Synthesis of meso-substituted chlorins via tetrahydrobilene-a intermediates

Article abstract of DOI:10.1021/jo0104835

Chlorin building blocks incorporating a geminal dimethyl group in the reduced ring and synthetic handles in specific patterns at the perimeter of the macrocycle are expected to have utility in biomimetic and materials chemistry. A prior route employed condensation of a dihydrodipyrrin (Western half) and a bromodipyrromethane-monocarbinol (Eastern half), followed by oxidative cyclization of the putative dihydrobilene-a to form the meso-substituted zinc chlorin in yields of ～10%. The limited stability of the dihydrodipyrrin precluded study of the chlorin-forming process. We now have refined this methodology. A tetrahydrodipyrrin Western half (2,3,4,5-tetrahydro-1,3,3-trimethyldipyrrin) has been synthesized and found to be quite stable. The condensation of the Western half and an Eastern half (100 mM each) proceeded smoothly in CH₃CN containing 100 mM TFA at room temperature for 30 min. The resulting linear tetrapyrrole, a 2,3,4,5-tetrahydrobilene-a, also is quite stable, enabling study of the conversion to chlorin. Refined conditions for the oxidative cyclization were found to include the following: the tetrahydrobilene-a (10 mM), AgTf (3-5 molar equiv), Zn(OAc)₂ (15 molar equiv), and 2,2,6,6-tetramethylpiperidine (15 molar equiv) in CH₃CN at reflux exposed to air for 4-6 h, affording the zinc chlorin. The chlorin-forming process could be implemented in either a two-flask process or a one-flask process. The two-flask process was applied to form six zinc chlorins bearing substituents such as pentafluorophenyl, 3,5-di-tert-butylphenyl, TMS-ethyl benzoate, iodophenyl, or ethynylphenyl (deprotection of the TMS-ethynyl group occurred during the oxidative cyclization process). The stepwise yields (isolated) for the condensation and oxidative cyclization processes forming the tetrahydrobilene and zinc chlorin were 32-72% and 27-62%, respectively, giving overall yields of zinc chlorin from the Eastern and Western halves of 12-45%. Taken together, the refinements introduced enable 100-mg quantities of chlorin building blocks to be prepared in a facile and rational manner.

Full text of DOI:10.1021/jo0104835

7342
J . Org. Chem. 2001, 66, 7342-7354
Syn th esis of Meso-Su bstitu ted Ch lor in s via Tetr a h yd r obilen e-a
In ter m ed ia tes
Masahiko Taniguchi, Doyoung Ra, Guoning Mo, Thiagarajan Balasubramanian, and
J onathan S. Lindsey*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
Received May 11, 2001
Chlorin building blocks incorporating a geminal dimethyl group in the reduced ring and synthetic
handles in specific patterns at the perimeter of the macrocycle are expected to have utility in
biomimetic and materials chemistry. A prior route employed condensation of a dihydrodipyrrin
(Western half) and a bromodipyrromethane-monocarbinol (Eastern half), followed by oxidative
cyclization of the putative dihydrobilene-a to form the meso-substituted zinc chlorin in yields of
∼10%. The limited stability of the dihydrodipyrrin precluded study of the chlorin-forming process.
We now have refined this methodology. A tetrahydrodipyrrin Western half (2,3,4,5-tetrahydro-
1,3,3-trimethyldipyrrin) has been synthesized and found to be quite stable. The condensation of
the Western half and an Eastern half (100 mM each) proceeded smoothly in CH3CN containing
100 mM TFA at room temperature for 30 min. The resulting linear tetrapyrrole, a 2,3,4,5-
tetrahydrobilene-a, also is quite stable, enabling study of the conversion to chlorin. Refined
conditions for the oxidative cyclization were found to include the following: the tetrahydrobilene-a
(10 mM), AgTf (3-5 molar equiv), Zn(OAc)2 (15 molar equiv), and 2,2,6,6-tetramethylpiperidine
(15 molar equiv) in CH3CN at reflux exposed to air for 4-6 h, affording the zinc chlorin. The chlorin-
forming process could be implemented in either a two-flask process or a one-flask process. The
two-flask process was applied to form six zinc chlorins bearing substituents such as pentafluo-
rophenyl, 3,5-di-tert-butylphenyl, TMS-ethyl benzoate, iodophenyl, or ethynylphenyl (deprotection
of the TMS-ethynyl group occurred during the oxidative cyclization process). The stepwise yields
(isolated) for the condensation and oxidative cyclization processes forming the tetrahydrobilene
and zinc chlorin were 32-72% and 27-62%, respectively, giving overall yields of zinc chlorin from
the Eastern and Western halves of 12-45%. Taken together, the refinements introduced enable
100-mg quantities of chlorin building blocks to be prepared in a facile and rational manner.
In tr od u ction
and Western half is performed in a two-flask procedure
involving acid-catalyzed condensation to give a dihydro-
bilene-a, followed by metal-mediated oxidative cyclization
to give the chlorin. The Eastern half, a bromodipyr-
romethane-monocarbinol, is readily available by the
acylation and bromination of a dipyrromethane at the
1- and 9-positions, respectively, followed by reduction.
The Western half is a dihydrodipyrrin (1). The Western
half has limited stability and generally must be prepared
from the stable nitrohexanone-pyrrole precursor and used
within a few days.
In our initial search for routes to a suitable Western
half, we investigated the synthesis of a tetrahydrodipyr-
rin via an intermediate tetrahydrodipyrrin N-oxide (com-
prised of a pyrrole and a pyrroline N-oxide).4 The
formation of N-oxides by cyclization followed by deoxy-
genation affords a convenient entry to a number of
nitrogen heterocycles.5 Indeed, pyrroline N-oxides played
a central role throughout Todd’s studies related to the
synthesis of vitamin B12.6 Battersby et al. synthesized a
tetrahydrodipyrrin N-oxide, converted it to the corre-
sponding tetrahydrodipyrrin, and upon reaction with a
The synthesis of chlorins is an area of active interest
owing to the photochemical properties of these green
pigments.1 We recently developed a synthetic route that
provides access to chlorin building blocks bearing sub-
stituents at the meso- and/or â-positions.2,3 In addition
to selected patterns of functional group handles at the
perimeter of the macrocycle, each chlorin bears a geminal
dimethyl group to lock in the hydrogenation level yet
lacks steric congestion or other unwanted functionality
around the reduced ring. The synthesis involves the
construction of an Eastern half and a Western half, which
are joined to form the chlorin macrocycle in the final step
(Scheme 1). This convergent coupling of the Eastern half
(1) (a) J acobi, P. A.; Lanz, S.; Ghosh, I.; Leung, S. H.; Lo¨wer, F.;
Pippin, D. Org. Lett. 2001, 3, 831-834. (b) Montforts, F.-P.; Kutzki,
O. Angew. Chem. Int. Ed. 2000, 39, 599-601. (c) Silva, A. M. G.; Tome´,
A. C.; Neves, M. G. P. M. S.; Cavaleiro, J . A. S. Tetrahedron Lett. 2000,
41, 3065-3068. (d) Shea, K. M.; J aquinod, L.; Khoury, R. G.; Smith,
K. M. Tetrahedron. 2000, 56, 3139-3144. (e) Burns, D. H.; Shi, D. C.;
Lash, T. D. Chem. Commun. 2000, 299-300. (f) Krattinger, B.; Callot,
H. J . Eur. J . Org. Chem. 1999, 1857-1867. (g) Zheng, G.; Dougherty,
T. J .; Pandey, R. K. Chem. Commun. 1999, 2469-2470. (h) J ohnson,
C. K.; Dolphin, D. Tetrahedron Lett. 1998, 39, 4619-4622. (i) Mironov,
A. F.; Efremov, A. V.; Efremova, O. A.; Bonnett, R.; Martinez, G. J .
Chem. Soc., Perkin Trans. 1 1998, 3601-3608.
(4) Ref 2, Supporting Information.
(5) (a) Katritzky, A. R.; Lagowski, J . M. Chemistry of the Heterocyclic
N-Oxides, Academic Press: London and New York, 1971; pp 166-231.
(b) Ochiai, E. Aromatic Amine Oxides, Elsevier: Amsterdam, 1967;
pp 184-209. (c) Albini, A.; Pietra, S. Heterocyclic N-Oxides, CRC
Press: Boca Raton, 1991; pp 120-134.
(2) Strachan, J .-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey,
J . S. J . Org. Chem. 2000, 65, 3160-3172.
(3) Balasubramanian, T.; Strachan, J .-P.; Boyle, P. D.; Lindsey, J .
S. J . Org. Chem. 2000, 65, 7919-7929.
10.1021/jo0104835 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/09/2001

Synthesis of Meso-Substituted Chlorins
J . Org. Chem., Vol. 66, No. 22, 2001 7343
Sch em e 1. Ch lor in Syn th esis via a
rahydrodipyrrin N-oxide 3, but attempted deoxygenation
of the cyclic nitrone to form the tetrahydrodipyrrin
Western half 4 afforded an unknown byproduct.4 We
resorted to the cyclization of the nitrohexanone-pyrrole
2 to give the dihydrodipyrrin 1 directly (without isolating
the N-oxide) in yields of 20-30%.2,3 The tetrahydrodipyr-
rin 4 remained quite attractive due to lack of π-conjuga-
tion between the pyrrole and pyrroline rings. We antici-
pated that compared with the dihydrodipyrrin Western
half 1, the tetrahydrodipyrrin 4 should (1) be more stable
and (2) exhibit greater reactivity at the pyrrolic R-position
to acid-catalyzed condensation, thereby facilitating for-
mation of the corresponding tetrahydrobilene-a interme-
diate. We have since reinvestigated the synthesis of the
tetrahydrodipyrrin Western half by deoxygenation of the
corresponding N-oxide 3.
Dih yd r obilen e-a
In this paper, we describe a number of refinements that
greatly facilitate access to meso-substituted chlorin
building blocks. The synthesis of a new Western half (4)
based on the tetrahydrodipyrrin nucleus is achieved by
the deoxygenation of the corresponding N-oxide 3 under
nonacidic conditions. The resulting tetrahydrobilene-a is
stable, which enabled refinements to the conditions for
both the condensation and the oxidation. We also have
investigated a one-flask procedure for chlorin formation.
Two new Eastern halves have been prepared for en-
hanced solubility of the resulting chlorin building blocks
in organic solvents. The meso-substituted chlorin build-
ing blocks are of interest in the synthesis of multichlorin
arrays.
Resu lts a n d Discu ssion
Syn th esis of a Tetr a h yd r od ip yr r in Wester n Ha lf.
The synthesis of the unsubstituted tetrahydrodipyrrin
Western half 4 is shown in Scheme 2. The desired
nitrohexanone-pyrrole 2 was prepared from pyrrole-2-
carboxaldehyde by reaction with nitromethane, affording
2-(2-trans-nitrovinyl)pyrrole, followed by reduction with
sodium borohydride and fluoride-mediated Michael ad-
dition of mesityl oxide. Reductive cyclization of 2 in the
presence of Zn in acetic acid at room temperature (but
exothermic) as specified by Battersby7 afforded the
N-oxide 3 in <40% yield. A byproduct, observable by TLC
1-bromo-9-bromomethyldipyrrin in the presence of copper
acetate obtained the copper chlorin in 6.9% yield (2.8
mg).7 Though the pyrrole component in Battersby’s
Western half was substituted with one ester and two
alkyl groups, the route employed also proved suitable for
our synthesis of a tetrahydrodipyrrin N-oxide incorporat-
ing an unsubstituted pyrrole unit.4 Thus, cyclization of
nitrohexanone-pyrrole 2 afforded the corresponding tet-
1
analysis and estimated by H NMR spectroscopy to be
present in ∼3:2 ratio (byproduct/3), was isolated and
assigned the annulated “pyrrolo-desmethyltropane” struc-
1
ture shown for 5. Noteworthy features of the H NMR
spectrum of 5 include the following: (1) the presence of
two resonances due to the pyrrole R-proton and â-proton,
in contrast to the three resonances due to the R- and
â-protons exhibited by the N-oxide 3, and (2) disappear-
ance of the singlets assigned to the amino and pyrrolic
NH protons upon exchange with D2O. The structure of 5
was confirmed by X-ray crystallography (Supporting
Information). The formation of such a cyclic byproduct
cannot occur with pyrrole precursors bearing a full
complement of alkyl substituents at the R- and â-posi-
tions.7 The same reaction performed in acetic acid diluted
1:1 with ethanol and held at 0 °C, with portionwise
addition of the Zn, resulted in a >9:1 ratio of 3:5. The
residual byproduct 5 was readily removed by chroma-
tography. Under these improved conditions, the desired
N-oxide 3 was isolated in 86% yield.
(6) (a) Bonnett, R.; Brown, R. F. C.; Clark, V. M.; Sutherland, I. O.;
Todd, A. J . Chem. Soc. 1959, 2094-2102. (b) Bonnett, R.; Clark, V.
M.; Todd, A. J . Chem. Soc. 1959, 2102-2104. (c) Brown, R. F. C.; Clark,
V. M.; Todd, A. J . Chem. Soc. 1959, 2105-2108. (d) Brown, R. F. C.;
Clark, V. M.; Sutherland, I. O.; Todd, A. J . Chem. Soc. 1959, 2109-
2116. (e) Brown, R. F. C.; Clark, V. M.; Lamchen, M.; Todd, A. J . Chem.
Soc. 1959, 2116-2122. (f) Clark, V. M.; Sklarz, B.; Todd, A. J . Chem.
Soc. 1959, 2123-2127. (g) Bowering, W. D. S.; Clark, V. M.; Thakur,
R. S.; Lord Todd. Ann. 1963, 669, 106-113. (h) Brown, R. F. C.; Clark,
V. M.; Lord Todd. J . Chem. Soc. 1965, 2337-2340. (i) Brown, R. F. C.;
Clark, V. M.; Lord Todd. Tetrahedron, Suppl. 8, Part 1, 1966, 15-26.
(j) Black, D. St. C.; Clark, V. M.; Odell, B. G.; Sutherland, I. O.; Lord
Todd. J . Chem. Soc., Perkin Trans. 1 1976, 1942-1943. (k) Black, D.
St. C.; Clark, V. M.; Odell, B. G.; Lord Todd. J . Chem. Soc., Perkin
Trans. 1 1976, 1944-1950. (l) Black, D. St. C.; Clark, V. M.; Thakur,
R. S.; Lord Todd. J . Chem. Soc., Perkin Trans. 1 1976, 1951-1954.
(m) Alderson, G. W.; Black, D. St. C.; Clark, V. M.; Lord Todd. J . Chem.
Soc., Perkin Trans. 1 1976, 1955-1960.
The next step involved deoxygenation of N-oxide 3 to
give the tetrahydrodipyrrin 4. Numerous methods have
been developed for the deoxygenation of heterocyclic
(7) Battersby, A. R.; Fookes, C. J . R.; Snow, R. J . J . Chem. Soc.,
Perkin Trans. 1 1984, 2725-2732.

7344 J . Org. Chem., Vol. 66, No. 22, 2001
Taniguchi et al.
Sch em e 2
ported by rearrangement of tetrahydrodipyrrin deriva-
tives (formed as intermediates in amine + ketoaldehyde
condensations in studies of aging) and a plausible mech-
anism proposed involving electrophilic attack of the
pyrroline imine at the pyrrole 3-position.10
Application of a procedure for the deoxygenation of
N-oxides with Ti(0)/THF at room temperature11 to 3
resulted in a variety of decomposition products as deter-
mined by 1H NMR spectroscopy. Upon repeating the
deoxygenation procedure with the addition of 2 molar
equiv of triethylamine to the Ti(0)/THF slurry (to neu-
tralize the HCl liberated from the preparation of Ti(0))
prior to addition to the solution of 3 in THF, the desired
deoxygenated product 4 was obtained as a crystalline
solid following column chromatography. The tetrahy-
drodipyrrin 4 is quite stable, exhibiting negligible de-
composition over 1 month upon storage at 0 °C.
In vestiga tion of th e Syn th esis of Ch lor in s. Our
prior synthesis of chlorins involved (1) formation of the
bromodipyrromethane-monocarbinol (Eastern half) by
NaBH4 reduction of the carbonyl group in the Eastern
half precursor, (2) acid-catalyzed condensation of the
Eastern half and the Western half to obtain the dihy-
drobilene-a, and (3) oxidative metal-mediated cyclization
to give the chlorin.2,3 All three steps were done in
succession on the same day. However, condensation of 4
and 6a -OH (100 mM TFA in CH3CN at room tempera-
ture) followed by oxidation under the conditions employed
with 1 (excess AgIO3, Zn(OAc)2 and piperidine in anhy-
drous toluene at 80 °C) gave chlorin Zn -8a in only 7%
yield. Similarly, reaction of 4 and 6c-OH afforded chlorin
Zn -8c in 10% yield.
Stu dies of th e Con den sation . To understand whether
the low yields of chlorin originated in the condensation
process or the metal-mediated oxidative cyclization pro-
cess, we sought to isolate the putative tetrahydrobilene-
a, a linear tetrapyrrole derivative formed by condensation
of the Western half and the Eastern half. The condensa-
tion of 4 and Eastern half 6a -OH (100 mM each) was
performed at room temperature in CH3CN containing 100
mM TFA (eq 1). TLC analysis of the reaction mixture
after 3 min showed the presence of a new component.
Chromatographic workup after 30 min afforded the
N-oxides bearing various functional groups.5 For the
tetrahydrodipyrrin N-oxide, the ideal deoxygenation
method must not be strongly acidic to avoid polymerizing
the pyrrole unit and must not cause reduction of the
imine. The deoxygenation of 3 was examined with a
variety of reagents8 at room temperature and at elevated
temperatures, but the N-oxide was resistant to deoxy-
genation with each of these reagents as determined by
TLC or 1H NMR analysis. In addition, NaBH4/THF9
reduced the N-oxide and the double bond affording
several products. Treatment with TiCl3 in a buffered NH4-
OAc solution7 gave byproduct 5 (obtained previously but
not identified)4 rather than the desired pyrroline 4. This
failure is in contrast to the successful transformation
(75% yield) achieved by Battersby and co-workers upon
applying the same method to a tetrahydrodipyrrin N10-
oxide, which differed from 3 only in bearing one ester
and two alkyl substituents on the pyrrole unit.7 Similar
pyrrolo[3.2.1]azabicyclooctane products have been re-
1
tetrahydrobilene-a 7a in 72% yield. The H NMR spec-
trum of the tetrahydrobilene-a showed resonances char-
acteristic of the respective Western half 4 and Eastern
half precursor 6a . The three signals (7.75, 8.05, 9.29 ppm)
assigned to the pyrrolic NH units each appeared as a
broad multiplet. The appearance of multiple signals is
not unexpected; the tetrahydrobilene-a contains three
chiral centers, and the isolated product can comprise up
to eight diastereomers. Bilanes and derivatives are
known to be sensitive to oxidation as well as attack by
electrophilic species (e.g., acids) and to undergo inter-
molecular exchange of the pyrrole rings.12 However, the
tetrahydrobilene-a sample showed no decomposition upon
storage as a solid for several months or in a solution of
CDCl3 for more than 2 weeks under argon near 0 °C.
The surprising stability of the tetrahydrobilene-a and
access to ∼500 mg quantities of this compound enabled
us to explore the reaction conditions of the separate
condensation and oxidation steps. To modify the condi-
(8) Zn, NaOH/methanol (a); Zn, aqueous NH4Cl/THF (b); FeSO4,
aqueous NH4Cl/CH3CN (c); Mg or Fe, AcONH4/methanol (d); Ph3P/
toluene (e, f); S/toluene (g); NaN3/toluene (h); Zn, NaI, Me3SiCl/CH3-
CN (i). (a) den Hertog, H. J .; Henkens, C. H.; Van Roon, J . H. Rec.
Trav. Chim. Pays-Bas 1952, 71, 1145-1151. (b) Aoyagi, Y.; Abe, T.;
Ohta, A. Synthesis 1997, 891-894. (c) Talik, T.; Plazek, E. Roczniki
Chem. 1961, 35, 463-473. (d) Hahn, W. E.; Lesiak, J . Polish J . Chem.
1985, 59, 627-629. (e) Lu, X.; Sun, J .; Tao, X. Synthesis 1982, 185-
186. (f) Read, R. W.; Spear, R. J .; Norris, W. P. Aust. J . Chem. 1983,
36, 1227-1237. (g) Relyea, D. I.; Tawney, P. O.; Williams, A. R. J .
Org. Chem. 1962, 27, 477-481. (h) Di Nunno, L.; Florio, S. La Chim.
E
L’Ind. (Milan) 1975, 57, 243-244. (i) Morita, T.; Kuroda, K.;
Okamoto, Y.; Sakurai, H. Chem. Lett. 1981, 921-924.
(9) (a) Kawazoe, Y.; Tachibana, M. Chem. Pharm. Bull. 1965, 13,
1103-1107. (b) Kawazoe, Y.; Araki, M. Chem. Pharm. Bull. 1968, 16,
839-847.
(10) Xu, G.; Sayre, L. M. Chem. Res. Toxicol. 1999, 12, 862-868.
(11) Malinowski, M. Synthesis 1987, 732-734.
(12) Xue, T.; Scott, A. I. Tetrahedron Lett. 1998, 39, 6651-6654.

Synthesis of Meso-Substituted Chlorins
J . Org. Chem., Vol. 66, No. 22, 2001 7345
F igu r e 1. Effect of the concentration of TFA on the condensa-
tion of Eastern half (6a -OH) and Western half (4). The yield
shown refers to the amount of chlorin formed upon treatment
of the crude product to the oxidation conditions (analogous to
a one-flask reaction) followed by UV-vis spectroscopy.
fragments that can recombine to form products with
undesired substitution patterns (i.e., scrambling).14 We
have found that dipyrromethane-carbinols (and the re-
sulting porphyrinogens) are stable to modest concentra-
tions of TFA in CH3CN but that scrambling occurs within
30 min upon exposure to 100 mM TFA.15,16 LD-MS
analysis of the crude reaction mixture showed no scram-
bling with condensations employing 100 mM TFA. The
absence of scrambling in the condensation of the Eastern
and Western halves at higher acid concentration than
in dipyrromethane condensations can be explained by
consideration of the basicity of the different reactants.
The weakly basic nature of the pyrrolic unit in a
dipyrromethane (protonated 2-methylpyrrole has pKa )
-0.21)17 provides little capacity for buffering of the acid
in reactions of the dipyrromethane. By comparison, the
pyrroline motif in the Western half is basic (protonated
2,4,4-trimethyl-∆1-pyrroline has pKa ) 7.6).18 With equal
concentrations of TFA and the Western half (100 mM
each), the latter likely buffers the former, affording an
effective acidity within the range that safely avoids
acidolysis of the dipyrromethane or tetrahydrobilene-a
species.
The time course of the condensation for reaction with
100 mM TFA at room temperature is shown in Figure 2.
These results show that the reaction is rapid and the
yield changes only slightly over the course of 2 h, with a
slight peak around 30 min. In summary, a condensation
for 30 min at room temperature in CH3CN containing
100 mM TFA results in the highest yield of chlorin.
Stu d ies of th e Meta l-Med ia ted Oxid a tive Cycliza -
tion . The motivation for employing an oxidant, base,
metal complex, and a silver salt for converting the
tions of the condensation, the concentration of TFA and
the reaction time were examined. The condensation of
Western half 4 and Eastern half 6a -OH was performed
for a given period of time; for quantitation, the resulting
tetrahydrobilene-a 7a was subjected to the oxidative
cyclization to form the chlorin. The yield of chlorin Zn -
8a was then determined by UV-vis spectroscopy. Refined
conditions for the oxidative cyclization were employed
(vide infra); these conditions employ AgTf, Zn(OAc)2, and
2,2,6,6-tetramethylpiperidine in CH3CN at reflux exposed
to air for 4.5 h.
The effect of the concentration of TFA (10-316 mM)
was examined at room temperature for condensations of
30 min in CH3CN. The results are shown in Figure 1.
The chlorin was formed in 36% yield upon use of 100 mM
TFA. By contrast, the reaction of the dihydrodipyrrin 1
with 10 mM reactants and 10 mM TFA2,13 gave chlorin
in ∼10% yield.
Two possible side reactions during acid-catalyzed
condensation were of considerable concern, including
rearrangement of the Western half (4 f 5) and acidolysis
yielding mixtures of chlorins and porphyrins: (1) A likely
mechanism for formation of byproduct 5 involves elec-
trophilic attack of the positively charged imine (or
nitrone) on the 3-position of the pyrrole.10 Treatment of
4 (100 mM) under the same acid catalysis conditions
employed in chlorin formation (100 mM TFA in CH3CN
at room temperature) gave a ratio of 95:5 for compounds
4/5 after 30 min but ∼20:80 after 12 h. The same reaction
with 1 M TFA gave a ratio of ∼15:85 after 30 min. These
results show that the rearrangement of the Western half
4 to the byproduct 5 occurs under acid catalysis, but the
reaction is too slow to be competitive with the condensa-
tion with an Eastern half giving the tetrahydrobilene-a.
(2) A key concern upon exposure of dipyrromethanes to
acidic media is the occurrence of acidolysis yielding
(13) Strachan, J .-P.; O′Shea, D. F.; Balasubramanian, T.; Lindsey,
J . S. J . Org. Chem. 2001, 66, 642.
(14) Littler, B. J .; Ciringh, Y.; Lindsey, J . S. J . Org. Chem. 1999,
64, 2864-2872.
(15) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J .; Lindsey, J . S. J .
Org. Chem. 2000, 65, 7323-7344.
(16) Rao, P. D.; Littler, B. J .; Geier, G. R., III; Lindsey, J . S. J . Org.
Chem. 2000, 65, 1084-1092.
(17) Chiang, Y.; Whipple, E. B. J . Am. Chem. Soc. 1963, 85, 2763-
2767.
(18) Bonnett, R.; Clark, V. M.; Giddey, A.; Todd, A. J . Chem. Soc.
1959, 2087-2093.

7346 J . Org. Chem., Vol. 66, No. 22, 2001
Taniguchi et al.
Ta ble 1. Effects of Solven t on Ch lor in F or m a tion
(7a f Zn -8a )a
solvent
T (°C)
yieldb (%)
CH3CN
reflux
reflux
120 °C
reflux
120 °C
reflux
reflux
reflux
reflux
reflux
reflux
60
58
57
44
42
THFc
DMF
1,2-dichloroethane
DMSO
toluene
39
ethanol
pyridine
CHCl3
dioxane
methanol
35
34d
19
17
<1d
a
All reactions were performed under the standard conditions
employing the following components: tetrahydrobilene-a (7a ) (10
mM), AgTf (3 molar equiv), Zn(OAc)2 (15 molar equiv), and 2,2,6,6-
tetramethylpiperidine (15 molar equiv) under the specified condi-
b
tions (solvent, temperature) exposed to air for 4.5 h. Determined
F igu r e 2. Effect of the duration of the condensation of
Eastern half (6a -OH) and Western half (4) on the ultimate
yield of chlorin. The yield (average of two experiments) shown
refers to the amount of chlorin formed upon treatment of the
crude product to the oxidation conditions (analogous to a one-
flask reaction) followed by UV-vis spectroscopy.
by absorption spectroscopy (ꢀ609 ) 43 600 M-1 cm-1) in toluene.
c Reagent-grade THF gave a slightly higher yield of chlorin (Zn -
d
8a ) compared to that with distilled THF. The long wavelength
λmax was at 612 nm.
problem was that iodinated chlorin byproducts were
occasionally obtained. To avoid AgIO3, we reexamined the
use of high-potential quinones such as p-chloranil and
DDQ, which are effective oxidants in the two-step one-
flask synthesis of porphyrins.20 We previously attempted
to use p-chloranil but the chlorin product formed gave
an incorrect molecule ion peak upon LD-MS analysis. The
use of p-chloranil with the tetrahydrobilene-a gave two
covalent chlorin-hydroquinone byproducts in greater
yields than that of the desired chlorin (see the Supporting
Information for isolation and characterization). Ulti-
mately, we found that oxidation occurred without a
deliberately added oxidant other than exposure of the hot
reaction mixture to air. It is likely that the oxidant in
the previous reaction conditions employing AgIO3 also
was O2. With this finding in hand, an iterative optimiza-
tion led to the following reaction conditions: AgTf (3
molar equiv), Zn(OAc)2 (15 molar equiv), and 2,2,6,6-
tetramethylpiperidine (15 molar equiv) in a solvent
exposed to air. The cleanliness of these reactions enabled
the yield of chlorin to be determined by UV-vis spec-
troscopy. The following sections describe the optimization
of the oxidative cyclization conditions.
tetrahydrobilene-a to the chlorin can be understood by
examination of Scheme 3, which shows proposed steps
in the transformation. While little is known either about
the intermediates or the sequence of events in this
process, consideration of the formal transformations in
the overall process guided our thinking in the develop-
ment of reaction conditions. The role of the oxidant is to
remove six electrons and six protons. The role of the base
is to neutralize the acetic acid (2 equiv) formed upon zinc
insertion, to neutralize the HBr formed upon aromati-
zation, and perhaps to facilitate imine-enamine tau-
tomerization. The role of the metal complex is to template
the electrocyclization. The role of the silver salt is to
facilitate dehydrobromination.19 The overall process is
expected to be more complex than illustrated by Scheme
3. For example, complexation and tautomerization may
be interspersed among stepwise oxidation processes.
The conversion of the tetrahydrobilene-a 7a to the zinc
chlorin Zn -8a was examined under a variety of condi-
tions. The conditions employed previously used AgIO3 (15
molar equiv), Zn(OAc)2 (15 molar equiv), and piperidine
(15 molar equiv) in toluene at 80 °C for 2 h.2,3 The same
conditions with 7a gave the desired zinc chlorin Zn -8a ;
the yield was low (7% overall yield), but a more severe
We first examined the conversion of 7a to Zn -8a in 10
solvents of diverse polarity and composition (Table 1).
Sch em e 3. P r ocesses a n d P ossible In ter m ed ia tes in Ch lor in F or m a tion

Synthesis of Meso-Substituted Chlorins
J . Org. Chem., Vol. 66, No. 22, 2001 7347
Ta ble 2. Effects of Ba se on Ch lor in F or m a tion
(7a f Zn -8a )a
yieldb (%)
base
THF
CH3CN
2,2,6,6-tetramethylpiperidine
triethylamine
piperidine
65
35
72
57
41c
<1
31c
<1
2,5-di-tert-butylpyridine
a
All reactions were performed under the standard conditions
employing the following components: tetrahydrobilene-a (7a ) (10
mM), AgTf (3 molar equiv), Zn(OAc)2 (15 molar equiv), and
specified base (15 molar equiv) at reflux in the specified solvent
b
exposed to air for 4.5 h. Determined by absorption spectroscopy
(ꢀ609 ) 43 600 M-1 cm-1) in toluene. c The long wavelength λmax
was at 612 nm.
Ta ble 3. Effects of Am ou n t of AgTf on Ch lor in
F or m a tion (7a f Zn -8a )a
F igu r e 3. Spectral evolution of the conversion of 7a to Zn -
8a upon treatment under the oxidative cyclization conditions
[tetrahydrobilene-a (7a ) (10 mM), AgTf (3 molar equiv), Zn-
(OAc)2 (15 molar equiv), 2,2,6,6-tetramethylpiperidine (15
molar equiv) in CH3CN at reflux in air]. The absorption due
to the Soret band and the Qy(0,0) band steadily increases while
the absorption at 505 nm rises and declines with time. (The
clipping of the Soret band absorption in the spectra at 2 and
5 h is an instrumental artifact.)
molar equiv of AgTf
yieldb (%)
1
2
3
5
10
15
46
60
63
68
7
c
a
All reactions were performed under the standard conditions
employing the following components: tetrahydrobilene-a (7a ) (10
mM), AgTf (specified amount), Zn(OAc)2 (15 molar equiv), 2,2,6,6-
tetramethylpiperidine (15 molar equiv) at reflux in CH3CN
of 2,2,6,6-tetramethylpiperidine. The rigorous exclusion
of oxygen proved difficult, and the omission of this
putative reagent was not examined.
The concentration dependence of the reaction was
examined by performing the reaction of tetrahydro-
bilene-a 7a at 1, 3, or 10 mM and scaling the concentra-
tions of the reagents linearly. The yield of chlorin was
essentially constant over this 10-fold change in concen-
tration.
b
exposed to air for 4.5 h. Determined by absorption spectroscopy
(ꢀ609 ) 43,600 M-1 cm-1) in toluene. c The broad bands in the
absorption spectrum precluded accurate yield determination.
Ta ble 4. Om ission Exp er im en ts to Test Oxid a tive
Cycliza tion Con d ition s (7A f Zn -8A)a
yieldb (%)
conditions
THF
CH3CN
The time course of the reaction was monitored by
absorption spectroscopy. The spectral evolution of the
oxidative cyclization process is shown in Figure 3. Within
1 min, a sharp absorption band is evident at 505 nm,
which resembles that of a bis(dipyrrinato)zinc(II) chro-
mophore4,21 though such an assignment is not certain (see
the Supporting Information). A zinc-dipyrrin complex
could form by chelation of a partially oxidized product of
the initial tetrahydrobilene-a (not shown in Scheme 3).
The peak at 505 nm increased for 15 min and then
decreased. The absorption spectra also show the appear-
ance after 8 min of the characteristic chlorin peaks at
413 and 609 nm, which continue growing in over 1 h.
After 1 h, more than 40% of tetrahydrobilene-a 7a had
been converted into chlorin Zn -8a . The yield of chlorin
as a function of time was readily assessed based on the
intensity of the peak at 609 nm. The resulting yield
versus time plot is shown in Figure 4. The formation of
the chlorin Zn -8a is essentially complete within 5 h.
no omission (standard conditions)
omission of AgTf
omission of Zn(OAc)2
58
15
-
60
35
0
c
c
omission of 2,2,6,6-tetramethylpiperidine
-
<1
a
All reactions were performed under the following conditions
(with omission of the specified component): tetrahydrobilene-a (7a )
(10 mM), AgTf (3 molar equiv), Zn(OAc)2 (15 molar equiv), and
2,2,6,6-tetramethylpiperidine (15 molar equiv) at reflux in the
b
specified solvent exposed to air for 4.5 h. Determined by absorp-
tion spectroscopy (ꢀ609 ) 43 600 M-1 cm-1) in toluene. c Not
examined.
The solvents CH3CN, THF, and DMF proved superior
(∼60% yield), but we focused on CH3CN and THF for
further studies because of their ease of handling. Bat-
tersby also found CH3CN to be the best solvent in his
studies of chlorin formation.7
Four amine bases were examined (Table 2) in THF or
CH3CN. Of the four, 2,2,6,6-tetramethylpiperidine gave
the best results in both CH3CN and THF (72%, 65%).
Piperidine, which was used in the previous method,2,3
gave a lower yield than 2,2,6,6-tetramethylpiperidine.
We examined the amount of AgTf required for the
reaction (Table 3). When a large excess of AgTf was used,
little chlorin (Zn -8a ) was formed. The best result was
obtained using 2-5 molar equiv of AgTf.
To establish the absolute requirement for each of the
reagents in the chlorin-forming reaction, omission experi-
ments were performed (Table 4). In the absence of AgTf,
chlorin was formed at only one-half to one-fourth of the
normal level. No chlorin was observed in the absence of
zinc acetate, and only a trace was obtained in the absence
(19) Cromwell, N. H.; Ayer, R. P.; Foster, P. W. J . Am. Chem. Soc.
1960, 82, 130-132.
(20) Lindsey, J . S. In The Porphyrin Handbook; Kadish, K. M.,
Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000;
Vol. 1, pp 45-118.
(21) (a) Granick, S.; Gilder, H. In Advances in Enzymology; Nord,
F. F., Ed.; Interscience: New York, 1947; Vol. 7, pp 358-363. (b)
J ohnson, A. W.; Kay, I. T.; Markham, E.; Price, R.; Shaw, K. B. J .
Chem. Soc. 1959, 3416-3424. (c) Motekaitis, R. J .; Martell, A. E. Inorg.
Chem. 1970, 9, 1832-1839. (d) March, F. C.; Couch, D. A.; Emerson,
K.; Fergusson, J . E.; Robinson, W. T. J . Chem. Soc. A 1971, 440-448.
(e) Murakami, Y.; Matsuda, Y.; Kobayashi, S. J . Chem. Soc., Dalton
Trans. 1973, 1734-1737. (f) Hill, C. L.; Williamson, M. M. J . Chem.
Soc., Chem. Commun. 1985, 1228-1229. (g) Bru¨ckner, C.; Karunarat-
ne, V.; Rettig, S. J .; Dolphin, D. Can. J . Chem. 1996, 74, 2182-2193.

7348 J . Org. Chem., Vol. 66, No. 22, 2001
Taniguchi et al.
F igu r e 4. Yield of chlorin Zn -8a as a function of time upon
treatment of 7a to the oxidation conditions [tetrahydrobilene-
a (7a ) (10 mM), AgTf (3 molar equiv), Zn(OAc)2 (15 molar
equiv), 2,2,6,6-tetramethylpiperidine (15 molar equiv) in CH3-
CN at reflux in air]. The yield was determined by absorption
spectroscopy (ꢀ609 ) 43,600 M-1 cm-1) in toluene. Legend: b,
THF; O, CH3CN.
In summary, the conditions for converting the tetrahy-
drobilene-a into the chlorin are as follows: tetrahydro-
bilene-a (10 mM), AgTf (3-5 molar equiv), Zn(OAc)2 (15
molar equiv), and 2,2,6,6-tetramethylpiperidine (15 molar
equiv) in CH3CN at reflux in air for 4-6 h. These
conditions were applied to a larger-scale synthesis of
chlorin Zn -8a . Thus, a 75.8-mg sample of tetrahydro-
bilene-a 7a was converted to 45 mg of chlorin Zn -8a (62%
yield).
On e-F la sk P r oced u r e for Syn th esis of Ch lor in s.
The condensation yielding a tetrahydrobilene-a and
subsequent oxidative cyclization yielding the chlorin has
heretofore been implemented in a sequential two-flask
procedure. The first step is an intermolecular reaction
and should not require dilute conditions; the second step
is an intramolecular cyclization and should proceed in
greater yield under dilute conditions. Accordingly, we
investigated a one-flask procedure employing 100 mM
reactants in the condensation procedure and 10 mM
reactants in the cyclization procedure. After condensation
of Western Half 4 and Eastern half 6a -OH using 100 mM
of TFA in CH3CN, the reaction mixture was diluted 10-
fold by addition of CH3CN. The components for the
oxidation were added [AgTf (3 molar equiv), Zn(OAc)2 (15
molar equiv), and 2,2,6,6-tetramethylpiperidine (30 molar
equiv rather than 15 equiv, to neutralize the TFA)], and
the mixture was refluxed with exposure to air. After 18
h, chromatographic workup afforded chlorin Zn -8a in
31% yield (eq 2). Although this one-flask approach is
simple and readily implemented, the two-flask process
affords a higher yield (45%) of chlorin.
thesis of meso-substituted dipyrromethanes,22 monoacy-
lation of a dipyrromethane,16 and monobromination of a
dipyrromethane.2 Thus, a dipyrromethane (9) was treated
with ethylmagnesium bromide followed by a pyridyl
thioester (10, 11, or 12)2,23 affording the corresponding
monoacyldipyrromethane (13b -e) in 54-60% yield
(Scheme 4). Bromination of the latter by treatment with
NBS in THF at -78 °C afforded the desired precursor to
the Eastern halves 6b-e in 65-84% yield.24
The synthesis of meso-substituted chlorin building
blocks was carried out by the two-flask method as shown
in Scheme 5. This route is to be compared with the
previous route shown in Scheme 1. In each case, the new
Western half 4 was employed. In these preparative
syntheses, the oxidative cyclization process was moni-
tored by absorption spectroscopy, showing the rise and
fall of the intermediate (λabs ∼505 nm) and the formation
of the chlorin (λabs ∼609 nm). In general, the oxidative
cyclization was nearly complete at 4-8 h, but the
reactions were often continued for up to 24 h.
The various meso-substituted chlorins prepared via
this method are shown in Chart 1. The data shown are
for reactions with 0.3-1.0 mmol of 4, and then 0.10-
0.23 mmol of tetrahydrobilene-a. The synthesis of chlorin
Zn -8a provides a benchmark for yield comparisons. The
reaction of 4 and 6a -OH afforded tetrahydrobilene 7a in
72% yield; oxidative conversion of the latter afforded Zn -
8a in 62% yield. The scaled-up oxidative conversion
beginning with 0.79 mmol of 7a afforded 208 mg of
Exten sion to th e Syn th esis of Meso-Su bstitu ted
Ch lor in s. We investigated the synthesis of meso-
substituted chlorins bearing two types of substituents:
(1) strong electron-withdrawing groups and (2) synthetic
handles at defined locations at the perimeter of the
macrocycle. The former help to establish the scope of the
methodology and the latter enable construction of chlorin-
containing model systems in biomimetic or materials
chemistry.
(22) Littler, B. J .; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea,
D. F.; Boyle, P. D.; Lindsey, J . S. J . Org. Chem. 1999, 64, 1391-1396.
(23) Goto, T.; Onaka, M.; Mukaiyama, T. Chem. Lett. 1980, 51-52.
(24) While all of the tetrahydrobilenes (7a -f) were stable for a
period of g1 month, the Eastern half precursors (1-bromo-9-aroyl-
dipyrromethanes) exhibited a range of stability. Compounds 6a -c or
6d showed decomposition after a few days or one week, respectively,
while 6e and 6f were stable for >1 month.
The synthesis of meso-substituted Eastern halves
follows established methodology for the one-flask syn-

Synthesis of Meso-Substituted Chlorins
J . Org. Chem., Vol. 66, No. 22, 2001 7349
Sch em e 4
Sch em e 5. Ch lor in Syn th esis via a
Tetr a h yd r obilen e-a
chlorin Zn -8a (43% yield; 30% overall). The reaction of
the bis(pentafluorophenyl)-substituted Eastern half with
4 gave the tetrahydrobilene 7b in 32% yield and the
chlorin Zn -8b in 38% yield. Several chlorin building
blocks were prepared. The reaction of the Eastern half
bearing a TMS-protected ester (6c-OH) with 4 gave the
tetrahydrobilene 7c and chlorin Zn -8c in reasonable
yields (55%, 41%). An iodo-substituted chlorin (Zn -8d )
was prepared by reaction of the corresponding Eastern
half 6d . We attempted to prepare a chlorin bearing a
trimethylsilyl-protected ethyne by reaction of Eastern
half 6e. The tetrahydrobilene 7e was formed smoothly.
However, oxidative cyclization afforded the chlorin with
the ethyne lacking the trimethylsilyl protecting group
(Zn -7e). The synthesis of a similar trimethylsilyl-
protected ethyne chlorin was attempted with oxidative
cyclization of tetrahydrobilene 7f in THF rather than
CH3CN, and again the deprotected ethynyl chlorin (Zn -
8f) was obtained. In two cases, a comparison was made
of the oxidative cyclization in CH3CN or in THF; in each
case (7d , 7e), the yield of zinc chlorin was slightly higher
in THF. Zinc chlorins Zn -7d and Zn -7e both incorporate
the 3,5-di-tert-butyl group for increased solubility in
organic solvents. In no case was scrambling yielding a
mixture of chlorins detected.
45, 12, or 23% in the current method. Note that the
deprotected ethynyl chlorin Zn -8f was obtained herein
in 30% yield, in contrast to the 9% yield of the protected
ethynyl chlorin by the previous method.2
Ou tlook
We have refined a number of steps in the synthesis of
meso-substituted chlorin building blocks. The limitations
of the prior synthesis included the following: (1) chlorin
was obtained in yields of ∼10% and quantities of ∼5-20
mg; (2) the Western half (a dihydrodipyrrin) had a short
shelf life; (3) the putative dihydrobilene-a intermediate
was not isolated or quantitated; (4) the use of AgIO3 in
the oxidation method in some cases resulted in iodinated
chlorin byproducts. The refined method described herein
affords a Western half (a tetrahydrodipyrrin) in good
yield which is stable and can be prepared in multigram
quantities. The Western half and the Eastern half
undergo smooth condensation with mild acid catalysis,
affording a stable tetrahydrobilene-a intermediate. No
scrambling yielding a mixture of products, as can occur
with dipyrromethanes under acid catalysis,14-16 was
detected under these conditions. Studies of the oxidative
cyclization of the tetrahydrobilene-a intermediate re-
vealed simple conditions [AgTf, Zn(OAc)2, and 2,2,6,6-
tetramethylpiperidine in CH3CN at reflux exposed to air]
that afford chlorin in a clean manner. Several zinc
chlorins were synthesized in yields of 12-45% (based on
the Eastern half and Western half precursors) and in
quantities of 27-208 mg. The isolation of the intermedi-
It is noteworthy that in each synthesis the intermedi-
ate tetrahydrobilene-a was isolated in substantial quan-
tities (73-460 mg), characterized, and found to be
reasonably stable. The yields of chlorins were 2-4-fold
greater than those obtained previously where compari-
sons could be made. For example, the prior synthetic
method afforded chlorins Zn -8a , Zn -8b, or Zn -8c in
yields of 10, 6, or 10%,2 respectively, to be compared with

7350 J . Org. Chem., Vol. 66, No. 22, 2001
Taniguchi et al.
Ch a r t 1
ate tetrahydrobilene-a in each case enabled determina-
tion of the yields of the separate condensation and
oxidative cyclization processes.
mg.27-31 All other routes require an oxidant, are per-
formed thermally in the presence of a metal salt, and
afford the metallochlorin rather than the free base
chlorin. Battersby’s pioneering studies to convert 2,3,4,5-
tetrahydrobiladiene-ac25 or 2,3-dihydrobiladiene-ab25,26
species to the corresponding chlorin employed copper
reagents; this approach afforded copper chlorins in yields
of e7.4% and quantities of e3 mg.7,25,26 However, the
reaction with copper reagents in the presence of air
sometimes affords the copper oxochlorin rather than the
copper chlorin.7 The use of zinc in place of copper provides
distinct advantages because (1) the zinc chlorin is easily
demetalated and (2) air can be employed as the oxidant
without forming the oxochlorin. Relatively few tetra-
pyrrole intermediates in chlorin syntheses have been
characterized.7,26,29 The tetrahydrobilene-a intermediates
The conversion of the 2,3,4,5-tetrahydrobilene-a to the
chlorin requires a 6e-, 6H+ oxidation. This change in
oxidation level is identical to that in the conversion of a
porphyrinogen to a porphyrin.20 Other methods for form-
ing chlorins by cyclization of a linear tetrapyrrole derived
from an Eastern half and a Western half employ lesser
changes in oxidation level. The intermediates (and oxida-
tion required) in such syntheses include a 2,3-dihydro-
bilene-a (4e-, 4H+),2,3 a 2,3,4,5-tetrahydrobiladiene-ac
(4e-, 4H+),7,25 a 2,3-dihydrobiladiene-ab (2e-, 2H+),26,27
and a 2,3-dihydrobilatriene (no change in oxidation level)
(Chart 2; also see the Supporting Information for
nomenclature).27-31 The dihydrobilatriene was converted
to the free base chlorin via a photochemical process in
yields reaching 54% and in quantities reaching 10
(28) Dutton, C. J .; Fookes, C. J . R.; Battersby, A. R. J . Chem. Soc.,
Chem. Commun. 1983, 1237-1238.
(25) Snow, R. J .; Fookes, C. J . R.; Battersby, A. R. J . Chem. Soc.,
Chem. Commun. 1981, 524-526.
(29) Battersby, A. R.; Dutton, C. J .; Fookes, C. J . R.; Turner, S. P.
D. J . Chem. Soc., Perkin Trans. 1 1988, 1557-1567.
(30) Battersby, A. R.; Dutton, C. J .; Fookes, C. J . R. J . Chem. Soc.,
Perkin Trans. 1 1988, 1569-1576.
(26) Battersby, A. R.; Fookes, C. J . R.; Snow, R. J . J . Chem. Soc.,
Perkin Trans. 1 1984, 2733-2741.
(27) Battersby, A. R.; Dutton, C. J .; Fookes, C. J . R.; Turner, S. P.
D. J . Chem. Soc., Chem. Commun. 1983, 1235-1237.
(31) Battersby, A. R.; Turner, S. P. D.; Block, M. H.; Sheng, Z.-C.;
Zimmerman, S. C. J . Chem. Soc., Perkin Trans. 1 1988, 1577-1586.

Synthesis of Meso-Substituted Chlorins
J . Org. Chem., Vol. 66, No. 22, 2001 7351
(Fisher certified A.C.S.) for use in the condensation process
was distilled from CaH2 and stored over powdered molecular
sieves. Nitromethane was stored over CaCl2. Anhydrous
methanol was prepared by drying over CaH2 for 12 h followed
by distillation. Other solvents were used as received.
Ch a r t 2. Tetr a p yr r ole In ter m ed ia tes in Ch lor in
Syn th eses (Most Su bstitu en ts Om itted for Cla r ity)
Non com m er cia l Com p ou n d s. The compounds 2,2 6a ,2
6b,2 6f,2 9a -d ,22 9e,33 10,2 12,2 13a ,2 13b,2 and 13f2 were
prepared as described in the literature.
2,3,4,5-Tetr a h yd r o-1,3,3-tr im eth yld ip yr r in N10-Oxid e
(3). Following a general procedure,7 to a vigorously stirred
solution of 2 (1.26 g, 5.29 mmol) in 25 mL of acetic acid and
25 mL of ethanol at 0 °C, zinc dust (8.64 g, 132 mmol) was
added slowly in small portions for 5 min. The reaction mixture
was stirred at 0 °C for 15 min and then was filtered through
Celite. The filtrate was concentrated under high vacuum. The
resulting brown solid was purified by column chromatography
[silica; packed and eluted with ethyl acetate/CH2Cl2 (1:1), then
eluted with CH2Cl2/methanol (9:1)] affording a brown oil that
solidified to brownish crystals on standing at room tempera-
ture (943 mg, 86%): mp 85-87 °C; 1H NMR δ 1.12 (s, 3H),
1.17 (s, 3H), 2.04 (s, 3H), 2.28, 2.44 (AB, 2J ) 17.6 Hz, 2H),
2.95-3.10 (m, 2H), 3.82-3.96 (m, 1H), 5.85-5.97 (m, 1H),
6.02-6.11 (m, 1H), 6.64-6.72 (m, 1H), 10.50-10.72 (br, 1H);
13C NMR δ 13.9, 23.4, 26.3, 28.5, 37.8, 47.7, 81.9, 107.0, 107.9,
118.1, 129.2, 147.3; FAB-MS obsd 206.1415, calcd 206.1419
(C12H18N2O).
2,3,4,5-Tetr a h yd r o-1,3,3-tr im eth yld ip yr r in (4). Follow-
ing a general procedure for the deoxygenation of N-oxides11
with slight modification, TiCl4 (2.87 mL, 26.2 mmol) was slowly
added with stirring to dry THF (60 mL) under argon at 0 °C.
To the resulting yellow solution was slowly added LiAlH4 (665
mg, 17.5 mmol). The resulting black mixture was stirred at
room temperature for 15 min, and then triethylamine (23.0
mL, 164 mmol) was added. The black mixture was then poured
into a solution of 3 (725 mg, 3.65 mmol) in dry THF (45 mL).
The mixture was stirred for 30 min at room temperature, and
then water (45 mL) was added. The mixture was filtered. The
filtrate was extracted with CH2Cl2. The organic layer was dried
(Na2SO4) and evaporated under reduced pressure. The result-
ing yellow oil was purified by chromatography (silica, ethyl
acetate) to give a pale yellow oil, which solidified to a pale
yellow solid on cooling (448 mg, 65%): mp 53-54 °C; 1H NMR
obtained herein from saturated starting materials (tet-
rahydrodipyrrin Western half, bromodipyrromethane-
monocarbinol Eastern half) are stable and readily char-
acterized. In summary, the approach we have developed
enables study of the separate condensation and oxidative
cyclization process, employs relatively mild conditions,
and affords access to workable quantities of chlorin
building blocks.
2
δ 0.94 (s, 3H), 1.10 (s, 3H), 2.04 (s, 3H), 2.28, 2.44 (AB, J )
16.9 Hz, 2H), 2.59 (ABX, 3J ) 11.7 Hz, 2J ) 14.7 Hz, 1H), 2.77
(ABX, 3J ) 3.3 Hz, 2J ) 14.7 Hz, 1H), 3.57-3.68 (m, 1H), 5.90-
5.97 (m, 1H), 6.05-6.13 (m, 1H), 6.67-6.73 (m, 1H), 9.70-
9.92 (br, 1H); 13C NMR δ 20.3, 22.6, 27.0, 27.9, 41.8, 54.1, 80.1,
105.1, 107.1, 116.3, 131.4, 174.6; FAB-MS obsd 191.1551, calcd
191.1548 (C12H18N2).
5,11-Dia za -1,9,9-t r im et h ylt r icyclo[6.2.1.02,6]u n d eca -
2(6),3-d ien e (5). To a vigorously stirred solution of 2 (2.00 g,
8.39 mmol) in 40 mL of acetic acid at room temperature was
added zinc dust (13.7 g, 210 mmol) all at once (Ca u tion : the
reaction is exothermic). The reaction mixture was stirred at
room temperature without temperature control for 1 h. The
mixture was filtered through Celite. The filtrate was removed
under vacuum, and CH2Cl2 (100 mL) was added. The solution
was washed with 10% aqueous Na2CO3 (100 mL). The organic
layer was separated and chromatographed, affording 3 (143
mg, 8.2%). The aqueous layer was extracted with CH2Cl2 (3 ×
100 mL), and the resulting organic layer was dried (Na2SO4)
and concentrated to give a dark pink solid that still contained
about 10% of the N-oxide (720 mg). Recrystallization (CHCl3)
afforded dark pink crystals (254 mg, 16%): mp 145 °C; 1H
NMR δ 0.95 (s, 3H), 1.21 (s, 3H), 1.50 (s, 3H), 1.59, 1.74 (AB,
Exp er im en ta l Section
1
Gen er a l Meth od s. H NMR (300 MHz) and 13C NMR (75
MHz) spectra were collected at room temperature in CDCl3.
The protons at the perimeter of the chlorins generally exhib-
ited first-order spectra. Absorption spectra were obtained in
toluene at room temperature. Chlorins were analyzed by laser
desorption mass spectrometry (LD-MS) in the absence of a
matrix.32 Fast atom bombardment mass spectrometry (FAB-
MS) data are reported for the molecule ion or protonated
molecule ion. Pyrrole was distilled at atmospheric pressure
from CaH2. Melting points are uncorrected. p-Iodobenzalde-
hyde was obtained from Karl Industries, Inc. All other reagents
and starting materials were obtained from Aldrich. Column
chromatography was performed with flash silica (Baker). The
reduction yielding the Eastern half was performed following
a standard procedure for forming dipyrromethane-carbinols.16
Solven t s. THF was distilled from sodium benzophenone
ketyl as required. Toluene was distilled from CaH2. CH3CN
3
2J ) 11.7 Hz, 2H), 1.83-1.97 (br, 1H), 2.64 (ABX, J < 1 Hz,
3
2
2J ) 16.1 Hz, 1H), 2.86 (ABX, J ) 5.1 Hz, J ) 16.1 Hz, 1H),
3.36 (ABX, 3J < 1 Hz, 2J ) 5.1 Hz, 1H), 5.92-5.99 (m, 1H),
6.54-6.60 (m, 1H), 7.72-7.92 (br, 1H); 13C NMR δ 24.5, 27.3,
28.5, 34.3, 42.0, 58.6, 60.6, 65.4, 103.4, 116.0, 123.6, 129.2;
FAB-MS obsd 191.1553, calcd 191.1548 (C12H18N2). The same
(32) (a) Fenyo, D.; Chait, B. T.; J ohnson, T. E.; Lindsey, J . S. J .
Porphyrins Phthalocyanines 1997, 1, 93-99. (b) Srinivasan, N.; Haney,
C. A.; Lindsey, J . S.; Zhang, W.; Chait, B. T. J . Porphyrins Phthalo-
cyanines 1999, 3, 283-291.
(33) Cho, W.-S.; Kim, H.-J .; Littler, B. J .; Miller, M. A.; Lee, C.-H.;
Lindsey, J . S. J . Org. Chem. 1999, 64, 7890-7901.

7352 J . Org. Chem., Vol. 66, No. 22, 2001
Taniguchi et al.
product was obtained in 63% yield upon treatment of 3 in THF
with TiCl3 in aqueous ammonium acetate (pH ) 6).4
(435 mg, 11.5 mmol) in 20 mL of anhydrous THF/methanol
(4:1), affording 6a -OH. The solvent was evaporated and the
residue was dissolved in 11.5 mL of the anhydrous CH3CN
(100 mM 6a -OH). Then Western half 4 (219 mg, 1.15 mmol,
100 mM) and TFA (89 µL, 1.15 mmol, 100 mM) were added.
The reaction mixture was stirred at room temperature for 30
min under an atmosphere of argon. Then 10% aqueous
NaHCO3 (50 mL) was added and the mixture was extracted
with distilled CH2Cl2 (100 mL). The combined organic layers
were washed with water, dried (Na2CO3) and concentrated in
vacuo without heating. The resulting brown solid was purified
by chromatography [silica, hexanes/ethyl acetate (5:1), and
then ethyl acetate] to give a brown solid (502 mg, 69%). The
sample was shown to be pure by TLC [silica, hexanes/ethyl
acetate (5:1); silica, ethyl acetate]. LD-MS proved ineffective
for characterizing the tetrahydrobilene-a. This material could
Stu d ies of th e Wester n Ha lf (4) + Ea ster n Ha lf (6a -
OH) Con d en sa tion . A sample of 6a (64.6 mg, 140 µmol) was
reduced with NaBH4 (53.0 mg, 1.40 mmol) in 4 mL of
anhydrous THF/methanol (4:1). The resulting 6a -OH and 4
(26.6 mg, 140 µmol) were dissolved in 7 mL of anhydrous CH2-
Cl2, then 0.5 mL portions of the solution were placed in each
of 14 vials (each vial contains 10 µmol of 6a -OH and 4). The
solvent was evaporated and then 0.1 mL of CH3CN containing
the desired TFA concentration (10 to 316 mM) was added.
After the desired reaction time (1 min to 2 h), the solution
was diluted with 0.9 mL of CH3CN [containing AgTf (7.7 mg,
30 µmol) and 2,2,6,6-tetramethylpiperidine (25.3 µL, 150
µmol)]. Then Zn(OAc)2 (27.5 mg, 150 µmol) was added, and
the mixture was refluxed for 4.5 h. The reaction yield was
determined by UV-vis spectroscopy. In the yield determina-
tions, CH3CN was added to each reaction mixture to bring the
volume to 4.0 mL (thereby negating any possible error due to
solvent evaporation during the reflux period). A 25 µL aliquot
was then removed and transferred to a cuvette containing 4
mL of toluene. Quantitation was then based on the absorption
at 609 nm (ꢀ609 ) 43 600 M-1 cm-1).
1
be characterized by mp, H NMR spectroscopy, and FAB-MS.
The metal-mediated oxidative cyclization to form the zinc
chlorin (Zn -8a ) was carried out as specified above. The
tetrahydrobilene-a (7a ), typically as a brown solid, was dis-
solved in CH3CN [502 mg (0.79 mmol) in 79 mL; 10 mM] under
an atmosphere of air. This solution was treated with Zn(OAc)2
(2.16 g, 11.8 mmol), AgTf (609 mg, 2.37 mmol) and 2,2,6,6-
tetramethylpiperidine (1.99 mL, 11.8 mmol). The reaction
mixture was refluxed for 24 h. The reaction mixture was
concentrated under reduced pressure. The residue was chro-
matographed [silica, hexanes/CH2Cl2 (2:1)] to give a blue solid
(208 mg, 43%; 30% overall yield). Analytical data were
consistent with literature values.2
On e-F la sk P r oced u r e for Ch lor in F or m a tion , Exem -
plified for Zn (II)-17,18-dih ydr o-10-m esityl-18,18-dim eth yl-
5-(4-m eth ylp h en yl)p or p h yr in (Zn -8a ). A sample of 6a (231
mg, 0.500 mmol) was reduced with NaBH4 (185 mg, 5.00
mmol) in 20 mL of anhydrous THF/methanol (4:1). The
resulting 6a -OH was dissolved in 5 mL of anhydrous CH3CN,
and then 4 (94 mg, 0.50 mmol) and TFA (39 µL, 0.50 mmol)
were added. The reaction mixture was stirred at room tem-
perature for 30 min under argon, and then the reaction
mixture was diluted with 45 mL of CH3CN. AgTf (385 mg, 1.50
mmol), Zn(OAc)2 (1.38 g, 7.50 mmol), and 2,2,6,6-tetrameth-
ylpiperidine (2.53 mL, 15.0 mmol, 30 molar equiv) were added.
The resulting mixture was refluxed for 18 h exposed to air.
The reaction mixture was concentrated under reduced pres-
sure. The residue was chromatographed [silica, hexanes/CH2-
Cl2 (2:1)], affording a blue solid (118 mg, 31%). Analytical data
were consistent with literature values.2
Stu d ies of th e Meta l-Med ia ted Oxid a tive Cycliza tion .
A solution of tetrahydrobilene 7a (63.5 mg, 100 µmol) in 10
mL of anhydrous CH2Cl2 was divided into 0.5 mL portions in
each of 20 vials (each vial contains 5 µmol of 7a ). For the study
examining the effect of the reaction solvent, CH2Cl2 was then
evaporated, and 0.5 mL of the solvent of interest was added.
The corresponding reagents for the oxidation [2,2,6,6-tetra-
methylpiperidine (13 µL, 77 µmol) and Zn(OAc)2 (14 mg, 76
µmol)] were added, and the mixture was refluxed for 4.5 h.
The yield of chlorin was determined by UV-vis spectroscopy.
In the yield determinations, CH2Cl2 was added to each reaction
mixture to bring the volume to 4.0 mL (thereby negating any
possible error due to solvent evaporation during the reflux
period). A 50 µL aliquot was then removed and transferred to
a 4 mL cuvette (containing toluene). Quantitation was then
based on the absorption at 609 nm (ꢀ609 ) 43 600 M-1 cm-1).
19-Br om o-2,3,4,5-tetr ah ydr o-15-m esityl-1,3,3-tr im eth yl-
10-(4-m eth ylp h en yl)bilen e-a (7a ). A sample of 6a (461 mg,
1.00 mmol) was reduced with NaBH4 (370 mg, 10.0 mmol) in
20 mL of anhydrous THF/methanol (4:1). The resulting 6a -
OH was dissolved in 10 mL of anhydrous CH3CN, and then 4
(188 mg, 1.00 mmol) and TFA (77 µL, 1.0 mmol) were added.
The reaction mixture was stirred at room temperature for 30
min under argon. Then 10% aqueous NaHCO3 (50 mL) was
added, and the mixture was extracted with distilled CH2Cl2
(3 × 20 mL). The combined organic layers were washed with
water, dried (Na2CO3), and concentrated in vacuo without
heating. The resulting brown solid was purified by chroma-
tography [silica, hexanes/ethyl acetate (5:1), and then ethyl
acetate] to give a brown solid (460 mg, 72%): mp 67-70 °C;1H
NMR δ 0.90 (bs, 3H), 1.07 (bs, 3H), 1.91 (bs, 3H), 2.04 (bs,
6H), 2.25 (bs, 3H), 2.26-2.30 (m, 2H), 2.31 (bs, 3H), 2.48-
2.60 (m, 1H), 2.66-2.72 (m, 1H), 3.52-3.63 (m, 1H), 5.28-
5.32 (m, 1H), 5.67-5.81 (m, 6H), 6.00-6.04 (m, 1H), 6.77-
6.83 (m, 2H), 7.06-7.11 (m, 4H), 7.67-7.79 (m, 1H), 7.99-
8.13 (m, 1H), 9.23-9.32 (m, 1H); FAB-MS obsd 635.2749, calcd
635.2730 (C38H43BrN4).
(S)-2-P yr id yl 3,5-d i-ter t-b u t ylb en zot h ioa t e (11). To a
stirred solution of 2-mercaptopyridine (2.78 g, 25.0 mmol) in
CH2Cl2 (50 mL) was added a solution of 3,5-di-tert-butylbenzoyl
chloride (6.31 g, 25.0 mmol) in CH2Cl2 (125 mL) over 10 min.
After 5 h, TLC showed complete consumption of the 2-mer-
captopyridine, and then 2 N NaOH was added. The organic
phase was isolated, washed with water, then dried (Na2SO4),
and the solvent was removed to afford a white solid. The solid
was recrystallized in hexane affording a white solid (5.05 g,
1
62%): mp 73-74 °C; H NMR δ 1.36 (s, 18H), 7.31-7.36 (m,
1H), 7.67-7.70 (m, 1H), 7.75-7.80 (m, 2H), 7.85-7.88 (m, 2H),
8.66-8.69 (m, 1H); 13C NMR δ 32.0, 35.7, 122.6, 124.2, 128.9,
131.4, 136.9, 137.7, 151.1, 152.3, 152.5, 190.8. Anal. Calcd for
C
20H25NOS: C, 73.35; H, 7.69; N, 4.28. Found: C, 73.40; H,
Zn (II)-17,18-d ih yd r o-10-m esit yl-18,18-d im et h yl-5-(4-
m eth ylp h en yl)p or p h yr in (Zn -8a ). A solution of 7a (75.8 mg,
0.120 mmol) in CH3CN (12 mL) was treated with Zn(OAc)2
(328 mg, 1.79 mmol), AgTf (91.9 mg, 0.360 mmol), and 2,2,6,6-
tetramethylpiperidine (300 µL, 1.79 mmol). The reaction
mixture was refluxed for 24 h exposed to air. The reaction
mixture was concentrated under reduced pressure, and then
the residue was chromatographed [silica, hexanes/CH2Cl2 (2:
1)] to give a blue solid (45 mg, 62%). Analytical data were
consistent with literature values.2
Tw o-F la sk P r oced u r e for Ch lor in F or m a tion , Exem -
plified for Zn (II)-17,18-Dih ydr o-10-m esityl-18,18-dim eth yl-
5-(4-m eth ylp h en yl)p or p h yr in (Zn -8a ). The synthesis of the
tetrahydrobilene-a (7a ) was carried out as specified above. A
sample of 6a (531 mg, 1.15 mmol) was reduced with NaBH4
7.75; N, 4.23.
1-(4-Meth ylben zoyl)-5-[4-[2-(tr im eth ylsilyl)eth oxyca r -
bon yl]p h en yl]d ip yr r om eth a n e (13c). Following a general
procedure,16 EtMgBr (13.1 mL, 13.1 mmol), 1.0 M in THF) was
added to a solution of 9c (2.00 g, 5.46 mmol) in dry THF (10
mL) at room temperature under argon. The mixture was
stirred at room temperature for 10 min and then cooled to -78
°C. A solution of (S)-2-pyridyl 4-methylbenzothioate (10) (1.25
g, 5.45 mmol) in dry THF (10 mL) was added. The reaction
mixture was maintained at -78 °C for 10 min, and then the
cooling bath was removed. After 3 h, the reaction was
quenched with 100 mL of saturated aqueous NH4Cl. The
reaction mixture was extracted with CH2Cl2, washed with
water, and then dried (Na2SO4) and concentrated under
reduced pressure to give a dark foam. Column chromatography

Synthesis of Meso-Substituted Chlorins
J . Org. Chem., Vol. 66, No. 22, 2001 7353
[silica packed with hexanes/ethyl acetate (10:1), eluted with
hexanes/ethyl acetate (5:1)] afforded a golden amorphous solid
(1.42 g, 54%): mp 67-70 °C; H NMR δ 0.07 (s, 9H), 1.11 (t,
the procedure for preparing 6c, reaction of 13e (1.00 g, 1.87
mmol) with NBS (333 mg, 1.87 mmol) followed by column
chromatography [silica hexanes/ethyl acetate (5:1)] afforded
1
1
J ) 8.1 Hz, 2H), 2.42 (s, 3H), 4.39 (t, J ) 8.1 Hz, 2H), 5.62 (s,
1H), 5.95-5.99 (m, 1H), 6.06-6.10 (m, 1H), 6.12-6.16 (m, 1H),
6.64-6.68 (m, 1H), 6.77-6.81 (m, 1H), 7.16-7.30 (m, 4H), 7.67
(d, J ) 7.3 Hz, 2H), 7.89 (d, J ) 7.3 Hz, 2H), 8.52-8.68 (br,
1H), 10.30-10.42 (br, 1H); 13C NMR δ -0.8, 18.0, 22.2, 44.6,
63.9, 108.6, 109.0, 111.3, 118.7, 121.4, 128.9, 129.6, 129.7,
130.1, 130.4, 130.8, 131.6, 136.1, 141.4, 143.1, 146.5, 167.1,
185.3. Anal. Calcd for C29H32N2O3Si: C, 71.87; H, 6.65; N, 5.78.
Found: C, 71.78; H, 6.61; N, 5.89.
a golden amorphous solid (914 mg, 80%): mp 118 °C dec; H
NMR δ 0.23 (s, 9H), 1.33 (s, 18H), 5.56 (s, 1H), 5.86-5.91 (m,
1H), 6.01-6.04 (m, 1H), 6.08-6.12 (m, 1H), 6.74-6.79 (m, 1H),
7.15 (d, J ) 8.1 Hz, 2H), 7.29 (d, J ) 8.1 Hz, 2H), 7.58-7.67
(m, 3H), 8.94-9.06 (br, 1H), 10.62-10.76 (br, 1H); 13C NMR δ
0.6, 32.1, 35.6, 44.8, 95.3, 98.7, 105.3, 110.3, 111.1, 111.4, 122.0,
122.8, 124.2, 126.7, 128.8, 131.9, 132.7, 132.9, 138.3, 141.2,
141.3, 151.5, 186.9. Anal. Calcd for C35H41BrN2OSi: C, 68.50;
H, 6.73; N, 4.56. Found: C, 68.48; H, 6.87; N, 4.47.
1-(3,5-Di-t er t -b u t ylb e n zoyl)-5-(4-iod op h e n yl)d ip yr -
r om eth a n e (13d ). Following the procedure for preparing 13c,
reaction of 9d (1.80 g, 5.10 mmol) and 11 (1.70 g, 5.10 mmol)
followed by column chromatography [silica hexanes/ethyl
acetate (5:1)] afforded a golden amorphous solid (1.63 g,
19-Br om o-2,3,4,5-tetr a h yd r o-1,3,3-tr im eth yl-10,15-bis-
(p en ta flu or op h en yl)bilen e-a (7b). Treatment of 6b (176
mg, 0.300 mmol) with NaBH4 (113 mg, 3.00 mmol) in 10 mL
of anhydrous THF/methanol (4:1) afforded 6b-OH. The reac-
tion of 6b-OH and 4 (57 mg, 0.30 mmol) in 3 mL of anhydrous
CH3CN containing TFA (23 µL, 0.30 mmol) for 30 min under
argon followed by the standard workup afforded a brown solid
(73 mg, 32%): mp 56-58 °C;1H NMR δ 0.90 (bs, 3H), 1.11 (s,
3H), 1.92 (bs, 3H), 2.23-2.42 (m, 2H), 2.50-2.72 (m, 2H),
3.52-3.62 (m, 1H), 5.73-6.08 (m, 8H), 8.27-8.46 (m, 1H),
8.58-8.70 (m, 1H), 9.72-9.85 (m, 1H); FAB-MS obsd 759.1181,
1
56%): mp 119-120 °C; H NMR δ 1.34 (s, 18H), 5.51 (s, 1H),
5.93-5.97 (m, 1H), 6.07-6.14 (m, 2H), 6.57-6.63 (m, 1H),
6.73-6.77 (m, 1H), 6.92 (d, J ) 8.1 Hz, 2H), 7.49 (d, J ) 8.1
Hz, 2H), 7.60-7.67 (m, 3H), 8.57-8.70 (br, 1H), 10.38-10.52
(br, 1H); 13C NMR δ 32.1, 35.6, 44.4, 93.3, 108.1, 108.5, 109.1,
111.3, 118.1, 118.8, 121.8, 124.1, 126.7, 130.9, 131.9, 138.3,
141.4, 141.8, 151.5, 186.6. Anal. Calcd for C30H33IN2O: C,
63.83; H, 5.89; N, 4.96. Found: C, 63.59; H, 5.95; N, 4.83.
1-(3,5-Di-ter t-bu tylben zoyl)-5-[4-[2-(tr im eth ylsilyl)eth -
yn yl]p h en yl]d ip yr r om eth a n e (13e). Following the proce-
dure for preparing 13c, reaction of 9e (2.00 g, 6.28 mmol) and
11 (2.06 g, 6.28 mmol) followed by column chromatography
[silica hexanes/ethyl acetate (5:1)] afforded a golden amorphous
calcd 759.1215 (C34H25BrF10N4). Anal. Calcd for C34H25
-
BrF10N4: C, 53.77; H, 3.32; N, 7.38. Found: C, 53.51; H, 3.41;
N, 6.97.
Zn (II)-17,18-d ih yd r o-18,18-d im eth yl-5,10-bis(p en ta flu -
or op h en yl)p or p h yr in (Zn -8b). Following the procedure for
preparing Zn -8a , a solution of 7b (77.7 mg, 0.102 mmol) in
CH3CN (10 mL) containing the oxidative cyclization reagents
was refluxed for 24 h exposed to air. Standard workup and
chromatography [silica, hexanes/CH2Cl2 (2:1)] gave a greenish
blue solid (28.2 mg, 38%). Analytical data were consistent with
literature values.2
19-Br om o-2,3,4,5-t e t r a h yd r o-1,3,3-t r im e t h yl-10-(4-
m eth ylp h en yl)-15-[4-[2-(tr im eth ylsilyl)eth oxyca r bon yl]-
p h en yl]bilen e-a (7c). Treatment of 6c (282 mg, 0.500 mmol)
with NaBH4 (189 mg, 5.00 mmol) in 30 mL of anhydrous THF/
methanol (4:1) afforded 6c-OH. The reaction of 6c-OH and 4
(94 mg, 0.50 mmol) in 5 mL of anhydrous CH3CN with TFA
(39 µL, 0.50 mmol) for 30 min under argon followed by the
standard workup afforded a brown solid (203 mg, 55%): mp
81-83 °C;1H NMR δ 0.14 (bs, 9H), 0.96 (bs, 3H), 1.14 (bs, 3H),
1.15 (t, J ) 8.1 Hz, 2H), 1.92-1.97 (m, 3H), 2.24-2.43 (m, 2H),
2.38 (bs, 3H), 2.53-2.67 (m, 1H), 2.71-2.80 (m, 1H), 3.57-
3.68 (m, 1H), 4.47 (t, J ) 8.1 Hz, 2H), 5.32-5.43 (m, 2H), 5.72-
5.84 (m, 4H), 5.84-5.90 (m, 1H), 6.05-6.10 (m, 1H), 7.10-
7.18 (m, 4H), 7.24-7.34 (m, 2H), 7.90-8.06 (m, 1H), 7.96-
8.04 (m, 2H), 8.21-8.46 (m, 1H), 9.23-9.36 (m, 1H); FAB-MS
obsd 737.2907, calcd 737.2886 (C41H49BrN4O2Si).
Zn (II)-17,18-dih ydr o-18,18-dim eth yl-5-(4-m eth ylph en yl)-
10-[4-[2-(t r i m e t h y ls i ly l)e t h o x y c a r b o n y l]p h e n y l]-
p or p h yr in (Zn -8c). Following the procedure for preparing Zn -
8a , a solution of 7c (110 mg, 0.150 mmol) in CH3CN (15 mL)
containing the oxidative cyclization reagents was refluxed for
14 h exposed to air. Standard workup and chromatography
[silica, hexanes/CH2Cl2 (1:2)] gave a blue solid (43 mg, 41%):
1H NMR δ 0.18 (s, 9H), 1.12 (t, J ) 5.5 Hz, 2H), 2.03 (s, 6H),
2.66 (s, 3H), 4.52 (s, 2H), 4.65 (t, J ) 5.5 Hz, 2H), 7.48 (d, J )
8.1 Hz, 2H), 7.94 (d, J ) 8.1 Hz, 2H), 8.13 (d, J ) 8.1 Hz, 2H),
8.31 (d, J ) 4.4 Hz, 1H), 8.34 (d, J ) 8.1 Hz, 2H), 8.42 (d, J )
4.4 Hz, 1H), 8.57-8.70 (m, 6H); LD-MS obsd 710.78; FAB-MS
obsd 712.2232, calcd 712.2212 (C41H40N4O2SiZn); λabs 413, 609
nm.
19-Br om o-10-(3,5-d i-ter t-bu tylp h en yl)-2,3,4,5-tetr a h y-
d r o-15-(4-iod op h en yl)-1,3,3-tr im eth ylbilen e-a (7d ). Treat-
ment of 6d (322 mg, 0.500 mmol) with NaBH4 (189 mg, 5.00
mmol) in 30 mL of anhydrous THF/methanol (4:1) afforded
6d -OH. The reaction of 6d -OH and 4 (94 mg, 0.50 mmol) in 5
mL of anhydrous CH3CN containing TFA (39 µL, 0.50 mmol)
for 30 min under argon followed by standard workup afforded
a brown solid (163 mg, 40%): mp 70-73 °C;1H NMR δ 0.91
(bs, 3H), 1.06 (bs, 3H), 1.25 (bs, 18H), 1.83-1.87 (m, 3H), 2.17-
2.34 (m, 2H), 2.51-2.62 (m, 1H), 2.66-2.76 (m, 1H), 3.52-
3.59 (m, 1H), 5.22-5.27 (m, 1H), 5.29-5.35 (m, 1H), 5.66-
1
solid (2.00 g, 60%): mp 108 °C dec; H NMR δ 0.23 (s, 9H),
1.34 (s, 18H), 5.57 (s, 1H), 5.93-5.97 (m, 1H), 6.06-6.16 (m,
2H), 6.58-6.62 (m, 1H), 6.75-6.80 (m, 1H), 7.10 (d, J ) 8.1
Hz, 2H), 7.28 (d, J ) 8.1 Hz, 2H), 7.60-7.68 (m, 3H), 8.62-
8.70 (br, 1H), 10.45-10.52 (br, 1H); 13C NMR δ 0.7, 32.1, 35.6,
44.7, 94.9, 105.6, 108.4, 108.9, 111.4, 118.8, 122.1, 122.5, 124.2,
126.7, 128.9, 131.3, 131.8, 132.8, 138.4, 142.1, 142.4, 151.5,
186.8. Anal. Calcd for C35H42N2OSi: C, 78.60; H, 7.92; N, 5.24.
Found: C, 78.75; H, 7.96; N, 5.20.
1-Br om o-9-(4-m et h ylben zoyl)-5-[4-[2-(t r im et h ylsilyl)-
eth oxyca r bon yl]p h en yl]d ip yr r om eth a n e (6c). Following
a general procedure,2,3 a solution of 13c (470 mg, 0.970 mmol)
in 25 mL of dry THF was cooled to -78 °C under argon. NBS
(173 mg, 0.970 mmol) was added, and the reaction mixture
was stirred for 1 h at -78 °C. Hexanes (50 mL) and water (50
mL) were added, and the mixture was allowed to warm to room
temperature. The organic phase was extracted with CH2Cl2
and dried (Na2SO4). The solvent was removed under reduced
pressure without heating. Column chromatography [silica;
hexanes/ethyl acetate (4:1)] afforded a light brown powder (444
mg, 81%): mp 152 °C dec; 1H NMR δ 0.07 (s, 9H), 1.11 (t, J )
8.1 Hz, 2H), 2.16 (s, 3H), 4.39 (t, J ) 8.1 Hz, 2H), 5.57 (s, 1H),
5.89-5.93 (m, 1H), 6.02-6.06 (m, 1H), 6.09-6.13 (m, 1H),
6.76-6.80 (m, 1H), 7.17 (d, J ) 8.1 Hz, 2H), 7.23 (d, J ) 8.1
Hz, 2H), 7.60 (d, J ) 8.1 Hz, 2H), 7.84 (d, J ) 8.1 Hz, 2H),
9.10-9.26 (br, 1H), 10.82-10.94 (br, 1H); 13C NMR δ -0.9,
17.9, 22.2, 44.6, 63.8, 98.8, 105.0, 110.4, 110.8, 111.2, 122.1,
128.7, 129.5, 129.8, 130.1, 130.3, 131.7, 132.4, 141.2, 143.2,
145.9, 167.0, 185.7. Anal. Calcd for C29H31BrN2O3Si: C, 61.81;
H, 5.54; N, 4.97. Found: C, 61.96; H, 5.53; N, 4.93.
1-Br om o-9-(3,5-d i-ter t-bu tylben zoyl)-5-(4-iod op h en yl)-
d ip yr r om eth a n e (6d ). Following the procedure for preparing
6c, reaction of 13d (800 mg, 1.42 mmol) with NBS (253 mg,
1.42 mmol) followed by column chromatography [silica hex-
anes/ethyl acetate (4:1)] afforded a light brown powder (770
mg, 84%): mp 88-91 °C; 1H NMR δ 1.34 (s, 18H), 5.51 (s, 1H),
5.87-5.91 (m, 1H), 6.02-6.05 (m, 1H), 6.09-6.13 (m, 1H),
6.75-6.79 (m, 1H), 6.96 (d, J ) 8.1 Hz, 2H), 7.51 (d, J ) 8.1
Hz, 2H), 7.60-7.64 (m, 3H), 8.91-9.00 (br, 1H), 10.59-10.72
(br, 1H); 13C NMR δ 32.1, 35.6, 44.5, 93.5, 98.8, 110.4, 111.1,
111.4, 122.2, 124.2, 126.9, 130.9, 132.0, 132.6, 138.2, 138.4,
140.7, 141.3, 151.6, 187.0. Anal. Calcd for C30H32BrIN2O: C,
56.00; H, 5.01; N, 4.35. Found: C, 56.15; H, 5.19; N, 4.22.
1-Br om o-9-(3,5-d i-ter t-b u t ylb en zoyl)-5-[4-[2-(t r im et h -
ylsilyl)et h yn yl]p h en yl]d ip yr r om et h a n e (6e). Following

7354 J . Org. Chem., Vol. 66, No. 22, 2001
Taniguchi et al.
5.88 (m, 5H), 5.97-6.03 (m, 1H), 6.87-6.93 (m, 2H), 7.00-
7.07 (m, 3H), 7.54-7.62 (m, 2H), 7.79-7.94 (m, 1H), 8.08-
8.28 (m, 1H), 9.08-9.22 (m, 1H); FAB-MS obsd 817.2317, calcd
817.2342 (C42H50BrIN4). Anal. Calcd for C42H50BrIN4: C, 61.69;
H, 6.16; N, 6.85. Found: C, 61.57; H, 6.21; N, 6.70.
bilen e-a (7f). Treatment of 6f (309 mg, 0.600 mmol) with
NaBH4 (226 mg, 6.00 mmol) in 40 mL of anhydrous THF/
methanol (4:1) afforded 6f-OH. The reaction of 6f-OH and 4
(113 mg, 0.600 mmol) in 6 mL of anhydrous CH3CN containing
TFA (46 µL, 0.60 mmol) for 30 min under argon followed by
the standard workup afforded a brown solid (273 mg, 66%):
mp 77-79 °C; 1H NMR δ 0.27 (bs, 9H), 0.90 (bs, 3H), 1.08 (bs,
3H), 1.85 (bs, 3H), 2.27-2.31 (m, 2H), 2.32 (bs, 3H), 2.49-
2.57 (m, 1H), 2.66-2.71 (m, 1H), 3.52-3.56 (m, 1H), 5.23-
5.27 (m, 2H), 5.68-5.72 (m, 4H), 5.80-5.84 (m, 1H), 5.99-
6.03 (m, 1H), 7.05-7.07 (m, 2H), 7.07-7.10 (m, 4H), 7.35-
7.39 (m, 2H), 7.84-7.96 (m, 1H), 8.16-8.37 (m, 1H), 9.16-
9.28(m,1H);FAB-MSobsd689.2713,calcd689.2675(C40H45BrN4Si).
Anal. Calcd for C40H45BrN4Si: C, 69.65; H, 6.58; N, 8.12.
Found: C, 69.17; H, 6.69; N, 7.74.
Zn (II)-10-(4-et h yn yl]p h en yl)-17,18-d ih yd r o-18,18-d i-
m et h yl-5-(4-m et h ylp h en yl)p or p h yr in (Zn -8f). Following
the procedure for preparing Zn -8a , a solution of 7f (158 mg,
0.229 mmol) in THF (23 mL) containing the oxidative cycliza-
tion reagents was refluxed for 24 h exposed to air. Standard
workup and chromatography [silica, hexanes/CH2Cl2 (2:1)]
gave a greenish blue solid (61 mg, 45%). Deprotection of the
trimethylsilylethyne apparently occurred under these condi-
tions: 1H NMR δ 2.03 (s, 6H), 2.66 (s, 3H), 3.27 (s, 1H), 4.51
(s, 2H), 7.48 (d, J ) 8.1 Hz, 2H), 7.81 (d, J ) 8.1 Hz, 2H), 7.94
(d, J ) 8.1 Hz, 2H), 8.03 (d, J ) 8.1 Hz, 2H), 8.34 (d, J ) 4.5
Hz, 1H), 8.41 (d, J ) 4.5 Hz, 1H), 8.58 (s, 1H), 8.60-8.64 (m,
2H), 8.64-8.68 (m, 2H), 8.69 (d, J ) 4.5 Hz, 1H); LD-MS obsd
591.68; FAB-MS obsd 592.1620, calcd 592.1605 (C37H28N4Zn);
λabs 413, 609 nm.
Zn (II)-5-(3,5-d i-ter t-bu tylp h en yl)-17,18-d ih yd r o-10-(4-
iod op h en yl)-18,18-d im eth ylp or p h yr in (Zn -8d ). Following
the procedure for preparing Zn -8a , a solution of 7d (81.7 mg,
0.100 mmol) in CH3CN (10 mL) containing the oxidative
cyclization reagents was refluxed for 20 h exposed to air.
Standard workup and chromatography [silica, hexanes/CH2-
Cl2 (1:2)] gave a blue solid (32 mg, 40%): 1H NMR δ 1.49 (s,
18H), 2.03 (s, 6H), 4.51 (s, 2H), 7.72 (t, J ) 1.5 Hz, 1H), 7.80
(d, J ) 8.1 Hz, 2H), 7.91 (t, J ) 1.5 Hz, 2H), 8.01 (d, J ) 8.1
Hz, 2H), 8.35 (d, J ) 4.5 Hz, 1H), 8.44 (d, J ) 4.5 Hz, 1H),
8.58 (s, 1H), 8.61-8.63 (m, 2H), 8.65-8.69 (m, 2H), 8.72 (d, J
) 4.5 Hz, 1H); LD-MS obsd 791.60; FAB-MS obsd 792.1667,
calcd 792.1689 (C42H41IN4Zn); λabs 412, 609 nm.
19-Br om o-10-(3,5-d i-ter t-bu tylp h en yl)-2,3,4,5-tetr a h y-
dr o-1,3,3-tr im eth yl-15-[4-[2-(tr im eth ylsilyl)eth yn yl]ph en -
yl]bilen e-a (7e). Treatment of 6e (307 mg, 0.500 mmol) with
NaBH4 (189 mg, 5.00 mmol) in 30 mL of anhydrous THF/
methanol (4:1) afforded 6e-OH. The reaction of 6e-OH and 4
(94 mg, 0.50 mmol) in 5 mL of anhydrous CH3CN containing
TFA (39 µL, 0.50 mmol) for 30 min under argon followed by
the standard workup afforded a brown solid (233 mg, 59%):
mp 61-63 °C;1H NMR δ 0.24 (bs, 9H), 0.90 (bs, 3H), 1.06 (bs,
3H), 1.25 (bs, 18H), 1.83-1.90 (m, 3H), 2.21-2.47 (m, 2H),
2.49-2.62 (m, 1H), 2.66-2.75 (m, 1H), 3.51-3.60 (m, 1H),
5.25-5.35 (m, 2H), 5.65-5.88 (m, 5H), 5.96-6.02 (m, 1H),
6.97-7.04 (m, 3H), 7.04-7.14 (m, 2H), 7.32-7.42 (m, 2H),
7.81-7.96 (m, 1H), 8.07-8.21 (m, 1H), 9.08-9.20 (m, 1H);
FAB-MS obsd 787.3802, calcd 787.3771 (C47H59BrN4Si).
Zn (II)-5-(3,5-di-ter t-bu tylph en yl)-10-(4-eth yn yl]ph en yl)-
17,18-d ih yd r o-18,18-d im eth ylp or p h yr in (Zn -8e). Follow-
ing the procedure for preparing Zn -8a , a solution of 7e (118
mg, 0.150 mmol) in CH3CN (15 mL) containing the oxidative
cyclization reagents was refluxed for 12 h exposed to air.
Standard workup and chromatography [silica, hexanes/CH2-
Cl2 (2:1)] gave a blue solid (28 mg, 27%). Deprotection of the
trimethylsilylethyne apparently occurred under these condi-
tions: 1H NMR δ 1.49 (s, 18H), 2.02 (s, 6H), 3.26 (s, 1H), 4.50
(s, 2H), 7.72 (t, J ) 1.5 Hz, 1H), 7.81 (d, J ) 8.1 Hz, 2H), 7.92
(t, J ) 1.5 Hz, 2H), 8.03 (d, J ) 8.1 Hz, 2H), 8.35 (d, J ) 4.5
Hz, 1H), 8.45 (d, J ) 4.5 Hz, 1H), 8.58 (s, 1H), 8.59-8.62 (m,
2H), 8.64 (s, 1H), 8.66 (d, J ) 4.5 Hz, 1H), 8.72 (d, J ) 4.5 Hz,
1H); LD-MS obsd 689.45; FAB-MS obsd 690.2748, calcd
690.2701 (C44H42N4Zn); λabs 413, 609 nm.
Ack n ow led gm en t. This work was funded by the
NIH (G.M.36238). Mass spectra were obtained at the
Mass Spectrometry Laboratory for Biotechnology. Par-
tial funding for the Facility was obtained from the North
Carolina Biotechnology Center and the National Science
Foundation. We thank Dr. Paul D. Boyle for collecting
the X-ray data for 5.
Su p p or tin g In for m a tion Ava ila ble: Isolation and char-
acterization of chlorin byproducts obtained under nonoptimal
conditions for the oxidative cyclization process; a discussion
of possible oxidized intermediates during the oxidative cy-
clization process; a brief description of nomenclature of tet-
rapyrrole species; 1H NMR spectra for 3-5, 7a ,c,e,f; spectral
data (1H NMR, LD-MS) for all new chlorins; X-ray structural
data for 5. This material is available free of charge via the
Internet at http://pubs.acs.org.
19-Br om o-2,3,4,5-t e t r a h yd r o-1,3,3-t r im e t h yl-10-(4-
m eth ylp h en yl)-15-[4-[2-(tr im eth ylsilyl)eth yn yl]p h en yl]-
J O0104835