Synthesis of tetrahydropyrrolo[1,2-a ]quinoxalines and tetrahydro-pyrido[1, 2-a ]quinoxalines via a one-pot CuI-catalyzed aryl amination-hydrolysis- condensation process

Article abstract of DOI:10.1055/s-0030-1258030

CuI-catalyzed coupling of 2-halotrifluoroacetanilides with l-proline or pipecolinic acid in DMSO at 90-110 C followed by in situ hydrolysis at 100 C afforded tetrahydropyrrolo[1,2-a]quinoxalines or tetrahydropyrido[1,2-a] quinoxalines. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258030

LETTER
2285
Synthesis of Tetrahydropyrrolo[1,2-a]quinoxalines and Tetrahydro-
pyrido[1,2-a]quinoxalines via a One-Pot CuI-Catalyzed Aryl Amination–
Hydrolysis–Condensation Process
T
etrahydropyrro
a
lo[1,2-
a
]q
n
a
t
nd
T
etr
i
ahydro
n
pyrido[1,2-
a
g
]quinoxaline
s
Xu,a Yongwen Jiang,b Dawei Ma*b
a
Department of Chemistry, Fudan University, Shanghai 200433, P. R. of China
b
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: madw@mail.sioc.ac.cn
Received 27 May 2010
tetrahydropyrido[1,2-a]quinoxalines. A significant draw-
back of this procedure is that only o-nitrohalobenzenes
bearing electron-donating groups are suitable substrates.
Recently, Tanimori and co-workers reported that CuI-
catalyzed coupling reaction of o-bromoanilines with race-
mic amino acids followed by condensative cyclization
gave tetrahydropyrrolo[1,2-a]quinoxalines and tetrahy-
dropyrido[1,2-a]quinoxalines.1a In this case the coupling
reaction was conducted at 125 °C, which might lead to ra-
cemization of the amino acid moiety if enantiopure amino
acids were utilized. We revealed that the ortho-substitu-
tion effect caused by NHCOCF3 could facilitate some
Ullmann-type coupling reactions at relatively low reac-
tion temperatures.7 As an extension of this work, we
investigated the coupling reaction of 2¢-halotrifluoroacet-
anilides with L-proline.8 We envisaged that if this reaction
proceeded under milder conditions, enantiopure pyrro-
lo[1,2-a]quinoxalines could be obtained upon hydrolysis
of the amide part in the coupling products and subsequent
intramolecular condensation as indicated in Scheme 1.
Abstract: CuI-catalyzed coupling of 2-halotrifluoroacetanilides
with L-proline or pipecolinic acid in DMSO at 90–110 °C followed
by in situ hydrolysis at 100 °C afforded tetrahydropyrrolo[1,2-
a]quinoxalines or tetrahydropyrido[1,2-a]quinoxalines.
Key words: catalysis, coupling, heterocycle, quinoxaline, one-pot
process
Tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydro-
pyrido[1,2-a]quinoxalines and their derivatives have of-
ten been used for developing pharmaceutical agents.1
Antitumor agent 1 (Figure 1),2 vascular smooth muscle
relaxant 2,3 antitrypanosomal compound 3,4 and PARP-1
inhibitor 45 are some successful examples.
F
N
N
N
O
N
O
N
O
H
N
Bn
HO2C
With the above idea in mind, we selected the reaction of
2-iodotrifluoroacetanilide with L-proline as a model to ex-
plore the optimized coupling conditions. It was found that
under the catalysis of 10 mol% CuI and K2CO3, this reac-
tion took place at 60 °C in DMSO. However, only 50%
yield of the coupling product was obtained mainly be-
cause of incomplete conversion. The complete conversion
and excellent coupling yield (95%) was only seen when
the reaction temperature was raised to 90 °C. We next ex-
plored the optimized conditions for one-pot conversion of
the coupling products to pyrrolo[1,2-a]quinoxalines. Af-
ter some experiments, we were pleased to find that adding
water to the coupling reaction mixture followed by heat-
ing at 100 °C provided the desired product 8a in good
yield with little racemization (Table 1, entry 1). When less
reactive bromotrifluoroacetanilide was used, the coupling
reaction required a higher temperature (110 °C) and using
Cs2CO3 as the base to complete. In this case 8a was isolat-
ed in 76% yield and 90% ee after hydrolysis (entry 2).
Based on these results, we next attempted to synthesize
substituted tetrahydropyrrolo[1,2-a]quinoxalines using
functionalized 2¢-halotrifluoroacetanilides. To our de-
light, both electron-rich and electron-deficient 2¢-halotri-
fluoroacetanilides were found compatible for this process,
affording the corresponding products 8b–j. In most cases,
1
2
N
N
Me
N
O2N
N
H
O
Me
N
O
H
3
4
Figure 1 Some bioactive tetrahydropyrrolo[1,2-a]quinoxalines and
tetrahydropyrido[1,2-a]quinoxalines
The most typical approach for construction of these two
classes of heterocycles is dependent on employing o-ni-
trohalobenzenes as the starting materials.6 After nucleo-
philic aromatic substitution of these aryl halides with
proline and pipecolinic acid, reduction of the nitro group
and subsequent condensative cyclization produced the
corresponding tetrahydropyrrolo[1,2-a]quinoxalines and
SYNLETT 2010, No. 15, pp 2285–2288
Advanced online publication: 19.08.2010
DOI: 10.1055/s-0030-1258030; Art ID: W08310ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

2286
L. Xu et al.
LETTER
HO2C
X
N
CuI
+
Z
COOH
Z
base, solvent
N
H
NHCOCF3
NHCOCF3
5
6
7
N
– COCF3
Z
condensative cyclization
N
H
O
8
Scheme 1 One-pot coupling–hydrolysis–condensation approach to enantiopure tetrahydropyrrolo[1,2-a]quinoxaline
Table 1 Synthesis of Tetrahydropyrrolo[1,2-a]quinoxalines 8 via a
slight racemization occurred with the products having ee
values ranging from 91% to 99%. When 4¢-acyl-2¢-
iodotrifluoroacetanilide was used, 8f was isolated with
70% ee (entry 9), presumably because of the strong elec-
tron-withdrawing effect of the acyl group.
CuI-Catalyzed One-Pot Processa (continued)
L-proline, CuI (10 mol%)
X
N
K2CO3, DMSO
Z
Z
90 °C (X = I) or 110 °C (X = Br)
then H2O, 100 °C
NHCOCF3
N
H
O
5
8
Table 1 Synthesis of Tetrahydropyrrolo[1,2-a]quinoxalines 8 via a
CuI-Catalyzed One-Pot Processa
Entry
X
I
Time Product
Yield ee (%)
(%)c
(h)b
17
L-proline, CuI (10 mol%)
X
N
K2CO3, DMSO
Z
Z
90 °C (X = I) or 110 °C (X = Br)
then H2O, 100 °C
MeOC
N
NHCOCF3
N
H
O
9e
75
70
5
8
N
H
O
Entry
X
Time Product
Yield ee (%)
(%)c
(h)b
8f
Me
N
10
I
Br
13
10
74
72
95
96
N
11d
1
I
Br
15
10
78
76
97
90
2d
N
H
O
O
N
O
H
8g
8a
Me
N
F
N
3
I
Br
17
10
78
72
95
95
12
I
10
60
99
4d
N
H
N
H
O
Me
8h
8b
N
Cl
N
5
I
Br
18
12
77
76
91
94
13
I
6
30f
70
97
94
6d
MeO
N
O
N
O
H
H
8i
8c
N
MeO2C
N
14d
Br
14
7
8
I
I
17
24
85
83
91
95
F3C
N
O
N
O
H
H
8j
8d
a Reaction conditions: 2-iodotrifluoroacetanilide (0.5 mmol), L-pro-
line (1.5 mmol), CuI (0.05 mmol), K2CO3 (1 mmol), DMSO (4 mL),
90 °C (for bromide, 110 °C), then H2O (3 mL) was added and the mix-
ture was heated to 100 °C.
F3C
N
N
O
H
b For coupling step.
c Isolated yield.
8e
d Cs2CO3 was used.
e Amount of CuI used: 20 mol%.
f Deiodination product was isolated in about 35% yield.
Synlett 2010, No. 15, 2285–2288 © Thieme Stuttgart · New York

LETTER
Tetrahydropyrrolo[1,2-a]quinoxalines and Tetrahydropyrido[1,2-a]quinoxalines
2287
Table 2 Synthesis of Tetrahydropyrido[1,2-a]quinoxalines 9 via a
The electronic nature of the substituted 2-halotrifluoroac-
etanilides also had a significant influence on the rate of the
coupling step. In case of 4¢-acyl-2¢-iodotrifluoroacetanil-
ide, increasing the catalytic loading was required to com-
plete the conversion (entry 9). This phenomenon indicated
that electron-rich aryl halides are more reactive than elec-
tron-deficient ones, which is consistent with that observed
in other coupling reactions.7 In the case of 5¢-methoxy-2¢-
iodotrifluoroacetanilide, although coupling reaction pro-
ceeded quite fast, low yield was observed mainly because
severe deiodination occurred (entry 13).
CuI-Catalyzed One-Pot Processa (continued)
pipecolinic acid, CuI (10 mol%)
N
X
K2CO3, DMSO
Z
Z
90 °C (X = I) or 110 °C (X = Br)
then H2O, 100 °C
N
H
O
NHCOCF3
5
9
Entry
X
Time (h) Product
Yield (%)b
N
7c
Br
12
70
Table 2 Synthesis of Tetrahydropyrido[1,2-a]quinoxalines 9 via a
CuI-Catalyzed One-Pot Processa
F3C
N
H
O
9g
pipecolinic acid, CuI (10 mol%)
N
X
K2CO3, DMSO
Z
Z
N
8c
9c
Br
Cl
11
43
90
40
90 °C (X = I) or 110 °C (X = Br)
then H2O, 100 °C
N
H
O
NHCOCF3
5
9
N
H
O
Entry
X
I
Time (h) Product
Yield (%)b
9h
a Reaction conditions: 2-halotrifluoroacetanilide (0.5 mmol), pipe-
colinic acid (1.5 mmol), CuI (0.05 mmol), K2CO3 (1 mmol), DMSO
(4 mL), 90 °C (for bromides and chloride, 110 °C), then H2O (3 mL)
was added and the mixture was heated to 100 °C.
b Isolated yield.
Me
N
1
13
78
N
H
O
c Cs2CO3 was used as the base.
Me
9a
By switching the coupling partner from L-proline to pipe-
colinic acid, we were able to obtain tetrahydropyrido[1,2-
a]quinoxalines with good to excellent yields (Table 2). In-
terestingly, when 5-methoxy-2-iodotrifluoroacetanilide
was used, tricyclic product 9b was isolated in a good
yield, indicating that pipecolinic acid is more reactive
than L-proline as a coupling partner in this case (compare
entry 2 with entry 13 of Table 1). 2-Chlorotrifluoroaceta-
nilide was also compatible with these reaction conditions,
giving 9h in a moderate yield (entry 9).
N
2
I
13
12
12
12
12
86
84
75
92
60
MeO
N
O
H
9b
N
3
I
O2N
N
O
H
9c
In conclusion, we have developed a new method for as-
sembling tetrahydropyrrolo[1,2-a]quinoxalines and tet-
rahydropyrido[1,2-a]quinoxalines,9 which relied on a
one-pot amination–hydrolysis–condensation process of 2-
halotrifluoroacetanilides with L-proline and pipecolinic
acid. A considerable number of functional groups such as
halo, nitro, ester and keto groups are tolerated under these
reaction conditions, thereby allowing diverse synthesis of
these heterocycles.10
F
N
4c
5c
6c
Br
Br
Br
N
H
O
9d
Me
N
N
O
H
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
9e
Cl
N
Acknowledgment
N
O
The authors are grateful to the National Natural Science Foundation
of China (grants 20621062 and 20872156) for their financial sup-
port.
H
9f
Synlett 2010, No. 15, 2285–2288 © Thieme Stuttgart · New York

2288
L. Xu et al.
LETTER
(8) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
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References and Notes
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(9) General Procedure for the Synthesis of Quinoxaline
Derivatives: A Schlenk tube was charged with 2-iodo-
trifluoroacetanilide (0.5 mmol), CuI (10 mg, 0.02 mmol),
L-proline (or pipecolinic acid) (1.5 mmol), and K2CO3 (1.0
mmol) (for bromide, Cs2CO3 was used). The tube was
evacuated and backfilled with argon. DMSO (4 mL) was
added into the tube. The reaction mixture was stirred at 90
°C (for bromide, 110 °C) for 10–24 h. Then H2O (3 mL) was
added and the reaction mixture was stirred at 100 °C for 8–
12 h. After the reaction mixture was cooled, sat. NH4Cl (10
mL) solution was added. The mixture was extracted with
EtOAc and the organic layer was washed with H2O, brine
and dried over Na2SO4. After concentration in vacuo, the
residue was purified by column chromatography on silica
gel (eluting with 6:1 → 4:1 PE–EtOAc) to provide the
desired product.
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Synlett 2010, No. 15, 2285–2288 © Thieme Stuttgart · New York

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