Metal-Free Direct C-H Cyanoalkylation of Quinoxalin-2(1 H)-Ones by Organic Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.9b00657

Green and efficient C-C bond cleavage/cyanoalkylation of quinoxalin-2(1H)-ones and other heteroarenes under visible light or sunlight irradiation is described. The reaction proceeds under mild conditions at room temperature without transition-metal catalysts and extra bases. Notably, the products enable facile transformations to various significant organic compounds.

Full text of DOI:10.1021/acs.joc.9b00657

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Article
Metal-Free Direct C-H Cyanoalkylation of
Quinoxalin-2(1H)-ones by Organic Photoredox Catalysis
Wei Zhang, Yu-Liang Pan, Chen Yang, Li Chen, Jin-Pei Cheng, and Xin Li
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 29 May 2019
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Metal-Free
Direct
C-H
Cyanoalkylation
of
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Quinoxalin-2(1H)-ones by Organic Photoredox Catalysis
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Wei Zhang,§ Yu-Liang Pan,§ Chen Yang, Li Chen, Xin Li* and Jin-Pei Cheng
State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071.
Email: xin_li@nankai.edu.cn.
Abstract: A green and efficient C-C bond cleavage/cyanoalkylation of heteroarenes
under visible-light or sunlight irradiation are described. The reaction proceeds under
mild conditions at room temperature without transition-metal catalysts and extra bases.
Notably, the products enable facile transformations to various significant organic
compounds.
Introduction
Alkylnitriles represent a privileged class of structural motifs found in several
nitrile-containing natural products and pharmaceuticals.1 and 2 Owing to their biological
and pharmaceutical properties, efficient incorporation of a cyanoalkyl group into
structurally diverse molecules has attracted much attention. Cyanoalkylation is the
most useful reaction, because the cyano group can be readily converted into other
functional groups.3 The traditional approach of the cyanoalkylation, is to generate
carbanions from simple alkylnitriles to react with electrophiles.4 This method is
requiring the utilization of strong bases, which is usually incompatible with
base-sensitive substrates. On the other hand, the generation of metalated nitriles is an
attractive alternative route to activate alkylnitriles.5 However, these reactions are
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usually conducted at high temperature and the scope is usually limited. In addition,
radical cyanoalkylation also represent an efficient approach to alkylnitriles.6-8
Recently, much efforts in this area have been emphasized on cyanomethylation using
α-cyanomethyl radicals.6 In comparison, cyanoalkylation based on distal
cyano-substituted alkyl radicals has been rarely studied, presumably due to the lack of
suitable approaches for radical initiation. The cyclobutanone oxime used as an
equivalent of γ-cyanoalkyl radical (Scheme 1), which using AIBN as a radical initiator,
was firstly reported by Zard and co-workers.8 Very recently, ring-opening of
cyclobutanone oxime derivatives have been explored with transition metal catalysis,
photoredox catalysis and organocatalysis.7 Although much endeavours have been paid
in this area as mentioned above, as we know, direct catalytic distal radical
cyanoalkylation methodologies under metal-free conditions are still rare.
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Scheme 1. The method for ring-opening of cyclobutanone oxime derivatives
Quinoxalin-2(1H)-ones are distributed in many compounds of enormous practical
importance, ranging from bioactive natural products to pharmaceutical agents and
material science.9 Chemists have devoted extensive efforts to the synthesis of these
aza-heterocycles. Direct modification of easily available quinoxalin-2(1H)-ones leads
a rapid way to obtain diverse derivatives.10-15 To date, several important advances
have been established, such as radical arylation, phosphonation, amination, acylation,
and trifluoromethylation of quinoxalin-2(1H)-ones. In comparison, C-H alkylation of
quinoxalin-2(1H)-ones is still rare. In particular, the 3-alkylquinoxalin-2(1H)-one
moiety as an important pharmacophore has appeared in numerous biological
molecules (Figure 1).16 Therefore, the development of environmentally benign and
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synthetically efficient protocols to introduce alkyl substituents at the 3-position of
quinoxalin-2(1H)-ones is still highly desirable, which might advance their use in new
drug discovery and development.
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Figure 1. Selected biological structures bearing a 3-alkylquinoxalin-2(1H)-one unit.
Visible-light photocatalysis has received wide attention from synthetic chemists in
the past decade.17 The outstanding feature is its ability to generate various high active
species under mild conditions, which promoted the development of synthetic
chemistry. Currently, cheap organic dyes have been proven to be a reliable option to
the replacement of those metal photoredox catalysts in many valuable
transformations.17d,e To the best of our knowledge, direct C −H cyanoalkylation of
heteroarenes at room temperature without transition-metal catalyst has not been
realized. Herein we developed extremely mild conditions to access the direct
cyanoalkylation of quinoxalin-2(1H)-ones or other heteroarenes with cyclobutanone
oxime esters under metal-free conditions. It is valuable noted that the reaction system
is simple, no extra bases is needed and excess starting materials can easily be
recycled.
Results and Discussion
Initially, we chose the 1-methylquinoxalin-2(1H)-one 1a and cyclobutanone O-acyl
oxime 2a as model substrates to optimize the reaction conditions. The results are
illustrated in Table 1. When the model reaction was carried out using 2 mol% Eosin Y
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as photocatalyst in CH2Cl2 at room temperature under an argon atmosphere, the
desired product 3a was obtained in quantitative yield (Table 1, entry 1). Next, other
organic photocatalysts, such as DCA, MB, Rose Bengal, Acridinium salt were
investigated. Unfortunately, none of them showed good efficiency (Table 1, entries
2-5). Several solvents were then screened. As a result, all the other examined solvents
gave the poor results than CH2Cl2 (Table 1, entries 6-10). The yield of the product
remained approximately the same when the loading of the photocatalyst was further
decreased to 1 mol% (Table 1, entry 11), accompanied by an extension of the reaction
time. Control experiments indicated that photocatalysts, inert-atmosphere and
blue-light sources were essential for the reaction efficiency (Table 1, entries 12-14).
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Table 1. Optimization of the reaction conditions.a
Entry
Photocatalyst
EosinY
Time(h) Solvent Yield(%)b
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7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
DMF
>99%
NR
NR
NR
80
Rose Bengal
DCA
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MB
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Acridinium salt
EosinY
12
7
NR
NR
EosinY
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EosinY
EosinY
EosinY
EosinY
-
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36
7
MeOH
PhCH3
H2O
65
80
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11c
12
NR
97
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CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
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NR
NR
NR
13d
14e
EosinY
EosinY
a Unless noted otherwise, Reaction conditions: 1a (0.15 mmol, 1.5 equiv), 2a (0.1 mmol, 1 equiv)
and photocatalysts (0.002 mmol, 2.0 mol %) in indicated solvent (1.0 ml) at room temperature
b
c
under an atmosphere of argon and the irradiation of 6w blue LEDs. Isolated yield. The catalyst
loading was 1.0 mol %. d Under air. e In the dark. NR: no reaction.
With the optimal conditions in hand, we first examined the scope of various
quinoxalin-2(1H)-ones 1 with cyclobutanone O-acyl oxime 2a (Scheme 2). Various
quinoxalin-2(1H)-ones bearing electron-donating and electron-withdrawing
substituents on the arene rings exhibited good reaction efficiency, affording the
corresponding 3-cyanopropylated products 3b-3k in good to excellent yields. An
array of functional groups including fluoro, chloro, bromo, nitro, cyano, methoxyl and
naphthyl were well tolerated under the optimal conditions. After that, we screened
different protecting groups of nitrogen. As a result, all of the protecting groups tested
were tolerated, furnishing the corresponding products 3l-3o in excellent yields.
N-unsubstituted quinoxalin-2(1H)-one was also proceeded smoothly, giving the
desired product 3p in 60% yield.
Scheme 2. Substrate scope of quinoxalin-2(1H)-ones ab
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a
Reaction conditions:
1
(0.15 mmol, 1.5 equiv), 2a (0.1 mmol, 1 equiv), and Eosin Y
(0.001 mmol, 1.0 mol %) in DCM (1.0 ml) at room temperature under an atmosphere of
b
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argon and the irradiation of 6W blue LEDs. Isolated yield. The structure of 3a was
determined by X-ray analysis.19
Encouraged by these results, we continued to investigate the substrate generality
with a range of representative cyclobutanone O-acyl oximes 2 with 1a under standard
conditions (Scheme 3). To our delight, nonsymmetrical cyclobutanone derived acyl
oximes 2b-2d with benzyl, methyl and allyl groups at the 2-position were all well
tolerated to furnish the expected products 3q-3s (67-99% yields). Symmetric
monosubstituted O-acyl oximes 2e-2i with various functional groups, such as cyano,
ester, ether and phenyl substituents at the 3-position, also proceeded smoothly to
deliver the products 3t-3x (42-99% yields). Furthermore, disubstituted substrates 2j-2l
were also compatible with our photocatalytic system, generating desired products
3y-3aa in 52-65% yields. In addition, both 1-Cbz-3-azetidinone and oxetan-3-one
derived O-acyl oximes 2m and 2n participated in the reaction very well to give the
products 3ab-3ac in good yields. Once again, the reaction of
benzocyclobutenone-derived substrate 2o proved to be suitable for the reaction, in
which 3ad was formed as the sole product in 99% yield.
Scheme 3. Substrate scope of cyclobutanone oxime esters ab
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a
Reaction conditions: 1a (0.15 mmol, 1.5 equiv),
2 (0.1 mmol, 1 equiv), and Eosin Y
(0.001 mmol, 1.0 mol %) in DCM (1.0 ml) at room temperature under an atmosphere of
argon and the irradiation of 6W blue LEDs. b Isolated yield.
In contrast to transition-metal catalyzed ring-opening of cyclobutanone oximes,18
a
range of the more challenging unstrained oxime esters 4a-4c from cyclopentanone,
cyclohexanone and camphor (Scheme 4) could also participate in this cyanoalkylation
strategy very well to give the desired products 5a-5c in 46-90% yields. These results
demonstrated the advantages of this procedure. To further explore the potential of our
photocatalytic system, we attempted to apply this strategy to a series of significant
natural bioactive skeletons, such as benzothiazole, benzoxazole and isoquinoline, that
are readily accessible from commercial feedstocks (Scheme 5). As a result, treatment
of 6a-6c with 2a in standard condition furnished expected products 7a-7c in 42-52%
yields.
Scheme 4. Substrate scope of cyclopentanone and cyclohexanone oxime esters
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Scheme 5. Substrate scope of other significant heteroarenes
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To evaluate the prospective utility of the methodology, a large-scale reaction, the
transformation of the product and a sunlight-driven experiment were performed
(Scheme 6). Notably, the scalability of this procedure was demonstrated by a 2
mmol of 2a with 3 mmol of 1a, which proceeded smoothly to deliver the product 3a
in 85% yield. It is worthy noted that the cyano group was a synthetically versatile
precursor. We then selected several key transformations to highlight the potential of
the product. Conversion of 3a into ester 8a or carboxylic acid 10a could be easily
achieved with good yields by hydrolysis in the presence of acid. Moreover, selective
reduction of the nitrile group could be achieved by using NaBH4 to afford the
secondary amine 9a in 65% yield. In addition, the oxidation of 3a with H2O2
delivered amides 11a in 83% yield. To our delight, the reaction was also proceeded
well in the sunlight, gave the product 3a in 85 % yield.
Scheme 6. Synthetic Utility of the Methodology a
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a The image in the scheme 6 was photographed by Yu-Liang Pan
In order to gain more insight into the mechanism of this reaction, some experiments
were carried out (Scheme 7). The reaction was obviously suppressed when 2 equiv of
radical scavenger TEMPO or PhSeSePh were added under the standard conditions.
Instead, the radical trapping adducts were obtained in 14% and 70% yields,
respectively. These evidence implied that iminyl radical-mediated C-C bond cleavage
and formation of cyanoalkyl radical might be involved in the reaction. Stern-Volmer
fluorescence quenching experiments clearly demonstrated that the excited state of the
photocatalyst can be quenched by the cyclobutanone oxime derivatives (Figure S2).
Based on the above results and previous related literature, a possible mechanism was
proposed (Scheme 7). Initially, the photocatalyst Eosin Y is irradiated to the excited
states Eosin Y * (Eox= ‐ 1.58V vs Ag/AgCl),16e which is oxidatively quenched by
7e
+
O-acyl oxime (E2a= ‐ 1.60V vs Ag/AgCl)
with the generation of a Eosin Y
complex, a iminyl radical A and alkoxy anion. This process is similar to the Xiao’s
7e
work using fac-Ir(ppy)3 as the photocatalyst. Subsequently, the iminyl radical A
undergoes a ring-opening by homolytic C-C bond cleavage to form a highly reactive
cyanoalkyl radical B. Addition of B to 1-methylquinoxalin-2(1H)-one 1a produces
+
radical intermediate C, which undergoes single-electron oxidation by Eosin Y
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complex with the regeneration of ground-state Eosin Y, closing the photocatalytic
cycle. Finally, intermediate D by loss of H+ assisted with alkoxy anion to afford the
product 3a.
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Scheme 7. Experiment for mechanistic study and a proposed mechanism
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Conclusions
In summary, cyanoalkylation of quinoxalin-2(1H)-ones or other heteroarenes has been
achieved with organic photoredox catalysis. This reaction provides a green and
efficient approach to construct long-chain nitriles moieties, which are valuable in
pharmaceutical chemistry. The reaction shows good functional group tolerance and
wide substrate scope, accessing to
a
wide range of 3-cyanoalkylated
quinoxalin-2(1H)-ones, which could be a potential biological and pharmaceutically
active molecule. Notably, the established methodology is also applicable for the
cyanoalkylation of other heteroarenes, such as benzothiazole, benzoxazole and
isoquinoline. The products can be easily converted to some significant organic
compounds. Preliminary mechanistic evidence suggests that the cyanoalkyl radicals
are involved in the process.
Experimental Section
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General Experimental Procedures. Unless otherwise noted, materials were
purchased from commercial suppliers and used without further purification. The
purchased solvents were degassed by three cycles of freeze-pump-thaw before use in
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1
the reaction. H NMR spectra were recorded in on 400 MHz spectrometer. Chemical
shifts are reported in ppm from tetramethylsilane with the solvent resonance as the
internal standard. The following abbreviations were used to designate chemical shift
mutiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. All
first-order splitting patterns were assigned on the basis of the appearance of the
multiplet. Splitting patterns that could not be easily interpreted are designated as
multiplet (m). 13C NMR were recorded on 100 MHz with complete proton decoupling
spectrophotometer. Mass spectra were measured using agilent 6520 Q-TOF micro
spectrometer. The light source in detail and the material of the irradiation vessel see
the SI (Figure S1).
Most substrates 1 and 2 were synthesized according to the reported literatures. 7, 10-15
In addition, 1b and 1j were new compounds.
General Experimental Procedure for the Synthesis of product 3
1 (0.15 mmol), 2 (0.1 mmol) and Eosin Y (1 mol %) were dissolved in DCM (1 mL).
Then, the resulting mixture was degassed via ‘freeze-pump-thaw’ procedure (3 times).
After that, the solution was stirred at a distance of ~5 cm from a 6 W blue LEDs
(450-460 nm) at room temperature about 10-24 h until the reaction was completed as
monitored by TLC analysis. The crude product was purified by flash chromatography
on silica gel (petroleum ether/ethylacetate 3:1~2:1) directly to give the desired
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product 3.
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4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3a) yellow solid, 22 mg,
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97% yield; mp 98-100 °C. H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.0, 1.2 Hz,
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1H), 7.57-7.53 (m, 1H), 7.37-7.30 (m, 2H), 3.70 (s, 3H), 3.08 (t, J = 6.8 Hz, 2H), 2.54
13
(t, J = 7.2 Hz, 2H), 2.22 (m, 2H); C NMR {1H} (100 MHz, CDCl3) δ158.5, 154.7,
133.1, 132.5, 130.1, 129.8, 123.8, 119.6, 113.6, 32.3, 29.1, 22.0, 16.8; HRMS (ESI):
m/z [M + Na]+ calcd for C13H13N3ONa:250.0951, , found:250.0954.
4-(4,8-dimethyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3b) yellow solid,
21.1 mg, 88% yield; mp 120-122 °C. 1H NMR (400 MHz, CDCl3) δ7.43 (t, J = 7.6 Hz,
1H), 7.21 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.69 (s, 3H), 3.10 (t, J = 6.8
13
Hz, 2H), 2.67 (s, 3H), 2.58 (t, J = 7.2 Hz, 2H), 2.25 (m, 2H); C NMR{1H} (100
MHz, CDCl3) δ156.4, 154.7, 138.5, 133.1, 131.0, 129.7, 125.0, 119.7, 111.6, 32.1,
29.2, 21.9, 17.5, 16.6; HRMS (ESI): m/z [M + Na]+ calcd for C14H15N3ONa: 264.1107,
found: 264.1110.
4-(7-chloro-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3c) yellow
solid, 25.2 mg, 96% yield; mp 106-108 °C. 1H NMR (400 MHz, CDCl3) δ7.83 (d, J =
2.4 Hz, 1H), 7.51 (dd, J = 8.8, 2.4 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 3.71 (s, 3H), 3.11
(t, J = 7.2 Hz, 2H), 2.57 (t, J = 7.2 Hz, 2H), 2.24 (m, 2H); 13C NMR{1H} (100 MHz,
CDCl3) δ 160.0, 154.4, 133.0, 131.8, 130.0, 129.2, 129.1, 119.5, 114.8, 32.3, 29.2,
21.8, 16.7; HRMS (ESI): m/z [M + Na]+ calcd for C13H12ClN3ONa: 284.0561,
found:284.0565.
4-(7-bromo-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3d) yellow
solid, 30.5mg, 99.9% yield; mp 96-98 °C. 1H NMR (400 MHz, CDCl3) δ7.67-7.65 (m,
1H), 7.46-7.43 (m, 2H), 3.66 (s, 3H), 3.05 (t, J = 6.8 Hz, 2H), 2.53 (t, J = 7.2 Hz, 2H),
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2.20 (m, 2H); C NMR{1H} (100 MHz, CDCl3) δ158.9, 154.4, 134.1, 131.3, 131.0,
127.0, 124.1, 119.5, 116.8, 32.3, 29.2, 21.9, 16.7; HRMS (ESI): m/z [M + Na]+ calcd
for C13H12BrN3ONa: 328.0056, found:328.0060.
4-(6-bromo-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3e) yellow
solid, 29.1 mg, 95% yield; mp 87-89 °C. 1H NMR (400 MHz, CDCl3) δ 7.68-7.66 (m,
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2.21 (m, 2H); C NMR{1H} (100 MHz, CDCl3) δ158.9, 154.4, 134.1, 131.3, 131.0,
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127.0, 124.1, 119.5, 116.8, 32.3, 29.2, 21.9, 16.8; HRMS (ESI): m/z [M + Na]+ calcd
for C13H12BrN3ONa: 328.0056, found:328.0058.
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4-(7-fluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3f) yellow solid,
22 mg, 90% yield; mp 93-95 °C. 1H NMR (400 MHz, CDCl3) δ7.53 (dd, J = 8.8, 2.8
Hz, 1H), 7.34-7.26 (m, 2H), 3.71 (s, 3H), 3.10 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.2 Hz,
2H), 2.22 (m, 2H); 13C NMR{1H} (100 MHz, CDCl3) δ160.1, 158.7 (d, J = 244.8 Hz),
154.4, 133.1 (d, J = 11.1 Hz), 129.7 (d, J = 2.2 Hz), 119.5, 117.8 (d, J = 23.9 Hz),
115.3 (d, J = 22.7 Hz), 114.8 (d, J = 8.9 Hz), 32.4, 29.4, 21.8, 16.8; HRMS (ESI): m/z
[M + Na]+ calcd for C13H12FN3ONa: 268.0857, found:268.0860
4-(6,7-dichloro-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3g) yellow
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solid, 20.7 mg, 70% yield; mp 135-137 °C. H NMR (400 MHz, CDCl3) δ 7.90 (s,
1H), 7.39 (s, 1H), 3.65 (s, 3H), 3.07 (t, J = 6.8 Hz, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.19
(m, 2H); 13C NMR{1H} (100 MHz, CDCl3) δ160.1, 154.1, 134.1, 132.5, 131.5, 130.6,
127.5, 119.4, 115.2, 32.3, 29.4, 21.7, 16.7; HRMS (ESI): m/z [M + Na]+ calcd for
C13H11Cl2N3ONa: 318.0171, found:318.0175.
4-(4-methyl-6-nitro-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3h) yellow solid,
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17.8 mg, 65% yield; mp 132-134 °C. H NMR (400 MHz, CDCl3) δ 8.25-8.20 (m,
2H), 8.00 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H), 3.18 (t, J = 7.2 Hz, 2H), 2.59 (t, J = 7.2 Hz,
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2H), 2.27 (m, 2H); C NMR{1H} (100 MHz, CDCl3) δ162.8, 154.2, 147.7, 135.8,
133.5, 130.9, 119.3, 118.3, 109.7, 32.6, 29.6, 21.6, 16.8; HRMS (ESI): m/z [M + Na]+
calcd for C13H12N4O3Na: 295.0802, found: 295.0804.
3-(3-cyanopropyl)-1-methyl-2-oxo-1,2-dihydroquinoxaline-6-carbonitrile (3i) yellow
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solid, 21.4 mg, 85% yield; mp 133-135 °C. H NMR (400 MHz, CDCl3) δ7.92-7.90
(m, 1H), 7.61-7.59 (m, 2H), 3.71 (s, 3H), 3.13 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.6 Hz,
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2H), 2.23 (m, 2H); C NMR{1H} (100 MHz, CDCl3) δ162.2, 154.2, 134.6, 133.5,
130.8, 126.7, 119.4, 118.1, 117.9, 113.2, 32.5, 29.3, 21.7, 16.8; HRMS (ESI): m/z [M
+ Na]+ calcd for C14H12N4ONa: 275.0903, found:275.0906.
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4-(7-methoxy-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3j) yellow
solid, 24.9 mg, 97% yield; mp 136-138 °C. 1H NMR (400 MHz, CDCl3) δ7.33 (d, J =
2.8 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.21 (dd, J = 9.2, 2.8 Hz, 1H), 3.93 (s, 3H),
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NMR{1H} (100 MHz, CDCl3) δ159.0, 156.0, 154.4, 133.3, 127.3, 119.6, 119.2, 114.6,
111.2, 55.8, 32.5, 29.2, 22.1, 16.7; HRMS (ESI): m/z [M + Na]+ calcd for
C14H15N3O2Na: 280.1056, found:280.1060.
4-(4-methyl-3-oxo-3,4-dihydrobenzo[g]quinoxalin-2-yl)butanenitrile (3k) yellow
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solid, 25.8 mg, 93% yield; mp 138-140 °C. H NMR (400 MHz, CDCl3) δ 8.31 (s,
1H), 7.93 (dd, J = 26.4, 8.4 Hz, 2H), 7.63-7.53 (m, 2H), 7.51-7.47 (m, 1H), 3.75 (s,
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3H), 3.12 (t, J = 7.2 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.25 (m, 2H); C NMR{1H}
(100 MHz, CDCl3) δ159.0, 154.6, 133.5, 131.8, 131.6, 129.7, 128.9, 128.4, 127.9,
127.2, 125.4, 119.6, 110.1, 32.4, 29.1, 22.0, 16.8; HRMS (ESI): m/z [M + Na]+ calcd
for C17H15N3ONa: 300.1107, found:300.1111.
4-(4-allyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3l) yellow solid, 23.2 mg,
92% yield; mp 77-79 °C. 1H NMR (400 MHz, CDCl3) δ7.83 (dd, J = 8.0, 1.6 Hz, 1H),
7.53-7.49 (m, 1H), 7.36-7.32 (m, 1H), 7.29 (dd, J = 8.4, 0.4 Hz, 1H), 5.98-5.88 (m,
1H), 5.27 (dd, J = 10.4, 0.8 Hz, 1H), 5.16 (dd, J = 17.2, 0.4 Hz, 1H), 4.90 (dt, J = 5.2,
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1.8 Hz, 2H), 3.10 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.24 (m, 2H); C
NMR{1H} (100 MHz, CDCl3) δ158.5, 154.3, 132.7, 132.3, 130.5, 130.0, 129.9, 123.7,
119.6, 118.2, 114.3, 44.5, 32.3, 22.0, 16.8; HRMS (ESI): m/z [M + Na]+ calcd for
C15H15N3ONa: 276.1107, found:276.1112.
4-(3-oxo-4-propyl-3,4-dihydroquinoxalin-2-yl)butanenitrile (3m) yellow solid, 24.2
mg, 95% yield; mp 79-81 °C. 1H NMR (400 MHz, CDCl3) δ7.83 (dd, J = 7.6, 1.2 Hz,
1H), 7.53 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.36-7.30 (m, 2H), 4.23-4.19 (m, 2H), 3.08
(t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.6 Hz, 2H), 2.23 (m, 2H), 1.84-1.74 (m,2H), 1.05 (t, J
= 7.6 Hz, 3H); 13C NMR{1H} (100 MHz, CDCl3) δ 158.5, 154.5, 132.8, 132.3, 130.0,
129.9, 123.5, 119.6, 113.7, 43.9, 32.3, 22.1, 20.6, 16.8, 11.4; HRMS (ESI): m/z [M +
Na]+ calcd for C15H17N3ONa: 278.1264, found:278.1266.
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4-(4-benzyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3n) yellow solid, 29 mg,
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96% yield; mp 108-110 °C. H NMR (400 MHz, CDCl3) δ7.84 (d, J = 8.0, 1H),
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7.45-7.40 (m, 1H), 7.34-7.22 (m, 7H), 5.50 (s, 2H), 3.15 (t, J = 7.2 Hz, 2H), 2.58 (t, J
= 7.6 Hz, 2H), 2.27 (m, 2H); 13C NMR{1H} (100 MHz, CDCl3) δ158.6, 154.8, 135.1,
132.8, 132.4, 130.0, 129.9,129.0, 127.8, 126.9, 123.8, 119.7, 114.5, 46.0, 32.4, 22.1,
16.8; HRMS (ESI): m/z [M + Na]+ calcd for C19H17N3ONa: 326.1264,
found:326.1268.
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4-(3-oxo-4-pentyl-3,4-dihydroquinoxalin-2-yl)butanenitrile (3o) yellow solid, 28.2 mg,
99% yield; mp 77-79 °C. 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.0, 1.2 Hz, 1H),
7.54 (ddd, J = 16.0, 7.3, 1.6 Hz, 1H), 7.35-7.30 (m, 2H), 4.25-4.18 (m, 2H), 3.08 (t, J
= 7.2 Hz, 2H), 2.54 (t, J = 6.8 Hz, 2H), 2.22 (m, 2H), 1.79-1.71 (m, 2H), 1.47-1.35 (m,
4H), 0.92 (t, J = 6.8 Hz, 3H); 13C NMR{1H} (100 MHz, CDCl3) δ158.5, 154.4, 132.8,
132.3, 130.0, 129.9, 123.5, 119.7, 113.6, 42.4, 32.2, 29.1, 27.0, 22.4, 22.1, 16.8, 14.0;
HRMS (ESI): m/z [M + Na]+ calcd for C17H21N3ONa: 306.1577, found:306.1579.
4-(3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3p) yellow solid, 12.7 mg, 60%
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yield; mp 181-183 °C. H NMR (400 MHz, DMSO-d6) δ12.37 (s, 1H), 7.74 (d, J =
7.4 Hz, 1H), 7.50 (td, J = 7.7, 1.4 Hz, 1H), 7.30 (d, J = 7.6 Hz, 2H), 2.91 (t, J = 7.2
Hz, 2H), 2.65 (t, J = 7.1 Hz, 2H), 2.05 (m, 2H); 13C NMR{1H} (100 MHz, DMSO-d6)
δ 160.2, 154.6, 131.8, 131.5, 129.5, 128.1, 123.0, 120.6, 115.2, 31.3, 21.6, 15.9;
HRMS (ESI): m/z [M + Na]+ calcd for C12H11N3ONa: 236.0794, found:236.0797.
(R)-4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-5-phenylpentanenitrile
(3aa)
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yellow solid, 31.4 mg, 99% yield; mp 95-97 °C. H NMR (400 MHz, CDCl3) δ
7.87-7.83 (m, 1H), 7.58-7.52 (m, 1H), 7.39-7.26 (m, 6H), 7.21-7.16 (m, 1H),
3.86-3.84 (m, 1H), 3.71 (s, 3H), 3.27-3.20 (m, 1H), 2.39-2.22 (m, 3H), 2.03-1.98 (m,
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1H); C NMR{1H} (100 MHz, CDCl3) δ 160.4, 154.6, 139.3, 133.0, 132.5, 130.3,
130.0, 129.2, 128.5, 126.4, 123.8, 119.7, 113.7, 42.6, 39.3, 29.2, 27.1, 15.1; HRMS
(ESI): m/z [M + Na]+ calcd for C20H19N3O: 340.1420, found:340.1425.
(S)-4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)pentanenitrile (3ab) yellow solid,
20.7 mg, 86% yield; mp 80-82 °C. 1H NMR (400 MHz, CDCl3) δ7.83 (dd, J = 8.0, 1.2
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Hz, 1H), 7.55 (ddd, J = 16.0, 7.3, 1.5 Hz, 1H), 7.38-7.30 (m, 2H), 3.71 (s, 3H),
3.67-3.58 (m, 1H), 2.47-2.32 (m, 3H), 2.04-1.94 (m, 1H), 1.32 (d, J = 7.2 Hz, 3H); 13C
NMR{1H} (100 MHz, CDCl3) δ 161.8, 154.5, 133.0, 132.5, 130.1, 130.0, 123.7, 119.8,
113.7, 35.5, 29.6, 29.2, 18.5, 15.2; HRMS (ESI): m/z [M + H]+ calcd for C14H15N3O:
242.1288, found: 242.1290.
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(R)-4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)hept-6-enenitrile (3ac) yellow oil,
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17.8 mg, 67% yield; H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 8.0, 1.2 Hz, 1H),
7.56 (ddd, J = 16.0, 7.3, 1.6 Hz, 1H), 7.38-7.33 (m, 2H), 5.83-5.75 (m, 1H), 5.08-4.99
(m, 2H), 3.71 (s, 3H), 3.69-3.62 (m, 1H), 2.66-2.58 (m, 1H), 2.41-2.30 (m, 4H),
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2.13-2.04 (m, 1H); C NMR{1H} (100 MHz, CDCl3) δ 160.5, 154.6, 135.4, 132.9,
132.5, 130.2, 130.0, 123.7, 119.8, 117.4, 113.7, 40.2, 37.3, 29.3, 27.4, 15.1; HRMS
(EI): m/z [M + Na]+ calcd for C16H17N3O: 290.1264, found: 290.1266.
2-((4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)methyl)succinonitrile (3ad) yellow
solid, 22.2 mg, 88% yield; mp 139-141 °C. 1H NMR (400 MHz, CDCl3) δ7.87 (d, J =
8.0, 1H), 7.61 (t, J = 7.6, 1H), 7.41-7.34 (m, 2H), 3.81 (m, 1H), 3.72 (s, 3H),
3.51-3.34 (m, 2H), 2.97 (d, J = 6.8 Hz, 1H); 13C NMR{1H} (100 MHz, CDCl3) δ154.3,
153.8, 133.2, 132.1, 131.0, 130.1, 124.1, 118.9, 115.7, 113.9, 34.7, 29.3, 25.1, 20.7;
HRMS (ESI): m/z [M + H]+ calcd for C14H13N4O: 253.1084, found:253.1087.
tert-butyl 3-cyano-2-((4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)methyl)propanoate
(3ae) yellow solid, 32.7 mg, 99% yield; mp 117-119 °C. 1H NMR (400 MHz, CDCl3)
δ7.78 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (ddd, J = 8.5, 7.2, 1.2 Hz, 1H), 7.36-7.31 (m, 2H),
3.70 (s, 3H), 3.44-3.38 (m, 2H), 3.30-3.23 (m, 1H), 2.88-2.74 (m, 2H), 1.41 (s, 9H);
13C NMR{1H} (100 MHz, CDCl3) δ171.1, 156.7, 154.6, 133.1, 132.2, 130.2, 129.7,
123.8, 118.0, 113.7, 81.9, 39.3, 34.5, 29.1, 27.9,19.2; HRMS (ESI): m/z [M + Na]+
calcd for C18H21N3O3Na: 350.1475, found:350.1478.
ethyl 3-cyano-2-((4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)methyl)propanoate (3af)
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brown solid, 24.8 mg, 83% yield; mp 75-77 °C. H NMR (400 MHz, CDCl3) δ 7.77
(dd, J = 8.0, 1.2 Hz, 1H), 7.56 (ddd, J = 16.0, 7.3, 1.6 Hz, 1H), 7.36-7.31 (m, 2H),
4.19 (q, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.51-3.45 (m, 2H), 3.31 (dd, J = 19.2, 8.8 Hz,
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δ172.0, 156.4, 154.6, 133.1, 132.2, 130.3, 129.8, 123.8, 117.9, 113.7, 61.5, 38.5, 34.3,
29.1, 19.1, 14.1; HRMS (ESI): m/z [M + H]+ calcd for C16H18N3O3: 300.1343,
found:300.1345.
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3-(benzyloxy)-4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile
(3ag)
brown oil, 14 mg, 42% yield; 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 8.0, 1.2 Hz,
1H), 7.57 (ddd, J = 15.6, 8.4, 1.6 Hz, 1H), 7.39-7.35 (m, 1H), 7.31-7.26 (m, 3H),
7.22-7.19 (m, 3H), 4.73-4.66 (m, 2H), 4.43-4.40 (m, 1H), 3.65 (s, 3H), 3.42 (dd, J =
15.2, 6.4 Hz, 1H), 3.18 (dd, J = 15.2, 6.5 Hz, 1H), 2.78 (qd, J = 16.8, 4.8 Hz, 2H); 13C
NMR{1H} (100 MHz, CDCl3) δ156.4, 154.7, 137.4, 133.2, 132.5, 130.3, 130.0, 128.3,
128.1, 127.8, 123.8, 117.7, 113.7, 72.4, 72.1, 38.6, 29.1, 23.7; HRMS (ESI): m/z [M +
Na]+ calcd for C20H19N3O2Na: 356.1369, found:356.1375.
4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-3-phenylbutanenitrile (3ah) yellow
solid, 23 mg, 76% yield; mp 143-145 °C.1H NMR (400 MHz, CDCl3) δ7.83 (dd, J =
8.0, 1.2 Hz, 1H), 7.57-7.53 (m, 1H), 7.40-7.29 (m, 6H), 7.27-7.23 (m, 1H), 3.92-3.85
(m, 1H), 3.69 (s, 3H), 3.48-3.34 (m, 2H), 2.88-2.75 (m, 2H); 13C NMR{1H} (100
MHz, CDCl3) δ 157.4, 154.8, 141.6, 133.1, 132.5, 130.2, 129.9, 128.9, 127.5, 127.4,
123.8, 118.5, 113.7, 38.9, 38.6, 29.7, 29.2, 24.3; HRMS (ESI): m/z [M + H]+ calcd for
C19H18N3O: 304.1444, found:304.1448.
3-methyl-4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-3-phenylbutanenitrile (3ai)
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yellow solid, 16.5 mg, 52% yield; mp 119-121 °C. H NMR (400 MHz, CDCl3) δ
7.75 (dd, J = 7.6, 1.2 Hz, 1H), 7.56-7.51 (m, 1H), 7.44-7.41 (m, 2H), 7.35-7.26 (m,
4H), 7.25-7.20 (m, 1H), 3.64 (s, 3H), 3.52-3.37 (m, 2H), 3.25-3.10 (m, 2H), 1.69 (s,
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3H); C NMR{1H} (100 MHz, CDCl3) δ 157.3, 155.1, 144.6, 133.0, 132.2, 130.3,
129.9, 128.5, 126.9, 125.6, 123.7, 118.6, 113.6, 42.9, 41.1, 29.6, 29.3, 26.0; HRMS
(ESI): m/z [M + H]+ calcd for C20H20N3O: 318.1601, found:318.1605.
3-methyl-4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-3-(p-tolyl)butanenitrile (3aj)
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yellow oil, 21.6 mg, 57% yield; H NMR (400 MHz, CDCl3) δ7.77 (dd, J = 7.6, 0.8
Hz, 1H), 7.56-7.52 (m, 1H), 7.35-7.28 (m, 4H), 7.13 (d, J = 8.0 Hz, 2H), 3.65 (s, 3H),
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3.50-3.36 (m, 2H), 3.22-3.08 (m, 2H), 2.30 (s, 3H); 13C NMR{1H} (100 MHz, CDCl3)
δ 157.5, 155.2, 141.8, 136.5, 133.0, 132.3, 130.2, 130.0, 129.2, 125.5, 123.7, 118.7,
113.6, 42.9, 40.8, 29.6, 29.3, 26.0, 20.9; HRMS (ESI): m/z [M + Na]+ calcd for
C21H21N3ONa: 354.1577, found:354.1581.
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tert-butyl4-(cyanomethyl)-4-((4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)methyl)pipe
ridine-1-carboxylate (3ak) yellow oil, 26 mg, 65% yield; 1H NMR (400 MHz, CDCl3)
δ7.82 (dd, J = 8.0, 1.2 Hz, 1H), 7.57 (ddd, J = 16.0, 7.2, 1.6 Hz, 1H), 7.38-7.30 (m,
2H), 3.71 (s, 3H), 3.63-3.50 (m, 4H), 3.19 (s, 2H), 2.78 (s, 2H), 1.77-1.72 (m, 2H),
1.67-1.61 (m, 2H), 1.45 (s, 9H); 13C NMR{1H} (100 MHz, CDCl3) δ157.2, 147.3,
133.0, 132.3, 130.9, 130.5, 130.0, 128.8, 123.8, 113.7, 79.7, 38.7, 37.7, 36.0, 34.4,
29.4, 28.4, 26.9; HRMS (ESI): m/z [M + H]+ calcd for C22H29N4O3: 397.2234, found:
397.2237.
benzyl (cyanomethyl)((4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)methyl)carbamate
1
(3al) yellow solid, 34.4 mg, 95% yield; mp 109-111 °C. H NMR (400 MHz, CDCl3)
δ 7.84-7.81 (m, 1H), 7.62-7.56 (m, 1H), 7.45-7.32 (m, 4H), 7.20 (d, J = 0.8 Hz, 3H),
5.27-5.15 (m, 2H), 4.88-4.85 (m, 2H), 4.54-4.43 (m, 2H), 3.70 (s, 3H); 13C NMR{1H}
(100 MHz, CDCl3) δ 156.1, 153.4, 135.8, 133.1, 132.2, 130.7, 130.3, 128.6, 128.4,
128.1, 127.8, 124.0, 115.7, 113.7, 68.1, 49.3, 37.0, 28.9; HRMS (ESI): m/z [M + Na]+
calcd for C20H18N4O3Na: 385.1271, found:385.1275.
2-((4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)methoxy)acetonitrile (3am) yellow
solid, 15.6 mg, 68% yield; mp 109-111 °C. 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J
= 8.0, 0.4 Hz, 1H), 7.64-7.60 (m, 1H), 7.42-7.35 (m, 2H), 4.97 (s, 2H), 4.59 (s, 2H),
13
3.73 (s, 3H); C NMR{1H} (100 MHz, CDCl3) δ 154.1, 153.9, 133.2, 132.4, 131.0,
130.5, 124.1, 115.8, 113.8, 70.0, 56.6, 29.0; HRMS (ESI): m/z [M + H]+ calcd for
C12H12N3O2: 230.0924, found:230.0927.
2-((4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)methyl)benzonitrile (3an) white solid,
27.5 mg, 99% yield; mp 142-144°C. 1H NMR (400 MHz, CDCl3) δ7.78 (d, J = 7.6 Hz,
1H), 7.69 (d, J = 7.6 Hz, 1H), 7.56-7.49 (m, 2H), 7.44-7.43 (m, 1H), 7.37-7.29 (m,
13
3H), 4.51 (s, 2H), 3.70 (s, 3H); C NMR{1H} (100 MHz, CDCl3) δ 157.3, 154.5,
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140.9, 133.3, 133.0, 132.6, 132.6, 130.5, 130.3, 130.2, 127.1, 123.7, 118.2, 113.9,
113.6, 39.0, 29.2; HRMS (ESI): m/z [M + H]+ calcd for C17H14N3O: 276.1131, found:
276.1135.
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1,5-dimethylquinoxalin-2(1H)-one (1b) 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H),
7.49 (t, J = 7.8 Hz, 1H), 7.27-7.16 (m, 2H), 3.70 (s, 1H), 2.69 (s, 3H); 13C NMR{1H}
(100 MHz, CDCl3) δ155.0, 148.3, 139.2, 133.4, 132.0, 130.8, 125.1, 111.7, 28.9, 17.6.
HRMS (ESI): m/z [M + Na]+ calcd for C10H10N2NaO: 197.0685, found: 197. 0685.
6-methoxy-1-methylquinoxalin-2(1H)-one (1j) 1H NMR (400 MHz, CDCl3) δ
8.32-8.31 (m, 1H), 7.38-7.36 (m, 1H), 7.27-7.21 (m, 2H), 3.90 (s, 3H), 3.70 (s, 3H);
13C NMR{1H} (100 MHz, CDCl3) δ 156.1, 150.5, 134.0, 127.5, 120.4, 114.7, 113.0,
111.7, 55.8, 29.0. HRMS (ESI): m/z [M + Na]+ calcd for C10H10N2NaO2: 213.0634,
found: 213. 0645.
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General procedure for synthesis of products 5
1a (0.15 mmol), 4 (0.1 mmol) and Eosin Y (1 mol %) were dissolved in DCM (1 mL).
Then, the resulting mixture was degassed via ‘freeze-pump-thaw’ procedure (3 times).
After that, the solution was stirred at a distance of ~5 cm from a 6 W blue LEDs
(450-460 nm) at room temperature until the reaction was completed as monitored by
TLC analysis. The crude product was purified by flash chromatography on silica gel
(petroleum ether/ethylacetate 5:1~2:1) directly to give the desired product 5.
5-methyl-5-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)hexanenitrile (5a) colorless
1
oil, 24.2 mg, 90% yield; H NMR (400 MHz, CDCl3) δ7.88-7.86 (m, 1H), 7.58-7.53
(m, 1H), 7.38-7.29 (m, 2H), 3.71 (s, 3H), 2.34 (td, J = 7.2, 1.8 Hz, 2H), 2.18-2.13 (m,
2H), 1.62-1.54 (m, 2H), 1.50 (s, 6H); 13C NMR{1H} (100 MHz, CDCl3) δ 163.5,
153.7, 133.2, 132.1, 130.2, 130.0, 123.4, 119.8, 113.4, 42.5, 39.3, 28.9, 26.1, 21.6,
17.7; HRMS (ESI): m/z [M + Na]+ calcd for C16H19N3ONa: 292.1420,
found:292.1426.
(R)-6-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-6-phenylhexanenitrile (5b) yellow
solid, 17.2mg, 52% yield; mp 102-104 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J
= 8.0, 0.8 Hz, 1H), 7.55-7.51 (m, 1H), 7.45-7.43 (m, 2H), 7.38-7.34 (m, 1H),
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7.30-7.25 (m, 3H), 7.21-7.17 (m, 1H), 4.67 (t, J = 7.6 Hz, 1H), 3.63 (s, 3H), 2.38-2.29
(m, 3H), 2.13-2.04 (m, 1H), 1.75-1.67 (m, 2H), 1.53-1.39 (m, 2H); 13C NMR{1H}
(100 MHz, CDCl3) δ 160.7, 154.5, 141.1, 133.0, 132.7, 130.1, 129.9, 128.6,
128.5,126.8, 123.5, 119.7, 113.5; HRMS (ESI): m/z [M + Na]+ calcd for
C21H21N3ONa: 354.1577, found:354.1580.
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2-((3S)-2,2,3-trimethyl-3-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)cyclopentyl)ace
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tonitrile (5c) colorless oil, 14.2mg, 46% yield; H NMR (400 MHz, CDCl3) δ7.87(dd,
J = 8.0, 1.5 Hz, 1H), 7.56-7.52 (m,1H), 7.37-7.27 (m,2H), 3.70 (s, 3H), 3.37 (dd, J =
13.1, 6.5 Hz, 1H), 2.45 (d, J = 14.2 Hz, 1H), 2.39-2.22 (m,2H), 2.00-1.95 (m,1H),
13
1.93-1.90 (m,2H), 1.58 (s, 3H), 1.02 (d, J = 2.8 Hz, 6H); C NMR{1H} (100 MHz,
CDCl3) δ 163.6, 153.8, 133.3, 131.8, 130.2, 129.8, 123.4, 119.8, 113.4, 53.5, 47.0,
45.3, 42.4, 41.0, 28.9, 28.8, 27.8, 23.8, 17.3; HRMS (ESI): m/z [M + H]+ calcd for
C19H24N3O: 310.1914, found: 310.1914.
General procedure for synthesis of products 7
6 (0.15 mmol), 2a (0.1 mmol) and Eosin Y (1 mol %) were dissolved in DCM (1 mL).
Then, the resulting mixture was degassed via ‘freeze-pump-thaw’ procedure (3 times).
After that, the solution was stirred at a distance of ~5 cm from a 6 W blue LEDs
(450-460 nm) at room temperature until the reaction was completed as monitored by
TLC analysis. The crude product was purified by flash chromatography on silica gel
(petroleum ether/ethylacetate 5:1~3:1) directly to give the desired product 7.
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4-(benzo[d]thiazol-2-yl)butanenitrile (7a) colorless oil, 10.5mg, 52% yield; H NMR
(400 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.50-7.46
(m,1H), 7.41-7.36(m,1H), 3.28 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.33-2.26
(m, 2H); 13C NMR{1H} (100 MHz, CDCl3) δ 168.8, 153.2, 135.0, 126.2, 125.1,122.7,
121.6, 119.0, 32.5, 24.8, 16.6; HRMS (ESI): m/z [M + H]+ calcd for C11H11N2S:
203.0637, found:203.0640.
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4-(benzo[d]oxazol-2-yl)butanenitrile (7b) colorless oil, 7.8mg, 42% yield, H NMR
(400 MHz, CDCl3) δ 7.69-7.65 (m, 1H), 7.52-7.48 (m, 1H), 7.35-7.31 (m, 2H), 3.12 (t,
13
J = 7.2 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.29 (m, 2H); C NMR{1H} (100 MHz,
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CDCl3) δ 164.7, 150.8, 141.1, 124.9, 124.4, 119.8, 118.8, 110.5, 27.1, 22.4, 16.6;
HRMS (ESI): m/z [M + H]+ calcd for C11H11N2O: 187.0866, found:187.0863.
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4-(isoquinolin-1-yl)butanenitrile (7c) yellow oil, 8.9mg, 47%, H NMR (400 MHz,
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CDCl3) 8.45 (d, J = 5.6 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H),
7.74-7.70 (m, 1H), 7.67-7.63 (m,1H), 7.58 (d, J = 5.6 Hz, 1H), 3.49 (t, J = 7.2 Hz,
2H), 2.55 (t, J = 6.8 Hz, 2H), 2.31 (m, 2H); 13C NMR{1H} (100 MHz, CDCl3) δ 159.1,
141.2, 136.4, 130.4, 127.7, 127.6, 127.0, 124.8, 120.0, 119.7, 32.8, 24.4, 17.0; HRMS
(ESI): m/z [M + H]+ calcd for C13H13N2: 197.1073, found:197.1073.
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Conversation of 3a into ester 8a
To a solution of 4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3a, 22.7
mg, 0.1 mmol) in EtOH (1 mL) in a 10 ml two-neck flask were added H2O (5 drops)
and H2SO4 (conc., 0.4 mL). The reaction mixture was heated at 90 °C for 9 h. After
cooling to room temperature, the reaction mixture was slowly quenched with
saturated aqueous NaHCO3 to pH 8 and extracted with DCM (10 mL × 3). The
combined organic phases were washed with brine (15 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by silica gel
chromatography using hexane/ethyl acetate (2:1) to afford the pure product 8a.
ethyl 4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanoate (8a) colorless oil, 21.6
mg, 79% yield; 1H NMR (400 MHz, CDCl3) δ 7.83-7.81 (m, 1H), 7.55-7.50 (m, 1H),
7.36-7.27 (m, 2H), 4.11 (q, J = 7.2Hz, 2H), 3.70 (s, 3H), 2.99 (t, J = 7.6 Hz, 2H), 2.47
13
(t, J = 7.6 Hz, 2H), 2.17 (p, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 2H); C NMR{1H}
(100 MHz, CDCl3) δ 173.4, 160.0, 154.8, 133.0, 132.6, 129.7, 129.7, 123.5, 113.6,
60.3, 33.9, 33.2, 29.0, 21.6, 14.2; HRMS (ESI): m/z [M + Na]+ calcd for
C15H18N2NaO3: 297.1210, found:297.1214.
Conversation of 3a into secondary amine 9a
To a solution of 4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3a, 22.7
mg, 0.1 mmol), (Boc)2O (43.6 mg, 0.2 mmol) and CoCl2 (26 mg, 0.2mmol) in
MeOH(1mL) was cooled to 0°C and was added in portions. The reaction was stirred
for 12 h at room temperatureand then quenched with water and filtered over celite
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(washings with DCM). The crude product was purified by column chromatography to
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afford the pure product 9a.
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tert-butyl
(3-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)propyl)carbamate
(9a)
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colorless oil, 21.2 mg, 64% yield; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.6 Hz,
1H), 7.53 (t, J = 8.0 Hz, 1H), 7.36-7.29 (m, 2H), 4.80 (s, 1H), 3.70 (s, 3H), 3.19 (q, J
= 5.6 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H), 1.84 (p, J = 7.2 Hz, 2H), 1.62 (p, J = 7.2 Hz,
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2H), 1.44 (s, 9H); C NMR{1H} (100 MHz, CDCl3) δ 160.6, 156.0, 154.9, 133.1,
132.7, 129.7, 123.6, 113.6, 99.9, 79.0, 40.4, 33.6, 29.7, 29.1, 28.4, 23.6; HRMS (ESI):
m/z [M + Na]+ calcd for C18H25N3NaO3: 354.1788, found:354.1793.
Conversation of 3a into carboxylic acid 10a
A
25
ml
two-neck
flask
was
charged
with
4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3a, 22.7 mg, 0.1 mmol)
and a mixture of acetic acid, concentrated sulfuric acid and H2O (3/3/1, 2ml), The
solution was heated under reflux for 4 h. After cooling to room temperature the
mixture was diluted with water and extracted 5 times with 5 mL of CH2Cl2. The
combined organic phases were washed with 5 mL of a saturated aqueous
NaCl-solution, dried over Na2SO4 and concentrated under reduced pressure The
residue was subjected to column chromatography to afford the pure product 10a.
4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanoic acid (10a) yellow oil, 20.9
mg, 85% yield; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H), 7.55-7.50 (m,
1H), 7.37-7.28 (m, 2H), 3.70 (s, 3H), 3.02 (t, J = 7.2 Hz, 2H), 2.51 (t, J = 7.6 Hz, 2H),
13
2.16 (p, J = 7.2 Hz, 2H); C NMR{1H} (100 MHz, CDCl3) δ 178.6, 159.9, 154.9,
133.1, 132.6, 129.8, 129.7, 123.7, 113.6, 33.5, 33.0, 29.1, 21.4; HRMS (ESI): m/z [M
+ Na]+ calcd for C13H14N2NaO3: 269.0897, found:269.0901.
Conversation of 3a into amide 11a
To a solution of ethyl 4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanenitrile (3a,
22.7 mg, 0.1 mmol), 7.0 mg K2CO3 (0.05 mmol) and 1 mL DMSO. Then, 0.6 mL aq.
H2O2 (0.6 mmol, 30%) was dropped in room temperature. The mixture was then
stirred for 6 h, after that the reaction mixture was added 0.5 mL sat. Na2S2O3 and 5
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mL sat. NaHCO3 at 0 C, the resulting mixture was subjected to extraction with ethyl
acetate (2 x 15 mL). The combined organic phase was washed with brine (2 x 10 mL),
dried over Na2SO4, concentrated in vacuo, and the residue was subjected to flash
chromatography (Eluent: ethyl acetate/petroleum ether 1:2) to give amide 11a.
4-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)butanamide (11a) colorless oil, 20.3
mg, 83% yield; 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 8.0 Hz, 1H), 7.60-7.56 (m,
1H), 7.52 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.73 (s, 1H), 3.61 (s, 3H), 2.79
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(t, J = 7.2 Hz, 2H), 2.14 (t, J = 7.2 Hz, 2H), 1.91 (p, J = 7.2 Hz, 2H); C NMR{1H}
(100 MHz, CDCl3) δ174.5, 160.3, 154.6, 133.4, 132.4, 130.2, 129.3, 123.8, 115.1,
35.1, 33.3, 29.4, 22.4; HRMS (ESI): m/z [M + Na]+ calcd for C13H15N3NaO2:
268.1056, found:268.1060.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website at DOI: .
AUTHOR INFORMATION
Corresponding Author
*xin_li@nankai.edu.cn.
Author Contributions
§W. Z. and §Y.- L. P contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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We are grateful to the National Natural Science Foundation (Grant Nos. 21390400).
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REFERENCES
(1) Fleming, F. F. Nitrile-containing natural products. Nat. Prod. Rep. 1999, 16, 597.
(2) Fleming, F. F.; Yao, L.; Ravikumar, P. C. Funk, L. Shook, B. C. Nitrile-Containing
Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore. J. Med. Chem. 2010, 53, 7902.
(3) (a) Rappoport, Z. in Chemistry of the Cyano Group, John Wiley & Sons, London, 1970, p.
121; (b) Fatiadi, A. J. in The Chemistry of Functional Groups, Part 2, ed. Pappoport, Z.; Patai,S.
John Wiley & Sons, London, 1983, p. 1057; (c) Fleming, F. F.; Wang, Q. Unsaturated Nitriles:ꢁ
Conjugate Additions of Carbon Nucleophiles to a Recalcitrant Class of Acceptors. Chem. Rev.
2003, 103, 2035.
(4) (a) Bunlaksananusorn, T.; Rodriguez, A. L.; Knochel, P. t-BuOK-Catalyzed addition
of ketones andnitriles to vinylic silanes, phosphines and thio derivatives. Chem. Commun. 2001,
745; (b) Rodriguez, A. L.; Bunlaksananusorn, T.; Knochel, P. Potassium tert-Butoxide Catalyzed
Addition of Carbonyl Derivatives to Styrenes. Org. Lett. 2000, 2, 3285.
(5) (a) Barker, G.; Alshawish, M. R.; Skilbeck M. C.; Coldham, I. Remarkable Configurational
Stability of Magnesiated Nitriles. Angew. Chem., Int. Ed., 2013, 52, 7700; (b) Purzycki, M.; Liu,
W.; Hilmersson. G.; Fleming, F. F. Metalated nitriles: N- and C-coordination preferences of Li,
Mg, and Cu cations. Chem. Commun. 2013, 49, 4700; (c) Sadhukhan, A.; Hobbs, M. C.; Meijer, A.
J. H. M.; Coldham, I. Highly enantioselective metallation-substitution alpha to a chiral nitrile.
Chem. Sci. 2017, 8, 1436; (d) Yang, X.; Fleming, F. F. C- and N-Metalated Nitriles: The
Relationship between Structure and Selectivity. Acc. Chem. Res. 2017, 50, 2556.
(6) For selected recent examples for radical cyanomethylation, see: (a) Zhang, W.; Yang, C.; Pan,
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