T-BuOK-Mediated Oxidative Dehydrogenative C(sp3)-H Arylation of 2-Alkylazaarenes with Nitroarenes

Article abstract of DOI:10.1021/acs.joc.7b00732

The first transition-metal free and regioselective C(sp³)-H arylation of 2-alkylazaarenes with nitroarenes has been achieved via t-BuOK-mediated dehydrogenative C(sp³)-C(sp²) coupling. This reaction provides an efficient a

Full text of DOI:10.1021/acs.joc.7b00732

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Note
t-BuOK-Mediated Oxidative C(sp3)-H Arylation
of 2-Alkylazaarenes with Nitroarenes
Shuai-Shuai Li, Shiheng Fu, Liang Wang, Lubin Xu, and Jian Xiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00732 • Publication Date (Web): 24 Jul 2017
Downloaded from http://pubs.acs.org on July 24, 2017
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t-BuOK-Mediated Oxidative C(sp3)-H Arylation of
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2-Alkylazaarenes with Nitroarenes
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Shuai-Shuai Li, Shiheng Fu, Liang Wang, Lubin Xu and Jian Xiao*
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College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, 266109, China
Corresponding author: Jian Xiao
E-mail address: chemjianxiao@163.com
ORCID: 0000-0003-4272-6865
Graphic Abstract
Abstract: The first transition-metal free and regioselective C(sp3)-H arylation of 2-alkylazaarenes
with nitroarenes has been achieved via t-BuOK-mediated dehydrogenative C(sp3)-C(sp2) coupling.
This reaction provides an efficient access to the biologically important and synthetically useful
2-benzyl-substituted azaarenes under mild conditions without the need of prefunctionalization of
2-alkylazaarenes or using the specialized arylating agents.
The azaarene unit is a privileged pharmacophore existing in numerous pharmacologically and
biologically active compounds.1 Among the family of these compounds, the 2-benzyl-substituted
azaarenes have drawn much attention from the organic and medicinal communities owing to their
biological and medicinal importance.2 For example, compound (A)2a and compound (B)2b are used
in the treatment of arrhythmia disease and inhibition of phosphodiesterase-4, respectively. In
addition, some representative pharmacologically important agents incorporating this skeleton are
also listed, such as P2×3 and P2×2/3 receptor antagonist (C),2c antihistamine drug (D),2d
psychoactive drug (E)2e and amino acid transporter B0AT2 inhibitor (F)2f (Figure 1).
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Figure 1. Representative Examples of Biologically Active Pharmaceuticals
Due to the high significance of 2-benzyl-substituted azaarenes, several efficient and facile
methodologies for the benzylic arylation of 2-alkylazaarenes have been developed in the last few
years.3-5 In 2008, Fagnou and Charette realized the palladium-catalyzed direct benzylic C−H
arylation of 2-alkylpyridine N-oxides and N-iminopyridinium ylides with aryl halides, respectively
(Scheme 1, eq 1).4 Later, the continuous exploration of arylation of benzylic C(sp3)−H bond of
unactivated 2-alkylazaarenes was reported by Knochel, Liu, Li, Walsh and Glorius groups, etc
(Scheme 1, eq 2).5 Despite the significant progress, all these arylation reactions necessitate the use
of noble transition-metals (Pd or Rh), which are not only expensive but also detrimental to the
environment. Morevoer, these transition-metal-involved process are quite troublesome in final
product purification, especially in the pharmaceutical industry. Lastly, the pre-functionalization of
starting materials, the employment of costly ligands as well as the harsh reaction conditions also
abate their practicality. Therefore, the development of transition-metal-free, environmentally
benign and practical methods for the synthesis of arylated 2-alkylazaarenes has become urgent and
increasingly important in organic synthesis.
Recently, t-BuOK-mediated C-C coupling reactions emerged as efficient and environmentally
friendly alternatives to transition-metal catalyzed reactions.6-13 The breakthrough was achieved by
Itami,8 Shi,9 Lei and Kwong,10 Shirakawa and Hayashi11 groups, who independently reported the
t-BuOK promoted biaryl coupling of aromatic compounds and haloarenes without any exogenous
transition-metals. Very recently, the t-BuOK catalyzed direct silylation of aromatic heterocycles
with hydrosilanes was discovered by Grubbs and coworkers to furnish heteroarylsilanes in a single
step.12
However,
to
the
best
of
our
knowledge,
the
facile
oxidative
Cross-Dehydrogenative-Coupling (CDC) of two C-H bonds from readily accessible starting
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materials via C(sp3)-H arylation has rarely been reported despite their atom-economy and high
efficiency.13
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During our synthetic journey towards transition-metal free C(sp3)−H bond functionalization of
2-alkylazaarenes, we reported the first organocatalytic reaction of 2-alkylazaarenes with carbonyl
groups and double bonds.14 As our continuous research in manipulation of 2-alkylazaarenes under
transition-metal free conditions, herein we reported the t-BuOK-mediated CDC arylation of
2-alkylazaarenes with readily accessible and inexpensive nitroarenes15 via regioselective benzylic
C(sp3)-H bond functionalization under mild conditions (Scheme 1, eq 3).
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Scheme 1. C(sp3)-H Arylation of 2-Alkylazaarenes
The model reaction was initiated between methylquinoxaline 1a and 1,3-dinitrobenzene 2a at
room temperature. However, only trace amount of product was observed when the reaction was
carried out in DMSO using LiOH as a base under air (Table 1, entry 1). To our delight, the desired
cross-coupling product 3a was obtained in moderate yield when NaOH, KOH and CsOH were
used instead of LiOH (Table 1, entries 2-4). The stronger base NaH could promote this reaction to
give the product in comparatively higher yield, but the best result was given with t-BuOK (Table 1,
entries 5-6). However, the carbonates and organic bases were all invalid in this coupling reaction
(Table 1, entries 7-12). Subsequently, the screening of the solvents revealed that DMSO was the
irreplaceable solvent for this reaction and the other solvents failed to yield the product (entries
13-17). Thus, the optimized reaction condition was used DMSO as a solvent, employing 2.0 equiv.
t-BuOK as a base at room temperature.
Table 1. Optimization of the Reaction Conditionsa
entry
base
solvent
yield (%)b
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LiOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
CH3CN
Dioxane
DCE
trace
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2
NaOH
KOH
3
30
4
CsOH
40
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NaH
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t-BuOK
K2CO3
Cs2CO3
Et3N
65
7
NR
trace
NR
NR
trace
NR
NR
NR
NR
NR
NR
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DMAP
DBU
Morphine
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
DMF
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), base (2.0 equiv.) in 2 mL solvent at room temperature under
air, 12 h. b Isolated yield after column chromatography.
Next, we continued to examine the efficiency of the different coupling partners under the
optimized conditions (Table 2). Firstly, various 2-alkylazaarenes were examined to investigate the
generality of this protocol. Notably, the electronically and sterically diverse substituents located at
2-alkylazaarenes manifested significant effect in terms of the efficiency of this reaction. As an
example, when 2-methyl-3-phenylquinoxaline was employed as a coupling partner, only 40%
yield of the expected product 3b was obtained, which was possibly due to the steric hindrance of
phenyl group. Quinoxalines with electron-withdrawing group such as nitro-group 3c could give
satisfactory yield, but electron-donating groups were not tolerated in this reaction, which might be
ascribed to the decreased acidity of methyl group. Intriguingly, when steric hindered
2-methylquinoxaline N-oxide was subjected to this reaction, the desired product 3d was isolated in
85% yield, which indicated that the electronic factor had stronger impact on this transformation
than the steric hindrance. Subsequently, 2-methylquinoline derivatives were used instead of
quinoxalines. Similarly, the substrates with electron-withdrawing groups installed on the phenyl
ring of quinolines were well tolerated to furnish the desired products in good yields (3e-3g). These
outcomes demonstrated the importance of electronic property of substituents on phenyl ring once
more. Remarkably, comparatively higher yields (3h-3i) were observed when sulfonyl group was
Table 2. The Scope of 2-Alkylazaarenesa
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a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), t-BuOK (2.0 equiv.) in 2 mL DMSO at room temperature under
air, isolated yield after column chromatography.
linked to methyl group which might be ascribed to the highly reactive C(sp3)−H bond. Apart from
2-methylquinoline derivatives, 2-methylpyrazine and 4-methylpyrimidine also proceeded
smoothly to give the corresponding products 3j and 3k in 57% and 75% yields, respectively.
Interestingly, 2-methyloxazole and 2-methylthiazole proved to be amenable to the established
strategy as well, and the corresponding products were obtained in good results (3l-3q). Especially,
2-methylbenzoxazole and 2-methylbenzothiazole with nitro-group on the phenyl ring displayed
comparatively higher reactivity in this process (3m and 3o). Additionally, 2-methylthiazole was
also tolerated, giving rise to the desired product 3q in 40% yield.
Subsequently, various nitroarenes were tested to further demonstrate the generality of this
protocol. Satisfyingly, nitrobenzene, 1-nitronaphthalene and nitro-substituted azaarenes were all
good coupling partners to deliver the arylated products in moderate to good yields (3r-3v).
However, both electron-donating and -withdrawing substituents incorporated into nitrobenzene
were not compatible with the present protocol even heating up the reaction system. It was worth
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mentioning that the substitution occurred at the para-position of nitro group exclusively and the
ortho-substituted products were not detected.
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In order to illustrate the real role of DMSO in this oxidative reaction, several control
experiments were performed. Although no reaction occurred in the pure dioxane solvent (Table 1,
entry 15), the reaction did proceed with significant yield when 20 equiv. of DMSO was added to
the dioxane (Scheme 2, eq a). Furthermore, higher yield of 3a could be obtained along with the
increase of DMSO (Scheme 2, eq b) and 60% yield of 3a had been furnished when employing
DMSO as a co-solvent (Scheme 2, eq c). These results highlighted the irreplaceable role of DMSO
played in the yielding of 3a. Moreover, when the reaction was carried out under N2 atmosphere,
good yield of 3a still could be obtained (Scheme 2, eq d). The above control experiments implied
that DMSO might act as an oxidant16 rather than O2 in this oxidative CDC process, which was
different from the previous reports pertaining to t-BuOK-mediated process.13
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Scheme 2. Control Experiments
In addition, deuterium experiments were carried out to probe the effect of t-BuOK in the
1
reaction (Scheme 3). As expected, no deuterium rate was observed from H NMR when 1a were
stirred in D2O and DMSO at room temperature (Scheme 3, eq a). However, 15% deuterium rate of
methyl group was observed when the reaction mixture was performed in the presence of D2O and
t-BuOK (Scheme 3, eq b).17 The deuterium experiments displayed that t-BuOK played an
important role to deprotonate the methyl group.
Scheme 3. Deuterium Experiments
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In order to further investigate the mechanism of the reaction, the KIE experiment between 1a
and [D]-1a in methyl group was performed (Scheme 4). The deuterium kinetic isotopic effects
were determined to be 6.7, indicating that the cleavage of C(sp3)−H bond might be involved in the
rate-determining step.
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Scheme 4. KIE Experiment
On the basis of the control experiments, deuterium experiments and regioselective outcome, a
plausible mechanism was proposed (Scheme 5).13b-c Initially, an enamine anion intermediate is
generated in the presence of t-BuOK and subsequent nucleophilic attack occurs at the para
position of nitrobenzene. As a consequence, the anionic adduct A is formed, which undergoes
resonance to generate intermediate B. Subsequently, both of them was oxidized by DMSO to yield
the arylated the product 3a, releasing Me2S as a side product. The presence of Me2S has been
detected by crude 1H NMR after the reaction ends up (See Supporting Information).
Scheme 5. A Plausible Mechanism
CONCLUSION
In summary, we have developed a t-BuOK-mediated oxidative cross-coupling reaction of
2-alkylazaarenes with nitroarenes under mild conditions. This is the first transition-metal-free and
regioselective C(sp3)-H arylation of 2-alkylazaarenes, providing an array of 2-benzyl-substituted
azaarenes in good yields without the use of specialized arylating agents. In addition to the reaction
solvent, DMSO also acts as an oxidant in this arylation process. This strategy provides an
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alternative method to arylate 2-alkylazaarenes efficiently and will find applications in the future,
in light of the importance of arylated 2-alkylazaarenes in natural products and pharmaceuticals.
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Experimental Section
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All the reactions were performed in sealed tube and monitored by TLC (0.2 mm silica
gel-coated HSGF 254 plates). The products were purified by flash column chromatography
(200-300 mesh silica gel) eluted with the gradient of petroleum ether and ethyl acetate. Proton
nuclear magnetic resonance spectra (1H NMR) were recorded on a Bruker 500 MHz NMR
spectrometer (CDCl3 or DMSO-d6 solvent). The chemical shifts were reported in parts per million
(ppm), downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.26, singlet) or
dimethyl sulfoxide-d6 (δ 2.54, singlet). Multiplicities were given as: s (singlet); d (doublet); t
(triplet); q (quartet); dd (doublets of doublet) or m (multiplets). The number of protons for a given
resonance is indicated by nH. Coupling constants are reported as a J value in Hz. Carbon nuclear
magnetic resonance spectra (13C NMR) were reported in ppm using solvent CDCl3 (δ (ppm) =
77.16 ppm) as an internal standard. HRMS analyses were performed on a Waters XEVO QTOF
mass spectrometer. All the chemical reagents, unless otherwise noted, were purchased from
commercial companies and used without further purification. All reactions were performed in
flask and monitored by TLC (0.2 mm silica gel-coated HSGF 254 plate). The reaction mixtures
were purified by flash column chromatography (200-300 mesh silica gel) eluted with the gradient
of petroleum ether and ethyl acetate. The substrates 1c, 1d, 1h, 1i were prepared according to the
literatures18 and other substrates were commercially available.
General Procedure for Synthesis of 2-Benzyl Substituted Azaarenes
Potassium tert-butoxide (2.0 equiv., 0.4 mmol) was added to a solution of 2-methylquinoxaline 1a
(1.0 equiv., 0.2 mmol) and 1,3-dinitrobenzene 2a (2.0 equiv., 0.4 mmol) in DMSO (2 mL) under
air. The reaction mixture was stirred at room temperature for a night until 1a was completely
consumed up (TLC monitor). The reaction mixture was quenched by the addition of water (20
mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed
with brine (3 × 20 mL). Dried by MgSO4 and concentrated to afford the crude product. After
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completion, the reaction mixture was purified by flash chromatography eluting with ethyl acetate
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and petroleum ether (1:15 to 1:10) to give the product 3.
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2-(2,4-dinitrobenzyl)quinoxaline (3a). 12 h, 40.4 mg, 65% yield, brown solid; mp: 66-69 °C;
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1H NMR (500 MHz, CDCl3) δ 8.92 (d, J = 2.3 Hz, 1H), 8.88 (d, J = 5.3 Hz, 1H), 8.49 – 8.42 (m,
1H), 8.12 – 8.06 (m, 1H), 7.87 (ddd, J = 9.1, 5.4, 2.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.75 –
7.69 (m, 2H), 4.85 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 152.1, 149.5, 147.3, 145.3, 142.0,
141.6, 139.6, 134.8, 130.5, 130.0, 129.4, 129.2, 127.3, 120.7, 39.7 ppm. HRMS (ESI): calcd for
C15H10N4NaO4 [M+Na]+ : 333.0600, found 333.0605.
2-(2,4-dinitrobenzyl)-3-phenylquinoxaline (3b). 14 h, 30.9 mg, 40% yield, brown solid; mp:
50-52 °C; 1H NMR (500 MHz, CDCl3) δ 8.92 (d, J = 2.4 Hz, 1H), 8.40 (dd, J = 8.4, 2.4 Hz, 1H),
8.11 (dd, J = 8.2, 1.2 Hz, 1H), 7.83 (dt, J = 4.4, 2.1 Hz, 1H), 7.75 – 7.69 (m, 2H), 7.68 – 7.66 (m,
2H), 7.58 – 7.52 (m, 4H), 4.88 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 154.5, 151.0, 149.8,
147.2, 141.1, 141.0, 140.5, 138.3, 134.7, 130.2, 129.6, 129.3, 129.1, 128.9, 128.9, 127.2, 120.6,
40.9 ppm. HRMS (ESI): calcd for C21H15N4O4 [M+H]+ : 387.1093, found 387.1099.
2-(2,4-dinitrobenzyl)-6-nitroquinoxaline (3c). 14 h, 38.3 mg, 54% yield, brown solid; mp:
1
148-151 °C; H NMR (500 MHz, CDCl3) δ 9.07 (s, 1H), 8.99 (t, J = 2.5 Hz, 2H), 8.52 (dd, J =
8.4, 2.3 Hz, 1H), 8.48 (dd, J = 9.2, 2.5 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H),
4.92 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 155.6, 147.9, 147.6, 144.3, 140.5, 138.5, 135.2,
130.8, 127.7, 125.9, 124.0, 120.9, 40.2 ppm. HRMS (ESI): calcd for C15H10N5O6 [M+H]+ :
356.0631, found 356.0629.
2-benzoyl-3-(2,4-dinitrobenzyl)quinoxaline 1,4-dioxide (3d). 14 h, 75.8 mg, 85% yield, brown
solid; mp: 167-170 °C; 1H NMR (500 MHz, CDCl3) δ 8.93 (s, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.43
(d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.7 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H),
7.74 (t, J = 7.7 Hz, 1H), 7.68 (t, J = 7.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H),
4.69 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 189.6, 152.1, 149.6, 147.5, 144.1, 138.3, 136.6,
135.7, 135.3, 135.1, 134.8, 132.7, 130.6, 129.9, 129.6, 129.2, 127.5, 120.7, 118.8, 39.3 ppm.
HRMS (ESI): calcd for C22H15N4O7 [M+H]+ : 447.0941, found 447.0935.
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2-(2,4-dinitrobenzyl)-6-nitroquinoline (3e). 12 h, 36.8 mg, 52% yield, brown solid; mp:
178-180 °C; 1H NMR (500 MHz, CDCl3) δ 8.92 (d, J = 2.1 Hz, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.46
(dd, J = 8.4, 2.2 Hz, 1H), 8.41 (dd, J = 9.3, 2.3 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 9.2
Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 4.87 (s, 2H) ppm; 13C NMR (125 MHz,
CDCl3) δ 161.1, 149.8, 147.3, 145.6, 139.7, 138.8, 134.8, 131.0, 127.3, 125.8, 124.4, 123.4, 123.3,
120.6, 42.4 ppm. HRMS (ESI): calcd for C16H11N4O6 [M+H]+ : 355.0679, found 355.0682.
2-(2,4-dinitrobenzyl)-7-fluoroquinoline (3f). 14 h, 37.9 mg, 58% yield, brown solid; mp:
100-103 °C; 1H NMR (500 MHz, DMSO) δ 8.76 (s, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.34 (d, J = 8.2
Hz, 1H), 7.99 (dd, J = 16.9, 9.8 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.51 – 7.37 (m, 3H), 4.81 (s, 2H)
ppm; 13C NMR (125 MHz, DMSO) δ 163.4, 161.5, 159.2, 149.4, 147.8, 147.7, 146.4, 140.0, 136.9,
134.8, 130.5, 130.4, 127.3, 123.7, 121.0, 119.8, 116.4, 116.2, 111.8, 111.6, 40.9 ppm. HRMS
(ESI): calcd for C16H11FN3O4 [M+H]+ : 328.0734, found 328.0740.
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7-chloro-2-(2,4-dinitrobenzyl)quinoline (3g). 15 h, 35.7 mg, 52% yield, brown solid; mp:
130-133 °C; 1H NMR (500 MHz, DMSO) δ 8.77 (s, 1H), 8.52 (d, J = 8.1 Hz, 1H), 8.36 (d, J = 8.2
Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.55 (t, J = 10.0 Hz, 2H),
4.84 (s, 2H) ppm; 13C NMR (125 MHz, DMSO) δ 159.3, 149.4, 147.1, 146.5, 139.9, 136.9, 134.8,
134.2, 129.8, 127.4, 126.9, 126.8, 125.1, 122.0, 119.9, 40.9 ppm. HRMS (ESI): calcd for
C16H11ClN3O4 [M+H]+ : 344.0438, found 344.0440.
2-((2,4-dinitrophenyl)(phenylsulfonyl)methyl)quinoline (3h). 12 h, 73.6 mg, 82% yield, brown
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solid; mp: 171-173 °C; H NMR (500 MHz, CDCl3) δ 9.21 – 9.18 (m, 1H), 8.67 (d, J = 2.4 Hz,
1H), 8.53 (dd, J = 8.8, 2.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.83 (t, J =
6.7 Hz, 1H), 7.76 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.61 (qd, J = 8.3, 1.1 Hz, 4H), 7.50 (d, J = 8.4
Hz, 1H), 7.45 – 7.41 (m, 2H), 6.80 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ 150.3, 149.9,
147.9, 147.7, 137.5, 137.3, 135.9, 134.7, 132.4, 130.4, 129.9, 129.4, 129.3, 127.9, 127.7, 127.6,
126.3, 123.5, 119.9, 69.7 ppm. HRMS (ESI): calcd for C22H16N3O6S [M+H]+ : 450.0760, found
450.0764.
7-chloro-2-((2,4-dinitrophenyl)(phenylsulfonyl)methyl)quinoline (3i). 12 h, 71.5 mg, 74% yield,
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brown solid; mp: 207-210 °C; H NMR (500 MHz, DMSO) δ 9.02 – 8.97 (m, 1H), 8.67 (dd, J =
7.3, 2.3 Hz, 2H), 8.49 (d, J = 8.5 Hz, 1H), 8.07 (dd, J = 15.0, 5.3 Hz, 2H), 7.74 – 7.71 (m, 2H),
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7.70 (d, J = 5.9 Hz, 1H), 7.68 (d, J = 7.4 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 6.78 (s, 1H) ppm; 13
C
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NMR (125 MHz, DMSO) δ 151.7, 150.0, 147.5, 147.1, 137.6, 136.7, 135.0, 135.0, 134.9, 130.6,
130.0, 129.4, 129.1, 128.4, 127.6, 126.6, 125.8, 124.3, 119.7, 68.8 ppm. HRMS (ESI): calcd for
C22H15ClN3O6S [M+H]+ : 484.0370, found 484.0375.
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2-(2,4-dinitrobenzyl)pyrazine (3j). 12 h, 29.8 mg, 57% yield, brown solid; mp: 56-58 °C; H
NMR (500 MHz, CDCl3) δ 8.89 (d, J = 2.4 Hz, 1H), 8.64 (d, J = 1.2 Hz, 1H), 8.46 – 8.42 (m, 2H),
8.41 – 8.39 (m, 1H), 7.72 (t, J = 6.7 Hz, 1H), 4.64 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ
152.9, 149.3, 147.25, 145.0, 144.3, 143.3, 139.8, 134.9, 127.4, 120.7, 38.8 ppm. HRMS (ESI):
calcd for C11H8N4NaO4 [M+Na]+ : 283.0443, found 283.0443.
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4-(2,4-dinitrobenzyl)pyrimidine (3k). 13 h, 39 mg, 75% yield, brown solid; mp: 50-53 °C; H
NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 8.90 (d, J = 2.3 Hz, 1H), 8.67 (d, J = 5.2 Hz, 1H), 8.50 –
8.38 (m, 1H), 7.73 (t, J = 6.7 Hz, 1H), 7.33 (d, J = 5.2 Hz, 1H), 4.58 (s, 2H) ppm; 13C NMR (125
MHz, CDCl3) δ 165.4, 158.9, 157.5, 149.3, 147.4, 139.0, 135.0, 127.4, 121.0, 120.7, 41.1 ppm.
HRMS (ESI): calcd for C11H9N4O4 [M+H]+ : 261.0624, found 261.0629.
2-(2,4-dinitrobenzyl)benzo[d]oxazole (3l). 16 h, 28.7 mg, 48% yield, brown solid; mp:
84-87 °C; 1H NMR (500 MHz, CDCl3) δ 8.96 (d, J = 2.3 Hz, 1H), 8.46 (dd, J = 8.4, 2.4 Hz, 1H),
7.75 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 6.9, 1.9 Hz, 1H), 7.49 (dd, J = 7.1, 1.7 Hz, 1H), 7.31 (pd, J
= 7.4, 1.4 Hz, 2H), 4.77 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 162.2, 151.0, 149.0, 147.7,
141.0, 136.7, 134.4, 127.8, 125.4, 124.7, 121.1, 120.1, 110.7, 33.2 ppm. HRMS (ESI): calcd for
C14H10N3O5 [M+H]+ : 300.0620, found 300.0619.
2-(2,4-dinitrobenzyl)-6-nitrobenzo[d]oxazole (3m). 15 h, 36.5 mg, 53% yield, brown solid; mp:
58-60 °C; 1H NMR (500 MHz, CDCl3) δ 9.04 (d, J = 2.4 Hz, 1H), 8.54 (dd, J = 8.4, 2.3 Hz, 1H),
8.42 (d, J = 2.1 Hz, 1H), 8.28 (dd, J = 8.8, 2.1 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8
Hz, 1H), 4.85 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 167.1, 150.1, 148.9, 148.0, 146.1,
145.5, 135.6, 134.7, 128.1, 121.4, 120.9, 120.2, 107.4, 33.8 ppm. HRMS (ESI): calcd for
C14H9N4O7 [M+H]+ : 345.0471, found 345.0468.
2-(2,4-dinitrobenzyl)benzo[d]thiazole (3n). 14 h, 28.4 mg, 45% yield, brown solid; mp:
155-158 °C; 1H NMR (500 MHz, CDCl3) δ 8.94 (d, J = 2.4 Hz, 1H), 8.45 (dd, J = 8.5, 2.4 Hz, 1H),
7.93 (d, J = 8.2 Hz, 1H), 7.85 (dd, J = 8.0, 0.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.46 (ddd, J = 8.3,
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7.3, 1.2 Hz, 1H), 7.38 (td, J = 7.7, 1.2 Hz, 1H), 4.91 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ
165.8, 153.0, 148.9, 147.5, 138.8, 135.5, 134.4, 127.7, 126.5, 125.6, 123.2, 121.8, 120.9, 37.6 ppm.
HRMS (ESI): calcd for C14H10N3O4S [M+H]+: 316.0392, found 316.0383.
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2-(2,4-dinitrobenzyl)-6-nitrobenzo[d]thiazole (3o). 14 h, 46.8 mg, 65% yield, brown solid; mp:
136-138 °C; 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J = 2.3 Hz, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.51
(dt, J = 14.0, 5.0 Hz, 1H), 8.32 (dd, J = 9.0, 2.3 Hz, 1H), 7.99 (dd, J = 8.9, 3.3 Hz, 1H), 7.85 –
7.81 (m, 1H), 4.97 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 172.1, 156.6, 148.8, 147.8, 145.3,
137.7, 135.9, 134.7, 128.0, 123.5, 122.0, 121.2, 118.3, 38.3 ppm. HRMS (ESI): calcd for
C14H9N4O6S [M+H]+ : 361.0243, found 361.0240.
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5-chloro-2-(2,4-dinitrobenzyl)benzo[d]thiazole (3p). 14 h, 40.5 mg, 58% yield, brown solid; mp:
82-84 °C; 1H NMR (500 MHz, CDCl3) δ 8.92 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.79
(d, J = 8.5 Hz, 1H), 7.73 (t, J = 10.2 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 4.89 (s, 2H) ppm; 13C
NMR (125 MHz, CDCl3) δ 167.9, 153.7, 148.8, 147.5, 138.4, 134.5, 133.7, 132.5, 127.8, 126.1,
123.0, 122.4, 120.9, 37.7 ppm. HRMS (ESI): calcd for C14H9ClN3O4S [M+H]+ : 350.0002, found
350.0006.
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2-(2,4-dinitrobenzyl)thiazole (3q). 14 h, 21.2 mg, 40 yield, brown solid; mp: 45-47 °C; H
NMR (500 MHz, CDCl3) δ 8.88 (s, 1H), 8.41 (t, J = 9.7 Hz, 1H), 7.73 (t, J = 10.0 Hz, 1H), 7.68 (s,
1H), 7.29 (s, 1H), 4.81 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 164.9, 148.8, 147.3, 142.9,
139.5, 134.3, 127.6, 120.8, 119.9, 36.4 ppm. HRMS (ESI): calcd for C10H8N3O4S [M+H]+ :
266.0236, found 266.0230.
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2-(4-nitrobenzyl)quinoxaline (3r). 14 h, 27.6 mg, 52% yield, brown solid; mp: 78-81 °C; H
NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 8.19 (d, J = 8.7 Hz, 2H), 8.08 (ddd, J = 9.6, 7.9, 1.1 Hz,
2H), 7.77 (tdd, J = 8.5, 7.0, 1.6 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 4.48 (s, 2H) ppm; 13C NMR
(125 MHz, CDCl3) δ 154.1, 147.2, 145.6, 145.5, 142.3, 141.6, 130.6, 130.1, 129.9, 129.5, 129.3,
124.2, 42.6 ppm. HRMS (ESI): calcd for C15H12N3O2 [M+H]+ : 266.0930, found 266.0926.
2-((8-nitroquinolin-5-yl)methyl)quinoxaline (3s). 12 h, 46.2 mg, 73% yield, brown solid; mp:
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134-137 °C; H NMR (500 MHz, CDCl3) δ 9.00 (dd, J = 4.3, 1.6 Hz, 1H), 8.85 – 8.79 (m, 1H),
8.20 (dd, J = 8.3, 1.6 Hz, 1H), 8.11 – 8.03 (m, 2H), 7.88 (d, J = 8.6 Hz, 1H), 7.76 (pd, J = 7.0, 1.7
Hz, 2H), 7.63 (dd, J = 8.5, 4.3 Hz, 1H), 7.53 (dd, J = 8.3, 4.3 Hz, 1H), 4.53 (s, 2H) ppm; 13C NMR
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(125MHz, CDCl3) δ 153.0, 152.6, 148.6, 145.7, 142.2, 141.7, 139.9, 135.8, 130.5, 130.1, 129.9,
129.9, 129.5, 129.3, 128.3, 127.8, 122.9, 38.1 ppm. HRMS (ESI): calcd for C18H13N4O2 [M+H]+ :
317.1039, found 317.1040.
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2-((4-nitronaphthalen-1-yl)methyl)quinoxaline (3t). 14 h, 50.4 mg, 80% yield, brown solid; mp:
112-115 °C; 1H NMR (500 MHz, CDCl3) δ 8.70 – 8.67 (m, 1H), 8.55 (d, J = 8.7 Hz, 1H), 8.28 (d,
J = 8.5 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.08 – 8.04 (m, 2H), 7.75 (dddd, J = 14.9, 8.4, 7.0, 1.5
Hz, 2H), 7.70 – 7.66 (m, 1H), 7.60 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 4.89 (s,
2H) ppm; 13C NMR (125 MHz, CDCl3) δ 154.2, 146.6, 145.3, 142.2, 141.5, 141.3, 132.9, 130.48,
129.8, 129.4, 129.3, 129.2, 127.9, 126.2, 125.7, 125.0, 123.9, 123.6, 41.0 ppm. HRMS (ESI):
calcd for C19H14N3O2 [M+H]+ : 316.1086, found 316.1080.
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2-((5-nitroisoquinolin-8-yl)methyl)quinoxaline (3u). 12 h, 41.1 mg, 65% yield, brown solid; mp:
126-129 °C; 1H NMR (500 MHz, CDCl3) δ 9.29 (s, 1H), 8.80 (d, J = 5.3 Hz, 1H), 8.66 (t, J = 5.4
Hz, 1H), 8.09 – 8.04 (m, 2H), 8.02 – 7.97 (m, 1H), 7.75 – 7.69 (m, 3H), 7.64 (d, J = 6.1 Hz, 1H),
4.58 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 152.7, 152.4, 146.4, 146.0, 145.4, 142.1, 141.6,
133.0, 131.0, 130.5, 129.9, 129.6, 129.4, 129.2, 128.0, 127.7, 114.6, 38.6 ppm. HRMS (ESI):
calcd for C18H13N4O2 [M+H]+ : 317.1039, found 317.1035.
2-((5-nitroquinolin-8-yl)methyl)quinoxaline (3v). 14 h, 44.2 mg, 70% yield, brown solid; mp:
121-123 °C; 1H NMR (500 MHz, CDCl3) δ 9.00 (dd, J = 4.2, 1.6 Hz, 1H), 8.84 – 8.81 (m, 1H),
8.25 – 8.16 (m, 2H), 8.10 – 8.06 (m, 1H), 8.05 – 8.00 (m, 1H), 7.83 – 7.79 (m, 1H), 7.78 – 7.71 (m,
2H), 7.58 (dd, J = 8.7, 4.2 Hz, 1H), 4.58 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 153.0, 151.8,
147.1, 147.1, 145.5, 142.2, 141.7, 133.1, 131.4, 130.6, 130.5, 129.9, 129.4, 129.3, 129.0, 123.6,
120.6, 38.4 ppm. HRMS (ESI): calcd for C18H13N4O2 [M+H]+ : 317.1039, found 317.1042.
General Procedure for Deuterium Experiment
a. 2-Methylquinoxaline 1a (1.0 equiv., 0.2 mmol) was added in DMSO (2 mL) and D2O (0.2 mL)
under air. The reaction mixture was stirred at room temperature for 10 min. The reaction mixture
was quenched by the addition of water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The
combined organic phases were washed with brine (3 × 20 mL). Dried by MgSO4 and concentrated
1
to afford the crude product. The deuterium rate was obtained from H NMR (See Supporting
Information, S2 and S3).
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b. Potassium tert-butoxide (2.0 equiv., 0.4 mmol) was added to a solution of 2-methylquinoxaline
1a (1.0 equiv., 0.2 mmol) in DMSO (2 mL) and D2O (0.2 mL) under air. The reaction mixture was
stirred at room temperature for 10 min. The reaction mixture was quenched by the addition of
water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were
washed with brine (3 × 20 mL). Dried by MgSO4 and concentrated to afford the crude product.
The deuterium rate was obtained from 1H NMR (See Supporting Information, S3 and S4).
General Procedure for KIE Experiment
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Potassium tert-butoxide (2.0 equiv., 0.4 mmol) was added to a solution of 2-methylquinoxaline 1a
(0.2 mmol), [D]-1a (0.2 mmol) and 1,3-dinitrobenzene 2a (1.0 equiv., 0.4 mmol) in DMSO (2 mL)
under air. The reaction mixture was stirred at room temperature for 10 h. The reaction mixture was
quenched by the addition of water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The
combined organic phases were washed with brine (3 × 20 mL). Dried by MgSO4 and concentrated
to afford the crude product. After completion, the reaction mixture was purified by flash
chromatography eluting with ethyl acetate and petroleum ether (1:15 to 1:10) to give the product
3a-D/H. The deuterium rate was obtained from 1HNMR (See Supporting Information, S5).
ACKNOWLEDGMENTS
We are grateful to Shandong Provincial Natural Science Foundation for Distinguished Young
Scholars (JQ201604) and General Project (ZR2016BM07). Financial supports from Qingdao
Special Research Foundation of Science and Technology (16-6-2-29-nsh) and Talents of High
Level Scientific Research Foundation (Nos. 6631112323, 6631115015, 6631110309) of
Qingdao Agricultural University are also gratefully acknowledged. We thank Central
Laboratory of Qingdao Agriculture University for NMR determination.
Supporting Information
NMR spectra of the products. This material is available free of charge via the Internet at http:
//pubs.acs.org.
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