Synthesis of Cyclo-2,2′:4′,4″:2″,2?:4?,4″″: 2″″,2″″′:4″″′,4-sexipyridine

Article abstract of DOI:10.1021/jo962236k

Preparation of the title compound (2) by use of Stille couplings and a Kroehnke pyridine synthesis is described. By application of the Stille coupling reaction, preparation and functionalization of quater- and quinquepyridines 26, 27, and 28 were achieved. Elaboration of quinquepyridine 27 to the pyridinium salt 30 bearing a protected enal allowed for the synthesis of 2 by a one-pot deprotection/Kroehnke reaction in nine steps from 4,4′-bipyridine. Use of the Kroehnke pyridine synthesis has been applied to prepare sexipyridine dibromide 19, but attempts to induce a macrocyclization via metal-mediated (Pd/Ni/Cu) aryl-aryl coupling procedures proved unsuccessful. Acetylene-bridged sexipyridines 3a and 3b incorporating 2,2′-bipyridine units proved to be inaccessible via sp-sp² or sp-sp coupling protocols.

Full text of DOI:10.1021/jo962236k

2
774
J . Org. Chem. 1997, 62, 2774-2781
Syn th esis of Cyclo-2,2′:4′,4′′:2′′,2′′′:4′′′,4′′′′:2′′′′,2′′′′′:4′′′′′,4-sexip yr id in e
T. Ross Kelly,* Yean-J ang Lee, and Richard J . Mears
Department of Chemistry, E. F. Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02167
Received December 3, 1996X
Preparation of the title compound (2) by use of Stille couplings and a Kr o¨ hnke pyridine synthesis
is described. By application of the Stille coupling reaction, preparation and functionalization of
quater- and quinquepyridines 26, 27, and 28 were achieved. Elaboration of quinquepyridine 27 to
the pyridinium salt 30 bearing a protected enal allowed for the synthesis of 2 by a one-pot
deprotection/Kr o¨ hnke reaction in nine steps from 4,4′-bipyridine. Use of the Kr o¨ hnke pyridine
synthesis has been applied to prepare sexipyridine dibromide 19, but attempts to induce a
macrocyclization via metal-mediated (Pd/Ni/Cu) aryl-aryl coupling procedures proved unsuccessful.
Acetylene-bridged sexipyridines 3a and 3b incorporating 2,2′-bipyridine units proved to be
2
inaccessible via sp-sp or sp-sp coupling protocols.
In tr od u ction
matrix. This paper describes our efforts to prepare the
parent compound 2 and the two simple acetylenic analogs
3
a and 3b.
The design of metal-chelating organic ligands that
To date, only two examples, 4a and 4b, of cyclic
assemble into structurally defined architectures when
chelated to metals continues to be a major research topic
7
oligopyridines have been reported, and in both cases the
nitrogen atoms are directed toward the center of the
molecule, i.e. “endo”.8 A number of cyclic bipyridines
1
in the field of supramolecular chemistry. Such struc-
tures have possible applications as selective catalysts and
9
joined by flexible spacer units have been reported.
2
filters or as media for electron transfer in mixed valency
However, none of these structural types possesses the
required symmetry or structural rigidity necessary for
the formation of predictable molecular networks.
structures with the potential to act as molecular wires
or switches.3 To this end, we hoped to prepare a ligand
with D3h symmetry,4 exploiting the well-documented5
chelating properties of the 2,2′-bipyridine system with a
diverse range of metals. The molecules we envisioned
to possess both the desired symmetry and the potential
to form predictable chelated network structures (e.g.,
6
organic zeolites ) were cyclic sexipyridines of the general
form 1 where X could be varied to change the pore size
of the network and/or to embed functionalities within the
*
Author to whom correspondence should be addressed. Tel: (617)
5
52-3621. Fax: (617) 552-2705.
X
Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) (a) Zaworotko, M. J . Chem. Soc. Rev. 1994, 283. (b) Moore, J .
S.; Lee, S. Chem. Ind. (London) 1994, 557. (c) Abrahams, B. F.;
Hoskins, B. F.; Michail, D, M.; Robson, R. Nature 1994, 369, 727. (d)
Hunter, C. A. Angew. Chem., Int. Ed. Engl. 1995, 34, 1079. (e) Fujita,
M.; Kwon, Y. J .; Washizu, S.; Ogura, K. J . Am. Chem. Soc. 1994, 116,
1
1
151. (f) Drain, C. M.; Lehn, J .-M. J . Chem. Soc., Chem. Commun.
994, 2313. (g) Hanan, G. S.; Arana, C. R.; Lehn, J .-M.; Fenske, D.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1122. (h) Baxter, P. N. W.;
Lehn, J .-M.; Fisher, J .; Youinou, M.-T. Angew. Chem., Int. Ed. Engl.
1
994, 33, 2284. (i) De Munno, G.; J ulve, M.; Nicolo, F.; Lloret, F.; Faus,
J .; Ruiz, R.; Sinn, E. Angew. Chem., Int. Ed. Engl. 1993, 32, 613.
2) (a) Service, R. F. Science 1994, 265, 1363. (b) Holderich, W.;
(
Hesse, M.; N a¨ umann, F. Angew. Chem., Int. Ed. Engl. 1988, 27, 226
and references therein. (c) Amato, I. Science 1993, 259, 891. (d)
Subramanian, S.; Zaworotko, M. J . Angew. Chem., Int. Ed. Engl. 1995,
3
4, 2127.
3) (a) Ward, M. D. Chem. Soc. Rev. 1995, 121. (b) Sauvage, J .-P.;
(
Collin, J .-P.; Chambron, J .-C.; Guillerez, S.; Condret, C.; Balzani, V.;
Barigelletti, F.; De Cola, L.; Flamigni, L. Chem. Rev. 1994, 94, 993.
(c) Benniston, A. C.; Grosshenny, V.; Harriman, A.; Ziesel, R. Angew
Chem., Int. Ed. Engl. 1994, 33, 1884. (d) Marfurt, J .; Zhao, W.; Walder,
L. J . Chem. Soc., Chem. Commun. 1994, 51. (e) Ward, M. D. Chem.
Ind. (London) 1996, 568.
(7) (a) Newkome, G. R.; Lee, H.-W. J . Am. Chem. Soc. 1983, 105,
5956. (b) Toner, J . L. Tetrahedron Lett. 1983, 24, 2707.
(8) As a convenient way of distinguishing between molecules such
as 4a , where the nitrogens are on the inside (endo), and 2, where the
nitrogens are on the outside (extra, as in extraterrestrial), we suggest
4a be named endo-sexipyridine and 2 extra-sexipyridine.
(9) (a) Kaes, C.; Hosseini, M. W.; Ruppert, R.; De Cian, A.; Fischer,
J . J . Chem. Soc., Chem. Commum. 1995, 1445. (b) Newkome, G. R.;
Gupta, V. K.; Sauer, J . D. In Pyridine and its Derivatives: The
Chemistry of Heterocyclic Compounds; Newkome, G. R., Ed.; J ohn
Wiley: New York, 1984; Vol. 14, Part 5, Chapter 3, pp 447-633.
(
4) Other ligands with D3h symmetry include 2,4,6-tri(4-pyridyl)-
,3,5-triazine (Batten, S. R.; Hoskins, B. F.; Robson, R. J . Am. Chem.
Soc. 1995, 117, 5385) and 1,4,5,8,9,12-hexaazatriphenylene (HAT)
Nasielski-Hinkens, R.; Benedek-Vamos, M.; Maetens, D.; Nasielski,
J . J . Organomet. Chem. 1981, 217, 179).
1
(
(
5) Gillard, R. D. Coord. Chem. Rev. 1975, 6, 187.
(6) (a) Venkaraman, D.; Gardner, G. B.; Lee, S.; Moore, J . S. J . Am.
Chem. Soc. 1995, 117, 11600. (b) Moore, J . S. Nature 1995, 374, 495.
c) Ward, M. D. Nature 1995, 374, 764.
(
S0022-3263(96)02236-0 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Cyclosexipyridine
Sch em e 1
J . Org. Chem., Vol. 62, No. 9, 1997 2775
palladium source with and without CuI as the cocatalyst,
in benzene13 and DMF containing 2 molar equiv of a
14
3 2
base (Et N or i-Pr
NH),12 or conducted the experiment
in neat amine15 (90-130 °C/4-24 h/sealed tube), but in
no cases were any coupling products observed. Our
failure to couple these reagents may lie in the poor
reactivity of 7 toward aromatic coupling, as a trial
reaction of 7 with bromobenzene afforded the diphenyl
derivative 9 in only 21% yield.
Having acetylene 7 in hand, we also investigated the
oxidative homocoupling (eq 1) of this molecule, hoping
to prepare sexipyridine 3b. A Glaser coupling under the
conditions of Hay16 or the Vogtle procedure in air, or
under an atmosphere of argon, failed to afford any
coupled products. Disappointingly, attempts to induce
17
1
8
a palladium-mediated coupling using chloroacetone also
failed to give any of the desired product. This inability
2
to access acetylene-bridged oligobipyridines by sp-sp or
sp-sp coupling protocols led us to change focus and in-
vestigate the synthesis of the “unbridged” sexipyridine
2
.
Our first attempts to synthesize sexipyridine 2 sought
to take advantage of the wide range of aryl-aryl coupling
methodologies to form the target molecule via an in-
tramolecular coupling reaction.19 With this strategy in
mind, we hoped to prepare dibromide 19 by a Kr o¨ hnke
reaction20 between the bis-pyridinium salt 16 and alde-
hyde 18 (Scheme 2). Diamine 10 was prepared from 4,4′-
bipyridine using the Chichibabin reaction;21 a subsequent
diazotization and hydrolysis generated the pyridone 11
Resu lts a n d Discu ssion
Our initial attempts to prepare ligands such as 1-3
focused on the preparation of sexipyridine 3a . When the
three 2,2′-bipyridine systems are connected by 0-n
acetylene spacer units, variation of spacer units has the
potential to allow tuning of the cavity sizes of any
network structures formed, an important consideration
in 86% overall yield. The pyridone was then subjected
in the design of size-selective filters2 or catalysts. We
a
2b
22
to bromination with POBr
3
,
affording dibromide 12 in
had hoped to prepare the precursor dibromide 8 (Scheme
60% yield; surprisingly, the dichloro analogue of 12 is
1
0
1
) and complete the synthesis by a mono-Sonogashira
coupling with (trimethylsilyl)acetylene, removal of the
trimethylsilyl group, and a final cyclization/coupling to
the desired product. Dibromide 5 was prepared (three
(13) (a) Bumagin, N. A.; Ponomaryov, A. B.; Beletskaya, I. P.
Synthesis 1984, 729. (b) Takehashi, S.; Kuroyama, Y.; Sonogashira,
K.; Hagihara, N. Synthesis 1980, 627.
(14) Chen, Q.-Y.; Yang, Z.-Y. Tetrahedron Lett. 1986, 27, 1171.
steps, 24% overall yield) according to literature proce-
(15) Tilley, J . W.; Zawoiski, S. J . Org. Chem. 1988, 53, 386.
(16) Hay, A. S. J . Org. Chem. 1962, 27, 3320.
dures,11 and a subsequent Sonogashira coupling using the
(
17) Berscheid, R.; V o¨ gtle, F. Synthesis 1992, 59.
1
2
method of Ziesel yielded the doubly substituted (tri-
methylsilyl)acetylene 6. In our hands, formation of
significant amounts of monocoupled material was ob-
served using only 2.5 equiv of (trimethylsilyl)acetylene;
we found it necessary to use 6 equiv of (trimethylsilyl)-
acetylene to drive the reaction to completion. Removal
(18) Rossi, R.; Carpita, A.; Bigelli, C. Tetrahedron Lett. 1985, 26,
523.
(19) (a) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int.
Ed. Engl. 1990, 29, 977. (b) Knight, D. W. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 3, pp 505-509.
(20) (a) Kr o¨ hnke, F. Synthesis 1976, 1. (b) Constable, E. C.; Lewis,
J . Tetrahedron 1982, 1, 303. (c) Constable, E. C.; Ward, M. D.; Corr,
J . Inorg. Chim. Acta 1988, 141, 201. (d) Constable, E. C.; Ward, M.
D.; Tocher, D. A. J . Chem. Soc., Dalton Trans. 1991, 1675. (e) Con-
stable, E. C.; Chotalia, R. J . Chem. Soc., Chem. Commun. 1992, 65.
2 3
of the trimethylsilyl group with K CO in methanol
surrendered the diacetylene 7 in 39% overall yield from
dibromide 5; the spectral data for both acetylene com-
pounds 6 and 7 agree with those reported.12
Palladium-catalyzed coupling of the acetylene 7 with
dibromide 5 to produce 8 proved to be an insurmountable
problem, despite myriad attempts. We attempted the
(
21) Leffler, M. T. Org. React. 1942, 1, 91.
(22) POBr was prepared by a procedure developed by Dr. S. Christie
3
in our laboratories, which is carried out as follows: Into a beaker
containing PBr (37 mL, 0.40 mol) cooled to 5 °C, bromine (20.6 mL,
3
.40 mol) was introduced dropwise while the mixture was stirred with
0
a glass rod, giving a deep orange solid. To this solid was slowly
introduced water (7.2 mL, 0.40 mol) (CARE: EXOTHERMIC), and
mixing was continued between additions. The resulting orange slush
was transferred to a round-bottomed flask and distilled under vacuum
(20 Torr) using a warm condenser (to prevent solidification in and
blocking of the condenser). Fractions were collected between 92 and
120 °C (head temperature). Yield fraction 1 (<100 °C head temper-
ature, 37.7 g, 33%), total yield (98.7 g, 87%). The first fraction collected
(<100 °C) was a pale orange semisolid and was found to be superior
to higher boiling fractions (colorless, crystalline solid mass) for the
bromination of pyridone 11.
3 4 2 3 2
coupling reactions using Pd(PPh ) or PdCl (PPh ) as the
(
10) (a) Sonogashira, K. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 521-
49. (b) Nicolaou, K. C.; Sorensen, E. J . Classics in Total Synthesis;
VCH Publishers: New York, 1996; p 582.
11) (a) Wenkert, D.; Woodward, R. B. J . Org. Chem. 1983, 48, 283.
Nakashima, K.; Shinkai, S. Chem. Lett. 1994, 1267.
12) Suffert, J .; Ziesel, R. Tetrahedron Lett. 1991, 32, 757.
5
(
(

2
776 J . Org. Chem., Vol. 62, No. 9, 1997
Kelly et al.
Sch em e 2
using I
2
/pyridine gave lower yields (<45%) of the corre-
sponding bis-pyridinium iodide of 16. Bromo aldehyde
1
7 was prepared from 2-aminopicoline in four steps, 12%
2
9
overall yield, by a reported procedure; subsequent
Wittig reaction with (triphenylphosphoranylidene)acet-
aldehyde afforded an 84% yield of aldehyde 18.
A
Kr o¨ hnke reaction between bis-pyridinium salt 16 and
aldehyde 18 in acetic acid afforded the dibromide 19 in
1
7%. A number of unidentified pyridine products are also
1
formed in this reaction; olefinic signals ( H NMR) in the
crude products lead us to postulate that a competing 1,2-
addition to the aldehyde 18 may occur. Use of DMF or
methanol2 as the solvent was found to give lower yields
0a
(ca. 3% and 6%, respectively); in these latter cases, even
greater amounts of competing olefinic products were
observed in the crude products.
Intramolecular coupling of the dibromide 19 was
examined exhaustively using palladium-, nickel-, and
copper-mediated coupling processes. A one-pot halogen-
3
0
metal exchange /Stille coupling between 0.5 molar equiv
of hexamethylditin and dibromide 19, using either Pd-
3 4 2 3 2
(PPh ) or PdCl (PPh ) , inexplicably gave only mixtures
of starting material and the bis(trimethylstannane)
derivative of 19. Nickel coupling by in-situ preparation
3
1
of Ni(0) (NiBr
2 3 2 4
(PPh ) /Zn/Et NI/DMF or THF) was
found to give mixtures of starting materials and debro-
3
2
minated products using 1 and 4 equiv of Ni(0) (a
treatment with KCN33 during workup was used to cleave
any metal complexes). Use of preformed Ni(0) (Ni(COD)
2
2
/
,2′-bipyridine/DMF)34 gave polypyridines by intermo-
lecular coupling; even at a 50× dilution factor (0.001 M
vs 0.050 M) these polymeric materials were the only
products observed. Finally, dibromide 19 was found to
3
5
be unreactive to Ullmann coupling in DMF or DMF
with catalytic palladium.36 Use of biphenyl as solvent
in the Ullmann reaction was also found to be unsuccess-
ful. At temperatures <280 °C no reaction was observed,
even after 48 h; at higher temperatures only debromi-
nation products were observed. Such a result is consis-
37
the only 2,2′-dihalo-4,4′-bipyridine to be reported23 in the
literature, and our procedure represents the first route
to access such compounds without the use of autoclave
techniques. Conversion to bis(ethoxyvinyl)bipyridine 14
20e
tent with the observation by Constable that 2-bromo-
terpyridines are unreactive toward Ullmann coupling
procedures. It is striking that cyclization of 19 to 2 could
not be achieved despite the many advances in methods
2
4
utilized the stannane 13 which serves as a masked
acyl25 or R-haloacyl group for introduction of these
substituents into aromatic systems via a Stille coupling
process.27 Coupling of the stannane 13 with dibromide
26
19b
for achieving biaryl couplings and this research group’s
26a,38
considerable experience
in achieving such couplings.
1
2 proceeded smoothly to give an 86% yield of the desired
Perhaps geometric constraints of a relatively rigid system
prevent the organometallic intermediates from achieving
the necessary conformation.
bis(ethoxyvinyl)bipyridine 14, and bromination with NBS
under aqueous conditions gave the bis(bromoacetyl)bi-
pyridine 15 in 93% yield. This compound was surpris-
ingly stable in light of its subsequent facile substitution
reaction with pyridine: 15 could be recrystallized from
hot ethanol:water mixtures without evidence of any
solvolysis and stored in a freezer indefinitely. Finally,
reaction of 15 with a stoichiometric amount of pyridine
in acetone gave an 89% yield of the bis-pyridinium salt
Our lack of success with metal-mediated coupling
reactions led us to examine the Kr o¨ hnke reaction as a
7b
means of cyclization, as demonstrated by Toner in the
(
28) King, L. C. J . Am. Chem. Soc. 1944, 66, 894.
(29) Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya, C.;
Watanabe, M.; Yokoyama, K. Chem. Pharm. Bull. 1990, 38, 2446.
(
30) Azizian, H.; Eaborn, C.; Pidcock, A. J . Organomet. Chem. 1981,
1
6. An alternative procedure involving acid hydrolysis
2
15, 49.
of the (ethoxyvinyl)bipyridine 14, followed by an Ortol-
(31) Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Bull. Chem.
eva-King28 reaction on the resulting bis(methyl ketone)
Soc. J pn. 1990, 63, 80.
32) Stoichiometric amounts of Ni(0) were used for coupling reac-
(
tions, cf. Constable, E. C.; Hannon, M. J .; Edwards, A. J .; Raithby, P.
R. J . Chem. Soc., Dalton Trans. 1994, 2669.
(33) Constable, E. C.; Elder, S. M.; Healy, J .; Tocher, D. A. J . Chem.
Soc., Dalton Trans. 1990, 1669.
(
23) Darragh, J . I. Brit. Patent 1,491,254, 1977; Chem. Abstr. 1978,
8
1
8, 190594j. Ruetman, S. H. U.S. Patent 3,819,558, 1971; Chem. Abstr.
974, 81, 91363g.
(
(
24) Soderquist, J . A.; Hsu, G. J .-H. Organometallics 1982, 1, 830.
25) (a) Kwon, H. B.; McKee, B. H.; Stille, J . K. J . Org. Chem. 1990,
(34) (a) Yamamoto, T.; Etori, H. Macromolecules 1995, 28, 3371. (b)
Yamamoto, T.; Maruyama, T.; Zhao, Z.; 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.
5
5, 3114. (b) Cheney, D. L.; Paquette, L. A. J . Org. Chem. 1989, 54,
334.
3
(
26) (a) Kelly, T. R.; Lang, F. J . Org. Chem. 1996, 61, 4623. (b)
Gaudry, M.; Marquet, A. Bull. Soc. Chim. Fr. 1969, 11, 4169.
27) Kosugi, M.; Sumiya, T.; Obara, Y.; Suzuki, M.; Sano, H.; Migata,
T. Bull. Chem. Soc. J pn. 1987, 60, 767.
(35) Fanta, P. E. Synthesis 1974, 9.-
(36) Shimizu, N.; Kitamura, T.; Watanabe, K.; Yamaguchi, T.;
Shigyo, H.; Ohta, T. Tetrahedron Lett. 1993, 34, 3421.
(37) Burstall, F. H. J . Chem. Soc. 1938, 108, 1662.
(

Synthesis of Cyclosexipyridine
Sch em e 3
J . Org. Chem., Vol. 62, No. 9, 1997 2777
Sch em e 4
synthesis of the substituted endo-sexipyridines 4b. A
Kr o¨ hnke reaction between dialdehyde 22 (Scheme 3) and
the previously prepared bis-pyridinium salt 16 would
afford the desired sexipyridine 2. Preparation of the
aldehyde involved a Sonogashira coupling of the dibro-
mide 5 with propiolaldehyde diethyl acetal to afford the
diacetal 20 in 81% yield. A subsequent partial hydro-
genation over Lindlar’s catalyst and hydrolysis of the
acetal group gave the (Z,Z)-dialdehyde 22 in 72% overall
yield from diacetal 20 although a facile isomerization
(
∼1-2 h) to the (E,E)-isomer was observed in acidic,
aqueous solutions. The final step involved a double
Kr o¨ hnke reaction between dialdehyde 22 and bis-pyri-
dinium salt 16. The reaction was examined at concen-
trations of 0.07 and 0.007 M in acetic acid, DMF,
methanol, and formamide.39 In all cases, only black
insoluble material was produced, possibly oligo/polypy-
ridines formed by “linear” Kr o¨ hnke reactions; no in-
soluble products were observed to be formed when the
reagents (dialdehyde 22 or bis-pyridinium salt 16) were
separately subjected to the reaction conditions.
intramolecular Kr o¨ hnke reaction could be favored by
dilution (eq 2).
Attempts to prepare the trimethylstannane derivative
3 2 2 3 2
of aldehyde 18 ((Me Sn) /PdCl (PPh ) /dioxane/130 °C) for
subsequent coupling with quaterpyridine 26 (Scheme 4)
were unsuccessful, resulting in unidentified degradation
products from which the aldehyde and olefinic signals
We hoped that synthesis of a suitably protected ana-
logue of quinquepyridine 23 would circumvent the prob-
1
were observed to be absent in the H NMR spectrum. The
instability of the R,â-unsaturated aldehyde group neces-
sitated protection of the aldehyde group to enable further
progress by a route involving a number of Stille coupling
reactions. Choosing a 1,3-dioxolane as a protecting group
for the aldehyde to be carried through the synthesis
balanced the stability of this group to the conditions
employed in subsequent Stille couplings and the aqueous
conditions used for NBS bromination, with the require-
ment that it be removed under the conditions of the
Kr o¨ hnke reaction to allow a one-pot deprotection/
Kr o¨ hnke pyridine formation to occur. Synthesis of the
pyridinium salt 30 utilized aldehyde 18 and dibromide
lem of linear (oligopolymerization) and that a single,
1
2, both prepared earlier, as starting materials. Protec-
tion of the aldehyde 18 under standard acetalization
conditions40 yielded dioxolane 24, which was subjected
to a palladium-mediated halogen-metal exchange with
(
38) For examples, see: (a) Kelly, T. R.; Bowyer, M. C.; Bhaskar,
K. V.; Bebbington, D.; Garcia, A.; Lang, F.; Kim, M. H.; J ette, M. P. J .
Am. Chem. Soc. 1994, 116, 3657. (b) Kelly, T. R.; Garcia, A.; Lang, F.;
Walsh, J . J .; Bhaskar, K. V.; Boyd, M. R.; G o¨ tz, R.; Keller, P. A.; Walter,
R.; Bringmann, G. Tetrahedron Lett. 1994, 35, 7621. (c) Kelly, T. R.;
Xu, W.; Sundaresan, J . Tetrahedron Lett. 1993, 34, 6173. (d) Kelly,
T. R.; Kim, M. H. J . Org. Chem. 1992, 57, 1593. (e) Kelly, T. R.;
Bridger, G. J .; Zhao, C. J . Am. Chem. Soc. 1990, 112, 8024. (f) Kelly,
T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161.
(39) van Esch, J . H.; Hoffmann, M. A. M.; Nolte, R. J . M. J . Org.
Chem. 1983, 48, 283.
(40) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley: New York, 1991; pp 188-193.

2
778 J . Org. Chem., Vol. 62, No. 9, 1997
Kelly et al.
hexamethylditin to give stannane 25 in 77% overall yield
from 18. Stille coupling with the quaterpyridine 26,
prepared from dibromide 12 in 29% yield by a one-pot
halogen-metal exchange/Stille coupling, afforded the
quinquepyridine 27. The yields of this reaction were
found to be very sensitive to the palladium catalyst used,
the best yields being observed with freshly prepared41
nitrogen. The black solid was filtered off under a blanket of
nitrogen44 and washed with hexane. The dry solid was
cautiously introduced to a rapidly stirred solution of dilute HCl
(300 mL of 2.0 M HCl) at 0 °C. The solution was acidified
with concd HCl to pH 5 and filtered, and the filtrate neutral-
ized with solid NaOH. After the resulting precipitate was
collected and washed with CHCl , the residue was dried in a
3
pistol at 25 Torr to give the diamine 10 (16.1 g, 91%) as a
brown solid of sufficient purity for subsequent reaction. An
analytical sample was obtained by repeated refluxing with
activated carbon in ethanol and filtration, until a colorless
solution was obtained. The product was isolated by evaporat-
ing the solvent in vacuo to give the pure product as a colorless,
Pd(PPh
gave a 50% yield of the disubstituted quinquepyridine
8. Bromination of quinquepyridine 28 with NBS in wet
3 4
) . A further Stille coupling with stannane 13
2
THF to give 29 was immediately followed by 29’s conver-
sion to the mono-pyridinium salt 30 in 83% overall yield
by a procedure analogous to the one used in the prepara-
tion of bis-pyridinium salt 16. It was observed that the
bromo ketone 29 was not stable at room temperature and
underwent slow (20-30%) decomposition over the course
of 2-3 days to give unidentified degradation products;
this instability is in marked contrast to the stability of
bis(bromoacetyl)bipyridine 15.
1
amorphous solid: mp 289-290 °C (sealed tube); H NMR
(
6
DMSO-d ) δ 6.08 (br s, 4H), 6.64 (d, J ) 1.6 Hz, 2H), 6.69
13C NMR
(
dd, J ) 5.2, 1.6 Hz, 2H), 7.98 (d, J ) 5.2 Hz, 2H);
(DMSO-d
6
) δ 104.9, 109.6, 146.7, 148.7, 160.5; IR (KBr) 3459
-
1
+
cm ; EIMS m/ z (rel int) 186 (100, M ). Anal. Calcd for
C
5
10
H
10
N
4
: C, 64.50; H, 5.41; N, 30.09. Found: C, 64.11; H,
.31; N, 29.91.
,2′-Dih yd r oxy-4,4′-bip yr id in e (11). To a rapidly stirred
2
solution of diamine 10 (10.0 g, 0.053 mol) in concd sulfuric
acid (25 mL) and water (150 mL) at 0 °C was added a solution
of sodium nitrite (125 mL of a 0.88 M solution in water, 0.11
mol) dropwise over 6 h with the temperature being carefully
maintained between 0 and 5 °C. The reaction mixture was
then stirred at this temperature for another 2 h, warmed to
room temperature, and stirred overnight. Filtration of the
resulting suspension and drying of the solid in vacuo (pistol,
The final step of the synthesis was the acetal depro-
tection-Kr o¨ hnke reaction. Using acetic acid at reflux,
all the starting material was observed to have been
1
consumed within 5-6 h. Upon examination of the H
NMR spectrum of the crude products, we were pleased
to observe the desired product as the only aromatic
component; sexipyridine 2 was secured in 81% yield after
workup. The success of the reaction may originate in the
slow deprotection of the dioxolane group, thus maintain-
ing a low concentration of the reactive aldehyde 23, so
favoring the intramolecular cyclization. Attempts to
purify 2 beyond simple solvent washing were frustrated
by the extreme insolubility of this compound. This
solubility problem and the tendency of the compound to
1
2 5
00 °C, P O desiccant) afforded the pyridone 11 (9.50 g, 0.051
mol, 94%) as a light brown solid. A pure sample was obtained
by recrystallization from acetic acid, giving 11 as a colorless
4
5
1
solid: mp 376-377 °C (sealed tube, lit. mp 355 °C); H NMR
(DMSO-d ) δ 6.44 (dd, J ) 7.2, 1.2 Hz, 2H), 6.59 (d, J ) 1.2
Hz, 2H), 7.46 (d, J ) 7.2 Hz, 2H), 11.73 (br s, 2H); C NMR
DMSO-d ) δ 103.3, 117.2, 136.1, 149.2, 162.4; IR (KBr) 3434,
6
1
3
(
6
-
1
+
1
645 cm ; EIMS m/ z (rel int) 188 (100, M ), 159 (20), 133
44), 104 (30). Anal. Calcd for C10 : C, 63.83; H, 4.28;
N, 14.89. Found: C, 63.60; H, 4.26; N, 14.92.
(
8 2 2
H N O
6
exhibit NMR signal broadening in solution (DMSO-d )
prevented the acquisition of 13C NMR data for this
compound. Attempts to sublime this compound under
vacuum (0.05 Torr) resulted in charring between 480 and
2
,2′-Dibr om o-4,4′-bip yr id in e (12). A stirred mixture of
22
pyridone 11 (0.800 g, 4.25 mmol) and freshly prepared POBr
3
(8.0 g, 28 mmol) in anisole (8.0 mL) was heated at 145 °C for
2 days. After cooling, the reaction mixture was poured into
ice water (300 mL) and basified with saturated sodium
carbonate solution until the pH was 8-9. The mixture was
4
90 °C without any evidence of sublimation, but the
1
simplicity (three resonances) of the H NMR (see Sup-
porting Information) and low (see Supporting Informa-
tion) and high resolution mass spectra document its
existence. Notwithstanding our success in preparing the
compound, the problems associated with its purification
and the impracticality of this route for the preparation
of significant quantities of cyclosexipyridine 2 have
prevented further investigations toward the application
of this compound to the generation of network structures.
In conclusion, we have accomplished the first synthesis
of cyclo-2,2′:4′,4′′:2′′,2′′′:4′′′,4′′′′:2′′′′,2′′′′′:4′′′′′,4-sexipyridine
extracted with CH
were dried over anhydrous sodium sulfate and evaporated in
vacuo. Purification of the residue by flash chromatography
2
Cl
2
(3 × 300 mL); the combined extracts
46
(silica gel, 1:1 CH
2 2 2
Cl :Et O) and recrystallization from ethanol
gave dibromide 12 (0.831 g, 2.64 mmol, 60%) as colorless, fine
1
needles: mp 188.5-191 °C; H NMR (CDCl
3
) δ 7.45 (dd, J )
.2, 1.6 Hz, 2H), 7.70 (dd, J ) 1.6, 0.8 Hz, 2H), 8.51 (dd, J )
.2, 0.8 Hz, 2H); 13C NMR (CDCl
) δ 120.5, 125.8, 143.3, 146.8,
51.0; EIMS m/ z (rel int) 316, 314, 312 (48, 100, 52, M ), 235,
2 2
33 (77, 79), 208, 206 (28, 30). Anal. Calcd for C10 Br N :
5
5
1
2
3
+
H
6
C, 38.25; H, 1.93; N, 8.92; Br, 50.90. Found: C, 38.24; H, 1.83;
N, 8.89; Br, 50.68.
(2) and highlighted the versatility of the Kr o¨ hnke reac-
tion for the preparation of oligopyridines inaccessible via
aryl-aryl coupling methodologies. Moreover, during the
course of our investigations we have prepared a number
of synthetically useful dibromo bi-, quater-, and sexipy-
ridines (12, 26, and 19) which should be of general
interest as intermediates in the preparation of function-
alized oligopyridines.
2,2′-Bis(r-eth oxyvin yl)-4,4′-bip yr id in e (14). Dibromide
12 (1.300 g, 4.14 mmol), bis(triphenylphosphine)palladium(II)
2
4
chloride (0.290 g, 0.41 mmol), and vinylstannane 13 (1.50
mL, 9.11 mmol) were introduced to a sealable tube containing
anhydrous dioxane (20 mL) and the reaction mixture de-
gassed.2 The tube was sealed and heated for 20 h at 130 °C;
after cooling, the solution was filtered and evaporated in vacuo.
The filtrate residue was subjected to flash chromatography
6a
(silica gel, 1:1 CH
2 2 2
Cl :Et O) to give the bis(ethoxyvinyl)-
bipyridine 14 (1.053 g, 86%) as a colorless solid. An analytical
Exp er im en ta l Section 42
(
43) The yield is particularly dependent on the quality of the sodium
2
,2′-Dia m in o-4,4′-bip yr id in e (10). A stirred mixture of
amide; the NaNH2 should be handled under an atmosphere of nitrogen,
and if a yellow color develops it should be disposed of, see: Merck Index,
4
3
4
,4′-bipyridine (15.0 g, 0.095 mol) and sodium amide (51.0
g, 1.3 mol) in p-cymene (200 mL) was refluxed for 2 days under
1
1th ed.; Merck & Co., Inc.: Rahway, NJ , 1989; entry 8519.
44) Filtration under vacuum results in exothermic reaction of the
(
excess sodium amide with atmospheric moisture, resulting in charring/
destruction of the product.
(45) Dehmlow, E. V.; Sleegers, A. Liebigs Ann. Chem. 1992, 953.
(46) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(
41) Coulson, D. R. Inorganic Syntheses; Angelici, R., Ed.; J ohn
Wiley: New York, 1990; Vol. 28, p 107.
42) For typical experimental protocols, see ref 26a.
(

Synthesis of Cyclosexipyridine
J . Org. Chem., Vol. 62, No. 9, 1997 2779
1
sample was obtained by recrystallization from cyclohexane to
amorphous solid: mp 317-318 °C; H NMR (CDCl
3
) δ 7.58
1
surrender pure 14 as colorless plates: mp 133-134 °C; H
(dd, J ) 4.8, 1.6 Hz, 2H), 7.65 (dd, J ) 5.2, 1.6 Hz, 2H), 7.77
(dd, J ) 4.8, 1.6 Hz, 2H), 7.89 (dd, J ) 1.6, 0.8 Hz, 2H), 8.54
(dd, J ) 5.2, 0.8 Hz, 2H), 8.77 (dd, J ) 1.6, 0.8 Hz, 2H), 8.86
(dd, J ) 4.8, 0.8 Hz, 2H), 8.87 (dd, J ) 4.8, 0.8 Hz, 2H), 8.90
(dd, J ) 1.6, 0.8 Hz, 2H); EIMS m/ z (rel int) 624, 622, 620
(52, 100, 48, M ), 543, 541 (34, 31), 192, 191 (48, 59), 105 (100).
30 18 2 6
Anal. Calcd for C H Br N : C, 57.90; H, 2.92; N, 13.50; Br,
25.68. Found: C, 57.84; H, 3.00; N, 13.36; Br, 25.82.
4,4′-Bis(3,3-d ieth oxyp r op yn yl)-2,2′-bip yr id in e (20). A
solution of dibromide 5 (0.100 g, 0.32 mmol), bis(triphenyl-
phosphine)palladium(II) chloride (0.010 g, 0.014 mmol), cop-
per(I) iodide (0.003 g, 0.02 mmol) and propionaldehyde diethyl
NMR (CDCl ) δ 1.47 (t, J ) 7.2 Hz, 6H), 4.01 (q, J ) 7.2 Hz,
3
4
H), 4.43 (d, J ) 2.2 Hz, 2H), 5.48 (d, J ) 2.2 Hz, 2H), 7.47
(
dd, J ) 5.2, 1.6 Hz, 2H), 7.94 (d, J ) 1.6 Hz, 2H), 8.67 (d,
1
3
J ) 5.2 Hz, 2H); C NMR (CDCl
1
3
) δ 14.4, 63.5, 85.3, 116.8,
+
20.6, 146.2, 149.5, 154.4, 158.0; EIMS m/ z (rel int) 296 (3,
+
M ), 281 (78), 255 (80), 104 (92), 99 (100). Anal. Calcd for
: C, 72.95; H, 6.80; N, 9.45. Found: C, 73.32; H,
.74; N, 9.35.
,2′-Bis(br om oa cetyl)-4,4′-bip yr id in e (15). Into a round-
bottomed flask were introduced bis(R-ethoxyvinyl)bipyridine
4 (0.339 g, 1.14 mmol), THF (35 mL), and water (8 mL). To
C
6
18
H
20
N
2
O
2
2
1
acetal (0.20 mL, 1.4 mmol) in Et
00 °C in a sealed tube for 24 h. Filtration and evaporation
of the filtrate in vacuo gave a brown solid which was subjected
to flash chromatography (silica gel, 95:5 CH Cl :EtOAc) af-
3
N (5.0 mL) was heated at
this vigorously stirred solution was added NBS (0.427 g, 2.40
mmol) in one portion, and stirring was continued at room
temperature for 15 min, during which time a pale yellow solid
precipitated from solution. Evaporation of the THF in vacuo,
filtration of the resulting solid, and washing with water gave
the bis(bromoacetyl)bipyridine 15 (0.422 g, 93%). An analyti-
cal sample was obtained by recrystallization from 1:1 water:
1
2
2
fording the bis-acetylene 20 as a pale brown solid. Recrys-
tallization from ethanol gave pure 20 (0.105 g, 81%) as
1
colorless, wooly needles: mp 113-114 °C; H NMR (CDCl
3
) δ
1
.28 (t, J ) 7.2 Hz, 12H), 3.67 (dq, J ) 9.6, 7.2 Hz, 4H), 3.82
EtOH to give pure bis(bromoacetyl)bipyridine 15 as colorless
1
(dq, J ) 9.6, 7.2 Hz, 4H), 7.36 (dd, J ) 5.2, 1.6 Hz, 2H), 8.46
needles: mp 121-123 °C dec; H NMR (CDCl
3
) δ 4.88 (s, 4H),
1
3
(
dd, J ) 1.6, 0.8 Hz, 2H), 8.64 (dd, J ) 4.8, 0.8 Hz, 2H);
C
7
.82 (dd, J ) 4.8, 1.6 Hz, 2H), 8.39 (d, J ) 1.6 Hz, 2H), 8.86
NMR (CDCl ) δ 15.1, 61.2, 82.6, 89.0, 91.5, 123.5, 125.9, 131.2,
3
13
(
1
d, J ) 4.8 Hz, 2H); C NMR (CDCl
3
) δ 31.8, 120.3, 125.2,
1
+
48
1
49.2, 155.5; EIMS m/ z (rel int) 409 (25, [M + H] ), 363
100), 261 (70), 233 (83). Anal. Calcd for C24 : C, 70.57;
H, 6.91; N, 6.86. Found: C, 70.29; H, 6.70; N, 6.78.
Z,Z)-4,4′-Bis(3,3-d ie t h oxy-1-p r op e n yl)-2,2′-b ip yr i-
d in e (21). To a stirred suspension of Lindlar catalyst (0.600
g of 5% Pd on CaCO poisoned with Pb, Aldrich no. 20,573-7)
in ethyl acetate (5.0 mL) was introduced a solution of acetylene
0 (0.200 g, 0.49 mmol) in ethyl acetate (5.0 mL) under an
-
46.0, 150.3, 152.4, 192.2; IR (KBr) 1715 cm ; CIMS m/ z (rel
(
28 2 4
H N O
+
int) 401, 399, 397 (49, 100, 52, M + H ), 321, 319 (78, 81), 241
77). Anal. Calcd for C14 : C, 42.24; H, 2.53; N, 7.04;
Br, 40.15. Found: C, 41.93; H, 2.38; N, 6.92; Br, 39.95.
,2′-Bis(2-p yr id in iu m yla cetyl)-4,4′-bip yr id in e Dibr o-
(
2 2 2
H10Br N O
(
2
3
m id e (16). To a solution of dibromide 15 (0.952 g, 2.39 mmol)
in anhydrous acetone (40 mL) at room temperature was
introduced pyridine (0.426 mL, 5.27 mmol), and the reaction
mixture was stirred under a nitrogen atmosphere for 12 h.
Evaporation of the reaction mixture in vacuo gave a light
2
atmosphere of hydrogen. The uptake of hydrogen (24 mL, 0.98
mmol) was measured quantitatively using a modification of a
reported hydrogenation apparatus, after which the solution
was filtered through Celite and evaporated in vacuo. The
crude residue was recrystallized from hexane to give the pure
49
brown solid which was washed with CHCl
give bis-pyridinium salt 16 (1.18 g, 89%) which was pure
3
(3 × 20 mL) to
enough to use in subsequent reactions: mp 185-215 °C dec;
(
Z,Z)-diacetal 21 (0.168 g, 84%) as colorless needles: mp 69-
1
H NMR (DMSO-d
6
) δ 6.56 (s, 4H), 8.29 (dd, J ) 7.2, 5.2 Hz,
1
7
4
6
3
0 °C; H NMR (CDCl ) δ 1.25 (t, J ) 7.2 Hz, 12H), 3.64 (m,
4
8
5
1
H), 8.36 (dd, J ) 5.2, 1.6 Hz, 2H), 8.47 (d, J ) 1.6 Hz, 2H),
H), 5.21 (d, J ) 7.2 Hz, 2H), 6.00 (dd, J ) 12.0, 7.2 Hz, 2H),
.69 (d, J ) 12.0 Hz, 2H), 7.38 (dd, J ) 5.2, 1.6 Hz, 2H), 8.35
.75 (t, J ) 7.2 Hz, 2H), 9.02 (d, J ) 5.2 Hz, 4H), 9.07 (d, J )
1
3
.2 Hz, 2H); C NMR (DMSO-d
45.2, 146.4, 146.4, 150.8, 151.6, 191.2; IR (KBr) 1725 cm
: C, 50.91; H, 3.62; N, 10.07.
Found: C, 50.85; H, 3.51; N, 9.79.
-[4-(2-Br om op yr id in yl)]-2-p r op en a l (18). To a solution
6
) δ 66.7, 119.4, 126.6, 127.8,
13
(
s, 2H), 8.65 (d, J ) 5.2 Hz, 2H); C NMR (CDCl ) δ 15.2,
3
-
1
.
6
0.9, 97.8, 121.0, 123.4, 130.4, 133.3, 144.5, 149.2, 156.1; EIMS
Anal. Calcd for C24
H
20Br
2
N
4
O
2
+
m/ z (rel int) 413 (100, [M + H] ), 367 (93), 321 (86). Anal.
Calcd for C24 : C, 69.88; H, 7.82; N, 6.79. Found: C,
32 2 4
H N O
69.82; H, 7.82; N, 6.69.
3
2
9
of aldehyde 17 (2.318 g, 12.46 mmol) in toluene (100 mL)
was introduced (triphenylphosphoranylidene)acetaldehyde (3.80
g, 12.5 mmol). The solution was stirred at room temperature
under nitrogen for 24 h and then evaporated in vacuo to give
a tan, amorphous solid. Flash chromatography (silica gel,
4,4′-Bis(3-oxo-1-p r op en yl)-2,2′-bip yr id in e (22). To a
vigorously stirred solution of diacetal 21 (0.200 g, 0.49 mmol)
in acetone (16 mL) was introduced a solution of oxalic acid
(8.0 mL of a 4.0% solution in acetone, 3.6 mmol) and water
(8.0 mL). After 30 min, the acetone was evaporated in vacuo
CH
solid: mp 115-116 °C; H NMR (CDCl
.4 Hz, 1H), 7.35 (d, J ) 16.0 Hz, 1H), 7.38 (dd, J ) 4.8, 1.2
Hz, 1H), 7.61 (d, J ) 1.2 Hz, 1H), 8.46 (d, J ) 4.8 Hz, 1H),
2
Cl
2
) afforded the aldehyde 18 (2.21 g, 84%) as a colorless
2 3
(<25 °C) and the aqueous solution basified with solid Na CO
1
3
) δ 6.82 (dd, J ) 16.0,
and extracted with ethyl acetate (2 × 30 mL); the combined
extracts were dried over anhydrous sodium sulfate and
evaporated in vacuo. The crude product was found to contain
a (∼1:9) mixture of (E,E)- and (Z,Z)-isomers (no (E,Z) was
observed) of aldehyde 22 (0.111 g, 86%) and was pure enough
7
9
1
.77 (d, J ) 7.4 Hz, 1H); 13C NMR (CDCl
32.9, 143.3, 143.8, 146.9, 151.0, 192.4; IR (KBr) 1678 cm
3
) δ 120.7, 126.4,
-
1
;
+
EIMS m/ z (rel int) 213, 211 (42, 42, M ), 132 (100), 104 (39),
7 (42). Anal. Calcd for C BrNO: C, 45.31; H, 2.85; N, 6.60;
Br, 37.68. Found: C, 45.24; H, 2.69; N, 6.59; Br, 37.38.
,2′′′′′-Dibr om o-4,4′:2′,2′′:4′′,4′′′:2′′′,2′′′′:4′′′′,4′′′′′-sexip yr i-
7
8 6
H
(
47) As the purity of this compound increased, its solubility de-
creased markedly. In crude reaction mixtures, it is soluble in CHCl
and CH Cl , but upon purification it becomes only sparingly soluble
in hot DMSO-d
. 1The low solubility of this compound prevented the
acquisition of its C NMR spectrum.
48) Confirmation of assignment as [M + H] : HRMS calcd for
409.2127, found 409.2125.
(49) For the hydrogenation apparatus used to quantitatively mea-
sure the uptake of H , see: Vogel, A. I.; Furniss, B. S.; Hannaford, A.
3
2
2
2
d in e (19). Into a round-bottomed flask were introduced bis-
pyridinium salt 16 (0.400 g, 0.72 mmol), aldehyde 18 (0.335
g, 1.58 mmol), NH OAc (2.00 g, 26 mmol), and acetic acid (40
4
mL). The solution was heated at reflux for 3 h, giving a dark
brown solution which was evaporated in vacuo and the residue
6
3
+
(
24 29 2 4
C H N O
2
J .; Smith, P. W. G.; Tatchell, A. R. In Vogel’s Textbook of Practical
Organic Chemistry, 5th ed.; Longman Scientific & Technical: Harlow,
2 2
dissolved in CH Cl (200 mL). This stirred solution was
triturated by dropwise addition of petroleum ether (1000 mL)
via a dropping funnel, and the precipitate was collected by
filtration. This precipitate was purified by dissolving in a
minimum (ca. 80 mL) of refluxing chloroform and cooling to
give a tan precipitate which was collected by filtration yielding
essentially pure sexipyridine 19 (0.096 g, 21%). An analytical
sample was obtained by washing 19 with hot pyridine47 and
chloroform to give the analytically pure product as a colorless,
1
991; p 89. We found that degassing of the reaction solution was
necessary for a successful hydrogenation, but hydrogenation occurred
during evacuation/regassing (H
2
) cycles (×3), making quantitative
measurement difficult. By insertion of a pressure equalizing dropping
funnel containing the alkyne solution above the reaction flask contain-
ing the Lindlar catalyst solution, it was possible to degas without
concommitant hydrogenation. Following degassing, the alkyne solu-
tion was quickly dropped into the catalyst solution whereupon
hydrogenation commenced.

2
780 J . Org. Chem., Vol. 62, No. 9, 1997
Kelly et al.
for use in subsequent reactions. An analytical sample of the
Z,Z)-isomer was isolated by recrystallization from hexane/
8.84 (d, J ) 4.8 Hz, 2H); 13C NMR (CDCl
3
) δ 119.0, 120.7,
(
121.7, 126.0, 143.3, 145.3, 148.4, 150.2, 150.9, 156.5; EIMS
+
benzene; pure (E,E)-isomer was obtained by allowing the
reaction mixture to isomerize for 4 h at room temperature
before workup and then isolation by the same procedure as
m/ z (rel int) 470, 468, 466 (65, 100, 57, M ), 389, 387 (90, 88).
2 4
Anal. Calcd for C20H12Br N : C, 51.31; H, 2.58; N, 11.97; Br,
34.14. Found: C, 51.04; H, 2.84; N, 11.77; Br, 34.45.
1
used for the (Z,Z)-isomer. (Z,Z)-22: mp 148-149 °C; H NMR
2-Br om o-4′′′′-[2-(1,3-d ioxola n -2-yl)et h en yl]-4,4′:2′,2′′:
4′′,4′′′:2′′′,2′′′′-q u in qu ep yr id in e (27). Into a sealable tube
were introduced quaterpyridine 26 (0.123 g, 0.26 mmol),
stannane 25 (0.098 g, 0.29 mmol), freshly prepared tetrakis-
(triphenylphosphine)palladium(0) (0.020 g, 0.020 mmol), and
anhydrous dioxane (10 mL). The tube was sealed and heated
at 130-140 °C for 24 h. After cooling, the solution was filtered,
the filtrate evaporated in vacuo, and the residue subjected to
flash chromatography (silica gel, 1:1 CH Cl :Et O, and then
(
2
3
CDCl ) δ 6.37 (dd, J ) 11.6, 8.0 Hz, 2H), 7.33 (d, J ) 4.8 Hz,
H), 7.64 (d, J ) 11.6 Hz, 2H), 8.49 (s, 2H), 8.75 (d, J ) 4.8
13
Hz, 2H), 10.02 (d, J ) 8.0 Hz, 2H); C NMR (CDCl
1
3
) δ 121.2,
24.0, 133.1, 142.7, 145.4, 149.6, 155.8, 191.33; IR (KBr) 1682
-1
+
cm ; EIMS m/ z (rel int) 264 (53, M ), 207 (100). Anal. Calcd
for C16 : C, 72.72; H, 4.58; N, 10.60. Found: C, 72.63;
H, 4.46; N, 10.30. (E,E)-22: mp 243-244 °C; H NMR (CDCl
δ 6.97 (dd, J ) 16.0, 7.6 Hz, 2H), 7.47 (dd, J ) 5.2, 1.2 Hz,
H), 7.53 (d, J ) 16.0 Hz, 2H), 8.61 (d, J ) 1.6 Hz, 2H), 8.79
12 2 2
H N O
1
3
)
2
2
2
2
5:95 MeOH:CHCl ). The quinquepyridine 27 (0.055 g, 37%)
3
1
3
(
d, J ) 5.2 Hz, 2H), 9.81 (d, J ) 7.6 Hz, 2H); C NMR (CDCl
3
)
was isolated as a white, amorphous solid: mp 243-246 °C dec;
1
δ 119.7, 122.1, 132.3, 142.3, 149.0, 150.2, 156.5, 193.0; IR (KBr)
H NMR (CDCl ) δ 4.04 (m, 4H), 5.52 (d, J ) 5.6 Hz, 1H), 6.53
3
-
1
+
1
676 cm ; CIMS m/ z (rel int) 265 (100, M + H ), 239 (7).
Anal. Calcd for C16 C, 72.72; H, 4.58; N, 10.60.
Found: C, 72.63; H, 4.41; N, 10.45.
-Br om o-4-[2-(1,3-d ioxola n -2-yl)eth en yl]p yr id in e (24).
Into a flask were introduced aldehyde 18 (4.00 g, 18.9 mmol),
anhydrous ethylene glycol (2.06 mL, 36.9 mmol), p-TsOH‚H
0.120 g, 0.63 mmol), and anhydrous benzene (520 mL). The
flask was fitted with a Soxhlet condenser whose thimble
contained anhydrous MgSO ; this apparatus was flushed with
nitrogen and the solution refluxed for 3 days, replacing the
MgSO thimble each day. Evaporation of the reaction mixture
in vacuo and flash chromatography (basic alumina (50-200
µm), CHCl ) of the residue gave the acetal 24 (4.60 g, 95%) as
(dd, J ) 16.0, 5.6 Hz, 1H), 6.85 (d, J ) 16.0 Hz, 1H), 7.36 (d,
J ) 5.2 Hz, 1H), 7.56 (d, J ) 5.2 Hz, 1H), 7.64 (d, J ) 5.2 Hz,
1H), 7.72 (d, J ) 5.2 Hz, 1H), 7.76 (d, J ) 5.2 Hz, 1H), 7.89 (s,
1H), 8.52 (s, 1H), 8.53 (d, J ) 5.2 Hz, 1H), 8.68 (d, J ) 5.2 Hz,
12 2 2
H N O :
2
1H), 8.75-8.88 (m, 6H); 13C NMR (CDCl
) δ 65.2, 102.9, 118.9,
3
2
O
119.0, 119.1, 119.2, 120.7, 121.4, 121.5, 121.6, 122.0, 125.9,
130.5, 131.9, 143.2, 144.4, 145.1, 146.6, 146.9, 148.5, 149.6,
150.0, 150.1, 150.2, 150.8, 156.1, 156.2, 156.8, 156.9. EIMS
(
+
4
m/ z (rel int) 565, 563 (64, 59, M ), 520 (100). Anal. Calcd for
30 5 2
C H22BrN O : C, 63.84; H, 3.93; N, 12.40. Found: C, 64.08;
H, 3.74; N, 12.58.
4
4′′′′-[2-(1,3-Dioxola n -2-yl)et h en yl]-2-(r-et h oxyvin yl)-
4,4′:2′,2′′:4′′,4′′′:2′′′,2′′′′-qu in qu ep yr id in e (28). To a sealable
tube were introduced quinquepyridine 27 (0.084 g, 0.15 mmol),
vinylstannane 13 (0.028 mL, 0.18 mmol), freshly prepared
tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.01 mmol),
and anhydrous dioxane (10 mL). The tube was sealed and the
reaction mixture heated at 130-140 °C overnight. After
cooling, the suspension was filtered and the solid washed with
CH Cl . The filtrate and wash were combined and evaporated
3
1
a colorless solid: mp 52-53 °C; H NMR (CDCl
4
6
3
) δ 4.00 (m,
H), 5.44 (d, J ) 5.0 Hz, 1H), 6.36 (dd, J ) 16.0, 5.0 Hz, 1H),
.64 (d, J ) 16.0 Hz, 1H), 7.22 (dd, J ) 5.2, 1.2 Hz, 1H), 7.45
1
3
(
3
d, J ) 1.2 Hz, 1H), 8.30 (d, J ) 5.2 Hz, 1H); C NMR (CDCl )
δ 65.1, 102.3, 120.2, 125.5, 130.1, 131.6, 142.7, 146.0, 150.2;
EIMS m/ z (rel int) 257, 255 (94, 95, M ), 176 (21), 99 (100).
+
Anal. Calcd for C10
1.20. Found: C, 46.80; H, 3.66; N, 5.47; Br, 31.16.
-[2-(1,3-Dioxolan -2-yl)eth en yl]-2-(tr im eth ylstan n yl)py-
r id in e (25). Into a sealable tube were introduced acetal 24
0.250 g, 0.98 mmol), bis(triphenylphosphine)palladium(II)
2
H10BrNO : C, 46.90; H, 3.94; N, 5.47; Br,
2
2
3
and the residue subjected to flash chromatography (silica gel,
CH Cl , and then 1:1 CH Cl :Et O) to give quinquepyridine
4
2
2
2
2
2
1
28 (0.042 g, 50%) as a yellow solid: mp 105-120 °C dec; H
(
NMR (CDCl ) δ 1.48 (t, J ) 6.8 Hz, 3H), 4.04 (m, 6H), 4.45 (d,
3
chloride (0.025 g, 0.04 mmol), hexamethylditin (0.404 mL, 1.90
mmol), and anhydrous dioxane (10 mL). The solution was
degassed and the tube sealed and heated at 135 °C for 12 h.
Filtration of the resulting black suspension through a Celite
pad gave a yellow oil after evaporation of the filtrate in vacuo.
J ) 2.0 Hz, 1H), 5.50 (d, J ) 2.0 Hz, 1H), 5.51 (d, J ) 5.6 Hz,
1H), 6.68 (dd, J ) 16, 5.6 Hz, 1H), 6.84 (d, J ) 16 Hz, 1H),
7.34 (d, J ) 5.2 Hz, 1H), 7.59 (d, J ) 5.2 Hz, 1H), 7.61 (d, J )
5.2 Hz, 1H), 7.70 (d, J ) 5.2 Hz, 1H), 7.72 (d, J ) 5.2 Hz, 1H),
8.03 (s, 1H), 8.50 (s, 1H), 8.67 (d, J ) 5.2 Hz, 1H), 8.70 (d, J
) 5.2 Hz, 1H), 8.77 (s, 1H), 8.81-8.84 (m, 4H), 8.86 (s, 1H);
5
0
Flash chromatography [basic alumina (50-200 µm), CH
gave the stannane 25 (0.269 g, 81%) as a pale yellow oil: 1H
NMR (CDCl
2 2
Cl ]
13
C NMR (CDCl ) δ 14.9, 64.0, 65.5, 85.8, 103.2, 117.4, 119.3,
3
3
) δ 0.33 (s, 9H), 3.99 (m, 4H), 5.43 (d, J ) 5.8 Hz,
H), 6.33 (dd, J ) 16.0, 5.8 Hz, 1H), 6.67 (d, J ) 16.0 Hz, 1H),
.11 (dd, J ) 4.8, 1.6 Hz, 1H), 7.41 (d, J ) 1.6 Hz, 1H), 8.69
119.4, 119.5, 119.6, 121.3, 121.8, 121.9, 122.1, 122.2, 130.8,
132.3, 144.7, 146.6, 147.0, 147.1, 147.4, 149.9, 150.0, 150.2,
150.3, 154.9, 156.4, 156.8, 156.9, 157.2, 158.5, 158.6; FABMS
1
7
(
1
3
+
d, J ) 4.8 Hz, 1H); C NMR (CDCl
3
) δ -9.6, 65.0, 102.8,
m/ z (rel int) 556 (100, [M + H] ), 528 (30), 484 (23); HRMS
+
1
19.6, 128.7, 129.5, 132.4, 140.2, 150.6, 173.6; EIMS m/ z (rel
calcd for C H N O [M + H] 556.2346, found 556.2348.
3
4
30
5
3
+
120
int) 341 (51, M , Sn), 326 (100), 165 (85), 135 (79); HRMS
2-(Br om oa cetyl)-4′′′′-[2-(1,3-d ioxola n -2-yl)eth en yl]-4,4′:
2′,2′′:4′′,4′′′:2′′′,2′′′′-qu in qu ep yr id in e (29). To a solution of
quinquepyridine 28 (0.030 g, 0.054 mmol) in THF (20 mL) at
room temperature were introduced water (1.0 mL) and N-
bromosuccinimide (0.011 g, 0.062 mmol). This mixture was
stirred at room temperature for 1 h. The solvent was
evaporated in vacuo and the residue partitioned between
CH Cl2 and water (50 mL:50 mL). The CH Cl2 layer was
1
16
calcd for C13
H
19NO
2
Sn 337.0433, found 337.0433.
2
,2′′′-Dibr om o-4,4′:2′2′′:4′′,4′′′-qu a ter p yr id in e (26). Into
a sealable tube were introduced dibromide 12 (0.400 g, 1.27
mmol), freshly prepared tetrakis(triphenylphosphine)pal-
ladium(0) (0.033 g, 0.03 mmol), hexamethylditin (0.100 mL,
0
.48 mmol), and anhydrous dioxane (10 mL). The solution was
degassed and the tube sealed and heated at 140 °C for 48 h.
On cooling, the reaction mixture was filtered, the filtrate
evaporated in vacuo, and the residue subjected to flash
chromatography (silica gel, CH Cl , and then 1:1 CHCl :Et O)
2 2 3 2
to give almost pure quaterpyridine 26. The product was
washed (to remove residual triphenylphosphine oxide) with a
2 2
small volume of CH Cl (4 mL) at room temperature and the
insoluble material collected by filtration, giving pure 26 (0.085
g, 29%) as a colorless, amorphous solid. An analytical sample
2
2
separated and dried over anhydrous sodium sulfate; evapora-
tion in vacuo gave bromo ketone 29 (0.032 g, 98%) as a
colorless solid (unstable in solution or >20-25 °C): mp 76-
1
95 °C dec; H NMR (CDCl ) δ 3.98-4.09 (m, 4H), 4.89 (s, 2
3
H), 5.50 (d, J ) 5.6 Hz, 1H), 6.51 (dd, J ) 16.4, 5.6 Hz, 1H),
6.83 (d, J ) 16.4 Hz, 1H), 7.33 (d, J ) 4.8 Hz, 1H), 7.62 (d, J
) 4.8 Hz, 1H), 7.69 (d, J ) 4.8 Hz, 1H), 7.72 (d, J ) 4.8 Hz,
1H), 7.90 (d, J ) 5.2 Hz, 1H), 8.45 (s, 1H), 8.49 (s, 1H), 8.66
(d, J ) 5.2 Hz, 1H), 8.79-8.85 (m, 7H); 13C NMR (CDCl ) δ
was obtained as fine wooly needles by recrystallization from
3
1
ethanol: mp 262-263 °C; H NMR (CDCl
3
) δ 7.58 (dd, J )
32.1, 65.1, 102.9, 118.9, 118.95, 119.0, 119.1, 120.4, 121.4,
121.5, 121.6, 122.0, 125.4, 130.5, 131.9, 144.4, 145.4, 146.6,
146.9, 147.1, 149.6, 149.9, 149.95, 150.0, 150.2, 152.2, 156.1,
4
1
.8, 1.6 Hz, 2H), 7.63 (dd, J ) 5.2, 1.6 Hz, 2H), 7.88 (d, J )
.6 Hz, 2H), 8.53 (d, J ) 5.2 Hz, 2H), 8.75 (d, J ) 1.6 Hz, 2H),
-
1
1
51.2, 156.7, 156.8, 192.3. IR (KBr) 1715 cm . Due to the
(50) Stannane 25 was observed to undergo facile destannylation on
instability of bromo ketone 29, this sample was not sent out
silica gel.
for combustion analysis or HRMS.

Synthesis of Cyclosexipyridine
′′′′-[2-(1,3-Dioxolan -2-yl)eth en yl]-2-(2-pyr idin iu m ylacet-
yl)-4,4′:2′,2′′:4′′,4′′′:2′′′,2′′′′-qu in qu ep yr id in e Br om id e (30).
A mixture of bromo ketone 29 (0.032 g, 0.053 mmol) and
pyridine (0.010 mL, 0.12 mmol) in acetone (30 mL) was stirred
at room temperature for 12 h. The solvent was evaporated in
J . Org. Chem., Vol. 62, No. 9, 1997 2781
4
solid washed with CHCl
sexipyridine 2 (0.013 g, 81%) as a dark brown solid. This solid
was found to be only sparingly soluble in hot DMSO-d and
insoluble in all other solvents examined: H NMR (DMSO-
3
and isolated by filtration to give
6
1
d ) δ 7.69 (d, J ) 5.2 Hz, 6H), 8.47 (s, 6H), 8.89 (d, J ) 5.2 Hz,
6
vacuo, and the residue dissolved in CHCl
3
and then introduced
6H); UV λmax (EtOH) 240 nm (ꢀ ) 8800), 286 (ꢀ ) 2800); IR
+
dropwise to cyclohexane while stirring. The resulting precipi-
tate was collected by filtration and dried in vacuo to afford
mono(pyridinium salt) 30 (0.031 g, 85%) as a light brown solid
(KBr) 2961, 1640, 1098, 1035; EIMS m/ z (rel int) 462 (1, M ),
453 (48) 265 (100) (see Supporting Information); HRMS calcd
for C30
18 6
H N 462.1593, found 462.1582.
(
unstable >20-25 °C) that was used immediately for the final
1
step: H NMR (DMSO-d
.6 Hz, 1H), 6.57 (s, 2H), 6.63 (dd, J ) 16.4, 5.6 Hz, 1H), 6.95
d, J ) 16.4 Hz, 1H), 7.69 (d, J ) 4.8 Hz, 1H), 8.04 (d, J ) 4.8
Hz, 1H), 8.06 (d, J ) 4.8 Hz, 1H), 8.28 (t, J ) 7.0 Hz, 2H),
6
) δ 3.98-4.09 (m, 4H), 5.48 (d, J )
Ack n ow led gm en t. We thank Dr. Steven D. R.
Christie and Mr. Andreas Szabados for early experi-
ments and the National Institutes of Health for partial
financial support.
5
(
8
8
8
.30 (d, J ) 4.8 Hz, 1H), 8.37 (d, J ) 5.2 Hz, 1H), 8.47 (s, 1H),
.49 (s, 1H), 8.72 (d, J ) 5.2 Hz, 1H), 8.75 (t, J ) 7.0 Hz, 1H),
.80 (s, 1H), 8.85-9.05 (m, 8H). Due to the instability of 30,
1
Su p p or tin g In for m a tion Ava ila ble: 400 MHz H NMR
this sample was not sent for combustion analysis. Mass
spectra for this compound did not display a molecular ion or
interpretable fragment ions suitable for HRMS; this was also
observed to be the case with bis(pyridinium salt) 16.
Cyclo-2,2′:4′,4′′:2′′,2′′′:4′′′,4′′′′:2′′′′,2′′′′′:4′′′′′,4-se xip yr i-
d in e (2). A solution of mono(pyridinium salt) 30 (0.024 g,
spectra for compounds lacking combustion analysis data (25,
27-30 and 2); also contained are the MS of 2 and experimental
1
H and 13C NMR data for compounds 6, 7, and 9
procedures,
(20 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
0
.035 mmol) and ammonium acetate (0.170 g, 2.2 mmol) in
acetic acid (50 mL) was heated at reflux for 19 h. After cooling,
the solvent was evaporated in vacuo and the resulting black
J O962236K