Triethyl phosphite mediated domino reaction: Direct conversion of ω-nitroalkenes into N-heterocycles

Article abstract of DOI:10.1002/anie.200605260

(Chemical Equation Presented) Dominos on cycles: Several N-heterocycles, such as 3,4-dihydro-2H-1,4-benzoxazines, 1,2,3,4-tetrahydroquinoxalines, and 1,2,3,4-tetrahydroquinolines, can be obtained through a novel domino reaction mediated by triethyl phosph

Full text of DOI:10.1002/anie.200605260

Angewandte
Chemie
DOI: 10.1002/anie.200605260
Domino reactions
Triethyl Phosphite Mediated Domino Reaction: Direct Conversion of
w-Nitroalkenes Into N-Heterocycles
Elena Meris¸or, Jürgen Conrad, Iris Klaiber, Sabine Mika, and Uwe Beifuss*
Dedicated to Professor Dr. Lutz F. Tietze on the occasion of his 65th birthday
The development of new synthetic methods for N-hetero-
cycles is an important topic of research in organic synthesis
because of their potential application as pharmaceuticals.[1] So
far, reductive cyclizations of nitro compounds[2] have been
predominantly employed to construct indoles and related N-
heteroaromatic compounds. The best known methods include
the synthesis of indoles following the procedures of Leim-
gruber–Batcho,[3,4] Bartoli,[3,5] and Reissert,[3] the transition-
metal-catalyzed reductive N-heteroannulation of o-nitrostyr-
enes,[6] and the Cadogan cyclization.[7] Still little is known
about their application to the synthesis of saturated N-
heterocycles. Another method for the reductive cyclization of
aromatic nitro compounds is the transformation of w-nitro
ketones under reducing conditions.[8] In addition, the poten-
best be accomplished with phosphites. For example, 3,3-
dimethylallyl-2-nitrophenyl ether (1a) was heated with
triethyl phosphite (EtO)3P to reflux for two hours to give 3-
isopropenyl-3,4-dihydro-2H-1,4-benzoxazine (2a) as the
main product in 57% yield (Scheme 1). The N-ethyl deriv-
Scheme 1. Domino reaction of 1a with (EtO)3P under thermal
conditions.
À
tial of the nitroso-ene reaction for the formation of C N
bonds has by no means been exhausted.[9] In particular, there
is a lack of methods for the one-step generation of the nitroso
group from easily accessible precursors. Furthermore, the
primary product of the nitroso-ene reaction is a hydroxyl-
amine instead of the much more interesting amine.
ative of 2a, 4-ethyl-3-isopropenyl-3,4-dihydro-2H-1,4-benz-
oxazine (3a) was formed as a side product in 8% yield.
Longer reaction times (12h) decreased the yield of 2a to
50%, but increased the yield of 3a to 15%.
Our aim was to join the nitroso-ene reaction and two
reduction reactions to create a novel domino process.[10] To
this end, the nitro group of a w-nitroalkene was first to be
reduced to give the corresponding nitroso group which then,
as the enophile, should undergo an intramolecular ene
reaction with the alkene to produce the corresponding
hydroxylamine. Final reduction of the NOH group would
then deliver the cyclic amine.
Here we describe the reductive cyclization of w-nitro-
alkenes to saturated N-heterocycles in a single step. As an
example, we chose the transformation of allyl 2-nitrophenyl
ethers 1 into substituted 3,4-dihydro-2H-1,4-benzoxazines 2,
since this structural element occurs in numerous biologically
active compounds.[11] A further advantage of allyl 2-nitro-
phenyl ethers is that they are accessible from the most simple
substrates in a single step and in high yields. After some
preliminary experiments, which included Pd-catalyzed reac-
tions with CO, we found that this novel domino process can
We assumed that 3a is formed by the N-ethylation of 2a
with triethyl phosphate (EtO)3PO, which was produced by
oxidation of (EtO)3P. This assumption was corroborated by
the experimental finding that 2a was recovered unchanged
after heating in (EtO)3P (reflux, 8 h), whereas heating 2a with
(EtO)3PO (reflux, 6 h) gave 3a in 70% yield. The formation
of N-alkylated side products was also observed with other
phosphites such as trimethyl and triisopropyl phosphite.
In addition, we investigated whether the new transforma-
tion could also be applied to allyl 2-nitrophenyl ethers that
were substituted in their aromatic nucleus. The cyclization
precursors 1b–k were synthesized from the reaction of the
corresponding substituted o-nitrophenols with prenyl bro-
mide under standard conditions (K2CO3, acetone, reflux) in
yields of 85–96%.
The precursors 1b–k were heated with (EtO)3P (reflux, 1–
3 h) to give the substituted 3-isopropenyl-3,4-dihydro-2H-1,4-
benzoxazines 2b–k as the main products with yields of 52–
64% (Table 1). Again, in about half the cyclizations, N-
ethylation was observed as a side reaction to give the
[*] Dipl.-Chem. E. Meris¸or, Dr. J. Conrad, I. Klaiber, S. Mika,
Prof. Dr. U. Beifuss
substituted
4-ethyl-3-isopropenyl-3,4-dihydro-2H-1,4-ben-
Institut für Chemie
Universität Hohenheim
zoxazines 3b,d,e,f,k (yields of 1–6%).
As one of the well-known advantages of the use of
microwaves (MW) is reaction acceleration,[12] we repeated the
cyclization of 1a under microwave conditions (300 W, 2008C).
Although the reaction time could be reduced from 2h to
30 min it was not possible to suppress the formation of 3a in
Garbenstrasse 30, 70599 Stuttgart (Germany)
Fax : (+49)711-459-22951
E-mail: ubeifuss@uni-hohenheim.de
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Domino reaction of 1b–k with (EtO)3P under thermal con-
ditions.
group must be reduced to a nitroso group, which then reacts
as an enophile intramolecularly with the 2-methylpropenyl
group to form the hydroxylamine. Finally, the hydroxylamine
would be reduced to give the amine 2 (Scheme 2).
Entry
1
R1
R2
t [h]
Product 2
Product 3
(yield [%])[a]
(yield [%])[a]
1
2
3
4
5
6
7
8
9
b
c
d
e
f
g
h
i
Me
OMe
F
Cl
Br
CO2Me
H
H
H
Cl
H
H
H
H
H
H
Me
F
CO2Me
Me
3
1
1
1
1
2
1
2
63
60
52
64
55
58
57
58
60
60
5
–
6
3
2
–
–
–
–
1
Scheme 2. Potential reaction mechanism.
The finding that the 3-methylallyl ether 4 led to the
formation of 5 in 51% yield, whereas the allyl ether 6 without
any terminal methyl group does not react at all (Scheme 3)
j
k
1.5
1
10
[a] Yieldsrefer to isolated, analytically pure product.
13% yield, along with 2a in 47% yield. Finally, we examined
the effect of solvents on the course of the reaction. Precursor
1a was treated with (EtO)3P in toluene under both thermal
(closed vial, 2008C, 3 h) and microwave conditions (closed
vial, 300 W, 2008C, 30 min). Surprisingly, both conditions led
to exclusive formation of 2a in 45 and 55% yields, respec-
tively. Similar results were obtained with solvents such as
cumene and o-dichlorobenzene. As a result of the suppression
of the side product 3a, the higher yield of 2a, and the shorter
reaction time, the reductive cyclizations of 1b–k were
repeated under microwave conditions in toluene (Table 2).
All cyclizations proceeded with complete selectivity within
15–30 min with formation of 2b–k in yields of 57–65%. The
results demonstrate that halide and ester functionalities are
well tolerated in these transformations.
Scheme 3. Investigations into the reaction mechanism.
supports both mechanisms. Even though we cannot make a
definite statement about the mechanism, since both high
yields of cyclization products 2 were achieved and the
products that would be expected from nitrenes were not
observed, we assume the nitroso-ene pathway is operating.
Notably the new reductive cyclization is not only an
effective means to construct the 3,4-dihydro-2H-1,4-benzox-
azine skeleton, but also may be extended to the one-step
synthesis of 1,2,3,4-tetrahydroquinoxalines 8 and 1,2,3,4-
tetrahydroquinolines 10 (Scheme 4).
We considered both an intramolecular nitroso-ene reac-
tion[9] and the reaction of a nitrene[13] as the reaction
mechanism. In the case of a nitroso-ene reaction, the nitro
Table 2: Domino reaction of 1b–k with (EtO)3P in toluene under
microwave conditions.
Entry
1
R1
R2
t [min]
Product 2
(yield [%])[a]
Scheme 4. One-step synthesis of 1,2,3,4-tetrahydroquinoxaline (8) and
1,2,3,4-tetrahydroquinoline (10).
1
2
3
4
5
6
7
8
9
b
c
d
e
f
g
h
i
Me
OMe
F
Cl
Br
CO2Me
H
H
H
Cl
H
H
H
H
H
H
Me
F
CO2Me
Me
20
30
15
20
20
20
25
25
25
20
57
58
60
63
64
60
58
61
60
65
Here we describe the first domino reaction in which w-
nitroalkenes are converted into saturated N-heterocycles. The
reductive cyclization reaction mediated by triethyl phosphite
allows access to substituted 3,4-dihydro-2H-1,4-benzoxazines,
1,2,3,4-tetrahydroquinoxalines, and 1,2,3,4-tetrahydroquino-
lines. Investigations into the scope and mechanism of this
reaction are ongoing.
j
k
10
[a] Yieldsrefer to isolated, analytically pure product.
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[3] Review: R. J. Sundberg in Comprehensive Heterocyclic Chemis-
Experimental Section
try, Vol. 2 (Eds.: A. Katritzky, C. W. Rees, E. F. V. Scriven),
Pergamon, New York, 1996, pp. 119 – 206.
[4] R. D. Clark, D. B. Repke, Heterocycles 1984, 22, 195 – 221.
[5] A. Ricci, M. Fochi, Angew. Chem. 2003, 115, 1482– 1484; Angew.
Chem. Int. Ed. 2003, 42, 1444 – 1446.
[6] a) B. C. Söderberg, J. A. Shriver, J. Org. Chem. 1997, 62, 5838 –
5845; b) M. Akazome, T. Kondo, Y. Watanabe, J. Org. Chem.
1994, 59, 3375 – 3380.
Cyclization of 1 under microwave conditions: Precursor 1 (1 mmol),
(EtO)3P (6 mmol), and toluene (3 mL) were sealed in a septum
reaction vial (10 mL) and irradiated with microwaves (Discover,
CEM; 2450 MHz; 300 W; 2008C; 15–30 min). After removal of
(EtO)3P and (EtO)3PO (10À1 mbar), the residue was taken up in
EtOAc (25 mL) washed with brine (3 ” 20 mL). After drying over
MgSO4 and concentration in vacuo, the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc 20:1).
[7] J. I. G. Cadogan, Synthesis 1969, 11 – 17.
[8] R. Stoermer, M. Franke, Ber. Dtsch. Chem. Ges. 1898, 31, 752–
759.
Received: December 31, 2006
Published online: March 20, 2007
[9] W. Adam, O. Krebs, Chem. Rev. 2003, 103, 4131 – 4146.
[10] L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, 2006.
[11] B. Achari, S. B. Mandal, P. K. Dutta, C. Chowdhury, Synlett 2004,
2449 – 2467.
[12] C. O. Kappe, Angew. Chem. 2004, 116, 6408 – 6443; Angew.
Chem. Int. Ed. 2004, 43, 6250 – 6284.
[13] B. C. G. Söderberg, Curr. Org. Chem. 2000, 4, 727 – 764.
Keywords: benzoxazines· cyclization · domino reactions·
.
ene reaction · microwaves
[1] T. Eicher, S. Hauptmann, The Chemistry of Heterocycles, 2 nd
ed., Wiley-VCH, Weinheim, 2003.
[2] N. Ohno, The Nitro Group in Organic Synthesis, Wiley-VCH,
New York, 2001.
Angew. Chem. Int. Ed. 2007, 46, 3353 –3355
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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