Chemoselective Nitrosylation of Anilines and Alkynes via Fragmentary or Complete NO Incorporation

Article abstract of DOI:10.1016/j.chempr.2018.03.008

The cycloaddition reactions have been explored extensively and provided an efficient strategy for the synthesis of cyclic compounds. Traditionally, the reaction partners were in extenso incorporated into the cyclic products without fragmentation. From a different perspective, if certain fragmentations via chemical-bond cleavage are involved in this cycloaddition reaction, it would change the assembly sequence and enable more product diversity. Here, we report a chemoselective nitrosylation of anilines and alkynes through fragmentary or complete NO radical incorporation. The formation of multiple C–N bonds, an unexpected C–N bond, and N=O bond cleavage make this fragmentary cycloaddition reaction an efficient approach to 2,5-dihydrooxazoles, 1H-1,2,3-triazole 2-oxides or quinoxaline N-oxides. Facile operation in open-air, metal-free, and mild conditions renders this protocol particularly practical and attractive. A series of mechanistic studies and density functional theory calculations were also conducted, which help to explain the fragmentary or complete NO incorporation processes, broadening the field of new reaction discovery. Exploring novel structures and developing convenient and direct methods to achieve them are an essential issue in synthetic chemistry. In traditional cycloaddition reactions, the reaction partners are in extenso incorporated into the cyclic compound products. In contrast, the fragmentary incorporation of the reaction partners via chemical-bond cleavage in cycloaddition reactions would change the assembly sequence and enable more product diversity. However, fragmentary incorporation in cycloaddition reactions remains a challenging issue because of the high bond-dissociation energy and poor selectivity. This paper reports a fragmentary cycloaddition reaction that enables a series of new structures through a controllable radical process. This work also reveals the diversity of transformation of free radical intermediates. The accessible products might also trigger some interest in pharmaceutical science and materials science. Cycloaddition reactions provide an efficient strategy for the synthesis of cyclic compounds and have been well developed. However, cycloaddition reactions with fragmentary partner incorporation via the cleavage of multiple bonds, which allows for more structural diversity than traditional cycloaddition reactions, have seldom been reported. Here, we describe a chemoselective nitrosylation of anilines and alkynes through fragmentary or complete NO radical incorporation for an efficient approach to 2,5-dihydrooxazoles, 1H-1,2,3-triazole 2-oxides, or quinoxaline N-oxides.

Full text of DOI:10.1016/j.chempr.2018.03.008

Article
Chemoselective Nitrosylation of Anilines and
Alkynes via Fragmentary or Complete NO
Incorporation
Jun Pan, Xinyao Li, Fengguirong
Lin, Jianzhong Liu, Ning Jiao
jiaoning@pku.edu.cn
HIGHLIGHTS
TBN (tBuONO)
Fragmentary or complete NO
radical incorporation in
cycloaddition reactions
+
O
N
R2
H
R1= Me
R2
R2
R1= H
O
+
Ar
N
H
A chemoselective nitrosylation of
anilines and alkynes
N
R1
N
R2
N
R3
R2
NO
R1= Alkyl other than Me
Formation of multiple C–N bonds
and an unexpected C–N bond, as
well as N=O bond cleavage
fragmentary incorporation
O
N
N
R2
N
R2
Cycloaddition reactions provide an efficient strategy for the synthesis of cyclic
compounds and have been well developed. However, cycloaddition reactions with
fragmentary partner incorporation via the cleavage of multiple bonds, which
allows for more structural diversity than traditional cycloaddition reactions, have
seldom been reported. Here, we describe a chemoselective nitrosylation of
anilines and alkynes through fragmentary or complete NO radical incorporation
for an efficient approach to 2,5-dihydrooxazoles, 1H-1,2,3-triazole 2-oxides, or
quinoxaline N-oxides.
Pan et al., Chem 4, 1–16
June 14, 2018 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.03.008

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ration, Chem (2018), https://doi.org/10.1016/j.chempr.2018.03.008
Article
Chemoselective Nitrosylation of Anilines
and Alkynes via Fragmentary
or Complete NO Incorporation
Jun Pan,1,3 Xinyao Li,1,3 Fengguirong Lin,1 Jianzhong Liu,1 and Ning Jiao1,2,4,
*
The Bigger Picture
SUMMARY
Exploring novel structures and
developing convenient and direct
methods to achieve them are an
essential issue in synthetic
The cycloaddition reactions have been explored extensively and provided an
efficient strategy for the synthesis of cyclic compounds. Traditionally, the
reaction partners were in extenso incorporated into the cyclic products without
fragmentation. From a different perspective, if certain fragmentations via
chemical-bond cleavage are involved in this cycloaddition reaction, it would
change the assembly sequence and enable more product diversity. Here, we
report a chemoselective nitrosylation of anilines and alkynes through fragmen-
tary or complete NO radical incorporation. The formation of multiple C–N
bonds, an unexpected C–N bond, and N=O bond cleavage make this fragmen-
tary cycloaddition reaction an efficient approach to 2,5-dihydrooxazoles, 1H-
1,2,3-triazole 2-oxides or quinoxaline N-oxides. Facile operation in open-air,
metal-free, and mild conditions renders this protocol particularly practical and
attractive. A series of mechanistic studies and density functional theory calcula-
tions were also conducted, which help to explain the fragmentary or complete
NO incorporation processes, broadening the field of new reaction discovery.
chemistry. In traditional
cycloaddition reactions, the
reaction partners are in extenso
incorporated into the cyclic
compound products. In contrast,
the fragmentary incorporation of
the reaction partners via chemical-
bond cleavage in cycloaddition
reactions would change the
assembly sequence and enable
more product diversity. However,
fragmentary incorporation in
cycloaddition reactions remains a
challenging issue because of the
high bond-dissociation energy
and poor selectivity. This paper
reports a fragmentary
INTRODUCTION
Cycloaddition reactions, including [2 + 2 + 1], [3 + 2 + 1], have been widely used in
organic synthesis.1–6 Traditionally, the reaction partners were completely incorpo-
rated into the cyclic products. Theoretically, on the other hand, they might be split
into two or more parts and then be fragmentarily incorporated in the cyclic products
(Scheme 1A). However, to the best of our knowledge, this kind of fragmentary cyclo-
addition with reaction partner incorporation via chemical bond cleavage remains un-
known. Exploring novel reactions through mechanistic design is universally used by
synthetic chemists. Enamine and imine, which can tautomerize to each other, are a
class of well-developed intermediates in organic chemistry.7–11 Although various
methodologies involving enamine and imine intermediates have been developed
in organic synthesis,12–18 single-electron oxidation of electron-rich enamine inter-
mediates to trigger radical reactions is still rare despite the high activity of the
in-situ-generated radical intermediates.19–22 Recently, reactions through C–H23–27
and C–C28–34 cleavage have been powerful strategies for direct transformation of
simple substrates. Thus, the combination of a single-electron transfer (SET) process
with the generation of very active radical intermediates and C–H/C–C functionaliza-
tion would potentially open the door to a new field of reaction discovery.
cycloaddition reaction that
enables a series of new structures
through a controllable radical
process. This work also reveals the
diversity of transformation of free
radical intermediates. The
accessible products might also
trigger some interest in
pharmaceutical science and
materials science.
We have been interested in the development of a methodology based on iminium
intermediates through a single-electron-transfer (SET) and deprotonation process
followed by the capture of O2 or N3 radicals.35–38 Recently, tert-butyl nitrite (TBN) has
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been shown to be a very useful building block as a source of N, NO, or NO2 for the con-
struction of corresponding N-containing compounds under mild conditions.39–43 Using
substituted N-ethylidene-anilines 1 as the substrates, we recently reported an efficient
approach to quinoxaline N-oxides 2 (Scheme 1B).44 The proposed reaction mechanism
starts with single-electron oxidation and deprotonation of imine substrates to generate
methyl imine radical intermediate A, which can then be trapped by NO radical to form
intermediate B, and finally C–H annulation delivers the desired product.
Inspired by this chemistry (Scheme 1B) and the methodologies with tautomerization
of enamine and imine intermediates,12–18 we envisioned that enamines 6, generated
in situ from the addition of anilines and alkynes, might be suitable candidates for
single-electron oxidation affording the radical intermediates A (Scheme 1C). In
this way, the previous two-component approach to quinoxaline N-oxides could be
extended to a three-component one, which would enhance the overall efficiency
and extend the substrate scope significantly (Scheme 1C). Moreover, according to
the proposed mechanism, we were also curious about what novel transformation
might occur if N-substituted enamines 7 were used to block the known path (Scheme
1C). In fact, an unexpected 2,5-dihydrooxazole 8 and 1H-1,2,3-triazole 2-oxide 9 was
obtained from N-methyl aniline and other N-alkylanilines, which attracted our atten-
tion because of the unexpected C–N as well as N=O bond cleavage and rearrange-
ment (Scheme 1C). Here, we report a chemoselective nitrosylation of anilines and
alkynes for the efficient construction of 2,5-dihydrooxazoles, 1H-1,2,3-triazole 2-ox-
ides, and quinoxaline N-oxides through fragmentary or complete NO radical
incorporation (Scheme 1C). The formation of multiple C–N bonds, an unexpected
C–N bond, and N=O bond cleavage make this chemistry more interesting and
meaningful. We carried out a series of mechanistic studies to seek an explanation
for this selective skeleton assembly and [3 + 2 + 1] cycloaddition processes.
Moreover, this transformation features facile operation in open-air, transition-
metal-free, and mild conditions for the preparation of N-heterocyclic compounds.
RESULTS AND DISCUSSION
Inspired by the previous strategies using TBN as the building block,39–44 we initiated
our investigation by performing the reaction of aniline 3a with dimethyl butynedioate
(5a) in the presence of TBN by using CH3CN as the solvent (Table 1). To our delight,
after the reaction mixture was stirred at 60ꢀC for 15 min, the desired product quinoxa-
line N-oxide 2a, confirmed by X-ray single-crystal diffraction, was isolated in 76%
yield (entry 1; see also Figure S115). To further improve the reactivity, we examined
a series of additives, nevertheless no significant enhancement was observed (entry 2;
see also Table S1). Lower temperature with longer reaction time resulted in moderate
yield of the product (Table 1, entry 3), which indicates the reaction can work well un-
der milder conditions. Gratifyingly, screening of several different solvents increased
the yield to 83% at room temperature (Table 1, entries 5–8). Fluorinated solvents
seemed to be particularly helpful in this reaction, with hexafluoroisopropanol
(HFIP) and trifluoroethanol giving 80% and 83% yield, respectively, which is consis-
tent with their positive effect on reactions where free radicals or cationic species
are involved.45,46 Other NO sources were also examined but only lower efficiencies
were observed (see Table S1). Finally, 2a was obtained in 82% yield under the
optimized conditions in CF3CH2OH at room temperature (condition A, entry 8).
1State Key Laboratory of Natural and Biomimetic
Drugs, School of Pharmaceutical Sciences,
Peking University, 100191 Beijing, China
2State Key Laboratory of Elemento-organic
Chemistry, Nankai University, Weijin Road 94,
Tianjin 300071, China
3These authors contributed equally
4Lead Contact
Activation of the C–N bond has become a hot topic in organic synthesis recently, in
which most efforts have focused on the amination transformation.47–51 However, the
utilization of alkyl adjacent to the N atom as the migrant group to participate in
*Correspondence: jiaoning@pku.edu.cn
https://doi.org/10.1016/j.chempr.2018.03.008
2
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A
The traditional [3+2+1],[2+2+1], and the fragmentary cyclization via bond cleavage
Fragmentary
cyclization
via bond cleavage
5
5
2
5
Traditional
cycloaddition
3
6
4
1
4
6
3
2
1
6
1
4
+
3
2
well-known
unknown
2
3
2
1
1
2
1
1
2
3
B
Previous work with substituted N-ethylidene-anilines (ref. 44)
O
N
H
H
NO
Ar
H
N
H
NO
HAT
HAT
TBN
N
A
Ar
N
B
Ar
N
Ar
1
2
C
Hypothesis of enamine intermediates generated in situ from anilines and alkynes
tBuONO (TBN)
R2
H
R2
R2
R2
R2
H
R2
R2
NO
H
H
tBuO +
HAT
NO
+
N
N
N
R1
6, 7
NH
R1
R2
3/6, R1 = H
A
A'
3, 4
5
O
N
NO
O
N
N
R2
R2
O
R2
N
N
N
R2
R2
N
2
R2
NO
8
9
this work: new reactivity and chemoselective control
Scheme 1. Cycloaddition of Anilines for the Construction of Heterocycles
annulation has never been achieved. As already mentioned, we wanted to know
what would happen with mono-substituted aniline when the pathway discussed
above was blocked. Therefore, N-methylaniline (4a) was subjected to the same
conditions as simple aniline. Surprisingly, an unexpected 2,5-dihydrooxazole 8a
was obtained in 37% yield (entry 9), the core ring of which came from three indepen-
dent components. Increasing the reaction temperature to 60ꢀC for only 15 min
increased the yield of 8a to 52% (entry 10). The use of several additives could not
further improve the efficiency (entry 11; see also Table S2). Interestingly, it turned
out that HFIP solvent was superior to trifluoroethanol in this case, and other non-fluo-
rinated solvents undermined the reactivity (entries 12–17). Finally, under the opti-
mized conditions in HFIP at 60ꢀC (condition B, entry 17, Table 1), the reaction of
N-methylaniline (4a) produced 8a in 72% yield.
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Table 1. Optimization for the Reaction of Aniline (3a) and N-Methylaniline (4a) with Dimethyl Butynedioate (5a)
O
E
H
O
E
Condition B
Condition A
N
E
E
+
H
N
N
N
R
N
E
NO
E
5a
E = COOMe
4a: R = Me
3a: R= H
E = COOMe
8a
2a
Entry
1
Aniline
3a
Solvent
CH3CN
CH3CN
CH3CN
toluene
DCE
T (oC)
Time
Yield (%)a
2a, 79 (76)
2a, <60
2a, 64
60
60
25
25
25
25
25
25
25
60
60
60
60
60
60
60
60
15 min
2b
3
3a
15 min
3a
overnight
overnight
overnight
overnight
overnight
overnight
overnight
15 min
4
3a
2a, 45
5
3a
2a, 51
6
3a
THF
2a, 56
7
3a
HFIP
2a, 80 (79)
2a, 83 (82)
8a, 38
8
3a
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
MeNO2
1,4-dioxane
CH3CN
toluene
DCE
9
4a
10
11c
12
13
14
15
16
17
4a
8a, 52 (52)
8a, <52
8a, 15
4a
15 min
4a
15 min
4a
15 min
8a, 29
4a
15 min
8a, 31
4a
15 min
8a, 25
4a
15 min
8a, 33
4a
HFIP
15 min
8a, 73 (72)
Reaction conditions: condition A: 3a (0.5 mmol), 5a (0.55 mmol), and TBN (3 equiv) in CF3CH2OH (1 mL) at 25ꢀC overnight; condition B: 4a (0.5 mmol),
5a (0.55 mmol), and TBN (2.2 equiv) in HFIP (1 mL) at 60ꢀC for 15 min. E = CO2Me.
aYields were determined by 1H NMR. The numbers in parentheses are isolated yields.
bTBAI, KI, and NaBr (0.05 mmol) were used as the additives.
cKI, TBAI, Cs2CO3, Li2CO3, and DBU (0.05–0.1 mmol) were used as the additives.
With the established cycloaddition conditions in hand, we examined the scope of
N-methylanilines 4 in terms of functional group diversity and substitution pattern
under condition B (Figure 1; see also Figures S1–S32). The reaction proved
to be tolerant of different substitution patterns on the aromatic core (8a–8k).
N-Methylanilines substituted with the halogens (F, Cl, and Br) afforded
the corresponding 2,5-dihydrooxazoles in moderate yields (8dꢁ8f), which could
be used for further functionalization. Phenyl-substituted N-methylaniline was
smoothly converted into the product 8h, confirmed by X-ray single-crystal
diffraction (see also Figure S114). The unsaturated alkynyl substituent was
also tolerated in this transformation (8l). Interestingly, 9H-fluoren-2-amine
smoothly led to the more complex polycyclic compound in moderate yields
(8m). Diethyl but-2-ynedioate also worked well to afford 2,5-dihydrooxazole in
61% yield (8n). Notably, when the methyl group in 4a was replaced with an ethyl
group, the corresponding product 8o was successfully formed, although in lower
yield.
Furthermore, we evaluated the scope and generality of primary anilines 3 in this
transformation (Figure 2; see also Figures S33–S74). Substituents at different
4
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NO
N
NHMe
E
E
E
TBN (2.2 equiv)
+
N
Ar
Ar
4
HFIP (1 mL)
60 oC, 15 min
O
E
5
8 E = COOMe
8a, R = H, 72%
8b, R = Me, 76%
8c, R = OMe, 75%
8d, R = F, 63%
8e, R = Cl, 55%
8f, R = Br, 56%
8g, R = NHAc, 65%
8h, R = Ph, 69%
NO
E
E
N
N
O
R
8h
NO
NO
N
NO
N
E
E
E
NO
N
E
E
N
E
E
E
N
O
N
N
N
O
O
O
8j, 69%
8k, 71%
8l, 55%
8i, 67%
NO
NO
E
E
NO
EEt
E
EEt
E
N
N
N
N
N
O
N
O
O
8o, 24%
8n, 61%
8m, 60%
Figure 1. Substrate Scope of N-Methylaniline
For the reaction conditions, see entry 17 in Table 1. The yields are isolated yields based on the
aniline substrates. E = CO2Me, EEt = CO2Et.
positions of the aryl ring of aniline (para-, meta-, ortho-position and multi-
substituted) did not undermine the reactivity with good functional group compati-
bility (2a–2p). Halo-substituted anilines were well tolerated, leading to halo-
substituted products (2e–2h). Electron-donating groups such as alkyl (2b, 2m–2o,
2i, and 2q), methoxy (2c and 2j), and benzyloxy (2k) were well compatible with this
transformation, affording the quinoxaline N-oxides in moderate to good yields.
The naphthyl-substituted and phenyl-substituted anilines worked well, forming the
corresponding quinoxaline N-oxides 2q and 2d, respectively. The unsaturated
group alkynyl was tolerated in this system (2l). The morpholinyl substituent that
was studied frequently in pharmaceutic sciences was compatible for preparing cor-
responding quinoxaline N-oxide 2r. Diethyl but-2-ynedioate also worked well to
afford quinoxaline N-oxide 2s. The trifluoromethyl-substituted alkynes worked
well and highly selectively afforded the corresponding trifluoromethyl-substituted
quinoxaline N-oxides 2t and 2u in moderate yields.
Unfortunately, the electron-deficient anilines did not work well, presumably because
of the slow initial hydroamination step under the standard conditions. To expand the
substrate scope, we chose the enamine intermediate as substrate and raised the
temperature to improve the activity of the intermediates (Figure 3; see also Figures
S75–S86). In this way, electron-withdrawing groups, such as ester and carbonyl
groups, were well tolerated under the new conditions (2v and 2w). Moreover, the
phenyl-substituted alkynes also performed well under these conditions and afforded
the corresponding quinoxaline N-oxides in moderate yields (2x–2aa).
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O
NH2
E
E
TBN (3 equiv)
N
E
E
+
Ar
Ar
CF3CH2OH (1 mL)
25 oC , Overnight
N
2
2a
3
5
2a, R = H, 82%
2b, R = Me, 88%
2c, R = OMe, 68%
2d, R = Ph, 51%
2e, R = F, 77%
2f, R = Cl, 54%
2g, R = Br, 64%
2h, R = I, 61%
O
N
2i, R = Me, 55%
O
N
R
E
E
2j, R = OMe, 68%
2k, R = OBn, 56%
2l, R = C CH, 37%
E
E
N
R
N
O
O
O
N
N
E
E
Me
Me
N
E
E
Me
E
Me
N
N
N
E
Me
Me
2m, 61%
2n, 58%
2o, 69%
O
N
O
N
O
O
N
E
E
E
E
N
E
N
N
Cl
N
E
Et
2p, 58%
2q, 63%
2r, 40%
O
O
O
N
EEt
EEt
N
E
N
EEt
N
N
CF3
N
CF3
2s, 69%
2t, 62%
2u, 64%
Figure 2. Substrate Scope of Anilines and Electron-Withdrawing Alkynes
For the reaction conditions, see entry 8 in Table 1. The yields are isolated yields based on the aniline
substrates. E = CO2Me, EEt = CO2Et.
Potential Application in the Synthesis of Bioactive Molecules
To illustrate the practicality of this reaction, we then conducted a gram-scale experiment
under the standard conditions, and the desired products 2,5-dihydrooxazole 8b and
quinoxaline N-oxide 2b were obtained in 69% and 81% yield, respectively. The products
were isolated by direct recrystallization from the reaction mixture without any routine
work-up procedure or column chromatography (equations 1 and 2 in Figure 4).
The products could be deoxidized into quinoxaline derivatives (10a and equation 3
in Figure 4; see also Figures S89 and S90). The hydrolysis of the products worked
smoothly and the corresponding products were isolated through filtration (10b
and equation 3 in Figure 4; see also Figures S91 and S92). The N-nitrosamines 8b
can also be deprotected under a H2 atmosphere with Pd/C as the catalyst to deliver
10c in moderate yield (10c and equation 4 in Figure 4; see also Figures S93 and S94).
The NO moiety attached to the N atom in the 8b could also transfer and then be
oxidized, realizing the formal nitration of the aromatic ring to provide 10d (equation
4 in Figure 4; see also Figures S95 and S96).
6
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O
R2
TBN (3 equiv)
H
N
R2
R1
N
Ar
CF3CH2OH (1 mL)
60 oC , 15 min
Ar
R1
N
6
2
O
O
O
N
EtO2C
N
E
E
Ac
N
E
E
EEt
Ph
N
N
N
2w, 47%
2x, 50%
2v, 43%
O
O
O
N
EEt
4-OMePh
N
EEt
Ph
N
EEt
Ph
N
Me
N
MeO
N
2y, 67%
2z, 63%
2aa, 45%
Figure 3. Expansion of the Substrate Scope
Reaction conditions: 6 (0.5 mmol), CF3CH2OH (1 mL), stirred at 60ꢀC for 15 min. The yields are
isolated yields based on the aniline substrates. E = CO2Me, EEt = CO2Et.
Morpholinyl-substituted quinoxaline N-oxide 11 with trypanocidal activity was ob-
tained in 43% yield (equation 5 in Figure 5; see also Figures S97 and S98).52 The
saccharide skeleton attached to anilines was also well compatible in this reaction
(equation 6 in Figure 5; see also Figures S99 and S100). Decoration of aminoglutethi-
mide, a kind of aromatase inhibitor, also went smoothly to afford 13 in 66% yield
(equation 7 in Figure 5; see also Figures S101 and S102). Moreover, the products
could be easily converted to antibacterial activity compounds 14 (equation 8 in Fig-
ure 5).53,54 In addition, another two classes of novel structural motif isoxazolo[4,5-b]
quinoxaline 9-oxides 15 and 1,2,3-triazole 2-oxides 9, confirmed by X-ray single-crys-
tal diffraction, were discovered (equations 9 and 10 in Figure 5; see also Figures S87,
S88, S103, S104, S116, and S117). Constructing fused tricyclic compounds and the
special triazole 2-oxides from simple substrates in only one step and incorporating
multiple heteroatoms into one ring make this strategy highly efficient and practical.
To gain further insight into the mechanism of the transformation of N-methylanilines,
we conducted control experiments. The enamine 7a was isolated in 99% yield under
condition B without TBN (equation 11 in Figure 6; see also Figures S107 and S108).
The desired product 8a was obtained in 71% yield with the formed enamine 7a as the
substrate under the optimized conditions, which demonstrates that enamine is
involved in this transformation. A labeling experiment with N-(methyl-d3)aniline
4a-d3 revealed that methyl shift may proceed via the cleavage of C–N and the forma-
tion of C–O and C–N (equation 12 in Figure 6; see also Figures S3 and S4). A cross-
labeling experiment showed that methyl shift proceeded in an intermolecular pro-
cess (equation 13 in Figure 6).
Alternatively, to further explore the mechanism for quinoxaline N-oxide formation, we
designed and performed another set of control experiments . The enamine 6a was iso-
lated in 97% yield under condition A without TBN (equation 14 in Figure 6; see also Fig-
ures S105 and S106). This provided the desired quinoxaline N-oxide 2a in 83% yield un-
der the optimized conditions (equation 14 in Figure 6), which demonstrates that the
enamine was involved in this transformation. Interestingly, the oxime compound 16
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NO
E
E
N
Conditions B
Conditions A
N
(1)
(2)
4b
+
5a
5a
O
10 mmol
8b, 69% (2.21g)
O
N
E
E
3b
+
N
7.5 mmol
2b, 81% (2.07g)
O
N
E
E
Me
N
CO2H
CO2H
Me
PBr3
NaOH (1 M)
reflux
2b
(3)
(4)
DMF, rt
N
N
10b 75%
10a 97%,
H
E
N
H
N
NO2
E
E
[RhCp*Cl2]2 (4 mol%)
AgSbF6 (16 mol%)
E
Pd/C , H2
N
N
8b
DCM, 40 oC
CH3CN , 80 oC
O
O
10d 52%
10c 51%,
Figure 4. Gram-Scale Experiments and Further Transformations
was isolated in 68% yieldin the reactionof 6c at room temperature, which was confirmed
by X-ray single-crystal diffraction (equation 15 in Figure 6; see also Figures S109, S110,
and S118). When the formed oxime16 was used in this transformation, the desired prod-
uct 2x was obtained in 70% yield (equation 16 in Figure 6). These results demonstrate
that the oxime intermediates and their tautomerism nitroso-substituted imines are
most likely the key intermediates of this transformation.
Furthermore, when the reaction of aniline 3a and alkyne 5a was monitored by elec-
tron paramagnetic resonance (EPR) spectroscopy in the presence of the free radical
spin-trapping agent 5,5-dimethyl-1-pyrroline N-oxide (DMPO), a signal with six
peaks (g = 2.007, aN = 15.5 G, aHb = 23.6 G; Scheme 2A; see also Figure S111), cor-
responding to a carbon-centered radical55 was observed. In addition, the calculated
hyperfine splittings of this signal are approximately equal to the reported values44
(g = 2.011, aN = 15.3 G, aHb = 22.4 G), indicating that both carbon-centered rad-
icals mainly belong to the same type of carbon-centered radical adjacent to the
C=N group. However, the signal did not appear in the absence of TBN (Scheme
2B; see also Figure S112) or the substrates (Scheme 2C; see also Figure S113). These
results indicate that the C-centered radical (A, Scheme 1C), which is most likely a key
intermediate, instead of the N-centered radical (A0, Scheme 1C) was involved in the
reaction of aniline 3a and alkyne 5a with TBN. However, no signal appeared in the
reaction of N-methylaniline 4a and alkyne 5a with TBN under condition B, indicating
that pathway b (Scheme 3) is different from pathway a (Scheme 3).
On the basis of all these results and previous reports, a proposed mechanism is de-
picted in Scheme 3. The reasonable initial step of this transformation is the formation
of enamine intermediate 6/7, as well as the hemolysis of TBN, to generate the tert-
butoxy radical and NO radical. For the reaction of anilines 3, H abstraction of the
N–H bond by tert-butoxy radical occurs to generate radical intermediate A, which
undergoes radical coupling with the NO radical to afford the nitroso intermediate
8
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O
O
N
COOEt
CF3
Cl
NH2
N
COOEt
CF3
Conditions A
+
(5)
N
Cl
N
43%
O
3r
11 trypanocidal activity
NH2
O
N
R =
Conditions A
Conditions A
O
O
E
E
R
AcO
5a
+
+
(6)
(7)
AcO
OAc
N
3s
OAc
R
12 61%
NH2
O
N
R =
E
E
R
O
5a
NH
N
3t
R
13 66%
O
Aminoglutethimide: Aromatase inhibitors
O
R1,R2=
O
O
NH
O
N
N
R1
EEt
EEt
ref. 52
and -COOEt
(8)
H
N
N
R2
NaOOC
S
N
2s
antibacterial activity
14
O
TBN (3 e.q.)
TBHP (1.5 e.q.)
COOMe
N
H
O
N
N
(9)
CF3CH2OH , 60 o
C
N
COOMe
44%
6a
15
O
R= Et
R=Bn
42%
57%
N
H
N
N
Conditions B
N
COOMe
(10)
R
5a
+
COOMe
4
R=allyl 47%
9
O
N
N
N
COOMe
COOMe
9
Figure 5. Potential Applications and More Transformations
B. The nitroso intermediate B further undergoes H abstraction to produce radical
intermediate C. The cyclic intermediate D is then generated by the subsequent cycli-
zation of C. Finally, aromatization of D through radical H abstraction by the tert-
butoxy radical leads to the final product 2.
For N-methylaniline involved in pathway b, the presence of the N-methyl substituent
blocks H abstraction without the N–H bond. Then, single-electron oxidation of
enamine intermediate 7 occurs to provide radical cation F, which can be further trap-
ped by NO radicals to afford iminium ion G. Then, deprotonation is preferred fol-
lowed by cyclization to form the four-membered ring I.56,57 The ring-opening
Chem 4, 1–16, June 14, 2018
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E
NO
E
E
N
N
Conditions B
without TBN
Conditions B
5a
4a +
N
(11)
(12)
E
O
8a, 71%
7a, 99%
NO
E
H
N
E
N
Conditions B
CD3
5a
N
+
O
100%D
4a-d3
D
D
8a-d2,51%
H
N
CD3
NO
E
E
N
Conditions B
4a-d3
N
+
5a
O
(13)
+
R
H/D
H
N
D/H
8a R = H, 25%
CH3
8a-d2 R = H, 25%
4g
AcHN
8g R = NHAc, 38%
8g-d2 R = NHAc, 28%
4a-d3 : 4g : 5 = 1 : 1 : 2.2
E
O
N
H
N
E
E
Conditions A
Conditions A
5a
3a +
(14)
(15)
E
without TBN
N
6a, 97%
2a, 83%
O
COOEt
COOEt
H
N
N
COOEt
TBN
N
N
+
CF3CH2OH (1 mL)
25 oC, overnigtht
Ph
Ph OH
N
Ph
6c
2x, 24 %
16, 68%
COOEt
COOEt
NO
N
N
N
Ph OH
Ph
16
16'
O
N
COOEt
COOEt
Ph
HFIP (1 mL)
N
N
TBN
+
(16)
60 oC, 15 min
Ph OH
N
16
2x, 70%
Figure 6. Mechanistic Studies
reaction of I can then occur to afford diradical intermediate J,36,37 which undergoes
an intermolecular methyl shift process with intermediate I or L to form intermediate
K. The cyclization of intermediate K with the assistance of tBuOꢁ produces species L,
which undergoes another intermolecular methyl shift process to give interme-
diate M. Further nitrosylation affords the final product 8.
10
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Scheme 2. Electron Paramagnetic Resonance Studies of the Transformation
The EPR spectra (X band, 9.7 GHz, room temperature) in the presence of the radical trap DMPO (2.5 3 10ꢁ2 M) at room temperature. (A) 3a (0.5 mmol), 5a
(0.55 mmol), TBN (1.5 mmol), and CF3CH2OH (1 mL) with stirring at 60ꢀC under air for 30 s; (B) without TBN; (C) without 3a and 5a.
To better understand this metal-free [3 + 2 + 1] C–H cyclization, we performed prelim-
inary density functional theory (DFT) calculations to investigate the model reaction of
aniline 3a and alkyne 5a with TBN (Figure 7; for more details, see Figure S119 and Table
S3).58 We propose that the reaction begins with homolysis of TBN into the NO radical
and tert-butoxy radical,39,40,59,60 which is endergonic by 22.4 kcal/mol. The cascade
annulation reaction initiates into hydroamination of alkyne 5a as an exothermic step
by 18.7 kcal/mol to provide stable enamine 6a. Then, the abstraction of a hydrogen
atom in the N–H bond of 6a by in-situ-formed tert-butoxy radical via transition state
TS1a with an activation free energy of 16.1 kcal/mol afforded radical intermediate
INT1, which is an irreversible process. The INT1 formed undergoes radical coupling
with the NO radical to form intermediate INT2, which is slightly endergonic by
2.9 kcal/mol. Further abstraction of a hydrogen atom in the C–H bond of INT2 by
tert-butoxy radical is facile by overcoming the free-energy barrier of 18.8 kcal/mol.
This process is significantly exoergic by 77.9 kcal/mol. The following electrocyclic reac-
tion of INT3 readily proceeds through TS3 with only an activation free energy of
16.7 kcal/mol to furnish cyclic intermediate INT4. Finally, the aromatization process
involving the abstraction of a hydrogen atom in INT4 by tert-butoxy radical
affords the final quinoxaline N-oxide 2a by releasing a large amount of energy,
149.0 kcal/mol. DFT calculations suggest that the tert-butoxy radical and NO radical
are the active species. The first abstraction of a hydrogen atom in the N–H bond of 6a
by tert-butoxy radical is the rate-determining step, and the subsequent electrocyclic re-
action of a radical intermediate serves as the key step, in good agreement with the
experimental observations.
The pyrolysis of tert-butoxy radical through TS0 requires a free-energy barrier of
31.7 kcal/mol to give methyl radical with the release of acetone. Although the methyl
radical is more stable by 14.4 kcal/mol than the tert-butoxy radical, H abstraction by
methyl radical was calculated to be unfavorable (Figure 7).
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homolysis
tBuONO (TBN)
tBuO +
NO
O
E
O
N
N
O
N
O
N
E
E
R
N
H
H
E
E
E
N
E
E
E
E
N
6, R= H
H
+
E
N
N
N
2
3, 4
E
5
NO
tBuO
tBuOH
tBuO
tBuOH
A
B
C
D
tBuOH
pathway a
tBuO
R
N
E
tBuO
tBuO
E
E
E
E
H
E
N
E
6, 7
N
E
N
N
N
E
N
N
E
O
tBuO
O
N
E
E
O
J
O
E
N
7, R= Me
NO
FH
tBuOH
G
H
I
pathway b
E
E
E
N
R2
E
R1
=
Ph
R1
or
N
I or L
O
N
O
N
E
O
N
NO
E
E
tBuOH tBuO
E
E
H
R2 = H, Me or NO
E
E
E
E
N
N
N
tBuO
N
H
N
N
N
N
O
O
O
O
8
R2
E
L
M
NO
K
H
N
E
N
N
Ph
R1
Ph
R1
N
O
Scheme 3. Proposed Mechanism
The DFT calculations on the reaction of N-methylaniline (4a) and alkyne 5a showed
that the first step corresponds to hydroamination of alkyne 5a as an exothermic
step by 12.8 kcal/mol to provide stable enamine 7a (Figure 8; for more details,
see the Supplemental Information). Then single-electron oxidation of enamine in-
termediate 7a occurs to provide radical cation intermediate INT5, which requires a
free energy of 27.4 kcal/mol. The further capture by NO radicals is slightly
‡
E
GTFE
kcal/mol
DFT calculation
‡
E
E
N
H
‡
tBuO
E
E = CO2Me
E
N
H
O
N
‡
H
Me
Me
E
O
TS1b
H
OtBu
N
0.0
TS1a
3.9
E
N
CH4
‡
E
N
TS2a
-13.7
O
N
E
-2.6
‡
O
-18.7 Me
tBuOH
NH2
-18.7
H
TS2b
-19.4
H
tBuO
E
E
N
+
E
E
E
E
NO
NO
-32.5
tBuOH
-33.2
E
-36.0
CH4
N
TS3
-62.6
N
-35.4
INT1
E
N
H
6a
E
N
H
tBuO
Me
5a 3a
O
N
TS3
O
N
E
N
E
N
6a
E
E
-61.2
-70.6
E
E
-72.0
-79.3
E
-77.9
E
O
Me
N
O
N
tBuO
tBuOH
N
H
INT1
H
O
N
E
E
N
INT2
O
N
E
E
CH4
INT2
E
E
E
E
O
‡
N
N
INT4
Me
Me
TS0
N
Me
INT4
N
-149.0
-151.1
INT3
O
N
tBuO
22.4
+
NO
INT3
O
N
O
E
E
31.7
E
E
+
Me
0.0
N
N
8.0
TBN
2a
2a
Figure 7. DFT-Computed Energy Profiles for the N-Incorporation Reaction of Aniline 3a and Alkyne 5a with TBN
12
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N
E
E
N
GTFE
kcal/mol
O
Ph
INT6
18.8
14.6
tBuO
0.0
tBuO
tBuOH
E
tBuO
-12.8
NO
E
N
O
Ph
PhNHMe
E
N
E
4a
N
E
+
Ph
E
E
INT5
INT8
-32.8
Ph
5a
E
N
-43.2
7a
E
N
N
E
E
N
E
O
O
Ph
E
HN
O
Ph
N
E
N
E = CO2Me
Ph
-90.1
INT7
INT7'
INT9
Figure 8. DFT-Computed Energy Profiles for the N,O-Incorporation Reaction of Aniline 4a and
Alkyne 5a with TBN
endergonic by 4.2 kcal/mol to afford imine cation INT6. Then, deprotonation by
tert-butoxy anion is preferred to provide INT7, which is significantly exothermic.
The following cyclization of INT7 requires a free energy of 10.4 kcal/mol to form
the four-membered ring INT8. The ring-opening reaction of INT8 can occur to
afford a diradical intermediate, which undergoes an intramolecular or intermo-
lecular methyl shift exothermic process to form intermediate INT9. Finally, the
abstraction of a hydrogen atom in the N–H bond followed by radical coupling
with the NO radical affords the product 8a.
In conclusion, we have developed a chemoselective nitrosylation of anilines
and alkynes for the efficient construction of 2,5-dihydrooxazoles, 1H-1,2,3-triazole
2-oxides, and quinoxaline N-oxides through fragmentary or complete NO radical
incorporation. C–H bond cleavage, the formation of multiple C–N bonds, unex-
pected C–N bond cleavage, and N=O bond cleavage are involved in this chem-
istry. Facile operation in open-air, metal-free, and mild conditions at room
temperature or 60ꢀC makes this protocol particularly practical and attractive. A
reasonable mechanism consistent with labeling experiments, isolation of the
intermediates, DFT calculations, and EPR measurements is provided. Further
studies to design new reactions and synthetic applications are ongoing in our
laboratory.
EXPERIMENTAL PROCEDURES
Representative Procedure for the Complete Incorporation Approach to
Quinoxaline N-Oxides
To a 10 mL Schlenk flask containing anilines 3 (0.5 mmol), electron-withdrawing
alkynes 5 (0.55 mmol) were added and then the flask allowed to stand for 5 min. A
magnetic stir bar and CF3CH2OH (1 mL) were added to the mixture and stirred for
2 min. TBN (1.5 mmol) was then added to the mixture in 10 s, and the mixture was
plugged and stirred at 25ꢀC overnight. The reaction mixture was diluted with AcOEt,
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and the solution was concentrated under vacuum. Finally, the mixture was purified
through column chromatography to afford the pure products 2.
Representative Procedure for the Fragmentary Cycloaddition Approach to
2,5-Dihydrooxazoles
To a 10 mL Schlenk flask containing N-methylanilines 4 (0.5 mmol), electron-with-
drawing alkynes 5 (0.55 mmol) were added and the flask was allowed to stand for
5 min. A magnetic stir bar and HFIP (1 mL) were added to the mixture and stirred at
60ꢀC for 2 min. TBN (1.1 mmol) was then added to the mixture in 10 s, and the
mixture was plugged and stirred at 60ꢀC for 15 min. The reaction mixture was
diluted with AcOEt and the solution was concentrated under vacuum. Finally,
the mixture was purified through column chromatography to afford the pure
products 8.
DATA AND SOFTWARE AVAILABILITY
The data for the X-ray crystallographic structures of products 2a, 8h, 9, 15, and 16
in this article have been deposited in the Cambridge Crystallographic Data
Center under accession numbers CCDC: 1828890, 1828891, 1828892, 1828893,
and 1828894, respectively.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 119
figures, 3 tables, and 5 data files and can be found with this article online at
https://doi.org/10.1016/j.chempr.2018.03.008.
ACKNOWLEDGMENTS
Financial support from the National Natural Science Foundation of China (nos.
21632001 and 21772002), National Basic Research Program of China (973 Program)
(grant no. 2015CB856600), National Young Top-notch Talent Support Program, and
Peking University Health Science Center (no. BMU20160541) is greatly appreciated.
We thank Hao Wu in this group for reproducing the results of 2u and 2aa. This work is
dedicated to Professor Jin-Pei Cheng on the occasion of his 70th birthday.
AUTHOR CONTRIBUTIONS
J.P., X.L., and N.J. conceived and designed the experiments; J.P. carried out most of
the experiments; X.L. carried out most of the calculations; J.P., X.L., and N.J.
analyzed the data; F.L. and J.L. carried out some experiments; J.P., X.L., and N.J.,
wrote the paper; N.J. directed the project.
DECLARATION OF INTERESTS
The authors declare no competing financial interests.
Received: August 4, 2017
Revised: November 19, 2017
Accepted: March 11, 2018
Published: April 19, 2018
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