Exploring the Application of the Negishi Reaction of HaloBODIPYs: Generality, Regioselectivity, and Synthetic Utility in the Development of BODIPY Laser Dyes

Article abstract of DOI:10.1021/acs.joc.6b00350

The generality of the palladium-catalyzed C-C coupling Negishi reaction when applied to haloBODIPYs is demonstrated on the basis of selected starting BODIPYs, including polyhalogenated and/or asymmetrical systems, and organozinc reagents. This reaction is an interesting synthetic tool in BODIPY chemistry, mainly because it allows a valuable regioselective postfunctionalization of BODIPY chromophores with different functional groups. In this way, functional patterns that are difficult to obtain by other procedures (e.g., asymmetrically functionalized BODIPYs involving halogenated positions) can now be made. The regioselectivity is achieved by controlling the reaction conditions and is based on almost-general reactivity preferences, and the nature of the involved halogens and their positions. This ability is exemplified by the preparation of a series of new BODIPY dyes with unprecedented substitution patterns allowing noticeable lasing properties.

Full text of DOI:10.1021/acs.joc.6b00350

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Article
Exploring the Application of the Negishi Reaction of
HaloBODIPYs: Generality, Regioselectivity and Synthetic
Utility in the Development of BODIPY Laser Dyes
Eduardo Palao, Gonzalo Duran-Sampedro, Santiago de la Moya, Miriam Madrid, Carmen García-
Lopez, Antonia R Agarrabeitia, Bram Verbelen, Wim Dehaen, Noël Boens, and Maria José Ortiz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00350 • Publication Date (Web): 07 Apr 2016
Downloaded from http://pubs.acs.org on April 12, 2016
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Exploring the Application of the Negishi Reaction of HaloBODIPYs: Generality,
Regioselectivity and Synthetic Utility in the Development of BODIPY Laser Dyes
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Eduardo Palao,† Gonzalo DuranꢀSampedro,† Santiago de la Moya,*,† Miriam Madrid,†
Carmen GarcíaꢀLópez,† Antonia R. Agarrabeitia,† Bram Verbelen,‡ Wim Dehaen,‡ Nöel
Boens‡ and María J. Ortiz*,†
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†Department of Organic Chemistry I, Universidad Complutense de Madrid, Facultad de
Ciencias Químicas, Ciudad Universitaria s/n, Eꢀ28040 Madrid, Spain
‡Department of Chemistry, KU Leuven, Celestijnenlaan 200 f, Bꢀ3001 Leuven, Belgium
KEYWORDS: CꢀC coupling reactions; BODIPYs; Laser Dyes; Regioselectivity
355 nm pumping
X
R
8
7
5
1
3
Efficient tunable
[R-Zn]
6
2
N
N
N
N
Pd
B
B
Vis laser emission
F
F
F
F
(45-95%)
Unprecedented substitution
patterns by Negishi reactions
ABSTRACT: The generality of the palladiumꢀcatalyzed CꢀC coupling Negishi reaction
when applied to haloBODIPYs is demonstrated on the basis of selected starting
BODIPYs, including polyhalogenated and/or asymmetrical systems, and organozinc
reagents. This reaction is an interesting synthetic tool in BODIPY chemistry, mainly
because it allows a valuable regioselective postꢀfunctionalization of BODIPY
chromophores with different functional groups. In this way, functional patterns that are
difficult to obtain by other procedures (e.g., asymmetrically functionalized BODIPYs
involving halogenated positions) can now be made. The regioselectivity is achieved by
controlling the reaction conditions, and is based on almostꢀgeneral reactivity
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preferences, and nature of the involved halogens and their positions. This ability is
exemplified by the preparation of a series of new BODIPY dyes with unprecedented
substitution patterns allowing noticeable lasing properties.
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INTRODUCTION
During the last two decades, BODIPYs (4,4ꢀdifluoroꢀ4ꢀboraꢀ3a,4aꢀdiazaꢀsꢀindacenes,
also known as boron dipyrromethenes or boron dipyrrins)1 have become important
molecules for the development of valuable photonic tools,2 such as chemosensors,3 laser
dyes,4 potential photodynamic therapy agents,5 or photoactive organic materials for
photovoltaic devices.6 The vast increase in the use of these dyes is undoubtedly due to
their many excellent characteristics, such a bright fluorescence in the visible (Vis)
spectral range, and a good robustness towards light and chemicals.2
The synthetic accessibility when constructing BODIPYs is certainly another major
reason for the attractiveness of these dyes. Functionalized BODIPYs can be obtained
from suitably functionalized pyrroles (preꢀfunctionalization),7 or the desired functional
pattern can be introduced in a later stage after the construction of the BODIPY core
(postꢀfunctionalization).8 In particular, postꢀfunctionalization, which requires the use of
reactive BODIPYs is highly attractive. This is because postꢀfunctionalization limits the
manipulation of unstable pyrrole derivatives, and allows the straightforward
introduction of a greater variety of functional groups. In fact, with a limited synthetic
effort, a large number of functional groups can be introduced onto the BODIPY core by
postꢀfunctionalization methodologies.8 However, introducting certain functionalities
(e.g., alkyl groups substituted with additional reactive functional groups) or achieving
certain functional patterns onto the BODIPY core (e.g., involving reactive functional
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groups) cannot easily be done by postꢀfuctionalization methods, and are thus instead
prepared by complex preꢀfunctionalization routes.9
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Among the palladium catalyzed CꢀC coupling reactions, Negishi reaction on easily
accessible haloBODIPYs could offer a solution for these problematic cases , due to the
high functionalꢀgroup compatibility (including the labile BODIPY BF2 group) of
organozinc reagents ([RꢀZn]) compared to other organometal compounds. Strickingly,
Negishi reaction has been scarcely used in the development of BODIPY dyes, despite
its demonstrated utility in the synthesis of advanced photonic materials.10 In fact, the
unique Negishi reactions of BODIPYs (involving 3,5ꢀdihaloBODIPYs; Scheme 1) were
reported by us recently.10b In this seminal work, 8ꢀ(4ꢀmethylphenyl)ꢀ3,5ꢀdihaloBODIPY
(1) was used as the starting material to exemplify the effectiveness of Negishi reaction
to prepare alkylated derivatives 2. This was done by introducing one or two identical
alkyl groups (i.e., diꢀ vs. monoꢀcoupling) selectively onto the BODIPY core.
Furthemore, two different alkyl groups could be introduced by using two consecutive
controlled Negishi reactions.
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Scheme 1. Preliminary Negishi reactions of 3,5ꢀdihaloBODIPYs
On the basis of these preliminary results, we became interested in studying the
versatility and selectivity of the Negishi reaction when applied to haloBODIPYs. For
this purpose, we have used different starting halogenated and (poly)halogenated
BODIPYs, including those bearing different halogens (chlorine, bromine and iodine),
on different BODIPY positions, and having different starting symmetries (symmetrical
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vs. asymmetrical haloBODIPYs). The results obtained from this systematic study have
allowed us to establish straightforward synthetic protocols to obtain unprecedented
substitution patterns onto the BODIPY core, surmounting the limits imposed by the
known preꢀ and postꢀfunctionalization methods. The utility of these protocols has been
exemplified by the preparation of a series of new alkylated BODIPYs, including
halogenated ones, with noticeable lasing properties.2d,4a,11
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RESULTS AND DISCUSSION
Generality and regioselectivity. Since our preliminary results confirmed that the
Negishi reaction works well in symmetrical 3,5ꢀdihaloBODIPYs (at least for the
essayed BODIPYs and organozinc reagents; Scheme 1),10b our first objective was to
explore the feasibility of similar CꢀC couplings in symmetrical 2,6ꢀdihaloBODIPYs.
For this purpose we selected a small series of related 2,6ꢀdihaloBODIPYs (3a-i, Table
1) to test the influence of the halogen involved (chlorine, bromine vs. iodine; e.g., cf. 3a,
3b and 3c), and of the BODIPY substrate (e.g., cf. 3c and 3d, or 3f, 3h and 3i for
stereoelectronic effects, or 3b, 3e and 3g for electronic effects without steric influence).
The starting BODIPYs were also selected on the basis of their synthetic accessibility.
Thus, 2,6ꢀdichloroBODIPY 3a,12 2,6ꢀdibromoBODIPY 3b,13 and 2,6ꢀdiiodoBODIPYs
3c5a and 3i14 were prepared straighforwardly using described procedures, which involve
electrophilic halogenation of the corresponding parent (nonꢀhalogenated) BODIPY as
the key step. For example, dibromoBODIPYs 3e and 3g were obtained by electrophilic
bromination of the corresponding parent BODIPY with Nꢀbromosuccinimide (NBS) or
pyridine hydrobromide perbromide (PyHBr3) (60% and 68% isolated yield,
respectively; see Experimental Section), whereas 2,6ꢀdiiodoBODIPYs 3d, 3f and 3h
were obtained by electrophilic iodination of the corresponding nonꢀhalogenated parent
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BODIPY with commercial ICl (69%, 70%, 93% and 85% isolated yield, respectively;
see Experimental Section). The reactivity of these substrates in a Negishi reaction was
tested at room temperature (r.t.) by coupling with commercial Me2Zn using
Pd(PPh3)2Cl2 as preꢀcatalyst in toluene (Table 1).
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Table 1. Negishi methylation of 2,6ꢀdihaloBODIPYs (Scheme 2).a
4 (yield)b
ꢀ
Entry
3
X
Cl
Cl
Br
I
R1
R2
H
R3
H
1
pꢀTol
pꢀTol
pꢀTol
pꢀTol
pꢀTol
H
3a
3a
3b
3c
3d
3e
3f
2c
3
H
H
4a (69)c
4a (41)d
4a (42)e
4b (40)f
4c (70)
4c (71)
4d (59)g
4d (68)g
4e (69)h
H
H
4
H
H
5
I
H
Me
Me
Me
Me
Me
Me
6
Br
I
H
7
H
H
8
Br
I
Me
H
3g
3h
3i
9
Me
H
10
I
Me
Me
aMe2Zn (1.2 M in toluene); Pd(PPh3)2Cl2 (10 mol%); toluene as solvent; r.t. (for details, see
b
c
Experimental Section). Isolated yield. XPhos (10 mol%) was added to the reaction mixture
d
e
(see Experimental Section). 5a (10%) and 6 (9%) were also isolated (Figure 1). 6 (11%) and
f
7a (11%) were also isolated (Figure 1). 5b (16%), and 7b (14%) were isolated also
(Figure 1). g8a (13%). h8b (9%) were isolated also (Figure 1).
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In contranst to what was found previously with the Negishi dimethylation of mesoꢀ
tolylated 1 (Scheme 1), where the nature of the involved halogen atom (chlorine vs.
bromine) did not have any appreciable influence on the obtained yield (ca. 80%),10b the
dimethylation yield of related mesoꢀtolylated 3 under similar reaction conditions
showed a clear dependence on the nature of the halogen involved (chlorine vs. bromine;
see entries 1 and 3 in Table 1). Thus, the dichlorinated dye 3a, which is expected to be
less reactive when compared with related dibrominated dye 3b, did indeed not react
under the selected reaction conditions. However, when a more efficient palladium
catalytic system, involving 2ꢀdicyclohexylphosphinoꢀ2′,4′,6′ꢀtriisopropylbiphenyl
(XPhos) as electronꢀrich phosphine ligand,15 was used instead reaction did ocurr (cf.
entries 1 and 2 in Table 1). These results demonstrate the higher Negishi reactivity of
3,5ꢀdihaloBODIPYs compared to the related 2,6ꢀdihaloBODIPYs. On the other hand,
no significant differences were observed for dibrominated 3b vs. diiodinated 3c
compounds under the selected conditions (cf. entries 3 and 4 in Table 1), neither for
dibrominated 3e or 3g vs. related diiodinated 3f or 3h (cf. entries 6 and 7, or 8 and 9,
respectively, in Table 1).
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Changing the hydrogens at the 3,5ꢀpositions of BODIPY by methyl groups, did not
seems to influence the reactivity, although the steric hindrance around of the reactive Cꢀ
halogen bond was increased (cf. entries 4 and 5 in Table 1). There was also no effect on
the reactivity observed when an additional neighboring methyl group was introduced on
the system (cf. entries 9 and 10 in Table 1). On the other hand, the presence of pꢀtolyl
(pꢀTol) group instead of hydrogen at the meso (8) position produced a noticeable lower
yield (cf. entries 3 and 6, and 4 and 7 in Table 1), which could be due to differential
electronic effect, but not to difference in steric hindrance. However, appreciable
reactivity differences could not be detected when changing meso hydrogen by meso
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methyl (cf. entries 6 and 8, and 7 and 9 in Table 1); i.e., where only different inductive
effects are involved. Interestingly, the loss of Negishi reactivity towards dimethylation
observed for mesoꢀtolylated 2,6ꢀdihaloBODIPYs 3bꢀd and 3g-i was accompanied by the
detection of minor sideꢀproducts (see 5ꢀ8 in Figure 1, and Table 1), whose competitive
formation could explain the lower yields for the formation of desired compound 4.
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Figure 1. Minor sideꢀproducts isolated after Negishi methylation of 3b-d, 3g-i (Table 1).
Once it was confirmed that Negishi reaction can be applied to standard BODIPYs
halogenated at their 2,6ꢀ, or 3,5ꢀpositions, we became interested in investigating if such
synthetical valuable CꢀC forming reactions could be applied also when the reactive
halogen is located at other BODIPY positions (i.e., at 1,7 or 8). For this purpose, we
selected the methylation of the syntheticallyꢀaccessible symmetrical 1,7ꢀ
dibromoBODIPY 97c and 8ꢀchloroBODIPY 1016 (Scheme 2) under the same reaction
conditions (i.e., excess of Me2Zn, Pd(PPh3)2Cl2 as the preꢀcatalyst, and toluene as the
solvent; see Experimental Section). The expected 1,7ꢀdimethylated and 8ꢀmethylated
BODIPYs (11 and 12, respectively) were obtained in excellent yields (Scheme 2), even
starting from 10, where a less reactive chlorinated position is involved.
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Comparison of these last two results with those obtained for the methylation of related
symmetrical BODIPYs halogenated at 2,6 (Table 1) or 3,5 (Scheme 1) position using
the same coupling conditions, seems to show the following preferences (halogen and
BODIPY position) for the Negishi reaction in haloBODIPYs: I > Br > Cl; 8 > 3,5 ~ 1,7
> 2,6. The halogen preference agrees with that found for related palladiumꢀcatalyzed Cꢀ
C couplings in other halogenated electronꢀpoor aromatic systems (e.g., halopyridines);17
whereas the position preference agrees with that reported for Suzuki and Shonogashira
reactions in chlorinated BODIPYs.8a,8dꢀe,18
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Scheme 2. Negishi methylations in 1,7ꢀdihalo and 8ꢀhaloBODIPYs (for details, see
Experimental Section).
In our preliminary communication on the Negishi coupling of 3,5ꢀdihaloBODIPYs,10b
we demonstrated that the controlled Negishi coupling of a single halogenated position
in symmetrical 3,5ꢀdihaloBODIPYs (partial Negishi coupling leading to stillꢀ
halogenated systems) is possible under stoichiometrically controlled reaction conditions
(Scheme 1). This is highly interesting for two reasons: (1) the higher accessibility to
starting polyhalogenated BODIPYs involving symmetrical halogenated positions; (2)
the utility of the obtained asymmetrical haloBODIPYs as synthetic intermediates in the
preparation of other asymmetrical BODIPY derivatives (e.g., by a subsequent coupling
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reaction).10b Regarding this, the influence of the halogenated BODIPY positions on the
reactivity of the Negishi reaction (see above) prompted us to test if this difference could
be used to allow a controlled partial Negishi coupling in asymmetrical polyhalogenated
BODIPY systems. We selected trihaloBODIPYs 13ꢀ15 (Scheme 3) as the starting
asymmetrical polyhalogenated systems due to their synthetic accessibility. Thus,
tribromoBODIPY 13 was prepared in a straightforward fashion by electrophilic
bromination of the corresponding nonꢀhalogenated parent BODIPY with Br2 (75%
isolated yield; see Experimental Section), whereas tribromoBODIPY 14 was obtained as
minor product in the preparation of 3e (28% isolated yield; see Experimental Section).
On the other hand, dichloroBODIPY 15 was obtained following a described
procedure.12
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Methylation reactions (using Me2Zn) essayed on asymmetrical polyhaloBODIPYs 13-
15 (Scheme 3) demonstrated the possibility of undergoing partial Negishi reactions in
such systems, by selecting properly the reaction conditions on the basis of the expected
reactivity of the involved halogenated positions. Thus, for 1,2,3ꢀtribromoBODIPY 13,
where two similar highlyꢀreactive 1 and 3 brominated positions are involved, it was
possible to obtain a separable mixture of monomethylated 16 and dimethylated 17 (34%
and 26% isolated yield, respectively) when ca. 1 mol equiv. of Me2Zn was used under
standard reaction conditions (10 mol% Pd(PPh3)2Cl2; Scheme 3). However, when the
same starting tribromoBODIPY was treated under the same conditions with a large
excess of Me2Zn (20 mol equiv.) a separable mixture of major dimethylated 17 and
minor trimethylated 18 was obtained (57% and 33% isolated yield, respectively;
Scheme 3). On the other hand, using an ample excess of Me2Zn together with XPhos as
an additive allows the isolation of trimethylated 18 as the major reaction product (77%
isolated yield; Scheme 3). These results confirm the higher reactivity of the 1ꢀ and 3ꢀ
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BODIPY positions, when compared to the 2ꢀpositions, as well as the mentioned
4
5
6
influence of stereolectronic factors in such reactivity.
7
Me
Me
Br
8
9
ca. 1 mol Me2Zn
Et
Br
+
17 (26%)
N
N
Pd(PPh3)2Cl2
B
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F
F
Me
Me
16 (34%)
Me
Me
Me
Me
Me
Me
Me
Me
Br
Br
excees Me2Zn
Pd(PPh3)2Cl2
Et
Br
+ 18 (33%)
Et
Br
N
N
N
N
B
B
F
F
F
F
13
17 (57%)
Me
Me
Me
Me
Me
Me
excees Me2Zn
Et
Me
N
N
Pd(PPh3)2Cl2 / XPhos
B
F
Ac
18 (77%)
Br
Br
N
N
B
F
F
Me
Me
Me
Br
19 (65%)
excees Me2Zn
Pd(PPh3)2Cl2
Br
Br
+
N
N
B
F
F
Me
Me
Me
Br
14
N
N
B
F
F
Me
Me
20 (24%)
Me
Me
Me
Me
Me
excees Me2Zn
Pd(PPh3)2Cl2
Et
Cl
Et
Cl
N
N
N
N
B
B
F
F
F
F
Me
Me
Cl
21 (70%)
15
Scheme 3. Selectivity of Negishi methylation of asymmetrical polyhalogentated BODIPYs (for
details, see Experimental Section).
Similar reactivity was confirmed for asymmetrical haloBODIPYs 14 and 15 (Scheme 3
and note the different reactivity depending on position and stereoelectronic factors).
Thus, the treatment of tribromoBODIPY 14 with excess of Me2Zn, using the less
reactive catalyst under standard reaction conditions, allowed the formation of a
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separable mixture of major monomethylated 19 and minor dimethylated 20 (65% and
24 % isolated yield, respectively; Scheme 3), whereas dichlorinated 15 under the same
conditions gave monomethylated 21 (70% isolated yield) as the only reaction product.
The structures of BODIPYs 16, 17, 19 and 20, according to the aboveꢀmentioned
regioselectivity, were inequivocally assigned by 1D and 2D NMR experimts (see
Experimental Section).
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12
13
14
15
16
17
18
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In our preliminary communication on the Negishi coupling,10b we also demonstrated
utility of this reaction to introduce other alkyl groups than methyl, as well as alkynyl
and aryl groups at the halogenated positions of symmetrical 3,5ꢀdibromoBODIPYs
(Scheme 1). To check this possibility of these reactions at other BODIPY positions, we
studied at small, but representative, series of reactions shown in Scheme 4. Criteria of
accessibility for the chosen starting haloBODIPYs and organozinc reagents were taken
into account for the selection.
Thus, Negishi ethylation of 10,16 228b and 2312 under simple standard conditions (excess
of Et2Zn and 10 mol% Pd(PPh3)2Cl2; Scheme 4) yielded the corresponding expected
ethylated BODIPY according to the demonstrated general reactive preference for the
halogenated position (8 > 3,5 ~ 1,7 > 2,6; Scheme 3). Thus, it was possible to easily
ethylate 8ꢀchloroBODIPY 10 to form 8ꢀethylBODIPY 25 in an excellent yield (Scheme
4). It was also possible to undergo the partial ethylation of 2,3,5,6ꢀtetrabromoBODPYs
22, without reacting the less reactive 2ꢀ and 6ꢀpositions, to generate 3,5ꢀdiethylBODIY
26 (Scheme 4). Noticeably, it was even possible to conduct the partial ethylation of 5,7ꢀ
dichloroBODIPY 23, which involves more similar reactive positions, to generate
selectively major 5ꢀethylBODIPY 27 together with minor 5,7ꢀdiethylBODIPY 28
(Scheme 4).
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Scheme 4. Additional Negishi reactions of different haloBODIPYs (for details, see
Experimental Section).
The reactivity of the 2,6ꢀpositions towards Negishi reaction could be enhanced by using
iodoBODIPYs. In fact, we were able to arylate and alkynylate these iodinated positions
under standard catalytic conditions (10 mol% of Pd(PPh3)2Cl2). Thus, as an example,
the highly stericalꢀhindered positions of 2,6ꢀdiiodoBODIPY 3i14 were easily phenylated
using commercial PhZnBr to yield 2,6ꢀdiphenylBODIPY 29 (Scheme 4). On the other
hand, photophysicalꢀinteresting
π
ꢀextended 2ꢀ(phenylethynyl)BODIPYs14,19 30a-b
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could be straightforwardly obtained by Negishi phenylethynylation of the corresponding
2ꢀiodoBODIPYs 24a-b (Scheme 3). The novel starting maerial 24b was obtained
similarly to 24a,5a by iodination of the corresponding nonꢀhalogenated parent BOPIPY20
with ICl (see Experimental Section).
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19
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Certain electronꢀpoor enough BODIPYs conveniently substituted in specific positions
with good leaving groups (e.g., polyhaloBODIPYs with halogen located at 1,7 or/and
3,5 BODIPY positions) are known to undergo aromatic nucleophilic substitution (SNAr)
easily.5a,8f,21 Therefore, SNAr could be competitive with the Negisthi reaction in some of
the above studied cases (i.e., the organozinc reagent acting as a nucleophile without
requiring any palladium catalyst). To test this possibility, we selected
polyhaloBODIPYs 15 and 22 (Schemes 3 y 4, respectively), which are specially
activated for SNAr. These BODIPYs were reacted with organozinc reagent in absence of
palladium, but maintining the rest of the reaction conditions previously essayed for
them (Scheme 5), showing no reaction in the case of 15, and partial reaction in the case
of 22 to afford monoehtylated 31 (22% isolated yield). Therefore, it is concluded that
SNAr could compite with the Negishi reaction in special cases involving strongly
activated BODIPYs, as it ocurrs for polybrominated 22. Nonetheless, this competitive
pathway is surpassed by the faster Negishi one.
Scheme 5. Nucleophilic aromatic substitution vs. Negishi reaction in parallel conditions (for
details, see Experimental Section).
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Photophysical properties and laser activity. Most of the above conducted Negishi
reactions allowed the straightforward synthesis (as single or major reaction products)
unprecedented BODIPY dyes with interesting substitution patterns (most of them
involving asymmetrical chromophoric systems with multiple alkyl groups). These
compounds could be interesting as potential laser dyes.2d,11 8ꢀ(4ꢀ
methylphenyl)BODIPYs (e.g., see 4a in Table 1) and polybromoBODIPYs (e.g., see 19
in Scheme 3) were discarded for this study due to their expected poor fluorescence.22
Nonetheless, the fluorescence ability of the selected BODIPYs (17, 18, 20, 21, 25, 27
and 30b; Schemes 3 and 4) was tested before studying their lasing behavior (Table 2).
The compounds investigated exhibited the typical absorption and fluorescence spectra
of BODIPY dyes,2,11 with maximum absorption at ca. 500 nm, which can in somes
cases be shifted up to ca. 530 nm by wellꢀknown stereolectronic effects in BODIPYs
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(e.g., in π
ꢀextended 30b).14,19 The Stokes shifts also agreed with those values expected
for similar BODIPY chromophores.11 The different fluorescence ability of the studied
BODIPYs (quantum yields from 0.27 to 1.00; Table 2) can be explained also by known
factors quenching the fluorescence of BODIPYs, such as loss of symmetry, presence of
heavy atoms, conformational flexibility, etc.2bꢀc,11c,22 Thus, as examples, the fluorescent
quantum yield of quasi symmetrical 18 is similar to that observed for symmetrical
PM546 (4,4ꢀdifluoroꢀ1,3,5,7,8ꢀpentamethylBODIPY),whereas asymmetrical and
chlorinated 21 exhibited a clear loss of fluorescence (Table 2 and Scheme 3). However,
similar asymmetrical and chlorinated 27 (Scheme 4), but halogenated at the 3ꢀposition
instead of the 2ꢀposition, exhibited a noticeable high fluorescent quantum yield (0.88;
Table 2), which demonstrated the importance of the position of the substitution pattern
for balancing opposite factors affecting photophysical properties. Also remarkable is the
extraordinarily high fluorescence quantum yield (
Φ
= 1.00) measured for structurallyꢀ
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simple symmetrical 25 (Scheme 4), which is superior to that measured for the
4
5
6
commercial BODIPY laser dye PM546 under the same solution conditions (Table 2).
7
8
Table 2. Basic phothophysical properties,a and lasing behaviorb of selected BODIPYs
9
10
11
12
13
14
15
16
17
18
19
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22
23
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in ethyl acetate solution. Commercial PM546 has been included for comparison.
[c]g
Eff.h
(%)
c
d
i
λabs
λem
ꢀνe
λlas
Dye
Φf
(cmꢀ1)
402
764
686
424
425
367
615
1094
(nm)
541 j
582
560
572
554
510
543
600
(mM)
(nm)
494
514
517
526
513
491
502
533
(nm)
502
535
536
538
521
500
518
566
PM546
17
0.85
0.51
0.81
0.55
0.27
1.00
0.88
0.43
2.5j
0.5
0.5
2.0
1.0
0.7
2.0
1.0
23 j
26
44
30
35
55
46
18
20
21
25
27
18
30b
b
c
aDye concentration ca 10ꢀ5 M. Under transversal pumping at 355 nm. Maximum absorption
d
wavelength. Maximum emission wavelength upon irradiation at the maximum absorption.
f
eStokes shift. Fluorescence quantum yield. gOptimal concentration for maximum laser
efficiency. hLaser efficiency. iPeak wavelength for the laser emission. jData from reference 4b.
According to their absorption properties, the lasing action of the selected new dyes was
studied under pumping at 355 nm dye solutions in ethyl acetate (see Experimental
Section). All the solutions, placed in a simple planeꢀplane nonꢀtunable resonator,
exhibited broadꢀlineꢀwidth laser emission (pump threshold energy of ~0.8 mJ,
divergence of 5 mrad; pulse duration of 8 ns fullꢀwidth at half maximum (FWHM)). To
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optimize the laser action from the different dyes, we first analyzed the dependence of
the lasing properties with the dye concentration in ethyl acetate solution, by varying the
optical densities from 8 to 30 while keeping all other experimental parameters constant.
In all cases, the studied dye solutions followed the typical behavior, with the laser
efficiency (Eff.; defined as the ratio between the energy of the dye laser output and the
input energy incident on the sample surface) first increasing with the dye concentration
until an optical density (ca. 15) where a maximum efficiency is reached. From this point
on, further increasing the dye concentration resulted in a loss of the laser efficiency.
This fact can be accounted for an increase of the reꢀabsorption/reꢀemission processes,
with deleterious effect on the laser action. The results obtained are collected in Table 2,
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where the wavelength for the peak of the laser emission (λlas) and the laser efficiency
(Eff.) are presented, as well as the corresponding optimal concentration ([c]) for each
dye solution. To facilitate the interpretation and comparison of the obtained lasing
results, Figure 2 shows the laser emission spectra of the studied dye solutions, the
height of the peak being proportional to the laser efficiency.
Figure 2. Laser emission spectra for the studied selected BODIPYs (data from Table 2).
The comparison of the results collected in Table 2 (or Figure 2) with the photophysical
properties in the same table demonstrates that the lasing behavior of the studied dyes in
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ethyl acetate solution correlates well with their photophysical properties: the higher the
fluorescence quantum yield, the higher is the laser efficiency, the longer the
fluorescence wavelength, the more redꢀshifted becomes the lasing emission. Noticeably,
the measured maximum laser efficiencies (up to 55%) were superior to that exhibited by
the commercial laser dye PM546,4b with the only exception of 30b (Table 2), and
required a minor optimal concentration, which is a valuable advantage when developing
dye lasers. Thus, for example, alkylBODIPYs 18 and 25 exhibited laser efficiencies
much higher than those exhibited by PM546 (44% and 55%, vs. 23%; Table 2) by using
significant smaller dye concentrations (0.5 mM and 0.7 mM, vs. 2.5 mM; Table 2). In
this regard, the high laser efficiency measured for 25, despite its extraordinarely simple
(almost naked) structure (Scheme 4), must be highlighted. On the other hand, the laser
behavior of bromoBODIPYs 17 and 20 is also remarkable, with both exhibiting highꢀ
enough laser efficiencies (26% and 30%, vs. 23%; Table 2) despite the expected adverse
heavyꢀatom effect.5e,22
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Finally, it must be emphasized that the laser emissions of the studied series of Negishiꢀ
accesible BODIPYs are well distributed into a wide spectral range (510ꢀ600 nm; Figure
2). In other words, the laser emission can be fineꢀtuned by the substitution pattern of the
BODIPY chromophore, which is achieved using straightforward Negishi reactions
involving easily accessible haloBODIPYs.
CONCLUSION
We have systematically studied the workability of the Negishi reaction when applied to
haloBODIPYs, showing it interest as a valuable synthetic tool for the development of
BODIPY dyes. The high accessibility to haloBODIPYs and organozinc reagents, as well
as the known high compatibility of these organometal reagents with multiple functional
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groups, undoubtedly makes Negishi reaction to be an unavoidable synthetic tool to take
into account when planning the synthesis of a new BODIPY dye, mainly when reactive
groups are required in the final dye structure. Interestingly, it is shown that the Negishi
reaction of haloBODIPYs is deeply affected by the involved BODIPY position, as well
as by the nature of the halogen atom, making possible to conduct partial
(regiocontrolled) functionalizations in polyhalogenated systems by selecting properly
the reaction conditions. The soꢀobtained stillꢀhalogenated BODIPYs are valuable
synthetic intermediates to other asymmetrical BODIPYs, which cannot be easily
prepared by different synthetic routes. To exemplify this synthetic advantage, we have
conducted Negishi of accessible haloBODIPYs to generate easily a small series of
unprecedented alkylated BODIPYs with specific substitution patterns, most of them
umprecedented. The study of the lasing behavior of these new dyes has allowed
discovering unexpected noticeable lasing properties for unconventional BODIPY laser
dyes, which becames to demonstrate the capacity of the Negishi reaction for the
development of smarter BODIPY dyes for advanced photonic applications.
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EXPERIMENTAL SECTION
General remarks. All starting materials and reagents were commercially, unless
indicated otherwise, and used without further purifications. Common solvents were
dried and distilled by standard procedures. Flash chromatography was performed using
silica gel (230ꢀ400 mesh). Melting points were determined on a standard melting point
1
apparatus, and are uncorrected. NMR spectra were recorded at 20 ºC in CDCl3. H
chemical shifts are dated in ppm relative to tetramethylsilane (δ = 0.00 ppm) as internal
reference. 13C chemical shifts are dated in ppm with CDCl3 (
δ
= 77.67 ppm) as the
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internal standard. DEPT 135 experiment was used to assignate the type of carbon
nucleous (C vs. CH vs. CH2 vs. CH3). In specific cases, combination of 2D HMQC and
HMBC experiments with selective gradientꢀenhanced 1D NOESY experiments was
used to unequivocally discern between regioisomeric structures (in these cases, the
unequivocal assignation of NMR signals is dated). FTIR spectra were obtained from
neat samples using the ATR technique. High resolution mass spectrometry HRMS) was
conduced using the EI technique and electrostatic sector and magnetic sector mass
analyzers.
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Photophysical properties were measured for diluted (ca. 10ꢀ5 M) dye solutions in acethyl
acetate. UVꢀVis absorption and fluorescence spectra were recorded on standard
spectrophotometer and spectrofluorimeter, respectively. The fluorescence spectra were
corrected from the wavelength dependence of the detector sensibility. Commercial
BODIPY PM546 was used as the reference dye (
Φ
= 0.85 in ethyl acetate).4b
Lasing properties were measured for liquid solutions of dyes contained in 1 cm opticalꢀ
path rectangular quartz cuvettes carefully sealed to avoid solvent evaporation during the
experiments. The liquid solutions were transversely pumped at 355 nm, with 5 mJ, 8 ns
FWHM pulses from the thirdꢀharmonic of a Qꢀswitched Nd:YAG laser at a repetition
rate of up to 10 Hz. The exciting pulses were lineꢀfocused onto the cuvette, providing
pump fluences on the active medium in the range 110ꢀ180 mJ/cm2. The oscillation
cavity (2 cm length) consisted of a 90% reflectivity aluminum mirror, with the lateral
face of the cuvette acting as output coupler.
Synthesis of halogenated BODIPYs
Halogenated BODIPYs 3a,12 3b,13 3c,5a 3i,14 9,7c 10,16 15,12 22,8c 23,12 and 24a5a were
synthesized by the corresponding described methods.
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4,4ꢀDifluoroꢀ2,6ꢀdiiodoꢀ3,5ꢀdimethylꢀ8ꢀ(4ꢀmethylphenyl)BODIPY (3d). To a solution of
4,4ꢀdifluoroꢀ3,5ꢀdimethylꢀ8ꢀ(4ꢀmethylphenyl)BODIPY23 (40 mg, 0.13 mmol) in a
CH2Cl2/MeOH mixture (10 mL/10 mL) was added dropwise a solution of ICl (0.32 mL,
0.32 mmol) in MeOH (5 mL), and the mixture stirred at r. t. for 10 min. The solvent was
evapored under vacuum and the crude product was dissolved in CH2Cl2, washed with
water, dried over MgSO4, filtered and concentrated to dryness. Flash chromatography
on silica gel using hexane/EtOAc (98:2) afforded 3d (50 mg, 69%) as a red solid.
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1H NMR (300 MHz, CDCl3)
tolyl), 6.89 (s, 2H, 2CH), 2.58 (s, 6H, 2CH3), 2.38 (s, 3H, CH3) ppm. 13C NMR (75
δ 7.29 (d, J = 8.1 Hz, 2H, tolyl), 7.23 (d, J = 8.1 Hz, 2H,
MHz, CDCl3)
δ
158.4, 141.8, 141.2, 136.8 (CH), 135.2, 130.4, 130.3 (CH), 129.3 (CH),
2921, 1556, 1437, 1231, 1124,
21.5 (CH3), 15.5 (CH3) ppm, (CꢀI) not observed. FTIR
υ
998 cmꢀ1. HRMS m/z 561.9377 (calcd for C18H15BF2I2N2: 561.9384).
2,6ꢀDibromoꢀ4,4ꢀdifluoroꢀ3,5ꢀdimethylBODIPY (3e) and 1,2,6ꢀtribromoꢀ4,4ꢀdifluoroꢀ
3,5ꢀdimethylBODIPY (14). To a solution of 4,4ꢀdifluoroꢀ3,5ꢀdimethylBODIPY24 (41
mg, 0.19 mmol) in dry CH2Cl2 (10 mL) was added, under argon atmosphere, PyHBr3
(125 mg, 0.39 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was washed
with saturated aqueous NH4Cl and water, dried over MgSO4, filtered and concentrated
to dryness. Flash chromatography using hexane/CH2Cl2 (95:5) afforded
tribromoBODIPY 14 (24 mg, 28%) and dibromoBODIPY 3e (58 mg, 60%), as red
solids.
1
3e: H NMR (700 MHz, CDCl3)
δ 6.96 (s, 2H, 2CH), 6.94 (s, 1H, CH), 2.53 (s, 6H,
2CH3) ppm. 13C NMR (176 MHz, CDCl3)
2926, 1545, 1450, 1254, 1100, 989 cmꢀ1. HRMS
δ 156.7, 133.3, 130.0 (CH), 126.2 (CH),
109.0 (CꢀBr), 13.5 (CH3) ppm. FTIR
υ
m/z 375.9199 (calcd for C11H9BBr2F2N2: 375.9193).
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14: M.p.: 215ꢀ217 ºC. H NMR (700 MHz, CDCl3)
δ 7.08 (s, 1H, CH), 7.05 (s, 1H,
CH), 2.56 (s, 3H, CH3), 2.53 (s, 3H, CH3) ppm. 13C NMR (176 MHz, CDCl3)
δ
158.2,
5
6
7
8
9
155.2, 133.7, 131.9, 130.8 (CH), 124.5 (CH), 121.2 (CꢀBr), 110.9 (CꢀBr), 110.1 (CꢀBr),
2928, 1525, 1453, 1214, 1076, 1065, 993 cmꢀ1.
14.1 (CH3), 13.7 (CH3) ppm. FTIR
υ
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HRMS m/z 453.8286 (calcd for C11H8BBr3F2N2: 453.8298).
4,4ꢀDifluoroꢀ2,6ꢀdiiodoꢀ3,5ꢀdimethylBODIPY (3f). According to the procedure
described for 3d, 4,4ꢀdifluoroꢀ3,5ꢀdimethylBODIPY24 (102 mg, 0.47 mmol) in
CH2Cl2/MeOH (10 mL/10 mL), and a solution of 1.7 mL of ICl (1 M in CH2Cl2, 1.17
mmol) in MeOH (5 mL) were reacted for 15 min. Flash chromatography on silica gel
using hexane/CH2Cl2 (8:2) afforded diiodoBODIPY 3f (150 mg, 68%) as a red solid.
1H NMR (300 MHz, CDCl3)
ppm. 13C NMR (75 MHz, CDCl3)
2921, 1555, 1447, 1235, 1114, 991 cmꢀ1. HRMS m/z 471.8909
δ 7.06 (s, 2H, 2CH), 6.88 (s, 1H, CH), 2.54 (s, 6H, 2CH3)
δ
159.5, 136.5 (CH), 135.3, 125.1 (CH), 77.2 (CꢀI),
15.6 (CH3) ppm. FTIR
υ
(calcd for C11H9BF2I2N2: 471.8915).
2,6ꢀDibromoꢀ4,4ꢀdifluoroꢀ3,5,8ꢀtrimethylBODIPY (3g). To a solution of 4,4ꢀdifluoroꢀ
3,5,8ꢀtrimethylBODIPY20 (51 mg, 0.22 mmol) in dry THF (5 mL) was added, under
argon atmosphere, Nꢀbromosuccinimide (78 mg, 0.44 mmol) in dry THF (5 mL), and
the mixture stirred at r.t. for 24 h. Flash chromatography using hexane/EtOAc (98:2)
afforded dibromoBODIPY 3g (51 mg, 70%) as a redꢀorange solid.
1H NMR (300 MHz, CDCl3)
ppm. 13C NMR (75 MHz, CDCl3)
2923, 1565, 1457, 1254, 1080, 1072, 980 cmꢀ1. HRMS
δ 7.09 (s, 2H, 2CH), 2.51 (s, 6H, 2CH3), 2.34 (s, 3H, CH3)
δ
155.3, 140.3, 133.9, 127.6 (CH), 108.6 (CꢀBr), 15.8
(CH3), 13.7 (CH3) ppm. FTIR
υ
m/z 389.9334 (calcd for C12H11BBr2F2N2: 389.9348).
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4,4ꢀDifluoroꢀ2,6ꢀdiiodoꢀ3,5,8ꢀtrimethylBODIPY (3h). According to the same procedure
described for 3d (see above), 4,4ꢀdifluoroꢀ3,5,8ꢀtrimethylBODIPY20 (120 mg, 0.52
mmol) in CH2Cl2/MeOH (10 mL/10 mL), and 1.13 mL of ICl (1 M in CH2Cl2, 1.13
mmol) in MeOH (5 mL) were reacted for 20 min. Flash chromatography on silica gel
using hexane/CH2Cl2 (5:5) afforded diiodoBODIPY 3h (235 mg, 93%) as a red solid.
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1H NMR (300 MHz, CDCl3)
ppm. 13C NMR (75 MHz, CDCl3)
2920, 1566, 1422, 1245, 1126, 1061, 991 cmꢀ1. HRMS m/z
δ 7.25 (s, 2H, 2CH), 2.54 (s, 6H, 2CH3), 2.35 (s, 3H, CH3)
δ
157.9, 139.1, 135.7, 133.7 (CH), 77.2 (CꢀI), 15.4
(CH3) ppm. FTIR
υ
485.9066 (calcd for C12H11BF2I2N2: 485.9071).
1,2,3ꢀTribromoꢀ6ꢀethylꢀ4,4ꢀdifluoroꢀ5,7,8ꢀtrimethylBODIPY (13). To a solution of 2ꢀ
ethylꢀ4,4ꢀdifluoroꢀ1,3,8ꢀtrimethylBODIPY7a (170 mg, 0.65 mmol) in dry CH2Cl2 (20
mL) was added, under argon atmosphere, Br2 (0.033 mL, 0.65 mmol), and the mixture
was stirred at r.t. for 90 min. The mixture was treated with saturated aqueous Na2S2O3,
decanted, and the organic layer washed with water, dried over MgSO4, filtered and
concentrated to dryness. Flash chromatography using hexane/CHCl3 (8:2) afforded
tribromoBODIPY 13 (242 mg, 75%) as a red solid.
M.p.: 260ꢀ263 ºC. 1H NMR (700 MHz, CDCl3)
2.37 (q, J = 7.7 Hz, 2H, CH2) 2.30 (s, 3H, CH3), 1.00 (t, J = 7.7 Hz, 3H, CH3) ppm. 13C
δ 2.76 (s, 3H, CH3), 2.50 (s, 3H, CH3),
NMR (176 MHz, CDCl3)
δ 164.1, 142.5, 139.1, 137.6, 135.6, 130.0, 120.4 (CꢀBr),
112.4 (CꢀBr), 111.2 (CꢀBr), 17.3 (CH3), 17.2 (CH2), 15.1 (CH3), 14.3 (CH3), 13.5 (CH3)
2973, 1578, 1396, 1369, 1211, 1190, 1085, 978 cmꢀ1. HRMS m/z
ppm. FTIR
υ
495.8758 (calcd for C14H14BBr3F2N2: 495.8766).
4,4ꢀDifluoroꢀ2ꢀiodoꢀ3,5,8ꢀtrimethylBODIPY (24b). According to the same procedure
described for 3d (see above), 4,4ꢀdifluoroꢀ3,5,8ꢀtrimethylBODIPY20 (50 mg, 0.26
mmol) in CH2Cl2/MeOH mixture (7 mL/7 mL), and 0.31 mL of ICl (1 M in CH2Cl2,
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0.31 mmol) in MeOH (5 mL) were reacted for 2 h. Flash chromatography on silica gel
using hexane/CH2Cl2 (8:2) afforded diiodoBODIPY 3h (24 mg, 22%) and iodoBODIPY
24b (50 mg, 65%) as orangeꢀred solids.
9
24b: M.p.: 149ꢀ151 ºC. 1H NMR (300 MHz, CDCl3)
δ 7.15 (s, 1H, CH), 7.10 (d, J = 4.2
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Hz, 1H, CH), 6.25 (d, J = 4.2 Hz, 1H, CH), 2.54 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.37
(s, 3H, CH3) ppm. 13C NMR (75 MHz, CDCl3)
δ
159.2, 155.4, 139.6, 135.4, 135.3,
131.9 (CH), 128.7 (CH), 120.2 (CH), 75.1 (CꢀI), 15.3 (CH3), 15.0 (CH3) ppm. FTIR
υ
2928, 1565, 1418, 1237, 1110, 1051, 998 cmꢀ1. HRMS m/z 360.0100 (calcd for
C12H12BF2IN2: 360.0106).
General procedure for Negishi reactions
Method A. A Schlenk tube was capped with a rubber septum, air evacuated, and
backfilled with argon (this sequence was repited three times). Then, the halogenated
BODIPY (1 mol), Pd(PPh3)2Cl2 (10 mol%) and dry toluene (1ꢀ2 mL) were added under
argon atmosphere. R2Zn or RZnBr (0.7ꢀ20 mol) were added dropwise, and the mixture
was stirred at r.t. for 5ꢀ120 min. The reaction solution was then filtered (CH2Cl2 was
used for elution and washing), the solvent removed under vacuum, and the obtained
residue submitted to flash chromatography on silica gel.
Method A+XPhos. XPhos (10 mol%) was also added.
Method B. To a flameꢀdried 100 mL twoꢀneck flask was added phenylacetylene (5.5
mol) and dry THF (5 mL). Then, BuLi (1.6 M in hexane, 5.5 mol) was added dropwise
under argon atmosphere at ꢀ78 ºC, and the resulting mixture stirred for 30 min. Then, a
solution of ZnBr2 (5.5 mol) in dry THF (2 mL) was added over the mixture at ꢀ78 ºC,
and 5 min later the reaction was allowed to reach r.t. Then, the halogenated BODIPY (1
mol), Pd(PPh3)2Cl2 (10 mol%) and dry toluene (10 mL) were added over the mixture at
r.t., and the resulting reaction mixture was stirred for 1ꢀ4 h. Finally, the reaction mixture
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was disolved with EtOAc and the resulting solution washed with 10% HCl, saturated
aqueous NaHCO3 and water, dried over MgSO4, filtered and concentrated to dryness.
The resulting residue was submitted to flash chromatography on silica gel.
9
Negishi reaction of BODIPY 3a and Me2Zn: According to method A, BODIPY 3a12 (31
mg, 0.09 mmol), Pd(PPh3)2Cl2 (6 mg, 0.009 mmol) in dry toluene (1 mL), and 1.5 ml of
Me2Zn (1.2 M in toluene, 1.8 mmol) were reacted for 24 h. Flash chromatography using
hexane/EtOAc (95:5) afforded unreacted starting BODIPY 3a (26 mg, 82%).
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According to method A+XPhos, BODIPY 3a (30 mg, 0.085 mmol), Pd(PPh3)2Cl2 (6
mg, 0.009 mmol) and XPhos (4 mg, 0.009 mmol) in dry toluene (1 mL), and 0.6 mL of
Me2Zn (1.2 M in toluene, 0.68 mmol) were reacted for 60 min. Flash chromatography
using hexane/EtOAc (95:5) afforded BODIPY 4a (18 mg, 69%) as a brown solid.
1H NMR (700 MHz, CDCl3)
δ 7.62 (s, 2H, 2CH), 7.36 (d, J = 8.4 Hz, 2H, tolyl), 7.24
(d, J = 8.4 Hz, 2H, tolyl), 6.58 (s, 2H, 2CH), 2.39 (s, 3H, CH3), 2.03 (s, 6H, 2CH3) ppm.
13C NMR (176 MHz, CDCl3)
δ
145.3, 143.5 (CH), 140.9, 134.7, 131.3, 130.5 (CH),
129.7 (CH), 129.2, 129.0 (CH), 21.5 (CH3), 11.7 (CH3) ppm. FTIR
υ 2922, 1567, 1519,
1312, 1255, 1090, 988 cmꢀ1. HRMS m/z 310.1443 (calcd for C18H17BF2N2: 310.1450).
Negishi reaction of BODIPY 3b and Me2Zn: According to method A, BODIPY 3b13 (35
mg, 0.08 mmol), Pd(PPh3)2Cl2 (6 mg, 0.009 mmol) in dry toluene (1 mL), and 1.3 mL
of Me2Zn (1.2 M in toluene, 1.6 mmol) were reacted for 120 min. Flash
chromatography using hexane/EtOAc (97:3) afforded BODIPYs 4a (10 mg, 41%) and
5a (3 mg, 10%) as brown solids, and bis(BODIPY) 6 (4 mg, 9%) as a purple solid.
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5a: H NMR (700 MHz, CDCl3)
δ 7.78 (s, 1H, CH), 7.62 (s, 1H, CH), 7.36 (d, J = 7.7
Hz, 2H, tolyl), 7.26 (d, J = 7.7 Hz, 2H, tolyl), 6.75 (s, 1H, CH), 6.70 (s, 1H, CH), 2.40
(s, 3H, CH3), 2.06 (s, 3H, CH3) ppm. 13C NMR (176 MHz, CDCl3)
δ
147.6 (CH), 145.9,
141.6, 140.1 (CH), 135.6, 133.9, 131.8 (CH), 131.3, 130.7, 130.5 (CH), 129.3 (CH),
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129.1 (CH), 104.8 (CꢀBr), 21.5 (CH3), 11.8 (CH3) ppm. FTIR υ 2950, 2921, 1567,
1544, 1358, 1250, 1098, 1065, 988 cmꢀ1. HRMS m/z 374.0411 (calcd for
7
8
C17H14BBrF2N2: 374.0400).
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6: M. p.: 168ꢀ169 ºC. H NMR (700 MHz, CDCl3)
δ 7.94 (s, 2H, 2CH), 7.71 (s, 2H,
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2CH), 7.39 (d, J = 7.7 Hz, 4H, tolyl), 7.28 (d, J = 7.7 Hz, 2H, tolyl), 6.79 (s, 2H, 2CH),
6.64 (s, 2H, 2CH), 2.42 (s, 6H, 2CH3), 2.05 (s, 6H, 2CH3) ppm. 13C NMR (176 MHz,
CDCl3)
δ
145.7, 145.6, 141.3, 139.6 (CH), 135.5, 135.0, 131.1, 130.6 (CH), 130.5 (CH),
2932, 1566, 1524,
130.3, 129.3 (CH), 123.7 (CH), 21.5 (CH3), 11.7 (CH3) ppm. FTIR
υ
1310, 1235, 1190, 978 cmꢀ1. HRMS m/z: 590.2440 (calcd for C34H28B2F4N4: 590.2434).
Negishi reaction of BODIPY 3c and Me2Zn: According to the method A, BODIPY 3c5a
(48 mg, 0.09 mmol), Pd(PPh3)2Cl2 (6 mg, 0.009 mmol) in dry toluene (2 mL), and
Me2Zn (0.9 mL, 1.2 M in toluene, 1.08 mmol) were reacted for 2 h. Flash
chromatography using hexane/EtOAc (98:2) afforded BODIPYs 4a (12 mg, 42%) and
7a (3 mg, 11%) as brown solids, and bis(BODIPY) 6 (6 mg, 11%) as a purple solid.
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7a: H NMR (700 MHz, CDCl3)
δ 7.77 (s, 1H, CH), 7.75 (s, 1H, CH), 7.38 (d, J = 7.7
Hz, 2H, tolyl), 7.25 (d, J = 7.7 Hz, 2H, tolyl), 6.80 (d, J = 3.5 Hz, 1H, CH), 6.65 (s, 1H,
CH), 6.41 (d, J = 3.5 Hz, 1H, CH), 2.39 (s, 3H, CH3), 2.03 (s, 3H, CH3) ppm. 13C NMR
(176 MHz, CDCl3)
δ 146.4, 144.4 (CH), 142.1 (CH), 141.1, 137.2, 135.1, 134.5, 131.2,
130.5 (CH), 130.3 (CH), 129.4 (CH), 129.1 (CH), 117.5 (CH), 21.5 (CH3), 11.7 (CH3)
2920, 1569, 1534, 1310, 1245, 1093, 978 cmꢀ1. HRMS m/z 296.1286
ppm. FTIR
υ
(calcd for C17H15BF2N2: 296.1294).
Negishi reaction of BODIPY 3d with Me2Zn. According to method A, BODIPY 3d (62
mg, 0.111 mmol), Pd(PPh3)2Cl2 (8 mg, 0.011 mmol) in dry toluene (2 mL), and 1.9 mL
of Me2Zn (1.2 M in toluene, 2.22 mmol) were reacted for 60 min. Flash
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chromatography using hexane/EtOAc (98:2) afforded BODIPYs 5b (8 mg, 16%) as a
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red solid, 4b (15 mg, 40%) as a brownꢀred solid, and 7b (5 mg, 14%) as a purple solid.
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4b: H NMR (700 MHz, CDCl3)
δ 7.29 (d, J = 7.7 Hz, 2H, tolyl), 7.19 (d, J = 7.7 Hz,
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2H, tolyl), 6.41 (s, 2H, 2CH), 2.47 (s, 6H, 2CH3), 2.37 (s, 3H, CH3), 1.92 (s, 6H, 2CH3)
ppm. 13C NMR (176 MHz, CDCl3)
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δ
155.3, 140.4, 139.8, 132.8, 131.7, 130.3 (CH),
128.8 (CH), 128.4 (CH), 127.7, 21.4 (CH3), 12.7 (CH3), 11.1 (CH3) ppm. FTIR
υ 2934,
1566, 1540, 1312, 1250, 1099, 979 cmꢀ1. HRMS m/z 338.1755 (calcd for C20H21BF2N2:
338.1764).
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5b: H NMR (300 MHz, CDCl3)
δ 7.28 (d, J = 8.1 Hz, 2H, tolyl), 7.20 (d, J = 8.1 Hz,
2H, tolyl), 6.70 (s, 1H, CH), 6.54 (s, 1H, CH), 2.54 (s, 3H, CH3), 2.51 (s, 3H, CH3),
13
2.37 (s, 3H, CH3), 1.94 (s, 3H, CH3) ppm. C NMR (75 MHz, CDCl3)
δ 160.2, 154.1,
140.7, 140.4, 134.5, 133.7, 133.6 (CH), 131.0, 130.6 (CH), 130.3 (CH), 129.0 (CH),
74.4 (CꢀI), 21.4 (CH3), 15.1 (CH3), 13.1 (CH3), 11.2 (CH3) ppm. FTIR 2919, 1573,
υ
1544, 1420, 1236, 1129, 1084, 970 cmꢀ1. HRMS m/z 450.0569 (calcd for C19H18BF2N2I:
450.0575).
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7b: H NMR (700 MHz, CDCl3)
δ 7.29 (d, J = 7.7 Hz, 2H, tolyl), 7.19 (d, J = 7.7 Hz,
2H, tolyl), 6.58 (d, J = 3.5 Hz, 1H, CH), 6.48 (s, 1H, CH), 6.13 (d, J = 3.5 Hz, 1H, CH),
2.55 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.37 (s, 3H, CH3), 1.94 (s, 3H, CH3) ppm. 13C
NMR (176 MHz, CDCl3) δ 157.5, 155.3, 141.5, 140.0, 134.0, 133.4, 132.8, 131.5, 130.4
(CH), 129.4 (CH), 129.0 (CH), 128.8 (CH), 118.1 (CH), 21.4 (CH3), 14.8 (CH3), 12.8
2920, 1560, 1556, 1323, 1245, 1090, 989 cmꢀ1. HRMS
(CH3), 11.2 (CH3) ppm. FTIR
υ
m/z 324.1600 (calcd for C19H19BF2N2: 324.1607.
Negishi reaction of BODIPY 3e with Me2Zn. According to method A, BODIPY 3e (39
mg, 0.103 mmol), Pd(PPh3)2Cl2 (8 mg, 0.010 mmol) in dry toluene (1 mL), and 1.7 mL
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of Me2Zn (1.2 M in toluene, 2.07 mmol) were reacted for 24 h. Flash chromatography
using hexane/EtOAc (95:5) afforded BODIPY 4c7c (18 mg, 70%) as an orange solid.
Negishi reaction of BODIPY 3f with Me2Zn. According to the method A, BODIPY 3f
(62 mg, 0.13 mmol), Pd(PPh3)2Cl2 (9 mg, 0.013 mmol) in dry toluene (2 mL), and
Me2Zn (2.2 mL, 1.2 M in toluene, 2.65 mmol) were reacted for 3 h. Flash
chromatography using hexane/CH2Cl2 (8:2) afforded BODIPY 4c7c (23 mg, 71%) as an
orange solid.
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Negishi reaction of BODIPY 3g with Me2Zn. According to method A, BODIPY 3g (24
mg, 0.06 mmol), Pd(PPh3)2Cl2 (4 mg, 0.006 mmol) in dry toluene (1 mL) and 1 mL of
Me2Zn (1.2 M in toluene, 1.2 mmol) were reacted for 4 h. Flash chromatography using
hexane/EtOAc (98:2) afforded BODIPYs 4d7c (9.3 mg, 59%) and 8a20 (2 mg, 13%) as
orange solids.
Negishi reaction of BODIPY 3h with Me2Zn. According to method A, BODIPY 3h (120
mg, 0.25 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol) in dry toluene (2 mL), and 2.48
mL of Me2Zn (1.2 M in toluene, 2.98 mmol) were reacted for 40 min. Flash
chromatography using hexane/EtOAc (95:5) afforded BODIPYs 4d7c (44 mg, 68%) and
8a20 (8 mg, 13%) as orange solids.
Negishi reaction of BODIPY 3i with Me2Zn. According to method A, BODIPY 3i14 (50
mg, 0.1 mmol), Pd(PPh3)2Cl2 (8 mg, 0.011 mmol) in dry toluene (2 mL), and 1 mL of
Me2Zn (1.2 M in toluene, 1.2 mmol) were reacted for 40 min. Flash chromatography
using hexane/CH2Cl2 (5:5) afforded BODIPYs 4e11a (20 mg, 69%) and 8b11a (PM546)
(3 mg, 9%) as orange solids.
Negishi reaction of BODIPY
9
with Me2Zn. According to method A, BODIPY 97c (17
mg, 0.042 mmol), Pd(PPh3)2Cl2 (3 mg, 0.004 mmol) in dry toluene (1 mL), and 0.7 mL
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of Me2Zn (1.2 M in toluene, 0.84 mmol) were reacted for 1 h. Flash chromatography
using hexane/AcOEt (98:2) afforded BODIPY 1124 (11 mg, 95%) as an orange solid.
Negishi reaction of BODIPY 10 with Me2Zn. According to method A, BODIPY 1016 (30
mg, 0.13 mmol), Pd(PPh3)2Cl2 (9 mg, 0.013 mmol) in dry toluene (1 mL), and 0.9 mL
of Me2Zn (1.2 M in toluene, 1.08 mmol) were reacted for 30 min. Flash
chromatography using hexane/EtOAc (8:2) afforded BODIPY 1225 (23 mg, 85%) as a
yellow solid.
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Negishi reactions of BODIPY 13 with Me2Zn. According method A, BODIPY 13 (30
mg, 0.06 mmol), Pd(PPh3)2Cl2 (4 mg, 0.006 mmol) in dry toluene (1 mL), and 0.035
mL of Me2Zn (1.2 M in toluene, 0.04 mmol) were reacted for 24 h. Flash
chromatography using hexane/CHCl3 (9:1) afforded BODIPYs 16 (9 mg, 34%) and 17
(6 mg, 26%) as red solids, and BODIPY 13 (9 mg, 30%).
According to method A, BODIPY 13 (40 mg, 0.08 mmol), Pd(PPh3)2Cl2 (6 mg, 0.008
mmol) in dry toluene (1 mL) and 1.3 mL of Me2Zn (1.2 M in toluene, 1.6 mmol) were
reacted for 22 h. Flash chromatography using hexane/CH2Cl2 (9:1) afforded BODIPYs
17 (17 mg, 57%) and 18 (8 mg, 33%) as red solids.
According to method A+XPhos, BODIPY 13 (30 mg, 0.06 mmol), Pd(PPh3)2Cl2 (4 mg,
0.006 mmol), XꢀPhos (3 mg, 0.006 mmol) in dry toluene (1 mL), and 1 mL of Me2Zn
(1.2 M in toluene, 1.2 mmol) were reacted for 24 h. Flash chromatography using
hexane/CH2Cl2 (9:1) afforded BODIPY 18 (14 mg, 77%) as a red solid.
16: M.p.: 222ꢀ224 ºC. 1H NMR (700 MHz, CDCl3)
δ 2.78 (s, 3H, CH3ꢀC8), 2.51 (s, 3H,
CH3ꢀC3), 2.47 (s, 3H, CH3ꢀC5), 2.36 (q, J = 7.7 Hz, 2H, CH2), 2.30 (s, 3H, CH3ꢀC7),
1.00 (t, J = 7.7 Hz, 3H, CH3) ppm. 13C NMR (176 MHz, CDCl3)
δ
160.3 (C5), 146.1
(C3), 141.1 (C7), 140.0 (C8), 136.0 (C6), 134.2 (C7a), 128.1 (C8a), 113.7 (C1), 109.6
(C2), 17.2 (CH3ꢀC8), 17.1 (CH2), 14.9 (CH3ꢀC7), 14.4 (CH3ꢀCH2), 13.6 (CH3ꢀC3), 13.1
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(CH3ꢀC5) ppm. FTIR
υ
2922, 2853, 1563, 1465, 1192, 1075, 1029 cmꢀ1. HRMS m/z
5
6
431.9812 (calcd for C15H17BBr2F2N2: 431.9820).
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17: M.p.: 174ꢀ177 ºC. 1H NMR (700 MHz, CDCl3)
δ 2.52 (s, 3H, CH3ꢀ8), 2.47 (s, 3H,
9
CH3ꢀC3), 2.45 (s, 3H, CH3ꢀC5), 2.34 (q, J = 7.7 Hz, 2H, CH2), 2.33 (s, 3H, CH3ꢀC1),
2.27 (s, 3H, CH3ꢀC7), 0.98 (t, J = 7.7 Hz, 3H, CH3) ppm. 13C NMR (176 MHz, CDCl3)
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27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ
156.3 (C5), 148.0 (C3), 140.4 (C8), 139.0 (C7), 135.1 (C1), 134.2 (C6), 132.8 (C7a),
130.2 (C8a), 109.7 (C2), 17.1 (CH3ꢀC8), 17.0 (CH2), 16.0 (CH3ꢀC1), 14.7 (CH3ꢀCH2),
14.6 (CH3ꢀC7), 13.3 (CH3ꢀC3), 12.7 (CH3ꢀC5) ppm. FTIR 2923, 2854, 1557, 1471,
υ
1205, 1070, 995 cmꢀ1. HRMS m/z 368.0863 (calcd for C16H20BBrF2N2: 368.0871).
1
18: M.p.: 222ꢀ224 ºC. H NMR (700 MHz, CDCl3)
δ 2.53 (s, 3H, CH3), 2.42 (s, 3H,
CH3), 2.41 (s, 3H, CH3), 2.33 (q, J = 7.7 Hz, 2H, CH2), 2.26 (s, 3H, CH3), 2.25 (s, 3H,
CH3), 1.87 (s, 3H, CH3), 0.97 (t, J = 7.7 Hz, 3H, CH3) ppm. 13C NMR (176 MHz,
CDCl3)
δ 152.2, 151.7, 139.6, 136.8, 136.3, 132.3, 131.6, 125.9, 17.1 (CH2), 16.9
(CH3), 14.9 (CH3), 14.6 (CH3), 14.4 (CH3), 12.6 (CH3), 12.4 (CH3), 9.1 (CH3) ppm.
2965, 2922, 2856, 1556, 1477, 1318, 1207, 1047, 979, 958 cmꢀ1. HRMS m/z
FTIR
υ
304.1912 (calcd for C17H23BF2N2: 304.1922).
Negishi reaction of BODIPY 14 with Me2Zn. According to method A, BODIPY 14 (23.5
mg, 0.051 mmol), Pd(PPh3)2Cl2 (4 mg, 0.005 mmol) in dry toluene (1 mL), and 0.9 mL
Me2Zn (1.2 M in toluene, 1.02 mmol) were reacted for 4 h. Flash chromatography using
hexane/AcOEt (98:2) afforded BODIPYs 19 (13 mg, 65%) and 20 (4 mg, 24%) as
brown solids.
1
19: M.p.: 200ꢀ204 ºC. H NMR (700 MHz, CDCl3)
δ 6.97 (s, 1H, CHꢀ8), 6.89 (s, 1H,
CHꢀC7), 2.52 (s, 3H, CH3ꢀC3), 2.50 (s, 3H, CH3ꢀC5), 2.15 (s, 3H, CH3ꢀC1) ppm. 13C
NMR (176 MHz, CDCl3)
δ
157.7 (C3), 154.0 (C5), 141.0 (C8a), 133.2 (C1), 132.1
29
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