An unexpected coupling-reduction tandem reaction for the synthesis of alkenyl-substituted BODIPYs

Article abstract of DOI:10.1039/c9cc07730h

We report an unexpected coupling-reduction tandem reaction as a general and efficient one-pot synthesis of alkenyl-substituted boron dipyrromethene (BODIPY) from chlorinated-BODIPY and alkyne. This unique synthesis combined the Sonogashira coupling reaction and reduction reaction without adding an additional reagent, which shows higher yields, broader substrate scope and faster reaction rate compared with the conventional methods of the Knoevenagel reaction and Heck coupling reaction.

Full text of DOI:10.1039/c9cc07730h

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An unexpected coupling–reduction tandem
reaction for the synthesis of alkenyl-substituted
BODIPYs†
Cite this: Chem. Commun., 2019,
55, 13761
Received 2nd October 2019,
Accepted 22nd October 2019
Kun-Xu Teng, Li-Ya Niu,
Jie Li, Lu Jia and Qing-Zheng Yang
*
DOI: 10.1039/c9cc07730h
rsc.li/chemcomm
We report an unexpected coupling–reduction tandem reaction as a
general and efficient one-pot synthesis of alkenyl-substituted boron
dipyrromethene (BODIPY) from chlorinated-BODIPY and alkyne. This
unique synthesis combined the Sonogashira coupling reaction and
reduction reaction without adding an additional reagent, which shows
higher yields, broader substrate scope and faster reaction rate com-
pared with the conventional methods of the Knoevenagel reaction and
Heck coupling reaction.
Boron dipyrromethene (BODIPY) dyes1 are widely used in bio-
imaging,2 photodynamic therapy3 and opto-electronic materials4
since they have several attributes such as high molar absorption
coefficients and fluorescence quantum yields, sharp absorption
and emission peaks, and excellent biocompatibility and photo-
stability. Typical BODIPY dyes manifest absorption/emission
maxima in the range between 470 and 530 nm.1a However,
bioapplications (e.g. bioimaging, photodynamic therapy) generally
Scheme 1 Synthesis of alkenyl-substituted BODIPYs.
require dyes to absorb at longer wavelengths in the far-red or NIR from several drawbacks, such as low yield, limited substrate adapta-
region to minimize the light scattering and absorption by water, tion range, low reaction efficiency and slow reaction rate. The Heck
tissues and cells and increase the depth of light penetration.5
coupling reaction, through palladium-catalyzed coupling reactions
Various methods have been developed to synthesize BODIPY between 3,5-dichloro-BODIPYs and aromatic alkenyl compounds, is
derivatives with a long absorption/emission wavelength by the another possible method to synthesize alkenyl-substituted BODIPYs.
modification of the BODIPY core.6 The commonly used strategies However, as far as we know, only one example11 was reported to
include aryl, ethynylaryl and styryl substitution on BODIPY cores7 prepare alkenyl-substituted BODIPYs by this method probably due
and aromatic ring fusion.8 Replacing the meso-carbon atom with to the limitations of the substrates and difficulty in purification.
an aza-nitrogen atom to form an aza-BODIPY is another common Herein, we report an unexpected coupling–reduction tandem
method.9 Among them, the most widely used method is expanding reaction to synthesize the 3- and/or 5-alkenyl-substituted BODIPYs
the conjugated system of BODIPY through the substitution of from chlorinated-BODIPY and alkyne compounds (Scheme 1).
aromatic alkenyl groups on the 3- and/or 5-positions (Scheme 1). To This method employed one-pot synthesis by the Sonogashira
obtain such structures, the conventional method of Knoevenagel coupling reaction, followed by the reduction reaction using an
reaction is used,10 which involves condensation of 3,5-dimethyl- excess of alkyne substrates without adding any additional reagent.
BODIPYs with aromatic aldehydes. However, this method suffers It provides a promising facile and efficient strategy for the
synthesis of alkenyl-substituted BODIPYs with high yield, fast
Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of
reaction rate, and broad substrate adaptation scope.
Chemistry, Beijing Normal University, Beijing 100875, P. R. China.
The Sonogashira reaction is a widely used cross-coupling
E-mail: qzyang@bnu.edu.cn
reaction to synthesize alkyne derivatives.12 We tried to synthe-
† Electronic supplementary information (ESI) available: Experimental details, and
size the alkyne-substituted BODIPY 4a by this coupling reaction
NMR and HRMS spectra for all new compounds. CCDC 1952785. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c9cc07730h with chlorinated-BODIPY 1a and an excess of phenylacetylene
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2a (Scheme S1, ESI†). To our surprise, instead of getting 4a, the
main product obtained was identified as alkenyl-substituted
1
BODIPY 3a by H and 13C NMR spectroscopy as well as HRMS
(Fig. S1, ESI†). The HRMS manifested a peak at 384.1615, which
was assigned as [3a]+. Proton signals from the H1 and H2 of 3a
in the 1H-NMR spectrum (Fig. S1, ESI†) show two doublets with
coupling constants larger than 16, suggesting the presence of a
trans double bond. In the 13C-NMR spectrum, the carbon
signals of alkyne were not observed and new signals were
observed in the low field, implying that the alkyne converted
into olefin (Fig. S1, ESI†). The single-crystal X-ray analysis of 3a
further confirms the formation of a trans double bond (Fig. S2,
ESI†). To our delight, this reaction is an unprecedented strategy
to obtain the alkenyl-substituted BODIPYs in high yield simply
under the conditions of the Sonogashira coupling reaction.
Furthermore, reductive cross-coupling reactions of alkynes provide
an excellent opportunity for alkene synthesis. Whereas this
approach is rarely reported and often requires the addition of a
Fig. 1 Deuteration experiment and 1H-NMR of the product.
reducing agent.13 To the best of our knowledge, this is the first bond may come from the terminal hydrogen of the alkyne. To
example of the synthesis of alkenes through coupling–reduction further confirm our hypothesis, we performed the reaction of
tandem reaction without adding an additional reagent.
4a with deuterated terminal alkyne phenylacetylene-d 6a in
To understand the mechanism of this reaction, we separated anhydrous DMF and triethylamine. We didn’t observe the
1
the side product of the reaction which was characterized as signals of protons of the double bond in the H-NMR spectra
1,4-diphenylbuta-1,3-diyne 5a (Fig. S3, ESI†). This result suggests of the product 7a (Fig. 1). On the basis of these results, we
that phenylacetylene may serve as a reducing reagent to produce conclude that the hydrogens of the double bond in 3a are
alkenyl-substituted BODIPY. We further studied the distribution derived from the terminal alkyne.
of the product at different proportions of phenylacetylene to
On the basis of the above results, a possible mechanism for
chlorinated BODIPY 1a (Scheme S1, ESI†). The treatment of the Sonogashira-reduction tandem reaction has been proposed
BODIPY 1a with o1 equiv. of 2a gave alkyne-substituted BODIPY as shown in Scheme 2. Firstly, in the presence of base, the
4a. As the proportion of 2a increased to 1–3 equiv., both 4a and 3a catalytic Pd(0) of complex A was generated by the reduction of a
were obtained. If the ratio of 2a was increased to over 3 equiv., higher valent Pd(II) via reductive elimination.12b Subsequently,
alkyne-substituted BODIPY 3a became the major product with an in Pd-cycle-1, it facilitated the formation of complex B by
isolated yield of 79%. We propose that this unique coupling oxidation addition with chlorinated BODIPY 1. The next step
reaction occurs in two steps, which is a highly efficient tandem would connect with the Cu-cycle to generate complex C, which
connection of the Sonogashira coupling reaction and reduction gives the coupled alkyne 4 after reductive elimination with
reaction by an excess of phenylacetylene. As expected, the reaction regeneration of the catalyst complex A. Alternatively, complex
of BODIPY 4a with 2 equiv. of phenylacetylene under identical A can be oxidized by compounds 2 to give complex D, and then
conditions produced BODIPY 3a and 5a in similar yields proving complex E is obtained by addition and hydrogenation reaction
the reduction of alkyne by phenylacetylene. We further investi- with compound 4.14 The following step is a p-coordination of
gated the conditions of the reduction reaction and detailed results the alkyne, producing complex F where the acetylenic proton is
are listed in Table S1 (ESI†). When two catalysts Pd(PPh3)2Cl2 and acidified, and, with the synergistic action of the PPh3 ligand,
CuI were added to this reaction, the yield of the reaction was as the ortho ligand is hydrogenated to release the final product 3
high as 94% (Table S1, entry 1, ESI†). The absence of CuI had no and complex G. Complex G then transforms into complex A by
influence on the reaction (Table S1, entry 2, ESI†). However, no reductive elimination with concomitant production of 5a,
product 3a was detected without Pd(PPh3)2Cl2 or TEA (Table S1, completing Pd-cycle 2.
entries 3 and 4, ESI†), indicating that Pd(PPh3)2Cl2 and base are
We optimized the reaction conditions for the Sonogashira-
necessary in the reduction reaction. Moreover, no target product reduction tandem reaction with BODIPY 1a and phenylacety-
was obtained when this reaction was performed in air (Table S1, lene 2a as model substrates (Table 1). The reaction produced 3a
entry 7, ESI†). Next, we explored the effect of temperature on the with good yield in DMF and toluene, but a negligible amount of
reduction reaction and determined that the reaction was most 3a in acetonitrile, 1,4-dioxane and DMSO (Table 1, entries 1–5).
efficient at 80 1C (Table S1, entries 5 and 6, ESI†).
The type of base is an important factor for this reaction.
We further studied where the hydrogen of the double bond A similar yield was obtained when DIPEA was used instead of
came from. When the quantity of 2a was reduced to 1 equiv., TEA (Table 1, entry 6). We screened other inorganic bases, such
the yield decreased about 50%, suggesting that 4a and 2a as K2CO3 and Cs2CO3, which only afforded poor yields due to
reacted in a 1 : 2 ratio (Table S1, entry 8, ESI†). From the above their poor solubility in organic solvents (Table 1, entries 7 and 8).
observations, we speculate that the hydrogen of the double Moreover, the absence of CuI results in a severe drop in yield
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Scheme 3 Reaction scope of BODIPY and alkyne.
Finally, we varied the amount of phenylacetylene 2a, as well as the
reaction time (Table 1, entries 12 and 13), and no further
improvement of the yield was achieved.
With the mechanism and optimal conditions identified, we
further explored the scope and generality of this coupling
reaction (Scheme 3). We studied the effect of different alkynyl
substituents on the reaction (Scheme 3, products 3a–3i). In
general, both electron-donating and -withdrawing groups on
the alkyne are well tolerated to give the target products in good
yields. Even an alkyne substrate containing heterocyclic rings
obtained the target product in an ideal yield by this reaction
(Scheme 3, products 3j and 3k). Then we explored the reaction of
3,5-dichloro-BODIPY with alkyne. To our delight, 3,5-dialkenyl-
BODIPYs were also obtained in high yields (Scheme 3, products 3l
and 3m). And we had synthesized compound 3n in 76% yield,
which was difficult to obtain by conventional methods.
Scheme 2 Proposed mechanism.
Table 1 Optimization of the reaction conditionsa
These BODIPY derivatives manifest sharp absorption with high
molar absorption coefficients (Table 2). They exhibit strong
Entry
Catalyst 1
Solvent
Base
Yieldb (%)
1
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
DMF
TEA
TEA
TEA
TEA
79
75
12
N.R.
N.R.
76
56
43
7
12
28
79
79
2
Toulene
MeCN
1,4-Dioxane
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
3c
4
Table 2 Photophysical properties of BODIPY derivatives in dichloro-
methane
5
6
7
8
TEA
DIPEA
Cs2CO3
K2CO3
TEA
TEA
TEA
Entry
labs (nm)
eb (L molÀ1 cmÀ1
)
lem (nm)
Fd
a
c
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
562
568
566
567
561
564
572
568
565
576
556
632
659
565
76 500
76 700
61 400
72 600
67 000
51 200
88 300
62 600
48 400
70 000
37 700
46 100
34 700
47 000
585
590
589
592
583
584
598
586
581
602
574
652
681
578
0.78
0.83
0.94
0.88
0.77
0.73
0.85
0.68
0.61
0.53
0.50
0.81
0.61
0.74
9d
10
11
12e
13f
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
TEA
TEA
DMF
a
Reaction conditions: 1a (0.10 mmol), 2a (0.30 mmol), Pd(PPh3)2Cl2
(0.005 mmol), CuI (0.005 mmol), base (0.30 mmol), solvent (3 mL), heating
b
at 80 1C under N2 for 1 hour. Isolated yield. c Heating at 80 1C for 3 hours.
e
f
d Without CuI. Reaction stopped after 6 hours. 4 equiv. of 2a was used.
N.R. = no reaction.
(Table 1, entry 9), indicating the indispensability of the copper
catalyst. The yield of the product lowered when Pd(PPh3)2Cl2 was
a
b
Absorption maximum. Extinction coefficients calculated at the
c
d
absorption maxima. Fluorescence emission maxima. Absolute
replaced by Pd(OAc)2 or Pd(PPh3)4 (Table 1, entries 10 and 11). fluorescence quantum yields.
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Conflicts of interest
There are no conflicts to declare.
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13764 | Chem. Commun., 2019, 55, 13761--13764
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