Facile synthesis of unsubstituted β,β′-linked diformyldipyrromethanes

Article abstract of DOI:10.1021/jo802114h

(Chemical Equation Presented) Unsubstituted β,β′-linked diformyldipyrromethanes are promising precursors for the synthesis of novel poly dipyrromethene ligands and N-confused porphyrins. A strategy has been developed to selectively synthesize unsubstituted β,β′-linked diformyldipyrromethanes in moderate yields starting from 2-formylpyrrole.

Full text of DOI:10.1021/jo802114h

Facile Synthesis of Unsubstituted ꢀ,ꢀ′-Linked
Diformyldipyrromethanes
Zhan Zhang, Ji-Young Shin, and David Dolphin*
FIGURE 1. Unsubstituted ꢀ,ꢀ′-linked diformyldipyrromethane 3 and
Department of Chemistry, UniVersity of British Columbia,
2036 Main Mall, VancouVer, British Columbia,
V6T 1Z1, Canada
its configurational isomers.
investigated methods of selectively preparing unsubstituted ꢀ,ꢀ′-
linked diformyldipyrromethanes.
daVid.dolphin@ubc.ca
To direct a linker to the ꢀ position, ꢀ,ꢀ′-linked dipyr-
romethanes are normally prepared using R-blocked pyrroles as
starting materials.6 However, R-substituted dipyrromethanes are
usually not suitable for NCP synthesis because the crowding
caused by substituents discourages formation of conjugated
macrocycles.7 Since removing R-substituents can present a
significant challenge, this route is limited to the synthesis of
unsubstituted ꢀ,ꢀ′-linked dipyrromethanes. The isolation of ꢀ,ꢀ′-
linked meso-substituted dipyrromethanes was reported by Sessler
and his colleagues,8 but these compounds only occur as minor
byproduct in the condensation reactions of aldehyde and pyrrole.
As a result, efficient synthetic pathways to unsubstituted ꢀ,ꢀ′-
linked dipyrromethanes and related derivatives have not been
well developed.
To circumvent both the pitfalls of R-blocked starting materials
and the reactive R-position, we chose a strategy of reducing
the reactivity of the R-position, which eventually led us to using
protected 2-formylpyrrole as a precursor. 1-(Pyrrol-2-ylmeth-
ylene) pyrrolidinium perchlorate 5,9 an iminium salt of
2-formylpyrrole 4, was an attractive candidate. It was previously
used to prepare ꢀ-halogenated compounds10 and the positively
charged R-group exhibited an exclusively ꢀ-directing effect in
halogenation reactions. Furthermore, using 5 as substrate also
has advantages such as quantitative conversion from com-
mercially available 4, protection of the reactive formyl group,
and facile regeneration of the formyl group.10
ReceiVed September 23, 2008
Unsubstituted ꢀ,ꢀ′-linked diformyldipyrromethanes are prom-
ising precursors for the synthesis of novel poly dipyr-
romethene ligands and N-confused porphyrins. A strategy
has been developed to selectively synthesize unsubstituted
ꢀ,ꢀ′-linked diformyldipyrromethanes in moderate yields
starting from 2-formylpyrrole.
It is well-known in pyrrole chemistry that the R position
dominates in most electrophilic reactions. As a result, the
synthesis of R,R′-linked species such as dipyrromethanes1 is
rather facile, while selectively setting up a linker at a ꢀ position
has remained a synthetic challenge. Exploration into the
synthesis of novel ꢀ,ꢀ′-linked synthons increases the structural
variety and thus the number of applications in porphyrin and
other chemistries. For example, unsubstituted ꢀ,ꢀ′-linked di-
formyldipyrromethanes are precursors of interesting R-free
bis(dipyrromethene) ligands2 for supra-molecular chemistry.3
They are also potential precursors of N-confused porphyrins
(NCPs)4 (Figure 1), which have attracted increasing attention
due to their unique properties.5 For these reasons, we have
The ꢀ,ꢀ′-linked diformyldipyrromethane 3 was initially
synthesized from iminium salt 5 and dimethoxymethane at room
temperature following a modified procedure for acid-catalyzed
condensation of aldehyde and pyrrole1a (Scheme 1). After
column chromatography, ꢀ,ꢀ′-linked 3 was obtained as a white
powder with a 25% yield, while 50-60% of 2-formylpyrrole
was recovered. Although the yield was not high, this reaction
was highly regioselective with no undesired R,R′-linked or R,ꢀ′-
linked products being produced.
(1) (a) Lee, C.-H.; Lindsey, J. S. Tetrahedron 1994, 50, 11427–11440. (b)
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. (c) Laha, J. K.;
Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey, J. S. Org. Process
Res. DeV. 2003, 7, 799–812. (d) Paine, J. B., III. In The Porphyrins; Dolphin,
D., Ed.; Academic Press: New York, 1978; Vol 1, pp 182-190.
(2) Zhang, Z.; Shin, J.-Y.; Dolphin, D. Presented in part at the 236th ACS
National Meeting, Philadelphia, PA, August 17-21, 2008: Abstracts of Papers;
American Chemical Society; INOR#208.
The ꢀ,ꢀ′-linked structure of compound 3 was characterized
by 1H NMR spectroscopy. Both the chemical shifts and coupling
pattern of 3 exhibited characteristics distinct from authentic R,R′-
(3) (a) Zhang, Y.; Thompson, A.; Rettig, S. J.; Dolphin, D. J. Am. Chem.
Soc. 1998, 120, 13537–13538. (b) Thompson, A.; Dolphin, D. J. Org. Chem.
2000, 65, 7870–7877. (c) Zhang, Y.; Wang, Z.; Yan, C.; Li, G.; Ma, J.
Tetrahedron Lett. 2000, 41, 7717–7721. (d) Chen, Q.; Dolphin, D. Can. J. Chem.
2002, 80, 1668–1675. (e) Chen, Q.; Zhang, Y.; Dolphin, D. Tetrahedron Lett.
2002, 43, 8413–8416.
(4) (a) Chmielewski, P. J.; Latos-Grau¨yn˜ski, L.; Rachlewicz, K.; Glowiak,
T. Angew. Chem., Int. Ed. Engl. 1994, 33, 779–781. (b) Furuta, H.; Asano, T.;
Ogawa, T. J. Am. Chem. Soc. 1994, 116, 767–768. (c) Furuta, H.; Maeda, H.;
Osuka, A. J. Org. Chem. 2001, 66, 8563–8572.
(6) (a) Paine, J. B., III; Dolphin, D. Can. J. Chem. 1978, 56, 1710–1712. (b)
Pandey, R. K.; Leung, S. H.; Forsyth, T. P.; Smith, K. M. Tetrahedron Lett.
1994, 35, 8995–8998.
(7) (a) Schumacher, H.-K.; Frank, B. Angew. Chem., Int. Ed. Engl. 1989,
28, 1243–1245. (b) Chen, Q.; Dolphin, D. Can. J. Chem. 2003, 81, 988–991.
(8) Dolensky´, B.; Kroul´ık, J.; Kra´l, V.; Sessler, J. L.; Dvoøa´kova´, H.; Bouø,
P.; Berna´tkova´, M.; Bucher, C.; Lynch, V. J. Am. Chem. Soc. 2004, 126, 13714–
13722.
(9) Perchlorates are known as oxidizers and explosives. Although the authors
found 5 is safe under the reaction conditions, safety precautions are necessary.
(10) (a) Sonnet, P. E. J. Org. Chem. 1971, 36, 1005–1007. (b) Mitsui, T.;
Kimoto, M.; Sato, A.; Yokoyama, S.; Hirao, I. Bioorg. Med. Chem. Lett. 2003,
13, 4515–4518.
(5) (a) Harvey, J. D.; Ziegler, C. J. Coord. Chem. ReV. 2003, 247, 1–19. (b)
Ghosh, A. Angew. Chem., Int. Ed. 2004, 43, 1918–1931. (c) Maeda, H.; Furuta,
H. Pure Appl. Chem. 2006, 78, 29–44.
10.1021/jo802114h CCC: $40.75
Published on Web 11/11/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9515–9517 9515

SCHEME 1. Synthesis of ꢀ,ꢀ′-Linked Diformyldipyrro-
methane 3
linked 1.11 In d6-DMSO, two broad singlets (7.04 and 6.82 ppm)
were observed for 3 in the aromatic region (Figure 2) and thus
the linker must be located at the ꢀ positions.12 To confirm its
structure, a single crystal of 3 was grown by vapor diffusion of
hexane into a THF solution. X-ray diffraction analysis confirmed
a ꢀ,ꢀ′-linked structure as expected.13
FIGURE 2. 1H NMR spectra of (a) 3 and (b) 1 in d6-DMSO.
TABLE 1. Acid-Catalyzed Condensations of Acetals and Iminium
Salt 5
To optimize the formation of 3, reaction conditions such as
acid catalysts, reaction temperature and solvents were surveyed.
It was found that other Lewis acids including tin(IV) chloride,
titanium(IV) chloride, indium(III) chloride and ytterbium(III)
triflate were not able to facilitate the formation of 3; aluminum
chloride did catalyze the reaction, to produce 3, but in much
lower yield (<2%). Brønsted acids such as trifluoroacetic acid,
methanesulfonic acid, p-toluenesulfonic acid and sulfuric acid
could not replace BF3 ·OEt2. Increasing the reaction temperature
from 25 to 80 °C increased the yield of ꢀ,ꢀ′-linked product
(3). Unfortunately, undesired R,R′-linked or R,ꢀ′-linked side-
products (1 or 2) were observed when the temperature was
higher than 65 °C. The reactions could be carried out in either
methylene chloride, chloroform or acetonitrile, but solubility
was better in acetonitrile, which was deemed the preferred
solvent. Acetone, however, is to be avoided for the reaction
since it was found that 5 reacted with acetone to form a new
species 6,14 similar to a reaction reported by Johnson and his
colleagues15 using dipyrromethenes. Under the optimal condi-
tions for the reaction, 3 could be obtained in a 30% yield and
over 60% of 4 was recovered. Attempts to increase the yields
by using microwave irradiation or other protecting groups were
also made. Unfortunately, microwave irradiation didn’t improve
the yields and less electron-withdrawing protecting groups such
as cyanovinyl always led to the formation of R,R′-linked
products. The advantage of the iminium group is its strong
electron-withdrawing character which results in the high regi-
oselectivity but also accounts for the low reactivity.
entry
R
T (°C)
time (h)
product
yield (%)
1
2
3
4
5
6
7
8
Ph5
C6F5
60
60
60
60
60
60
60
60
60
60
60
20
10
10
10
48
10
10
10
10
10
10
10
10
7
8
9
45.7
40.8
37.6
16.9
68.1
55.1
39.1
34.9
35.3
25.0
29.7
25.0
4-MeOPh
2,4,6-Me3Ph
4-(NO2)Ph
4-(MeCO2)Ph
4-ClPh
4-MePh
2,6-Cl2Ph
Me
10
11
12
13
14
15
16
3
9a
10
11
12
H
H
3
a Acetonitrile was used as solvent except for entry 9 where chlo-
roform was used.
were relatively more productive than those with electron-
donating group(s).
(2) Ketals were unreactive with 5 under the same conditions.
(3) The formation of 10 was retarded and the yield was low
probably due to steric hindrance (entry 4 in Table 1).
(4) Preparation of 15 should not be performed in acetonitrile.
For some unknown reason, the expected product was not
obtained in acetonitrile while a good yield was achieved in
chloroform (entry 9 in Table 1).
The mechanism of Lewis-acid-promoted nucleophilic sub-
stitution reactions of acetals can be either SN1 or SN2 depending
on reaction conditions and substrates.17 The reactions discussed
here were performed in polar solvents and thus likely occurred
via an SN1 mechanism.18 The high reactivities of acetals over
corresponding aldehydes are in accordance with the studies made
by Mayr et al.19
This method for the synthesis of unsubstituted ꢀ,ꢀ′-linked
diformyldipyrromethanes is applicable to a wide range of aryl
acetals and aliphatic acetals (Table 1). Several interesting
phenomena were observed in the experiments:
(1) The relative reactivities of reactants toward 5 followed
the sequence: aromatic acetals > aliphatic acetals . aldehydes.16
Additionally, aromatic acetals with electron-withdrawing group(s)
(11) Taniguchi, M.; Balakumar, A.; Fan, D.; McDowell, B. E.; Lindsey, J. S.
J. Porphyrins Phthalocyanines 2005, 9, 554–574.
(12) Interestingly, split peaks were observed for 3 in d3-acetonitrile which
might be attributed to intramolecular hydrogen bonding; nevertheless, the
chemical shifts still showed an obvious difference from those of authentic 1.
Peak-assignments for R and ꢀ-Hs were based on the HH COSY NMR data. See
Figure S30 in the Suppporting Information.
(13) See the Supporting Information.
(14) The structure of 6 was confirmed by X-ray crystallography. See the
Supporting Information.
(17) (a) Denmark, S. E.; Willson, T. M. In SelectiVities in Lewis Acid
Promoted Reactions; Schinzer, D., Ed.; Kluwer Academic Publishers: Dordrecht,
1989; pp 247-263. (b) Santelli, M.; Pons, J.-M. Lewis Acids and SelectiVity in
Organic Synthesis; CRC Press: Boca Raton, FL, 1996; pp 185-230.
(18) (a) Denmark, S. E.; Willson, T. M. J. Am. Chem. Soc. 1989, 111, 3475–
3476. (b) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.; Yamamoto, H.;
Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 6107–6115.
(19) (a) von der Bru¨ggen, U.; Lammers, R.; Mayr, H. J. Org. Chem. 1988,
53, 2920–2925. (b) Mayr, H.; Gorath, G. J. Am. Chem. Soc. 1995, 117, 7862–
7868.
(15) Bamfield, P.; Johnson, A. W.; Leng, J. J. Chem. Soc. 1965, 7001–7005.
(16) Aldehydes give less than 10% yields of products.
9516 J. Org. Chem. Vol. 73, No. 23, 2008

2-carboxaldehyde 4 was recovered. Further elution with ethyl
acetate/methylene chloride (1:4 v:v) provided 3 as white crystals:
In conclusion, we have established an efficient method of
preparing novel unsubstituted ꢀ,ꢀ′-linked diformyldipyrro-
methanes. Although the yields are not outstanding, considering
the high selectivity, recoverability of unconverted reactants and
the fact that there is no other known method to make such
compounds, this method represents a promising route to the
preparation of various synthons for N-confused porphyrins and
novel polydipyrromethene ligands. Studies on the application
to porphyrin and supramolecular chemistry are currently
underway.
1
mp 153-154 °C; H NMR (300 MHz, d6-DMSO) δ 11.87 (br s,
2H, NH), 9.39 (s, 2H, CHO), 7.04 (s, 2H, ꢀ-H), 6.82 (s, 2H, R-H),
1
3.62 (s, 2H, meso-CH2); H NMR (300 MHz, CD3CN) δ 9.93 (br
s, 2H, NH), 9.42 (d, J ) 0.7 Hz, 2H, CHO), 6.97 (m, 2H, ꢀ-H),
6.82 (m, 2H, R-H), 3.69 (s, 2H, meso-CH2); 13C NMR (75 MHz,
d6-DMSO) δ 178.9, 132.6, 125.7, 125.3, 119.9, 23.5. MS (EI) m/z
202 (M+). Elemental Anal. calcd for C11H10N2O2: C, 65.34; H, 4.98;
N, 13.85. Found: C, 65.53; H, 5.15; N, 14.00.
Acknowledgment. This work was supported by the Natural
Sciences and Engineering Research Council (NSERC) of
Canada. We thank the NMR and mass spectroscopy laboratories
of the Department of Chemistry at UBC. We also thank Dr.
Brian O. Patrick in the X-ray crystallography laboratory of the
Department of Chemistry at UBC.
Experimental Section
General Procedure for Synthesis of ꢀ,ꢀ′-Linked Diformyl-
Dipyrromethanes: Synthesis of 4,4′-Methylenebis(1H-pyrrole-
2-carbaldehyde) (3). A solution of 5 (2.48 g, 10 mmol) and
dimethoxymethane (5 mmol) in anhydrous acetonitrile (50 mL) was
treated with boron trifluoride diethyl etherate (1 mL, 1.2 equiv)
and heated at 60 °C for 10 h. The reaction was quenched with
aqueous NaHCO3 and the solution was extracted with ethyl acetate
(2 × 100 mL). After drying over anhydrous Na2SO4 and evapora-
tion, the reaction mixture was separated by column chromatography
on silica gel. Using CH2Cl2 initially as eluent, unreacted pyrrole-
Supporting Information Available: Experimental proce-
dures, spectroscopic data, and data for the X-ray diffraction
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO802114H
J. Org. Chem. Vol. 73, No. 23, 2008 9517