Iptycene-Derived pyridazines and phthalazines

Article abstract of DOI:10.1021/jo702000d

(Chemical Equation Presented) The synthesis of new heterocyclic oligo(phenylene) analogues based on soluble, nonaggregating 1,2-diazines is reported. Improved palladium-catalyzed reductive coupling methods were developed to allow for the preparation of la

Full text of DOI:10.1021/jo702000d

Iptycene-Derived Pyridazines and Phthalazines
Jean Bouffard, Robert F. Eaton,† Peter Mu¨ller, and Timothy M. Swager*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts AVenue, Cambridge,
Massachusetts 02139
tswager@mit.edu
ReceiVed September 12, 2007
The synthesis of new heterocyclic oligo(phenylene) analogues based on soluble, nonaggregating 1,2-
diazines is reported. Improved palladium-catalyzed reductive coupling methods were developed to allow
for the preparation of large quantities of iptycene-derived bipyridazines and biphthalazines, and the
controlled synthesis of well-defined oligomers up to sexipyridazine. Crystallographic, spectroscopic, and
computational evidence indicate that in these analogues, hindrance at the ortho position is relaxed relative
to poly(phenylenes). The resulting building blocks are promising for incorporation in conjugated electronics
materials, and as new iptycene-derived ligands for transition metals.
Introduction
have been prepared and explored for materials applications.
Iptycene-derived thiophenes and pyrroles have been incorporated
in conjugated polymers,7 porphyrins,8 phthalocyanines,9 and
related macrocycles.10 Iptycene-derived pyridines have also been
reported11 but, to the best of our knowledge, have yet to be
Molecules of the iptycene family, as exemplified by their
simplest member triptycene, have been the object of much
interest by numerous research groups, including our own. In
particular, iptycenes have been incorporated in organic materials
and polymers for applications that include conjugated polymer
sensors,1 high mechanical performance polymers,2 liquid crys-
tals,3 low-κ dielectrics,4 gas absorption/storage,5 and host-guest
chemistry.6 In the bulk of these examples, the introduction of
molecular voids, or internal free volume, has been proposed to
be at the origin of the exceptional materials properties. By
contrast, only a few heterocyclic members of the iptycene family
(7) (a) Williams, V. E.; Swager, T. M. Macromomecules 2000, 33, 4069-
4073. (b) Tsai, Y. C.; Davis, J.; Compton, R. G.; Ito, S.; Ono, N.
Electroanalysis 2001, 13, 7-12 and references therein.
(8) (a) Uno, H.; Watanabe, H.; Yamashita, Y.; Ono, N. Org. Biomol.
Chem. 2005, 3, 448-453. (b) Schwenninger, R.; Scho¨gl, J.; Maynollo, J.;
Gruber, K.; Ochsenbein, P.; Bu¨rgi, H.-B.; Konrat, R.; Kra¨utler, B. Chem.
Eur. J. 2001, 7, 2676-2686. (c) Schwenninger, R.; Ramondenc, Y.; Wurst,
K.; Scho¨gl, J.; Kra¨utler, B. Chem. Eur. J. 2000, 6, 1214-1223. (d)
Ramondenc, Y.; Schwenninger, R.; Phan, T.; Gruber, K.; Kratky, C.;
Kra¨utler, B. Angew. Chem. Ind. Ed. 1994, 33, 889-891.
(9) (a) Oliver, S. W.; Smith, T. D. J. Chem. Soc. Perkin Trans. II 1987,
1579-1582. (b) Kopranenkov, V. N.; Rumyantseva, G. I.; Luk’yanets, E.
A. Zh. Obshch. Khim. 1972, 42, 2586. (c) Kopranenkov, V. N.; Rumyant-
seva, G. I. Zh. Obshch. Khim. 1975, 45, 1555-1559. (d) Gal’pern, M. A.;
Shalaev, V. K.; Shatsskaya, T. A.; Shishkanova, L. S.; Skvarchenko, V.
R.; Luk’yanets, E. A. Zh. Obshch. Khim. 1983, 53, 2601-2606. (e)
Shatskaya, T. A.; Gal’pern, M. G.; Skvarchenko, V. R.; Luk’yanets, E. A.
Zh. Obshch. Khim. 1986, 56, 392-397.
† Deceased.
(1) (a) Yang, J.-S.; Swager, T. M. J. Am. Chem. Soc. 1998, 120, 5321-
5322. (b) (a) Yang, J.-S.; Swager, T. M. J. Am. Chem. Soc. 1998, 120,
11864-11873.
(2) (a) Tsui, N. T; Paraskos, A. J.; Torun, L.; Swager, T. M.; Thomas,
E. L. Macromolecules 2006, 39, 3350-3358. (b) Tsui, N. T.; Torun, L.;
Pate, B. D.; Paraskos, A. J.; Swager, T. M.; Thomas, E. L. AdV. Funct.
Mater. 2007, 17, 1595-1602.
(3) (a) Long, T. M.; Swager, T. M. J. Mater. Chem. 2002, 12, 3407-
3412. (b) Norvez, S. J. Org. Chem. 1993, 58, 2414-2418.
(4) Long, T. M.; Swager, T. M. J. Am. Chem. Soc. 2003, 125, 14113-
14119.
(5) Ghanem, B. S.; Msayib, K. J.; McKeown, N. B.; Harris, K. D. M.;
Pan, Z.; Budd, P. M.; Butler, A.; Selbie, J.; Book, D.; Walton, A. Chem.
Commun. 2007, 67-69.
(6) (a) Han, T.; Zong, Q.-S.; Chen, C.-F. J. Org. Chem. 2007, 72, 3108-
3111. (b) Peng, X.-X.; Lu, H.-Y.; Han, T.; Chen, C.-F. Org. Lett. 2007, 9,
895-898 and references therein.
(10) (a) Tome´, J. P. C.; Cho, D.-G.; Sessler, J. L.; Neves, M. G. P. M.
S.; Tome´, A. C.; Silva, A. M. S.; Cavaleiro, J. A. S. Tetrahedron Lett.
2006, 47, 3131-3134. (b) Silva, A. M. G.; Tome´, A. C.; Neves, M. G. P.
M. S.; Cavaleiro, J. A. S.; Kappe, C. O. Tetrahedron Lett. 2005, 46, 4723-
4726.
(11) (a) Skvarchenko, V. R.; Koshkina, N. P. Zh. Org. Khim. 1979, 15,
2367-2370. (b) Skvarchenko, V. R.; Koshkina, N. P.; Abramov, A. V. Zh.
Org. Khim. 1981, 17, 1018-1023. (c) Skcarchenko, V. R.; Koshkina, N.
P. Zh. Org. Khim. 1982, 17, 2410-2414. (d) Skvarchenko, V. R.; Lapteva,
V. L.; Gorbunova, M. A. Zh. Org. Khim. 1990, 26, 2588-2590.
10.1021/jo702000d CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/15/2007
10166
J. Org. Chem. 2007, 72, 10166-10180

Iptycene-DeriVed Pyridazines and Phthalazines
SCHEME 1
elaborated into larger functional molecules or assemblies. We
are aware of three reports of iptycene-derived pyridazines,12 but
details regarding their preparation, characterization, and proper-
ties are scarce. In this paper, we present the synthesis and
characterization of iptycene-derived pyridazines and phthala-
zines, and their elaboration into building blocks for materials
applications.
coordination sites of the heterocyclic nitrogen atoms17 for the
preparation of metal-containing materials and polymers, with a
special interest for design of phosphorescent conjugated poly-
mers for lighting and sensing applications.18,19
Synthesis of Iptycene-Derived Pyridazines. Our initial
synthetic approach focused on the Diels-Alder cycloaddition
between anthracene and dimethylacetylene dicarboxylate
(DMAD),20 followed by treatment with hydrazine and halogena-
tion with a phosphorus(V) halide. However, as indicated in a
previous report,21 treatment of the adduct 1a with hydrazine
under various reaction conditions exclusively afforded the
reduced 5-membered N-aminoimide 7 (Scheme 2). Following
the procedure of Mizzoni and Spoerri,22 reaction of the bicyclic
maleic anhydride 3a, obtained from the adduct 1a after
saponification with sodium hydroxide and dehydration with
oxalyl chloride, with hydrazine monohydrochloride in refluxing
acetic acid afforded the desired 6-membered cyclic hydrazide
4a in excellent yields. Treatment with neat phosphorus oxy-
chloride or molten phosphorus oxybromide afforded the diha-
lides 5a,d in good yields. Due to the high cost of phosphorus
oxybromide and the requirement of several equivalents of the
reagent for a reaction in the melt, large-scale preparation of the
dibromide may benefit from the alternate use of phosphorus
Results and Discussion
Design Considerations. Our interest in the development of
1,2-diazine-derived building blocks for materials applications
spawned from three principal design considerations. First,
electron-poor building blocks can confer a number of attractive
characteristics, including resistance to photooxidation13 and a
lowered barrier to electron injection (n-doping),14 which can
translate to devices operating at lower voltages and with
extended lifetimes. Second, as part of a long-standing interest
toward the control of conformation in conjugated polymers,15
we hypothesized that when compared to the analogous poly-
(phenylene)s bearing hydrogens in ortho positions, poly(1,2-
diazine)s would exhibit less steric hindrance and would favor,
with potential hydrogen bonding, planarization and therefore
more extended π-conjugation16 (Scheme 1). Consequently,
iptycene-derived poly(1,2-diazine)s could exhibit a fully copla-
nar conjugated backbone, yet remain soluble due to the limited
propensity of iptycene-derived molecules to aggregate and
π-stack in the solid state. Third and finally, we can exploit the
pentoxide and tetra-n-butylammonium bromide in toluene,23
a
(17) For examples of pyridazine-based metal complexes: (a) Plasseraud,
L.; Maid, H.; Hampel, F.; Saalfrank, R. W. Chem. Eur. J. 2001, 7, 4007-
4011. (b) Slater, J. W.; Lyndon, D. P.; Alcock, N. W.; Rourke, J. P.
Organometallics 2001, 20, 4418-4423. (c) Marquis, A.; Kintzinger, J.-P.;
Graff, R.; Baxter, P. N.; Lehn, J.-M. Angew. Chem., Ind. Ed. 2002, 41,
2760-2764 and references cited therein.
(18) (a) Thomas, S. W., III; Venkatesan, K.; Mu¨ller, P.; Swager, T. M.
J. Am. Chem. Soc. 2006, 128, 16641-16648. (b) Thomas, S. W., III; Yagi,
S.; Swager, T. M. J. Mater. Chem. 2005, 15, 2829-2835. (c) Sandee, A.
J.; Williams, C. K.; Evans, N. R.; Davies, J. E.; Boothby, C. E.; Ko¨hler,
A.; Friend, R. H.; Holmes, A. B. J. Am. Chem. Soc. 2004, 126, 7041-
7048. (d) Liu, S.-J.; Zhao, Q.; Deng, Y.; Xia, Y.-J.; Lin, J.; Fan, Q.-L.;
Wang, L.-H.; Huang, W. J. Phys. Chem. C 2007, 111, 1166-1175. (e)
Zhang, M.; Lu, P.; Wang, X.; He, L.; Xia, H.; Zhang, W.; Yang, B.; Liu,
L.; Yang, L.; Yang, M.; Ma, Y.; Feng, J.; Wang, J.; Tamai, N. J. Phys.
Chem. B 2004, 108, 13185-13190. (f) Chen, X.; Liao, J.-L.; Liang, Y.;
Ahmed, M. O.; Tseng, H.-E.; Chen, S.-A. J. Am. Chem. Soc. 2003, 125,
636-637.
(12) (a) Becker, H.; Ho, P. T.; Kolb, H. C.; Loren, S.; Norrby, P.-O.;
Sharpless, K. B. Tetrahedron Lett. 1994, 35(40), 7315-7318. (b) Gorgues,
A.; Le Coq, A. J. Chem. Soc. Chem. Commun. 1979, 767-768. (c)
Baumgartner, P.; Hugel. G. Bull. Soc. Chim. Fr. 1954, 1005-1011.
(13) (a) Kim, Y.; Swager, T. M. Chem. Commun. 2005, 372-374. (b)
Lux, A.; Holmes, A. B.; Cervini, R.; Davies, J. E.; Moratti, S. C.; Gru¨ner,
J.; Cacialli, F.; Friend, R. H. Synth. Met. 1997, 84, 293-294.
(14) For reviews: (a) Hughes, G.; Bryce, M. R. J. Mater. Chem. 2005,
94-107. (b) Newman, C. R.; Frisbie, C. D.; da Silva Filho, D. A.; Bre´das,
J.-L.; Ewbank, P. C.; Mann, K. R. Chem. Mater. 2004, 16, 4436-4451.
(c) Kraft, A.; Grimsdale, A. C.; Holmes, A. B. Angew. Chem., Int. Ed.
1998, 37, 402-428. Recent examples: (d) Yoon, M.-H.; Facchetti, A.; Stern,
C. E.; Marks, T. J. J. Am. Chem. Soc. 2006, 128, 5792-5801. (e) Facchetti,
A.; Mushrush, M.; Yoon, M.-H.; Hutchison, G. R.; Ratner, M. A.; Marks,
T. J. J. Am. Chem. Soc. 2004, 126, 13859-13874.
(19) Phosphorescent cyclometalated (C^N) transition metal complexes
derived from the building blocks described in this paper will be reported
elsewhere.
(20) (a) Okamoto, I.; Ohwada, T.; Shudo, K. J. Org. Chem. 1996, 61,
3155-3166. (b) Smet, M.; Corens, D.; van Meervelt, L.; Dehaen, W.
Molecules 2000, 5, 179-181.
(15) (a) Nesterov, E. E.; Zhu, Z.; Swager, T. M. J. Am. Chem. Soc. 2005,
127, 10083-10088. (b) Zhu, Z.; Swager, T. M. J. Am. Chem. Soc. 2002,
124, 9670-9671. (c) Kim, J.; Levitsky, I. A.; McQuade, D. T.; Swager, T.
M. J. Am. Chem. Soc. 2002, 124, 7710-7718. (d) Kim, J.; Swager, T. M.
Nature 2001, 401, 1030-1034.
(16) (a) Cuccia, L. A.; Lehn, J.-M.; Homo, J.-C.; Schmutz, M. Angew.
Chem., Int. Ed. 2000, 39, 233-237. (b) Ohkita, M.; Lehn, J.-M.; Baum,
G.; Fenske, D. Chem. Eur. J. 1999, 5, 3471-3481. (c) Howard, S. T. J.
Am. Chem. Soc. 1996, 118, 10269-10274. (d) Yasuda, T.; Sakai, Y.;
Aramaki, S.; Yamamoto, T. Chem. Mater. 2005, 17, 6060-6068.
(21) Chatuvedi, J.; Verma, S. M. Indian J. Chem. Sect. B 1990, 29, 9-13.
(22) (a) Mizzoni, R. H.; Spoerri, P. E. J. Am. Chem. Soc. 1951, 73, 1873-
1874. (b) Mizzoni, R. H.; Spoerri, P. E. J. Am. Chem. Soc. 1954, 76, 2201-
2203.
(23) (a) Song, Z. J.; Zhao, M.; Desmond, R.; Devine, P.; Tschaen, D.
M.; Tillyer, R.; Frey, L.; Heid, R.; Xu, F.; Foster, B.; Li, J.; Reamer, R.;
Volante, R.; Grabowski, E. J. J.; Dolling, U. H.; Reider, P. J.; Okada, S.;
Kato, Y.; Mano, E. J. Org. Chem. 1999, 64, 9658-9667. (b) Kato, Y.;
Okada, S.; Tomimoto, K.; Mase, T. Tetrahedron Lett. 2001, 42, 4849-
4851.
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Bouffard et al.
SCHEME 2
preparation that offered yields comparable to that of phosphorus
oxybromide in the melt. Selective SNAr reaction with sodium
methoxide in tetrahydrofuran24 affords the methoxy chloride 6
in excellent yield. It is worthy of note that the entire sequence
of reactions up to the methoxy chloride 6 does not require
chromatographic purification beyond that of a simple plug
filtration, allowing for the expeditious preparation of large
quantities (multigram) of these building blocks.
More soluble analogues of the pyridazine building blocks (1-
6b,c) were obtained through the same synthetic route starting
with alkylated anthracenes. Since 2,6-di-tert-butylanthracene is
not easily obtained in large quantities,25 and results in racemic
mixtures of the chiral intermediate iptycenes, we sought to
prepare symmetrically 2,3,6,7-tetrasubstituted anthracenes bear-
ing solubilizing alkyl groups. Only a few symmetrically 2,3,6,7-
tetrasubstituted anthracenes, such as 2,3,6,7-tetramethylan-
thracene26 and 2,3,6,7-tetramethoxyanthracene,27 are readily
available in large quantities at a minimal synthetic or monetary
cost. Given the uncertainty that these analogues would provide
the desired improvement in solubility of the resulting building
blocks, we optimized a double Friedel-Crafts annulation route
that provides the exceptionally soluble octamethyloctahydro-
pentacene 8 in large quantities (up to 50 g) and in excellent
yield in a single step starting from the readily available 9,10-
dihydroanthracene and 2,5-dichloro-2,5-dimethylhexane (Scheme
2).
Synthesis of Iptycene-Derived Phthalazines. A synthesis
of iptycene-derived phthalazines that parallels that of iptycene-
derived pyridazines has been developed (Scheme 3). The Diels-
Alder cycloaddition of the exocyclic diene 9a with dimethyl
acetylenedicarboxylate (DMAD),28 followed by an oxidative
rearomatization with potassium permanganate in the presence
of a phase-transfer catalyst,29 afforded the dimethyl phthalate
11a. Unlike the corresponding dimethyl maleate 1a, this
compound reacts with hydrazine to yield the desired phthalhy-
drazide 12a, which undergoes chlorination with phosphorus
oxychloride to give 13a. Subsequent treatment with sodium
methoxide affords the methoxy chloride 14a. A more soluble,
alkylated analogue was prepared starting from the previously
reported Diels-Alder adduct 15.8c The exocyclic diene 9b was
obtained after a series of functional group transformations and
carried through the previously described synthetic route to
prepare the alkylated phthalazine 13b.
Symmetrical and Unsymmetrical Cross-Couplings. Transi-
tion metal-catalyzed cross-coupling reactions, especially with
Ni0 and Pd0, are the pinnacle of methodologies for the
construction of conjugated materials. Consequently, we explored
cross-coupling reactions with newly synthesized halopyridazines
(5a-d, 6a-c) to generate symmetrically or unsymmetrically
3,6-disubstituted iptycene-derived pyridazines (Scheme 4 and
Table 1). The pyridazine ring was found to be sufficiently
(24) Lee, J. I.; Park, H.; Yun, Y. S.; Kwon, S. K. J. Korean Chem. Soc.
2001, 45, 386-390.
(25) See the Supporting Information for discussion.
(26) (a) Hinshaw, J. C. Org. Prep. Proced. Int. 1972, 4, 211-213. (b)
Godinez, C. E.; Zepeda, G.; Mortko, C. J.; Dang, H.; Garcia-Garibay, M.
A. J. Org. Chem. 2004, 69, 1652-1662.
(27) (a) Robinson, G. M. J. Chem. Soc. Trans. 1915, 107, 267-276. (b)
Miao, Q.; Nguyen, T.-Q.; Someya, T.; Blanchet, G. B.; Nuckolls, C. J.
Am. Chem. Soc. 2003, 125, 10284-10287.
(28) Butler, D. N.; Snow, R. A. Can. J. Chem. 1975, 53, 256-262.
(29) Poulose, A.; Croteau, R. J. Chem. Soc., Chem. Commun. 1979, 243-
244
10168 J. Org. Chem., Vol. 72, No. 26, 2007

Iptycene-DeriVed Pyridazines and Phthalazines
SCHEME 3
SCHEME 4
coupling product 23 is only obtained in poor yield. We also
observe a counter-statistical bias during cross-coupling of the
dichloride 5a with <1 equiv of the organometallic reagent,
which precludes the clean formation of the mono-cross-coupled
products (e.g., 25). Therefore, it was found to be preferable to
perform the cross-coupling of the chloromethoxypyridazine 6a,
and to subsequently convert the intermediate 22 to the corre-
sponding chloropyrizadine (Scheme 5). Alternately, if one
requires a monosubstituted pyridazine, hydrodechlorination of
the chloromethoxypyridazine 6a followed by deprotection and
chlorination yields the chloropyridazine 30.
electron deficient and activated for oxidative addition with
standard palladium catalysts even for the nominally less reactive
chlorides. Concomitantly, the high degree of electronic activa-
tion of the chloropyridazines accelerates nucleophilic aromatic
substitution by nucleophiles such as amines, hydroxide, or
alkoxides. These side reactions prevent Suzuki-Miyaura cross-
coupling reactions of the chloropyridazines under typical
biphasic reactions conditions (e.g., toluene-aqueous base)
without significant competing hydrolysis. The Suzuki-Miyaura
couplings proceed smoothly, however, in anhydrous dioxane
in the presence of cesium fluoride as a base. These reaction
conditions also appear optimal for Stille cross-coupling reac-
tions. A nickel-catalyzed Negishi cross-coupling reaction was
also adequate for the preparation of the 3,6-bis(bithienyl)
derivative 20 in yields comparable to those obtained with the
corresponding Stille reaction. Improved reactivity with increased
electron-rich character of the nucleophilic cross-coupling partner
was observed in most cases. Thus, forcing conditions30 are
required for the reaction between the chloromethoxypyridazine
6a and 2,4-difluorobenzeneboronic acid, and the desired cross-
Reductive Dimerizations. We have explored chemistries that
would allow dimerization, and ultimately polymerization of the
novel iptycene-derived diazines.31 Having demonstrated that the
chloro and bromo diazines are good electrophilic partners in
cross-coupling reactions, we sought to prepare the corresponding
nucleophilic cross-coupling partners. Many attempts for the
preparation of iptycene-derived pyridazines metalated at the 3-
and/or the 6-position to yield the corresponding Kumada,
Negishi, Stille, or Suzuki-Miyaura reagents were unsuccessful.
Attempts to homopolymerize the dihalopyridazines 5a-d with
bis(boronates)32 or bis(stannanes)16d,33 were similarly unsuc-
cessful. These limitations are likely the result of the known
instability and/or susceptibility to protodemetalation of metalated
(31) Polymers incorporating iptycene-derived pyridazines will be reported
elsewhere.
(32) Rabindranath, A. R.; Zhu, Y.; Heim, I.; Tieke, B. Macromolecules
2006, 39, 8250-8256.
(33) (a) Nielsen, C. B.; Bjørnholm, T. Org. Lett. 2004, 6, 3381-3384.
(b) Zhu, Y.; Champion, R. D.; Jenekhe, S. A. Macromolecules 2006, 39,
8712-8719. (c) Devasagayaraj, A.; Tour, J. M. Macromolecules 1999, 32,
6425-6430. (d) Xu, J.; Ng, S. C.; Chan, H. S. O. Tetrahedron Lett. 2001,
42, 5327-5329.
(30) Korenaga, T.; Kosaki, T.; Fukumura, R.; Ema, T.; Sakai, T. Org.
Lett. 2005, 7, 4916-4917.
J. Org. Chem, Vol. 72, No. 26, 2007 10169

Bouffard et al.
TABLE 1. Cross-Coupling Reactions
t
a Conditions (see the Supporting Information for details): (A) 5% Pd(PPh3)4, CsF, p-dioxane, 100-110 °C; (B) 1.5% Pd2(dba)3, 6% Bu3P‚HBF4, CsF,
t
p-dioxane, 100-110 °C; (C) 5% Ni(dppp)Cl2, THF, 60 °C; (D) 5% Pd2(dba)3, 12% Bu3P‚HBF4, CsF, Ag2O, DMF, 100 °C.
SCHEME 5
electron-poor nitrogen heterocycles.34 In fact, although 3-ha-
lopyridazines are commonly employed as electrophilic partners
in cross-coupling reactions, we are only aware of two reports
where pyridazines metalated in the 3-position are used as
nucleophilic partners in standard cross-coupling reactions.35
Furthermore, to address the difficulties associated with electron-
deficient heterocyclic couplings, alternate methods based on the
direct arylation of pyridazine N-oxides with aryl halides through
C-H bond activation have been developed.36 Nevertheless, we
considered these alternate methodologies to be ill-suited for our
(34) (a) Matondo, H.; Souirti, S.; Baboule`ne, M. Synth. Commun. 2003,
33, 795-800. (b) Gros, P.; Doudouh, A.; Fort, Y. Tetrahedron Lett. 2004,
45, 6239-6241. (c) Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004,
45, 685-687. (d) Darabantu, M.; Boully, L.; Turck, A.; Ple´, N. Tetrahedron
2005, 61, 2897-2905. (e) Bouillon, A.; Lancelot, J.-C.; de Oliveira Santos,
J. S.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2003, 59, 10043-
10049. (f) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2000, 57,
9813-9816. (g) Fischer, F. C.; Havinga, E. Recl. TraV. Chim. Pays-Bas
1974, 93, 21-24. (h) Gilman, H.; Spatz, S. M. J. Org. Chem. 1951, 16,
1485-1494.
(35) (a) Boger, D. L.; Miyauchi, H.; Du, W.; Hardouin, C.; Fecik, R.
A.; Cheng, H.; Hwang, I.; Hedrick, M. P.; Leung, D.; Acevedo, O.;
Guimaraes, C. R. W.; Jorgensen, W. L.; Cravatt, B. F. J. Med. Chem. 2005,
48, 1849-1856. (b) Imin, P.; Imit, M.; Jamal, R.; Nurulla, I. Gongneng
Gaofenzi Xuebao (J. Funct. Polym.) 2005, 18, 290-294.
(36) (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc.
2005, 127, 18020-18021. (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem.,
Ind. Ed. 2006, 45, 7781-7786.
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Iptycene-DeriVed Pyridazines and Phthalazines
SCHEME 6
targets. Inspired by reports of nickel- and palladium-mediated
reductive homocoupling of chloropyridazines,37 the reductive
homopolymerization of the dihalopyridazines 5a-d was ex-
plored. Reductive homopolymerization attempts under Yama-
moto conditions (Ni(cod)2, bpy)38 did not yield the desired
homopolymers and dehalogenated low molecular weight materi-
als were the dominant products. Various attempts directed at
the improvement of this reaction by varying the transition metal
(pre-)catalyst39 and stoichiometric reductant40 were similarly
unsuccessful.
Prompted by the observations that electron-poor arenes or
heteroarenes were poor nucleophilic partners in cross-coupling
reactions with the halopyridazines (vide supra), and that
oxidative addition to the halopyridazine electrophilic partner
did not appear to be limiting, the dimerization of the 3-chlo-
ropyridazines 6a-c bearing an electron-donating methoxy group
at the para position was explored. Homocoupling of 6a
following the protocol described by Lehn and Baxter,37a using
30% NiBr2(PPh3)3, nBu4NI, and zinc dust in N,N′-dimethylfor-
mamide, afforded only 11% of dimer 31a. Addition of 2,2′-
bipyridine as a ligand and increasing the catalyst loading to 300
mol % resulted in a moderate yield (60-65%) of the dimer
31a, with significant quantities of the hydrodehalogenated
methoxypyridazine 28 as a byproduct. These observations
suggest that catalytic turnover is very limited in this system.
However, it was found that the use of catalytic amounts of a
palladium precatalyst with zinc dust as the stoichiometric
reductant41 enabled the reductive homocoupling to efficiently
afford the dimer 31a. Further optimization of the reaction
conditions (5% Pd(PPh3)2Cl2, 10% PPh3, Zn, DMF, 100 °C)
enabled the homocoupling to proceed reliably and cleanly in
excellent yields (93-95%). Interestingly, after screening a
variety of ligands and precatalysts for this transformation, we
found the use of either Pd(PPh3)2Cl2/PPh3 or Pd(PPh3)4 to be
optimal, and the use of advanced catalytic systems (e.g., bulky
trialkylphosphines, biaryldialkylphosphines, NHCs, etc.) did not
result in an improvement of the reaction.
(37) (a) Baxter, P. N. W.; Lehn, J.-M.; Baum, G.; Fenske, D. Chem.
Eur. J. 2000, 6 (24), 4510-4517. (b) Boully, L.; Darabantu, M.; Turck,
A.; Ple´, N. J. Heterocycl. Chem. 2005, 42, 1423-1428.
Since the alkylated methoxy chloride 6b has been prepared
as an unresolved mixture of enantiomers, the reductive homo-
coupling resulted in the diastereoisomeric dimethoxy dimers
(38) (a) Yamamoto, T.; Morita, A.; Miyazaki, Y.; Maruyama, T.;
Wakayama, H.; Zhou, Z.-h.; Nakamura, Y.; Kanbara, T.; Sasaki, S.; Kubota,
K. Macromolecules 1992, 25, 1214-1223. (b) Yamamoto, T.; Maruyama,
T.; Zhou, Z.-h.; Ito, T.; Fukuda, T.; Yoneda, Y.; Begum, F.; Ikeda, T.;
Sasaki, S.; Takezoe, H.; Fukuda, A.; Kubota, K. J. Am. Chem. Soc. 1994,
116, 4832-4845.
(41) (a) Lee, T.-S.; An, J. H.; Kim, J.; Bae, J.-Y. Bull. Korean Chem.
Soc. 2001, 22, 375-378. (b) Jutand, A.; Mosleh, A. Synlett 1993, 8, 568-
570. (c) Amatore, C.; Carre´, E.; Jutand, A.; Tanaka, H.; Ren, Q.; Torii, S.
Chem. Eur. J. 1996, 2, 957-966. (d) Jutand, A.; Mosleh, A. J. Org. Chem.
1997, 62, 261-274.
(39) Ni, Pd, and Cu pre-catalysts, various combinations of transition metal
salt/complexes, and ligands were screened.
(40) Zn0, Mg0, Al0, In0, Ni0 complexes, Mn0, Sn0, hydroquinones, and
1,1,2,2-tetra(pyrrolidin-1-yl)ethene (a TDAE analogue) were screened.
J. Org. Chem, Vol. 72, No. 26, 2007 10171

Bouffard et al.
SCHEME 7
31b, Ci, and rac-31b, C2 (Scheme 6). The isomers are obtained
in a 1:1 ratio, and may be separated by column chromatography.
Despite their remarkably similar structures, the diastereomers
exhibit distinct spectroscopic features. The 1H NMR spectra of
the mixture of diastreomers shows the four distinct, well-
resolved resonances of each of the chemically nonequivalent
tert-butyl groups, the two distinct resonances of the methoxy
groups, and although the signals of the two “external” bridge-
head protons overlap, the pair of “internal” bridgehead proton
signals are spaced more than 0.2 ppm apart. Attempts at
obtaining X-ray quality single crystals of either isomer of 31b,
32b, and 33b were unsuccessful. Moreover, while COSY and
conditions surveyed. The reductive dimerization of the chlo-
romethoxyphthalazine 14a was best accomplished with zinc dust
in N,N-dimethylformamide in the presence of a catalytic amount
of a palladium precatalyst. The isolated yields of the dimethoxy-
biphthalazine 35 were poor (17%) in comparison to the
analogous reaction carried out with the chloromethoxypyridazine
6a (up to 95%). Furthermore, under these reaction conditions
the reaction mixture rapidly displayed a deep purple hue, which
disappeared upon aqueous workup. By contrast, no coloration
develops in the reductive dimerization of the pyridazines 6a-
c. This intriguing difference in the chemical behavior of
otherwise similarly behaved species is highlighted by the
isolation of 2,3-dicyanotriptycene (36)42 in 23% yield from the
reaction mixture when 13a is used as a starting material.
The transformation of a chlorophthalazine into a 1,2-
dicyanobenzene is not unprecedented. Yanilkin and co-workers43
have reported that both the chemical reduction with metallic
potassium and the electrochemical reduction of 1-chloro-4-X-
phthalazines (X ) Cl, OPh, OMe, OEt, OiPr) in N,N-dimeth-
ylformamide yield the radical anion of phthalonitrile. The
situation observed with the chlorophthalazines 13a and 14a
appears slightly more complex. While treatment of 13a with
zinc dust in DMF in the absence of a palladium catalyst affords
2,3-dicyanotriptycene 36, the reaction is much slower than in
the presence of 0.1 equiv of Pd(PPh3)2Cl2 and 0.2 equiv of PPh3.
In the latter case, the deep blue-purple hue attributed to the
radical anion of 2,3-dicyanotriptycene 36 appears within 2 h at
60 °C. By contrast, in the absence of a palladium catalyst, the
color only arises after several hours at 120 °C. The reaction
with the more electron rich chloromethoxyphthalazine 14a is
markedly slower. In the absence of a palladium catalyst, 14a is
only slowly degraded with zinc dust in DMF at 120 °C, and
2,3-dicyanotriptycene 36 and the protodehalogenated 1-meth-
oxyphthalazine are the only identifiable trace byproducts (3%
and 5%, respectively). Finally, the reaction of 14a with zinc
dust in DMF in the presence of a palladium catalyst (0.1 equiv
of Pd(PPh3)2Cl2 and 0.2 equiv of PPh3) requires a reaction
temperature higher than that for 13a (100 °C) to yield dimethoxy
dimer 35 as the sole identifiable product by 1H NMR. The deep-
1
NOE H NMR experiments gave self-consistent results, it has
been impossible to unequivocally assign the structure of each
isomer. Reductive coupling of the alkylated methoxy chloride
6c gave the symmetrically alkylated dimer 31c. The isolation
and purification of 31c were hindered by its limited solubility
in most organic solvents with the exception of hot toluene,
carbon disulfide, and heavier chlorinated solvents (e.g., tri- and
tetrachloroethylene, tetrachloroethane). It is surprising that, while
the symmetrically alkylated anthracene 8 and monomeric
intermediates 1c-6c are considerably more soluble in typical
organic solvents than either of their parent compounds 1a-6a
or tert-butyl-substituted 1b-6b counterparts, the dimers 31c,
32c, and 33c are markedly less soluble than their parent
compounds 31a-33a or tert-butyl-substituted counterparts
31b-33b.
The dimethoxy dimers 31a-c could be converted to the
corresponding dihalides by cleavage of the methoxy groups with
hydrobromic acid in acetic acid, followed by treatment with a
phosphorus(V) oxyhalide to give the dihalo dimers 33a-d in
moderate to good yields. Treatment of the dichloride 33a with
sodium methoxide in THF afforded the chloro methoxy dimer
34 in low yield (28%, 47% based on recovered starting material).
The nucleophilic substitution of 5a-c to 6a-c is selective for
the monomethoxy product due to the deactivating effect of the
first methoxy group for further ring substitution. By contrast,
the conversion from 33a to 34 shows little selectivity, and
consequently, a mixture of the starting dichloro dimer 33a, the
chloro methoxy dimer 34, and the dimethoxy dimer 31a is
obtained.
(42) (a) Gal’pern, M. A.; Shalaev, V. K.; Shatsskaya, T. A.; Shishkanova,
L. S.; Skvarchenko, V. R.; Luk’yanets, E. A. Zh. Obshch. Khim. 1983, 53,
2601-2606. (b) Shatsskaya, T. A.; Gal’pern, M. G.; Skvarchenko, V. R.;
Luk’yanets, E. A. Vest. MoskoV. UniV. Khim. 1986, 41, 64-66.
(43) Yankilin, V. V.; Buzykin, B. I.; Morozov, V. I.; Nastapova, N. V.;
Maksimyuk, N. I.; Eliseenkova, R. M. Zh. Obshch. Khim. 2001, 71, 1726-
1737.
The reductive coupling of dichlorophthalazine 13a and
chloromethoxyphthalazine 14a was similarly explored (Scheme
7). In parallel with what was observed with the corresponding
pyridazines (5a-c, 6a-c), the dichlorophthalazine 13a did not
participate in reductive homopolymerization under the reaction
10172 J. Org. Chem., Vol. 72, No. 26, 2007

Iptycene-DeriVed Pyridazines and Phthalazines
SCHEME 8
purple color of the reaction mixture suggests that traces of 2,3-
dicyanotriptycene 36 are nonetheless generated. These constitute
evidence for the involvement of the palladium catalyst in the
reductive heterocyclic ring-opening reactions, though the exact
nature of this involvement has not been elucidated. These
competing side reactions were directly observed with the
iptycene-derived phthalazines (13a, 14a), but not with the
analogous pyridazines (5a-c, 6a-c), possibly because they
might show a more negative reduction potential. One is tempted
to speculate that, were such competing pathways to occur, they
might, along with protodehalogenation, be significant limitations
to the synthesis of homopolymers of 5a-d through reductive
coupling routes (vide supra).
Higher Oligopyridazines Through Controlled Approaches.
Optimized reductive coupling conditions were applied to the
preparation of extended oligopyridazines (Scheme 8). Under
these conditions, the reductive coupling of the chloro methoxy
dimer 34 proceeds smoothly in good yield (76%) to afford the
quaterpyridazine 37. Unlike previously reported quaterpy-
ridazines, which showed poor solubility,37a the tetramer 37 is
freely soluble in a variety of common organic solvents, such as
chloroform, dichloromethane, toluene, ethyl acetate, tetrahy-
drofuran, and acetone. The comparatively high solubility of 37
is attributed to the iptycene scaffold, which prevents the strong
π-π stacking interactions in the solid state that impede
dissolution. When an excess (4 equiv) of the chloro methoxy
dimer 34 is reductively coupled in the presence of the dichloro
dimer 33a, the tetramer 37 (24%) and small quantities of the
hexamer (38) (∼10-15%) can be obtained after chromato-
graphic separation. This hexamer represents, to the best of our
knowledge, the first example of a fully characterized sexipy-
ridazine. Interestingly, the solubility of the hexamer 38 is
qualitatively comparable to that of tetramer 37.
of the pyridazine or phthalazine would be at least accessible, if
not energetically favored through increased conjugation, for
pyridazines and phthalazines attached to five-membered-ring
heterarenes and six-membered-ring heterarenes bearing no ortho
substituents (e.g., 2-thienyl, 3-pyridazinyl, etc.). Furthermore,
we postulated that a secondary hydrogen-bonding interaction
between the heteroatom of a heteraryl group and the bridgehead
hydrogen of the iptycene framework might provide an additional
enthalpic stabilization term.
(a) X-ray Crystallography. We examined the structure of
several of the iptycene-derived diazine building blocks by X-ray
crystallography to ascertain the validity of the coplanarization
hypotheses. In conducting this analysis it is important to bear
in mind that intermolecular interactions and close-packing can
affect the conformation of molecules in the solid state such that
they are not necessarily representative of their “free” (or
solvated) preferred conformations. The structures obtained for
seven compounds are presented in Figure 1. The 2-thienyl
derivative 19 adopts a quasicoplanar conformation of the teraryl
fragment, as predicted (N-C-C-S dihedral angles: 5.05(15)°
and 8.4(2)°). Interestingly, a cisoid, synperiplanar (N-C-C-
S) rotamer is observed, as opposed to the predicted transoid,
antiperiplanar rotamer, illustrating at once the negligible steric
clash between the bridgehead hydrogen of the iptycene and the
adjacent hydrogen on the 5-membered ring, and the absence of
involvement of a stabilizing S-H hydrogen-bonding interac-
tion.44 Furthermore, within the crystal structure of 19 is also
present another rotamer where the teraryl fragment is not planar
but oblique (N-C-C-S dihedral angles: 29.84(16)° and
120.30(19)°), as is observed for the bis(3,4-ethylenedioxy)-
thiophene-2-yl derivative 21 (N-C-C-S dihedral angles:
33.79(16)° and 37.54(15)°). These observations suggest that the
2-thienyl group can freely, or with a minimal energy barrier,
rotate about the biaryl linkage. In contrast, and as expected, a
phenyl substituent, as in the 2,4-difluorophenyl derivative 23,
does not adopt a coplanar conformation about the biaryl linkage
(N-C-C-C(F) dihedral angle 127.56(10)°).
Planarity and Conjugation of Biaryls Obtained from
Iptycene-Derived Pyridazines and Phthalazines. We have
used this small library of compounds containing iptycene-
derived pyridazines and phthalazines to test our hypothesis that
coplanarity of the biaryl linkages will be the preferred confor-
mation. The vast majority of the compounds herein described
are crystalline, and as a result a number of structures were
determined by X-ray crystallography. NMR spectroscopy and
computational studies also provide additional insight into the
conformations of these molecules. We expected that a fully
coplanar conformation about the biaryl linkage at the 3-position
The pyridazine and phthalazine dimers 31a, 33a, and 35 do
not adopt a coplanar conformation about the biaryl linkages,
despite the predicted stabilization through increased conjugation
(44) Stabilizing S-N interactions that favor a synperiplanar (cisoid)
rotamer have been proposed in related compounds. See ref 16d and
references therein.
J. Org. Chem, Vol. 72, No. 26, 2007 10173

Bouffard et al.
FIGURE 1. X-ray crystal structures of iptycene-derived pyridazines and phthalazines. Fifty percent probability thermal ellipsoids. Hydrogens and
solvent molecules were omitted for clarity. See the Supporting Information for details.
and the possibility of weak N-H intramolecular hydrogen
bonding. The inclination of the diazine rings with respect to
another varies greatly in this series, from the dimethoxy dimer
31a (N-C-C-N dihedral angle 113.70(13)°) to the dichloro
dimer 33a (N-C-C-N dihedral angle 135.07(15)°), with an
intermediate value for the phthalazine dimer 35 (N-C-C-N
dihedral angle 127.4(2)°). For the former pair of compounds, it
is unlikely that the steric and electronic parameters are affected
by the substitution of a methoxy group for a chlorine atom at
a position remote to the biaryl linkage. These results suggest
that, at least within this bracket of torsion angles, the potential
energy curve for rotation about the biaryl linkage must be
shallow enough that intermolecular interactions and close
packing overcome an inherently preferred rotamer. Finally, the
structure of the tetramer 37 reveals that a further extension of
the conjugation might favor coplanarization of the oligoheteraryl
segments, even though an overall loss of linearity of the structure
due to bending is witnessed (N-C-C-N dihedral angles
141.58(17)°, 141.07(17)°, 141.51(16)°). It should finally be
stressed that X-ray crystallography provided no evidence of
intramolecular hydrogen bonding between the iptycene and a
proximal heteroatom in any of the structures herein described.
molecule. This peak is not split by any adjacent nucleus, and is
in a region that is free of other signals, hence it is a key
diagnostic in NMR identification of compounds. We sought to
take advantage of local ring current anisotropy to provide an
indirect way of evaluating the coplanarity of the iptycene-derived
pyridazine and phthalazine structures in solution. For a simple
arylated iptycene-derived pyridazine (e.g., 18), were the aryl
groups to be completely coplanar with the pyridazine ring, one
would expect the bridgehead hydrogen to experience the
influence of ring current anisotropy induced by the three arenes
of the iptycene-derived pyridazine scaffold, in addition to that
induced by the pendant aryl group. The resulting NMR signal
would be shifted downfield, in a situation reminescent of the
“bay” protons in phenanthrene and other fused polycyclic
aromatic hydrocarbons. Conversely, if the pendant aryl group
lies predominantly perpendicular to the plane of the pyridazine
ring, the bridgehead hydrogen signal should shift upfield
(Scheme 9).
In the monomeric iptycene-derived pyridazines bearing non-
carbon substituents at the 3,6-positions (5a-d, 6a-c, 28, 30),
the observed chemical shift45 of the proximal bridgehead
hydrogen is within a narrow range (δ 5.61-5.85 ppm). This
range is even narrower (δ 5.72-5.85 ppm) if the outlying signals
1
(b) NMR Spectroscopy. The H NMR resonance of the
bridgehead hydrogen of triptycene appears at 5.41 ppm in
CDCl3. This value is unusually high for a sp3-hybridized
hydrocarbon, as expected due to the inductive effects and ring
current anisotropy of the three aromatic rings of the triptycene
(45) All chemical shift comparisons refer to the spectra taken in CDCl3,
referenced to the solvent resonance and expressed in ppm vs tetramethyl-
silane.
10174 J. Org. Chem., Vol. 72, No. 26, 2007

Iptycene-DeriVed Pyridazines and Phthalazines
SCHEME 9
hydrogen supports both the assignment of the proximal bridge-
head hydrogen and a preferred or time-averaged rotamer in
which the fluorinated arene is perpendicular to the plane of the
pyridazine. The NMR signal assignment for 23 is further
1
evidenced by the presence of through-space H-19F coupling
(J ) 4.0 Hz), where the proximal bridgehead hydrogen is split
by the ortho fluorine of the aromatic ring (Figure 2), a feature
previously studied in fluorinated iptycenes.47 We also observe
through-space 13C-19F coupling where the proximal bridgehead
carbon is split by the ortho fluorine (J ) 4.5 Hz). These through-
space couplings are indicative of the short H-F (2.541 Å) and
C-F (2.9965(12) Å) distances imposed by the molecular
architecture as revealed in the X-ray structure for 23, which
are shorter than the sum of the van der Waals radii.
corresponding to the sterically congested 5c, 6c (δ 5.61-5.69
ppm), and the pyridazines unsubstituted at the 6-position, such
as in 28 and 30 (δ 5.56-5.60 ppm), are excluded. The fact that
the chemical shift of the bridgehead hydrogen in iptycene-
derived pyridazines is ∼0.2-0.4 ppm higher than that of simple
triptycenes likely reflects the electron-deficient nature of the
pyridazine ring. Unsymmetrically 1,4-disubstituted iptycene-
derived pyridazines (6a-c, 22-30) show two singlets corre-
sponding to each of the bridgehead hydrogens, but the chemical
shift difference between the two can be minimal, as observed
for the bridgehead hydrogens proximal to the chloro and the
methoxy substituents in 6a (∆δ e0.03 ppm).
Substitution by a phenyl group (18, 22, 24, 27) results only
in a minimal shift of the signal assigned to the bridgehead
hydrogen proximal to the phenyl substituent46 relative to those
next to a halogen or a methoxy group (∆δ -0.08 to +0.08 ppm).
This suggests either that the influence of the additional ring
current anisotropy does not affect the proximal bridgehead
hydrogen, or that the average influence of the rotamer population
distribution within the NMR time scale gives no change in the
chemical shift of phenyl-substituted iptycene-derived py-
ridazines. The latter is plausible considering that a phenyl ring
will likely prefer to be oblique or gauche with respect to the
plane of the pyridazine ring to avoid the eclipsing of the ortho
hydrogens by the proximal bridgehead hydrogen. Substitution
by a 3,4-ethylenedioxythiophen-2-yl group (21) has a similar
effect (e.g., 5a f 21 ∆δ ) +0.12 ppm). This is in agreement
with the solid-state structure in which the substituent group is
synclinal with respect to the plane of the pyridazine ring (N-
C-C-S dihedral angle ∼35°).
In a third series, wherein the pendant arene is a 5- or
6-membered heterocycle devoid of a substituent in at least one
ortho position, such as 2-thienyl or 3-pyridazinyl, the bridgehead
hydrogen resonance48 is shifted downfield. Iptycene-derived
pyridazines bearing a 2-thienyl substituent (e.g., 19, 20, 25)
experience a dramatic shift (e.g., 5a f 19 ∆δ ) +0.43 to 6.27
ppm) consistent with the hypothesis that a coplanar rotamer is
favored. This is also supported by the observation of the same
rotamer by X-ray crystallography for 19 (vide supra). Iptycene-
derived pyridazine dimers (31a-c, 33a-d, 34) and higher
oligomers (37, 38) also show a similar behavior. The signal
assigned to the “internal” bridgehead hydrogens, which are
proximal to the second pyridazine ring, are also shifted
considerably downfield compared to the “external” bridgehead
hydrogens that are proximal to a methoxy group or a halogen.
For example, the “internal” bridgehead hydrogen of the dichloro
dimer 33a has a chemical shift of δ 6.37 ppm, while the
“external” bridgehead hydrogen resonates at δ 5.99 ppm (Figure
2). Furthermore, spectra of the unsymmetrical dimer (34) and
the higher oligomers (37, 38) are consistent with the hypothesis
that the shift is caused by the ring current anisotropy of an
adjacent coplanar arene. The dimer 34 displays two downfield
signals above 6.20 ppm and two upfield signals around 6.00
ppm, the tetramer 37 displays three “internal”, downfield signals
and one “external”, upfield signal, and finally the hexamer 38
shows five “internal”, downfield signals and one “external”,
upfield signal. The extent of this chemical shift difference varies
between the different compounds, ranging from ∆δ ) +0.07
to 1.00 ppm. The two highest values (∆δ ) +0.69 and 1.00
ppm) belong to the symmetrically alkylated dimers 33c and 31c,
which are expected to greatly favor an antiperiplanar or anticlinal
(N-C-C-N) rotamer due to the additional steric clash between
the alkyl groups that a synclinal rotamer would incur.
Substitution by the 2,4-difluorophenyl group (23) results in
a more significant upfield shift of the proximal bridgehead
hydrogen (e.g., 6a f 23 ∆δ ) -0.36 to 5.43 ppm). This is the
lowest chemical shift observed for bridgehead hydrogens among
all of the iptycene-derived pyridazines herein reported. A
coplanar conformation of the pendant arene and the pyridazine
ring in 23 would be energetically demanding due to the steric
clash between the ortho fluorine and the proximal bridgehead
hydrogen for the antiperiplanar (N-C-C-C(F)) rotamer, and
due to electronic and dipole-dipole repulsion for the syn-
periplanar rotamer. Among the compounds studied, the fluori-
nated derivative 23 is the most likely to show a predominantly
perpendicular orientation between the pendant arene ring and
the pyridazine ring (vide infra). A real, although weak, NOE
signal enhancement (1.0%) of the ortho proton of the difluo-
rophenyl ring upon irradiation of the proximal bridgehead
The iptycene-derived phthalazine dimer 35 may not be
directly compared to the other molecules of the series, due to
the greater distance between the bridgehead hydrogen and the
aryl substituent. Parallel conclusions can nonetheless be made
on the basis of its 1H NMR spectrum. The monomers 13a and
14a display 1H NMR signals assigned to the bridgehead
hydrogens at 5.79, 5.72, and 5.69 ppm, while the proximal
phthalazine hydrogens are assigned to signals at 8.25, 8.16, and
(47) (a) Ohki, M. Acc. Chem. Res. 1990, 23, 351-356. (b) Yamamoto,
G.; Ohki, M. Tetrahedron Lett. 1985, 26, 457-460. (c) Yamamoto, G.; Ohki,
M. J. Org. Chem. 1984, 49, 1913-1917.
(48) The assignments are confirmed by an NOE enhancement of ortho
protons of the 2-thienyl substituents (+9.3-12.1%) upon irradiation of the
proximal bridgehead protons. For 3-pyridazinyl substituents, NOE enhance-
ments were observed only between the bridgehead protons and the proximal
hydrogens within the iptycene scaffold. See the Supporting Information
for details.
(46) This assignment is confirmed by a NOE enhancement of the ortho
proton of the phenyl ring (+6.0-7.3%) upon irradiation of the proximal
bridgehead hydrogen. See the Supporting Information for details.
J. Org. Chem, Vol. 72, No. 26, 2007 10175

Bouffard et al.
FIGURE 2. Comparative 1H NMR spectra of the iptycene bridgehead region illustrating the shifts experienced by hydrogens that are proximal to
a coplanar arene (20, 33a “internal” H) and by the hydrogens that are proximal to an oblique (27) or perpendicular (23) arene.
8.13 ppm. In the dimeric iptycene-derived phthalazine 35, the
corresponding signals are observed at 8.29, 7.82, 5.67, and 5.45
ppm. On the basis of these assignments, and under the
assumption that the signals that experience the more dramatic
shifts correspond to the internal protons of the dimer,49 it appears
that a significant shielding occurs for both the internal bridge-
head hydrogen (∆δ ) -0.24 ppm) and the internal phthalazine
hydrogen (∆δ ) -0.31 ppm). Thus, we conclude that the
preferred (or averaged) rotamer of 35 is not synperiplanar but
instead oblique or perpendicular, as for 23.
(c) Modeling. To further support the hypothesis that copla-
narization and conjugation may be favored or at the minimum
less disfavored in aryl-substituted, iptycene-derived, pyridazine-
or phthalazine-based molecular materials, ab initio calculations
were performed as follows.50 Molecular geometries (gas phase)
were first minimized with the B3LYP functional and the
6-31G+(d,p) basis set (6-31G(d,p) for the iptycene dimers). The
energies of the rotamers about the biaryl linkage were then
individually calculated every 5° with the B3LYP functional and
the 6-31G+(d,p) basis set, and the energy of the coplanar
rotamer is reported relative to that of the minimum energy
conformation. Calculations were also performed on a series of
model compounds for the purpose of comparison, and the results
are summarized in Table 2. While these results do not
necessarily provide an accurate estimate of the barrier to
atropisomerization,51 they provide a means of comparison and
facilitate the investigation of structure-property relationships
with respect to the ease of coplanarization. The bipyridazine A
illustrates the working hypothesis for coplanarization, and favors
a coplanar and flat conformation with an antiperiplanar (transoid)
orientation with respect to the torsion angle formed by the
N-C-C-N atoms of the biaryl junction. A second local energy
minimum, which is 8 kcal/mol less stable, that parallels the
preferred rotamer of biphenyl B is found between 45° and 50°.
The iptycene-derived pyridazine dimers (31a and 33a) do not
minimize in a perfectly coplanar structure. The iptycene
bridgehead hydrogen creates a slight steric clash, resulting in a
coplanar rotamer that is less stable by 3-4 kcal/mol, a value
comparable to the barrier to rotation about the C-C bonds of
substituted or branched alkanes. The torsion angle at the energy
minimum is of ∼145°, a value greater than that observed in
the crystal structures of 31a and 33a, but approaching those
found in the crystal structure of 37. We take this to be additional
evidence that the preferred conformation of these molecules in
a free or solvated state is more coplanar than in the crystal. It
is noteworthy that the relative energy of the coplanar rotamer
remains lower than in the analogous pyridazine bearing an
o-methyl group (F, 6 kcal/mol) or than in the corresponding
biphthalazine (H, 8 kcal/mol), and this fact is attributed to the
“tying back” of the bridgehead hydrogen within the iptycene
scaffold. The relative energy of the coplanar rotamer is also far
lower than in molecules with one (22, 20 kcal/mol; 23, 25 kcal/
mol) or two (J, 53 kcal/mol; K, 83 kcal/mol) of the pyridazine
rings replaced by the corresponding aromatic hydrocarbon. A
(49) NOE enhancements between bridgehead protons and proximal
iptycene and phthalazine hydrogens allow for the identification of two sets
of signals that face either inward or outward from the dimer 35. The actual
assignment of each of these sets to either the “internal” or “external” face
must, however, rely on a chemical shift argument.
(50) Calculations were performed using the Gaussian 03 software
package: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
(51) (a) The calculated barrier to rotation about the C-C biaryl linakge
does not account for other molecular motion (torsion, stretching, bending,
etc.) that, when combined with rotation, can provide additional lower energy
pathways to atropisomeric inversion. As an illustration, the calculated barrier
for rotation about the biaryl axis of binaphthyl L is of ∼128 kcal/mol, while
the experimental value is of 23.5 kcal/mol (ref 51b). (b) Eliel, E. L.; Wilen,
S. H; Mander, L. N. Stereochemistry of Organic Compounds; Wiley-
Interscience: New York, 1999, and references therein.
10176 J. Org. Chem., Vol. 72, No. 26, 2007

Iptycene-DeriVed Pyridazines and Phthalazines
TABLE 2. Computational Modeling Results (B3LYP 6-31G+(d,p)50,51
a Dihedral angle at energy minimum. b Relative energy of the coplanar rotamer with respect to that of the minimum energy conformation, in kcal/mol.
c Energy minimum.
significant lowering of the relative energy of the coplanar
rotamer is also encountered with 2-thienyl substituents, as
corroborated by X-ray crystal structures and NMR spectroscopy.
The relative energy of the coplanar rotamer is no more than 4
kcal/mol less stable for D, while for the analogous 2-thienyl
arene G the difference is 7 kcal/mol. The difference remains
lower in the unsubstituted 2-phenylthiophene B (0.6 kcal/mol),
paralleling that observed between 33a (or 31a) and C. Signifi-
cant reduction of the relative energy of the coplanar conformer
is also present in the bi(phthalazines) (H, 8 kcal/mol; 35, 7 kcal/
mol) relative to the hydrocarbon analogues (L, 128 kcal/mol;
M, 126 kcal/mol).
(d) UV-Vis and IR Spectroscopy. We have postulated the
possibility of a stabilizing hydrogen-bonding interaction between
the bridgehead hydrogen and a proximal heteroatom. A close
inspection of the infrared spectra of a selection of the com-
pounds52 did not reveal evidence for these types of interactions.
Given that neither computational modeling nor crystallography
indicates such an interaction, we conclude that the involvement
of hydrogen bonding is at best a very small stabilizing effect.
Biaryls and oligoaryls in which coplanar rotamers are favored
generally exhibit extended π-conjugation. In oligo p-phenylenes,
the extended conjugation caused by the addition of aryl rings
results in a bathochromic shift of the absorption maxima and
in an increase of the molar absorptivity.53 This situation is,
however, not paralleled in the iptycene-derived pyridazine
oligomers,54 suggesting that the less polarizable pyridazine rings
display less efficient electron delocalization. Furthermore, the
fact that most of the new compounds presented herein are
nonfluorescent55 also supports a lack of efficient electron
delocalization.56 Hence, there would appear to be a minimal
electronic driving force for planarization.
Conclusions
In conclusion, we have reported a practical, scalable synthesis
of attractive heterocyclic iptycene building blocks. These
methods permit the introduction of solubilizing groups, the
general application of cross-coupling reactions for the prepara-
tion of (het)aryl-substituted iptycene-derived 1,2-diazines, and
finally the access to dimers and higher oligomers through
reductive couplings. The relaxation of steric hindrance at the
ortho positions is supported by crystallographic, spectroscopic,
and computational studies. The incorporation of these building
blocks as structural components of traditional and conjugated
polymers and their use as cyclometalling ligands for transition
metals are the object of ongoing research.
Experimental Section
Typical Procedures for the Preparation of the Monomeric
Pyridazines (“a” series): (a) 9,10-Dihydro-9,10-etheno-11,12-
anthracenedicarboxylic Acid, Cyclic Hydrazide (4a). Crystals
(54) See the Supporting Information for details.
(55) With the notable exception of the thiophene derivatives (e.g., 19
and 20) that are strongly fluorescent (see ref 16d).
(56) Edelmann, M. J.; Raimundo, J.-M.; Utesch, N. F.; Diderich, F.;
Boudon, C.; Gisselbrecht, J.-P.; Gross, M. HelV. Chim. Acta 2002, 85,
2195-2213.
(52) See the Supporting Information for details.
(53) Matsuoka, S.; Fujii, H.; Yamada, T.; Pac, C.; Ishida, A.; Takamuku,
S.; Kusaba, M.; Nakashima, N.; Yanagida, S.; Hashimoto, K.; Sakata, T.
J. Phys. Chem. 1991, 95, 5802-5808.
J. Org. Chem, Vol. 72, No. 26, 2007 10177

Bouffard et al.
1
of anhydride 3a (41.1 g, 150 mmol) were crushed in a mortar, and
then added to a refluxing solution of NH2NH2‚HCl (23 g, 336
mmol) in AcOH (800 mL). The resulting mixture is refluxed
overnight to yield a colorless, clear solution. The reaction mixture
is cooled, and poured into ca. 3 L of H2O. The resulting precipitate
is filtered and dried under reduced pressure to yield 4a as a
yellow solid (50.9 g, 85% over two crops). Mp 255-256 °C; H
NMR (300 MHz, CDCl3) δ 8.21 (s, 2H), 7.90 (s, 4H), 1.81 (s,
8H), 1.45 (s, 24H); 13C NMR (75 MHz, CDCl3) δ 143.8, 130.7,
124.7, 123.9, 35.3, 34.9, 32.9; HR-MS (EI) calcd for C30H38 [M]+
398.2968, found 398.2973.
Typical Procedures for the Preparation of Monomeric Ph-
thalazines (“a” series): (a) 9,10-Dihydro-9,10-[1′,2′]benzenoan-
thracene-2,3-dicarboxylic Acid, Cyclic Hydrazide (12a). Anhy-
drous hydrazine (6.0 mL, ca. 190 mmol) was added to a refluxing
solution of phthalate 11a (4.50 g, 12 mmol) in EtOH (60 mL) under
a nitrogen atmosphere. The resulting mixture was then refluxed
overnight. After cooling to room temperature and evaporation of
the solvents under reduced pressure, trituration of the crude product
in water followed by filtration and drying under vacuum yields the
cyclic hydrazide 12a as a white solid (4.03 g, 98%). Mp >330 °C;
1H NMR (500 MHz, (CD3)2SO) δ 8.12 (s, 2H), 7.51-7.49 (dd,
4H, J ) 8.5, 5.5 Hz), 7.05-7.04 (dd, 4H, J ) 5.5, 3.5 Hz), 5.95
(s, 2H); 13C NMR (125 MHz, (CD3)2SO) δ 155.6, 149.1, 144.2,
125.7, 125.5, 124.1, 119.8, 52.4; HR-MS (ESI) calcd for C22H14N2O2
[M + H]+ 339.1128, found 339.1118.
(b) 1,4-Dichloro-6,11-dihydro-6,11-[1′,2′]benzeno-2,3-diaza-
tetracene (13a). Cyclic hydrazide 12a (3.38 g, 10 mmol) was
refluxed overnight in neat POCl3 (35 mL). After the solution was
cooled to room temperature, the excess POCl3 was evaporated under
reduced pressure and the residue was redissolved in ca. 35 mL of
PhMe. Solvents were again evaporated under reduced pressure, and
the residue was dissolved in CH2Cl2 (∼100 mL). A few grams of
neutral alumina was added, and the resulting suspension was
triturated for 1 h. The contents were then passed through an alumina
plug and eluted first with CH2Cl2, then EtOAc. Evaporation of the
solvents yields the crude dichloride, which may be further purified
by column chromatography on SiO2 with use of progressively more
polar 15:4:1 f 10:4:1 hexanes:dichloromethane:ethyl acetate (v/
v/v) as the mobile phase to yield 13a as a yellow solid (1.86 g,
1
white solid (43.6 g, 100%). Mp >330 °C; H NMR (500 MHz,
(CD3)2SO) δ 11.99 and 11.40 (2 br, 2H), 7.54-7.51 (dd, 4H, J )
5.3, 3.2 Hz), 7.06-7.03 (dd, 4H, J ) 5.4, 3.2 Hz), 5.85 (s, 2H);
13C NMR (125 MHz, (CD3)2SO) δ ∼157 (br) and ∼150 (br) and
∼147 (br) (CdO tautomers in solution), 144.0, 125.4, 124.4, 47.2;
IR (KBr) 3435, 3069, 1642, 718; HR-MS (ESI) calcd for C18H12
N2O2 [M + H]+ 289.0972, found 289.0978.
(b) 1,4-Dichloro-9,10-dihydro-9,10-[1′,2′]benzeno-2,3-diazaan-
thracene (5a). Cyclic hydrazide 4a (11.52 g, 40 mmol) was refluxed
overnight in neat POCl3 (125 mL). The mixture was cooled, and
the excess POCl3 was evaporated under reduced pressure. The
brown gummy residue was redissolved in PhMe (ca. 100 mL), and
evaporated again under reduced pressure to eliminate more of the
residual POCl3. The residue was then dissolved in CH2Cl2 (ca. 200
mL), triturated with neutral alumina for 1 h, filtered over a neutral
alumina plug, and eluted first with CH2Cl2, then with EtOAc.
Evaporation of the solvents under reduced pressure yields 5a as an
1
off-white solid (11.19 g, 86%). Mp 227-228 °C; H NMR (500
MHz, CDCl3) δ 7.56-7.54 (dd, 4H, J ) 5.4, 3.2 Hz), 7.15-7.13
(dd, 4H, J ) 5.4, 3.2 Hz), 5.84 (s, 2H); 13C NMR (75 MHz, CDCl3)
δ 151.5, 147.4, 142.0, 126.8, 125.2, 50.4; IR (KBr) 3072, 3050,
2987, 1528, 1459, 1308, 1195; HR-MS (EI) calcd for C18H10Cl2N2
[M]+ 324.0221, found 324.0216.
(c) 1-Chloro-9,10-dihydro-4-methoxy-9,10-[1′,2′]benzeno-2,3-
diazaanthracene (6a). In a septum-capped Schlenk flask is placed
the dichloride 5a (11.00 g, 33.8 mmol) and solid, dry NaOMe
(2.38 g, 44.1 mmol). The flask is evacuated and back-filled with
argon five times, and dry tetrahydrofuran (ca. 200 mL) is then
added. The resulting mixture is rapidly stirred at room temperature
for ca. 22 h, after which TLC indicates complete consumption of
the starting material. The cloudy reaction mixture is poured in sat.
NaHCO3 (ca. 150 mL). The organic phase is separated, and the
aqueous layer is extracted with three portions of ethyl acetate (ca.
50 mL). The combined organic layers are washed with brine, dried
over anhydrous magnesium sulfate, and filtered. Evaporation of
the solvents under reduced pressure yields 6a a fluffy white solid
1
50%). Mp 330 °C dec; H NMR (500 MHz, CDCl3) δ 8.25 (s,
2H), 7.53-7.51 (dd, 4H, J ) 5.0, 3.0 Hz), 7.12-7.10 (dd, 4H, J )
5.5, 3.5 Hz), 5.79 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 154.8,
151.9, 142.8, 126.5, 126.1, 124.5, 119.7, 54.0; HR-MS (ESI) calcd
for C22H12N2Cl2 [M + Na]+ 397.0270, found 397.0271.
(c) 1-Chloro-6,11-dihydro-4-methoxy-6,11-[1′,2′]benzeno-2,3-
diazatetracene (14a). Dichloride 13a (750 mg, 2.0 mmol) and solid
NaOMe (140 mg, 2.6 mmol) were placed in a Schlenk flask, and
the contents were evacuated and back-filled with argon five times.
Dry THF (10 mL) was added and the resulting mixture was stirred
at room temperature overnight. The reaction mixture was then
dumped in an excess of sat. NaHCO3, and extracted with EtOAc.
The combined organic layers were washed with brine and dried
with MgSO4, and the solvents were evaporated under reduced
pressure to yield a crude product that was purified by column
chromatography on SiO2 with use of progressively more polar 15:
4:1 f 10:4:1 hexanes:dichloromethane:ethyl acetate (v/v/v) to
afford 14a as an off-white solid (559 mg, 76%). Mp 289 °C dec;
1H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 8.13 (s, 1H), 7.50-
7.46 (dq, 4H), 7.09-7.07 (m, 4H), 5.72 (s, 1H), 5.69 (s, 1H), 4.23
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.9, 150.4, 150.1, 143.40,
143.39, 126.3, 126.2, 124.4, 124.3. 119.9, 119.3, 117.7, 55.3, 54.2,
54.1; HR-MS (ESI) calcd for C23H15ClN2O [M + H]+ 371.0946,
found 371.0943.
Typical Procedure for Cross-Coupling Reactions: 9,10-
Dihydro-1-methoxy-4-phenyl-9,10-[1′,2′]benzeno-2,3-diazaan-
thracene (22). In a Schlenk flask were added the methoxy chloride
6a (3.00 g, 9.35 mmol), PhB(OH)2 (2.1 g, 17.2 mmol), CsF (4.6
mg, 30 mmol), and Pd(PPh3)4 (600 mg, 0.52 mmol). The flask was
evacuated and back-filled with argon five times, then dry dioxane
(25 mL) was added. The solution was stirred at 115 °C for 48 h.
After cooling to room temperature, the reaction mixture was passed
on a SiO2 plug and eluted with EtOAc. Evaporation of the solvents
yields a crude product that was purified by column chromatography
on SiO2 with use of progressively more polar 90:10 f 75:25
1
(10.72 g, 99%). Mp 181-183 °C; H NMR (500 MHz, CDCl3) δ
7.50-7.47 (m, 4H), 7.09-7.07 (m, 4H), 5.79 (d, 2H), 4.16 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 160.7, 147.7, 147.5, 143.1, 143.0,
138.1, 126.2, 126.1, 124.9, 124.8, 55.4, 50.5, 47.2; IR (KBr) 3045,
2949, 1568, 1458, 1305, 1208, 730; HR-MS (ESI) calcd for C19H13-
ClN2O [M + H]+ 321.0789, found 321.0790.
(d) 1,1,4,4,8,8,11,11-Octamethyl-1,2,3,4,8,9,10,11-octahydro-
pentacene (8). 9,10-Dihydroanthracene (27 g, 150 mmol) and 2,5-
dichloro-2,5-dimethylhexane (75 g, 410 mmol) were placed in a
1-L Schlenk flask, and the contents were evacuated and back-filled
with argon five times. Dry CH2Cl2 (ca. 600 mL) was added to the
flask and the resulting solution was then cooled to -78 °C in a
dry ice/acetone bath, at which point the contents turned into a loose
sludge or slurry. To the reaction mixture was then slowly added
TiCl4 (86 g, 450 mmol) over the course of ca. 10-20 min. The
reaction mixture was stirred overnight as it was allowed to slowly
warm to room temperature. As the reaction progresses gases
(presumably HCl) are slowly evacuated through a connection to
an oil bubbler. The contents of the reaction mixture were poured
over crushed ice (∼600 mL) and extracted with CH2Cl2. The
combined organic layers were washed with sat. NaHCO3 and dried
over MgSO4 and the solvent was evaporated under reduced pressure.
The crude solid was purified by passage through a SiO2 plug first
with hexanes, then with CH2Cl2 as eluant. After evaporation of the
solvents the resulting solid was further purified by suspending and
triturating in boiling EtOH (ca. 1.5 L). After isolation by filtration
and drying under vacuum, the anthracene 8 is obtained as a pale
10178 J. Org. Chem., Vol. 72, No. 26, 2007

Iptycene-DeriVed Pyridazines and Phthalazines
hexanes:ethyl acetate (v/v) to afford 22 as a white solid (3.09 g,
91%). Mp 213-215 °C; H NMR (500 MHz, CDCl3) δ 7.72-
2.0 mmol) and solid NaOMe (125 mg, 2.3 mmol) were placed in
a Schlenk flask, and the contents were evacuated and back-filled
with argon five times. Dry THF (∼50 mL) was added and the
resulting mixture was stirred at room temperature for 2 days.
Solvents were then evaporated under reduced pressure and the
residue was purified by chromatography on SiO2 with use of 10:
4:1 hexanes:dichloromethane:ethyl acetate (v/v/v) as the mobile
phase to yield first unreacted starting material 33a (0.48 g recovery),
followed by the desired chloro methoxy dimer 34 as a white solid
(0.32 g, 28% or 47% based on recovered starting material) and
finally the dimethoxy dimer 31a (0.10 g). Mp 318 °C dec; 1H NMR
(500 MHz, CDCl3) δ 7.59-7.57 (d, 2H, J ) 7.0 Hz), 7.54-7.53
(d, 2H, J ) 7.0 Hz), 7.51-7.50 (d, 2H, J ) 7.0 Hz), 7.45-7.44
(d, 2H, J ) 7.0 Hz), 7.14-7.02 (m, 8H), 6.40 (s, 1H), 6.23 (s,
1H), 6.01 (s, 1H), 5.96 (s, 1H), 4.36 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 160.8, 152.7, 151.9, 149.8, 149.3, 148.8, 146.3, 143.9,
143.5, 143.1, 142.5, 136.5, 126.5, 126.2, 126.0, 125.8, 125.7, 125.4,
124.8, 124.5, 55.5, 50.3, 50.2. 50.0, 46.7; HR-MS (ESI) calcd for
C37H23 ClN4O [M + H]+ 575.1633, found 575.1613.
1
7.70 (d, 2H, J ) 7.0 Hz), 7.63-7.60 (t, 2H, J ) 7.3 Hz), 7.58-
7.56 (d, 1H, J ) 7.0 Hz), 7.53-7.52 (d, 2H, J ) 6.5 Hz), 7.42-
7.40 (d, 2H, J ) 6.0 Hz), 7.10-7.04 (m, 4H), 5.90 (s, 1H), 5.81
(s, 1H), 4.20 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.1, 153.8,
147.1, 143.85, 143.79, 136.6, 135.2, 129.4, 129.0, 128.9, 126.0,
125.9, 124.8, 124.5, 55.1, 50.4, 46.8; IR (KBr) 3043, 2945, 1570,
1458, 1315, 1265, 736; HR-MS (ESI) calcd for C25H18N2O [M +
H]+ 363.1492, found 363.1485.
Typical Procedures for the Preparation of Dimers and Higher
Oligomers by Reductive Coupling (“a” series): (a) 1,1′-Bi(9,-
10-dihydro-4-methoxy-9,10-[1′′,2′′]benzeno-2,3-diazaanthrace-
nyl) (31a). In a septum-capped Schlenk flask are placed the
methoxy chloride 6a (7.50 g, 23 mmol), activated zinc dust (9.1 g,
140 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (820
mg, 1.2 mmol), and triphenylphosphine (612 mg, 2.3 mmol). The
flask is evacuated and back-filled with argon five times, and dry
dimethylformamide (ca. 90 mL) is added. The resulting mixture is
stirred at 100 °C for ca. 20 h, after which TLC indicates complete
consumption of the starting material. The reaction mixture is then
poured into a large excess of aq Na2EDTA and triturated for a few
hours. Filtration of the precipitates yields a crude product that is
purified by column chromatography on silica gel with use of 10:
4:1 hexanes:dichloromethane:ethyl acetate (v/v/v) as the mobile
phase, to yield the pure 31a as a white solid (6.34 g, 95%). Mp
(e) 1,1′-Bi(6,11-dihydro-4-methoxy-6,11-[1′′,2′′]benzeno-2,3-
diazatetracenyl) (35). In a septum-capped Schlenk flask are placed
the methoxy chloride 14a (185 mg, 0.5 mmol), activated zinc dust
(195 mg, 3.0 mmol), trans-dichlorobis(triphenylphosphine)palladium-
(II) (35 mg, 0.05 mmol), and triphenylphosphine (26 mg, 0.10
mmol). The flask is evacuated and back-filled with argon five times,
and dry dimethylformamide (3 mL) is then added. The resulting
mixture is stirred at 100 °C for ca. 20 h, after which TLC indicates
complete consumption of the starting material. The reaction mixture
is poured into a large excess of aq Na2EDTA and triturated for a
few hours. Filtration of the precipitates yields a crude product that
is purified by column chromatography on silica gel with use of
5:1 dichloromethane:ethyl acetate (v/v) as the mobile phase, yielding
the pure dimer 35 as a white solid (37 mg, 17%). Mp >310 °C
1
>330 °C; H NMR (500 MHz, CDCl3) δ 7.52-7.50 (d, 4H, J )
7 Hz), 7.41-7.40 (d, 4H, J ) 7 Hz), 7.07-6.99 (m, 8H), 6.14 (s,
2H), 5.93 (s, 2H), 4.36 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
160.6, 150.2, 149.4, 144.2, 143.7, 136.2, 126.0, 125.7, 125.4, 124.4,
55.4, 50.2, 46.8; IR (KBr) 3044, 2949, 1568, 1457, 1347, 1263,
729; HR-MS (ESI) calcd for C38H26N4O2 [M + H]+ 571.2129,
found 571.2122.
1
dec; H NMR (500 MHz, CDCl3) δ 8.29 (s, 2H), 7.82 (s, 2H),
(b) 1,1′-Bi(9,10-dihydro-9,10-[1′′,2′′]benzeno-2,3-diazaanthra-
cenyl)-4,4′(3H,3′H)-dione (32a). Dimethoxy dimer 31a (6.00 g,
10.5 mmol) was added to a stirred solution of hydrogen bromide
in acetic acid (33% by wt, 60 mL) and the mixture was heated to
90 °C overnight. Upon warming dissolution occurs and a violent
gas release is observed. The mixture is then cooled and most of
the solvent is evaporated under reduced pressure. The resulting solid
is suspended and triturated for several hours in a solution of sodium
acetate (ca. 25 g in 200 mL of H2O). Filtration affords 32a as a
pale beige solid (5.20 g, 91%). Mp >330 °C; 1H NMR (500 MHz,
(CD3)2SO) δ 13.59 (s, 2H), 7.56-7.55 (d, 4H, J ) 7 Hz), 7.39-
7.38 (d, 4H, J ) 7 Hz), 7.00-6.99 (m, 8H), 6.03 (s, 2H), 5.98 (s,
2H); 13C NMR (125 MHz, (CD3)2SO) δ 158.3, 150.4, 146.3, 143.9,
143.7, 138.4, 125.4, 125.3, 124.8, 124.2, 49.7, 46.4; HR-MS (ESI)
calcd for C36H22N4O2 [M + H]+ 543.1816, found 543.1838.
(c) 1,1′-Bi(4-chloro-9,10-dihydro-9,10-[1′′,2′′]benzeno-2,3-di-
azaanthracenyl) (33a). The deprotected dimer 32a (4.00 g, 74
mmol) was stirred overnight at 90 °C in ca. 80 mL of neat POCl3.
The mixture was cooled, and the excess POCl3 was evaporated
under reduced pressure. The brown gummy residue was redissolved
in PhMe (ca. 50 mL) and evaporated again under reduced pressure
to eliminate more of the residual POCl3. The residue was then
dissolved in CH2Cl2 (ca. 80 mL), triturated with neutral alumina
for 1 h, filtered through a neutral alumina plug, and eluted first
with CH2Cl2, then with EtOAc. Evaporation of the solvents under
reduced pressure, followed by purification by chromatography on
SiO2 with use of 10:4:1 hexanes:dichloromethane:ethyl acetate (v/
v/v) as the mobile phase yields the pure 33a as a white solid (2.84
g, 66%). Mp >330 °C; 1H NMR (500 MHz, CDCl3) δ 7.58-7.56
(d, 4H, 7 Hz), 7.49-7.48 (d, 4H, 7 Hz), 7.13-7.06 (m, 8H), 6.37
(s, 2H), 5.99 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 152.4, 151.8,
149.2, 146.6, 142.9, 142.4, 126.6, 126.4, 125.7, 124.9, 50.20, 50.17;
IR (KBr) 3044, 2988, 1531, 1459, 1287, 1194, 705; HR-MS (ESI)
calcd for C36H20Cl2N4 [M + H]+ 579.1138, found 579.1117.
(d) 6-Chloro-4,4′,5,5′-bis(9,10-dihydroanthracen-9,10-diyl)-
6′-methoxy-3,3′-bipyridazine (34). Dichloro dimer 33a (1.16 g,
7.44-7.42 (d, 4H, J ) 6.5 Hz), 7.32-7.31 (d, 4H, J ) 7.0 Hz),
7.05-6.97 (m, 8H), 5.67 (s, 2H), 5.45 (s, 2H), 4.38 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 161.0, 152.4, 149.3, 149.1, 143.58,
143.55, 127.6, 126.04, 126.03, 124.5, 124.1, 120.4, 118.8, 117.1,
55.3, 54.2, 53.9; HR-MS (ESI) calcd for C46H30N4O2 [M + H]+
671.2442, found 671.2446.
(f) Quaterpyridazine (37). In a septum-capped Schlenk flask
are placed the chloro methoxy dimer 34 (115 mg, 0.20 mmol),
activated zinc dust (78 mg, 1.2 mmol), trans-dichlorobis(triph-
enylphosphine)palladium(II) (14 mg, 0.02 mmol), and triph-
enylphosphine (11 mg, 0.04 mmol). The flask is evacuated and
back-filled with argon five times, and dry dimethylformamide (3
mL) is then added. The resulting mixture is stirred at 100 °C for
ca. 20 h. After cooling to room temperature, the mixture is diluted
with dichloromethane (∼5 mL) and SiO2 (∼300 mg) is added.
Evaporation of the solvents under reduced pressure affords a crude
product dispersed on silica gel that is purified by column chroma-
tography on silica gel with use of progressively more polar 10:4:1
f 5:4:1 hexanes:dichloromethane:ethyl acetate (v/v/v) as the mobile
phase, yielding the pure tetramer 37 as a pale yellow solid (82 mg,
1
79%). Mp >210 °C dec; H NMR (500 MHz, CDCl3) δ 7.58-
7.56 (m, 4H), 7.52-7.50 (m, 4H), 7.46-7.44 (m, 4H), 7.43-7.41
(m, 4H), 7.13-7-07 (m, 16H), 6.41 (s, 2H), 6.18 (s, 2H), 6.09 (s,
2H), 6.01 (s, 2H), 4.44 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
160.9, 152.7, 152.6, 150.3, 150.0, 147.8, 147.4, 144.1, 143.7, 143.5,
143.3, 136.4, 126.3, 126.2, 126.1, 125.9, 125.4, 125.3, 125.2, 124.6,
55.5, 50.5, 50.0, 49.8, 46.9; IR (KBr) 3043, 2951, 1569, 1459, 1379,
1299, 730; HR-MS (ESI) calcd for C74H46N8O2 [M + H]+
1079.3816, found 1079.3782.
(g) Sexipyridazine (38). In a septum-capped Schlenk flask are
placed the chloro methoxy dimer 34 (230 mg, 0.40 mmol), the
dichloro dimer 33a (58 mg, 0.10 mmol), activated zinc dust (235
mg, 3.6 mmol), trans-dichlorobis(triphenylphosphine)palladium-
(II) (42 mg, 0.06 mmol), and triphenylphosphine (32 mg, 0.12
mmol). The flask is evacuated and back-filled with argon five times,
J. Org. Chem, Vol. 72, No. 26, 2007 10179

Bouffard et al.
and dry dimethylformamide (3 mL) is then added. The resulting
mixture is stirred at 100 °C for ca. 24 h. After cooling to room
temperature, the mixture is diluted with dichloromethane (∼5 mL)
and SiO2 (∼300 mg) is added. Evaporation of the solvents under
reduced pressure affords a crude product dispersed on silica gel
that is purified by column chromatography on silica gel with use
of progressively more polar 10:4:1 f 5:4:1 hexanes:dichlo-
romethane:ethyl acetate (v/v/v) as the mobile phase, yielding first
fractions containing the tetramer 37, followed by fractions of lower
Rf containing the hexamer 38. Further purification by preparative
thin layer chromatography on SiO2 with use of 8:8:2 hexanes:
dichloromethane:ethyl acetate (v/v/v) as the mobile phase affords
the hexamer 38 as a pale yellow solid (20 mg, 13%) with an
estimated purity of 90-95% by NMR that could not be further
upped by chromatography or crystallization. Mp >330 °C; 1H NMR
(500 MHz, CDCl3) δ 7.61-7.57 (m, 4H), 7.56-7.55 (m, 4H),
7.53-7.48 (m, 16H), 7.16-7.11 (m, 24H), 6.45 (s, 2H), 6.24 (s,
2H), 6.22 (s, 2H), 6.21 (s, 2H), 6.17 (s, 2H), 6.04 (s, 2H), 4.47 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 161.0, 153.1, 152.9, 152.8,
152.5, 150.3, 150.0, 148.1, 148.0, 147.9, 147.5, 144.1, 143.8, 143.5,
143.4, 143.3, 136.5, 126.5, 126.4, 126.3, 126.1, 125.9, 125.5, 125.5,
125.4, 125.3, 125.2, 124.6, 55.6, 50.6, 50.1 (3), 49.8, 46.9; IR (KBr)
3042, 2950, 2926, 1570, 1459, 1374, 1297, 729; HR-MS (ESI) calcd
for C110H66N12O2 [M + 2H]2+ 794.2789, found 794.2773.
Acknowledgment. This work was supported in part by a
NSERC fellowship (J.B.), the Office of Naval Research and
the National Science Foundation. We thank Dr. Changsik Song
for a gift of 2,2′-bithiophen-5-yltributylstannane, and Dr. Phoebe
Kwan for a gift of 2-tributylstannyl-3,4-ethylenedioxythiophene.
We thank the Department of Chemistry Instrumentation Facility
at MIT for HR-MS and NMR assistance.
Supporting Information Available: Complete experimental
procedures and characterization data including copies of the 1H and
13C NMR spectra for all new compounds, crystallographic data (in
CIF format), Cartesian coordinates of the minimized structures and
potential energy curve of rotamers about the biaryl linkage, and
UV-vis and IR spectra of selected compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO702000D
10180 J. Org. Chem., Vol. 72, No. 26, 2007