Application of α-amino acids for the transition-metal-free synthesis of pyrrolo[1,2-: A] quinoxalines

Article abstract of DOI:10.1039/c7ob01688c

A practical and concise protocol for the efficient synthesis of pyrrolo[1,2-a]quinoxalines from readily available α-amino acids and 2-(1H-pyrrol-1-yl)anilines under transition metal-free conditions has been established. This protocol, which includes the formation of new C-C and C-N bonds, features a wide substrate scope with a broad range of functional group tolerance.

Full text of DOI:10.1039/c7ob01688c

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Application of α-amino acids for the transition-metal-free
synthesis of pyrrolo[1,2-a]quinoxalines
Huanhuan Liu,a Feiyu Zhou,a Wen Luo,a Yuxin Chen,a Chenyang Zhanga and Chen Ma* a,b
Received 00th January 20xx,
Accepted 00th January 20xx
A practical and concise protocol for the efficient synthesis of pyrrolo[1,2-a]quinoxalines from readily available α-amino
acids and 2-(1H-pyrrol-1-yl)anilines under transition metal-free conditions has been established. This protocol, which
includes formation of new C-C and C-N bonds, features a wide substrate scope with a broad range of functional group
tolerance.
DOI: 10.1039/x0xx00000x
www.rsc.org/
transition metals and complex ligands. The other kind of
reactions is carried out without metal catalysts. Moreover,
reports on metal-free decarboxylative coupling reactions of
carboxylic acids14 are few while reports are much less when it
comes to α-amino acids.15
Introduction
The pyrrolo[1,2-a]quinoxaline motif is an important building
block present in various biologically active compounds and is
considered to be a privileged substructure for drug design.
Pyrrolo[1,2-a]quinoxalines
pharmacological activities, especially as antileishmanial,1
antiplasmodial,2 anticancer,3 receptors,4
5-HT3
are
associated
with
our previous work
antimycobacterial,5 antiviral,6 inhibitors of the human protein
kinase CK27 and central dopamine antagonist.8 Moreover,
some derivatives have been proven to be promising in
electronic and optical applications.9
R2
N
X
N
N
Cu(OAc)2
K3PO4
R1
R1
+
HOOC
NH2
R2
X=Br, I
Due to their wide applications, considerable attention has
been attracted to developing diverse methodologies for the
construction of these compounds. Pioneering work by
Cheeseman and Tuck demonstrated a direct method for the
synthesis of pyrrolo[1,2-a]quinoxaline from 2-(1H-pyrrol-1-
yl)aniline and HCO2H.10 More powerful synthetic methods
developed by us11 and others12 have emerged in recent years.
Despite these achievements, limitations remain. These
strategies are somewhat limited in functional group
compatibility, because they need strong and corrosive Lewis
acids as catalysts.
this work
R2
N
N
N
(NH4)2S2O8
R1
R1
+
HOOC
NH2
R2
NH2
metal/acid/base free
Scheme 1 Different protocols for the syntheses of pyrrolo[1,2-
a]quinoxalines using primary α-amino acids
Meanwhile, α-amino acids which are often seen as green
reactants are more readily available, stable, cheap, renewable
and structurally diverse carbon feedstock and are widely
employed to form carbon−carbon and carbon−heteroatom
bonds. In 2015, our group realized a copper-catalyzed aerobic
oxidative synthesis of pyrrolo[1,2-a]quinoxaline derivatives
from unprotected amino acids (Scheme 1).11a This method
involved a Cu catalyst and K3PO4 as the base at relatively high
temperature. To the best of our knowledge, metal-free
oxidative decarboxylation of primary α-amino acids still
remains a significant challenge. The above-mentioned elegant
results, together with our continuing interest in the synthesis
of pyrrolo[1,2-a]quinoxalines by using domino methodology
and amino acid chemistry prompted us to explore a metal-free
and efficient protocol for the synthesis of pyrrolo[1,2-
a]quinoxalines with primary α-amino acids and 2-(1H-pyrrol-1-
yl)anilines.
Decarboxylative coupling reactions have developed
remarkably in recent years. In general, the decarboxylative
coupling reactions can be classified into two categories in
terms of reactants. The first category is mediated with
transition metals (generally silver, palladium, copper, nickel,
cobalt etc.).13 In spite of their high efficiency and selectivity,
these decarboxylative couplings usually require expensive
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With the optimized conditions in hand, the scope of 2-(1H-
pyrrol-1-yl)anilines was firstly investigated. As shown in Table
2, 2-(1H-pyrrol-1-yl)anilines having different substituents on
the aromatic ring were all efficiently engaged in the reaction to
give the products in moderate to high yields. Satisfactorily,
substrates bearing an electron-donating group, such as methyl,
tert-butyl or methoxyl, were tolerated to give the desired
Results and discussion
Table 1. Optimization of Reaction Conditionsa
products in 70% to 95% yields (3b-3f). Representatives with a
entry
1
catalyst
Ag2O
Ag2CO3
AgNO3
AgOTf
AgTFA
AgOTs
—
oxidant
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
—
solvent
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DCE/H2O
DMF/H2O
CH3CN/H2O
Dioxane/H2O
H2O
yield, %b
29
fluoro group also proceeded well to give 3g and 3h in 68% and
86% yields, respectively. Notably, the tandem transformation
also exhibited tolerance for chloro, trifluoromethyl and
2
46
trifluoromethoxy groups, albeit in somewhat low yields (3k
-
3
91
3m). In addition to the monosubstituted 2-(1H-pyrrol-1-
yl)anilines, the disubstituted 1i and 1j also smoothly furnished
3i and 3j in 74% and 61% yields. It is worth mentioning that 2-
(1H-pyrrol-1-yl)pyridin-3-amine 1n was a viable substrate
yielding 3n in 36% yield.
4
81
5
77
6
90
7
92
8
AgNO3
—
trace
48
Table 2. Scope of 2-(1H-pyrrol-1-yl)anilinesa,b
9
K2S2O8
10
11c
12
13
14
15
16
17d
18e
—
Na2S2O8
53
—
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
trace
<5
—
—
trace
trace
<5
—
—
—
DCE
11
—
DCE/H2O
DCE/H2O
21
—
45
aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (0.03 mmol), oxidant
(0.9 mmol) and solvent (4 mL, v/v = 1/1), 80 oC, under air, 10 h. bIsolated yield.
cAt 60 oC. dUnder nitrogen. eUnder oxygen.
At the outset of this study, we employed 2-(1H-pyrrol-1-
yl)aniline 1a and valine 2a as the model substrates to optimize
2-
the reaction conditions (Table 1). Using the typical Ag+/S2O8
catalytic decarboxylative system, the yield of 3a was 29% in
DCE-H2O (1:1) at 80 oC under air (entry 1). Then, different
catalysts were screened (entries 2-6), and AgNO3 showed the
best activity. Surprisingly, we found that the silver catalyst was
not essential for the reaction (entry 7). The further experiment
aReaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), (NH4)2S2O8 (0.9 mmol) and
DCE/H2O (4 mL, v/v = 1/1), 80 oC, under air, 10 h. bIsolated yield.
2-
proved that S2O8 was indispensable for this transformation
Encouraged by the above promising results, we next turned
our attention to explore the scope of α-amino acids as shown
in Table 3. Normally, a series of pyrrolo[1,2-a]quinoxalines
which contain the moieties of α-amino acids were constructed
efficiently under the optimal reaction conditions. In terms of
both short- and long-chain amino acids, the corresponding
(entry 8). The use of other oxidants, such as K2S2O8 and
Na2S2O8, led to the reduction of yield (entries 9 and 10). Trace
amount of 3a was obtained at a lower temperature of 60 oC
(entry 11). Upon examing the effects of different solvent
systems on the reaction, DCE/H2O was found to be the best
choice (entries 7 vs 12-16). In addition, we changed air
atmosphere to nitrogen or oxygen to give 3a in 21% and 45%
yields, respectively (entries 17 and 18). Finally, the above
results demonstrated that the reaction was the most
productive utilizing (NH4)2S2O8 as the oxidant in DCE/H2O at 80
oC within 10 h in air.
products were received in 53% to 79% yields (3o-3r, 3v). For
alanine, it was transformed into 3s in only 26% yield,
presumably due to the low stability of the radical intermediate
generated from the decarboxylation process. It should be
noted that trace amount of 3t and very poor yield of 3u were
obtained. This result indicated that steric hindrance is one of
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the important factors affecting the yields in our protocol. with a satisfactory yield of 82%. Attachment of a 3-Me group
What’s more, 3w could be synthesized in 55% yield from to the indole ring or a 5-Me group to the benzene ring both
phenylglycine or 66% yield from 2-amino-2-(cyclohexa-1,4- can increase the yield of the desired compounds (4b
-
4c). The
optimized conditions were mild enough to be compatible with
a broad range of halogenated substrates, exclusively affording
the products 4d 4f in 75-93% yields. There was no doubt that
dien-1-yl)acetic acid.
-
Table 3. Scope of α-amino acidsa,b
the halogen groups could be further transformed into other
functional groups easily.
To shed light on the possible mechanism of this
transformation, several control experiments were carried out.
Phenylglycine was treated with 3 equiv of (NH4)2S2O8 in the
absence of 2-(1H-pyrrol-1-yl)anilines under the standard
conditions (Scheme 2a), and benzaldehyde was collected in 85%
yield. Subsequently, we got 3w in 77% yield when 2j was
substituted for benzaldehyde in the reaction with 1a under the
standard conditions (Scheme 2b). Taken together, the
oxidative decarboxylation of phenylglycine to benzaldehyde
was proposed as a key step in this transformation. To
investigate the reaction mechanism in more depth, 5 equiv of
TEMPO was employed as a radical scavenger under the
standard conditions (Scheme 2c). As a result, the reaction was
completely suppressed, which could indicate that this
transformation involved radical intermediates.
N
N
N
N
N
N
N
N
3a 92%
61%
3o 77%
3p
79%
3q
N
N
N
N
N
Ph
N
N
N
3s 26%
trace
3t
3r 62%
3u 31%
N
N
N
N
Ph
Ph
3v 53%
3w 55% from
66% from
HOOC
HOOC
NH2
NH2
Scheme 2 Control Experiments
aReaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), (NH4)2S2O8 (0.9 mmol)
and DCE/H2O (4 mL, v/v = 1/1), 80 oC, under air, 10 h. bIsolated yield.
Table 4. Scope of 2-(1H-indol-1-yl)anilinesa,b
A
plausible pathway for the formation of 4-
isopropylpyrrolo[1,2-a]quinoxaline 3a is illustrated in Scheme
3 according to the above results and previous research.11a,14,15
Initially, homolytic cleavage of (NH4)2S2O8 under thermal
conditions resulted in the formation of two sulfate radical
anion (SO4•-), which could react with 2a through a hydrogen
abstraction and decarboxylation process to afford radical
iminium intermediate could be generated by oxidation of
radical . Then, hydrolysis of led to isobutyraldehyde. Finally,
5. An
6
5
6
dehydration condensation of isobutyraldehyde with 1a
released an imine intermediate which could undergo
intramolecular electrophilic addition and oxidation to afford
aReaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), (NH4)2S2O8 (0.9 mmol)
and DCE/H2O (4 mL, v/v = 1/1), 80 oC, under air, 10 h. bIsolated yield.
the final product 3a
.
We envisioned that replacement of the pyrrole ring with
indole ring would supply opportunities to afford a new class of
indole-fused quinoxaline analogues through a similar process.
To our delight, the polycyclic quinoxaline 4a was constructed
Scheme 3 Proposed Reaction Mechanism
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General experimental procedure for 2-(1H-indol-1-
yl)anilines11b
A mixture of 1-fluoro-2-nitrobenzene (2 mmol), indole (2 mmol)
and NaOH (2 mmol) in DMSO (4 mL) was stirred vigorously for
2h at room temperature. After cooling, the reaction mixture
was poured into water (30 mL) and extracted with EtOAc three
times (3×30 mL). The combined organic layers were dried with
MgSO4 and the solvent was removed in vacuo to afford a
residue. The residue was added to iron powder (16 mmol) and
NH4Cl (1 mmol) in water (30 mL) and refluxed for 4 h. After
cooling, the reaction mixture was poured into water (100 mL)
and extracted with ethyl acetate three times (3×30 mL). The
combined organic layers were dried with MgSO4 and the
solvent was removed in vacuo to afford a residue. The residue
was purified by column chromatography on silica gel using
petroleum ether / ethyl acetate as eluent to provide the
desired product.
Conclusions
In this paper, we present our efforts toward the (NH4)2S2O8-
mediated oxidative decarboxylative coupling of primary α-
amino acids with 2-(1H-pyrrol-1-yl)anilines, affording a variety
of pyrrolo[1,2-a]quinoxalines. This reaction can be carried out
smoothly under mild and metal-free conditions. Moreover, the
transformation could tolerate water and air. A proposed
pathway for the formation of pyrrolo[1,2-a]quinoxaline
derivatives is illustrated. This metal-free strategy could provide
a new method for drug design and innovation.
General experimental procedure for 3 and 4
A sealed tube equipped with a magnetic stirring bar was
charged with substituted 2-(1H-pyrrol-1-yl)anilines
1 (0.3
mmol), α-amino acids 2 (0.6 mmol), (NH4)2S2O8 (0.9 mmol) in
DCE/H2O (2 mL/2mL). The mixture was allowed to stir under
air at 80 °C, 10 h. After that, the reaction was cooled to room
temperature, filtered through a short silica gel column eluting
with dichloromethane. The filtrate was diluted with brine (60
mL) and extracted with dichloromethane twice (2×30 mL). The
combined organic layers were dried with MgSO4 and the
solvent was removed in vacuo to afford a residue. The residue
was purified by column chromatography on silica gel using
petroleum ether/ethyl acetate as eluent to provide the desired
product.
Experimental
General procedure
Reagents except 2-(1H-pyrrol-1-yl)anilines were commercially
available and were used without further purification. All
reactions were monitored by thin-layer chromatography (TLC).
Melting points were determined on an XD-4 digital micro
4-isopropylpyrrolo[1,2-a]quinoxaline (3a)12a
. yellow solid
(58.0 mg, 92%). Mp = 58-59 °C; 1H NMR (CDCl3, 400 MHz, ppm):
δ 7.95 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.89 (dd, J1 = 2.8 Hz, J2 =
1.2 Hz, 1H), 7.82 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 7.47-7.38 (m,
2H), 6.92 (dd, J1 = 4.0 Hz, J2 = 1.2 Hz, 1H), 6.84 (dd, J1 = 4.0 Hz,
J2 = 2.8 Hz, 1H), 3.51 (quin, J = 6.8 Hz, 1H) , 1.47 (d, J = 6.8 Hz,
6H); 13C NMR (CDCl3, 100 MHz, ppm): δ 161.7, 136.1, 129.7,
127.3, 126.8, 125.4, 124.9, 113.9, 113.5, 113.2, 105.8, 33.3,
21.1; HRMS called for: C14H15N2 [M+H]+ 211.1230, found
211.1241.
melting point apparatus. H NMR and 13C NMR spectra were
1
recorded on a Bruker Avance 500 (500 MHz), 400 (400 MHz) or
300 (300 MHz) spectrometer, using CDCl3 as solvent and
tetramethylsilane (TMS) as internal standard. HRMS spectra
were determined on a Q-TOF6510 spectrograph (Agilent).
General experimental procedure for 2-(1H-pyrrol-1-
yl)anilines11b
A mixture of substituted 2-nitroaniline (20 mmol) and 2,5-
dimethoxytetrahydrofuran (20 mmol) in acetic acid (100 mL)
was refluxed for 2 h with vigorous stirring. After cooling, the
reaction mixtures were poured into water (300 mL) and
extracted with EtOAc three times (3×50 mL). The organic layers
were dried with MgSO4 and the solvent was removed in vacuo
to afford a residue. The residue was added to iron powder (80
mmol) and NH4Cl (20 mmol) in water (50 mL) and reflux for 4 h.
After cooling, the reaction mixtures were poured into water
(300 mL) and extracted with ethyl acetate three times (3×50
mL). The combined organic layers were dried with MgSO4 and
the solvent was removed in vacuo to afford a residue. The
residue was purified by column chromatography on silica gel
using petroleum ether / EtOAc = 100: 1 as eluent to provide
the desired product.
4-isopropyl-8-methylpyrrolo[1,2-a]quinoxaline (3b). yellow
1
solid (58.5 mg, 87%). Mp = 40-41 °C; H NMR (CDCl3, 400 MHz,
ppm): δ 7.86-7.82 (m, 2H), 7.61 (s, 1H), 7.25-7.21 (m, 1H), 6.90
(dd, J1 = 3.6 Hz, J2 = 1.2 Hz, 1H), 6.83 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz,
1H), 3.50 (quin, J = 6.8 Hz, 1H), 2.52 (s, 3H), 1.46 (d, J = 6.8 Hz,
6H); 13C NMR (CDCl3, 100 MHz, ppm): δ 160.7, 137.2, 134.0,
129.3, 127.0, 126.2, 125.5, 113.7, 113.6, 113.2, 105.6, 33.2,
21.7, 21.1; HRMS called for: C15H17N2 [M+H]+ 225.1386, found
225.1381.
4-isopropyl-9-methylpyrrolo[1,2-a]quinoxaline (3c). yellow
1
solid (53.1 mg, 79%). Mp = 81-82 °C; H NMR (CDCl3, 300 MHz,
ppm): δ 8.30 (q, J = 1.2 Hz, 1H), 7.87 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz,
1H), 7.34-7.24 (m, 2H), 6.98 (dd, J1 = 4.2 Hz, J2 = 1.2 Hz, 1H),
6.85 (dd, J1 = 4.2 Hz, J2 = 3.0 Hz, 1H), 3.57-3.43 (m, 1H), 2.93 (s,
3H), 1.49 (d, J = 6.9 Hz, 6H); 13C NMR (CDCl3, 75 MHz, ppm): δ
161.1, 137.8, 130.3, 128.2, 127.5, 126.8, 125.2, 124.4, 119.6,
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112.5, 105.1, 32.9, 24.0, 21.1; HRMS called for: C15H17N2 125.4, 125.2, 114.0, 113.5, 112.9, 105.4, 33.2, 21.1, 20.2, 19.5;
[M+H]+ 225.1386, found 225.1385.
HRMS called for: C16H19N2 [M+H]+ 239.1543, found 239.1548.
7-(tert-butyl)-4-isopropylpyrrolo[1,2-a]quinoxaline
(3d). 7,8-difluoro-4-isopropylpyrrolo[1,2-a]quinoxaline (3j). yellow
yellow oil (66.2 mg, 83%). H NMR (CDCl3, 400 MHz, ppm): δ solid (45.0 mg, 61%). Mp = 99-100 °C; 1H NMR (CDCl3, 400 MHz,
8.01 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.75 (d, J = 8.8 ppm): δ 7.75-7.70 (m, 2H), 7.59 (dd, J1 = 10.8 Hz, J2 = 6.8 Hz,
Hz, 1H), 7.53 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 6.93-6.92 (m, 1H), 1H), 6.93 (d, J = 3.2 Hz, 1H), 6.86 (dd, J1 = 3.6 Hz, J2 = 2.8 Hz,
6.84 (dd, J1 = 3.6 Hz, J2 = 2.8 Hz, 1H), 3.53 (t, J = 6.8 Hz, 1H), 1H), 3.48 (quin, J = 6.8 Hz, 1H), 1.43 (d, J = 6.8 Hz, 6H); 13C NMR
1.52 (d, J = 6.8 Hz, 6H), 1.44 (s, 9H); 13C NMR (CDCl3, 100 MHz, (CDCl3, 100 MHz, ppm): δ 162.2, 150.4 (dd, J1 = 248 Hz, J2 = 14
ppm): δ 161.6, 148.2, 135.9, 126.1, 125.4, 125.0, 124.5, 113.8, Hz, 1C), 149.1 (dd, J1 = 245 Hz, J2 = 14 Hz, 1C), 132.8, 125.0,
113.14, 113.06, 105.6, 34.7, 33.4, 31.5, 21.2; HRMS called for: 123.6 (d, J = 8 Hz, 1C), 117.3 (d, J = 18 Hz, 1C), 114.3, 113.9,
1
C18H23N2 [M+H]+ 267.1856, found 267.1855.
106.3, 102.1 (d, J = 22 Hz, 1C), 33.2, 21.0; HRMS called for:
4-isopropyl-8-methoxypyrrolo[1,2-a]quinoxaline (3e). yellow C14H13F2N2 [M+H]+ 247.1041, found 247.1040.
solid (68.4 mg, 95%). Mp = 82-83 °C; 1H NMR (CDCl3, 500 MHz, 8-chloro-4-isopropylpyrrolo[1,2-a]quinoxaline (3k). yellow
1
ppm): δ 7.89 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.24 (d, solid (33.7 mg, 46%). Mp = 79-80 °C; H NMR (CDCl3, 400 MHz,
J = 2.5 Hz, 1H), 7.02 (dd, J1 = 9.0 Hz, J2 = 3.0 Hz, 1H), 6.89 (d, J = ppm): δ 7.87-7.80 (m, 3H), 7.38 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H),
3.5 Hz, 1H), 6.85 (t, J = 3.5 Hz, 1H), 3.94 (s, 3H), 3.50 (t, J = 1.8 6.94 (d, J = 3.6 Hz, 1H), 6.86 (t, J = 3.2 Hz, 1H), 3.50 (quin, J =
Hz, 1H), 1.46 (d, J = 7.0 Hz, 6H); 13C NMR (CDCl3, 125 MHz, 6.8 Hz, 1H), 1.46 (d, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 100 MHz,
ppm): δ 159.0, 158.6, 130.8, 127.9, 125.4, 113.6, 113.4, 112.4, ppm): δ 161.9, 134.7, 132.1, 130.9, 127.8, 125.32, 125.27,
105.4, 97.5, 55.8, 33.1, 21.1; HRMS called for: C15H17N2O 114.2, 113.8, 113.7, 106.3, 33.2, 21.0; HRMS called for:
[M+H]+ 241.1335, found 241.1337.
C14H14ClN2 [M+H]+ 245.0840, found 245.0846.
4-isopropyl-7-methoxypyrrolo[1,2-a]quinoxaline (3f). yellow 4-isopropyl-7-(trifluoromethyl)pyrrolo[1,2-a]quinoxaline (3l).
solid (50.4 mg, 70%). Mp = 51-52 °C; 1H NMR (CDCl3, 400 MHz, yellow solid (27.5 mg, 33%). Mp = 66-67 °C; 1H NMR (CDCl3,
ppm): δ 7.84 (dd, J1 = 2.4 Hz, J2 = 0.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 400 MHz, ppm): δ 8.26 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.91 (d, J
1H), 7.43 (d, J = 2.0 Hz, 1H), 7.09 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, = 8.4 Hz, 1H), 7.69 (dd, J1 = 8.8 Hz, J2 = 1.6 Hz, 1H), 6.99 (d, J =
1H), 6.91 (d, J = 3.2 Hz, 1H), 6.82 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 3.6 Hz, 1H), 6.91 (t, J = 3.6 Hz, 1H), 3.51 (t, J = 6.8 Hz, 1H), 1.47
1H), 3.92 (s, 3H), 3.50 (t, J = 7.2 Hz, 1H), 1.47 (d, J = 6.8 Hz, 6H); (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz, ppm): δ 163.3,
13C NMR (CDCl3, 100 MHz, ppm): δ 162.2, 157.0, 137.2, 125.1, 135.8, 129.3, 127.3, 126.9, 125.5, 125.4, 123.22, 123.19, 122.7,
121.5, 116.1, 114.5, 113.7, 113.0, 110.9, 105.5, 55.8, 33.3, 21.1; 120.0, 114.8, 114.3, 114.2, 106.9, 33.2, 21.0; HRMS called for:
HRMS called for: C15H17N2O [M+H]+ 241.1335, found 241.1341. C15H14F3N2 [M+H]+ 279.1104, found 279.1112.
7-fluoro-4-isopropylpyrrolo[1,2-a]quinoxaline (3g). yellow 4-isopropyl-7-(trifluoromethoxy)pyrrolo[1,2-a]quinoxaline
solid (46.5 mg, 68%). Mp = 83-84 °C; 1H NMR (CDCl3, 400 MHz, (3m). yellow solid (32.6 mg, 37%). Mp = 62-63 °C; 1H NMR
ppm): δ 7.83 (dd, J1 = 2.4 Hz, J2 = 0.8 Hz, 1H), 7.74 (dd, J1 = 8.8 (CDCl3, 400 MHz, ppm): δ 7.90 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H),
Hz, J2 = 4.8 Hz, 1H), 7.63 (dd, J1 = 9.6 Hz, J2 = 2.8 Hz, 1H), 7.18- 7.34 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 6.87 (s, 1H), 3.51 (t, J = 6.8
7.13 (m, 1H), 6.92 (dd, J1 = 4.0 Hz, J2 = 0.8 Hz, 1H), 6.82 (dd, J1 = Hz, 1H), 1.46 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz,
4.0 Hz, J2 = 2.8 Hz, 1H), 3.49 (quin, J = 6.8 Hz, 1H), 1.45 (d, J = ppm): δ 163.2, 145.9, 136.9, 125.9, 125.3, 121.9, 121.5, 119.8,
6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz, ppm): δ 163.0, 161.0 (d, 119.3, 114.6, 113.8, 106.5, 33.2, 21.0; HRMS called for:
J = 241 Hz, 1C), 137.4, 137.3, 125.2, 123.9, 115.1 (d, J = 22 Hz, C15H14F3N2O [M+H]+ 295.1053, found 295.1057.
1C), 114.6 (d, J = 9 Hz, 1C), 114.3 (d, J = 6 Hz, 1C), 113.4, 106.2, 6-isopropylpyrido[3,2-e]pyrrolo[1,2-a]pyrazine (3n). yellow
1
33.2, 21.1; HRMS called for: C14H14FN2 [M+H]+ 229.1136, found solid (22.8 mg, 36%). Mp = 72-73 °C; H NMR (CDCl3, 400 MHz,
229.1143.
ppm): δ 8.48 (dd, J1 = 4.4 Hz, J2 = 1.2 Hz, 1H), 8.36 (d, J = 1.2 Hz,
8-fluoro-4-isopropylpyrrolo[1,2-a]quinoxaline (3h). yellow 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.40 (dd, J1 = 8.0 Hz, J2 = 4.4 Hz,
solid (58.8 mg, 86%). Mp = 78-79 °C; 1H NMR (CDCl3, 400 MHz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.87 (t, J = 3.2 Hz, 1H), 3.50 (t, J =
ppm): δ 7.93 (dd, J1 = 8.8 Hz, J2 = 6.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 6.8 Hz, 1H), 1.46 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz,
1H), 7.48 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.15 (td, J1 = 8.8 Hz, J2 ppm): δ 162.9, 146.0, 139.5, 136.8, 130.9, 126.9, 121.3, 115.4,
= 2.8 Hz, 1H), 6.91 (d, J = 3.6 Hz, 1H), 6.86 (t, J = 3.2 Hz, 1H), 113.7, 107.3, 33.2, 21.1; HRMS called for: C13H14N3 [M+H]+
3.49 (quin, J = 6.8 Hz, 1H), 1.45 (d, J = 6.8 Hz, 6H); 13C NMR 212.1182, found 212.1185.
(CDCl3, 100 MHz, ppm): δ 162.2 (d, J = 245 Hz, 1C), 160.8 (d, J = 4-(sec-butyl)pyrrolo[1,2-a]quinoxaline (3o). yellow oil (51.7
1
2 Hz, 1C), 132.7, 131.5 (d, J = 10 Hz, 1C), 127.9 (d, J = 11 Hz, 1C), mg, 77%). H NMR (CDCl3, 300 MHz, ppm): δ 7.97 (dd, J1 = 7.6
125.1, 114.1, 113.8, 112.8 (d, J = 23 Hz, 1C), 106.0, 100.5 (d, J = Hz, J2 = 1.6 Hz, 1H), 7.92 (q, J = 1.2 Hz, 1H), 7.85-7.81 (m, 1H),
27 Hz, 1C), 33.2, 21.0; HRMS called for: C14H14FN2 [M+H]+ 7.49 (qd, J1 = 7.2 Hz, J2 = 2.0 Hz, 2H), 6.94 (dd, J1 = 4.0 Hz, J2 =
229.1136, found 229.1143.
1.2 Hz, 1H), 6.86 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 3.29 (sext, J =
4-isopropyl-7,8-dimethylpyrrolo[1,2-a]quinoxaline
(3i). 7.2 Hz, 1H), 2.14-2.00 (m, 1H), 1.85-1.71 (m, 1H), 1.45 (d, J =
yellow solid (52.8 mg, 74%). Mp = 65-66 °C; 1H NMR (CDCl3, 6.8 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz,
400 MHz, ppm): δ 7.81 (s, 1H), 7.71 (s, 1H), 7.54 (s, 1H), 6.87 (d, ppm): δ 161.3, 136.1, 129.7, 127.2, 126.8, 126.0, 124.9, 114.0,
J = 3.6 Hz, 1H), 6.79 (t, J = 3.2 Hz, 1H), 3.48 (quin, J = 6.8 Hz, 113.5, 113.3, 106.0, 40.5, 28.6, 19.0, 12.4; HRMS called for:
1H), 2.39 (d, J = 17.6 Hz, 6H), 1.45 (d, J = 6.8 Hz, 6H); 13C NMR C15H17N2 [M+H]+ 225.1386, found 225.1398.
(CDCl3, 100 MHz, ppm): δ 160.7, 136.1, 134.2, 133.7, 129.8,
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ARTICLE
Journal Name
4-propylpyrrolo[1,2-a]quinoxaline (3p)12a
.
yellow solid (38.4 7.88 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.56-7.50 (m, 4H), 7.47-
1
mg, 61%). Mp = 48-49 °C; H NMR (CDCl3, 300 MHz, ppm): δ 7.44 (m, 1H), 7.00 (dd, J1 = 4.0 Hz, J2 = 1.2 Hz, 1H), 6.90 (dd, J1 =
7.95-7.90 (m, 2H), 7.84 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.49- 4.0 Hz, J2 = 2.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz, ppm): δ
7.40 (m, 2H), 6.93 (dd, J1 = 4.0 Hz, J2 = 1.2 Hz, 1H), 6.86 (dd, J1 = 154.4, 138.4, 136.2, 130.2, 129.9, 128.7, 128.6, 127.5, 127.2,
4.0 Hz, J2 = 2.8 Hz, 1H), 3.03-2.99 (m, 2H), 1.97-1.91 (m, 2H), 125.4, 125.3, 114.7, 114.0, 113.7, 108.8; HRMS called for:
1.10 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz, ppm): δ 157.4, C17H13N2 [M+H]+ 245.1073, found 245.1076.
135.9, 129.4, 127.2, 126.9, 126.1, 125.1, 114.2, 113.6, 113.5, 6-isopropylindolo[1,2-a]quinoxaline (4a). yellow solid (64.0
106.4, 37.8, 22.0, 14.3; HRMS called for: C14H15N2 [M+H]+ mg, 82%). Mp = 105-106 °C; 1H NMR (CDCl3, 400 MHz, ppm): δ
211.1230, found 211.1229.
8.45 (t, J = 7.6 Hz, 2H), 8.00 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 8.0
4-isobutylpyrrolo[1,2-a]quinoxaline (3q)12a
.
yellow solid (53.1 Hz, 1H), 7.56-7.48 (m, 2H), 7.43 (q, J = 7.6 Hz, 2H), 7.18 (s, 1H),
mg, 79%). Mp = 43-44 °C; H NMR (CDCl3, 400 MHz, ppm): δ 3.59 (q, J = 6.8 Hz, 1H), 1.51 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3,
7.92 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.87 (q, J = 1.2 Hz, 1H), 100 MHz, ppm): δ 163.1, 136.0, 132.9, 130.2, 130.0, 129.1,
7.80 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.44-7.39 (m, 2H), 6.88 127.7, 124.0, 123.9, 122.6, 122.5, 114.62, 114.56, 99.3, 33.1,
(dd, J1 = 4.0 Hz, J2 = 1.2 Hz, 1H), 6.82 (dd, J1 = 3.6 Hz, J2 = 2.8 Hz, 21.0; HRMS called for: C18H17N2 [M+H]+ 261.1386, found
1H), 2.87 (d, J = 7.6 Hz, 2H), 2.41 (quin, J = 6.8 Hz, 1H), 1.01 (d, 261.1398.
1
J = 6.4 Hz, 6H); 13C NMR (CDCl3, 100 MHz, ppm): δ 156.9, 136.0, 6-isopropyl-7-methylindolo[1,2-a]quinoxaline (4b). yellow
129.5, 127.2, 126.8, 126.6, 125.1, 114.1, 113.6, 113.4, 106.6, solid (72.3 mg, 88%). Mp = 116-117 °C; 1H NMR (CDCl3, 400
44.7, 28.5, 22.9; HRMS called for: C15H17N2 [M+H]+ 225.1386, MHz, ppm): δ 8.44 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 2H), 7.96 (d, J =
found 225.1384.
8.0 Hz, 2H), 7.54-7.52 (m, 2H), 7.47-7.45 (m, 1H), 7.38-7.36 (m
4-benzylpyrrolo[1,2-a]quinoxaline (3r). yellow solid (48.0 mg, 1H), 3.87 (quin, J = 6.4 Hz, 1H), 2.84 (s, 3H), 1.49 (d, J = 6.4 Hz,
62%). Mp = 101-102 °C; 1H NMR (CDCl3, 300 MHz, ppm): δ 8.00 6H); 13C NMR (CDCl3, 100 MHz, ppm): δ 163.8, 131.9, 130.4,
(dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.88 (q, J = 1.2 Hz, 1H), 7.82 (dd, 130.2, 129.5, 127.5, 125.9, 124.3, 123.6, 121.9, 120.5, 114.40,
J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.51-7.41 (m, 4H), 7.29-7.24 (m, 2H), 114.36, 32.6, 21.23, 21.18, 11.4; HRMS called for: C19H19N2
7.21-7.16 (m, 1H), 6.86 (dd, J1 = 4.0 Hz, J2 = 1.2 Hz, 1H), 6.80 [M+H]+ 275.1543, found 275.1544.
(dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 4.37 (s, 2H); 13C NMR (CDCl3, 75 6-isopropyl-3,7-dimethylindolo[1,2-a]quinoxaline (4c). yellow
MHz, ppm): δ 155.2, 138.0, 135.8, 129.7, 128.9, 128.5, 127.34, solid (81.2 mg, 94%). Mp = 130-131 °C; 1H NMR (CDCl3, 400
127.25, 126.6, 125.8, 125.1, 114.3, 113.7, 113.6, 107.2, 42.5; MHz, ppm): δ 8.41 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H),
HRMS called for: C18H15N2 [M+H]+ 259.1230, found 259.1235.
7.95 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.45
. yellow solid (14.2 (t, J = 7.2 Hz, 1H), 7.33 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 3.85 (q,
4-methylpyrrolo[1,2-a]quinoxaline (3s)12a
1
mg, 26%). Mp = 132-133 °C; H NMR (CDCl3, 400 MHz, ppm): δ J = 6.8 Hz, 1H), 2.84 (s, 3H), 2.49 (s, 3H), 1.49 (d, J = 6.8 Hz, 6H);
7.91-7.89 (m, 2H), 7.82-7.80 (m, 1H), 7.48-7.39 (m, 2H), 6.89- 13C NMR (CDCl3, 100 MHz, ppm): δ 163.7, 135.6, 133.2, 131.7,
6.83 (m, 2H), 2.73 (s, 3H); 13C NMR (CDCl3, 75 MHz, ppm): δ 130.0, 129.7, 128.3, 128.1, 125.9, 124.0, 121.6, 120.4, 114.3,
153.6, 135.9, 129.2, 127.3, 126.9, 126.3, 125.1, 114.2, 113.6, 114.1, 107.5, 32.6, 21.3, 20.7, 11.3; HRMS called for: C20H21N2
113.5, 106.5, 22.0; HRMS called for: C12H11N2 [M+H]+ 183.0917, [M+H]+ 289.1699, found 289.1711.
found 183.0910.
4-cyclohexylpyrrolo[1,2-a]quinoxaline (3u)12c
3-fluoro-6-isopropyl-7-methylindolo[1,2-a]quinoxaline (4d).
1
.
yellow oil (23.3 yellow solid (65.7 mg, 75%). Mp = 158-159 °C; H NMR (CDCl3,
mg, 31%). 1H NMR (CDCl3, 400 MHz, ppm): δ 7.95 (d, J = 7.2 Hz, 400 MHz, ppm): δ 8.38 (dd, J1 = 10.8 Hz, J2 = 2.8 Hz, 2H), 7.97 (d,
1H), 7.90 (d, J = 1.2 Hz, 1H), 7.83 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, J = 8.4 Hz, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H),
1H), 7.46-7.41 (m, 2H), 6.95 (d, J = 3.2 Hz, 1H), 6.85 (t, J = 3.2 7.47 (t, J = 7.6 Hz, 1H), 7.23-7.21 (m, 1H), 3.86 (quin, J = 6.8 Hz,
Hz, 1H), 3.17 (td, J1 = 11.6 Hz, J2 = 3.2 Hz, 1H), 2.04-1.89 (m, 7H), 1H), 2.84 (s, 3H), 1.47 (d, J = 6.4 Hz, 6H); 13C NMR (CDCl3, 100
1.50-1.44 (m, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ 161.1, MHz, ppm): δ 165.1, 160.2, 157.0, 131.7, 130.0, 127.0 (d, J =
129.6, 127.2, 126.8, 125.6, 125.0, 114.0, 113.5, 113.3, 105.8, 244 Hz, 1C), 125.6, 121.9, 120.7, 115.4, 115.2, 115.0, 114.5,
43.6, 31.3, 26.6, 26.1; HRMS called for: C17H19N2 [M+H]+ 114.2, 114.0, 32.7, 21.2, 11.3; HRMS called for: C19H18FN2
251.1543, found 251.1544.
4-hexylpyrrolo[1,2-a]quinoxaline (3v)12a
[M+H]+ 293.1449, found 293.1455.
.
yellow solid (40.1 mg, 3-chloro-6-isopropyl-7-methylindolo[1,2-a]quinoxaline (4e).
1
1
53%). Mp = 38-39 °C; H NMR (CDCl3, 400 MHz, ppm): δ 7.94 yellow solid (85.9 mg, 93%). Mp = 141-142 °C; H NMR (CDCl3,
(dd, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.87 (q, J = 1.2 Hz, 1H), 7.80 (dd, 500 MHz, ppm): δ 8.32 (dd, J1 = 10.8 Hz, J2 = 6.8 Hz, 2H), 7.94-
J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.46-7.39 (m, 2H), 6.90 (dd, J1 = 4.0 7.89 (m, 2H), 7.54-7.51 (m, 1H), 7.46-7.41 (m, 2H), 3.81 (t, J =
Hz, J2 = 1.2 Hz, 1H), 6.83-6.82 (m, 1H), 3.03 (t, J = 8.0 Hz, 2H), 5.6 Hz, 1H), 2.82 (s, 3H), 1.45 (d, J = 5.2 Hz, 6H); 13C NMR
1.92 (t, J = 8.0 Hz, 2H), 1.51 (t, J = 7.6 Hz, 2H), 1.37-1.34 (m, 4H), (CDCl3, 125 MHz, ppm): δ 165.1, 136.7, 131.7, 130.2, 128.99,
0.92 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm): δ 128.96, 128.4, 127.1, 125.6, 124.6, 122.1, 120.7, 115.2, 114.1,
157.6, 136.0, 129.4, 127.3, 126.8, 126.0, 125.0, 114.1, 113.6, 108.7, 32.8, 21.2, 11.3; HRMS called for: C19H18ClN2 [M+H]+
113.4, 106.2, 36.0, 31.7, 29.5, 28.6, 22.6, 14.1; HRMS called for: 309.1153, found 309.1150.
C17H21N2 [M+H]+ 253.1699, found 253.1707.
3-bromo-6-isopropyl-7-methylindolo[1,2-a]quinoxaline (4f).
1
4-phenylpyrrolo[1,2-a]quinoxaline (3w). yellow solid (40.3 mg, yellow solid (87.6 mg, 83%). Mp = 145-146 °C; H NMR (CDCl3,
55%; 48.3 mg, 66%). Mp = 99-100 °C; 1H NMR (CDCl3, 500 MHz, 400 MHz, ppm): δ 8.34 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 8.8 Hz,
ppm): δ 8.06 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 8.01-7.99 (m, 3H), 1H), 8.07 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.59-7.53 (m, 2H),
6 | J. Name., 2012, 00, 1-3
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ARTICLE
12 For selected examples, see: (a) J. Li, J. Zhang, H. Yang, Z. Gao
and G. Jiang, J. Org. Chem., 2017, 82, 765-769; (b) M. d. F.
Pereira and V. Thiery, Org. Lett., 2012, 14, 4754-4757; (c) Z.
He, M. Bae, J. Wu and T. F. Jamison, Angew. Chem., Int. Ed.,
2014, 53, 14451-14455; (d) J. Zhu, H. Xie, Z. Chen, S. Li and Y.
Wu, Chem. Commun., 2011, 47, 1512-1514; (e) Y. Wang and
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2014, 79, 2491-2500..
7.47 (t, J = 7.2 Hz, 1H), 3.81 (t, J = 5.6 Hz, 1H), 2.82 (s, 3H), 1.45
(d, J = 5.2 Hz, 6H); 13C NMR (CDCl3, 100 MHz, ppm): δ 165.1,
131.9, 131.8, 130.2, 130.0, 129.4, 124.7, 122.1, 120.7, 115.8,
115.6, 114.2, 32.8, 21.2, 11.3; HRMS called for: C19H18BrN2
[M+H]+ 353.0648, found 353.0641.
Acknowledgements
13 For Ag-catalyzed decarboxylative couplings, see: (a) Q. Gui, L.
Hu, X. Chen, J. Liu and Z. Tan, Chem. Commun., 2015, 51,
We are grateful to the National Science Foundation of China
(No. 21572117) and the State Key Laboratory of Natural and
Biomimetic Drugs of Peking University (No. K20140208) for
financial support of this research.
13922-13924; (b) Y. Zhu, X. Li, X. Wang, X. Huang, T. Shen, Y.
Zhang, X. Sun, M. Zou, S. Song and N. Jiao, Org. Lett., 2015,
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Angew. Chem., Int. Ed., 2014, 53, 6105-6109; (d) X.-Q. Chu, Y.
Zi, H. Meng, X.-P. Xu and S.-J. Ji, Chem. Commun., 2014, 50
,
7642-7645; (e) D. N. Mai and R. D. Baxter, Org. Lett., 2016,
18, 3738-3741; Pd-catalyzed decarboxylative couplings, see:
Notes and references
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1
J. Guillon, I. Forfar, M. Mamani-Matsuda, V. Desplat, M.
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R. Shang, Y. Fu, Y. Wang, Q. Xu, H.-Z. Yu and L. Liu, Angew.
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C. Zhang, P. Wang, Y. Zhang and H. Ge, Chem. - Eur. J., 2014,
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17, 4476-4478.
2
(a) N. Primas, P. Suzanne, P. Verhaeghe, S. Hutter, C. Kieffer,
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14 For selected examples, see: (a) S. Lu, Y. Gong and D. Zhou, J.
Org. Chem., 2015, 80, 9336-9341; (b) H. Wang, L.-N. Guo, S.
Wang and X.-H. Duan, Org. Lett., 2015, 17, 3054-3057; (c) M.
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Organic & Biomolecular Chemistry
Page 8 of 8
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DOI: 10.1039/C7OB01688C
Application of unprotected α-amino acids for the
transition-metal-free synthesis of pyrrolo[1,2-a]quinoxalines in
aqueous solution
Huanhuan Liu, Feiyu Zhou, Wen Luo, Yuxin Chen, Chenyang Zhang, and Chen Ma*
A practical and concise protocol for the efficient synthesis of pyrrolo[1,2-a]quinoxalines from
readily available α-amino acids and 2-(1H-pyrrol-1-yl)anilines under transition metal-free
conditions has been established. This protocol, which includes formation of new C-C and C-N
bonds, features a wide substrate scope with a broad range of functional group tolerance.