Synthesis of 1-formyldipyrromethanes

Article abstract of DOI:10.1021/jo060119b

1-Formyldipyrromethanes are versatile precursors to porphyrins and chlorins. Two methods of synthesis of 1-formyldipyrromethanes have been investigated: (1) Vilsmeier formylation followed by selective removal of the unwanted 1,9-diformyldipyrromethane by

Full text of DOI:10.1021/jo060119b

dipyrromethanes, employing a S-2-pyridyl thioate (Mukaiyama
reagent) as an acylating agent for use with the magnesium salt
of the dipyrromethane (eq 1).8 On the other hand, no methods
for selective 1-formylation of dipyrromethanes have been
developed. Battersby reported a rational, albeit lengthy, six-
step synthesis of 1-formyldipyrromethane (2a) by using N-mesyl
2-chloromethylpyrrole and an acetal of pyrrole-2-carboxalde-
hyde as building blocks.9 The most direct method at present
for preparing 1-formyldipyrromethanes entails statistical Vils-
meier formylation of a dipyrromethane followed by extensive
chromatography. Here, we report two simple methods for more
expeditious syntheses of 1-formyldipyrromethanes.
Synthesis of 1-Formyldipyrromethanes
Marcin Ptaszek, Brian E. McDowell, and
Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
ReceiVed January 19, 2006
1-Formyldipyrromethanes are versatile precursors to por-
phyrins and chlorins. Two methods of synthesis of 1-formyl-
dipyrromethanes have been investigated: (1) Vilsmeier
formylation followed by selective removal of the unwanted
1,9-diformyldipyrromethane by dialkyltin complexation and
(2) reaction with mesitylmagnesium bromide (MesMgBr)
followed by formylation with phenyl formate. The two
approaches are complementary (acidic versus basic condi-
tions; statistical versus selective formylation). The latter was
found to be more efficient for the preparation of 1-formyl-
dipyrromethanes.
A. Statistical Vilsmeier Formylation and Selective Com-
plexation. Treatment of dipyrromethane (1a)10 with the Vils-
meier reagent afforded the expected mixture of the 1-formyl-
dipyrromethane (2a) and 1,9-diformyldipyrromethane (3a)
(Scheme 1). To facilitate separation of the formyldipyrromethane
species, the mixture was treated with Bu2SnCl2 and TEA in
CH2Cl2 at room temperature. The tin-complexation process11
is selective for the 1,9-diformyl species, yielding a hydrophobic
1,9-diformyldipyrromethane-dibutyltin complex (Bu2Sn-3)12
and the uncomplexed 1-formyldipyrromethane. The mixture was
separated by flash chromatography to afford the desired
1-formyldipyrromethane 2a. Similar treatment of dipyrromethane
1b or 1c afforded 1-formyldipyrromethane 2b6,13 or 2c. This
procedure proved viable for small-scale preparations, but partial
decomplexation upon chromatographic separation limited larger
scale implementation (see the Supporting Information).
B. Selective Formylation. 1. Survey of Routes. Several
approaches were explored to achieve selective formylation.
Attempts to decrease the reactivity of one of the pyrrole rings
in the dipyrromethane by selective N-tosylation of the dipyrro-
methane, or preparation of an N-tosylated dipyrromethane from
N-tosylpyrrole, were unsuccessful, although an N-mesylpyrrole
was used in the rational synthesis of 1-formyldipyrrometh-
ane.9 The rational synthesis of 1-acyldipyrromethanes, which
entails acylation of the magnesium salt of the dipyrromethane
with an appropriate S-2-pyridyl thioate, works well with aryl
or alkyl substituents (eq 1).8 However, attempts to extend this
method to include 1-formylation were thwarted because we were
unable to prepare the requisite pyridyl thioformate. Thus, the
The rational synthesis of substituted porphyrins and chlorins
relies heavily on dipyrromethane building blocks (1).1,2 The
desired reactivity of dipyrromethanes is attained by the introduc-
tion of functional groups at the 1- and 9-positions. Because such
R-pyrrolic positions exhibit high reactivity toward electrophiles,
1,9-difunctionalization (acylation,1 aminomethylation,3 bromi-
nation,4 chlorination,5 and formylation6,7) of dipyrromethanes
can be done in a relatively straightforward manner. A more
challenging task is the selective synthesis of 1-substituted
dipyrromethanes, given the comparable reactivity of the 1- and
9-positions. Indeed, treatment of a dipyrromethane with an
equimolar amount of an electrophilic reagent usually results in
a statistical mixture of unreacted starting material, the desired
1-substituted product, and the 1,9-disubstituted derivative. We
previously developed a method for selective 1-acylation of
(1) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S. J. Org.
Chem. 2000, 65, 7323-7344.
(2) Taniguchi, M.; Ra, D.; Mo, G.; Balasubramanian, T.; Lindsey, J. S.
J. Org. Chem. 2001, 66, 7342-7354.
(3) Fan, D.; Taniguchi, M.; Yao, Z.; Dhanalekshmi, S.; Lindsey, J. S.
Tetrahedron 2005, 61, 10291-10302.
(8) Rao, P. D.; Littler, B. J.; Geier, G. R., III; Lindsey, J. S. J. Org.
Chem. 2000, 65, 1084-1092.
(9) Abell, A. D.; Nabbs, B. K.; Battersby, A. R. J. Org. Chem. 1998,
63, 8163-8169.
(10) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.;
Lindsey, J. S. Org. Process Res. DeV. 2003, 7, 799-812.
(11) Tamaru, S.-I.; Yu, L.; Youngblood, W. J.; Muthukumaran, K.;
Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2004, 69, 765-777.
(12) Taniguchi, M.; Balakumar, A.; Fan, D.; McDowell, B. E.; Lindsey,
J. S. J. Porphyrins Phthalocyanines 2005, 9, 554-574.
(13) Brin˜as, R. P.; Bru¨ckner, C. Tetrahedron 2002, 58, 4375-4381.
(4) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey, J. S.
J. Org. Chem. 2000, 65, 3160-3172.
(5) Rohand, T.; Baruah, M.; Qin, W.; Boens, N.; Dehaen, W. Chem.
Commun. 2006, 266-268.
(6) Bru¨ckner, C.; Posakony, J. J.; Johnson, C. K.; Boyle, R. W.; James,
B. R.; Dolphin, D. J. Porphyrins Phthalocyanines 1998, 2, 455-465.
(7) (a) Sessler, J. L.; Seidel, D.; Bucher, C.; Lynch, V. Tetrahedron 2001,
57, 3743-3752. (b) Wickramasinghe, A.; Jaquinod, L.; Nurco, D. J.; Smith,
K. M. Tetrahedron 2001, 57, 4261-4269.
10.1021/jo060119b CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/15/2006
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J. Org. Chem. 2006, 71, 4328-4331

TABLE 1. Examination of Electrophiles for Dipyrromethane
Substitution
SCHEME 1
in recovery of starting material. The reaction of the magnesium
salt of 1b with DMF at -78 °C provided unreacted starting
material (entry 4). The use of 2-cyanoethyl formate as formy-
lating agent also gave no improvement.
application of methods developed for the synthesis of thiofor-
mates14 with pyridyl-2-thiol and (1) formyl acetate or (2) formic
acid and DCC failed to give S-2-pyridyl methanethioate. On
the other hand, Fischer’s formylation of alkylpyrroles by reac-
tion of the pyrrole-Grignard reagent with ethyl formate (eq
2)15 prompted us to examine a broad selection of formylating
agents for the Grignard-mediated formylation of a dipyrro-
methane.
Upon examining the reaction mixture obtained with methyl
formate (entry 3), a significant byproduct was found to be the
1,11-diformyldipyrromethane (5). This product is dominant
when the formylating reagent is added to the magnesium salt
of the dipyrromethane at 0 °C. We found that the N-formyl
group could be smoothly and quantitatively hydrolyzed by
treatment with 2 M aqueous NaOH as illustrated in eq 3.17 Thus,
treatment of 1b with EtMgBr and methyl formate gave the crude
mixture of 2b and 5b (accompanied by several minor, unidenti-
fied byproducts), which upon treatment with 2 M aqueous NaOH
followed by column chromatography gave 2b in 28% yield.
As a first approach, we considered the selective introduction
of latent formyl synthons. Thus, reaction of ethyl chloroformate
with 2-mercaptopyridine afforded the Mukaiyama reagent
O-ethyl S-2-pyridyl carbonothioate (4) in 92% yield. Reaction
of 4 and 1b under standard conditions (treatment of 1b with 2
molar equiv of EtMgBr at room temperature and then with 4 at
-78 °C in THF) afforded 1-(ethoxycarbonyl)dipyrromethane
1b-E in 45% yield (Table 1, entry 1). However, reduction of
1b-E with DIBAL-H at -78 °C (in THF or CH2Cl2) afforded
the corresponding alcohol without any detected aldehyde.
Alternatively, treatment of 1b with EtMgBr followed by p-tosyl
cyanide16 afforded 1-cyanodipyrromethane 1b-N in 31% yield,
together with an unidentified byproduct (putative 3-cyanodipyr-
romethane). The difficulty in separating 1b-N from the byprod-
uct made this route unattractive (entry 2). Following Fischer’s
approach, reaction of 1b with EtMgBr followed by methyl
formate afforded the desired 2b in 20% yield, accompanied by
several byproducts (entry 3). Attempts to improve the yield and
purity failed: the reaction in toluene instead of THF gave
essentially the same results, whereas reaction at -78 °C for 15
min rather than 1 h, or use of 1 mol equiv of EtMgBr, resulted
Additional refinements to the formylation method entailed
use of MesMgBr rather than EtMgBr18 and phenyl formate
rather than methyl formate. Thus, the standard formylation
method entailed treatment of a solution of dipyrromethane in
THF at room temperature with 2 molar equiv of MesMgBr and
then at -78 °C with 2 molar equiv of phenyl formate. After 2
h, the reaction mixture was quenched with saturated aqueous
NH4Cl, and the crude mixture was treated with 2 M aqueous
NaOH. The 1-formyldipyrromethane was isolated using column
chromatography.
2. Scope. We applied the refined procedure with 11 dipyr-
romethanes bearing various 5-substituents (Table 2). Dipyr-
romethanes 1a-e,10 1f,19 1g,18 1h,19 1i,1 1j,20 and 1k21 were
(14) (a) Pohl, E. R.; Hupe, D. J. J. Am. Chem. Soc. 1980, 102, 2763-
2768. (b) Sprecher, M.; Nov, E. Synth. Commun. 1992, 22, 2949-2954.
(15) Fischer, H.; Siedel, W.; Le Thierry d’Ennequin, L. Liebigs Ann.
1933, 500, 137-202.
(16) Nagasaki, I.; Suzuki, Y.; Iwamoto, K.-I.; Higashino, T.; Miyashita,
A. Heterocycles 1997, 46, 443-450.
(17) Bergauer, M.; Gmeiner, P. Synthesis 2001, 2281-2288.
(18) Zaidi, S. H. H.; Loewe, R. S.; Clark, B. A.; Jacob, M. J.; Lindsey,
J. S. Org. Process Res. DeV. 2006, 10, 304-314.
(19) Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea,
D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391-1396.
J. Org. Chem, Vol. 71, No. 11, 2006 4329

TABLE 2. Scope of Grignard-Mediated 1-Formylation of
Dipyrromethanes
dipyrromethanes bearing a 5-alkyl substituent. The formylation
procedure was scaled up with 50 mmol of 1b, affording 4.5 g
of 2b (36% yield).
In summary, the two methods for 1-formylation are comple-
mentary both in conditions (acidic versus basic) and in selectiv-
ity (statistical Vilsmeier versus directed Grignard reaction). The
Grignard-mediated reaction is particularly attractive owing to
its simplicity, lack of formation of 1,9-diformyldipyrromethane,
and broad scope. The yields with nine dipyrromethanes ranged
from 28% to 65% and encompassed a variety of moieties
including alkyl, aryl, ether, dioxane, silyl ether, alkyne, iodo,
and pentafluorophenyl.
Experimental Section
General Procedure for Vilsmeier Formylation and Tin
Complexation, Exemplified for 1-Formyldipyrromethane (2a).
Following a procedure for the formylation of dipyrromethanes,6
DMF (10 mL) was treated with POCl3 (1.50 mL, 16.4 mmol) at
0 °C under argon, and the resulting solution was stirred for 10
min (Vilsmeier reagent). A solution of 1a (1.00 g, 6.84 mmol)
in DMF (23 mL) at 0 °C under argon was treated with the
freshly prepared Vilsmeier reagent (5.16 mL, 1.08 mol equiv), and
the resulting solution was allowed to stir for 1.5 h at 0 °C. Satu-
rated aqueous sodium acetate solution (76 mL) was added, and
the ice bath was removed. The mixture was then stirred for 4 h
and allowed to warm to room temperature. The mixture was
extracted with ethyl acetate. The organic extract was washed with
brine, dried (MgSO4), and filtered. The filtrate was concentrated
to afford a brown oil. Following a procedure for the dialkyltin
complexation of 1,9-diacyldipyrromethanes,11 the crude oil was
dissolved in CH2Cl2 (34 mL) and treated with TEA (2.85 mL,
20.5 mmol) and Bu2SnCl2 (2.08 g, 6.84 mmol). The mixture was
stirred for 30 min at room temperature. The solvent was re-
moved. The resulting oil was chromatographed [silica, hexanes/
ethyl acetate (9:1 to 1:1) containing 1% TEA] to afford a brown
solid (338 mg, 28% overall): mp 115-116 °C (lit.9 mp 118 °C);
1H NMR δ 4.04 (s, 2H), 6.06-6.13 (m, 1H), 6.14-6.18 (m, 2H),
6.70-6.72 (m, 1H), 6.93-6.95 (m, 1H), 8.62 (br s, 1H), 9.36 (s,
1H), 10.07 (br s, 1H); 13C NMR δ 26.9, 106.9, 108.7, 110.9, 117.9,
124.9, 127.7, 132.4, 142.5, 179.1. Anal. Calcd for C10H10N2O: C,
68.95; H, 5.79; N, 16.08. Found: C, 68.72; H, 5.77; N, 15.97.
General Procedure for the Grignard-Mediated Formylation
(Applied to 2a-i), Exemplified for 1-Formyl-5-phenyldipyr-
romethane (2b). A sample of 1b (1.11 g, 5.00 mmol) in THF (10
mL) was treated with MesMgBr (10.0 mL, 1 M in THF, 10 mmol).
After 10 min, the mixture was cooled to -78 °C. Phenyl formate
(1.09 mL, 10.0 mmol) was added in one portion. The reaction
mixture was stirred at -78 °C for 1 h. The cooling bath was
removed, and stirring was continued for 1 h. The reaction was
quenched by adding saturated aqueous NH4Cl (∼30 mL). The
resulting mixture was extracted with CH2Cl2. The organic extract
was washed (water, brine) and concentrated. The resulting oil was
dissolved in CH3CN (30 mL) and treated with 2 M aqueous NaOH
(30 mL). The resulting mixture was stirred vigorously at room
temperature for 1 h. Water (50 mL) was added, and the mixture
was extracted with CH2Cl2. The organic phase was washed
(saturated aqueous NH4Cl, water, brine), dried (Na2SO4), and
concentrated. The resulting dark oil was chromatographed [silica,
CH2Cl2 to CH2Cl2/ethyl acetate (10:1)] to afford a light brown
powder (0.457 g, 37%). The characterization data (1H NMR and
FAB-MS spectra) were consistent with those obtained for the title
compound prepared via Vilsmeier formylation (see the Supporting
Information).
a Product was observed but not isolated (see text).
prepared as described in the literature. In each application of
the formylation procedure, no 1,9-diformyldipyrromethane was
detected. The formylation method gave yields of 28-65% with
only two failures: (1) 5-(4-Nitrophenyl)dipyrromethane (1f)
gave a dark, tarry mixture upon addition of MesMgBr, and the
desired 1-formyldipyrromethane was not obtained upon treat-
ment with phenyl formate. (2) 5-(4-Methoxycarbonylphenyl)-
dipyrromethane (1g) afforded the desired monoformyl product
together with the corresponding 1,11-diformyldipyrromethane
(as determined by 1H NMR analysis of the crude reaction
mixture), but attempts to hydrolyze the crude mixture gave
multiple products, probably owing to ester hydrolysis. The yields
were ∼30% for dipyrromethanes bearing a 5-aryl or 5-H
substituent, whereas yields of ∼60% were obtained for the two
(20) Borbas, K. E.; Mroz, P.; Hamblin, M. R.; Lindsey, J. S. Bioconjugate
Chem. 2006, 17, in press.
(21) Balakumar, A.; Muthukumaran, K.; Lindsey, J. S. J. Org. Chem.
2004, 69, 5112-5115.
Grignard-Mediated Synthesis (50 mmol Scale) of 1-Formyl-
5-phenyldipyrromethane (2b). A sample of 1b (11.1 g, 50.0
mmol) in THF (100 mL) in a 500 mL round-bottomed flask was
4330 J. Org. Chem., Vol. 71, No. 11, 2006

treated with MesMgBr (100 mL, 100 mmol, 1 M in THF).
After 10 min, the mixture was cooled to -78 °C. Phenyl for-
mate (10.9 mL, 100 mmol) was added in one portion. The reac-
tion mixture was stirred at -78 °C for 1 h. The cooling bath was
removed, and stirring was continued for 1 h. The reaction was
quenched by adding saturated aqueous NH4Cl (∼200 mL). The
resulting mixture was extracted with CH2Cl2. The organic extract
was washed (water, brine) and concentrated. The resulting oil was
dissolved in CH3CN (150 mL) and treated with 2 M aqueous NaOH
(150 mL). The resulting mixture was stirred vigorously at room
temperature for 1 h. Water (∼200 mL) was added, and the mixture
was extracted with CH2Cl2. The organic phase was washed
(saturated aqueous NH4Cl, water, brine), dried (Na2SO4), and
concentrated. The resulting dark oil was chromatographed [silica,
7 × 26 cm, total 440 g, CH2Cl2 to CH2Cl2/ethyl acetate (10:1),
total volume ∼6 L] to afford a gray-yellow powder (4.55 g, 36%).
The characterization data (1H NMR spectrum and elemental
analysis) were consistent with those obtained for the title compound
prepared via Vilsmeier formylation (see the Supporting Informa-
tion).
Acknowledgment. This research was supported by the NIH
(GM-36238). Mass spectra were obtained at the Mass Spec-
trometry Laboratory for Biotechnology at North Carolina State
University. Partial funding for the facility was obtained from
the North Carolina Biotechnology Center and the National
Science Foundation.
Supporting Information Available: Complete Experimental
Section including procedures for the synthesis of all new com-
pounds; NMR spectra for selected compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060119B
J. Org. Chem, Vol. 71, No. 11, 2006 4331