A trans-AB-bacteriochlorin building block

Article abstract of DOI:10.1021/jo201967k

Synthetic bacteriochlorins are of interest for fundamental studies in photochemistry because of their strong absorption in the near-infrared spectral region and close similarity with natural bacteriochlorophylls. A de novo route to 5-methoxybacteriochlori

Full text of DOI:10.1021/jo201967k

Article
pubs.acs.org/joc
A trans-AB-Bacteriochlorin Building Block
Olga Mass and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204, United States
S
* Supporting Information
ABSTRACT: Synthetic bacteriochlorins are of interest for fundamental studies in photochemistry
because of their strong absorption in the near-infrared spectral region and close similarity with natural
bacteriochlorophylls. A de novo route to 5-methoxybacteriochlorins entails self-condensation of a
dihydrodipyrrin−acetal, which in turn is prepared from a 2-(2-nitroethyl)pyrrole species and an α,β-
unsaturated ketone−acetal (e.g., 1,1-dimethoxy-4-methylpent-3-en-2-one). Here, four new results are
reported concerning the synthesis of substituted bacteriochlorins. First, a new, scalable route to 1,1-
dimethoxy-4-methylpent-3-en-2-one removes a significant previous impediment to the overall route.
Second, the new route was employed to gain access to new α,β-unsaturated ketones and corresponding
dihydrodipyrrins bearing alternative substituents in place of the dimethoxy unit. Third, a dihydrodipyrrin
bearing a 1,3-dioxolan-2-yl moiety afforded the bacteriochlorin (30% yield) containing a 2-hydroxyethoxy substituent at the 5-
position. Fourth, subsequent bromination proceeded regioselectively at the 15-position to give a trans-(5,15)-AB-bacteriochlorin
building block. The linear 5,15-substitution pattern is attractive for a number of molecular designs. The results taken together
afford deeper understanding of the scope and limitations of the de novo route and also advance the capabilities for tailoring
synthetic bacteriochlorins.
corresponding trans-AB-bacteriochlorin building blocks (albeit
composed of a mixture of diastereomers, entry III).31
INTRODUCTION
■
A longstanding theme in tetrapyrrole chemistry has been the de
novo synthesis of building blocks for use in studies
encompassing the broad fields of biomimetic chemistry,
materials science, and clinical medicine. Porphyrins with up
to four distinct meso-substituents are readily available.1,2 The
chemistry of chlorins is less developed, but chlorin macrocycles
with substituents at designated meso- and β-pyrrole sites have
been prepared.3,4 For bacteriochlorins, synthetic access is under
active development. Bacteriochlorins are of considerable
interest owing to their strong absorption in the near-infrared
spectral region, which is attractive for solar energy applications,
low-energy photochemistry, and deep-tissue light-mediated
medical therapies.5,6 Realizing the scientific potential of
bacteriochlorins has been largely crimped, however, by the
limited means for synthesis of stable, tailorable bacteriochlorin
building blocks.7
Distinct methods for the synthesis of bacteriochlorins entail
semisynthesis procedures beginning with bacteriochlorophyll
a,8−14 hydrogenation15,16 of (or addition to)4,17−22 synthetic
porphyrins and chlorins, and de novo routes.5,23−28 Each has
strengths and limitations. Representative building blocks
available via such methods are shown in Chart 1. Derivatization
of bacteriochlorophyll a to form the imide ring stabilizes the
macrocycle and provides a convenient handle at the N-imide
site for derivatization (entry I).29 Still, few other sites are
available given the nearly full complement of β-substituents.
meso-Tetraarylbacteriochlorins (entry II) are readily synthe-
sized, yet the presence of four identical substituents may limit
the accessible architectures. Two variants on this approach
A rational, de novo route to synthetic bacteriochlorins25,28
that we have been developing affords the following features: (1)
resiliency of the macrocycles toward dehydrogenation upon
routine handling by virtue of a geminal-dimethyl group in each
reduced ring;25 (2) a relatively concise (8-step) synthesis;27,28
(3) characteristic bacteriochlorin absorption and photophysical
features;6,32 and (4) ability to introduce a variety of β-pyrrole
substituents.5,26,28 The synthetic route employs the acid-
mediated, room-temperature self-condensation of a dihydrodi-
pyrrin−acetal (Scheme 1). The use of TMSOTf in the presence
of 2,6-di-tert-butylpyridine (2,6-DTBP) results in the formation
of the 5-methoxybacteriochlorin in 8.4−63% yield, depending
on the nature of the β-pyrrolic substituents.28 The 5-
methoxybacteriochlorin BC-1 undergoes regioselective electro-
philic bromination at the 15-position,33 enabling further
derivatization at this site via diverse palladium-coupling
processes.29,33 In contrast, bromination of the 5-unsubstituted
bacteriochlorin BC-2 (available via BF3·OEt2 or other
catalysis)28 results in a mixture of mono- and dibromobacterio-
chlorins.33
While the de novo method has provided access to a larger
palette of substituted bacteriochlorins versus those via semi-
synthesis or porphyrin/chlorin reductive transformations,
numerous limitations have persisted: (1) the substituents at
the 2- and 12-positions are identical with each other (R), as are
those at the 3- and 13-position (R′) and (2) the 5-position has
heretofore been occupied either by −H or −OCH3.
Accordingly, access to trans-AB-bacteriochlorins akin to those
include (i) a strategy by Bruckner to achieve wavelength
̈
tunability30 and (ii) a strategy by Boyle wherein trans-AB-
Received: September 22, 2011
Published: October 28, 2011
porphyrins undergo vicinal dihydroxylation to afford the
© 2011 American Chemical Society
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Chart 1. Bacteriochlorophyll a and Bacteriochlorin Building
Scheme 1. De Novo Route to Bacteriochlorins
Blocks
of Boyle has not been available. A linear pattern of meso-AB-
substituents is attractive for the design of diverse molecular
architectures.
To achieve a trans-AB substituent pattern in bacteriochlorins,
we considered that alternative dihydrodipyrrin units could be
employed in the self-condensation. Because the acetal carbon of
the dihydrodipyrrin−acetal (i.e., the α-carbon at the 1-position)
forms the 5- and 15- carbons of the bacteriochlorin, alternative
substituents at the “acetal” α-carbon in lieu of the methoxy
group could be conveyed to the bacteriochlorin 5-position. The
15-position would then be accessible for bromination and
subsequent substitution processes. This analysis is consistent
with our current conceptualization of the mechanism of
formation of the 5-methoxybacteriochlorin (Scheme 2).
Treatment of the dihydrodipyrrin−acetal with TMSOTf affords
an oxocarbenium ion and eliminates one molecule of methanol
(as the trimethylsilyl ether); the oxocarbenium ion serves as the
electrophile for attack by the pyrrole of the other
dihydrodipyrrin−acetal. Repetition of this process eliminates
a second molecule of methanol and affords the 5,15-dimethoxy-
5,15-dihydrobacteriochlorin. Elimination of the third molecule
of methanol results in the aromatic bacteriochlorin macrocycle
containing the 5-methoxy substituent.25
bacteriochlorin, which contains a 5-(2-hydroxyethoxy) sub-
stituent. Bromination of the 5-(2-hydroxyethoxy)-
bacteriochlorin proceeded smoothly at the 15-position,
affording the bacteriochlorin with reactive functional groups
in a trans-AB architecture.
RESULTS AND DISCUSSION
■
Synthesis of New Michael Acceptors. Reconnais-
ance. The first reported synthesis of Michael acceptor 1a
was carried out in 56% yield when 2 mmol of mesityl oxide was
treated with 10 mol % of diphenyl diselenide and excess
ammonium peroxydisulfate in methanol (Scheme 3).34
A
subsequent scaled-up procedure (160-mmol scale) afforded 1a
in 29% yield.25 Significant drawbacks to the synthesis of 1a
remain: (i) the use of expensive and toxic diphenyl diselenide;
(ii) difficult purification including distillation followed by
extensive chromatography, and (iii) relatively low yield.
Moreover, the method has limited scope for introduction of
substituents other than the dimethoxymethyl unit, which gives
rise to the 5-methoxy substituent in the bacteriochlorin. Here, a
Here, we report the synthesis of a handful of dihydrodi-
pyrrins (containing diverse substituents at the 1-position) and
investigate their conversion to bacteriochlorins. The synthesis
of the dihydrodipyrrins was facilitated by the development of a
new route to the α,β-unsaturated ketone−acetal 1a (the
Michael acceptor in formation of the dihydrodipyrrin−acetal),
which also is reported herein. Among four new dihydrodi-
pyrrins, one was found to afford the corresponding
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Scheme 2. Key Steps in the Formation of 5-Methoxybacteriochlorin
Scheme 3. Prior and Envisaged Routes to Michael Acceptors
Scheme 4. New Scalable Synthesis of Michael Acceptors via a
Nitrile Intermediate
scalable and more versatile synthesis of Michael acceptors was
envisaged to entail reaction of 2-methyl-1-propenylmagnesium
bromide (4) with an acetal-containing nitrile or Weinreb amide
(N-methoxy-N-methylamide; Scheme 3). To our knowledge,
preparation of α,β-unsaturated ketones by reaction of a nitrile
and a vinyl Grignard reagent has not been reported previously.
Our attempts to prepare the 1,1-dialkoxy-α,β-unsaturated
ketones via the Weinreb amide method were not successful
(see the Supporting Information); however, we did prepare
such compounds via the nitrile method. The α,β-unsaturated
ketones bearing a single alkoxy group or other substituents
examined herein were prepared via the Weinreb amide method
(vide infra).
Synthesis of Michael Acceptors via Nitrile Method.
Treatment of trimethyl orthoformate with an equimolar
amount of trimethylsilyl cyanide in the presence of 10 mol %
of BF3·OEt2 afforded dimethoxyacetonitrile (5a).35,36 The
reaction was carried out at 255-mmol scale (11-fold larger
than the literature procedure35). Reaction of 5a with 1.2 molar
equiv of Grignard reagent 4 at room temperature for 2.5 h
followed by hydrolysis with saturated aqueous NH4Cl afforded
1a as the major product (Scheme 4). The two-step synthesis
was carried out with streamlined workup procedures:
distillation at atmospheric pressure gave 5a in 90% yield
(>90% purity), whereas distillation at reduced pressure gave 1a
in 57% yield (16.5 g, 90% purity). The formation of 1a is
accompanied by trace quantities of multiple products that could
not be fully separated by distillation; on the other hand, when
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column chromatography [silica, hexanes/ethyl acetate] was
employed, 1a was obtained in high purity yet only 29% yield.
The two-step synthesis of 1a also uses little solvent. The
conversion of trimethyl orthoformate to 5a is solvent-free, and
the conversion of 5a to 1a employs 2-methyl-1-propenylmag-
nesium bromide (4, available commercially as a 0.5 M solution
in THF) and no other solvent. In this regard, both reactions are
carried out at the highest possible concentration, an approach
commensurate with the objective of preparing multigram
quantities of the valuable intermediate 1a. Although the yield
of this transformation is not high, the nitrile method overcomes
the limitations of the prior synthesis with diphenyl diselenide
and, moreover, can be employed to prepare α,β-unsaturated
ketones with diverse functionalities at the methyl site.
The new route established for 1a was extended to two other
Michael acceptors. First, commercially available diethoxyaceto-
nitrile afforded diethoxymethyl Michael acceptor 1b in 45%
yield (Scheme 4). Second, treatment of 2-methoxy-1,3-
dioxolane with 1 molar equiv of trimethylsilyl cyanide in the
presence of a catalytic amount of In(OTf)3 for 1 h at 0 °C
afforded 1,3-dioxolane-2-carbonitrile. (An exploratory survey
showed BF3·OEt2, InCl3, and Yb(OTf)3 to give additional
byproduct as observed upon 1H NMR analysis of crude
samples.) The 1H NMR spectrum of the crude 1,3-dioxolane-2-
carbonitrile was consistent with literature data.37 The
dioxolane−nitrile was found to be unstable and, for this reason,
was used directly in the next step. Treatment of the crude
nitrile with 4 afforded 1c in 22% overall yield. Compound 1c
was found to be very unstable in air but could be stored in a
degassed ether solution at −20 °C for several months without
decomposition.
amine hydrochloride in THF with 5 molar equiv of
isopropylmagnesium chloride at −78 °C afforded 7h in 49%
yield. Compound 7h was prepared previously in three steps
from glyoxylic acid in 47% overall yield.41 The reaction of
Weinreb amide 7h with 1.1 molar equiv of 4 afforded Michael
acceptor 1h in 77% yield (Table 1).
Synthesis of New Dihydrodipyrrins. Following a general
approach to the synthesis of dihydrodipyrrins,28 nitroethylpyr-
role 828 was treated with 1.1−2.4 molar equiv of a Michael
acceptor (1c−h) in the presence of 3 molar equiv of DBU at
room temperature to afford the corresponding hexanone (2c−
h). The results are summarized in Table 2. The yields obtained
with the benchmark compounds for the series 1a → 2a → 3a
are provided for comparison (Table 2, entry 1).28 The TiCl3-
mediated reductive cyclization of 2c−f afforded dihydrodipyr-
rins 3c−f (Table 2, entries 2−5); however, analogous reaction
of 2g or 2h did not afford the corresponding dihydrodipyrrin,
yet all starting material was consumed (Table 2, entries 6 and
7). The crude 3g decomposed immediately after the reaction
workup. The reaction with 2h afforded unidentified products.
Self-Condensation Study. The self-condensation condi-
tions (5 equiv of TMSOTf and 20 equiv of 2,6-DTBP in
CH2Cl2) employed previously for dihydrodipyrrin−acetals
bearing a 1-(dimethoxymethyl) unit and diverse β-pyrrole
substituents28 were recently modified to use a lesser amount of
reagents (4 equiv of TMSOTf and 8 equiv of 2,6-DTBP).42
The latter conditions were applied with dihydrodipyrrins 3c−f.
The crude reaction mixtures (neutralized with saturated
aqueous NaHCO3 and washed with water) were analyzed for
the presence of bacteriochlorin macrocycles by TLC, laser-
desorption mass spectrometry (LD-MS), and UV−vis spec-
troscopy. The results are shown in Table 2. For comparison,
dihydrodipyrrin−acetal 3a affords bacteriochlorin BC-1 (Table
2, entry 1). Dihydrodipyrrin−dioxolane 3c also successfully
afforded a bacteriochlorin (Table 2, entry 2; vide infra),
whereas dihydrodipyrrin−dioxane 3d resulted in partial
decomposition and no bacteriochlorin (Table 2, entry 3).
Dihydrodipyrrin 3e, bearing a methoxymethyl group, gave only
a small LD-MS peak corresponding to a tetradehydrocorrin25,43
macrocycle, but the product was not isolated (Table 2, entry 4).
Dihydrodipyrrin 3f, bearing a phenoxymethyl group, gave
decomposition with no starting material or macrocycle
observed (Table 2, entry 5).
Synthesis of trans-AB-Bacteriochlorin Building
Block. The success of dihydrodipyrrin 3c in the survey
reaction prompted scale-up to fully characterize the resulting
bacteriochlorin. Thus, the self-condensation of dihydrodipyrrin
3c (0.76 mmol) in the presence of 4 molar equiv of TMSOTf
and 8 molar equiv of 2,6-DTBP in CH2Cl2 afforded
bacteriochlorin BC-3 in 30% yield; no other macrocycles
were observed by TLC and LD-MS analyses. Consistent with
the mechanistic picture shown in Scheme 2, bacteriochlorin
BC-3 contained a 2-(trimethylsilyloxy)ethoxy group at the 5-
position (Scheme 5). Treatment with 1.5 molar equiv of TBAF
at room temperature under argon cleaved the TMS group and
afforded the 5-(2-hydroxyethoxy)bacteriochlorin BC-4 in 83%
yield.
Bacteriochlorins with a 5-methoxy group undergo smooth
and selective bromination at the 15-position, whereas
bacteriochlorins lacking a 5-methoxy group typically afford a
mixture of bromobacteriochlorins.28,33 To examine whether the
hydroxyethoxy group directed selective bromination, bacterio-
chlorin BC-4 was treated with 1 molar equiv of NBS at room
Transacetalization of diethoxyacetal 1b with 1,3-propanediol
in benzene/TsOH afforded 1,3-dioxane 1d in 64% yield (eq 1).
This apparently simple approach could not be generalized:
attempted transacetalization of 1b with ethylene glycol afforded
a chromatographically inseparable mixture of 1c and an
unidentified byproduct (see the Supporting Information).
Synthesis of New Michael Acceptors via Weinreb Amides.
Treatment of α-methoxyacetic acid (6e) with 1,1′-carbon-
yldiimidazole (CDI) and N,O-dimethylhydroxylamine hydro-
chloride followed by 4 afforded methoxymethyl Michael
acceptor 1e in 22% yield (Table 1). The reaction of known
phenoxymethyl Weinreb amide 7f (prepared from phenoxy-
acetic acid (6f) and N,O-dimethylhydroxylamine hydrochloride
with CDI)38 with 1.1 molar equiv of 4 afforded phenoxymethyl
Michael acceptor 1f in nearly quantitative yield. Similarly,
treatment of α-methoxyphenylacetic acid (6g) with CDI
followed by triethylamine and N,O-dimethylhydroxylamine
hydrochloride afforded amide 7g in 58% yield. (The S-
enantiomer of 7g is described in the literature but without
characterization data.39) The reaction of 7g with 1.1 molar
equiv of 4 afforded α-methoxybenzyl Michael acceptor 1g in
87% yield.
A general procedure was followed to convert an ester to a
Weinreb amide.40 Thus, treatment of ethyl 1,3-dithiolane-2-
carboxylate (6h) and 2.5 molar equiv of N,O-dimethylhydroxyl-
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Table 1. Synthesis of Michael Acceptors via Weinreb Amides
a
b
Method A: (1) CDI, CH2Cl2, 0 °C to rt; (2) Me(MeO)NH·HCl, Et3N, CH2Cl2, 0 °C to rt; (3) 4, THF, −20 to 0 °C. Method B: (1) CDI,
c
CH2Cl2, 0 °C to rt; (2) Me(MeO)NH·HCl, Et3N, CH2Cl2, 0 °C to rt. Method C: (1) Me(MeO)NH·HCl; (2) i-PrMgCl, THF, −78 °C.
temperature. The resulting bacteriochlorin (BC-5) was
obtained in 64% yield and contained a bromine atom at the
15-position (established by NOESY). When TMS-protected
bacteriochlorin BC-3 was treated with 1 molar equiv of NBS,
bacteriochlorin BC-5 was obtained as well in 65% yield,
indicating that NBS acted both as a deprotecting and
brominating agent. Bacteriochlorin BC-5 contains two reactive
functional groups at opposing meso positions. Analogues of
BC-5 that bear diverse β-pyrrole substituents and the same
trans-AB substituents are expected to afford valuable building
blocks.
Outlook. A scalable synthesis was developed to gain access
to α,β-unsaturated ketones for use as Michael acceptors in the
preparation of bacteriochlorins. One method employed the
reaction of a nitrile and vinyl Grignard reagent. This new
approach and that with Weinreb amides afforded diverse
substituents in place of the dimethoxymethyl unit. Upon
screening of four new dihydrodipyrrins that bear distinct
electrophilic centers, the dihydrodipyrrin bearing a 1,3-
dioxolan-2-yl group (3c) was found to afford the corresponding
5-(2-hydroxyethoxy)bacteriochlorin (BC-4). Consistent with
the mechanism of 5-methoxybacteriochlorin formation, the
condensation of two molecules of a dihydrodipyrrin bearing a
1,3-dioxolan-2-yl group is accompanied by formal release of
three alcohol units, yet here the first two are integral to an
ethylene glycol molecule, whereas the third moiety is the
terminus of the hydroxyethoxy unit anchored at the 5-position
of the bacteriochlorin. Previously, the only type of 1-substituent
in a dihydrodipyrrin that afforded a bacteriochlorin was a
dimethoxymethyl unit (e.g., 3a).25,28 The resulting bacterio-
chlorin BC-4 and its 15-brominated derivative (BC-5) are
expected to be valuable building blocks, given the orthogonality
and linear arrangement of the functional groups disposed at the
5- and 15-positions. The singular success with the new
dihydrodipyrrin−acetal highlights the exacting structural
features of the dihydrodipyrrin electrophilic site for successful
self-condensation.
EXPERIMENTAL SECTION
■
General Methods. 1H NMR (300 MHz) and 13C NMR (100
MHz) spectra were collected at room temperature in CDCl3 unless
noted otherwise. Absorption spectra were obtained in toluene at room
temperature unless noted otherwise. Electrospray ionization mass
spectrometry [HRMS (ESI)] data are reported for the molecular ion
or cationized molecular ion. Laser-desorption mass spectrometry was
performed without a matrix. All commercially available materials
(including 4, 6e−h) were used as received. Noncommercially available
compounds 5a (11-fold larger scale),35,36 7f,38 and 828 were prepared
as described in the literature; in each case, the identity and purity were
1
established by H NMR spectroscopy.
1,1-Dimethoxy-4-methyl-3-penten-2-one (1a). Dimethoxy-
acetonitrile (5a, 18.7 g, 185 mmol) in a 1 L round-bottom flask
equipped with a stirring bar and a 500 mL addition funnel (all oven-
dried) was treated under argon with 4 (445 mL, 222 mmol, 0.5 M in
THF) over 30 min at 0 °C, followed by stirring for 2 h at room
temperature. The bright yellow-orange solution was treated with
saturated aqueous NH4Cl (500 mL), and the reaction mixture was
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Table 2. Synthesis and Self-Condensation of Dihydrodipyrrins
a
b
c
d
Ref 28. Ref 42. Unreacted starting material and decomposition observed. Decomposition.
vigorously stirred for 2 h. 1H NMR spectroscopy indicated the
completion of hydrolysis (disappearance of peaks at 5.89 ppm and
4.61 ppm (imine) and appearance of peaks at 6.34 ppm and 4.49
ppm). The aqueous phase was extracted with Et2O (3 × 350 mL), and
each organic extract was washed (brine). The combined organic
extract was dried (Na2SO4) and concentrated to an orange liquid.
Bulb-to-bulb distillation (95 °C/0.05 mmHg) afforded a yellow liquid
(16.5 g, 57%, 90% purity). When the procedure was repeated on the
same scale, but the crude product was purified by column
chromatography [silica, EtOAc/hexanes (5:1)], the title compound
was obtained in 29% yield. The characterization values (1H NMR
spectrum) were consistent with those in the literature.25,34 IR (neat)
3518, 2937, 2834, 1699, 1620, 1445, 1381, 1192, 1106, 1073, 988, 846
cm−1.
119.2, 160.1, 194.9. HRMS (ESI). Calcd for C10H18O3Na (M + Na)+:
209.1148. Found: 209.1148. IR (neat) 2976, 2880, 1697, 1620, 1444,
1380, 1317, 1235, 1104, 1060, 986, 845 cm−1
.
1-(1,3-Dioxolan-2-yl)-3-methyl-2-buten-1-one (1c). A solu-
tion of 2-methoxy-1,3-dioxolane (5.00 mL, 53.7 mmol) and
trimethylsilyl cyanide (7.16 mL, 53.7 mmol) in CH2Cl2 (107 mL) at
0 °C was treated under argon with In(OTf)3 (377 mg, 0.671 mmol).
After stirring for 1 h at 0 °C, the reaction mixture was quenched with
saturated aqueous NaHCO3. After extraction, the organic phase was
washed (water), dried (Na2SO4), and concentrated. The character-
ization values (1H NMR, 13C NMR) of the crude 1,3-dioxolane-2-
carbonitrile were consistent with reported values.37 A solution of the
crude 1,3-dioxolane-2-carbonitrile in THF (10 mL) at −20 °C under
argon was treated dropwise with 4 (107.4 mL, 53.7 mmol, 0.5 M in
THF). After stirring for 1 h at −10 °C, saturated aqueous NH4Cl (150
mL) was added, and the reaction mixture was stirred vigorously for 1 h
at room temperature. The reaction mixture was extracted with Et2O (3
× 150 mL). The combined organic extract was washed (water, brine),
dried, and concentrated. Column chromatography [silica, hexanes/
EtOAc (5:1)] afforded a pale yellow liquid (1.80 g, 22%). The title
1,1-Diethoxy-4-methyl-3-penten-2-one (1b). A sample of
diethoxyacetonitrile (5.00 g, 38.7 mmol) was subjected to the
procedure described for 1a. Chromatography [silica, EtOAc/hexanes
1
(1:9)] afforded a yellow liquid (3.27 g, 45%): H NMR δ 1.25 (t, J =
7.4 Hz, 6H), 1.95 (s, 3H), 2.20 (s, 3H), 3.52−3.74 (m, 4H), 4.58 (s,
1H), 6.40−6.42 (m, 1H); 13C NMR δ 15.4, 21.5, 28.4, 63.2, 103.3,
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argon. Saturated aqueous NH4Cl was added. The organic phase was
washed with water, dried (Na2SO4), and concentrated to a transparent
oil. The crude amide at −20 °C under argon was treated dropwise with
4 (28.7 mL, 14.4 mmol, 0.5 M in THF). The reaction mixture was
stirred for 2 h under argon at 0 °C, upon which a white precipitate was
formed. The mixture was diluted with Et2O and treated with saturated
aqueous NH4Cl. The ethereal extract was washed (water, brine), dried
(Na2SO4), concentrated, and chromatographed [silica, hexanes/
Scheme 5. Synthesis of a trans-AB-Bacteriochlorin
1
EtOAc (3:1)] to afford an orange liquid (360 mg, 22%): H NMR
δ 1.93 (s, 3H), 2.20 (s, 3H), 3.43 (s, 3H), 4.01 (s, 2H), 6.19−6.20 (m,
1H); 13C NMR δ 21.4, 28.2, 59.4, 78.5, 119.6, 158.3, 159.9, 197.9.
HRMS (ESI). Calcd for C7H12O2Na (M + Na)+: 151.0730. Found:
151.0731. IR (neat) 3451, 2979, 2935, 2825, 1699, 1618, 1447, 1379,
1227, 1200, 1109, 1038, 986, 934, 815 cm−1
.
4-Methyl-1-phenoxy-3-penten-2-one (1f). A solution of amide
7f (508 mg, 2.60 mmol) in THF (5.1 mL) at −20 °C under argon was
treated dropwise with 4 (5.70 mL, 2.85 mmol, 0.5 M in THF). The
reaction mixture was stirred for 2 h under argon at 0 °C, upon which a
white precipitate formed. The mixture was diluted with Et2O and
treated with saturated aqueous NH4Cl. The ethereal extract was
washed (water, brine), dried (Na2SO4), and concentrated to a slightly
yellow oil (480 mg, 97%) of sufficient purity to not require further
purification: 1H NMR δ 1.95 (s, 3H), 2.23 (s, 3H), 4.56 (s, 2H), 6.35−
6.37 (m, 1H), 6.88 (m, 2H), 6.91−7.00 (m, 1H), 7.27−7.32 (m, 2H);
13C NMR δ 21.6, 28.4, 73.4, 114.8, 119.4, 121.7, 129.8, 159.9, 196.4.
HRMS (ESI). Calcd for C12H14O2Na (M + Na)+: 213.0892. Found:
213.0886. IR (neat) 3520, 3041, 2911, 1702, 1686, 1600, 1495, 1436,
1379, 1211, 1152, 1121, 1031, 844, 754 cm−1
.
1-Methoxy-4-methyl-1-phenyl-3-penten-2-one (1g). Com-
pound 7g (585 mg, 2.80 mmol) was subjected to the procedure
described for preparation of 1f. Chromatography [silica, hexanes/
EtOAc (5:1)] afforded the title compound (495 mg, 87%): 1H NMR δ
1.87 (s, 3H), 2.14 (s, 3H), 3.39 (s, 3H), 4.64 (s, 1H), 6.27−6.28 (m,
1H), 7.32−7.38 (m, 5H); 13C NMR δ 21.4, 28.3, 57.4, 89.7, 119.3,
127.1, 128.4, 128.8, 136.8, 159.4, 197.8. HRMS (ESI). Calcd for
C13H16O2Na (M + Na)+: 227.1043. Found: 227.1041. IR (neat) 2933,
2826, 1686, 1618, 1445, 1379, 1199, 1099, 989 cm−1
.
1-(1,3-Dithiolan-2-yl)-3-methyl-2-buten-1-one (1h). Com-
pound 7h (250 mg, 1.30 mmol) was subjected to the procedure
described for preparation of 1f. Chromatography [silica, hexanes/
EtOAc (3:1)] afforded a yellow oil (189 mg, 77%): 1H NMR δ 1.95 (s,
3H), 2.19 (s, 3H), 3.31−3.35 (m, 4H), 4.87 (s, 1H), 6.23−6.24 (m,
1H); 13C NMR δ 21.4, 28.4, 39.2, 58.5, 120.3, 159.8, 193.3. HRMS
(ESI). Calcd for C8H12OS2Na (M + Na)+: 211.0222. Found:
211.0227. IR (neat) 3434, 2928, 1674, 1619, 1441, 1379, 1237,
1121, 1039 cm−1.
compound was found to be unstable in air even as a neat liquid but
could be stored without decomposition in a degassed solution of Et2O
(∼0.4 M) for 2 months at −20 °C. Data for the title compound: H
1
NMR δ 1.96 (s, 3H), 2.20 (s, 3H), 3.96−4.09 (m, 4H), 5.05 (s, 1H),
6.29−6.30 (m, 1H); 13C NMR δ 21.6, 28.5, 65.8, 102.7, 118.8, 161.2,
194.5. HRMS (ESI). Calcd for C8H12O3Na (M + Na)+: 179.0679.
Found: 179.0678. IR (neat) 3525, 2978, 2893, 1697, 1618, 1445, 1380,
1-(1,3-Dioxolan-2-yl)-3,3-dimethyl-4-nitro-5-(3-p-tolylpyr-
1236, 1162, 1101, 1033, 841 cm−1
.
rol-2-yl)-1-pentanone (2c). Following a literature procedure,28
a
1-(1,3-Dioxan-2-yl)-3-methyl-2-buten-1-one (1d). A solution
of 1b (1.06 g, 5.69 mmol) and 1,3-propanediol (0.600 mL, 8.30
mmol) in benzene (11.5 mL) was treated with p-toluenesulfonic acid
(542 mg, 2.85 mmol) at 80 °C for 4.5 h. Saturated aqueous NaHCO3
was added, and the mixture was extracted with Et2O. The organic
extract was washed (water), dried (Na2SO4), concentrated to a brown
liquid, and chromatographed [silica, hexanes/EtOAc (5:1)] to afford a
yellow liquid (620 mg, 64%, ≥95% purity): 1H NMR δ 1.40−1.45 (m,
1H), 1.96 (s, 3H), 2.20 (s, 3H), 2.12−2.25 (m, 1H), 3.83−3.92 (m,
2H), 4.20−4.26 (m, 2H), 4.79 (s, 1H), 6.40−6.42 (m, 1H); 13C NMR
δ 21.7, 25.9, 28.5, 67.3, 101.4, 119.0, 161.2, 192.1. HRMS (ESI). Calcd
for C9H14O3Na (M + Na)+: 193.0835. Found: 193.0833. IR (neat)
3480, 2975, 2863, 1726, 1618, 1446, 1380, 1240, 1149, 1103, 1034
cm−1.
1-Methoxy-4-methyl-3-penten-2-one (1e). According to a
reported procedure38 with some modifications, a solution of α-
methoxyacetic acid (6e, 1.17 g, 13.0 mmol) in anhydrous CH2Cl2 (20
mL) was treated portionwise with 1,1′-carbonyldiimidazole (2.54 g,
15.7 mmol) at 0 °C under argon. The reaction mixture was stirred for
30 min at room temperature, treated with triethylamine (2.18 mL, 15.7
mmol) and N,O-dimethylhydroxylamine hydrochloride (1.53 g, 15.6
mmol) at 0 °C, and stirred overnight at room temperature under
mixture of 1c (1.56 g, 9.99 mmol) and 8 (950 mg, 4.13 mmol) was
treated with DBU (2.54 mL, 13.1 mmol) at room temperature. When
no starting material was observed upon TLC analysis (3 h in this case),
the reaction mixture was diluted with EtOAc, and water was added.
The combined organic extract was washed (brine), dried (Na2SO4),
and concentrated to a brown oil. Column chromatography [silica,
1
hexanes/EtOAc (3:1)] afforded a brown oil (861 mg, 54%): H NMR
δ 1.11 (s, 3H), 1.20 (s, 3H), 2.37 (s, 3H), 2.50 (d, J = 18.4 Hz, 1H),
2.71 (d, J = 18.4 Hz, 1H), 3.19 (dd, J = 2.6 Hz, J = 15.5 Hz, 1H), 3.40
(dd, J = 11.4 Hz, J = 15.5 Hz, 1H), 3.98−4.03 (m, 4H), 4.93 (s, 1H),
5.13 (dd, J = 2.6 Hz, J = 11.4 Hz, 1H), 6.23−6.24 (m, 1H), 6.67−6.69
(m, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 8.07 (br,
1H); 13C NMR δ 21.2, 23.9, 24.1, 25.3, 36.7, 44.4, 65.7, 94.9, 102.0,
109.4, 117.7, 121.8, 123.4, 128.2, 129.3, 133.5, 135.5, 204.1. HRMS
(ESI). Calcd for C21H27N2O5 (M + H)+: 387.1914. Found: 387.1906.
1-(1,3-Dioxan-2-yl)-3,3-dimethyl-4-nitro-5-(3-p-tolylpyrrol-
2-yl)-1-pentanone (2d). Samples of 1d (268 mg, 1.58 mmol), 8
(302 mg, 1.31 mmol) and DBU (0.765 mL, 3.93 mmol) were
subjected (overnight) to the general procedure described for 2c.
Chromatography [silica, CH2Cl2/EtOAc (9:1)] afforded a brown solid
1
(186 mg, 35%): mp 45 °C (dec.); H NMR δ 1.11 (s, 3H), 1.19 (s,
3H), 1.40−1.44 (m, 1H), 2.07−2.21 (m, 1H), 2.37 (s, 3H), 2.60 (d, J
9484
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Article
= 18.8 Hz, 1H), 2.75 (d, J = 18.8 Hz, 1H), 3.20 (dd, J = 2.5 Hz, J =
15.6 Hz, 1H), 3.39 (dd, J = 11.7 Hz, J = 15.6 Hz, 1H), 3.79−3.88 (m,
2H), 4.17−4.23 (m, 2H), 4.68 (s, 1H), 5.16 (dd, J = 2.5 Hz, J = 11.7
Hz, 1H), 6.22−6.24 (m, 1H), 6.67−6.68 (m, 1H), 7.17−7.24 (m, 4H),
8.05−8.10 (br, 1H); 13C NMR δ 21.4, 24.2, 24.3, 25.4, 25.8, 36.8, 45.1,
67.3, 95.1, 100.7, 109.6, 117.7, 122.1, 123.7, 128.4, 129.5, 133.6, 135.6,
201.0. HRMS (ESI). Calcd for C22H28N2O5Na (M + Na)+: 423.1890.
Found: 423.1890.
1-(1,3-Dioxolan-2-yl)-2,3-dihydro-3,3-dimethyl-7-p-tolyldi-
pyrrin (3c). Following a reported procedure,28 in a first flask a
solution of 2c (940 mg, 2.43 mmol) in THF/MeOH (11.4 mL, 5:1) at
0 °C under argon was treated with NaOMe (395 mg, 7.32 mmol) for
40 min. In a second flask, TiCl3 (20 wt % TiCl3 in 3 wt % HCl, 9.30
mL, 14.7 mmol) in THF (9.5 mL) was treated with a solution of
NH4OAc (7.52 g, 97.7 mmol) in H2O (6.0 mL) that had been bubbled
with argon for 1 h. The solution from the first flask was transferred to
the second flask. The resulting reaction mixture was stirred overnight
under argon at room temperature. Ethyl acetate and water were added.
The organic extract was washed (brine), dried (Na2SO4), concen-
trated, and chromatographed [alumina, hexanes/EtOAc (3:1)] to
afford a yellow solid (255 mg, 31%): mp 185 °C (dec); 1H NMR (400
MHz) δ 1.20 (s, 6H), 2.39 (s, 3H), 2.61 (s, 2H), 4.01−4.12 (m, 4H),
5.64 (s, 1H), 6.10 (s, 1H), 6.26−6.29 (m, 1H), 6.85−6.87 (m, 1H),
1-Methoxy-4,4-dimethyl-5-nitro-6-[3-p-tolylpyrrol-2-yl]-2-
hexanone (2e). Samples of 1e (187 mg, 1.46 mmol), 8 (250 mg,
1.09 mmol) and DBU (0.636 mL, 3.27 mmol) were subjected (for 8
h) to the general procedure described for 2c. Chromatography [silica,
hexanes/EtOAc (3:1)] afforded a brown oil which solidified upon
1
storage at 1 °C (274 mg, 70%): mp 103−104 °C (dec); H NMR δ
1.09 (s, 3H), 1.20 (s, 3H), 2.36 (d, J = 17.6 Hz, 1H), 2.37 (s, 3H), 2.56
(d, J = 17.6 Hz, 1H), 3.22 (dd, J = 1.8 Hz, J = 15.8 Hz, 1H), 3.40 (s,
3H), 3.38 (dd, J = 9.9 Hz, J = 15.8 Hz, 1H), 3.90 (s, 2H), 5.14 (dd, J =
1.8 Hz, J = 9.9 Hz, 1H), 6.22−6.24 (m, 1H), 6.67−6.68 (m, 1H), 7.19
(d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 8.19 (br, 1H); 13C NMR
δ 21.3, 24.2, 24.5, 25.3, 37.0, 46.5, 59.5, 78.4, 95.0, 109.5, 117.7, 122.0,
123.7, 128.4, 129.4, 133.6, 135.7, 206.8. HRMS (ESI). Calcd for
C20H26N2O4Na (M + Na)+: 381.1785. Found: 381.1782. Anal. Calcd
for C20H26N2O4: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.04; H, 7.25;
N, 7.62.
7.21 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 10.82 (br, 1H); 13
C
NMR δ 21.3, 29.2, 40.7, 47.1, 66.0, 101.4, 106.6, 109.2, 119.4, 124.8,
126.8, 128.7, 129.4, 134.2, 135.4, 160.0, 173.4. HRMS (ESI). Calcd for
C21H25N2O2 (M + H)+: 337.1911. Found: 337.1911.
1-(1,3-Dioxan-2-yl)-2,3-dihydro-3,3-dimethyl-7-p-tolyldipyr-
rin (3d). A sample of 2d (255 mg, 0.422 mmol) was subjected to the
procedure described for preparation of 3c. Chromatography [silica,
hexanes/EtOAc (2:1)] afforded a light yellow solid (27 mg, 18%): mp
1
145 °C (dec); H NMR (400 MHz) δ 1.18 (s, 6H), 1.44−1.47 (m,
1H), 2.17−2.23 (m, 1H), 2.38 (s, 3H), 2.67 (s, 2H), 3.92−3.98 (m,
2H), 4.21−4.24 (m, 2H), 5.39 (s, 1H), 6.10 (s, 1H), 6.26−6.28 (m,
1H), 6.85−6.87 (m, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz,
2H), 10.92 (br, 1H); 13C NMR δ 21.4, 26.0, 29.3, 40.4, 48.0, 67.3,
99.9, 106.6, 109.1, 119.3, 124.6, 126.9, 128.7, 129.4, 134.3, 135.3,
160.2, 173.4. HRMS (ESI). Calcd for C22H27N2O2 (M + H)+:
351.2067. Found: 351.2064.
4,4-Dimethyl-5-nitro-1-phenoxy-6-(3-p-tolylpyrrol-2-yl)-2-
hexanone (2f). Samples of 1f (256 mg, 1.35 mmol), 8 (250 mg, 1.09
mmol) and DBU (0.635 mL, 3.26 mmol) were subjected (overnight)
to the general procedure described for 2c. Chromatography (silica,
1
CH2Cl2) afforded a brown oil (274 mg, 60%): H NMR δ 1.10 (s,
3H), 1.21 (s, 3H), 2.34 (s, 3H), 2.50 (d, J = 18.2 Hz, 1H), 2.72 (d, J =
18.2 Hz, 1H), 3.23 (dd, J = 2.7 Hz, J = 15.6 Hz, 1H), 3.40 (dd, J = 11.4
Hz, J = 15.6 Hz, 1H), 4.43 (d, J = 3.6 Hz, 2H), 5.20 (dd, J = 2.7 Hz, J
= 11.4 Hz, 1H), 6.23−6.24 (m, 1H), 6.69−6.67 (m, 1H), 6.86 (d, J =
8.8 Hz, 2H), 6.99−7.03 (m, 1H), 7.18−7.33 (m, 6H), 8.08 (br, 1H);
13C NMR δ 21.3, 24.2, 24.5, 25.3, 37.0, 46.7, 73.3, 94.8, 109.5, 114.6,
117.7, 121.9, 122.1, 123.7, 128.4, 129.4, 129.9, 133.5, 135.7, 157.7,
205.6. HRMS (ESI). Calcd for C25H28N2O4Na (M + Na)+: 443.1941.
Found: 443.1940.
2,3-Dihydro-1-(methoxymethyl)-3,3-dimethyl-7-p-tolyldi-
pyrrin (3e). A sample of 2e (150 mg, 0.419 mmol) was subjected to
the procedure described for preparation of 3c. Chromatography
[alumina, hexanes/EtOAc (5:1)] afforded a brown solid (28 mg,
22%). (The title compound decomposed upon attempted column
chromatography on silica gel.) Data for the title compound: mp 93−95
°C; 1H NMR δ 1.20 (s, 6H), 2.39 (s, 3H), 2.61 (s, 2H), 3.44 (s, 3H),
4.33 (s, 2H), 6.06 (s, 1H), 6.27−6.30 (m, 1H), 6.85−6.87 (m, 1H),
7.21 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 10.90 (br, 1H); 13
C
1-Methoxy-4,4-dimethyl-5-nitro-6-[3-p-tolylpyrrol-2-yl]-1-
phenyl-2-hexanone (2g). Samples of 1g (250 mg, 1.23 mmol), 8
(235 mg, 1.02 mmol) and DBU (0.600 mL, 3.06 mmol) were
subjected (overnight) to the general procedure described for 2c.
Chromatography [silica, hexanes/EtOAc (5:1)] afforded a brown oil
NMR δ 21.7, 29.7, 41.0, 50.6, 59.6, 73.3, 105.3, 109.5, 119.2, 124.5,
127.4, 129.0, 129.7, 134.7, 135.6, 160.8, 176.8. HRMS (ESI). Calcd for
C20H25N2O (M + H)+: 309.1961. Found: 309.1971.
2,3-Dihydro-3,3-dimethyl-1-(phenoxymethyl)-7-p-tolyldi-
pyrrin (3f). A sample of 2f (270 mg, 0.642 mmol) was subjected to
the procedure described for preparation of 3c. Chromatography [silica,
CH2Cl2/hexanes (1:1)] afforded a light brown oil, which quickly
1
(280 mg, 63%, a mixture of diastereomers): H NMR δ 0.96 (s, 3H),
0.97 (s, 3H), 1.04 (s, 3H), 1.09 (s, 3H), 2.36 (s, 3H), 2.37 (s, 3H),
2.40 (m, 2H), 2.56−2.62 (m, 1H), 2.69−2.75 (m, 1H), 3.09−3.12 (m
1H), 3.14−3.18 (m, 1H), 3.29−3.33 (m, 2H), 3.35 (s, 3H), 3.36 (s,
3H), 4.57 (s, 1H), 4.58 (s, 1H), 5.14−5.15 (m, 1H), 5.17−5.19 (m,
1H) 6.21−6.22 (m, 2H), 6.64−6.67 (m, 2H), 7.14−7.25 (m, 8H),
7.31−7.40 (m, 10H), 8.03 (br, 1H), 8.07 (br, 1H); 13C NMR δ 21.23,
21.25, 23.95, 23.99, 24.04, 24.2, 25.3, 25.4, 36.8, 36.9, 45.1, 45.5, 57.35,
57.42, 89.7, 89.8, 95.0, 95.1, 109.4, 109.5, 117.65, 117.66, 121.96,
122.00, 123.5, 123.6, 127.2, 127.4, 128.25, 128.33, 128.89, 128.98,
129.01, 129.1, 129.3, 133.59, 133.61, 135.5, 135.6, 206.4, 206.7. HRMS
(ESI). Calcd for C26H31N2O4 (M + H)+: 435.2278. Found: 435.2275.
1-(1,3-Dithiolan-2-yl)-3,3-dimethyl-4-nitro-5-(3-p-tolylpyr-
rol-2-yl)-1-pentanone (2h). Samples of 1h (180 mg, 0.958 mmol),
8 (200 mg, 0.869 mmol) and DBU (0.508 mL, 2.61 mmol) were
subjected (for 3.5 h) to the general procedure described for 2c.
Chromatography [silica, hexanes/EtOAc (3:1)] afforded a brown oil
1
turned dark brown (87.5 mg, 37%): H NMR δ 1.18 (s, 6H), 2.39 (s,
3H), 2.66 (s, 2H), 4.97 (s, 2H), 6.07 (s, 1H), 6.28−6.30 (m, 1H),
6.82−6.84 (m, 1H), 6.94−6.98 (m, 3H), 7.20−7.23 (d, J = 7.7 Hz,
2H), 7.29−7.37 (m, 4H), 10.78 (br, 1H); 13C NMR δ 21.4, 29.3, 40.8,
50.3, 68.3, 105.3, 109.3, 114.8, 119.1, 121.7, 122.7, 124.4, 128.7, 129.4,
129.9, 134.3, 135.4, 160.3, 175.4. HRMS (ESI). Calcd for C25H27N2O
(M + H)+: 371.2118. Found: 371.2105.
N-Methoxy-N-methyl-2-methoxy-2-phenylacetamide (7g).
According to a reported procedure with some modifications,38
a
solution of 6g (1.00 g, 6.02 mmol) in anhydrous CH2Cl2 (9.0 mL) at 0
°C under argon was treated portionwise with 1,1′-carbonyldiimidazole
(1.27 g, 7.83 mmol). The reaction mixture was stirred for 40 min at
room temperature, treated with triethylamine (1.2 mL, 8.6 mmol) and
N,O-dimethylhydroxylamine hydrochloride (826 mg, 8.43 mmol) at 0
°C, and stirred overnight at room temperature under argon. A sample
of 1 M HCl (10 mL) was added. The organic extract was washed with
water, dried (Na2SO4), and concentrated to give a transparent oil.
Chromatography [silica, hexanes/EtOAc (1:1)] afforded a transparent
1
(129 mg, 36%): H NMR (400 MHz) δ 1.12 (s, 3H), 1.16 (s, 3H),
2.37 (s, 3H), 2.63 (d, J = 18.0 Hz, 1H), 2.76 (d, J = 18.0 Hz, 1H), 3.23
(dd, J = 2.8 Hz, J = 15.5 Hz, 1H), 3.25−3.32 (m, 4H), 3.38 (dd, J =
11.4 Hz, J = 15.5 Hz, 1H), 4.74 (s, 1H), 5.14 (dd, J = 2.8 Hz, J = 11.4
Hz, 1H), 6.22−6.23 (m, 1H), 6.66−6.68 (m, 1H), 7.18 (d, J = 8.4 Hz,
2H), 7.23 (d, J = 8.4 Hz, 2H), 8.12 (br, 1H); 13C NMR δ 21.6, 24.4,
24.5, 25.7, 37.6, 39.4, 46.4, 58.6, 95.6, 109.9, 118.1, 122.3, 123.9, 128.6,
129.7, 133.9, 136.0, 202.1. HRMS (ESI). Calcd for C21H27N2O3S2 (M
+ H)+: 419.1453. Found: 419.1458.
1
oil (735 mg, 58%): H NMR δ 3.17 (s, 3H), 3.39 (s, 3H), 3.42 (br,
3H), 5.12 (s, 1H), 7.32−7.39 (m, 3H), 7.44−7.46 (m, 2H); 13C NMR
δ 32.6, 57.4, 61.2, 81.0, 127.5, 128.4, 128.9, 136.7, 172.0. HRMS (ESI).
Calcd for C11H15NO3Na (M + Na)+: 232.0944. Found: 232.0952. IR
(neat) 3504, 2938, 2823, 1675, 1455, 1385, 1197, 1176, 1111 cm−1.
9485
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Article
N-Methoxy-N-methyl-1,3-dithiolane-2-carboxamide (7h).
Following a general procedure with modifications,40 a vigorously
stirred slurry of 6h (1.50 mL, 10.5 mmol) and N,O-dimethylhydroxyl-
amine hydrochloride (2.57 g, 26.2 mmol) in THF (21 mL) at −78 °C
under argon was treated dropwise with isopropylmagnesium bromide
(52.5 mmol, 26.3 mL, 2 M in THF) over 40 min. The reaction mixture
was stirred for 1 h at −78 °C under argon. Saturated aqueous NH4Cl/
H2O (1:1) was added. The aqueous phase was extracted with ether (3
× 100 mL). The combined organic extract was washed (water, brine),
dried (Na2SO4), concentrated, and chromatographed [silica, EtOAc/
hexanes (2:1)] to afford a yellow oil that solidified upon storage at 1
°C (985 mg, 49%). The characterization values [1H NMR, 13C NMR,
HRMS (ESI) spectra] were consistent with those for the title
compound prepared via a different synthetic route.41
(Na2SO4), and concentrated. Chromatography (silica, CH2Cl2)
afforded a green solid (48 mg, 65%). The characterization values
(1H NMR, LD-MS spectra) were consistent with those reported
above.
ASSOCIATED CONTENT
* Supporting Information
■
S
Attempted syntheses and spectral data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jlindsey@ncsu.edu.
■
8,8,18,18-Tetramethyl-2,12-di-p-tolyl-5-[2-(trimethylsilyl-
oxy)ethoxy]bacteriochlorin (BC-3). Following a general proce-
dure,42 a solution of 3c (255 mg, 0.758 mmol) and 2,6-DTBP (1.36
mL, 6.06 mmol) in CH2Cl2 (42 mL) was treated with TMSOTf (0.55
mL, 3.0 mmol) at room temperature. The reaction mixture was stirred
for 22 h at room temperature. The reaction mixture was diluted with
CH2Cl2 and saturated aqueous NaHCO3. The organic phase was
washed (water, brine), dried (Na2SO4), and concentrated. Column
chromatography [silica, CH2Cl2/hexanes (1:1)] afforded a green solid
ACKNOWLEDGMENTS
■
This work was supported by a grant from the Chemical
Sciences, Geosciences and Biosciences Division, Office of Basic
Energy Sciences, of the U.S. Department of Energy (DE-FG02-
96ER14632). Mass spectra were obtained at the Mass
Spectrometry Laboratory for Biotechnology at North Carolina
State University. Partial funding for the facility was obtained
from the North Carolina Biotechnology Center and the
National Science Foundation.
1
(77 mg, 30%): mp 230−232 °C (dec.); H NMR δ −1.92 (br, 1H),
−1.80 (br, 1H), 0.34 (s, 9H), 1.89 (s, 6H), 1.91 (s, 6H), 2.61 (s, 6H),
4.32 (t, J = 4.4 Hz, 2H), 4.38 (s, 2H), 4.43 (s, 2H), 4.66 (t, J = 4.4 Hz,
2H), 7.56−7.58 (m, 4H), 8.08−8.15 (m, 4H), 8.68 (s, 2H), 8.78 (s,
1H), 8.81 (s, 1H), 9.07−9.08 (m, 1H); 13C NMR δ 0.22, 21.6, 31.10,
31.16, 45.94, 46.18, 47.9, 51.9, 62.6, 76.8, 79.3, 95.7, 95.8, 97.8, 116.8,
121.0, 129.9, 130.0, 130.3, 131.1, 131.3, 133.2, 133.8, 134.1, 134.2,
134.4, 134.8, 135.6, 137.0, 137.2, 137.5, 153.4, 159.6, 169.6, 170.0; LD-
MS obsd 681.8. HRMS (ESI). Calcd for C43H51N4O2Si (M + H)+:
683.3776. Found: 683.3762. λabs 355, 374, 512, 732 nm.
REFERENCES
■
(1) Lindsey, J. S. Acc. Chem. Res. 2010, 43, 300−311.
(2) Senge, M. O. Chem. Commun. 2011, 47, 1943−1960.
(3) Ptaszek, M.; Lahaye, D.; Krayer, M.; Muthiah, C.; Lindsey, J. S. J.
Org. Chem. 2010, 75, 1659−1673.
(4) Galezowski, M.; Gryko, D. T. Curr. Org. Chem. 2007, 11, 1310−
1338.
5-(2-Hydroxyethoxy)-8,8,18,18-tetramethyl-2,12-di-p-tolyl-
bacteriochlorin (BC-4). A solution of BC-3 (20 mg, 0.029 mmol) in
THF (3.0 mL) was treated with TBAF (44 μL, 0.044 mmol, 1 M in
THF) under argon at room temperature for 45 min. Water and
CH2Cl2 were added. The organic extract was washed (brine), dried
(Na2SO4), concentrated, and chromatographed (silica, CH2Cl2) to
afford a green solid (15 mg, 83%): mp 208−210 °C (dec.); 1H NMR δ
−1.85 (br, 1H), −1.75 (br, 1H), 1.90 (s, 6H), 1.91 (s, 6H), 2.60 (s,
3H), 2.61 (s, 3H), 2.62−2.68 (m, 1H), 4.31−4.37 (m, 2H), 4.40 (s,
4H), 4.70 (t, J = 4.0 Hz, 2H), 7.55−7.59 (m, 4H), 8.08−8.12 (m, 4H),
8.67 (s, 2H), 8.77 (s, 1H), 8.80 (s, 1H), 8.94 (s, 1H); 13C NMR δ
21.61, 21.64, 31.05, 31.20, 46.0, 46.3, 47.8, 52.1, 63.1, 78.9, 95.8, 96.0,
98.0, 116.0, 121.4, 129.8, 129.97, 130.03, 131.1, 131.3, 133.0, 133.6,
133.7, 134.2, 134.3, 135.3, 136.0, 137.1, 137.6, 137.7, 152.6, 160.1,
169.6, 170.3; LD-MS 610.0. HRMS (ESI). Calcd for C40H43N4O2 (M
+ H)+: 611.3381. Found: 611.3365. λabs 355, 374, 511, 731 nm.
15-Bromo-5-(2-hydroxyethoxy)-8,8,18,18-tetramethyl-2,12-
di-p-tolylbacteriochlorin (BC-5). A sample of BC-4 (14 mg, 0.023
mmol) in THF (11.5 mL) was treated with NBS (0.23 mL, 0.023
mmol, 100 mM in THF) at room temperature. After stirring for 1 h,
water and CH2Cl2 were added. The organic extract was washed
(brine), dried (Na2SO4), and concentrated. Chromatography (silica,
CH2Cl2) afforded a green solid (10 mg, 64%): mp 205−207 °C (dec.);
1H NMR (400 MHz, THF-d8) δ −2.01 (br, 1H), −1.82 (br, 1H), 1.90
(5) Taniguchi, M.; Cramer, D. L.; Bhise, A. D.; Kee, H. L.; Bocian, D.
F.; Holten, D.; Lindsey, J. S. New J. Chem. 2008, 32, 947−958.
(6) Yang, E.; Kirmaier, C.; Krayer, M.; Taniguchi, M.; Kim, H.-J.;
Diers, J. R.; Bocian, D. F.; Lindsey, J. S.; Holten, D. J. Phys. Chem. B
2011, 115, 10801−10816.
(7) Lindsey, J. S.; Mass, O.; Chen, C.-Y. New J. Chem. 2011, 35,
511−516.
(8) Wasielewski, M. R.; Svec, W. A. J. Org. Chem. 1980, 45, 1969−
1974.
(9) Osuka, A.; Wada, Y.; Maruyama, K.; Tamiaki, H. Heterocycles
1997, 44, 165−168.
(10) Fukuzumi, S.; Ohkubo, K.; Chen, Y.; Pandey, R. K.; Zhan, R.;
Shao, J.; Kadish, K. M. J. Phys. Chem. A 2002, 106, 5105−5113.
(11) Mironov, A. F.; Grin, M. A.; Tsiprovskiy, A. G.; Kachala, V. V.;
Karmakova, T. A.; Plyutinskaya, A. D.; Yakubovskaya, R. I. J.
Porphyrins Phthalocyanines 2003, 7, 725−730.
(12) Sasaki, S.-I.; Tamiaki, H. J. Org. Chem. 2006, 71, 2648−2654.
(13) Grin, M. A.; Mironov, A. F.; Shtil, A. A. Anti-Cancer Agents Med.
Chem. 2008, 8, 683−697.
(14) Tamiaki, H.; Kunieda, M. In Handbook of Porphyrin Science;
Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World Scientific
Publishing Co.: Singapore, 2011; Vol. 11, pp 223−290.
(15) Dorough, G. D.; Miller, J. R. J. Am. Chem. Soc. 1952, 74, 6106−
6108.
(s, 12 H), 2.47 (s, 6H), 4.17−4.22 (m, 2H), 4.47 (s, 2H), 4.47−4.50
(m, 1H), 4.51 (s, 2H), 4.67 (t, J = 4.4 Hz, 2H), 7.55−7.59 (m, 4H),
8.06−8.11 (m, 4H), 8.77 (s, 1H), 8.82 (s, 1H), 8.98−8.99 (m, 1H),
9.04−9.05 (m, 1H); 13C NMR (THF-d8) δ 21.6, 31.3, 31.5, 46.4, 46.9,
49.0, 55.0, 62.9, 81.3, 96.4, 98.4, 119.5, 121.6, 129.1, 129.8, 130.67,
130.70, 132.0, 132.1, 133.1, 133.9, 134.0, 134.6, 134.8, 135.4, 135.8,
137.0, 137.6, 138.1, 138.3, 158.0, 158.7, 169.1, 172.9; LD-MS, 688.4.
HRMS (ESI). Calcd for C40H41BrN4O2Na (M + Na)+: 711.2305.
Found: 711.2297. λabs 362, 378, 524, 734 nm.
(16) Whitlock, H. W. Jr.; Hanauer, R.; Oester, M. Y.; Bower, B. K. J.
Am. Chem. Soc. 1969, 91, 7485−7489.
(17) Shea, K. M.; Jaquinod, L.; Khoury, R. G.; Smith, K. M.
Tetrahedron 2000, 56, 3139−3144.
(18) Chen, Y.; Li, G.; Pandey, R. K. Curr. Org. Chem. 2004, 8, 1105−
1134.
Conversion of BC-3 to BC-5. A sample of BC-3 (73 mg, 0.11
mmol) in THF (53.5 mL) was treated with NBS (19 mg, 0.11 mmol)
at room temperature. After stirring for 1 h at room temperature, water
and CH2Cl2 were added. The organic phase was washed (brine), dried
(19) Pereira, N. A. M.; Serra, A. C.; Pinho e Melo, T. M. V. D. Eur. J.
Org. Chem. 2010, 6539−6543.
(20) Samankumara, L. P.; Zeller, M.; Krause, J. A.; Bruckner, C. Org.
̈
Biomol. Chem. 2010, 8, 1951−1965.
9486
dx.doi.org/10.1021/jo201967k|J. Org. Chem. 2011, 76, 9478−9487

The Journal of Organic Chemistry
Article
́
(21) Singh, S.; Aggarwal, A.; Thompson, S.; Tome, J. P. C.; Zhu, X.;
Samaroo, D.; Vinodu, M.; Gao, R.; Drain, C. M. Bioconjugate Chem.
2010, 21, 2136−2146.
(22) Pereira, N. A. M.; Fonseca, S. M.; Serra, A. C.; Pinho e Melo, T.
M. V. D.; Burrows, H. D. Eur. J. Org. Chem. 2011, 3970−3979.
(23) Minehan, T. G.; Cook-Blumberg, L.; Kishi, Y.; Prinsep, M. R.;
Moore, R. E. Angew. Chem., Int. Ed. 1999, 38, 926−928.
(24) Wang, W.; Kishi, Y. Org. Lett. 1999, 1, 1129−1132.
(25) Kim, H.-J.; Lindsey, J. S. J. Org. Chem. 2005, 70, 5475−5486.
(26) Ruzie,
Chem. 2008, 73, 5806−5820.
(27) Krayer, M.; Balasubramanian, T.; Ruzie,
Cramer, D. L.; Taniguchi, M.; Lindsey, J. S. J. Porphyrins
Phthalocyanines 2009, 13, 1098−1110.
́
C.; Krayer, M.; Balasubramanian, T.; Lindsey, J. S. J. Org.
́
C.; Ptaszek, M.;
(28) Krayer, M.; Ptaszek, M.; Kim, H.-J.; Meneely, K. R.; Fan, D.;
Secor, K.; Lindsey, J. S. J. Org. Chem. 2010, 75, 1016−1039.
(29) Krayer, M.; Yang, E.; Diers, J. R.; Bocian, D. F.; Holten, D.;
Lindsey, J. S. New J. Chem. 2011, 35, 587−601.
(30) Ogikubo, J.; Bruckner, C. Org. Lett. 2011, 13, 2380−2383.
̈
(31) Sutton, J. M.; Clarke, O. J.; Fernandez, N.; Boyle, R. W.
Bioconjugate Chem. 2002, 13, 249−263.
(32) Kobayashi, M.; Akiyama, M.; Kano, H.; Kise, H. In Chlorophylls
and Bacteriochlorophylls: Biochemistry, Biophysics, Functions and
Applications; Grimm, B., Porra, R. J., Rudiger, W., Scheer, H., Eds.;
̈
Springer: Dordrecht, The Netherlands, 2006; pp 79−94.
(33) Fan, D.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2007, 72,
5350−5357.
(34) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bartoli, D. J. Org. Chem.
1990, 55, 4523−4528.
(35) Utimoto, K.; Wakabayashi, Y.; Shishiyama, Y.; Inoue, M.;
Nozaki, H. Tetrahedron Lett. 1981, 22, 4279−4280.
(36) Kirchmeyer, S.; Mertens, A.; Arvanaghi, M.; Olah, G. A.
Synthesis 1983, 498−500.
(37) Suzuki, H.; Sakai, N.; Iwahara, R.; Fujiwaka, T.; Satoh, M.;
Kakehi, A.; Konakahara, T. J. Org. Chem. 2007, 72, 5878−5881.
(38) Beutner, G. L.; Kuethe, J. T.; Kim, M. M; Yasuda, N. J. Org.
Chem. 2009, 74, 789−794.
(39) Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991, 113,
9694−9696.
(40) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461−
5464.
(41) Balasubramaniam, S.; Aidhen, I. S. Synlett 2007, 959−963.
(42) Krayer, M.; Yang, E.; Kim, H.-J.; Kee, H. L.; Deans, R. M.;
Sluder, C. E.; Diers, J. R.; Kirmaier, C.; Bocian, D. F.; Holten, D.;
Lindsey, J. S. Inorg. Chem. 2011, 50, 4607−4618.
(43) Aravindu, K.; Krayer, M.; Kim, H.-J.; Lindsey, J. S. New J. Chem.
2011, 35, 1376−1384.
9487
dx.doi.org/10.1021/jo201967k|J. Org. Chem. 2011, 76, 9478−9487