Highly efficient synthesis and solid-state characterization of 1,2,4,5-tetrakis(alkyl- and arylamino)benzenes and cyclization to their respective benzobis(imidazolium) salts

Article abstract of DOI:10.1021/ol060349c

New synthetic methodology to a variety of 1,2,4,5-tetraaminobenzenes and their corresponding benzobis(imidazolium) salts has been accomplished. Palladium-catalyzed coupling of various 1,2,4,5-tetrabromo- or 1,2,4,5-tetrachlorobenzenes with aryl- or tert-a

Full text of DOI:10.1021/ol060349c

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1831-1834
Highly Efficient Synthesis and
Solid-State Characterization of
1,2,4,5-Tetrakis(alkyl- and
arylamino)benzenes and Cyclization to
Their Respective Benzobis(imidazolium)
Salts
Dimitri M. Khramov, Andrew J. Boydston, and Christopher W. Bielawski*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
bielawski@cm.utexas.edu
Received February 10, 2006
ABSTRACT
New synthetic methodology to a variety of 1,2,4,5-tetraaminobenzenes and their corresponding benzobis(imidazolium) salts has been
accomplished. Palladium-catalyzed coupling of various 1,2,4,5-tetrabromo- or 1,2,4,5-tetrachlorobenzenes with aryl- or tert-alkylamines afforded
the respective tetrakis(N-substituted)aminobenzenes in excellent yields. This enabled comparative solid-state structural analyses of this elusive
class of electron-rich arenes with their oxidized derivatives. The tetraamines were found to undergo formylative cyclization to the corresponding
benzobis(imidazolium) salts in good to excellent yields.
We have recently launched a program on the broad study
and application of benzobis(imidazolium)s and benzobis-
(imidazolylidene)s in organic and organometallic materials
chemistry.1 These difunctional compounds are readily pre-
pared in multigram quantities and in excellent yields via
formylative cyclization of their respective tetraaminoarene
precursors followed by subsequent alkylation with primary
alkyl halides. While modular in many regards, the inherent
limitations of this methodology included incompatibility of
incorporating N-aryl and bulky N-alkyl substituents into the
benzobis(imidazole) nucleus. To overcome these limitations,
we targeted a general and highly efficient synthetic route to
a range of 1,2,4,5-tetrakis(alkyl- and arylamino)benzenes.
Herein, we disclose details on these advances and include a
comparative solid-state study of substituted 1,2,4,5-tetra-
aminobenzenes and their respective 2,5-diamino-1,4-benzo-
quinonediimines. In addition, we describe the cyclization of
the tetraamines to their corresponding benzobis(imidazolium)
salts.
As a general class of highly electron-rich arenes, tetra-
aminobenzenes have seen a rich diversity of chemical
applications. For example, 1,2,4,5-tetraaminobenzene2 (1)
and its oxidized derivative, 2,5-diamino-1,4-benzoquinone-
diimine3 (2), have found great utility in organic, organo-
metallic, and macromolecular chemistry. They have found
(2) (a) Nietzki, R.; Hagenbach, E. Ber. Dtsch. Chem. Ges. 1887, 20,
328. (b) Nietzki, R. Ber. Dtsch. Chem. Ges. 1887, 20, 2114.
(3) (a) Fischer, O.; Hepp, E. Ber. Dtsch. Chem. Ges. 1888, 21, 676.
(b) Kimich, C. Ber. Dtsch. Chem. Ges. 1875, 8, 1026.
(1) (a) Boydston, A. J.; Williams, K. A.; Bielawski, C. W. J. Am. Chem.
Soc. 2005, 127, 12496. (b) Kamplain, J. W.; Bielawski, C. W. Chem.
Commun. 2006, DOI: 10.1039/b518246h.
10.1021/ol060349c CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/04/2006

potential and utility as ditopic ligands in coordination
chemistry,4 as pH-dependent chromophores,5 as difunctional
monomers in the synthesis of main-chain organometallic6
and supramolecular polymers,7 and as π-complexation
partners in supramolecular systems.8
Scheme 1. Synthesis of
1,2,4,5-Tetrakis(tert-butylamino)benzene (4) and Its Related
2,5-Diamino-1,4-benzoquinonediimine (5)
While 19 is commercially available (as its tetrahydrochlo-
ride salt), access to its N,N′,N′′,N′′′-tetra(alkyl and aryl)
derivatives remains synthetically challenging due to the high
propensity of these electron-rich arenes to oxidize during
isolation. For example, Braunstein obtained a variety of
N,N′,N′′,N′′′-tetraalkyl-2,5-diamino-1,4-benzoquinonedi-
imines by reducing their respective 1,2,4,5-tetraamido-
benzenes under aerobic conditions.4h,5 More recently, in a
breakthrough report by Harlan,10 exhaustive Buchwald-
Hartwig11 Pd-catalyzed amination of 1,2,4,5-tetrabromo-
benzene with 2,6-dimethylaniline provided mixtures of the
respective tetrakis(arylamino)benzene and azophenine in a
promising 26% yield.12 We envisioned that the incorporation
of large N-substituents could slow down (or even eliminate)
undesired oxidative pathways and facilitate isolation of the
targeted tetraamines.
HCl13 (IPr‚HCl):Pd(OAc)214 (2:1 stoichiometry; 2 mol % Pd
catalyst relative to 3) as the catalyst precursor.15 Surprisingly,
after less than 2 h at 110 °C, a colorless solid precipitated
from the reaction solution, which was subsequently isolated
in 96% yield via filtration under a cone of nitrogen.16 The
1H NMR spectrum of this compound exhibited a single,
diagnostic signal at δ 6.53 ppm (solvent ) CDCl3), which
was indicative of a highly symmetric structure consistent with
the desired 1,2,4,5-tetrakis(tert-butylamino)benzene (4). To
confirm, a crystal suitable for X-ray crystallography was
obtained by slow cooling of a hot saturated solution of 4 in
toluene; an ORTEP diagram of the corresponding structure
is shown in Figure 1 (left). Notably, the four nitrogen atoms
Inspired by Harlan’s report,10 we examined the Pd-
catalyzed cross coupling of tert-butylamine (t-BuNH2) with
1,2,4,5-tetrabromobenzene (3) under basic conditions as
shown in Scheme 1. The reaction was performed in toluene
(0.2 M) with 1,3-bis(2,6-diisopropylphenyl)imidazolylidene‚
(4) (a) Shimakoshi, H.; Hirose, S.; Ohba, M.; Shiga, T.; Okawa, H.;
Hisaeda, Y. Bull. Chem. Soc. Jpn. 2005, 78, 1040. (b) Frantz, S.; Rall, J.;
Hartenback, I.; Scheid, T.; Zalis, S.; Kaim, W. Chem. Eur. J. 2004, 10,
149. (c) Haas, Y.; Zilberg, S. J. Am. Chem. Soc. 2004, 126, 8991. (d) Groselj,
U.; Bevk, D.; Jakse, R.; Meden, A.; Pirc, S.; Recnik, S.; Stanovnik, B.;
Svete, J. Tetrahedron: Asymmetry 2004, 15, 2367. (e) Beckmann, U.; Bill,
E.; Weyhermueller, T.; Wieghardt, K. Inorg. Chem. 2003, 42, 1045. (f)
Gordon-Wylie, S. W.; Blanton, W. B.; Claus, B. L.; Horwitz, C. P.; Collins,
T. J.; Boskovic, C.; Christou, G. Inorg. Synth. 2002, 33, 1. (g) Chichak,
K.; Jacquemard, U.; Branda, N. R. Eur. J. Inorg. Chem. 2002, 2, 357. (h)
Siri, O.; Braunstein, P. Chem. Commun. 2000, 22, 2223. (i) Masui, H.;
Freda, A. L.; Zerner, M. C.; Lever, A. B. P. Inorg. Chem. 2000, 39, 141.
(j) Aukauloo, A.; Ottenwaelder, X.; Ruiz, R.; Poussereau, S.; Pei, Y.;
Journaux, Y.; Fleurat, P.; Volatron, F.; Cervera, B.; Munoz, M. C. Eur. J.
Inorg. Chem. 1999, 7, 1067. (k) Gordon-Wylie, S. W.; Claus, B. L.; Horwitz,
C. P.; Leychkis, Y.; Workman, J.; Marzec, A. J.; Clark, G. R.; Rickard, C.
E. F.; Conklin, B. J.; Sellers, S.; Yee, G. T.; Collins, T. J. Chem. Eur. J.
1998, 4, 2173. (l) Rall, J.; Stange, A. F.; Hubler, K.; Kaim, W. Angew.
Chem., Int. Ed. 1998, 37, 2681. (m) Espenson, J. H.; Kirker, G. W. Inorg.
Chim. Acta 1980, 40, 105. (n) Merrell, P. H.; Maheu, L. J. Inorg. Chim.
Acta 1978, 28, 47. (o) Hasty, E. F.; Colburn, T. J.; Hendrickson, D. N.
Inorg. Chem. 1973, 12, 2414.
Figure 1. ORTEP representations of the X-ray crystal structures
of 1,2,4,5-tetrakis(tert-butylamino)benzene (4) (left) and N,N′,N′′,N′′′-
tetrakis(tert-butyl)-2,5-diamino-1,4-benzoquinonediimine (5) (right),
showing non-hydrogen atoms as 50% thermal ellipsoids.18
were found to be coplanar with nearly equivalent N-C
(1.43-1.44 Å) and aryl C-C (1.39-1.41 Å) bond distances.
In addition, the tert-butyl groups on the nitrogen atoms were
(11) (a) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetra-
hedron 2002, 58, 2041. (b) Wolfe, J. P.; Wagaw, S.; Marcox, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (c) Hartwig, J. F. Angew.
Chem., Int. Ed. 1998, 37, 2046. (d) Louie, J.; Hartwig, J. F. Tetrahedron
Lett. 1995, 36, 3609.
(5) (a) Elhabiri, M.; Siri, O.; Sornosa-tent, A.; Albrecht-Gary, A.-M.;
Braunstein, P. Chem. Eur. J. 2004, 10, 134. (b) Siri, O.; Braunstein, P.;
Rohmer, M.-M.; Benard, M.; Welter, R. J. Am. Chem. Soc. 2003, 125,
13793.
(6) Archer, R. D.; Illingsworth, M. L.; Rau, D. N.; Hardiman, C. J.
Macromolecules 1985, 18, 1371.
(7) Kleij, A. W.; Kuil, M.; Tooke, D. M.; Lutz, M.; Spek, A. L.; Reek,
J. N. H. Chem. Eur. J. 2005, 11, 4743.
(12) In a related example, Pd-catalyzed aryl amination was used to
synthesize 1,2,4,5-tetra(morpholino)benzene in 76% yield via coupling of
1,2,4,5-tetrabromobenzene with morpholine, see: Witulski, B.; Senft, S.;
Thum, A. Synlett 1998, 504.
(8) Staab, H. E.; Elbl-Weiser, K.; Krieger, C. Eur. J. Org. Chem. 2000,
2, 327.
(9) Ruggli, P.; Fischer, R. HelV. Chim. Acta 1945, 28, 1270.
(10) Wenderski, T.; Light, K. M.; Ogrin, D.; Bott, S. G.; Harlan, C. J.
Tetrahedron Lett. 2004, 45, 6851.
(13) (a) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang, C.;
Nolan, S. P. J. Organomet. Chem. 2002, 653, 69. (b) The use of 1,3-bis-
(2,6-diisopropylphenyl)imidazolinylidene‚HCl (H2IPr‚HCl) in lieu of IPr‚
HCl afforded comparable results.
(14) PdCl2 was found to be equally effective as Pd(OAc)2.
1832
Org. Lett., Vol. 8, No. 9, 2006

situated above and below the plane of the arene ring with
dihedral angles of 100-110°.
Table 1. Synthesis of 1,2,4,5-Tetrakis(alkyl- and
arylamino)benzenesa
To compare 4 directly with its corresponding 2,5-diamino-
1,4-benzoquinonediimine, the tetraamine was dissolved in
CHCl3 and stirred under an atmosphere of oxygen at room
1
temperature.17 The H NMR spectrum (solvent ) CDCl3)
of this compound exhibited a signal at δ 5.53 ppm that was
consistent4h,5,10 with quinoid-derivative 5 (Scheme 1). Crys-
tals of 5 suitable for X-ray analysis were also obtained, which
allowed for direct comparison of the related species. As
shown in Figure 1 (right), the ORTEP diagram of 5 exhibited
not only coplanar tert-butyl groups (with dihedral angles of
175-179°), but also varied N-C (N1-C1, 1.35 Å and N2-
C2, 1.29 Å) and quinone C-C (1.51, 1.37, and 1.44 Å) bond
lengths. This type of bonding pattern has been previously
described and is fully consistent with related azophenine
solid-state structures.4h,5,10 To our knowledge, this is the first
example of a crystalline 1,2,4,5-tetrakis(alkylamino)benzene
and a direct comparison with its oxidized derivative. More
importantly, the collective data suggested that the syn-
thetic methodology detailed above was successful in prepar-
ing and isolating bona fide N,N′,N′′,N′′′-tetraalkyl-1,2,4,5-
tetraaminobenzenes.
tetrahalobenzene
entry
X
R
amine
tBuNH2
AdNH2
PhNH2
MesNH2
2-MeOPhNH2
tBuNH2
tBuNH2
product yield, %
1
2
3
4
5
6
7
Br
Br
Br
Br
Br
Br
Cl
H
H
H
H
H
4
96
90
76
94
96
99
94
6
7
8
10
11
4
Me
H
a General reaction conditions: IPr‚HCl (0.04 equiv); Pd(OAc)2 (0.02
equiv); NaOtBu (4.1 equiv); RNH2 (4.1-10 equiv); solvent ) toluene,
temperature ) 110 °C. Isolated yields are indicated. tBuNH2 ) tert-
butylamine; AdNH2 ) 1-adamantylamine; PhNH2 ) aniline; MesNH2 )
2,4,6-trimethylaniline; 2-MeOPhNH2 ) o-anisidine.
Prompted by these results and using the protocol described
above, a variety of other amines were probed for their ability
to couple with 3. As expected, the coupling of 1-adamantyl-
amine (AdNH2) with 3 afforded similar results as tBuNH2
(90% yield; Table 1, entry 2). Arylamines including aniline,
relatively bulky mesitylamine,19 and electron-rich o-anisidine
were also found to successfully couple to 3 in excellent yields
(entries 3-5). Unfortunately, primary (e.g., 1-butylamine),
secondary (e.g., cyclohexylamine), or electron-deficient aryl-
amines (e.g., nitro- and chloroanilines) either resulted in no
reaction or afforded complex product mixtures.20 It is
noteworthy that cross-coupling of 2,3,5,6-tetrabromo-p-
xylene and 1,2,4,5-tetrachlorobenzene with tBuNH2 afforded
the corresponding tetraamines in 99% and 94% yields,
respectively (entries 6 and 7). The former result suggested
that the bulky IPr-ligated Pd catalyst was not impeded by
the presence of steric bulk ortho to both sites of amination
and the latter was a testament to the high activity of this
catalyst system.
After the 1,2,4,5-tetrakis(alkyl- and arylamino)benzenes
were synthesized, their relative susceptibilities toward oxida-
tion were qualitatively investigated.21 The amines were
independently dissolved in aerated CDCl3 and examined by
1H NMR spectroscopy periodically over time. In general,
the 1,2,4,5-tetrakis(alkylamino)benzenes were found to oxi-
dize slower (τ1/2 ∼ days) than their N-aryl analogues (τ1/2
∼
hours). However, the electron-rich N-anisidyl derivative 10
was exceptional and was found to exhibit stability compa-
rable to that of the N-alkyl derivatives (4 and 6). The most
stable tetraamine was the xylene derivative 11, which resisted
oxidation even after dissolution in aerated solvents for several
weeks. These results may be rationalized by examining
individual steric and electronic contributors which may
kinetically and/or thermodynamically inhibit nitrogenyl
formation.22
(15) Aside from IPr and H2IPr, a variety of other ligands for Pd including
bulky phosphines (PCy3, rac-BINAP, PtBu3) and imidazolylidenes (1,3-
bis(2,6-di-tert-butyl)imidazolylidene, 1,3-bis(2,6-dimesityl)imidazolylidene)
were screened, but did not afford appreciable yields of product.
(16) Residual inorganic salts were removed by filtering chloroform
solutions of the tetraaminobenzenes followed by evaporation.
(17) Use of an oxygen atmosphere effects azophenine formation more
rapidly than use of aerated solvents.
(18) Selected bond lengths (Å) and angles (deg): For 4: N1-C1,
1.429(2); N2-C2, 1.441(2); C1-C2, 1.411(2); C2-C3, 1.394(2); C1-C3A,
1.394(2); C2-C1-N1, 121.1(1); C1-C2-N2, 119.6(1); C2-C1-N1-C4,
109.8(1); C1-C2-N2-C8, 99.8(2). For 5: N1-C1, 1.349(1); N2-C2,
1.294(1); C1-C2, 1.513(1); C1-C3A, 1.367(1); C2-C3, 1.437(1); N1-
C1-C2, 113.0(1); N2-C2-C1, 113.9(1); C4-N1-C1-C2, 175.1(1); C1-
C2-N2-C8, 179.3(1).
(19) A solution to the crystal structure of 1,2,4,5-tetrakis(mesitylamino)-
benzene (8) was also determined; key bond distances (Å) and angles
(deg): N1-C1, 1.413(2); N2-C3, 1.424(2); C1-C2, 1.391(2); C2-C3,
1.398(2); C1-C3A, 1.404(2); C3A-C1-N1, 118.9(1); C1A-C3-N2,
118.5(1); C4-N1-C1-C3A, 173.9(2); C1A-C3-N2-C13, 172.9(2).
Using the procedure described in the text, the corresponding azophenine
(9) was synthesized and a solution to its corresponding crystal structure
was determined; key bond lengths (Å) and angles (deg): N1-C1, 1.293(2);
N2-C3, 1.357(2); C1-C2, 1.440(2); C2-C3, 1.356(2); C1-C3A, 1.494(2);
N1-C1-C3A, 115.6(1); N2-C3-C1A, 114.2(1); C3A-C1-N1-C4,
176.9(1); C1A-C3-N2-C13, 171.3(1). See the Supporting Information
for additional details.
In an attempt to prepare partially aminated arenes, a Pd-
catalyzed cross-coupling reaction was performed with 2
molar equiv of tBuNH2 relative to 1,2,4,5-tetrabromobenzene.
To our surprise, only the tetraaminated product (4) and
unreacted starting materials were observed, even in crude
reaction mixtures. In fact, identical results were obtained
when substoichiometic amounts of tBuNH2 or AdNH2 were
used, which suggested that reactivity enhancements were
occurring upon subsequent aminations. In contrast, the use
(21) Oxidative susceptibilities of the 1,2,4,5-tetraminobenzenes can be
greatly reduced through protonation with HCl prior to isolation.
(22) For discussions comparing relative stabilites of electron deficient
arylamines, see: (a) Li, Z.; Cheng, J.-P. J. Org. Chem. 2002, 68, 7350. (b)
Kemnitz, C. R.; Karney, W. L.; Borden, W. T. J. Am. Chem. Soc. 1998,
120, 3499. (c) Miura, Y.; Kitagishi, Y.; Ueno, S. Bull. Chem. Soc. Jpn.
1994, 67, 3282.
(20) Efforts toward optimizing these reactions are underway.
Org. Lett., Vol. 8, No. 9, 2006
1833

of aniline as a coupling partner in the Pd-catalyzed reaction
afforded a complex mixture of aminated products.23
were sluggish (reaction time: 24 h), good to excellent yields
of product were obtained.28 Notably, the electron-rich N-
anisidyl substrate 10 underwent clean cyclization to afford
product in only 2 h (92% yield). Unfortunately, mesitylated
derivatives 8 and 13 were reluctant to undergo cyclization
under these conditions.
In summary, we have developed an efficient synthetic and
isolation protocol for preparing 1,2,4,5-tetrakis(alkyl- and
arylamino)benzenes, two elusive classes of electron-rich
arenes. Their structures were unambiguously proven with
X-ray crystallography and compared with their oxidized
derivatives. Immediate efforts will concentrate on expanding
the substrate scope of this reaction and elucidating its unique
substitution pattern. The tetraamines were successfully
cyclized to give the desired bis(azolium) compounds in good
to excellent yields. Currently we are also investigating
applications of bis(azolium) salts for direct formation of
nonchelating bis(carbene)s and their respective bimetallic
complexes.29
Thus far we have demonstrated that various tetrakis(alkyl-
and arylamino)arenes can be prepared via aryl amination
from their corresponding tetrahaloarene. However, in situ-
ations when the requisite polyhalogenated arenes are not
readily available (e.g., 3,3′,4,4′-tetrachlorobiphenyl24), a
complementary route to the respective tetrakis(amino)arenes
would be desirable. As shown in Scheme 2, mesityl bromide
Scheme 2. Synthesis of
N,N′,N′′,N′′′-Tetramesityl-3,3′-diaminobenzidine
Acknowledgment. We are grateful to the U.S. Army
Research Office (W911NF-05-1-0430) and the University
of Texas at Austin for generously supporting this work.
was coupled to commericially available 3,3′-diaminobenz-
idine 12 with use of the catalyst system and conditions
discussed above to afford the corresponding N,N′,N′′,N′′′-
tetramesityl-3,3′-diaminobenzidine (13) in 47% yield (Scheme
2).25
With the tetraamines in hand, we were poised to prepare
the corresponding N-aryl and N-alkyl benzobis(imidazolium)
salts through a formylative cyclization methodology.26 As
shown in Scheme 3, ring closure was effected by subjecting
Supporting Information Available: Detailed experi-
mental procedures, characterization of all new compounds,
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL060349C
(23) The mechanistic implications of these findings are currently under
investigation in our laboratories.
(24) Lehmler, H.-J.; Robertson, L. W.; Kania-Korwel, I. Chemosphere
2004, 56, 735.
Scheme 3. Cyclization of 1,2,4,5-Tetraaminobenzenes to
(25) The aryl amination reaction was determined to be quantitative by
1H NMR spectroscopy; however, the isolation of 13 was challenged by its
high solubility in common solvents.
Their Respective Benzobis(imidazolium) Salts
(26) A similar approach utilizing aryl amination of 1,2-dibromobenzene
followed by cyclization has been reported: Rivas, R. M.; Riaz, U.; Giessart,
A.; Smulik, J. A.; Diver, S. T. Org. Lett. 2001, 3, 2673. For syntheses of
related benzimidazolium and benzimidazolylidene compounds, see: (a)
Huynh, H. V.; Holtgrewe, C.; Pape, T.; Koh, L. L.; Hahn, F. E.
Organometallics 2006, 25, 245. (b) Hahn, F. E.; Jahnke, M. C.; Gomez-
Benitez, V.; Morales-Morales, D.; Pape, T. Organometallics 2005, 24, 6458.
(c) Hahn, F. E.; Wittenbecher, L.; Le Van, D.; Frohlich, R. Angew. Chem.,
Int. Ed. 2000, 39, 541.
(27) Shorter reaction times were observed with HBF4, which may be
related to the higher solubilities of bis(benzobisimidazolium) tetrafluoro-
borate salts as compared to their analogous chloride salts.
(28) The overall yield of 16 from 1,2,4,5-tetrabromobenzene was
improved to 84% by using a one-pot, two-step procedure. See the Supporting
Information for additional details.
the tetraamines noted above to acidified (HCl or HBF4)27
HC(OEt)3 solutions at elevated temperatures (the N-alkylated
derivatives 4 and 6 required 65 °C whereas the N-arylated
derivatives 7 and 10 required 140 °C). Although cyclizations
(29) Khramov, D. M.; Boydston, A. J.; Bielawski, C. W. Manuscript in
preparation.
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Org. Lett., Vol. 8, No. 9, 2006