Efficient silver-mediated acetalation of β,β′- functionalized chlorins

Article abstract of DOI:10.1055/s-2008-1078505

We present a novel synthetic strategy to 2,2-dialkoxy-3-oxochlorins [M = 2H, Ni(II), Cu(II)] (i.e., acetaloxochlorins). Reaction of the corresponding 2,3-dioxochlorin with stoichiometric amounts of silver triflate (AgOTf) in the presence of excess alcohol yields the desired acetaloxochlorins within several hours of reflux in up to 90% yield for n-alcohols, and in 25-89% yields for functionalized alcohol substrates. Similar reaction conditions applied to 2-diazo-3-oxochlorins generates the 2,2-dialkoxy-3-oxochlorins (12-60% yields) accompanied by alkoxyporphyrins (10-27% yields). Electronic spectroscopy reveals for the acetaloxochlorins characteristic π-π* absorption features throughout the visible region and their X-ray crystal structures exhibit marked distortion from planarity of the π-conjugated macrocycle due in part to the steric bulk at the periphery. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078505

1882
LETTER
Efficient Silver-Mediated Acetalation of b,b¢-Functionalized Chlorins
Efficient
S
ilver-
i
Media
l
te
d
A
ce
l
talation
m
of
b
,
b¢-Functional
a
izedChlori
n
ns n Köpke, Maren Pink, Jeffrey M. Zaleski*
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
Fax +1(812)8558300; E-mail: zaleski@indiana.edu
Received 3 February 2008
further examine the PQQ mechanism of action.15–19 Simi-
lar reactivity on the periphery of an aromatic tetrapyrrole
(e.g., chlorin) might consequently allow for selective ring
modification under mild conditions. The benefit of such a
Abstract: We present a novel synthetic strategy to 2,2-dialkoxy-3-
oxochlorins [M = 2H, Ni(II), Cu(II)] (i.e., acetaloxochlorins). Reac-
tion of the corresponding 2,3-dioxochlorin with stoichiometric
amounts of silver triflate (AgOTf) in the presence of excess alcohol
yields the desired acetaloxochlorins within several hours of reflux synthetic method is highlighted by the verity that porphy-
in up to 90% yield for n-alcohols, and in 25–89% yields for func-
tionalized alcohol substrates. Similar reaction conditions applied to
rinoids with peripheral acetal functionalities are rare and
have only been isolated thus far as by-products in low
2-diazo-3-oxochlorins generates the 2,2-dialkoxy-3-oxochlorins
yields (10–32%) during photolysis of diazo-oxochlo-
(12–60% yields) accompanied by alkoxyporphyrins (10–27%
rins,20,21 and by reacting very strong nucleophiles such as
yields). Electronic spectroscopy reveals for the acetaloxochlorins
sodium methoxide with nitroporphyrins.12
characteristic p–p* absorption features throughout the visible re-
gion and their X-ray crystal structures exhibit marked distortion
from planarity of the p-conjugated macrocycle due in part to the
steric bulk at the periphery.
Besides the acid- or metal-catalyzed condensation condi-
tions for the transformation of ketones to acetals, these
functional groups can be generated via Lewis acid in-
duced nitrogen extrusion from diazoketones.22–24 This
Key words: chlorin, silver triflate, acetal, pyrroloquinoline qui-
nine, PQQ
particular route finds application in accessing small or-
ganic frameworks such as 2,2-dihydroxy-1,3-indanedione
(ninhydrin),23 which has earned attention in forensic sci-
The facile electronic, spectroscopic, and chemical proper-
ties of aromatic tetrapyrroles make these frameworks at-
tractive for application in chemistry, biology, and
nanomaterials research.1–5 Specifically, the intense ab-
sorption bands of the chlorin backbone throughout the vis-
ible region, as well as the chemical versatility of the
conjugated macrocycle, have led to precisely modulated
tetrapyrroles such as confused porphyrins,6 porpholac-
tones,7 and b-pyrrole-modified constructs that expand
conjugation upon reaction.8–11 In this theme, synthetic
methods that provide opportunities for additional func-
tionalization of the porphyrinoid periphery, supramolecu-
lar design, or covalent attachment to biologically relevant
substrates would be advantageous.
ence due to its color-forming reaction with amino acids
and amines found in fingerprint residues. Consequently,
porphyrinoids with a ninhydrin-like dialkoxy functional-
ity at the periphery may hold potential for in situ labeling
reagents due to their distinctive electronic absorption and
emission properties.
In addition to enabling chemical modification on the mac-
rocycle periphery, convenient acetal installation may also
serve as a straightforward method to regulate the polarity
of the porphyrinoid. The importance of adjustable polarity
of weakly soluble constructs for applications that utilize
porphyrinoids has recently been illustrated in a report by
Weissleder and co-workers25 during their preparation of
porphyrin-based polymeric nanoparticles that eradicate
tumors in mouse models. Here, the porpholactol deriva-
tive was a superior photosensitizer to the parent porphyrin
as the increased polarity of the latter enhanced release of
compound from the nanoparticle delivery vehicle.
Due to their substitutional flexibility, incorporation of oxy
functionalities such as hydroxyl, ketone, or acetal moi-
eties at the porphyrinoid periphery allows access to these
sites for subsequent functionalization.12 Acetal formation
often utilizes weak nucleophiles and can proceed under
acid- or metal-catalyzed conditions (e.g., acetalation of
ketones).13 It is fascinating that nature provides parallel
reactivity in bacterial systems by means of the quinopro-
tein cofactor pyrroloquinoline quinine (PQQ) in the Lewis
acid catalyzed oxidative metabolism of alcohols,14 with
PQQ serving as the primary redox cofactor.14–16 Addition-
ally, the high chemical reactivity of the quinine unit of
PQQ toward nucleophilic substrates has drawn particular
attention and resulted in a number of model compounds to
To date, specifically modified chlorins are chemically ac-
cessible by modifications of natural products and chloro-
phylls or by total synthesis.26–29 Whatever the synthetic
route of choice, the stability of the products against forma-
tion of more stable porphyrins (e.g., via hydrolysis) is cru-
cial. As a result, in recent years several routes to such
locked chlorins have been developed,26,30 with an efficient
approach presented by Gryko and Galezowski.26 These
methods enhance the chemical stability of chlorins and
thereby help to fulfill a requirement for an optimal photo-
sensitizer.2
SYNLETT 2008, No. 12, pp 1882–1888
x
x
.x
x
.2
0
0
8
Toward the objective of selective modification of p-con-
jugated porphyrinoids our group established a novel syn-
Advanced online publication: 19.06.2008
DOI: 10.1055/s-2008-1078505; Art ID: S01308ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Silver-Mediated Acetalation of b,b¢-Functionalized Chlorins
1883
thesis to diazo-oxochlorins from dioxochlorins31 and
showed how both dioxochlorins32 and diazo-
oxochlorins21 can generate unique azeteoporphyrinoids
containing pyrrole-ring-contracted peripheries. General
synthetic advances in porphyrinoid periphery modifica-
tion as such may pave the way to synthetically tailor the
b-pyrrole position via established organic transforma-
tions. To this end, herein we report selective modification
of dioxochlorins (M1, Scheme 1) and diazo-oxochlorins
(M2, Scheme 2) by a convenient method utilizing Lewis
acidic silver triflate (AgOTf) to generate 2,2-dialkoxy-3-
oxochlorins. The significance of this porphyrinoid alter-
ation is also highlighted by the ability to regenerate the
porphyrinoid macrocycle, eliminating tedious and low-
yielding tetrapyrrole starting material synthesis.
Table 1 Reaction Conditions and Yields for Acetalation of M1
Entry M1 Substrate Time Product Yield
(h)
(%)
1
2
Cu1 n-propanol (a)
8
Cu3a
Cu3b
Cu3c
Cu3d
Cu3e
Cu3f
Ni3b
Ni3d
Ni3e
H3e
79
80
90
64
25
89
70
59
27
35
Cu1 n-butanol (b)
6
3
Cu1 n-pentanol (c)
4
4
Cu1 2-methoxyethanol (d)
Cu1 2-chloroethanol (e)
Cu1 2-methylpropanol (f)
5
5
4
6
5
7
Ni1
Ni1
Ni1
H1
n-butanol (b)
4
8
2-methoxyethanol (d)
2-chloroethanol (e)
2-chloroethanol (e)
5
Reaction of 2,3-dioxochlorins M1 in the presence of one
equivalent of AgOTf and primary alcohols a–f in p-di-
oxane resulted in the formation of 2,2-dialkoxy-3-
oxochlorins33,34 as illustrated in Scheme 1 (Table 1). The
reaction yields demonstrated a dependence of this trans-
formation on the nature of the alcohol. While the presence
of electron-withdrawing group (EWG) functionalities
(i.e., OMe, Cl) decreased the efficiency of the reaction
(entries 4, 5, 8–10, Table 1), substrates devoid of EWG
fragments resulted in excellent yields, directly reflecting
competitive polarization of the nucleophile. This state-
ment was further supported by the yield obtained for 2-
methylpropanol (substrate f, entry 6, Table 1), which gave
Cu3f in 89% yield, while n-propanol (substrate a) formed
Cu3a in 79% yield (entry 1, Table 1). Consequently, the
additional methyl group enhances the efficiency for aceta-
lation due to an increased inductive effect rather then di-
minishing product formation due to greater steric bulk.
9
3
10
3
polarity by periphery substitution. While n-pentanol (sub-
strate c) resulted in formation of the least polar dialkoxy-
oxochlorins and hence was eluted on silica gel using
hexanes–CH2Cl2 (8:1), 2-methoxyethanol (substrate d)
generated a fairly polar analogue, requiring addition of
10% EtOAc to CH2Cl2 for its isolation.
Motivated by the method for ninhydrin derivatization, we
postulated that acetal-functionalized porphyrinoids (e.g.,
M3) could also be generated by such a route utilizing dia-
zo-oxochlorins (M2). Indeed, reaction of diazo-oxochlor-
in Cu2 with n-butanol in the presence of one equivalent of
Ag(OTf) resulted in the formation of the desired 2,2-di-
butoxy-3-oxochlorin Cu3b.34,35 However, the isolated
yield for Cu3b was low (34%), and the reaction produced
an additional product in 27% yield, which was identified
as 2-butoxy-5,10,15,20-tetraphenylporphyrin Cu4b
(Scheme 2).34,35 These observations are in contrast to that
Although the yields varied widely (70–90% for a–c vs.
25–35% for e), the reactivity illustrates the applicability
of this synthetic methodology for influencing compound
a R =
Ph
Ph
Ph
R
Ph
Ph
Ph
Ph
1 equiv AgOTf
b R =
c R =
d R =
e R =
f R =
N
M
N
N
M
N
HOR
p-dioxane
O
O
O
O
R
N
N
N
N
– H2O
O
O
Ph
Cl
M3a
–f
M1
Scheme 1 Synthesis of 2,2-dialkoxy-3-oxochlorins from 2,3-dioxochlorins by Ag(I)-mediated acetalation
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bu
N
M
N
N
M
N
N
M
N
O
1 equiv AgOTf
p-dioxane
N2
O
Bu
OBu
O
+
N
N
N
N
N
N
excess
O
(b)
HO
Ph
Ph
Ph
Cu2
Ni2
Cu3b 34%
Ni3b 60%
Cu4b 27%
Ni4b 19%
Scheme 2 Ag(I)-mediated diazo-oxochlorin conversion to the 2,2-dibutoxy-3-oxochlorin and 2-butoxyporphyrin products
Synlett 2008, No. 12, 1882–1888 © Thieme Stuttgart · New York

1884
T. Köpke et al.
LETTER
for the formation of Cu3b from dioxochlorin Cu1, which chromatography.40 This reaction profile represents a syn-
did not yield any Cu4b as a by-product. Comparable re- thetic strategy toward periphery modification of porphy-
sults were obtained when Ni2 reacted with n-butanol un- rinoids that does not require buildup of a novel
der similar conditions to yield chlorin Ni3b in 60% yield macrocyclic precursor, while providing convenient and
and porphyrin Ni4b in 19% yield.34 Mechanistically, selective access to 2,3-dioxochlorins. Since all molecular
while formation of M3 from dioxochlorins13 M1 and di- products M1–M3 are stable against dehydrogenation to
azo-oxochlorins22–24 M2 reflects the established literature form the corresponding porphyrins, these compounds also
reports, isolation of M4b by the latter route suggests that represent novel locked chlorins which are similar to the
product formation involves a major competing pathway. examples reported by Crossley et al.12
Isolation of alkoxyporphyrins M4 suggests that the Ag(I)
cation is involved in a redox event that translates into tau-
tomerization to yield hydroxyporphyrins (e.g., 2-hy-
Combining the previous synthetic work established by our
group (i.e., synthesis of M2 from M1) with the results ob-
tained for the AgOTf-assisted acetalation of diazo-
droxy-5,10,15,20-tetraphenylporphyrin, CuOH) which
oxochlorins (M2) and the possibility of subsequent acetal
subsequently undergo condensation reactions with appro-
deprotection, the cumulative synthetic approach may be
priate alcohol substrates. A proposed mechanism for con-
considered within the framework of macrocycle recycling
(Scheme 4). The broad interest in synthetic routes that in-
clude fewer chemical steps, combined with the generally
low yields of commonly applied multistep macrocycle
formation reactions emphasize the advantages of such
chlorin recycling.
version of Cu2 is illustrated in Scheme 3. Here, an
electron-deficient carbene intermediate (Cu2¢) oxidizes
the substrate alcohol by H-atom abstraction to form a ke-
tochlorin (Cu-keto), which ultimately tautomerizes to its
corresponding enol (Cu-enol),36,37 the hydroxyporphyrin
CuOH. To support this hypothesis, the proposed Cu-enol
species, the readily available hydroxyporphyrin CuOH
was reacted with one equivalent of AgOTf and n-butanol
Beyond synthetic methodology, the X-ray crystal struc-
tures of periphery-modified porphyrinoids often possess
distortions from planarity that can derive from both the
(substrate b) in p-dioxane under reflux for 20 hours. The
size of the central cation, as well as the steric bulk associ-
reaction produced Cu4b in 37% isolated yield.38 Hence,
ated with periphery modification.41 The presence of
the acetalation of diazo-oxochlorins occurs via a Ag(I)-
Cu(II), for example, gently distorts porphyrinoids from
mediated carbene intermediate that competes with a redox
planarity, while their free-base analogues usually possess
process involving substrate oxidation.
smaller out-of-plane deformations.31 In contrast, the X-
ray crystal structures42 of Cu1, H3e, Cu3a, and Cu3d in
R
OH
Figure 1 exhibit comparable distortions for each macrocy-
cle independent of central metal, suggesting that the acetal
fragment strongly influences the macrocycle planarity.
Such effects upon chlorin acetalation may structurally in-
fluence periphery interactions in abiological applica-
tions.43
H
H
N
N
O
O
R
O
Cu2'
Cu-keto
Crystallographically, the X-ray crystal structure of Cu3a
is noncentrosymmetric and contains two independent
molecules in the asymmetric unit. Cu3d was found to
have 0.25 methanol molecules per formula unit. All ace-
taloxochlorins possess a C=O bond that ranges between
1.20–1.21 Å while the acetal C–O bonds that connect the
substituents onto the macrocycle range between 1.35–
1.45 Å. For Cu1, the C=O bond lengths are with 1.300 Å
(C2–O2) and 1.265 Å (C3–O3) noticeably longer, indicat-
ing conjugation of the carbonyl functionalities with the p-
system of the macrocycle. These values, however, are not
surprising considering the previously published C=O
H
H
Ag+ / ROH
– H2O
N
N
OR
OH
Cu4
Cu-enol
(CuOH)
Scheme 3 Carbene-derived keto-enol tautomerization resulted in
formation of CuOH and subsequent condensation to yield Cu4
One of the synthetic advantages of acetal fragments in or- bond lengths for Ni1 by Brückner et al.,44 who reported
ganic synthesis is their ability to function as protecting values of 1.230(9) Å and 1.250(9) Å for the nickel-con-
groups for carbonyls.39 Acetals can straightforwardly be taining 2,3-dioxochlorin analogue.
removed by reaction with an aqueous acid to regenerate
It is well understood that periphery modifications can also
the original carbonyl functionality. Therefore, it is not sur-
affect the electronic properties of tetrapyrrole chro-
prising that similar reactivity can be achieved for the ace-
taloxochlorins M3 as well. Utilizing a modified literature
procedure,20 heating of Cu3b for two hours at 70 °C in a
solution of p-dioxane–n-butanol (1:4) in the presence of
aqueous HCl (10%) resulted in isolation of dioxochlorin
Cu1 in 70% yield after purification by silica gel column
mophores.41,45,46 For example, Kadish and co-workers47
demonstrated systematic red-shift in lmax of all absorption
features upon increasing the number of bromines installed
at the b-pyrrole positions of zinc porphyrins. Although not
as pronounced, similar effects were observed for the 2,2-
Synlett 2008, No. 12, 1882–1888 © Thieme Stuttgart · New York

LETTER
Efficient Silver-Mediated Acetalation of b,b¢-Functionalized Chlorins
1885
Ph
Ph
N
M
N
N2
O
N
N
Ph
Ph
M2
i
ii
64–73%
34–60%
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R
N
M
N
N
M
N
O
O
O
R
O
iii
70%
N
N
N
N
O
Ph
M1
M3
Scheme 4 Chlorin derivatization and macrocycle recycling. Reagents and conditions: (i) TsNHNH2, Zn(OAc)2·2H2O⋅MeOH⋅CH2Cl2; (ii)
AgOTf, ROH, p-dioxane; (iii) aq HCl (10%).
dialkoxy-3-oxochlorins. As the absorption spectra of parison to their copper analogues, the porphyrinoid
Cu3b, Cu3d, and Cu3e in Figure 1 illustrate, for the pre- containing substrate e (i.e, Ni3e) showed the furthest red-
sented acetaloxochlorins introduction of peripheral shifted electronic feature. The Soret absorption band of
EWGs caused measurable red-shifts for the overall ab- Ni3e (lmax = 438 nm) was also bathochromically shifted
sorption profile (Figure 2). The Soret absorption band of in comparison to that for Ni3d (lmax = 436 nm) and Ni3b
Cu3e (lmax = 435 nm) was slightly red-shifted in compar- (lmax = 435 nm). The lowest energy Q-band features fol-
ison to that for Cu3d (lmax = 433 nm) and Cu3b (lmax
=
lowed this trend and appeared at lmax = 632 nm for Ni3b,
max = 634 nm for Ni3d, and lmax = 637 nm for Ni3e, re-
432 nm). For the Q-bands, while the lowest energy feature
l
of Cu3b appeared at lmax = 630 nm, the presence of the spectively.
methoxy functionality (Cu3d) within the alkoxy chain
In summary, herein we describe a novel synthetic ap-
caused this absorption features to shift bathochromically
to lmax = 632 nm. If the methoxy functionality was ex-
changed for chloride (i.e., Cu3e) the Q-band further shift-
ed to lmax = 635 nm, thereby mirroring the results reported
by Kadish, even though for Cu3d and Cu3e the EWGs
were not in direct contact with the b-pyrrole carbons. The
same trend was observed within the series of Ni3b, Ni3d,
and Ni3e (spectra not shown). While the individual ab-
sorption profiles were red-shifted by ca. 2–3 nm in com-
proach to transform both oxochlorins and diazo-oxochlo-
rins into peripheral acetal functionalized analogues.
Acetal functionalization allows for fine-tuning of the
chemical reactivity, solubility, polarity, and electronic ab-
sorption features. Since the synthetic transformation of
chlorins with diverse substituents often requires multistep
syntheses and suffers from reactions that regenerate por-
phyrin, dialkoxyoxochlorins may prove fruitful in the fu-
ture as building blocks for the development of model
Figure 1 Front and lateral views for the molecular structures of Cul, H3e, Cu3a, and Cu3d; H atoms are omitted for clarity and thermal
ellipsoide are illustrated at 50% probability
Synlett 2008, No. 12, 1882–1888 © Thieme Stuttgart · New York

1886
T. Köpke et al.
LETTER
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Figure 2 Electronic absorption spectra for dialkoxyoxochlorins
Cu3b, Cu3d, and Cu3e, with the Q-band region enlarged in the inset
heme analogues. Furthermore, the stability of these chlo-
rins to oxidative porphyrin formation under acidic condi-
tions stabilizes these compounds at the chlorin redox
level. Beyond the reactivity advantages, the ability to in-
corporate these constructs in a synthetic cycle with
oxochlorins and diazo-oxochlorins demonstrates the po-
tential for future chlorin periphery modifications without
the need for individual macrocycle framework assembly.
Installation of electron-withdrawing groups onto the ace-
tal moiety causes bathochromic shifts in the electronic
spectra of these compounds, especially for the low-energy
features (i.e., Q-bands). Finally, solid-state X-ray crystal
structure characterization reveals nonplanar distortions
for all 2,2-dialkoxy-3-oxochlorins with the structure of
H3e showing an unusual saddled conformation relative to
that generally observed for free-base porphyrinoids.10,31,48
(22) Bachmann, S.; Fielenbach, D.; Jorgensen, K. A. Org.
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Acknowledgment
(31) Köpke, T.; Pink, M.; Zaleski, J. M. Synlett 2006, 2183.
(32) Köpke, T.; Pink, M.; Zaleski, J. M. Chem. Commun. 2006,
4940.
The support of Indiana University and the Argonne National Labo-
ratory are gratefully acknowledged. ChemMatCARS Sector 15 is
principally supported by the National Science Foundation/Depart-
ment of Energy under grant number CHE-0535644. Use of the Ad-
vanced Photon Source was supported by the U. S. Department of
Energy, Office of Science, Office of Basic Energy Sciences, under
Contract No. DE-AC02-06CH11357.
(33) General Procedure for Isolation of M3 Derivatives from
M1: To a solution of dioxochlorin M1 (0.015 mmol) in
CH2Cl2–alcohol (1:1.5, 5 mL, a–f respectively), silver
triflate (1 equiv) was added and the resulting mixture was
stirred under reflux for several hours (Table 1). After
completion of the reaction the mixture was cooled to r.t. and
poured into H2O (35 mL). The obtained porphyrinoids were
extracted using EtOAc (3 × 10 mL) and the combined
organic layers were concentrated under reduced pressure.
The crude compounds were purified by silica gel column
chromatography using solvent gradients of hexanes, CH2Cl2,
and EtOAc.
(34) Product Characterization Data: Cu3a: MALDI (TOF):
m/z (isotope pattern) = 807.2 [M]. HRMS (ESI): m/z [M +
Na+] calcd for C50H40N4O3CuNa: 830.2294; found:
830.2267. UV–Vis (CH2Cl2):lmax = 346, 383, 432, 592, 630
nm. IR: 2961, 2924, 1734, 1599, 1539, 1489, 1441, 1384,
1344, 1319, 1225, 1153, 1086, 1073, 1029, 1009, 995, 791,
752, 700, 502 cm–1.
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(6) Pawlicki, M.; Latos-Grazynski, L. J. Org. Chem. 2005, 70,
9123.
(7) Crossley, M. J.; King, L. G. J. Chem. Soc., Chem. Commun.
1984, 920.
Cu3b: MALDI (TOF): m/z (isotope pattern) = 835.4 [M].
HRMS (CI): m/z [M+] calcd for C52H44N4O3Cu: 835.2704;
Synlett 2008, No. 12, 1882–1888 © Thieme Stuttgart · New York

LETTER
Efficient Silver-Mediated Acetalation of b,b¢-Functionalized Chlorins
1887
found: 835.2710. UV–Vis (CH2Cl2): lmax = 346, 383, 432,
HRMS (CI): m/z calcd for C48H36N4OCu: 747.2180; found:
747.2168. UV–Vis (CH2Cl2): lmax = 417, 537, 578 nm. IR:
2955, 2920, 2851, 1586, 1556, 1537, 1516, 1489, 1440,
1384, 1334, 1302, 1240, 1178, 1155, 1070, 1046, 1036,
1005, 994, 796, 783, 759, 715, 703, 502 cm–1.
Ni4b: MALDI (TOF): m/z (isotope pattern) = 742.3 [M].
HRMS (CI): m/z [M+] calcd for C48H36N4ONi: 742.2237;
found: 742.2217. UV–Vis (400 MHz, CH2Cl2): lmax = 413,
530, 570 nm. 1H NMR (400 MHz, CD2Cl2): d = 8.60–8.70
(m, 6 H, b-pyrrolic H), 7.95–8.00 [m, 5 H, (1 H, b-pyrrolic
H, 4 H, meso-ArH)], 7.57–7.81 (m, 16 H, meso-ArH), 4.11–
4.14 (t, J = 6.0, 6.0 Hz, 2 H, OCH2R), 1.42–1.45 (m, 2 H,
OCH2CH2R), 1.16–1.23 (m, 2 H, OCH2CH2CH2R), 0.85–
0.89 (t, J = 7.2, 7.2 Hz, 3 H, OCH2CH2CH2CH3). IR: 2954,
2922, 2854, 1588, 1525, 1491, 1455, 1440, 1382, 1350,
1322, 1243, 1212, 1180, 1154, 1070, 1007, 970, 837, 790,
752, 715, 700, 555, 503 cm–1.
592, 630 nm. IR: 2960, 2922, 1734, 1599, 1540, 1508, 1489,
1441, 1318, 1233, 1225, 1152, 1091, 1074, 1040, 1009, 995,
890, 833, 791, 752, 710, 700, 502 cm–1.
Cu3c: MALDI (TOF): m/z (isotope pattern) = 863.4 [M].
HRMS (ESI): m/z [M + Na+] calcd for C54H48N4O3CuNa:
886.2920; found: 886.2905. UV–Vis (CH2Cl2): lmax = 346,
383, 432, 592, 630 nm. IR: 2960, 2928, 2856, 1734, 1599,
1557, 1539, 1508, 1489, 1459, 1441, 1430, 1344, 1319,
1269, 1232, 1150, 1093, 1074, 1026, 1009, 995, 880, 833,
793, 756, 718, 700, 502 cm–1.
Cu3d: MALDI (TOF): m/z (isotope pattern) = 839.5 [M].
HRMS (CI): m/z [M+] calcd for C50H40N4O5Cu: 839.2289;
found: 839.2286. UV–Vis (CH2Cl2): lmax = 347, 388, 435,
595, 635 nm. IR: 2924, 1733, 1598, 1539, 1501, 1489, 1440,
1343, 1318, 1231, 1197, 1151, 1127, 1094, 1072, 1029,
1009, 994, 883, 833, 790, 758, 710, 717, 700, 670, 553, 504
cm–1.
Cu3e: MALDI (TOF): m/z (isotope pattern) = 849.3 [M +
H+]. HRMS (ESI): m/z [M+] calcd for C48H34N4O3Cl2Cu:
848.1377; found: 848.1395. UV–Vis (CH2Cl2): lmax = 347,
388, 435, 595, 635 nm. IR: 2954, 2920, 2851, 1733, 1635,
1598, 1456, 1440, 1384, 1344, 1269, 1230, 1147, 1096,
1070, 1009, 832, 794, 759, 715, 701, 502 cm–1.
Cu3f: MALDI (TOF): m/z (isotope pattern) = 835.2 [M].
HRMS (CI): m/z [M+] calcd for C52H44N4O3Cu: 835.2704;
found: 835.2722. UV–Vis (CH2Cl2): lmax = 346, 383, 432,
592, 630 nm. IR: 2957, 2920, 2870, 1734, 1599, 1541, 1489,
1468, 1365, 1344, 1318, 1232, 1151, 1088, 1073, 1042,
1009, 997, 833, 791, 751, 734, 700, 502 cm–1.
Ni3b: MALDI (TOF): m/z (isotope pattern) = 830.4 [M].
HRMS (EI): m/z [M+] calcd for C52H44N4O3Ni: 830.2761;
found: 830.2735. UV–Vis (CH2Cl2): lmax = 344, 386, 435,
596, 632 nm. 1H NMR (400 MHz, CD2Cl2): d = 8.24–8.30
(m, 3 H, b-pyrrolic H), 8.16 (s, 2 H, b-pyrrolic H), 7.90–7.91
(d, J = 4.0 Hz, 1 H, b-pyrrolic H), 7.72–7.77 (m, 4 H, meso-
ArH), 7.34–7.62 (m, 16 H, meso-ArH), 3.35–3.50 (m, 4 H,
OCH2R), 1.20–1.35 (m, 4 H, OCH2CH2R), 1.04–1.16 (m, 4
H, OCH2CH2CH2R), 0.68–0.71 (t, J = 7.2, 7.6 Hz, 6 H,
OCH2CH2CH2CH3). IR: 2954, 2925, 2868, 1734, 1599,
1552, 1490, 1441, 1365, 1349, 1325, 1177, 1152, 1089,
1070, 1010, 892, 843, 834, 793, 751, 715, 700, 503 cm–1.
Ni3d: MALDI (TOF): m/z (isotope pattern) = 834.5 [M].
HRMS (CI): m/z [M+] calcd for C50H40N4O5Ni: 834.2347;
found: 834.2344. UV–Vis (CH2Cl2): lmax = 345, 388, 436,
597, 634 nm. 1H NMR (400 MHz, CD2Cl2): d = 8.34–8.40
(m, 3 H, b-pyrrolic H), 8.26 (s, 2 H, b-pyrrolic H), 8.00–8.02
(d, J = 4.8 Hz, 1 H, b-pyrrolic H), 7.84–7.86 (m, 4 H, meso-
ArH), 7.23–7.47 (m, 16 H, meso-ArH), 3.60–3.75 (m, 4 H,
OCH2CH2OCH3), 3.33–3.34 (t, J = 4.8, 4.8 Hz, 4 H,
OCH2CH2OCH3), 3.16 (s, 6 H, OCH2CH2OCH3). IR: 2950,
2922, 2868, 1733, 1599, 1553, 1490, 1441, 1349, 1325,
1232, 1199, 1152, 1129, 1071, 1007, 888, 843, 793, 751,
715, 700, 502 cm–1.
Ni3e: MALDI (TOF): m/z (isotope pattern) = 842.5 [M].
HRMS (CI): m/z [M+] calcd for C48H34N4O3Cl2Ni:
842.1356; found: 842.1347. UV–Vis (CH2Cl2): lmax = 347,
388, 438, 598, 637 nm. 1H NMR (400 MHz, CD2Cl2): d =
8.34–8.39 (m, 3 H, b-pyrrolic H), 8.26–8.27 (m, 2 H, b-
pyrrolic H), 8.06–8.07 (d, J = 4.0 Hz, 1 H, b-pyrrolic H),
7.83–7.88 (m, 4 H, meso-ArH), 7.31–7.32 (m, 2 H, meso-
ArH), 7.48–7.66 (m, 14 H, meso-ArH), 3.80–3.85 (m, 4 H,
alkoxy-OCH2R), 3.40–3.45 (m, 4 H, alkoxy-OCH2CH2Cl).
IR: 2954, 2922, 2854, 1732, 1599, 1557, 1441, 1384, 1349,
1233, 1210, 1153, 1099, 1071, 1013, 793, 751, 716, 701,
555, 503 cm–1.
H3e: MALDI (TOF): m/z (isotope pattern) = 787.5 [M+].
HRMS (CI): m/z [M+] calcd for C48H36N4O3Cl2: 786.2184;
found: 786.2159. 1H NMR (400 MHz, CD2Cl2): d = 8.70–
8.71 (d, J = 4.0 Hz, 2 H, b-pyrrolic H), 8.42–8.58 (m, 4 H, b-
pyrrolic H), 8.00–8.16 (m, 6 H, b-pyrrolic H), 7.88–7.94 (m,
2 H, meso-ArH), 7.56–7.80 (m, 12 H, meso-ArH), 3.88–3.96
(m, 2 H, alkoxy-OCH2R), 3.68–3.76 (m, 2 H, alkoxy-
OCH2R), 3.40–3.50 (m, 4 H, alkoxy-OCH2CH2Cl), –1.97
(s, 1 H, pyrrolic NH), –2.16 (s, 1 H, pyrrolic NH).
(35) General Procedure for Isolation of M3b and M4b
Derivatives from M2: Diazo-oxochlorin M2 (0.015 mmol)
was dissolved in p-dioxane (2 mL) and n-butanol (b; 8 mL),
followed by the addition of silver triflate (1 equiv). The
resulting mixture was stirred under reflux for 20 h which
resulted in the formation of two new species. After
consumption of all starting material the reaction mixture was
cooled to r.t. The solution was poured into H2O (35 mL) and
the porphyrinoid products were extracted with EtOAc (3 ×
10 mL). The solvent of the combined organic layers was
evaporated under reduced pressure and the crude
compounds were purified by silica gel column
chromatography using the eluent hexanes–CH2Cl2 (3:1).
(36) Crossley, M. J.; Field, L. D.; Harding, M. M.; Sternhell, S.
J. Am. Chem. Soc. 1987, 109, 2335.
(37) Crossley, M. J.; Harding, M. M.; Sternhell, S. J. Org. Chem.
1988, 53, 1132.
(38) Isolation of Cu4b from CuOH: [2-Hydroxy-5,10,15,20-
tetraphenylporphyrinato]Cu(II) (CuOH, 0.0145 mmol) was
dissolved in p-dioxane (2 mL) and reacted with AgOTf (1
equiv) and n-butanol (b, 8 mL) under reflux for 20 h. The
resulting mixture was cooled to r.t. and poured into H2O (35
mL). Extraction with EtOAc (3 × 10 mL), subsequent
concentration and silica gel column chromatography
purification gave Cu4b in 37% yield.
(39) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991.
(40) Hydrolysis of 2,2-Alkoxy-3-oxochlorin Cu3b to Yield
Cu1: Heating of a solution of Cu3b (0.006 mmol) in p-
dioxane–n-butanol (1:4) for 2 h at 70 °C in the presence of
aq HCl (10%, 3 mL) resulted in the formation of
dioxochlorin Cu1. The reaction mixture was cooled to r.t.,
poured into H2O (25 mL), and the green compound was
extracted with EtOAc (3 × 10 mL). Cu1 was purified by
silica gel column chromatography and isolated in 70% yield.
(41) Haddad, R. E.; Gazeau, S.; Pecaut, J.; Marchon, J.-C.;
Medforth, C. J.; Shelnutt, J. A. J. Am. Chem. Soc. 2003, 125,
1253.
(42) Crystals suitable for X-ray diffraction studies were obtained
from slow diffusion of methanol into a CH2Cl2 solution.
Crystallographic data (excluding structure factors) for the
Cu4b: MALDI (TOF): m/z (isotope pattern) = 747.3 [M].
Synlett 2008, No. 12, 1882–1888 © Thieme Stuttgart · New York

1888
T. Köpke et al.
LETTER
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication data CCDC 668819 (Cu1), and CCDC 676199
(Cu3a), CCDC 676200 (Cu3d), CCDC 676201 (H3e).
Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44 (1223)336033; e-mail:
V = 7794 (6) Å3, T = 120 (2) K, space group Pna21, Z = 8,
r
49595. A total of 68079 reflections were measured, of which
19029 (Rint = 0.039) were unique. Final residuals were R1 =
0.0439 and wR2 = 0.1191 [for 17428 observed reflections
with I > 2s(I), 1058 parameters] with GOF 1.165 and largest
residual peak 0.615 eÅ–3 and hole –0.985 eÅ–3.
calcd = 1.378 Mgm–3, m = 0.329 mm–1, 2qmax = 39°, l = 0.
deposit@ccdc.cam.ac.uk].
Crystal data for Cu3d: black, 0.10 × 0.01 × 0.005 mm,
C50.25H41N4O5.25Cu, M = 848.41, monoclinic, a = 35.9629
(12) Å, b = 9.0840 (4) Å, c = 24.6129 (7) Å, a = 90°, b =
99.771 (2)°, g = 90°, V = 7924.1 (5) Å3, T = 120 (2) K, space
group C2/c, Z = 8, rcalcd = 1.422 Mgm–3, m = 0.328 mm–1,
2qmax = 39°, l = 0. 49595. A total of 35420 reflections were
measured, of which 9407 (Rint = 0.0759) were unique. Final
residuals were R1 = 0.0439 and wR2 = 0.1191 [for 7865
observed reflections with I > 2s(I), 553 parameters] with
GOF 1.064 and largest residual peak 0.755 eÅ–3 and hole
–1.432 eÅ–3.
Crystal data for Cu1: red, 0.18 × 0.18 × 0.12 mm,
C44H26N4O2Cu, M = 706.23, tetragonal, a = 15.231 (5) Å, b
= 15.231 (5) Å, c = 13.452 (7) Å, a = b = g = 90°, V = 3121
(2) Å3, T = 120 (2) K, space group I42d, Z = 4, rcalcd = 1.503
Mgm–3, m = 0.749 mm–1, 2qmax = 53°, Mo–Ka (l = 0.71073).
A total of 12518 reflections were measured, of which 1609
(Rint = 0.0722) were unique. Final residuals were R1 =
0.0312 and wR2 = 0.0756 [for 1480 observed reflections
with I > 2s(I), 129 parameters] with GOF 1.088 and largest
residual peak 0.224 eÅ–3 and hole –0.262 eÅ–3. Crystal data
for H3e: black plate, 0.10 × 0.05 × 0.005 mm,
(43) Eller, L. R.; Stepien, M.; Fowler, C. J.; Lee, J. T.; Sessler, J.
L.; Moyer, B. A. J. Am. Chem. Soc. 2007, 129, 11020.
(44) Daniell, H. W.; Williams, S. C.; Jenkins, H. A.; Bruckner, C.
Tetrahedron Lett. 2003, 44, 4045.
(45) Brückner, C.; McCarthy, J. R.; Daniell, H. W.; Pendon, Z.
D.; Ilagan, R. P.; Francis, T. M.; Ren, L.; Birge, R. R.; Frank,
H. A. Chem. Phys. 2003, 294, 285.
(46) Gouterman, M. The Porphyrins, Vol. III; Academic Press,
Inc: New York, 1978, 1–165.
(47) D’Souza, F.; Zandler, M. E.; Tagliatesta, P.; Ou, Z.; Shao, J.;
Van Caemelbecke, E.; Kadish, K. M. Inorg. Chem. 1998, 37,
4567.
C48.50H37N4O3Cl3, M = 656.72, triclinic, a = 12.5326 (11) Å,
b = 13.6716 (8) Å, c = 24.8275 (13) Å, a = 88.026 (2)°, b =
82.395 (3)°, g = 70.255 (3)°, V = 3968.4 (5) Å3, T = 100 (2)
K, space group P1, Z = 4, rcalcd = 1.390 Mgm–3, m = 0.152
mm–1, 2qmax = 39°, l = 0.49595. A total of 53708 reflections
were measured, of which 18775 (Rint = 0.0654) were unique.
Final residuals were R1 = 0.1176 and wR2 = 0.3112 [for
11771 observed reflections with I > 2s(I), 1061 parameters]
with GOF 1.033 and largest residual peak 1.907 eÅ–3 and
hole –1.486 eÅ–3.
Crystal data for Cu3a: black, 0.10 × 0.02 × 0.01 mm,
C50H40N4O3Cu, M = 808.40, orthorhombic, a = 24.4909 (14)
Å, b = 9.1896 (4) Å, c = 34.6315 (15) Å, a = b = g = 90°,
(48) Chandra, T.; Kraft, B. J.; Huffman, J. C.; Zaleski, J. M.
Inorg. Chem. 2003, 42, 5158.
Synlett 2008, No. 12, 1882–1888 © Thieme Stuttgart · New York

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