Synthesis of Bronzaphyrin NS

Full text of DOI:10.1021/jo961849u

1168
J . Org. Chem. 1997, 62, 1168-1172
Syn th esis of Br on za p h yr in NS
Martin R. J ohnson*
Chemistry Department, The George Washington University,
Washington, DC 20052
Received September 30, 1996
In tr od u ction
The chemistry of porphyrin analogs and homologs has
enjoyed a period of extended growth. Most of the isomers
of porphyrin [1.1.1.1] have now been synthesized,1 as well
as a number of sapphyrin, corrin, and other macrocycles
fitting the broad definition of “pentaplanar”.2 “Penta-
planar” is a term describing an aromatic macrocycle
consisting of five-membered rings linked by sp2-hybrid-
ized atoms.3,4 This paper focuses on some members of
the [2.0.0.2.0.0] family of annulenes (Figure 1a). This
subset of the [2.0.0.2.0.0] family is known as the “bronza-
phyrins” because of their color in solution.5 Due to their
heteroatoms’ placement and the availability of labile
protons on the interior perimeter, the bronzaphyrins as
a family are potential “binucleating porphyrins” that may
be able to hold two metal ions within a single aromatic
macrocyclic ring. Those made so far are bronzaphyrin
SS (1) and OS (2); bronzaphyrin OO (3) has not yet been
isolated and may be too electrophilic to survive under
ambient conditions. The final members of this series,
bronzaphyrins NS (4), NN (5), and NO (6), have been
synthetically unattainable because of the extreme in-
solubility of the precursor terpyrrole dialdehydes made
thus far (Figure 1b): Both 7a 6 and 7b7 are virtually
insoluble in both THF and dioxane, the only acceptable
solvents for the McMurry coupling of porphycene ho-
mologs. These observations prompted the synthesis of
the much more soluble, ergo synthetically fecund, hexyl
homolog 7c reported herein, and subsequently 4.
F igu r e 1.
â-keto esters.8 Although an old class of compounds, their
synthesis on a large scale has been either difficult or
expensive to undertake due to the water- and oxygen-
sensitivity of most methods.9 By contrast, Meier’s acyl-
exchange method is run in air, tolerates minor amounts
of water, is scalable, uses inexpensive reagents, and is
adaptable to many functional groups. The calcium
chelate of ethyl acetoacetate 8 is first prepared in
dichloromethane suspension. This chelate readily un-
dergoes acyl exchange with any acid chloride to give a
chelated ester that is hydrolyzed, separated, and distilled.
Ethyl 3-oxononanoate 9 has been routinely prepared in
80-100 g batches with yields as high as 70%, although
yields around 40% are more typical.
Knorr synthesis using 9 gave a 40-45% yield of pyrrole
10, which was treated with SO2Cl2 to give the aldehyde
11. Stetter coupling of 11 gave the dipyrrolylbutanedione
12, which gave terpyrrole ester 13 in 90% yield upon
refluxing with NH4OAc/Ac2O/HOAc. Ester 13, when
treated with NaOH in refluxing ethylene glycol for 30
min, decarboxylated readily to give the highly air-
sensitive, but thermally robust, terpyrrole 14. Vilsmier-
Clezy formylation of 14 with PhCOCl/DMF gave the
dication 15, which was isolated by filtration. Hydrolysis
of 15 to give the desired aldehyde 7c turned out to be
nontrivial and was eventually achieved by use of
[Et4N+]2[CO32-] in DMF. Both 15 and 7c are tempera-
ture sensitive, and care must be taken to keep the
hydrolysis below 50 °C to achieve good purity and yield.
Macrocycle 4 was made by crossed McMurry coupling
of 7c with aldehyde 16,10 yielding a mixture of dihydro
precursors 17, 18, and 19. These precursors air oxidize
to give only the two products 1 and 4. Apparently 5 is
Resu lts a n d Discu ssion
This approach to 7c (Scheme 1) was rendered practical
by a reported patent application for the synthesis of
* Current address: 191 Estates Drive, Piedmont, CA 94611. E-
mail: mrj@usa.net
(1) Sessler, J . L. Angew. Chem., Int. Ed. Engl. 1994, 33, 1348-1350.
(2) (a) Sessler, J . L.; Burrell, A. K. Top. Curr. Chem. 1991, 161, 177-
273. (b) Vogel, E. Pure Appl. Chem. 1993, 65, 143-152. (c) Sapphyrin
review: Sessler, J . L.; Cyr, M.; Burrell, A. K. Tetrahedron 1992, 48,
9661-9672.
(3) The term “expanded porphyrin” has been applied frequently to
this class of compounds; however, there are examples of pentaplanar
“contracted porphyrins”, and the term “expanded porphyrin” has been
used to describe a variety of macrocycles, many of which have saturated
portions in the core of the ring and/or cannot bind metal ions. The
term “pentaplanar” is suggested as a topographically and electronically
precise term by the author. For those nonplanar, nonaromatic mac-
rocycles that otherwise qualify as pentaplanar, the term “pentaform”
may be preferable. For example, ref 4a-e describes several uncharged
poly- and perthiophene “pentaform” annulenes with varying topologies
([2.0.0.2.0.0], [2.0.2.0], [2.0.2.0.2.0], and [2.1.2.1]). Of these, only
tetrathia[22]annulene[2.1.2.1] is aromatic4b and, therefore, “pentapla-
nar”.
(8) Meier, J . Chem. Abstr. 1993, 118, 168706.
(4) Thiophene-containing annulenes: (a) Kozaki, M.; Parakka, J .
P.; Cava, M. P. J . Org. Chem. 1996, 61, 3657-3661. (b) Hu, Z.; Atwood,
J . L.; Cava, M. P. J . Org. Chem. 1994, 59, 8071-8075. (c) Hu, Z. Y.;
Cava, M. P. Tetrahedron Lett. 1994, 35, 3493-3496. (d) Hu, Z.;
Scordilis-Kelley, C.; Cava, M. P. Tetrahedron Lett. 1993, 34, 1879-
1882. (e) Elinger, F.; Gieren, A.; Hu¨bner, Th.; Lex, J .; Merz, A.;
Neidlein, R.; Salbeck, J . Monatsh. Chem. 1993, 124, 931-943.
(5) (a) Miller, D. C.; J ohnson, M. R.; Ibers, J . A. J . Org. Chem. 1994,
59, 2877-2879. (b) J ohnson, M. R.; Miller, D. C.; Bush, K.; Becker, J .
J .; Ibers, J . A. J . Org. Chem. 1992, 57, 4414-4417.
(9) (a) Benetti, S.; Romagnoli, R.; De Risi, C.; Spalluto, G.; Zanirato,
V. Chem. Rev. 1995, 95, 1065-1114. (b) The reaction of Meldrum’s
acid with acid chlorides represents an additional possible route to large-
scale synthesis of â-keto esters: Oikawa, Y.; Yoshioka, T.; Sugano, K.;
Yonemitsu, O. Organic Syntheses; Wiley: New York, 1990; Collect. Vol.
VI, pp 359-262. (c) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J . Org.
Chem. 1978, 43, 2087-2088.
(10) The use of solid TiCl4‚2THF in sealed preweighed bottles makes
it possible to dispense with most of the rigors traditionally associated
with handling liquid TiCl4; with practice the Ti0 reagent can be
prepared from scratch in 2 h and in warm humid air if the solid
TiCl4‚2THF is efficaciously handled.
(6) Merrill, B.; LeGoff, E. J . Org. Chem. 1990, 112, 2810-2813.
(7) J ohnson, M. R. Unpublished data.
S0022-3263(96)01849-X CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 4, 1997 1169
Sch em e 1a
a
Key: (a) Ca(OH)2/CH2Cl2; (b) heptanoyl chloride; (c) NaNO2/H2HOAc; (d) Zn/HOAc/70-80 °C; (e) SO2Cl2/HOAc/70 °C; (f) divinyl sulfone/
Et3N/Stetter’s thiazole/p-dioxane/70-75 °C/18 h; (g) NH4OAc/Ac2O/HOAc, reflux 18 h; (h) NaOH/(CH2OH)2/reflux; (i) PhCOCl/DMF/85
°C/11 h; (j) [Et4N+]2[CO32-]/DMF 55 f 45 °C; (k) TiCl4‚2THF/Zn0/THF/reflux 18 h; (l) air oxidation.
unstable; a control reaction, in which 7c was the only
aldehyde present, gave only an insoluble black solid.11
Products 1 and 4 have nearly identical chromatographic
profiles, and their separation was enabled by the solubil-
ity of 4 in hot hexane. Remaining traces of 1 were
removed by chromatography.
Compound 4, like 1, gives metallic green crystals that
produce an orange solution when dissolved. A compari-
son of the three known bronzaphyrins’ UV-vis spectra
is given in Figure 2. They all display the same Q-Soret
band structure, well accounted for by Platt’s perimeter
model,12 with a split Soret region at 380-540 nm,
multiple Q peaks at 700-900 nm, and an absorbance
minimum at 600 nm that accounts for the orange color
in solution. The proton NMR of 4 in CDCl3 (Figure 3) is
consistent with its structure; noteworthy is the concen-
tration dependence of the resonances of the internal
pyrrole resonances as well as certain external ring
protons, attributable to aggregation effects. Under con-
ditions of high dilution, the internal pyrrole resonances
are very broad and centered at -0.9 (fwhm ≈ 0.5 ppm)
and -5.3 (fwhm ≈ 0.18 ppm). At near saturation, they
are sharper and further upfield (-2.3, fwhm 0.2 ppm;
F igu r e 2. UV-vis spectra (THF, 10 µM) of bronzaphyrins 1,
(11) A prior experiment, conducted with D. C. Miller and J . A. Ibers,
2, and 4.
using 7b and more rigorous anaerobic manipulation of the reaction
and workup, gave
a quenched solution that was colorless; upon
-6.8, fwhm 0.1 ppm). The three ring resonances in the
region 10.08-10.11 also coalesce into a single peak and
shift upfield as concentration increases. EI mass spec-
troscopy gives a strong parent peak at m/e ) 711,
exposure to air it slowly turned pale red and then brown. The colorless
solution, when treated with methanolic CuII(OAc)2, instantly gave a
brilliant deep purple color that also quickly turned brown. No products
were isolable from this reaction.
(12) Platt, J . R. J . Chem. Phys. 1949, 17, 484-495.

1170 J . Org. Chem., Vol. 62, No. 4, 1997
Notes
F igu r e 3. 1H NMR (300 MHz, CDCl3) of 4.
(150 mL). The mixture was then stirred for another 12 h and
acidified to pH 0.5-1 with concd HCl. After 30 min of stirring,
the organic layer was separated, washed with 5% Na2CO3 (250
mL) and water (2 × 250 mL), and then dried (Na2SO4), and
volatiles were removed on a rotary evaporator. The liquid
residue was cooled to e-10 °C15 to precipitate heptanoyl amide,
which was removed by cold vacuum filtration. The filtrate was
fractionally distilled in vacuo, the fraction boiling at 71-91 °C/
0.15 Torr collected (80 g, 0.4 mol, 57%). The distillates from
several runs were combined and refractionated, the fraction
boiling at 80 °C/0.01 Torr (lit.16 bp 87 °C/0.8 Torr) used in the
next step.
suggesting a reduced chlorin-like analog of 4 formed
instead of 4 itself; however, both proton and 13C spectra
of 4 are consistent with a fully aromatic structure and
not a chlorin analog.13
The family of bronzaphyrins is potentially binucleating,
with two centers for ion chelation, each site sharing the
two central heteroatoms. Preliminary results indicate
that, of the-first row transition metals, only Cu2+ shows
affinity for 4 and causes rapid autoxidation of the ligand.
The final member of the bronzaphyrin series, bronza-
phyrin NO 6, represents the current best hope for
achieving wide-ranging binucleating ability in a single
planar macrocycle. An experiment to this effect has
given encouraging results and will be expanded upon in
a further communication.
2,4-Dica r beth oxy-3-h exyl-5-m eth ylp yr r ole (10). A three-
necked 5 L round-bottom flask was equipped with a stir paddle,
thermometer, Claisen adapter, and dropping funnel and charged
with ethyl 3-oxononanoate (300 g, 1.5 mol) in glacial acetic acid
(1400 mL). Sodium nitrite (NaNO2, 109.5 g, 1.58 mol) in water
(300 mL) was added dropwise, maintaining a temperature of
e15 °C with an ice bath. After the addition was complete (∼30
min), the clear yellow solution was stirred for an additional 2
h. A heating mantle was then placed under the flask and the
flask fitted with a powder funnel. The dropping funnel was
charged with ethyl acetoacetate (200 g, 1.54 mol). Powdered
zinc (200 g, 3 mol) was slowly added portionwise; when the flask
contents reached 65 °C, ethyl acetoacetate addition commenced,
keeping the temperature between 80 and 90 °C. After all the
reactants were added, the contents were stirred at 80-90 °C
for an additional 1 h, cooled in an ice bath to 40 °C with vigorous
stirring, and poured over crushed ice (∼5 Kg). The resulting
ice-cold suspension was thoroughly admixed to fully precipitate
the crude product. This product was collected by filtration,
washed well with water, dissolved in 1400 mL of ethanol, and
filtered to remove traces of zinc. The stirred solution was heated
to boiling and neutralized with powdered NaHCO3 until no more
effervescence was observed at the boiling point. The solution
was then filtered or decanted into a 2 L round-bottom flask and
ethanol removed on the rotary evaporator. The residue was
diluted with 1 L of hexane and dried (MgSO4). Saponified
pyrrole salts (if present) precipitated from the hexane solution
in 10-30 min. The hexane solution was cooled to -20 °C and
the precipitate collected by filtration, washed with cold hexane,
and dried in air for 2 days to give the product pyrrole (134 g
first crop, 186 g total, 0.6 mol, 40%), mp ) 75-78 °C. Anal.
Exp er im en ta l Section
Elemental analyses were performed by Atlantic Microlabs,
Norcross, GA. Mass spectra were obtained from C. Lambert of
the University of Maryland, College Park, MD. 1H and 13C NMR
spectral data were collected on a Bruker AC-300 NMR spec-
trometer at 300 and 75 MHz, respectively, in CDCl3 with TMS
as reference. Compounds 1 and 2 were made by literature
methods.5 Anhydrous THF (Aldrich Chemical, Milwaukee, WI)
was distilled over Na0/benzophenone and degassed with argon
for 30 min prior to use. Triethylamine (Fisher Scientific,
Atlanta, GA) was distilled from CaH2 prior to use. TiCl4‚2THF
in 5 g wax-sealed bottles was obtained from Aldrich and opened
within 10 s of addition. Divinyl sulfone, 3,4-dimethyl-5-(2-
hydroxyethyl)thiazolium iodide, heptanoyl chloride, Et4NOH,
zinc dust, and anhydrous DMF were obtained from Aldrich and
used as received. All other reagents and solvents were obtained
from Fisher Scientific and used as received.
Eth yl 3-Oxon on a n oa te (9). A three-necked round-bottomed
flask was equipped with a reflux condenser, a high torque paddle
stirrer, thermometer, and dropping funnel and was charged with
powdered CaO (40.32 g, 0.72 mol) and CH2Cl2 (700 mL). To the
stirred suspension was added ethyl acetoacetate (91 g, 0.70
moles) over a 1/2 h period, maintaining a temperature between
20 and 30 °C.14 After the mixture was stirred for an additional
30 min, heptanoyl chloride (113 g, 0.76 mol) was added over 1.5
h at 25-35 °C (ice bath). The mixture was stirred for 12 h at
room temperature. A solution of ammonium chloride (0.72 mol,
38.52 g) in water (280 mL) was added, followed by concd NH4OH
(14) Constant attention must be paid to the stirring mixture. After
10 min, rapid solidification occurs and stirring must be increased at
this point in order to avoid formation of a solid matrix. When properly
monitored, the result is a viscous slurry. If a solid matrix forms, more
CH2Cl2 must be added and the matrix broken up into small pieces and
stirred until homogenous. The reaction outcome is unaffected by these
extra steps.
(13) The elemental compositions of dihydrobronzaphyrin and bronza-
phyrin are within experimental error of each other and cannot be used
to distinguish between the two.
(15) Dry ice added to the residue works well.
(16) Katzenellenbogen, J . A.; Utawanit, T. J . Am. Chem. Soc. 1974,
96, 6153-6158.

Notes
J . Org. Chem., Vol. 62, No. 4, 1997 1171
Calcd for C17H27NO4: C, 66.0; H, 8.8; N, 4.5. Found: C, 65.95;
H, 8.58; N, 4.51. 1H NMR (CDCl3) δ: 0.88 (t, 3 H, CH2CH2-
CH2CH2CH2CH3); 1.29 (m, 2 H, CH2CH2CH2CH2CH2CH3); 1.36,
1.37(2 × q, 8 H, 2 × OCH2CH3 + CH2CH2CH2CH2CH2CH3);
1.50-1.63 (m, 4 H, CH2CH2CH2CH2CH2CH3); 2.52 (s, 3 H, CH3);
3.03 (t, 2 H, CH2CH2CH2CH2CH2CH3); 4.29, 4.33 (2 × q, 4 H, 2
× OCH2CH3); 9.1 (br s, 1 H, NH). 13C NMR (CDCl3) δ: 14.0,
14.3, 14.3, 22.6, 25.8, 29.6, 31.3, 31.7, 59.4, 60.2, 112.8, 117.5,
136.0, 139.1, 161.6, 165.2.
4.35, 4.36 (2 × q, 8 H, 4 × OCH2CH3); 6.61 (d, 4 H, pyrrole CH);
9.17 (br s, 2 H, NH); 12.64 (br s, 1 H, NH). 13C NMR (CDCl3) δ:
14.1, 14.2, 14.4, 22.7, 26.1, 29.7, 31.3, 31.8, 60.3, 60.4, 109.2,
111.7, 115.6, 118.7, 124.2, 132.1, 135.8, 161.2, 165.8, 169.1.
Anal. Calcd for C36H51N3O8: C, 66.1; H, 6.4; N, 7.9. Found: C,
66.03; H, 6.40; N, 7.88.
4,4′′-Di-n -h exyl-2,2′:5′,2′′-ter p yr r ole (14). In a fume hood,
a 2 L three-necked round-bottom flask was equipped with a
magnetic stir egg, argon inlet, thermometer, and addition funnel,
positioned over a strong magnetic stirrer (an Ikamag RCT was
used), and a Bunsen burner clamped horizontally and pointing
to the bottom edge of the flask. This setup was charged with
ester 13 (13 g, 20 mmol), NaOH (20 g, 500 mmol), and ethylene
glycol (200 mL). The addition funnel was replaced with an
empty condenser topped with a still head, and the argon flow
commenced, followed by stirring and flame heating of the flask
contents. The contents dissolved after a few minutes and came
to a boil. After 10 mL of liquid had distilled, the condenser water
was turned on and reflux commenced. The flask contents were
at a temperature of 185-200 °C. The still head was removed
and replaced with a bubbler and the argon flow rate reduced.
The flask contents were stirred for 30 min at reflux and allowed
to cool to room temperature under argon. Degassed water (1 L)
was added. The resultant precipitate was collected by filtration
under an argon blanket, washed well with degassed water, and
dried in vacuo for 2 days to give the product terpyrrole 14 (7 g,
19 mmol, 95%) as a light tan to dark green powder, used directly
in the synthesis of 16 without further purification.
Tetr a eth yla m m on iu m Ca r bon a te. A solution of tetra-
ethylammonium hydroxide (35% w/v, 400 mL) in water was
poured into a Dewar flask and diluted with an equal volume of
ethanol. Dry ice (1 kg) was added and the flask covered and
allowed to sit for 24 h. The solvents were removed under
reduced pressure, and the solid product (optionally) was dried
in air for 1 week. The product thus obtained (100% yield) was
used in the step below without further purification.
2,5′′-Difor m yl-4,4′′-di-n -h exyl-2,2′:5′,2′′-ter pyr r ole (7c). The
above terpyrrole 14 (7 g, 19 mmol) was dissolved in argon-purged
DMF (50 mL) and cooled to -10 °C in a 100 mL two-necked
round-bottom flask equipped with a stir bar and a thermometer.
Benzoyl chloride (13.4 g, 95 mmol) was dropped in over 30 s,
keeping the temperature at -10 °C with a cold bath. After the
flask contents had solidified, the flask was placed in an oil bath,
2,3-Dica r beth oxy-3-h exylp yr r ole-5-ca r boxa ld eh yd e (11).
To a solution of hexylpyrrole 10 (154.5 g, 0.5 mole) in HOAc (1.5
L) maintained at 67-70 °C was added dropwise SO2Cl2 (140 g,
1.04 mol) over 10-15 min. A vigorous evolution of SO2 ensued.
The solution was stirred for an additional 30 min at 70-72 °C,
followed by the addition of H2O (200 mL). The reaction mixture
was then divided into two halves. Each half was poured into a
2 L separatory funnel, diluted with an additional 700 mL of H2O,
and extracted three times with ligroin (500 mL, 2 × 250 mL).
The ligroin extracts were combined, concentrated to 1-1.2 L,
and washed with water (3 × 500 mL). The ligroin was
completely removed on the rotary evaporator and the residue
diluted to 1.2 L with EtOH. The ethanolic solution was brought
to a boil with stirring and treated with NaHCO3 (50-100 g) until
no more effervescence was observed at the boiling point. The
solution was cooled and filtered and the ethanol completely
removed under high vacuum. The solid residue was dissolved
in warm hexane (800 mL) and air cooled for 10-30 min to allow
carboxyl salts to precipitate. These salts were filtered, and the
clear solution was placed in a freezer. The precipitate was
collected by filtration, washed with cold hexane, and dried to
give the product 11 (100-101 g, 0.31 mol, 62%), mp 65-68 °C.
1H NMR (CDCl3) δ: 0.89 (t, 3 H, CH2CH2CH2CH2CH2CH3); 1.31
(m, 4 H, CH2CH2CH2CH2CH2CH3); 1.40 , 1.41 (2 × q, 8 H, 2 ×
OCH2CH3 + CH2CH2CH2CH2CH2CH3); 1.50-1.61 (m, 2 H,
CH2CH2CH2CH2CH2CH3); 3.08 (t, 2 H, CH2CH2CH2CH2CH2CH3);
4.38, 4.39 (2 × q, 4 H, 2 × OCH2CH3); 9.89 (br s, 1 H, NH);
10.27 (s, 1 H, CHO). 13C NMR (CDCl3) δ: 14.1, 14.3, 22.6, 25.2,
29.5, 31.1, 31.7, 60.8, 61.2, 120.2, 123.5, 133.5, 136.2, 160.3,
163.5, 182.7. Anal. Calcd for C17H25NO5: C, 63.1; H, 7.8; N,
4.3. Found: C, 63.20; H, 7.80; N, 4.38.
1,4-Bis[3,5-b is(et h oxyca r b on yl)-4-n -h exyl-2-p yr r olyl]-
1,4-bu ta n ed ion e (12). A mixture of aldehyde 11 (196 g, 0.606
mol), divinyl sulfone (35.8 g, 0.303 mol), 3,4-dimethyl-5-(2-
hydroxyethyl)thiazolium iodide (25 g, 0.09 mol), and Et3N (18.4
g, 0.18 mol) in dry dioxane (1200 mL) was stirred at 70-75 °C
for 18 h. The dioxane was completely removed under high
vacuum, the residue taken up in 1 L hot hexane, and filtered.
The cooled filtrate was placed in a freezer for 12 h. The solid so
obtained was collected by filtration and again recrystallized from
hexane; cooling to room temperature gave a precipitate that was
collected by filtration, washed with hexane, and dried to give
product 12 (120 g, 0.18 mol, 59%), mp 85-85 °C. 1H NMR
(CDCl3) δ: 0.89 (t, 6 H, CH2CH2CH2CH2CH2CH3); 1.31 (m, 8 H,
CH2CH2CH2CH2CH2CH3); 1.37, 1.41 (2 × q, 16 H, 2 × OCH2CH3
+ CH2CH2CH2CH2CH2CH3); 1.48-1.67 (m, 4 H, CH2CH2CH2-
CH2CH2CH3); 2.91 (t, 4 H, CH2CH2CH2CH2CH2CH3); 3.36 (s, 4
H, C()O))CH2CH2C()O)); 4.35, 4.40 (2 × q, 8 H, 2 × OCH2CH3);
9.88 (br s, 2 H, NH). 13C NMR (CDCl3) δ: 13.8, 13.9, 14.0, 22.4,
25.2, 29.2, 31.0, 31.4, 60.8, 61.0, 119.5, 123.4, 133.5, 136.2, 160.3,
163.5, 190.4. Anal. Calcd for C36H52N2O10: C, 64.3; H, 7.8; N,
4.2. Found: C, 64.51; H, 7.84; N, 4.1.
and the contents were held under N2
at 85 °C for 11 h. The
resulting hot solution was poured into a 100 mL beaker where
it promptly solidified. The solid was allowed to cool to room
temperature. DMF was removed by vacuum filtration with a
rubber dam, leaving a copper-colored solid, salt 15. The filtrate
was cooled to -20 °C and gave an additional small amount of
15. The solid 15 was suspended in fresh DMF (80 mL) in a 150
mL beaker, heated briefly to 70 °C until fully dissolved, and then
cooled to 55 °C. Tetraethylammonium carbonate (17.6 g, 57
mmol) was added in chunks, resulting in gas evolution. The
solution was stirred for 1-2 h and transferred to a 250 mL one-
necked round-bottom flask. DMF was removed under reduced
pressure (0.1 Torr); a Ku¨gelrohr set to 50 °C helped to remove
the last 10 mL of solvent. The residue, muddy with DMF, was
diluted to 100 mL with ethanol and stirred vigorously until
homogenous. The solid was collected by filtration, washed with
hot ethanol, and dried to give the product aldehyde 7c (5.36 g,
12.7 mmol, 64%) as a canary yellow powder, mp ) 253-255 °C.
1H NMR (DMSO-d6) δ: 0.85 (t, 6 H, CH2CH2CH2CH2CH2CH3);
1.29 (br, 12 H, CH2CH2CH2CH2CH2CH3); 1.60 (m, 4 H, CH2-
CH2CH2CH2CH2CH3); 2.70 (t, 4 H, CH2CH2CH2CH2CH2CH3);
6.46 (d, 2 H, pyrrole CH); 6.77 (s, 2 H, pyrrole CH); 9.51 (s, 2 H,
CHO); 11.34 (br s, 1 H, NH); 11.74 (br s, 2 H, NH). 13C NMR
(DMSO-d6, 39.5 ppm) δ: 13.6, 21.8, 24.6, 28.2, 30.7, 30.8, 107.0,
3,5,3′′,5′′-Tet r a k is(et h oxyca r b on yl)-4,4′′-d i-n -h exyl-2,2′:
5′,2′′-ter p yr r ole (13). Butanedione 12 (67.3 g, 0.1 mol) was
refluxed under N2 for 18 h with ammonium acetate (200 g) and
acetic anhydride (80 mL) in acetic acid (1 L). Most of the solvent
was removed under reduced pressure. The residue was diluted
with CH2Cl2 (500 mL) and water (500 mL) and transferred to a
separatory funnel. The organic layer was separated and washed
with water (500 mL) and saturated NaHCO3 (500 mL). The
organic layer was dried (Na2SO4) and concentrated on the rotary
evaporator with addition of hexane. The evaporation was
stopped when precipitate began to form. The precipitate was
collected by filtration, washed with hexane, and dried in the dark
to give the product 13 (58.6 g, 90 mmol, 90%) as a yellow
microcrystalline powder, mp 127-128 °C. 1H NMR (CDCl3) δ:
0.9 (t, 6 H, CH2CH2CH2CH2CH2CH3); 1.31-1.41 (m, 24 H, 4 ×
OCH2CH3 + 2 × CH2CH2CH2CH2CH2CH3); 1.55 (m, 4 H,
CH2CH2CH2CH2CH2CH3); 3.06 (t, 4 H, CH2CH2CH2CH2CH2CH3);
109.1, 125.0, 128.5, 132.2, 137.8, 175.6. Anal. Calcd for C26H35
-
N3O2: C 74.1; H, 8.4; N, 10.0. Found: C, 74.16; H, 8.33; N,
10.02.
Br on za p h yr in NS (4). A 1 L, three-necked round-bottom
flask with a 34/45 center was equipped with a stir egg, inlet
valve, and side stopper, charged with zinc dust (1.96 g, 30 mmol),
and placed in an oven at 140 °C for 30 min alongside a condenser
equipped with an inlet valve. The two pieces were removed from
the oven, assembled, and evacuated while being cooled to room
temperature. After backfilling with argon through the con-
denser, argon flow was established through the flask inlet and

1172 J . Org. Chem., Vol. 62, No. 4, 1997
Notes
the condenser removed, and TiCl4‚2THF (5 g, 15 mmol) was
quickly added through the center hole. The condenser was
reconnected and the condenser valve replaced with a rubber
septum/bubbler. THF (100 mL) was added by cannula to the
flask, and the contents were held at reflux for 30 min, establish-
ing the characteristic black color of Ti0. Aldehydes 7c (316 mg,
0.75 mmol) and 16 (265 mg, 0.75 mmol) in THF (250 mL) were
added by cannula to the flask over 5 min, and the contents were
held at reflux for 18 h. The reaction was cooled to room
temperature and quenched by the slow addition of 10% w/v
Na2CO3 (50 mL). The THF was rotovapped off at 45 °C, the
water decanted, and the residue taken up in CHCl3 (150 mL)
and dried (Na2SO4). The resulting black liquid was concentrated
to 50 mL (45 °C) and passed through silica (CHCl3 eluent). The
overlapping orange bands were collected and concentrated to
dryness (45 °C), leaving a green residue. This residue was
extracted by 3 × 30 min reflux with hexane (3 × 150 mL). The
hexane extracts were combined and concentrated to dryness,
giving impure 4. Traces of 1 that remained were removed by
elution through a 2 × 30 cm silica column (CHCl3 eluent), 1
running slightly faster than 4. The main band of 4 was collected
and recrystallized from hexane and then CH2Cl2/MeOH to give
the product 4 (15 mg, 0.02 mmol, 3%) as metallic green flat
needles. 1H NMR (high dilution in CDCl3) δ: -5.7 (br, 1 H,
NH); -1.4 (v br, 2 H, NH); 1.03 (t, J ) 7.2 Hz, 6 H,
CH2CH2CH2CH3); 1.94 (pent, J ) 7.4 Hz, 4 H, CH2CH2CH2-
CH2CH2CH3); 2.57 (m, 8 H, CH2CH2CH3 + CH2CH2CH2-
CH2CH2CH3); 4.29 (m, 8 H, CH2CH2CH3 + CH2CH2CH2CH2-
CH2CH3); 9.95, 10.08, 10.09, 10.11, 10.41, 10.91 (5 × s, 5 × 2 H,
ring CH). 13C NMR (CDCl3) δ: 14.3, 14.8, 22.9, 25.6, 29.2, 29.7,
30.0, 30.8, 32.1, 106.9, 107.4, 119.9, 122.8, 127.0, 128.4, 132.8,
133.2, 136.4, 140.7, 144.2, 145.0. MS m/e: 711 (100), 644 (15),
625 (4), 596 (4), 356 (7). HRMS: calcd for C46H55N5S 709.41785,
found 709.41756. UV-vis (THF) λ (log ꢀ): 460 (5.10), 486 sh
(4.90), 795-96 (4.73), 850 (4.80).
Ack n ow led gm en t. This work was supported by the
Petroleum Research Fund (ACS-PRF 29869-G3). The
author wishes to thank Robert Christian for assistance
with the synthesis of 9 and Utembe Djawotho for
assistance with the synthesis of 10.11
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectrum
of 4; 1H and 13C NMR spectra of 7c and 10-13; tabulated
absorbance values (10 µM, THF) of 1, 2, and 4 (12 pages). This
material is contained in libraries on microfiche, 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.
CH2CH2CH2CH2CH2CH3); 1.46-1.56 (m, 10H, CH2CH2CH3
+
CH2CH2CH2CH2CH2CH3); 1.67 (pent, J ) 7.9 Hz, 4 H, CH2CH2-
J O961849U