Expanded scope of synthetic bacteriochlorins via improved acid catalysis conditions and diverse dihydrodipyrrin-acetals

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Expanded Scope of Synthetic Bacteriochlorins via Improved Acid

Catalysis Conditions and Diverse Dihydrodipyrrin-Acetals

Michael Krayer, Marcin Ptaszek, Han-Je Kim, Kelly R. Meneely, Dazhong Fan,

Kristen Secor, and Jonathan S. Lindsey*

Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204

jlindsey@ncsu.edu

Received December 2, 2009

Bacteriochlorins are attractive candidates for a wide variety of photochemical studies owing to their

strong absorption in the near-infrared spectral region. The prior acid-catalysis conditions

[BF₃O(Et)₂in CH₃CN at room temperature] for self-condensation of a dihydrodipyrrin-acetal

3

(bearing a geminal dimethyl group in the pyrroline ring) typically afforded a mixture of three

macrocycles: the expected 5-methoxybacteriochlorin (MeOBC-type), a 5-unsubstituted bacterio-

chlorin (HBC-type), and a free base B,D-tetradehydrocorrin (TDC-type). Here, a broad survey of

>20 acids identified four promising acid catalysis conditions of which TMSOTf/2,6-di-tert-

butylpyridine in CH₂Cl₂at room temperature was most attractive owing to formation of the

5-methoxybacteriochlorin as the sole macrocycle regardless of the pyrrolic substituents in the

dihydrodipyrrin-acetal (electron-withdrawing, electron-donating, or no substituent). Eleven new

dihydrodipyrrin-acetals were prepared following standard routes. Application of the new acid

catalysis conditions has afforded diverse bacteriochlorins (e.g., bearing alkyl/ester, aryl/ester, diester,

and no substituents) in a few days from commercially available starting materials. Consideration of

the synthetic steps and yields for formation of the dihydrodipyrrin-acetal and bacteriochlorin

underpins evaluation of synthetic plans for early installation of bacteriochlorin substituents via

the dihydrodipyrrin-acetal versus late installation via derivatization of β-bromobacteriochlorins.

Treatment of the 5-methoxybacteriochlorins with NBS gave regioselective 15-bromination when no

pyrrolic substituents were present or when each pyrrole contained two substituents; on the other

hand, the presence of a β-ethoxycarbonyl group caused loss of regioselectivity. The 15 new

bacteriochlorins prepared herein exhibit a long-wavelength absorption band in the range 707-759

nm, providing tunable access to the near-infrared region. Taken together, this study expands the

scope of available bacteriochlorins for fundamental studies and diverse applications.

Introduction

the presence of an intense (ε ∼10⁵M^-1cm^-1) long-wavelength

absorption band located in the near-infrared region (700-900

nm).¹The near-infrared (NIR) absorption band opens the

door to photochemical studies with light of lower energy than

that in the ultraviolet or visible regions, and enables capture of

the large fraction of solar light in the NIR spectral region.²In

Bacteriochlorins, tetrahydroporphyrins containing alter-

nating pyrrole and pyrroline rings, are distinguished from

other members of the tetrapyrrole family of macrocycles by

(1) Kobayashi, M.; Akiyama, M.; Kano, H.; Kise, H. In Chlorophylls and

Bacteriochlorophylls: Biochemistry, Biophysics, Functions and Applications;

(2) Stromberg, J. R.; Marton, A.; Kee, H. L.; Kirmaier, C.; Diers, J. R.;

Muthiah, C.; Taniguchi, M.; Lindsey, J. S.; Bocian, D. F.; Meyer, G. J.;

Holten, D. J. Phys. Chem. C 2007, 111, 15464–15478.

€

Grimm, B., Porra, R. J., Rudiger, W., Scheer, H., Eds.; Springer: Dordrecht,

The Netherlands, 2006; pp 79-94.

1016 J. Org. Chem. 2010, 75, 1016–1039

Published on Web 01/20/2010

DOI: 10.1021/jo9025572

r

2010 American Chemical Society

Krayer et al.

JOCFeatured Article

this regard, bacteriochlorophylls a, b, and g contain the

bacteriochlorin chromophore and provide the basis for

light-harvesting processes and electron-transfer reactions

in bacterial photosynthesis (Chart 1).³While the biosynth-

esis⁴and spectroscopy¹of bacteriochlorophylls remain fer-

tile areas of investigation, the synthetic chemistry of

bacteriochlorins is relatively undeveloped.^5-7The develop-

ment of robust and versatile routes for preparing and

modifying bacteriochlorin macrocycles is essential for fun-

damental studies of their chemical and physical properties

and understanding the intricacies of their roles in photosyn-

thetic processes.

CHART 1

The ability to tailor synthetic bacteriochlorins with peri-

pheral substituents should enable a host of important prop-

erties to be tuned in a systematic manner. The properties

include the following: (i) the position of the near-infrared

absorption band, (ii) redox potentials, (iii) metal chelate

stability, (iv) solubility, (v) supramolecular interactions in-

cluding self-assembly, and (vi) amenability as constituents in

diverse photochemical applications ranging from artificial

photosynthesis to medicine. One approach to the synthesis of

bacteriochlorins relies on semisynthesis, namely modifica-

tion of existing bacteriochlorophylls.^5,7A second approach

entails reduction or derivatization of porphyrins or chlor-

ins.⁵Both approaches have merit but both lack the poten-

tial versatility of de novo synthetic routes wherein the

bacteriochlorin chromophore is constructed directly

from acyclic precursors. For example, the fully unsubsti-

tuted bacteriochlorin (lacking β-pyrrole substituents) is

a key benchmark for all spectroscopic and photo-

chemical studies of bacteriochlorophylls, yet has hardly

been investigated.⁸Similarly, incorporation of bacterio-

chlorins into multipigment arrays to explore energy- and

electron-transfer reactions, as has been done vigorously

with porphyrins,⁹has been comparatively untouched.¹⁰

The dearth of such studies stems from synthetic limita-

tions in the creation of suitable bacteriochlorin macro-

cycles.

hydrocorrin (TDC-T) (Scheme 1).¹¹Each macrocycle contains a

geminal dimethyl group in each pyrroline ring, which makes

these compounds oxidatively stable under routine handling. By

contrast, bacteriochlorophylls derived from photosynthetic bac-

teria are prone to adventitious dehydrogenation upon handling

outside of their natural physiological environment, giving rise to

chlorins and/or porphyrins.¹²

The formation of three macrocycles from the self-con-

densation was both a limitation of the synthetic route and

an opportunity to access distinct compounds. Alteration of

the concentrations of the acid [BF₃O(Et)₂from 10-500

3

Over the past few years we have been working to develop a

synthetic route to bacteriochlorins. The route entails the

acid-catalyzed self-condensation of a dihydrodipyrrin-

acetal, wherein the pyrroline ring contains a geminal dimethyl

group integral to the ring and the acetal moiety located

at the R-position. The first dihydrodipyrrin-acetal examined

(1-T) contained a p-tolyl group attached to the β-pyrrole ring

mM] and the acetal (1-T from 2.5-50 mM) was found to

shift the product distribution considerably. Indeed, distinct

conditions were identified that would favor a given macro-

cycle, with isolation of a much lesser quantity of one of the

other macrocycles: the preparative synthesis with 18 mM 1-T

and 140 mM BF₃O(Et)₂gave predominantly HBC-T

3

(49%); 5 mM 1-T and 50 mM BF₃O(Et)₂gave predomi-

3

(R¹= p-tolyl, R²= H). Treatment of 1-T with BF₃O(Et)₂

3

nantly MeOBC-T (30%); and 11 mM 1-T and 10 mM

BF₃O(Et)₂gave predominantly TDC-T (66%).¹¹A study

in CH₃CN afforded a mixture of two free base bacterio-

chlorins (HBC-T, MeOBC-T) and a free base B,D-tetrade-

3

reported here showed that the yield of MeOBC-T was

increased to 46% upon use of 18 mM 1-T and 45 mM

BF₃O(Et)₂, but the product was accompanied by HBC-T

(3) Scheer, H. In Chlorophylls and Bacteriochlorophylls: Biochemistry,

€

3

Biophysics, Functions and Applications; Grimm, B., Porra, R. J., Rudiger, W.,

and TDC-T in yields of 6% and 11%, respectively (see

Supporting Information). Nevertheless, conditions that af-

ford a single macrocycle in good yield have heretofore not

been identified.

Scheer, H., Eds.; Springer: Dordrecht, The Netherlands, 2006; pp 1-26.

(4) Chew, A. G. M.; Bryant, D. A. Annu. Rev. Microbiol. 2007, 61, 113–

129.

(5) Chen, Y.; Li, G.; Pandey, R. K. Curr. Org. Chem. 2004, 8, 1105–1134.

(6) Galezowski, M.; Gryko, D. T. Curr. Org. Chem. 2007, 11, 1310–1338.

(7) Grin, M. A.; Mironov, A. F.; Shtil, A. A. Anti-Cancer Agents Med.

Chem. 2008, 8, 683–697.

(8) 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.

(9) Harvey, P. D. In The Porphyrin Handbook; Kadish, K. M., Smith, K.

M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2003; Vol. 18, pp

63-250.

(10) Muthiah, C.; Kee, H. L.; Diers, J. R.; Fan, D.; Ptaszek, M.; Bocian,

D. F.; Holten, D.; Lindsey, J. S. Photochem. Photobiol. 2008, 84, 786–801.

(11) Kim, H.-J.; Lindsey, J. S. J. Org. Chem. 2005, 70, 5475–5486.

The self-condensation route, developed upon examination

of the synthesis of 2,12-di-p-tolylbacteriochlorins,¹¹has

been extended to other dihydrodipyrrin-acetals to afford

(12) (a) Limantara, L.; Koehler, P.; Wilhelm, B.; Porra, R. J.; Scheer, H.

Photochem. Photobiol. 2006, 82, 770–780. (b) Kozyrev, A. N.; Chen, Y.;

Goswami, L. N.; Tabaczynski, W. A.; Pandey, R. K. J. Org. Chem. 2006, 71,

1949–1960.

J. Org. Chem. Vol. 75, No. 4, 2010 1017

Krayer et al.

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SCHEME 1. Self-Condensation of a Dihydrodipyrrin-Acetal

Resulting in Three Macrocycles

concentration of acid catalysts,¹⁵and the expected strong

influence of substituents attached to the pyrrole nucleus

in the dihydropyrrin-acetal unit, we embarked on a systema-

tic study of the effects of acid catalysts on a basis set

of substituted dihydrodipyrrin-acetals. A key issue was

whether conditions could be identified that make use of

acids milder than BF₃O(Et)₂yet form the HBC- or

3

MeOBC-type bacteriochlorin in good yield and in selective

fashion.

In this paper, we describe the study of reaction conditions

for the self-condensation of dihydrodipyrrin-acetals to give

bacteriochlorins. The paper is divided into three major

parts. Part I describes the preparation of a collection of

dihydrodipyrrin-acetals with electron-withdrawing, elec-

tron-donating, or no substituents at the R¹and R²positions

(Chart 2). Part II describes a two-tiered search for Lewis

acids for the self-condensation of the dihydrodipyrrin-

acetals. The first tier entailed a survey of >20 acids applied

to the condensation of 1-T and 1-Br. From this broad

ranging survey, four acids were identified that afforded

promising results. The second tier applied the four acids

to a basis set of dihydrodipyrrin-acetals, while systemati-

cally varying both the concentration of the dihydrodipyr-

rin-acetal and the acid. The results of this study provide

access to new bacteriochlorins, provide insights into the

reactivity of precursors to bacteriochlorins, and also inform

synthetic planning for the preparation of substituted bac-

teriochlorins either by prefunctionalizing the precursors to

bacteriochlorins or by introducing substituents in intact

bacteriochlorin macrocycles. Part III describes a bromina-

tion study of three new MeOBC-type bacteriochlorins,

which were readily accessed through the methods developed

herein.

Results

I. Synthesis of Dihydrodipyrrin-Acetals. The generic syn-

thesis of dihydrodipyrrin-acetals entails five steps from a

pyrrole as shown in Scheme 2. The steps include formylation

to give the pyrrole-2-carboxaldehyde (2), nitro-aldol (Henry)

condensation to give the nitrovinylpyrrole and subsequent

reduction to give the 2-(2-nitroethyl)pyrrole (3), Michael

addition with the R,β-unsaturated ketone-acetal 4¹¹to give

the nitrohexanone-pyrrole (5), and McMurry-type ring clo-

sure to give the dihydrodipyrrin-acetal (1). Since the first

synthesis of the p-tolyl-substituted dihydrodipyrrin-acetal

1-T,¹¹considerable effort has been devoted to the develop-

ment of improved and general procedures for this overall

transformation. The key improvements include smooth condi-

tions for installing the nitroethyl group,¹⁶a solventless method

for the Michael addition,¹⁷and mild conditions for form-

ing the pyrroline ring;¹⁸all of these are carried out with limited

chromatography so as to enable synthesis at the multigram

scale.¹⁸Such methods were developed largely for a scalable

synthesis of the known⁸1-Br and have been applied herein

bacteriochlorins bearing 3,13-dibromo,⁸2,12- or 3,13-bis-

(swallowtail) [CH(CH₂CH₂OCH₃)₂],¹³or 3,13-dimesityl sub-

stituents.¹⁴Application of the conditions identified with 1-T

gave uneven results with these other dihydrodipyrrin-acetals.

For example, treatment of the bromodihydrodipyrrin-acetal

(1-Br, R¹= H, R²= Br) at 5 mM with 50 mM BF₃O(Et)₂

3

gave HBC-Br as the predominant macrocycle and only in

15% yield. Similar low yields also were obtained with the

other dihydrodipyrrin-acetals. The ability to obtain a single

target macrocycle in reasonable yield is essential for progress

in bacteriochlorin chemistry. Given the known sensitivity

of tetrapyrrole macrocycle formation to the nature and

(15) Lindsey, J. S. Acc. Chem. Res. 2010, 43, DOI: 10.1021/ar900212t.

(16) Ptaszek, M.; Bhaumik, J.; Kim, H.-J.; Taniguchi, M.; Lindsey, J. S.

Org. Process Res. Dev. 2005, 9, 651–659.

(17) Kim, H.-J.; Dogutan, D. K.; Ptaszek, M.; Lindsey, J. S. Tetrahedron

2007, 63, 37–55.

ꢀ

(18) Krayer, M.; Balasubramanian, T.; Ruzie, C.; Ptaszek, M.; Cramer,

D. L.; Taniguchi, M.; Lindsey, J. S. J. Porphyrins Phthalocyanines 2009, 13,

ꢀ

(13) Borbas, K. E.; Ruzie, C.; Lindsey, J. S. Org. Lett. 2008, 10, 1931–

1934.

(14) McDowell, B. E. Ph.D. Thesis, North Carolina State University,

2007.

1098–1110.

1018 J. Org. Chem. Vol. 75, No. 4, 2010

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CHART 2. Dihydrodipyrrin-Acetals for the Self-Condensation

to Bacteriochlorins

SCHEME 2. Synthesis of Dihydrodipyrrin-Acetals

where possible for the synthesis of the dihydrodipyrrin-acetals.

In this regard, a refined synthesis of known dihydrodipyrrin-

acetals 1-T¹¹and 1-H¹⁷at substantial scale (>350 mg) has been

carried out.

The synthesis of each dihydrodipyrrin-acetal begins with a

corresponding pyrrole. Pyrroles 6-EtEt,¹⁹6-Py,²⁰6-AnEs,²¹

6-MeEs,²²6-ArEs,²³6-Ar,²⁴and 6-TEs¹¹were prepared

according to the literature, whereas 6-EsEs was obtained

commercially. Dihydrodipyrrin-acetal 1-EtEs required the

(19) Milgram, B. C.; Eskildsen, K.; Richter, S. M.; Scheidt, W. R.;

Scheidt, K. A. J. Org. Chem. 2007, 72, 3941–3944.

(20) Smith, N. D.; Huang, D.; Cosford, N. D. P. Org. Lett. 2002, 4, 3537–

3539.

(21) Massa, S.; Di Santo, R.; Mai, A.; Botta, M.; Artico, M.; Panico, S.;

Simonetti, G. Farmaco 1990, 45, 833–846.

(22) Cheng, D. O.; Bowman, T. L.; LeGoff, E. J. Heterocycl. Chem. 1976,

13, 1145–1147.

(23) Balasubramanian, T.; Lindsey, J. S. Tetrahedron 1999, 55, 6771–

6784.

J. Org. Chem. Vol. 75, No. 4, 2010 1019

Krayer et al.

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synthesis of pyrrole 6-EtEs. The Wittig reaction of pro-

pionaldehyde and (carbethoxymethylene)triphenylphos-

phorane (following a procedure for a methyl homologue)²⁵

afforded the corresponding R,β-unsaturated esters, which

upon treatment with p-toluenesulfonyl methylisocyanide

(TosMIC) via the van Leusen method²⁶gave pyrrole 6-EtEs

(eq 1). Similar treatment of ethyl acrylate with TosMIC gave

pyrrole 6-Es (eq 2).

(iii) The Michael addition reaction of 3 typically was

carried out under solventless conditions for 16 h at room

temperature using 1.2 equiv of the Michael acceptor 4 and

DBU to afford the nitrohexanone-pyrrole 5. The reaction of

3-EtEt with 2 equiv of DBU for 5 h at room temperature gave

5-EtEt in 29% yield, whereas 3-EsEs with 10 equiv of 4 at

room temperature for 15 min gave 5-EsEs in 20% yield.

Fewer equivalents and longer reaction times resulted in

lower yields. The Michael addition of 3-Es or 3-Py was

carried out using 3 equiv of 4 and 3 equiv of DBU for 1 h

at room temperature to afford 5-Es or 5-Py in 66% or 27%

yield, respectively.

(iv) Nitrohexanone-pyrroles 5were converted to the dihydro-

dipyrrin-acetals 1 by reductive cyclization using NaOMe

and a buffered solution of TiCl₃at room temperature for

16 h, except for 5-Py, which required longer reaction time

(48 h) and higher temperature (35 °C). Dihydrodipyrrin-

acetal 1-EtEt was extremely unstable and began decom-

posing within a few minutes. Accordingly, complete char-

acterization was not obtained for 1-EtEt, and the attempted

self-condensation studies did not result in significant bac-

teriochlorin formation (vide infra).

(v) Dihydrodipyrrin-acetal 1-TEs was synthesized in a

streamlined fashion from pyrrole 6-TEs without character-

ization of all intermediates.

The synthesis of each dihydrodipyrrin-acetal generally

followed established methods; however, the conditions for

each synthetic step (especially time and temperature) can

vary considerably due to the different reactivity imparted by

the pyrrole substituents. Key observations concerning the

synthesis of the various dihydrodipyrrin-acetals are as fol-

lows:

Each dihydrodipyrrin-acetal was characterized by ¹H

NMR and ¹³C NMR spectroscopy and by ESI-MS. Dihydro-

dipyrrin-acetals bearing electron-withdrawing substituents

(e.g., CO₂Et) were stable and could be stored at -10 °C

for several months. Dihydrodipyrrin-acetals bearing no

substituents (1-H) or electron-donating substituents (1-EtEt)

began decomposing within hours or minutes, respectively,

and consequently were used immediately in the self-conden-

sation reaction, typically after quick purification on an

alumina column.

(i) Vilsmeier-Haack formylation proceeded at room tem-

perature in 2-3 h for 3-(ethoxycarbonyl)-4-ethylpyrrole (6-

EtEs) and 3,4-diethylpyrrole (6-EtEt), at room temperature

overnight for 3-ethoxycarbonylpyrrole (6-Es) and 3-(4-

pyridyl)pyrrole (6-Py), and at 80 °C for 24 h for 3,4-bis-

(ethoxycarbonyl)pyrrole (6-EsEs). Formylation of the un-

symmetrical pyrroles 6-EtEs, 6-MeEs, 6-Es, and 6-Py

predominantly took place at the R-position distal to the ester

or pyridyl substituent. A single-crystal X-ray structure of 2-

Py provided proof of regioselectivity of formylation (see the

Supporting Information). The minor regioisomer (with sub-

stitution at the proximal R-position) was easily separated by

column chromatography and was not further characterized.

Note that formylpyrrole 2-Py is poorly soluble in a variety of

solvents, which made handling and purification difficult.

(ii) The formylpyrroles 2 were converted to nitroethylpyr-

roles 3 via the nitro-aldol condensation and subsequent

reduction of the vinyl group. For the compounds containing

ester substituents (3-EtEs, 3-EsEs, and 3-Es), the reduction

was carried out using NaBH₄instead of LiBH₄to avoid

possible reduction of the ester groups. Nitroethylpyrroles 3-

EtEs, 3-EsEs, 3-Es, and 3-Py (containing electron-withdraw-

ing substituents) were stable under routine handling and

could be purified via column chromatography, while the

electron-rich 3-EtEt decomposed rapidly when subjected to

silica or alumina column chromatography and was therefore

used in crude form for the subsequent Michael addition.

II. Acid Catalysis Conditions for Bacteriochlorin Forma-

tion. Bacteriochlorin formation (Scheme 1) requires reaction

of the nucleophilic R-pyrrolic position and the electrophilic

acetal moiety of the dihydrodipyrrin-acetal. The MeOBC-

type macrocycles form solely by condensation processes

whereas an unknown reduction step (2e^-/2H^þ) occurs to

give the HBC-type macrocycles.¹¹A chief goal here was to

find broadly applicable conditions that selectively afford a

single bacteriochlorin macrocycle rather than a mixture of

the MeOBC-type and HBC-type macrocycles. The acid

likely serves to increase the electrophilicity of the acetal

carbon. In this regard, the acid catalysis is expected to

resemble the well-known acid-mediated hydrolysis of acetals

as well as the Mukaiyama aldol condensation of acetals and

silyl ethers.²⁷Accordingly, in the initial broad survey we

focused mainly on Lewis acids that are reported to be active

in acetal hydrolysis and Mukaiyama aldol condensations.

Mild acid catalysts known to afford superior results in

reactions leading to porphyrins also were examined.¹⁵

1. Broad Survey of Acid Catalysts. The previous study

employed dihydrodipyrrin-acetal 1-T at 2.5-50 mM and

BF₃O(Et)₂at 10-500 mM in CH₃CN, catalysis conditions

3

that emerged from a short survey of a set of acids all in

(24) Balasubramanian, T.; Strachan, J.-P.; Boyle, P. D.; Lindsey, J. S. J.

Org. Chem. 2000, 65, 7919–7929.

(25) Kandula, S. R. V.; Kumar, P. Tetrahedron: Asymmetry 2005, 16,

3268–3274.

(26) van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen, D.

Tetrahedron Lett. 1972, 13, 5337–5340.

(27) Miura, K.; Hosomi, A. In Main Group Metals in Organic Synthesis;

Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, pp

409-592.

1020 J. Org. Chem. Vol. 75, No. 4, 2010

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TABLE 1. Lewis Acids Identified from the Self-Condensation Survey of 1-T and 1-Br^a

1

R¹

R²

acid

Bi(OTf)₃

Hf(OTf)₄xH₂O

time (h)

HBC-T (%)

7.6

13

1.5

MeOBC-T (%)

1-T

p-tolyl

H

19

15

13

32

28

18

17

3

HfCl₄

TMSOTf/2,6-DTBP^b

-

c

1

R¹

R²

acid

time (h)

HBC-Br (%)

MeOBC-Br (%)

1-Br

H

Br

Bi(OTf)₃

Hf(OTf)₄xH₂O

HfCl₄

19

16

13

30

33

6.5

trace^d

-

3

c

-

c

TMSOTf/2,6-DTBP^b

-

25

^aAll reactions were carried out in CH₂Cl₂at room temperature with 10 mM 1-T or 1-Br, and 50 mM acid. Yields were determined by absorption

spectroscopy of samples isolated by chromatography (limit of detection ∼0.4%). ^b50 mM TMSOTf and 500 mM 2,6-DTBP. ^cNot detected. ^dObserved in

small quantity by TLC but no yield determined.

CH₃CN.¹¹Here, >20 Lewis acids^28,29were investigated for

the self-condensation of 1-T in solvents less polar than

CH₃CN, such as CH₂Cl₂or toluene. The reactions were

conducted with 10 mM dihydrodipyrrin-acetal (0.02 or 0.03

mmol scale) and 50 mM acid. The reactions were followed by

TLC and UV-vis spectroscopy. Reactions that showed at

least traces of bacteriochlorin in the crude reaction mixture

by UV-vis spectroscopy (Q_yabsorption >700 nm) were

quenched by the addition of TEA. Bacteriochlorins were

isolated by chromatography, whereupon yields were deter-

mined spectroscopically [assuming ε_Qy= 130000 M^-1cm^-1

and ε_Qy= 120000 M^-1cm^-1for HBC-type and MeOBC-

type bacteriochlorins, respectively].¹¹The acids were

grouped as follows on the basis of the results with 1-T in

CH₂Cl₂for up to 48 h at room temperature: (a) little reaction

occurred and starting material was recovered [Sn(OAc)₄,

Al(acac)₃, LiOTf]; (b) the starting material was con-

sumed but little or no macrocycle formation was observed

[Cu(OTf)₂, ZrCp₂Cl₂, Pd(O₂CCF₃)₂, Bu₂GeCl₂, AlMe₃,

TMSOTf]; (c) TDC-T was predominantly formed

[Dy(OTf)₃, Eu(OTf)₃, Pr(OTf)₃, Er(OTf)₃, Yb(NTf₂)₃, Ga-

(OTf)₃, In(OTf)₃]; and (d) HBC-T or MeOBC-T was formed

identified for bacteriochlorin formation are summarized in

Table 1. Among the catalysts, TMSOTf/2,6-DTBP appeared

superior given that this catalyst system afforded exclusively

the 5-methoxybacteriochlorin. Indeed, the dibromobacter-

iochlorin MeOBC-Br is a new compound, as this was not

obtained previously⁸via BF₃O(Et)₂catalysis.

3

A number of other studies were carried out with 1-Br.

Attempts to replace Bi(OTf)₃withtheless expensiveanalogue

BiCl₃gave little or no bacteriochlorin even with inclusion of

various additives. Attempts to use other amines (2,6-lutidine,

diisopropylethylamine, DBU, 2,3,5-collidine, imidazole,

dicyclohexylmethylamine) in place of 2,6-DTBP in conjunc-

tion with TMSOTf generally failed to give any bacteriochlor-

in, as did use of related silicon-based species (TMSOTf/InCl₃,

TMSNTf₂, and TIPSOTf/2,6-DTBP) except TMSI/2,6-

DTBP, which afforded MeOBC-Br in 30% yield. Examina-

tion of other solvents (CH₂Cl₂, CH₃CN, toluene, CH₃NO₂,

ClCH₂CH₂Cl) in conjunction with Bi(OTf)₃or TMSOTf/2,6-

DTBP gave no improvements although some of the solvents

also supported formation of bacteriochlorins. These studies

are described in the Supporting Information.

The formation of TDC-type macrocycles has only been

indicated by TLC analysis (TDC-T has been fully character-

ized previously¹¹), and such ring-contracted macrocycles

were not separated or completely characterized. Some Lewis

acids identified during the broad survey were especially

efficient in forming TDC-type macrocycles. Tentatively as-

signed on the basis of TLC analysis, the efficiency appears to

decrease in order of Yb(OTf)₃∼ Yb(NTf₂)₃> Sc(OTf)₃∼

Er(OTf)₃> Dy(OTf)₃∼ Eu(OTf)₃> Ln(OTf)₃.

in >5% yield [Sn(OTf)₂, Bi(OTf)₃, Hf(OTf)₄xH₂O, HfCl₄,

3

TMSOTf/2,6-di-tert-butylpyridine (2,6-DTBP)³⁰].

An extension of this survey to 1-Br gave the same general

grouping of acids, although a number of the active catalysts

(except TMSOTf/2,6-DTBP) tended to give the HBC- versus

the MeOBC-type macrocycle. On the basis of the broad

survey of acid catalysts with 1-T and 1-Br, the best conditions

2. Application of New Acid Catalysis Conditions. The most

promising acids identified in the broad survey were applied to

the self-condensation of dihydrodipyrrin-acetals 1-Br, 1-T, 1-H,

1-EtEs, 1-EtEt, and 1-EsEs at various concentrations of the

dihydrodipyrrin-acetal and the acid. The most promising acid

and solvent combinations (all in CH₂Cl₂) were as follows: Bi-

(OTf)₃, Hf(OTf)₄, HfCl₄, and TMSOTf/2,6-DTBP. In addition,

(28) (a) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH:

Weinheim, Vols. 1 and 2, 2000. (b) Acid Catalysis in Modern Organic Synthesis;

Yamamoto, H., Ishihara, K. Eds.; Wiley-VCH:Weinheim, 2008.

(29) (a) Gaspard-Iloughmane, H.; Le Roux, C. Eur. J. Org. Chem. 2004,

2517–2532. (b) Dilman, A. D.; Ioffe, S. L. Chem. Rev. 2003, 103, 733–772. (c)

Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002,

102, 2227–2302.

(30) Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44, 4259–

4275.

J. Org. Chem. Vol. 75, No. 4, 2010 1021

Krayer et al.

JOCFeatured Article

TABLE 2. Self-Condensation of Dihydrodipyrrin-Acetals^a

bacteriochlorins (% yields)

entry

reactant

Lewis acid

Bi(OTf)₃

Hf(OTf)₄xH₂O

HfCl₄

TMSOTf/2,6-DTBP

HBC-T

MeOBC-T

1

2

3

4

5

1-T

3.4

15

25

2.9

32

3

c

-

c

-

27

c

BF₃O(Et)₂/CH₃CN

3

-

bacteriochlorins (% yields)

entry

reactant

Lewis acid

Bi(OTf)₃

Hf(OTf)₄xH₂O

HfCl₄

TMSOTf/2,6-DTBP

HBC-Br

MeOBC-Br

6

7

8

9

10

1-Br

6.2

3.6

c

-

3

c

-

33

c

-

13

c

BF₃O(Et)₂/CH₃CN

3

-

bacteriochlorins (% yields)

entry

reactant

Lewis acid

Bi(OTf)₃

Hf(OTf)₄xH₂O

HfCl₄

TMSOTf/2,6-DTBP

HBC-H

MeOBC-H

11

12

13

14

15

1-H

7.8

3.4

9.6

c

-

3

c

-

21

c

-

c

BF₃O(Et)₂/CH₃CN

3

1.9

-

bacteriochlorins (% yields)

entry

reactant

Lewis acid

Bi(OTf)₃

Hf(OTf)₄xH₂O

HfCl₄

TMSOTf/2,6-DTBP

HBC-EtEs

MeOBC-EtEs

16

17

18

19

20

1-EtEs

2.9

1.1

7.4

15

0.9

4.5

42

3

c

-

28

c

BF₃O(Et)₂/CH₃CN

3

-

bacteriochlorins (% yields)

entry

reactant

Lewis acid

Bi(OTf)₃

Hf(OTf)₄xH₂O

HfCl₄

TMSOTf/2,6-DTBP

HBC-EtEt

MeOBC-EtEt

21

22

23

24

25

1-EtEt

<1

-

<1

-

c

3

c

-

c

BF₃O(Et)₂/CH₃CN

3

bacteriochlorins (% yields)

entry

reactant

Lewis acid

Bi(OTf)₃

Hf(OTf)₄xH₂O

HBC-EsEs

MeOBC-EsEs

c,d

26

27

28

29

30

1-EsEs^b

-

c,d

-

3

c,d

HfCl₄

TMSOTf/2,6-DTBP

BF₃O(Et)₂/CH₃CN

-

c,d

-

8.5^d

c,d

-

3

^aAll reactions were carried out with 18 mM dihydrodipyrrin-acetal at room temperature and in CH₂Cl₂except those with BF₃O(Et)₂, which

employed CH₃CN. The acid concentrations were 140 mM [Bi(OTf)₃, Hf(OTf)₄xH₂O, HfCl₄, and BF₃O(Et)₂] or 90 mM [TMSOTf with 360 mM 2,6-

DTBP]. Each reaction was carried out for 16 h unless noted otherwise. Yields were determined by absorption spectroscopy of samples isolated by

3

chromatography (limit of detection ∼0.4%). ^bReaction for 48 h. ^cNot detected. ^dUnreacted dihydrodipyrrin-acetal remained.

BF₃O(Et)₂in CH₃CN was used for comparison with prior

3

1/TMSOTf/2,6-DTBP=5 mM/25 mM/100 mM and 18 mM/

80 mM/320 mM. In total, each of the six dihydrodipyrrin-

acetals was subjected to 10 different reaction conditions.

The results from reactions of the six dihydrodipyrrin-

acetals at higher concentrations (18 mM 1) are provided in

Table 2. The results at lower concentrations (5 mM 1) are

provided in the Supporting Information. A number of trends

emerged from this study. First, TMSOTf/2,6-DTBP af-

forded the highest yield and the greatest selectivity of macro-

cycle formation for most of the dihydrodipyrrin-acetals.

Indeed, the bacteriochlorins MeOBC-T, MeOBC-Br,

MeOBC-H, MeOBC-EtEs, and MeOBC-EsEs were the only

observed macrocycles, with no isolable amounts of the

data from the self-condensation of 1-T and 1-Br.

In our previous work,¹¹the self-condensation of 1-T using

BF₃O(Et)₂in CH₃CN at nearly equimolar concentrations

3

of 1-T and BF₃O(Et)₂(10 and 11 mM, respectively) gave

3

TDC-T as the major macrocyclic product. At concentrations

of 5 mM 1-T and 50 mM BF₃O(Et)₂the major product was

3

MeOBC-T, whereas at concentrations of 18 mM 1-T and 140

mM BF₃O(Et)₂the major product was HBC-T. According

3

to these results the two concentrations chosen for the self-

condensation study were 5 mM 1/50 mM acid and 18 mM

1/140 mM acid, except for the reactions using TMSOTf/2,6-

DTBP. The latter were carried out with concentrations of

1022 J. Org. Chem. Vol. 75, No. 4, 2010

Krayer et al.

JOCFeatured Article

TABLE 3. Preparative Synthesis of Bacteriochlorins^a

reactant

1-Br^b

scale (mmol of 1)

product

% yield

isolated amount (mg)

0.61

1.7

2.1

0.53

0.076

2.2

0.33

0.21

0.077

MeOBC-Br

MeOBC-H

HBC-EtEs

MeOBC-EtEs

MeOBC-EsEs

MeOBC-Es

MeOBC-AnEs

MeOBC-MeEs

MeOBC-ArEs

32

44

41

40

63

8.4

32

48

36

55

150

250

64

16.5

50

40

29

13

1-H^c

1-EtEs^d

1-EtEs^b

1-EsEs^b,e

1-Es^b

1-AnEs^c

1-MeEs^c

1-ArEs^b

^aAll reactions were carried out at room temperature for 16 h unless noted otherwise. ^b18 mM reactant, 90 mM TMSOTf, and 360 mM 2,6-DTBP in

CH₂Cl₂. ^c5 mM reactant, 25 mM TMSOTf, and 100 mM 2,6-DTBP. ^d18 mM reactant and 140 mM BF₃O(Et)₂in CH₃CN. ^eReaction for 4 days.

3

corresponding HBC-type macrocycles. Second, the next best

among the new acid conditions was Bi(OTf)₃, which in each

case afforded a mixture of the HBC-type and MeOBC-type

macrocycles. Third, the only dihydrodipyrrin-acetal that

failed to afford significant quantities of bacteriochlorin

was the electron-rich 1-EtEt (used immediately upon

preparation), which was observed to be quite unstable

(vide supra). The reaction mixture from 1-EtEt with catalysis

by Bi(OTf)₃showed absorption bands at 350, 374, 500, and

719 nm (in CH₂Cl₂) and molecule ion peaks at m/z 482.4

(HBC-EtEt) and 512.6 (MeOBC-EtEt), but the overall yield

was very low. Finally, we note that the use of the original acid

treatment of MeOBC-T with NBS cleanly afforded the

corresponding 15-bromobacteriochlorin. The ability to se-

lectively brominate the 15-position of MeOBC-T enabled the

synthesis of diverse bacteriochlorins.^10,31,32However, it was

unclear whether the selective 15-bromination was unique to

MeOBC-T and, in particular, whether the selectivity for 15-

bromination of MeOBC-T stems solely from the electronic

effect of the 5-methoxy substituent or is aided by the steric

effects of the 2,12-di-p-tolyl substituents. The new 5-methoxy-

bacteriochlorins obtained herein allowed further studies to

probe such issues.

To investigate the electronic effect of the 5-methoxy sub-

stituent, MeOBC-H (lacking any β substituents) was treated

with NBS (1 equiv) in THF at room temperature for 1 h. The

reaction proceeded cleanly to afford a single new product

upon examination by TLC analysis. While the resonances of

each proton in the ¹H NMR spectrum were not assigned due

to the overlapping chemical shifts of the meso and β protons,

the disappearance of a cross peak in the NOESY-NMR

stemming from the -CH₂- at the 17-position and the proton

at the 15-position suggested that bromination took place at

the 15-position to afford MeOBC-H-Br¹⁵. For further con-

firmation, putative MeOBC-H-Br¹⁵was subjected to palla-

dium coupling conditions³³to substitute the bromine atom

with a methoxy group. ¹H NMR spectroscopy of the result-

ing dimethoxybacteriochlorin gave a simplified spectrum

consistent with the nominal C_2hsymmetry of the product

BC-OMe^5,15, thereby confirming the regioselective 15-bro-

mination in the preceding step (Scheme 3). By contrast,

treatment of unsubstituted HBC-H with NBS (1 equiv) in

THF resulted in a mixture of at least three bromobacterio-

chlorins (TLC analysis), which upon LD-MS analysis

showed peaks (m/z = 448.1, 526.1) consistent with mono-

and dibromobacteriochlorins. Thus, given the presence of

sterically unhindered meso and β-pyrrole sites, the electronic

effect of the 5-methoxy group alone directs bromination

preferentially to the 15-position.

catalysts [BF₃O(Et)₂/CH₃CN] at the specified concentra-

3

tions with several dihydrodipyrrin-acetals herein tended to

give exclusively the HBC-type macrocycle, as observed for

HBC-T, HBC-Br, HBC-H (albeit in very low yield), and

HBC-EtEs (Table 2). The selective formation of HBC-Br

was observed previously,⁸but HBC-T and MeOBC-T have

been obtained previously from 1-T using BF₃O(Et)₂in 49%

3

and 30% yield, respectively.¹¹

The best conditions identified in each case were employed at

a 0.076-2.2 mmol scale to obtain complete characterization

and isolated (gravimetric) yields of each macrocycle. The yields

obtained in the larger scale reactions generally corres-

ponded well to those obtained in the small-scale survey reac-

tions (Table 3). The only discrepancy was for MeOBC-EsEs,

which was observed in 8.5% yield in the microscale study

(2 day reaction) but in 63% upon scaleup (4 day reaction).

The TMSOTf/2,6-DTBP acid catalysis conditions also

were applied to dihydrodipyrrin-acetals 1-Es, 1-AnEs, 1-

MeEs, and 1-ArEs to give bacteriochlorins MeOBC-

Es, MeOBC-AnEs, MeOBC-MeEs, and MeOBC-ArEs in

8.4%, 32%, 48%, and 36% yield, respectively (Table 3).

However, the same conditions applied to 1-Py resulted in

very low yield of MeOBC-Py (<1%). The low yield may

stem from incompatibility of the pyridyl moiety of 1-Py with

the acid catalysis conditions for the self-condensation pro-

cess. Nonetheless, the new acid catalysis conditions have

afforded eight new 5-methoxybacteriochlorins in reasonable

yield, in each case without noticeable accompaniment of

other macrocycles.

Treatment of the 5-methoxybacteriochlorin MeOBC-Es

with NBS (1 equiv) in THF at room temperature for 1 h

afforded a mixture of mono- and dibrominated bacterio-

chlorins. Column chromatography afforded four fractions:

(i) the β-substituted bromobacteriochlorin MeOBC-Es-

Br¹²(15%), (ii) a mixture of mono- and dibrominated

bacteriochlorins (LD-MS m/z = 622.2, m/z = 700.1) that

III. Bromination of MeOBC-Type Bacteriochlorins. Pre-

viously, our group has explored the bromination of the

p-tolyl-substituted bacteriochlorins HBC-T and MeOBC-T

to obtain bacteriochlorin building blocks.³¹Bromination of

HBC-T occurred at the β and/or meso positions to afford a

mixture of mono- and dibromobacteriochlorins; by contrast,

(32) Muthiah, C.; Taniguchi, M.; Kim, H.-J.; Schmidt, I.; Kee, H. L.;

Holten, D.; Bocian, D. F.; Lindsey, J. S. Photochem. Photobiol. 2007, 83,

1513–1528.

(33) Gao, G.-Y.; Ruppel, J. V.; Allen, D. B.; Chen, Y.; Zhang, X. P. J.

Org. Chem. 2007, 72, 9060–9066.

(31) Fan, D.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2007, 72, 5350–5357.

J. Org. Chem. Vol. 75, No. 4, 2010 1023

Krayer et al.

JOCFeatured Article

SCHEME 3. Regioselective 15-Bromination of MeOBC-H

SCHEME 4. Bromination of MeOBC-Es

SCHEME 5. Regioselective 15-Bromination of MeOBC-EtEs

was not analyzed further, (iii) remaining starting material

MeOBC-Es (30%), and (iv) the 15-bromobacteriochlorin

MeOBC-Es-Br¹⁵(13%) (Scheme 4). Thus, the 3,13-bis-

(ethoxycarbonyl) substituents interfere with the directive

influence of the 5-methoxy group.

The same bromination conditions were applied to 5-

methoxybacteriochlorin MeOBC-EtEs, which contains an

ethoxycarbonyl and an ethyl group in each pyrrole and hence

cannot undergo β-pyrrole bromination. In this case, the 15-

bromobacteriochlorin MeOBC-EtEs-Br¹⁵was obtained as

the only isolated product in 59% yield (Scheme 5).

IV. Characterization. The bacteriochlorins were charac-

1

terized by H NMR spectroscopy, ¹³C NMR spectroscopy

(where sufficient sample permitted), high-resolution mass

spectrometry (ESI-MS), and absorption spectroscopy. The

bacteriochlorins for which insufficient sample was available

for ¹³C NMR spectroscopy include MeOBC-Es, MeOBC-

Py, and the brominated series of bacteriochlorins. The

bacteriochlorins prepared herein exhibit characteristic bac-

teriochlorin absorption spectra,¹with near-UV bands and a

long-wavelength band in the NIR region of comparable

intensity. The long-wavelength (Q_y) absorption band ap-

pears in the spectral region of 707-759 nm (Table 4). The

fwhm of the Q_yband was 13-24 nm. The sharpness of the

bands renders the synthetic bacteriochlorins well suited for

elaboration as biomedical imaging probes^34,35or as fluor-

escent markers in polychromatic flow cytometry.⁸The Q_y

band of the MeOBC-type bacteriochlorins shows a hypso-

chromic shift of 4-20 nm upon comparison to the HBC-type

analogues. The position of the Q_xband also varies among the

substituted bacteriochlorins. The spectra of selected bacter-

iochlorins in CH₂Cl₂are shown in Figure 1. The spectra

displayed include those of all available pairs of bacterio-

chlorins wherein the members of a pair differ only in the

presence a 5-methoxy versus 5-H group. The spectrum of

MeOBC-EsEs, the 5-methoxybacteriochlorin with the long-

est wavelength Q_yband among those prepared herein, also

is displayed.

(34) Kee, H. L.; Nothdurft, R.; Muthiah, C.; Diers, J. R.; Fan, D.;

Ptaszek, M.; Bocian, D. F.; Lindsey, J. S.; Culver, J. P.; Holten, D.

Photochem. Photobiol. 2008, 84, 1061–1072.

(35) Kee, H. L.; Diers, J. R.; Ptaszek, M.; Muthiah, C.; Fan, D.;

Lindsey, J. S.; Bocian, D. F.; Holten, D. Photochem. Photobiol. 2009, 85,

909–920.

1024 J. Org. Chem. Vol. 75, No. 4, 2010

Krayer et al.

JOCFeatured Article

TABLE 4. Long-Wavelength Absorption Band of 15 New Bacteriochlorins

^aAll data are in CH₂Cl₂at room temperature.

Discussion

routes to bacteriochlorin target molecules given the available

methods for introduction of substituents into dihydrodipyr-

rin-acetal precursors versus derivatization of intact bacter-

iochlorin macrocycles.

1. Overview of Acid Conditions. The development of

syntheses of tetrapyrrole macrocycles that entail acid-cata-

lyzed condensation of pyrrolic or pyrromethane substrates

has an obvious requirement for the identification of suit-

able acid-catalysis conditions. The search for acid-catalysis

conditions in tetrapyrrole chemistry remains a largely em-

pirical process. The acid-catalysis conditions identified

The development of robust access to bacteriochlorins

requires new methods of synthesis as well as conditions that

support the conversion of diverse precursors to this valuable

class of macrocycles. The identification of mild acid catalysis

conditions for the self-condensation of dihydrodipyrrin-

acetals is essential for the widespread use of the de novo

synthetic route. Here we first discuss the new acid catalysis

conditions and the scope of bromination of intact bacterio-

chlorins and then consider tactics for planning synthetic

J. Org. Chem. Vol. 75, No. 4, 2010 1025

Krayer et al.

JOCFeatured Article

as obtained with a mild Lewis acid. Examples of mild Lewis

acids employed for room-temperature reaction include

InCl₃, Yb(OTf)₃, Sc(OTf)₃, or Dy(OTf)₃in CH₂Cl₂;⁴⁰Yb-

(OTf)₃/2,6-DTBP in CH₂Cl₂;⁴¹Sc(OTf)₃/2,6-DTBP in

CH₂Cl₂;⁴²and Yb(OTf)₃in methanolic CH₃CN.³⁷Scram-

bling is not an issue in the reaction of a dihydrodipyrrin-

acetal to form the bacteriochlorin; however, the only acid

catalysis conditions used heretofore for the self-condensation

of dihydrodipyrrin-acetals entailed BF₃O(Et)₂in CH₃CN,¹¹

3

which resembled the conditions employed some 10-20 years

ago for porphyrin-forming reactions.¹⁵The mixtures of three

macrocycles (HBC-, MeOBC-, and TDC-type macrocycles)

along with the low and varying yields obtained upon applica-

tion of BF₃O(Et)₂to other dihydrodipyrrin-acetals prompted

3

exploration of conditions to achieve greater selectivity and

higher yields.

The systematic survey herein of >20 different acids,

different additives and solvents identified Bi(OTf)₃, Hf(OTf)₄,

HfCl₄, and TMSOTf/2,6-DTBP in CH₂Cl₂as the best cata-

lysts for the self-condensation of dihydrodipyrrin-acetals to

give the bacteriochlorin macrocycle. Bi(OTf)₃, Hf(OTf)₄,

and HfCl₄usually gave mixtures of HBC- and MeOBC-type

macrocycles in low to moderate yields for the dihydrodipyr-

rin-acetals examined herein. BF₃O(Et)₂usually gave HBC-

3

type macrocycles in low yields (<5%) with the exception of

HBC-EtEs (41% yield). However, TMSOTf/2,6-DTBP in

CH₂Cl₂gave the MeOBC-type macrocycle in yields of up to

63% for the various dihydrodipyrrin-acetals, to the apparent

exclusion of other macrocycles. We also note that whereas

the use of BF₃O(Et)₂catalysis with 1-Br in some instances

3

gave a chlorin impurity,⁸we did not observe any chlorin

impurities upon application of the new acid catalysis condi-

tions to the set of dihydrodipyrrin-acetals shown in Chart 2

and Scheme 2.

The role of 2,6-DTBP is not well understood, as no

reaction intermediates were isolated. The hindered base

2,6-DTBP⁴³can act as a proton sponge but does not bind

to bulky Lewis acids and, hence, has been employed to

discriminate Lewis and Brønsted acid catalysis.⁴¹Lewis

acids are known to promote formation of Brønsted acids

in the presence of water or other XH species, thereby

providing a source of protons.⁴⁴In fact, protonation of the

bacteriochlorin is observed via UV-vis spectroscopy of the

crude self-condensation reaction mixtures [with Bi(OTf)₃,

FIGURE 1. Absorption spectra in CH₂Cl₂at room temperature of

bacteriochlorins (normalized at the Q_ybands): (A) entire spectra;

(B) magnification of the Q_yregion. The labels and colors in the

graph are as follows: HBC-type bacteriochlorin (;) and MeOBC-

type bacteriochlorin (--); MeOBC-H (a, green), HBC-H (A, green),

MeOBC-Br (b, light blue), HBC-Br (B, light blue), MeOBC-T (c,

orange), HBC-T (C, orange), MeOBC-EtEs (d, magenta), HBC-

EtEs (D, magenta), and MeOBC-EsEs (e, black).

through extensive searching for the synthesis of porphyrins

(via aldehyde and pyrrole, aldehyde and dipyrromethanes,

or dipyrromethane-carbinol condensations)¹⁵have subse-

quently been applied to the synthesis of their precursors (e.g.,

dipyrromethanes, bilanes)^36,37as well as hydroporphyrin

macrocycles such as chlorins^38,39and bacteriochlorins.¹¹

The initial conditions developed for room-temperature porphy-

rin-forming reactions typically employed a relatively strong

Brønsted or Lewis acid in a solvent of modest polarity (e.

Hf(OTf)₄, or HfCl₄in CH₂Cl₂; or BF₃O(Et)₂in CH₃CN]

3

as evidenced by the bathochromic shift of the Q_yband

[e.g., HBC-T shifts from 737 nm (neutral) to 796 nm

(protonated)]. It is not clear to what extent the Brønsted

acid plays a role in formation of the bacteriochlorin and/or

distribution of macrocycles (HBC-, MeOBC-, and TDC-

type). However, exclusive formation of MeOBC-type

macrocycles with TMSOTf and 2,6-DTBP (which serves

as a Brønsted acid scavenger) suggests that a Brønsted acid

is necessary during the in situ reduction process to form

g., TFA or BF₃O(Et)₂in CH₂Cl₂). The migration to reac-

3

tions where acidolytic scrambling of more elaborate precur-

sors (such as dipyrromethanes) was a potential problem

entailed the development of milder catalysis conditions, such

(36) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.;

Lindsey, J. S. Org. Process Res. Dev. 2003, 7, 799–812.

(40) Geier, G. R. III; Callinan, J. B.; Rao, P. D.; Lindsey, J. S. J.

Porphyrins Phthalocyanines 2001, 5, 810–823.

(37) Dogutan, D. K.; Zaidi, S. H. H.; Thamyongkit, P.; Lindsey, J. S. J.

Org. Chem. 2007, 72, 7701–7714.

(41) Speckbacher, M.; Yu, L.; Lindsey, J. S. Inorg. Chem. 2003, 42, 4322–

4337.

(38) (a) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey,

J. S. J. Org. Chem. 2000, 65, 3160–3172. (b) Strachan, J.-P.; O’Shea, D. F.;

Balasubramanian, T.; Lindsey, J. S. J. Org. Chem. 2001, 66, 642.

(39) Ptaszek, M.; McDowell, B. E.; Taniguchi, M.; Kim, H.-J.; Lindsey,

J. S. Tetrahedron 2007, 63, 3826–3839.

(42) Zaidi, S. H. H.; Fico, R. M., Jr.; Lindsey, J. S. Org. Process Res. Dev.

2006, 10, 118–134.

(43) Brown, H. C.; Kanner, B. J. Am. Chem. Soc. 1966, 88, 986–992.

(44) Barrett, A. G. M.; Braddock, D. C.; Henschke, J. P.; Walker, E. R. J.

Chem. Soc., Perkin Trans. 1 1999, 873–878.

1026 J. Org. Chem. Vol. 75, No. 4, 2010

Krayer et al.

JOCFeatured Article

HBC-type macrocycles. TMSOTf/base combinations such

as TMSOTf/2,6-lutidine have been reported to give effec-

tive deprotection of acetals via an unstable pyridinium

salt.⁴⁵However, use of 2,6-lutidine herein as an additive

gave only a trace amount of bacteriochlorin (see the

Supporting Information). 2,6-DTBP has been used in

combination with TMSOTf for the Lewis acid catalyzed

SCHEME 6. Distinct Routes for the Preparation of β-Pyrrole-

Substituted Bacteriochlorins

aldol-type reaction of enol silyl ethers and acetals.³⁰

A

silylated pyridinium triflate is proposed as the actual

silylating agent for the acetal substrate, generating a better

leaving group to form the carboxonium triflate and there-

by accomplishing the aldol reaction.³⁰

2. Regioselective Bromination. TMSOTf/2,6-DTBP in

CH₂Cl₂provides generic, mild, and selective reaction condi-

tions for the formation of MeOBC-type macrocycles in

higher yields than previously obtained for self-condensation

of dihydrodipyrrin-acetals. A further advantage of such

conditions is that a number of MeOBC-type bacteriochlor-

ins undergo regioselective 15-bromination, providing an

avenue for derivatization of the bacteriochlorin as a molec-

ular building block in the construction of larger architec-

tures.^10,31,32The bacteriochlorin lacking the 5-methoxy

group (HBC-T), by contrast, gives a mixture of brominated

bacteriochlorins.³¹Although further studies are required to

explore the scope of halogenation, the 5-methoxybacterio-

chlorins now known to give regioselective 15-bromination

include the unsubstituted parent bacteriochlorin (MeOBC-

H), the 2,12-di-p-tolylbacteriochlorin (MeOBC-T), and a

bacteriochlorin bearing substituents at all of the β-pyrrole

sites (MeOBC-EtEs). The results with the latter bacterio-

chlorin may point to a general result, whereupon blocking

each β-pyrrole position results in the 15-position as the least

hindered of the three open sites (10, 15, 20).

3. Tactical Considerations in Synthetic Planning. The route

to bacteriochlorins described herein relies on the preparation

of dihydrodipyrrin-acetals and their subsequent self-conden-

sation to form the bacteriochlorin macrocycle. Two possible

routes to installing a desired functional group on the bacterio-

chlorin macrocycle can be envisioned: (1) a prefunctionaliza-

tion approach, where the desired substituent is installed on

the pyrrole precursor and carried through the dihydrodipyr-

rin-acetal to the bacteriochlorin, and (2) a postfunctionaliza-

tion approach, where a halobacteriochlorin is derivatized

with diverse groups (Scheme 6). The former route has been

exploited for the synthesis of bacteriochlorins bearing p-

tolyl,¹¹mesityl,¹⁴or swallowtail¹³substituents, whereas the

latter has been employed in the derivatization of dibromo-

bacteriochlorin HBC-Br via a range of palladium coupling

reactions,^8,46as well as subsequent aldol condensations, ami-

dations, aminoalkylations, and quaternization processes.⁴⁷

The stability of the synthetic bacteriochlorins toward

various reaction conditions (e.g., palladium coupling reac-

tions, aldol condensations) makes the postfunctionalization

route attractive and has resulted in a wide range of synthetic

bacteriochlorins. However, introduction of certain substitu-

ents, such as alkyl groups, may be difficult to accomplish via

functionalization of a halobacteriochlorin. The introduction

of a desired substituent early in the synthesis avoids the

palladium-coupling step used for derivatizing the halobac-

teriochlorin and may afford a shorter synthesis. For exam-

ple, the synthesis of the bromodihydrodipyrrin-acetal (1-Br)

requires two additional steps (protection and deprotection of

the pyrrole NH),¹⁸while the synthesis of each of the dihydro-

dipyrrin-acetals described herein did not require any

protective measures. The results obtained herein for a

wide variety of substituted dihydrodipyrrin-acetals point

out the advantages and limitations of the prefunctionaliza-

tion route:

(a) Pyridyl Substituent. The dihydrodipyrrin-acetal 1-Py

(containing a pyridyl group) was synthesized to explore the

possibility of preparing a pyridyl-substituted bacteriochlorin.

The only known synthetic amine-substituted bacteriochlorins

contain alkylamines (prepared by derivatization of HBC-Br,⁴⁶

Scheme 6) rather than pyridyl units. However, the difficulties in

preparing 1-Py (low solubility and low yields) along with the

very low yields for formation of MeOBC-Py suggests that

pyridyl-substituted bacteriochlorins should be prepared via

derivatization of intact bacteriochlorins (e.g., HBC-Br).

(b) One Neutral Aryl Substituent. Dihydrodipyrrin-acetal

1-T gave MeOBC-T in 32% yield, indicating the attractive-

ness of the prefunctionalization route.

(c) One Ester Substituent. Dihydrodipyrrin-acetal 1-Es

gave MeOBC-Es in only 8.4% yield; this bacteriochlorin

could in principle be prepared via derivatization of the

analogous dibromobacteriochlorin. In this regard, the

3,13-dibromobacteriochlorin lacking the 5-methoxy group

(HBC-Br) was converted to the corresponding methyl ester

via a palladium-mediated carbonylation process.⁴⁶

(d) One Ester and One Neutral Alkyl/Aryl Substituent.

Dihydrodipyrrin-acetal 1-EtEs gave the resulting bacterio-

chlorins HBC-EtEs and MeOBC-EtEs in a straightforward

(45) Fujioka, H.; Okitsu, T.; Sawama, Y.; Murata, N.; Li, R.; Kita, Y. J.

Am. Chem. Soc. 2006, 128, 5930–5938.

ꢀ

(46) Ruzie, C.; Krayer, M.; Balasubramanian, T.; Lindsey, J. S. J. Org.

Chem. 2008, 73, 5806–5820.

ꢀ

(47) Ruzie, C.; Krayer, M.; Lindsey, J. S. Org. Lett. 2009, 11, 1761–1764.

J. Org. Chem. Vol. 75, No. 4, 2010 1027

Krayer et al.

JOCFeatured Article

manner with relatively good yields for each step, stable and

readily purifiable intermediates, and selective reaction con-

ditions to give the distinct macrocycles. Accordingly, up to

250 mg of bacteriochlorin (HBC-EtEs, MeOBC-EtEs) was

obtained in about one week from the simple precursors

(ethoxycarbonylmethylene)triphenylphosphorane and pro-

pionaldehyde. Analogous dihydrodipyrrin-acetals (1-AnEs,

1-MeEs, and 1-ArEs) gave the corresponding 5-methoxy-

bacteriochlorins in 32%, 48%, and 36% yield, respectively.

Such substituent patterns are best achieved by the prefunc-

tionalization approach.

(e) Two Ester Substituents. The self-condensation of 1-

EsEs to give MeOBC-EsEs bearing four electron-withdraw-

ing substituents proceeded in excellent yield (63% after 4

days). However, the synthesis of 1-EsEs was rather difficult,

with low yields especially for the Michael addition and the

subsequent reductive cyclization. The low yields may stem

from competing intermolecular cyclization between the

nitronate anion and the ester substituents at the 3-position

of the pyrrole. Regardless, the self-condensation conditions

may be applied to other dihydrodipyrrin-acetals bearing two

electron-withdrawing substituents such as a dicyanodihydro-

dipyrrin-acetal.

(f) No Substituent. The dihydrodipyrrin-acetal lacking any

substituents (1-H) provides access to unsubstituted bacterio-

chlorins HBC-H and MeOBC-H in sizable quantities within

about 5 days starting from commercially available pyrrole-

2-carboxaldehyde. The unsubstituted bacteriochlorin HBC-

H, which is a valuable benchmark compound for diverse

studies, was previously synthesized by the more cumbersome

Pd-mediated debromination of the dibromobacteriochlorin

HBC-Br.⁸

(g) Two Alkyl Groups. The dihydrodipyrrin-acetal 1-EtEt

bears two electron-donating groups and was rather unstable.

The attempted self-condensation of 1-EtEt gave <1% yield

of bacteriochlorin, which could stem from decomposition of

1-EtEt before or upon treatment to the acidic self-condensa-

tion conditions. Thus, the synthesis of 2,3,12,13-tetraalkyl-

bacteriochlorins appears very difficult via self-condensation

of the corresponding dihydrodipyrrin-acetal. Alternative,

postfunctionalization approaches can be envisioned by

transformation of dialkylbacteriochlorins bearing derivatiz-

able groups (dibromo, diacetyl, dicyano). Such bacterio-

chlorins should be available via the methods established

herein.

Experimental Section

A. Refined Synthesis of Dihydrodipyrrin-Acetal 1-T.¹¹Ethyl

3-(4-Methylphenyl)prop-2-enoate (7). A solution of p-tolualde-

hyde (24.0 g, 200 mmol) and (carbethoxymethylene)triphenylphos-

phorane (76.6 g, 220 mmol) in CH₂Cl₂(250 mL) was refluxed for

24 h. The reaction mixture was cooled to room temperature and

filtered. The filtrate was concentrated and diluted with diethyl ether.

The ether solution was washed (saturated brine), dried (Na₂SO₄),

concentrated, and chromatographed [silica, hexanes/ethyl acetate

(3:1)] togiveacolorlessoil(36.8g, 97%):¹HNMRδ1.33 (t, J=7.2

Hz, 3H), 2.36(s, 3H), 4.26(q, J= 7.2 Hz, 2H), 6.39 (d, J= 15.6Hz,

1H), 7.17 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.66 (d, J =

15.6 Hz, 1H); ¹³CNMR δ14.5, 21.6, 60.5, 117.3, 128.2, 129.8, 131.9,

140.8, 144.7, 167.3. Anal. Calcd for C₁₂H₁₄O₂: C, 75.76; H, 7.42.

Found: C, 75.72; H, 7.36.

3-(Ethoxycarbonyl)-4-(4-methylphenyl)pyrrole (6-TEs).

A

suspension of TosMIC (14.3 g, 73.5 mmol) and 7 in dry ether/

DMSO (2:1) (150 mL) was added dropwise under argon to a

suspension of NaH (4.20 g, 105 mmol) in ether (70 mL). The

mixture was stirred at room temperature for 5 h. Water (200 mL)

was added into the mixture. The aqueous phase was extracted

twice with ethyl acetate (400 mL). The organic fraction was

dried (Na₂SO₄) and concentrated to a brown solid. The brown

solid was suspended in diethyl ether (50 mL). The suspension

was sonicated and filtered, affording a pale yellow solid (11.3 g,

71%): mp 154-155 °C; ¹H NMR δ 1.25 (t, J = 7.2 Hz, 3H), 2.37

(s, 3H), 4.22 (q, J = 7.2 Hz, 2H), 6.77-6.78 (m, 1H), 7.16 (d, J =

8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.49-7.50 (m, 1H),

8.38-8.54 (br, 1H); ¹³C NMR δ 14.5, 21.4, 59.8, 114.1, 118.2,

125.3, 126.9, 128.6, 129.4, 131.9, 136.3, 165.0. Anal. Calcd for

C₁₄H₁₅NO₂: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.17; H, 6.72;

N, 5.88.

3-(4-Methylphenyl)pyrrole (6-T). A mixture of 6-TEs (10.3 g,

45.0 mmol) and ethylene glycol (100 mL) in a 250 mL round-

bottom flask was bubbled with argon for 10 min, whereupon

NaOH (18.0 g, 450 mmol; 40-80 mesh) was added. The flask

was heated at 120 °C for 30 min, and then the temperature was

raised to 160 °C. After 3 h, the reaction mixture was cooled to

room temperature. Saturated brine (200 mL) was added. The

aqueous mixture was extracted with CH₂Cl₂. The organic layer

was dried (Na₂SO₄), concentrated, and chromatographed

(silica, CH₂Cl₂) to give a pale yellow solid (6.61 g, 93%): mp

92-93 °C (lit.¹¹mp 92-93 °C); ¹H NMR δ 2.34 (s, 3H),

6.51-6.53 (m, 1H), 6.81-6.82 (m, 1H), 7.04-7.06 (m, 1H),

7.15 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 8.16-8.30 (br,

1H); ¹³C NMR δ 21.3, 106.7, 114.4, 118.9, 125.2, 125.4, 129.5,

133.1, 135.3. Anal. Calcd for C₁₁H₁₁N: C, 84.04; H, 7.05; N,

8.91. Found: C, 83.90; H, 7.10; N, 8.84.

2-Formyl-3-(4-methylphenyl)pyrrole (2-T). A solution of 6-T

(6.29 g, 40.0 mmol) in DMF (12.8 mL) and CH₂Cl₂(300 mL)

cooled to 0 °C under argon was treated dropwise with POCl₃

(4.40 mL, 48.0 mmol). After 1 h, the ice bath was removed. The

flask was allowed to warm to room temperature with stirring for

18 h. The reaction mixture was cooled to 0 °C, whereupon 2.5 M

aqueous NaOH (350 mL) was added. The mixture was extracted

with CH₂Cl₂. The organic phase was washed with saturated

brine, dried (Na₂SO₄), and concentrated. The residue was

chromatographed [silica, CH₂Cl₂/ethyl acetate (9:1)] to give a

yellow solid. The ¹H NMR spectrum showed two regioisomers

in 12:1 ratio. The yellow solid was dissolved in ethyl acetate.

Hexanes was added to cause precipitation, and the resulting

mixture [containing hexanes/ethyl acetate (3:1)] was cooled at

-20 °C. The resulting yellow precipitate was isolated and

proved to be a single regioisomer (4.97 g, 67%): mp 148-

149 °C (lit.¹¹mp 149-150 °C); ¹H NMR δ 2.41 (s, 3H),

6.42-6.44 (m, 1H), 7.10-7.11 (m, 1H), 7.26 (d, J = 8.0 Hz,

2H), 7.40 (d, J = 8.0 Hz, 2H), 9.40-9.55 (br, 1H), 9.64 (s, 1H);

In summary, the comparative utility of the prefunctiona-

lization route depends on a number of factors including

access to starting pyrroles, compatibility of substituents

during the synthesis of the dihydrodipyrrin-acetal, and yield

and cleanliness upon bacteriochlorin formation versus avail-

ability of the target bacteriochlorin via a postfunctionali-

zation approach. The ready availability of stable bacterio-

chlorins bearing diverse substituents at the β-pyrrolic and

meso-positions opens the door to examination of a wide

variety of derivatization chemistries that have heretofore not

been applied to bacteriochlorins, including novel iridium and

rhodium catalysts that have found utility for the regioselec-

tive borylation of porphyrins and corrins.⁴⁸Taken together,

this study contributes to the scope of available bacterio-

chlorins for fundamental studies and diverse applications.

(48) Shinokubo, H.; Osuka, A. Chem. Commun. 2009, 1011–1021.

1028 J. Org. Chem. Vol. 75, No. 4, 2010

Krayer et al.

JOCFeatured Article

¹³C NMR δ 21.4, 111.7, 125.6, 128.9, 129.3, 129.7, 130.9, 137.2,

137.9, 180.0. Anal. Calcd for C₁₂H₁₁NO: C, 77.81; H, 5.99; N,

7.56. Found: C, 77.85; H, 5.94; N, 7.58.

1H), 6.10 (s, 1H), 6.28-6.29 (m, 1H), 6.87-6.88 (m, 1H), 7.22 (d, J

= 7.6 Hz, 2H), 7.35 (d, J = 7.6 Hz, 2H), 10.80-10.90 (br, 1H); ¹³

C

NMR δ 21.4, 29.3, 40.5, 48.4, 54.8, 103.0, 106.3, 109.3, 119.2,

124.7, 126.9, 128.7, 129.4, 134.3, 135.4, 160.1, 174.2. Anal. Calcd

for C₂₁H₂₆N₂O₂: C, 74.52; H, 7.74; N, 8.28. Found: C, 74.22; H,

7.78; N, 8.10.

3-(4-Methylphenyl)-2-(2-nitroethyl)pyrrole (3-T). A solution

of acetic acid (2.00 mL, 35.5 mmol) in anhydrous THF (2.00

mL) under argon at 0 °C was treated with n-propylamine

(2.72 mL, 33.0 mmol). The resulting n-propylammonium

acetate mixture was kept at 0 °C for 10 min and then added

dropwise to a solution of 2-T (5.55 g, 30.0 mmol) and CH₃NO₂

(9.72 mL, 180 mmol) in anhydrous THF (28 mL) at 0 °C. After

30 min, the ice bath was removed, and the resulting mixture was

stirred at room temperature. The color of the mixture changed

from yellow to dark red during the course of the reaction. After

3 h, the reaction mixture was diluted with CH₂Cl₂and washed

with saturated aqueous NaHCO₃. The organic phase was dried

(Na₂SO₄) and concentrated under high vacuum to give an

orange-brown solid. The crude solid was dissolved in a mixed

solvent of CHCl₃(150 mL) and 2-propanol (48 mL), to which

silica (36 g) was then added. The mixture was stirred vigorously,

and NaBH₄(2.27 g, 60.0 mmol) was added in one batch. After

3 h, the mixture was filtered. The filter cake was washed with

CH₂Cl₂. The filtrate was concentrated and chromatographed

[silica, hexanes/CH₂Cl₂(2:1)] to afford a yellow solid (3.12 g,

45%): mp 81-82 °C (lit.¹¹mp 81-82 °C); ¹H NMR (400 MHz)

δ 2.37 (s, 3H), 3.44 (t, J = 6.6 Hz, 2H), 4.55 (t, J = 6.6 Hz, 2H),

6.28-6.29 (m, 1H), 6.73-6.75 (m, 1H), 7.18-7.26 (m, 4H),

8.21-8.38 (br, 1H); ¹³C NMR δ 21.3, 24.3, 75.4, 109.8, 117.7,

122.1, 123.4, 128.2, 129.6, 133.4, 135.9. Anal. Calcd for

C₁₃H₁₄N₂O₂: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.80; H,

5.94; N, 12.00.

1,1-Dimethoxy-4,4-dimethyl-6-[3-(4-methylphenyl)pyrrol-2-yl]-5-

nitrohexan-2-one (5-T). A mixture of 3-T (2.99 g, 13.0 mmol) and 4

(2.26 g, 14.3 mmol) was treated with DBU (5.83 mL, 39.0 mmol) at

room temperature. The reaction mixture became dark and the

temperature rose. After 16 h, the reaction mixture was diluted with

ethyl acetate and washed with water. The organic layer was dried

(Na₂SO₄) and concentrated. The residue was chromatographed

[silica, hexanes/ethyl acetate (3:1)] to give a pale yellow solid (3.18 g,

63%): mp 99-100 °C (lit.¹¹mp 98-100 °C); ¹H NMR δ 1.10 (s,

3H), 1.20 (s, 3H), 2.37 (s, 3H), 2.53, 2.71 (AB, ²J = 18.9 Hz, 2H),

3.21 (ABX, ³J = 2.4 Hz, ²J = 15.4 Hz, 1H), 3.37 (ABX, ³J = 11.7

Hz, ²J = 15.4 Hz, 1H), 3.41 (s, 6H), 4.33 (s, 1H), 5.22 (ABX, ³J =

2.4 Hz, ³J = 11.7 Hz, 1H), 6.23-6.25 (m, 1H), 6.67-6.69 (m, 1H),

7.19 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 8.06-8.16 (br,

1H); ¹³C NMR δ 21.3, 24.1, 24.3, 25.3, 36.8, 45.1, 55.2, 95.0, 104.7,

109.5, 117.7, 122.1, 123.7, 128.4, 129.4, 133.6, 135.7, 203.7. Anal.

Calcd for C₂₁H₂₈N₂O₅: C, 64.93; H, 7.27; N, 7.21. Found: C, 65.11;

H, 7.27; N, 7.08.

B. Refined Synthesis of Dihydrodipyrrin-Acetal 1-H. 2-(2-

Nitroethyl)pyrrole (3-H).^16,17Following a general procedure,¹⁸

a stirred mixture of pyrrole-2-carboxaldehyde (2-H, 9.51 g,

0.100 mol), potassium acetate (7.84 g, 0.0800 mol), and methyl-

amine hydrochloride (5.38 g, 0.0800 mol) in absolute ethanol (35

mL) was treated with nitromethane (13.6 mL, 0.250 mol). The

mixture was stirred for 2 h, whereupon water was added. The

mixture was extracted with CH₂Cl₂. The organic phase was

dried (Na₂SO₄) and concentrated to a dark yellow solid. The

crude solid material was dissolved in freshly distilled THF (450

mL), and the solution was cooled to -10 °C. The solution was

treated with 90% LiBH₄(2.64 g, 0.110 mol) all at once under

vigorous stirring. The reaction mixture was stirred for ∼15 min

at -10 °C, whereupon the reaction mixture was quenched by

slowly adding a cold saturated aqueous NH₄Cl solution. The

mixture was extracted with ethyl acetate, and the organic layer

was washed with brine, dried (Na₂SO₄), and concentrated to a

yellow oil (13.5 g). The yellow oil turned brown within a few

hours. The ¹H NMR data were consistent with those previously

reported,¹⁶and indicated that the product was about 90% pure.

The title compound was used directly in the next step without

further purification.

1,1-Dimethoxy-4,4-dimethyl-5-nitro-6-(2-pyrrolyl)-2-hexanone

(5-H).¹⁷Following a general procedure,¹⁷a mixture of crude 3-H

(13.5 g, 96.3 mmol) and 4 (18.2 g, 116 mmol, 1.2 equiv) was

treated with DBU (43 mL, 0.29 mol). The reaction mixture was

stirred at room temperature for 16 h under argon. A saturated

solution of cold aqueous NH₄Cl was added. The mixture was

extracted with ethyl acetate, and the organic layer was washed

with brine, dried (Na₂SO₄), and concentrated. Column chroma-

tography (silica, CH₂Cl₂) afforded a pale brown solid (7.5 g, 25%

from 2-H): mp 73-75 °C (lit.¹¹mp 74-75 °C); ¹H NMR δ 1.14

2

(s, 3H), 1.23 (s, 3H), 2.60, 2.72 (AB, J = 18.6 Hz, 2H), 3.03

(ABX, ³J = 2.4 Hz, ²J = 15.6 Hz, 1H), 3.36 (ABX, ³J = 11.8 Hz,

²J = 15.6 Hz, 1H), 3.43 (s, 3H), 3.44 (s, 3H), 4.36 (s, 1H), 5.15

3

(ABX, J = 2.4 Hz, J = 11.8 Hz, 1H), 5.97-5.99 (m, 1H),

6.08-6.11 (m, 1H), 6.65-6.67 (m, 1H), 8.00-8.13 (brs, 1H); ESI-

MSobsd299.1603, calcd299.1601[(Mþ H)^þ,M=C₁₄H₂₂N₂O₅].

Anal. Calcd for C₁₄H₂₂N₂O₅: C, 56.36; H, 7.43; N, 9.39. Found: C,

56.62; H, 7.55; N, 9.53.

2,3-Dihydro-1-(1,1-dimethoxymethyl)-3,3-dimethyldipyrrin (1-H).¹⁷

Following a general procedure,¹⁸inafirstflask,asolutionof5-H (2.02

g, 6.90 mmol) in freshly distilled THF (16 mL) and anhydrous MeOH

(1.0 mL) at 0 °C was treated with NaOMe (1.11 g, 20.7 mmol). The

mixture was stirred and degassed by bubbling argon through the

solution for 45 min. In a second flask purged with argon, TiCl₃(34.7

mL, 20 wt % in 3% HCl solution, 55 mmol), 70 mL of THF, and

NH₄OAc (35.1 g, 460 mmol) were combined under argon, and the

mixture was degassed by bubbling argon for 45 min. Then, the first

flask mixture was transferred via cannula to the buffered TiCl₃

mixture. The resulting mixture was stirred at room temperature for

16 h under argon. The reaction mixture was then poured over a pad of

Celite and eluted with ethyl acetate. The eluant was washed with

saturated aqueous NaHCO₃. The organic layer was dried (Na₂SO₄)

and concentrated. Column chromatography (neutral alumina,

CH₂Cl₂) afforded a yellow oil (482 mg, 29%), which darkened within

a few minutes: ¹H NMR δ 1.21 (s, 6H), 2.61 (s, 2H), 3.45 (s, 6H), 5.02

(s, 1H), 5.88 (s, 1H), 6.15-6.18 (m, 2H), 6.83-6.86 (m, 1H),

10.59-10.70 (brs, 1H); ¹³C NMR δ 29.3, 40.2, 48.3, 54.8, 103.0,

107.7, 108.7, 109.4, 119.6, 130.9, 159.5, 174.1; ESI-MS obsd 249.15978,

calcd 249.16030 [(M þ H)^þ, M = C₁₄H₂₀N₂O₂].

2,3-Dihydro-1-(1,1-dimethoxymethyl)-3,3-dimethyl-7-(4-methyl-

phenyl)dipyrrin (1-T). Following a general procedure,¹¹a solution

of 5-T (777 mg, 2.00 mmol) in anhydrous THF (20 mL) was

bubbled with argon for 10. min and then treated with NaOMe (541

mg, 10.0 mmol). The mixture was stirred at room temperature for

1 h (the first flask). In the second flask, TiCl₃(8.6 wt % TiCl₃in 28

wt % HCl, 14.9 mL, 10. mmol) and water (80 mL) were mixed

and bubbled with argon for 15 min; NH₄OAc (61.7 g, 800 mmol)

was added to adjust the pH of the buffered mixture at 6.0, and then

THF (6 mL) was added. The reaction mixture was bubbled with

argon for 30 min. The mixture in the first flask that contained the

nitronate anion of 5-T was transferred via a cannula to the second

flask. The resulting mixture was stirred at room temperature under

argon. After 6 h, saturated aqueous NaHCO₃(600 mL) was added

into the reaction mixture. Then the mixture was extracted with

ethyl acetate. The organic layer was dried (Na₂SO₄) and concen-

trated. The residue was passed over a short column [alumina,

hexanes/ethyl acetate (3:1)] to give a light yellow solid (364 mg,

54%): mp 104-105 °C (lit.¹¹mp 104-105 °C); H NMR (400

MHz) δ 1.19 (s, 6H), 2.39 (s, 3H), 2.62 (s, 2H), 3.46 (s, 6H), 5.03 (s,

1

J. Org. Chem. Vol. 75, No. 4, 2010 1029

Krayer et al.

JOCFeatured Article

C. Synthesis of Dihydrodipyrrin-Acetal 1-EtEs. 3-(Ethoxycarbonyl)-

4-ethylpyrrole (6-EtEs). Following a known procedure for a homo-

logue,²⁵a solution of (ethoxycarbonylmethylene)triphenylphos-

phorane (34.8 g, 0.100 mol) in benzene (100 mL) was treated with

propionaldehyde (6.8 mL, 0.090 mol). The reaction mixture was

refluxed for 2 h and then concentrated to dryness. Diethyl ether was

added to the resulting white solid, and the white solid was removed

75.5, 114.8, 123.4, 124.3, 125.1, 165.5; ESI-MS obsd 241.1181,

calcd 241.1183 [(M þ H)^þ, M = C₁₁H₁₆N₂O₄].

6-(4-(Ethoxycarbonyl)-3-ethylpyrrol-2-yl)-1,1-dimethoxy-4,4-

dimethyl-5-nitrohexan-2-one (5-EtEs). Following a general pro-

cedure,¹⁷a mixture of 3-EtEs (5.1 g, 21 mmol) and 4 (4.0 g, 25

mmol, 1.2 equiv) was treated with DBU (10 mL, 64 mmol). The

reaction mixture was stirred at room temperature for 16 h under

argon. A saturated solution of cold aqueous NH₄Cl was added.

The mixture was extracted with ethyl acetate, and the organic

layer was washed with brine, dried (Na₂SO₄), and concentrated.

Column chromatography [silica, CH₂Cl₂/ethyl acetate (9:1)]

afforded a pale brown solid (3.2 g, 38%): mp 107-110 °C; ¹H

NMR δ 1.15 (t, 3 H), 1.15 (s, 3 H), 1.25 (s, 3 H), 1.32 (t, J = 7.2

Hz, 3 H), 2.46-2.81 (m, 4 H), 3.02 (d, J = 2.2 Hz, 1 H), 3.27 (m,

1 H), 3.43 (s, 3 H), 3.44 (s, 3 H), 4.25 (q, J = 7.3 Hz, 2 H), 4.36 (s,

1 H), 5.13 (dd, J = 11.7, 2.20 Hz, 1 H), 7.27 (d, J = 1.8 Hz, 1 H),

8.26 (brs, 1 H); ¹³C NMR δ 14.6, 16.2, 18.2, 24.48, 24.51, 24.6,

36.7, 45.3, 55.48, 55.51, 59.5, 94.8, 105.0, 114.8, 123.3, 124.1,

125.2, 165.2, 203.9; ESI-MS obsd 399.2123, calcd 399.2126 [(M

þ H)^þ, M = C₁₉H₃₀N₂O₇]. Anal. Calcd for C₁₉H₃₀N₂O₇: C,

57.27; H, 7.59; N, 7.03. Found: C, 57.18; H, 7.52; N, 6.98.

8-(Ethoxycarbonyl)-2,3-dihydro-1-(1,1-dimethoxymethyl)-7-

ethyl-3,3-dimethyldipyrrin (1-EtEs). Following a general proce-

dure,¹⁸in a first flask, a solution of 5-EtEs (3.2 g, 8.0 mmol) in

freshly distilled THF (16 mL) and anhydrous MeOH (1.0 mL) at

0 °C was treated with NaOMe (1.3 g, 24 mmol). The mixture was

stirred and degassed by bubbling argon through the solution for

45 min. In a second flask purged with argon, TiCl₃(32 mL,

20 wt % in 3% HCl solution, 51 mmol), 80 mL of THF, and

NH₄OAc (32 g, 418 mmol) were combined under argon, and the

mixture was degassed by bubbling argon for 45 min. Then, the

first flask mixture was transferred via cannula to the buffered

TiCl₃mixture. The resulting mixture was stirred at room

temperature for 16 h under argon. The reaction mixture was

then poured over a pad of Celite and eluted with ethyl acetate.

The eluant was washed with a saturated aqueous solution of

NaHCO₃. The organic layer was dried (Na₂SO₄) and concen-

trated. Column chromatography (silica, CH₂Cl₂) afforded a

€

by filtration using a Buchner funnel. The filtrate was concentrated,

resulting in the R,β-unsaturated ester as a colorless sweet-smelling oil

(crude 10. g, 87%), which was directly used in the next step.

Following the van Leusen method,²⁶the crude R,β-unsaturated

ester (8.13 g, 63.4 mmol) and TosMIC (12.6 g, 63.4 mmol) in diethyl

ether/DMSO (300 mL, 2:1) were slowly added via an addition

funnel to a suspension of NaH (5.0 g, 60% in oil suspension, 0.12

mol) in 100 mL of diethyl ether. The resulting exotherm caused the

mixture to reflux. The reaction was stirred at room temperature for

16 h. Water was added carefully, and the mixture was extracted with

diethyl ether. The organic layer was concentrated and dried

(Na₂SO₄). Column chromatography (silica, CH₂Cl₂) afforded the

title compound as an oil (7.5 g, 71% from the crude R,β-unsaturated

ester): ¹HNMRδ1.21(t, J=7.4Hz,3H),1.33(t,J= 7.2 Hz, 3 H),

2.76(q, J=7.4, 1.10Hz, 2H), 4.27(q, J= 7.2 Hz, 2 H), 6.54 (t, J=

1.8 Hz, 1 H), 7.38 (d, J = 3.0 Hz, 1 H), 8.57 (brs, 1 H); ¹³C NMR δ

14.8, 19.7, 59.6, 114.4, 116.3, 124.8, 128.29, 149.9, 165.8; ESI-MS

obsd 168.1019, calcd 168.1019 [(M þ H)^þ, M = C₉H₁₃NO₂].

4-(Ethoxycarbonyl)-2-formyl-3-ethylpyrrole (2-EtEs). The

Vilsmeier reagent was prepared by treatment of dry DMF (30

mL) with POCl₃(4.6 mL, 49 mmol) at 0 °C and stirring of the

resulting mixture for 10 min. In a separate flask, a solution of 6-

EtEs (7.5 g, 45 mmol) in DMF (150 mL) was treated with the

freshly prepared Vilsmeier reagent at 0 °C. The resulting mixture

was stirred at 0 °C for 1 h and then 2 h at room temperature. The

reaction mixture was treated with a mixture of saturated aqu-

eous sodium acetate/CH₂Cl₂[400 mL, 1:1 (v/v)] and stirred for

1 h. The water phase was separated and extracted with CH₂Cl₂.

The combined organic phase was washed with a saturated LiCl

solution, dried (Na₂SO₄), and concentrated. The resulting solid

was dissolved in warm EtOH (∼50 mL) and cooled to -15 °C.

The resulting solid was filtered, washed with a small amount of

cold EtOH, and dried to afford a light brown solid (6.5 g, 75%):

mp 84-86 °C; ¹H NMR δ 1.28 (t, J = 7.4 Hz, 3H), 1.36 (t, J =

7.2 Hz, 3H), 3.08 (q, J = 7.4 Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H),

7.60 (d, J = 3.3 Hz, 1H), 9.42 (brs, 1H), 9.71 (s, 1H); ¹³C NMR δ

14.6, 17.2, 17.8, 60.2, 116.7, 131.0, 141.2, 164.1, 178.7, 202.3;

ESI-MS obsd 196.0971, calcd 196.0968 [(M þ H)^þ, M =

C₁₀H₁₃NO₃]. Anal. Calcd for C₁₀H₁₃NO₃: C, 61.53; H, 6.71;

N, 7.18. Found: C, 61.60; H, 6.86; N, 7.12.

4-(Ethoxycarbonyl)-3-ethyl-2-(2-nitroethyl)pyrrole (3-EtEs).

Following a general procedure,¹⁸a stirred mixture of 2-EtEs

(8.7 g, 44 mmol), potassium acetate (3.5 g, 36 mmol), and

methylamine hydrochloride (2.4 g, 36 mmol) in absolute ethanol

(16 mL) was treated with nitromethane (6.0 mL, 0.11 mol). The

mixture was stirred for 2 h, whereupon water was added. The

reaction mixture was filtered, and the filtered material was

washed with water and a small amount of cold ethanol. The

filtered material was dried under high vacuum to afford a yellow

solid, which was used directly in the next step. The crude solid

material was dissolved in CHCl₃/2-propanol (3:1, 346 mL).

Silica (34 g) and NaBH₄(2.2 g, 58 mmol) were added, and the

mixture was stirred at room temperature under argon for 2 h.

The reaction mixture was filtered, and the filtrate was concen-

trated. The resulting crude was dissolved in CH₂Cl₂. The

organic solution was washed (water, brine), dried (Na₂SO₄),

and concentrated to afford a pale brown solid (5.2 g, 48%): mp

95-97 °C; ¹H NMR δ 1.14 (t, J = 7.4 Hz, 3 H), 1.33 (t, J = 7.2

Hz, 3 H), 2.68 (q, J = 7.4 Hz, 2 H), 3.25 (t, J = 6.5 Hz, 2 H), 4.26

(q, J = 7.2 Hz, 2 H), 4.54 (t, J = 6.5 Hz, 2 H), 7.31 (d, J = 3.3

Hz, 1 H), 8.42 (brs, 1 H); ¹³C NMR δ 14.6, 16.5, 18.2, 23.5, 59.7,

1

yellow oil (1.3 g, 46%): H NMR δ 1.17 (t, J = 7.4 Hz, 3H),

1.23 (s, 6H), 1.34 (t, J = 7.2 Hz, 3H), 2.63 (s, 2H), 2.82 (q, J =

7.4 Hz, 2H), 3.45 (s, 6H), 4.27 (q, J = 7.2 Hz, 2H), 5.02 (s, 1H),

5.86 (s, 1H), 7.42 (d, J = 3.0 Hz, 1H), 10.82 (brs, 1H); ¹³C NMR

δ 14.7, 16.6, 18.2, 29.4, 40.5, 48.5, 54.8, 59.4, 102.8, 104.6, 114.3,

125.3, 126.4, 128.3, 160.2, 165.6, 174.8, 202.2; ESI-MS obsd

349.2123, calcd 349.2122 [(M þ H)^þ, M = C₁₉H₂₈N₂O₄].

D. Synthesis of Dihydrodipyrrin-Acetal 1-EtEt. 3,4-Diethyl-

2-formylpyrrole (2-EtEt). The Vilsmeier reagent was prepared

by treatment of dry DMF (34 mL) by POCl₃(4.6 mL, 49 mmol)

at 0 °C and stirring of the resulting mixture for 10 min. In a

separate flask, a solution of 3,4-diethylpyrrole (6-EtEt, 5.0 g, 41

mmol) in DMF (130 mL) was treated with the freshly prepared

Vilsmeier reagent at 0 °C. The reaction mixture was stirred at

room temperature for 2 h under argon. A saturated solution of

cold aqueous NaOAc was added. The mixture was extracted

with ethyl acetate, and the organic layer was washed with brine,

dried (Na₂SO₄), and concentrated. Column chromatography

(silica, CH₂Cl₂) afforded a pale brown solid (3.3 g, 54%): mp

42-45 °C; ¹H NMR δ 1.20 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2

Hz, 3H), 2.46 (q, J = 7.2 Hz, 2H), 2.73 (q, J = 7.2 Hz, 2H),

6.88-6.92 (m, 1H), 9.58 (s, 1H), 9.95 (brs, 1H); ¹³C NMR δ 14.9,

17.2, 17.3, 17.9, 124.4, 127.4, 129.1, 137.5, 177.7; ESI-MS obsd

152.1069, calcd 152.1070 [(M þ H)^þ, M = C₉H₁₃NO].

3,4-Diethyl-2-(2-nitroethyl)pyrrole (3-EtEt). Following a gen-

eral procedure,¹⁸a stirred mixture of 2-EtEt (3.3 g, 22 mmol),

potassium acetate (1.7 g, 17 mmol), and methylamine hydro-

chloride (1.2 g, 17 mmol) in absolute ethanol (8.0 mL) was

treated with nitromethane (3.0 mL, 55 mmol). The mixture was

stirred for 2 h, whereupon water was added. The mixture was

1030 J. Org. Chem. Vol. 75, No. 4, 2010

Krayer et al.

JOCFeatured Article

brown solid (3.6 g, 64%): mp 62-64 °C; H NMR δ 1.35 (t,

J = 7.2 Hz, 3H), 1.40 (t, J = 7.2 Hz, 3 H), 4.32 (q, J = 7.2 Hz,

2H), 4.43 (q, J = 7.2 Hz, 2H), 7.60 (d, J = 2.2 Hz, 1H), 9.90 (s,

1H), 10.41 (brs, 1H); ¹³C NMR δ 14.4, 14.5, 61.1, 62.0, 118.6,

124.5, 128.9, 132.7, 162.9, 163.4, 181.2; ESI-MS obsd 240.0862,

calcd 240.0866 [(M þ H)^þ, M = C₁₁H₁₃NO₅]. Anal. Calcd for

C₁₁H₁₃NO₅: C, 55.23; H, 5.48; N, 5.86. Found: C, 55.47; H, 5.43;

N, 5.81.

1

extracted with CH₂Cl₂. The organic phase was dried (Na₂SO₄)

and concentrated to a dark red solid. The crude solid material

was dissolved in freshly distilled THF (40 mL), and the solution

was cooled to -10 °C. The solution was treated with 90% LiBH₄

(0.20 g, 8.7 mmol) all at once under vigorous stirring. The

reaction mixture was stirred for ∼30 min at 0 °C, whereupon

the reaction mixture was quenched by slowly adding a cold

saturated aqueous NH₄Cl solution. The mixture was extracted

with ethyl acetate, and the organic layer was washed with brine,

dried (Na₂SO₄), and concentrated to a yellow oil (2.1 g, 49%).

The yellow oil turned brown within a few minutes. The ¹H NMR

data indicated that the product was about 90% pure. The title

compound was used directly in the next step, without further

purification, due to its limited stability.

6-(3,4-Diethylpyrrol-2-yl)-1,1-dimethoxy-4,4-dimethyl-5-nitro-

hexan-2-one(5-EtEt). Following a general procedure,¹⁷a mixture

of 3-EtEt (14.1 g, 72.2 mmol) and 4 (13.7 g, 86.6 mmol, 1.2 equiv)

was treated with DBU (21.6 mL, 142 mmol). The reaction

mixture was stirred at room temperature for 5 h under argon.

A saturated solution of cold aqueous NH₄Cl was added. The

mixture was extracted with ethyl acetate, and the organic layer

was washed with brine, dried (Na₂SO₄), and concentrated.

Column chromatography [silica, CH₂Cl₂] afforded a yellow oil

(8.7 g, 34%): ¹H NMR δ 1.10 (t, J = 7.6 Hz, 3H), 1.14 (s, 3H),

1.16 (t, J = 7.6 Hz, 3H), 1.25 (s, 3H), 2.34-2.44 (m, 4H), 2.65

(AB, ²J = 18.8 Hz, 2H), 3.00 (ABX, ³J = 2.8 Hz, ²J = 12.8 Hz,

1H), 3.26 (ABX, ³J = 11.6 Hz, ²J = 13.4 Hz, 1H), 3.42 (s, 3H),

3.43 (s, 3H), 4.36 (s, 1H), 5.12 (ABX, ³J = 2.4 Hz, ³J = 9.2 Hz,

1H), 6.37 (m, 1H), 7.52-7.83 (brs, 1H); ¹³C NMR δ 14.6, 16.2,

17.6, 18.6, 24.4, 24.5, 25.0, 36.7, 45.3, 55.4, 95.1, 104.9, 113.8,

121.7, 121.8 125.1, 203.8; ESI-MS obsd 355.2234, calcd 355.2227

[(M þ H)^þ, M = C₁₈H₃₀N₂O₅].

3,4-Bis(ethoxycarbonyl)-2-(2-nitroethyl)pyrrole (3-EsEs). A

stirred mixture of 2-EsEs (3.5 g, 15 mmol), potassium acetate

(1.2 g, 12 mmol), and methylamine hydrochloride (0.80 g, 12

mmol) in absolute ethanol (6.0 mL) was treated with nitro-

methane (2.0 mL, 37 mmol). The mixture was stirred for 4 h,

whereupon water was added. The reaction mixture was filtered,

and the filtered material was washed with water, followed by

water/ethanol (1:1). The filtered material was dried under high

vacuum to afford a yellow solid, which was used directly in

the next step. The crude solid material (3.1 g, 11 mmol) was

dissolved in CHCl₃/2-propanol (3:1, 133 mL). Silica (13 g) and

NaBH₄(0.50 g, 13 mmol) were added, and the mixture was

stirred at room temperature under argon for 30 min. The

reaction mixture was filtered, and the filtrate was concentrated

to give a solid residue. The latter residue was dissolved in

CH₂Cl₂, washed (water, brine), dried (Na₂SO₄), and concen-

trated. Column chromatography [silica, CH₂Cl₂/ethyl acetate

(9:1)] afforded a white solid (2.5 g, 60%): mp 160-163 °C; ¹H

NMR δ 1.34 (m, 6H), 3.48 (t, J = 6.3 Hz, 2H), 4.29 (m, 4H), 4.71

(t, J = 6.3 Hz, 2H), 7.21 (d, J = 3.0 Hz, 1H), 8.96 (brs, 1H); ¹³

C

NMR δ 14.45, 14.52, 25.0, 60.7, 60.8, 74.8, 113.5, 117.4, 123.5,

133.8, 164.2, 164.8; ESI-MS obsd 285.1081, calcd 285.1081 [(M

þ H)^þ, M = C₁₂H₁₆N₂O₆]. Anal. Calcd for C₁₂H₁₆N₂O₆: C,

50.70; H, 5.67; N, 9.85. Found: C, 50.90; H, 5.57; N, 9.68.

6-(3,4-Bis(ethoxycarbonyl)pyrrol-2-yl)-1,1-dimethoxy-4,4-dimeth-

7,8-Diethyl-2,3-dihydro-1-(1,1-dimethoxymethyl)-3,3-dimethyl-

dipyrrin (1-EtEt). Following a general procedure,¹⁸in a first flask,

a solution of 5-EtEt (8.5 g, 24 mmol) in freshly distilled THF (60

mL) and anhydrous MeOH (2 mL) at 0 °C was treated with

NaOMe (3.9 g, 72 mmol). The mixture was stirred and degassed

by bubbling argon through the solution for 45 min. In a second

flask purged with argon, TiCl₃(131 mL, 20 wt % in 3% HCl

solution, 210 mmol), 245 mL of THF, and NH₄OAc (102 g, 1.32

mol) were combined under argon, and the mixture was degassed

by bubbling argon for 45 min. Then the first flask mixture was

transferred via cannula to the buffered TiCl₃mixture. The result-

ing mixture was stirred at room temperature for 16 h under argon.

The reaction mixture was then poured over a pad of Celite and

eluted with ethyl acetate. The eluant was washed with saturated

aqueous NaHCO₃. The organic layer was dried (Na₂SO₄) and

concentrated. Column chromatography [neutral alumina,

CH₂Cl₂/hexanes (1:1)] afforded a yellow oil (560 mg, 7.6%): ¹H

NMR δ 1.04-1.24 (m, 6H), 1.20 (s, 6H), 2.30-2.57 (m, 4H), 2.59

(s, 2H), 3.41 (s, 6H), 4.99 (s, 1H), 5.86 (s, 1H), 6.58 (s, 1H), 10.32

(brs, 1H). The limited stability of this compound thwarted ¹³C

NMR spectroscopy and mass spectrometric analysis.

E. Synthesis of Dihydrodipyrrin-Acetal 1-EsEs. 3,4-Bis-

(ethoxycarbonyl)-2-formylpyrrole (2-EsEs). The Vilsmeier re-

agent was prepared by treatment of dry DMF (30 mL) with

POCl₃(2.8 mL, 30 mmol) at 0 °C and stirring of the resulting

mixture for 10 min. In a separate flask, a solution of diethyl 3,4-

pyrroledicarboxylate (6-EsEs, 5.0 g, 24 mmol) in DMF (80 mL)

was treated with the freshly prepared Vilsmeier reagent at 0 °C.

The resulting mixture was heated to 80 °C in an oil bath and

stirred under argon for 24 h. The reaction mixture was treated

with a mixture of saturated aqueous sodium acetate/CH₂Cl₂

[300 mL, 1:1 (v/v)] and stirred for 1 h at room temperature. The

water phase was separated and extracted with CH₂Cl₂. The

combined organic phase was washed with saturated aqueous

LiCl, dried (Na₂SO₄), and concentrated. Column chromato-

graphy [silica, hexanes/ethyl acetate (1:1)] afforded a light

yl-5-nitrohexan-2-one (5-EsEs). Following a general procedure,¹⁷

a

mixture of 3-EsEs (1.76 g, 6.20 mmol) and 4 (9.8 g, 62 mmol, 10

equiv) was treated with DBU (2.80 mL, 18.6 mmol). The reaction

mixture was stirred at room temperature for 15 min under argon. A

saturated solution of cold aqueous NH₄Cl was added. The mixture

was extracted with ethyl acetate, and the organic layer was washed

with brine, dried (Na₂SO₄), and concentrated. Column chromato-

graphy [silica, CH₂Cl₂/ethyl acetate (9:1)] afforded a yellow oil (0.56

g, 20%): ¹H NMR δ 1.16 (s, 3H), 1.21-1.44 (m, 6H), 1.59 (s, 3H),

2.68 (m, 2H), 3.25-3.38 (m, 1H), 3.42 (s, 3H), 3.44 (s, 3H),

3.52-3.62 (m, 1H), 4.20-4.37 (m, 4H), 4.39 (s, 1H), 5.12-5.30

(m, 1H), 7.14 (d, J = 2.9 Hz, 1H), 8.83 (brs, 1H); ¹³C NMR δ 14.5,

23.9, 24.2, 25.2, 26.2, 36.8, 45.0, 56.0, 60.7, 74.4, 94.5, 104.7, 113.5,

117.1, 124.1, 129.7, 133.5, 164.4, 164.8, 203.6; ESI-MS obsd

465.1845, calcd 465.1844 [(M þ Na)^þ, M = C₂₀H₃₀N₂O₉].

7,8-Bis(ethoxycarbonyl)-2,3-dihydro-1-(1,1-dimethoxymethyl)-

3,3-dimethyldipyrrin (1-EsEs). Following a general procedure,¹⁸

in a first flask, a solution of 5-EsEs (0.56 g, 1.3 mmol) in freshly

distilled THF (3.0 mL) and anhydrous MeOH (0.5 mL) at 0 °C

was treated with NaOMe (0.18 g, 3.8 mmol). The mixture was

stirred and degassed by bubbling argon through the solution

for 45 min. In a second flask purged with argon, TiCl₃(6.4 mL,

20 wt % in 3% HCl solution, 10. mmol), 13 mL of THF, and

NH₄OAc (6.5 g, 84 mmol) were combined under argon, and the

mixture was degassed by bubbling argon for 45 min. Then the

first flask mixture was transferred via cannula to the buffered

TiCl₃mixture. The resulting mixture was stirred at room tem-

perature for 16 h under argon. The reaction mixture was then

poured over a pad of Celite and eluted with ethyl acetate. The

eluant was washed with saturated aqueous NaHCO₃. The or-

ganic layer was dried (Na₂SO₄) and concentrated. Column

chromatography (silica, CH₂Cl₂) afforded a yellow oil (80 mg,

16%): ¹H NMR δ 1.24 (s, 6H), 1.33 (t, J = 6.5 Hz, 3H), 1.37 (t,

J = 6.6 Hz, 3H), 2.65 (s, 2H), 3.45 (s, 6H), 4.28 (q, J = 7.2 Hz,

2H), 4.34 (q, J = 7.2 Hz, 2H), 5.04 (s, 1H), 6.50 (s, 1H), 7.32 (d,

J. Org. Chem. Vol. 75, No. 4, 2010 1031

Krayer et al.

JOCFeatured Article

J = 2.8 Hz, 1H), 11.36 (brs, 1H); ¹³C NMR δ 14.5, 14.6, 29.1,

40.8, 48.7, 54.8, 60.3, 60.5, 102.5, 105.1, 112.9, 116.6, 124.8, 135.3,

149.9, 164.6, 164.8, 165.3, 177.9, 202.2; ESI-MS obsd 393.2022,

calcd 393.2020 [(M þ H)^þ, M = C₂₀H₂₈N₂O₆].

6-[4-(Ethoxycarbonyl)pyrrol-2-yl]-1,1-dimethoxy-4,4-dimeth-

yl-5-nitro-2-hexanone (5-Es). Following a general procedure,¹⁷

a

mixture of 3-Es (2.13 g, 10.0 mmol) and 4 (4.69 g, 30.0 mmol,

3 equiv) was treated with DBU (4.7 mL, 30 mmol). The reaction

mixture was stirred at room temperature for 1 h under argon. A

saturated solution of cold aqueous NH₄Cl was added. The

mixture was extracted with ethyl acetate, and the organic layer

was washed with brine, dried (Na₂SO₄), and concentrated.

Column chromatography [silica, ethyl acetate/hexanes (1:1)]

F. Synthesis of Dihydrodipyrrin-Acetal 1-Es. 3-Ethoxycarbo-

nylpyrrole (6-Es). Following the van Leusen method,²⁶ethyl

acrylate (7.2 g, 66 mmol) and TosMIC (12.8 g, 65.6 mmol) in

diethyl ether/DMSO (300 mL, 2:1) were slowly added via an

addition funnel to a suspension of NaH (5.3 g, 60% in oil

suspension, 0.13 mol) in 100 mL of diethyl ether. The mixture

started to reflux due to the exothermic reaction. The reaction

was stirred at room temperature for 3 h. Water was added

carefully, and the mixture was extracted with diethyl ether (3 ꢀ

50 mL). The combined organic layer was concentrated and dried

(Na₂SO₄). Column chromatography [silica, ethyl acetate/hex-

anes (1:3)] afforded a colorless oil (5.12 g, 56%): ¹H NMR δ 1.33

(t, J = 7.2 Hz, 3H), 4.27 (q, J = 7.2 Hz, 2H), 6.59-6.65 (m, 1H),

6.70-6.76 (m, 1H), 7.34-7.48 (m, 1H), 9.61 (brs, 1H); ¹³C NMR

δ 14.6, 60.1, 109.9, 116.7, 119.0, 123.7, 202.1; ESI-MS obsd

140.0708, calcd 140.0706 [(M þ H)^þ, M = C₇H₇NO₂]. In some

cases a minor reaction product also was isolated (∼8%) that is

tentatively assigned to the Michael addition of the pyrrole and

ethyl acrylate: ¹H NMR δ 1.26 (t, J = 7.2 Hz, 3H), 1.32 (t, J =

7.2 Hz, 3H), 2.63 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H),

4.16 (q, J = 7.2 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 6.32-6.34 (m,

1H), 7.28-7.30 (m, 1H), 9.04-9.19 (brs, 1H).

1

afforded a light brown oil (2.44 g, 66%): H NMR δ 1.13 (s,

3H), 1.21 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H), 2.60, 2.72 (AB, ²J =

18.6 Hz, 2H), 3.02 (ABX, ³J = 2.2 Hz, ²J = 15.2 Hz, 1H), 3.33

3

(ABX, J = 12.0 Hz, ²J = 15.2 Hz, 1H), 3.42 (s, 3H), 3.43 (s,

3H), 4.25 (q, J = 7.2 Hz, 2H), 4.37 (s, 1H), 5.16 (ABX, ³J = 2.2

Hz, ³J = 12.0 Hz, 1H), 6.38-6.41 (m, 1H), 7.27-7.30 (m, 1H),

8.79 (brs, 1H); ¹³C NMR δ 14.6, 24.38, 24.46, 26.6, 36.6, 45.2,

55.3, 59.9, 94.5, 104.8, 108.5, 116.9, 123.8, 127.5, 165.2, 203.9;

ESI-MS obsd 393.1642, calcd 393.1632 [(M þ H)^þ, M =

C₁₇H₂₆N₂O₇].

8-(Ethoxycarbonyl)-1-(1,1-dimethoxymethyl)-3,3-dimethyl-

2,3-dihydrodipyrrin (1-Es). Following a general procedure,¹⁸in a

first flask, a solution of5-Es (2.30 g, 6.21mmol) infreshly distilled

THF (13 mL) and anhydrous MeOH (1.0 mL) at 0 °C was treated

with NaOMe (540 mg, 19.8 mmol). The mixture was stirred and

degassed by bubbling argon through the solution for 45 min. In a

second flask purged with argon, TiCl₃(34.3 mL, 20 wt % in 3%

HCl solution, 54 mmol), 73 mL of THF, and NH₄OAc (26 g, 340

mmol) were combined under argon, and the mixture was de-

gassed by bubbling argon for 45 min. Then, the first flask mixture

was transferred via cannula to the buffered TiCl₃mixture. The

resulting mixture was stirred at room temperature for 16 h under

argon. The reaction mixture was then poured over a pad of Celite

and eluted with ethyl acetate. The eluant was washed with

saturated aqueous NaHCO₃. The organic layer was dried

(Na₂SO₄) and concentrated. Column chromatography [silica,

hexanes/ethyl acetate (1:1)] afforded a light yellow oil (710 mg,

36%): ¹H NMR δ 1.21 (s, 6H), 1.34, (t, J = 7.2 Hz, 3H), 2.63 (s,

2H), 3.46 (s, 6H), 4.28 (q, J = 7.2 Hz, 2H), 5.03 (s, 1H), 5.83 (s,

1H), 6.52-6.53 (m, 1H), 7.43-7.45 (m, 1H), 10.92-11.06 (brs,

1H); ¹³C NMR δ 14.7, 29.2, 40.3, 48.4, 54.8, 59.8, 102.7, 106.9,

109.6, 116.7, 124.9, 131.7, 161.3, 165.3, 175.6; ESI-MS obsd

321.1810, calcd 321.1809 [(M þ H)^þ, M = C₁₇H₂₄N₂O₄].

G. Synthesis of Dihydrodipyrrin-Acetal 1-Py. 2-Formyl-4-(4-

pyridyl)pyrrole (2-Py). The Vilsmeier reagent was prepared by

treatment of dry DMF (55 mL) with POCl₃(4.0 mL, 44 mmol) at

0 °C and stirring of the resulting mixture for 10 min. In a

separate flask, a solution of 3-(4-pyridyl)pyrrole (6-Py, 5.78 g,

40.1 mmol) in DMF (135 mmol) was treated with the freshly

prepared Vilsmeier reagent at 0 °C. The resulting mixture was

stirred at 0 °C for 1 h and then 16 h at room temperature. The

reaction mixture was treated with a mixture of saturated aqu-

eous sodium acetate/ethyl acetate [400 mL, 1:1 (v/v)] and stirred

for 1 h. The water phase was separated and extracted with ethyl

acetate (2 ꢀ 200 mL). The combined organic phase was washed

with saturated aqueous LiCl, dried (Na₂SO₄), and concentrated.

Column chromatography [silica, hexanes/ethyl acetate 1:5)]

afforded two separate isomeric components. The first com-

pound eluted was the minor isomer (54.6 mg, 9%) and was

not fully characterized. The second compound eluted, the title

compound, was the major constituent (1.8 g, 54%): mp 222-

4-Ethoxycarbonyl-2-formylpyrrole (2-Es). The Vilsmeier re-

agent was prepared by treatment of dry DMF (20 mL) with

POCl₃(3.6 mL, 38 mmol) at 0 °C and stirring of the resulting

mixture for 10 min. In a separate flask, a solution of 2-Es (4.81 g,

34.6 mmol) in DMF (120 mL) was treated with the freshly

prepared Vilsmeier reagent at 0 °C. The resulting mixture was

stirred at 0 °C for 1 h and then 15 h at room temperature. The

reaction mixture was treated with a mixture of saturated aqu-

eous sodium acetate/CH₂Cl₂[400 mL, 1:1 (v/v)] and stirred for

1 h. The water phase was separated and extracted with CH₂Cl₂.

The combined organic phase was washed with saturated aqu-

eous LiCl, dried (Na₂SO₄), concentrated, and chromatographed

[silica, hexanes/ethyl acetate (1:1)] to afford a white solid (3.8 g,

65%): mp 84-85 °C; ¹H NMR δ 1.37 (t, J = 7.2 Hz, 3H), 4.33

(q, J = 7.2 Hz, 2H), 77.42 (s, 1H), 7.73-7.75 (m, 1H), 9.56 (s,

1H), 10.60 (brs, 1H); ¹³C NMR δ 14.6, 60.6, 119.3, 122.0, 130.3,

133.2, 163.9, 180.3; ESI-MS obsd 168.0659, calcd 168.0655 [(M

þ H)^þ, M = C₈H₉NO₃].

4-(Ethoxycarbonyl)-2-(2-nitroethyl)pyrrole (3-Es). A stirred

mixture of 2-Es (3.7 g, 22 mmol), potassium acetate (1.7 g, 18

mmol), and methylamine hydrochloride (1.2 g, 18 mmol) in

absolute ethanol (8 mL) was treated with nitromethane (3.0 mL,

55 mmol). The mixture was stirred for 2 h, whereupon water was

added. The reaction mixture was filtered, and the filtered

material was washed with water and a small amount of cold

ethanol. The filtered material was dried under high vacuum to

afford a yellow solid, which was used directly in the next step.

The crude solid material was dissolved in CHCl₃/2-propanol

(3:1, 250 mL). Silica (24 g) and NaBH₄(1.5 g, 40 mmol) were

added, and the mixture was stirred at room temperature under

argon for 1 h. The reaction mixture was filtered, and the filtrate

was concentrated. The crude reaction mixture was dissolved in

CH₂Cl₂, washed (water, brine), dried (Na₂SO₄) and concen-

trated to afford a pale brown solid (2.25 g, 48%): mp 118-119

°C; ¹H NMR δ 1.33 (t, J = 7.2 Hz, 3H), 3.29 (t, J = 6.4 Hz, 2H),

4.27 (q, J = 7.2 Hz, 2H), 4.61 (t, J = 6.4 Hz, 2H), 6.37-6.46 (m,

1H), 7.30-7.37 (m, 1H), 8.81 (brs, 1H); ¹³C NMR δ 14.6, 25.3,

60.1, 75.1, 108.4, 117.2, 123.8, 127.5, 165.1; ESI-MS obsd

213.0873, calcd 213.0870 [(M þ H)^þ, M = C₉H₁₂N₂O₃]. Anal.

Calcd for C₉H₁₂N₂O₄: C, 50.94; H, 5.70; N, 13.20. Found: C,

51.14; H, 5.83; N, 12.99.

1

225 °C; H NMR (acetone-d₆) δ 7.54 (m, 1H), 7.62-7.68 (m,

2H), 7.91 (s, 1H), 8.43-8.47 (m, 2H), 9.63 (s, 1H), 11.42 (brs,

1H); ¹³C NMR (acetone-d₆) δ 92.5, 116.9, 119.6, 124.3, 142.0,

150.4, 166.1, 179.1; Anal. Calcd for C₁₀H₈N₂O: C, 69.76; H,

4.68; N, 16.27. Found: C, 69.59; H, 4.71; N, 16.07; ESI-MS obsd

173.0702, calcd 173.0709 [(M þ H)^þ, M = C₁₀H₈N₂O].

2-(2-Nitroethyl)-4-(4-pyridyl)pyrrole (3-Py). Following a gen-

eral procedure,¹⁸a stirred mixture of 2-Py (1.80 g, 10.5 mmol),

1032 J. Org. Chem. Vol. 75, No. 4, 2010

Krayer et al.

JOCFeatured Article

potassium acetate (0.82 g, 8.4 mmol), and methylamine hydro-

chloride (0.56 g, 8.4 mmol) in absolute ethanol (4.0 mL) was

treated with nitromethane (1.44 mL, 26.5 mmol). The mixture

was stirred for 2 h, whereupon water was added. The reaction

mixture was filtered, and the filtered material was washed with

water and a small amount of cold ethanol. The filtered material

was dried under high vacuum to afford a yellow solid, which was

used directly in the next step. The crude solid material was

dissolved in freshly distilled THF (100 mL), and the solution was

cooled to -10 °C. The solution was treated with 90% LiBH₄

(254 mg, 10.5 mol) all at once under vigorous stirring. The

reaction mixture was stirred for ∼15 min at -10 °C, whereupon

the reaction mixture was quenched by slowly adding a cold

saturated aqueous NH₄Cl solution. The mixture was extracted

with ethyl acetate, and the organic layer was washed with brine,

dried (Na₂SO₄), concentrated, and chromatographed [silica,

hexanes/ethyl acetate (1:9)] to yield a tan solid (821 mg, 36%,

two steps): mp 159.5-160.5 °C; ¹H NMR δ 3.37 (t, J = 6.9 Hz,

2H), 4.65 (t, J = 6.9 Hz, 2H), 6.44-6.48 (m, 1H), 7.22-7.26 (m,

1H), 7.45 (d, J = 6.6 Hz, 2H), 8.39 (d, J = 6.6 Hz, 2H), 8.69 (brs,

1H); ¹³C NMR (acetone-d₆) δ 25.6, 75.0, 104.6, 117.5, 119.4,

121.8, 129.1, 144.5, 149.3; ESI-MS obsd 218.0924, calcd

218.0924 [(M þ H)^þ, M = C₁₁H₁₁N₃O₂]. Anal. Calcd for

C₁₁H₁₂N₃O₂: C, 60.82; H, 5.10; N, 19.34. Found: C, 60.93 H,

5.09; N, 19.08.

(200 mL) under argon was cooled to 0 °C, whereupon POCl₃(7.2

mL, 77.2 mmol) was added dropwise. After 1 h, the flask was

warmed to room temperature and stirred overnight (∼16 h). The

reaction was quenched at 0 °C with 2.5 M aqueous NaOH (690

mL). The mixture was poured into water (∼1 L) and extracted with

CH₂Cl₂, and the combined organic layers were washed with water

and brine, dried (Na₂SO₄), and concentrated. The residue was

chromatographed [silica, CH₂Cl₂/ethyl acetate (9:1)] to afford a

white solid (11.7 g, 68%): ¹H NMR δ 1.23 (t, J = 7.2 Hz, 3H), 3.86

(s, 3H), 4.21 (q, J = 7.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 7.40 (d,

J = 8.5 Hz, 2H), 7.74 (d, J = 2.5 Hz, 1H), 9.37 (s, 1H), 10.49 (brs,

1H); ¹³C NMR δ 14.1, 55.2, 59.9, 113.1, 116.1, 123.2, 130.7, 130.8,

132.0, 137.8, 159.6, 163.6, 181.0; FAB-MS obsd 273.0995, calcd

273.1001 (C₁₅H₁₅NO₄). Anal. Calcd for C₁₅H₁₅NO₄: C, 65.92; H,

5.53; N, 5.13. Found: C, 66.03; H, 5.48; N, 5.13.

4-(Ethoxycarbonyl)-3-(4-methoxyphenyl)-2-(2-nitroethyl)pyrrole

(3-AnEs). Following a general procedure,¹¹a mixture of 2-AnEs

(11.7 g, 42.8 mmol), acetic acid (1.4 mL, 5.43 mmol), n-propyl-

amine (1.8 mL, 21.9 mmol) and nitromethane (7.0 mL, 128 mmol)

in THF/MeOH (5:1) under argon was stirred at room temperature

for 17 h. CH₂Cl₂was added, and the reaction was quenched with

brine. The organic layer was dried (Na₂SO₄) and concentrated. The

residue was dissolved in CHCl₃/2-propanol (280 mL, 3:1), and 51 g

of silica gel was added. NaBH₄(3.24, 85.6 mmol) was added in

portions at room temperature, and the mixture was stirred for 2 h.

The reaction mixture was filtered, and the filter cake was washed

with CH₂Cl₂/MeOH (9:1). The filtrate was concentrated. Crystal-

lization from ethyl acetate/hexanes (1:2) afforded the title com-

pound (4.42 g, 32%): ¹H NMR δ 1.17 (t, J = 7.1 Hz, 3H), 3.19 (t,

J = 6.3 Hz, 2H), 3.83 (s, 3H), 4.13 (q, J = 7.1 Hz, 2H), 4.41 (t, J =

6.3 Hz, 2H), 6.92 (d, J= 8.3 Hz, 2H), 7.18 (d, J= 8.3 Hz, 2H), 7.38

(d, J = 2.5 Hz, 1H), 8.58 (s, 1H); ¹³C NMR δ 14.2, 23.4, 55.2, 59.5,

75.1, 113.4, 115.3, 123.7, 124.0, 125.0, 126.4, 131.2, 158.6, 164.5;

FAB-MS obsd 318.1214, calcd 318.1216 (C₁₆H₁₈N₂O₅). Anal.

Calcd for C₁₆H₁₈N₂O₅: C, 60.37; H, 5.70; N, 8.80. Found: C,

60.31; H, 5.77; N, 8.65.

6-[4-(Ethoxycarbonyl)-3-(4-methoxyphenyl)pyrrol-2-yl]-1,1-

dimethoxy-4,4-dimethyl-5-nitro-2-hexanone (5-AnEs). A mix-

ture of 3-AnEs (3. 86 g, 12.1 mmol) and 4 (2.3 g, 15 mmol) was

treated with DBU (2.7 mL, 18 mmol). CH₃CN (15 mL) was

added to the reaction mixture to dissolve the nitroethylpyrrole

compound completely. The reaction mixture was stirred at

room temperature for 15 h, diluted with ethyl acetate (40 mL),

and washed with water and brine. The organic layer was dried

(Na₂SO₄) and concentrated. The resulting oil was chromato-

graphed [silica, CH₂Cl₂/ethyl acetate (9:1)] to afford the title

compound (3.17 g, 55%): ¹H NMR δ 0.99 (s, 3H), 1.02 (s, 3H),

1.17 (t, J = 7.2, 3H), 2.52 (m, 2H), 3.06 (m, 2H), 3.38 (s, 6H),

3.81 (s, 3H), 4.13 (q, J = 7.1 Hz, 2H), 4.30 (s, 2H), 4.98 (m, 1H),

6.91 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.30 (d, J =

3.2 Hz, 1H), 8.91 (s, 1H); ¹³C NMR δ 14.1, 23.5, 23.7, 24.6,

36.2, 44.5, 54.8, 55.0, 59.2, 74.3, 94.5, 104.2, 113.1, 114.7, 123.8,

124.9, 126.5, 131.1, 131.2, 158.3, 164.7, 203.2; FAB-MS obsd

476.2151, calcd 476.2159 (C₂₄H₃₂N₂O₈).

8-(Ethoxycarbonyl)-1-(1,1-dimethoxymethyl)-3,3-dimethyl-7-

(4-methoxyphenyl)-2,3-dihydrodipyrrin (1-AnEs). Following a

general procedure,¹¹a solution of 5-AnEs (500 mg, 1.05 mmol)

in anhydrous THF (12.2 mL) under argon was treated with

NaOMe (283 mg, 5.25 mmol). The reaction mixture was de-

gassed by bubbling argon through the solution for 10 min and

then stirred for 1 h at room temperature. In a second flask, TiCl₃

[8.6 wt % TiCl₃in 28 wt % HCl, 9.54 g, 5.3 mmol], H₂O (42 mL),

NH₄OAc (40.0 g, 519 mmol), and THF (2.8 mL) were combined.

The mixture was degassed by bubbling argon for 10 min. The

solution in the first flask containing the nitronate anion of 5-

AnEs was transferred via a cannula to the buffered TiCl₃

mixture in the second flask. The resulting mixture was stirred

at room temperature for 5 h under argon. Then, the mixture was

1,1-Dimethoxy-4,4-dimethy1-6-[4-(4-pyridyl)pyrrol-2-y1]-5-nitro-

2-hexanone (5-Py). Following a general procedure,¹⁷a mixture of 3-

Py (500 mg, 2.30 mmol) and 4 (1.10 g, 6.91 mmol, 3 equiv) was

treated with DBU (1.03 mL, 6.91 mmol). The reaction mixture was

stirred at room temperature for 1 h under argon. A saturated

solution of cold aqueous NH₄Cl was added. The mixture was

extracted with ethyl acetate, and the organic layer was washed with

brine, dried (Na₂SO₄), and concentrated. Column chromatography

[silica, ethyl acetate] afforded an amorphous tan solid (235 mg,

27%): ¹HNMRδ1.12 (s, 3H), 1.20 (s, 3H), 1.32 (t, J= 7.2 Hz, 3H),

2.57, 2.72 (AB, ²J = 18.6 Hz, 2H), 3.05 (ABX, ³J = 2.2 Hz, ²J =

15.2 Hz, 1H), 3.36 (ABX, ³J = 12.0 Hz, ²J = 15.2 Hz, 1H), 3.40 (s,

3H), 3.41 (s, 3H), 4.25 (t, J = 7.2 Hz, 2H), 4.35 (s, 1H), 5.23 (ABX,

³J = 2.2 Hz, ³J = 12.0 Hz, 1H), 6.32 (s, 1H), 7.09 (s, 1H), 7.31 (d,

J = 6.13 Hz, 2H), 8.44 (d, J = 6.13 Hz, 2H), 9.37 (brs, 1H); ¹³

C

NMR δ 24.4, 24.5, 26.9, 36.7, 45.3, 55.4, 94.6, 104.7, 105.5, 116.8,

119.7, 122.4, 128.5, 143.6, 149.8, 204.0; ESI-MS obsd 376.1869,

calcd 376.1867 [(M þ H)^þ, M = C₁₉H₂₅N₃O₅].

1-(1,1-Dimethoxymethyl)-3,3-dimethy1-8-(4-pyridyl)-2,3-dihydro-

dipyrrin (1-Py). Following a general procedure,¹⁸in a first flask, a

solution of 5-Py (135 mg, 0.360 mmol) in freshly distilled THF (3.0

mL) and anhydrous MeOH (100 μL) at 0 °C was treated with

NaOMe (30 mg, 1.10 mmol). The mixture was stirred and degassed

by bubbling argon through the solution for 45 min. In a second flask

purged with argon, TiCl₃(3.3 mL, 20 wt % in 3% HCl solution, 5.2

mmol), 7.0 mL of THF, and NH₄OAc (2.5 g, 32 mmol) were

combined under argon, and the mixture was degassed by bubbling

argon for 45 min. Then, the first flask mixture was transferred via

cannula to the buffered TiCl₃mixture. The resulting mixture was

stirred at room temperature for 48 h under argon at 35 °C. The

reaction mixture was then poured over a pad of Celite and eluted

with ethyl acetate. The eluant was washed with saturated aqueous

NaHCO₃. The organic layer was dried (Na₂SO₄) and concentrated.

Column chromatography [silica, hexanes/ethyl acetate (1:1)] af-

1

forded a yellow amorphous solid (35.0 mg, 30%): H NMR δ

1.23 (s, 6H), 2.65 (s, 2H), 3.48 (s, 6H), 5.05 (s, 1H), 5.89 (s, 1H), 6.49

(s, 1H), 7.27-7.31 (m, 1H), 7.35-7.41 (m, 2H), 8.36-8.60 (m, 2H),

10.90 (brs, 1H); ¹³CNMRδ29.3, 40.4, 48.5, 54.8, 102.8 106.7, 107.0,

118.1, 119.6, 122.4, 132.7, 143.6, 150.1, 161.2, 175.4; ESI-MS obsd

326.1870, calcd 326.1863 [(M þ H)^þ, M = C₁₉H₂₃N₃O₂].

H. Synthesis of Dihydrodipyrrin-Acetal 1-AnEs. 4-(Ethoxy-

carbonyl)-2-formyl-3-(4-methoxyphenyl)pyrrole (2-AnEs). A solu-

tion of 6-AnEs (15.5 g, 63.2 mmol) in DMF (16.6 mL) and CH₂Cl₂

J. Org. Chem. Vol. 75, No. 4, 2010 1033

Krayer et al.

JOCFeatured Article

poured into a vigorously stirred solution of saturated aqueous

NaHCO₃(320 mL) plus ethyl acetate (110 mL). After 20 min,

the mixture was extracted with ethyl acetate. The combined

organic layers were dried (NaSO₄) and concentrated. The

resulting oil was chromatographed [silica, hexanes/ethyl acetate

(1:1)] to afford the title compound (196 mg, 44%): ¹H NMR δ

1.14 (s, 6H), 1.20 (t, J = 7.0 Hz, 3H), 2.62 (s, 2H), 3.46 (s, 6H),

3.85 (s, 3H), 4.16 (q, J = 7.0 Hz, 2H), 5.04 (s, 1H), 5.78 (s, 1H),

6.94 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.53 (m, 1H),

11.17 (s, 1H); ¹³C NMR δ 14.2, 28.9, 40.2, 48.2, 54.2, 55.1, 59.2,

102.5, 105.2, 112.9, 114.3, 124.2, 125.2, 126.8, 129.3, 131.9,

158.3, 161.1, 164.8, 175.1; FAB-MS obsd 426.2172, calcd

426.2155 (C₂₄H₃₀N₂O₅).

resulting mixture was stirred at room temperature for 20 h. The

reaction mixture was diluted with ethyl acetate, washed twice

with brine, dried (Na₂SO₄), and concentrated. Column chromato-

graphy [silica, CH₂Cl₂CH₂Cl₂/ethyl acetate (10:1)] provided a

light-brown oil which slowly solidified to a light-brown solid

(0.666 g, 87%): mp 95-97 °C; ¹H NMR δ 1.13 (s, 3H), 1.22 (s,

3H), 1.30 (t, J = 7.1 Hz, 3H), 2.19 (s, 3H), 2.65 (d, J = 18.5 Hz,

1H), 2.73 (d, J = 18.5 Hz, 1H), 2.94-3.00 (m, 1H), 3.21-3.30

(m, 1H), 3.41 (s, 3H), 3.42 (s, 3H), 4.22 (q, J = 7.1 Hz, 2H), 4.35

(s, 1H), 5.07-5.12 (m, 1H), 7.24 (app d, J = 3.2 Hz, 1H), 8.50

(brs, 1H); ¹³C NMR (75 MHz) δ 10.2, 14.6, 24.36, 24.42, 24.7,

36.6, 45.2, 55.4, 59.5, 94.2, 104.9, 115.4, 118.3, 123.7, 123.8,

165.5, 203.9; ESI-MS obsd 385.1972, calcd 385.1969 [(M þ H)^þ,

M = C₁₈H₂₈N₂O₇).

I. Synthesis of Dihydrodipyrrin-Acetal 1-MeEs. 4-Ethoxycar-

bonyl-2-formyl-3-methylpyrrole (2-MeEs). A solution of Vils-

meier reagent was prepared by treatment of dry DMF (7.0 mL)

with POCl₃(1.13 mL, 12.4 mmol) at 0 °C and stirring of the

resulting mixture for 10 min. In a separate flask, a solution of

3-ethoxycarbonyl-4-methylpyrrole (6-MeEs, 1.53 g, 10.0 mmol)

in DMF (30 mL) was treated with the freshly prepared Vilsmeier

reagent at 0 °C. The resulting mixture was stirred at 0 °C for 1 h

and then 2 h at room temperature. The reaction mixture was

treated with a mixture of saturated aqueous potassium acetate

and CH₂Cl₂[100 mL, 1:1 (v/v)] and stirred for 30 min. The water

phase was separated and extracted with CH₂Cl₂. The combined

organic phase was washed (water, brine), dried (Na₂SO₄), and

concentrated. The resulting solid was dissolved in warm EtOH

(∼10 mL) and cooled to -15 °C. The resulting solid was filtered,

washed with a small amount of cold EtOH, and dried to afford a

white solid with a light-pink filtrate (1.097 g, 58%). Alterna-

tively, in lieu of recrystallization, the crude product was chro-

matographed [silica, CH₂Cl₂/ethyl acetate (4:1)] to obtain the

product in 76% yield. Data for recrystallized sample: mp

123-125 °C; ¹H NMR δ 1.35 (t, J = 7.1 Hz, 3H), 2.60 (s, 3H),

4.30 (q, J = 7.1 Hz, 2H), 7.62-7.64 (m, 1H), 9.71 (s, 1H), 9.72

(brs, 1H); ¹³C NMR (75 MHz) δ 10.2, 14.6, 60.2, 117.6, 130.6,

130.7, 134.37, 164.4, 178.6; ESI-MS obsd 182.08088, calcd

182.08117 [(M þ H)^þ, M = C₉H₁₁NO₃].

8-Ethoxycarbonyl-1-(1,1-dimethoxymethyl)-3,3,7-trimethyl-

dipyrrin (1-MeEs). Following a general procedure,¹⁸a solution

of 5-MeEs (0.563 g, 1.46 mmol) in THF (13 mL) was treated

with NaOMe (1.0 mL, 5.5 mmol, 30% in MeOH) and stirred

for 30 min (flask 1). In a second flask a solution of TiCl₃(1.35 g,

8.77 mmol) in THF (15 mL) was prepared. In a third flask, a

solution of NH₄Cl (4.04 g, 76.3 mmol) in H₂O (15 mL) was

prepared. The contents of the two latter flasks were degassed

by three freeze-pump-thaw cycles and combined. To the

resulting mixture, the contents of flask 1 were transferred by

cannula, and the resulting mixture was stirred for 12 h.

Saturated aqueous NaHCO₃was added, and the resulting

mixture was then extracted with ethyl acetate. The organic

phase was washed with brine, dried (Na₂SO₄), and concen-

trated. Column chromatography [silica, CH₂Cl₂/ethyl acetate

(10:1] afforded a light-orange solid (0.188 g, 38%): ¹H NMR δ

1.23 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H), 2.34 (s, 3H), 2.63 (s, 2H),

3.45 (s, 6H), 4.27 (q, J = 7.1 Hz, 2H), 5.02 (s, 1H), 5.88 (s, 1H),

7.42 (app d, J = 3.2 Hz, 1H), 10.92 (brs, 1H); ¹³C NMR (75

MHz) δ 10.5, 14.7, 29.4, 40.5, 48.5, 54.8, 59.4, 102.8, 104.7,

115.1, 119.6, 125.1, 128.9, 160.1, 165.9, 174.8; ESI-MS obsd

335.1971; calcd 335.1965 [(M þ H)^þ, M = C₁₈H₂₆N₂O₄].

J. Synthesis of Dihydrodipyrrin-Acetal 1-ArEs. 4-(Ethoxy-

carbonyl)-2-formyl-3-(4-iodophenyl)pyrrole (2-ArEs). A solution

of 6-ArEs (4.77 g, 14.0 mmol) in DMF (4.47 mL) and CH₂Cl₂

(104 mL) under argon was cooled to 0 °C, whereupon POCl₃(1.57

mL, 16.8 mmol) was added dropwise. After 1 h, the flask was

warmed to room temperature and stirred overnight (∼17 h). The

reaction was quenched at 0 °C by the addition of 2.5 M aqueous

NaOH (100 mL). The mixture was poured into water (200 mL) and

extracted with CH₂Cl₂. The combined organic layers were washed

(water, brine), dried (Na₂SO₄), and concentrated to give a dark

brown solid. The solid was dissolved in ethyl acetate (∼100 mL),

and the solution was passed through a bed of silica. The collected

eluant was concentrated to give a brown solid. Cooling of the

solution (CH₂Cl₂/hexanes) at ∼-16 °C resulted in precipitation of

a white solid (2.96 g, 57%): mp 175-176 °C; ¹H NMR δ 1.23 (t,

J = 7.2 Hz, 3H), 4.21 (q, J= 7.2 Hz, 2H), 7.20 (d, J= 8.2 Hz, 2H),

7.74 (d, J = 3.2 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 9.36 (s, 1H),

9.95-10.10 (brs, 1H); ¹³C NMR δ 14.4, 60.4, 94.6, 116.8, 130.3,

130.8, 130.9, 132.8, 136.2, 137.1, 163.4, 180.7. Anal. Calcd for

C₁₄H₁₂INO₃: C, 45.55; H, 3.28; N, 3.79. Found: C, 45.56; H, 3.29;

N, 3.69.

4-(Ethoxycarbonyl)-3-methyl-2-(2-nitroethyl)pyrrole (3-MeEs).

Following a general procedure,¹⁸a suspension of 2-MeEs (3.73

g, 20.6 mmol) in nitromethane (185 mL) was treated with methyl-

amine hydrochloride (1.67 g, 24.7 mmol) and KOAc (2.23 g, 22.6

mmol). The reaction mixture was stirred at room temperature until

TLC analysis showed disappearance of the starting material

(∼2 h). The reaction mixture was filtered. The filtered material

was washed with a small amount of cold methanol and water and

dried under high vacuum to afford a yellow solid which was used

directly in the next step: mp 204-207 °C; ¹H NMR (DMSO-d₆,

400 MHz) δ 1.27 (t, J = 7.1 Hz, 3H), 2.38 (s, 3H), 4.20 (q, J = 7.1

Hz, 2H), 7.82 (s, 1H), 7.87 (d, J = 13.2 Hz, 1H), 7.96 (d, J = 13.2

Hz, 1H), 11.63 (brs, 1H). The resulting yellow solid was suspended

in dry THF (80 mL), cooled to 0 °C, and treated with LiBH₄(0.444

g, 20.4 mmol) and stirred at 0 °C for 75 min. The reaction mixture

was quenched by the addition of saturated aqueous NH₄Cl. The

resulting mixture was extracted with CH₂Cl₂. The organic extract

was washed with water and brine, dried (Na₂SO₄), and concen-

trated. The resulting solid was dissolved in CH₂Cl₂(with

sonication) and chromatographed [silica, CH₂Cl₂f CH₂Cl₂/ethyl

acetate (1:1)] to provide a yellow solid (1.77 g, 38%): mp 144-145

°C; ¹H NMR δ 1.33 (t, J = 7.1 Hz, 3H), 2.23 (s, 3H), 3.25 (t, J =

7.1 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.53 (t, J = 7.1 Hz, 2H), 7.30

(app d, J = 3.2 Hz, 1H), 8.34 (brs, 1H); ¹³C NMR δ 10.3, 14.7,

23.5, 59.7, 75.1, 115.6, 118.2, 123.8, 123.9, 165.6; ESI-MS obsd

227.10257, calcd 227.10262 [(M þ H)^þ, M = C₁₀H₁₄N₂O₄].

6-(4-Ethoxycarbonyl-3-methylpyrrol-2-yl)-1,1-dimethoxy-4,4-

dimethyl-5-nitrohexan-2-one (5-MeEs). Following a general pro-

cedure,¹⁷a mixture of 3-MeEs (0.452 g, 2.00 mmol) and 4 (0.632

g, 4.00 mmol) was treated with DBU (0.912 g, 6.00 mmol). The

4-(Ethoxycarbonyl)-3-(4-iodophenyl)-2-(2-nitroethyl)pyrrole

(3-ArEs). Following a general procedure,¹¹a stirred solution of

acetic acid (276 μL, 4.66 mmol) in methanol (0.66 mL) under

argon at 0 °C was treated dropwise with n-propylamine (362 μL,

4.40 mL). The resulting n-propylammonium acetate mixture

was stirred for 5 min at 0 °C and then added dropwise to a stirred

solution of 2 (2.95 g, 8.00 mmol) in nitromethane (20 mL) and

THF (20 mL) at 0 °C. The resulting mixture was stirred for

15 min at 0 °C and then was stirred at room temperature. The

reaction was monitored with TLC analysis. After 4 h, due to

incomplete reaction, the same amount of n-propylammonium

1034 J. Org. Chem. Vol. 75, No. 4, 2010

Krayer et al.

JOCFeatured Article

acetate mixture, which was prepared from acetic acid (276 μL,

4.66 mmol) and n-propylamine (362 μL, 4.40 mL), was added to

the reaction mixture. After 2 h, CH₂Cl₂(60 mL) was added to

the reaction mixture, and the organic phase was washed with

water and brine. The organic layer was dried (Na₂SO₄) and

concentrated under high vacuum to afford a yellowish-brown

solid. The solid was dissolved with a solution of CHCl₃(40 mL)

and 2-propanol (13.4 mL). Silica (9.6 g) was added to the

mixture. The mixture was stirred vigorously, and NaBH₄(604

mg, 16.0 mmol) was added in one batch. After 20 min, a portion

of NaBH₄(100 mg, 2.64 mmol) was added once more. After 20

min, TLC analysis showed complete consumption of the vinyl-

pyrrole. The mixture was filtered, and the filter cake was washed

[CH₂Cl₂/ethyl acetate (4:1)]. The filtrate was concentrated, and

the resulting brown solid was dissolved in ethyl acetate (∼100

mL). The solution was filtered through a bed of silica (ethyl

acetate) to afford a brown solid. The solid was dissolved in ethyl

acetate; the subsequent addition of hexanes afforded a white

solid (1.71 g, 52%): mp 155-157 °C; ¹H NMR δ 1.17 (t, J = 7.2

Hz, 3H), 3.20 (t, J = 6.4 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 4.42

(t, J = 6.4 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 3.2 Hz,

1H), 7.70 (d, J = 8.2 Hz, 2H), 8.67-8.77 (brs, 1H); ¹³C NMR δ

14.4, 23.4, 59.9, 75.3, 93.0, 115.3, 123.5, 124.2, 125.4, 132.4,

134.1, 137.3, 164.5. Anal. Calcd for C₁₅H₁₅IN₂O₄: C, 43.50; H,

3.65; N, 6.76. Found: C, 43.23; H, 3.68; N, 6.50.

K. Synthesis of Dihydrodipyrrin-Acetal 1-Ar. 6-[3-(4-Iodo-

phenyl)pyrrol-2-yl]-1,1-dimethoxy-4,4-dimethyl-5-nitro-2-hexa-

none (5-Ar). Following a general procedure,¹¹CsF (1.10 g, 9.25

mmol, freshly dried by heating to 100 °C under vacuum for 1 h)

was placed in a flask under argon. A mixture of 3-Ar (992 mg,

2.90 mmol) and 4 (4.59 g, 29.0 mmol) in dry acetonitrile (29 mL)

was transferred by cannula to the flask containing CsF. The

mixture was heated at 65 °C for 7 h, whereupon TLC analysis

showed the reaction to be complete. The reaction mixture was

filtered through a bed of alumina [ethyl acetate/hexanes (1:2)],

and the filtrate was concentrated. The resulting oil was dried for

16 h under high vacuum. Purification of the solid residue by

recrystallization [hexanes/CH₂Cl₂(10:1)] gave a light brown

solid (390 mg, 26%): ¹H NMR δ 1.09 (s, 3H), 1.19 (s, 3H), 2.54,

3

2.72 (AB, ²J = 18.8 Hz, 2H), 3.15 (ABX, J_BX= 2.4 Hz,

²J_AB= 15.6 Hz, 1H), 3.40 (ABX, ³J_AX= 12.4 Hz, ²J_AB= 15.6

Hz, 1H), 4.41 (s, 3H), 4.42 (s, 3H), 5.24 (ABX, ³J_BX= 2.4 Hz,

²J_AX= 12.4 Hz, 1H,), 6.21 (t, J = 2.8 Hz, 1H), 6.68 (t, J = 2.8

Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 8.19

(brs, 1H); ¹³C NMR δ 24.2, 24.3, 25.2, 45.1, 55.4, 91.3, 94.6,

104.8, 109.3, 118.1, 122.5, 122.7, 130.4, 136.1, 137.7, 203.8;

FAB-MS obsd 500.0818, calcd 500.0808 (C₂₀H₂₅IN₂O₅). Anal.

Calcd for C₂₀H₂₅IN₂O₅: C, 48.01; H, 5.04; N, 5.60. Found: C,

48.05; H, 5.05; N, 5.61.

1-(1,1-Dimethoxymethyl)-3,3-dimethyl-7-(4-iodophenyl)-2,3-

6-[4-(Ethoxycarbonyl)-3-(4-iodophenyl)pyrrol-2-yl]-1,1-dimethoxy-

4,4-dimethyl-5-nitro-2-hexanone (5-ArEs). A mixture of 3-ArEs (1.50

g, 3.62 mmol) and 4 (865 mg, 5.43 mmol) in CH₃CN (5 mL) was

treated with DBU (1.62 mL, 10.9 mmol). The reaction mixture was

stirred at room temperature for 24 h, diluted with ethyl acetate (45

mL), and washed with water and brine. The organic layer was dried

(Na₂SO₄) and concentrated. The resulting oil was chromatographed

[ethyl acetate/hexanes (1:1)] to afford a light brown oil (966 mg,

47%): ¹H NMR δ 1.03 (s, 3H), 1.06 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H),

2.47, 2.65 (AB, ²J= 19.0 Hz, 2H), 2.90 (ABX, ³J=2.4Hz,²J= 15.6

Hz, 1H), 3.23 (ABX, ³J = 11.6 Hz, ²J = 15.6 Hz, 1H), 3.416 (s, 3H),

3.420 (s, 3H), 4.12 (q, J= 7.2 Hz, 2H), 4.30 (s, 1H), 5.11 (ABX, ³J=

2.4 Hz, ³J = 11.6 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 3.2

Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 8.38-8.46 (brs, 1H); ¹³C NMR δ

14.4, 24.16, 24.18, 24.8, 36.7, 45.0, 55.4, 59.8, 92.8, 94.6, 104.8, 115.2,

123.7, 124.3, 125.3, 132.6, 134.2, 137.1, 164.6, 203.7; ESI-MS obsd

573.1093, calcd 573.1092 [(M þ H)^þ, M = C₂₃H₂₉IN₂O₇].

dihydrodipyrrin (1-Ar). Following a general procedure,¹¹

a

solution of 5-Ar (150 mg, 0.300 mmol) in anhydrous THF

(3.0 mL) under argon was treated with NaOMe (81 mg, 1.5

mmol), and the mixture was stirred for 1 h at room tempera-

ture. In a second flask, TiCl₃[8.6 wt % TiCl₃in 28 wt % HCl,

2.24 mL, 4.8 mmol], H₂O (12 mL), NH₄OAc (9.25 g, 120 mmol)

and THF (0.8 mL) were combined followed by degassed by

bubbling argon for 10 min. The solution in the first flask

containing the nitronate anion of 5-Ar was transferred via a

cannula to the buffered TiCl₃mixture in the second flask. The

resulting mixture was stirred at room temperature for 5 h under

argon. Then, the mixture was extracted with ethyl acetate. The

combined organic layers were washed (5% aqueous NaHCO₃

and water) and dried (NaSO₄). The solvent was removed under

reduced pressure at room temperature. The crude product was

passed through a short column [alumina, hexanes/ethyl acetate

(2:1)] to afford a light yellow solid (26 mg, 19%): mp 143-

144 °C; ¹H NMR δ 1.20 (s, 6H), 2.63 (s, 2H), 3.46 (s, 6H),

5.04 (s, 1H), 6.03 (s, 1H), 6.27 (t, J = 2.8 Hz, 1H), 6.88 (t,

J = 2.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz,

2H), 10.90 (brs, 1H); ¹³C NMR δ 29.3, 29.9, 40.5, 48.4, 54.8,

90.9, 102.9, 105.6, 109.0, 119.5, 123.4, 127.2, 130.7, 136.7,

137.7, 160.9, 174.9; FAB-MS obsd 450.0832, calcd 450.0804

(C₂₀H₂₃IN₂O₂).

8-(Ethoxycarbonyl)-1-(1,1-dimethoxymethyl)-3,3-dimethyl-7-

(4-iodophenyl)-2,3-dihydrodipyrrin (1-ArEs). Following a gener-

al procedure,¹¹a solution of 5-ArEs (550 mg, 0.961 mmol) in

anhydrous THF (9.6 mL) under argon was treated with NaOMe

(260 mg, 4.80 mmol), and the mixture was stirred for 1 h at room

temperature. In a second flask, TiCl₃[8.6 wt % TiCl₃in 28 wt %

HCl, 7.18 mL, 4.8 mmol], H₂O (38 mL), NH₄OAc (29.6 g, 384

mmol), and THF (2.4 mL) were combined. The mixture was

degassed by bubbling argon for 10 min. The solution in the first

flask containing the nitronate anion of 5-ArEs was transferred

via a cannula to the buffered TiCl₃mixture in the second flask.

The resulting mixture was stirred at room temperature for 5 h

under argon. Then, the mixture was extracted with ethyl acetate.

The combined organic layers were washed (5% aqueous NaH-

CO₃, water) and then dried (NaSO₄). The solvent was removed

under reduced pressure at room temperature. The crude product

was passed through a short column [alumina, hexanes/ethyl

acetate (2:1)] to afford a light yellow oil (160 mg, 32%): ¹H

NMR δ 1.15 (s, 6H), 1.20, (t, J = 7.2 Hz, 3H), 2.63 (s, 2H), 3.46

(s, 6H), 4.16 (q, J = 7.2 Hz, 2H), 5.05 (s, 1H), 5.71 (s, 1H), 7.12

(d, J = 8.2 Hz, 2H), 7.53 (d, J = 3.2 Hz, 1H), 7.71 (d, J = 8.2

Hz, 2H), 11.17 (brs, 1H); ¹³C NMR δ 14.5, 29.1, 40.6, 48.6, 54.8,

59.7, 92.5, 102.6, 104.9, 114.4, 123.4, 125.7, 129.7, 133.1, 134.4,

136.8, 162.1, 164.9, 176.1; ESI-MS obsd 523.1081, calcd

523.1088 [(M þ H)^þ, M = C₂₃H₂₇IN₂O₄].

L. Synthesis of Dihydrodipyrrin-Acetal 1-TEs. 8-(Ethoxy-

carbonyl)-1-(1,1-dimethoxymethyl)-3,3-dimethyl-7-(4-methylyphenyl)-

2,3-dihydrodipyrrin (1-TEs). A solution of 6-TEs (3.70 g, 16.1 mmol)

in DMF (5.14 mL) and CH₂Cl₂(120 mL) under argon was cooled to

0 °C, whereupon POCl₃(1.77 mL, 19.0 mmol) was added dropwise.

After 1 h, the flask was warmed to room temperature and stirred

overnight (10 h). The reaction was quenched at 0 °C by the addition of

2.5 M aqueous NaOH (100 mL). The mixture was poured into water

(200 mL) and then extracted with CH₂Cl₂. The extracted organic

solution was washed with water and brine, dried (Na₂SO₄), and

concentrated. The residue was chromatographed [silica, CH₂Cl₂/ethyl

acetate (4:1)] to give 2-TEs as a light brown solid (2.43 g, 59%): mp

129-130 °C; ¹H NMR δ 1.22 (t, J = 7.2 Hz, 3H), 2.41 (s, 3H), 4.20

(q, J = 7.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz,

2H), 7.73 (d, J = 0.8 Hz, 1H), 9.38 (s, 1H), 9.94-10.12 (brs, 1H); ¹³

C

NMR δ14.4, 21.5, 60.3, 116.8, 128.2, 128.7, 130.4, 130.9, 137.9, 138.3,

163.6, 181.2; Anal. Calcd for C₁₅H₁₅NO₃: C, 70.02; H, 5.88; N, 5.44.

Found: C, 69.86; H, 5.90; N, 5.44.

J. Org. Chem. Vol. 75, No. 4, 2010 1035

Krayer et al.

JOCFeatured Article

Following a general procedure,¹¹a stirred solution of acetic

acid (134 μL, 2.33 mmol) in methanol (0.33 mL) under argon at

0 °C was treated dropwise with n-propylamine (181 μL,

2.20 mL). The resulting n-propylammonium acetate mixture

was stirred for 5 min at room temperature, then added dropwise

to a stirred solution of 2-TEs (1.03 g, 4.00 mmol) in nitro-

methane (10 mL) and THF (3.0 mL) at 0 °C. The resulting

mixture was stirred for 15 min, and then stirring was continued

for 3 h at room temperature. CH₂Cl₂(30 mL) was added to the

reaction mixture, and the resulting organic phase was washed

with water and brine. The organic layer was dried (Na₂SO₄) and

concentrated under high vacuum to afford a brownish orange

solid. The solid was dissolved with a solution of CHCl₃(20 mL)

and 2-propanol (6.7 mL). Silica (4.8 g) was added to the mixture.

The mixture was stirred vigorously, and NaBH₄(302 mg,

8.00 mmol) was added in one batch. After 20 min, a further

portion of NaBH₄(100 mg, 2.64 mmol) was added. After

10 min, TLC analysis showed complete consumption of the

vinylpyrrole. The mixture was filtered, and the filter cake was

washed with CH₂Cl₂. The filtrate was concentrated and the

resulting brown oil was filtered through a bed of silica (CH₂Cl₂/

ethyl acetate, 4:1) to afford a brown solid. The solid was

dissolved in ethyl acetate; the subsequent addition of hexanes

gave 3-TEs as a light brown solid (598 mg, 49%): mp 155-

156 °C; ¹H NMR δ 1.16 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 3.20

(t, J = 6.4 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 4.42 (t, J = 6.4 Hz,

2H), 7.14 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.39 (d,

J = 3.2 Hz, 1H), 8.56-8.66 (brs, 1H); ¹³C NMR δ 14.4, 21.4,

23.5, 59.7, 75.3, 115.4, 123.9, 124.6, 125.2, 128.9, 130.2, 131.3, 136.8,

164.7; FAB-MS obsd 302.1288, calcd 302.1267 (C₁₆H₁₈N₂O₄).

A mixture of 3-TEs (3.02 g, 10.0 mmol) and 4 (1.90 g, 12.0

mmol) was treated with DBU (4.49 mL, 30.0 mmol). CH₃CN (3

mL) was added to the reaction mixture to dissolve the ni-

troethylpyrrole compound 3-TEs completely. The reaction

mixture was stirred at room temperature for 24 h, diluted with

ethyl acetate (100 mL), and washed with water and brine. The

organic layer was dried (Na₂SO₄) and concentrated. The result-

ing oil was chromatographed [silica, ethyl acetate/hexanes (1:2)]

to afford 5-TEs as a light yellow oil (3.63 g, 79%): ¹H NMR δ

1.02 (s, 3H), 1.05 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H), 2.37 (s, 3H),

2.46, 2.63 (AB, ²J = 18.8 Hz, 2H), 2.96 (ABX, ³J = 2.4 Hz, ²J =

15.6 Hz, 1H), 3.22 (ABX, ³J = 11.6 Hz, ²J = 15.6 Hz, 1H), 3.397

(s, 3H), 3.400 (s, 3H), 4.08-4.16 (m, 2H), 4.30 (s, 1H), 5.06

(ABX, ³J = 2.4 Hz, ³J = 11.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H),

7.19 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 3.4 Hz, 1H), 8.32-8.40

(brs, 1H); ¹³C NMR δ 14.3, 21.4, 23.8, 24.0, 24.9, 36.5, 44.7,

55.06, 55.08, 59.5, 94.9, 104.5, 115.0, 124.1, 124.6, 125.0, 128.6,

130.2, 131.4, 136.3, 164.8, 203.5; FAB-MS obsd 483.2122, calcd

483.2107 [(M þ Na)^þ, M =C₂₄H₃₂N₂O₇].

was chromatographed [alumina, hexanes/ethyl acetate (1:1)] to

afford the title compound (1-TEs) as a light yellow oil (441 mg,

51%): ¹H NMR δ 1.14 (s, 6H), 1.20, (t, J = 7.2 Hz, 3H), 2.40 (s,

3H), 2.61 (s, 2H), 3.46 (s, 6H), 4.16 (q, J = 7.2 Hz, 2H), 5.04 (s,

1H), 5.79 (s, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz,

2H), 7.52 (d, J = 3.2 Hz, 1H), 11.14-11.22 (brs, 1H); ¹³C NMR

δ 14.5, 21.5, 29.1, 40.5, 48.5, 54.8, 59.5, 102.7, 105.6, 114.6,

124.8, 125.5, 128.5, 129.6, 131.0, 131.7, 136.2, 161.4, 165.1,

175.4; FAB-MS obsd 410.2193, calcd 410.2206 (C₂₄H₃₀N₂O₄);

λ

_abs(CH₂Cl₂) 341 nm.

M. Bacteriochlorin Syntheses. 5-Methoxy-8,8,18,18-tetra-

methyl-2,12-bis(4-methylphenyl)bacteriochlorin (MeOBC-T) by

Use of BF₃O(Et)₂. A solution of BF₃O(Et)₂(301 μL, 2.50

3

mmol) in CH₃CN (6 mL) was slowly added to a solution of 1-T

(338 mg, 1.00 mmol) in CH₃CN (50 mL). The reaction mixture

was stirred at room temperature for 12 h under an air

atmosphere. TEA (1.00 mL, 7.17 mmol) was added to the

reaction mixture. Then the reaction mixture was concentrated.

The residue was chromatographed [silica, 10 cm dia ꢀ 30 cm,

hexanes/CH₂Cl₂(1:1)] to afford HBC-T (16.1 mg, 6%),

MeOBC-T (133 mg, 46%), and TDC-T (33.0 mg, 11%). Char-

acterization data (¹H NMR, LD-MS, FAB-MS, absorption

spectrum) of MeOBC-T were consistent with the previous

results.¹¹

3,13-Dibromo-5-methoxy-8,8,18,18-tetramethylbacteriochlorin

(MeOBC-Br). A solution of 1-Br (200 mg, 0.611 mmol, 18 mM)

in anhydrous CH₂Cl₂(34 mL) was treated first with 2,6-DTBP

(2.78 mL, 12.2 mmol, 360 mM) and second with TMSOTf (560

μL, 3.07 mmol, 90mM). The reactionmixturewas stirred atroom

temperature for 16 h. The reaction mixturewas concentrated, and

the residue was chromatographed [silica, hexanes/CH₂Cl₂(1:1)].

A single green band was collected and concentrated to give

1

the title compound as a green solid (55 mg, 32%): H NMR

δ -1.98 (brs, 1H), -1.77 (brs, 1H), 1.93 (s, 6H), 1.94 (s, 6H), 4.35

(s, 3H), 4.40 (s, 2H), 4.42 (s, 2H), 8.50-8.56 (m, 2H), 8.72 (d,

J = 2.48 Hz, 1H), 8.74-8.80 (m, 2H); ¹³C NMR δ 30.0, 31.0,

31.2, 45.8, 46.0, 47.5, 51.9, 64.7, 96.5, 97.1, 105.4, 112.5, 124.4,

124.9, 135.7, 169.8; ESI-MS obsd 557.05222, calcd 557.05516

[(M þ H)^þ, M = C₂₅H₂₆Br₂N₄O]; λ_abs(CH₂Cl₂) 360, 369, 504,

722 nm.

8,8,18,18-Tetramethylbacteriochlorin (HBC-H) by Use of

Bi(OTf)₃. A solution of 1-H (65.6 mg, 0.264 mmol, 5 mM) in

anhydrous CH₂Cl₂(53 mL) was treated with Bi(OTf)₃(1.73 g,

2.64 mmol, 50 mM). The reaction mixture was stirred at room

temperature for 16 h. Excess TEA (100. μL, 0.717 mmol) was

added to the reaction mixture. The reaction mixture was con-

centrated, and the residue was chromatographed [silica,

CH₂Cl₂/hexanes (1:1)]. The first green band (HBC-H, 5.2 mg,

11%) and the second green band (MeOBC-H, 4.9 mg, 9%) were

collected. Further elution with CH₂Cl₂afforded a TDC-type

macrocycle, which was not completely characterized.

Following a general procedure,¹¹a solution of 5-TEs (1.00 g,

2.17 mmol) in anhydrous THF (22 mL) under argon was treated

with NaOMe (586 mg, 10.9 mmol). The reaction mixture was

bubbled with argon for 10 min and then stirred for 1 h at room

temperature (first flask). In a second flask, TiCl₃[8.6 wt % TiCl₃

in 28 wt % HCl, 16.2 mL, 11 mmol] and H₂O (87 mL) were

combined. The mixture was bubbled with argon for 10 min.

Then, NH₄OAc (66.9 g, 868 mmol) was slowly added under

argon bubbling to buffer the mixture to pH 6.0 (pH paper). THF

(6.5 mL) was added to the dark buffered mixture. The mixture

was bubbled with argon for a further 10 min. The mixture in the

first flask containing the nitronate anion of 5-TEs was trans-

ferred via a cannula to the buffered TiCl₃mixture in the second

flask. The resulting mixture was stirred at room temperature for

5 h under argon. Then the mixture was poured into a vigorously

stirred solution of saturated aqueous NaHCO₃(320 mL) and

ethyl acetate (110 mL). After 20 min, the mixture was extracted

with ethyl acetate. The organic layers were combined, washed

with water, dried (NaSO₄), and concentrated. The resulting oil

5-Methoxy-8,8,18,18-tetramethylbacteriochlorin (MeOBC-H).

A solution of 1-H (422 mg, 1.70 mmol, 5 mM) in anhydrous

CH₂Cl₂(340 mL) was treated first with 2,6-DTBP (7.50 mL, 34.0

mmol, 100 mM) and second with TMSOTf (1.53 mL, 8.50 mmol,

25 mM). The reaction mixture was stirred at room temperature for

16 h. The reaction mixture was concentrated, and the residue was

chromatographed [silica, CH₂Cl₂/hexanes (1:1)]. A single green

band was collected (MeOBC-H, 150 mg, 44%). Further elution

with CH₂Cl₂did not afford any TDC-type macrocycle. Data for

HBC-H: ¹H NMR δ -2.40 to -2.36 (brs, 2H), 1.98 (s, 12H), 4.48

(s, 4H), 8.72-8.75 (m, 2H), 8.74 (s, 2H), 8.75-8.80 (m, 2H), 8.84

(s, 2H); ESI-MS obsd 371.2225, calcd 371.2230 [(M þ H)^þ, M =

C₂₄H₂₆N₄]; λ_abs(CH₂Cl₂) 339, 364, 488, 713 nm. Data for

1

MeOBC-H: H NMR δ -2.28 (brs, 1H), -2.13 (brs, 1H), 1.95

(s, 6H), 1.97 (s, 6H), 4.42 (s, 2H), 4.48 (s, 2H), 8.60-8.79 (m, 5H),

8.93 (m, 2H); ¹³C NMR δ 31.3, 31.4, 45.8, 46.1, 47.7, 52.0, 65.4,

96.9, 97.1, 98.0, 117.4, 120.2, 122.9, 123.7, 135.6, 137.1, 137.2,

1036 J. Org. Chem. Vol. 75, No. 4, 2010

Krayer et al.

JOCFeatured Article

152.7, 159.7, 169.6; ESI-MS obsd 401.2330, calcd 401.2336 [(M þ

H)^þ, M = C₂₅H₂₈N₄O]; λ_abs(CH₂Cl₂) 343, 353, 365, 499, 709 nm.

3,13-Bis(ethoxycarbonyl)-2,12-diethyl-8,8,18,18-tetramethyl-

bacteriochlorin (HBC-EtEs). A solution of 1-EtEs (742 mg, 2.13

mmol, 18 mM) in anhydrous CH₃CN (118 mL) was treated with

6H), 1.94 (s, 6H), 4.27 (s, 3H), 4.39 (s, 2H), 4.41 (s, 2H),

4.65-4.83 (m, 4H), 8.57 (s, 1H), 8.64 (s, 1H), 8.86 (d, J = 2.48

Hz, 1H), 9.21 (d, J = 2.48 Hz, 1H), 9.68 (s, 1 H); ESI-MS obsd

545.2762, calcd 545.2758 [(M þ H)^þ, M = C₃₁H₃₆N₄O₅]; λ_abs

(CH₂Cl₂) 354, 374, 524, 735 nm.

BF₃O(Et)₂(2.1 mL, 17 mmol, 140 mM). The reaction mixture

5-Methoxy-8,8,18,18-tetramethyl-2,12-bis(4-pyridyl)bacterio-

chlorin (MeOBC-Py). A solution of 1-Py (33 mg, 0.10 mmol, 18

mM) in anhydrous CH₂Cl₂(5.6 mL) was treated first with 2,6-

DTBP (462 μL, 2.03 mmol, 360 mM) and second with TMSOTf

(93 μL, 0.51 mmol, 90 mM). The reaction mixture was stirred at

room temperature for 16 h. The reaction mixture was concen-

trated, and the residue was chromatographed (silica, ethyl

acetate). A single green band was collected and concentrated

to give the title compound as a green solid (<1 mg, 0.7%

determined spectroscopically assuming ε_Qy=120000 M^-1cm^-1):

¹H NMR δ -1.78 (brs, 1H), -1.55 (brs, 1H), 1.96 (s, 6H), 1.98 (s,

6H), 3.68 (s, 3H), 4.37 (s, 2H), 4.40 (s, 2H), 8.02-8.08 (m, 2H),

8.09-8.13 (m, 2H), 8.63-8.67 (m, 2H), 8.67-8.70 (m, 1H),

8.77-8.80 (m, 1H), 8.83-8.90 (m, 3H), 8.94-9.02 (m, 2H); ESI-

MS obsd 555.2865, calcd 555.2867 [(M þ H)^þ, M =

C₃₅H₃₄N₆O]; λ_abs(CH₂Cl₂) 364, 515, 734 nm.

3

was stirred at room temperature for 16 h. Excess TEA (2.5 mL)

was added to the reaction mixture. The reaction mixture was

concentrated, and the residue was chromatographed (silica,

CH₂Cl₂). A single green band was isolated and concentrated

to afford the title compound as a purple solid (250 mg, 41%): ¹H

NMR δ -1.43 (brs, 2H), 1.72 (t, J = 7.15 Hz, 6H), 1.74 (t, J =

7.43 Hz, 6H), 1.94 (s, 12H), 4.14 (q, J = 7.43 Hz, 4H), 4.78 (q,

J = 7.15 Hz, 4H), 8.64 (s, 2H), 9.66 (s, 2H); ¹³C NMR δ

14.9,17.9, 21.0, 31.2, 46.1, 52.1, 61.1, 94.6, 98.8, 119.2, 133.6,

135.0, 141.9, 160.7, 166.7, 171.2; ESI-MS obsd 571.3271, calcd

571.3279 [(M þ H)^þ, M = C₃₄H₄₂N₄O₄]; λ_abs(CH₂Cl₂) 353,

382, 519, 759 nm. Further elution did not afford any TDC-type

macrocycle.

3,13-Bis(ethoxycarbonyl)-2,12-diethyl-5-methoxy-8,8,18,18-

tetramethylbacteriochlorin (MeOBC-EtEs). A solution of 1-

EtEs (185 mg, 0.531 mmol, 18 mM) in anhydrous CH₂Cl₂(30

mL) was treated first with 2,6-DTBP (2.35 mL, 10.6 mmol, 360

mM) and second with TMSOTf (0.478 mL, 2.65 mmol, 90

mM). The reaction mixture was stirred at room temperature

for 16 h. The reaction mixture was concentrated, and the

residue was chromatographed (silica, CH₂Cl₂). A single green

band was isolated and concentrated to afford the title com-

pound as a purple solid (64 mg, 40%): ¹H NMR δ -1.84 (brs,

1H), -1.56 (brs, 1H), 1.56-1.80 (m, 12H), 1.93 (s, 6H), 1.94 (s,

6H), 3.83 (d, J = 7.7 Hz, 2H), 4.15 (d, J = 7.7 Hz, 2H), 4.22 (s,

3H), 4.36 (s, 2H), 4.40 (s, 2H), 4.78 (q, J = 7.2 Hz, 4H), 8.53 (s,

1H), 8.66 (s, 1H), 9.61 (s, 1H); ¹³C NMR δ 14.8, 14.9, 17.7, 17.9,

20.3, 21.0, 31.2, 31.3, 45.8, 46.1, 48.1, 51.9, 61.0, 62.0, 64.6,

93.8, 95.3, 97.8, 118.4, 124.5, 128.0, 132.1, 134.2, 135.1, 135.3,

135.8, 141.9, 155.9, 160.7, 166.8, 168.2, 169.1, 171.7; ESI-MS

obsd 601.3384, calcd 601.3384 [(M þ H)^þ, M = C₃₅-

H₄₄N₄O₅]; λ_abs(CH₂Cl₂) 356, 378, 520, 739 nm. Further elution

with CH₂Cl₂did not afford any TDC-type macrocycle.

2,3,12,13-Tetrakis(ethoxycarbonyl)-5-methoxy-8,8,18,18-tetra-

methylbacteriochlorin (MeOBC-EsEs). A solution of 1-EsEs (30

mg, 0.076 mmol, 18 mM) in anhydrous CH₂Cl₂(4.25 mL) was

treated first with 2,6-DTBP (339 μL, 1.53 mmol, 360 mM) and

second with TMSOTf (69 μL, 0.38 mmol, 90 mM). The reaction

mixture was stirred at room temperature for 4 days (until no

starting material 1-EsEs remained by TLC analysis). The reaction

mixture was concentrated, and the residue was chromatographed

(silica, CH₂Cl₂). A single purple band was collected and concen-

trated to give the title compound as a purple solid (16.5 mg, 63%):

¹H NMR δ -1.12 (brs, 1H), -0.87 (brs, 1H), 1.54-1.74(m, 12H),

1.91 (s, 6H), 1.92 (s, 6H), 4.22 (s, 3H), 4.30 (s, 2H), 4.32 (s, 2H),

4.74 (m, 8H), 9.06 (s, 1H), 9.13 (s, 1H), 9.66 (s, 1H); ¹³C NMR δ

14.6, 14.7, 14.7, 14.8, 30.4, 31.0, 31.1, 46.2, 46.3, 47.6, 51.6, 61.5,

62.1, 62.2, 62.4, 64.6, 98.1, 98.7, 98.9, 125.0, 127.3, 133.4, 133.9,

135.4, 136.9, 157.0, 163.5, 164.6, 165.7, 165.9, 168.2, 172.0, 174.5;

ESI-MS obsd 689.3185, calcd 689.3182 [(M þ H)^þ, M =

C₃₇H₄₄N₄O₉]; λ_abs(CH₂Cl₂) 360, 548, 758 nm. Further elution

with CH₂Cl₂did not afford any TDC-type macrocycle.

3,13-Bis(ethoxycarbonyl)-5-methoxy-2,12-bis(4-methoxyphenyl)-

8,8,18,18-tetramethylbacteriochlorin (MeOBC-AnEs). A solution

of 1-AnEs (0.140 g, 0.329 mmol) in anhydrous CH₂Cl₂(66 mL)

was treated first with 2,6-DTBP (1.47 mL, 6.58 mmol) and second

with TMSOTf (0.298 mL, 1.64 mmol). The resulting mixture was

stirred at room temperature for 16 h. The reaction mixture was

concentrated and chromatographed [silica, CH₂Cl₂/ethyl acetate

(10:1)] to afford a pink greenish solid (39.7 mg, 32%): ¹H NMR δ

-1.60 (brs, 1H), -1.31 (brs, 1H), 1.36 (t, J = 7.1 Hz, 3H), 1.44 (t,

J = 7.1 Hz, 3H), 1.82 (s, 6H), 1.86 (s, 1H), 4.03 (s, 3H), 4.04 (s, 3H),

4.26 (s, 3H), 4.35 (s, 2H), 4.40 (s, 2H), 4.54 (q, J = 7.1 Hz, 2H), 4.62

(q, J = 7.1 Hz, 2H), 7.25-7.28 (m, 2H þ 2H, partially overlapped

with the CHCl₃signal), 7.85 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4

Hz, 2H), 8.44 (s, 1H), 8.55 (s, 1H), 9.58 (s, 1H); ¹³CNMR(75MHz)

δ 14.4, 14.6, 30.9, 31.0, 45.8, 46.2, 48.1, 51.8, 55.7, 60.9, 62.0, 64.5,

96.1, 98.0, 98.2, 113.5, 114.4, 119.3, 124.7, 126.7, 128.1, 128.2,

133.06, 133.14, 133.48, 133.51, 134.6, 135.0, 135.4, 138.4, 156.4,

159.6, 159.8, 161.2, 166.6, 168.8, 169.0, 172.5; LD-MS 756.6; ESI-

MS obsd 757.3588, calcd 757.3596 [(M þ H)^þ, M = C₄₅H₄₈N₄O₇];

λ_abs360, 377, 526, 749 nm.

3,13-Bis(ethoxycarbonyl)-5-methoxy-2,8,8,12,18,18-hexam-

ethylbacteriochlorin (MeOBC-MeEs). A solution of 1-MeEs

(70 mg, 0.21 mmol) in CH₂Cl₂(42 mL) was treated first with

2,6-DTBP (0.930 mL, 4.14 mmol) and second with TMSOTf

(0.190 mL, 1.05 mmol). The resulting mixture was stirred at

room temperature for 13 h. The reaction mixture was concen-

trated and chromatographed (silica, CH₂Cl₂) to afford a dark-

green solid (29 mg, 48%): ¹H NMR δ -1.83 (brs, 1H), -1.57

(brs, 1H), 1.65 (t, J = 7.2 Hz, 3H), 1.72 (t, J = 7.1 Hz, 3H), 1.94

(s, 6H), 1.95 (s, 6H), 3.40 (s, 3H), 3.66 (s, 3H), 4.24 (s, 3H), 4.38

(s, 2H), 4.42 (s, 2H), 4.75-4.83 (m, 4), 8.52 (s, 1H), 8.66 (s, 1H),

9.62 (s, 1H); ¹³C NMR δ 11.8, 13.6, 14.8, 15.0, 31.2, 31.3, 45.8,

46.1, 48.1, 51.9, 61.0, 62.0, 64.5, 93.9, 95.6, 97.7, 119.3, 125.1,

128.1, 133.0, 134.97, 135.04, 155.9, 160.7, 166.9, 168.1, 169.0,

171.7; LD-MS obsd 573.0 ESI-MS obsd 573.3071; calcd

573.3071 [(M þ H)^þ, M = C₃₃H₄₀N₄O₅); λ_abs357, 380, 520,

738 nm.

3,13-Bis(ethoxycarbonyl)-5-methoxy-8,8,18,18-tetramethyl-

bacteriochlorin (MeOBC-Es). A solution of 1-Es (700 mg, 2.18

mmol) in anhydrous CH₂Cl₂(121 mL) was treated first with

2,6-DTBP (10.0 mL, 43.8 mmol) and second with TMSOTf

(2.00 mL, 10.9 mmol). The reaction mixture was stirred at

room temperature for 16 h. The reaction mixture was concen-

trated, and the residue was chromatographed (silica, CH₂Cl₂).

A single green band was collected and concentrated to give the

3,13-Bis(ethoxycarbonyl)-5-methoxy-2,12-bis(4-iodophenyl)-

8,8,18,18-tetramethylbacteriochlorin (MeOBC-ArEs). A solu-

tion of 1-ArEs (40 mg, 0.077 mmol) in anhydrous CH₂Cl₂(4.25

mL) was treated first with 2,6-DTBP (338 mL, 1.53 mmol) and

second with TMSOTf (69 mL, 0.38 mmol). The reaction

mixture was stirred at room temperature for 16 h. The reaction

mixture was concentrated, and the residue was chromato-

graphed [silica, CH₂Cl₂/hexanes (2:1)]. A single purple band

was collected and concentrated to give the title compound as a

purple solid (13 mg, 36%): ¹H NMR δ -1.55 (brs, 1H), -1.27

1

title compound as a purple solid (50 mg, 8.4%): H NMR δ

-1.67 (brs, 1H), -1.43 (brs, 1H), 1.63-1.72 (m, 6H), 1.93 (s,

J. Org. Chem. Vol. 75, No. 4, 2010 1037

Krayer et al.

JOCFeatured Article

(brs, 1H), 1.33 (t, J = 7.0 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H), 1.81

(s, 6H), 1.85 (s, 6H), 4.24 (s, 3H), 4.34 (s, 2H), 4.40 (s, 2H), 4.52

(q, J = 7.2 Hz, 2H), 4.62 (q, J = 7.2 Hz, 2H), 7.58-7.69 (m,

2H), 7.80 (d, J = 8.3 Hz, 2H), 7.98-8.13 (m, 4H), 8.35 (s, 1H),

8.47 (s, 1H), 9.60 (s, 1 H); ¹³C NMR δ 14.4, 14.6, 30.9, 31.0,

45.9, 46.3, 48.1, 51.8, 61.1, 62.2, 64.6, 94.1, 94.7, 95.9, 98.0,

98.4, 119.3, 128.3, 132.4, 132.7, 133.7, 133.94, 134.07, 134.2,

135.0, 135.6, 135.7, 137.1, 137.2, 138.0, 157.0, 161.7, 166.2,

168.4, 169.4; ESI-MS obsd 948.1239, calcd 948.1222 (C₄₃H₄₂-

I₂N₄O₅); λ_abs(CH₂Cl₂) 373, 528, 751 nm.

NMR δ -1.73 (brs, 1H), -1.44 (brs, 1H), 1.62-1.72 (m, 6H),

1.92 (s, 6H), 1.94 (s, 6H), 4.24 (s, 3H), 4.35 (s, 2H), 4.41 (s, 2H),

4.73 (q, J = 7.2 Hz, 2H), 4.81 (q, J = 7.2 Hz, 2H), 8.63 (s, 1H),

8.67 (s, 1H), 9.20-9.23 (m, 1 H), 9.68 (s, 1 H); ESI-MS obsd

623.1863, calcd 623.1864 [(M þ H)^þ, M = C₃₁H₃₅BrN₄O₅];

λ_abs(CH₂Cl₂) 354, 365, 375, 523, 740 nm. Data for MeOBC-

Es-Br¹⁵: ¹H NMR δ -1.60 (brs, 1H), -1.39 (brs, 1H), 1.92 (s,

6H), 1.93 (s, 6H), 4.28 (s, 3H), 4.37 (s, 2H), 4.41 (s, 2H),

4.67-4.82 (m, 4H), 8.53 (s, 1H), 8.59 (s, 1H), 8.79-8.83 (m,

1H), 8.86-8.89 (m, 1H); ESI-MS obsd 623.1872, calcd

623.1864 [(M þ H)^þ, M = C₃₁H₃₅BrN₄O₅]; λ_abs(CH₂Cl₂)

366, 525, 724 nm.

N. Bromination and Derivatization of Bacteriochlorins. 15-

Bromo-5-methoxy-8,8,18,18-tetramethylbacteriochlorin (MeOBC-

H-Br¹⁵). A solution of MeOBC-H (50.0 mg, 0.125 mmol) in

THF (50 mL) was treated at once with NBS (22.0 mg, 0.125 mmol,

in 1.0 mL of THF) at room temperature for 1 h. TLC analysis

[silica, hexanes/CH₂Cl₂(1:1)] showed only one spot. The reaction

mixture was diluted with CH₂Cl₂and washed with saturated

aqueous NaHCO₃. The organic layer was dried (Na₂SO₄), con-

centrated and chromatographed [silica, hexanes/CH₂Cl₂(1:1)] to

15-Bromo-3,13-bis(ethoxycarbonyl)-2,12-diethyl-5-methoxy-

8,8,18,18-tetramethylbacteriochlorin (MeOBC-EtEs-Br¹⁵). A

solution of MeOBC-EtEs (30 mg, 0.050 mmol) in THF (20

mL) was treated with NBS (9.0 mg, 0.050 mmol, in 500 μL

THF) at room temperature for 1 h. TLC analysis (silica,

CH₂Cl₂) showed only one spot. The reaction mixture was

diluted with CH₂Cl₂and washed with saturated aqueous

NaHCO₃. The organic layer was dried (Na₂SO₄), concentrated

and chromatographed (silica, CH₂Cl₂) to afford a green solid

1

afford a green solid (51 mg, 86%): H NMR δ -2.33 (brs, 1H),

-2.08 (brs, 1H), 1.95 (s, 6H), 1.96 (s, 6H), 4.40 (s, 2H), 4.48 (s, 3H),

4.50 (s, 2H), 8.63 (s, 1H), 8.68 (s, 1H), 8.70-8.75 (m, 2H),

8.95-8.99 (m, 1H), 9.00-9.04 (m, 1 H); ESI-MS obsd 478.1372,

calcd 478.1363 [M^þ, M=C₂₅H₂₇N₄O]; λ_abs(CH₂Cl₂) 348, 358, 369,

512, 712 nm.

1

(20 mg, 59%): H NMR δ -1.95 (brs, 1H), -1.72 (brs, 1H),

1.55-1.67 (m, 6H), 1.74 (m, 6H), 1.92 (s, 6H), 1.93 (s, 6H),

3.74-3.92 (m, 4H), 4.24 (s, 3H), 4.35 (s, 2H), 4.42 (s, 2H),

4.66-4.83 (m, 4H), 8.52 (s, 1H), 8.59 (s, 1H); ESI-MS obsd

679.2494, calcd 679.2490 [(M þ H)^þ, M = C₃₅H₄₃BrN₄O₅]; λ_abs

(CH₂Cl₂) 357, 366, 375, 519, 726 nm.

5,15-Dimethoxy-8,8,18,18-tetramethylbacteriochlorin (BC-

OMe^5,15). Following a general procedure,³³in an oven-dried

Schlenk flask equipped with a stirring bar, MeOBC-H-Br¹⁵

(58.4 mg, 0.122 mmol), Pd₂(dba)₃, bis(2-diphenylphosphino-

phenyl)ether (13.2 mg, 0.0244 mmol), and Cs₂CO₃(92.0 mg,

0.244 mmol) were dried under high vacuum for 1 h. Toluene

(12.2 mL) containing methanol (20 mL, 0.487 mmol) was

added to the Schlenk flask, and the mixture was degassed by

three freeze-pump-thaw cycles. The flask was then placed in

an oil bath, and the reaction mixture was stirred at 100 °C for

24 h. After being cooled to room temperature, the reaction

mixture was filtered through Celite. The filtrate was eluted

with ethyl acetate, and the eluent was concentrated. Column

chromatography [silica, hexanes/CH₂Cl₂(1:1)] afforded in the

following order the starting material (11 mg), debrominated

starting material MeOBC-H (17 mg), and the title compound

(15 mg, 29%): ¹H NMR (THF-d₈) δ -2.38 (brs, 2H), 1.96 (s,

12H), 4.41 (s, 4H), 4.45 (s, 6H), 8.70-8.75 (m, 1H), 8.75 (s,

1H), 8.89-8.96 (m, 1 H); ¹H NMR (CD₂Cl₂) δ -2.36 (brs, 2H),

1.97 (s, 12H), 4.42 (s, 4H), 4.48 (s, 6H), 8.71 (s, 2H), 8.72-8.77

(m, 2H), 8.91-9.01 (m, 2H); ESI-MS obsd 431.2435, calcd

431.2442 [(M þ H)^þ, M = C₂₆H₃₀N₄O₂]; λ_abs(CH₂Cl₂) 347,

357, 367, 510, 707 nm. Note: the title compound is only

sparingly soluble in a wide range of solvents including ethyl

acetate, THF, acetone, DMF, DMSO, and carbon disulfide.

15-Bromo-3,13-bis(ethoxycarbonyl)-5-methoxy-8,8,18,18-tetra-

methylbacteriochlorin (MeOBC-Es-Br¹⁵) and 12-Bromo-3,13-

bis(ethoxycarbonyl)-5-methoxy-8,8,18,18-tetramethylbacterio-

chlorin (MeOBC-Es-Br¹²). A solution of MeOBC-Es (16 mg,

0.030 mmol) in THF (12 mL) was treated at once with NBS (5.3

mg, 0.030 mmol, in 100 μL of THF) at room temperature for

1 h. TLC analysis [silica, CH₂Cl₂/hexanes (4:1)] showed four

spots. The reaction mixture was diluted with CH₂Cl₂and

washed with saturated aqueous NaHCO₃. The organic layer

was dried (Na₂SO₄), concentrated, and chromatographed

[silica, CH₂Cl₂/hexanes (4:1)] to afford four fractions: the first

purple band (MeOBC-Es-Br¹², 2.8 mg, 15%) was pure; the

second purple band consisted of a mixture of mono- and

dibromobacteriochlorins on the basis of mass spectrometric

data (LD-MS m/z=622.2, 700.1) and was not further analyzed;

the third purple band was recovered starting material

(MeOBC-Es, 4.9 mg); and the fourth purple band (MeOBC-

Es-Br¹⁵, 2.4 mg, 13%) was pure. Data for MeOBC-Es-Br¹²: ¹H

O. Broad Acid Survey with Two Dihydrodipyrrin-Acetals.

Each reaction was carried out in a 4-mL conical microreaction

vial containing 10 mM of starting dihydrodipyrrin-acetal and 50

mM acid. When employed, additives were used at 500 mM

concentrations. Each vial was equipped with a conical stir bar

and fitted with a Teflon septum. Reactions were done on a 0.02

mmol scale of 1-T or 1-Br (commensurate with accurate weigh-

ing of solid acids). The vials and stir bars were dried in an oven

(120 °C). A 10 mM solution of dihydrodipyrrin-acetal (1-T or 1-

Br) was prepared in the appropriate anhydrous solvent. Anhy-

drous solvents (CH₂Cl₂, CH₃CN) were reagent grade and were

used as received.

In the case of solid acids, the appropriate amount of neat acid

was placed in a microreaction vial under argon flow from an

inverted glass funnel connected to an argon line. The acid was

then treated with 2.00 mL of the previously prepared 10 mM

dihydrodipyrrin-acetal solution. For example, for the reaction

of 1-T in CH₂Cl₂containing Bi(OTf)₃, 65.6 mg (0.100 mmol) of

Bi(OTf)₃was placed in an oven-dried microreaction vial. Then

2.00 mL of the 10 mM solution (CH₂Cl₂) of 1-T was added. The

solid acids generally did not fully dissolve and resulted in

heterogeneous reaction mixtures. Note that we use the term

concentration regardless of heterogeneity for ease of compar-

ison. In the case of liquid acids, the previously prepared 10 mM

dihydrodipyrrin-acetal solution (10 mM, 2.00 mL) was placed in

the microreaction vial, under argon, and treated with the

appropriate amount of the acid using a microsyringe. When

an additive was used, the order of addition was as follows:

dihydrodipyrrin-acetal solution, (2) additive, and (3) the acid.

For example, for the reaction of 1-T with TMSOTf/2,6-DTBP in

CH₂Cl₂, 2.00 mL of the previously prepared 10 mM dihydrodi-

pyrrin-acetal solution was added to a microreaction vial, under

argon. Then 225 μL of 2,6-DTBP was added, followed by 18 μL

of TMSOTf.

The reactions were stirred at room temperature. The progress

of the reactions was monitored by TLC and absorption spec-

troscopy. The first time point was typically at 30 min. If no

substantial amount of bacteriochlorin was observed after 30

min, the reaction mixture was stirred overnight and checked

again after 13 h, 16 h and 19 h. When bacteriochlorin formation

was observed after 30 min, the reaction was checked more

1038 J. Org. Chem. Vol. 75, No. 4, 2010

Krayer et al.

JOCFeatured Article

frequently (after 1 h, 2 h, 3 h, and 16 h). Reactions were

determined to be complete when all starting dihydrodipyrrin-

acetal had been consumed (as determined by TLC) and there

were no changes in the absorption spectra. The maximum

duration for the self-condensation reaction was 48 h.

For TLC analysis, a 1 μL sample was directly taken from the

reaction vial and spotted on the TLC plate [silica, hexanes/

CH₂Cl₂(1:1)]. TLC analysis gave information about the consumption

of starting material, formation of HBC- and/or MeOBC-type

macrocycles, and formation of TDC-type macrocycles. In gen-

eral HBC-type macrocycles have the highest R_fvalue (least

polar), followed by MeOBC-type macrocycles, then starting

dihydrodipyrrin-acetal, and finally TDC-type macrocycles

(most polar). For example, the R_fvalues for HBC-Br,

MeOBC-Br, 1-Br, and TDC-Br in hexanes/CH₂Cl₂(1:1) are

0.75, 0.59, 0.49, and 0.25 respectively.

Reactions were done on a 0.02-mmol scale for the lower con-

centration (5 mM 1/50 mM acid) reactions, and 0.036 mmol

scale for the higher concentration (18 mM 1/140 mM acid)

reactions. Therefore, a 5 mM and 18 mM 1 solution was pre-

pared in the appropriate anhydrous solvent; 4.00 mL of the

5 mM solution was added to each microreaction vial for the

lower concentration reactions, and 2.00 mL of the 18 mM

solution was added to each microreaction vial for the higher

concentration reactions. The limit of detection by absorption

spectroscopy was ∼1.5% for the 5-mM reactions and ∼0.4% for

the 18-mM reactions. The cap of each reaction vial was sealed

with Teflon tape to limit solvent evaporation during the course

of the reaction. The reaction mixture and vial were weighed at

the start and before quenching, which verified that there was no

significant solvent loss. The data from this study are provided in

Table 2 and the Supporting Information.

For absorption spectroscopic analysis, a 5 μL sample was

taken from the reaction vial, diluted in 2.5 mL of CH₂Cl₂/EtOH

(3:1) in a UV-vis cuvette, and checked for the presence of the

characteristic bacteriochlorin Q_yabsorption band (>700 nm).

Then, one drop of TEA was added to the cuvette to neutralize

any putative protonated bacteriochlorins, whereupon the ab-

sorption spectrum was measured again. When the total yield of

bacteriochlorin was lower than ∼5% (no prominent Q_yabsorp-

tion >700 nm), the reaction mixture was not further analyzed.

When there was no further progression in the reaction (based on

changes in the absorption spectrum), and the total yield of

bacteriochlorin was greater than ∼5% (prominent Q_yabsorp-

tion >700 nm), the reaction mixture was neutralized by excess

TEA, concentrated and the bacteriochlorins (if two were

present) were separated by column chromatography [silica,

hexanes/CH₂Cl₂(1:1)]. The fractions containing bacterio-

chlorin(s) were collected, concentrated and the yield was deter-

mined spectroscopically assuming ε_Qy= 130,000 M^-1cm^-1for

HBC-type macrocycles and ε_Qy= 120,000 M^-1cm^-1for

MeOBC-type macrocycles.¹¹TDC-type macrocycles, if present,

were not isolated for the survey reactions. The intensity of the

TLC spot attributed to the TDC-type macrocycles were visually

compared to those for HBC-and MeOBC-type macrocycles by

TLC analysis. The data from this study are provided in Table 1

and the Supporting Information.

Q. TiCl₃Reagent for Reductive Cyclization. Over the course

of this study three different procedures were employed concern-

ing the TiCl₃reagent for use in the reductive cyclization reac-

tion. (i) The earliest conditions^11,17,24,38employed a solution

containing 8.6 wt % TiCl₃in 28 wt % HCl, available commer-

cially or prepared as follows: 5.0 g of solid TiCl₃(32 mmol) in a

250-mL flask was treated with 44.0 g of concentrated aqueous

HCl (36.7 mL, 37.3 wt %, d = 1.19 g/mL, 0.45 mol) followed by

9.1 g of H₂O (0.51 mol). The resulting solution had a measured

density of 1.20 g/mL. These conditions required large amounts

of NH₄OAc to buffer the mixture to pH 6. (ii) A subsequent

approach^13,18entailed the use of solid TiCl₃without HCl, which

significantly reduced the amount of NH₄OAc necessary to

buffer the TiCl₃mixture but was cumbersome with regards to

handling solid TiCl₃on the open bench. (iii) The most recent

procedure¹⁸makes use of a commercially available TiCl₃solu-

tion [20 wt % in 3% HCl, d = 1.22 g/mL], which is readily

handled and allows for the use of relatively small amounts of

NH₄OAc as a buffering agent. While each procedure is effective,

this latter approach appears superior in ease of handling TiCl₃

and modest buffer requirement.

Acknowledgment. This work was funded by the Division

of Chemical Sciences, Geosciences, and Biosciences, Office

of Basic Energy Sciences of the U.S. Department of Energy

through Grant No. DE-FG02-96ER14632. The Department

of Chemistry of North Carolina State University and the

State of North Carolina provided funding for the Apex2

diffractometer. We thank Mr. Mark Deaver, Mr. Finith

Jernigan, Mr. Kyle M. Flack, and Ms. Jessie Dwan for

technical assistance.

P. Focused Acid Survey with Diverse Dihydrodipyrrin-Acetals.

Each dihydrodipyrrin-acetal (1) was subjected to five Lewis

acids (four of which were identified from the broad survey)

under two different concentration conditions (empirically

chosen),¹¹for a total of 10 self-condensation conditions. The

acids used were Bi(OTf)₃in CH₂Cl₂, Hf(OTf)₄in CH₂Cl₂, HfCl₄

in CH₂Cl₂, TMSOTf/2,6-DTBP in CH₂Cl₂, and BF₃O(Et)₂in

3

CH₃CN. The concentrations employed were 5 mM 1/50 mM

acid, and 18 mM 1/140 mM acid, except for the reactions using

TMSOTf/2,6-DTBP, which were carried out at concentrations

of 5 mM/25 mM/100 mM and 18 mM/90 mM/360 mM for

1/TMSOTf/2,6-DTBP.

Supporting Information Available: Acid catalysis survey

data; discussion of refined syntheses of 1-T and 1-H; X-ray

data for 2-Py; spectral data for all new compounds. This

material is available free of charge via the Internet at http://

pubs.acs.org.

The reactions were carried out and analyzed in a similar

fashion to the broad acid survey with the following exceptions.

J. Org. Chem. Vol. 75, No. 4, 2010 1039

Article Doi

Expanded scope of synthetic bacteriochlorins via improved acid catalysis conditions and diverse dihydrodipyrrin-acetals

DOI: 10.1021/jo9025572

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Article abstract of DOI:10.1021/jo9025572

Full text of DOI:10.1021/jo9025572

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