Palladium-catalyzed decarboxylative acylation of N-nitrosoanilines with α-oxocarboxylic acids

Article abstract of DOI:10.1021/acs.joc.5b02535

A palladium-catalyzed oxidative C-H bond decarboxylative acylation of N-nitrosoanilines using α-oxocarboxylic acid as the acyl source is described. The catalyst Pd(OAc)₂ and oxidant (NH₄)₂S₂O₈ enabled ortho-acylation of N-nitrosoanilines at room temperature, affording an array of N-nitroso-2-aminobenzophenones in moderate to excellent yields.

Full text of DOI:10.1021/acs.joc.5b02535

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Note
Palladium-Catalyzed decarboxylative Acylation of
N-Nitrosoanilines with alpha-oxocarboxylic acids
Yinuo Wu, Lei Sun, Yunyun Chen, Qian Zhou, Jia-Wu Huang, Hui Miao, and Hai-Bin Luo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02535 • Publication Date (Web): 08 Jan 2016
Downloaded from http://pubs.acs.org on January 10, 2016
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The Journal of Organic Chemistry
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Palladiumꢀcatalyzed decarboxylative acylation of Nꢀ
nitrosoanilines with αꢀoxocarboxylic acids
Yinuo Wu*, Lei Sun, Yunyun Chen, Qian Zhou, JiaꢀWu Huang, Hui Miao and HaiꢀBin Luo*
School of Pharmaceutical Sciences, Sun Yatꢀsen University, Guangzhou, People’s Republic of China
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wyinuo3@mail.sysu.edu.cn, luohb77@mail.sysu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
KEYWORDS: Decarboxylative acylation, Palladium catalyzed, Nꢀnitrosoanilines
ABSTRACT. A palladiumꢀcatalyzed oxidative CꢀH bond decarboxylative acylation of Nꢀ
nitrosoanilines using αꢀoxocarboxylic acid as the acyl source is described. The catalyst Pd(OAc)2 and
oxidant (NH4)2S2O8 enabled orthoꢀacylation of Nꢀnitrosoanilines at room temperature, affording an array
of Nꢀnitrosoꢀ2ꢀaminobenzophenones in moderate to excellent yields.
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Aryl ketones are important structural motifs and resourceful intermediates for preparing natural
products and biologically active compounds.1 The traditional method for accessing aryl ketone is the
FriedelꢀCraft acylation of arenes in the presence of AlCl3, which usually give poor regioselectivity when
using substituted arenes,2 or the oxidation of secondary alcohol by oxidant, which is limited to specific
structures.3 With the growing demand for aryl ketones in the synthesis of fine chemicals and
pharmaceutical intermediates,4 developing an efficient synthetic method with easily available acylating
reagents under mild reaction conditions becomes more desirable.5
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Transitionꢀmetalꢀcatalyzed decarboxylative crossꢀcoupling reactions have emerged as a promising
tool for diaryl ketones in recent years. Goossen et al. first reported the Pdꢀcatalyzed decarboxylative
acylation for the formation of unsymmetric diaryl ketone with αꢀoxocarboxylic carboxylate salts as acyl
anion equivalents.6 Ge and coꢀworkers disclosed that the orthoꢀacylation of acetanilides could be done
by employing αꢀoxocarboxylic acid via a Pdꢀcatalyzed decarboxylative acylation pathway.7 After these
pioneer works, a variety of directing groups, such as azos,8 oximes,9 acetamides,10 and indoles,11 etc.
have been involved in the CꢀH bonds acylation with αꢀoxocarboxylic acids. In these reactions, aryl
ketones with high selectivities and tolerance of functional groups were obtained. Despite of these
achievements, the decarboxylative crossꢀcoupling reactions were still relatively unexplored. Many
efficient and useful directing groups haven’t been involved in the decarboxylative acylation yet.
The Nꢀnitroso group has been proved to be an efficient directing group for assisting CꢀH bonds
activation,12 which is also an important moiety that can be transformed to a diversity of synthetically
useful intermediates, such as amine, hydrazine, αꢀcarbanion intermediates, diazonium salts and Cꢀ
nitroso compounds (Scheme 1).13 Recently, we reported a palladiumꢀcatalyzed acylation of Nꢀ
nitrosoanilines with toluene as acylation reagent, in which the nitroso group acted as a traceless directing
group and provided a variety of Nꢀalkylꢀ2ꢀaminobenzophenones in good yields.14 Considering the
importance of Nꢀnitroso group in organic synthesis, it is necessary to develop a mild method to keep Nꢀ
nitroso group reserved during the CꢀH bonds activation for further transformation. In continuing our
former works on palladium catalyzed CꢀH activation,15ꢀ17 herein, we reported a palladium catalyzed
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decarboxylative orthoꢀacylation of Nꢀnitrosoanilines with αꢀoxocarboxylic acids, providing the Nꢀ
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nitrosoꢀ2ꢀaminobenzophenones in high yields at room temperature (Scheme 2).
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Scheme 1. Transformation of the nitroso group.
Scheme 2. Palladium catalyzed acylation of Nꢀnitrosoanilines.
We began to investigate the practicability of using αꢀoxocarboxylic acid as the acyl source in the
coupling of Nꢀnitrosoanilines (Table 1). NꢀMethylꢀNꢀnitrosoaniline and phenylglyoxylic acid were used
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as the prototypical substrates in the model reaction. As we expected, the desired product 3ab was
obtained in 73% yield in the presence of oxidant K2S2O8 (Table 1, Entry 1). A screening of oxidants
showed that (NH4)2S2O8 gave the best results while Ag2CO3, BQ (1,4ꢀBenzoquinone) and Cu(OAc)2
were found to be inferior (Entries 1ꢀ5). Commonly used organic solvents were screened. Diglyme gave
higher yield while other solvents such as DCE, DMF, dioxane, and THF afforded lower yields (Entries
6ꢀ9). Lowering the reaction temperature to room temperature gave the desired product in 96% yield
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o
while raising the temperature to 120 C only gave 76% yield (Entry 10 and 11). These results were
possibly due to the minimization of reagent decomposition. Decreasing the stoichiometry of oxidant has
no negative effect on the yields (Entry 11 and 12). Further studies showed that the catalyst Pd(OAc)2
gave better result than Pd(TFA)2, PdCl2 and Pd(MeCN)2Cl2 (Entries 12ꢀ15). We also tested the influence
of catalyst loading and found that the reaction proceeded smoothly at room temperature in the presence
of 2 mol% Pd(OAc)2 with an extended reaction time (Entry 16).
Table 1: Initial optimization of reaction conditionsa
Entry
Metal
Oxidant
(equiv.)
Temp
(oC)
80
Solvent
Yield
(%)b
73
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2S2O8 (4)
DCE
DCE
(NH4)2S2O8 (4)
Ag2CO3 (4)
BQ (4)
80
81
80
DCE
13
80
DCE
Trace
Trace
90
Cu(OAc)2 (4)
(NH4)2S2O8 (4)
(NH4)2S2O8 (4)
80
DCE
80
Diglyme
Dioxane
80
65
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8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
(NH4)2S2O8 (4)
(NH4)2S2O8 (4)
(NH4)2S2O8 (4)
(NH4)2S2O8 (4)
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
80
80
120
rt
THF
84
79
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7
8
9
DMF
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16
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
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96
rt
97(93)c
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rt
83
rt
56
Pd(MeCN)2Cl2 (NH4)2S2O8 (2)
rt
79
d
Pd(OAc)2
(NH4)2S2O8 (2)
rt
92
aReaction conditions: NꢀMethylꢀNꢀnitrosoaniline 1a (1.0 mmol), Pd(OAc)2 (5 mol%), Phenylglyoxylic
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b
c
acid 2b (2 mmol), solvent (4 mL) were stirred for 18 h under air. GC yields were reported. Isolated
yield in the parentheses. d 2 mol% Pd(OAc)2 was used, 48h.
With our optimized reaction conditions in hand, we next began to explore its versatility in the
decarboxylative acylation utilizing differently substituted αꢀoxocarboxylic acids (Table 2). 1ꢀ
naphthalenyl and 2ꢀnaphthalenyl oxocarboxylic acid gave good product yields (3ac, 3ad). Electronꢀ
donating paraꢀ or metaꢀmethoxy phenylglyoxylic acid gave slightly lower yield of the product (3af, 3al,
3am). The reaction showed good tolerance towards the halogen groups. Fluoro/chloro/bromo substituted
phenylglyoxylic acids were good coupling partners and gave the desired products in high yields (3ag,
3ah, 3ak, 3an, 3aq, 3ar). Worthy of mention was that the bromo group remained intact during the
reaction (3ah, 3ak), which may offer potentially structural transformation via traditional metal catalyzed
crossꢀcoupling reactions.18 orthoꢀSubsituted substrates were also found to be favoured (3ao-3ar),
although the yield was lower compared with others. The electronꢀwithdrawing group trifluomethyl
substituted phenylglyoxylic acid gave desired products in good yields (3ai). Furthurmore, we employed
various aliphatic αꢀoxocarboxylic acids in the reaction, only the 2ꢀoxopropanoic acid could be involved
in the reaction and afforded the desired product in low yield (3as).
Table 2. Palladiumꢀcatalyzed acylation of NꢀmethylꢀNꢀnitrosoaniline with substituted αꢀoxocarboxylic
acidsa
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Me
ON
Me
N
N
O
1
2
3
4
O
N
O
H
HO
5 mol% Pd(OAc)2
R
R
+
O
(NH4)2S2O8, rt, 18 h
3ab-as
5
2b-s
1a
6
7
Me
ON
Me
ON
Me
ON
N
O
N
O
N
O
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3ab, 93%
3ac, 91%
3ad, 85%
Me
ON
Me
ON
Me
ON
N
O
N
O
N
O
Me
OMe
Cl
3ae
, 90%
3af
3ag
, 89%
, 88%
Me
ON
Me
ON
Me
ON
N
O
N
O
N
O
Me
CF3
Br
Br
3ah, 83%
3ai, 76%
3aj, 92%
Me
ON
Me
ON
Me
ON
N
O
N
O
N
O
OMe
OMe
OMe
3ak
, 85%
3al
, 86%
3am
, 83%
Me
ON
Me
ON
Me
ON
N
O
Me
N
O
Me
N
O
F
Me
Me
Me
3an
3ao
3ap
, 71%
, 92%
O
, 80%
Me
ON
Me
ON
Me
ON
N
F
N
O
Cl
N
O
3aq
, 88%
3ar
3as
, 81%
, 35%
aReaction conditions: NꢀmethylꢀNꢀnitrosoaniline 1a (1.0 mmol), Pd(OAc)2 (5 mol%), Substituted
glyoxylic acid 2b-2s (2 mmol), (NH4)2S2O8 (2 mmol), diglyme (4 mL) were stirred for 18 h under air.
Isolated yields were reported. Reaction times were not optimized for every substrate.
Various substituted Nꢀnitrosoanilines (1a-k) were also examined and the results were compiled in
Table 3. Different alkyl groups substituted Nꢀnitrosoanilines reacted well with the phenylglyoxylic acid
under the optimal conditions (3ab-3cb). A variety of function groups, including F, Br, Cl were tolerated
under these reaction conditions and no significant electronic effect was found (3gb -3jb). We tested Nꢀ
nitrosoanilines with the methyl group substituted at different position and proved that the steric
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hindrance would affect the yields greatly. For the metaꢀsubstituted substrates, the acylation only
happened on the position with the less steric hindrance. To our surprise, the orthoꢀmethylꢀNꢀ
nitrosoaniline was compatible in this catalyst system and gave moderate yield, which is not common in
the decarboxylative acylation.7ꢀ11 We also tried to apply this system in the acylation of Nꢀnitrosoꢀ1,2,3,
4ꢀtetrahydroquinoline and Nꢀnitrosoindoline. The results showed that the Nꢀnitrosoꢀ1,2,3,4ꢀ
tetrahydroquinoline allowed the acylation and gave the corresponding benzophenone in high yield (3kb)
while the 1ꢀnitrosoindoline could not be involved in the reaction (3lb).
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Table 3. Pdꢀcatalyzed orthoꢀacylation of substituted NꢀalkylꢀNꢀnitrosoanilines a
aReaction conditions: Substituted Nꢀnitrosoaniline 1a-1l (1.0 mmol), Pd(OAc)2 (5 mol%),
phenylglyoxylic acid 2b (2 mmol), (NH4)2S2O8 (2 mmol), diglyme (4 mL) were stirred for 18 h under
air. Isolated yields were reported. Reaction times were not optimized for each substrate
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The acylation of NꢀmethylꢀNꢀnitrosoꢀ4ꢀchloroaniline 3h was performed in gram scale, giving the
desired product 3hb with 82% yield (Scheme 3). Furthermore, we conducted some transformations of
the compound 3hb to access some biologically active compounds. For example, the nitroso group of
3hb could be removed to give the Nꢀmethylꢀ4ꢀchloroꢀ2ꢀaminobenzophenones, which could lead to the
top selling drug Diazepam 4 by the a sequential cyclization with ethyl glycinate.21 Besides that, both the
indoline 5 and indole 6 could be synthesized from the compound 3hb via simple procedures.22
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Scheme 3. The synthetic transformation of NꢀMethylꢀNꢀnitrosoꢀ2ꢀaminobenzophenones
Although a reaction mechanism is not clear at this stage, we suggest that this transformation began
with the orthoꢀpalladation of Nꢀnitrosoaniline 1a with Pd(OAc)2 to provide the 5ꢀmembered
palladacycle,7,12 which can be subsequently reacted with αꢀoxocarboxylic acids to afford cyclopalladated
complex (Scheme 4). Decarboxylation of cyclopalladated complex followed by reductive elimination
provides our desired product 3ab. Finally, the regenerated Pd(0) catalyst can be reoxidized to the active
Pd(II) catalyst in the presence of (NH4)2S2O8.
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Scheme 4. A proposed reaction mechanism.
In summary, we have succeeded in showing that αꢀoxocarboxylic acids could act as the acyl
sources in the oxidative coupling of Nꢀnitrosoanilines at room temperature. A wide range of Nꢀnitrosoꢀ
2ꢀaminobenzophenones were obtained in moderate to high yield. Fluoro, bromo, chloro, methoxy,
trifluoromethyl groups were compatible in this catalytic system. We believe this strategy for accessing
Nꢀnitrosoꢀ2ꢀaminobenzophenones will be useful in the synthesis of various biologically active
compounds and natural products.
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EXPERIMENTAL SECTION
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General Information. Unless otherwise noted, all reagents were purchased from commercial suppliers
and used without purification. Thin layer chromatography was performed on precoated silica gel 60 F254
plates. Silica gel (230ꢀ400 mesh) was used for column chromatography. 1H NMR spectra were recorded
on a 400 MHz spectrometer. Spectra were referenced internally to the residual proton resonance in
CDCl3 (δ 7.26 ppm), or with TMS (δ 0.00 ppm) as the internal standard. Chemical shifts (δ) were
reported as part per million (ppm) in δ scale downfield from TMS. 13C NMR spectra were recorded on a
100 MHz spectrometer and the spectra were referenced to CDCl3 (δ 77.0 ppm, the middle peak).
Coupling constants (J) were reported in Hertz (Hz). Highꢀresolution mass spectra (HRMS) were
obtained on an ITꢀTOF mass spectrometer.
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General experimental procedures and characterizations.
Palladium catalyzed acylation of N-nitrosoanilides. Substituted Nꢀnitrosoanilide (1.0 mmol) and the
Pd(OAc)2 (11.2 mg, 0.05 mmol) were loaded into a seal tube equipped with a Teflonꢀcoated magnetic
stir bar. Diglyme (4.0 mL) was added into the tube. The solution was stirred for about 1 to 2 minutes
until the solid was dissolved. Substituted phenylglyoxylic acid (2.0 mmol), (NH4)2S2O8 (2.0 mmol) were
loaded into the tube. The tube was stirred at room temperature for 18 hours. After completion of
reaction as judged by TLC, the reaction was quenched with saturated K2CO3 and diluted with EtOAc.
The organic layer was separated, washed with brine and dried over Na2SO4. The filtrate was
concentrated under reduced pressure. The crude products were purified by flash column chromatography
(EtOAc: petroleum ether; 1:5) on silica gel (230ꢀ400 mesh) to afford the desired product.
1
Nꢀ(2ꢀbenzoylphenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3ab) Yellow oil, 93 % (223 mg); H
NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.0 Hz, 2H), 7.68 – 7.64 (m, 1H), 7.62 (d, J = 6.1 Hz, 1H), 7.53
13
(t, J = 7.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.41 – 7.35 (m, 2H), 3.26 (s, 3H); C NMR (101 MHz,
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CDCl3) δ 195.2, 140.7, 136.9, 134.3, 133.4, 131.6, 130.2, 129.6, 128.5, 128.5, 128.1, 123.2, 34.5;
HRMS (ESIꢀTOF) m/z: [M + Na]+
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2
3
Calcd for C14H12N2O2Na 263.0791; Found 263.0783.
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Nꢀ(2ꢀ(2ꢀnaphthoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3ac) Yellow oil, 91 % (264 mg);
1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 7.4 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 7.9 Hz,
1H), 7.77 – 7.69 (m, 2H), 7.63 – 7.60 (m, 1H), 7.57 (dd, J = 8.0, 4.9 Hz, 3H), 7.44 (d, J = 8.0 Hz, 1H),
7.42 – 7.37 (m, 1H), 3.16 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.1, 140.7, 135.7, 134.4, 134.2,
132.3, 131.9, 131.6, 130.3, 129.5, 128.7, 128.6, 128.1, 127.8, 126.9, 124.7, 123.3, 34.5; HRMS (ESIꢀ
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TOF) m/z: [M + Na]+
Calcd for C18H14N2O2Na 313.0947; Found 313.0940.
Nꢀ(2ꢀ(1ꢀnaphthoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3ad) Yellow oil, 85 % (247 mg);
1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.1 Hz,
1H), 7.76 – 7.69 (m, 2H), 7.62 – 7.58 (m, 1H), 7.54 (d, J = 6.8 Hz, 3H), 7.42 (d, J = 8.0 Hz, 1H), 7.38
(d, J = 7.7 Hz, 1H), 3.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 196.4, 141.1, 138.7, 135.2, 133.5,
132.0, 131.1, 130.3, 128.4, 128.2, 128.1, 126.7, 125.8, 123.9, 123.8, 116.8, 99.9, 34.6; HRMS (ESIꢀ
TOF) m/z: [M + Na]+
Calcd for C18H14N2O2Na 313.0947; Found 313.0939.
NꢀmethylꢀNꢀ(2ꢀ(4ꢀmethylbenzoyl)phenyl)nitrous amide (Table 2, product 3ae) Yellow oil, 90 % (229
mg); 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.63 (m, 1H), 7.63 – 7.57 (m, 3H), 7.52 (t, J = 7.5 Hz, 1H),
7.45 – 7.41 (m, 1H), 7.19 (d, J = 7.9 Hz, 2H), 3.24 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
194.9, 144.4, 140.6, 134.5, 134.3, 131.4, 130.1, 129.8, 129.2, 128.0, 123.4, 34.6, 21.7; HRMS (ESIꢀ
TOF) m/z: [M + Na]+
Calcd for C15H14N2O2Na 277.0947; Found 277.0936.
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Nꢀ(2ꢀ(4ꢀmethoxybenzoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3af) Yellow oil, 88 % (238
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2
3
1
mg); H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.9 Hz, 2H), 7.67 – 7.61 (m, 1H), 7.60 – 7.56 (m, 1H),
4
5
6
7.51 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H), 3.25 (s, 3H); 13C
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8
NMR (101 MHz, CDCl3) δ 193.8, 163.9, 140.5, 134.8, 132.1, 131.2, 129.9, 129.6, 128.1, 123.6, 113.8,
9
55.5, 34.8; HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C15H14N2O3Na 293.0897; Found 293.0889.
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Nꢀ(2ꢀ(4ꢀchlorobenzoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3ag) Yellow oil, 89 % (245
mg); 1H NMR (400 MHz, CDCl3) δ 7.70ꢀ7.68 (m, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.61ꢀ7.58 (m, 1H), 7.53
(t, J = 7.5 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 3.27 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 193.9, 140.5, 139.9, 135.3, 133.7, 131.8, 130.9, 130.1, 128.9, 128.0, 122.9, 34.3; HRMS (ESIꢀ
TOF) m/z: [M + Na]+
Calcd for C14H11N2O2ClNa 297.0401; Found 297.0392.
Nꢀ(2ꢀ(4ꢀbromobenzoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3ah) Yellow oil, 83 % (265
1
mg); H NMR (400 MHz, CDCl3) δ 7.71 – 7.66 (m, 1H), 7.62 – 7.54 (m, 5H), 7.53 (d, J = 2.1 Hz, 1H),
7.43 (d, J = 8.0 Hz, 1H), 3.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 194.0, 140.5, 135.7, 133.7, 131.9,
131.7, 131.0, 130.1, 128.6, 128.0, 122.9, 34.3; HRMS (ESIꢀTOF) m/z: [M + Na]+
C14H11N2O2BrNa 340.9896; Found 340.9884.
Calcd for
NꢀmethylꢀNꢀ(2ꢀ(4ꢀ(trifluoromethyl)benzoyl)phenyl)nitrous amide (Table 2, product 3ai) Yellow oil,
78% (240 mg); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 2H), 7.74 – 7.68 (m, 1H), 7.66 (d, J =
8.2 Hz, 2H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.55 (td, J = 7.5, 1.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 3.28
13
(s, 3H); C NMR (101 MHz, CDCl3) δ 193.8, 140.6, 139.9, 134.3, 133.3, 132.0, 130.1, 129.7, 128.0,
125.5 (d, J = 3.7 Hz). 122.6, 119.2, 33.9; HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for
C15H11N2O2F3Na 331.0665; Found 331.0663.
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NꢀmethylꢀNꢀ(2ꢀ(3ꢀmethylbenzoyl)phenyl)nitrous amide (Table 2, product 3aj) Yellow oil, 92% (234
mg); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 8.5
Hz, 2H), 7.45 (dd, J = 14.5, 7.7 Hz, 2H), 7.35 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 3.24 (s, 3H),
2.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.3, 140.7, 138.4, 136.8, 134.4, 134.3, 131.5, 130.2,
130.0, 128.3, 128.0, 127.0, 123.3, 34.6, 21.3; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C15H14N2O2Na 277.0947; Found 277.0940.
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Nꢀ(2ꢀ(3ꢀbromobenzoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3ak) Yellow oil, 85% (270
1
mg); H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.71 (dd, J = 7.7, 1.4 Hz, 1H), 7.68 – 7.66 (m, 1H),
7.64 (d, J = 1.0 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.45 – 7.42 (m, 1H), 7.31 – 7.25
13
(m, 1H), 3.29 (s, 3H); C NMR (101 MHz, CDCl3) δ 193.5, 140.6, 138.8, 136.1, 133.4, 132.2, 131.9,
130.2, 130.1, 128.1, 128.0, 122.8, 122.7, 34.2; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C14H11N2O2BrNa 340.9896; Found 340.9886.
Nꢀ(2ꢀ(3ꢀmethoxybenzoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3al) Yellow oil, 86% (232
1
mg); H NMR (400 MHz, CDCl3) δ 7.68 – 7.63 (m, 1H), 7.61 (d, J = 6.1 Hz, 1H), 7.52 (t, J = 7.0 Hz,
1H), 7.42 (d, J = 8.1 Hz, 1H), 7.32 – 7.29 (m, 1H), 7.28 – 7.23 (m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.07
(dd, J = 8.1, 1.6 Hz, 1H), 3.80 (s, 3H), 3.25 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.9, 159.7, 140.6,
138.2, 134.3, 131.5, 130.2, 129.4, 128.0, 123.2, 122.5, 120.0, 113.5, 55.5, 34.5; HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C15H14N2O3Na 293.0897; Found 293.0892.
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Nꢀ(2ꢀ(3,4ꢀdimethoxybenzoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3am) Yellow oil, 83%
(249 mg); 1H NMR (400 MHz, CDCl3) δ 7.71 – 7.65 (m, 1H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.58 – 7.53
(m, 1H), 7.50 – 7.42 (m, 2H), 7.23 (dd, J = 8.4, 2.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.93 (d, J = 7.3
Hz, 6H), 3.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, 153.8, 149.2, 140.5, 134.7, 131.2, 129.9,
129.7, 128.0, 125.5, 123.7, 111.2, 109.9, 56.1, 56.0, 34.8; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C16H16N2O4Na 323.1002; Found 323.0993.
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Nꢀ(2ꢀ(3ꢀfluorobenzoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3an) Yellow oil, 80% (215
mg); 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.9, 5.4 Hz, 2H), 7.70 – 7.65 (m, 1H), 7.59 (dd, J =
7.7, 1.7 Hz, 1H), 7.54 (dd, J = 7.4, 1.1 Hz, 1H), 7.43 (dd, J = 8.0, 1.1 Hz, 1H), 7.07 (dd, J = 8.9, 8.3 Hz,
2H), 3.27 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.5, 167.1, 164.5, 140.5, 134.0, 133.3 (d, J = 3.0
Hz), 132.2, 132.1, 131.6, 130.0, 128.0, 123.1, 115.7 (d, J = 22.1 Hz). 34.3; HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd for C14H11N2O2FNa 281.0697; Found 281.0684.
Nꢀ(2ꢀ(2,4ꢀdimethylbenzoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3ao) Yellow oil, 80%
1
(215 mg); H NMR (400 MHz, CDCl3) δ 7.64 (t, J = 7.4 Hz, 2H), 7.53 – 7.49 (m, 1H), 7.36 (d, J = 7.7
Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.88 (d, J = 9.5 Hz, 1H), 3.15 (s, 3H), 2.47 (s, 3H), 2.31
13
(s, 3H); C NMR (101 MHz, CDCl3) δ 196.5, 142.5, 140.7, 139.9, 136.0, 134.4, 132.8, 131.7, 130.7,
130.5, 128.2, 125.7, 123.3, 34.5, 21.4, 20.8; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C16H16N2O2Na 291.1104; Found 291.1101.
NꢀmethylꢀNꢀ(2ꢀ(2,4,6ꢀtrimethylbenzoyl)phenyl)nitrous amide (Table 2, product 3ap) Yellow oil, 71%
(200 mg); 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.60 (m, 2H), 7.50 (td, J = 7.6, 1.3 Hz, 1H), 7.40 (dd, J
= 7.8, 1.2 Hz, 1H), 6.85 (s, 2H), 3.32 (s, 3H), 2.30 (s, 3H), 2.09 (s, 6H); 13C NMR (101 MHz, CDCl3) δ
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198.5, 141.2, 139.5, 136.3, 135.6, 135.4, 133.3, 132.1, 129.4, 128.9, 127.0, 35.6, 21.1, 20.0; HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H18N2O2Na 305.1260; Found 305.1249.
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Nꢀ(2ꢀ(2ꢀfluorobenzoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3aq) Yellow oil, 88% (227
mg); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 2H), 7.75 – 7.70 (m, 1H), 7.66 (d, J = 8.1 Hz,
2H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.55 (td, J = 7.5, 1.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 3.28 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 193.6, 167.1, 164.6, 140.5, 134.0, 132.3 (d, J = 9.5 Hz), 132.2, 131.6,
130.0, 128.0, 123.1, 115.8, 115.6, 34.3; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C14H11N2O2FNa
281.0697; Found 281.0686.
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Nꢀ(2ꢀ(2ꢀchlorobenzoyl)phenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3ar) Yellow oil, 81% (223
1
mg); H NMR (400 MHz, CDCl3) δ 7.76 – 7.68 (m, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz,
13
1H), 7.41 (d, J = 8.4 Hz, 3H), 7.34 – 7.30 (m, 1H), 3.24 (s, 3H); C NMR (101 MHz, CDCl3) δ 193.7,
141.9, 141.0, 137.4, 134.4, 132.8, 132.4, 131.3, 131.3, 130.5, 128.6, 126.8, 124.1, 34.6; HRMS (ESIꢀ
TOF) m/z: [M + Na]+ Calcd for C14H11N2O2ClNa 297.0401; Found 297.0394.
Nꢀ(2ꢀacetylphenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3as) Yellow oil, 35% (62 mg); 1H NMR
(400 MHz, CDCl3) δ 7.74 (dd, J = 7.7, 1.6 Hz, 1H), 7.67 – 7.62 (m, 1H), 7.53 (td, J = 7.6, 1.2 Hz, 1H),
7.38 (dd, J = 7.9, 1.0 Hz, 1H), 3.45 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199.7, 139.8,
135.5, 132.2, 129.2, 128.6, 124.5, 34.9, 29.4; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C9H10N2O2Na 201.0634; Found 201.0638.
Nꢀ(2ꢀbenzoylphenyl)ꢀNꢀethylnitrous amide (Table 2, product 3bb) Yellow oil, 94% (239 mg); 1H NMR
(400 MHz, CDCl3) δ 7.74 (dd, J = 8.4, 1.3 Hz, 2H), 7.71 – 7.66 (m, 1H), 7.61 (dd, J = 7.6, 1.6 Hz, 1H),
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7.57 – 7.51 (m, 2H), 7.47 (m, 1H), 7.41 (t, J = 7.7 Hz, 2H), 3.87 (q, J = 7.2 Hz, 2H), 1.13 (t, J = 7.2 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 195.2, 139.6, 136.9, 134.9, 133.3, 131.3, 130.1, 129.8, 128.4, 127.9,
123.4, 41.7, 11.4; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H14N2O2Na 277.0947; Found
277.0950.
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Nꢀ(2ꢀbenzoylphenyl)ꢀNꢀbutylnitrous amide (Table 2, product 3cb) Yellow oil, 85% (240 mg); 1H NMR
(400 MHz, CDCl3) δ 7.72 (dd, J = 8.4, 1.3 Hz, 2H), 7.65 (ddd, J = 8.0, 7.3, 1.7 Hz, 1H), 7.58 – 7.55 (m,
1H), 7.52 (dd, J = 7.4, 1.2 Hz, 2H), 7.45 (dd, J = 3.3, 0.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 3.82 – 3.73
13
(m, 2H), 1.51 – 1.43 (m, 2H), 1.26 (dd, J = 15.1, 7.5 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H); C NMR (101
MHz, CDCl3) δ 195.3, 139.9, 136.9, 134.7, 133.4, 131.3, 130.1, 129.8, 128.4, 127.8, 123.3, 46.3, 28.3,
20.4, 13.6; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H18N2O2Na 305.1260; Found 305.1252.
Nꢀ(2ꢀbenzoylꢀ4ꢀmethylphenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3db) Yellow oil, 86% (219
1
mg); H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 8.2
Hz, 1H), 7.44 – 7.36 (m, 3H), 7.31 (d, J = 8.1 Hz, 1H), 3.21 (s, 3H), 2.46 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 195.4, 138.4, 137.0, 133.7, 133.3, 132.2, 130.6, 130.2, 129.6, 128.5, 123.3, 34.7, 21.0; HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H14N2O2Na 277.0947; Found 277.0944.
Nꢀ(2ꢀbenzoylꢀ5ꢀmethylphenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3eb) Yellow oil, 75% (191
mg); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.1 Hz, 2H), 7.54 – 7.50 (m, 2H), 7.39 (d, J = 7.7 Hz,
2H), 7.36 – 7.32 (m, 1H), 7.24 (s, 1H), 3.22 (s, 3H), 2.51 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.3,
142.5, 140.8, 133.7, 133.2, 130.4, 130.1, 129.6, 129.2, 128.7, 128.4, 124.0, 34.7, 21.5; HRMS (ESIꢀ
TOF) m/z: [M + Na]+ Calcd for C15H14N2O2Na 277.0947; Found 277.0944.
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Nꢀ(2ꢀbenzoylꢀ6ꢀmethylphenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3fb) Yellow oil, 68% (173
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2
3
1
mg); H NMR (400 MHz, Chloroformꢀd) δ 7.74 (d, J = 7.2 Hz, 2H), 7.56 – 7.51 (m, 2H), 7.49 – 7.44
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7
8
9
(m, 1H), 7.44 – 7.42 (m, 1H), 7.41 – 7.38 (m, 2H), 3.25 (s, 3H), 2.27 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 195.7, 139.5, 137.9, 136.9, 136.1, 133.6, 133.5, 130.1, 128.8, 128.4, 127.3, 36.4, 17.9; HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H14N2O2Na 277.0947; Found 277.0939.
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Nꢀ(2ꢀbenzoylꢀ4ꢀbromophenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3gb) Yellow oil, 83% (265
1
mg); H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 8.5, 2.3 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.70 (m,
2H), 7.58 – 7.53 (m, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.31 (d, J = 8.5 Hz, 1H), 3.21 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 193.5, 139.6, 136.3, 135.7, 134.4, 133.7, 132.9, 129.6, 128.6, 124.5, 121.7, 34.2;
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C14H11N2O2BrNa 340.9896; Found 340.9885.
Nꢀ(2ꢀbenzoylꢀ4ꢀchlorophenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3hb) Yellow oil, 86 % (236
mg); 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.68 (m, 2H), 7.65 – 7.61 (m, 1H), 7.59 (d, J = 2.5 Hz, 1H),
13
7.58 – 7.54 (m, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.38 (d, J = 8.5 Hz, 1H), 3.21 (s, 3H); C NMR (101
MHz, CDCl3) δ 193.6, 139.1, 136.3, 135.5, 134.0, 133.7, 131.5, 130.0, 129.6, 128.6, 124.4, 34.3;
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C14H11N2O2ClNa 297.0401; Found 297.0393.
Nꢀ(2ꢀbenzoylꢀ4ꢀfluorophenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3ib) Yellow oil, 87% (225 mg);
1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 8.4, 1.3 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 2.1
Hz, 1H), 7.43 – 7.41 (m, 1H), 7.41 – 7.39 (m, 1H), 7.40 – 7.36 (m, 1H), 7.33 (dd, J = 8.3, 2.7 Hz, 1H),
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3.22 (s, 3H); C NMR (101 MHz, CDCl3) δ 193.6, 160.3, 136.3 (d, J = 18.1 Hz), 133.8, 129.6, 128.6,
125.6 (d, J = 8.7 Hz), 118.6, 118.3, 117.2, 117.0, 34.8; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C14H11N2O2FNa 281.0697; Found 281.0689.
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Nꢀ(2ꢀbenzoylꢀ5ꢀfluorophenyl)ꢀNꢀmethylnitrous amide (Table 2, product 3jb) Yellow oil, 90% (232 mg);
1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.7 Hz, 2H), 7.65 (dd, J = 8.6, 6.1 Hz, 1H), 7.54 (t, J = 7.4
Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.24 (td, J = 8.2, 2.3 Hz, 1H), 7.17 (dd, J = 9.1, 2.3 Hz, 1H), 3.21 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 194.1, 165.2, 162.6, 136.9, 133.5, 132.4 (d, J = 9.6 Hz), 130.1 (d, J
= 3.5 Hz,), 129.5, 128.6, 115.0, 114.8, 110.6, 110.3, 34.1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C14H11N2O2FNa 281.0697; Found 281.0689.
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(1ꢀnitrosoꢀ1,2,3,4ꢀtetrahydroquinolinꢀ8ꢀyl)(phenyl)methanone. (Table 2, product 3kb) Yellow oil, 81%
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(216 mg); H NMR (400 MHz, CDCl3) δ 7.75 – 7.66 (m, 2H), 7.48 (dd, J = 10.4, 4.4 Hz, 1H), 7.44 –
7.37 (m, 3H), 7.36 (d, J = 3.1 Hz, 1H), 7.36 – 7.32 (m, 1H), 3.72 (t, J = 6.5 Hz, 2H), 2.91 – 2.80 (m,
2H), 2.11 – 2.00 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 195.3, 139.9, 136.9, 134.7, 133.4, 131.3,
130.1, 129.8, 128.4, 127.8, 123.3, 46.3, 28.3, 20.4, 13.6; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C16H14N2O2Na 289.0947; Found 289.0942.
Typical Experimental Procedure for the synthesis of compound 4. A mixture of Fe powder (4 mmol),
NH4Cl (3 mmol), compound 3hb (1 mmol) were weighted in a flask. Ethanol (8 mL) were added and
the mixture was stirred at 80 °C for 6 h. After the compound 3hb was dissappeared in the TLC, glycine
ethyl ester hydrochloride (1.2 mmol) and AcOH (2 mmol) was added. The mixture was then refluxed for
3 h. After removal of the solvent, the residue was dilute NH4OH (adjust PH= 8). CH2Cl2 was added to
extract the crude product. The crude product was crystallized from ether/hexane (1:1) to obtain pure
compound 4.
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7ꢀchloroꢀ1ꢀmethylꢀ5ꢀphenylꢀ1Hꢀbenzo[e][1,4]diazepinꢀ2(3H)ꢀone (Scheme 3, compound 4) White soild,
67% (190 mg); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.7 Hz, 2H), 7.51 (dd, J = 8.8, 2.5 Hz, 1H),
7.47 (d, J = 7.3 Hz, 1H), 7.41 (dd, J = 8.2, 6.5 Hz, 2H), 7.30 (d, J = 6.2 Hz, 1H), 7.29 (s, 1H), 4.83 (d, J
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= 10.8 Hz, 1H), 3.77 (d, J = 10.8 Hz, 1H), 3.39 (s, 3H); C NMR (101 MHz, CDCl3) δ 170.0, 169.0,
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142.6, 138.2, 131.5, 130.7, 130.1, 130.0, 129.5, 129.3, 128.4, 122.5, 57.0, 34.9.
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Typical Experimental Procedure for the synthesis of compound 5: Potassium tꢀbutoxide (1.1 mmol)
was added to the solution of compound 3hb (1 mmol) in 40 ml of tetrahydorfuran. the mixture was
stirred at ꢀ10oC for 30 minutes. After that, 20 ml of glacial acetic acid was added and the reaction
mixture was then partitioned betweed ether and water. The organic phase was separated, dried over
sodium sulfate and evaporated. The residue was crystallized from ether/hexane (1:1) to give the
compound 5 (73%) as a white solid.
5ꢀchloroꢀ1ꢀnitrosoꢀ3ꢀphenylindolinꢀ3ꢀol (Scheme 3, compound 5) White soild, 73% (201 mg); 1H NMR
(400 MHz, DMSOꢀd6) δ 7.96 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 8.5, 2.1 Hz, 1H), 7.42 – 7.31 (m, 5H),
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7.15 (d, J = 2.1 Hz, 1H), 6.69 (s, 1H), 4.34 (d, J = 14.7 Hz, 1H), 4.23 (d, J = 14.7 Hz, 1H); C NMR
(101 MHz, DMSOꢀd6) δ 144.3, 140.7, 139.4, 131.4, 130.6, 128.8, 128.0, 126.0, 125.8, 113.7, 77.5, 63.4.
Typical Experimental Procedure for the synthesis of compound 6: Raney nickel (0.2 mmol) was added
to the solution of compound 3hb (1 mmol) in 10ml of tetrahydrofuran. The system was stirred at room
temperature for 1 hour until uptake of hydrogen had stopped. After removing the catalyst by filtration,
the filtrate was evaporated under reduced pressure and redissolved in 5 ml menhtanol. 2 drops of
concentrated hydrochloric acid was added. The mixture was then stirred at 100o h for 5 minutes. Water
was added to the mixture and the final product compound 6 was precipitated as a white solid (55%).
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5ꢀchloroꢀ3ꢀphenylꢀ1Hꢀindole (Scheme 3, compound 6) White soild, 55% (125 mg); 1H NMR (400 MHz,
CDCl3) δ 8.31 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.66 – 7.60 (m, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.39 (d, J
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= 2.5 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.20 (dd, J = 8.6, 2.0 Hz, 1H); C
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NMR (101 MHz, CDCl3) δ 135.0, 134.8, 128.9, 127.7, 127.5, 126.9, 126.3, 123.0, 122.8, 119.3, 118.3,
112.3.
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ACKNOWLEDGMENT.
We thank the National Natural Science Foundation of China (No. 21402243, 81522041, and
81373258), The Fundamental Research Funds for the Central Universities (Sun Yatꢀsen
University) (No. 13ykpy09), Medical Scientific Research Foundation of Guangdong Province
(No. B2014105) for financial support.
Supporting Information Available: Copies of H NMR, and 13C NMR spectra. This material is
1
available free of charge via the Internet at http://pubs.acs.org.
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