A short route to 3-alkynyl-4-bromo(chloro)cinnolines by Richter-type cyclization of ortho-(dodeca-1,3-diynyl)aryltriaz-1-enes

Article abstract of DOI:10.1016/j.tetlet.2009.08.103

Cleavage of ortho-(dodeca-1,3-diynyl)triazenes in HCl or HBr medium and subsequent cyclization of the resulting diazonium salts is investigated. In the absence of a strong electron-withdrawing substituent, the reaction affords 3-alkynyl-4-bromo(chloro)cin

Full text of DOI:10.1016/j.tetlet.2009.08.103

Tetrahedron Letters 50 (2009) 6358–6360
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A short route to 3-alkynyl-4-bromo(chloro)cinnolines by Richter-type
cyclization of ortho-(dodeca-1,3-diynyl)aryltriaz-1-enes
*
Olga V. Vinogradova, Viktor N. Sorokoumov, Irina A. Balova
Saint-Petersburg State University, 26 Universitetskij pr., Petrhoff, St. Petersburg, 198504, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Cleavage of ortho-(dodeca-1,3-diynyl)triazenes in HCl or HBr medium and subsequent cyclization of the
resulting diazonium salts is investigated. In the absence of a strong electron-withdrawing substituent,
the reaction affords 3-alkynyl-4-bromo(chloro)cinnolines as the only product. A methoxycarbonyl group
promotes hydrolysis of 4-halocinnolines which results in the formation of by-products: furo[3,2-c]cinn-
oline and cinnolinone. Substitution of bromine in 3-(alk-1-ynyl)-4-bromocinnolines is achieved with
methylamine, Na2S and ethynylbenzene affording pyrrolo[3,2-c]cinnoline, thieno[3,2-c]cinnoline and
3,4-diethynylcinnoline, respectively.
Received 23 May 2009
Revised 10 August 2009
Accepted 28 August 2009
Available online 2 September 2009
Keywords:
ortho-(Alka-1,3-diynyl)aryltriazenes
ortho-(Alka-1,3-diynyl)arenediazonium
salts
Ó 2009 Elsevier Ltd. All rights reserved.
Richter cyclization
3-Alkynyl-4-halocinnolines
Synthesis: pyrrolo[3,2-c]cinnolines,
thieno[3,2-c]cinnoline, 3,4-
diethynylcinnoline
Many recent studies have shown the cyclization of functionally
substituted aryl- and hetarylacetylenes to be an efficient method
for preparing a wide variety of fused nitrogen heterocyclic systems
such as indoles,1 indolo[1,2-c]quinazolines,2 quinolines3 and iso-
quinolines,4 furopyridine,5 and pyrazolopyridines.6
In particular, ortho-ethynylsubstituted aryltriazenes have been
used to produce an isoindazole and/or a cinnoline, depending on
the conditions.7 Cleavage of a triazene moiety with aqueous hydro-
genchlorideorhydrogenbromidefavorsRichtercyclization8 toyield
cinnoline derivatives via generation of an o-ethynenearyldiazonium
salt.9 While the cyclization of o-substituted ethynylarenes is well-
known, there are only a few examples of cyclization of buta-1,3-diy-
nyl derivatives, due to their poor stability and availability.
We recently reported the Richter-type cyclization of o-(alka-
1,3-diynyl)arenediazonium salts, which were generated by diazoti-
zation of the corresponding arylamines.10,11 The reaction leads to
3-alkynyl-4-chloro(bromo)cinnolines, but the yields of the target
products were moderate due to the formation of by-products dur-
ing the reaction.11 The use of aryltriazenes for the Richter cycliza-
tion would be more promising in the case of diacetylene
derivatives, since this approach would allow separate diazotization
and cyclization steps. Herein, we present our studies on the cycli-
zation of ortho-(dodeca-1,3-diynyl)arenediazonium salts obtained
from the corresponding diacetylene derivatives of aryltriazenes
by cleavage with hydrobromic or hydrochloric acid.
Starting compounds
2 were prepared in excellent yields
via cross-coupling of iodotriazenes 112 with dodeca-1,3-diyne
under Sonogashira conditions. The latter was obtained from the
internal isomer using the ‘diacetylene zipper’ reaction (Scheme
1). Undoubtedly, this approach can be extended to other homologs,
as the methodology of sequential ‘diacetylene zipper’ and Sono-
gashira reactions was tested on a related series of internal diynes
for the synthesis of functionalized (alka-1,3-diynyl)arenes.13
C4H9
C4H9
1. LAETA
2. H2O
Et
N
Ph
X
Ph
X
Et
N
N
N
N
N
C8H17
2
H
C8H17
I
Pd(PPh3)4, CuI
Et3N
8 h, rt
Y
Y
2a-c
1a-c
LAETA : lithium 2-aminoethylamide
2a 2b
: X=H, Y=Br (79%); : X=Br, Y=CH3 (78%);
2c: X=H, Y=COOMe (95%)
* Corresponding author.
Scheme 1. Synthesis of ortho-(dodeca-1,3-diynyl)aryltriazenes via Pd/Cu-catalyzed
E-mail address: irinabalova@yandex.ru (I.A. Balova).
cross-coupling of iodotriazenes with dodeca-1,3-diyne.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.103

O. V. Vinogradova et al. / Tetrahedron Letters 50 (2009) 6358–6360
6359
C8H17
C8H17
Ph
X
Et
N
N
N
N
N
N
N
N
Y
HN
Y
C8H17
C8H17
+
X
X
X
O
2
Hal
O
HBr (HCl)
+
Y
Y
3a-c,
Hal = Br
2a,b,c
4
5
3d-f, Hal = Cl
Scheme 2. Richter cyclization of ortho-(dodeca-1,3-diynyl)aryltriazenes.
a low yield of cinnoline 3a as the only product (Table 1, entry 1).
Cyclization under these conditions is complicated by significant
resinification. The use of concentrated HBr proved to be more
favorable leading to a reduced cyclization time and dramatically
increased yields for 3-alkynyl-4-bromo-cinnolines 3a and b (Table
1, entries 2 and 3). The lower yields of 4-chlorocinnolines com-
pared to the bromo derivatives can be explained by the lower sta-
bility of the former (Table 1, entries 4 and 5).
Moreover, in the presence of aqueous HCl the reaction took
longer, which led to additional resinification of the reaction mix-
ture and lower product yields. Thus, a reduction in the yield was
observed for compound 3d when the reaction was run for 24 h (Ta-
ble 1, entry 6). Diethyl ether was also tested as a solvent, and in
this case, 3-alkynyl-4-bromocinnoline 3a was obtained in good
yield (Table 1, entry 7).
Table 1
Studies on the Richter reaction of ortho-(dodeca-1,3-diynyl)aryltriazenes and the
yields of products14,15
Entry Triazene
X
Y
Solvent
(reaction (concentration)
time, h)
HHal
Products,
yield (%)
3
4
5
1
2
2a
2a
2b
2a
2b
2a
2a
2c
2c
2c
H
H
Br
Br
Acetone
(5)
Acetone
(2)
Acetone
(2)
Acetone
(5)
Acetone
(5)
Acetone
(24)
HBr (1M)a
HBrconcd
HBrconcd
HCl (6M)
HClconcd
HCl (6M)
HBrconcd
HBrconcd
HClconcd
HBrconcd
3a,
13
3a,
55
3b,
75
3d,
38
3e,
34
3d,
26
3a,
75
—
—
—
—
—
—
—
—
—
—
—
—
—
—
3
Br CH3
Br
Br CH3
4
H
5
6
H
H
H
H
H
Br
Br
It was reported earlier, that either cyclization of o-ethynylaryl-
triazenes in dilute acids or extended reaction times led to the
7
Et2O (2)
formation of cinnolinones, as
a result of hydrolysis of 4-
bromo(chloro)cinnolines.9 In our case, irrespective of the cycliza-
tion conditions, no products of 4-halocinnoline hydrolysis were
detected in reactions with compounds 2a and b. Different results
were obtained for the triazene 2c possessing an electron-with-
drawing group on the aromatic ring. In spite of the concentrated
acid media, the methoxycarbonyl group promotes hydrolysis of
4-halocinnolines within the usual reaction time, and results in
the additional formation of furo[3,2-c]cinnoline 4 and cinnolinone
5 (Table 1, entries 8 and 9). However, bromocinnoline 3c was ob-
tained as the major product when the reaction mixture was
quenched after 30 min (Table 1, entry 10).
8
COOMe Acetone
3c, 4,
5,
(2)
COOMe Acetone
(2)
COOMe Acetone
(0.5)
17
3f,
15
5
4,
17
25
9
10
3c, 4,
41
5,
10
3
a
Same conditions used for the cyclization of ortho-ethynyltriazenes.9
The influence of the substituent and reaction conditions were
considered for the Richter-type cyclization of o-(dodeca-1,3-diy-
nyl)aryltriazenes 2 (Scheme 2, Table 1). Compared to monoacety-
lene derivatives,9 cyclization of diacetylene analogs is slower and
required more acidic conditions. Thus, in the presence of 20 equiv
of 1 M HBr, cyclization of 2a was complete within 5 h and afforded
4-Chloro-3-ethynylcinnolines were shown to be interesting
starting materials for the synthesis of fused heterocycles by nucle-
ophilic substitution of chlorine and subsequent cyclization involv-
ing the triple bond.16 It was reported earlier that their reactions
C8H17
C8H17
O
N
O
Br
N
C8H17
O
S
Na2S
MeNH2
N
H
MeO
HO
MeOH, 65 oC
5 h
EtOH, 78 oC
5 h
N
N
N
N
N
6a (51%)
3c
7 (51%)
C8H17
O
N
Ph
EtO
N
Br
C10H21
C10H21
N
Ph
6b (10%)
N
N
Pd(PPh3)4, CuI
Et3N, 50 oC, 12 h
N
N
3g
8 (76%)
Scheme 3. Reactions of 4-bromo-3-(alk-1-ynyl)cinnolines 3c,g with MeNH2, NaS2 and phenylacetylene.

6360
O. V. Vinogradova et al. / Tetrahedron Letters 50 (2009) 6358–6360
with nucleophiles, such as primary amines or hydrazines followed
by cyclization, occurred at high temperature in the presence of
Cu(I) as catalyst.16
Next we studied the reactivity of 4-bromo-3-decynylcinnoline
3c in reactions with methylamine and Na2S (Scheme 3). In contrast
to previous work,16 nucleophilic substitution–cyclization proce-
eded as a tandem process under rather mild conditions to give
References and notes
1. (a) Barluenga, J.; Trincado, M.; Rublio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed.
2003, 42, 2406; (b) Muhammad, A.; Knight, D. W. Tetrahedron Lett. 2004, 45,
539; (c) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037.
2. Battistuzzi, G.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M. Org. Lett. 2002, 4,
1355.
3. Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763.
4. (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86; (b) Kirsch, G.; Hesse, S.
Synthesis 2003, 5, 717; (c) Dai, G.; Larock, R. C. Org. Lett. 2002, 4, 193.
5. Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4,
2409.
6. (a) Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J. J. Heterocycl. Chem. 2002,
39, 1229; (b) Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J. Heterocycles
2002, 57, 2255.
7. (a) Kimball, D. B.; Hayes, A. G.; Haley, M. M. Org. Lett. 2000, 2, 3825; (b) Kimball,
D. B.; Herges, R.; Haley, M. M. J. Am. Chem. Soc. 2002, 124, 1572; (c) Kimball, D.
B.; Weakley, T. J. R.; Haley, M. M. J. Org. Chem. 2002, 67, 6395; (d) Kimball, D. B.;
Weakley, T. J. R.; Herges, R.; Haley, M. M. J. Am. Chem. Soc. 2002, 124, 13463; (e)
Shirtcliff, L. D.; Hayes, A. G.; Haley, M. M.; Koehler, F.; Hess, K.; Herges, R. J. Am.
Chem. Soc. 2006, 128, 9711.
pyrrolo[3,2-c]cinnolines
6
or thieno[3,2-c]cinnoline 7. The
methoxycarbonyl group underwent hydrolysis or substitution of
the methoxy group by MeNH2 or EtOH under the reaction
conditions.
The bromine at C-4 of the cinnoline system can also be replaced
easily with an ethynyl moiety via Sonogashira reaction, as shown
for compound 3g.17 This reaction leads to a cinnoline, possessing
an enediyne system (Scheme 3).
In conclusion, the generation of o-(alka-1,3-diynyl)aryldiazo-
nium salts from aryltriazenes for use in the Richter cyclization
is a useful approach in comparison with diazotization of diynyl-
arylamines,11 and avoids side reactions. This cyclization provides
a short route to 3-alkynyl-4-bromo(chloro)cinnolines which are
obtained in good yields when a strong electron-withdrawing
substituent is not present on the benzene ring. Their application
in the synthesis of fused heterocycles containing a cinnoline sys-
tem as well as for preparation of cinnoline derivatives possessing
an enediyne moiety has been demonstrated.
8. von Richter, V. Ber. Dtsch. Chem. Ges. 1883, 16, 677.
9. Bräse, S.; Dahmen, S.; Heuts, J. Tetrahedron Lett. 1999, 40, 677.
10. Vinogradova, O. V.; Sorokoumov, V. N.; Vasylevsky, S. F.; Balova, I. A.
Tetrahedron Lett. 2007, 48, 4907.
11. Vinogradova, O. V.; Sorokoumov, V. N.; Vasylevsky, S. F.; Balova, I. A. Russ.
Chem. Bull. 2008, 57, 1693.
12. Iodoaryltriazenes 1 were synthesised from iodoarylamines according to the
procedure described by: (a) Stashkevich, O. M.; Pilugin, G. T.; Stashkevich, V. V..
In Methods of Preparation of Chemicals and Reagents; Lastovski, R. P., Ed.; IREA:
Moscow, 1969; Vol. 18, pp 158–162; (b) Vernin, G.; Siv, C.; Metzger, J.;
Parkanyi, C. Synthesis 1977, 691.
13. Balova, I. A.; Morozkina, S. N.; Sorokoumov, V. N.; Vinogradova, O. V.; Knight, D.
W.; Vasilevsky, S. F. Eur. J. Org. Chem 2005, 882.
14. All compounds were characterized by NMR, MS, and CHN analysis and yields
refer to isolated products.
Acknowledgement
15. A typical reaction procedure is as follows: to a solution of aryltriazene 2
(2 mmol) in acetone (10 mL) or diethyl ether (10 mL), concentrated HBr or HCl
(20 equiv) was added quickly at 10 °C. The reaction mixture was stirred at
room temperature for the specified time (see Table 1). The reaction mixture
was diluted with water (10 mL) and extracted with EtOAc (3 Â 20 mL). The
combined organic layer was washed with water and brine until neutral, pH,
and then dried over CaCl2. Chloro cinnolines were purified by column
chromatography, and bromo analogs were crystallized from Et2O–hexane.
16. Ames, D. E.; Bull, D. Tetrahedron 1982, 38, 383.
This work was supported by the Russian Fund for Basic Re-
search, Grant 05-03-32504.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.103.
17. 4-Bromo-3-(dodec-1-ynyl)cinnoline 3g was obtained by diazotization of the
corresponding arylamine, see Ref. 11.