 3H), 6.53 (t, J = 8.0 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 8.4 Hz, 1H), 7.17–7.30 (m, 1H), 7.33–7.44 (m, 4H), 7.50–7.53
7.00–7.02 (m, 1H), 7.30–7.34 (m, 1H), 7.44 (dd, J1 = 4.0 Hz, J2 = (m, 2H), 8.53 (d, J = 6.4 Hz, 1H). 13C NMR (150 MHz, CDCl3)
1.2 Hz, 1H), 7.52 (dd, J1 = 4.8 Hz, J2 = 0.8 Hz, 1H), 7.73 (dd, J1 = δ 22.8, 43.4, 112.0, 113.2, 116.9, 128.0, 129.0, 130.7, 135.0,
8.0 Hz, J2 = 1.6 Hz, 1H), 7.83 (brs, 1H). 13C NMR (100 MHz, 135.8, 140.7, 151.1, 199.3. HRMS calcd for C16H18NO: 240.1383
CDCl3) δ 29.6, 111.2, 114.0, 118.1, 127.5, 132.3, 133.4, 133.6, [M + H]+, found: 240.1383.
134.7, 145.1, 151.9, 189.6. HRMS calcd for
218.0634 [M + H]+, found: 218.0634.
C
12H12NOS:
Phenyl(1,2,3,4-tetrahydroquinolin-8-yl)methanone (5r). Yellow
oil (85 mg, 72%). H NMR (400 MHz, CDCl3) δ 1.84–1.90 (m,
1
(4-Methyl-2-(methylamino)phenyl)(phenyl)methanone (5k). 2H), 2.74 (t, J = 6.4 Hz, 2H), 3.38–3.41 (m, 2H), 6.27–6.31 (m,
1
Yellow oil (67 mg, 60%). H NMR (400 MHz, CDCl3) δ 2.38 (s, 1H), 6.97 (d, J = 6.8 Hz, 1H), 7.16–7.21 (m, 1H), 7.32–7.42 (m,
3H), 2.99 (d, J = 5.2 Hz, 3H), 6.39 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 3H), 7.48–7.51 (m, 2H), 8.72 (brs, 1H). 13C NMR (100 MHz,
1H), 6.59 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.44–7.48 (m, 2H), CDCl3) δ 20.6, 27.9, 41.2, 112.8, 115.8, 122.6, 128.0, 128.8,
7.49–7.54 (m, 1H), 7.59–7.62 (m, 2H), 8.66 (brs, 1H). 13C NMR 130.4, 133.5, 134.0, 141.0, 149.3, 199.2. HRMS calcd for
(100 MHz, CDCl3) δ 22.3, 29.4, 111.2, 115.1, 115.2, 128.0, C16H16NO: 238.1226 [M + H]+, found: 238.1225.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7737–7747 | 7745

View Article Online
Paper
Organic & Biomolecular Chemistry
Procedures for the synthesis of 6 and the spectroscopic data
of 6
over anhydrous Na2SO4, and concentrated under vacuum. The
residue was purified by column chromatography on silica gel
and eluted with ethyl acetate/petroleum ether (30 : 1) to give 5a
in a yield of 65%.
To
a
reaction tube equipped with
a
stir bar were
added
(2-bromophenyl)(2-(methylamino)phenyl)methanone
t
(5c, 0.5 mmol), DMSO (2 mL) and BuOK (0.5 mmol). The
mixture was stirred at room temperature. Upon completion of
the reaction as monitored by TLC, ethyl acetate (5 mL) and
water (5 mL) were added, and the layers were separated. The
aqueous layer was extracted with ethyl acetate (5 mL × 3). The
combined organic layers were washed with saturated brine,
dried over Na2SO4, and concentrated under reduced pressure.
The crude product was purified by column chromatography on
silica gel with petroleum ether/ethyl acetate (4 : 1) as the eluent
to give 6 in a yield of 95% (99 mg).
Mechanistic studies
Control experiment (I). To a reaction tube equipped with a
stir bar were sequentially added N-methylaniline (1a,
0.5 mmol), tert-butyl nitrite (2, 1 mmol) and DCE (2 mL) with
stirring. The solution was stirred at 40 °C for 10 min. It was
then concentrated under vacuum. The crude product was puri-
fied by column chromatography on silica gel and eluted with
ethyl acetate/petroleum ether (10 : 1) to give N-methyl-N-phe-
nylnitrous amide (A) in a yield of 94%.
N-Methyl-N-phenylnitrous amide (A).17 Brown oil (64 mg,
94%). 1H NMR (400 MHz, CDCl3) δ 3.45 (d, J = 0.8 Hz, 3H),
7.34–7.38 (m, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ 31.5, 119.2, 127.3, 129.5,
142.3.
To a reaction tube equipped with a stir bar were sequen-
tially added N-methyl-N-phenylnitrous amide (A, 0.5 mmol),
tert-butyl nitrite (2,
(0.025 mmol) and 2-oxo-2-phenylacetic acid (3a, 1 mmol) with
stirring. The solution was stirred at 40 °C for 20 h. Upon com-
pletion, it was diluted with brine (5 mL) and extracted with
EtOAc (8 mL × 3). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under vacuum. The crude
product was purified by column chromatography on silica gel
and eluted with ethyl acetate/petroleum ether (10 : 1) to give 4a
in a yield of 92%.
Control experiment (II). To a reaction tube equipped with a
stir bar were sequentially added N-methyl-N-phenylnitrous
amide (A, 0.5 mmol), DCE (2 mL), Pd(OAc)2 (0.025 mmol) and
2-oxo-2-phenylacetic acid (3a, 1.0 mmol) with stirring. The
solution was then stirred at 40 °C for 20 h. Subsequent treat-
ment of the resulting mixture showed that the desired
N-nitroso-2-aminobenzophenone product 4a was formed only
in a trace amount.
To
a
reaction tube equipped with
a stir bar were
added
(2-bromophenyl)(2-(methylamino)phenyl)methanone
(5c, 0.5 mmol), DMF (2 mL), CuI (0.1 mmol) and K2CO3
(0.5 mmol). The mixture was stirred at 90 °C for 10 h. Upon
completion of the reaction as monitored by TLC, ethyl acetate
(5 mL) and water (5 mL) were added, and the layers were separ-
ated. The aqueous layer was extracted with ethyl acetate
(5 mL × 3). The combined organic layers were washed with
saturated brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel with petroleum ether/ethyl
acetate (4 : 1) as the eluent to give 6 in a yield of 85% (89 mg).
10-Methylacridin-9(10H)-one (6).18 Yellowish solid, mp
1 mmol), DCE (2 mL), Pd(OAc)2
1
185–186 °C. H NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 7.29 (t,
J = 7.2 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.70–7.74 (m, 2H), 8.57
(dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 2H). 13C NMR (100 MHz, CDCl3)
δ 33.6, 114.7, 121.2, 122.5, 127.8, 133.8, 142.6, 178.1.
Gram-scale synthesis of 4a and 5a
To a reaction tube equipped with a stir bar were sequentially
added N-methylaniline (1a, 5 mmol), tert-butyl nitrite (2,
15 mmol), DCE (15 mL), Pd(OAc)2 (0.25 mmol) and 2-oxo-2-
phenylacetic acid (3a, 10 mmol) with stirring. The solution
was stirred at 40 °C for 20 h. Upon completion of the reaction,
the reaction mixture was diluted with brine (20 mL) and
extracted with EtOAc (30 mL × 3). The combined organic phase
was dried over anhydrous Na2SO4 and concentrated under
vacuum. The residue was purified by column chromatography
on silica gel and eluted with ethyl acetate/petroleum ether
(10 : 1) to give 4a in a yield of 85%.
Conflicts of interest
There are no conflicts of interest to declare.
To a reaction tube equipped with a stir bar were sequen-
tially added N-methylaniline (1a, 5 mmol), tert-butyl nitrite (2,
15 mmol), DCE (15 mL), Pd(OAc)2 (0.25 mmol) and 2-oxo-2-
Acknowledgements
phenylacetic acid (3a, 10 mmol) with stirring. The solution We are grateful to the National Natural Science Foundation of
was stirred at 40 °C for 20 h. Then, iron powder (20 mmol) China (NSFC) (Grant No. 21572047), Program for Innovative
and NH4Cl (15 mmol) were added to the resulting mixture. Research Team in Science and Technology in Universities of
The tube was sealed and the reaction mixture was stirred at Henan Province (15IRTSTHN003), Program for Science and
80 °C for 10 h. After being cooled to room temperature, it was Technology Innovation Talents in Universities of Henan
diluted with brine (30 mL) and EtOAc (50 mL), and then Province (15HASTIT005), and Plan for Scientific Innovation
filtered and separated. The aqueous phase was extracted with Talents of Henan Province (184200510012) for financial
EtOAc (50 mL × 2). The combined organic layers were dried support.
7746 | Org. Biomol. Chem., 2018, 16, 7737–7747
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
Int. Ed., 2015, 54, 8374; (c) X. Chen, X. Cui and Y. Wu, Org.
Lett., 2016, 18, 3722; (d) W. Ji, H. Tan, M. Wang, P. Li and
L. Wang, Chem. Commun., 2016, 52, 1462; (e) G. Bogonda,
Y. Kim and K. Oh, Org. Lett., 2018, 20, 2711.
Notes and references
1 (a) J.-P. Liou, C.-W. Chang, J.-S. Song, Y.-N. Yang, C.-F. Yeh,
H. Y. Tseng, Y.-K. Lo, Y.-L. Chang, C.-M. Chang and
H.-P. Hsieh, J. Med. Chem., 2002, 45, 2556; (b) P. S. Fier and 12 (a) Y. Wu, L. Sun, Y. Chen, Q. Zhou, J.-W. Huang, H. Miao
A. M. Whittaker, Org. Lett., 2017, 19, 1454; (c) X. Zheng,
Y. Zheng, L. Peng, Y. Xiang and A. Tong, J. Phys. Chem. C,
2017, 121, 21610.
2 J. Zhang, D. Zhu, C. Yu, C. Wang and Z. Wang, Org. Lett.,
2010, 12, 2841 and references cited therein.
and H.-B. Luo, J. Org. Chem., 2016, 81, 1244; (b) J.-P. Yao
and G.-W. Wang, Tetrahedron Lett., 2016, 57, 1687;
(c) L. Zhang, Z. Wang, P. Guo, W. Sun, Y.-M. Li, M. Sun and
C. Hua, Tetrahedron Lett., 2016, 57, 2511.
13 (a) P. Chauhary, S. Gupta, N. Muniyappan, S. Sabiah and
J. Kandasamy, Green Chem., 2016, 18, 2323; (b) S. L. Yedage
and B. M. Bhanage, J. Org. Chem., 2017, 82, 5769; (c) P. Li
and X. Jia, Synthesis, 2018, 50, 711; (d) P. Sau, S. K. Santra,
A. Rakshit and B. K. Patel, J. Org. Chem., 2017, 82,
6358; (e) P. Sau, A. Rakshit, A. Modi, A. Behera and
B. K. Patel, J. Org. Chem., 2018, 83, 1056; (f) B. A. Mir,
S. J. Singh, R. Kumar and B. K. Patel, Adv. Synth. Catal.,
2018, 19, 3801; (g) T. Alaime, M. Daniel, M.-A. Hiebel,
E. Pasquinet, F. Suzenet and G. Guillaumet, Chem.
Commun., 2018, 54, 8411; (h) S. Azeez, P. Chaudhary,
P. Sureshbabu, S. Sabiah and J. Kandasamy, Org. Biomol.
Chem., 2018, 16, 6902.
14 (a) Z. Shu, Y. Zhou, Y. Zhang and J. Wang, Org. Chem.
Front., 2014, 1, 1123; (b) B. Liu, R.-J. Song, X.-H. Ouyang,
Y. Li, M. Hua and J.-H. Li, Chem. Commun., 2015, 51,
12819; (c) J. Yu and M. Li, Org. Biomol. Chem., 2015, 13,
7397; (d) M.-M. Wang, X.-S. Ning, J.-P. Qu and Y.-B. Kang,
ACS Catal., 2017, 7, 4000.
3 J. Chen, L. Ye and W. Su, Org. Biomol. Chem., 2014, 12,
8204.
4 D. Pintori and M. F. Greaney, Org. Lett., 2010, 12, 168.
5 S. Butini, E. Gabellieri, P. B. Huleatt, G. Campiani,
S. Franceschini, M. Brindisi, S. Ros, S. Coccone, I. Fiorini,
E. Novellino, G. Giorgi and S. Gemma, J. Org. Chem., 2008,
73, 8458.
6 (a) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu and Y. Zhang,
Org. Chem. Front., 2015, 2, 1107; (b) T. Gensch,
M. N. Hopkinson, F. Glorius and J. Wencel-Delord, Chem.
Soc. Rev., 2016, 45, 2900; (c) W. Rao and B. Shi, Org. Chem.
Front., 2016, 3, 1028; (d) F. Wang, S. Yu and X. Li, Chem.
Soc. Rev., 2016, 45, 6462.
7 (a) H. K. Potturi, R. K. Gurung and Y. Hou, J. Org. Chem.,
2012, 77, 626 and references cited therein; (b) J. Zhang,
J. Jiang, Y. Li and X. Wang, J. Org. Chem., 2013, 78, 11366.
8 J. Lee, L. Chen, A. H. West and G. B. Richter-Addo, Chem.
Rev., 2002, 102, 1019.
9 (a) B. Liu, Y. Fan, Y. Gao, C. Sun, C. Xu and J. Zhu, J. Am. 15 (a) I. Zumeta, T. Kluge, C. Mendicute-Fierro, C. Wagner,
Chem. Soc., 2013, 135, 468; (b) T. Gao and P. Sun, J. Org.
Chem., 2014, 79, 9888; (c) Y. Wu, L.-J. Feng, X. Lu,
F.-Y. Kwong and H.-B. Luo, Chem. Commun., 2014, 50,
L. Ibarlucea, T. Rüffer, V. San Nacianceno, D. Steinborn
and M. A. Garralda, Organometallics, 2014, 33, 788;
(b) X. Chen, X. Cui and Y. Wu, Org. Lett., 2016, 18, 2411.
15352; (d) J. Dong, Z. Wu, Z. Liu, P. Liu and P. Sun, J. Org. 16 (a) V. Hernandez-Olmos, A. Abdelrahman, A. El-Tayeb,
Chem., 2015, 80, 12588; (e) D.-D. Li, Y.-X. Cao and
G.-W. Wang, Org. Biomol. Chem., 2015, 13, 6958;
(f) Y. Liang and N. Jiao, Angew. Chem., Int. Ed., 2016, 55,
4035; (g) X. Hu, X. Chen, Y. Shao, H. Xie, Y. Deng, Z. Ke,
H. Jiang and W. Zeng, ACS Catal., 2018, 8, 1308;
(h) Q. Peng, J. Hu, J. Huo, H. Yuan, L. Xu and X. Pan, Org.
Biomol. Chem., 2018, 16, 4471.
D. Freudendahl, S. Weinhausen and C. E. Müller, J. Med.
Chem., 2012, 55, 9576; (b) M. A. Beniddir, E. Le Borgne,
B. I. Iorga, N. Loaëc, O. Lozach, L. Meijer, K. Awang and
M. Litaudon, J. Nat. Prod., 2014, 77, 1117; (c) Z. Zheng,
L. Dian, Y. Yuan, D. Zhang-Negrerie, Y. Du and K. Zhao,
J. Org. Chem., 2014, 79, 7451; (d) J. Wen, S. Tang, F. Zhang,
R. Shi and A. Lei, Org. Lett., 2017, 19, 94.
10 Y. Wei, P. Hu, M. Zhang and W. Su, Chem. Rev., 2017, 117, 17 P. Chaudhary, R. Korde, S. Gupta, P. Sureshbabu, S. Sabiah
8864 and references cited therein. and J. Kandasamy, Adv. Synth. Catal., 2018, 360, 556.
11 (a) L. Yu, P. Li and L. Wang, Chem. Commun., 2013, 49, 18 S. S. Bhojgude, T. Roy, R. G. Gonnade and A. T. Biju,
2368; (b) H. Tan, H. Li, W. Ji and L. Wang, Angew. Chem.,
Org. Lett., 2016, 18, 5424.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7737–7747 | 7747