Table 1. Direct VNS of the 3-Hydrogen of BODIPY
Scheme 1. Mechanism of the VNS of the 3-Hydrogen of a
BODIPY Dye
yield
[%]c
product
LGa
Br
R
base
timeb
3a
3a
3b
3a
3b
3b
3c
COOMe
COOMe
COOtBu
COOMe
COOtBu
COOtBu
COMe
KOtBu
DBUd
KOtBu
KOtBu
DBUd
DBUd
DBUd
DBUd
K2CO3
DBUd
DBUd
DBUd
30 min
1 h
56
67
54
43
55
69
42
65
63
74
65
65
Br
Br
30 min
1 h
Cl
SPh
Mbzte
Br
14 h
15 min
14 h
As demonstrated previously, nucleophiles rapidly attack
R-unsubstituted BODIPY dyes at the 3-carbon, forming σH-
adducts, but due to the reversibility of this addition, there is
no net conversion unless oxidation can take place.6 Con-
versely, in the vicarious hydrogen substitution mechanism,
outlined in Scheme 1, the placement of a leaving group on the
nucleophile favors a base-mediated elimination/rearomati-
zation from intermediate 4 to the substitution product 3.
From the initial VNS reactions, it became clear that a
sufficiently strong base could affect the elimination, and
optimized procedures were rapidly reached. The VNS of
hydrogen allows introduction of several carbon nucleo-
philes in good yield, and as such BODIPY dyes substituted
with acetate esters (3a and 3b), malonate ester (3e), and
ketones (3c and 3d) were preparedin a single step(Table 1).
The leaving group can be varied, and even thioethers
derived from thiophenol and 2-mercaptobenzothiazole
act as leaving groups. Often, the reactions are particularly
fast, and after only a few minutes of stirring the mixture in
DMF with base, all the starting material is consumed to
yield the substituted products 3.
As an illustration of the generality of the method, VNS of
hydrogen with a phenacyl nucleophile was also applied to
BODIPY dyes with a phenyl or thiomethyl group at the
meso position (3f and 3g). The latter is of particular interest
as palladium catalyzed substitution of the reactive thioether
handle has been shown to be a powerful method for further
elaboration.8
While examining the scope of the reaction we realized that
the addition of nitronate nucleophiles could provide an entry
to the prevalent styrylated BODIPY fluorophores. Such
styrylated BODIPY dyes can be prepared from adequately
substituted pyrroles, but this linear synthesis had only limited
synthetic applications.9 Other routes to these interesting long-
wavelength absorbing dyes are transition metal catalyzed
3d
3d
3e
3fg
3gh
Br
COPh
15 min
14 h
Br
f
COPh
f
15 min
15 min
15 min
Br
Br
COPh
COPh
a LG = leaving group. b Reaction time at room temperature. c Yields
are isolated yields for a single reaction at 0.2 mmol of 1 scale. d DBU =
1,8-diazabicyclo[5.4.0]undec-7-ene. e Mbzt =2-Mercaptobenzothia-
zole. f 2-Bromodiethyl malonate, EtOOCCH(Br)COOEt, was used as
g
h
the leaving group carrying the nucleophile. R0 = Phenyl. R0 = S-
Thiomethyl.
cross-coupling reactions on halogenated4b and borylated
BODIPY dyes,10 but the direct condensation of activated
methyl substituents with aromatic aldehydes in a Knoevena-
gel type reaction is by far the most used.11 Products prepared
in this fashion have found use as chemosensors, sensitizers for
solar cells, and novel fluorescent materials.12
Despite this widespread use, the relatively harsh condi-
tions generally used for the Knoevenagel type reaction, i.e.,
reflux in toluene with buffered acetic acid or base, often
lead to lowered yields. Conversely, the synthesis of styry-
lated pyrroles as starting materials for the corresponding
BODIPY dyes requires several steps.13
In search of a solution to this problem, it was reasoned
that a reversible nucleophilic Michael type addition to
nitrostyrene should form a stabilized nitronate anion 7
(Scheme 2). Reminiscent of the Baylis-Hillman reaction,14
this anion could then attack the BODIPY dye at the
3-carbon, to yield σH-adduct 8. Completing the VNS of
hydrogen, nitrous acid is eliminated from this σH-adduct
under the influence of a base. The resulting intermediate 9
subsequently eliminates the nucleophile, and from
(11) (a) Rurack, K.; Kollmannsberger, M.; Daub, J. Angew. Chem.,
Int. Ed. 2001, 40, 385–387. (b) Atilgan, S.; Ozdemir, T.; Akkaya, E. U.
Org. Lett. 2008, 10, 4065–4067.
~
(8) Pena-Cabrera, E; Aguilar-Aguilar, A.; Gonzalez-Dominguez,
M.; Lager, E.; Zamudio-Vazquez, R.; Godoy-Vargas, J.; Villanueva-
(12) Rousseau, T.; Cravin, A.; Bura, T.; Ulrich, G.; Ziessel, R.;
Roncali, J. Chem. Commun. 2009, 1673–1675.
Garcia, F. Org. Lett. 2007, 9, 3985–3988.
(13) (a) Smith, J. R.; Campbell, S. A.; Ratcliffe, N. M.; Dunleavy, M.
Synth. Met. 1994, 63, 233–243. (b) Smith, J. R.; Ratcliffe, N. M.;
Campbell, S. A. Synth. Met. 1995, 73, 171–182.
(14) Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T.
Org. Lett. 2005, 7, 147–150.
(9) Kang, H.; Haugland, R. P. Ethenyl-substituted dipyrromethene-
boron difluoride dyes, US 5187288 A, 1993.
(10) Chen, J.; Mizumura, M.; Shinokubo, H.; Osuka, A. Chem.;
Eur. J. 2009, 15, 5942–5949.
Org. Lett., Vol. 13, No. 6, 2011
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