A simple way to some sophisticated fused nitrogen heterocycles

Article abstract of DOI:10.1055/s-2004-830894

Selected nitroarenes were found to react with arylmethylene compounds prone to form benzylic-type carbanion to give fused nitrogen heterocycles in the presence of silylating agent.

Full text of DOI:10.1055/s-2004-830894

LETTER
1929
A Simple Way to Some Sophisticated Fused Nitrogen Heterocycles
S
Z
ophisticate
d
F
b
used
N
itroge
i
n
H
eter
g
ocycle
s
niew Wróbel*
Institute of Organic ChemistryPolish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: wrobel@icho.edu.pl
Received 14 June 2004
Nucleophilic character of benzylic anions is similar to that
of allylic ones. On the other hand, the extent of charge
distribution to the particular aromatic carbon atoms and
considerable aromatic energy make the difference and can
have some implications in more difficult cyclization step.
Although electrophilic addition to benzylic carbanion
carrying some negative charge at ortho position is not a
common reaction, the issue is well documented for
isoelectronic phenolate anions. Generally this pathway is
favored by unpolar solvents and small cations.4
Abstract: Selected nitroarenes were found to react with arylmeth-
ylene compounds prone to form benzylic-type carbanion to give
fused nitrogen heterocycles in the presence of silylating agent.
Key words: nitroarenes, cyclizations, heterocycles, carbanions, nu-
cleophilic aromatic substitution
Simplicity of preparative method is a virtue that cannot be
overestimated in organic synthesis. Many synthetic pa-
pers explore the problem of synthesizing sophisticated
molecules from simple starting materials in a short and
straightforward way.
1
We have already reported that nitrogen-containing 6-
membered ring can be constructed in a reaction of ni-
troarenes with allylic carbanions in the presence of Lewis
acids. The reaction was found to proceed for cinnamyl and
allyl sulfones as carbanion precursors, in selected cases
also nitriles or phosphonates could also be employed.1
Both a and g positions of the carbanion were engaged in
formation of six-membered ring – the former in the nu-
cleophilic addition to the nitroarenes and the latter in the
final cyclization step of the intermediate nitroso com-
pound (Scheme 1).
Equation 1
–3
The very first results presented here support the general
idea and seem promising. Thus, heating 4-choronitroben-
zene with benzyl cyanide in the presence of bis-trimethyl-
silylacetamide (BSA) and DBU as a base in toluene
results in formation of 3-chloro-9-cyanoacridine (3a) in
2
0% yield. Further examples of reactions of nitroarenes
with benzylic CH acids are collected in Table 1. The best
results were obtained for thienyl-2-methyl 4-tolyl sulfone,
which can be rationalized considering less aromatic, thus
more reactive, double bonds of the ring. Reactions of this
substrate with numerous bicyclic nitroarenes revealed a
competition of two reaction paths. Depending on the ni-
troarene structure, and sometimes also on the reaction
conditions, the reaction led to the formation of the expect-
ed, fused pyridine ring (3a–h), or to the anthranile deriv-
ative (4e–g). The latter was formed as a by-product in a
comparable yield (entry 6 and 7), or even as the only iso-
lated product (entry 5).
Scheme 1
Tentative mechanistic scheme of the reaction, apparently
The objective of the presented approach is to extend this
type of transformation to benzylic carbanions, in which
anionic center together with a conjugated, unsubstituted
ortho position of the aromatic ring could play the same
role as does allylic moiety, giving access to more com-
plex, fused nitrogen heterocycles (Equation 1).
similar to the proposed previously for the reactions of al-
3
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l
y
l
i
c
c
a
r
b
a
n
i
o
n
s
,
i
s
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e
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Scheme 2. The first step of the process is formation of s
adduct 5 from carbanion of 2 and nitroarene 1. Silylation
of the nitro oxygen followed by elimination of silanol an-
ion produces nitroso compound 8, readily deprotonated to
form mesomeric anion 9. There are at least two possible
ways in which further cyclization to the product 3 can
occur. One of them involves addition of the negatively
charged ortho position of the phenyl ring to the nitroso
group (structure 9-III) to form 10, subsequent sililation
and elimination of silanol (9-III→10→12→3). The
SYNLETT 2004, No. 11, pp 1929–1932
0
6
.0
9
.2
0
0
4
Advanced online publication: 05.08.2004
DOI: 10.1055/s-2004-830894; Art ID: G22104ST
©
Georg Thieme Verlag Stuttgart · New York

1
930
Z. Wróbel
LETTER
Table 1 Reactions of Nitroarenes with Active Methylene Compounds
Entry ArNO2
Ar¢CH Y
React. systema Time
Products
2
Yield (%) 4c
b
Yield (%)
b
(
d)
3
3
1
A
A
3a
22
–
–
2
14
3b
18
–
–
3
4
B
B
7
4
3c
59
25
–
–
–
–
3d
5
6
B
B
4
4
–
–
4e
4f
52
34
3f
20
7
B/C
7
4
3g
15/40
4g
50/44
8
B
3h
42
–
–
a
Reaction conditions: Common: nitroarene (1 mmol), arylmethylene comp. (1.2 mmol); A: BSA (2.5 mmol), DBU (5 mmol), toluene (7 mL),
9
0 °C; B: BSA (2.5 mmol), DBU (2.5 mmol), MeCN (8 mL), 20 °C; C: BSA (6 mmol), DBU (2 mmol), MeCN (8 mL), 20 °C.
Isolated yield.
The structures of 4 are as shown on Figure 1.
b
c
second way consists of electrocyclization of the initially requires anionic form 9-II, and would be prevented by
silylated quinone oxime 11 (9-II→11→12→3).
silylation of the latter to 11. Thus, this silylation step may
be the crucial one for the competition. Supporting this
conclusion is an observation, which increasing the amount
At present there are no experimental data, which could
support definitely one or the other path. It is worth to men-
tion, however, that a compound of a structure similar to
of the silylating agent used in the reaction changes the 3/
6
4
products ratio in favor of the pyridine derivative (pro-
1
1, namely 13, has been isolated, characterized and found
5
cedure C vs. B, entry 7). On the other hand, the results of
the reactions carried out under the same reaction condi-
tions, but resulting in products of different type (e.g. entry
to cyclize photochemically.
The mesomeric anion 9 is also the intermediate in a com-
petitive formation of anthranile-type products 4. This pro-
cess of cyclization, via addition–elimination sequence,
5
and 8) show, that the structure of the nitroarene can be
critical for the fate of the intermediate 9, which in the case
Synlett 2004, No. 11, 1929–1932 © Thieme Stuttgart · New York

LETTER
Sophisticated Fused Nitrogen Heterocycles
1931
Scheme 2
References
(
(
(
(
1) Wróbel, Z. Tetrahedron Lett. 1997, 38, 4913.
2) Wróbel, Z. Tetrahedron 1998, 54, 2606.
3) Wróbel, Z. Eur. J. Org. Chem. 2000, 521.
4) Curtin, D. Y.; Dybrig, D. H. J. Am. Chem. Soc. 1962, 84,
25.
2
(
(
5) Wróbel, Z. Synlett 2001, 1927.
1
6) Selected analytical data ( H NMR: 400 MHz, DMSO-d , d in
6
1
ppm, J in Hz; HRMS 70 eV). Compound 3a: H NMR:
Figure 1
d = 7.95–8.00 (m, 1 H), 8.04 (dd, J = 9.4, 2.2, 1 H), 8.05–
8
.09 (m, 1 H), 8.28 (dd, J = 2.2, 0.4, 1 H), 8.32–8.36 (m, 2
of 8-nitroquinoline seems to be much more prone to sub-
sequent addition-elimination process due to better delo-
calization of the charge in the intramolecular addition
intermediate, as compared to that in the case of 6-nitro
isomer (Figure 2).
H), 8.37 (dd, J = 9.4, 0.4, 1 H). HRMS: m/z calcd for
C H N Cl: 238.0298; found: 238.031. Mp 204–207 °C (lit.
mp 208 °C). Compound 3b: d = 7.07 (ddd, J = 8.6, 6.7, 1.2,
7
1
4
7
2
1
1
H), 8.07 (ddd, J = 8.8, 6.7, 1.5, 1 H), 8.13 (dd, J = 9.3, 2.1,
H), 8.28 (dd, J = 9.3, 0.6, 1 H), 8.31–8.35 (m, 2 H), 8.43
7
9
(
dd, J = 2.1, 0.6, 1 H). HRMS: m/z calcd for C H N Br:
14 7 2
2
3
81.979; found: 281.980. Compound 3c: d = 2.36 (s, 3 H),
.92 (s, 3 H), 7.43 (d, J = 9.2, 1 H), 7.40 (AA¢part, 2 H), 7.79
(
8
d, J = 5.9, 1 H), 7.93 (XX¢ part, 2 H), 8.43 (d, J = 9.2, 1 H),
.49 (d, J = 5.9, 1 H). HRMS: m/z calcd for C H N S O :
18 14 2 2 3
3
70.0446; found: 370.0440. Compound 3d: d = 2.32 (s, 3
H), 4.10 (s, 3 H), 7.44 (AA¢ part, 2 H), 7.81–7.88 (m, 3 H),
7
.85 (s, 1 H), 7.86 (d, J = 5.7, 1 H), 7.97 (XX¢ part, 2 H),
Figure 2
8.22–8.25 (m, 1 H), 8.45 (d, J = 5.7, 1 H). HRMS: m/z calcd
for C H NS O : 419.0650; found: 419.0645. Compound
3f: d = 2.36 (s, 3 H), 4.24 (s, 3 H), 7.26–7.28 (m, 2 H), 7.72
(dd, J = 8.3, 4.4, 1 H), 7.76 (d, J = 5.8, 1 H), 7.95–7.97 (m,
2
3
17
2
3
Although in majority of the examples the yields of the
products are low to moderate, the main advantage of this
methodology is its simplicity. It gives easy access to cer-
tain sophisticated nitrogen-containing heterocyclic mole-
cules from simple and available starting materials.
Separation of products is also straightforward, in many
cases the product precipitates from the reaction mixture so
it can be isolated by filtration. Both synthetic and mecha-
nistic studies aimed at broadening the scope of this poten-
tially useful reaction are in progress.
2
1
H), 8.02 (d, J = 5.8, 1 H), 8.27 (s, 1 H), 9.12 (dd, J = 4.4,
.8, 1 H), 9.67 (dd, J = 8.3, 1.8, 1 H). HRMS: m/z calcd for
C H N S O : 420.0602; found: 420.0587. Compound 3g:
2
2
16
2
2
3
d = 2.37 (s, 3 H), 7.29–7.35 (m, 4 H), 7.60–7.64 (m, 2 H),
7
1
.71 (ddd, J = 8.2, 7.1, 1.5, 1 H), 7.78 (ddd, J = 8.2, 7.1, 1.5,
H), 7.83 (d, J = 5.8, 1 H), 8.08–8.12 (m, 2 H), 8.15 (ddd,
J = 8.2, 1.5, 0.5, 1 H), 8.20 (d, J = 5.8, 1 H), 9.46 (ddd,
+
J = 8.2, 1.5, 0.5, 1 H), 9.60 (s, 1 H). MS: 563 [M ].
Compound 3h: d = 2.29 (s, 3 H), 7.06–7.11 (m, 2 H), 7.36
Synlett 2004, No. 11, 1929–1932 © Thieme Stuttgart · New York

1
932
Z. Wróbel
LETTER
(
dd, J = 8.5, 4.4, 1 H), 7.50–7.55 (m, 2 H), 7.76 (d, J = 5.8,
H), 7.26 (dd, J = 5.1, 3.7, 1 H), 7.58 (dd, J = 5.1, 1.1, 1 H),
7.60 (dd, J = 8.0, 4.5, 1 H), 7.73 (dd, J = 3.7, 1.1, 1 H), 8.82
(dd, J = 8.0, 1.8, 1 H), 9.05 (dd, J = 4.5, 1.8, 1 H).
1
H), 8.10 (d, J = 8.10, 1 H), 8.14 (d, J = 9.4, 1 H), 8.2 (d,
J = 9.4, 1 H), 8.86 (dd, J = 4.4, 1.4, 1 H), 9.57 (dd, J = 8.5,
.4, 1 H). HRMS: m/z calcd for C H N S O : 390.0497;
1
Compound 4g: 7.30 (dd, J = 5.1, 3.8, 1 H), 7.38–7.42 (m, 2
H), 7.65–7.70 (m, 3 H), 7.88–7.92 (m, 1 H), 7.93 (dd,
J = 3.8, 1.2, 1 H), 8.46 (s, 1 H), 8.56–8.59 (m, 1 H). MS: 425
2
1
14
2
2
2
found: 390.0493. Compound 4e: d = 7.24 (dd, J = 5.0, 3.7, 1
H), 7.27 (d, J = 9.2, 1 H), 7.57 (dd, J = 8.0, 4.5, 1 H), 7.60
(
+
dd, J = 5.0, 1.1, 1 H), 7.64 (d, J = 9.2, 1 H), 7.81 (dd,
[M ].
J = 3.7, 1.1, 1 H), 8.05 (dd, J = 8.0, 1.6, 1 H), 8.94 (dd,
J = 4.5, 1.6, 1 H). Compound 4f: d = 4.15 (s, 3 H), 6.93 (s, 1
(7) Allais, A.; Poittevin, A. Ger. Pat. 2026080, 1970; Chem.
Abstr. 1971, 74, 53577.
Synlett 2004, No. 11, 1929–1932 © Thieme Stuttgart · New York