Richter cyclization and co-cyclization reactions of triazene-masked diazonium ions

Article abstract of DOI:10.1016/j.tetlet.2010.10.122

The conventional Richter cyclization involves diazotization of 2-alkynylanilines with HX (aq) (X = Br or Cl) and NaNO₂, followed by spontaneous ring closure to give a mixture of 4-halocinnoline and 4-cinnolinone products. The different products

Full text of DOI:10.1016/j.tetlet.2010.10.122

Tetrahedron Letters 51 (2010) 6882–6885
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Richter cyclization and co-cyclization reactions of triazene-masked
diazonium ions
⇑
Annelies Goeminne, Peter J. Scammells, Shane M. Devine, Bernard L. Flynn
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville Vic. 3052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The conventional Richter cyclization involves diazotization of 2-alkynylanilines with HX (aq) (X = Br or
Cl) and NaNO2, followed by spontaneous ring closure to give a mixture of 4-halocinnoline and 4-cinnoli-
none products. The different products result from competing attack of XÀ and H2O, respectively, upon an
intermediate 2-alkynylphenyl diazonium ion during the cyclization step. In order to improve the
chemoselectivity of this reaction, we have utilized triazenes as masked diazonium ions. These can be
unmasked using MeSO3H in anhydrous solvents and the resultant 2-alkynylphenyl diazonium ion
cyclized chemoselectively by the incorporation of a specifically added nucleophile. This process has been
extended to tethered nucleophiles, leading to a Richter induced co-cyclization process to give ring-fused
cinnolines.
Received 25 August 2010
Revised 6 October 2010
Accepted 22 October 2010
Available online 30 October 2010
Keywords:
Richter reaction
Triazenes
Cinnolines
Domino reaction
Ó 2010 Elsevier Ltd. All rights reserved.
Cinnolines are a valuable heterocyclic class from which a
number of biologically active compounds have been identified,
including anti-cancer, fungicidal, antibacterial, and anxiolytic com-
pounds, among others.1 The first cinnolines were prepared by von
Richter over 125 years ago by diazotization of 2-alkynylanilines 1
and heating to form cinnolinones 4 as the major product (Scheme
1).2 Although it was the first reported method for the synthesis of
cinnolines, it was subsequently superseded by the related Bor-
sche–Herbert and Widman–Stoermer reactions as the preferred
methods of preparing these heterocycles, due to the greater ease
with which the starting materials could be accessed and the in-
creased generality of the reactions.1,3 However, with the emer-
gence of efficient palladium-mediated coupling methods for
accessing 2-alkynylanilines 1 (e.g., Sonogashira coupling) the syn-
thetic potential of the Richter reaction has been enhanced signifi-
cantly.4,5 Recent studies into the mechanism of the Richter
reaction have revealed that the initially formed diazonium ion 2
cyclizes to 3 and 4 at room temperature upon competitive nucleo-
philic attack of the halide and water (Nu = XÀ or H2O), respectively
(2 solid arrows).1a,6,7 Heating this mixture, as initially performed
by Richter, hydrolyzes 3 into 4. Depending on the nature of substit-
a-carbon and attack of the nucleophile at the b-carbon to give
products 6/7.
While diazoniums 2, used in most studies to date, have gener-
ally been formed from the treatment of 2-alkynylanilines 1 with
HBr (aq) or HCl (aq) and NaNO2, they can also be formed by the
reaction of (2-alkynylphenyl)triazenes 5 with HBr (aq) or HCl
(aq) (Scheme 1).5 While only a few examples of the use of triazenes
5 in the Richter reaction exist, similar chemoselectivity issues have
been reported, where selective formation of either 3 or 4 is compli-
cated by the competitive formation of the other (see also below).5a
While hydrolysis of 3 can be used to gain selective access to cinn-
olinones 4, albeit under forcing conditions, chemoselective access
to 3 is more difficult. In this respect, Fedenock and coworkers have
utilized high concentrations of chloride ions during the Richter
reaction of 2-alkynylanilines 1 to favor formation of 3 (X = Cl).7
However, we have found this to be problematic, particularly for
the selective formation of bromides 3 (X = Br). In many cases the
cinnolinone 4 still prevails and/or brominated by-products are
formed, which is known to be an issue for diazotizations involving
HBr.4c We anticipated that triazenes 5 might prove more useful
substrates for highly selective formation of variously substituted
cinnolines by using an acid that has a non-nucleophilic conjugate
uents R1/2, cyclization can be redirected through the
a-carbon of
À
the alkyne to give indazoles 6 and 7 (2 dashed arrows), instead
of cinnolines.6,7 When R1 in 2 is a C5 electron-withdrawing group
(i.e., EWG para to the alkyne) or R2 is an electron-donating group,
the alkyne becomes polarized so as to favor cyclization through the
base (e.g., MeSO3H) to form a stable diazonium 2-MeSO3 that
can then be treated with a nucleophile to afford variously substi-
tuted cinnolinones 3/4/8 (Scheme 2). In order to form 4-halocinn-
À
olines 3 selectively, 2-MeSO3 could be formed in an anhydrous
solvent and a tetraalkylammonium halide added to induce cycliza-
tion to 3, avoiding competitive formation of 4. Alternatively,
selective formation of cinnolinone 4 could be achieved by using
MeSO3H in an aqueous solvent, favoring direct attack of
⇑
Corresponding author.
E-mail address: bernard.flynn@pharm.monash.edu.au (B.L. Flynn).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.122

A. Goeminne et al. / Tetrahedron Letters 51 (2010) 6882–6885
6883
H3O, H2O
60-70 ºC
X
O
R2
R2
R2
+
Nu
R1
R1
N
N
HX (aq),
NaNO2
R1
N
N
H
R2
β
α
NH2
3
4
Nu = H2O
or
1
R1
HX (aq)
X
N
O
X
R2
R2
N
R2
2
R1= C5-EWG
2 = EDG
+
R1
N
R1
N
R
R1
N
N
N
H
X = Br or Cl
N
NR2
6
7
5
H3O, H2O
rt
Scheme 1. Cinnolines and indazoline via Richter-type reaction pathways.
À
2-MeSO3 by water to give 4 directly, avoiding interception of 2 by
XÀ to give 3 (as above).8 Potentially, this concept could be ex-
tended to other suitable nucleophiles, including tethered nucleo-
philes to give other substituted cinnolines 8. Herein, we report
our preliminary studies toward this approach, with a particular fo-
cus on its application to the selective formation of 3 and 4 and a
preliminary investigation of other nucleophiles 8.
10 using sodium dithionite in acetone gave 11, which was reacted
with HBF4 (aq), NaNO2 and piperidine giving 13 in moderate yield
(40%, over two-steps). Initial attempts to couple 12 and 13 to ter-
minal alkynes 14 using standard Sonogashira conditions5 met with
mixed results, and in many cases, competitive homo-coupling of
the alkyne limited our access to triazenes 5. This was overcome
by using
a copper-free variant of the Sonogashira reaction
A series of (2-alkynylphenyl)triazenes 5a–h were prepared
from commercially available aryl iodides 9 and 10 (Scheme 3).
Treatment of 9 with HCl (aq), NaNO2, and piperidine afforded 2-
iodoaryl triazene 12 in excellent yield (95%). Nitro reduction of
[Pd(PPh3)4 in pyrrolidine],9 which proved to be a particularly effec-
tive method for accessing (2-alkynylphenyl)triazenes 5a–h (75–
99%).10 While triazenes 12, 13, and 5a–h were stable under storage
conditions, they were not stable to mass spectral analysis and were
only partially characterized. Nonetheless, the 1H NMR spectra of
these were highly diagnostic and the cyclization products of each
were fully characterized, supporting the structural assignment of
the triazenes.11
R2 2 x MeSO3H
R2
Nu
N
Nu
R2
Given the proven utility of 4-bromocinnolines 15 as substrates
in palladium-mediated coupling reactions,5 our attention was first
given to accessing these in an efficient and general manner
(Scheme 4, entries 1–11, Table 1). Cyclization of 5a–h, using
previously described conditions, HBr (aq) 48% w/v in acetone
(Method A, see below),12 worked well for many substrates giving
the desired 4-bromocinnoline 15 in good yield (entries 1–8, Table
1). However, there were some notable exceptions. In the case of 5c,
where R2 is an electron-donating, 4-methoxyphenyl group, the 4-
bromocinnoline 15c (10%) was only isolated as the minor product
(entry 3, Table 1). Unsurprisingly, the reaction proceeded predom-
inantly through an exo-cyclization pathway to give the indazole
17c (55%) as the major product. Interestingly, in the case of cycli-
zation of 5f to form 15f (entry 6, Table 1), the major product was
the co-cyclized pyrano-fused product 18f. Substrate 5h also gave
a low yield of 4-bromocinnoline 15h (21%), with a significant
amount of the cinnolinone 16h (63%) being formed (entry 8, Table
1). Accordingly, the combination of commercially available N-
alkylpyridinium bromide salt, 1-(2-ethoxy-2-oxoethyl)pyridinium
bromide, and MeSO3H in dichloromethane (Method B)12 was ex-
plored as an alternative method for cyclizing (2-alkynylphe-
nyl)triazenes 5 to 4-bromocinnolines 15.13 Only a selected set of
substrates were reacted in this manner (entries 9–11, Table 1). In
the case of 5e, cyclization to 15e (95%) using Method B proceeded
in a comparable yield to that using Method A (compare entries 5
and 9, Table 1). In order to achieve selective formation of 15f, com-
pound 5f was first acetylated to give acetate 20 (100%), which was
then cyclized using Method B to give 21 (84%) and deacetylated to
produce 15f (87%) (Scheme 5 and entry 10 Table 1). Method B
proved particularly effective in the cyclization of 5h, where the
anhydrous reaction conditions completely avoided the formation
of any cinnolinone 16h, giving only 15h (99%) (entry 11, Table 1).
R1
R1
MeSO3.R2NH2
R1
N
N
N
NR2
N
N
MeSO3
3
(Nu = X)
5
-
2
4 (Nu = OH)
-MeSO3
8 (Nu = other)
Scheme 2. Proposed chemoselective Richter cyclization.
9: HCl (aq), NaNO2,
piperidine
I
11: HBF4 (aq), NaNO2,
I
piperidine
N
R1
N
N
R1
Y
9 R1 = H, Y = NH2
12 R1 = H, 95% (from 9)
10 R1 = OMe, Y = NO2
11 R1 = OMe, Y = NH2
13 R1 = OMe, 40% (from 10)
Na2S2O4,
acetone
R2
Pd(PPh3)4 (3-5 mol%),
pyrrolidine
N
R1
N
N
R2
14
5a R1 = H, R2 = n-Pr, 93%
5b R1 = H, R2 = Ph, 99%
5c R1 = H, R2 = p-MeO-C6H4, 98%
5d R1 = OMe, R2 = n-Pr, 83%
5e R1 = H, R2 = -(CH2)2OH, 88%
5f R1 = H, R2 = -(CH2)3OH, 94%
5g R1 = H, R2 = -(CH2)4OH, 97%
5h R1 = H, R2 = -CH2O-3-MeO-C6H4, 75%
Scheme 3. Synthesis of 2-(alkynyl)phenyltriazenes 5.

6884
A. Goeminne et al. / Tetrahedron Letters 51 (2010) 6882–6885
O
Br
N
Br
N
X
R2
Method B
X
1-3
N
N
N
N
R1
N
N
N
R1
18e n = 1
15
18f
n = 2
n = 3
21
5f X = OH
20 X = OAc (100%)
X = OAc (84%)
Ac2O, Et3N,
DMAP
K2CO3,
MeOH / H2O
18g
15f X = OH (87%)
H
Scheme 5. Formation of 15f (entry 10, Table 1).
Method E
H , Br
R2 = (CH2)1-3OH
Method A , B
R2
5h into 16h using Method C returned mostly starting material
(not shown) and the reaction was repeated using H2SO4 and heat-
ing to 50 °C (Method D) to give 16h in reasonable yield (55%).
We next extended the principle of using independent sources of
acid and nucleophile to co-cyclization reactions of substrates bear-
ing tethered nucleophiles. Thus, treatment of 5e–g with MeSO3H
in dichloromethane (Method E) produced compounds 18e–g in
good yields (66–80%) (entries 20–22, Table 1). However, in the case
of 18g, the product rapidly hydrolyzed to give 16g upon chroma-
tography (silica gel or neutral alumina) and 18g could only be ob-
tained in a semi-pure, crude form.
In conclusion, 2-(alkynylphenyl)triazenes 5 represent conve-
nient and effective substrates in modified Richter reactions giving
chemoselective access to 4-bromocinnoline, cinnolinones, ring-
fused cinnolines, and indazoles. Further investigation of the scope
and limitations of this co-cyclization process is currently
underway.
N
R1
N
N
5
H , H2O
Method C , D
H , H2O
Method C
R2 = EDG
OMe
O
O
R2
N
N
N
R1
N
H
H
16
17c
Scheme 4. Cyclization of 2-alkynylaryl triazenes 5 under different conditions (see
Table 1).
Acknowledgment
Table 1
Cyclization of triazenes 5 (Scheme 4)
This work was supported by an Australian Research
Council Linkage Grant (LP0562615) and Bionomics Pty Ltd (www.
bionomics.com.au).
Entry
5
R1
R2
Methoda
Product (yield %)
1
2
3
5a
5b
5c
H
H
H
n-Pr
Ph
4-MeOC6H4
A
A
A
15a (95)
15b (94)
15c (10),
17c (55)
15d (98)
15e (92)
15f (10),
18f (54)
15g (86)
15h (21),
16h (63)
15e (95)
15f (66)
15h (99)
16a (86)
16b (73)
17c (72)
16d (83)
16e (61)
16f (68)
16g (83)
16h (55)
18e (66)
18f (68)
18g (80)c
Supplementary data
4
5
6
5d
5e
5f
OMe
H
H
n-Pr
(CH2)2OH
(CH2)3OH
A
A
A
Supplementary data (experimental details and copies of 1H
NMR and 13C NMR spectra for all other compounds) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.10.122.
7
8
5g
5h
H
H
(CH2)4OH
CH2O–(3-MeOC6H4)
A
A
9
10
11
12
13
14
15
16
17
18
19
20
21
22
5e
5f
H
H
H
H
H
H
OMe
H
H
H
H
H
H
(CH2)2OH
(CH2)3OH
CH2O–(3-MeOC6H4)
n-Pr
B
Bb
B
C
C
C
C
C
C
C
D
E
References and notes
5h
5a
5b
5c
5d
5e
5f
5g
5h
5e
5f
1. For reviews on cinnolines, see: (a) Vinogradova, O. V.; Balova, I. A. Chem.
Heterocycl. Compd. 2008, 44, 501–522; (b) Simpson, J. C. E. Condensed
Pyridazine and Pyrazine Rings. The Chemistry of Heterocyclic Compounds In
Weisberg, A., Ed.; Interscience: New York, London, 1953. p 3; (c) Singerman, G.
M. In The Chemistry of Heterocyclic Compounds; Castle, R. N., Ed.; Interscience:
New York, 1973; Vol. 27,. p 1 (d) Leonard, N. J. Chem. Rev. 1945, 37, 269; (e)
Jacobs, T. L. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New York,
1957; Vol. 6,. p 136 (f) Haider, N.; Holzer, W. Sci. Synth., Product Class 9:
Cinnolines 2004, 16, 251–313; (g) Brown, D. J. Cinnolines and Phthalazines; John
Wiley & Sons, 2005. Suppl. II.
Ph
4-MeOC6H4
n-Pr
(CH2)2OH
(CH2)3OH
(CH2)4OH
CH2O–(3-MeOC6H4)
(CH2)2OH
(CH2)3OH
(CH2)4OH
E
E
2. von Richter, V. Ber. Dtsch. Chem. Ges. 1883, 16, 677–683.
3. (a) Widman, O. Ber. Dtsch. Chem. Ges. 1884, 17, 722–727; (b) Stoermer, R.;
Fincke, H. Ber. Dtsch. Chem. Ges. 1909, 42, 3115–3132; (c) Borsche, W.; Herbert,
A. Liebigs Ann. Chem. 1941, 546, 293–303.
5g
H
a
Method A: 48% aq HBr, acetone. Method B: MeSO3H, 1-(2-ethoxy-2-oxoeth-
yl)pyridinium bromide, CH2Cl2. Method C: MeSO3H, acetone containing 10–30%
water. Method D: H2SO4, 1:1 acetone and water mixture heated to 50 °C for 20 h.
Method E: MeSO3H, CH2Cl2.
4. (a) Villemin, D.; Goussu, D. Heterocycles 1989, 29, 1255–1261; (b) Le Fur, N.;
Mojovic, L.; Turck, A.; Ple, N.; Queguiner, G.; Reboul, V.; Perrio, S.; Metzner, P.
Tetrahedron 2004, 60, 7983–7994; (c) Vinogradova, O. V.; Sorokoumov, V. N.;
Vasilevskii, S. F.; Balova, I. A. Russ. Chem. Bull. 2008, 57, 1725–1733.
5. (a) Vinogradova, O. V.; Sorokoumov, V. N.; Balova, I. A. Tetrahedron Lett. 2009,
50, 6358–6360; (b) Bräse, S.; Dahmen, S.; Heuts, J. Tetrahedron Lett. 1999, 40,
6201–6203; (c) Bui, C. T.; Flynn, B. L. Mol. Divers. Pub. Online March 2010, doi:
10.1007/s11030-010-9235-8.
b
Involves additional steps of protection and deprotection, see Scheme 5.
c
Yield based on recovered mass balance and 1H NMR of the crude product.
6. (a) Vasilevsky, S. F.; Tretyakov, E. V. Synth. Commun. 1994, 24, 1733–1736; (b)
Vasilevsky, S. F.; Tretyakov, E. V. Liebigs Ann. Chem. 1995, 775–779; (c)
Zolnikova, N. A.; Fedenok, L. G.; Polyakov, N. E. Org. Prep. Proced. Int. 2006, 38,
476–480.
7. (a) Fedenok, L. G.; Zolnikova, N. A. Tetrahedron Lett. 2003, 44, 5453–5455; (b)
Fedenok, L. G.; Barabanov, I. I.; Bashurova, V. S.; Bogdanchikov, G. A.
Tetrahedron 2004, 60, 2137–2145; (c) Zol’nikova, N. A.; Fedenok, L. G.;
Peresypkina, E. V.; Virovets, A. V. Russ. J. Org. Chem. 2007, 43, 790–792; (d)
We next turned to the use of triazenes 5 as substrates in direct
cyclization to cinnolinones 16 (Scheme 4), where H2O replaces XÀ
as the nucleophile. Treatment of triazenes 5a–g with MeSO3H in
aqueous acetone (Method C)12 produced cinnolinones 16a,b,d–g
and indazole 17c at room temperature in good to excellent yields
(61–86%) (entries 12–18, Table 1). Our initial attempt to convert

A. Goeminne et al. / Tetrahedron Letters 51 (2010) 6882–6885
6885
Shvartsberg, M. S.; Ivanchikova, I. D.; Fedenok, L. G. Tetrahedron Lett. 1994, 35,
6749–6752; (e) Fedenok, L. G.; Barabanov, I. I.; Ivanchikova, I. D. Tetrahedron
Lett. 1999, 40, 805–808; (f) Fedenok, L. G.; Barabanov, I. I.; Ivanchikova, I. D.
Tetrahedron 2001, 57, 1331–1334; (g) Duan, J.-X.; Cai, X.; Meng, F.; Lan, L.; Hart,
C.; Matteucci, M. J. Med. Chem. 2007, 50, 1001–1006.
and 1-(2-ethoxy-2-oxoethyl)pyridinium bromide (1.2 mmol) in anhydrous
CH2Cl2 (10 mL) at 0 °C and then stirred at room temperature for 1 h. The
resulting mixture was then diluted with CH2Cl2 (15 mL) and washed with
saturated NaHCO3 (aq) (20 mL). The organic phase was washed with H2O
(20 mL), dried over MgSO4, and concentrated under reduced pressure. The
resultant solid residue was suspended in Et2O (2 mL) filtered and washed with
cold Et2O (4 mL).
8. For
a previous report on the use of H2SO4 in the diazotization of 2-
alkynylanilines 1 to give 4-cinnolinones, see Ref. 7f .
9. Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993, 34, 6403–6406.
10. General coupling procedure for the formation of 5a–h: The iodoaryl
piperidinetriazene 12 or 13 (1 equiv) was dissolved in pyrrolidine (0.5 M)
and N2 (g) was bubbled through for 0.25 h. Pd(PPh3)4 was added and the
reaction heated to 60 °C. A solution of the appropriate alkyne (2 equiv) in
pyrrolidine (1 M) was added via syringe in small portions over 2 h. After
complete addition of the alkyne, the mixture was left stirring at 60 °C
overnight. After cooling to room temperature, H2O was added and the
mixture was extracted with Et2O. The organic phase was washed with
saturated NH4Cl (aq), dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by column chromatography over
silica gel to give 5.
Method C: MeSO3H (5 mmol) was added dropwise to a stirred solution of 5
(1 mmol) in an acetone and H2O mixture (1:1 to 9:1, depending on solubility,
10 mL) at 0 °C (ice bath). The mixture was stirred at room temperature for 20 h.
Acetone was evaporated and generally the product precipitated and was
filtered and rinsed with H2O. Where no precipitate formed, the aqueous
residue was neutralized with saturated NaHCO3 (aq) and extracted with EtOAc
(20 mL). Crude products were generally of good purity, however, further
purification could be achieved by crystallization from hot EtOH (1–3 mL) or by
washing the crude solid with Et2O (2–3 mL). See Supplementary data for the
variation of this procedure used to access 16h, in Method D.
Method E: MeSO3H (2.5 mmol) was added dropwise to a solution of 5 (1 mmol)
in anhydrous CH2Cl2 (10 mL) at 0 °C and then stirred at room temperature for
24 h. The resultant mixture was diluted with CH2Cl2 and washed with
saturated NaHCO3 (aq) (20 mL). The organic phase was washed with H2O,
dried over MgSO4, concentrated under reduced pressure and the product
purified by column chromatography on silica gel (CH2Cl2/MeOH 40:1, 20:1,
10:1) to give 18e and 18f. In the case of 18g, the product decomposed during
chromatography, giving mostly 16f (hydrolysis). Accordingly, 18g could only
be isolated in crude form.
11. See Supplementary data.
12. Method A: The triazene 5 (1 mmol) was dissolved in acetone (10 mL) and
cooled in an ice bath. A solution of 48% HBr (aq) (8 mmol) was added dropwise
and the mixture stirred at room temperature until all starting material was
consumed (0.2–2 h). The acetone was evaporated and the residue was taken up
in CHCl3 (15 mL) and washed with H2O (15 mL). The organic phase was dried
(MgSO4) and concentrated under reduced pressure and the product purified by
column chromatography on neutral alumina (deactivation II).
13. Tetrabutylammonium bromide can also be used but co-eluted with a number
of products during column chromatography.
Method B: MeSO3H (2.5 mmol) was added dropwise to a solution of 5 (1 mmol)