Tailoring a bacteriochlorin building block with cationic, amphipathic, or lipophilic substituents

Article abstract of DOI:10.1021/jo800736c

(Chemical Equation Presented) Bacteriochlorins are attractive candidates for photodynamic therapy (PDT) of diverse medical indications owing to their strong absorption in the near-infrared (NIR) region, but their use has been stymied by lack of access to stable, synthetically malleable molecules. To overcome these limitations, a synthetic free base 3,13-dibromobacteriochlorin (BC-Br³Br¹³) has been exploited as a building block in the synthesis of diverse bacteriochlorins via Pd-mediated coupling reactions (Sonogashira, Suzuki, and reductive carbonylation). Each bacteriochlorin is stable to adventitious dehydrogenation by virtue of the presence of a geminal dimethyl group in each pyrroline ring. The target bacteriochlorins bear cationic, lipophilic, or amphipathic substituents at the 3- and 13- (β-pyrrolic) positions. A dicarboxybacteriochlorin was converted to amide derivatives via the intermediate diacid chloride. A diformylbacteriochlorin was subjected to reductive amination to give aminomethyl derivatives. A set of 3,5-disubstituted aryl groups bearing lipophilic or amphipathic groups was introduced via Suzuki coupling. Altogether 22 free base bacteriochlorins have been prepared. Eight aminoalkylbacteriochlorins were quaternized with methyl iodide at two or four amine sites per molecule, which resulted in water solubility. Each bacteriochlorin exhibits a Q_y absorption band in the range of 720-772 nm. The ability to introduce a wide variety of peripheral functional groups makes these bacteriochlorins attractive candidates for diverse applications in photomedicine including PDT in the NIR region.

Full text of DOI:10.1021/jo800736c

Tailoring a Bacteriochlorin Building Block with Cationic,
Amphipathic, or Lipophilic Substituents
Christian Ruzié, Michael Krayer, Thiagarajan Balasubramanian,† and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
ReceiVed April 2, 2008
Bacteriochlorins are attractive candidates for photodynamic therapy (PDT) of diverse medical indications
owing to their strong absorption in the near-infrared (NIR) region, but their use has been stymied by lack
of access to stable, synthetically malleable molecules. To overcome these limitations, a synthetic free
base 3,13-dibromobacteriochlorin (BC-Br3Br13) has been exploited as a building block in the synthesis
of diverse bacteriochlorins via Pd-mediated coupling reactions (Sonogashira, Suzuki, and reductive
carbonylation). Each bacteriochlorin is stable to adventitious dehydrogenation by virtue of the presence
of a geminal dimethyl group in each pyrroline ring. The target bacteriochlorins bear cationic, lipophilic,
or amphipathic substituents at the 3- and 13- (ꢀ-pyrrolic) positions. A dicarboxybacteriochlorin was
converted to amide derivatives via the intermediate diacid chloride. A diformylbacteriochlorin was subjected
to reductive amination to give aminomethyl derivatives. A set of 3,5-disubstituted aryl groups bearing
lipophilic or amphipathic groups was introduced via Suzuki coupling. Altogether 22 free base
bacteriochlorins have been prepared. Eight aminoalkylbacteriochlorins were quaternized with methyl iodide
at two or four amine sites per molecule, which resulted in water solubility. Each bacteriochlorin exhibits
a Qy absorption band in the range of 720-772 nm. The ability to introduce a wide variety of peripheral
functional groups makes these bacteriochlorins attractive candidates for diverse applications in
photomedicine including PDT in the NIR region.
Introduction
oxygen, which yields singlet O2 and/or other reactive oxygen
species to kill target cells. This tripartite approach relies on
delivery of both light and the photosensitizer to the affected
tissue. The delivery of the photosensitizer to the target tissue
can be achieved by active targeting methods (e.g., conjugates
with antibodies or receptor ligands) or by passive means owing
to the nature of the substituents appended to the photosensitizer.8,9
Upon delivery in vivo, the ability to excite the photosensitizer
depends on the wavelength of light employed; in soft tissue,
wavelengths in the NIR region (700-900 nm) afford the deepest
Photodynamic therapy (PDT) is an emerging approach for
treatment of a wide variety of medical indications ranging from
solid tumors to microbial infections.1–7 The essence of PDT
entails illumination of a photosensitizer in the presence of
† Visiting scientist, NIRvana Pharmaceuticals, Inc.
(1) Wainright, M. J. Antimicrob. Chemother. 1998, 42, 13–28.
(2) Bonnett, R. Chemical Aspects of Photodynamic Therapy; Gordon and
Breach Science Publishers: Amsterdam, The Netherlands, 2000.
(3) Macdonald, I. J.; Dougherty, T. J. J. Porphyrins Phthalocyanines 2001,
5, 105–129.
(4) Maisch, T.; Szeimies, R.-M.; Jori, G.; Abels, C. Photochem. Photobiol.
Sci. 2004, 3, 907–917.
(7) Juzeniene, A.; Peng, Q.; Moan, J. Photochem. Photobiol. Sci. 2007, 6,
1234–1245.
(5) Hamblin, M. R.; Hasan, T. Photochem. Photobiol. Sci. 2004, 3, 436–
450.
(8) Boyle, R. W.; Dolphin, D. Photochem. Photobiol. 1996, 64, 469–485.
(9) (a) Konan, Y. N.; Gurny, R.; Alle´mann, E. J. Photochem. Photobiol. B
2002, 66, 89–106. (b) Verma, S.; Watt, G. M.; Mai, Z.; Hasan, T. Photochem.
Photobiol. 2007, 83, 996–1005.
(6) Allison, R. R.; Downie, G. H.; Cuenca, R.; Hu, X.-H.; Childs, C. J. H.;
Sibata, C. H. Photodiag. Photodyn. Ther. 2004, 1, 27–42.
5806 J. Org. Chem. 2008, 73, 5806–5820
10.1021/jo800736c CCC: $40.75 2008 American Chemical Society
Published on Web 06/25/2008

Tailoring a Bacteriochlorin Building Block
penetration.10 Thus, an ideal photosensitizer would absorb light
in the same NIR spectral region.
CHART 1
A large number of compounds with PDT activity are now
available.2,6,11,12 Extensive studies with tetrapyrrole macrocycles
have been carried out, largely with porphyrins and to a lesser
extent chlorins8,13 despite the lack of absorption in the NIR
region of either type of macrocycle. Such studies have revealed
the types of peripheral substituents that are suitable for passive
targeting of tetrapyrrole macrocycles. The presence of cationic
(ammonium) substituents results in uptake by many types of
bacteria more avidly than by mammalian cells;1,4,5,14 examples
include the dicationic porphyrin XF73,15,16 which exhibits
antimicrobial PDT at the 5 nM level, and the polycationic
product17,18 obtained with the polylysine conjugate of chlorin
e6 (Chart 1). A variety of substituents have been employed with
chlorins to achieve passive targeting of tumors as well as rapid
systemic clearance; representative examples include phenolic
substituents (Foscan19 and analogue20), alkyl carboxylic acids
(the water-soluble aspartyl derivative of chlorin e6),21 and
lipophilic groups (Photochlor).22
To obtain photosensitizers with NIR absorption, more recent
work has focused on bacteriochlorins, which absorb strongly
in the 700-800 nm region.23 The primary source of bacterio-
chlorins has stemmed from derivatives of the bacterial photo-
synthetic pigment bacteriochlorophyll a.24 Two such derivatives
(WST 925–28 and WST 1129,30) are shown in Chart 2. Two
significant problems with derivatives of the bacteriochlorophylls
include limited synthetic malleability owing to the presence of
(10) Dawson, J. B.; Barker, D. J.; Ellis, D. J.; Grassam, E.; Cotterill, J. A.;
Fisher, G. W.; Feather, J. W. Phys. Med. Biol. 1980, 25, 695–709.
(11) Photodynamic Tumor Therapy. 2nd and 3rd Generation Photosensitizers;
Moser, J. G., Ed.; Harwood Academic Publishers: Amsterdam, The Netherlands,
1998.
(12) Detty, M. R.; Gibson, S. L.; Wagner, S. J. J. Med. Chem. 2004, 47,
3897–3915.
(13) (a) Sternberg, E. D.; Dolphin, D.; Bru¨ckner, C. Tetrahedron 1998, 54,
4151–4202. (b) Nyman, E. S.; Hynninen, P. H. J. Photochem. Photobiol. B 2004,
73, 1–28.
(14) Jori, G.; Fabris, C.; Soncin, M.; Ferro, S.; Coppellotti, O.; Dei, D.;
Fantetti, L.; Chiti, G.; Roncucci, G. Lasers Surg. Med. 2006, 38, 468–481.
(15) Maisch, T.; Bosl, C.; Szeimies, R.-M.; Lehn, N.; Abels, C. Antimicrob.
Agents Chemother. 2005, 49, 1542–1552.
(16) Maisch, T.; Bosl, C.; Szeimies, R.-M.; Love, B.; Abels, C. Photochem.
Photobiol. Sci. 2007, 6, 545–551.
(17) Soukos, N. S.; Hamblin, M. R.; Hasan, T. Photochem. Photobiol. 1997,
65, 723–729.
(18) Soukos, N. S.; Ximenez-Fyvie, L. A.; Hamblin, M. R.; Socransky, S. S.;
Hasan, T. Antimicrob. Agents Chemother. 1998, 42, 2595–2601.
(19) Bonnett, R.; Djelal, B. D.; Nguyen, A. J. Porphyrins Phthalocyanines
2001, 5, 652–661.
(20) (a) Bourre´, L.; Simonneaux, G.; Ferrand, Y.; Thibaut, S.; Lajat, Y.;
Patrice, T. J. Photochem. Photobiol. B 2003, 69, 179–192. (b) Ferrand, Y.;
Bourre´, L.; Simonneaux, G.; Thibaut, S.; Odobel, F.; Lajat, Y.; Patrice, T. Bioorg.
Med. Chem. Lett. 2003, 13, 833–835.
(21) Hargus, J. A.; Fronczek, F. R.; Vicente, M. G. H.; Smith, K. M.
Photochem. Photobiol. 2007, 83, 1006–1015.
(22) Pandey, R. K.; Sumlin, A. B.; Constantine, S.; Aoudia, M.; Potter, W. R.;
Bellnier, D. A.; Henderson, B. W.; Rodgers, M. A.; Smith, K. M.; Dougherty,
T. J. Photochem. Photobiol. 1996, 64, 194–204.
a nearly full complement of substituents about the perimeter of
the macrocycle24 and susceptibility to adventitious dehydroge-
nation (yielding the chlorin or porphyrin, which lack the NIR
absorption).28,31,32 By contrast with the latter limitation, toly-
porphin A,33,34 one of a series of bacteriochlorin pigments35
from the Pacific alga Tolypothrix nodosa, is a stable compound
(23) Kobayashi, M.; Akiyama, M.; Kano, H.; Kise, H. In AdVances in
Photosynthesis and Respiration; Grimm, B., Porra, R. J., Ru¨diger, W., Scheer,
H., Eds.; Springer: Dordrecht, The Netherlands, 2006; Vol. 25, pp 79-94.
(24) Chen, Y.; Li, G.; Pandey, R. K. Curr. Org. Chem. 2004, 8, 1105–1134.
(25) Chen, Q.; Huang, Z.; Luck, D.; Beckers, J.; Brun, P.-H.; Wilson, B. C.;
Scherz, A.; Salomon, Y.; Hetzel, F. W. Photochem. Photobiol. 2002, 76, 438–
445.
(26) Koudinova, N. V.; Pinthus, J. H.; Brandis, A.; Brenner, O.; Bendel, P.;
Ramon, J.; Eshhar, Z.; Scherz, A.; Salomon, Y. Int. J. Cancer 2003, 104, 782–
789.
(29) Brandis, A.; Mazor, O.; Neumark, E.; Rosenbach-Belkin, V.; Salomon,
Y.; Scherz, A. Photochem. Photobiol. 2005, 81, 983–993.
(30) Mazor, O.; Brandis, A.; Plaks, V.; Neumark, E.; Rosenbach-Belkin, V.;
Salomon, Y.; Scherz, A. Photochem. Photobiol. 2005, 81, 342–351.
(31) Limantara, L.; Koehler, P.; Wilhelm, B.; Porra, R. J.; Scheer, H.
Photochem. Photobiol. 2006, 82, 770–780.
(27) Weersink, R. A.; Forbes, J.; Bisland, S.; Trachtenberg, J.; Elhilali, M.;
Bru´n, P. H.; Wilson, B. C. Photochem. Photobiol. 2005, 81, 106–113.
(28) Vakrat-Haglili, Y.; Weiner, L.; Brumfeld, V.; Brandis, A.; Salomon,
Y.; McIlroy, B.; Wilson, B. C.; Pawlak, A.; Rozanowska, M.; Sarna, T.; Scherz,
A. J. Am. Chem. Soc. 2005, 127, 6487–6497.
(32) Kozyrev, A. N.; Chen, Y.; Goswami, L. N.; Tabaczynski, W. A.; Pandey,
R. K. J. Org. Chem. 2006, 71, 1949–1960.
J. Org. Chem. Vol. 73, No. 15, 2008 5807

Ruzié et al.
tively at the 15-position.40 The resulting 15-bromobacteriochlo-
rin (I) has been derivatized via a variety of Pd-mediated coupling
reactions; however, the 2,12-di-p-tolyl groups result in a
hydrophobic, crystalline product that is unsuited for most PDT
applications. The same route has been exploited to prepare a
bacteriochlorin (II) bearing branched alkyl (“swallowtail”) rather
than p-tolyl groups at the 2- and 12-positions; although lipophilic
and attractive for selected PDT studies, the synthesis of the
swallowtail precursor to the bacteriochlorin was quite lengthy.41
Extension of this synthetic route has recently afforded a 3,13-
dibromobacteriochlorin, BC-Br3Br13, which lacks the 5-meth-
oxy and 2,12-di-p-tolyl groups and is a valuable building block
for transformation into bacteriochlorin derivatives.42 We
examined the functionalization of the 3- and 13-positions by
Sonogashira, Stille, and Suzuki coupling reactions as a means
to tune the position of the long-wavelength absorption band.42
The substituents introduced included formyl, vinyl, phenylethy-
nyl, and acetyl groups; the position of the long-wavelength
absorption band could be shifted from 713 nm (no ꢀ-pyrrolic
or meso substituents) to 771 nm (3,13-diformyl substituents).
All of the resulting bacteriochlorins were soluble in organic
solvents such as toluene.
CHART 2
In this paper, we describe the derivatization of BC-Br3Br13
with groups of a systematic range of polarity for passive
targeting in PDT. The paper is divided into three parts. Part I
describes the introduction of diverse aminoalkyl groups, which
upon quaternization have yielded cationic substituents. The
resulting bacteriochlorins are soluble in water. Part II describes
the preparation of diverse arylboronic acids bearing substituents
to impart amphipathic or lipophilic character, and their introduc-
tion via Suzuki coupling to the bacteriochlorin nucleus. Part
III compares the absorption spectral properties of the bacterio-
chlorins. Taken together, these studies establish the foundation
for tailoring stable bacteriochlorins with diverse substituents for
use in PDT applications ranging from microbial infections to
oncological indications.
Results and Discussion
I. Cationic Bacteriochlorins. A simple approach that we
first investigated entailed conversion of dibromobacteriochlorin
BC-Br3Br13 to the corresponding dicyanobacteriochlorin, which
we envisaged could be further derivatized in a number of ways.
Treatment of BC-Br3Br13 to conditions for cyanation of aryl
bromides [Zn(CN)2 in the presence of Pd(PPh3)4 in DMF at
100 °C]43 afforded the zinc chelate of the 3,13-dicyanobac-
teriochlorin (ZnBC-1) in 89% yield (Scheme 1). The formation
of the zinc chelate was unexpected, given the frequent difficul-
ties in metalating bacteriochlorins,44 but not unprecedented.29,45
Attempted transformation of the dicyano moieties of ZnBC-1
by reduction with LAH failed to give the corresponding
methylamine, and hydrolysis of ZnBC-1 with MeOH and HCl
resulted only in demetalation to give the free base dicyanobac-
teriochlorin BC-1. The zinc chelate ZnBC-1 also was deliber-
owing to the presence of a geminal dialkyl group in each
pyrroline ring. Tolyporphin A has been examined as a photo-
sensitizer;36 however, the preparation of derivatives thereof has
apparently not been reported, and the total synthesis of such
compounds is arduous.37,38
We recently developed a de novo synthetic pathway to
bacteriochlorins39 that contain a geminal dimethyl group in each
pyrroline ring. As with the tolyporphins, this structural attribute
blocks adventitious dehydrogenation and thereby affords a stable
macrocycle. This synthetic route has afforded a 5-methoxy-2,12-
di-p-tolylbacteriochlorin, which undergoes bromination selec-
(33) Prinsep, M. R.; Caplan, F. R.; Moore, R. E.; Patterson, G. M. L.; Smith,
C. D. J. Am. Chem. Soc. 1992, 114, 385–387.
(34) Minehan, T. G.; Kishi, Y. Angew. Chem., Int. Ed. 1999, 38, 923–925.
(35) (a) Prinsep, M. R.; Patterson, G. M. L.; Larsen, L. K.; Smith, C. D.
Tetrahedron 1995, 51, 10523–10530. (b) Prinsep, M. R.; Patterson, G. M. L.;
Larsen, L. K.; Smith, C. D. J. Nat. Prod. 1998, 61, 1133–1136.
(36) Morlie`re, P.; Mazie`re, J.-C.; Santus, R.; Smith, C. D.; Prinsep, M. R.;
Stobbe, C. C.; Fenning, M. C.; Golberg, J. L.; Chapman, J. D. Cancer Res.
1998, 58, 3571–3578.
(40) Fan, D.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2007, 72, 5350–
5357.
(41) Borbas, K. E.; Ruzié, C.; Lindsey, J. S. Org. Lett. 2008, 10, 1931–
1934.
(42) Taniguchi, M.; Cramer, D. L.; Bhise, A. D.; Kee, H. L.; Bocian, D. F.;
Holten, D.; Lindsey, J. S. New J. Chem. 2008, 32, 947–958.
(43) Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik, B.;
King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887–890.
(44) Hartwich, G.; Fiedor, L.; Simonin, I.; Cmiel, E.; Scha¨fer, W.; Noy, D.;
Scherz, A.; Scheer, H. J. Am. Chem. Soc. 1998, 120, 3675–3683.
(37) Minehan, T. G.; Cook-Blumberg, L.; Kishi, Y.; Prinsep, M. R.; Moore,
R. E. Angew. Chem., Int. Ed. 1999, 38, 926–928.
(38) Wang, W.; Kishi, Y. Org. Lett. 1999, 1, 1129–1132.
(39) Kim, H.-J.; Lindsey, J. S. J. Org. Chem. 2005, 70, 5475–5486.
5808 J. Org. Chem. Vol. 73, No. 15, 2008

Tailoring a Bacteriochlorin Building Block
TABLE 1. Pd-Mediated Carbonylation
SCHEME 1
ately demetalated with TFA in CHCl3 to give the free base
bacteriochlorin BC-1. The difficulty in manipulating the cyano
group prompted examination of other more malleable one-
carbon functional groups.
A. Carbonylation. Pd-mediated CO-insertion with hetero-
cyclic halides followed by treatment with a variety of nucleo-
philes has afforded diverse substituted heterocycles,46,47 and has
been used with bromochlorins to give formylchlorins.48 This
methodology was applied to BC-Br3Br13 with different nucleo-
philes (hydride donor, water, alcohol, amine) to obtain the
corresponding bacteriochlorin bearing dialdehyde, diacid, diester,
and diamide groups. The CO-insertion reaction with a catalytic
amount of palladium reagent gave multiple products and
predominantly the unreacted BC-Br3Br13. By contrast, the use
of stoichiometric amounts of the palladium reagent led in each
case to the desired compound in good yields.
a The 3-formyl-13-desbromobacteriochlorin also was isolated (25%
yield).
carbonyl insertion conditions were employed followed by
quenching with different nucleophiles to obtain the desired
substituted bacteriochlorins. Quenching with NaOH afforded
the diacid BC-3 (entry 2), while use of sodium methoxide in
methanol gave diester BC-4 (entry 3). Upon quenching with
the sodium salt of an amine, the amide BC-5 or BC-6 was
obtained (Table 1, entries 4 and 5). Although the synthesis of
amides BC-5 and BC-6 was straightforward by this method,
the yields were not high, and an additional bacteriochlorin side
product having two CO-insertions, a known side reaction under
these conditions,47 was observed. The similarity of this byprod-
uct to the target compound rendered purification somewhat
difficult, hence the conversion of diacid BC-3 to the corre-
sponding diacid chloride was investigated as a means of
preparing amides.
B. Acid Chloride Derivatization. The formation of the
bacteriochlorin diacid chloride was performed by adding excess
oxalyl chloride to a green suspension of the diacid BC-3 in
CH2Cl2 at room temperature under an inert atmosphere. After
being stirred for 6 h at room temperature, the suspension gave
rise to a clear pink solution (λmax of the Qx and Qy bands at 554
and 787 nm, versus 518 and 748 nm for the diacid), signaling
formation of the diacid chloride. The volatile components were
removed under reduced pressure, and the product was dried
under high vacuum. The crude diacid chloride was dissolved
in 1,2-dichloroethane and then treated with excess N-methyl-
piperazine to obtain bacteriochlorin-diamide BC-6 in 53% yield.
Thus, reaction of BC-Br3Br13 with Pd(PPh3)4 in toluene/DMF
at 70 °C under an atmosphere of CO for 2 h and subsequent
treatment with Bu3SnH afforded diformylbacteriochlorin BC-2
in 60% yield along with the 3-formyl-13-desbromobacterio-
chlorin in 25% yield (Table 1, entry 1). The diformylbacterio-
chlorin BC-2 is a known compound that was previously
prepared in very small quantity by oxidative cleavage of the
corresponding divinylbacteriochlorin.42 The same Pd-mediated
(45) (a) Fajer, J.; Borg, D. C.; Forman, A.; Felton, R. H.; Dolphin, D.; Vegh,
L. Proc. Natl. Acad. Sci. U.S.A. 1974, 71, 994–998. (b) Barkigia, K. M.; Miura,
M.; Thompson, M. A.; Fajer, J. Inorg. Chem. 1991, 30, 2233–2236. (c)
Vasudevan, J.; Stibrany, R. T.; Bumby, J.; Knapp, S.; Potenza, J. A.; Emge,
T. J.; Schugar, H. J. J. Am. Chem. Soc. 1996, 118, 11676–11677. (d) Tamiaki,
H.; Yagai, S.; Miyatake, T. Bioorg. Med. Chem. 1998, 6, 2171–2178. (e) Kunieda,
M.; Tamiaki, H. J. Org. Chem. 2005, 70, 820–828. (f) Kunieda, M.; Yamamoto,
K.; Sasaki, S.-i.; Tamiaki, H. Chem. Lett. 2007, 36, 936-937. (g) Fukuzumi,
S.; Ohkubo, K.; Zheng, X.; Chen, Y.; Pandey, R. K.; Zhan, R.; Kadish, K. M.
J. Phys. Chem. B 2008, 112, 2738–2746.
(46) (a) Heck, R. F. AdV. Catal. 1977, 26, 323–349. (b) Schoenberg, A.;
Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318–3326. (c) Moser, W. R.;
Wang, A. W.; Kildahl, N. K. J. Am. Chem. Soc. 1988, 110, 2816–2820.
(47) Ozawa, F.; Soyama, H.; Yanagihara, H.; Aoyama, I.; Takino, H.; Izawa,
K.; Yamamoto, T.; Yamamoto, A. J. Am. Chem. Soc. 1985, 107, 3235–3245.
(48) Muthiah, C.; Bhaumik, J.; Lindsey, J. S. J. Org. Chem. 2007, 72, 5839–
5842.
J. Org. Chem. Vol. 73, No. 15, 2008 5809

Ruzié et al.
SCHEME 2
SCHEME 3
One of the desired amines for reductive amination was
synthesized as shown in Scheme 3. Reaction50 of the Boc
derivative of diethanolamine51 with acetic anhydride gave the
diacetate 1. Exposure of the latter to TFA resulted in the
diacetate of diethanolamine (2), a known compound previously
prepared as the hydrochloride salt by an alternative route.52
Reductive amination was carried out at modest concentrations
with sodium triacetoxyborohydride53 in 1,2-dichloroethane
containing acetic acid. Reductive amination of BC-2 with
dimethylamine, 1-methylpiperazine, or bis(3-dimethylamino-
propyl)amine afforded BC-9, BC-10, or BC-11, respectively.
Attempted purification of crude BC-9, BC-10, and BC-11 with
silica gel column chromatography proved difficult due to the
high polarity of the products, and resulted in loss of a large
amount of product. Hence, the crude bacteriochlorin products,
which were quite clean, were used without chromatographic
1
purification. Each bacteriochlorin was examined by H NMR
spectroscopy, mass spectrometry (LD-MS54 or ESI-MS), and
absorption spectroscopy. Each bacteriochlorin gave the expected
characterization data, including a parent molecule ion (with the
exception of BC-11 where loss of one dialkylamino unit was
observed). 1H NMR spectroscopy of each crude product showed
no starting material BC-2, and the product was estimated to be
approximately 90% pure on the basis of NMR integration. Each
crude product was sufficiently pure for subsequent quaternization
(vide infra). Similar reductive amination of BC-2 with 2 afforded
the acetoxy-protected diethanolamine-bacteriochlorin. Depro-
tection of the latter in MeOH with K2CO3 afforded tetrahydroxy-
bacteriochlorin BC-12 in 33% yield following silica column
chromatography (Scheme 4).
D. Sonogashira Coupling. A complementary approach for
introducing a tertiary amine group into the bacteriochlorin side
chain was investigated via Sonogashira coupling. Thus, reaction
of BC-Br3Br13 with 3-dimethylamino-1-propyne in the presence
of Pd(PPh3)2Cl2 and CuI in triethylamine at 60 °C for 43 h
afforded diethynylbacteriochlorin BC-13 in 67% yield. While
such conditions55 would typically give the copper chelate of a
porphyrin or chlorin,56,57 no copper insertion into the bacterio-
chlorin was observed. The alkynes in BC-13 were reduced to
the fully saturated alkyl moieties by catalytic hydrogenation to
obtain dialkylbacteriochlorin BC-14 in 83% yield (Scheme 5).
E. Quaternization. To achieve water solubility and to
explore the utility of the bacteriochlorins in antimicrobial
Although the yield of BC-6 via the acid chloride was compa-
rable to that upon direct carboxamide formation (47%, vide
supra), the purification of the bacteriochlorin-diamide obtained
via the acid chloride was simpler. Similar treatment of the crude
diacid chloride with bis(2-methoxyethyl)amine or bis(3-di-
methylaminopropyl)amine afforded bacteriochlorin-diamide
BC-7 or BC-8 in 57% or 42% yield, respectively (Scheme 2).
It is worth mentioning that addition of pyridine during the amide
formation step led to the decomposition of the diacid chloride;
on the other hand, use of excess amine in each coupling reaction
afforded smooth formation of the target bacteriochlorin-diamide.
C. Reductive Amination. Conversion of the diformylbac-
teriochlorin BC-2 to aminomethyl derivatives was examined
via reductive amination, a process previously demonstrated with
an aminophenylporphyrin49 and a formylphenylbacteriochlorin40
under mild conditions in dilute solution at room temperature.
(50) Mori, M.; Tonogaki, K.; Kinoshita, A. Org. Synth. 2005, 81, 1–13.
(51) Ochiai, H.; Ohtani, T.; Ishida, A.; Kusumi, K.; Kato, M.; Kohno, H.;
Odagaki, Y.; Kishikawa, K.; Yamamoto, S.; Takeda, H.; Obata, T.; Nakai, H.;
Toda, M. Bioorg. Med. Chem. 2004, 12, 4645–4665.
(52) Dimo, I.; Bonnemain, B.; Hardouin, M. J.-C.; Lautrou, J. EP 118347,
1984.
(53) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849–3862.
(54) Srinivasan, N.; Haney, C. A.; Lindsey, J. S.; Zhang, W.; Chait, B. T. J.
Porphyrins Phthalocyanines 1999, 3, 283–291.
(55) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467–4470. (b) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara,
N. Synthesis 1980, 627–630.
(56) Wagner, R. W.; Johnson, T. E.; Li, F.; Lindsey, J. S. J. Org. Chem.
1995, 60, 5266–5273.
(49) (a) Lindsey, J. S.; Mauzerall, D. C. J. Am. Chem. Soc. 1982, 104, 4498–
4450. (b) Lindsey, J. S.; Delaney, J. K.; Mauzerall, D. C.; Linschitz, H. J. Am.
Chem. Soc. 1988, 110, 3610–3621.
(57) Taniguchi, M.; Kim, M. N.; Ra, D.; Lindsey, J. S. J. Org. Chem. 2005,
70, 275–285.
5810 J. Org. Chem. Vol. 73, No. 15, 2008

Tailoring a Bacteriochlorin Building Block
SCHEME 4
SCHEME 5
PDT,1,4,5 the amine-containing bacteriochlorins were subjected
to conditions for quaternization.58 Thus, the overnight reaction
of bacteriochlorin BC-5 with excess methyl iodide in CHCl3 at
room temperature resulted in precipitation of the corresponding
diiodide salt BC-5′. Similarly, bacteriochlorins BC-6, BC-8,
BC-9, BC-10, BC-11, BC-13, and BC-14 were converted to
the corresponding diiodide or tetraiodide salt in excellent yield.
BC-10 and BC-11 apparently underwent methylation only at
the distal nitrogen(s) on each side chain, affording bacterio-
chlorins BC-10′ and BC-11′, which contain a total of two and
four positive charges, respectively. Evidence in support of this
Each cationic bacteriochlorin was purified by washing the
crude precipitate with organic solvents such as ether and CH2Cl2/
hexanes. The cationic bacteriochlorins were characterized by
ESI-MS, and by 1H NMR spectroscopy in methanol-d4 or
DMSO-d6. Absorption spectra were collected in water. Each
cationic bacteriochlorin was readily soluble in water, giving
rapid dissolution at room temperature and homogeneous solu-
tions of at least 100 µm concentrations. The absorption spectra
were characteristic of bacteriochlorins,23 with relatively little
change from those of the neutral bacteriochlorin precursors (vide
infra). Although the cationic bacteriochlorins were soluble at
modest concentration in water, higher quality 1H NMR spectra
typically were obtained in polar organic solvents than in water.
To further examine water solubility, an aqueous solution of
bacteriochlorin BC-9′ or BC-10′ was prepared (∼1 mM, from
∼1 µmol bacteriochlorin in 1 mL of deionized water) at room
temperature. After standing for 1 week, bacteriochlorin BC-9′
showed no precipitation, whereas BC-10′ showed a small
amount of precipitation. Both bacteriochlorins were recovered
intact with no noticeable degradation.
1
interpretation stems from H NMR spectroscopy. In BC-10, a
singlet at 2.34 ppm (6 protons) is attributed to the N-methyl
group, whereas in BC-10′, the singlet appears at 3.19 ppm and
integrates for 12 protons. Similarly for BC-11 and BC-11′, the
N-methyl peak resonates at 2.21 (24 protons) and 3.10 ppm (36
protons), respectively. More complex spectra would be expected
if the proximal nitrogens were methylated preferentially, and a
greater number of charges if both distal and proximal nitrogens
were quaternized. The eight cationic bacteriochlorins obtained
in this manner are shown in Chart 3. It deserves emphasis that
the pyrrolic or pyrrolinic nitrogens did not methylate under these
conditions. Moreover, the bacteriochlorins employed in crude
form (BC-9, BC-10, and BC-11) gave the corresponding
1
quaternary salts that were clean by H NMR spectroscopy.
All of the cationic bacteriochlorins shown in Chart 3 have
some structural resemblance to the dicationic porphyrin XF73,
which is one of the most potent antibacterial PDT agents (Chart
(58) Okada, E.; Tone, H.; Tsukushi, N.; Otsuki, Y.; Takeuchi, H.; Hojo, M.
Heterocycles 1997, 45, 339–345.
J. Org. Chem. Vol. 73, No. 15, 2008 5811

Ruzié et al.
CHART 3
1),15,16 yet are of comparable if not smaller size, lack the aryl
moieties, and absorb in the NIR as desired for in vivo PDT
applications. The eight bacteriochlorins provide a set of
compounds for examination of structure-activity relationships
while maintaining the NIR absorption. Several comparisons can
be made: (i) side-chain linkages s BC-6′ and BC-8′ contain
amide substituents and have as counterparts the methylene
analogues BC-10′ and BC-11′; (ii) structural rigidity s BC-6′
is a structurally rigid analogue of BC-5′, and BC-13′ is a
structurally rigid analogue of BC-14′; (iii) number of positive
charges s BC-8′ and BC-11′ contain four cationic groups
whereas the six other bacteriochlorins contain only two cationic
groups; and (iv) location of charge s BC-9′ and analogue BC-
14′ contain methylammonium versus propylammonium substit-
uents, which place the charge close to or more remote from the
macrocycle, respectively.
II. Amphipathic or Lipophilic Bacteriochlorins. A comple-
mentary design was sought to obtain amphipathic or lipophilic
bacteriochlorins. We turned to the introduction of 3,5-disubsti-
tuted aryl moieties to the bacteriochlorin nucleus via Suzuki
coupling. The nature of the substituents at the 3- and 5-positions
can be varied to tailor the hydrophobicity. This design approach
required the preparation of 3,5-disubstituted arylboronic acids
and esters, where two distinct types of substituents were
employed: alkoxy groups and alkylaminocarbonyl groups.
A. Arylboronic Acids and Esters. The two types of 3,5-
substituents required distinct synthetic pathways to obtain the
corresponding boronic acid derivatives. The first pathway relied
on 5-bromoresorcinol (3),59 which was alkylated to give the
bis(hydroxyethyl) ether (and its TBDMS derivative) as well as
the MOM-protected derivative (Scheme 6). 5-Bromoresorcinol
was obtained by demethylation of 3,5-dimethoxy-1-bromoben-
zene with BBr3. Treatment of 3 and K2CO3 with 2 equiv of
ethylene carbonate in DMF (following a procedure for the
preparation of a bis(hydroxyethyl ether) of resorcinol60) afforded
1-bromo-3,5-bis(2-hydroxyethoxy)benzene (4). Protection61 of
the diol 4 with tert-butylchlorodimethylsilane in the presence
of DBU gave 5. On the other hand, treatment62 of 3 with
chloromethyl methyl ether afforded the MOM-protected 6.
Metalation of 5 or 6 with BuLi, quenching with B(OiPr)3, and
treatment of the resulting boronic acid species with pinacol
afford arylboronic ester 7 or 8, respectively.
(59) Dol, G. C.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Eur. J. Org.
Chem. 1998, 359–364.
(60) Summer, C. E., Jr.; Hitch, B. J.; Bernard, B. L. WO 9116292, 1991.
(61) Kim, S.; Chang, H. Bull. Chem. Soc. Jpn. 1985, 58, 3669–3670.
(62) Weyermann, P.; Diederich, F.; Gisselbrecht, J.-P.; Boudon, C.; Gross,
M. HelV. Chim. Acta 2002, 85, 571–598.
5812 J. Org. Chem. Vol. 73, No. 15, 2008

Tailoring a Bacteriochlorin Building Block
SCHEME 6
SCHEME 7
The second pathway entailed introduction of amides at the
3,5-positions of the arylboronic acid (Scheme 7). Oxidation63
of 3,5-diformylphenylboronic acid in aqueous NaOH solution
containing KMnO4 followed by acidification afforded crude
5-boronoisophthalic acid (9), a known compound prepared
previously by a different route,64 which upon treatment with
pinacol afforded crude 3,5-dicarboxyphenyldioxaborolane 10.
Conversion of the latter to the diacid chloride by reaction with
oxalyl chloride in dichloromethane with a catalytic amount of
DMF afforded a versatile intermediate for acylation. Treatment
of the diacid chloride with dialkylamine 2 or bis(2-(tert-
butyldimethylsilyloxy)ethyl)amine (11)65 in THF containing
triethylamine gave the tertiary amide 12 or 13, respectively.
Compounds 12 and 13 gave satisfactory characterization data,
including elemental analysis data for 13, which was obtained
as a solid (12 was an oil and was not so characterized).
B. Suzuki Coupling. Suzuki coupling of BC-Br3Br13 with
the arylboronic acid derivatives was carried out under similar
conditions used previously with porphyrins,66 chlorins,57 and
bacteriochlorins.40,42 The conditions are quite standard for
Suzuki reactions [Pd(PPh3)4 in DMF/toluene (2:1) containing
K2CO3 at 90 °C] except for the modest concentration of the
bromo-porphyrinic substrate and the boronic ester, which in this
case are approximately 3 and 9 mM, respectively. Thus, reaction
of BC-Br3Br13 with dioxaborolane 7, 8, or 13 gave BC-15, BC-
16, or BC-17, respectively (Table 2). In the case of the
dioxaborolane 12, the instability of the acetyl protective groups
with K2CO3 caused us to carry out the reaction with K3PO4 to
afford BC-18. BC-19 was obtained via a Suzuki coupling
reaction with the boronic acid 9 in a mixture of ethanol/water.
C. Side-Chain Manipulation. Several members of the set
of diarylbacteriochlorins were subjected to manipulation of the
side chains to obtain amphipathic products. The deprotection
of the four TBDMS groups of BC-15 was achieved with TBAF
in anhydrous media67 to afford the tetrakis(hydroxyethoxy)bac-
teriochlorin BC-20. Cleavage of the MOM groups of BC-16
was carried out in a mixture of 10% HCl in MeOH to afford
the bacteriochlorin BC-21 bearing four phenolic OH groups.
The phenol moieties of the latter were alkylated with methyl
(63) de Filippis, A.; Morin, C.; Thimon, C. Synth. Commun. 2001, 32, 2669–
2676.
(66) (a) Zhou, X.; Zhou, Z.-Y.; Mak, T. C. W.; Chan, K. S. J. Chem. Soc.,
Perkin Trans. 1 1994, 2519–2520. (b) Yu, L.; Lindsey, J. S. Tetrahedron 2001,
57, 9285–9298.
(64) Wang, Q.-C.; Ma, X.; Qu, D.-H.; Tian, H. Chem.-Eur. J. 2006, 12, 1088–
1096.
(65) Grote Gansey, M. H. B.; Steemers, F. J.; Verboom, W.; Reinhoudt, D. N.
(67) Kolb, H. C.; Ley, S. V.; Slawin, A. M. Z.; Williams, D. J. J. Chem.
Soc., Perkin Trans. 1 1992, 2735–2762.
Synthesis 1997, 643–648.
J. Org. Chem. Vol. 73, No. 15, 2008 5813

Ruzié et al.
TABLE 2. Suzuki Coupling
SCHEME 8
bacteriochlorin rather than chlorin chromophore, thereby af-
fording absorption in the NIR rather than the red spectral region.
III. Spectral Properties. The bacteriochlorins prepared herein
exhibit characteristic bacteriochlorin absorption spectra,23 with
near-UV bands and a long-wavelength band in the NIR region
of comparable intensity. The long-wavelength (Qy) absorption
band for the 22 neutral (noncationic) bacteriochlorins appeared
in the range of 720-772 nm. The fwhm of the Qy band was
13-24 nm. The spectra are tabulated in Table 3; representative
spectra for the neutral bacteriochlorins in CH2Cl2 are shown in
Figure 1. The Qy band of the free base bacteriochlorins (neutral
bacteriochlorins in CH2Cl2) shifted bathochromically in the
following trend as a consequence of the nature of the 3,13-
substituents: alkyl (720 nm, BC-14) or aminomethyl (722 nm,
BC-9) < bromo (729 nm, BC-Br3Br13) < 3° amide (732 nm,
BC-6) < aryl (736 nm, BC-15) < 2° amide (744 nm, BC-5) <
cyano (749 nm, BC-1) or ethynyl (749 nm, BC-13) <
methoxycarbonyl (754 nm, BC-4) < formyl (772 nm, BC-2).
The zinc chelate of the dicyanobacteriochlorin (ZnBC-1)
absorbs at 761 nm, indicating a 12-nm bathochromic shift upon
metalation of the free base bacteriochlorin BC-1. For the
diarylbacteriochlorins, the location of the Qy band (736-739
nm) was insensitive to the nature of the substituents (alkoxy,
carboxy, aminocarbonyl) at the 3- and 5-positions of the aryl
ring. Taken together, these data represent a significant expansion
concerning the effects of substituents on the spectral properties
a K3PO4 used in place of K2CO3. b EtOH/H2O (1:1) used in place of
DMF/toluene (2:1). c Boronic acid.
bromoacetate to give bacteriochlorin-tetraester BC-22. On the
other hand, attempted cleavage of the eight TBDMS groups of
BC-17 (using similar conditions as those for BC-15) did not
afford the expected tetrahydroxy-bacteriochlorin. An alternative
route to obtain the same target bacteriochlorin envisaged
cleavage of the eight acetyl groups of BC-18. However,
treatment of BC-18 in the presence of K2CO3 and MeOH gave
hydrolysis of the amide, thereby yielding the bacteriochlorin-
tetraacid BC-19 as the major product (Scheme 8). Purification
of BC-19 was achieved by reversed-phase chromatography with
water as the eluant.
The eight diarylbacteriochlorins BC-15 to BC-22 encompass
a range of polarity that extends from rather lipophilic (BC-15,
BC-16, BC-22) to more amphipathic (BC-17, BC-18, BC-20,
BC-21) to quite polar (BC-19). Bacteriochlorin BC-21 closely
resembles the Foscan analogue (Chart 1) yet contains the
5814 J. Org. Chem. Vol. 73, No. 15, 2008

Tailoring a Bacteriochlorin Building Block
TABLE 3. Absorption Spectral Features of 3,13-Disubstituted
Bacteriochlorins
bacteriochlorin
Qy (nm)a
fwhm (nm)a
substituent
BC-Br3Br13
ZnBC-1
BC-1
BC-2
BC-3
BC-4
BC-5
BC-6
BC-7
729
761
749
772
748b
754
744
732
730
730
722
722
722
724
749
720
736
737
738
739
734c
736
737
737
746d
736d
734d
733d
726d
726d
753d
722d
15
16
14
bromo
cyano
cyano
formyl
carboxy
methoxycarbonyl
2° amide
3° amide
3° amide
22
18b
18
22
21
20
18
14
13
18
16
15
14
20
21
BC-8
BC-9
3° amide
aminomethyl
aminomethyl
aminomethyl
aminomethyl
ethynyl
BC-10
BC-11
BC-12
BC-13
BC-14
BC-15
BC-16
BC-17
BC-18
BC-19
BC-20
BC-21
BC-22
BC-5′
BC-6′
BC-8′
BC-9′
BC-10′
BC-11′
BC-13′
BC-14′
alkyl
3,5-dialkoxyphenyl
3,5-dialkoxyphenyl
3,5-diacylphenyl
3,5-diacylphenyl
3,5-dicarboxyphenyl
3,5-dialkoxyphenyl
3,5-dihydroxyphenyl
3,5-dialkoxyphenyl
2° amide
3° amide
3° amide
aminomethyl
aminomethyl
aminomethyl
ethynyl
21
24
21c
20
22
21
27d
23d
20d
16d
16d
18d
18d
17d
alkyl
a All data were obtained in CH2Cl2 at room temperature unless noted
otherwise. b In THF. c In methanol. d In water.
FIGURE 1. Absorption spectra in CH2Cl2 at room temperature of
bacteriochlorins (normalized at the Qy bands). (A) Entire spectra and
(B) expansion of the Qy region. The labels and the colors in the graph
are as follows: BC-9 (a, orange, 722 nm), BC-Br3Br13 (b, black, 729
nm), BC-6 (c, green, 732 nm), BC-15 (d, light blue, 736 nm), BC-5
(e, dark blue, 744 nm), BC-1 (f, pink, 749 nm), BC-4 (g, light brown,
754 nm), and ZnBC-1 (h, red, 761 nm).
of bacteriochlorins,68–70 and are consistent with those for prior
bacteriochlorins where comparisons can be made.42
The cationic bacteriochlorins exhibited absorption spectra in
water that closely resembled those of the neutral precursor
bacteriochlorins in organic media. The Qy absorption band
remained quite sharp (fwhm ) 16-27 nm) even in water, and
was typically characterized by a bathochromic shift of 2-4 nm
for the quaternized bacteriochlorins in water versus the neutral
bacteriochlorins in CH2Cl2. One exception was BC-9′, which
exhibited a bathochromic shift of 11 nm versus that of BC-9.
In BC-9′, the positively charged nitrogen is separated from the
bacteriochlorin π-system by only a single methylene group.
contained substituents (alkoxy, alkylaminocarbonyl, and carboxy
groups) at the 3- and 5-positions, which provided further sites
for structural modification. The quaternization of aminoalkyl
moieties introduced 2 or 4 cationic moieties and thereby
imparted water solubility. This extensive level of alteration of
the local environment of the bacteriochlorin can be accomplished
while retaining the absorption spectral features characteristic
of bacteriochlorins. The ability to introduce diverse functional
groups and structural motifs enables the local environment of
the synthetic bacteriochlorin to be tailored across a very broad
range of polarity, from hydrophilic to amphipathic to lipophilic,
which represents a desirable attribute for the development of
novel NIR-active compounds for applications in photomedicine.
Outlook
A dibromobacteriochlorin bearing a stabilizing geminal
dimethyl group in each pyrroline ring provides a versatile
scaffold for synthetic elaboration via Pd-mediated coupling
reactions. The Pd-coupling reactions enabled the attachment of
cyano, formyl, carboxy, methoxycarbonyl, alkylaminocarbonyl,
ethynyl, and aryl moieties onto the bacteriochlorin nucleus. The
formyl moiety enabled derivatization via reductive amination,
whereas the carboxy group was converted to the acid chloride
to facilitate amide formation. The aryl moieties employed herein
Experimental Section
tert-Butyl Bis(2-acetoxyethyl)carbamate (1). Following a re-
ported procedure for acylation,50 a solution of tert-butyl bis(2-
hydroxyethyl)carbamate (1.03 g, 5.00 mmol) in pyridine (10 mL)
at 0 °C was treated dropwise with acetic anhydride (1.88 mL, 20.0
mmol). The reaction mixture was stirred overnight at room
temperature and then concentrated under vacuum. The resulting
residue was subjected to column chromatography [silica, hexanes
f hexanes/ethyl acetate (1:1)] to afford a colorless oil (1.32 g,
(68) Pandey, R. K.; Constantine, S.; Tsuchida, T.; Zheng, G.; Medforth, C. J.;
Aoudia, M.; Kozyrev, A. N.; Rodgers, M. A. J.; Kato, H.; Smith, K. M.;
Dougherty, T. J. J. Med. Chem. 1997, 40, 2770–2779.
(69) Fukuzumi, S.; Ohkubo, K.; Chen, Y.; Pandey, R. K.; Zhan, R.; Shao,
J.; Kadish, K. M. J. Phys. Chem. A 2002, 106, 5105–5113.
(70) Sasaki, S.-I.; Tamiaki, H. J. Org. Chem. 2006, 71, 2648–2654.
J. Org. Chem. Vol. 73, No. 15, 2008 5815

Ruzié et al.
91%): 1H NMR δ 1.46 (s, 9H), 2.06 (s, 3H), 2.07 (s, 3H), 3.48 (t,
J ) 5.8 Hz, 2H), 3.52 (t, J ) 5.8 Hz, 2H), 4.16 (t, J ) 5.7 Hz,
2H), 4.20 (t, J ) 5.7 Hz, 2H); 13C NMR δ 20.8, 28.2, 46.8, 46.9,
62.3, 62.6, 80.1, 155.1, 170.8. ESI-MS obsd 312.1417, calcd
312.1417 [(M + Na)+, M ) C13H23NO6].
added, and the mixture was stirred for 1 h. Ethyl acetate was added,
and the organic layer was separated, dried over Na2SO4, and
concentrated under reduced pressure. The crude mixture was
dissolved in a mixture of THF/toluene (40 mL, 1:1), to which
pinacol (0.118 g, 1.00 mmol) was added. The crude mixture was
warmed in a hot water bath and concentrated under vacuum. A
mixture of THF/toluene (40 mL, 1:1) was added, and the mixture
again was concentrated under vacuum. Dichloromethane was added,
and the mixture was washed with water (5 × 20 mL). The resulting
residue was subjected to column chromatography [silica, hexanes/
ethyl acetate (4:1)] to afford a white solid (0.209 g, 38%): mp 55
°C; 1H NMR δ 0.10 (s, 12H), 0.91 (s, 18H), 1.33 (s, 12H), 3.95 (t,
J ) 5.1 Hz, 4H), 4.05 (t, J ) 5.1 Hz, 4H), 6.59 (t, J ) 2.0 Hz,
1H), 6.94 (d, J ) 2.0 Hz, 2H); 13C NMR δ -5.2, 18.4, 24.8, 25.9,
62.0, 69.3, 83.8, 105.8, 112.3, 159.6; ESI-MS obsd 553.3550, calcd
553.3546 [(M + H)+, M ) C28H53BO6Si2]. Anal. Calcd for
C28H53BO6Si2: C, 60.85; H, 9.67. Found: C, 61.06; H, 9.89.
2-(3,5-Bis(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (8). A solution of TMEDA (343 µL, 2.30 mmol)
in anhydrous THF (10 mL) at -78 °C was treated with n-
butyllithium (924 µL, 2.5 M in hexanes, 2.30 mmol). After stirring
for 30 min at -78 °C, a solution of 6 (0.400 g, 1.44 mmol) in
anhydrous THF (10 mL) was added dropwise, and the mixture was
stirred for 1 h at -78 °C. Triisopropylborate (1.04 mL, 7.20 mmol)
was added. The mixture was stirred for 2 h at -78 °C, and then
allowed to warm overnight to room temperature. A saturated
solution of aqueous NH4Cl was added, and the mixture was stirred
for 1 h. Ethyl acetate was added, and the organic layer was
separated, dried over Na2SO4, and concentrated under reduced
pressure. The resulting crude material was dissolved in a mixture
of THF/toluene (40 mL, 1:1), and pinacol (1.20 g, 14.4 mmol) was
added. The crude mixture was concentrated under vacuum. A
mixture of THF/toluene (40 mL, 1:1) was added, and again the
mixture was concentrated under vacuum. Dichloromethane was
added, and the mixture was washed with water (5 × 20 mL). Drying
of the residue and crystallization from diethyl ether at -20 °C
2-[(2-Acetoxyethyl)amino]ethyl Acetate (2). A solution of 1
(1.16 g, 4.00 mmol) in CH2Cl2 (20 mL) was treated with TFA (5.96
mL, 80.0 mmol). The reaction mixture was stirred for 30 min at
room temperature, and then treated with a saturated aqueous solution
of K3PO4. The organic layer was separated, found to contain 61
mg of impure compound, and discarded. The aqueous layer was
extracted three times with ethyl acetate. The combined ethyl acetate
extract was dried over Na2SO4 and concentrated under vacuum.
The resulting colorless oil quickly turned brown and was used
1
without further purification (470 mg, 62%): H NMR δ 2.07 (s,
6H), 3.10 (t, J ) 4.8 Hz, 4H), 4.27 (t, J ) 4.8 Hz, 4H), 5.25 (br s,
1H); 13C NMR 20.7, 47.3, 61.6, 170.9; ESI-MS obsd 190.1077,
calcd 190.1073 [(M + H)+, M ) C8H15NO4].
1-Bromo-3,5-bis(2-hydroxyethoxy)benzene (4). A solution of
3 (0.645 g, 3.41 mmol) in anhydrous DMF (10 mL) was treated
with K2CO3 (1.41 g, 10.2 mmol). The mixture was stirred for 30
min, and then ethylene carbonate (0.601 g, 6.82 mmol) was added.
The mixture was stirred for 3 h at reflux, and then solvent was
removed under vacuum. Water (10 mL) was added, the mixture
was stirred at 0 °C, and the solid was collected by filtration. The
filtered material was subjected overnight to high vacuum to give
1
the title compound (0.740 g, 78%): H NMR (acetone-d6) δ 3.86
(m, 4H), 4.00 (t, J ) 5.9 Hz, 2H), 4.07 (t, J ) 4.6 Hz, 4H), 6.50
(t, J ) 1.8 Hz, 1H), 6.70 (d, J ) 1.8 Hz, 2H); 13C NMR (acetone-
d6) δ 61.0, 61.1, 71.0, 101.5, 111.1, 123.2, 161.9; ESI-MS obsd
277.0069, calcd 277.0069 [(M + H)+, M ) C10H13O479Br].
Colorless needles were obtained upon crystallization in hot toluene:
mp 78 °C. Anal. Calcd for C10H13BrO4: C, 43.34; H, 4.73. Found:
C, 43.64; H, 4.72.
1-Bromo-3,5-bis[2-(tert-butyldimethylsilyloxy)ethoxy]benz-
ene (5). A solution of 4 (0.277 g, 1.00 mmol) in anhydrous CH2Cl2
(5 mL) was treated with DBU (329 µL, 2.20 mmol) and tert-
butylchlorodimethylsilane (0.332 g, 2.20 mmol). The reaction
mixture was stirred for 20 min at room temperature, and then
concentrated under vacuum. The resulting residue was subjected
to column chromatography [silica, hexanes/ethyl acetate (95:5)] to
afford a white solid (0.490 g, 97%): mp 36 °C; 1H NMR δ 0.10 (s,
12H), 0.91 (s, 18H), 3.95 (t, J ) 4.5 Hz, 4H), 3.98 (t, J ) 4.5 Hz,
4H), 6.40 (t, J ) 2.0 Hz, 1H), 6.67 (d, J ) 2.0 Hz, 2H); 13C NMR
δ -5.2, 18.4, 25.9, 61.8, 69.6, 100.9, 110.5, 122.8, 160.5; ESI-MS
obsd 505.1802, calcd 505.1799 [(M + H)+, M ) C22H41O4Si279Br].
Anal. Calcd for C22H41BrO4Si2: C, 52.26; H, 8.17. Found: C, 52.09;
H, 8.31.
1-Bromo-3,5-bis(methoxymethoxy)benzene (6). A solution of
3 (0.378 g, 2.00 mmol) in anhydrous acetonitrile (5 mL) was cooled
to 0 °C in an ice bath and treated with K2CO3 (2.21 g, 16.0 mmol).
The mixture was stirred for 30 min, and then MOM-Cl (607 µL,
8.0 mmol) was added. The mixture was stirred overnight at room
temperature, whereupon the solvent was removed under vacuum.
Water (10 mL) was added to the residue, and the mixture was
extracted with ethyl acetate (3 × 50 mL). The resulting residue
was subjected to column chromatography [silica, hexanes/ethyl
acetate (95:5)] to afford a colorless oil (0.551 g, 85%): 1H NMR δ
3.47 (s, 6H), 5.13 (s, 4H), 6.66 (s, 1H), 6.88 (s, 2H); 13C NMR δ
56.1, 94.4, 103.9, 113.1, 122.7, 158.7; ESI-MS obsd 277.0069, calcd
277.0069 [(M + H)+, M ) C10H13O479Br].
1
provided a colorless solid (0.278 g, 60%): mp 46 °C; H NMR δ
1.33 (s, 12H), 3.48 (s, 6H), 5.18 (s, 4H), 6.82 (t, J ) 2.2 Hz, 1H),
7.12 (d, J ) 2.2 Hz, 2H); 13C NMR δ 24.8, 56.0, 83.9, 94.3, 108.3,
115.3, 157.8; ESI-MS obsd 325.1822, calcd 325.1816 [(M + H)+,
M ) C16H25BO6]. Anal. Calcd for C16H25BO6: C, 59.28; H, 7.77.
Found: C, 59.54; H, 7.87.
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalic Acid
(10). A solution of 3,5-diformylphenylboronic acid (1.00 g, 5.60
mmol) in aqueous sodium hydroxide (9 mL of a 2.5 M solution)
was treated with a freshly prepared solution of potassium perman-
ganate (414 mg, 2.62 mmol) in water (15 mL). This addition was
repeated twice at 1 h intervals. After the solution was stirred
overnight, ethanol (5 mL) was added and the mixture was stirred
at 50 °C for 10 min. After cooling and filtration on Celite, the filtrate
was acidified to pH 2.5 with 0.5 M hydrochloric acid. Filtration of
the resulting precipitate gave 5-boronoisophthalic acid (9) as a white
1
powder (0.793 g, 67%): mp >300 °C; H NMR (DMSO-d6) 8.42
(br s, 2H), 8.50 (s, 1H), 8.61 (s, 2H), 13.18 (br s, 2H); 13C NMR
(DMSO-d6) 130.3, 131.5, 139.1, 166.9; ESI-MS obsd 211.0410,
calcd 211.0408 [(M + H)+, M ) C10H7BO6]. The compound did
not give satisfactory elemental analysis without assuming the
presence of a hemihydrate (Anal. Calcd for 2C8H7BO6 ·H2O: C,
43.88; H, 3.68. Found: C, 43.82; H, 3.64) yet was sufficiently pure
for boronate ester formation. A mixture of crude 9 (0.210 g, 1.00
mmol) and pinacol (0.118 g, 1.00 mmol) was treated with a mixture
of THF/toluene (40 mL, 1:1). The crude mixture was concentrated
to dryness under vacuum. This procedure (solvents addition/
evaporation) was repeated twice. Crystallization of the white powder
in diethyl ether afforded white crystals (0.280 g, 96%): mp >300
2-(3,5-Bis[2-(tert-butyldimethylsilyloxy)ethoxy]phenyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (7). A solution of 5 (0.506 g,
1.00 mmol) in anhydrous THF (5 mL) was cooled to -78 °C.
n-Butyllithium (640 µL, 2.5 M in hexanes, 1.6 mmol) was added
dropwise, the mixture was stirred 1 h at -78 °C, and then
triisopropylborate (722 µL, 5.00 mmol) was added. The mixture
was stirred for 2 h at -78 °C, and then allowed to warm overnight
to room temperature. A saturated solution of aqueous NH4Cl was
1
°C; H NMR (DMSO-d6) δ 1.32 (s, 12H), 8.42 (d, J ) 1.8 Hz,
2H), 8.56 (t, J ) 1.8 Hz, 1H), 13.34 (s, 2H); 13C NMR (DMSO-
d6) δ 24.6, 84.3, 130.8, 132.6, 138.8, 166.4; ESI-MS obsd 293.1198,
calcd 293.1190 [(M + H)+, M ) C14H17BO6]. The title compound
5816 J. Org. Chem. Vol. 73, No. 15, 2008

Tailoring a Bacteriochlorin Building Block
so obtained did not quite give a satisfactory elemental analysis
(Anal. Calcd for C14H17BO6: C, 57.57; H, 5.87. Found: C, 58.01;
H, 5.98) yet was sufficiently pure for conversion to the acid chloride
and subsequent amidation.
3,13-Dicyano-8,8,18,18-tetramethylbacteriochlorin (BC-1). A
mixture of ZnBC-1 (7.0 mg, 0.015 mmol) in CHCl3 (1 mL) was
treated with TFA (23 µL, 0.31 mmol). The resulting red solution
was stirred at room temperature, and the progress of the reaction
was monitored by TLC and absorption spectroscopy. After 4 h,
the reaction mixture was diluted with CH2Cl2 (30 mL) and saturated
aqueous NaHCO3 solution (20 mL) was added. The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (20
mL). The combined organic extract was washed with water (30
mL) and brine (30 mL), dried (Na2SO4), and filtered. The filtrate
was concentrated to afford a green solid. The crude product was
dissolved in a minimum amount of CH2Cl2 and chromatographed
[silica, hexanes/CH2Cl2/ethyl acetate (8:1:1 f 1:1:1)] to obtain the
first band (green, the title compound; 4.0 mg, 63%) and the second
band (pink, the starting material; 2.5 mg). Data for the title
N1,N1,N3,N3-Tetrakis[2-(acetoxy)ethyl]-5-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)isophthalamide (12). A suspension of 10
(0.200 g, 0.684 mmol) in anhydrous CH2Cl2 (20 mL) was treated
with 10 µL of anhydrous DMF, and the mixture was cooled to 0
°C. Then oxalyl chloride (294 µL, 3.42 mmol) was added dropwise.
The mixture was refluxed for 6 h, and then the solvent was removed
under vacuum. The residue was dried under high vacuum. The crude
mixture was dissolved in anhydrous THF (10 mL), and this solution
was added dropwise to a solution of 2 (0.259 g, 1.37 mmol) and
triethylamine (475 µL, 3.42 mmol) in anhydrous THF (20 mL) at
0 °C. The mixture was stirred for 1 h at 0 °C, and then allowed to
warm overnight to room temperature. The solvent was removed
under vacuum. Water (10 mL) was added to the residue, and the
mixture was extracted with ethyl acetate (3 × 50 mL). The
combined organic extract was dried over Na2SO4 and concentrated
under vacuum. The resulting residue was subjected to column
chromatography [silica, hexanes/ethyl acetate (4:1)] to afford a
colorless oil (76 mg, 17%): 1H NMR δ 1.33 (s, 12H), 2.09 (s, 12H),
3.59 (br s, 4H), 3.79 (br s, 4H), 4.11 (br s, 4H), 4.36 (br s, 4H),
7.48 (t, J ) 1.7 Hz, 1H), 7.87 (d, J ) 1.7 Hz, 2H); 13C NMR δ
20.7, 24.8, 44.4, 48.6, 61.2, 61.9, 84.3, 127.4, 133.8, 135.9, 170.7,
171.6; ESI-MS obsd 635.2980, calcd 635.2981 [(M + H)+, M )
C30H43BN2O12].
1
compound: H NMR δ -1.65 (br s, 2H), 1.94 (s, 12H), 4.43 (s,
4H), 8.67 (s, 2H), 8.98 (s, 2H), 9.03 (s, 2H); LD-MS obsd 420.7;
ESI-MS obsd 421.2123, calcd 421.2135 [(M + H)+, M )
C26H24N6]; λabs (CH2Cl2) 346, 371, 515, 749 nm.
3,13-Diformyl-8,8,18,18-tetramethylbacteriochlorin (BC-2).
Following a procedure for reductive carbonylation,48 a mixture of
BC-Br3Br13 (104 mg, 0.200 mmol) and Pd(PPh3)4 (463 mg, 0.400
mmol) was dried under vacuum for 1 h. The reaction flask was
filled with CO gas, and anhydrous DMF/toluene [10 mL, (1:1)]
was added. CO gas was bubbled through the stirred reaction mixture
for 2 h at 70 °C. After 2 h, the reaction mixture was treated with
Bu3SnH (107 µL, 0.400 mmol), and then stirred for 10 min. The
reaction mixture was then cooled to room temperature and filtered
through a short Celite column, which was eluted with ethyl acetate.
The filtrate was concentrated and subjected to column chromatog-
raphy [silica, CH2Cl2]. The 3-formyl-13-desbromobacteriochlorin
(20 mg, 25%) eluted first, followed by the expected title compound
(50 mg, 60%): 1H NMR δ -1.17 (br s, 2H), 1.95 (s, 12H), 4.42 (s,
4H), 8.65 (s, 2H), 9.12 (s, 2H), 9.58 (s, 2H), 11.14 (s, 2H); LD-
MS obsd 426.8; ESI-MS obsd 427.2124, calcd 427.2128 [(M +
H)+, M ) C26H26N4O2]; λabs (CH2Cl2) 362, 537, 772 nm. Data for
N1,N1,N3,N3-Tetrakis[2-(tert-butyldimethylsilyloxy)ethyl]-5-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalamide (13).
A suspension of 10 (0.292 g, 1.00 mmol) in anhydrous CH2Cl2
(20 mL) was treated with 10 µL of anhydrous DMF, and the mixture
was cooled to 0 °C. Then oxalyl chloride (430. µL, 5.00 mmol)
was added dropwise. The mixture was refluxed for 6 h, and then
the solvent was removed under vacuum. The residue was dried
under high vacuum. The crude mixture was dissolved in anhydrous
THF (10 mL), and this solution was added dropwise to a solution
of 11 (0.667 g, 2.00 mmol) and triethylamine (694 µL, 5.00 mmol)
in anhydrous THF (20 mL) at 0 °C. The mixture was stirred for
1 h at 0 °C, and then allowed to warm overnight to room
temperature. The solvent was removed under vacuum. Water (10
mL) was added to the residue, and the mixture was extracted with
ethyl acetate (3 × 50 mL). The organic extract was dried over
Na2SO4 and concentrated under vacuum. The resulting residue was
subjected to column chromatography [silica, hexanes/ethyl acetate
(4:1)] to afford a colorless oil that slowly solidified upon cooling
1
3-formyl-8,8,18,18-tetramethylbacteriochlorin: H NMR δ -0.66
(br s, 1 H), -0.42 (br s, 1 H), 1.86 (s, 12 H), 4.21 (s, 2 H), 4.25
(s, 2 H), 8.30 (s, 1 H), 8.38 (s, 1 H), 8.40 (s, 1 H), 8.54 (m, 2 H),
8.79 (d, J ) 1.65 Hz, 1 H), 9.32 (s, 1 H), 11.09 (s, 1 H); ESI-MS
obsd 399.2181, calcd 399.2179 [(M + H)+, M ) C25H26N4O]; λabs
(CH2Cl2) 315, 515, 731 nm.
3,13-Dicarboxy-8,8,18,18-tetramethylbacteriochlorin (BC-3).
Following a procedure for Pd-mediated CO insertion in chlorins,48
a mixture of BC-Br3Br13 (21 mg, 0.040 mmol) and Pd(PPh3)4 (91
mg, 0.080 mmol) was dried in a Schlenk flask for 1 h. A mixture
of DMF and toluene (2 mL each, degassed for 10 min) was added
to the flask, and CO gas was bubbled through the reaction mixture
for 2 h at 70 °C. The initially green mixture turned pink red. The
bubbling of CO was stopped, and aqueous NaOH (0.50 mL, 2 M)
was introduced to the flask through a syringe. The reaction mixture
was allowed to cool to room temperature in 30 min. Water (10
mL), 2 M aqueous NaOH (2 mL), and CH2Cl2 (10 mL) were added.
The layers were separated. The organic layer was extracted with
H2O (5 mL) and 2 M aqueous NaOH (2 mL). The combined
aqueous layer was washed with CH2Cl2 (3 × 20 mL). The aqueous
layer was carefully acidified to pH 5 with 2 M aqueous HCl to
precipitate the product. The solid was collected upon centrifugation
and dried under high vacuum to obtain a pink red solid (14 mg,
1
to give a colorless solid (0.531 g, 57%): mp 73 °C; H NMR δ
-0.03 (s, 12H), 0.06 (s, 12H), 0.82 (s, 18H), 0.89 (s, 18H), 1.28
(s, 12H), 3.43 (t, J ) 5.7 Hz, 4H), 3.60 (t, J ) 5.7 Hz, 4H), 3.66
(t, J ) 5.7 Hz, 4H), 3.85 (t, J ) 5.7 Hz, 4H), 7.44 (t, J ) 1.7 Hz,
1H), 7.81 (d, J ) 1.7 Hz, 2H); 13C NMR δ -5.5, -5.4, 18.2, 24.8,
25.9, 48.0, 52.2, 60.9, 61.1, 84.0, 127.4, 133.7, 136.5, 171.4; ESI-
MS obsd 923.6027, calcd 923.6018 [(M
C46H91BN2O8Si4]. Anal. Calcd for C46H91BN2O8Si4: C, 59.83; H,
9.93; N, 3.03. Found: C, 59.55; H, 9.93; N, 3.03.
+ M )
H)+,
Zn(II)-3,13-Dicyano-8,8,18,18-tetramethylbacteriochlorin (Zn-
BC-1). Following a general procedure for cyanation of aryl
bromides,43 a mixture of BC-Br3Br13 (70.0 mg, 0.133 mmol),
Zn(CN)2 (77.0 mg, 0.656 mmol), and Pd(PPh3)4 (35 mg, 0.030
mmol) was heated to 100 °C in DMF (12 mL) in a Schlenk flask
under anaerobic conditions. After 3 h, the reaction mixture was
allowed to cool to room temperature and filtered through a pad of
Celite, then the flask and Celite were rinsed with ethyl acetate (30
mL × 3). The filtrate was concentrated, and the resulting red-pink
solid was chromatographed [silica, hexanes/CH2Cl2/ethyl acetate
1
76%): H NMR (THF-d8) δ -1.52 (br s, 2H), 1.95 (s, 12H), 4.46
(s, 4H), 8.80 (s, 2H), 9.25 (s, 2H), 9.86 (s, 2H), 11.75 (br s, 2H);
LD-MS obsd 458.8; ESI-MS obsd 458.1946, calcd 458.1948
(C26H26N4O4); λabs (THF) 348, 375, 518, 748 nm.
3,13-Bis(methoxycarbonyl)-8,8,18,18-tetramethylbacteriochlo-
rin (BC-4). The carbonylation was performed with 10.5 mg (0.0200
mmol) of BC-Br3Br13 following the above procedure for BC-3.
After 2 h at 70 °C, the reaction mixture was quenched with excess
NaOMe (22 mg, 0.50 mmol) in MeOH (1 mL) to obtain a purple
1
(3:1:1 f 1:1:1)] to afford a pink-purple solid (57 mg, 89%): H
NMR (CDCl3/CD3OD, (9:1)) δ 1.86 (s, 12H), 4.32 (s, 4H), 8.41
(s, 2H), 8.70 (s, 2H), 8.93 (s, 2H); LD-MS obsd 482.1; ESI-MS
obsd 482.1189, calcd 482.1197 (C26H22N6Zn); λabs (CH2Cl2) 339,
377, 538, 761 nm.
1
solid (7.0 mg, 72%): H NMR δ -1.46 (br s, 2H), 1.92 (s, 12H),
J. Org. Chem. Vol. 73, No. 15, 2008 5817

Ruzié et al.
4.25 (s, 6H), 4.41 (s, 4H), 8.61 (s, 2H), 9.17 (s, 2H), 9.72 (s, 2H);
ESI-MS obsd 487.2327, calcd 487.2339 [(M + H)+, M )
C28H30N4O4]; λabs (CH2Cl2) 350, 377, 522, 754 nm.
and 787 nm, respectively, indicating the formation of diacid
chloride. The reaction mixture was concentrated under reduced
pressure and dried under high vacuum. The resulting solid was
dissolved in 1,2-dichloroethane (4 mL) and then treated with
N-methylpiperazine (200 µL) at room temperature. The stirring was
continued overnight. The reaction mixture was diluted with CH2Cl2
(30 mL) and H2O (20 mL) was added. The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (30 mL). The
combined organic extract was washed with H2O (40 mL) and brine
(40 mL), dried (Na2SO4), and filtered. The filtrate was concentrated
to obtain a green solid. The crude product was dissolved in a
minimum amount of CH2Cl2 and chromatographed [silica, CH2Cl2/
MeOH (97:3 f 90:10)] to obtain the title compound as a green
solid (7.2 mg, 53%). The data were consistent with those for a
sample obtained by Method A.
3,13-Bis[(2-(dimethylamino)ethylamino)carbonyl]-8,8,18,18-
tetramethylbacteriochlorin (BC-5). The carbonylation was per-
formed with 21 mg (0.040 mmol) of BC-Br3Br13 following the
above procedure for BC-3. After 2 h at 70 °C, the bubbling of CO
gas was stopped and the sodium salt of N,N-dimethylaminoethyl-
amine in N,N-dimethylaminoethylamine (0.5 mL) [freshly prepared
by adding N,N-dimethylaminoethylamine (1.0 mL, 9.2 mmol) to
NaH (20 mg, 0.83 mmol, 95%) under an inert atmosphere] was
introduced via syringe. The heat was turned off and the reaction
mixture was allowed to cool to room temperature in 30 min. CH2Cl2
(20 mL) was added, and the reaction mixture was filtered through
a pad of Celite, which was rinsed with CH2Cl2 until the filtrate
was colorless. The filtrate was treated with saturated aqueous NH4Cl
(30 mL). The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (30 mL). The combined organic extract was
washed with H2O (40 mL) and brine (40 mL), dried (Na2SO4), and
filtered. The filtrate was concentrated to afford a green solid. The
crude product was dissolved in a minimum amount of CH2Cl2 and
chromatographed [silica, eluant composition: 95 mL of CH2Cl2
containing 3 mL of MeOH and 2 mL of MeOH that was saturated
3,13-Bis(N,N-dimethylaminomethyl)-8,8,18,18-tetramethyl-
bacteriochlorin (BC-9). A solution of BC-2 (5.7 mg, 0.012 mmol)
in 1,2-dichloroethane (1.0 mL) was treated with molecular sieves
4 Å (two or three beads) and dimethylamine (60 µL, 0.12 mmol,
2.0 M in THF). The mixture was stirred at room temperature under
argon for 5 min before adding NaBH(OAc)3 (10. mg, 0.048 mmol)
all at once, followed by glacial acetic acid (1.4 µL, 0.024 mmol).
The reaction was complete after 4 h as determined by TLC (silica,
CH2Cl2). After 4 h, the mixture was quenched by the addition of
saturated aqueous NaHCO3 (2 mL) and ethyl acetate. The organic
layer was separated, dried (Na2SO4), and concentrated to yield a
1
with NH3] to obtain a green solid (12.6 mg, 53%): H NMR δ
-1.64 (br s, 2H), 1.90 (s, 12H), 2.43 (s, 12H), 2.77 (t, J ) 6 Hz,
4H), 3.86(t, J ) 6 Hz, 4H), 4.40 (s, 4H), 7.50 (br s, 2H), 8.61 (s,
2H), 8.89 (s, 2H), 9.75 (s, 2H); LD-MS obsd 599.7; ESI-MS obsd
300.1948, calcd 300.1944 [(M + 2H)2+, M ) C34H46N8O2]; λabs
(CH2Cl2) 348, 373, 512, 744 nm.
1
green solid (6 mg, ∼90% pure, ∼95% yield): H NMR δ -2.26
(br s, 2H), 1.96 (s, 12H), 2.59 (s, 12H), 4.48 (s, 4H), 4.67 (s, 4H),
8.63 (s, 2H), 8.66 (s, 2H), 8.92 (s, 2H); ESI-MS obsd 243.1741,
calcd 243.1729 [(M + 2H)2+, M ) C30H40N6]; λabs (CH2Cl2) 343,
369, 492, 722 nm.
3,13-Bis[(2-(trimethylammonio)ethylamino)carbonyl]-8,8,18,18-
tetramethylbacteriochlorin Diiodide (BC-5′). Following a stan-
dard procedure for amine quaternization,58 a solution of BC-5 (7.0
mg, 0.012 mmol) in CHCl3 (1 mL, stabilized with EtOH) was
treated with MeI (30 µL, 0.48 mmol, 40 equiv) under argon. The
mixture was stirred at room temperature for 24 h. At this time a
solid had settled on the walls and bottom of the vial. Excess methyl
iodide and solvent were removed under reduced pressure at ambient
temperature. Purification of the crude product was achieved by
adding anhydrous diethyl ether to the crude product (5.0 mL). The
mixture was sonicated for 2 min in a benchtop sonication bath.
The mixture was centrifuged and the supernatant was removed,
leaving the desired product as a solid. The resulting solid was dried
3,13-Bis[bis(2-hydroxyethyl)aminomethyl]-8,8,18,18-tetra-
methylbacteriochlorin (BC-12). Following the procedure described
for the preparation of BC-9, reductive amination of BC-2 (5.0 mg,
0.012 mmol) with 2 (45 mg, 0.24 mmol) at 36 °C for 16 h gave a
green solid. TLC analysis showed the disappearance of BC-2. LD-
MS analysis of the crude product showed a dominant peak at m/z
772.5 (calcd 772.4, C42H56N6O8). The crude product was depro-
tected by dissolution in MeOH (10 mL) and treatment with K2CO3
(260 mg, 0.48 mmol). After the mixture was stirred at 60 °C for
1 h, the deprotection was complete as determined by TLC (silica,
CH2Cl2). The mixture was quenched by the addition of water and
ethyl acetate. The organic layer was separated and the aqueous layer
was extracted twice with ethyl acetate. The combined organic
extract was dried (Na2SO4) and concentrated to yield a green solid.
The crude mixture was subjected to column chromatography [silica,
ethyl acetate/methanol (9:1 f 4:1)], and the fractions containing
the desired product were combined and concentrated. The resulting
product was dissolved in a minimum amount of CH2Cl2 (∼0.5 mL),
and hexanes (∼10 mL) was added. The resulting precipitate was
1
under high vacuum to afford a pink-red solid (7.5 mg, 71%): H
NMR (CD3OD) δ 1.98 (s, 12H), 3.42 (s, 18H), 3.88 (t, J ) 6.4
Hz, 4H), 4.20 (t, J ) 6.4 Hz, 4H), 4.45 (s, 4H), 8.80 (s, 2H), 9.15
(s, 2H), 9.69 (s, 2H); ESI-MS obsd 314.2106, calcd 314.2101 (M2+
,
M ) C36H52N8O2]; λabs (H2O) 346, 371, 513, 746 nm. An alternative
purification procedure was as follows: The crude product was
dissolved in a minimum amount of MeOH (∼1 mL) and diethyl
ether (∼15 mL) was added. The resulting precipitate was filtered
and washed with CH2Cl2/hexanes [2 mL (1:2), then 2 mL (2:1)].
3,13-Bis(4-methylpiperazin-1-ylcarbonyl)-8,8,18,18-tetra-
methylbacteriochlorin (BC-6). Method A: The carbonyl insertion
reaction was performed with 21 mg (0.040 mmol) of BC-Br3Br13
following a procedure similar to that described above for BC-5.
After 2 h at 70 °C, the reaction mixture was quenched with the
sodium salt of N-methylpiperazine in N-methylpiperazine (0.5 mL)
1
collected to yield a green solid (2.4 mg, 33%): H NMR δ -2.21
(br s, 2H), 1.91 (s, 2H), 1.93 (s, 2H), 1.95 (s, 12H), 3.09 (t, J )
5.13 Hz, 8H), 3.80 (t, J ) 5.13 Hz, 8H), 4.46 (s, 4H), 4.97 (s, 4H),
8.63 (s, 2H), 8.68 (s, 2H), 8.89 (s, 2H); ESI-MS obsd 604.3730,
calcd 604.3731 (C34H48N6O4); λabs (CH2Cl2) 343, 369, 494, 724
nm.
3,13-Bis(3-(N,N-dimethylamino)prop-1-ynyl)-8,8,18,18-tetra-
methylbacteriochlorin (BC-13). Following a general procedure
for Sonogashira coupling,55 a mixture of BC-Br3Br13 (21 mg, 0.040
mmol), PdCl2(PPh3)2 (3.2 mg, 0.0045 mmol), CuI (1.0 mg, 0.0052
mmol), and 3-dimethylamino-1-propyne (50. µL, 0.46 mmol) in
triethylamine (2 mL) was heated to 60 °C for 43 h in a Schlenk
flask under anaerobic conditions. The reaction was complete as
monitored by TLC. The reaction mixture was allowed to cool to
room temperature. The reaction mixture was diluted with CH2Cl2
(10 mL) and filtered through a pad of Celite. The flask and the
solids were rinsed with CH2Cl2 (3 × 10 mL). The filtrate was
concentrated and chromatographed [silica, CH2Cl2/MeOH (97:3 f
1
to obtain the title compound as a green solid (11.8 mg, 47%): H
NMR δ -1.95 (br s, 2H), 1.93 (s, 12H), 2.40 (s, 6H), 2.45 (m,
4H), 2.75 (m, 4H), 3.79 (m, 4H), 4.18 (m, 4H), 4.40 (s, 4H), 8.63
(s, 2H), 8.69 (s, 2H), 8.95 (s, 2H); LD-MS obsd 622.8; ESI-MS
obsd 623.3807, calcd 623.3816 [(M + H)+, M ) C36H46N8O2];
λ
abs (CH2Cl2) 345, 368, 500, 732 nm. Method B: The diacid BC-3
(10. mg, 0.022 mmol) in a 10-mL round-bottomed flask under inert
atmosphere was suspended in CH2Cl2 (4.0 mL). To this green
suspension were added DMF (10 µL) and oxalyl chloride (20 µL),
and the resulting mixture was stirred at room temperature for 6 h.
The reaction mixture became a clear pink solution and the
absorption spectrum showed a shift of the Qx and Qy bands to 554
1
95:5)] to obtain a green solid (14.2 mg, 67%): H NMR δ -1.99
5818 J. Org. Chem. Vol. 73, No. 15, 2008

Tailoring a Bacteriochlorin Building Block
(br s, 2H), 1.92 (s, 12H), 2.63 (s, 12H), 3.88 (s, 4H), 4.42 (s, 4H),
8.56 (s, 2H), 8.72 (s, 2H), 8.97 (s, 2H); LD-MS obsd 533.3; ESI-
MS obsd 267.1736, calcd 267.1729 [(M + 2H)2+, M ) C34H40N6];
chromatography [silica, hexanes/ethyl acetate (3:1)] to afford a green
solid (31.3 mg, 56%): H NMR δ -1.98 (s, 2H), -0.08 (s, 24H),
1
0.10 (s, 24H), 0.76 (s, 36H), 0.90 (s, 36H), 1.98 (s, 12H), 3.75 (br
s, 16H), 3.81 (br t, J ) 5.6 Hz, 8H), 3.98 (br t, J ) 5.6 Hz, 8H),
4.43 (s, 4H), 7.66 (s, 2H), 8.23 (s, 4H), 8.70 (s, 2H), 8.79 (s, 2H),
8.86 (s, 2H); 13C NMR δ -5.4, 18.2, 25.8, 31.0, 45.9, 48.2, 51.7,
52.4, 61.3, 96.7, 97.5, 121.2, 124.2, 130.2, 133.1, 134.0, 134.9,
137.3, 137.9, 158.8, 170.3, 171.4; LD-MS obsd 1962.1; ESI-MS
λabs (CH2Cl2) 348, 375, 505, 749 nm. The reaction under the copper-
free Sonogashira conditions49 gave a poor yield and multiple
products.
3,13-Bis(3-N,N-dimethylaminopropyl)-8,8,18,18-tetramethyl-
bacteriochlorin (BC-14). A mixture of BC-13 (5.5 mg, 0.010
mmol) and Pd/C (3.0 mg, 10% Pd on carbon, 0.0030 mmol) under
an inert atmosphere was treated with ethyl acetate and ethanol (1
mL each). The mixture was stirred at room temperature under a
H2 balloon for 20 h. The mixture was filtered through a pad of
Celite and rinsed with ethyl acetate and ethanol until the filtrate
was colorless. The filtrate was concentrated and chromatographed
[silica, CH2Cl2/MeOH/conc. NH4OH (94:5:1 f 92:7:1)] to obtain
a green solid (4.5 mg, 83%): 1H NMR δ -2.42 (br s, 2H), 1.94 (s,
12H), 2.34 (s, 12H), 2.44 (m, 4H), 2.62 (m, 4H), 3.87 (t, J ) 10
Hz, 4H), 4.45 (s, 4H), 8.52 (s, 2H), 8.60 (s, 2H), 8.79 (s, 2H);
LD-MS obsd 541.5; ESI-MS obsd 541.3997, calcd 541.4013 [(M
+ H)+, M ) C34H48N6]; λabs (CH2Cl2) 343, 369, 490, 720 nm.
3,13-Bis[3,5-bis(2-(tert-butyldimethylsilyloxy)ethoxy)phenyl]-
8,8,18,18-tetramethylbacteriochlorin (BC-15). A mixture of BC-
Br3Br13 (10. mg, 0.019 mmol), Pd(PPh3)4 (6.6 mg, 0.0057 mmol,
30 mol %), anhydrous K2CO3 (15.0 mg, 0.110 mmol), and 7 (31
mg, 0.057 mmol) was dried in a Schlenk flask for 15 min. Toluene
(4 mL) and DMF (2 mL) were added, and the mixture was degassed
by 2 “freeze-pump-thaw” cycles. The mixture was placed in a
preheated oil bath and heated overnight at 90 °C. After cooling to
room temperature, the suspension was filtered through Celite. The
filtrate was concentrated under vacuum. The resulting residue was
subjected to column chromatography [silica, hexanes/ethyl acetate
obsd 980.6088, calcd 980.6099 [(M
104H182N8O12Si8]; λabs (CH2Cl2) 355, 372, 499, 738 nm.
3,13-Bis[3,5-(bis(2-(acetoxy)ethyl)aminocarbonyl)phenyl]-
+
2H)2+
,
M
)
C
8,8,18,18-tetramethylbacteriochlorin (BC-18). A mixture of BC-
Br3Br13 (10. mg, 0.019 mmol), Pd(PPh3)4 (6.6 mg, 0.0057 mmol,
30 mol %), anhydrous K3PO4 (40.0 mg, 0.190 mmol), and 12 (36.0
mg, 0.0570 mmol) was dried in a Schlenk flask for 15 min. Toluene
(2 mL) and DMF (3 mL) were added, and the mixture was degassed
by 2 “freeze-pump-thaw” cycles. The mixture was placed in a
preheated oil bath and heated overnight at 90 °C. After cooling to
room temperature, the suspension was filtered over Celite. The
filtrate was concentrated under vacuum. The resulting residue was
subjected to column chromatography [silica, CH2Cl2/MeOH (97:
3)] to afford a green solid (13 mg, 49%): 1H NMR -1.93 (s, 2H),
1.86 (br s, 12H), 1.98 (s, 12H), 2.09 (br s, 12H), 3.83 (br s, 8H),
3.91 (br s, 8H), 4.23 (br s, 8H), 4.44 (s, 4H), 4.47 (br s, 8H), 7.66
(t, J ) 1.4 Hz, 2H), 8.25 (d, J ) 1.4 Hz, 4H), 8.73 (s, 2H), 8.84
(d, J ) 1.9 Hz, 2H), 8.88 (s, 2H); LD-MS obsd 1384.5; ESI-MS
obsd 1383.6022, calcd 1383.6031 [(M + H)+, M ) C72H86N8O20];
λabs (CH2Cl2) 356, 372, 500, 739 nm.
3,13-Bis(3,5-dicarboxyphenyl)-8,8,18,18-tetramethylbacterio-
chlorin (BC-19). A mixture of BC-Br3Br13 (10. mg, 0.019 mmol),
Pd(PPh3)4 (6.6 mg, 0.0060 mmol, 30 mol %), anhydrous K2CO3
(21 mg, 0.15 mmol), and 9 (16 mg, 0.076 mmol) was dried in a
Schlenk flask for 15 min. Ethanol (3 mL) and water (3 mL) were
added, and the mixture was degassed by 2 “freeze-pump-thaw”
cycles. The mixture was placed in a preheated oil bath and heated
overnight at 90 °C. After cooling to room temperature, ethanol was
removed under vacuum, and the resulting aqueous suspension was
filtered through Celite. The filtrate was concentrated under vacuum.
The resulting residue was subjected to reversed-phase column
chromatography [C-18 silica, water] to afford after freeze-drying
1
(7:3)] to afford a green solid (12.2 mg, 53%): H NMR δ -2.02
(s, 2H), 0.17 (s, 24H), 0.96 (s, 36H), 1.98 (s, 12H), 4.10 (t, J )
5.0 Hz, 8H), 4.26 (t, J ) 5.0 Hz, 8H), 4.43 (s, 4H), 6.74 (s, 2H),
7.34 (s, 4H), 8.71 (s, 2H), 8.78 (s, 2H), 8.97 (s, 2H); 13C NMR δ
-5.1, 18.5, 26.0, 31.0, 45.9, 51.7, 62.1, 69.6, 96.4, 97.6, 100.6,
110.1, 120.6, 133.2, 134.8, 135.6, 138.5, 158.4, 160.3, 170.0; LD-
MS obsd 1219.9; ESI-MS obsd 1219.7121, calcd 1219.7160 [(M
+ H)+, M ) C68H106N4O8Si4]; λabs (CH2Cl2) 349, 372, 498, 736
nm.
1
a green solid (6.2 mg, 47%): H NMR (CD3OD) δ 2.02 (s, 12H),
3,13-Bis[3,5-bis(methoxymethoxy)phenyl]-8,8,18,18-tetra-
methylbacteriochlorin (BC-16). A mixture of BC-Br3Br13 (20.
mg, 0.038 mmol), Pd(PPh3)4 (13.2 mg, 0.0114 mmol, 30 mol %),
anhydrous K2CO3 (31.0 mg, 0.228 mmol), and 8 (37.0 mg, 0.114
mmol) was dried in a Schlenk flask for 15 min. Toluene (4 mL)
and DMF (2 mL) were added, and the mixture was degassed by 2
“freeze-pump-thaw” cycles. The mixture was placed in a
preheated oil bath and heated overnight at 90 °C. After cooling to
room temperature, the suspension was filtered over Celite. The
filtrate was concentrated under vacuum. The resulting residue was
subjected to column chromatography [silica, hexanes/ethyl acetate
4.52 (s, 4H), 8.84 (s, 2H), 8.85 (s, 2H), 8.89 (d, J ) 1.6 Hz, 4H),
8.97 (s, 2H), 9.10 (s, 2H); 13C NMR (CD3OD) δ 31.4, 46.9, 52.6,
97.6, 98.7, 122.0, 130.4, 134.4, 134.5, 136.3, 136.9, 139.9, 160.1,
171.4, 175.4; ESI-MS obsd 698.2363, calcd 698.2371 (C40H34N4O8);
λabs (H2O) 347, 366, 500, 737 nm; λabs (methanol) 350, 368, 497,
734 nm.
3,13-Bis[3,5-bis(2-hydroxyethoxy)phenyl]-8,8,18,18-tetra-
methylbacteriochlorin (BC-20). Following a reported proce-
dure,67 a solution of BC-15 (12 mg, 0.0098 mmol) in anhydrous
THF (5 mL) was treated with molecular sieves 4 Å (20 mg) and
TBAF (118 µL, 1 M in THF, 0.110 mmol). After 30 min, the
suspension was diluted with ethyl acetate (10 mL) and poured into
saturated aqueous NH4Cl (10 mL). The aqueous layer was extracted
with ethyl acetate, and the organic extract was dried over Na2SO4
and concentrated under vacuum. The resulting residue was subjected
to column chromatography [silica, ethyl acetate/MeOH (98:2 to 96:
1
(7:3)] to afford a green solid (17.6 mg, 61%): H NMR δ -1.99
(s, 2H), 1.97 (s, 12H), 3.63 (s, 12H), 4.43 (s, 4H), 5.39 (s, 8H),
7.01 (s, 2H), 7.56 (s, 4H), 8.71 (s, 2H), 8.80 (s, 2H), 9.00 (s, 2H);
13C NMR δ 31.04, 45.9, 51.7, 56.2, 94.8, 96.5, 97.6, 103.7, 112.8,
120.6, 133.1, 134.8, 135.1, 138.7, 158.5, 158.6, 170.0; LD-MS obsd
763.7; ESI-MS obsd 762.3626, calcd 762.3623 (C44H50N4O8); λabs
(CH2Cl2) 350, 373, 499, 737 nm.
1
4)] to afford a green solid (4.0 mg, 53%): H NMR δ -2.00 (s,
2H), 1.98 (s, 12H), 2.15 (br s, 4H), 4.10 (br s, 8H), 4.32 (br t, J )
4.0 Hz, 8H), 4.45 (s, 4H), 6.78 (s, 2H), 7.32 (s, 4H), 8.71 (s, 2H),
8.78 (s, 2H), 8.95 (s, 2H); LD-MS obsd 762.8; ESI-MS obsd
762.3634, calcd 762.3623 (C44H50N4O8); λabs (CH2Cl2) 349, 372,
498, 736 nm.
3,13-Bis(3,5-dihydroxyphenyl)-8,8,18,18-tetramethylbacterio-
chlorin (BC-21). A sample of BC-16 (17.5 mg, 0.0229 mmol) was
treated with a solution of 10% HCl in MeOH (10 mL), and the
mixture was refluxed for 30 min. After the mixture was allowed to
cool to room temperature, the solution was neutralized by addition
of saturated aqueous NaHCO3. The resulting mixture was extracted
3,13-Bis[3,5-(bis(2-(tert-butyldimethylsilyloxy)ethyl)ami-
nocarbonyl)phenyl]-8,8,18,18-tetramethylbacteriochlorin (BC-
17). A mixture of BC-Br3Br13 (15.0 mg, 0.0285 mmol), Pd(PPh3)4
(10. mg, 0.0085 mmol, 30 mol %), anhydrous K2CO3 (24.0 mg,
0.171 mmol), and 13 (79.0 mg, 0.0855 mmol) was dried in a
Schlenk flask for 15 min. Toluene (4 mL) and DMF (2 mL) were
added,whereuponthemixturewasdegassedby2“freeze-pump-thaw”
cycles. The mixture was placed in a preheated oil bath and heated
overnight at 90 °C. After cooling to room temperature, the
suspension was filtered over Celite. The filtrate was concentrated
under vacuum. The resulting residue was subjected to column
J. Org. Chem. Vol. 73, No. 15, 2008 5819

Ruzié et al.
with ethyl acetate. The organic extract was washed with saturated
aqueous NaCl, dried over Na2SO4, and concentrated under vacuum.
The resulting residue was subjected to column chromatography
[silica, hexanes/ethyl acetate (1:9)] to afford a green solid (11.4
Attempted Deprotection of BC-18. A solution of BC-18 (9.0
mg, 0.0065 mmol) in MeOH (8 mL) and H2O (2 mL) was treated
with K2CO3 (14. mg, 0.10 mmol). The mixture was stirred overnight
at room temperature without any change, and then heated for 6 h
at 60 °C. After the solution was cooled to room temperature,
solvents were removed under vacuum. The resulting residue was
subjected to reversed-phase column chromatography [C-18 silica,
water] to afford after freeze-drying the unexpected product BC-19
(2.5 mg, 55%).
1
mg, 85%): H NMR (acetone-d6) δ -1.97 (s, 2H), 1.98 (s, 12H),
4.48 (s, 4H), 6.66 (s, 2H), 7.25 (s, 4H), 8.65 (br s, 4H), 8.90 (s,
2H), 8.92 (s, 2H), 9.02 (s, 2H); 13C NMR (acetone-d6) δ 31.2, 46.6,
52.2, 97.5, 98.4, 102.8, 110.5, 121.5, 133.9, 135.8, 136.8, 139.2,
159.3, 159.9, 170.9; LD-MS obsd 586.7; ESI-MS obsd 586.2579,
calcd 586.2574 (C36H34N4O4); λabs (CH2Cl2) 350, 373, 499, 737
nm.
Acknowledgment. This work was supported by a grant from
the NIH (GM36238) to J.S.L. and by a Burroughs-Wellcome
fellowship to M.K. T.B. was supported by a grant (R41AI072854)
from the National Institute of Allergy and Infectious Diseases
to NIRvana Pharmaceuticals, Inc. The content is solely the
responsibility of the authors and does not necessarily represent
the official views of the NIAID or the NIH. Mass spectra were
obtained at the Mass Spectrometry Laboratory for Biotechnology
at North Carolina State University. Partial funding for the facility
was obtained from the North Carolina Biotechnology Center
and the NSF.
3,13-Bis[3,5-bis(methoxycarbonylmethoxy)phenyl]-8,8,18,18-
tetramethylbacteriochlorin (BC-22). A solution of BC-21 (6.4
mg, 0.011 mmol) in anhydrous acetonitrile (5 mL) was treated with
anhydrous K2CO3 (9.0 mg, 0.065 mmol). After the solution was
stirred for 30 min at room temperature, methyl bromoacetate (6.2
µL, 0.065 mmol) was added, and the resulting mixture was refluxed
overnight. After the mixture was cooled to room temperature, water
was added and the resulting mixture was extracted with ethyl
acetate. The organic extract was washed (brine), dried (Na2SO4),
and concentrated under vacuum. The resulting residue was subjected
to column chromatography [silica, hexanes/ethyl acetate (1:9)] to
1
afford a green solid (6.2 mg, 65%): H NMR δ -2.00 (s, 2H),
Supporting Information Available: Experimental section
including characterization data for 11 bacteriochlorins prepared
by reductive amination or quaternization, and spectral data for
selected compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
1.98 (s, 12H), 3.89 (s, 12H), 4.44 (s, 4H), 4.85 (s, 8H), 6.76 (s,
2H), 7.37 (s, 4H), 8.71 (s, 2H), 8.76 (s, 2H), 8.92 (s, 2H); 13C
NMR δ 31.0, 45.9, 51.7, 52.5, 65.6, 96.6, 97.6, 101.0, 110.9, 120.7,
133.1, 134.8, 134.9, 139.0, 158.7, 159.2, 169.3, 170.2; LD-MS obsd
875.2; ESI-MS obsd 874.3410, calcd 874.3419 (C48H50N4O12); λabs
(CH2Cl2) 351, 372, 498, 737 nm.
JO800736C
5820 J. Org. Chem. Vol. 73, No. 15, 2008