An improved method for the synthesis of F -BODIPYs from dipyrrins and bis(dipyrrin)s

Article abstract of DOI:10.1021/ol300681w

An improved methodology for the synthesis of F-BODIPYs from dipyrrins and bis(dipyrrin)s is reported. This strategy employs lithium salts of dipyrrins as intermediates that are then treated with only 1 equiv of boron trifluoride diethyletherate to obtain the corresponding F-BODIPYs. This scalable route to F-BODIPYs renders high yields with a facile purification process involving merely filtration of the reaction mixture through Celite in many cases.

Full text of DOI:10.1021/ol300681w

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2158–2161
An Improved Method for the Synthesis of
F-BODIPYs from Dipyrrins and
Bis(dipyrrin)s
Travis Lundrigan, Alexander E. G. Baker, Lauren E. Longobardi, Tabitha E. Wood,†
Deborah A. Smithen, Sarah M. Crawford, T. Stanley Cameron, and Alison Thompson*
Department of Chemistry, Dalhousie University, P.O. Box 15000, Halifax, NS,
B3H 4R2, Canada
Alison.Thompson@dal.ca
Received March 17, 2012
ABSTRACT
An improved methodology for the synthesis of F-BODIPYs from dipyrrins and bis(dipyrrin)s is reported. This strategy employs lithium salts of
dipyrrins as intermediates that are then treated with only 1 equiv of boron trifluoride diethyletherate to obtain the corresponding F-BODIPYs. This
scalable route to F-BODIPYs renders high yields with a facile purification process involving merely filtration of the reaction mixture through Celite
in many cases.
Compounds containing the 4,4-difluoro-4-bora-3a,4a-
diaza-s-indacene (F-BODIPY)1À3 framework are known
for their high thermal and photochemical stability, chemi-
cal robustness, and chemically tunable fluorescence prop-
erties, making them a highly desirable synthetic target.
F-BODIPYs are generally synthesized by trapping a
dipyrrin4,5 as its BF2 complex through a reaction with
BF3•OEt2 and NEt3.2 To the best of our knowledge, all
F-BODIPY formation reactions reported in the literature
use an excess of both the amine base and BF3•OEt2.
Bis(dipyrrin)s consist of two dipyrrins attached through
a linker.4,5 Given the large number of reported F-BODI-
PYs, it is surprising that there are few examples of bis-
(F-BODIPY)s. There are two examples of meso-H, R-linked
bis(F-BODIPY)s with varying alkyl substituents about
the BODIPY core.6 In addition, there is a closely related
example containing a meso-phenyl substituent. Two ex-
amples of bis(F-BODIPY)s attached via long fatty acid/
phospholipid chains through their R-positions are com-
mercially available.7 A bis(F-BODIPY) attached via a long
glycoside chain through the R-position8 has also been
reported.
We first attempted to synthesize bis(F-BODIPY)s using
traditional methods(excessNEt3 and BF3•OEt2 indichlor-
omethane solution).2 However, these reactions resulted in
complex mixtures that could not be successfully purified.
Similar difficulties have been reported previously in the
synthesis of bis(F-BODIPY)s.9
To investigate the formation of F-BODIPYs in more
detail, and to optimize the reaction conditions for eventual
application toward the synthesis of bis(F-BODIPY)s, we
† Current address: Department of Chemistry, The University of Winnipeg,
515 Portage Avenue, Winnipeg, Manitoba, R3B 2E9, Canada.
(1) Benstead, M.; Mehl, G. H.; Boyle, R. W. Tetrahedron 2011, 67,
3573–3601.
(2) Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891–4932.
(3) Ziessel, R.; Ulrich, G.; Harriman, A. New. J. Chem. 2007, 31, 496–
501.
€
€
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(6) Broring, M.; Kruger, R.; Link, S.; Kleeberg, C.; Kohler, S.; Xie,
X.; Ventura, B.; Flamigni, L. Chem.;Eur. J. 2008, 14, 2976–2983.
(7) Bis-BODIPYÒ FL C11-PC <http://products.invitrogen.com/
ivgn/product/B7701> last accessed March 14th, 2012; Red/Green
BODIPYÒ PC-A2 <http://products.invitrogen.com/ivgn/product/
A10072> last accessed March 14th, 2012.
€
€
€
(4) Wood, T. E.; Thompson, A. Chem. Rev. 2007, 107, 1831–1861.
(5) Wood, T. E.; Uddin, I. M.; Thompson, A. In Handbook of
Porphyrin Science; Kadish, K. M., Smith, K., Guilard, R., Eds. 2010, p
235-284.
(8) Bergstrom, F.; Mikhalyov, I.; Hagglof, P.; Wortmann, R.; Ny, T.;
˚
Johansson, L. B.-A. J. Am. Chem. Soc. 2001, 124, 196–204.
(9) Broring, M.; Kruger, R.; Link, S.; Kleeberg, C.; Kohler, S.; Xie,
X.; Ventura, B.; Flamigni, L. Chem.;Eur. J. 2008, 14, 2976–2983.
€
€
€
r
10.1021/ol300681w
Published on Web 04/04/2012
2012 American Chemical Society

worked with a simple alkyl substituted dipyrrin hydrobro-
mide salt (1HBr, Scheme 1). Our goal was to find the ratio
of NEt3/BF3/1HBr at which the greatest conversion of
dipyrrin to its corresponding F-BODIPY was achieved: we
postulated that these conditions could be applied to the
synthesis of bis(F-BODIPY)s. The amine base is essential
for the observed reactivity: when the dipyrrin HBr salt was
treated with BF3•OEt2 alone, no reaction occurred. To
analyze the outcome of the reactions, the ratio of free-base
(1) to F-BODIPY (1BF2) was determined via integration of
Interestingly, we found that this general procedure for
the synthesis of F-BODIPYs often suffers from irrepro-
ducible results when the dipyrrin hydrobromide salt is
unsymmetrical. Indeed, when attempting to synthesize
F-BODIPY 2BF2 from the unsymmetrical hydrobromide
salt 2HBr we were surprised to isolate a mixture of three
products, as shown in Scheme 2.
Scheme 2. Synthesis of Scrambled F-BODIPYs from an Un-
symmetrical Dipyrrin
1
the meso-H peaks in the H NMR spectra of the crude
reaction mixtures recorded after workup.
Scheme 1. Synthesis of 1 and 1BF2 from Dipyrrin Hydrobro-
mide Salt 1HBr
Using X-ray crystallographic analysis, we unambigu-
ously confirmed the presence of the desired unsymmetrical
F-BODIPY (2BF2) along with two (scrambled) symmetri-
cal F-BODIPY products (3BF2 and 4BF2) (see Supporting
Information). Attempts were made to optimize the reac-
tion by modifying the choice of solvent and adjusting the
temperature and the equivalents of BF3•OEt2 and NEt3. In
all cases, a mixture of 2BF2, 3BF2, and 4BF2, separable
only via recrystallization, was isolated with 2BF2 as the
major product.
Finally, the general conditions for the synthesis of
F-BODIPYs often cause problems in larger scale reactions
(>1 g). Indeed, during F-BODIPY formation reactions, a
BF3•NEt3 adduct11 byproduct is formed. Purification via
column chromatography is usually required to remove this
adduct, which generally has a higher Rf value than the
desired F-BODIPY product. In our experience on larger
scales, the presence of this adduct makes product isolation
challenging at both the extraction and purification stages.
The problems that arise when synthesizing bis-
(F-BODIPY)s, F-BODIPYs of unsymmetrical dipyrrins,
and simple F-BODIPYs on a large scale highlight the need
for the development of a targeted synthetic approach to
F-BODIPYs. To address this challenge, we sought an amine-
free procedure for the synthesis of F-BODIPYs. This
strategy necessitates the need for formation of the dipyrri-
nato anion prior to the addition of BF3•OEt2. We have
previously developed methodology for the synthesis and
isolation of dipyrrinato lithium salts using either n-BuLi12
or, more successfully, LiHMDS.13 Dipyrrinato lithium
salts have been successfully employed as precursors to
Table 1. Proportions of 1 and 1BF2 from the Dipyrrin Hydro-
bromide Salt 1HBr upon Varying the Equivalents of BF3•OEt2
ratio of
equiv of
equiv of
NEt3
products
entry
BF3•OEt2
(1:1BF2)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
9
6
6
6
6
6
6
6
6
1:0
33:1
7.7:1
4.7:1
2.4:1
1.2:1
1:5
0:1
When equal equivalents of BF3•OEt2 and NEt3 were
used (Table 1, entry 6), we saw almost equal amounts of 1
and 1BF2 in the product mixture. It was only when the
equivalents of BF3•OEt2 exceeded the equivalents of NEt3
that we began to see the desired product 1BF2 forming in
large proportions (Table 1, entries 7 and 8). In fact, using 9
equiv of BF3•OEt2 and 6 equiv of NEt3 ensured that 1HBr
was converted solely to 1BF2 (Table 1, entry 8), and these
are indeed the conditions routinely used for the formation
of F-BODIPYs from dipyrrin HBr salts.10
(11) Fox, A.; Hartman, J. S.; Humphries, R. E. J. Chem. Soc., Dalton
Trans. 1982, 1275–1283.
(12) Cipot-Wechsler, J.; Al-Sheikh Ali, A.; Chapman, E. E.; Cameron,
T. S.; Thompson, A. Inorg. Chem. 2007, 46, 10947–10949.
(13) Al-Sheikh Ali, A.; Cipot-Wechsler, J.; Crawford, S. M.; Selim,
O.; Stoddard, R. L.; Cameron, T. S.; Thompson, A. Can. J. Chem. 2010,
88, 725–735.
(10) Crawford, S. M.; Thompson, A. Org. Lett. 2010, 12, 1424–1427.
Org. Lett., Vol. 14, No. 8, 2012
2159

dipyrrinato metal complexes,12À14 and we envisioned that
they could also be suitable precursors to F-BODIPYs.
We started by using a series of isolated dipyrrinato
lithium salts, prepared using LiHMDS and the corre-
sponding dipyrrin HBr salt.13 We were delighted to find
that when these dipyrrinato lithium salts were treated with
just 1 equiv of BF3•OEt2 the resulting F-BODIPYs could
be isolated in high yields. Furthermore, we found that
isolation of the intermediate dipyrrinato lithium salt was
unnecessary: generation of the lithium salt from the corre-
sponding dipyrrin and/or dipyrrin hydrobromide salt in
situ (using 1.1 or 2.2 equiv of LiHMDS, respectively),
followed by the addition of 1 equiv of BF3•OEt2, gave
comparable yields of the resulting F-BODIPYs, with
purification requiring merely a filtration through Celite
to remove the LiF byproduct.
Table 2. Synthesis of F-BODIPYs from Dipyrrinato Lithium
Salts Using 1 equiv of BF3•OEt2
To demonstrate the utility of this newly developed
methodology, we synthesized a variety of F-BODIPYs
(Scheme 3, Table 2) including those with meso-H and
meso-Ph substituents. Substituted and unsubstituted pyr-
rolic skeletons were well-tolerated by the new methodol-
ogy, as were conjugated and alkanoate esters. In all cases,
isolation of the desired product was facile: the reaction
mixtures were filtered over a pad of Celite (or Celite and
silica) to produce yields typically >80%. Notably, the
unsymmetrical F-BODIPY 2BF2 was synthesized in high
yield using this method, without the observation of
scrambled products (Table 2, entry 2).
Furthermore, this new procedure is scalable (Table 2,
entry 3). As the reaction only requires 1 equiv of BF3•OEt2,
and no NEt3, the previously observed BF3•NEt3 bypro-
duct is not produced and therefore isolation of the
F-BODIPY products is significantly easier. Furthermore,
the reaction was scaled to 1 g, outside of the glovebox,
under an inert atmosphere using anhydrous conditions to
result in a 94% isolated yield of 3BF2 (Table 2, entry 3c). It
should be noted that the F-BODIPY 3BF2 could also be
prepared by reacting the free-base dipyrrin 3 with 1 equiv
of BF3•OEt2 (without formation of the intermediate
lithium dipyrrinato complex), such as with the formation
of Cl-BODIPYs.15 However, this reaction produced lower
yields (50%) compared to the method involving in situ
formation of the lithium salt (94%).
a Glovebox, 50 mg scale. b Glovebox, 250 mg scale. c Inert atmo-
sphere conditions outside of glovebox, 1 g scale.
in situ as the F-BODIPY upon the addition of 6 equiv of
TEA and 9 equiv of BF3•OEt2:2 using this approach, we
obtained 5BF2 in 50% yield from the corresponding di-
pyrromethane, after column chromatography (Scheme 4).
We compared this approach to our new strategy, again
starting from the dipyrromethane. Thus, 3.3 equiv of
LiHMDS and then just 1 equiv of BF3•OEt2 were added
to the reaction mixture directly after the oxidation reaction
involving DDQ. The reaction was performed under nitro-
gen, and the workup required an acid/base wash followed
by a simple filtration through a pad of silica, rather than
chromatography per se, to afford pure 5BF2 in 52% yield
on an 800 mg scale, outside the glovebox, again demonstrat-
ing scalability and practicality. Thus, our new methodol-
ogy is easily melded with the much-trusted route from
dipyrromethanes that bypasses the need to isolate/purify
dipyrrins or their HX salts.
Scheme 3. Synthesis of F-BODIPYs from Dipyrrinato Lithium
Salts Using 1 equiv of BF3•OEt2
A common approach for synthesizing F-BODIPYs in-
volves oxidation of the corresponding dipyrromethane
with DDQ to form the free-base dipyrrin which is trapped
(15) Lundrigan, T.; Crawford, S. M.; Cameron, T. S.; Thompson, A.
Chem. Commun. 2012, 48, 1003–1005.
(14) Scharf, A. B.; Betley, T. A. Inorg. Chem. 2011, 50, 6837–6845.
2160
Org. Lett., Vol. 14, No. 8, 2012

Scheme 4. Synthesis of F-BODIPYs via in Situ Trapping of
Dipyrrins
Scheme 5. Synthesis of bis(F-BODIPY)s
of the free-base dipyrrin and only 1 equiv of BF3•OEt2.
This strategy has significant benefits over traditional con-
ditions for synthesizing F-BODIPYs (excess BF3•OEt2
and NEt3), and we anticipate widespread application
toward the synthesis of these fluorescent compounds. In
our new methodology, NEt3 isnot required and therefore a
BF3•NEt3 adduct byproduct is not formed: filtration
through Celite suffices for most purifications. The strategy
may be applied to the isolated free-base dipyrrin, or to the
approach involving trapping the dipyrrin in situ once it has
formed via oxidation of the corresponding dipyrromethane.
Indeed, using our new strategy for the synthesis of
F-BODIPYs via in situ trapping of dipyrrins, themselves
formed after oxidation of dipyrromethanes, gives compar-
able yields and simpler purifications than the usual ap-
proach. Our methodology avoids the synthesis of scrambled
byproducts in the formation of F-BODIPYs. Furthermore,
using this new methodology bis(F-BODIPY)s were synthe-
sized in yields appreciably higher than have previously been
attained.
Given the success of this improved methodology for
F-BODIPY formation, the same conditions were applied
to bis(dipyrrin)s in an attempt to synthesize bis(F-BODIPY)s
in appreciable yields (Scheme 5). To solutions of the free-
base bis(dipyrrin)s 9 and 10 in dichloromethane, LiHMDS
in tetrahydrofuran was added dropwise. The reaction
mixtures were stirred for 2 h to allow formation of the
dilithium salts to occur. Solutions of BF3•OEt2 in dichlor-
omethane were then added dropwise, and the reaction
mixtures were stirred for another 3 h. Upon completion,
the reaction mixtures were filtered through Celite. The
crude materials were purified over silica to give the desired
bis(F-BODIPY)s 9BF2 and 10BF2 in isolatedyields of 54%
and 45%, respectively, significantly higher than those
previously obtained for bis(F-BODIPY)s.
Acknowledgment. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada (NSERC).
Supporting Information Available. Experimental pro-
cedures, characterization data for new compounds, and
selected copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed an improved metho-
dology for F-BODIPY formation utilizing the lithium salt
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
2161