Microwave-assisted reductive cyclization of N-allyl 2-nitroanilines: A new approach to substituted 1,2,3,4-tetrahydroquinoxalines

Article abstract of DOI:10.1055/s-2007-984884

N-Allyl 2-nitrophenyl amines can be efficiently cyclized to yield alkenyl-1,2,3,4-tetrahydroquinoxalines in a single reaction step by means of a new microwave-assisted reductive domino process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984884

LETTER
2033
Microwave-Assisted Reductive Cyclization of N-Allyl 2-Nitroanilines:
A New Approach to Substituted 1,2,3,4-Tetrahydroquinoxalines
M
icrowave-Ass
l
iste
d
R
e
e
ductive
C
n
yclizationof
a
N
-Allyl2-Nitroa
n
M
ilines erisor, Jürgen Conrad, Sabine Mika, Uwe Beifuss*
Bioorganische Chemie, Institut für Chemie, Universität Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
Fax +49(711)45922951; E-mail: ubeifuss@uni-hohenheim.de
Received 7 May 2007
rahydroquinoxalines 2a–d12 were isolated as the main
products with yields ranging from 55% to 60%
(Scheme 1, Table 1).
Abstract: N-Allyl 2-nitrophenyl amines can be efficiently cyclized
to yield alkenyl-1,2,3,4-tetrahydroquinoxalines in a single reaction
step by means of a new microwave-assisted reductive domino
process.
Et
Key words: cyclizations, domino reactions, ene reactions, micro-
waves, tetrahydroquinoxalines
H
N
NO2
N
i
N
R
N
R
N
R
The applications of 1,2,3,4-tetrahydroquinoxalines as
promising prostaglandin D2 receptor antagonists1 and
vasopressin V2 receptor antagonists2 underline the impor-
tance of this heterocyclic skeleton for the development of
new pharmaceuticals. Due to their role as model com-
pounds for tetrahydrofolic acid the synthesis of 1,2,3,4-
tetrahydroquinoxalines is also important in the field of
bioorganic chemistry.3
1
2
3
Scheme 1 Reductive cyclization of protected N-prenyl 2-nitroanili-
nes 1 under thermal conditions in neat (EtO)3P. Reagents and condi-
tions: (i) (EtO)3P (6 equiv), reflux 2–12 h.
Table 1 Synthesis of 3-Isopropenyl-1,2,3,4-tetrahydroquinoxalines
2 and 3 under Thermal Conditions in Neat (EtO)3P
Entry
1
R
Time
(h)
2
Yield (%)
of 2
3
Yield (%)
of 3
Despite the marked interest in 1,2,3,4-tetrahydroquin-
oxalines there are only a limited number of synthetic
methods available. A classic strategy to 1,2,3,4-tetra-
hydroquinoxalines is the reduction of suitably substituted
quinoxalines.4 Alternatively, more recent approaches to
1,2,3,4-tetrahydroquinoxalines include the metal-mediat-
ed reaction between substituted 1,2-diaminobenzenes
with 1,4-butene diol or acetates5 as well as the Lewis acid
promoted addition of allyl stannanes to o-quinonedi-
imines.6 Suitably substituted nitroarenes are not only used
as a substrate for tetrahydroquinoxaline syntheses in a
domino reduction/Michael addition,7 but are also em-
ployed in other domino processes.8–10
1
2
3
4
a
b
c
CO2Me
CO2Bn
CO2t-Bu
Ph
2
2
a
b
c
60
59
55a
57
a
b
c
6
4
2
–
d
12
d
d
<2
a In addition, 4 (12%, Figure 1) was isolated.
H
N
Altogether there is a strong demand for new and efficient
methods for the synthesis of the 1,2,3,4-tetrahydroquin-
oxaline skeleton. Recently, we discovered a new domino
process that allows the transformation of allyl 2-nitro-
phenyl ethers into substituted 3,4-dihydro-2H-1,4-benz-
oxazines in a single synthetic operation.11 Whether a new
synthetic method is able to gain major importance will
greatly depend on its scope and limitations. Here we re-
port on the successful application of this new reductive
domino process to the preparation of substituted 1,2,3,4-
tetrahydroquinoxalines. First, the easily accessible pro-
tected N-allyl 2-nitroanilines 1a–d were reacted with tri-
ethyl phosphite [(EtO)3P] under argon. After heating
under reflux for 2–12 hours the 3-isopropenyl-1,2,3,4-tet-
N
H
4
Figure 1
In these reactions, 4-ethyl-3-isopropenyl-1,2,3,4-tetrahy-
droquinoxalines 3a,b,d13 were also formed as side prod-
ucts in small amounts (2–6%) (Scheme 1, Table 1). It is
assumed that the formation of these N-ethylated com-
pounds is due to the ethylation of 2 with (EtO)3PO, which
is produced during the reaction by oxidation of (EtO)3P.
The conversion of tert-butyl carbamate 1c is unusual since
the Boc group is partially cleaved under the reaction con-
ditions. Apart from 55% of 2c, an additional 12% of 2-iso-
propenyl-1,2,3,4-tetrahydroquinoxaline (4; Figure 1) was
isolated.
SYNLETT 2007, No. 13, pp 2033–2036
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3
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0
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Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-984884; Art ID: G10607ST
© Georg Thieme Verlag Stuttgart · New York
In contrast, the transformation of the unprotected N-pre-
nyl 2-nitroaniline (5a) with (EtO)3P under thermal condi-

2034
E. Merisor et al.
LETTER
tions exclusively gave N-ethylated products, namely 1- on the Cadogan cyclization under microwave condi-
ethyl-3-isopropenyl-1,2,3,4-tetrahydroquinoxaline (6a, tions.17b
30%) and 1,4-diethyl-2-isopropenyl-1,2,3,4-tetrahydro-
quinoxaline (7a, 40%) (Scheme 2).
It turned out that indeed the reaction times of the reductive
cyclization of N-allyl 2-nitroanilines could be dramatical-
ly shortened in some cases (Scheme 4, Table 2 and
Scheme 5, Table 3). For example, the reaction time
required to transform 1d could be reduced from 12 hours
Et
H
N
NO2
N
i
to 30 minutes (Scheme 4, Table 2, entry 4).
N
N
N
H
Et
Et
Et
6a
7a
5a
H
N
NO2
30%
40%
N
i
Scheme 2 Reductive cyclization of the unprotected N-prenyl 2-ni-
troaniline (5a) under thermal conditions in neat (EtO)3P. Reagents
and conditions: (i) (EtO)3P (6 equiv), reflux, 12 h.
N
R
N
R
N
R
2
3
1
Both an intramolecular nitroso ene reaction14 and the re-
action of a nitrene15 may be considered as the reaction
mechanism (Scheme 3). With a nitroso ene reaction, we
may assume that the reaction of the protected N-prenyl 2-
nitroanilines 1 with phosphite begins with the reduction of
the nitro group. The nitroso group so formed then under-
goes an intramolecular ene reaction with the 2-methylpro-
penyl group of the molecule, resulting in the formation of
a cyclic hydroxyl amine that is finally reduced by the
phosphite to yield the cyclic amine 2 (Scheme 3). In the
case of a nitrene mechanism, we assume that the nitro
group is first reduced to the corresponding nitrene, which
then abstracts a hydrogen atom from the 2-methyl-
propenyl group and yields both an NH radical and a me-
somerically stabilized propenyl radical, which undergo
intramolecular cyclization to give 2 (Scheme 3).16
Scheme 4 Reductive cyclization of protected N-prenyl 2-nitroanili-
nes 1 under microwave conditions in neat (EtO)3P. Reagents and
conditions: (i) (EtO)3P (6 equiv), MW (300 W), 200 °C.
Table 2 Synthesis of 3-Isopropenyl-1,2,3,4-tetrahydroquinoxalines
2 and 3 under Microwave Conditions in Neat (EtO)3P
Entry 1
R
Time
(min)
2
Yield (%)
of 2
3
Yield (%)
of 3
1
2
3
4
a
b
c
CO2Me 35
CO2Bn 35
CO2t-Bu 35
Ph 30
a
b
c
60
58
36a
56
a
b
c
4
4
–
d
d
d
<2
a In addition, 4 (28%, Figure 1) was isolated.
H
In contrast, the formation of the N-ethylated products
could not be suppressed by using microwaves, as can be
shown by the cyclizations of 1a–d and, even more
noticeably, by the transformation of 5a–d which exclu-
sively yielded the mono- and diethylated products 6a–d
and 7a–d, respectively (Scheme 5, Table 3).
OH
N
O
N
(EtO)3P
(EtO)3P
1
1
2
N
R
N
R
H
H
The reactions of 5a–d also demonstrate that the reductive
domino process tolerates substrates that are substituted at
the aromatic nucleus.
N
N
(EtO)3P
2
N
R
N
R
Et
NO2
H
N
R
R
N
R
i
H
N
N
N
N
H
Et
Et
5
6
7
N
R
Scheme 5 Reductive cyclization of the unprotected N-prenyl 2-ni-
troanilines 5a–d under microwave conditions in neat (EtO)3P.
Reagents and conditions: (i) (EtO)3P (6 equiv), MW (300 W), 200 °C.
Scheme 3 Possible reaction mechanisms
H
On the basis of these results we examined whether (a) the
reaction times of the reductive cyclization and, (b) the
proportion of N-ethylated products could be decreased by
conducting the domino reactions of 1 and 5 under micro-
wave conditions.17a Recently, Dehaen et al. have reported
Cl
N
N
H
8
Figure 2
Synlett 2007, No. 13, 2033–2036 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Reductive Cyclization of N-Allyl 2-Nitroanilines
2035
type of cyclization. When, for example, 1a was reacted
with (EtO)3P in toluene under microwave conditions, the
heterocycle 2a was isolated in good yield (70%) after 35
min. These reaction conditions18 led to the exclusive pro-
duction of 2a, while formation of the N-ethylated side
product 3a was completely suppressed (Scheme 7,
Table 4, entry 1).
Table 3 Synthesis of Substituted 1,2,3,4-Tetrahydroquinoxalines 6
and 7 under Microwave Conditions in Neat (EtO)3P
Entry
5
R
Time
(min)
6
Yield (%)
of 6
7
Yield (%)
of 7
1
2
3
4
a
b
c
H
35
35
a
b
c
40
46
45
26
a
b
c
23
21
17
4
Me
Similarly good results were observed with the reductive
cyclizations of 1b–d (Scheme 7, Table 4, entries 2–4).
Again, the cyclization of 1c was an exception since partial
cleavage of the Boc group of 2c also occurred under these
reaction conditions (Scheme 7, Table 4, entry 3). Surpris-
ingly, the secondary 2-nitroanilines 5a–d did not react un-
der these conditions at all; the substrates could be
retrieved unchanged after one hour irradiation at 200 °C.
The same holds true for the N-crotyl 2-nitroaniline (9).
OMe 35
Cla
35
d
d
d
a In addition, 8 (38%; Figure 2) was isolated.
Et
N
H
N
NO2
i
N
N
N
H
Another benefit of the novel tetrahydroquinoxaline syn-
thesis is the easy accessibility of the substrates. Com-
pounds of type 1 could be obtained in high yields by
reacting 2-nitrophenylisocyanate (12) with the alcohols
13a–c (MeOH, BnOH, t-BuOH) to give 14a–c,19 followed
by allylation of the carbamates 14a–c with prenyl bromide
(15)20,21 (Scheme 8).
Et
Et
10
11
9
25%
40%
E/Z = 6:1
Scheme 6 Reductive cyclization of the unprotected N-crotyl 2-ni-
troaniline (9) under thermal conditions in neat (EtO)3P. Reagents and
conditions: (i) (EtO)3P (6 equiv), reflux, 12 h.
Furthermore the question arose whether the presence of a
dimethyl allyl group is essential to the cyclization process
or whether it can be achieved with a crotyl group instead.
Heating the N-crotyl 2-nitroaniline (9) with triethyl phos-
phite led to the formation of 1-ethyl-3-vinyl-1,2,3,4-tetra-
hydroquinoxaline (10) in 25% yield and 1,4-diethyl-2-
vinyl-1,2,3,4-tetrahydroquinoxaline (11) in a yield of
40% (Scheme 6). This clearly demonstrates that variation
of the allylic component also works.
NO2
NO2
CO2R1
i
R1OH
14a R1 = Me
14b R1 = Bz
14c R1 = tBu
83%
85%
99%
N
NCO
H
14
13
12
NO2
ii
1a R1 = Me 93%
1b R1 = Bz 94%
1c R1 = tBu 97%
N
Finally, the influence of solvents on the reaction was
studied. After some experimentation (EtO)3P in toluene
was identified as the most suitable combination for this
CO2R1
1
Scheme 8 Preparation of protected N-prenyl 2-nitroanilines 1a–c.
Reagents and conditions: (i) petroleum ether, reflux; (ii) NaH, DME,
0 °C or t-BuOK, THF, –78 °C, 15, r.t.
H
N
NO2
i
The approach to the secondary amines 5a–d is even sim-
pler in that they can be obtained in one step by reaction of
the corresponding substituted 2-nitroanilines 16a–d with
prenyl bromide (15) in very good yields (Scheme 9).22
N
R
N
R
2
1
Scheme 7 Reductive cyclization of protected N-prenyl 2-nitroani-
lines 1 in (EtO)3P–toluene. Reagents and conditions: (i) (EtO)3P
(6 equiv), toluene, MW (300 W), 200 °C.
NO2
R
NO2
NH2
R
i
5a R = H
5b R = Me
82%
92%
Table 4 Synthesis of Substituted 3-Isopropenyl-1,2,3,4-tetrahydro-
quinoxalines 2a–d under Microwave Conditions in (EtO)3P–Toluene
N
5c R = OMe 92%
5d R = Cl
93%
H
16
5
Entry
1
R
Time
(min)
2
Yield (%)
of 2
Scheme 9 Preparation of unprotected secondary 2-nitroanilines 5a–
d. Reagents and conditions: (i) benzene, reflux, 50% NaOH, 15,
PhCH2N+Et3Cl–.
1
2
3
4
a
b
c
CO2Me
CO2Bn
CO2t-Bu
Ph
35
35
35
35
a
b
c
70
67
36a
60
In summary, the efficient conversion of N-allyl 2-nitro-
anilines into substituted 1,2,3,4-tetrahydroquinoxalines
by means of a (EtO)3P-mediated reductive domino reac-
tion has been presented.
d
d
a In addition, 4 (28%, Figure 1) was isolated.
Synlett 2007, No. 13, 2033–2036 © Thieme Stuttgart · New York

2036
E. Merisor et al.
LETTER
2¢), 114.4 (C-5), 116.9 (C-7), 123.9 (C-9), 124.61 (C-8),
125.4 (C-6), 137.09 (C-10), 144.3 (C-1¢), 155.3 (C=O). MS
(EI, 70 eV): m/z (%) = 232 (100) [M+], 218 (8), 199 (14), 191
(40), 173 (21), 157 (18), 131 (40), 106 (7), 77 (7). Anal.
Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found:
C, 67.43; H, 7.01; N, 11.99.
Acknowledgment
We thank Mrs. I. Klaiber and Dr. R. Frank for the recording of
spectra.
References and Notes
2''
(1) Torisu, K.; Kobayashi, K.; Iwahashi, M.; Nakai, Y.; Onoda,
T.; Nagase, T.; Sugimoto, I.; Okada, Y.; Matsumoto, R.;
Nanbu, F.; Ohuchida, S.; Nakai, H.; Toda, M. Bioorg. Med.
Chem. 2004, 12, 5361.
(2) Ohtake, Y.; Naito, A.; Hasegawa, H.; Kawano, K.;
Morizono, D.; Taniguchi, M.; Tanaka, Y.; Matsukawa, H.;
Naito, K.; Oguma, T.; Ezure, Y.; Tsuriya, Y. Bioorg. Med.
Chem. 1999, 7, 1247.
2'
1''
5
1'
N 4
10
3'
6
7
3
2
9
N1
8
Me
O
O
3a
(3) (a) Barrows, T. H.; Farina, P. R.; Chrzanowski, R. L.;
Benkovic, P. A.; Benkovic, S. J. J. Am. Chem. Soc. 1976, 98,
3678. (b) Fisher, G. H.; Schultz, H. P. J. Org. Chem. 1974,
39, 631. (c) Benkovic, S. J.; Barrows, T. H.; Farina, P. R.
J. Am. Chem. Soc. 1973, 95, 8414.
(4) (a) Pitts, M. R.; Harrison, J. R.; Moody, C. J. J. Chem. Soc.,
Perkin Trans. 1 2001, 955. (b) Taylor, E. C.; McKillop, A.
J. Am. Chem. Soc. 1965, 87, 1984. (c) Cavagnol, J. C.;
Wiselogle, F. Y. J. Am. Chem. Soc. 1947, 69, 795.
(5) (a) Yang, S.-C.; Liu, P.-C.; Feng, W.-H. Tetrahedron Lett.
2004, 45, 4951. (b) Yang, S.-C.; Shue, Y.-J.; Liu, P.-C.
Organometallics 2002, 21, 2013. (c) Massacret, M.; Lhoste,
P.; Sinou, D. Eur. J. Org. Chem. 1999, 129.
(6) Nair, V.; Dhanya, R.; Rajesh, C.; Bhadbhade, M. M.; Manoj,
K. Org. Lett. 2004, 6, 4743.
(7) Bunce, R. A.; Herron, D. M.; Ackerman, M. L. J. Org.
Chem. 2000, 65, 2847.
(8) (a) Bunce, R. A.; Herron, D. M.; Hale, L. Y. J. Heterocycl.
Chem. 2003, 40, 1031. (b) Rylander, P. N. Hydrogenation
Methods; Academic Press: New York, 1985, 82–93.
(9) Tapia, R. A.; Centella, C. R.; Valderrama, J. A. Synth.
Commun. 1999, 29, 2163.
(10) (a) LaBarbera, D. V.; Skibo, E. B. Bioorg. Med. Chem.
2005, 13, 387. (b) Krchňák, V.; Smith, J.; Vagner, J.
Tetrahedron Lett. 2001, 42, 2443.
Figure 4
(13) Selected Data for 3a (Figure 4):
Rf 0.59 (PE–EtOAc, 20:1). IR (ATR): 2980, 2958 (Me,
CH2), 1702 (C=O), 1602, 1504 (C=C), 1438, 1375, 1344
(COO–), 1217, 1190, 1145, 1062 (=COC), 899, 733 cm–1.
UV–Vis (EtOH): lmax (log e) = 310 (2.49), 258 (2.41), 223
(2.35) nm. 1H NMR (300 MHz, CDCl3): d = 1.17 (t, 3J = 7.1
Hz, 3 H, 2¢¢-Me), 1.80 (s, 3 H, 3¢-Me), 3.15–3.27 (over-
lapped, 2 H, 1¢¢-CH2), 3.52 (dd, 2J = 13.1 Hz, 3J = 7.1 Hz, 1
H, 2-H), 3.76 (s, 3 H, OMe), 3.94 (t, 3J = 7.1 Hz, 1 H, 3-H),
4.37 (dd, 2J = 12.9 Hz, 3J = 7.1 Hz, 1 H, 2-H), 4.81 (br s, 1
H, 2¢-H), 4.93 (br s, 1 H, 2¢-H), 6.62 (dd, 3J = 8.1 Hz, 4J = 1.1
Hz, 1 H, 5-H), 6.75 (ddd, 3J = 7.8, 8.1 Hz, 4J = 1.2 Hz, 1 H,
7-H), 7.06 (ddd, 3J = 7.8, 8.1 Hz, 4J = 1.2 Hz, 1 H, 6-H), 7.4
(br s, 1 H, 8-H). 13C NMR (75 MHz, CDCl3): d = 11.76 (C-
2¢¢), 19.60 (C-3¢), 43.50 (C-1¢¢), 43.82 (C-2), 53.12 (OMe),
62.76 (C-3), 110.56 (C-2¢), 113.5 (C-5), 115.1 (C-7), 124.3
(C-9), 124.7 (C-8), 125.8 (C-6), 137.9 (C-10), 143.06 (C-1¢),
155.4 (C=O). MS (EI, 70 eV): m/z (%) = 260 (100) [M+], 245
(16), 231 (26), 219 (58), 213 (12), 190 (34), 171 (20), 159
(30), 131 (27), 119 (6), 92 (3), 77 (12), 41 (3), 28 (3). HRMS
(EI): m/z [M+] calcd for C15H20N2O2: 260.1525; found:
260.1507.
(11) Merisor, E.; Conrad, J.; Klaiber, I.; Mika, S.; Beifuss, U.
Angew. Chem. Int. Ed. 2007, 46, 3353.
(12) Selected Data for 2a (Figure 3):
(14) Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131.
(15) (a) Söderberg, B. C. G. Curr. Org. Chem. 2000, 4, 727.
(b) Cadogan, J. I. G. Q. Rev., Chem. Soc. 1968, 22, 222.
(16) Scheme 3 shows a mechanism involving a triplet nitrene.
However, the occurrence of a singlet nitrene cannot be ruled
out.
(17) (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(b) Appukkuttan, P.; Van der Eycken, E.; Dehaen, W. Synlett
2005, 127.
(18) General Procedure for the Synthesis of Alkenyl-1,2,3,4-
tetrahydroquinoxalines under Microwave Conditions:
A solution of 1a (1 mmol), (EtO)3P (6 mmol) and toluene (3
mL) in a 10-mL septum-sealed reaction vial was irradiated
with microwaves (DiscoverTM by CEM; 2450 MHz; 300 W;
200 °C). After removal of (EtO)3P and (EtO)3PO (10–1 mbar)
the residue was taken up in EtOAc (25 mL) and washed with
brine (3 × 20 mL). The residue obtained after drying over
MgSO4 and after concentration in vacuo was purified by
flash chromatography on silica gel (PE–EtOAc, 20:1).
(19) Hoeke, F. Recl. Trav. Chim. Pays-Bas 1935, 54, 505.
(20) Mohri, K.; Suzuki, K.; Usui, M.; Isobe, K.; Tsuda, Y. Chem.
Pharm. Bull. 1995, 43, 159.
Rf 0.40 (PE–EtOAc, 20:1). IR (ATR): 3376 (NH), 2952,
2854 (Me, CH2), 1691 (C=O), 1604, 1501 (C=C), 1435,
1382, 1372 (COO–), 1232, 1211, 1146, 1061 (=COC), 900,
760, 741 cm–1. UV–Vis (EtOH): lmax (log e) = 307 (2.48),
253 (2.40), 220 (2.34) nm. 1H NMR (300 MHz, CDCl3): d =
1.85 (s, 3 H, 3¢-Me), 3.58 (dd, 2J = 12.3 Hz, 3J = 6.2 Hz, 1 H,
2-H), 3.81 (s, 3 H, OMe), 3.98 (dd, 3J = 3.4, 6.2 Hz, 1 H, 3-
H), 4.02 (dd, 2J = 12.3 Hz, 3J = 3.3 Hz, 1 H, 2-H), 4.98 (br s,
1 H, 2¢-H), 5.05 (br s, 1 H, 2¢-H), 6.65 (dd, 3J = 8.0 Hz, 4J =
1.4 Hz, 1 H, 5-H), 6.70 (ddd, 3J = 7.4, 8.2 Hz, 4J = 1.5 Hz, 1
H, 7-H), 6.97 (ddd, 3J = 7.4, 7.9 Hz, 4J = 1.4 Hz, 1 H, 6-H),
7.48 (br s, 1 H, 8-H). 13C NMR (75 MHz, CDCl3): d = 19.57
(C-3¢), 45.25 (C-2), 53.24 (OMe), 56.72 (C-3), 112.87 (C-
2'
H
5
N 4
1'
10
3'
6
7
3
2
9
N1
8
Me
O
O
(21) Greshock, T. J.; Funk, R. L. J. Am. Chem. Soc. 2002, 124,
754.
2a
(22) Broggini, G.; Garanti, L.; Molteni, G.; Zecchi, G. Synthesis
1996, 1076.
Figure 3
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