Synthesis of dipyrrins bearing chirality adjacent to the conjugated skeleton - Electron-poor pyrroles exhibit dramatically reduced nucleophilicity

Article abstract of DOI:10.1139/V08-101

With the aim of furthering our investigations into the asymmetric complexation of dipyrrinato ligands, a dipyrrin bearing a stereogenic centre directly adjacent to the conjugated skeleton was synthesized. The electronwithdrawing nature of the chiral 4-(2,2,2-trifluoro-1-hydroxyethyl)- substituent significantly reduced the nucleophilicity of corresponding pyrroles, such that 2,2′-symmetrically substituted bis(dipyrrin)s bearing this motif were inaccessible. Furthermore, solutions of mononuclear dipyrrinato complexes were found to be less stable to acid-catalyzed decomplexation than the corresponding dinuclear complexes.

Full text of DOI:10.1139/V08-101

951
Synthesis of dipyrrins bearing chirality adjacent to
the conjugated skeleton — Electron-poor pyrroles
exhibit dramatically reduced nucleophilicity
Cory S. Beshara, Beth M. Pearce, and Alison Thompson
Abstract: With the aim of furthering our investigations into the asymmetric complexation of dipyrrinato ligands, a
dipyrrin bearing a stereogenic centre directly adjacent to the conjugated skeleton was synthesized. The electron-
withdrawing nature of the chiral 4-(2,2,2-trifluoro-1-hydroxyethyl)- substituent significantly reduced the nucleophilicity
of corresponding pyrroles, such that 2,2′-symmetrically substituted bis(dipyrrin)s bearing this motif were inaccessible.
Furthermore, solutions of mononuclear dipyrrinato complexes were found to be less stable to acid-catalyzed
decomplexation than the corresponding dinuclear complexes.
Key words: dipyrrin, dipyrromethene, complexation, electron-poor pyrrole, chirality.
Résumé : Dans le cadre de nos travaux sur la complexation asymétrique des ligands dipyrrinato, on a effectué la
synthèse d’une dipyrrine portant un centre stéréogène directement adjacent du squelette conjugué. La nature électro-
affinitaire du substituant chiral 4-(2,2,2-trifluoro-1-hydroxyéthyle) réduit d’une façon significative le caractère nucléo-
phile des pyrroles correspondants et, en conséquence, des bis(dipyrrines) substituées d’une façon symétrique dans les
positions 2 et 2′ et portant ce motif ne sont pas accessibles. De plus, on a observé que les solutions de complexes
dipyrrinato mononucléaires sont moins stables vis-à-vis les décomplexations catalysées par les acides que les complexes
binucléaires correspondants.
Mots-clés : dipyrrine, complexation, pyrrole déficient en électron, chiralité.
[Traduit par la Rédaction] Beshara et al. 957
Introduction
theses of dinuclear bis(dipyrrinato) helicates, the chiral aux-
iliary is attached through a pendent ester or amide linkage
and thus the chiral centre itself is quite remote from the heli-
cal axis.
The asymmetric synthesis of dipyrrinato complexes is a
field of current interest because dipyrrins (1) give mono-
anionic, planar, bidentate ligands that complex to a wide
variety of metal ions. For example, chiral fluorescent boron-
dipyrrinato (BODIPY) (2) complexes have been synthesized
through the use of chiral dipyrrins (3–5), and chiral metal-
organic frameworks incorporating dipyrrinato ligands are
also known (6). 2,2′-Bis(dipyrrin)s (Fig. 1) with methylene,
ethylene, or propylene linkers joining the dipyrrinato units
generate dinuclear (M2L2) double helicates with tetrahed-
rally coordinated metal ions, and mononuclear (ML)
helicates are formed if the alkyl linker is four atoms or more
in length (7). The incorporation of chiral auxiliaries within
the ligand allows the diastereoselective synthesis of
helicates. Indeed, excellent diastereoselectivity has been ob-
tained in the synthesis of mononuclear bis(dipyrrinato)
helicates bearing templating BINOL and tartrate moieties
attached via ethanoate groups within the linker (8). How-
ever, the most successful asymmetric synthesis of dinuclear
bis(dipyrrinato) helicates to date gives a diastereomeric ratio
of only 69:31 (9–11). In all reported diastereoselective syn-
Cognizant that the degree of stereoselectivity depends
upon the effectiveness of the chiral auxiliary in inducing
asymmetric complexation and thus the distance between the
site of the auxiliary and the helical axis, we explored the
value of incorporating a chiral centre directly adjacent to the
dipyrrin; such a motif is somewhat rare for pyrroles (12–17)
and extremely rare for dipyrrins (16, 18, 19). β-Keto pyrroles
are readily available through Knorr-type syntheses (20, 21)
and asymmetric reduction would generate a chiral alcohol.
Further derivitization would serve to incorporate the pyrrole
into a dipyrrin and thus place a chiral centre directly adja-
cent to the dipyrrinato unit (Fig. 2). Previous studies involv-
ing haematoporphyrin have shown that such hydroxyl groups
are labile under mildly acidic conditions thus introducing the
possibility of racemization through reversible elimination
and addition. The lability is caused by the electron-rich na-
ture of the pyrrole ring facilitating racemization at the
pseudobenzylic position. Kumadaki provided a viable solu-
tion to potential racemization of this nature through the use
Received 3 March 2008. Accepted 17 May 2008. Published on the NRC Research Press Web site at canjchem.nrc.ca on 15 August
2008.
C.S. Beshara, B.M. Pearce, and A. Thompson.1 Department of Chemistry, Dalhousie University, Halifax, NS B3H 4J3, Canada.
1Corrresponding author (e-mail: alison.thompson@dal.ca).
Can. J. Chem. 86: 951–957 (2008)
doi:10.1139/V08-101
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Can. J. Chem. Vol. 86, 2008
Fig. 1. Complexation of bis(dipyrrin)s with varying linker length.
Scheme 1. Synthesis of 5.
Scheme 2. Synthesis of boron-dipyrrinato complex 6.
Fig. 2. Retrosynthetic incorporation of chirality adjacent to
dipyrrin core.
tions (16, 18, 19), but we were concerned that the MacDon-
ald-type coupling conditions (48% HBr, MeOH–THF) (1)
might have afforded some racemization as exposure of
enantiopure S-3 to the same conditions resulted in loss of
stereochemical integrity with the recovered material having
only 76:24 er. To investigate its stereochemical purity a
sample of the dipyrrin prepared from enantiopure S-3 was
converted into the corresponding BODIPY complex 6 (2)
(Scheme 2). Because boron-dipyrrinato complexes are
achiral at boron and amenable to chromatography, the
enantiopurity of 6, established by chiral HPLC, would reveal
the enantiopurity of S-5 by correlation.
of 4-(2,2,2-trifluoro-1-hydroxyethyl)-substituted pyrroles
(18, 19) in the construction of homochiral haemato-
porphyrins (16). We herein report our work with 4-(2,2,2-
trifluoro-1-hydroxyethyl)-substituted dipyrrins. Our goals
included the investigation of: the syntheses of dipyrrins and
2,2′-bis(dipyrrin)s
incorporating
4-(2,2,2-trifluoro-1-
HPLC-analysis (Fig. S1) was used to determine that S-6,
synthesized using S-3, had retained its enantiopurity during
the MacDonald-type coupling step.2 Thus, with a source of
enantiopure S-5 in hand, and having secured both the syn-
thesis and the stereochemical stability of dipyrrins bearing
the 4-(2,2,2-trifluoro-1-hydroxyethyl)-group, we progressed
to investigating the stability of the corresponding complexes
and assessing the influence of the electron-withdrawing
substituent, essential for the stability of the chiral centre
upon complexation. Racemic 5 was treated with zinc acetate
under standard conditions (10) to give the homoleptic zinc
complex 7 in 64% yield. The efficiency of complexation was
then improved through the use of zinc perchlorate instead of
the acetate salt and lithium hydroxide as base; complexation
using enantiopure S-5 was conducted in the same manner
(Scheme 3). Although the zinc complex (7) was noticeably
less stable under mildly acidic conditions (silica gel, aque-
ous extractions, wet solvents) than dipyrrinato complexes
not bearing electron-withdrawing groups, isolation of 7 in
good yield was achieved by rapid precipitation from the
methanolic reaction mixture upon the addition of water.
Mass spectrometry confirmed the formation of a mono-
nuclear ML2 complex.
hydroxyethyl)-substituents; the stereochemical stability of
4-(2,2,2-trifluoro-1-hydroxyethyl)-substituted dipyrrins; the
ability of 4-(2,2,2-trifluoro-1-hydroxyethyl)-substituted di-
pyrrinato units to undergo complexation; and the potential of
the 4-(2,2,2-trifluoro-1-hydroxyethyl) group to influence
diastereoselective complexation, either as an alcohol or as
bulkier ether or ester derivatives.
Results and discussion
Synthesis of the first dipyrrin bearing a 4-(2,2,2-trifluoro-
1-hydroxyethyl)-substitutent was achieved according to
Scheme 1. Benzyl 3,5-dimethyl-pyrrole-2-carboxylate (1)
(22) was converted to the corresponding trifluoroacetoxy-
substituted pyrrole 2 using triflouroacetic acid (TFAA) under
acidic conditions (23). Reduction of 2 with borane gave
racemic alcohol 3, and the use of the CBS protocol gave S-3
with 99:1 enantiomeric ratio (er), akin to that reported by
Kumadaki and co-workers (16). Hydrogenolysis of the
benzyl ester, followed by thermolytic decarboxylation, gave
the corresponding α-free pyrrole that was reacted directly
with 4-ethyl-2-formyl-3,5-dimethylpyrrole (4) (24) under
MacDonald-type coupling conditions (1) to afford the requi-
site racemic dipyrrin 5, and the single enantiomer S-5.
The literature supports the stereochemical stability of the
2,2,2-trifluoro-1-hydroxyethyl moiety under acidic condi-
Efforts turned to the investigation of the stereochemical
outcome of the complexation reactions to determine whether
5 had undergone complexation with simple diastereo-
2 Supplementary data for this article are available on the journal Web site (canjchem.nrc.ca) or may be purchased from the Depository of Un-
published Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 3784. For more in-
formation on obtaining material refer to cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml.
© 2008 NRC Canada

Beshara et al.
953
Scheme 3. Complexation of 5 and possible stereochemical out-
Fig. 3. Mononuclear complex 8 and dinuclear complex 9.
comes.
nuclear and dinuclear analogues has not appeared. Using ab-
sorption spectroscopy, solutions of mononuclear 7, bearing the
4-(2,2,2-trifluoro-1-hydroxyethyl)- substituent, were compared
with solutions of the peralkyl mononuclear complex 8 (28) and
the peralkyl dinuclear complex 9 (29) (Fig. 3). Studies at a va-
riety of concentrations in technical-grade CH2Cl2 indicated that
solutions of mononuclear complexes 7 and 8 are less stable to
acid-catalyzed decomplexation than the dinuclear complex 9;
spectrophotometric-grade CH2Cl2 did not cause any
decomplexation. These studies are important as dipyrrinato
complexes are typically exposed to a range of solvents (includ-
ing water) during work-up, purification, and analysis. As men-
tioned previously, the electron-deficient nature of 7 was a
concern in terms of complex stability, and thus discovering that
dinuclear dipyrrinato complexes are more stable than their
mononuclear analogues suggested that the 4-(2,2,2-trifluoro-1-
hydroxyethyl)- substituent might be more appropriate for use in
bis(dipyrrinato) ligands. Furthermore, although S-5 is unsym-
metrical and thus gives an A–B dipyrrinato ligand that gener-
ates tetrahedrally coordinated Zn(II) helicates, formally the
helicity is a consequence only of the two differently substituted
pyrrolic units, that is, 4-ethyl versus 4-(2,2,2-trifluoro-1-
hydroxyethyl).
To increase the degree of asymmetry within the ligands, to
thus improve both the stereoselectivity of complexation and
the resolution by chiral HPLC, and to study the more stable
dinuclear dipyrrinato complexes, we turned to the prepara-
tion of a bis(dipyrrin) bearing the chiral 4-(2,2,2-trifluoro-1-
hydroxyethyl)- substituent directly adjacent to the conju-
gated skeleton. Retrosynthetic analysis (Fig. 4) of the sym-
metrical bis(dipyrrin) 10 reveals that the 2,2′-dipyrroles 11
and 12 are essential intermediates in the synthetic sequence,
with successful condensation of 11 with 4 giving the re-
quired bis(dipyrrin). Three routes to 12 were envisaged, and
each was investigated.
Trifluoroacylation of 13 (30), followed by reduction of the
two trifluoromethyl ketones, was thought to be the most di-
rect route to 12. Unfortunately treatment of 13 with TFA and
TFAA, under the conditions that had been successful for the
synthesis of 2, did not produce the required material and in-
stead gave, tentatively, the pyrrolo-[3,2-f]-indole 18 where
presumably mono-trifluoracylation had been followed by
acid-catalyzed intramolecular condensation (Scheme 4) (31–
33). Since indolic 18 does not feature the required prochiral
signature, we sought an alternative route for the synthesis of
12.
We thus investigated the synthesis of 12 through the
homocoupling of 14 (34), itself prepared by mono-oxidation
of 15 (16) using Pb(OAc)4 (Scheme 5). Homocouplings of
this type, using 2-methylene pyrroles, are commonplace for
the synthesis of symmetrical dipyrromethanes and involve
selectivity. Previously, NMR and circular dichroism (CD)
spectroscopy, alongside chiral HPLC analysis, have been ex-
tremely useful for the evaluation of diastereoselective reac-
tions involving dipyrrinato ligands. The neutral complexes
are amenable to chromatography, and the helical nature of
the chromophoric dipyrrinato units fixed in space through
coordination to metal ions renders CD data very useful. As 5
constitutes an unsymmetrical A–B ligand architecture, the
tetrahedrally coordinated metal ion in 7 gives rise to helicity.
Thus, the complexation of racemic 5 allows for the possible
production of eight (23 = 8) stereoisomers; R and S for the
stereocentres on the ligands, and M and P for the metal
centre (Scheme 3). Two species in each enantiomeric set
(R,S,P – S,R,P and R,S,M – S,R,M) are identical, simplifying
the possible outcomes to three (racemic) stereoisomers, with
a 1:2:1 statistical ratio.
HPLC analysis of the crude product mixture obtained us-
ing racemic 5 showed one signal due to dipyrrinato com-
plex(es) and two minor non-dipyrrinato impurities. The
ChiralPak®-IA column used herein had previously proven to
be superior for the resolution of dipyrrinato complexes and
attempts to resolve the signals of 7 with other columns were
1
unsuccessful. The H NMR spectrum for the same product
mixture was not useful for assigning stereoisomers but the
13C nucleus allowed for improved resolution. The stereo-
genic carbon atom bearing the trifluoromethyl group nor-
mally appears as a quartet in the 13C NMR spectrum with
JCF ≈ 33 Hz. Indeed, 5 exhibits a quartet with JCF = 32 Hz at
a chemical shift of 65.8 ppm for this carbon atom. For the
product mixture, the stereogenic carbon atom gave signals in
the 64 ppm range that appeared as a pair of quartets of equal
intensity (JCF = 33 Hz), indicative either of a mixture of iso-
mers or of two non-equivalent dipyrrinato units within a sin-
gle ML2 complex. Preparative HPLC served to separate the
dipyrrinato complex(es) from the impurities, and 13C NMR
spectra of the isolated material retained the characteristic 1:1
pair of quartets. We identified that decomposition did not oc-
cur during HPLC, because NMR spectra of the initial prod-
uct mixture and the material after preparative HPLC (and
recombination of all fractions) were identical. Complex S-7
was prepared from S-5 (Scheme 3). With enantiopure ligand,
the product mixture was found to exhibit identical HPLC
and NMR characteristics to 7 (prepared from racemic
dipyrrin 5), thus suggesting that the chiral HPLC column
was unable to resolve isomers of 7.
Although the coordination abilities of dipyrrin ligands have
been reported previously (25–27), a comparison of mono-
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Can. J. Chem. Vol. 86, 2008
Fig. 4. Retrosynthetic analysis of bis(dipyrrin) 10.
Scheme 4. Synthesis of 18.
Scheme 5. Synthesis and attempted homocoupling of 14.
initial ring-protonation followed by the loss of an equivalent
of formaldehyde to give in situ 5-unsubstituted pyrroles that
then produce dipyrromethanes through condensation with re-
maining starting material (21, 35). However, treatment of 14
with HCl served only to effect substitution to give 19 and
milder conditions (Montmorillonite K-10 clay (36)) gave no
reaction at all. Presumably electron-poor 14 is resilient to
ring-protonation and thus substitution dominates (12) under
forcing conditions, preventing the typical nucleophilic chem-
istry of pyrroles from occurring; the presence of the elec-
tron-withdrawing ester and 2,2,2-trifluoro-1-acetoxyethyl
substituents serves to inhibit the traditional nucleophilicity
of the pyrrolic unit such that dipyrrins cannot be accessed
using these intermediates.
Scheme 6. Synthesis and attempted coupling of 16.
Our final attempts to synthesize 12 required the condensa-
tion of a 5-unsubstituted pyrrole with 14, in effect pre-
preparing the same intermediate that was not formed in situ
within the previous strategy; this strategy is often imple-
mented for the synthesis of unsymmetrical dipyrromethanes
(1). Thus, 16 was prepared via iodinative decarboxylation of
17 (16) followed by dehalogenation of the resulting
iodopyrrole (Scheme 6). Attempted reaction of 16 with 14
met with failure and only starting materials were recovered.
Once again, the classic nucleophilicity of pyrroles was ab-
sent for these electron-deficient pyrroles bearing both ester
and (2,2,2-trifluoro-1-acetoxyethyl) substituents. In an at-
tempt to reduce the electron-withdrawing nature of the 4-
substituent in pyrrole 20, the O-acyl protecting group was
omitted from the synthesis and the free alcohol was exposed
to the decarboxylation conditions. Unfortunately, these
conditions resulted only in decomposition and the de-
carboxylated product could not be isolated.
poor reactivity of pyrroles substituted with the 4-(2,2,2-
trifluoro-1-hydroxyethyl)- substituent have prevented our
synthesis of a bis(dipyrrin) bearing this chiral moiety adja-
cent to the conjugated skeleton. The conflicting require-
ments of (i) electron-withdrawing groups to stabilize the
stereocentre adjacent to the pyrrolic core and (ii) adequate
nucleophilicy of the pyrrolic heterocycle render the (2,2,2-
trifluoro-1-hydroxyethyl)- substituent an inappropriate group
with which to introduce chirality directly adjacent to the
pyrrolic core.
Challenges associated with the low or unusual reactivity
of electron-deficient pyrroles are not new. Indeed, Handy
and co-workers have described problems associated with the
N-protection of poly-halogenated pyrroles (37) and Clezy
has made observations concerning problems in constructing
dipyrromethanes using electron-deficient pyrroles (30). The
© 2008 NRC Canada

Beshara et al.
955
In summary, a dipyrrin containing a chiral 4-(2,2,2-
trifluoro-1-acetoxyethyl)- substituent directly adjacent to the
pyrrolic core was prepared and complexed with Zn(II). Al-
though the corresponding mononuclear helicate was isolated
in good yield, complexation occurred with poor selectivity.
Attempts to prepare an analogous bis(dipyrrin), a skeleton
that was found to be generally more stable in solution than
the monomeric homologue, were thwarted by the low reac-
tivity of electron-deficient pyrroles. These results again dem-
onstrate that the balance between the reactivity and stability
of pyrroles is a fine balance indeed (38, 39): the search con-
tinues for moieties that facilitate the introduction of chirality
directly adjacent to the pyrrolic core without concurrent
inhibition of pyrrolic reactivity.
After three days the mixture was filtered through celite and
concentrated to facilitate the precipitation of the carboxylic
acid (87%), which was then suspended in ethanolamine
(25 mL), and the mixture was heated to 170 °C for 45 min,
after which the mixture was poured into ice water and ex-
tracted with CH2CH2 (3 × 20 mL). The combined organic
layers were washed with water (50 mL) and then brine
(50 mL), followed by drying over sodium sulfate and
concentratation. The residue was dissolved in CHCl3 and re-
concentrated to yield the α-free intermediate as a yellow
crystalline solid (72%). This pyrrole (0.384 g, 1.99 mmol)
and 4 (0.190 g, 2.00 mmol) were dissolved in 1:1 MeOH–
THF (25 mL) and 48% aq hydrogen bromide (0.300 mL)
was added to the solution. After stirring overnight at room
temperature, the mixture was concentrated until very little
solvent remained. Ether, pre-treated with sodium
borohydride, was then added until a copious precipitate was
present. Filtration and drying in air gave the title compound
General experimental
All reagents were purchased from Sigma-Aldrich and
used as received, except phosphoric acid that was purchased
from Fischer Scientific and reagent grade acetonitrile that
was purchased from Caledon. Dry THF and CH2Cl2 were
obtained from a solvent purification system and stored under
nitrogen unless otherwise indicated. Dry ether was obtained
via distillation from benzophenone sodium ketal. Unless oth-
erwise indicated all glassware was flame-dried under vac-
uum prior to use, followed by a nitrogen fill. Column flash
chromatography was performed using Silicycle Ultra Pure
Silica Gel 60, 230–400 mesh. TLC was performed using
Silicycle Ultra Pure Silica Gel 60 aluminum-backed plates,
visualized under UV light, and stained using an ethanolic
vanillin dip. Absorption spectroscopy was performed with
samples in quartz cuvettes with a standard path-length of
1
as a red solid (0.399 g, 57%); mp 190–230 °C. H NMR
(500 MHz, DMSO-d6) δH: 1.04 (t, JHH = 8 Hz, 3H), 2.34 (s,
3H), 2.42–2.45 (m, 5H), 2.58 (s, 3H), 2.60 (s, 3H), 5.27 (q,
JHF = 8 Hz, 1H), 6.83 (bs, 1H), 7.45 (s, 1H), 12.52 (bs, 1H),
12.69 (bs, 1H). 13C NMR (125 MHz, DMSO-d6) δC : 10.7,
11.1, 13.6, 14.2, 15.0, 17.4, 65.8 (q, JCF = 32 Hz), 121.9,
122.3, 126.2, 126.4 (q, JCF = 281 Hz), 128.5, 132.6, 143.9,
145.2, 151.7, 158.1. 19F NMR (235 MHz, CDCl3) δF : -78.2
(d, JHF = 8 Hz). MS-ESI m/z: 327.1 (M + 1 – Br)–.
N,N′-Difluoroboryl-[2,3-dimethyl-4-(1-hydroxy-2,2-2-
trifluoroethyl)-5-(3,5-dimethyl-4-ethylpyrrol-2-
ylmethylidene)pyrrolato-kN] (6)
To a suspension of 5 (1.00 g, 2.4 mmol) in CH2Cl2
(15 mL) under a nitrogen atmosphere was added, first, NEt3
(6.37 mL, 45 mmol) and, second, BF3·OEt2 (6.33 mL,
51.3 mmol) giving a colour change from brown-orange to
dark orange-pink. After stirring the solution (the suspension
becomes a solution after the addition of BF3·OEt2) for one
hour at room temperature the reaction mixture was concen-
trated. The residue was taken up in Et2O and run through a
plug of silica to remove baseline material and then further pu-
rified using chromatography and 1:50 to 1:10 ethyl acetate –
hexanes as eluent to yield the title compound as a pink-red
solid (0.395 g, 46%); mp 175–178 °C. Rf (1:5 ethyl acetate –
1
cm. HPLC separations were performed using a
Chiralpak®-IA column composed of amylose tris(3,5-
dimethylphenylcarbamate) with particle size of 5 µm; the an-
alytical column had an ID of 0.46 cm and the preparatory
column an ID of 2 cm with both columns having a length of
25 cm. The chiral analytical column used for the determina-
tion of er in compound S-3 was the Chiralpak® AD-RH, also
composed of amylose tris(3,5-dimethylphynylcarbamate) but
with a silica support (ID 0.46 cm; length 15 cm). NMR
spectroscopy utilized 500 MHz, 400 MHz, and 250 MHz
spectrometers at 300 K, as indicated. All H and 13C chemi-
1
1
hexanes): 0.19. UV (nm) λmax : 514. H NMR (500 MHz,
cal shifts (δ) are referenced to TMS at 0 ppm in the solvents
indicated and are reported on the ppm scale. All coupling
constants (J) are reported in Hz. 19F NMR spectra were ref-
erenced to CFCl3 as an external standard at 0 ppm. Mass
spectra were obtained using double focusing magnetic sector
(EI) and TOF (ESI) spectrometers. Compounds 1 (22), 2 (3),
3 (16), 4 (24), 8 (28), 9 (29), 13 (30), 15 (16), and 17 (16)
were prepared according to known procedures. WARNING:
Perchlorate salts are powerful oxidants and care should be
taken to avoid exothermic or explosive conditions.
CDCl3) δH : 1.07 (t, JHH = 7.5 Hz, 3H), 2.17 (s, 3H), 2.27 (s,
3H), 2.39 (q, JHH = 7.5 Hz, 2H), 2.52 (s, 3H), 2.54 (s, 3H),
2.55 (d, JHH = 3 Hz, 1H), 5.04 (qd, JHF = 7 Hz, JHH = 3 Hz,
1H), 7.03 (s, 1H). 13C NMR (125 MHz, CDC13) δC : 9.7,
10.3, 13.2 (2C), 14.6, 17.6, 67.7 (q, JCF = 33 Hz), 119.9,
120.2, 125.3 (q, JCF = 280 Hz), 131.7, 134.1, 134.5, 138.0,
139.4, 152.6, 159.8. 19F NMR (235 MHz, CDCl3) δF : –78.77
(d, JFH = 7 Hz), –146.16 to –146.85 (m). MS-ESI m/z: 354.3
(28%), 355.3 [(M – F)+, 100%)], 356.3 (26%), 374.1 (20%).
2,3-Dimethyl-4-(2,2-2-trifluoroethyl-1-hydroxy-)-5-(3,5-
dimethyl-4-ethylpyrrol-2-ylmethylidene)pyrrole
hydrobromide (5)
Pd–C catalyst (10% on C, 0.306 g, 10 mol%) was added
to a solution of pyrrole 3 (1.00 g, 3.06 mmol) in THF
(40 mL) through a stream of nitrogen and the reaction mix-
ture was then stirred under a hydrogen (1.0 atm) atmosphere.
Zinc bis[2,3-dimethyl-4-(2,2-2-trifluoroethyl-1-hydroxy-)-5-
(3,5-dimethyl-4-ethylpyrrol-2-ylmethylidene)pyrrolato-kN]
(7)
Dipyrromethene salt 5 (1.00 g, 2.5 mmol) was dissolved
in methanol (80 mL) and lithium hydroxide monohydrate
(0.932 g, 9 mmol) was added directly to the solution causing
a dramatic shift in colour from orange-red to yellow.
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956
Can. J. Chem. Vol. 86, 2008
Zinc(II) perchlorate (CAUTION, 1.30 g, 5.0 mmol) was then
added and the yellow solution turned orange immediately.
The mixture was stirred for one hour followed by dilution
with water to precipitate the desired product, which was iso-
lated by filtration as a very fine orange powder after drying
overnight in a vacuum oven at room temperature (0.763 g,
of nitrogen. A hydrogen atmosphere was maintained utiliz-
ing a balloon and needle through a septum and the reaction
was stirred for 0.5 h. The product was partially purified us-
ing flash column chromatography and 1:5 EtOAc–hexanes
as eluent to yield the title compound as a white solid which
1
was used without further purification (0.080 g, 57%). H
1
85%); mp 197–198 °C. H NMR (500 MHz, CDCl3) δH:1.01
(t, JHH = 7.5 Hz, 3H), 1.02 (t, JHH = 7.5 Hz, 3H), 1.89–1.94
NMR (500 MHz, acetone-d6) δH : 2.12 (s, 3H), 2.40 (s, 3H),
5.31 (s, 2H), 6.20 (q, JHF = 7 Hz, 1H), 7.00 (d, JHH = 3 Hz,
1H), 7.32–7.42 (m, 5H), 9.50 (bs, 1H).
(m, 3H), 1.95–2.20 (m, 3H), 2.20 (bs, 1H), 2.22 (d, JHH
=
1.5 Hz, 3H), 2.35–2.40 (m, 5H), 5.00–5.05 (m, 1H), 7.04 (s,
1H). 13C NMR (125 MHz, CDC13) δC : 10.6, 10.7, 15.1,
Benzyl 4-(1-acetoxy-2,2,2-trifluoroethyl)-5-chloromethyl-
3-methylpyrrole-2-carboxylate (19)
To a solution of benzyl 5-acetoxymethyl-4-(1-acetoxy-2,2,2-
15.5, 15.6, 18.2, 68.1 (q, JCF = 33 Hz), 68.1 (q, JCF
=
33 Hz), 117.9, 121.8, 125.6 (q, J = 280 Hz), 132.3, 134.8,
134.9, 137.8, 139.6, 153.3, 161.5. 19F NMR (235 MHz,
CDCl3) δF : –78.9 (d, J = 7.5 Hz). MS-ESI m/z: 327.2
(ligand), 715.1 (M + 1)+, 737.1 (M + Na)+.
trifluoroethyl)-3-methylpyrrole-2-carboxylate
(278.6
mg,
0.652 mmol) in dichloromethane (DCM, 20 mL) under nitro-
gen was added HCl (1 mol/L in ether, 3.129 mL) and the solu-
tion was stirred at room temperature overnight. The solution
was washed with 5% aqueous sodium bicarbonate (3 × 10 mL)
and the aqueous layer extracted using DCM (3 × 20 mL). The
organic layers were combined, dried over sodium sulfate, fil-
tered, and concentrated in vacuo to give the product as a light
Benzyl 5-acetoxymethyl-4-(1-acetoxy-2,2,2-
trifluoroethyl)-3-methylpyrrole-2-carboxylate (14)
According to a published procedure (18), to a solution of
benzyl 4-(1-acetoxy-2,2,2-trifluoroethyl)-3,5-methylpyrrole-
2-carboxylate (381.5 mg, 1.03 mmol) in acetic acid (9 mL)
under N2 at room temperature was added Pb(OAc)4
(490.7 mg, 1.107 mmol) as a solid with stirring. The result-
ing mixture was stirred at 50 °C and monitored using TLC.
After full conversion was apparent (4 h), the reaction mix-
ture was cooled to room temperature and then diluted with
ethylene glycol (1.0 mL). Distilled water (20 mL) was added
to the solution, and the product was extracted using di-
chloromethane (3 × 50 mL). The organic layer was washed
with 5% sodium bicarbonate (3 × 50 mL) and dried over so-
dium sulfate, and the solvent removed in vacuo to give the
1
pink solid (111 mg, 40%). H NMR (500 MHz, CDCl3) δH:
2.20 (3H, s), 2.39 (3H, s), 4.63 (1H, d, J = 13.0 Hz), 4.79
(1H, d, J = 13.0 Hz), 5.33 (2H, d, J = 12.5 Hz), 5.36 (1H, d,
J = 12.5 Hz), 6.24 (1H, q), 7.35–7.43 (5H, m), 9.52 (1H, bs).
13C NMR (125 MHz, CDCl3) δC: 10.5, 20.7, 36.5, 66.1 (q,
J = 139 Hz), 66.5, 113.8, 120.1, 123.7 (q, J = 1114 Hz), 127.9,
128.4, 128.5, 128.8, 131.0, 135.9, 161.1, 168.6. 19F NMR
(235 MHz, CDCl3) δF: –7.06. MS-ESI m/z for
C18H17ClF3NO4 calcd.: 403.0798; found: 402.0717.
1
Benzyl 4-(1-acetoxy-2,2,2-trifluoroethyl)-5-
product (34) as a white solid (435.6 mg, 99%). H NMR
methoxymethyl-3-methylpyrrole-2-carboxylate (20)
To a solution of benzyl 4-(1-acetoxy-2,2,2-trifluoroethyl)-5-
chloromethyl-3-methylpyrrole-2-carboxylate (50 mg, 0.124 mmol)
in methanol (2 mL) at room temperature was added concd.
HCl (12 mol/L, 0.07 mL), and the mixture was then stirred
at room temperature for 4 h. The solvent was removed in
vacuo, and the crude mixture was purified using preparative
TLC and 70:30 hexane–ethyl acetate as the eluent to give the
product as a colourless oil (16.2 mg, 33%). 1H NMR
(500 MHz, CDCl3) δH : 2.15 (3H, s), 2.41 (3H, s), 3.40
(3H, s), 4.52 (1H, d, J = 13.5 Hz), 4.55 (1H, d, J = 13.5 Hz),
5.31 (2H, s), 6.20 (1H, q, J = 7.5 Hz), 7.34–7.43 (5H, m),
9.20 (1H, bs). 13C NMR (125 MHz, CDCl3) δC : 10.7, 20.6,
58.8, 66.1, 66.2, 66.2 (q, J = 138.5 Hz), 111.7, 118.7, 123.9
(q, J = 1114 Hz), 128.4, 128.6, 133.5, 136.3, 161.0, 168.6.
19F NMR (235 MHz, CDCl3) δF : –76.93. MS-ESI m/z for
C19H20F3NO5Na calcd.: 422.1191; found: 422.1175.
(500 MHz, CDCl3) δH : 2.06 (3H, s), 2.17 (3H, s), 2.39
(3H, s), 5.16 (2H, q, J = 13.5 Hz), 5.31 (2H, d, J = 12.5 Hz),
5.33 (1H, d, J = 12.5 Hz), 6.23 (1H, q, J = 7.0 Hz), 7.33–
7.42 (5H, m), 9.45 (1H, bs). 13C NMR (125 MHz, CDCl3)
δC : 10.5, 20.6, 20.9, 57.2, 66.3, 66.3 (q, J = 139 Hz), 114.2,
119.7, 123.7 (q, J = 1114 Hz), 127.7, 128.3, 128.4, 128.7,
130.3, 136.1. 19F NMR (235 MHz, CDCl3) δF: –76.62. MS-
ESI m/z for C20H20F3NNaO6 calcd.: 450.1140; found:
450.1130.
Benzyl 4-(1-acetoxy-2,2,2-trifluoroethyl)-3-
methylpyrrole-2-carboxylate (16)
Water (2 mL) and dichloroethane (DCE, 4 mL) were
added to a flask containing pyrrole 17 (0.16 g, 0.40 mmol)
and sodium bicarbonate (0.11 g, 1.3 mmol). Sodium iodide
(0.16 g, 1.1 mmol) and iodine (0.48 g, 1.9 mmol) were
added to the biphasic reaction mixture, which was heated at
reflux temperature for an hour. After the mixture cooled to
room temperature, sodium bisulfite was added very slowly
as a solid, to quench the excess iodine (quenching was com-
plete with loss of colour and cessation of effervescence).
The layers were then separated and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried with magnesium sulfate followed by con-
centration to give the iodopyrrole as an off-white solid. The
crude product was suspended in ethanol (4 mL) followed by
the addition of sodium acetate (0.045 g, 0.55 mmol) and
platinum(IV) oxide (0.014 g, 0.06 mmol) through a stream
Acknowledgements
This research was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC). We are
grateful to the Canada Foundation for Innovation and the
Nova Scotia Research Innovation Trust for research infra-
structure. The Sumner and Ryan Foundations (CSB) and a
Belle Crowe Scholarship (BMP) financially supported this
work.
© 2008 NRC Canada

Beshara et al.
957
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© 2008 NRC Canada