A novel convenient approach towards pyrrolo[1,2-b]pyridazines through a domino coupling-isomerization-condensation reaction

Article abstract of DOI:10.1039/c3ob40157j

A novel Pd/Cu catalyzed domino reaction for the synthesis of functionalized pyrrolo[1,2-b]pyridazines from readily accessible (hetero)aryl propargyl alcohols and 1-amino-2-bromopyrroles was developed. This cascade process involves a Sonogashira cross-coupling reaction, an isomerization and an intramolecular condensation.

Full text of DOI:10.1039/c3ob40157j

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
A novel convenient approach towards pyrrolo[1,2-b]-
pyridazines through a domino coupling–isomerization–
condensation reaction†
Cite this: Org. Biomol. Chem., 2013, 11,
2574
Received 24th January 2013,
Accepted 24th February 2013
Meng Wang, Cun Tan, Qian He, Yuyuan Xie and Chunhao Yang*
DOI: 10.1039/c3ob40157j
www.rsc.org/obc
A novel Pd/Cu catalyzed domino reaction for the synthesis of derivatives can be obtained from the reactions of 1-aminopyr-
functionalized pyrrolo[1,2-b]pyridazines from readily accessible roles with β-dicarbonylic compounds2f or with 3,3-dimethoxy-
(hetero)aryl propargyl alcohols and 1-amino-2-bromopyrroles was propionitriles.2a However, most of these approaches have
developed. This cascade process involves a Sonogashira cross- some disadvantages: tedious multistep synthetic opera-
coupling reaction, an isomerization and an intramolecular tions,2a,6,9 inconvenient preparation of the raw material,3e,5
condensation.
long reaction times,7–9 low atom economy4,5 and low yields.3e,g,7
So it is still imperative to develop new methods to construct
pyrrolo[1,2-b]pyridazine scaffolds and their library efficiently.
Transition metal-catalyzed reactions have considerably revo-
lutionized synthetic methodology as well as pharmaceutical
and other industries. The Sonogashira coupling reaction10 is
one of the most powerful methods for the construction of
carbon–carbon bonds under milder conditions. Consequently,
an increasing number of processes performing this reaction
have been widely developed. In 2000, Müller and coworkers
found a coupling–isomerization reaction (CIR) of electron-poor
aryl halides and aryl propargyl alcohols to prepare 1,3-diaryl-
propenones.11 This reaction worked through a palladium/
copper-catalyzed Sonogashira coupling followed by a base-cata-
lyzed isomerization to an α,β-unsaturated enone product. In
the past few years, by incorporating the CIR into a domino
reaction, a series of heterocycles12 such as pyrazolines,11a pyri-
midines,12a 1,5-benzoheteroazepines,12b pyrroles,12c enimi-
nes,12d annelated 2-amino pyridines,12e aryl chalcones,12f
1-acetyl-2-amino-cyclohexa-1,3-dienes12g and 2-arylquinolines12h
have been synthesized. Encouraged by these intriguing reac-
tions, our group reported a domino coupling–isomerization–
condensation sequence towards functionalized naphthalenes,
quinolines, and isoquinolines.13 In our continuing pursuit of
the development of various bioactive heterocycles, we envi-
sioned that 2-halo-1-aminopyrroles would react with aryl pro-
pargyl alcohols via a domino process to furnish substituted
pyrrolo[1,2-b]pyridazines under the conditions of the CIR
(Scheme 1). Here we wish to report a novel synthetic approach
towards pyrrolo[1,2-b]pyridazine derivatives.
Pyrrolo[1,2-b]pyridazine is an attractive nitrogen-containing
scaffold in medicinal chemistry, materials chemistry and syn-
thetic chemistry.1 Many pyrrolo[1,2-b]pyridazine derivatives
displayed their potential therapeutic usefulness,2 including as
MEK inhibitors,2a antibacterial and antifungal agents,2b
DGAT1 inhibitors,2c TRPV1 antagonists,2d CRF1 receptor anta-
gonists,2f allosteric inhibitors of AKT.2e Meanwhile, the optical
and electrochemical properties of pyrrolo[1,2-b]pyridazines
aroused great concern and strong interest for their fascinating
functions in materials science.3 They were reported as highly
blue-emitting moieties3d,e,g,h and were expected to be good
emissive materials for organic light-emitting diodes
(OLEDs).3a,b Their polymers provided potential use as optical
switches or modulators.3c Therefore, much effort has been
devoted to the syntheses of pyrrolo[1,2-b]pyridazine derivati-
ves.1a,c One of the most used synthetic strategies involves cyclo-
addition reactions, such as the 1,3-dipolar cycloaddition of
substituted pyridazines3a,b,d,4 or mesoionic oxazolo[3,2-b]pyri-
dazines5 to acetylenic esters, or pyridazinium N-ylides to acti-
vated olefinic or acetylenic dipolarophiles,1c,2b,3e,g,6 the [3 + 2]
cycloaddition of pyridazines to alkylidene-cyclopropanes.7
Another strategy usually adopted is based on condensation
reactions, such as the condensation of cyanacetic acid hydra-
zide with nitriles,8 the condensation of Boc-protected 1-amino-
pyrroles with chalcones.9 Additionally, pyrrolo[1,2-b]pyridazine
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P.R. China.
E-mail: chyang@simm.ac.cn; Fax: +86-21-50806770; Tel: +86-21-50806770
Initially we chose methyl 1-amino-5-bromo-pyrrole-2-car-
boxylate (1) and 1-(3-methoxyphenyl)prop-2-yn-1-ol (2a) as the
starting materials. Considering the successful application of
MW (microwave) irradiation in CIR11c,12f–h,13 and the synthesis
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40157j
2574 | Org. Biomol. Chem., 2013, 11, 2574–2577
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
dioxane, DMF or CH3CN (entries 7, 10–13). When the reaction
was conducted under conventional thermal heating for 2 h, 3a
was also obtained in excellent yield (85%, entry 14).
Using the optimized conditions (2 mol% Pd(PPh3)4, 1 mol%
CuI, 5 equiv. DBU, toluene, MW, 100 °C), as shown in
Table 2, various 1-aryl prop-2-yn-1-ols were tested. Most aryl
propargyl alcohols gave acceptable to high yields. Both elec-
tronic and steric factors displayed an important role in this
process. Generally, electron-rich prop-2-yn-1-ols provided the
desired products in higher yields than electron-poor propargyl
alcohols did. Aryl propargyl alcohols with electron-donating
groups at the meta- and para-position afforded good yields (3a,
3c, 3d, 3f). However, electron-donating groups at the ortho-posi-
tion gave moderate yields due to the steric hindrance effects
(3b, 3e). Moreover, substrates possessing weak electron-with-
drawing groups such as chloride and fluoride were also suc-
cessfully employed in the reaction (3i–3l). While aryl propargyl
alcohols with strong electron-withdrawing substituents or poly-
halide showed less reactivity than unsubstituted phenyl (3m,
3n vs. 3h). Prop-2-yn-1-ols containing heterocycles were fully
tolerated and gave the corresponding pyrrolo[1,2-b]pyridazines
in good to excellent yields (3o–3q). Similarly, electron-with-
drawing pyridyl propargyl alcohol provided a lower yield (3q vs.
3h) and the electron-rich thienyl substituent gave excellent
yield (3p). Additionally, propargyl alcohol with naphthalenyl or
biphenyl groups worked smoothly in this domino reaction (3r,
3s). Not surprisingly, alkenyl-substituted propargyl alcohol
gave the product in poor yield (3t). This might be due to the
difficulty of isomerization to the dienone for the electron-
donating alkenyl group.
Scheme 1 (a) Coupling–isomerization reaction (CIR) of aryl halides and aryl
propargyl alcohols. (b) Our work.
of pyrrolo[1,2-b]pyridazines,2b,3e,g we decided to perform this
domino reaction under MW irradiation at first (Table 1).
As anticipated, this protocol yielded the desired product
methyl 2-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazine-7-carboxy-
late (3a) in 59% yield by using Pd(PPh3)4 as the catalyst (entry
2). Other Pd-catalysts were less effective (entries 1 and 3). The
optimization procedure reveals that an excess of the propargyl
alcohol 2a is favorable (entries 4 and 5). When the reaction
was conducted at 115 °C and 100 °C, the same results were
obtained (entries 5 and 7), while lower temperatures (80 °C)
reduced the yield greatly (entry 6). The yield also decreased
slightly by reducing the amount of base DBU (1,8-diazabicyclo
[5.4.0]undec-7-ene) to 2 equiv. (entry 9 vs. 7). No product was
obtained using the base DIPEA (N,N-diisopropylethylamine)
(entry 8). This outcome means that a weak base cannot
promote the reaction. Different solvents were further screened
and the reaction in toluene gave better results than in THF,
In conclusion, a novel and straightforward palladium/
copper-catalyzed synthetic approach towards pyrrolo[1,2-b]-
Table 1 Optimization procedures for the reaction of 1 and 2aa
Entry
Pd catalyst
Solvent
Base [equiv.]
Equiv. of 2a
Conditions
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
THF
THF
THF
THF
THF
THF
THF
THF
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DIPEA(5)
DBU(2)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
1
1
1
1.5
2
2
2
2
2
2
2
2
2
115 °C, 5 min
115 °C, 5 min
115 °C, 5 min
115 °C, 15 min
115 °C, 15 min
80 °C, 15 min
100 °C, 15 min
100 °C, 15 min
100 °C, 15 min
100 °C, 15 min
100 °C, 15 min
100 °C, 15 min
100 °C, 15 min
Reflux, 2 h
46(62c)
59
Trace
76
89
76
89
/
82
91
9
THF
10
11
12
13
14d
Toluene
Dioxane
DMF
CH3CN
Toluene
85
67
46
85
2
a Reaction conditions: 1-amino-2-halopyrrole 1 (0.4 mmol), 2 mol% Pd catalyst, 1 mol% CuI, 2 mL of dry solvent heating in a microwave reactor
under N2. b Yield isolated by column chromatography. c 20 mol% PPh3 was added as the ligand. d The reaction was heated in an oil bath.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2574–2577 | 2575

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 2 Synthesis of pyrrolo[1,2-b]pyridazinesa
pyrrolo[1,2-b]pyridazine derivatives with biological activity are
currently in progress in our laboratory.
Acknowledgements
This work was financially supported by the Ministry of Science
and Technology of China (“Key New Drug Creation and Manu-
facturing Program” 2012ZX09301001-001, 2012ZX09103101-
071), the Chinese Academy of Sciences (“Interdisciplinary
Cooperation Team” Program for Science and Technology Inno-
vation), the National Natural Science Foundation of China
(NSFC) (grant number 21072205), and SKLDR/SIMM
(SIMM1203ZZ-0103).
Notes and references
1 For selected reviews on pyrrolo[1,2-b]pyridazines, see:
(a) D. E. Kuhla and J. O. Lombardino, Adv. Heterocycl.
Chem., 1977, 21, 1; (b) G. Jones, in Comprehensive Hetero-
cyclic Chemistry II, ed. Editors-in-Chief: A. R. Katritzky,
C. W. Rees and E. F. V. Scriven, Pergamon, Oxford, 1996,
Vol. 8, p. 287; (c) F. Dumitraşcu and D. G. Dumitrescu,
ARKIVOC, 2008, 2008, 232; (d) I. I. Mangalagiu, Curr. Org.
Chem., 2011, 15, 730.
2 For some selected recent examples on therapeutic useful-
ness of pyrrolo[1,2-b]pyridazines, see: (a) Z. Chen,
S. H. Kim, S. A. Barbosa, T. Huynh, D. R. Tortolani,
K. J. Leavitt, D. D. Wei, V. Manne, C. S. Ricca and J. Gullo-
Brown, Bioorg. Med. Chem. Lett., 2006, 16, 628;
(b) R. M. Butnariu and I. I. Mangalagiu, Bioorg. Med.
Chem., 2009, 17, 2823; (c) B. M. Fox, K. Iio, K. Li, R. Choi,
T. Inaba, S. Jackson, S. Sagawa, B. Shan, M. Tanaka and
A. Yoshida, Bioorg. Med. Chem. Lett., 2010, 20, 6030;
(d) I. Dorange, R. Forsblom, I. Macsari, M. Svensson,
J. Bylund, Y. Besidski, J. Blid, D. Sohn and Y. Gravenfors,
Bioorg. Med. Chem. Lett., 2012, 22, 6888; (e) J. G. Kettle,
S. Brown, C. Crafter, B. R. Davies, P. Dudley, G. Fairley,
P. Faulder, S. Fillery, H. Greenwood and J. Hawkins, J. Med.
Chem., 2012, 55, 1261; (f) T. Saito, T. Obitsu, H. Kohno,
I. Sugimoto, T. Matsushita, T. Nishiyama, T. Hirota,
H. Takeda, N. Matsumura, S. Ueno, A. Kishi, Y. Kagamiishi,
H. Nakai and Y. Takaoka, Bioorg. Med. Chem., 2012, 20,
1122.
a Reaction conditions: methyl 1-amino-5-bromo-pyrrole-2-carboxylate 1
(0.4 mmol), propargyl alcohols (0.8 mmol), DBU (2.0 mmol), 2 mol%
Pd(PPh3)4, 1 mol% CuI, 2 mL of dry toluene heating in a microwave
reactor under N2 at 100 °C. Yield isolated by column chromatography.
b The reaction was refluxed in an oil bath for 36 hours.
3 For some selected examples on optical and electrochemical
properties of pyrrolo[1,2-b]pyridazines, see: (a) Y. Cheng,
B. Ma and F. Wudl, J. Mater. Chem., 1999, 9, 2183;
(b) T. Mitsumori, M. Bendikov, J. Sedó and F. Wudl, Chem.
Mater., 2003, 15, 3759; (c) T. Mitsumori, I. M. Craig,
I. B. Martini, B. J. Schwartz and F. Wudl, Macromolecules,
2005, 38, 4698; (d) K. Swamy, M. S. Park, S. J. Han,
S. K. Kim, J. H. Kim, C. Lee, H. Bang, Y. Kim, S. J. Kim and
J. Yoon, Tetrahedron, 2005, 61, 10227; (e) G. N. Zbancioc
and I. I. Mangalagiu, Synlett, 2006, 804; (f) M. Vasilescu,
R. Bandula, O. Cramariuc, T. Hukka, H. Lemmetyinen,
pyridazines has been developed. This rapid synthesis paved
the way to construct a diversified pyrrolo[1,2-b]pyridazine
library under mild conditions. This cascade process involves a
Sonogashira coupling reaction, an isomerization to chalcones
and finally an intramolecular condensation. The starting
material, (hetero)aryl propargyl alcohols, can be easily gener-
ated by simple addition of ethynylmagnesium bromide to alde-
hydes. Operational simplicity and high atom economy of this
process should be beneficial for its applications. Further
studies expanding the synthetic scope and the screening for
2576 | Org. Biomol. Chem., 2013, 11, 2574–2577
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
T. T. Rantala and F. Dumitrascu, J. Photochem. Photobiol., A,
2008, 194, 308; (g) G. Zbancioc and I. I. Mangalagiu, Tetra-
J. Organomet. Chem., 2002, 653, 46; (c) E.-I. Negishi and
L. Anastasia, Chem. Rev., 2003, 103, 1979.
hedron, 2010, 66, 278; (h) G. N. Zbancioc, T. Huhn, 11 For the CIR, see, for example: (a) T. J. J. Müller, M. Ansorge
U. Groth, C. Deleanu and I. I. Mangalagiu, Tetrahedron,
2010, 66, 4298.
4 R. L. Letsinger and R. Lasco, J. Org. Chem., 1956, 21, 764.
5 F. Dumitraşcu, M. R. Caira, B. Drăghici, M. T. Căproiu and
D. G. Dumitrescu, Synlett, 2008, 813.
6 A. F. Khlebnikov, E. I. Kostik and R. R. Kostikov, Synthesis,
1993, 568.
7 A. I. Siriwardana, I. Nakamura and Y. Yamamoto, J. Org.
Chem., 2004, 69, 3202.
8 (a) F M. Abdelrazek, Synth. Commun., 2005, 35, 2251;
(b) F M. Abdelrazek, S. A. Ghozlan and F. A. Michael,
J. Heterocycl. Chem., 2007, 44, 63.
9 R. R. Sagyam, R. Buchikonda, J. P. Pitta, H. Vurimidi,
P. R. Padi and M. R. Ghanta, Beilstein J. Org. Chem., 2009,
DOI: 10.3762/bjoc.5.66.
and D. Aktah, Angew. Chem., Int. Ed., 2000, 39, 1253;
(b) R. U. Braun, M. Ansorge and T. J. J. Müller, Chem.–Eur.
J., 2006, 12, 9081; (c) T. J. J. Müller, Adv. Synth. Catal., 2006,
348, 2565.
12 For recent functionalized heterocycles syntheses through
the CIR, see, for example: (a) T. J. J. Müller, R. Braun and
M. Ansorge, Org. Lett., 2000, 2, 1967; (b) R. U. Braun,
K. Zeitler and T. J. J. Müller, Org. Lett., 2000, 2, 4181;
(c) R. U. Braun, K. Zeitler and T. J. J. Müller, Org. Lett.,
2001, 3, 3297; (d) O. G. Dediu, N. A. M. Yehia and
T. J. J. Müller, Z. Naturforsch., B: Chem. Sci., 2004, 59, 443;
(e) O. G. Schramm, n. Dediu, T. Oeser and T. J. J. Müller,
J. Org. Chem., 2006, 71, 3494; (f) W. W. Liao and T. Müller,
Synlett, 2006, 3469; (g) O. G. Schramm and T. J. Müller,
Synlett, 2006, 1841; (h) O. G. Schramm, T. Oeser, M. Kaiser,
R. Brun and T. J. Müller, Synlett, 2008, 359.
10 For the Sonogashira coupling reaction, see, for example:
(a) S. Takahashi, Y. Kuroyama, K. Sonogashira and 13 Y. Wang, C. Tan, X. Zhang, Q. He, Y. Xie and C. Yang,
N. Hagihara, Synthesis, 1980, 627; (b) K. Sonogashira,
Eur. J. Org. Chem., 2012, 2012, 6622.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2574–2577 | 2577