Double N-arylation reaction of polyhalogenated 4,4'-bipyridines. Expedious synthesis of functionalized 2,7-diazacarbazoles

Article abstract of DOI:10.3762/bjoc.8.26

Unusual 2,7-diazacarbazoles were prepared in one step from readily available tetra-halogenated 4,4'-bipyridines by using a double N-arylation reaction in the presence of the Pd-XPhos catalyst system. Moderate to good yields were obtained in this site-sele

Full text of DOI:10.3762/bjoc.8.26

Double N-arylation reaction of polyhalogenated
4,4’-bipyridines. Expedious synthesis of
functionalized 2,7-diazacarbazoles
Mohamed Abboud1,2, Emmanuel Aubert2 and Victor Mamane*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 253–258.
1Structure et Réactivité des Systèmes Moléculaires Complexes
(SRSMC), UMR CNRS-UHP 7565 Nancy Université, BP 70239, Bd
des Aiguillettes, 54506 Vandoeuvre-les-Nancy, France and
2Cristallographie, Résonance Magnétique et Modélisations (CRM2),
UMR CNRS-UHP 7036 Nancy Université, BP 70239, Bd des
Aiguillettes, 54506 Vandoeuvre-les-Nancy, France
doi:10.3762/bjoc.8.26
Received: 25 November 2011
Accepted: 27 January 2012
Published: 14 February 2012
Associate Editor: J. Aubé
Email:
Victor Mamane* - victor.mamane@srsmc.uhp-nancy.fr
© 2012 Abboud et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
4,4’-bipyridine; cross-coupling; crystal packing; diazacarbazole; X-ray
diffraction
Abstract
Unusual 2,7-diazacarbazoles were prepared in one step from readily available tetra-halogenated 4,4’-bipyridines by using a double
N-arylation reaction in the presence of the Pd–XPhos catalyst system. Moderate to good yields were obtained in this site-selective
Buchwald–Hartwig double amination. The functionalization of these tricyclic derivatives was performed by using Pd-catalyzed
cross-coupling reactions such as the Stille and Suzuki couplings. Two compounds were analyzed by X-ray diffraction and show π–π
stacking involving the diazacarbazole moieties and the phenyl rings of functionalized groups.
Introduction
Only a few examples of the preparation of diazacarbazoles have [24]. One example was found in a patent concerning the syn-
been reported [1-5] and up to date no general method is avail- thesis of 3,6-diazacarbazole by using a palladium-catalyzed
able in the literature. However, these diaza analogues of double N-arylation of 4,4’-dichloro-3,3’-bipyridine, itself
carbazoles [6] have shown interesting biological [7-10] and obtained after a long reaction sequence [25-27]. In another
photophysical [11-13] properties and have been used as ligands patent, an intramolecular Buchwald–Hartwig amination [28,29]
in catalysis [14].
was used to generate a 2,7-diazacarbazole derivative in low
yield [30].
The double palladium-catalyzed N-arylation strategy for the
synthesis of carbazoles has been extensively used in the litera- Recently, we reported a one-step preparation of tetrahalo-
ture [15-22]. The methodology was further applied for the genated 4,4’-bipyridines 2 starting from 2,5-dihalopyridines 1
preparation of dithienopyrroles [23] and dibenzothienopyrroles [31]. Herein, we report on the synthesis of functionalized 2,7-
253

Beilstein J. Org. Chem. 2012, 8, 253–258.
diazacarbazoles 3 through the double N-arylation of 2. Consid-
ering compound 2a, the C–Br over C–Cl regioselectivity was
not obvious since under Suzuki conditions with 2 equiv of
4-formylbenzeneboronic acid (4), compound 5, resulting from a
C–Cl functionalization, was obtained as the major product from
a complex mixture (Scheme 1) [32].
Scheme 2: Ligand effect in the double N-arylation of 2a with 6a.
entry 7) whereas no cyclized product was observed with other
electron-deficient anilines 6h–j and carbamate 7 (Figure 1).
Other methods to react 7 with bipyridine 2a were tested without
success, including the use of Cs2CO3 in dioxane [40] instead of
t-BuONa in toluene, and the CuI–DMEDA catalyzed reaction
[41].
Scheme 1: Cross-coupling reactions of bipyridines 2.
Results and Discussion
The efficiency of the double amination reaction of 2a with
4-pentylaniline (6a) was investigated with several ligands in
toluene at 120 °C, and in the presence of Pd2(dba)3 as the
source of metal catalyst (Scheme 2). Ligands such as Xantphos
[33], biaryl monophosphines [34] and t-Bu3P [35] were tested
since they were found to be very effective in the selective C-5
amination of 2-chloro-5-bromopyridines [36,37]. The use of the
chelating Xantphos ligand (L1) led to a poor yield of 3a,
whereas t-Bu3P (L2) and JohnPhos (L3) afforded product 3a
with a moderate yield. The more hindered monophosphine
ligands SPhos (L4) and XPhos (L5) showed good results, with
an optimum yield of 61% achieved with XPhos [38]. The bulk
of the phosphine ligand enhances the stability and the activity of
the catalytic system [39] thus allowing the use of an elevated
temperature (120 °C) necessary for the double N-arylation reac-
tion [20].
Table 1: Double N-arylation of 2a with aromatic amines 6 catalyzed by
a palladium–XPhos complex.a
entry
R
6
3
yield (%)
1
2
3
4
5
6
7
C5H11
OMe
SMe
H
6a
6b
6c
6d
6e
6f
3a
3b
3c
3d
3e
3f
61
55
50
61
56
49
29
Cl
F
Encouraged by these results, we further explored the scope and
limitations of the Pd2(dba)3–XPhos catalyst system (Table 1).
Under the standard conditions summarized in Table 1 (footnote
a), the double N-arylation of 2a with various aromatic amines 6
furnished 2,7-diazacarbazoles 3 with good chemoselectivities.
Moderate to good yields were generally obtained in this reac-
CF3
6g
3g
aGeneral reaction conditions: 2a (0.26 mmol), 6 (0.234 mmol),
Pd2(dba)3 (0.026 mmol), XPhos (0.078 mmol), t-BuONa (0.78 mmol),
toluene (0.2 M), 120 °C, sealed tube.
tion (Table 1, entries 1–6). Aniline 6g bearing an electron with- We then turned our attention to the preparation of
drawing trifluoromethyl group led to a low yield of 3g (Table 1, functionalized diazacarbazoles 3 by means of cross-coupling
254

Beilstein J. Org. Chem. 2012, 8, 253–258.
Figure 1: Unsuccessful substrates in the double N-arylation of 2a.
reactions. Initial experiments with 2,7-diazacarbazole 3a
showed a rather low reactivity of the C–Cl bonds in the 3- and
6-positions. Indeed, the Stille coupling [42] of 3a with 2-tri-
butylstannylpyridine (8) afforded a mixture of mono- and
di-functionalized compounds 9a and 9b in 40% and 33% yields,
respectively. The Suzuki coupling [43] of 3a with boronic acid
4 was less efficient giving only the mono-functionalized com-
pound 10 in 42% yield (Scheme 3) while no conversion was
observed with 4-methylthiobenzene boronic acid.
Scheme 4: Functionalized diazacarbazoles 12a–c from bipyridine 2b.
(Supporting Information File 1). In both compounds the diaza-
carbazole moieties are almost, but not rigorously, planar, as evi-
denced by the dihedral angles between the pyridyl rings
(2.86(9)° for 3b; 2.09(14)° and 3.15(14)° for 12c). Due to steric
hindrance, the methoxyphenyl groups are twisted from the di-
azacarbazole mean plane (dihedral angles of 50.90(4)° for 3b,
59.00(6)° and 48.45(5)° for 12c). On the opposite, the methyl-
sulfanylphenyl groups in 12c are almost coplanar with the di-
azacarbazole moiety (dihedral angles of 2.17(15)°/13.92(11)°
and 8.30(14)°/13.86(11)°).
In both compounds the crystal packing is governed by π–π
stacking, forming infinite columns in which molecules interact
through diazacarbazole moieties (interplanar distances are
3.558 Å for 3b, 3.270 Å and 3.404 Å for 12c). The
methoxyphenyl group is also involved in this π–π interaction in
Scheme 3: Functionalization of diazacarbazole 2a.
Better results were obtained by means of a reverse sequence. 3b (interplanar distance of 3.415 Å) but not in 12c: In this latter
First, the C-2- and C-2’-positions of bipyridine 2b were crystal structure, it contributes to the cohesion of the molecular
functionalized by a selective Suzuki coupling to give the new columns through C–H···π hydrogen bonds (H···π = 2.83 Å)
bipyridine derivatives 11a,b, which underwent the double (Figure 2a). However, in 12c the methylsulfanylphenyl groups
N-arylation to afford 3,6-difunctionalized 2,7-diazacarbazoles are implied in the π–π stacking (interplanar distances of 3.261 Å
12a–c in good overall yields (Scheme 4).
and 3.549 Å). Such neighboring molecular columns interact
through C–H···π,N,O,Cl (3b) or C–H···π,N,O,S (12c) hydrogen
Single crystals of compounds 3b and 12c were obtained from bonds and form infinite channels parallel to the [10] and [100]
evaporation of n-hexane and chloroform solutions, respectively. directions for 3b and 12c, respectively (Figure 2b). The free-
Whereas 3b crystallizes with one molecule per asymmetric unit diameter apertures of these channels are 5.39 Å × 3.52 Å and
in space group C2/c, the more functionalized 12c diaza- 4.87 Å × 2.64 Å for 3b and 12c respectively (i.e., van der Waals
carbazole is described by the less symmetric P−1 space group radii taken into account), large enough to accommodate
with two crystallographically independent molecules n-hexane and chloroform molecules, which are disordered.
255

Beilstein J. Org. Chem. 2012, 8, 253–258.
Figure 2: (a) ORTEP views showing the π–π (dashed lines) and selected C–H···π (dotted-dashed line) interactions in 3b (up) and 12c (down). Atomic
displacement ellipsoids are drawn at the 50% level of probability; all other hydrogen atoms are omitted for clarity. Disordered solvent molecules are
not shown. (b) Space-filling views showing the channels along [010] in 3b (up) and [100] in 12c (down). Disordered solvent molecules occupying
these channels are not shown.
Conclusion
Bruker micrOTOFQ. All reagents were used as received. TLC
In summary, we have described an efficient approach for the was performed on silica gel plates and visualized with an UV
synthesis of uncommon 2,7-diazacarbazoles from readily avail- lamp (254 nm). Chromatography was performed on silica gel
able tetrahalogenated 4,4’-bipyridines. By use of the palladium- (70–230 mesh).
catalyzed double N-arylation of electron-rich anilines as the key
reaction, the diazacarbazoles were regioselectively generated. General procedure for the preparation of 3,6-dichloro-9-
Crystal structure determination shows that these molecules aryl-2,7-diazacarbazole 3a–g. Argon was bubbled into a mix-
interact mainly through π–π stacking. The reported synthesis ture of 2a (100 mg, 0.26 mmol), amine 6 (0.234 mmol),
should widen the use of diazacarbazoles for biological and elec- Pd2(dba)3 (24 mg, 0.026 mmol), XPhos (37 mg, 0.078 mmol),
tronic applications; the easy insertion of substituents of different and NaOt-Bu (75 mg, 0.78 mmol) in toluene (1.5 mL) for
sizes is expected to influence the dominating molecular π–π 15 min. The mixture was then heated at 120 °C in a sealed tube
stacking, which in turn may influence the solid-state properties for 24 h. After cooling, the mixture was filtered through a pad
of the prepared material [44,45].
of silica gel (dichloromethane/ethyl acetate 1/1). The filtrate
was concentrated to give a residue, which was purified by
column chromatography (silica gel: cyclohexane/ethyl acetate)
Experimental
All reactions were performed under an atmosphere of argon in to afford diazacarbazole 3. The spectral and analytical data are
oven-dried glassware. Toluene was distilled over sodium/ given in Supporting Information File 1.
benzophenone and stored over sodium. Melting points
were measured on a Totoli apparatus. Proton and carbon
Supporting Information
NMR spectra were recorded on Bruker AMX-400, AC-200 or
AC-250 Fourier transform spectrometers with an internal
Supporting Information File 1
deuterium lock. Chemical shifts are quoted in parts per
million (ppm) downfield of tetramethylsilane. Coupling
constants J are quoted in Hz. Mass spectra with electronic
impact (MS–EI) were recorded from a Shimadzu QP 2010
apparatus. High resolution mass spectra were recorded from a
Characterization data and NMR spectra of all compounds,
including X-ray structure determination of 3b and 12c.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-26-S1.pdf]
256

Beilstein J. Org. Chem. 2012, 8, 253–258.
23.Koeckelberghs, G.; De Cremer, L.; Vanormelingen, W.; Dehaen, W.;
Verbiest, T.; Persoons, A.; Samyn, C. Tetrahedron 2005, 61, 687.
doi:10.1016/j.tet.2004.10.106
Acknowledgments
This work was supported by CNRS and Nancy Université. The
authors thank Brigitte Fernette for NMR analysis and the
Service Commun de Diffraction X (Nancy Université) for
providing access to crystallographic experimental facilities.
24.Balaji, G.; Valiyaveettil, S. Org. Lett. 2009, 11, 3358.
doi:10.1021/ol901133m
25.Sugita, S.; Kato, E.; Kimura, K. Manufacturing Method of
Nitrogen-Containing Polycyclic Heterocyclic Compound. JP
2008069122, March 27, 2008.
References
26.Sugita, S.; Kato, E. Method for Producing Nitrogen-Containing
Condensed Heterocyclic Compound. JP 2010260815, Nov 18, 2010.
27.Sugita, S.; Kato, E.; Fujisawa, R. Producing Method of Nitrogen
Containing Condensed Heterocyclic Compound. US 20110184176,
July 28, 2011.
1. Smith, A. E.; Clapham, K. M.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B.
Eur. J. Org. Chem. 2008, 1458. doi:10.1002/ejoc.200701156
2. Wallace, M. B.; Scorah, N.; Vu, P. H.; Brown, J. W.; Stafford, J. A.;
Dong, Q. Tetrahedron Lett. 2010, 51, 1739.
doi:10.1016/j.tetlet.2010.01.095
28.Wolfe, J. P.; Wagaw, S.; Marcoux, J.-L.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. doi:10.1021/ar9600650
29.Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. doi:10.1021/ar970282g
30.Bartels, B.; Weinbrenner, S.; Marx, D.; Diefenbach, J.; Dunkern, T.;
Menge, W. M. P. B.; Christiaans, J. A. M. Benzyl-substituted
Tetracyclic Heterocyclic Compounds as PDE5 Inhibitors. WO
2010015589, Feb 11, 2010.
3. Molina, P.; Fresneda, P. M.; Delgado, S. J. Org. Chem. 2003, 68, 489.
doi:10.1021/jo026508x
4. Hostyn, S.; Van Baelen, G.; Lemière, G. L. F.; Maes, B. U. W.
Adv. Synth. Catal. 2008, 350, 2653. doi:10.1002/adsc.200800077
5. Shumaila, A. M. A.; Puranik, V. G.; Kusurkar, R. S. Tetrahedron Lett.
2011, 52, 2661. doi:10.1016/j.tetlet.2011.03.060
6. Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
doi:10.1021/cr020059j
31.Abboud, M.; Mamane, V.; Aubert, E.; Lecomte, C.; Fort, Y.
J. Org. Chem. 2010, 75, 3224. doi:10.1021/jo100152e
32.Abboud, M.; Kadimi, A.; Mamane, V.; Aubert, E.
Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2010, 66, 381.
doi:10.1107/S0108270110024261
7. Bahekar, R. H.; Jain, M. R.; Jadav, P. A.; Goel, A.; Patel, D. N.;
Prajapati, V. M.; Gupta, A. A.; Modi, H.; Patel, P. R.
Bioorg. Med. Chem. 2007, 15, 5950. doi:10.1016/j.bmc.2007.05.075
8. Nguyen, C. H.; Bisagni, E.; Pepin, O.; Pierré, A.; de Cointet, P.
J. Med. Chem. 1987, 30, 1642. doi:10.1021/jm00392a021
9. Arendt, C.; Babin, D.; Bedel, O.; Gouyon, T.; Levit, M.; Mignani, S.;
Moorcroft, N.; Papin, D.; Li, R. Azacarboline Derivatives, Preparation
Thereof, and Therapeutic Use Thereof as Kinase Inhibitors. WO
2009150381, Dec 17, 2009.
33.Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H.
Acc. Chem. Res. 2001, 34, 895. doi:10.1021/ar000060+
34.Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
doi:10.1021/ar800036s
35.Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
doi:10.1002/1521-3773(20021115)41:22<4176::AID-ANIE4176>3.0.CO
;2-U
10.Cook, J. M.; Van Linn, M. L.; Yin, W. Aza-beta-carbolines and Methods
of Using Same. WO 2009143445, Nov 26, 2009.
36.Ji, J.; Li, T.; Bunnelle, W. H. Org. Lett. 2003, 5, 4611.
doi:10.1021/ol0357696
11.Fukuzaki, E. Organic Electroluminescent Element. JP 2009224762,
Oct 1, 2009.
37.Stroup, B. W.; Szklennik, P. V.; Forster, C. J.; Serrano-Wu, M. H.
Org. Lett. 2007, 9, 2039. doi:10.1021/ol070695+
38.The absence of Pd2(dba)3 and ligand led to a complete recovery of
both starting compounds 2a and 6a.
12.Sugita, S. Organic Electroluminescence Device, Display Device and
Lighting Device. JP 2007123392, May 17, 2007.
13.Sekine, N.; Oshiyama, T.; Nishizeki, M.; Katoh, E. Material for Organic
Electroluminescent Device, Display and Illuminating Device. WO
2006100925, Sept 28, 2006.
39.Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 13978. doi:10.1021/ja037932y
14.Palkovits, R.; von Malotki, C.; Baumgarten, M.; Müllen, K.; Baltes, C.;
Antonietti, M.; Kuhn, P.; Weber, J.; Thomas, A.; Schüth, F.
ChemSusChem 2010, 3, 277. doi:10.1002/cssc.200900123
15.Nozaki, K.; Takahashi, K.; Nakano, K.; Hiyama, T.; Tang, H.-Z.;
Fujiki, M.; Yamaguchi, S.; Tamao, K. Angew. Chem., Int. Ed. 2003, 42,
2051. doi:10.1002/anie.200250648
40.Qin, L.; Cui, H.; Zou, D.; Li, J.; Wu, Y.; Zhu, Z.; Wu, Y.
Tetrahedron Lett. 2010, 51, 4445. doi:10.1016/j.tetlet.2010.06.083
41.DMEDA = N, N’-Dimethylethylenediamine. See: Martin, R.; Larsen, C.
H.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 3379.
doi:10.1021/ol7014225
42.Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704.
doi:10.1002/anie.200300638
16.Nakano, K.; Hidehira, Y.; Takahashi, K.; Hiyama, T.; Nozaki, K.
Angew. Chem., Int. Ed. 2005, 44, 7136. doi:10.1002/anie.200502855
17.Kawaguchi, K.; Nakano, K.; Nozaki, K. J. Org. Chem. 2007, 72, 5119.
doi:10.1021/jo070427p
43.Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
doi:10.1021/cr00039a007
44.Park, S.-Y.; Ebihara, M.; Kubota, Y.; Funabiki, K.; Matsui, M. Dye Pigm.
2009, 82, 258. doi:10.1016/j.dyepig.2009.01.014
45.Thomas, R.; Varghese, S.; Kulkarni, G. U. J. Mater. Chem. 2009, 19,
4401. doi:10.1039/b902937k
18.Kuwahara, A.; Nakano, K.; Nozaki, K. J. Org. Chem. 2005, 70, 413.
doi:10.1021/jo048472+
19.Ueno, A.; Kitawaki, T.; Chida, N. Org. Lett. 2008, 10, 1999.
doi:10.1021/ol800602v
20.Kitawaki, T.; Hayashi, Y.; Ueno, A.; Chida, N. Tetrahedron 2006, 62,
6792. doi:10.1016/j.tet.2006.04.087
21.Kitawaki, T.; Hayashi, Y.; Chida, N. Heterocycles 2005, 65, 1561.
doi:10.3987/COM-05-10418
22.Zhou, Y. B.; Verkade, J. G. Adv. Synth. Catal. 2010, 352, 616.
doi:10.1002/adsc.200900846
257

Beilstein J. Org. Chem. 2012, 8, 253–258.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.8.26
258