Synthesis of tailored hydrodipyrrins and their examination in directed routes to bacteriochlorins and tetradehydrocorrins

Article abstract of DOI:10.1039/c7nj01892d

The chemistry of reduced tetrapyrroles is less developed than that of the fully unsaturated (porphyrin) analogues, yet is of comparable importance given the natural roles of hydroporphyrins (e.g., chlorophylls, bacteriochlorophylls) and contracted hydropo

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Synthesis of tailored hydrodipyrrins and their
examination in directed routes to bacteriochlorins
Cite this:DOI: 10.1039/c7nj01892d
and tetradehydrocorrins†
ab
Shaofei Zhang,a Muthyala Nagarjuna Reddy,a Olga Mass,a Han-Je Kim,
a
Gongfang Hua and Jonathan S. Lindsey
*
The chemistry of reduced tetrapyrroles is less developed than that of the fully unsaturated (porphyrin)
analogues, yet is of comparable importance given the natural roles of hydroporphyrins (e.g., chlorophylls,
bacteriochlorophylls) and contracted hydroporphyrins (cobalamin). The self-condensation of a 1-(dimethoxy-
methyl)-2,3-dihydro-3,3-dimethyldipyrrin (termed
a dihydrodipyrrin-acetal) affords the corresponding
bacteriochlorin or tetradehydrocorrin with the outcome potentially controllable by choice of the catalysis
conditions. The ability to install distinct patterns of substituents about the perimeter of the synthetic
macrocycles is essential for biomimetic studies. Here, 18 new target (and 9 intermediate) hydrodipyrrins
encompassing a range of dipyrrin saturation levels (dihydro, tetrahydro, hexahydro) and equipped with
diverse a-pyrrole (-H, -SMe, -SPh, -Br, -Me, -CO2R, dioxaborolanyl) and a-pyrroline (methyl, formyl,
dimethoxymethyl, oxo, methoxy, methylthio, iminomethyl, ethoxycarbonylvinyl, dicyanovinyl) substituents
have been prepared and examined in the directed synthesis of bacteriochlorins. The routes – inspired by a
directed route to chlorins – rely on condensation of two hydrodipyrrins to produce a hydrobilin followed
by ring closure to form the macrocycle. Four new unsymmetrically substituted bacteriochlorins were
obtained in very low yields; as an offshoot, efficient routes to three new tetradehydrocorrins (nickel
chelates) were discovered, including two B,D-tetradehydrocorrins (pyrroline–pyrrole A–D ring junction) and
one B,C-tetradehydrocorrin (pyrroline–pyrroline A–D ring junction). Taken together, this study deepens our
understanding of the chemistry of hydrodipyrrins and hydrobilins as precursors to hydroporphyrins.
Received 29th May 2017,
Accepted 17th August 2017
DOI: 10.1039/c7nj01892d
rsc.li/njc
constitute the fundamental macrocycle of bacteriochlorophylls,
and their counterpart in the ring contracted series, tetradehydro-
Introduction
Hydroporphyrins play central roles in biological energy trans- corrins (Scheme 1). The latter stand halfway between the fully
duction and in catalysis yet have been far less examined than unsaturated macrocycle, an octadehydrocorrin3–5 and the 8eÀ,
porphyrins from the standpoint of synthesis and model systems 8H+ reduced macrocycle, a corrin. An octadehydrocorrin is a
chemistry. The comparative deficiency stems from the relative formal tautomer of the well-known corrole. While corroles6,7 and
ease of the synthesis of the respective macrocycles. The hydro- corrins8–11 have been extensively studied, the reduced analogues
porphyrins of interest include chlorins and bacteriochlorins, intermediate between corroles and corrins have received less
which absorb in the red and near-infrared spectral regions, and attention owing to synthetic challenges given the complexity of
are dihydroporphyrins and tetrahydroporphyrins, respectively.1,2 the macrocycles.12
A more expansive, yet less explored, set of hydroporphyrins entails
Early syntheses of bacteriochlorins have relied on hydro-
the ring-contracted macrocycles ranging from octadehydrocorrins genation of (or addition to) synthetic porphyrins and chlorins.13–15
to corrins. Of particular interest here are bacteriochlorins, which The first de novo synthesis of bacteriochlorins targeted an analogue
of the naturally occurring (but likely non-photosynthetic) bacterio-
chlorin tolyporphin A (Scheme 2A).16,17 While an elegant
solution for the architecturally complex macrocycle, the length
of the synthesis has stymied applications to a broader set of
bacteriochlorins. The de novo synthesis (Scheme 2B, top) of
non-natural bacteriochlorins relies on the self-condensation of a
dihydrodipyrrin-acetal18,19 or dihydrodipyrrin-carboxaldehyde,20 and
is compatible with diverse substituents at the b-pyrrolic positions.
a Department of Chemistry, North Carolina State University, Raleigh,
North Carolina 27695-8204, USA. E-mail: jlindsey@ncsu.edu
b Department of Science Education, Gongju National University of Education,
Gongju, Korea
† Electronic supplementary information (ESI) available: Synthesis and character-
ization of diverse hydrodipyrrins; results upon exploration of directed routes to
bacteriochlorins; data from screening of reaction conditions; and spectral data
for all new compounds. See DOI: 10.1039/c7nj01892d
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Scheme 1 Natural hydroporphyrins (bacteriochlorophyll a, cobalamin), and equivalence of bacteriochlorin and tetradehydrocorrin saturation levels.
A complementary route (Scheme 2B, bottom) employs a Northern– chlorin synthesis through an analogous directed synthesis of
Southern (N–S) self-condensation of a dihydrodipyrrin-acetal, bacteriochlorins, where both reacting halves were necessarily
which affords the same bacteriochlorins as the Eastern–Western dihydrodipyrrins. The terminal substituents of the two hydro-
(E–W) route but the structure and method for construction of dipyrrins for the Western half (1 or 2) and Eastern half (3)
the dihydrodipyrrin-acetals more readily enable incorporation were chosen – by analogy with the chlorin synthesis – such that
of meso-substituents,21 although meso-phenyl groups have neither could undergo self-condensation (Scheme 3, bottom).26
recently been incorporated via the E–W route.22 The key struc- Yet, treatment with a Lewis acid did not give the desired linear
tural difference between the dihydrodipyrrins for the E–W and tetrapyrrole (a hydrobilin), but rather a green product that was
N–S route is the location of the gem-dimethyl group at the 3- or found to be a B,D-tetradehydrocorrin (TDC-1, TDC-2) bearing a
2-position relative to the 1-(dimethoxy)methyl unit. A recent methyl group at the A–D ring junction. The B,D-tetradehydrocorrins
de novo route constructs the bacteriochlorin macrocycle as well contain a linear polyene chromophore (coincidentally embedded in
as the isocyclic ring in a one-flask reaction from a linear a macrocycle) and as such lack the intense absorption character-
tetrapyrrole, which includes Nazarov cyclization and electro- istics of bacteriochlorins.18 The B,D-tetradehydrocorrin macrocycle
philic aromatic substitution (Scheme 2C). The linear tetrapyrrole is known as a competing byproduct with bacteriochlorins upon
in turn is prepared by Knoevenagel condensation starting from E–W dihydrodipyrrin-acetal self-condensation under certain acid-
two dihydrodipyrrins.23 Each bacteriochlorin shown in Scheme 2 catalysis conditions,27 yet in the directed reaction attempted here
contains a gem-dialkyl group in each pyrroline ring; the gem- the B,D-tetradehydrocorrin was the sole macrocycle obtained.
dialkyl group blocks adventitious dehydrogenation.24 Inspection Tetradehydrocorrins are potentially valuable ligands for studies
of all of the routes in Scheme 2 shows the critical importance in catalysis, given the rich chemistry of the natural corrins,8,9,11
of access to hydrodipyrrins bearing a gem-dialkyl group in although the cobalt complex of TDC-2 proved to be unstable
the pyrroline ring and distinct substituents at the respective toward electrochemical cycling.26
a-positions of the pyrrole and pyrroline units.25
The aforementioned precedents suggested that investigation of
An unmet challenge in bacteriochlorin synthesis concerns a set of hydrodipyrrins bearing a broader selection of terminal
access to unsymmetrically substituted macrocycles with diverse (1,9-, or a-) substituents might lead to unsymmetrically substituted
groups on the respective pyrrole and pyrroline rings. In the bacteriochlorins rather than tetradehydrocorrins, and also that
synthesis of chlorins, which contain only one pyrroline ring, more stable tetradehydrocorrins would likely require an A–D ring
the use of a hydrodipyrrin Western half and a dipyrromethane junction between two pyrrolines rather than one pyrroline and
Eastern half naturally affords a directed synthesis (Scheme 3, one pyrrole. The exploration of routes to such architectures
top).24 Accordingly, unsymmetrically substituted chlorins are requires access to new hydrodipyrrins. In this paper, we describe
readily available by virtue of the substitution of the respective the synthesis of hydrodipyrrins bearing a variety of terminal
distinct halves. We attempted to extend the features of the substituents, and exploratory studies of directed syntheses of
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Scheme 2 Building bacteriochlorin macrocycles: (A) Kishi’s route to tolyporphin A analogues,16,17 (B) the Eastern–Western strategy (top)18–20 and
Northern–Southern strategy (bottom),21 and (C) the Knoevenagel–Nazarov strategy.23
Scheme 3 Directed route to chlorins (top) and attempted analogous route for bacteriochlorins that instead afforded B,D-tetradehydrocorrins (bottom).
bacteriochlorins. The paper is divided into three parts. In part I, blocks, which bear distinct groups at the a-pyrrole or a-pyrroline
we describe the preparation of 10 target hydrodipyrrin building position; the synthesis28–32 and examination of 8 other target
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hydrodipyrrin building blocks is described in the ESI.† that were sought but to date have not been prepared. The
Altogether 27 hydrodipyrrins have been prepared (including 9 syntheses of S1–S8, exploratory routes to T1–T3, and exploratory
intermediates), which extends a collection of 33 hydrodipyrrins routes to bacteriochlorins using S1–S8 are described in the ESI.†
prepared previously.25 Part II describes the use of the 10 hydro- Among the eighteen new hydrodipyrrins, the dihydrodipyrrins
dipyrrin building blocks in approaches to bacteriochlorins as well wherein the pyrroline ‘‘X,Y’’ substituent contains an electrophilic
as ring-contracted analogues, namely tetradehydrocorrins. The single carbon include OHC– (4a-c, 7), (MeO)2CH– (5a, 5b, 6, S4,
synthetic route to bacteriochlorins remains based on the de novo S5), and tert-butyliminomethyl (4c-Im); those that contain an
route to chlorins. Part III describes the chemical characterization electrophilic pyrroline position (no carbon substituent) include
of the resulting new bacteriochlorins and tetradehydrocorrins.
S6–S8; and those that contain an electrophilic alkenyl moiety
include 8, S2 and S3. Compound S1 is a tetrahydrodipyrrin that
bears a (MeO)2CH– substituent at the pyrroline position,
whereas 9 is a tetrahydrodipyrrin that bears a methyl substituent
at the pyrroline 1-position. The pyrrole ‘‘W,Z’’ substituents
include ethoxycarbonyl (4a, 5a), methyl (4b, 5b), H– (4c, 4c-Im,
Results and discussion
Reconnaissance
The directed joining of two dipyrrolic species in the synthesis 8, 9, S1, S2, S6–S8), tert-butoxycarbonyl (S3), methylthio (6),
of chlorins begins by condensation at the a-pyrrole position of phenylthio (S4), bromo (7), and borolanyl (S5). Other pyrrole
the dipyrromethane and the a-substituent (carboxaldehyde or substituents were incorporated to explore reactivity features, to
carbinol) of the hydrodipyrrin to form a linear tetrapyrrole facilitate synthesis, or based on the availability of reactants.
(a hydrobilin33,34); subsequent metal-mediated oxidative cycliza- Some of the hydrodipyrrins resemble traditional Eastern or
tion gives the chlorin. While very little is known about the exact Western halves in chlorin chemistry whereas others do not; in
sequence of steps and the reactivity of specific intermediates in general, such distinction is less meaningful here given that the
the oxidative cyclization,35 the process is reliable with good bacteriochlorin (or tetradehydrocorrin) contains two pyrroline
overall efficiency.
and two pyrrole units, and each hydrodipyrrin contains one
In the chlorin synthesis, four distinct terminal substituents pyrroline and one pyrrole unit.
(pyrrole-H, pyrroline-CH3/enamine, pyrrole-CHR(OH), pyrrole-Br)
The nomenclature of hydrodipyrrins is displayed at the bottom
are present, two of which carry a substituted methyl group destined of Chart 1. In addition to the change in saturation level indicated
to become a meso carbon (Scheme 3, top). In the undirected E–W by di-, tetra-, and hexa-hydro prefixes, a further distinction
and N–S routes to bacteriochlorins, one dihydrodipyrrin undergoes concerns the location of the gem-dimethyl group on the
self-condensation, wherein only two distinct terminal substituents pyrroline ring. Two routes have been employed for construction
are present (pyrrole-H, pyrroline-CH(OMe)2), one of which is the of the hydrodipyrrins,24 which stem from the pioneering work
latent meso carbon (Scheme 2B). A directed synthesis of bacterio- of teams led by Battersby and by Jacobi. The Battersby route36
chlorins requires two hydrodipyrrins with four distinct terminal affords the 3,3-dimethyl substituent pattern whereas that of
substituents. Many combinations are possible of terminal sub- Jacobi28 affords the 2,2-dimethyl pattern.
stituents (W, X, Y, Z), and the saturation level can be di-, tetra-, or
Synthesis of hydrodipyrrins
hexa-hydrodipyrrin (Scheme 4), yet the sine qua non is that (1) a
pair of substituents on a given hydrodipyrrin (W,X; Y,Z) must be The synthesis of tetrahydrodipyrrins bearing 1-methyl groups is
incompatible with self-condensation, (2) one of W,X and one of well established.37 Here, reductive cyclization of nitrohexanone
Y,Z (or both of one pair and neither of the other pair) must convey 1020 in the presence of zinc dust and ammonium acetate
a meso carbon to complete the macrocycle, and (3) W must react in THF gave tetrahydrodipyrrin 9 in 63% yield (Scheme 5,
with/at Y not Z, and X must react with/at Z not Y.
lower right).
To explore various directed routes, 18 target hydrodipyrrins
Several new dihydrodipyrrins were prepared that contain
have been prepared as well as nine intermediates or byproducts blocking units (to prevent self-condensation) at the a-pyrrole
(27 hydrodipyrrins altogether). Chart 1 shows ten target hydro- position; such groups were introduced at the beginning of the
dipyrrins (4a–c, 4c-Im, 5a, 5b, 6–9) that led to a successful route (Scheme 5, left). Pyrrole–carboxaldehydes 11a,38 11b,39
reaction, eight hydrodipyrrins (S1–S8) that did not prove fruit- and 11c19 are known; 11a and 11b were prepared in a two-step
ful in macrocyclization, and three hydrodipyrrin targets (T1–T3) procedure starting from a Paal–Knorr synthesis, whereas 11c
Scheme 4 Hydrodipyrrin terminal substituents W, X, Y, and Z in a directed synthesis of bacteriochlorins.
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Chart 1 Eighteen hydrodipyrrins prepared for studies of macrocycle formation (4a–8, S1–S8; top and middle). Three desired target hydrodipyrrins
(T1–T3, middle right). Dipyrrin and hydrodipyrrin nomenclature (bottom).
was prepared in a two-step procedure starting from a van required 2-(2-nitroethyl)pyrrole with the a,a-dimethoxy deriva-
Leusen synthesis. The electron-withdrawing ethoxycarbonyl tive of mesityl oxide (13b).19
group stabilizes the pyrrole ring during subsequent transfor-
Dihydrodipyrrin-acetal 6 bears a methylthio group as the
mations. Pyrrole–carboxaldehydes 11a–c were converted19 to pyrrole blocking unit (Scheme 5, right). Thus, 2-methylthio-
nitroethylpyrroles 12a–c via a Henry reaction and reduction pyrrole 1640 underwent formylation selectively at the 5-position
with NaBH4. Treatment of 12a–c with a,b-unsaturated ketone to give 17, which upon Henry reaction and reduction gave the
mesityl oxide (13a) in the presence of DBU at room temperature corresponding (2-nitroethyl)pyrrole 18. Then, 18 was reacted with
afforded the corresponding nitrohexanones 14a–c. Subsequent 1,1-dimethoxy-4-methyl-3-penten-2-one (13b),41 giving nitrohexa-
TiCl3-mediated reductive cyclization afforded dihydrodipyrrins none 19 in 48% yield. TiCl3-Mediated reductive cyclization gave
15a–c, which upon oxidation with SeO2 gave dihydrodipyrrin- dihydrodipyrrin-acetal 6. The methylthio group has been used
carboxaldehydes 4a–c.20 Aldehydes 4a,b were converted to the as a protecting group for the pyrrole a-position in porphyrin
corresponding dihydrodipyrrin-acetals 5a,b by exposure to chemistry.40,42
trimethyl orthoformate in the presence of p-toluenesulfonic
The bromination of known hydrodipyrrin-carboxaldehyde
acid (TsOH).21 Dihydrodipyrrin-acetal 5c (the dimethyl acetal 2020 was achieved most effectively by using 1 molar equivalent
of 4c) was prepared previously by Michael addition of the of NBS in THF at À78 1C, affording 7 in 45% yield (Scheme 6).
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Scheme 5 Synthesis of hydrodipyrrins.
The successful reaction required the use of quite dilute condi-
The ability to oxidize the 1-methyl group of a dihydrodipyrrin20
tions (B10 mM). Compound 7 was prone to decomposition opened the opportunity to elaborate the resulting 1-carboxaldehyde.
upon dissolution in chlorinated solvents and during chromato- Thus, the reaction of 2123 with SeO2 followed by methenylation with
graphy on silica, and slowly decomposed in the solid state at Ph3PQCHCO2Et afforded the corresponding dihydrodipyrrin (8)
room temperature. On the other hand, 7 was stable for weeks in bearing an ethyl acrylate moiety at the 1-position (Scheme 6).
the solid state at À20 1C, and could be weighed out at room
Exploration of hydrodipyrrin macrocyclizations leading chiefly
to bacteriochlorins
temperature without special precautions. Treatment of the
dihydrodipyrrin-carboxaldehyde 4c with t-BuNH2 in dichloro-
methane at room temperature for 2 h gave the corresponding Ten new hydrodipyrrins (Chart 1) were employed here along
dihydrodipyrrin-imine 4c-Im in 63% yield. The imine (a yellow with four prior hydrodipyrrins (3,26 5c,19 21,23 2220) in studies
solid) was quite stable compared to the precursor carboxalde- of bacteriochlorin and tetradehydrocorrin formation. We first
hyde (a yellow oil).
present reactions that mainly afforded bacteriochlorins.
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Scheme 6 Manipulation of dihydrodipyrrin-carboxaldehydes (left and center), and extension at the 1-methyl site of a dihydrodipyrrin (right).
Dihydrodipyrrins without a pyrrole blocking unit. The con-
Montforts and Kutzki reported a synthetic route to chlorins
densation of 22 (a dihydrodipyrrin) and 5c was carried out with the from a linear tetrapyrrole–metal complex, wherein an ester group
expectation that the electron-withdrawing group (–CO2Et) at the served as a blocking unit and then was cleaved in refluxing 1,2,4-
b-pyrrole position in dihydrodipyrrin 5c would decrease the reactivity trichlorobenzene (214 1C).45 Treatment of dihydrodipyrrin 21 and
of the pyrrole ring and perhaps thereby suppress the self- dihydrodipyrrin-acetal 5a in dichloromethane with Cu(OTf)2
condensation of 5c. The reaction was carried out in a two-step gave a copper(II) complex as a red-purple gel (Scheme 7C).
process of acid-catalyzed condensation followed by metal-templated The copper(II) complex is paramagnetic and so a meaningful
oxidative cyclization (Scheme 7A). The reaction mixture was exam- 1H NMR spectrum could not be obtained, but it was character-
ined by absorption spectroscopy and laser-desorption mass spectro- ized by mass spectrometry (LD-MS and ESI-MS). The absorption
metry (LD-MS). The best result was achieved with condensation at spectrum of this complex in dichloromethane displayed a weak
room temperature in CH2Cl2 containing Bi(OTf)3 followed by treat- broad band in the 450–600 nm region (ESI†). The complex was
ment with 10 molar equiv. of InCl3 and 10 molar equiv. of 2,2,6,6- robust, as treatment with TFA/H2SO4 containing a few drops of
tetramethylpiperidine (TMPi) in CH3CN or toluene under reflux 1,3-propanedithiol, conditions known to demetalate copper
exposed to air (see the ESI† for survey conditions). The resulting chlorins,46,47 did not cause demetalation. Treatment of the
unsymmetrically substituted bacteriochlorin InBC-1 was obtained in copper-complex with sodium hydroxide at high temperature
8% yield (estimated spectroscopically43). Some amount of tetra- gave the corresponding copper(II)bacteriochlorin CuBC-3.
dehydrocorrin and a trace amount of a free base bacteriochlorin Several reaction variables, including temperature, solvents or inert
(obtained from the self-condensation of 5c) were also observed.
environment, were examined. The highest yield (2%, estimated
The dihydrodipyrrin-imine 4c-Im was examined in conden- spectroscopically48) was obtained in degassed ethylene glycol at
sation with tetrahydrodipyrrin 9 in the presence of Bi(OTf)3, 160 1C under argon. The major by-products detected (by absorp-
followed by cyclization using InCl3/TMPi in refluxing toluene, tion spectroscopy and LD-MS) appeared to be oxobacteriochlorins
whereupon InBC-1 was obtained in 2% yield (Scheme 7A). The and tetradehydrocorrins. Attempted demetalation of CuBC-3 by
tetrahydrodipyrrin 9 is ostensibly more nucleophilic than the using TFA/concentrated H2SO4/1,3-propanedithiol caused decom-
analogous dihydrodipyrrin 22, and the imine 4c-Im is potentially position of the bacteriochlorin.
more directly reactive than the acetal 5c. Screening of several
factors (e.g., concentration of reactants, equivalents of metal DMF containing a copper(II) reagent is an established approach
triflates), however, did not lead to improved yields.
to the corresponding copper(II)porphyrin.49 An analogous ring-
The cyclization of a 1,8-dimethyl-a,c-biladiene in refluxing
Hydrodipyrrins with various blocking units. The reaction closure strategy for forming a bacteriochlorin was examined
of a dihydrodipyrrin-acetal with a 1-methyldihydrodipyrrin here. First, condensation of 21 and 5b in the presence of
afforded a tetradehydrocorrin (Scheme 3).26 Here, 1-methyltetra- Cu(OTf)2 in CH2Cl2 for 2 h gave a copper(II)-complex as a red-
hydrodipyrrin 9 was examined instead of a 1-methyldihydro- purple gel, which was characterized by mass spectrometry
dipyrrin (Scheme 7B). The reaction of 9 with dihydrodipyrrin- and absorption spectroscopy. Subsequent heating in DMF
carboxaldehyde 7 was examined under various conditions, which containing CuCl2 (15 equiv.) gave the corresponding dioxo-
entailed TsOHÁH2O (5 equiv.) in CH2Cl2/methanol at room bacteriochlorin CuBC-4 (Scheme 7D) in 2% overall yield (estimated
temperature for the condensation (akin to that in the de novo spectroscopically48). Battersby et al. reported a similar observa-
synthesis of chlorins44), and thermal cyclization under the above tion in studies of the conversion of tetrahydrobiladienes to
conditions (InCl3/TMPi in toluene at 80 1C). The best conditions the corresponding chlorin, wherein a copper(II)oxochlorin was
afforded InBC-2 in only 1% yield (estimated spectroscopically43). obtained.47 In short, each of the routes shown in Scheme 7
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Scheme 7 Routes to metallobacteriochlorins.
affords a bacteriochlorin (or dioxobacteriochlorin) albeit in an intense band around 333 nm and a broad intense band
minuscule yield. ranging from 500–700 nm. The sum of all the spectroscopic
We next explored a synthetic route to bacteriochlorins using evidence led to the unusual 1,20-dihydrobacteriochlorin 23.
4a and 21. The acids that were examined for the condensation
Exploration of hydrodipyrrin macrocyclizations leading chiefly
to B,D-tetradehydrocorrins
included BF3ÁOEt2, Sc(OTf)3, Bi(OTf)3, Ga(OTf)3, InCl3, Yb(OTf)3,
TMSOTf/2,6-di-tert-butylpyridine (DTBP) and TFA. Reactions were
conducted with 10 mM dihydrodipyrrin (21 and 4a, 0.010 mmol
Hydrodipyrrin with 1-acrylate for directed reaction. The
scale) and 20 mM acid in CH2Cl2 (except for BF3ÁOEt2 in CH3CN) reaction leading to tetradehydrocorrins entails attack of the
with monitoring by LD-MS and absorption spectroscopy. The pyrrole of one hydrodipyrrin on the imine carbon of a second
targeted hydrobilin was not detected under these conditions; a hydrodipyrrin (Scheme 3). To direct reaction at the 1-carbon
trace amount of the major component was isolated and char- substituent (destined to become the meso-carbon) and thereby
acterized by LD-MS (found m/z = 966) and absorption spectro- construct the bacteriochlorin macrocycle, a dihydrodipyrrin (8)
scopy. To verify this observation, a condensation was carried out was employed wherein a Michael-like acceptor is located at
of two molar equiv. of 21 and one molar equiv. of 4a catalyzed by the 1-position (Scheme 9, left). The Michael acceptor is ethyl
Ga(OTf)3, followed by aeration in refluxing methanol (Scheme 8). acrylate, in which case nucleophilic attack is expected at the
Chromatography afforded (3% yield) a blue-green compound, b-position of the a,b-unsaturated ester versus the pyrroline imine
which was characterized by 1H NMR spectroscopy (methine and carbon. The reaction of 8 with 9-bromodihydrodipyrrin-1-acetal
pyrrolic protons at d 4.88, 5.71, 5.90, 6.34, and 6.87 ppm) and 3 parallels that leading to TDC-1 or TDC-2 but was expected to
ESI-MS. The absorption spectrum in dichloromethane showed afford the corresponding bacteriochlorin bearing a –CH2CO2Et
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Scheme 8 Frustrated route to bacteriochlorins.
Scheme 9 Formation of new B,D-tetradehydrocorrins.
substituent at the 15-position. The reaction catalyzed by The methylthio group is believed to be located at the b-pyrrole
Ga(OTf)3 afforded the B,D-tetradehydrocorrin TDC-3 rather position of the macrocycle.
than the desired bacteriochlorin. Attempted rearrangement
The location of the methylthio group at the pyrrole
(under diverse acids27) of the tetradehydrocorrin to the corres- a-position in dihydrodipyrrin 6 – expected on the basis of the
ponding bacteriochlorin failed. Such rearrangement has been synthesis from known pyrrole 16 – was confirmed by the strong
demonstrated previously for tetradehydrocorrins that bear a coupling signal between the two neighboring b-pyrrolic protons
dimethoxymethyl unit at the 19-position of the A–D ring in the COSY spectrum (see the ESI†). ESI-MS analysis of TDC-4
junction.27 The use of the more potent dicyanovinyl Michael showed a molecular ion peak (m/z = 509.2733) consistent with
acceptor in lieu of the ethyl acrylate failed to afford an isolable the molecular formula C32H36N4S (calcd 509.2733 for M + H+).
macrocycle (ESI†).
The 1H NMR spectrum indicated only five peripheral alkenyl
Dihydrodipyrrin with -SMe as a blocking unit. An analogue protons (five singlets in the range of d 5.3–6.6 ppm). Absorption
of dihydrodipyrrin 3 containing a methylthio (6) rather than spectroscopy and 2-dimensional NMR experiments confirmed
bromo group blocking the 9-pyrrolic position was examined the tetradehydrocorrin chromophore. NOESY or COSY experi-
next. The acidic conditions investigated for the condensation ments did not give any direct evidence concerning the location
of dihydrodipyrrin 22 and 6 included BF3ÁOEt2, TMSOTf/ of the methylthio group on the macrocycle, hence the proposed
DTBP, Bi(OTf)3, Ga(OTf)3, Sc(OTf)3, and Yb(OTf)3 (all in CH2Cl2, structure must be regarded as provisional in the absence of a
except BF3ÁOEt2 in CH3CN). The progress of the reaction was single-crystal X-ray diffraction analysis.
monitored by TLC and by LD-MS. All these conditions failed
A possible explanation for the formation of b-methylthio-
to afford the expected hydrobilin. Surprisingly, Yb(OTf)3 and tetradehydrocorrin TDC-4 is shown in Scheme 10. Condensa-
Sc(OTf)3 gave the B,D-tetradehydrocorrin TDC-4 directly (Scheme 9, tion of 22 and 6 produces the hydrobilin intermediate I, which
right). The effects of the concentration of reagents, equivalents is likely to assume more of a lockwasher rather than planar
of Lewis acid, solvent, and the presence/absence of proton conformation owing to the steric bulk of the juxtaposed methyl
scavenger (DTBP) were also studied. The use of dilute reactants and methylthio groups across the A–D gap. Further cyclization
(1 mM) in CH2Cl2 containing Yb(OTf)3 (5 mM) at room tem- ensues as shown in II to give the A–D ring closure of the corrin
perature for 16 h afforded a 50% isolated yield of TDC-4. analogue III. Thiiranium formation gives IV, which upon loss of
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Scheme 10 Possible mechanism for the methylthio shift and related literature precedent.
the b-proton gives the b-methylthiotetradehydrocorrin TDC-4. The compounds described in the body of the paper were
This proposed mechanism is precedented by arylthio migration generally characterized by 1H and 13C NMR spectroscopy
from the a- to b-position of pyrrole, as shown in the bottom of as well as accurate-mass ESI-MS; the macrocycles were also
Scheme 10. Protonation of a-arylthiopyrrole II-pyr affords III-pyr, examined by absorption spectroscopy. In some cases 13C NMR
which undergoes thiiranium formation to give IV-pyr; subsequent spectra were not obtained due to small quantities, paramagnetic
rearrangement gives the b-arylthiopyrrole V.50,51 The rearrangement samples (copper bacteriochlorins), or exploratory syntheses
of I leading to TDC-4 is driven by the reaction of the pyrrole that did not lead to fruitful results (e.g., S1–S8 and others in
a-position with the electrophilic iminium ion (shown for II), whereas the ESI†). The four new bacteriochlorins were obtained in
the rearrangement of II-pyr is driven by an analogous electrophilic minute quantities, the low yields of which were estimated by
process, protonation of the pyrrole a-position. The proposed mecha- absorption spectroscopy. The tetradehydrocorrins, on the other
nism suggests calculations to address the relative energies of the hand, were obtained in sufficient quantities for yields to be
intermediates as well as the conformation of the hydrobilin(s).
determined by isolation, and the compounds were examined in
detail as described below.
Tetradehydrocorrin TDC-3 was characterized by 1H and
Concise synthesis of a B,C-tetradehydrocorrin
The facile reaction of the pyrrole unit in dihydrodipyrrin 21 with the 13C NMR spectroscopy, ESI-MS and absorption spectroscopy.
carboxaldehyde of dihydrodipyrrin 4a (Scheme 8) prompted exam- Five peripheral protons resonate in the range of d 5.4–6.7 ppm.
ination of a route to a 7,8,12,13-tetradehydrocorrin (Scheme 11). The methylene protons in each pyrroline ring display an AB
Acid-catalyzed condensation of dihydrodipyrrin 21 and 4-bromo- splitting pattern (d 2.0–2.5, 2.7 ppm). In addition, two doublets
benzaldehyde (24) was found to give biladiene 25 in 88% yield. (d 6.0, 7.4 ppm) can be assigned to the two alkenyl protons in
Biladiene 25 underwent facile oxidation during column chroma- the acrylate substituent. The absorption spectrum (Fig. 1A)
tography or in a solution open to the air. Following a reported shows an intense band at 340 nm, a shoulder at 438 nm and
method to prepare nickel(II)-octadehydrocorrins,52,53 treatment of a broad band from 500–900 nm, all of which are characteristic
25 with nickel acetate tetrahydrate and sodium acetate in reflux- of B,D-tetradehydrocorrin macrocycles.18
ing methanol for 30 min followed by dilute hydrochloric acid
TDC-4 exhibits an absorption spectrum (Fig. 1B) with lmax at
afforded the B,C-tetradehydrocorrin nickel chloride NiTDC-5 in 318 nm, a weak shoulder at 438 nm, and a weak, broad band
82% yield. A defining feature of the B,C-tetradehydrocorrin is the from 500–900 nm. The 1H NMR, 13C NMR, gHMQC, and NOESY
presence of two pyrroline rings at the A–D ring junction, versus spectra of TDC-4 were obtained, and all protons were assigned
the pyrroline–pyrrole rings at the A–D junction in the prior (see the ESI†). Distinctive features in the 1H NMR spectrum
B,D-tetradehydrocorrins (TDC-1–4).
include the following: (1) an AB splitting pattern assigned to the
two methylene protons of the pyrroline unit distal from the A–D
ring junction; (2) five singlets in the range of d 5.3–6.6 ppm
Characterization
The synthetic studies described above led to 27 new hydrodipyrrins, assigned to the five peripheral alkenyl protons; and (3) two
four new bacteriochlorins, and three new tetradehydrocorrins. broad peaks in the low-field region assigned to the NH protons.
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Fig. 1 Absorption spectra of TDC-3 (A), TDC-4 (B), NiTDC-5 (C) and
1,20-dihydrobacteriochlorin 23 (D) in CH2Cl2 at room temperature.
Scheme 11 Synthesis of a B,C-tetradehydrocorrin.
The tetradehydrocorrin nickel chloride (NiTDC-5) was char- gives rise to a pair of doublets in the range of d 4.4–4.7 ppm.
acterized by 1H and 13C NMR spectroscopy, ESI-MS and absorp- Mass spectrometric analysis in each case gave the molecular
tion spectroscopy. NiTDC-5 has a C2 axis (assuming that the ion peak as well as a peak consistent with loss of chloride. The
1,19-dimethyl groups are trans to one another; if cis, there is a absorption and fluorescence spectra of InBC-1 and InBC-2 in
plane of symmetry) bisecting the A–D ring junction, hence toluene are shown in Fig. 2, with the respective Qy(0,0) absorp-
the two meso-protons are identical with each other, and the tion band at 773 and 765 nm, and the Qy(0,0) fluorescence
two b-pyrrolic protons are identical with each other. Two singlets maximum at 789 and 775 nm.
(6.86, 7.30 ppm) observed in the 1H NMR spectrum are assigned
The copper bacteriochlorins CuBC-3 and CuBC-4 were character-
to the meso-protons and the b-pyrrolic protons, respectively. ized by LD-MS, ESI-MS, and absorption spectroscopy. 1H NMR
An AB splitting pattern, assigned to the two methylene protons spectroscopy typically is not applicable for copper(II) bacteriochlorins.
of both pyrroline units, was also observed (d 2.44, 2.64 ppm). Fluorescence is not expected (and none was found) in these two
A high-resolution mass spectrum showed an intense molecular cases. The absorption spectra of CuBC-3 and CuBC-4 in toluene
ion with loss of chloride (or other apical ion) at m/z 904.9973, are shown in Fig. 2, with the Qy(0,0) band at 744 and 711 nm,
with the expected isotopic pattern for nickel. The absorption respectively. The absorption spectrum of CuBC-4 showed typical
spectrum showed an intense absorption at 349 nm and a broad features of an oxobacteriochlorin, including (1) a hypsochromic
band from 500–700 nm with lmax at 605 nm (Fig. 1C).
shift of the Qy band, and (2) a bathochromic shift and apparent
The unusual structure 23 (1,20-dihydrobacteriochlorin) exhibits hypochromic effect in the By band.56
an absorption spectrum (Fig. 1D) that is consistent with the
The spectral data including the position, intensity, and full-width
absorption of a similar metal-free 1,20-dihydroporphyrin reported at half-maximum (fwhm) of the long-wavelength absorption band
by Smith et al.54,55
and emission band; and intensity ratios of the Qy to B band are
The indium bacteriochlorins InBC-1 and InBC-2 were char- listed in Table 1. The spectral data of indium(III)bacteriochlorins
acterized by 1H NMR spectroscopy, LD-MS, ESI-MS, absorption (InBC-5 and InBC-6) are also listed as benchmarks (Chart 2).43
spectroscopy, and fluorescence spectroscopy. Because both Comparison of these spectral data leads to some interesting
macrocycles are unsymmetrically substituted, each peripheral findings: (1) the wavelengths of the Qy bands are in the
proton resonates uniquely (an apparent singlet) in the range of following order: InBC-6 (782 nm) 4 InBC-1 (773 nm) 4 InBC-2
d 8.5–10.0 ppm. In addition, the two gem-dimethyl groups give (765 nm) B InBC-5 (763 nm), indicating that an unsymmetrically
rise to four singlets, and the CH2 group in each pyrroline ring substituted bacteriochlorin can finely tune the position of
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Chart 2 Benchmark bacteriochlorins.
equipped with various entities at the a-pyrrole or a-pyrroline
position and various degrees of saturation (dihydro, tetrahydro,
hexahydro) have been prepared as building blocks for use in
studies of macrocycle formation. Among these, 10 hydrodipyrrins
(1 tetrahydrodipyrrin and 9 dihydrodipyrrins) with a-pyrrole (H,
methylthio, bromo, methyl, and ethoxycarbonyl) or a-pyrroline
(methyl, formyl, dimethoxymethyl, and iminomethyl) substituents
have afforded reactions leading to a bacteriochlorin or tetra-
dehydrocorrin. Unsymmetrically substituted bacteriochlorins
were prepared by the use of dihydrodipyrrins bearing various
a-pyrrolic substituents (H, bromo, methyl, and ethoxycarbonyl).
Two B,D-tetradehydrocorrins were produced by acid-catalyzed
condensation using one hydrodipyrrin with a methylthio or
bromo group as the blocking unit at the 9-pyrrole site, and a
Fig. 2 Absorption spectra (A) and fluorescence spectra (B) of bacterio-
chlorins in toluene at room temperature (normalized at the Qy band). The second hydrodipyrrin with a methyl or ethyl acrylate group at the
labels and colors in the graph are as follows: InBC-1 (red trace), InBC-2
(black trace), CuBC-3 (magenta trace) and CuBC-4 (blue trace). The
emission spectra are drawn in dashed lines.
1-pyrroline position. A B,C-tetradehydrocorrin was obtained upon
condensation of two equivalents of a 1-methyldihydrodipyrrin and
an aryl aldehyde. These studies provide insights into the synthetic
chemistry of hydrodipyrrins and hydrobilins as well as processes
the Qy band with narrow bandwidth (fwhm B20 nm). (2) The leading to tetrapyrrole macrocycles. While our interests lie
Stokes shift is in the following order: InBC-1 (263 cmÀ1) 4 strongly toward bacteriochlorins rather than corrin analogues,
InBC-2 (169 cmÀ1) 4 InBC-5 (103 cmÀ1) B InBC-6 (49 cmÀ1). The we note that the synthesis of corrin analogues has been relatively
larger Stokes shift of unsymmetrically substituted bacteriochlorins, unexplored.10,12,57 Access to the entire slate of dehydrocorrins
compared with those of symmetrically substituted ones, indicates (hexadehydro-, tetradehydro-, and didehydrocorrins) ranging
more substantial structure changes upon photoexcitation.
from A,B,C,D-octadehydrocorrins to corrins themselves would be
exceptionally valuable for probing the structural features leading
to the emergence of corrin-like properties. A strong motivation for
the study of such complexes stems from the growing interest in
using earth-abundant metals as catalysts for transformations such
Outlook
A significant advance in routes to tetradehydrocorrins (B,C- and as photosynthetic hydrogen evolution.58
B,D-types) has been achieved, yet the objective of the research –
The origin of the facile formation of tetradehydrocorrins
gaining access to unsymmetrically substituted bacteriochlorins versus bacteriochlorins remains unclear. The electrocyclization
– remains challenging. Herein, 18 new target hydrodipyrrins of an 18p-system has been proposed in the synthesis of
Table 1 Spectral properties of bacteriochlorinsa
Qy(0, 0)
abs fwhm
(nm)
Qy(0, 0)
em fwhm
(nm)
By(0, 0)b
abs l (nm)
Bx(0, 0)b
abs l (nm)
Qx(0, 0)
abs l (nm)
Qy(0, 0)
abs l (nm)
Qy(0, 0)
em l (nm)
Dabs–em
(cmÀ1
)
IQ /IB
c
Bacteriochlorins
y
InBC-1
InBC-2
CuBC-3
CuBC-4
InBC-5d
InBC-6d
353
350
337
388
350
354
391
389
385
434
388
395
550
539
511
528
539
559
773
765
744
711
763
782
25
22
33
24
23
21
789
775
—
—
769
785
24
25
—
—
31
23
263
169
—
—
103
49
1.4
1.2
1.0
0.76
1.1
1.3
a
b
c
In toluene at room temperature. The two Soret features are labeled Bx(0,0) and By(0,0), but the bands may be of mixed parentage. Ratio of the
d
peak intensities of the Qy(0,0) band to the Soret (B) maximum. Data from ref. 42.
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isobacteriochlorins and chlorins.24,59,60 Early studies on the vibronic studies, (2) preparation and photophysical studies of
synthesis of vitamin B12 proposed a 16p-electrocyclization of a unsymmetrically substituted dioxobacteriochlorins (analogues
secocorrin-diradical to construct the corrin macrocycle, wherein of native tolyporphin A), and (3) introduction of distinct sub-
the diradical was created upon H-atom abstraction.61 While more stituents (e.g. hydrophobic/hydrophilic substituents) on the
recent analysis has prompted a turn away from this mechanism,62 opposite sides of the macrocycle for self-assembly and photo-
the tetradehydrocorrins reported herein do not require H-atom physical studies.
abstraction to form the requisite precursor polyene. Scheme 12
shows these two competitive electrocyclization processes, starting
from a hydrobilin (assuming M2+ as the metal center) to produce
a bacteriochlorin or B,D-tetradehydrocorrin; examples of the
Experimental section
General methods
latter include TDC-1 and TDC-2 (Scheme 3) as well as TDC-3
and TDC-4 (Scheme 9). A similar 16p-electrocyclization, with a 1H NMR and 13C NMR spectra were collected at room tempera-
difference in the location of the double bond, could afford the ture in CDCl3 unless noted otherwise. Electrospray ionization
B,C-tetradehydrocorrin NiTDC-5 (Scheme 11). While it has mass spectrometry (ESI-MS) data are reported for the molecular
proved tempting over the years to ascribe some hydroporphyrin ion or protonated molecular ion. Bromination was performed
macrocyclizations to electrocyclization processes, such pathways in using freshly recrystallized NBS (from water). THF used in all
the absence of stereochemical evidence or solvent effect studies reactions was freshly distilled from Na/benzophenone ketyl.
are mere conceptual guideposts. Moreover, a 16p-electrocyclization All commercially available materials were used as received.
is not the only possible pathway leading to the tetradehydrocorrin. Non-commercial compounds 3,26 5c,19 10,20 11a,38 11b,39
In some examples, the tetradehydrocorrin might be produced 11c,19 12c,19 13b,41 16,40 20,20 2123 and 2220 (as well as 13c,41
through a more traditional nucleophile–electrophile reaction 13d,63 S9,25 S12,20 S13,19 S17,19 S19,21 S24,25 S26,20 S32,25 S33,25
(e.g., pyrrole + pyrroline reaction giving TDC-4 in Schemes 9 S34,64 and S35;25 ESI†) were prepared as described in the
and 10, or pyrroline a-carbanion + imine reaction leading to literature and assessed for purity by 1H NMR spectroscopy.
NiTDC-5 in Scheme 11) activated by the acid catalyst. A number Estimates of the yields by absorption spectroscopy was carried
of proposed intermediates and associated mechanisms should out using interrogation of the long-wavelength absorption band
be amenable to calculation to gauge their energetics and hence (Qy) with e = 100 000 MÀ1 cmÀ1 for indium bacteriochlorins43
their chemical likelihood.
and e = 130 000 MÀ1 cmÀ1 for copper bacteriochlorins.48
To improve the yields of bacteriochlorins for the reactions
9-Ethoxycarbonyl-1-formyl-2,3-dihydro-3,3,7,8-tetramethyl-
reported herein, at least two advances are required: (1) a new dipyrrin (4a). Following a general procedure,20 a solution of 15a
approach to join the respective hydrodipyrrins; and (2) a new (50. mg, 0.18 mmol) in 1,4-dioxane (5.0 mL) was treated with
blocking unit in the hydrobilin. The choice of the blocking/ SeO2 (60. mg, 0.54 mmol) under argon and stirred at room
leaving group in the hydrobilin is a key aspect of a successful temperature. The progress of the reaction was monitored by
macrocyclization. Although low yields and small quantities of absorption spectroscopy. After 30 min, the reaction mixture was
bacteriochlorin severely limit the present applications in syn- diluted with ethyl acetate, washed with water and brine, dried
thetic chemistry, some research opportunities may be available. (Na2SO4) and concentrated. Chromatography [silica, CH2Cl2]
Examples include (1) incorporation of 13C/15N isotopes at one gave a red-orange solid (32 mg, 59%): 1H NMR (400 MHz)
or more specific sites on the p-system of the bacteriochlorin for d 1.27 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H), 2.09 (s, 3H), 2.28 (s, 3H),
Scheme 12 Possible 16p/18p-electrocyclizations.
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2.73 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 6.14 (s, 1H), 10.00 (s, 1H), reaction mixture was diluted with ethyl acetate, washed with
10.84 (br, 1H); 13C NMR (100 MHz) d 9.1, 10.4, 14.6, 29.3, water and brine, dried (Na2SO4) and concentrated to an orange-
41.2, 46.2, 60.1, 110.8, 121.5, 122.7, 126.8, 130.2, 161.6, 162.7, red solid (crude 4a). The residue was dissolved in trimethyl
170.5, 190.3; ESI-MS obsd 303.1699, calcd 303.1703 [(M + H)+, orthoformate (5.0 mL) and then TsOHÁH2O (205 mg, 1.08 mmol)
M = C17H22N2O3]; labs (CH2Cl2) 459 nm.
was added at room temperature. After 1 h, the reaction mixture
8-Ethoxycarbonyl-1-formyl-2,3-dihydro-3,3,7,9-tetramethyl- was diluted with ethyl acetate and quenched by the addition of
dipyrrin (4b). Following a general procedure,20 a solution of 15b saturated aqueous NaHCO3 solution. The separated organic
(50. mg, 0.18 mmol) in 1,4-dioxane (5.0 mL) was treated with phase was washed with water, dried (Na2SO4), concentrated and
SeO2 (60. mg, 0.54 mmol) under argon and stirred at room chromatographed [silica, CH2Cl2, then hexane/ethyl acetate
temperature. The progress of the reaction was monitored by (1 : 1)] to afford an orange-yellow oil (80 mg, 64%): 1H NMR
absorption spectroscopy. After 15 min, the reaction mixture (300 MHz) d 1.23 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H), 2.04 (s, 3H),
was diluted with ethyl acetate, washed with water and brine, 2.27 (s, 3H), 2.64 (s, 2H), 3.49 (s, 6H), 4.30 (q, J = 7.2 Hz, 2H),
dried (Na2SO4) and concentrated. Chromatography [silica, 5.01 (s, 1H), 5.83 (s, 1H), 10.90 (br, 1H); 13C NMR (100 MHz)
CH2Cl2] gave a red-orange solid (36 mg, 66%): 1H NMR d 8.9, 10.5, 14.7, 29.2, 40.6, 48.1, 55.2, 59.7, 103.3, 104.3, 119.1,
(400 MHz) d 1.25 (s, 6H), 1.37 (t, J = 6.8 Hz, 3H), 2.35 (s, 3H), 119.4, 126.8, 130.8, 161.8, 162.6, 176.1; ESI-MS obsd 349.21218,
2.57 (s, 3H), 2.72 (s, 2H), 4.29 (q, J = 6.8 Hz, 2H), 6.16 (s, 1H), calcd 349.21128 [(M + H)+, M = C19H28N2O4].
9.97 (s, 1H), 10.57 (br, 1H); 13C NMR (100 MHz) d 11.3, 14.6,
14.8, 29.3, 41.1, 45.9, 59.4, 111.2, 112.2, 125.0, 126.4, 139.6, 159.7, tetramethyldipyrrin (5b). Following a general procedure,21
166.0, 168.5, 189.9; ESI-MS obsd 303.1699, calcd 303.1703 solution of 15b (207 mg, 0.720 mmol) in 1,4-dioxane (15 mL)
[(M + H)+, M = C17H22N2O3]; labs (CH2Cl2) 473 nm.
was treated with SeO2 (240. mg, 2.16 mmol) and stirred at room
8-Ethoxycarbonyl-2,3-dihydro-1-(1,1-dimethoxymethyl)-3,3,7,9-
a
8-Ethoxycarbonyl-1-formyl-2,3-dihydro-3,3-dimethyl-7-p- temperature. The progress of the reaction was monitored by
tolyldipyrrin (4c). Following a general procedure,20 a solution of absorption spectroscopy. After 15 min, the reaction mixture was
dihydrodipyrrin 15c (123 mg, 0.350 mmol) in 1,4-dioxane diluted with ethyl acetate, washed with brine and water, dried
(7.0 mL) was treated with SeO2 (117 mg, 1.05 mmol) under and concentrated to give an orange-red solid. The resulting
argon and stirred at room temperature for 60 min. Ethyl acetate residue (crude 4b) was dissolved in trimethyl orthoformate
(50 mL) was added, and the mixture was washed with saturated (7.2 mL), and TsOHÁH2O (415 mg, 2.16 mmol) was added at
aqueous NaHCO3 solution, water and brine. The organic layer room temperature under argon. After 1 h, the reaction mixture
was dried (Na2SO4), concentrated and chromatographed [silica, was diluted with ethyl acetate, washed with water, dried
hexanes/ethyl acetate (4 : 1)] to afford a yellow oil (50.1 mg, (Na2SO4), and concentrated. Column chromatography [silica,
39%): 1H NMR (300 MHz) d 1.17 (s, 6H), 1.21 (t, J = 7.2 Hz, hexanes/ethyl acetate (3 : 1)] afforded a yellow oil (130 mg, 52%):
3H), 2.41 (s, 3H), 2.71 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 6.08 1H NMR (400 MHz) d 1.22 (s, 6H), 1.35 (t, 3H), 2.30 (s, 3H), 2.53
(s, 1H), 7.23–7.29 (m, 4H), 7.63 (d, J = 3.0 Hz, 1H), 10.0 (s, 1H), (s, 3H), 2.62 (s, 2H), 3.47 (s, 6H), 4.27 (q, 2H), 5.02 (s, 1H), 5.84
11.1 (br, 1H); 13C NMR (100 MHz) d 14.3, 21.4, 29.1, 41.1, 46.1, (s, 1H), 10.7 (br, 1H); 13C NMR (100 MHz) d 11.1, 14.55, 14.60,
59.6, 112.4, 115.2, 127.3, 128.4, 129.4, 130.8, 136.9, 161.7, 164.5, 29.2, 40.4, 48.3, 54.6, 59.0, 102.7, 104.4, 111.1, 120.3, 125.9,
169.8, 189.9; ESI-MS obsd 365.1860, calcd 365.1860 [(M + H)+, 136.8, 158.9, 166.4, 173.9; ESI-MS obsd 349.2113, calcd 349.2122
M = C22H24N2O3]; labs (CH2Cl2) 451 nm.
[(M + H)+, M = C19H28N2O4].
1-[(N-tert-Butyl)iminomethyl]-8-ethoxycarbonyl-2,3-dihydro-
2,3-Dihydro-1-(1,1-dimethoxymethyl)-3,3-dimethyl-9-methyl-
3,3-dimethyl-7-p-tolyldipyrrin (4c-Im). A solution of 4c (22 mg, thiodipyrrin (6). Following a general procedure,19 In a first
0.060 mmol) in CH2Cl2 (6.0 mL) was treated with tert-BuNH2 flask, a solution of 19 (2.28 g, 6.63 mmol) in anhydrous THF
(25 mL, 0.24 mmol) under argon. The resulting mixture was (50 mL) under argon was treated with NaOMe (1.79 g,
stirred at room temperature and monitored by absorption 33.1 mmol). The mixture was bubbled with argon for 10 min
spectroscopy. After 2 h, the mixture was concentrated to afford and stirred for 1 h at room temperature. In a second flask, TiCl3
a brownish yellow solid (16 mg, 63%): mp 165–166 1C; 1H NMR (20 wt% TiCl3 in 3 wt% HCl, 21 mL, 33 mmol) and water
(300 MHz) d 1.16 (s, 6H), 1.20 (t, J = 7.2 Hz, 3H), 1.30 (s, 9H), (264 mL) were combined. The solution was bubbled with argon
2.40 (s, 3H), 2.81 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 5.86 (s, 1H), for 10 min, NH4OAc (51 g, 0.66 mol) was slowly added to buffer
7.19–7.30 (m, 4H), 7.56 (d, J = 3.0 Hz, 1H), 8.28 (s, 1H), 11.25 (br, the solution to pH 6.0, and then THF (18 mL) was added under
1H); 13C NMR (100 MHz) d 14.4, 21.4, 21.5, 29.1, 29.6, 40.3, 48.0, argon. After 30 min, the solution in the first flask was trans-
58.9, 59.4, 106.6, 114.7 125.4, 125.8, 128.4, 129.8, 130.8, 131.4, ferred via a cannula to the solution in the second flask. The
136.2, 153.5, 162.7, 165.0, 173.9; ESI-MS obsd 420.2658, calcd resulting mixture was stirred at room temperature for 14 h
420.2645 [(M + H)+, M = C26H33N3O2]; labs (CH2Cl2) 406 nm.
9-Ethoxycarbonyl-2,3-dihydro-1-(1,1-dimethoxymethyl)-3,3,7,8- added. The mixture was extracted with ethyl acetate. The
tetramethyldipyrrin (5a). Following a general procedure,21
organic layer was dried (Na2SO4), concentrated and chromato-
under argon. Then saturated aqueous NaHCO3 (500 mL) was
a
solution of 15a (104 mg, 0.361 mmol) in 1,4-dioxane (10.0 mL) graphed [alumina, hexanes/ethyl acetate (3 : 1)] to give a yellow
was treated with SeO2 (120. mg, 1.08 mmol) under argon and oil (0.28 g, 14%): 1H NMR (300 MHz) d 1.20 (s, 6H), 2.39 (s, 3H),
stirred at room temperature. The progress of the reaction 2.62 (s, 2H), 3.48 (s, 6H), 5.04 (s, 1H), 5.80 (s, 1H), 6.11 (m, 1H),
was monitored by absorption spectroscopy. After 15 min, the 6.25 (m, 1H), 10.58 (br, 1H); 13C NMR (100 MHz) d 21.5, 29.3,
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40.3, 48.2, 55.1, 103.1, 107.1, 110.7, 114.8, 123.3, 132.8, (t, J = 2.4 Hz, 1H), 6.77 (t, J = 2.4 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H),
160.5, 174.9; ESI-MS obsd 295.1477, calcd 295.1475 [(M + H)+, 7.32 (d, J = 8.2 Hz, 1H), 10.2 (br, 1H); 13C NMR (75 MHz) d 20.6,
M = C15H22N2O2S].
21.2, 22.9, 26.5, 27.2, 42.0, 54.3, 80.1, 108.1, 116.0 127.8, 128.1,
9-Bromo-1-formyl-2,3-dihydro-7-(4-iodophenyl)-3,3-dimethyl- 129.1, 134.4, 134.7, 174.5; ESI-MS obsd 281.2017, calcd 281.2012
dipyrrin (7). Following a general procedure,26 a solution of 20 [(M + H)+, M = C19H24N2].
(30. mg, 0.074 mmol) in THF (7.4 mL) was treated with NBS
2-Ethoxycarbonyl-3,4-dimethyl-5-(2-nitroethyl)pyrrole (12a).
(13 mg, 0.074 mmol) in one portion at À78 1C under argon. The Following a general procedure,19 samples of 11a (24 g, 0.12 mol),
reaction mixture was stirred at À78 1C for 1 h. Then hexanes/ nitromethane (19 mL, 0.36 mol), KOAc (13 g, 0.13 mol) and
Et3N (20 mL, 99 : 1) was added. The dry ice/acetone bath was CH3NH2ÁHCl (8.8 g, 0.13 mol) were stirred in MeOH (150 mL)
removed, and water (50 mL) was added. After the mixture for 3 h. The mixture was diluted with water (500 mL) and extracted
warmed to room temperature, ethyl acetate was added. The with CH2Cl2 (3 Â 100 mL). The combined extract was washed
organic extract was washed (brine and water), dried (Na2SO4), with brine (100 mL), dried and concentrated to give an orange-
concentrated and chromatographed [silica, hexane/CH2Cl2 red solid, which was dissolved in absolute ethanol (500 mL) and
(3 : 1)] to give an orange-red solid (16 mg, 45%): 1H NMR treated with NaBH4 (7.5 g, 0.20 mol). After 30 min, the mixture
(300 MHz) d 1.21 (s, 6H), 2.73 (s, 2H), 6.18 (s, 1H), 6.27 (d, J = was concentrated. The residue was taken up in water (200 mL),
3.0 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 10.02 and the solution was acidified with acetic acid to pH B5. The
(s, 1H), 10.80 (br, 1H); ESI-MS obsd 482.9568, calcd 482.9564 mixture was extracted with CH2Cl2. The extract was washed with
[(M + H)+, M = C18H16N2OBrI]. Note: compound 7 was prone to water and brine, dried (Na2SO4) and concentrated. Chromato-
decomposition upon dissolution in chlorinated solvents and graphy [silica, hexanes/ethyl acetate (3 : 1)] gave a yellow solid
1
during chromatography on silica, but was stable for weeks upon (10.3 g, 36%): mp 118–119 1C; H NMR (300 MHz) d 1.35 (t, J =
storage in the solid state at À20 1C.
7.2 Hz, 3H), 1.95 (s, 3H), 2.24 (s, 3H), 3.28 (t, J = 6.9 Hz, 2H), 4.30
7-(4-Bromophenyl)-1-(3-ethoxy-3-oxo-prop-1-enyl)-2,3-dihydro- (q, J = 7.2 Hz, 2H), 4.54 (t, J = 7.2 Hz, 2H), 8.80 (br, 1H); 13C NMR
3,3-dimethyldipyrrin (8). A solution of dihydrodipyrrin 21 (75 MHz) d 8.9, 10.9, 14.7, 24.4, 60.4, 74.4, 118.6, 118.7, 127.5,
(100 mg, 0.290 mmol) in 1,4-dioxane (6.0 mL) was treated with 127.6, 162.7; ESI-MS obsd 241.11828, calcd 241.11761 [(M + H)+,
SeO2 (110 mg, 0.991 mmol) at room temperature. The reaction M = C11H16N2O4].
progress was monitored with absorption spectroscopy. After
3-Ethoxycarbonyl-2,4-dimethyl-5-(2-nitroethyl)pyrrole (12b).
60 min, the reaction mixture was poured into saturated aqueous Following a general procedure,19 samples of 11b (7.35 g,
NaHCO3 solution. Then ethyl acetate (20 mL) was added. The 37.7 mmol), nitromethane (6.0 mL, 0.11 mol), KOAc (4.44 g,
organic layer was separated, dried (Na2SO4) and concentrated. 45.2 mmol) and CH3NH2ÁHCl (3.05 g, 45.2 mmol) were stirred
The residue was purified by passage through a short silica together in MeOH (40 mL) for 6 h. The mixture was diluted with
column with elution by CH2Cl2. The crude aldehyde was dis- water (300 mL) and extracted with CH2Cl2 (100 mL Â 3). The
solved in dry CH2Cl2 (6.0 mL) and treated with (ethoxycarbonyl- combined extract was washed with brine (100 mL), dried and
methylene)triphenylphosphorane (100 mg, 0.287 mmol). The concentrated to give an orange-red solid, which was dissolved
reaction mixture was stirred at room temperature for 20 h, and in absolute ethanol (200 mL) and treated with NaBH4 (2.83 g,
then concentrated to a solid. Chromatography [silica, hexanes/ 75.4 mmol). After 30 min, the mixture was concentrated. The
CH2Cl2 (1: 1)] gave a red solid (33 mg, 26%): mp 128–130 1C residue was taken up in water (200 mL), and the solution was
(dec.); 1H NMR (300 MHz) d 1.23 (s, 6H), 1.35 (t, J = 6.9 Hz, 3H), acidified with acetic acid. The mixture was extracted with CH2Cl2.
2.69 (s, 2H), 4.28 (q, J = 6.9 Hz, 2H), 6.11 (s, 1H), 6.29 (m, 1H), The extract was washed with water and brine, dried (Na2SO4),
6.26 (d, J = 16.2 Hz, 1H), 6.94 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), concentrated and chromatographed [silica, hexanes/ethyl acetate
7.52 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 16.2 Hz, 1H), 10.98 (br, 1H); (1 : 1)] to give a yellow solid (5.72 g, 63%): mp 127–129 1C;
13C NMR (75 MHz) d 14.4, 29.3, 41.2, 48.0, 61.2, 107.6, 109.4, 1H NMR (300 MHz) d 1.34 (t, J = 7.2 Hz, 3H), 2.17 (s, 3H),
119.9, 120.7, 127.6, 127.8, 130.3, 131.7, 135.8, 139.2, 162.0, 166.1, 2.44 (s, 3H), 3.20 (t, J = 6.9 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 4.50
169.9, 200.8; ESI-MS obsd 427.1010, calcd 427.1016 [(M + H)+, (t, J = 6.6 Hz, 2H), 8.35 (br, 1H); 13C NMR (100 MHz) d 10.9, 14.0,
M = C22H23BrN2O2].
2,3,4,5-Tetrahydro-1,3,3-trimethyl-7-p-tolyldipyrrin (9). Following obsd 241.11762, calcd 241.11828 [(M + H)+, M = C11H16N2O4].
a general procedure,25 a mixture of 10 (22 mg, 0.060 mmol) and
6-(5-Ethoxycarbonyl-3,4-dimethylpyrrol-2-yl)-4,4-dimethyl-5-
NH4OAc (16 mg, 0.24 mmol) in THF (6.0 mL) was treated with nitrohexan-2-one (14a). Following a general procedure,20
14.5, 23.3, 59.3, 75.0, 111.2, 118.4, 120.6, 135.4, 166.5; ESI-MS
a
zinc dust (16 mg, 0.24 mmol) under argon. The resulting mixture of 12a (6.69 g, 27.9 mmol) and 13a (8.23 g, 84.0 mmol)
mixture was stirred at room temperature. After 2 h, ethyl acetate was treated with DBU (12.5 mL, 84.0 mmol) at room tempera-
was added, and the mixture was filtered. The filtrate cake ture. After 16 h, the reaction mixture was diluted with ethyl
was washed with ethyl acetate. The filtrate was washed with acetate and washed with aqueous HCl (0.5 M), saturated
water/brine, dried (Na2SO4), concentrated and chromatographed aqueous NaHCO3 solution, and then brine. The organic layer
(silica, ethyl acetate) to afford a viscous yellow oil (16 mg, 63%): was dried (Na2SO4) and filtered. The filtrate was concentrated.
1H NMR (300 MHz) d 0.95 (s, 3H), 1.11 (s, 3H), 2.07 (s, 3H), The resulting residue was chromatographed (silica, CH2Cl2) to
2
3
2.36–2.39 (m, 5H), 2.63 (ABX, J = 15.3 Hz, J = 12.3, 1H), 3.02 give a pale-yellow solid (3.70 g, 44%): mp 130–131 1C; 1H NMR
(ABX, 2J = 15.3 Hz, 3J = 2.4, 1H), 3.70 (AB, J = 11.7 Hz, 1H), 6.31 (300 MHz) d 1.13 (s, 3H), 1.27 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H),
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1.92 (s, 3H), 2.15 (s, 3H), 2.21 (s, 3H), 2.50 (AB, 2J = 17.4 Hz, 2H), was dried, filtered and concentrated. Chromatography (silica,
2.98 (ABX, 2J = 15.3 Hz, 3J = 2.4 Hz, 1H), 3.27 (ABX, 2J = 15.3 Hz, CH2Cl2) afforded a light yellow solid (1.02 g, 32%): mp 116–118 1C;
3J = 11.7 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 5.12 (ABX, 2J = 11.7 Hz, 1H NMR (300 MHz) d 1.21 (s, 6H), 1.37 (t, J = 6.9 Hz, 3H), 2.03
3J = 2.4 Hz, 1H), 8.65 (br, 1H); 13C NMR (100 MHz) d 8.9, 10.7, (s, 3H), 2.24 (s, 3H), 2.27 (s, 3H), 2.52 (s, 2H), 4.29 (q, J = 6.9 Hz,
14.7, 24.2, 24.6, 25.2, 32.0, 37.0, 51.5, 60.1, 93.6, 118.5, 118.6, 2H), 5.68 (s, 1H), 11.16 (br, 1H); 13C NMR (75 MHz) d 8.9, 10.5,
127.1, 127.5, 161.8, 207.0; ESI-MS obsd 339.19145, calcd 339.19091 14.6, 21.0, 29.2, 41.5, 53.9, 59.5, 101.2, 118.4, 126.8, 131.3, 161.8,
[(M + H)+, M = C17H26N2O5].
6-(4-Ethoxycarbonyl-3,5-dimethylpyrrol-2-yl)-4,4-dimethyl-5- M = C17H24N2O2].
nitrohexan-2-one (14b). Following a general procedure,20
8-Ethoxycarbonyl-2,3-dihydro-1,3,3,7,9-pentamethyldipyrrin
163.9, 178.7; ESI-MS obsd 289.19105, calcd 289.19081 [(M + H)+,
a
mixture of 12b (5.72 g, 23.8 mmol) and 13a (7.00 g, 71.4 mmol) (15b). Following a general procedure,20 a solution of 14b
was treated with DBU (10.7 mL, 71.4 mmol) at room tempera- (6.08 g, 18.0 mmol) in THF/methanol (10 : 1, 20 mL) under
ture. After 16 h, the reaction mixture was diluted with ethyl argon was treated with NaOMe (2.92 g, 54.0 mmol). The mixture
acetate and washed with brine and water (200 mL Â 3). The was stirred at room temperature for 50 min. In a second flask,
organic layer was dried, filtered, concentrated and chromato- NH4OAc (68 g, 0.88 mol) in distilled THF/water (150 mL/50 mL)
graphed [silica, hexanes/ethyl acetate (1 : 1)] to give a yellow oil was bubbled with argon for 30 min. Then TiCl3 (20 wt% in
1
(6.08 g, 75%): H NMR (300 MHz) d 1.12 (s, 3H), 1.24 (s, 3H), 3 wt% HCl solution, 93 mL, 0.14 mol) was added, the mixture
1.33 (t, J = 7.2 Hz, 3H), 2.15 (s, 6H), 2.40 (s, 3H), 2.50 (AB, was degassed by bubbling argon for another 30 min. Then, the
2
2J = 17.4 Hz, 2H), 2.94 (ABX, J = 15.3 Hz, 3J = 2.4 Hz, 1H), 3.22 first flask mixture was transferred via cannula to the buffered
(ABX, 2J = 15.3 Hz, 3J = 11.4 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 5.05 TiCl3 solution. The resulting mixture was stirred at room
(ABX, 2J = 11.4 Hz, 3J = 2.4 Hz, 1H), 8.26 (br, 1H); 13C NMR temperature for 16 h under argon. The mixture was then filtered
(100 MHz) d 10.7, 13.8, 14.4, 23.9, 24.0, 24.2, 31.7, 36.6, 51.1, through a pad of Celite, washed with ethyl acetate. The eluent
59.0, 94.1, 110.8, 118.3, 120.5, 135.3, 166.3, 207.3; ESI-MS obsd was washed with saturated aqueous NaHCO3, then brine and
339.19178, calcd 339.19145 [(M + H)+, M = C17H26N2O5].
water. The organic layer was dried, filtered and concentrated.
6-(4-Ethoxycarbonyl-3-p-tolylpyrrol-2-yl)-4,4-dimethyl-5-nitro- Column chromatography (silica, CH2Cl2) afforded a light yellow
hexa-2-one (14c). Following a general procedure,20 a mixture of solid (3.32 g, 59%): mp 98–99 1C; 1H NMR (300 MHz) d 1.20
12c (1.81 g, 6.00 mmol) and 13a (0.820 mL, 7.20 mmol) was (s, 6H), 1.35 (t, J = 7.2 Hz, 3H), 2.20 (s, 3H), 2.29 (s, 3H), 2.49
treated with DBU (2.70 mL, 18.0 mmol) at room temperature. (s, 2H), 2.53 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H), 5.68 (s, 1H), 10.88 (br,
The reaction mixture became dark and was stirred for 16 h at 1H); 13C NMR (100 MHz) d 11.2, 14.7, 14.8, 20.9, 29.4, 41.4, 53.9,
room temperature. Ethyl acetate (100 mL) was added. The 59.1, 101.5, 111.0, 119.0, 126.4, 136.4, 160.4, 166.8, 176.5; ESI-MS
mixture was washed with water and brine. The organic layer obsd 289.19102, calcd 289.19105 [(M + H)+, M = C17H24N2O2].
was dried (Na2SO4) and concentrated. Column chromatography
8-Ethoxycarbonyl-2,3-dihydro-1,3,3-trimethyl-7-p-tolyldipyrrin
[silica, hexanes/ethyl acetate (3 : 2)] afforded a light yellow (15c). Following a general procedure,20 in a first flask, a solution
solid (1.22 g, 51%): mp 150–152 1C; 1H NMR (300 MHz) d of 14c (1.20 g, 3.00 mmol) in freshly distilled THF (30.0 mL) was
0.99 (s, 3H), 1.03 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H), 2.04 (s, 3H), 2.36 treated with NaOMe (825 mg, 15.0 mmol). The reaction mixture
(s, 3H), 2.27, 2.45 (AB, J = 17.7 Hz, 2H), 2.95 (ABX, 2J = 15.6 Hz, was stirred and degassed by bubbling argon through the
3
3J = 2.4 Hz, 1H), 3.19 (ABX, 2J = 15.6 Hz, J = 11.4 Hz, 1H), 4.12 solution for 45 min. In a second flask purged with argon, TiCl3
(q, J = 7.2 Hz, 2H), 4.97 (ABX, 2J = 11.4, 3J = 2.4 Hz, 1H), 7.13–7.17 (20 wt% in 2N HCl solution, 21 mL, 33 mmol) and 120 mL of
(m, 4H), 7.31 (d, J = 3.0 Hz, 1H), 8.65 (br, 1H); 13C NMR (100 MHz) H2O were combined under argon, and the mixture was degassed
d 14.4, 21.5, 23.9, 24.2, 24.9, 31.8, 37.0, 51.2, 59.6, 94.9, 115.2, by bubbling argon for 10 min. Then, NH4OAc (92.4 g, 1.20 mol)
124.1, 124.7, 125.2, 128.7, 130.4, 131.5, 136.5, 164.8, 206.8; ESI-MS was slowly added under argon bubbling to buffer the mixture to
obsd 401.2085, calcd 401.2071 [(M + H)+, M = C22H28N2O5].
pH 6.0. The mixture was further bubbled with argon for 30 min.
9-Ethoxycarbonyl-2,3-dihydro-1,3,3,7,8-pentamethyldipyrrin (15a). The mixture in the first flask was transferred via cannula to the
Following a general procedure,20 in a first flask, a solution of 14a buffered TiCl3 mixture. The resulting mixture was stirred at
(3.70 g, 10.9 mmol) in THF/methanol (10 : 1, 20 mL) under argon was room temperature for 16 h under argon. Then saturated aqueous
treated with NaOMe (1.78 g, 33.0 mmol). The mixture was NaHCO3 (250 mL) was added. The mixture was filtered over a
stirred at room temperature for 50 min. In a second flask, pad of Celite and eluted with ethyl acetate. The filtrate was
NH4OAc (41 g, 0.54 mol) in distilled THF (140 mL) was bubbled washed with water and brine. The organic layer was dried
with argon for 15 min. Then TiCl3 (20 wt% in 3 wt% HCl (Na2SO4), concentrated and chromatographed [silica, hexanes/
solution, 56 mL, 87 mmol) was added, and the mixture was ethyl acetate (9 : 1)] to afford a yellow solid (422 mg, 40%): mp
1
degassed by bubbling argon for another 30 min. Then, the first 83–85 1C; H NMR (300 MHz) d 1.13 (s, 6H), 1.21 (t, J = 7.2 Hz,
flask mixture was transferred via cannula to the buffered TiCl3 3H), 2.23 (s, 3H), 2.40 (s, 3H), 2.51 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H),
solution. The resulting mixture was stirred at room tempera- 5.67 (s, 1H), 7.19–7.30 (m, 4H), 7.51 (d, J = 2.7 Hz, 1H), 11.4
ture for 16 h under argon. The mixture was then filtered (br, 1H); 13C NMR (100 MHz) d 14.3, 20.7, 21.3, 29.0, 41.2, 53.8,
through a pad of Celite, and the filtered material was washed 59.2, 102.2, 114.2, 123.4, 124.7, 128.2, 129.9, 130.8, 131.8,
with ethyl acetate. The eluent was washed with saturated 135.7, 162.5, 165.0, 177.7; ESI-MS obsd 351.2075, calcd 351.2067
aqueous NaHCO3, then brine and water. The organic layer [(M + H)+, M = C22H26N2O2]; labs (CH2Cl2) 330 nm.
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2-Formyl-5-methylthiopyrrole (17). Following
Paper
a
general (Na2SO4) and concentrated. The resulting residue was dissolved
procedure,19 a solution of 16 (7.1 g, 63 mmol) in CH2Cl2 in methanol (8.0 mL) and refluxed for 5 h exposed to air. The
(120 mL) and DMF (7.1 mL, 94 mL) was treated dropwise with solution quickly turned green. Then the solution was concen-
POCl3 (8.7 mL, 94 mmol) under argon at 0 1C. After 1 h, the ice trated. The residue was dissolved in CH2Cl2, washed with brine
bath was removed, and the reaction mixture was allowed to and water, dried (Na2SO4) and concentrated. Chromatography
warm to room temperature. The reaction mixture was stirred [silica, hexanes/ethyl acetate (4 : 1)] afforded a green solid
1
for 20 h before being cooled to 0 1C again, whereupon 2.0 M (2.2 mg, 2.8%): H NMR (300 MHz) d 1.02 (t, J = 6.9 Hz, 3H),
NaOH (50 mL) was added. The reaction mixture was extracted 1.14 (s, 3H), 1.18 (s, 3H), 1.26 (s, 3H), 1.31 (s, 3H), 1.32 (s, 3H),
with CH2Cl2 (3 Â 50 mL). The organic extract was washed 1.34 (s, 3H), 1.60 (s, 3H), 1.89 (s, 2H), 2.08 (s, 3H), 2.30 (s, 3H),
(brine), dried (Na2SO4), concentrated and chromatographed 2.48 (s, 2H), 2.55 (AB, J = 18 Hz, 1H), 2.90 (AB, J = 18 Hz, 1H),
[silica, CH2Cl2/ethyl acetate (9 : 1)] to afford a dark red solid 3.10 (AB, J = 18 Hz, 2H), 4.07 (m, 2H), 4.88 (s, 1H), 5.71 (s, 1H),
1
(4.5 g, 51%): mp 96–98 1C; H NMR (300 MHz) d 2.52 (s, 3H), 5.90 (s, 1H), 6.34 (d, J = 3.0 Hz, 1H), 6.87 (s, 1H), 7.19–7.24
6.28 (m, 1H), 6.96 (m, 1H), 9.36 (s, 1H), 10.98 (br, 1H); 13C NMR (m, 4H), 7.45–7.50 (m, 4H), 10.53 (br, 1H), 11.15 (br, 1H), 12.67 (br,
(75 Hz) d 17.7, 112.9, 123.6, 133.9, 136.9, 178.1; ESI-MS obsd 1H); ESI-MS obsd 966.2793, calcd 966.2826 [M+, M = C53H56Br2N6O2];
142.0323, calcd 142.0321 [(M + H)+, M = C6H7NOS].
labs (CH2Cl2) 333, 637 nm.
2-(2-Nitroethyl)-5-methylthiopyrrole (18). Following a general
7,10,13-Tris(4-bromophenyl)-2,3,17,18-tetrahydro-1,3,3,17,17,19-
procedure,19 a solution of 17 (4.70 g, 33.3 mmol), potassium hexamethylbiladiene-ac (25). A solution of 4-bromobenzaldehyde
acetate (3.91 g, 40.0 mmol) and methylamine hydrochloride (24, 5.3 mg, 0.029 mmol) and dihydrodipyrrin 21 (20. mg,
(2.75 g, 40.0 mmol) in absolute ethanol (40 mL) was treated with 0.058 mmol) in CH2Cl2 (3.0 mL) was treated with Ga(OTf)3
nitromethane (5.5 mL, 100 mmol). The mixture was stirred for (45 mg, 0.087 mmol) and stirred at room temperature for 20 h.
4 h and monitored by TLC analysis [silica, CH2Cl2/ethyl acetate Saturated aqueous NaHCO3 solution was added, whereupon the
(3: 1)]. Then, water was added. The mixture was extracted with mixture was extracted with CH2Cl2. The combined organic
CH2Cl2. The organic phase was dried and concentrated to give a extract was combined, washed with brine, dried (Na2SO4) and
red solid. The crude solid was dissolved in a mixture of CHCl3 concentrated to a magenta solid (22 mg, 88%), which was
(75 mL) and 2-propanol (24 mL), to which silica (23 g) was then characterized and used in the next step without further purifica-
added. The mixture was stirred vigorously, and NaBH4 (1.90 g, tion: 1H NMR (300 MHz) d 1.14 (s, 12H), 1.98 (s, 6H), 2.44 (s, 4H),
50.0 mmol) was added in several batches. After 1 h, the mixture 5.51 (s, 1H), 5.84 (s, 2H), 6.09 (d, J = 3.0 Hz, 2H), 7.27–7.31 (m,
was filtered. The filter cake was washed with CH2Cl2. The filtrate 6H), 7.44–7.50 (m, 6H), 10.93 (br, 2H); 13C NMR (75 MHz) d 20.6,
was concentrated and chromatographed (silica, CH2Cl2) to 29.2, 41.3, 44.1, 53.8, 102.2, 107.6, 119.1, 120.9, 122.6, 126.9,
afford an orange-red oil (2.59 g, 42%): 1H NMR (300 MHz) 130.0, 130.7, 131.5, 131.8, 133.0, 136.3, 141.3, 161.7, 177.1. The
d 2.32 (s, 3H), 3.28 (t, J = 6.6 Hz 2H), 4.59 (t, J = 6.6 Hz, 2H), compound was easily oxidized and gave m/z of the corres-
5.97 (m, 1H), 6.25 (m, 1H), 8.16 (br, 1H); 13C NMR (100 MHz) d ponding oxidized product (–2H): ESI-MS obsd 849.0779, calcd
21.6, 25.6, 75.0, 108.5, 115.5, 121.4, 128.4; ESI-MS obsd 187.0541, 849.0798 [(M + H)+, M = C43H39Br3N4].
calcd 187.0536 [(M + H)+, M = C7H10N2O2S].
Chloroindium(III)-13-ethoxycarbonyl-8,8,18,18-tetramethyl-
1,1-Dimethoxy-4,4-dimethyl-5-nitro-6-(5-methylthiopyrrol-2- 2,12-di-p-tolylbacteriochlorin (InBC-1)
yl)hexan-2-one (19). Following a general procedure,19 a mixture
Method A. A solution of dihydrodipyrrins 22 (7.0 mg, 0.025 mmol)
of 18 (2.59 g, 13.9 mmol) and 13b (4.39 g, 27.8 mmol) was and 5c (10. mg, 0.025 mmol) in CH2Cl2 (2.5 mL) was treated with
treated with DBU (4.3 mL, 28 mmol) at room temperature. After Bi(OTf)3 (33 mg, 0.050 mmol). After stirring for 20 min at room
16 h, the reaction mixture was diluted with ethyl acetate and temperature, the reaction mixture was quenched by the addition
washed with water. The organic layer was dried (Na2SO4), of Et3N (0.06 mmol, 8 mL) and then concentrated. The resulting
concentrated and chromatographed [silica, hexanes/ethyl acetate crude product was dissolved in CH2Cl2 (2.5 mL), and the stock
1
(3: 1)] to give a red oil (2.28 g, 48%): H NMR (300 MHz) d 1.14 solution was distributed among five microvials. The solution in
(s, 3H), 1.22 (s, 3H), 2.29 (s, 3H), 2.65 (AB, 2J = 18.9 Hz, 2H), each vial was concentrated to a solid. The resulting solids were
2.98 (ABX, 2J = 15.6 Hz, 3J = 2.4 Hz, 1H), 3.32 (ABX, 2J = 15.6 Hz, dissolved in the indicated solvent. Then each solution was treated
3J = 12.0 Hz, 1H), 3.43 (s, 3H), 3.44 (s, 3H), 4.37 (s, 1H), 5.14 (ABX, with InCl3 (11 mg, 0.050 mmol) and TMPi (9 mL, 0.05 mmol) and
3
2J = 12.0 Hz, J = 2.4 Hz, 1H), 5.93 (m, 1H), 6.20 (m, 1H), 8.10 each reaction mixture was stirred at the indicated temperature.
(br, 1H); 13C NMR (100 MHz) d 21.8, 24.3, 24.4, 27.0, 36.6, 45.1, The progress of each microreaction was monitored by absorption
55.4, 94.5, 104.9, 109.1, 115.7, 121.4, 128.6, 203.7; ESI-MS obsd spectroscopy. After 1.5 h, each microreaction mixture was diluted
345.1473, calcd 345.1479 [(M + H)+, M = C15H24N2O5S].
with CH2Cl2. Water was added to each microvial, and the organic
10-[7-(4-Bromophenyl)-2,3-dihydro-1,3,3-trimethyldipyrrin-9- extract was separated, washed with brine, dried (Na2SO4), con-
yl]-13-(4-bromophenyl)-1-ethoxycarbonyl-2,3,7,7,17,17-hexamethyl- centrated and chromatographed [silica, CH2Cl2/ethyl acetate
1,20-dihydrobacteriochlorin (23). A mixture of 21 (24 mg, (4 : 1)] to give the indium bacteriochlorin. The bacteriochlorin
0.079 mmol) and 4a (54 mg, 0.16 mmol) in dry CH2Cl2 yields were determined spectroscopically (Table S1, ESI†). The
(8.0 mL) was treated with Ga(OTf)3 (123 mg, 0.24 mmol) and highest yield was obtained for the reaction carried out in
stirred under argon at room temperature for 20 h. The mixture toluene (8%, estimated by absorption spectroscopy at 773 nm,
was diluted with CH2Cl2, washed with brine thoroughly, dried e assumed43 = 100 000 MÀ1 cmÀ1).
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Method B. A solution of 4c-Im (25 mg, 0.060 mmol) and 9 688.1462 [M+, M = C35H38BrCuN4O2]; labs (CH2Cl2) 540 nm. The
(17 mg, 0.060 mmol) in CH2Cl2 (6.0 mL) was treated with residue was dissolved in ethylene glycol (6.0 mL) and treated
Bi(OTf)3 (79 mg, 0.12 mmol). After stirring for 15 min at room with powdered NaOH (228 mg, 5.70 mmol). The mixture was
temperature, the reaction mixture was quenched by the addition degassed by bubbling with argon, then heated to 160 1C under
of TMPi (0.10 mL, 0.60 mmol) and then concentrated to a brown argon, and stirred for 1 h. The mixture was allowed to cool to
solid. The residue was dissolved in toluene (6.0 mL) and treated room temperature, then diluted with ethyl acetate (100 mL) and
with InCl3 (133 mg, 0.60 mmol) and TMPi (0.10 mL, 0.60 mmol). washed thoroughly with brine and water. The resulting organic
The reaction mixture was stirred at 80 1C. Absorption spectro- phase was dried (Na2SO4), concentrated and chromatographed
scopy of the reaction mixture showed the formation of the [silica, hexanes/CH2Cl2 (1: 1)] to give a green solid (2% yield,
indium bacteriochlorin. After 2 h, the reaction mixture was estimated by absorption spectroscopy at 744 nm, e assumed48
=
diluted with ethyl acetate (50 mL). The organic extract was 130 000 MÀ1 cmÀ1): MALDI-MS obsd 612.9; ESI-MS obsd 613.1012,
washed with brine and water, dried (Na2SO4), concentrated and calcd 613.1022 [M+, M = C32H31BrCuN4]; labs (toluene) 337, 385,
chromatographed [silica, hexanes/ethyl acetate (3 : 2 to 1 : 1)] to 511, 744 nm.
1
afford InBC-1 as a pink solid (1 mg, 2%): H NMR (400 MHz)
Copper(II)-2-(4-bromophenyl)-13-ethoxycarbonyl-8,8,12,18,18-
d 1.28 (t, J = 7.2 Hz, 3H), 1.76 (s, 3H), 1.78 (s, 3H), 1.94 (s, 3H), pentamethyl-7,17-dioxobacteriochlorin (CuBC-4). A mixture of
2.06 (s, 3H), 2.60 (s, 6H), 4.31–4.61 (m, 6H), 7.47 (d, J = 8.0 Hz, dihydrodipyrrin-acetal 5b (20. mg, 0.057 mmol) and dihydrodi-
2H), 7.56 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.99 pyrrin 21 (20. mg, 0.057 mmol) in CH2Cl2 (6 mL) was treated
(d, J = 8.0 Hz, 2H), 8.43 (s, 1H), 8.62 (s, 1H), 8.67 (s, 1H), 8.69 with Cu(OTf)2 (25 mg, 0.068 mmol) at room temperature under
(s, 1H), 9.68 (s, 1H); MALDI-MS found 769.8; ESI-MS obsd argon for 90 min. Then saturated aqueous NaHCO3 solution
769.1810, calcd 769.1806 [(M À H)À, M = C41H40ClInN4O2]; ESI-MS was added to the reaction mixture, which was then extracted
obsd 735.2175, calcd 735.2185 [(M À Cl)+, M = C41H40ClInN4O2]; with CH2Cl2. The combined organic extract was washed with
labs (toluene) 353, 391, 550, 773 nm; lem (lexe = 550 nm) 789 nm. brine and water, dried (Na2SO4) and concentrated to a red-
Chloroindium(III)-12-(4-iodophenyl)-8,8,18,18-tetramethyl-2- purple solid with the following characterization data: MALDI-MS
p-tolylbacteriochlorin (InBC-2). A solution of 9 (3.1 mg, obsd 689.2; ESI-MS obsd 688.1444, calcd 688.1469 [M+, M =
0.011 mmol) and 7 (5.3 mg, 0.011 mmol) in CH2Cl2 (1.1 mL)
C35H38BrCuN4O2]; labs (CH2Cl2) B 550 nm. The residue was
was treated with TsOHÁH2O (10. mg, 0.055 mmol). After stirring dissolved in DMF (10 mL) and treated with anhydrous CuCl2
for 50 min at room temperature, the reaction mixture was (115 mg, 0.858 mmol). The mixture was degassed by bubbling
quenched by the addition of TMPi (19 mL, 0.11 mmol) and then argon for 10 min and then heated to 120 1C for 20 h under
concentrated. The resulting residue was dissolved in toluene argon. The mixture was allowed to cool to room temperature
(1.1 mL) and treated with InCl3 (24 mg, 0.11 mmol) and TMPi and then diluted with ethyl acetate (100 mL) and washed
(19 mL, 0.11 mmol). The reaction mixture was stirred at 90 1C. thoroughly with water (4 Â 100 mL). The organic phase was
The reaction progress was monitored by absorption spectro- dried (Na2SO4), concentrated and chromatographed [silica,
scopy. After 2 h, the reaction mixture was diluted with ethyl hexanes/ethyl acetate (4 : 1 then 3 : 1)] to give a green solid
acetate. The organic extract was washed with brine and water, (2% yield, estimated by absorption spectroscopy at 711 nm,
dried (Na2SO4), concentrated and chromatographed [silica, CH2Cl2 e assumed48 = 130 000 MÀ1 cmÀ1): MALDI-MS obsd 700.1; ESI-MS
then CH2Cl2/ethyl acetate (4 : 1)] to afford a pink solid (1%, obsd 718.0836, calcd 718.0846 [(M + H3O)+, M = C34H29BrCuN4O4];
estimated by absorption spectroscopy at 765 nm, e assumed43
100 000 MÀ1 cmÀ1): 1H NMR (400 MHz) d 1.82 (s, 3H), 1.84
=
labs (toluene) 388, 434, 528, 711 nm.
7-(4-Bromophenyl)-1-(3-ethoxy-3-oxo-prop-1-enyl)-7,8,17,18-
(s, 3H), 2.07 (s, 3H), 2.08 (s, 3H), 2.60 (s, 3H), 4.43 (AB, 2J = tetradehydro-3,3,13,13-tetramethyl-17-p-tolylcorrin (TDC-3).
16.8 Hz, 3J = 4.4 Hz, 2H), 4.64 (AB, 2J = 18.0 Hz, 2H), 7.57 (d, J = A solution of 3 (33 mg, 0.079 mmol) and 8 (33 mg, 0.077 mmol)
8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 8.08 in CH2Cl2 (7.7 mL) was treated with Ga(OTf)3 (120 mg, 0.235 mmol)
(d, J = 8.4 Hz, 2H), 8.73 (s, 1H), 8.75 (s, 1H), 8.77 (m, 2H), 8.78 at room temperature under argon. After 2 h, TLC analysis indi-
(s, 1H), 8.82 (s, 1H); MALDI-MS obsd 812.4; ESI-MS obsd cated the completion of the reaction. Saturated aqueous NaHCO3
810.0476, calcd 810.0472 [M+, M = C37H33ClIInN4]; obsd 775.0780, solution was added. The organic extract was dried (Na2SO4) and
calcd 775.0783 [(M À Cl)+, M = C37H33ClIInN4]; labs (toluene) concentrated. Chromatography [silica, CH2Cl2/hexanes (1 : 1)] gave
350, 389, 539, 765 nm; lem (lexe = 539 nm) 775 nm.
a green solid (12 mg, 21%): 1H NMR (400 MHz) d 1.23–1.26
Copper(II)-2-(4-bromophenyl)-8,8,12,13,18,18-hexamethylbacterio- (m, 15H), 1.97 (d, J = 12.8 Hz, 1H), 2.38 (s, 3H), 2.46 (d, J =
chlorin (CuBC-3). A mixture of dihydrodipyrrin-acetal 5a (20. mg, 12.8 Hz, 1H), 2.67–2.78 (AB, J = 17.6 Hz, 2H), 4.12 (q, J = 6.8 Hz,
0.057 mmol) and dihydrodipyrrin 21 (20. mg, 0.057 mmol) in 2H), 5.43 (s, 1H), 5.58 (s, 1H), 6.00 (d, J = 15.2 Hz, 1H), 6.09 (s,
CH2Cl2 (6 mL) was treated with Cu(OTf)2 (50 mg, 0.14 mmol) at 1H), 6.23 (d, J = 3.2 Hz, 1H), 6.68 (d, J = 1.6 Hz, 1H), 7.19–7.23
room temperature under argon for 90 min. Then saturated (m, 3H), 7.37–7.42 (m, 5H), 7.62 (d, J = 8.4 Hz, 1H), 11.43
aqueous NaHCO3 solution was added to the reaction mixture, (br, 1H), 11.99 (br, 1H); 13C NMR (75 MHz) d 14.4, 21.3, 25.9,
which was then extracted with CH2Cl2. The combined organic 28.1, 29.0, 30.0, 40.7, 48.9, 49.3, 52.3, 60.5, 73.7, 92.5, 97.0,
extract was washed with brine and water, dried (Na2SO4) and 102.5, 103.0, 116.4, 122.0, 123.1, 126.0, 128.0, 129.4, 130.2,
concentrated to a red-purple gum with the following character- 131.9, 132.2, 134.4, 135.0, 142.2, 142.4, 147.9, 149.7, 152.9,
ization data: MALDI-MS obsd 689.2; ESI-MS obsd 688.1469, calcd 164.1, 167.0, 170.1, 181.8, 200.9; LD-MS obsd 701.2, calcd
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701.2 [(M + H)+]; ESI-MS obsd 700.2388, calcd 700.2407 [(M+), Conflicts of interest
M = C41H41BrN4O2]; labs (CH2Cl2) 340, 438, 693 (br) nm.
There are no conflicts to declare.
7,8,17,18-Tetradehydro-1,3,3,13,13-pentamethyl-7-p-tolyl-18-
methylthiocorrin (TDC-4). A solution of 22 (11 mg, 0.040 mmol)
and 6 (12 mg, 0.040 mmol) in CH2Cl2 (40 mL) was treated with
Yb(OTf)3 (124 mg, 0.200 mmol) under argon at room tempera-
Acknowledgements
This work was funded by the Division of Chemical Sciences,
Geosciences, and Biosciences, Office of Basic Energy Sciences
of the US Department of the Energy (FG02-05ER15661). Mass
spectra were obtained at the Mass Spectrometry Laboratory
for Biotechnology at North Carolina State University or the
Mass Spectrometry Laboratory at Duke University. We thank
ture and stirred for 3 h. Then, saturated aqueous NaHCO3
solution (50 mL) was added. The organic extract was washed
with brine and water, dried (Na2SO4), concentrated, and
chromatographed [silica, hexanes/ethyl acetate (3 : 1)] to give a
dark green solid (10.1 mg, 50%): 1H NMR (400 MHz) d 1.05
(s, 3H), 1.23 (s, 3H), 1.27 (s, 3H), 1.40 (s, 3H), 1.67 (s, 3H), 2.00
(d, J = 12.8 Hz, 1H), 2.33 (s, 3H), 2.43 (s, 3H), 2.51 (d, J = 12.8 Hz,
1H), 2.69 (d, J = 17.6 Hz, 1H), 2.76 (d, J = 17.6 Hz, 1H), 5.54
(s, 1H), 5.56 (s, 1H), 5.80 (s, 1H), 6.14 (m, 1H), 6.85 (m, 1H), 7.29
(d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 10.88 (br, 1H), 11.61
(br, 1H); 13C NMR (100 MHz) d 21.6, 21.9, 27.3, 29.0, 29.3, 29.9,
30.0, 40.6, 49.4, 49.9, 52.4, 72.1, 94.1, 95.6, 102.2, 106.8, 110.4,
127.1, 128.6, 129.8, 130.3, 139.0, 143.7, 148.3, 148.5, 149.4,
163.6, 170.5, 179.7; ESI-MS obsd 509.2732, calcd 509.2733
[(M + H)+, M = C32H36N4S]; labs (CH2Cl2) 318, 438, 661 (br) nm.
7,10,13-Tris(4-bromophenyl)-7,8,12,13-tetradehydro-1,3,3,17,
17,19-hexamethylcorrinatonickel(II) chloride (NiTDC-5). Biladiene
25 (22 mg, 0.026 mmol), nickel acetate tetrahydrate (30. mg,
0.12 mmol) and sodium acetate (30. mg, 0.36 mmol) were
dissolved in methanol (3.0 mL) and heated to reflux for
30 min. The solution quickly turned to an indigo color. The
resulting solution was concentrated, poured into water and
extracted with CH2Cl2. The combined extract was dried (Na2SO4),
concentrated to dryness, and chromatographed on alumina. The
column was eluted with CH2Cl2 until the eluate was colorless
and then with methanol/CH2Cl2 (1: 10). The indigo-colored
fraction was collected, shaken with aq HCl solution (20 mL,
0.5 M), dried (Na2SO4) and concentrated. The residue was
crystallized (CH2Cl2/hexanes) as dark blue needles (20 mg,
82%): 1H NMR (700 MHz) d 1.56 (s, 12H), 1.63 (s, 6H), 2.44
(AB, J = 10.4 Hz, 2H), 2.64 (AB, J = 10.4 Hz, 2H), 6.86 (s, 2H), 7.30
(s, 2H), 7.42 (m, 6H), 7.71 (m, 6H); 13C NMR (175 MHz) d 29.0,
29.2, 29.8, 32.1, 44.6, 51.9, 85.1, 103.6, 123.6, 124.3, 130.7, 131.2,
131.9, 132.3, 132.6, 133.8, 134.7, 148.9, 154.9, 156.4, 173.3;
MALDI-MS obsd 905.5; ESI-MS obsd 904.9973, calcd 904.9995
[M+, M = C43H38Br3N4Ni]; labs (CH2Cl2) 349, 601 nm.
´
Dr Dorothee Lahaye for exploratory work.
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