Conversion of 4,4-difluoro-4-bora-3a, 4a-diaza-s-indacenes (F-BODIPYs) to dipyrrins with a microwave-promoted deprotection strategy

Article abstract of DOI:10.1021/ol902908j

Chemical eqation presented 4,4-Difluoro-4-bora-3a,4a-diaza-s- indacenes (F-BODIPYs) have been deprotected to give the corresponding free-base dipyrrins by heating a solution of the F-BODIPY in tert-butanol under 600 W of microwave irradiation in the presence of 6 equiv of potassium tert-butoxide for 40 min at 92 C. Investigations of BODIPY modification at the meso position have also been undertaken and a meso-butyl product has been isolated.

Full text of DOI:10.1021/ol902908j

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1424-1427
Conversion of 4,4-Difluoro-4-bora-3a,
4a-diaza-s-indacenes (F-BODIPYs) to
Dipyrrins with a Microwave-Promoted
Deprotection Strategy
Sarah M. Crawford and Alison Thompson*
Department of Chemistry, Dalhousie UniVersity, Halifax, NoVa Scotia, B3H 4J3, Canada
alison.thompson@dal.ca
Received December 17, 2009
ABSTRACT
4,4-Difluoro-4-bora-3a,4a-diaza-s-indacenes (F-BODIPYs) have been deprotected to give the corresponding free-base dipyrrins by heating a
solution of the F-BODIPY in tert-butanol under 600 W of microwave irradiation in the presence of 6 equiv of potassium tert-butoxide for 40 min
at 92 °C. Investigations of BODIPY modification at the meso position have also been undertaken and a meso-butyl product has been isolated.
Compounds containing the 4,4-difluoro-4-bora-3a,4a-diaza-
s-indacene (F-BODIPY) framework have wide applications
as dyes, as fluorescent probes in biological systems, and as
materials for incorporation into electroluminescent devices.1
Such wide utility bespeaks their high thermal and photo-
chemical stability, as well as their chemical robustness and
tunable fluorescence properties.2-4 Use of substituents other
than fluorine at the boron center of the BODIPY core is
currently under wide investigation with the goal of identify-
ing BODIPYs with exotic spectroscopic properties. Indeed,
a variety of B-aryl (C-BODIPY) and B-alkynyl (E-BODIPY)
derivatives have been synthesized with organolithium or
Grignard reagents.5-9 Furthermore, B-alkoxy and B-aryloxy
derivatives (both termed O-BODIPYs) have been synthesized
via fluorine displacement with sodium alkoxides or alcohols
in the presence of Lewis acids.10-13 More recently, BODIPY
borenium cations have been synthesized by way of fluoride
abstraction,14 and three examples of BODIPY boronium
cations with a DMAP ligand coordinating to the boron center
have also been reported.14,15
F-BODIPYs are routinely synthesized in high yields by
trapping the parent dipyrrin as its BF2 complex. According
to a recently reported procedure F-BODIPYs can be gener-
ated from R-formyl pyrroles in one pot, without isolation
(or even work-up) of the parent dipyrrin.16 F-BODIPYs are
chemically robust and, as they are highly stable and
fluorescent, are easily purified at each consecutive syn-
thetic step in a derivitization strategy. In contrast, the
(9) Ulrich, G.; Goze, C.; Guardigli, M.; Roda, A.; Ziessel, R. Angew.
(1) Benniston, A. C.; Copley, G. Phys. Chem. Chem. Phys. 2009, 11,
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501
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10868–10875
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Commun. 2008, 4593–4595.
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(16) Wu, L.; Burgess, K. Chem. Commun. 2008, 4933–4935.
.
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10.1021/ol902908j  2010 American Chemical Society
Published on Web 03/01/2010

parent dipyrrins are historically difficult to chemically
manipulate and purify, presumably by virtue of the
inherent azafulenium and pyrrolic nitrogen moieties.17
Strategies have been developed to protect the dipyrrin as
a zinc18 or tin19 complex prior to functionalization, to thus
facilitate purification, although these strategies are limited
by the lability of such dipyrrinato complexes under acidic
conditions.
Ideally, dipyrrins could be protected as stable BODIPY
compounds, chemically modified, purified, and then depro-
tected to give functionalized dipyrrins. However, to our
knowledge, the boron center has not been removed from
BODIPYs to generate the parent dipyrrin. Here we disclose
the first reported method by which to generate dipyrrins from
their corresponding F-BODIPY analogues.20
irreproducible crude yield of around 23%. This extremely
encouraging result prompted further investigations. When the
reaction was carried out under microwave irradiation, we
were delighted to observe that the desired free-base 1b was
generated in high yield: heating a sealed mixture of 1a and
6 equiv of potassium tert-butoxide in tert-butanol to 92 °C
under 600 W microwave irradiation (see the Supporting
Information for technical details), followed by an aqueous
basic work-up, gave the parent dipyrrin 1b in 92% isolated
yield (Table 1, entry 1).
Table 1. Optimization of Microwave-Assisted Deprotection of
BODIPY 1a
reagent
solvent time/min temp/°C yield/%
Several strategies might be applied to deprotect F-
BODIPYs and return the parent dipyrrin: (i) protonation of
the dipyrrinato nitrogen atoms and release of the -BF2
moiety; (ii) nucleophilic attack at the boron center and
cleavage of the B-N bonds to give the dipyrrinato anion;
(iii) nucleophilic attack at the meso-position and cleavage
of the N-B bonds, with subsequent protonation and elimina-
tion of the nucleophile to return the dipyrrin; or (iv) attack
at the (planar) nitrogen atoms.
1
2
3
4
5
6
tBuOK (6 equiv)
tBuOK (3 equiv)
NaH (6 equiv)
NaH (6 equiv)
LiHMDS (6 equiv) DMF
KI (6 equiv) DMF
tBuOH
tBuOH
DMF
15
15
15
92
92
92
92
0a
0b
0b
0b
0a
DMF
15
15
120
165
165
165
a Starting material recovered quantitatively. b Decomposition.
As F-BODIPYs are stable to strong acid, and cognizant
that boron-oxygen bonds are stronger than boron-nitrogen
bonds,21 we investigated the use of oxygen-based reagents
to effect cleavage of the B-N bonds in F-BODIPYs.
Small oxygen-based nucleophilies are known to react with
BODIPYs to give O-BODIPYs, and so the less nucleo-
philic potassium tert-butoxide was selected as a potential
deprotection agent.
meso-Aryl dipyrrins are more stable than meso-unsubsti-
tuted dipyrrins,17 and so F-BODIPY 1a was chosen for
deprotection studies, with the free-base dipyrrin 1b as the
target product (Scheme 1). The reaction was attempted at
Heating the reaction mixture under 600 W of microwave
irradiation at 82 and 72 °C resulted in the complete
consumption of starting material, but as the temperature was
decreased the degree of decomposition increased (Figure S1,
Supporting Information). The use of other stoichiometries
of 1a:tert-butoxide was investigated (Table 1, entry 2), as
were other non-nucleophilic bases (lithium hexamethyldisi-
lazane and sodium hydride), but NMR spectroscopic analysis
indicated the formation of only trace amounts of 1b,
alongside many decomposition products (Table 1, entries
3-5). The use of iodide was also investigated (as a
nucleophile), but only starting material was recovered (Table
1, entry 6). Interestingly when sodium isopropoxide was used
with 1a, in place of potassium tert-butoxide, the O-BODIPY
with two B-isopropoxide groups was isolated in 47% yield
along with trace amounts of deprotected product. These
results indicate that the non-nucleophilic nature and steric
bulk of the tert-butoxide are important to the observed
deprotection reactivity.
Scheme 1
.
Deprotection of BODIPY 1a with tBuOK under
Microwave Irradiation
The optimized method was applied to deprotect a series of
F-BODIPYs (Table 2), with a 40-min reaction time proving to
be optimal. meso-Aryl F-BODIPYs 1a and 2a were deprotected
successfully in high isolated yield as was the meso-unsubstituted
analogue 3a. The ꢀ- and meso-unsubstitued dipyrrins 4a and
5a16 were also deprotected (CAUTION 4b is a sternutator).
This method was applied to the unsymmetrical F-BODIPY 6a22
to give 6b in excellent isolated yield.
A series of BODIPYs with substituents on the boron center
were investigated to explore the scope of the deprotection
reaction. The O-BODIPYs 7a and 8a, both bearing two
B-alkoxy substituents, could not be deprotected under the
optimized conditions, and starting material was quantitatively
atmospheric pressure with conventional heating at 85 °C for
24 h, and the corresponding dipyrrin was isolated in an
(17) Wood, T. E.; Thompson, A. Chem. ReV. 2007, 107, 1831–1861.
(18) Sa´ez D´ıaz, R. I.; Bennett, S. M.; Thompson, A. ChemMedChem
2009, 4, 742–745.
(19) Tamaru, S.; Yu, L. H.; Youngblood, W. J.; Muthukumaran, K.;
Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2004, 69, 765–777.
(20) Liras, M.; Banuelos Prieto, J.; Pintado-Sierra, M.; Garcia-Moreno,
I.; Costela, A.; Infantes, L.; Sastre, R.; Amat-Guerri, F. Org. Lett. 2007, 9,
4183–4186.
(21) Ho¨pfl, H. In Group 13 Chemistry I: Fundamental New DeVelop-
ments; Mingos, D. M. P., Ed.; Springer-Verlag: Duesseldorf, Germany,
2002; Vol. 103, pp 1-56.
(22) Beshara, C. S.; Pearce, B. M.; Thompson, A. Can. J. Chem. 2008,
10, 951–957.
Org. Lett., Vol. 12, No. 7, 2010
1425

Although BODIPY 3a has been synthesized on large scale
in high yields (see the Supporting Information for a 5 g scale
procedure giving a 91% isolated yield) the scale of the
microwave-promoted reaction is limited by the size of the sealed
microwave vessels available. Isolated yields of 3b on scales
larger that 500 mg are also limited by purification methods, as
this material is only of moderate stability and decomposes
during column chromatography. Similar problems are encoun-
tered in the large-scale purification of 1b; fortunately, the
majority of the crude dipyrrin products are pure enough to be
used in subsequent reactions without purification.
Table 2. Microwave-Assisted Deprotection of F-BODIPY
Derivatives (6 equiv tBuOK, tBuOH, 92 °C, 600 W, 40 min)
Once a successful deprotection strategy had been found,
the possibilities for synthetic modification of F-BODIPY
derivatives were investigated. Our goal was to modify the
meso-position of the F-BOIDPY and compound 3a was
selected for modification studies. The double bond at the
meso-position in the F-BODIPY could be subject to nucleo-
philic attack similar to that observed in analogous porphyrin
and metallo-porphyrin examples.24,25 However, some org-
anolithium reagents are known to attack the boron center to
give C-BODIPYs,26 so the reactions were conducted at low
temperature in attempts to limit undersirable reactivity.
Treatment of 3a with n-butyllithium resulted in loss of the
typical dipyrrin color. The addition of 2,3-dichloro-5,6-dicy-
anobenzoquinone (DDQ) resulted in the return of the charac-
teristic dipyrrin hue, and subsequent isolation of meso-butyl
F-BODIPY 14 in 61% yield (Scheme 2). On the basis of the
Scheme 2. Alkylation of BODIPYs 3a and 16 with nBuLi
a All yields are isolated yields. b Isolated as its zinc complex. c Starting
material recovered.
recovered even after an extended reaction time. Interestingly,
with one B-alkoxy substituent, as in 9a, the deprotection was
successful and dipyrrin 3b was obtained in an isolated yield
of 75%. This result again infers the importance of a steric
component to the success of the deprotection. With two
B-methyl groups (C-BODIPY 10a), the deprotection was also
unsuccessful. The meso-benzyl and meso-methyl BODIPYs
12a and 11a, respectively, were deprotected successfully in
high yield to generate the corresponding unstable meso-
substituted dipyrrins,23 which were isolated as their HCl salts
(to prevent tautomerization to the vinylic dipyrroles) through
a modification of the work-up procedure. Attempts to remove
trace amounts of tert-butanol from compound 11b resulted
in conversion to the vinylic dipyrrole, which was, unsur-
prisingly, unstable in solution.
color changes that occurred during the reaction, we propose
that the reaction proceeds through an addition-elimination
mechanism. After the initial nucleophilic attack of the butyl
anion at the meso-position an intermediate (13) is formed, and
loss of hydride gives F-BODIPY 14 as the final product.14,15
(24) Feng, X.; Senge, M. O. J. Chem. Soc., Perkin Trans. 1 2001, 1030–
1038
.
(25) Senge, M. O. Acc. Chem. Res. 2005, 38, 733–743
(26) Ulrich, G.; Goze, C.; Goeb, S.; Retailleau, P.; Ziessel, R. New
J. Chem. 2006, 30, 982–986.
.
(23) Al-Sheikh Ali, A.; Cipot-Wechsler, J.; Cameron, T. S.; Thompson,
A. J. Org. Chem. 2009, 74, 2866–2869.
1426
Org. Lett., Vol. 12, No. 7, 2010

As expected, F-BOIDPY 15 also underwent alkylation with
nBuLi to give 16 (Scheme 2). Given our demonstrated
success with removal of the BF2 moiety from meso-alkylated
F-BODIPYs 11a and 12a, these two reactions constitute a
new route to meso-substituted free-base dipyrrins.
When 3a was treated with phenyllithium at -78 °C, only
starting material was observed. No products were observed
until the temperature reached above -30 °C, and the starting
material was not consumed until the reaction reached room
temperature. Treatment of 3a with phenyllithium at -45 °C
followed by warming to room temperature resulted in the
isolation of C-BODIPY 17 with two B-phenyl groups
(Scheme 3) in low yield, with no production of the meso-
the phenyl group. Treatment of F-BODIPY 15 with phenyl
lithium results in a mixture of products in which C-BODIPY
18 was the major product.
In summary, a one-step method for generating dipyrrins
in high isolated yields from their F-BODIPY analogues under
microwave irradiation has been developed. The operationally
facile method is general for meso-substituted, meso-unsub-
stituted, symmetrical, and unsymmetrical F-BODIPYs. The
mechanisms of the transformation and the deprotection of
electron-poor BODIPYs are currently under investigation,
as is the application of this method in the widespread
synthesis and purification of dipyrrins. Furthermore, F-
BODIPY molecules can also be treated with n-butyllithium
to generate the corresponding meso-butyl-substituted F-
BODIPYs in moderate to low yields.
Scheme 3. Alkylation of BODIPYs 3a and 15 with PhLi
Acknowledgment. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada. The authors would like to thank Dr. C. S. Beshera
(Dalhousie University) for the synthesis of compound 6a and
Dr. K. Burgess (Texas A&M University) and L. Wu (Texas
A&M University) for the gift of 5a.
Supporting Information Available: Experimental pro-
cedures and NMR characterization data for all previously
unpublished compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
substituted product. The meso-position of F-BODIPY 3a is
presumably too sterically hindered to allow the approach of
OL902908J
Org. Lett., Vol. 12, No. 7, 2010
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