Multifold bond cleavage and formation between meoh and quinoxalines (or benzothiazoles): Synthesis of carbaldehyde dimethyl acetals

Article abstract of DOI:10.1021/jo302450f

A K₂S₂O₈-mediated direct cross-coupling of quinoxalines (or benzothiazoles) with methanol leading to 2-quinoxalinyl (or 2-benzothiazolyl) carbaldehyde dimethyl acetals has been achieved. 2-Quinoxalinyl carbaldehyde dimethyl acetals were readily converted into 2-quinoxalinyl carbaldehydes in good to excellent yields under acidic conditions. Preliminary mechanistic studies suggest that the reaction proceeds via multifold bond cleavage and formation between methanol and N-heterocycles involving a dioxygen-participated radical process. This method allows for the synthesis of a variety of 2-quinoxalinyl (or 2-benzothiazolyl) carbaldehyde dimethyl acetals directly via cross-coupling of simple N-heterocyclic C-H bond and methanol under aldehyde-, acid-, and transition-metal-free conditions.

Full text of DOI:10.1021/jo302450f

Article
pubs.acs.org/joc
Multifold Bond Cleavage and Formation between MeOH and
Quinoxalines (or Benzothiazoles): Synthesis of Carbaldehyde
Dimethyl Acetals
Yunkui Liu,*,†,‡ Bo Jiang,† Wei Zhang,† and Zhenyuan Xu†
†State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology,
Hangzhou 310014, People’s Republic of China
‡College of Chemistry & Materials Engineering, Wenzhou University, Zhejiang Province, Wenzhou 325027,
People’s Republic of China
S
* Supporting Information
ABSTRACT: A K2S2O8-mediated direct cross-coupling of
quinoxalines (or benzothiazoles) with methanol leading to
2-quinoxalinyl (or 2-benzothiazolyl) carbaldehyde dimethyl
acetals has been achieved. 2-Quinoxalinyl carbaldehyde dimethyl
acetals were readily converted into 2-quinoxalinyl carbaldehydes
in good to excellent yields under acidic conditions. Preliminary
mechanistic studies suggest that the reaction proceeds via
multifold bond cleavage and formation between methanol and
N-heterocycles involving a dioxygen-participated radical process. This method allows for the synthesis of a variety of 2-quinoxalinyl
(or 2-benzothiazolyl) carbaldehyde dimethyl acetals directly via cross-coupling of simple N-heterocyclic C−H bond and methanol
under aldehyde-, acid-, and transition-metal-free conditions.
represents an aldehyde-free strategy for the synthesis of acetals,
but transition-metal catalysts and/or expensive hypervalent iodine
reagents have to be used in these reactions (Scheme 1B).11
Direct cross-coupling between a heterocyclic C−H bond and
1,3-dioxolane could realize aldehyde-free synthesis of acetals,
but the method suffered from low selectivity (Scheme 1C).20e In
light of the recent success in the C−H bond functionalization7,8
and the great advantages of the methanol economy,1 we
envisioned that the direct cross-coupling of a C−H bond with
methanol via multifold bond cleavage and formation would be
an ideal alternative strategy for the aldehyde-free synthesis of
aldehyde acetals (Scheme 1D). In 2004, Minisci et al.6d reported
a silver-catalyzed direct cross-coupling of protonated lepidine
with methanol to access formylated lepidine. Herein, we report
on the one-pot synthesis of a variety of 2-quinoxalinyl (or
2-benzothiazolyl) carbaldehyde dimethyl acetals directly via
cross-coupling between quinoxaline (or benzothiazole) C−H
bond and methanol under aldehyde-, acid-, and transition-metal-
free conditions.12
INTRODUCTION
■
Methanol is a fundamental raw material in chemical industries
that is annually prepared in large scale from the fossil-fuel-based
syn-gas.1 Preparation of methanol from the biomass-based
syn-gas2 or via the direct hydrogenation of carbon dioxide3 is
currently in progress, which will further add its feature of
sustainability. Hence, there is a significant interest in the
utilization of this readily available, inexpensive, and sustainable
feedstock for the production of useful commodity chemicals as
well as other complex organic molecules.1,4−6 As far as the
functionalization of methanol (C−H, C−O, and O−H) is
concerned,1,4−6 it is still a hard task to achieve direct C(sp3)−H
functionalization, much less to accomplish multifold C(sp3)−H
functionalization of this smallest alcohol with high selectivity,6,7a
although much progress in the α-C(sp3)−H activation/
functionalization of alcohols has been made in recent years.7,8
Therefore, it is highly desirable to develop effective ways for the
(multifold) C(sp3)−H functionalization of methanol.
On the other hand, acetals, known as masked aldehydes or
ketones, are fundamental industrial products as well as useful
precursors for the conversion to other functional groups.9 The
preparation of aldehyde acetals basically relies on aldehydes as
the reactants catalyzed by a Lewis- or Brϕnsted acid (Scheme 1A).9,10
This strategy is usually associated with several persistent
disadvantages including the need for aldehydes as substrates,
limited functionality and/or substrate (especially for hetero-
cycles) compatibility under acidic conditions, and the use of
environmentally harmful acid catalysts.9,10e,h Direct oxidation of
terminal alkenes to aldehyde acetals in the presence of alcohols
RESULTS AND DISCUSSION
■
The motivation of this research originated in our recent study
on the regiospecific preparation of nitroarenes via palladium-
catalyzed direct ortho-nitration of aromatic C−H bonds assisted
by a nitrogen donor.13 In solvent screening investigations, a
reaction of 2-phenylquinoxaline 1a with AgNO2 (2 equiv based
Received: November 9, 2012
© XXXX American Chemical Society
A
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Scheme 1. Strategies for the Synthesis of Aldehyde (Dimethyl) Acetals
on 1a) and K2S2O8 (2 equiv) catalyzed by Pd(OAc)2
(10 mol %) was conducted in anhydrous methanol at 130 °C
for 48 h. No desired nitration product was formed, but
3-phenylquinoxaline-2-carbaldehyde dimethyl acetal 2a was
unexpectedly isolated in 12% yield instead (entry 1, Table 1). It
was found that in the absence of AgNO2 and Pd(OAc)2 2a
could also be produced in 26% yield at 130 °C for 24 h (entry 2,
Table 1), indicating that AgNO2 and Pd(OAc)2 did not
participate in the reaction. Our interest in the conciseness of
the reaction to furnish 2-quinoxalinyl carbaldehyde dimethyl
acetals from simple starting materials prompted us to optimize
the reaction conditions so as to make the reaction synthetically
valuable (Table 1). We were pleased to find that the yield of 2a
could be significantly improved to 56% when 5 equiv of K2S2O8
was used at 130 °C for 12 h (entry 3, Table 1). A higher yield
(72%) of 2a could be obtained by lowering the temperature
to 110 °C and shortening the reaction time to 6 h (entry 5,
Table 1). Further increasing the amount of K2S2O8 resulted in a
decrease in the yield of 2a (entry 8, Table 1). When hydrated
methanol (containing 0.2 wt % of water) was used, the reaction
produced 2a in 42% yield along with a formylated product 3a in
24% yield (entry 10, Table 1). A range of other oxidants were
surveyed, all showed lower efficiency than K2S2O8 for the
reaction (entries 11−18, Table 1). The reaction did not occur
in the absence of K2S2O8 (entry 22, Table 1). When ethanol
was used as the substrate and solvent under otherwise identical
conditions as the entry 5, the reaction failed to give the desired
product (entry 23, Table 1).
such as cyano and thiophene could be well-tolerated under the
reaction conditions, as demonstrated in the dimethoxymethy-
lation of 1j and 1p with methanol, respectively (entries 10 and
16, Table 2). The reaction time should be controlled within
0.75 h for a monodimethoxymethylation of 1q, otherwise a
2-fold dimethoxymethylation of 1q at the 2- and 3-position
would happen (entry 17, Table 2). When substrate 1s bearing a
cyclopropyl group was subjected to the oxidative reaction
conditions, the cyclopropyl group remained intact in the
dimethoxymethylation process and the desired product was
obtained in 65% yield (entry 19, Table 2). The subsequent
conversion of 2 to 3 was readily accomplished in 1,4-dioxane in
the presence of an aqueous solution of HCl (1 N) at 70 °C for
6 h,14 thus a broad range of 2-quinoxalinyl carbaldehydes15
could be conveniently prepared from quinoxalines and methanol
via a two-step process in synthetically useful yields (81−95%,
entries 1−20 except 9, Table 2). A one-pot procedure for the
synthesis of 3a without the purification of 2a was also tried, and
3a was obtained in 65% yield based on 1a (entry 1, Table 2).
The reaction showed highly regiospecific fashion, in all cases the
dimethoxymethylation took place at the α-position of a nitrogen
atom of the quinoxaline ring. The regioselectivity of the
dimethoxymethylation was unambiguously established on the
basis of the spectral analyses, which was further confirmed by
X-ray diffraction analysis of a related derivative 2i (Figure S1,
Supporting Information).
Next, exploration of the present protocol for the dimeth-
oxymethylation of a range of benzothiazoles was carried out.
In most cases, the reaction proceeded smoothly to furnish
corresponding 2-benzothiazolyl carbaldehyde dimethyl acetals
in synthetically acceptable yields (39−76%, 5a−5h, Table 3).
It generally required longer reaction times for the dimethox-
ymethylation of benzothiazoles to be completed than that of
quinoxalines (Table 3 vs Table 2). It was found that substrate 4
bearing electron-deficient groups generally furnished the
desired products in higher yields than those bearing electron-
rich groups (5c−5h vs 5b, Table 3). The position where a
substituent placed on the phenyl ring of benzothiazoles had a
significant effect on the reaction outcome. For example, while
Under the established reaction conditions, the scope of the
K2S2O8-mediated direct cross-coupling of quinoxalines 1 with
methanol was investigated (Table 2). A variety of quinoxaline
derivatives 1, equipped with halo, aryl, alkyl, cyano, methoxy,
and heterocyclic groups, could be smoothly dimethoxymethy-
lated with methanol to furnish various 2-quinoxalinyl
carbaldehyde dimethyl acetals 2 in moderate to excellent yields
(63−97%, entries 1−20, Table 2). It was found that 1 sub-
stituted with aryl groups at the 3-position generally gave higher
yields of desired products than those substituted with alkyl groups
(entries 1−16 vs 17−20, Table 2). Note that acid-sensitive groups
B
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a
Table 1. Screening for Optimal Conditions
Table 3. K2S2O8-mediated Direct Dimethoxymethylation of
Benzothiazoles (or Benzoxazole) with Methanol
ab
,
b
entry
oxidant (equiv)
temp (°C)
time (h)
yield of 2a (%)
c
1
K2S2O8 (2)
K2S2O8 (2)
K2S2O8
130
130
130
110
110
110
110
110
90
48
24
12
12
6
12
d
2
26 (28 )
3
56
62
72
68
49
61
0
4
K2S2O8
5
K2S2O8
6
K2S2O8
3
7
K2S2O8 (3)
K2S2O8 (7)
K2S2O8
6
8
6
9
12
6
e
f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
K2S2O8
110
110
110
110
110
110
110
110
110
110
110
110
110
110
42 (24 )
trace
trace
21
(PhCOO)2
12
12
12
12
12
12
12
12
6
g
TBHP
h
CAN
i
DDQ
trace
25
(NH4)2S2O8
j
BQ
0
tBuOOtBu
PhI(OAc)2
K2S2O8
K2S2O8
K2S2O8
none
trace
trace
a
Reaction conditions: 4 or 6 (0.2 mmol), K2S2O8 (5 equiv) in
anhydrous MeOH (6 mL), 110 °C, 12 h unless otherwise noted.
k
30
b
c
d
Isolated yields. Reaction time is 15 h. Reaction time is 22 h.
l
6
46
mn
,
6
17
0
the 6-position substituted benzothiazoles could be smoothly
dimethoxymethylated (5b−5h, Table 3), those with the 4-, 5-,
or 7-position substituted benzothiazoles were inert substrates
for the reaction (5i−5l, Table 3). Benzoxazole 6 failed to give
the desired acetal under the standard conditions (7, Table 3).
In addition, more N-containing heterocycles including pyr-
idine, quinoline, isoquinoline, acridine, 4-methyl quinoline,
pteridine-2,4(1H,3H)-dione, 2,4(1H,3H)-pyrimidine-dione
were investigated for the present reaction. Unfortunately, all
these substrates failed to give desired products. At present
stage, the substrate scope is still limited to only quinoxalines
and benzothiazoles. The exact reason that why the present
12
6
o
K2S2O8
0
a
Reaction conditions: 1a (0.2 mmol), oxidant (5 equiv) in anhydrous
b
c
MeOH (6 mL) unless otherwise noted. Isolated yields. In the
presence of AgNO2 (2 equiv) and Pd(OAc)2 (10 mol %). Reaction
d
e
temperature is 110 °C. Hydrated methanol (containing 0.2 wt % of
f
g
water) was used. Yield of 3a. TBHP = tert-Butyl hydroperoxide.
h
i
CAN = cerium ammonium nitrate. DDQ = 2,3-Dichloro-5,6-
j
k
dicyano-1,4-benzoquinone. BQ = Benzoquinone. 2 mL of methanol
was used. 4 mL of methanol was used. 0.4 mL of MeOH (24 equiv)
l
m
n
and 4 mL of 1,2-dichloroethane were used. 70% of 1a was recovered.
o
Ethanol was used as the substrate and solvent.
Table 2. K2S2O8-mediated Synthesis of 2-Quinaoxalinyl Carbaldehyde Dimethyl Acetals 2 and Their Subsequent Conversion
a b
,
to 3
c
c
entry
R1, R2 (1)
Ph, H (1a)
product
yield (%) (2/3)
entry
R1, R2 (1)
Ph, Me (1k)
product
yield (%) (2/3)
d
1
2
3
4
5
6
7
8
9
2a/3a
2b/3b
2c/3c
2d/3d
2e/3e
2f/3f
72/84(65 )
11
12
13
14
15
16
17
18
19
20
2k/3k
2l/3l
89/93
87/91
91/95
91/89
88/91
86/91
4-MeC6H4, H (1b)
4-MeOC6H4, H (1c)
3-MeOC6H4, H (1d)
2-MeOC6H4, H (1e)
4-PhC6H4, H (1f)
4-FC6H4, H (1g)
63/85
71/89
85/87
92/87
91/87
92/89
95/90
4-MeOC6 H4, Me (1l)
4-ClC6H4, Me (1m)
Ph, Cl (1n)
2m/3m
2n/3n
2o/3o
2p/3p
2q/3q
2r/3r
2s/3s
2t/3t
4-FC6H4, Cl (1o)
2-thiophenyl, H (1p)
H, H (1q)
f
2g/3g
2h/3h
2i/3i
66 /87
4-ClC6H4, H (1h)
4-BrC6H4, H (1i)
4-CNC6H4, H (1j)
Et, H (1r)
69/84
65/81
71/86
e
97/--
cyclopropyl, H (1s)
iPr, Me (1t)
10
2j/3j
88/90
a
Reaction conditions for the synthesis of 2:1 (0.2 mmol), K2S2O8 (5.0 equiv) in anhydrous MeOH (6 mL) at 110 °C for 6 h unless otherwise noted.
b
c
d
Reaction conditions for the synthesis of 3:2 (0.2 mmol), 1 N HCl (3 mL) in 1,4-dioxane (5 mL) at 70 °C for 6 h. Isolated yields. Isolated yield
e
f
based on 1a via one-pot procedure without the purification of 2a. It is difficult to get pure 3i. Reaction time is 0.75 h.
C
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Scheme 2. Preliminary Mechanistic Studies
reaction is so sensitive to the substrate structure has not been
fully understood, according to the proposed mechanism (vide
infra, Scheme 3), we speculate that the occurrence of the present
reaction may mainly depend on whether the corresponding
reaction intermediates (e.g., heterocycle-substituted methanol
species) could form or not.
Further conducting a reaction of 3a with MeOD under other-
wise identical conditions still produced 2a in a similar yield
(65%) without the formation of 2a-D (eq 5, Scheme 2). Direct
reaction of 1a with formaldehyde dimethyl acetal 9 in the
presence of K2S2O8 resulted in the recovery of 1a quantitatively,
thus the possibility of formaldehyde dimethyl acetal 9 as a
reaction intermediate was unlikely (eq 6, Scheme 2). When the
preparative 2-hydroxymethyl-3-phenylquinoxaline 10 was trea-
ted with methanol or methanol-d1 (>99% D-enrichment of the
hydroxyl proton) in the presence of 3 equivalent of K2S2O8 at
110 °C for 6 h, 2a was obtained as the major product along with
trace amount of 3a without the detection of 2a-D (for the case
of methanol-d1) (eq 7, Scheme 2). Surprisingly, conducting a
reaction of 10-D (>90% D-enrichment of the hydroxyl proton)
with MeOD under otherwise identical conditions could afford
2a-D and 2a in a total yield of 80% with a ratio of 86:14 (eq 8,
Scheme 2), suggesting 10 being the possible intermediate. The
reaction of 1a and MeOH under the standard conditions gave
a decreased yield of 2a (26%) in the presence of 2 equiv of
TEMPO and failed to give 2a by using 5 equiv of TEMPO
(eq 9, Scheme 2), demonstrating that the reaction may involve
a radical process.16 Note that the dimethoxymethylation of 1a
with MeOH hardly took place when degassed MeOH was used
Preliminary experiments were done to gain a mechanistic
insight into the dimethoxymethylation reaction (Scheme 2). A
13C-labeling experiment unambiguously established that all the
three carbon atoms in the dimethoxymethyl group of the target
acetals originated from methanol (eq 1, Scheme 2). When the
dimethoxymethylation of 1a was performed in methanol-d1
(>99% D-enrichment of the hydroxyl proton), 2a-D and 2a
were obtained in a total yield of 68% with a ratio of 95:5,
suggesting 95% D-enriched at the methine proton of 2a (eq 2,
Scheme 2). A treatment of 1a-D (70% D-enrichment) with
MeOH furnished acetal 2a in 70% yield without the formation
of 2a-D (eq 3, Scheme 2). These results suggest that the C−H
and C−O bonds in one molecule of MeOH were all cleaved in the
course of the dimethoxymethylation, and the methine proton of
the resulting CH(OMe)2 moiety finally derived from the hydroxy
proton of methanol. A treatment of the preparative 3-phenyl-
quinoxaline-2-carbaldehyde 3a with MeOH under the standard
conditions could afford 2a in 69% yield (eq 4, Scheme 2).
D
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Scheme 3. Proposed Mechanism
were performed with EI source, and high resolution mass spectra
(HRMS) were obtained on a TOF MS instrument with EI or ESI
source.
Starting Materials. The starting materials 1q, 4a, 6, 9 and 13 are
commercially available. 1a−1t (except 1q) were prepared according
to the literature.22−24 4b−4l were prepared according to the
literature.25,26
under argon atmosphere (eq 10, Scheme 2), implying that
dioxygen possibly participated in the reaction process.17,18
On the basis of the above-mentioned mechanistic experiments,
a proposed mechanism was depicted in Scheme 3. First, potassium
peroxydisulphate may be decomposed to sulfate radical anion
upon heating.19 Then methoxy radicals, hydroxymethyl radicals,
and protons were produced via reactions of methanol with
sulfate radical anions.19 The Minisci hydroxymethylation reaction
involving hydroxymethyl radicals and 1a in the presence of
K2S2O8 and protons led to the formation of the intermediate
10.6d,19,20 Reaction of 10 with K2S2O8 may produce a radical
species C which subsequently isomerized to form a radical
species D.21 Oxidation of D to aldehyde 3a occurred in the
presence of dioxygen via a trioxy radical species E.18 Acetalization
of E by methanol finally gave dimethyl acetal 2a.9
Characterization of Unknown Starting Materials. 6,7-
Dichloro-2-(4-fluorophenyl)quinoxaline (1o). Yellow solid; mp
1
213−215 °C; H NMR (CDCl3, 500 MHz): δ 9.30 (s, 1H), 8.27−
8.20 (m, 4H), 7.30−7.26 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ
164.6 (d, J = 250.6 Hz), 151.5, 143.8, 141.0, 140.2, 135.1, 134.1, 132.2
(d, J = 3.2 Hz), 130.1, 129.8, 129.6 (d, J = 8.4 Hz, 2C), 116.4 (d, J =
21.8 Hz, 2C); LRMS (EI): m/z (%) = 292 (100) [M]+; HRMS (EI)
for C14H7Cl2FN2 [M]+: calcd 291.9970, found 291.9989.
2-Isopropyl-6,7-dimethylquinoxaline (1t). Orange oil; 1H NMR
(CDCl3, 500 MHz): δ 8.68 (s, 1H), 7.81 (s, 2H), 3.31−3.26 (m,
1H), 2.48 (s, 6H), 1.44 (s, 3H), 1.43 (s, 3H); 13C NMR (CDCl3,
125 MHz): δ 160.9, 143.7, 141.0, 140.3, 140.2, 139.2, 128.11,
128.08, 34.8, 22.1 (2C), 20.2, 20.1; LRMS (EI): m/z (%) = 200 (45)
[M]+; HRMS (EI) for C13H16N2 [M]+: calcd 200.1313, found
200.1325.
CONCLUSION
■
In summary, we have described a direct and green access to
2-quinoxalinyl (or 2-benzothiazolyl) carbaldehyde dimethyl
acetals via dimethoxymethylation of N-heterocyclic C−H bond
with methanol under aldehyde-, acid-, and transition-metal-free
conditions.
General Procedure for K2S2O8-mediated Dimethoxymethylation
of Quinoxalines. Quinoxalines 1 (0.2 mmol), K2S2O8 (270 mg,
1.0 mmol), and anhydrous MeOH (6.0 mL) were sequentially added
to a 25-mL Schlenk flask equipped with a high-vacuum PTFE valve-to-
glass seal (Figure 1). Then the flask was sealed and stirred at 110 °C
for 6 h. Upon completion, the resulting mixture was diluted with CH2Cl2
(10 mL) and filtered through Celite. After evaporation of the solvent
under vacuum, the residue was purified by column chromatography
on neutral alumina (200−300 mesh) using petroleum ether-EtOAc
(6:1, v/v) as the eluent to give pure 2.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise stated, commercial
reagents were used directly without further purifications. MeOH was
distilled over magnesium prior to use. MeOD (>99% D-enrichment of
the hydroxyl proton) was dried over molecular sieve before use. Other
solvents for reactions were dried and distilled prior to use according to
standard methods. Column Chromatography was performed on silica
gel (100−200 mesh) or neutral alumina (200−300 mesh) with
2-(dimethoxymethyl)-3-phenylquinoxaline (2a).
solvents specified below. Melting points are uncorrected. H and 13C
1
NMR spectra were recorded on a spectrometer at 25 °C in CDCl3 at
500 MHz, 125 MHz, respectively, with TMS as internal standard. 19F
NMR spectra were recorded on a spectrometer at 25 °C in CDCl3 at
376 MHz, with CF3COOH as external standard. Chemical shifts (δ)
are expressed in ppm and coupling constants J are given in Hz. The IR
spectra were recorded on an FT-IR spectrometer. GC-MS experiments
Purification by column chromatography on neutral alumina with
200−300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid
E
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2-(Dimethoxymethyl)-3-(3-methoxyphenyl)quinoxaline (2d).
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow oil (52.7 mg,
85%); Rf = 0.37; IR (neat): ν = 3032, 2926, 2866, 1598, 1509, 1448,
1
1371 cm−1; H NMR (CDCl3, 500 MHz): δ 8.32−8.30 (m, 1H),
8.17−8.15 (m, 1H), 7.82−7.78 (m, 2H), 7.45 (t, J = 7.5 Hz, 1H),
7.32−7.28 (m, 2H), 7.08−7.06 (m, 1H), 5.63 (s, 1H), 3.89 (s, 3H),
3.46 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 159.6, 153.8, 149.4,
141.6, 140.8, 139.2, 130.6, 130.0, 129.7, 129.5, 129.2, 121.7, 115.1,
114.8, 100.9, 55.3, 54.4 (2C); LRMS (ESI): m/z (%) = 311.14 (100)
[M + H]+; HRMS (ESI) for C18H19N2O3 [M + H]+: calcd 311.1396,
found 311.1381.
Figure 1. Schlenk flask used in the reaction: (a) before reaction; (b)
after reaction.
(40.4 mg, 72%); mp 91−92 °C; Rf = 0.36; IR (neat): ν = 3060, 2927,
2-(Dimethoxymethyl)-3-(2-methoxyphenyl)quinoxaline (2e).
1
2862, 1596, 1503, 1448, 1372 cm−1; H NMR (CDCl3, 500 MHz): δ
8.31 (dd, J1 = 8.0 Hz, J2 = 2.5 Hz, 1H), 8.15 (dd, J1 = 8.0 Hz, J2 = 2.5
Hz, 1H), 7.82−7.78 (m, 2H), 7.75−7.73 (m, 2H), 7.56−7.52 (m, 3H),
5.61 (s, 1H), 3.45 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 154.0,
149.4, 141.7, 140.7, 138.0, 130.6, 129.9, 129.6, 129.3 (2C), 129.14,
129.11, 128.4 (2C), 101.0, 54.3 (2C); LRMS (ESI): m/z (%) = 281.21
(100) [M + H]+; HRMS (ESI) for C17H17N2O2 [M + H]+: calcd
281.1290, found 281.1291.
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a white solid (57.1
mg, 92%); mp 76−79 °C; Rf = 0.35; IR (neat): ν = 3032, 2926, 2866,
2-(Dimethoxymethyl)-3-p-tolylquinoxaline (2b).
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 8.33
(dd, J1 = 7.0 Hz, J2 = 3.5 Hz, 1H), 8.17 (dd, J1 = 6.9 Hz, J2 = 3.3 Hz,
1H), 7.80−7.78 (m, 2H), 7.51−7.48 (m, 1H), 7.42 (dd, J1 = 7.4 Hz,
J2 = 1.7 Hz, 1H), 7.16 (t, J = 7.3 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H),
5.52 (s, 1H), 3.78 (s, 3H), 3.52 (s, 3H), 3.21 (s, 3H); 13C NMR
(CDCl3, 125 MHz): δ 156.5, 152.4, 151.1, 141.8, 140.9, 130.7 (2C),
130.3, 129.9, 129.8, 129.1, 127.3, 121.1, 110.8, 101.1, 55.4, 54.9, 53.9;
LRMS (ESI): m/z (%) = 310.97 (100) [M + H]+; HRMS (ESI) for
C18H19N2O3 [M + H]+: calcd 311.1396, found 311.1387.
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (37.1
mg, 63%); mp 72−73 °C; Rf = 0.35; IR (neat): ν = 3032, 2926, 2866,
2-(Biphenyl-4-yl)-3-(dimethoxymethyl)quinoxaline (2f).
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 8.30
(dd, J1 = 7.0 Hz, J2 = 1.5 Hz, 1H), 8.15 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz,
1H), 7.82−7.77 (m, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.5 Hz,
2H), 5.64 (s, 1H), 3.46 (s, 6H), 2.47 (s, 3H); 13C NMR (CDCl3, 125
MHz): δ 154.1, 149.4, 141.8, 140.6, 139.2, 135.1, 130.5, 129.8, 129.7
(2C), 129.3 (3C), 129.2, 100.9, 54.3 (2C), 21.4; LRMS (ESI): m/z
(%) = 295 (100) [M + H]+; HRMS (ESI) for C18H19N2O2 [M + H]+:
calcd 295.1447, found 295.1433.
2-(Dimethoxymethyl)-3-(4-methoxyphenyl)quinoxaline (2c).
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (64.8
mg, 91%); mp 116−119 °C; Rf = 0.38; IR (neat): ν = 3032, 2926,
1
2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ
8.31 (dd, J1 = 8.0 Hz, J2 = 2.5 Hz, 1H), 8.17 (dd, J1 = 8.0 Hz, J2 = 2.5
Hz, 1H), 7.86−7.77 (m, 6H), 7.69 (d, J = 8.5 Hz, 2H), 7.49 (dd, J1 =
8.0 Hz, J2 = 7.5 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 5.70 (s, 1H), 3.49 (s,
6H); 13C NMR (CDCl3, 125 MHz): δ 153.7, 149.4, 142.1, 141.8,
140.7, 140.5, 136.9, 130.7, 130.0, 129.9 (2C), 129.7, 129.2, 128.9 (2C),
127.7, 127.2 (2C), 127.18 (2C), 101.1, 54.3 (2C); LRMS (ESI):
m/z (%) = 357.05 (100) [M + H]+; HRMS (ESI) for C23H21N2O2
[M + H]+: calcd 357.1603, found 357.1593.
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (44.1
mg, 71%); mp 76−78 °C; Rf = 0.33; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 8.30
2-(Dimethoxymethyl)-3-(4-fluorophenyl)quinoxaline(2g).
(dd, J1 = 7.0 Hz, J2 = 3.0 Hz, 1H), 8.14 (dd, J1 = 7.0 Hz, J2 = 2.5 Hz,
1H), 7.82−7.73 (m, 4H), 7.08 (dd, J1 = 8.5 Hz, J2 = 2.0 Hz, 2H), 5.65
(s, 1H), 3.91 (s, 3H), 3.48 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ
160.5, 153.7, 149.3, 141.8, 140.5, 130.9 (2C), 130.5, 130.3, 129.7,
129.6, 129.0, 113.9 (2C), 100.9, 55.4, 54.2 (2C); LRMS (ESI): m/z
(%) = 311.18 (100) [M + H]+; HRMS (ESI) for C18H19N2O3
[M + H]+: calcd 311.1396, found 311.1389.
F
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Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a white solid (54.9
mg, 92%); mp 78−80 °C; Rf = 0.38; IR (neat): ν = 3032, 2926, 2866,
2-(Dimethoxymethyl)-6,7-dimethyl-3-phenylquinoxaline (2k).
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 8.30
(dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 8.14 (dd, J1 = 7.5 Hz, J2 = 2.5 Hz,
1H), 7.82−7.76 (m, 4H), 7.23 (dd, J1 = 7.5 Hz, J2 = 7.0 Hz, 2H),
5.58 (s, 1H), 3.46 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 163.5 (d,
4
1JF−C = 248.8 Hz), 153.0, 149.3, 141.7, 140.6, 134.1 (d, JF−C = 3.8
3
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (54.9
mg, 89%); mp 77−80 °C; Rf = 0.36; IR (neat): ν = 3032, 2926, 2866,
Hz), 131.4 (d, JF−C = 7.5 Hz, 2C), 130.7, 130.1, 129.6, 129.1, 115.4
(d, JF−C = 22.5 Hz, 2C), 101.5, 54.3 (2C); 19F NMR (CDCl3, 376
MHz): δ −112.3 (s); LRMS (ESI): m/z (%) = 299.17 (100)
[M + H]+; HRMS (ESI) for C17H16FN2O2 [M + H]+: calcd 299.1196,
found 299.1188.
2
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 8.05
(s, 1H), 7.89 (s, 1H), 7.73−7.71 (m, 2H), 7.54−7.50 (m, 3H), 5.58
(s, 1H), 3.43 (s, 6H), 2.512 (s, 3H), 2.508 (s, 3H); 13C NMR (CDCl3,
125 MHz): δ 153.1, 148.4, 141.3, 140.8, 140.6, 139.8, 138.3, 129.4
(2C), 128.9, 128.7, 128.4 (2C), 128.2, 101.0, 54.2 (2C), 20.43, 20.37;
LRMS (ESI): m/z (%) = 309.03 (100) [M + H]+; HRMS (ESI) for
C19H21N2O2 [M + H]+: calcd 309.1603, found 309.1596.
2-(Dimethoxymethyl)-3-(4-methoxyphenyl)-6,7-dimethylqui-
noxaline (2l).
2-(4-Chlorophenyl)-3-(dimethoxymethyl)quinoxaline (2h).
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (59.8
mg, 95%); mp 91−92 °C; Rf = 0.32; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 8.30
(d, J = 9.5 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.84−7.80 (m, 2H), 7.74
(dd, J1 = 8.5 Hz, J2 = 1.5 Hz, 2H), 7.53 (dd, J1 = 8.5 Hz, J2 = 1.5 Hz,
2H), 5.58 (s, 1H), 3.47 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ
152.8, 149.2, 141.6, 140.7, 136.5, 135.5, 130.84 (2C), 130.77, 130.2,
129.6, 129.2, 128.6 (2C), 101.5, 54.3 (2C); LRMS (ESI): m/z (%) =
315.17 (100) [M + H]+; HRMS (ESI) for C17H16ClN2O2 [M + H]+:
calcd 315.0900, found 315.0891.
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (58.9
mg, 87%); mp 97−98 °C; Rf = 0.34; IR (neat): ν = 3032, 2926, 2866,
1598, 1509, 1448, 1371 cm−1; 1H NMR (CDCl3, 500 MHz): δ 8.04 (s,
1H), 7.88 (s, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H),
5.61 (s, 1H), 3.90 (s, 3H), 3.46 (s, 6H), 2.51 (s, 6H); 13C NMR
(CDCl3, 125 MHz): δ 160.3, 152.7, 148.4, 141.2, 140.8, 140.3, 139.5,
130.9 (2C), 130.7, 128.6, 128.1, 113.9 (2C), 101.1, 55.4, 54.1 (2C),
20.4, 20.3; LRMS (ESI): m/z (%) = 339.30 (100) [M + H]+; HRMS
(ESI) for C20H23N2O3 [M + H]+: calcd 339.1709, found 339.1703.
2-(4-Chlorophenyl)-3-(dimethoxymethyl)-6,7-dimethylquinoxa-
line (2m). Purification by column chromatography on neutral alumina
2-(4-Bromophenyl)-3-(dimethoxymethyl)quinoxaline (2i).
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a light yellow solid
(69.7 mg, 97%); mp 91−93 °C; Rf = 0.33; IR (neat): ν = 3032, 2926,
1
2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ
8.29 (dd, J1 = 7.5 Hz, J2 = 2.5 Hz, 1H), 8.14 (dd, J1 = 7.0 Hz, J2 = 3.0
Hz, 1H), 7.84−7.80 (m, 2H), 7.69−7.66 (m, 4H), 5.58 (s, 1H), 3.46
(s, 6H); 13C NMR (CDCl3, 125 MHz): δ 152.9, 149.2, 141.7, 140.7,
137.0, 131.6 (2C), 131.1 (2C), 130.8, 130.3, 129.7, 129.2, 123.9, 101.5,
54.3 (2C); LRMS (ESI): m/z (%) = 359.15 (100) [M + H]+; HRMS
(ESI) for C17H16BrN2O2 [M + H]+: calcd 359.0395, found 359.0389.
4-(3-(Dimethoxymethyl)Quinoxalin-2-yl)benzonitrile (2j).
with 200−300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow
oil (62.4 mg, 91%); Rf = 0.35; IR (neat): ν = 3032, 2926, 2866, 1598,
1509, 1448, 1371 cm−1; 1H NMR (CDCl3, 500 MHz): δ 8.03 (s, 1H),
7.86 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 5.54
(s, 1H), 3.43 (s, 6H), 2.50 (s, 3H), 2.49 (s, 3H); 13C NMR (CDCl3,
125 MHz): δ 151.8, 148.2, 141.5, 140.9, 140.7, 139.7, 136.8, 135.2,
130.9 (2C), 128.6, 128.5 (2C), 128.1, 101.5, 54.2 (2C), 20.41, 20.38;
LRMS (ESI): m/z (%) = 343.26 (100) [M + H]+; HRMS (ESI) for
C19H20ClN2O2 [M + H]+: calcd 343.1213, found 343.1209.
6,7-Dichloro-2-(dimethoxymethyl)-3-phenylquinoxaline (2n).
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a white solid (53.7
mg, 88%); mp 112−113 °C; Rf = 0.32; IR (neat): ν = 3032, 2926,
1
2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ
8.30−8.28 (m, 1H), 8.17−8.15 (m, 1H), 7.93 (d, J = 8.4 Hz, 2H),
7.86−7.82 (m, 4H), 5.54 (s, 1H), 3.45 (s, 6H); 13C NMR (CDCl3,
125 MHz): δ 152.1, 149.2, 142.8, 141.5, 140.7, 131.9 (2C), 131.1
(2C), 130.7, 130.3, 129.6, 129.2, 118.6, 112.9, 102.7, 54.5 (2C); LRMS
(ESI): m/z (%) = 306.19 (100) [M + H]+; HRMS (ESI) for
C18H16N3O2 [M + H]+: calcd 306.1243, found 306.1233.
Purification by column chromatography on neutral alumina with
200−300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid
(63.6 mg, 91%); mp 90−91 °C; Rf = 0.31; IR (neat): ν = 3032, 2926,
1
2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ
8.43 (s, 1H), 8.28 (s, 1H), 7.75−7.73 (m, 2H), 7.57−7.55 (m, 3H),
G
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5.60 (s, 1H), 3.46 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 155.1,
150.6, 140.5, 139.4, 137.3, 135.4, 134.7, 130.2, 129.8, 129.6, 129.3
(2C), 128.5 (2C), 100.8, 54.4 (2C); LRMS (ESI): m/z (%) = 349.16
(100) [M + H]+; HRMS (ESI) for C17H15Cl2N2O2 [M + H]+: calcd
349.0511, found 349.0499.
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a brown oil (32.1 mg,
69%); Rf = 0.38; IR (neat): ν = 3032, 2926, 2866, 1598, 1509, 1448,
1371 cm−1; 1H NMR (CDCl3, 500 MHz): δ 8.13 (dd, J1 = 8.2 Hz, J2 =
1.4 Hz, 1H), 8.06 (dd, J1 = 8.1 Hz, J2 = 1.4 Hz, 1H), 7.76−7.69 (m,
2H), 5.59 (s, 1H), 3.51 (s, 6H), 3.23 (q, J = 7.5 Hz, 2H), 1.42 (t, J =
7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz): δ 157.8, 150.3, 141.8,
139.6, 130.0, 129.2, 129.0, 128.4, 106.1, 55.1 (2C), 27.6, 12.9; LRMS
(ESI): m/z (%) = 233.02 (100) [M + H]+; HRMS (ESI) for
C13H17N2O2 [M + H]+: calcd 233.1290, found 233.1284.
6,7-Dichloro-2-(dimethoxymethyl)-3-(4-fluorophenyl)quinoxaline
(2o).
2-Cyclopropyl-3-(dimethoxymethyl)quinoxaline (2s).
Purification by column chromatography on neutral alumina with
200−300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a white solid
(64.6 mg, 88%); mp 77−80 °C; Rf = 0.33; IR (neat): ν = 3032, 2926,
1
2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ
8.42 (s, 1H), 8.26 (s, 1H), 7.80−7.77 (m, 2H), 7.28−7.23 (m, 2H), 5.56
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow oil (31.7 mg,
65%); Rf = 0.38; IR (neat): ν = 3032, 2926, 2866, 1598, 1509, 1448,
1371 cm−1; 1H NMR (CDCl3, 500 MHz): δ 8.10 (dd, J1 = 8.5 Hz, J2 =
1.0 Hz, 1H), 7.93 (dd, J1 = 8.3 Hz, J2 = 1.3 Hz, 1H), 7.71−7.63 (m,
2H), 5.73 (s, 1H), 3.54 (s, 6H), 2.84−2.79 (m, 1H), 1.32−1.31 (m,
2H), 1.13−1.11 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 157.6,
150.0, 142.0, 139.2, 129.9, 129.2, 128.3 (2C), 106.0, 55.0 (2C), 13.4,
11.1 (2C); LRMS (ESI): m/z (%) = 245.05 (100) [M + H]+; HRMS
(ESI) for C14H17N2O2 [M + H]+: calcd 245.1290, found 245.1281.
2-(Dimethoxymethyl)-3-isopropyl-6,7-dimethylquinoxaline (2t).
(s, 1H), 3.47 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 163.7 (d, 1JF−C
=
=
=
4
248.6 Hz), 154.0, 150.5, 140.4, 139.2, 135.5, 134.8, 133.4 (d, JF−C
3
2
3.4 Hz), 131.5 (d, JF−C = 8.2 Hz, 2C), 130.2, 129.7, 115.6 (d, JF−C
21.7 Hz, 2C), 101.3, 54.4 (2C); 19F NMR (CDCl3, 376 MHz):
δ −111.4 (s); LRMS (ESI): m/z (%) = 367.17 (100) [M + H]+; HRMS
(ESI) for C17H14Cl2FN2O2 [M + H]+: calcd 367.0416, found 367.0404.
2-(Dimethoxymethyl)-3-(thiophen-2-yl)quinoxaline (2p).
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a taupe solid (49.2
mg, 86%); mp 63−65 °C; Rf = 0.36; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 8.25
Purification by column chromatography on neutral alumina with 200−
300 mesh (petroleum ether/EtOAc, 6/1, v/v) as a light yellow solid
(38.9 mg, 71%); mp 81−83 °C; Rf = 0.40; IR (neat): ν = 3032, 2926,
(d, J = 9.5 Hz, 1H), 8.12 (d, J = 9.5 Hz, 1H), 7.95 (d, J = 3.5 Hz, 1H),
7.81−7.75 (m, 2H), 7.59 (d, J = 5.0 Hz, 1H), 7.22 (dd, J1 = 5.0 Hz,
J2 = 4.0 Hz, 1H), 5.88 (s, 1H), 3.54 (s, 6H); 13C NMR (CDCl3, 125
MHz): δ 147.8, 147.2, 141.6, 141.3, 140.0, 130.8, 130.4, 129.89,
129.86, 129.5, 128.9, 128.2, 101.4, 54.1 (2C); LRMS (ESI): m/z (%) =
287.13 (100) [M + H]+; HRMS (ESI) for C15H15N2O2S [M + H]+:
calcd 287.0854, found 287.0847.
1
2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ
7.86 (s, 1H), 7.81 (s, 1H), 5.59 (s, 1H), 3.79 (heptet, J = 6.8 Hz, 1H),
3.48 (s, 6H), 2.48 (s, 3H), 2.47 (s, 3H), 1.35 (d, J = 6.8 Hz, 6H); 13C
NMR (CDCl3, 125 MHz): δ 160.7, 148.6, 141.1, 140.3, 139.2, 138.5,
128.3, 127.7, 106.2, 54.9 (2C), 30.7, 22.3 (2C), 20.20, 20.18; LRMS
(ESI): m/z (%) = 275.10 (100) [M + H]+; HRMS (ESI) for
C16H23N2O2 [M + H]+: calcd 275.1760, found 275.1749.
2-(Dimethoxymethyl)quinoxaline14 (2q).
General Procedure for the Conversion of 2 to 3. The conversions
of 2 to 3 were followed according to the literature procedure.14
General Procedure: To a solution of 2 (0.2 mmol) in 1,4-dioxane
(5 mL) was added an aqueous solution of HCl (1N, 3 mL), and the
resulting mixture was heated slowly in an oil bath to an external
temperature of 70 °C for 6 h. Upon cooling, the mixture was extracted
with diethyl ether (2 × 20 mL). The diethyl ether layer was dried over
MgSO4 and concentrated under reduced pressure. Crude product was
crystallization from ethanol or purified by column chromatography
on silica gel (100−200 mesh) using petroleum ether-EtOAc (6:1, v/v)
as the eluent.
Reaction time: 0.75 h; purification by column chromatography on
neutral alumina with 200−300 mesh (petroleum ether/EtOAc, 6/1,
v/v) as a brown solid (26.9 mg, 66%); mp 83−85 °C (lit.14 mp 85−
86 °C); Rf = 0.40; IR (neat): ν = 3032, 2926, 2866, 1598, 1509,
1448, 1371 cm−1; 1H NMR (CDCl3, 500 MHz): δ 9.11 (s, 1H), 8.18−
8.14 (m, 2H), 7.82−7.79 (m, 2H), 5.58 (s, 1H), 3.51 (s, 6H); 13C
NMR (CDCl3, 125 MHz): δ 152.1, 143.9, 142.5, 141.4, 130.3 (2C),
129.6, 129.3, 103.9, 54.2 (2C); LRMS (ESI): m/z (%) = 205.24 (100)
[M + H]+.
3-Phenylquinoxaline-2-carbaldehyde (3a).
2-(Dimethoxymethyl)-3-ethylquinoxaline (2r).
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (39.3 mg,
84%); mp 130−132 °C; Rf = 0.40; IR (neat): ν = 3060, 2927, 2862,
1
1596, 1503, 1448, 1372 cm−1; H NMR (CDCl3, 500 MHz): δ 10.34
H
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(s, 1H), 8.33 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 8.15 (dd, J1 = 8.0 Hz,
J2 = 1.0 Hz, 1H), 7.97−7.94 (m, 1H), 7.91−7.87 (m, 1H), 7.73−7.71
(m, 2H), 7.59−7.57 (m, 3H); 13C NMR (CDCl3, 125 MHz): δ 191.3,
154.5, 145.0, 142.8, 141.0, 136.6, 133.1, 130.9, 130.3, 129.9, 129.8
(2C), 129.4, 128.7 (2C); GC-MS (EI, 70 eV): m/z (%) = 234 (100)
[M+]; HRMS (EI) for C15H10N2O [M+]: calcd 234.0793, found
234.0789.
3-(2-Methoxyphenyl)quinoxaline-2-carbaldehyde (3e).
3-p-Tolylquinoxaline-2-carbaldehyde (3b).
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (46.0 mg,
87%); mp 114−118 °C; Rf = 0.38; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 10.13
(s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.91−7.85
(m, 2H), 7.73 (dd, J1 = 8.1 Hz, J2 = 1.7 Hz,1H), 7.53 (dt, J1 = 1.7 Hz,
J2 = 8.3 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H),
3.76 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 190.4, 156.5, 151.5,
146.5, 143.3, 140.8, 132.4, 131.8, 131.0, 130.6, 130.3, 129.3, 125.9,
121.8, 110.8, 55.3; GC-MS (EI, 70 eV): m/z (%) = 264 (100) [M+];
HRMS (EI) for C16H12N2O2 [M+]: calcd 264.0899, found 264.0888.
2-(Biphenyl-4-yl)quinoxaline-2-carbaldehyde (3f).
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a white solid (42.2 mg,
85%); mp 123−126 °C; Rf = 0.42; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 10.33
(s, 1H), 8.31 (dd, J1 = 8.5 Hz, J2 = 1.0 Hz, 1H), 8.21 (dd, J1 = 8.5 Hz,
J2 = 1.0 Hz, 1H), 7.94−7.85 (m, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.38 (d,
J = 8.5 Hz, 2H), 2.48 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 191.3,
154.5, 145.1, 142.9, 140.9, 140.1, 133.7, 132.9, 130.7, 130.3, 129.9,
129.5(2C), 129.4 (2C), 21.4; GC-MS (EI, 70 eV): m/z (%) = 248
(100) [M+]; HRMS (EI) for C16H12N2O [M+]: calcd 248.0950, found
248.0944.
3-(4-Methoxyphenyl)quinoxaline-2-carbaldehyde (3c).
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (54.0 mg,
87%); mp 163−165 °C; Rf = 0.41; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 10.40
(s, 1H), 8.33 (dd, J1 = 8.5 Hz, J2 = 1.0 Hz, 1H), 8.24 (dd, J1 = 8.5 Hz,
J2 = 0.5 Hz, 1H), 7.97−7.87 (m, 2H), 7.83−7.79 (m, 4H), 7.70 (d, J =
8.5 Hz, 2H), 7.52−7.40 (m, 3H); 13C NMR (CDCl3, 125 MHz): δ
191.4, 154.1, 145.1, 142.9, 142.8, 141.0, 140.3, 135.5, 133.1, 130.9,
130.4, 130.3 (2C), 129.4, 128.9 (2C), 127.8, 127.4 (2C), 127.3 (2C);
GC-MS (EI, 70 eV): m/z (%) = 310 (100) [M+]; HRMS (EI) for
C21H14N2O [M+]: calcd 310.1106, found 310.1108.
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (47.0 mg,
89%); mp 146−150 °C; Rf = 0.42; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 10.34
3-(4-Fluorophenyl)quinoxaline-2-carbaldehyde (3g).
(s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.95−7.84
(m, 2H), 7.71 (dd, J1 = 11.6 Hz, J2 = 2.9 Hz, 2H), 7.10 (dd, J1 = 11.6
Hz, J2 = 2.9 Hz, 2H), 3.92 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ
191.5, 161.2, 154.0, 145.0, 142.8, 140.8, 133.0, 131.5 (2C), 130.6,
130.3, 129.2, 128.7, 114.3 (2C), 55.5; GC- MS (EI, 70 eV): m/z (%) =
264 (100) [M+]; HRMS (EI) for C16H12N2O2 [M+]: calcd 264.0899,
found 264.0885.
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a light yellow solid (44.9
mg, 89%); mp 160−165 °C; Rf = 0.41; IR (neat): ν = 3032, 2926,
3-(3-Methoxyphenyl)quinoxaline-2-carbaldehyde (3d).
1
2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ
10.33 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.98−
7.95 (m, 1H), 7.92−7.90 (m, 1H), 7.73−7.71 (m, 2H), 7.28−7.24 (m,
1
2H); 13C NMR (CDCl3, 125 MHz): δ 191.4, 163.9 (d, JF−C = 248.8
Hz), 153.1, 144.9, 142.8, 141.0, 133.2, 132.8 (d, 4JF−C = 2.5 Hz), 131.8
(d, 3JF−C = 8.8 Hz, 2C), 131.0, 130.2, 129.4, 115.7 (d, 2JF−C = 21.3 Hz,
2C); 19F NMR (CDCl3, 376 MHz): δ −111.2; GC-MS (EI, 70 eV):
m/z (%) = 252 (100) [M+]; HRMS (EI) for C15H9FN2O [M+]: calcd
252.0699, found 252.0683.
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (46.0 mg,
87%); mp 115−116 °C; Rf = 0.41; IR (neat): ν = 3032, 2926, 2866,
3-(4-Chlorophenyl)quinoxaline-2-carbaldehyde (3h).
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 10.33
(s, 1H), 8.33 (dd, J1 = 8.4 Hz, J2 = 1.0 Hz, 1H), 8.23 (dd, J1 = 8.5 Hz,
J2 = 1.0 Hz, 1H), 7.97−7.93 (m, 1H), 7.91−7.87 (m, 1H), 7.48 (t, J =
7.9 Hz, 1H), 7.29−7.23 (m, 2H), 7.11 (dd, J1 = 8.3 Hz, J2 = 2.7 Hz,
1H), 3.91 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 191.1, 159.9,
154.4, 145.1, 142.8, 141.1, 137.8, 133.1, 131.0, 130.4, 129.8, 129.4,
122.4, 115.8, 115.1, 55.5; GC-MS (EI, 70 eV): m/z (%) = 264 (56)
[M+]; HRMS (EI) for C16H12N2O2 [M+]: calcd 264.0899, found
264.0890.
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (48.4 mg,
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90%); mp 184−188 °C; Rf = 0.40; IR (neat): ν = 3032, 2926, 2866,
1598, 1509, 1448, 1371 cm−1; 1H NMR (CDCl3, 500 MHz): δ
10.33(s, 1H), 8.32 (dd, J1 = 8.4 Hz, J2 = 1.0 Hz, 1H), 8.22 (dd, J1 = 8.3
Hz, J2 = 1.0 Hz, 1H), 7.98−7.95 (m, 1H), 7.92−7.89 (m, 1H), 7.66
(d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H); 13C NMR (CDCl3, 125
MHz): δ 191.4, 153.0, 144.9, 142.8, 141.0, 136.3, 135.2, 133.3, 131.1
(3C), 130.2, 129.4, 128.8 (2C); GC-MS (EI, 70 eV): m/z (%) = 268
(100) [M+]; HRMS (EI) for C15H9ClN2O [M+]: calcd 268.0403,
found 268.0394.
3-(4-Chlorophenyl)-6,7-dimethylquinoxaline-2-carbaldehyde (3m).
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a light yellow solid
(56.4 mg, 95%); mp 189−194 °C; Rf = 0.40; IR (neat): ν = 3032,
4-(3-Formylquinoxalin-2-yl)benzonitrile (3j).
1
2926, 2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500
MHz): δ 10.28 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 7.63 (d, J = 8.5 Hz,
2H), 7.51 (d, J = 8.5 Hz, 2H), 2.56 (s, 6H); 13C NMR (CDCl3, 125
MHz): δ 191.6, 152.3, 144.9, 144.0, 142.1, 141.8, 140.1, 135.9, 135.5,
131.1 (2C), 129.0, 128.7 (2C), 128.3, 20.8, 20.5; GC-MS (EI, 70 eV):
m/z (%) = 296 (100) [M+]; HRMS (EI) for C17H13ClN2O [M+]:
calcd 296.0716, found 296.0709.
6,7-Dichloro-3-phenylquinoxaline-2-carbaldehyde (3n).
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a light yellow solid
(46.7 mg, 90%); mp 215−220 °C; Rf = 0.39; IR (neat): ν = 3032,
1
2926, 2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500
MHz): δ 10.32 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 9.0 Hz,
1H), 8.01−7.96 (m, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.5 Hz,
2H); 13C NMR (CDCl3, 125 MHz): δ 191.6, 151.9, 144.7, 142.6,
141.5, 141.2, 133.7, 132.1 (2C), 131.6, 130.4 (2C), 130.2, 129.5, 118.5,
113.4; GC-MS (EI, 70 eV): m/z (%) = 259 (83) [M+]; HRMS (EI)
for C16H9N3O [M+]: calcd 259.0746, found 259.0749.
Purification by column chromatography on silica gel with 100−
200 mesh (petroleum ether/EtOAc, 6/1, v/v) as a light yellow solid
(54.0 mg, 89%); mp 151−154 °C; Rf = 0.39; IR (neat): ν = 3032,
1
6,7-Dimethyl-3-phenylquinoxaline-2-carbaldehyde (3k).
2926, 2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500
MHz): δ 10.30 (s, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.72−7.70 (m, 2H),
7.60−7.56 (m, 3H); 13C NMR (CDCl3, 125 MHz): δ 190.5,
155.2, 145.8, 141.4, 139.6, 138.1, 135.89, 135.84, 130.5, 130.3, 129.9,
129.8 (2C), 128.7 (2C); GC-MS (EI, 70 eV): m/z (%) = 302 (100)
[M+]; HRMS (EI) for C15H8Cl2N2O [M+]: calcd 302.0014, found
302.0018.
6,7-Dichloro-3-(4-fluorophenyl)quinoxaline-2-carbaldehyde (3o).
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (48.8 mg,
93%); mp 140−143 °C; Rf = 0.41; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 10.30
(s, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.71−7.69 (m, 2H), 7.57−7.55
(m, 3H), 2.57 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 191.4, 153.9,
144.6, 144.2, 141.9, 140.2, 136.9, 129.8 (2C), 129.6, 129.1, 128.6,
128.5 (2C), 128.3, 20.8, 20.5; GC-MS (EI, 70 eV): m/z (%) = 262
(100) [M+]; HRMS (EI) for C17H14N2O [M+]: calcd 262.1106, found
262.1120.
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a light yellow solid
(58.5 mg, 91%); mp 196−199 °C; Rf = 0.40; IR (neat): ν = 3032,
1
2926, 2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500
3-(4-Methoxyphenyl)-6,7-dimethylquinoxaline-2-carbaldehyde (3l).
MHz): δ 10.29 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.72−7.70 (m, 2H),
7.28−7.25 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 190.8, 164.1 (d,
1JF−C = 249.8 Hz), 153.9, 145.6, 141.4, 139.5, 138.3, 136.0, 132.1,
131.9 (d, 3JF−C = 8.5 Hz, 2C), 130.5, 129.9, 115.8 (d, 2JF−C = 21.9 Hz,
2C); 19F NMR (CDCl3, 376 MHz): δ −110.2 (s); GC-MS (EI,
70 eV): m/z (%) = 320 (100) [M+]; HRMS (EI) for C15H7Cl2FN2O
[M+]: calcd 319.9919, found 319.9909.
3-(Thiophen-2-yl)quinoxaline-2-carbaldehyde (3p).
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (53.2 mg,
91%); mp 212−214 °C; Rf = 0.41; IR (neat): ν = 3032, 2926,
1
2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz):
δ 10.30 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 7.67 (dd, J1 = 8.7 Hz,
J2 = 2.7 Hz, 2H), 7.08 (dd, J1 = 8.7 Hz, J2 = 2.5 Hz, 2H), 3.91(s, 3H),
2.55 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 191.7, 161.0, 153.5,
144.4, 144.2, 142.0, 141.5, 140.0, 131.5 (2C), 129.2, 129.1, 128.2,
114.2 (2C), 55.4, 20.8, 20.4; GC-MS (EI, 70 eV): m/z (%) = 292
(100) [M+]; HRMS (EI) for C18H16N2O2 [M+]: calcd 292.1212,
found 292.1226.
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a yellow solid (43.7 mg,
91%); mp 102−106 °C; Rf = 0.40; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 10.44
(s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.92−7.89
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(m, 1H), 7.84−7.81 (m, 2H), 7.63 (d, J = 5.0 Hz, 1H), 7.27 (dd, J1 =
5.0 Hz, J2 = 4.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δ 191.5,
147.3, 144.3, 142.7, 140.4, 140.2, 133.2, 131.3, 130.8, 130.6, 130.1,
129.0, 128.3; GC-MS (EI, 70 eV): m/z (%) = 240 (100) [M+]; HRMS
(EI) for C13H8N2OS [M+]: calcd 240.0357, found 240.0351.
Quinoxaline-2-carbaldehyde27 (3q).
(s, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 4.25 (heptet, J = 6.8 Hz, 1H), 2.54
(s, 3H), 2.53 (s, 3H), 1.39 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 125
MHz): δ 194.2, 161.2, 144.0, 143.7, 142.0, 140.5, 139.6, 128.7, 128.0,
30.8, 21.7 (2C), 20.6, 20.2; GC-MS (EI, 70 eV): m/z (%) = 228 (100)
[M+]; HRMS (EI) for C14H16N2O [M+]: calcd 228.1263, found
228.1247.
General Procedure for K2S2O8-mediated Dimethoxymethy-
lation of Benzothiazoles. Benzothiazoles 4 (0.2 mmol), K2S2O8
(270 mg, 1.0 mmol), and anhydrous MeOH (6.0 mL) were seq-
uentially added to a 25-mL Schlenk flask equipped with a high-vacuum
PTFE valve-to-glass seal. Then the flask was sealed and stirred at 110
°C for 12 h. Upon completion, the resulting mixture was diluted with
CH2Cl2 (10 mL) and filtered through Celite. After evaporation of the
solvent under vacuum, the residue was purified by column
chromatography on neutral alumina (200−300 mesh) using petroleum
ether-EtOAc (6:1, v/v) as the eluent to give pure 5.
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a brown solid (27.5 mg,
87%); mp 104−106 °C (lit.27 mp 107 −108 °C); Rf = 0.42; IR (neat):
ν = 3032, 2926, 2866, 1598, 1509, 1448, 1371 cm−1; 1H NMR
(CDCl3, 500 MHz): δ 10.30 (s, 1H), 9.44 (s, 1H), 8.27−8.21 (m, 2H),
7.97−7.90 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 192.7, 146.0,
144.5, 142.5, 141.9, 132.9, 131.1, 130.5, 129.6; GC- MS (EI, 70 eV):
m/z (%) = 158 (100) [M+].
2-(Dimethoxymethyl)Benzo[D]Thiazole (5a).
3-Ethylquinoxaline-2-carbaldehyde (3r).
Reaction time: 15 h; purification by column chromatography on
neutral alumina with 200−300 mesh (petroleum ether/EtOAc, 6/1,
v/v) as a yellow oil (26.8 mg, 64%); Rf = 0.40; IR (neat): ν = 3032,
1
2926, 2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500
MHz): δ 8.10 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.52−7.49
(m, 1H), 7.44−7.40 (m, 1H), 5.71 (s, 1H), 3.51 (s, 6H); 13C NMR
(CDCl3, 125 MHz): δ 168.7, 153.1, 135.2, 126.1, 125.5, 123.7, 121.8,
100.7, 53.7 (2C); GC-MS (EI, 70 eV): m/z (%) = 209 (14) [M+];
HRMS (EI) for C10H11NO2S [M+]: calcd 209.0511, found 209.0505.
2-(Dimethoxymethyl)-6-methylbenzo[d]thiazole (5b).
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a brown solid (31.3 mg,
84%); mp 117−121 °C; Rf = 0.41; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 10.33
(s, 1H), 8.21 (dd, J1 = 8.6 Hz, J2 = 0.9 Hz, 1H), 8.12 (dd, J1 = 8.2 Hz,
J2 = 0.8 Hz, 1H), 7.92−7.89 (m, 1H), 7.83−7.80 (m, 1H), 3.45 (q, J =
7.4 Hz, 2H), 1.41 (t, J = 7.4 Hz, 3H),; 13C NMR (CDCl3, 125 MHz):
δ 193.9, 158.3, 145.0, 143.0, 140.7, 132.8, 129.94, 129.91, 128.8, 28.7,
12.8; GC-MS (EI, 70 eV): m/z (%) = 186 (100) [M+]; HRMS (EI)
for C11H10N2O [M+]: calcd 186.0793, found 186.0797.
3-Cyclopropylquinoxaline-2-carbaldehyde (3s).
Reaction time: 15 h; purification by column chromatography on
neutral alumina with 200−300 mesh (petroleum ether/EtOAc, 6/1,
v/v) as a yellow oil (17.4 mg, 39%); Rf = 0.41; IR (neat): ν = 3032,
1
2926, 2866, 1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500
MHz): δ 7.96 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.31 (dd, J1 = 8.3 Hz,
J2 = 1.2 Hz, 1H), 5.70 (s, 1H), 3.50 (s, 6H), 2.50 (s, 3H); 13C NMR
(CDCl3, 125 MHz): δ 167.5, 151.2, 135.7, 135.3, 127.7, 123.2, 121.5,
100.7, 53.6 (2C), 21.5; GC-MS (EI, 70 eV): m/z (%) = 223 (23) [M+];
HRMS (EI) for C11H13NO2S [M+]: calcd 223.0667, found 223.0658.
2-(Dimethoxymethyl)-6-fluorobenzo[d]thiazole (5c).
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a brown solid (32.1 mg,
81%); mp 107−109 °C; Rf = 0.41; IR (neat): ν = 3032, 2926, 2866,
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 10.37
(s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.86−7.83
(m, 1H), 7.76−7.73 (m, 1H), 3.49−3.44 (m, 1H), 1.39−1.38 (m, 2H),
1.23−1.20 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 194.4, 158.7,
144.7, 143.3, 140.2, 132.8, 130.0, 129.3, 128.6, 13.0, 12.3 (2C);
GC-MS (EI, 70 eV): m/z (%) = 198 (100) [M+]; HRMS (EI) for
C12H10N2O [M+]: calcd 198.0793, found 198.0799.
Reaction time: 12 h; purification by column chromatography on
neutral alumina with 200−300 mesh (petroleum ether/EtOAc, 6/1,
v/v) as a white solid (31.3 mg, 69%); mp 62−65 °C; Rf = 0.41; IR
(neat): ν = 3032, 2926, 2866, 1598, 1509, 1448, 1371 cm−1; 1H NMR
(CDCl3, 500 MHz): δ 8.03 (dd, J1 = 9.0 Hz, J2 = 4.8 Hz, 1H), 7.60
(dd, J1 = 8.1 Hz, J2 = 2.6 Hz, 1H), 7.26−7.22 (m, 1H), 5.68 (s, 1H),
3-Isopropyl-6,7-dimethylquinoxaline-2-carbaldehyde (3t).
4
3.51 (s, 6H); 13C NMR (CDCl3, 125 MHz): δ 168.5 (d, JF−C = 3.4
1
3
Hz), 160.7 (d, JF−C = 244.7 Hz), 149.7, 136.3 (d, JF−C = 11.4 Hz),
124.7 (d, 3JF−C = 9.3 Hz), 114.9 (d, 2JF−C = 25.0 Hz), 107.9 (d, 2JF−C
=
Purification by column chromatography on silica gel with 100−200
mesh (petroleum ether/EtOAc, 6/1, v/v) as a light yellow solid (39.3
mg, 86%); mp 124−127 °C; Rf = 0.42; IR (neat): ν = 3032, 2926, 2866,
26.5 Hz), 100.5, 53.7 (2C); 19F NMR (CDCl3, 376 MHz): δ −115.7;
GC-MS (EI, 70 eV): m/z (%) = 227 (12) [M+]; HRMS (EI) for
C10H10FNO2S [M+]: calcd 227.0416, found 227.0408.
1
1598, 1509, 1448, 1371 cm−1; H NMR (CDCl3, 500 MHz): δ 10.30
K
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6-Chloro-2-(dimethoxymethyl)benzo[d]thiazole (5d).
Ethyl 2-(Dimethoxymethyl)benzo[d]thiazole-6-carboxylate (5h).
Reaction time: 12 h; purification by column chromatography on
neatral alumina with 200−300 mesh (petroleum ether/EtOAc, 6/1,
v/v) as a yellow solid (34.1 mg, 70%); mp 60−61 °C; Rf = 0.39; IR
(neat): ν = 3032, 2926, 2866, 1598, 1509, 1448, 1371 cm−1; 1H NMR
(CDCl3, 500 MHz): δ 8.0 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 2.0 Hz,
1H), 7.46 (dd, J1 = 8.7 Hz, J2 = 2.2 Hz, 1H), 5.68 (s, 1H), 3.50
(s, 6H); 13C NMR (CDCl3, 125 MHz): δ 169.3, 151.7, 136.4, 131.6,
127.0, 124.5, 121.4, 100.5, 53.7 (2C); GC-MS (EI, 70 eV): m/z (%) =
243 (14) [M+]; HRMS (EI) for C10H10ClNO2S [M+]: calcd 243.0121,
found 243.0112.
Reaction time: 22 h; purification by column chromatography on
neatral alumina with 200−300 mesh (petroleum ether/EtOAc, 6/1,
v/v) as a yellow solid (35.4 mg, 63%); mp 72−74 °C; Rf = 0.36; IR
(neat): ν = 3032, 2926, 2866, 1598, 1509, 1448, 1371 cm−1; 1H NMR
(CDCl3, 500 MHz): δ 8.68 (d, J = 0.5 Hz, 1H), 8.19 (dd, J1 = 8.6 Hz,
J2 = 1.5 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 5.73 (s, 1H), 4.44 (q, J = 7.1
Hz, 2H), 3.53 (s, 6H), 1.44 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3,
125 MHz): δ 172.4, 166.1, 155.8, 135.1, 127.8, 127.3, 124.1, 123.4,
100.5, 61.3, 53.8 (2C), 14.3; GC-MS (EI, 70 eV): m/z (%) = 281 (2)
[M+]; HRMS (EI) for C13H15NO4S [M+]: calcd 281.0722, found
281.0728.
6-Bromo-2-(dimethoxymethyl)benzo[d]thiazole (5e).
Mechanistic Studies. 13C Labeling Experiment. 2-Phenylquinoxa-
line 1a (0.2 mmol), K2S2O8 (270 mg, 1.0 mmol), and anhydrous
13CH3OH (99% 13C-enrichment, 6.0 mL) were sequentially added to a
25-mL Schlenk flask equipped with a high-vacuum PTFE valve-to-glass
seal. Then the flask was sealed and stirred at 110 °C for 6 h. Upon
completion, the resulting mixture was diluted with CH2Cl2 (10 mL)
and filtered through Celite. After evaporation of the solvent under
vacuum, the residue was purified by column chromatography on
neutral alumina (200−300 mesh) using petroleum ether−EtOAc (6:1,
v/v) as the eluent to give pure 8 as a yellow solid (39.1 mg, 69%).
Reaction time: 12 h; purification by column chromatography on
neatral alumina with 200−300 mesh (petroleum ether/EtOAc, 6/1,
v/v) as a white solid (43.8 mg, 76%); mp 100−103 °C; Rf = 0.39; IR
(neat): ν = 3032, 2926, 2866, 1598, 1509, 1448, 1371 cm−1; 1H NMR
(CDCl3, 500 MHz): δ 8.05 (d, J = 1.9 Hz, 1H), 7.93 (d, J = 8.7 Hz,
1H), 7.59 (dd, J1 = 8.7 Hz, J2 = 1.9 Hz, 1H), 5.68 (s, 1H), 3.50
(s, 6H); 13C NMR (CDCl3, 125 MHz): δ 169.3, 151.9, 136.9, 129.7,
124.8, 124.4, 119.2, 100.4, 53.7 (2C); GC-MS (EI, 70 eV): m/z (%) =
287 (13) [M+]; HRMS (EI) for C10H10BrNO2S [M+]: calcd 286.9616,
found 286.9607.
1
Analytical Data of 8. H NMR (CDCl3, 500 MHz): δ 8.32 (dd,
J1 = 9.8 Hz, J2 = 2.6 Hz, 1H), 8.17 (dd, J1 = 9.8 Hz, J2 = 2.6 Hz, 1H),
1
13
1
7.83−7.74 (m, 4H), 7.56−7.54 (m, 3H), 5.62 (dt, J C‑ H = 162.6 Hz,
3
1
3
13
13
1
13
1
1
J
= 4.7 Hz, 1H), 3.46 (dd, J
= 142.9 Hz, J
= 4.6 Hz,
C‑ H
C‑ H
C‑ H
6H); 13C NMR (CDCl3, 125 MHz): For spectrum being obtained
from 3 times of scans: δ 100.9 (13CH(O13CH3)2), 54.3 (13CH-
(O13CH3)2); For spectrum being obtained from 500 times of scans: δ
154.0 (d, J = 9.0 Hz), 149.4 (d, J = 63.2 Hz), 141.7, 140.7 (d, J = 4.5 Hz),
137.9, 130.7, 130.0, 129.7, 129.3, 129.2, 129.1, 128.5, 101.0, 54.3; LRMS
(ESI): m/z (%) = 284.12 (100) [M + H]+.
2-(Dimethoxymethyl)-6-(trifluoromethyl)benzo[d]thiazole (5f).
Dimethoxymethylation of 1a in MeOD. 2-Phenylquinoxaline 1a
(41.2 mg, 0.2 mmol), K2S2O8 (270 mg, 1.0 mmol), and anhydrous
MeOD (>99% D-enrichment of the hydroxyl group, 6.0 mL) were
sequentially added to a 25-mL Schlenk flask equipped with a high-
vacuum PTFE valve-to-glass seal. Then the flask was sealed and stirred
at 110 °C for 6 h. Upon completion, the resulting mixture was diluted
with CH2Cl2 (10 mL) and filtered through Celite. After evaporation
of the solvent under vacuum, the residue was purified by column
chromatography on neutral alumina (200−300 mesh) using petroleum
ether−EtOAc (6:1, v/v) as the eluent to give a yellow solid (38.1 mg,
68%) which contains 2a-D and 2a with a ratio of 95:5.
Reaction time: 12 h; purification by column chromatography on
neatral alumina with 200−300 mesh (petroleum ether/EtOAc, 6/1,
v/v) as a white solid (40.5 mg, 73%); mp 113−116 °C; Rf = 0.38; IR
(neat): ν = 3032, 2926, 2866, 1598, 1509, 1448, 1371 cm−1; 1H NMR
(CDCl3, 500 MHz): δ 8.24 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.75 (dd,
J1 = 1.5 Hz, J2 = 8.7 Hz, 1H), 5.73 (s, 1H), 3.53 (s, 6H); 13C NMR
(CDCl3, 125 MHz): δ 172.1, 155.0, 135.3, 127.8 (q, J = 32.6 Hz),
125.2, 124.1, 123.1 (q, J = 7.7 Hz), 119.6 (q, J = 4.2 Hz), 100.4, 53.8
(2C); 19F NMR (CDCl3, 376 MHz): δ −62.3 (s); GC-MS (EI, 70
eV): m/z (%) = 277 (1) [M+]; HRMS (EI) for C11H10F3NO2S [M+]:
calcd 277.0384, found 277.0388.
Analytical Data of 2a-D/2a (95/5). 1H NMR (CDCl3, 500
MHz): δ 8.32 (dd, J1 = 9.9 Hz, J2 = 2.6 Hz, 1H), 8.16 (dd, J1 = 9.9 Hz,
J2 = 2.6 Hz, 1H), 7.82−7.74 (m, 4H), 7.57−7.53 (m, 3H), 5.62
(s, 0.05H, 2a), 3.46 (s, 6H); LRMS (ESI) for 2a-D: m/z (%) = 282.19
(100) [M + H]+.
2-(Dimethoxymethyl)benzo[d]thiazole-6-carbonitrile (5g).
Dimethoxymethylation of 1a in a Mixture of MeOH and
MeOD (1:1, v/v). 2-Phenylquinoxaline 1a (41.2 mg, 0.2 mmol),
K2S2O8 (270 mg, 1.0 mmol), and anhydrous MeOH (3.0 mL), MeOD
(>99% D-enrichment of the hydroxyl group, 3.0 mL) were
sequentially added to a 25-mL Schlenk flask equipped with a high-
vacuum PTFE valve-to-glass seal. Then the flask was sealed and stirred
at 110 °C for 6 h. Upon completion, the resulting mixture was diluted
with CH2Cl2 (10 mL) and filtered through Celite. After evaporation
of the solvent under vacuum, the residue was purified by column
chromatography on neutral alumina (200−300 mesh) using petroleum
ether−EtOAc (6:1, v/v) as the eluent to give a yellow solid (39.2 mg,
70%) that was identified as compound 2a without the detection of
Reaction time: 12 h; purification by column chromatography on
neatral alumina with 200−300 mesh (petroleum ether/EtOAc, 6/1,
v/v) as a yellow solid (24.3 mg, 52%); mp 124−126 °C; Rf = 0.37; IR
(neat): ν = 3032, 2926, 2866, 1598, 1509, 1448, 1371 cm−1; 1H NMR
(CDCl3, 500 MHz): δ 8.29 (d, J = 1.0 Hz, 1H), 8.17 (d, J = 8.5 Hz,
1H), 7.76 (dd, J1 = 8.5 Hz, J2 = 1.4 Hz, 1H), 5.72 (s, 1H), 3.52 (s,
6H); 13C NMR (CDCl3, 125 MHz): δ 173.4, 155.4, 135.8, 129.2,
126.8, 124.6, 118.5, 109.2, 100.3, 53.9 (2C); GC-MS (EI, 70 eV): m/z
(%) = 234 (1) [M+]; HRMS (EI) for C11H10N2O2S [M+]: calcd
234.0463, found 234.0466.
1
2a-D by H NMR.
Dimethoxymethylation of 1a-D with MeOH. Preparation of
Intermediate 12. 12 was synthesized according to the literature
procedure.23 Acetophenone-methyl-d3 1128 (0.38 g, 3.0 mmol), CH2Cl2
L
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The Journal of Organic Chemistry
Article
(15 mL), CH3OH (6 mL), and TBA·Br3 were added to a 50-mL flask.
The mixture was stirred at 30 °C for 2 h until the light yellow took
place. Then the solvent was removed under vacuum and the residue
was diluted with water (10 mL) and extracted with ether (3 × 20 mL).
The organic layer was then dried over Na2SO4, filtered and evaporated.
The crude product was directly used for the next step.
(0 or 0.4 mmol), and anhydrous DCE (6.0 mL), were sequentially
added to a 25-mL Schlenk flask equipped with a high-vacuum PTFE
valve-to-glass seal. Then the flask was sealed and stirred at 110 °C for
6 h. GC-MS analysis showed that none of 2a was detected and 1a was
recovered quantitatively.
Reaction of Intermediate 10 (or 10-D) with MeOH and/or
MeOD. Preparation of Intermediate 10 and 10-D. The intermediate
10 was prepared via reduction of 3a by NaBH4 in wet THF according
to a reported literature.29 10 was readily converted to 10-D in the
presence of NaH and D2O in THF according to reported literature.30
1
Analytical Data of 10. White solid; mp 142−143 °C; H NMR
(CDCl3, 500 MHz): δ 8.25−8.23 (m, 2H), 7.86−7.84 (m, 2H), 7.67−
7.65 (m, 2H), 7.58−7.57 (m, 3H), 5.00 (s, 2H), 2.89 (br s, 1H); 13C
NMR (CDCl3, 125 MHz): δ 153.3, 152.1, 141.8, 139.5, 137.0, 130.3,
130.1, 129.7, 129.5, 128.9 (2C), 128.6 (2C), 128.1, 62.5; HRMS (ESI)
for C15H13N2O [M + H]+: calcd 237.1028, found 237.1022.
Reaction of 10 with MeOH or MeOD. 10 (47.3 mg, 0.2 mmol),
K2S2O8 (162 mg, 0.6 mmol), and anhydrous MeOH (or MeOD
(>99% Deuterium-enrichment), 6.0 mL), were sequentially added to a
25-mL Schlenk flask equipped with a high-vacuum PTFE valve-to-glass
seal. Then the flask was sealed and stirred at 110 °C for 6 h. Upon
completion, the resulting mixture was diluted with CH2Cl2 (10 mL)
and filtered through Celite. After evaporation of the solvent under
vacuum, the residue was purified by column chromatography on
neutral alumina (200−300 mesh) using petroleum ether−EtOAc (6:1,
v/v) as the eluent to give 2a (for reaction with MeOH, 84%; for
reaction with MeOD, 82%).
Preparation of Intermediate 1a-D. 1a-D was synthesized
according to literature procedure.22 To a suspension of 12 (0.41 g,
2.0 mmol) and HClO4·SiO224 (0.2 g) in CH3CN (10 mL) was dropwise
added a solution of o-phenyldiamine 13 (0.26 g, 2.4 mmol) in CH3CN
(2 mL) and the mixture was stirred at room temperature for 5 h. After
completion (monitored by TLC), the reaction mixture was filtered and
washed with CH2Cl2 (20 mL). The filtrate was concentrated and the
residue was purified by column chromatography on silica gel (100−200
mesh) using petroleum ether−EtOAc (6:1, v/v) as the eluent to obtain
1a-D (70% Deuterium enrichment) as a yellow solid (0.33 g, 78%).
1
Analytical Data of 1a-D (70% Deuterium Enrichment). H
NMR (CDCl3, 500 MHz): δ 9.35 (s, 0.30H, assigned to non-
deuterated 1a), 8.23−8.13 (m, 4H), 7.82−7.75 (m, 2H), 7.61−7.54
(m, 2H); 13C NMR (CDCl3, 125 MHz): δ 151.8 (d, J = 6.9 Hz),
143.4, 143.0 (t, J = 27.5 Hz), 142.3 (d, J = 3.7 Hz), 141.6 (d, J = 2.7
Hz), 136.8, 130.3, 130.2, 129.6, 129.5, 129.1, 127.6; GC-MS (EI,
70 eV): m/z (%) = 207 (100) [M+]; HRMS (EI) for C14H9DN2: calcd
207.0907, found 207.0912.
Reaction of 10-D with MeOD. 10-D (>90% Deuterium-enrichment
in hydroxyl proton, 47.3 mg, 0.2 mmol), K2S2O8 (162 mg, 0.6 mmol),
and anhydrous MeOD (>99% Deuterium-enrichment, 6.0 mL), were
sequentially added to a 25-mL Schlenk flask equipped with a high-
vacuum PTFE valve-to-glass seal. Then the flask was sealed and stirred
at 110 °C for 6 h. Upon completion, the resulting mixture was diluted
with CH2Cl2 (10 mL) and filtered through Celite. After evaporation
of the solvent under vacuum, the residue was purified by column
chromatography on neutral alumina (200−300 mesh) using petroleum
ether−EtOAc (6:1, v/v) as the eluent to give 2a-D and 2a in a total
Dimethoxymethylation of 1a-D with MeOH. 1a-D (41.2 mg,
0.2 mmol, 70% Deuterium-enrichment), K2S2O8 (270 mg, 1.0 mmol),
and anhydrous MeOH (6.0 mL), were sequentially added to a 25-mL
Schlenk flask equipped with a high-vacuum PTFE valve-to-glass
seal. Then the flask was sealed and stirred at 110 °C for 6 h. Upon
completion, the resulting mixture was diluted with CH2Cl2 (10 mL)
and filtered through Celite. After evaporation of the solvent under
vacuum, the residue was purified by column chromatography on
neutral alumina (200−300 mesh) using petroleum ether−EtOAc (6:1,
v/v) as the eluent to give a yellow solid (39.2 mg, 70%) which was
1
yield of 80% with a ratio of 86:14 determined by H NMR.
Effect of Radical Scavenger TEMPO on the Reaction. 1a (41.2
mg, 0.2 mmol), K2S2O8 (270 mg, 1.0 mmol), TEMPO (62.5 mg,
0.4 mmol, 2 equiv; or 156.2 mg, 1.0 mmol, 5 equiv), and anhydrous
MeOH (6.0 mL) were sequentially added to a 25-mL Schlenk flask
equipped with a high-vacuum PTFE valve-to-glass seal. Then the flask
was sealed and stirred at 110 °C for 6 h. For entry 2, upon completion,
the resulting mixture was diluted with CH2Cl2 (10 mL) and filtered
through Celite. After evaporation of the solvent under vacuum, the
residue was purified by column chromatography on neutral alumina
(200−300 mesh) using petroleum ether−EtOAc (6:1, v/v) as the eluent
to give 2a (14.6 mg, 26%, TEMPO = 2 equiv; 0 mg, 0%, TEMPO =
5 equiv).
Reaction of 1a with MeOH under Degassed Reaction
Conditions. 1a (41.2 mg, 0.2 mmol), K2S2O8 (270 mg, 1.0 mmol),
and anhydrous MeOH (6.0 mL) were sequentially added to a 25-mL
Schlenk flask equipped with a high-vacuum PTFE valve-to-glass seal.
Then the resultant mixture in the sealed tube was frozen by immersion
of the flask in liquid N2. When MeOH was completely frozen, the flask
was opened to the vacuum (high vacuum) and pumped for 2−3 min,
with the flask still immersed in liquid N2. The flask was then closed
and warmed until MeOH completely melted. This process was
repeated three times and after the last cycle the flask was backfilled
with an inert Ar gas. Then the sealed flask was stirred at 110 °C for
6 h. Upon completion, the resulting mixture was diluted with CH2Cl2
(10 mL) and filtered through Celite. After evaporation of the solvent
under vacuum, the residue was analyzed by GC-MS.
1
identified as 2a without the detection of 2a-D by H NMR.
Reaction of Intermediate 3a with MeOH. 3a (46.8 mg, 0.2
mmol), K2S2O8 (270 mg, 1.0 mmol), and anhydrous MeOH (6.0 mL),
were sequentially added to a 25-mL Schlenk flask equipped with
a high-vacuum PTFE valve-to-glass seal. Then the flask was sealed
and stirred at 110 °C for 6 h. Upon completion, the resulting mixture
was diluted with CH2Cl2 (10 mL) and filtered through Celite. After
evaporation of the solvent under vacuum, the residue was purified by
column chromatography on neutral alumina (200−300 mesh) using
petroleum ether−EtOAc (6:1, v/v) as the eluent to give a major
1
product (38.6 mg, 69%) which was identified as 2a by H NMR and
GC-MS. The reaction also gave a minor product 14 which was
identified as methyl 3-phenylquinoxaline-2-carboxylate by GC-MS
(m/z: 264 [M]+).
Reaction of Intermediate 3a with MeOD. 3a (46.8 mg, 0.2
mmol), K2S2O8 (270 mg, 1.0 mmol), and anhydrous MeOD (>99%
Deuterium-enrichment, 6.0 mL), were sequentially added to a 25-mL
Schlenk flask equipped with a high-vacuum PTFE valve-to-glass seal.
Then the flask was sealed and stirred at 110 °C for 6 h. Upon
completion, the resulting mixture was diluted with CH2Cl2 (10 mL)
and filtered through Celite. After evaporation of the solvent under
vacuum, the residue was purified by column chromatography on
neutral alumina (200−300 mesh) using petroleum ether−EtOAc (6:1,
v/v) as the eluent to give a major product (36.4 mg, 65%) which was
1
identified as 2a by H NMR and GC-MS. The reaction also gave a
ASSOCIATED CONTENT
■
minor product methyl 3-phenylquinoxaline-2-carboxylate 14 (GC-MS,
S
* Supporting Information
m/z: 264 [M]+).
X-ray structural data (CIF) of compound 2i, charts for
Direct Reaction of 1a with Formaldehyde Dimethyl Acetal 9.
1a (41.2 mg,, 0.2 mmol), K2S2O8 (270 mg, 1.0 mmol), CF3COOH
1
mechanistic studies as well as copies of H NMR, 13C NMR,
M
dx.doi.org/10.1021/jo302450f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
and 19F NMR spectra of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: ykuiliu@zjut.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of China
(No. 21172197) and Zhejiang Province (No. Y4100201), the
Foundation of Science and Technology Department of Zhejiang
Province (2011R09002-09), and the opening Foundation of
Zhejiang Provincial Top Key Discipline is gratefully acknowledged.
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